PMID- 26731558 TI - Tenascin-C, a Prognostic Determinant of Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: Tenascin-C, an adhesion modulatory extracellular matrix molecule, is highly expressed in numerous human malignancies; thus, it may contribute to carcinogenesis and tumor progression. We explored the clinicopathological significance of Tenascin-C as a prognostic determinant of esophageal squamous cell carcinoma (ESCC). METHODS: In ESCC patient tissues and cell lines, the presence of isoforms were examined using western blotting. We then investigated Tenascin-C immunohistochemical expression in 136 ESCC tissue samples. The clinical relevance of Tenascin-C expression and the correlation between Tenascin C expression and expression of other factors related to cancer-associated fibroblasts (CAFs) were also determined. RESULTS: Both 250 and 350 kDa sized isoforms of Tenascin-C were expressed only in esophageal cancer tissue not in normal tissue. Furthermore, both isoforms were also identified in all of four CAFs derived from esophageal cancer tissues. Tenascin-C expression was remarkably higher in ESCC than in adjacent non-tumor esophageal epithelium (p < 0.001). Tenascin-C expression in ESCC stromal fibroblasts was associated with patient's age, tumor (pT) stage, lymph node metastasis, clinical stage, and cancer recurrence. Tenascin-C expression in cancer cells was correlated with an increase in tumor-associated macrophage (TAM) population, cancer recurrence, and hypoxia inducible factor1alpha (HIF1alpha) expression. Moreover, Tenascin-C overexpression in cancer cells and stromal fibroblasts was an independent poor prognostic factor for overall survival (OS) and disease-free survival (DFS). In the Cox proportional hazard regression model, Tenascin-C overexpression in cancer cells and stromal fibroblasts was a significant independent hazard factor for OS and DFS in ESCC patients in both univariate and multivariate analyses. Furthermore, Tenascin-C expression in stromal fibroblasts of the ESCC patients was positively correlated with platelet-derived growth factor alpha (PDGFRalpha), PDGFRbeta, and smooth muscle actin (SMA) expression. The 5-year OS and DFS rates were remarkably lower in patients with positive expressions of both Tenascin-C and PDGFRalpha (p < 0.001), Tenascin-C and PDGFRbeta (p < 0.001), Tenascin-C and SMA (p < 0.001), Tenascin-C and fibroblast activation protein (FAP) (p < 0.001), and Tenascin-C and fibroblast-stimulating protein-1 (FSP1) (p < 0.001) in ESCC stromal fibroblasts than in patients with negative expressions of both Tenascin-C and one of the abovementioned CAF markers. CONCLUSION: Our results show that Tenascin-C is a reliable and significant prognostic factor in ESCC. Tenascin-C may thus be a potent ESCC therapeutic target. PMID- 26731559 TI - MicroRNA-21 expression and its pathogenetic significance in cutaneous melanoma. AB - Identification of prognostic biomarkers is timely for melanoma as clinicians seek ways to stratify patients for molecular therapy. MicroRNAs are promising as tissue biomarkers because they can be assayed directly from formalin-fixed paraffin-embedded clinical samples. We previously reported that microRNA-21 (miR 21) was strongly expressed in melanoma relative to naevi and now sought to further assess the significance of this by assessing its relationship with its putative target, PTEN. Clinical melanoma samples were analysed by immunohistochemical analysis for PTEN, stem-loop qRT-PCR for miR-21 and PCR for BRAF/NRAS mutation status. Cell lines were investigated for the effect of anti miR-21 on PTEN. A total of 81 clinical melanocytic tumour samples were investigated, with uniformly high PTEN expression in the nucleus and cytoplasm of naevi and with preferential loss of PTEN expression in the nucleus of melanoma cells. miR-21 expression was inversely associated with nuclear PTEN expression but not with cytoplasmic PTEN expression. An anti-miR-21 preferentially altered nuclear PTEN in melanoma cell lines. The presence of a BRAF or NRAS mutation had no significant effect on miR-21 expression. These data suggest miR-21 may exert an oncogenic effect in melanoma by favouring redistribution of PTEN to the nucleus. PMID- 26731560 TI - BRAF inhibition for advanced locoregional BRAF V600E mutant melanoma: a potential neoadjuvant strategy. AB - Selective BRAF inhibitors (BRAFi) yield objective responses in 50% of patients with metastatic BRAF V600E mutant melanoma. Adding an MEK inhibitor increases this response rate to 70%. Limited data are available on the outcomes of unresectable stage III patients, and it remains unclear whether BRAF-targeted therapy can be utilized as a neoadjuvant strategy. Data on patients with advanced locoregional BRAF V600E mutant melanoma treated with BRAF-targeted therapy at Moffitt Cancer Center were analyzed to determine response rates, subsequent resection rates after tumor downsizing, pathologic responses, and patient survival. Fifteen patients with locoregional disease treated with BRAF-targeted therapy, either BRAFi alone (vemurafenib; 11 patients) or a combination of BRAFi and an MEK inhibitor (dabrafenib plus trametinib or placebo; four patients), were identified. The median age was 50 years; the median follow-up was 25.4 months. The median BRAF-targeted therapy treatment duration was 6.0 months (range 1.2 29.4 months). Response Evaluation Criteria In Solid Tumors-based evaluation demonstrated objective response in 11 patients (73.3%). Six patients underwent resection of the remaining disease after therapy. Pathological analysis showed complete pathologic response (n=2), partial pathologic response (n=2), or no pathologic response (n=2). Four of six patients undergoing surgery have been alive for more than 2 years, including three patients currently free from active disease. No complications attributable to BRAF-targeted therapy were observed in the perioperative period. Dose reduction or discontinuation because of toxicities occurred in 10/15 patients. Neoadjuvant BRAF-targeted therapy may be effective in advanced locoregional BRAF V600E mutant melanoma patients in increasing resectability, yielding pathological responses, and achieving prolonged survival. PMID- 26731561 TI - Overexpression of hepatocyte growth factor and an oncogenic CDK4 variant in mice alters corneal stroma morphology but does not lead to spontaneous ocular melanoma. PMID- 26731562 TI - Diagnostic approach to melanocytic lesion of unknown malignant potential. PMID- 26731563 TI - Ovarian cancer: epidemiology and risk factors. AB - The present overview of ovarian cancer epidemiology summarizes the main results for a network of case-control studies in Italy and from the Collaborative Group on Epidemiological Studies of Ovarian Cancer. There are consistent inverse relations between parity, oral contraceptive use and the risk of ovarian cancer. For other menstrual and hormonal factors (i.e. early age at menarche and late menopause), there are established associations, but of limited impact on ovarian cancer incidence on a population level. Serous and endometrioid ovarian cancers (but not mucinous or clear cell types) are related to current and recent use of hormone replacement therapy in menopause. There are no strong associations with alcohol and tobacco overall, but a direct link for tobacco with (borderline) mucinous cancers, of limited impact, however, on overall ovarian cancer mortality. There are direct associations of ovarian cancer risk with height and BMI, as well as possible relations with selected dietary factors - in the absence, however, of consistent findings - and a possible inverse association with physical activity. There is a strong association with a family history of ovarian cancer (and a few selected other neoplasms, including colorectum and endometrium). Recognized risk factors explain only a limited proportion of ovarian cancer cases on a population level. A key reason for the recent favourable trends of ovarian cancer incidence and mortality in several high income countries is the widespread use of oral contraceptive in the generations born after 1930. PMID- 26731564 TI - Amblyopia in children (aged 7 years or less). AB - INTRODUCTION: Amblyopia is reduced visual acuity not immediately correctable by glasses, in the absence of ocular pathology. It is commonly associated with squint (strabismus) or refractive errors resulting in different visual inputs to each eye during the sensitive period of visual development (aged <7-8 years). The cumulative incidence is estimated at 2% to 4% in children aged up to 7 years. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of medical treatments for amblyopia in children aged 7 years or less? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 70 studies. After deduplication and removal of conference abstracts, 51 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 37 studies and the further review of 14 full publications. Of the 14 full articles evaluated, two systematic reviews were updated and three RCTs and two follow-up studies were added at this update. We performed a GRADE evaluation for nine PICO combinations. CONCLUSIONS: In this systematic overview we categorised the efficacy for three interventions, based on information about the effectiveness and safety of glasses, occlusion, or penalisation with atropine. PMID- 26731565 TI - Nortriketones: Antimicrobial Trimethylated Acylphloroglucinols from Manuka (Leptospermum scoparium). AB - Four trimethylated acylphloroglucinols (5-8) have been isolated from manuka (Leptospermum scoparium) foliage. Apart from myrigalone A (8), which has previously been isolated from European bog myrtle (Myrica gale), these compounds have not been characterized before. The nortriketones are structurally similar to the bioactive tetramethylated beta-triketones from manuka, but have one less ring methyl group. Two oxidized trimethylated compounds, 9 and 10, were also isolated, but these are likely isolation artifacts. When evaluated for antibacterial activity against Gram-positive bacteria, myrigalone A (8) was slightly less potent (MIC 64 MUg/mL) than the corresponding tetramethylated compound, grandiflorone (4) (MIC 16-32 MUg/mL). Unlike their tetramethylated analogues, the nortriketones were inactive against the herbicide target enzyme p hydroxyphenylpyruvate dioxygenase. The Raman spectra of leaf oil glands in different manuka varieties can be used to distinguish plants that contain nortriketones from those that accumulate triketones. PMID- 26731566 TI - Long-Term Changes in Drug Craving and Nutritional Status of Opioid Addicts with Nucleus Accumbens Ablative Stereotactic Neurosurgery at Five Years Postoperatively. AB - BACKGROUND: The nucleus accumbens (NAcc) has been proven to be associated with drug and food craving. NAcc ablative neurosurgery has been suggested to modulate the balance of the brain reward system and thus alleviate drug dependence in patients. It has been hypothesized that it would also alleviate food craving in patients as well as altering their nutritional status. AIMS: This study aimed to estimate the effect of NAcc neurosurgery on drug craving and nutritional status in patients with drug dependence at 5 years postoperatively. METHODS: The study included 100 patients with NAcc surgery and 92 patients without surgery. Body mass index (BMI) and body fat percentage (BF%) were examined to assess nutritional status, and questionnaires were administered to assess drug craving. RESULTS: Compared with the nonsurgery group and the relapse patients from the surgery group, the nonrelapse patients from the surgery group had higher BMI and BF% but lower drug craving. There were no significant differences between the nonsurgery group and the relapse patients in BMI, but the relapse patients had higher drug craving than the nonsurgery group. CONCLUSIONS: Long-term follow-up suggested that NAcc ablative neurosurgery would alleviate drug craving and yield a better nutritional status if individuals sustained abstinence. It would increase drug craving but would not ruin the nutritional status of patients even when individuals relapsed postoperatively. PMID- 26731568 TI - Correction: Tumor Angiogenesis and Vascular Patterning: A Mathematical Model. PMID- 26731567 TI - A Latex Metabolite Benefits Plant Fitness under Root Herbivore Attack. AB - Plants produce large amounts of secondary metabolites in their shoots and roots and store them in specialized secretory structures. Although secondary metabolites and their secretory structures are commonly assumed to have a defensive function, evidence that they benefit plant fitness under herbivore attack is scarce, especially below ground. Here, we tested whether latex secondary metabolites produced by the common dandelion (Taraxacum officinale agg.) decrease the performance of its major native insect root herbivore, the larvae of the common cockchafer (Melolontha melolontha), and benefit plant vegetative and reproductive fitness under M. melolontha attack. Across 17 T. officinale genotypes screened by gas and liquid chromatography, latex concentrations of the sesquiterpene lactone taraxinic acid beta-D-glucopyranosyl ester (TA-G) were negatively associated with M. melolontha larval growth. Adding purified TA-G to artificial diet at ecologically relevant concentrations reduced larval feeding. Silencing the germacrene A synthase ToGAS1, an enzyme that was identified to catalyze the first committed step of TA-G biosynthesis, resulted in a 90% reduction of TA-G levels and a pronounced increase in M. melolontha feeding. Transgenic, TA-G-deficient lines were preferred by M. melolontha and suffered three times more root biomass reduction than control lines. In a common garden experiment involving over 2,000 T. officinale individuals belonging to 17 different genotypes, high TA-G concentrations were associated with the maintenance of high vegetative and reproductive fitness under M. melolontha attack. Taken together, our study demonstrates that a latex secondary metabolite benefits plants under herbivore attack, a result that provides a mechanistic framework for root herbivore driven natural selection and evolution of plant defenses below ground. PMID- 26731569 TI - Single molecule Raman spectra of porphycene isotopologues. AB - Single molecule surface-enhanced resonance Raman scattering (SERRS) spectra have been obtained for the parent porphycene (Pc-d0) and its deuterated isotopologue (Pc-d12), located on gold and silver nanoparticles. Equal populations of "hot spots" by the two isotopologues are observed for 1 : 1 mixtures in a higher concentration range of the single molecule regime (5 * 10(-9) M). For decreasing concentrations, hot spots are preferentially populated by undeuterated molecules. This is interpreted as an indication of a lower surface diffusion coefficient of Pc-d12. The photostability of single Pc molecules placed on nanoparticles is strongly increased in comparison with polymer environments. Trans tautomeric species dominate the spectra, but the analysis of time traces reveals transient intermediates, possibly due to rare cis tautomeric forms. PMID- 26731570 TI - Luminescence quantum yields of gold nanoparticles varying with excitation wavelengths. AB - Luminescence quantum yields (QYs) of gold nanoparticles including nanorods, nanobipyramids and nanospheres are measured elaborately at a single nanoparticle level with different excitation wavelengths. It is found that the QYs of the nanostructures are essentially dependent on the excitation wavelength. The QY is higher when the excitation wavelength is blue-detuned and close to the nanoparticles' surface plasmon resonance peak. A phenomenological model based on the plasmonic resonator concept is proposed to understand the experimental findings. The excitation wavelength dependent QY is attributed to the wavelength dependent coupling efficiency between the free electron oscillation and the intrinsic plasmon resonant radiative mode. These studies should contribute to the understanding of one-photon luminescence from metallic nanostructures and plasmonic surface enhanced spectroscopy. PMID- 26731571 TI - Sex differences in the circadian profiles of melatonin and cortisol in plasma and urine matrices under constant routine conditions. AB - Conflicting evidence exists as to whether there are differences between males and females in circadian timing. The aim of the current study was to assess whether sex differences are present in the circadian regulation of melatonin and cortisol in plasma and urine matrices during a constant routine protocol. Thirty-two healthy individuals (16 females taking the oral contraceptive pill (OCP)), aged 23.8 +/- 3.7 (mean +/- SD) years, participated. Blood (hourly) and urine (4 hourly) samples were collected for measurement of plasma melatonin and cortisol, and urinary 6-sulfatoxymelatonin (aMT6s) and cortisol, respectively. Data from 28 individuals (14 females) showed no significant differences in the timing of plasma and urinary circadian phase markers between sexes. Females, however, exhibited significantly greater levels of plasma melatonin and cortisol than males (AUC melatonin: 937 +/- 104 (mean +/- SEM) vs. 642 +/- 47 pg/ml.h; AUC cortisol: 13581 +/- 1313 vs. 7340 +/- 368 mmol/L.h). Females also exhibited a significantly higher amplitude rhythm in both hormones (melatonin: 43.8 +/- 5.8 vs. 29.9 +/- 2.3 pg/ml; cortisol: 241.7 +/- 23.1 vs. 161.8 +/- 15.9 mmol/L). Males excreted significantly more urinary cortisol than females during the CR (519.5 +/- 63.8 vs. 349.2 +/- 39.3 mol) but aMT6s levels did not differ between sexes. It was not possible to distinguish whether the elevated plasma melatonin and cortisol levels observed in females resulted from innate sex differences or the OCP affecting the synthetic and metabolic pathways of these hormones. The fact that the sex differences observed in total plasma concentrations for melatonin and cortisol were not reproduced in the urinary markers challenges their use as a proxy for plasma levels in circadian research, especially in OCP users. PMID- 26731572 TI - Association of peripheral inflammation with body mass index and depressive relapse in bipolar disorder. AB - Bipolar I disorder (BD) is associated with increased inflammation, which is believed to be central to disease etiology and progression. However, BD patients also have high rates of obesity, itself an inflammatory condition, and the relative contributions of mood illness and obesity to inflammation are unknown. Moreover, the impact of inflammation on clinical illness course has not been well studied. The objectives of this analysis were therefore: (1) to determine if inflammation in BD is mood illness-related or secondary to elevated body mass index (BMI), and (2) to investigate the impact of inflammation on prospectively ascertained relapse into depression and mania. We measured the serum levels of 7 inflammatory cytokines (TNF-alpha, gamma-interferon, monocyte chemoattractant protein-1 [MCP-1], IL-1alpha, IL-2, IL-6, and IL-8) and 2 anti-inflammatory cytokines (IL-4 and IL-10) in 52 early-stage BD patients and 22 healthy subjects. In patients, a multivariate multiple regression model that controlled for psychotropic medications found that higher BMI, but not recent (past-6-month) mood episodes, predicted greater inflammatory cytokines (p=.05). Healthy subjects also had a BMI-related increase in inflammatory cytokines (p<.01), but it was counter-balanced by a compensatory increase in anti-inflammatory cytokines (p=.02), reducing their total inflammatory burden from higher BMI. In patients, linear regression showed that two inflammatory cytokines predicted depressive relapse in the 12 months after cytokine measurement: IL-1alpha (p<.01) and MCP-1 (p<.01). These results suggest that elevated BMI is a significant contributor to inflammation in BD, more so even than recent mood illness severity. They also point to inflammation as an important predictor of illness course, particularly depressive relapse. PMID- 26731574 TI - Evidence of estrogen modulation on memory processes for emotional content in healthy young women. AB - PURPOSE: It is well accepted that emotional content can affect memory, interacting with the encoding and consolidation processes. The aim of the present study was to verify the effects of estrogens in the interplay of cognition and emotion. METHODS: Images from the International Affective Pictures System, based on valence (pleasant, unpleasant and neutral), maintaining arousal constant, were viewed passively by two groups of young women in different cycle phases: a periovulatory group (PO), characterized by high level of estrogens and low level of progesterone, and an early follicular group (EF), characterized by low levels of both estrogens and progesterone. The electrophysiological responses to images were measured, and P300 peak was considered. One week later, long-term memory was tested by means of free recall. FINDINGS: Intra-group analysis displayed that PO woman had significantly better memory for positive images, while EF women showed significantly better memory for negative images. The comparison between groups revealed that women in the PO phase had better memory performance for positive pictures than women in the EF phase, while no significant differences were found for negative and neutral pictures. According to the free recall results, the subjects in the PO group showed greater P300 amplitude, and shorter latency, for pleasant images compared with women in the EF group. CONCLUSION: Our results showed that the physiological hormonal fluctuation of estrogens during the menstrual cycle can influence memory, at the time of encoding, during the processing of emotional information. PMID- 26731573 TI - Late pregnancy thyroid-binding globulin predicts perinatal depression. AB - Previously we found that late pregnancy total and free thyroxine (TT4, FT4) concentrations were negatively related to greater pre and/or postpartum depressive symptoms. In a much larger cohort, the current study examined whether these thyroid indices measured earlier in the third trimester (31-33 weeks) predict subsequent perinatal depression and anxiety ratings as well as syndromal depression. Thyroid-binding globulin (TBG) concentrations increase markedly during pregnancy and may be an index of sensitivity to elevated estrogen levels. TBG was examined in this study because prior findings suggest that postpartum depression is related to sensitivity to mood destabilization by elevated sex hormone concentrations during pregnancy. Our cohort was 199 euthyroid women recruited from a public health obstetrics clinic (63.8% Hispanic, 21.6% Black). After screening and blood draws for hormone measures at pregnancy weeks 31-33, subjects were evaluated during home visits at pregnancy weeks 35-36 as well as postpartum weeks 6 and 12. Evaluations included psychiatric interviews for current and life-time DSM-IV psychiatric history (M.I.N.I.-Plus), subject self ratings and interviewer ratings for depression and anxiety (Edinburgh Postnatal Depression Scale, Montgomery-Asberg Depression Rating Scale; Spielberger State Trait Anxiety Inventory, Hamilton Anxiety Inventory), as well as a standardized interview to obtain life-time trauma history. Numerous covariates were included in all regression analyses. Trauma and major depression history were robustly significant predictors of depression and anxiety ratings over the study period when these variables were analyzed individually or in a combined model including FT4 or TBG (p<.001). When analyzed alone, FT4 levels were a less strong but still significant predictor of all depression and anxiety ratings (p<.05) while TBG levels was a significant or nearly significant predictor of most ratings. FT4, TBG and trauma history, but not major depression history, were significant individual predictors of syndromal depression during the study period (p<.05) in single predictor models. In models combining each with trauma and major depression history, FT4 and TBG generally were not significantly predictive of depression or anxiety ratings, and FT4 was also not a significant predictor of syndromal depression: however, in the combined model TBG was a particularly strong predictor of perinatal syndromal depression (p=.005) and trauma history was also significant (p=.016). Further study of the interactions among TBG, FT4, sex hormones, trauma history and perinatal depression may provide insights into the pathophysiological basis of individual variance in vulnerability to mood destabilization by the hormone conditions of pregnancy. PMID- 26731575 TI - Multi-responsive photothermal-chemotherapy with drug-loaded melanin-like nanoparticles for synergetic tumor ablation. AB - Photothermal-chemotherapy (PT-CT) is a promising strategy for cancer treatment, but its development is hindered by the issues regarding to the long-term safety of carriers and imperfect drug release profiles. In this article, we use polyethylene glycol-modified polydopamine nanoparticles (PDA-PEG) as an outstanding PT-CT agent for cancer treatment. PDA-PEG possesses excellent biocompatibility and photothermal effect, and could easily load anticancer drugs such as doxorubicin (DOX) and 7-ethyl-10-hydroxycamptothecin (SN38) via pi-pi stacking and/or hydrogen binding. Moreover, the drug-loaded PDA-PEG showed great stability and drug-retaining capability in physiological condition, and could respond to multiple stimuli including near infrared light, pH and reactive oxygen species to trigger the release of loaded anticancer drugs. The in vitro and in vivo studies demonstrated that PDA-PEG-mediated PT-CT showed synergetic effect for cancer therapy. PMID- 26731576 TI - Mg(II)-Catechin nanoparticles delivering siRNA targeting EIF5A2 inhibit bladder cancer cell growth in vitro and in vivo. AB - Emerging evidence indicates that combination of two or more therapeutic strategies can synergistically enhance antitumor activity in cancer therapy. Here, we established a green method of generating nanocomposite particles that can be fabricated using catechin, a natural anti-cancer compound from green tea, and Mg(2+) in an easy one-step approach at room temperature. We show that Mg(II) Catechin nanocomposite particles (Mg(II)-Cat NPs) have good biocompatibility and high cellular uptake also can load and effectively deliver small interfering RNA (siRNA) into cells in vitro and to tumor site in vivo. Mg(II)-Cat NPs by themselves had tumor-suppression effects. When complexed with siRNA that targets oncogene eukaryotic translation initiation factor 5A2 (EIF5A2), Mg(II) Cat/siEIF5A2 complex had further enhanced anti-tumor activity. Mechanistically, we show that Mg(II)-Cat/siEIF5A2 inhibits oncogenic PI3K/Akt signal pathway. More importantly, Mg(II)-Cat/siEIF5A2 had tumor suppression effect in a clinically relevant rat in-situ bladder cancer model. Our studies demonstrated that combination of Mg(II)-Cat NPs and siRNA is a promising therapeutic modality of combining chemotherapy with gene therapy in order to afford higher therapeutic efficacy and provided a proof of principle for such modality in a pre-clinical setting. PMID- 26731577 TI - 3D scaffolds in breast cancer research. AB - Breast tumors grow in a tissue microenvironment containing extracellular matrix (ECM), adipocytes, stromal cells, fluids, and blood vessels. This natural yet complex physiopathological territory is dynamically remodeled in favor of tumor growth and metastasis. The environment-mimicking 3D cultures have shown compelling advantages in the studies of tumor cell biology, and are of intensive research for the development of alternative systems to improve therapeutic efficacies against tumors. This review focuses on the most recent advances in scaffolding techniques, the cell-ECM and cell-cell interactions in scaffold cultures, the distinct physical properties and signaling regulation of cancer cell growth within the scaffolds, the sensitivities of the cancer cells to drugs in 3D culture, and the use of scaffolds for drug delivery into tumors. PMID- 26731580 TI - "Meglio e La Piccola Certezza Che la Gran Bugia" (The Little Truth is Better than the Big Lie)--Leonardo da Vinci. PMID- 26731579 TI - Expanding the 3-O-Sulfate Proteome--Enhanced Binding of Neuropilin-1 to 3-O Sulfated Heparan Sulfate Modulates Its Activity. AB - Binding of proteins to heparan sulfate is driven predominantly by electrostatic interactions between positively charged amino acid residues in the protein and negatively charged sulfate groups located at various positions along the polysaccharide chain. Although many heparin/heparan-sulfate-binding proteins have been described, few exhibit preferential binding for heparan sulfates containing relatively rare 3-O-sulfated glucosamine residues. To expand the "3-O-sulfate proteome," affinity matrices were created from Chinese hamster ovary (CHO) cell heparan sulfate engineered in vitro with and without 3-O-sulfate groups. Fractionation of different animal sera yielded several proteins that bound specifically to columns containing 3-O-sulfated heparan sulfate modified by two members of the heparan sulfate 3-O-sulfotransferase superfamily, Hs3st1 and Hs3st2. Neuropilin-1 was analyzed in detail because it has been implicated in angiogenesis and axon guidance. We show that 3-O-sulfation enhanced the binding of neuropilin-1 to heparan sulfate immobilized on plastic plates and to heparan sulfate present on cultured cells. Chemoenzymatically synthesized 3-O-sulfated heparan sulfate dodecamers protected neuropilin-1 from thermal denaturation and inhibited neuropilin-1-dependent, semaphorin-3a-induced growth cone collapse of neurons derived from murine dorsal root ganglia. The effect of 3-O-sulfation was cell autonomous and specific to Hs3st2 based on collapse assays of neurons derived from Hs3st1- and Hs3st2-deficient mice. Finally, 3-O-sulfated heparan sulfate enhanced the inhibition of endothelial cell sprouting by exogenous heparan sulfate. These findings demonstrate a reliable method to identify members of the 3-O-sulfate proteome and that 3-O-sulfation of heparan sulfate can modulate axonal growth cone collapse and endothelial cell sprouting. PMID- 26731578 TI - Fibroblast growth factor 2 dimer with superagonist in vitro activity improves granulation tissue formation during wound healing. AB - Site-specific chemical dimerization of fibroblast growth factor 2 (FGF2) with the optimal linker length resulted in a FGF2 homodimer with improved granulation tissue formation and blood vessel formation at exceptionally low concentrations. Homodimers of FGF2 were synthesized through site-specific linkages to both ends of different molecular weight poly(ethylene glycols) (PEGs). The optimal linker length was determined by screening dimer-induced metabolic activity of human dermal fibroblasts and found to be that closest to the inter-cysteine distance, 70 A, corresponding to 2 kDa PEG. A straightforward analysis of the kinetics of second ligand binding as a function of tether length showed that, as the polymerization index (the number of monomer repeat units in the polymer, N) of the tether decreases, the mean time for second ligand capture decreases as ~N(3/2), leading to an enhancement of the number of doubly bound ligands in steady-state for a given (tethered) ligand concentration. FGF2-PEG2k-FGF2 induced greater fibroblast metabolic activity than FGF2 alone, all other dimers, and all monoconjugates, at each concentration tested, with the greatest difference observed at low (0.1 ng/mL) concentration. FGF2-PEG2k-FGF2 further exhibited superior activity compared to FGF2 for both metabolic activity and migration in human umbilical vein endothelial cells, as well as improved angiogenesis in a coculture model in vitro. Efficacy in an in vivo wound healing model was assessed in diabetic mice. FGF2-PEG2k-FGF2 increased granulation tissue and blood vessel density in the wound bed compared to FGF2. The results suggest that this rationally designed construct may be useful for improving the fibroblast matrix formation and angiogenesis in chronic wound healing. PMID- 26731581 TI - Grundvoraussetzungen herzchirurgischer Einheiten zur Behandlung von Patienten mit angeborenen Herzfehlern. AB - This document defines fundamental structures of congenital cardiac surgery departments in Germany. It has been developed by the executive boards of the German Society for Thoracic and Cardiovascular Surgery (GSTCVS) and the German Society of Pediatric Cardiology (GSPC) in collaboration with the working group for Congenital and Pediatric Heart Surgery of the GSTCVS.This updated consensus paper is based on a previous publication of the European Association for Cardiothoracic Surgery (EACTS) and is a refinement and adaptation of its initial version published by the GSTCVS in 2005. In Germany, pediatric cardiology and cardiac surgery facilities caring for patients with congenital cardiac defects are subject to certain regulations. For example, in 2010 the Federal Joint Committee implemented the resolution on Quality Assurance Measures in the Provision of Cardiac Surgical Care for Children and Adolescents (directive congenital cardiac surgery) which regulates structural and process quality compulsorily. To date, fundamental and considerable differences of the respective departments persist.Congenital cardiac surgery departments have to provide the whole spectrum of the cardiac surgical therapy from the neonate to the adult with congenital cardiac defects (with the exception of heart transplantation) continuously and with the appropriate experience. Furthermore, the departments have to prove their constant scientific activity and ensure that they facilitate education and training for the specialty certification in cardiac surgery. The responsible surgeons of all congenital cardiac surgery departments commit to participate in the currently voluntary national quality assurance for congenital cardiac defects of the GSTCVS and the GSPC and perform an individual surgical outcome assessment and risk stratification. This is supplemented by the willingness for external certification specific to the individual and the facilitation of peer review procedures for quality assurance purposes. Additional measures, such as collaboration in clinical research and ongoing interdisciplinary education and training, are preferable. PMID- 26731582 TI - Fate of Tebuthiuron and Hexazinone in Green-Cane Harvesting System. AB - In Brazil, fire prior to sugar cane harvesting has to be phased out by 2017, but it has already been phased out in up to 85-90% of the cropped area. The new system is called green cane and has entirely changed weed management practices. The main goal of this study was to evaluate the effects of the straw presence as well as humic acid (HA), formulation, soil type, and aging on the sorption and leaching of (14)C-tebuthiuron and hexazinone. Both herbicides presented low sorption for all treatments (Kd,app <= 3.25 L kg(-1)), but it was higher for tebuthiuron in the clayer soil (LVd). Straw and aging only slightly enhanced sorption. The HA effects were not clear. Sorption was mostly affected by herbicide and soil type. Straw may promote physical trapping (~40% of applied amount), which cannot be accessed by "batch" sorption (~15% of the applied amount is sorbed), attenuating leaching of highly mobile herbicides in green-cane systems. To properly assess leaching through straw residues under laboratory condition, rainfall distribution is very important. PMID- 26731583 TI - Telemedicine: The Value Challenge. PMID- 26731584 TI - Limberg Flap Is Rhombic, Not Rhomboid. PMID- 26731585 TI - Delayed Partial Breast Reconstruction and Vascularized Lymph Node Transfer by a Superficial Circumflex Iliac Artery Perforator Flap. PMID- 26731586 TI - Chronic Osteomyelitis of the Manubrio-Clavicular Joint following Breast Augmentation. PMID- 26731587 TI - Determining the Duration of Leech Therapy in the Treatment of Acute Venous Congestion in Prefabricated Free Flaps. PMID- 26731588 TI - Four-Flap Breast Reconstruction with Bilateral Stacked Flaps. PMID- 26731589 TI - Financial Planning for the Plastic Surgery Residency Applicant. PMID- 26731590 TI - Transcriptome Analysis of Pig In Vivo, In Vitro-Fertilized, and Nuclear Transfer Blastocyst-Stage Embryos Treated with Histone Deacetylase Inhibitors Postfusion and Activation Reveals Changes in the Lysosomal Pathway. AB - Genetically modified pigs are commonly created via somatic cell nuclear transfer (SCNT). Treatment of reconstructed embryos with histone deacetylase inhibitors (HDACi) immediately after activation improves cloning efficiency. The objective of this experiment was to evaluate the transcriptome of SCNT embryos treated with suberoylanilide hydroxamic acid (SAHA), 4-iodo-SAHA (ISAHA), or Scriptaid as compared to untreated SCNT, in vitro-fertilized (IVF), and in vivo (IVV) blastocyst-stage embryos. SAHA (10 MUM) had the highest level of blastocyst development at 43.9%, and all treatments except 10 MUM ISAHA had the same percentage of blastocyst development as Scriptaid (p<0.05). Two treatments, 1.0 MUM ISAHA and 1.0 MUM SAHA, had higher mean cell number than No HDACi treatment (p<0.021). Embryo transfers performed with 10 MUM SAHA- and 1 MUM ISAHA-treated embryos resulted in the birth of healthy piglets. GenBank accession numbers from up- and downregulated transcripts were loaded into the Database for Annotation, Visualization and Integrated Discovery to identify enriched biological themes. HDACi treatment yielded the highest enrichment for transcripts within the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway, lysosome. The mean intensity of LysoTracker was lower in IVV embryos compared to IVF and SCNT embryos (p<0.0001). SAHA and ISAHA can successfully be used to create healthy piglets from SCNT. PMID- 26731591 TI - Generation of Arbas Cashmere Goat Induced Pluripotent Stem Cells Through Fibroblast Reprogramming. AB - Various factors affect the process of obtaining stable Arbas cashmere goat embryonic stem cells (ESCs), for example, the difficulty in isolating cells at the appropriate stage of embryonic development, the in vitro culture environment, and passage methods. With the emergence of induced pluripotent stem cell (iPSC) technology, it has become possible to use specific genes to induce somatic cell differentiation in PSCs. We transferred OCT4, SOX2, c-MYC, and KLF4 into Arbas cashmere goat fetal fibroblasts, then induced and cultured them using a drug inducible system to obtain Arbas goat iPSCs that morphologically resembled mouse iPSCs. After identification, the obtained goat iPSCs expressed ESC markers, had a normal karyotype, could differentiate into embryoid bodies in vitro, and could differentiate into three germ layer cell types and form teratomas in vivo. We used microarray gene expression profile analysis to elucidate the reprogramming process. Our results provide the experimental basis for establishing cashmere goat iPSC lines and for future in-depth studies on molecular mechanism of cashmere goat somatic cell reprogramming. PMID- 26731592 TI - Correction: Cellular Reprogramming: 2015; 17/2:95-105. PMID- 26731593 TI - Applicability of a novel immunoassay based on surface plasmon resonance for the diagnosis of Chagas disease. AB - BACKGROUND: We defined the methodological criteria for the interpretation of the results provided by a novel immunoassay based on surface plasmon resonance (SPR) to detect antibodies anti-Trypanosoma cruzi in human sera (SPRCruzi). Then, we evaluated its applicability as a diagnostic tool for Chagas disease. METHODS: To define the cut-off point and serum dilution factor, 57 samples were analyzed at SPRCruzi and the obtained values of SPR angle displacement (DeltathetaSPR) were submitted to statistical analysis. Adopting the indicated criteria, its performance was evaluated into a wide panel of samples, being 99 Chagas disease patients, 30 non-infected subjects and 42 with other parasitic/infectious diseases. In parallel, these samples were also analyzed by ELISA. RESULTS: Our data demonstrated that 1:320 dilution and cut-off point at ?thetaSPR=17.2 m degrees provided the best results. Global performance analysis demonstrated satisfactory sensitivity (100%), specificity (97.2%), positive predictive value (98%), negative predictive value (100%) and global accuracy (99.6%). ELISA and SPRCruzi showed almost perfect agreement, mainly between chagasic and non infected individuals. However, the new immunoassay was better in discriminate Chagas disease from other diseases. CONCLUSION: This work demonstrated the applicability of SPRCruzi as a feasible, real time, label free, sensible and specific methodology for the diagnosis of Chagas disease. PMID- 26731594 TI - Effects of Serum Uric Acid on Estimated GFR in Cardiac Surgery Patients: A Pilot Study. AB - BACKGROUND: The aim of the study was to investigate the effects of serum uric acid (SUA) on acute kidney injury (AKI) in patients undergoing cardiac surgery. METHODS: Prospectively collected data from a previous study were analyzed to investigate the relationship between SUA and AKI as assessed by neutrophil gelatinase-associated lipocalin (NGAL), serum creatinine (SCr) and kinetic estimated glomerular filtration rate (KeGFR). RESULTS: Patients undergoing cardiovascular surgery (n = 37) were included. SUA was measured at postoperative 1 h. Statistically significant correlations were present between SUA and NGAL measured at postoperative 1 h (r = 0.39, p = 0.008), 6 h (r = 0.31, p = 0.029) and 24 h (r = 0.31, p < 0.001), respectively. Significant correlations were also noted between SUA and SCr measured on postoperative day 1 (r = 0.41, p = 0.006), day 2 (r = 0.29, p = 0.042) and day 3 (r = 0.42, p = 0.009). Negative correlations were demonstrated between SUA and day 1 (r = -0.44, p = 0.007), day 2 (r = -0.43, p = 0.007), day 3 (r = -0.44, p = 0.006 and day 4 KeGFR (r = -0.35, p = 0.035). The inverse relationship of SUA and KeGFR was also demonstrated with a different method (Jelliffe) of measurement. CONCLUSIONS: A reduction in glomerular filtration rate (GFR) can lead to a rise in SUA. However, in this study, we are able to show that SUA at 1 h (maximal dilution time) effectively predicts subsequent changes in urinary NGAL, SCr, KeGFR, and the development of AKI. Thus, these findings suggest that uric acid precedes and predicts acute changes in renal function and cannot be ascribed to a simple relationship in which a reduced GFR raises SUA. PMID- 26731595 TI - Outcomes of Limb-Sparing Surgery Using Two Generations of Metal Endoprosthesis in 45 Dogs With Distal Radial Osteosarcoma. A Veterinary Society of Surgical Oncology Retrospective Study. AB - OBJECTIVE: To report outcomes in dogs with distal radial osteosarcoma (OSA) treated with metal endoprosthesis limb-sparing surgery and compare outcomes between 2 generations of endoprosthesis. STUDY DESIGN: Multi-institutional retrospective case series. ANIMALS: Forty-five dogs with distal radial OSA treated with endoprosthesis and chemotherapy. METHODS: Data of dogs treated with either first-generation endoprosthesis (GEN1) or second-generation endoprosthesis (GEN2) were sourced from medical records and radiographs. Surgical outcomes included postoperative lameness assessment and the presence, severity, and time to onset of complications. Oncologic outcomes included presence of local recurrence or metastasis, time to onset of local recurrence, metastasis-free interval (MFI), and survival time. Results for surgical and oncologic outcomes were compared between GEN1 and GEN2. RESULTS: Twenty-eight dogs received GEN1 and 17 dogs received GEN2. There were 39 complications (96%, 14 minor, 29 major) including infection (78%), implant-related complication (36%), and local recurrence (24%). Metastatic frequency was 67% and median MFI was 188 days (95% confidence interval [CI]: 126-250 days). Survival time ranged from 34 days to 6.1 years with a median of 289 days (95% CI: 207-371 days). There was no significant difference in complication severity, frequency, time to complication, MFI, or survival time between dogs receiving GEN1 and GEN2. CONCLUSION: There was no significant difference in outcomes between dogs receiving GEN1 and GEN2 for limb sparing surgery of the radius. Metastatic frequency and survival time for metal endoprosthesis were similar to that of amputation with curative intent chemotherapy. PMID- 26731596 TI - Surgical Navigation Improves the Precision and Accuracy of Tibial Component Alignment in Canine Total Knee Replacement. AB - OBJECTIVE: The goal of this study was to determine whether computer-assisted surgical navigation improves the accuracy of tibial component alignment in canine total knee replacement (TKR). STUDY DESIGN: Retrospective radiographic review and prospective ex vivo study. SAMPLE POPULATION: Canine TKR radiographs (n = 17 sets) and canine cadaveric stifles (n = 12). METHODS: Radiographs from TKR surgical workshops were reviewed to determine the incidence and magnitude of tibial component malalignment. Tibial component alignment was compared after either standard ("surgeon-guided") component placement or computer-assisted ("navigation-guided") placement. Results were compared against the current recommendations of a neutral (0 degrees varus-valgus) ostectomy in the frontal plane and 6 degrees of caudal slope in the sagittal plane. A prospective cadaveric study was then undertaken by performing TKR in 12 canine stifle joints. RESULTS: Malalignment of >3 degrees in the frontal and sagittal planes was identified in 12% and 24% of the radiographs from the retrospective review, respectively. Surgical navigation reduced both the mean error (P = .007) and the variability in frontal plane alignment (P < .001) as compared with surgeon-guided procedures. The mean error in sagittal plane alignment was not significantly different (P = .321), but variability in alignment was significantly lower when navigation was used (P = .008). CONCLUSION: Surgical navigation significantly improved accuracy and decreased variability in tibial component alignment in canine TKR. Clinical trials would be required to determine whether these improvements in surgical accuracy lead to better clinical outcomes in terms of joint function and a reduction in long-term implant wear. PMID- 26731597 TI - Vagus Nerve Stimulator Placement in Dogs: Surgical Implantation Technique, Complications, Long-Term Follow-Up, and Practical Considerations. AB - OBJECTIVE: To describe a modified implantation procedure of a vagus nerve stimulation (VNS) device in dogs and to report short- and long-term complications. STUDY DESIGN: Descriptive, experimental study. ANIMALS: Healthy, adult Beagle dogs (n = 10). METHODS: A VNS Therapy((r)) System was implanted in the left cervical region of anesthetized dogs. During and within 48 hours after surgery, electrocardiography (ECG) and impedance testing of the system were performed. Dogs were monitored daily and the impedance of the system was determined regularly until VNS devices were surgically removed 3 years after implantation. RESULTS: The implantation procedure was successful in all dogs without intraoperative complications. ECG monitoring and impedance tests were within normal limits during and within 48 hours after surgery. Postoperative seroma formation was common (70%). One dog developed an irreversible Horner's syndrome leading to removal of the device 5 months after implantation. Another dog developed trauma-induced damage of the lead requiring surgical revision. The device could be safely removed in all dogs; however, electrodes were left in place to avoid nerve damage. At removal, the anchor tether was dislodged in 40% of dogs and the lead was twisted in 50% of dogs. CONCLUSION: Implantation of a VNS Therapy((r)) System is safe and feasible in dogs; however, seroma formation, twisting of the lead, and dislodgement of the anchor tether were common. Practical improvements in the technique include stable device placement, use of a compression bandage, and exercise restriction. Regular evaluation of lead impedance is important, as altered values can indicate serious complications. PMID- 26731598 TI - Nasopharyngeal Dimensions From Computed Tomography of Pugs and French Bulldogs With Brachycephalic Airway Syndrome. AB - OBJECTIVE: To describe the nasopharyngeal airway dimensions of two brachycephalic breeds and to localize the area of smallest airway dimensions. STUDY DESIGN: Prospective, descriptive, computed tomographic imaging study. ANIMALS: Thirty pugs and 30 French bulldogs with brachycephalic upper airway syndrome. METHODS: The thickness and length of the soft palate, cross-sectional area of the airway passage dorsal to the soft and hard palates, and cross-sectional area of the frontal sinus were measured and normalized to each dog's skull index and body weight before statistical comparison between breeds. Nasopharyngeal turbinates and surrounding airway space, and a possible relationship between the canine tooth angulation and the severity of airway obstruction were assessed. RESULTS: Pugs had significantly smaller cross-sectional areas of the airway dorsal to the soft and hard palates than French bulldogs. In both breeds, the smallest nasopharyngeal cross-sectional areas were located dorsal to the caudal end of the soft palate. The soft palate of pugs was significantly shorter than that of French bulldogs and also significantly thinner when normalized to each dog's skull index. Pugs more commonly exhibited nasopharyngeal turbinates. Pugs had significantly smaller air-filled cavities at the location of the frontal sinus. No correlation between the nasopharyngeal dimensions and canine tooth angulation was observed. CONCLUSION: Computed tomographic assessment of the upper airway morphology showed the smallest nasopharyngeal cross-sectional areas were located dorsal to the caudal end of the soft palate in both breeds. Pugs had a smaller nasopharyngeal cross-sectional area despite smaller soft palate dimensions than French bulldogs. PMID- 26731599 TI - Frequency of Dehiscence in Hand-Sutured and Stapled Intestinal Anastomoses in Dogs. AB - OBJECTIVE: To determine the frequency of dehiscence of hand-sutured and stapled intestinal anastomoses in the dog and compare the surgery duration for the methods of anastomosis. STUDY DESIGN: Historical cohort study. SAMPLE POPULATION: Two hundred fourteen client-owned dogs undergoing hand-sutured (n = 142) or stapled (n = 72) intestinal anastomoses. METHODS: Medical records from 5 referral institutions were searched for dogs undergoing intestinal resection and anastomosis between March 2006 and February 2014. Demographic data, presence of septic peritonitis before surgery, surgical technique (hand-sutured or stapled), surgery duration, surgeon (resident versus faculty member), indication for surgical intervention, anatomic location of resection and anastomosis, and if dehiscence was noted postoperatively were retrieved. Estimated frequencies were summarized and presented as proportions and 95% confidence intervals (CI) and continuous outcomes as mean (95% CI). Comparisons were made across methods of anastomosis. RESULTS: Overall, 29/205 dogs (0.14, 95% CI 0.10-00.19) had dehiscence, including 21/134 dogs (0.16, 0.11-0.23) undergoing hand-sutured anastomosis and 8/71 dogs (0.11, 0.06-0.21) undergoing stapled anastomosis. There was no significant difference in the frequency of dehiscence across anastomosis methods (chi(2), P = .389). The mean (95% CI) surgery duration of 140 minutes (132-147) for hand- sutured anastomoses and 108 minutes (99-119) for stapled anastomoses was significantly different (t-test, P < .001). CONCLUSION: No significant difference in frequency of dehiscence was noted between hand- sutured and stapled anastomoses in dogs but surgery duration is significantly reduced by the use of staples for intestinal closure. PMID- 26731600 TI - Alleviation of Epiphora by Canaliculosinostomy into the Caudal Maxillary Sinus in the Horse. AB - OBJECTIVE: To describe a technique of canaliculosinostomy into the caudal maxillary sinus to alleviate epiphora secondary to nasolacrimal duct obstruction and to report the long-term outcome in 5 horses. STUDY DESIGN: Case series. ANIMALS: Five client-owned horses. METHODS: Case records of all horses presented for chronic epiphora to a single equine hospital that underwent surgical treatment were reviewed. All included horses had a Jones test or dacryocystography to confirm nasolacrimal duct obstruction. All horses were anesthetized and canaliculosinostomy was created from the medial canthus of the eye into the caudal maxillary sinus using a Steinmann pin and Jacob's chuck. A Foley catheter was placed normograde through the stoma. The inflated bulb held the Foley in place in the sinus, while the proximal end was pulled through the upper eyelid and sutured to the skin on the head. The Foley catheter was maintained in place for 3 weeks and then removed under sedation. RESULTS: Five horses were included. There were no intraoperative difficulties or complications. One horse dislodged the Foley catheter 3 days postoperatively. No other postoperative complications occurred. Followup was available for all horses. One horse was euthanatized for unrelated reasons 10 weeks postoperative at which time epiphora was resolved. The remaining 4 horses had resolution of epiphora at followup (24-46 months postoperative). CONCLUSION: This report describes a simple technique for canaliculosinostomy into the caudal maxillary sinus and long-term outcome in 4 of 5 horses, all of which had resolution of epiphora. This technique can be used to resolve epiphora of various etiologies. PMID- 26731601 TI - Surgical Correction of Traumatic Lateral Patellar Luxation. AB - OBJECTIVE: To report successful surgical repair of a grade IV lateral patellar luxation in a 437-kg heifer. STUDY DESIGN: Case report. ANIMAL: Seventeen-month old Holstein heifer (437 kg). METHODS: Diagnosis of traumatic lateral patellar luxation was made based on physical examination, and confirmed on radiographs. Arthroscopic examination of the stifle assessed joint changes. Lateral patellar luxation was surgically repaired using lateral release of the patella and medial imbrication of the joint capsule. RESULTS: The heifer presented nonweight-bearing lameness of the left hind limb (5/5 lameness score). Unilateral grade IV lateral patellar luxation was diagnosed based on physical examination and radiography. Arthroscopic examination of the stifle showed synovitis and cartilage eburnation of the medial articular surface of the patella and of the lateral trochlear ridge of the femur. Lateral release of the patella and medial imbrication of the joint capsule was performed. The heifer remained lame (4.5/5 lameness score) and developed severe disuse muscle atrophy after surgery. By day 112, the heifer was walking easily and was completely weight bearing on the left hindlimb but did have a gait alteration (2/5 lameness score). On day 229, the heifer calved for the first time and lameness was no longer evident. CONCLUSION: This report documents successful surgical treatment of traumatic lateral patellar luxation in a large heifer but additional case evaluation is required to provide an accurate prognosis for this condition and treatment in large cattle. PMID- 26731602 TI - The Effect of Intravenous Regional Perfusion of the Distal Limb With Amikacin Sulfate on Wounds Healing by Second Intention in Horses. AB - OBJECTIVE: To compare the gross and histological effects of intravenous regional limb perfusion (IVRLP) using amikacin sulfate on second intention healing of distal limb wounds in adult horses with healing in untreated wounds. STUDY DESIGN: In vivo experimental study. ANIMALS: Adult horses (n = 7). METHODS: Two full thickness wounds (2.5 * 2.5 cm) were created aseptically on the dorsal aspect of each metacarpus and maintained under sterile bandages. One forelimb was randomly selected from each horse for IVRLP on days 2, 3, and 4 post-wounding. Sequential biopsies were taken from 1 wound on each limb to evaluate the histological effects of IVRLP. Photographs were obtained of nonbiopsied wounds from days 2 to 62 for gross assessment and wound measurement. Wound size and contraction, healing rate during and immediately after IVRLP treatment, total healing rate, and histological scores for edema, hemorrhage, inflammatory infiltrate, and fibrovascular proliferation were compared. RESULTS: No differences were observed between groups for wound size, wound contraction, healing rates during or after IVRLP treatment periods, or total healing rate. Wound size over time was larger in the IVRLP group compared with the control group; however, this difference did not reach statistical significance. Mononuclear cell infiltration was greater in the IVRLP group compared with controls. No differences were observed for other histological variables. All wounds healed without the formation of exuberant granulation tissue. CONCLUSION: Treatment for 3 consecutive days with IVRLP using amikacin sulfate did not negatively affect surgical wounds healing by second intention in the distal limb of horses. PMID- 26731603 TI - Ability of the Tightrope((r)) and Percutaneous Lateral Fabellar Suture Techniques to Control Cranial Tibial Translation. PMID- 26731604 TI - Can Continuous Positive Airway Pressure Reduce the Risk of Stroke in Obstructive Sleep Apnea Patients? A Systematic Review and Meta-Analysis. AB - BACKGROUND AND PURPOSE: Obstructive sleep apnea (OSA) has been shown to increase the risk of stroke. Although continuous positive airway pressure (CPAP) is considered the treatment of choice for OSA, whether treating OSA with CPAP reduces the risk of stroke remains unclear. We aimed to evaluate the effects of CPAP on incidence of stroke in patients with OSA. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of all published studies that provided the number of incident strokes in OSA patients in light of their treatment status with CPAP. RESULTS: We identified 8 relevant studies: one randomized controlled study (RCT), 5 cohort studies, and 2 studies using administrative health data. The two overlapping cohort studies in women and the elderly and the 2 studies using administrative health data had analyzed the impact of CPAP on stroke apart from cardiac events, whereas the others had focused on the overall cardiovascular events. Based on a meta-analysis of the cohort studies, treatment with CPAP was associated with a lower incidence of stroke and cardiac events with relative risks of 0.27 [0.14-0.53], and 0.54 [0.38 0.75], respectively, although this could not be reproduced in the RCT and the studies using administrative data. CONCLUSIONS: Treating with CPAP in patients with OSA might decrease the risk of stroke, although there is some conflicting evidence. Such effect was more pronounced in stroke than in cardiac events. Future studies analyzing stroke apart from cardiac disease would be of interest. PMID- 26731605 TI - Subacute effects of low dose lead nitrate and mercury chloride exposure on kidney of rats. AB - Lead nitrate and mercury chloride are the most common heavy metal pollutants. In the present study, the effects of lead and mercury induced nephrotoxicity were studied in Wistar rats. Lead nitrate (LN, 45 mg/kg b.w/day) and mercury chloride (MC, 0.02 mg/kg b.w/day) and their combination were administered orally for 28 days. Four groups of rats were used in the study: control, LN, MC and LN plus MC groups. Serum biochemical parameters, lipid peroxidation, antioxidant enzymes and histopathological changes in kidney tissues were investigated in all treatment groups. LN and MC caused severe histopathological changes. It was shown that LN, MC and also co-treatment with LN and MC exposure induced significant increase in serum urea, uric acid and creatinine levels. There were also statistically significant changes in antioxidant enzyme activities (SOD, CAT, GPx and GST) and lipid peroxidation (MDA) in all groups except control group. In this study, we showed that MC caused more harmful effects than LN in rats. PMID- 26731606 TI - Glycosylation of a Fasciclin-Like Arabinogalactan-Protein (SOS5) Mediates Root Growth and Seed Mucilage Adherence via a Cell Wall Receptor-Like Kinase (FEI1/FEI2) Pathway in Arabidopsis. AB - Fundamental processes that underpin plant growth and development depend crucially on the action and assembly of the cell wall, a dynamic structure that changes in response to both developmental and environmental cues. While much is known about cell wall structure and biosynthesis, much less is known about the functions of the individual wall components, particularly with respect to their potential roles in cellular signaling. Loss-of-function mutants of two arabinogalactan protein (AGP)-specific galactosyltransferases namely, GALT2 and GALT5, confer pleiotropic growth and development phenotypes indicating the important contributions of carbohydrate moieties towards AGP function. Notably, galt2galt5 double mutants displayed impaired root growth and root tip swelling in response to salt, likely as a result of decreased cellulose synthesis. These mutants phenocopy a salt-overly sensitive mutant called sos5, which lacks a fasciclin like AGP (SOS5/FLA4) as well as a fei1fei2 double mutant, which lacks two cell wall-associated leucine-rich repeat receptor-like kinases. Additionally, galt2gal5 as well as sos5 and fei2 showed reduced seed mucilage adherence. Quintuple galt2galt5sos5fei1fei2 mutants were produced and provided evidence that these genes act in a single, linear genetic pathway. Further genetic and biochemical analysis of the quintuple mutant demonstrated involvement of these genes with the interplay between cellulose biosynthesis and two plant growth regulators, ethylene and ABA, in modulating root cell wall integrity. PMID- 26731607 TI - DNA-damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival. AB - Hematopoietic stem cells (HSCs) maintain blood cell production life-long by their unique abilities of self-renewal and differentiation into all blood cell lineages. Growth arrest and DNA-damage-inducible 45 alpha (GADD45A) is induced by genotoxic stress in HSCs. GADD45A has been implicated in cell cycle control, cell death and senescence, as well as in DNA-damage repair. In general, GADD45A provides cellular stability by either arresting the cell cycle progression until DNA damage is repaired or, in cases of fatal damage, by inducing apoptosis. However, the function of GADD45A in hematopoiesis remains controversial. We revealed the changes in murine HSC fate control orchestrated by the expression of GADD45A at single cell resolution. In contrast to other cellular systems, GADD45A expression did not cause a cell cycle arrest or an alteration in the decision between cell survival and apoptosis in HSCs. Strikingly, GADD45A strongly induced and accelerated the differentiation program in HSCs. Continuous tracking of individual HSCs and their progeny via time-lapse microscopy elucidated that once GADD45A was expressed, HSCs differentiate into committed progenitors within 29 hours. GADD45A-expressing HSCs failed to long-term reconstitute the blood of recipients by inducing multilineage differentiation in vivo. Importantly, gamma irradiation of HSCs induced their differentiation by upregulating endogenous GADD45A. The differentiation induction by GADD45A was transmitted by activating p38 Mitogen-activated protein kinase (MAPK) signaling and allowed the generation of megakaryocytic-erythroid, myeloid, and lymphoid lineages. These data indicate that genotoxic stress-induced GADD45A expression in HSCs prevents their fatal transformation by directing them into differentiation and thereby clearing them from the system. PMID- 26731608 TI - Active Surveillance versus Surgery of Nonfunctioning Pancreatic Neuroendocrine Neoplasms <=2 cm in MEN1 Patients. AB - BACKGROUND: The aim of this study was to evaluate the efficacy of conservative treatment for nonfunctioning pancreatic neuroendocrine neoplasms (NF-PNEN) <=2 cm in multiple endocrine neoplasia type 1 (MEN1)-affected patients compared with surgical treatment. METHODS: The databases of 4 tertiary referral institutions (San Raffaele Scientific Institute, Milan; Philipps-Universitat Marburg, Marburg; University of Padua, Padua; Royal Free Hospital, London) were analyzed. A comparison of conservative management and surgery at initial diagnosis of NF-PNEN <=2 cm between 1997 and 2013 was performed. RESULTS: Overall, 27 patients (45%) underwent up-front surgery and 33 patients (55%) were followed up after the initial diagnosis. A higher proportion of patients in the surgery group were female (70 vs. 33%, p = 0.004). Patients were mainly operated on in the period 1997-2007 as compared with the period 2008-2013 (n = 17; 63 vs. 37%; p = 0.040). The rate of multifocal tumors was higher in the surgery group (n = 24; 89%) than in the 'no surgery' group (n = 22; 67%; p = 0.043). After a median follow-up of 126 months, 1 patient deceased due to postoperative complications within 30 days after surgery. The 5-, 10-, and 15-year progression-free survival (PFS) rates were 63, 39, and 10%, respectively. The median PFS was similar in the two groups. Overall, 13 patients (32.5%) were operated on after initial surgical or conservative treatment. The majority of the surgically treated patients had stage 1 (77.5%), T1 (77.5%), and G1 (85%) tumors. CONCLUSIONS: NF-PNEN <=2 cm in MEN1 patients are indolent neoplasms posing a low oncological risk. Surgical treatment of these tumors at initial diagnosis is rarely justified in favor of conservative treatment. PMID- 26731609 TI - Accurate Ionization Potentials and Electron Affinities of Acceptor Molecules III: A Benchmark of GW Methods. AB - The performance of different GW methods is assessed for a set of 24 organic acceptors. Errors are evaluated with respect to coupled cluster singles, doubles, and perturbative triples [CCSD(T)] reference data for the vertical ionization potentials (IPs) and electron affinities (EAs), extrapolated to the complete basis set limit. Additional comparisons are made to experimental data, where available. We consider fully self-consistent GW (scGW), partial self-consistency in the Green's function (scGW0), non-self-consistent G0W0 based on several mean field starting points, and a "beyond GW" second-order screened exchange (SOSEX) correction to G0W0. We also describe the implementation of the self-consistent Coulomb hole with screened exchange method (COHSEX), which serves as one of the mean-field starting points. The best performers overall are G0W0+SOSEX and G0W0 based on an IP-tuned long-range corrected hybrid functional with the former being more accurate for EAs and the latter for IPs. Both provide a balanced treatment of localized vs delocalized states and valence spectra in good agreement with photoemission spectroscopy (PES) experiments. PMID- 26731610 TI - Polyketide Ring Expansion Mediated by a Thioesterase, Chain Elongation and Cyclization Domain, in Azinomycin Biosynthesis: Characterization of AziB and AziG. AB - The azinomycins are a family of potent antitumor agents with the ability to form interstrand cross-links with DNA. This study reports on the unusual biosynthetic formation of the 5-methyl naphthoate moiety, which is essential for effective DNA association. While sequence analysis predicts that the polyketide synthase (AziB) catalyzes the formation of this naphthoate, 2-methylbenzoic acid, a truncated single-ring product, is formed instead. We demonstrate that the thioesterase (AziG) acts as a chain elongation and cyclization (CEC) domain and is required for the additional two rounds of chain extension to form the expected product. PMID- 26731611 TI - 4-Acyl Pyrrole Derivatives Yield Novel Vectors for Designing Inhibitors of the Acetyl-Lysine Recognition Site of BRD4(1). AB - Several human diseases, including cancer, show altered signaling pathways resulting from changes in the activity levels of epigenetic modulators. In the past few years, small-molecule inhibitors against specific modulators, including the bromodomain and extra-terminal (BET) bromodomain family of acetylation readers, have shown early promise in the treatment of the genetically defined midline carcinoma and hematopoietic malignancies. We have recently developed a novel potent inhibitor of BET proteins, 1 (XD14[ Angew. Chem., Int. Ed. 2013, 52, 14055]), which exerts a strong inhibitory potential on the proliferation of specific leukemia cell lines. In the study presented here, we designed analogues of 1 to study the potential of substitutions on the 4-acyl pyrrole backbone to occupy additional sites within the substrate recognition site of BRD4(1). The compounds were profiled using ITC, DSF, and X-ray crystallography. We could introduce several substitutions that address previously untargeted areas of the substrate recognition site. This work may substantially contribute to the development of therapeutics with increased target specificity against BRD4 related malignancies. PMID- 26731612 TI - Beyond symptom management: Family relations, unmet needs of persons living with severe mental illnesses, and potential implications for social work in South Africa. AB - This study examined the quality of family relationships and its associations with the severity of unmet needs of individuals admitted to a tertiary psychiatric hospital in South Africa. The quality of family relations and perceived unmet needs were assessed using the Lehman Quality of Life Interview and Camberwell Assessment of Needs, respectively. The results show that higher total unmet needs were associated with lower quality of family relations. The main areas of serious unmet needs included accessing government benefits and information, and establishing social relations. The results have implications for hospital-based social workers beyond managing psychiatric symptoms in South Africa. PMID- 26731613 TI - Risk of Colorectal Cancer After Solid Organ Transplantation in the United States. AB - Solid organ transplant recipients have increased colorectal cancer (CRC) risk. We assessed CRC risk among transplant recipients and identified factors contributing to this association. The US transplant registry was linked to 15 population-based cancer registries (1987-2010). We compared CRC risk in recipients to the general population by using standardized incidence ratios (SIRs) and identified CRC risk factors by using Poisson regression. Based on 790 cases of CRC among 224 098 transplant recipients, the recipients had elevated CRC risk (SIR 1.12, 95% confidence interval [CI] 1.04 to 1.20). The increase was driven by an excess of proximal colon cancer (SIR 1.69, 95% CI 1.53 to 1.87), while distal colon cancer was not increased (SIR 0.93, 95% CI 0.80 to 1.07), and rectal cancer was reduced (SIR 0.64, 95% CI 0.54 to 0.76). In multivariate analyses, CRC was increased markedly in lung recipients with cystic fibrosis (incidence rate ratio [IRR] 12.3, 95% CI 6.94 to 21.9, vs. kidney recipients). Liver recipients with primary sclerosing cholangitis and inflammatory bowel disease also had elevated CRC risk (IRR 5.32, 95% CI 3.73 to 7.58). Maintenance therapy with cyclosporine and azathioprine was associated with proximal colon cancer (IRR 1.53, 95% CI 1.05 to 2.23). Incidence was not elevated in a subgroup of kidney recipients treated with tacrolimus and mycophenolate mofetil, pointing to the relevance of the identified risk factors. Transplant recipients have increased proximal colon cancer risk, likely related to underlying medical conditions (cystic fibrosis and primary sclerosing cholangitis) and specific immunosuppressive regimens. PMID- 26731614 TI - Sundew-Inspired Adhesive Hydrogels Combined with Adipose-Derived Stem Cells for Wound Healing. AB - The potential to harness the unique physical, chemical, and biological properties of the sundew (Drosera) plant's adhesive hydrogels has long intrigued researchers searching for novel wound-healing applications. However, the ability to collect sufficient quantities of the sundew plant's adhesive hydrogels is problematic and has eclipsed their therapeutic promise. Inspired by these natural hydrogels, we asked if sundew-inspired adhesive hydrogels could overcome the drawbacks associated with natural sundew hydrogels and be used in combination with stem cell-based therapy to enhance wound-healing therapeutics. Using a bioinspired approach, we synthesized adhesive hydrogels comprised of sodium alginate, gum arabic, and calcium ions to mimic the properties of the natural sundew-derived adhesive hydrogels. We then characterized and showed that these sundew-inspired hydrogels promote wound healing through their superior adhesive strength, nanostructure, and resistance to shearing when compared to other hydrogels in vitro. In vivo, sundew-inspired hydrogels promoted a "suturing" effect to wound sites, which was demonstrated by enhanced wound closure following topical application of the hydrogels. In combination with mouse adipose-derived stem cells (ADSCs) and compared to other therapeutic biomaterials, the sundew-inspired hydrogels demonstrated superior wound-healing capabilities. Collectively, our studies show that sundew-inspired hydrogels contain ideal properties that promote wound healing and suggest that sundew-inspired-ADSCs combination therapy is an efficacious approach for treating wounds without eliciting noticeable toxicity or inflammation. PMID- 26731627 TI - Hydrofluorocarbon (HFC) Emissions in China: An Inventory for 2005-2013 and Projections to 2050. AB - Many hydrofluorocarbons (HFCs) that are widely used as substitutes for ozone depleting substances (now regulated under the Montreal Protocol) are very potent greenhouse gases (GHGs). China's past and future HFC emissions are of great interest because China has emerged as a major producer and consumer of HFCs. Here, we present for the first time a comprehensive inventory estimate of China's HFC emissions during 2005-2013. Results show a rapid increase in HFC production, consumption, and emissions in China during the period and that the emissions of HFC with a relatively high global warming potential (GWP) grew faster than those with a relatively low GWP. The proportions of China's historical HFC CO2 equivalent emissions to China's CO2 emissions or global HFC CO2-equivalent emissions increased rapidly during 2005-2013. Using the "business-as-usual" (BAU) scenario, in which HFCs are used to replace a significant fraction of hydrochlorofluorocarbons (HCFCs) in China (to date, there are no regulations on HFC uses in China), emissions of HFCs are projected to be significant components of China's and global future GHG emissions. However, potentials do exist for minimizing China's HFC emissions (for example, if regulations on HFC uses are established in China). Our findings on China's historical and projected HFC emission trajectories could also apply to other developing countries, with important implications for mitigating global GHG emissions. PMID- 26731628 TI - Tracking the Neurodevelopmental Correlates of Mental State Inference in Early Childhood. AB - Between ages 4 and 6, children become better at inferring what others are thinking and feeling. However, the neural correlates of these advances are understudied. The current study investigated the relation between performance on a face-based mental state inference task and white matter characteristics. Two tracts of interest, the uncinate fasciculus (UF) and inferior longitudinal fasciculus, were analyzed due to their involvement in social-emotional and face processing, respectively. Findings demonstrate a significant relation between fractional anisotropy in the UF and task performance in 4- but not 6-year-old children. Findings have implications for typical and atypical populations. PMID- 26731629 TI - Etiology and Epidemiology of Diarrhea in Hospitalized Children from Low Income Country: A Matched Case-Control Study in Central African Republic. AB - BACKGROUND: In Sub-Saharan Africa, infectious diarrhea is a major cause of morbidity and mortality. A case-control study was conducted to identify the etiology of diarrhea and to describe its main epidemiologic risk factors among hospitalized children under five years old in Bangui, Central African Republic. METHODS: All consecutive children under five years old hospitalized for diarrhea in the Pediatric Complex of Bangui for whom a parent's written consent was provided were included. Controls matched by age, sex and neighborhood of residence of each case were included. For both cases and controls, demographic, socio-economic and anthropometric data were recorded. Stool samples were collected to identify enteropathogens at enrollment. Clinical examination data and blood samples were collected only for cases. RESULTS: A total of 333 cases and 333 controls was recruited between December 2011 and November 2013. The mean age of cases was 12.9 months, and 56% were male. The mean delay between the onset of first symptoms and hospital admission was 3.7 days. Blood was detected in 5% of stool samples from cases. Cases were significantly more severely or moderately malnourished than controls. One of the sought-for pathogens was identified in 78% and 40% of cases and controls, respectively. Most attributable cases of hospitalized diarrhea were due to rotavirus, with an attributable fraction of 39%. Four other pathogens were associated with hospitalized diarrhea: Shigella/EIEC, Cryptosporidium parvum/hominis, astrovirus and norovirus with attributable fraction of 9%, 10%, 7% and 7% respectively. Giardia intestinalis was found in more controls than cases, with a protective fraction of 6%. CONCLUSIONS: Rotavirus, norovirus, astrovirus, Shigella/EIEC, Cryptosporidium parvum/hominis were found to be positively associated with severe diarrhea: while Giardia intestinalis was found negatively associated. Most attributable episodes of severe diarrhea were associated with rotavirus, highlighting the urgent need to introduce the rotavirus vaccine within the CAR's Expanded Program on Immunization. The development of new medicines, vaccines and rapid diagnostic tests that can be conducted at the bedside should be high priority for low resource countries. PMID- 26731630 TI - Steric and Dynamic Parameters Influencing In Situ Cycloadditions to Form Triazole Inhibitors with Crystalline Acetylcholinesterase. AB - Ligand binding sites on acetylcholinesterase (AChE) comprise an active center, at the base of a deep and narrow gorge lined by aromatic residues, and a peripheral site at the gorge entry. These features launched AChE as a reaction vessel for in situ click-chemistry synthesis of high-affinity TZ2PA6 and TZ2PA5 inhibitors, forming a syn-triazole upon cycloaddition within the gorge from alkyne and azide reactants bound at the two sites, respectively. Subsequent crystallographic analyses of AChE complexes with the TZ2PA6 regioisomers demonstrated that syn product association is accompanied by side chain reorganization within the gorge, freezing-in-frame a conformation distinct from an unbound state or anti complex. To correlate inhibitor dimensions with reactivity and explore whether in situ cycloaddition could be accelerated in a concentrated, crystalline template, we developed crystal-soaking procedures and solved structures of AChE complexes with the TZ2PA5 regioisomers and their TZ2/PA5 precursors (2.1-2.7 A resolution). The structures reveal motions of residue His447 in the active site and, unprecedentedly, residue Tyr341 at the gorge mouth, associated with TZ2 binding and coordinated with other side chain motions in the gorge that may guide AChE toward a transient state favoring syn-triazole formation. Despite precursor binding to crystalline AChE, coupling of rapid electric field fluctuations in the gorge with proper alignments of the azide and alkyne reactants to form the triazole remains a likely limiting step. These observations point to a prime requirement for AChE to interconvert dynamically between sequential conformations to promote favorable electrostatic factors enabling a productive apposition of the reactants for reactivity. PMID- 26731631 TI - Polar Versus Non-polar Local Ordering at Mobile Sites in Proteins: Slowly Relaxing Local Structure Analysis of (15)N Relaxation in the Third Immunoglobulin Binding Domain of Streptococcal Protein G. AB - We developed recently the slowly relaxing local structure (SRLS) approach for studying restricted motions in proteins by NMR. The spatial restrictions have been described by potentials comprising the traditional L = 2, K = 0, 2 spherical harmonics. However, the latter are associated with non-polar ordering whereas protein-anchored probes experience polar ordering, described by odd-L spherical harmonics. Here we extend the SRLS potential to include the L = 1, K = 0, 1 spherical harmonics and analyze (15)N-(1)H relaxation from the third immunoglobulin-binding domain of streptococcal protein G (GB3) with the polar L = 1 potential (coefficients c0(1) and c1(1)) or the non-polar L = 2 potential (coefficients c0(2) and c2(2)). Strong potentials, with ?c0(1)? ~ 60 for L = 1 and ?c0(2)? ~ 20 for L = 2 (in units of kBT), are detected. In the alpha-helix of GB3 the coefficients of the rhombic terms are c1(1) ~ c2(2) ~ 0; in the preceding (following) chain segment they are ?c1(1)? ~ 6 for L = 1 and ?c2(2)? ~ 14 for L = 2 (?c1(1)? ~ 3 for L = 1 and ?c2(2)? ~ 7 for L = 2). The local diffusion rate, D2, lies in the 5 * 10(9)-1 * 10(11) s(-1) range; it is generally larger for L = 1. The main ordering axis deviates moderately from the N-H bond. Corresponding L = 1 and L = 2 potentials and probability density functions are illustrated for residues A26 of the alpha-helix, Y3 of the beta1-strand, and L12 of the beta1/beta2 loop; they differ considerably. Polar/orientational ordering is shown to be associated with GB3 binding to its cognate Fab fragment. The polarity of the local ordering is clearly an important factor. PMID- 26731632 TI - The protective effect of Hypericum connatum on stress-induced escape deficit in rat is related to its flavonoid content. AB - Context Hypericum perforatum L. (Hypericaceae), used in moderate depression treatment, is active in experimental tests for antidepressant activity. For H. connatum Lam., a South American species lacking hyperforin, antidepressant effects have not been demonstrated. Objective This study evaluates the antidepressant-like effect of H. connatum in rats and identifies the components involved in this activity. Materials and methods First, the effects of acute and 14-d oral administrations of an extract derived from H. connatum aerial parts were studied using the Escape Deficit (ED) test. Next, methanol-extracted flavonoid-enriched fractions B and C and fraction-purified flavonoids (quercetin, rutin and isoquercitrin) were evaluated in the ED test after acute administration. To rule out possible confounding effects of the flavonoids, we examined nociceptive threshold using the tail-flick test and anxious behaviour using the elevated plus maze (EPM) test. Results Hypericum connatum increased reactivity of unavoidable stress-exposed rats after acute (0.5 and 1 g/kg: ED = 18.6/30 and 19.8/30, respectively) and repeated administration (0.5 g/kg twice daily: ED = 17.8/30). Protective effects were observed for fractions B and C (250 mg/kg: ED = 18.1/30 and 18.8/30, respectively), quercetin (2.5, 5 and 10 mg/kg: ED = 15.3/30, 18.3/30 and 21.6/30, respectively), rutin (5 and 10 mg/kg: ED = 15.4/30 and 13.0/30, respectively) and isoquercitrin (2.5 mg/kg: ED = 19.2/30). The flavonoids did not modify nociceptive threshold or performance in the EPM test. Discussion and conclusion Hypericum connatum showed protective activity in the ED test, a correlate of potential antidepressant-like effects that appeared to be related to the flavonoid components of this species. PMID- 26731634 TI - Scalable Robust Principal Component Analysis Using Grassmann Averages. AB - In large datasets, manual data verification is impossible, and we must expect the number of outliers to increase with data size. While principal component analysis (PCA) can reduce data size, and scalable solutions exist, it is well-known that outliers can arbitrarily corrupt the results. Unfortunately, state-of-the-art approaches for robust PCA are not scalable. We note that in a zero-mean dataset, each observation spans a one-dimensional subspace, giving a point on the Grassmann manifold. We show that the average subspace corresponds to the leading principal component for Gaussian data. We provide a simple algorithm for computing this Grassmann Average ( GA), and show that the subspace estimate is less sensitive to outliers than PCA for general distributions. Because averages can be efficiently computed, we immediately gain scalability. We exploit robust averaging to formulate the Robust Grassmann Average (RGA) as a form of robust PCA. The resulting Trimmed Grassmann Average ( TGA) is appropriate for computer vision because it is robust to pixel outliers. The algorithm has linear computational complexity and minimal memory requirements. We demonstrate TGA for background modeling, video restoration, and shadow removal. We show scalability by performing robust PCA on the entire Star Wars IV movie; a task beyond any current method. Source code is available online. PMID- 26731633 TI - Body mass and weight thresholds for increased prosthetic joint infection rates after primary total joint arthroplasty. AB - BACKGROUND AND PURPOSE: Obesity increases the risk of deep infection after total joint arthroplasty (TJA). Our objective was to determine whether there may be body mass index (BMI) and weight thresholds indicating a higher prosthetic joint infection rate. PATIENTS AND METHODS: We included all 9,061 primary hip and knee arthroplasties (mean age 70 years, 61% women) performed between March 1996 and December 2013 where the patient had received intravenous cefuroxime (1.5 g) perioperatively. The main exposures of interest were BMI (5 categories: < 24.9, 25-29.9, 30-34.9, 35-39.9, and >= 40) and weight (5 categories: < 60, 60-79, 80 99, 100-119, and >= 120 kg). Numbers of TJAs according to BMI categories (lowest to highest) were as follows: 2,956, 3,350, 1,908, 633, and 214, respectively. The main outcome was prosthetic joint infection. The mean follow-up time was 6.5 years (0.5-18 years). RESULTS: 111 prosthetic joint infections were observed: 68 postoperative, 16 hematogenous, and 27 of undetermined cause. Incidence rates were similar in the first 3 BMI categories (< 35), but they were twice as high with BMI 35-39.9 (adjusted HR = 2.1, 95% CI: 1.1-4.3) and 4 times higher with BMI >= 40 (adjusted HR = 4.2, 95% CI: 1.8-9.7). Weight >= 100 kg was identified as threshold for a significant increase in infection from the early postoperative period onward (adjusted HR = 2.1, 95% CI: 1.3-3.6). INTERPRETATION: BMI >= 35 or weight >= 100 kg may serve as a cutoff for higher perioperative dosage of antibiotics. PMID- 26731635 TI - Dissimilarity-Based Sparse Subset Selection. AB - Finding an informative subset of a large collection of data points or models is at the center of many problems in computer vision, recommender systems, bio/health informatics as well as image and natural language processing. Given pairwise dissimilarities between the elements of a 'source set' and a 'target set,' we consider the problem of finding a subset of the source set, called representatives or exemplars, that can efficiently describe the target set. We formulate the problem as a row-sparsity regularized trace minimization problem. Since the proposed formulation is, in general, NP-hard, we consider a convex relaxation. The solution of our optimization finds representatives and the assignment of each element of the target set to each representative, hence, obtaining a clustering. We analyze the solution of our proposed optimization as a function of the regularization parameter. We show that when the two sets jointly partition into multiple groups, our algorithm finds representatives from all groups and reveals clustering of the sets. In addition, we show that the proposed framework can effectively deal with outliers. Our algorithm works with arbitrary dissimilarities, which can be asymmetric or violate the triangle inequality. To efficiently implement our algorithm, we consider an Alternating Direction Method of Multipliers (ADMM) framework, which results in quadratic complexity in the problem size. We show that the ADMM implementation allows to parallelize the algorithm, hence further reducing the computational time. Finally, by experiments on real-world datasets, we show that our proposed algorithm improves the state of the art on the two problems of scene categorization using representative images and time-series modeling and segmentation using representative models. PMID- 26731636 TI - Learning Discriminative Bayesian Networks from High-Dimensional Continuous Neuroimaging Data. AB - Due to its causal semantics, Bayesian networks (BN) have been widely employed to discover the underlying data relationship in exploratory studies, such as brain research. Despite its success in modeling the probability distribution of variables, BN is naturally a generative model, which is not necessarily discriminative. This may cause the ignorance of subtle but critical network changes that are of investigation values across populations. In this paper, we propose to improve the discriminative power of BN models for continuous variables from two different perspectives. This brings two general discriminative learning frameworks for Gaussian Bayesian networks (GBN). In the first framework, we employ Fisher kernel to bridge the generative models of GBN and the discriminative classifiers of SVMs, and convert the GBN parameter learning to Fisher kernel learning via minimizing a generalization error bound of SVMs. In the second framework, we employ the max-margin criterion and build it directly upon GBN models to explicitly optimize the classification performance of the GBNs. The advantages and disadvantages of the two frameworks are discussed and experimentally compared. Both of them demonstrate strong power in learning discriminative parameters of GBNs for neuroimaging based brain network analysis, as well as maintaining reasonable representation capacity. The contributions of this paper also include a new Directed Acyclic Graph (DAG) constraint with theoretical guarantee to ensure the graph validity of GBN. PMID- 26731637 TI - Exploring Local and Overall Ordinal Information for Robust Feature Description. AB - This paper aims to build robust feature descriptors by exploring intensity order information in a patch. To this end, the local intensity order pattern (LIOP) and the overall intensity order pattern (OIOP) are proposed to effectively encode intensity order information of each pixel in different aspects. Specifically, LIOP captures the local ordinal information by using the intensity relationships among all the neighbouring sampling points around a pixel, while OIOP exploits the coarsely quantized overall intensity order of these sampling points. These two kinds of patterns are then separately aggregated into different ordinal bins, leading to two kinds of feature descriptors. Furthermore, as these two kinds of descriptors could encode complementary ordinal information, they are combined together to obtain a discriminative and compact mixed intensity order pattern descriptor. All these descriptors are constructed on the basis of relative relationships of intensities in a rotationally invariant way, making them be inherently invariant to image rotation and any monotonic intensity changes. Experimental results on image matching and object recognition are encouraging, demonstrating the superiorities of our descriptors over the state of the art. PMID- 26731638 TI - Go-ICP: A Globally Optimal Solution to 3D ICP Point-Set Registration. AB - The Iterative Closest Point (ICP) algorithm is one of the most widely used methods for point-set registration. However, being based on local iterative optimization, ICP is known to be susceptible to local minima. Its performance critically relies on the quality of the initialization and only local optimality is guaranteed. This paper presents the first globally optimal algorithm, named Go ICP, for Euclidean (rigid) registration of two 3D point-sets under the L2 error metric defined in ICP. The Go-ICP method is based on a branch-and-bound scheme that searches the entire 3D motion space SE(3). By exploiting the special structure of SE(3) geometry, we derive novel upper and lower bounds for the registration error function. Local ICP is integrated into the BnB scheme, which speeds up the new method while guaranteeing global optimality. We also discuss extensions, addressing the issue of outlier robustness. The evaluation demonstrates that the proposed method is able to produce reliable registration results regardless of the initialization. Go-ICP can be applied in scenarios where an optimal solution is desirable or where a good initialization is not always available. PMID- 26731639 TI - Tracking Interacting Objects Using Intertwined Flows. AB - In this paper, we show that tracking different kinds of interacting objects can be formulated as a network-flow mixed integer program. This is made possible by tracking all objects simultaneously using intertwined flow variables and expressing the fact that one object can appear or disappear at locations where another is in terms of linear flow constraints. Our proposed method is able to track invisible objects whose only evidence is the presence of other objects that contain them. Furthermore, our tracklet-based implementation yields real-time tracking performance. We demonstrate the power of our approach on scenes involving cars and pedestrians, bags being carried and dropped by people, and balls being passed from one player to the next in team sports. In particular, we show that by estimating jointly and globally the trajectories of different types of objects, the presence of the ones which were not initially detected based solely on image evidence can be inferred from the detections of the others. PMID- 26731640 TI - Joint Color-Spatial-Directional Clustering and Region Merging (JCSD-RM) for Unsupervised RGB-D Image Segmentation. AB - Recent advances in depth imaging sensors provide easy access to the synchronized depth with color, called RGB-D image. In this paper, we propose an unsupervised method for indoor RGB-D image segmentation and analysis. We consider a statistical image generation model based on the color and geometry of the scene. Our method consists of a joint color-spatial-directional clustering method followed by a statistical planar region merging method. We evaluate our method on the NYU depth database and compare it with existing unsupervised RGB-D segmentation methods. Results show that, it is comparable with the state of the art methods and it needs less computation time. Moreover, it opens interesting perspectives to fuse color and geometry in an unsupervised manner. PMID- 26731641 TI - Explore Efficient Local Features from RGB-D Data for One-Shot Learning Gesture Recognition. AB - Availability of handy RGB-D sensors has brought about a surge of gesture recognition research and applications. Among various approaches, one shot learning approach is advantageous because it requires minimum amount of data. Here, we provide a thorough review about one-shot learning gesture recognition from RGB-D data and propose a novel spatiotemporal feature extracted from RGB-D data, namely mixed features around sparse keypoints (MFSK). In the review, we analyze the challenges that we are facing, and point out some future research directions which may enlighten researchers in this field. The proposed MFSK feature is robust and invariant to scale, rotation and partial occlusions. To alleviate the insufficiency of one shot training samples, we augment the training samples by artificially synthesizing versions of various temporal scales, which is beneficial for coping with gestures performed at varying speed. We evaluate the proposed method on the Chalearn gesture dataset (CGD). The results show that our approach outperforms all currently published approaches on the challenging data of CGD, such as translated, scaled and occluded subsets. When applied to the RGB-D datasets that are not one-shot (e.g., the Cornell Activity Dataset-60 and MSR Daily Activity 3D dataset), the proposed feature also produces very promising results under leave-one-out cross validation or one-shot learning. PMID- 26731643 TI - Heme metabolism in stress regulation and protein production: From Cinderella to a key player. AB - Heme biosynthesis is a highly conserved pathway which is present in all kingdoms, from Archaea to higher organisms such as plants and mammals. The heme molecule acts as a prosthetic group for different proteins and enzymes involved in energy metabolism and reactions involved in electron transfer. Based on our recent findings and other recent reports, we here illustrate that heme is more than a co factor. We also discuss the necessity to gain more insight into the heme biosynthesis pathway regulation, as this interacts closely with overall stress control. Understanding heme biosynthesis and its regulation could impact our ability to develop more efficient yeast cell factories for heterologous protein production. PMID- 26731642 TI - Reduced Cerebral Perfusion Pressure during Lung Transplant Surgery Is Associated with Risk, Duration, and Severity of Postoperative Delirium. AB - RATIONALE: Delirium is common following lung transplant and is associated with poorer clinical outcomes. The extent to which intraoperative hemodynamic alterations may contribute to postoperative delirium among lung transplant recipients has not been examined. OBJECTIVES: To examine the impact of intraoperative hemodynamic changes on neurobehavioral outcomes among lung transplant recipients. METHODS: Intraoperative hemodynamic function during lung transplant was assessed in a consecutive series of patients between March and November 2013. Intraoperative cerebral perfusion pressure was assessed every minute in all patients. Following lung transplant, patients were monitored for the presence and severity of delirium using the Confusion Assessment Method and the Delirium Rating Scale until hospital discharge. MEASUREMENTS AND MAIN RESULTS: Sixty-three patients received lung transplants, of whom 23 (37%) subsequently developed delirium. Lower cerebral perfusion pressure was associated with increased risk of delirium (odds ratio [OR], 2.08 per 10-mm Hg decrease; 95% confidence interval [CI], 1.02-4.24; P = 0.043), longer duration of delirium (OR, 1.7 d longer per 10-mm Hg decrease; 95% CI, 1.1-2.7; P = 0.022), and greater delirium severity (b = -0.81; 95% CI, -1.47 to -0.15; P = 0.017). CONCLUSIONS: Poorer cerebral perfusion pressure during lung transplant is associated with greater risk for delirium following transplant, as well as greater duration and severity of delirium, independent of demographic and medical predictors. PMID- 26731644 TI - Hybrid foraging search: Searching for multiple instances of multiple types of target. AB - This paper introduces the "hybrid foraging" paradigm. In typical visual search tasks, observers search for one instance of one target among distractors. In hybrid search, observers search through visual displays for one instance of any of several types of target held in memory. In foraging search, observers collect multiple instances of a single target type from visual displays. Combining these paradigms, in hybrid foraging tasks observers search visual displays for multiple instances of any of several types of target (as might be the case in searching the kitchen for dinner ingredients or an X-ray for different pathologies). In the present experiment, observers held 8-64 target objects in memory. They viewed displays of 60-105 randomly moving photographs of objects and used the computer mouse to collect multiple targets before choosing to move to the next display. Rather than selecting at random among available targets, observers tended to collect items in runs of one target type. Reaction time (RT) data indicate searching again for the same item is more efficient than searching for any other targets, held in memory. Observers were trying to maximize collection rate. As a result, and consistent with optimal foraging theory, they tended to leave 25-33% of targets uncollected when moving to the next screen/patch. The pattern of RTs shows that while observers were collecting a target item, they had already begun searching memory and the visual display for additional targets, making the hybrid foraging task a useful way to investigate the interaction of visual and memory search. PMID- 26731645 TI - Physiological and morphological characterization of ganglion cells in the salamander retina. AB - Retinal ganglion cells (RGCs) integrate visual information from the retina and transmit collective signals to the brain. A systematic investigation of functional and morphological characteristics of various types of RGCs is important to comprehensively understand how the visual system encodes and transmits information via various RGC pathways. This study evaluated both physiological and morphological properties of 67 RGCs in dark-adapted flat mounted salamander retina by examining light-evoked cation and chloride current responses via voltage-clamp recordings and visualizing morphology by Lucifer yellow fluorescence with a confocal microscope. Six groups of RGCs were described: asymmetrical ON-OFF RGCs, symmetrical ON RGCs, OFF RGCs, and narrow-, medium- and wide-field ON-OFF RGCs. Dendritic field diameters of RGCs ranged 102 490 MUm: narrow field (<200 MUm, 31% of RGCs), medium field (200-300 MUm, 45%) and wide field (>300 MUm, 24%). Dendritic ramification patterns of RGCs agree with the sublamina A/B rule. 34% of RGCs were monostratified, 24% bistratified and 42% diffusely stratified. 70% of ON RGCs and OFF RGCs were monostratified. Wide-field RGCs were diffusely stratified. 82% of RGCs generated light-evoked ON OFF responses, while 11% generated ON responses and 7% OFF responses. Response sensitivity analysis suggested that some RGCs obtained separated rod/cone bipolar cell inputs whereas others obtained mixed bipolar cell inputs. 25% of neurons in the RGC layer were displaced amacrine cells. Although more types may be defined by more refined classification criteria, this report is to incorporate more physiological properties into RGC classification. PMID- 26731647 TI - Visual working memory representations guide the detection of emotional faces: An ERP study. AB - We investigated the correlates of the influences exerted by visual working memory (VWM) on attentional selection of emotional faces using electrophysiological method. Participants performed a search task to detect happy or angry faces among groups of neutral faces while simultaneously keeping in VWM a colour cue presented initially. A visual working memory test was required at last to ensure that the cue had been maintained in VWM. Happy faces elicited a larger amplitude N2pc ERP component when VWM features matched the target face (valid condition) and a smaller amplitude when VWM features matched a distractor face (invalid condition), compared with the neutral condition (wherein VWM features did not match any face in the search array). Additionally, angry faces elicited a greater N2pc amplitude in valid trials than in neutral and invalid trials. Although VWM could guide the attentional deployment of angry and happy faces, the guidance was subject to an anger superiority effect. PMID- 26731646 TI - Encoding and estimation of first- and second-order binocular disparity in natural images. AB - The first stage of processing of binocular information in the visual cortex is performed by mechanisms that are bandpass-tuned for spatial frequency and orientation. Psychophysical and physiological evidence have also demonstrated the existence of second-order mechanisms in binocular processing, which can encode disparities that are not directly accessible to first-order mechanisms. We compared the responses of first- and second-order binocular filters to natural images. We found that the responses of the second-order mechanisms are to some extent correlated with the responses of the first-order mechanisms, and that they can contribute to increasing both the accuracy, and depth range, of binocular stereopsis. PMID- 26731648 TI - Improving the Prediction of Prostate Cancer Overall Survival by Supplementing Readily Available Clinical Data with Gene Expression Levels of IGFBP3 and F3 in Formalin-Fixed Paraffin Embedded Core Needle Biopsy Material. AB - BACKGROUND: A previously reported expression signature of three genes (IGFBP3, F3 and VGLL3) was shown to have potential prognostic value in estimating overall and cancer-specific survivals at diagnosis of prostate cancer in a pilot cohort study using freshly frozen Fine Needle Aspiration (FNA) samples. METHODS: We carried out a new cohort study with 241 prostate cancer patients diagnosed from 2004-2007 with a follow-up exceeding 6 years in order to verify the prognostic value of gene expression signature in formalin fixed paraffin embedded (FFPE) prostate core needle biopsy tissue samples. The cohort consisted of four patient groups with different survival times and death causes. A four multiplex one-step RT-qPCR test kit, designed and optimized for measuring the expression signature in FFPE core needle biopsy samples, was used. In archive FFPE biopsy samples the expression differences of two genes (IGFBP3 and F3) were measured. The survival time predictions using the current clinical parameters only, such as age at diagnosis, Gleason score, PSA value and tumor stage, and clinical parameters supplemented with the expression levels of IGFBP3 and F3, were compared. RESULTS: When combined with currently used clinical parameters, the gene expression levels of IGFBP3 and F3 are improving the prediction of survival time as compared to using clinical parameters alone. CONCLUSION: The assessment of IGFBP3 and F3 gene expression levels in FFPE prostate cancer tissue would provide an improved survival prediction for prostate cancer patients at the time of diagnosis. PMID- 26731650 TI - Correction: Continuous Theta Burst Stimulation over the Left Dorsolateral Prefrontal Cortex Decreases Medium Load Working Memory Performance in Healthy Humans. PMID- 26731649 TI - Genetic Structure of a Local Population of the Anopheles gambiae Complex in Burkina Faso. AB - Members of the Anopheles gambiae species complex are primary vectors of human malaria in Africa. Population heterogeneities for ecological and behavioral attributes expand and stabilize malaria transmission over space and time, and populations may change in response to vector control, urbanization and other factors. There is a need for approaches to comprehensively describe the structure and characteristics of a sympatric local mosquito population, because incomplete knowledge of vector population composition may hinder control efforts. To this end, we used a genome-wide custom SNP typing array to analyze a population collection from a single geographic region in West Africa. The combination of sample depth (n = 456) and marker density (n = 1536) unambiguously resolved population subgroups, which were also compared for their relative susceptibility to natural genotypes of Plasmodium falciparum malaria. The population subgroups display fluctuating patterns of differentiation or sharing across the genome. Analysis of linkage disequilibrium identified 19 new candidate genes for association with underlying population divergence between sister taxa, A. coluzzii (M-form) and A. gambiae (S-form). PMID- 26731651 TI - Being in a "Green" Building Elicits "Greener" Recycling, but Not Necessarily "Better" Recycling. AB - Previous observational work revealed that transient populations in a sustainable building disposed of waste more accurately when compared to patrons in a non sustainable building. The current study uses an experimental design to replicate this observed effect and to investigate whether or not the built environment influences motivational factors to impact behavior. We find support that a building designed and built to communicate an atmosphere of sustainability can influence waste disposal behavior. Participants in the sustainable building used the garbage receptacle significantly less and compensated by tending to select the containers and organics receptacle more, which actually resulted in more errors overall. Our findings suggest that building atmospherics can motivate people to recycle more. However, atmospherics alone do not appear to be sufficient to elicit the desired performance outcome. PMID- 26731652 TI - Impacts of Human Recreation on Brown Bears (Ursus arctos): A Review and New Management Tool. AB - Increased popularity of recreational activities in natural areas has led to the need to better understand their impacts on wildlife. The majority of research conducted to date has focused on behavioral effects from individual recreations, thus there is a limited understanding of the potential for population-level or cumulative effects. Brown bears (Ursus arctos) are the focus of a growing wildlife viewing industry and are found in habitats frequented by recreationists. Managers face difficult decisions in balancing recreational opportunities with habitat protection for wildlife. Here, we integrate results from empirical studies with expert knowledge to better understand the potential population-level effects of recreational activities on brown bears. We conducted a literature review and Delphi survey of brown bear experts to better understand the frequencies and types of recreations occurring in bear habitats and their potential effects, and to identify management solutions and research needs. We then developed a Bayesian network model that allows managers to estimate the potential effects of recreational management decisions in bear habitats. A higher proportion of individual brown bears in coastal habitats were exposed to recreation, including photography and bear-viewing than bears in interior habitats where camping and hiking were more common. Our results suggest that the primary mechanism by which recreation may impact brown bears is through temporal and spatial displacement with associated increases in energetic costs and declines in nutritional intake. Killings in defense of life and property were found to be minimally associated with recreation in Alaska, but are important considerations in population management. Regulating recreation to occur predictably in space and time and limiting recreation in habitats with concentrated food resources reduces impacts on food intake and may thereby, reduce impacts on reproduction and survival. Our results suggest that decisions managers make about regulating recreational activities in time and space have important consequences for bear populations. The Bayesian network model developed here provides a new tool for managers to balance demands of multiple recreational activities while supporting healthy bear populations. PMID- 26731653 TI - Automatic Synthesis of Anthropomorphic Pulmonary CT Phantoms. AB - The great density and structural complexity of pulmonary vessels and airways impose limitations on the generation of accurate reference standards, which are critical in training and in the validation of image processing methods for features such as pulmonary vessel segmentation or artery-vein (AV) separations. The design of synthetic computed tomography (CT) images of the lung could overcome these difficulties by providing a database of pseudorealistic cases in a constrained and controlled scenario where each part of the image is differentiated unequivocally. This work demonstrates a complete framework to generate computational anthropomorphic CT phantoms of the human lung automatically. Starting from biological and image-based knowledge about the topology and relationships between structures, the system is able to generate synthetic pulmonary arteries, veins, and airways using iterative growth methods that can be merged into a final simulated lung with realistic features. A dataset of 24 labeled anthropomorphic pulmonary CT phantoms were synthesized with the proposed system. Visual examination and quantitative measurements of intensity distributions, dispersion of structures and relationships between pulmonary air and blood flow systems show good correspondence between real and synthetic lungs (p > 0.05 with low Cohen's d effect size and AUC values), supporting the potentiality of the tool and the usefulness of the generated phantoms in the biomedical image processing field. PMID- 26731654 TI - Effects of Conservation Tillage on Topsoil Microbial Metabolic Characteristics and Organic Carbon within Aggregates under a Rice (Oryza sativa L.)-Wheat (Triticum aestivum L.) Cropping System in Central China. AB - Investigating microbial metabolic characteristics and soil organic carbon (SOC) within aggregates and their relationships under conservation tillage may be useful in revealing the mechanism of SOC sequestration in conservation tillage systems. However, limited studies have been conducted to investigate the relationship between SOC and microbial metabolic characteristics within aggregate fractions under conservation tillage. We hypothesized that close relationships can exist between SOC and microbial metabolic characteristics within aggregates under conservation tillage. In this study, a field experiment was conducted from June 2011 to June 2013 following a split-plot design of a randomized complete block with tillage practices [conventional intensive tillage (CT) and no tillage (NT)] as main plots and straw returning methods [preceding crop residue returning (S, 2100-2500 kg C ha-1) and removal (NS, 0 kg C ha(-1))] as subplots with three replications. The objective of this study was to reveal the effects of tillage practices and residue-returning methods on topsoil microbial metabolic characteristics and organic carbon (SOC) fractions within aggregates and their relationships under a rice-wheat cropping system in central China. Microbial metabolic characteristics investigated using the Biolog system was examined within two aggregate fractions (>0.25 and <0.25 mm). NT treatments significantly increased SOC concentration of bulk soil, >0.25 aggregate, and <0.25 mm aggregate in the 0-5 cm soil layer by 5.8%, 6.8% and 7.9% relative to CT treatments, respectively. S treatments had higher SOC concentration of bulk soil (12.9%), >0.25 mm aggregate (11.3%), and <0.25 mm aggregate (14.1%) than NS treatments. Compared with CT treatments, NT treatments increased MBC by 11.2%, 11.5%, and 20%, and dissolved organic carbon (DOC) concentration by 15.5%, 29.5%, and 14.1% of bulk soil, >0.25 mm aggregate, and <0.25 mm aggregate in the 0-5 cm soil layer, respectively. Compared with NS treatments, S treatments significantly increased MBC by 29.8%, 30.2%, and 24.1%, and DOC concentration by 23.2%, 25.0%, and 37.5% of bulk soil, >0.25 mm aggregate, and <0.25 mm aggregate in the 0-5 cm soil layer, respectively. Conservation tillage (NT and S) increased microbial metabolic activities and Shannon index in >0.25 and <0.25 mm aggregates in the 0 5 cm soil layer. Redundancy analysis showed that the SOC and its fractions (DOC and MBC) were closely correlated with microbial metabolic activities. Structural equation modelling showed that the increase in microbial metabolic activities directly improved SOC by promoting DOC in >0.25 mm aggregate in the upper (0-5 cm) soil layer under conservation tillage systems, as well as directly and indirectly by promoting DOC and MBC in <0.25 mm aggregate. Our results suggested that conservation tillage increased SOC in aggregates in the topsoil by improving microbial metabolic activities. PMID- 26731656 TI - Correction: Skill-Specific Changes in Somatosensory Nogo Potentials in Baseball Players. PMID- 26731655 TI - Nanoscale Imaging Reveals a Tetraspanin-CD9 Coordinated Elevation of Endothelial ICAM-1 Clusters. AB - Endothelial barriers have a central role in inflammation as they allow or deny the passage of leukocytes from the vasculature into the tissue. To bind leukocytes, endothelial cells form adhesive clusters containing tetraspanins and ICAM-1, so-called endothelial adhesive platforms (EAPs). Upon leukocyte binding, EAPs evolve into docking structures that emanate from the endothelial surface while engulfing the leukocyte. Here, we show that TNF-alpha is sufficient to induce apical protrusions in the absence of leukocytes. Using advanced quantitation of atomic force microscopy (AFM) recordings, we found these structures to protrude by 160 +/- 80 nm above endothelial surface level. Confocal immunofluorescence microscopy proved them positive for ICAM-1, JAM-A, tetraspanin CD9 and f-actin. Microvilli formation was inhibited in the absence of CD9. Our findings indicate that stimulation with TNF-alpha induces nanoscale changes in endothelial surface architecture and that--via a tetraspanin CD9 depending mechanism--the EAPs rise above the surface to facilitate leukocyte capture. PMID- 26731657 TI - A Novel Method to Predict Genomic Islands Based on Mean Shift Clustering Algorithm. AB - Genomic Islands (GIs) are regions of bacterial genomes that are acquired from other organisms by the phenomenon of horizontal transfer. These regions are often responsible for many important acquired adaptations of the bacteria, with great impact on their evolution and behavior. Nevertheless, these adaptations are usually associated with pathogenicity, antibiotic resistance, degradation and metabolism. Identification of such regions is of medical and industrial interest. For this reason, different approaches for genomic islands prediction have been proposed. However, none of them are capable of predicting precisely the complete repertory of GIs in a genome. The difficulties arise due to the changes in performance of different algorithms in the face of the variety of nucleotide distribution in different species. In this paper, we present a novel method to predict GIs that is built upon mean shift clustering algorithm. It does not require any information regarding the number of clusters, and the bandwidth parameter is automatically calculated based on a heuristic approach. The method was implemented in a new user-friendly tool named MSGIP--Mean Shift Genomic Island Predictor. Genomes of bacteria with GIs discussed in other papers were used to evaluate the proposed method. The application of this tool revealed the same GIs predicted by other methods and also different novel unpredicted islands. A detailed investigation of the different features related to typical GI elements inserted in these new regions confirmed its effectiveness. Stand-alone and user friendly versions for this new methodology are available at http://msgip.integrativebioinformatics.me. PMID- 26731658 TI - Hepatitis C Virus Increases Occludin Expression via the Upregulation of Adipose Differentiation-Related Protein. AB - The hepatitis C virus (HCV) life cycle is closely associated with lipid metabolism. In particular, HCV assembly initiates at the surface of lipid droplets. To further understand the role of lipid droplets in HCV life cycle, we assessed the relationship between HCV and the adipose differentiation-related protein (ADRP), a lipid droplet-associated protein. Different steps of HCV life cycle were assessed in HCV-infected human Huh-7 hepatoma cells overexpressing ADRP upon transduction with a lentiviral vector. HCV infection increased ADRP mRNA and protein expression levels by 2- and 1.5-fold, respectively. The overexpression of ADRP led to an increase of (i) the surface of lipid droplets, (ii) the total cellular neutral lipid content (2.5- and 5-fold increase of triglycerides and cholesterol esters, respectively), (iii) the cellular free cholesterol level (5-fold) and (iv) the HCV particle production and infectivity (by 2- and 3.5-fold, respectively). The investigation of different steps of the HCV life cycle indicated that the ADRP overexpression, while not affecting the viral replication, promoted both virion egress and entry (~12-fold), the latter possibly via an increase of its receptor occludin. Moreover, HCV infection induces an increase of both ADRP and occludin expression. In HCV infected cells, the occludin upregulation was fully prevented by the ADRP silencing, suggesting a specific, ADRP-dependent mechanism. Finally, in HCV-infected human livers, occludin and ADRP mRNA expression levels correlated with each other. Alltogether, these findings show that HCV induces ADRP, which in turns appears to confer a favorable environment to viral spread. PMID- 26731659 TI - Xeroderma pigmentosum, complementation group D expression in H1299 lung cancer cells following benzo[a]pyrene exposure as well as in head and neck cancer patients. AB - DNA repair genes play critical roles in response to carcinogen-induced and anticancer therapy-induced DNA damage. Benzo[a]pyrene (BaP), the most carcinogenic polycyclic aromatic hydrocarbon (PAH), is classified as a group 1 carcinogen by International Agency for Research on Cancer. The aims of this study were to (1) evaluate the effects of BaP on DNA repair activity and expression of DNA repair genes in vitro and (2) examine the role of xeroderma pigmentosum, complementation group D (XPD) mRNA expression in human head and neck cancers. Host cell reactivation assay showed that BaP inhibited nucleotide excision repair in H1299 lung cancer cells. DNA repair through the non-homologous end-joining pathway was not affected by BaP. Real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) and Western blot demonstrated that XPD was downregulated by BaP treatment. BaP exposure did not apparently affect expression of another 11 DNA repair genes. BaP treatment increased the DNA damage marker gamma-H2AX and ultraviolet (UV) sensitivity, supporting an impairment of DNA repair in BaP-treated cells. XPD expression was also examined by quantitative RT PCR in 68 head and neck cancers, and a lower XPD mRNA level was found in smokers' cancer specimens. Importantly, reduced XPD expression was correlated with patient 5-year overall survival rate (35 vs. 56%) and was an independent prognostic factor (hazard ratio: 2.27). Data demonstrated that XPD downregulation was correlated with BaP exposure and human head and neck cancer survival. PMID- 26731660 TI - 'Candidatus Liberibacter asiaticus', Causal Agent of Citrus Huanglongbing, Is Reduced by Treatment with Brassinosteroids. AB - Huanglongbing (HLB) constitutes the most destructive disease of citrus worldwide, yet no established efficient management measures exist for it. Brassinosteroids, a family of plant steroidal compounds, are essential for plant growth, development and stress tolerance. As a possible control strategy for HLB, epibrassinolide was applied to as a foliar spray to citrus plants infected with the causal agent of HLB, 'Candidatus Liberibacter asiaticus'. The bacterial titers were reduced after treatment with epibrassinolide under both greenhouse and field conditions but were stronger in the greenhouse. Known defense genes were induced in leaves by epibrassinolide. With the SuperSAGE technology combined with next generation sequencing, induction of genes known to be associated with defense response to bacteria and hormone transduction pathways were identified. The results demonstrate that epibrassinolide may provide a useful tool for the management of HLB. PMID- 26731662 TI - The first taxonomic revaluation of the Iranian water frogs of the genus Pelophylax (Anura: Ranidae) using sequences of the mitochondrial genome. AB - The Eurasian water frog species and their geographic ranges have undergone considerable changes in the last four decades, but the Iranian populations have largely remained unknown. All the Iranian populations of water frogs, despite their vast distribution range have attributed to a single species: Rana ridibunda. In order to understand the phylogenetic relationships and taxonomic status of water frogs of Iran, we collected samples from many populations across the country and used the mitochondrial DNA sequence variation. A data set with a final sequence length of 616 nucleotides was generated for Cyt b from 70 individuals of Pelophylax in which there are 422 invariable sites, 174 variable sites of which 123 were parsimony informative. In total, 43 haplotypes were found (Hd: 0.9752). The result demonstrated that, two major clades with strong support can be identified within the Iranian water frogs. One of these clades that include north western and southwestern populations forms a monophyletic group along with P. bedriagae samples from Turkey. The second clade consists of water frog populations of north and northeastern parts of Iran which in turn is subdivided into two subclades. Inclusion of water frog samples from adjacent areas showed that the second clade of our study is, most likely, a distinct taxonomic entity at species rank with its two subclades indicating two diagnosable subspecies for the clade. In conclusion, we suggest that two distinct species, P. bedriagae and Pelophylax sp., with its two subspecies, should be identified as water frogs of Iran. In Addition, another traditionally reported water frog of Iran, P.ridibundus, most likely should be excluded from the Iranian water frog's checklist. PMID- 26731661 TI - A role for airway taste receptor modulation in the treatment of upper respiratory infections. AB - Taste receptors, initially identified in the oral epithelium, have since been shown to be widely distributed, being found in the upper and lower respiratory tracts, gastrointestinal epithelium, thyroid, and brain. The presence of taste receptors in the nasal epithelium has led to the discovery of their role in innate immunity, defending the paranasal sinuses against pathogens. This article addresses the current paradigm for understanding the role of extraoral taste receptors, specifically the T2R38 bitter taste receptor and the T1R2+3 sweet taste receptor, in respiratory innate defenses and presents evidence for the use of these and other taste receptors as therapeutic targets in the management of chronic rhinosinusitis. Future studies should focus on understanding the polymorphisms of taste receptors beyond T2R38 to fully elucidate their potential therapeutic use and lay the groundwork for their modulation in a clinical setting to decrease the health impact and economic burden of upper respiratory disease. PMID- 26731664 TI - Nanoscale mapping of heterogeneity of the polarization reversal in lead-free relaxor-ferroelectric ceramic composites. AB - Relaxor/ferroelectric ceramic/ceramic composites have shown to be promising in generating large electromechanical strain at moderate electric fields. Nonetheless, the mechanisms of polarization and strain coupling between grains of different nature in the composites remain unclear. To rationalize the coupling mechanisms we performed advanced piezoresponse force microscopy (PFM) studies of 0.92BNT-0.06BT-0.02KNN/0.93BNT-0.07BT (ergodic/non-ergodic relaxor) composites. PFM is able to distinguish grains of different phases by characteristic domain patterns. Polarization switching has been probed locally, on a sub-grain scale. k Means clustering analysis applied to arrays of local hysteresis loops reveals variations of polarization switching characteristics between the ergodic and non ergodic relaxor grains. We report a different set of switching parameters for grains in the composites as opposed to the pure phase samples. Our results confirm ceramic/ceramic composites to be a viable approach to tailor the piezoelectric properties and optimize the macroscopic electromechanical characteristics. PMID- 26731665 TI - Cytochrome P450 for Citreohybridonol Synthesis: Oxidative Derivatization of the Andrastin Scaffold. AB - A biosynthetic gene cluster similar to that for andrastin A (1) was discovered in Emericella variecolor NBRC 32302. Ctr-P450, a cytochrome P450 uniquely present in the cluster, was coexpressed with the andrastin A biosynthetic genes, leading to the production of the antifeedant agent citreohybridonol (4), along with four new andrastin derivatives. The results revealed the unusual multifunctionality of Ctr P450 and indicated that this approach can be applied for further natural product diversification. PMID- 26731663 TI - Resveratrol Induces Apoptosis-Like Death and Prevents In Vitro and In Vivo Virulence of Entamoeba histolytica. AB - Entamoeba histolytica causes amoebiasis, an infection that kills 100,000 individuals each year. Metronidazole and its derivatives are currently used against this protozoan, but these drugs present adverse effects on human health. Here, we investigated the effect of resveratrol (a natural compound) on E. histolytica trophozoites viability, as well as its influence on the parasite virulence. Trophozoites growth was arrested by 72 MUM resveratrol and the IC50 was determined as 220 MUM at 48 h. Cells appeared smaller, rounded and in clusters, with debris-containing vacuoles and with abnormally condensed chromatin. Resveratrol triggered reactive oxygen species production. It caused lipid peroxidation and produced phosphatidylserine externalization and DNA fragmentation this latter evidenced by TUNEL assays. It also provoked an increase of intracellular Ca2+ concentration, activated calpain and decreased superoxide dismutase activity, indicating that an apoptosis-like event occurred; however, autophagy was not detected. Cytopathic activity, phagocytosis, encystment and in vivo virulence were diminished dramatically by pre-incubation of trophozoites with resveratrol, evidencing that resveratrol attenuated the trophozoite virulence in vitro. Interestingly, after the inoculation of virulent trophozoites, animals treated with the drug did not develop or developed very small abscesses. Our findings propose that resveratrol could be an alternative to contend amoebiasis. PMID- 26731666 TI - Parameterizing Spatial Models of Infectious Disease Transmission that Incorporate Infection Time Uncertainty Using Sampling-Based Likelihood Approximations. AB - A class of discrete-time models of infectious disease spread, referred to as individual-level models (ILMs), are typically fitted in a Bayesian Markov chain Monte Carlo (MCMC) framework. These models quantify probabilistic outcomes regarding the risk of infection of susceptible individuals due to various susceptibility and transmissibility factors, including their spatial distance from infectious individuals. The infectious pressure from infected individuals exerted on susceptible individuals is intrinsic to these ILMs. Unfortunately, quantifying this infectious pressure for data sets containing many individuals can be computationally burdensome, leading to a time-consuming likelihood calculation and, thus, computationally prohibitive MCMC-based analysis. This problem worsens when using data augmentation to allow for uncertainty in infection times. In this paper, we develop sampling methods that can be used to calculate a fast, approximate likelihood when fitting such disease models. A simple random sampling approach is initially considered followed by various spatially-stratified schemes. We test and compare the performance of our methods with both simulated data and data from the 2001 foot-and-mouth disease (FMD) epidemic in the U.K. Our results indicate that substantial computation savings can be obtained--albeit, of course, with some information loss--suggesting that such techniques may be of use in the analysis of very large epidemic data sets. PMID- 26731667 TI - Bortezomib Does Not Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin alpha2 Chain-Deficient Muscular Dystrophy. AB - Congenital muscular dystrophy with laminin alpha2 chain-deficiency, also known as MDC1A, is a severe neuromuscular disorder for which there is no cure. Patients with complete laminin alpha2 chain-deficiency typically have an early onset disease with a more severe muscle phenotype while patients with residual laminin alpha2 chain expression usually have a milder disease course. Similar genotype phenotype correlations can be seen in the dy3K/dy3K and dy2J/dy2J mouse models of MDC1A, respectively, with dy3K/dy3K mice presenting the more severe phenotype. Recently, we demonstrated that the proteasome inhibitor bortezomib partially improves muscle morphology and increases lifespan in dy3K/dy3K mice. Here, we explore the use of bortezomib in dy2J/dy2J animals. However, bortezomib neither improved histological hallmarks of disease nor increased muscle strength and locomotive activity in dy2J/dy2J mice. Altogether our data suggest that proteasome inhibition does not mitigate muscle dysfunction caused by partial laminin alpha2 chain-deficiency. Still, it is possible that proteasome inhibition could be useful as a supportive therapy in patients with complete absence of laminin alpha2 chain. PMID- 26731668 TI - Retinoid Homeostatic Gene Expression in Liver, Lung and Kidney: Ontogeny and Response to Vitamin A-Retinoic Acid (VARA) Supplementation from Birth to Adult Age. AB - Vitamin A (VA, retinol) metabolism is homeostatically controlled, but little is known of its regulation in the postnatal period. Here, we determined the postnatal trajectory of VA storage and metabolism in major compartments of VA metabolism-plasma, liver, lung, and kidney from postnatal (P) day 1 to adulthood. We also investigated the response to supplementation with VARA, a combination of VA and 10% all-trans-retinoic acid that previously was shown to synergistically increase retinol uptake and storage in lung. Nursling pups of dams fed a VA marginal diet received an oral dose of oil (placebo) or VARA on each of four neonatal days: P1, P4, P7, and P10; and again as adults. Tissues were collected 6 h after the final dosing on P1, P4, P10, and at adult age. Gene transcripts for Lrat and Rbp4 in liver and Raldh-1 and Raldh-3 in lung, did not differ in the neonatal period but were higher, P<0.05, in adults, while Cyp26B1, Stra6, megalin, and Raldh-2 in lung did not differ from perinatal to adult ages. VARA supplementation increased total retinol in plasma, liver and lung, with a dose-by dose accumulation in neonatal liver and lung, while transcripts for Lrat in liver, megalin in kidney, Cyp26A1/B1 in liver and lung, respectively, and Stra6 in lung, were all increased, suggesting pathways of VA uptake, storage and RA oxidation were each augmented after VARA. VARA decreased hepatic expression of Rbp4, responsible for VA trafficking from liver to plasma, and, in lung, of Raldh 1 and Raldh-2, which function in RA production. Our results define retinoid homeostatic gene expression from neonatal and adult age and show that while supplementation with VARA acutely alters retinol content and retinoid homeostatic gene expression in neonatal and adult lung, liver and kidney, VARA supplementation of neonates increased adult-age VA content only in the liver. PMID- 26731669 TI - SeqFeatR for the Discovery of Feature-Sequence Associations. AB - Specific selection pressures often lead to specifically mutated genomes. The open source software SeqFeatR has been developed to identify associations between mutation patterns in biological sequences and specific selection pressures ("features"). For instance, SeqFeatR has been used to discover in viral protein sequences new T cell epitopes for hosts of given HLA types. SeqFeatR supports frequentist and Bayesian methods for the discovery of statistical sequence feature associations. Moreover, it offers novel ways to visualize results of the statistical analyses and to relate them to further properties. In this article we demonstrate various functions of SeqFeatR with real data. The most frequently used set of functions is also provided by a web server. SeqFeatR is implemented as R package and freely available from the R archive CRAN (http://cran.r project.org/web/packages/SeqFeatR/index.html). The package includes a tutorial vignette. The software is distributed under the GNU General Public License (version 3 or later). The web server URL is https://seqfeatr.zmb.uni-due.de. PMID- 26731670 TI - Stability of the Plasmodium falciparum AMA1-RON2 Complex Is Governed by the Domain II (DII) Loop. AB - Plasmodium falciparum is an obligate intracellular protozoan parasite that employs a highly sophisticated mechanism to access the protective environment of the host cells. Key to this mechanism is the formation of an electron dense ring at the parasite-host cell interface called the Moving Junction (MJ) through which the parasite invades. The MJ incorporates two key parasite components: the surface protein Apical Membrane Antigen 1 (AMA1) and its receptor, the Rhoptry Neck Protein (RON) complex, the latter one being targeted to the host cell membrane during invasion. Crystal structures of AMA1 have shown that a partially mobile loop, termed the DII loop, forms part of a deep groove in domain I and overlaps with the RON2 binding site. To investigate the mechanism by which the DII loop influences RON2 binding, we measured the kinetics of association and dissociation and binding equilibria of a PfRON2sp1 peptide with both PfAMA1 and an engineered form of PfAMA1 where the flexible region of the DII loop was replaced by a short Gly-Ser linker (DeltaDII-PfAMA1). The reactions were tracked by fluorescence anisotropy as a function of temperature and concentration and globally fitted to acquire the rate constants and corresponding thermodynamic profiles. Our results indicate that both PfAMA1 constructs bound to the PfRON2sp1 peptide with the formation of one intermediate in a sequential reversible reaction: A<->B<->C. Consistent with Isothermal Titration Calorimetry measurements, final complex formation was enthalpically driven and slightly entropically unfavorable. Importantly, our experimental data shows that the DII loop lengthened the complex half-life time by 18-fold (900 s and 48 s at 25 degrees C for Pf and DeltaDII-Pf complex, respectively). The longer half-life of the Pf complex appeared to be driven by a slower dissociation process. These data highlight a new influential role for the DII loop in kinetically locking the functional binary complex to enable host cell invasion. PMID- 26731671 TI - Bias control in clinical trials: masking or blinding. PMID- 26731673 TI - I2-induced SC-SC transformation within two-dimensional Zn(ii)-triazole framework: an ideal detector of cyano-containing molecules. AB - A novel interpenetrated 2D + 2D -> 2D architechture {[Zn(BTPS)(TPA)].1.5DMF.H2O}n () has been constructed under solvothermal conditions. Interestingly, I2-induced single-crystal-to-single-crystal transformation to {[Zn(BTPS)(I)(TPA)1.5].1.5H2O}n () showed a 2D + 1D -> 2D array. Luminescent properties indicated that represents the first example of selective recognition toward cyano-containing molecules. PMID- 26731672 TI - Clinical Validation of the 2005 ISUP Gleason Grading System in a Cohort of Intermediate and High Risk Men Undergoing Radical Prostatectomy. AB - In 2005, the International Society of Urological Pathology (ISUP) introduced several modifications to the original Gleason system that were intended to enhance the prognostic power of Gleason score (GS). The objective of this study was to clinically validate the 2005 ISUP Gleason grading system for its ability to detect metastasis. We queried our institutional RP database for men with NCCN clinically localized intermediate to high-risk disease undergoing radical prostatectomy (RP) between 1992 and 2010 with no additional treatment until the time of metastatic progression. A case-cohort design was utilized. A total of 333 available RP samples were re-reviewed and GS was reassigned per the 2005 ISUP Gleason system. Cumulative incidence of metastasis was 0%, 8.4%, 24.5% and 44.4% among specimens that were downgraded, unchanged, had one point GS increase and two point GS increase, respectively. The hazard ratio for metastasis raised in GS 8 and 9 compared to GS 7 from 2.77 and 5.91 to 3.49 and 9.31, respectively. The survival c-index of GS increased from 0.70 to 0.80 when samples were re-graded at 5 years post RP. The c-index of the reassigned GS was higher than the original GS (0.77 vs 0.64) for predicting PCSM at 10 years post RP. The regraded GS improved the prediction of metastasis and PCSM. This validates the updated Gleason grading system using an unambiguous clinical endpoint and highlights the need for reassignment of Gleason grading according to 2005 ISUP system when considering comparisons of novel biomarkers to clinicopathological variables in archival cohorts. PMID- 26731674 TI - Apparel-related participation barriers: ability, adaptation and engagement. AB - PURPOSE: To document apparel-related barriers faced by people with disabilities (PWD) and their families as they attempted to engage in various aspects of social participation, and explore the often invisible relationship between apparel related barriers and disablement. METHOD: For this qualitative research, we used focus groups to interview PWD, their caregivers and/or parents and health providers to document the experience of apparel-related barriers to community or social participation. A constructivist grounded theory approach was used to analyse interview transcripts and noted. RESULTS: Participant's responses were grouped into categories of unmet need for adaptive apparel as well as a list of specific apparel-related barriers that participants struggled to navigate in daily life; including functional, cultural and sensory-based issues. CONCLUSIONS: The lack of adequate accessible apparel for PWD exacerbated barriers to community participation and disablement, and identified the need for innovation in design, production, distribution and sale, of adaptive clothing. Implications for Rehabilitation The lack of adaptive or appropriate clothing or apparel for people living with disabilities can become a barrier, preventing engagement in meaningful activities, yet these barriers are not often explicitly identified. Cultural issues regarding clothing and the process of dressing may become unspoken barriers to engagement in meaningful activities, impacting the way care services are assigned. Rehabilitation professionals may need to take clothing and apparel-related issues faced by their clients into account, so that opportunities for social participation can be maximised. PMID- 26731675 TI - Prevalence of Multiple Sclerosis in the City of Volta Redonda - Rio De Janeiro, Brazil Using the Capture-Recapture Method. AB - BACKGROUND: Multiple sclerosis (MS) prevalence in Latin America was estimated in some regions and it was found to range from 0.75 to 30/100,000. The reasons for variation in rates of prevalence around the world still are not clear, but there are environmental and genetic explanations to this phenomenon. This study aimed at estimating the MS prevalence in Volta Redonda, Brazil. METHOD: Three sources of cases ascertainment were used and the method of capture-recapture was applied for assessing the corrected prevalence in the city of Volta Redonda in November 2012. The capture-recapture method uses data from incomplete lists and allows calculating the number of unregistered cases. Data were analyzed using a log linear model. RESULTS: A total of 40 MS cases was found by withdrawing overlaps of sources and it was estimated that a total number of 40 cases (95% CI 13.5 118.8) were not detected by the sources. The corrected prevalence of MS was, then, 30.7/100,000. CONCLUSION: Our study was the first in Brazil to use the capture-recapture method to assess the prevalence of MS, demonstrating the highest prevalence rate so far. It is necessary to perform other similar studies and in other regions of the country using the same method for a better evaluation of the true prevalence of MS our country. PMID- 26731676 TI - Long-Term Effectiveness of a Lifestyle Intervention for the Primary Prevention of Type 2 Diabetes in a Low Socio-Economic Community--An Intervention Follow-Up Study on Reunion Island. AB - In type 2 diabetes (T2D) prevention research, evidence for maintenance of risk factor reduction after three years of follow-up is needed. The objective of this study was to evaluate the long-term effectiveness of a combined lifestyle intervention aiming at controlling body weight (BW) and waist circumference (WC) in non-diabetic, overweight/obese adults living in a low socio-economic community. On Reunion Island, 445 adults living in deprived areas, aged 18-40 and at high-risk for T2D, were included in an intervention versus control trial for primary prevention (2001-2002). The intervention promoted a healthy diet and moderate regular physical activity, through actions strengthening individuals or community and improving living conditions. The control group received a one-shot medical information and nutritional advices. After the end of the trial (2003), 259 of the subjects participated in a follow-up study (2010-2011). The outcomes were the nine-year changes from baseline in BW, body mass index (BMI) and WC measurements, separately. Statistical analyses were performed on an intention-to treat basis, using available and imputed datasets. At inclusion, T2D risk factors were prevalent: family history of diabetes in first-degree relatives (42%), women with a personal history of gestational diabetes (11%), total obesity (43%, median BMI 29.1 kg/m2) and central obesity (71%). At follow-up, the adjusted effect on imputed dataset was significant for WC -2.4 cm (95% confidence interval: -4.7 to 0.0 cm, p = 0.046), non-significant for BW -2.2 kg (-4.6 to +0.2 kg, p = 0.073) and BMI -0.81 kg/m2 (-1.69 to +0.08 kg/m2, p = 0.074). A specific long-term effect was the increased likelihood of reduction in adiposity: BW loss, BMI reduction, and WC reduction were more frequent in the intervention group. In the context of low socio-economic communities, our data support the assumption of long-term effect of lifestyle interventions targeting total obesity and central obesity two major drivers of T2D. PMID- 26731677 TI - Rotational and Isotopic Effects in the H2 + OH(+) -> H + H2O(+) Reaction. AB - Initial state selected time-dependent wave packet and quasi-classical trajectory methods are employed to study the effects of reactant rotational excitations and isotopic substitutions on the title reaction. The coupled-channel (CC) and/or centrifugal sudden (CS) integral cross sections are calculated quantum mechanically. It was found that the CS cross sections are slightly smaller than the CC counterparts over the collision energy range studied. The quantum dynamical and quasi-classical trajectory results agree reasonably well and both indicate that the rotational excitation of H2 enhances the reaction in all energies, whereas the rotational excitation of OH(+) promotes the reaction more strongly at low collision energies but has a negligible effect at high collision energies. In addition, there exist significant isotopic substitution effects: The reaction cross section of the D2 + OH(+) reaction is much lower than those of the H2 + OH(+) and HD + OH(+) reactions, which are quite close. PMID- 26731678 TI - Crisis on campus: Eating disorder intervention from a developmental-ecological perspective. AB - OBJECTIVE: The purpose of this article is to review a crisis intervention using the developmental-ecological protocol (Collins and Collins, 2005) with a college student presenting with symptomatology of an active eating disorder. PARTICIPANTS: Participants included University Wellness Center employees responding to the crisis. METHODS: Methods include an informal review of the crisis intervention response and application of the ABCDE developmental ecological crisis model. RESULTS: Results reported include insight into crisis intervention when university counseling and health center is not available as resources. CONCLUSIONS: ABCDE Developmental-ecological model recommendations for university faculty and staff are included. PMID- 26731679 TI - Patient Preferences and Shared Decision Making in the Treatment of Substance Use Disorders: A Systematic Review of the Literature. AB - BACKGROUND: Shared Decision Making (SDM) as means to the involvement of patients in medical decision making is increasingly demanded by treatment guidelines and legislation. Also, matching of patients' preferences to treatments has been shown to be effective regarding symptom reduction. Despite promising results for patients with substance use disorders (SUD) no systematic evaluation of the literature has been provided. The aim is therefore to give a systematic overview of the literature of patient preferences and SDM in the treatment of patients with SUD. METHODS: An electronic literature search of the databases Medline, Embase, Psyndex and Clinical Trials Register was performed. Variations of the search terms substance use disorders, patient preferences and SDM were used. For data synthesis the populations, interventions and outcomes were summarized and described according to the PRISMA statement. Methodological quality of the included articles was assessed with the Mixed Methods Appraisal Tool. RESULTS: N = 25 trials were included in this review. These were conducted between 1986 and 2014 with altogether n = 8.729 patients. Two studies found that patients with SUD preferred to be actively involved in treatment decisions. Treatment preferences were assessed in n = 18 studies, where the majority of patients preferred outpatient compared with inpatient treatment. Matching patients to preferences resulted in a reduction on substance use (n = 3 studies), but the majority of studies found no significant effect. Interventions for SDM differed across patient populations and optional therapeutic techniques. DISCUSSION: Patients with substance use disorders should be involved in medical treatment decisions, as patients with other health conditions. A suitable approach is Shared Decision Making, emphasizing the patients' preferences. However, due to the heterogeneity of the included studies, results should be interpreted with caution. Further research is needed regarding SDM interventions in patient populations with substance use disorders. PMID- 26731680 TI - Renal dysfunction in cirrhosis: pathophysiology, diagnosis, and management. AB - The development of decompensation in patients with cirrhosis is associated with increased mortality. Renal function gradually deteriorates with significant hemodynamic changes associated with decompensated liver disease, but may also rapidly decrease in response to precipitating events. Newer definitions of renal dysfunction may result in early diagnosis, this along with the use of sensitive markers helps in accurate determination of renal function in cirrhosis. Although renal dysfunction progresses slowly in cirrhotic patients, it is associated with increased mortality. Prompt intervention with appropriate management reduces the risk of renal dysfunction, as well as improving survival and quality of life. Appropriate management may include the removal of precipitating causes and use of pharmacological agents supporting circulatory dysfunction. Outcomes following treatment of this condition remain a major concern, especially in patients who develop hepatorenal syndrome. Transplantation of the liver or kidney and liver may be the only option when other modalities of treatment fail. Early transplantation may benefit these patients. PMID- 26731681 TI - Axial, Helical, and Planar Chirality in Directly Linked Basket-Handle Porphyrin Arrays. AB - The single-electron oxidative dimerization of basket-handle porphyrins (BHPs) with different coordinated metal ions [Cu(II), Ni(II), Pd(II), Zn(II)] yielded directly meso-meso linked dimers in excellent yields. The synthetic protocol is suited for coupling substrates with different meso-substituents (H, Br, aryl, alkyl) opposite to the coupling site. Experimental findings concerning reactivities and selectivities were in good agreement with theoretical investigations using ALIE calculations. The dimers, which all are axially chiral, were resolved into their enantiomers by HPLC on a chiral phase. ECD spectra were measured in the stopped-flow mode and compared with results from quantum-chemical ECD calculations to assign the absolute configuration. One directly linked dimer was further oxidized to a fused system, which possessed a stable helical chirality. Its absolute configuration was again assigned by ECD investigations. Furthermore, functionalized BHPs and tetraarylporphyrins were coupled under Suzuki conditions to give dimers and trimers with either beta-meso or beta-beta linkages. Because of the steric shielding of one of the BHP hemispheres, the products were formed with full diastereoselectivity regarding all porphyrin porphyrin axes. The stereostructures of these arrays were investigated by quantum chemical calculations (DFT-D3, TD DFT, and sTD DFT), and the absolute configurations were assigned for all chiral representatives. PMID- 26731682 TI - An update regarding the treatment of nonallergic rhinitis. AB - PURPOSE OF REVIEW: The review presents some information on known options for treatment of nonallergic rhinitis (NAR) with introduction to new therapies. The merits and limitations of recent advancements in pharmacotherapy of this common problem are briefly discussed as well. RECENT FINDINGS: Intranasal corticosteroids are first-line therapy for NAR. Fluticasone propionate and beclomethasone remain the only topical corticosteroids approved for NAR. The use of azelastine - another first-line option - has also been found to be effective even though NAR is a nonallergic entity by definition. Combination of fluticasone propionate and azelastine is a promising option in achieving better symptom reduction. Coadministration of intranasal corticosteroid and topical decongestants is an attractive topic that requires additional safety studies before recommending treatment. Although promising, no scientifically valid recommendation can be made for treatment of NAR with capsaicin. Surgical options in patients with refractory NAR are limited. New studies demonstrate a lack of correlation between objective outcome of radiofrequency ablation of the inferior turbinate and subjective patient symptoms. SUMMARY: The heterogeneity in clinical presentation makes NAR treatment a daily challenge for otolaryngologists. The diversity of clinical studies with use of unique outcome measures limit systematic reviews which may be instrumental in providing strong recommendations. PMID- 26731683 TI - Postnasal drip and postnasal drip-related cough. AB - PURPOSE OF REVIEW: This article describes the pathophysiology and management of postnasal drip (PND) with and without cough. RECENT FINDINGS: PND is a common complaint in primary care and ear-nose-throat offices, and is often, but not always, associated with chronic cough. Because it lacks objective testing and its symptoms can be vague and variable, PND has become a catch-all diagnosis for a variety of nasal and throat-related symptoms. Studies have shown that the traditional pathophysiology of PND related to sinonasal disease does not clearly lead to chronic cough and that the cough from PND may be related to an airway sensory hypersensitivity rather than actual irritation from inflamed nasal secretions. SUMMARY: The article summarizes the current recommendations on evaluation and management of PND as well as brings to discussion new therapies and hypothesis regarding its pathophysiology. PMID- 26731685 TI - Transient Accumulation of NO2- and N2O during Denitrification Explained by Assuming Cell Diversification by Stochastic Transcription of Denitrification Genes. AB - Denitrifying bacteria accumulate [Formula: see text], NO, and N2O, the amounts depending on transcriptional regulation of core denitrification genes in response to O2-limiting conditions. The genes include nar, nir, nor and nosZ, encoding [Formula: see text]-, [Formula: see text]-, NO- and N2O reductase, respectively. We previously constructed a dynamic model to simulate growth and respiration in batch cultures of Paracoccus denitrificans. The observed denitrification kinetics were adequately simulated by assuming a stochastic initiation of nir transcription in each cell with an extremely low probability (0.5% h-1), leading to product- and substrate-induced transcription of nir and nor, respectively, via NO. Thus, the model predicted cell diversification: after O2 depletion, only a small fraction was able to grow by reducing [Formula: see text]. Here we have extended the model to simulate batch cultivation with [Formula: see text], i.e., [Formula: see text], NO, N2O, and N2 kinetics, measured in a novel experiment including frequent measurements of [Formula: see text]. Pa. denitrificans reduced practically all [Formula: see text] to [Formula: see text] before initiating gas production. The [Formula: see text] production is adequately simulated by assuming stochastic nar-transcription, as that for nirS, but with a higher probability (0.035 h-1) and initiating at a higher O2 concentration. Our model assumes that all cells express nosZ, thus predicting that a majority of cells have only N2O-reductase (A), while a minority (B) has [Formula: see text]-, NO- and N2O-reductase. Population B has a higher cell-specific respiration rate than A because the latter can only use N2O produced by B. Thus, the ratio [Formula: see text] is low immediately after O2 depletion, but increases throughout the anoxic phase because B grows faster than A. As a result, the model predicts initially low but gradually increasing N2O concentration throughout the anoxic phase, as observed. The modelled cell diversification neatly explains the observed denitrification kinetics and transient intermediate accumulations. The result has major implications for understanding the relationship between genotype and phenotype in denitrification research. PMID- 26731687 TI - Validation and reliability of the Turkish Utian Quality-of-Life Scale in postmenopausal women. AB - OBJECTIVE: There are a limited number of menopause-specific quality-of-life scales for the Turkish population. This study was conducted to evaluate the validity and reliability of the Turkish Utian Quality-of-Life Scale in postmenopausal women. METHODS: The study group was comprised of 250 postmenopausal women who applied to a training and research hospital's menopause clinic in Turkey. A survey form and the Turkish Utian quality-of-Life Scale were used to collect data, and the Turkish version of Short Form-36 was used to evaluate reliability with an equivalent form. Language-validity, content validity, and construct-validity methods were used to assess the validity of the scale, and Cronbach's alpha coefficient calculation and the equivalent-form reliability methods were used to assess the reliability of the scale. RESULTS: The Turkish Utian Quality-of-Life Scale was determined to be a valid and reliable instrument for measuring the quality of life of postmenopausal women. Confirmatory factor analysis demonstrates that the instrument fits well with 23 items and a four-factor model. The Cronbach's alpha coefficient for the quality of-life domains were as follows: 0.88 overall, 0.79 health, 0.78 emotional, 0.76 sexual, and 0.75 occupational. Reliability of the instrument was confirmed through significant correlations between scores on the Turkish version of the Utian Quality-of-Life Scale and the Turkish version of the Short Form-36 (r = 0.745, P < 0.001). CONCLUSIONS: This research emphasizes that the Turkish Utian Quality-of-Life Scale is reliable and valid in postmenopausal women-it is a useful instrument for measuring quality of life during menopause. PMID- 26731686 TI - Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause. AB - OBJECTIVE: The aim of this study is to confirm the local beneficial effects of intravaginal dehydroepiandrosterone (DHEA, Prasterone) on moderate to severe dyspareunia or pain at sexual activity, the most frequent symptom of vulvovaginal atrophy due to menopause or genitourinary syndrome of menopause (GSM). METHODS: In a prospective, randomized, double-blind, and placebo-controlled phase III clinical trial, the effect of daily intravaginal 0.50% DHEA (6.5 mg) (Prasterone, EndoCeutics) was examined on four coprimary objectives, namely percentage of parabasal cells, percentage or superficial cells, vaginal pH, and moderate to severe pain at sexual activity (dyspareunia) identified by the women as their most bothersome vulvovaginal atrophy symptom. The intent-to-treat population included 157 and 325 women in the placebo and DHEA-treated groups, respectively. RESULTS: After daily intravaginal administration of 0.50% DHEA for 12 weeks, when compared to baseline by the analysis of covariance test, the percentage of parabasal cells decreased by 27.7% over placebo (P < 0.0001), whereas the percentage of superficial cells increased by 8.44% over placebo (P < 0.0001), vaginal pH decreased by 0.66 pH unit over placebo (P < 0.0001), and pain at sexual activity decreased by 1.42 severity score unit from baseline or 0.36 unit over placebo (P = 0.0002). On the other hand, moderate to severe vaginal dryness present in 84.0% of women improved at 12 weeks by 1.44 severity score unit compared to baseline, or 0.27 unit over placebo (P = 0.004). At gynecological evaluation, vaginal secretions, epithelial integrity, epithelial surface thickness, and color all improved by 86% to 121% over the placebo effect (P < 0.0001 for all comparisons with placebo). Serum steroid levels remained well within the normal postmenopausal values according to the involved mechanisms of intracrinology. The only side effect reasonably related to treatment is vaginal discharge due to melting of the vehicle at body temperature and this was reported in about 6% of the participants. CONCLUSIONS: The daily intravaginal administration of 0.50% (6.5 mg) DHEA (Prasterone) has shown clinically and highly statistically significant effects on the four coprimary parameters suggested by the US Food and Drug Administration. The strictly local action of Prasterone is in line with the absence of significant drug-related adverse events, thus showing the high benefit-to-risk ratio of this treatment based upon the novel understanding of the physiology of sex steroids in women. PMID- 26731688 TI - Use of hormone therapy and isoflavones and mammographic density in Spain. AB - OBJECTIVE: The use of some forms of hormone therapy (HT) is associated with an increase in mammographic density-a major risk factor for breast cancer. The role of isoflavones, however, is unclear. Here, we quantify the prevalence of HT and isoflavone use among postmenopausal Spanish women, determine associated risk factors, and explore the relationship between these therapies and mammographic density. METHODS: This cross-sectional study included 2,754 postmenopausal women who underwent breast cancer screening in seven geographical areas. Mammographic density was evaluated using Boyd's semiquantitative scale. Multinomial logistic regression models were adjusted to assess risk factors associated with both therapies. Ordinal regression models were fitted to study the association between HT and isoflavone consumption with mammographic density. RESULTS: The prevalence of ever-use of HT was 12%, whereas that of the current use was 2.3%. Isoflavone lifetime prevalence was 3.7%, and current use was 1.7%. The most common HT types were tibolone and estrogens. Surgical menopause, oral contraceptive use, educational level, population density, and years since menopause were positively associated with HT, whereas body mass index and parity were inversely associated. Mammographic density was not associated with current or past HT use. However, women who reported having consumed isoflavones in the past and those who started their use after menopause had a higher mammographic density when compared with never-users (odds ratio 1.98, 95% CI 1.21-3.25, P = 0.007; and odds ratio 1.60, 95% CI 1.01-2.53, P = 0.045 respectively). CONCLUSIONS: Our results show a low prevalence of HT and isoflavone use in postmenopausal Spanish women. In this population, HT use was not associated with mammographic density, whereas some categories of isoflavone users had higher density. PMID- 26731689 TI - Relationship between Twinkle Artefacts and in vivo Biochemical Composition of Kidney Stones. AB - INTRODUCTION: Our aim was to predict the chemical composition of kidney stones according to their twinkle artefact (TA) features obtained by in vivo color Doppler ultrasonography and to determine the potential factors affecting the formation and intensity of TAs. MATERIALS AND METHODS: A total of 101 patients who met the inclusion criteria were included in the study. All patients were evaluated for TAs using color Doppler ultrasonography. All stones were subjected to chemical analysis. The relationships between the TA and the size and chemical composition of the stone, presence of hydronephrosis and body mass index (BMI) were evaluated statistically. RESULTS: According to the results of the chemical analysis, 66 (65.3%) were calcium oxalate stones. It was found that the in vivo TA intensity did not predict cystine and calcium oxalate monohydrate stones (p > 0.05) and the intensity of TAs increases with increasing BMI (p = 0.002). CONCLUSION: The present study is the first to show that TAs may not be reliable in overweight patients. The TAs could not predict the chemical composition of stones; so future comprehensive in vivo studies will clarify the role of TAs in the prediction of the stone type preoperatively. PMID- 26731690 TI - Occurrence of 13 volatile organic compounds in foods from the Canadian total diet study. AB - Volatile organic compounds (VOCs) are ubiquitous in the environment due to evaporation and incomplete combustion of fuels, use of consumer and personal care products, etc. and they can accumulate in foods. Some VOCs in foods can also be formed during food processing and preparation and migrate from food packaging. In this pilot study, a GC-MS method based on headspace solid-phase microextraction (SPME) was validated and used to analyse selected individual foods which can be consumed directly and 153 different total diet composite food samples for 13 VOCs. Vinyl chloride was not detected in any of the 153 composite food samples, while the other 12 VOCs were detected at various frequencies, with m-xylene being the most frequently detected (in 151 of the 153 samples), followed by toluene (145), 1,3,5-trimethylbenzene (140), ethylbenzene (139), styrene (133), 1,2,4 trimethylbenzene (122), benzene (96), p-dichlorobenzene (95), n-butylbenzene (55), chloroform (45), naphthalene (45) and trichloroethylene (31). Concentrations of the 12 VOCs in most of the food composite samples were low, with the 90th percentiles from 1.6 ng g(-1) for n-butylbenzene to 20 ng g(-1) for toluene. However, some VOCs were detected at higher levels with maxima, for example, of 948 ng g(-1) for m-xylene and 320 ng g(-1) for ethylbenzene in chewing gum, 207 ng g(-1) for styrene and 157 ng g(-1) for toluene in herbs and spices. VOCs were detected at higher levels in most of the individual food items than their corresponding composite samples, for example, the average chloroform concentration in the individual canned soft drinks was 20 ng g(-1) compared with 3.0 ng g(-1) in their composite, and the average toluene concentration in the individual canned citrus juice was 96 ng g(-1) compared with 0.68 ng g(-1) in their composite. Thus, for determination of VOCs in foods which can be consumed directly, their individual food items should be analysed whenever possible for accurate exposure assessment. PMID- 26731691 TI - The Sensitivity of Moss-Associated Nitrogen Fixation towards Repeated Nitrogen Input. AB - Nitrogen (N2) fixation is a major source of available N in ecosystems that receive low amounts of atmospheric N deposition. In boreal forest and subarctic tundra, the feather moss Hylocomium splendens is colonized by N2 fixing cyanobacteria that could contribute fundamentally to increase the N pool in these ecosystems. However, N2 fixation in mosses is inhibited by N input. Although this has been shown previously, the ability of N2 fixation to grow less sensitive towards repeated, increased N inputs remains unknown. Here, we tested if N2 fixation in H. splendens can recover from increased N input depending on the N load (0, 5, 20, 80, 320 kg N ha(-1) yr(-1)) after a period of N deprivation, and if sensitivity towards increased N input can decrease after repeated N additions. Nitrogen fixation in the moss was inhibited by the highest N addition, but was promoted by adding 5 kg N ha(-1) yr(-1), and increased in all treatments during a short period of N deprivation. The sensitivity of N2 fixation towards repeated N additions seem to decrease in the 20 and 80 kg N additions, but increased in the highest N addition (320 kg N ha(-1) yr(-1)). Recovery of N in leachate samples increased with increasing N loads, suggesting low retention capabilities of mosses if N input is above 5 kg N ha(-1) yr(-1). Our results demonstrate that the sensitivity towards repeated N additions is likely to decrease if N input does not exceed a certain threshold. PMID- 26731692 TI - The Influence of Tissue Ischemia Time on RNA Integrity and Patient-Derived Xenografts (PDX) Engraftment Rate in a Non-Small Cell Lung Cancer (NSCLC) Biobank. AB - INTRODUCTION: Bio-repositories are invaluable resources to implement translational cancer research and clinical programs. They represent one of the most powerful tools for biomolecular studies of clinically annotated cohorts, but high quality samples are required to generate reliable molecular readouts and functional studies. The objective of our study was to define the impact of cancer tissue ischemia time on RNA and DNA quality, and for the generation of Patient Derived Xenografts (PDXs). METHODS: One-hundred thirty-five lung cancer specimens were selected among our Institutional BioBank samples. Associations between different warm (surgical) and cold (ex-vivo) ischemia time ranges and RNA quality or PDXs engraftment rates were assessed. RNA quality was determined by RNA integrity number (RINs) values. Fresh viable tissue fragments were implanted subcutaneously in NSG mice and serially transplanted. RESULTS: RNAs with a RIN>7 were detected in 51% of the sample (70/135), with values of RIN significantly lower (OR 0.08, P = 0.01) in samples preserved for more than 3 hours before cryopreservation. Higher quality DNA samples had a concomitant high RIN. Sixty three primary tumors (41 adenocarcinoma) were implanted with an overall engraftment rate of 33%. Both prolonged warm (>2 hours) and ex-vivo ischemia time (>10 hours) were associated to a lower engraftment rate (OR 0.09 P = 0.01 and OR 0.04 P = 0.008, respectively). CONCLUSION: RNA quality and PDXs engraftment rate were adversely affected by prolonged ischemia times. Proper tissue collection and processing reduce failure rate. Overall, NSCLC BioBanking represents an innovative modality, which can be successfully executed in routine clinical settings, when stringent Standard Operating Procedures are adopted. PMID- 26731694 TI - Synthesis and biophysical properties of (L)-aTNA based G-quadruplexes. AB - Novel G-quadruplex structures are constructed by acyclic (L)-threninol nucleic acid and their synthesis and biophysical properties are described. Pyrene excimer fluorescence and circular dichroism (CD) data revealed that four strands of aTNA are oriented in antiparallel direction. PMID- 26731693 TI - Myocardial Infarct Segmentation From Magnetic Resonance Images for Personalized Modeling of Cardiac Electrophysiology. AB - Accurate representation of myocardial infarct geometry is crucial to patient specific computational modeling of the heart in ischemic cardiomyopathy. We have developed a methodology for segmentation of left ventricular (LV) infarct from clinically acquired, two-dimensional (2D), late-gadolinium enhanced cardiac magnetic resonance (LGE-CMR) images, for personalized modeling of ventricular electrophysiology. The infarct segmentation was expressed as a continuous min-cut optimization problem, which was solved using its dual formulation, the continuous max-flow (CMF). The optimization objective comprised of a smoothness term, and a data term that quantified the similarity between image intensity histograms of segmented regions and those of a set of training images. A manual segmentation of the LV myocardium was used to initialize and constrain the developed method. The three-dimensional geometry of infarct was reconstructed from its segmentation using an implicit, shape-based interpolation method. The proposed methodology was extensively evaluated using metrics based on geometry, and outcomes of individualized electrophysiological simulations of cardiac dys(function). Several existing LV infarct segmentation approaches were implemented, and compared with the proposed method. Our results demonstrated that the CMF method was more accurate than the existing approaches in reproducing expert manual LV infarct segmentations, and in electrophysiological simulations. The infarct segmentation method we have developed and comprehensively evaluated in this study constitutes an important step in advancing clinical applications of personalized simulations of cardiac electrophysiology. PMID- 26731695 TI - S4AC Case Study: Enhancing Underserved Seniors' Access to Health Promotion Programs. AB - The Seniors Support Services for South Asian Community (S4AC) project was developed in response to the underutilization of available recreation and seniors' facilities by South Asian seniors who were especially numerous in a suburban neighbourhood in British Columbia. Addressing the problem required the collaboration of the municipality and a registered non-profit agency offering a wide range of services and programs to immigrant and refugee communities. Through creative outreach and accommodation, the project has engaged more than 100 Punjabi-speaking seniors annually in diverse exercise activities. Case study research methods with staff and current and former senior participants of S4AC include participant observation, individual interviews, and focus groups. Viewed through the critical interpretive lens of the "candidacy framework", findings reveal the myriad ways in which access to health promotion and physical activity for immigrant older adults is a complex iterative process of negotiation at multiple levels. PMID- 26731696 TI - A proof-of-concept study showing antibiotics to be more effective in irritable bowel syndrome with than without small-intestinal bacterial overgrowth: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Antibiotics relieve symptoms in half of the unselected patients with irritable bowel syndrome (IBS); however, their efficacy if selected according to small-intestinal bacterial overgrowth (SIBO) is unknown. AIMS: The aim of this study was to evaluate (a) symptom resolution among IBS patients with or without SIBO on norfloxacin treatment, and (b) its efficacy in obtaining negative SIBO test results as compared with placebo. METHOD: Eighty IBS patients (Rome III) were evaluated for SIBO by gut aspirate culture. Patients with (>=10 CFU/ml) and those without SIBO were separately randomized (computer-generated stratified) to 800 mg/day norfloxacin for 10 days or placebo. Global symptom score (blindly), Rome III criteria, aspirate culture, and glucose hydrogen breath test (GHBT) were assessed before and 1 month after treatment, and patients were followed up for 6 months. RESULTS: Although norfloxacin was more effective at reducing the symptom score at 1 month among patients with compared with those without SIBO [15/80, 19% on culture, four on GHBT too; 6.5 (2-13) vs. 2 (0-10), P=0.01; 8.5 (2-16) vs. 5 (0-12), P<0.001] but not placebo, the scores were comparable at 6 months [3 (1 10) vs. 9 (5-19), P=NS]. Symptoms more often resolved to turn Rome III negative in SIBO patients treated with norfloxacin compared with placebo at 1 month (7/8, 87.5 vs. 0/7, P=0.004); of the other 65 patients, 8/32 (25%) treated with norfloxacin but none of the 33 treated with placebo turned Rome III negative. Patients without SIBO and a colony count of 10-10 CFU/ml responded more than those with a colony count less than 10 CFU/ml. Overall, 15/40 (37.5%) patients responded to norfloxacin. At 6 months, 2/8 (25%) with and 5/32 (15.6%) without SIBO remained Rome III negative following norfloxacin. All 4/8 consenting patients treated with norfloxacin became SIBO negative (two each by culture+GHBT and GHBT alone), but 0/7 patients treated with placebo became SIBO negative. CONCLUSION: Norfloxacin is superior to placebo in relieving symptoms of SIBO associated IBS. PMID- 26731697 TI - Night work is associated with glycemic levels and anthropometric alterations preceding diabetes: Baseline results from ELSA-Brasil. AB - Night work has been suggested as a risk factor for diabetes. Individuals with high triglyceride levels, high LDL cholesterol, low HDL cholesterol and obesity, especially abdominal obesity, have a greater chance of developing diabetes. The aim of this study was to analyze glycemic levels, total cholesterol, HDL-C, LDL C, triglycerides and the anthropometric alterations that precede diabetes, considering their possible association with nigh work among a non-diabetic population. Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) comprises of 15,105 civil servants (35-74 years old) at baseline (2008-2010). The following parameters were analyzed: serum cholesterol (total cholesterol, HDL-C, LDL-C), triglycerides and glucose drawn from 12-hour fasting blood sample, glycated hemoglobin and 2-hour plasma glucose obtained after a 75 g oral glucose tolerance test, BMI, hip and waist measurements using standard equipment and techniques. Participants with diabetes, retired workers and day workers with previous experience of night work were excluded. Generalized linear models, a gamma regression model with an identity link function, were performed to test the association of night work with metabolic and anthropometric variables. The study sample consisted of 3918 men and 4935 women; 305 (7.8%) and 379 (7.7%) of the participants were men and women who worked at night, respectively. Among the men, the exposure to night work was associated with an increase in BMI (b-value = 0.542; p = 0.032) and waist circumference (b-value = 1.66; p = 0.014). For women, increased fasting plasma glucose (b-value = 2.278; p < 0.001), glycated hemoglobin (b-value = 0.099, p < 0.001) and 2 hour plasma glucose (b-value = 5.479, p = 0.001) were associated with night work after adjustments. No significant associations between night work and triglycerides, LDL-C, HDL-C, total cholesterol levels or waist-hip ratio were found. The influences of night work on metabolic and anthropometric factors suggest night work as a potential risk factor for type 2 diabetes. Further studies are needed to investigate the inconclusive data on gender differences in the associations. PMID- 26731698 TI - Structural and Kinetic Characterization of Diazabicyclooctanes as Dual Inhibitors of Both Serine-beta-Lactamases and Penicillin-Binding Proteins. AB - Avibactam is a diazabicyclooctane beta-lactamase inhibitor possessing outstanding but incomplete efficacy against multidrug-resistant Gram-negative pathogens in combination with beta-lactam antibiotics. Significant pharmaceutical investment in generating derivatives of avibactam warrants a thorough characterization of their activity. We show here through structural and kinetic analysis that select diazabicyclooctane derivatives display effective but varied inhibition of two clinically important beta-lactamases (CTX-M-15 and OXA-48). Furthermore, these derivatives exhibit considerable antimicrobial activity (MIC <= 2 MUg/mL) against clinical isolates of Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp. Imaging of cell phenotype along with structural and biochemical experiments unambiguously demonstrate that this activity, in E. coli, is a result of targeting penicillin-binding protein 2. Our results suggest that structure activity relationship studies for the purpose of drug discovery must consider both beta-lactamases and penicillin-binding proteins as targets. We believe that this approach will yield next-generation combination or monotherapies with an expanded spectrum of activity against currently untreatable Gram-negative pathogens. PMID- 26731699 TI - Long-Term Follow-Up of a Homozygous Familial Hypercholesterolemic Patient Receiving Regular Double Filtration Plasmapheresis - Case Report and Literature Review. AB - Homozygous familial hypercholesterolemia (HoFH) is a very rare condition (1 case per 1 million people) with a dismal outcome due to inevitable coronary artery disease that occurs when left untreated. Lipoprotein apheresis (LA), previously known as low-density lipoprotein (LDL) apheresis, is very effective in reducing LDL-cholesterol (LDL-C) if HoFH is refractory to aggressive drug therapy and diet control. In this study, we report a case with HoFH, who presented with xanthomata over the 4 limbs when she was 3 years old. When she was 11 years old, she began treatment with semi-selective LA with double filtration plasmapheresis (DFPP) once per week because HoFH was refractory to high-dose statin and diet control. LDL-C was reduced from 8.2 +/- 0.9 to 2.69 +/- 0.75 mmol/l (reduction rate = 67.3 +/- 6.1%). The xanthomata over the 4 limbs were nearly completely resolved after 2 years of DFPP. Two years later, after the initiation of DFPP, we performed coronary angiography and echocardiography for regular checkup in the absence of chest pain, and the result was negative. To date (11 years after initiation of DFPP), she has not complained of any chest pain, shown intolerance to exercise, or exhibited ST-T change on electrocardiography. At the age of 20, multidetector computed tomography showed no significant stenosis over the coronary arteries. At the most recent follow-up visit, she was found to have good heart function and no xanthomata. LA is effective in the treatment of HoFH when drug therapy and diet control fail. With this treatment, pre-existing xanthomata can regress and coronary artery disease can be prevented. PMID- 26731700 TI - Elastic and hierarchical porous carbon nanofibrous membranes incorporated with NiFe2O4 nanocrystals for highly efficient capacitive energy storage. AB - Flexible membranes created from porous carbon nanofibers (CNFs) hold great promise in the next generation wearable energy storage devices, but challenges still remain due to the poor mechanical properties of porous carbon nanofibers. Here, we report a facile strategy to fabricate elastic and hierarchical porous CNF membranes with NiFe2O4 nanocrystals embedded via multicomponent electrospinning and nano-doping methods. Benefiting from the scattering effect of NiFe2O4 nanocrystals and graphitized carbon layers for the condensed stress, the resultant CNF membranes exhibit an enhanced elasticity with a bending radius <12 MUm, rapid recovery from the deformations, and a superior softness. Quantitative pore size distribution and fractal analysis reveal that the CNFs possessed tunable porous structures with a high surface area of 493 m(2) g(-1) and a pore volume of 0.31 cm(3) g(-1). Benefiting from the robust mechanical stability, hierarchical porous structures and good electrochemical properties, the NiFe2O4 doped CNF membranes demonstrate a high electrical capacitance of 343 F g(-1), and good reversibility with a cycling efficiency of 97.4% even after 10,000 cycles. The successful synthesis of elastic porous CNF membranes also provided a versatile platform for the design and development of functional CNF based materials for various applications. PMID- 26731701 TI - A Computed Tomographic Morphometric Study of the Pediatric Occipital Bone Thickness: Implications for Pediatric Occipitocervical Fusion. AB - STUDY DESIGN: This study is a computed tomographic-based morphometric analysis of the pediatric occipital bones as related to pediatric occipitocervical fusion. OBJECTIVE: To quantify reference data concerning the thicknesses of the immature occipital bones to guide the pediatric occipitocervical fusion. SUMMARY OF BACKGROUND DATA: To the best of our knowledge, no published study has provided insight into the thicknesses of pediatric occiputs with different age groups. METHODS: 80 pediatric patients were divided into 4 age groups, and their occiputs were studied on Philips Brilliance 256 iCT scan. RESULTS: The mean thickness +/- standard deviations of the pediatric occipital bones with different age groups is shown. The median and the paramedian regions are always thicker than the more lateral regions at each age group and the thickest point in the occiputs is mostly at the external occipital protuberance. The mean thickness of occiputs showed an obvious significant difference between each 2 age groups and no significant difference between male and female in different age groups except the group 4. CONCLUSION: Our investigation provides insight into the anatomy of occiputs in pediatric population and preoperative CT evaluation must be required to further decrease the risk of occipitocervical fusion. PMID- 26731702 TI - Exogenous Crosslinking Restores Intradiscal Pressure of Injured Porcine Intervertebral Discs: An In Vivo Examination Using Quantitative Discomanometry. AB - STUDY DESIGN: In vivo examination of intradiscal pressure by quantitative discomanometry (QD). OBJECTIVE: To determine whether an injectable, exogenous crosslinking could acutely restore intradiscal pressure of stab-injured discs in vivo by short-term treatment. SUMMARY OF BACKGROUND DATA: Disc biomechanical performance depends on its integrity associated with the intradiscal pressure and mechanical properties. Genipin crosslink augmentation has demonstrated the in vitro biomechanical capability to improve intervertebral joint stability and increase mechanical properties of the annulus fibrosus. METHODS: 4 lumbar discs on each of 8 swine were randomly assigned to 4 groups: intact, injured, untreated, and crosslinked. A 16G needle was stabbed into the annulus fibrosus to create the disc injury model. An injection of 0.33% genipin solution was delivered into the annulus to treat the injury. QD technique was performed to examine the intradiscal pressure for the intact and injured discs at the time of surgery, while untreated and crosslinked discs were measured 1-week postsurgery. 4 QD parameters were analyzed and compared across the 4 groups: leakage pressure and volume, and saturation pressure and volume. RESULTS: The leakage and saturation pressures of the injured group were significantly lower than those of the intact group (P = 0.004 and P = 0.01, respectively). The leakage and saturation pressures of untreated discs were statistically equivalent to the injured levels, but with a 2-times higher saturation volume. Relative to the untreated group, the leakage pressure and saturation pressure of genipin crosslinked discs had a 617% (P = 0.008) and a 473% increase (P = 0.007), respectively. CONCLUSION: A large disc injury produced by annular puncture immediately lowered intradiscal pressure when left untreated. Genipin crosslinking can restore intradiscal pressure acutely in vivo without any obvious morbidity associated with the injection. PMID- 26731703 TI - Comparison of Intrawound Vancomycin Utility in Posterior Instrumented Spine Surgeries Between Patients With Tumor and Nontumor Patients. AB - STUDY DESIGN: Retrospective cohort study of consecutive patients. OBJECTIVE: To compare the efficacy of intrawound vancomycin to prevent postoperative surgical site infection (SSI) between patients with spinal tumor and nontumor spine patients. SUMMARY OF BACKGROUND DATA: Recent studies have suggested that intrawound vancomycin is a promising method for reducing the SSI rate in spine surgery. However, the patient population in which it is most effective remains unknown. METHODS: Medical records of a consecutive series of patients with tumor and nontumor spine patients who underwent open posterior instrumented surgeries at our institution between October 2011 and June 2014 were reviewed. 1 gram of vancomycin powder was evenly sprayed into the surgical site before drain placement. The SSI rates before and after vancomycin use were compared. Changes in SSI rates, which reflected the utility of vancomycin, were compared between patients with tumor and nontumor patients. RESULTS: A total of 334 patients were enrolled including 25 patients with tumor and 129 nontumor patients in the "before" period, and 27 patients with tumor and 153 nontumor patients in the "after" period. Baseline characteristics in both patients with tumor and nontumor patients did not differ between periods. The SSI rate of nontumor patients was significantly reduced with intrawound vancomycin application (7.0% [9/129] vs. 0.7% [1/153], P = 0.011). However, the SSI rate in patients with tumor was not reduced (8.0% [2/25] vs. 14.8% [4/27], P = 0.442). 3 of the 4 patients with tumor who developed SSI after vancomycin use had previous radiotherapy, whereas only 1 SSI occurred in 14 patients with tumor without radiotherapy in the same period. CONCLUSION: Intrawound vancomycin may be beneficial for nontumor spine patients who undergo open posterior instrumented surgeries, but may not for those with spinal tumors. The poor physical health status, major surgical trauma, and tumor related adjuvant treatments of patients with spinal tumor may contribute to this disparity. PMID- 26731704 TI - Polymorphism of rs2767485 in Leptin Receptor Gene is Associated With the Occurrence of Adolescent Idiopathic Scoliosis. AB - STUDY DESIGN: A genetic association study of leptin receptor (LEPR) gene with adolescent idiopathic scoliosis (AIS) in the Chinese Han population. OBJECTIVE: To determine whether LEPR gene polymorphisms are associated with the predisposition and/or disease severity of AIS. SUMMARY OF BACKGROUND DATA: Patients with AIS were reported to have lower body mass index (BMI), abnormal leptin bioavailability, and systemic lower bone mass, which implied that leptin/LEPR signaling pathway may be implicated in the etiology of AIS. Previous association study of the polymorphisms in leptin gene did not show significant differences between AIS cases and controls. However, no study has been done to investigate the relationship between genetic polymorphisms of the LEPR gene and susceptibility to AIS. METHODS: 570 patients with AIS aged 10 to 18 years were enrolled, and 570 age-matched healthy subjects were recruited as controls. 6 single nucleotide polymorphisms (SNPs) (rs1137101, rs1137100, rs4655555, rs2767485, rs1751492, and rs8179183) of LEPR gene were selected. The polymorphisms were genotyped using the polymerase chain reaction (PCR)-based Invader assay. Case-control study was performed to define the contribution of the 6 SNPs to predisposition of AIS. 1-way analysis of variance (ANOVA) test was used to compare the mean Cobb angles and BMI among patients with different genotypes in case-only analyses. Statistical significance was set at P < 0.05. RESULTS: Both the genotype and allele frequencies of SNP rs2767485 were significantly different between the patient with AIS and the control groups. No significant difference of allele frequency was noted in other 5 SNPs between the patients with AIS and the normal controls. Both the mean maximum Cobb angles and BMI of different genotype AIS groups were similar to each other for all the 6 SNPs (P > 0.05). CONCLUSION: Polymorphism of rs2767485 in LEPR gene is associated with the occurrence of AIS, suggesting LEPR is a predisposition gene. PMID- 26731705 TI - Functional Limitations Due to Lumbar Stiffness in Adults With and Without Spinal Deformity. AB - STUDY DESIGN: Cross-sectional analysis. OBJECTIVE: To compare Lumbar Stiffness Disability Index (LSDI) scores between asymptomatic adults and patients with spinal deformity. SUMMARY OF BACKGROUND DATA: The LSDI was designed and validated as a tool to assess functional impacts of lumbar spine stiffness and diminished spinal flexibility. Baseline disability levels of patients with adult spinal deformity (ASD) are high as measured by multiple validated outcome tools. Baseline lumbar stiffness-related disability has not been assessed in adults with and without spinal deformity. METHODS: The LSDI and Scoliosis Research Society 22r (SRS-22r) were submitted to a group of asymptomatic adult volunteers. Additionally, a multicenter cross-sectional cohort analysis of patients with ASD from 10 centers was conducted. Baseline LSDI and SRS-22r were completed for both operatively and nonoperatively treated patients with deformity. RESULTS: The LSDI was completed by 176 asymptomatic volunteers and 693 patients with ASD. Mean LSDI score for asymptomatic volunteers was 3.4 +/- 6.3 out of a maximum score of 100, with significant correlation between increasing age and higher (worse) LSDI score (r = 0.30, P = 0.0001). Of the patients with spinal deformity undergoing analysis, 301 subsequently underwent surgery and 392 were subsequently treated nonoperatively. Operative patients had significantly higher preoperative LSDI scores than both nonoperative patients and asymptomatic volunteers (29.9 vs. 17.3 vs. 3.4, P < 0.0001 for both). For patients with ASD, significant correlations were found between LSDI and SRS-22 Pain and Function subscales (r = -0.75 and 0.76, respectively; P < 0.0001 for both). CONCLUSION: LSDI scores are low among asymptomatic volunteers, although stiffness-related disability increases with increasing age. Patients with ASD report substantial stiffness-related disability even prior to surgical fusion. Stiffness-related disability correlates with pain- and function-related disability measures among patients with spinal deformity. PMID- 26731706 TI - Spine Computed Tomography Radiation Dose Reduction: Protocol Refinement Based on Measurement Variation at Simulated Lower Radiation Acquisitions. AB - STUDY DESIGN: Retrospective dose-simulation comparison. OBJECTIVE: To determine if sufficient detail for preoperative analysis of bony anatomy can be acquired at substantially lower doses than those typically used. SUMMARY OF BACKGROUND DATA: Computed tomography (CT) is a preoperative planning tool for spinal surgery. The pediatric population is at risk to express the harmful effects of ionizing radiation. Preoperative CT scans are presently performed at standard pediatric radiation doses not tailored for surgical planning. METHODS: We used the validated GE Noise Injection software to retrospectively modify existing spine and chest CT scans from 10 patients to create CT images that simulated a standard dose (100%), 50% dose, and 25% dose scans. 4 orthopedic surgeons and a pediatric radiologist, blinded to dose, measured minimum medial-lateral pedicle width and maximum anterior-posterior bony length along the axis of presumed pedicle screw placement. A total of 90 axial images were generated to create our sample set. Measurements were evaluated for accuracy, precision, and consistency. RESULTS: For any given rater, there was no clinically relevant difference between measurements at the different dose levels and no apparent degradation in precision at the different dose levels. Consistent variation was observed between raters, the likely result of individual differences in measurement approach. CONCLUSION: Spinal CT scans done for preoperative planning can be performed at 25% of current radiation doses without a loss in surgical planning measurement accuracy or precision. These 25% dose-reduced scans would have average Computed Tomography Dose Index volume dose levels of roughly 1.0 to 2.5 mGy (depending on patient size) and size-specific dose estimates of roughly 2.5 mGy representing a substantial dose savings compared to current practice for many sites. Standardization of consistent landmarks may be useful to further improve inter rater concordance. PMID- 26731707 TI - Universal No-fault Compensation is Associated With Improved Return to Work Rates in Spine Fusion. AB - STUDY DESIGN: Retrospective cohort study and systematic literature review. OBJECTIVE: To examine the influence of "universal no-fault compensation" upon return-to-work rates in patients undergoing lumbar spinal fusion, and then to make comparison with workers' compensation (WC) and non-workers' compensation (non-WC) claimants. SUMMARY OF BACKGROUND DATA: Compensation has an adverse influence upon outcomes and return to work in lumbar spinal fusion. It is unclear whether this is due to the compensation per se, or due to the features of WC including its adversarial environment, delayed resolution of claims, and need for disability enhancement to promote compensation. The New Zealand Accident Compensation Corporation (ACC) is a universal no-fault system offering early treatment and salary reimbursement. Given the differing features of these compensation systems, comparison of return-to-work rates may give insight into the differing outcomes for the two compensation systems. METHODS: From a cohort of 428 patients undergoing lumbar spinal fusion, 178 patients covered by ACC system underwent a structured interview to determine pre-injury, pre-surgical, and post-surgical work status. A systematic literature review was performed relating to lumbar spine fusion, return to work, and WC. RESULTS: The return-to work rate for the ACC patients in work at the time of their injury was 81%. The systematic review of 21 studies including 2519 subjects revealed a return-to-work rate of 40% for WC patients, and 74% for non-WC patients (P < 0.001). There was a significantly greater return-to-work rate for ACC patients than WC patients (P < 0.001), but no difference between ACC and non-WC patients. CONCLUSION: The return to-work rates for a universal no-fault compensation system are higher than those under WC cover, and are compatible with non-WC cases. This suggests that the features of WC may contribute to the inferior return-to-work rates. PMID- 26731708 TI - Alendronate Prevents Intervertebral Disc Degeneration Adjacent to a Lumbar Fusion in Ovariectomized Rats. AB - STUDY DESIGN: A model of disc degeneration adjacent to a lumbar fusion in osteoporotic rats. OBJECTIVE: We determined the effect of alendronate (ALN) on the disc degeneration adjacent to a lumbar fusion in ovariectomized rats. SUMMARY OF BACKGROUND DATA: Adjacent-segment disc degeneration (ASDD) is one of the negative sequelae of spinal fusion. Previous studies have shown that ALN can alleviate disc degeneration. However, no data have been documented regarding the effect of ALN on ASDD after posterolateral lumbar fusion (PLF) in osteoporosis. METHODS: 50 female Sprague-Dawley rats underwent either a sham operation (sham) (n = 20) or bilateral ovariectomy (OVX) (n = 30). 4 weeks later, all but 10 rats from each group underwent PLF consisting of an intertransverse process spinal fusion using autologous-iliac-bone grafts with spinous-process wire fixation at the L4-L5 segment. Animals were subcutaneously administered vehicle (V) or ALN (70 MUg/kg/wk) for 12 weeks post-PLF as follows: Sham+V, OVX+V, PLF+V, OVX+PLF+V, and OVX+PLF+ALN. Fusion status was analyzed by manual palpation and radiography. Adjacent-segment disc was assessed by histological, histomorphometric, immunohistochemical, and mRNA analysis. L6 vertebrae microstructures were evaluated by microcomputed tomography. RESULTS: The fused segments showed clear evidence of fusion based on manual palpation and radiographs. The OVX+PLF+V group showed more severe degenerative alterations and higher histological scores in the disc than the Sham+V, OVX+V, and PLF+V groups (P < 0.05). Compared with the OVX+PLF+V group, the OVX+PLF+ALN group exhibited significantly improved bone mass and vertebrae microstructures (P < 0.05), an increased disc height, and a decreased endplate calcification area (P < 0.05). ALN also significantly decreased Col-I, MMP-13, and ADAMTS-4 expression and increased Col-II and Aggrecan expression in the disc matrix (P < 0.05). CONCLUSION: ALN effectively alleviated ASDD post-PLF in ovariectomized rats. These data indicate that ALN can be used as a potential therapeutic agent to attenuate ASDD progression in osteoporosis. PMID- 26731709 TI - Relevant Anatomic and Morphological Measurements of the Rat Spine: Considerations for Rodent Models of Human Spine Trauma. AB - STUDY DESIGN: Basic science study measuring anatomical features of the cervical and lumbar spine in rat with normalized comparison with the human. OBJECTIVE: The goal of this study is to comprehensively compare the rat and human cervical and lumbar spines to investigate whether the rat is an appropriate model for spine biomechanics investigations. SUMMARY OF BACKGROUND DATA: Animal models have been used for a long time to investigate the effects of trauma, degenerative changes, and mechanical loading on the structure and function of the spine. Comparative studies have reported some mechanical properties and/or anatomical dimensions of the spine to be similar between various species. However, those studies are largely limited to the lumbar spine, and a comprehensive comparison of the rat and human spines is lacking. METHODS: Spines were harvested from male Holtzman rats (n = 5) and were scanned using micro- computed tomography and digitally rendered in 3 dimensions to quantify the spinal bony anatomy, including the lateral width and anteroposterior depth of the vertebra, vertebral body, and spinal canal, as well as the vertebral body and intervertebral disc heights. Normalized measurements of the vertebra, vertebral body, and spinal canal of the rat were computed and compared with corresponding measurements from the literature for the human in the cervical and lumbar spinal regions. RESULTS: The vertebral dimensions of the rat spine vary more between spinal levels than in humans. Rat vertebrae are more slender than human vertebrae, but the width-to depth axial aspect ratios are very similar in both species in both the cervical and lumbar regions, especially for the spinal canal. CONCLUSION: The similar spinal morphology in the axial plane between rats and humans supports using the rat spine as an appropriate surrogate for modeling axial and shear loading of the human spine. PMID- 26731710 TI - Distraction Arthrodesis of the C1-C2 Facet Joint with Preservation of the C2 Root for the Management of Intractable Occipital Neuralgia Caused by C2 Root Compression. AB - STUDY DESIGN: Prospective observational cohort study. OBJECTIVE: To compare the outcomes of our new technique, distraction arthrodesis of C1-C2 facet joint with C2 root preservation (Study group), to those of conventional C1-C2 fusion with C2 root transection (Control group) for the management of intractable occipital neuralgia caused by C2 root compression. SUMMARY OF BACKGROUND DATA: We are not aware of any report concerning C2 root decompression during C1-C2 fusion. MATERIALS AND METHODS: Inclusion criteria were visual analogue scale (VAS) score for occipital neuralgia 7 or more; C2 root compression at the collapsed C1-C2 neural foramen; and follow-up 12 months or more. The Study group underwent surgery with our new technique including (1) C1-C2 facet joint distraction and bone block insertion while preserving the C2 root; and (2) use of C1 posterior arch screws instead of conventional lateral mass screws during C1-C2 segmental screw fixation. The Control group underwent C2 root transection with C1-C2 segmental screw fixation and fusion. We compared the prospectively collected outcomes data. RESULTS: There were 15 patients in the Study group and 8 in the Control group. Although there was no significant difference in the VAS score for the occipital neuralgia between the 2 groups preoperatively (8.2 +/- 0.9 vs. 7.9 +/- 0.6, P = 0.39), it was significantly lower in the Study group at 1, 3, and 6 months postoperatively (P < 0.01, respectively). At 12 months, it was 0.4 +/- 0.6 versus 2.5 +/- 2.6 (P = 0.01). There was no significant difference in improvement in the VAS score for neck pain and neck disability index and Japanese Orthopedic Association recovery rate, which are minimally influenced by occipital neuralgia. CONCLUSION: Our novel technique of distraction arthrodesis with C2 root preservation can be an effective option for the management of intractable occipital neuralgia caused by C2 root compression. PMID- 26731711 TI - To the Editor: "Re: Controversy: Acute Cauda Equina Syndrome Caused by a Disk Lesion: Is Emergent Surgery the Correct Option?" by Mahadevappa et al; "Surgical Decompression Remains the Standard of Care," by McLain et al. PMID- 26731713 TI - MicroRNA Regulates Hepatocytic Differentiation of Progenitor Cells by Targeting YAP1. AB - MicroRNA expression profiling in human liver progenitor cells following hepatocytic differentiation identified miR-122 and miR-194 as the microRNAs most strongly upregulated during hepatocytic differentiation of progenitor cells. MiR 194 was also highly upregulated following hepatocytic differentiation of human embryonic stem cells (hESCs). Overexpression of miR-194 in progenitor cells accelerated their differentiation into hepatocytes, as measured by morphological features such as canaliculi and expression of hepatocytic markers. Overexpression of miR-194 in hESCs induced their spontaneous differentiation, a phenotype accompanied with accelerated loss of the pluripotent factors OCT4 and NANOG and decrease in mesoderm marker HAND1 expression. We then identified YAP1 as a direct target of miR-194. Inhibition of YAP1 strongly induced hepatocytic differentiation of progenitor cells and YAP1 overexpression reversed the miR-194 induced hepatocytic differentiation of progenitor cells. In conclusion, we identified miR-194 as a potent inducer of hepatocytic differentiation of progenitor cells and further identified YAP1 as a mediator of miR-194's effects on hepatocytic differentiation and liver progenitor cell fate. Stem Cells 2016;34:1284-1296. PMID- 26731714 TI - BK Polyomavirus Infection and Renourinary Tumorigenesis. AB - BK polyomavirus (BKPyV) infection represents a major problem in transplantation, particularly for renal recipients developing polyomavirus-associated nephropathy (PyVAN). The possibility that BKPyV may also be oncogenic is not routinely considered. Twenty high-grade renourinary tumors expressing polyomavirus large T antigen in the entirety of the neoplasm in 19 cases, including the metastases in six, have been reported in transplant recipients with a history of PyVAN or evidence of BKPyV infection. Morphological and phenotypical features consistent with inactivation of the tumor suppressors pRB and p53 were found in the bladder tumors, suggesting a carcinogenesis mechanism involving the BKPyV large tumor oncoprotein/antigen. The pathogenesis of these tumors is unclear, but given the generally long interval between transplantation and tumor development, the risk for neoplasms after BKPyV infections may well be multifactorial. Other elements potentially implicated include exposure to additional exogenous carcinogens, further viral mutations, and cell genomic instability secondary to viral integration, as occurs with the Merkel cell PyV-associated carcinoma. The still scarce but increasingly reported association between longstanding PyVAN and renourinary neoplasms requires a concerted effort from the transplant community to better understand, diagnose, and treat the putative association between the BKPyV and these neoplasms. PMID- 26731715 TI - Clinical and Radiologic Outcome of a Less Invasive, Low-Cost Surgical Technique of Osteoplastic Decompressive Craniectomy. AB - BACKGROUND: Decompressive craniectomy (DC) has many technical details with significant constraining logistic/economic considerations in low-resource practice areas. We present a less invasive, cost-saving, and evidence-based technique of DC evolving in our practice. METHODS: Earlier, we reported a technique of hinge decompressive craniectomy (hDC), in which the frontotemporoparietal skull flap is hinged on the temporal muscle. In this article we describe further refinements of this temporal muscle hDC : The scalp flap is raised in a galeal-skeletonizing plane preserving the subgaleal fascia on the pericranium, ready for use for duraplasty after durotomy. We performed a descriptive analysis of the clinical outcome of this surgical technique in a prospective consecutive cohort of patients with traumatic brain injury (TBI). The primary and secondary clinical outcome measures were in-hospital mortality and survival, respectively, and the immediate as well as long-term surgical wound issues. RESULTS: There were 40 cases, 38 men (95%) and 2 women over a 40-month period with a mild (n = 8), moderate (n = 17), or severe TBI (n = 15). As assessed by the computed tomography Rotterdam score, life-threatening significant brain injury was present in 90%. Poor clinical outcome occurred in about a third of cases (32.5%) mainly in the severe TBI group (77% of poor outcome) and not in the mild TBI group. Surgical site complications occurred in four patients (10%) CONCLUSIONS: The presented modified temporal muscle hDC technique offers significant economic advantages over the traditional surgical method of DC without added complications. Analysis of the clinical data in a consecutive prospective cohort of patients with potentially fatal TBI who underwent this surgical procedure showed a good outcome in at least two thirds. PMID- 26731717 TI - Pilocarpine-induced epilepsy alters the expression and daily variation of the nuclear receptor RORalpha in the hippocampus of rats. AB - It is widely known that there is an increase in the inflammatory responses and oxidative stress in temporal lobe epilepsy (TLE). Further, the seizures follow a circadian rhythmicity. Retinoic acid receptor-related orphan receptor alpha (RORalpha) is related to anti-inflammatory and antioxidant enzyme expression and is part of the machinery of the biological clock and circadian rhythms. However, the participation of RORalpha in this neurological disorder has not been studied. The aim of this study was to evaluate the RORalpha mRNA and protein content profiles in the hippocampus of rats submitted to a pilocarpine-induced epilepsy model at different time points throughout the 24-h light-dark cycle analyzing the influence of the circadian rhythm in the expression pattern during the acute, silent, and chronic phases of the experimental model. Real-time PCR and immunohistochemistry results showed that RORalpha mRNA and protein expressions were globally reduced in both acute and silent phases of the pilocarpine model. However, 60days after the pilocarpine-induced status epilepticus (chronic phase), the mRNA expression was similar to the control except for the time point 3h after the lights were turned off, and no differences were found in immunohistochemistry. Our results indicate that the status epilepticus induced by pilocarpine is able to change the expression and daily variation of RORalpha in the rat hippocampal area during the acute and silent phases. These findings enhance our understanding of the circadian pattern present in seizures as well as facilitate strategies for the treatment of seizures. PMID- 26731718 TI - Free flaps for reconstruction of soft tissue defects in lower extremity: A meta analysis on microsurgical outcome and safety. AB - BACKGROUND: Microsurgical free flaps for reconstruction of soft tissue defects in lower extremity have evolved into a reliable procedure over last decades; however, there lacked high level of evidence. METHODS: A systematic literature research was performed including studies between 2000 and 2014 in English, German, and Chinese (PubMed, EMBASE). Publications were selected applying inclusion/exclusion criteria. Postoperative complications were statistically analyzed with metaprop command of R GUI 3.0.1. RESULTS: Alltogether 30 articles overlooking 1,397 free flaps were included. The rate of total flap loss was 6.0% (95% confidence interval [CI] = 4.0%-8.0%, PQ (P values of Q statistics) = 0.03); the thrombosis rate was 6.0% (95% CI = 4.0%-9.0%, PQ = 0.01); the hematoma rate was 4.0% (95% CI = 3.0%-5.0%, PQ = 0.79); the partial necrosis rate was 6.0% (95% CI = 4.0%-10.0%, PQ < 0.01); the early infection rate was 4.0% (95% CI = 2.0%-6.0%, PQ = 0.03), and the dehiscence rate was 3.0% (95% CI = 2.0%-5.0%, PQ = 0.12). Reconstruction for diabetic foot may be not associated with a significant increase of procedural risk (Total flap loss rate = 6%, 95% CI = 3.0% 9.0%, PQ = 0.44). CONCLUSIONS: Microsurgical reconstruction of soft tissue defects in the lower extremity reconstruction could be regarded safe and reliable. A standardization of report of perioperative parameters and clinical outcomes is needed. (c) 2016 Wiley Periodicals, Inc. Microsurgery 36:511-524, 2016. PMID- 26731716 TI - A population-based study of active and drug-resistant epilepsies in Northern Italy. AB - Drug-resistant epilepsy (DRE) is defined by the International League Against Epilepsy as a failure of adequate trials of two tolerated, appropriately chosen, and used antiepileptic drugs to achieve sustained seizure freedom. Our aim was to calculate the following: (1) the prevalence of active epilepsy and DRE in a well defined population of Northern Italy and (2) the proportion of incident cases developing DRE. The study population (146,506; year 2008) resided in the province of Lecco, Northern Italy. The medical records of 123 general practitioners were reviewed to identify patients with epilepsy, diagnosed by a neurologist during the period 2000-2008. The point prevalence of active epilepsy and DRE was calculated on December 31, 2008. A total of 747 prevalent patients with epilepsy, 684 patients with active epilepsy, and 342 incident cases were identified. The frequency of DRE was 15.6% (107/684) of all active epilepsies and 10.5% (36/342) of incident cases. The point prevalence was 0.73 per 1000. The standardized prevalence of DRE was 0.7 per 1000 (Italian population) and 0.8 per 1000 (world population). Our data indicate that 1/6 patients with active epilepsy in the general population has DRE, and 1/10 patients with newly diagnosed epilepsy will develop DRE within nine years from the diagnosis. PMID- 26731719 TI - Human conjunctival goblet cells express the membrane associated mucin MUC16: Localization to mucin granules. AB - MUC16 is an extraordinarily large 22,152 amino acid membrane spanning mucin that has been shown to be present in the glycocalyx of the apical cells of the human cornea and conjunctiva where it interfaces with the tear film. The ectodomain of the molecule has been demonstrated in tears, where it has been presumed to be from surface epithelial cells. Data presented here from multiple assays, including immunohistochemistry, immunoelectron microscopy, in situ hybridization, and RT-PCR of RNA isolated from goblet cells isolated by laser capture microdissection, demonstrate that the membrane tethered mucin is also expressed by conjunctival goblet cells both in humans and in mice. The mucin is present in mucin granules and appears to be localized to the mucin granule membrane. Correlation analyses of the amounts of the goblet cell secreted mucin MUC5AC and the amounts of MUC16 and of MUC1 another membrane tethered mucin ectodomain found in human tear samples demonstrated that MUC5AC amounts correlated to the amounts of MUC16 but not to MUC1. These data suggest that goblet cells are a second source of the mucin in tears. The function of the membrane tethered mucin in the mucin granule remains to be determined. PMID- 26731720 TI - Factors Controlling the Stable Nitrogen Isotopic Composition (delta15N) of Lipids in Marine Animals. AB - Lipid extraction of biomass prior to stable isotope analysis is known to cause variable changes in the stable nitrogen isotopic composition (delta15N) of residual biomass. However, the underlying factors causing these changes are not yet clear. Here we address this issue by comparing the delta15N of bulk and residual biomass of several marine animal tissues (fish, crab, cockle, oyster, and polychaete), as well as the delta15N of the extracted lipids. As observed previously, lipid extraction led to a variable offset in delta15N of biomass (differences ranging from -2.3 to +1.8 0/00). Importantly, the total lipid extract (TLE) was highly depleted in 15N compared to bulk biomass, and also highly variable (differences ranging from -14 to +0.7 0/00). The TLE consisted mainly of phosphatidylcholines, a group of lipids with one nitrogen atom in the headgroup. To elucidate the cause for the 15N-depletion in the TLE, the delta15N of amino acids was determined, including serine because it is one of the main sources of nitrogen to N-containing lipids. Serine delta15N values differed by -7 to +2 0/00 from bulk biomass delta15N, and correlated well with the 15N depletion in TLEs. On average, serine was less depleted (-30/00) than the TLE (-7 0/00), possibly due to fractionation during biosynthesis of N-containing headgroups, or that other nitrogen-containing compounds, such as urea and choline, or recycled nitrogen contribute to the nitrogen isotopic composition of the TLE. The depletion in 15N of the TLE relative to biomass increased with the trophic level of the organisms. PMID- 26731721 TI - FOXP3+ Regulatory T Cells in Hepatic Fibrosis and Splenomegaly Caused by Schistosoma japonicum: The Spleen May Be a Major Source of Tregs in Subjects with Splenomegaly. AB - Schistosoma eggs cause chronic liver inflammation and a complex disease characterized by hepatic fibrosis (HF) and splenomegaly (SplM). FOXP3+ Tregs could regulate inflammation, but it is unclear where these cells are produced and what roles they play in human schistosomiasis. We investigated blood and spleen FOXP3+ Tregs in Chinese fishermen with lifelong exposure to Schistosoma japonicum and various degrees of liver and spleen disease. FOXP3+ Tregs accounted for 4.3% of CD4+ T cells and 41.2% of FOXP3+CD4+ T cells; they could be divided into CD45RA-FOXP3hi effector (eTregs) and CD45RA+FOXP3low naive Tregs. Blood Treg levels were high in severe HF (+1.3; p = 0.004) and in SplM (+1.03, p = 0.03). Multivariate regression showed that severe HF (+0.85, p = 0.01) and SplM (+0.97; p = 0.05) were independently associated with the higher proportion of Tregs in the blood. This effect was mostly due to an increase in the proportion of eTregs in the blood of HF+++ (+0.9%; p = 0.04) and SplM (+0.9%; p = 0.04) patients. The proportion of eTregs expressing CXCR3 in the blood was lower in the HF+++ patients (37.4 +/- 5.9%) than in those with milder fibrosis (51.7 +/- 2%; p = 0.009), whereas proportion were similar for cells expressing CD25hi, CCR7, and CTLA-4. Splenectomy improves symptoms and was associated with decreases in blood FOXP3+ Treg (-2.5; p<0.001) and eTreg (-1.3; p = 0.03) levels. SplM spleens contained a high proportion of eTregs with CXCR3, CCR5 and CTLA4 upregulation and CCR7 downregulation. This, and the strong expression of ligands of CXCR3 and CCR5 in the liver (n = 8) but not in the spleen suggested that spleen eTregs migrated to Th1-infiltrated liver tissues. Such migration may be attenuated in hepatosplenic patients due to lower levels of CXCR3 expression on Tregs (p = 0.009). Thus, higher blood Treg levels are associated with severe liver disease and splenomegaly. Our data are consistent with the hypothesis that the spleen is a major source of Tregs in subjects with splenomegaly. In most cases, Tregs migrate to the Th1-infiltrated liver and the lower levels of CXCR3+ Tregs in the blood of patients with severe schistosomiasis suggest that decreases in Treg migration sites of inflammation may aggravate the disease. PMID- 26731722 TI - Diabetes and Body Mass Index Are Associated with Neuropathy and Prognosis in Colon Cancer Patients Treated with Capecitabine and Oxaliplatin Adjuvant Chemotherapy. AB - BACKGROUND: There are few background data on the impact of clinical factors on neurotoxicity and prognosis in patients treated with adjuvant capecitabine and oxaliplatin (CAPOX) chemotherapy. METHODS: 102 stage II high-risk and stage III colorectal cancer patients were treated for 6 months with adjuvant CAPOX, then they were followed up. Associations between clinical variables, metabolic syndrome components, smoking and neurotoxicity were evaluated by the x03C7;2 test. The Kaplan-Meier product limit method was applied to graph disease-free survival (DFS). Univariate analysis was done with the log-rank test. Cox's proportional hazards regression was used to analyze the effect of several risk factors on DFS. RESULTS: Significant associations were found between diabetes (p < 0.001), BMI (p = 0.01) and the occurrence of chronic neurotoxicity. After a median follow-up of 46 months, 14 patients (13.7%) had suffered recurrence. An analysis of the prognostic factors for DFS showed that prognosis is unfavorable for patients with high lymph-nodal involvement (HR: 5.23, p = 0.0007), diabetes (HR: 4.86; p = 0.03) and a BMI >=25 (HR: 3.69, p = 0.002). DISCUSSION: Common mediators in diabetes and obesity could be involved in peripheral neuropathy and in stimulating micro-metastases. Further studies are necessary to explain this interesting connection between diabetes, obesity and colon cancer. PMID- 26731723 TI - Micro-RNAs associated with the evolution of ovarian cancer cisplatin resistance. AB - OBJECTIVES: Ovarian cancer (OVCA) is the leading cause of mortality among women with gynecologic malignancy, in part due to the development of chemoresistance. We sought to identify micro-RNAs (miRNAs) associated with in vitro development of OVCA chemoresistance that may also represent potential targets for therapy. METHODS: In this study, four OVCA cell lines (A2780CP, A2780S, IGROV1, and OVCAR5) were serially treated with cisplatin in parallel with measurements of miRNA expression changes. RESULTS: Nine miRNAs were found to be associated with increasing cisplatin resistance (IC50) (p<0.01); however, only 5 of these miRNAs have publically available information. Pathway analysis identified 15 molecular signaling pathways that were represented by genes predicted to be targets of the 5 miRNAs (false discovery rate<0.05), 11 of which are associated with the epithelial-mesenchymal transition (EMT). Further analysis identified 2 of those pathways as being associated with overall survival in 218 patients with OVCA. CONCLUSIONS: Collectively, this panel of miRNAs associated with in vitro evolution of OVCA cisplatin resistance and the pathways identified to be associated with EMT and overall patient survival provide a framework for further investigations into EMT as a therapeutic target in patients with OVCA. PMID- 26731724 TI - Temsirolimus in women with platinum-refractory/resistant ovarian cancer or advanced/recurrent endometrial carcinoma. A phase II study of the AGO-study group (AGO-GYN8). AB - OBJECTIVES: To evaluate activity and toxicity of mTOR inhibitor temsirolimus in patients with platinum-refractory/resistant ovarian cancer (OC) or advanced/recurrent endometrial carcinoma (EC). METHODS: Women with epithelial ovarian, fallopian tube or primary peritoneal cancer were eligible, when they had progression during treatment with a platinum based regimen or within 6 months after receiving a platinum based regimen and a previous taxane treatment. Women with advanced/recurrent EC, no longer amenable to curative surgery and/or radiotherapy were eligible when they had no previous or only adjuvant chemotherapy. Preceding endocrine therapy for metastatic/recurrent disease was allowed. Patients received weekly IV infusions of 25mg temsirolimus. Primary endpoint was progression free survival rate after 4 months (OC) or 6 months (EC). A two stage design was applied. RESULTS: Forty-four patients (OC: n=22; EC: n=22) were enrolled and received temsirolimus treatment. Median age was 56 years (OC) or 63 years (EC). After eight weeks of treatment, 10 of 21 evaluable patients in the OC cohort and 8 of 20 evaluable patients in the EC cohort had progressive disease. Thus efficacy did not meet the predefined levels during the first stage of recruitment and the trial was stopped. Some patients in both cohorts had long lasting PFS (>7 months). Toxicity of temsirolimus was mild. CONCLUSIONS: Temsirolimus treatment was well tolerated in our patients, but did not meet the predefined efficacy criteria. In our study as in other trials on rapalogs in OC or EC, a few patients had long lasting disease stabilisations. PMID- 26731725 TI - Prognostic significance of highly sulfated chondroitin sulfates in ovarian cancer defined by the single chain antibody GD3A11. AB - OBJECTIVE: The extracellular matrix (ECM) of ovarian cancer may provide a number of potential biomarkers. Chondroitin sulfate (CS), a class of sulfated polysaccharides, is abundantly present in the ECM of ovarian cancer. Structural alterations of CS chains (i.e. sulfation pattern) have been demonstrated to play a role in cancer development and progression. In this study we investigate the potential of highly sulfated CS as a biomarker in ovarian cancer using the single chain antibody GD3A11 selected by the phage display technology. METHODS: The specificity of the antibody was determined by an indirect ELISA. GD3A11 epitope expression was assessed by immunohistochemistry in healthy organs, benign and malignant ovarian tumors (N=359) and correlated to clinical parameters. The CHST15 gene, responsible for the biosynthesis of highly sulfated CS was evaluated for mutation and methylation status. RESULTS: The GD3A11 epitope was minimally expressed in normal organs. Intense expression was observed in the ECM of different ovarian cancer subtypes, in contrast to benign ovarian tumors. Expression was independent of tumor grade, FIGO stage, and the use chemotherapy. For the aggressive ovarian cancer phenotype, intense expression was identified as an independent predictor for poor prognosis. CHST15 gene analysis showed no mutations nor an altered methylation status. CONCLUSION: Specific highly sulfated CS motifs expressed in the tumoral ECM hold biomarker potential in ovarian cancer patients. These matrix motifs constitute a novel class of biomarkers with prognostic significance and may be instrumental for innovative diagnostic and therapeutic applications (e.g. targeted therapy) in management of ovarian cancer. PMID- 26731726 TI - Progestin treatment decreases CD133+ cancer stem cell populations in endometrial cancer. AB - OBJECTIVES: Endometrial cancer is a hormonally responsive malignancy. Response to progestins is associated with estrogen receptor (ER) and progesterone receptor (PR) status. CD133 is a marker of endometrial cancer stem cells. We postulated that CD133+ cells express ER and PR and that progestin therapy differentially regulates CD133+ cells. METHODS: The Ishikawa (ER/PR positive) and KLE (ER/PR negative) cell lines were examined for the presence of CD133 populations. Cell lines were treated with 30.4MUM medroxyprogesterone 17-acetate (MPA) for 6days. After treatment, cell counts, apoptosis assays and CD133+ populations were examined. In a clinical project, we identified 12 endometrial cancer patients who were treated with progestin drugs at our institution. Using immunohistochemistry, CD133, ER, PR, and androgen receptor (AR) expression was scored and evaluated for change over time on serial biopsies. RESULTS: CD133+ populations were identified in Ishikawa and KLE cell lines. MPA treatment resulted in a significant reduction in the percentage of live cells (Ishikawa, P=0.036; KLE, P=0.0002), significant increase in apoptosis (Ishikawa, P=0.01; KLE, P=0.0006) and significant decrease in CD133+ populations (Ishikawa, P<0.0001; KLE, P=0.0001). ER, PR, AR and CD133 were present in 96.4%, 96.4%, 89.3% and 100% of patient samples respectively. Paralleling the in vitro results, CD133 expression decreased in patients who had histologic response to progestin treatment. CONCLUSION: CD133+ populations decreased after treatment with MPA in an in vitro model and in patients responding to treatment with progestins. Progestin treatment differentially decreases CD133+ cells. PMID- 26731727 TI - The importance of para-aortic lymph nodes in sentinel lymph node mapping for endometrial cancer by using hysteroscopic radio-isotope tracer injection combined with subserosal dye injection: Prospective study. AB - OBJECTIVE: The objective of this study is to evaluate the detection rate and diagnostic accuracy of sentinel lymph node (SN) mapping using hysteroscopic sub endometrial injection of 99m-Technetium labeled phytate (Radio-isotope; RI method) and subserosal Indocyanine green (ICG) injection (Dye method) in patients with endometrial cancer. METHODS: From April 2009 to December 2012, prospective evaluation of 57 Japanese endometrial cancer patients undergoing SN mapping using RI method combined with Dye method was done. To combine RI method or no was determined by a status of RI supply of the tracer injection day. As for 32 cases, both (RI+Dye) methods were used and 23 cases were performed only in Dye method. The primary endpoint was estimation of sensitivity and negative predictive value (NPV) of SN, and analysis of the distribution of SNs with metastasis. RESULTS: At least one SN was detected in 100% and average number of detected SNs was 6.0 in RI+Dye method. Sensitivity and NPV were 100%, 100%, respectively. From results of SN mapping, 62.8% of SNs were present in pelvic and 37.1% in para-aortic lymph nodes (PAN). Total 56.3% of lymph nodes with metastasis were present in pelvic and 43.8% in PAN, and the distribution has no difference with SN mapping results (P=0.602). Among 13 cases with metastatic SNs, 76.9% cases showed metastasis in PAN. CONCLUSIONS: This SN mapping procedure for endometrial cancer patients revealed high detection rate, sensitivity, NPV, and also indicated the importance of the SN exploration in PAN area. PMID- 26731729 TI - Correction: Investigation of Susceptibility Genes Triggering Lachrymal/Salivary Gland Lesion Complications in Japanese Patients with Type 1 Autoimmune Pancreatitis. PMID- 26731728 TI - Label-Free Quantitative Proteomic Analysis of Puccinia psidii Uredospores Reveals Differences of Fungal Populations Infecting Eucalyptus and Guava. AB - Puccinia psidii sensu lato (s.l.) is the causal agent of eucalyptus and guava rust, but it also attacks a wide range of plant species from the myrtle family, resulting in a significant genetic and physiological variability among populations accessed from different hosts. The uredospores are crucial to P. psidii dissemination in the field. Although they are important for the fungal pathogenesis, their molecular characterization has been poorly studied. In this work, we report the first in-depth proteomic analysis of P. psidii s.l. uredospores from two contrasting populations: guava fruits (PpGuava) and eucalyptus leaves (PpEucalyptus). NanoUPLC-MSE was used to generate peptide spectra that were matched to the UniProt Puccinia genera sequences (UniProt database) resulting in the first proteomic analysis of the phytopathogenic fungus P. psidii. Three hundred and fourty proteins were detected and quantified using Label free proteomics. A significant number of unique proteins were found for each sample, others were significantly more or less abundant, according to the fungal populations. In PpGuava population, many proteins correlated with fungal virulence, such as malate dehydrogenase, proteossomes subunits, enolases and others were increased. On the other hand, PpEucalyptus proteins involved in biogenesis, protein folding and translocation were increased, supporting the physiological variability of the fungal populations according to their protein reservoirs and specific host interaction strategies. PMID- 26731730 TI - The Big-Five Personality Traits, Maternal Smoking during Pregnancy, and Educational Qualifications as Predictors of Tobacco Use in a Nationally Representative Sample. AB - OBJECTIVE: To investigate the associations between the Big-Five personality traits, parental social class, maternal smoking status during pregnancy, childhood cognitive ability, education and occupation, and tobacco use in a longitudinal birth cohort study. METHOD: 17,415 babies born in Great Britain in 1958 and followed up at 11, 33, and 50 years of age. Lifelong tobacco use status (ever/never) and current tobacco use status (yes/no) at age 50 years were the outcome measures respectively. RESULTS: Logistic regression analyses showed that among the 5,840 participants with complete data, whilst maternal smoking status, educational qualifications, and all the big-5 personality traits were significant predictors of adult lifelong tobacco use; educational qualifications, own occupational levels, traits Extraversion, Conscientiousness, and Openness were significant predictors of current smoking status. In lifelong measure men tended to have a greater rate of tobacco use than women (52.1% in men and 49.2% in women). However, the sex effect on lifelong tobacco use ceased to be significant once a set of socio-economic and psychological variables in childhood and adulthood were taken into account. CONCLUSION: Educational qualifications and the Big-Five personality traits were significantly associated with both current and lifelong tobacco use status. PMID- 26731731 TI - "Candidatus Fokinia solitaria", a Novel "Stand-Alone" Symbiotic Lineage of Midichloriaceae (Rickettsiales). AB - Recently, the family Midichloriaceae has been described within the bacterial order Rickettsiales. It includes a variety of bacterial endosymbionts detected in different metazoan host species belonging to Placozoa, Cnidaria, Arthropoda and Vertebrata. Representatives of Midichloriaceae are also considered possible etiological agents of certain animal diseases. Midichloriaceae have been found also in protists like ciliates and amoebae. The present work describes a new bacterial endosymbiont, "Candidatus Fokinia solitaria", retrieved from three different strains of a novel Paramecium species isolated from a wastewater treatment plant in Rio de Janeiro (Brazil). Symbionts were characterized through the full-cycle rRNA approach: SSU rRNA gene sequencing and fluorescence in situ hybridization (FISH) with three species-specific oligonucleotide probes. In electron micrographs, the tiny rod-shaped endosymbionts (1.2 x 0.25-0.35 MUm in size) were not surrounded by a symbiontophorous vacuole and were located in the peripheral host cytoplasm, stratified in the host cortex in between the trichocysts or just below them. Frequently, they occurred inside autolysosomes. Phylogenetic analyses of Midichloriaceae apparently show different evolutionary pathways within the family. Some genera, such as "Ca. Midichloria" and "Ca. Lariskella", have been retrieved frequently and independently in different hosts and environmental surveys. On the contrary, others, such as Lyticum, "Ca. Anadelfobacter", "Ca. Defluviella" and the presently described "Ca. Fokinia solitaria", have been found only occasionally and associated to specific host species. These last are the only representatives in their own branches thus far. Present data do not allow to infer whether these genera, which we named "stand alone lineages", are an indication of poorly sampled organisms, thus underrepresented in GenBank, or represent fast evolving, highly adapted evolutionary lineages. PMID- 26731732 TI - Ribosomal DNA and Plastid Markers Used to Sample Fungal and Plant Communities from Wetland Soils Reveals Complementary Biotas. AB - Though the use of metagenomic methods to sample below-ground fungal communities is common, the use of similar methods to sample plants from their underground structures is not. In this study we use high throughput sequencing of the ribulose-bisphosphate carboxylase large subunit (rbcL) plastid marker to study the plant community as well as the internal transcribed spacer and large subunit ribosomal DNA (rDNA) markers to investigate the fungal community from two wetland sites. Observed community richness and composition varied by marker. The two rDNA markers detected complementary sets of fungal taxa and total fungal composition clustered according to primer rather than by site. The composition of the most abundant plants, however, clustered according to sites as expected. We suggest that future studies consider using multiple genetic markers, ideally generated from different primer sets, to detect a more taxonomically diverse suite of taxa compared with what can be detected by any single marker alone. Conclusions drawn from the presence of even the most frequently observed taxa should be made with caution without corroborating lines of evidence. PMID- 26731733 TI - Selecting Superior De Novo Transcriptome Assemblies: Lessons Learned by Leveraging the Best Plant Genome. AB - Whereas de novo assemblies of RNA-Seq data are being published for a growing number of species across the tree of life, there are currently no broadly accepted methods for evaluating such assemblies. Here we present a detailed comparison of 99 transcriptome assemblies, generated with 6 de novo assemblers including CLC, Trinity, SOAP, Oases, ABySS and NextGENe. Controlled analyses of de novo assemblies for Arabidopsis thaliana and Oryza sativa transcriptomes provide new insights into the strengths and limitations of transcriptome assembly strategies. We find that the leading assemblers generate reassuringly accurate assemblies for the majority of transcripts. At the same time, we find a propensity for assemblers to fail to fully assemble highly expressed genes. Surprisingly, the instance of true chimeric assemblies is very low for all assemblers. Normalized libraries are reduced in highly abundant transcripts, but they also lack 1000s of low abundance transcripts. We conclude that the quality of de novo transcriptome assemblies is best assessed through consideration of a combination of metrics: 1) proportion of reads mapping to an assembly 2) recovery of conserved, widely expressed genes, 3) N50 length statistics, and 4) the total number of unigenes. We provide benchmark Illumina transcriptome data and introduce SCERNA, a broadly applicable modular protocol for de novo assembly improvement. Finally, our de novo assembly of the Arabidopsis leaf transcriptome revealed ~20 putative Arabidopsis genes lacking in the current annotation. PMID- 26731734 TI - Redirection of the Reaction Specificity of a Thermophilic Acetolactate Synthase toward Acetaldehyde Formation. AB - Acetolactate synthase and pyruvate decarboxylase are thiamine pyrophosphate dependent enzymes that convert pyruvate into acetolactate and acetaldehyde, respectively. Although the former are encoded in the genomes of many thermophiles and hyperthermophiles, the latter has been found only in mesophilic organisms. In this study, the reaction specificity of acetolactate synthase from Thermus thermophilus was redirected to catalyze acetaldehyde formation to develop a thermophilic pyruvate decarboxylase. Error-prone PCR and mutant library screening led to the identification of a quadruple mutant with 3.1-fold higher acetaldehyde forming activity than the wild-type. Site-directed mutagenesis experiments revealed that the increased activity of the mutant was due to H474R amino acid substitution, which likely generated two new hydrogen bonds near the thiamine pyrophosphate-binding site. These hydrogen bonds might result in the better accessibility of H+ to the substrate-cofactor-enzyme intermediate and a shift in the reaction specificity of the enzyme. PMID- 26731735 TI - Effect of Acute Intermittent CPAP Depressurization during Sleep in Obese Patients. AB - BACKGROUND: Obstructive Sleep Apnea (OSA) describes intermittent collapse of the airway during sleep, for which continuous positive airway pressure (CPAP) is often prescribed for treatment. Prior studies suggest that discontinuation of CPAP leads to a gradual, rather than immediate return of baseline severity of OSA. The objective of this study was to determine the extent of OSA recurrence during short intervals of CPAP depressurization during sleep. METHODS: Nine obese (BMI = 40.4 +/- 3.5) subjects with severe OSA (AHI = 88.9 +/- 6.8) adherent to CPAP were studied during one night in the sleep laboratory. Nasal CPAP was delivered at therapeutic (11.1 +/- 0.6 cm H20) or atmospheric pressure, in alternating fashion for 1-hour periods during the night. We compared sleep architecture and metrics of OSA during CPAP-on and CPAP-off periods. RESULTS: 8/9 subjects tolerated CPAP withdrawal. The average AHI during CPAP-on and CPAP-off periods was 3.6 +/- 0.6 and 15.8 +/- 3.6 respectively (p<0.05). The average 3% ODI during CPAP-on and CPAP-off was 4.7 +/- 2 and 20.4 +/- 4.7 respectively (p<0.05). CPAP depressurization also induced more awake (p<0.05) and stage N1 (p<0.01) sleep, and less stage REM (p<0.05) with a trend towards decreased stage N3 (p = 0.064). CONCLUSION: Acute intermittent depressurization of CPAP during sleep led to deterioration of sleep architecture but only partial re-emergence of OSA. These observations suggest carryover effects of CPAP. PMID- 26731736 TI - Economic Evaluation of Interventions for Prevention of Hospital Acquired Infections: A Systematic Review. AB - OBJECTIVE: This systematic review sought to assess the costs and benefits of interventions preventing hospital-acquired infections and to evaluate methodological and reporting quality. METHODS: We systematically searched Medline via PubMed and the National Health Service Economic Evaluation Database from 2009 to 2014. We included quasi-experimental and randomized trails published in English or German evaluating the economic impact of interventions preventing the four most frequent hospital-acquired infections (urinary tract infections, surgical wound infections, pneumonia, and primary bloodstream infections). Characteristics and results of the included articles were extracted using a standardized data collection form. Study and reporting quality were evaluated using SIGN and CHEERS checklists. All costs were adjusted to 2013 US$. Savings-to cost ratios and difference values with interquartile ranges (IQRs) per month were calculated, and the effects of study characteristics on the cost-benefit results were analyzed. RESULTS: Our search returned 2067 articles, of which 27 met the inclusion criteria. The median savings-to-cost ratio across all studies reporting both costs and savings values was US $7.0 (IQR 4.2-30.9), and the median net global saving was US $13,179 (IQR 5,106-65,850) per month. The studies' reporting quality was low. Only 14 articles reported more than half of CHEERS items appropriately. Similarly, an assessment of methodological quality found that only four studies (14.8%) were considered high quality. CONCLUSIONS: Prevention programs for hospital acquired infections have very positive cost-benefit ratios. Improved reporting quality in health economics publications is required. PMID- 26731737 TI - Molecular Comparison of Bacterial Communities on Peripheral Intravenous Catheters and Matched Skin Swabs. AB - Skin bacteria at peripheral intravenous catheter (PIVC) insertion sites pose a serious risk of microbial migration and subsequent colonisation of PIVCs, and the development of catheter related bloodstream infections (CRBSIs). Common skin bacteria are often associated with CRBSIs, therefore the bacterial communities at PIVC skin sites are likely to have major implications for PIVC colonisation. This study aimed to determine the bacterial community structures on skin at PIVC insertion sites and to compare the diversity with associated PIVCs. A total of 10 PIVC skin site swabs and matching PIVC tips were collected by a research nurse from 10 hospitalised medical/surgical patients at catheter removal. All swabs and PIVCs underwent traditional culture and high-throughput sequencing. The bacterial communities on PIVC skin swabs and matching PIVCs were diverse and significantly associated (correlation coefficient = 0.7, p<0.001). Methylobacterium spp. was the dominant genus in all PIVC tip samples, but not so for skin swabs. Sixty-one percent of all reads from the PIVC tips and 36% of all reads from the skin swabs belonged to this genus. Staphylococcus spp., (26%), Pseudomonas spp., (10%) and Acinetobacter spp. (10%) were detected from skin swabs but not from PIVC tips. Most skin associated bacteria commonly associated with CRBSIs were observed on skin sites, but not on PIVCs. Diverse bacterial communities were observed at skin sites despite skin decolonization at PIVC insertion. The positive association of skin and PIVC tip communities provides further evidence that skin is a major source of PIVC colonisation via bacterial migration but microbes present may be different to those traditionally identified via culture methods. The results provide new insights into the colonisation of catheters and potential pathogenesis of bacteria associated with CRBSI, and may assist in developing new strategies designed to reduce the risk of CRBSI. PMID- 26731738 TI - RLetters: A Web-Based Application for Text Analysis of Journal Articles. AB - While textual analysis of the journal literature is a burgeoning field, there is still a profound lack of user-friendly software for accomplishing this task. RLetters is a free, open-source web application which provides researchers with an environment in which they can select sets of journal articles and analyze them with cutting-edge textual analysis tools. RLetters allows users without prior expertise in textual analysis to analyze word frequency, collocations, cooccurrences, term networks, and more. It is implemented in Ruby and scripts are provided to automate deployment. PMID- 26731739 TI - Association between the AUC0-24/MIC Ratio of Vancomycin and Its Clinical Effectiveness: A Systematic Review and Meta-Analysis. AB - BACKGROUND: A target AUC0-24/MIC ratio of 400 has been associated with its clinical success when treating Staphylococcus aureus infections but is not currently supported by state-of-the-art evidence-based research. OBJECTIVE: This current systematic review aimed to evaluate the available evidence for the association between the AUC0-24/MIC ratio of vancomycin and its clinical effectiveness on hospitalized patients and to confirm the existing target value of 400. METHODS: PubMed, Embase, Web of Sciences, the Cochrane Library and two Chinese literature databases (CNKI, CBM) were systematically searched. Manual searching was also applied. Both RCTs and observational studies comparing the clinical outcomes of high AUC0-24/MIC groups versus low AUC0-24/MIC groups were eligible. Two reviewers independently extracted the data. The primary outcomes were mortality and infection treatment failure. Risk ratios (RRs) with 95% confidence intervals (95%CIs) were calculated. RESULTS: No RCTs were retrieved. Nine cohort studies were included in the meta-analysis. Mortality rates were significantly lower in high AUC0-24/MIC groups (RR = 0.47, 95%CI = 0.31-0.70, p<0.001). The rates of infection treatment failure were also significantly lower in high AUC/MIC groups and were consistent after correcting for heterogeneity (RR = 0.39, 95%CI = 0.28-0.55, p = 0.001). Subgroup analyses showed that results were consistent whether MIC values were determined by broth microdilution (BMD) method or Etest method. In studies using the BMD method, breakpoints of AUC0-24/MIC all fell within 85% to 115% of 400. CONCLUSIONS: This meta-analysis demonstrated that achieving a high AUC0-24/MIC of vancomycin could significantly decrease mortality rates by 53% and rates of infection treatment failure by 61%, with 400 being a reasonable target. PMID- 26731740 TI - Cognitive Changes during Prolonged Stay at High Altitude and Its Correlation with C-Reactive Protein. AB - Hypersensitive C-reaction protein (hsCRP) may be a risk factor for cognitive impairment resulting from Alzheimer's disease (AD), stroke, and vascular dementia. This study explored the correlation of peripheral blood hsCRP level with cognitive decline due to high altitude exposure. The study was conducted on 100 male military participants who had never been to high altitude. Cerebral oxygen saturation monitoring, event related potentials (P300, N200) detection, and neurocognitive assessment was performed and total hsCRP, interleukin-6 (IL 6), and homocysteine was estimated at 500 m altitude, 3650 m altitude, 3 day, 1, and 3 month post arriving at the base camp (4400 m), and 1 month after coming back to the 500 m altitude. High altitude increased brain oxygen saturation, prolonged P300 and N200 latencies, injured cognitive functions, and raised plasma hsCRP levels. But they all recovered in varying degrees at 1 and 3 month post arriving at the base camp (4400 m). P300 latencies and hsCRP levels were strongly correlated to cognitive performances. These results suggested that cognitive deterioration occurred during the acute period of exposure to high altitude and may recover probably owning to acclimatization after extended stay at high altitude. Plasma hsCRP is inversely correlated to neurological cognition and it may be a potential biomarker for the prediction of high altitude induced cognitive dysfunction. PMID- 26731741 TI - Methanol-Promoted Lipid Remodelling during Cooling Sustains Cryopreservation Survival of Chlamydomonas reinhardtii. AB - Cryogenic treatments and cryoprotective agents (CPAs) determine the survival rate of organisms that undergo cryopreservation, but their mechanisms of operation have not yet been characterised adequately. In particular, the way in which membrane lipids respond to cryogenic treatments and CPAs is unknown. We developed comparative profiles of the changes in membrane lipids among cryogenic treatments and between the CPAs dimethyl sulfoxide (DMSO) and methanol (MeOH) for the green alga Chlamydomonas reinhardtii. We found that freezing in liquid nitrogen led to a dramatic degradation of lipids, and that thawing at warm temperature (35 degrees C) induced lipid remodelling. DMSO did not protect membranes, but MeOH significantly attenuated lipid degradation. The presence of MeOH during cooling (from 25 degrees C to -55 degrees C at a rate of 1 degrees C/min) sustained the lipid composition to the extent that membrane integrity was maintained; this phenomenon accounts for successful cryopreservation. An increase in monogalactosyldiacylglycerol and a decrease in diacylglycerol were the major changes in lipid composition associated with survival rate, but there was no transformation between these lipid classes. Phospholipase D-mediated phosphatidic acid was not involved in freezing-induced lipid metabolism in C. reinhardtii. Lipid unsaturation changed, and the patterns of change depended on the cryogenic treatment. Our results provide new insights into the cryopreservation of, and the lipid metabolism in, algae. PMID- 26731742 TI - Production and Identification of Wheat-Agropyron cristatum 2P Translocation Lines. AB - Agropyron cristatum (L.) Gaertn. (2n = 28, PPPP), a wild relative of common wheat, possesses many potentially valuable traits that can be transferred to common wheat through breeding programs. The wheat-A. cristatum disomic addition and translocation lines can be used as bridge materials to introduce alien chromosomal segments to wheat. Wheat-A. cristatum 2P disomic addition line II-9-3 was highly resistant to powdery mildew and leaf rust, which was reported in our previous study. However, some translocation lines induced from II-9-3 have not been reported. In this study, some translocation lines were induced from II-9-3 by 60Co-gamma irradiation and gametocidal chromosome 2C and then identified by cytological methods. Forty-nine wheat-A. cristatum translocation lines were obtained and various translcoation types were identified by GISH (genomic in situ hybridization), such as whole-arm, segmental and intercalary translocations. Dual color FISH (fluorescent in situ hybridization) was applied to identify the wheat chromosomes involved in the translocations, and the results showed that A. cristatum 2P chromosome segments were translocated to the different wheat chromosomes, including 1A, 2A, 3A, 4A, 5A, 6A, 7A, 3B, 5B, 7B, 1D, 4D and 6D. Many different types of wheat-A. cristatum alien translocation lines would be valuable for not only identifying and cloning A. cristatum 2P-related genes and understanding the genetics and breeding effects of the translocation between A. cristatum chromosome 2P and wheat chromosomes, but also providing new germplasm resources for the wheat genetic improvement. PMID- 26731743 TI - Validation of a Cariogenic Biofilm Model to Evaluate the Effect of Fluoride on Enamel and Root Dentine Demineralization. AB - Due to gingival recession both enamel and root dentine are at risk of developing caries. Both tissues are exposed to a similar environment, however there is not a validated model to evaluate the effect of fluoride on these dental substrates simultaneously. Hence, this study aimed to validate a caries model to evaluate the effect of fluoride to prevent demineralization on enamel and root-dentine. Streptococcus mutans UA159 biofilms were formed on saliva-coated bovine enamel and root dentine slabs (n = 12 per group) mounted in the same well of culture plates. The biofilms were exposed 8*/day to 10% sucrose and treated 2*/day with fluoridated solutions containing 0, 150, 450, or 1,350 ppm F; thus, simulating the use of low to high fluoride concentration toothpastes. The pH values of the culture medium was monitored 2*/day as a biofilm acidogenicity indicator. After 96 h, biofilms were collected for fluoride concentration analysis. The percentage of surface hardness loss (%SHL) was calculated for slabs. The fluoride uptake by the enamel and dentine was also determined. The model showed a dose-response because the biofilm and fluoride uptake increased and %SHL decreased at increasing fluoride concentrations (p < 0.05). Fluoride in the biofilm formed on dentine and fluoride uptake by dentine were higher than those for enamel. With the same fluoride concentration treatment, the percentage of reduction of demineralization was lower for dentine than for enamel. In conclusion, the model was validated in terms of a dose-response effect of fluoride on enamel and root dentine. Furthermore, the findings support the clinical data, suggesting that higher fluoride concentrations are necessary to control caries of root dentine than of enamel. PMID- 26731745 TI - Platoon Interactions and Real-World Traffic Simulation and Validation Based on the LWR-IM. AB - Platoon based traffic flow models form the underlying theoretical framework in traffic simulation tools. They are essentially important in facilitating efficient performance calculation and evaluation in urban traffic networks. For this purpose, a new platoon-based macroscopic model called the LWR-IM has been developed in [1]. Preliminary analytical validation conducted previously has proven the feasibility of the model. In this paper, the LWR-IM is further enhanced with algorithms that describe platoon interactions in urban arterials. The LWR-IM and the proposed platoon interaction algorithms are implemented in the real-world class I and class II urban arterials. Another purpose of the work is to perform quantitative validation to investigate the validity and ability of the LWR-IM and its underlying algorithms to describe platoon interactions and simulate performance indices that closely resemble the real traffic situations. The quantitative validation of the LWR-IM is achieved by performing a two-sampled t-test on queues simulated by the LWR-IM and real queues observed at these real world locations. The results reveal insignificant differences of simulated queues with real queues where the p-values produced concluded that the null hypothesis cannot be rejected. Thus, the quantitative validation further proved the validity of the LWR-IM and the embedded platoon interactions algorithm for the intended purpose. PMID- 26731744 TI - Number of Children and Telomere Length in Women: A Prospective, Longitudinal Evaluation. AB - Life history theory (LHT) predicts a trade-off between reproductive effort and the pace of biological aging. Energy invested in reproduction is not available for tissue maintenance, thus having more offspring is expected to lead to accelerated senescence. Studies conducted in a variety of non-human species are consistent with this LHT prediction. Here we investigate the relationship between the number of surviving children born to a woman and telomere length (TL, a marker of cellular aging) over 13 years in a group of 75 Kaqchikel Mayan women. Contrary to LHT's prediction, women who had fewer children exhibited shorter TLs than those who had more children (p = 0.045) after controlling for TL at the onset of the 13-year study period. An "ultimate" explanation for this apparently protective effect of having more children may lay with human's cooperative breeding strategy. In a number of socio-economic and cultural contexts, having more chilren appears to be linked to an increase in social support for mothers (e.g., allomaternal care). Higher social support, has been argued to reduce the costs of further reproduction. Lower reproductive costs may make more metabolic energy available for tissue maintenance, resulting in a slower pace of cellular aging. At a "proximate" level, mechanisms involved may include the actions of the gonadal steroid estradiol, which increases dramatically during pregnancy. Estradiol is known to protect TL from the effects of oxidative stress as well as increase telomerase activity, an enzyme that maintains TL. Future research should explore the potential role of social support as well as that of estradiol and other potential biological pathways in the trade-offs between reproductive effort and the pace of cellular aging within and among human as well as in non-human populations. PMID- 26731746 TI - Osteopontin That Is Elevated in the Airways during COPD Impairs the Antibacterial Activity of Common Innate Antibiotics. AB - Bacterial infections of the respiratory tract contribute to exacerbations and disease progression in chronic obstructive pulmonary disease (COPD). There is also an increased risk of invasive pneumococcal disease in COPD. The underlying mechanisms are not fully understood but include impaired mucociliary clearance and structural remodeling of the airways. In addition, antimicrobial proteins that are constitutively expressed or induced during inflammatory conditions are an important part of the airway innate host defense. In the present study, we show that osteopontin (OPN), a multifunctional glycoprotein that is highly upregulated in the airways of COPD patients co-localizes with several antimicrobial proteins expressed in the airways. In vitro, OPN bound lactoferrin, secretory leukocyte peptidase inhibitor (SLPI), midkine, human beta defensin-3 (hBD-3), and thymic stromal lymphopoietin (TSLP) but showed low or no affinity for lysozyme and LL-37. Binding of OPN impaired the antibacterial activity against the important bacterial pathogens Streptococcus pneumoniae and Pseudomonas aeruginosa. Interestingly, OPN reduced lysozyme-induced killing of S. pneumoniae, a finding that could be explained by binding of OPN to the bacterial surface, thereby shielding the bacteria. A fragment of OPN generated by elastase of P. aeruginosa retained some inhibitory effect. Some antimicrobial proteins have additional functions. However, the muramidase-activity of lysozyme and the protease inhibitory function of SLPI were not affected by OPN. Taken together, OPN can contribute to the impairment of innate host defense by interfering with the function of antimicrobial proteins, thus increasing the vulnerability to acquire infections during COPD. PMID- 26731747 TI - Environmental Risk Factors and Amyotrophic Lateral Sclerosis: An Umbrella Review and Critical Assessment of Current Evidence from Systematic Reviews and Meta Analyses of Observational Studies. AB - BACKGROUND: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both environmental and genetic factors. Our study aimed at summarising the environmental risk factors for ALS, assessing the evidence for diverse biases, and pinpointing risk factors with high epidemiological credibility. METHODS: We searched PubMed from inception to August 20, 2015, to identify systematic reviews and meta-analyses of observational studies examining associations between environmental factors and ALS. For each meta-analysis, we estimated the summary effect size by the use of random-effects and fixed-effects models, the 95% CI, the 95% prediction interval (PI), and the between-study heterogeneity. We assessed the evidence of small-study effects and excess significance bias. RESULTS: Sixteen unique meta-analyses of different risk factors and ALS were considered. Of them, 5 were statistically significant at p < 0.001 under the random-effects model. Only one factor presented robust evidence for a convincing association. This association pertained to chronic occupational exposure to lead (random-effects OR 1.81, 95% CI 1.39-2.35). CONCLUSIONS: A small number of published meta-analyses on environmental factors and risk of ALS was identified, a phenomenon that could be attributed to the challenges in studying a rare neurological disease. More observational studies with adequate sample size and study design are needed to clarify the environmental component of ALS pathogenesis. PMID- 26731748 TI - Hypoxia Decreases Invasin-Mediated Yersinia enterocolitica Internalization into Caco-2 Cells. AB - Yersinia enterocolitica is a major cause of human yersiniosis, with enterocolitis being a typical manifestation. These bacteria can cross the intestinal mucosa, and invade eukaryotic cells by binding to host beta1 integrins, a process mediated by the bacterial effector protein invasin. This study examines the role of hypoxia on the internalization of Y. enterocolitica into intestinal epithelial cells, since the gastrointestinal tract has been shown to be physiologically deficient in oxygen levels (hypoxic), especially in cases of infection and inflammation. We show that hypoxic pre-incubation of Caco-2 cells resulted in significantly decreased bacterial internalization compared to cells grown under normoxia. This phenotype was absent after functionally blocking host beta1 integrins as well as upon infection with an invasin-deficient Y. enterocolitica strain. Furthermore, downstream phosphorylation of the focal adhesion kinase was also reduced under hypoxia after infection. In good correlation to these data, cells grown under hypoxia showed decreased protein levels of beta1 integrins at the apical cell surface whereas the total protein level of the hypoxia inducible factor (HIF-1) alpha was elevated. Furthermore, treatment of cells with the HIF-1 alpha stabilizer dimethyloxalylglycine (DMOG) also reduced invasion and decreased beta1 integrin protein levels compared to control cells, indicating a potential role for HIF-1alpha in this process. These results suggest that hypoxia decreases invasin-integrin-mediated internalization of Y. enterocolitica into intestinal epithelial cells by reducing cell surface localization of host beta1 integrins. PMID- 26731749 TI - Toward Quantitative Whole Organ Thermoacoustics With a Clinical Array Plus One Very Low-Frequency Channel Applied to Prostate Cancer Imaging. AB - Thermoacoustics has the potential to provide quantitative images of intrinsic tissue properties, most notably electrical conductivity in Siemens/meter, much as shear wave elastography provides tissue stiffness in kilopascal. Although thermoacoustic imaging with optical excitation has been commercialized for small animals, it has not yet made the transition to clinic for whole organ imaging in humans. The purpose of this work was to develop and validate specifications for a clinical ultrasound array for quantitative whole organ thermoacoustic imaging. Imaging a large organ requires exciting thermoacoustic pulses throughout the volume and broadband detection of those pulses because tomographic image reconstruction preserves frequency content. Applying the half-wavelength limit to a [Formula: see text] inclusion inside a 7.5-cm diameter organ requires measurement sensitivity to frequencies ranging from 4 MHz to 10 kHz, respectively. A dual-transducer system utilizing a P4-1 array connected to a Verasonics V1 system as well as a focused single-element transducer sensitive to lower frequencies was developed. Very high-frequency (VHF) irradiation generated thermoacoustic pulses throughout a [Formula: see text] volume. In the VHF regime, electrical conductivity drives thermoacoustic signal production. Simultaneous acquisition of thermoacoustic pulses by both transducers enabled comparison of transducer performance. Data from the clinical array generated a stack of 96 images with a separation of 0.3 mm, whereas the single-element transducer imaged only in a single plane. In-plane resolution and quantitative accuracy were quantified at isocenter. The array provided volumetric imaging capability with superior resolution whereas the single-element transducer provided superior quantitative accuracy in axial images. Combining axial images from both transducers preserved resolution of the P4-1 array and improved image contrast. Neither transducer was sensitive to frequencies below 50 kHz, resulting in a dc offset and low-frequency shading over fields of view exceeding 15 mm. Fresh human prostates were imaged ex vivo and volumetric reconstructions reveal structures rarely seen in diagnostic images. In conclusion, quantitative whole-organ thermoacoustic tomography will be feasible by sparsely interspersing transducer elements sensitive to the low end of the ultrasonic range. PMID- 26731750 TI - First evidence of transmission of an HIV-1 M/O intergroup recombinant virus. AB - OBJECTIVE: Despite the genetic divergence between HIV-1 groups M and O, HIV-1 M/O intergroup recombinants were reported. Actually, there is no data on the transmissibility of such recombinant forms. During a surveillance of HIV genetic diversity in Cameroon, we investigated the possible direct transmission of an HIV 1 M/O recombinant virus in an HIV-infected couple. METHODS: Consecutive samples obtained from the couple were analysed for detection of dual HIV-1 groups M and O infections, and HIV-1 M/O recombinant forms. Analyses were performed using a serological and molecular algorithm based on HIV serotyping and group-specific PCRs targeting the polymerase and envelope genes. Pattern characterization of the strains found in both patients was based on complete genome sequencing. Phylogenetic and similarity profile analyses were performed to investigate the genetic relationship between viruses from both spouses and the previously described recombinant forms. RESULTS: The sero-molecular algorithm data showed a group O serotype confirmed by molecular analysis in the envelope regions, whereas molecular tests identified HIV-1 group M in the polymerase. Phylogenetic analyses and similarity profiles of the full-length genome sequences showed that both spouses were infected with a unique recombinant virus having two recombination breakpoints in the vpr gene and LTR region. No phylogenetic link was found with the previous M/O recombinants. CONCLUSION: We provide, for the first time, molecular evidence of direct transmission of an HIV-1 M/O recombinant, highlighting the potential spread of these divergent viruses. The importance of HIV-1 recombination on genetic evolution and public health when implying divergent strains as group O has to be carefully considered. PMID- 26731751 TI - The presence of protective cytotoxic T lymphocytes does not correlate with shorter lifespans of productively infected cells in HIV-1 infection. AB - OBJECTIVES AND DESIGN: CD8+ cytotoxic T lymphocytes (CTL) are important in the control of HIV infection. Although CTL are thought to reduce the lifespan of productively infected cells, CD8+ T-cell depletion in simian immunodeficiency virus-infected rhesus-macaques showed no effect on the lifespan of productively infected cells. As CD8+ T-cell responses that successfully delay HIV disease progression occur only in a minority of HIV-infected individuals, we studied the hypothesis that the ability of CTL to reduce the lifespan of productively infected cells is limited to protective CTL responses only. METHODS: We correlated features of CD8+ T cells that are associated with control of HIV infection, namely restriction by protective human leukocyte antigen (HLA) alleles, and/or a broad, high or poly-functional Gag-specific CD8+ T-cell response, to the lifespan of productively infected cells in 36 HIV-infected individuals, by measuring their plasma viral load declines immediately after start of combined antiretroviral therapy. RESULTS: The average lifespan of productively HIV-infected cells varied greatly between individuals, from 1.01 to 3.68 days (median 1.82 days) but was not different between individuals with or without the protective HLA molecules B27 or B57 (P=0.76, median 1.94 and 1.79 days, respectively). Although the CD8+ T-cell response against HIV Gag was the dominant HIV-specific T-cell response, its magnitude (r=0.02, P = 0.5), breadth (r = 0.03, P = 0.4), and poly-functionality (r = 0.01, P = 0.8), did not correlate with the lifespan of productively HIV-infected cells. CONCLUSION: The features of CD8+ T-cell responses that have clearly been associated with control of HIV infection do not correlate with a reduced lifespan of productively infected cells in vivo. This suggests that protective CD8+ T cells exert their effect on target-cells before onset of productive infection, or via noncytolytic mechanisms. PMID- 26731752 TI - HIV-induced immunosuppression is associated with colonization of the proximal gut by environmental bacteria. AB - OBJECTIVES: To evaluate the impact of HIV infection on colonization resistance in the proximal gut. DESIGN: It was a case-control study. METHODS: We contrasted microbiota composition between eight HIV-1-infected patients and eight HIV negative controls to characterize community alteration and detect exogenous bacteria in the esophagus, stomach, and duodenum, as well as the mouth using a universal 16s ribosomal RNA gene survey and correlated the findings with HIV serostatus and peripheral blood T-cell counts. RESULTS: HIV infection was associated with an enrichment of Proteobacteria (P=0.020) and depletion of Firmicutes (P = 0.005) in the proximal gut. In particular, environmental species Burkholderia fungorum and Bradyrhizobium pachyrhizi colonized the duodenum of HIV patients who had abnormal blood CD4 T-cell counts but were absent in HIV-negative controls or HIV patients whose CD4 cell counts were normal. The two species coexisted and exhibited a decreasing trend proximally toward the stomach and esophagus and were virtually absent in the mouth. B. fungorum always outnumbered B. pachyrhizi in a ratio of approximately 15 to 1 regardless of the body sites (P < 0.0001, r = 0.965). Their abundance was inversely correlated with CD4 cell counts (P = 0.004) but not viral load. Overgrowth of potential opportunistic pathogens for example, Prevotella, Fusobacterium, and Ralstonia and depletion of beneficial bacteria, for example, Lactobacillus was also observed in HIV patients. CONCLUSIONS: The colonization of the duodenum by environmental bacteria reflects loss of colonization resistance in HIV infection. Their correlation with CD4 cell counts suggests that compromised immunity could be responsible for the observed invasion by exogenous microbes. PMID- 26731753 TI - Preexposure prophylaxis-selected drug resistance decays rapidly after drug cessation. AB - OBJECTIVE: Resistance to emtricitabine plus tenofovir disoproxil fumarate (FTC/TDF) or TDF alone used as preexposure prophylaxis (PrEP) has been detected in individuals who initiated PrEP during unrecognized acute HIV infection and, rarely, in PrEP breakthrough infections. PrEP-selected resistance could alter future treatment options, and therefore we sought to determine how long resistance persisted after PrEP cessation. METHODS: The Partners PrEP Study was a randomized placebo-controlled trial of FTC/TDF or TDF as PrEP for HIV prevention. We previously reported that PrEP-related mutations (K65R, K70E or M184IV) were detected by 454 sequencing following seroconversion in nine individuals who acquired HIV during the Partners PrEP Study. In the current study, we used 454 sequencing to detect and quantify PrEP-related mutations in HIV RNA-positive plasma samples prior to seroconversion, as well as in plasma from 6, 12, and 24 months after PrEP cessation from these nine individuals. RESULTS: HIV RNA positive, antibody-negative samples were available prior to seroconversion for four of nine individuals with resistance detected at seroconversion. In all four cases, K65R, K70E and M184IV were not detected prior to seroconversion, suggesting PrEP-related resistance was selected and not transmitted. All PrEP selected mutations were no longer detectable by 6 months after PrEP cessation and remained undetectable at 12 and 24 months in the absence of antiretroviral therapy. CONCLUSION: Using highly sensitive assays, PrEP-selected resistance in plasma decays below detection by 6 months following drug cessation and remains undetectable for at least 24 months. Even high levels of resistance mutations during acute infection decay rapidly in the absence of ongoing PrEP exposure. PMID- 26731754 TI - Changes in oxidized lipids drive the improvement in monocyte activation and vascular disease after statin therapy in HIV. AB - BACKGROUND: Oxidative stress plays a significant role in atherosclerosis development. HIV infection has been linked with heightened cardiovascular disease risk. HMG-CoA reductase inhibitors may reduce oxidative stress and subsequently subclinical vascular disease in HIV. DESIGN/METHODS: This is a randomized, placebo-controlled trial to evaluate the effect of rosuvastatin in HIV-infected adults on stable antiretroviral therapy with low-density lipoprotein less than 130 mg/dl and increased inflammation or T-cell activation on subclinical vascular disease. Changes over 48 weeks in oxidative stress markers, oxidized low density lipoprotein (oxLDL) and F2-isoprostane/creatinine ratio (F2-IsoP/Cr), were compared between groups. Spearman correlation and multivariable linear regression were used to evaluate relationships between changes in markers of oxidative stress, inflammation and monocyte activation and carotid intima media thickness (CIMT). RESULTS: One hundred and forty-seven adults enrolled (72 to rosuvastatin and 75 to placebo). In the rosuvastatin group, oxLDL decreased significantly over 24 weeks compared to placebo [mean absolute change in log oxLDL for rosuvastatin -0.2 +/- 0.468 log U/l (P < 0.001 within-group) vs. placebo -0.018 +/- 0.456 log U/l (P = 0.83 within-group); P = 0.004 between groups] and this change was linked with changes in soluble CD14 and proportion of patrolling monocytes (CD14dimCD16). Although oxLDL levels increased after initially declining and were not different from placebo at week 48, the early improvement in oxLDL was associated with improved CIMT at week 48. Changes in F2 IsoP/Cr were not significant between groups. CONCLUSION: Rosuvastatin decreases oxLDL levels early after initiation and is associated with decreased monocyte activation. Early improvement in oxLDL is linked with improved CIMT in treated HIV infection. PMID- 26731755 TI - Topical cidofovir to treat high-grade anal intraepithelial neoplasia in HIV infected patients: a pilot clinical trial. AB - OBJECTIVE: To evaluate the efficacy of 1% topical cidofovir cream for the treatment of anal high-grade squamous intraepithelial lesions (HSILs) in HIV infected individuals. DESIGN: Single-arm, open-label, pilot clinical trial. METHODS: The study medication was applied intraanally three times per week for 4 weeks. Lesions were assessed with high-resolution anoscopy and biopsy at weeks 12 and 24. The primary endpoint was complete remission (CR) at week 12, defined as clinical and histological remission. We also evaluated partial remission defined as regression to low-grade squamous intraepithelial lesion. RESULTS: We included 17 HIV-infected patients with intraanal HSIL. Median (interquartile range) age was 36 years (28-41), median (interquartile range) CD4 cell count was 545 cells/MUl (358-630), and viral load was less than 50 copies/ml in 93.7%. Two patients were lost to follow-up, one of them did not apply treatment. At 12 weeks, in the intention-to-treat population, 10 out of 16 patients [62.5%; 95% confidence interval (CI), 38.2-85.7%] had achieved CR. At 24 weeks, seven of the 10 patients (70%; 95% CI, 47-93%) remained in CR, but two out of 10 patients (20%; 95% CI, 0-40%) presented HSIL. One patient did not attend the visit at 24 weeks. Three patients with persistent HSIL at 12 weeks improved at 24 weeks (partial response in one and CR in two). The mean number of human papillomavirus genotypes decreased from 5.2 to 2.7 at 12 weeks (P = 0.002). Local adverse effects were frequent (81%), although there were no discontinuations because of adverse events. CONCLUSION: One percent topical cidofovir could be an appropriate alternative therapy in HIV-infected patients with anal HSIL. CLINICAL TRIAL: gov unique identifier: NCT01946009. PMID- 26731756 TI - Successful sofosbuvir-based therapy in HIV/hepatitis C virus coinfected liver transplant recipients with recurrent hepatitis C virus infection. AB - OBJECTIVE: Recurrent hepatitis C virus (HCV) infection contributes to unfavourable outcomes in HIV/HCV coinfected liver transplant recipients. Direct acting antiviral (DAA) therapies for HCV offer an opportunity to improve patient and allograft survival in this patient population. We evaluated treatment outcomes with sofosbuvir (SOF)-based DAA therapy among HIV/HCV coinfected liver transplant recipients. DESIGN: Single centre prospective cohort study. METHODS: We identified eight HIV/HCV coinfected liver transplant recipients who were prospectively followed in the Northwestern University Viral Hepatitis Registry and who received SOF-based DAA therapy. We evaluated responses to therapy, including sustained HCV viral response 12 weeks after therapy completion (SVR12) and adverse effects. RESULTS: Seven recipients (87.5%) completed 12 weeks of SOF based therapy: SOF/simeprevir for genotype 1 (n = 6), SOF/ribavirin for genotype 2 (n = 1). Of persons who completed therapy, all achieved SVR12. Strategies for the management of expected and observed drug interactions consequent to the addition of simeprevir to preexisting complex medication regimens included modifications of HIV antiretroviral regimens (n = 4) and tacrolimus dosing (n = 4) and frequent monitoring of tacrolimus trough levels. Minor adverse effects were observed after DAA initiation. One episode of allograft rejection and one death occurred that were deemed unlikely related to HCV therapy. CONCLUSION: High rates of HCV treatment success and no treatment-limiting adverse effects were observed in this HIV/HCV liver transplant cohort. Complex drug interactions were successfully managed in the context of multidisciplinary specialty care. Further studies are needed to assess the long-term effects of DAA therapy on patient and allograft survival among HIV/HCV coinfected liver transplant recipients. PMID- 26731757 TI - Improvements in the continuum of HIV care in an inner-city emergency department. AB - OBJECTIVE: The Johns Hopkins Hospital Emergency Department has served as a window on the HIV epidemic for 25 years, and as a pioneer in emergency department-based screening/linkage-to-care (LTC) programs. We document changes in the burden of HIV and HIV care metrics to the evolving HIV epidemic in inner-city Baltimore. DESIGN/METHODS: We analyzed seven serosurveys conducted on 18 ,144 adult Johns Hopkins Hospital Emergency Department patients between 1987 and 2013 as well as our HIV-screening/LTC program (2007, 2013) for trends in HIV prevalence, cross sectional annual incidence estimates, undiagnosed HIV, LTC, antiretrovirals treatment, and viral suppression. RESULTS: HIV prevalence in 1987 was 5.2%, peaked at more than 11% from 1992 to 2003 and declined to 5.6% in 2013. Seroprevalence was highest for black men (initial 8.0%, peak 20.0%, last 9.9%) and lowest for white women. Among HIV-positive individuals, proportion of undiagnosed infection was 77% in 1987, 28% in 1992, and 12% by 2013 (P < 0.001). Cross-sectional annual HIV incidence estimates declined from 2.28% in 2001 to 0.16% in 2013. Thirty-day LTC improved from 32% (2007) to 72% (2013). In 2013, 80% of HIV-positive individuals had antiretrovirals ARVs detected in sera, markedly increased from 2007 (27%) (P < 0.001). Proportion of HIV-positive individuals with viral suppression (<400 copies/ml) increased from 23% (2001) to 59% (2013) (P < 0.001). CONCLUSION: Emergency department-based HIV testing has evolved from describing the local epidemic to a strategic interventional role, serving as a model for early HIV detection and LTC. Our contribution to community based HIV-screening and LTC program parallels declines in undiagnosed HIV infection and incidence, and increases in antiretroviral use with associated viral suppression in the community. PMID- 26731758 TI - Antiretroviral exposure during pregnancy and adverse outcomes in HIV-exposed uninfected infants and children using a trigger-based design. AB - OBJECTIVE: To evaluate the safety of in-utero antiretroviral exposure in children born to mothers with HIV, using a trigger-based design. DESIGN: The Surveillance Monitoring of ART Toxicities Study is a prospective cohort study conducted at 22 US sites to evaluate safety of in-utero antiretroviral drug exposure in HIV uninfected children born to HIV-infected mothers. Children meeting predefined clinical or laboratory thresholds have more intensive evaluations to determine whether they meet criteria for adverse events. METHODS: Adverse event "cases" were defined for the following domains: growth, hearing, language, neurology, neurodevelopment, metabolic, hematologic/clinical chemistry and blood lactate. We used adjusted log-binomial models to calculate relative risks (RR) of case status overall and within individual domains for various antiretroviral exposures during pregnancy. RESULTS: Among 2680 youth enrolled between 2007 and 2012 (48% female, 66% black, 33% Hispanic), 48% met a trigger and 25% were defined as a case in at least one domain. Language (13.2%) and metabolic (11.4%) cases were most common. After adjustment for birth cohort and other factors, there was no association of any antiretroviral regimen, drug class, or individual drug with meeting overall case criteria (case in any domain). Within individual domains, zidovudine (74% exposed) was associated with increased risk of metabolic case [RR = 1.69, 95%confidence interval (CI) 1.08-2.64] and didanosine plus stavudine (<1% exposed) with increased risk of both neurodevelopmental (RR = 12.40, 95%CI 5.29 29.08) and language (RR = 4.84, 95%CI 1.14-20.51) cases. CONCLUSION: Our findings support current recommendations for combination antiretroviral therapy during pregnancy, although higher risk of metabolic disorder with zidovudine exposure warrants further study. PMID- 26731759 TI - The evolving contribution of emergency department testing studies: from risk to care. PMID- 26731760 TI - The importance of masculinity and gender norms for understanding institutional responses to HIV testing and treatment strategies. PMID- 26731761 TI - Prioritizing strategies to reduce AIDS-related mortality for men in sub-Saharan Africa: authors' reply. PMID- 26731762 TI - Use of mobile phone technology to improve the quality of point-of-care testing in a low-resource setting. PMID- 26731763 TI - De Novo Assembly and Characterization of Early Embryonic Transcriptome of the Horseshoe Crab Tachypleus tridentatus. AB - The horseshoe crab Tachypleus tridentatus is a unique marine species and a potential model for marine invertebrate. Limited genomic and transcriptional data are currently available to understand the molecular mechanisms underlying the embryonic development of T. tridentatus. Here, we reported for the first time the de novo transcriptome assembly for T. tridentatus at embryonic developmental stage using Illumina RNA-seq platform. Approximate 38 million reads were obtained and further assembled into 133,212 unigenes. Sequence homology analysis against public databases revealed that 33,796 unigenes could be annotated with gene descriptions. Of the annotated unigenes, we identified a number of key components of several conserved metazoan signaling pathways (Hedgehog, Wnt, TGF-beta and Notch pathways) and other important regulatory genes involved in embryonic development. Targeted searching of Pax family genes which play critical roles in the formation of tissue and organ during embryonic development identified a complete set of Pax family genes. Moreover, the full length T. tridentatus Pax1/9a (TtPax1/9a) and Pax1/9b (TtPax1/9b) cDNA sequences were determined based on the transcriptome, demonstrating the immediate application of our database. Using quantitative real time PCR, we analyzed the expression patterns of TtPax1/9a and TtPax1/9b in different tissues of horseshoe crab. Taking advantage of Drosophila model, we further found that TtPax1/9b, but not TtPax1/9a, can partly rescue the Drosophila homolog Poxm dysfunction-caused lethality at the larval stage. Our study provides the embryonic transcriptome of T. tridentatus which could be immediately used for gene discovery and characterization, functional genomics studies in T. tridentatus. This transcriptome database will also facilitate the investigations of molecular mechanisms underlying embryonic development of T. tridentatus and other marine arthropods as well. PMID- 26731764 TI - Scleral Buckling versus Vitrectomy for Retinal Detachment Repair: Comparison of Visual Fields and Nerve Fiber Layer Thickness. AB - PURPOSE: To compare visual field loss and retinal nerve fiber layer (RNFL) defects in cases of rhegmatogenous retinal detachment (RRD) treated with scleral buckle (SB) versus pars plana vitrectomy (PPV) and C3F8 injection. METHODS: This was a prospective, comparative interventional study of 50 eyes with primary RRD, treated with PPV (25 eyes) or SB (25 eyes). All measurements took place at least 9 months following successful and uncomplicated surgical treatment. The visual field total deviation (TD) values for preoperative attached and detached areas were calculated and compared separately. The optic nerve head morphology was studied with Heidelberg retinal tomography (HRT), and the RNFL using spectral domain optical coherence tomography. RESULTS: The preoperative detached areas demonstrated more affected TD values (in dB) compared to the preoperative attached areas (-6.9 +/- 5.2 vs. -4.3 +/- 3.3 for the SB group and -9.6 +/- 5.2 vs. -7.8 +/- 5.1 for the PPV group; p = 0.001) in both groups. The preoperative attached areas of the SB group showed better TD values (calculated mean values) compared to the preoperative attached areas of the PPV group (-4.3 +/- 3.3 vs. 7.8 +/- 5.1, p = 0.007). The RNFL and HRT values showed no statistically significant difference between the two groups. CONCLUSIONS: It seems that the preoperative detached retina, despite successful reattachment, suffers permanent damage as a result of the detachment, irrespective of the method of treatment. In the PPV group, the postoperative functionality of the preoperative attached areas was detected to be worse compared to the postoperative functionality of the preoperative attached areas of the SB group. We postulate that this fact could be attributed to an additional traumatizing factor (possibly fluid-air exchange or gas injection) in patients with RRD treated with PPV. PMID- 26731765 TI - Efficient, Edge-Aware, Combined Color Quantization and Dithering. AB - In this paper, we present a novel algorithm to simultaneously accomplish color quantization and dithering of images. This is achieved by minimizing a perception based cost function, which considers pixel-wise differences between filtered versions of the quantized image and the input image. We use edge aware filters in defining the cost function to avoid mixing colors on the opposite sides of an edge. The importance of each pixel is weighted according to its saliency. To rapidly minimize the cost function, we use a modified multi-scale iterative conditional mode (ICM) algorithm, which updates one pixel a time while keeping other pixels unchanged. As ICM is a local method, careful initialization is required to prevent termination at a local minimum far from the global one. To address this problem, we initialize ICM with a palette generated by a modified median-cut method. Compared with previous approaches, our method can produce high quality results with a fewer visual artifacts but also requires significantly less computational effort. PMID- 26731766 TI - The Elicitation Interview Technique: Capturing People's Experiences of Data Representations. AB - Information visualization has become a popular tool to facilitate sense-making, discovery and communication in a large range of professional and casual contexts. However, evaluating visualizations is still a challenge. In particular, we lack techniques to help understand how visualizations are experienced by people. In this paper we discuss the potential of the Elicitation Interview technique to be applied in the context of visualization. The Elicitation Interview is a method for gathering detailed and precise accounts of human experience. We argue that it can be applied to help understand how people experience and interpret visualizations as part of exploration and data analysis processes. We describe the key characteristics of this interview technique and present a study we conducted to exemplify how it can be applied to evaluate data representations. Our study illustrates the types of insights this technique can bring to the fore, for example, evidence for deep interpretation of visual representations and the formation of interpretations and stories beyond the represented data. We discuss general visualization evaluation scenarios where the Elicitation Interview technique may be beneficial and specify what needs to be considered when applying this technique in a visualization context specifically. PMID- 26731767 TI - ThermalPlot: Visualizing Multi-Attribute Time-Series Data Using a Thermal Metaphor. AB - Multi-attribute time-series data plays a vital role in many different domains, such as economics, sensor networks, and biology. An important task when making sense of such data is to provide users with an overview to identify items that show an interesting development over time, including both absolute and relative changes in multiple attributes simultaneously. However, this is not well supported by existing visualization techniques. To address this issue, we present ThermalPlot, a visualization technique that summarizes combinations of multiple attributes over time using an items position, the most salient visual variable. More precisely, the x-position in the ThermalPlot is based on a user-defined degree-of-interest (DoI) function that combines multiple attributes over time. The y-position is determined by the relative change in the DoI value ( ?DoI) within a user-specified time window. Animating this mapping via a moving time window gives rise to circular movements of items over time-as in thermal systems. To help the user to identify important items that match user-defined temporal patterns and to increase the technique's scalability, we adapt the level of detail of the items' representation based on the DoI value. Furthermore, we present an interactive exploration environment for multi-attribute time-series data that ties together a carefully chosen set of visualizations, designed to support analysts in interacting with the ThermalPlot technique. We demonstrate the effectiveness of our technique by means of two usage scenarios that address the visual analysis of economic development data and of stock market data. PMID- 26731768 TI - Pose Estimation for Augmented Reality: A Hands-On Survey. AB - Augmented reality (AR) allows to seamlessly insert virtual objects in an image sequence. In order to accomplish this goal, it is important that synthetic elements are rendered and aligned in the scene in an accurate and visually acceptable way. The solution of this problem can be related to a pose estimation or, equivalently, a camera localization process. This paper aims at presenting a brief but almost self-contented introduction to the most important approaches dedicated to vision-based camera localization along with a survey of several extension proposed in the recent years. For most of the presented approaches, we also provide links to code of short examples. This should allow readers to easily bridge the gap between theoretical aspects and practical implementations. PMID- 26731769 TI - Tree Modeling with Real Tree-Parts Examples. AB - We introduce a 3D tree modeling technique that utilizes examples of real trees to enhance tree creation with realistic structures and fine-level details. In contrast to previous works that use smooth generalized cylinders to represent tree branches, our method generates realistic looking tree models with complex branching geometry by employing an exemplar database consisting of real-life trees reconstructed from scanned data. These trees are sliced into representative parts (denoted as tree-cuts), representing trunk logs and branching structures. In the modeling process, tree-cuts are positioned in space in an intuitive manner, serving as efficient proxies that guide the creation of the complete tree. Allometry rules are taken into account to ensure reasonable relations between adjacent branches. Realism is further enhanced by automatically transferring geometric textures from our database onto tree branches as well as by guided growing of foliage. Our results demonstrate the complexity and variety of trees that can be generated with our method within few minutes. We carry a user study to test the effectiveness of our modeling technique. PMID- 26731770 TI - What May Visualization Processes Optimize? AB - In this paper, we present an abstract model of visualization and inference processes, and describe an information-theoretic measure for optimizing such processes. In order to obtain such an abstraction, we first examined six classes of workflows in data analysis and visualization, and identified four levels of typical visualization components, namely disseminative, observational, analytical and model-developmental visualization. We noticed a common phenomenon at different levels of visualization, that is, the transformation of data spaces (referred to as alphabets) usually corresponds to the reduction of maximal entropy along a workflow. Based on this observation, we establish an information theoretic measure of cost-benefit ratio that may be used as a cost function for optimizing a data visualization process. To demonstrate the validity of this measure, we examined a number of successful visualization processes in the literature, and showed that the information-theoretic measure can mathematically explain the advantages of such processes over possible alternatives. PMID- 26731771 TI - LOPES II--Design and Evaluation of an Admittance Controlled Gait Training Robot With Shadow-Leg Approach. AB - Robotic gait training is gaining ground in rehabilitation. Room for improvement lies in reducing donning and doffing time, making training more task specific and facilitating active balance control, and by allowing movement in more degrees of freedom. Our goal was to design and evaluate a robot that incorporates these improvements. LOPES II uses an end-effector approach with parallel actuation and a minimum amount of clamps. LOPES II has eight powered degrees of freedom (hip flexion/extension, hip abduction/adduction, knee flexion/extension, pelvis forward/aft and pelvis mediolateral). All other degrees of freedom can be left free and pelvis frontal- and transversal rotation can be constrained. Furthermore arm swing is unhindered. The end-effector approach eliminates the need for exact alignment, which results in a donning time of 10-14 min for first-time training and 5-8 min for recurring training. LOPES II is admittance controlled, which allows for the control over the complete spectrum from low to high impedance. When the powered degrees of freedom are set to minimal impedance, walking in the device resembles free walking, which is an important requisite to allow task specific training. We demonstrated that LOPES II can provide sufficient support to let severely affected patients walk and that we can provide selective support to impaired aspects of gait of mildly affected patients. PMID- 26731772 TI - Use of a Portable Assistive Glove to Facilitate Rehabilitation in Stroke Survivors With Severe Hand Impairment. AB - Treatment options for stroke survivors with severe hand impairment are limited. Active task practice can be restricted by difficulty in voluntarily activating finger muscles and interference from involuntary muscle excitation. We developed a portable, actuated glove-orthosis, which could be employed to address both issues. We hypothesized that combining passive cyclical stretching (reducing motoneuronal hyperexcitability) imposed by the device with active-assisted, task oriented training (rehabilitating muscle activation) would improve upper extremity motor control and task performance post-stroke. Thirteen participants who experienced a stroke 2-6 months prior to enrollment completed 15 treatment sessions over five weeks. Each session involved cyclically stretching the long finger flexors (30 min) followed by active-assisted task-oriented movement practice (60 min). Outcome measures were completed at six intervals: three before and three after treatment initiation. Overall improvement in post-training scores was observed across all outcome measures, including the Graded Wolf Motor Function Test, Action Research Arm Test, and grip and pinch strength (p <= 0.02), except finger extension force. No significant change in spasticity was observed. Improvement in upper extremity capabilities is achievable for stroke survivors even with severe hand impairment through a novel intervention combining passive cyclical stretching and active-assisted task practice, a paradigm which could be readily incorporated into the clinic. PMID- 26731773 TI - Graphical Representation and Similarity Analysis of Protein Sequences Based on Fractal Interpolation. AB - A new graphical representation of protein sequences is introduced in this paper. Nine main physicochemical properties of amino acids were used to obtain a 2D discrete point set for protein sequences by applying principal component analysis. The fractal method was then employed to interpolate discrete points in constructing a graphical representation of protein sequences. Fractal dimension of the protein curve was used to analyze the similarity of protein sequences by comparing the distance of vectors representing segments of protein sequences. The Jeffrey's and Matusita distance was modified in the similarity comparison of protein sequences with different lengths. Nine different species from Nicotinamide adenine dinucleotide (NADH) dehydrogenase 5 (ND5) protein sequences were tested as an example to demonstrate our method. Finally, a linear correlation and significance analysis was used to compare our results with other graphical representations referring to the ClustalW result. To confirm the validity of our method, eight species in NADH dehydrogenase 6 (ND6) protein families and twenty-seven species in beta-globin protein families were also analyzed. Experimental results show that the proposed method is effective for the similarity analysis of proteins. PMID- 26731774 TI - Fully Parallel Electrical Impedance Tomography Using Code Division Multiplexing. AB - Electrical Impedance Tomography (EIT) has been dominated by the use of Time Division Multiplexing (TDM) and Frequency Division Multiplexing (FDM) as methods of achieving orthogonal injection of excitation signals. Code Division Multiplexing (CDM), presented in this paper is an alternative that eliminates temporal data inconsistencies of TDM for fast changing systems. Furthermore, this approach eliminates data inconsistencies that arise in FDM when frequency bands of current injecting electrodes are chosen over frequencies that have large changes in the imaged object's impedance. To the authors knowledge no fully functional wideband system or simulation platform using simultaneous injection of Gold codes currents has been reported. In this paper, we formulate, simulate and develop a fully functional pseudo-random (Gold) code driven EIT system with 15 excitation currents and 16 separate voltage measurement electrodes. In the work we verify the use of CDM as a multiplexing modality in simultaneous injection EIT, using a prototype system with an overall bandwidth of 15 kHz, and attainable speed of 462 frames/s using codes with a period of 31 chips. Simulations and experiments are performed using the Electrical Impedance and Diffuse Optics Reconstruction Software (EIDORS). We also propose the use of image processing on reconstructed images to establish their quality quantitatively without access to raw reconstruction data. The results of this study show that CDM can be successfully used in EIT, and gives results of similar visual quality to TDM and FDM. Achieved performance shows average position error of 3.5% and size error of 6.2%. PMID- 26731775 TI - A 6.45 MUW Self-Powered SoC With Integrated Energy-Harvesting Power Management and ULP Asymmetric Radios for Portable Biomedical Systems. AB - This paper presents a batteryless system-on-chip (SoC) that operates off energy harvested from indoor solar cells and/or thermoelectric generators (TEGs) on the body. Fabricated in a commercial 0.13 MUW process, this SoC sensing platform consists of an integrated energy harvesting and power management unit (EH-PMU) with maximum power point tracking, multiple sensing modalities, programmable core and a low power microcontroller with several hardware accelerators to enable energy-efficient digital signal processing, ultra-low-power (ULP) asymmetric radios for wireless transmission, and a 100 nW wake-up radio. The EH-PMU achieves a peak end-to-end efficiency of 75% delivering power to a 100 MUA load. In an example motion detection application, the SoC reads data from an accelerometer through SPI, processes it, and sends it over the radio. The SPI and digital processing consume only 2.27 MUW, while the integrated radio consumes 4.18 MUW when transmitting at 187.5 kbps for a total of 6.45 MUW. PMID- 26731776 TI - A Double-Side CMOS-CNT Biosensor Array With Padless Structure for Simple Bare-Die Measurements in a Medical Environment. AB - This paper presents a double-side CMOS-carbon nanotube (CNT) sensor array for simple bare-die measurements in a medical environment based on a 0.35 MUm standard CMOS process. This scheme allows robust measurements due to its inherent back-side rectifying diodes with a high latch-up resistance. In particular, instead of using pads, only two contact metal structures: a wide ring structure around the sensor area on the front side and a plate structure at the backside are used for both power and single I/O line. The back-side rectification is made possible by creating VDD and VSS through the back-side and front-side, respectively. The single I/O line is conditioned such that it doubles as either the power source or the ground, depending on whether the chip is face down or face up. A modified universal asynchronous receiver/transmitter (UART) serial communication scheme with pulse based I/O signal transmission is developed to reduce the power degradation during the signaling intervals. In addition, communication errors and I/O power dissipation for the receiver path are minimized by using level sensitive switch control and double sampling difference amplifier. In order to implement these special functions, a controller chip with a special I/O protocol is designed. Using this controller chip, issuing commands and receiving data can both be performed on a single line and the results are flexibly measured through either the backside or the front side of the chip contacts. As a result, a stable operation of under 150 mW maximum power at 2 MHz data rate can be achieved. The double-side chips with 32 * 32 and 64 * 64 sensor arrays occupy areas of 1.9 * 2.3 mm(2) and 3.7 * 3.9 mm(2), respectively. PMID- 26731778 TI - A Proposal for Local $k$ Values for $k$ -Nearest Neighbor Rule. AB - The k -nearest neighbor ( k -NN) classifier is one of the most widely used methods of classification due to several interesting features, including good generalization and easy implementation. Although simple, it is usually able to match and even outperform more sophisticated and complex methods. One of the problems with this approach is fixing the appropriate value of k . Although a good value might be obtained using cross validation, it is unlikely that the same value could be optimal for the whole space spanned by the training set. It is evident that different regions of the feature space would require different values of k due to the different distributions of prototypes. The situation of a query instance in the center of a class is very different from the situation of a query instance near the boundary between two classes. In this brief, we present a simple yet powerful approach to setting a local value of k . We associate a potentially different k to every prototype and obtain the best value of k by optimizing a criterion consisting of the local and global effects of the different k values in the neighborhood of the prototype. The proposed method has a fast training stage and the same complexity as the standard k -NN approach at the testing stage. The experiments show that this simple approach can significantly outperform the standard k -NN rule for both standard and class imbalanced problems in a large set of different problems. PMID- 26731779 TI - Adaptive Fault-Tolerant Synchronization Control of a Class of Complex Dynamical Networks With General Input Distribution Matrices and Actuator Faults. AB - This paper is concerned with the problem of adaptive fault-tolerant synchronization control of a class of complex dynamical networks (CDNs) with actuator faults and unknown coupling weights. The considered input distribution matrix is assumed to be an arbitrary matrix, instead of a unit one. Within this framework, an adaptive fault-tolerant controller is designed to achieve synchronization for the CDN. Moreover, a convex combination technique and an important graph theory result are developed, such that the rigorous convergence analysis of synchronization errors can be conducted. In particular, it is shown that the proposed fault-tolerant synchronization control approach is valid for the CDN with both time-invariant and time-varying coupling weights. Finally, two simulation examples are provided to validate the effectiveness of the theoretical results. PMID- 26731780 TI - Sampled-Data Synchronization Analysis of Markovian Neural Networks With Generally Incomplete Transition Rates. AB - This paper investigates the problem of sampled-data synchronization for Markovian neural networks with generally incomplete transition rates. Different from traditional Markovian neural networks, each transition rate can be completely unknown or only its estimate value is known in this paper. Compared with most of existing Markovian neural networks, our model is more practical because the transition rates in Markovian processes are difficult to precisely acquire due to the limitations of equipment and the influence of uncertain factors. In addition, the time-dependent Lyapunov-Krasovskii functional is proposed to synchronize drive system and response system. By applying an extended Jensen's integral inequality and Wirtinger's inequality, new delay-dependent synchronization criteria are obtained, which fully utilize the upper bound of variable sampling interval and the sawtooth structure information of varying input delay. Moreover, the desired sampled-data controllers are obtained. Finally, two examples are provided to illustrate the effectiveness of the proposed method. PMID- 26731781 TI - Predicting Drug-Target Interactions With Multi-Information Fusion. AB - Identifying potential associations between drugs and targets is a critical prerequisite for modern drug discovery and repurposing. However, predicting these associations is difficult because of the limitations of existing computational methods. Most models only consider chemical structures and protein sequences, and other models are oversimplified. Moreover, datasets used for analysis contain only true-positive interactions, and experimentally validated negative samples are unavailable. To overcome these limitations, we developed a semi-supervised based learning framework called NormMulInf through collaborative filtering theory by using labeled and unlabeled interaction information. The proposed method initially determines similarity measures, such as similarities among samples and local correlations among the labels of the samples, by integrating biological information. The similarity information is then integrated into a robust principal component analysis model, which is solved using augmented Lagrange multipliers. Experimental results on four classes of drug-target interaction networks suggest that the proposed approach can accurately classify and predict drug-target interactions. Part of the predicted interactions are reported in public databases. The proposed method can also predict possible targets for new drugs and can be used to determine whether atropine may interact with alpha1B- and beta1- adrenergic receptors. Furthermore, the developed technique identifies potential drugs for new targets and can be used to assess whether olanzapine and propiomazine may target 5HT2B. Finally, the proposed method can potentially address limitations on studies of multitarget drugs and multidrug targets. PMID- 26731782 TI - Evolutionary Dynamic Multiobjective Optimization Via Kalman Filter Prediction. AB - Evolutionary algorithms are effective in solving static multiobjective optimization problems resulting in the emergence of a number of state-of-the-art multiobjective evolutionary algorithms (MOEAs). Nevertheless, the interest in applying them to solve dynamic multiobjective optimization problems has only been tepid. Benchmark problems, appropriate performance metrics, as well as efficient algorithms are required to further the research in this field. One or more objectives may change with time in dynamic optimization problems. The optimization algorithm must be able to track the moving optima efficiently. A prediction model can learn the patterns from past experience and predict future changes. In this paper, a new dynamic MOEA using Kalman filter (KF) predictions in decision space is proposed to solve the aforementioned problems. The predictions help to guide the search toward the changed optima, thereby accelerating convergence. A scoring scheme is devised to hybridize the KF prediction with a random reinitialization method. Experimental results and performance comparisons with other state-of-the-art algorithms demonstrate that the proposed algorithm is capable of significantly improving the dynamic optimization performance. PMID- 26731783 TI - Optimal Modality Selection for Cooperative Human-Robot Task Completion. AB - Human-robot cooperation in complex environments must be fast, accurate, and resilient. This requires efficient communication channels where robots need to assimilate information using a plethora of verbal and nonverbal modalities such as hand gestures, speech, and gaze. However, even though hybrid human-robot communication frameworks and multimodal communication have been studied, a systematic methodology for designing multimodal interfaces does not exist. This paper addresses the gap by proposing a novel methodology to generate multimodal lexicons which maximizes multiple performance metrics over a wide range of communication modalities (i.e., lexicons). The metrics are obtained through a mixture of simulation and real-world experiments. The methodology is tested in a surgical setting where a robot cooperates with a surgeon to complete a mock abdominal incision and closure task by delivering surgical instruments. Experimental results show that predicted optimal lexicons significantly outperform predicted suboptimal lexicons (p <; 0.05) in all metrics validating the predictability of the methodology. The methodology is validated in two scenarios (with and without modeling the risk of a human-robot collision) and the differences in the lexicons are analyzed. PMID- 26731784 TI - Output Synchronization of Nonidentical Linear Multiagent Systems. AB - In this paper, the problem of output synchronization is investigated for the heterogeneous network with an uncertain leader. It is assumed that parameter perturbations influence the nonidentical linear agents, whose outputs are controlled to track the output of an uncertain leader. Based on the hierarchical structure of the communication graph, a novel control scheme is proposed to guarantee the output synchronization. As there exist parameter uncertainties in the models of the agents, the internal model principle is used to gain robustness versus plant parameter uncertainties. Furthermore, as the precise model of the leader is also not available, the adaptive control principle is adopted to tune the parameters in the local controllers. The developed new technique is able to simultaneously handle uncertainties in the follower parameters as well as the leader parameters. The agents in the upper layers will be treated as the exosystems of the agents in the lower layers. The local controllers are constructed in a sequential order. It is shown that the output synchronization can be achieved globally asymptotically and locally exponentially. Finally, a simulation example is given to illustrate the effectiveness and potential of the theoretic results obtained. PMID- 26731785 TI - Modeling and Analysis of Group Dynamics in Alcohol-Consumption Environments. AB - High-risk drinking is considered a major concern in public health, being the third leading preventable cause of death in the United States. Several studies have been conducted to understand the etiology of high-risk drinking and to design prevention strategies to reduce unhealthy alcohol-consumption and related problems, but there are still major gaps in identifying and investigating the key components that affect the consumption patterns during the drinking event. There is a need to develop tools for the design of methodologies to not only identify such dangerous patterns but also to determine how their dynamics impact the event. In this paper, based on current empirical evidence and observations of drinking events, we model a human group that is in an alcohol-consumption scenario as a dynamical system whose behavior is driven by the interplay between the environment, the network of interactions between the individuals, and their personal motivations and characteristics. We show how this mathematical model complements empirical research in this area by allowing us to analyze, simulate, and predict the drinking group behaviors, to improve the methodologies for field data collection, and to design interventions. Through simulations and Lyapunov stability theory, we provide a computational and mathematical analysis of the impact of the model parameters on the predicted dynamics of the drinking group at the drinking event level. Also, we show how the dynamical model can be informed using data collected in situ and to generate information that can complement the analysis. PMID- 26731786 TI - Distributed Adaptive Neural Network Output Tracking of Leader-Following High Order Stochastic Nonlinear Multiagent Systems With Unknown Dead-Zone Input. AB - This paper studies the problem of distributed output tracking consensus control for a class of high-order stochastic nonlinear multiagent systems with unknown nonlinear dead-zone under a directed graph topology. The adaptive neural networks are used to approximate the unknown nonlinear functions and a new inequality is used to deal with the completely unknown dead-zone input. Then, we design the controllers based on backstepping method and the dynamic surface control technique. It is strictly proved that the resulting closed-loop system is stable in probability in the sense of semiglobally uniform ultimate boundedness and the tracking errors between the leader and the followers approach to a small residual set based on Lyapunov stability theory. Finally, two simulation examples are presented to show the effectiveness and the advantages of the proposed techniques. PMID- 26731787 TI - Event-Triggered Schemes on Leader-Following Consensus of General Linear Multiagent Systems Under Different Topologies. AB - This paper investigates the leader-following consensus for multiagent systems with general linear dynamics by means of event-triggered scheme (ETS). We propose three types of schemes, namely, distributed ETS (distributed-ETS), centralized ETS (centralized-ETS), and clustered ETS (clustered-ETS) for different network topologies. All these schemes guarantee that all followers can track the leader eventually. It should be emphasized that all event-triggered protocols in this paper depend on local information and their executions are distributed. Moreover, it is shown that such event-triggered mechanism can significantly reduce the frequency of control's update. Further, positive inner-event time intervals are assured for those cases of distributed-ETS, centralized-ETS, and clustered-ETS. In addition, two methods are proposed to avoid continuous communication between agents for event detection. Finally, numerical examples are provided to illustrate the effectiveness of the ETSs. PMID- 26731788 TI - Minimal-Approximation-Based Decentralized Backstepping Control of Interconnected Time-Delay Systems. AB - A decentralized adaptive backstepping control design using minimal function approximators is proposed for nonlinear large-scale systems with unknown unmatched time-varying delayed interactions and unknown backlash-like hysteresis nonlinearities. Compared with existing decentralized backstepping methods, the contribution of this paper is to design a simple local control law for each subsystem, consisting of an actual control with one adaptive function approximator, without requiring the use of multiple function approximators and regardless of the order of each subsystem. The virtual controllers for each subsystem are used as intermediate signals for designing a local actual control at the last step. For each subsystem, a lumped unknown function including the unknown nonlinear terms and the hysteresis nonlinearities is derived at the last step and is estimated by one function approximator. Thus, the proposed approach only uses one function approximator to implement each local controller, while existing decentralized backstepping control methods require the number of function approximators equal to the order of each subsystem and a calculation of virtual controllers to implement each local actual controller. The stability of the total controlled closed-loop system is analyzed using the Lyapunov stability theorem. PMID- 26731789 TI - Asynchronous Filtering for Discrete-Time Fuzzy Affine Systems With Variable Quantization Density. AB - This paper is concerned with the problem of asynchronous Hinfinity filtering for a class of discrete-time Takagi-Sugeno fuzzy affine systems against time-varying signal transmission delays and measurement quantization. The asynchrony refers to the situation that the plant state and the filter state belong to different local state space regions, and the quantization density can be adjusted to satisfy different performance requirements at different time instants. By transforming the filtering error system into an input-output form consisting of two interconnected subsystems, sufficient conditions on the existence of the desired asynchronous filter are established via the scaled small gain theorem to ensure that the closed-loop system is asymptotically stable with a prescribed Hinfinity performance index with the aid of a novel piecewise Lyapunov-Krasovskii functional and the S -procedure approach. Finally, a practical example of cart pendulum with a modified model is provided to illustrate the effectiveness of the obtained theoretical results. PMID- 26731790 TI - Childhood Exposure to Ambient Air Pollutants and the Onset of Asthma: An Administrative Cohort Study in Quebec. AB - BACKGROUND: Although it is well established that air pollutants can exacerbate asthma, the link with new asthma onset in children is less clear. OBJECTIVE: We assessed the association between the onset of childhood asthma with both time of birth and time-varying exposures to outdoor air pollutants. METHOD: An open cohort of children born in the province of Quebec, Canada, was created using linked medical-administrative databases. New cases of asthma were defined as one hospital discharge with a diagnosis of asthma or two physician claims for asthma within a 2 year period. Annual ozone (O3) levels were estimated at the child's residence for all births 1999-2010, and nitrogen dioxide (NO2) levels during 1996 2006 were estimated for births on the Montreal Island. Satellite based concentrations of fine particles (PM2.5) were estimated at a 10 km * 10 km resolution and assigned to residential postal codes throughout the province (1996 2011). Hazard ratios (HRs) were assessed with Cox models for the exposure at the birth address and for the time-dependent exposure. We performed an indirect adjustment for secondhand smoke (SHS). RESULTS: We followed 1,183,865 children (7,752,083 person-years), of whom 162,752 became asthmatic. After controlling for sex and material and social deprivation, HRs for an interquartile range increase in exposure at the birth address to NO2 (5.45 ppb), O3 (3.22 ppb), and PM2.5 (6.50 MUg/m3) were 1.04 (95% CI: 1.02, 1.05), 1.11 (95% CI: 1.10, 1.12), and 1.31 (95% CI: 1.28, 1.33), respectively. Effects of O3 and PM2.5 estimated with time varying Cox models were similar to those estimated using exposure at birth, whereas the effect of NO2 was slightly stronger (HR = 1.07; 95% CI: 1.05, 1.09). CONCLUSIONS: Asthma onset in children appears to be associated with residential exposure to PM2.5, O3 and NO2. CITATION: Tetreault LF, Doucet M, Gamache P, Fournier M, Brand A, Kosatsky T, Smargiassi A. 2016. Childhood exposure to ambient air pollutants and the onset of asthma: an administrative cohort study in Quebec. Environ Health Perspect 124:1276-1282; http://dx.doi.org/10.1289/ehp.1509838. PMID- 26731792 TI - Effects of Three Oral Nutritional Supplements on Human Hydration Indices. AB - Urine color (Ucol) as a hydration assessment tool provides practicality, ease of use, and correlates moderately to strongly with urine specific gravity (Usg) and urine osmolality (Uosm). Indicative of daily fluid turnover, along with solute and urochrome excretion in 24-hr samples, Ucol may also reflect dietary composition. Thus, the purpose of this investigation was to determine the efficacy of Ucol as a hydration status biomarker after nutritional supplementation with beetroot (880 mg), vitamin C (1000 mg), and riboflavin (200 mg). Twenty males (Mean +/- SD; age, 21 +/- 2 y; body mass, 82.12 +/- 15.58 kg; height, 1.77 +/- 0.06 m) consumed a standardized breakfast and collected all urine voids on one control day (CON) and 1 day after consuming a standardized breakfast and a randomized and double-blinded supplement (SUP) over 3 weeks. Participants replicated exercise and diet for one day before CON, and throughout CON and SUP. Ucol, Usg, Uosm, and urine volume were measured in all 24-hr samples, and Ucol and Usg were measured in all single samples. Ucol was a significant predictor of single sample Usg after all supplements (p < .05). Interestingly, 24-hr Ucol was not a significant predictor of 24-h Usg and Uosm after riboflavin supplementation (p = .20, p = .21). Further, there was a significant difference between CON and SUP 24-h Ucol only after riboflavin supplementation (p < .05). In conclusion, this investigation suggests that users of the UCC (urine color chart) should consider riboflavin supplementation when classifying hydration status and use a combination of urinary biomarkers (e.g., Usg and Ucol), both acutely and over 24 hr. PMID- 26731791 TI - Genome-Wide Analysis of DNA Methylation and Fine Particulate Matter Air Pollution in Three Study Populations: KORA F3, KORA F4, and the Normative Aging Study. AB - BACKGROUND: Epidemiological studies have reported associations between particulate matter (PM) concentrations and cancer and respiratory and cardiovascular diseases. DNA methylation has been identified as a possible link but so far it has only been analyzed in candidate sites. OBJECTIVES: We studied the association between DNA methylation and short- and mid-term air pollution exposure using genome-wide data and identified potential biological pathways for additional investigation. METHODS: We collected whole blood samples from three independent studies-KORA F3 (2004-2005) and F4 (2006-2008) in Germany, and the Normative Aging Study (1999-2007) in the United States-and measured genome-wide DNA methylation proportions with the Illumina 450k BeadChip. PM concentration was measured daily at fixed monitoring stations and three different trailing averages were considered and regressed against DNA methylation: 2-day, 7-day and 28-day. Meta-analysis was performed to pool the study-specific results. RESULTS: Random effect meta-analysis revealed 12 CpG (cytosine-guanine dinucleotide) sites as associated with PM concentration (1 for 2-day average, 1 for 7-day, and 10 for 28 day) at a genome-wide Bonferroni significance level (p <= 7.5E-8); 9 out of these 12 sites expressed increased methylation. Through estimation of I2 for homogeneity assessment across the studies, 4 of these sites (annotated in NSMAF, C1orf212, MSGN1, NXN) showed p > 0.05 and I2 < 0.5: the site from the 7-day average results and 3 for the 28-day average. Applying false discovery rate, p value < 0.05 was observed in 8 and 1,819 additional CpGs at 7- and 28-day average PM2.5 exposure respectively. CONCLUSION: The PM-related CpG sites found in our study suggest novel plausible systemic pathways linking ambient PM exposure to adverse health effect through variations in DNA methylation. CITATION: Panni T, Mehta AJ, Schwartz JD, Baccarelli AA, Just AC, Wolf K, Wahl S, Cyrys J, Kunze S, Strauch K, Waldenberger M, Peters A. 2016. A genome-wide analysis of DNA methylation and fine particulate matter air pollution in three study populations: KORA F3, KORA F4, and the Normative Aging Study. Environ Health Perspect 124:983 990; http://dx.doi.org/10.1289/ehp.1509966. PMID- 26731793 TI - Case Study: Competition Nutrition Intakes During the Open Water Swimming Grand Prix Races in Elite Female Swimmer. AB - The nutritional intake of elite open water swimmers during competition is not well established, and therefore this case study aims to provide new insights by describing the feeding strategies adopted by an elite female swimmer (28 yrs; height; 1.71 m; body mass: 60 kg; body fat: 16.0%) in the FINA open water Grand Prix 2014.Seven events of varying distances (15-88 km) and durations (3-12 hrs) were included. In all events, except one, feeds were provided from support boats. Swimmer and support staff were instructed to track in detail all foods and beverages consumed during the events. Nutritional information was gathered from the packaging and dietary supplements labels and analyzed by nutrition software. Mean carbohydrate (CHO) and protein intake reached 83 +/- 5 g.h-1 and 12 +/- 8 g.h-1, respectively. Fat intake was neglected (~1 g.h-1). Mean in-race energy intake reached 394 +/- 26 kcal.h-1. Dietary supplements in the form of sport beverages and gels, containing multitransportable CHO, provided 40 +/- 4 and 49 +/- 6% of all CHO energy, respectively. Caffeine (3.6 +/- 1.8 mg.kg-1 per event) and sodium (423 +/- 16 mg.h-1) were additionally supplemented in all events. It was established that continuous intake of high doses of CHO and sodium and moderate dose of caffeine were an essential part of the feeding strategy for elite-level high intensity ultra-endurance open-water swimming races. A well scheduled and well-prepared nutrition strategy is believed to have ensured optimal individual performance during Grand Prix events. PMID- 26731794 TI - High-Resolution Ultrasound Imaging With Unified Pixel-Based Beamforming. AB - This paper describes the development and evaluation of a new beamforming strategy based on pixel-based focusing for ultrasound linear array systems. We first implement conventional pixel-based beamforming in which the transmitted wave is assumed as spherical and diverging from the centre of the transmit subaperture. This assumed wave-shape is only valid within a limited angle on each side of the beam and this restricts the number of different subaperture positions from which data can be combined to improve image quality. By analyzing the field patterns, we propose a new unified pixel-based beamforming algorithm that better adapts to the non-spherical wave-shape of the transmit beam. This approach enables us to select the best-possible signal from each transducer waveform for data superposition. In simulations and a phantom study, we show that the unified pixel based beamformer offers significant improvements in image quality compared to other delay-and-sum methods but at a higher computational cost. The new algorithm also demonstrates robust performance in a limited in vivo study. Overall, the results show that it is potentially of value in clinical applications. PMID- 26731795 TI - Erratum to "Tissue-Dependent and Spatially-Variant Positron Range Correction in 3D PET". PMID- 26731796 TI - Biomedical and Health Informatics for Diabetes. PMID- 26731797 TI - Design, Implementation, and Wide Pilot Deployment of FitForAll: An Easy to use Exergaming Platform Improving Physical Fitness and Life Quality of Senior Citizens. AB - Many platforms have emerged as response to the call for technology supporting active and healthy aging. Key requirements for any such e-health systems and any subsequent business exploitation are tailor-made design and proper evaluation. This paper presents the design, implementation, wide deployment, and evaluation of the low cost, physical exercise, and gaming (exergaming) FitForAll (FFA) platform system usability, user adherence to exercise, and efficacy are explored. The design of FFA is tailored to elderly populations, distilling literature guidelines and recommendations. The FFA architecture introduces standard physical exercise protocols in exergaming software engineering, as well as, standard physical assessment tests for augmented adaptability through adjustable exercise intensity. This opens up the way to next generation exergaming software, which may be more automatically/smartly adaptive. 116 elderly users piloted FFA five times/week, during an eight-week controlled intervention. Usability evaluation was formally conducted (SUS, SUMI questionnaires). Control group consisted of a size-matched elderly group following cognitive training. Efficacy was assessed objectively through the senior fitness (Fullerton) test, and subjectively, through WHOQoL-BREF comparisons of pre-postintervention between groups. Adherence to schedule was measured by attendance logs. The global SUMI score was 68.33+/ 5.85%, while SUS was 77.7. Good usability perception is reflected in relatively high adherence of 82% for a daily two months pilot schedule. Compared to control group, elderly using FFA improved significantly strength, flexibility, endurance, and balance while presenting a significant trend in quality of life improvements. This is the first elderly focused exergaming platform intensively evaluated with more than 100 participants. The use of formal tools makes the findings comparable to other studies and forms an elderly exergaming corpus. PMID- 26731800 TI - Identifying the Hippocratic. PMID- 26731799 TI - Chest Wall and Spinal Tuberculous Abscess. PMID- 26731801 TI - On 'Hippocratic' and 'Non-Hippocratic' Medical Writings. PMID- 26731802 TI - The Hippocratic Aphorisms in Ptolemaic and Roman Times. PMID- 26731803 TI - [Notes on the tableau of medicine and from Hippocrates to Plato]. PMID- 26731804 TI - The Treatise Affections in the Context of the Hippocratic Corpus. PMID- 26731805 TI - The Peripatetic Hippocrates and Other Monists in the Anonymus Londiniensis. PMID- 26731807 TI - Is There a 'Hippocratic' Response to the Attack on Medicine? PMID- 26731806 TI - Tracking the Hippocratic Woozle: Pseudepigrapha and the Formation of the Corpus. PMID- 26731808 TI - Perceiving the Coherence of the Perceiving Body: Is There Such a Thing as a 'Hippocratic' View on Sense Perception and Cognition? PMID- 26731809 TI - [Hippocrates] On Glands. PMID- 26731810 TI - Regimen in the Hippocratic Corpus: Diaita and Its Problems. PMID- 26731811 TI - Towards a Hippocratic Anthropology: On Ancient Medicine and the Origins of Humans. PMID- 26731812 TI - On Regimen and the Question of Medical Dreams in the Hippocratic Corpus. PMID- 26731813 TI - Teeth in the Hippocratic Corpus. PMID- 26731814 TI - Hippocratic and Aristophanic Recipes: A Comparative Study. PMID- 26731815 TI - Hippocratic and Non-Hippocratic Approaches to Lovesickness. PMID- 26731816 TI - 'According to both Hippocrates and the Truth': Hippocrates as Witness to the Truth, from Apollonius of Citium to Galen. PMID- 26731817 TI - Bodily Features in the Corpus Hippocraticum: On the Classification of Individuals into Groups. PMID- 26731818 TI - [What Hippocratic (iotapipiochirhoalphatauepsiloniotaosigma) means: the response of Galen]. PMID- 26731819 TI - Author, Argument and Exegesis: A Rhetorical Analysis of Galen's In Hippocratis de natura hominis commentaria tria. PMID- 26731820 TI - Galen on Hippocratic Physics. PMID- 26731821 TI - First the ESBLs, now the Carbapenemases: Where will it End? PMID- 26731822 TI - Treatment and Outcome of Carbapenem-Resistant Gram-Negative Bacilli Blood-Stream Infections in a Tertiary Care Hospital. AB - CONTEXT: Infections caused by carbapenem-resistant bacteria constitute a major challenge for current medical practice. OBJECTIVE: To describe treatment and outcome of carbapenem-resistant Gram-negative bacilli (GNB) blood-stream infection (BSI) caused by these organisms at a tertiary care hospital in Mumbai. METHODS: Carbapenem-resistant isolates from blood cultures were collected from January 2013 to April 2013. Identification and antimicrobial susceptibility testing were performed using Vitek 2 analyzer (Biomerieux Ltd.). Carbapenemase production was detected by modified Hodge's test (MHT). Patient's medical history, treatment and co-morbid conditions were noted. Outcomes of BSIs were evaluated. RESULTS: Forty-two isolates of carbapenem-resistant GNB isolated from BSIs were Enterobacteriaceae spp. (19), Acinetobacter baumannii (15), and Pseudomonas aeruginosa (8). Colistin had maximum in vitro activity with 97% against Enterobacteriaceae, 100% against Acinetobacter, and 100% activity against Pseudomonas aeruginosa isolates. Positivity of MHT was 92.9%. Outcome of colistin mono and combination therapy was comparable with 83% and 79%, respectively. Outcome of colistin and carbapenem combination therapy was found to be 100 percent. CONCLUSIONS: High incidences of bacteremia by carbapenem-resistant GNB including Enterobacteriaceae is a worrisome trend. Treatment options are compromised and only available option is colistin which has its own limitation. Colistin monotherapy may be non-inferior compared to combination therapy for treating BSIs caused by isolates with minimum inhibitory concentration (MIC) for colistin as <=0.5 mg/l. Combined use of the colistin and carbapenem may provide good therapeutic options for BSI caused by carbapenem-resistant GNB and warrants further investigations. PMID- 26731823 TI - Left Ventricular Diastolic Dysfunction in Primary Hypertension and its Relation with Leisure Time Physical Activity. AB - OBJECTIVE: Left ventricular diastolic dysfunction with preserved ejection fraction is associated with an increased risk of morbidity and mortality. Population-based survey studied the associations between diastolic dysfunction in primary hypertension and its association with lifestyle--as one of risk factors. Exercise prevents and prolongs the degenerative changes but whether leisure time physical activity (LTPA) is associated with similar effects is being studied here. METHODS: Total 301 patients of age 30-60 year old with essential hypertension were included in prospective observational study. Patients were classified according to their leisure time physical activity and subjected for echocardiography and color Doppler. RESULTS: Out of 301 patients, 149 (49.66%) were sedentary during leisure time, out of which 114 (76.5%) were having diastolic dysfunction and 35 (23.5%) were normal, while 104 (34.66%) were having moderate physical activity in which 66 (63%) were normal. Twenty-nine (60%) of 48 vigorously active were found to be normal. By using Fisher's exact test p-value was < 0.05. CONCLUSION: In this study, a sedentary lifestyle is found to be associated with a rapid decline of ventricular compliance. Physical activity in any form has definite protective role in prevention of degenerative changes occurring inside the body. PMID- 26731824 TI - An Open Label, Prospective, Single Centre Study to Evaluate the Efficacy and Safety of Fixed Dose Combination of Rabeprazole (Enteric-Coated, EC) 20 mg + Domperidone (Sustained Release, SR) 30 mg Capsule in Treatment of Patients with Laryngopharyngeal Reflux Disease. AB - OBJECTIVE: To evaluate the efficacy, safety and tolerability of fixed dose combination of Rabeprazole (enteric-coated, EC) 20 mg + Domperidone (sustained release, SR) 30 mg for treatment of laryngopharyngeal reflux disease (LPRD). DESIGN: A prospective, single centre, open-label, non-comparative, observational study SETTING: The study was conducted at an otolaryngology clinic in India between May 2012 and November 2012. PATIENTS: Patients (>18 yrs) with suspicious LPR-related symptoms, reflux symptom index (RSI) score >13 and reflux finding score (RFS) >7, willing to undergo rigid laryngoscopy and requiring fixed dose combination of Rabeprazole (enteric-coated, EC) 20 mg + Domperidone (sustained release, SR) 30 mg capsule treatment according to the investigator's discretion were eligible for enrolment in the study. METHODS: Fixed dose combination of Rabeprazole (enteric-coated, EC) 20 mg + Domperidone (sustained release, SR) 30 mg capsule treatment was given for a total duration of 90 days and efficacy was assessed by the change in RFS and RSI score at Day 90. The safety and tolerability of the study drug was assessed by monitoring adverse events, vital signs and physical examination. RESULTS: Overall, 50 patients were enrolled and completed the study. After 12 weeks of fixed dose combination of Rabeprazole (enteric-coated, EC) 20 mg + Domperidone (sustained release, SR) 30 mg capsule treatment there was a significant change in mean RSI scores [mean (SD) RSI: 19.18 (3.24) at baseline to 2.52 (2.31) at end of study; (p<0.0001)] as well as mean RFS score [mean (SD) RFS: 12.62 (1.48) at baseline to 0.30 (0.51) at end of study; (p<0.0001)]. No adverse event was reported by any patient during the study period. CONCLUSION: Twelve weeks of treatment with combination of fixed dose combination of Rabeprazole (enteric-coated, EC) 20 mg + Domperidone (sustained release, SR) 30 mg capsule significantly improved reflux symptoms in patients with LPR. The combination was found to be safe and well tolerated. PMID- 26731825 TI - Psychological Insulin Resistance in Patients with Type 2 Diabetes. AB - AIMS/HYPOTHESIS: To identify risk factors associated with psychological insulin resistance (PIR) in Indian type 2 diabetes (T2DM) population. METHODS: Patients with T2DM, aged 18 years, undergoing treatment with oral hypoglycaemic agents and providing written informed consent were considered eligible for the study. Patient's data was collected by face-to-face interaction using 5 validated diabetes questionnaires--Diabetes Attitude Scale, Diabetes Knowledge Test, Diabetes Self-Efficacy Scale, Interpersonal Processes of Care Survey-29, and Barriers to Insulin Treatment scale. Demographic variables, categories of patients based on their annual family income, education, glycosylated haemoglobin (HbA1c), occupation and type of healthcare setup were correlated with overall scores of validated questionnaires. Statistical analyses were performed using Pearson correlation coefficients, analysis of variance, two-group t-test and hierarchical multiple regression. RESULTS: One hundred ninty-eight patients with T2DM were enrolled where 63% were males, 52% had HbA1c <7% (<53 mmol/mol), 32% were in service, 35% had the annual family income between Rs 100,000-500,000, 50% were graduates and 81% were enrolled from private healthcare set ups. Significant high opposition to use insulin was observed in females, patients based at home, patients with insufficient education, and patients visiting government set-ups compared to males, service-class patients, graduates, and patients approaching private set-ups, respectively. CONCLUSIONS: In India, major factors contributing to PIR were fear of injection or fear of pain during injection, fear of hypoglycemia, social stigma and lack of education. Effective interpersonal interactions with healthcare providers could help to counteract PIR, especially in patients who are not sufficiently literate highlighting the need of skilled healthcare staffs in Indian public hospitals. PMID- 26731826 TI - Echocardiography in a Patient on Mechanical Ventilation. AB - Cardiopulmonary interactions or effects of spontaneous and mechanical ventilation (MV) were first documented in the year 1733. Stephen Hales showed that the blood pressure of healthy individual fell during spontaneous inspiration and he later went on to discover the ventilator. A year later Kussmaul described pulsus paradoxus (inspiratory absence of radial pulse) in patients with tubercular pericarditis. Echocardiography can help to diagnose a wide variety of cardiovascular diseases and can guide therapeutic decisions in patients on mechanical ventilation. PMID- 26731827 TI - Writing Introduction: Laying the Foundations of a Research Paper. AB - The Introduction section explains the rationale for undertaking the study and clearly describes the main purpose of conducting it. It should be focused, succinct and crisp. Providing an extensive and detailed literature review, not stating the hypothesis of the objectives with clarity and not providing focused information are some of the common mistakes that the authors should steer clear of. PMID- 26731828 TI - Herpes Zoster of Mandibular Division of Trigeminal Nerve (V3). PMID- 26731829 TI - An Interesting Case of Bilateral Lung Consolidation. AB - Organising pneumonia is a histopathological entity characterised by intra alveolar buds of granulation tissue, intermixed myofibroblasts and connective tissue. Cryptogenic organising pneumonia (COP) is characterised by this particular histopathological pattern, along with typical clinical and imaging features, when no other underlying aetiology is found. COP (previously known as bronchiolitis obliterans organising pneumonia [BOOP]) is one of the rare variants of interstitial pneumonias. This condition is characterised by a rapid clinical and radiological improvement with steroid treatment. Here we are reporting a case of COP in adult female with discussion on approach and basic pathophysiology of this type of pneumonia. PMID- 26731830 TI - A Novel Variant of Bartter's Syndrome. AB - Bartter's syndrome, a rare disorder affecting the renal tubular potassium handling, is characterized by metabolic alkalosis, hypokalemia and renal salt wasting. Here we describe a patient with Bartter's syndrome with hitherto undescribed clinical features and also discuss the various possibilities leading to such variant of Bartter's syndrome. PMID- 26731831 TI - Pulmonary Hypoplasia Wrongly Diagnosed and Treated as Pulmonary Tuberculosis. AB - Pulmonary hypoplasia (PH), a rare congenital anomaly is observed with incomplete development of the lung, and may be associated with anomalies in other body systems. The clinical presentation varies with the extent of hypoplasia and the patient may be asymptomatic or may present with severe respiratory distress in the neonatal, infancy or childhood period. A six year old girl suffering from right sided hypoplasia was hospitalized with common presenting chest symptoms. She had taken antituberculosis treatment for past three years and was thought to be an MDR suspect. The child was thoroughly investigated was diagnosed to be a case of PH and is under followup. PMID- 26731832 TI - Herpes Zoster Infection Presenting with Urinary Retention and Constipation. AB - Herpes zoster is a sporadic disease that results from the reactivation of latent Varicella zoster virus infection (VZV) from the dorsal root ganglion. We report a case of herpes zoste of lumbosacral region presenting as acute retention of urine and constipation, an uncommon presentation. PMID- 26731833 TI - Classical Cardiovascular Manifestations of Marfan Syndrome. AB - Presence of multiple cardiovascular manifestations of the Marfan syndrome in the same patient is not commonly encountered. We present a 49 year-old lady with this syndrome who presented with decompensated heart failure. Evaluation revealed presence of extensive Stanford type A aortic dissection alongwith severe aortic and mitral incompetence. However, the patient declined surgery and was discharged on medical management. At a year's follow-up, she had dyspnea of NYHA class II with persistent cardiovascular findings. PMID- 26731834 TI - Dengue Fever and Takotsubo Cardiomyopathy. AB - A young male admitted for dengue fever and systemic involvement developed ECG abnormalities on third day, in the form of prolonged QT interval and deep and symmetrical inversion of T wave. Echocardiography revealed akinesia of mid and apical segments and well contracting basal segments, typical of Takotsubo cardiomyopathy or stress cardiomyopathy. These changes were transient and echocardiography findings reverted to normal kinesis of left ventricle without any treatment or without any residual left ventricle dysfunction. PMID- 26731835 TI - Foreign Body in Left Main Bronchus. AB - Tracheobronchial foreign body (TFB) aspiration is rare in adults, although incidence rates increases with advancing age. We report a case of foreign body in left main bronchus in an adult female who had no risk factor. She was successfully treated with removal of betel nuts by bronchoscopy. Unusual presentation and high index of suspicion can help in proper management. PMID- 26731836 TI - Idiopathic Pyoderma Gangrenosum as a Novel Manifestation of the HIV Immune Reconstitution Inflammatory Syndrome: A Report of Three Cases. AB - The initiation of antiretroviral treatment for individuals with HIV may be accompanied by a paradoxical flare of underlying inflammatory diseases, the recurrence of dormant infections, or worsening of prior treated opportunistic infections, termed the immune reconstitution inflammatory syndrome (IRIS). Cutaneous manifestations of IRIS are common. Pyoderma gangrenosum is a neutrophilic dermatosis postulated to reflect disrupted innate immune regulation causing altered neutrophil chemotaxis. It is uncommonly reported in association with HIV. In this case series, we present three cases of IRIS manifesting with pyoderma gangrenosum in individuals with HIV from India and the United States to raise awareness of this previously undescribed presentation and discuss the treatment challenges in the management of these patients. PMID- 26731837 TI - Rethinking the Postgraduate Teaching Program and Examinations in Today's India. AB - Postgraduate medical education has undergone drastic changes in the developed and developing countries on par with advancements in technology. The Indian examination system which we imbibed from the British requires a rethinking and restructuring to keep pace with the changing trends shown by the Federation of the Royal Colleges of UK. In this manuscript we look at the strengths and weaknesses of different examination systems. We suggest changes in the theory examination which should be objectively based rather than the outdated essay and short notes. We discuss positive and proactive changes to reform our clinical examination system to enable a just and fair assessment of the candidate in a strictly time bound fashion. PMID- 26731838 TI - Fondaparinux in Acute Coronary Syndromes. AB - Anticoagulant therapy is a major component in the management of acute coronary syndromes (ACS). Anticoagulant-associated adverse events like heparin-induced thrombocytopenia, bleeding complications and need of close monitoring of anticoagulation led to focus on developing agents causing anticoagulation without affecting primary haemostasis. Fondaparinux, a new-age synthetic anticoagulant, acts by inhibiting factor Xa. It is simple to administer and has low inter and intra-subject variability. Moreover, there is no risk of significant drug interactions and no need for monitoring the platelet count. Efficacy of fondaparinux has been studied in various disorders including prevention of venous thromboembolism in major orthopaedic surgery, abdominal surgery and acutely ill medical patients, treatment of venous thromboembolism, non-ST-elevation acute coronary syndromes and ST-elevation acute myocardial infarction. This article covers the review of fondaparinux and its practical advantages mainly in the management of ACS including non-ST-elevation acute coronary syndromes and ST elevation acute myocardial infarction. PMID- 26731839 TI - Introduction to the Series. PMID- 26731840 TI - Pioneers in Conventional and Molecular Diagnosis. PMID- 26731841 TI - Splenic Infarction in Polycythemia Vera: Can the Spleen be Saved? PMID- 26731842 TI - Successful Management of Highly Drug-Resistant Tuberculosis with Individualized Drug Susceptibility Testing. PMID- 26731843 TI - [Increased medical knowledge through and for the MMP]. PMID- 26731844 TI - [Essential oils and their influence on the actions of drugs: some examples]. AB - There is a general belief that herbal products, thus essential oils too, are safe because they are natural. Together with the increased appearance of common and self-initiative usage of herbal preparations there is also an increased need of knowing and understanding possible interactions with concomitantly taken drugs. Since essential oils are mixtures of multiple active volatile compounds it is very likely for essential oils and especially their constituents also to interact with drugs. The presented treatise will reveal some of such interactions. Most of them are pharmacokinetic ones, while pharmacodynamic interactions seem to be less studied. While some of these interactions may have a negligible impact on the effect of drugs--and it was the aim of this paper to demonstrate the impact of volatile oils on the effect of drugs when applied together--other mutual effects may be rather harmful. Under certain circumstances it could be possible to use the effects of these interactions also for the benefit of the patients, but further clinical investigations are needed. PMID- 26731845 TI - [Safety of folic acid]. AB - Improving dietary folate intake is a central public health goal. However, critical voices have become louder warning of too high intake of folic acid. Safety concerns of a high folic acid exposure are usually limited to synthetic folic acid contained in drugs and food supplements. Against this background, the present article focuses on two matters: (a) How do the absorption and metabolism of synthetic folic acid differ from that of other folates? (b) How has the longterm safety of folic acid to be judged, especially regarding the risk of colorectal cancer, autism, asthma, impaired immune defence, masking vitamin B12 deficiency and interactions with the methotrexate metabolism? PMID- 26731846 TI - [Clinical guidelines--helpful recommendations or biased documents?]. AB - Pharmacists have to know the recommendations of clinical guidelines. In a best case scenario, clinical guidelines are helpful documents which summarise the current knowledge for the diagnosis and treatment of a defined disease. But pharmacists have to make sure that the recommendations are not biased. Therefore, critical appraisal of clinical guidelines is necessary. PMID- 26731847 TI - [Guidelines from a legal perspective. How authentic are they under freedom of therapy and treatment errors? (BGH-review)]. PMID- 26731848 TI - [Can Menthol be used during pregnancy for example, as a tea, inhalation or rub?]. PMID- 26731849 TI - [On the life of a journal]. PMID- 26731850 TI - [Direct antiviral substances. New drugs for the treatment of chronic hepatitis C]. PMID- 26731851 TI - [Current management of hepatitis C]. AB - During the last decade, the therapeutic management of hepatitis C virus (HCV) infection has changed dramatically. Due to the recent approval of several directly acting antiviral agents (DAAs) such as sofosbuvir, daclatasvir, or ledipasvir, HCV eradication is possible in the vast majority of HCV infected individuals by DAA combinations with or without pegylated interferon-alpha. This review summarized these exciting developments with a focus on current recommendations for the treatment of chronic hepatitis C. PMID- 26731852 TI - [Costs of modern treatment of chronic hepatitis C]. PMID- 26731853 TI - [Instructions for aggregated evidence: Systematic reviews and meta-analyses (part 1)]. AB - High-quality, up-to-date, systematic reviews comprehensively summarize the evidence from clinical studies for a focused clinical question. A meta-analyses is a quantitative summary of results from individual studies and often part of a systematic review. Important features of a systematic review are a focused research question, a comprehensive, reproducible search for primary studies, selection of studies using clear and transparent eligibility criteria, and a standardized critical appraisal of the methodological quality of included studies. PMID- 26731854 TI - [Oral anticoagulants 2.0]. PMID- 26731855 TI - [Novel oral anticoagulants--issues in clinical practice]. AB - The novel oral anticoagulants (NOAC) dabigatran, apixaban, edoxaban and rivaroxaban target either thrombin or factor Xa for the prevention and treatment of thrombosis. A short introduction of the main indications for an oral anticoagulation is followed by the pharmacology of each drug, their effectiveness, selected drug-drug interactions and adverse drug events, especially bleeding. The article represents clinical aspects for the perioperative management, the possibilities for monitoring of each drug, the application in patients with renal impairment as well as different advantages and disadvantages. PMID- 26731856 TI - [Management of bleeding complications associated with NOAC]. AB - New oral anticoagulant drugs (NOAC) represent a promising alternative to the classical anticoagulant therapy with vitamin K antagonists like phenprocoumon or warfarin. Meanwhile, these substances are well implemented in the management of several indications with elevated thromboembolic risk, e.g. atrial fibrillation. Nevertheless, it is not easy to use these substances and even in the phase III studies side effects of significant bleeding occurred. Thus, patients should be closely monitored for signs of bleeding or anaemia. In the clinical setting, the therapists meet the challenge to primarily ensure a sufficient anticoagulation but to concomitantly avoid any occurrence of a serious bleeding complication. However, this optimum is not reached in many cases: Patients frequently present with relevant bleeding or a serious bleeding occurs in surgery. This article presents a short overview of possible actions to manage such a bleeding complication. PMID- 26731857 TI - [Pharmaceutical care of a patient with oral anticoagulation and renal impairment]. AB - Atrial fibrillation is one of the most important indications for oral anticoagulation. Besides vitamin K antagonists, the novel oral anticoagulants dabigatran, apixaban, edoxaban and rivaroxaban are one therapy option in patients with atrial fibrillation. The following case report describes an 83-year-old female patient treated with dabigatran for secondary stroke prevention. Due to different factors, the renal function of the patient decreases significantly (acute on chronic renal failure), resulting in a re-evaluation of the current treatment. This case report is an example of decision-making 'for and against' novel oral anticoagulants versus vitamin K antagonists. PMID- 26731858 TI - [Instructions for aggregated evidence: About reviews, systematic reviews and meta analyses (part 2)]. AB - Valid systematic reviews are essential for a safe navigation through the existing literature on a specific clinical topic. In the second part of our training to "Reviews, systematic reviews and meta-analyses", we explain how the results of systematic reviews and meta-analyses should be presented and how they should be interpreted. We describe the forest plot, with which you can get a quick overview of the results of numerous studies, the funnel plot, which can be useful for identifying a publication bias, and report on sensitivity and subgroup analyses, which are of great importance to discover the source of heterogeneity between individual studies. Finally, at the end of our article series, we hopefully convinced you of the importance to make up your own mind about the interpretation of the results of aggregated evidence. PMID- 26731859 TI - ["Choosing wisely" in Germany]. AB - The campain "Choosing wisely" aims to reduce unnecessary tests and treatments which might harm patients. The Association of the Scientific Medical Societies in Germany is developing an adoption of the main principles to implement a similar project in Germany. PMID- 26731860 TI - [Topical budesonide for the intestines approved]. PMID- 26731861 TI - [Evaluation studies of "Pro-health Programme for 2013-2016" implemented in State Higher Vocational School in Suwalki]. AB - INTRODUCTION: Evaluation studies (evaluation) is an act of gathering, analyzing and assessing the data in order to supply knowledge necessary to take decisions about future actions. It is a process of systemic gathering of information on personnel, products as well as workings, characteristics and results of programmes. It is a systematized study, observation and interpretation of the data. The aim of the evaluation of Pro-health Programme implemented in State Higher Vocational School of Suwalki has been the assessment of students' attitudes and behaviours following the introduction of the programme. What we have been interested is whether the students got involved in the implementation of the programme and the manner in which activites conducted within the framework of the project have changed their lifestyle. These activities should be correlated with the students' participation in evaluation studies that make it possible to correct errors arising in the course of implementation of the pro health programme and to diagnose problems as well as search for solutions adequately adjusted to the encountered ambiguities. MATERIAL AND THE METHODS: In the academic year 2013/2014 in prof. E. Szczepanik State Higher Vocational School of Suwalki an authorial survey reasearch on pro-health attitudes of students of selected medical fields of study. They were planned as long-standing activities (2013-2016) aimed at verification of students' pro-health attitudes in the researched higher education institute. As essential role of evaluation studies, forecasting long-term effects and intended or unintended outcomes that transcend the time and site of the implementation of the programme were the reasons for undertaking the studies described hereinbelow. RESULTS: Less than half of the researched students is of the opinion that the pro-health programme implemented in State Higher Vocational School fulfils its objectives. Moreover, an overwhelming majority of the respondents think that tasks implemented within the framework of the pro-health programme have had an influence on shaping their pro health awareness. CONCLUSIONS: 1. Evaluation of pro-health awareness should lead to changes in pro-health attitudes of the surveyed population. 2. Both the experience gained during the health improving activities and the student evaluation questionnaire analysis should lead to strengthening the main motivating factors that promote health improving. PMID- 26731862 TI - Levels of exhaled carbon monoxide in healthy active and passive smokers. AB - BACKGROUND: Cigarette smoke is the major and most common indoor source of carbon monoxide. CO combines with haemoglobin to form carboxyhaemoglobin (COHb) which hinders oxygen transport and causes myocardial infarction and coronary heart disease. CO damages the endothelium of large and medium arteries and contributes to the development of atherosclerosis. MATERIAL AND METHOD: Participants in the study included 148 active and 306 passive smokers. In both groups the largest proportion of respondents were aged 30-49. Numbers of male and female participants were identical among the active smokers, while the majority of the passive smokers were women. Majority of the participants in both groups lived in large towns (over 100,000 inhabitants). The levels of exhaled CO were measured with Micro+smokerlyzer distributed in Poland by Synecpol. Every participant was provided with relevant instructions and the test was conducted by trained researchers. RESULTS: The mean level of exhaled carbon monoxide in active smokers was 12.57 ppm with higher levels found in men. The highest mean level of eCO was found in participants with body weight between 60 kg and 80 kg (mean eCO = 13.39 ppm). The highest levels were observed in participants living in towns with 51,000-100,000 inhabitants. In passive smokers, the mean level of exhaled carbon monoxide was 3.55 +/- 1.26 ppm with higher levels found in men. CONCLUSIONS: For non-smokers, the study identified a significant relationship between the level of exhaled CO and the participants' gender (p < 0.05), weight (p = 0.003), and height (p = 0.0005). For smokers, there is a relationship between the level of eCO and the daily cigarette consumption (p = 0.01), the type of cigarettes most frequently smoked (p < 0.05) and the favoured cigarette brand (p = 0.005). PMID- 26731863 TI - [Tobacco smoking as a cofactor for the development of cervical cancer]. AB - Etiopathogenesis of cervical cancer is mainly related to persistent HPV infection. However in neoplastic transformation participate additional factors, one of the main is tobacco smoking. Nowadays, in Poland is conduced prophylactic program with the target to decrease incidence and mortality according to cervical cancer. The basis of this program is Pap smears, histological diagnostics and colposcopy. AIM OF STUDY: The aim of this paper was evaluation of correlation between histopatological changes uterin cervix in respect of tobacco smoking and immunohistochemistry LI capsid protein test. MATERIAL AND METHODS: From 3520 patients with incorrect Pap smears selected 36 cases (medium age 36) with incorrect Pap smears and histology. Used immunohistochemical methods (with HRP system) for evaluation of L1 protein. RESULTS: In group with positive L1 test significant part were smokers and those who quite smoking. The results revealed directly relate between cigarette. PMID- 26731864 TI - [Influence of dietary supplementation on newborn weight]. AB - The usage of multivitamin supplements for expectant mothers ought to always consult with a physician responsible for an expectant mother. Dietary supplements ought to be good chose to individual needs so that it can in an optimal way aid the health of an expectant mother and the progress of baby. The specialist literature and my ones researches show that a supplementary diet with multivitamin supplements and preparations with a folic acid in pregnancy can affect the mass of a neonate and increaser it. One should considers the implementation of multivitamin supplements by women from a risk group of the disorder development of an embryo. It should be mentioned that not only complications as a result of too low body mass of a neonate but also too high body mass can redound to many irregularities and disorders during a pregnancy. To them we can include a higher rate of caesareans and an increase in a perinatal mortality of neonates. So that is way the decision of including a supplementary diet should be made very carefully and individually for every patient. The aim of carried out researches was estimation the influence of supplementary diet on the body mass of a neonate. One hundred respondents were covered by the research--the patients of "Maternity and Gynaecology Ward" with the obstetric, perinatology and reproduction ward in the Voivodship Hospital in Poznan. My own researches show that the most important source of knowledge about a diet during a pregnancy is a gynaecologist, the Internet and families of surveyed women. Most of surveyed persons know that a diet has got an impact on a growing up embryo and they consider that a diet should be supplementary. It was noticed both side effects and positive effects of supplementary diet with multivitamin supplements. The key issue of my thesis is the fact that taken a folic acid before getting pregnant and a regular supplementary diet with multivitamin supplements for pregnants increases the chance of a higher body mass of a neonate and the diet is supplementary faster in a pregnancy the body mass of a neonate is higher. PMID- 26731865 TI - [Analysis of the problem of addiction in the elderly]. AB - Demographic changes observed in recent decades around the world lead to the aging of societies at a rapid rate. The increasing number of elder people is a result of extending the average length of human life. Elder people are struggling with many problems--loneli- ness, disability or financial problems. The problem can also be addiction, usually suspected in young people. The aim of the study was to evaluate the prevalence of addiction--smoking, drinking alcohol, use of medicines and drugs, watching television or using the Internet--in the elderly. Additional objective was to assess the problem of sleep disorders and the purchase of OTC drugs, dietary supplements and vitamin preparations in this population. Examined group consisted of 104 people aged over 65 years, of whom only 23 were smokers and 86 were consumers of various alcohols. None of the respondents confirmed any contact with drugs and the use of addiction treatment. Only 4 respondents did not watch any TV programs and 37 did not use the Internet (nor themselves nor with the help of others). 94 respondents used drugs and non-prescription preparations. 57 responders did not experienced sleep disorders. PMID- 26731866 TI - [Smoking among 15-year-olds in Poland depending on selected sociodemographic factors--trends 2006-2014]. AB - International HBSC (Health Behavior in School-aged Children) studies provide an unique opportunity to monitor trends in health behaviours. The purpose of the present study is to describe current trends in the prevalence and determinants of daily smoking among Polish adolescents. Materials and methods: Analyses were based on data from the samples of 15-year-olds who participated in the HBSC study in 2005/2006, 2009/2010 and 2013/2014 (total N = 5722). A dichotomous variable was created, representing daily smoking. Family socioeconomic status was described by a subjective indicator (PFW--perceived family well-off) and neighborhood well-off Daily smoking rates decreased in 2006-2014, however gender influenced. An upward trend was observed in girls. Gender convergence in smoking was due to coexisting increase of rates in girls and decrease in boys. Based on the data from the combined sample, daily smoking was more prevalent in poor families and in regions with more local problems, which applied both to boys and girls. An increase risk of smoking in rich families was observed only in 2006. In the last survey only local area status remained in the final model. Conclusions: Preliminary results of the new HBSC study conducted in Poland suggest unfavorable trends in tobacco smoking mostly in adolescent girls. It is worth to pay attention to the environmental aspects of smoking in adolescence and to analyze both the impact of family and neighborhood well-off. PMID- 26731867 TI - [The results of treatment of gastric cancer in the Provincial Hospital in Zielona Gora]. AB - INTRODUCTION: Gastric cancer is the third leading cause of death from cancer worldwide in both sexes, following lung and breast cancer. The incidence of gastric cancer in Poland is approximately 5% in men and approximately 2.5% in women, among the complete incidence of cancers. Deaths from gastric cancer in men in Poland in 2009 amounted to 6.6%, while in women--4.6%. The highest mortality rate in men is observed in the Lubuskie, Podkarpackie, Slaskie and Opolskie provinces. European average 5-year survival in the EUROCARE-4 study is 24.5%. AIM: The aim of this paper was to assess the treatment of gastric cancer in the Department of General and Oncological Surgery of the Provincial Hospital in Zielona Gora. MATERIALS AND METHODS: The retrospective analysis of 109 patients with gastric cancer, operated in the years 2003-2007, was performed. The analysis included patients scheduled for admission with the histopathological confirmation of adenocarcinoma, prepared to and subjected to laparotomy. The post-operative intrahospital deaths were estimated up to 30 days after surgery. The analysis of the survival rates was performed up to 1, 6, 12, 36 and 60 months since lapatoromy. All the continuous variables with the standard distribution were expressed as the mean +/- standard deviation, while the total survival rates were assessed by means of the Kaplan-Meier method. RESULTS: 55 patients (50.5%) underwent the radical surgical procedure intended to cure them. The remaining 54 patients (49.5%) could not be qualified for the radical surgical procedures. In 35 cases (32%) underwent laparotomy with biopsy, in 19 cases (17%) palliative surgery (intestinal bypass, gastrostomy, palliative resection). Out of 55 patients underwent the radical surgical procedure 9 patients died after the procedure (16.4%). The survival rates calculated for all the patients revealed that 21.1% patients survived 5 years after the surgery. CONCLUSIONS: Almost a half of the patients (49.5%) who were admitted for treatment had an advanced stage of the disease that could not be qualified for the radical surgical procedures. The distant results of surgical treatment are non-satisfactory due to the fact that the disease was so advanced. 5-year-long survival rates (21.1% in our data) are higher that the ones listed in the EUROCARE-4 test for Poland (14.4%), but lower than the European average (24.5%). PMID- 26731868 TI - Teeth whitening versus the influence of extrinsic factors on teeth stains. AB - The improvement of teeth colour is the effect of using whitening toothpastes, professional removal of dental deposits, pulpless teeth and vital teeth whitening. The aim of the study was evaluation of various methods of teeth whitening in relation to sex and age of the investigated as well as the extrinsic factors causing teeth stains such as cigarette smoking, consumption of coffee and tea. Questionnaire survey was conducted in the group of 204 patients, reporting for a dental treatment at the Chair and Department of Conservative Dentistry with Endodontics of the Medical University of Lublin as well as private dental practice in Lublin. Questionnaire survey was elaborated for the needs of the planned investigation and included questions concerning, among others, socio demographic data of the investigated, methods of teeth whitening, cigarette smoking, consumption of coffee and tea. Statistic analysis was performed with the use of descriptive statistics, Chi2 test, Mann-Whitney test. The values of p < 0.05 were considered statistically essential. Women used whitening toothpastes more frequently in comparison with men (chi2 = 7.96, p < 0.01). People who declared drinking at least one coffee cup used whitening toothpastes more frequently in comparison with the people drinking coffee occasionally and those who didn't drink it (chi2 = 9.99, p < chi0.05). PMID- 26731869 TI - [Effects of active and passive smoking during pregnancy on the development of gestational hypertension and fetal hypotrophy]. AB - In prenatal life the fetus can be exposed to more incentires which affect the mother. In case of both active and passive smoking by pregnant women many pernicious substances contained in tobacco smoke can influence the foetus. The components of tobacco smoke can contribute to various antenatal complications. The aim of present work was to assess if the data given by the patient in anonymous questionnaire go along with the real exposure to components of smoke assessed on the basis of concentration of nicotine metabolite- cotinine in mother's serum and next to assess the risk of development of gestational hypertension and hypotrophy. The biological material was extracted with means of liquid-liquid technique and next we performed laboratory determinations with means of liquid chro- matography with sectrophotometric detection, in which norephedrine is used as inner sample. The study was carried out on 106 women in perinatal period who give birth from single, full term pregnancy. On the basis of questionnaire data considering the concentration of cotinine, the patients were divided into three groups: I group--active smokers (n = 27), II group--passive smokers (n = 32), III group--not exposed to tobacco smoke (n = 41). The average concentration of cotinine in blood serum in the first group was 129.6 ng/ml, second group--5.1 ng/ ml, but in all patients from the control group the concentration of cotinine was below the detection level. Gestational hypertension was diagnosed in 17 women (16%) and hypotrophy of the foetus was diagnosed in 15 patients (14%). Tobacco smoking didn't influence the development of gestational hypertension and hypotrophy showered it is more often observed in women exposed to components of tobacco smoke during pregnancy. PMID- 26731870 TI - [Structure of poison xenobiotic based on results of toxicological analysis from Toxicological Laboratory in Krakow in years 2003 and 2013]. AB - The aim of the study was to present changes in structure of toxicological analysis performed for hospitals in south-east Poland in last decennium. Material for the study were data from Toxicological Laboratory in Krakow in years 2003 and 2013. Total number of toxicological analysis decreased by about 30% in the period. The decline was related to analysis of ethanol, drugs of abuse (amphetamines, opiates, THC) and medicines. The number of determinations of acetylocholinoesterase activity (AChE)--marker of exposition to organophosphate and carbamate pesticides and carboxyhemoglobin (COHb)--marker of exposition to carbon monoxide also declined. The number of analysis of toxic alcohols (methanol and ethylene glycol) raised. The demand for determinations of new toxic substances (new drugs of abuse, "spices") appeared in the studied period. Advanced analytical methods (gas chromatography (GC), high performance liquid chromatography (HPLC), atomic absorption spectrometry (AAS) came into use in day to-day routine. Changes in structure and numbers of determinations performed in regional toxicology laboratory reflects different trends. Prevalence of rapid tests for determination of drugs of abuse and alcohol in general medical laboratories caused decrease of number of the analysis in specialized toxicology laboratory. On the other hand growing demand for specialized analysis: new drugs of abuse, spices, new drugs, toxic alcohols and heavy metals was observed in last decennium. PMID- 26731871 TI - [Environmental tobacco smoke--assessment of formaldehyde concentration in urine samples of exposed medicine students]. AB - Environmental Tobacco Smoke (ETS) is ranked as one of the factors of confirmed carcinogenicity to human. It consists of the mixture of smoke exhaled by the smoker as well as the sidestream smoke and contains many times higher concentrations of some toxic substances in comparison to the amount of toxic compounds inhaled by a smoker. From many years the issue of passive smoking has been the subject of many research and still not all of its aspects of affecting human health have been explored. Apart from the tobacco varieties, also diverse additives added during the process of tobacco manufacturing, including particularly carbohydrates, influence the composition of the environmental tobacco smoke. During smoking they can undergo many complex transformations, as a result of which toxic components of the environmental tobacco smoke are formed, carbonyl compounds in particular, like aldehydes. They are marked by a significant chemical reactivity which enables them to modify amino groups of proteins leading to the changes in their structure, biological functions and often antigenicity. Therefore their influence to the human body is the cause of numerous adverse health effects caused by the increase in free radical processes which can constitute to the source of these compounds. Well known representative of this group of xenobiotics is formaldehyde as a compound that reflects well the environmental exposure to carbonyl compounds. The considerable source of this compound is tobacco smoke. Therefore analysis of formaldehyde in body fluids is a valuable biomonitoring tool of exposure to it. The aim of this study was the evaluation of formaldehyde concentration in urine samples of medicine students exposed to ETS. The study material consisted of 149 urine samples of students from School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia. The concentration of formaldehyde in urine samples was determined by a spectrophotometric method using the Purpald reagent. To verify the collected questionnaire data regarding exposure to constituents of tobacco smoke, the immuno-enzymatic method was used to determine main nicotine metabolites in tested urine samples. This enabled dividing the investigated students' group into active smokers, passively exposed to tobacco smoke and not exposed. Analysis of obtained results showed that mean concentration of formaldehyde in urine of active smokers (68.45 +/- 58.67 umol/l) and passive smokers (79.23 +/- 53.64 umol/l) were significantly higher in comparison to not exposed students (42.99 +/- 30.29 umol/l). Mean concentrations of formaldehyde in urine samples of active and passive smokers are comparable. The results of our study allow to conclude that passive exposure to tobacco smoke is an equivalent source of exposure to active smoking regarding formaldehyde adverse influence to human. Applied method enables to quick evaluation of formaldehyde concentration in biological samples. PMID- 26731872 TI - [Influence of smoking on pregnency course and fetal development]. AB - Smoking is a significant factor which affects not only reproduction and the process of pregnancy but also the offspring. Endangering for tobacco smoke and nicotine either passive or active has an important influence for shortening the time of pregnancy, the weight of the newborn and the Placenta. The occurrence of complications connected with smoking is probably correlated with the amount of cigarettes smoked per day. The aim of the paper was to analyse the influence of passive and active smoking on the course of pregnancy. The study involved a group of 113 women who gave birth in Gynaecological and Obstetrics Clinical Hospital of the Karol's Marcinkowski University of Medical Sciences in Poznan during the period from January to June 2011. Based on data gained from documentation and mothers three groups were separated: 22 women who were active smokers, 32 passive smokers and 59 women from control group who have never been smoking. There were analyzed selected obstetric data and term of pregnancy, condition and weight of newborn, blood pH and alkaline balance from umbilical vessels. In research there were no correlation between groups and/or results of researches of blood Ph, alkaline balance from umbilical vessels and the assessment of the newborn in Apgar score at 1, 3, 5 minute. In fact passive smoking women were younger (the average 27.84) than actively smoking woman (30.23) and non-smokers (30.25) (p = 0.03). The most of small as for their gestational age infants were in the group of active smoking women (14%). Non-smokers more often did have a miscarriage (84%) in the past than other groups (active smokers 60%, passive 33%) (p = 0.04). Smoking women usually come from countryside or small towns, they were not marriage and they had preterm delivery. In this group there was found the biggest percent of too small newborns for their gestational age--14%. PMID- 26731873 TI - [Protection against tobacco smoke--compounds and substances of natural orgin]. AB - Tobacco smoke contains thousands of ingredients, including those causing serious respiratory and cardiovascular diseases, and which are carcinogens or cancer promoters. Plants and plant products have antioxidant properties and have a protective role against cancer defined as chemoprevention. This paper presents an overview of published experiments on the protective effect against tobacco smoke or its by compounds and raw materials of natural origin, from plants mainly. These were: N-acetyl-L-cysteine, vitamin C, A and E, beta-carotene, lycopene, andrographolide, farnesol, resveratrol, marigold and tea. These studies were carried out on experimental animals or animal or human cells, which were exposed to cigarette smoke or its extract, or components of tobacco smoke. The studies have shown that the mentioned compounds and raw materials have a protective effect against the harmful effects of tobacco smoke. Mechanisms of action were different--the increase of the level of glutathione and antioxidant enzymes, prevention DNA strand breakage and lipid peroxidation, increased accumulation of the transcription factor Nrf2 that controls the expression of antioxidant genes. Authors frequently suggested that the investigated compounds and the materials may have similar protective effects against tobacco smoke in humans. PMID- 26731874 TI - [Smoking cessation during hospitalization on cardiology ward]. AB - Among the modifiable risk factors smoking has the most impact on cardiovascular mortality. Among patients with cardiovascular disease benefits of quitting smoking outweigh those associated with commonly prescribed drugs. Hospitalization in the ward seems to be a good time to motivate the patient to take this step. In our paper we present the effectiveness of different methods to achieve this goal. PMID- 26731875 TI - [Historical trends in prevalence of tobacco smoking among women]. AB - The paper contain a brief historical introduction about tobacco and smoking trends among women over the years--from cigarettes introduction to the present (years 1840-2014). Particular attention was paid to the historical backgrounds and marketing strategies of tobacco companies, which tried to reach each of women. Moreover, this paper described the dangers of smoking, which have been proven by scientists over the years and the impact of this knowledge on the tobacco industry and cigarettes consumption by women. PMID- 26731876 TI - Effect of tobacco smoking on human gingival and periodontal fibroblasts. A systematic review of literature. AB - Influence of smoking tobacco on the oral cavity has been showcased, based on a review of the relevant literature. The effect of tobacco smoke, as well as its components, on the morphology and motility of human gingival and periodontal ligament fibroblasts in health, periodontal disease, and in neoplasms, has been described. PMID- 26731877 TI - Terrorist Event Training in US Medical Schools. A Survey of Chemical, Biologic, Radiologic, Nuclear, and High-Yield Explosives Training in US Medical Schools. AB - September 11, 2001 saw the dawn of the US-led global war on terror, a combined diplomatic, military, social, and cultural war on terrorist activities. Chemical, biological, radiological, nuclear, and high-yield explosives (CBRNE), as a group of tactics, are often the preferred weapons of terrorists across the globe. We undertook a survey of US medical schools to determine what their self-reported level of training for terrorist events encompasses during the four years of undergraduate medical education. METHODS: We surveyed 170 medical schools in the US and Puerto Rico using a five-question, internet-based survey, followed by telephone calls to curriculum offices for initial nonresponders. We used simple descriptive statistics to analyze the data. RESULTS: A majority of US medical schools that completed the survey (79 schools or 65.3%) have no required lecture or course on CBRNE or terrorist activities during the first or second year (preclinical years). Ninety-eight out of the 121 respondents (81.0%), however, believed that CBRNE training was either very important or somewhat important, as reflected in survey answers. CONCLUSIONS: Most physician educators believe that training in CBRNE is important; however this belief has not resulted in widespread acceptance of a CBRNE curriculum in US medical schools. PMID- 26731878 TI - Incidence and Risk Factors for Postoperative Urinary Retention: A Retrospective, Observational Study with a Literature Review of Preventive Strategies. AB - OBJECTIVE: To determine the incidence of postoperative urinary retention (POUR) in our surgical patients and review house staff practices in management. METHODS: A chart review of patients with POUR, identified through billing codes, was performed. In addition, a house staff survey was conducted to assess whether straight catheterization (SC) or indwelling urinary catheter (IUC) was preferred at different bladder volumes. RESULTS: The incidence of POUR was 2.2% (n = 43). This resulted in eight urology consults, seven discharges with an IUC, and three readmissions. There were significant disparities between the house staff survey results and actual practices. The mean volume for IUC insertion on the house staff survey was 365 cc compared to 739 cc from our patient cohort. Twenty percent of respondents chose to use SC at bladder volumes in excess of 700 cc. CONCLUSION: Management of POUR remains highly variable. Best practice guidelines are required to standardize our management of this complication. PMID- 26731879 TI - Idiopathic Infantile Hypercalcemia, Presenting in Adulthood--No Longer Idiopathic Nor Infantile: Two Case Reports and Review. AB - We present two unrelated cases of young adults with hypercalcemia, hypercalciuria, and nephrocalcinosis. Both had suppressed intact parathyroid hormone levels and high 1,25 vitamin D levels after only brief, low-dose, over the-counter vitamin supplementation. Neither had evidence of a granulomatous disorder. Their presentation mimicked that of 1,25 hydroxy vitamin D intoxication. In both patients, the diagnosis of idiopathic infantile hypercalcemia was confirmed with immeasurably low 24,25 vitamin D levels. Both were found to have a loss-of-function mutation in the CYP24A1 gene, which encodes the vitamin D-metabolizing enzyme 25-hydroxyvitamin D 24-hydroxylase. PMID- 26731880 TI - Changing the Graduate Medical Education Funding Path to Reduce the Price of Health Care Services. AB - An analysis of the current Graduate Medical Education (GME) funding stream reveals undesired aspects that limit the number of graduates and may tend to raise the price of health care services. The author shows that a different model of GME funding changes the economic dynamics and takes advantage of economic forces to increase the supply of graduates, while potentially reducing the price of health care services. PMID- 26731881 TI - A Temporal Correlation Between Electrocardiogram and Computed Tomography in Acquired Postpneumonectomy Dextrocardia. AB - Herein, we describe a temporal correlation between the electrocardiographic changes and the chest computed tomographic findings in a 73-year-old woman who underwent a right pneumonectomy (RP) for lung adenocarcinoma. PMID- 26731882 TI - Address of the New President. PMID- 26731884 TI - We Can't Wait for Tomorrow. PMID- 26731883 TI - Address of the Retiring President. PMID- 26731885 TI - HIV Testing, Patient Choice, and Diminishing Delaware's HIV Burden. PMID- 26731886 TI - Large Granular Lymphocytic Leukemia: A Tale of Two LGLs. AB - Large granular lymphocytic (LGL) leukemia is a fairly uncommon hematological malignancy, generally indolent in nature. Two patients with this entity receiving care at the Helen F. Graham Cancer Center and Research Institute (HFGCCRI) are described, who together illustrate the great range of severity that can exist in this disease. One patient, SM, presented with life-threatening anemia, yet another patient, TD, presented merely with asymptomatic lymphocytosis. Management differed accordingly, comprising methotrexate therapy for SM and active surveillance for TD. Recognizing the full spectrum of this condition is key to formulating an appropriate management plan. PMID- 26731887 TI - Serotonin Syndrome: Difficult to Diagnose but Critical to Treat. PMID- 26731888 TI - Subvalvular Aortic Stenosis. AB - Obstruction of the left ventricular outflow tract (LVOT) occurs in six out of 10,000 live births. The obstruction occurs in the aortic valve level in 71 percent, in subvalvular level in 14 percent, and supravalvular level in 8 percent of cases. Subvalvular aortic stenosis (AS) can be either a fixed stenosis resulting from subaortic membrane or a dynamic stenosis because of hypertrophic cardiomyopathy. Here, we report a patient with subaortic membrane who became symptomatic in her sixth decade of life. Echocardiography is the preferred diagnostic modality. Indications for surgery include symptoms, LVOT gradient of 50 mmHg or more, and development of significant aortic regurgitation. PMID- 26731889 TI - [Fundamental Evaluation and Clinical Usefulness of Lipoprotein Analysis System with Anion-Exchange Chromatography]. AB - We established a method for measurement of the cholesterol concentrations of high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL C), intermediate density lipoprotein cholesterol (IDL-C) and very low density lipoprotein cholesterol (VLDL-C) by using high performance liquid chromatography (HPLC) with anion-exchange column. The HPLC method has been covered by insurance in 2013, and HLC-729LPII (LPII) system constructed by this method has come on the market in 2014. We evaluated the fundamental precision data of lipoprotein cholesterol values measured by HLC-729 LPII. The within-day and between-day assay coefficients of variation of lipoprotein cholesterol values were 1.4-10.7 (%CV). The lipoprotein profiles of patients with type 2 diabetes mellitus (T2DM, n = 60) without dialysis therapy were measured by LPII. HDL-C obtained by LPII was highly correlated with that obtained by direct assay. LDL-C obtained by LPII was highly correlated with those obtained by direct assay and calculated by Friedewald's formula. In addition, IDL-C obtained by LPII was negatively correlated with estimated Glomerular Filtration Ratio (eGFR). These results suggest that the new HPLC method can be applied to estimate lipoprotein profile of T2DM patients. Particularly, IDL cholesterol may be useful for the evaluation of impaired lipid metabolism in T2DM patients without dialysis therapy, but it remains to be cleared. PMID- 26731890 TI - [Peripheral T-Cell Lymphoma, Not Otherwise Specified Occurring After the Treatment of Relapsed Follicular Lymphoma]. AB - A 77-year-old-man was diagnosed with follicular lymphoma (FL), grade 3A. After six courses of R-THP-COP (rituximab, pirarubicin, cyclophosphamide, vincristine and prednisolone) therapy, he achieved complete remission (CR). He achieved a second CR after radiotherapy, a third CR after six courses of bendamustine /rituximab (BR) therapy, and a fourth CR after six courses of BR therapy. However 2 months after the last chemotherapy, his tumor progressed rapidly and he died. Autopsy results showed medium and large lymphoid cells with pleomorphic, irregular nuclei and prominent nucleoli infiltrated in multiple lymph nodes, the liver, the lung, and the spleen. The lymphoid cells were positive for CD3, CD8, granzymeB, TIA-1 and negative for CD4, CD20, CD79a, CD10, and CD56. Autopsy diagnosis was peripheral T-cell lymphoma, not otherwise specified. Occurrence of lymphoma in T-cell lineage should be considered, if the course of low-grade B cell lymphomas, such as FL rapidly progresses. PMID- 26731891 TI - [Noninvasive Estimation of Liver Fibrosis and Hepatocellular Carcinoma Development Using WFA(+)-M2BP in Chronic Hepatitis C Patients]. AB - Wisteria floribunda agglutinin (WFA) -positive human Mac-2-binding protein (WFA(+)-M2BP) is a new glycol marker related to liver fibrosis. The aim of the present study was to evaluate WFA(+)-M2BP as a predictor of liver fibrosis and hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. A total of 115 patients with chronic hepatitis C who underwent liver biopsy were included, and the diagnostic accuracy of WFA(+)-M2BP for liver fibrosis was evaluated. A case-control study was conducted including 14 patients with chronic hepatitis C who developed HCC and 52 controls to estimate the utility of WFA(+) M2BP as a predictor of HCC development. WFA(+)-M2BP increased stepwisely with the progression of liver fibrosis (p < 0.001). The cumulative incidence of HCC development was significantly higher in patients with WFA(+)-M2BP >= 4.2 (p < 0.001) or in those with time-course changes in WFA(+)-M2BP (DeltaWFA(+) M2BP/year) =0.3(p=0.03). Multivariate analyses demonstrated that WFA(+)-M2BP >= 4.2 [hazard ratio (HR): 4.1, p = 0.04], AWFA'-M2BP/year >= 0.3 (HR: 5.5, p=0.008), and AFP >= 10 ng/mL (HR: 4.7, p = 0.03) were independent predictive factors of HCC development. Based on these data, we developed a simple scoring system to predict HCC development using these three factors. Using these scores, patients were classified into four groups; the cumulative incidence of HCC development significantly increased with increasing scores (p < 0.001). WFA(+) M2BP measurements were useful as a predictor of liver fibrosis and HCC development. Furthermore, real-time monitoring of WFA(+)-M2BP may be a novel predictor of HCC development. PMID- 26731892 TI - [Reactivation of Hepatitis B Virus and Guidelines for Its Prevention]. AB - Since the discovery of hepatitis B virus (HBV) as Australia antigen by Dr. Baruch Blumberg in 1964, significant advances have been made in understanding the pathophysiology of HBV infection, and in developing therapy for infected patients. Today, the progression of chronic hepatitis B to cirrhosis or hepatocellular carcinoma can be prevented using nucleic acid analogs. HBV is thought to be eliminated from patients with acute hepatitis B after they are cured. However, a 1996 study showed that cured hepatitis B patients were positive for HBV DNA and the HBV-specific cytotoxic T-cell response approximately 5 years after acute infection. These results indicate that HBV persists in the livers of patients who have been cured of acute HBV infection. HBV can be activated in chronic hepatitis B patients following steroid treatment. Recent clinical reports described cases of malignant lymphoma with fulminant hepatitis B arising during or after immunosuppressive regimens, such as R-CHOP therapy. Prior to immunosuppressive treatment, such patients are negative for HBs antigen and/or positive for HBs antibody, indicative of previous HBV infection. Sixteen cases of fulminant hepatitis B due to HBV reactivation in previously HBV-infected patients were collected between 2004 and 2009, and all of them had fatal prognoses despite treatment with nucleic acid analogs. Hence, guidelines for the prevention of HBV reactivation in immunosuppressive therapy were originally formulated by the Intractable Hepatobiliary Disease Study Group in 2009, and recently updated by the Japanese Society of Hepatology in 2013. The usefulness of these guidelines has been confirmed by several research groups. Dissemination and further improvement of the guidelines are necessary to prevent HBV reactivation in various types of patient receiving immunosuppressive or anti-cancer treatments. PMID- 26731893 TI - [Risk Management of HBV Reactivation: Construction of Check System]. AB - In recent years, reactivation of HBV in patients receiving cancer chemotherapy or immunosuppressive therapy has been a problem. Generally, HBV-DNA levels are elevated prior to HBsAg concentration, and then hepatic dysfunction is observed in the process of hepatitis by HBV reactivation. Therefore, the monitoring of HBV DNA is useful for the prediction of hepatic dysfunction, and nucleoside/nucleoside analogue (NA) administration is able to prevent this HBV reactivation. According to these facts, "Guidelines for the Prevention of HBV Reactivation in Patients Receiving Immunosuppressive Therapy or Chemotherapy", 2009 (revised as "JSH Guidelines for the Management of Hepatitis B Virus Infection", 2013) is established, and the diagnostic algorithm of HBsAg, anti HBc, anti-HBs, and HBV-DNA has relevant descriptions. Combination therapy with rituximab and steroid for malignant lymphoma has a high risk of leading to fulminant hepatitis and, consequently, the guidelines are widely followed in such cases. We introduced the improvement of electronic medical recording and ordering systems in collaboration with hepatologists, and such a system has been widely used. Although the monitoring of HBV-DNA levels is required every 1-3 months, the guidelines are not followed strictly in cases such as rheumatoid disease and solid tumors only with chemotherapy or steroid treatment. Since a DNA assay is complicated and expensive, cost-effective, time-saving, and highly sensitive/specific measurements are required as well. Therefore, Lumipulse HBsAg HQ (CLIA method) with high sensitivity is expected to be used for the monitoring of HBV reactivation. PMID- 26731894 TI - [How to Interpret and Use Routine Laboratory Data--Our Methods to Interpret Routine Laboratory Data--Chairmen's Introductory Remarks]. AB - In the reversed clinicopathological conference (R-CPC), three specialists in laboratory medicine interpreted routine laboratory data independently in order to understand the detailed state of a patient. R-CPC is an educational method to use laboratory data appropriately, and it is also important to select differential diagnoses in a process of clinical reasoning in addition to the present illness and physical examination. Routine laboratory tests can be performed repeatedly at a relatively low cost, and their time-series analysis can be performed. Interpretation of routine laboratory data is almost the same as taking physical findings. General findings are initially checked and then the state of each organ is examined. Although routine laboratory tests cost little, we can gain much more information from them about the patient than physical examinations. PMID- 26731895 TI - [How to Interpret Data of Routine Laboratory Tests (Basic Laboratory Tests)- Various Methods to Interpret Routine Laboratory Data in 3 Clinical Laboratory Facilities--A Method at Shinshu University Hospital]. AB - Routine laboratory tests are the most frequently performed among clinical laboratory tests, and they can provide important information for the diagnosis and treatment of patients. They are more useful when several data are combined to interpret the pathophysiological state of a patient. Changes of routine laboratory data are important even when they are within their reference ranges, and they sometimes show a more detailed condition of the patient. In this symposium, we demonstrated our method at Shinshu University Hospital, involving the evaluation of 13 conditions of the whole body or each organ by simultaneously interpreting some to several laboratory data. PMID- 26731896 TI - [An Accurate Diagnosis is Possible with a Systematic Analysis of Routine Laboratory Data]. AB - Routine laboratory tests are ordered for almost all in- and outpatients. A systematic analysis of routine laboratory data can give doctors valuable clinical information about patients. In some cases, a correct diag- nosis can be made using laboratory data alone. In our laboratory, we use five processes to evaluate routine laboratory data. Firstly, we estimate the patient's general condition based on A/G, Hb, TP, Alb, ChE, and platelet (PLT) levels. Secondly, we look for inflammation and malignancy based on WBC, CRP, PLT, fibrinogen, and ESR levels and the protein electrophoresis pattern. Thirdly, we examine the major organs, especially the liver and kidney. We check the liver for hepatocyte damage, obstruction, hepatic synthetic function, infection, and malignancy. We estimate GFR and check the kidney for any localized damage. We then check the chemistry, hematology, and immunology. Finally, we form a conclusion after a comprehensive interpretation of the above four processes. With this systematic approach, any members of the laboratory unit can easily estimate the exact pathological status of the patient. In this case study, marked change of TP indicated non-selective loss from the skin; namely a burn. Tissue injury and infections due to different focuses were the most likely causes of severe inflammation. Neither the liver nor kidney was severely damaged. Continual bleeding and hemolysis through the clinical course probably caused anemia. Hypooxygenic respiratory failure and metabolic alkalosis were confirmed by blood gasses. Multiple organ failure was suggested. PMID- 26731897 TI - [Application of Mass Spectrometry to the Diagnosis of Cancer--Chairman's Introductory Remarks]. AB - In this symposium, the latest application of mass spectrometry to laboratory medicine, i.e., to the early diagnosis of cancer, was introduced. Dr. Masaru YOSHIDA, who has been using metabolome analysis to discover biomarker candidates for gastroenterological diseases, presented an automated early diagnosis system for early stages of colon cancer based on metabolome analysis and using a minute amount of blood. On the other hand, Dr. Sen TAKEDA, who has developed a new approach by employing both mass spectrometry and machine-learning for cancer diagnosis, presented a device for the clinical diagnosis of cancer using probe electrospray ionization (PESI) and machine-learning called the dual penalized logistic regression machine (dPLRM). PMID- 26731898 TI - [Fragments Woven into a Whole: A New Approach to the Diagnosis of Cancer through Mass Spectrometry and Machine-Learning]. AB - Conventionally, a definitive diagnosis of cancer is derived from histopathological diagnostics based on morphological criteria that are difficult to standardize on a quantifiable basis. On the other hand, while molecular tumor markers and blood biochemical profiles give quantitative values evaluated by objective criteria, these parameters are usually generated by deductive methods such as peak extraction. Therefore, some of the data that may contain useful information on specimens are discarded. To overcome the disadvantages of these methods, we have developed a new approach by employing both mass spectrometry and machine-learning for cancer diagnosis. Probe electrospray ionization (PESI) is a derivative of electrospray ionization that uses a fine acupuncture needle as a sample picker as well as an ion emitter for mass spectrometry. This method enables us to ionize very small tissue samples up to a few pico liters in the presence of physiological concentrations of inorganic salts, without the need for any sample pretreatment. Moreover, as this technique makes it possible to ionize all components with minimal suppression effects, we can retrieve much more molecular information from specimens. To make the most of data enriched with lipid compounds and substances with lower molecular weights such as carbohydrates, we employed machine-learning named the dual penalized logistic regression machine (dPLRM). This method is completely different from pattern matching in that it discriminates categories by projecting the spectral data into a mathematical space with very high dimensions, where final judgment is made. We are now approaching the final clinical trial to validate the usefulness of our system. PMID- 26731899 TI - [Alternative Splicing Detection as a Biomarker for Cancer Diagnosis: A Novel Progressive Mechanism of Acute Lymphoblastic Leukemia with Alternative Splicing as a Biomarker Candidate]. AB - Alternative splicing is an important mechanism that links to transcription and contributes to protein diversity. Disturbed alternative splicing is frequently observed in cancers, but its precise mechanism remains largely unknown. FUSE binding protein (FBP) -interacting repressor (FIR) is a transcriptional repressor of the c-myc gene. Previous studies indicated that a splice variant of FIR, FIRDeltaexon2, that lacks exon2 in the transcriptional repressor domain, was increased in colorectal cancers, hepatocellular carcinomas, and leukemia cells. Furthermore, FIRDeltaexon2 activated c-myc transcription by disabling wild-type FIR as a dominant-negative form of FIR. Recently, somatic mutations of the SF3B1 (SAP155) gene, a subunit of the SF3B spliceosome complex, were found in myelodysplastic leukemia. In this study, FIR heterozygous knockout (FIR(+/-)) was established as a dominant-negative model of FIR in the C57BL/6 mouse. FIR(+/-) mice showed an increased c-myc mRNA expression level, particularly in peripheral blood, although FIR(+/-) mice had no apparent pathogenic phenotype. Therefore, an increased c-myc mRNA expression level alone is not enough for leukemogenesis. Nevertheless, FIR(+/-)TP53(-/-) mice generated acute T-cell lymphoblastic leukemia (T-ALL) with increased organ and/or bone marrow invasion. In conclusion, alternative splicing of FIR, generating FIRDeltaexon2, contributes to not only colorectal carcinogenesis but also leukemogenesis independent of the c-Myc activation pathway. Finally, we will discuss our hypothesis that FIRDeltaexon2 interferes with FBW7, that FIRDeltaexon2 inhibits PP1 in the EGFR pathway, and that FIR haploinsufficiency is potentially associated with protein expression through transcriptional and post-transcriptional mechanisms. PMID- 26731900 TI - [Liquid Biopsy and Laboratory Medicine]. AB - Recent progress in cancer biology has revealed the fact that molecular profiles of primary and metastatic cancer are not necessarily the same. Furthermore, evidence of intra-tumor heterogeneity has been disclosed repeatedly. In addition to these, acquiring resistances to chemoradiation therapy is far more rapid than typical predictions. Under these circumstances, physicians are realizing that one biopsy is not enough to predict the direction of cancer progression or extension. Repeated biopsy was proposed in this context. For "re-biopsy", acquiring blood is much easier compared to regular biopsies of acquiring body tissues. Therefore, CTC or Cell-free DNA is one of the hot topics in clinical and molecular diagnostic fields. The term "liquid biopsy" is used to include these two materials. We utilized a CTC isolation device based on microfluidic principles. Procedures for the extraction of DNA from plasma (Cell-free DNA) is also available. Based on this background, we performed a feasibility study of NGS (Next Generation Sequencing) by analyzing materials from advanced gastrointestinal cancer patients. We have successfully acquired NGS results using these liquid biopsies. We have also investigated the possibility of storing CTCs by evaluating procedures after cytospin using H1975 cells with various fixation conditions under a DIC microscope examination. Because of the paucity of the number of isolated CTCs, H1975 cells were used for this purpose. After cytospin, 95% ETOH and then -80 degrees C storage provided the best results. Attempts at not only NGS but also storage in this sequence of studies have opened new fields of liquid biopsy in clinical laboratories. PMID- 26731901 TI - [Biomarker for Hematopoietic Tumors--Aiming for Personalized Diagnosis of Leukemia Stem Cells]. AB - Biomarkers are defined as characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Biomarkers obtained by PCR or flow cytometry are used for the diagnosis and subtyping of hematopoietic tumor cases. They are also used to predict the effectiveness of molecular-targeted therapies and detect minimal residual leukemia cells. In order to cure leukemia, it is necessary to eradicate leukemia stem cells. For that purpose, biomarkers to identify and characterize the leukemia stem cells in each case are needed. Therefore, we examined molecules involved in various stemness-related signaling pathways, especially NOTCH signaling in acute leukemia cells. In T-lymphoblastic leukemia cells, which often have activating NOTCH1 mutations, NOTCH works in oncogenic signaling. Although acute myeloid leukemia (AML) cells express NOTCH and NOTCH ligands, it is still controversial whether NOTCH is oncogenic or tumor suppressive. To utilize the expression and activation of NOTCH as a leukemia stem cell biomarker, further investigation is required. Other stemness-related signaling molecules such as WNT, HEDGEHOG, HIF, and mTOR are also under investigation to assess whether they can be used as stem cell biomarkers in a clinical setting. PMID- 26731902 TI - A CULT FOLLOWING. PMID- 26731903 TI - FAST TRACK. MELISSA ZIPPIN. PMID- 26731904 TI - Site Specifics. Six tips for developing a user-testing enterprise. PMID- 26731905 TI - 7 Ways to Manage a Crisis. How to tell the stories that nobody wants to have to tell. PMID- 26731906 TI - Signed, Sealed, Delivered. Six ways to use personalization to boost the impact of your organization's e-mail marketing strategy. PMID- 26731907 TI - 10 million people can't be wrong. PMID- 26731908 TI - Branding emotion. PMID- 26731909 TI - 10 Minutes With ROBERT SIEGEL. PMID- 26731910 TI - POSITIVE INFLUENCE? Junk food, spending bans may not help those with impulse problems. PMID- 26731911 TI - Insight from a Nurse Leader on Board! PMID- 26731912 TI - Listen to the Spirit: Insights from a Meeting of the Oklahoma Holistic Nurses Association. PMID- 26731913 TI - Sleeping Giant Awakened as Nurses Mocked on National Television Talk Show. PMID- 26731914 TI - Is it Worth the Risk? 12-Hour Shifts and Nurse Fatigue. PMID- 26731915 TI - The Baseline Is Being Well. PMID- 26731916 TI - The Promise of Integrative Nursing. AB - The U.S. health care system requires transformative changes that reduce risk and improve overall well-being while increasing access, quality, safety, and affordability. Integrative nursing can serve as a road map to care that is culturally safe, personalized, and meaningful. Using exemplar case studies, we explore both opportunities and challenges to care that advances the health and well-being of persons, families, and communities through caring/healing relationships. PMID- 26731917 TI - The Revival of Placemaking. AB - Placemaking is both a philosophy and a process that brings the past alive in the present by using many disciplines to enhance the environment and meet the needs of the community, however defined by its citizens. A healthy environment is a necessary part of the process of placemaking, whether the place is a neighborhood, city, or nation. A mandate of urban designers should be to bring together many disciplines to engage in planning a healthy, inviting community. Community health nurses should be major players in this coalition. This article reviews the current thinking about placemaking and the role of the community health nurse. PMID- 26731918 TI - Back to Work: Manager Support of Nurses With Chronic Sorrow. AB - Death: No one likes to think about it, never mind talk about it. The purpose of this article is to show the importance of the role of the nurse manager in supporting nurses who are returning to the bedside after a significant loss. Significant personal loss may lead to a phenomenon called chronic sorrow. Bereaved nurses with chronic sorrow experience grief-related feelings as a result of caring for patients who are suffering and dying. Qualified nurses may leave bedside nursing for nonclinical roles, or leave the profession altogether, because of constant exposure to this stress. It is critical that nursing management is perceptive to the particular needs of bereaved nurses to best reintegrate them into their nursing positions. PMID- 26731920 TI - Food First: Nutrition as the Foundation for Health. AB - The principles of integrative nursing advocate that food be considered as a primary intervention for health promotion, risk reduction, and generally improved well-being. Food provides information to the body, signaling basic biological functions and normalizing physiological processes. Health care professionals should query patients about their nutritional intake, recognizing that adjustments in the types of foods consumed can often address long-standing symptoms that create distress, including pain, fatigue, anxiety, and gastrointestinal dysfunction. A Food First approach to care offers a novel approach that champions whole person/whole systems emergent health and well being. PMID- 26731919 TI - Having Heart. AB - A heart comes in many forms. This article shares the experience of behavioral health nurses caring for a suicidal patient who needs a heart. As a team, the nurses and their patient shared the journey of what it takes to achieve an optimum quality of life with a left ventricular assist device (LVAD) while battling mental illness. PMID- 26731921 TI - Integrative Nursing Principles in Action: A Summary From the First International Integrative Nursing Symposium. AB - The first International Integrative Nursing Symposium was held in May 2015 in Reykjavik, Iceland, to foster discourse about providing whole person/whole systems care that is relationship-based and person-centered. A discussant format was used to ensure that symposium participants could fully operationalize the principles of integrative nursing in practice, research, education, and policy development. Sessions varied widely to communicate the full spectrum of nursing scholarship with participants envisioning a future when all nursing care is integrative. PMID- 26731922 TI - It Was Not on My Christmas List. AB - A nurse with newly diagnosed cancer presents her stream-of-consciousness impressions of this event, its meaning for her life, and the ways in which the gift of kindness makes a difference. PMID- 26731923 TI - From High Touch to High Tech: A Conversation With Maureen O'Hara, BSN, RN, OCN. AB - An oncology nurse talks about her 42-year career at Stanford Medical Center. The technological and pharmacological advances she has seen in that time have changed the face of oncology nursing practice and transformed many previously fatal cancers into curable diseases or chronic illnesses compatible with well-being. The increasing complexity of care requires multidisciplinary collaboration and brings with it new ethical dilemmas. She cautions nurses to make the best use of technology without losing their critical thinking skills, basic assessment skills, and common sense. PMID- 26731924 TI - A New Threat to the Nursing Workforce: Take a Stand! AB - The consequences of a sedentary lifestyle have been extensively studied, and the findings have been broadly reported in scientific journals as well as all forms of media. The development of cancer, cardiovascular disease, metabolic syndrome, venous thromboembolism, and extensive musculoskeletal strain can all result from prolonged immobility and repetitive computer use. Health care workers in the ambulatory setting are impacted by immobility because of the nature of their work. A workstation wellness intervention involved evidence-based activities for employees who have limited physical activity in the course of a workday, with the goal of promoting health. The participants engaged in a 4-week program of intermittent stretching, drinking water, and standing or walking during their workday. Participants reported a statistically significant increase in knowledge about workstation ergonomics (p = .0034) and the impact of prolonged sitting. There was also a statistically significant increase in the number of participants who became more aware about the number of times they stand up/walk and stretch at their workstation. Participants reported that the new bundle of activities was sustainable. This workstation wellness intervention is an inexpensive and simple self-directed wellness program that can increase knowledge, change behavior, and improve health perception among employees who work in sedentary jobs. PMID- 26731925 TI - Dance Lessons. AB - Nursing has been described as an art and a science. The scientific aspect of nursing can be learned in nursing school and in years of practice. However, the art of nursing is enriched by each nurse's connection with life experiences. The purpose of this article is to highlight my particular life experience with dance and to show how studying dance has helped me become the strong nursing leader I am today. PMID- 26731926 TI - Nursing and Daoism: Wading in the River of Practice. AB - The study of philosophy has shaped and continues to shape thinking in many disciplines. One may not initially associate philosophy with a grounding idea in the nursing profession; however, its ideas fit the contour of the discipline and foster critical thinking. The philosophical nurse examines his or her practice in depth to understand human processes and deepen thinking through the teachings of philosophy. The following discussion is an overview of Daoism (the "Way") and its main ideas; these ideas will then be applied to nursing practice and human response to illness. The analogy of a flowing river helps to enrich and enlighten our understanding of Daoist teachings. The practitioner cannot fight the flow of a river, just as the practitioner cannot prevent illness from occurring in one's existence. We can only supply the interventions to encourage equilibrium and maintain harmony. There will be obstacles; however, the practitioner who realizes that these obstacles are part of the "Way" will find understanding and a deeper knowledge base in caring for patients. PMID- 26731927 TI - Living With Chronic Pain. AB - A health educator who has reflex sympathetic dystrophy, an autoimmune condition involving chronic pain, shares her knowledge about living life to the fullest while dealing with a chronic health condition. Her advice encompasses dealing with the health care system, managing information, and obtaining physical and emotional self-care. PMID- 26731929 TI - Data, collaboration reduce sepsis mortality rates, improve use of ICU resources. AB - Two different hospital systems have made sizable dents in their sepsis mortality rates through a collaborative process between emergency and ICU staff. At Northwest Hospital in Randallstown, MD, success occurred, in part, by lowering the threshold for transfer of emergency patients with signs of sepsis to the ICU. Voorhees, NJ-based Kennedy Health has lowered sepsis mortality rates by taking steps to integrate the care of sepsis patients between the ED and the ICU, and slashing the time required to deliver bundle-oriented care. Research conducted at Northwest Hospital shows that sepsis mortality decreased by nearly half, going from 14.38% before intervention to 7.85% following implementation of the lower ICU thresholds. Clinical leaders at Kennedy Health report that they have lowered sepsis mortality from the mid-20% range to less than 12% through a collaborative approach involving all stakeholders. Sources from both hospitals stress the importance of using data to achieve buy-in to improvement efforts, and giving interventions enough time to take hold. PMID- 26731928 TI - The Nursing Salon Experience: A Tale of Hosting Conversations. PMID- 26731930 TI - Mobile stroke units bring treatment to patients, potentially improving long-term outcomes. AB - At least three U.S. medical centers are evaluating the benefits of deploying specially equipped mobile stroke units to respond to emergency calls for patients with suspected strokes. Most of these units contain CT scanners, lab facilities, and other functionality capable of determining whether a patient would benefit from clot-busting therapy. Such drugs can then be administered to appropriate patients before a patient even arrives in the ED. Early findings from the approach show that care can be accelerated, potentially improving stroke outcomes and reducing longer-term costs. In Houston, a mobile stroke unit dispatches along with EMS when a call involves a potential stroke victim. If the mobile stroke unit team determines that a patient is a candidate for clot-busting therapy, clinicians can administer the therapy, accelerating potentially brain-saving care. In a nine-week period, researchers reported that they treated about two patients per week with clot-busting drugs, 40% of whom received treatment within the first hour of onset. Further, none of the patients who received the drugs experienced intracerebral hemorrhage, and half of them recovered fully from their strokes within 90 days. PMID- 26731931 TI - TJC praises top hospitals in annual report. PMID- 26731932 TI - Nursing salary hikes remain modest despite labor shortages and looming demographic shifts. PMID- 26731933 TI - Engaging Our Communities and Transforming Health Care. PMID- 26731934 TI - Teamwork and Communication Training Improve Quality and Safety. PMID- 26731935 TI - HANDLING WITH CARE. New approach treats victims of gun violence like substance abusers. PMID- 26731936 TI - SENIOR WELCOME. Health system relies on redesign, APNs and PAs to relieve doctor shortage. PMID- 26731937 TI - Texas Health Resources and UT Southwestern form clinical network. PMID- 26731938 TI - PATIENT SAFETY. Three Questions with: John Lynch III. PMID- 26731939 TI - VIRTUAL A REALITY. Build it and they won't come. PMID- 26731940 TI - ACA. Getting up to speed for open enrollment. PMID- 26731941 TI - MOST WIRED. How Most Wired hospitals are using social media. PMID- 26731942 TI - Nurse helps low-income patients navigate health care. PMID- 26731943 TI - ARE YOU CONNECTED TO THE REVOLUTION? Six ways the health care consumer will change--is changing--our world. PMID- 26731944 TI - Umbdenstock Takes Stock. PMID- 26731945 TI - A Better Approach to PARKINSON'S. AB - People with Parkinson's disease are admitted to the hospital 50 percent more than their peers and experience longer hospital stays. Can teams of providers and patients, working mostly outside the hospital, improve care and save costs? PMID- 26731946 TI - 4 ways that clinical lab designs are changing. AB - New technology and work processes are transforming how clinical labs function. Well-designed spaces provide maximum flexibility so that they can be adapted as health care continues to evolve. PMID- 26731947 TI - Habilita and its mission. PMID- 26731948 TI - Early and long term outcome in older dysvascular amputees. AB - In this short report are analyzed, as reported in the scientific literature, the major complications and prognostic factors of clinical andfunctional outcomes in subjects lower limb amputees, mainly from vascular causes, referring to the bio psycho-social model. PMID- 26731949 TI - [Epidemiology of amputations: from medical causes to traumatic ones and at work]. AB - The aim of our work is to describe the epidemiology of amputees. Through the causes, the treatment procedures and finally the social and economic impact that these complex patients determine in the health system. Although the epidemiological picture may be affected by some investigation limits, which mainly depend on the indicators used and on the scientific knowledge of the observation time, it remains an useful tool of knowledge both for clinicians and experts in health planning. PMID- 26731950 TI - [Amputee rehabilitation: taking charge, functional assessment and goal setting]. AB - Patients with lower limb amputations need the help of a multi-professional care team. There is no single professional who encompasses the skills required by patients who generally present multiple pathologies: skills in the care of wounds which are often dehiscent, knowledge of prosthetics, considering the fast evolving technologies in the field, psychological skills, essential to help the patient face their somatic conditions and resultant changes in body image. The physiatrist manages a care team which must prioritise treatments and intervention methods, and define practicable objectives in both the short and long term. The article details the basic principles to be followed for each patient so as to not overlook any of the aspects which combine to create a process which is neither simple nor quick, and focuses on the first parts of the treatment, from admittance until the choice of the temporary prosthesis. PMID- 26731951 TI - [WHICH IN SURGERY OF LOWER LIMB AMPUTATION]. AB - Lower limb amputation is in effect decisive surgery in the treatment of ischemic gangrene whether nature of post-traumatic or secondary to arterial disease of the lower limbs. The amputation is not however to be considered debulking surgery. The demolition regards the limb behind which we do not have the presence scotomize amputee who requires to be accompanied in dealing with a new life that has as its main objective the autonomy scope family and society. The search for a good level of amputation surgery then makes reconstructive surgery. The level of amputation will allow in fact the use ofprincipals able to guarantee the total autonomy. After an analysis of surgical techniques the author will then analyze the latest devices available in the permit to pursue the best possible level of amputation even in cases where the disease is starting to discourage the doctor. PMID- 26731952 TI - [Hyperbaric oxygen therapy as adjuvant in stump surgical wound healing]. AB - Oxygen is an essential gas. Oxygen is also a biological medicine. Hyperbaric oxygen therapy is a treatment which is based on the respiration of pure oxygen in a particular pressurised environment (hyperbaric chamber). The pressure allows the diffusion of oxygen into the blood at a concentration which is ten/fifteen/twenty times the normal level. The increase in oxygen in bodily liquids stimulates the synthesis of a gas, nitric oxide (NO), which has a powerful anti-inflammatory effect and promotes the formation of new blood vessels (also through the employment of stem cells) thus accelerating the healing of wounds. Hyperbaric oxygen therapy reactivates metabolic processes which have stopped and is able to help the recovery and obvious improvement of patients suffering from several serious illnesses. Hyperbaric oxygen therapy is a medicine, and as such requires careful dosage, monitoring of its results, and prevention of possible side effects. PMID- 26731953 TI - [Pre-prosthetics: role of the physiotherapist in the treatment of the residual limb and prosthetic preparation of the person]. AB - The rehabilitation of amputees requires a multi-discipline approach. Within the work of the team, physiotherapy plays a central role both in terms of the technical skills made available to the patient, as well as in terms of the psychological-motivational support offered to the amputee during treatment. The pre-prosthetic phase of rehabilitation is the beginning of a complex rehabilitative process during which starts with an assessment of the general clinical condition of the patient and their residual capacities, so as to develop personalised rehabilitative strategies based upon the needs of the amputee. This whole process aims to get the amputee standing with a prosthetic as quickly as possible, thus allowing the social reintegration of the amputee. PMID- 26731954 TI - [The prosthetic phase: the prosthesis, the prostheses]. AB - The technological evolution that has characterized the last two decades, both in terms of materials, electronics and automations, has made available new solutions in the field of design and manufacturing of lower limb prostheses allowing to overcome some of the historical limitations of such devices. The aim of this work is to give an overview of the components of a prosthetic device for lower limb amputations, investigating the functional aspects that guide the clinical and technical choices towards the most suitable solutions according to the somatic features, rehabilitation needs and lifestyle of the amputee subject. PMID- 26731955 TI - [The path to customized prosthesis: role of the occupational therapist in the recovery of autonomy]. AB - The aim of the rehabilitative treatment of the amputee is to facilitate the reintegration of the patient into daily life: within social, family, and working contexts. Occupational therapy relates to 'doing', to everyday life. These are the activities carried out by individuals during daily life: catching the bus, driving a car, cooking a meal, playing cards or changing a light bulb. During the process of rehabilitation of the amputee the occupational therapist must evaluate the residual capacities of the patient, discover their needs and requirements so as to develop suitable rehabilitative strategiesfor retraining motor-skills, acceptance of the new living conditions, and social reintegration. PMID- 26731956 TI - [Bioelectric prostheses: review of classifications and control strategies]. AB - Bioelectric prosthesis are those mechatronical devices able to substitute the total or partial loss of a limb or a system, and controlled by the patient thanks to wilful bioelectric signals, such as muscular contractions (electromyographic signals, EMG) or activation of specific encephalic areas (which can be revealed by encephalogram, EEG). At the end of an analysis of the devices currently in literature and on the market, the present paper collects and synthesize the possible classification strategies of these prosthetic devices, paying particular attention also to the classification obtained by possible control strategies of the prosthesis. This summary aims to support and sustain physicians and patients along the identification of the most appropriate prosthesis, for the specific subject, the choice of the "optimal" device, must consider also patient needs and expectations, possible pathological constraints and technological complexity of the system. This paper presents, after a brief theoretical introduction about the background, a short description of materials and methods implemented in order to identify classification typologies; the main results, collected in 2 tables, will be then described, and commented highlighting advantages and limbs of the proposed classifications. PMID- 26731957 TI - Clinical gait analysis for amputees: innovation wishlist and the perspectives offered by the outwalk protocol. AB - Clinical gait analysis (CGA) has shown potentials for the prosthetics field and has been found effective for scientific purposes and to design general rehabilitation models. However, intrinsic limitations of the "artificial" laboratory environment usually result in recording performances not representative patients' real-life gait. In order to promote the diffusion of CGA in the clinical decision-making process, a framework for developing novel, more ecological CGA applications is presented. Moreover, the Outwalk protocol, based on wearable sensors and developed within this framework guidelines, is described and validated for its inter-rater agreement on a population of transtibial amputees walking in a real-life scenario. Results show the possibility of drawing precise conclusions over different aspects of amputees' gait and prostheses' performance in every-day life conditions. PMID- 26731958 TI - [The esthetics of lower limb prosthesis]. AB - The amputation, which is upper or lower limb, entails important consequences and often traumatic into subject amputee from a physical, psychological, interpersonal and social point of view. It acts on the body image unleashing different psychological disorders and alterations in the social and professional reality. The aesthetic prosthesis can be considered a good support to help the person regain a new body image of themselves, facilitating the process of physical rehabilitation and social integration. PMID- 26731959 TI - [Mirror, mirror of the wall: mirror therapy in the treatment of phantom limbs and phantom limb pain]. AB - Phantom limb and phantom limb pain control are pivotal points in the sequence of intervention to bring the amputee to functional autonomy. The alterations of perception and sensation, the pain of the residual limb and the phantom limb are therefore aspects of amputation that should be taken into account in the "prise en charge" of these patients. Within the more advanced physical therapies to control phantom and phantom limb pain there is the use of mirrors (mirror therapy). This article willfocus on its use and on the possible side effects induced by the lack of patient selection and a conflict of body schema restoration through mirror therapy with concurrent prosthetic training and trauma acceptance. Advice on the need to select patients before treatment decisions, with regard to their psychological as well as clinical profile (including time since amputation and clinical setting), and the need to be aware of the possible adverse effects matching different and somehow conflicting therapeutic approaches, are put forward. Thus a coordinated sequence of diagnostic, prognostic and therapeutic procedures carried out by an interdisciplinary rehabilitation team that works globally on all patients' problems is fundamental in the management of amputees and phantom limb pain. Further studies and the development of a multidisciplinary network to study this and other applications of mirror therapy are needed. PMID- 26731960 TI - [The reorganization of the schema and body image of the amputee]. AB - The paper deals with the psychological problems related to the amputee's experience. The stages of the reorganization of the body image and the problems that may arise, are described. In this process the phantom limb syndrome represents an important paradigm for study and reflection. PMID- 26731961 TI - [The function, activity and participation: the occupational reintegration]. AB - The return to work is a significant outcome after amputation. To reach this goal it is necessary to measure properly this process. Unfortunately, for amputee, we have different scales but often focused on specific groups of problems The International Classification of funtioning (ICF) can constitute the frame of reference where to converge scales available and according to which define problems related to disability. For the person amputated the theme of the return to work arises differently for the conditions traumatic and non-traumatic. For the first return to work is a priority given the younger age. For the latter, given the advanced age, the return to work is likely to be a measure of the success of rehabilitation is not particularly relevant. PMID- 26731962 TI - [Survival and success rate of dental implants treated with high intensity laser]. AB - Clinical and radiological evaluations were conducted in patients with high energy Nd : glass laser-treated dental implants. These patients underwent dental implantation surgery between 1997 and 2006. Strict success criteria were used for the examination and analysis of implants. Based on clinical and radiological evaluation, success and survival rates of laser surface treated dental implants were similar to those of sandblasted, acid-etched surface implants frequently reported in the literature. Specific surface morphology and high degree of purity of laser surface treated dental implants ensure excellent osseointegration and a good clinical performance also on the long-term. PMID- 26731963 TI - [Calcifications in the maxillofacial area]. AB - Among patients presenting for dental treatment we could reveal various calcifications on panoramic x-rays or on cone beam computed tomography (CBCT) Calcifications is more likely to occur in vessels, ligaments, glandular tissues and is usually associated with chronic inflammation or scarring. The purpose of this article is to describe the imaging characteristics of commonly observed calcifications of the maxillofacial area with presenting our own cases such as: tonsilloliths, calcified lymph nodes, elongeated styloid process (calcified stylohyoid chain), phleboliths, carotid atheromas, calcified laryngeal cartilage. PMID- 26731964 TI - [Complex treatment of a large radicular cyst in the anterior region of the maxilla. Case report]. AB - As opposed to other odontogenic cysts, the radicular cyst is always produced by intraradicular infection, therefore it is important to eliminate the cause of the inflammation as well. During the healing of the radicular cyst, the infected tooth should be treated by extraction or root canal treatment completed by surgical intervention. The presented case is a 77 year-old male patient with Type II Diabetes, who required oral surgery and endodontic treatment. Despite of the age and diabetes of the patient, the bone regeneration was rapid and complete. Seven months after starting the treatment, the size of the cyst decresed significantly and by 12th month it was perfectly healed. PMID- 26731965 TI - [Oral health-related quality of life associations to periodontal conditions]. AB - The clinical form and severity of periodontal of periodontal disorders may have negative effects on oral health related quality of life (OHQoL). The oral health impact profile questionnaire (OHIP-14) is the most frequently used instrument to evaluate the effects of intraoral disorders on the perception of well-being of patients. The modified OHIP-14 was used with 45 people (29 were in the chronic periodontitis and 16 in the control group) to evaluate the effects of periodontal conditions on OHQoL. In the periodontitis group significantly higher level of impact was observed in questions connected to aesthetics, psychological discomfort, physical pain and functional limitation. Higher periodontal probing depth was frequently associated with self-report of pain either in the anterior or posterior dental regions. There was also a significant correlation between the functional limitation and the number of missing teeth, the bleeding on probing and the probing depth. It is concluded that the periodontal disorders may have negative effects on certain parameters of OHQoL, hence during periodontal investigation the dental clinician should ask anamnestic questions in relation to quality of life. PMID- 26731967 TI - The 2015 Nobel Prize Laureates in Physiology or Medicine. PMID- 26731966 TI - [Effect of BMP-2 treatment on the morphology and proliferation of human embryonic palatal derived mesenchymal preosteoblast cells]. AB - In dental implantation missing tooth or teeth are replaced by artificial root. To reduce the time required for the integration newest trends are the enhancement of bone formation around the implant by bioactive molecules, growth factors. Such a molecule is bone morphogenetic protein-2 (BMP-2) accepted by US Food and Drug Administration (FDA). In these kind of applications effect of BMP-2 is tested in vitro on appropriate cell lines. One of these cell lines is the osteoblast like human embrionic palatal mesenchymal cell line (HEPM). In our experiments the effect of BMP-2 homodimer treatment was investigated on the differentiation of HEPM cells to osteoblasts reflected by changes in morphology, and proliferation after a short, 3 days BMP-2 treatment. Results showed that after three days BMP-2 treatment facilitates cell attachment on a concentration dependent manner however changes in cell morphology and proliferation could not be observed. Continuing the BMP-2 treatment inhibitory effect was measured in cell proliferation, which may refer to cell differentiation. PMID- 26731968 TI - Assessment of the periodontal health and community periodontal index in the Army of Serbia. AB - BACKGROUND/AIM: Promotion of oral health in military population is not only a significant component of general health, but also of the military readiness and represents the strategic orientation of each country. The basic task of military dentistry is to provide oral health of military personnel and to enable their operational readiness at the optimal level. The aim of the study was to assess the periodontal condition in Serbian military population using the community periodontal index of treatment needs (CPITN), and the influence of general life habits and local risk factors on periodontal health. METHODS: This prospective cross-sectional pilot study was conducted on 101 examinees at the mean age of 38.94 +/- 11.63 years who had dental check-ups at the Dental Clinic of the Military Medical Academy in Belgrade. All the categories of military personnel aged 20-64 years were divided into five groups. The frequency distribution of general and local factors on periodontal health, oral hygiene index, and the assessment of the mean number of sextants by CPITN compared to age were examined. RESULTS: The examinees at the age of 51-60 years had the best oral hygiene index (0.95 +/- 0.65), whereas the oldest population had the worst (1.63 +/- 0.42). Only one person (5.6%) at the age group of 51-60 years had a completely healthy periodontium. Observed in relation to the age groups, the mean values of sextants increased linearly, but in general population, the most frequent CPITN categories were in sextant with the periodontal pockets 4-5 mm (score 3). CONCLUSIONS: Compared to the results from other countries shown by the World Health Organization, the periodontal condition in our examinees is below the average. The appropriate preventive program preparation and its implementation are needed, including primarily the appropriate training on oral hygiene, as well as education based on periodontal disease prevention and treatment. PMID- 26731969 TI - Etiology and mechanisms of ulnar and median forearm nerve injuries. AB - BACGRAUND/AIM: Most often injuries of brachial plexus and its branches disable the injured from using their arms and/or hands. The aim of this study was to investigate the etiology and mechanisms of median and ulnar forearm nerves injuries. METHODS: This retrospective cohort study included 99 patients surgically treated in the Clinic of Neurosurgery, Clinical Center of Serbia, from January 1st, 2000 to December 31st, 2010. All data are obtained from the patients' histories. RESULTS: The majority of the injured patients were male, 81 (81.8%), while only 18 (18.2%) were females, both mainly with nerve injuries of the distal forearm--75 (75.6%). Two injury mechanisms were present, transection in 85 patients and traction and contusion in 14 of the patients. The most frequent etiological factor of nerve injuries was cutting, in 61 of the patients. Nerve injuries are often associated with other injuries. In the studied patients there were 22 vascular injuries, 33 muscle and tendon injuries and 20 bone fractures. CONCLUSION: The majority of those patients with peripheral nerve injuries are represented in the working age population, which is a major socioeconomic problem. In our study 66 out of 99 patients were between 17 and 40 years old, in the most productive age. The fact that the majority of patients had nerve injuries of the distal forearm and that they are operated within the first 6 months after injury, promises them good functional prognosis. PMID- 26731970 TI - Quality-of life of the elderly in urban and rural areas in Serbia. AB - BACKGROUND/AIM: The number of elderly people in the world is growing, in Serbia as well. Serbia is already among the top ten countries with the oldest population, it is the fact. Aging influences the quality of life in different ways. The aim of this study was to assess the health-related quality of life of the elderly in urban and rural areas in Serbia. METHODS: The study included 100 elderly people aged 65 years and above in urban and rural areas in Serbia. The next questionnaires were used: a socio-demographic questionnaire and a Serbian version of standardized European Euro-QoL questionnaire (EQ-5D-3L), as a basic index for the assessment and description of the quality of life. RESULTS: In the structure of the respondents, according to the achieved social contacts (p = 0.012), the life of those with family members (p = 0.009), and health status (p = 0.000), in relation to the place of residence there was a statistically significant difference. There was a significant difference (p = 0.040), predominantly poor score for anxiety/depression within the rural population. The average value of quality of life in urban and rural areas was not statistically significant (p = 0.720). For those living in rural areas there was a statistically significant positive correlation between anxiety/depression and age, wealth status, marital status, living with family members and achieving social contacts, while a negative correlation was observed between anxiety/depression and education. CONCLUSION: On the basis of the data of our study, we can say that the presence of anxiety/depression among older people is greater in rural than in urban areas. The results of this study show that the perception of anxiety/depression among older in rural areas is bigger with the age and poverty increasing, the loss of a spouse, life without family members, lack of achievement of social contacts and lower education. PMID- 26731971 TI - Adverse drug reactions in hospitalized cardiac patients: characteristics and risk factors. AB - BACKGROUND/AIM: Adverse drug reactions (ADRs) appear more frequently than actually reported and registered. The main goal of our work was to analyze risk factors, incidence and characteristics of ADRs in hospitalized cardiac patients. METHODS: This prospective study included 200 patients, hospitalized at Cardiology Center of the Clinical Centre of Montenegro. ADRs were collected using specially designed questionnaire, based on the list of symptoms and signs that could point out to potential ADRs. Data from medical charts of patients, lab tests and other available parameters were observed and combined with the data from questionnaire. Severity of ADRs were assessed as serious or nonserious according to the World Health Organization criteria. Causality was assessed using the Naranjo probability scale. RESULTS: A total of 34% of all the patients experienced at least one ADR. The most common ADRs occurred as nervous system disorders, less frequent were cardiovascular disorders, while the immune system disorders were the rarest. Sixteen percent of all ADRs were characterized as serious, most often caused by carvedilol and amiodarone. The majority of patients (97.3%) recovered without consequences. The multivariate analysis showed independent significant associations between ADRs and age, gender, comorbidities and polypragmasia. CONCLUSION: ADRs represent a significant issue in hospitalized cardiac patients population. The most significant predictors for ADRs in observed population were age, comorbidity, number of medications used during hospitalization and patients' gender. Preventive measures such as pharmacotherapy rationalization and continual education of health care professionals could reduce the frequency of ADRs appearance in patients with detected risk factors. PMID- 26731972 TI - Impact of Ki-67 and E-cadherin expression on lymphovascular invasion in upper urinary tract urothelial carcinoma. AB - BACGROUND/AIM: Upper urinary tract urothelial carcinoma (UUT-UC) constitutes 5% of malignant neoplasms arising from transitional epithelium, but is more invasive than bladder cancer. Lzmphovascular invasion (LVI) is associated with biologically aggressive carcinoma and with occult metastases. The aim of this study was to investigate the correlation between LVI and immunohistochemical expression of two frequently routinely applied immunohistochemical biomarkers, Ki 67 and E-cadherin, in UUT-UC. METHODS: The specimens from 106 patients with UUT UC who had undergone nephroureterectomy were analyzed for pathologic parameters and LVI, while Ki-67 and E-cadherin expression were assessed by immunohistochemistry. RESULTS: Ki-67 was overexpressed in 38% of the cases, while 45% of tumors demonstrated aberrant E-cadherin staining. The presence of LVI was significantly associated with tumor stage, grade, non-papillary growth, nodular invasion pattern, high Ki-67 labeling index and altered E-cadherin expression. Analyzing logistic regression models, we have shown that tumor properties such as stage, grade, growth and invasion pattern (p < 0.001), as well as the expression of Ki-67 and E-cadherin (p < 0.001) significantly predicted the presence of LVI. In the first model, only solid tumor architecture (p < 0.05) and nodular invasion pattern (p < 0.05) were significant predictors of LVI. In the second model, Ki-67 expression was found to improve the prediction of LVI (p < 0.05). CONSLUSION: Our results suggest that Ki-67 overexpression is an independent predictor of LVI in UUT-UC, indicating the progression of the disease. E-cadherin staining adds no valuable information to LVI probability assessment. This emphasizes the importance of Ki-67 staining of UUT-UC sections in routine pathological practice. Patients with Ki-67 overexpression, especially in solid tumors with nodular invasion, should be monitored more closely after surgery. PMID- 26731973 TI - Graft stability after endothelial keratoplasty. AB - BACGROUND/AIM: Techniques for replacing the corneal endothelium have been improved. The host-graft interface is the key to graft adhesion and visual recovery. The aim of this study was to establish graft stability after Descemet stripping with endothelial keratoplasty (DSEK), compare it to the graft stability after endothelial keratoplasty with the intact posterior corneal layers (nDSEK) in the rabbit cornea, and to investigate the nature of wound healing. METHODS: Adult white rabbits (n = 20) were divided in two experimental groups: ten rabbits underwent monocular DSEK, and ten rabbits underwent endothelial keratoplasty without Descemet stripping (nDSEK). On the second postoperative day a horizontal dislocation of the graft was tried using the Lindstrom roller in each animal. Corneas were processed for the light microscopy study. RESULTS: Rolling the Lindstrom instrument over the corneal surface did not cause horizontal dislocation in any of the operated eyes. In the DSEK group light microscopy revealed the lack of inflammation and fibrosis at the clearly distinctive donor recipient interface (DRI). Retrocorneal membrane was found in two eyes. In nDSEK group, the host Descemet's membrane (DM) was intact without endothelial cells, with good graft apposition, without inflammation, fibrosis, or retrocorneal membrane. CONCLUSION: This study suggests that there is no difference in graft stability in DSEK compared to nDSEK in rabbit corneas. Wounds healed at DRI by hypocellular scarring only in both experimental groups. PMID- 26731974 TI - Pseudomonas aeruginosa serotypes and resistance to antibiotics from wound swabs. AB - INTRODUCTION/AIM: Pseudomonas aeruginosa (P. aeruginosa) is the most common cause of wound infections, following the disruption of the skin or mucous membranes integrity. The aim of this study was to analyze of the presence P. aeruginosa in wound swabs, antibiotics susceptibility testing, determination of the minimum inhibitory concentrations (MICs) of antibiotics, testing of the metallo-beta lactamases (MBLs) production, isolates serotyping and analysis of the most common serotypes resistance. METHODS: A total of 90 outpatients and 55 intpatients wound swabs were cultivated. Wound swabs were taken from the patients with wound infections symptoms. Antibiotics susceptibility testing was performed to: meropenem, imipenem, piperacillin-tazobactam, ceftazidime, cefepime, amikacin, gentamicin, netilmicin, of loxacin, ciprofloxacin and colistin (HiMedia). Polyvalent and monovalent antisera for agglutination (Biorad) were used in P. aeruginosa agglutination. RESULTS: P. aeruginosa was isolated from 36.55% wound swabs (36.66% of the inpatients wounds and 36.36% of the outpatients). The analyzed isolates showed the highest degree of sensitivity to colistin (100%) and meropenem (93.44%) and the lowest to cefepime (19.54%). The majority of the inpatients isolates had 12 ug/mL (28.57%) MIC for piperacillin-tazobactam and 16 ug/ml (28.57%) for the outpatients. The most common MICs for ciprofloxacin were 0.19 ug/mL (31.81%) for the nosocomial isolates, and 0.25 ug/mL (28.57%) for the outpatients' ones. The most common ICs for amikacin of the nosocomial isolates were 6 ug/ml (40.90%), and for the outpatients ones 4 ug/mL (33.33%). Five (9.43%) isolates produced MBLs. The most common serotypes were P11 (22.64%), P6 (15.09%) and P1 (11.32%). CONCLUSION: Neither the increased presence of P. aeruginosa was noticed in wounds swabs, nor the antibiotic resistance in the nosocomial isolates compared to those from outpatients. The analyzed isolates had the higest sensitivity to colistin and meropenem, and the lowest to cefepime. PMID- 26731975 TI - Surgical dislocation of the hip in patients with femoroacetabular impingement: Surgical techniques and our experience. AB - BACKGROUND/AIM: Arthrosis of the hip is the most common cause of a hip joint disorders. The aim of this study was to present our experience in the application of a safe surgical dislocation of the hip in patients with minor morphological changes in the hip joint, which, through the mechanism of femoroacetabular impingement, cause damage to the acetabular labrum and adjacent cartilage as an early sign of the hip arthrosis. METHODS: We have operated 51 patients with different morphological bone changes in the hip area and resultant soft tissue damage of the acetabular labrum and its adjacent cartilage. Surgical technique that we applied in this group of patients, was. adapted to our needs and capabilities and it was minimaly modified compared to the original procedure. RESULTS: The surgical technique presented in this paper, proved to be a good method of treatment of bone and soft tissue pathomorphological changes of the hip in patients with femoroacetabular impingement. We had no cases with avascular necrosis of the femoral head, and two patients had nonunion of the greater trochanter, 9 patients developed paraarticular ossification, without subjective symptoms, while 3 patients suffered from postoperative pain in the groin during more energetic physical activities. CONCLUSION: Utilization of our partly modified surgical technique of controlled and safe dislocation of the hip can solve all the bone and soft tissue problems in patients with femoroacetibular impingement to stop already developed osteoarthritis of the hip or to prevent mild form of it. PMID- 26731976 TI - Effects of Rusanda Spa balneotherapy combined with calcipotriol on plaque psoriasis. AB - BACKGROUND/AIM: Treatment of psoriasis is very complex and there are no still universal, nor unique treatment modalities. Apart from conventional treatment, which includes topical calcipotriol (vitamin D3 analogue), balneotherapy is drawing increased attention worldwide. Being part of climatotherapy, balneotherapy is defined as the use of natural environmental factors in the treatment of health conditions, whereas in the treatment of psoriasis it means the use of mineral baths and peloids. The aim of this study was to examine the therapeutic efficacy of mineral waters and peloids of the Rusanda Spa on plaque psoriasis in patients also treated with calcipotriol. METHODS: The study included 60 patients divided into two groups. The first group included patients treated with mineral waters, peloids and calcipotriol in the Rusanda Spa, while the second one included those treated only with calcipotriol. The study took 21 days, and each patient was followed up for at least one month after ending the treatment. The treatment efficacy was measured by psoriasis area severity index (PASI) scores on the days 0, 7, 14 and 21 during the treatment and 30 after the end of the therapy. RESULTS: After a 3-week treatment in the Rusanda Spa, the first group showed a decrease in PASI score by 59.45%, whereas in the group of outpatients treated by calcipotriol it was 39.34%. On the day 30 following the treatment, the first group presented with the PASI score reduction of 58.44%, and the second group of 34.78%. The therapeutic efficacy of mineral waters and peloids combined with calcipotriol showed to be significantly higher in regard to monotherapy with calcipotriol (p < 0.05). In regard to clinical symptoms, the best results were obtained in the reduction of desquamation (p < 0.001). CONCLUSION: The results of our study show that in the treatment of plaque-type psoriasis, topical calcipotriol combined with Spa Rusanda balineotherapy is more effective than topical calcipotriol alone. Randomized controlled trials are needed to confirm the effects of balneotherapy as monotherapy in treatment of this type of psoriasis. PMID- 26731977 TI - Determination of 5-caffeoylquinic acid (5-CQA) as one of the major classes of chlorogenic acid in commercial tea and coffee samples. AB - BACKGROUND/AIM: Tea and coffee are one of the most widely consumed beverages in the world due to their beneficial health effects which are largely associated with their phenolic compounds composition, including chlorogenic acid. The main aim of this study was to determine 5-caffeoylquinic acid (5-CQA), as one of the major classes of chlorogenic acid, in various commercial tea and coffee samples present at the Serbian market. METHODS: A high-performance liquid chromatography (HPLC) method for determination of 5-CQA in plant extracts was applied to determine the content of this active compound in commercial tea and coffee samples. Mobile phase was aqueous 1.5% acetic acid-methanol (80:20, v/v) with the flow rate of 0.8 mL/min. Run time was 15 min and column temperature 25 degrees C. The detection was performed at 240 nm. RESULTS: The HPLC method was modified and revalidated. The 5-CQA content varied depending on the type of tea (white, green, black tea and mate) and the processing technology. Green tea had the highest 5 CQA content (16 mg/100 mL) among the analyzed tea samples. The content of 5-CQA in coffee samples ranged 0-36.20 mg/g of coffee and 0-46.98 mg/100 mL of beverage, showing that the content varied depending on the type of coffee, coffee processing technology and the formulation. CONCLUSION: The modified and revalidated HPLC method showed a good accuracy, repeatability, selectivity and robustness. The highest amount of 5-CQA was determined in green tea in comparison to white, black and mate tea because the increased oxidation level decreases the amount of 5-CQA. The obtained results for commercial coffee samples indicated that the formulation was the most important factor determining the amount of 5 CQA. It can be concluded that plant material selection, processing conditions and formulation have great influence on the amount of chlorogenic acid (5-CQA) in the final tea and coffee products. PMID- 26731978 TI - Allergic asthma and rhinitis comorbidity. PMID- 26731979 TI - Non-functional parathyroid cyst--diagnostic pitfall: A case-report. AB - INTRODUCTION: Parathyroid cysts are relative rare and they may be misdiagnosed with thyroid nodules. Parathyroid cysts are characterized by elevated level of parathyroid hormone (PTH) in cystic fluid. CASE REPORT. We reported about middle aged woman with palpable node in the left thyroid lobe. Ultrasound showed anechoic 40 x 25 mm lesion in the left thyroid lobe. Fine needle aspiration (FNA) obtained 13 mL colorless, watery cystic fluid. PTH value in cystic fluid was ten fold more in comparison with serum PTH. Serum PTH was slightly elevated, D vitamin was under the reference range, serum calcium and phosphorus were normal as well as thyroid hormones. Thyroglobulin antibodies (TgAb) and thyroid peroxidase antibodies (TPOAb) were not detected. Radionuclide parathyroid scintigraphy indicated at physiological metaiodbenzyl-guamidine (MIBG) distribution. After six monthsof vitamin D supplementation, serum calcium, phosphorus, vitamin D and PTH were normal. This finding was indicative that was a nonfunctional parathyroid cyst. CONCLUSION: This case report points out that thyroid cystic lesions with thin walls, and reverberation in ultrasound, must be observed as a potential parathyroid cyst. These cysts require caution during diagnostic aspiration because of danger of hypercalcemic crises due to FNA, which can be a life-threatening condition. PMID- 26731980 TI - Rare solitary fibrous tumor of the stomach: A case report. AB - INTRODUCTION: Solitary fibrous tumors are rare soft tissue tumors of submesothelial origin and variable malignant potential. The most common localization is pleural, whereas only 0.6% are of extrapleural localization. Solitary fibrous tumor of the peritoneum, especially of gastric serosa is an extremely rare form of this tumor. CASE REPORT: We presented a 65-year-old female patient with solitary fibrous tumor of the stomach. Histopathological analysis of removed tissue showed the presence of tumor tissue built of spindle cells, elongated nuclei with moderately abundant cytoplasm. Cells were in a noncohesive arrangement, in smaller areas distributed in the form of palisade. There were amounts of hipocellular connective tissue, hyalinised, with small foci of dystrophic calcification. Mitoses were rare (less than 3/10 HPF). Blood vessels surrounded the connective tissue. Reviewed material did not contain elements of the parent organ. Immunohistochemically there were positivity on CD34 and vimentin, and negativity to S100, SMA, CD117, dezmin, and Ki-67 is < 2%. The change was diagnosed as a solitary fibrous tumor. CONCLUSION: Considering that benign solitary fibrous tumors of extrathoracic localizations are extremely rare neoplasms with unpredictable biological behavior and the possibility of recurrence, a long-term clinical and endoscopic follow-up on yearly basis of patients with this disease is recommended. PMID- 26731981 TI - Good's syndrome with increasing gammadelta T-lymphocyte subpopulation: A case report. AB - INTRODUCTION: Good's syndrome is a rare cause of adult-onset immunodeficiency associated with thymoma. Good's syndrome should be considered in patients older than 40 years with the history of frequent infections. An abnormal immunoglobulin profile needs further investigation and flow cytometry which is crucial for establishing the diagno- sis of Good's syndrome. CASE REPORT: We present a 56- year-old men with Good's syndrome diagnosed after a two-year history of recurrent infections. Examination of immune status of the patient showed decreased serum levels of all immunoglobulins. Flow cytometry of peripheral blood lym-phocyte revealed markedly reduced peripheral B cells, CD4 T-cell lymphopenia, inverted CD4/CD8 T-cell-ratio 0.37 (CD4--20.82%, CD8--70.7%). Analysis of the subpopulations of T-lymphocytes showed relative increasing gammadelta T cell receptor (TCR) T lymphocytes. Computed tomography scan of the chest showed a mediastinal mass compatible with thymoma of the diameter of 40 mm. After initiation of intravenous immunoglobulins the patient was in the good clinical condition and without bacterial complications. As the patient refused the operative treatment we continued to control the mediastinal tumor mass which did not increase during a 3-year follow-up. CONCLUSION: The presented patient had a typical immunological finding for Good's syndrome, but also the increase in gammadelta TCR T-lymphocyte subpopulation for which it is difficult to determine whether this is pathogenetic or secondary reactive event. PMID- 26731982 TI - Discover, Develop & Validate--Advance and Prospect of Tumor Biomarkers. AB - Tumor biomarkers can serve as tools for early detection, diagnosis, prognosis, therapeutic target, response predicting, therapy monitoring of tumors or can be used as surrogate endpoints. Their abilities to assist various clinical decisions make them indispensable tools for current oncotherapies. Therefore, in the past decades, significant effort has been put into finding sensitive, specific, noninvasive, inexpensive, and clinically feasible tumor biomarkers. This review will summarize the recent progress made in different kinds of tumor biomarkers, introduce a promising and versatile novel tumor biomarker called DEK oncoprotein, and lastly, discuss the prospects of tumor biomarkers. PMID- 26731983 TI - Artesunate Attenuates Lung Injury in Paraquat-Intoxicated Rats via Downregulation of Inflammatory Cytokines. AB - BACKGROUND: The present study was designed to analyze the dynamic changes in transforming growth factor beta 1 (TGF-beta1), interleukin (IL)-10, and tumor necrosis factor alpha (TNF-alpha) in paraquat (PQ)-intoxicated rats and to evaluate the effects of artesunate on PQ-induced lung injury. METHODS: Sixty healthy male Sprague-Dawley (SD) rats were randomly assigned to the control (n = 10), PQ (n = 25), and artesunate-treated PQ (n = 25) groups. The plasma levels of TGF-betal, IL-10, and TNF-alpha were measured at 0 (control), 12, 24, 48, and 72 hours after PQ poisoning. The pathological changes in the lung tissues were also examined. RESULTS: Signs of PQ poisoning began to show at 12 hours after PQ administration; the levels of serum TGF-beta1, IL-10, and TNF-alpha were significantly increased (p < 0.01), compared with the control group. The effects of artesunate treatment were evident at 12 hours after PQ poisoning and became statistically significant at 48 hours, compared with the control and PQ groups, respectively (p < 0.05, p < 0.01). CONCLUSIONS: The PQ-induced lung injury was attenuated by artesunate treatment. IL-10, TNF-alpha, and TGF-beta1 may play an important role in PQ-induced lung injury, which can be prevented by artesunate treatment. PMID- 26731984 TI - An Association Study Identifies Two Single Nucleotide Polymorphisms on Chromosome 11q23.3 as a Risk Locus for Acute Myocardial Infarction in the Chinese Han Population. AB - BACKGROUND: To evaluate whether the Chinese Han population harbors genetic markers associated with risk of acute myocardial infarction (MI), which have previously been identified in other ethnic populations. METHODS: According to predefined criteria, 549 Chinese patients with acute MI and 551 Chinese subjects (controls) without a history of coronary artery disease (CAD) were selected for the study. Three prevalent single nucleotide polymorphisms (SNPs; rs1412444(LIPA), rs662799(APOA5) and rs964184(ZNF259)) associated with CAD and MI in other ethnic populations, were selected for sequence and association analyses within blood DNA of the Chinese Han population. RESULTS: Only two SNPs, rs662799 (APOA5) and rs964184 (ZNF259) found at two independent loci, were associated with risk of MI in the Chinese Han population. Using Bonferroni correction methods, significant differences in the association of these two SNPs (rs662799 (p = 0.0228) and rs964184 (p = 0.0060)) between Chinese patients with MI versus controls were revealed. CONCLUSIONS: We identified a significant association between two SNPs (rs964184 and rs662799) on chromosome 11q23.3 and MI risk in the Chinese Han population, which extends their clinical relevance to predicting the risk of MI in diverse ethnic populations. PMID- 26731985 TI - miR-31 Overexpression Exacerbates Atherosclerosis by Targeting NOX4 in apoE(-/-) Mice. AB - BACKGROUND: Increasing evidence has shown that microRNAs are involved in apoptosis in different cells. However, the role of miR-31 in atherosclerosis (AS) has never been elucidated. In the present study, we identified the impact of miR 31 on atherosclerosis in macrophages. METHODS: The level of miR-31 in macrophages was examined in apoE-/- mice. Cell viability and apoptosis were examined in macrophage cells transfected with miR-31 mimics, inhibitors or negative control. In addition, the impact of NOX4 on cell apoptosis was tested with a specific siRNA targeting NADPH oxidase 4 (NOX4). RESULTS: An enhanced level of miR-31 was found in macrophage cells of apoE-/- mice, suggesting that miR-31 might contribute to abnormal cell proliferation of macrophage cells. Upregulation of miR-31 decreased cell viability and induced macrophage cell apoptosis. Moreover, knockdown of NOX4 reduced cell migration capacity and enhanced cell apoptosis. CONCLUSIONS: The current data suggested that miR-31 contributed to macrophage apoptosis by regulating the expression of NOX4. PMID- 26731986 TI - miR-31 Reduces Cell Growth of Papillary Thyroid Carcinoma by RNA-Binding Protein HuR. AB - BACKGROUND: Increasing evidence suggests that microRNAs are widely involved in cancer progression and metastasis. However, the specific role of miR-31 in papillary thyroid carcinoma (PTC) is still largely unknown. METHODS: The level of miR-31 and HuR was detected in 30 pairedcancerous and noncancerous tissue samples using real time PCR. The impact of miR-31 on PTC cell viability and apoptosis was explored using MTT assay and flow cytometry, respectively. To explore the effect of miR-31 on HuR expression, luciferase reporter assay was used. RESULTS: In papillary thyroid carcinoma patients, miR-31 was significantly down regulated. Furthermore, down regulation of miR-31 increased the proliferation, migration, and invasion of ovarian carcinoma cells. Vice versa, over expression of miR-31 repressed cell invasion and viability. The luciferase reporter assay revealed that HuR was a target for miR-31. Further analysis defined that knockdown of HuR resulted in enhanced cell viability and decreased cell migration rate. CONCLUSIONS: Down regulation of miR-31 contributed to the malignant progression of papillary thyroid carcinoma cells by targeting HuR. PMID- 26731987 TI - Epidermal Growth Factor Receptor Inconsistency by Immunohistochemistry Method Using Different Monoclonal Antibodies in Colorectal Cancer Patients. AB - BACKGROUND: Targeted therapy is typically used to treat colorectal cancer (CRC). The epidermal growth factor receptor (EGFR) was recognized as a potential therapeutic target. Does the EGFR protein express consistently using different monoclonal antibodies in clinics? METHODS: One hundred and sixty-four patients (mean age 61.80 +/- 12.78 years) who suffered from CRC were selected at Mackay Memorial Hospital in Taiwan. Formalin-fixed and paraffin-embedded tissue sections from all patients were tested simultaneously using two commercial antibodies, Dako-EGFR (mouse monoclonal anti-EGFR clone 2-18C9, pharmDx) and NCL-EGFR (NCL EGFR-384, Novocastra) monoclonal antibodies, to study the commutability or equality of the qualities of EGFR expression by standard immunohistochemistry (IHC) procedures. RESULTS: The EGFR expressions that were obtained by IHC staining using different monoclonal antibodies with Dako-EGFR (46.95%) and NCL EGFR (32.32%) were fairly concordant. CONCLUSIONS: Although IHC is a convenient and feasible method for detecting the expression of EGFR, it yields controversial staining results concerning EGFR expression using various commercial antibodies in a CRC tumor section. PMID- 26731988 TI - Predictive Significance of Peripheral Blood Smears in Patients with Fever of Unknown Origin: A Retrospective Study of 2871 Cases. AB - BACKGROUND: Fever of unknown origin (FUO) is a common manifestation and diagnostic problem especially in primary care. Pointing out a diagnosis of FUO often requires numerous noninvasive and invasive procedures. Peripheral blood (PB) smear examination frequently provides many timely and valuable diagnostic clues in various disorders. Few assessments of PB smear morphologic examinations used in the diagnostic evaluation of FUO have been reported. METHODS: To determine whether PB smears have important roles in exploring the causes of FUO, we collected PB smears of 2871 FUO patients from Beijing Chao-yang Hospital affiliated to Capital Medical University from September 2012 to August 2014. Combined with relevant clinical data, we analyzed the PB morphologic features in all the FUO patients. RESULTS: We found the presence of atypical lymphocytes (64.33%), nuclear left shift (46.33%), toxic granulation, vacuolization, and 4 cases of malaria in FUO patients, markedly more than the health control group (p < 0.05), and morphologically consistent with the diagnosis of infectious diseases. Notably, the presence of blasts or immature cells in 26 cases (9%o) and the abnormal changes of leukocytes, erythrocytes or platelets in 4 cases provided predictive information for exploring the causes of FUO, followed by bone marrow smears and other procedures to further confirm the diagnosis as hematological diseases, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), Evans syndrome, agranulocytosis, immune thrombocytopenic purpura (ITP). CONCLUSIONS: Our findings demonstrate that a timely and careful observing of PB smears is helpful for clarifying the diagnosis and contributes to appropriate treatment in patients with FUO. PMID- 26731989 TI - ADMA--a Possible Marker for Early Therapeutic Outcome in Acute Stroke. AB - BACKGROUND: Ischemic acute stroke is a leading cause for mortality and invalidity in recent years. Clinical trials show the role of ADMA as endogenous inhibitor of nitric oxide synthase and its connection to acute stroke. An early decrease of serum ADMA levels might help in recovery of the blood stream in patients with acute stroke and non-affective changes in the brain. METHODS: We compared 18 patients with acute stroke before and after thrombolysis and 21 patients (without history of cardiovascular disease, diabetes, kidney and liver injury, non smokers) before and after thrombolysis. All results were compared to 30 healthy persons. Patients were evaluated by NIHSS, with ultrasound, CT and laboratory methods (traditional risk factors and CRP, D-dimmer, homocysteine, and ADMA). RESULTS: Classic vascular factors showed statistical significance in patients with acute stroke. Serum hsCRP levels and D-dimer in our study showed no connection to acute stroke. We found a statistically significant correlation in patients with stroke between ADMA and homocysteine levels (r = 0.469, p < 0.001). We found no significant difference between basic serum ADMA concentrations in groups with stroke who underwent different treatment (r = -0.449, p < 0.001). In patients with thrombolysis ADMA concentrations are reduced earlier, which also shows that earlier clinical recovery leads to no brain damaging effects. CONCLUSIONS: Through its pathophysiological changes, ADMA might be a predictor for acute stroke (along with already known risk factors) and can be a marker for the outcome of stroke, depending on the treatment. PMID- 26731990 TI - Association of APPL1 Gene Polymorphism with Non-Alcoholic Fatty Liver Disease Susceptibility in a Chinese Han Population. AB - BACKGROUND: The adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1 (APPL1) has been suggested to play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The aim of this article is to explore the relationship between APPL1 rs4640525 polymorphism and the susceptibility of NAFLD in a Chinese Han population. METHODS: In this study, rs4640525, a significant single nucleotide polymorphism, in the APPL1 gene was detected by the polymerase chain reaction-restriction fragment length polymorphism method, followed by extracting genomic DNA from peripheral blood leukocytes from patients with NAFLD (n = 280) and matched controls (n = 281). RESULTS: The frequency of both the GG genotype and the G carrier (CG+GG) genotype were higher in NAFLD subjects compared with control subjects (all p < 0.05). The G allele frequency was 0.3036 in the NAFLD group and 0.2206 in the control group, showing a significant difference (p < 0.05). What is more, multivariate logistic regression analysis suggested that the GG genotype, G carrier genotype, body mass index, waist circumference, white blood cells, total cholesterol, alanine aminotransferase, and gamma-glutamyl-transferase might be associated with an increased susceptibility of NAFLD (all p < 0.05). CONCLUSIONS: The article provides evidence that GG genotype and G carrier (CG+GG) genotypes of the rs4640525 polymorphism in the APPL1 gene may be suitable susceptibility biomarkers for NAFLD. PMID- 26731991 TI - Prognostic Value of MicroRNA-125 in Various Human Malignant Neoplasms: a Meta Analysis. AB - BACKGROUND: To date, many studies have reported that microRNAs participate in human carcinogenesis as tumor suppressors or oncogenes and may play important roles as prognostic biomarkers of cancer. The aim of this meta-analysis was to assess the prognostic value of circulating miR-125 in human malignant neoplasms by summarizing the results from all available studies. METHODS: A systematic literature review was carried out using PubMed and Embase. We extracted and estimated the hazard ratios (HRs) for overall survival, which enabled comparison of the high and low expression levels of miR-125 in patients included in the available studies. The analysis was carried out using Stata version 12.0. RESULTS: A total of 15 articles including 1,606 patients were included in this meta-analysis. For overall survival, the pooled HR of higher miR-125 expression in human malignant neoplasms was 0.90 (95% confidence interval [CI]: 0.58 - 1.38, p = 0.000). Subgroup analysis showed that higher miR-125a expression may predict better survival in patients with cancer (HR = 0.56, 95% CI: 0.41 - 0.76, p = 0.226). However, higher miR-125b expression may predict poorer survival in colorectal cancer (HR = 2.32, 95% CI: 1.35 - 3.99, p = 0.513), non-small cell lung cancer (HR = 2.33, 95% CI: 1.78 - 3.03, p = 0.519), and prostate cancer (HR = 1.60, 95% CI: 1.01 - 2.54, p = 0.292), but better survival in hepatocellular carcinoma (HR = 0.52, 95% CI: 0.34 - 0.81, p = 0.696). CONCLUSIONS: These results suggest that different members of the miR-125 family may have different functions in various cancers. Furthermore, miR-125a or miR-125b may be important clinical prognostic biomarkers for cancer patients. PMID- 26731992 TI - Serum Retinol-Binding Protein-4 Level is a High Risk Factor for Coronary Heart Disease in Chinese. AB - BACKGROUND: Recent evidence suggests that retinol-binding protein-4 (RBP4) is involved in the pathogenesis of cardiovascular diseases. This study aimed to evaluate whether serum RBP4 level is a high risk factor for coronary heart disease (CHD) in Chinese. METHODS: Two hundered ten consecutive patients hospitalized at the Department of Cardiology between September 2012 and September 2014 were enrolled, including 148 males and 62 females, with an average age 63.89 +/- 13.05 years. The patients were divided into the carotid artery plaque-free group (130 cases) and carotid atherosclerosis plaque group (80 cases), or into the no CHD group (160 cases) and CHD group (50 cases). Data of cardiovascular risk factors were collected from each patient and analyzed. Serum RBP4 level was determined using an enzyme-linked immunosorbent assay. Results: The age, serum RBP4 level, smoking, and hypertension were independently associated with carotid artery plaque formation, while serum RBP4 level, hypertension, diabetes, and carotid artery plaque formation were independently associated with CHD. CONCLUSIONS: Elevated serum RBP4 level is one of the important risk factors for both carotid artery plaque formation and CHD in Chinese. Early detection and control of serum RBP level may help in the prevention, diagnosis, and therapy of CHD. PMID- 26731993 TI - High Expression of IncRNA-PCNA-AS1 in Human Gastric Cancer and its Clinical Significances. AB - BACKGROUND: Long noncoding RNAs (IncRNAs) have been demonstrated to be associated with human cancer. However, the clinical value of most lncRNAs to serve as the biomarkers for gastric cancer remains largely unknown. In this study, we examined the relationship between the expression levels of IncRNA, PCNA antisense RNA 1 (PCNA-AS1), and clinicopathological characteristics of gastric cancer. METHODS: A total of 90 tissue samples from patients with gastric cancer were collected, and the IncRNA PCNA-AS1 levels in cancer and paired non-cancer tissues was detected by real-time quantitative RT-PCR (qRT-PCR). The relationship between PCNA-AS1 levels and the clinicopathological characteristics were then evaluated. RESULTS: PCNA-AS1 expression levels were increased in 68 of 90 gastric cancer tissues (75.56%) and were associated with invasion (p = 0.038), but not associated with other clinicopathological characteristics. The expression levels of PCNA-AS1 were also related with immunohistochemical biomarkers of BRCA1 (p = 0.043) and RRM1 (p = 0.023). CONCLUSIONS: These data indicated that IncRNA-PCNA-AS1 may participate in the gastric cancer carcinogenesis and development and may serve as a new biomarker for patients with gastric cancer. PMID- 26731994 TI - Assessment of Hepatic Disorders in Patients with Type 2 Diabetes by Means of a Panel of Specific Biomarkers for Liver Injury. AB - BACKGROUND: Modern biomarkers for the assessment of liver cell damage are indicative for distinct hepato-cellular deteriorations. We investigated the prevalence of these markers in healthy subjects and patients with early stage type 2 diabetes mellitus (T2DM) on metformin monotherapy. METHODS: The study was performed with blood from 36 healthy subjects (17 females, age: 43 +/- 12.4 years, BMI: 22.6 +/- 1.5 kg/m2) and 32 T2DM patients (15 females, age: 57 +/- 7.9 years, BMI: 35.0 +/- 6.3 kg/m2, HbA1c: 7.3 +/- 0.8%). Parameters for liver cell damage included ALT and AST and alpha-glutathione-S-transferase (alpha-GST, acute liver injury), keratin 18 (K18, cell necrosis), caspase-cleaved K18 (ccK18, cell apoptosis), and collagen IV (C-IV, fibrosis). In addition, insulin, intact proinsulin, and hsCRP were determined for staging insulin resistance, beta-cell dysfunction, and chronic systemic inflammation. RESULTS: Differences were seen for mean ALT (T2DM: 36 +/- 19 U/L vs. control: 20 +/- 8 U/L, p < 0.001) but not for mean AST (26 +/- 15 U/L vs. 25 +/- 5 U/L, n.s.). All other biomarkers but insulin were higher in the T2DM group (intact proinsulin: 10 +/- 6 pmol/L vs. 2 +/- 1 pmol/L; hsCRP: 4.8 +/- 2.7 mg/L vs. 1.1 +/- 0.8 mg/L, alpha-GST: 17.3 +/- 12.2 MUg/L vs. 9.5 +/- 0.2 MUg/L, K18: 235 +/- 125 U/L vs. 100 +/- 33 U/L, ccK18: 280 +/- 158 U/L vs. 167 +/- 35 U/L, C-IV: 114 +/- 28 MUg/L vs. 92 +/- 20 MUg/L, all p < 0.001). Elimination of seven T2DM patients with elevated ALT or AST values did not change the overall results, which were also independent from the stage of the underlying diabetes disorders. CONCLUSIONS: Potential indications of liver cell damage were detected in T2DM patients with more specific biomarkers, which would not have been detected by ALT and AST alone. PMID- 26731995 TI - Penetration Potential of a Silver Diamine Fluoride Solution on Dentin Surfaces. An Ex Vivo Study. AB - BACKGROUND: Occurrence of open dentinal tubules as a cause of dental hypersensitivity is a very common pnenomenon in patients. The aim of this in vitro study was to assess the effect of a silver diamine fluoride solution (Ag(NH3)2 F) on human dentin samples. METHODS: A total of five fully retained wisdom teeth were selected for this study. The crowns of the teeth were separated from the roots and the occlusal enamel surface was removed. All dentin samples were treated for 60 seconds with phosphoric acid (36%) and rinsed thoroughly to remove the smear layer. Then the desensitizing agent (Riva Star, SDI; 38% Ag(NH3)2 F) was placed according to the manufacturer's instruction. Three dentin samples were prepared for element analysis using an electron beam microprobe analyzer (JEOL JXA 8900RL). The Ag concentrations in the dentin samples were measured in depths ranging from 5 to 40 MUm. The other two dentin samples were vertically fractured and accordingly prepared for visualization with SEM (Zeiss DSM). RESULTS: The application of the desensitizing agent on the dentin areas demonstrated an increased Ag concentration (JEOL JXA 8900RL). On the dentin surface an Ag concentration of 1.7 weight % (? 0.7) was measured, but at a depth of 20 MUm only 0.3 weight % (+/- 0.1) were detected. In depths greater than 40 MUm the Ag concentration was below the detection limit. The SEM results showed that deposits could be found in a covering on the dentin layer and in the dentinal tubules to a depth of 20 MUm. CONCLUSIONS: In this ex vivo study, the effect of silver diamine fluoride on dentin surfaces could be demonstrated. The desensitizing agent formed a film on the dentin surface and in some dentinal tubules deposits were detected. These findings can explain a certain desensitizing effect, but a direct translation to in vivo conditions can only be done with caution. PMID- 26731996 TI - Effect of Dental Pulp Stem Cells (DPSCs) in Repairing Rabbit Alveolar Bone Defect. AB - BACKGROUND: The aim of this research was to analyze the ability of dental pulp stem cells (DPSCs) in repairing rabbit alveolar bone defect. METHODS: First, DPSCs were isolated from the pulp tissue of the anterior teeth and molars of young rabbits and cultured in vitro. Subsequently, cell cloning efficiency, anti vimentin, and anti-CD44 immunohistochemical staining were investigated. Second, bone defect models were made in rabbit alveolar toothless jaw. The bone defects in the control group were filled with 0.25 g bio-oss bone mixed with PBS solution, while the bone defects in the experimental group were filled with 0.25 g bio-oss bone mixed with 1 x 108 DPSCs/L. Animals were sacrificed six weeks after the surgery, the alveolar tissue was collected for paraffin sections, HE staining, and immunohistochemistry of bone sialoprotein (BSP). RESULTS: The immunocytochemistry results of surface markers showed a positive staining of vimentin and CD44 in the DPSCs forming low density colonies after inoculation. The alveolar tissue of the control group showed a small amount of erythrocytes highlighted by HE staining, with no visible new bone formation except for a few osteoblasts, with a weakly positive BSP immunohistochemical staining. HE staining in the experimental group showed that the inflammatory exudate was significantly absorbed, some new bone tissue was present, with many osteoblasts around the bone defects, and with a strong positive BSP immunohistochemical staining, which was statistically significant compared to the control group (p < 0.05). CONCLUSIONS: DPSCs possess the ability to differentiate into bone cells, promoting the repair and regeneration of alveolar bone defects. PMID- 26731997 TI - Association between Affinity of Anti-HCV Antibodies and Viral Load in Patients with HCV Infection: a New Method to Estimate Patients' Immune Status. AB - BACKGROUND: The status of immune response to HCV infection cannot be accurately predicted by the HCV antibody test alone. Our paper aims to explore differences in total activity, quantity, and affinity of anti-HCV antibodies in patients with HCV infection, proposing a novel measurement of antibody affinity and providing a promising understanding into immune response to HCV. METHODS: Serum samples from 106 patients with HCV infection were collected. Anti-HCV antibodies, HCV RNA, ALT, and AST were measured. The samples were divided into three groups based on ALT, AST level (both normal, one abnormal, and both abnomal) and HCV-RNA level (negative, low viral load, and high viral load). Differences in total activity, quantity, and affinity of anti-HCV antibodies were analyzed. RESULTS: The quantity of anti-HCV antibodies in the normal ALT and AST groups were significantly lower than that of the other two groups (p < 0.05). In contrast, the antibody affinity of the normal ALT and AST groups was significantly higher than that detected in the other two groups (p < 0.05). The total activity and quantity of anti-bodies in the low and high viral load groups were significantly higher than those measured in the HCV RNA-negative group (p < 0.05). The HCV RNA negative group had a significantly higher antibody affinity than the other two groups (p < 0.05). HCV-RNA level was negatively correlated with affinity (p < 0.05). CONCLUSIONS: Our results indicate that the total activity, quantity, and affinity of anti-HCV antibodies may reflect viral load in patients infected with HCV and could serve as valuable information for clinical applications. PMID- 26731998 TI - Evaluation of a New Multiparametric Microspot Array for Serodiagnosis of Lyme Borreliosis. AB - BACKGROUND: Laboratory diagnosis of Lyme borreliosis follows a two-step algorithm, starting with a screening assay with maximum sensitivity followed by a confirmatory assay of positive results with respect to specificity. Line immunoassays with single recombinant antigen lines are the established confirmatory test method, although result interpretation is not standardized. The present study evaluates suitability of the multiplex test SeraSpot Anti-Borrelia IgG/IgM (SeraSpot) as confirmatory test in serodiagnosis of Lyme disease. METHODS: For this retrospective study, serum samples from patients with suspicion of Lyme borreliosis were analyzed. For determination of specificity, blood donor samples as well as rheumatoid factor (RF), ANA, and EBV positive sera were investigated. The SeraSpot IgG/IgM results were compared with the recomBead Borrelia IgG/IgM (recomBead) test as alternative multiplex-based method. RESULTS: In comparison to the recomBead test the sensitivity of SeraSpot was determined 95% for IgG/IgM detection. The analysis of blood donors revealed a specificity of >= 96.0% for SeraSpot IgG/IgM and of 97.3% for recomBead IgG/IgM. RF positive samples tested negative by both assays (specificity of 100%). ANA and EBV antibody positive samples resulted in specificities of 90% (SeraSpo IgG/IgM) and >= 94% (recomBead IgG/IgM) and >= 91% (SeraSpot IgG/IgM) and >= 91% (recomBead IgG/IgM). The intra- and interassay coefficient of variation (CV) and the lot-to lot reproducibility of the SeraSpot assay ranged between 1 - 9% for the different Borrelia IgG and IgM antigens. Potentially interfering substances (bilirubin F, bilirubin C, hemoglobin, lipid factor, and rheumatoid factor) did not influence the SeraSpot assays. CONCLUSIONS: Our evaluation data confirm that new multiplex assay generations such as SeraSpot Anti-Borrelia IgG/IgM are reliable and robust test systems suitable for application as confirmatory tests for serodiagnosis of Lyme borreliosis. PMID- 26731999 TI - Association of Apolipoprotein A1, B with Stenosis of Intracranial and Extracranial Arteries in Patients with Cerebral Infarction. AB - BACKGROUND: To investigate the distribution of stenosis of intracranial and extracranial arteries of Han population patients suffering from cerebral infarction in the city of Quanzhou in Fujian and to determine the correlation of apolipoprotein A1 and apolipoprotein B with intracranial and extracranial atherosclerosis stenosis. METHODS: For this study, we enrolled patients with cerebral infarction between December 2009 and October 2012 at the Neurology Department of The Second Affiliated Hospital of Fujian Medical University. All patients were examined by computed tomography angiography (CTA). Past medical history, demographic data, and biochemical markers were collected. Multiple logistic regression analysis was used to study the association between apo A1, apo B, and cerebral atherosclerosis stenosis. RESULTS: A total of 412 patients were included in this study. 137 cases (33.3%) were classified as the intracranial atherosclerosis stenosis (ICAS) group, 74 cases (18.0%) as the combined intracranial and extracranial atherosclerosis stenosis (COAS) group, 44 cases (0.7%) as the extracranial atherosclerosis stenosis (ECAS) group, and 157 cases (38.1%) as the non-cerebral atherosclerosis stenosis (NCAS) group. Middle cerebral arteries (43.8%) were the most common lesions of intracranial arterial atherosclerosis stenosis. Extracranial carotid stenosis (30.7%) were more likely to be stenoses in the extracranial internal carotid arteries. Compared with the NCAS group, apo B was significantly higher (p < 0.001), apo A1 was significantly lower in the ICAS group and COAS group (p = 0.02 and p = 0.030). Compared with the mild atherosclerosis stenosis group, apo B was higher in the severe extracranial atherosclerosis stenosis group (p = 0.03), apo A1 was lower in the severe intracranial atherosclerosis stenosis group (p < 0.001). The multiple logistic regression analyses showed that when apo A1 > 1.28 g/L, it was an independent protective factor of intracranial stenosis (OR, 0.39), apo B was an independent risk factor of the cerebral atherosclerosis stenosis group, and when apo B > 1.16, it is significantly associated with the cerebral atherosclerosis stenosis group (ICAS: OR, 6.41) (ECAS: OR, 5.15). CONCLUSIONS: 1. The occurrence of atherosclerosis stenosis in intracranial arteries is more frequent than that in extracranial arteries in population with cerebral infarction; 2. Apo B is an independent risk factor of intracranial and extracranial arterial stenosis, apo A1 is associated with the degree of intracranial stenosis and an independent protector of intracranial stenosis. PMID- 26732000 TI - Diagnostic and Long-Term Prognostic Value of Sensitive Troponin I in Symptomatic Patients Suspected of Acute Heart Failure. AB - BACKGROUND: To evaluate the diagnostic and prognostic value of sensitive troponin I (TnI) in patients with acute dyspnea and/or peripheral edema suspected of having acute heart failure (AHF). METHODS: This single centre prospective clinical study evaluates 372 patients presenting with acute dyspnea and/or peripheral edema to the emergency department (ED). Measurements of TnI and NT proBNP were performed at the initial presentation in the ED. All patients were followed up to 5 years. The diagnostic value of TnI compared to NT-proBNP for AHF diagnosis as well as long-term prognostic values for all cause mortality and AHF related rehospitalization were evaluated. RESULTS: TnI plus NT-proBNP improved the diagnosis of AHF (improvement of accuracy (75%, 95% CI 71% - 79%), specificity (68%, 95% CI 62% - 74%), PPV (54%, 95% CI 47% - 62%), and NRI +0.15) compared to NT-proBNP alone (p = 0.0001). TnI levels showed independent prognostic value for all-cause mortality and AHF related rehospitalization after 1 and 5 years (range of AUCs 0.64 - 0.72; p = 0.03 or lower). Highest TnI levels of the 4th quartile revealed an up to 5.5 times higher risk of death within 1 and 5 years (range of HRs: 2.5 - 5.5; p = 0.0001). TnI added significantly to multivariable Cox prediction models even after adjusting for NT-proBNP, particularly in AHF patients (range of HRs: 2.1 - 2.7; p <= 0.05). CONCLUSIONS: TnI improves AHF diagnosis when combined with NT-proBNP. TnI identifies patients with high 1- and 5-year all-cause mortality and AHF-related rehospitalization risk and adds prognostic value to NT-proBNP. PMID- 26732001 TI - Analytical Performance of Multiplex Real-Time PCR for Six Sexually Transmitted Pathogens. AB - BACKGROUND: Most organisms that cause sexual transmitted diseases (STDs) are fastidious pathogens that are difficult to detect with conventional microbiological methods and the proportions of multiple infections were noted up to 39.3% among the STI-positive subjects. However, only a few multiplex PCR and multiplex real-time PCR tests that can screen more than six microorganisms that cause STDs have been assessed. METHODS: A total of 114 endocervical swabs (ThinPrep PAPTEST PreservCyt Solution, Hologic Inc., Marlborough, MA, USA) were collected from healthy Korean women. Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Mycoplasma genitalium (MG), Mycoplasma hominis (MH), Ureaplasma urealyticum (UU), and Trichomonas vaginalis (TV) were detected by uniplex PCR with Seeplex kits and by multiplex real-time PCR with Real-Q Kits (Biosewoom Inc., Seoul, Korea). To evaluate analytical sensitivity, plasmids containing target genes from CT, NG, MG, MH, UU, and TV were serially diluted five times with saline buffer and replicated eight times per dilution. RESULTS: Real-Q STIs Kit assays showed 100% sensitivity for detecting MH, MG, CT, TV, NG and 94.1% sensitivity for detecting UU. In addition, it showed 100% specificity for UU, MH, MG, CT, TV, and NG. The analytic sensitivity of UU (95% probit = 17.3 copy/MUL, 95% CI = 11.6 to 138.6) and MH (95% probit = 30.9 copy/MUL, 95% CI = 20.6 to 169.9) was relatively lower than for others pathogens. Thus, the cutoff Ct value of < 45 for UU and MH and a cutoff Ct value of < 38 for CT, MH, NG, TV could minimize differences in detection limit among the six STIs (95% probit values = 5.3 to 14.6) and to optimize overall diagnostic performance. CONCLUSIONS: For medical applications of a multiplex real-time PCR assay, one kind of cutoff value, which is according to manufacturer's instructions, was generally used without the consideration of lowest actual detectable concentration of each target substance. However, analytical performance at the low concentration limit often defines the ability of the test to diagnose disease and determine treatment endpoints. Therefore, suitable cutoffs for negative or positive screens by multiplex real-time PCR should be evaluated for accurate diagnosis. PMID- 26732002 TI - Post-Infectious Organizing Pneumonia: an Indistinguishable and Easily Misdiagnosed Organizing Pneumonia. AB - BACKGROUND: Post-infectious organizing pneumonia (OP) is a rare clinical entity associated with nonspecific clinical features and can be easily misdiagnosed. This study aimed to investigate the clinical feature differences between cryptogenic organizing pneumonia (COP) and post-infectious OP. METHODS: We retrospectively analyzed clinical data on demographic characteristics, clinical manifestations, laboratory findings, radiological findings, treatments, outcomes, and prognosis of 31 cases of COP and 26 cases of post-infectious OP. Patients were treated in Beijing Chao-yang Hospital between July 2005 and January 2013. RESULTS: Compared with patients with COP, patients with post-infectious OP are more prone to show fever (88.5% vs. 38.7%, p < 0.05) and crackles (46.2% vs. 6.5%, p < 0.05). The elevation of PCT serum levels is more obvious in the early stage of post-infectious OP (5.24 +/- 1.96 vs. 0.28 +/- 0.09) and bilateral lung consolidations and patchy shadows are the most common radiological findings (70.2%). Pathogens are more prone to be confirmed within 48 hours after admission and the diagnosis time is longer (10.0 +/- 0.8 vs. 7.2 +/- 0.4 days). The incidence of mechanical ventilation (50% vs. 19.4%) and the utilization rate of antibiotics are higher (100.0% vs. 70.9%). The dosage (0.58 +/- 0.04 vs. 0.78 +/- 0.04 mg) and utilization time of glucocorticoids (5.7 +/- 0.4 vs. 7.9 +/- 0.8 months) are obviously reduced. CONCLUSIONS: The morbidity of post-infectious OP is not uncommon. PCT serum level is helpful in the diagnosis and differential diagnosis, but invasive procedures like bronchoscopic or surgical lung biopsy are the golden-standard methods to confirm diagnosis. Similar to COP, antibiotics are effective in the early stage of post-infectious OP, but glucocorticoids are effective in the late stage. The prognosis of post-infectious OP is good. PMID- 26732003 TI - Reference Intervals for Routine Blood Tests in 468 Healthy Mongolian Children. AB - BACKGROUND: To establish reference intervals for routine blood parameters of healthy Mongolian children in the Inner Mongolia Daxingan region. METHODS: Venous blood samples from 468 children aged 7 - 13 years were analyzed with a Sysmex XE 5000 Automated Hematology Analyzer. Statistical analysis was used to compare findings with the National Clinical Laboratory Procedures and to analyze according to gender and ethnic group. RESULTS: The reference range for each blood cell parameter is as follows: WBC (x 109/L): 3.44 - 9.27 for males, 3.79 - 9.79 for females; RBC (x 1012/L): 4.25 - 5.36 for males, 4.20 - 5.21 for females; HGB (g/L): 118 - 149. HCT (%): 34.9 - 43.4; MCV (fl): 75.1 - 88.2 for males, and 76.6 - 90.6 for females; MCH (pg): 25.5 - 30.3 for males, and 25.7 - 31.0 for females; MCHC (g/L): 327 - 356 for males, 323 - 353 for females; PLT (109): 109 - 209; NEUT %: 34.6 - 71.9; LYMPH %: 19.8 - 56.8; MONO %: 2.8 - 9.5 for males, and 3.1 - 7.9 for females; EO %: 0.0 - 3.6; BASO %: 0.0 - 1.0 for males, and 0.0 - 0.9 for females. There were significant differences between genders with respect to the WBC, RBC, MCV, MCH, MCHC, MONO %, and BASO % parameters (p < 0.05), but not other parameters (p > 0.05). CONCLUSIONS: The blood parameters of children can vary with geography, nationality, gender, and other variables. Therefore, it is necessary to obtain reference intervals for Mongolian children according to their gender and age. PMID- 26732004 TI - The Higher Prevalence of Non-Alcoholic versus Alcoholic Steatohepatitis in Alcoholics. AB - BACKGROUND: The aim of this study was to evaluate the prevalence of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH) in alcoholics by non-invasive biochemical markers: AshTest and NashTest. METHODS: The tested group consisted of 142 alcoholic patients. All biochemical markers were assessed using the recommended methods. RESULTS: The highest values of AshTest and NashTest were observed in the highest H3 score and N2 score, respectively. The distribution of AshTest scores was the following: H0 - 94.1%, H1 - 5.2%, H2 - 0%, and H3 - 0.7%, while for NashTest was: N0 - 56.6%, N1 - 38.2% and N2 - 5.1%. In summary, alcoholic steatohepatitis was present only in 5.9% of alcoholics and non alcoholic steatohepatitis in 43.3% of patients. Co-occurrence of ASH and NASH was observed in 3.7% of patients. The BMI, mean glucose, and triglyceride levels were significantly different between NashTest scores, but not between AshTest scores. These results may evidence that non-alcoholic steatohepatitis is associated with metabolic risk factors such as diabetes mellitus, dyslipidemia, and obesity. The MCV value and AST/ALT ratio were higher in alcoholic steatohepatitis than in non alcoholic steatohepatitis. CONCLUSIONS: In conclusion, the prevalence of non alcoholic steatohepatitis in alcoholics is higher than of alcoholic steatohepatitis, as estimated by non-invasive tests. Co-occurrence of alcoholic steatohepatitis and non-alcoholic steatohepatitis in alcoholic patients is low and the high prevalence of non-alcoholic steatohepatitis is related with high occurrence of metabolic risk factors. PMID- 26732005 TI - Xpert MTB/RIF Assay for Pulmonary Tuberculosis and Rifampicin Resistance in Children: a Meta-Analysis. AB - BACKGROUND: The Xpert MTB/RIF assay has been recommended by WHO to replace conventional microscopy, culture, and drug resistance tests. It simultaneously detects both Mycobacterium tuberculosis infection (TB) and resistance to rifampicin (RIF) within two hours. The objective was to review the available research studies on the accuracy of the Xpert MTB/RIF assay for diagnosing pulmonary TB and RIF-resistance in children. METHODS: A comprehensive search of Pubmed and Embase was performed up to October 28, 2014. We identified published articles estimating the diagnostic accuracy of the Xpert MTB/RIF assay in children with or without HIV using culture or culture plus clinical TB as standard reference. QUADAS-2 tool was used to evaluate the quality of the studies. A summary estimation for sensitivity, specificity, diagnostic odds ratios (DOR), and the area under the summary ROC curve (AUC) was performed. Meta analysis was used to establish the overall accuracy. RESULTS: 11 diagnostic studies with 3801 patients were included in the systematic review. The overall analysis revealed a moderate sensitivity and high specificity of 65% (95% CI: 61 69%) and 99% (95% CI: 98 - 99%), respectively, and a pooled diagnostic odds ratio of 164.09 (95% CI: 111.89 - 240.64). The AUC value was found to be 0.94. The pooled sensitivity and specificity for paediatric rifampicin resistance were 94.0% (95% CI: 80.0 - 93.0%) and 99.0% (95% CI: 95.0 - 98.0%), respectively. Hence, the Xpert MTB/RIF assay has good diagnostic and rifampicin performance for paediatric pulmonary tuberculosis. CONCLUSIONS: The Xpert MTB/RIF is sensitive and specific for diagnosing paediatric pulmonary TB. It is also effective in detecting rifamnicin resistance. It can, therefore, be used as an initial diagnostic tool. PMID- 26732006 TI - Thrombophilia Markers in Patients with Recurrent Early Miscarriage. AB - BACKGROUND: This study was to investigate the association between thrombophilia and REM by the change of thrombophilia markers and to evaluate their contribution in diagnosis and treatment of REM. METHODS: 199 women with REM history were divided into two groups within the study group: 151 pregnant (REM-P) and 48 nonpregnant (REM-NP). In addition, 121 healthy age-matched women without REM history were divided into two groups of the control group: 75 pregnant (Control P) and 46 nonpregnant (Control-NP). Lupus anticoagulant (LA), anticardiolipin antibodies (ACA), and anti-beta2-glycoprotein-I antibodies (anti-beta2GPI-ab) and coagulation-related factors such as protein S (PS), protein C (PC), anti-thrombin III (AT-III), and D-dimer were analysed. The prevalence of antiphospholipid antibodies (aPL) and the coagulation-related factors between groups were compared. RESULTS: The overall prevalence of aPL positivity in REM-P (14.57%) showed a difference compared with REM-NP (2.66%) but not for aCL, anti-beta2GPI ab or LA alone. There were significant differences in the mean levels of protein S, protein C, and AT-III in REM-P. The mean values of protein C (90.3 +/- 28.42%) and protein S (71.80 +/- 24.68%) in the aPL positive study group were similar with that of the aPL negative study group (p = 0.406, p = 0.880). Comparing with the aPL negative study group, the mean value of AT-III (87.71 +/- 21.84%) was significantly lower (p = 0.018), while the mean value of D-dimer (0.98 +/- 1.1 mg/L FEU) was significantly higher (p = 0.013). CONCLUSIONS: We briefly address the role of the prevalence of aPL and the related coagulation factors for predicting a prethrombotic state in patients with REM. The results of the use of anticoagulants for treating REM are encouraging. PMID- 26732007 TI - Elevation of Serum Levels of High-Sensitivity Procalcitonin, C-reactive Protein, and Amyloid A in a Prepubertal Child with Mumps Orchitis. AB - BACKGROUND: Serum CRP concentrations are significantly elevated at the acute phase in patients with mumps orchitis, but little is known currently about other inflammatory biomarkers. METHODS: We report the measurements of serum inflammatory biomarkers [high-sensitivity procalcitonin (hs-PCT), C-reactive protein (CRP) and amyloid A] in a child with mumps orchitis. RESULTS: The patient's serum levels of CRP, hs-PCT, and amyloid A were highly increased at the acute phase, but returned to normal levels at convalescence. CONCLUSIONS: This case suggests that hs-PCT and amyloid A may not be useful for distinguishing between mumps orchitis accompanied by highly elevated serum concentrations of CRP and systemic bacterial infections. PMID- 26732008 TI - A Case of Sinusitis Caused by Schizophyllum Commune and Bacteria in Acute Myelocytic Leukemia. AB - Schizophyllum commune infections have been rarely reported. Here we reported a rare case of sinusitis in an acute myelocytic leukemia patient, who was co infected by Escherichia coli, Stenotrophomonas maltophilia, and basidiomycetous fungi (Schizophyllum commune) in sinuses. Considering the in vitro and in vivo anti-fungal activity of voriconazole, it might be a good option to treat Schizophyllum commune infections when antifungal susceptibility testing is not available. When severe side effects occur, amphotericin B or itraconazole might be subsequent choice. PMID- 26732009 TI - Detection of sCD21 in Human Blood Using ELISA is Influenced by Ethylenediaminetetraacetic Acid (EDTA) Containing Blood Collection Tubes. AB - BACKGROUND: CD21 is a 145 kDa membrane glycoprotein expressed mainly on B-cells and follicular dendritic cells. It is involved in activation, survival and proliferation of B-cells. CD21 can be cleaved to give soluble CD21 (sCD21), which is constantly shed in healthy people whereas the level of sCD21 is low in patients suffering from various autoimmune diseases. METHODS: Blood was collected from 12 healthy donors into Heparin, EDTA and gel-separation tubes. Furthermore, plasma from 6 healthy donors was combined and EDTA or EGTA was subsequently added to analyze its influence on sCD21 levels measured by ELISA. RESULTS: Differences in sCD21 levels were observed dependent on blood collection tubes used. sCD21 levels measured by ELISA were significantly higher if heparin/gel containing tubes were used compared to EDTA blood collection tubes. Upon addition of EDTA/EGTA to plasma drawn using Heparin blood collection tubes, sCD21 levels decrease to amounts found in EDTA-containing blood collection tubes suggesting calcium as the responsible factor rather than magnesium. CONCLUSIONS: EDTA influences sCD21 levels determined by ELISA and therefore sCD21 measurements should be carried out using one type of blood collection tube throughout the experiment/medical examination. PMID- 26732010 TI - Up-front Screening for the JAK2 V617F Mutation in Patients Presenting with Thrombosis other than Splanchnic Vein Thrombosis. PMID- 26732012 TI - Chasing a ghost?--Issues with the determination of circulating levels of endotoxin in human blood. AB - Reliable quantification of bacterial products such as endotoxin is important for the diagnosis of Gram-negative infection and for the monitoring of its treatment. Further, it is important to identify patients with persistent subclinical level of bacterial products in their systemic circulation as data from animal studies also suggest this may be correlated with the onset of metabolic syndrome. In this review, we first aim to describe the principles of the Limulus amoebocyte lysate (LAL) test, an assay that is used to quantify endotoxin, and the various shortcomings that must be addressed before it can become a reliable means of quantifying endotoxin in samples derived from blood. We then review published data regarding endotoxin levels in healthy subjects and those with sepsis, inflammatory bowel disease, liver disorders and metabolic disorders such as obesity and diabetes. We also review the evidence regarding influence of macronutrients in augmenting the levels of systemic endotoxin. The results of this review show that reported mean levels of endotoxin in the systemic circulation of healthy humans and of those with various clinical disorders vary over a wide range. Further, this review shows that a significant proportion of this variation can be related to the method that was used to prepare plasma and serum samples prior to assay and its ability to reduce the effect of various blood borne factors that interfere with the LAL assay. PMID- 26732013 TI - Owariensisone: a new iridolactone from the whole plant of Brillantaisia owariensis P. Beauv. AB - From the whole plant of Brillantaisia owariensis P. Beauv, a new iridolactone, owariensisone (1) together with six known compounds (nepetin-7-O-glucoside, choline, sucrose, mannitol, xylitol, 1-O-palmitoyl-2-eicosanoyl-3-O-(6-amino-6 deoxy)-beta-d-glucopyranosyl-glycerol) were isolated. Structures of these compounds were established by direct interpretation of their spectral data, mainly HR-TOFESIMS, 1-D NMR ((1)H and (13)C) and 2-D NMR ((1)H-(1)H COSY, HSQC, HMBC, NOESY, TOCSY and DOCSY) and by comparison with the literature. PMID- 26732014 TI - Small but not isolated: a population genetic survey of the tropical tree Cariniana estrellensis (Lecythidaceae) in a highly fragmented habitat. AB - Here, we explore the mating pattern and genetic structure of a tropical tree species, Cariniana estrellensis, in a small population in which progeny arrays (n=399), all adults (n=28) and all seedlings (n=39) were genotyped at nine highly informative microsatellite loci. From progeny arrays we were able to identify the source tree for at least 78% of pollination events. The gene immigration rates, mainly attributable to pollen, were high, varying from 23.5 to 53%. Although gene dispersal over long distance was observed, the effective gene dispersal distances within the small population were relatively short, with mean pollination distances varying from 69.9 to 146.9 m, and seed dispersal distances occurring up to a mean of 119.6 m. Mating system analyses showed that C. estrellensis is an allogamous species (tm=0.999), with both biparental inbreeding (tm-ts=-0.016) and selfing rates (s=0.001) that are not significantly different from zero. Even though the population is small, the presence of private alleles in both seedlings and progeny arrays and the elevated rates of gene immigration indicate that the C. estrellensis population is not genetically isolated. However, genetic diversity expressed by allelic richness was significantly lower in postfragmentation life stages. Although there was a loss of genetic diversity, indicating susceptibility of C. estrellensis to habitat fragmentation, no evidence of inbreeding or spatial genetic structure was observed across generations. Overall, C. estrellensis showed some resilience to negative genetic effects of habitat fragmentation, but conservation strategies are needed to preserve the remaining genetic diversity of this population. PMID- 26732015 TI - Direct and indirect genetic effects of sex-specific mitonuclear epistasis on reproductive ageing. AB - Mitochondria are involved in ageing and their function requires coordinated action of both mitochondrial and nuclear genes. Epistasis between the two genomes can influence lifespan but whether this also holds for reproductive senescence is unclear. Maternal inheritance of mitochondria predicts sex differences in the efficacy of selection on mitonuclear genotypes that should result in differences between females and males in mitochondrial genetic effects. Mitonuclear genotype of a focal individual may also indirectly affect trait expression in the mating partner. We tested these predictions in the seed beetle Callosobruchus maculatus, using introgression lines harbouring distinct mitonuclear genotypes. Our results reveal both direct and indirect sex-specific effects of mitonuclear epistasis on reproductive ageing. Females harbouring coadapted mitonuclear genotypes showed higher lifetime fecundity due to slower senescence relative to novel mitonuclear combinations. We found no evidence for mitonuclear coadaptation in males. Mitonuclear epistasis not only affected age-specific ejaculate weight, but also influenced male age-dependent indirect effects on traits expressed by their female partners (fecundity, egg size, longevity). These results demonstrate important consequences of sex-specific mitonuclear epistasis for both mating partners, consistent with a role for mitonuclear genetic constraints upon sex specific adaptive evolution. PMID- 26732016 TI - Collecting Biospecimens From an Internet-Based Prospective Cohort Study of Inflammatory Bowel Disease (CCFA Partners): A Feasibility Study. AB - BACKGROUND: The Internet has successfully been used for patient-oriented survey research. Internet-based translational research may also be possible. OBJECTIVE: Our aim was to study the feasibility of collecting biospecimens from CCFA Partners, an Internet-based inflammatory bowel disease (IBD) cohort. METHODS: From August 20, 2013, to January 4, 2014, we randomly sampled 412 participants, plus 179 from a prior validation study, and invited them to contribute a biospecimen. Participants were randomized to type (blood, saliva), incentive (none, US $20, or US $50), and collection method for blood. The first 82 contributors were also invited to contribute stool. We used descriptive statistics and t tests for comparisons. RESULTS: Of the 591 participants, 239 (40.4%) indicated interest and 171 (28.9%) contributed a biospecimen. Validation study participants were more likely to contribute than randomly selected participants (44% versus 23%, P<.001). The return rate for saliva was higher than blood collected by mobile phlebotomist and at doctors' offices (38%, 31%, and 17% respectively, P<.001). For saliva, incentives were associated with higher return rates (43-44% versus 26%, P=.04); 61% contributed stool. Fourteen IBD-associated single nucleotide polymorphisms were genotyped, and risk allele frequencies were comparable to other large IBD populations. Bacterial DNA was successfully extracted from stool samples and was of sufficient quality to permit quantitative polymerase chain reaction for total bacteria. CONCLUSIONS: Participants are willing to contribute and it is feasible to collect biospecimens from an Internet based IBD cohort. Home saliva kits yielded the highest return rate, though mobile phlebotomy was also effective. All samples were sufficient for genetic testing. These data support the feasibility of developing a centralized collection of biospecimens from this cohort to facilitate IBD translational studies. PMID- 26732018 TI - Preparation and hemostatic property of low molecular weight silk fibroin. AB - Effective hemorrhage control becomes increasingly significant in today's military and civilian trauma, while the topical hemostats currently available in market still have various disadvantages. In this study, three low molecular weight silk fibroins (LMSF) were prepared through hydrolysis of silk fibroin in a ternary solvent system of CaCl2/H2O/EtOH solution at different hydrolysis temperatures. Fourier transform infrared spectroscopy analysis showed that the content of beta sheet structure in the LMSF decreased with the increase in hydrolysis temperature. The results of thromboelastographic and activated partial thromboplastin time methods showed that the LMSF hydrolyzed at 50 degrees C can significantly strengthen the coagulation in blood and activate the intrinsic pathway of coagulation cascade. In the murine hepatic injury model, the LMSF hydrolyzed at 50 degrees C can promote the blood clotting and decrease the blood loss and bleeding time. Based on these results, it can be suggested that the developed LMSF has the excellent hemostatic effect and may be a promising material in clinical hemostatic application. PMID- 26732017 TI - Assessment of the effeCt of lIfestyle iNtervention plus water-soluble ciNnAMon extract On loweriNg blood glucose in pre-diabetics, a randomized, double-blind, multicenter, placebo controlled trial: study protocol for a randomized controlled trial. AB - BACKGROUND: The World Health Organization predicts that by 2030 diabetes will be the seventh leading cause of death in the world. Multiple studies have tried to determine if cinnamon is an effective treatment for diabetes. Cinnamon extract is an insulin sensitizer, protects mesangial cells, decreases inflammatory markers, and lowers glucose, lipids, and blood pressure in patients with type 2 diabetes, so we developed a protocol to study whether ingestion of water-soluble cinnamon extract prevents progression from pre-diabetes to diabetes. METHODS/DESIGN: This is a randomized, double-blind, placebo-controlled trial comparing cinnamon extract versus placebo in subjects with pre-diabetes who have committed to participate in a lifestyle change program. The trial will be conducted at five sites and will include 428 subjects who take cinnamon extract or placebo for 1 year. Follow-up for these subjects will be for a total of 2 years (nine study visits). The primary outcomes to be assessed are 1) conversion of patients from pre-diabetes to diabetes and 2) impact of water-soluble cinnamon extract on hepatic transaminases, renal function, and QT interval on electrocardiogram. Secondary outcomes include changes in HbA1c, lipids, waist circumference, weight, blood pressure, and fasting plasma glucose. The trial protocol has been approved by the Institutional Review Board of the US Air Force 59th Medical Wing, Wilford Hall Ambulatory Surgical Center (Protocol FWH20110035H). Investigator-sponsored Investigational New Drug status (114078) was granted by the US Food and Drug Administration. DISCUSSION: This study will provide high-quality evidence of the efficacy of water-soluble cinnamon extract in conjunction with lifestyle intervention for preventing patients with pre-diabetes from converting to diabetes. Additionally, it will provide important safety information about water soluble cinnamon extract. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01301521 , 18 February 2011. PMID- 26732019 TI - Evaluation of cardiac modulation in children in response to apnea/hypopnea using the Phone Oximeter(TM). AB - Individuals with sleep disordered breathing (SDB) can experience changes in automatic cardiac regulation as a result of frequent sleep fragmentation and disturbance in normal respiration and oxygenation that accompany most apnea/hypopnea events. In adults, these changes are reflected in enhanced sympathetic and reduced parasympathetic activity. In this study, we examined the autonomic cardiac regulation in children with and without SDB, through spectral and detrended fluctuation analysis (DFA) of pulse rate variability (PRV). PRV was measured from pulse-to-pulse intervals (PPIs) of the photoplethysmogram (PPG) recorded from 160 children using the Phone Oximeter(TM) in the standard setting of overnight polysomnography. Spectral analysis of PRV showed the cardiac parasympathetic index (high frequency, HF) was lower (p < 0.01) and cardiac sympathetic indices (low frequency, LF and LF/HF ratio) were higher (p < 0.01) during apnea/hypopnea events for more than 95% of children with SDB. DFA showed the short- and long-range fluctuations of heart rate were more strongly correlated in children with SDB compared to children without SDB. These findings confirm that the analysis of the PPG recorded using the Phone Oximeter(TM) could be the basis for a new screening tool for assessing PRV in non-clinical environment. PMID- 26732020 TI - Clinicopathological significance of TERT promoter mutation in papillary thyroid carcinomas: a systematic review and meta-analysis. AB - BACKGROUND: The prognostic value of the telomerase reverse transcriptase (TERT) promoter mutation, resulting in poor clinical outcomes of papillary thyroid carcinoma (PTC), has been generally confirmed. To data, there is no high-level evidence approving the association of TERT promoter mutation and aggressive clinical behaviours in PTC. To systematically evaluate it, a systematic review and meta-analysis of the published literatures were carried out. METHODS: We conducted a systematic search in PubMed, EMBASE, OVID and Web of Science databases for relevant studies. We selected all the studies that reported clinicopathological features of PTC patients with information available on TERT promoter mutation status. Individual study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, as were Mantel-Haenszel pooled odds ratios for the combined studies. RESULTS: Eight eligible trials involved 2035 patients were included in the analysis. The average prevalence of the TERT promoter mutation was 10.32%. Compared with the wild-type TERT promoter gene, the TERT promoter mutation was associated with male gender, lymph node metastasis, extrathyroidal extension, distant metastasis, advanced TNM stage III/IV, poor clinical outcome (persistence or recurrence) and mortality. The associations were generally consistent across the different study populations. CONCLUSIONS: Thus, our findings from this large meta-analysis definitively demonstrate that TERT promoter mutation-positive PTC is more likely to manifest with aggressive clinicopathological characteristics. In appropriate clinical settings, testing for the TERT promoter mutation is likely to be useful in assisting the risk stratification and management of PTC. PMID- 26732022 TI - Enhanced Sodium Ion Storage Behavior of P2-Type Na(2/3)Fe(1/2)Mn(1/2)O2 Synthesized via a Chelating Agent Assisted Route. AB - On the basis of resource abundance and low cost, high capacity layered P2-type Na2/3Fe1/2Mn1/2O2 material is regarded as a potential cathode material for sodium ion batteries but suffers from its unstable structure during cycling. In this work, P2-type Na2/3Fe1/2Mn1/2O2 layered materials were synthesized by a chelating agent assisted sol-gel method with NH3.H2O. With the addition of NH3.H2O and the control of the synthesis conditions, highly active material with a more stable structure and better electrochemical performance was obtained. Furthermore, the influences of structure changes during different voltage ranges (1.5-4.0 V and 1.5-4.3 V vs Na(+)/Na) on the Na(+) storage behaviors were also evaluated and compared. It is confirmed that, when being charged to 4.2 V, an OP4-type phase emerges, which can reduce the damage by the gilding of the MeO2 layers but leads to an unstable crystal structure. For long-term cycling, it is preferred to cut off at 4.0 V rather than at 4.3 V. For the optimized P2-type Na2/3Fe1/2Mn1/2O2 calcined at 900 degrees C, a discharge capacity of 92 mAh/g remains after 40 cycles in the voltage range of 1.5-4.0 V, and the Coulombic efficiency remains 100%. PMID- 26732023 TI - Cerebrospinal fluid viral escape and acute encephalitis in a patient on boosted protease inhibitor monotherapy. AB - Although currently available data suffice to support the use of protease inhibitor monotherapy in selected patients, there is concern about the antiviral activity of this regimen in the long term and in viral sanctuaries, such as the central nervous system. We report a case of encephalitis related to viral escape while receiving darunavir/ritonavir monotherapy in a carefully selected patient for participation in a clinical trial. PMID- 26732024 TI - Virology and epidemiology analyses of global adenovirus-associated conjunctivitis outbreaks, 1953-2013. AB - This study aimed to compare the virology and epidemiology of epidemic keratoconjunctivitis (EKC), pharyngoconjunctival fever (PCF) and acute haemorrhagic conjunctivitis (AHC) outbreaks worldwide caused by the human adenovirus (HAdV) from 1953 to 2013. Eighty-three hexon sequences from 76 conjunctivitis outbreaks were analysed and subtyped using Mega 5.05, Clustal X and SimPlot software. Epidemiology was performed for the area, age and seasonal distribution. A phylogenetic analysis indicated that all the isolates could be divided into three subgenetic lineages, without a common ancestor. The major causes of the outbreaks were Ad8, Ad7 and Ad2 co-infection with enterovirus 70 (EV70) in EKC, PCF and AHC, respectively. The epidemiological findings suggested that EKC and AHC were circulating predominantly in Asia during the early winter and spring, whereas PCF was circulating mainly in China, Australia and the United States during the summer. This study suggests that EKC, AHC and PCF outbreaks have different circulating patterns throughout the world and are caused by different adenovirus serotypes. A global surveillance system should be established to monitor conjunctivitis outbreaks in the future. PMID- 26732025 TI - Cow's milk and rice fermented with Lactobacillus paracasei CBA L74 prevent infectious diseases in children: A randomized controlled trial. AB - BACKGROUND & AIM: Fermented foods have been proposed for the prevention of infectious diseases. We evaluated the efficacy of fermented foods in reducing common infectious diseases (CIDs) in children attending daycare. METHODS: Prospective randomized, double-blind, placebo-controlled trial (registered under Clinical Trials.gov identifier NCT01909128) on healthy children (aged 12-48 months) consuming daily cow's milk (group A) or rice (group B) fermented with Lactobacillus paracasei CBA L74, or placebo (group C) for three months during the winter season. The main study outcome was the proportion of children who experienced at least one CID. All CIDs were diagnosed by family pediatricians. Fecal concentrations of innate (alpha- and beta-defensins and cathelicidin LL-37) and acquired immunity biomarkers (secretory IgA) were also evaluated. RESULTS: 377 children (193 males, 51%) with a mean (SD) age of 32 (10) months completed the study: 137 in group A, 118 in group B and 122 in group C. Intention-to-treat analysis showed that the proportion of children who experienced at least one CID was lower in group A (51.8%) and B (65.9%) compared to group C (80.3%). Per protocol analysis showed that the proportion of children presenting upper respiratory tract infections was lower in group A (48.2%) and group B (58.5%) compared with group C (70.5%). The proportion of children presenting acute gastroenteritis was also lower in group A (13.1%) and group B (19.5%) compared with group C (31.1%). A net increase of all fecal biomarkers of innate and acquired immunity was observed for groups A and B compared to group C. Moreover, there was a negative association between fecal biomarkers and the occurrence of CID. CONCLUSION: Dietary supplementation with cow's milk or rice fermented with L. paracasei CBA L74 prevents CIDs in children attending daycare possibly by means of a stimulation of innate and acquired immunity. PMID- 26732026 TI - Clinical application of probiotics in type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled study. AB - BACKGROUND & AIMS: Type 2 diabetes has been associated with dysbiosis and one of the possible routes to restore a healthy gut microbiota is by the regular ingestion of probiotics. We aimed to investigate the effects of probiotics on glycemic control, lipid profile, inflammation, oxidative stress and short chain fatty acids in T2D. METHODS: In a double-blind, randomized, placebo-controlled trial, 50 volunteers consumed daily 120 g/d of fermented milk for 6 wk. Participants were assigned into two groups: probiotic group, consuming fermented milk containing Lactobacillus acidophilus La-5 and Bifidobacterium animalis subsp lactis BB-12 (109 colony-forming units/d, each) and control group, consuming conventional fermented milk. Anthropometric measurements, body composition, fasting blood and faecal samples were taken at baseline and after 6 wk. RESULTS: 45 subjects out of 50 (90%) completed follow-up. After 6 wk, there was a significant decrease in fructosamine levels (-9.91 mmol/L; p = 0.04) and hemoglobin A1c tended to be lower (-0.67%; p=0.06) in probiotic group. TNF-alpha and resistin were significantly reduced in probiotic and control groups (-1.5 and -1.3 pg/mL, -.1 and -2.8 ng/mL, respectively), while IL-10 was significantly reduced (- 0.65 pg/mL; p <0.001) only in the control group. Fecal acetic acid was increased in both groups (0.58 and 0.59% in probiotic and control groups, respectively; p <0.01). There was a significant difference between groups concerning mean changes of HbA1c (+0.31 for control group vs -0.65 for probiotic group; p=0.02), total cholesterol (+0.55 for control group vs -0.15 for probiotic group; p=0.04) and LDL-cholesterol (+0.36 for control group vs -0.20 for probiotic group p=0.03). CONCLUSIONS: Probiotic consumption improved the glycemic control in T2D subjects, however, the intake of fermented milk seems to be involved with others metabolic changes, such as decrease in inflammatory cytokines (TNF-alpha and resistin) and increase in the acetic acid. PMID- 26732027 TI - Influence of nutrition on somatotropic axis: Milk consumption in adult individuals with moderate-severe obesity. AB - BACKGROUND & AIMS: Nutrition is the major environmental factor that influences the risk of developing pathologies, such as obesity. Although a number of recent reviews pinpoint a protective effects of milk on body weight and obesity related co-morbidities, an inaccurate estimate of milk might contribute to hamper its beneficial effects on health outcomes. Seven-day food records provide prospective food intake data, reducing recall bias and providing extra details about specific food items. Milk intake stimulates the somatotropic axis at multiple levels by increasing both growth hormone (GH) and insulin-like growth factor-1 (IGF-1) secretion. On the other hand, obesity is associated with reduced spontaneous and stimulated GH secretion and basal IGF-1 levels. Aim of this study was to evaluate the milk consumption by using the 7-days food record in obese individuals and to investigate the association between milk intake and GH secretory status in these subjects. METHODS: Cross-sectional observational study carried out on 281 adult individuals (200 women and 81 men, aged 18-74 years) with moderate-severe obesity (BMI 35.2-69.4 kg/m2). Baseline milk intake data were collected using a 7 day food record. Anthropometric measurements and biochemical profile were determined. The GH/IGF-1 axis was evaluated by peak GH response after GHRH + ARGININE and IGF 1 standard deviation score (SDS). RESULTS: The majority of individuals (72.2%) reported consuming milk; 250 mL low-fat milk was the most frequently serving of milk consumed, while no subjects reported to consume whole milk. Milk consumers vs no milk consumers presented the better anthropometric measurements and metabolic profile. At the bivariate proportional odds ratio model, after adjusting for BMI, age and gender, milk consumption was associated the better GH status (OR = 0.60; p < 0.001). Among milk consumers, subjects consuming 250 mL reduced-fat milk vs 250 mL low-fat milk presented the better anthropometric measurements and metabolic profile. At the bivariate proportional odds ratio model, after adjusting for BMI, age and gender, the consume of 250 mL reduced-fat milk was associated better GH status (OR = 0.54; p = 0.003). CONCLUSIONS: A novel positive association between milk consumption, GH status, and metabolic profile in obese individuals was evidenced. Regardless of the pathogenetic mechanisms, this novel association might be relevant in a context where commonly obese individuals skip breakfast, and suggests the need of a growing cooperation between Nutritionists and Endocrinologists in the management of the obese patients. PMID- 26732029 TI - Combined progesterone (IM + V) versus vaginal progesterone for luteal support in cleavage-stage embryo transfer cycles of good prognosis patients. AB - Many reports led to the consensus on the use of progesterone (P) for luteal-phase support. Vaginal P application is the method of choice due to its simplicity and high patient convenience but is hampered by application difficulties and personal or cultural aversions. Inappropriate vaginal P use may alter successful implantation, leading physicians to consider alternate P application routes. A worldwide survey revealed that intramuscular plus vaginal P (combined P) is the method used in nearly one-third of in vitro fertilization (IVF) cycles, particularly in Asia and North America; unfortunately, the outcomes of this approach have not been clearly elucidated. In the current analysis, we evaluated any additional benefit of short course parenteral P in addition to vaginal P capsules during a specific period in terms of implantation, pregnancy rates, miscarriages and ectopic pregnancies in cleavage stage embryo transfer (ET) cycles of good-prognosis patients. Despite significantly higher implantation rates in the combined arm, clinical and ongoing pregnancies were comparable in both groups, whereas a trend toward increased pregnancy rates was observed with combined support. The available data are too limited to draw conclusions. PMID- 26732028 TI - Breastfeeding and thyroid cancer risk in women: A dose-response meta-analysis of epidemiological studies. AB - BACKGROUND & AIMS: The association between breastfeeding and thyroid cancer risk is not consistent from epidemiological studies. To better clarify the association including assessing a potential dose-response relationship, we conducted a comprehensive meta-analysis. METHODS: We searched PubMed (MEDLINE) up to November 2015 for prospective studies or case-control studies that evaluated the association between breastfeeding and risk of thyroid cancer. Effect estimates were pooled using a fixed-effects model. RESULTS: Nine reports (2 prospective studies, 6 case-control studies and 1 pooled analysis of 14 case-control studies) involving 2423 cases and 350,081 non-cases were identified. After pooling relevant studies, there was a significant inverse association between ever breastfeeding and risk of thyroid cancer (RR = 0.91, 95% CI 0.83-0.99), with minor heterogeneity (I(2) = 10.1%). The dose-response analysis revealed a significant linear relationship between the duration of breastfeeding and risk of thyroid cancer. The summary RR for an increment of 1 month of breastfeeding with risk of thyroid cancer was 0.983 (95% CI 0.98-0.99). When focusing on cohort studies, a more prominent linear dose-response relationship was detected, with the combined RR for every increment of 1 month of breastfeeding to be 0.965 (95% CI 0.96-0.97). CONCLUSIONS: This meta-analysis suggests that breastfeeding is potentially inversely associated with thyroid cancer risk. Also longer duration of breastfeeding may further decreases thyroid cancer risk. If validated in large scale prospective studies, our findings may have implications for impacting women's decision in breastfeeding. PMID- 26732030 TI - Infrared optical absorption in low-spin Fe(2+)-doped SrTiO3. AB - Band gap engineering in SrTiO3 and related titanate perovskites has long been explored due to the intriguing properties of the materials for photocatalysis and photovoltaic applications. A popular approach in the materials chemistry community is to substitutionally dope aliovalent transition metal ions onto the B site in the lattice to alter the valence band. However, in such a scheme there is limited control over the dopant valence, and compensating defects often form. Here we demonstrate a novel technique to controllably synthesize Fe(2+)- and Fe(3+)-doped SrTiO3 thin films without formation of compensating defects by co doping with La(3+) ions on the A site. We stabilize Fe(2+)-doped films by doping with two La ions for every Fe dopant, and find that the Fe ions exhibit a low spin electronic configuration, producing optical transitions in the near infrared regime and degenerate doping. The novel electronic states observed here offer a new avenue for band gap engineering in perovskites for photocatalytic and photovoltaic applications. PMID- 26732031 TI - A stable Alq3@MOF composite for white-light emission. AB - A stable mesoporous blue-emitting MOF NENU-521 was successfully constructed. NENU 521 can serve as a host for encapsulating Alq3 to obtain tunable and efficient white-light emission. The Alq3@NENU-521 composite possesses excellent stability and can be used as a promising white phosphor in WLEDs. PMID- 26732032 TI - How soft is a single protein? The stress-strain curve of antibody pentamers with 5 pN and 50 pm resolutions. AB - Understanding the mechanical functionalities of complex biological systems requires the measurement of the mechanical compliance of their smallest components. Here, we develop a force microscopy method to quantify the softness of a single antibody pentamer by measuring the stress-strain curve with force and deformation resolutions, respectively, of 5 pN and 50 pm. The curve shows three distinctive regions. For ultrasmall compressive forces (5-75 pN), the protein's central region shows that the strain and stress are proportional (elastic regime). This region has an average Young's modulus of 2.5 MPa. For forces between 80 and 220 pN, the stress is roughly proportional to the strain with a Young's modulus of 9 MPa. Higher forces lead to irreversible deformations (plastic regime). Full elastic recovery could reach deformations amounting to 40% of the protein height. The existence of two different elastic regions is explained in terms of the structure of the antibody central region. The stress strain curve explains the capability of the antibody to sustain multiple collisions without any loss of biological functionality. PMID- 26732033 TI - Using Olfaction and Unpleasant Reminders to Reduce the Intention-behavior Gap in Hand Washing. AB - Lack of hand washing is a leading cause of food borne illnesses. To successfully increase hand hygiene compliance, interventions must have continual engagement with employees. This study used a real-time prospective memory (PM) scenario to measure the effectiveness of a control and sensory reminders of disgust to influence hand washing behavior and performance. First, a model of hand washing performance was built by having six participants' hands contaminated with GermGlo (a florescent micro-particle) and then washed their hands using predetermined protocols while monitored by an electronic hand hygiene verification (HHV) system. Next, eighty Hispanic/Latino participants, in a between-group experimental design, performed a PM experiment while one of four reminders were present (hand washing poster, disgusting image, disgusting sound, and disgusting odor) as the HHV recorded their hand washing performance. Visual cues, typical of hand washing campaigns, were not as effective at increasing hand hygiene compliance as disgust-induced sensory cues. Furthermore, olfactory disgust showed a significantly higher probability that individuals would engage in hand washing behaviors than all other conditions. This study provides new insight into the effectiveness of different senses and emotion to reduce the intention-behavior gap associated with modifying behaviors, and broadens current PM research to a real-time application. PMID- 26732034 TI - Systematic review of the association between chronic social stress and telomere length: A life course perspective. AB - Our aim was to examine whether chronic social stress is associated with telomere length throughout the life course, following our protocol published in 2014. Structured searches were conducted in MEDLINE (PubMed interface), EMBASE (OVID interface), Cochrane Central (OVID interface) and grey from their start date onwards. Reference lists of retrieved citations were hand searched for relevant studies. Eighteen studies published until May 1, 2015 investigating the association between chronic social stress (as defined by poverty, exposure to violence, or family caregiving) and telomere length in healthy or diseased adults and children were independently selected by 2 reviewers. Sixteen of those studies were cross-sectional and two had a longitudinal design. Studies differed in type of stress exposure, method to measure telomere length and cell type. As meta analysis could not be conducted, the data were synthesized as a narrative review. Based on this comprehensive review, chronic social stress accompanies telomere shortening in both early and adult exposures, with most eligible studies showing a significant relationship. We discuss the significance of chronic stress of social origin and the potential for social interventions through public policies and we recommend methodological improvements that would allow for future meta analysis. PMID- 26732035 TI - Nrf2 signaling and redox homeostasis in the aging heart: A potential target to prevent cardiovascular diseases? AB - Aging process is often accompanied with a high incidence of cardiovascular diseases (CVD) due to the synergistic effects of age-related changes in heart morphology/function and prolonged exposure to injurious effects of CVD risk factors. Oxidative stress, considered a hallmark of aging, is also an important feature in pathologies that predispose to CVD development, like hypertension, diabetes and obesity. Approaches directed to prevent the occurrence of CVD during aging have been explored both in experimental models and in controlled clinical trials, in order to improve health span, reduce hospitalizations and increase life quality during elderly. In this review we discuss oxidative stress role as a main risk factor that relates CVD with aging. As well as interventions that aim to reduce oxidative stress by supplementing with exogenous antioxidants. In particular, strategies of improving the endogenous antioxidant defenses through activating the nuclear factor related-2 factor (Nrf2) pathway; one of the best studied molecules in cellular redox homeostasis and a master regulator of the antioxidant and phase II detoxification response. PMID- 26732036 TI - "Modern Abbreviated Computer Navigation of the Femur Reduces Blood Loss in Total Knee Arthroplasty". PMID- 26732037 TI - Factors Affecting Readmission Cost After Primary Total Knee Arthroplasty in Michigan. AB - BACKGROUND: The increasing readmission risk of primary total knee arthroplasty (TKA) represents a significant economic burden and public health challenge. Many have investigated the predictors of readmissions after TKA while little work has studied the associated readmission costs. This article investigated the factors affecting readmission cost after primary TKA at the time of initial discharges using clinical and resource-use information and compared the factors between 2 payer groups (Medicare-or-Medicaid and non-Medicare-nor-Medicaid groups). METHODS: We used data from the Michigan State Inpatient Database of the Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. We identified readmissions after primary TKA in 2012 using International Classification of Diseases, Ninth Revision, code 81.54. Total readmission cost was modeled using multivariate regression to identify predictors. RESULTS: Of 1358 readmissions after primary TKA, 949 were in the Medicare-or-Medicaid group, and 409 were in the non-Medicare-nor-Medicaid group. The overall mean and median total readmission costs were $9335 (standard deviation $10,528) and $6810, respectively. Significant predictors of total readmission cost for the Medicare or-Medicaid group included length of stay (P < .001), discharge disposition (P < .001), number of chronic conditions (P = .001), and total cost of initial admission (P < .001). Only total cost of initial admission was significant in predicting total readmission cost for the non-Medicare-nor-Medicaid group (P < .001). CONCLUSION: Total cost of initial admission was a significant predictor of total readmission cost in both Medicare-or-Medicaid and non-Medicare-nor-Medicaid groups, independent of length of stay and number of chronic conditions. PMID- 26732038 TI - Inter-Rater and Intra-Rater Repeatability and Reliability of EOS 3-Dimensional Imaging Analysis Software. AB - BACKGROUND: Quantifying ideal component position for the acetabulum and stem during total hip arthroplasty (THA) has been described by many methods. A new imaging method using low-dose digital stereoradiography, the EOS imaging system, is a biplanar low-dose X-ray system that allows for 3-dimensional modeling of lower limbs and semiautomated measurement of pelvic parameters and implant alignment. METHODS: Twenty-five patients who underwent primary THA by a single surgeon between October 2014 and December 2014 were retrospectively selected. Only patients with unilateral THA without associated spine pathologies were included, totaling 16 right hips and 9 left hips. There were 8 men and 17 women in the cohort, with a mean age of 67 years (range, 53-82). Three individuals performed measurements of pelvic parameters and implant alignment on 3 separate occasions. An interclass correlation of >0.75 was accepted as evidence of excellent agreement and a confirmation of measurement reliability. RESULTS: Before reviewing patient radiographs, 4 pelvic phantom models were analyzed using the EOS 3-dimensional software to verify accuracy. All anatomic and implant measurements performed by the 3 independent reviewers showed interobserver and intraobserver agreement with interclass correlation >0.75. CONCLUSION: Three dimensional modeling of hip implants with the EOS imaging system is a reasonable option for the evaluation of component position after THA. PMID- 26732040 TI - Diagnostic value of contrast-enhanced ultrasound in solid thyroid nodules with and without enhancement. AB - We aimed to investigate different enhancement patterns of solid thyroid nodules on contrast-enhanced ultrasound (CEUS) and then to evaluate the corresponding diagnostic performance in the differentiation of benign and malignant nodules with and without enhancement. 229 solid thyroid nodules in 196 patients who had undergone both conventional ultrasound and CEUS examinations were classified into enhancement and non-enhancement groups. Besides, different enhancement patterns in the enhancement group were characterised with five indicators including arrival time, mode of entrance, echo intensity, homogeneity, and washout time. Then aforementioned indicators were compared between benign and malignant nodules of different sizes (<10 mm and >10 mm), and diagnostic performance of significant enhancement indicators was calculated. As for the enhancement group, there were statistically significant differences of <10 mm subgroup among three CEUS indicators including arrival time, mode of entrance, and washout time between malignant and benign thyroid nodules (p < 0.05), while all CEUS indicators showed statistically significant differences in the total group and >=10 mm subgroup (p < 0.05). All the five CEUS indicators displayed better diagnostic performance with specificity (92.86, 92.14, 95.71, 90.71, and 90.71 %, respectively) and diagnostic accuracy (80.79, 79.48, 74.67, 75.11, and 81.66 %, respectively), while the sensitivity and negative predictive value of non-enhancement were 95.51 and 95.83 %, respectively, with an accuracy of 77.29 %. CEUS is a very promising diagnostic technique that could improve the diagnostic accuracy of identifying benign thyroid lesions to spare a large number of patients an unnecessary invasive procedure. PMID- 26732041 TI - Re-ablation I-131 activity does not predict treatment success in low- and intermediate-risk patients with differentiated thyroid carcinoma. AB - The aim of this study was to evaluate the efficacy of different radioactive iodine (I-131) activities used for re-ablation, to compare various combinations of treatment activities, and to identify predictors of re-ablation failure in low and intermediate-risk differentiated thyroid carcinoma (DTC) patients. The study included 128 consecutive low- and intermediate-risk patients with DTC with ablation failure after total thyroidectomy. Patient characteristics, T status, tumor size, lymph node involvement, postoperative remnant size on whole-body scintigraphy, serum thyroglobulin (Tg), thyroid-stimulating hormone (TSH), anti Tg antibody (TgAb), and Tg/TSH ratio were analyzed as potential predictors of the re-ablation success. Re-ablation was successful in 113 out of 128 patients (88.3 %). Mean first I-131 activity was 2868 +/- 914 MBq (77.5 +/- 24.7 mCi) and mean second I-131 activity 3004 +/- 699 MBq (81.2 +/- 18.9 mCi). There was no association between the first, second, and cumulative activity with re-ablation treatment outcome. Treatment failure was associated with higher Tg levels prior to re-ablation (Tg2) (OR 1.16, 95 % CI 1.05-1.29, P = 0.003) and N1a status (OR 3.89, 95 % CI 1.13-13.41, P = 0.032). After excluding patients with positive-to negative TgAb conversion, Tg2 level of 3.7 ng/mL predicted treatment failure with a sensitivity of 75.0 %, specificity of 80.5 %, and a negative predictive value of 97.1 %. Patients with positive-to-negative TgAb conversion had higher failure rates (OR 2.96, 95 % CI 0.94-9.29). Re-ablation success was high in all subgroups of patients and I-131 activity did not influence treatment outcome. Tg may serve as a good predictor of re-ablation failure. Patients with positive-to-negative TgAb conversion represent a specific group, in whom Tg level should not be used as a predictive marker of treatment outcome. PMID- 26732042 TI - Brown adipose tissue localization using 18F-FDG PET/MRI in adult. PMID- 26732039 TI - Considering GH replacement for GH-deficient adults with a previous history of cancer: a conundrum for the clinician. AB - Previous studies have shown that GH and IGF-I may enhance tumorigenesis, metastasis, and cell proliferation in humans and animals. Evidence supporting this notion is derived from animal model studies, epidemiological studies, experience from patients with acromegaly, molecular therapeutic manipulation of GH and IGF-I actions, and individuals with GH receptor and congenital IGF-I deficiencies. Prior exposure to radiation therapy, aging, family history of cancer, and individual susceptibility may also contribute to increase this risk. Therefore, the use of GH replacement in patients with a history of cancer raises hypothetical safety concerns for patients, caregivers, and providers. Studies of GH therapy in GH-deficient adults with hypopituitarism and childhood cancer survivors have not convincingly demonstrated an increased cancer risk. Conversely, the risk of occurrence of a second neoplasm (SN) in childhood cancer survivors may be increased, with meningiomas being the most common tumor; however, this risk appears to decline over time. In light of these findings, if GH replacement is to be considered in patients with a previous history of cancer, we propose this consideration to be based on each individual circumstance and that such therapy should only be initiated at least 2 years after cancer remission is achieved with the understanding that in some patients (particularly those with childhood cancers), GH may potentially increase the risk of SNs. In addition, close surveillance should be undertaken working closely with the patient's oncologist. More long-term data are thus needed to determine if GH replacement in GH-deficient adults with a history of cancer is associated with the development of de novo tumors and tumor recurrence. PMID- 26732043 TI - Evolutionary mechanism of the defects in the fluoride-containing phosphate based glasses induced by gamma radiation. AB - In the laser driven inertial confinement fusion (ICF) experimental target chamber, like the 3omega (351 nm) laser irradiation, the irradiation of gamma ray and X-rays, will also cause the formation and increase of various defects in the investigated series of fluoride-containing phosphate based glasses that have potential use in novel high performance color separation optics. The induced defects contribute to the increase of absorption in the UV region, which will make the UV performance of these laser glasses deteriorated. Some of the induced defects can be bleached to some extent through the subsequent thermal treatment process, resulting from the release and capture of the electrons in conduction band. Through the gamma radiation and post-heat treatment experiments, a general model of the evolutionary mechanism of the defects in these fluoride-containing phosphate based glasses was proposed. PMID- 26732044 TI - Quality improvement education to improve performance on ulcerative colitis quality measures and care processes aligned with National Quality Strategy priorities. AB - Studies on inflammatory bowel disease (IBD) have reported suboptimal approaches to patient care. In the United States, the findings have motivated leading gastroenterology organizations to call for initiatives that support clinicians in aligning their practices with quality measures for IBD and priorities of the National Quality Strategy (NQS). We designed and implemented a quality improvement (QI) education program on ulcerative colitis in which patient charts were audited for 30 gastroenterologists before (n = 300 charts) and after (n = 290 charts) they participated in QI-focused educational activities. Charts were audited for nine measures, selected for their alignment with four NQS priorities: making care safer, ensuring patient engagement, promoting communication, and promoting effective treatment practices. Four of the measures, including guideline-directed vaccinations and assessments of disease type and activity, were part of the CMS Physician Quality Reporting System (PQRS). The other five measures involved counseling patients on various topics in ulcerative colitis management, documentation of side effects, assessment of adherence status, and simplification of dosing. The gastroenterologists also completed baseline and post-education surveys designed to assess qualitative outcomes. One of the educational interventions was a private audit feedback session conducted for each gastroenterologist. The sessions were designed to support participants in identifying measures reflecting suboptimal care quality and developing action plans for improvement. In continuous improvement cycles, follow-up interventions included QI tools and educational monographs. Across the nine chart variables, post-education improvements ranged from 0% to 48%, with a mean improvement of 15.9%. Survey findings revealed improvements in self-reported understanding of quality measures and intentions to apply them to practice, and lower rates of perceived significant barriers to high-quality care. The findings indicate the potential for QI education to support gastroenterologists in improving their performance on key measures of care quality for patients with ulcerative colitis. PMID- 26732045 TI - Pulmonary responses to pathogen-specific antigens in latent Mycobacterium tuberculosis infection. AB - In this study, we used ELISPOT to quantify frequencies of bronchoalveolar lavage (BAL) and peripheral blood T cells capable of producing IFNgamma in response to PPD, antigen 85B, and Mtb-specific antigens CFP-10 and ESAT-6 in individuals with latent tuberculosis infection (LTBI) and Mtb-naive controls. Compared to peripheral blood, BAL cells of LTBI subjects displayed significant enrichment for T cells responding to PPD, antigen 85B, and CFP-10, but not to ESAT-6. Baseline BAL cells of LTBI subjects displayed significant production of Mig (CXCL9) in response to PPD, antigen 85B, and CFP-10 as well. These findings suggest that enrichment for Mtb-specific T cells within BAL is not unique to active pulmonary tuberculosis and may, to the contrary, contribute to protection from re-infection in Mtb immune individuals. PMID- 26732046 TI - Direct observation of mineral-organic composite formation reveals occlusion mechanism. AB - Manipulation of inorganic materials with organic macromolecules enables organisms to create biominerals such as bones and seashells, where occlusion of biomacromolecules within individual crystals generates superior mechanical properties. Current understanding of this process largely comes from studying the entrapment of micron-size particles in cooling melts. Here, by investigating micelle incorporation in calcite with atomic force microscopy and micromechanical simulations, we show that different mechanisms govern nanoscale occlusion. By simultaneously visualizing the micelles and propagating step edges, we demonstrate that the micelles experience significant compression during occlusion, which is accompanied by cavity formation. This generates local lattice strain, leading to enhanced mechanical properties. These results give new insight into the formation of occlusions in natural and synthetic crystals, and will facilitate the synthesis of multifunctional nanocomposite crystals. PMID- 26732047 TI - Formation of alpha-SF5-Enolate Enables Preparation of 3-SF5-Quinolin-2-ones, 3 SF5-Quinolines, and 3-SF5-Pyridin-2-ones: Evaluation of their Physicochemical Properties. AB - This study describes, for the first time, the generation of a SF5 -substituted ester enolate from benzyl SF5 -acetate under soft enolization conditions, which in turn participates in aldol addition reactions in high yield. The reaction was applied in the synthesis of 3-SF5 -quinolin-2-ones, 3-SF5 -quinolines, and 3-SF5 pyridin-2-ones, none of which have previously been reported. To provide guidelines for their use in drug discovery, the physicochemical properties of these building blocks were determined and compared with those of their CF3 - and t-Bu-analogues. PMID- 26732048 TI - High affinity targeting of CD23 inhibits IgE synthesis in human B cells. AB - The low-affinity IgE receptor FcepsilonRII (CD23) is part of the regulatory system controlling IgE synthesis in human B cells and exists in membrane and soluble forms. Binding of IgE to CD23 has been described to have stabilizing effects and to prevent cleavage of CD23. Previous experiments using anti-CD23 antibodies reduced IgE synthesis but were difficult to interpret as the antibody Fc part might also mediate feedback mechanisms. The purpose of this study was to investigate the regulatory role of CD23, by using designed ankyrin repeat proteins (DARPins) that specifically recognize CD23. Anti-CD23 DARPins were isolated by ribosome display and were produced as monovalent and bivalent constructs. Affinities to CD23 were measured by surface plasmon resonance. IgE synthesis and up-regulation of CD23 in human peripheral B cells were induced by IL-4 and anti-CD40 antibody. We assessed CD23 expression and its stabilization by FACS and used an ELISA for detecting soluble CD23. IgE synthesis was measured by ELISA and real-time PCR. Surface plasmon resonance revealed affinities of the DARPins to CD23 in the pico-molar range. Anti-CD23 DARPins strongly inhibited binding of IgE to CD23 and share thus a similar binding epitope as IgE. The DARPins stabilized membrane CD23 and reduced IgE synthesis in an isotype specific manner. Furthermore, the anti-CD23 DARPins decreased IgE transcript through inhibition of mature Cepsilon RNA synthesis suggesting a posttranscriptional control mechanism. This study demonstrates that targeting CD23 alone is sufficient to inhibit IgE synthesis and suggests that a negative signaling occurs directly through the CD23 molecule. PMID- 26732049 TI - Customizable engineered blood vessels using 3D printed inserts. AB - Current techniques for tissue engineering blood vessels are not customizable for vascular size variation and vessel wall thickness. These critical parameters vary widely between the different arteries in the human body, and the ability to engineer vessels of varying sizes could increase capabilities for disease modeling and treatment options. We present an innovative method for producing customizable, tissue engineered, self-organizing vascular constructs by replicating a major structural component of blood vessels - the smooth muscle layer, or tunica media. We utilize a unique system combining 3D printed plate inserts to control construct size and shape, and cell sheets supported by a temporary fibrin hydrogel to encourage cellular self-organization into a tubular form resembling a natural artery. To form the vascular construct, 3D printed inserts are adhered to tissue culture plates, fibrin hydrogel is deposited around the inserts, and human aortic smooth muscle cells are then seeded atop the fibrin hydrogel. The gel, aided by the innate contractile properties of the smooth muscle cells, aggregates towards the center post insert, creating a tissue ring of smooth muscle cells. These rings are then stacked into the final tubular construct. Our methodology is robust, easily repeatable and allows for customization of cellular composition, vessel wall thickness, and length of the vessel construct merely by varying the size of the 3D printed inserts. This platform has potential for facilitating more accurate modeling of vascular pathology, serving as a drug discovery tool, or for vessel repair in disease treatment. PMID- 26732050 TI - An ionic charge-transfer dyad prepared cost-effectively from a tetrathiafulvalene carboxylate anion and a TMPyP cation. AB - Great progress has been made in combining a TTF moiety with a porphyrin unit by covalent bonds, but only a few examples were reported in which TTF and porphyrin assembled by noncovalent interactions. In contrast to the energy- and time consuming synthetic procedures for the covalent system, the assembly of a non covalent ionic system would be a cost-effective way to construct donor-acceptor ensembles. Herein a new type of ionic TTF-porphyrin dyad is obtained. A methylated tetra(4-pyridyl) porphyrin (5,10,15,20-tetrakis-(N-methyl-4-pyridyl) porphyrin, TMPyP) is selected as the cation, and TTF-bicarboxylate (L(1)) or TTF tetracarboxylate (L(2)) is used as the anion. Crystal structures of two TTF-TMPyP ionic D-A compounds, TMPyP-(HL(1))4.3H2O (1) and TMPyP-(H2L(2))2.5H2O (2), were characterized by single-crystal X-ray diffraction. The strong ionic interaction enhances the charge-transfer between the regular mixed-stacking donors and acceptors, which are investigated comprehensively by spectral, electrochemical and theoretical studies. The variation in properties between L(1) and L(2) is of great advantage to understand the influence factors for charge-transfer. The charge-transfer properties can be modulated not only by the nature of the donor or the acceptor, but also the cation-anion ratio in the salt, which shows great flexibility of the D-A ionic dyad in the design and preparation of new charge transfer systems. PMID- 26732051 TI - Impact of host and histopathological factors on the discrepancies in estrogen receptor, and progesterone receptor, and HER2 status between core needle biopsy and surgically excised tumors. AB - PURPOSE: The high reliability and utility of core needle biopsy (CNB) have been previously described. Our aim in this study was to clarify the host and histopathological factors influencing the discrepancies in ER, PgR, and HER2 status between CNB and surgically excised tumors (SET). METHODS: All patients diagnosed with operable invasive breast cancer in our hospital between January 2005 and April 2015 were included in the study; patients who required neoadjuvant chemotherapy were excluded. ER, PgR, and HER2 expression were assessed between paired CNB and SET samples. ER and PgR status were determined using immunohistochemistry(IHC). HER2 status was determined using IHC and scored from 0 to 3+. Fluorescence in-situ hybridization analysis was carried out in HER2 2+ cases. The cut off point for ER and PgR positivity was set at 1%. RESULTS: A total of 1307 patients were assessed. The concordance rates of ER, PgR, and HER2 status in CNB and SET were 95%, 84% and 97%, respectively. Factors of discrepancy were nuclear grade, histological type, and menopausal status for ER and PgR, and none detected for HER2. The discrepancy factors were assessed with univariate and multivariate analysis. CONCLUSIONS: Using the largest known dataset to date of paired samples from a single institution, we evaluated the accuracy of CNB and the discrepancy factors between CNB and SET in breast cancer patients. We conclude that CNB for ER and PgR assessment in postmenopausal patients before treatment should be used with caution. Further research will contribute to increased CNB accuracy, improving patient treatment decisions. PMID- 26732052 TI - Factors affecting healthcare service utilization of mothers who had children with diarrhea in Ethiopia: evidence from a population based national survey. AB - INTRODUCTION: Appropriate healthcare-seeking practices of mothers are important to prevent child death. This study aimed to investigate factors associated with mothers' healthcare services utilization for managing childhood diarrhea (CDD) in Ethiopia. METHODS: A secondary data analysis was performed using data from the Ethiopian Demographic and Health Survey 2011. Binary and multivariable logistic regressions were carried out to identify factors associated with mothers' healthcare services utilization for CDD. RESULTS: About 35% (95% confidence interval (CI): 32.67-37.33%) of mothers visited healthcare institutions (HCIs) for CDD. Those mothers with children aged 6-11 months were 2.16 times more likely to use HCIs for CDD (adjusted odds ratio (AOR)=2.16, 95%CI: 1.32-3.53) compared to mothers who had children under 6 months of age. Urban mothers were 1.68 times more likely to use HCIs for CDD compared to rural mothers (AOR=1.68, 95%CI: 1.06 2.67). Those mothers who had information about oral rehydration salts (ORSs) were 2.66 times more likely to use HCIs for CDD compared to those mothers who had no information about ORS (AOR=2.66, 95%CI: 1.93-3.67). Mothers who attended antenatal care were 1.34 times more likely to use HCIs for CDD than mothers who never attended antenatal care (AOR=1.34, 95%CI: 1.04-1.74). Mothers who had postnatal checkups were 1.53 times more likely to use HCIs for CDD compared to mothers who had no postnatal checkups (AOR=1.53, 95%CI: 1.02-2.30). Those mothers who participated in community conversation were 1.67 times more likely to use HCIs for CDD than those mothers who had no information about community conversation (AOR=1.67, 95%CI: 1.15-2.39). CONCLUSIONS: Healthcare services utilization for CDD was found to be poor in Ethiopia. Urban residency, older age of the child, awareness of ORSs, antenatal care attendance, postnatal check and attending community conversation were factors associated with healthcare services utilization for CDD. Interventions to improve mothers' healthcare service utilization for CDD treatment should target rural households. Promotions of appropriate CDD treatment during ANC, postnatal checkup and community conversation are the recommended interventions. PMID- 26732053 TI - Overexpression of SIRT6 in the hippocampal CA1 impairs the formation of long-term contextual fear memory. AB - Histone modifications have been implicated in learning and memory. Our previous transcriptome data showed that expression of sirtuins 6 (SIRT6), a member of Histone deacetylases (HDACs) family in the hippocampal cornu ammonis 1 (CA1) was decreased after contextual fear conditioning. However, the role of SIRT6 in the formation of memory is still elusive. In the present study, we found that contextual fear conditioning inhibited translational expression of SIRT6 in the CA1. Microinfusion of lentiviral vector-expressing SIRT6 into theCA1 region selectively enhanced the expression of SIRT6 and impaired the formation of long term contextual fear memory without affecting short-term fear memory. The overexpression of SIRT6 in the CA1 had no effect on anxiety-like behaviors or locomotor activity. Also, we also found that SIRT6 overexpression significantly inhibited the expression of insulin-like factor 2 (IGF2) and amounts of proteins and/or phosphoproteins (e.g. Akt, pAkt, mTOR and p-mTOR) related to the IGF2 signal pathway in the CA1. These results demonstrate that the overexpression of SIRT6 in the CA1 impaired the formation of long-term fear memory, and SIRT6 in the CA1 may negatively modulate the formation of contextual fear memory via inhibiting the IGF signaling pathway. PMID- 26732054 TI - Clinical and economic burden of idiopathic pulmonary fibrosis: a retrospective cohort study. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating condition with a variable course. Not uncommonly, IPF patients are hospitalized for respiratory related causes, including disease worsening. This study aimed to characterize the prevalence, and economic and health care burden of IPF. METHODS: Retrospective insurance claims data collected yearly between January 1, 2009 and December 31, 2011, were used to determine prevalence and calculate all-cause and respiratory related resource utilization and costs. Patients had at least one inpatient claim or two outpatient claims for IPF (ICD-9-CM code 516.3). Results for health care burden are reported for the 2011 cohort (similar findings in 2009-2010). Costs are reported in 2011 US dollars ($). RESULTS: Patients with IPF had a mean age of 69.8-71.3 years. Overall prevalence for IPF was 28.8, 28.1 and 19.8 per 100,000 insured persons in 2009, 2010 and 2011. In each year, prevalence increased with age. In 2011, 37.7% of patients were hospitalized at least once for any cause; 19.5% for respiratory-related reasons. Also in 2011, the mean number of all-cause outpatient visits and respiratory-related office visits was 18.5 and 5.7 per patient, respectively. All-cause health care costs in 2011 were $59,379 per patient; 36.6% of costs ($21,732) were respiratory related. CONCLUSIONS: The prevalence of IPF in this claims database increased with age, with a notable increase in those over 65 years. IPF is associated with a large economic and health care burden. Additional research is needed to determine how such burden might be reduced. PMID- 26732056 TI - Promoting the management of acute upper gastrointestinal bleeds among junior doctors: a quality improvement project. AB - Though they are knowledgeable, foundation year one (FY1) doctors can lack skills and confidence in acute situations due to inexperience. This was witnessed when a new FY1 on call attended an acute upper gastrointestinal bleed (UGIB), a common emergency with a 10% in hospital mortality rate. We aimed to improve FY1s' ability to manage these critical patients through simulation based teaching, before and after the introduction of an algorithm summarising current guidelines. After assessing the FY1s' perceived level of confidence in managing UGIBs, they individually attended a simulation session which evaluated specific aspects of their assessment and management plans. Immediate debriefing and subsequent teaching sessions reinforced learning points, with an algorithm instituted as an aide memoire to improve efficiency. A repeat simulation session assessed improvements in both subjective confidence and objective management targets. All FY1s expressed improved confidence in managing patients with UGIBs. There were improvements across the board in their assessment and management, notably: verbalisation of concern for hypotension increased to 100% (from 60%), two points of intravenous access requested in 100% of cases (from 53%), and a 76 second reduction in time to call for senior support. Collectively, these individual aspects led to improved patient care. Effective management of acute patients is best learnt through exposure, and simulation based teaching provides a safe but powerful modality to aid transition from textbook theory to ward situations. Algorithms can streamline care and hasten the stabilisation of patients. This project reinforces generic competencies that FY1s can translate to their management of not only UGIBs, but many acute presentations, providing a convincing argument for broader simulation use in FY1 teaching. PMID- 26732055 TI - The importance of the granulocyte-colony stimulating factor in oncology. AB - Granulocyte-colony stimulating factor (G-CSF) is a glycoprotein, the second CSF, sharing some common effects with granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin-3 (IL-3) and interleukin-5 (IL-5). G-CSF is mainly produced by fibroblasts and endothelial cells from bone marrow stroma and by immunocompetent cells (monocytes, macrophages). The receptor for G-CSF (G-CSFR) is part of the cytokine and hematopoietin receptor superfamily and G-CSFR mutations cause severe congenital neutropenia. The main action of G-CSF - G-CSFR linkage is stimulation of the production, mobilization, survival and chemotaxis of neutrophils, but there are many other G-CSF effects: growth and migration of endothelial cells, decrease of norepinephrine reuptake, increase in osteoclastic activity and decrease in osteoblast activity. In oncology, G-CSF is utilized especially for the primary prophylaxis of chemotherapy-induced neutropenia, but it can be used for hematopoietic stem cell transplantation, it can produce monocytic differentiation of some myeloid leukemias and it can increase some drug resistance. The therapeutic indications of G-CSF are becoming more and more numerous: non neutropenic patients infections, reproductive medicine, neurological disturbances, regeneration therapy after acute myocardial infarction and of skeletal muscle, and hepatitis C therapy. PMID- 26732057 TI - Corrigendum: Down-regulation of miR-206 is associated with Hirschsprung disease and suppresses cell migration and proliferation in cell models. PMID- 26732059 TI - Future Prospects for the Total Artificial Heart. AB - A total artificial heart (TAH) is the sole remaining option for patients with biventricular failure who cannot be rescued by left ventricular assist devices (LVADs) alone. However, the pulsatile TAH in clinical use today has limitations: large pump size, unknown durability, required complex anticoagulation regimen, and association with significant postsurgical complications. That pump is noisy; its large pneumatic driving lines traverse the body, with bulky external components for its drivers. Continuous-flow pumps, which caused a paradigm shift in the LVAD field, have already contributed to the rapidly evolving development of TAHs. Novel continuous-flow TAHs are only in preclinical testing or developmental stages. We here review the current state of TAHs, with recommended requirements for the TAH of the future. PMID- 26732060 TI - Green synthesis, characterization and catalytic activity of natural bentonite supported copper nanoparticles for the solvent-free synthesis of 1-substituted 1H 1,2,3,4-tetrazoles and reduction of 4-nitrophenol. AB - In this study, Cu nanoparticles were immobilized on the surface of natural bentonite using Thymus vulgaris extract as a reducing and stabilizing agent. The natural bentonite-supported copper nanoparticles (Cu NPs/bentonite) were characterized by FTIR spectroscopy, X-ray diffraction (XRD), X-ray fluorescence (XRF), field emission scanning electron microscopy (FE-SEM), energy dispersive X ray spectroscopy (EDS), transmission electron microscopy (TEM), selected area electron diffraction (SAED) and Brunauer-Emmett-Teller (BET) analysis. Afterward, the catalytic performance of the prepared catalyst was investigated for the solvent-free synthesis of 1-substituted 1H -1,2,3,4-tetrazoles and reduction of 4 nitrophenol (4-NP) in water. It was found that the Cu NPs/bentonite is a highly active and recyclable catalyst for related reactions. PMID- 26732061 TI - Sensor-based variable-rate fungicide application in winter wheat. AB - BACKGROUND: Currently, no technology for the automatic detection of diseases while moving agricultural equipment through fields is available on the market. An alternative approach of target-oriented fungicide spraying was tested to adapt the local dose rates of spray liquid in winter wheat to local differences in the plant surface and biomass by using a camera sensor. RESULTS: A linear correlation was found between the sensor values and two plant parameters, namely the leaf area index and biomass. The spray volume was linearly adapted to the local sensor value in a field trial. The camera sensor was used to operate the dosing system (gauge) at the field boom sprayer. A total of 8% of spray liquid was saved compared with common uniform spraying. CONCLUSIONS: Because no differences exist in yield and disease incidence between the sensor-based and uniformly sprayed plot, this new technology, which uses plants as targets for fungicide dosages, could be an alternative to the present common dosage practices on a hectare basis. (c) 2016 Society of Chemical Industry. PMID- 26732058 TI - Mottled Mice and Non-Mammalian Models of Menkes Disease. AB - Menkes disease is a multi-systemic copper metabolism disorder caused by mutations in the X-linked ATP7A gene and characterized by progressive neurodegeneration and severe connective tissue defects. The ATP7A protein is a copper (Cu)-transporting ATPase expressed in all tissues and plays a critical role in the maintenance of copper homeostasis in cells of the whole body. ATP7A participates in copper absorption in the small intestine and in copper transport to the central nervous system (CNS) across the blood-brain-barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). Cu is essential for synaptogenesis and axonal development. In cells, ATP7A participates in the incorporation of copper into Cu-dependent enzymes during the course of its maturation in the secretory pathway. There is a high degree of homology (>80%) between the human ATP7A and murine Atp7a genes. Mice with mutations in the Atp7a gene, called mottled mutants, are well established and excellent models of Menkes disease. Mottled mutants closely recapitulate the Menkes phenotype and are invaluable for studying Cu-metabolism. They provide useful models for exploring and testing new forms of therapy in Menkes disease. Recently, non-mammalian models of Menkes disease, Drosophila melanogaster and Danio rerio mutants were used in experiments which would be technically difficult to carry out in mammals. PMID- 26732062 TI - An open framework crystal structure and physical properties of RbCuAl(PO4)2. AB - The novel phosphate RbCuAl(PO4)2 was prepared by hydrothermal synthesis at 553 K. Its crystal structure was determined using single-crystal X-ray diffraction data and refined against F(2) to R = 0.026. The compound crystallizes in the monoclinic space group P21/c, with unit-cell parameters a = 5.0723(8) A, b = 14.070(2) A, c = 9.352(1) A, beta = 100.41(1), V = 656.4(2) A(3), and Z = 4. The crystal structure is based on an open 3D aluminophosphate framework built by AlO5 bipyramids and PO4 tetrahedra sharing oxygen vertices. Channels in the [100] and [001] directions accommodate Rb(+) cations and chains of Cu-centered octahedra alternatively sharing cis- and trans-edges. The new phase is characterized by the structure type established for isotypic iron phosphates KMFe(PO4)2, where M = Fe/Ni, Ni, Mg or Co. It also shows topological relationships with Pb2Ni(PO4)2 and Fe(3+)Fe(2+)0.5(H2O)2(HPO4)2 structures. The RbCuAl(PO4)2 exhibits rather peculiar physical properties evidenced in specific heat and magnetization measurements. It releases a significant part of magnetic entropy well above the Neel temperature TN = 10.5 K and possesses a spontaneous magnetic moment at lower temperatures. The origin of the spontaneous moment is ascribed to the canting of a pristine antiferromagnetic structure due to the interchain Dzyaloshinskii Moriya exchange interaction. PMID- 26732064 TI - A thoracic spinal bone giant cell tumor in a skeletally immature girl. A case report and literature review. AB - PURPOSE: Giant cell tumors (GCT) are benign primary bone tumors, locally aggressive, affecting in long bones in young adults during the third decade. It is rare to experience this lesion in skeletally immature patients. GCT are related to a risk of local recurrence and malignant transformation. METHOD: We report a rare case of a giant cell tumor of the thoracic spine in a skeletally immature girl presenting with a painful right scoliosis. RESULTS: MRI, CT scan, and bone scintigraphy were discordant and the percutaneous biopsy non contributive. CONCLUSION: A marginal "en bloc" resection was performed and revealed the GCT. Based on a literature review, the diagnosis and the surgical management of this case are discussed. PMID- 26732063 TI - Current approaches to the clinical assessment of syncope in pediatric population. AB - INTRODUCTION: Syncope is one of the most common clinical problem in children. This disorder is characterized by transient, spontaneously self-terminating loss of consciousness with brief duration and complete recovery. This situation is usually alarming for the families of patients. The mechanism of syncope is transient global brain hypoperfusion to levels below those tolerated by cerebrovascular autoregulation. Syncope can occur with many different etiologies in the pediatric population. CLASSIFICATION: Syncopes are divided into three major categories as neurally mediated syncope, cardiovascular-mediated syncope, and non-cardiovascular syncope. CLINICAL FEATURES: The major challenge in the assessment of children with syncope is that most children are asymptomatic at the time of their presentation, therefore making a careful and detailed history and a comprehensive physical examination essential in all patients. A trigger stimulus is detected in some cases, and this is an important clinical clue for the diagnosis. Cardiac causes of syncope in children are rare but can be life threatening and have the highest risk of morbidity and mortality. Misdiagnosis of epilepsy is common in patients presenting with syncope; therefore, the differential diagnosis between epileptic seizures and syncope is very important. It should be remembered that the evaluation of syncope in children is costly and diagnostic workup has a limited diagnostic yield. CONCLUSION: The aim of this article is to present different types of syncope and to provide new practical clinical approaches to the diagnosis, investigation, and management in the pediatric population. PMID- 26732065 TI - The investigation of the prenatal and postnatal alcohol exposure-induced neurodegeneration in rat brain: protection by betaine and/or omega-3. AB - PURPOSE: We aim to study the effect of neurodegeneration on the brain of rat pups caused by prenatal and postnatal ethanol exposure with modified liquid diet to elucidate protective effects of betaine and omega-3 supplementation. When ethanol is consumed during prenatal and postnatal periods, it may result in fetal alcohol syndrome (FAS) in the offspring. METHODS: Rats were divided into control, ethanol, ethanol + betaine, ethanol + omega-3, ethanol + omega-3 + betaine groups. The effect of betaine and omega-3 in response to ethanol-induced changes on the brain, by biochemical analyses cytochrome c, caspase-3, calpain, cathepsin B and L, DNA fragmentation, histological and morfometric methods were evaluated. RESULTS: Caspase-3, calpain, cathepsin B, and cytochrome c levels in ethanol group were significantly higher than control. Caspase-3, calpain levels were decreased in ethanol + betaine, ethanol + omega-3, and ethanol + omega-3 + betaine groups compared to ethanol group. Cathepsin B in ethanol + omega-3 + betaine group was decreased compared to ethanol, ethanol + betaine groups. Cathepsin L and DNA fragmentation were found not statistically significant. We found similar results in histological and morfometric parameters. CONCLUSION: We found that pre- and postnatal ethanol exposure is capable of triggering necrotic cell death in rat brains, omega-3, and betaine reduce neurodegeneration. Omega-3 and betaine may prove beneficial for neurodegeneration, particularly in preventing FAS. PMID- 26732067 TI - Mutant generation by allelic exchange and genome resequencing of the biobutanol organism Clostridium acetobutylicum ATCC 824. AB - BACKGROUND: Clostridium acetobutylicum represents a paradigm chassis for the industrial production of the biofuel biobutanol and a focus for metabolic engineering. We have previously developed procedures for the creation of in frame, marker-less deletion mutants in the pathogen Clostridium difficile based on the use of pyrE and codA genes as counter selection markers. In the current study we sought to test their suitability for use in C. acetobutylicum. RESULTS: Both systems readily allowed the isolation of in-frame deletions of the C. acetobutylicum ATCC 824 spo0A and the cac824I genes, leading to a sporulation minus phenotype and improved transformation, respectively. The pyrE-based system was additionally used to inactivate a putative glycogen synthase (CA_C2239, glgA) and the pSOL1 amylase gene (CA_P0168, amyP), leading to lack of production of granulose and amylase, respectively. Their isolation provided the opportunity to make use of one of the key pyrE system advantages, the ability to rapidly complement mutations at appropriate gene dosages in the genome. In both cases, their phenotypes were restored in terms of production of granulose (glgA) and amylase (amyP). Genome re-sequencing of the ATCC 824 COSMIC consortium laboratory strain used revealed the presence of 177 SNVs and 49 Indels, including a 4916-bp deletion in the pSOL1 megaplasmid. A total of 175 SNVs and 48 Indels were subsequently shown to be present in an 824 strain re-acquired (Nov 2011) from the ATCC and are, therefore, most likely errors in the published genome sequence, NC_003030 (chromosome) and NC_001988 (pSOL1). CONCLUSIONS: The codA or pyrE counter selection markers appear equally effective in isolating deletion mutants, but there is considerable merit in using a pyrE mutant as the host as, through the use of ACE (Allele-Coupled Exchange) vectors, mutants created (by whatever means) can be rapidly complemented concomitant with restoration of the pyrE allele. This avoids the phenotypic effects frequently observed with high copy number plasmids and dispenses with the need to add antibiotic to ensure plasmid retention. Our study also revealed a surprising number of errors in the ATCC 824 genome sequence, while at the same time emphasising the need to re-sequence commonly used laboratory strains. PMID- 26732066 TI - A phase 1/2 study of carfilzomib in Japanese patients with relapsed and/or refractory multiple myeloma. AB - We conducted a phase 1/2 study of single-agent carfilzomib in Japanese patients with relapsed/refractory multiple myeloma. Safety, pharmacokinetics and pharmacodynamics of carfilzomib were examined in phase 1. The primary endpoint in phase 2 was the overall response rate (ORR). Carfilzomib was administered in a twice-weekly, consecutive-day dosing schedule. In Phase 1, doses of 15 or 20 mg/m(2) were administered on this schedule or 20 mg/m(2) on Days 1 and 2 of Cycle 1 and then 27 mg/m(2) in the 20/27 mg/m(2) cohort. Patients had a median of five prior therapies, including bortezomib and an immunomodulatory agent. The dose level did not reach the maximum tolerated dose. The most common adverse events were haematological. Notably, carfilzomib either induced new hypertension (n = 4) or aggravated previously existing hypertension (n = 6) in 10 of 50 patients. Four of the eight patients who previously experienced peripheral neuropathy (PN) experienced a recurrence with carfilzomib use, but no new cases of PN occurred. The ORR of the 20/27 mg/m(2) 40 patient cohort was similar to that in the pivotal US study. The dose was efficacious and tolerable in heavily pre-treated Japanese patients; however, meticulous control of hypertension may be necessary for further carfilzomib use. PMID- 26732068 TI - Nephrology training in Australia and New Zealand: A survey of outcomes and adequacy. AB - BACKGROUND: Advanced training programmes in nephrology should provide broad exposure to all aspects of nephrology. In Australia and New Zealand (ANZ), the Advanced Training Committee in Nephrology oversees training, and recent increases in trainee numbers have led to concern about dilution of experience. AIM: To investigate early career paths of nephrologists in ANZ and determine the adequacy of training by comparing self-determined competency and skill relevance among recently graduated nephrologists. METHODS: In 2015, the Advanced Training Committee in Nephrology administered an online survey during the annual subscription for members of the Australian and New Zealand Society of Nephrology. Nephrologists who were awarded Fellowship after 2002 were invited to participate. RESULTS: The survey was completed by 113 Fellows with 8 respondents excluded (response rate 44.1%). Initial post-Fellowship work included full-time public hospital appointments (34.3%) or undertaking full-time higher research degrees (41.9%). The majority reported securing their desired employment. Respondents indicated adequate training in most clinical skills; however, responses of 'well trained' in home haemodialysis (41.8%), conservative care (42.9%), automated peritoneal dialysis (38.8%), and assessment of kidney transplant recipients (48%) and living kidney donors (34.7%) were less adequate. Although considered highly relevant to current practice, responses of 'well trained' were low for management and research skills, including complaint management (16.3%), private practice management (2%), health system knowledge (14.3%) and regulations (6.1%), ethics approval (23.5%), research funding (11.2%) and quality assurance (26.5%). CONCLUSION: Nephrology training in ANZ generally meets clinical needs and most secure their desired employment. Training in management and research are areas for improvement. PMID- 26732069 TI - Sleep disturbances associated with sleep enuresis: A questionnaire study. AB - PURPOSE: Sleep enuresis (SE) is the second most common sleep complaint in childhood. It has been associated with bladder hyperactivity, excessive urine production and deeper sleep. Several sleep disorders have been described in association with SE like parasomnias and sleep apnea. The aim of this study was to analyze the presence of sleep disturbances in children with SE through the use of Sleep Disturbance Scale for Children (SDSC) compared to normal children matched for age and sex. METHODS: A questionnaire evaluation was performed in 76 enuretic and 112 normal children through the Sleep Disturbance Scale for Children (SDSC) validated for Portuguese language. The Scale is grouped into six subscales: Disorders in Initiating and Maintaining Sleep (DIMS), Sleep Breathing Disorders (SBD), Disorders of Arousal (DA), Sleep-Wake Transition Disorders (SWTD), Disorders Of Excessive Somnolence (DOES), and Nocturnal Hyperhidrosis (SHY). Children with renal and neurological problems were excluded from both groups. RESULTS: Enuretics scored higher in several of the subscales (SBD, DOA, SWTD) and also in the total scale scores while scored low in the DIMS subscale. No differences were found for the DOES and SHY subscales. CONCLUSIONS: Enuretic children showed a high comorbidity with other sleep disturbances like sleep disordered breathing and parasomnias. The novel finding of this study is that we found a decreased incidence of DIMS that is consistent with the parental perception of a more deep sleep and a high arousal threshold in SE. PMID- 26732070 TI - Changes of vitellogenin and Lipase in captive Sterlet sturgeon Acipenser ruthenus females during previtellogenesis to early atresia. AB - Plasma chemistry, lipid metabolism and vitellogenin gene expression of captive Sterlet sturgeon Acipenser ruthenus were studied in different maturity stages. A total of 32 fish were sampled, and maturity stages were identified on the basis of histological criteria and direct observation. Females were classified to four groups: previtellogenic, vitellogenic, post-vitellogenic, and atresia. Blood, gonad and liver tissue samples were taken through non-lethal biopsy. Our results showed that plasma levels of glucose, cholesterol, triacylglycerol, high-density lipoprotein, low-density lipoprotein, very low-density lipoprotein, calcium, phosphorus, alkaline phosphatase activity, albumin and total protein increased during ovarian development and were highest at post-vitellogenic stage. The lowest amounts in atresia stage demonstrate that lipid and energy imbalance was related to reabsorption and digestion of the yolk. These results suggested that the VLDL was the main plasma lipoprotein component of Sterlet. We determined that lipoprotein lipase and hepatic lipase activity increased during vitellogenesis process which suggested the role of lipase enzymes in regulating blood lipid metabolism. RT-PCR analysis indicates that Vitellogenin (VTG) mRNA could be detected both in livers and ovaries of female Sterlet. Throughout the study, the expression level of VTG gene showed an increase both in ovaries and in livers reaching its peak at late vitellogenesis stage. This strongly indicated a relation between VTG mRNA and ovarian development. PMID- 26732071 TI - Glanduliferins A and B, two new glucosylated steroids from Impatiens glandulifera, with in vitro growth inhibitory activity in human cancer cells. AB - Impatiens glandulifera has been imported from Himalaya in Europe and is considered as an invasive alien plant whose spreading arouses increasing interest among scientific literature. Via anti-cancer bioguiding, two new glucosylated steroids, named glanduliferins A and B, were isolated from the dried stem of I. glandulifera plants, together with the well-known alpha-spinasterol and 2-methoxy 1,4-naphthoquinone, which are also isolated from roots and leaves. They were characterized as 17-(2-hydroxy-2-pentamethylcyclopropyl-ethyl)-10,13-dimethyl 2,3,4,5,6,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopents[a]phenathren-3-O (4-O-acetyl)-alpha-D-glucopyranoside and 17-(4-ethyl-1,5-dimethyl-hex-2-enyl) 10,13-dimethyl-2,3,4,5,6,9,10,11,12,13,14,15,16,17-tetradecahydro-1H cyclopents[a]phenathren-3-O-(6-O-acetyl)-beta-D-glucopyranoside using various NMR and HRESIMS techniques and chemical methods. In vitro determination of the growth inhibitory activity of the four isolated compounds using the MTT colorimetric assay revealed mean IC50 growth inhibitory value of ~30 MUM for glanduliferin A while glanduliferin B and alpha-spinasterol were poorly active till 100 MUM. 2 methoxy-1,4-naphthoquinone revealed to be active in the single micromolar digit range as previously described. Quantitative videomicroscopy analyses of the effects of glanduliferins A and B suggested cytostatic rather than cytotoxic activity in U373 glioblastoma (GBM) cells. PMID- 26732072 TI - Enhancement of Contralesional Motor Control Promotes Locomotor Recovery after Unilateral Brain Lesion. AB - There have been controversies on the contribution of contralesional hemispheric compensation to functional recovery of the upper extremity after a unilateral brain lesion. Some studies have demonstrated that contralesional hemispheric compensation may be an important recovery mechanism. However, in many cases where the hemispheric lesion is large, this form of compensation is relatively limited, potentially due to insufficient connections from the contralesional hemisphere to the paralyzed side. Here, we used a new procedure to increase the effect of contralesional hemispheric compensation by surgically crossing a peripheral nerve at the neck in rats, which may provide a substantial increase in connections between the contralesional hemisphere and the paralyzed limb. This surgical procedure, named cross-neck C7-C7 nerve transfer, involves cutting the C7 nerve on the healthy side and transferring it to the C7 nerve on the paretic side. Intracortical microstimulation, Micro-PET and histological analysis were employed to explore the cortical changes in contralesional hemisphere and to reveal its correlation with behavioral recovery. These results showed that the contralesional hemispheric compensation was markedly strengthened and significantly related to behavioral improvements. The findings also revealed a feasible and effective way to maximize the potential of one hemisphere in controlling both limbs. PMID- 26732073 TI - Identification of Entamoeba moshkovskii in Treated Waste Water Used for Agriculture. AB - We conducted an observational study to determine the prevalence of Entamoeba spp., in samples collected in a waste water treatment plant that provides water for agricultural irrigation. Samples were collected weekly over a period of 10 weeks at representative contamination stages from within the treatment plant. Protozoan identification was performed via light microscopy and culture. PCR amplification of small subunit rRNA gene sequences of E. histolytica/dispar/moshkovskii was performed in culture positive samples. Light microscopy revealed the presence of Entamoeba spp., in 70% (14/20) of the raw waste water samples and in 80% (8/10) of the treated water samples. PCR amplification after culture at both 24 and 37 degrees C revealed that 100% (29/29) of the raw waste water samples and 78.6% (11/14) of the treated waste water were positive for E. moshkovskii. We report the first isolation of E. moshkovskii in Colombia, confirmed by PCR. Recent reports of E. moshkovskii pathogenic potential suggest this finding could constitute a public health risk for people exposed to this water. PMID- 26732074 TI - Bringing Back a Healthy Buzz? Invertebrate Parasites and Reintroductions: A Case Study in Bumblebees. AB - Reintroductions can play a key role in the conservation of endangered species. Parasites may impact reintroductions, both positively and negatively, but few case studies of how to manage parasites during reintroductions exist. Bumblebees are in decline at regional and global scales, and reintroductions can be used to re-establish extinct local populations. Here we report on how the risks associated with parasites are being managed in an ongoing reintroduction of the short-haired bumblebee, Bombus subterraneus, to the UK. Disease risk analysis was conducted and disease risk management plans constructed to design a capture quarantine-release system that minimised the impacts on both the bumblebees and on their natural parasites. Given that bumblebee parasites are (i) generalists, (ii) geographically ubiquitous, and (iii) show evidence of local adaptation, the disease risk management plan was designed to limit the co-introduction of parasites from the source population in Sweden to the destination site in the UK. Results suggest that this process at best eliminated, or at least severely curtailed the co-introduction of parasites, and ongoing updates of the plan enabled minimization of impacts on natural host-parasite dynamics in the Swedish source population. This study suggests that methods designed for reintroductions of vertebrate species can be successfully applied to invertebrates. Future reintroductions of invertebrates where the parasite fauna is less well known should take advantage of next-generation barcoding and multiple survey years prior to the start of reintroductions, to develop comprehensive disease risk management plans. PMID- 26732076 TI - Genesis of charge orders in high temperature superconductors. AB - One of the most puzzling facts about cuprate high-temperature superconductors in the lightly doped regime is the coexistence of uniform superconductivity and/or antiferromagnetism with many low-energy charge-ordered states in a unidirectional charge density wave or a bidirectional checkerboard structure. Recent experiments have discovered that these charge density waves exhibit different symmetries in their intra-unit-cell form factors for different cuprate families. Using a renormalized mean-field theory for a well-known, strongly correlated model of cuprates, we obtain a number of charge-ordered states with nearly degenerate energies without invoking special features of the Fermi surface. All of these self-consistent solutions have a pair density wave intertwined with a charge density wave and sometimes a spin density wave. Most of these states vanish in the underdoped regime, except for one with a large d-form factor that vanishes at approximately 19% doping of the holes, as reported by experiments. Furthermore, these states could be modified to have a global superconducting order, with a nodal-like density of states at low energy. PMID- 26732075 TI - Immunity in the spleen and blood of mice immunized with irradiated Toxoplasma gondii tachyzoites. AB - Toxoplasma gondii infection induces a strong and long-lasting immune response that is able to prevent most reinfections but allows tissue cysts. Irradiated, sterilized T. gondii tachyzoites are an interesting vaccine, and they induce immunity that is similar to infection, but without cysts. In this study, we evaluated the cellular immune response in the blood and spleen of mice immunized with this preparation by mouth (v.o.) or intraperitoneally (i.p.) and analyzed the protection after challenge with viable parasites. BALB/c mice were immunized with three i.p. or v.o. doses of irradiated T. gondii tachyzoites. Oral challenge with ten cysts of the ME-49 or VEG strain at 90 days after the last dose resulted in high levels of protection with low parasite burden in the immunized animals. There were higher levels of specific IgG, IgA and IgM antibodies in the serum, and the i.p. immunized mice had higher levels of the high-affinity IgG and IgM antibodies than the orally immunized mice, which had more high-affinity IgA antibodies. B cells (CD19(+)), plasma cells (CD138(+)) and the CD4(+) and CD8(+) T cell populations were increased in both the blood and spleen. Cells from the spleen of the i.p. immunized mice also showed antigen-induced production of interleukin-10 (IL-10), interferon gamma (IFN-gamma) and interleukin 4 (IL-4). The CD4(+) T cells, B cells and likely CD8(+) T cells from the spleens of the i.p. immunized mice proliferated with a specific antigen. The protection was correlated with the spleen and blood CD8(+) T cell, high-affinity IgG and IgM and antigen-induced IL-10 and IL-4 production. Immunization with irradiated T. gondii tachyzoites induces an immune response that is mediated by B cells and CD4(+) and CD8(+) T cells, with increased humoral and cellular immune responses that are necessary for host protection after infection. The vaccine is similar to natural infection, but free of tissue cysts; this immunity restrains infection at challenge and can be an attractive and efficient model for vaccine development in toxoplasmosis. PMID- 26732078 TI - Anemia and transfusion in the neonate. AB - Neonatal anemia is a frequent occurrence in neonatal intensive care units. Red blood cell transfusion criteria in case of blood loss are clearly defined but optimal hemoglobin or hematocrit thresholds of transfusion for anemia due to decreased production or increased destruction are less evident. This review focuses on the causes of anemia in the newborn period and the most recent evidence-based treatment options, including transfusion and erythropoiesis stimulating agents. PMID- 26732077 TI - Altered Lamin A/C splice variant expression as a possible diagnostic marker in breast cancer. AB - BACKGROUND: Lamin A/C alternative splice variants (Lamin A, Lamin C, Lamin ADelta10 and Lamin ADelta50) have been implicated in cell cycle regulation, DNA replication, transcription regulation, cellular differentiation, apoptosis and aging. In addition, loss of Lamin A/C expression has been observed in several cancers, including breast cancer, and it has been found that Lamin A/C suppression may lead to cancer-like aberrations in nuclear morphology and aneuploidy. Based on these observations, we hypothesized that Lamin A/C transcript variant quantification might be employed for the diagnosis of breast cancer. METHODS: Newly designed TaqMan qRT-PCR assays for the analysis of Lamin A/C splice variants were validated and their use as biomarkers for the diagnosis of breast cancer was assessed using 16 normal breast tissues and 128 breast adenocarcinomas. In addition, the expression levels of the Lamin A/C transcript variants were measured in samples derived from seven other types of cancer. RESULTS: We found that the expression level of Lamin C was significantly increased in the breast tumors tested, whereas the expression levels of Lamin A and Lamin ADelta50 were significantly decreased. No significant change in Lamin ADelta10 expression was observed. Our data also indicated that the Lamin C : Lamin A mRNA ratio was increased in all clinical stages of breast cancer. Additionally, we observed increased Lamin C : Lamin A mRNA ratios in liver, lung and thyroid carcinomas and in colon, ovary and prostate adenocarcinomas. CONCLUSIONS: From our data we conclude that the Lamin C : Lamin A mRNA ratio is increased in breast cancer and that this mRNA ratio may be of diagnostic use in all clinical stages of breast cancer and, possibly, also in liver, lung, thyroid, colon, ovary and prostate cancers. PMID- 26732079 TI - Perinatal hematology. PMID- 26732080 TI - Reply to: methotrexate administration directly into the fourth ventricle in children with malignant fourth ventricular brain tumors: a pilot clinical trial. PMID- 26732082 TI - Response of symptomatic brain metastases from HER-2 overexpressing breast cancer with T-DM1. PMID- 26732081 TI - The diagnostic accuracy of multiparametric MRI to determine pediatric brain tumor grades and types. AB - Childhood brain tumors show great histological variability. The goal of this retrospective study was to assess the diagnostic accuracy of multimodal MR imaging (diffusion, perfusion, MR spectroscopy) in the distinction of pediatric brain tumor grades and types. Seventy-six patients (range 1 month to 18 years) with brain tumors underwent multimodal MR imaging. Tumors were categorized by grade (I-IV) and by histological type (A-H). Multivariate statistical analysis was performed to evaluate the diagnostic accuracy of single and combined MR modalities, and of single imaging parameters to distinguish the different groups. The highest diagnostic accuracy for tumor grading was obtained with diffusion perfusion (73.24%) and for tumor typing with diffusion-perfusion-MR spectroscopy (55.76%). The best diagnostic accuracy was obtained for tumor grading in I and IV and for tumor typing in embryonal tumor and pilocytic astrocytoma. Poor accuracy was seen in other grades and types. ADC and rADC were the best parameters for tumor grading and typing followed by choline level with an intermediate echo time, CBV for grading and Tmax for typing. Multiparametric MR imaging can be accurate in determining tumor grades (primarily grades I and IV) and types (mainly pilocytic astrocytomas and embryonal tumors) in children. PMID- 26732083 TI - Impairment of stress granule assembly via inhibition of the eIF2alpha phosphorylation sensitizes glioma cells to chemotherapeutic agents. AB - Malignant gliomas are a lethal type of brain tumors that poorly respond to chemotherapeutic drugs. Several therapy resistance mechanisms have been characterized. However, the response to stress through mRNA translational control has not been evaluated for this type of tumor. A potential target would involve the alpha subunit of eukaryotic translation initiation factor (eIF2alpha) that leads to assembly of stress granules (SG) which are cytoplasmic granules mainly composed by RNA binding proteins and untranslated mRNAs. We assessed whether glioma cells are capable of assembling SG after exposure to different classes of chemotherapeutic agents through evaluation of the effects of interfering in this process by impairing the eIF2alpha signaling. C6 and U87MG cells were exposed to bortezomib, cisplatin, or etoposide. Forced expression of a dominant negative mutant of eIF2alpha (eIF2alpha(DN)) was employed to block this pathway. We observed that exposure to drugs stimulated SG assembly. This was reduced in eIF2alpha(DN)-transfected cells and this strategy enhanced chemotherapeutically induced cell death for all drugs. Our data suggest that SG assembly occurs in glioma cells in response to chemotherapeutic drugs in an eIF2alpha-dependent manner and this response is relevant for drug resistance. Interfering with eIF2alpha signaling pathway may be a potential strategy for new co-adjuvant therapies to treat gliomas. PMID- 26732084 TI - Bond strength evaluation of cyanoacrylate-based adhesives and screws for bone fixation. AB - INTRODUCTION: Bone graft is a very common procedure that is performed when bone volume needs to be increased before a dental implant. Screws and miniplates are the clinical standards for osteosynthesis. However, some disadvantages for this method have been reported, including artifacts on radiological images, infection, screw loosening, and the need to remove screws that interfere with the dental implants. Bone adhesives are a promising alternative for bone graft surgery. PURPOSE: The aim of this study was to compare the shear bond strength of two cyanoacrylate-based adhesives and titanium screws for bone graft fixation. METHODS: Pig jaw samples were cut into rectangular bars (2 * 6 * 20 mm) and bonded with a 5-mm overlap of N-butyl cyanoacrylate and ethyl cyanoacrylate, and 1.5-mm titanium screws were inserted into the center of the contact area. The blocks were fixed on a shear bond strength device that was coupled to a universal testing machine. The maximum force (N) was recorded on a computer and divided by the bonded area (in mm(2)) in order to calculate the bond strength (MPa). The data were statistically analyzed with ANOVA and Tukey's test (alpha = 0.05). RESULTS: The shear bond strengths of the screws were significantly higher than both cyanoacrylate adhesives, which presented statistically similar bond strength means, and have the biomechanical potential to be used for bone fixation. CONCLUSIONS: Ethyl cyanoacrylate is an inexpensive adhesive that has multiple purposes and can be considered as an alternative for bone fixation. PMID- 26732085 TI - Confusion: delirium and dementia - a smartphone app to improve cognitive assessment. AB - Older patients with dementia and delirium are more prone to adverse events in hospital, but formal cognitive assessment to identify these vulnerable patients on admission is often not carried out by junior doctors. A smartphone app was created and provided on hospital wards to facilitate the use of standard cognitive assessments for delirium and dementia. Before the introduction of the app, 36% of patients over 75 years old were assessed cognitively. After the app, the percentage of cognitive assessments improved to 63%. Improvements in cognitive assessments were most marked after individual teaching of the doctors on the wards in the use of the app and on making the app available on the ward tablets. The results of the study suggest that the introduction of a smartphone app for junior doctors can improve performance in cognitive assessment of older people. PMID- 26732086 TI - Early diagnosis of gestational trophoblastic neoplasia based on trajectory classification with compartment modeling. AB - BACKGROUND: In randomized clinical trials or observational studies, it is common to collect biomarker values longitudinally on a cohort of individuals. The investigators may be interested in grouping individuals that share similar changes of biomarker values and use these groups for diagnosis or therapeutic purposes. However, most classical model-based classification methods rely mainly on empirical models such as splines or polynomials and do not reflect the physiological processes. METHODS: A model-based classification method was developed for longitudinal biomarker measurements through a pharmacokinetic model that describes biomarker changes over time. The method is illustrated using data on human Chorionic Gonadotrophic Hormone measurements after curettage of hydatidiform moles. RESULTS: The resulting classification was linked to the evolution toward gestational trophoblastic neoplasia and may be used as a tool for early diagnosis. The diagnostic accuracy of the pharmacokinetic model was more reproducible than the one of a purely mathematical model that did not take into account the biological processes. CONCLUSION: The use of pharmacokinetic models in model-based classification approaches can lead to clinically useful classifications. PMID- 26732088 TI - Self-management abilities and quality of life among frail community-dwelling individuals: the role of community nurses in the Netherlands. AB - The objective of the study was to determine whether community nurses in the Netherlands improve self-management abilities and quality of life of frail community-dwelling people. This longitudinal study was performed in the context of a larger evaluation study of the 'Zichtbare Schakels'(Visible Link) programme, conducted to determine the quality of care provided by community nurses to community-dwelling frail people in Rotterdam, the Netherlands. For the current study, clients seen by community workers in Rotterdam between July 2013 and November 2014 participated. Data were gathered via personal interviews by the community nurses as part of care delivery at the start (T0; n = 220) and end of care delivery (T1; n = 111 - the remaining 109 clients were still receiving care) to evaluate and improve quality of care. We measured client's quality of life (using the EQ5D), self-management abilities (using the Self-Management Ability Scale) and background characteristics. Results showed that clients seen by the community nurses especially experience problems when it comes to usual activities and pain/discomfort. Furthermore, quality of life was much worse among clients of the community nurses (0.51) than among frail older (aged >=70 years) people in Rotterdam (0.61), Dutch patients with chronic illnesses [CVD (0.83), COPD (0.79) or diabetes (0.83)] and older (aged >=65 years) people who had recently been hospitalised (0.80). Significant improvements were seen in client's self management and quality of life over time. Self-management abilities at T0 and changes in self-management abilities (T1 - T0) clearly predicted quality of life at T1. Investing in community health nurses may be beneficial for the improvement of self-management abilities and quality of life among very frail people in the community. PMID- 26732089 TI - Response to Karabulut. PMID- 26732090 TI - How to Conduct Multimethod Field Studies in the Operating Room: The iPad Combined With a Survey App as a Valid and Reliable Data Collection Tool. AB - BACKGROUND: Tablet computers such as the Apple iPad are progressively replacing traditional paper-and-pencil-based data collection. We combined the iPad with the ready-to-use survey software, iSurvey (from Harvestyourdata), to create a straightforward tool for data collection during the Anesthesia Pre-Induction Checklist (APIC) study, a hospital-wide multimethod intervention study involving observation of team performance and team member surveys in the operating room (OR). OBJECTIVE: We aimed to provide an analysis of the factors that led to the use of the iPad- and iSurvey-based tool for data collection, illustrate our experiences with the use of this data collection tool, and report the results of an expert survey about user experience with this tool. METHODS: We used an iPad- and iSurvey-based tool to observe anesthesia inductions conducted by 205 teams (N=557 team members) in the OR. In Phase 1, expert raters used the iPad- and iSurvey-based tool to rate team performance during anesthesia inductions, and anesthesia team members were asked to indicate their perceptions after the inductions. In Phase 2, we surveyed the expert raters about their perceptions regarding the use of the iPad- and iSurvey-based tool to observe, rate, and survey teams in the ORs. RESULTS: The results of Phase 1 showed that training data collectors on the iPad- and iSurvey-based data collection tool was effortless and there were no serious problems during data collection, upload, download, and export. Interrater agreement of the combined data collection tool was found to be very high for the team observations (median Fleiss' kappa=0.88, 95% CI 0.78-1.00). The results of the follow-up expert rater survey (Phase 2) showed that the raters did not prefer a paper-and-pencil-based data collection method they had used during other earlier studies over the iPad- and iSurvey based tool (median response 1, IQR 1-1; 1=do not agree, 2=somewhat disagree, 3=neutral, 4=somewhat agree, 5=fully agree). They found the iPad (median 5, IQR 4.5-5) and iSurvey (median 4, IQR 4-5) to be working flawlessly and easy to use (median 5, IQR 4-5). Expert ratings also showed that the anesthesia team members (ie, the surveyed doctors and nurses) who used the iPad- and iSurvey-based tool in the OR liked it (median 4, IQR 3-4.5). CONCLUSIONS: The combination of the iPad and iSurvey provides an efficient and unobtrusive method to observe teams in their natural environment in the OR and to survey team members immediately after completing their task (ie, anesthesia induction). The expert raters positively evaluated the use of the device and user perceptions. Considering these comprehensive results, we can recommend the use of the iPad- and iSurvey-based tool for studying team performance and team member perceptions in the OR. PMID- 26732091 TI - Vitamin D deficiency in patients admitted to the general ward with breast, lung, and colorectal cancer in Buenos Aires, Argentina. AB - A high prevalence of hypovitaminosis D has been reported in cancer patients. Low levels of 25-(OH)-vitamin D were found in 158 of 162 (97.5%) inpatients with breast, lung, and colorectal cancer under active treatment, with severe deficiency (<20 ng/ml) in 77.2% and mild deficiency (20-30 ng/ml) in 20.4%. PURPOSE: A high prevalence of vitamin D deficiency has been reported in cancer patients. Nevertheless, vitamin D serum levels have been checked in few patients. Information about the frequency of hypovitaminosis D in cancer patients in Argentina is unknown. The aim of the study was to assess the frequency of vitamin D deficiency in patients with breast, lung, and colorectal cancer. METHODS: A prospective observational study was designed for cancer patients admitted to the general ward in 2014. The patients included had breast, lung, and colorectal cancer. All of them were under active treatment. The serum level of 25-(OH) vitamin D [25-(OH)-D] was measured and categorized as sufficiency (>30 ng/ml), mild deficiency (20-30 ng/ml), and severe deficiency (<20 ng/ml). RESULTS: A total of 162 patients were included, 98.2% were in stages III-IV. Median level of 25-(OH)-D was 15.3 ng/ml (range 4.1-103.6 ng/ml). Serum levels <30 ng/ml were found in 158 (97.5%) patients, severe deficiency in 125 cases (77.2%) and mild deficiency in 33 cases (20.4%). In patients under chemo/hormone therapy, the median level was 15.3 ng/ml (range 4.1-103.6 ng/ml) and in those under concurrent therapy was 17.1 ng/ml (range 7.4-58.5 ng/ml); p = 0.1944. There were no statistical differences in severe or mild deficiency of vitamin D among breast, lung, and colorectal cancer patients. CONCLUSION: The study found a high prevalence of vitamin D deficiency in hospitalized cancer patients under active treatment. Many authors have recommended dosing vitamin D levels in this population; normalizing serum levels is difficult. PMID- 26732087 TI - NMDA Receptor Function During Senescence: Implication on Cognitive Performance. AB - N-methyl-D-aspartate (NMDA) receptors, a family of L-glutamate receptors, play an important role in learning and memory, and are critical for spatial memory. These receptors are tetrameric ion channels composed of a family of related subunits. One of the hallmarks of the aging human population is a decline in cognitive function; studies in the past couple of years have demonstrated deterioration in NMDA receptor subunit expression and function with advancing age. However, a direct relationship between impaired memory function and a decline in NMDA receptors is still ambiguous. Recent studies indicate a link between an age associated NMDA receptor hypofunction and memory impairment and provide evidence that age-associated enhanced oxidative stress might be contributing to the alterations associated with senescence. However, clear evidence is still deficient in demonstrating the underlying mechanisms and a relationship between age-associated impaired cognitive faculties and NMDA receptor hypofunction. The current review intends to present an overview of the research findings regarding changes in expression of various NMDA receptor subunits and deficits in NMDA receptor function during senescence and its implication in age-associated impaired hippocampal-dependent memory function. PMID- 26732092 TI - Association Between Parental Social Interaction and Behavior Problems in Offspring: a Population-Based Study in Japan. AB - PURPOSE: Research in parental social support has chiefly examined received social support. Studies have suggested that provided social support may also be protective for child mental health problems. We aim to investigate the association between parental social interaction (both received and provided social support) and offspring behavior problems. METHODS: We analyzed the data of 982 households, including 1538 children aged 4 to 16 years, from the Japanese Study of Stratification, Health, Income, and Neighborhood (J-SHINE) survey conducted over 2010-2011. We used a 5-point Likert scale to assess social interaction including parental emotional and instrumental support received from and provided to the spouse, other co-residing family members, non-co-residing family members or relatives, neighbors, and friends. Behavior problems in offspring were assessed using parental responses to the Strengths and Difficulties Questionnaire. Associations between parental social interaction and behavior problems were analyzed using ordered logistic regression. RESULTS: We found that higher maternal social interaction is significantly associated with lower odds of both difficult and prosocial behavior problems, while the same associations were not found for paternal social interaction. Further, maternal provided social support showed an independent negative association with prosocial behavior problems in offspring, even when adjusted for received maternal social support and paternal social interaction. CONCLUSIONS: This study showed that maternal social interaction, but not paternal social interaction, might have a protective effect on offspring behavior problems. Further study is required to investigate the effect of the intervention to increase social participation among mothers whose children have behavior problems. PMID- 26732093 TI - The Heterogeneity of Illness Behaviors in Patients with Medically Unexplained Physical Symptoms. AB - PURPOSE: To investigate the heterogeneity of illness behavior in patients with medically unexplained physical symptoms (MUPS), we clustered patients in regard to their degree of engaging in different aspects of illness behavior and identified related variables with these behaviors. METHOD: A sample of N = 224 patients attending treatment in primary care with a history of MUPS (at least two symptoms) was investigated by analyzing different aspects of illness behavior with the self-reported number of doctor visits during the last 6 months and the Scale for the Assessment of Illness Behavior (SAIB; e.g., expression of symptoms). RESULTS: Two distinct clusters were identified by cluster analysis: a low (n = 106) and a high (n = 118) illness behavior clusters. The high illness behavior cluster exhibited a significantly higher rate of health anxiety than the low illness behavior cluster. Regression analysis revealed a particular effect of sex in the high illness behavior cluster: whereas being male was associated with increased illness behavior as measured by the SAIB, being female was linked to a higher number of doctor visits. Increased health anxiety was associated with the SAIB illness behavior in both clusters. Depression and anxiety did not show incremental associations with all aspects of illness behavior. CONCLUSION: Knowledge of the pattern of illness behavior in patients with MUPS enables us to improve psychological treatments that directly address specific aspects of illness behavior or health anxiety. Differences between sexes in illness behaviors require more differentiated consideration in future research. PMID- 26732094 TI - The soluble form of BMPRIB is a novel therapeutic candidate for treating bone related disorders. AB - Bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the TGF-beta superfamily. Recently, several soluble BMP receptors, such as ActRIIA-Fc, ActRIIB-Fc, and ALK1-Fc, are undergoing clinical trials. Both BMPRIA and BMPRIB are type I BMP receptors, and while BMPRIA-Fc has been reported to have bone-increasing properties, there have been no investigations concerning the biological functions of BMPRIB-Fc. Therefore, comparing the effects of BMPRIA Fc and BMPRIB-Fc in vivo should be helpful in revealing the differences in biological function between BMPRIA and BMPRIB, and would also aid in the evaluation of BMPRIB-Fc as a therapeutic agent. Here, we produced Tg chimeras in which BMPRIA-Fc and BMPRIB-Fc proteins circulated at high concentrations (36.8 121.4 MUg/mL). Both Tg chimeras showed a significant increase of bone volume and strength. Using histological analysis, adenoma of the glandular stomach was observed only in BMPRIA-Fc chimeras suggesting the tumorigenic activity of this protein. Administration of recombinant BMPRIB-Fc protein to normal mice also increased bone volumes. Finally, treatment with BMPRIB-Fc decreased the area of osteolytic regions in a mouse model of breast cancer metastasis. In conclusion, our data suggest that BMPRIB-Fc can be used for the treatment of bone-related disorders with a lower risk than BMPRIA-Fc. PMID- 26732095 TI - Oncogenic BRAF Deletions That Function as Homodimers and Are Sensitive to Inhibition by RAF Dimer Inhibitor LY3009120. AB - We have identified previously undiscovered BRAF in-frame deletions near the alphaC-helix region of the kinase domain in pancreatic, lung, ovarian, and thyroid cancers. These deletions are mutually exclusive with KRAS mutations and occur in 4.21% of KRAS wild-type pancreatic cancer. siRNA knockdown in cells harboring BRAF deletions showed that the MAPK activity and cell growth are BRAF dependent. Structurally, the BRAF deletions are predicted to shorten the beta3/alphaC-helix loop and hinder its flexibility by locking the helix in the active alphaC-helix-in conformation that favors dimer formation. Expression of L485-P490-deleted BRAF is able to transform NIH/3T3 cells in a BRAF dimer dependent manner. BRAF homodimer is confirmed to be the dominant RAF dimer by proximity ligation assays in BRAF deletion cells, which are resistant to the BRAF inhibitor vemurafenib and sensitive to LY3009120, a RAF dimer inhibitor. In tumor models with BRAF deletions, LY3009120 has shown tumor growth regression, whereas vemurafenib is inactive. SIGNIFICANCE: This study discovered oncogenic BRAF deletions with a distinct activation mechanism dependent on the BRAF dimer formation in tumor cells. LY3009120 is active against these cells and represents a potential treatment option for patients with cancer with these BRAF deletions, or other atypical BRAF mutations where BRAF functions as a dimer. PMID- 26732097 TI - Optimising calcium monitoring post thyroid and parathyroid surgery. AB - There is a risk of hypocalcaemia following total thyroidectomy and parathyroidectomy surgery, with the nadir being two to five days post operatively.[1] This project examined and improved the post-operative monitoring of serum calcium in patients undergoing these procedures at the Royal Devon and Exeter (RD&E) Hospital over a ten month period in 2013. A retrospective audit was undertaken, identifying whether serum calcium was monitored according to guideline; ie measured within the first 24 hours of surgery and daily thereafter until the patient was normocalcaemic.[2-3] The audit showed an overall compliance in 79% (n = 34) of cases. Of the non-compliant cases (n=9), seven also suffered hypocalcaemia. The current process was mapped by a flow chart and used as a basis for discussing experiences and identifying areas for improvement. Interventions implemented included a patient leaflet, a process flow chart displayed in the team office and in the weekend handover book, standard text for use in discharge summaries describing the process to GPs, the issuing of prescriptions or actual supplements for patients felt to be at high risk of hypocalcaemia, and finally education to the wider surgical junior doctor team. Percentage compliance with guidelines was compared before and after intervention with a re-audit undertaken in April 2014. Significant improvement was shown, with 100% of re-audit cases compliant (n=41), and all seven cases of hypocalcaemia were managed in full compliance with guideline. PMID- 26732098 TI - Optimizing chronic transfusion therapy for survivors of hemoglobin Barts hydrops fetalis. PMID- 26732096 TI - Mechanical effects of left ventricular midwall fibrosis in non-ischemic cardiomyopathy. AB - BACKGROUND: Left ventricular (LV) mid-wall fibrosis (MWF), which occurs in about a quarter of patients with non-ischemic cardiomyopathy (NICM), is associated with high risk of pump failure. The mid LV wall is the site of circumferential myocardial fibers. We sought to determine the effect of MWF on LV myocardial mechanics. METHODS: Patients with NICM (n = 116; age: 62.8 +/- 13.2 years; 67% male) underwent late gadolinium enhancement cardiovascular magnetic resonance (CMR) and were categorized according to the presence (+) or absence (-) of MWF. Feature tracking (FT) CMR was used to assess myocardial deformation. RESULTS: Despite a similar LVEF (24.3 vs. 27.5%, p = 0.20), patients with MWF (32 [24%]) had lower global circumferential strain (Ecc: -6.6% vs. -9.4 %, P = 0.004), but similar longitudinal (Ell: -7.6 % vs. -9.4 %, p = 0.053) and radial (Err: 14.6% vs. 17.8% p = 0.18) strain. Compared with - MWF, + MWF was associated with reduced LV systolic, circumferential strain rate (-0.38 +/- 0.1 vs. -0.56 +/- 0.3 s(-1), p = 0.005) and peak LV twist (4.65 vs. 6.31 degrees , p = 0.004), as well as rigid LV body rotation (64 % vs. 28 %, P <0.001). In addition, +MWF was associated with reduced LV diastolic strain rates (DSRcc: 0.34 vs. 0.46 s(-1); DSRll: 0.38 vs. 0.50s(-1); DSRrr: -0.55 vs. -0.75 s(-1); all p <0.05). CONCLUSIONS: MWF is associated with reduced LV global circumferential strain, strain rate and torsion. In addition, MWF is associated with rigid LV body rotation and reduced diastolic strain rates. These systolic and diastolic disturbances may be related to the increased risk of pump failure observed in patients with NICM and MWF. PMID- 26732099 TI - Psychosocial impact of visual impairment and coping strategies in female ex Service personnel. AB - PURPOSE: To examine how vision loss affects the psychosocial well-being of female ex-Service personnel and how they cope with their visual impairment. METHOD: A cross-sectional study was conducted consisting of two study phases. During phase 1, a questionnaire was undertaken via the telephone with nine female ex-Service personnel (all under 55 years of age) using clinical screening measures to identify the probable presence of the following mental health disorders: depression (Patient Health Questionnaire-9), anxiety (Generalised Anxiety Disorder Assessment), post-traumatic stress disorder (PTSD, PTSD Checklist Civilian) and alcohol misuse (Alcohol Use Disorders Identification Test). In phase 2, eight of the participants were interviewed face to face regarding the impact being visually impaired had had on their daily lives. RESULTS: Approximately 1 in 10 women screened positive for probable depression, probable PTSD or alcohol misuse; 1 in 5 fulfilled the criteria for probable anxiety disorder. Participants struggled to adjust to the loss of vision and its impact on their lives. They reported low self-esteem, feeling down and social withdrawal. As time went by, the women were able to apply various coping strategies such as having a positive attitude, relearning skills and integrating low vision aids in their daily routine. However, some coping strategies, such as alcohol misuse and lack of help-seeking when needed, hindered participants' success in adjusting to their visual impairment. CONCLUSIONS: Sustaining a visual impairment negatively affects psychosocial well-being in female ex-Service personnel. Over time, participants learnt to cope with the challenges and limitations associated with being visually impaired. PMID- 26732100 TI - The low-temperature magnetostructure and magnetic field response of Pr0.9Ca0.1MnO3: the roles of Pr spins and magnetic phase separation. AB - With the goal of elucidating the background of photoinduced ferromagnetism phenomena observed in the perovskite structured (Pr,Ca) manganites, the low temperature magnetostructure of the material Pr0.9Ca0.1MnO3 was revised using cold neutron powder diffraction, SQUID magnetometry and ab initio calculations. Particular emphasis was placed on determining the presence of nanoscale magnetic phase separation. Previously published results of a canted A-AFM average ground state were reproduced to a good precision both experimentally and theoretically, and complemented by investigating the effects of an applied magnetic field of 2.7 T on the magnetostructure. Explicit evidence of nanoscale magnetic clusters in the material was obtained based on high-resolution neutron diffractograms. Along with several supporting arguments, we present this finding as a justification for extending the nanoscale magnetic phase separation model of manganites to the material under discussion despite its very low Ca doping level in the context of the model. In the light of the new data, we also conclude that the low temperature magnetic moment of Pr must be ca. 300% larger than previously thought in this material, close to the high spin value of 2MUB per formula unit. PMID- 26732102 TI - Controversies in varicocele repair--much ado about nothing? PMID- 26732101 TI - Plasmakinetic enucleation of prostate versus 160-W laser photoselective vaporization for the treatment of benign prostatic hyperplasia. AB - To evaluate the safety and efficacy of plasmakinetic enucleation of the prostate (PKEP) for the treatment of symptomatic benign prostatic hyperplasia (BPH) compared with 160-W lithium triboride laser photoselective vaporization of the prostate (PVP). From February 2011 to July 2012, a prospective nonrandomized study was performed. One-hundred one patients underwent PKEP, and 110 underwent PVP. No severe intraoperative complications were recorded, and none of the patients in either group required a blood transfusion. Shorter catheterization time (38.14 +/- 23.64 h vs 72.54 +/- 28.38 h, P< 0.001) and hospitalization (2.32 +/- 1.25 days vs 4.07 +/- 1.23 days, P< 0.001) were recorded in the PVP group. At 12-month postoperatively, the PKEP group had a maintained and statistically improvement in International Prostate Symptom Score (IPSS) (4.07 +/- 2.07 vs 5.00 +/- 2.10; P< 0.001), quality of life (QoL) (1.08 +/- 0.72 vs 1.35 +/- 0.72; P= 0.007), maximal urinary flow rate (Qmax) (24.75 +/- 5.87 ml s-1 vs 22.03 +/- 5.04 ml s-1 ; P< 0.001), postvoid residual urine volume (PVR) (14.29 +/- 6.97 ml vs 17.00 +/- 6.11 ml; P= 0.001), and prostate-specific antigen (PSA) value (0.78 +/- 0.57 ng ml-1 vs 1.27 +/- 1.07 ng ml-1 ; P< 0.001). Both PKEP and PVP relieve low urinary tract symptoms (LUTS) due to BPH with low complication rates. PKEP can completely remove prostatic adenoma while the total amount of tissue removed by PVP is less than that can be removed by PKEP. Based on our study of the follow up, PKEP provides better postoperative outcomes than PVP. PMID- 26732103 TI - Low serum testosterone predicts upgrading and upstaging of prostate cancer after radical prostatectomy. AB - Often, pathological Gleason Score (GS) and stage of prostate cancer (PCa) were inconsistent with biopsy GS and clinical stage. However, there were no widely accepted methods predicting upgrading and upstaging PCa. In our study, we investigated the association between serum testosterone and upgrading or upstaging of PCa after radical prostatectomy (RP). We enrolled 167 patients with PCa with biopsy GS <=6, clinical stage <=T2c, and prostate-specific antigen (PSA) <10 ng ml-1 from April 2009 to April 2015. Data including age, body mass index, preoperative PSA level, comorbidity, clinical presentation, and preoperative serum total testosterone level were collected. Upgrading occurred in 62 (37.1%) patients, and upstaging occurred in 73 (43.7%) patients. Preoperative testosterone was lower in the upgrading than nonupgrading group (3.72 vs 4.56, P< 0.01). Patients in the upstaging group had lower preoperative testosterone than those in the nonupstaging group (3.84 vs 4.57, P= 0.01). In multivariate logistic regression analysis, as both continuous and categorical variables, low serum testosterone was confirmed to be an independent predictor of pathological upgrading (P = 0.01 and P= 0.01) and upstaging (P = 0.01 and P = 0.02) after RP. We suggest that low serum testosterone (<3 ng ml-1 ) is associated with a high rate of upgrading and upstaging after RP. It is better for surgeons to ensure close monitoring of PSA levels and imaging examination when selecting non-RP treatment, to be cautious in proceeding with nerve-sparing surgery, and to be enthusiastic in performing extended lymph node dissection when selecting RP treatment for patients with low serum testosterone. PMID- 26732104 TI - Prospective randomized comparison of transumbilical two-port laparoscopic and conventional laparoscopic varicocele ligation. AB - We have established a novel method named transumbilical two-port laparoscopic varicocele ligation (TTLVL) for varicocele, which is still needed to evaluate. In this study, 90 patients with left idiopathic symptomatic varicoceles of grades II III according to the Dubin grading system were randomly assigned to TTLVL (n = 45) and conventional laparoscopic varicocele ligation (CLVL) (n = 45). The demographic, intraoperative, postoperative, and follow-up data were recorded and compared between the two groups. All the procedures in the two groups were completed successfully with no intraoperative complications and no conversions to open surgery. No significant difference was found in the operative time, resuming ambulation, bowel recovery, postoperative hospital stay, and postoperative resolution of scrotal pain between the two groups (P > 0.05). However, the postoperative mean visual analog pain scale scores for TTLVL group were all less at 24 h, 48 h, 72 h, and 7 days postoperatively compared to CLVL (P = 0.001, 0.010, 0.006, and 0.027, respectively). The mean patient scar assessment questionnaire score in postoperative month 3 was 29.7 for TTLVL group compared with 32.1 for CLVL group (P < 0.001). There was no testicular atrophy observed in both groups during the follow-up period. The study shows that TTLVL is a safe, feasible, and effective minimally invasive surgical alternative to CLVL for the treatment of varicocele. Compared with CLVL, TTLVL may decrease postoperative pain and improve the cosmetic outcomes. PMID- 26732105 TI - Novel insights into the pathophysiology of varicocele and its association with reactive oxygen species and sperm DNA fragmentation. AB - Varicocele has been associated with reduced male reproductive potential. With the advances in biomolecular techniques, it has been possible to better understand the mechanisms involved in testicular damage provoked by varicocele. Current evidence suggests the central role of reactive oxygen species (ROS) and the resultant oxidative stress (OS) in the pathogenesis of varicocele-associated male subfertility although the mechanisms have not yet been fully described and it is likely to be multifactorial. Excessive ROS is associated with sperm DNA fragmentation, which may mediate the clinical manifestation of poor sperm function and fertilization outcome related to varicocele. Testing of ROS/OS and DNA fragmentation has the potential to provide additional diagnostic and prognostic information compared to conventional semen analysis and may guide therapeutic management strategies in individual patient. PMID- 26732107 TI - Two-micrometer thulium laser resection of the prostate-tangerine technique in benign prostatic hyperplasia patients with previously negative transrectal prostate biopsy. AB - The 2-MUm thulium laser resection of the prostate-tangerine technique (TmLRP-TT) has been introduced as a minimally invasive treatment for benign prostatic hyperplasia (BPH). This study was undertaken to assess the clinical efficacy and safety of TmLRP-TT for the treatment of BPH patients with previously negative transrectal prostate biopsy. A prospective analysis of 51 patients with previously negative transrectal prostate biopsy who underwent surgical treatment using TmLRP-TT was performed from December 2011 to December 2013. Preoperative status, surgical details, and perioperative complications were recorded. The follow-up outcome was evaluated with subjective and objective tests at 1 and 6 months. TmLRP-TT was successfully completed in all patients. Mean prostate volume, operative duration, and catheterization time were 93.3 +/- 37.9 ml, 69.5 +/- 39.5 min, and 6.5 +/- 1.3 days, respectively. The mean International Prostate Symptom Score, quality of life score, maximum urinary flow rate, and post-void residual urine volume changed notably at 6-month follow-up (22.5 +/- 6.9 vs 6.1 +/- 3.2, 4.8 +/- 1.3 vs 1.1 +/- 0.9, 7.3 +/- 4.5 vs 18.9 +/- 7.1 ml s-1 , and 148.7 +/- 168.7 vs 28.4 +/- 17.9 ml). Two (3.9%) patients required blood transfusion perioperatively, while 3 (5.9%) patients experienced transient hematuria postoperatively, and 2 (3.9%) patients received 3 days recatheterization due to clot retention. TmLRP-TT is a safe and effective minimally invasive technique for patients with previously negative transrectal prostate biopsy during the 6-month follow-up. This promising technology may be a feasible surgical method for previously negative transrectal prostate biopsy in the future. PMID- 26732106 TI - Proteomic signatures of infertile men with clinical varicocele and their validation studies reveal mitochondrial dysfunction leading to infertility. AB - To study the major differences in the distribution of spermatozoa proteins in infertile men with varicocele by comparative proteomics and validation of their level of expression. The study-specific estimates for each varicocele outcome were combined to identify the proteins involved in varicocele-associated infertility in men irrespective of stage and laterality of their clinical varicocele. Expression levels of 5 key proteins (PKAR1A, AK7, CCT6B, HSPA2, and ODF2) involved in stress response and sperm function including molecular chaperones were validated by Western blotting. Ninety-nine proteins were differentially expressed in the varicocele group. Over 87% of the DEP involved in major energy metabolism and key sperm functions were underexpressed in the varicocele group. Key protein functions affected in the varicocele group were spermatogenesis, sperm motility, and mitochondrial dysfunction, which were further validated by Western blotting, corroborating the proteomics analysis. Varicocele is essentially a state of energy deprivation, hypoxia, and hyperthermia due to impaired blood supply, which is corroborated by down regulation of lipid metabolism, mitochondrial electron transport chain, and Krebs cycle enzymes. To corroborate the proteomic analysis, expression of the 5 identified proteins of interest was validated by Western blotting. This study contributes toward establishing a biomarker "fingerprint" to assess sperm quality on the basis of molecular parameters. PMID- 26732108 TI - Prognostic factors for a favorable outcome after varicocele repair in adolescents and adults. AB - The effect of varicocele repair on male fertility remains controversial. It would be helpful to determined which men would benefit most from varicocele repair, and target repair efforts at those individuals. A detailed review of the literature on prognostic factors for varicocele repair was performed using the PubMed NLM database. We found that the best predictor of postvaricocelectomy semen parameters is the preoperative semen parameters. The greatest improvements in semen parameters were found in men with larger varicoceles. While there is controversy, higher testosterone, younger age and larger testis size, in some studies predict for improvements in semen parameters postvaricocelectomy. A nomogram has been developed to predict the postvaricocelectomy semen parameters based on the preoperative semen parameters, varicocele grade and the age of the man (www.fertilitytreatmentresults.com). Limited data consistently demonstrates the greatest improvements in DNA fragmentation rates in men with higher baseline DNA fragmentation rates. With respect to reproductive outcomes, higher baseline sperm density consistently predicts for natural pregnancy or assisted reproductive technology (ART) pregnancy rates. In addition, varicocele repair does seem to reduce the need for more invasive modalities of ART. In conclusion, we can now start to use specific parameters such as baseline semen quality, varicocele grade and patient age to predict post-repair semen quality and fertility potential following varicocelectomy. PMID- 26732109 TI - Body mass index effects sperm quality: a retrospective study in Northern China. AB - Excess weight and obesity have become a serious problem in adult men of reproductive age throughout the world. The purpose of this retrospective study was to assess the relationships between body mass index and sperm quality in subfertile couples in a Chinese Han population. Sperm analyses were performed and demographic data collected from 2384 male partners in subfertile couples who visited a reproductive medical center for treatment and preconception counseling. The subjects were classified into four groups according to their body mass index: underweight, normal, overweight, and obese. Of these subjects, 918 (38.3%) had a body mass index of >25.0 kg m-0 2 . No significant differences were found between the four groups with respect to age, occupation, level of education, smoking status, alcohol use, duration of sexual abstinence, or the collection time of year for sperm. The results clearly indicated lower sperm quality (total sperm count, sperm concentration, motile sperm, relative amounts of type A motility, and progressive motility sperm [A + B]) in overweight and obese participants than in those with normal body mass index. Normal sperm morphology and sperm volume showed no clear difference between the four groups. This study indicates that body mass index has a negative effect on sperm quality in men of subfertile couples in a Northern Chinese population. Further study should be performed to investigate the relationship between body mass index and sperm quality in a larger population. PMID- 26732110 TI - The importance of laparoscopy in the surgical reconstruction of inguinal vas injury. PMID- 26732111 TI - The evolution and refinements of varicocele surgery. AB - Varicoceles had been recognized in clinical practice for over a century. Originally, these procedures were utilized for the management of pain but, since 1952, the repairs had been mostly for the treatment of male infertility. However, the diagnosis and treatment of varicoceles were controversial, because the pathophysiology was not clear, the entry criteria of the studies varied among centers, and there were few randomized clinical trials. Nevertheless, clinicians continued developing techniques for the correction of varicoceles, basic scientists continued investigations on the pathophysiology of varicoceles, and new outcome data from prospective randomized trials have appeared in the world's literature. Therefore, this special edition of the Asian Journal of Andrology was proposed to report much of the new information related to varicoceles and, as a specific part of this project, the present article was developed as a comprehensive review of the evolution and refinements of the corrective procedures. PMID- 26732112 TI - Comparison of intraperitoneal and intratesticular ozone therapy for the treatment of testicular ischemia-reperfusion injury in rats. AB - We compare the efficacy of intratesticular ozone therapy with intraperitoneal ozone therapy in an experimental rat model. For this purpose, 24 rats were divided into four groups including sham-operated, torsion/detorsion, torsion/detorsion plus intraperitoneal ozone (O-IP), and torsion/detorsion plus intratesticular ozone (O-IT). The O-IP ozone group received a 4 mg kg-1 intraperitoneal injection of ozone, and the O-IT group received the same injection epididymally. At 4 h after detorsion, the rats were sacrificed and orchiectomy materials were assessed histopathologically. Spermatogenesis in the seminiferous tubules and damage to the Sertoli cells were histopathologically evaluated in the testes using the Johnsen scoring system. i-NOS and e-NOS activities in the testis tissue were also evaluated. Torsion-detorsion caused a decreased Johnsen score and increased apoptosis of spermatogonial and Sertoli cells. Ozone injection prevented increases in Johnsen score and i-NOS level. e NOS level of the O-IP group was significantly lower than that of the O-IP group, and i-NOS level of the O-IT group was significantly lower than that of the O-IP group. Local ozone therapy is more effective than systemic ozone therapy at improving IRI-related testicular torsion. Our study is the first to show that the efficacy of intratesticular implementation of ozone therapy is higher than that of intraperitoneal ozone therapy. PMID- 26732113 TI - Cost-effectiveness of varicocele surgery in the era of assisted reproductive technology. AB - The advent of innovative techniques for addressing infertility has made for exciting times in the arena of andrology. The success of microTESE for retrieving sperm has enabled azoospermic men to have the opportunity to father biological children when it was previously impossible. The ability to offer a variety of assisted reproductive techniques that includes intracytoplasmic sperm injection has opened the door for couples with male factor infertility who were otherwise untreatable. With the multitude of options available to infertile couples, however, comes an unsurprising degree of controversy regarding what treatments should be offered and when. Complicating the picture is the question of if and when varicocele repair should be undertaken, and the financial implications of the treatment decisions that are made. The infertile couple with varicocele warrants careful consideration. The overall efficacy of varicocele repair as well as cost-effectiveness of repair compared to immediate microTESE in azoospermic men and assisted reproductive technology in men with suboptimal semen parameters will be reviewed. PMID- 26732114 TI - The Current Use of Mass Spectrometry in Combination with Oth er Separation Techniques in Drug Discovery Arena. AB - Mass spectrometry (LC-MS or LC-MS/MS) appears in all phases of drug discovery and drug development areas. Starting with the screening and identification of a therapeutic agent and further measuring its in vivo and in vitro properties include: absorption, distribution, metabolism, excretion and toxicity (ADMET) and also pharmacokinetic (PK) and pharmacodynamic (PD) quantitative parameters of drug candidate. Mass spectrometry also serves as a necessary tool also to confirm purity and stability of analyzed new chemical entities (NCEs)/new molecular entities (NMEs) as well as for the analysis of degradation products from the synthesis and following on every stages of drug discovery. PMID- 26732115 TI - Molecular Modeling, de novo Design and Synthesis of a Novel, Extracellular Binding Fibroblast Growth Factor Receptor 2 Inhibitor Alofanib (RPT835). AB - BACKGROUND: Fibroblast growth factor (FGF) receptors (FGFRs) play a key role in tumor growth and angiogenesis. The present report describes our search for an extracellularly binding FGFR inhibitor using a combined molecular modeling and de novo design strategy. METHODS: Based upon crystal structures of the receptor with its native ligand and knowledge of inhibiting peptides, we have developed a computational protocol that predicts the putative binding of a molecule to the extracellular domains of the receptor. This protocol, or scoring function, was used in combination with the de novo synthesis program 'SYNOPSIS' to generate high scoring and synthetically accessible compounds. RESULTS: Eight compounds belonging to 3 separate chemical classes were synthesized. One of these compounds, alofanib (RPT835), was found to be an effective inhibitor of the FGF/FGFR2 pathway. The preclinical in vitro data support an allosteric inhibition mechanism of RPT835. RPT835 potently inhibited growth of KATO III gastric cancer cells expressing FGFR2, with GI50 value of 10 nmol/L. CONCLUSION: These results provide strong rationale for the evaluation of compound in advanced cancers. PMID- 26732116 TI - Design, Synthesis, and Cytotoxicity of Novel 2,4,6-Trisubstituted 1,3,5- triazines Bearing Aryl Hydrazone Moiety as Potent Antitumor Agent. AB - A novel series of 2,4,6-trisubstituted 1,3,5-triazine derivatives bearing aryl hydrazone moiety were designed and synthesized under the guidance of scaffold hopping and bioisosterism from the autophagy inhibitor VLX600. The target compounds were evaluated for cytotoxicity against HT-29 by MTT assay with VLX600 as positive control. Then, ten potent target compounds (5c-5f, 5i-5r, 5s, 5t) were further evaluated against two cancer cell lines H460 and A549 and one normal cell line WI-38. Most of them exhibited significant cytotoxicity against one or more cell lines. Particularly, a promising compound 5f was identified, which exhibited the most potent cytotoxicity against HT-29, H460 and A549 cancer cell lines with IC50 values of 0.047 MUM, 0.071 MUM and 0.071 MUM, respectively, which was 10- to 62-folds more potent than VLX600 (IC50 = 0.47 MUM, 4.1 MUM, 4.4 MUM). The preliminary structure-activity relationships (SARs) of the compounds were also discussed. PMID- 26732117 TI - Antiplasmodial Limonoids from Trichilia rubescens (Meliaceae). AB - Two new limonoids, named rubescins D-E (1-2) along with eight known compounds, including five havanensin type limonoids, TS1 (3), TS3 (4), rubescins A-C (5-7) and three known phytosterols, beta-sitosterol, stigmasterol and its 3beta-O glucopyranoside derivative were isolated from the roots and stem bark of Trichilia rubescens, collected from Cameroon. The structures of the new compounds were determined by detailed analyses of 1D and 2D NMR spectra, in combination with high-resolution mass spectrometry data and by comparison with related data from literature. Anti-plasmodial activities of some of the isolated limonoids 1, 2, 4, 6 and 7 were evaluated against erythrocytic stages of strain 3D7 Plasmodium falciparum. Compounds 2 and 4 exhibited significant anti-plasmodial in vitro activity with IC50 values of 1.13 and 0.79 MUM, respectively. PMID- 26732118 TI - Primary prevention of CVD: modification of diet in people with hypertension. AB - INTRODUCTION: Hypertension (persistent diastolic blood pressure of 90 mmHg or greater or systolic blood pressure 140 mmHg or greater) affects 20% to 35% of the world's adult population and increases the risk of cardiovascular disease, end stage renal disease, and mortality. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of selected dietary modification for people with hypertension? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2013 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 669 studies. After deduplication and removal of conference abstracts, 464 records were screened for inclusion in this overview. Appraisal of titles and abstracts led to the exclusion of 376 studies and the further review of 88 full publications. Of the 88 full articles evaluated, three systematic reviews and three RCTs were added. We performed a GRADE evaluation for eight PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for five interventions based on information about the effectiveness and safety of calcium supplements, a low-salt diet (including the DASH diet), magnesium supplements, a Mediterranean diet, and potassium supplements. PMID- 26732119 TI - Pulsatilla Saponin D Inhibits Autophagic Flux and Synergistically Enhances the Anticancer Activity of Chemotherapeutic Agents Against HeLa Cells. AB - Pulsatilla saponin D (SB365), a saponin isolated from rhizoma of Pulsatilla chinensis (Bunge) Regel, exhibited anticancer activities in various cancer types. In the present study, we identified that SB365 was a potent inhibitor of autophagic flux in several cancer cell lines. SB365 induced a robust accumulation of autophagosomes as evidenced by monodansylaervarine (MDC) staining and increased protein levels of LC3-II. However, SB365 caused the accumulation of p62, a substrate that should be degraded through the autophagy-lysosomal pathway. These results indicated that SB365 was an inducer of autophagosome formation, but an inhibitor of autophagic flux. Interestingly, we found that SB365 synergistically enhanced the anticancer activity of chemotherapeutic agents against cervical cancer HeLa cells. Furthermore, our study demonstrated that SB365 increased the phosphorylation of ERK and inhibited the phosphorylation of mTOR and p70S6K, suggesting that their roles in the effects of SB365 on autophagy. These results suggest that SB365 could be a promising adjuvant anticancer agent. PMID- 26732120 TI - Effectiveness of an individualized program of muscular strength and endurance with aerobic training for improving germ cell cancer-related fatigue in men undergoing chemotherapy: EFICATEST study protocol for a randomized controlled trial. AB - BACKGROUND: Patients with testicular germ cell cancer (GCC) have a high cure rate; however, cancer-related fatigue is the most common complication among patients with GCC undergoing treatment with chemotherapy. Although exercise is widely recommended, information about the physio-pathological effects of cancer therapy on skeletal muscle is very limited. Our aim is to evaluate the effects of an individualized program of muscular strength and endurance with aerobic training on cancer-related fatigue. METHODS/DESIGN: The present study is a randomized controlled trial comparing an individualized program of muscular strength and endurance with aerobic training compared to a control group. We will conduct this trial in patients undergoing chemotherapy, recruited by the Department of Oncology of Virgen de la Victoria Hospital (Malaga). Patients will be included and evaluated before the first cycle of chemotherapy and assigned randomly to the experimental or control group. Cancer-related fatigue, physical condition and biological samples will be measured at the beginning and at the end of an 8-week intervention by the same evaluator, who will be unaware of the allocation of participants to each group. Furthermore, there will be monitoring for 6 months (24 weeks) after training for all outcome variables. DISCUSSION: This study hopes to offer patients with GCC an individualized exercise program with aerobic training for cancer-related fatigue. Such a scheme, if beneficial, could be implemented successfully within public health. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02433197 . Date of registration: 13 April 2015. PMID- 26732122 TI - Self-assemblies of gamma-CDs with pentablock copolymers PMA-PPO-PEO-PPO-PMA and endcapping via atom transfer radical polymerization of 2-methacryloyloxyethyl phosphorylcholine. AB - Pentablock copolymers PMA-PPO-PEO-PPO-PMA synthesized via atom transfer radical polymerization (ATRP) were self-assembled with varying amounts of gamma-CDs to prepare poly(pseudorotaxanes) (PPRs). When the concentration of gamma-CDs was lower, the central PEO segment served as a shell of the micelles and was preferentially bent to pass through the gamma-CD cavity to construct double-chain stranded tight-fit PPRs characterized by a channel-like crystal structure. With an increase in the amount of gamma-CDs added, they began to accommodate the poly(methyl acrylate) (PMA) segments dissociated from the core of the micelles. When more gamma-CDs were threaded and slipped over the segments, the gamma-CDs were randomly distributed along the pentablock copolymer chain to generate single chain-stranded loose-fit PPRs and showed no characteristic channel-like crystal structure. All the self-assembly processes of the pentablock copolymers resulted in the formation of hydrogels. After endcapping via in situ ATRP of 2 methacryloyloxyethyl phosphorylcholine (MPC), these single-chain-stranded loose fit PPRs were transformed into conformational identical polyrotaxanes (PRs). The structures of the PPRs and PRs were characterized by means of (1)H NMR, GPC, (13)C CP/MAS NMR, 2D (1)H NOESY NMR, FTIR, WXRD, TGA and DSC analyses. PMID- 26732123 TI - Changing an ingrained culture: Improving the safety of oxygen therapy at University Hospitals Bristol NHS Foundation Trust. AB - Oxygen is one of the most commonly administered drugs in UK hospitals. Our quality improvement project aimed to increase the safety of oxygen therapy at University Hospitals Bristol NHS Foundation Trust. We aimed to increase the rate of oxygen prescribing and increase the percentage of nurses signing appropriately for oxygen titration and administration. We hypothesised this would result in a higher percentage of patients achieving their appropriate oxygen saturations. Our project ran on several acute medical and surgical wards. We tested several interventions with a plan, do, study, act method of continuous data collection. We firstly focussed on the education of junior doctors and then the wider multi disciplinary team with a trust-wide "safety focus". We utilised patient safety systems already in place in the hospital, such as the clinical risk register and incident reporting system. We also trialled an intervention that was successfully implemented by another group in a different trust in the UK. Oxygen prescription increased from 44.4% to 76.9% over the duration of the project. Appropriate nursing signatures increased from 26.6% to 60%. The number of patients achieving appropriate target saturations rose from 61.8% to 76.7%. The most successful interventions were the trust safety briefing and oxygen safety hangers. Our project has showed the importance of integrating new projects within safety schemes already available. Persistence and careful intervention are key to changing strongly engrained cultures in large organisations. Interventions that have proved to be successful in other trusts can be implemented to enact change. PMID- 26732121 TI - Factors involved in the etiology of temporomandibular disorders - a literature review. AB - BACKGROUND AND AIM: This review aims at presenting a current view on the most frequent factors involved in the mechanisms causing temporomandibular disorders (TMD). METHOD: We conducted a critical review of the literature for the period January 2000 to December 2014 to identify factors related to TMD development and persistence. RESULTS: The etiology of TMD is multidimensional: biomechanical, neuromuscular, bio-psychosocial and biological factors may contribute to the disorder. Occlusal overloading and parafunctions (bruxism) are frequently involved as biomechanical factors; increased levels of estrogen hormones are considered biological factors affecting the temporo-mandibular-joint. Among bio psychosocial factors, stress, anxiety or depression, were frequently encountered. CONCLUSIONS: The etiopathogenesis of this condition is poorly understood, therefore TMDs are difficult to diagnose and manage. Early and correct identification of the possible etiologic factors will enable the appropriate treatment scheme application in order to reduce or eliminate TMDs debilitating signs and symptoms. PMID- 26732124 TI - Alteration of Bacterial Antibiotic Sensitivity After Short-Term Exposure to Diagnostic Ultrasound. AB - BACKGROUND: Many pathogenic bacteria show different levels of antibiotic resistance. Furthermore, a lot of hospital-acquired infections are caused by highly resistant or multidrug-resistant Gram-negative bacteria. According to WHO, patients with drug-resistant infections have higher morbidity and mortality. Moreover, patients infected with bacteria that are resistant to antibiotics considerably consume more healthcare resources. OBJECTIVES: In this study, we explored a physical method of converting drug-resistant bacteria to drug sensitive ones. MATERIALS AND METHODS: This is an in vitro case-control study, performed at the Ionizing and Non-ionizing Radiation Protection Research Center (INIRPRC), Shiraz University of Medical Sciences (SUMS), Shiraz, Iran in 2014. All experiments were carried out using Gram-negative bacteria Klebsiella pneumonia and E. coli and Gram-positive Staphylococcus aureus and Streptococcus group A, isolated from hospitalized patients. The bacterial strains were obtained from the Persian Type Culture Collection, IROST, Iran (Klebsiella pneumonia PTCC 1290) and Bacteriology Department of Shahid Faghihi Teaching Hospital, Shiraz, Iran (E. coli, Staphylococcus aureus, and Streptococcus group A). The bacteria in culture plates were exposed to diagnostic ultrasound using a MyLab70XVG sonography system for 5 minutes. Then, the bacteria were cultured on Mueller Hinton agar and incubated at 35 degrees C for 18 hours. Finally, antibiotic susceptibility test was performed and the inhibition zone in both control and exposed groups were measured. Three replicate agar plates were used for each test and the inhibition zones of the plates were recorded. RESULTS: Compared with the results obtained from unexposed bacteria, statistically significant variations of sensitivity to antibiotics were found in some strains after short-term exposure. In particular, we found major differences (making antibiotic-resistant bacteria susceptible or vice versa) in the diameters of inhibition zones in exposed and non-exposed samples of Klebsiella pneumonia and Streptococcus. CONCLUSIONS: This study clearly shows that short-term exposure of microorganisms to diagnostic ultrasonic waves can significantly alter their sensitivity to antibiotics. We believe that this physical method of making the antibiotic-resistant population susceptible can open new horizons in antibiotic therapy of a broad range of diseases, including tuberculosis. PMID- 26732125 TI - Evaluation of serum markers in the LRF CLL4 trial: beta2-microglobulin but not serum free light chains, is an independent marker of overall survival. AB - Chronic lymphocytic leukemia (CLL) is characterized by heterogeneous clinical behavior and there is a need for improved biomarkers. The current study evaluated the prognostic significance of serum free light chains (sFLC, kappa, and lambda) and other serum markers (bar, serum thymidine kinase (sTK), soluble CD23, and LDH) together with established biomarkers in 289 patients enrolled into the LRF CLL4 trial. In a multivariable analysis of serum markers alone, higher big and kappa light chains were statistically significant in predicting disease progression and higher blg, and sTK in predicting mortality. In multivariable analysis for overall survival the following were independently significant: beta2M levels, immunoglobulin gene (IGHV) mutational status (>98% homology), age, 17p13 deletions (>10%), and CD38 expression. beta2M is the only serum marker that retained clear independent value as a biomarker in the LRF CLL4 trial and remains powerfully prognostic requiring evaluation in any future method of risk stratifying patients. PMID- 26732127 TI - Natural products such as adhesives in oil paintings. AB - The study and analysis of the materials employed in artistic paintings provide deeper knowledge about the history of the work of art, including restoration efforts made in the past, and the development of painting techniques through the centuries. Gas chromatography coupled to mass spectrometry is the main analytical technique employed, as it proved to be the most suitable technique for the analysis of complex mixtures, thanks to its combination of sensitivity, wide range of applicability and versatility. Further, MUFT-IR technique has also been employed to get a preliminary screening of the samples taken from paintings. In this paper, the analytical protocol based on these two techniques has been applied for analysing natural terpenic resins; its performance has been tested on microsamples collected from paintings of valuable artistic interest. PMID- 26732126 TI - Reactive oxygen and nitrogen species disturb Ca(2+) oscillations in insulin secreting MIN6 beta-cells. AB - Disturbances in pulsatile insulin secretion and Ca(2+) oscillations in pancreatic beta-cells are early markers of diabetes, but the underlying mechanisms are still incompletely understood. Reactive oxygen/nitrogen species (ROS/RNS) are implicated in reduced beta-cell function, and ROS/RNS target several Ca(2+) pumps and channels. Thus, we hypothesized that ROS/RNS could disturb Ca(2+) oscillations and downstream insulin pulsatility. We show that ROS/RNS production by photoactivation of aluminum phthalocyanine chloride (AlClPc) abolish or accelerate Ca(2+) oscillations in the MIN6 beta-cell line, depending on the amount of ROS/RNS. Application of the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase (SERCA) inhibitor thapsigargin modifies the Ca(2+) response to high concentrations of ROS/RNS. Further, thapsigargin produces effects that resemble those elicited by moderate ROS/RNS production. These results indicate that ROS/RNS interfere with endoplasmic reticulum Ca(2+) handling. This idea is supported by theoretical studies using a mathematical model of Ca(2+) handling adapted to MIN6 cells. Our results suggest a putative link between ROS/RNS and disturbed pulsatile insulin secretion. PMID- 26732128 TI - Soil carbon sequestration and biochar as negative emission technologies. AB - Despite 20 years of effort to curb emissions, greenhouse gas (GHG) emissions grew faster during the 2000s than in the 1990s, which presents a major challenge for meeting the international goal of limiting warming to <2 degrees C relative to the preindustrial era. Most recent scenarios from integrated assessment models require large-scale deployment of negative emissions technologies (NETs) to reach the 2 degrees C target. A recent analysis of NETs, including direct air capture, enhanced weathering, bioenergy with carbon capture and storage and afforestation/deforestation, showed that all NETs have significant limits to implementation, including economic cost, energy requirements, land use, and water use. In this paper, I assess the potential for negative emissions from soil carbon sequestration and biochar addition to land, and also the potential global impacts on land use, water, nutrients, albedo, energy and cost. Results indicate that soil carbon sequestration and biochar have useful negative emission potential (each 0.7 GtCeq. yr(-1) ) and that they potentially have lower impact on land, water use, nutrients, albedo, energy requirement and cost, so have fewer disadvantages than many NETs. Limitations of soil carbon sequestration as a NET centre around issues of sink saturation and reversibility. Biochar could be implemented in combination with bioenergy with carbon capture and storage. Current integrated assessment models do not represent soil carbon sequestration or biochar. Given the negative emission potential of SCS and biochar and their potential advantages compared to other NETs, efforts should be made to include these options within IAMs, so that their potential can be explored further in comparison with other NETs for climate stabilization. PMID- 26732129 TI - Which Patients Does the SPRINT Study Not Apply To and What Are the Appropriate Blood Pressure Goals in These Populations? PMID- 26732130 TI - Tailored Synthesis of Octopus-type Janus Nanoparticles for Synergistic Actively Targeted and Chemo-Photothermal Therapy. AB - A facile, reproducible, and scalable method was explored to construct uniform Au@poly(acrylic acid) (PAA) Janus nanoparticles (JNPs). The as-prepared JNPs were used as templates to preferentially grow a mesoporous silica (mSiO2 ) shell and Au branches separately modified with methoxy-poly(ethylene glycol)-thiol (PEG) to improve their stability, and lactobionic acid (LA) for tumor-specific targeting. The obtained octopus-type PEG-Au-PAA/mSiO2 -LA Janus NPs (PEG-OJNP-LA) possess pH and NIR dual-responsive release properties. Moreover, DOX-loaded PEG-OJNP-LA, upon 808 nm NIR light irradiation, exhibit obviously higher toxicity at the cellular and animal levels compared with chemotherapy or photothermal therapy alone, indicating the PEG-OJNP-LA could be utilized as a multifunctional nanoplatform for in vitro and in vivo actively-targeted and chemo-photothermal cancer therapy. PMID- 26732131 TI - Unexpectedly prolonged washout period of exogenous testosterone after discontinuation of intramuscular testosterone undecanoate depot injection (Nebido((r)) or Reandron((r)) ) in men with congenital hypogonadotrophic hypogonadism. PMID- 26732132 TI - On the need for increased rigour and care in the conduct and interpretation of network meta-analyses in drug development. AB - The rise over recent years in the use of network meta-analyses (NMAs) in clinical research and health economic analysis is little short of meteoric driven, in part, by a desire from decision makers to extend inferences beyond direct comparisons in controlled clinical trials. But is the increased use and reliance of NMAs justified? Do such analyses provide a reliable basis for the relative effectiveness assessment of medicines and, in turn, for critical decisions relating to healthcare access and provisioning? And can such analyses also be used earlier, as part of the evidence base for licensure? Despite several important publications highlighting inherently unverifiable assumptions underpinning NMAs, these assumptions and associated potential for serious bias are often overlooked in the reporting and interpretation of NMAs. A more cautious, and better informed, approach to the use and interpretation of NMAs in clinical research is warranted given the assumptions that sit behind such analyses. PMID- 26732134 TI - Electropolymerization of Uniform Polyaniline Nanorod Arrays on Conducting Oxides as Counter Electrodes in Dye-Sensitized Solar Cells. AB - Conventional techniques for the synthesis of oriented polyaniline (PANI) nanostructures are often complex or time consuming. Through an innovative reduced graphene oxide (rGO) modified FTO and a low-potential electropolymerization strategy, the rapid and template-free growth of a highly ordered PANI nanorod array on the FTO substrate is realized. The highly ordered nanostructure of the PANI array leads to a high electrocatalytic activity and chemical stability. The importance of the polymerization potential and rGO surface modification to achieve this nanostructure is revealed. Compared to platinum, the PANI nanorod array exhibits an enhanced performance and stability as counter electrodes in dye sensitized solar cells, with a 17.6 % enhancement in power conversion efficiency. PMID- 26732136 TI - Preventing the co-prescription of tamoxifen and fluoxetine in General Practice. AB - In 2010 a population-based cohort study showed that there was decreased efficacy of the breast cancer drug tamoxifen when used in combination with fluoxetine, a commonly used SSRI antidepressant. The aim of this project was to identify patients who may be affected by this co-prescription and suggest a change in medication. The project was conducted across two GP practices in Clevedon (The Riverside Practice & The Green Practice), Bristol. The patients were all from the active patients register at each surgery. A search was conducted to find all those on tamoxifen and fluoxetine, using the EMIS computer system. These patients would then be sent a letter to attend clinic. The new data would then be discussed with them before recommending a change of antidepressant (typically to sertraline). Three patients were found to be on both medications. They were all called into clinic and changed from fluoxetine to sertraline. Furthermore a presentation was given to all GPs at the two surgeries alerting them to the new guidelines. A message was also set up to flash on the computer system whenever an attempt was made to co-prescribe the two drugs. All the patients on tamoxifen in these two practices are now receiving the optimum treatment. Furthermore interventions have been put in place to ensure that this remains the case in future. Another data collection should be conducted in one year. This project provides a good example of how this problem could be resolved at other GP surgeries. PMID- 26732135 TI - Is there association between vitamin D levels, apelin 36, and visfatin in PCOS? AB - AIM: We aimed to evaluate vitamin D, apelin-36, and visfatin levels in patients with polycystic ovary syndrome (PCOS). MATERIAL AND METHOD: The study was completed in six months, including a total of 110 patients who were admitted to the obstetrics and gynecology polyclinic. Patients with a diagnosis of PCOS were divided into two subgroups according to their vitamin D levels. Thirty-four patients had <10 ng/ml of vitamin D deficiency and 21 patients had 10-30 ng/ml of vitamin D insufficiency, with each being defined as a subgroup. RESULTS: Average apelin-36 and visfatin levels in PCOS patients were 2.52 +/- 0.68 nmol/L and 72.63 +/- 22:31 ng/ml, in the control group they were 0.92 +/- 0.33 nmol/L, 24.66 +/- 6 ng/ml, respectively. The difference found in PCOS patients was statistically significant (p = 0.0001, p = 0.0001). CONCLUSION: In conclusion, the present study shows that in PCOS patients with low levels of vitamin D, insulin resistance is greater and apelin-36 serum levels were significantly higher. Although there are different opinions in the literature on this subject, we believe that when vitamin D levels are brought to an optimal level in PCOS patient, it can prevent the negative effects of adipokines in the pathogenesis of PCOS. PMID- 26732133 TI - Annual Research Review: Discovery science strategies in studies of the pathophysiology of child and adolescent psychiatric disorders--promises and limitations. AB - BACKGROUND: Psychiatric science remains descriptive, with a categorical nosology intended to enhance interobserver reliability. Increased awareness of the mismatch between categorical classifications and the complexity of biological systems drives the search for novel frameworks including discovery science in Big Data. In this review, we provide an overview of incipient approaches, primarily focused on classically categorical diagnoses such as schizophrenia (SZ), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD), but also reference convincing, if focal, advances in cancer biology, to describe the challenges of Big Data and discovery science, and outline approaches being formulated to overcome existing obstacles. FINDINGS: A paradigm shift from categorical diagnoses to a domain/structure-based nosology and from linear causal chains to complex causal network models of brain-behavior relationship is ongoing. This (r)evolution involves appreciating the complexity, dimensionality, and heterogeneity of neuropsychiatric data collected from multiple sources ('broad' data) along with data obtained at multiple levels of analysis, ranging from genes to molecules, cells, circuits, and behaviors ('deep' data). Both of these types of Big Data landscapes require the use and development of robust and powerful informatics and statistical approaches. Thus, we describe Big Data analysis pipelines and the promise and potential limitations in using Big Data approaches to study psychiatric disorders. CONCLUSIONS: We highlight key resources available for psychopathological studies and call for the application and development of Big Data approaches to dissect the causes and mechanisms of neuropsychiatric disorders and identify corresponding biomarkers for early diagnosis. PMID- 26732137 TI - New sequestrate fungi from Guyana: Jimtrappea guyanensis gen. sp. nov., Castellanea pakaraimophila gen. sp. nov., and Costatisporus cyanescens gen. sp. nov. (Boletaceae, Boletales). AB - Jimtrappea guyanensis gen. sp. nov., Castellanea pakaraimophila gen. sp. nov., and Costatisporus cyanescens gen. sp. nov. are described as new to science. These sequestrate, hypogeous fungi were collected in Guyana under closed canopy tropical forests in association with ectomycorrhizal (ECM) host tree genera Dicymbe (Fabaceae subfam. Caesalpinioideae), Aldina (Fabaceae subfam. Papilionoideae), and Pakaraimaea (Dipterocarpaceae). Molecular data place these fungi in Boletaceae (Boletales, Agaricomycetes, Basidiomycota) and inform their relationships to other known epigeous and sequestrate taxa within that family. Macro- and micromorphological characters, habitat, and multi-locus DNA sequence data are provided for each new taxon. Unique morphological features and a molecular phylogenetic analysis of 185 taxa across the order Boletales justify the recognition of the three new genera. PMID- 26732138 TI - Melatonin relieves neuropathic allodynia through spinal MT2-enhanced PP2Ac and downstream HDAC4 shuttling-dependent epigenetic modification of hmgb1 transcription. AB - Melatonin (MLT; N-acetyl-5-methoxytryptamine) exhibits analgesic properties in chronic pain conditions. While researches linking MLT to epigenetic mechanisms have grown exponentially over recent years, very few studies have investigated the contribution of MLT-associated epigenetic modification to pain states. Here, we report that together with behavioral allodynia, spinal nerve ligation (SNL) induced a decrease in the expression of catalytic subunit of phosphatase 2A (PP2Ac) and enhanced histone deacetylase 4 (HDAC4) phosphorylation and cytoplasmic accumulation, which epigenetically alleviated HDAC4-suppressed hmgb1 gene transcription, resulting in increased high-mobility group protein B1 (HMGB1) expression selectively in the ipsilateral dorsal horn of rats. Focal knock-down of spinal PP2Ac expression also resulted in behavioral allodynia in association with similar protein expression as observed with SNL. Notably, intrathecal administration with MLT increased PP2Ac expression, HDAC4 dephosphorylation and nuclear accumulation, restored HDAC4-mediated hmgb1 suppression and relieved SNL sensitized behavioral pain; these effects were all inhibited by spinal injection of 4P-PDOT (a MT2 receptor antagonist, 30 minutes before MLT) and okadaic acid (OA, a PP2A inhibitor, 3 hr after MLT). Our findings demonstrate a novel mechanism by which MLT ameliorates neuropathic allodynia via epigenetic modification. This MLT-exhibited anti-allodynia is mediated by MT2-enhanced PP2Ac expression that couples PP2Ac with HDAC4 to induce HDAC4 dephosphorylation and nuclear import, herein increases HDAC4 binding to the promoter of hmgb1 gene and upregulates HMGB1 expression in dorsal horn neurons. PMID- 26732140 TI - Social capital, collective efficacy and the provision of social support services and amenities by municipalities in the Netherlands. AB - Differential provision of local services and amenities has been proposed as a mechanism behind the relationship between social capital and health. The aim of this study was to investigate whether social capital and collective efficacy are related to the provision of social support services and amenities in Dutch municipalities, against a background of decentralisation of long-term care to municipalities. We used data on neighbourhood social capital, collective efficacy (the extent to which people are willing to work for the common good), and the provision of services and amenities in 2012. We included the services municipalities provide to support informal caregivers (e.g. respite care), individual services and support (e.g. domiciliary help), and general and collective services and amenities (e.g. lending point for wheelchairs). Data for social capital were collected between May 2011 and September 2012. Social capital was measured by focusing on contacts between neighbours. A social capital measure was estimated for 414 municipalities with ecometric measurements. A measure of collective efficacy was constructed based on information about the experienced responsibility for the liveability of the neighbourhood by residents in 2012, average charity collection returns in municipalities in 2012, voter turnout at the municipal elections in 2010 and the percentage of blood donors in 2012. We conducted Poisson regression and negative binomial regression to test our hypotheses. We found no relationship between social capital and the provision of services and amenities in municipalities. We found an interaction effect (coefficient = 3.11, 95% CI = 0.72-5.51, P = 0.011) of social capital and collective efficacy on the provision of support services for informal caregivers in rural municipalities. To gain more insight in the relationship between social capital and health, it will be important to study the relationship between social capital and differential provision of services and amenities more extensively and in different contexts. PMID- 26732139 TI - Large-Scale Fusion of Gray Matter and Resting-State Functional MRI Reveals Common and Distinct Biological Markers across the Psychosis Spectrum in the B-SNIP Cohort. AB - To investigate whether aberrant interactions between brain structure and function present similarly or differently across probands with psychotic illnesses [schizophrenia (SZ), schizoaffective disorder (SAD), and bipolar I disorder with psychosis (BP)] and whether these deficits are shared with their first-degree non psychotic relatives. A total of 1199 subjects were assessed, including 220 SZ, 147 SAD, 180 psychotic BP, 150 first-degree relatives of SZ, 126 SAD relatives, 134 BP relatives, and 242 healthy controls (1). All subjects underwent structural MRI (sMRI) and resting-state functional MRI (rs-fMRI) scanning. Joint-independent component analysis (jICA) was used to fuse sMRI gray matter and rs-fMRI amplitude of low-frequency fluctuations data to identify the relationship between the two modalities. jICA revealed two significantly fused components. The association between functional brain alteration in a prefrontal-striatal-thalamic-cerebellar network and structural abnormalities in the default mode network was found to be common across psychotic diagnoses and correlated with cognitive function, social function, and schizo-bipolar scale scores. The fused alteration in the temporal lobe was unique to SZ and SAD. The above effects were not seen in any relative group (including those with cluster-A personality). Using a multivariate-fused approach involving two widely used imaging markers, we demonstrate both shared and distinct biological traits across the psychosis spectrum. Furthermore, our results suggest that the above traits are psychosis biomarkers rather than endophenotypes. PMID- 26732141 TI - Persistence of Upper-Airway Symptoms During CPAP Compromises Adherence at 1 Year. AB - BACKGROUND: The most common adverse effects of CPAP are related to the upper airways. We evaluated upper-airway symptoms before and after a CPAP trial as well as their effect on CPAP adherence. We also evaluated the effect of humidification added to CPAP therapy on upper-airway symptoms. METHODS: We followed for 1 y 536 subjects with obstructive sleep apnea scheduled consecutively for CPAP initiation. Subjects completed visual analog questionnaires on nasal stuffiness, rhinorrhea, and mouth dryness (0 = no symptoms, 100 = severe symptoms). RESULTS: Before CPAP initiation, mean nasal stuffiness score was 29.6 +/- 24.9, rhinorrhea score was 16.0 +/- 21.7, and mouth dryness score was 43.8 +/- 33.1. In subjects who quit CPAP treatment before the 1-y follow-up, the increase in rhinorrhea score during CPAP initiation was significant, 5.3 (95% CI 0.5-9.5, P = .02), and in those using CPAP at 1 y, nasal stuffiness score and mouth dryness score decreased significantly during initiation, -5.1 (95% CI -7.9 to -2.4, P < .001) and -21.2 (-25.5 to -17.4, P < .001). Mouth dryness score decreased significantly with CPAP regardless of humidification: change with humidification, -18.1 (95% CI -22.1 to -14.3), P < .001; change without, -10.5 (95% CI -16.9 to -4.1), P = .002. Humidification also prevented the aggravation of rhinorrhea (change, -0.4 [95% CI -2.6 to 1.9], P = .75) and alleviated nasal stuffiness (change -5.3 [95% CI -7.8 to -2.6], P < .001) with CPAP, whereas its absence induced a significant rise in symptom scores: change in rhinorrhea, 11.5 (95% CI 7.1-16.7), P < .001; change in nasal stuffiness, 8.5 (95% CI 3.9-13.5, P < .001). CONCLUSIONS: The severity of upper-airway symptoms before CPAP does not predict CPAP use at 1 y, whereas CPAP non-users at 1 y had smaller or no alleviation in symptom scores during initiation compared with those who continued CPAP treatment. PMID- 26732142 TI - Prophylactic Use of Nebulized Hypertonic Saline in Mechanically Ventilated Children: A Randomized Blinded Pilot Study. AB - BACKGROUND: Mucolytic agents, such as nebulized hypertonic saline, may improve airway clearance and shorten the duration of mechanical ventilation, but prospective blinded studies in children undergoing mechanical ventilation are lacking. METHODS: Children <18 y old who had been intubated for <12 h and had an expected duration of mechanical ventilation of >48 additional h were prophylactically given 3 mL of either nebulized hypertonic saline or placebo (0.9% saline) 4 times/d. The primary outcome was duration of mechanical ventilation. Ventilator parameters and the presence of wheezing were recorded before and after study drug administration. RESULTS: The duration of mechanical ventilation was significantly longer in children treated with hypertonic saline (208.1 [interquartile range 136.3-319.8] h) versus those treated with placebo (129.5 [interquartile range 74.4-146.1] h) (P = .03 by Wilcoxon rank-sum test). After adjusting for baseline levels of PEEP, the duration of mechanical ventilation did not differ between groups. Mechanical ventilation parameters, including dead space and dynamic compliance, did not differ between measurements taken before study drug administration versus measurements taken after. New onset wheezing following study drug administration was rare (1.0% with hypertonic saline vs 3.0% with placebo, P = .36 by chi-square test). CONCLUSIONS: Administering prophylactic nebulized hypertonic saline to mechanically ventilated children did not improve clinically relevant outcomes, including duration of mechanical ventilation. Wheezing after hypertonic saline treatment was rare. PMID- 26732143 TI - Three-dimensional Sponges with Super Mechanical Stability: Harnessing True Elasticity of Individual Carbon Nanotubes in Macroscopic Architectures. AB - Efficient assembly of carbon nanotube (CNT) based cellular solids with appropriate structure is the key to fully realize the potential of individual nanotubes in macroscopic architecture. In this work, the macroscopic CNT sponge consisting of randomly interconnected individual carbon nanotubes was grown by CVD, exhibiting a combination of super-elasticity, high strength to weight ratio, fatigue resistance, thermo-mechanical stability and electro-mechanical stability. To deeply understand such extraordinary mechanical performance compared to that of conventional cellular materials and other nanostructured cellular architectures, a thorough study on the response of this CNT-based spongy structure to compression is conducted based on classic elastic theory. The strong inter-tube bonding between neighboring nanotubes is examined, believed to play a critical role in the reversible deformation such as bending and buckling without structural collapse under compression. Based on in-situ scanning electron microscopy observation and nanotube deformation analysis, structural evolution (completely elastic bending-buckling transition) of the carbon nanotubes sponges to deformation is proposed to clarify their mechanical properties and nonlinear electromechanical coupling behavior. PMID- 26732144 TI - Hybridization following population collapse in a critically endangered antelope. AB - Population declines may promote interspecific hybridization due to the shortage of conspecific mates (Hubb's 'desperation' hypothesis), thus greatly increasing the risk of species extinction. Yet, confirming this process in the wild has proved elusive. Here we combine camera-trapping and molecular surveys over seven years to document demographic processes associated with introgressive hybridization between the critically endangered giant sable antelope (Hippotragus niger variani), and the naturally sympatric roan antelope (H. equinus). Hybrids with intermediate phenotypes, including backcrosses with roan, were confirmed in one of the two remnant giant sable populations. Hybridization followed population depletion of both species due to severe wartime poaching. In the absence of mature sable males, a mixed herd of sable females and hybrids formed and grew progressively over time. To prevent further hybridization and recover this small population, all sable females were confined to a large enclosure, to which sables from the other remnant population were translocated. Given the large scale declines in many animal populations, hybridization and introgression associated with the scarcity of conspecific mates may be an increasing cause of biodiversity conservation concern. In these circumstances, the early detection of hybrids should be a priority in the conservation management of small populations. PMID- 26732145 TI - CrossNorm: a novel normalization strategy for microarray data in cancers. AB - Normalization is essential to get rid of biases in microarray data for their accurate analysis. Existing normalization methods for microarray gene expression data commonly assume a similar global expression pattern among samples being studied. However, scenarios of global shifts in gene expressions are dominant in cancers, making the assumption invalid. To alleviate the problem, here we propose and develop a novel normalization strategy, Cross Normalization (CrossNorm), for microarray data with unbalanced transcript levels among samples. Conventional procedures, such as RMA and LOESS, arbitrarily flatten the difference between case and control groups leading to biased gene expression estimates. Noticeably, applying these methods under the strategy of CrossNorm, which makes use of the overall statistics of the original signals, the results showed significantly improved robustness and accuracy in estimating transcript level dynamics for a series of publicly available datasets, including titration experiment, simulated data, spike-in data and several real-life microarray datasets across various types of cancers. The results have important implications for the past and the future cancer studies based on microarray samples with non-negligible difference. Moreover, the strategy can also be applied to other sorts of high-throughput data as long as the experiments have global expression variations between conditions. PMID- 26732146 TI - A systematic review of reported reassortant viral lineages of influenza A. AB - BACKGROUND: Most previous evolutionary studies of influenza A have focussed on genetic drift, or reassortment of specific gene segments, hosts or subtypes. We conducted a systematic literature review to identify reported claimed reassortant influenza A lineages with genomic data available in GenBank, to obtain 646 unique first-report isolates out of a possible 20,781 open-access genomes. RESULTS: After adjusting for correlations, only: swine as host, China, Europe, Japan and years between 1997 and 2002; remained as significant risk factors for the reporting of reassortant viral lineages. For swine H1, more reassortants were observed in the North American H1 clade compared with the Eurasian avian-like H1N1 clade. Conversely, for avian H5 isolates, a higher number of reported reassortants were observed in the European H5N2/H3N2 clade compared with the H5N2 North American clade. CONCLUSIONS: Despite unavoidable biases (publication, database choice and upload propensity) these results synthesize a large majority of the current literature on novel reported influenza A reassortants and are a potentially useful prerequisite to inform further algorithmic studies. PMID- 26732148 TI - Impact of cancer and cancer treatment on male fertility. AB - While cancer, and especially testicular cancer and Hodgkin's disease, affects male fertility in many ways, the current increase of survival of male cancer patients of reproductive age or earlier has emerged as a new challenge to their subsequent ability to father children. Cancer treatments, including surgery, radiotherapy and chemotherapy, can have a transitory as well as a permanent detrimental impact on male fertility. Gonadotoxic effects and the length of time for sperm recovery after radiotherapy depends not only on initial semen quality, but also on gonadal dosage and the delivery method after chemotherapy, on the type of regimens and dosages and on the spermatogenesis phase that each drug impacts. Combination treatment with radiotherapy and chemotherapy will induce more gonadotoxicity than either modality alone. Although efforts to prevent gonadal toxicity in cancer treatment are routinely applied, sperm cryopreservation remains the gold standard to maintain male fertility after cancer survival. Fertility preservation for prepubertal boys presents the greatest problem due to the absence of mature sperm in their gonads. In this area, research efforts are concentrated on cryopreservation of immature gametes and, in particular, techniques for their maturation and proliferation after thawing. PMID- 26732149 TI - The impact of obesity on male fertility. AB - Obesity in men of reproductive age is globally on the increase. There is clear evidence from epidemiological studies that obesity impacts negatively on male fertility; it is associated with hypogonadism, although it is less consistently linked to impaired spermatogenesis and tests of sperm function, including DNA fragmentation. Sperm from obese men used for in vitro fertilisation/intra cytoplasmic sperm injection is associated with a greater number of pregnancy losses and is less likely to result in live births. There are also increasing data from animal studies that paternal obesity may impact negatively on the reproductive and metabolic health of offspring and grand-offspring. It has been suggested that high-fat dietary exposures could affect the epigenetic content of sperm or the endocrine content of seminal fluid and thus impact early fetal development. Experimental and epidemiological data show that male fertility, and offspring health, can be improved by weight loss in obese and overweight males. PMID- 26732147 TI - A short half-life of ULBP1 at the cell surface due to internalization and proteosomal degradation. AB - The expression of NKG2D ligands (NKG2D-L) flag stressed cells for immune recognition and destruction. A precise control of the cell surface expression of these proteins is therefore required to ensure an appropriate immune response and it is becoming clear that NKG2D ligand expression is regulated at multiple levels. We now report that the surface stability of the human glycosyl phosphatidyl-inositol (GPI)-anchored ligand ULBP1 (UL16-binding protein) at the plasma membrane is lower than other ULBP molecules. This difference in stability is due neither to shedding nor to a higher internalization rate of ULBP1 but rather occurs because of a rapid degradation of ULBP1 protein after internalization from the cell surface that is blocked by proteasome inhibition. These data indicate that, in addition to the known transcriptional and post translational mechanisms, surface expression of human NKG2D-L is also regulated by protein turnover and that the brief residence of ULBP1 could contribute to the fine tuning of immune responses. PMID- 26732150 TI - Klinefelter Syndrome and medical treatment: hypogonadism and beyond. AB - Klinefelter syndrome (KS), though described more than 70 years ago, still imposes significant diagnostic challenges. Based on data from epidemiological studies, KS is associated with increased morbidity and mortality. Although the pathophysiology and etiology behind these observations are as yet not well understood, a significant contribution of hypogonadism, central to the syndrome, is traditionally suspected. However, other unknown effects inherent to the syndrome also seem to modify the disease pattern. Herein we show that KS is under diagnosed since only roughly 25% of patients are diagnosed and the mean age of diagnosis is during adult life. KS is associated with increased morbidity resulting in loss of 2-5 years in lifespan with increased mortality from different diseases and a poor socioeconomic profile. Small testes, hypergonadothrophic hypogonadism and cognitive impairment are usually found. The accompanying hypogonadism can lead to altered body composition and a risk of developing metabolic syndrome, type 2 diabetes and cardiovascular disease. Cancer risk is generally not different from that observed in the background population, although specific cancers like breast cancer and extragonadal germ cell tumors are seen more frequently in KS. The mainstay of medical treatment is testosterone replacement therapy to both attenuate acute and long-term consequences of hypogonadism and possibly prevent the frequent comorbidity. We believe that the diagnostic challenges should be tackled more efficiently, while there is also a pressing need to generate better evidence for timing and the proper dose of testosterone replacement. We advocate for a multidisciplinary setup with the inclusion of pediatricians, speech therapists, general practitioners, psychologists, infertility specialists, urologists and endocrinologists. PMID- 26732151 TI - Male contraception: a clinically-oriented review. AB - Despite the variety of available female contraceptive methods, many pregnancies (~50%) are still undesired. Many men (>60%) want to participate equally with their partner in family planning; however, male contraceptive methods (MCMs) account for only 14% of those used worldwide and no pharmaceutical MCM is available so far. The only two MCMs currently available are condoms, which despite protecting against sexually transmitted diseases have high failure rates (~19%), and vasectomy, which though very efficient (99%) is poorly reversible (<50%). Among MCMs under investigation, male hormonal contraceptives (MHCs) are those that have come closest to commercialization. The action of MHCs relies on the disruption of spermatogenesis that exogenous androgen administration evokes by suppressing the hypophyseal-gonadal axis. Various regimens of androgens as monotherapy or in combination with progestins have been tested in clinical trials achieving a Pearl Index <1.0 (equal to that of the female oral contraceptive pill); however, concerns regarding the variable response rates observed (non-responders: 5-20%), the impracticality of parenteral administration and long-term prostate-associated or cardiovascular morbidity have deflected the interest of the pharmaceutical industry from further research. Non hormonal contraception methods may be, at least theoretically, more specific by selectively disrupting spermatogenesis and sperm transport or fertilizing ability. Nevertheless, only a few have been tested in clinical trials (Reversible Inhibition of Sperm Under Guidance, RISUG, and Intra Vas Plugs); most of them are still in pre-clinical development or have been abandoned due to toxicity (gossypol). Consequently, until a reliable, safe and practical MCM is developed, women will continue to bear most of the contraception burden. PMID- 26732152 TI - A short evolutionary history of FSH-stimulated spermatogenesis. AB - It is well established in various experimental models that luteinizing hormone (LH) stimulated testosterone (T) production of Leydig cells is the key endocrine stimulus of spermatogenesis. The role of the other gonadotrophin, follicle stimulating hormone (FSH), is as yet somewhat unclear given that several clinical conditions and experimental models, including men with inactivating FSH receptor (R) mutation and male Fshb and Fshr knockout mice, maintain fairly normal spermatogenesis and fertility. Furthermore, FSH treatment of male infertility has produced at best modest results. On the other hand, there are animal species (e.g. teleost fishes and the Djungarian hamster) where spermatogenesis is primarily FSH-dependent. The purpose of this article is to briefly review the gonadotrophin dependence of spermatogenesis in several model species and examine how it has shifted during evolution from FSH to LH dominance. The information may provide new insight into the role of FSH treatment of male infertility. PMID- 26732153 TI - The Sertoli cell as the orchestra conductor of spermatogenesis: spermatogenic cells dance to the tune of testosterone. AB - Spermatogenesis is contingent upon hormones and growth factors acting through endocrine and paracrine pathways either in vivo or in vitro. Sertoli cells (SCs) furnish essential factors for the successful advancement of spermatogenesis and spermiogenesis. Moreover, receptors for follicle stimulating hormone (FSH) and testosterone, which are the main hormonal regulators of spermatogenesis, are identified on SCs. Testosterone, FSH and luteinizing hormone are known to determine the destiny of germ cells and in their absence germ cells undergo apoptosis. Bcl-2 family proteins determine one signaling pathway which seems to be crucial for the homeostasis of male gametes. In addition to paracrine signals, germ cell development also relies on signals generated by SCs via direct membrane contact. The regulatory peptide somatostatin has an important role in the regulation of the proliferation of the male germ cells. Activin A, follistatin and FSH control germ cell development. In vitro culture systems have provided initial evidence supporting the achievement of the completion of the first and second male meiotic division in vitro. This review article provides an overview of the literature regarding the hormonal pathways governing spermatogenesis and spermiogenesis. PMID- 26732154 TI - Testicular Descent. PMID- 26732155 TI - Hypogonadism as a possible link between metabolic diseases and erectile dysfunction in aging men. AB - There is evidence demonstrating that sexual complaints represent the most specific symptoms associated with late onset hypogonadism, while central obesity is the most specific sign. In obese men, hypogonadism can further worsen the metabolic profile and increase abdominal fat. In addition, although hypogonadism can exacerbate obesity-associated erectile dysfunction (ED), recent data suggest that a direct contribution of fat-derived factors could be hypothesized. In particular, an animal model recently documented that fat accumulation induces several hepatic pro-inflammatory genes closely linked to corpora cavernosa endothelial dysfunction. Lifestyle modifications and weight loss are the first steps in the treatment of ED patients with obesity or metabolic diseases. In symptomatic hypogonadal men with metabolic impairment and obesity, combining the effect of testosterone substitution with lifestyle modifications could result in better outcomes. PMID- 26732156 TI - Neoadjuvant therapy for advanced pancreatic neuroendocrine tumors: an emerging treatment modality? AB - OBJECTIVE: Complete surgical resection is the only potentially curative treatment of localized pancreatic neuroendocrine tumors. Unfortunately, a significant proportion of these patients present with unresectable locally advanced tumors or massive metastatic disease. Recently, a new therapeutic approach for this subset of patients has emerged consisting of neoadjuvant therapy followed by surgical exploration in responders. DESIGN: We searched MEDLINE for the purpose of identifying reports regarding neoadjuvant treatment modalities for advanced pancreatic neuroendocrine tumors. RESULTS: We identified 12 studies, the vast majority of which were either case reports or small case series. Treatment options included chemotherapy, radiotherapy, peptide receptor radionuclide therapy, biological agents or various combinations of them. CONCLUSIONS: Increasing evidence supports the application of neoadjuvant protocols in advanced pancreatic neuroendocrine tumors aiming at tumor downsizing, thus rendering curative resection feasible. Given that prospective and controlled randomized clinical trials from high-volume institutions are not feasible, expert panel consensus is needed to define the optimal treatment algorithm. PMID- 26732157 TI - Ketonemia and ketonuria in gestational diabetes mellitus. AB - BACKGROUND: The use of capillary blood 3-beta-hydroxybutyrate (3HB) is a more precise method than urine ketones measurement for the diagnosis of diabetic ketoacidosis. Fasting ketonuria is common during normal pregnancy, while there is evidence that it is increased among pregnant women with Gestational Diabetes Mellitus (GDM) who are on a diet. 3HB levels have been related to impaired offspring psychomotor development. Reports with concomitant measurement of blood and urine ketones in women with GDM who followed a balanced diet are lacking. OBJECTIVE: To compare the prevalence of fasting ketonemia and ketonuria in women with GDM following the Institute of Medicine diet instructions and assess their possible relation with metabolic parameters and therapeutic interventions. RESEARCH DESIGN AND METHODS: 180 women with GDM were studied. In each patient, in successive visits, capillary blood and urine ketones were simultaneously measured. The total measurements were 378, while the average number of measurements per patient was 2.1. RESULTS: The prevalence of ketonuria was significantly higher than that of ketonemia (x(2)=21.33, p <0.001). Significantly higher mean 3HB levels were observed with respect to ketonuria severity (p=0.001). Bedtime carbohydrate intake was associated with significantly lower 3HB levels (p=0.035). Insulin treatment was associated with significant 3HB levels reduction (p=0.032). Body weight reduction per week between two serial visits was associated with increased 3HB levels (p=0.005). Multiple linear regression analysis showed that weight loss remained the only independent predictor of 3HB levels. CONCLUSIONS: The presence of ketonemia was significantly lower than the presence of ketonuria. Weight loss per week was the only independent factor found to be associated with increased levels of 3HB. The clinical significance of this small increase requires further investigation. PMID- 26732158 TI - Presence of the RET Cys634Tyr mutation and Gly691Ser functional polymorphism in Iranian families with multiple endocrine neoplasia type 2A. AB - PURPOSE: Multiple Endocrine Neoplasia type 2A (MEN2A) is a complex autosomal dominant inherited syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and primary parathyroid hyperplasia. In patients with only one or two clinical features, identification of a germ line RET (REarranged in Transfection) mutation is required to make the diagnosis and initiate genetic counseling. METHODS: We analyzed blood DNA from three Iranian families with three generations of MEN2A including 20 affected individuals with MTC and four with pheochromocytoma. RET hotspots were amplified in probands and sequenced for mutation detection. RESULT: The causative mutation in all families was found to be the Cys634Tyr missense substitution. The presence of a functional SNP resulting in Gly691Ser was also detected in exon 11 of 15 affected cases. Four patients showed both of these RET variations. CONCLUSION: Our study shows that the Cys634Tyr missense substitution and the Gly691Ser polymorphism are recurrent in Iranian patients, since our families are unrelated. All asymptomatic carriers of the Cys634Tyr high-risk activating mutation were referred for prophylactic thyroidectomy. PMID- 26732159 TI - Sheehan's syndrome in Xinjiang: Clinical characteristics and laboratory evaluation of 97 patients. AB - OBJECTIVE: To evaluate the clinical and hormonal characteristics of patients with Sheehan's syndrome in Xinjiang, China. METHODS: 97 cases diagnosed as Sheehan's syndrome in our hospital from 1999 to 2013 were retrospectively reviewed. The medical history, physical examination findings and hormonal profiles were documented and analyzed. RESULTS: The mean age at diagnosis was 43.7+/-12.4 years, with a mean diagnostic delay of 9.1+/-9.5 years (range, 1 month-35 years). 10 of our patients (10.3%) had a home birth. 96 of our patients (99.0%) had a history of obstetric hemorrhage. The most common clinical presentation included amenorrhea (80/97, 82.5%), agalactia (2/97, 74.2%) and loss of axillary or pubic hair (83/97, 85.6%). Seventy two of our patients (74.2%) failed to lactate and 80 of our patients (82.5%) failed to resume menstruation. Hypothalamic dysfunction included the hypothalamic-pituitary-gonadal axis (HPG) (LH deficiency: 77/83 patients, 92.8%; FSH deficiency: 73/83 patients, 88%; E2 deficiency: 62 of 82 patients,75.6%), the hypothalamic-pituitary-thyroid (HPT) axis (TSH deficiency: 77/93 patients, 82.8%, TT3 deficiency: 70/ 87 patients, 80.5%, TT4 deficiency: 72/87 patients, 82.8%) and the hypothalamus-pituitary-adrenal (HPA) axis (ACTH deficiency: 19/37 patients, 51.4%, cortisol deficiency: 49/64, 76.6%). CONCLUSIONS: Sheehan's syndrome is still common in Xinjiang, especially in rural areas. Long diagnosis delay in most of the patients indicates that women might be lacking correct diagnosis and treatment. Physicians need to be aware of the most important clues for diagnosis such as lack of lactation in the postpartum period and failure to resume menstruation. PMID- 26732160 TI - Progesterone pretreatment increases the stress response to social isolation in ewes. AB - OBJECTIVE: In rodents, progesterone (P4) pretreatment increases anxiety and response to stressors. Social isolation is a stressor that generates physiological and behavioural stress responses in sheep. The aim of the study was to compare the stress response of anoestrous ewes previously treated or not with P4 to the social isolation test. DESIGN: Ten ewes received P4 treatment during 13 d (group P4-W) and another 10 remained untreated as controls (group Con). The ewes were individually isolated in a novel place during 10 min, 24 h after the end of P4 pretreatment and their behaviours were recorded. Cortisol and P4 concentrations as well as body surface temperature were recorded before and after the test. RESULTS: Ewes of the P4-W group presented higher cortisol levels 0, 10, 20 and 30 min after the social isolation and had greater area under the curve of cortisol compared to Con ewes (41,785%+/-4,156% vs. 25,682%+/-4,565% during 75 min). Progesterone and body surface temperature increased after social isolation, with no differences between P4-W and Con ewes. There were no differences in behavioural responses to social isolation. CONCLUSIONS: P4 pretreatment appears to augment the stress response to social isolation in anoestrous ewes. PMID- 26732161 TI - Long-term follow-up results of growth hormone therapy for patients with adult growth hormone deficiency. AB - OBJECTIVE: We evaluated the long-term effects of growth hormone (GH) on markers of quality of life, glucose metabolism, and lipid metabolism to validate the adequacy of long-term GH replacement therapy for adult GH deficiency (AGHD). DESIGN: Eighty-three of 100 sequentially followed patients who received GH therapy were selected for this study. Forty-nine were men aged 26 to 78 years (mean, 52 years) and 34 were women aged 20 to 78 years (mean, 56 years). The GH releasing peptide-2 stimulation test and arginine stimulation test were used to diagnose AGHD. The adult hypopituitarism questionnaire (AHQ) and biochemical parameters such as cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, and gyrated hemoglobin (HbA1c) were determined before treatment, at 6 months of treatment, and at 1, 2, 3, 4, 5, 6, 7, and 8 years of treatment. Considering age and sex as factors potentially influencing the effect of GH therapy, the patients were divided into age groups of <60 and >=60 years and sex groups of men and women. Repeated measured analysis of variance (ANOVA) was employed. RESULTS: ANOVA demonstrated significant changes in mean AHQ scores during follow-up. Comparison of individual AHQ scores with baseline values revealed sequential improvements, stabilization, and decline in QOL. A significant elevation in HbA1c level was demonstrated. LDL-C and HDL-C levels changed significantly upon GH treatment regardless of sex or age. Levels of glucose, TC or TG did not change significantly. CONCLUSIO: The effect of GH therapy on QOL showed sequential improvements and stabilization until 6-year follow-up. PMID- 26732162 TI - The growth endocrine axis and inflammatory responses after laparoscopic cholecystectomy. AB - OBJECTIVE: It is well known that conventional surgery leads to detrimental immune and catabolic responses, thus there is growing interest in the effect of minimally invasive techniques on postoperative endocrine and immune function. The aim of this prospective study was to evaluate the growth hormone (GH)/insulin like growth factor-1 (IGF-1)/IGF binding protein-3 (IGFBP-3) axis and acute phase (interleukin-6, IL-6, and C-reactive protein, CRP) responses in patients who underwent laparoscopic cholecystectomy. DESIGN: Twenty-nine patients (16 women, 13 men; age: 58+8 years) with a history of uncomplicated symptomatic cholelithiasis participated in the study. Blood samples were collected prior to and at 24 hrs and 48 hrs after laparoscopic cholecystectomy. Serum concentrations of GH, IGF-1, IGFBP-3, and IL-6 were determined by standard sandwich enzyme linked immunosorbent assay (ELISA), while CRP was measured by nephelometry. ANOVA with repeated measures and Tukey's post-hoc test were used to evaluate changes in serum measurements. RESULTS: The laparoscopic cholecystectomy resulted in a significant postoperative increase in circulating levels of IL-6 (p=0.031), which is the main cytokine responsible for inducing the acute inflammatory response, and of the acute phase protein CRP (p=0.005). A significant increase in GH levels at 24 hrs (p=0.034) and decrease of IGF-1 on both postoperative days were also found (p=0.045, 0.044), while no changes were documented in IGFBP-3 levels. Significant correlations were revealed between postoperative levels of the acute phase proteins and growth axis hormones (p<0.05 - 0.001). CONCLUSIONS: Our findings suggest that laparoscopic cholecystectomy induces acute phase endocrine and immune responses. These changes may represent a state of systemic inflammation and GH resistance, compatible with possible cytokine-induced anti anabolic or catabolic effects even after this minimally invasive cholecystectomy. PMID- 26732163 TI - Multiple endocrine neoplasia type 1 associated with a new germline Men1 mutation in a family with atypical tumor phenotype. AB - BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant hereditary disorder associated with the development of endocrine tumors due to reduced expression of the tumor suppressor protein menin. Recent studies indicate a general role of menin in carcinogenesis, affecting the prevalence and clinical course of common non-endocrine tumors such as breast cancer, hepatocellular carcinoma and melanoma. Here we report a new germline missense mutation of Men1 in a German family with atypical tumor phenotype over three generations. Based on the type of mutation, we discuss possible changes in menin function leading to atypical tumorigenesis and present the clinical significance of such findings. CASE PRESENTATION: A German family with a history of primary hyperparathyroidism presented to our Hospital for further evaluation. Members of the family demonstrated many different atypical tumors, such as renal cell carcinoma, papillary thyroid cancer and prostate cancer. DNA sequencing from peripheral blood revealed a novel mutation: Ser38Cys [TCC>TGC] in exon 2, codon 38 of Men1. This novel mutation is located in a region of menin which is responsible for interactions with the transcription factor JunD. This factor has recently been associated with prostate cancer. DNA sequencing of two of the atypical tumors (prostate cancer, papillary thyroid cancer) did not reveal a loss of heterozygosity, indicating an impact on menin expression and function in the heterozygous state, in line with results in +/-Men1 mutant mice developing prostate cancer. CONCLUSION: The results and clinical course of disease in this case indicate the potential role of menin in the development of non-endocrine or atypical-endocrine tumors in MEN1 patients. Further investigations are needed to clarify both the general role of menin and the importance of specific mutations in carcinogenesis. Nevertheless, in families with uncommon manifestations of the syndrome early diagnostic adjustments should be considered. PMID- 26732164 TI - Pasireotide for malignant insulinoma. AB - Malignant insulinoma usually has a poor prognosis, as no efficient medical treatment is available. The somatostatin analogs octreotide and lanreotide have limited ability to control the hypoglycemic events. Pasireotide is a multi receptor targeted somatostatin-analog with improved affinity for SSTR5. There is to date no reported treatment experience with this drug in such tumors. CASE DESCRIPTION: A 72-year-old patient with a G2 stage IV insulinoma, who underwent excision of the primary pancreatic tumor and multiple hepatic metastases, required further treatment for recurrent hypoglycemic events. The glycemic control achieved with pasireotide LAR was better compared with lanreotide and everolimus. However, none of these treatments showed tumor anti-proliferative effects. CONCLUSIONS: Pasireotide monthly injections achieved improved glycemic control in a patient with malignant insulinoma and recurrent hypoglycemic events compared with other medical treatments. PMID- 26732165 TI - TSH-secreting pituitary adenomas treated by gamma knife radiosurgery: our case experience and a review of the literature. AB - A 43-year-old woman, previously misdiagnosed as having primary hyperthyroidism and treated with antithyroid drugs, presented to us with overt hyperthyroidism, high levels of thyroid hormones and elevated thyroid-stimulating hormone (TSH). MUagnetic resonance imaging (MRI) revealed a pituitary microadenoma extending suprasellarly. The patient responded favorably to initial treatment with somatostatin analogs for 2 years but due to the escape phenomenon, TSH levels escalated and hyperthyroidism relapsed. Transsphenoidal adenomectomy was applied but recurrence was again observed due to incomplete tumor removal. Gamma knife radiosurgery was finally employed 5.5 years ago, resulting in complete disease remission without evidence of long-term complications to date. Thyrotropin secreting adenomas (TSHomas) are rare with an estimated prevalence of about one case per million. We retrieved from the literature 14 cases of TSHomas treated by gamma knife radiosurgery and compared the outcomes. Our results demonstrate the efficacy and safety of gamma knife radiosurgery for achieving remission in most of the cases, suggesting validation of this technique as an effective treatment option for the management of recurrent TSHomas. PMID- 26732166 TI - Landmarks in the history of adrenal surgery. PMID- 26732167 TI - Does ambient light at night reduce total melatonin production? PMID- 26732168 TI - Betaones, stones and androgen deprivation therapy. PMID- 26732169 TI - Diversity in endocrinology practice: the case of Ramadan. PMID- 26732170 TI - Central precocious puberty due to hypothalamic hamartoma in neurofibromatosis type 1. PMID- 26732171 TI - Nanopore sensing at ultra-low concentrations using single-molecule dielectrophoretic trapping. AB - Single-molecule techniques are being developed with the exciting prospect of revolutionizing the healthcare industry by generating vast amounts of genetic and proteomic data. One exceptionally promising route is in the use of nanopore sensors. However, a well-known complexity is that detection and capture is predominantly diffusion limited. This problem is compounded when taking into account the capture volume of a nanopore, typically 10(8)-10(10) times smaller than the sample volume. To rectify this disproportionate ratio, we demonstrate a simple, yet powerful, method based on coupling single-molecule dielectrophoretic trapping to nanopore sensing. We show that DNA can be captured from a controllable, but typically much larger, volume and concentrated at the tip of a metallic nanopore. This enables the detection of single molecules at concentrations as low as 5 fM, which is approximately a 10(3) reduction in the limit of detection compared with existing methods, while still maintaining efficient throughput. PMID- 26732172 TI - Discovering new mTOR inhibitors for cancer treatment through virtual screening methods and in vitro assays. AB - Mammalian target of rapamycin (mTOR) is an attractive target for new anticancer drug development. We recently developed in silico models to distinguish mTOR inhibitors and non-inhibitors. In this study, we developed an integrated strategy for identifying new mTOR inhibitors using cascaded in silico screening models. With this strategy, fifteen new mTOR kinase inhibitors including four compounds with IC50 values below 10 MUM were discovered. In particular, compound 17 exhibited potent anticancer activities against four tumor cell lines, including MCF-7, HeLa, MGC-803, and C6, with IC50 values of 1.90, 2.74, 3.50 and 11.05 MUM. Furthermore, cellular studies and western blot analyses revealed that 17 induces cell death via apoptosis by targeting both mTORC1 and mTORC2 within cells and arrests the cell cycle of HeLa at the G1/G0-phase. Finally, multi-nanosecond explicit solvent simulations and MM/GBSA analyses were carried out to study the inhibitory mechanisms of 13, 17, and 40 for mTOR. The potent compounds presented here are worthy of further investigation. PMID- 26732174 TI - Corrigendum: 3D Structural Fluctuation of IgG1 Antibody Revealed by Individual Particle Electron Tomography. PMID- 26732173 TI - Osmotic stress induces the phosphorylation of WNK4 Ser575 via the p38MAPK-MK pathway. AB - The With No lysine [K] (WNK)-Ste20-related proline/alanine-rich kinase (SPAK)/oxidative stress-responsive kinase 1 (OSR1) pathway has been reported to be a crucial signaling pathway for triggering pseudohypoaldosteronism type II (PHAII), an autosomal dominant hereditary disease that is characterized by hypertension. However, the molecular mechanism(s) by which the WNK-SPAK/OSR1 pathway is regulated remain unclear. In this report, we identified WNK4 as an interacting partner of a recently identified MAP3K, apoptosis signal-regulating kinase 3 (ASK3). We found that WNK4 is phosphorylated in an ASK3 kinase activity dependent manner. By exploring the ASK3-dependent phosphorylation sites, we identified Ser575 as a novel phosphorylation site in WNK4 by LC-MS/MS analysis. ASK3-dependent WNK4 Ser575 phosphorylation was mediated by the p38MAPK-MAPK activated protein kinase (MK) pathway. Osmotic stress, as well as hypotonic low chloride stimulation, increased WNK4 Ser575 phosphorylation via the p38MAPK-MK pathway. ASK3 was required for the p38MAPK activation induced by hypotonic stimulation but was not required for that induced by hypertonic stimulation or hypotonic low-chloride stimulation. Our results suggest that the p38MAPK-MK pathway might regulate WNK4 in an osmotic stress-dependent manner but its upstream regulators might be divergent depending on the types of osmotic stimuli. PMID- 26732175 TI - The Knowledge and Skills Assessment (KASA) tool in the Australian Dementia Behaviour Management Advisory Service: development and initial testing. AB - BACKGROUND: As the global population ages, it is important that the professional care workforce is well prepared to support the needs of people with dementia. In Australia, the Dementia Behaviour Management Advisory Service (DBMAS) supports people with dementia and their carers through an interdisciplinary team approach. To provide DBMAS Behaviour Consultants with a tool to guide them in their professional development, this project aimed to develop a self-assessment tool to enable self-reflection on clinical competencies required for working in the service and identification of areas where further development would be required. METHODS: A multi-stage process was applied in the development of the tool, including review of the relevant literature and focus groups with DBMAS Behaviour Consultants and Team Leaders. The tool encompasses both skills and knowledge in working with people with dementia and caregivers. A pilot study including 14 DBMAS consultants was conducted to assess the utility of the measure and ensure variability of ratings across knowledge and skill areas relative to time working in DBMAS. RESULTS: The Knowledge and Skills Assessment (KASA) was developed and is now used in DBMAS service both with novice Behaviour Consultants and more experienced staff, and is also being used as an on-line version, accompanied with case vignettes. CONCLUSIONS: The KASA provides a valuable self-assessment tool for professional care staff working in dementia care, but would nevertheless still warrant further testing of its psychometric characteristics. PMID- 26732177 TI - The difference of disease perception by juvenile idiopathic arthritis patients and their parents: analysis of the JAMAR questionnaire. AB - BACKGROUND: The JAMAR (Juvenile Arthritis Multidimensional Assessment Report) has been developed to evaluate the perception of the patient and his parents on different items: well-being, pain, functional status, quality of life, disease activity, disease course, side effects of medication, therapeutic compliance and satisfaction with illness outcome. Our aim was to compare disease's perception by JIA patients and their parents. METHODS: We included into the study 100 consecutive patients over 7 years of age. We asked both parent and child to complete the JAMAR questionnaire. For each patient we recorded demographic and disease related data. We examined the level of disagreement between children and parents for the quantitative items of the JAMAR: VAS Pain, VAS Disease Activity, VAS Well Being, Juvenile Arthritis Functional Score, HRQoL. Then we looked for a relation between discordance-rate and demographic and clinical variables. RESULTS: Children and parents' median scores for all five items were similar. Individual dyads agreement was low, with a large amount of pairs (80) discordant for at least one item. We found higher MD VAS and JADAS in more discordant dyads, suggesting that when the disease is more active discordance between child and parent increase. CONCLUSION: The JAMAR questionnaire is an important tool that helps clinicians to detect divergent child and parent's disease perceptions. It is essential that both patients and parents fill the JAMAR questionnaire for a complete clinical and psychosocial evaluation. PMID- 26732178 TI - High value cost conscious care for diabetic patients at a community hospital. AB - At New York Methodist Hospital (Brooklyn, NY), the pattern of ordering glucose testing was studied by a multidisciplinary committee because the medicine residents were placing inpatient chemstrip orders at their own discretion. It was found that chemstrip orders were being placed at inappropriate frequencies, and occasionally on inappropriate patients. The staff and residents were educated on daily rounds in order to achieve the goal of reducing unwarranted fingersticks, consequently increasing patient satisfaction and reducing wasted time, resources, and costs. From April 2014 through March 2015 there were 274,889 fingersticks in the inpatient setting and following the intervention the number of fingersticks had decreased to 238,187, representing a significant decrease. PMID- 26732176 TI - Automatic stage identification of Drosophila egg chamber based on DAPI images. AB - The Drosophila egg chamber, whose development is divided into 14 stages, is a well-established model for developmental biology. However, visual stage determination can be a tedious, subjective and time-consuming task prone to errors. Our study presents an objective, reliable and repeatable automated method for quantifying cell features and classifying egg chamber stages based on DAPI images. The proposed approach is composed of two steps: 1) a feature extraction step and 2) a statistical modeling step. The egg chamber features used are egg chamber size, oocyte size, egg chamber ratio and distribution of follicle cells. Methods for determining the on-site of the polytene stage and centripetal migration are also discussed. The statistical model uses linear and ordinal regression to explore the stage-feature relationships and classify egg chamber stages. Combined with machine learning, our method has great potential to enable discovery of hidden developmental mechanisms. PMID- 26732179 TI - Pre-placement psychological status and staff retention in a call centre. AB - BACKGROUND: There is a general lack of studies on staff retention and mental health status at the beginning of or prior to employment in call centres. AIMS: To evaluate the relationship between psychological status at the beginning of employment and staff retention after 6 months of employment. METHODS: The psychological well-being of new starters was evaluated using a questionnaire and Beck Depression Inventory (BDI). Early leavers were identified through a second survey performed 6 months later. RESULTS: Out of a cohort of 135 new starters, all of the 100 randomly selected employees returned their questionnaires. By the second round of the survey 6 months later, 30 employees had left. There was no significant difference between the BDI scores of leavers and those who remained in the company. Binary logistic regression showed no significant associations between leaving the company and gender, previous history of mental health diagnosis and history of mental health treatment. However, there was a significant association between age (25 or over) and leaving the company within the first 6 months of employment (odds ratio [OR] = 2.5; 95% confidence interval [CI] 1.04-6.01; P < 0.05). CONCLUSIONS: Previous mental health conditions or psychological status at the beginning of employment did not appear to contribute significantly to call centre employees leaving within 6 months. Further similar studies in other occupational sectors are recommended. PMID- 26732180 TI - Location, vocation, procreation: how choice influences life expectancy in doctors. AB - BACKGROUND: Stress and mortality are negatively correlated and it is generally accepted that certain professions are more stressful than others. Medical graduates begin as a relatively homogenous population who then choose vastly different career options making doctors an ideal population in which to try to assess whether job stress is likely to be causal to increased mortality. AIMS: To establish the influence of various modifiable risk factors on the life expectancy of UK doctors. METHODS: We analysed a decade of obituaries from the British Medical Journal published between January 2003 and December 2012. Data included age at death (AAD), specialty, region (deanery), marriage status and children. RESULTS: A total of 3068 obituaries were eligible for inclusion. Mean AAD was 78.5 years. Male sex was associated with a significantly increased AAD by an additional 3.8 years (95% CI 2.4-5.2 years, P < 0.001). Public health, obstetrics and gynaecology and laboratory medicine specialties were all associated with significantly increased AAD (P < 0.05). London and Northern Ireland deaneries were both associated with significantly increased AAD (P < 0.05). Each additional child was associated with a relative increase in AAD of +1.1 years (95% CI 0.7 1.4 years, P < 0.001). CONCLUSIONS: Our results show that location and career choices may affect life expectancy. While this does not necessarily reflect quality of life, the additional years of life gained from having extra children have a positive effect on your quantity of life. PMID- 26732181 TI - Age-dependent prognostic value of exercise capacity and derivation of fitness associated biologic age. AB - OBJECTIVE: Given the aging population and prevalence of sedentary behaviour in the USA, we investigated the impact of differences in exercise capacity associated with age on long-term outcomes. We derived fitness-associated 'biologic age' as a tool to encourage positive lifestyle changes. METHODS: This retrospective cohort study included 57085 patients without established coronary artery disease or heart failure (median age 53 years, 49% women, 29% black) who underwent clinically-referred treadmill stress testing at the Henry Ford Health System from 1991 to 2009. Patients were followed for 10.4+/-5 and 5.4+/-4 years for all-cause mortality and myocardial infarction (MI), respectively. We calculated hazard ratios associated with exercise capacity by age deciles using Cox regression models, adjusting for demographic and haemodynamic data, medical history, and medication use. Fitness-associated 'biologic age' was derived as the chronologic age with equivalent mortality or MI risk. RESULTS: There were 6356 deaths and 1646 MIs during follow-up. Exercise capacity declined with increasing age. Higher exercise capacity was strongly associated with greater survival, with per-MET HR ranging from 0.82 (95% CI 0.78 to 0.86) in patients under 40 years of age, to 0.88 (95% CI 0.87 to 0.90) in those over 70 years of age. Biologic age varied markedly-up to three decades-within each age decile, and was a stronger predictor of mortality (C-statistic 0.81 vs 0.77) and MI (C-statistic 0.72 vs 0.68) than chronologic age. CONCLUSIONS: Higher exercise capacity remained a powerful predictor of survival despite lower average exercise capacity at older ages, reinforcing its importance in patients of all ages. Fitness-associated biologic age was a stronger predictor of survival than chronologic age, and may be a useful clinical tool for facilitating patient discussions regarding the impact of exercise capacity on long-term risk. PMID- 26732183 TI - Variation in primary PCI in England. PMID- 26732182 TI - Patient and hospital determinants of primary percutaneous coronary intervention in England, 2003-2013. AB - OBJECTIVE: Primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI) is insufficiently implemented in many countries. We investigated patient and hospital characteristics associated with PPCI utilisation. METHODS: Whole country registry data (MINAP, Myocardial Ischaemia National Audit Project) comprising PPCI-capable National Health Service trusts in England (84 hospital trusts; 92 350 hospitalisations; 90 489 patients), 2003 2013. Multilevel Poisson regression modelled the relationship between incidence rate ratios (IRR) of PPCI and patient and trust-level factors. RESULTS: Overall, standardised rates of PPCI increased from 0.01% to 86.3% (2003-2013). While, on average, there was a yearly increase in PPCI utilisation of 30% (adjusted IRR 1.30, 95% CI 1.23 to 1.36), it varied substantially between trusts. PPCI rates were lower for patients with previous myocardial infarction (0.95, 0.93 to 0.98), heart failure (0.86, 0.81 to 0.92), angina (0.96, 0.94 to 0.98), diabetes (0.97, 0.95 to 0.99), chronic renal failure (0.89, 0.85 to 0.90), cerebrovascular disease (0.96, 0.93 to 0.99), age >80 years (0.87, 0.85 to 0.90), and travel distances >30 km (0.95, 0.93 to 0.98). PPCI rates were higher for patients with previous percutaneous coronary intervention (1.09, 1.05 to 1.12) and among trusts with >5 interventional cardiologists (1.30, 1.25 to 1.34), more visiting interventional cardiologists (1-5: 1.31, 1.26 to 1.36; >=6: 1.42, 1.35 to 1.49), and a 24 h, 7-days-a-week PPCI service (2.69, 2.58 to 2.81). Half of the unexplained variation in PPCI rates was due to between-trust differences. CONCLUSIONS: Following an 8 year implementation phase, PPCI utilisation rates stabilised at 85%. However, older and sicker patients were less likely to receive PPCI and there remained between-trust variation in PPCI rates not attributable to differences in staffing levels. Compliance with clinical pathways for STEMI is needed to ensure more equitable quality of care. PMID- 26732184 TI - Intrinsic interface states in InAs-AlSb heterostructures. AB - We examine the formation of intrinsic interface states bound to the plane of In Sb chemical bonds at InAs-AlSb interfaces. Careful parameterization of the bulk materials in the frame of the extended-basis spds (*)tight-binding model and recent progress in predictions of band offsets severely limit the span of tight binding parameters describing this system. We find that a heavy-hole-like interface state bound to the plane of In-Sb bonds exists for a large range of values of the InSb-InAs band offset. PMID- 26732185 TI - In Situ XPS Chemical Analysis of MnSiO3 Copper Diffusion Barrier Layer Formation and Simultaneous Fabrication of Metal Oxide Semiconductor Electrical Test MOS Structures. AB - Copper/SiO2/Si metal-oxide-semiconductor (MOS) devices both with and without a MnSiO3 barrier layer at the Cu/SiO2 interface have been fabricated in an ultrahigh vacuum X-ray photoelectron spectroscopy (XPS) system, which allows interface chemical characterization of the barrier formation process to be directly correlated with electrical testing of barrier layer effectiveness. Capacitance voltage (CV) analysis, before and after tube furnace anneals of the fabricated MOS structures showed that the presence of the MnSiO3 barrier layer significantly improved electric stability of the device structures. Evidence of improved adhesion of the deposited copper layer to the MnSiO3 surface compared to the clean SiO2 surface was apparent both from tape tests and while probing the samples during electrical testing. Secondary ion mass spectroscopy (SIMS) depth profiling measurements of the MOS test structures reveal distinct differences of copper diffusion into the SiO2 dielectric layers following the thermal anneal depending on the presence of the MnSiO3 barrier layer. PMID- 26732186 TI - The role of light in Chagas disease infection risk in Colombia. AB - BACKGROUND: Chagas disease is the most important vector-borne disease in Latin America and Rhodnius prolixus is the main vector in Colombia. Control strategies in this region have shown poor outcomes due to the insect's ability to disperse between the sylvatic and the domestic habitat. Because insect migration to houses is responsible to sustain contact rates between vectors and humans, understanding the risk factors that promote migration could be important in designing control strategies. In this respect, it has been reported that adult triatomines have the ability to move over long ranges at night attracted by artificial light. Thus, light bulbs could be playing a critical role in house invasion. The main objective of this study is to understand the role of artificial light, or simply light, in house infestation by R. prolixus. METHODS: To investigate the role of light, we combined fieldwork in the village of Chavinave, Casanare, Colombia and a mathematical model of Rhodnius prolixus dynamics. The model allowed us to simulate insect mobility and distribution in the village based on field results. We created 11 scenarios representing different amounts of light in the village (from 0 to 100%, with increments of 10%) with 100 simulations each for a time of 1000 days (2.7 years) and compare the results between the scenarios. RESULTS: None of the Gomez-Nunez traps were positive at any stage of the study, suggesting that insects do not colonize houses. The model predicts that with current village connections the proportion of houses that have visiting insects should be around 98%. Additionally we showed that an increase in light allows for insect spreading and migration to previously un-infested areas. CONCLUSIONS: Increments in light could increase the contact rates between vectors and humans; a two-fold increase in human cases for a 30% increase in the use and visibility of light on this particular village was estimated with the model. PMID- 26732188 TI - Efficient strategy for the selective determination of dopamine in human urine by molecularly imprinted solid-phase extraction. AB - An efficient molecularly imprinted solid-phase extraction protocol was developed for the separation of dopamine (DA) from human urine. After successful validation of the analytical method using high-performance liquid chromatography coupled with fluorescence detection, a new strategy for the selective determination of DA in the presence of norepinephrine and epinephrine in human urine was presented. In the proposed protocol, the LODs and quantification for DA were 166 +/- 36 and 500 +/- 110 nmol/L, respectively, and the total recoveries of DA in the range of 1-15 MUmol/L varied between 98.3 and 101.1%. DA was detected in the real urine samples at the level of 47-167 MUg/L (0.250-0.895 MUmol/L). The superiority of the novel analytical strategy was shown by comparison with the results obtained for a commercially available imprinted sorbent. PMID- 26732187 TI - Effect of Intensive Salt-Restriction Education on Clinic, Home, and Ambulatory Blood Pressure Levels in Treated Hypertensive Patients During a 3-Month Education Period. AB - The authors tested the hypothesis that low-salt diet education by nutritionists would lower blood pressure (BP) levels in treated hypertensive patients. The amount of urinary salt excretion and clinic, home, and ambulatory BP values at baseline and at 3 months were measured in 95 patients with hypertension. After randomization to a nutritional education group (E group, n=51) or a control group (C group, n=44), the C group received conventional salt-restriction education and the E group received intensive nutritional education aimed at salt restriction to 6 g/d by nutritionists. From baseline to the end of the study, 24-hour urinary sodium excretion was significantly lowered in the E group compared with the C group (6.8+/-2.9 g/24 h vs 8.6+/-3.4 g/24 h, P<.01). Morning home systolic BP tended to be lowered in the E group (P=.051), and ambulatory 24-hour systolic BP was significantly lowered in the E group (-4.5+/-1.3 mm Hg) compared with the C group (2.8+/-1.3 mm Hg, P<.001). Intensive nutritional education by nutritionists was shown to be effective in lowering BP in treated hypertensive patients. PMID- 26732189 TI - Assessment of cadmium levels in human breast milk and the affecting factors: A systematic review, 1971-2014. AB - BACKGROUND: This is a first systematic review summarizing 43 years of research from 36 countries for the assessment of cadmium in breast milk, a suitable matrix in human biomonitoring. OBJECTIVES: To report from the published literature the levels of cadmium in breast milk, and the affecting factors causing increase in cadmium concentrations. In addition, to gather several quantitative data that might be useful to evaluate the international degrees of maternal and infant exposure. METHODS: We reviewed the literature published between 1971 and 2014, available on Pubmed, Science Direct, and Google Scholar, reporting quantitative data about cadmium levels in human breast milk. Information about the aim of the study, name of the country, period of collection of samples, size of samples, sampling method, time of lactation, mother's age, area of residence, cadmium concentration, and other data were extracted. RESULTS: Sixty-seven studies were selected and included in this systematic review. Some concentrations greatly exceed the limit set by the World Health Organization (WHO); however, about 50% of the studies had less than 1 ug/L cadmium concentration (recommended by the WHO); as well as many factors have shown their implication in breast milk contamination. CONCLUSIONS: Breast milk is a pathway of maternal excretion of cadmium. It is also a biological indicator of the degree of environmental pollution and cadmium exposure of the lactating woman and the nourished infant. Therefore, preventive measures and continuous monitoring are necessary. PMID- 26732190 TI - Research publications for academic career advancement: An idea whose time has come. But is this the right way? PMID- 26732191 TI - The clinical development process for a novel preventive vaccine: An overview. AB - Each novel vaccine candidate needs to be evaluated for safety, immunogenicity, and protective efficacy in humans before it is licensed for use. After initial safety evaluation in healthy adults, each vaccine candidate follows a unique development path. This article on clinical development gives an overview on the development path based on the expectations of various guidelines issued by the World Health Organization (WHO), the European Medicines Agency (EMA), and the United States Food and Drug Administration (USFDA). The manuscript describes the objectives, study populations, study designs, study site, and outcome(s) of each phase (Phase I-III) of a clinical trial. Examples from the clinical development of a malaria vaccine candidate, a rotavirus vaccine, and two vaccines approved for human papillomavirus (HPV) have also been discussed. The article also tabulates relevant guidelines, which can be referred to while drafting the development path of a novel vaccine candidate. PMID- 26732192 TI - Evaluation of factors associated with relapse in telaprevir-based triple therapy for chronic hepatitis C. AB - BACKGROUND AND RATIONALE: Most patients with chronic hepatitis C show virological response to telaprevir-based triple therapy, and achieve an end-of-treatment response (ETR). However, some patients showing ETR develop virological relapse. This study was carried out to evaluate factors associated with relapse after triple therapy. MATERIALS AND METHODS: A prospective, multicentric study was conducted in chronic hepatitis C patients who received telaprevir-based triple therapy. We evaluated independent variables such as age, with or without cirrhosis, prior treatment response to interferon (IFN) therapy, IL28B genotype, core amino acid (aa) 70 mutation, drug adherence, white blood cell counts, hemoglobin level, and serum low-density lipoprotein (LDL) cholesterol level. The characteristics of the patients who relapsed after achieving ETR were compared with those who did not. RESULTS: Among 168 patients, 157 patients achieved ETR (93.5%) and 11 discontinued. Of these 157 patients, relapse occurred in 21 patients (13.4%). Nineteen patients (90.5%) of 21 relapsed patients had the IL28B non-TT genotype (P = 1.79 * 10 -9 ). Multivariate analysis identified core amino acid 70 [P = 0.018, crude odds ratio (OR): 6.927] and the IL28B genotype (P = 3.758 * 10 -5 , crude OR: 39.311) as significantly independent factors that influenced the relapse-related variables. Among the 49 patients with the IL28B non-TT, 18 patients had core aa70 mutation and 31 patients had core aa70 wild type. In addition, 66.7% (12/18) of those with core aa70 mutation and 22.6% (7/31) of those with core aa70 wild-type developed relapse (P = 0.005). DISCUSSION: Core aa70 mutation and the IL28B non-TT genotype were identified as independent factors that influenced relapse after achievement of ETR for telaprevir-based triple therapy. PMID- 26732193 TI - Analysis of sparse data in logistic regression in medical research: A newer approach. AB - BACKGROUND AND OBJECTIVE: In the analysis of dichotomous type response variable, logistic regression is usually used. However, the performance of logistic regression in the presence of sparse data is questionable. In such a situation, a common problem is the presence of high odds ratios (ORs) with very wide 95% confidence interval (CI) (OR: >999.999, 95% CI: <0.001, >999.999). In this paper, we addressed this issue by using penalized logistic regression (PLR) method. MATERIALS AND METHODS: Data from case-control study on hyponatremia and hiccups conducted in Christian Medical College, Vellore, Tamil Nadu, India was used. The outcome variable was the presence/absence of hiccups and the main exposure variable was the status of hyponatremia. Simulation dataset was created with different sample sizes and with a different number of covariates. RESULTS: A total of 23 cases and 50 controls were used for the analysis of ordinary and PLR methods. The main exposure variable hyponatremia was present in nine (39.13%) of the cases and in four (8.0%) of the controls. Of the 23 hiccup cases, all were males and among the controls, 46 (92.0%) were males. Thus, the complete separation between gender and the disease group led into an infinite OR with 95% CI (OR: >999.999, 95% CI: <0.001, >999.999) whereas there was a finite and consistent regression coefficient for gender (OR: 5.35; 95% CI: 0.42, 816.48) using PLR. After adjusting for all the confounding variables, hyponatremia entailed 7.9 (95% CI: 2.06, 38.86) times higher risk for the development of hiccups as was found using PLR whereas there was an overestimation of risk OR: 10.76 (95% CI: 2.17, 53.41) using the conventional method. Simulation experiment shows that the estimated coverage probability of this method is near the nominal level of 95% even for small sample sizes and for a large number of covariates. CONCLUSIONS: PLR is almost equal to the ordinary logistic regression when the sample size is large and is superior in small cell values. PMID- 26732195 TI - Simplifying the upper limb peripheral motor screen: Proposing the "K" sign. AB - The well-recognized erosion of pathoanatomic correlations in basic medical training, combined with the increasing everyday pressures of time-efficacy in patient examination, continue to place strain on junior clinicians. Over the years, many refinements to tried-and-true basic physical examination techniques have been described, allowing improvement in diagnostic yield. A multitude of "screening" techniques are available for physical assessment; however, such approaches are often nonstandardized and inconsistently taught and applied in the clinical realm. Great interexaminer inconsistency in the documentation of many forms of screening techniques also substantively undermines their respective clinical value. The current work presents a novel refinement/combination of previously described examination approaches for the assessment of peripheral upper limb (UL) motor function--the "K" sign. Having been successfully applied in both the acute and ambulatory clinical settings for several years, we feel that the technique has a useful role as a rapid and specific screening technique that is easily taught, learnt, and applied. Arguably, its employment serves to improve time efficacy in the screening examination, and may even improve diagnostic yield through its reliable reproducibility and provision of direct bilateral comparison. Its inherent simplicity also lends itself well to high levels of uptake (and retention) by medical students and junior clinicians alike. On top of presenting the simple screening test itself, we offer a simple means of subsequent notation for the patient's case note record, again in the hope of standardization and endurance of clinical value beyond the time of patient examination. PMID- 26732194 TI - Impact factor of medical education journals and recently developed indices: Can any of them support academic promotion criteria? AB - Journal Impact Factor (JIF) has been used in assessing scientific journals. Other indices, h- and g-indices and Article Influence Score (AIS), have been developed to overcome some limitations of JIF. The aims of this study were, first, to critically assess the use of JIF and other parameters related to medical education research, and second, to discuss the capacity of these indices in assessing research productivity as well as their utility in academic promotion. The JIF of 16 medical education journals from 2000 to 2011 was examined together with the research evidence about JIF in assessing research outcomes of medical educators. The findings were discussed in light of the nonnumerical criteria often used in academic promotion. In conclusion, JIF was not designed for assessing individual or group research performance, and it seems unsuitable for such purposes. Although the g- and h-indices have demonstrated promising outcomes, further developments are needed for their use as academic promotion criteria. For top academic positions, additional criteria could include leadership, evidence of international impact, and contributions to the advancement of knowledge with regard to medical education. PMID- 26732196 TI - Poisoning in secondary hospital. PMID- 26732197 TI - Toxicoepidemiology of acute poisoning cases in a secondary care hospital in rural South India: A 5-year analysis. PMID- 26732198 TI - Undergraduate research in India hoping for a new dawn. PMID- 26732199 TI - Lymphocytic hypophysitis in nonpregnant middle-aged females mimicking pituitary adenoma. PMID- 26732200 TI - Calculating incidence in cross-sectional studies. PMID- 26732201 TI - Prevalence of autism spectrum disorders among children (1-10 years of age): Findings of a midterm report from Northwest India. PMID- 26732202 TI - A SERS-active sensor based on heterogeneous gold nanostar core-silver nanoparticle satellite assemblies for ultrasensitive detection of aflatoxinB1. AB - A surface-enhanced Raman scattering (SERS) sensor based on gold nanostar (Au NS) core-silver nanoparticle (Ag NP) satellites was fabricated for the first time to detect aflatoxinB1 (AFB1). We constructed the SERS sensor using AFB1 aptamer (DNA1)-modified Ag satellites and a complementary sequence (DNA2)-modified Au NS core. The Raman label (ATP) was modified on the surface of Ag satellites. The SERS signal was enhanced when the satellite NP was attached to the Au core NS. The AFB1 aptamer on the surface of Ag satellites would bind to the targets when AFB1 was present in the system, Ag satellites were then removed and the SERS signal decreased. This SERS sensor showed superior specificity for AFB1 and the linear detection range was from 1 to 1000 pg mL(-1) with the limit of detection (LOD) of 0.48 pg mL(-1). The excellent recovery experiment using peanut milk demonstrated that the sensor could be applied in food and environmental detection. PMID- 26732203 TI - Investigating the synergistic mechanism between ibrutinib and daunorubicin in acute myeloid leukemia cells. PMID- 26732204 TI - Associations among temporomandibular disorders, chronic neck pain and neck pain disability in computer office workers: a pilot study. AB - Neck pain is the most common musculoskeletal complaint among computer office workers. There are several reports about the coexistence of neck pain and temporomandibular disorders (TMD). However, there are no studies investigating this association in the context of work involving computers. The purpose of this study was to verify the association between TMD and neck pain in computer office workers. Fifty-two female computer workers who were divided into two groups: (i) those with self-reported chronic neck pain and disability (WNP) (n = 26) and (ii) those without self-reported neck pain (WONP) (n = 26), and a control group (CG) consisting of 26 women who did not work with computers participated in this study. Clinical assessments were performed to establish a diagnosis of TMD, and craniocervical mechanical pain was assessed using manual palpation and pressure pain threshold (PPT). The results of this study showed that the WNP group had a higher percentage of participants with TMD than the WONP group (42.30% vs. 23.07%, chi(2) = 5.70, P = 0.02). PPTs in all cervical sites were significantly lower in the groups WNP and WONP compared to the CG. Regression analysis revealed TMD, neck pain and work-related factors to be good predictors of disability (R(2) = 0.93, P < 0.001). These results highlighted the importance of considering the work conditions of patients with TMD, as neck disability in computer workers is explained by the association among neck pain, TMD and unfavourable workplace conditions. Consequently, this study attempted to emphasise the importance of considering work activity for minimising neck pain-related disability. PMID- 26732205 TI - The Ag shell thickness effect of Au@Ag@SiO2 core-shell nanoparticles on the optoelectronic performance of dye sensitized solar cells. AB - To tailor the Au@Ag@SiO2 LSPR effect by varying the Ag shell thickness, the Au@Ag@SiO2 core-ultra-thin shell nanoparticles are fabricated and introduced into DSSC for improving light harvesting and decreasing the recombination of photo carriers. The Au@Ag@SiO2 electrode exhibits a photo-conversion efficiency of 23.42% (486.7 nm, 10 mW cm(-2)). PMID- 26732207 TI - [A premature infant with increased bleeding tendency: what if the family history of bleeding disorders is negative?]. AB - BACKGROUND: Haemophilia A is an X-chromosome recessive hereditary disorder and occurs in 1 in 5000 boys. In 30-50% of patients with haemophilia the family history of bleeding disorders is negative. CASE DESCRIPTION: We report on a premature male infant, born at 33 weeks of gestation, who exhibited prolonged bleeding from venipuncture sites the day after birth. The family history was negative for bleeding disorders. Initially he received vitamin K supplementation but, when the bleeding persisted, more detailed diagnostics revealed a prolonged aPTT. Factor VIII activity was 1% of the reference value and the neonate appeared to have a Grade I intraventricular haemorrhage on cerebral ultrasound. He was therefore treated with factor VIII. CONCLUSION: Early recognition and diagnostics in neonates with an increased bleeding tendency is important, even when the family history of bleeding disorders is negative. PMID- 26732206 TI - Probing-directed identification of novel structured RNAs. AB - Transcripts often harbor RNA elements, which regulate cell processes co- or post transcriptionally. The functions of many regulatory RNA elements depend on their structure, thus it is important to determine the structure as well as to scan genomes for structured elements. State of the art ab initio approaches to predict structured RNAs rely on DNA sequence analysis. They use 2 major types of information inferred from a sequence: thermodynamic stability of an RNA structure and evolutionary footprints of base-pair interactions. In recent years, chemical probing of RNA has arisen as an alternative source of structural information. RNA probing experiments detect positions accessible to specific types of chemicals or enzymes indicating their propensity to be in a paired or unpaired state. There exist several strategies to integrate probing data into RNA secondary structure prediction algorithms that substantially improve the prediction quality. However, whether and how probing data could contribute to detection of structured RNAs remains an open question. We previously developed the energy-based approach RNASurface to detect locally optimal structured RNA elements. Here, we integrate probing data into the RNASurface energy model using a general framework. We show that the use of experimental data allows for better discrimination of ncRNAs from other transcripts. Application of RNASurface to genome-wide analysis of the human transcriptome with PARS data identifies previously undetectable segments, with evidence of functionality for some of them. PMID- 26732208 TI - [An 87-year-old man with a rough skin on his buttocks]. AB - An 87-year-old man consulted the general practitioner with skin lesions on his buttocks. Dermatological findings were erythema without a sharp border, vesicles or crusts. He had a habit of sprawling in his seat, which is the cause of senile gluteal dermatosis, also named sitter's sign or grandfather's disease. After having a better sit habit the skin healed within a few weeks, without application of dermal therapy. PMID- 26732209 TI - [Increase in laparoscopic hysterectomy: shift in indications and dilemmas]. AB - Hysterectomy is still one of the most frequently performed gynaecological procedures. The use of the laparoscopic approach has increased over recent years and a shift in indication has been observed. However, not every clinic or gynaecologist is able to provide laparoscopic hysterectomy for more challenging patients. Therefore, referral to an expert centre is of the highest importance in order to offer the patient the least invasive approach to hysterectomy. The advantages of the laparoscopic approach have become more evident over recent years. The widespread introduction of minimally invasive surgery means that surgeons are encountering new challenges, such as the rapid introduction of new instruments, the absolute increased incidence of rare complications and the provision of post-operative counselling on recovery. Maintaining knowledge of these matters is essential in order to secure the quality of care. PMID- 26732210 TI - [Epistaxis following skull trauma]. AB - BACKGROUND: Epistaxis is a common problem, which is usually benign in nature. In some cases, however, epistaxis is a symptom of a severe underlying condition. CASE DESCRIPTION: A 20-year-old male was treated conservatively following head injury with craniofacial and base-of-skull fractures. Recurrent episodes of epistaxis occurred some weeks after treatment. Further investigation showed an extradural dissecting aneurysm of the left internal carotid artery (ICA), projecting into the sphenoid sinus. The aneurysm was treated endovascularly by placing a coil in the aneurism and a stent in the artery. On the basis of this case study we describe the diagnostics and treatment of patients with posttraumatic posterior epistaxis. CONCLUSION: In cases if delayed epistaxis following head injury the physician should be alert for the possibility of trauma to the ICA. This is a potentially life-threatening situation that requires prompt treatment. PMID- 26732211 TI - [A man with an abnormal dimple in his upper leg]. AB - A 29 year-old man presented with muscle weakness and an abnormal dimple near his hamstrings after a complicated anterior cruciate ligament reconstruction of his right knee. MRI demonstrated atrophy of the semitendinosus muscle. He received physiotherapy after which he functionally recovered. PMID- 26732212 TI - [Brain damage caused by exposure to organic solvents; diagnostics and disease course of chronic solvent-induced encephalopathy]. AB - Since 1997 more than 3,000 patients have been referred to one of the two Dutch Solvent Teams with health problems that may have been caused by long-term occupational exposure to organic solvents. A diagnosis of 'chronic solvent induced encephalopathy' was made in approximately 500 patients. The diagnostics of this disease is based on five elements: (a) symptoms in line with the diagnosis; (b) relevant exposure to an organic solvent with neurotoxic effects; (c) a clear temporal relationship between the onset of symptoms and exposure to a solvent with neurotoxic effects; (d) exclusion of other causes for the symptoms; and (e) impairment on neuropsychological assessment. Exposure to organic solvents can cause chronic health effects, which may even persist years after exposure has ceased. In general, no more serious deterioration of health is observed after exposure has ceased. PMID- 26732213 TI - [A man with a swollen ring finger]. AB - A 30-year-old man visited the emergency department with a cut in his left forefinger. A coincidental finding during examination was a pre-existing swollen left ring finger. Radiography showed the formation of a new joint in the left ring finger after a volar dislocation of the proximal interphalangeal joint 2 years before. PMID- 26732214 TI - [Drop in suicide rate after first psychosis: a comparison with the situation two decades ago]. AB - OBJECTIVE: Over two decades ago a study reported that a percentage as high as 11% of the patients with a psychotic disorder in the northern Netherlands died by committing suicide. The primary objective of the current study was to replicate these findings in the same geographical area. A secondary objective was to investigate potential predictors of suicide. DESIGN: Retrospective cohort study. METHOD: From patient files we identified the current status of all patients who experienced their first episode of psychosis and participated in the Psychosis Recent Onset Groningen-Survey (PROGR-S) between 2000 and 2009. The PROGR-S is a diagnostic protocol for persons with suspected first psychosis. Kaplan-Meier survival analysis was used to identify the current suicide risk in this group and this was compared with the 1973-1988 patients using a log rank test. We also determined the standardized mortality rate in relation to the general population. Cox regression analysis was used to assess significant predictors of suicide. RESULTS: The suicide risk dropped drastically over the course of two decades from 11% to 2.4%. Older age was the strongest predictor of suicide. The standardized mortality rate was 41.6. CONCLUSION: Despite the significant decline in suicide after a first episode of psychosis, the risk of suicide should be given the highest priority in psychiatric psychosis care, as it is very high at 4162% compared with the suicide risk in general population. PMID- 26732215 TI - [Suicide behavior before and after the start with antidepressants: a high persistent risk in the first month of treatment among the young]. AB - OBJECTIVE: A causal relationship between antidepressants (ADs) and high risk of suicide behavior at young age has been suggested. We analyzed the rates of suicide attempts during treatment with AD in comparison with the rates before treatment initiation for different ages. DESIGN: Observational retrospective cohort study. METHOD: Claims of insurance company Achmea were used to establish the risk of a suicide attempt before and after start of treatment among patients with a first registered AD prescription in 2006-2011 (n = 66,196). RESULTS: Among those aged < 25 years, a high rate of suicide attempts during the month before the start was found (376.3/10,000 person yrs). A non-significant increase in the first month (p = 0.212) was found and a non-significant trend to lower values thereafter (p = 0.3050). Among those >= 25 years, a clear decrease to lower rates immediately after the start was observed (p < 0.025). The highest rates of suicide were found among those > 40 years during the first month. Female gender was, but treatment characteristics were not associated with early attempts at young age. CONCLUSION: Among young AD users, high pre-treatment risk of suicide attempts was present and persisted during the early phases after the start. This contrasted with the clear decrease in risk among those aged >= 25 years, suggesting lower immediate effectiveness of ADs to prevent suicidal behavior at young ages. Caution should be exercised to infer a causal relationship or to use data on attempts to predict risk of suicide during AD use. PMID- 26732216 TI - [Worker participation as a treatment goal: new guideline "Rheumatoid Arthritis and Participation in Work"]. AB - Participation in work is important for every individual and for society as a whole. Despite large improvements in the outcomes of rheumatoid arthritis as a consequence of earlier diagnosis and more effective drug strategies, the disease continues to lead to restrictions in work participation in a substantial proportion of patients. The Dutch Rheumatology Association (NVR) has therefore developed a multidisciplinary guideline, "Rheumatoid Arthritis and Participation in Work". The main aim of this guideline is to improve early recognition by healthcare providers of disease related problems in work participation and to guide the development of a work-directed individual treatment plan. The ultimate goal is to prevent long-term sickness absences and work disability in patients with rheumatoid arthritis. PMID- 26732217 TI - [Need for improvement in education on appropriate prescribing in elderly patients]. AB - Prescribing errors can cause great harm to patients. In the Netherlands, it is estimated that 7000 preventable medication-related hospitals admissions occur annually, caused in many cases by prescribing errors. Elderly patients are at greatest risk, since this patient demographic is most likely to be prescribed multiple medications. Robust education on appropriate prescribing is essential for all clinicians with the authority to prescribe. Currently, some issues still require improvement in the Netherlands: a) education continues to focus heavily on basic pharmacology knowledge instead of patient related pharmacotherapy skills, b) an appropriate assessment procedure on pharmacotherapy knowledge and skills is often lacking, c) there is no mandatory requirement for physicians to maintain their knowledge and skills in the field of pharmacotherapy during their working career. In this article we discuss means to improve this situation, with the overall aim to ensure that all vulnerable elderly patients are in safe hands with each physician. PMID- 26732218 TI - [Resilience and patient safety: how can health care regulations contribute?]. AB - The discussion on patient safety in the Netherlands appears to have reached an impasse. Healthcare professionals are feeling uncomfortable with the enormous increase in the numbers of norms and guidelines, the focus on error and the pressure from external parties. In this article, based on the conference Safety II and beyond - resilience meets regulation, held in Rotterdam, the Netherlands in June 2015, we discuss the underlying problems and propose an alternative approach to the concept of patient safety and to measures to guarantee this safety. PMID- 26732219 TI - [Urinary incontinence in the elderly can be treated]. AB - A recent survey on the use of drugs for incontinence in the elderly stated that only anticholinergic drugs used for urge incontinence have a slight positive effect on incontinence episodes. However, this does not mean that there are no potential treatments for incontinence in the frail elderly. The Dutch surveillance on problems in the care sector, the 'National prevalence survey of care problems' ('Landelijke prevalentiemeting zorgproblemen'), shows that between 2004 and 2014 the prevalence of urinary incontinence dropped from 76% to 49%. This fall in prevalence is due to the policies developed by institutions, and by training for nurses and physicians. Successful treatment begins with assessment of functionality (mobility and cognition), assessment of relevant multimorbidity and reconsideration of the use of drugs with an impact on continence. As a next step, bladder retraining and pelvic floor exercises may be used if the elderly person is able to perform these exercises independently. An anticholinergic drug can be tried as a last resort if there is urge incontinence and there are no contraindications. PMID- 26732220 TI - [The first malaria vaccine: a significant milestone]. AB - RTS,S is the first vaccine to have received a positive opinion from the European Medicines Agency (EMA) under Article 58, for vaccination of young children aged from 6 weeks up to 17 months against malaria caused by Plasmodium falciparum and against hepatitis B. Although vaccine efficacy is modest and wanes rapidly, a substantial number of cases of clinical malaria can be averted, particularly in settings with high disease burden. Further evaluations are needed regarding safety, and more specifically regarding efficacy against severe malaria and mortality. The current formulation, however, is a milestone as a gold standard and represents a basis for further required improvements. Evaluation of the benefits, risks and feasibility are anticipated at global and national levels. PMID- 26732221 TI - [Which is the preferred perioperative beta-blocker?]. AB - Guidelines on perioperative cardiovascular evaluation and management of patients undergoing non-cardiac surgery recommend initiation of beta-blocker therapy in at risk patients who are undergoing intermediate- to high-risk surgery. Continuation of therapy in patients already receiving beta-blockers is also recommended. Recent literature, however, reported an increased risk of perioperative cardiovascular mortality among patients who continued with existing beta blockade; most patients in this study were using metoprolol. There are important pharmacodynamic and pharmacokinetic differences between various beta-blockers, and these differences may explain the differences in clinical effects. Metoprolol has less beta1 receptor affinity compared with atenolol and bisoprolol, and beta1 receptor polymorphisms affect the clinical effects of metoprolol. Furthermore, metoprolol is dependent on activity of the CYP2D6 liver enzyme, which results in clinically important differences in plasma concentration. It is, therefore, wise to follow the European guidelines and to initiate beta-blocker therapy in the perioperative period with either atenolol or bisoprolol. PMID- 26732222 TI - [The WKKGZ, a new act with far-reaching consequences for physicians]. AB - The introduction of the Act on Quality, Complaints and Disputes in Health care (WKKGZ) on 1 January 2016, brings changes for physicians in the Netherlands. Even though not all the implications of the Act are yet known, it is clear that the new provisions on quality entail a substantial increase in the administrative workload. With respect to the right of complaint a great deal will change for physicians and other care providers. Independent complaints committees are no longer mandatory. They are to be replaced by dispute settlement authorities that are able to make binding decisions with the possibility of awarding damages for patient claims. The legal position of physicians is not satisfactorily regulated in a well-balanced way in all areas, and deserves further attention. PMID- 26732223 TI - [Sodium-glucose co-transporter 2 inhibitor for diabetes?]. AB - Following initial expectations, raised by the results of the United Kingdom Prospective Diabetes Study, intervention studies aimed at tight glucose control did not reduce cardiovascular disease. The EMPA-REG OUTCOME, an empagliflozin intervention study in over 7,000 patients with type 2 diabetes mellitus and a history of cardiovascular disease, for the first time showed a rapid reduction in cardiovascular mortality. The diversity in global recruitment centres and level of glucose control during the intervention may limit the generalisability of these promising results in a high-risk population to generally well-controlled Dutch patients. PMID- 26732224 TI - [High mortality following psychosis: not only due to suicide]. AB - In the 1980s about 8.5% of patients in northern Netherlands with a psychotic disorder died due to suicide within five years of follow-up. Liemburg, Castelein and colleagues investigated whether this percentage had recently decreased. They found suicide in 2.4% of patients with recent psychosis after an average follow up of 5 years. Although causality cannot be inferred from a naturalistic study such as theirs, it is plausible that the decreased suicide rate is associated with improvements in the care for psychotic patients. Preventing suicide is invaluable. However, given the alarmingly high mortality due to somatic diseases in patients with schizophrenia, other measures to substantially decrease the high mortality associated with schizophrenia are also warranted. PMID- 26732225 TI - [Preference for endovascular aortic aneurysm repair: results of RCTs versus nationwide audits]. AB - This short comment puts into perspective the value of randomised controlled clinical trials in comparison with nationwide audits in the field of aortic aneurysm treatment. RCTs represent greater scientific value but nationwide audits represent daily practices and seem to be more appropriate for shared decision making. PMID- 26732226 TI - [Hypersexuality and other impulse control disorders in Parkinson's disease]. AB - Impulse control disorders (ICD) in Parkinson's disease (PD) pose a therapeutic challenge. This article provides a description of the symptoms and management strategies of ICD in PD. We present two men aged 52 and 69 with ICD, especially hypersexuality, in response to dopaminergic medication. In the first case the symptoms of hypersexuality and gambling decreased after reducing the dose of the dopamine-agonist. In the second case the hypersexuality symptoms decreased after addition of naltrexon. It is important to recognize the symptoms of ICD in PD because of the large impact on social and relational functioning. It is of great importance to repeatedly ask the patient and their partner about these symptoms, since feelings of shame and guild hamper spontaneous report. The first step of treatment consists of reducing the dose of dopaminergic medication and/or to switch from dopamine-agonist to levodopa. Although the research on effective treatment options has been limited so far, treatment alternatives from the addiction field seem promising. PMID- 26732227 TI - Comparison of the catalytic activity for the Suzuki-Miyaura reaction of (eta(5) Cp)Pd(IPr)Cl with (eta(3)-cinnamyl)Pd(IPr)(Cl) and (eta(3)-1-t-Bu indenyl)Pd(IPr)(Cl). AB - Complexes of the type (eta(3)-allyl)Pd(L)(Cl) and (eta(3)-indenyl)Pd(L)(Cl) are highly active precatalysts for the Suzuki-Miyaura reaction. Even though allyl and indenyl ligands are similar to cyclopentadienyl (Cp) ligands, there have been no detailed comparative studies exploring the activity of precatalysts of the type (eta(5)-Cp)Pd(L)(Cl) for Suzuki-Miyaura reactions. Here, we compare the catalytic activity of (eta(5)-Cp)Pd(IPr)(Cl) (IPr = 1,3-bis(2,6-diisopropylphenyl)-1,3 dihydro-2H-imidazol-2-ylidene, Cp) with two commercially available catalysts (eta(3)-cinnamyl)Pd(IPr)(Cl) (Cin) and (eta(3)-1-t-Bu-indenyl)Pd(IPr)(Cl) ( (tBu) Ind). We show that Cp gives slightly better catalytic activity than Cin, but significantly inferior activity than (tBu) Ind. This order of activity is rationalized by comparing the rates at which the precatalysts are activated to the monoligated Pd(0) active species along with the tendency of the starting precatalysts to comproportionate with monoligated Pd(0) to form inactive Pd(I) dimers. As part of this work the Cp supported Pd(I) dimer (MU-Cp)(MU-Cl)Pd2(IPr)2 (Cp (Dim) ) was synthesized and crystallographically characterized. It does not readily disproportionate to form monoligated Pd(0) and consequently Cp (Dim) is a poor catalyst for the Suzuki-Miyaura reaction. PMID- 26732228 TI - Morphological and dietary responses of chipmunks to a century of climate change. AB - Predicting how individual taxa will respond to climatic change is challenging, in part because the impacts of environmental conditions can vary markedly, even among closely related species. Studies of chipmunks (Tamias spp.) in Yosemite National Park provide an important opportunity to explore the reasons for this variation in response. While the alpine chipmunk (T. alpinus) has undergone a significant elevational range contraction over the past century, the congeneric and partially sympatric lodgepole chipmunk (T. speciosus) has not experienced an elevational range shift during this period. As a first step toward identifying the factors underlying this difference in response, we examined evidence for dietary changes and changes in cranial morphology in these species over the past century. Stable isotope analyses of fur samples from modern and historical museum specimens of these species collected at the same localities indicated that signatures of dietary change were more pronounced in T. alpinus, although diet breadth did not differ consistently between the study species. Morphometric analyses of crania from these specimens revealed significant changes in cranial shape for T. alpinus, with less pronounced changes in shape for T. speciosus; evidence of selection on skull morphology was detected for T. alpinus, but not for T. speciosus. These results are consistent with growing evidence that T. alpinus is generally more responsive to environmental change than T. speciosus, but emphasize the complex and often geographically variable nature of such responses. Accordingly, future studies that make use of the taxonomically and spatially integrative approach employed here may prove particularly informative regarding relationships between environmental conditions, range changes, and patterns of phenotypic variation. PMID- 26732229 TI - Training in General Surgery Ward Call: A Resident-Student Buddy System. AB - There is a paucity of literature regarding medical student experiences of after hours hospital ward call. It was observed at our institution that medical students had minimal experience in ward call, yet were required to undertake such shifts as interns after graduation. We implemented a buddy system in which a medical student shadowed a general surgery resident for a ward call shift. Final year medical students were recruited from the local university at a tertiary teaching hospital after institutional approval. Each student attended a 4 hour evening shift on a general surgery ward with a supervising resident. A survey detailing attitudes and expectations of ward call was completed before and after the experience. Nine students enrolled in the project. Familiarity of expectations of what is required of an intern on a ward call shift improved significantly after the experience (3.1/5 to 4.1/5, p = 0.002). After hours work experience was reported as useful both before and after the study (4.5/5 to 4.7/5, p = 0.47). Students and doctors involved unanimously felt the experience was worthwhile. After hours ward call experience is useful for a final year medical student. More studies are required to further define the role of after hours ward call experiences during medical training. PMID- 26732230 TI - Sodium-glucose co-transporter-2 inhibitors as add-on therapy to insulin: rationale and evidences. AB - Sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are recently approved class of anti-hyperglycaemic agents for the treatment of type 2 diabetes mellitus (T2DM). SGLT-2I inhibits renal glucose reabsorption, thereby ensuing urinary glucose excretion in a dose-dependent manner. This caloric loss and osmotic diuresis, secondary to increased urinary glucose excretion, has a unique potential to counter insulin induced weight gain and fluid retention, with little potential of hypoglycemic exacerbation. Also, as these agents act independently of insulin secretion or action, they are effective even in long-standing diabetes with depleted beta-cell reserve. Improvement in insulin sensitivity, as observed with SGLT-2I can also facilitate insulin action. Furthermore, significant reduction in total daily insulin dosage and reduction of body weight as observed during combination therapy renders SGLT-2I, a near-ideal partner to insulin. This review aims to evaluate the safety and efficacy of currently used SGLT-2I as an add-on to insulin therapy in the treatment of T2DM. PMID- 26732232 TI - Electrocatalytic Generation of Amidyl Radicals for Olefin Hydroamidation: Use of Solvent Effects to Enable Anilide Oxidation. AB - Oxidative generation of synthetically important amidyl radicals from N-H amides is an appealing and yet challenging task. Previous methods require a stoichiometric amount of a strong oxidant and/or a costly noble-metal catalyst. We report herein the first electrocatalytic method that employs ferrocene (Fc), a cheap organometallic reagent, as the redox catalyst to produce amidyl radicals from N-aryl amides. Based on this radical-generating method, an efficient intramolecular olefin hydroamidation reaction has been developed. PMID- 26732231 TI - Pre-emptive analgesia and its supraspinal mechanisms: enhanced descending inhibition and decreased descending facilitation by dexmedetomidine. AB - KEY POINTS: Despite the clinical importance of pre-emptive analgesia, the mechanisms by which it attenuates pain associated with central sensitization are poorly understood. We find that fentanyl and the alpha2-adrenoceptor agonist dexmedetomidine (Dex) differ significantly in their modulatory actions on noxious mechanical and noxious heat-evoked nociception in vivo. Unlike fentanyl, Dex modified descending control of nociception by decreasing the threshold for descending inhibition and/or increasing the threshold for descending facilitation. Dex exhibited after-actions on activities of thalamus in prolongation of noxious heat-evoked paw withdrawal latency that persisted for at least 7 days. This study provides insight into the organization of thalamic modulation in pre-emptive analgesia. ABSTRACT: We investigated and compared the antinociceptive effects of intraperitoneal administration of fentanyl (2-60 MUg kg(-1)) and dexmedetomidine (Dex, 1-10 MUg kg(-1); a highly selective alpha2 adrenoceptor agonist) in the regulation of nociception assessed by measuring noxious paw withdrawal reflexes in rats. Fentanyl elevated noxious mechanical paw withdrawal threshold and prolonged paw withdrawal heat latency within 1-1.5 h (P < 0.05). Dex failed to affect the mechanical paw withdrawal threshold, yet significantly prolonged the paw withdrawal heat latency in a bi-phasic manner; a short transient 1-1.5 h period followed by a second, slowly developing increase in latency that persisted for at least 7 days (P < 0.05). Lesion of the dorsolateral funiculus (DLF) did not influence fentanyl-induced antinociceptive effects, indicating peripheral and spinal antinociceptive mechanisms. By contrast, the Dex-induced second, but not the first, phase of the prolonged paw withdrawal heat latency was significantly blocked by the lesion of either DLF or thalamic ventromedial (VM) nuclei, and was attenuated by intracerebral administration of either atipamezole (alpha2-adrenoceptor antagonist) or WAY 100635 (5-HT1A receptor antagonist) into the VM nuclei (P < 0.05). Upon intramuscular 5.8% saline-induced muscle nociception, pre-emptive injection of fentanyl enhanced mechanical hyperalgesia and blocked heat hypoalgesia, whereas Dex significantly prevented the occurrence of mechanical hyperalgesia and enhanced heat hypoalgesia. It is suggested that Dex, but not fentanyl, significantly enhances descending inhibition and/or decreases descending facilitation to modulate pain and nociception. The present study provides novel insight into thalamus-mediated mechanisms in pre-emptive analgesia. PMID- 26732233 TI - Pedicled perforator flaps for covering the elbow region. A case report. AB - Covering the elbow soft tissue defects is a difficult task for the plastic surgeon. Because of, the important anatomical structures situated superficially and the high tendency for stiffness of the elbow, the reconstructive method must be chosen carefully. Traditionally the free flaps were the choice method for elbow reconstruction. In our department, we use the perforator pedicled flaps for covering elbow defects, as a viable alternative to the free microsurgical transfer. This paper presents a successful case of covering an elbow soft tissue defect in a male patient. By using a local pedicled flap we replaced "like with like" to obtain a very good cosmetic result. The lack of microsurgical anastomosis allowed an early physical therapy. PMID- 26732234 TI - Synthesis and disproof of the structure proposed for the tetrahydrofuranol isolated from Michelia compressa var. lanyuensis (Magnoliaceae). AB - The previously proposed structure for a tetrahydrofuranol isolated from the leaves of Michelia compressa var. lanyuensis (Magnoliaceae) was synthesised in an enantiopure form using diethyl D-tartarate as the starting material. The synthetic sample showed spectroscopic data incompatible with those for the natural product and thus unequivocally disproved the previously assigned structure. PMID- 26732235 TI - Breaking Object Correspondence Across Saccadic Eye Movements Deteriorates Object Recognition. AB - Visual perception is based on information processing during periods of eye fixations that are interrupted by fast saccadic eye movements. The ability to sample and relate information on task-relevant objects across fixations implies that correspondence between presaccadic and postsaccadic objects is established. Postsaccadic object information usually updates and overwrites information on the corresponding presaccadic object. The presaccadic object representation is then lost. In contrast, the presaccadic object is conserved when object correspondence is broken. This helps transsaccadic memory but it may impose attentional costs on object recognition. Therefore, we investigated how breaking object correspondence across the saccade affects postsaccadic object recognition. In Experiment 1, object correspondence was broken by a brief postsaccadic blank screen. Observers made a saccade to a peripheral object which was displaced during the saccade. This object reappeared either immediately after the saccade or after the blank screen. Within the postsaccadic object, a letter was briefly presented (terminated by a mask). Observers reported displacement direction and letter identity in different blocks. Breaking object correspondence by blanking improved displacement identification but deteriorated postsaccadic letter recognition. In Experiment 2, object correspondence was broken by changing the object's contrast polarity. There were no object displacements and observers only reported letter identity. Again, breaking object correspondence deteriorated postsaccadic letter recognition. These findings identify transsaccadic object correspondence as a key determinant of object recognition across the saccade. This is in line with the recent hypothesis that breaking object correspondence results in separate representations of presaccadic and postsaccadic objects which then compete for limited attentional processing resources (Schneider, 2013). Postsaccadic object recognition is then deteriorated because less resources are available for processing postsaccadic objects. PMID- 26732237 TI - Optical design of ZnO-based antireflective layers for enhanced GaAs solar cell performance. AB - A series of hierarchical ZnO-based antireflection coatings with different nanostructures (nanowires and nanosheets) is prepared hydrothermally, followed by means of RF sputtering of MgF2 layers for coaxial nanostructures. Structural analysis showed that both ZnO had a highly preferred orientation along the <0001> direction with a highly crystalline MgF2 shell coated uniformly. However, a small amount of Al was present in nanosheets, originating from Al diffusion from the Al seed layer, resulting in an increase of the optical bandgap. Compared with the nanosheet-based antireflection coatings, the nanowire-based ones exhibited a significantly lower reflectance (~2%) in ultraviolet and visible light wavelength regions. In particular, they showed perfect light absorption at wavelength less than approximately 400 nm. However, a GaAs single junction solar cell with nanosheet-based antireflection coatings showed the largest enhancement (43.9%) in power conversion efficiency. These results show that the increase of the optical bandgap of the nanosheets by the incorporation of Al atoms allows more photons enter the active region of the solar cell, improving the performance. PMID- 26732236 TI - An Ultra-High Field Magnetic Resonance Spectroscopy Study of Post Exercise Lactate, Glutamate and Glutamine Change in the Human Brain. AB - During strenuous exercise there is a progressive increase in lactate uptake and metabolism into the brain as workload and plasma lactate levels increase. Although it is now widely accepted that the brain can metabolize lactate, few studies have directly measured brain lactate following vigorous exercise. Here, we used ultra-high field magnetic resonance spectroscopy of the brain to obtain static measures of brain lactate, as well as brain glutamate and glutamine after vigorous exercise. The aims of our experiment were to (a) track the changes in brain lactate following recovery from exercise, and (b) to simultaneously measure the signals from brain glutamate and glutamine. The results of our experiment showed that vigorous exercise resulted in a significant increase in brain lactate. Furthermore, both glutamate and glutamine were successfully resolved, and as expected, although contrary to some previous reports, we did not observe any significant change in either amino acid after exercise. We did however observe a negative correlation between glutamate and a measure of fitness. These results support the hypothesis that peripherally derived lactate is taken up by the brain when available. Our data additionally highlight the potential of ultra high field MRS as a non-invasive way of measuring multiple brain metabolite changes with exercise. PMID- 26732238 TI - A straightforward access to ruthenium-coordinated fluorophosphines from phosphorous oxyacids. AB - The transformation of phosphorous oxyacids into the corresponding fluorophosphines was mediated by [RuCp(PPh3)2Cl] under mild reaction conditions using a soft deoxofluorinating agent. The reaction is selective, proceeds with high yields and can be extended to a wide range of phosphorous oxyacids once coordinated to the ruthenium synthon [RuCp(PPh3)2](+) as their hydroxyphosphine tautomer. Deoxofluorination of phenylphosphinic acid was also mediated by [RuCp(R)(CH3CN)3]PF6, where Cp(R): Cp = C5H5, Cp* = C5Me5, and [Ru(eta(6)-p cymene)(MU-Cl)Cl]2. X-Ray single crystal structures of the two new derivatives, [RuCp(PPh3)2{PhP(OH)2}]CF3SO3 and [Ru(eta(6)-p-cymene)Cl2{PhP(OH)2}] have been determined. PMID- 26732240 TI - Efficacy of Trigonella foenum-graecum Seed Extract in Reducing Metabolic and Inflammatory Alterations Associated With Menopause. AB - BACKGROUND: Several experimental and clinical studies support beneficial effects of Trigonella foenum-graecum (fenugreek) in the management of metabolic diseases and inflammatory disorders. OBJECTIVES: The purpose of this study was to examine the effect of T. foenum-graecum seed extract in reducing the metabolic and inflammatory alternations associated with menopause. MATERIALS AND METHODS: In this experimental study, 49 rats were divided into seven groups: (I) sham control, (II) ovariectomized-control, (III and IV) ovariectomized treated with 50 and 150 mg/kg of T. foenum-graecum seed ethanolic extract, (V and VI) ovariectomized treated with 50 and 150 mg/kg of T. foenum-graecum hexanic extract, (VII) ovariectomized-positive control treated with 10 ug/kg of estradiol. The extracts were injected intraperitoneally one day after ovariectomy and the treatments were lasted for 42 days. RESULTS: Fasting blood glucose and body weight gain increased significantly in the ovariectomized-control group compared with that in the sham animals (P < 0.05). Administration of estradiol and T. foenum-graecum (50 and 150 mg/dL of hexanic extract and 150 mg/kg of ethanolic extract) significantly diminished the increase in glucose and body weight (P < 0.05). The serum level of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in the ovariectomized control group was significantly higher than those in the sham animals (P < 0.05). Both hexanic and ethanolic extracts as well as estradiol were able to decrease level of these cytokines in the serum of ovariectomized rats (P < 0.05). CONCLUSIONS: The results of the present study show that administration of T. foenum-graecum corrects metabolic and inflammatory alterations associated with ovariectomy and has a potential for the management of menopause. PMID- 26732241 TI - Improving handovers across a North London Mental Health Trust. AB - The GMC Survey June 2011 highlighted that trainees in Barnet, Enfield and Haringey Mental Health Trust (BEH-MHT) were dissatisfied with the Trust's handover process. At this time there were no Trust guidelines on handovers. A quality improvement project was developed to create a consistent out of hours handover process and to improve staff satisfaction thereafter. Handover guidelines were implemented throughout the Trust on 1/2/12. An audit was carried out to measure staff compliance with handovers. A questionnaire was sent out to staff before and after implementation of the guidelines to assess satisfaction with handovers. The audit results highlighted that handovers occurred relatively consistently across the Trust following implementation of the guidelines. The questionnaire results showed an improvement in staff satisfaction with the handover process. The clinical implication of this project is an improved process of out of hours handover across BEH-MHT. PMID- 26732239 TI - Melatonin inhibits MMP-9 transactivation and renal cell carcinoma metastasis by suppressing Akt-MAPKs pathway and NF-kappaB DNA-binding activity. AB - Renal cell carcinoma (RCC) is the most lethal of all urological malignancies because of its potent metastasis potential. Melatonin exerts multiple tumor suppressing activities through antiproliferative, proapoptotic, and anti angiogenic actions and has been tested in clinical trials. However, the antimetastastic effect of melatonin and its underlying mechanism in RCC are unclear. In this study, we demonstrated that melatonin at the pharmacologic concentration (0.5-2 mm) considerably reduced the migration and invasion of RCC cells (Caki-1 and Achn). Furthermore, we found that melatonin suppressed metastasis of Caki-1 cells in spontaneous and experimental metastasis animal models. Mechanistic investigations revealed that melatonin transcriptionally inhibited MMP-9 by reducing p65- and p52-DNA-binding activities. Moreover, the Akt-mediated JNK1/2 and ERK1/2 signaling pathways were involved in melatonin regulated MMP-9 transactivation and cell motility. Clinical samples revealed an inverse correlation between melatonin receptor 1A (MTNR1A) and MMP-9 expression in normal kidney and RCC tissues. In addition, a higher survival rate was found in MTNR1A(high) /MMP-9(low) patients than in MTNR1A(low) /MMP-9(high) patients. Overall, our results provide new insights into the role of melatonin-induced molecular regulation in suppressing RCC metastasis and suggest that melatonin has potential therapeutic applications for metastastic RCC. PMID- 26732242 TI - Development of a mental health smartphone app: perspectives of mental health service users. AB - BACKGROUND: Current mental health policy emphasises the importance of service user involvement in the delivery of care. Information Technology can have an effect on quality and efficiency of care. AIMS: The aim of this study is to gain the viewpoint of service users from a local mental health service in developing a mental health app. METHOD: A qualitative descriptive approach was used. Eight volunteers aged 18-49 years were interviewed with the aid of a semi-structured questionnaire. RESULTS: Interviewees defined a good app by its ease of use. Common themes included availability of contact information, identifying triggers, the ability to rate mood/anxiety levels on a scale, guided relaxation techniques, and the option to personalise the app. The researchers will aim to produce an app that is easily accessible, highly personalisable and will include functions highlighted as important (i.e. contact information, etc.). CONCLUSIONS: This research will assist in the development of an easy-to-use app that could increase access to services, and allow service users to take an active role in their care. In previous studies, apps were developed without the involvement of service users. This study recognises the important role of service users in this area. PMID- 26732244 TI - Time-resolved and in-situ X-ray scattering methods beyond photoactivation: Utilizing high-flux X-ray sources for the study of ubiquitous non-photoactive proteins. AB - X-ray scattering technique, comprising of small-angle/wide-angle X-ray scattering (SAXS/WAXS) techniques is increasingly used to characterize the structure and interactions of biological macromolecules and their complexes in solution. It is a method of choice to characterize the flexible, partially folded and unfolded protein systems. X-ray scattering is the last resort for proteins that cannot be investigated by crystallography or NMR and acts as a complementary technique with different biophysical techniques to answer challenging scientific questions. The marriage of the X-ray scattering technique with the fourth dimension "time" yields structural dynamics and kinetics information for protein motions in hierarchical timescales from picoseconds to days. The arrival of the high-flux X ray beam at third generation synchrotron sources, exceptional X-ray optics, state of-the-art detectors, upgradation of X-ray scattering beamlines with microfluidics devices and advanced X-ray scattering data analysis procedures are the important reasons behind the shining years of X-ray scattering technique. The best days of the X-ray scattering technique are on the horizon with the advent of the nanofocus X-ray scattering beamlines and fourth generation X-ray lightsources, i.e., free electron lasers (XFELs). Complementary to the photon triggered time-resolved X-ray scattering techniques, we will present an overview of the time-resolved and in-situ X-ray scattering techniques for structural dynamics of ubiquitous non-photoactive proteins. PMID- 26732245 TI - A Brief Survey of State-of-the-Art BioSAXS. AB - In the field of structural biology, Small Angle X-ray Scattering (SAXS) has undergone a tremendous evolution in the last two decades. From a craft reserved to a few experts in the late 80's, it has now turned into a high-throughput technique, following the same trend as macromolecular crystallography. Synchrotron radiation has played a key role in this evolution, by providing intense X-ray beams of high optical quality that made possible the recording of statistically meaningful data from weakly scattering biological solutions in a reasonable time. This, in turn, prompted the development of powerful and specific software for data analysis and modeling. In this mini-review, mainly addressed towards a broad readership, representing as many potential users, we try to summarize the latest aspects of evolution of BioSAXS, both conceptually and from the point of view of instrumentation. We emphasize the need for complementary experimental or computational techniques used in combination with SAXS. The great potential of these multi-pronged approaches is illustrated by a series of very recent studies covering the various ways and means of using BioSAXS. PMID- 26732246 TI - Progress in protein crystallography. AB - Macromolecular crystallography evolved enormously from the pioneering days, when structures were solved by "wizards" performing all complicated procedures almost by hand. In the current situation crystal structures of large systems can be often solved very effectively by various powerful automatic programs in days or hours, or even minutes. Such progress is to a large extent coupled to the advances in many other fields, such as genetic engineering, computer technology, availability of synchrotron beam lines and many other techniques, creating the highly interdisciplinary science of macromolecular crystallography. Due to this unprecedented success crystallography is often treated as one of the analytical methods and practiced by researchers interested in structures of macromolecules, but not highly competent in the procedures involved in the process of structure determination. One should therefore take into account that the contemporary, highly automatic systems can produce results almost without human intervention, but the resulting structures must be carefully checked and validated before their release into the public domain. PMID- 26732243 TI - Microfluidic approaches to synchrotron radiation-based Fourier transform infrared (SR-FTIR) spectral microscopy of living biosystems. AB - A long-standing desire in biological and biomedical sciences is to be able to probe cellular chemistry as biological processes are happening inside living cells. Synchrotron radiation-based Fourier transform infrared (SR-FTIR) spectral microscopy is a label-free and nondestructive analytical technique that can provide spatiotemporal distributions and relative abundances of biomolecules of a specimen by their characteristic vibrational modes. Despite great progress in recent years, SR-FTIR imaging of living biological systems remains challenging because of the demanding requirements on environmental control and strong infrared absorption of water. To meet this challenge, microfluidic devices have emerged as a method to control the water thickness while providing a hospitable environment to measure cellular processes and responses over many hours or days. This paper will provide an overview of microfluidic device development for SR FTIR imaging of living biological systems, provide contrast between the various techniques including closed and open-channel designs, and discuss future directions of development within this area. Even as the fundamental science and technological demonstrations develop, other ongoing issues must be addressed; for example, choosing applications whose experimental requirements closely match device capabilities, and developing strategies to efficiently complete the cycle of development. These will require imagination, ingenuity and collaboration. PMID- 26732247 TI - Crystallization and X-ray Crystallographic Analysis of the Adhesive SpaC Pilin Subunit in the SpaCBA Pilus of Gut-adapted Lactobacillus rhamnosus GG. AB - Gram-positive Lactobacillus rhamnosus GG, a gut-adapted commensalic (and probiotic) strain, is known to express sortase-assembled pili on its cell surface. These SpaCBA-called pili consist of three different types of building blocks; the SpaA backbone-pilin subunit and the SpaB and SpaC ancillary pilins. SpaC is a relatively large (~90kDa) multi-domain fimbrial adhesin, and while it is located primarily at the SpaCBA pilus tip, occasionally, it can also be detected throughout the length of pilus backbone. Functionally, SpaC mainly accounts for SpaCBA pilus-mediated interactions with intestinal mucus, collagen, and human gut epithelial cells. Moreover, SpaC adhesiveness is also perceived to have a causal relationship with SpaCBA pilus-induced host-cell immune responses. In order to improve the mechanistic understanding of SpaC and its adhesive properties by structural investigation, we purified and successfully crystallized a recombinant construct of the near full-length SpaC protein (residues 36-856) in the presence of magnesium ions. X-ray diffraction data were collected to 2.6 A resolution. The SpaC crystal belongs to the space group P21212 with unit cell parameters a = 116.5, b = 128.3, c = 136.5 A and contains two molecules in the asymmetric unit. Presence of conserved metal ion-dependent adhesion site containing von Willebrand factor type A domain suggests its likely role in the function of SpaC. PMID- 26732248 TI - Chondrocytes Cocultured with Stromal Vascular Fraction of Adipose Tissue Present More Intense Chondrogenic Characteristics Than with Adipose Stem Cells. AB - Partial replacement of chondrocytes by stem cells has been proposed to improve the performance of autologous chondrocyte implantation (ACI). Our previous studies showed that the increased cartilage production in pellet cocultures of chondrocytes and mesenchymal stem cells (MSCs) is due to a trophic role of the MSCs by stimulating chondrocyte proliferation and matrix production rather than MSCs actively undergoing chondrogenic differentiation. The aim of this study is to compare the trophic effects of stromal vascular fraction cells (SVF) and in vitro expanded adipose stem cells (ASC). SVF and culture-expanded ASC (n = 9) were cocultured with primary human chondrocytes in pellets. By glycosaminoglycan (GAG) and DNA assays, we showed that coculture pellets of SVF and chondrocytes have more GAG deposition than that of ASC and chondrocytes. Results of the short tandem repeats analysis indicated that the increase in the chondrocyte proportion in the coculture pellets is more pronounced in the SVF coculture group than in the ASC coculture group. Using flow cytometry and microarray, we demonstrated that SVF and ASC have different characteristics in cell surface markers and gene expression profiles. SVF is more heterogeneous than ASC, whereas ASC is more enriched in cells from the mesenchymal lineage than SVF. By subcutaneous implantation into nude mice, we showed that constructs of SVF and chondrocytes are better in depositing cartilage matrix than the mixture of ASC and chondrocytes. Taken together, SVF is better than ASC in terms of forming cartilage matrix in pellet coculture and in coimplantation models omitting the need for prior cell expansion. Our study suggests that the SVF in combination with primary human chondrocytes may be a good cell combination for one-stage cartilage repair. PMID- 26732249 TI - Access and utilisation of social and health services as a social determinant of health: the case of undocumented Latin American immigrant women working in Lleida (Catalonia, Spain). AB - Although Spain has social and healthcare systems based on universal coverage, little is known about how undocumented immigrant women access and utilise them. This is particularly true in the case of Latin Americans who are overrepresented in the informal labour market, taking on traditionally female roles of caregivers and cleaners in private homes. This study describes access and utilisation of social and healthcare services by undocumented Latin American women working and living in rural and urban areas, and the barriers these women may face. An exploratory qualitative study was designed with 12 in-depth interviews with Latin American women living and working in three different settings: an urban city, a rural city and rural villages in the Pyrenees. Interviews were recorded, transcribed and analysed, yielding four key themes: health is a tool for work which worsens due to precarious working conditions; lack of legal status traps Latin American women in precarious jobs; lack of access to and use of social services; and limited access to and use of healthcare services. While residing and working in different areas of the province impacted the utilisation of services, working conditions was the main barrier experienced by the participants. In conclusion, decent working conditions are the key to ensuring undocumented immigrant women's right to social and healthcare. To create a pathway to immigrant women's health promotion, the 'trap of illegality' should be challenged and the impact of being considered 'illegal' should be considered as a social determinant of health, even where the right to access services is legal. PMID- 26732250 TI - A new way to synthesize superconducting metal-intercalated C60 and FeSe. AB - Doping with the optimum concentration of carriers (electrons or holes) can modify the physical properties of materials. Therefore, improved ways to achieve carrier doping have been pursued extensively for more than 50 years. Metal-intercalation is one of the most important techniques for electron doping of organic / inorganic solids, and has produced superconductors from insulators and metallic solids. The most successful examples are metal-intercalated graphite and C60 superconductors. Metal intercalation has been performed using solid-reaction and liquid solvent techniques. However, precise control of the quantity of intercalants in the target solids can be difficult to achieve using these methods, as that quantity depends largely on the initial conditions. Here we report an electrochemical method for metal-intercalation, and demonstrate the preparation of superconductors using organic and inorganic materials (C60 and FeSe). The metal atoms are effectively intercalated into the spaces in C60 and FeSe solids by supplying an electric current between electrodes in a solvent that includes electrolytes. The recorded superconducting transition temperatures, Tc's, were the same as those of metal-intercalated C60 and FeSe prepared using solid-reaction or liquid solvent techniques. This technique may open a new avenue in the search for organic / inorganic superconductors. PMID- 26732251 TI - A zero power harmonic transponder sensor for ubiquitous wireless MUL liquid volume monitoring. AB - Autonomous liquid-volume monitoring is crucial in ubiquitous healthcare. However, conventional approach is based on either human visual observation or expensive detectors, which are costly for future pervasive monitoring. Here we introduce a novel approach based on passive harmonic transponder antenna sensor and frequency hopping spread spectrum (FHSS) pattern analysis, to provide a very low cost wireless MUL-resolution liquid-volume monitoring without battery or digital circuits. In our conceptual demonstration, the harmonic transponder comprises of a passive nonlinear frequency multiplier connected to a metamaterial-inspired 3-D antenna designed to be highly sensitive to the liquid-volume within a confined region. The transponder first receives some FHSS signal from an interrogator, then converts such signal to its harmonic band and re-radiates through the antenna sensor. The harmonic signal is picked up by a sniffer receiver and decoded through pattern analysis of the high dimensional FHSS signal strength data. A robust, zero power, absolute accuracy wireless liquid-volume monitoring is realized in the presence of strong direct coupling, background scatters, distance variance as well as near-field human-body interference. The concepts of passive harmonic transponder sensor, metamaterial-inspired antenna sensor, and FHSS pattern analysis based sensor decoding may help establishing cost-effective, energy-efficient and intelligent wireless pervasive healthcare monitoring platforms. PMID- 26732252 TI - Aliskiren Reduces Hepatic steatosis and Epididymal Fat Mass and Increases Skeletal Muscle Insulin Sensitivity in High-Fat Diet-Fed Mice. AB - Aliskiren has been found to reduce chronic injury and steatosis in the liver of methionine-choline-deficient (MCD) diet-fed mice. This study investigated whether aliskiren has an anti-steatotic effect in HFD-fed mice, which are more relevant to human patients with non-alcoholic fatty liver disease than MCD mice. Mice fed with 4-week normal chow or HFD randomly received aliskiren (50 mg/kg/day) or vehicle via osmotic minipumps for further 4 weeks. Aliskiren reduced systemic insulin resistance, hepatic steatosis, epididymal fat mass and increased gastrocnemius muscle glucose transporter type 4 levels with lower tissue angiotensin II levels in the HFD-fed mice. In addition, aliskiren lowered nuclear peroxisome proliferator-activated receptor gamma and its down-signaling molecules and increased cytochrome P450 4A14 and carnitine palmitoyltransferase 1A (CPT1a) in liver. In epididymal fat, aliskiren inhibited expressions of lipogenic genes, leading to decrease in fat mass, body weight, and serum levels of leptin and free fatty acid. Notably, in the gastrocnemius muscle, aliskiren increased phosphorylation of insulin receptor substrate 1 and Akt. Based on these beneficial effects on liver, peripheral fat and skeletal muscle, aliskiren is a promising therapeutic agent for patients with NAFLD. PMID- 26732253 TI - A small-molecule compound belonging to a class of 2,4-disubstituted 1,3,4 thiadiazine-5-ones suppresses Salmonella infection in vivo. AB - Therapeutic strategies that target bacterial virulence have received considerable attention. The type III secretion system (T3SS) is important for bacterial virulence and represents an attractive therapeutic target. A novel compound with a predicted T3SS inhibitory activity named CL-55 (N-(2,4-difluorophenyl)-4-(3 ethoxy-4-hydroxybenzyl)-5-oxo-5,6-dihydro-4H-[1,3,4]-thiadiazine-2-carboxamide) was previously characterized by low toxicity, high levels of solubility, stability and specific efficiency toward Chlamydia trachomatis in vitro and in vivo. In this study, we describe the action of CL-55 on Salmonella enterica serovar Typhimurium. We found that CL-55 does not affect Salmonella growth in vitro but suppresses Salmonella infection in vivo. The i.p. injection of CL-55 at a dose of 10 mg kg(-1) for 4 days significantly (500-fold) decreased the numbers of Salmonella in the spleen and peritoneal lavages and increased the survival rates in susceptible (BALB/c, I/St) and resistant (A/Sn) mice. Twelve days of therapy led to complete eradication of Salmonella in mice. Moreover, no pathogen was found 4-6 weeks post treatment. CL-55 was not carcinogenic or mutagenic, did not increase the level of chromosomal aberrations in bone marrow cells and had low toxicity in mice, rats and rabbits. Pharmacokinetic studies have shown that CL-55 rapidly disappears from systemic blood circulation and is distributed in the organs. Our data demonstrates that CL-55 affects S. enterica serovar Typhimurium in vivo and could be used as a substance in the design of antibacterial inhibitors for pharmaceutical intervention of bacterial virulence for infection. PMID- 26732254 TI - JBIR-76 and JBIR-77, modified naphthoquinones from Streptomyces sp. RI-77. PMID- 26732255 TI - Oxysporizoline, an antibacterial polycyclic quinazoline alkaloid from the marine mudflat-derived fungus Fusarium oxysporum. PMID- 26732256 TI - Structure and absolute configuration of drimentine I, an alkaloid from Streptomyces sp. CHQ-64. PMID- 26732257 TI - Isolation of growth inhibitors of the snow rot pathogen Pythium iwayamai from an arctic strain of Trichoderma polysporum. AB - Growth inhibitors were isolated from an arctic strain of Trichoderma polysporum, and the structures were elucidated and the in vitro inhibitory effects of these compounds against Pythium iwayamai were investigated. Eleven compounds were isolated; four showed a concentration-dependent growth-inhibitory effect against P. iwayamai. None of these compounds have been reported previously as substances with antimicrobial activity against P. iwayamai. One of these four compounds inhibited the growth of the pathogen at 33 MUg ml(-1) concentration during a 15 day incubation at 20 degrees C. This effect was comparable to that of chloroneb (1: 1,4-dichloro-2,5-dimethoxybenzene), a fungicide with activity against P. iwayamai. Thus, the results of the present study show that the arctic strain of T. polysporum can be an effective source of antibiotics with activity against the snow rot pathogen, P. iwayamai. PMID- 26732258 TI - The Petasis-Ferrier rearrangement: developments and applications. AB - In the mid-1990s, Petasis reexamined a promising but infrequently used rearrangement strategy, the so-called Ferrier-type-II reaction, and provided it with a modern update. Previously, Ferrier had developed a strategy where carbohydrate derivatives would undergo a fragmentation/aldol-type recombination sequence, generating a carbocycle, albeit under the promotion of stoichiometric mercury salts. Petasis' new variant showed the promise to effectively and stereoselectively convert a range of cyclic vinyl acetals to useful tetrahydrofurans and tetrahydropyrans, using less toxic promoters. Since these first reports, the 'Petasis-Ferrier rearrangement' has represented a vibrant area of research and innovation for organic chemists. With numerous applications in complex natural product total synthesis, the utility of the reaction has been resoundingly established. Recent developments have extended the reaction to a broader synthetic context, allowing for in situ generation of rearrangement substrates and more liberal interpretation of what fragmentation/recombination reactions warrant the designation of a Petasis-Ferrier rearrangement. PMID- 26732259 TI - [Bony avulsion of the extensor tendon at the end joint and Mallet fracture]. PMID- 26732260 TI - [Fracture or avulsion of the extensor tendon: Anatomy of the extensor apparatus of the hand]. PMID- 26732261 TI - Ileostomy closure by colorectal surgeons results in less major morbidity: results from an institutional change in practice and awareness. AB - PURPOSE: Previous institutional analysis of ileostomy closure revealed substantial morbidity. This subsequent study aimed at determining if a change in clinical practice resulted in reduced complication rates. METHODS: Between June 2004 and January 2014, all consecutive adult patients undergoing ileostomy closure were retrospectively identified. Postoperative outcome after change in clinical practice consisting of routine participation of a colorectal surgeon, stapled side-to-side anastomosis and increased clinical awareness (cohort B) was compared with our previously published historical control group (cohort A). The primary outcome was major morbidity, defined as Clavien-Dindo grade three or higher. Independent risk factors of major morbidity were identified using multivariable analysis. RESULTS: In total, 165 patients underwent ileostomy closure in cohort A, and 144 patients in cohort B. At baseline, more primary diverting ileostomies were present in cohort A (94 vs. 82%; p = 0.001) with a similar rate of loop and end-ileostomy between the two cohorts (p = 0.331). A significant increase in colorectal surgeon participation (89 vs. 53%; p < 0.001) and stapled side-to-side anastomosis was observed (63 vs. 16%; p < 0.001). The major morbidity rate was 11% in cohort A, which significantly reduced to 4% in cohort B (p = 0.03). Surgery being performed or supervised by a colorectal surgeon (odds ratio [OR] 0.28, 95% CI 0.11-0.67) and loop-ileostomy compared to end-ileostomy (OR 0.18, 95% CI 0.07-0.52) were independently associated with lower major morbidity. CONCLUSION: Ileostomy closure appears to be more complex surgery then generally considered, especially end-ileostomy closure. Postoperative outcome could be significantly improved by a change in surgical practice. PMID- 26732263 TI - Intestinal volvulus related to malrotation in adults. PMID- 26732262 TI - Meta-analysis of the laparoscopic versus open colorectal surgery within fast track surgery. AB - BACKGROUND: Laparoscopic methods and fast-track surgery (FTS) can enhance recovery and reduce postoperative hospital stay. However, whether laparoscopic surgery can provide short-term benefits within FTS is controversial. Thus, we conducted a meta-analysis of published studies to evaluate the effect of laparoscopic colorectal surgery within FTS. METHODS: We searched PubMed, EMBASE, Cochrane Library, and Ovid databases for eligible studies. Endpoints were duration of postoperative hospital stay, time to first bowel movement, total postoperative complication rate, readmission rate, mortality within 30 days after surgery, and conversation rate of laparoscopic surgery. RESULTS: Four randomized controlled trials and six clinical controlled trials (1510 patients) were eligible for analyses. Duration of postoperative hospital stay (weighted mean difference, -1.65 days; p < 0.001), time to first bowel movement (-1.13 days; p < 0.001), total postoperative complication rate (risk ratio [RR], 0.65; p < 0.001), readmission rate (0.46; p < 0.001), and mortality (0.45; p < 0.001) were significantly reduced in the laparoscopic surgery group. Overall conversion rate of laparoscopic surgery was 11.1%. Subgroup analyses based on each FT element demonstrated that studies without the element "prevention of hypothermia," "no bowel preparation," or "no routine use of drains" did not show significant differences between two groups with regard to duration of postoperative hospital stay or total prevalence of postoperative complications. CONCLUSION: Within FTS, laparoscopic methods can significantly shorten postoperative hospital stay, accelerate postoperative recovery, and enhance safety in colorectal surgery. The FT elements "prevention of hypothermia," "no bowel preparation," and "no routine use of drains" may play important parts in the combined effect of these two methods. PMID- 26732264 TI - Matching novel face and voice identity using static and dynamic facial images. AB - Research investigating whether faces and voices share common source identity information has offered contradictory results. Accurate face-voice matching is consistently above chance when the facial stimuli are dynamic, but not when the facial stimuli are static. We tested whether procedural differences might help to account for the previous inconsistencies. In Experiment 1, participants completed a sequential two-alternative forced choice matching task. They either heard a voice and then saw two faces or saw a face and then heard two voices. Face-voice matching was above chance when the facial stimuli were dynamic and articulating, but not when they were static. In Experiment 2, we tested whether matching was more accurate when faces and voices were presented simultaneously. The participants saw two face-voice combinations, presented one after the other. They had to decide which combination was the same identity. As in Experiment 1, only dynamic face-voice matching was above chance. In Experiment 3, participants heard a voice and then saw two static faces presented simultaneously. With this procedure, static face-voice matching was above chance. The overall results, analyzed using multilevel modeling, showed that voices and dynamic articulating faces, as well as voices and static faces, share concordant source identity information. It seems, therefore, that above-chance static face-voice matching is sensitive to the experimental procedure employed. In addition, the inconsistencies in previous research might depend on the specific stimulus sets used; our multilevel modeling analyses show that some people look and sound more similar than others. PMID- 26732265 TI - A neural signature of rapid category-based target selection as a function of intra-item perceptual similarity, despite inter-item dissimilarity. AB - Previous work on visual search has suggested that only a single attentional template can be prioritized at any given point in time. Grouping features into objects and objects into categories can facilitate search performance by maximizing the amount of information carried by an attentional template. From infancy to adulthood, earlier studies on perceptual similarity have shown that consistent features increase the likelihood of grouping features into objects (e.g., Quinn & Bhatt, Psychological Science. 20:933-938, 2009) and objects into categories (e.g., shape bias; Landau, Smith, & Jones, Cognitive Development. 3:299-321, 1988). Here we asked whether lower-level, intra-item similarity facilitates higher-level categorization, despite inter-item dissimilarity. Adults participated in four visual search tasks in which targets were defined as either one item (a specific alien) or a category (any alien) with either similar features (e.g., circle belly shape and circle back spikes) or dissimilar features (e.g., circle belly shape and triangle back spikes). Using behavioral and neural measures (i.e., the N2pc event-related potential component, which typically emerges 200 ms poststimulus), we found that intra-item feature similarity facilitated categorization, despite dissimilar features across the category items. Our results demonstrate that feature similarity builds novel categories and activates a task-appropriate abstract categorical search template. In other words, grouping at the lower, item level facilitates grouping at the higher, category level, which allows us to overcome efficiency limitations in visual search. PMID- 26732266 TI - Intracardiac echocardiography to diagnose pannus formation after aortic valve replacement. AB - A 66-year-old female, under regular follow-up for 20 years after aortic valve replacement (19-mm Carbomedics), presented dyspnea on effort and hypotension during hemodialysis. A transthoracic echocardiogram showed elevation of transvalvular velocity up to 4 m/s, but the structure around the aortic prosthesis was difficult to observe due to artifacts. Fluoroscopy revealed normal motion of the leaflets of the mechanical valve. Intracardiac echocardiography (ICE) revealed a pannus-like structure in the left ventricular outflow tract. Transesophageal echocardiogram also revealed this structure. ICE can visualize structural abnormalities around a prosthetic valve after cardiac surgery even in patients in whom conventional imaging modalities failed. PMID- 26732267 TI - Non-functional plastid ndh gene fragments are present in the nuclear genome of Norway spruce (Picea abies L. Karsch): insights from in silico analysis of nuclear and organellar genomes. AB - Many genes have been lost from the prokaryote plastidial genome during the early events of endosymbiosis in eukaryotes. Some of them were definitively lost, but others were relocated and functionally integrated to the host nuclear genomes through serial events of gene transfer during plant evolution. In gymnosperms, plastid genome sequencing has revealed the loss of ndh genes from several species of Gnetales and Pinaceae, including Norway spruce (Picea abies). This study aims to trace the ndh genes in the nuclear and organellar Norway spruce genomes. The plastid genomes of higher plants contain 11 ndh genes which are homologues of mitochondrial genes encoding subunits of the proton-pumping NADH-dehydrogenase (nicotinamide adenine dinucleotide dehydrogenase) or complex I (electron transport chain). Ndh genes encode 11 NDH polypeptides forming the Ndh complex (analogous to complex I) which seems to be primarily involved in chloro respiration processes. We considered ndh genes from the plastidial genome of four gymnosperms (Cryptomeria japonica, Cycas revoluta, Ginkgo biloba, Podocarpus totara) and a single angiosperm species (Arabidopsis thaliana) to trace putative homologs in the nuclear and organellar Norway spruce genomes using tBLASTn to assess the evolutionary fate of ndh genes in Norway spruce and to address their genomic location(s), structure, integrity and functionality. The results obtained from tBLASTn were subsequently analyzed by performing homology search for finding ndh specific conserved domains using conserved domain search. We report the presence of non-functional plastid ndh gene fragments, excepting ndhE and ndhG genes, in the nuclear genome of Norway spruce. Regulatory transcriptional elements like promoters, TATA boxes and enhancers were detected in the upstream regions of some ndh fragments. We also found transposable elements in the flanking regions of few ndh fragments suggesting nuclear rearrangements in those regions. These evidences support the hypothesis that, at least in Picea, ndh translocations from the plastid to the nuclear genome have occurred, and that there might have been a functional machinery at some time during evolution to accommodate them within a nuclear-encoded environment, or attempts to form it. PMID- 26732268 TI - Association genetics in Populus reveals the interactions between Pto-miR160a and its target Pto-ARF16. AB - MicroRNAs (miRNAs) play important roles in the regulation of gene expression in various biological processes. However, the interactions between miRNAs and their targets are largely unknown in plants. As a powerful tool for identification of variation associated with traits, association genetics provides another strategy for exploration of interactions between miRNAs and their targets. Here, we conducted expression analysis and association mapping to evaluate the interaction between Pto-miR160a and its target Pto-ARF16 in Populus tomentosa. By examining the expression patterns of Pto-MIR160a and Pto-ARF16, we identified a significant, negative correlation between their expression levels, indicating that Pto-miR160a may affect the expression of Pto-ARF16. Among the single nucleotide polymorphisms (SNPs) identified in this study, one common SNP in the pre-miRNA region of Pto-miR160a altered its predicted secondary structure while another common SNP in the predicted miRNA target site changed the binding affinity of Pto-miR160a. Linkage disequilibrium (LD) analysis revealed low LD levels of Pto-MIR160a and Pto-ARF16, indicating that they are suitable for candidate gene-based association analysis. Single SNP-based association analysis identified 19 SNPs (false discovery rate Q < 0.05) in Pto-MIR160a and Pto-ARF16 associated with three phenotypic traits. Epistasis analysis further identified 36 SNP-SNP interactions between SNPs in Pto-MIR160a and SNPs in Pto-ARF16, reflecting the possible genetic interaction of Pto-miR160a and Pto-ARF16. Taking these results together, our study identified SNPs in Pto-MIR160a and Pto-ARF16 associated with tree growth and wood properties, providing SNPs with potential applications in marker-assisted breeding and evidence for the genetic interaction of Pto-miR160a and Pto-ARF16. PMID- 26732269 TI - Decompressive Craniectomy in Patients with Traumatic Brain Injury: Are the Usual Indications Congruent with Those Evaluated in Clinical Trials? AB - BACKGROUND: In patients with traumatic brain injury (TBI), multicenter randomized controlled trials have assessed decompressive craniectomy (DC) exclusively as treatment for refractory elevation of intracranial pressure (ICP). DC reliably lowers ICP but does not necessarily improve outcomes. However, some patients undergo DC as treatment for impending or established transtentorial herniation, irrespective of ICP. METHODS: We performed a population-based cohort study assessing consecutive patients with moderate-severe TBI. Indications for DC were compared with enrollment criteria for the DECRA and RESCUE-ICP trials. RESULTS: Of 644 consecutive patients, 51 (8 %) were treated with DC. All patients undergoing DC had compressed basal cisterns, 82 % had at least temporary preoperative loss of >=1 pupillary light reflex (PLR), and 80 % had >5 mm of midline shift. Most DC procedures (67 %) were "primary," having been performed concomitantly with evacuation of a space-occupying lesion. ICP measurements influenced the decision to perform DC in 18 % of patients. Only 10 and 16 % of patients, respectively, would have been eligible for the DECRA and RESCUE-ICP trials. DC improved basal cistern compression in 76 %, and midline shift in 94 % of patients. Among patients with >=1 absent PLR at admission, DC was associated with lower mortality (46 vs. 68 %, p = 0.03), especially when the admission Marshall CT score was 3-4 (p = 0.0005). No patients treated with DC progressed to brain death. Variables predictive of poor outcome following DC included loss of PLR(s), poor motor score, midline shift >=11 mm, and development of perioperative cerebral infarcts. CONCLUSIONS: DC is most often performed for clinical and radiographic evidence of herniation, rather than for refractory ICP elevation. Results of previously completed randomized trials do not directly apply to a large proportion of patients undergoing DC in practice. PMID- 26732270 TI - Conivaptan, a Selective Arginine Vasopressin V1a and V2 Receptor Antagonist Attenuates Global Cerebral Edema Following Experimental Cardiac Arrest via Perivascular Pool of Aquaporin-4. AB - BACKGROUND: Cerebral edema is a major cause of mortality following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Arginine vasopressin (AVP) and water channel aquaporin-4 (AQP4) have been implicated in the pathogenesis of CA evoked cerebral edema. In this study, we examined if conivaptan, a V1a and V2 antagonist, attenuates cerebral edema following CA/CPR in wild type (WT) mice as well as mice with targeted disruption of the gene encoding alpha-syntrophin (alpha-syn(-/-)) that demonstrate diminished perivascular AQP4 pool. METHODS: Isoflurane-anesthetized adult male WT C57Bl/6 and alpha-syn(-/-) mice were subjected to 8 min CA/CPR and treated with either bolus IV injection (0.15 or 0.3 mg/kg) followed by continuous infusion of conivaptan (0.15 mg/kg/day or 0.3 mg/kg/day), or vehicle infusion for 48 h. Serum osmolality, regional brain water content, and blood-brain barrier (BBB) disruption were determined at the end of the experiment. Sham-operated mice in both strains served as controls. RESULTS: Treatment with conivaptan elevated serum osmolality in a dose-dependent manner. In WT mice, conivaptan at 0.3 mg dose significantly attenuated regional water content in the caudoputamen (81.0 +/- 0.5 vs. 82.5 +/- 0.4% in controls; mean +/- SEM) and cortex (78.8 +/- 0.2 vs. 79.4 +/- 0.2% in controls), while conivaptan at 0.15 mg was not effective. In alpha-syn(-/-) mice, conivaptan at 0.3 mg dose did not attenuate water content compared with controls. Conivaptan (0.3 mg/kg/day) attenuated post-CA BBB disruption at 48 h in WT mice but not in alpha-syn(-/-) mice. CONCLUSIONS: Continuous IV infusion of conivaptan attenuates cerebral edema and BBB disruption following CA. These effects of conivaptan that are dependent on the presence of perivascular pool of AQP4 appear be mediated via its dual effect on V1 and V2 receptors. PMID- 26732271 TI - The Contributions - and Collapse - of Lamarckian Heredity in Pasteurian Molecular Biology: 1. Lysogeny, 1900-1960. AB - This article shows how Lamarckism was essential in the birth of the French school of molecular biology. We argue that the concept of inheritance of acquired characters positively shaped debates surrounding bacteriophagy and lysogeny in the Pasteurian tradition during the interwar period. During this period the typical Lamarckian account of heredity treated it as the continuation of protoplasmic physiology in daughter cells. Felix d'Herelle applied this conception to argue that there was only one species of bacteriophage and Jules Bordet applied it to develop an account of bacteriophagy as a transmissible form of autolysis and to analyze the new phenomenon of lysogeny. In a long-standing controversy with Bordet, Eugene Wollman deployed a more morphological understanding of the inheritance of acquired characters, yielding a particulate, but still Lamarckian, account of lysogeny. We then turn to Andre Lwoff who, with several colleagues, completed Wollman's research program from 1949 to 1953. We examine how he gradually set aside the Lamarckian background, finally removing inheritance of acquired characters from the resulting account of bacteriophagy and lysogeny. In the conclusion, we emphasize the complex dual role of Lamarckism as it moved from an assumed explanatory framework to a challenge that the nascent molecular biology had to overcome. PMID- 26732272 TI - Do Patients After Reexcision Due to Involved or Close Margins Have the Same Risk of Local Recurrence as Those After One-Step Breast-Conserving Surgery? AB - PURPOSE: To explore whether patients after a reexcision due to involved or close margins have the same risk of local recurrence (LR) than those after a one-step breast-conserving surgery (BCS); to learn whether the presence of residual cancer in the reexcision specimen influences the probability of LR. METHODS: We reviewed demographic, clinical, radiologic, and pathologic records of a cohort of women diagnosed with invasive cancer or carcinoma-in situ who underwent BCS surgery as final surgical treatment between January 1, 2003, and December 31, 2011. Univariable and multivariable Cox regression analyses were used to evaluate influencing factors of LR. RESULTS: A total of 2657 patients were eligible for inclusion onto this study. LR was observed in 67 patients (2.5 %) after a median follow-up of 52 months. Reexcision surgery was performed in 486 patients (18.3 %). The 5-year LR-free survival rate was 94.5 % in the reexcision group and 98.0 % in the group with one-step BCS surgery (p < 0.001). In multivariable Cox regression analyses including different covariates patients with a reexcision had a two to eightfold higher risk of LR. Residual cancer in the reexcision specimen did not influence the LR rate (hazard ratio 1.1, p = 0.779). CONCLUSIONS: This study suggests the importance of a complete tumor resection ideally within one surgical procedure. Therefore, rigorous preoperative planning, multidisciplinary decision making, and additional intraoperative techniques (e.g., ultrasound, specimen radiography, and/or cavity shaved margin) should be used to avoid the need for reexcision. PMID- 26732273 TI - Regional Therapies for Advanced Cancer: Update for 2016. PMID- 26732274 TI - Patterns and Predictors of Weight Loss After Gastrectomy for Cancer. AB - BACKGROUND: Weight loss following gastrectomy for patients with gastric cancer has not been well characterized. We assessed the impact of patient and procedure specific variables on postoperative weight loss following gastrectomy for cancer. METHODS: A prospectively maintained gastric cancer database identified patients undergoing gastrectomy for cancer. Clinical and pathologic characteristics, baseline body mass index (BMI), and postoperative weights were extracted. Change in weight was analyzed by percent change in weight and absolute change in BMI. Random coefficients models were used to test whether the rate of change in weight over time differed by factors of interest. RESULTS: Of 376 consecutive patients who underwent resection for gastric adenocarcinoma, 55 % were male, median age 66 years, and mean preoperative BMI 27.1 (range 16.2-45.6). Total gastrectomy was associated with more weight loss than subtotal gastrectomy at 1 year (15 vs. 6 %, early stage; 17 vs. 7 %, late stage). Maximum weight change was observed at 6-12 months after operation and remained stable or improved at 2 years. For early- and late-stage patients, median percent weight loss at 1 year was greater for BMI >= 30 versus BMI < 30 (14 vs. 8 %, early stage; 15 vs. 9 %, late stage). CONCLUSIONS: The extent of weight loss after gastrectomy for gastric cancer is dependent on preoperative BMI and extent of gastric resection. Maximum weight change is expected by 12 months after operation and will stabilize or improve over time. PMID- 26732275 TI - Percutaneous Treatment of Localized Infiltrative Hepatocellular Carcinoma Developing on Cirrhosis. AB - BACKGROUND: Infiltrating hepatocellular carcinoma (HCC) is characterized by a difficult diagnosis, dismal prognosis, and limited therapeutic options. We describe long-term results of percutaneous treatment of infiltrative HCC, i.e., multibipolar radiofrequency ablation (mbpRFA) and percutaneous intra-arterial ethanol injection (PIAEI). METHODS: All cirrhotic patients with localized (up to two segments) infiltrating HCC treated by mbpRFA or PIAEI between 2002 and 2012 were included. Survival was analyzed using the Kaplan-Meier method, log-rank test, and Cox univariate followed by multivariate analyses. RESULTS: Fifty-one patients were considered eligible for mbpRFA (n = 20) or PIAEI (n = 31). Cirrhosis etiologies were alcohol (67 %), hepatitis C (33 %), hepatitis B (16 %), and/or NASH (16 %). HCC were multinodular in 31 % of cases, with a median main tumor size of 60 mm (range 30-200) and macrovascular invasion in 59 % of cases. The median serum level of alphafetoprotein was 125 ng/ml (range 2-215,000). Treatment-related adverse events occurred in 58 %, mainly postablation syndrome (31 %), and one death (2 %). Median overall survival was 18.3 months, with 63, 35, 20, and 12 % survival at 1, 2, 3, and 4 years, respectively. Baseline serum bilirubin >normal [hazard ratio (HR) 2.98; 95 % confidence interval (CI) 1.38 6.50; P = 0.0057] and tumor burden >70 mm (HR 1.02; 95 % CI 1.003-1.04; P = 0.0221) were associated with poorer overall survival. The radiological response using mRECIST criteria and an alphafetoprotein decrease 1 month post-procedure was associated with increased overall survival (P = 0.0002 and P = 0.024, respectively). DISCUSSION: Despite its overall poor prognosis, localized infiltrating HCC can be safely treated using percutaneous approaches, with potential survival benefits for these difficult-to-treat patients. PMID- 26732276 TI - Synthesis of PtM (M=Co, Ni)/Reduced Graphene Oxide Nanocomposites as Electrocatalysts for the Oxygen Reduction Reaction. AB - A series of PtM (M=Co, Ni)/reduced graphene oxide (rG-O) nanocomposites were successfully synthesized through a facile hydrothermal method. The as-synthesized nanocomposites were characterized using transmission electron microscopy and high resolution transmission electron microscopy, X-ray diffraction, inductively coupled plasma-atomic emission spectrometer, and X-ray photoelectron spectroscopy. The electrochemical performance and oxygen reduction reaction (ORR) activity of PtM/rG-O nanocomposites were evaluated using cyclic voltammetry and the rotating disk electrode method. The results show that the addition of the reductant (1,2-hexadecanediol, HAD) in the reaction system slightly improved the ORR activity of PtM/rG-O nanocomposites with a negligible influence on the size and morphology of alloy NPs. Furthermore, PtNi/rG-O nanocomposites displayed the higher electrochemical stability than PtCo/rG-O nanocomposites. These results provide a facile strategy for the synthesis of Pt-based alloy NPs/rG-O nanocomposites for applications in catalysis and energy-related processes. PMID- 26732277 TI - Electromechanical Behavior of Chemically Reduced Graphene Oxide and Multi-walled Carbon Nanotube Hybrid Material. AB - In this paper, we propose strain-sensitive thin films based on chemically reduced graphene oxide (GO) and multi-walled carbon nanotubes (MWCNTs) without adding any further surfactants. In spite of the insulating properties of the thin-film-based GO due to the presence functional groups such as hydroxyl, epoxy, and carbonyl groups in its atomic structure, a significant enhancement of the film conductivity was reached by chemical reduction with hydro-iodic acid. By optimizing the MWCNT content, a significant improvement of electrical and mechanical thin film sensitivity is realized. The optical properties and the morphology of the prepared thin films were studied using ultraviolet-visible spectroscopy (UV-Vis) and scanning electron microscope (SEM). The UV-Vis spectra showed the ability to tune the band gap of the GO by changing the MWCNT content, whereas the SEM indicated that the MWCNTs were well dissolved and coated by the GO. Investigations of the piezoresistive properties of the hybrid nanocomposite material under mechanical load show a linear trend between the electrical resistance and the applied strain. A relatively high gauge factor of 8.5 is reached compared to the commercial metallic strain gauges. The self-assembled hybrid films exhibit outstanding properties in electric conductivity, mechanical strength, and strain sensitivity, which provide a high potential for use in strain-sensing applications. PMID- 26732279 TI - Collective agency and the concept of 'public' in public involvement: A practice oriented analysis. AB - BACKGROUND: Public involvement activities are promoted as measures for ensuring good governance in challenging fields, such as biomedical research and innovation. Proponents of public involvement activities include individual researchers as well as non-governmental and governmental organizations. However, the concept of 'public' in public involvement deserves more attention by researchers because it is not purely theoretical: it has important practical functions in the guidance, evaluation and translation of public involvement activities. DISCUSSION: This article focuses on collective agency as one property a public as a small group of participants in a public involvement activity could exhibit. It introduces a prominent theoretical approach to collective agents as one specific kind of social entities and demonstrates how this approach can be applied to current practice in public involvement activities. A brief discussion of different types of representation as they are used in the existing literature on this topic is also included because representation and collective agency can be closely related to each other. Suggestions and ideas that are derived from this reasoning include the proposal to use a 'validity check' for the generation of collective agents as a regular element of certain types of public involvement activities, the consequences of combining collective agency and representativeness as a further property a public could exhibit, and standards for reporting the content of public involvement activities in scientific publications. This article discusses the importance of the concept of 'public' in public involvement activities, with a focus on biomedical research and innovation. It introduces various practically relevant ideas that are based on a theoretical analysis of collective agency as an important property a public can possess. PMID- 26732278 TI - Harpagophytum Procumbens Ethyl Acetate Fraction Reduces Fluphenazine-Induced Vacuous Chewing Movements and Oxidative Stress in Rat Brain. AB - Long-term treatment with fluphenazine is associated with manifestation of extrapyramidal side effects, such as tardive dyskinesia. The molecular mechanisms related to the pathophysiology of TD remain unclear, and several hypotheses, including a role for oxidative stress, have been proposed. Harpagophytum procumbens is an herbal medicine used mainly due to anti-inflammatory effects, but it also exhibits antioxidant effects. We investigated the effect of ethyl acetate fraction of H. procumbens (EAF HP) in fluphenazine-induced orofacial dyskinesia by evaluating behavioral parameters at different times (vacuous chewing movements (VCM's) and locomotor and exploratory activity), biochemical serological analyses, and biochemical markers of oxidative stress of the liver, kidney, cortex, and striatum. Chronic administration of fluphenazine (25 mg/kg, intramuscular (i.m) significantly increased the VCMs at all analyzed times (2, 7, 14, and 21 days), and this was inhibited by EAF HP (especially at a dose of 30 mg/kg). Fluphenazine decreased locomotion and exploratory activity, and EAF HP did not improve this decrease. Fluphenazine induced oxidative damage, as identified by changes in catalase activity and ROS levels in the cortex and striatum, which was reduced by EAF HP, especially in the striatum. In the cortex, EAF HP was protective against fluphenazine-induced changes in catalase activity but not against the increase in ROS level. Furthermore, EAF HP was shown to be safe, since affected serum biochemical parameters or parameters of oxidative stress in the liver and kidney. These findings suggest that the H. procumbens is a promising therapeutic agent for the treatment of involuntary oral movements. PMID- 26732280 TI - A microfluidic platform enabling single-cell RNA-seq of multigenerational lineages. AB - We introduce a microfluidic platform that enables off-chip single-cell RNA-seq after multi-generational lineage tracking under controlled culture conditions. We use this platform to generate whole-transcriptome profiles of primary, activated murine CD8+ T-cell and lymphocytic leukemia cell line lineages. Here we report that both cell types have greater intra- than inter-lineage transcriptional similarity. For CD8+ T-cells, genes with functional annotation relating to lymphocyte differentiation and function--including Granzyme B--are enriched among the genes that demonstrate greater intra-lineage expression level similarity. Analysis of gene expression covariance with matched measurements of time since division reveals cell type-specific transcriptional signatures that correspond with cell cycle progression. We believe that the ability to directly measure the effects of lineage and cell cycle-dependent transcriptional profiles of single cells will be broadly useful to fields where heterogeneous populations of cells display distinct clonal trajectories, including immunology, cancer, and developmental biology. PMID- 26732282 TI - Exposure to hypobaric hypoxia results in higher oxidative stress compared to normobaric hypoxia. AB - Sixteen healthy exercise trained participants underwent the following three, 10-h exposures in a randomized manner: (1) Hypobaric hypoxia (HH; 3450m terrestrial altitude) (2) Normobaric hypoxia (NH; 3450m simulated altitude) and (3) Normobaric normoxia (NN). Plasma oxidative stress (malondialdehyde, MDA; advanced oxidation protein products, AOPP) and antioxidant markers (superoxide dismutase, SOD; glutathione peroxidase, GPX; catalase; ferric reducing antioxidant power, FRAP) were measured before and after each exposure. MDA was significantly higher after HH compared to NN condition (+24%). SOD and GPX activities were increased (vs. before; +29% and +54%) while FRAP was decreased (vs. before; -34%) only after 10h of HH. AOPP significantly increased after 10h for NH (vs. before; +83%), and HH (vs. before; +99%) whereas it remained stable in NN. These results provide evidence that prooxidant/antioxidant balance was impaired to a greater degree following acute exposure to terrestrial (HH) vs. simulated altitude (NH) and that the chamber confinement (NN) did likely not explain these differences. PMID- 26732281 TI - Sustained high prevalence of viral hepatitis and sexually transmissible infections among female sex workers in China: a systematic review and meta analysis. AB - BACKGROUND: The 1980's economic boom has been associated with a rapid expansion of China's sex industry over the past three decades. Consequently, the spread of sexually transmitted infections (STIs) and hepatitis infections among female sex workers (FSW) has become an important public health issue in China. This study identifies prevalence and risks of hepatitis and STIs in Chinese FSWs. METHOD: Four electronic databases were searched for Chinese and English language peer reviewed studies conducted between 01/2000-12/2011 that reported prevalence of hepatitis and STIs (excluding HIV) among Chinese FSW. Following the PRISMA guidelines, meta-analysis was used to estimate pooled prevalence and 95% confidence intervals for each infection. RESULT: Three hundred and thirty nine articles (34 in English and 305 in Chinese) investigating 603,647 FSWs in 29 Chinese provinces were included in this review. Over the period 2000-2011, the seroprevalence of active hepatitis B and hepatitis C among FSW were 10.7% (7.3 15.5%) and 1.0% (0.7-1.3%), respectively. The most prevalent STI was human papillomavirus (HPV, 27.0% [10.1-55.1%]), followed by herpes simplex virus-2 (HSV 2, 15.8% [11.7-20.9%]), chlamydia (13.7% [12.1-15.4%]), gonorrhoea (6.1% [5.3 7.0%]), syphilis (5.2% [4.8-5.7%]), genital warts (3.3% [2.5-4.2%]) and Trichomonas vaginitis (2.1% [1.5-24.2%]). Disease burden of both hepatitis and STI among FSW were concentrated in South Central and Southwest China. In particular, chlamydia and syphilis demonstrated a significant declining trend during the studied period (P < 0.05). Compared with the general Chinese population, FSW had significantly higher prevalence of all STIs except Trichomonas vaginitis. Further, compared to the general FSW population, HIV positive FSW had significantly higher prevalence of syphilis, chlamydia, HSV-2 and Trichomonas vaginitis. CONCLUSION: Prevalence of hepatitis and STIs remained high and mostly stable among Chinese FSW over the period of 2000-2011. Targeted STI and hepatitis surveillance and interventions should be strengthened among Chinese FSWs, especially those who are HIV-positive. PMID- 26732283 TI - Inflammatory myofibroblastic tumors in children. AB - BACKGROUND: Inflammatory myofibroblastic tumor (IMFT) is an uncommon neoplasm in children. METHODS: Retrospective review from 1993 to 2014 of patients <=18years of age with a histopathologic diagnosis of IMFT treated at two tertiary centers. RESULTS: Thirty-two patients were diagnosed with IMFT. Mean (+/-SD) age was 9.3+/ 5.7years at diagnosis. Tumor location was variable: abdomen/pelvis (28%), head/neck region (22%), intrathoracic (22%), genitourinary (9%), bowel (6%) liver (6%), and musculoskeletal (6%). Median follow-up was 2.6+/-4.6years, with 3 recurrences and 2 deaths, which occurred only after recurrence. Positive microscopic margin after resection was associated with recurrence, compared to those that had a negative margin (40% vs. 0%, p=0.04). Recurrence was associated with increased mortality (67% vs 0%, p=0.01). Time from first symptoms to resection was shorter in those with recurrence (25.8+/-22 vs. 179+/-275days, p=0.01) and in nonsurvivors (44.0+/-8.0 vs. 194.3+/-53.4days, p=0.02). Adjuvant chemotherapy, not including steroid monotherapy, either given before or after resection, was administered more often to nonsurvivors (100% vs 4%, p=0.009), and use of corticosteroids was also higher in the nonsurvivors (100% vs. 15%, p=0.04). CONCLUSIONS: IMFT is a rare pediatric neoplasm with variable locations. Complete excision is critical for cure. Proposed guidelines for diagnosis, treatment and surveillance of theses tumors in children are reported. PMID- 26732284 TI - Stereotactic radiosurgery for deep intracranial arteriovenous malformations, part 2: Basal ganglia and thalamus arteriovenous malformations. AB - The aim of this review is to critically analyze the outcomes following stereotactic radiosurgery (SRS) for arteriovenous malformations (AVM) of the basal ganglia and thalamus. The management of these deep-seated lesions continues to challenge neurosurgeons. Basal ganglia and thalamic AVM show a higher risk of hemorrhage, and an associated devastating morbidity and mortality, as compared to AVM in more superficial locations. Any of the currently available treatment modalities may fail or result in iatrogenic neurologic deterioration. Recent evidence from A Randomized Trial of Unruptured Brain AVM (ARUBA) further deters aggressive approaches that carry a significant risk of treatment-related adverse events. Microsurgical resection, endovascular embolization and SRS all play a role in the treatment of AVM. SRS is an effective therapeutic option for AVM of the thalamus and basal ganglia that are deemed high risk for resection. SRS offers acceptable obliteration rates, with generally lower risks of hemorrhage occurring during the latency period compared to the AVM natural history. Considering that incompletely obliterated lesions still harbor the potential for rupture, additional treatments such as repeat SRS and microsurgical resection should be considered when complete obliteration is not achieved by an initial SRS procedure. Patients with AVM of the basal ganglia and thalamus require continued clinical and radiologic observation and follow-up after SRS, even after angiographic obliteration has been confirmed. PMID- 26732285 TI - Anaplastic hemangiopericytoma in the frontal horn of the lateral ventricle. AB - Intracranial hemangiopericytomas are uncommon tumors, and their intraventricular occurrence is even rarer. We report a 40-year-old man who presented with raised intracranial pressure. His MRI showed a 3.3 * 3.2 * 3.2 cm heterogeneously enhancing lesion in the left frontal horn obstructing the foramen of Monro and causing hydrocephalus. The tumor was excised through an anterior interhemispheric, transcallosal approach, and histopathology revealed an anaplastic hemangiopericytoma (World Health Organization grade III). To our knowledge this is the first report of this rare pathology being located within the frontal horn of the lateral ventricle. PMID- 26732286 TI - Enhanced expression of soluble human papillomavirus L1 through coexpression of molecular chaperonin in Escherichia coli. AB - The major recombinant capsid protein L1 of human papillomavirus (HPV) is widely used to produce HPV prophylactic vaccines. However, the quality of soluble and active expression of L1 in Escherichia coli was below the required amount. Coexpression with the chaperonin GroEL/ES enhanced L1 expression. Overexpressing GroEL/ES increased the soluble expression level of glutathione S-transferase fused L1 (GST-L1) by approximately ~3 fold. The yield of HPV type 16 L1 pentamer (L1-p) was ~2 fold higher than that in a single expression system after purification through size-exclusion chromatograph. The expression and purification conditions were then optimized. The yield of L1-p was enhanced by ~5 fold, and those of HPV types 18 and 58 L1-p increased by ~3 and ~2 folds, respectively, compared with that in the single expression system. Coexpressing the mono-site mutant HPV16 L1 L469A with GroEL/ES increased L1-p yield by ~7 fold compared with strains expressing the wild-type L1 gene. L1-p was then characterized using circular dichroism spectra, UV-vis cloud point, dynamic light scattering and transmission electron microscope analyses. Results indicated that the conformation and biological characteristics of L1-p were identical to that of native L1. Hence, overexpressing chaperonin in E. coli can increase the expression level of GST-L1 and L1-p production after purification. This finding may contribute to the development of a platform for prophylactic HPV vaccines. PMID- 26732287 TI - Magnetization switching by combining electric field and spin-transfer torque effects in a perpendicular magnetic tunnel junction. AB - Effective manipulation of magnetization orientation driven by electric field in a perpendicularly magnetized tunnel junction introduces technologically relevant possibility for developing low power magnetic memories. However, the bipolar orientation characteristic of toggle-like magnetization switching possesses intrinsic difficulties for practical applications. By including both the in-plane (T//) and field-like (T?) spin-transfer torque terms in the Landau-Lifshitz Gilbert simulation, reliable and deterministic magnetization reversal can be achieved at a significantly reduced current density of 5*10(9) A/m(2) under the co-action of electric field and spin-polarized current, provided that the electric-field pulse duration exceeds a certain critical value tauc. The required critical tauc decreases with the increase of T? strength because stronger T? can make the finally stabilized out-of-plane component of magnetization stay in a larger negative value. The power consumption for such kind of deterministic magnetization switching is found to be two orders of magnitude lower than that of the switching driven by current only. PMID- 26732288 TI - Mass-gathering Events: The Role of Advanced Nurse Practitioners in Reducing Referrals to Local Health Care Agencies. AB - Introduction: The introduction of advanced practitioner roles has challenged the traditional boundaries of health care. While studies have been undertaken to understand the role of physicians in respect of mass-gathering medicine, the role of advanced nurse practitioners (ANPs) has not been investigated. Problem Does the presence of an ANP reduce the referral rates of patients presenting for medical care at mass-gathering events to external health care resources? METHODS: A prospective observational study was undertaken to determine whether the presence of an ANP would reduce the patient referral rate to external health care services by first aiders and paramedics working within an event medical team. Patients identified as requiring referral were reviewed by an ANP as part of the on-site medical provision for four mass-gathering events in the south of England. Additionally, information was gathered identifying which patients would have been transported to hospital by ambulance compared to those actually transported following ANP review. Statistical analysis was undertaken for three key measures (referrals to all local health resources, referrals to hospital-based acute services, and transfers to hospital by ambulance). RESULTS: A rounded total of 842,000 people attended four mass-gathering events held over 14 days. Of these, 652 presented for medical care, many self-referring. Using a one-tailed Fisher's Exact Test and Phi analysis, this study demonstrated statistically significant reductions in the overall referral of patients to all external health care resources (P<.001; phi=0.44), to the emergency department (ED; P<.001; phi=0.43), and a reduction in ambulance transport (P<.001; phi=0.42). Effect size analysis demonstrated a medium-sized effect evident for all of the above, which was also demonstrated in economic terms. The event medical team would have referred 105 (16.3%) of the 652 patient presentations to external health care services; 47 (7.2%) would have been transported by ambulance. In comparison, the ANP referred 23 patients (3.5%) with 11 (1.7%) being transported by ambulance. It also was noted that the first aiders and paramedics could be more selective in their referral habits that were focused primarily on the ED. CONCLUSIONS: Appropriately trained and experienced ANPs working within event medical teams have a positive impact on referral rates from mass-gathering events. PMID- 26732290 TI - Corrigendum: Identification of novel alleles of the rice blast resistance gene Pi54. PMID- 26732289 TI - Ocular and cutaneous manifestation of leptospirosis acquired in Albania: A retrospective analysis with implications for travel medicine. AB - Albania is an attractive tourism destination with an increasing volume of travel. As a Mediterranean country some tropical infectious diseases are present in certain areas of Albania, including leptospirosis, which is a zoonotic infectious disease prevalent around the world. The goal of this retrospective study is to describe the ocular and cutaneous manifestations of leptospirosis in Albanian patients and raise awareness to travelers travelling in and out of the country. METHODS: We retrospectively studied 107 cases of leptospirosis, treated at "Mother Teresa" University Hospital Center, in Tirana, Albania between January 2009 and December 2014. All cases included in the analysis had a clinical and epidemiological presentation suggestive of leptospirosis, confirmed with ELISA (enzyme linked immunoassay) positive for IgM antibodies against Leptospira. RESULTS: There were 89.7% males (n = 96) and 10.2% females (n = 11). Mean age at the time of diagnoses was 43.7 +/- 17.8 years old (range 17-78). All patients were native and residents of Albania. Conjunctival suffusion was present in 81.3% of the cases, whereas subconjunctival hemorrhage was seen in 12 patients (11.2%). Uveitis was seen in 38.3% of the cases and all patients with uveitis presented a severe systemic disease. A cutaneous rash was present in 58.8% of patients. Other cutaneous manifestations include jaundice in 62.6% and intense pruritus in 5.6% of cases. CONCLUSIONS: Ocular and cutaneous involvement happens more frequently in patients with Leptospirosis, than it was thought to be. Therefore the clinician should be more careful in his systemic evaluation of the disease. PMID- 26732291 TI - Application of syndromic surveillance on routinely collected cattle reproduction and milk production data for the early detection of outbreaks of Bluetongue and Schmallenberg viruses. AB - This study aimed to evaluate the use of routinely collected reproductive and milk production data for the early detection of emerging vector-borne diseases in cattle in the Netherlands and the Flanders region of Belgium (i.e., the northern part of Belgium). Prospective space-time cluster analyses on residuals from a model on milk production were carried out to detect clusters of reduced milk yield. A CUSUM algorithm was used to detect temporal aberrations in model residuals of reproductive performance models on two indicators of gestation length. The Bluetongue serotype-8 (BTV-8) epidemics of 2006 and 2007 and the Schmallenberg virus (SBV) epidemic of 2011 were used as case studies to evaluate the sensitivity and timeliness of these methods. The methods investigated in this study did not result in a more timely detection of BTV-8 and SBV in the Netherlands and BTV-8 in Belgium given the surveillance systems in place when these viruses emerged. This could be due to (i) the large geographical units used in the analyses (country, region and province level), and (ii) the high level of sensitivity of the surveillance systems in place when these viruses emerged. Nevertheless, it might be worthwhile to use a syndromic surveillance system based on non-specific animal health data in real-time alongside regular surveillance, to increase the sense of urgency and to provide valuable quantitative information for decision makers in the initial phase of an emerging disease outbreak. PMID- 26732292 TI - Transabdominal-pelvic-perineal (TAPP) anterolateral thigh flap: A new reconstructive technique for complex defects following extended abdominoperineal resection. AB - BACKGROUND: Abdominoperineal resection (APR) following radiotherapy is associated with a high rate of perineal wound complications. The anterolateral thigh (ALT) flap, combined with the vastus lateralis (VL) muscle, can cover complex perineal and pelvic anteroposterior defects. This is used for the first time transabdominally through the pelvis and the perineum (TAPP) in the infero posterior directions; this technique has been described and illustrated in this study. METHODS: Among over 90 patients who underwent perineal reconstruction between May 2004 and June 2011, six patients presented high-grade tumours invading perineum, pelvis and sacrum, thereby resulting in a continuous anteroposterior defect. ALT + VL TAPP reconstructions were performed after extended APR and, subsequently, sacrectomy. Patients were examined retrospectively to determine demographics, operative time, complications (general and flap-related), time to complete healing and length of hospital stay. Long term flap coverage, flap volume stability and functional and aesthetic outcomes were assessed. RESULTS: Mean operating time of the reconstruction was 290 min. No deaths occurred. One patient presented partial flap necrosis. Another patient presented a novel wound dehiscence after flap healing, due to secondary skin dissemination of the primary tumour. Following volumetric flap analysis on serial post-operative CT scans, no significant flap atrophy was observed. All flaps fully covered the defects. No late complications such as fistulas or perineal hernias occurred. Donor-site recovery was uneventful with no functional deficits. CONCLUSIONS: The use of the ALT + VL flap transabdominally is an innovative method to reconstruct exceptionally complex perineal and pelvic defects extending up to the lower back. This flap guarantees superior bulk, obliterating all pelvic dead space, with the fascia lata (FL) supporting the pelvic floor. PMID- 26732293 TI - Assessing safety of negative-pressure wound therapy over pedicled muscle flaps: A retrospective review of gastrocnemius muscle flap. AB - The use of negative-pressure wound therapy (NPWT) for management of open wounds and immobilization of split-thickness skin grafts (STSGs) over wounds has been well described. However, there is a concern for potential compromise of flap viability when NPWT is used for skin grafts over pedicled muscle flaps. We have used NPWT to immobilize STSGs in eight patients who underwent a pedicled gastrocnemius muscle flap operation in our department. We applied a negative pressure of -75 mmHg on the muscle flaps for 5 days postoperatively. All wounds healed successfully, with a 97.5 +/- 5.5% mean STSG uptake. No flap necrosis was observed. In our series, the use of NPWT for fixation of STSGs over pedicled gastrocnemius muscle flap was effective and had no negative impact on flap viability. PMID- 26732294 TI - Re: 'Preoperative color Doppler ultrasound assessment in planning of SCIP flaps'. PMID- 26732295 TI - Preoperative color Doppler ultrasonographic examination in the planning of thoracodorsal artery perforator flap with capillary perforators. AB - INTRODUCTION: The thoracodorsal artery perforator flap with capillary perforators (TAPcp) is based on capillary perforators arising from the descending branch of the thoracodorsal artery and can overcome the drawbacks of the conventional TAP flap, which results in anatomical variations due to the presence of a dominant muscle or septocutaneous perforators. We applied color Doppler ultrasonography (US) to preoperatively visualize capillary perforators of the descending branch of thoracodorsal artery to facilitate successful flap elevation. PATIENTS AND METHODS: Using preoperative color Doppler US, we examined seven flaps in seven patients who had undergone reconstruction with TAPcp flaps between January 2014 and April 2015. Capillary perforators with diameters <0.5 mm were identified in the anterior border of the latissimus dorsi (LD) muscle. Perforator courses and their penetration points were marked to guide dissection. RESULTS: All seven TAPcp flaps were successfully harvested without pedicle damage or perfusion disorders. No serious postoperative complications occurred such as total necrosis or absorption of the transferred adipose flap. In all seven cases, capillary perforators and the descending branch of the thoracodorsal artery were found almost exactly where the preoperative color Doppler US was targeted. CONCLUSION: Using the technique described herein, capillary perforators of the descending branch of the thoracodorsal artery are easily visualized, and TAPcp flaps can be easily used for various kinds of reconstruction. Moreover, this technique is quick and safe to administer. PMID- 26732296 TI - Clock genes-dependent acetylation of complex I sets rhythmic activity of mitochondrial OxPhos. AB - Physiology of living beings show circadian rhythms entrained by a central timekeeper present in the hypothalamic suprachiasmatic nuclei. Nevertheless, virtually all peripheral tissues hold autonomous molecular oscillators constituted essentially by circuits of gene expression that are organized in negative and positive feed-back loops. Accumulating evidence reveals that cell metabolism is rhythmically controlled by cell-intrinsic molecular clocks and the specific pathways involved are being elucidated. Here, we show that in vitro synchronized cultured cells exhibit BMAL1-dependent oscillation in mitochondrial respiratory activity, which occurs irrespective of the cell type tested, the protocol of synchronization used and the carbon source in the medium. We demonstrate that the rhythmic respiratory activity is associated to oscillation in cellular NAD content and clock-genes-dependent expression of NAMPT and Sirtuins 1/3 and is traceable back to the reversible acetylation of a single subunit of the mitochondrial respiratory chain Complex I. Our findings provide evidence for a new interlocked transcriptional-enzymatic feedback loop controlling the molecular interplay between cellular bioenergetics and the molecular clockwork. PMID- 26732297 TI - Direct non transcriptional role of NF-Y in DNA replication. AB - NF-Y is a heterotrimeric transcription factor, which plays a pioneer role in the transcriptional control of promoters containing the CCAAT-box, among which genes involved in cell cycle regulation, apoptosis and DNA damage response. The knock down of the sequence-specific subunit NF-YA triggers defects in S-phase progression, which lead to apoptotic cell death. Here, we report that NF-Y has a critical function in DNA replication progression, independent from its transcriptional activity. NF-YA colocalizes with early DNA replication factories, its depletion affects the loading of replisome proteins to DNA, among which Cdc45, and delays the passage from early to middle-late S phase. Molecular combing experiments are consistent with a role for NF-Y in the control of fork progression. Finally, we unambiguously demonstrate a direct non-transcriptional role of NF-Y in the overall efficiency of DNA replication, specifically in the DNA elongation process, using a Xenopus cell-free system. Our findings broaden the activity of NF-Y on a DNA metabolism other than transcription, supporting the existence of specific TFs required for proper and efficient DNA replication. PMID- 26732298 TI - Both diet and gene mutation induced obesity affect oocyte quality in mice. AB - Obesity was shown to cause reproductive dysfunctions such as reduced conception, infertility and early pregnancy loss. However, the possible effects of obesity on oocyte quality are still not fully understood. In this study we investigated the effects of both diet and gene mutation induced obesity on impairments in mouse oocyte polarization, oxidative stress, and epigenetic modifications. Our results showed that high-fat diet induced obesity (HFD) and gene mutation induced obesity (ob/ob) could both impair oocyte meiotic maturation, disrupt spindle morphology, and reduce oocyte polarity. Oocytes from obese mice underwent oxidative stress, as shown by high DHE and ROS levels. Abnormal mitochondrial distributions and structures were observed in oocytes from obese groups of mice and early apoptosis signals were detected, which suggesting that oxidative stress had impaired mitochondrial function and resulted in oocyte apoptosis. Our results also showed that 5 mC levels and H3K9 and H3K27 methylation levels were altered in oocytes from obese mice, which indicated that DNA methylation and histone methylation had been affected. Our results showed that both HFD and ob/ob induced obesity affected oocyte maturation and that oxidative stress-induced early apoptosis and altered epigenetic modifications may be the reasons for reduced oocyte quality in obese mice. PMID- 26732300 TI - Recent advancement on micro-/nano-spherical lens photolithography based on monolayer colloidal crystals. AB - Highly ordered nanostructures have gained substantial interest in the research community due to their fascinating properties and wide applications.Micro-/nano spherical lens photolithography (SLPL) has been recognized as an inexpensive, inherently parallel, and high-throughput approach to the creation of highly ordered nanostructures. SLPL based on monolayer colloidal crystals (MCCs) of self assembled colloidal micro-/nano-spheres have recently made remarkable progress in overcoming the constraints of conventional photolithography in terms of cost, feature size, tunability, and pattern complexity. In this review, we highlight the current state-of-the-art in this field with an emphasis on the fabrication of a variety of highly ordered nanostructures based on this technique and their demonstrated applications in light emitting diodes, nano-patterning semiconductors, and localized surface plasmon resonance devices. Finally, we present a perspective on the future development of MCC-based SLPL technique, including a discussion on the improvement of the quality of MCCs and the compatibility of this technique with other semiconductor micromachining process for nanofabrication. PMID- 26732301 TI - Erratum to 'The periodicity of Plasmodium vivax and Plasmodium falciparum in Venezuela'. PMID- 26732302 TI - Ossifying fibromyxoid tumor: morphology, genetics, and differential diagnosis. AB - Ossifying fibromyxoid tumor (OFMT) is a soft tissue neoplasm of uncertain differentiation and intermediate (rarely metastasizing) biologic potential, with typical morphologic features, of an encapsulated, lobulated tumor comprising uniform polygonal cells within fibromyxoid stroma, which is surrounded by or contains metaplastic bone, classically as a peripheral rim of lamellar bone. Ossifying fibromyxoid tumor can arise at almost any site, although most frequently occurs within the extremities and trunk. Although most behave in a benign fashion, tumors can rarely show atypical or malignant features. It is now established that OFMTs represent translocation-associated tumors, with up to 85% associated with recurrent gene rearrangements, mostly involving the PHF1 gene (including in typical, atypical, and malignant neoplasms), with EP400-PHF1 in approximately 40% of tumors, and ZC3H7B-BCOR, MEAF6-PHF1, and EPC1-PHF1 fusions also described. Correct diagnosis is clinically important to ensure correct treatment and prognostication, both to avoid overdiagnosing OFMT as a malignant neoplasm such as osteosarcoma and also because of the propensity for aggressive behavior in a small number of OFMT. We review OFMT, with emphasis on the morphologic spectrum, recent molecular genetic findings, and the differential diagnosis. PMID- 26732303 TI - Mg(++) requirement for MtHK binding, and Mg(++) stabilization of mitochondrial membranes via activation of MtHK & MtCK and promotion of mitochondrial permeability transition pore closure: A hypothesis on mechanisms underlying Mg(++)'s antioxidant and cytoprotective effects. AB - Evidence points to magnesium's antioxidant, anti-necrotic, and anti-apoptotic effects in cardio- and neuroprotection. With magnesium being involved in over 300 biochemical reactions, the mechanisms underlying its cytoprotective and antioxidant effects have remained elusive. The profound anti-apoptotic, anabolic, and antioxidant effects of mitochondrion bound hexokinase (MtHk), and the anti apoptotic, anti-necrotic, and antioxidant functions of mitochondrial creatine kinase (MtCK) have been established over the past few decades. As powerful regulators of the mitochondrial permeability transition pore (PTP), MtHK and MtCK promote anti-apoptosis and anti-necrosis by stabilizing mitochondrial outer and inner membranes. In this article, it is proposed that magnesium is essentially and directly involved in mitochondrial membrane stabilization via (i) Mg(++) ion requirement for the binding of mitochondrial hexokinase (ii) Mg(++)'s allosteric activation of mitochondrial bound hexokinase, and stimulation of mitochondrial bound creatine kinase activities, and (iii) Mg(++) inhibition of PTP opening by Ca(++) ions. These effects of Mg(++) ions are indirectly supplanted by the stimulatory effect of magnesium on the Akt kinase survival pathway. The "Magnesium/Calcium Yin Yang Hypothesis" proposes here that because of the antagonistic effects of Ca(++) and Mg(++) ions in the presence of high Ca(++) ion concentration at MtHK, MtCK, and PTP, magnesium supplementation may provide cytoprotective effects in the treatment of some degenerative diseases and cytopathies with high intracellular [Ca(++)]/ [Mg(++)] ratio at these sites, whether of genetic, developmental, drug induced, ischemic, immune based, toxic, or infectious etiology. PMID- 26732304 TI - Traffic lights: putting a stop to unsafe patient transfers. AB - Poor handover between doctors is a recognised cause of error in hospitals.[1] Watford General Hospital is a busy acute trust in southern England, where high admission rates necessitate timely patient transfers from the acute admissions unit (AAU) to the medical wards. We found that doctors were infrequently informed of patient transfers, and they rarely handed over patient care when a patient was moved. Our aim was to minimise preventable harm to patients by prompting handover of clinically unstable patients, and patients with outstanding investigations or referrals, at the time of transfer. We introduced a traffic light tool to categorise patients on the medical take as red, amber, or green according to their clinical status at time of admission to AAU. The traffic light colour, which was assigned both on paper and electronically, was designed to prompt a verbal handover between doctors at the time of patient transfer from AAU. PMID- 26732305 TI - Pulsed field magnetization in rare-earth kagome systems. AB - The rare-earth kagome systems R 3Ga5SiO14 (R = Nd or Pr) exhibit cooperative paramagnetism at low temperatures. Evidence for correlated spin clusters in these weakly frustrated systems has previously been obtained from neutron scattering and from ESR and NMR results. The present pulsed field (0-60 T, 25 ms) magnetization measurements made on single crystals of Nd3Ga5SiO14 (NGS) and Pr3Ga5SiO14 (PGS) at temperatures down to 450 mK have revealed striking differences in the magnetic responses of the two materials. For NGS the magnetization shows a low field plateau, saturation in high transient fields, and significant hysteresis while the PGS magnetization does not saturate in transient fields up to 60 T and shows no hysteresis or plateaus. Nd(3+) is a Kramers ion while Pr(3+) is a non-Kramers ion and the crystal field effects are quite different in the two systems. For the conditions used in the experiments the magnetization behavior is not in agreement with Heisenberg model predictions for kagome systems in which easy-axis anisotropy is much larger than the exchange coupling. The extremely slow spin dynamics found below 4 K in NGS is, however, consistent with the model for Kramers ions and provides a basis for explaining the pulsed field magnetization features. PMID- 26732306 TI - Lithium-Boron (Li-B) Monolayers: First-Principles Cluster Expansion and Possible Two-Dimensional Superconductivity. AB - Recent works demonstrated that the superconductivity at two-dimensional (2-D) can be achieved in Li-decorated graphene (Nature Phys. 2012, 8, 131 and Proc. Natl. Acad. Sci. 2015, 112, 11795). Inspired by the progress made in graphene, we predict by using the first-principles calculations that Li-incorporated B monolayers (Li-B monolayers) can be alternative 2-D superconductors. First principles cluster expansion approach was used to evaluate the structural diversity and energetic stability of the 2-D Li-B monolayers by treating them as ternary Lix?yB1-x-y pseudoalloys (? refers to B hexagonal hole). After thoroughly exploring the Li-B configuration space, several well-ordered and stable Li-B monolayers were identified. Detailed analyses regarding the electronic structures and lattice dynamics properties of the predicted Li-B monolayers were performed. Compared with the non-superconducting pure B-sheet, some predicted Li-B monolayers can exhibit the phonon-mediated superconducting properties above the liquid helium temperature. PMID- 26732307 TI - Electroacupuncture relieves labour pain and influences the spinal dynorphin/kappa opioid receptor system in rats. AB - BACKGROUND: The dynorphin (DYN)/kappa-opioid receptor (KOR) system plays a key role in the control of labour pain. Our previous clinical study reported that electroacupuncture (EA) provided intrapartum analgesia, but the underlying mechanisms of action have not been fully elucidated. AIMS: To observe the effect of EA on labour pain and to explore the underlying mechanisms of action in a rat model. METHODS: Copulation-confirmed pregnant rats (n=120) were given castor oil to induce labour. Rats remained untreated (control group, n=20) or received either meperidine (an opioid that is commonly used to treat labour pain, n=20) or EA at SP6, LI4, SP6+LI4 or SP10 (four groups, n=20 each). Labour pain was evaluated by the warm water tail-flick test. Serum DYN values were measured by ELISA. Protein and mRNA expression of prodynorphin (PDYN, the precursor protein of DYN) and KOR were analysed by Western blotting and real-time PCR, respectively. RESULTS: EA treatment at all acupuncture point combinations studied significantly relieved labour pain and increased serum DYN concentrations, to a degree similar to that achieved with meperidine. EA notably enhanced protein expression of KOR and PDYN and mRNA expression in the lumbar spinal cord but not in the cerebral cortex. The size of effect varied by EA group in the order: SP6>LI4>SP6+LI4>SP10 for all parameters measured, indicating differential effects relating to acupuncture point selection/combination. CONCLUSIONS: The present study indicates that EA relieves labour pain, at least in part, by regulation of the spinal DYN/KOR system in a rat model. PMID- 26732308 TI - Determining the drift potential of Venturi nozzles compared with standard nozzles across three insecticide spray solutions in a wind tunnel. AB - BACKGROUND: Previous research has sought to adopt the use of drift-reducing technologies (DRTs) for use in field trials to control diamondback moth (DBM) Plutella xylostella (L.) (Lepidoptera: Plutellidae) in canola (Brassica napus L.). Previous studies observed no difference in canopy penetration from fine to coarse sprays, but the coverage was higher for fine sprays. DBM has a strong propensity to avoid sprayed plant material, putting further pressure on selecting technologies that maximise coverage, but often this is at the expense of a greater drift potential. This study aims to examine the addition of a DRT oil that is labelled for control of DBM as well and its effect on the drift potential of the spray solution. The objectives of the study are to quantify the droplet size spectrum and spray drift potential of each nozzle type to select technologies that reduce spray drift, to examine the effect of the insecticide tank mix at both (50 and 100 L ha(-1) ) application rates on droplet size and spray drift potential across tested nozzle type and to compare the droplet size results of each nozzle by tank mix against the drift potential of each nozzle. RESULTS: The nozzle type affected the drift potential the most, but the spray solution also affected drift potential. The fine spray quality (TCP) resulted in the greatest drift potential (7.2%), whereas the coarse spray quality (AIXR) resulted in the lowest (1.3%), across all spray solutions. The spray solutions mixed at the 100 L ha(-1) application volume rate resulted in a higher drift potential than the same products mixed at the 50 L ha(-1) mix rate. The addition of the paraffinic DRT oil was significant in reducing the drift potential of Bacillus thuringiensis var. kurstkai (Bt)-only treatments across all tested nozzle types. The reduction in drift potential from the fine spray quality to the coarse spray quality was up to 85%. CONCLUSION: The addition of a DRT oil is an effective way to reduce the spray solution drift potential across all nozzle types and tank mixes evaluated in this study. The greatest reduction in drift potential can be achieved by changing nozzle type, which can reduce the losses of the spray to the surrounding environment. Venturi nozzles greatly reduce the drift potential compared with standard nozzles by as much as 85% across all three insecticide spray solutions. Results suggest that a significant reduction in drift potential can be achieved by changing the nozzle type, and can be achieved without a loss in control of DBM. (c) 2016 Society of Chemical Industry. PMID- 26732310 TI - Online solid-phase extraction with high-performance liquid chromatography and mass spectrometry for the determination of five tannins in traditional Chinese medicine injections. AB - A rapid analytical method based on online solid-phase extraction with high performance liquid chromatography and mass spectrometry has been established and applied to the determination of tannin compounds that may cause adverse effects in traditional Chinese medicine injections. Different solid-phase extraction sorbents have been compared and the elution buffer was optimized. The performance of the method was verified by evaluation of recovery (>=40%), repeatability (RSD <= 6%), linearity (r(2) >= 0.993), and limit of quantification (<=0.35 MUg/mL). Five tannin compounds, gallic acid, cianidanol, gallocatechin gallate, ellagic acid, and penta-O-galloylglucose, were identified with concentrations ranging from 3.1-37.4 MUg/mL in the analyzed traditional Chinese medicine injections. PMID- 26732311 TI - Retraction. PMID- 26732309 TI - Modeling leukocyte trafficking at the human blood-nerve barrier in vitro and in vivo geared towards targeted molecular therapies for peripheral neuroinflammation. AB - Peripheral neuroinflammation is characterized by hematogenous mononuclear leukocyte infiltration into peripheral nerves. Despite significant clinical knowledge, advancements in molecular biology and progress in developing specific drugs for inflammatory disorders such as rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis, there are currently no specific therapies that modulate pathogenic peripheral nerve inflammation. Modeling leukocyte trafficking at the blood-nerve barrier using a reliable human in vitro model and potential intravital microscopy techniques in representative animal models guided by human observational data should facilitate the targeted modulation of the complex inflammatory cascade needed to develop safe and efficacious therapeutics for immune-mediated neuropathies and chronic neuropathic pain. PMID- 26732312 TI - Transition-metal catalyzed valorization of lignin: the key to a sustainable carbon-neutral future. AB - The development of a sustainable, carbon-neutral biorefinery has emerged as a prominent scientific and engineering goal of the 21st century. As petroleum has become less accessible, biomass-based carbon sources have been investigated for utility in fuel production and commodity chemical manufacturing. One underutilized biomaterial is lignin; however, its highly crosslinked and randomly polymerized composition have rendered this biopolymer recalcitrant to existing chemical processing. More recently, insight into lignin's molecular structure has reinvigorated chemists to develop catalytic methods for lignin depolymerization. This review examines the development of transition-metal catalyzed reactions and the insights shared between the homogeneous and heterogeneous catalytic systems towards the ultimate goal of valorizing lignin to produce value-added products. PMID- 26732313 TI - Romidepsin in relapsed/refractory T-cell lymphomas: Italian experience and results of a named patient program. AB - Clinical trial results indicate that romidepsin, a histone deacetylase inhibitor, is a promising treatment in relapsed/refractory T-cell lymphomas (TCLs). This retrospective multicenter study was conducted in patients with relapsed/refractory TCL treated with romidepsin monotherapy through a Named Patient Program (NPP) in Italy. Principal endpoints were overall response rate (ORR), safety, and overall survival (OS). The ORR in 33 evaluable patients was 24.2% with an ORR in the cutaneous TCL of 35.7%. Global OS was 39.3% at 30 months. There were not any specific differences on hematological and extrahematological adverse events. Data from patients treated with romidepsin outside a controlled clinical trial give additional information about the clinical use, efficacy, and toxicity of the drug given to relapsed or refractory TCL patients in a real life context as TCLs are rare diseases and more information is needed. These findings suggest that romidepsin is effective and safe for heavily pretreated TCL patients. PMID- 26732314 TI - Progress in defining clinically meaningful changes for clinical trials in nonrenal manifestations of SLE disease activity. AB - Since the 2002 Dusseldorf meeting, one new agent, Benlysta, has been approved by the US Food and Drug Administration for systemic lupus erythematosus. Experiences from the field in conducting trials of all the agents tested during this period have provided valuable practical insights. There has been incremental progress in defining the minimal clinically important difference (MCID) of key disease manifestations and the view is largely that of the health care providers and not that of the person suffering the disease. This basic methodological work on the MCID should improve the efficiency and the clinical relevance of future trials and their design. PMID- 26732315 TI - Does Increased Spending on Pharmaceutical Marketing Inhibit Pioneering Innovation? AB - The pharmaceutical industry has been criticized for developing and aggressively marketing drugs that do not provide significant health benefits relative to existing drugs but retain the benefits of patent protection. Critics argue that drug marketing increases health care expenditures and provides a disincentive for pioneering drug innovation. However, evidence that marketing expenditures have any relationship to new drug approvals has been anecdotal. We hypothesized that, at publicly traded pharmaceutical firms, increased marketing expenditures will result in a reduced volume of pioneering new drugs in comparison to less innovative new drugs. We also hypothesized that additional research and development spending will result in an increased volume of pioneering new drugs in comparison to less innovative drugs. Results confirm our hypotheses. Specific policy recommendations for altering firms' incentives for the development of pioneering drugs are provided. PMID- 26732316 TI - Business Associations, Conservative Networks, and the Ongoing Republican War over Medicaid Expansion. AB - A major component of the Affordable Care Act involves the expansion of state Medicaid programs to cover the uninsured poor. In the wake of the 2012 Supreme Court decision upholding and modifying reform legislation, states can decide whether to expand Medicaid-and twenty states are still not proceeding as of August 2015. What explains state choices about participation in expansion, including governors' decisions to endorse expansion or not as well as final state decisions? We tackle this puzzle, focusing closely on outcomes and battles in predominantly Republican-led states. Like earlier scholars, we find that partisan differences between Democrats and Republicans are central, but we go beyond earlier analyses to measure added effects from two dueling factions within the Republican coalition: statewide business associations and cross-state networks of ideologically conservative organizations. Using both statistical modeling and case studies, we show that GOP-leaning or GOP-dominated states have been most likely to embrace the expansion when organized business support outweighs pressures from conservative networks. Our findings help make sense of ongoing state-level debates over a core part of health reform and shed new light on mounting policy tensions within the Republican Party. PMID- 26732317 TI - Medicaid Contradictions: Adding, Subtracting, and Redeterminations in Illinois. AB - States are required to conduct annual Medicaid redeterminations. How these redeterminations are undertaken is crucial to determining the nature of Medicaid coverage. There can be wide variations in the proportion of clients disenrolled, with potentially large numbers of people disenrolled each year. This case study of Illinois Medicaid shows how, as the Affordable Care Act added people, redeterminations were taking people off the rolls-about 25 percent of all Medicaid clients were disenrolled in one year. Many of these people were no longer eligible, but it appears that a larger number were in fact eligible but simply failed to comply with administrative requirements in a timely way. Balancing between the two imperatives of program integrity and continuity of care is a difficult act for Medicaid programs. The Illinois experience also illustrates impacts on information technology and outsourcing of eligibility functions, not to mention budget considerations. PMID- 26732318 TI - Iowa Wavering on Medicaid: From Expansion to Modernization. AB - Iowa is one of six states to expand Medicaid through section 1115 waivers. Iowa's alternative approach to Medicaid expansion, known as the Iowa Health and Wellness Plan, was the result of a bipartisan compromise, motivated by the pending expiration of a preexisting section 1115 waiver that served sixty-five thousand Iowans. The Iowa Health and Wellness Plan emphasizes personal responsibility and private involvement. Key features include beneficiary premiums, incentives for healthy behaviors, and premium assistance for some beneficiaries to purchase insurance in the health insurance marketplace. However, Iowa has struggled to implement its expansion as initially envisioned, due largely to the lack of private insurers willing and able to insure new Medicaid enrollees in the marketplace. In 2016 Iowa will dramatically increase the role of managed care in Medicaid, with the vast majority of beneficiaries receiving almost all Medicaid services through a capitated managed care organization. This article highlights the local factors driving expansion, the interplay of the state and federal political landscape, the challenges of providing consumer choice within Iowa's marketplace, and the future of Iowa's Medicaid program under managed care. PMID- 26732319 TI - Informed or Misinformed Consent? Abortion Policy in the United States. AB - Since 2010, the United States has witnessed a dramatic expansion of state-based restrictions on abortion. The most common of these are informed consent statutes, which require that a woman seeking an abortion receive a state-authored informational packet before the abortion procedure can be performed. These laws, in addition to requiring the provision of information about alternatives to and risks of abortion, all also require details of embryological and fetal development. This article presents the findings of a comprehensive study of state authored informed consent materials regarding embryological and fetal development. To conduct this study, we recruited a panel of experts in human anatomy to assess the accuracy of these materials in the context of the constitutional standard established inPlanned Parenthood of Southeastern Pennsylvania et al. v. Robert P. Casey et al.(505 U.S. 833 (1992)): that such information must be "truthful" and "nonmisleading." We find that nearly one-third of the informed consent information is medically inaccurate, that inaccurate information is concentrated primarily in the earlier weeks of pregnancy and is clustered around particular body systems. We discuss the implications of our findings for the question of the constitutionality of informed consent laws as they have been implemented in practice. PMID- 26732320 TI - Measuring Medicaid Physician Participation Rates and Implications for Policy. AB - Policy makers continue to debate Medicaid expansion under the Affordable Care Act, and concerns remain about low provider participation in the program. However, there has been little research on how various measures of physician participation may reflect different elements of capacity for care within the Medicaid program and how these distinct measures correlate with one another across states. Our objectives were to describe several alternative measures of provider participation in Medicaid using recently publicly available data, to compare state rankings across these different metrics, and to discuss potential advantages and disadvantages of each measure for research and policy purposes. Overall, we find that Medicaid participation as measured by raw percentages of physicians taking new Medicaid patients is only weakly correlated with population based measures that account for both participation rates and the numbers of physicians per capita or physicians per Medicaid beneficiary. Participation rates for all physicians versus primary care physicians also offer different information about state-level provider capacity. Policy makers should consider multiple dimensions of provider access in assessing policy options in Medicaid, and further research is needed to evaluate the linkages between these provider based measures and beneficiaries' perceptions of access to care in the program. PMID- 26732321 TI - Histopathology of breast cancer after magnetic resonance-guided high-intensity focused ultrasound and radiofrequency ablation. AB - AIMS: Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablation and radiofrequency ablation (RFA) are being researched as possible substitutes for surgery in breast cancer patients. The histopathological appearance of ablated tissue has not been studied in great detail. This study aimed to compare histopathological features of breast cancer after MR-HIFU ablation and RFA. METHODS AND RESULTS: MR-HIFU ablation and RFA were performed in and ex-vivo. Tumours in six mastectomy specimens were partially ablated with RFA or MR-HIFU. In-vivo MR-HIFU ablation was performed 3-6 days before excision; RFA was performed in the operation room. Tissue was fixed in formalin and processed to haematoxylin and eosin (H&E) and cytokeratin-8 (CK-8)-stained slides. Morphology and cell viability were assessed. Ex-vivo ablation resulted in clear morphological changes after RFA versus subtle differences after MR-HIFU. CK-8 staining was decreased or absent. H&E tended to underestimate the size of thermal damage. In-vivo MR-HIFU resulted in necrotic-like changes. Surprisingly, some ablated lesions were CK-8-positive. Histopathology after in-vivo RFA resembled ex vivo RFA, with hyper-eosinophilic stroma and elongated nuclei. Lesion borders were sharp after MR-HIFU and indistinct after RFA. CONCLUSION: Histopathological differences between MR-HIFU-ablated tissue and RF-ablated tissue were demonstrated. CK-8 was more reliable for cell viability assessment than H&E when used directly after ablation, while H&E was more reliable in ablated tissue left in situ for a few days. Our results contribute to improved understanding of histopathological features in breast cancer lesions treated with minimally invasive ablative techniques. PMID- 26732322 TI - Physiological Roles of Adipokines, Hepatokines, and Myokines in Ruminants. AB - Since the discovery of leptin secreted from adipocytes, specialized tissues and cells have been found that secrete the several peptides (or cytokines) that are characterized to negatively and positively regulate the metabolic process. Different types of adipokines, hepatokines, and myokines, which act as cytokines, are secreted from adipose, liver, and muscle tissue, respectively, and have been identified and examined for their physiological roles in humans and disease in animal models. Recently, various studies of these cytokines have been conducted in ruminants, including dairy cattle, beef cattle, sheep, and goat. Interestingly, a few cytokines from these tissues in ruminants play an important role in the post-parturition, lactation, and fattening (marbling) periods. Thus, understanding these hormones is important for improving nutritional management in dairy cows and beef cattle. However, to our knowledge, there have been no reviews of the characteristics of these cytokines in beef and dairy products in ruminants. In particular, lipid and glucose metabolism in adipose tissue, liver tissue, and muscle tissue are very important for energy storage, production, and synthesis, which are regulated by these cytokines in ruminant production. In this review, we summarize the physiological roles of adipokines, hepatokines, and myokines in ruminants. This discussion provides a foundation for understanding the role of cytokines in animal production of ruminants. PMID- 26732323 TI - Intestinal Alkaline Phosphatase: Potential Roles in Promoting Gut Health in Weanling Piglets and Its Modulation by Feed Additives - A Review. AB - The intestinal environment plays a critical role in maintaining swine health. Many factors such as diet, microbiota, and host intestinal immune response influence the intestinal environment. Intestinal alkaline phosphatase (IAP) is an important apical brush border enzyme that is influenced by these factors. IAP dephosphorylates bacterial lipopolysaccharides (LPS), unmethylated cytosine guanosine dinucleotides, and flagellin, reducing bacterial toxicity and consequently regulating toll-like receptors (TLRs) activation and inflammation. It also desphosphorylates extracellular nucleotides such as uridine diphosphate and adenosine triphosphate, consequently reducing inflammation, modulating, and preserving the homeostasis of the intestinal microbiota. The apical localization of IAP on the epithelial surface reveals its role on LPS (from luminal bacteria) detoxification. As the expression of IAP is reported to be downregulated in piglets at weaning, LPS from commensal and pathogenic gram-negative bacteria could increase inflammatory processes by TLR-4 activation, increasing diarrhea events during this phase. Although some studies had reported potential IAP roles to promote gut health, investigations about exogenous IAP effects or feed additives modulating IAP expression and activity yet are necessary. However, we discussed in this paper that the critical assessment reported can suggest that exogenous IAP or feed additives that could increase its expression could show beneficial effects to reduce diarrhea events during the post weaning phase. Therefore, the main goals of this review are to discuss IAP's role in intestinal inflammatory processes and present feed additives used as growth promoters that may modulate IAP expression and activity to promote gut health in piglets. PMID- 26732324 TI - Identification of Single Nucleotide Polymorphism Marker and Association Analysis of Marbling Score in Fas Gene of Hanwoo. AB - The Fas (APO-1, TNFRSF6) gene known as a member of the tumor necrosis factor receptor superfamily was selected for DNA marker development in Korean cattle. It is a cell membrane protein and mediates programmed cell death (apoptosis). We discovered single nucleotide polymorphisms (SNPs) within Fas gene in order to develop novel DNA markers related to economical traits at the genomic level. The sequences of whole exon and 1 kb range of both front and back of the gene were determined by direct-sequencing methods using 24 cattle. A total of 55 SNPs were discovered and we selected 31 common polymorphic sites considering their allele frequencies, haplotype-tagging status and linkage disequilibrium (LD) for genotyping in larger-scale subjects. The SNPs were confirmed genotype through the SNaPshot method (n = 274) and were examined for a possible genetic association between Fas polymorphisms and marbling score. So, the SNPs that were identified significant are g.30256G>C, g.31474C>A, g.31940A>G, and g.32982G>A. These results suggest that SNPs of Fas gene were associated with intramuscular fat content of meat quality traits in Korean cattle. PMID- 26732325 TI - Association between Single Nucleotide Polymorphisms of the Major Histocompatibility Complex Class II Gene and Newcastle Disease Virus Titre and Body Weight in Leung Hang Khao Chickens. AB - The aim of the present study was to investigate the effect of single nucleotide polymorphisms in the major histocompatibility complex (MHC) class II gene on resistance to Newcastle disease virus and body weight of the Thai indigenous chicken, Leung Hang Khao (Gallus gallus domesticus). Blood samples were collected for single nucleotide polymorphism analysis from 485 chickens. Polymerase chain reaction sequencing was used to classify single nucleotide polymorphisms of class II MHC. Body weights were measured at the ages of 3, 4, 5, and 7 months. Titres of Newcastle disease virus at 2 weeks to 7 months were determined and the correlation between body weight and titre was analysed. The association between single nucleotide polymorphisms and body weight and titre were analysed by a generalized linear model. Seven single nucleotide polymorphisms were identified: C125T, A126T, C209G, C242T, A243T, C244T, and A254T. Significant correlations between log titre and body weight were found at 2 and 4 weeks. Associations between single nucleotide polymorphisms and titre were found for C209G and A254T, and between all single nucleotide polymorphisms (except A243T) and body weight. The results showed that class II MHC is associated with both titre of Newcastle disease virus and body weight in Leung Hang Khao chickens. This is of concern because improved growth traits are the main goal of breeding selection. Moreover, the results suggested that MHC has a pleiotropic effect on the titre and growth performance. This mechanism should be investigated in a future study. PMID- 26732326 TI - The Prediction of the Expected Current Selection Coefficient of Single Nucleotide Polymorphism Associated with Holstein Milk Yield, Fat and Protein Contents. AB - Milk-related traits (milk yield, fat and protein) have been crucial to selection of Holstein. It is essential to find the current selection trends of Holstein. Despite this, uncovering the current trends of selection have been ignored in previous studies. We suggest a new formula to detect the current selection trends based on single nucleotide polymorphisms (SNP). This suggestion is based on the best linear unbiased prediction (BLUP) and the Fisher's fundamental theorem of natural selection both of which are trait-dependent. Fisher's theorem links the additive genetic variance to the selection coefficient. For Holstein milk production traits, we estimated the additive genetic variance using SNP effect from BLUP and selection coefficients based on genetic variance to search highly selective SNPs. Through these processes, we identified significantly selective SNPs. The number of genes containing highly selective SNPs with p-value <0.01 (nearly top 1% SNPs) in all traits and p-value <0.001 (nearly top 0.1%) in any traits was 14. They are phosphodiesterase 4B (PDE4B), serine/threonine kinase 40 (STK40), collagen, type XI, alpha 1 (COL11A1), ephrin-A1 (EFNA1), netrin 4 (NTN4), neuron specific gene family member 1 (NSG1), estrogen receptor 1 (ESR1), neurexin 3 (NRXN3), spectrin, beta, non-erythrocytic 1 (SPTBN1), ADP-ribosylation factor interacting protein 1 (ARFIP1), mutL homolog 1 (MLH1), transmembrane channel-like 7 (TMC7), carboxypeptidase X, member 2 (CPXM2) and ADAM metallopeptidase domain 12 (ADAM12). These genes may be important for future artificial selection trends. Also, we found that the SNP effect predicted from BLUP was the key factor to determine the expected current selection coefficient of SNP. Under Hardy-Weinberg equilibrium of SNP markers in current generation, the selection coefficient is equivalent to 2*SNP effect. PMID- 26732327 TI - Variance Component Quantitative Trait Locus Analysis for Body Weight Traits in Purebred Korean Native Chicken. AB - Quantitative trait locus (QTL) is a particular region of the genome containing one or more genes associated with economically important quantitative traits. This study was conducted to identify QTL regions for body weight and growth traits in purebred Korean native chicken (KNC). F1 samples (n = 595) were genotyped using 127 microsatellite markers and 8 single nucleotide polymorphisms that covered 2,616.1 centi Morgan (cM) of map length for 26 autosomal linkage groups. Body weight traits were measured every 2 weeks from hatch to 20 weeks of age. Weight of half carcass was also collected together with growth rate. A multipoint variance component linkage approach was used to identify QTLs for the body weight traits. Two significant QTLs for growth were identified on chicken chromosome 3 (GGA3) for growth 16 to18 weeks (logarithm of the odds [LOD] = 3.24, Nominal p value = 0.0001) and GGA4 for growth 6 to 8 weeks (LOD = 2.88, Nominal p value = 0.0003). Additionally, one significant QTL and three suggestive QTLs were detected for body weight traits in KNC; significant QTL for body weight at 4 weeks (LOD = 2.52, nominal p value = 0.0007) and suggestive QTL for 8 weeks (LOD = 1.96, Nominal p value = 0.0027) were detected on GGA4; QTLs were also detected for two different body weight traits: body weight at 16 weeks on GGA3 and body weight at 18 weeks on GGA19. Additionally, two suggestive QTLs for carcass weight were detected at 0 and 70 cM on GGA19. In conclusion, the current study identified several significant and suggestive QTLs that affect growth related traits in a unique resource pedigree in purebred KNC. This information will contribute to improving the body weight traits in native chicken breeds, especially for the Asian native chicken breeds. PMID- 26732328 TI - Nutritional Characteristics of Forage Grown in South of Benin. AB - In order to provide recommendations on the most useful forage species to smallholder farmers, eleven grass and eleven legume forages grown in Abomey Calavi in Republic of Benin were investigated for nutritive value (i.e. chemical composition and energy content) and fermentation characteristics (i.e. gas and volatile fatty acid production, organic matter degradability). The in vitro gas production technique was used, incubating the forages for 120 h under anaerobic condition with buffalo rumen fluid. Compared to legume, tropical grass forages showed lower energy (8.07 vs 10.57 MJ/kg dry matter [DM]) and crude protein level (16.10% vs 19.91% DM) and higher cell wall content (neutral detergent fiber: 63.8% vs 40.45% DM), respectively. In grass forages, the chemical composition showed a quite high crude protein content; the in vitro degradability was slightly lower than the range of tropical pasture. The woody legumes were richer in protein and energy and lower in structural carbohydrates than herbaceous plants, however, their in vitro results are influenced by the presence of complex compounds (i.e. tannins). Significant correlations were found between chemical composition and in vitro fermentation characteristics. The in vitro gas production method appears to be a suitable technique for the evaluation of the nutritive value of forages in developing countries. PMID- 26732329 TI - Dynamics Associated with Prolonged Ensiling and Aerobic Deterioration of Total Mixed Ration Silage Containing Whole Crop Corn. AB - This study investigated the dynamics associated with prolonged ensiling and aerobic deterioration of whole crop corn (WCC) silages and total mixed ration (TMR) silages containing WCC (C-TMR silages) to clarify the differences that account for the enhanced aerobic stability of TMR silages. Laboratory-scale barrel silos were randomly opened after 7, 14, 28, and 56 d of ensiling and were subjected to analyses of fermentation quality, microbial and temperature dynamics during aerobic exposure. WCC and C-TMR silages were both well preserved and microorganisms were inhibited with prolonged ensiling, including lactic acid bacteria. Yeast were inhibited to below the detection limit of 500 cfu/g fresh matter within 28 d of ensiling. Aerobic stability of both silages was enhanced with prolonged ensiling, whereas C-TMR silages were more aerobically stable than WCC silages for the same ensiling period. Besides the high moisture content, the weak aerobic stability of WCC silage is likely attributable to the higher lactic acid content and yeast count, which result from the high water-soluble carbohydrates content in WCC. After silo opening, yeast were the first to propagate and the increase in yeast levels is greater than that of other microorganisms in silages before deterioration. Besides, increased levels of aerobic bacteria were also detected before heating of WCC silages. The temperature dynamics also indicated that yeast are closely associated with the onset of the aerobic deterioration of C-TMR silage, whereas for WCC silages, besides yeast, aerobic bacteria also function in the aerobic deterioration. Therefore, the inclusion of WCC might contribute to the survival of yeast during ensiling but not influence the role of yeast in deterioration of C-TMR silages. PMID- 26732330 TI - Effect of Fodder Tree Species with Condensed Tannin Contents on In vitro Methane Production. AB - The objective was to evaluate the effect of fodder tree species (FTS) with condensed tannin contents: Cordia elaeagnoides, Platymiscium lasiocarpum, Vitex mollis, and Haematoxylon brasiletto, on in vitro methane (CH4) production at 24 h post incubation. The analysis was performed using the in vitro gas production technique, with three levels of inclusion/species: 600, 800, and 1,000 mg and with 4 replicates/species/level of inclusion. The substrate was incubated at 39 degrees C, and the gas and CH4 production were recorded at 4, 8, 12, and 24 h post incubation. The data collected was analyzed through Pearson correlation, polinomial regression and fixed effects models. There were negative correlations between FTS-total gas volume (r = -0.40; p<0.001); FTS-volume of CH4 produced (r = -0.40; p<0.001) and between the inclusion level-volume of CH4 produced (r = 0.20; p<0.001). As well as a positive correlation between hours post incubation total gas volume (r = 0.42; p<0.001) and between hours post incubation-volume of CH4 produced (r = 0.48; p<0.001). The FTS: C. elaeagnoides, V. mollis, and H. brasiletto have potential, in the three inclusion levels analyzed, to reduce CH4 emission on in vitro trials (>32.7%), taking into account the total CH4 production at 24 h of the forage used as reference (Avena sativa). It's suggested that C. elaeagnoides-according to its crude protein, neutral detergent fiber, and condensed tannins content- is the best alternative within the FTS analyzed, for feeding ruminants and for the control of CH4 emissions during the dry season. PMID- 26732331 TI - Effects of Elevated Crude Glycerin Concentrations on Feedlot Performance and Carcass Characteristics in Finishing Steers. AB - Twenty crossbred steers (400+/-40.1 kg of initial body weight) were used to assess the effects of a dietary supplementation with crude glycerin (CG) as a substitute for corn grain on performance, carcass traits, and meat quality. Four isocaloric and isonitrogenous diets were offered to the experimental animals (5 steers per treatment) for 121 days using randomized complete block design. The steers individually received dietary treatments containing 0%, 7%, 14%, and 21% of CG (88.91% pure) on a dry matter (DM) basis. The diets were offered ad libitum as total mixed rations twice daily. Weight gain and carcass traits were determined. At the end of the experimental period, the harvest data and carcass characteristics of the steers were recorded, and meat quality was determined. No significant effect of CG inclusion was observed in any of the growth performance and carcass characteristics traits studied. Also, there were no apparent effects of diets (p>0.05) on meat quality (pH, water holding capacity, drip losses, and cooking losses). The study concluded that CG could be used as a substitute for corn grain up to the level of approximately 21% of DM in the diets of finishing steers. PMID- 26732332 TI - The Differences in Chemical Composition, Physical Quality Traits and Nutritional Values of Horse Meat as Affected by Various Retail Cut Types. AB - The effects of retail cut type on chemical, quality and nutritional characteristics of horse meat were studied. Jeju female breed horses (n = 9) at 32-mo-old were slaughtered and the carcasses at 24 h post-mortem were fabricated into 10 retail cuts including: tender-loin, loin, strip-loin, shoulder-chuck roll, shoulder-clod, top-round, outside-round, brisket, short-plate-brisket, and shank. The results revealed that all of parameters (chemical, meat quality and nutritional composition) examined significantly (p<0.05) differed between the cuts. The chemical composition range (minimum to maximum) of cuts was found as such: moisture 65.06% to 71.69%; protein 19.07% to 21.28%; collagen 1.40% to 2.45%; fat 2.56% to 12.14% and cholesterol 55.76 to 79.50 mg/100 g. Shoulder chuck-roll had the highest pH and water-holding capacity, while top-round had the highest cooking loss. Shear force ranged between the cuts from 2.80 kg/cm(2) to 4.98 kg/cm(2). The Cu, Fe, and Zn contents ranged between the cuts from 1.52 mg/kg to 2.75 mg/kg, 21.25 mg/kg to 30.85 mg/kg, and 16.51 mg/kg to 40.42 mg/kg, respectively. Additionally, most of the cuts studied showed favorable polyunsaturated fatty acid/saturated fatty acid, n-3/n-6 and essential amino acid/non-essential amino acid ratios. PMID- 26732333 TI - Consumer Attitudes Toward Storing and Thawing Chicken and Effects of the Common Thawing Practices on Some Quality Characteristics of Frozen Chicken. AB - In this study, a survey was conducted to both evaluate the consumers' general attitudes for purchasing and storing the raw chicken and determine the thawing practices used for defrosting frozen chicken at home. About 75% of the consumers indicated purchasing chicken meat at least once a week or more. Furthermore, the majority (82.16%) of those who stored at least a portion of the raw chicken stated freezing the raw chicken meat at home. Freezing the chicken meat was considered to have no effect on the quality by 43.49% of the consumers while 56.51% thought that freezing had either negative or positive effects on the quality. The survey study indicated that top five most commonly used thawing practices included thawing on the kitchen counter, thawing in the refrigerator, thawing in the warm water, thawing in the microwave, and thawing under tap water. In addition, an experimental study was conducted to determine the effects of these most commonly used thawing practices on some quality characteristics of the chicken meat including pH, drip loss, cooking loss, color analysis and textural profile analysis. Although, L* value for thawing on the kitchen counter was the lowest, after cooking, none of the thawing treatments have a significant effect on the color values. Thawing in the microwave produced the highest drip loss of 3.47% while the lowest drip loss of 0.62% was observed with thawing in the refrigerator. On the other hand, thawing in the microwave and refrigerator caused the lowest cooking loss values of 18.29% and 18.53%, respectively. Nevertheless, there were no significant differences among textural parameter values of the defrosted and then cooked samples using the home based thawing practices, indicating similar quality characteristics among the samples. PMID- 26732334 TI - Ethanol Extracts from Mistletoe (Viscum album L.) Act as Natural Antioxidants and Antimicrobial Agents in Uncooked Pork Patties during Refrigerated Storage. AB - The antioxidant potential of mistletoe (Viscum album L. var. coloratum Ohwi; VAL) extract in uncooked pork patties was evaluated. Three concentrations of VAL extract (0.1 [T1], 0.5% [T2] and 1.0% [T3]) along with 0.02% ascorbic acid as a positive control (V) were added to ground pork and pork patties were prepared. Incorporation of VAL extract decreased (p<0.05) the pH of the pork patties throughout the storage time and reduced (p<0.01) the thiobarbituric acid reactive substance values after day 14 of storage. Total plate counts of the VAL extract treated samples and V-treated samples were also significantly lower (p<0.01) than that of the control (C) throughout the storage period. In addition, odor scores of the VAL extract-treated patties were lower than those of the C- or V-treated samples on 3rd day of the storage period. These results demonstrated that the VAL extract acts as a natural antioxidant in uncooked pork products. PMID- 26732335 TI - Effect of Fat Level and the Ripening Time on Quality Traits of Fermented Sausages. AB - The objective of this study was to investigate the effect of the fat reduction on the physicochemical and microbiological characteristics of fermented sausages during ripening and drying. Low fat fermented sausages were produced with different fat levels (30%, 20%, 10%, and 5%) under ripening conditions and fermented process. Samples from each treatment were taken for physicochemical and microbiological analyses on the 0, 1, 2, 3, 4, 5, 7, 10, 14, and 21st day of ripening. In proximate analysis, the fat reduction in sausages produced an increase in moisture, protein and ash contents during ripening and drying (p<0.05). The weight losses were significantly higher in high fat formulations during the first 4 days, whereas those were higher in low fat ones after 10 days of storage (p<0.05). Fat reduction was responsible for an increase in shear force values after 3 days of storage. The volatile basic nitrogen (VBN) value of the low fat samples was significantly higher (p<0.05). Low fat sausages reduced the extent of lipid oxidation. The lower fat level produced redder sausages. Total plate bacteria and Pseudomonas counts of sausages showed no significant differences. Production of low fat sausages resulted in the physicochemical and microbiological attributes equal to or better than the high fat sausages without negative effects, except only a higher VBN and weight loss. PMID- 26732336 TI - Cloning and Characterization of an Endoglucanase Gene from Actinomyces sp. Korean Native Goat 40. AB - A gene from Actinomyces sp. Korean native goat (KNG) 40 that encodes an endo-beta 1,4-glucanase, EG1, was cloned and expressed in Escherichia coli (E. coli) DH5alpha. Recombinant plasmid DNA from a positive clone with a 3.2 kb insert hydrolyzing carboxyl methyl-cellulose (CMC) was designated as pDS3. The entire nucleotide sequence was determined, and an open-reading frame (ORF) was deduced. The ORF encodes a polypeptide of 684 amino acids. The recombinant EG1 produced in E. coli DH5alpha harboring pDS3 was purified in one step using affinity chromatography on crystalline cellulose and characterized. Sodium dodecyl sulfate polyacrylamide gel electrophoresis/zymogram analysis of the purified enzyme revealed two protein bands of 57.1 and 54.1 kDa. The amino terminal sequences of these two bands matched those of the deduced ones, starting from residue 166 and 208, respectively. Putative signal sequences, a Shine-Dalgarno-type ribosomal binding site, and promoter sequences related to the consensus sequences were deduced. EG1 has a typical tripartite structure of cellulase, a catalytic domain, a serine-rich linker region, and a cellulose-binding domain. The optimal temperature for the activity of the purified enzyme was 55 degrees C, but it retained over 90% of maximum activity in a broad temperature range (40 degrees C to 60 degrees C). The optimal pH for the enzyme activity was 6.0. Kinetic parameters, Km and Vmax of rEG1 were 0.39% CMC and 143 U/mg, respectively. PMID- 26732337 TI - Effect of Polysaccharides from Acanthopanax senticosus on Intestinal Mucosal Barrier of Escherichia coli Lipopolysaccharide Challenged Mice. AB - To investigate the role of polysaccharide from Acanthopanax senticosus (ASPS) in preventing lipopolysaccharide (LPS)-induced intestinal injury, 18 mice (at 5 wk of age) were assigned to three groups with 6 replicates of one mouse each. Mice were administrated by oral gavage with or without ASPS (300 mg/kg body weight) for 14 days and were injected with saline or LPS at 15 days. Intestinal samples were collected at 4 h post-challenge. The results showed that ASPS ameliorated LPS-induced deterioration of digestive ability of LPS-challenged mice, indicated by an increase in intestinal lactase activity (45%, p<0.05), and the intestinal morphology, as proved by improved villus height (20.84%, p<0.05) and villus height:crypt depth ratio (42%, p<0.05), and lower crypt depth in jejunum (15.55%, p<0.05), as well as enhanced intestinal tight junction proteins expression involving occludin-1 (71.43%, p<0.05). ASPS also prevented intestinal inflammation response, supported by decrease in intestinal inflammatory mediators including tumor necrosis factor alpha (22.28%, p<0.05) and heat shock protein (HSP70) (77.42%, p<0.05). In addition, intestinal mucus layers were also improved by ASPS, as indicated by the increase in number of goblet cells (24.89%, p<0.05) and intestinal trefoil peptide (17.75%, p<0.05). Finally, ASPS facilitated mRNA expression of epidermal growth factor (100%, p<0.05) and its receptor (200%, p<0.05) gene. These results indicate that ASPS can prevent intestinal mucosal barrier injury under inflammatory conditions, which may be associated with up regulating gene mRNA expression of epidermal growth factor and its receptor. PMID- 26732338 TI - Effects of Gestational Housing on Reproductive Performance and Behavior of Sows with Different Backfat Thickness. AB - The present study investigated the effects of back-fat thickness at d 107 of gestation and housing types during gestation on reproductive performance and behavior of sows. A total of 64 crossbred sows (Landrace*Yorkshire) in their 3 to 4 parities were allotted to one of four treatments (n = 16) over two consecutive parities. During each parity, sows were assigned to two gestational housing types (stall or group housing) and two level of back-fat thickness (<20 or >=20) at d 107 of gestation. Gestating sows were transferred from gestational crates to stalls or pens (group housing) 5 weeks before farrowing. All sows were moved to farrowing crates on d 109 of gestation. At weaning, back-fat thickness changes were lesser (p<0.05) in sows having back-fat thickness <20 mm than that of sows with >=20 mm back-fat thickness at 107 d of gestation. Group housed sows had greater (p<0.05) feed intake and shorter (p<0.05) weaning-to-estrus interval than that of sows in stalls. At weaning, back-fat thickness changes were lesser (p<0.05) in group housed sows than that of sows in stalls. The number of piglets at weaning, growth rate and average daily gain were greater (p<0.05) in group housed sows than that of sows in stalls. During gestation, walking duration was more (p<0.05) in group housed sows. Group housed sows had lesser (p<0.05) farrowing duration and greater (p<0.05) eating time than that of sows in stalls. Result obtained in present study indicated that sows with >=20 mm back-fat thickness at 107 days had better reproductive performance. Additionally, group housing of sows during last five week of gestation improved the performance and behavior and reproductive efficiency of sows. PMID- 26732339 TI - Monitoring Activity for Recognition of Illness in Experimentally Infected Weaned Piglets Using Received Signal Strength Indication ZigBee-based Wireless Acceleration Sensor. AB - In this experiment, we proposed and implemented a disease forecasting system using a received signal strength indication ZigBee-based wireless network with a 3-axis acceleration sensor to detect illness at an early stage by monitoring movement of experimentally infected weaned piglets. Twenty seven piglets were divided into control, Salmonella enteritidis (SE) infection, and Escherichia coli (EC) infection group, and their movements were monitored for five days using wireless sensor nodes on their backs. Data generated showed the 3-axis movement of piglets (X-axis: left and right direction, Y-axis: anteroposterior direction, and Z-axis: up and down direction) at five different time periods. Piglets in both infected groups had lower weight gain and feed intake, as well as higher feed conversion ratios than the control group (p<0.05). Infection with SE and EC resulted in reduced body temperature of the piglets at day 2, 4, and 5 (p<0.05). The early morning X-axis movement did not differ between groups; however, the Y axis movement was higher in the EC group (day 1 and 2), and the Z-axis movement was higher in the EC (day 1) and SE group (day 4) during different experimental periods (p<0.05). The morning X and Y-axis movement did not differ between treatment groups. However, the Z-axis movement was higher in both infected groups at day 1 and lower at day 4 compared to the control (p<0.05). The midday X-axis movement was significantly lower in both infected groups (day 4 and 5) compared to the control (p<0.05), whereas the Y-axis movement did not differ. The Z-axis movement was highest in the SE group at day 1 and 2 and lower at day 4 and 5 (p<0.05). Evening X-axis movement was highest in the control group throughout the experimental period. During day 1 and 2, the Z-axis movement was higher in both of the infected groups; whereas it was lower in the SE group during day 3 and 4 (p<0.05). During day 1 and 2, the night X-axis movement was lower and the Z-axis movement was higher in the infected piglets (p<0.05). Overall, the movement of infected piglets was altered, and the acceleration sensor could be successfully employed for monitoring pig activity. PMID- 26732340 TI - Retraction Notice. PMID- 26732341 TI - Poly(1,2,3-triazolium)s: a new class of functional polymer electrolytes. AB - Poly(ionic liquid)s (PILs) are a unique class of polyelectrolytes having properties suited for modern technological applications such as electrochemical devices (batteries, supercapacitors, light-emitting electrochemical cells), ion gated field effect transistors, electrochromic devices, fuel cells, dye sensitized solar cells, catalysis, or soft robotics. Their structure and properties can be finely tuned by unlimited combinations issued from extended pools of cationic and anionic building blocks. In a constant quest for the development of solid polymer electrolytes with enhanced physical, mechanical and (electro)chemical properties, a new class of PILs based on 1,2,3-triazolium cations has been recently developed. Their preparation takes advantage of the beneficial features of the multiple combinations between the Click chemistry philosophy with macromolecular engineering techniques to afford tunable and highly functional ion conducting materials thus stretching out the actual boundaries of PILs macromolecular design. This feature article summarizes the different strategies developed so far for the synthesis of 1,2,3-triazolium-based PILs (TPILs) since their first introduction in 2013. PMID- 26732342 TI - Comparison of Ribosomal RNA Removal Methods for Transcriptome Sequencing Workflows in Teleost Fish. AB - RNA sequencing (RNA-Seq) is becoming the standard for transcriptome analysis. Removal of contaminating ribosomal RNA (rRNA) is a priority in the preparation of libraries suitable for sequencing. These methods have been well documented in mammals but typically require some optimization for lower vertebrates. Three commercial kits, including Dynabeads mRNA Purification Kit, RiboMinus Eukaryote System v2, and Ribo-Zero Gold rRNA Removal Kit were examined for the ability to remove rRNAs from rainbow trout (Oncorhynchus mykiss) RNA isolations. Total RNA was isolated from liver and muscle tissue samples (n = 24) and rRNAs removed using one of the three kits. Samples were analyzed visually on the Agilent Bioanalyzer and by Illumina RNA-seq, screening for Oncorhynchus rRNAs. There were significant differences between the kits in regards to their ability to remove rRNA, ranging from 2.74% - 10.94% rRNA sequences left behind per kit on average. Using the Bioanalyzer to evaluate ribosomal contamination in rRNA-depleted samples for RNA-Seq was good for detecting samples with higher concentrations of rRNA (>5%), but not very accurate at lower levels. Although all three kits were able to remove a substantial portion of the rRNA from different fish tissues, the Ribo-Zero Gold rRNA Removal Kit eliminated significantly more contaminating ribosomal RNAs than the others. PMID- 26732343 TI - Horner syndrome in glandular fever: a case report. AB - OBJECTIVE: This study aimed to present and discuss the case of a patient with known glandular fever who presented with Horner syndrome. CASE REPORT: A 35-year old patient with known glandular fever developed acute unilateral Horner syndrome, a previously undescribed complication of this common illness. Magnetic resonance imaging and magnetic resonance angiography showed that enlarged intra carotid sheath lymphoid tissue was likely to be the underlying cause of sympathetic nerve disruption. The case is described, the anatomy of the sympathetic chain is discussed and possible alternative pathophysiological mechanisms are reviewed. CONCLUSION: This is the first report in the worldwide literature of Horner syndrome arising as a result of compression from enlarged lymph nodes in glandular fever. PMID- 26732344 TI - High-pressure high-temperature phase diagram of organic crystal paracetamol. AB - High-pressure high-temperature (HPHT) Raman spectroscopy studies have been performed on the organic crystal paracetamol in a diamond anvil cell utilizing boron-doped heating diamond anvil. Isobaric measurements were conducted at pressures up to 8.5 GPa and temperature up to 520 K in five different experiments. Solid state phase transitions from monoclinic Form I -> orthorhombic Form II were observed at various pressures and temperatures as well as transitions from Form II -> unknown Form IV. The melting temperature for paracetamol was observed to increase with increasing pressures to 8.5 GPa. This new data is combined with previous ambient temperature high-pressure Raman and x ray diffraction data to create the first HPHT phase diagram of paracetamol. PMID- 26732345 TI - Quetiapine Inhibits Microglial Activation by Neutralizing Abnormal STIM1-Mediated Intercellular Calcium Homeostasis and Promotes Myelin Repair in a Cuprizone Induced Mouse Model of Demyelination. AB - Microglial activation has been considered as a crucial process in the pathogenesis of neuroinflammation and psychiatric disorders. Several antipsychotic drugs (APDs) have been shown to display inhibitory effects on microglial activation in vitro, possibly through the suppression of elevated intracellular calcium (Ca(2+)) concentration. However, the exact underlying mechanisms still remain elusive. In this study, we aimed to investigate the inhibitory effects of quetiapine (Que), an atypical APD, on microglial activation. We utilized a chronic cuprizone (CPZ)-induced demyelination mouse model to determine the direct effect of Que on microglial activation. Our results showed that treatment with Que significantly reduced recruitment and activation of microglia/macrophage in the lesion of corpus callosum and promoted remyelination after CPZ withdrawal. Our in vitro studies also confirmed the direct effect of Que on lipopolysaccharide (LPS)-induced activation of microglial N9 cells, whereby Que significantly inhibited the release of nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha). Moreover, we demonstrated that pretreatment with Que, neutralized the up-regulation of STIM1 induced by LPS and declined both LPS and thapsigargin (Tg)-induced store-operated Ca(2+) entry (SOCE). Finally, we found that pretreatment with Que significantly reduced the translocation of nuclear factor kappa B (NF-kappaB) p65 subunit from cytoplasm to nuclei in LPS-activated primary microglial cells. Overall, our data suggested that Que may inhibit microglial activation by neutralization of the LPS-induced abnormal STIM1-mediated intercellular calcium homeostasis. PMID- 26732346 TI - Constraining future terrestrial carbon cycle projections using observation-based water and carbon flux estimates. AB - The terrestrial biosphere is currently acting as a sink for about a third of the total anthropogenic CO2 emissions. However, the future fate of this sink in the coming decades is very uncertain, as current earth system models (ESMs) simulate diverging responses of the terrestrial carbon cycle to upcoming climate change. Here, we use observation-based constraints of water and carbon fluxes to reduce uncertainties in the projected terrestrial carbon cycle response derived from simulations of ESMs conducted as part of the 5th phase of the Coupled Model Intercomparison Project (CMIP5). We find in the ESMs a clear linear relationship between present-day evapotranspiration (ET) and gross primary productivity (GPP), as well as between these present-day fluxes and projected changes in GPP, thus providing an emergent constraint on projected GPP. Constraining the ESMs based on their ability to simulate present-day ET and GPP leads to a substantial decrease in the projected GPP and to a ca. 50% reduction in the associated model spread in GPP by the end of the century. Given the strong correlation between projected changes in GPP and in NBP in the ESMs, applying the constraints on net biome productivity (NBP) reduces the model spread in the projected land sink by more than 30% by 2100. Moreover, the projected decline in the land sink is at least doubled in the constrained ensembles and the probability that the terrestrial biosphere is turned into a net carbon source by the end of the century is strongly increased. This indicates that the decline in the future land carbon uptake might be stronger than previously thought, which would have important implications for the rate of increase in the atmospheric CO2 concentration and for future climate change. PMID- 26732347 TI - A biofidelic computational model of the female pelvic system to understand effect of bladder fill and progressive vaginal tissue stiffening due to prolapse on anterior vaginal wall. AB - Treatment of anterior vaginal prolapse (AVP), suffered by over 500,000 women in the USA, is a challenge in urogynecology because of the poorly understood mechanics of AVP. Recently, computational modeling combined with finite element method has been used to model AVP through the study of pelvic floor muscle and connective tissue impairments on the anterior vaginal wall (AVW). Also, the effects of pelvic organ displacements on the AVW were studied numerically. In our current work, an MRI-based full-scale biofidelic computational model of the female pelvic system composed of the urinary bladder, vaginal canal, and the uterus was developed, and a novel finite element method framework was employed to simulate vaginal tissue stiffening and also bladder filling due to expansion for the first time. A mesh convergence study was conducted to choose a computationally efficient mesh, and a non-linear hyperelastic Yeoh's material model was adopted for the study. The AVW displacements, mechanical stresses, and strains were estimated at varying degrees of bladder fills and vaginal tissue stiffening. Both bladder filling and vaginal stiffening were found to increase the stress concentration on the AVW with varying trends, which have been discussed in detail in the paper. To our knowledge, this study is the first to estimate the individual and combined effects of bladder filling and vaginal tissue stiffening due to prolapse on the AVW. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26732348 TI - Adult survivors of childhood cancer are at high risk of cardiac abnormalities, study finds. PMID- 26732350 TI - Improving the recording of surgical drain output. AB - Monitoring the output from surgical drains is an important part of post-operative care and is often undertaken poorly. Failure to have accurate documentation of daily outputs may delay the removal of drains and increase the risk of complications. Following discussions with medical and nursing staff we listed eight key criteria that should be routinely monitored for surgical drains. A baseline measurement demonstrated only 20% compliance with these criteria. As such we decided to design a chart, after discussing with the multidisciplinary team, with adequate space to document drain output clearly. Post-intervention data collection showed a reasonable uptake of the chart (70%) with overall criteria compliance increasing to 55%. We made further interventions designed to raise awareness of the chart, which increased chart uptake to 79% and compliance to 63%, leading to the adoption of the chart by the department. Twelve months after introducing the chart we conducted a final data collection which demonstrated the chart was now being used in 100% of patients and that overall criteria compliance had increased to 78%. While some of the key criteria are still not documented for all patients, we have demonstrated that the introduction of a simple and well-designed drain chart can significantly improve the documentation of drain output, thereby improving patient safety and discharge efficiency. PMID- 26732351 TI - Oxidative Coupling of Aryl Boron Reagents with sp(3)-Carbon Nucleophiles: The Enolate Chan-Evans-Lam Reaction. AB - Reported is a versatile new oxidative method for the arylation of activated methylene species. Under mild reaction conditions (RT to 40 degrees C), Cu(OTf)2 mediates the selective coupling of functionalized aryl boron species with a variety of stabilized sp(3) -nucleophiles. Tertiary malonates and amido esters can be employed as substrates to generate quaternary centers. Complementing either traditional cross-coupling or SN Ar protocols, the transformation is chemoselective in the presence of halogen electrophiles, including aryl bromides and iodides. Substrates bearing amide, sulfonyl, and phosphonyl groups, which are not amenable to coupling under mild Hurtley-type conditions, are suitable reaction partners. PMID- 26732349 TI - Factors associated with choice of biologic among children with Juvenile Idiopathic Arthritis: results from two UK paediatric biologic registers. AB - OBJECTIVE: The objectives of this study were to describe patients starting first line biologics for JIA, to describe characteristics over time among patients starting etanercept, and to describe patterns of second biologic prescribing. METHODS: The British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study, and the Biologics for Children with Rheumatic Diseases study are ongoing prospective observational cohorts, collecting data on patients starting biologic therapy for JIA. Patients registered from 1 January 2010 starting their first biologic were compared between therapies. Patients starting etanercept before 2010 were included to analyse changes in etanercept prescribing. The pathway of patients starting a second biologic was recorded in all patients. RESULTS: To 26 August 2014, 931 patients were recruited starting a first-line biologic (142 Biologics for Children with Rheumatic Diseases; 789 British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study). From 2010, patients with systemic JIA (sJIA) were almost exclusively prescribed anakinra or tocilizumab. Choice between anti-TNF therapies was largely driven by history of chronic anterior uveitis (CAU). When investigating trends in patients starting etanercept over time, disease duration at etanercept start, patients with sJIA, a history of CAU, and those who received concomitant oral corticosteroids decreased over time. Patients who started a second biologic from 1 January 2010 showed a similar stratification. CONCLUSION: Although etanercept remains the most common biologic prescribed for JIA, there has been a clear shift towards the use of alternative biologics, largely driven by disease subtype and history of CAU. This channelling of children towards specific therapies should be considered carefully in future studies and in clinical guidelines and ongoing research. PMID- 26732352 TI - Production of interleukins 4 and 10 in children with hepatic involvement in the course of Toxocara spp. infection. AB - Toxocara spp. infestations present with a wide spectrum of symptoms, from general inflammation of internal organs with eosinophilic granuloma formulation through ocular or brain involvement. There is also an asymptomatic form. The known factors that influence the clinical form of the disease are the intensity of the infestation, the localization of the larvae, the age of the patient, the efficiency of the immune system and the history of reinfection. The aim of our study was to evaluate the production of interleukins 4 (IL-4) and 10 (IL-10) in children in the course of Toxocara spp. infections with hepatic involvement. The analysis of peripheral leucocytes, eosinophils, immunoglobulin E, and IL-4 and IL 10 concentrations presented significantly higher values in children with radiologically confirmed liver granuloma than in uncomplicated hepatomegaly. Based on statistical analysis, we confirmed the IL-4/IL-10 ratio variation in the analysed groups: patients with liver lesions showed a ratio of <1, while children without granulomas had a ratio of >2. The relevant analysis confirmed a positive statistical correlation in both seropositive groups for IgE and IL-4, and only in the granuloma group for IgE and IL-10. PMID- 26732353 TI - Construction of a Super-Competent Bacillus subtilis 168 Using the P mtlA -comKS Inducible Cassette. AB - Competence is a physiological state that enables Bacillus subtilis 168 to take up and internalize extracellular DNA. In practice, only a small subpopulation of B. subtilis 168 cells becomes competent when they enter stationary phase. In this study, we developed a new transformation method to improve the transformation efficiency of B. subtilis 168, specially in rich media. At first, different competence genes, namely comK, comS, and dprA, were alone or together integrated into the chromosome of B. subtilis 168 under control of mannitol-inducible P mtlA promoter. Overexpression of both comK and comS increased the transformation efficiency of B. subtilis REG19 with plasmid DNA by 6.7-fold compared to the wild type strain 168. This transformation efficiency reached its maximal level after 1.5 h of induction by mannitol. Besides, transformability of the REG19 cells was saturated in the presence of 100 ng dimeric plasmid or 3000 ng chromosomal DNA. Studying the influence of global regulators on the development of competence pointed out that important competence development factors, such as Spo0A, ComQXPA, and DegU, could be removed in REG19. On the other hand, efficient REG19 transformation remained highly dependent on the original copies of comK and comS regardless of the presence of P mtlA -comKS. Finally, novel plasmid-free strategies were used for transformation of REG19 based on Gibson assembly. PMID- 26732354 TI - Systemic Inflammation in Cachexia - Is Tumor Cytokine Expression Profile the Culprit? AB - Cachexia affects about 80% of gastrointestinal cancer patients. This multifactorial syndrome resulting in involuntary and continuous weight loss is accompanied by systemic inflammation and immune cell infiltration in various tissues. Understanding the interactions among tumor, immune cells, and peripheral tissues could help attenuating systemic inflammation. Therefore, we investigated inflammation in the subcutaneous adipose tissue and in the tumor, in weight stable and cachectic cancer patients with same diagnosis, in order to establish correlations between tumor microenvironment and secretory pattern with adipose tissue and systemic inflammation. Infiltrating monocyte phenotypes of subcutaneous and tumor vascular-stromal fraction were identified by flow cytometry. Gene and protein expression of inflammatory and chemotactic factors was measured with qRT-PCR and Multiplex Magpix((r)) system, respectively. Subcutaneous vascular-stromal fraction exhibited no differences in regard to macrophage subtypes, while in the tumor, the percentage of M2 macrophages was decreased in the cachectic patients, in comparison to weight-stable counterparts. CCL3, CCL4, and IL-1beta expression was higher in the adipose tissue and tumor tissue in the cachectic group. In both tissues, chemotactic factors were positively correlated with IL-1beta. Furthermore, positive correlations were found for the content of chemoattractants and cytokines in the tumor and adipose tissue. The results strongly suggest that the crosstalk between the tumor and peripheral tissues is more pronounced in cachectic patients, compared to weight stable patients with the same tumor diagnosis. PMID- 26732355 TI - Lysyl Oxidase, a Targetable Secreted Molecule Involved in Cancer Metastasis. AB - Secondary metastatic cancer remains the single biggest cause of mortality and morbidity across most solid tumors. In breast cancer, 100% of deaths are attributed to metastasis. At present, there are no "cures" for secondary metastatic cancer of any form and there is an urgent unmet clinical need to improve the tools available in our arsenal against this disease, both in terms of treatment, but also prevention. Recently, we showed that hypoxic induction of the extracellular matrix modifying enzyme lysyl oxidase (LOX) correlates with metastatic dissemination to the bone in estrogen receptor negative breast cancer and is essential for the formation of premetastatic osteolytic lesions. We showed that in models of breast cancer metastasis, targeting LOX, or its downstream effects, significantly inhibited premetastatic niche formation and the resulting metastatic burden, offering preclinical validation of this enzyme as a therapeutic target for metastatic breast cancer. Our work is the latest in an emerging body of work supporting the targeting of LOX and calls for greater efforts in developing therapeutics against this extracellular secreted factor in the prevention of cancer progression across multiple solid tumor types. PMID- 26732356 TI - Recovering Substantive Factor Loadings in the Presence of Acquiescence Bias: A Comparison of Three Approaches. AB - Researchers are often advised to write balanced scales (containing an equal number of positively and negatively worded items) when measuring psychological attributes. This practice is recommended to control for acquiescence bias (ACQ). However, little advice has been given on what to do with such data if the researcher subsequently wants to evaluate a 1-factor model for the scale. This article compares 3 approaches for dealing with the presence of ACQ bias, which make different assumptions: an ipsatization approach based on the work of Chan and Bentler (CB; 1993), a confirmatory factor analysis (CFA) approach that includes an ACQ factor with equal loadings (Billiet & McClendon, 2000; Mirowsky & Ross, 1991), and an exploratory factor analysis (EFA) approach with a target rotation (Ferrando, Lorenzo-Seva, & Chico, 2003). We also examine the "do nothing" approach which fits the 1-factor model to the data ignoring the presence of ACQ bias. Our main findings are that the CFA method performs best overall and that it is robust to the violation of its assumptions, the EFA and the CB approaches work well when their assumptions are strictly met, and the "do nothing" approach can be surprisingly robust when the ACQ factor is not very strong. PMID- 26732357 TI - Theory and Analysis of Total, Direct, and Indirect Causal Effects. AB - Mediation analysis, or more generally models with direct and indirect effects, are commonly used in the behavioral sciences. As we show in our illustrative example, traditional methods of mediation analysis that omit confounding variables can lead to systematically biased direct and indirect effects, even in the context of a randomized experiment. Therefore, several definitions of causal effects in mediation models have been presented in the literature (Baron & Kenny, 1986 ; Imai, Keele, & Tingley, 2010 ; Pearl, 2012 ). We illustrate the stochastic theory of causal effects as an alternative foundation of causal mediation analysis based on probability theory. In this theory we define total, direct, and indirect effects and show how they can be identified in the context of our illustrative example. A particular strength of the stochastic theory of causal effects are the causality conditions that imply causal unbiasedness of effect estimates. The causality conditions have empirically testable implications and can be used for covariate selection. In the discussion, we highlight some similarities and differences of the stochastic theory of causal effects with other theories of causal effects. PMID- 26732358 TI - A Cautious Note on Auxiliary Variables That Can Increase Bias in Missing Data Problems. AB - The treatment of missing data in the social sciences has changed tremendously during the last decade. Modern missing data techniques such as multiple imputation and full-information maximum likelihood are used much more frequently. These methods assume that data are missing at random. One very common approach to increase the likelihood that missing at random is achieved consists of including many covariates as so-called auxiliary variables. These variables are either included based on data considerations or in an inclusive fashion; that is, taking all available auxiliary variables. In this article, we point out that there are some instances in which auxiliary variables exhibit the surprising property of increasing bias in missing data problems. In a series of focused simulation studies, we highlight some situations in which this type of biasing behavior can occur. We briefly discuss possible ways how one can avoid selecting bias-inducing covariates as auxiliary variables. PMID- 26732359 TI - Adjusting Incremental Fit Indices for Nonnormality. AB - A variety of indices are commonly used to assess model fit in structural equation modeling. However, fit indices obtained from the normal theory maximum likelihood fit function are affected by the presence of nonnormality in the data. We present a nonnormality correction for 2 commonly used incremental fit indices, the comparative fit index and the Tucker-Lewis index. This correction uses the Satorra-Bentler scaling constant to modify the sample estimate of these fit indices but does not affect the population value. We argue that this type of nonnormality correction is superior to the correction that changes the population value of the fit index implemented in some software programs. In a simulation study, we demonstrate that our correction performs well across a variety of sample sizes, model types, and misspecification types. PMID- 26732360 TI - Quantile Mediation Models: A Comparison of Methods for Assessing Mediation Across the Outcome Distribution. AB - Recent introduction of quantile regression methods to analysis of epidemiologic data suggests that traditional mean regression approaches may not suffice for some health outcomes such as Body Mass Index (BMI). In the same vein, the traditional mean-based approach to mediation modeling may not be sufficient to capture the potentially different mediating effects of behavioral interventions across the outcome distribution. By combining methods for estimating conditional quantiles with traditional mediation modeling techniques, mediation effects can be estimated for any quantile of the outcome distribution (so-called quantile mediation effects). Estimation and inference techniques for quantile mediation effects are compared through simulation studies, and recommendations are given. The quantile mediation methods are further compared with the traditional mean based regression approaches to mediation analysis through analysis of data from Healthy Places, a trial that is examining the effects of the community-built environment on resident obesity risk. We found the magnitudes of indirect (mediating) effects of walkability on BMI and waist circumference were substantially larger for the upper quantiles compared with the median or mean. Results suggest that restricting the examination of mediation to the mean of the outcome distribution provides an incomplete picture of proposed mediating mechanisms and in some cases may miss important mediational relationships to outcomes. PMID- 26732361 TI - Structural Equation Models in a Redundancy Analysis Framework With Covariates. AB - A recent method to specify and fit structural equation modeling in the Redundancy Analysis framework based on so-called Extended Redundancy Analysis (ERA) has been proposed in the literature. In this approach, the relationships between the observed exogenous variables and the observed endogenous variables are moderated by the presence of unobservable composites, estimated as linear combinations of exogenous variables. However, in the presence of direct effects linking exogenous and endogenous variables, or concomitant indicators, the composite scores are estimated by ignoring the presence of the specified direct effects. To fit structural equation models, we propose a new specification and estimation method, called Generalized Redundancy Analysis (GRA), allowing us to specify and fit a variety of relationships among composites, endogenous variables, and external covariates. The proposed methodology extends the ERA method, using a more suitable specification and estimation algorithm, by allowing for covariates that affect endogenous indicators indirectly through the composites and/or directly. To illustrate the advantages of GRA over ERA we propose a simulation study of small samples. Moreover, we propose an application aimed at estimating the impact of formal human capital on the initial earnings of graduates of an Italian university, utilizing a structural model consistent with well-established economic theory. PMID- 26732362 TI - Corrigendum. PMID- 26732363 TI - Caregiver coping with the mentally ill: a qualitative study. AB - BACKGROUND: Mental illness is a disease that affects millions of people every year. It not only causes stress to the mentally ill patients, but also for the family members who provide them the care. The family caregivers, therefore need some form of coping strategies in dealing with their mentally ill family members. AIMS: This qualitative study aims at identifying and analysing the coping strategies adopted by the family caregivers in dealing with their mentally ill family members. METHOD: A total of 15 family caregivers from the state of Kedah, Malaysia participated in the face-to-face semi structured interview. RESULTS: The study findings identified an array of coping strategies used by the family caregivers, including religious coping, emotional coping, acceptance, becoming engaged in leisure activities, and the use of traditional healing to help them cope with their mentally ill members. Suggestions and conclusions: Study suggests that the family caregivers should engage themselves in social support groups to learn about and obtain the positive coping strategies used by other caregivers who have similar experiences in caring for the mentally ill. Study also suggests that they should get appropriate training from the mental health professionals in order to enhance the caregivers' coping skills. PMID- 26732364 TI - Improved charge carrier separation in barium tantalate composites investigated by laser flash photolysis. AB - Charge carrier dynamics in phase pure Ba5Ta4O15 and in a Ba5Ta4O15-Ba3Ta5O15 composite have been studied by means of diffuse reflectance laser flash photolysis spectroscopy in the presence and absence of an electron donor, in order to reveal the reason for the improved photocatalytic performance of the latter. For the first time the transient absorption of trapped electrons with a maximum at around 650 nm and of trapped holes with a transient absorption maximum at around 310 nm is reported for tantalates. The decay kinetics of the photogenerated charge carriers could be fitted by second order reaction kinetics, and the direct recombination of the trapped electrons with the trapped holes was proven. In the absence of an electron donor, no difference in the decay behavior between the phase pure material and the composite material is found. In the presence of methanol, for the pure phase Ba5Ta4O15 the recombination of the charge carriers could not be prevented and the trapped electrons also recombine with the CH2OH radical formed via the methanol oxidation by the trapped holes. However, in the composite, the electron can be stored in the system, the CH2OH radical injects an electron into the conduction band of the second component of the composite, i.e., Ba3Ta5O15. Thus, the electrons are available for an extended period to induce reduction reactions. PMID- 26732365 TI - Cobaltoceniumethynyl gold(I) as an unusual heterodinuclear bioorganometallic fragment to study the biological properties of alkynyl gold complexes. AB - A cobaltoceniumethynyl gold(i) complex with a triphenylphosphane ligand triggered efficient cytotoxic effects in cancer cells in contrast to a derivative with two cobaltocenium moieties. The complex effectively inhibited the enzyme thioredoxin reductase (TrxR) suggesting this enzyme as a possible biological target. The cellular uptake of both metal fragments of the active complex was studied by atomic absorption spectroscopy and indicated a high biological stability of the complex. PMID- 26732366 TI - Adenosine triphosphate inhibits melatonin synthesis in the rat pineal gland. AB - Adenosine triphosphate (ATP) is released onto the pinealocyte, along with noradrenaline, from sympathetic neurons and triggers P2Y1 receptors that enhance beta-adrenergic-induced N-acetylserotonin (NAS) synthesis. Nevertheless, the biotransformation of NAS into melatonin, which occurs due to the subsequent methylation by acetylserotonin O-methyltransferase (ASMT; EC 2.1.1.4), has not yet been evaluated in the presence of purinergic stimulation. We therefore evaluated the effects of purinergic signaling on melatonin synthesis induced by beta-adrenergic stimulation. ATP increased NAS levels, but, surprisingly, inhibited melatonin synthesis in an inverse, concentration-dependent manner. Our results demonstrate that enhanced NAS levels, which depend on phospholipase C (PLC) activity (but not the induction of gene transcription), are a post translational effect. By contrast, melatonin reduction is related to an ASMT inhibition of expression at both the gene transcription and protein levels. These results were independent of nuclear factor-kappa B (NF-kB) translocation. Neither the P2Y1 receptor activation nor the PLC-mediated pathway was involved in the decrease in melatonin, indicating that ATP regulates pineal metabolism through different mechanisms. Taken together, our data demonstrate that purinergic signaling differentially modulates NAS and melatonin synthesis and point to a regulatory role for ATP as a cotransmitter in the control of ASMT, the rate limiting enzyme in melatonin synthesis. The endogenous production of melatonin regulates defense responses; therefore, understanding the mechanisms involving ASMT regulation might provide novel insights into the development and progression of neurological disorders since melatonin presents anti-inflammatory, neuroprotective, and neurogenic effects. PMID- 26732367 TI - The effect of aeration and recirculation on a sand-based hybrid constructed wetland treating low-strength domestic wastewater. AB - The Duplex-constructed wetland (CW) is a hybrid system composed of a vertical flow (VF) CW on top of a horizontal flow filter (HFF). Each compartment is designed to play a different role: aerobic treatment in the VF CW due to intermittent feeding and anoxic treatment in the HFF due to saturated conditions. Three Duplex-CWs were used in this study: Control, Aerated and Recirculating. The role of each compartment was tested for pollutant removal and micro-invertebrate abundance. In all systems, the VF CW removed mainly organic matter, solids and NH4(+)-N. Pathogens were removed in both compartments. Likewise, total nitrogen removal occurred in both compartments, only the Recirculating HFF was not able to denitrify the nitrogen due to the slightly more oxic conditions as compared to the other systems. All systems met discharge guidelines for organic matter, but only the Control and Aerated systems met those for total nitrogen. At the applied loading rates, the pollutant removal was not significantly enhanced by the use of aeration and recirculation. Therefore, operation as in the Control system, without aeration or recirculation, is recommended for the tested Duplex-CWs. If artificial aeration will be used in CWs, the support material should be carefully selected to allow a proper air distribution. PMID- 26732369 TI - Erratum. PMID- 26732370 TI - Delirium awareness - Improving recognition and management through education and use of a care pathway. AB - Delirium occurs in 10-20% of medical patients on admission and a further 10-30% develop delirium as an inpatient. Delirium is associated with increased length of stay, morbidity, mortality, and risk of institutional placement. There is poor knowledge of delirium recognition and management, and a need to raise awareness and training of all staff. NICE have produced guidelines for diagnosis, prevention and management of delirium. A retrospective departmental audit demonstrated that delirium was under-recognised i.e. only 5.7% of discharges in one year. A staff questionnaire revealed poor knowledge of types of delirium and a significant underestimation of prevalence, with poor identification of risk factors. A multi-professional group was formed to raise staff awareness and develop a care pathway for delirium. A 19 bed acute elderly care ward was identified for the project. Ward based and departmental educational meetings were held. A Trust based awareness programme was also provided. Information leaflets on delirium were produced for patients, carers and families and posters at ward level. Environmental changes (signage) at ward level were introduced to improve the environment for patients. A delirium care pathway was created to encourage documentation of mental score, assessment of delirium, review of reversible medical causes and a nursing care plan. This pathway was reviewed regularly on ward rounds and feedback given to staff present. Following these interventions the notes of 106 consecutive discharges were reviewed over an 11-week period. 99% of at risk patients were screened for delirium. 35% of patients were diagnosed with delirium increasing the recognition rate from 5.7%. There was significant improvement among the staff in recognizing and managing patients with delirium through the use of a delirium care pathway. Education improves understanding and awareness of delirium and a care pathway focuses attention on this area, improving patient safety and quality of care. PMID- 26732368 TI - Anti-inflammatory effects of indirubin derivatives on influenza A virus-infected human pulmonary microvascular endothelial cells. AB - Influenza A virus (IAV) poses global threats to human health. Acute respiratory distress syndrome and multi-organ dysfunction are major complications in patients with severe influenza infection. This may be explained by the recent studies which highlighted the role of the pulmonary endothelium as the center of innate immune cells recruitment and excessive pro-inflammatory cytokines production. In this report, we examined the potential immunomodulatory effects of two indirubin derivatives, indirubin-3'-(2,3-dihydroxypropyl)-oximether (E804) and indirubin-3' oxime (E231), on IAV (H9N2) infected-human pulmonary microvascular endothelial cells (HPMECs). Infection of H9N2 on HPMECs induced a high level of chemokines and cytokines production including IP-10, RANTES, IL-6, IFN-beta and IFN-gamma1. Post-treatment of E804 or E231 could significantly suppress the production of these cytokines. H9N2 infection rapidly triggered the activation of innate immunity through phosphorylation of signaling molecules including mitogen activated protein kinases (MAPKs) and signal transducer and activator of transcription (STAT) proteins. Using specific inhibitors or small-interfering RNA, we confirmed that indirubin derivatives can suppress H9N2-induced cytokines production through MAPKs and STAT3 signaling pathways. These results underscore the immunomodulatory effects of indirubin derivatives on pulmonary endothelium and its therapeutic potential on IAV-infection. PMID- 26732371 TI - miRNA Digger: a comprehensive pipeline for genome-wide novel miRNA mining. AB - MicroRNAs (miRNAs) are important regulators of gene expression. The recent advances in high-throughput sequencing (HTS) technique have greatly facilitated large-scale detection of the miRNAs. However, thoroughly discovery of novel miRNAs from the available HTS data sets remains a major challenge. In this study, we observed that Dicer-mediated cleavage sites for the processing of the miRNA precursors could be mapped by using degradome sequencing data in both animals and plants. In this regard, a novel tool, miRNA Digger, was developed for systematical discovery of miRNA candidates through genome-wide screening of cleavage signals based on degradome sequencing data. To test its sensitivity and reliability, miRNA Digger was applied to discover miRNAs from four organs of Arabidopsis. The results revealed that a majority of already known mature miRNAs along with their miRNA*s expressed in these four organs were successfully recovered. Notably, a total of 30 novel miRNA-miRNA* pairs that have not been registered in miRBase were discovered by miRNA Digger. After target prediction and degradome sequencing data-based validation, eleven miRNA-target interactions involving six of the novel miRNAs were identified. Taken together, miRNA Digger could be applied for sensitive detection of novel miRNAs and it could be freely downloaded from http://www.bioinfolab.cn/miRNA_Digger/index.html. PMID- 26732372 TI - Size-dependent redox behavior of iron observed by in-situ single nanoparticle spectro-microscopy on well-defined model systems. AB - Understanding the chemistry of nanoparticles is crucial in many applications. Their synthesis in a controlled manner and their characterization at the single particle level is essential to gain deeper insight into chemical mechanisms. In this work, single nanoparticle spectro-microscopy with top-down nanofabrication is demonstrated to study individual iron nanoparticles of nine different lateral dimensions from 80 nm down to 6 nm. The particles are probed simultaneously, under same conditions, during in-situ redox reaction using X-ray photoemission electron microscopy elucidating the size effect during the early stage of oxidation, yielding time-dependent evolution of iron oxides and the mechanism for the inter-conversion of oxides in nanoparticles. Fabrication of well-defined system followed by visualization and investigation of singled-out particles eliminates the ambiguities emerging from dispersed nanoparticles and reveals a significant increase in the initial rate of oxidation with decreasing size, but the reactivity per active site basis and the intrinsic chemical properties in the particles remain the same in the scale of interest. This advance of nanopatterning together with spatially-resolved single nanoparticle X-ray absorption spectroscopy will guide future discourse in understanding the impact of confinement of metal nanoparticles and pave way to solve fundamental questions in material science, chemical physics, magnetism, nanomedicine and nanocatalysis. PMID- 26732373 TI - Statistical modeling of the spatial variability of environmental noise levels in Montreal, Canada, using noise measurements and land use characteristics. AB - The availability of noise maps to assess exposure to noise is often limited, especially in North American cities. We developed land use regression (LUR) models for LAeq24h, Lnight, and Lden to assess the long-term spatial variability of environmental noise levels in Montreal, Canada, considering various transportation noise sources (road, rail, and air). To explore the effects of sampling duration, we compared our LAeq24h levels that were computed over at least five complete contiguous days of measurements to shorter sampling periods (20 min and 24 h). LUR models were built with General Additive Models using continuous 2-min noise measurements from 204 sites. Model performance (adjusted R2) was 0.68, 0.59, and 0.69 for LAeq24h, Lnight, and Lden, respectively. Main predictors of measured noise levels were road-traffic and vegetation variables. Twenty-minute non-rush hour measurements corresponded well with LAeq24h levels computed over 5 days at road-traffic sites (bias: -0.7 dB(A)), but not at rail ( 2.1 dB(A)) nor at air (-2.2 dB(A)) sites. Our study provides important insights into the spatial variation of environmental noise levels in a Canadian city. To assess long-term noise levels, sampling strategies should be stratified by noise sources and preferably should include 1 week of measurements at locations exposed to rail and aircraft noise. PMID- 26732374 TI - Dermal bioaccessibility of flame retardants from indoor dust and the influence of topically applied cosmetics. AB - Despite extensive literature on their potential adverse health effects, there is a lack of information on human dermal exposure to organic flame retardant chemicals (FRs). This study applies an in vitro physiologically based extraction test to provide new insights into the dermal bioaccessibility of various FRs from indoor dust to synthetic sweat/sebum mixture (SSSM). The bioaccessible fractions of alpha-, beta- and gamma-hexabromocyclododecane (HBCD) and tetrabromobisphenol A (TBBPA) to 1:1 (sweat/sebum) mixture were 41%, 47%, 50% and 40%, respectively. For Tris-2-chloroethyl phosphate (TCEP), tris (1-chloro-2-propyl) phosphate (TCIPP) and tris-1,3-dichloropropyl phosphate (TDCIPP), bioaccessible fractions were 10%, 17% and 19%. Composition of the SSSM and compound-specific physicochemical properties were the major factors influencing the bioaccessibility of target FRs. Except for TBBPA, the presence of cosmetics (moisturising cream, sunscreen lotion, body spray and shower gel) had a significant effect (P<0.05) on the bioaccessibility of the studied FRs. The presence of cosmetics decreased the bioaccessibility of HBCDs from indoor dust, whereas shower gel and sunscreen lotion enhanced the bioaccessibility of target PFRs. Our bioaccessibility data were applied to estimate the internal exposure of UK adults and toddlers to the target FRs via dermal contact with dust. Our worst case scenario exposure estimates fell far below available health-based limit values for TCEP, TCIPP and TDCIPP. However, future research may erode the margin of safety for these chemicals. PMID- 26732375 TI - Chronic aflatoxin exposure in children living in Bhaktapur, Nepal: Extension of the MAL-ED study. AB - Exposure to aflatoxin, a mycotoxin common in maize and groundnuts, has been associated with childhood stunting in sub-Saharan Africa. In an effort to further our understanding of growth impairment in relation to mycotoxins and other risk factors, biospecimens from a cohort of children enrolled in the Bhaktapur, Nepal MAL-ED study were assessed for aflatoxin exposure at 15, 24, and 36 months of age. Exposure was assessed through a well-established serum biomarker, the AFB1 lysine adduct. In this manuscript, the levels of aflatoxin exposure in the Nepal cohort were compared with those observed in aflatoxin studies, with child growth parameters as a health outcome. Results from this preliminary analysis demonstrated chronic aflatoxin exposure in children residing in Bhaktapur with a geometric mean of 3.62 pg AFB1-lysine/mg albumin. The range of exposure in this population is similar to those in African populations where associations with aflatoxin biomarkers and poor child growth have been observed. Future work will analyze the relationships between aflatoxin levels, growth, and other risk factors collected by the MAL-ED study. PMID- 26732376 TI - A systematic evaluation of chemicals in hydraulic-fracturing fluids and wastewater for reproductive and developmental toxicity. AB - Hydraulic-fracturing fluids and wastewater from unconventional oil and natural gas development contain hundreds of substances with the potential to contaminate drinking water. Challenges to conducting well-designed human exposure and health studies include limited information about likely etiologic agents. We systematically evaluated 1021 chemicals identified in hydraulic-fracturing fluids (n=925), wastewater (n=132), or both (n=36) for potential reproductive and developmental toxicity to triage those with potential for human health impact. We searched the REPROTOX database using Chemical Abstract Service registry numbers for chemicals with available data and evaluated the evidence for adverse reproductive and developmental effects. Next, we determined which chemicals linked to reproductive or developmental toxicity had water quality standards or guidelines. Toxicity information was lacking for 781 (76%) chemicals. Of the remaining 240 substances, evidence suggested reproductive toxicity for 103 (43%), developmental toxicity for 95 (40%), and both for 41 (17%). Of these 157 chemicals, 67 had or were proposed for a federal water quality standard or guideline. Our systematic screening approach identified a list of 67 hydraulic fracturing-related candidate analytes based on known or suspected toxicity. Incorporation of data on potency, physicochemical properties, and environmental concentrations could further prioritize these substances for future drinking water exposure assessments or reproductive and developmental health studies. PMID- 26732377 TI - Fine particles, genetic pathways, and markers of inflammation and endothelial dysfunction: Analysis on particulate species and sources. AB - Studies have found associations between PM2.5 and cardiovascular events. The role of different components of PM2.5 is not well understood. We used linear mixed effects models with the adaptive LASSO penalty to select PM2.5 species and source(s), separately, that may be associated with markers of inflammation and endothelial dysfunction, with adjustment for age, obesity, smoking, statin use, diabetes mellitus, temperature, and season as fixed effects in a large longitudinal cohort of elderly men. We also analyzed these associations with source apportionment models and examined genetic pathway-air pollution interactions within three relevant pathways (oxidative stress, metal processing, and endothelial function). We found that independent of PM2.5 mass vanadium (V) was associated with intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). An IQR increase (3.2 ng/m(3)) in 2-day moving average V was associated with a 2.5% (95% CI: 1.2-3.8%) change in ICAM-1 and a 3.9% (95% CI: 2.2-5.7%) change in VCAM-1, respectively. In addition, an oil combustion source rich in V was linked to these adhesion molecules. People with higher allelic risk profiles related to oxidative stress may have greater associations (P-value of interaction=0.11). Our findings suggest that particles derived from oil combustion may be associated with inflammation and endothelial dysfunction, and it is likely that oxidative stress plays a role in the associations. PMID- 26732378 TI - Is there a relationship between tea intake and maternal whole blood heavy metal concentrations? AB - The aim of this analysis was to examine the association between tea intake during pregnancy and maternal and infant metal exposures. Data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian pregnancy cohort, were used. All participants with a gestational age of ?20 weeks (n=1954) with available biomarkers were included. Geometric means (GMs) for lead, arsenic, mercury, cadmium and manganese in maternal (first and third trimesters) and cord blood, as well as speciated arsenic in maternal urine in the first trimester, were calculated for participants who drank regular, green or herbal tea and for those who did not. Differences between groups were examined using chi-square tests. Adjusted least squares geometric means (LSGMs) were estimated by tea intake, controlling for factors such as country of birth, coffee intake and maternal smoking. Concentrations of all metals were above the limits of detection in most participants in the first trimester: lead (GM): 0.62 MUg/dl), mercury (GM: 2.99 nmol/l); cadmium (GM 1.93 nmol/l), arsenic (GM 9.75 nmol/l) and manganese (GM 160.1 nmol/l). Adjusted LSGMs for lead in the first trimester were higher for tea drinkers than for those who were non-tea drinkers (LSGM 0.65 MUg/dl, 95%CI: 0.62, 0.69 and 0.61 MUg/dl, 95%CI: 0.59, 0.62), and there was evidence of a dose-response relationship for green and herbal tea. Those who consumed herbal tea in the third trimester had significantly higher third trimester maternal and cord blood lead concentrations than non-herbal tea drinkers. This study provides evidence of an association between blood lead concentrations and green or herbal tea consumption. However, the GM blood lead concentrations of the highest tea consumers were still less than 1 MUg/dl and within the normal range of blood lead concentrations in the Canadian population. PMID- 26732379 TI - Expression of bax and bcl2 Genes in MDMA-induced Hepatotoxicity on Rat Liver Using Quantitative Real-Time PCR Method through Triggering Programmed Cell Death. AB - BACKGROUND: 3-4methylenedioxymethamphetamine (MDMA) is a synthetic and psychoactive drug, which is known popularly as Ecstasy and has toxic effects on human organs. OBJECTIVES: Considering the potential toxic interaction, this study was performed to quantify the expression of bax and bcl2 genes in MDMA-induced hepatotoxicity on rat liver. Subsequently, we evaluated pentoxifylline as a possible protective drug on hepatotoxicity. MATERIALS AND METHODS: Adult male Wistar rats weighting 250 - 300 grams were used in the study. The rats were equally distributed into four experimental groups (5 rat/group). MDMA was dissolved in PBS and injected intraperitoneally (IP) including untreated control, MDMA (MDMA dissolved in PBS), treated-1 (MDMA followed by PTX) and treated-2 (PTX followed by MDMA). All animals given MDMA received 3 doses of 7.5mg/kg with two hours gap between doses. Liver tissue was removed after anaesthetizing. Subsequently, RNA isolation, cDNA synthesis and Real-Time PCR were performed. Finally, data analyzed statistically to determine significantly differences between the groups (P value < 0.05). RESULTS: Using Real-Time quantitative PCR results, the gene expression ratio of bcl2 were calculated 93.80+/-20.64, 340.45 +/- 36.60 and 47.13 +/- 5.84 fold in MDMA, treated-1 and treated-2 groups, respectively. Furthermore, this ratio for bax gene obtained 2.13+/-0.33 fold in MDMA, 1.55 +/- 0.26 fold in treated-1 and 10.44 +/- 1.56 fold in treated-2 groups. CONCLUSIONS: The present study focused on molecular mechanism of MDMA in programmed cell death using gene expression quantification of a pro-apoptotic and anti-apoptoic gene in MDMA-induced hepatotoxocity. The results showed that MDMA prompted apoptosis in liver and pentoxifylline protected against hepatotoxicity before and after taking MDMA. PMID- 26732380 TI - Efficient and automated large-scale detection of structural relationships in proteins with a flexible aligner. AB - BACKGROUND: The total number of known three-dimensional protein structures is rapidly increasing. Consequently, the need for fast structural search against complete databases without a significant loss of accuracy is increasingly demanding. Recently, TopSearch, an ultra-fast method for finding rigid structural relationships between a query structure and the complete Protein Data Bank (PDB), at the multi-chain level, has been released. However, comparable accurate flexible structural aligners to perform efficient whole database searches of multi-domain proteins are not yet available. The availability of such a tool is critical for a sustainable boosting of biological discovery. RESULTS: Here we report on the development of a new method for the fast and flexible comparison of protein structure chains. The method relies on the calculation of 2D matrices containing a description of the three-dimensional arrangement of secondary structure elements (angles and distances). The comparison involves the matching of an ensemble of substructures through a nested-two-steps dynamic programming algorithm. The unique features of this new approach are the integration and trade off balancing of the following: 1) speed, 2) accuracy and 3) global and semiglobal flexible structure alignment by integration of local substructure matching. The comparison, and matching with competitive accuracy, of one medium sized (250-aa) query structure against the complete PDB database (216,322 protein chains) takes about 8 min using an average desktop computer. The method is at least 2-3 orders of magnitude faster than other tested tools with similar accuracy. We validate the performance of the method for fold and superfamily assignment in a large benchmark set of protein structures. We finally provide a series of examples to illustrate the usefulness of this method and its application in biological discovery. CONCLUSIONS: The method is able to detect partial structure matching, rigid body shifts, conformational changes and tolerates substantial structural variation arising from insertions, deletions and sequence divergence, as well as structural convergence of unrelated proteins. PMID- 26732381 TI - Side-specific effect of yolk testosterone elevation on second-to-fourth digit ratio in a wild passerine. AB - Second-to-fourth digit ratio is a widely investigated sexually dimorphic morphological trait in human studies and could reliably indicate the prenatal steroid environment. Conducting manipulative experiments to test this hypothesis comes up against ethical limits in humans. However, oviparous tetrapods may be excellent models to experimentally investigate the effects of prenatal steroids on offspring second-to-fourth digit ratio. In this field study, we injected collared flycatcher (Ficedula albicollis) eggs with physiological doses of testosterone. Fledglings from eggs with elevated yolk testosterone, regardless of their sex, had longer second digits on their left feet than controls, while the fourth digit did not differ between groups. Therefore, second-to-fourth digit ratio was higher in the testosterone-injected group, but only on the left foot. This is the first study which shows experimentally that early testosterone exposure can affect second-to-fourth digit ratio in a wild population of a passerine bird. PMID- 26732383 TI - A randomized Phase III trial of thoracoscopic versus open esophagectomy for thoracic esophageal cancer: Japan Clinical Oncology Group Study JCOG1409. AB - A randomized Phase III study was commenced in May 2015 to confirm the non inferiority of thoracoscopic esophagectomy to open esophagectomy in terms of overall survival for clinical Stage I-III esophageal cancer. A total of 300 patients will be accrued from Japanese institutions over 6 years. The primary endpoint is overall survival. The secondary endpoints are relapse-free survival, proportion of patients with R0 resection, proportion of patients who underwent re operation, adverse events, postoperative respiratory function change, postoperative quality-of-life score (EORTC QLQ-C30), and proportion of patients who need conversion from thoracoscopic surgery to open surgery. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000017628. PMID- 26732382 TI - Forkhead box protein k1 recruits TET1 to act as a tumor suppressor and is associated with MRI detection. AB - OBJECTIVE: Today, more and more evidence suggests that Foxk proteins (Foxk1 and Foxk2) work as transcriptional repressors in different kinds of cancer, but whether Foxk1 has a role in mediating tumorigenesis in breast cancer, the evidence is rare. METHODS: MCF-7 cells transfected with shFoxk1 displayed a mesenchymal morphology and reduced the expression of E-cadherin, and increased the expression of N-cadherin. Transwell invasion assay and living imaging assay show that the overexpression of Foxk1 could inhibit metastasis in vitro and in vivo. Ribonucleic acid sequencing revealed that the knockdown of Foxk1 resulted in the up-regulation of different oncogenes, which was implicated in metastasis and tumor angiopoiesis. Quantitative chromatin immunoprecipitation, chromatin immunoprecipitation and Luciferase reporter assays suggested that Foxk1 could bind to the promoter of epithelial-mesenchymal transition inducer Twist and vascular endothelial growth factor, VEGF. Mass Spectrometry, co immunoprecipitation assays and glutathione-S-transferase pull-down assay detected that Foxk1 was physically associated with Ten-eleven translocation 1, TET1, in vivo and in vitro. RESULTS: We reported that the mean expression level of Foxk1 in breast cancer was significantly lower than the adjacent noncarcinoma tissue. The higher Foxk1 expression was associated with better prognosis. Endothelial tube formation assays indicated that Foxk1 might regulate breast cancer angiogenesis through transcriptional repression of vascular endothelial growth factor. Furthermore, in vivo magnetic resonance imaging revealed the overexpression of Foxk1 could enhance the detection of the tumors. Further, a strong negative correlation was observed between Foxk1 and Twsit or between Foxk1 and vascular endothelial growth factor, and the higher Foxk1 expression is correlated with better over all survivals and better relapse-free survivals. CONCLUSIONS: Together, our data indicated the function of Foxk1 as a tumor suppressor in facilitating angiogenesis and metastasis in breast cancer. PMID- 26732384 TI - Diagnostic performance and safety of NMK36 (trans-1-amino-3 [18F]fluorocyclobutanecarboxylic acid)-PET/CT in primary prostate cancer: multicenter Phase IIb clinical trial. AB - OBJECTIVE: We performed a multicenter Phase IIb clinical trial of NMK36, a novel amino acid analog for positron emission tomography containing trans-1-amino-3 [(18)F]fluorocyclobutanecarboxylic acid, to evaluate its safety and diagnostic performance for primary prostate cancer. METHODS: Sixty-eight subjects with primary prostate cancer scheduled for radical prostatectomy or hormone therapy underwent whole-body positron emission tomography/computed tomography after injection of NMK36. The diagnostic performances of NMK36-positron emission tomography/computed tomography were evaluated for (i) regional lymph node metastasis: comparison with contrast-enhanced computed tomography under setting reference standard (histopathology or 6-month follow-up), (ii) bone metastasis: concordance rate with conventional imaging (combination of bone scintigraphy and contrast-enhanced computed tomography) and (iii) primary lesion: comparison with histopathological findings. RESULTS: The accuracy of NMK36-positron emission tomography/computed tomography and contrast-enhanced computed tomography for regional lymph node metastasis were 85.5 and 87.3%, respectively. NMK36-positron emission tomography/computed tomography showed positive findings for regional lymph nodes with short-axis diameters of 5-9 mm at 23 regions in 13 patients of hormone therapy cohort, but they were not confirmed with reference standard in this study. The concordance rate of NMK36-positron emission tomography/computed tomography with conventional imaging for bone metastases was 83.3%, and seven patients had positive findings only by NMK36-positron emission tomography/computed tomography. The sensitivity and specificity of NMK36-positron emission tomography/computed tomography for primary lesion in six-segment analysis was 92.5 and 90.1%, respectively. Seven of non-serious adverse events were observed in six patients. CONCLUSIONS: This study showed the comparable diagnostic performance of NMK36-positron emission tomography/computed tomography compared with conventional imaging. Some lesions of lymph node and bone were positive solely by NMK36-positron emission tomography/computed tomography, which needs to be confirmed with reference standard in future study to evaluate the usefulness of NMK36-positron emission tomography/computed tomography in staging prostate cancer. PMID- 26732385 TI - How musical are music video game players? AB - Numerous studies have shown that formal musical training is associated with sensory, motor, and cognitive advantages in individuals of various ages. However, the nature of the observed differences between musicians and nonmusicians is poorly understood, and little is known about the listening skills of individuals who engage in alternative types of everyday musical activities. Here, we show that people who have frequently played music video games outperform nonmusicians controls on a battery of music perception tests. These findings reveal that enhanced musical aptitude can be found among individuals who play music video games, raising the possibility that music video games could potentially enhance music perception skills in individuals across a broad spectrum of society who are otherwise unable to invest the time and/or money required to learn a musical instrument. PMID- 26732386 TI - Cryptotanshinone inhibits TNF-alpha-induced early atherogenic events in vitro. AB - Endothelial dysfunction has been implicated in the pathogenesis of atherosclerosis. Salvia miltiorrhiza (danshen) is a traditional Chinese medicine that has been effectively used to treat cardiovascular disease. Cryptotanshinone (CTS), a major lipophilic compound isolated from S. miltiorrhiza, has been reported to possess cardioprotective effects. However, the anti-atherogenic effects of CTS, particularly on tumor necrosis factor-alpha (TNF-alpha)-induced endothelial cell activation, are still unclear. This study aimed to determine the effect of CTS on TNF-alpha-induced increased endothelial permeability, monocyte adhesion, soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), monocyte chemoattractant protein 1 (MCP-1) and impaired nitric oxide production in human umbilical vein endothelial cells (HUVECs), all of which are early events occurring in atherogenesis. We showed that CTS significantly suppressed TNF-alpha-induced increased endothelial permeability, monocyte adhesion, sICAM-1, sVCAM-1 and MCP-1, and restored nitric oxide production. These observations suggest that CTS possesses anti-inflammatory properties and could be a promising treatment for the prevention of cytokine induced early atherogenesis. PMID- 26732387 TI - Pseudoaneurysm after pertrochanteric femur fracture: a case report. AB - Vascular injury as a consequence of dislocated bone fragments after hip fractures is a rare complication. We report a case of a 78-year-old male who developed a pseudoaneurysm of the profunda femoris artery during rehabilitation after intramedullary fixation for a pertrochanteric hip fracture. As this procedure was minimally invasive, open reposition and fixation of the dislocated lesser trochanter were not performed. The pseudoaneurysm was diagnosed through duplex ultrasound and CT angiography and treated with thrombin injections and an endovascular Wallgraft covered stent. The imaging features are described in the article. Although a pseudoaneurysm is a rare complication after hip fractures, the development should be considered, in particular when symptoms such as pulsatile swelling or venous engorgement are presented. PMID- 26732388 TI - Transition state theory demonstrated at the micron scale with out-of-equilibrium transport in a confined environment. AB - Transition state theory (TST) provides a simple interpretation of many thermally activated processes. It applies successfully on timescales and length scales that differ several orders of magnitude: to chemical reactions, breaking of chemical bonds, unfolding of proteins and RNA structures and polymers crossing entropic barriers. Here we apply TST to out-of-equilibrium transport through confined environments: the thermally activated translocation of single DNA molecules over an entropic barrier helped by an external force field. Reaction pathways are effectively one dimensional and so long that they are observable in a microscope. Reaction rates are so slow that transitions are recorded on video. We find sharp transition states that are independent of the applied force, similar to chemical bond rupture, as well as transition states that change location on the reaction pathway with the strength of the applied force. The states of equilibrium and transition are separated by micrometres as compared with angstroms/nanometres for chemical bonds. PMID- 26732389 TI - Laparoscopic Completion Pancreatectomy for Local Recurrence in the Pancreatic Remnant after Pancreaticoduodenectomy: Case Reports and Review of the Literature. PMID- 26732390 TI - Enolase of Streptococcus Suis Serotype 2 Enhances Blood-Brain Barrier Permeability by Inducing IL-8 Release. AB - Streptococcus suis serotype 2 (SS2) is an emerging zoonosis, and meningitis is the most frequent clinical manifestation, but mechanism of its virulent factor, enolase (Eno), is unknown in meningitis. In this study, Eno was inducibly expressed and added to an in vitro Transwell co-culture model of the blood-brain barrier (BBB) consisted of porcine brain microvascular endothelial cells (PBMECs) and astrocytes (ACs), the results showed that Eno induces a significant increase in BBB permeability and promotes the release of IL-8 et al. cytokines. Furthermore, IL-8 could significantly destroy the integrity of the BBB model in vitro. In mice models administered Eno for 24 h, Eno could significantly promote Evans blue (EB) moving from the blood to the brain and significantly increased the serum and brain levels of IL-8, as detected by ELISA. While G31P (IL-8 receptor antagonist) significantly decreased the concentration of EB in the brains of mice injected with Eno. The present study demonstrated that SS2 Eno may play an important role in disrupting BBB integrity by prompting IL-8 release. PMID- 26732391 TI - Vascular Response to Experimental Stent Malapposition and Under-Expansion. AB - Up to 80% of all endovascular stents have malapposed struts, and while some impose catastrophic events others are inconsequential. Thirteen stents were implanted in coronary arteries of seven healthy Yorkshire pigs, using specially designed cuffed balloons inducing controlled stent malapposition and under expansion. Optical coherence tomography (OCT) imaging confirmed that 25% of struts were malapposed (strut-wall distance 30% of the pooled SCNA breakpoint variation, with the explanatory power ranging from 13 to 32% for different cancer types and SCNA types. In addition to confirming previously identified features [e.g. long interspersed element-1 (L1) and short interspersed nuclear elements], we also identified several novel informative features, including distance to telomere, distance to centromere and low complexity repeats. The results of the MLR analyses were additionally confirmed on an independent SCNA data set obtained from the catalogue of somatic mutations in cancer database. Using a rare-event logistic regression model and an extremely randomized tree classifier, we revealed that genomic features are informative for defining common SCNA breakpoint hotspots. Our findings shed light on the molecular mechanisms of SCNA generation in cancer. PMID- 26732430 TI - Practicality of the suicidal germination approach for controlling Striga hermonthica. AB - BACKGROUND: Purple witchweed (Striga hermonthica), Orobanchaceae, is an obligate root-parasitic weed of important cereal crops. The parasite is a copious seed producer, and a huge seed bank develops soon after the onset of the initial infestation. To germinate, a Striga seed requires a pretreatment in a moist warm environment and a subsequent exposure to an exogenous stimulant. One approach to reduce the seed bank is artificially to induce germination of the seeds in the absence of or away from the host roots. A newly developed germination stimulant for S. hermonthica, designated as T-010, was evaluated for efficacy in greenhouse and field experiments under artificial Striga infestation. RESULTS: T-010 displayed germination-inducing activity in soil. Formulated T-010 applied at 0.1, 1 and 10 kg ai ha-1 to potted soil containing S. hermonthica seeds, previously conditioned by judicious irrigation, reduced Striga emergence by 94-100%. Results of a field trial showed that formulated T-010, at the same rates as for the pot experiment, delayed and reduced Striga emergence by 33% and increased sorghum shoot and head dry weight by 18.7-40.2% and 187-241% respectively. CONCLUSION: These findings demonstrated, for the first time, the technical feasibility of suicidal germination for controlling S. hermonthica. Optimising structure, formulation and application protocol of germination stimulants should be the main goal for further improvement of the technology. (c) 2016 Society of Chemical Industry. PMID- 26732431 TI - Synthesis of stationary phases that provide group recognition for polychlorinated biphenyls by porogenic fragment template imprinting. AB - Molecular recognition based on imprinted polymers results from the polymerization of functional monomers and cross-linkers in the presence of a target analyte (i.e. template), with subsequent removal of the template to create synthetic binding sites. However, complete removal of the template is difficult to achieve, thereby leading to template leaching, which adversely affects real-world analytical applications. To overcome this challenge, the present study utilizes porogenic fragment template imprinting techniques to provide an alternative synthetic strategy to generate molecularly imprinted polymers with molecular recognition toward polychlorinated biphenyls. Thereafter, thus-generated imprinted polymers have been applied as stationary phases in molecularly imprinted solid-phase extraction for preconcentrating six "indicator polychlorinated biphenyls" in both organic and aqueous media. Recoveries of up to 98.9% (imprinted polymers) versus 73.0% (conventional C18 ) in an organic phase, and up to 97.4% (imprinted polymers) versus 89.4% (C18 ) in an aqueous phase have been achieved corroborating the utility of this advanced sorbent material. Finally, porogenic fragment template imprinting strategies have yielded molecularly imprinted polymers that are useful for the quantitative determination of polychlorinated biphenyls in environmental matrices, which provides a low-cost strategy for tailoring stationary phases that avoid template leaching in applications in solid-phase extraction as well as liquid chromatography. PMID- 26732427 TI - Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry. AB - Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 * 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 * 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 * 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P <= 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer. PMID- 26732433 TI - Dose optimization by altering the operating potential and tube current exposure time product in dental cone beam CT: a systematic review. AB - OBJECTIVES: Current guidelines highlight the need to optimize exposure parameters on CBCT equipment to levels that are as low as diagnostically acceptable. This systematic review aimed to answer the question "Can altering operating potential (kV) and tube current exposure time product (mAs) on CBCT machines reduce radiation dose to patients undergoing dental and/or maxillofacial scans without a detrimental impact on image quality/diagnostic accuracy?" METHODS: Studies were selected and results reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. For each individual study, two authors (RG and JD or KH) independently extracted data using a specifically designed collection form, and an overall quality value was assigned using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Any disagreements in the overall quality value of a study were resolved by discussion between the current authors. RESULTS: Nearly 75% of studies were considered to be of low or very low methodological quality using the GRADE system, and more studies stated that their results applied only in the specific situations they had investigated. However, most studies demonstrated that patient dose reduction is possible without a clinically relevant reduction in image quality. CONCLUSIONS: For many CBCT machines, it should be possible to optimize one, or more, of the investigated exposure parameters and therefore reduce patient radiation dose, while maintaining diagnostic image quality for some diagnostic tasks. However, more rigorous research is still required. PMID- 26732434 TI - 'Dual hit' metabolic modulator LDCA selectively kills cancer cells by efficient competitive inhibition of LDH-A. AB - Herein, we synthesize and elucidate the potential of a novel 'dual hit' molecule, LDCA, to constitutively block lactate dehydrogenase isoform-A (LDH-A) to selectively subvert apoptosis and rigorously attenuate breast tumor progression in a mouse model, comprehensively delineating the therapeutic prospectus of LDCA in the field of cancer metabolics. PMID- 26732429 TI - Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women. AB - Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 * 10(-13)), rs72658409 at 9p21.3 (per allele OR = 0.77; P = 1.41 * 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 * 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings. PMID- 26732432 TI - Increased occurrence of protein kinase CK2 in astrocytes in Alzheimer's disease pathology. AB - BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease. In addition to the occurrence of amyloid deposits and widespread tau pathology, AD is associated with a neuroinflammatory response characterized by the activation of microglia and astrocytes. Protein kinase 2 (CK2, former casein kinase II) is involved in a wide variety of cellular processes. Previous studies on CK2 in AD showed controversial results, and the involvement of CK2 in neuroinflammation in AD remains elusive. METHODS: In this study, we used immunohistochemical and immunofluorescent staining methods to investigate the localization of CK2 in the hippocampus and temporal cortex of patients with AD and non-demented controls. We compared protein levels with Western blotting analysis, and we investigated CK2 activity in human U373 astrocytoma cells and human primary adult astrocytes stimulated with IL-1beta or TNF-alpha. RESULTS: We report increased levels of CK2 in the hippocampus and temporal cortex of AD patients compared to non-demented controls. Immunohistochemical analysis shows CK2 immunoreactivity in astrocytes in AD and control cases. In AD, the presence of CK2 immunoreactive astrocytes is increased. CK2 immunopositive astrocytes are associated with amyloid deposits, suggesting an involvement of CK2 in the neuroinflammatory response. In U373 cells and human primary astrocytes, the selective CK2 inhibitor CX-4945 shows a dose-dependent reduction of the IL-1beta or TNF-alpha induced MCP-1 and IL-6 secretion. CONCLUSIONS: This data suggests that CK2 in astrocytes is involved in the neuroinflammatory response in AD. The reduction in pro-inflammatory cytokine secretion by human astrocytes using the selective CK2 inhibitor CX-4945 indicates that CK2 could be a potential target to modulate neuroinflammation in AD. PMID- 26732435 TI - Disruption of hippocampal synaptic transmission and long-term potentiation by psychoactive synthetic cannabinoid 'Spice' compounds: comparison with Delta9 tetrahydrocannabinol. AB - There has been a marked increase in the availability of synthetic drugs designed to mimic the effects of marijuana. These cannabimimetic drugs, sold illicitly as 'Spice' and related products, are associated with serious medical complications in some users. In vitro studies suggest that synthetic cannabinoids in these preparations are potent agonists at central cannabinoid CB1 receptors (CB1Rs), but few investigations have delineated their cellular effects, particularly in comparison with the psychoactive component of marijuana, Delta9 tetrahydrocannabinol (Delta9 -THC). We compared the ability of three widely abused synthetic cannabinoids and Delta9 -THC to alter glutamate release and long term potentiation in the mouse hippocampus. JWH-018 was the most potent inhibitor of hippocampal synaptic transmission (EC50 ~15 nM), whereas its fluoropentyl derivative, AM2201, inhibited synaptic transmission with slightly lower potency (EC50 ~60 nM). The newer synthetic cannabinoid, XLR-11, displayed much lower potency (EC50 ~900 nM) that was similar to Delta9 -THC (EC50 ~700 nM). The effects of all compounds occurred via activation of CB1Rs, as demonstrated by reversal with the selective antagonist/inverse agonist AM251 or the neutral CB1R antagonist PIMSR1. Moreover, AM2201 was without effect in the hippocampus of transgenic mice lacking the CB1R. Hippocampal slices exposed to either synthetic cannabinoids or Delta9 -THC exhibited significantly impaired long-term potentiation (LTP). We find that, compared with Delta9 -THC, the first-generation cannabinoids found in Spice preparations display higher potency, whereas a recent synthetic cannabinoid is roughly equipotent with Delta9 -THC. The disruption of synaptic function by these synthetic cannabinoids is likely to lead to profound impairments in cognitive and behavioral function. PMID- 26732436 TI - Leprosy in Denmark 1980-2010: a review of 15 cases. AB - BACKGROUND: Leprosy, caused by Mycobacterium leprae, is a chronic and progressive granulomatous disease affecting mainly the skin and the peripheral nervous system. If left unrecognized, the infection can lead to permanent nerve damage and disability. The clinical presentation depends on the immune response of the patient and can result in a wide spectrum of symptoms. Leprosy is a rare encounter in Scandinavia but remains endemic in some parts of the world, with some areas reporting an increasing incidence. We performed a retrospective record review of leprosy cases in Denmark from 1980 to 2010 with the purpose of presenting the most common geographical, demographic and clinical findings and to discuss the diagnostic and therapeutic challenges of patients with leprosy. CASE PRESENTATION: In total 15 cases were reviewed. The majority (87%) of leprosy patients in Denmark were born in South- and Southeast Asia, and were presumed to have contracted the infection in their countries of origin. Patients were predominately young males (mean age: 28.6 years). Anaesthetic skin lesion with or without nerve enlargement were the most common clinical presentations (73%). Immunological leprosy reactions were seen in 40% of the cases. Diagnoses were based on clinical findings and skin biopsies. Treatment length varied but all patients received multidrug regimens. CONCLUSION: Leprosy should be kept in mind when encountering patients with suspicious skin lesions originating from leprosy endemic areas or with history of travel or work in the tropics. Due to the long incubation period with symptoms presenting long after immigration or return, clinicians often do not have the diagnosis in mind. The wide spectrum of symptoms and immunological reactions further complicates the diagnostic process. Treatment of leprosy and the complicated immunological reactions, which frequently accompanies the infection, should be performed in collaboration with a specialist. PMID- 26732437 TI - A phase I study of elesclomol sodium in patients with acute myeloid leukemia. PMID- 26732438 TI - Resistant Superbugs: Race against Time. PMID- 26732440 TI - The Physiological Suppressing Factors of Dry Forage Intake and the Cause of Water Intake Following Dry Forage Feeding in Goats - A Review. AB - The goats raised in the barn are usually fed on fresh grass. As dry forage can be stored for long periods in large amounts, dry forage feeding makes it possible to feed large numbers of goats in barns. This review explains the physiological factors involved in suppressing dry forage intake and the cause of drinking following dry forage feeding. Ruminants consume an enormous amount of dry forage in a short time. Eating rates of dry forage rapidly decreased in the first 40 min of feeding and subsequently declined gradually to low states in the remaining time of the feeding period. Saliva in large-type goats is secreted in large volume during the first hour after the commencement of dry forage feeding. It was elucidated that the marked suppression of dry forage intake during the first hour was caused by a feeding-induced hypovolemia and the loss of NaHCO3 due to excessive salivation during the initial stages of dry forage feeding. On the other hand, it was indicated that the marked decrease in feed intake observed in the second hour of the 2 h feeding period was related to ruminal distension caused by the feed consumed and the copious amount of saliva secreted during dry forage feeding. In addition, results indicate that the marked decreases in dry forage intake after 40 min of feeding are caused by increases in plasma osmolality and subsequent thirst sensations produced by dry forage feeding. After 40 min of the 2 h dry forage feeding period, the feed salt content is absorbed into the rumen and plasma osmolality increases. The combined effects of ruminal distension and increased plasma osmolality accounted for 77.6% of the suppression of dry forage intake 40 min after the start of dry forage feeding. The results indicate that ruminal distension and increased plasma osmolality are the main physiological factors in suppression of dry forage intake in large-type goats. There was very little drinking behavior observed during the first hour of the 2 h feeding period most water consumption occurring in the second hour. The cause of this thirst sensation during the second hour of dry forage feeding period was not hypovolemia brought about by excessive salivation, but rather increases in plasma osmolality due to the ruminal absorption of salt from the consumed feed. This suggests the water intake following dry forage feeding is determined by the level of salt content in the feed. PMID- 26732439 TI - A Behavioral and Electrophysiological Investigation of the Effect of Bilingualism on Lexical Ambiguity Resolution in Young Adults. AB - Previous research suggests that bilinguals demonstrate superior cognitive control processes than monolinguals. The goal of the current investigation was to examine whether this "bilingual advantage" is observed in a language processing task that requires inhibition, i.e., lexical ambiguity processing. Monolingual and bilingual participants read sentences that biased the reading of a terminal homonym toward the subordinate or dominant reading (e.g., The doctor asked her to step onto the scale.). A relatedness judgment was made on target words that were related to the contextually appropriate (e.g., balance) or inappropriate meaning (e.g., skin), or unrelated to either meaning (e.g., shoe) while electrophysiological recording took place. The results revealed subtle processing differences between monolinguals and bilinguals that were evident in electrophysiological measures, but not in behavioral measures. These findings suggest that monolinguals rely on context to access the contextually appropriate meaning of a homonym to a greater extent than bilinguals, while bilinguals demonstrate simultaneous activation of both meanings. PMID- 26732441 TI - Variance Components and Genetic Parameters Estimated for Fat and Protein Content in Individual Months of Lactation: The Case of Tsigai Sheep. AB - The objective of this study was to assess variance components and genetic parameters for fat and protein content in Tsigai sheep using multivariate animal models in which fat and protein content in individual months of lactation were treated as different traits, and univariate models in which fat and protein content were treated as repeated measures of the same traits. Test day measurements were taken between the second and the seventh month of lactation. The fixed effects were lactation number, litter size and days in milk. The random effects were animal genetic effect and permanent environmental effect of ewe. The effect of flock-year-month of test day measurement was fitted either as a fixed (FYM) or random (fym) effect. Heritabilities for fat content were estimated between 0.06 and 0.17 (FYM fitted) and between 0.06 and 0.11 (fym fitted). Heritabilities for protein content were estimated between 0.15 and 0.23 (FYM fitted) and between 0.10 and 0.18 (fym fitted). For fat content, variance ratios of permanent environmental effect of ewe were estimated between 0.04 and 0.11 (FYM fitted) and between 0.02 and 0.06 (fym fitted). For protein content, variance ratios of permanent environmental effect of ewe were estimated between 0.13 and 0.20 (FYM fitted) and between 0.08 and 0.12 (fym fitted). The proportion of phenotypic variance explained by fym effect ranged from 0.39 to 0.43 for fat content and from 0.25 to 0.36 for protein content. Genetic correlations between individual months of lactation ranged from 0.74 to 0.99 (fat content) and from 0.64 to 0.99 (protein content). Fat content heritabilities estimated with univariate animal models roughly corresponded with heritability estimates from multivariate models: 0.13 (FYM fitted) and 0.07 (fym fitted). Protein content heritabilities estimated with univariate animal models also corresponded with heritability estimates from multivariate models: 0.18 (FYM fitted) and 0.13 (fym fitted). PMID- 26732442 TI - Study of Genetic Diversity among Simmental Cross Cattle in West Sumatra Based on Microsatellite Markers. AB - A study was conducted to assess the genetic diversity among Simmental Cross cattle in West Sumatra using microsatellite DNA markers. A total of 176 individual cattle blood samples was used for obtaining DNA samples. Twelve primers of microsatellite loci as recommended by FAO were used to identify the genetic diversity of the Simmental Cross cattle population. Multiplex DNA fragment analysis method was used for allele identification. All the microsatellite loci in this study were highly polymorphic and all of the identified alleles were able to classify the cattle population into several groups based on their genetic distance. The heterozygosity values of microsatellite loci in this study ranged from 0.556 to 0.782. The polymorphism information content (PIC) value of the 12 observed loci is high (PIC>0.5). The highest PIC value in the Simmental cattle population was 0.893 (locus TGLA53), while the lowest value was 0.529 (locus BM1818). Based on the genetic distance value, the subpopulation of the Simmental Cross-Agam and the Simmental Cross Limapuluh Kota was exceptionally close to the Simmental Purebred thus indicating that a grading-up process has taken place with the Simmental Purebred. In view of the advantages possessed by the Simmental Cross cattle and the evaluation of the genetic diversity results, a number of subpopulations in this study can be considered as the initial (base) population for the Simmental Cross cattle breeding programs in West Sumatra, Indonesia. PMID- 26732443 TI - Relationship between Single Nucleotide Polymorphisms in the Peroxisome Proliferator-Activated Receptor Gamma Gene and Fatty Acid Composition in Korean Native Cattle. AB - The peroxisome proliferator-activated receptor gamma (PPARgamma) gene plays an important role in the biosynthesis process controlled by a number of fatty acid transcription factors. This study investigates the relationships between 130 single-nucleotide polymorphisms (SNPs) in the PPARgamma gene and the fatty acid composition of muscle fat in the commercial population of Korean native cattle. We identified 38 SNPs and verified relationships between 3 SNPs (g.1159-71208 A>G, g.42555-29812 G>A, and g.72362 G>T) and the fatty acid composition of commercial Korean native cattle (n = 513). Cattle with the AA genotype of g.1159 71208 A>G and the GG genotype of g.42555-29812 G>A and g.72362 G>T had higher levels of monounsaturated fatty acids and carcass traits (p<0.05). The results revealed that the 3 identified SNPs in the PPARgamma gene affected fatty acid composition and carcass traits, suggesting that these 3 SNPs may improve the flavor and quality of beef in commercial Korean native cattle. PMID- 26732444 TI - Effects of Rice Bran, Flax Seed, and Sunflower Seed on Growth Performance, Carcass Characteristics, Fatty Acid Composition, Free Amino Acid and Peptide Contents, and Sensory Evaluations of Native Korean Cattle (Hanwoo). AB - This study was conducted to evaluate the effect of dietary supplementation with rice bran, flax seed, or sunflower seed to finishing native Korean cattle (Hanwoo) on growth performances, carcass characteristics, fatty acid composition, free amino acid and peptide contents, and sensory evaluations of Longissimus muscle (LM). A total of 39 Hanwoo steers (average age of 22.2 mo and average body weight (BW) of 552.2 kg) were randomly divided into Control, rice bran (RB), flax seed (FS), or Sunflower seed (SS) groups. The steers were group fed for 273 d until they reached an average age of 31.2 mo. Final BW was 768.2, 785.8, 786.2, and 789.0 kg, and average daily gain was 0.79, 0.85, 0.82, and 0.84 kg for the Control, RS, FS, and SS groups, respectively (p>0.05). Fat thickness of the FS group (19.8 mm) was greater (p<0.05) than that of the other groups. Final yield grade converted into numerical values was 2.0 for the RB group, 1.7 for the Control and SS groups, and 1.4 for the FS group. Marbling degrees for the Control, SS, RB, and FS groups were 5.3, 5.1, 4.7, and 4.6, respectively. Percentages of palmitic acid (C16:0), stearic acid (C18:0), and arachidic acid (C20:0) in the LM were not different among the groups. Palmitoleic (C16:1) acid was higher (p<0.05) in the SS group. The concentration of oleic acid was highest (p<0.05) in the Control group (47.73%). The level of linolenic acid (C18:3) was 2.3 times higher (p<0.05) in the FS group compared to the other groups. Methionine concentration was (p<0.05) higher in FS (1.7 mg/100 g) and SS (1.2 mg/100 g) steers than in the Control or RB groups. Glutamic acid and alpha aminoadipic acid (alpha-AAA) contents were (p<0.05) higher in the FS group compared to the other groups. LM from the FS group had numerically higher (p>0.05) scores for flavor, umami, and overall palatability in sensory evaluations. In conclusion, supplementation of flax seed to diets of finishing Hanwoo steers improved sensory evaluations which might have been caused by increases in flavor related amino acids such as methionine, glutamic acid and alpha-AAA and peptides, anserine and carnosine, and their complex reactions. PMID- 26732445 TI - Effects of Cellulase Supplementation on Nutrient Digestibility, Energy Utilization and Methane Emission by Boer Crossbred Goats. AB - This study examined the effect of supplementing exogenous cellulase on nutrient and energy utilization. Twelve desexed Boer crossbred goats were used in a replicated 3*3 Latin square design with 23-d periods. Dietary treatments were basal diet (control, no cellulase), basal diet plus 2 g unitary cellulase/kg of total mixed ration dry matter (DM), and basal diet plus 2 g compound cellulase/kg of total mixed ration DM. Three stages of feeding trials were used corresponding to the three treatments, each comprised 23 d, with the first 14 d as the preliminary period and the following 9 d as formal trial period for metabolism trial. Total collection of feces and urine were conducted from the 4th d of the formal trial, and gas exchange measures were determined in indirect respiratory chambers in the last 3 d of the formal trial. Results showed that cellulase addition had no effect (p>0.05) on nutrient digestibility. Dietary supplementation of cellulase did not affect (p>0.05) N intake and retention in goats. Gross energy (GE) intake, fecal energy and urinary energy excretion, heat production were not affected (p>0.05) by the cellulase supplementation. Total methane emission (g/d), CH4 emission as a proportion of live weight or feed intake (DM, organic matter [OM], digestible DM or digestible OM), or CH4 energy output (CH4-E) as a proportion of energy intake (GE, digestible energy, or metabolizable energy), were similar (p>0.05) among treatments. There was a significant (p<0.001) relationship between CH4 and live weight (y = 0.645x+0.2, R(2) = 0.54), CH4 and DM intake (y = 16.7x+1.4, R(2) = 0.51), CH4 and OM intake (y = 18.8x+1.3, R(2) = 0.51) and CH4-E and GE intake. Results from this study revealed that dietary supplementation of cellulase may have no effect on nutrient digestibility, nitrogen retention, energy metabolism, and methane emission in goat. PMID- 26732446 TI - Effects of Candida norvegensis Live Cells on In vitro Oat Straw Rumen Fermentation. AB - This study evaluated the effect of Candida norvegensis (C. norvegensis) viable yeast culture on in vitro ruminal fermentation of oat straw. Ruminal fluid was mixed with buffer solution (1:2) and anaerobically incubated with or without yeast at 39 degrees C for 0, 4, 8, 16, and 24 h. A fully randomized design was used. There was a decrease in lactic acid (quadratic, p = 0.01), pH, (quadratic, p = 0.02), and yeasts counts (linear, p<0.01) across fermentation times. However, in vitro dry matter disappearance (IVDMD) and ammonia-N increased across fermentation times (quadratic; p<0.01 and p<0.02, respectively). Addition of yeast cells caused a decrease in pH values compared over all fermentation times (p<0.01), and lactic acid decreased at 12 h (p = 0.05). Meanwhile, yeast counts increased (p = 0.01) at 12 h. C. norvegensis increased ammonia-N at 4, 8, 12, and 24 h (p<0.01), and IVDMD of oat straw increased at 8, 12, and 24 h (p<0.01) of fermentation. Yeast cells increased acetate (p<0.01), propionate (p<0.03), and butyrate (p<0.03) at 8 h, while valeriate and isovaleriate increased at 8, 12, and 24 h (p<0.01). The yeast did not affect cellulolytic bacteria (p = 0.05), but cellulolytic fungi increased at 4 and 8 h (p<0.01), whereas production of methane decreased (p<0.01) at 8 h. It is concluded that addition of C. norvegensis to in vitro oat straw fermentation increased ruminal fermentation parameters as well as microbial growth with reduction of methane production. Additionally, yeast inoculum also improved IVDMD. PMID- 26732447 TI - (1)H-Nuclear Magnetic Resonance-Based Plasma Metabolic Profiling of Dairy Cows with Fatty Liver. AB - Fatty liver is a common metabolic disorder of dairy cows during the transition period. Historically, the diagnosis of fatty liver has involved liver biopsy, biochemical or histological examination of liver specimens, and ultrasonographic imaging of the liver. However, more convenient and noninvasive methods would be beneficial for the diagnosis of fatty liver in dairy cows. The plasma metabolic profiles of dairy cows with fatty liver and normal (control) cows were investigated to identify new biomarkers using (1)H nuclear magnetic resonance. Compared with the control group, the primary differences in the fatty liver group included increases in beta-hydroxybutyric acid, acetone, glycine, valine, trimethylamine-N-oxide, citrulline, and isobutyrate, and decreases in alanine, asparagine, glucose, gamma-aminobutyric acid glycerol, and creatinine. This analysis revealed a global profile of endogenous metabolites, which may present potential biomarkers for the diagnosis of fatty liver in dairy cows. PMID- 26732448 TI - Evaluation of Different Yeast Species for Improving In vitro Fermentation of Cereal Straws. AB - Information on the effects of different yeast species on ruminal fermentation is limited. This experiment was conducted in a 3*4 factorial arrangement to explore and compare the effects of addition of three different live yeast species (Candida utilis 1314, Saccharomyces cerevisiae 1355, and Candida tropicalis 1254) at four doses (0, 0.25*10(7), 0.50*10(7), and 0.75*10(7) colony-forming unit [cfu]) on in vitro gas production kinetics, fiber degradation, methane production and ruminal fermentation characteristics of maize stover, and rice straw by mixed rumen microorganisms in dairy cows. The maximum gas production (Vf), dry matter disappearance (IVDMD), neutral detergent fiber disappearance (IVNDFD), and methane production in C. utilis group were less (p<0.01) than other two live yeast supplemented groups. The inclusion of S. cerevisiae reduced (p<0.01) the concentrations of ammonia nitrogen (NH3-N), isobutyrate, and isovalerate compared to the other two yeast groups. C. tropicalis addition generally enhanced (p<0.05) IVDMD and IVNDFD. The NH3-N concentration and CH4 production were increased (p<0.05) by the addition of S. cerevisiae and C. tropicalis compared with the control. Supplementation of three yeast species decreased (p<0.05) or numerically decreased the ratio of acetate to propionate. The current results indicate that C. tropicalis is more preferred as yeast culture supplements, and its optimal dose should be 0.25*10(7) cfu/500 mg substrates in vitro. PMID- 26732449 TI - Rumen Degradability and Small Intestinal Digestibility of the Amino Acids in Four Protein Supplements. AB - The supplementation of livestock feed with animal protein is a present cause for public concern, and plant protein shortages have become increasingly prominent in China. This conflict may be resolved by fully utilizing currently available sources of plant protein. We estimated the rumen degradability and the small intestinal digestibility of the amino acids (AA) in rapeseed meal (RSM), soybean meal (SBM), sunflower seed meal (SFM) and sesame meal (SSM) using the mobile nylon bag method to determine the absorbable AA content of these protein supplements as a guide towards dietary formulations for the dairy industry. Overall, this study aimed to utilize protein supplements effectively to guide dietary formulations to increase milk yield and save plant protein resources. To this end, we studied four cows with a permanent rumen fistula and duodenal T shape fistula in a 4*4 Latin square experimental design. The results showed that the total small intestine absorbable amino acids and small intestine absorbable essential amino acids were higher in the SBM (26.34% and 13.11% dry matter [DM], respectively) than in the SFM (13.97% and 6.89% DM, respectively). The small intestine absorbable Lys contents of the SFM, SSM, RSM and SBM were 0.86%, 0.88%, 1.43%, and 2.12% (DM basis), respectively, and the absorbable Met contents of these meals were 0.28%, 1.03%, 0.52%, and 0.47% (DM basis), respectively. Among the examined food sources, the milk protein score of the SBM (0.181) was highest followed by those of the RSM (0.136), SSM (0.108) and SFM (0.106). The absorbable amino acid contents of the protein supplements accurately reflected protein availability, which is an important indicator of the balance of feed formulation. Therefore, a database detailing the absorbable AA should be established. PMID- 26732450 TI - Effects of Graded Levels of Isomaltooligosaccharides on the Performance, Immune Function and Intestinal Status of Weaned Pigs. AB - The objective of this study was to investigate the effects of graded levels of isomaltooligosaccharides (IMO) on the performance, immune function and intestinal microflora and intestinal mucosal morphology of weaned pigs. In a 28-day experiment, one hundred eighty, twenty eight-day-old, crossbred (Duroc*Large White*Landrace), weaned pigs, with an initial body weight of 8.19+/-1.45 kg, were fed either an unsupplemented corn-soybean meal based diet or similar diets supplemented with 0.2%, 0.4%, 0.6%, or 0.8% IMO added at the expense of corn. Each treatment was replicated six times with six pigs (three barrows and three gilts) per pen. From day 0 to 14, weight gain was linearly increased (p<0.05), while gain:feed (p<0.05) was linearly improved and diarrhea rate (p = 0.05) linearly declined as the IMO level increased. On d 14, the level of the immunoglobulins IgA, IgM, and IgG in the serum of pigs were linearly increased (p<0.05) with increasing IMO supplementation. Interleukin-6 (IL-6) was linearly (p<0.05) and quadratically (p<0.05) decreased as IMO intake increased. From day 15 to 28, there was a trend for weight gain to be linearly increased, and IL-2 was linearly (p<0.05) increased as IMO supplementation increased on d 28. Over the entire experiment, weight gain was linearly increased (p<0.05), while gain:feed (p<0.05) was linearly improved and diarrhea rate (p<0.05) was linearly decreased as the IMO level increased. Supplementation with IMO had no effect on the intestinal microflora of pigs in the ileum and cecum of pigs, as well as the villus height and crypt depth in the ileum and jejunum (p>0.05). These results indicate that dietary inclusion of IMO increases weight gain, gain:feed and enhanced the immune status of pigs, and could be a valuable feed additive for use in weaned pigs, particularly during the period immediately after weaning. PMID- 26732452 TI - Evaluation of Honey and Rice Syrup as Replacements for Sorbitol in the Production of Restructured Duck Jerky. AB - The aim of this study was to evaluate the potential of natural humectants such as honey and rice syrup to replace sorbitol in the production of restructured duck jerky. Each humectant was mixed at 3%, 6%, and 10% (wt/wt) concentrations with the marinating solution. The values of water activity and the moisture-to-protein ratio of all of the samples were maintained below 0.75. Jerky samples treated with honey retained more moisture than those exposed to other treatments. Among all samples, those treated with 10% sorbitol produced the highest processing yield and the lowest shear force values. The highest L* value and the lowest b* value were observed for the sorbitol-treated sample, followed by the rice syrup- and honey-treated samples. Duck jerky samples treated with 10% honey showed the highest scores for the sensory parameters evaluated. The overall acceptability scores of samples treated with rice syrup were comparable with those of samples treated with sorbitol. Microscopic observation of restructured duck jerky samples treated with honey showed stable forms and smaller pores when compared with other treatments. PMID- 26732451 TI - Effect of the Ratio of Raw Material Components on the Physico-chemical Characteristics of Emulsion-type Pork Sausages. AB - This study was conducted to investigate the effects of raw material ratio on the physicochemical characteristics of emulsion-type pork sausages. Experiment design was divided into 12 treatments, based on protein level (P), fat level (3P, 3.5P, and 4P), and water level (4P+10, 4P+15, 4P+20, and 4P+25). The pH and shear force values were significantly higher in T7 (3.5P fat and 4P+20 water) than those of other treatments. The lightness and redness were greatly reduced by increasing the quantity of water. The treatments containing 3P fat and 4P+20 water had the highest values of cohesiveness, springiness, gumminess, and chewiness. On the whole, when the protein (P) and fat (3P, 3.5P, 4P) levels were fixed, an increase over the appropriate moisture level deteriorated many physicochemical characteristics. PMID- 26732453 TI - Is Hiding Foot and Mouth Disease Sensitive Behavior for Farmers? A Survey Study in Sri Lanka. AB - Foot and mouth disease (FMD) has a long history in Sri Lanka and was found to be endemic in various parts of the country and constitutes a constant threat to farmers. In Sri Lanka, currently there is no regular, nationwide vaccination programme devised to control FMD. Therefore, improving farmers' knowledge regarding distinguishing FMD from other diseases and ensuring prompt reporting of any suspicion of FMD as well as restricting movement of animals are critical activities for an effective FMD response effort. Therefore, the main purpose of this study was to clarify the relationship between farmers' knowledge levels and their behaviors to establish a strategy to control FMD. In our study, item count technique was applied to estimate the number of farmers that under-report and sell FMD-infected animals, although to do so is prohibited by law. The following findings were observed: about 63% of farmers have very poor knowledge of routes of FMD transmission; 'under-reporting' was found to be a sensitive behavior and nearly 23% of the farmers were reluctant to report FMD-infected animals; and 'selling FMD-infected animals' is a sensitive behavior among high-level knowledge group while it is a non-sensitive behavior among the low-level knowledge group. If farmers would understand the importance of prompt reporting, they may report any suspected cases of FMD to veterinary officials. However, even if farmers report honestly, they do not want to cull FMD-infected animals. Thus, education programs should be conducted not only on FMD introduction and transmission, but also its impact. Furthermore, consumers may criticize the farmers for culling their infected animals. Hence, not only farmers, but also consumers need to be educated on the economic impact of FMD and the importance of controlling an outbreak. If farmers have a high knowledge of FMD transmission, they consider selling FMD-infected animals as a sensitive behavior. Therefore, severe punishment should be levied for selling FMD-infected animals. PMID- 26732454 TI - Resveratrol-loaded Nanoparticles Induce Antioxidant Activity against Oxidative Stress. AB - Resveratrol acts as a free radical scavenger and a potent antioxidant in the inhibition of numerous reactive oxygen species (ROS). The function of resveratrol and resveratrol-loaded nanoparticles in protecting human lung cancer cells (A549) against hydrogen peroxide was investigated in this study. The 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulphonic acid (ABTS) assay was performed to evaluate the antioxidant properties. Resveratrol had substantially high antioxidant capacity (trolox equivalent antioxidant capacity value) compared to trolox and vitamin E since the concentration of resveratrol was more than 50 MUM. Nanoparticles prepared from beta-lactoglobulin (beta-lg) were successfully developed. The beta lg nanoparticle showed 60 to 146 nm diameter in size with negatively charged surface. Non-cytotoxicity was observed in Caco-2 cells treated with beta-lg nanoparticles. Fluorescein isothiocynate-conjugated beta-lg nanoparticles were identified into the cell membrane of Caco-2 cells, indicating that nanoparticles can be used as a delivery system. Hydrogen peroxide caused accumulation of ROS in a dose- and time-dependent manner. Resveratrol-loaded nanoparticles restored H2O2 induced ROS levels by induction of cellular uptake of resveratrol in A549 cells. Furthermore, resveratrol activated nuclear factor erythroid 2-related factor 2 Kelch ECH associating protein 1 (Nrf2-Keap1) signaling in A549 cells, thereby accumulation of Nrf2 abundance, as demonstrated by western blotting approach. Overall, these results may have implications for improvement of oxidative stress in treatment with nanoparticles as a biodegradable and non-toxic delivery carrier of bioactive compounds. PMID- 26732455 TI - Body Temperature Monitoring Using Subcutaneously Implanted Thermo-loggers from Holstein Steers. AB - Body temperature (BT) monitoring in cattle could be used to early detect fever from infectious disease or physiological events. Various ways to measure BT have been applied at different locations on cattle including rectum, reticulum, milk, subcutis and ear canal. In other to evaluate the temperature stability and reliability of subcutaneous temperature (ST) in highly fluctuating field conditions for continuous BT monitoring, long term ST profiles were collected and analyzed from cattle in autumn/winter and summer season by surgically implanted thermo-logger devices. Purposes of this study were to assess ST in the field condition as a reference BT and to determine any location effect of implantation on ST profile. In results, ST profile in cattle showed a clear circadian rhythm with daily lowest at 05:00 to 07:00 AM and highest around midnight and rather stable temperature readings (mean+/-standard deviation [SD], 37.1 degrees C to 37.36 degrees C+/-0.91 degrees C to 1.02 degrees C). STs are 1.39 degrees C to 1.65 degrees C lower than the rectal temperature and sometimes showed an irregular temperature drop below the normal physiologic one: 19.4% or 36.4% of 54,192 readings were below 36.5 degrees C or 37 degrees C, respectively. Thus, for BT monitoring purposes in a fever-alarming-system, a correction algorithm is necessary to remove the influences of ambient temperature and animal resting behavior especially in winter time. One way to do this is simply discard outlier readings below 36.5 degrees C or 37 degrees C resulting in a much improved mean+/ SD of 37.6 degrees C+/-0.64 degrees C or 37.8 degrees C+/-0.55 degrees C, respectively. For location the upper scapula region seems the most reliable and convenient site for implantation of a thermo-sensor tag in terms of relatively low influence by ambient temperature and easy insertion compared to lower scapula or lateral neck. PMID- 26732456 TI - Kinetics of particle coarsening with allowance for Ostwald ripening and coagulation. AB - The evolution of particle coarsening due to a combined effect of Ostwald ripening and coagulation at the concluding stage of phase transition processes in metastable media is considered. A complete analytical solution of integro differential equations with a memory kernel is found in special self-similar variables for supersaturated solutions and supercooled liquids. It is shown that the particle distribution function becomes narrower and bell-shaped when decreasing the metastability level. The analytical solutions obtained are in good agreement with experimental data. PMID- 26732458 TI - Promoting high quality research with life-limited children and their families: Establishment of a joint research group between Together for Short Lives and the Association for Paediatric Palliative Medicine. PMID- 26732457 TI - Efficacy of Fostera PRRS modified live virus vaccine against a Canadian heterologous virulent field strain of porcine reproductive and respiratory syndrome virus. AB - Vaccination is a useful option to control infection with porcine reproductive and respiratory syndrome virus (PRRSV), and several modified live-PRRSV vaccines have been developed. These vaccines have shown some efficacy in reducing the incidence and severity of clinical disease as well as the duration of viremia and virus shedding but have failed to provide sterilizing immunity. The efficacy of modified live-virus (MLV) vaccines is greater against a homologous strain compared with heterologous PRRSV strains. The objective of this study was to evaluate the efficacy of Fostera PRRS MLV vaccine in protecting against challenge with a heterologous field strain widely circulating in the swine herds of eastern Canada. Forty-six piglets were divided into 4 groups: nonvaccinated nonchallenged; nonvaccinated-challenged; vaccinated-challenged; and vaccinated nonchallenged. The animals were vaccinated at 23 d of age with Fostera PRRS and challenged 23 d later with a heterologous field strain of PRRSV (FMV12-1425619). Overall, the vaccine showed some beneficial effects in the challenged animals by reducing the severity of clinical signs and the viral load. A significant difference between nonvaccinated and vaccinated animals was detected for some parameters starting 11 to 13 d after challenge, which suggested that the cell mediated immune response or other delayed responses could be more important than pre-existing PRRSV antibodies in vaccinated animals within the context of protection against heterologous strains. PMID- 26732459 TI - A hybrid of thiazolidinone with the hydroxamate scaffold for developing novel histone deacetylase inhibitors with antitumor activities. AB - A series of novel histone deacetylase (HDAC) inhibitors were designed, synthesized and evaluated based on the strategies of a hybrid of the classic pharmacophore of HDAC inhibitors with the thiazolidinone scaffold. Some of the compounds 12i showed potent HDAC1 inhibition with nM IC50 values, more importantly, compound displayed much better anti-metastatic effects than vorinostat (SAHA) against migration of the A549 cell line. Further mechanism exploration implied that compound 12i may inhibit tumor metastasis via modulating the epithelial-mesenchymal transition (EMT) and upregulating the acetylation of alpha-tubulin. PMID- 26732461 TI - Adult Verbal Abstract Reasoning Assessment Instruments and their Clinimetric Properties. AB - OBJECTIVE: This systematic review aims to identify, examine, and compare tests used to measure and assess verbal abstract reasoning (VAR). METHOD: Seven tests were identified through a systematic search of electronic databases, neuropsychological textbooks, and online catalogs. Clinical utility, normative data, and psychometric properties (internal consistency, test-retest reliability, and construct validity) of current test versions were evaluated using recent studies. A modified version of the CanChild Outcome Measures Rating Form, and structured quality assessment criteria were used in the evaluation process. RESULTS: The WAIS-IV Similarities subtest was ranked the highest, followed by the Shipley-2 Abstraction test and Gorham's Proverbs test. These three tests had sufficient validity to recommend their use, however some caution is advised for the latter two in terms of construct purity, and age of normative data, respectively. Other tests reviewed were the Delis-Kaplan Executive Functioning System Proverbs subtest, the Stanford-Binet Intelligence Scale fifth edition Verbal Analogies subtests, the Conceptual Level Analogy Test, and the Verbal Concept Attainment Test. For the majority of tests, construct validity was lacking while reliabilities were sufficient. CONCLUSIONS: Lack of sound psychometric evidence limits the range of options for the practitioner to choose a test with confidence to assess VAR. While there is merit in the clinical utility of the majority of assessment instruments evaluated in this review, caution is recommended before deciding to use a test that does not carry sufficient psychometric evidence to support its use. Further research is recommended to improve the library of tests available to clinicians and researchers. PMID- 26732460 TI - Validation of In utero Tractography of Human Fetal Commissural and Internal Capsule Fibers with Histological Structure Tensor Analysis. AB - Diffusion tensor imaging (DTI) and tractography offer the unique possibility to visualize the developing white matter macroanatomy of the human fetal brain in vivo and in utero and are currently under investigation for their potential use in the diagnosis of developmental pathologies of the human central nervous system. However, in order to establish in utero DTI as a clinical imaging tool, an independent comparison between macroscopic imaging and microscopic histology data in the same subject is needed. The present study aimed to cross-validate normal as well as abnormal in utero tractography results of commissural and internal capsule fibers in human fetal brains using postmortem histological structure tensor (ST) analysis. In utero tractography findings from two structurally unremarkable and five abnormal fetal brains were compared to the results of postmortem ST analysis applied to digitalized whole hemisphere sections of the same subjects. An approach to perform ST-based deterministic tractography in histological sections was implemented to overcome limitations in correlating in utero tractography to postmortem histology data. ST analysis and histology-based tractography of fetal brain sections enabled the direct assessment of the anisotropic organization and main fiber orientation of fetal telencephalic layers on a micro- and macroscopic scale, and validated in utero tractography results of corpus callosum and internal capsule fiber tracts. Cross validation of abnormal in utero tractography results could be achieved in four subjects with agenesis of the corpus callosum (ACC) and in two cases with malformations of internal capsule fibers. In addition, potential limitations of current DTI-based in utero tractography could be demonstrated in several brain regions. Combining the three-dimensional nature of DTI-based in utero tractography with the microscopic resolution provided by histological ST analysis may ultimately facilitate a more complete morphologic characterization of axon guidance disorders at prenatal stages of human brain development. PMID- 26732462 TI - Evaluation of hypointense liver lesions during hepatobiliary phase MR imaging in normal and cirrhotic livers: is increasing flip angle reliable? AB - Gd-EOB-DTPA is a newly developed liver specific magnetic resonance contrast agent, which is widely used for focal liver lesion (FLL) detection and liver function evaluation. However, it has been demonstrated that hepatocytes uptake of Gd-EOB-DTPA obviously decreased in cirrhotic liver, and cirrhotic liver parenchyma may show reduced enhancement in hepatobiliary phase, which would result in decreased liver-to-lesion contrast (LLC) and liver to lesion signal intensity ratio (LLSIR). Therefore, it is important to improve the image quality in cirrhotic liver, as it may alter therapeutic strategy. In this paper, we have shown adjustments of the flip angle (FA) provides a simple step to achieve better image quality for evaluation of FLLs, especially to those patients with severe liver cirrhosis. On the basis of our quantitative analysis, both of the LLC and the LLSIR with high FA protocol were always higher than those of low FA protocol. Additionally, on high FA images, more FLLs were detected, peritumoral invasion was found, boundary of the tumor was more remarkably, and better visualization of bile duct was observed. In conclusion, for the patient with severe liver cirrhosis, increasing FA can obviously improve the image quality, which is helpful for FLLs depiction. PMID- 26732463 TI - Improving physician's adherence to completing vaccination schedules for patients with type 2 diabetes attending non-communicable diseases clinics in West Bay Health Center, Qatar. AB - Incomplete vaccination for patients with type 2 diabetes attending non communicable diseases (NCD) clinics is an issue that could affect patient's health and wellness negatively and puts patients at high risk of serious diseases. We aimed to improve physicians adherence to complete vaccination schedule for patients with type 2 diabetes attending NCD clinics in west bay health center according to American Diabetes Association (ADA) recommendation by 25% by January 2015. In the pre-intervention phase: the quality improvement team designed a checklist to collect the percentage of physician's adherence of prescription of the recommended vaccination for patients with type 2 diabetes. The percentage of complete vaccination in patients with diabetes attending NCD clinic in West Bay Health Center was 20% . In the intervention phase the intervention was in the form of: the creation a vaccination form and attached to the (NCD) progress note; to distribute and remind the physicians about the ADA guidelines vaccination recommendations; a summary of the vaccination schedule developed and attached to (NCD) form; development of vaccination reminder posters and posters in the waiting area, nurse station, and physician clinics and education and orientation sessions for NCD clinic staff. In the post-intervention phase the average percentage of complete vaccination in patients with diabetes attending NCD clinic in West Bay Health Center increased to 69%. PMID- 26732464 TI - Improving drug chart documentation in elective surgical patient admissions. AB - National Institute for Health and Care Excellence (NICE) guidelines state that all healthcare organisations should put policies in place for medication reconciliation on admission. At Croydon University Hospital a medication history had previously been taken in Foundation Year 1 (FY1) preoperative clinics. However, when these clinics were deemed unnecessary, this opportunity for drug chart documentation was lost, along with an awareness of this responsibility among the FY1s. As a result patients were being admitted to wards without adequate drug chart documentation which resulted in a serious untoward incident occurring. This project aimed to increase awareness among FY1s of this responsibility and as a result increase drug chart documentation in postoperative elective surgical patients. The drug charts of 40 postoperative elective surgical patients admitted to all surgical wards were reviewed over a 2 week period. 12.5% (4/32) of patients taking regular medication had these correctly prescribed, with 'high risk medication omissions' found in 7.5% (3/40). Documentation of an allergy status was absent in 17.5% (7/40) of patients, including 5% (2/40) of whom had a known drug allergy. To create awareness of this responsibility, first, a presentation was given to the FY1s, second, posters to prompt action were placed on the elective surgical wards, and finally, the Director of Medical Education emailed the FY1s reiterating these facts. We then reviewed the drug charts of 45 elective postoperative patients over a 2 week period following these interventions. The results showed: correct prescription of regular medications improved to 48% (16/33); 'high risk medication omissions' reduced to 4% (2/45); documentation of allergy status on the drug charts increased to 87% (39/45); failure to document a known drug allergy on the drug chart fell to 2% (1/45); and patients with a 'high risk medication omission' or an undocumented known drug allergy decreased from 12.5% (5/40) to 7 % (3/45). This study has highlighted an area in which medication reconciliation and drug chart documentation were inadequate, and posed a risk to patient safety. Interventions designed to educate the FY1s and inform them of their responsibility improved standards in regular medication prescription and allergy documentation. However, leaving the onus with the FY1s was not enough to achieve adequate drug chart documentation. Further project cycles may therefore require the implementation of a step within the patient admission protocol in the preoperative ward that requires the nursing staff to contact the team's doctor when the patient arrives in hospital to ensure satisfactory drug chart documentation. In addition, collaboration with the pharmacists could also allow a 'best possible medication history' to be taken on the day of admission and thus reduce risk to patient safety. PMID- 26732465 TI - Alexithymia in chronic and episodic migraine: a comparative study. AB - BACKGROUND: Alexithymia is a term used to describe a disorder where patients have difficulty in expressing their own feelings in words. AIMS: The analysis of alexithymia in patients suffering from chronic migraine (CM) or episodic migraine (EM) compared to healthy controls. METHODS: Two clinical samples formed by 80 CM patients (21 males and 59 females, mean age: 44.65) and 44 EM patients (8 males and 36 females, mean age: 42.18) were enrolled. A group of 67 healthy subjects served as controls (26 males and 41 females, mean age: 41.21). All subjects were requested to fill in the 20-item version of the Toronto Alexithymia Scale (TAS 20). RESULTS: We found a statistically significant difference between groups in Factor 1 (difficulty in describing feelings), F(2, 191) = 7.96, p < 0.001, and in TAS total, F(2, 191) = 5.37, p = 0.005. Post-hoc analyses revealed that CM patients had higher scores in TAS factor 1 and in TAS total than healthy controls. There were no significant differences between CM and EM patients, even if CM sufferers reported a trend towards higher scores in each TAS factor as well as in TAS total. CONCLUSIONS: Alexithymia emerges as a potential characteristic trait of migraine, regardless of disease severity. PMID- 26732466 TI - Graphene decorated with MoS2 nanosheets: a synergetic energy storage composite electrode for supercapacitor applications. AB - The two-dimensional (2D) transition metal dichalcogenide nanosheet-carbon composite is an attractive material for energy storage because of its high Faradaic activity, unique nanoconstruction and electronic properties. In this work, a facile one step preparation of a molybdenum disulfide (MoS2) nanosheet graphene (MoS2/G) composite with the in situ reduction of graphene oxide is reported. The structure, morphology and composition of the pure MoS2 and composites were comparatively analyzed by various characterization techniques. The electrochemical performance of the pure MoS2, graphene oxide and the MoS2/G composite electrode materials was evaluated by cyclic voltammogram, galvanostatic charge-discharge and electrochemical impedance spectroscopy. The MoS2/G composite showed a higher specific capacitance (270 F g(-1) at a current density of 0.1 A g(-1)) compared to the pure MoS2 (162 F g(-1)) in a neutral aqueous electrolyte. Moreover, the energy density of the composite electrode is also higher (12.5 Wh kg(-1)) with a high power density (2500 W kg(-1)) compared to the pure MoS2. In addition, the MoS2/G composite electrode showed excellent cyclic stability even after 1000 cycles. The enhancement in specific capacitance, excellent cyclic stability and high energy density of the composite electrode are mainly due to the interconnected conductive network of the composite as well as the synergetic effect of the pure MoS2 and graphene. The experimental results demonstrated that the MoS2/G composite is a promising electrode material for high-performance supercapacitors. PMID- 26732467 TI - Modeling sediment deposition from marine outfall jets. AB - This paper presents a two-dimensional model to study the sediment deposition from marine outfall jets. The introduced unidirectional coupling (fluid-sediment) is an appropriate choice in the case of low-concentrated particle-laden jets such as municipal wastewater discharge, where the concentration of particles is small enough and does not affect the hydrodynamic development of the jet in the nearfield. The sedimentation model takes advantage of the preferential concentration phenomenon. The deposition criterion states that the deposition of sediments begins when the vertical component of the entrainment velocity becomes smaller than the settling velocity. Once the deposition process begins, it is controlled by the settling velocity, entrainment velocity, volume flux, and sediment concentration. The deposition along the jet trajectory is expressed by an ordinary differential equation coupled with the liquid phase equations. Experiments of Lane-Serff and Moran [Sedimentation from Buoyant jets. J Hyd Eng. 2005;131(3):166-174], Cuthbertson and Davies [Deposition from particle-laden, round, turbulent, horizontal, buoyant jets in stationary and coflowing receiving fluids. J Hydr Eng. 2008;134(4):390-402], and Lee [Mixing of horizontal sediment laden jets [dissertation]. Hong Kong: University of Hong Kong; 2010], chosen from bibliography, are used to validate the model. These experiments cover the cases of horizontal and inclined buoyant jets in stationary ambient, horizontal buoyant jets in co-flow current and nonbuoyant horizontal jets in stationary ambient. Good agreement between the experiments and the obtained simulations is revealed. PMID- 26732468 TI - Spatial Relationship of Focal Impulses, Rotors and Low Voltage Zones in Patients With Persistent Atrial Fibrillation. AB - INTRODUCTION: Focal impulses (FI) and rotors are sources associated with the initiation and maintenance of atrial fibrillation (AF). Their ablation results in a lower recurrence rate. The aim of this study was to characterize for the first time the spatial relationship between such sources and atrial low voltage zones (LVZ) representing fibrosis. METHODS: Twenty-five consecutive patients undergoing their first ablation for persistent AF were included. Voltage mapping of both atria was done during AF. Endocardial mapping of FI and rotors (sources) was performed using a basket catheter and displayed using RhythmView(TM) (Topera Inc.) before ablation. Spatial relationship of LVZ and sources was analyzed. RESULTS: LVZs covered 13 +/- 12% of right atrial (RA) endocardial surface and 33 +/- 25% of left atrial (LA) endocardial surface. The median number of sources was 1 [1-3] in RA and 3 [1-4] in LA. Of LA sources, 18 (30%) were definitely not associated with LVZs or pulmonary vein (PV) antra. Of RA sources, 32 (84%) were remote from LVZ. During ablation of such sources substantial cycle length (CL) prolongation or AF conversion occurred in 11/23 patients (48%). Altogether, 8/11 (73%) of these pertinent sources were located remotely from LVZ and PV antra. CONCLUSIONS: There is a wide discrepancy in distribution of LVZ areas and sites of identified rotors. Site and incidence of FIRM sources appear to be unpredictable with atrial substrate mapping. Further prospective, randomized studies are necessary to elucidate the impact of additional ablation of such sources in patients with persistent or longstanding persistent AF. PMID- 26732469 TI - Temporal Control of Gelation and Polymerization Fronts Driven by an Autocatalytic Enzyme Reaction. AB - Chemical systems that remain kinetically dormant until activated have numerous applications in materials science. Herein we present a method for the control of gelation that exploits an inbuilt switch: the increase in pH after an induction period in the urease-catalyzed hydrolysis of urea was used to trigger the base catalyzed Michael addition of a water-soluble trithiol to a polyethylene glycol diacrylate. The time to gelation (minutes to hours) was either preset through the initial concentrations or the reaction was initiated locally by a base, thus resulting in polymerization fronts that converted the mixture from a liquid into a gel (ca. 0.1 mm min(-1)). The rate of hydrolytic degradation of the hydrogel depended on the initial concentrations, thus resulting in a gel lifetime of hours to months. In this way, temporal programming of gelation was possible under mild conditions by using the output of an autocatalytic enzyme reaction to drive both the polymerization and subsequent degradation of a hydrogel. PMID- 26732470 TI - Evaluation of neck node response after radiotherapy: minimizing equivocal results. PMID- 26732471 TI - Excretion of radionuclides in human breast milk after nuclear medicine examinations. Biokinetic and dosimetric data and recommendations on breastfeeding interruption. AB - PURPOSE: To review early recommendations and propose guidelines for breastfeeding interruption after administration of radiopharmaceuticals, based on additional biokinetic and dosimetric data. METHODS: Activity concentrations in breast milk from 53 breastfeeding patients were determined. The milk was collected at various times after administration of 16 different radiopharmaceuticals. The fraction of the activity administered to the mother excreted in the breast milk, the absorbed doses to various organs and tissues and the effective dose to the infant were estimated. RESULTS: The fraction of the administered activity excreted per millilitre of milk varied widely from 10(-10) to 10(-3) MBq/MBq administered. For (99m)Tc-labelled radiopharmaceuticals, the total fraction of the administered activity excreted in the milk varied from 0.0057 % for (99m)Tc-labelled red blood cells (RBC) to 19 % for (99m)Tc-pertechnetate. The effective dose to an infant per unit activity administered to the mother ranged from 6.7 * 10(-6) mSv/MBq for (99m)Tc-labelled RBC to 3.6 * 10(-2) mSv/MBq for (99m)Tc-pertechnetate. For the other radiopharmaceuticals, the total fraction of administered activity excreted in the milk varied from 0.018 % ((51)Cr-EDTA) to 48 % ((131)I-NaI). The effective dose ranged from 5.6 * 10(-5) mSvinfant/MBqmother ((51)Cr-EDTA) to 106 mSvinfant/MBqmother ((131)I-NaI). CONCLUSIONS: Based on an effective dose limit of 1 mSv to the infant and a typical administered activity, we recommend cessation of breastfeeding for (131)I-NaI and interruption of feeding for 12 h for (125)I-iodohippurate, (131)I-iodohippurate, (99m)Tc-pertechnetate and (99m)Tc MAA. During this 12-h period all breast milk should be expressed at least three times and discarded. For the other radiopharmaceuticals included in this study, no interruption of breastfeeding is necessary. PMID- 26732472 TI - Immune Checkpoint Blockade in Hepatocellular Carcinoma. PMID- 26732473 TI - Effect of functionalization on drug delivery potential of carbon nanotubes. AB - The main aim of the present investigation was to explore the effect of functionalization on drug delivery potential of carbon nanotubes (CNTs) and to compare the in vitro and in vivo cancer targeting potential of doxorubicin HCL (DOX)-loaded ox-/multi-walled CNTs (MWCNTs), DOX-loaded PEG-MWCNTs and DOX-loaded FA-PEG-MWCNTs. The DOX/PEG-FA-MWCNTs showed enhanced cytotoxicity and were most preferentially taken up by the cancerous cells. The obtained results also support the extended resistance time and sustained release profile of drug-loaded surface engineered MWCNTs. Overall, we concluded that the developed MWCNTs nanoformulations have higher cancer targeting potential. PMID- 26732474 TI - Ribosomal S6 kinase 4 (RSK4) expression in ovarian tumors and its regulation by antineoplastic drugs in ovarian cancer cell lines. AB - Survival rate in ovarian cancer depends on the stage of the disease. RSK4, which has been considered as a tumor suppressor factor, controls cells invasion due to its antiinvasive and antimetastatic properties. Modulation of RSK4 expression could be an important event to increase the survival rate in ovarian cancer patients. Thus, the goal of the present study was to establish the differences in RSK4 expression among normal, benign and malignant ovarian tissues and to determine whether antineoplastic drugs regulate its expression in SKOV3 and TOV 112D cells. RSK4 levels in 30 malignant ovarian tumors, 64 benign tumors and 36 normal ovary tissues were determined by reverse transcription polymerase chain reaction and Western blot. Modulation of RSK4 expression by two antineoplastic drugs (cisplatin and vorinostat) was also studied in the SKOV3 and TOV-112D ovarian cancer cell lines using the same techniques. RSK4 mRNA and protein levels were decreased in malignant ovarian tumors as compared to benign tumors and normal tissue. These low-RSK4 levels were significantly associated with advanced stages of ovarian cancer. RSK4 expression was increased after incubation of SKOV3 and TOV-112D cell lines with cisplatin and vorinostat for 24 h. The combination of these antineoplastic drugs did not produce a synergistic or additive effect. These results suggest that RSK4 is expressed at low levels in malignant ovarian tumors, which correlates with advanced stages of the disease. Additionally, RSK4 expression is regulated by cisplatin and vorinostat in two ovarian cancer cell lines. PMID- 26732475 TI - 27-Hydroxycholesterol stimulates cell proliferation and resistance to docetaxel induced apoptosis in prostate epithelial cells. AB - Although the causes of prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are not known, the role of oxidative stress, aging, and diet are suspected to increase the incidence of prostate complications. The cholesterol oxidation derivative (oxysterol) 27-hydroxycholesterol (27-OHC) is the most prevalent cholesterol metabolite in the blood. As aging, oxidative stress, and hypercholesterolemia are associated with increased risk of PCa and BPH, and because 27-OHC levels are also increased with aging, hypercholesterolemia, and oxidative stress, determining the role of 27-OHC in the progression of PCas and BPH is warranted. In this study, we determined the effect of 27-OHC in human prostate epithelial cells RWPE-1. We found that 27-OHC stimulates proliferation and increases androgen receptor (AR) transcriptional activity. 27-OHC also increased prostate-specific antigen expression and enhanced AR binding to the androgen response element compared to controls. Silencing AR expression with siRNA markedly reduced the 27-OHC-induced proliferation. Furthermore, 27-OHC blocked docetaxel-induced apoptosis. Altogether, our results suggest that 27-OHC may play an important role in PCa and BPH progression by promoting proliferation and suppressing apoptosis. PMID- 26732476 TI - Melatonin prevents abnormal mitochondrial dynamics resulting from the neurotoxicity of cadmium by blocking calcium-dependent translocation of Drp1 to the mitochondria. AB - Cadmium (Cd) is a persistent environmental toxin and occupational pollutant that is considered to be a potential risk factor in the development of neurodegenerative diseases. Abnormal mitochondrial dynamics are increasingly implicated in mitochondrial damage in various neurological pathologies. The aim of this study was to investigate whether the disturbance of mitochondrial dynamics contributed to Cd-induced neurotoxicity and whether melatonin has any neuroprotective properties. After cortical neurons were exposed to 10 MUM cadmium chloride (CdCl2 ) for various periods (0, 3, 6, 12, and 24 hr), the morphology of their mitochondria significantly changed from the normal tubular networks into punctuated structures within 3 hr. Following this pronounced mitochondrial fragmentation, Cd treatment led to signs of mitochondrial dysfunction, including excess reactive oxygen species (ROS) production, decreased ATP content, and mitochondrial membrane potential (?Psim) loss. However, 1 mM melatonin pretreatment efficiently attenuated the Cd-induced mitochondrial fragmentation, which improved the turnover of mitochondrial function. In the brain tissues of rats that were intraperitoneally given 1 mg/kg CdCl2 for 7 days, melatonin also ameliorated excessive mitochondrial fragmentation and mitochondrial damage in vivo. Melatonin's protective effects were attributed to its roles in preventing cytosolic calcium ([Ca(2+) ]i ) overload, which blocked the recruitment of Drp1 from the cytoplasm to the mitochondria. Taken together, our results are the first to demonstrate that abnormal mitochondrial dynamics is involved in cadmium induced neurotoxicity. Melatonin has significant pharmacological potential in protecting against the neurotoxicity of Cd by blocking the disbalance of mitochondrial fusion and fission. PMID- 26732478 TI - Terahertz beat oscillation of plasmonic electrons interacting with femtosecond light pulses. AB - Plasmon resonance in nanostructured metals is in essence collective oscillation of free electrons, which is driven by optical electric fields and oscillates at nearly the same frequency as the excitation photons. This is the basic physics for the currently extensively interested topics in optical metamaterials, optical switching, and logic optical "circuits" with potential applications in optical communication and optical computation. We present here an interference effect between photons and plasmon electrons, which is observed as multi-cycle beat oscillation. The beat frequency is in the range of 3~4 THz, which is equal to the difference between optical frequency of the photons and oscillation frequency of the plasmon electrons. Such beat oscillation evolves in a time scale of more than 1 ps, which is much longer than the optical pulse length, implying interaction between photons and pure damping plasmon-electrons. The discovered mechanisms might be important for exploring new approaches for THz generation. PMID- 26732477 TI - Intravital imaging of Ca(2+) signals in lymphocytes of Ca(2+) biosensor transgenic mice: indication of autoimmune diseases before the pathological onset. AB - Calcium ion (Ca(2+)) signaling is a typical phenomenon mediated through immune receptors, such as the B-cell antigen receptor (BCR), and it is important for their biological activities. To analyze the signaling of immune receptors together with their in vivo dynamics, we generated stable transgenic mice with the Foster/fluorescence resonance energy transfer (FRET)-based Ca(2+) indicator yellow cameleon 3.60 (YC3.60), based on the Cre/loxP system (YC3.60(flox)). We successfully obtained mice with specific YC3.60 expression in immune or nerve cells as well as mice with ubiquitous expression of this indicator. We established five-dimensional (5D) (x, y, z, time, and Ca(2+)) intravital imaging of lymphoid tissues, including the bone marrow. Furthermore, in autoimmune-prone models, the CD22(-/-) and C57BL/6- lymphoproliferation (lpr)/lpr mouse, Ca(2+) fluxes were augmented, although they did not induce autoimmune disease. Intravital imaging of Ca(2+) signals in lymphocytes may improve assessment of the risk of autoimmune diseases in model animals. PMID- 26732479 TI - A polymer scaffold for self-healing perovskite solar cells. AB - Advancing of the lead halide perovskite solar cells towards photovoltaic market demands large-scale devices of high-power conversion efficiency, high reproducibility and stability via low-cost fabrication technology, and in particular resistance to humid environment for long-time operation. Here we achieve uniform perovskite film based on a novel polymer-scaffold architecture via a mild-temperature process. These solar cells exhibit efficiency of up to ~ 16% with small variation. The unencapsulated devices retain high output for up to 300 h in highly humid environment (70% relative humidity). Moreover, they show strong humidity resistant and self-healing behaviour, recovering rapidly after removing from water vapour. Not only the film can self-heal in this case, but the corresponding devices can present power conversion efficiency recovery after the water vapour is removed. Our work demonstrates the value of cheap, long chain and hygroscopic polymer scaffold in perovskite solar cells towards commercialization. PMID- 26732480 TI - Brokering trust: estimating the cost of physician-assisted death. PMID- 26732481 TI - Experiencing Couple Relationships in the Line of Fire. AB - The study aims to explore the way civilians living in the line of fire experience the impact of exposure to warfare on their couple relationships. Semistructured interviews were conducted with 14 couples living on the Israeli side of the border with the Gaza Strip. Four themes emerged: Overall perception of the security situation's impact on the dyadic relationships, dyadic intimacy, role division and decision-making, and Couple's emotional coping: partnership versus separateness. The findings were organized along a continuum between impacted and not-impacted relationships. Couple's position on this continuum was not fixed and could change as a result of to the security situation or marital therapy. The findings were framed in concepts from Dialectic Theory and from the Family Adaptation Models. Implications for couple therapy in these situations were specified. PMID- 26732482 TI - Children born from infertility treatment are not at risk of developmental delays, study finds. PMID- 26732483 TI - Recent developments in antivirals against hepatitis B virus. AB - Chronic hepatitis B virus (HBV) infection (CHB) is a major cause of cirrhosis and hepatocellular carcinoma (HCC). Although the availability of HBV vaccines effectively reduces the incidence of HBV infection, the healthcare burden from CHB remains high. Several antiviral agents, such as (pegylated-) interferon-alpha and nucleos(t)ide analogs are approved by US FDA for chronic HBV infection management. Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) have been recommended as the first-line anti-HBV drugs for excellent viral suppression with a low risk of antiviral resistance, but the cost and need for essentially life long treatment are considerable challenges. And none of these current treatments can eradicate the intracellular virus. Given these issues, there is still an unmet medical need for an efficient HBV cure. We summarize here the key developments of antivirals against hepatitis B virus, including HBV replication cycle inhibitors and host immune regulators. PMID- 26732484 TI - Intrinsic, extrinsic and endoplasmic reticulum stress-induced apoptosis in RK13 cells infected with equine arteritis virus. AB - The modulation of the expression of caspases by viruses influences the cell survival of different cell types. Equine arteritis virus (EAV) induces apoptosis of BHK21 and Vero cell lines, but it is not known whether EAV induces apoptosis in RK13 cells, a common cell line routinely used in EAV diagnosis and research. In this study, we determined that caspase-3 expression was triggered after infection of RK13 cells with EAV in a time- and dose-dependent manner. We also detected caspase-8 and caspase-9 activation, indicating the stimulation of both extrinsic and intrinsic apoptosis pathways. Finally, we found caspase-12 activation, an indicator of endoplasmic reticulum stress-induced apoptosis. The variability observed in the apoptotic response in the different cell lines demonstrates that apoptosis depends on the distinctive sensitivity of each cell line used for investigation. PMID- 26732485 TI - The rescue and evaluation of FLAG and HIS epitope-tagged Asia 1 type foot-and mouth disease viruses. AB - The VP1 G-H loop of the foot-and-mouth disease virus (FMDV) contains the primary antigenic site, as well as an Arg-Gly-Asp (RGD) binding motif for the alphav integrin family of cell surface receptors. We anticipated that introducing a foreign epitope tag sequence downstream of the RGD motif would be tolerated by the viral capsid and would not destroy the antigenic site of FMDV. In this study, we have designed, generated, and characterized two recombinant FMDVs with a FLAG tag or histidine (HIS) inserted in the VP1 G-H loop downstream of the RGD motif +9 position. The tagged viruses were genetically stable and exhibited similar growth properties with their parental virus. What is more, the recombinant viruses rFMDV-FLAG and rFMDV-HIS showed neutralization sensitivity to FMDV type Asia1-specific mAbs, as well as to polyclonal antibodies. Additionally, the r1 values of the recombinant viruses were similar to that of the parental virus, indicating that the insertion of FLAG or HIS tag sequences downstream of the RGD motif +9 position do not eradicate the antigenic site of FMDV and do not affect its antigenicity. These results indicated that the G-H loop of Asia1 FMDV is able to effectively display the foreign epitopes, making this a potential approach for novel FMDV vaccines development. PMID- 26732486 TI - Orf virus IL-10 reduces monocyte, dendritic cell and mast cell recruitment to inflamed skin. AB - Orf virus (ORFV) is a zoonotic parapoxvirus that causes pustular dermatitis of sheep, and occasionally humans. Despite causing sustained infections, ORFV induces only a transient increase in pro-inflammatory signalling and the trafficking of innate immune cells within the skin seems to be impaired. An explanation for this tempered response to ORFV infection may lie in its expression of a homolog of the anti-inflammatory cytokine, interleukin (IL)-10. Using a murine model in which inflammation was induced by bacterial lipopolysaccharide, we examined the effects of the ORFV-IL-10 protein on immune cell trafficking to and from the skin. ORFV-IL-10 limited the recruitment of blood-derived Gr-1(int)/CD11b(int) monocytes, CD11c(+ve)/MHC-II(+ve) dendritic cells and c-kit(+ve)/FcepsilonR1(+ve) mature mast cells into inflamed skin. ORFV IL-10 also suppressed the activation of CD11c(+ve)/MHC-II(+ve) dendritic cells within the skin, reducing their trafficking to the draining lymph node. These findings suggest that expression of IL-10 by ORFV may contribute to the impaired trafficking of innate immune cells within infected skin. PMID- 26732487 TI - Pattern of circulation of MCMV mimicking natural infection upon oronasal inoculation. AB - Cytomegaloviruses may infect mammals via oronasal route. However, up till now it remains unclear how this exposure leads to a general infection and shedding. To address this issue, BALB/c female mice were oronasally inoculated with either the highly passaged murine cytomegalovirus (MCMV) Smith or the low passaged MCMV HaNa1. Virus titration showed a productive virus replication of both strains in the nasal mucosa from 1 dpi until the end of the experiment (14 dpi), in lungs from 5 until 14 dpi, and in submandibular glands from 7 until 14 dpi. In contrast to MCMV HaNa1, MCMV Smith also established a low level productive infection in abdominal organs (spleen, liver and kidneys) from 5 dpi (spleen), 7 dpi (liver), and 10 dpi (kidneys) until the end of the experiment. Co-culture showed that for both strains, cell-associated virus was detected in a non-infectious form in nasopharynx-associated lymphoid tissues (NALT) from 1 until 14 dpi, in submandibular lymph nodes from 3 until 5 dpi, in deep cervical lymph nodes from 3 until 14 dpi, in mediastinal lymph nodes from 7 until 14 dpi, in spleen from 5 until at least 10 dpi and in the peripheral blood mononuclear cells (PBMC) at 7 and 10 dpi. The present study shows that upon oronasal exposure, MCMV first enters the nasal mucosa and NALT, from where the virus disseminates to the spleen possibly via the draining lymphatic system and blood; a subsequent cell associated viremia transports MCMV to submandibular glands and for MCMV Smith also to liver and kidneys, where a second productive replication starts. PMID- 26732488 TI - Molecular dissection of a dahlia isolate of potato spindle tuber viroid inciting a mild symptoms in tomato. AB - The dahlia isolate of potato spindle tuber viroid (PSTVd) accumulates slowly and induces mild disease symptoms in tomato (Solanum lycopersicum, cv. Rutgers) plants in contrast to the intermediate isolate (PSTVd-I). The dahlia isolate (PSTVd-D) differs from PSTVd-I in eight locations: 42 and 43 in the terminal left (TL); 64/65, 311, and 312/313 in the pathogenicity (P); 118 and 126 in the variable (V); and 201 in the terminal right (TR) domains. To investigate the molecular determinants in the PSTVd-D genome responsible for the attenuation of symptom severity and lower replication/accumulation in tomato plants, a series of mutants between PSTVd-D and PSTVd-I were constructed by focusing first on the mutations in the TL and P domains in the left-hand half of the molecule. Then, more detailed analysis was performed on the three mutations at positions 118, 126, and 201 in the V and TR domains. One of these mutations is located around the boundary of the right border of the RY-motif, a predicted recognition site of Virp1, a viroid-binding protein. Of 14 mutants (seven based on PSTVd-D and the other seven based on PSTVd-I) examined, 11 propagated stably and three lost infectivity. Mutations in the TL and P domains (42U, 43C, 310U/C, and U or UU insertion to 311/312 in PSTVd mild types) majorly influenced the expression of mild-like symptoms. In contrast, when each of the mutations at 118, 126, and 201 in the V and TR domains were exchanged independently, they minimally influenced systemic accumulation and symptom expression. Mutants based on PSTVd-D with PSTVd I-type mutations at nucleotide positions 118, 126, and/or 201 showed mild symptoms similar to PSTVd-D, but their systemic accumulation was a little faster than PSTVd-D. In contrast, mutants based on PSTVd-I with PSTVd-D-type mutations at 118, 126, and/or 201 nucleotide positions showed severe symptoms similar to PSTVd-I, and the systemic accumulation was similar to or a little slower than PSTVd-I. The nucleotide at position 201 could be changed to U, G, or A, but C was not acceptable for replication. Because introduction of C at the position 201 can change the loop structure at the right boundary of the RY-motif's consensus sequence, the loop structure may influence recognition by Virp1. PMID- 26732489 TI - Phylogeography of the inshore fish, Bostrychus sinensis, along the Pacific coastline of China. AB - This study assesses the phylogeography of the Chinese four-eyed sleeper (Bostrychus sinensis) with one mitochondrial and one nuclear genes and two morphological characters. Phylogenetic and population genetic analyses of the sequences reveals two phylogeographic lineages from the East and South China Seas, which are corroborated by the morphological data. The vicariance of the two lineages is attributed to the Pleistocene Ice Age exposure of the Taiwan Strait and consequent connection of Taiwan to the mainland, which thereby introduced an ecological barrier to gene flow between populations in the East and South China Seas. The distributions of the two lineages now overlap in the East China Sea and this secondary contact is attributed to biased northward migration along the two main currents of the Taiwan Strait following its interglacial re-flooding. In conclusion, this study reinforces the importance of "vicariance, then secondary contact" due to Late Pliocene and Pleistocene sea-level changes to the phylogeography of marine species. Specifically, it corroborates the importance of Pleistocene sea-level changes in the Taiwan Strait to the phylogeography of Chinese inshore species. PMID- 26732490 TI - Evolutionary trends in the distylous genus Pulmonaria (Boraginaceae): Evidence of ancient hybridization and current interspecific gene flow. AB - The distylous genus Pulmonaria contains approximately 18 species that are widely distributed across Eurasia. Previous studies have shown that species delimitation in the genus is problematic, but have not yet explored the evolutionary history of the genus. Premating reproductive barriers between European species appear to be weak, as several species have strongly overlapping distribution areas, flower at the same time and share the same pollinators, suggesting that hybridization may have contributed to the evolutionary history of Pulmonaria. To test this hypothesis, phylogenetic analyses of nuclear ITS and plastid data (rps16, trnH psbA, rpl16) from 48 allopatric and four sympatric populations were performed to (1) provide a molecular phylogeny for nine of the most common Pulmonaria species in Europe, (2) detect current and ancient hybridization events, and (3) assess the contribution of hybridization versus incomplete lineage sorting to the inferred phylogenetic patterns. Our results showed that gene trees displayed widespread, strongly supported incongruence associated with the conflicting position of hybrid samples rather than incomplete lineage sorting. Evidence was found of different degrees of hybridization, ranging from current interspecific gene flow at secondary contact zones to introgression at the population level and at least one event of hybrid speciation. Overall, these results suggest that hybridization and introgression were - and could still be - important processes affecting speciation in the genus Pulmonaria. PMID- 26732491 TI - Neural Network Model of Memory Retrieval. AB - Human memory can store large amount of information. Nevertheless, recalling is often a challenging task. In a classical free recall paradigm, where participants are asked to repeat a briefly presented list of words, people make mistakes for lists as short as 5 words. We present a model for memory retrieval based on a Hopfield neural network where transition between items are determined by similarities in their long-term memory representations. Meanfield analysis of the model reveals stable states of the network corresponding (1) to single memory representations and (2) intersection between memory representations. We show that oscillating feedback inhibition in the presence of noise induces transitions between these states triggering the retrieval of different memories. The network dynamics qualitatively predicts the distribution of time intervals required to recall new memory items observed in experiments. It shows that items having larger number of neurons in their representation are statistically easier to recall and reveals possible bottlenecks in our ability of retrieving memories. Overall, we propose a neural network model of information retrieval broadly compatible with experimental observations and is consistent with our recent graphical model (Romani et al., 2013). PMID- 26732492 TI - N-Glycosylation of Cholera Toxin B Subunit: Serendipity for Novel Plant-Made Vaccines? AB - The non-toxic B subunit of cholera toxin (CTB) has attracted considerable interests from vaccinologists due to strong mucosal immunomodulatory effects and potential utility as a vaccine scaffold for heterologous antigens. Along with other conventional protein expression systems, various plant species have been used as production hosts for CTB and its fusion proteins. However, it has recently become clear that the protein is N-glycosylated within the endoplasmic reticulum of plant cells-a eukaryotic post-translational modification that is not present in native CTB. While functionally active aglycosylated variants have been successfully engineered to circumvent potential safety and regulatory issues related to glycosylation, this modification may actually provide advantageous characteristics to the protein as a vaccine platform. Based on data from our recent studies, I discuss the unique features of N-glycosylated CTB produced in plants for the development of novel vaccines. PMID- 26732493 TI - NON-YELLOWING2 (NYE2), a Close Paralog of NYE1, Plays a Positive Role in Chlorophyll Degradation in Arabidopsis. PMID- 26732494 TI - Arabidopsis NRT1.5 Mediates the Suppression of Nitrate Starvation-Induced Leaf Senescence by Modulating Foliar Potassium Level. AB - Nitrogen deficiency induces leaf senescence. However, whether or how nitrate might affect this process remains to be investigated. Here, we report an interesting finding that nitrate-instead of nitrogen-starvation induced early leaf senescence in nrt1.5 mutant, and present genetic and physiological data demonstrating that nitrate starvation-induced leaf senescence is suppressed by NRT1.5. NRT1.5 suppresses the senescence process dependent on its function from roots, but not the nitrate transport function. Further analyses using nrt1.5 single and nia1 nia2 nrt1.5-4 triple mutant showed a negative correlation between nitrate concentration and senescence rate in leaves. Moreover, when exposed to nitrate starvation, foliar potassium level decreased in nrt1.5, but adding potassium could essentially restore the early leaf senescence phenotype of nrt1.5 plants. Nitrate starvation also downregulated the expression of HAK5, RAP2.11, and ANN1 in nrt1.5 roots, and appeared to alter potassium level in xylem sap from nrt1.5. These data suggest that NRT1.5 likely perceives nitrate starvation derived signals to prevent leaf senescence by facilitating foliar potassium accumulation. PMID- 26732495 TI - Single Nucleotide Polymorphisms in CBLB, a Regulator of T-Cell Response, Predict Radiation Pneumonitis and Outcomes After Definitive Radiotherapy for Non-Small Cell Lung Cancer. AB - BACKGROUND: The immune system has important roles in tumor development and outcomes after cancer treatment. We evaluated whether single-nucleotide polymorphisms (SNPs) in the gene encoding casitas B-lineage lymphoma b protein (Cbl-b), an E3 ubiquitin ligase that maintains immune tolerance by negatively regulating T-cell activation and function, were associated with outcomes after treatment of non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Samples from 393 patients with NSCLC treated with definitive radiotherapy at a single institution between March 1998 and February 2009 were used to genotype 3 potentially functional SNPs in CBLB (rs1042852 C>T, rs2305035 G>A, and rs7649466 C>G). We evaluated associations between these SNPs and local recurrence-free survival, distant metastasis-free survival, overall survival, and risk of radiation pneumonitis (RP). RESULTS: Having the rs2305035 A variant genotypes (AA or AG) was associated with better local recurrence-free survival (median 15.8 vs. 15.3 months; adjusted hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.60 0.98; P = .033), distant metastasis-free survival (median 15.4 vs. 14.0 months; adjusted HR, 0.74; 95% CI, 0.57-0.96; P = .024) and overall survival (median 23.5 vs. 22.8 months; adjusted HR, 0.72; 95% CI, 0.56-0.93; P = .013) after adjustment in a Cox proportional hazard model. Patients with these genotypes were also at greater risk of developing grade 3 or higher RP than were patients with GG genotypes in an adjusted Cox proportional hazard model. CONCLUSION: This is the first report that rs2305035 genotypes in CBLB were associated with clinical and RP risk among patients with NSCLC treated with definitive radiotherapy. These findings could assist in generating hypothesis for further mechanistic studies. PMID- 26732496 TI - Climate-driven sympatry may not lead to foraging competition between congeneric top-predators. AB - Climate-driven sympatry may lead to competition for food resources between species. Rapid warming in the West Antarctic Peninsula (WAP) is coincident with increasing gentoo penguin and decreasing Adelie penguin populations, suggesting that competition for food may exacerbate the Adelie penguin decline. On fine scales, we tested for foraging competition between these species during the chick rearing period by comparing their foraging behaviors with the distribution of their prey, Antarctic krill. We detected krill aggregations within the horizontal and vertical foraging ranges of Adelie and gentoo penguins, and found that krill selected for habitats that balance the need to consume food and avoid predation. In overlapping Adelie and gentoo penguin foraging areas, four gentoo penguins switched foraging behavior by foraging at deeper depths, a strategy which limits competition with Adelie penguins. This suggests that climate-driven sympatry does not necessarily result in competitive exclusion of Adelie penguins by gentoo penguins. Contrary to a recent theory, which suggests that increased competition for krill is one of the major drivers of Adelie penguin population declines, we suggest that declines in Adelie penguins along the WAP are more likely due to direct and indirect climate impacts on their life histories. PMID- 26732498 TI - Controlling reactivity by remote protonation of a basic side group in a bifunctional photoacid. AB - 6-Hydroxy-2-naphthoic acid and its sulfonate derivatives belong to a family of bifunctional photoacids where the -OH group acts as a proton donor and the -COO( ) group acts as a proton acceptor. Upon electronic excitation, the -OH group becomes more acidic and the -COO(-) group turns more basic. Change in the ionization state of one functional group causes a change (switch) in the reactivity of the other functional group. Using picosecond time-resolved and steady state spectroscopy, we find clear evidence for an ultrafast reactivity switch caused by a diffusional proton transfer through the water solvent between the two functional groups with no evidence of a concerted proton transfer. PMID- 26732497 TI - The structure of a prophenoloxidase (PPO) from Anopheles gambiae provides new insights into the mechanism of PPO activation. AB - BACKGROUND: Phenoloxidase (PO)-catalyzed melanization is a universal defense mechanism of insects against pathogenic and parasitic infections. In mosquitos such as Anopheles gambiae, melanotic encapsulation is a resistance mechanism against certain parasites that cause malaria and filariasis. PO is initially synthesized by hemocytes and released into hemolymph as inactive prophenoloxidase (PPO), which is activated by a serine protease cascade upon recognition of foreign invaders. The mechanisms of PPO activation and PO catalysis have been elusive. RESULTS: Herein, we report the crystal structure of PPO8 from A. gambiae at 2.6 A resolution. PPO8 forms a homodimer with each subunit displaying a classical type III di-copper active center. Our molecular docking and mutagenesis studies revealed a new substrate-binding site with Glu364 as the catalytic residue responsible for the deprotonation of mono- and di-phenolic substrates. Mutation of Glu364 severely impaired both the monophenol hydroxylase and diphenoloxidase activities of AgPPO8. Our data suggested that the newly identified substrate-binding pocket is the actual site for catalysis, and PPO activation could be achieved without withdrawing the conserved phenylalanine residue that was previously deemed as the substrate 'placeholder'. CONCLUSIONS: We present the structural and functional data from a mosquito PPO. Our results revealed a novel substrate-binding site with Glu364 identified as the key catalytic residue for PO enzymatic activities. Our data offered a new model for PPO activation at the molecular level, which differs from the canonical mechanism that demands withdrawing a blocking phenylalanine residue from the previously deemed substrate-binding site. This study provides new insights into the mechanisms of PPO activation and enzymatic catalysis of PO. PMID- 26732499 TI - Use of emergency department imaging in patients with minor trauma. AB - BACKGROUND: Advanced radiographic studies have detrimental risks, yet the prevalence of CT utilization in patients with minor trauma presenting to the emergency department (ED) has never been fully evaluated. Our objective was to evaluate the frequency of CT imaging in patients presenting to the ED for minor trauma. MATERIALS AND METHODS: A retrospective analysis of the California Office of Statewide Health Planning and Development Emergency Department and Ambulatory Surgery Data from 2005 to 2013 was performed. A total of 8,535,831 patients were identified using the following inclusion criteria: adult patients (age >=18 y); with a traumatic ECODE diagnosis and injury severity score <9; and discharge to home. The primary study outcome measurement was the prevalence of CT imaging for each year in the study period. We performed univariate and multivariate analysis to evaluate clinical and hospital-level factors related to CT use in this population. We also performed a trend analysis using Poisson logistic regression to assess the trend of imaging scans over the study period. RESULTS: Of the study population, 5.9% received at least one CT study during their ED visit. The proportion of patients with at least one CT scan increased from 3.51% in 2005 to 7.17% in 2013 (P < 0.005). Adjusted predictors for CT included age 18-24 y or >45 y (P < 0.005), Medicare and self-pay patients (P < 0.005), fall injuries (P < 0.005), motor vehicle collision injuries (P < 0.005), and patients seen at level I/II trauma centers (P = 0.005). CONCLUSIONS: Even after clinical and demographic predictors were adjusted for, there was a 1.97-fold increase in CT among minor trauma patients from 2005-2013. PMID- 26732500 TI - Minimal Invasive Internal Liver Retractor in Conventional and Trans-umbilical Single-Incision Laparoscopic Sleeve Gastrectomy: Video Report. AB - BACKGROUND: Sleeve gastrectomy (SG) is a safe and efficient procedure with comparable results between conventional and single-incision approach in selected patients. However, the critical point in both approaches is the retraction of the hypertrophic and fatty left lobe of the liver which increases technical difficulties and limit the exposure of the hiatus. Traditional liver retractors require an additional sub-xiphoid incision for insertion and cause post-operative pain as well as iatrogenic liver injuries. Various techniques have been described to allow adequate liver retraction through smaller incisions or fewer ports without compromising patient safety. However, some disadvantages of these methods are the need for incision of the liver ligament or diaphragmatic crura puncture rendering the device difficult to reposition. MATERIALS AND METHODS: Two morbidly obese patients underwent a SG by conventional laparoscopy and by trans-umbilical single-incision using a novel minimal invasive internal liver retractor: the Versa Lifter Band(r). RESULTS: This soft and flexible internal retractor was fully repositionable and adjustable intraoperatively. The time required to complete the liver retraction was 4 min 12 s in conventional surgery and 5 min 23 s in single-incision approach. Liver retraction was always satisfying resulting in limited intra-operative difficulties without the need of additional retractors/ports or conversion in both patients. No adverse outcomes occurred during the intra and post-operative periods without rise in aspartate aminotransferase and alanine-aminotransferase serum levels. CONCLUSION: In our preliminary experience, this internal liver retractor was easy to handle and provided an effective and safe retraction with good exposure of the surgical field and improved ergonomy in single incision as well as reduced port laparoscopic SG. PMID- 26732501 TI - Improving the use of phlebotomy services in a paediatric inpatient setting. AB - The aim of this project was to improve the use of the current Paediatric Phlebotomy service. The main problem identified was the lack of a system to notify medical teams of unsuccessful blood requests. A phlebotomy process map was constructed to help analyse reasons why failure to notify occurred. Pre and post intervention audits were conducted using the number of unsuccessful blood requests notified as a baseline measurement. The initial intervention was modified based on feedback during the process. A 44% improvement in the number of unsuccessful blood requests notified and a potential cost savings of L6240 was demonstrated in the post-intervention audit. Further work is required as to whether these improvements can be increased, sustained and be cost effective. PMID- 26732502 TI - Fenugreek increases insulin-stimulated creatine content in L6C11 muscle myotubes. AB - PURPOSE: Creatine uptake by muscle cells is increased in the presence of insulin. Accordingly, compounds with insulin-like actions may also augment creatine uptake. The aim of this study was to investigate whether Trigonella foenum graecum (fenugreek), an insulin mimetic, increases total intracellular creatine levels in vitro. METHODS: Total cellular creatine content was measured fluorometrically in L6C11 muscle myotubes treated for 1, 4, and 24 h with 0.5 mM creatine (CR), CR and 20 MUg/mL fenugreek seed extract (CR + FEN), CR and 100 nM insulin (CR + INS), and CR + INS + FEN (n = 6 per treatment group). Alterations in the expression of the sodium- and chloride-dependent creatine transporter, SLC6A8, and key signaling proteins in the PI3-K/Akt pathway were determined. RESULTS: Compared to control (CON), CR + INS + FEN increased total creatine content after 4 h (P < 0.05), whereas all conditions increased SLC6A8 protein expression above CON at this time (P < 0.05). Changes in insulin signaling were demonstrated via increases in AktThr308 phosphorylation, with CR + INS > CON and CR at 1 h (P < 0.05) and with CR + INS + FEN > CON, CR, and CR + INS at 4 h (P < 0.05). In contrast, no changes in PKCzeta/lambda or GLUT4 phosphorylation were detected. CONCLUSION: Fenugreek, when combined with insulin, modulates creatine content via a mechanism which is independent of the activity of SLC6A8, suggesting that an alternative mechanism is responsible for the regulation and facilitation of insulin-mediated creatine uptake in skeletal muscle cells. PMID- 26732504 TI - Improving the education and experience of foundation doctors in general surgery. AB - Reduced working hours and fragmentation of the surgical firm has resulted in a gradual change in FY1 duties. Locally, FY1 doctors were no longer routinely seeing surgical emergency admissions, while FY1s informally reported reduced confidence in dealing with surgical emergencies. The goal of this project was to assess the current training of FY1 doctors within the unit, and to attempt to improve this by increasing exposure to surgical emergencies. Two months into their four month surgical rotation, FY1s completed an anonymous online survey that focused on their confidence in dealing with emergency surgical admissions. Working practice was then changed by the creation of a formal emergency foundation year one (FY1) rota, and the introduction of a baton bleep. The expectation was that all emergency admissions would be clerked by an FY1 doctor. The cohort were asked to repeat the survey after implementation of change. Across all areas assessed, the confidence and experience of the junior doctors was improved. Initially 70% of FY1s felt exposure to emergency surgical cases was inadequate, falling to 0% after the intervention. This was associated with a rise in the average number of acute cases clerked by each FY1 per week from 1.2 to 4.0. At baseline, only 30% of those surveyed felt that they were gaining the skills and experience necessary to prepare them for an FY2 job in general surgery, and after the intervention this increased to 100%. The increased pressures of service provision within reduced working hours does not necessitate the exclusion FY1 doctors from the assessment and management of surgical emergencies. We have demonstrated that preserving this exposure is a priority in the training of junior doctors, resulting in more experienced and confident medical staff. PMID- 26732505 TI - Plasmonic MoO3-x@MoO3 nanosheets for highly sensitive SERS detection through nanoshell-isolated electromagnetic enhancement. AB - Plasmonic MoO3-x@MoO3 nanosheets obtained from surface oxidation of MoO3-x were employed as a SERS substrate for methylene blue detection. They exhibit extraordinary sensitivity comparable to noble metals, which is attributed to shell-isolated electromagnetic enhancing by the plasmonic MoO3-x core and elimination of the photocatalytic degradation by the MoO3 shell. PMID- 26732503 TI - The properties of spontaneous mutations in the opportunistic pathogen Pseudomonas aeruginosa. AB - BACKGROUND: Natural genetic variation ultimately arises from the process of mutation. Knowledge of how the raw material for evolution is produced is necessary for a full understanding of several fundamental evolutionary concepts. We performed a mutation accumulation experiment with wild-type and mismatch repair deficient, mutator lines of the pathogenic bacterium Pseudomonas aeruginosa, and used whole-genome sequencing to reveal the genome-wide rate, spectrum, distribution, leading/lagging bias, and context-dependency of spontaneous mutations. RESULTS: Wild-type base-pair mutation and indel rates were ~10(-10) and ~10(-11) per nucleotide per generation, respectively, and deficiencies in the mismatch-repair system caused rates to increase by over two orders of magnitude. A universal bias towards AT was observed in wild-type lines, but was reversed in mutator lines to a bias towards GC. Biases for which types of mutations occurred during replication of the leading versus lagging strand were detected reciprocally in both replichores. The distribution of mutations along the chromosome was non-random, with peaks near the terminus of replication and at positions intermediate to the replication origin and terminus. A similar distribution bias was observed along the chromosome in natural populations of P. aeruginosa. Site-specific mutation rates were higher when the focal nucleotide was immediately flanked by C:G pairings. CONCLUSIONS: Whole-genome sequencing of mutation accumulation lines allowed the comprehensive identification of mutations and revealed what factors of molecular and genomic architecture affect the mutational process. Our study provides a more complete view of how several mechanisms of mutation, mutation repair, and bias act simultaneously to produce the raw material for evolution. PMID- 26732506 TI - Diluted serum from calorie-restricted animals promotes mitochondrial beta-cell adaptations and protect against glucolipotoxicity. AB - beta-cells quickly adjust insulin secretion to oscillations in nutrients carried by the blood, acting as fuel sensors. However, most studies of beta-cell responses to nutrients do not discriminate between fuel levels and signaling components present in the circulation. Here we studied the effect of serum from calorie-restricted rats versus serum from rats fed ad libitum, diluted tenfold in the medium, which did not contribute significantly to the pool of nutrients, on beta-cell mitochondrial function and dynamics under regular and high-nutrient culture conditions. Insulin secreting beta-cell derived line (INS1) cells incubated with serum from calorie-restricted rats (CR serum) showed higher levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC 1alpha) and active nitric oxide synthase. The expression of mitofusin-2 (Mfn-2) and optic atrophy 1 (OPA-1), proteins involved in mitochondrial fusion, was increased, while the levels of the mitochondrial fission mediator dynamin related protein 1 (DRP-1) were reduced. Consistent with changes in mitochondrial dynamics protein levels, CR serum treatment increased mitochondrial fusion rates, as well as their length and connectivity. These changes in mitochondrial morphology were associated with prolonged glucose-stimulated insulin secretion and mitochondrial respiration. When combining CR serum and high levels of glucose and palmitate (20 and 0.4 mm, respectively), an in vitro model of type II diabetes, we observed that signaling promoted by CR serum was enough to overcome glucolipotoxicity, as indicated by CR-mediated prevention of mitochondrial fusion arrest and reduced respiratory function in INS1 cells under glucolipotoxicity. Overall, our results provide evidence that non-nutrient factors in serum have a major impact on beta cell mitochondrial adaptations to changes in metabolism. PMID- 26732507 TI - Challenges of Long-Term MRSA Management in a Complex Continuing Care Setting. PMID- 26732508 TI - The "good death": An integrative literature review. AB - OBJECTIVE: The "good death" is a dynamic concept and has evolved over time to become a "revivalist" good death: a planned, peaceful, and dignified death, at home, surrounded by family members. As the "good death" continues to evolve, the key questions are: How do cultural perceptions of death and dying change? What are the forces that shape Western attitudes and beliefs around death and dying? And how does the "good death" discourse frame the dying experience in contemporary society? The purpose of this manuscript is to describe the underlying discourse in the literature on the "good death" in Western societies. METHOD: An integrative literature review of data from experimental and nonexperimental sources in PubMed, CINAHL, PsychINFO, and SocINDEX of 39 articles from 1992 to 2014. RESULTS: Four main themes emerged from reviewing 39 articles on the "good death": (1) the "good death" as control, (2) the wrong "good death," (3) the threatened "good death," and (4) the denial of dying. SIGNIFICANCE OF RESULTS: Evolving in response to prominent social attitudes and values, the contemporary "good death" is a powerful, constraining discourse that limits spontaneity and encourages one way to die. Social, political, and demographic changes now threaten the stability of the "good death"; dying is framed as an increasingly negative or even unnecessary process, thus marginalizing the positive aspects of dying and rendering dying absent, invisible. PMID- 26732509 TI - Successful treatment of methicillin-resistant Staphylococcus aureus osteomyelitis with combination therapy using linezolid and rifampicin under therapeutic drug monitoring. AB - Linezolid is an effective antibiotic against most gram-positive bacteria including drug-resistant strains such as methicillin-resistant Staphylococcus aureus. Although linezolid therapy is known to result in thrombocytopenia, dosage adjustment or therapeutic drug monitoring of linezolid is not generally necessary. In this report, however, we describe the case of a 79-year-old woman with recurrent methicillin-resistant S. aureus osteomyelitis that was successfully treated via surgery and combination therapy using linezolid and rifampicin under therapeutic drug monitoring for maintaining an appropriate serum linezolid concentration. The patient underwent surgery for the removal of the artificial left knee joint and placement of vancomycin-impregnated bone cement beads against methicillin-resistant S. aureus after total left knee implant arthroplasty for osteoarthritis. We also initiated linezolid administration at a conventional dose of 600 mg/h at 12-h intervals, but reduced it to 300 mg/h at 12 h intervals on day 9 because of a decrease in platelet count and an increase in serum linezolid trough concentration. However, when the infection exacerbated, we again increased the linezolid dose to 600 mg/h at 12-h intervals and performed combination therapy with rifampicin, considering their synergistic effects and the control of serum linezolid trough concentration via drug interaction. Methicillin-resistant S. aureus infection improved without reducing the dose of or discontinuing linezolid. The findings in the present case suggest that therapeutic drug monitoring could be useful for ensuring the therapeutic efficacy and safety of combination therapy even in patients with osteomyelitis who require long-term antibiotic administration. PMID- 26732510 TI - Efficacy of SDHI fungicides, including benzovindiflupyr, against Colletotrichum species. AB - BACKGROUND: Colletotrichum species cause anthracnose diseases on many plants and crops. A new generation of succinate dehydrogenase inhibitors (SDHIs) was developed recently. The inhibitory activity of the five SDHI fungicides against Colletotrichum species was determined in this study. RESULTS: Isolates of C. gloeosporioides, C. acutatum, C. cereale and C. orbiculare were insensitive (naturally resistant) to boscalid, fluxapyroxad and fluopyram on YBA agar medium. In contrast, these isolates were relatively sensitive to penthiopyrad, except for C. orbiculare. Most interestingly, benzovindiflupyr showed highest inhibitory activity against all of these four species. Benzovindiflupyr was effective against C. gloeosporioides and C. acutatum on apple and peach fruit, as well as on cucumber plants inoculated with C. orbiculare. The sdhB, sdhC and sdhD genes encoding the subunits of fungicide-targeted succinate dehydrogenase were sequenced, but, despite high polymorphisms, no apparent resistance mutations were found in Colletotrichum species. CONCLUSIONS: This is the first report on the activity of benzovindiflupyr against Colletotrichum species. The broad-spectrum efficacy of benzovindiflupyr within the Colletotrichum genus might be exploited when designing disease management strategies against various pathogens on a wide range of crops. Other mechanism(s) than fungicide target-site modification may be responsible for differential sensitivity of Colletotrichum species to SDHI fungicides. (c) 2016 Society of Chemical Industry. PMID- 26732511 TI - Impaired encoding of rapid pitch information underlies perception and memory deficits in congenital amusia. AB - Recent theories suggest that the basis of neurodevelopmental auditory disorders such as dyslexia or specific language impairment might be a low-level sensory dysfunction. In the present study we test this hypothesis in congenital amusia, a neurodevelopmental disorder characterized by severe deficits in the processing of pitch-based material. We manipulated the temporal characteristics of auditory stimuli and investigated the influence of the time given to encode pitch information on participants' performance in discrimination and short-term memory. Our results show that amusics' performance in such tasks scales with the duration available to encode acoustic information. This suggests that in auditory neuro developmental disorders, abnormalities in early steps of the auditory processing can underlie the high-level deficits (here musical disabilities). Observing that the slowing down of temporal dynamics improves amusics' pitch abilities allows considering this approach as a potential tool for remediation in developmental auditory disorders. PMID- 26732512 TI - Fructose-1,6-bisphosphate aldolase of Neisseria meningitidis binds human plasminogen via its C-terminal lysine residue. AB - Neisseria meningitidis is a leading cause of fatal sepsis and meningitis worldwide. As for commensal species of human neisseriae, N. meningitidis inhabits the human nasopharynx and asymptomatic colonization is ubiquitous. Only rarely does the organism invade and survive in the bloodstream leading to disease. Moonlighting proteins perform two or more autonomous, often dissimilar, functions using a single polypeptide chain. They have been increasingly reported on the surface of both prokaryotic and eukaryotic organisms and shown to interact with a variety of host ligands. In some organisms moonlighting proteins perform virulence-related functions, and they may play a role in the pathogenesis of N. meningitidis. Fructose-1,6-bisphosphate aldolase (FBA) was previously shown to be surface-exposed in meningococci and involved in adhesion to host cells. In this study, FBA was shown to be present on the surface of both pathogenic and commensal neisseriae, and surface localization and anchoring was demonstrated to be independent of aldolase activity. Importantly, meningococcal FBA was found to bind to human glu-plasminogen in a dose-dependent manner. Site-directed mutagenesis demonstrated that the C-terminal lysine residue of FBA was required for this interaction, whereas subterminal lysine residues were not involved. PMID- 26732514 TI - Item bank development, calibration and validation for patient-reported outcomes in female urinary incontinence. AB - PURPOSE: Current patient-reported outcomes for female urinary incontinence (UI) are limited by their inability to be tailored. Our objective is to describe the development and field testing of seven item banks designed to measure domains identified as important UI in females (UIf). We also describe the calibration and validation properties of the UIf-item banks, which allow for more efficient computerized adaptive testing (CAT) in the future. METHODS: The UIf-measures included 168 items covering seven domains: Stress UI (SUI), overactive bladder (OAB), urinary frequency, physical, social and emotional health impact and adaptation. Items underwent rigorous qualitative development and psychometric testing across two sites. Items were calibrated using item response theory and evaluated for internal consistency, construct validity and responsiveness. RESULTS: A total of 750 women (249 SUI, 249 OAB and 252 mixed UI) participated. Mean age was 55 +/- 14 years, and 23 % were Hispanic and 80 % white. In addition to face and content validity, the measures demonstrated good internal consistency (coefficient alpha 0.92-0.98) and unidimensionality. There was evidence for construct validity with moderate-to-strong correlations with the UDI (r's >= 0.6) and IIQ (r's = >=0.6) scales. The measures were responsive to change for SUI treatment (paired t test p < .001, ES range 1.3-2.9; SRM range 1.3-2.5) and OAB treatment (paired t test p < .05 for all domains except social health impact and adaptation, ES range 0.3-1.5, SRM range 0.4-1.0). The measures were responsive based on concurrent changes with the UDI and IIQ (p < 0.05). CAT versions were developed and pilot-tested. CONCLUSIONS: The UIf-item banks demonstrate good psychometric characteristics and are a sufficiently valid set of customizable tools for measuring UI symptoms and life impact. PMID- 26732516 TI - "Chase CRP", "Review patient": Improving the Quality of Weekend Medical Handover at a London Teaching Hospital. AB - Clinical handover has been identified as a "major preventable cause of harm" by the Royal College of Physicians (RCP). Whilst working at a London teaching hospital from August 2013, we noted substandard weekend handover of medical patients. The existing pro forma was filled incompletely by day doctors so it was difficult for weekend colleagues to identify unwell patients, with inherent safety implications. Furthermore, on-call medical staff noted that poor accessibility of vital information in patients' files was affecting acute clinical management. We audited the pro formas over a six week period (n=83) and the Friday ward round (WR) entries for medical inpatients over two weekends (n=84) against the RCP's handover guidance. The results showed poor documentation of several important details on the pro formas, for example, ceiling of care (4%) and past medical history (PMH) (23%). Problem lists were specified on 62% of the WR entries. We designed new handover pro formas and 'Friday WR sheets' to provide prompts for this information and used Medical Meetings and emails to explain the project's aims. Re-audit demonstrated significant improvement in all parameters; for instance, PMH increased to 52% on the pro formas. Only 10% of Friday WR entries used our sheet. However, when used, outcomes were much better, for example, problem list documentation increased to 100%. In conclusion, our interventions improved the provision of crucial information needed to prioritise and manage patients over the weekend. Future work should further highlight the importance of safe handover to all doctors to induce a shift in culture and optimise patient care. PMID- 26732515 TI - Tripartite degrons confer diversity and specificity on regulated protein degradation in the ubiquitin-proteasome system. AB - Specific signals (degrons) regulate protein turnover mediated by the ubiquitin proteasome system. Here we systematically analyse known degrons and propose a tripartite model comprising the following: (1) a primary degron (peptide motif) that specifies substrate recognition by cognate E3 ubiquitin ligases, (2) secondary site(s) comprising a single or multiple neighbouring ubiquitinated lysine(s) and (3) a structurally disordered segment that initiates substrate unfolding at the 26S proteasome. Primary degron sequences are conserved among orthologues and occur in structurally disordered regions that undergo E3-induced folding-on-binding. Posttranslational modifications can switch primary degrons into E3-binding-competent states, thereby integrating degradation with signalling pathways. Degradation-linked lysines tend to be located within disordered segments that also initiate substrate degradation by effective proteasomal engagement. Many characterized mutations and alternative isoforms with abrogated degron components are implicated in disease. These effects result from increased protein stability and interactome rewiring. The distributed nature of degrons ensures regulation, specificity and combinatorial control of degradation. PMID- 26732513 TI - Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements. AB - Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM, BLM, WRN, ATR, MRE11, NBS1, and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed - these mechanisms will predominantly affect gene expression - or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C (JMJD2C) as a novel candidate gene for mental retardation. PMID- 26732517 TI - Volume-outcome relationship for peripheral endovascular interventions: a review of existing literature. AB - The incidence and prevalence of peripheral vascular disease has been increasing. When coexistent with coronary artery disease (CAD), it has shown to predict higher mortality along with poorer quality-of-life consequently leading to a marked increase in healthcare costs. Broadly, there has been an increase in utilization of endovascular techniques in the management of peripheral vascular diseases. An inverse relation between volume and outcomes has been noted in these procedures. Additionally, improved resource utilization has also been noted with higher hospital and operator volumes. This has led to proposals to regionalize these procedures to high volume hospitals. There have also been calls to introduce the idea of having a set threshold of procedures for providers. This review presents an overview of published literature on the volume-outcome relationship affecting the outcomes of peripheral endovascular procedures. PMID- 26732518 TI - Gelatine modified monetite as a bone substitute material: An in vitro assessment of bone biocompatibility. AB - Calcium phosphate phases are increasingly used for bone tissue substitution, and the load bearing properties of these inherently brittle biomaterials are increased by inclusion of organic components. Monetite prepared using mineralization of gelatine pre-structured through phosphate leads to a significantly increased biaxial strength and indirect tensile strength compared to gelatine-free monetite. Besides the mechanical properties, degradation in physiological solutions and osteoblast and osteoclast cell response were investigated. Human bone marrow stromal cells (hBMSCs) showed considerably higher proliferation rates on the gelatine modified monetite than on polystyrene reference material in calcium-free as well as standard cell culture medium (alpha MEM). Osteogenic differentiation on the material was comparable to polystyrene in both medium types. Osteoclast-like cells derived from monocytes were able to actively resorb the biomaterial. Osteoblastic differentiation and perhaps even more important the cellular resorption of the biomaterial indicate that it can be actively involved in the bone remodeling process. Thus the behavior of osteoblasts and osteoclasts as well as the adequate degradation and mechanical properties are strong indicators for bone biocompatibility, although in vivo studies are still required to prove this. STATEMENT OF SIGNIFICANCE: New and unique? A low temperature precipitationprocessforcalcium anhydrous hydrogen phosphateallows for the first time to produce monolithic compact composites of monetite and gelatine. The composite is degradable and resorbable. To prove that, the question arises: what is bone biocompatibility? The reaction of both mayor cell types of bone represents this biocompatibility. Therefore, human bone marrow stromal cells were seeded revealing the materials pro-osteogenic properties. Monocyte cultivation, becoming recently focus of interest, revealed the capability of the biomaterial to be actively resorbed by derived osteoclast-like cells. Not new but necessary ismechanical characterization, which is often only investigated as uniaxial property. Here, a biaxial method is applied, to characterize the materials properties closer to its application loads. PMID- 26732519 TI - Limited Supraclavicular Radiation Field in Breast Cancer With >= 10 Positive Axillary Lymph Nodes. AB - PURPOSE: The present study was conducted to evaluate the patterns of recurrence and factors related to axillary or supraclavicular recurrence (ASR) and to suggest the probable indications of supraclavicular radiotherapy (SCRT) field modification for breast cancer patients with >= 10 axillary lymph node (LN) metastases who had received the current standard systemic management and limited field SCRT. MATERIALS AND METHODS: We performed a retrospective study of patients with breast cancer with >= 10 axillary LN metastases who had received standard surgery with postoperative RT, including limited SCRT (level III and supraclavicular area) and taxane-based adjuvant chemotherapy (except for neoadjuvant chemotherapy), from January 2000 to June 2012. ASR was defined as recurrence to levels I to III of the axillary or supraclavicular area. RESULTS: The present study included 301 patients with breast cancer with >= 10 axillary LN metastases. The median follow-up period was 59.1 months (range, 7.4-167.9 months). Overall, 32 cases (10.6%) of locoregional recurrence were observed, and 27 patients (9.0%) exhibited ASR. Additionally, 16 patients (5.3%) developed recurrence in levels I or II of the axillary area, which are not included in the SCRT field. ASR-free survival was significantly related to the LN ratio (LNR) in both univariate and multivariate analysis. CONCLUSION: ASR was the most prevalent locoregional recurrence pattern in patients with breast cancer with >= 10 axillary LN metastases, and LNR was a significant prognostic factor for the development of ASR. Modification of the SCRT field, including the full axilla, should be considered in patients with a greater LNR. PMID- 26732520 TI - Activation of the ventral and dorsal striatum during cue reactivity in Internet gaming disorder. AB - Studies conducted in drug addiction suggest a transition in processing of drug related cues from the ventral to the dorsal component of the striatum. However, this process has not been studied in a behavioral addiction. Assessment of this process in a non-drug addiction can provide insight into the pathophysiology of both substance and behavioral addictions. Thirty-nine male Internet gaming disorder (IGD) subjects and 23 male matched healthy controls (HCs) participated in functional magnetic resonance imaging during performance of a cue-reactivity task involving alternating presentation of Internet gaming-related stimuli (game cues) and general Internet surfing-related stimuli (control cues). Cue-induced neural activations in the ventral and dorsal striatum (DS) were compared between IGD and HC participants. Associations between cue-reactivity within these regions and cue-induced craving and severity and duration of IGD were also explored. IGD participants exhibited higher cue-induced activations within both the ventral and DS when compared with HCs. Within the IGD group, activity within the left ventral striatum (VS) was correlated negatively with cue-induced craving; positive associations were found between activations within the DS (right putamen, pallidum and left caudate) and duration of IGD. Cue-induced activity within the left putamen was negatively associated with right VS volumes among IGD participants. Consistent with studies in substance addictions, our results suggest that a transition from ventral to dorsal striatal processing may occur among individuals with IGD, a condition without the impact of substance intake. PMID- 26732521 TI - Impregnation of Fenofibrate on mesoporous silica using supercritical carbon dioxide. AB - Low oral bioavailability can be circumvented by the formulation of the poorly water soluble drug in ordered mesoporous silica (OMS-L-7). Fenofibrate is an orally administered, poorly water-soluble active pharmaceutical ingredient (API), used clinically to lower lipid levels. Fenofibrate was loaded into silica using two methods: incipient wetness and supercritical impregnation. This study investigates the impact of loading and the impact of varying supercritical carbon dioxide (scCO2) processing conditions. The objective is to enhance Fenofibrate loading into silica while reducing degree of the drug crystallinity, so as to increase the drug's dissolution rate and its bioavailability. The comparison of both impregnation processes was made in terms of impregnation yields and duration as well as physical characterization of the drug. While incipient wetness method led to a Fenofibrate loading up to 300 mgdrug/gsilica in 48 h of impregnation, the supercritical impregnation method yielded loading up to 485 mgdrug/gsilica in 120 min of impregnation duration, at 16 MPa and 308 K, with a low degree of crystallinity (about 1%) comparable to the crystallinity observed via the solvent method. In addition to the enhancement of impregnation efficiency, the supercritical route provides a solvent-free alternative for impregnation. PMID- 26732522 TI - New insights into eutectic cream skin penetration enhancement. AB - The manner in which the eutectic cream EMLA enhances the percutaneous penetration of lidocaine and prilocaine into human skin is still not fully understood. The purpose of this study was to investigate if the modification of drug aggregation played a role in the way EMLA facilitates delivery. Light scattering analysis of lidocaine alone in water gave a critical aggregation concentration (CAC) of 572 MUM and a mean aggregate size of 58.8 nm. The analysis of prilocaine in identical conditions gave a CAC of 1177 MUM and a mean aggregate size of 105.7 +/- 24.8 nm. When the two drugs were mixed at their eutectic 1:1 ratio in water the CAC reduced to 165.8 MUM and the aggregate size was 43.82 nm. This lidocaine prilocaine interaction in water was further modified upon addition of polyoxyethylene hydrogenated castor oil, the surfactant in the EMLA aqueous phase, to produce aggregates of <20 nm. The physical characterisation data suggested that it was the EMLA cream's surfactant that modified the drug molecular interactions in the aqueous continuous phase and caused a 6 fold higher drug penetration through human epidermal tissue compared to the oil formulations tested in this study. PMID- 26732523 TI - Communication from the periphery to the hypothalamus through the blood-brain barrier: An in vitro platform. AB - One of the major routes of communication from the peripheral systems to the hypothalamus, the core structure of body homeostasis, is the humoral transmission through the blood-brain barrier (BBB). The BBB cultures are the in vitro model of choice to depict the mechanisms behind blood-brain interplay. Still, this strategy excludes the integration of the brain tissue response and, therefore, the resulting output might be limited. In this study, two in vitro assays were established: BBB coculture model and hypothalamic organotypic cultures. The combination of these two assays was used as a platform to address the two critical steps in the humoral transmission through the BBB to the brain: blood BBB/BBB-brain. The in vitro model of the BBB was performed according to a coculture system using a brain microvascular endothelial cell line (bEnd.3) and primary astrocytes. The expression of junctional molecules as claudin-5, ZO-1, occludin and VE-cadherin was observed in the bEnd.3 cell-cell contact, confirming the BBB phenotype of these endothelial cells. Moreover, the transendothelial electrical resistance (TEER) values (71.1+/-9.4Omega* cm(2)) and the permeability coefficients (Pe) obtained in the transendothelial flux test (3.3+/-0.11*10( 6)cm/sec) support high integrity of the established barrier. The hypothalamic organotypic cultures were prepared from 8-days-old C57Bl/6 mice brains, based on the air-medium interface culture method. High cell viability (82+/-9.6%) and a dense neuronal network were achieved. The stimulation with dexamethasone resulted in an increased neuropeptide (NPY) expression, confirming the responsiveness of the neuronal system of these organotypic cultures. After optimization and characterization of each assay, the functionality of the platform was validated through the evaluation of the hypothalamic response to deep wound encompassing skin and muscle in mice. Results allowed to identify increased NPY activity in hypothalamic slices in response to peripheral signals within the plasma from wounded animals when compared with non-injured animals after surpassing and/or interacting with the BBB. This differential NPY response between the different animal conditions validated the functionality of the in vitro platform. In conclusion, this approach can be greatly anticipated as a useful tool for studying biologic or pharmacological circulating molecules and their impact on the hypothalamic activity. PMID- 26732524 TI - Defining the appropriate starting dose of lenalidomide in chronic lymphocytic leukemia: remember the old fable of the hare and the tortoise. PMID- 26732525 TI - Predictors of Post-concussion Rehabilitation Outcomes at Three-month Follow-up. AB - OBJECTIVE: To determine factors related to three-month follow-up outcomes for individuals participating in an outpatient rehabilitative treatment program for mild traumatic brain injury (TBI). METHOD: Fifty participants underwent neuropsychological screening prior to treatment initiation and completed the Mayo Portland Adaptability Inventory-4 (MPAI-4) at treatment initiation, discharge from treatment, and three months following discharge. RESULTS: Regression models indicated that information garnered from the neuropsychological screening prior to treatment initiation (e.g., mood symptoms and prior psychiatric history) accounted for unique variance in three-month post-discharge outcomes on several MPAI-4 subscales. Specifically, after controlling for baseline MPAI-4 ratings, higher Beck Depression Inventory-second edition (BDI-II) scores were associated with worse MPAI-4 Ability scores at three-month follow-up, and the presence of a psychiatric history was associated with worse MPAI-4 Adjustment scores at three month follow-up. CONCLUSIONS: Neuropsychological screening prior to the initiation of treatment for mild TBI can help to identify patients who may be at greater risk for poorer rehabilitation outcomes, thus allowing for the implementation of specific interventions to address these risk factors. PMID- 26732526 TI - Active Search on Carcasses versus Pitfall Traps: a Comparison of Sampling Methods. AB - The study of insect succession in cadavers and the classification of arthropods have mostly been done by placing a carcass in a cage, protected from vertebrate scavengers, which is then visited periodically. An alternative is to use specific traps. Few studies on carrion ecology and forensic entomology involving the carcasses of large vertebrates have employed pitfall traps. The aims of this study were to compare both sampling methods (active search on a carcass and pitfall trapping) for each coleopteran family, and to establish whether there is a discrepancy (underestimation and/or overestimation) in the presence of each family by either method. A great discrepancy was found for almost all families with some of them being more abundant in samples obtained through active search on carcasses and others in samples from traps, whereas two families did not show any bias towards a given sampling method. The fact that families may be underestimated or overestimated by the type of sampling technique highlights the importance of combining both methods, active search on carcasses and pitfall traps, in order to obtain more complete information on decomposition, carrion habitat and cadaveric families or species. Furthermore, a hypothesis advanced on the reasons for the underestimation by either sampling method showing biases towards certain families. Information about the sampling techniques indicating which would be more appropriate to detect or find a particular family is provided. PMID- 26732527 TI - Copper-catalyzed tandem Ullmann type C-N coupling and dehydrative cyclization: synthesis of imidazo[1,2-c]quinazolines. AB - A simple and efficient one-pot protocol has been demonstrated for the synthesis of imidazo[1,2-c]quinazoline derivatives through a copper catalyzed tandem reaction between substituted 2-(2-bromophenyl)-1H-imidazoles and formamide. The synthetic protocol involves initial Ullmann-type C-N coupling followed by intramolecular dehydrative cyclization. The method uses readily available 2-(2 bromophenyl)-1H-imidazoles as the starting materials to afford imidazo[1,2 c]quinazolines in moderate to good yields and provided 610 mg (71%) yield of 3a from a gram scale reaction. PMID- 26732529 TI - Editorial: Plasticity in Multiple Sclerosis: From Molecular to System Level, from Adaptation to Maladaptation. PMID- 26732528 TI - Presence of unique glyoxalase III proteins in plants indicates the existence of shorter route for methylglyoxal detoxification. AB - Glyoxalase pathway, comprising glyoxalase I (GLY I) and glyoxalase II (GLY II) enzymes, is the major pathway for detoxification of methylglyoxal (MG) into D lactate involving reduced glutathione (GSH). However, in bacteria, glyoxalase III (GLY III) with DJ-1/PfpI domain(s) can do the same conversion in a single step without GSH. Our investigations for the presence of DJ-1/PfpI domain containing proteins in plants have indicated the existence of GLY III-like proteins in monocots, dicots, lycopods, gymnosperm and bryophytes. A deeper in silico analysis of rice genome identified twelve DJ-1 proteins encoded by six genes. Detailed analysis has been carried out including their chromosomal distribution, genomic architecture and localization. Transcript profiling under multiple stress conditions indicated strong induction of OsDJ-1 in response to exogenous MG. A member of OsDJ-1 family, OsDJ-1C, showed high constitutive expression at all developmental stages and tissues of rice. MG depletion study complemented by simultaneous formation of D-lactate proved OsDJ-1C to be a GLY III enzyme that converts MG directly into D-lactate in a GSH-independent manner. Site directed mutagenesis of Cys-119 to Alanine significantly reduces its GLY III activity indicating towards the existence of functional GLY III enzyme in rice-a shorter route for MG detoxification. PMID- 26732530 TI - Analytical linear energy transfer model including secondary particles: calculations along the central axis of the proton pencil beam. AB - In proton therapy, the relative biological effectiveness (RBE) depends on various types of parameters such as linear energy transfer (LET). An analytical model for LET calculation exists (Wilkens' model), but secondary particles are not included in this model. In the present study, we propose a correction factor, L sec, for Wilkens' model in order to take into account the LET contributions of certain secondary particles. This study includes secondary protons and deuterons, since the effects of these two types of particles can be described by the same RBE-LET relationship. L sec was evaluated by Monte Carlo (MC) simulations using the GATE/GEANT4 platform and was defined by the ratio of the LET d distributions of all protons and deuterons and only primary protons. This method was applied to the innovative Pencil Beam Scanning (PBS) delivery systems and L sec was evaluated along the beam axis. This correction factor indicates the high contribution of secondary particles in the entrance region, with L sec values higher than 1.6 for a 220 MeV clinical pencil beam. MC simulations showed the impact of pencil beam parameters, such as mean initial energy, spot size, and depth in water, on L sec. The variation of L sec with these different parameters was integrated in a polynomial function of the L sec factor in order to obtain a model universally applicable to all PBS delivery systems. The validity of this correction factor applied to Wilkens' model was verified along the beam axis of various pencil beams in comparison with MC simulations. A good agreement was obtained between the corrected analytical model and the MC calculations, with mean-LET deviations along the beam axis less than 0.05 keV MUm(-1). These results demonstrate the efficacy of our new correction of the existing LET model in order to take into account secondary protons and deuterons along the pencil beam axis. PMID- 26732531 TI - Establishing how psychological therapies work: the importance of mediation analysis. AB - This editorial reviews the literature regarding psychological studies that are designed to address the question of not just whether, psychological interventions effect change, but how. The practicalities and implications of assessing mechanisms of treatments are considered with examples from the fields of Cognitive Behavioural Therapy (CBT) and Mindfulness. The potential for elucidating theoretical mechanisms, developing new theoretical models and modifying treatment approaches are described. In addition an overview of different types of statistical methods available to researchers for assessing mediation is given. Structural Equation Modelling (SEM) is a recommended approach. The review concludes with a summary of optimum study conditions adopted by researchers for establishing mediating effects. PMID- 26732532 TI - Active site-directed plasmin inhibitors: Extension on the P2 residue. AB - Based on the structure of YO-2 [N-(trans-4-aminomethylcyclohexanecarbonyl)-l Tyr(O-picolyl)-NH-octyl], active site-directed plasmin (Plm) inhibitors were explored. The picolyl moiety in the Tyr(O-picolyl) residue (namely, the P2 residue) was replaced with smaller or larger groups, such as hydrogen, tert butyl, benzyl, (2-naphthyl)methyl, and (quinolin-2-yl)methyl. Those efforts produced compound 17 {N-(trans-4-aminomethylcyclohexanecarbonyl)-l-Tyr[O (quinolin-2-yl)methyl]-NH-octyl} [IC50=0.22 and 77MUM for Plm and urokinase (UK), respectively], which showed not only 2.4-fold greater Plm inhibition than YO-2, but also an improvement in selectivity (Plm/UK) by 35-fold. The docking experiments of the Plm-17 complexes disclosed that the amino group of the tranexamyl moiety interacted with the side-chain of Asp753 which formed S1 site. PMID- 26732533 TI - Assessing the Magnitude of Effect of Bone Structures on Shockwave Lithotripsy Fragmentation: Results from an In Vitro Study. AB - INTRODUCTION: Several anatomic and clinical factors have been implicated in the failure rates of shock wave lithotripsy (SWL), including the attenuating effects of bony structures. We designed an in vitro model that incorporates the lumbar spine, including vertebral bodies and transverse processes along the pathway of shockwaves, to mimic the clinical scenario during SWL of upper ureteral stones. We hypothesized that the presence of bone structures in the SWL pathway significantly affects the fragmentation rate. MATERIALS AND METHODS: An ordnance gelatin (OG) model was conceptualized and created to allow a pig's lumbar spine to be embedded within it. Artificial urinary calculi weighing 2 +/- 0.1 g (1.2-cm diameter) were prepared using BegoStone plaster. The trial was divided into two arms: group 1 models had OG only and served as the control and group 2 models had the bone embedded in the gelatin with stone wells placed above the transverse processes. Twenty-four stones per group were subjected to SWL using the STORZ MODULITH SLX-F2 lithotripter, using the same treatment parameters. Fragments were sieved through 2- and 4-mm filters, and the fragmentation coefficients (FC) were calculated. The Mann-Whitney test was used to compare FC between the two groups. RESULTS: The mean fragmentation rate of group 1 was statistically significantly higher compared with group 2 using a 4-mm sieve (43% vs 0.62%, p < 0.001) and the 2-mm filter (18% vs 0.52%, p < 0.001). CONCLUSIONS: The presence of bone structures dramatically reduces the fragmentation rate of phantom stones using an OG in vitro model. The OG model is inexpensive and simple to use to simulate clinical situations during SWL. PMID- 26732535 TI - Random phase approximation correlation energy using a compact representation for linear response functions: application to solids. AB - A new approach was recently presented to compute correlation energies within the random phase approximation using Lanczos chains and an optimal basis set (Rocca 2014 J. Chem. Phys. 140 18A501). This novel method avoids the explicit calculation of conduction states and represents linear response functions on a compact auxiliary basis set obtained from the diagonalization of an approximate dielectric matrix that contains only the kinetic energy contribution. Here, we extend this formalism, originally implemented for molecular systems, to treat periodic solids. In particular, the approximate dielectric matrix used to build the auxiliary basis set is generalized to avoid unphysical negative gaps, that make the model inefficient. The numerical convergence of the method is discussed and the accuracy is demonstrated considering a set including three covalently bonded (C, Si, and SiC) and three weakly bonded (Ne, Ar, and Kr) solids. PMID- 26732536 TI - Oxyhydroxide Nanosheets with Highly Efficient Electron-Hole Pair Separation for Hydrogen Evolution. AB - The facile electron-hole pair recombination in earth-abundant transition-metal oxides is a major limitation for the development of highly efficient hydrogen evolution photocatalysts. In this work, the thickness of a layered beta-CoOOH semiconductor that contains metal/hydroxy groups was reduced to obtain an atomically thin, two-dimensional nanostructure. Analysis by ultrafast transient absorption spectroscopy revealed that electron-hole recombination is almost suppressed in the as-prepared 1.3 nm thick beta-CoOOH nanosheet, which leads to prominent electron-hole separation efficiencies of 60-90 % upon irradiation at 350-450 nm, which are ten times higher than those of the bulk counterpart. X-ray absorption spectroscopy and first-principles calculations demonstrate that [HO CoO6-x] species on the nanosheet surface promote H(+) adsorption and H2 desorption. An aqueous suspension of the beta-CoOOH nanosheets exhibited a high hydrogen production rate of 160 MUmol g(-1) h(-1) even when the system was operated for hundreds of hours. PMID- 26732534 TI - Targeting Oncogenic Mutant p53 for Cancer Therapy. AB - Among genetic alterations in human cancers, mutations in the tumor suppressor p53 gene are the most common, occurring in over 50% of human cancers. The majority of p53 mutations are missense mutations and result in the accumulation of dysfunctional p53 protein in tumors. These mutants frequently have oncogenic gain of-function activities and exacerbate malignant properties of cancer cells, such as metastasis and drug resistance. Increasing evidence reveals that stabilization of mutant p53 in tumors is crucial for its oncogenic activities, while depletion of mutant p53 attenuates malignant properties of cancer cells. Thus, mutant p53 is an attractive druggable target for cancer therapy. Different approaches have been taken to develop small-molecule compounds that specifically target mutant p53. These include compounds that restore wild-type conformation and transcriptional activity of mutant p53, induce depletion of mutant p53, inhibit downstream pathways of oncogenic mutant p53, and induce synthetic lethality to mutant p53. In this review article, we comprehensively discuss the current strategies targeting oncogenic mutant p53 in cancers, with special focus on compounds that restore wild-type p53 transcriptional activity of mutant p53 and those reducing mutant p53 levels. PMID- 26732537 TI - Developing nursing leadership in social media. AB - AIM: A discussion on how nurse leaders are using social media and developing digital leadership in online communities. BACKGROUND: Social media is relatively new and how it is used by nurse leaders and nurses in a digital space is under explored. DESIGN: Discussion paper. DATA SOURCES: Searches used CINAHL, the Royal College of Nursing webpages, Wordpress (for blogs) and Twitter from 2000-2015. Search terms used were Nursing leadership + Nursing social media. IMPLICATIONS FOR NURSING: Understanding the development and value of nursing leadership in social media is important for nurses in formal and informal (online) leadership positions. Nurses in formal leadership roles in organizations such as the National Health Service are beginning to leverage social media. Social media has the potential to become a tool for modern nurse leadership, as it is a space where can you listen on a micro level to each individual. In addition to listening, leadership can be achieved on a much larger scale through the use of social media monitoring tools and exploration of data and crowd sourcing. Through the use of data and social media listening tools nursing leaders can seek understanding and insight into a variety of issues. Social media also places nurse leaders in a visible and accessible position as role models. CONCLUSION: Social media and formal nursing leadership do not have to be against each other, but they can work in harmony as both formal and online leadership possess skills that are transferable. If used wisely social media has the potential to become a tool for modern nurse leadership. PMID- 26732538 TI - Photocatalytic activity and reusability of ZnO layer synthesised by electrolysis, hydrogen peroxide and heat treatment. AB - In this study, the zinc oxide (ZnO) layer was synthesised on the surface of Zn plates by three different techniques, i.e. electrolysis, hydrogen peroxide and heat treatment. The synthesised ZnO layers were characterised using scanning electron microscopy, X-ray diffraction, UV-visible diffuse reflectance and photoluminescence spectroscopy. The photocatalytic activity of the ZnO layer was further assessed against methylene blue (MB) degradation under UV irradiation. The photocatalytic degradation of MB was achieved up to 84%, 79% and 65% within 1 h for ZnO layers synthesised by electrolysis, heat and hydrogen peroxide treatment, respectively. The reusability results show that electrolysis and heat treated ZnO layers have considerable photocatalytic stability. Furthermore, the results confirmed that the photocatalytic efficiency of ZnO was directly associated with the thickness and enlarged surface area of the layer. Finally, this study proved that the ZnO layers synthesised by electrolysis and heat treatment had shown better operational stability and reusability. PMID- 26732539 TI - How to Create an Embryo Penetration Route. AB - Numerous past investigations into human implantation have tended to pay attention to the mechanism of embryo adhesion to endometrial cells or embryo invasion into endometrial stromal tissue. For successful pregnancy, however, embryo penetration through the endometrial epithelial cell (EEC) sheet is also absolutely required. To improve the performance of assisted reproductive technology, implantation studies should also focus on EEC dynamics, in particular, the action of EECs during embryo penetration. Although only EEC apoptosis has been proposed as a mechanism for the formation of the embryo penetration route, we have also recently reported that characteristic EEC collective motion, regulated by the epithelial to mesenchymal transition, also plays a key role in permitting embryo penetration. We review here how EECs form embryo penetration routes in light of our findings. PMID- 26732540 TI - Transcriptome and biomineralization responses of the pearl oyster Pinctada fucata to elevated CO2 and temperature. AB - Ocean acidification and global warming have been shown to significantly affect the physiological performances of marine calcifiers; however, the underlying mechanisms remain poorly understood. In this study, the transcriptome and biomineralization responses of Pinctada fucata to elevated CO2 (pH 7.8 and pH 7.5) and temperature (25 degrees C and 31 degrees C) are investigated. Increases in CO2 and temperature induced significant changes in gene expression, alkaline phosphatase activity, net calcification rates and relative calcium content, whereas no changes are observed in the shell ultrastructure. "Ion and acid-base regulation" related genes and "amino acid metabolism" pathway respond to the elevated CO2 (pH 7.8), suggesting that P. fucata implements a compensatory acid-base mechanism to mitigate the effects of low pH. Additionally, "anti oxidation"-related genes and "Toll-like receptor signaling", "arachidonic acid metabolism", "lysosome" and "other glycan degradation" pathways exhibited responses to elevated temperature (25 degrees C and 31 degrees C), suggesting that P. fucata utilizes anti-oxidative and lysosome strategies to alleviate the effects of temperature stress. These responses are energy-consuming processes, which can lead to a decrease in biomineralization capacity. This study therefore is important for understanding the mechanisms by which pearl oysters respond to changing environments and predicting the effects of global climate change on pearl aquaculture. PMID- 26732541 TI - Cannabinoid-induced autophagy: Protective or death role? AB - Autophagy, the "self-digestion" mechanism of the cells, is an evolutionary conserved catabolic process that targets portions of cytoplasm, damaged organelles and proteins for lysosomal degradation, which plays a crucial role in development and disease. Cannabinoids are active compounds of Cannabis sativa and the most prevalent psychoactive substance is Delta(9)-tetrahydrocannabinol (THC). Cannabinoid compounds can be divided in three types: the plant-derived natural products (phytocannabinoids), the cannabinoids produced endogenously (endocannabinoids) and the synthesized compounds (synthetic cannabinoids). Various studies reported a cannabinoid-induced autophagy mechanism in cancer and non-cancer cells. In this review we focus on the recent advances in the cannabinoid-induced autophagy and highlight the molecular mechanisms involved in these processes. PMID- 26732542 TI - Sonographic detection of central nervous system defects in the first trimester of pregnancy. AB - The fetal central nervous system can already be examined in the first trimester of pregnancy. Acrania, alobar holoprosencephaly, cephaloceles, and spina bifida can confidently be diagnosed at that stage and should actively be looked for in every fetus undergoing first-trimester ultrasound. For some other conditions, such as vermian anomalies and agenesis of the corpus callosum, markers have been identified, but the diagnosis can only be confirmed in the second trimester of gestation. For these conditions, data on sensitivity and more importantly specificity and false positives are lacking, and one should therefore be aware not to falsely reassure or scare expecting parents based on first-trimester findings. This review summarizes the current knowledge of first-trimester neurosonography in the normal and abnormal fetus and gives an overview of which diseases can be diagnosed. PMID- 26732543 TI - SPECT/NIRF Dual Modality Imaging for Detection of Intraperitoneal Colon Tumor with an Avidin/Biotin Pretargeting System. AB - We describe herein dual-modality imaging of intraperitoneal colon tumor using an avidin/biotin pretargeting system. A novel dual-modality probe, (99m)Tc-HYNIC lys(Cy5.5)-PEG4-biotin, was designed, synthesized and characterized. Single photon emission computed tomography/ computed tomography (SPECT/CT) imaging and near infrared fluorescence (NIRF) imaging were developed using intraperitoneal LS180 human colon adenocarcinoma xenografts. Following avidin preinjection for 4 hours, (99m)Tc-HYNIC-lys(Cy5.5)-PEG4-biotin could successfully detect colon tumors of different sizes inside the abdominal region using both modalities, and the imaging results showed no differences. Biodistribution studies demonstrated that the tumors had a very high uptake of the probe (99m)Tc-HYNIC-lys(Cy5.5)-PEG4 biotin (12.74 +/- 1.89% ID/g at 2 h p.i.), and the clearance from blood and other normal tissues occured very fast. The low tumor uptake in the non-pretargeted mice (1.63 +/- 0.50% ID/g at 2 h p.i.) and tumor cell staining results showed excellent tumor binding specificity of the pretargeting system. The ability of the novel probe to show excellent imaging quality with high tumor-to-background contrast, a high degree of binding specificity with tumors and excellent in vivo biodistribution pharmacokinetics should prove that the avidin/biotin based dual modality pretargeting probe is a promising imaging tool during the entire period of tumor diagnosis and treatment. PMID- 26732545 TI - Intracellular Doppler Signatures of Platinum Sensitivity Captured by Biodynamic Profiling in Ovarian Xenografts. AB - Three-dimensional (3D) tissue cultures are replacing conventional two-dimensional (2D) cultures for applications in cancer drug development. However, direct comparisons of in vitro 3D models relative to in vivo models derived from the same cell lines have not been reported because of the lack of sensitive optical probes that can extract high-content information from deep inside living tissue. Here we report the use of biodynamic imaging (BDI) to measure response to platinum in 3D living tissue. BDI combines low-coherence digital holography with intracellular Doppler spectroscopy to study tumor drug response. Human ovarian cancer cell lines were grown either in vitro as 3D multicellular monoculture spheroids or as xenografts in nude mice. Fragments of xenografts grown in vivo in nude mice from a platinum-sensitive human ovarian cell line showed rapid and dramatic signatures of induced cell death when exposed to platinum ex vivo, while the corresponding 3D multicellular spheroids grown in vitro showed negligible response. The differences in drug response between in vivo and in vitro growth have important implications for predicting chemotherapeutic response using tumor biopsies from patients or patient-derived xenografts. PMID- 26732544 TI - B Cells in the Multiple Sclerosis Central Nervous System: Trafficking and Contribution to CNS-Compartmentalized Inflammation. AB - Clinical trial results of peripheral B cell depletion indicate abnormal proinflammatory B cell properties, and particularly antibody-independent functions, contribute to relapsing MS disease activity. However, potential roles of B cells in progressive forms of disease continue to be debated. Prior work indicates that presence of B cells is fostered within the inflamed MS central nervous system (CNS) environment, and that B cell-rich immune cell collections may be present within the meninges of patients. A potential association is reported between such meningeal immune cell collections and the subpial pattern of cortical injury that is now considered important in progressive disease. Elucidating the characteristics of B cells that populate the MS CNS, how they traffic into the CNS and how they may contribute to progressive forms of the disease has become of considerable interest. Here, we will review characteristics of human B cells identified within distinct CNS subcompartments of patients with MS, including the cerebrospinal fluid, parenchymal lesions, and meninges, as well as the relationship between B cell populations identified in these subcompartments and the periphery. We will further describe the different barriers of the CNS and the possible mechanisms of migration of B cells across these barriers. Finally, we will consider the range of human B cell responses (including potential for antibody production, cytokine secretion, and antigen presentation) that may contribute to propagating inflammation and injury cascades thought to underlie MS progression. PMID- 26732547 TI - Aspergillus flavus Conidia-derived Carbon/Sulfur Composite as a Cathode Material for High Performance Lithium-Sulfur Battery. AB - A novel approach was developed to prepare porous carbon materials with an extremely high surface area of 2459.6 m(2)g(-1) by using Aspergillus flavus conidia as precursors. The porous carbon serves as a superior cathode material to anchor sulfur due to its uniform and tortuous morphology, enabling high capacity and good cycle lifetime in lithium sulfur-batteries. Under a current rate of 0.2 C, the carbon-sulfur composites with 56.7 wt% sulfur loading deliver an initial capacity of 1625 mAh g(-1), which is almost equal to the theoretical capacity of sulfur. The good performance may be ascribed to excellent electronic networks constructed by the high-surface-area carbon species. Moreover, the semi-closed architecture of derived carbons can effectively retard the polysulfides dissolution during charge/discharge, resulting in a capacity of 940 mAh g(-1) after 120 charge/discharge cycles. PMID- 26732546 TI - Examining the Dynamic Structure of Daily Internalizing and Externalizing Behavior at Multiple Levels of Analysis. AB - Psychiatric diagnostic covariation suggests that the underlying structure of psychopathology is not one of circumscribed disorders. Quantitative modeling of individual differences in diagnostic patterns has uncovered several broad domains of mental disorder liability, of which the Internalizing and Externalizing spectra have garnered the greatest support. These dimensions have generally been estimated from lifetime or past-year comorbidity patters, which are distal from the covariation of symptoms and maladaptive behavior that ebb and flow in daily life. In this study, structural models are applied to daily diary data (Median = 94 days) of maladaptive behaviors collected from a sample (N = 101) of individuals diagnosed with personality disorders (PDs). Using multilevel and unified structural equation modeling, between-person, within-person, and person specific structures were estimated from 16 behaviors that are encompassed by the Internalizing and Externalizing spectra. At the between-person level (i.e., individual differences in average endorsement across days) we found support for a two-factor Internalizing-Externalizing model, which exhibits significant associations with corresponding diagnostic spectra. At the within-person level (i.e., dynamic covariation among daily behavior pooled across individuals) we found support for a more differentiated, four-factor, Negative Affect-Detachment Hostility-Disinhibition structure. Finally, we demonstrate that the person specific structures of associations between these four domains are highly idiosyncratic. PMID- 26732548 TI - Changes in the metabolome of rats after exposure to arginine and N carbamylglutamate in combination with diquat, a compound that causes oxidative stress, assessed by 1H NMR spectroscopy. AB - Numerous factors can induce oxidative stress in animal production and lead to growth retardation, disease, and even death. Arginine and N-carbamylglutamate can alleviate the effects of oxidative stress. However, the systematic changes in metabolic biochemistry linked to oxidative stress and arginine and N carbamylglutamate treatment remain largely unknown. This study aims to examine the effects of arginine and N-carbamylglutamate on rat metabolism under oxidative stress. Thirty rats were randomly divided into three dietary groups (n = 10 each). The rats were fed a basal diet supplemented with 0 (control), 1% arginine, or 0.1% N-carbamylglutamate for 30 days. On day 28, the rats in each treatment were intraperitoneally injected with diquat at 12 mg per kg body weight or sterile solution. Urine and plasma samples were analyzed by metabolomics. Compared with the diquat group, the arginine + diquat group had significantly lower levels of acetamide, alanine, lysine, pyruvate, tyrosine, alpha-glucose, and beta-glucose in plasma; N-carbamylglutamate + diquat had higher levels of 3 hydroxybutyrate, 3-methylhistidine, acetone, allantoin, asparagine, citrate, phenylalanine, trimethylamine-N-oxide, and tyrosine, and lower levels of low density lipoprotein, lipid, lysine, threonine, unsaturated lipid, urea, and very low density lipoprotein (P < 0.05) in plasma. Compared with the diquat group, the arginine + diquat group had significantly higher levels of citrate, creatinine, homogentisate, and alpha-ketoglutarate while lower levels of acetamide, citrulline, ethanol, glycine, isobutyrate, lactate, malonate, methymalonate, N acetylglutamate, N-methylnicotinamide, propionate, and beta-glucose (P < 0.05) in urine. Compared with the diquat group, the N-carbamylglutamate + diquat group had significantly higher levels of allantoin, citrate, homogentisate, phenylacetylglycine, alpha-ketoglutarate, and beta-glucose while lower levels of acetamide, acetate, acetone, benzoate, citrulline, ethanol, hippurate, lactate, N acetylglutamate, nicotinamide, ornithine, and trigonelline (P < 0.05) in urine. Overall, these results suggest that arginine and N-carbamylglutamate can alter the metabolome associated with energy metabolism, amino acid metabolism, and gut microbiota metabolism under oxidative stress. PMID- 26732549 TI - Mechanism and stability of spectrally pure green up-conversion emission in Yb(3+)/Ho(3+) co-doped Ba5Gd8Zn4O21 phosphors. AB - A series of green-emitting up-conversion (UC) phosphors Ba5Gd8Zn4O21:Yb(3+),Ho(3+) were prepared by a modified sol-gel method, and X-ray diffraction (XRD) patterns were measured to characterize the crystal structure. The obtained UC samples emit dazzling green light and their spectra are composed of strong green emission peaking at 544 nm and negligible red emission peaking at 666 nm with the excitation of a 980 nm near-infrared (NIR) laser diode, assigned to (5)F4/(5)S2 -> (5)I8 and (5)F5 -> (5)I8 transitions of Ho(3+), respectively. The dependence of UC spectra on dopant contents, temperature and pumping power was employed to analyze UC emission color stability. The possible UC mechanisms and processes were proposed based on dependence of the UC emission intensity on pump power, and the lifetimes of green emission ((5)F4/(5)S2 -> (5)I8) were also investigated to better comprehend the energy transfer (ET) process. The origin of spectrally pure green-emitting was discussed in detail by analyzing UC and down conversion (DC) spectra in both the visible and NIR region by comparing that of the UC phosphor CaIn2O4:Yb(3+)/Ho(3+) with highly efficient green emission. Results suggest that Ba5Gd8Zn4O21:Yb(3+),Ho(3+) phosphors with intense green emission and high color purity have potential applications in displays and illuminating technology. PMID- 26732550 TI - Development of Aortic Valve Disease in Familial Hypercholesterolemic Swine: Implications for Elucidating Disease Etiology. PMID- 26732551 TI - Synergistic Utility of Brain Natriuretic Peptide and Left Ventricular Strain in Patients With Significant Aortic Stenosis. AB - BACKGROUND: In aortic stenosis (AS), symptoms and left ventricular (LV) dysfunction represent a later disease state, and objective parameters that identify incipient LV dysfunction are needed. We sought to determine prognostic utility of brain natriuretic peptide (BNP) and left ventricular global longitudinal strain (LV-GLS) in patients with aortic valve area <1.3 cm(2). METHODS AND RESULTS: Five-hundred and thirty-one patients between January 2007 and December 2008 with aortic valve area <1.3 cm(2) (86% with aortic valve area <=1.1 cm(2)) and left ventricular ejection fraction >=50% who had BNP drawn <=90 days from initial echo were included. Society of Thoracic Surgeons (STS) score and mortality were recorded. Mean STS score, glomerular filtration rate, and median BNP were 11+/-5, 73+/-35 mL/min per 1.73 m , and 141 (60-313) pg/mL, respectively; 78% were in New York Heart Association class >=II. Mean LV-stroke volume index (LV-SVI) and LV-GLS were 39+/-10 mL/m(2) and -13.9+/-3%. At 4.7+/-2 years, 405 patients (76%) underwent aortic valve replacement; 161 died (30%). On multivariable survival analysis, age (hazard ratio [HR] 1.46), New York Heart Association class (HR 1.27), coronary artery disease (HR 1.72), decreasing glomerular filtration rate (HR 1.15), increasing BNP (HR 1.16), worsening LV-GLS (HR 1.13) and aortic valve replacement (time dependent) (HR 0.34) predicted survival (all P<0.01). For mortality, the c-statistic incrementally increased as follows (all P<0.01): STS score (0.60 [0.58-0.64]), STS score+BNP (0.67 [0.62 0.70]), and STS score+BNP+LV-GLS (0.74 [0.68-0.78]). CONCLUSIONS: In normal LVEF patients with significant aortic stenosis, BNP and LV-GLS provide incremental (additive not duplicative) prognostic information over established predictors, suggesting that both play a synergistic role in defining outcomes. PMID- 26732552 TI - Nurse Bullying: A Review And A Proposed Solution. AB - Nurse bullying is an extremely common phenomenon which has detrimental consequences to nurses, patients, health care institutions, and to the nursing profession itself. It has even been linked to increased patient mortality. This article demonstrates the critical need to resolve the issue of nurse bullying. It also shows that previous attempts of resolution have not been successful, which may be partly due to the fact that the problem is relatively unacknowledged outside the nursing profession. To resolve the problem of nurse bullying, we believe that the solution must include an incentive for institutions to implement the necessary interventions and to ensure that they are effective. We propose that a measurement pertaining to the level of nurse bullying be factored into the calculation of the value-based incentive payment in the Hospital Value-Based Purchasing program. To facilitate this, we propose that a survey be developed and implemented which is similar to the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. However, whereas the HCAHPS survey measures patients' perspectives of hospital care, this survey would measure nurses' perspectives of workplace bullying. PMID- 26732554 TI - Innovative polymeric system (IPS) for solvent-free lipophilic drug transdermal delivery via dissolving microneedles. AB - Lipophilic drugs are potential drug candidates during drug development. However, due to the need for hazardous organic solvents for their solubilization, these drugs often fail to reach the pharmaceutical market, and in doing so highlight the importance of solvent free systems. Although transdermal drug delivery systems (TDDSs) are considered prospective safe drug delivery routes, a system involving lipophilic drugs in solvent free or powder form has not yet been described. Here, we report, for the first time, a novel approach for the delivery of every kind of lipophilic drug in powder form based on an innovative polymeric system (IPS). The phase transition of powder form of lipophilic drugs due to interior chemical bonds between drugs and biodegradable polymers and formation of nano-sized colloidal structures allowed the fabrication of dissolving microneedles (DMNs) to generate a powerful TDDS. We showed that IPS based DMN with powder capsaicin enhances the therapeutic effect for treatment of the rheumatic arthritis in a DBA/1 mouse model compared to a solvent-based system, indicating the promising potential of this new solvent-free platform for lipophilic drug delivery. PMID- 26732553 TI - Targeted gene transfer to the brain via the delivery of brain-penetrating DNA nanoparticles with focused ultrasound. AB - Gene therapy holds promise for the treatment of many pathologies of the central nervous system (CNS), including brain tumors and neurodegenerative diseases. However, the delivery of systemically administered gene carriers to the CNS is hindered by both the blood-brain barrier (BBB) and the nanoporous and electrostatically charged brain extracelluar matrix (ECM), which acts as a steric and adhesive barrier. We have previously shown that these physiological barriers may be overcome by, respectively, opening the BBB with MR image-guided focused ultrasound (FUS) and microbubbles and using highly compact "brain penetrating" nanoparticles (BPN) coated with a dense polyethylene glycol corona that prevents adhesion to ECM components. Here, we tested whether this combined approach could be utilized to deliver systemically administered DNA-bearing BPN (DNA-BPN) across the BBB and mediate localized, robust, and sustained transgene expression in the rat brain. Systemically administered DNA-BPN delivered through the BBB with FUS led to dose-dependent transgene expression only in the FUS-treated region that was evident as early as 24h post administration and lasted for at least 28days. In the FUS-treated region ~42% of all cells, including neurons and astrocytes, were transfected, while less than 6% were transfected in the contralateral non FUS treated hemisphere. Importantly, this was achieved without any sign of toxicity or astrocyte activation. We conclude that the image-guided delivery of DNA-BPN with FUS and microbubbles constitutes a safe and non-invasive strategy for targeted gene therapy to the brain. PMID- 26732555 TI - TRAIL-coated leukocytes that prevent the bloodborne metastasis of prostate cancer. AB - Prostate cancer, once it has progressed from its local to metastatic form, is a disease with poor prognosis and limited treatment options. Here we demonstrate an approach using nanoscale liposomes conjugated with E-selectin adhesion protein and Apo2L/TRAIL (TNF-related apoptosis-inducing ligand) apoptosis ligand that attach to the surface of leukocytes and rapidly clear viable cancer cells from circulating blood in the living mouse. For the first time, it is shown that such an approach can be used to prevent the spontaneous formation and growth of metastatic tumors in an orthotopic xenograft model of prostate cancer, by greatly reducing the number of circulating tumor cells. We conclude that the use of circulating leukocytes as a carrier for the anti-cancer protein TRAIL could be an effective tool to directly target circulating tumor cells for the prevention of prostate cancer metastasis, and potentially other cancers that spread through the bloodstream. PMID- 26732556 TI - Nanotechnology for mesenchymal stem cell therapies. AB - Mesenchymal stem cells (MSC) display great proliferative, differentiative, chemotactic, and immune-modulatory properties required to promote tissue repair. Several clinical trials based on the use of MSC are currently underway for therapeutic purposes. The aim of this article is to examine the current trends and potential impact of nanotechnology in MSC-driven regenerative medicine. Nanoparticle-based approaches are used as powerful carrier systems for the targeted delivery of bioactive molecules to ensure MSC long-term maintenance in vitro and to enhance their regenerative potential. Nanostructured materials have been developed to recapitulate the stem cell niche within a tissue and to instruct MSC toward the creation of regeneration-permissive environment. Finally, the capability of MSC to migrate toward the site of injury/inflammation has allowed for the development of diagnostic imaging systems able to monitor transplanted stem cell bio-distribution, toxicity, and therapeutic effectiveness. PMID- 26732558 TI - Development of controlled release systems over the past 50years in the area of contraception. AB - The field of controlled release has contributed significantly to female reproductive health and in particular the prevention of unintended pregnancy. For at least 50years, there have been significant advances in controlled release dosage forms used for contraception. These advances have been driven by the need to provide women a wide array of products that address adherence problems noted with oral contraceptives. The first long-acting injectable product (Depo Provera(r)) was approved in the US in 1959. Since then, there has been an emphasis on development of long-acting reversible contraceptives. These products include implants, intrauterine systems, and vaginal rings. A shorter acting contraceptive option is the transdermal patch. Despite these advances there are still a large number of unplanned pregnancies around the world. New controlled release technologies will be needed to continue providing women safe and easy to use contraceptive products. PMID- 26732559 TI - [Not Available]. PMID- 26732557 TI - Delivery of ziconotide to cerebrospinal fluid via intranasal pathway for the treatment of chronic pain. AB - The purpose of the current study was to investigate the plausibility of delivery of ziconotide to the cerebrospinal fluid (CSF) via intranasal administration. Ziconotide was administered either in the form of solution or Kolliphor P 407 gels (KP 407) intranasally in Sprague-Dawley rats. The effect of incorporation of chitosan in the formulation was also investigated. Time course of drug in the CSF was investigated by collecting CSF from cisterna magna. Pharmacokinetics of ziconotide in CSF following intrathecal and intravenous (i.v.) administration of ziconotide was investigated. Upon intrathecal administration the elimination rate constant of ziconotide in CSF was found to be 1.01+/-0.34h(-1). The Cmax and Tmax of ziconotide in CSF following intravenous administration were found to be 37.78+/-6.8ng/mL and ~2h respectively. The time required to attain maximum concentration (Tmax) in CSF was less upon intranasal administration (15min) compared to i.v. administration (120min). Presence of chitosan enhanced the overall bioavailability of ziconotide from intranasal solution and gel formulations. The elimination rate constant of ziconotide in CSF following intranasal and intravenous administration of ziconotide solution was found to be 0.54+/-0.08h(-1) and 0.42+/-0.10h(-1) respectively. Whereas, intranasal administration of ziconotide in the form of in situ forming gel lowered the elimination rate significantly. These results suggest that intranasal administration could be a potential noninvasive and patient compliant method of delivering ziconotide to CSF to treat chronic pain. PMID- 26732562 TI - Association of Breakfast Intake With Incident Stroke and Coronary Heart Disease: The Japan Public Health Center-Based Study. AB - BACKGROUND AND PURPOSE: The association between breakfast intake and the risk of cardiovascular disease, including stroke, among Asian people remains unknown. We sought to prospectively investigate whether the omission of breakfast is related to increased risks of stroke and coronary heart disease in general Japanese populations. METHODS: A total of 82,772 participants (38,676 men and 44,096 women) aged 45 to 74 years without histories of cardiovascular disease or cancer were followed up from 1995 to 2010. Participants were classified as having breakfast 0 to 2, 3 to 4, 5 to 6, or 7 times/wk. The hazard ratios of cardiovascular disease were estimated using Cox proportional hazards models. RESULTS: During the 1 050 030 person-years of follow-up, we documented a total of 4642 incident cases, 3772 strokes (1051 cerebral hemorrhages, 417 subarachnoid hemorrhages, and 2286 cerebral infarctions), and 870 coronary heart disease. Multivariable analysis showed that those consuming no breakfast per week compared with those consuming breakfast everyday had hazard ratios (95% confidence interval; P for trend) of 1.14 (1.01-1.27; 0.013) for total cardiovascular disease, 1.18 (1.04-1.34; 0.007) for total stroke, and 1.36 (1.10-1.70; 0.004) for cerebral hemorrhage. Similar results were observed even after exclusion of early cardiovascular events. No significant association between the frequency of breakfast intake and the risk of coronary heart disease was observed. CONCLUSIONS: The frequency of breakfast intake was inversely associated with the risk of stroke, especially cerebral hemorrhage in Japanese, suggesting that eating breakfast everyday may be beneficial for the prevention of stroke. PMID- 26732561 TI - Interleukin-4 Is Essential for Microglia/Macrophage M2 Polarization and Long-Term Recovery After Cerebral Ischemia. AB - BACKGROUND AND PURPOSE: Interleukin-4 (IL-4) is a unique cytokine that may contribute to brain repair by regulating microglia/macrophage functions. Thus, we examined the effect of IL-4 on long-term recovery and microglia/macrophage polarization in 2 well-established stroke models. METHODS: Transient middle cerebral artery occlusion or permanent distal middle cerebral artery occlusion was induced in wild-type and IL-4 knockout C57/BL6 mice. In a separate cohort of wild-type animals, IL-4 (60 ng/d for 7 days) or vehicle was infused into the cerebroventricle after transient middle cerebral artery occlusion. Behavioral outcomes were assessed by the Rotarod, corner, foot fault, and Morris water maze tests. Neuronal tissue loss was verified by 2 independent neuron markers. Markers of classically activated (M1) and alternatively activated (M2) microglia were assessed by real-time polymerase chain reaction, immunofluorescence, and flow cytometry. RESULTS: Loss of IL-4 exacerbated sensorimotor deficits and impaired cognitive functions <=21 days post injury. In contrast to the delayed deterioration of neurological functions, IL-4 deficiency increased neuronal tissue loss only in the acute phase (5 days) after stroke and had no impact on neuronal tissue loss 14 or 21 days post injury. Loss of IL-4 promoted expression of M1 microglia/macrophage markers and impaired expression of M2 markers at 5 and 14 days post injury. Administration of IL-4 into the ischemic brain also enhanced long-term functional recovery. CONCLUSIONS: The cytokine IL-4 improves long-term neurological outcomes after stroke, perhaps through M2 phenotype induction in microglia/macrophages. These results are the first to suggest that immunomodulation with IL-4 is a promising approach to promote long-term functional recovery after stroke. PMID- 26732564 TI - Perceived Unmet Rehabilitation Needs 1 Year After Stroke: An Observational Study From the Swedish Stroke Register. AB - BACKGROUND AND PURPOSE: Met care demands are key aspects in poststroke quality of care. This study aimed to identify baseline predictors and 12-month factors that were associated with perceived unmet rehabilitation needs 1 year poststroke. METHODS: Data on patients who were independent in activities of daily living, hospitalized for acute stroke during 2008 to 2010, and followed up 1 year poststroke through a postal questionnaire were obtained from the Swedish stroke register. Patients reporting fulfilled rehabilitation needs were compared with those with unmet needs (Chi square test). RESULTS: The study included 37 383 patients, 46% female. At 12 months, 8019 (21.5%) patients reported unmet rehabilitation needs. Compared with those with met rehabilitation needs, patients reporting unmet rehabilitation needs were older (75.4 versus 72.4 years; P<0.0001); a higher proportion was activities of daily living-dependent (59% versus 31.9%; P<0.0001) and institutionalized (24.3% versus 11.5%; P<0.0001) at 12 months. Poststroke depression (32.3% versus 24.9%; P<0.0001) and insufficient pain medication were more common in patients with unmet needs (54.5% versus 32.3%; P<0.0001). Baseline predictors of unmet rehabilitation needs at 12 months in an age-adjusted model were severe stroke (odds ratio [OR]=3.04; confidence interval [CI]: 2.39-3.87), prior stroke (OR=1.63; CI: 1.53-1.75), female sex (OR=1.14; CI: 1.07-1.20), diabetes mellitus (OR=1.24; CI: 1.15-1.32), stroke other than ischemic (OR=1.26; CI: 1.20-1.32), and atrial fibrillation (OR=1.19; CI: 1.12-1.27). CONCLUSIONS: Unfulfilled rehabilitation needs 1 year poststroke are common and associated with high age, dependency, pain, and depression. Long term follow-up systems should, therefore, be comprehensive and address multiple domains of poststroke problems, rather than having a single-domain focus. PMID- 26732563 TI - Cardiovascular, Bleeding, and Mortality Risks of Dabigatran in Asians With Nonvalvular Atrial Fibrillation. AB - BACKGROUND AND PURPOSE: Whether dabigatran is associated with different risks of cardiovascular, bleeding events, and mortality from warfarin in Asian patients with nonvalvular atrial fibrillation remains unclear. METHODS: We used the Taiwan National Health Insurance Research Database to obtain 9940 and 9913 nonvalvular atrial fibrillation patients taking dabigatran and warfarin, respectively, from June 1, 2012, to December 31, 2013, as the dynamic cohort. Inverse probability of treatment weighting using propensity scores was used to balance covariates across 2 study groups. Patients were followed up until the first occurrence of any study outcome or end date of study. RESULTS: During a median follow-up period of 0.67 years, there were 526 outcomes for dabigatran group. The hazard ratios (95% confidence intervals) comparing dabigatran with warfarin (reference) were as follows: ischemic stroke, 0.62 (0.52-0.73; P<0.0001); myocardial infarction, 0.67 (0.43-1.05; P=0.0803); intracranial hemorrhage, 0.44 (0.32-0.60; P<0.0001); major gastrointestinal bleeding, 0.99 (0.66-1.49; P=0.9658); all hospitalized major bleeding, 0.58 (0.46-0.74; P<0.0001); and all-cause mortality, 0.45 (0.38-0.53; P<0.0001). Dabigatran did not increase the risk of myocardial infarction or major gastrointestinal bleeding in all age groups when compared with warfarin. Total 8772 patients (88%) took a 110-mg dose in dabigatran group. The magnitude of effect for each outcome of 110-mg was comparable with that of 150-mg dose in the subgroup analysis. CONCLUSIONS: In real-world practice, dabigatran was associated with a reduced risk of ischemic stroke, intracranial hemorrhage, all hospitalized major bleeding, and all-cause mortality compared with warfarin in Asian patients with nonvalvular atrial fibrillation. Dabigatran did not increase the risk of major gastrointestinal bleeding or myocardial infarction compared with warfarin. PMID- 26732565 TI - New Appraisal of Atrial Fibrillation Burden and Stroke Prevention. PMID- 26732566 TI - Response to Letter Regarding Article, "Hemorrhagic Moyamoya Disease in Children: Clinical, Angiographic Features, and Long-Term Surgical Outcome". PMID- 26732567 TI - Fluid-Attenuated Inversion Recovery Vascular Hyperintensities-Diffusion-Weighted Imaging Mismatch Identifies Acute Stroke Patients Most Likely to Benefit From Recanalization. AB - BACKGROUND AND PURPOSE: Fluid-attenuated inversion recovery vascular hyperintensities (FVH) beyond the boundaries of diffusion-weighted imaging (DWI) lesion (FVH-DWI mismatch) have been proposed as an alternative to perfusion weighted imaging (PWI)-DWI mismatch. We aimed to establish whether FVH-DWI mismatch can identify patients most likely to benefit from recanalization. METHODS: FVH-DWI mismatch was assessed in 164 patients with proximal middle cerebral artery occlusion before intravenous thrombolysis. PWI-DWI mismatch (PWITmax>6sec/DWI>1.8) was assessed in the 104 patients with available PWI data. We tested the associations between 24-hours complete recanalization on magnetic resonance angiography and 3-month favorable outcome (modified Rankin Scale score <=2), stratified on FVH-DWI (or PWI-DWI) status. RESULTS: FVH-DWI mismatch was present in 121/164 (74%) patients and recanalization in 50/164 (30%) patients. The odds ratio for favorable outcome with recanalization was 16.2 (95% confidence interval, 5.7-46.5; P<0.0001) in patients with FVH-DWI mismatch and 2.6 (95% confidence interval, 0.6-12.1; P=0.22) in those without FVH-DWI mismatch (P=0.048 for interaction). Recanalization was associated with favorable outcome in patients with PWI-DWI mismatch (odds ratios, 9.9; 95% confidence interval, 3.1 31.3; P=0.0001) and in patients without PWI-DWI mismatch (odds ratios, 7.0; 95% confidence interval, 1.1-44.1; P=0.047), P=0.76 for interaction. CONCLUSION: The FVH-DWI mismatch may rapidly identify patients with proximal occlusion most likely to benefit from recanalization. PMID- 26732560 TI - Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2. AB - BACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years. METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5*10(-6) and performed in silico association analyses in an independent sample of <=1003 cases and 7745 controls. RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5*10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2. CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke. PMID- 26732569 TI - Letter by Jiang Regarding Article, "Hemorrhagic Moyamoya Disease in Children: Clinical, Angiographic Features, and Long-Term Surgical Outcome". PMID- 26732568 TI - Role of Erythrocyte CD47 in Intracerebral Hematoma Clearance. AB - BACKGROUND AND PURPOSE: Enhancing hematoma clearance through phagocytosis may reduce brain injury after intracerebral hemorrhage. In the current study, we investigated the role of cluster of differentiation 47 (CD47) in regulating erythrophagocytosis and brain injury after intracerebral hemorrhage in nude mice. METHODS: This study was in 2 parts. First, male adult nude mice had an intracaudate injection of 30 MUL saline, blood from male adult wild-type (WT) mice, or blood from CD47 knockout mice. Second, mice had an intracaudate injection of 30 MUL CD47 knockout blood with clodronate or control liposomes. Clodronate liposomes were also tested in saline-injected mice. All mice then had magnetic resonance imaging to measure hematoma size and brain swelling. Brains were used for immunohistochemistry and Western blot. RESULTS: Erythrophagocytosis occurred in and around the hematoma. Injection of CD47 knockout blood resulted in quicker clot resolution, less brain swelling, and less neurological deficits compared with wild-type blood. Higher brain heme oxygenase-1 levels and more microglial activation (mostly M2 polarized microglia) at day 3 were found after CD47 knockout blood injection. Co-injection of clodronate liposomes, to deplete phagocytes, caused more severe brain swelling and less clot resolution. CONCLUSIONS: These results indicated that CD47 has a key role in hematoma clearance after intracerebral hemorrhage. PMID- 26732570 TI - Arterial Spin Labeling Magnetic Resonance Imaging Estimation of Antegrade and Collateral Flow in Unilateral Middle Cerebral Artery Stenosis. AB - BACKGROUND AND PURPOSE: Three-dimensional pseudocontinuous arterial spin labeling with multiple postlabeling delays has been used to assess cerebral blood flow (CBF). We used this modality to estimate antegrade and collateral flow in patients with unilateral middle cerebral artery stenosis. METHODS: Consecutive patients with unilateral middle cerebral artery 50% to 99% stenosis at 2 centers underwent pseudocontinuous arterial spin labeling with a postlabeling delays of 1.5 and 2.5 s. Mean CBF of bilateral middle cerebral artery territory at the postlabeling delays 1.5 and 2.5 s was measured. Early-arriving flow proportion was defined as (CBF 1.5 s at lesion side/CBF 2.5 s at normal side)*100%. Late arriving retrograde flow proportion was defined as ([CBF 2.5 s-CBF 1.5 s] at lesion side-[CBF 2.5 s-CBF 1.5 s] at normal side)/CBF 2.5 s at normal side*100%. Antegrade and collateral scales were evaluated in patients with conventional angiography. Spearman correlation coefficients were calculated between early arriving flow and late-arriving retrograde flow proportions on arterial spin labeling and antegrade and collateral scales on conventional angiography, respectively. RESULTS: Forty-one patients (46.0+/-12.0 years) were enrolled. The mean early-arriving flow proportion was 78.3+/-14.9%. The mean late-arriving retrograde flow proportion was 16.1+/-10.2%. In 21 patients with conventional angiography, Spearman correlation coefficient was 0.53 (95% confidence interval, 0.11-0.79) between antegrade grade and early-arriving flow proportion (P=0.01) and 0.81 (95% confidence interval, 0.56-0.92) between collateral grade and late arriving retrograde flow proportion (P<0.0001). CONCLUSIONS: Three-dimensional pseudocontinuous arterial spin labeling with 2 postlabeling delays may provide an empirical approach for estimating antegrade and collateral flow in patients with unilateral middle cerebral artery stenosis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02479243. PMID- 26732572 TI - Innovations in Stroke: The Use of PROMIS and NeuroQoL Scales in Clinical Stroke Trials. PMID- 26732571 TI - Lipoxin A4 Reduces Inflammation Through Formyl Peptide Receptor 2/p38 MAPK Signaling Pathway in Subarachnoid Hemorrhage Rats. AB - BACKGROUND AND PURPOSE: Lipoxin A4 (LXA4) has been reported to reduce inflammation in several neurological injury models. We studied the effects of LXA4 on neuroinflammation after subarachnoid hemorrhage (SAH) in a rat model. METHODS: Two hundred and thirty-eight Sprague-Dawley male rats, weight 280-320 g, were used. Exogenous LXA4 (0.3 and 1.0 nmol) were injected intracerebroventricularly at 1.5 hours after SAH. Neurological scores, brain water content, and blood-brain barrier were evaluated at 24 hours after SAH; Morris water maze and T-maze tests were examined at 21 days after SAH. The expression of endogenous LXA4 and its receptor formyl peptide receptor 2 (FPR2), as well as p38, interleukin-1beta, and interleukin-6 were studied either by ELISA or by Western blots. Neutrophil infiltration was observed by myeloperoxidase staining. FPR2 siRNA was used to knock down LXA4 receptor. RESULTS: The expression of endogenous LXA4 decreased, and the expression of FPR2 increased after SAH. Exogenous LXA4 decreased brain water content, reduced Evans blue extravasation, and improved neurological functions and improved the learning and memory ability after SAH. LXA4 reduced neutrophil infiltration and phosphorylation of p38, interleukin-1beta, and interleukin-6. These effects of LXA4 were abolished by FPR2 siRNA. CONCLUSIONS: Exogenous LXA4 inhibited inflammation by activating FPR2 and inhibiting p38 after SAH. LXA4 may serve as an alternative treatment to relieve early brain injury after SAH. PMID- 26732573 TI - Impaired Higher-Level Functional Capacity as a Predictor of Stroke in Community Dwelling Older Adults: The Ohasama Study. AB - BACKGROUND AND PURPOSE: Functional capacity is a predictor, as well as a consequence, of stroke. However, little research has been done to examine whether higher-level functional capacity above basic activities of daily living is a predictor of stroke. METHODS: We followed 1493 Japanese community-dwelling adults aged >=60 years (mean age, 70.1 years) who were independent in basic activities of daily living and had no history of stroke. Baseline data were collected using a self-administered questionnaire. Higher-level functional capacity was measured using the total score and 3 subscales (instrumental activities of daily living, intellectual activity, and social role) derived from the Tokyo Metropolitan Institute of Gerontology Index of Competence. Adjusted hazard ratios and 95% confidence intervals were calculated by the Cox proportional hazards model. RESULTS: During a mean follow-up of 10.4 years, 191 participants developed a first stroke. Impaired higher-level functional capacity based on total score of the Tokyo Metropolitan Institute of Gerontology Index of Competence was significantly associated with stroke (hazard ratio, 1.64; 95% confidence interval, 1.15-2.33). Among the 3 subscales, only intellectual activity was significantly associated with stroke (hazard ratio, 1.64; 95% confidence interval, 1.21-2.22). Social role was significantly associated with stroke only among those aged >=75 years (hazard ratio, 1.78; 95% confidence interval, 1.07 2.98). CONCLUSIONS: Impaired higher-level functional capacity, especially in the domain of intellectual activity, was a predictor of stroke, even among community dwelling older adults with independent basic activities of daily living at baseline. Monitoring of higher-level functional capacity might be useful to detect those at higher risk of developing stroke in the future. PMID- 26732575 TI - ULTRASONOGRAPHY: two years of globalization and the achievement of ESCI status. PMID- 26732574 TI - Long-term outcomes for women after obstetric fistula repair in Lilongwe, Malawi: a qualitative study. AB - BACKGROUND: Obstetric fistula affects a woman's life physically, psychosocially, and economically. Although surgery can repair the physical damage of fistula, the devastating consequences that affect a woman's quality of life may persist when she reintegrates into her community. This qualitative study assessed long-term outcomes among women who underwent obstetric fistula repair in Malawi. We explored three domains: overall quality of life before and after repair, fertility and pregnancy outcomes after repair, and understanding of fistula. METHODS: In-depth interviews were conducted in Chichewa with 20 women from seven districts across Central Malawi. All women were interviewed 1 to 2 years after surgical repair for obstetric fistula at the Fistula Care Centre in Lilongwe, Malawi. Interviews were independently coded and analyzed using content analysis. RESULTS: About half of women were married and nine of 20 women reported some degree of urinary incontinence. With the exception of relationship challenges, women's concerns before and after repair were different. Additionally, repair had resolved many of the concerns women had before repair. However, challenges, both directly and indirectly related to fistula, persisted. Improvements in quality of life at the individual level included feelings of freedom, confidence and personal growth, and improved income-earning ability. Interpersonal quality of life improvements included improved relationships with family and friends, reduced stigma, and increased participation with their communities. Nearly half of women desired future pregnancies, but many were uncertain about their ability to bear children and feared additional pregnancies could cause fistula recurrence. Most women were well informed about fistula development but myths about witchcraft and fear of delivery were present. Nearly all women would recommend fistula repair to other women, and many were advocates in their communities. CONCLUSIONS: Nearly all women believed their quality of life had improved at the individual and interpersonal levels since fistula repair, even among women who continued to have urinary incontinence. Contrary to other studies, women reported they were welcomed back by their communities and had limited challenges when reintegrating. Despite the overall improvements in quality of life, many continued to have relationship problems and were concerned about future fertility. These issues need to be further explored in other studies. PMID- 26732576 TI - Factors influencing the renal arterial Doppler waveform: a simulation study using an electrical circuit model (secondary publication). AB - PURPOSE: The goal of this study was to evaluate the effect of vascular compliance, resistance, and pulse rate on the resistive index (RI) by using an electrical circuit model to simulate renal blood flow. METHODS: In order to analyze the renal arterial Doppler waveform, we modeled the renal blood-flow circuit with an equivalent simple electrical circuit containing resistance, inductance, and capacitance. The relationships among the impedance, resistance, and compliance of the circuit were derived from well-known equations, including Kirchhoff's current law for alternating current circuits. Simulated velocity-time profiles for pulsatile flow were generated using Mathematica (Wolfram Research) and the influence of resistance, compliance, and pulse rate on waveforms and the RI was evaluated. RESULTS: Resistance and compliance were found to alter the waveforms independently. The impedance of the circuit increased with increasing proximal compliance, proximal resistance, and distal resistance. The impedance decreased with increasing distal compliance. The RI of the circuit decreased with increasing proximal compliance and resistance. The RI increased with increasing distal compliance and resistance. No positive correlation between impedance and the RI was found. Pulse rate was found to be an extrinsic factor that also influenced the RI. CONCLUSION: This simulation study using an electrical circuit model led to a better understanding of the renal arterial Doppler waveform and the RI, which may be useful for interpreting Doppler findings in various clinical settings. PMID- 26732577 TI - The phenology of winter rye in Poland: an analysis of long-term experimental data. AB - The study of the phenology of crops, although quite popular, has limitations, mainly because of frequent changes to crop varieties and management practices. Here, we present data on the phenology and yield of winter rye in western Poland collected between 1957 and 2012 from a long-term field experiment. Data were examined for trends through time and compared to climatological factors using regression analysis. Both annual air temperature and precipitation increased during the study period, equivalent to 2 degrees C and 186 mm, respectively, over the 52-year period for which met data were available. We detected significant delays in sowing date and recently in emergence, but significant advances were apparent in full flowering date equivalent to 4 days/decade. Yield and plant density experienced a step like change in 1986; yield increasing by ca. 70 % and plant density increasing by ca. 50 %, almost coinciding with a similar change in annual mean temperature, but most likely caused by a changed seed rate and use of herbicides. Future climate change is expected to have a greater impact on this crop, but farmers may be able to adapt to these changes by modifying water regimes, using new machinery and sowing new rye varieties. PMID- 26732578 TI - Effects of dietary DL-2-hydroxy-4(methylthio)butanoic acid supplementation on growth performance, indices of ascites syndrome, and antioxidant capacity of broilers reared at low ambient temperature. AB - This study examined the effects of dietary DL-2-hydroxy-4(methylthio)butanoic acid (DL-HMTBA) supplementation on growth performance, antioxidant capacity, and ascites syndrome (AS) in broilers reared at low ambient temperature (LAT) from 7 to 28 days of age. Eight hundred 7-day-old broilers were randomly assigned to two ambient temperatures (LAT and normal ambient temperature [NAT]), four supplemental DL-HMTBA levels (0.17, 0.34, 0.51, and 0.68 %) of the basal diet in a 2 * 4 factorial arrangement (ten replicate pens; ten birds/pen). LAT and NAT indicate temperatures of 12-14 and 24-26 degrees C in two chambers, respectively, and broilers were reared at these temperatures from 7 to 28 days of age. LAT significantly decreased body weight gain (P < 0.001), serum glutathione (GSH) content (day 14, P = 0.02; day 28, P = 0.045), glutathione peroxidase (GSH Px) activity, and total antioxidant capacity (T-AOC) at 21 days (P = 0.001, 0.015) and 28 days (P = 0.017, 0.010) and increased feed conversion ratio (FCR) (P < 0.001), serum malondialdehyde (day 21, P = 0.000) and protein carbonyl Level (day 14, P = 0.003; day 21, P = 0.035). As for incidence of AS, there were significant effects of LAT on red blood cell (RBC) count (P < 0.05), hematocrit (HCT) (P < 0.05), and the right to total ventricular weight ratio (RV/TV) at 21 days (P = 0.012) and 28 days (P = 0.046). Supplementation of DL-HMTBA markedly decreased RV/TV at day 28 (P = 0.021), RBC (day 21, P = 0.008), HCT (day 21, P < 0.001), mean cell hemoglobin (day 14, P = 0.035; day 21, P = 0.003), and serum protein carbonyl level (day 21, P = 0.009), while significantly increased serum GSH content (day 14, P = 0.022; day 28, P = 0.001), SOD and GSH-Px activities at 21 days of age (P < 0.001 and P = 0.037). The optimal supplemental DL-HMTBA levels in basal diet of broilers aged from 7 to 28 days under low or normal temperatures were similar, so the authors recommended supplemental of DL-HMTBA level was 0.46 %. PMID- 26732579 TI - Diclocor is superior to diclofenac sodium and quercetin in normalizing biochemical parameters in rats with collagen-induced osteoarthritis. AB - OBJECTIVE: The aim of the present study was to investigate anti-inflammatory activity of Diclocor in the setting of collagen-induced osteoarthritis in rats in comparison with its active monocomponents-diclofenac sodium and quercetin. METHODS: The study was conducted on the model of collagen-induced osteoarthritis and included measurement of sialic acids, glycoproteins, C-reactive protein, prostaglandin E2, 6-keto-prostaglandin F1alpha, thromboxane B2, and leukotriene B4. Lastly, morphologic study with morphometry was also performed. RESULTS: Diclocor is superior to quercetin and diclofenac sodium by the degree of pharmacological effect on some of the studied parameters. The differences between the values were statistically significant. CONCLUSION: Diclocor is a promising corrector of inflammatory and destructive joint diseases. Owing to the presence of both diclofenac sodium and quercetin in its composition, Diclocor exhibits a complex mechanism of anti-inflammatory action affecting cyclooxygenase and lipoxygenase ways of arachidonic acid biotransformation. PMID- 26732580 TI - A Rare Class of New Dimeric Naphthoquinones from Diospyros lotus have Multidrug Reversal and Antiproliferative Effects. AB - Three new dimeric naphthoquinones, 5,4'-dihydroxy-1'-methoxy-6,6'-dimethyl-7,3' binaphthyl-1,4,5',8'-tetraone (1), 5',8'-dihydroxy-5-methoxy-6,6'-dimethyl-7,3' binaphthyl-1,4,1',4'-tetraone (2) and 8,5',8'-trihydroxy-6,6'-dimethyl-7,3' binaphthyl-1,4,1',4'-tetraone (3), were isolated from the roots of Diospyros lotus. Their structures were elucidated by spectroscopic techniques, including 1D and 2D NMR, such as HSQC, HMBS, NOESY, and J-resolved. Compounds 1-3 were evaluated for their effects on the reversion of multidrug resistance (MDR) mediated by P-glycoprotein through use of the rhodamine-123 exclusion screening test on human ABCB1 gene transfected L5178Y mouse T-cell lymphoma. Compounds 1-3 were also assessed for their antiproliferative and cytotoxic effects on L5178 and L5178Y mouse T-cell lymphoma lines. Both 1 and 2 exhibited promising antiproliferative and MDR-reversing effects in a dose-dependent manner. The effects of the tested compounds on the activity of doxorubicin were observed to vary from slight antagonism to antagonism. PMID- 26732581 TI - The effects of the cerebral, cerebellar and vestibular systems on the head stabilization reflex. AB - The head stabilization reflex (HSR) is a brain stem reflex which appears in the neck muscles in response to sudden head position changes and brings the head to its previous position. The reflex mechanism has not been understood. The afferent fibers come from cervical muscle spindles, vestibular structures, and the accessory nerve, the efferents from the accessory nerve. In this study, we aim to investigate the roles of supraspinal neural structures and the vestibular system on the HSR. The patient group consisted of 86 patients (33 cerebral cortical lesion, 14 cerebellar syndrome and 39 vestibular inexcitability or hypoexcitability); the control group was composed of 32 healthy volunteers. Concentric needle electrodes were inserted into the sternocleidomastoid muscle (SCM) and the accessory nerves were stimulated with the electrical stimulator. A reflex response of about 45-55 ms was obtained from the contralateral SCM muscle. 50 % of cases had bilateral loss whereas 37 % of cases with unilateral cerebellar lesions had an ipsilateral reflex loss. Bilateral HSR loss was detected in 84 % of cases with bilateral cerebellar lesions. Bilateral reflex loss was observed in 70 % of patients with unilateral cortical lesions and 94 % of those with bilateral vestibular dysfunction. Ipsilateral HSR loss was observed in 55 % of cases with unilateral vestibular dysfunction. It was discovered that supraspinal structures and the vestibular system may have an excitatory effect on HSR. This effect may be lost in supra-segmental and vestibular dysfunctions. The localization value of HSR was found to be rather poor in our study. PMID- 26732582 TI - Isolated writer's cramp symptomatic to a brain tumour. PMID- 26732583 TI - The analysis of association between SNCA, HUSEYO and CSMD1 gene variants and Parkinson's disease in Iranian population. AB - Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. Both genetic and environmental factors are involved in the etiology of the disease. Many studies have revealed the susceptibility genes and variations for PD which need further confirmation. Here we evaluated the association of variations in SNCA, HUSEYO and CSMD1 genes with PD. A case-control study was conducted with 489 PD patients and 489 healthy controls. DNA was extracted from peripheral blood of all subjects and rs356220 and rs11931074 in SNCA, rs2338971 in HUSEYO and rs12681349 in CSMD1 were genotyped using PCR-RFLP method. The genotypes and allele frequencies were significantly different between case and control groups for rs356220, rs11931074 and rs2338971 but not for rs12681349. We provided further evidence that rs356220 is associated with increased risk of PD supporting previous studies in Caucasian-based and Japanese populations. The association of rs11931074 with decreased risk of PD was also significant. This study revealed the first evidence of the association of rs2338971 with increased risk of PD in the Iranian population. Nevertheless, these findings need further validation via more replication studies. PMID- 26732585 TI - A comparative study of the quality of care and glycemic control among ambulatory type 2 diabetes mellitus clients, at a Tertiary Referral Hospital and a Regional Hospital in Central Kenya. AB - BACKGROUND: Peripheral public health facilities remain the most frequented by the majority of the population in Kenya; yet remain sub-optimally equipped and not optimized for non-communicable diseases care. DESIGN AND METHODOLOGY: We undertook a descriptive, cross sectional study among ambulatory type 2 diabetes mellitus clients, attending Kenyatta National Referral Hospital (KNH), and Thika District Hospital (TDH) in Central Kenya. Systematic random sampling was used. HbA1c was assessed for glycemic control and the following, as markers of quality of care: direct client costs, clinic appointment interval and frequency of self monitoring test, affordability and satisfaction with care. RESULTS: We enrolled 200 clients, (Kenyatta National Hospital 120; Thika District Hospital 80); Majority of the patients 66.5% were females, the mean age was 57.8 years; and 58% of the patients had basic primary education. 67.5% had diabetes for less than 10 years and 40% were on insulin therapy. The proportion (95% CI) with good glycemic was 17% (12.0-22.5 respectively) in the two facilities [Kenyatta National Hospital 18.3% (11.5-25.6); Thika District Hospital 15% (CI 7.4-23.7); P = 0.539]. However, in Thika District Hospital clients were more likely to have a clinic driven routine urinalysis and weight, they were also accorded shorter clinic appointment intervals; incurred half to three quarter lower direct costs, and reported greater affordability and satisfactions with care. CONCLUSION: In conclusion, we demonstrate that in Thika district hospital, glycemic control and diabetic care is suboptimal; but comparable to that of Kenyatta National Referral hospital. Opportunities for improvement of care abound at peripheral health facilities. PMID- 26732584 TI - Depressive symptoms are associated with tumor necrosis factor alpha in systemic lupus erythematosus. AB - BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) is deeply related to pathogenesis of neurodevelopmental disorders, especially depression. The aim of this study was to explore potential relationships between sera TNF-alpha levels and mood and anxiety disorders in systemic lupus erythematosus (SLE) patients. METHODS: We included 153 consecutive SLE patients (women 148; median age 30; range 10-62) and 40 (women 37; mean age 28.5; range 12-59) age- and sex-matched healthy controls. Mood and anxiety disorders were determined through Beck Depression and Beck Anxiety Inventory. SLE patients were further assessed for clinical and laboratory SLE manifestations. TNF-alpha levels were measured by enzyme-linked immunosorbent assay using commercial kits. RESULTS: Depressive symptoms were identified in 70 (45.7 %) SLE patients and in 10 (25 %) healthy controls (p < 0.001). Anxiety symptoms were identified in 93 (60.7 %) SLE patients and in 16 controls (40 %) (p < 0.001). Sera TNF-alpha levels were increased in SLE patients with depressive symptoms (p < 0.001) and with anxiety symptoms (p = 0.014). A direct correlation between the severity of depressive symptoms and sera TNF-alpha levels (r = 0.22; p = 0.003) was observed. TNF-alpha levels were significantly increased in patients with active disease (p = 0.012). In addition, we observed a correlation between sera TNF-alpha levels and disease activity (r = 0.28; p = 0.008). In the multivariate analysis, sera TNF-alpha levels were independently associated with depressive symptoms (t = 3.28; 95 % CI 1.08-2.2; p = 0.002). CONCLUSIONS: Sera TNF-alpha levels are increased in SLE patients with mood and anxiety disorders. In SLE, sera TNF-alpha levels are independently associated with mood disorders. The etiology of mood disorders is still debated in SLE, but our findings suggest the presence of immunological basis for depression in SLE. PMID- 26732586 TI - Infection prevention and control of the Ebola outbreak in Liberia, 2014-2015: key challenges and successes. AB - Prior to the 2014-2015 Ebola outbreak, infection prevention and control (IPC) activities in Liberian healthcare facilities were basic. There was no national IPC guidance, nor dedicated staff at any level of government or healthcare facility (HCF) to ensure the implementation of best practices. Efforts to improve IPC early in the outbreak were ad hoc and messaging was inconsistent. In September 2014, at the height of the outbreak, the national IPC Task Force was established with a Ministry of Health (MoH) mandate to coordinate IPC response activities. A steering group of the Task Force, including representatives of the World Health Organization (WHO) and the United States Centers for Disease Control and Prevention (CDC), supported MoH leadership in implementing standardized messaging and IPC training for the health workforce. This structure, and the activities implemented under this structure, played a crucial role in the implementation of IPC practices and successful containment of the outbreak. Moving forward, a nationwide culture of IPC needs to be maintained through this governance structure in Liberia's health system to prevent and respond to future outbreaks. PMID- 26732587 TI - Plasmonic Au nanoparticles embedding enhances the activity and stability of CdS for photocatalytic hydrogen evolution. AB - The activity and stability of CdS for visible-light-driven hydrogen evolution could be significantly enhanced by embedding plasmonic Au nanoparticles. The plasmon resonance energy field of Au nanoparticles could increase the formation rate and lifetime of e(-)/h(+) pairs in CdS semiconductors. PMID- 26732590 TI - p38 MAPK Participates in the Mediation of GLT-1 Up-regulation During the Induction of Brain Ischemic Tolerance by Cerebral Ischemic Preconditioning. AB - Our previous study has proved that the up-regulation of glial glutamate transporter 1 (GLT-1) played an important role in the acquisition of brain ischemic tolerance after cerebral ischemic preconditioning (CIP) in rats. However, little is known about the mechanism involved in the up-regulation of GLT 1 in the process. The present study investigates whether p38 MAPK, ERK1/2, and/or JNK participates in the up-regulation of GLT-1 during the induction of brain ischemic tolerance by CIP. It was found that CIP significantly enhanced the expression of p-p38 MAPK without altering p-ERK1/2 and p-JNK expression in the CA1 hippocampus. Inhibition of p38 MAPK function by its selective inhibitor SB203580 or knockdown p38 MAPK expression by its antisense oligodeoxynucleotides (AS-ODNs) suppressed the induction of brain ischemic tolerance. Furthermore, p38 MAPK was activated earlier than the up-regulation of GLT-1 in the CA1 hippocampus after CIP. Meanwhile, the expression of p-p38 MAPK by astrocytes was increased, and p38 MAPK AS-ODNs dose-dependently inhibited the up-regulation of GLT-1 after CIP. Taken together, it could be concluded that p38 MAPK participates in the mediation of GLT-1 up-regulation during the induction of brain ischemic tolerance after CIP. PMID- 26732589 TI - Downregulation of GABAA Receptor Recycling Mediated by HAP1 Contributes to Neuronal Death in In Vitro Brain Ischemia. AB - Downregulation of GABAergic synaptic transmission contributes to the increase in overall excitatory activity in the ischemic brain. A reduction of GABAA receptor (GABAAR) surface expression partly accounts for this decrease in inhibitory activity, but the mechanisms involved are not fully elucidated. In this work, we investigated the alterations in GABAAR trafficking in cultured rat hippocampal neurons subjected to oxygen/glucose deprivation (OGD), an in vitro model of global brain ischemia, and their impact in neuronal death. The traffic of GABAAR was evaluated after transfection of hippocampal neurons with myc-tagged GABAAR beta3 subunits. OGD decreased the rate of GABAAR beta3 subunit recycling and reduced the interaction of the receptors with HAP1, a protein involved in the recycling of the receptors. Furthermore, OGD induced a calpain-mediated cleavage of HAP1. Transfection of hippocampal neurons with HAP1A or HAP1B isoforms reduced the OGD-induced decrease in surface expression of GABAAR beta3 subunits, and HAP1A maintained the rate of receptor recycling. Furthermore, transfection of hippocampal neurons with HAP1 significantly decreased OGD-induced cell death. These results show a key role for HAP1 protein in the downmodulation of GABAergic neurotransmission during cerebral ischemia, which contributes to neuronal demise. PMID- 26732591 TI - Attenuation of Axonal Degeneration by Calcium Channel Inhibitors Improves Retinal Ganglion Cell Survival and Regeneration After Optic Nerve Crush. AB - Axonal degeneration is one of the initial steps in many traumatic and neurodegenerative central nervous system (CNS) disorders and thus a promising therapeutic target. A focal axonal lesion is followed by acute axonal degeneration (AAD) of both adjacent axon parts, before proximal and distal parts follow different degenerative fates at later time points. Blocking calcium influx by calcium channel inhibitors was previously shown to attenuate AAD after optic nerve crush (ONC). However, it remains unclear whether the attenuation of AAD also promotes consecutive axonal regeneration. Here, we used a rat ONC model to study the effects of calcium channel inhibitors on axonal degeneration, retinal ganglion cell (RGC) survival, and axonal regeneration, as well as the molecular mechanisms involved. Application of calcium channel inhibitors attenuated AAD after ONC and preserved axonal integrity as visualized by live imaging of optic nerve axons. Consecutively, this resulted in improved survival of RGCs and improved axonal regeneration at 28 days after ONC. We show further that calcium channel inhibition attenuated lesion-induced calpain activation in the proximity of the crush and inhibited the activation of the c-Jun N-terminal kinase pathway. Pro-survival signaling via Akt in the retina was also increased. Our data thus show that attenuation of AAD improves consecutive neuronal survival and axonal regeneration and that calcium channel inhibitors could be valuable tools for therapeutic interventions in traumatic and degenerative CNS disorders. PMID- 26732588 TI - Genetic, Immune-Inflammatory, and Oxidative Stress Biomarkers as Predictors for Disability and Disease Progression in Multiple Sclerosis. AB - The aim of this study was to evaluate the TNFbeta NcoI polymorphism (rs909253) and immune-inflammatory, oxidative, and nitrosative stress (IO&NS) biomarkers as predictors of disease progression in multiple sclerosis (MS). We included 212 MS patients (150 female, 62 male, mean (+/-standard deviation (SD)) age = 42.7 +/- 13.8 years) and 249 healthy controls (177 female, 72 male, 36.8 +/- 11 years). The disability was measured the Expanded Disability Status Scale (EDSS) in 2006 and 2011. We determined the TNFbeta NcoI polymorphism and serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, IL 4, IL-10, and IL-17, albumin, ferritin, and plasma levels of lipid hydroperoxides (CL-LOOH), carbonyl protein, advanced oxidation protein products (AOPPs), nitric oxide metabolites (NOx), and total radical-trapping antioxidant parameter (TRAP). The mean EDSS (+/-SD) in 2006 was 1.62 +/- 2.01 and in 2011 3.16 +/- 2.29, and disease duration was 7.34 +/- 7.0 years. IL-10, TNF-alpha, IFN-gamma, AOPP, and NOx levels were significantly higher and IL-4 lower in MS patients with a higher 2011 EDSS scores (>=3) as compared with those with EDSS < 3. The actual increases in EDSS from 2006 to 2011 were positively associated with TNF-alpha and IFN gamma. Increased IFN-gamma values were associated with higher pyramidal symptoms and increased IL-6 with sensitive symptoms. Increased carbonyl protein and IL-10 but lowered albumin levels predicted cerebellar symptoms. The TNFB1/B2 genotype decreased risk towards progression of pyramidal symptoms. Treatments with IFN beta and glatiramer acetate significantly reduced TNF-alpha but did not affect the other IO&NS biomarkers or disease progression. Taken together, IO&NS biomarkers and NcoI TNFbeta genotypes predict high disability in MS and are associated with different aspects of disease progression. New drugs to treat MS should also target oxidative stress pathways. PMID- 26732592 TI - Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot Marie-Tooth Disease. AB - Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with the majority of cases involving demyelination of peripheral nerves. The pathogenic mechanisms of demyelinating CMT remain unclear, and no effective therapy currently exists for this disease. The discovery that mutations in different genes can cause a similar phenotype of demyelinating peripheral neuropathy raises the possibility that there may be convergent mechanisms leading to demyelinating CMT pathogenesis. Increasing evidence indicates that ErbB receptor-mediated signaling plays a major role in the control of Schwann cell axon communication and myelination in the peripheral nervous system. Recent studies reveal that several demyelinating CMT-linked proteins are novel regulators of endocytic trafficking and/or phosphoinositide metabolism that may affect ErbB receptor signaling. Emerging data have begun to suggest that dysregulation of ErbB receptor trafficking and signaling in Schwann cells may represent a common pathogenic mechanism in multiple subtypes of demyelinating CMT. In this review, we focus on the roles of ErbB receptor trafficking and signaling in regulation of peripheral nerve myelination and discuss the emerging evidence supporting the potential involvement of altered ErbB receptor trafficking and signaling in demyelinating CMT pathogenesis and the possibility of modulating these trafficking and signaling processes for treating demyelinating peripheral neuropathy. PMID- 26732594 TI - Autophagy Promotes Microglia Activation Through Beclin-1-Atg5 Pathway in Intracerebral Hemorrhage. AB - Previous study demonstrates that intracerebral hemorrhage (ICH) promotes microglia activation and inflammation. However, the exact mechanism of microglia activation induced by ICH is not clear. In this experiment, microglia autophagy was examined using electron microscopy, conversion of light chain 3(LC3), and monodansylcadaverine (MDC) staining to detect autophagic vacuoles. We found that ICH induced microglia autophagy and activation. The suppression of autophagy using either pharmacologic inhibitors (3-methyladenine, bafilomycin A1) or RNA interference in essential autophagy genes (BECN1 and ATG5) decreased the microglia activation and inflammation in ICH. Moreover, autophagy inhibitors reduced brain damage in ICH. In conclusion, these data indicate that ICH contributes to microglia autophagic activation through BECN1 and ATG5 and provide the therapeutical strategy for ICH. PMID- 26732593 TI - Close Encounters of the First Kind: Innate Sensors and Multiple Sclerosis. AB - Although autoimmune diseases by definition imply adaptive immune system pathologies, growing evidence points to the relevance of innate receptors in modulating the initiation and progression of the autoreactive response. Multiple sclerosis (MS) is a chronic autoimmune disease characterised by central nervous system (CNS) demyelination, inflammation and axonal damage, in which the role of several pathogens such as herpes viruses have long been described as potential triggers. Encounters of these pathogens with altered innate receptors in susceptible individuals might drive pathological autoreactivity and inflammation, overcoming tolerance and causing subsequent CNS damage. In particular, functional and genetic studies reveal that Toll-like receptor (TLR) 2 and the Nod-like receptor (NLR) P3 could be involved in MS pathogenesis, whereas TLR3, the triggering receptor expressed on myeloid cells (TREM)-2 and the C-type lectin receptors (CLRs) MBL and MASP-3 would have a putative protective role. A better understanding of these interactions will provide important insights into the aetiopathogenesis of MS and could help design potential targets for novel therapies. PMID- 26732595 TI - L-Ascorbate Protects Against Methamphetamine-Induced Neurotoxicity of Cortical Cells via Inhibiting Oxidative Stress, Autophagy, and Apoptosis. AB - Methamphetamine (METH)-induced cell death contributes to the pathogenesis of neurotoxicity; however, the relative roles of oxidative stress, apoptosis, and autophagy remain unclear. L-Ascorbate, also called vitamin (Vit.) C, confers partial protection against METH neurotoxicity via induction of heme oxygenase-1. We further investigated the role of Vit. C in METH-induced oxidative stress, apoptosis, and autophagy in cortical cells. Exposure to lower concentrations (0.1, 0.5, 1 mM) of METH had insignificant effects on ROS production, whereas cells exposed to 5 mM METH exhibited ROS production in a time-dependent manner. We confirmed METH-induced apoptosis (by nuclear morphology revealed by Hoechst 33258 staining and Western blot showing the protein levels of pro-caspase 3 and cleaved caspase 3) and autophagy (by Western blot showing the protein levels of Belin-1 and conversion of microtubule-associated light chain (LC)3-I to LC3-II and autophagosome staining by monodansylcadaverine). The apoptosis as revealed by cleaved caspase-3 expression marked an increase at 18 h after METH exposure while both autophagic markers, Beclin 1 and LC3-II, marked an increase in cells exposed to METH for 6 and 24 h, respectively. Treating cells with Vit. C 30 min before METH exposure time-dependently attenuated the production of ROS. Vitamin C also attenuated METH-induced Beclin 1 and LC3-II expression and METH toxicity. Treatment of cells with Vit. C before METH exposure attenuated the expression of cleaved caspase-3 and reduced the number of METH-induced apoptotic cells. We suggest that the protective effect of Vit. C against METH toxicity might be through attenuation of ROS production, autophagy, and apoptosis. PMID- 26732596 TI - MiR-126 Regulates the ERK Pathway via Targeting KRAS to Inhibit the Glioma Cell Proliferation and Invasion. AB - The activity of some constitutive contained in the extracellular signal-regulated kinase (ERK) pathway plays crucial roles in glioma cell growth and proliferation. Emerging studies have reported that microRNA (miRNA) could regulate the ERK signal pathway by directly targeting various oncogenes. This study enabled us to discover that the average miR-126 expression was significantly decreased in glioblastoma tissues, and this significant decrease was related to high histopathological grades. Our experiment also demonstrated that the over expression of miR-126 suppressed glioma cell proliferation and invasion in vitro. Kirsten rat sarcoma viral oncogene (KRAS) which is involved in ERK pathway was directly targeted by miR-126 in glioma through binding to two sites in the 3' untranslated region (3'-UTR) of KRAS mRNA. Notably, the expression level of KRAS was positively correlated to the activity of ERK pathway and its downstream regulators (phosphorylation level of ERK (pERK) and c-Fos). Furthermore, the over expression of KRAS expression vector without the 3'-UTR partially reverses the tumor-suppressive effects of miR-126. Moreover, the up-regulation of miR-126 contributes to the aberrant activation of the ERK signaling and inhibits cell proliferation and invasion through targeting KRAS. Therefore, it was suspected that miR-126 may be a potential therapeutic target for high-grade glioma. PMID- 26732597 TI - GWAS-Linked Loci and Neuroimaging Measures in Alzheimer's Disease. AB - Recently, 19 susceptibility loci for Alzheimer's disease (AD) had been identified through AD genome-wide association studies (GWAS) meta-analysis. However, how they influence the pathogenesis of AD still remains largely unknown. We studied those loci with six MRI measures, abnormal glucose metabolism, and beta-amyloid (Abeta) deposition on neuroimaging in a large cohort from Alzheimer's Disease Neuroimaging Initiative (ADNI) database in order to provide clues of the mechanisms through which these genetic variants might be acting. As a result, single nucleotide polymorphisms (SNPs) at rs983392 within MS4A6A and rs11218343 within SOLR1 were both associated with the percentage of increase in the volume of left inferior temporal regions in the follow-up study. Meanwhile, rs11218343 at SORL1 and rs6733839 at BIN1 was associated with rate of volume change of left parahippocampal and right inferior parietal, respectively. Moreover, rs6656401 at CR1 and rs983392 at MS4A6A were both associated with smaller volume of right middle temporal at baseline. However, in addition to the APOE locus, we did not detect any influence on glucose metabolism and Abeta deposition. APOE epsilon4 allele was associated with almost all measures. Altogether, five loci (rs6656401 at CR1, rs983392within MS4A6A, rs11218343 at SORL1, rs6733839 at BIN1, and APOE epsilon4) have been detected to be associated with one or a few established AD related neuroimaging measures. PMID- 26732598 TI - Phosphatase 2A Inhibition Affects Endoplasmic Reticulum and Mitochondria Homeostasis Via Cytoskeletal Alterations in Brain Endothelial Cells. AB - The loss of endothelial cells (ECs) homeostasis is a trigger for cerebrovascular dysfunction that is a common event in several neurodegenerative disorders such as Alzheimer's disease (AD). The present work addressed the role of phosphatase 2A (PP2A) in cytoskeleton rearrangement, endoplasmic reticulum (ER) homeostasis, ER mitochondria communication and mitochondrial dynamics in brain ECs. For this purpose, rat brain endothelial (RBE4) cells were exposed to okadaic acid, a well known inhibitor of PP2A activity. An increase in the levels of tau phosphorylated on Ser396 and Thr181 residues was observed upon PP2A inhibition, concomitantly with the rearrangement of microtubules and actin cytoskeleton. Under these conditions, an increase in the levels of ER stress markers, namely GRP78, XBP1, p eIF2alphaSer51, and ERO1alpha, was observed. Moreover, PP2A inhibition upregulated the Sigma-1 receptor, an ER chaperone located at the ER-mitochondria interface, and enhanced inter-organelle Ca2+ transfer, culminating in mitochondrial Ca2+ overload and activation of mitochondria-dependent apoptosis. The inhibition of PP2A activity also promoted an alteration of the structural and spatial mitochondria network due to upregulation of mitochondrial fission (Drp1 and Fis1) and fusion (Mfn1, Mfn2 and OPA1) proteins, suggesting detrimental changes in mitochondrial dynamics. In accordance with our in vitro observations, brain vessels from 3xTg-AD mice showed a significant decrease in PP2A protein levels accompanied by an increase in tau phosphorylated on Ser396 and GRP78 protein levels. Collectively, these results suggest that the loss of cerebrovascular homeostasis that occurs in AD might be a downstream event of the compromised activity and/or expression of PP2A, which is observed in the brain of individuals affected with this devastating neurodegenerative disorder. PMID- 26732599 TI - Association Between Circulating Copeptin Level and Mortality Risk in Patients with Intracerebral Hemorrhage: a Systemic Review and Meta-Analysis. AB - Copeptin has been identified as a biomarker of disease severity and is associated with mortality risk in several common diseases. This study sought to determine the association between circulating copeptin level and mortality risk in patients with intracerebral hemorrhage. PubMed, Web of Science, and Wanfang Medicine Database were searched for studies assessing the association between circulating copeptin level and mortality risk in patients with intracerebral hemorrhage. The pooled hazard ratio (HR) of mortality was calculated and presented with 95 % confidence interval (95 % CI). Data from 1332 intracerebral hemorrhage patients were derived from 9 studies. Meta-analysis showed that intracerebral hemorrhage patients with poor prognosis had much higher copeptin levels than those survivors (standardized mean difference = 1.68, 95 % CI 1.26-2.11, P < 0.00001). Meta analysis of 8 studies with HRs showed that high circulating copeptin level was associated with higher risk of mortality in patients with intracerebral hemorrhage (HR = 2.42, 95 % CI 1.60-3.65, P < 0.0001). Meta-analysis of 6 studies with adjusted HRs showed that high circulating copeptin level was independently associated with higher risk of mortality in patients with intracerebral hemorrhage (HR = 1.67, 95 % CI 1.26-2.22, P = 0.0003). Our study suggests that there is an obvious association between circulating copeptin level and mortality in patients with intracerebral hemorrhage. High circulating copeptin level is independently associated with higher risk of mortality in patients with intracerebral hemorrhage. PMID- 26732601 TI - Act requires officials to review how US dietary guidelines are formulated. PMID- 26732600 TI - Deletion of mTOR in Reactive Astrocytes Suppresses Chronic Seizures in a Mouse Model of Temporal Lobe Epilepsy. AB - Germline and somatic mutations in key genes of the mammalian target of rapamycin (mTOR) pathway have been identified in seizure-associated disorders. mTOR mutations lead to aberrant activation of mTOR signaling, and, although affected neurons are critical for epileptogenesis, the role of mTOR activation in glial cells remains poorly understood. We previously reported a consistent activation of the mTOR pathway in astrocytes in the epileptic foci of temporal lobe epilepsy. In this study, it was demonstrated that mTOR deletion from reactive astrocytes prevents increases in seizure frequency over the disease course. By using a tamoxifen-inducible mTOR conditional knockout system and kainic acid, a model was developed that allowed astrocyte-specific mTOR gene deletion in mice with chronic epilepsy. Animals in which mTOR was deleted from 44 % of the astrocyte population exhibited a lower seizure frequency compared with controls. Down-regulation of mTOR significantly ameliorated astrogliosis in the sclerotic hippocampus but did not rescue mossy fiber sprouting. In cultured astrocytes, the mTOR pathway modulated the stability of the astroglial glutamate transporter 1 (Glt1) and influenced the ability of astrocytes to remove extracellular glutamate. Taken together, these data indicate that astrocytes with activated mTOR signaling may provide conditions that are favorable for spontaneous recurrent seizures. PMID- 26732603 TI - The place of selective hysterosalpingography and tubal canalization among sub fertile patients diagnosed with proximal tubal occlusion. AB - OBJECTIVE: To evaluate the efficacy of selective salpingography and tubal canalization (TC) procedure among patients diagnosed with proximal tubal occlusion (PTO). METHODS: We conducted a retrospective cohort study on 61 sub fertile patients aged 32.6 +/- 4.9 years that were referred between the years of 2011 and 2013 with the diagnosis of PTO by prior hysterosalpingography. Patients underwent TC and were classified as bilateral PTO or unilateral PTO. Information regarding the patient's reproductive outcome within the 12 months following the procedure was collected by a telephone survey. RESULTS: During the study period, 58/61 (95 %) patients underwent TC, resulting in bilateral open tubes in 54 patients (93.1 %). 53/58 (91.3 %) patients answered our survey. There were 23/53 (43.4 %) patients with a successful procedure who conceived after spontaneous or COH + IUI resulting in 15/23 live births (65.2 %). CONCLUSION: Tubal canalization is a safe and minimally invasive procedure that can be used effectively to restore patency in a proportion of cases of PTO thus avoiding the need for expensive and invasive procedures such as assisted reproductive techniques. PMID- 26732602 TI - Analysis of Plasmalogen Species in Foodstuffs. AB - Ethanolamine plasmalogen (PlsEtn), which is present at high levels in brains, is believed to be involved in neuronal protection. The present study was performed to search for PlsEtn resources in foodstuffs. The foodstuffs examined showed a wide range of PlsEtn contents from 5 to 549 MUmol/100 g wet wt. The marine invertebrates, blue mussel, and ascidian had high PlsEtn contents (over 200 MUmol/100 g wet wt). Profiling of the molecular species showed that the predominant fatty acids of PlsEtn species were 20:5 (EPA) and 22:6 (DHA) at the sn-2 position of the glycerol moiety in marine foodstuffs, whereas major PlsEtn species in land foodstuffs were 20:4. Following quantitative analysis by multiple reaction monitoring, the ascidian viscera were shown to contain the highest levels of 18:0/20:5-PlsEtn and 18:0/22:6-PlsEtn (86 and 68 MUmol/100 g wet wt, respectively). In order to evaluate a neuronal antiapoptotic effect of these PlsEtn species, human neuroblastoma SH-SY5Y cells were treated with ethanolamine glycerophospholipid (EtnGpl), purified from the ascidian viscera, under serum starvation conditions. Extrinsic EtnGpl from ascidian viscera showed stronger suppression of cell death induced by serum starvation than with bovine brain EtnGpl. The EtnGpl from ascidian viscera strongly suppressed the activation of caspase 3. These results suggest that PlsEtn, especially that containing EPA and DHA, from marine foodstuffs is potentially useful for a therapeutic dietary supplement preventing neurodegenerative diseases, such as Alzheimer's disease (AD). PMID- 26732605 TI - Encouraging Antibiotic Development and Endorsing Conservation: Tandem Approaches to Our Declining Antibiotic Reserves. PMID- 26732604 TI - Updated sesame genome assembly and fine mapping of plant height and seed coat color QTLs using a new high-density genetic map. AB - BACKGROUND: Sesame is an important high-quality oil seed crop. The sesame genome was de novo sequenced and assembled in 2014 (version 1.0); however, the number of anchored pseudomolecules was higher than the chromosome number (2n = 2x = 26) due to the lack of a high-density genetic map with 13 linkage groups. RESULTS: We resequenced a permanent population consisting of 430 recombinant inbred lines and constructed a genetic map to improve the sesame genome assembly. We successfully anchored 327 scaffolds onto 13 pseudomolecules. The new genome assembly (version 2.0) included 97.5 % of the scaffolds greater than 150 kb in size present in assembly version 1.0 and increased the total pseudomolecule length from 233.7 to 258.4 Mb with 94.3 % of the genome assembled and 97.2 % of the predicted gene models anchored. Based on the new genome assembly, a bin map including 1,522 bins spanning 1090.99 cM was generated and used to identified 41 quantitative trait loci (QTLs) for sesame plant height and 9 for seed coat color. The plant height related QTLs explained 3-24 % the phenotypic variation (mean value, 8 %), and 29 of them were detected in at least two field trials. Two major loci (qPH-8.2 and qPH-3.3) that contributed 23 and 18 % of the plant height were located in 350 and 928-kb spaces on Chr8 and Chr3, respectively. qPH-3.3, is predicted to be responsible for the semi-dwarf sesame plant phenotype and contains 102 candidate genes. This is the first report of a sesame semi-dwarf locus and provides an interesting opportunity for a plant architecture study of the sesame. For the sesame seed coat color, the QTLs of the color spaces L*, a*, and b* were detected with contribution rates of 3-46 %. qSCb-4.1 contributed approximately 39 % of the b* value and was located on Chr4 in a 199.9-kb space. A list of 32 candidate genes for the locus, including a predicted black seed coat-related gene, was determined by screening the newly anchored genome. CONCLUSIONS: This study offers a high-density genetic map and an improved assembly of the sesame genome. The number of linkage groups and pseudomolecules in this assembly equals the number of sesame chromosomes for the first time. The map and updated genome assembly are expected to serve as a platform for future comparative genomics and genetic studies. PMID- 26732606 TI - Does Sex Really Matter? Examining the Connections Between Spouses' Nonsexual Behaviors, Sexual Frequency, Sexual Satisfaction, and Marital Satisfaction. AB - We examined the interplay between husbands' and wives' positive and negative nonsexual interpersonal behaviors, frequency of sexual intercourse, sexual satisfaction, and feelings of marital satisfaction. To do this, we conducted an in-depth face-to-face interview and completed a series of telephone diaries with 105 couples during their second, third, and fourteenth years of marriage. Consistent with the argument that women's sexual response is tied to intimacy (Basson, 2000), multilevel analyses revealed that husbands' positive interpersonal behaviors directed toward their wives-but not wives' positivity nor spouses' negative behaviors (regardless of gender)-predicted the frequency with which couples engaged in intercourse. The frequency of sexual intercourse and interpersonal negativity predicted both husbands' and wives' sexual satisfaction; wives' positive behaviors were also tied to husbands' sexual satisfaction. When spouses' interpersonal behaviors, frequency of sexual intercourse, and sexual satisfaction were considered in tandem, all but the frequency of sexual intercourse were associated with marital satisfaction. When it comes to feelings of marital satisfaction, therefore, a satisfying sex life and a warm interpersonal climate appear to matter more than does a greater frequency of sexual intercourse. Collectively, these findings shed much-needed light on the interplay between the nonsexual interpersonal climate of marriage and spouses' sexual relationships. PMID- 26732607 TI - Improving accessibility of trust guidelines and protocols at the Great Western Hospital, Swindon. AB - Trust guidelines and policies outline recommendations for the management of common clinical and non-clinical situations, serving to standardise best practice. Prior to this project, there was no consolidated location for these documents. Lack of organisational structure and inadequate search functionality within the trust intranet led to time wasted locating information, acting outside of recognised best practice, and ultimately potentially compromising patient safety. We surveyed 55 junior doctors, 95% of respondents were dependent on guidelines on a daily basis. 20% spending greater than 5 minutes to locate protocols and 38% unable to locate some relevant documents at all. We analysed the time taken for junior doctors to locate six randomly selected protocols. Pre intervention mean time was 133 seconds (on six occasions doctors were unable to locate the guideline). All trust guidelines and protocols currently available on the intranet were collated, consolidated, and renamed according to content. These were then re-alphabetised and new search terms linked to each document. Existing links were then uploaded and a single web page made available via the trust intranet homepage. The new page was publicised by email, posters and interdepartmental presentations. In our post intervention survey, 97% of respondents were aware of the project and had made use of the page. All protocols were located during re-testing with 90% of those resurveyed stating it was easier to locate protocols. Overall, a reduction in the time and number of clicks required to locate protocols was demonstrated: mean time 16 seconds vs 133 seconds pre-intervention (n=60). 53% of guidelines located in <30s and 86% <2 minutes. PMID- 26732608 TI - Routine therapeutic drug monitoring of tyrosine kinase inhibitors by HPLC-UV or LC-MS/MS methods. AB - Analytical methods using high performance liquid chromatography coupled to ultraviolet detection (HPLC-UV) or liquid chromatography-tandem mass spectrometry (LC-MS/MS) have been reported for the quantification of oral tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, and dasatinib in biological fluids. An LC-MS/MS method can simultaneously assay multiple TKIs and their metabolites with high sensitivity and selectivity for low plasma concentrations less than 1 ng/mL. For quantification of imatinib, nilotinib, and dasatinib, a limit of quantification (LOQ) of less than 10 ng/mL, 10 ng/mL, and 0.1 ng/mL, respectively, in the clinical setting is necessary. Because simpler and more cost efficient methodology is desired for clinical analysis, plasma concentrations of imatinib and nilotinib (target trough concentrations of 1000 ng/mL and 800 ng/mL, respectively) could be assayed by an HPLC-UV method after comparison with results obtained from the standard LC-MS/MS method. However, in the quantification of dasatinib, the LC-MS/MS method that has high sensitivity and selectivity and is free from interference by endogenous impurities is superior to the HPLC-UV method. Highly precise analytical methods are needed for individualized treatment via dose adjustment of oral anticancer drugs, in particular those with low target plasma concentrations less than 10 ng/mL. PMID- 26732609 TI - A multicentre 2-cycle retrospective audit of postoperative haemorrhages from 2169 tonsillectomies. PMID- 26732610 TI - Familial 1.3-Mb 11p15.5p15.4 Duplication in Three Generations Causing Silver Russell and Beckwith-Wiedemann Syndromes. AB - Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) are 2 opposite growth-affecting disorders. The common molecular cause for both syndromes is an abnormal regulation of genes in chromosomal region 11p15, where 2 imprinting control regions (ICR) control fetal and postnatal growth. Also, many submicroscopic chromosomal disturbances like duplications in 11p15 have been described among SRS and BWS patients. Duplications involving both ICRs cause SRS or BWS, depending on which parent the aberration is inherited from. We describe to our knowledge the smallest familial pure 1.3-Mb duplication in chromosomal region 11p15.5p15.4 that involves both ICRs and is present in 3 generations causing an SRS or BWS phenotype. PMID- 26732612 TI - Electron-Hole Pair Effects in Polyatomic Dissociative Chemisorption: Water on Ni(111). AB - The influence of electron-hole pairs in dissociative chemisorption of a polyatomic molecule (water) on metal surfaces is assessed for the first time using a friction approach. The atomic local density dependent friction coefficients computed based on a free electron gas embedding model are employed in classical molecular dynamics simulations of the water dissociation dynamics on rigid Ni(111) using a recently developed nine dimensional interaction potential energy surface for the system. The results indicate that nonadiabatic effects are relatively small and they do not qualitatively alter the mode specificity in the dissociation. PMID- 26732611 TI - Effects of a petunia scaffold/matrix attachment region on copy number dependency and stability of transgene expression in Nicotiana tabacum. AB - Transgenes in genetically modified plants are often not reliably expressed during development or in subsequent generations. Transcriptional gene silencing (TGS) as well as post-transcriptional gene silencing (PTGS) have been shown to occur in transgenic plants depending on integration pattern, copy number and integration site. In an effort to reduce position effects, to prevent read-through transcription and to provide a more accessible chromatin structure, a P35S-beta glucuronidase (P35S-gus) transgene flanked by a scaffold/matrix attachment region from petunia (Petun-SAR), was introduced in Nicotiana tabacum plants by Agrobacterium tumefaciens mediated transformation. It was found that Petun-SAR mediates enhanced expression and copy number dependency up to 2 gene copies, but did not prevent gene silencing in transformants with multiple and rearranged gene copies. However, in contrast to the non-SAR transformants where silencing was irreversible and proceeded during long-term vegetative propagation and in progeny plants, gus expression in Petun-SAR plants was re-established in the course of development. Gene silencing was not necessarily accompanied by DNA methylation, while the gus transgene could still be expressed despite considerable CG methylation within the coding region. PMID- 26732613 TI - Real-time PCR assay to detect brown marmorated stink bug, Halyomorpha halys (Stal), in environmental DNA. AB - BACKGROUND: Early detection before establishment and identification of key predators are time-honored strategies towards effective eradication or control of invasive species. The brown marmorated stink bug (BMSB), Halyomorpha halys, is a recent exotic pest of several important crops in North America and Europe. Resulting widespread applications of insecticides have countered years of careful integrated pest management and are leading to the resurgence of other agricultural pests. Environmental DNA (eDNA) has been used effectively to detect aquatic invasives. RESULTS: We developed a real-time PCR (qPCR) assay for BMSB in a conserved region of the ribosomal DNA interspacer 1 (ITS1). We validated this assay on worldwide populations of BMSB and tested its specificity and sensitivity against other US Pentatomidae species and on guano of big brown bat, Eptesicus fuscus, which we confirmed is a BMSB predator in New Jersey. We also detected BMSB DNA after rapid (and inexpensive) HotSHOT DNA extractions of soiled paper from cages briefly holding BMSB, as well as from discarded exuviae. CONCLUSION: Given the high sensitivity of our assay to BMSB environmental DNA (eDNA) in terrestrial samples, this tool should become a cost-effective approach for using eDNA to detect terrestrial invasive species and their key predators. (c) 2016 Society of Chemical Industry. PMID- 26732615 TI - Cost-effectiveness of adherence-enhancing interventions: a systematic review. AB - Low patient adherence to health-related interventions is a major barrier to achieving healthcare goals and is associated with very high avoidable costs. Although several studies suggest that adherence-enhancing interventions can improve health outcomes, economic evaluations of these interventions are scarce. Systematic reviews published to date are limited to interventions to enhance adherence to pharmaceuticals or to specific diseases and interventions. The authors' objective was to examine the evidence regarding the cost-effectiveness of adherence-enhancing interventions in healthcare and what conclusion could be drawn about these interventions. The present systematic review included 43 original studies and assessed the current evidence regarding the cost effectiveness of a broad array of interventions aimed at enhancing adherence to medications, medical devices, screening tests and lifestyle behaviors. The authors found that although the majority of adherence-enhancing interventions were cost-effective or cost-saving, variation exists within different intervention types. Further research on the sustainability of adherence improvements is needed in order to accurately evaluate interventions' long-term benefits. PMID- 26732614 TI - A transcriptome-wide, organ-specific regulatory map of Dendrobium officinale, an important traditional Chinese orchid herb. AB - Dendrobium officinale is an important traditional Chinese herb. Here, we did a transcriptome-wide, organ-specific study on this valuable plant by combining RNA, small RNA (sRNA) and degradome sequencing. RNA sequencing of four organs (flower, root, leaf and stem) of Dendrobium officinale enabled us to obtain 536,558 assembled transcripts, from which 2,645, 256, 42 and 54 were identified to be highly expressed in the four organs respectively. Based on sRNA sequencing, 2,038, 2, 21 and 24 sRNAs were identified to be specifically accumulated in the four organs respectively. A total of 1,047 mature microRNA (miRNA) candidates were detected. Based on secondary structure predictions and sequencing, tens of potential miRNA precursors were identified from the assembled transcripts. Interestingly, phase-distributed sRNAs with degradome-based processing evidences were discovered on the long-stem structures of two precursors. Target identification was performed for the 1,047 miRNA candidates, resulting in the discovery of 1,257 miRNA--target pairs. Finally, some biological meaningful subnetworks involving hormone signaling, development, secondary metabolism and Argonaute 1-related regulation were established. All of the sequencing data sets are available at NCBI Sequence Read Archive (http://www.ncbi.nlm.nih.gov/sra/). Summarily, our study provides a valuable resource for the in-depth molecular and functional studies on this important Chinese orchid herb. PMID- 26732616 TI - Prevalence and factors associated with demoralization syndrome in patients with advanced disease: Results from a cross-sectional Portuguese study. AB - BACKGROUND: Demoralization syndrome (DS) within the context of the psychological experience at the end of life is an important and relevant medical issue and remains the subject of a growing area of research. METHOD: Ours was a cross sectional study designed to assess the prevalence and associated demographic, physical, psychiatric, and psychosocial factors for demoralization syndrome in Portuguese patients with advanced disease. RESULTS: Some 80 terminally ill patients were included in the analyses over a 28-month period of time. The prevalence of DS was found to be 52.5%. No statistical differences were observed among prevalence of DS within categories of all studied variables, with the exception of depression using DSM-IV criteria (prevalence ratio PR = 1.8, CI 95% = [1.18-2.74]) and desire for death (PR = 1.8, CI 95% = [1.25-2.56]). In the Poisson regression analyses predicting DS, none of the latter factors emerged as significant (DSM-IV criteria: PR = 1.6, CI 95% = [0.84-3.08]; and desire for death: PR = 1.5, CI 95% = [0.74-2.99]). Thirty percent of participants met both criteria for demoralization syndrome and depression using the DSM-IV. SIGNIFICANCE OF RESULTS: Prevalence of demoralization syndrome was high in this patient sample. Based on our results, we cannot determine if DS and depression are two distinct psychological entities. Identifying factors associated with DS could help provide efficacious interventions capable of diminishing suffering in terminally ill patients. PMID- 26732618 TI - Diffusion tensor tractography in a patient with memory impairment following encephalitis. PMID- 26732617 TI - Intrinsic factors influencing help-seeking behaviour in an acute stroke situation. AB - The proportion of stroke patients eligible for intravenous or intra-arterial treatment is still limited because many patients do not seek medical help immediately after stroke onset. The aim of our study was to explore which intrinsic factors and considerations influence help-seeking behaviour of relatively healthy participants, confronted with stroke situations. Semi structured interviews were conducted with 25 non-stroke participants aged 50 years or older. We presented 5 clinical stroke situations as if experienced by the participants themselves. Recognition and interpretation of symptoms were evaluated and various factors influencing help-seeking behaviour were explored in depth. We used the thematic synthesis method for data analysis. Five themes influencing help-seeking behaviour in a stroke situation were identified: influence of knowledge, views about seriousness, ideas about illness and health, attitudes towards others and beliefs about the emergency medical system. A correct recognition of stroke symptoms or a correct interpretation of the stroke situations did not automatically result in seeking medical help. Interestingly, similar factors could lead to different types of actions between participants. Many intrinsic, as well as social and environmental factors are of influence on help-seeking behaviour in an acute stroke situation. All these factors seem to play a complex role in help-seeking behaviour with considerable inter-individual variations. Accomplishing more patients eligible for acute stroke treatment, future research should focus on better understanding of all factors at various levels grounded in a theory of help-seeking behaviour. PMID- 26732619 TI - Changes in retinal nerve fiber layer thickness in patients with cerebral infarction: evidence of transneuronal retrograde degeneration. AB - We aimed to evaluate the thicknesses of the retinal nerve fiber layer (RNFL) in patients with cerebral infarction (CI) by using optical coherence tomography. This cross-sectional study evaluated 45 patients with CI (patient group) and 45 healthy subjects (control group). All subjects underwent a complete ophthalmic examination including optical coherence tomography. The average, temporal, nasal, inferior, and superior quadrant RNFL thicknesses and in each of 12 sectors around the optic nerve head were obtained. The side with the infarction was compared to the contralateral side among the patients with cerebral infarction, and their measurements were also compared to those of the control group. Patients who had CI only in the middle cerebral artery (MCA) and posterior cerebral artery (PCA) were included in this study. Correlations between the RNFL thicknesses and infarction features were also evaluated. The mean age of the patients was 61.6 +/ 12.4 years, and the mean age of the controls was 59.6 +/- 11.8 years (p = 0.65). Of the 45 patients with cerebral infarction, 35 (77.7 %) had infarction in the MCA territory, 10 (22.2 %) had infarction in the PCA territory and the mean duration of the disease was 20.2 +/- 29.1 months. The average, superior, inferior, and nasal RNFL thicknesses were significantly thinner in both eyes of the patients with CI than in the eyes of the control group (p < 0.05). The average and inferior RNFL thicknesses were significantly more affected in the ipsilateral eyes than in the contralateral eyes (p < 0.031 and p < 0.006, respectively). The amount of reduction in the RNFL thicknesses was not correlated with the infarction features. Significant thinning of the RNFL in patients with CI may result from transneuronal retrograde degeneration. Optical coherence tomography may provide useful information to confirm the process of trans synaptic retrograde degeneration. PMID- 26732620 TI - A novel antioxidant formulation designed to treat male infertility associated with oxidative stress: promising preclinical evidence from animal models. AB - STUDY QUESTION: Does a novel antioxidant formulation designed to restore redox balance within the male reproductive tract, reduce sperm DNA damage and increase pregnancy rates in mouse models of sperm oxidative stress? SUMMARY ANSWER: Oral administration of a novel antioxidant formulation significantly reduced sperm DNA damage in glutathione peroxidase 5 (GPX5), knockout mice and restored pregnancy rates to near-normal levels in mice subjected to scrotal heat stress. WHAT IS KNOWN ALREADY: Animal and human studies have documented the adverse effect of sperm DNA damage on fertilization rates, embryo quality, miscarriage rates and the transfer of de novo mutations to offspring. Semen samples of infertile men are known to be deficient in several key antioxidants relative to their fertile counterparts. Antioxidants alone or in combination have demonstrated limited efficacy against sperm oxidative stress and DNA damage in numerous human clinical trials, however these studies have not been definitive and an optimum combination has remained elusive. STUDY DESIGN, SIZE, DURATION: The efficacy of the antioxidant formulation was evaluated in two well-established mouse models of oxidative stress, scrotal heating and Gpx5 knockout (KO) mice, (n = 12 per experimental group), by two independent laboratories. Mice were provided the antioxidant product in their drinking water for 2-8 weeks and compared with control groups for sperm DNA damage and pregnancy rates. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the Gpx5 KO model, oxidative DNA damage was monitored in spermatozoa by immunocytochemical detection of 8-hydroxy-2'-deoxyguanosine (8OHdG). In the scrotal heat stress model, male fertility was tested by partnering with three females for 5 days. The percentage of pregnant females, number of vaginal plugs, resorptions per litter, and litter size were recorded. MAIN RESULTS AND ROLE OF CHANCE: Using immunocytochemical detection of 8OHdG as a biomarker of DNA oxidation, analysis of control mice revealed that around 30% of the sperm population was positively stained. This level increased to about 60% in transgenic mice deficient in the antioxidant enzyme, GPX5. Our results indicate that an 8 week pretreatment of Gpx5 KO mice with the antioxidant formulation provided complete protection of sperm DNA against oxidative damage. In mouse models of scrotal heat stress, only 35% (19/54) of female mice became pregnant resulting in 169 fetuses with 18% fetal resorption (30/169). This is in contrast to the antioxidant pretreated group where 74% (42/57) of female mice became pregnant, resulting in 427 fetuses with 9% fetal resorption (38/427). In both animal models the protection provided by the novel antioxidant was statistically significant (P < 0.01 for the reduction of 8OHdG in the spermatozoa of Gpx5 KO mice and P < 0.05 for increase in fertility in the scrotal heat stress model). LIMITATIONS, REASONS FOR CAUTION: It was not possible to determine the exact level of antioxidant consumption for each mouse during the treatment period. WIDER IMPLICATIONS OF THE FINDINGS: Recent clinical studies confirm moderate to severe sperm DNA damage in about 60% of all men visiting IVF centers and in about 80% of men diagnosed with idiopathic male infertility. Our results, if confirmed in humans, will impact clinical fertility practice because they support the concept of using an efficacious antioxidant supplementation as a preconception therapy, in order to optimize fertilization rates, help to maintain a healthy pregnancy and limit the mutational load carried by children. STUDY FUNDING/COMPETING INTERESTS: The study was funded by the Clermont Universite and the University of Madrid. P.G. is the Managing Director of CellOxess LLC, which has a commercial interest in the detection and resolution of oxidative stress. A.M. and A.P. are employees of CellOxess, LLC. J.R.D., A.G.-A. and R.J.A. are honorary members of the CellOxess advisory board. PMID- 26732621 TI - Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health. AB - STUDY QUESTION: How does a genetic variant in the FSHB promoter, known to alter FSH levels, impact female reproductive health? SUMMARY ANSWER: The T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) results in longer menstrual cycles and later menopause and, while having detrimental effects on fertility, is protective against endometriosis. WHAT IS KNOWN ALREADY: The FSHB promoter polymorphism (rs10835638; c.-211G>T) affects levels of FSHB transcription and, as a result, circulating levels of FSH. FSH is required for normal fertility and genetic variants at the FSHB locus are associated with age at menopause and polycystic ovary syndrome (PCOS). STUDY DESIGN, SIZE, DURATION: We used cross-sectional data from the UK Biobank to look at associations between the FSHB promoter polymorphism and reproductive traits, and performed a genome wide association study (GWAS) for length of menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included white British individuals aged 40-69 years in 2006-2010, in the May 2015 release of genetic data from UK Biobank. We tested the FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) for associations with 29, mainly female, reproductive phenotypes in up to 63 350 women and 56 608 men. We conducted a GWAS in 9534 individuals to identify genetic variants associated with length of menstrual cycle. MAIN RESULTS AND THE ROLE OF CHANCE: The FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; MAF 0.16) was associated with longer menstrual cycles [0.16 SD (c. 1 day) per minor allele; 95% confidence interval (CI) 0.12 0.20; P = 6 * 10(-16)], later age at menopause (0.13 years per minor allele; 95% CI 0.04-0.22; P = 5.7 * 10(-3)), greater female nulliparity [odds ratio (OR) = 1.06; 95% CI 1.02-1.11; P = 4.8 * 10(-3)] and lower risk of endometriosis (OR = 0.79; 95% CI 0.69-0.90; P = 4.1 * 10(-4)). The FSH-lowering T allele was not associated with other female reproductive illnesses or conditions in our study and we did not replicate associations with male infertility or PCOS. In the GWAS for menstrual cycle length, only variants near the FSHB gene reached genome-wide significance (P < 5 * 10(-9)). LIMITATIONS, REASONS FOR CAUTION: The data included might be affected by recall bias. Cycle length was not available for 25% of women still cycling (1% did not answer, 6% did not know and for 18% cycle length was recorded as 'irregular'). Women with a cycle length recorded were aged over 40 and were approaching menopause; however, we did not find evidence that this affected the results. Many of the groups with illnesses had relatively small sample sizes and so the study may have been under-powered to detect an effect. WIDER IMPLICATIONS OF THE FINDINGS: We found a strong novel association between a genetic variant that lowers FSH levels and longer menstrual cycles, at a locus previously robustly associated with age at menopause. The variant was also associated with nulliparity and endometriosis risk. These findings should now be verified in a second independent group of patients. We conclude that lifetime differences in circulating levels of FSH between individuals can influence menstrual cycle length and a range of reproductive outcomes, including menopause timing, infertility, endometriosis and PCOS. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 26732623 TI - A critical review of the effects of wearable cameras on memory. AB - The rise of "lifelogging" in this era of rapid technological innovation has led to great interest in whether or not such technologies could be used to rehabilitate memory. Despite the growing number of studies using lifelogging, such as with wearable cameras, there is a lack of a theoretical framework to support its effective use. The present review focuses on the use of wearable cameras. We propose that wearable cameras can be particularly effective for memory rehabilitation if they can evoke more than a mere familiarity with previous stimuli, and reinstate previous thoughts, feelings and sensory information: recollection. Considering that, in memory impairment, self-initiated processes to reinstate previous encoding conditions are compromised, we invoke the environmental support hypothesis as a theoretical motivation. Twenty-five research studies were included in this review. We conclude that, despite the general acceptance of the value of wearable cameras as a memory rehabilitation technique, only a small number of studies have focused on recollection. We highlight a set of methodological issues that should be considered for future research, including sample size, control condition used, and critical measures of memory and other domains. We conclude by suggesting that research should focus on the theory-driven measure of efficacy described in this review, so that lifelogging technologies can contribute to memory rehabilitation in a meaningful and effective manner. PMID- 26732622 TI - Human anogenital distance: an update on fetal smoke-exposure and integration of the perinatal literature on sex differences. AB - STUDY QUESTION: Do sex and maternal smoking effects on human fetal anogenital distance (AGD) persist in a larger study and how do these data integrate with the wider literature on perinatal human AGD, especially with respect to sex differences? SUMMARY ANSWER: Second trimester sex differences in AGD are broadly consistent with neonatal and infant measures of AGD and maternal cigarette smoking is associated with a temporary increase in male AGD in the absence of changes in circulating testosterone. WHAT IS KNOWN ALREADY: AGD is a biomarker of fetal androgen exposure, a reduced AGD in males being associated with cryptorchidism, hypospadias and reduced penile length. Normative fetal AGD data remain partial and windows of sensitivity of human fetal AGD to disruption are not known. STUDY DESIGN, SIZE, DURATION: The effects of fetal sex and maternal cigarette smoking on the second trimester (11-21 weeks of gestation) human fetal AGD were studied, along with measurement of testosterone and testicular transcripts associated with apoptosis and proliferation. PARTICIPANTS/MATERIALS, SETTING METHODS: AGD, measured from the centre of the anus to the posterior/caudal root of penis/clitoris (AGD(app)) was determined in 56 female and 70 male morphologically normal fetuses. These data were integrated with current literature on perinatal AGD in humans. MAIN RESULTS AND THE ROLE OF CHANCE: At 11-13 weeks of gestation male fetal AGD(app) was 61% (P< 0.001) longer than in females, increasing to 70% at 17-21 weeks. This sexual dimorphism was independent of growth characteristics (fetal weight, length, gonad weight). We confirmed that at 14-16 weeks of gestation male fetal AGD(app) was increased 28% (P < 0.05) by in utero cigarette smoke exposure. Testosterone levels were not affected by smoking. To develop normative data, our findings have been integrated with available data from in vivo ultrasound scans and neonatal studies. Inter study variations in male/female AGD differences lead to the conclusion that normalization and standardization approaches should be developed to enable confidence in comparing data from different perinatal AGD studies. LIMITATIONS, REASONS FOR CAUTION: Sex differences, and a smoking-dependent increase in male fetal AGD at 14-16 weeks, identified in a preliminary study, were confirmed with a larger number of fetuses. However, human fetal AGD should, be re-assessed once much larger numbers of fetuses have been studied and this should be integrated with more detailed analysis of maternal lifestyle. Direct study of human fetal genital tissues is required for further mechanistic insights. WIDER IMPLICATIONS OF THE FINDINGS: Fetal exposure to cigarette smoke chemicals is known to lead to reduced fertility in men and women. Integration of our data into the perinatal human AGD literature shows that more work needs to be done to enable reliable inter-study comparisons. STUDY FUNDING/COMPETING INTERESTS: The study was supported by grants from the Chief Scientist Office (Scottish Executive, CZG/1/109 & CZG/4/742), NHS Grampian Endowments (08/02), the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 212885 and the Medical Research Council, UK (MR/L010011/1). The authors declare they have no competing interests, be it financial, personal or professional. PMID- 26732625 TI - Room-temperature cobalt-catalyzed arylation of aromatic acids: overriding the ortho-selectivity via the oxidative assembly of carboxylate and aryl titanate reagents using oxygen. AB - A room temperature phosphine or NHC ligand-free cobalt-catalyzed arylation of (hetero)aromatic acids has been developed. It involves an oxidative cross coupling between carboxylate and aryl titanate reagents using oxygen as an oxidant, and the arylation at the position ortho, meta and para to the carboxylic acid group could all be achieved. As application, various (hetero)aromatic acids including xenalipin, tafamidis and the key intermediate for a cardioprotective compound have been efficiently synthesized. PMID- 26732624 TI - Genetically engineering self-organization of human pluripotent stem cells into a liver bud-like tissue using Gata6. AB - Human induced pluripotent stem cells (hiPSCs) have potential for personalized and regenerative medicine. While most of the methods using these cells have focused on deriving homogenous populations of specialized cells, there has been modest success in producing hiPSC-derived organotypic tissues or organoids. Here we present a novel approach for generating and then co-differentiating hiPSC-derived progenitors. With a genetically engineered pulse of GATA-binding protein 6 (GATA6) expression, we initiate rapid emergence of all three germ layers as a complex function of GATA6 expression levels and tissue context. Within 2 weeks we obtain a complex tissue that recapitulates early developmental processes and exhibits a liver bud-like phenotype, including haematopoietic and stromal cells as well as a neuronal niche. Collectively, our approach demonstrates derivation of complex tissues from hiPSCs using a single autologous hiPSCs as source and generates a range of stromal cells that co-develop with parenchymal cells to form tissues. PMID- 26732626 TI - Striatal dopaminergic reward response relates to age of first drunkenness and feedback response in at-risk youth. AB - Dopamine receptor concentrations, primarily in the striatum, are hypothesized to contribute to a developmental imbalance between subcortical and prefrontal control systems in emerging adulthood potentially biasing motivation and increasing risky behaviors. Positron emission tomography studies have found significant reductions in striatal dopamine D2 receptors, and blunted amphetamine induced dopamine release, in substance users compared with healthy controls. Extant literature is limited and inconsistent concerning vulnerability associated with having a family history of substance abuse (FH+). Some studies have reported familial liability associated with higher dopamine receptor levels, reduced dopamine response to stimulant challenges and decreased response to oral alcohol. However, other reports have failed to find group differences based on family history. We explored the interaction of familial liability and behavioral risk with multi-modal molecular and neural imaging of the dopaminergic system. Forty four young adult male subjects performed monetary incentive delay tasks during both [11 C]raclopride positron emission tomography and functional magnetic resonance imaging scans. FH+ subjects were identified as low (n = 24) or high risk (n = 9) based on early initiation of drunkenness. FH+ high-risk subjects exhibited heightened striatal dopamine response to monetary reward but did not differ in neural activations compared with FH+ low risk subjects and controls with no familial loading (n = 11). Across all subjects, a negative relationship was found between dopamine release and age of first drunkenness and a positive relationship with neural response to reward receipt. These results suggest that in at-risk individuals, higher dopamine transmission associated with monetary reward may represent a particularly useful neurobiological phenotype. PMID- 26732627 TI - Network dysfunction in alpha-synuclein transgenic mice and human Lewy body dementia. AB - OBJECTIVE: Dementia with Lewy bodies (DLB) is associated with the accumulation of wild-type human alpha-synuclein (SYN) in neurons and with prominent slowing of brain oscillations on electroencephalography (EEG). However, it remains uncertain whether the EEG abnormalities are actually caused by SYN. METHODS: To determine whether SYN can cause neural network abnormalities, we performed EEG recordings and analyzed the expression of neuronal activity-dependent gene products in SYN transgenic mice. We also carried out comparative analyses in humans with DLB. RESULTS: We demonstrate that neuronal expression of SYN in transgenic mice causes a left shift in spectral power that closely resembles the EEG slowing observed in DLB patients. Surprisingly, SYN mice also had seizures and showed molecular hippocampal alterations indicative of aberrant network excitability, including calbindin depletion in the dentate gyrus. In postmortem brain tissues from DLB patients, we found reduced levels of calbindin mRNA in the dentate gyrus. Furthermore, nearly one quarter of DLB patients showed myoclonus, a clinical sign of aberrant network excitability that was associated with an earlier age of onset of cognitive impairments. In SYN mice, partial suppression of epileptiform activity did not alter their shift in spectral power. Furthermore, epileptiform activity in human amyloid precursor protein transgenic mice was not associated with a left shift in spectral power. INTERPRETATION: We conclude that neuronal accumulation of SYN slows brain oscillations and, in parallel, causes aberrant network excitability that can escalate into seizure activity. The potential role of aberrant network excitability in DLB merits further investigation. PMID- 26732628 TI - Preexisting conditions in pediatric ALL patients: Spectrum, frequency and clinical impact. AB - INTRODUCTION: The etiology of acute lymphoblastic leukemia remains undisclosed in the majority of cases. A number of rare syndromic conditions are known to predispose to different forms of childhood cancer including ALL. The present study characterized the spectrum and clinical impact of preexisting diseases in a cohort of ALL patients from Germany, Austria and Switzerland with a focus on genetic diseases predisposing to cancer development. METHODS: Retrospective database and study chart review included all patients from Germany, Austria and Switzerland (n = 4939) enrolled into multicenter clinical trial AIEOP-BFM ALL 2000 between July 1999 and June 2009. Patients enrolled into study AIEOP-BFM ALL 2009 - which was initiated subsequent to AIEP-BFM ALL 2000 - who were reported with a cancer prone syndrome or chromosomal abnormality were additionally included in this study to increase conclusiveness of observations. RESULTS: A total of 233 patients with at least one reported condition could be identified. The following conditions were reported in more than one patient: Gilbert's disease (n = 13), neurofibromatosis type I (n = 8), ataxia telangiectasia (n = 8), thalassemia (n = 7), Nijmegen Breakage syndrome (n = 6), cystic fibrosis (n = 4), glucose-6-phosphate dehydrogenase deficiency (n = 4), Noonan syndrome (n = 2), Klinefelter syndrome (n = 2), alpha-1-antitrypsin deficiency (n = 2), primary ciliary dyskinesia (n = 2). Especially those syndromes with a known cancer predisposition (NF type I, Ataxia telangiectasia, Nijmegen Breakage syndrome etc.) were associated with certain general and ALL-related characteristics, high therapy-related toxicity and reduced survival. CONCLUSION: The spectrum of underlying diseases within ALL patients is dispersed. A small number of ALL patients are reported with cancer predisposition syndromes at initial diagnosis which are associated with high rates of therapy-related toxicity and a markedly reduced chance of survival. The true prevalence of these conditions within the ALL population remains unknown due to inapparent clinical presentation. A targeted clinical and/or genetic examination for certain diagnoses like NF type I, Ataxia telangiectasia or Nijmegen Breakage syndrome could identify patients who benefit from adjustment of antileukemic therapy or intensification of supportive care. PMID- 26732629 TI - De novo TUBB2B mutation causes fetal akinesia deformation sequence with microlissencephaly: An unusual presentation of tubulinopathy. AB - Tubulinopathies are increasingly emerging major causes underlying complex cerebral malformations, particularly in case of microlissencephaly often associated with hypoplastic or absent corticospinal tracts. Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. We report on an early foetal case with FADS and microlissencephaly due to TUBB2B mutation. Neuropathological examination disclosed virtually absent cortical lamination, foci of neuronal overmigration into the leptomeningeal spaces, corpus callosum agenesis, cerebellar and brainstem hypoplasia and extremely severe hypoplasia of the spinal cord with no anterior and posterior horns and almost no motoneurons. At the cellular level, the p.Cys239Phe TUBB2B mutant leads to tubulin heterodimerization impairment, decreased ability to incorporate into the cytoskeleton, microtubule dynamics alteration, with an accelerated rate of depolymerization. To our knowledge, this is the first case of microlissencephaly to be reported presenting with a so severe and early form of FADS, highlighting the importance of tubulin mutation screening in the context of FADS with microlissencephaly. PMID- 26732630 TI - An ethnobotanical study of plants used to treat liver diseases in the Maritime region of Togo. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Togo, many persons still rely on plants for healing, however very little is known about the medicinal practices of the indigenous people. The present study aimed to document the medicinal plant utilization for the management of liver diseases in the Maritime region of the country. METHODOLOGY: This was an ethnobotanical survey conducted in the Maritime region of Togo from June to August 2015. The data were gathered from 104 traditional healers (TH) by direct interviews using a semi-structured questionnaire. The calculated use values (UV) were used to analyze the importance of the cited plants. RESULTS: A total of 99 plant species belonging to 88 genera and 49 families were cited by the TH as curing the hepatic diseases. The most represented families were Caesalpiniaceae with 8 species, followed by Euphorbiaceae with 7 species, Apocynaceae and Asteraceae with 6 species each. The highest UV were recorded with Gomphrena celosioides (0.13), Xylopia ethiopica (0.12), Senna occidentalis (0.12), Bridelia ferruginea (0.12), Cymbopogon citratus (0.12), Kigellia Africana (0.09), Cassia sieberiana (0.08) and Sanseviera liberica (0.08), showing their importance in the management of liver dysfunction in the surveyed region. The main used parts were the leaves, followed by the roots, the whole plant, the rhizome and the bark, accounting for more than 10% each. The herbal medicines were mostly prepared in the form of decoction and administrated by oral route. CONCLUSION: This study showed that Maritime region of Togo has an important plant biodiversity that is exploited by the indigenous TH. However, some plants cited by the TH have not been studied for their possible hepatoprotective effects. These plants are therefore a starting point for biological screenings. PMID- 26732631 TI - Evaluation of the effects of active fractions of chinese medicine formulas on IL 1beta, IL-6, and TNF-alpha release from ANA-1 murine macrophages. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Yaotongning (YTN) is a traditional Chinese Medicine (TCM) that contains ten component medicinal materials (CMMs) and uses Chinese rice wine as a vehicle to enhance its efficacy. YTN has been used for rheumatoid arthritis (RA) treatment in China for decades and has been reported to have anti-inflammatory and analgesic effects, as well as to strengthen the immune system. AIM OF THE STUDY: The present work quantitatively evaluated the in vitro effects of active fractions from the ten CMMs that make up YTN and eight additional herbs commonly used in TCM formulas for RA treatment, as well as different combinations of these active fractions, on cellular immune response; the findings were used to determine which active fractions are responsible for promoting an immune response, and to assess whether YTN is superior to other similar formulas and whether YTN can be improved by simplifying its formula from the point of its cellular immunomodulatory activity. MATERIALS AND METHODS: Using the YTN formulation principles and some concepts in combinatorial chemistry, 27 TCM samples were designed by combining some or all of the active fractions of YTN and other eight herbs used for RA treatment. Release of interleukin-1beta (IL 1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) from ANA-1 murine macrophages was measured using an enzyme-linked immunosorbent assay (ELISA). The immunoregulatory effects of the TCM samples were evaluated by comparing their half-effective concentrations (EC50) for stimulating the release of these cytokines. RESULTS: Among the investigated active fractions, the flavonoids from Carthamus tinctorius (Fct), Davallia mariesii (Fdm), and Cinnamomum cassia Twig volatile oils (Vca) from the eight selected herbs effectively promoted IL-1beta and IL-6 release from ANA-1 cells. Saponins from the YTN CMM Glycyrrhiza uralensis (Sgu) were the most potent promoters of IL 1beta and TNF-alpha release. The aqueous extract of YTN CMM Eupolyphaga sinensis (Ves) strongly enhanced the release of IL-1beta, IL-6, and TNF-alpha from ANA-1 cells. The EC50 values for stimulating the secretion of IL-1beta, IL-6, and TNF alpha could be determined for only six samples. The full YTN formula and the sample containing 50% Glycyrrhiza uralensis saponins, 25% of the mixture of alkaloids, and 25% of the mixture of all flavonoids exhibited good comprehensive cellular immunomodulatory activity. The immunomodulatory activity of the complete YTN formula was better than that of the sample containing all active fractions of YTN without Chinese rice wine (the YTN vehicle). CONCLUSIONS: Sgu and Ves are the primary active fractions of YTN involved in stimulating immune responses. The YTN prescription was reasonably effective at promoting cellular immune responses. Chinese rice wine, the YTN vehicle, strengthened the immunoregulatory activity of YTN. The results of this study demonstrate that the YTN recipe could be improved by reducing the number of CMMs and altering some active fractions without reducing its activity to promote cellular immune responses. PMID- 26732632 TI - Evaluation of safety of modified-Danggui Buxue Tang in rodents:immunological, toxicity and hormonal aspects. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Radix Astragali (RA), Radix Angelicae Sinensis (RAS) and Folium Epimedii (FE) are three of the extensively applied herbs among traditional Chinese medicines for gynecological disorders and osteoporosis. A derivative herbal formula-RRF, consisting of the three medicines with a weight ratio of 5:1:5, is derived from a famous Chinese herbal formula-Danggui Buxue Tang (DBT). RRF has shown noteworthy perimenopause ameliorating effect in both ovariectomized rats and natural aging female rats, which might represent a promising candidate for the treatment of perimenopausal disorders. The aim of this study was to evaluate its immunological potential, chronic toxicity and reproductive effects by 26-week repeated daily administration in female rats, in order to optimize its safe use. MATERIALS AND METHODS: The effect of RRF on immunological function was studied by macrophage phagocytosis, immune organ index, serum immunoglobulin level as well as delayed type hypersensitivity (DTH) in mice. For toxicity assessment, acute toxicity study was performed according to fixed dose procedure with a single oral administration of RRF to mice. In the oral chronic toxicity, 120 female rats were administrated RRF orally in 0, 1100, 4400, or 8800mg/kg/day doses for 26 weeks. Clinical signs, mortality, body weights, feed consumption, haemato-biochemical parameters, organ weights, histopathology and reproductive hormone profiles were examined at the end of the 13- and 26-week dosing period, as well as after the 4-week recovery period. RESULTS: Oral administration of RRF at three doses (282, 564 and 1128mg/kg) significantly increased the indices of phagocytosis K, as compared with prednisone acetate (PR) group (p<0.05 or 0.01). Exposure of RRF dose-dependently boosted circulating serum IgM level (all p<0.01) in response to CRBC in PR induced mice. Furthermore, RRF treatment elicited a significant increment (all p<0.01) in DNFB-induced DTH response and the immune organ indices in a dose dependent manner in mice, in parellel to DNFB-induced group. In the single dose acute toxicity and repeated dose 90-day chronic toxicity investigations, no toxic signs/mortality were observed. RRF treatment did not cause any toxicologically significant changes in clinical signs, food consumption, body weight, relative organ weight, hematological parameters, clinical chemistry, gross pathology and histopathology between treatment and control groups. No treatment related gross/histopathological lesions were observed and no target organ was identified. Long-term repeated administration of RRF exerted a significant promotion on serum level of steroid hormone estradiol, progesterone and testosterone release, along with decrease of circulating pituitary follicle stimulating hormone, luteinizing hormone, and prolactin levels in female rats. The No Observed Adverse Effect Level (NOAEL) of RRF was determined to be over 8800mg/kg/day for elderly female rats, a dose that was equivalent to 50 times of human dose. CONCLUSION: The present investigation demonstrated that RRF possessed appreciable immunopotentiating activity and had a relatively wide margin of safety. Long-term treatment of RRF exhibited estrogenic properties, and retarded certain age associated degenerations. RRF might have the potential for further development as a safe and effective alternative/complementary to conventional medication in relieving perimenopausal symptoms. PMID- 26732633 TI - Plants used during maternity, menstrual cycle and other women's health conditions among Brazilian cultures. AB - ETHNOPHARMACOLOGICAL RELEVANCE: For innumerous clinical cases related to women's health and precarious medical care in developing countries, a large repertoire of plants have been used as popular medicines in order to fill this gap, which in a certain way creates health risks to users, since pharmacological and toxicological tests are still insufficient to guarantee their efficacy and safety. Besides therapeutic use, abortive plants are broadly used in countries where abortion is prohibited, increasing that risk even more. In this way, ethnopharmacological studies that register plants used for women's health can contribute not only to the selection of potential bioactives, enriching the repertoire of drugs available to females, above all in public health systems, but also questioning the safety of products that are used without prescription. AIMS AND OBJECTIVES: This review aims at determining plants applied by Brazilian cultures in the treatment of conditions related to maternity, menstrual cycle and other women's health particularities, and to supplement the lack of epidemiological data available to assess the health of indigenous, rural and other populations of Brazilian women. MATERIALS AND METHODS: A literature review was conducted of the collection at the Ethnobotanical and Ethnopharmacological Center of the Federal University of Sao Paulo (period covered: 1965 to 2012). All of the 343 articles were consulted and 31 articles mentioning therapeutic uses of interest were selected. Relevant information was extracted to compose Table 1 - Maternity, Table 2 - Menstrual Cycle and Table 3 - Other Conditions. Data was statistically analyzed in order to generate the discussion about plants used in healing contexts by different Brazilian ethnicities. A bibliographic review was performed using the Scopus database to collect the following information about the most cited plants: ethnobotany/ethnopharmacology of non-Brazilian cultures for women's health conditions, pharmacology, toxicology, and adverse reactions. RESULTS: A total of 319 species were cited for 22 indications related to women's health. Ninety-seven species were indicated for conditions related to maternity, 94 to the menstrual cycle and 232 to others. The same species could be present in more than one of these three categories. The most cited family was Fabaceae (13.5%), and the species were Ruta graveolens L. (1.76%) and Strychnos pseudoquina A. St.-Hil (1.76%). The most frequent part utilized, mode of preparation and route of administration were leaves (2.0%), tea (73.38%) and oral (87. 2%), respectively. The indications that showed the highest number of species were: to treat venereal diseases (69 species), abortive (54) and anti inflammatory for the ovaries and/or uterus (54). According to our bibliographic survey, among the 19 most indicated species in this review, only four are also used by non-Brazilian cultures for conditions related to women's health; 25% of them were pharmacologically investigated and it was possible to validate their ethnopharmacological/ethnobotanical use, 10.5% have presented well-described adverse reactions and for 42.1% of these species toxicological studies were performed. CONCLUSION: The survey raised important data about plants implemented in healing related to women's health conditions by Brazilian cultures and their practices. The compilation presented in this study enables the realization of further investigation regarding the development of herbal medicines and contributes to the incrementation of policies focused on these cultures. Further phytochemical, pharmacological and toxicological studies should be conducted, which will allow the discovery of pharmacological properties, bioactive constituents, and moreover, adequate posology, manner of use and adverse events. PMID- 26732634 TI - Rational design of ultrastable and reversibly photoswitchable fluorescent proteins for super-resolution imaging of the bacterial periplasm. AB - Phototransformable fluorescent proteins are central to several nanoscopy approaches. As yet however, there is no available variant allowing super resolution imaging in cell compartments that maintain oxidative conditions. Here, we report the rational design of two reversibly switchable fluorescent proteins able to fold and photoswitch in the bacterial periplasm, rsFolder and rsFolder2. rsFolder was designed by hybridisation of Superfolder-GFP with rsEGFP2, and inherited the fast folding properties of the former together with the rapid switching of the latter, but at the cost of a reduced switching contrast. Structural characterisation of the switching mechanisms of rsFolder and rsEGFP2 revealed different scenarios for chromophore cis-trans isomerisation and allowed designing rsFolder2, a variant of rsFolder that exhibits improved switching contrast and is amenable to RESOLFT nanoscopy. The rsFolders can be efficiently expressed in the E. coli periplasm, opening the door to the nanoscale investigation of proteins localised in hitherto non-observable cellular compartments. PMID- 26732635 TI - Evaluation of the effects of platelet-rich fibrin on bone regeneration in diabetic rabbits. AB - OBJECTIVES: This study aimed to investigate the effect of platelet-rich fibrin on bone regeneration in critical size defects in the calvaria of diabetic rabbits. STUDY DESIGN: In total, 40 male New Zealand rabbits, were divided into two groups a non-diabetic control group (Group A) and a diabetic experimental group (Group B). Two bicortical circular defects 15 mm in diameter were created in the parietal bone of each animal. Each group was further divided into four groups: subgroup E, the defect was left empty; subgroup PRF, the defects were filled only with PRF; subgroup AB, the defects were filled with autogenous bone; subgroup AB + PRF, the defects were filled with autogenous bone combined with PRF. The animals sacrificed at 4 weeks and 8 weeks. Bone formation was assessed by micro computed tomography (micro-CT) scanning, histological and histomorphometric analysis. RESULT: The total percent of new bone was the lowest in group A-E (6.77 +/- 0.21 at 4 weeks, 11.01 +/- 0.37 at 8 weeks) and highest in group A-AB + PRF (21.66 +/- 0.91 at 4 weeks, 37.46 +/- 1.25 at 8 weeks; p < 0.05). The mean percent of new bone was greatest in group B-AB + PRF at 4 and 8 weeks (16.87 +/- 0.92, 29.59 +/- 1.09, respectively) and lowest in group B-E (5.83 +/- 0.09 at 4 weeks, 7.36 +/- 1.02 at 8 weeks). CONCLUSION: This study, despite its limitations, showed that PRF can be used safely and that PRF induced bone healing in diabetic rabbits. PMID- 26732636 TI - Effect of sustained release of rhBMP-2 from dried and wet hyaluronic acid hydrogel carriers compared with direct dip coating of rhBMP-2 on peri-implant osteogenesis of dental implants in canine mandibles. AB - Hyaluronic acid (HA) hydrogel has been used as a carrier of recombinant human bone morphogenetic protein (rhBMP)-2 for sustained delivery. To enhance peri implant osteogenesis, a dried coating of rhBMP-2 HA hydrogel (BMP-HAH) on dental implants was designed; this approach provides the advantage of omitting in situ preparation of wet HA hydrogel. Sustained release of rhBMP-2 was more efficient for dried hydrogel over wet hydrogel. For both types, the released rhBMP-2 consistently led to enhanced alkaline phosphatase activity and osterix expression in human mesenchymal stromal cells. Histomorphometric analysis 4 weeks after placement of a dental implant in canine mandibles showed that the dried coating of BMP-HAH (10 MUg/ml, n = 6) resulted in a significantly greater bone area (BA) than the wet BMP-HAH (10 MUg/ml, n = 6) (p = 0.006) and implants without any coating (n = 6) (p = 0.022), while simple dip coating with rhBMP-2 (10 MUg/ml, n = 6) resulted in significantly greater BA than the other three groups (p < 0.0005). Bone-to-implant contact (BIC) was significantly different only between the dried and wet coating of BMP-HAH (p = 0.014). Our results suggest that a simple dip coating of rhBMP-2 is more effective for increased peri-implant osteogenesis compared to a coating of BMP-HAH with sustained release. PMID- 26732637 TI - A novel method for fusion of intra-oral scans and cone-beam computed tomography scans for orthognathic surgery planning. AB - AIM: To assess the feasibility of a new method to augment the three-dimensional virtual skull model with a detailed surface model of the dentition produced by intra-oral scanning, compared to the conventional triple scan procedure. MATERIALS & METHODS: In four patients who were planned for bimaxillary orthognathic surgery, the conventional triple scan procedure was carried out to create an augmented model. During scanning the patient wears a modified wax bite containing radio-opaque markers. An additional CBCT and laser scan of the wax bite and an intra-oral scan of the dentition were acquired. Surface-based and marker-based matching procedures were performed to integrate the intra-oral scans into the CBCT scan of the patient. The accuracy of the proposed method was assessed by measuring the distance between the occlusal surfaces of the registered intra-oral scans and the augmented model. RESULTS: Mean distances between the ios-dental cast registration and the augmented model were 0.30 mm (SD 0.20) and 0.27 mm (SD 0.20) for the upper and lower jaw, respectively. CONCLUSION: Intra-oral scans provide an accurate representation of the dental arches compared to the AlgiNot-dental casts and can be fused with CBCT scans. PMID- 26732638 TI - Computer-aided design-based preoperative planning of screw osteosynthesis for type B condylar head fractures: A preliminary study. AB - OBJECTIVE: To investigate the clinical application of a new computer-aided design - (CAD) based planning method for the treatment of type B condylar head fractures without fragmentation. METHODS: A total of 13 adult patients (19 sides) with type B condylar head fractures were included in the study. In all cases, imaging was performed using cone bean computed tomography (CBCT) preoperative, and Digital Imaging and Communications in Medicine (DICOM) files were imported into Simplant 11.04 software. The fracture of the mandibular condyle was reconstructed by a three-dimensional reconstruction module, and the simulation of reduction was achieved according to the morphological characteristics. Preoperative design was performed based on the CAD technology, and the three-dimensional interface was used to determine the length, location, and orientation of the positional screw. Osteosynthesis was performed with a single positional screw according to the optimum direction assessed in the preoperative planning CBCT, and the result was confirmed with postoperative CBCT scans and clinical follow-up. RESULTS: Preoperative computer-aided design was able to predict the length, location, and direction of the positional screw. Postoperative CBCT results demonstrated that 12 cases (18 sides) were consistent with preoperative design with exception of one case (one side) due to unexpected rupture of the fragment. Six-month follow up showed the condylar fractures were anatomically repositioned and that healing was excellent in 12 cases (18 sides) with minor displacement and resorption in one case (one side). Postoperative occlusion in all cases was excellent, and the maximum mouth opening improved from mean 1.2 cm preoperatively to a of mean 4.3 cm at 6 months postoperatively. The data for mandibular movements at 6 months postoperatively demonstrated the recovery of protrusion, without higher grade limitations for laterotrusion. In one case, there appeared to be mandibular deviation (<0.5 cm) with mouth opening. CONCLUSION: The new preoperative design provides relevant data for screw osteosynthesis to enhance the precision and effectiveness of open reduction and internal fixation type B condylar head fractures. PMID- 26732639 TI - Ultrasound-guided fine-needle aspiration cytology as a diagnostic tool in comparison to ultrasound and MRI for staging in oral- and oropharyngeal squamous cell tumors. AB - The aim of this retrospective study was to test the diagnostic performance of ultrasound guided fine-needle aspiration cytology (USFNAC) in comparison to ultrasound (US) and magnetic resonance imaging (MRI) for detecting lymph node metastases in patients with squamous cell carcinoma of the oral and oropharyngeal region. 143 patients with oral cavity and oropharyngeal squamous cell carcinoma were included in the study. US, USFNAC and MRI were routinely performed prior to neck dissection. The results of the imaging studies were compared to histopathology. The sensitivity of MRI was highest at 83%, followed by USFNAC and US at 81% and 73%, respectively. The specificity was highest for FNAC at 100%, followed by MRI and US at 76% and 45%, respectively. Positive predictive value was highest for USFNAC 100%, US 57%, MRI 75% and negative predictive value was 77%, 69% and 84%, respectively. In our patient group with oral and oropharyngeal carcinoma, MRI had a higher sensitivity than USFNAC and US alone. USFNAC provided additional staging information. Especially in an uncertain lymph node situation it can facilitate and optimize preoperative planning with a specificity of 100% regarding tissue entity of cervical lymph nodes. PMID- 26732640 TI - Therapeutic Evaluation of Biofeedback Therapy in the Treatment of Anterior Resection Syndrome After Sphincter-Saving Surgery for Rectal Cancer. AB - BACKGROUND: Anterior resection syndrome (ARS) is common after sphincter-saving surgery for rectal cancer. It includes changes in the frequency and urgency of bowel movements and fecal incontinence. The therapeutic efficacy of biofeedback on ARS is unclear. We sought to evaluate the effectiveness of biofeedback therapy in patients with ARS after anterior resection for rectal cancer and to investigate the associated factors for therapeutic success. PATIENTS AND METHODS: The study was designed as a retrospective review of the data from 61 patients with ARS collected from a prospectively maintained institutional cancer database. Therapeutic efficacy was evaluated using anorectal manometry, the number of bowel movements daily, and fecal incontinence scoring systems (Vaizey and/or Wexner scores). Changes of > 15% in the Vaizey and/or Wexner scores were considered to indicate effectiveness. Stepwise logistic regression models were performed to evaluate whether the associated factors influenced therapeutic efficacy. RESULTS: The parameters of anorectal manometry in patients with rectal cancer were significantly lower than those in control group (P < .01). After biofeedback therapy, significant improvements were observed in the incontinence scale scores (P < .001), number of bowel movements (P < .001), and anorectal manometry data (maximum resting pressure, P < .001; maximum squeeze pressure, P = .001; and rectal capacity, P = .015). In contrast, no significant difference in the rectal initial sensation threshold was observed (P = .089). Patients with fecal incontinence as the primary symptom experienced significant improvements in all variables (P < .01), except for the rectal initial sensation threshold (P = .125). Age at surgery, current smoking status, diabetes, treatment cycles, laparoscopic surgery, interval from surgery to biofeedback therapy, and the use of radiation therapy were closely associated with therapeutic success. On multivariate analysis, current smoking status (odds ratio [OR], 0.09; 95% confidence interval [CI], 0.01-0.87), number of biofeedback therapy cycles (OR, 0.01; 95% CI, 0.00-0.06), and laparoscopic surgery (OR, 11.53; 95% CI, 1.17 113.61) were factors contributing to biofeedback therapeutic success. CONCLUSION: Biofeedback therapy can improve the anal function of patients after restorative resection for rectal cancer. PMID- 26732641 TI - Contribution of alpha-smooth muscle actin and extracellular matrix to the in vitro reorganization of cardiomyocyte contractile system. AB - Cardiomyocytes in culture undergo reversible rearrangement of their contractile apparatus with the conversion of typical myofibrils into the structures of non muscle type and the loss of contractility. Along with these transformations, the cardiomyocytes gain the capacity to synthesize extracellular matrix. Here we show that during cultivation of rat neonatal cardiomyocytes, the inherent alpha cardiac actin isoform is transiently replaced by alpha-smooth-muscle actin, whose expression is accompanied by transformation of myofibrils into stress-fiber-like structures. The following down-regulation of alpha-smooth muscle actin parallels restoration of myofibrillar system and correlates with the accumulation of extracellular collagen and laminin, initially missing from the cardiomyocytes culture. PMID- 26732642 TI - Natural Orifice Transluminal Endoscopic Surgery-Assisted Laparoscopic Transvesical Bladder Diverticulectomy: Feasibility Study, Points of Technique, and Case Series with Medium-Term Follow-Up. AB - OBJECTIVES: To demonstrate the feasibility of our novel natural orifice transluminal endoscopic surgery (NOTES)-assisted approach with medium-term follow up. PATIENTS AND METHODS: From March 2012, we included all patients who presented to our clinic with symptomatic or complicated retentive bladder diverticula secondary to long-standing infravesical obstruction. After managing the primary cause, we proceeded in all cases to our novel NOTES-assisted approach. We followed up the patients with abdominal ultrasonography at 6 weeks and 12 months postoperatively. Success was determined as subjective relief of the symptoms and objective disappearance of the diverticula in postoperative retrograde cystogram (RGC). RESULTS: Between March 2012 and August 2014, eight diverticula were treated using our new technique. The surgery was uneventful. The mean operative time was 134.25 +/- 44.92 minutes. Blood loss was minimal (>50 mL). Retrograde cystography was performed on the 10th postoperative day. The introduction of the needle holder through the urethral natural orifice (NOTES) facilitated a more optimal direction of the needle holder for suturing the bladder wall due to its parallel position in relation to the trigone and posterolateral walls. This renders this step easier compared with suturing the bladder wall through the transvesical laparoscopic ports. One case had a grade IIIa complication according to the Clavien-Dindo classification of surgical complications. The study is limited by the small number of cases. CONCLUSION: Laparoscopic transvesical bladder diverticulectomy is a promising and safe procedure with good outcomes. Using the urethra (NOTES assisted) as an extra access to the bladder facilitates diverticular traction and bladder suturing without the need for extra ports. This technique can also be applied together with the novel T-laparoendoscopic single site surgery approach. PMID- 26732643 TI - Impact of point defects on the electronic and transport properties of silicene nanoribbons. AB - We study the impact of various point defects on the structural, electronic and ballistic transport properties of armchair silicene nanoribbons, using the density functional theory and the non equilibrium Green's function method. The effect of a Stone-Wales defect, an interior/edge vacancy and an edge dangling bond is examined. Our results show that structural imperfections can alter the electronic structure (energy band structure and density of states) of the nanoribbons and can either increase or decrease the ballistic current. The dependence of the transport properties on the position of the defects (sublattice A or B) and on their distance from the contact is also investigated. PMID- 26732644 TI - Impact and correction of the bladder uptake on 18 F-FCH PET quantification: a simulation study using the XCAT2 phantom. AB - The spill-in counts from neighbouring regions can significantly bias the quantification over small regions close to high activity extended sources. This effect can be a drawback for (18)F-based radiotracers positron emission tomography (PET) when quantitatively evaluating the bladder area for diseases such as prostate cancer. In this work, we use Monte Carlo simulations to investigate the impact of the spill-in counts from the bladder on the quantitative evaluation of prostate cancer when using (18)F-Fluorcholine (FCH) PET and we propose a novel reconstruction-based correction method. Monte Carlo simulations of a modified version of the XCAT2 anthropomorphic phantom with (18)F FCH biological distribution, variable bladder uptake and inserted prostatic tumours were used in order to obtain simulated realistic (18)F-FCH data. We evaluated possible variations of the measured tumour Standardized Uptake Value (SUV) for different values of bladder uptake and propose a novel correction by appropriately adapting image reconstruction methodology. The correction is based on the introduction of physiological background terms on the reconstruction, removing the contribution of the bladder to the final image. The bladder is segmented from the reconstructed image and then forward-projected to the sinogram space. The resulting sinograms are used as background terms for the reconstruction. SUV max and SUV mean could be overestimated by 41% and 22% respectively due to the accumulation of radiotracer in the bladder, with strong dependence on bladder-to-lesion ratio. While the SUVs measured under these conditions are not reliable, images corrected using the proposed methodology provide better repeatability of SUVs, with biases below 6%. Results also showed remarkable improvements on visual detectability. The spill-in counts from the bladder can affect prostatic SUV measurements of (18)F-FCH images, which can be corrected to less than 6% using the proposed methodology, providing reliable SUV values even in the presence of high radioactivity accumulation in the bladder. PMID- 26732646 TI - Anomalous Experiences, Trauma, and Symbolization Processes at the Frontiers between Psychoanalysis and Cognitive Neurosciences. AB - Anomalous or exceptional experiences are uncommon experiences which are usually interpreted as being paranormal by those who report them. These experiences have long remained difficult to explain, but current progress in cognitive neuroscience and psychoanalysis sheds light on the contexts in which they emerge, as well as on their underlying processes. Following a brief description of the different types of anomalous experiences, we underline how they can be better understood at the frontiers between psychoanalysis and cognitive neurosciences. In this regard, three main lines of research are discussed and illustrated, alongside clinical cases which come from a clinical service specializing in anomalous experiences. First, we study the links between anomalous experiences and hallucinatory processes, by showing that anomalous experiences frequently occur as a specific reaction to negative life events, in which case they mainly take the form of non-pathological hallucinations. Next, we propose to analyze these experiences from the perspective of their traumatic aspects and the altered states of consciousness they often imply. Finally, these experiences are considered to be the consequence of a hypersensitivity that can be linked to an increase in psychic permeability. In conclusion, these different processes lead us to consider anomalous experiences as primary forms of symbolization and transformation of the subjective experience, especially during, or after traumatic situations. PMID- 26732647 TI - Oleanolic Acid Induces the Type III Secretion System of Ralstonia solanacearum. AB - Ralstonia solanacearum, the causal agent of bacterial wilt, can naturally infect a wide range of host plants. The type III secretion system (T3SS) is a major virulence determinant in this bacterium. Studies have shown that plant-derived compounds are able to inhibit or induce the T3SS in some plant pathogenic bacteria, though no specific T3SS inhibitor or inducer has yet been identified in R. solanacearum. In this study, a total of 50 different compounds were screened and almost half of them (22 of 50) significantly inhibited or induced the T3SS expression of R. solanacearum. Based on the strong induction activity on T3SS, the T3SS inducer oleanolic acid (OA) was chosen for further study. We found that OA induced the expression of T3SS through the HrpG-HrpB pathway. Some type III effector genes were induced in T3SS inducing medium supplemented with OA. In addition, OA targeted only the T3SS and did not affect other virulence determinants. Finally, we observed that induction of T3SS by OA accelerated disease progress on tobacco. Overall our results suggest that plant-derived compounds are an abundant source of R. solanacearum T3SS regulators, which could prove useful as tools to interrogate the regulation of this key virulence pathway. PMID- 26732648 TI - Development of competence in the first year of graduate nursing practice: a longitudinal study. AB - AIM: To determine the extent to which competence develops in the first year of nursing practice in a paediatric setting. BACKGROUND: Among all the literature related to nursing competence, there have been few studies that have used a standardized tool to determine the development of professional nursing competence in the first year of practice. DESIGN: A quantitative longitudinal design was applied as part of a mixed methods study. METHODS: Forty seven nurses commencing a 12-month graduate nurse programme were invited to undertake a self-assessment of their level of competence at four time points; commencement, 3 months, 6 months and 12 months, between January 2013-February 2014. The assessment was completed using the Nurse Competence Scale; a questionnaire with 73 items across seven domains of competence. Each item is scored along a visual analogue scale (0 100). Response rates varied from 100% at commencement to 68% at 12 months. RESULTS: At commencement, the self-assessed level of overall competence was 41.4, 61.1 at 3 months, 72.9 at 6 months and 76.7 at 12 months. Similar patterns were seen for each domain. Mixed effects model analysis for longitudinal data revealed gains in competence for each of the domains and overall, was statistically significant from commencement to 3 months and 3 months to 6 months. While gains were made between 6-12 months, the results were not statistically significant. CONCLUSION: Graduate nurses showed significant gains in competence in the first 6 months of transition from nursing students to Registered Nurses. PMID- 26732649 TI - Spin-Selective Generation of Triplet Nitrenes: Olefin Aziridination through Visible-Light Photosensitization of Azidoformates. AB - Azidoformates are interesting potential nitrene precursors, but their direct photochemical activation can result in competitive formation of aziridination and allylic amination products. Herein, we show that visible-light-activated transition-metal complexes can be triplet sensitizers that selectively produce aziridines through the spin-selective photogeneration of triplet nitrenes from azidoformates. This approach enables the aziridination of a wide range of alkenes and the formal oxyamination of enol ethers using the alkene as the limiting reagent. Preparative-scale aziridinations can be easily achieved under continuous flow conditions. PMID- 26732650 TI - Exon-centric regulation of ATM expression is population-dependent and amenable to antisense modification by pseudoexon targeting. AB - ATM is an important cancer susceptibility gene that encodes a critical apical kinase of the DNA damage response (DDR) pathway. We show that a key nonsense mediated RNA decay switch exon (NSE) in ATM is repressed by U2AF, PUF60 and hnRNPA1. The NSE activation was haplotype-specific and was most promoted by cytosine at rs609621 in the NSE 3' splice-site (3'ss), which is predominant in high cancer risk populations. NSE levels were deregulated in leukemias and were influenced by the identity of U2AF35 residue 34. We also identify splice switching oligonucleotides (SSOs) that exploit competition of adjacent pseudoexons to modulate NSE levels. The U2AF-regulated exon usage in the ATM signalling pathway was centred on the MRN/ATM-CHEK2-CDC25-cdc2/cyclin-B axis and preferentially involved transcripts implicated in cancer-associated gene fusions and chromosomal translocations. These results reveal important links between 3'ss control and ATM-dependent responses to double-strand DNA breaks, demonstrate functional plasticity of intronic variants and illustrate versatility of intronic SSOs that target pseudo-3'ss to modify gene expression. PMID- 26732652 TI - Flow cytometric evaluation of the contribution of ionic silver to genotoxic potential of nanosilver in human liver HepG2 and colon Caco2 cells. AB - Exposure to nanosilver found in food- and cosmetics-related consumer products is of public concern because of the lack of information about its safety. In this study, two widely used in vitro cell culture models, human liver HepG2 and colon Caco2 cells, and the flow cytometric micronucleus (FCMN) assay were evaluated as tools for rapid predictive screening of the potential genotoxicity of nanosilver. Recently, we reported the genotoxicity of 20 nm nanosilver using these systems. In the current study presented here, we tested the hypothesis that the nanoparticle size and cell types were critical determinants of its genotoxicity. To test this hypothesis, we used the FCMN assay to evaluate the genotoxic potential of 50 nm nanosilver of the same shape, composition, surface charge and obtained from the same commercial source using the same experimental conditions and in vitro models (HepG2 and Caco2) as previously tested for the 20 nm silver. Results of our study show that up to the concentrations tested in these cultured cell test systems, the smaller (20 nm) nanoparticle is genotoxic to both the cell types by inducing micronucleus (MN). However, the larger (50 nm) nanosilver induces MN only in HepG2 cells, but not in Caco2 cells. Also in this study, we evaluated the contribution of ionic silver to the genotoxic potential of nanosilver using silver acetate as the representative ionic silver. The MN frequencies in HepG2 and Caco2 cells exposed to the ionic silver in the concentration range tested are not statistically significant from the control values except at the top concentrations for both the cell types. Therefore, our results indicate that the ionic silver may not contribute to the MN-forming ability of nanosilver in HepG2 and Caco2 cells. Also our results suggest that the HepG2 and Caco2 cell cultures and the FCMN assay are useful tools for rapid predictive screening of a genotoxic potential of food- and cosmetics-related chemicals including nanosilver. PMID- 26732651 TI - The recent ancestry of Middle East respiratory syndrome coronavirus in Korea has been shaped by recombination. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe cases of human respiratory disease. Since 2012, the victims have mainly come from the Middle East countries or sporadically from some other geographical regions seeded by the travelers who visited the Middle East. Such an introduction through travelling led to the emergence of a MERS-CoV outbreak in Korea in May 2015, which caused more than 140 confirmed human cases in less than a month. Using 70 complete genome sequences of MERS-CoV isolates, including the most recent sequences for the Korean and Chinese isolates, we reconstructed the phylogenetic relationships of the complete genome and the individual protein coding regions. The Korean MERS-CoV strain clustered in the previously established Hafr-Al-Batin 1_2013 clade together with two Saudi Arabian and one Chinese strain sampled in 2015. Although these four strains remained monophyletic in the entire protein coding region, this clade showed different phylogenetic relationships across the genome, indicating a shared unique recombination pattern that is different from previously reported putative recombination strains. Our findings suggest that the recent ancestor of the Korean and its related MERS-CoV strains is characterized by unique mosaic genome pattern that is different from other putative recombinants. PMID- 26732653 TI - Mammalian autophagy is essential for hepatic and renal ketogenesis during starvation. AB - Autophagy is an intracellular degradation system activated, across species, by starvation. Although accumulating evidence has shown that mammalian autophagy is involved in pathogenesis of several modern diseases, its physiological role to combat starvation has not been fully clarified. In this study, we analysed starvation-induced gluconeogenesis and ketogenesis in mouse strains lacking autophagy in liver, skeletal muscle or kidney. Autophagy-deficiency in any tissue had no effect on gluconeogenesis during starvation. Though skeletal muscle- and kidney-specific autophagy-deficiency did not alter starvation-induced increases in blood ketone levels, liver-specific autophagy-deficiency significantly attenuated this effect. Interestingly, renal as well as hepatic expression of HMG CoA synthase 2 increased with prolonged starvation. Furthermore, during starvation, mice lacking autophagy both in liver and kidney showed even lower blood ketone levels and physical activity than mice lacking autophagy only in liver. Starvation induced massive lipid droplet formation in extra-adipose tissues including liver and kidney, which was essential for ketogenesis. Moreover, this process was impaired in the autophagy-deficient liver and kidney. These findings demonstrate that hepatic and renal autophagy are essential for starvation-induced lipid droplet formation and subsequent ketogenesis and, ultimately, for maintaining systemic energy homeostasis. Our findings provide novel biological insights into adaptive mechanisms to combat starvation in mammals. PMID- 26732654 TI - Aberrant laryngeal location of Onchocerca lupi in a dog. AB - Onchocerca lupi (Spirurida, Onchocercidae) is an emerging vector-borne helminth that causes nodular lesions associated with acute or chronic ocular disease in dogs and cats. Since its first description in dogs in 1991, this zoonotic filarioid has been increasingly reported in Europe and the United States. An 8 year-old outdoor mixed-breed female dog from the Algarve (southern Portugal) was presented with a history of severe dyspnoea. Cervical and thoracic radiographs revealed a slight reduction in the diameter of the cervical trachea and a moderate increase in radiopacity of the laryngeal soft tissue. An exploratory laryngoscopy was performed, revealing filiform worms associated with stenosis of the thyroid cartilage and a purulent necrotic tissue in the larynx lumen. A single sessile nodule, protruding from the dorsal wall of the laryngeal lumen caused a severe reduction of the glottis and tracheal diameter. Fragments of the worms were morphologically and molecularly identified as O. lupi. Histological examination of the nodule showed a granulomatous reaction with sections of coiled gravid female nematodes. Following laryngoscopy, a tracheostomy tube was inserted to relieve dyspnoea and ivermectin (300 MUg/kg, once a week, for 8 weeks) combined with prednisolone was prescribed. The dog showed a complete recovery. Although O. lupi has been isolated in human patients from the spinal cord, this is the first report of an aberrant migration of O. lupi in a dog. The veterinary medical community should pay attention to aberrant location of O. lupi and consider onchocercosis as a differential diagnosis for airway obstruction in dogs. PMID- 26732655 TI - [Many faces of sarcoidosis]. AB - Sarcoidosis is a systemic, inflammatory, granulomatous disease of unknown origin that can involve any organ. More than 90% of patients have thoracic sarcoidosis, which most frequently presents with bilateral hilar lymphadenopathy. In approximately 20% of patients with thoracic sarcoidosis there is involvement of the lung parenchyma as well as mostly asymptomatic cardiac sarcoidosis in up to 55% of patients. Most patients are asymptomatic and the diagnosis is an incidental finding on chest X-ray or during clarification of unspecific symptoms, such as fatigue or cough. In approximately two thirds of patients the disease undergoes spontaneous remission and in one third the disease follows a chronic or even progressive course. Furthermore, sarcoidosis can also be manifested in the abdominal organs, the central nervous system (CNS) and the musculoskeletal system. These manifestations are frequently subclinical and require targeted diagnostics when sarcoidosis is clinically suspected. PMID- 26732656 TI - [Treatment of acute stroke]. PMID- 26732657 TI - [Erratum to: Treatment planning with functional MRI]. PMID- 26732658 TI - The human factor. PMID- 26732660 TI - Discriminately disposable after single use: the trophectoderm and its derivatives. PMID- 26732659 TI - Next-Generation Bacillus anthracis Live Attenuated Spore Vaccine Based on the htrA(-) (High Temperature Requirement A) Sterne Strain. AB - Anthrax is a lethal disease caused by the gram-positive spore-producing bacterium Bacillus anthracis. Live attenuated vaccines, such as the nonencapsulated Sterne strain, do not meet the safety standards mandated for human use in the Western world and are approved for veterinary purposes only. Here we demonstrate that disrupting the htrA gene, encoding the chaperone/protease HtrA (High Temperature Requirement A), in the virulent Bacillus anthracis Vollum strain results in significant virulence attenuation in guinea pigs, rabbits and mice, underlying the universality of the attenuated phenotype associated with htrA knockout. Accordingly, htrA disruption was implemented for the development of a Sterne derived safe live vaccine compatible with human use. The novel B. anthracis SterneDeltahtrA strain secretes functional anthrax toxins but is 10-10(4)-fold less virulent than the Sterne vaccine strain depending on animal model (mice, guinea pigs, or rabbits). In spite of this attenuation, double or even single immunization with SterneDeltahtrA spores elicits immune responses which target toxaemia and bacteremia resulting in protection from subcutaneous or respiratory lethal challenge with a virulent strain in guinea pigs and rabbits. The efficacy of the immune-protective response in guinea pigs was maintained for at least 50 weeks after a single immunization. PMID- 26732661 TI - Anti-Mullerian hormone gene polymorphism is associated with androgen levels in Chinese polycystic ovary syndrome patients with insulin resistance. AB - PURPOSE: The objective of the study was to investigate whether genetic polymorphisms of the anti-Mullerian hormone (AMH) and its specific receptor anti Mullerian hormone type II receptor (AMHRII) were associated with the hormone disorder and phenotype of polycystic ovary syndrome (PCOS). METHODS: This case control study included 141 PCOS patients and 123 normal women. Two polymorphisms of AMH and AMHRII and the clinical characteristics of participants such as body mass index (BMI), serum luteinizing hormone (LH), estradiol levels (E2), total testosterone levels (T), and homeostasis model assessment of insulin resistance (HOMA-IR) were analyzed with the case-control sample. Gene-gene interactions of AMH and AMHRII genes were analyzed based multifactor-dimensionality reduction method. RESULTS: A significant difference of AMH gene polymorphisms were observed in IR-PCOS women and controls. The AMH and AMHRII gene polymorphisms were not found a significant difference in non-IR-PCOS and normal groups. To IR-PCOS women, genotypes of AMH were closely related to the serum levels of LH (P = 0.000), testosterone (P = 0.000) and HOMA-IR (P = 0.038), while in the non-IR PCOS and normal groups, no relationship was found. No impact of AMH and AMHRII gene-gene interactions was demonstrated. CONCLUSIONS: Our research suggests that the diversity of AMH genotypes in the AMH signal pathway may be connected with the susceptibility and phenotype of PCOS with insulin resistance. PMID- 26732662 TI - gbtools: Interactive Visualization of Metagenome Bins in R. AB - Improvements in DNA sequencing technology have increased the amount and quality of sequences that can be obtained from metagenomic samples, making it practical to extract individual microbial genomes from metagenomic assemblies ("binning"). However, while many tools and methods exist for unsupervised binning with various statistical algorithms, there are few options for visualizing the results, even though visualization is vital to exploratory data analysis. We have developed gbtools, a software package that allows users to visualize metagenomic assemblies by plotting coverage (sequencing depth) and GC values of contigs, and also to annotate the plots with taxonomic information. Different sets of annotations, including taxonomic assignments from conserved marker genes or SSU rRNA genes, can be imported simultaneously; users can choose which annotations to plot. Bins can be manually defined from plots, or be imported from third-party binning tools and overlaid onto plots, such that results from different methods can be compared side-by-side. gbtools reports summary statistics of bins including marker gene completeness, and allows the user to add or subtract bins with each other. We illustrate some of the functions available in gbtools with two examples: the metagenome of Olavius algarvensis, a marine oligochaete worm that has up to five bacterial symbionts, and the metagenome of a synthetic mock community comprising 64 bacterial and archaeal strains. We show how instances of poor automated binning, sequencer GC% bias, and variation between samples can be quickly diagnosed by visualization, and demonstrate how the results from different binning tools can be combined and refined to yield manually curated bins with higher completeness. gbtools is open-source and written in R. The software package, documentation, and example data are available freely online at https://github.com/kbseah/genome-bin-tools. PMID- 26732663 TI - Flexibility in MOFs: do scalar and group-theoretical counting rules work? AB - We investigate the ability of counting rules drafted from engineering to predict the flexibility or rigidity of bar-and-joint or body-and-joint assemblies representing metal organic frameworks. We show that while scalar counting rules are not reliable, group-theoretical approaches are able to disentangle mechanisms from states of self-stress and to predict the existence of flexible mechanisms. We give several detailed examples of such calculations, highlighting the fact that behind an abstract exterior they are in fact easy to apply and similar to the method used to obtain molecular vibrations. We also correct a slight misinterpretation of the rigidity of IRMOF-1. PMID- 26732664 TI - Modeling and Experimental Demonstration of a Hopfield Network Analog-to-Digital Converter with Hybrid CMOS/Memristor Circuits. AB - The purpose of this work was to demonstrate the feasibility of building recurrent artificial neural networks with hybrid complementary metal oxide semiconductor (CMOS)/memristor circuits. To do so, we modeled a Hopfield network implementing an analog-to-digital converter (ADC) with up to 8 bits of precision. Major shortcomings affecting the ADC's precision, such as the non-ideal behavior of CMOS circuitry and the specific limitations of memristors, were investigated and an effective solution was proposed, capitalizing on the in-field programmability of memristors. The theoretical work was validated experimentally by demonstrating the successful operation of a 4-bit ADC circuit implemented with discrete Pt/TiO2 x /Pt memristors and CMOS integrated circuit components. PMID- 26732665 TI - Microfluidic perfusion systems for secretion fingerprint analysis of pancreatic islets: applications, challenges and opportunities. AB - A secretome signature is a heterogeneous profile of secretions present in a single cell type. From the secretome signature a smaller panel of proteins, namely a secretion fingerprint, can be chosen to feasibly monitor specific cellular activity. Based on a thorough appraisal of the literature, this review explores the possibility of defining and using a secretion fingerprint to gauge the functionality of pancreatic islets of Langerhans. It covers the state of the art regarding microfluidic perfusion systems used in pancreatic islet research. Candidate analytical tools to be integrated within microfluidic perfusion systems for dynamic secretory fingerprint monitoring were identified. These analytical tools include patch clamp, amperometry/voltametry, impedance spectroscopy, field effect transistors and surface plasmon resonance. Coupled with these tools, microfluidic devices can ultimately find applications in determining islet quality for transplantation, islet regeneration and drug screening of therapeutic agents for the treatment of diabetes. PMID- 26732667 TI - Autologous Fat Transplantation to the Reconstructed Breast Does not Hinder Assessment of Mammography and Ultrasound: A Cohort Study. AB - BACKGROUND: Autologous fat transplantation (AFT) to the breast can correct defects and be a part of a breast reconstruction to achieve a better aesthetic result. The impact of AFT on the radiological evaluation and detection of cancer remains unclarified. The aim of this study is to investigate whether AFT induces lasting modifications. METHODS: In the present study, a valuation was performed of 44 breasts from 37 patients examined with mammography and ultrasound before and after autologous fat transplantation. Breast radiologists evaluated the images using a study specific protocol. RESULTS: AFT did not hinder post operative assessment of mammograms or ultrasound. No detectable changes with serious clinical impact were found after injections of mean 177 ml (34-516) of fat in one to four sessions. The rate of oil cysts was significantly higher after AFT than pre-operatively (2.3 vs. 34.1 % p = 0.0013). Significantly more post operative oil cysts were detected after injection of larger volumes of fat (144 vs. 243 ml, p = 0.013). No significant differences were found in the post operative images regarding age at surgery, follow-up time, or time from previous breast surgery. CONCLUSION: AFT does not impair assessment of mammograms and ultrasound in patients who have a history of breast cancer surgery or prophylactic mastectomy. PMID- 26732668 TI - A Multimodal Imaging Protocol, (123)I/(99)Tc-Sestamibi, SPECT, and SPECT/CT, in Primary Hyperparathyroidism Adds Limited Benefit for Preoperative Localization. AB - INTRODUCTION: Focused parathyroidectomy in primary hyperparathyroidism (1 degrees HPT) is possible with accurate preoperative localization and intraoperative PTH monitoring (IOPTH). The added benefit of multimodal imaging techniques for operative success is unknown. METHOD: Patients with 1 degrees HPT, who underwent parathyroidectomy in 2012-2014 at a single institution, were retrospectively reviewed. Only the patients who underwent the standardized multimodal imaging workup consisting of (123)I/(99)Tc-sestamibi subtraction scintigraphy, SPECT, and SPECT/CT were assessed. RESULTS: Of 360 patients who were identified, a curative operation was performed in 96%, using pre-operative imaging and IOPTH. Imaging analysis showed that (123)I/(99)Tc-sestamibi had a sensitivity of 86% (95% CI 82 90%), positive predictive value (PPV) 93%, and accuracy 81%, based on correct lateralization. SPECT had a sensitivity of 77% (95% CI 72-82%), PPV 92% and accuracy 72%. SPECT/CT had a sensitivity of 75% (95% CI 70-80%), PPV of 94%, and accuracy 71%. There were 3 of 45 (7%) patients with negative sestamibi imaging that had an accurate SPECT and SPECT/CT. Of 312 patients (87%) with positive uptake on sestamibi (93% true positive, 7% false positive), concordant findings were present in 86% SPECT and 84% SPECT/CT. In cases where imaging modalities were discordant, but at least one method was true-positive, (123)I/(99)Tc sestamibi was significantly better than both SPECT and SPECT/CT (p < 0.001). The inclusion of SPECT and SPECT/CT in 1 degrees HPT imaging protocol increases patient cost up to 2.4-fold. CONCLUSION: (123)I/(99)Tc-sestamibi subtraction imaging is highly sensitive for preoperative localization in 1 degrees HPT. SPECT and SPECT/CT are commonly concordant with (123)I/(99)Tc-sestamibi and rarely increase the sensitivity. Routine inclusion of multimodality imaging technique adds minimal clinical benefit but increases cost to patient in high-volume setting. PMID- 26732669 TI - Pathologic Assessment of Pancreatic Fibrosis for Objective Prediction of Pancreatic Fistula and Management of Prophylactic Drain Removal After Pancreaticoduodenectomy: Reply. PMID- 26732666 TI - Ubiquitylation as a Rheostat for TCR Signaling: From Targeted Approaches Toward Global Profiling. AB - T cell receptor (TCR) signaling must be precisely tuned to limit collateral damage and prevent reactivity to self, while still allowing robust protective immune responses that control pathogen invasion. One process that can be used to promote, modify, or terminate TCR signaling is ubiquitylation. During ubiquitylation, ubiquitin is covalently attached to target proteins through a multistep process, in which E3 ubiquitin ligases promote the formation of ubiquitin chains on selected substrates. Ubiquitylation can facilitate protein protein interactions, direct a protein to a specific subcellular location, or initiate protein destruction. Like phosphorylation, ubiquitylation is a reversible process - deubiquitylating enzymes counteract ligase function by removing ubiquitin chains. This reversibility also allows for ubiquitin chain "editing." Based on an emerging wealth of information from genetic loss-of function studies showing that deregulation of ubiquitylation pathways leads to immune dysfunction, it has become increasingly apparent that the dynamic process of ubiquitylation is critical for normal immune cell function. In this review, we will describe how ubiquitylation acts as a key modulator and integrator of signaling downstream of TCR engagement. Specifically, we highlight the known roles of the substrate-specific E3 ligases and deubiquitylating enzymes in TCR signaling and T cell activation. While it is clear that ubiquitin enzymes tune T cell signaling and T cell function, elucidating the molecular mechanisms by which these proteins modulate T cells has met with significant challenges. Identifying substrates of these enzymes has been a particular challenge, and thus substrates of many E3 ligases and deubiquitylating enzymes remain largely unknown. To that end, we discuss the promise, and some practical considerations, of using proteomics-based techniques for unbiased identification of putative substrates of ubiquitin cascade proteins within primary T cells. These methods provide an exciting opportunity for further defining how TCR signals are regulated and for identifying new targets for therapeutic modulation. PMID- 26732670 TI - Retrospective Analyses of Esophageal Bypass Surgery for Patients with Esophagorespiratory Fistulas Caused by Esophageal Carcinomas. AB - BACKGROUND: Esophagorespiratory fistula (ERF) caused by esophageal carcinoma is a fatal complication. In our institution, esophageal bypass surgery has been indicated when possible. We herein retrospectively describe the clinical results of esophageal bypass surgery for ERF. PATIENTS AND METHODS: Between April 2001 and March 2015, 20 patients with ERF underwent esophageal bypass surgery. For these patients, the clinical safety, validity, and effectiveness of esophageal bypass surgery were examined and compared with the results of bypass surgery without ERF. RESULTS: Eight patients developed ERF at the initial diagnosis, while 10 patients developed ERF during and after chemoradiotherapy. Postoperative complications such as pneumonia, surgical site infection, and anastomotic leakage developed in 12, 5, and 1 patient, respectively. All the patients could eat solid foods at a median of 9 postoperative days. Two patients died within 30 days after the operation and 1 patient developed in-hospital death. Fourteen patients received chemo(radio)therapy after the operation. The median overall survival was 244 days and the one-year and three-year overall survival rates were 45.7 and 15.3 %, respectively. There was no significant difference in terms of the intraoperative findings, postoperative morbidities, and short-term and long-term clinical results between the two groups. CONCLUSION: Esophageal bypass surgery for ERF is not considered to be highly invasive or risky compared with bypass surgery without ERF. After the operation, respiratory symptoms caused by ERF may improve and oral intake can be achieved. Esophageal bypass surgery should therefore be aggressively performed for patients with a tolerable performance status. PMID- 26732672 TI - 3-Methyl-4,5-dihydro-oxepine, polyoxygenated seco-cyclohexenes and cyclohexenes from Uvaria flexuosa and their anti-inflammatory activity. AB - The phytochemical investigation of the methanolic extract of Uvaria flexuosa (Annonaceae) leaves led to the isolation of seven compounds including, 3-methyl 4,5-dihydro-oxepine (flexuvaroxepine A), four polyoxygenated seco-cyclohexene (flexuvarin A-D) and two polyoxygenated cyclohexene (flexuvarol A-B) derivatives, together with four known flavones. The structures of the isolated compounds were elucidated using different spectroscopic techniques. A plausible biogenetic route of the new compounds was discussed. The anti-inflammatory activity of the isolated compounds was evaluated by superoxide anion generation and elastase release assays. Among the tested compounds, flexuvarol B and chrysin showed the most potent anti-inflammatory effect by inhibiting superoxide anion generation and elastase release from human neutrophils in response to fMLP with IC50 2.25 5.55MUM. Moreover, 5-hydroxy-6,7-dimethoxy-flavone showed selective inhibitory activity on superoxide anion generation (IC50=1.19+/-0.34MUM). PMID- 26732673 TI - Multiple Concomitant Injuries in One Upper Extremity: A Case Report. AB - BACKGROUND: This report is about unusual multiple upper extremity concomitant injuries in an adult after a fall from a height. To the best of our knowledge this is the first reported case of concomitant ipsilateral occurrence of multiple common injuries, uncommonly occurring together in a single traumatic episode. CASE REPORT: A 36-year-old right-handed man fell through a skylight to the floor about 4 meters below. He presented with multiple concomitant injuries in his right upper extremity: elbow dislocation with radial head fracture associated with distal radius, ulnar styloid, and scaphoid fractures. CONCLUSIONS: The probable mechanism of injury along with the surgical treatment of these previously undescribed injuries is discussed to emphasize the need to clinically examine the whole upper extremity in severe injuries. The awareness of such an association for early recognition is paramount for excellent clinical results. PMID- 26732671 TI - Balancing workload, motivation and job satisfaction in Rwanda: assessing the effect of adding family planning service provision to community health worker duties. AB - BACKGROUND: Task shifting from higher cadre providers to CHWs has been widely adopted to address healthcare provider shortages, but the addition of any service can potentially add to an already considerable workload for CHWs. Objective measures of workload alone, such as work-related time and travel may not reflect howCHWs actually perceive and react to their circumstances. This study combined perception and objectivemeasures of workload to examine their effect on quality of services, worker performance, and job and clientsatisfaction. METHODS: Three hundred eighty-three CHWs from control and intervention districts, where the intervention group was trained to provide contraceptive resupply, completed diaries of work-related activities for one month. Interviews were also conducted with a subset of CHWs and their clients. RESULTS: CHW diaries did not reveal significant differences between intervention and control groups in time spent on service provision or travel. Over 90% of CHWs reported workload manageability, job satisfaction, and motivation to perform their jobs. Clients were highly satisfied with CHW services and most stated preference for future services from CHWs. CONCLUSION: The study demonstrated that adding resupply of hormonal contraceptives to CHWs' tasks would not place undue burden on them. Accordingly, the initiative was scaled up in all 30 districts in the country. PMID- 26732674 TI - Human cathelicidin, LL-37, inhibits respiratory syncytial virus infection in polarized airway epithelial cells. AB - BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract illness in young children worldwide. Treatment options for severe RSV disease remain limited and the development of therapeutic treatment strategies remains a priority. LL-37, a small cationic host defense peptide involved in anti-inflammatory and anti-bacterial responses, reduces replication of or infection by multiple viruses, including influenza virus, in vitro, and protects against lethal challenge with influenza virus in vivo. LL-37 also protects against RSV infection of HEp-2 cells in vitro; however, HEp-2 are not reflective of polarized airway epithelial cells and respond differently to RSV infection. An air-liquid interface (ALI) Calu-3 model that more closely mimics the human airway epithelium was established. Using this in vitro model, the effectiveness of LL-37 in preventing RSV infection and replication was examined. RESULTS: LL-37, when pre-incubated with virus prior to RSV infection (prophylactic), significantly reduced the level of viral genome detected in infected Calu-3 cells, and decreased chemokine expression associated with RSV infection in vitro. In contrast, therapeutic treatment of RSV-infected ALI Calu-3 at 24 h and 3 days post-infection had minimal impact on RSV infection. CONCLUSIONS: Differences in the efficacy of LL-37 at reducing RSV infection under prophylactic and therapeutic conditions may in part be ascribed to differences in the method of peptide exposure. However, the efficacy of LL-37 at reducing RSV infection under prophylactic conditions indicates that further studies examining the efficacy of LL-37 as a small peptide inhibitor of RSV are warranted. PMID- 26732675 TI - IL-10 downregulates CXCR3 expression on Th1 cells and interferes with their migration to intestinal inflammatory sites. AB - Inflammatory bowel disease (IBD) is characterized by chronic, uncontrolled inflammation in the intestinal mucosa. Although the etiology is poorly understood, it is widely accepted that loss of tolerance is involved in the development of IBD. Therefore, re-establishing tolerance or gut homeostasis is one of the key features in the development of new therapeutic strategies. Here we show that antigen targeting to DEC-205 on dendritic cells leads to an interleukin (IL)-10-dependent downregulation of C-X-C chemokine receptor 3 (CXCR3) expression on differentiated antigen-specific T helper type 1 (Th1) cells in vivo. This downregulation interferes with the migration of Th1 cells into the gut and protects mice against severe acute and relapsing intestinal inflammation. Moreover, CD4(+)CXCR3(+) T cells are highly enriched in the inflamed mucosa of IBD patients. Interference with this pathway may therefore be a promising approach for the treatment of IBD. In conclusion, we propose a hitherto undescribed mechanism by which IL-10 can act on effector T cells and orchestrate intestinal immune responses. PMID- 26732676 TI - Characterization of the human immune cell network at the gingival barrier. AB - The oral mucosa is a barrier site constantly exposed to rich and diverse commensal microbial communities, yet little is known of the immune cell network maintaining immune homeostasis at this interface. We have performed a detailed characterization of the immune cell subsets of the oral cavity in a large cohort of healthy subjects. We focused our characterization on the gingival interface, a particularly vulnerable mucosal site, with thin epithelial lining and constant exposure to the tooth adherent biofilm. In health, we find a predominance of T cells, minimal B cells, a large presence of granulocytes/neutrophils, a sophisticated network of professional antigen-presenting cells (APCs), and a small population of innate lymphoid cells (ILCs) policing the gingival barrier. We further characterize cellular subtypes in health and interrogate shifts in immune cell populations in the common oral inflammatory disease periodontitis. In disease, we document an increase in neutrophils and an upregulation of interleukin-17 (IL-17) responses. We identify the main source of IL-17 in health and Periodontitis within the CD4(+) T-cell compartment. Collectively, our studies provide a first view of the landscape of physiologic oral immunity and serve as a baseline for the characterization of local immunopathology. PMID- 26732677 TI - Neutrophil interactions with epithelial-expressed ICAM-1 enhances intestinal mucosal wound healing. AB - A characteristic feature of gastrointestinal tract inflammatory disorders, such as inflammatory bowel disease, is polymorphonuclear neutrophil (PMN) transepithelial migration (TEM) and accumulation in the gut lumen. PMN accumulation within the intestinal mucosa contributes to tissue injury. Although epithelial infiltration by large numbers of PMNs results in mucosal injury, we found that PMN interactions with luminal epithelial membrane receptors may also play a role in wound healing. Intercellular adhesion molecule-1 (ICAM-1) is a PMN ligand that is upregulated on apical surfaces of intestinal epithelial cells under inflammatory conditions. In our study, increased expression of ICAM-1 resulted in enhanced PMN binding to the apical epithelium, which was associated with reduced PMN apoptosis. Following TEM, PMN adhesion to ICAM-1 resulted in activation of Akt and beta-catenin signaling, increased epithelial-cell proliferation, and wound healing. Such responses were ICAM-1 dependent as engagement of epithelial ICAM-1 by antibody-mediated cross-linking yielded similar results. Furthermore, using an in-vivo biopsy-based, colonic-mucosal injury model, we demonstrated epithelial ICAM-1 has an important role in activation of epithelial Akt and beta-catenin signaling and wound healing. These findings suggest that post-migrated PMNs within the intestinal lumen can regulate epithelial homeostasis, thereby identifying ICAM-1 as a potential therapeutic target for promoting mucosal wound healing. PMID- 26732681 TI - Iatrogenic menopause following gynecological malignancy: time for action! PMID- 26732680 TI - Safety Issues Regarding Prescription Opioids. PMID- 26732678 TI - A dendritic cell targeted vaccine induces long-term HIV-specific immunity within the gastrointestinal tract. AB - Despite significant therapeutic advances for HIV-1 infected individuals, a preventative HIV-1 vaccine remains elusive. Studies focusing on early transmission events, including the observation that there is a profound loss of gastrointestinal (GI) CD4(+) T cells during acute HIV-1 infection, highlight the importance of inducing HIV-specific immunity within the gut. Here we report on the generation of cellular and humoral immune responses in the intestines by a mucosally administered, dendritic cell (DC) targeted vaccine. Our results show that nasally delivered alpha-CD205-p24 vaccine in combination with polyICLC, induced polyfunctional immune responses within naso-pulmonary lymphoid sites that disseminated widely to systemic and mucosal (GI tract and the vaginal epithelium) sites. Qualitatively, while alpha-CD205-p24 prime-boost immunization generated CD4(+) T-cell responses, heterologous prime-boost immunization with alpha-CD205 p24 and NYVAC gag-p24 generated high levels of HIV-specific CD4(+) and CD8(+) T cells within the GI tract. Finally, DC-targeting enhanced the amplitude and longevity of vaccine-induced immune responses in the GI tract. This is the first report of a nasally delivered, DC-targeted vaccine to generate HIV-specific immune responses in the GI tract and will potentially inform the design of preventative approaches against HIV-1 and other mucosal infections. PMID- 26732679 TI - Rhinovirus inhibits IL-17A and the downstream immune responses in allergic asthma. AB - The proinflammatory cytokine interleukin-17A (IL-17A) is known to mediate antimicrobial activity, but its role during rhinovirus (RV) infections and in asthma needs further investigation. Therefore, we addressed the role of IL-17A during allergic asthma and antiviral immune response in human and murine immunocompetent cells. In this study we found that asthmatic children with a RV infection in their upper airways have upregulated mRNA levels of the antiviral cytokine interferon type I (IFN)-beta and the transcription factor T-box 21 (TBX21) and reduced levels of IL-17A protein in their peripheral blood mononuclear cells (PBMCs). We also found that IL-17A inhibited RV1b replication in infected human lung epithelial cells A549. Furthermore, by using gene array analysis we discovered that targeted deletion of Il17a in murine lung CD4(+) T cells impaired Oas1g mRNA downstream of Ifnbeta, independently from RV infection. Additionally, in PBMCs of children with a RV infection in their nasalpharyngeal fluid OAS1 gene expression was found downregulated. Finally RV1b inhibited IL-17A production in lung CD4(+) T cells in a setting of experimental asthma. These results indicate that the RV1b inhibits IL-17A in T helper type 17 cells and IL 17A clears RV1b infection in epithelial cells. In both cases IL-17A contributes to fend off RV1b infection by inducing genes downstream of interferon type I pathway. PMID- 26732682 TI - The influence of body fat distribution patterns and body mass index on MENQOL in women living in an urban area. AB - OBJECTIVES: To investigate the influence of patterns of body fat distribution and body mass index (BMI) on menopause-specific quality of life in peri- and postmenopausal women living in an urban area. METHODS: A total of 214 peri- and postmenopausal women, mean age 55 years, with intact uterus and no history of hormonal treatment were recruited. Anthropometric measurements were conducted as standard techniques. The Menopause-specific Quality of Life (MENQOL) questionnaire was used to evaluate menopause-specific quality of life. The Mann Whitney U test and Kruskal-Wallis test were used to compare MENQOL between body fat patterns or BMI. RESULTS: According to the body fat distribution patterns, 53.3% were women of the android type and 46.7% were of the gynoid type. The android body pattern was associated with worsening of vasomotor and psychosocial domains (p < 0.05). However, overweight and obese women had slightly better scores in the sexual domain of the MENQOL. CONCLUSIONS: Peri- and postmenopausal women with the android body pattern have lower quality of life in the vasomotor and psychosocial domains while women with normal BMI have the slightly lower quality of life in the sexual domain. The maintenance of premenopausal body proportion might mitigate the menopause-specific quality of life. PMID- 26732684 TI - Will dapivirine redeem the promises of anti-HIV microbicides? Overview of product design and clinical testing. AB - Microbicides are being developed in order to prevent sexual transmission of HIV. Dapivirine, a non-nucleoside reverse transcriptase inhibitor, is one of the leading drug candidates in the field, currently being tested in various dosage forms, namely vaginal rings, gels, and films. In particular, a ring allowing sustained drug release for 1month is in an advanced stage of clinical testing. Two parallel phase III clinical trials are underway in sub-Saharan Africa and results are expected to be released in early 2016. This article overviews the development of dapivirine and its multiple products as potential microbicides, with particular emphasis being placed on clinical evaluation. Also, critical aspects regarding regulatory approval, manufacturing, distribution, and access are discussed. PMID- 26732683 TI - Pharmacokinetics of mefloquine and its effect on sulfamethoxazole and trimethoprim steady-state blood levels in intermittent preventive treatment (IPTp) of pregnant HIV-infected women in Kenya. AB - BACKGROUND: Intermittent preventive treatment in pregnancy with sulfadoxine/pyrimethamine is contra-indicated in HIV-positive pregnant women receiving sulfamethoxazole/trimethoprim prophylaxis. Since mefloquine is being considered as a replacement for sulfadoxine/pyrimethamine in this vulnerable population, an investigation on the pharmacokinetic interactions of mefloquine, sulfamethoxazole and trimethoprim in pregnant, HIV-infected women was performed. METHODS: A double-blinded, placebo-controlled study was conducted with 124 HIV infected, pregnant women on a standard regimen of sulfamethoxazole/trimethoprim prophylaxis. Seventy-two subjects received three doses of mefloquine (15 mg/kg) at monthly intervals. Dried blood spots were collected from both placebo and mefloquine arms four to 672 h post-administration and on day 7 following a second monthly dose of mefloquine. A novel high-performance liquid chromatographic method was developed to simultaneously measure mefloquine, sulfamethoxazole and trimethoprim from each blood spot. Non-compartmental methods using a naive-pooled data approach were used to determine mefloquine pharmacokinetic parameters. RESULTS: Sulfamethoxazole/trimethoprim prophylaxis did not noticeably influence mefloquine pharmacokinetics relative to reported values. The mefloquine half life, observed clearance (CL/f), and area-under-the-curve (AUC0->infinity) were 12.0 days, 0.035 l/h/kg and 431 ug-h/ml, respectively. Although trimethoprim steady-state levels were not significantly different between arms, sulfamethoxazole levels showed a significant 53% decrease after mefloquine administration relative to the placebo group and returning to pre-dose levels at 28 days. CONCLUSIONS: Although a transient decrease in sulfamethoxazole levels was observed, there was no change in hospital admissions due to secondary bacterial infections, implying that mefloquine may have provided antimicrobial protection. PMID- 26732685 TI - 2-Methoxyestradiol, an endogenous 17beta-estradiol metabolite, inhibits microglial proliferation and activation via an estrogen receptor-independent mechanism. AB - 17beta-Estradiol (estradiol) inhibits microglia proliferation. 2-Methoxyestradiol (2-ME) is an endogenous metabolite of estradiol with little affinity for estrogen receptors (ERs). We hypothesize that 2-ME inhibits microglial proliferation and activation and contributes to estradiol's inhibitory effects on microglia. We compared the effects of estradiol, 2-hydroxyestradiol [2-OE; estradiol metabolite produced by cytochrome P450 (CYP450)], and 2-ME [formed by catechol-O methyltransferase (COMT) acting upon 2-OE] on microglial (BV2 cells) DNA synthesis, cell proliferation, activation, and phagocytosis. 2-ME and 2-OE were approximately three- and 10-fold, respectively, more potent than estradiol in inhibiting microglia DNA synthesis. The antimitogenic effects of estradiol were reduced by pharmacological inhibitors of CYP450 and COMT. Inhibition of COMT blocked the conversion of 2-OE to 2-ME and the antimitogenic effects of 2-OE but not 2-ME. Microglia expressed ERbeta and GPR30 but not ERalpha. 2,3-Bis(4 hydroxyphenyl)-propionitrile (ERbeta agonist), but not 4,4',4''-(4-propyl-[1H] pyrazole-1,3,5-triyl)trisphenol (ERalpha agonist) or G1 (GPR30 agonist), inhibited microglial proliferation. The antiproliferative effects of estradiol, but not 2-OE or 2-ME, were partially reversed by ICI-182,780 (ERalpha/beta antagonist) but not by 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2 piperidinylethoxy)phenol]-1H-pyrazole (ERalpha antagonist) or G15 (GPR30 antagonist). Lipopolysaccharide increased microglia iNOS and COX-2 expression and phagocytosing activity of microglia; these effects were inhibited by 2-ME. We conclude that in microglia, 2-ME inhibits proliferation, proinflammatory responses, and phagocytosis. 2-ME partially mediates the effects of estradiol via ER-independent mechanisms involving sequential metabolism of estradiol to 2-OE and 2-ME. 2-ME could be of potential therapeutic use in postischemic stroke injuries. Interindividual differences in estradiol metabolism might affect the individual's ability to recover from stroke. PMID- 26732687 TI - Diabetic cardiomyopathy: role of the E3 ubiquitin ligase. AB - Diabetic cardiomyopathy (DCM) is the leading cause of mortality in diabetes. As the number of cases of diabetes continues to rise, it is urgent to develop new strategies to protect against DCM, which is characterized by cardiac hypertrophy, increased apoptosis, fibrosis, and altered insulin metabolism. The E3 ubiquitin ligases (E3s), one component of the ubiquitin-proteasome system, play vital roles in all of the features of DCM listed above. They also modulate the activity of several transcription factors involved in the pathogenesis of DCM. In addition, the E3s degrade both insulin receptor and insulin receptor substrates and also regulate insulin gene transcription, leading to insulin resistance and insulin deficiency. Therefore, the E3s may be a driving force for DCM. This review summarizes currently available studies to analyze the roles of the E3s in DCM, enriches our knowledge of how DCM develops, and provides a novel strategy to protect heart from diabetes. PMID- 26732688 TI - Influence of sumanene modifications with boron and nitrogen atoms to its hydrogen adsorption properties. AB - We investigate the influence of sumanene modifications on its adsorption properties towards the hydrogen molecule. The benzylic positions of sumanene were substituted with boron and nitrogen atoms, which changed its hydrogen storage properties. H2 binding energies were calculated using the LMP2, DFT and DFT-D3 approaches with several exchange-correlation functionals and the results indicate a physisorption mechanism. Physisorption was confirmed by fragment analysis and special attention was paid to non-covalent interactions. All non-covalent interactions, based on reduced density gradient surfaces, were identified and calculated for better understanding of the adsorption mechanism. Moreover, the significance of charge separation by inducing boron and nitrogen atoms is emphasized and special attention is paid to the z-component of the dipole moment of sumanene derivatives. PMID- 26732686 TI - Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer. AB - Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16-[(18)F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([(11)C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin + glucose euglycemic clamp conditions (120 mU.m(-2).min(-1)) to 3-h saline infusion. Lean controls (n = 10) were compared with glycemically controlled volunteers with T2DM (n = 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P < 0.01) and significantly increased myocardial oxygen consumption (P = 0.04) and perfusion (P = 0.01) in both groups. Insulin suppressed available nonesterified fatty acids (P < 0.0001), but fatty acid concentrations were higher in T2DM under both conditions (P < 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups (P < 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM (P = 0.003). Myocardial work efficiency was lower in T2DM (P = 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization (P = 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM. PMID- 26732689 TI - Looking into the crystal ball: biomarkers for outcomes of HBV infection. PMID- 26732690 TI - Improving pain assessment and managment in stroke patients. AB - Stroke patients can experience a variety of pain. Many stroke patients have co morbidities such as osteoporosis, arthritis or diabetes causing diabetic neuropathy. As well as pain from other long term conditions, stroke patients can experience central post-stroke pain, headaches, and musculoskeletal issues such as hypertonia, contractures, spasticity, and subluxations. These stroke patients can also have communication difficulties in the form of expressive dysphasia and/or global aphasia. Communication difficulties can result in these patients not expressing their pain and therefore not having it assessed, leading to inadequate pain relief that could impact their rehabilitation and recovery. By implementing an observational measurement of pain such as the Abbey pain scale, patients with communication difficulties can have their pain assessed and recorded. Initially 30% of patients on the acute stroke ward did not have their pain assessed and adequately recorded and 15% of patients had inadequate pain relief. The patient was assessed if they were in pain and therefore not receiving adequate pain relief by measuring their pain on the Abbey pain scale. After introducing the Abbey pain scale and creating a nurse advocate, an improvement was shown such that only 5% of patients did not have their pain recorded and all had adequate pain relief. PMID- 26732692 TI - NHS choir's number one hit puts health service in media spotlight over Christmas. PMID- 26732691 TI - Regression approaches in the test-negative study design for assessment of influenza vaccine effectiveness. AB - Influenza vaccination is the most practical means available for preventing influenza virus infection and is widely used in many countries. Because vaccine components and circulating strains frequently change, it is important to continually monitor vaccine effectiveness (VE). The test-negative design is frequently used to estimate VE. In this design, patients meeting the same clinical case definition are recruited and tested for influenza; those who test positive are the cases and those who test negative form the comparison group. When determining VE in these studies, the typical approach has been to use logistic regression, adjusting for potential confounders. Because vaccine coverage and influenza incidence change throughout the season, time is included among these confounders. While most studies use unconditional logistic regression, adjusting for time, an alternative approach is to use conditional logistic regression, matching on time. Here, we used simulation data to examine the potential for both regression approaches to permit accurate and robust estimates of VE. In situations where vaccine coverage changed during the influenza season, the conditional model and unconditional models adjusting for categorical week and using a spline function for week provided more accurate estimates. We illustrated the two approaches on data from a test-negative study of influenza VE against hospitalization in children in Hong Kong which resulted in the conditional logistic regression model providing the best fit to the data. PMID- 26732693 TI - Endoscopic dacryocystorhinostomy with and without silicone intubation: 4 years retrospective study. AB - The objective of this study is to assess different outcomes between endoscopic dacryocystorhinostomy (En-DCR) with and without silicone intubation. We retrospectively analyzed 84 patients (89 procedures), suffering from chronic epiphora for primary acquired nasolacrimal duct obstruction, treated with En-DCR and divided into two groups depending on silicone stent intubation. The surgical outcomes were evaluated at 7 post-operative controls using Munk's score criteria. Functional success was defined as absence of epiphora, no further episodes of dacryocystitis, and a patent ostium after fluorescein irrigation. 45 En-DCR with stent and 44 En-DCR without stent were performed. Success rate after 18 months follow-up were, respectively, 82.2 % in the stent group and 88.6 % in the non stent group (OR 0.59) with no statistical differences. The ostial size reduction has been reported in higher percentage in the stent group, mainly due to peristomal granuloma (OR 3.64), scar tissue formation (OR 2.25), and turbinoseptal synaechia (OR 1.76). The benefits of non-intubation are less patient discomfort, reduced surgical time and costs, simpler follow-up regimen and less intubation-associated complications. En-DCR without silicone stent intubation should be the first choice of procedure, stent intubation should be reserved in selected cases with poor local conditions pre and intra-operatively assessed. PMID- 26732695 TI - Comparative erythromycin and tylosin susceptibility testing of streptococci from bovine mastitis. AB - Tylosin, a 16-membered macrolide, is - besides other indications - used for the treatment of bovine mastitis. So far, there is only limited information available on the tylosin susceptibility of streptococci isolated from mastitis. The aim of the present study was to comparatively investigate 303 streptococci from bovine mastitis, including 101 Streptococcus agalactiae, 100 Streptococcus dysgalactiae and 102 Streptococcus uberis, for their tylosin and erythromycin susceptibility by broth microdilution and agar disk diffusion. Both tests followed the recommendations of the Clinical and Laboratory Standards Institute (CLSI). For erythromycin, the results were interpreted using the CLSI-approved clinical breakpoints. Moreover, erythromycin-resistant isolates were tested for the presence of macrolide resistance genes and for inducible macrolide resistance. In general, both testing methods showed a good correlation for the three streptococcal species, although for the erythromycin susceptibility testing 11 S. uberis isolates fell into the very major error category. All but one of the erythromycin-resistant isolates harbored at least one macrolide resistance gene, with the erm(B) gene being most common. Moreover, single isolates of S. agalactiae and S. dysgalactiae proved to be inducibly macrolide-resistant. Since inducible macrolide resistance can easily switch to constitutive resistance, tylosin should not be used for the treatment of infections caused by inducibly resistant streptococci. PMID- 26732694 TI - Comparison of GlideScope video laryngoscopy and Macintosh laryngoscope in ear nose and throat surgery. AB - AIM: Endotracheal intubation procedure employed during general anaesthesia is the most effective way for keeping the airways and respiration under control and has low risk of complications. We have aimed in this study to compare the first attempt success and duration of the endotracheal intubation process and its effects on haemodynamics using the Macintosh laryngoscope and the GlideScope video laryngoscope. METHODS: In this prospective randomized single-centre study, 100 patients of 18-65 years of age, and classified within the American Society of Anaesthesiologists' (ASA) I-II risk groups before elective ear-nose and throat surgery were included. The patients were randomly divided into two groups, designated as Group M, to be intubated using the Macintosh laryngoscope, and as Group G, to be intubated using the GlideScope video laryngoscope. The Mallampati scores, Cormack-Lehane classifications, intubation duration, number of attempts at intubation, the haemodynamic response and the complications were recorded. RESULTS: There were not intergroup differences with respect to the number of intubation attempts, the Mallampati and Cormack-Lehane classifications. Duration of intubation was found to be longer in group G. The haemodynamic response values of group M were higher than those of group G. Although there was no statistically significant difference between the two groups in the number of intubation attempts, two of the patients in group M were intubated in the second attempt. CONCLUSION: In our study, despite the longer intubation times in group G, the haemodynamic response was significantly lower in this group. It is believed that especially in cases with vital requirement of haemodynamic stability, the GlideScope video laryngoscope would be safer to employ. PMID- 26732696 TI - Measurement of wheelchair contact force with a low cost bench test. AB - In mechanical engineering, it is well established that contact between the tire and the ground is a key parameter in characterizing the dynamic behavior of vehicles and an important factor in design control. Therefore, it is an important part of dynamic simulation models for vehicles, including wheelchairs. This work presents a bench test designed to experimentally monitor and measure the forces transmitted to the ground by a moving wheel. The test bench is composed of a table and a track with a fixed wheel structure and powertrain system. The table is an integrated structure that measures the longitudinal and lateral forces produced by tire contact. This table allows characterization of the tire and tests the tire under varying loads at different slip and camber angles. Additionally, the test bench can also be used to evaluate other tires, such as caster tires. The performances of the new device are illustrated, and the results show the differences between tires, which are related to the dynamic behaviors of wheelchair model. Finally, preliminary experiments performed using the test bench have shown that it is able to monitor and measure the forces generated by the contact between the tire and the ground. PMID- 26732697 TI - Improving electronic information sharing for palliative care patients. AB - Coordination of services used by palliative care patients across care contexts is essential in providing patient centred care. In Lothian, Edinburgh, a baseline audit in 2008 of patients known to all four specialist palliative care teams revealed only 49% had information available to out of hours (OOH) general practitioners (GPs). This highlighted the poor handover and sharing of information, which are essential for providing quality care for palliative patients in accordance with their wishes, and for reducing inappropriate hospital admissions. A number of quality improvement measures have been introduced, some nationally in Scotland, such as the roll out of Electronic Palliative Care Summaries (ePCS) - an electronic register containing up to date information including patient wishes and latest treatment decisions. In addition there have been changes to the GP Quality Outcomes Framework encouraging the use of electronic records. Locally, at Marie Curie Hospice, drivers were implemented including hosting GP education evenings promoting ePCS use, alteration of hospice discharge letter format to complement ePCS completion, in addition to offering specialist nurse support and presence at GP practice palliative care register meetings. A re-audit in 2012 revealed that 75% of specialist palliative care patients had electronic information available to OOH services, and in 2013, 71% of patients. This represents a significant improvement in electronic information sharing across care contexts. Building on the progress of ePCS, a new Electronic Key Information Summary is currently being rolled out across Scotland. This quality improvement report reflects on the positive measures taken to address the important clinical need of effective electronic handover for specialist palliative care patients in Lothian. Furthermore, it highlights the ongoing requirement to continue to improve the quality and availability of electronically shared information for every patient known to palliative care services across care contexts. PMID- 26732698 TI - Transcriptomic profiles reveal the genome-wide responses of the harmful dinoflagellate Cochlodinium polykrikoides when exposed to the algicide copper sulfate. AB - BACKGROUND: Harmful algal blooms (HABs) caused by the dinoflagellate Cochlodinium polykrikoides lead to severe environmental impacts in oceans worldwide followed by huge economic losses. Algicide agent copper sulfate (CuSO4) is regard as an economical and effective agent for HABs mitigation; its biochemical and physiological effects were revealed in C. polykrikoides. However, molecular mechanisms of CuSO4 effect on the C. polykrikoides, even other HAB species, have not been investigated. The present study investigated the transcriptional response of C. polykrikoides against CuSO4 treatments, with the aim of providing certain molecular mechanism of CuSO4 effect on the C. polykrikoides blooms. RESULTS: RNA-seq generated 173 million reads, which were further assembled to 191,212 contigs. 43.3 %, 33.9 %, and 15.6 % of contigs were annotated with NCBI NR, GO, and KEGG database, respectively. Transcriptomic analysis revealed 20.6 % differential expressed contigs, which grouped into 8 clusters according to K means clustering analysis, responding to CuSO4; 848 contigs were up-regulated and 746 contigs were down-regulated more than 2-fold changes from 12 h to 48 h exposure. KEGG pathway analysis of eukaryotic homologous genes revealed the differentially expressed genes (DEGs) were involved in diverse pathway; amongst, the genes involved in the translation, spliceosome, and/or signal transduction genes were highly regulated. Most of photosystem related genes were down regulated and most of mitochondria related genes were up-regulated. In addition, the genes involved in the copper ion binding or transporting and antioxidant systems were identified. Measurement of chlorophyll fluorescence showed that photosynthesis was significantly inhibited by CuSO4 exposure. CONCLUSIONS: This study reported the first transcriptome of the C. polykrikoides. The widely differential expressed photosystem genes suggested photosynthetic machinery were severely affected, and may further contribute to the cell death. Furthermore, gene translation and transcription processes may be disrupted, inhibiting cell growth and proliferation, and possibly accelerating cell death. However, antioxidant systems resistant to CuSO4 caused stress; mitochondrion may compensate for photosynthesis efficiency decreasing caused energy deficiency. In addition, various signal transduction pathways may be involved in the CuSO4 induced regulation network in the C. polykrikoides. These data provide the potential transcriptomic mechanism to explain the algicide CuSO4 effect on the harmful dinoflagellate C. polykrikoides. PMID- 26732700 TI - Molecular Screening for Vel- Blood Donors in Southwestern Germany. AB - BACKGROUND: The SMIM1 protein carries the Vel blood group antigen, and homozygosity for a 17 bp deletion in the coding region of the SMIM1 gene represents the molecular basis of the Vel- blood group phenotype. We developed PCR-based methods for typing the SMIM1 17 bp (64-80del) gene deletion and performed a molecular screening for the Vel- blood type in German blood donors. METHODS: For SMIM1 genotyping, TaqMan-PCR and PCR-SSP methods were developed and validated using reference samples. Both methods were used for screening of donors with blood group O from southwestern Germany. Heterozygotes and homozygotes for the SMIM1 64-80del allele were serologically typed for the Vel blood group antigen. In addition, the rs1175550 SNP in SMIM1 was typed and correlated to the results of the phenotyping. RESULTS: Both genotyping methods, TaqMan-PCR and PCR SSP, represent reliable methods for the detection of the SMIM1 64-80del allele. Screening of 10,598 blood group O donors revealed 5 individuals homozygous for the deletional allele. They were confirmed Vel- by serological typing. Heterozygotes for the 64-80del allele showed different antigen expressions ranging from very weak to regular positive. CONCLUSION: Molecular screening of blood donors for the Vel- blood type is feasible and avoids the limitations of serological typing which might show false-negative results with heterozygous individuals. The identification of Vel- blood donors significantly contributes to the adequate blood supply of patients with anti-Vel. PMID- 26732699 TI - The role of the ribosome in the regulation of longevity and lifespan extension. AB - The most energy-consuming process that a cell must undertake to stay viable is the continuous biogenesis of ribosomes for the translation of RNA into protein. Given the inextricable links between energy consumption and cellular lifespan, it is not surprising that mutations and environmental cues that reduce ribosome biogenesis result in an extension of eukaryotic lifespan. This review goes into detail describing recent discoveries of different and often unexpected elements that play a role in the regulation of longevity by virtue of their ribosome biogenesis functions. These roles include controlling the transcription and processing of ribosomal RNA (rRNA), the translation of ribosomal protein (RP) genes, and the number of ribosomes overall. Together these findings suggest that a fundamental mechanism across eukaryotic species for extending lifespan is to slow down or halt the expenditure of cellular energy that is normally absorbed by the manufacturing and assembly of new ribosomes. PMID- 26732701 TI - Fluctuations in Electronic Energy Affecting Singlet Fission Dynamics and Mixing with Charge-Transfer State: Quantum Dynamics Study. AB - Singlet fission is a spin-allowed process by which a singlet excited state is converted to two triplet states. To understand mechanisms of the ultrafast fission via a charge transfer (CT) state, one has investigated the dynamics through quantum-dynamical calculations with the uncorrelated fluctuation model; however, the electronic states are expected to experience the same fluctuations induced by the surrounding molecules because the electronic structure of the triplet pair state is similar to that of the singlet state except for the spin configuration. Therefore, the fluctuations in the electronic energies could be correlated, and the 1D reaction coordinate model may adequately describe the fission dynamics. In this work we develop a model for describing the fission dynamics to explain the experimentally observed behaviors. We also explore impacts of fluctuations in the energy of the CT state on the fission dynamics and the mixing with the CT state. The overall behavior of the dynamics is insensitive to values of the reorganization energy associated with the transition from the singlet state to the CT state, although the coherent oscillation is affected by the fluctuations. This result indicates that the mixing with the CT state is rather robust under the fluctuations in the energy of the CT state as well as the high-lying CT state. PMID- 26732702 TI - Multipurpose effectiveness of Couroupita guianensis-synthesized gold nanoparticles: high antiplasmodial potential, field efficacy against malaria vectors and synergy with Aplocheilus lineatus predators. AB - Mosquito-borne diseases represent a deadly threat for millions of people worldwide. According to recent estimates, about 3.2 billion people, almost half of the world's population, are at risk of malaria. Malaria control is particularly challenging due to a growing number of chloroquine-resistant Plasmodium and pesticide-resistant Anopheles vectors. Newer and safer control tools are required. In this research, gold nanoparticles (AuNPs) were biosynthesized using a cheap flower extract of Couroupita guianensis as reducing and stabilizing agent. The biofabrication of AuNP was confirmed by UV-vis spectrophotometry, Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), energy-dispersive X-ray (EDX) spectroscopy, X-ray diffraction (XRD), zeta potential, and particle size analysis. AuNP showed different shapes including spheres, ovals, and triangles. AuNPs were crystalline in nature with face-centered cubic geometry; mean size was 29.2-43.8 nm. In laboratory conditions, AuNPs were toxic against Anopheles stephensi larvae, pupae, and adults. LC50 was 17.36 ppm (larva I), 19.79 ppm (larva II), 21.69 ppm (larva III), 24.57 ppm (larva IV), 28.78 ppm (pupa), and 11.23 ppm (adult). In the field, a single treatment with C. guianensis flower extract and AuNP (10 * LC50) led to complete larval mortality after 72 h. In standard laboratory conditions, the predation efficiency of golden wonder killifish, Aplocheilus lineatus, against A. stephensi IV instar larvae was 56.38 %, while in an aquatic environment treated with sub-lethal doses of the flower extract or AuNP, predation efficiency was boosted to 83.98 and 98.04 %, respectively. Lastly, the antiplasmodial activity of C. guianensis flower extract and AuNP was evaluated against CQ-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of Plasmodium falciparum. IC50 of C. guianensis flower extract was 43.21 MUg/ml (CQ-s) and 51.16 MUg/ml (CQ-r). AuNP IC50 was 69.47 MUg/ml (CQ-s) and 76.33 MUg/ml (CQ-r). Overall, our results showed the multipurpose effectiveness of C. guianensis synthesized AuNPs, since they may be proposed as newer and safer tools in the fight against CQ-r strains of P. falciparum and for field control of malaria vectors, in synergy with wonder killifish predators. PMID- 26732703 TI - Barium chloride induces redox status unbalance, upregulates cytokine genes expression and confers hepatotoxicity in rats-alleviation by pomegranate peel. AB - The present study was performed to establish the therapeutic efficacy of pomegranate peel against barium chloride induced liver injury. Adult rats were divided into four groups of six animals each: group I, serving as controls, received distilled water; group II received by their drinking water 67 ppm of BaCl2; group III received both 67 ppm of BaCl2 by the same way than group II and 5 % of pomegranate peel (PP) via diet; group IV received 5 % of PP. Analysis by HPLC/MS of PP showed its rich composition in flavonoids such as gallic acid, castalin, hyperin, quercitrin, syringic acid, and quercetin. The protective effects of pomegranate peel against hepatotoxicity induced by barium chloride were assessed using biochemical parameters and histological studies. Exposure of rats to barium caused oxidative stress in the liver as evidenced by an increase in malondialdehyde (MDA), lipid hydroperoxides (LOOHs), H2O2 and advanced oxidation protein product (AOPP) levels, and lactate dehydrogenase (LDH), gamma glutamyl transpeptidase (GGT), alanine aminotransferase (AST) and aspartate aminotransferase (ALT) activities, a decrease in catalase (CAT) and glutathione peroxidase (GPx) activities, glutathion (GSH), non-protein thiol (NPSH), vitamin C levels, and Mn-SOD gene expression. Liver total MT levels, MT-1, and MT-2 and pro-inflammatory cytokine genes expression like TNF-alpha, IL-1beta and IL-6 were increased. Pomegranate peel, supplemented in the diet of barium-treated rats, showed an improvement of all the parameters indicated above.The present work provided ethnopharmacological relevance of pomegranate peel against the toxic effects of barium, suggesting its beneficial role as a potential antioxidant. PMID- 26732704 TI - Water mutagenic potential assessment on a semiarid aquatic ecosystem under influence of heavy metals and natural radioactivity using micronuclei test. AB - The contamination of water bodies by heavy metals and ionizing radiation is a critical environmental issue, which can affect water quality and, thus, human health. This study aimed to evaluate the water quality of the Boqueirao de Parelhas Dam in the Brazilian semiarid region. A 1-year study (2013-2014) was performed through the assessment of physicochemical parameters, heavy metal content, and radioactivity along with the mutagenicity potential of water using micronuclei test in Orechromis niloticus (in vivo) and the cytokinesis-block micronucleus (CBMN) assay in human lymphocytes (in vitro). A deterioration of water organoleptics characteristics by the presence of high levels of sulfate and total solids was observed. High concentrations of aluminum, nickel, silver, and lead along with the alpha particle content were higher than the limits suggested by the World Health Organization and Brazilian legislation for drinking water. An increase in the frequency of micronuclei and nuclear abnormalities was observed in both experimental models. The results obtained confirmed the mutagenic potential present in water samples. This study highlights that geogenic agents affect water quality becoming a human health concern to be taken into account due to the relevance that this water reservoir has in the region. PMID- 26732705 TI - Metal uptake of Nerium oleander from aerial and underground organs and its use as a biomonitoring tool for airborne metallic pollution in cities. AB - The analysis of the airborne particulate matter-PM-incorporated to plant leaves may be informative of the air pollution in the surroundings, allowing their use as biomonitoring tools. Regarding metals, their accumulation in leaves can be the result of both atmospheric incorporation of metallic PM on aboveground plant organs and root uptake of soluble metals. In this study, the use of Nerium oleander leaves as a biomonitoring tool for metallic airborne pollution has been assessed. The metal uptake in N. oleander was assessed as follows: (a) for radicular uptake by irrigation with airborne metals as Pb, Cd, Cr, Ni, As, Ce and Zn (alone and in mixture) and (b) for direct leave exposure to urban PM. Plants showed a high resistance against the toxicity of metals under both single and multiple metal exposures. Except for Zn, the low values of translocation and bioaccumulation factors confirmed the excluder behaviour of N. oleander with respect to the metals provided by the irrigation. For metal uptake from airborne pollution, young plants grown under controlled conditions were deployed during 42 days in locations of the city of Zaragoza (700,000 h, NE Spain), differing in their level of traffic density. Samples of PM2.5 particles and the leaves of N. oleander were simultaneously collected weekly. High correlations in Pb concentrations were found between leaves and PM2.5; in a lesser extent, correlations were also found for Fe, Zn and Ti. Scanning electron microscopy showed the capture of airborne pollution particles in the large and abundant substomatal chambers of N. oleander leaves. Altogether, results indicate that N. Oleander, as a metal resistant plant by metal exclusion, is a suitable candidate as a biomonitoring tool for airborne metal pollution in urban areas. PMID- 26732706 TI - Two kinds of common prenatal screening tests for Down's syndrome: a systematic review and meta-analysis. AB - As the chromosomal examination of foetal cells for the prenatal diagnosis of Down's syndrome (DS) carries a risk of inducing miscarriage, serum screening tests are commonly used before invasive procedures. In this study, a total of 374 records from PubMed, EMBASE, and the ISI Science Citation Index databases were reviewed. As a result of duplication, insufficient data, and inappropriate article types, 18 independent articles containing 183,998 samples were used in the final systematic review and meta-analysis of the diagnostic performance of the serum triple screening test (STS) and the integrated screening test (INS). Data extracted from the selected studies were statistically analysed, and the presence of heterogeneity and publication bias was assessed using specific software. The overall sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and the area under the curve for the STS were 0.77 (95% confidence interval = 0.73-0.81), 0.94 (0.94-0.94), 9.78 (6.87-13.93), 0.26 (0.22-0.31), 44.72 (30.77-65.01), and 0.9064, respectively. For the INS, these values were 0.93 (0.90-0.95), 0.93 (0.93-0.93), 22.38 (12.47-40.14), 0.08 (0.05-0.11), 289.81 (169.08-496.76), and 0.9781, respectively. These results indicate that the INS exhibits better diagnostic value for DS. However, further research is needed to identify other biomarkers to improve prenatal screening tests. PMID- 26732707 TI - Glyphosate residues in rural groundwater, Nottawasaga River Watershed, Ontario, Canada. AB - BACKGROUND: The objective of this study was to investigate the occurrence of glyphosate residues (glyphosate and its metabolite AMPA) in shallow groundwater in a catchment dominated by agriculture, and to examine the potential for this groundwater to store and transmit these compounds to surface waters. RESULTS: Glyphosate residues were found in some of the groundwater samples collected in riparian (surface seeps), upland (mostly <20 m below ground) and wetland settings (<3 m below ground). Overall, glyphosate and AMPA were detected in 10.5 and 5.0%, respectively, of the groundwater samples analyzed as part of this study. All concentrations of glyphosate were well below Canadian guidelines for drinking water quality and for protection of aquatic life. Seasonal differences in concentrations in riparian seeps were possibly related to cycles of weather, herbicide application and degradation of glyphosate. Highest concentrations were at upland sites (663 ng L(-1) of glyphosate, 698 ng L(-1) of AMPA), apparently related to localized applications. Most glyphosate detections in wetlands were >0.5 km distant from possible areas of application, and, combined with other factors, suggest an atmospheric transport and deposition delivery mechanism. In both upland and wetland settings, highest glyphosate concentrations were sometimes not at the shallowest depths, indicating influence of hydrological factors. CONCLUSION: The glyphosate/AMPA detections in riparian seeps demonstrated that these compounds are persistent enough to allow groundwater to store and transmit glyphosate residues to surface waters. Detections in the wetlands support earlier evidence that atmospheric transport and deposition may lead to glyphosate contamination of environments not intended as targets of applications. This interpretation is further supported by detections of both glyphosate and AMPA in precipitation samples collected in the same watershed. (c) 2016 Her Majesty the Queen in Right of Canada Pest Management Science (c) 2016 Society of Chemical Industry. PMID- 26732708 TI - Fe2+ chelator proferrorosamine A: a gene cluster of Erwinia rhapontici P45 involved in its synthesis and its impact on growth of Erwinia amylovora CFBP1430. AB - Proferrorosamine A (proFRA) is an iron (Fe2+) chelator produced by the opportunistic plant pathogen Erwinia rhapontici P45. To identify genes involved in proFRA synthesis, transposon mutagenesis was performed. The identified 9.3 kb gene cluster, comprising seven genes, designated rosA-rosG, encodes proteins that are involved in proFRA synthesis. Based on gene homologies, a biosynthetic pathway model for proFRA is proposed. To obtain a better understanding of the effect of proFRA on non-proFRA producing bacteria, E. rhapontici P45 was co cultured with Erwinia amylovora CFBP1430, a fire-blight-causing plant pathogen. E. rhapontici P45, but not corresponding proFRA-negative mutants, led to a pink coloration of E. amylovora CFBP1430 colonies on King's B agar, indicating accumulation of the proFRA-iron complex ferrorosamine, and growth inhibition in vitro. By saturating proFRA-containing extracts with Fe2+, the inhibitory effect was neutralized, suggesting that the iron-chelating capability of proFRA is responsible for the growth inhibition of E. amylovora CFBP1430. PMID- 26732709 TI - Correction: Pyrido[1,2-a]pyrimidinium ions - a novel bridgehead nitrogen heterocycles: synthesis, characterisation, and elucidation of DNA binding and cell imaging properties. AB - Correction for 'Pyrido[1,2-a]pyrimidinium ions - a novel bridgehead nitrogen heterocycles: synthesis, characterisation, and elucidation of DNA binding and cell imaging properties' by Susanta Kumar Manna et al., Org. Biomol. Chem., 2015, 13, 8037-8047. PMID- 26732710 TI - [A personal transition: a new year, a new dress, a new brand]. PMID- 26732711 TI - [Neuroendocrine Tumors]. PMID- 26732713 TI - [Hair Analysis for the Retrospective and Prospective Consume-Monitoring: Substance Abuse, Abstinence- and Compliance Control]. AB - The possibilities and applications of modern hair analytics have rapidly developed in recent years. The compounds that can be detected in hair comprise, next to a multitude of drugs, also medications, alcohol markers, and endogenous compound like the stress hormone cortisol. Hair analysis is suitable for both forensic and clinical applications because it enables a retrospective overview of the consumption behavior during an extended time interval. PMID- 26732714 TI - [Urological Diseases in Men and their Prevention]. AB - The late-onset hypogonadism is defined as a reduction of blood testosterone values in aging males in combination with sexual symptoms. A hormone substitution is only necessary if desired by the patient. Erectile dysfunction is often caused by vasculopathy. Therefore, vascular risk factors should be evaluated. In case of cardiovascular disease a cardiologist should be addressed before initiating treatment. First line therapy consists of phosphodiesterase inhibitors. In lower urinary tract symptoms prostatic enlargement is the likely cause, but other causes have to be ruled out. Symptomatic therapy can be initiated if the patient is bothered. If voiding symptoms are predominant, alpha blockers or alpha reductase inhibitors are the treatment of choice. In case of storage symptoms, treatment can be started with muscarin receptor antagonists. PMID- 26732715 TI - [Assessment of Obstructive Sleep Apnoea in Primary Care]. AB - Obstructive sleep apnea is highly prevalent in the general population, but still the majority of patients remain undiagnosed and untreated. In primary care the diagnosis of obstructive sleep apnea should be considered in many clinical situations, especially if risk factors or typical comorbidities are present. Sleep history, daytime complaints and clinical examination in combination with screening questionnaires and screening sleep studies can help to confirm the diagnosis. PMID- 26732716 TI - [Anticonvulsive Therapy after the First Unprovoked Seizure - Pros and Cons]. AB - A first seizure is a critical life time event with severe consequences. A very thorough work-up is needed to find out the cause of the seizure and to number the risk of recurrence. Reasons for an anticonvulsive therapy are a pathologic EEG, a pathologic neurologic examination, the proof of a structural lesion, focal seizure onset or seizure onset while sleeping or classification as an epilepsy syndrome with high recurrence risk like juvenile myoclonic epilepsy or juvenile absence epilepsy. Psychological and social aspects like the patients or relatives fear of a further seizure, the risk of injury and occupational and recreational aspects must be considered as well. Reasons against an anticonvulsive therapy are mainly related to adverse effects like gain of weight and osteoporosis. PMID- 26732717 TI - [Lymphomas]. AB - Although malignant lymphoma is split in over 60 distinct entities, four of them, diffuse large B cell lymphoma, follicular-, Hodgkin's- and mantle cell lymphoma constitute more than half of all new cases. A recent major revision of the Ann Arbor staging system restricts the suffix "A" and "B" just to Hodgkin's lymphoma. Bone marrow exams are abandonned in Hodgkin's and restricted in DLBCL. PET exams at different time points are crucial. PET guided therapy will lead to a reduction of the use of chemo- and radiation therapy. Many new targeted drugs have been introduced. Their therapeutic index is impressive as is their price tag. The radiation and chemotherapy free treatment of malignant lymphoma is within reach. PMID- 26732718 TI - [Osteoarthritis of the knee improves also with nonsurgical therapy]. PMID- 26732719 TI - [Calcium administration does not reduce fracture risk or only marginally]. PMID- 26732721 TI - [Physician art column]. PMID- 26732723 TI - EV71 vaccine, a new tool to control outbreaks of hand, foot and mouth disease (HFMD). AB - On December 3rd 2015, the China Food and Drug Administration (CFDA) approved the first inactivated Enterovirus 71 (EV71) whole virus vaccine for preventing severe hand, foot and mouth disease (HFMD). As one of the few preventive vaccines for children's infectious diseases generated by the developing countries in recent years, EV71 vaccine is a blessing to children's health in China and worldwide. However, there are still a few challenges facing the worldwide use of EV71 vaccine, including the applicability against various EV71 pandemic strains in other countries, international requirements on vaccine production and quality control, standardization and harmonization on different pathogen monitoring and detecting methods, etc. In addition, the affordability of EV71 vaccine in other countries is a factor to be considered in HFMD prevention. Therefore, with EV71 vaccine commercially available, there is still a long way to go before reaching effective protection against severe HFMD after EV71 vaccines enter the market. In this paper, the bottlenecks and prospects for the wide use of EV71 vaccine after its approval are evaluated. PMID- 26732725 TI - Quantum dissipative effects on non-equilibrium transport through a single molecular transistor: The Anderson-Holstein-Caldeira-Leggett model. AB - The Anderson-Holstein model with Caldeira-Leggett coupling with environment is considered to describe the damping effect in a single molecular transistor (SMT) which comprises a molecular quantum dot (with electron-phonon interaction) mounted on a substrate (environment) and coupled to metallic electrodes. The electron-phonon interaction is first eliminated using the Lang-Firsov transformation and the spectral density function, charge current and differential conductance are then calculated using the non-equilibrium Keldysh Green function technique. The effects of damping rate, and electron-electron and electron-phonon interactions on the transport properties of SMT are studied at zero temperature. PMID- 26732724 TI - Antidepressant Drugs for Postsurgical Pain: Current Status and Future Directions. AB - Current treatments for postsurgical pain are often inadequate and adverse effects are substantial such that residual pain and/or side effects impair recovery. The recognition of analgesic efficacy with antidepressant drugs for chronic pain suggests the potential for efficacy in acute postsurgical pain. As reviewed here, current evidence suggests that approximately half of previous trials suggest efficacy of various antidepressants for acute postoperative pain. However, most trials are older with deficiencies including: lack of designation of a primary outcome, no assessment of movement-evoked pain, small size and limited safety assessment. Only one of three trials addressing prevention of chronic postsurgical pain suggested any efficacy; however, the evidence base for this indication is limited. Thus, current evidence does not yet support routine use of any one specific antidepressant for treatment of acute, or prevention of chronic, postsurgical pain. However, limitations in available trials are such that one cannot yet rule out the possibility that one or more antidepressant drugs may provide benefit in specific populations. Therefore, future larger trials should explore optimal dosing and duration of antidepressant treatment, procedure specificity, safety evaluation, and assessment of movement-evoked pain. PMID- 26732726 TI - Proteome responses of Citrobacter werkmanii BF-6 planktonic cells and biofilms to calcium chloride. AB - Calcium ions are well-known as intracellular second messengers that also have an important extracellular structural role for bacteria. Recently, we found that denser biofilms were formed by Citrobacter werkmanii BF-6 in the presence of 400 mM Ca(2+) than that of 12.5mM Ca(2+). Therefore, we employed two-dimensional (2 D) electrophoresis methods to investigate the proteome profiles of planktonic cells and biofilms in BF-6 under different concentrations of Ca(2+). Meanwhile, BF-6 biofilm architecture was also visualized with confocal laser scanning microscopy (CLSM). The results demonstrated that BF-6 biofilms formed at the bottom of microtiter plates when grown in the presence of 400 mM Ca(2+). A total of 151 proteins from planktonic cells and biofilms after exposure of BF-6 cells to 12.5 and 400 mM Ca(2+) were successfully identified. Different gene ontology (GO) and KEGG pathways were categorized and enriched for the above proteins. Growth in the presence of 400 mM Ca(2+) induced more complex signal pathways in BF-6 than 12.5mM Ca(2+). In addition, the biofilm architectures were also affected by Ca(2+). Our results show two different modes of biofilm enhancement for C. werkmanii in the presence of excess Ca(2+) and provide a preliminary expression of these differences based on proteomic assays. PMID- 26732727 TI - Seasonal proteome changes of nasal mucus reflect perennial inflammatory response and reduced defence mechanisms and plasticity in allergic rhinitis. AB - INTRODUCTION: Nasal mucus and its proteins are a defence against allergens. We sought to investigate dynamic proteome changes in allergic rhinitis upon environmental allergen provocation. METHODS: Nasal mucus was collected in and out of pollen season from allergic rhinitis patients (N=10) and healthy controls (N=12). Liquid chromatography-tandem mass spectrometry was performed. Proteins were identified by SwissProt database search and quantified from normalized areas under curve of precursor ion chromatograms. Gene enrichment analysis was performed with Cytoscape/BINGO software. RESULTS: In total 430 different proteins were detected in both groups, 203 (47.2%) were newly identified. In allergics CLU and IGKC were significantly more abundant in season (2.2 and 2.1-fold respectively). GSTP1 (0.5-fold), ELANE (0.4-fold), HIST1H2BK (0.3-fold), S100A8 (0.2-fold), S100A12 (0.2-fold) and ARHGDIB (0.1-fold) were significantly less abundant in season. In healthy controls UBC, TUBA1B, HBB and FABP5 were only present in season. Ig kappa chain V-I region DEE (5.3-fold), CLU (5.0-fold), TXN (4.3-fold), MSMB (3.2-fold) and Ig heavy chain V-III region BRO (2.7-fold) were significantly more abundant in season. MUC5B (0.5-fold), SLPI (0.2-fold) and S100P (0.2-fold) were significantly less abundant in season. CONCLUSION: Contrary to their symptoms allergic rhinitis patients show perennial inflammatory response lacking adequate reaction to allergens in season. BIOLOGICAL SIGNIFICANCE: Many studies dealing with allergic rhinitis are focused on the nasal epithelium. This is the first study to analyse the nasal mucus as primary defence barrier on a proteomic level in and out of pollen season and contrary to the leading opinion shows that allergic patients show a perennial inflammatory response with reduced reaction to allergens whereas healthy controls react on proteome basis towards enhanced defence in season despite lacking allergic sensitization. PMID- 26732728 TI - Apixaban used for the management of heparin-induced thrombocytopenia in a 72-year old woman with lung cancer. AB - Heparin-induced thrombocytopenia (HIT) is a serious adverse reaction to heparin treatment with a high risk of thrombosis. Heparin must be discontinued immediately and replaced with alternative anticoagulants that do not interact with HIT antibodies. In this case, a lung cancer patient, diagnosed with HIT was successfully treated with apixaban. PMID- 26732730 TI - How Accurately Do Consecutive Cohort Audits Predict Phase III Multisite Clinical Trial Recruitment in Palliative Care? AB - CONTEXT: Audits have been proposed for estimating possible recruitment rates to randomized controlled trials (RCTs), but few studies have compared audit data with subsequent recruitment rates. OBJECTIVES: To compare the accuracy of estimates of potential recruitment from a retrospective consecutive cohort audit of actual participating sites and recruitment to four Phase III multisite clinical RCTs. METHODS: The proportion of potentially eligible study participants estimated from an inpatient chart review of people with life-limiting illnesses referred to six Australian specialist palliative care services was compared with recruitment data extracted from study prescreening information from three sites that participated fully in four Palliative Care Clinical Studies Collaborative RCTs. The predominant reasons for ineligibility in the audit and RCTs were analyzed. RESULTS: The audit overestimated the proportion of people referred to the palliative care services who could participate in the RCTs (pain 17.7% vs. 1.2%, delirium 5.8% vs. 0.6%, anorexia 5.1% vs. 0.8%, and bowel obstruction 2.8% vs. 0.5%). Approximately 2% of the referral base was potentially eligible for these effectiveness studies. Ineligibility for general criteria (language, cognition, and geographic proximity) varied between studies, whereas the reasons for exclusion were similar between the audit and pain and anorexia studies but not for delirium or bowel obstruction. CONCLUSION: The retrospective consecutive case note audit in participating sites did not predict realistic recruitment rates, mostly underestimating the impact of study-specific inclusion criteria. These findings have implications for the applicability of the results of RCTs. Prospective pilot studies are more likely to predict actual recruitment. PMID- 26732731 TI - Clinicians' Perspectives on Managing Symptom Clusters in Advanced Cancer: A Semistructured Interview Study. AB - CONTEXT: Managing symptom clusters or multiple concurrent symptoms in patients with advanced cancer remains a clinical challenge. The optimal processes constituting effective management of symptom clusters remain uncertain. OBJECTIVES: To describe the attitudes and strategies of clinicians in managing multiple co-occurring symptoms in patients with advanced cancer. METHODS: Semistructured interviews were conducted with 48 clinicians (palliative care physicians [n = 10], oncologists [n = 6], general practitioners [n = 6], nurses [n = 12], and allied health providers [n = 14]), purposively recruited from two acute hospitals, two palliative care centers, and four community general practices in Sydney, Australia. Transcripts were analyzed using thematic analysis and adapted grounded theory. RESULTS: Six themes were identified: uncertainty in decision making (inadequacy of scientific evidence, relying on experiential knowledge, and pressure to optimize care); attunement to patient and family (sensitivity to multiple cues, prioritizing individual preferences, addressing psychosocial and physical interactions, and opening Pandora's box); deciphering cause to guide intervention (disaggregating symptoms and interactions, flexibility in assessment, and curtailing investigative intrusiveness); balancing complexities in medical management (trading off side effects, minimizing mismatched goals, and urgency in resolving severe symptoms); fostering hope and empowerment (allaying fear of the unknown, encouraging meaning making, championing patient empowerment, and truth telling); and depending on multidisciplinary expertise (maximizing knowledge exchange, sharing management responsibility, contending with hierarchical tensions, and isolation and discontinuity of care). CONCLUSION: Management of symptom clusters, as both an art and a science, is currently fraught with uncertainty in decision making. Strengthening multidisciplinary collaboration, continuity of care, more pragmatic planning of clinical trials to address more than one symptom, and training in symptom cluster management are required. PMID- 26732729 TI - miR-124-9-9* potentiates Ascl1-induced reprogramming of cultured Muller glia. AB - The Muller glia of fish provide a source for neuronal regeneration after injury, but they do not do so in mammals. We previously showed that lentiviral gene transfer of the transcription factor Achaete-scute homolog 1 (Ascl1/Mash1) in murine Muller glia cultures resulted in partial reprogramming of the cells to retinal progenitors. The microRNAs (miRNAs) miR-124-9-9* facilitate neuronal reprogramming of fibroblasts, but their role in glia reprogramming has not been reported. The aim of this study was to test whether (1) lentiviral gene transfer of miR-124-9-9* can reprogram Muller glia into retinal neurons and (2) miR-124-9 9* can improve Ascl1-induced reprogramming. Primary Muller glia cultures were generated from postnatal day (P) 11/12 mice, transduced with lentiviral particles, i.e., miR-124-9-9*-RFP, nonsense-RFP, Ascl1-GFP, or GFP-control. Gene expression and immunofluorescence analyses were performed within 3 weeks after infection. 1. Overexpression of miR-124-9-9* induced the expression of the proneural factor Ascl1 and additional markers of neurons, including TUJ1 and MAP2. 2. When Ascl1 and miR-124-9-9* were combined, 50 to 60% of Muller glia underwent neuronal reprogramming, whereas Ascl1 alone results in a 30 to 35% reprogramming rate. 3. Analysis of the miR-124-9-9* treated glial cells showed a reduction in the level of Ctdsp1 and Ptbp1, indicating a critical role for the REST pathway in the repression of neuronal genes in Muller glia. Our data further suggest that miR-124-9-9* and the REST complex may play a role in regulating the reprogramming of Muller glia to progenitors that underlies retinal regeneration in zebrafish. PMID- 26732732 TI - Examination of neurological prognostic markers in patients with respiratory syncytial virus-associated encephalopathy. AB - No biomarker has been established as a prognostic indicator of acute encephalopathy associated with various etiological factors. In this study, we examined useful prognostic biomarkers in patients with acute encephalopathy associated with respiratory syncytial virus (RSV) infection. The subjects were 11 children with RSV-associated encephalopathy admitted to our hospital. We measured the levels of interleukin (IL)-6, brain-derived neurotrophic factor (BDNF) and nitrogen oxide (NO)x in cerebrospinal fluid collected on the day of admission. Using the pediatric cerebral performance categories (PCPC) score as a prognostic indicator, we evaluated the association between the biomarkers and neurologic prognosis. Concerning neurologic prognosis, sequelae were noted in more than 50% of the subjects. There was no association between prognosis and age/sex. Increases in the levels of all biomarkers were observed in all subjects. IL-6 and BDNF levels were correlated with PCPC score, but not with NOx. Of the biomarkers investigated, the IL-6 and BDNF levels in cerebrospinal fluid were shown to be correlated with neurologic prognosis. Because many patients with this disease had severe sequelae, assessment should be conducted by early evaluation of the biomarkers examined in this study with respect to the clinical course. PMID- 26732733 TI - Over promised, over-sold and underperforming? - e-health in mental health. PMID- 26732735 TI - Green laser light irradiation enhances differentiation and matrix mineralization of osteogenic cells. AB - BACKGROUND AND OBJECTIVE: Low level laser therapy (LLLT) in both infrared and visible light is a therapeutic tool ever more proposed in clinical practice in different fields. The effect of near infrared LLLT has been described in a growing number of scientific publications related to bone tissue healing, both in vitro and in vivo. More recently, green visible light using potassium-titanyl phosphate KTiOPO4 (KTP, 532 nm) laser has been proposed in dermatology, urology, oral and maxillofacial surgery but has never been tested on bone tissue. The aim of the present work was to perform a preliminary in vitro study to analyze the effects of KTP laser, on the osteogenic differentiation of bone marrow stromal cells (BMSCs). MATERIALS AND METHODS: Using a power meter the first step of this study aimed to evaluate the real power emitted by the KTP laser device and the amount of energy absorbed by culture medium and plastic in order to calculate the appropriate irradiation parameters for cultured cells. Primary bone marrow stromal cells prepared from C57BL/6 mice were cultured and induced to differentiate in the osteogenic lineage in the presence or in the absence of KTP LLLT at a fluence of 4 J/cm(2) three times a week. Specific staining of the cells and the extracellular matrix, microscopic analysis as well as quantitative RT-PCR were used to assess cell proliferation and differentiation. RESULTS: We show here that KTP LLLT enhances the osteogenic differentiation of bone marrow stromal cells and the mineralization of their extracellular matrix. CONCLUSION: Our results highlight that this LLLT experimental protocol with green light (KTP, 532 nm) at 4 J/cm(2) has a positive effect on the osteogenic differentiation of murine bone marrow stromal cells. These preliminary results could be used as a basis to further investigate the effect of this KTP laser protocol on bone tissue engineering models in vivo and in vitro. PMID- 26732734 TI - Large-scale inference of protein tissue origin in gram-positive sepsis plasma using quantitative targeted proteomics. AB - The plasma proteome is highly dynamic and variable, composed of proteins derived from surrounding tissues and cells. To investigate the complex processes that control the composition of the plasma proteome, we developed a mass spectrometry based proteomics strategy to infer the origin of proteins detected in murine plasma. The strategy relies on the construction of a comprehensive protein tissue atlas from cells and highly vascularized organs using shotgun mass spectrometry. The protein tissue atlas was transformed to a spectral library for highly reproducible quantification of tissue-specific proteins directly in plasma using SWATH-like data-independent mass spectrometry analysis. We show that the method can determine drastic changes of tissue-specific protein profiles in blood plasma from mouse animal models with sepsis. The strategy can be extended to several other species advancing our understanding of the complex processes that contribute to the plasma proteome dynamics. PMID- 26732737 TI - Can we finally use spirometry in the clinical management of infants with respiratory conditions? PMID- 26732736 TI - Respiratory health and disease in a U.K. population-based cohort of 85 year olds: The Newcastle 85+ Study. AB - BACKGROUND: People aged 85 years and older are the fastest growing age group worldwide. This study assessed respiratory health, prevalence of respiratory disease and use of spirometry in respiratory diagnosis in a population-based cohort of 85 year olds to better understand respiratory health and disease in this sector of society. METHODS: A single year birth-cohort of 85 year olds participated in a respiratory assessment at their home or residential institution including self-reporting of symptoms and measurement of spirometry. General practice medical records were reviewed for respiratory diagnoses and treatments. FINDINGS: In the 845 participants, a substantial burden of respiratory disease was seen with a prevalence of COPD in medical records of 16.6% (n=140). A large proportion of the cohort had environmental exposures through past or current smoking (64.2%, n=539) and occupational risk factors (33.6%, n=269). Spirometry meeting reliability criteria was performed in 87% (n=737) of participants. In the subgroup with a diagnosis of COPD (n=123), only 75.6% (n=93) satisfied Global Initiative in Obstructive Lung Disease (GOLD) criteria for airflow obstruction, and in a healthy subgroup without respiratory symptoms or diagnoses (n=151), 44.4% (n=67) reached GOLD criteria for airflow obstruction and 43.3% (n=29) National Institute of Health and Care Excellence criteria for at least moderate COPD. INTERPRETATION: Spirometry can be successfully performed in the very old, aged 85 years, and may help identify respiratory diseases such as COPD. However interpretation in this age group using current definitions of COPD based on spirometry indices may be difficult and lead to overdiagnosis in a healthy group with transient symptoms. PMID- 26732738 TI - The natural history of severe asthma and influences of early risk factors: a population-based cohort study. AB - BACKGROUND: Severe asthma is associated with disproportionately high morbidity, but little is known about its natural history and how risk factors at first year of diagnosis modify its subsequent development. METHODS: Using administrative health data, we retrospectively followed patients 14-55 years of age with newly diagnosed severe asthma in British Columbia, Canada. Based on intensity of resource use (drug therapy) and occurrence of exacerbations, each patient-year was classified into mild, moderate, or severe asthma. We estimated the probability of transition between severity levels or to death over the study period using a four-state Markov model, and used this to assess the 10-year trajectory of severe asthma and the influence of baseline risk factors. RESULTS: We followed 13,467 patients. Ten years after incident severe asthma, 83% had transitioned to a less severe level (mild: 43%, moderate: 40%). Low socioeconomic status, high comorbidity burden, and high adherence (proportion of days covered (PDC) by asthma controller therapy) in the first year were independently associated with, respectively, 10%, 24% and 35% more time in severe asthma over the next 10 years. Sex was not associated with the clinical course. CONCLUSIONS: Most patients with incident severe asthma used fewer resources over time, indicating a long-term transition to milder asthma. Potentially modifiable risk factors for poor prognosis of severe asthma include low socioeconomic status and high comorbidity burden. The association between PDC and future asthma severity is likely due to residual confounding by disease severity. PMID- 26732739 TI - Percutaneous Externally Assembled Laparoscopic Instruments: Creation of a New Surgical Paradigm. AB - OBJECTIVES: Laparoendoscopic single-site surgery (LESS) and natural orifice transluminal endoscopic surgery (NOTES) produce excellent cosmetic outcomes, but are technically challenging. The objective of this study was to test the functionality and feasibility of a novel minimally invasive surgical paradigm, which maintains triangulation but uses special externally assembled instruments to minimize the postoperative cosmetic impact. METHODS: Percutaneous Externally Assembled Laparoscopic (PEAL) instruments have specialized 2.96-mm shafts with interchangeable 5-mm working tips that are assembled externally. First, 5-mm laparoscopic, PEAL, and 2-mm needlescopic instruments were tested to determine piercing force on fresh human cadaver organs. In a bench-top study, 20 subjects assembled and used PEAL instruments in five different skills tests that were also compared with the same tasks using conventional laparoscopic instruments. Finally, PEAL instrument functionality was tested in a four-porcine nephrectomy feasibility study. RESULTS: PEAL (2.80 lbF) and 5-mm laparoscopic instruments (2.28 lbF) had a significantly higher mean organ piercing perforation force compared with needlescopic instruments (1.39 lbF, p < 0.05). Average assembly time of PEAL instruments was 31.08 seconds (range: 19.83-43.85). There were no significant differences in the amount of time needed for completion of the bench top tasks between laparoscopic and PEAL instruments (p > 0.05 for all tasks). Four-porcine PEAL nephrectomies were completed with no complications and minimal blood loss (mean 7.5 mL). Mean operative time was 98.25 minutes (range 79-116). CONCLUSION: PEAL tools are easily assembled, have similar safety and efficacy compared with standard laparoscopic tools, and are less likely to injure organs compared with needlescopic instruments. They function well during laparoscopic nephrectomy and may decrease the invasiveness of conventional laparoscopic instrumentation. PMID- 26732740 TI - Atorvastatin Reduces the Survival of Candida albicans-Infected BALB/c Mice. AB - Several antimicrobial and immunosuppressive effects have been attributed to the statins class of antihyperlipidemia drugs. Several studies have also indicated clinical benefits for the use of statins during the management of infections and sepsis. To assess whether the immunosuppressive effects of statins outweigh their antimicrobial effects during a fungal infection BALB/c mice were administered Candida albicans via intraperitoneal injection. These mice received either a co injection of atorvastatin along with the infection, were treated with one injection of atorvastatin per day for 5 days prior to infection, or were infected and then treated with one injection of atorvastatin for 5 days afterward. Groups that received C. albicans without being treated with atorvastatin were included as controls along with a group that only received phosphate-buffered saline. Mouse survival was then monitored; additionally, serum IFN-gamma and IL-4 levels were determined by enzyme linked immunosorbent assay to assess pro-inflammatory and pro-humoral responses, respectively. Atorvastatin administration was capable of altering mouse survival rate with the lowest rate (11.1%) being observed in the group treated for 5 days prior to infection with atorvastatin compared to mice infected but not treated with atorvastatin (44.4%). IFN-gamma and IL-4 levels were depressed in all C. albicans-infected groups treated with atorvastatin. The possibility that statin administration may suppress or modulate particular components of the immune system during an infection in man should be further explored in large randomized controlled trials. PMID- 26732742 TI - Charging gold nanoparticles in ZnO by electric fields. AB - Controlling the plasmon resonance frequency of metal nanostructures holds promise for both fundamental and applied research in optics. The plasmon resonance frequency depends on the number of free electrons in the metal. By adding or removing electrons to a metal nano-object, the plasmon resonance frequency shifts. In this study we indirectly change the number of free electrons in gold nanoparticles by applying an electrical potential difference over a heterostructure consisting of a ZnO layer with embedded gold nanoparticles. The potential difference induces shifts of defect energy levels in the ZnO by the electric field. This results in an exchange of electrons between particles and matrix which in turn modifies the gold nanoparticle plasmon properties. The positive charge shifts the ZnO optical absorption peak from 377 nm to 386 nm and shifts the nanoparticle plasmon from 549 nm to 542 nm. This electro-optical effect is a promising way to obtain fast optical switching in a solid state composition. PMID- 26732743 TI - Clearing skeletal muscle with CLARITY for light microscopy imaging. AB - Viewing subcellular details over large tissue volumes is becoming an essential condition of the success of large-scale projects aimed at visualizing cell connections in whole organs or tissues. However, tissue opacity remains an obstacle to deep tissue imaging. This situation has brought renewed interest for techniques of tissue clearing; new protocols, such as CLARITY (Clear Lipid exchanged Acrylamide-hybridized Rigid Imaging/Immunostaining/In situ hybridization-compatible Tissue-hYdrogel), have recently been developed. So far, most of the tests of these techniques have been applied to brain or other soft tissues. Here we show that CLARITY clears mouse hindlimb skeletal muscles and maintains the basic structural features of muscle and its fibers. However, tagging with fluorescent markers was not successful. PMID- 26732741 TI - A Cell Biologist's Field Guide to Aurora Kinase Inhibitors. AB - Aurora kinases are essential for cell division and are frequently misregulated in human cancers. Based on their potential as cancer therapeutics, a plethora of small molecule Aurora kinase inhibitors have been developed, with a subset having been adopted as tools in cell biology. Here, we fill a gap in the characterization of Aurora kinase inhibitors by using biochemical and cell-based assays to systematically profile a panel of 10 commercially available compounds with reported selectivity for Aurora A (MLN8054, MLN8237, MK-5108, MK-8745, Genentech Aurora Inhibitor 1), Aurora B (Hesperadin, ZM447439, AZD1152-HQPA, GSK1070916), or Aurora A/B (VX-680). We quantify the in vitro effect of each inhibitor on the activity of Aurora A alone, as well as Aurora A and Aurora B bound to fragments of their activators, TPX2 and INCENP, respectively. We also report kinome profiling results for a subset of these compounds to highlight potential off-target effects. In a cellular context, we demonstrate that immunofluorescence-based detection of LATS2 and histone H3 phospho-epitopes provides a facile and reliable means to assess potency and specificity of Aurora A versus Aurora B inhibition, and that G2 duration measured in a live imaging assay is a specific readout of Aurora A activity. Our analysis also highlights variation between HeLa, U2OS, and hTERT-RPE1 cells that impacts selective Aurora A inhibition. For Aurora B, all four tested compounds exhibit excellent selectivity and do not significantly inhibit Aurora A at effective doses. For Aurora A, MK-5108 and MK-8745 are significantly more selective than the commonly used inhibitors MLN8054 and MLN8237. A crystal structure of an Aurora A/MK-5108 complex that we determined suggests the chemical basis for this higher specificity. Taken together, our quantitative biochemical and cell-based analyses indicate that AZD1152-HQPA and MK-8745 are the best current tools for selectively inhibiting Aurora B and Aurora A, respectively. However, MK-8745 is not nearly as ideal as AZD1152-HQPA in that it requires high concentrations to achieve full inhibition in a cellular context, indicating a need for more potent Aurora A selective inhibitors. We conclude with a set of "good practice" guidelines for the use of Aurora inhibitors in cell biology experiments. PMID- 26732744 TI - Phantom-based characterization of distortion on a magnetic resonance imaging simulator for radiation oncology. AB - One of the major issues potentially limiting treatment planning with solely MR images is the possibility of geometric distortion inherent in MR images. We designed a large distortion phantom containing a 3D array of spheres and proposed a three-dimensional (3D) approach to determine the distortion of MR image volume. The approach to overcome partially filled spheres is also presented. The phantom was assembled with a 3D array of spheres filled with contrast and was scanned with a 3T MRI simulator. A 3D whole-sphere or half-sphere template is used to match the image pattern. The half-sphere template is used when the normalized cross-correlation value for the whole-sphere template is below a predetermined threshold. Procrustes method was applied to remove the shift induced by rotation and translation of the phantom. Then the distortion map was generated. Accuracy of the method was verified using CT images of a small phantom of the same design. The analysis of the small phantom showed that the method is accurate with an average offset of estimated sphere center 0.12 +/- 0.04 mm. The Procrustes analysis estimated the rotation angle to be 1.95 degrees and 0.01 degrees , respectively, when the phantom was placed at 2 degrees and 0 degrees from the ceiling laser. The analysis showed that on the central plane through the magnet center, the average displacement is less than 1 mm for all radii. At distal planes, when the radius is less than 18 cm, the average displacement is less than 1 mm. However, the average displacement is over 1 mm but still less than 1.5 mm for larger radii. A large distortion phantom was assembled and analysis software was developed to characterize distortions in MRI scans. The use of two templates helps reduce the potential impact of residual air bubbles in some of the spheres. PMID- 26732745 TI - Perceptions matter: faculty caring, campus racial climate and academic performance. AB - AIM: Examine the influence of students' perception of faculty caring on academic performance and the moderating role of students' perceptions of campus racial climate. BACKGROUND: There is limited knowledge on how students' perceptions of faculty caring, campus racial climate and academic performance are linked. Understanding this nexus is crucial to improving nursing education. DESIGN: Secondary analysis of a cross-sectional data obtained from seven undergraduate nursing programs in Texas, USA. METHOD: Data were from 385 students enrolled in Medical-Surgical 1 over three semesters (March 2010-December 2010). Six sets of factor analytic scores derived from 31 original perceptions of faculty caring items served as predictors; one set of scores derived from seven original perceptions of campus racial climate items served as moderating variable in a regression model. Numeric grade was the outcome variable. RESULTS/FINDINGS: Perception of faculty having a positive outlook/compassion had an enhancing effect on performance. As students' perceptions of campus racial climate became increasingly discriminating, the positive association between perceptions of faculty's trust in students' judgment and academic performance became increasingly strong. CONCLUSION: Results highlight ways by which students' perception of micro-level social reality (dyadic interaction) might interact with their perception of meso-level social reality (social environment) to influence their academic performance. PMID- 26732746 TI - Exceptional preservation reveals gastrointestinal anatomy and evolution in early actinopterygian fishes. AB - Current knowledge about the evolutionary morphology of the vertebrate gastrointestinal tract (GIT) is hindered by the low preservation potential of soft tissues in fossils. Exceptionally preserved cololites of individual ?Saurichthys from the Middle Triassic of Switzerland provide unique insights into the evolutionary morphology of the GIT. The GIT of ?Saurichthys differed from that of other early actinopterygians, and was convergent to that of some living sharks and rays, in exhibiting up to 30 turns of the spiral valve. Dissections and literature review demonstrate the phylogenetic diversity of GIT features and signs of biological factors that influence its morphology. A phylogenetically informed analysis of a dataset containing 134 taxa suggests that body size and phylogeny are important factors affecting the spiral valve turn counts. The high number of turns in the spiral valve of ?Saurichthys and some recent sharks and rays reflect both energetically demanding lifestyles and the evolutionary histories of the groups. PMID- 26732747 TI - The quest for connection in interpersonal and therapeutic relationships. AB - OBJECTIVE: This paper focuses on the need for connection as a common core theme at the heart of both close relationships and therapeutic relationships and explores ways to connect these two research domains that have evolved as separate fields of study. Bowlby's attachment theory provides a strong conceptual and empirical base for linking human bonds and bonds in psychotherapy. METHOD: The growing body of research intersecting attachment and psychotherapy (1980-2014) is documented, and meta-analytic studies on attachment-outcome and attachment alliance links are highlighted. RESULTS: Five ways of studying attachment as a variable in psychotherapy are underscored: as moderator, as mediator, as outcome, client-therapist attachment match, and as process. By integrating conceptualizations and methods in studying relational narratives of client therapist dyads (Core Conflictual Relationship Theme), measures of alliance, and client attachment to therapist during psychotherapy, we may discover unique client-therapist relational dances. CONCLUSIONS: Future fine-grained studies on how to promote core authentic relational relearning are important to clinicians, supervisors and trainers, who all share the common quest to alleviate interpersonal distress and enhance wellbeing. Directions for advancing research on interpersonal and therapeutic relationships are suggested. Learning from each other, both researchers of close relationships and of psychotherapy relationships can gain a deeper and multidimensional understanding of complex relational processes and outcomes. PMID- 26732748 TI - Direct Detection of Supramolecular Reaction Centers in the Methanol-to-Olefins Conversion over Zeolite H-ZSM-5 by (13)C-(27)Al Solid-State NMR Spectroscopy. AB - Hydrocarbon-pool chemistry is important in methanol to olefins (MTO) conversion on acidic zeolite catalysts. The hydrocarbon-pool (HP) species, such as methylbenzenes and cyclic carbocations, confined in zeolite channels during the reaction are essential in determining the reaction pathway. Herein, we experimentally demonstrate the formation of supramolecular reaction centers composed of organic hydrocarbon species and the inorganic zeolite framework in H ZSM-5 zeolite by advanced (13)C-(27)Al double-resonance solid-state NMR spectroscopy. Methylbenzenes and cyclic carbocations located near Bronsted acid/base sites form the supramolecular reaction centers in the zeolite channel. The internuclear spatial interaction/proximity between the (13)C nuclei (associated with HP species) and the (27) Al nuclei (associated with Bronsted acid/base sites) determines the reactivity of the HP species. The closer the HP species are to the zeolite framework Al, the higher their reactivity in the MTO reaction. PMID- 26732749 TI - Discrepancy in compliance between the clinical and genetic diagnosis of choroidal hypoplasia in Danish Rough Collies and Shetland Sheepdogs. AB - Collie eye anomaly (CEA) is a congenital, inherited ocular disorder which is widespread in herding breeds. Clinically, the two major lesions associated with CEA are choroidal hypoplasia (CH) and coloboma, and both lesions are diagnosed based on ophthalmological examination. A 7.8-kb intronic deletion in the gene encoding non-homologous end-joining factor 1 (NHEJ1) has been reported to be the causative mutation underlying CH when present in the homozygous state. In this study, we have investigated the compliance between the clinical and genetic diagnosis of CH in the Danish Rough Collie and Shetland Sheepdog populations. Our results show that the deletion in NHEJ1 is not predictive for CH in the Danish Rough Collie population, whereas the clinical and genetic diagnosis is in accordance with each other in the Shetland Sheepdog population. Based on these results, it can be concluded that the intronic deletion in NHEJ1 is not the causative mutation but, rather, a marker linked to the locus underlying the trait in some populations but linked to both the wild-type and CH-causing locus in most dogs in the Danish Rough Collie population. PMID- 26732751 TI - Geometric reduction of dynamical nonlocality in nanoscale quantum circuits. AB - Nonlocality is a key feature discriminating quantum and classical physics. Quantum-interference phenomena, such as Young's double slit experiment, are one of the clearest manifestations of nonlocality, recently addressed as dynamical to specify its origin in the quantum equations of motion. It is well known that loss of dynamical nonlocality can occur due to (partial) collapse of the wavefunction due to a measurement, such as which-path detection. However, alternative mechanisms affecting dynamical nonlocality have hardly been considered, although of crucial importance in many schemes for quantum information processing. Here, we present a fundamentally different pathway of losing dynamical nonlocality, demonstrating that the detailed geometry of the detection scheme is crucial to preserve nonlocality. By means of a solid-state quantum-interference experiment we quantify this effect in a diffusive system. We show that interference is not only affected by decoherence, but also by a loss of dynamical nonlocality based on a local reduction of the number of quantum conduction channels of the interferometer. With our measurements and theoretical model we demonstrate that this mechanism is an intrinsic property of quantum dynamics. Understanding the geometrical constraints protecting nonlocality is crucial when designing quantum networks for quantum information processing. PMID- 26732750 TI - Effects of calcitriol on random skin flap survival in rats. AB - Calcitriol, a metabolite of vitamin D, is often used in osteoporosis clinics. However, the material has other bioactivities; for example, it accelerates angiogenesis, has anti-inflammatory properties, and inhibits oxidative stress. We investigated the effects of calcitriol in a random skin flap rat model. "McFarlane flap" models were established in 84 male Sprague Dawley rats, divided into two groups. One group received intraperitoneal injections of calcitriol (2 MUg/kg/day) whereas control rats received intraperitoneal injections of saline. The percentage flap survival area and tissue water content were measured 7 days later, which showed that calcitriol improved flap survival area and reduced tissue edema. It also increased the mean vessel density and upregulated levels of VEGF mRNA/protein, both of which promote flap angiogenesis. Moreover, it decreased leukocyte and macrophage infiltration, reduced the inflammatory proteins IL1beta and IL6, increased SOD activity, decreased MDA content, and upregulated the level of autophagy. Overall, our results suggest that calcitriol promotes skin flap survival by accelerating angiogenesis, having anti inflammatory effects, reducing oxidative stress, and promoting autophagy. PMID- 26732752 TI - Assessment of a land-locked Atlantic salmon (Salmo salar L.) population as a potential genetic resource with a focus on long-chain polyunsaturated fatty acid biosynthesis. AB - The natural food for Atlantic salmon (Salmo salar) in freshwater has relatively lower levels of omega-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFA) than found in prey for post-smolt salmon in seawater. Land-locked salmon such as the Gullspang population feed exclusively on freshwater type lipids during its entire life cycle, a successful adaptation derived from divergent evolution. Studying land-locked populations may provide insights into the molecular and genetic control mechanisms that determine and regulate n-3 LC-PUFA biosynthesis and retention in Atlantic salmon. A two factorial study was performed comparing land-locked and farmed salmon parr fed diets formulated with fish or rapeseed oil for 8 weeks. The land-locked parr had higher capacity to synthesise n-3 LC-PUFA as indicated by higher expression and activity of desaturase and elongase enzymes. The data suggested that the land-locked salmon had reduced sensitivity to dietary fatty acid composition and that dietary docosahexaenoic acid (DHA) did not appear to suppress expression of LC-PUFA biosynthetic genes or activity of the biosynthesis pathway, probably an evolutionary adaptation to a natural diet lower in DHA. Increased biosynthetic activity did not translate to enhanced n-3 LC-PUFA contents in the flesh and diet was the only factor affecting this parameter. Additionally, high lipogenic and glycolytic potentials were found in land-locked salmon, together with decreased lipolysis which in turn could indicate increased use of carbohydrates as an energy source and a sparing of lipid. PMID- 26732753 TI - Novel mutations in CRYGD are associated with congenital cataracts in Chinese families. AB - Congenital cataract disease is a clinically and genetically heterogeneous lens disorder. The purpose of this study was to identify the genetic defects and to investigate the relationships between disease-causing genes and lens morphology in congenital cataracts. Patients were given a physical examination, and their blood samples were collected for DNA extraction. Mutation analysis was performed by direct sequencing of the following candidate genes: CRYGC, CRYGD, CRYGS, GJA8, GJA3 and CRYAA. Mutational analysis of CRYGD identified a recurrent (p.P24T) mutation in two unrelated families with congenital coralliform cataracts and three novel (p.Q101X, p.E104fsX4 and p.E135X) mutations in three families with congenital nuclear cataracts. The p.E135X mutation is a de novo mutation. Haplotype analysis showed patients inherited the same CRYGD allele originated from father. The p.E135X mutation seen in two siblings suggests a mechanism of gonadal mosaicism in the father. PMID- 26732754 TI - Epigenome Editing: State of the Art, Concepts, and Perspectives. AB - Epigenome editing refers to the directed alteration of chromatin marks at specific genomic loci by using targeted EpiEffectors which comprise designed DNA recognition domains (zinc finger, TAL effector, or modified CRISPR/Cas9 complex) and catalytic domains from a chromatin-modifying enzyme. Epigenome editing is a promising approach for durable gene regulation, with many applications in basic research including the investigation of the regulatory functions and logic of chromatin modifications and cellular reprogramming. From a clinical point of view, targeted regulation of disease-related genes offers novel therapeutic avenues for many diseases. We review here the progress made in this field and discuss open questions in epigenetic regulation and its stability, methods to increase the specificity of epigenome editing, and improved delivery methods for targeted EpiEffectors. Future work will reveal if the approach of epigenome editing fulfills its great promise in basic research and clinical applications. PMID- 26732756 TI - Coarse graining of force fields for metal-organic frameworks. AB - We have adapted our genetic algorithm based optimization approach, originally developed to generate force field parameters from quantum mechanic reference data, to derive a first coarse grained force field for a MOF, taking the atomistic MOF-FF as a reference. On the example of the copper paddle-wheel based HKUST-1, a maximally coarse grained model, using a single bead for each three and four coordinated vertex, was developed as a proof of concept. By adding non bonded interactions with a modified Buckingham potential, the resulting MOF-FF CGNB is able to predict local deformation energies of the building blocks as well as bulk properties like the tbovs.pto energy difference or elastic constants in a semi-quantitative way. As expected, the negative thermal expansion of HKUST-1 is not reproduced by the maximally coarse grained model. At the expense of atomic resolution, substantially larger systems (up to tens of nanometers in size) can be simulated with respect to structural and mechanical properties, bridging the gap to the mesoscale. As an example the deformation of the [111] surface of HKUST 1 by a "tip" could be computed without artifacts from periodic images. PMID- 26732755 TI - Selenite Protection of Tellurite Toxicity Toward Escherichia coli. AB - In this work the influence of selenite on metal resistance in Escherichia coli was examined. Both synergistic and antagonistic resistance and toxicities were found upon co exposure with selenite. In wild type cells co-exposure to selenite had little effect on arsenic resistance, decreased resistance to cadmium and mercury but led to a dramatically increased resistance to tellurite of 32-fold. Due to the potential importance of thiol chemistry in metal biochemistry, deletion strains in gamma-glutamylcysteine synthetase (key step in glutathione biosynthesis, encoded by gshA), thioredoxin (trxA), glutaredoxin (grxA), glutathione oxidoreductase (gor), and the periplasmic glutathione transporter (cydD) were also evaluated for resistance to various metals in the presence of selenite. The protective effect of selenite on tellurite toxicity was seen in several of the mutants and was pronounced in the gshA mutant were resistance to tellurite was increased up to 1000-fold relative to growth in the absence of selenite. Thiol oxidation studies revealed a faster rate of loss of reduced thiol content in the cell with selenite than with tellurite, indicating differential thiol reactivity. Selenite addition resulted in reactive oxygen species (ROS) production equivalent to levels associated with H2O2 addition. Tellurite addition resulted in considerably lower ROS generation while vanadate and chromate treatment did not increase ROS production above that of background. This work shows increased resistance toward most oxyanions in mutants of thiol redox suggesting that metalloid reaction with thiol components such as glutathione actually enhances toxicity of some metalloids. PMID- 26732758 TI - Metabolic Engineering and Comparative Performance Studies of Synechocystis sp. PCC 6803 Strains for Effective Utilization of Xylose. AB - Wood sugars such as xylose can be used as an inexpensive carbon source for biotechnological applications. The model cyanobacterium Synechocystis sp. PCC 6803 lacks the ability to catabolize wood sugars as an energy source. Here, we generated four Synechocystis strains that heterologously expressed XylAB enzymes, which mediate xylose catabolism, either in combination with or without one of three xylose transporters, namely XylE, GalP, or Glf. Except for glf, which is derived from the bacterium Zymomonas mobilis ZM4, the heterologous genes were sourced from Escherichia coli K-12. All of the recombinant strains were able to utilize xylose in the absence of catabolite repression. When xylose was the lone source of organic carbon, strains possessing the XylE and Glf transporters were most efficient in terms of dry biomass production and xylose consumption and the strain lacking a heterologous transporter was the least efficient. However, in the presence of a xylose-glucose mixed sugar source, the strains exhibited similar levels of growth and xylose consumption. This study demonstrates that various bacterial xylose transporters can boost xylose catabolism in transgenic Synechocystis strains, and paves the way for the sustainable production of bio compounds and green fuels from lignocellulosic biomass. PMID- 26732757 TI - Prevalence and correlates of healthy lifestyle behaviors among early cancer survivors. AB - BACKGROUND: Healthy lifestyle behaviors have been demonstrated to be beneficial for positive health outcomes and the quality of life in cancer survivors. However, adherence to recommendations is low. More insight is needed in factors that may explain engagement in lifestyle behaviors to develop effective cancer aftercare interventions. This study assessed different factors, namely socio demographic, cancer-related, psychological, social cognitive factors (attitude, social support, self-efficacy) and intention, in relationship to five lifestyle behaviors (smoking, physical activity, alcohol, and fruit and vegetable consumption). METHODS: Early survivors of various types of cancer were recruited from eighteen Dutch Hospitals (n = 255). Distal factors (socio-demographic, cancer related, psychological), proximal factors (social cognitive), intention and five lifestyle behaviors (smoking, physical activity, alcohol, fruit and vegetable consumption) were assessed through a self-reported questionnaire. Cross sectional analyses (correlations and regression analyses) were conducted. RESULTS: The lifestyle of a small group (11%) of the cancer survivors was coherent with all five health recommendations, the majority (>80%) adhered to two, three of four recommendations, and only few (<7%) adhered to one or none recommendation. The highest prevalence in followed recommendations have been detected in physical activity (87.4%), refrain from smoking (82%), and alcohol consumption (75.4%). There was low adherence to the fruit recommendation (54.8%) and to the vegetable recommendation (27.4%). Only weak associations were found between the different behaviors. Each separate lifestyle behavior was influenced by different patterns of correlates. Self-efficacy, attitude, and intention were the strongest correlates in all examined behaviors, although with various contributions, while socio-demographic, cancer-related and psychological factors provided a much smaller contribution. CONCLUSIONS: Outcomes of engagement in healthy lifestyle behaviors were more positive in this study compared to other research in cancer survivors; however, there is room for improvements in adherence to all five lifestyle behaviors. Especially fruit consumption was poor and vegetable consumption even worse. Our findings emphasized that all examined lifestyle behaviors need to be encouraged, with taken into account that each lifestyle behavior may be influenced by a specific set of mainly social cognitive factors or intention. PMID- 26732759 TI - Fluoroless catheter ablation in adults: a single center experience. AB - BACKGROUND: Ablation procedures for arrhythmias have increased in frequency and complexity over the last decade. Improvements in technology have allowed for less reliance on fluoroscopy to guide these procedures. Ablation without fluoroscopy has been reported in small cohorts. We report a single center experience of fluoroless ablation after adoption of this technique for all endovascular ablations. METHODS: This retrospective study evaluated 107 consecutive patients who underwent a catheter ablation procedure for an atrial or ventricular arrhythmias after adoption of a completely fluoroless technique. No fluoroscopy was used in any case. A mapping system was utilized in all cases. Intracardiac echocardiography (ICE) catheters were utilized in 75 of the ablation cases (70.4%). Of the 107 patients who underwent EP study, three patients did not undergo ablation as they were non-inducible for SVT. Of the remaining 104 patients, 56 patients (53.8%) underwent ablation for atrial fibrillation, 23 patients (22.1%) for SVT, 10 patients (9.6%) for lone atrial flutter, and 16 patients (15.4%) for a ventricular arrhythmia including PVC, idiopathic VT or ventricular tachycardia. RESULTS: Catheters were able to be placed in 100% of patients without complication. Time to placement in the coronary sinus was 2.1 min +/- 1.4 min. Mean transseptal time was 3.54 min +/- 3 min. Mean procedure time for all ablations was 2 h 6 min +/- 50 min. There were no complications in the series of patients. CONCLUSIONS: Fluoroless ablation is feasible and safe with acceptable procedure times. Adoption of this technique is encouraged in order to eliminate unnecessary risk of fluoroscopy. PMID- 26732760 TI - 2015: Signaling Breakthroughs of the Year. AB - This year's signaling breakthroughs highlight insights into the pathogenesis or treatment of cancer, malaria, and neurodegenerative disorders; reveal molecular insights into cell death; and identify signals that could be leveraged to prevent plant parasitism or engineer bacteria as microbial fuel cells. PMID- 26732761 TI - Rosmarinic acid is a homoserine lactone mimic produced by plants that activates a bacterial quorum-sensing regulator. AB - Quorum sensing is a bacterial communication mechanism that controls genes, enabling bacteria to live as communities, such as biofilms. Homoserine lactone (HSL) molecules function as quorum-sensing signals for Gram-negative bacteria. Plants also produce previously unidentified compounds that affect quorum sensing. We identified rosmarinic acid as a plant-derived compound that functioned as an HSL mimic. In vitro assays showed that rosmarinic acid bound to the quorum sensing regulator RhlR of Pseudomonas aeruginosa PAO1 and competed with the bacterial ligand N-butanoyl-homoserine lactone (C4-HSL). Furthermore, rosmarinic acid stimulated a greater increase in RhlR-mediated transcription in vitro than that of C4-HSL. In P. aeruginosa, rosmarinic acid induced quorum sensing dependent gene expression and increased biofilm formation and the production of the virulence factors pyocyanin and elastase. Because P. aeruginosa PAO1 infection induces rosmarinic acid secretion from plant roots, our results indicate that rosmarinic acid secretion is a plant defense mechanism to stimulate a premature quorum-sensing response. P. aeruginosa is a ubiquitous pathogen that infects plants and animals; therefore, identification of rosmarinic acid as an inducer of premature quorum-sensing responses may be useful in agriculture and inform human therapeutic strategies. PMID- 26732762 TI - Inclusion bodies enriched for p62 and polyubiquitinated proteins in macrophages protect against atherosclerosis. AB - Autophagy is a catabolic cellular mechanism that degrades dysfunctional proteins and organelles. Atherosclerotic plaque formation is enhanced in mice with macrophages deficient for the critical autophagy protein ATG5. We showed that exposure of macrophages to lipids that promote atherosclerosis increased the abundance of the autophagy chaperone p62 and that p62 colocalized with polyubiquitinated proteins in cytoplasmic inclusions, which are characterized by insoluble protein aggregates. ATG5-null macrophages developed further p62 accumulation at the sites of large cytoplasmic ubiquitin-positive inclusion bodies. Aortas from atherosclerotic mice and plaques from human endarterectomy samples showed increased abundance of p62 and polyubiquitinated proteins that colocalized with plaque macrophages, suggesting that p62-enriched protein aggregates were characteristic of atherosclerosis. The formation of the cytoplasmic inclusions depended on p62 because lipid-loaded p62-null macrophages accumulated polyubiquitinated proteins in a diffuse cytoplasmic pattern. Lipid loaded p62-null macrophages also exhibited increased secretion of interleukin 1beta (IL-1beta) and had an increased tendency to undergo apoptosis, which depended on the p62 ubiquitin-binding domain and at least partly involved p62 mediated clearance of NLRP3 inflammasomes. Consistent with our in vitro observations, p62-deficient mice formed greater numbers of more complex atherosclerotic plaques, and p62 deficiency further increased atherosclerotic plaque burden in mice with a macrophage-specific ablation of ATG5. Together, these data suggested that sequestration of cytotoxic ubiquitinated proteins by p62 protects against atherogenesis, a condition in which the clearance of protein aggregates is disrupted. PMID- 26732764 TI - The Effect of Disruption of Prefrontal Cortical Function with Transcranial Magnetic Stimulation on Visual Working Memory. AB - It is proposed that feedback signals from the prefrontal cortex (PFC) to extrastriate cortex are essential for goal-directed processing, maintenance, and selection of information in visual working memory (VWM). In a previous study, we found that disruption of PFC function with transcranial magnetic stimulation (TMS) in healthy individuals impaired behavioral performance on a face/scene matching task and decreased category-specific tuning in extrastriate cortex as measured with functional magnetic resonance imaging (fMRI). In this study, we investigated the effect of disruption of left inferior frontal gyrus (IFG) function on the fidelity of neural representations of two distinct information codes: (1) the stimulus category and (2) the goal-relevance of viewed stimuli. During fMRI scanning, subjects were presented face and scene images in pseudo random order and instructed to remember either faces or scenes. Within both anatomical and functional regions of interest (ROIs), a multi-voxel pattern classifier was used to quantitatively assess the fidelity of activity patterns representing stimulus category: whether a face or a scene was presented on each trial, and goal relevance, whether the presented image was task relevant (i.e., a face is relevant in a "Remember Faces" block, but irrelevant in a "Remember Scenes" block). We found a reduction in the fidelity of the stimulus category code in visual cortex after left IFG disruption, providing causal evidence that lateral PFC modulates object category codes in visual cortex during VWM. In addition, we found that IFG disruption caused a reduction in the fidelity of the goal relevance code in a distributed set of brain regions. These results suggest that the IFG is involved in determining the task-relevance of visual input and communicating that information to a network of regions involved in further processing during VWM. Finally, we found that participants who exhibited greater fidelity of the goal relevance code in the non-disrupted right IFG after TMS performed the task with the highest accuracy. PMID- 26732763 TI - Comprehensive RNAi-based screening of human and mouse TLR pathways identifies species-specific preferences in signaling protein use. AB - Toll-like receptors (TLRs) are a major class of pattern recognition receptors, which mediate the responses of innate immune cells to microbial stimuli. To systematically determine the roles of proteins in canonical TLR signaling pathways, we conducted an RNA interference (RNAi)-based screen in human and mouse macrophages. We observed a pattern of conserved signaling module dependencies across species, but found notable species-specific requirements at the level of individual proteins. Among these, we identified unexpected differences in the involvement of members of the interleukin-1 receptor-associated kinase (IRAK) family between the human and mouse TLR pathways. Whereas TLR signaling in mouse macrophages depended primarily on IRAK4 and IRAK2, with little or no role for IRAK1, TLR signaling and proinflammatory cytokine production in human macrophages depended on IRAK1, with knockdown of IRAK4 or IRAK2 having less of an effect. Consistent with species-specific roles for these kinases, IRAK4 orthologs failed to rescue signaling in IRAK4-deficient macrophages from the other species, and only mouse macrophages required the kinase activity of IRAK4 to mediate TLR responses. The identification of a critical role for IRAK1 in TLR signaling in humans could potentially explain the association of IRAK1 with several autoimmune diseases. Furthermore, this study demonstrated how systematic screening can be used to identify important characteristics of innate immune responses across species, which could optimize therapeutic targeting to manipulate human TLR dependent outputs. PMID- 26732765 TI - A high-efficiency superhydrophobic plasma separator. AB - To meet stringent limit-of-detection specifications for low abundance target molecules, a relatively large volume of plasma is needed for many blood-based clinical diagnostics. Conventional centrifugation methods for plasma separation are not suitable for on-site testing or bedside diagnostics. Here, we report a simple, yet high-efficiency, clamshell-style, superhydrophobic plasma separator that is capable of separating a relatively large volume of plasma from several hundred microliters of whole blood (finger-prick blood volume). The plasma separator consists of a superhydrophobic top cover with a separation membrane and a superhydrophobic bottom substrate. Unlike previously reported membrane-based plasma separators, the separation membrane in our device is positioned at the top of the sandwiched whole blood film to increase the membrane separation capacity and plasma yield. In addition, the device's superhydrophobic characteristics (i) facilitates the formation of well-defined, contracted, thin blood film with a high contact angle; (ii) minimizes biomolecular adhesion to surfaces; (iii) increases blood clotting time; and (iv) reduces blood cell hemolysis. The device demonstrated a "blood in-plasma out" capability, consistently extracting 65 +/- 21.5 MUL of plasma from 200 MUL of whole blood in less than 10 min without electrical power. The device was used to separate plasma from Schistosoma mansoni genomic DNA-spiked whole blood with a recovery efficiency of >84.5 +/- 25.8%. The S. mansoni genomic DNA in the separated plasma was successfully tested on our custom-made microfluidic chip by using loop mediated isothermal amplification (LAMP) method. PMID- 26732766 TI - Dietary intake variability in the cycle of cytotoxic chemotherapy. AB - PURPOSE: This study was conducted to evaluate the dietary intake at different time points of the chemotherapeutic cycle. METHODS: Fifty-five ovarian cancer patients receiving at least 2 cycles of chemotherapy were deemed eligible for this study, of which 41 participants completed the study. Anthropometrical measurements and Subjective Global Assessment were used to estimate nutritional status. The dietary intake was evaluated by 3-day food records: 3 days prior to, the day of, and the following day after chemotherapy. RESULTS: Mean energy intake was the lowest on the day of chemotherapy and the highest 3 days before treatment (mean difference, 413.8 kcal; p < 0.001). Similarly, some vitamins and macro- and micronutrients (K, Ca, vit D, folate, vit C) failed to reach 50 % of the recommended dietary allowances. When dividing patients into BMI categories, the energy intake per kilogram of body weight, in the normal-weight patients, was statistically higher than that in overweight and obese subjects (23.6 vs. 20.9 vs. 12.3 kcal, respectively; p = 0.0015). Similarly, the statistically significant differences were observed by the intake of fats (0.80 vs. 0.69 vs. 0.39 g, p = 0.0283) and carbohydrates (3.52 vs. 3.05 vs. 1.71 g, p = 0.0004). CONCLUSIONS: Dietary intake varies in the cycle of chemotherapy, with the lowest intake at the day of cytotoxic treatment and the highest before the next chemotherapy. Further studies evaluating dietary intake in patients undergoing chemotherapy should include in the protocol the exact time point of dietary assessment. The intake of energy, fats, and carbohydrates differs significantly across BMI categories. PMID- 26732767 TI - Helplessness/hopelessness, minimization and optimism predict survival in women with invasive ovarian cancer: a role for targeted support during initial treatment decision-making? AB - PURPOSE: Women with advanced ovarian cancer generally have a poor prognosis but there is significant variability in survival despite similar disease characteristics and treatment regimens. The aim of this study was to determine whether psychosocial factors predict survival in women with ovarian cancer, controlling for potential confounders. METHODS: The sample comprised 798 women with invasive ovarian cancer recruited into the Australian Ovarian Cancer Study and a subsequent quality of life study. Validated measures of depression, optimism, minimization, helplessness/hopelessness, and social support were completed 3-6 monthly for up to 2 years. Four hundred nineteen women (52.5 %) died over the follow-up period. Associations between time-varying psychosocial variables and survival were tested using adjusted Cox proportional hazard models. RESULTS: There was a significant interaction of psychosocial variables measured prior to first progression and overall survival, with higher optimism (adjusted hazard ratio per 1 standard deviation (HR) = 0.80, 95 % confidence interval (CI) 0.65-0.97), higher minimization (HR = 0.79, CI 0.66-0.94), and lower helplessness/hopelessness (HR = 1.40, CI 1.15-1.71) associated with longer survival. After disease progression, these variables were not associated with survival (optimism HR = 1.10, CI 0.95-1.27; minimization HR = 1.12, CI 0.95-1.31; and helplessness/hopelessness HR = 0.86, CI 0.74-1.00). Depression and social support were not associated with survival. CONCLUSIONS: In women with invasive ovarian cancer, psychosocial variables prior to disease progression appear to impact on overall survival, suggesting a preventive rather than modifying role. Addressing psychosocial responses to cancer and their potential impact on treatment decision-making early in the disease trajectory may benefit survival and quality of life. PMID- 26732768 TI - Assessment of Noninvasive Regional Brain Oximetry in Posterior Reversible Encephalopathy Syndrome and Reversible Cerebral Vasoconstriction Syndrome. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) leads to small- and large-vessel circulatory dysfunction. While aggressive lowering of elevated blood pressure is the usual treatment for PRES, excessive blood pressure reduction may lead to ischemia or infarction, particularly when PRES is accompanied by reversible cerebral vasoconstriction syndrome (RCVS). Regional cerebral oximetry using near-infrared spectroscopy is a noninvasive modality that is commonly used intraoperatively and in intensive care settings to monitor regional cerebral oxygenation (rSO2) and may be useful in guiding treatment in select cases of PRES and RCVS. RESULTS: We report a case of a patient with PRES complicated by infarction and RCVS where the optimal blood pressure management was unclear. A decision was made to decrease blood pressure which resulted in an improved neurological examination and increase in rSO2 from 40% to 55% in at-risk brain. Infarcted brain as determined by diffusion-weighted magnetic resonance imaging and computed tomography perfusion imaging showed no change in rSO2 during the same time period. Furthermore, there was a qualitative change in the rSO2 mean arterial pressure (MAP) relationship, suggesting an alteration in cerebrovascular autoregulation as a result of lowering blood pressure. CONCLUSIONS: Regional cerebral oximetry can provide valuable diagnostic feedback in complicated cases of PRES and RCVS. PMID- 26732769 TI - Low Transmission of Airway Pressures to the Abdomen in Mechanically Ventilated Patients With or Without Acute Respiratory Failure and Intra-Abdominal Hypertension. AB - PURPOSE: Intra-abdominal pressure, measured at end expiration, may depend on ventilator settings and transmission of intrathoracic pressure. We determined the transmission of positive intrathoracic pressure during mechanical ventilation at inspiration and expiration into the abdominal compartment. METHODS AND RESULTS: We included 9 patients after uncomplicated cardiac surgery and 9 with acute respiratory failure. Intravesical pressures were measured thrice (reproducibility of 1.8%) and averaged, at the end of each inspiratory and expiratory hold maneuvers of 5 seconds. Transmission, the change in intra-abdominal over intrathoracic pressures from end inspiration to end expiration, was about 8%. End expiratory intra-abdominal pressure was lower than "total" intra-abdominal pressure over the entire respiratory cycle by 0.34 cm H2O. It was 0.73 cm H2O higher than "true" intra-abdominal pressure over the entire respiratory cycle, taking transmission into account. The percentage error was 3% for total and 10% for true pressure. Results did not differ among patients with or without acute respiratory failure and decreased respiratory compliance or between those with (>=12 mm Hg, n = 5) or without intra-abdominal hypertension. CONCLUSIONS: Transmitted airway pressure only slightly affects intra-abdominal pressure in mechanically ventilated patients, irrespective of respiratory compliance and baseline intra-abdominal pressure values. End-expiratory measurements referenced against atmospheric pressure may suffice for clinical practice. PMID- 26732770 TI - T-SPOT.TB in Detection of Active Tuberculosis During Pregnancy: A Retrospective Study in China. AB - BACKGROUND: Interferon-gamma release assays have not been validated in active TB among pregnant women. Therefore, the objective of this retrospective study was to estimate the diagnostic value of T-SPOT.TB in active TB among pregnant women. MATERIAL/METHODS: Between May 2012 and May 2015, 26 consecutive pregnant women with suspected TB were enrolled in our study. The clinicopathological characteristics and T-SPOT.TB results were reviewed and analyzed. RESULTS: Pregnant patients were divided into a TB group (n=21) and a Non-TB group (n=5). In the TB group, 5 patients had pulmonary TB, 5 had pulmonary TB+ extrapulmonary TB, and 11 had exclusively extrapulmonary TB. The most common site of extrapulmonary TB was pleural (n=11). Statistical analysis showed that the lymphocyte count in the TB group was lower than in the Non-TB group (P<0.05). For detection of active TB during pregnancy, T-SPOT.TB had a high sensitivity of 100.0% (84.5%-100.0%) and a specificity of 80.0% (37.6-96.4%). CONCLUSIONS: T SPOT.TB shows good performance in detection of active tuberculosis during pregnancy. Interferon gamma release assay for TB screening of pregnant women is recommended in clinical practice because it may be a more appropriate diagnostic tool than the tuberculin skin test. PMID- 26732771 TI - The suprascapular notch narrows with aging: a preliminary solution of the old conjecture based on a 3D-CT evaluation. AB - PURPOSE: The purpose of this study was to describe the morphology of the suprascapular notch in terms of age distribution. We hypothesized that the notch narrows with aging. METHODS: Seven hundred and sixty consecutive patients (465 men and 295 women) scheduled for a shoulder surgery were retrospectively reviewed. A 3D-CT of the shoulder was taken to evaluate the shape of the notch according to the Rengachary classification. The six types of Rengachary classification were arranged into three major categories according to transverse scapular ligament ossification and notch size as follows: the wide notch (type 1 and type 2); the narrow notch (type 3 and type 4); and the ossified notch (type 5 and type 6). Comparisons between categories were done with a one-way analysis of variance. RESULTS: There was a statistically significant difference among the three categories (P < .01): the narrow notch group (n = 442, 63.4 +/- 12.8 years) and the ossified notch group (n = 66, 65.9 +/- 10.6 years) were significantly older than the wide notch group (n = 252, 57.5 +/- 17.8 years), respectively. In patients with Rengachary type 5 shoulders, ossification was dominant on the medial side of the notch in 37 of 39 shoulders (92.3 %). CONCLUSION: The current study showed that morphological changes of the scapular notch are related to aging. The narrow notch and the ossified notch are seemed to be developed from the wide notch in terms of the ossification starting from the medial side. PMID- 26732772 TI - Discovery of variant infectious salmon anaemia virus (ISAV) of European genotype in British Columbia, Canada. AB - BACKGROUND: Infectious salmon anaemia (ISA) virus (ISAV) belongs to the genus Isavirus, family Orthomyxoviridae. ISAV occurs in two basic genotypes, North American and European. The European genotype is more widespread and shows greater genetic variation and greater virulence variation than the North American genotype. To date, all of the ISAV isolates from the clinical disease, ISA, have had deletions in the highly polymorphic region (HPR) on ISAV segment 6 (ISAV HPRDelta) relative to ISAV-HPR0, named numerically from ISAV-HPR1 to over ISAV HPR30. ISA outbreaks have only been reported in farmed Atlantic salmon, although ISAV has been detected by RT-PCR in wild fish. It is recognized that asymptomatically ISAV-infected fish exist. There is no universally accepted ISAV RT-qPCR TaqMan(r) assay. Most diagnostic laboratories use the primer-probe set targeting a 104 bp-fragment on ISAV segment 8. Some laboratories and researchers have found a primer-probe set targeting ISAV segment 7 to be more sensitive. Other researchers have published different ISAV segment 8 primer-probe sets that are highly sensitive. METHODS: In this study, we tested 1,106 fish tissue samples collected from (i) market-bought farmed salmonids and (ii) wild salmon from throughout British Columbia (BC), Canada, for ISAV using real time RT-qPCR targeting segment 8 and/or conventional RT-PCR with segment 8 primers and segment 6 HPR primers, and by virus isolation attempts using Salmon head kidney (SHK-1 and ASK-2) cell line monolayers. The sequences from the conventional PCR products were compared by multiple alignment and phylogenetic analyses. RESULTS: Seventy nine samples were "non-negative" with at least one of these tests in one or more replicates. The ISAV segment 6 HPR sequences from the PCR products matched ISAV variants, HPR5 on 29 samples, one sample had both HPR5 and HPR7b and one matched HPR0. All sequences were of European genotype. In addition, alignment of sequences of the conventional PCR product segment 8 showed they had a single nucleotide mutation in the region of the probe sequence and a 9-nucleotide overlap with the reverse primer sequence of the real time RT-qPCR assay. None of the classical ISAV segment 8 sequences in the GenBank have this mutation in the probe-binding site of the assay, suggesting the presence of a novel ISAV variant in BC. A phylogenetic tree of these sequences showed that some ISAV sequences diverted early from the classical European genotype sequences, while others have evolved separately. All virus isolation attempts on the samples were negative, and thus the samples were considered "negative" in terms of the threshold trigger set for Canadian federal regulatory action; i.e., successful virus isolation in cell culture. CONCLUSIONS: This is the first published report of the detection of ISAV sequences in fish from British Columbia, Canada. The sequences detected, both of ISAV-HPRDelta and ISAV-HPR0 are of European genotype. These sequences are different from the classical ISAV segment 8 sequences, and this difference suggests the presence of a new ISAV variant of European genotype in BC. Our results further suggest that ISAV-HPRDelta strains can be present without clinical disease in farmed fish and without being detected by virus isolation using fish cell lines. PMID- 26732773 TI - A systematic review of adolescent physiological development and its relationship with health-related behaviour: a protocol. AB - BACKGROUND: At any one time, there are one billion people worldwide who are in the second decade of their life, and 1.8 billion in the 10-24 age range. Whilst a great deal of focus has been placed on healthy early years development, the adolescent years are also a unique period of opportunity: exposure to health influencing behaviours such as alcohol consumption or cigarette smoking, may serve to establish patterns that have significant health consequences in later life. Although there is often an emphasis on risk-taking and detrimental health behaviours during adolescence, these years also provide significant opportunities for behaviour to be shaped in positive ways that may improve longer term health outcomes. However, it is firstly important to understand the complex physiological changes that are taking place within the human body during this period and their relationship with health-related behaviour. Such knowledge can help to inform health policy and intervention development. AIM: The aim of this study is to gain a comprehensive understanding of the relationship between physiological development and health-related behaviours in adolescence. METHODS: The principles of an integrative review will be used. Such reviews are of use where research has emerged in different fields, to combine existing knowledge and produce a more extensive understanding. Studies from a range of different methodological approaches, published or unpublished, will be included. A range of databases and literature depositories will be searched using a pre-defined search strategy. The review will include studies that focus on adolescents (nominally, those aged 10-24 years). We will seek papers that focus on both physiological development and health behaviour, or papers focusing solely on physiological development if there are clear implications for health behaviour. Studies with a focus on participants with specific health conditions will be excluded. Two reviewers will independently screen potential studies for eligibility and quality; members of the project team will act as third reviewers in the case of uncertainty or discrepancy. Further analyses (e.g. meta-analysis, meta-synthesis, meta-summary) will be decided upon, and sub-set analyses carried out. Finally, an integrative summation will be produced, giving a critical analysis of the results and providing conclusions and recommendations. PMID- 26732774 TI - Movement changes due to hemiplegia in stroke survivors: a hermeneutic phenomenological study. AB - PURPOSE: Meanings of movement for stroke survivors could give therapists significant insights, especially during maintenance phase. The purpose of this study was to examine how post-stroke users of a long-term elderly care facility had experienced changes in movement resulting from hemiplegia. METHOD: The participants of this study were 18 stroke survivors using a long-term elderly care facility. Based on phenomenology, between two and three interviews were conducted with each participant about their experiences with hemiplegia. Data analysis consisted of the following phases: 'data immersion', 'data transformation' and 'thematic analysis'. This study was approved by the ethics committee of the authors' institution. RESULTS: Participants experienced seven themes resulting from hemiplegia, perceiving themselves differently from the way they did before the stroke. The themes were as follows: 'inescapable dependence', 'sense of incompetence', 'lack of autonomy', 'symbol of deviation from normal', 'licence for amae', 'security of self-worth' and 'proof of effort'. CONCLUSIONS: The first four themes attempt to express participants' pain and difficulty in living with their present body; the last three attempt to express methods for coping with the present body in the company of others. Results will assist therapists to understand the significant needs of their clients in the maintenance phase. Implications for Rehabilitation Hemiplegia is paralysis of half of the body; it represents one kind of physical disability caused by stroke. Re-interpretation of how patients had experienced the changes of their movements after they had hemiplegia is helpful for the therapists to understand the significant needs for their clients. It may be especially relevant for therapists working with stroke survivors in the maintenance phase, whose functional recovery of physical movements is not expected to occur to a greater extent. PMID- 26732775 TI - Editorial. PMID- 26732776 TI - Diagnosis of Tuberculous Meningitis Using a Combination of Peripheral Blood T SPOT.TB and Cerebrospinal Fluid Interferon-gamma Detection Methods. AB - OBJECTIVE: To evaluate the effectiveness of combined peripheral blood T-SPOT.TB and cerebrospinal fluid interferon-gamma (cIFN-gamma) detection methods in the diagnosis of tuberculous meningitis (TBM). METHODS: A total of 30 individuals with TBM and 39 control individuals without TBM participated in this study. IFN gamma-secreting T cells were detected by enzyme-linked immunospot (ELISPOT), and cIFN-gamma was detected by enzyme-linked immunosorbent assay (ELISA). We collected cerebrospinal fluid from 10 patients in the TBM group on initial visit and at 4 weeks, to observe changes. RESULTS: The sensitivity and specificity of peripheral-blood T-SPOT.TB testing in the diagnosis of TBM were 70% and 87%, respectively. The area under the ROC curve of cIFN-gamma for TBM diagnosis was 0.819, and the corresponding sensitivity and specificity were 83% and 85%, respectively. When T-SPOT.TB and cIFN-gamma results were positive, the specificity and positive predictive value of TBM diagnosis reached 100%. CONCLUSIONS: Combined use of T-SPOT.TB and cIFN-gamma could improve the diagnosis efficiency of TBM. Dynamic observation of cIFN-gamma is also important in monitoring TBM because the level of this analyte significantly decreases after treatment. PMID- 26732777 TI - Serum Cystatin C and the Risk of Coronary Heart Disease in Ethnic Chinese Patients With Normal Renal Function. AB - BACKGROUND: Cystatin C, a marker for early stage chronic kidney dysfunction, mediates the pathogenesis of cardiovascular diseases. OBJECTIVE: To investigate whether serum cystatin C is an independent predictor of coronary heart disease (CHD) for patients without chronic kidney disease (CKD). METHODS: In this cross sectional study, we included 525 patients with CHD and 142 apparently healthy control individuals and acquired their demographic characteristics, medical histories, and listings of the concurrent medications they were taking. All patients with CHD underwent coronary angiography and other routine laboratory examinations. We quantified serum concentrations of cystatin C via particle enhanced immunonephelometric assay. RESULTS: Compared with controls, the patients with CHD had higher serum cystatin C levels (median: 1.17 mg/L, interquartile range [IQR]: 1.01 to 1.46 mg/L vs median: 0.98 mg/L, IQR: 0.80 to 1.06 mg/L, P <.001), lower levels of high-density lipoprotein cholesterol (P <.001), higher levels of low-density lipoprotein cholesterol (P <.001), triglyceride (P <.001), total cholesterol (P = .007) and high-sensitivity C-reactive protein (P <.001). No differences occurred in serum concentrations of creatinine or estimated glomerular filtration rate between CHD patients and healthy controls. Multivariate logistic regression indicated that levels of cystatin C (OR, 1.648; 95% confidence interval [CI], 1.454 to 1.868; P <.001) were most strongly correlated with CHD prevalence. CONCLUSIONS: Elevated serum cystatin C is a potential biochemical marker for the prediction of CHD, which suggests that mild preclinical renal dysfunction may be associated with the pathogenesis of CHD. PMID- 26732778 TI - The RIDA Allergy Screen Versus the Phadiatop Test in 430 Consecutive Patient Specimens. AB - OBJECTIVE: To compare the performances of the Phadiatop test and the RIDA qLine Allergy in specimens from the South Korean population. METHODS: We divided 430 consecutive patient specimens into 4 groups depending on the test results of the 2 assays. We evaluated the degree of agreement between the assays and used the ImmunoCAP sIgE test to identify the allergen-specific immunoglobulin E (IgE). RESULTS: Agreement between the 2 tests was significant (k = 0.614, P <.001). When tested with the ImmunoCAP allergen-specific immunoglobulin E (sIgE) test, 8 of 48 (16.7%) cases that tested RIDA qLine Allergy positive/Phadiatop negative yielded positive results and 34 of 35 (97.1%) RIDA qLine Allergy negative/Phadiatop positive cases yielded positive results in more than 1 of the 14 tested items. CONCLUSIONS: Our results suggest that the Phadiatop test is more accurate than the RIDA qLine Allergy in discrepant cases. PMID- 26732779 TI - QIAGEN Therascreen KRAS RGQ Assay, QIAGEN KRAS Pyro Assay, and Dideoxy Sequencing for Clinical Laboratory Analysis of KRAS Mutations in Tumor Specimens. AB - OBJECTIVE: To compare the performance of assays used to assess KRAS mutations in tumor specimens. METHODS: We analyzed DNA extracted from 30 formalin-fixed paraffin-embedded (FFPE) tumor specimens using the QIAGEN Therascreen KRAS RGQ and QIAGEN Pyro reagents, with dideoxy sequencing (colloquially considered to be the gold standard) as the reference method. RESULTS: We detected 22 codon 12 or 13 KRAS mutations using the Pyro assay, whereas the RGQ assay detected 19 mutations. For mutation detection, the clinical sensitivity was 86% for the RGQ assay compared with 100% for the Pyro but 100% for the KRAS mutations that the RGQ was predesigned to detect. The Pyro could detect rare mutations. The RGQ demonstrated a lower limit of detection compared with the Pyro; However, the Pyro required less DNA input than the RGQ. CONCLUSION: The 2 assays that we tested yielded comparable performance in detecting KRAS mutations, as we had expected based on assay design. Overall, the Pyro assay detects more mutations and requires less DNA input but is less analytically sensitive, compared with the RGQ assay. PMID- 26732780 TI - K2-EDTA and K3-EDTA Greiner Tubes for HbA1c Measurement. AB - OBJECTIVE: To determine whether K2-ethylenediaminetetraacetic acid (EDTA) and K3 EDTA Greiner tubes could be used interchangeably for glycosylated hemoglobin, type A1C (HbA1c) measurement via the Abbott Laboratories ARCHITECT chemiluminescent microparticle HbA1c assay on the ARCHITECT i2000SR immunoanalyzer at our university hospital. MATERIALS: We drew blood from a total of 45 outpatients into plastic Greiner Vacuette tubes, some of which were lined with K2-EDTA and others with K3-EDTA anticoagulant. Data are presented as median and interquartile range values. We used the Wilcoxon test and Passing-Bablok regression for tube comparison. RESULTS: For K2-EDTA tubes median HbA1c concentration was 54 mmol/mol (41 to 71 mmol/mol) and for K3-EDTA tubes 56 mmol/mol (43 to 69 mmol/mol). There was no statistically significant difference between K2-EDTA and K3-EDTA (bias= -1.29 mmol/mol; P = 0.24). Passing-Bablok regression showed that there is no constant and proportional error: y = -0.23 (95% CI[-3.52 to 0.69]) + 1.00( 95% CI[0.98 to 1.06]) x. CONCLUSION: In this study, we provide evidence for the lack of any clinically and statistically significant bias between K2-EDTA and K3-EDTA HbA1c measurements. Thus, Greiner tubes lined with K2-EDTA and those lined with K3-EDTA can safely be used interchangeably to measure HbA1c via the Abbott Laboratories ARCHITECT assay. PMID- 26732781 TI - Concurrent and Clonally Related Pediatric Follicular Lymphoma and Burkitt Lymphoma in a 5-Year-Old Boy. AB - Pediatric follicular lymphoma shares morphologic similarities with the adult form of the disease but lacks other classic features of adult lymphoma, including t(14;18) translocation, BCL2 overexpression, and transformation to aggressive higher-grade lymphoma. Herein, we report a novel case in which a 5-year-old boy (ethnicity unknown) had follicular lymphoma, along with concurrent high-grade and clonally related disease that fulfilled all of the morphologic, immunophenotypic, and genetic criteria for Burkitt lymphoma, including a t(8;14) translocation involving the MYC gene. To our knowledge, this case is the first reported instance of transformation of follicular lymphoma of any sort into true Burkitt lymphoma and the first reported instance of acquisition of MYC abnormalities in pediatric follicular lymphoma. PMID- 26732782 TI - Cervical FISH Testing for Triage and Support of Challenging Diagnoses: A Case Study of 2 Patients. AB - PATIENTS: A 29-year-old Caucasian woman (patient 1) and a 23-year-old Caucasian woman (patient 2).Chief Complaints: Abnormal Pap tests with high risk HPV positivity. HISTORY OF PRESENT ILLNESS: PATIENT 1: In June 2014, this patient was diagnosed with atypical squamous cells of uncertain significance (ASCUS) after a routine screening cervical Papanicolaou (Pap) test. Reflex high risk human papilloma virus (HPV) testing was performed; the results were positive (genotyping was not performed). Subsequent endocervical curettage showed a small focus of immature, atypical squamous cells with abnormally positive p16 staining and an abnormally increased proliferative index staining pattern (evaluated with Ki-67) (Images 1A-1C). These findings strongly suggested a high-grade lesion; nevertheless, due to the minute and focal nature of these findings, a diagnosis was rendered of squamous dysplasia, cannot exclude high grade dysplasia. Additional follow-up was recommended, and the option of a fluorescent in situ hybridization (FISH) assay (HPV-4C, using reagent manufactured by Cancer Genetics Italia S.r.l.) was also suggested as a method of triage to be performed using the same Thinprep collection media used to create the Pap test. The results of the FISH assay were positive, with 6.6% of cells showing gain of the 3q26 region (Image 1D). With this knowledge, the gynecologist performed a cervical loop electrosurgical excision procedure (LEEP), which revealed moderate squamous dysplasia (cervical intraepithelial neoplasia grade 2 [CIN 2]) supported by strong and abnormal p16/Ki-67 co-expression (Images 1E-1G). PATIENT 2: In June 2013, this patient was diagnosed with atypical glandular cells (AGUS) and was shown to have high-risk human papillomavirus (HPV) positivity. (Again, genotyping was not performed.) The subsequent biopsy showed mild reactive atypia of the glandular cells, which did not completely correlate with the atypical cells revealed by the Papanicolaou (Pap) test. Therefore, further follow-up was recommended. A fluorescent in situ hybridization (FISH) assay was performed on the specimen assayed via the AGUS Pap test; the FISH assay yielded positive results, showing many cells with a gain of 3q26 and 5p15 regions above the established cutoff values. A repeat Pap test was performed, which also was interpreted as indicating AGUS. Results of a second HPV-4C FISH assay showed numerous (14.6%) cells with a gain of 3q26 and 5p15 regions (Image 2A). Repeat cervical and endocervical biopsies showed scant atypical glands in otherwise generous biopsies (Image 2B). Supported by abnormal p16 and Ki-67 immunohistochemical staining results (Image 2C and 2D) and the knowledge of the abnormal FISH assay results, the pathologist diagnosed the patient with endocervical adenocarcinoma in situ (AIS). The results of a subsequent LEEP confirmed the diagnosis of endocervical adenocarcinoma in situ with negative resection margins. LABORATORY FINDINGS: Abnormal Papanicolaou (Pap) test results with high risk of human papilloma virus (HPV) positivity and scant lesional tissue, as revealed by cervical/endocervical biopsies. PMID- 26732783 TI - Prothrombin G20210A Mutation in a 53-Year-Old Male Patient with Deep Vein Thrombosis. AB - PATIENT: A 53-year-old man, ethnicity unknown. CHIEF COMPLAINT: Leg swelling and pain. HISTORY OF PRESENT ILLNESS: The patient has a history of atrial fibrillation that had been treated with 3 separate cardiac ablations, most recently in the year 2014. According to the patient, the symptoms had begun the day after his most recent cardiac ablation on June 27, 2014. The catheter for the procedure was inserted via the right femoral vein. The patient had returned to work, where he sits for an average of 8 hours per day, but his pain became unbearable, so he went to the emergency department on July 3, 2014. PREVIOUS MEDICAL HISTORY: In 2013, he was evaluated for a possible stroke. He reported consuming 1 to 2 alcoholic drinks per month, not using tobacco, and not being currently sexually active. He has no history of excessive bleeding or bruising. PREVIOUS SURGICAL HISTORY: The patient underwent an operation for an unruptured aneurysm in 2011; ablation for atrial fibrillation in 2006, 2009, and 2014; gastric bypass in 2006; left knee arthroscopy in 2010; and rotator cuff repair in 2013. FAMILY HISTORY: The patient's sister had died of a pulmonary embolism (age at time of death unknown). His father had died of a stroke at age 49 years. His mother, who is still living, has a history of intracranial aneurysms. PHYSICAL EXAMINATION RESULTS: The patient was alert and oriented; he cooperated with medical staff. His vital signs were normal, and all body systems were functioning normally. A large ecchymosis extended from his groin to his knee. PRINCIPAL LABORATORY FINDINGS: See Tables 1-5. PMID- 26732787 TI - Psychological Medicine in Bart's: improving access and awareness. AB - Providing good quality psychiatric services to patients who attend general hospital has been an area that has attracted a lot of interest.(1)(2) We know that more than one quarter of general hospital patients have a mental disorder, mental ill health impedes recovery from physical illness, and mental disorders are often unrecognised in patients with physical illness. By improving the quality of our service we hope that we can achieve better integration with the medical teams and thus tackle the aforementioned problems.(3)(4) In our trust, relevant work has been completed by the clinical health psychology team in Cardiac Rehabilitation wards. Our liaison team provides psychiatric assessment and treatment to inpatients at St Bartholomew's hospital that have been referred to us by our medical colleagues. We first observed that not all the medical teams are fully aware of the referral process and that they were keen on having training sessions and further education on the area of psychological medicine. Another area that we focused on during this process was making sure that we maintained quality of service provision while our service was in transition due to relocation. Ward based information sessions and meetings were held. An introductory session to psychiatry was also provided on medical induction. Information leaflets with referral process and contact numbers were produced for staff at ward level and for administrative support. A liaison psychiatry pathway was created to incorporate the changes that occurred after the relocation of our service. Following these interventions there was significant improvement among the staff in recognising and referring patients with psychiatric issues through the use of liaison psychiatry pathway. There was also increase in satisfaction amongst staff. Education improves understanding and awareness of mental illness and a care pathway focuses attention on this area, improving patient safety and quality of care.(5)(6). PMID- 26732789 TI - In this issue of Occupational Medicine. PMID- 26732790 TI - The hidden burden of OSA in safety critical workers: how should we deal with it? PMID- 26732788 TI - Metabolic correlates of subcutaneous and visceral abdominal fat measured by ultrasonography: a comparison with waist circumference. AB - BACKGROUND: The relative contribution of visceral (VAT) and subcutaneous (SAT) adipose tissue to cardiometabolic disease is controversial. The aim of this study was to evaluate whether dissecting abdominal fat in VAT and SAT using US may detect stronger and more specific association with MS, MS components, hyperuricemia and altered liver enzymes compared to waist circumference. METHODS: We performed a cross-sectional study on 2414 subjects aged 18 to 66 years (71 % women) followed at the International Center for the Assessment of Nutritional Status (ICANS, Milan, Italy). VAT and SAT were measured using ultrasonography. Multivariable logistic regression controlling for age and gender was used to evaluate the association of the parameters of interest (waist circumference (WC), VAT, SAT and VAT + SAT) with the MS (international harmonized definition), its components (high triglycerides, low HDL, high blood pressure, high glucose), high uric acid (>=7 mg/dl), high alanine transaminase (ALT, >= 30 U/l) and high gamma glutamyl-transferase (GGT, >= 30 U/l). RESULTS: VAT was independently associated with all the outcomes of interest, while SAT was independently associated with MS and only with high blood pressure and high ALT when we considered the single parameters of MS and NAFLD. VAT had the strongest association with high triglycerides, high ALT and high GGT. The VAT + SAT association had the strongest association with MS. WC had the strongest association with low HDL and high blood pressure. VAT and WC were similarly associated to high glucose and high uric acid. CONCLUSION: US-determined VAT and SAT are both independently associated with MS. Moreover, to our knowledge, we are the first to show that VAT, being associated to all of the MS components in addition to hyperuricemia and altered liver enzymes, performs equally or better than WC except for high blood pressure and low HDL. PMID- 26732791 TI - Ebola--what have we learned from the recent outbreak? PMID- 26732792 TI - Thomas Henry Thomas, No. 10. Washing and Tinning, Trefforest Tin-Plate Works 1874. PMID- 26732793 TI - Systematic review of the cardiovascular effects of occupational noise. AB - BACKGROUND: Cross-sectional studies of occupational noise and cardiovascular effects show an association between noise and hypertension but for coronary heart disease or other cardiovascular diseases (CVDs) the evidence is not convincing. AIMS: To assess possible associations between occupational noise exposure and the risk for cardiovascular effects in follow-up studies published after 1999. METHODS: We performed a systematic critical literature review of original articles from key literature databases of associations between workplace noise and health. The studies were identified by search in Ovid Medline, Ovid Embase, Web of Science, Scopus and ProQuest Health and Safety Sciences Abstracts. We selected prospective studies of adequate quality with a measure of association between occupational noise exposure and cardiovascular health for the meta analysis. RESULTS: Twelve papers, all prospective and mostly with high quality but with methodological shortcomings in exposure assessment, were included in the review and meta-analysis. Exposure to noise at work was consistently positively associated with hypertension [Hazard ratio (HR) = 1.68; 95% confidence interval (CI) 1.10-2.57] and CVD [relative risk (RR) = 1.34; 95% CI 1.15-1.56]. In addition, we found a trivial effect of noise exposure on CVD mortality (HR = 1.12; 95% CI 1.02-1.24). CONCLUSIONS: Occupational noise exposure is strongly associated with hypertension. For other cardiovascular effects, this meta analysis suggests a weak association, but the evidence is limited. More longitudinal studies on the effects of occupational noise on the cardiovascular system are warranted. PMID- 26732794 TI - Keeping hat making alive in Luton. PMID- 26732795 TI - Burnout in firefighters: a word on methodology. PMID- 26732796 TI - Understanding illness experiences of employees with common mental health problems. PMID- 26732797 TI - Re: Irritant hand dermatitis in health care workers. PMID- 26732798 TI - The Nordic Occupational Skin Questionnaire. PMID- 26732799 TI - Pore orientation effects on the kinetics of mesostructure loss in surfactant templated titania thin films. AB - The mesostructure loss kinetics are measured as a function of the orientation of micelles in 2D hexagonal close packed (HCP) columnar mesostructured titania thin films using in situ grazing incidence small angle X-ray scattering (GISAXS). Complementary supporting information is provided by ex situ scanning electron microscopy. Pluronic surfactant P123 acts as the template to synthesize HCP structured titania thin films. When the glass substrates are modified with crosslinked P123, the micelles of the HCP mesophase align orthogonal to the films, whereas a mix of parallel and orthogonal alignment is found on unmodified glass. The rate of mesostructure loss of orthogonally oriented (o-HCP) thin films (~60 nm thickness) prepared on modified substrate is consistently found to be less by a factor of 2.5 +/- 0.35 than that measured for mixed orientation HCP films on unmodified substrates. The activation energy for mesostructure loss is only slightly greater for films on modified glass (155 +/- 25 kJ mol(-1)) than on unmodified (128 kJ mol(-1)), which implies that the rate difference stems from a greater activation entropy for mesostructure loss in o-HCP titania films. Nearly perfect orthogonal orientation of micelles on modified surfaces contributes to the lower rate of mesostructure loss by supporting the anisotropic stresses that develop within the films during annealing due to continuous curing, sintering and crystallization into the anatase phase during high temperature calcination (>450 degrees C). Because the film thickness dictates the propagation of orientation throughout the films and the degree of confinement, thicker (~250 nm) films cast onto P123-modified substrates have a much lower activation energy for mesostructure loss (89 +/- 27 kJ mol(-1)) due to the mix of orientations found in the films. Thus, this kinetic study shows that thin P123-templated o-HCP titania films are not only better able to achieve good orthogonal alignment of the mesophase relative to thicker films or films on unmodified substrates, but that alignment of the mesophase in the films stabilizes the mesophase against thermally-induced mesostructure loss. PMID- 26732800 TI - Biosimilars: A consideration of the regulations in the United States and European union. AB - Biosimilars are defined as biological products that are highly similar to a reference product, notwithstanding minor differences in clinically inactive components. Biosimilars show no clinically meaningful differences in safety, purity, and potency of the product in comparison to the reference product. With the ever looming patent expiry of some major high cost biologics, biosimilar production is becoming ever more lucrative to companies. Europe (EU) set the precedent, followed by the United States (US) in early 2012, for the approval process for biosimilars. Therefore, the purpose of this paper is to explore the nature of the regulatory processes in the US and EU and to determine the requirements of each in the approval process of a biosimilar. The current Food and Drug Administration (FDA) and European Medicines Agency's (EMA) guidance documents for biosimilars were reviewed revealing a need for further clarifications, as well as specifically addressing Celltrion's and Sandoz's application for approval for the biosimilars infliximab and filgrastim, respectively. Currently, the FDA and EMA focus on comparability in terms of the clinical, pharmacokinetic (PK)/pharmacodynamic (PD), preclinical, biological activity, and physiochemical characterization results, as well as requiring a robust and consistent manufacturing process. Both the EU and US have prepared guidance documents for biosimilars that will result in biotherapeutics that are as safe and efficacious as the innovator product but the necessity exists to globally harmonize international nonproprietary naming nomenclature and clarify how the concept of pharmacovigilance, extrapolation, and interchangeability will be handled and regulated in the future. PMID- 26732801 TI - Prospective clinical and serological follow-up in early childhood reveals a high rate of subclinical RSV infection and a relatively high reinfection rate within the first 3 years of life. AB - Children encounter repeated respiratory tract infections during their early life. We conducted a prospective clinical and serological follow-up study to estimate the respiratory syncytial virus (RSV) primary infection and reinfection rates in early childhood. Sera were collected from 291 healthy children at the ages of 13, 24 and 36 months and antibody levels against RSV antigens were determined by enzyme immunoassay. The RT-PCR method was also used for identifying the possible presence of RSV in symptomatic patients. At ages 1, 2 and 3 years, 37%, 68% and 86%, respectively, of studied children were seropositive for RSV. In children seropositive at age 1 year, RSV reinfection rate was at least 37%. Only one of reinfected children showed evidence for a third reinfection by age 3 years. Of children who turned RSV seropositive between ages 1 and 2 years, the reinfection rate was 32% during the third year of life. The mean antibody levels at primary infection were very similar in all age groups. The average decrease of antibody levels was 25-30% within a year. In 66 cases RSV infection was identified by RT PCR. RSV infection rate in early childhood is 86% and reinfection rate is around 35%. This prospective serological follow-up study also provided evidence for the presence of RSV infections in children that did not show clinical signs warranting RSV RNA detection. PMID- 26732802 TI - Analysis of the sex ratio at birth in South Africa increased 9months after the 2010 FIFA World Cup. PMID- 26732804 TI - Performance improvement initiative: prevention of surgical site infection (SSI). AB - Mafraq Hospital performs an average of 10,000 surgeries every year. The impact of having high volume high risk surgical procedures calls for the need to ensure safe surgery and a prevention of surgical site infection (SSI). SSI represents a significant portion of healthcare-associated infections (HAIs). The impact on morbidity, mortality, and cost of care has resulted in identifying the need to reduce SSI as a top priority to prevent healthcare associated infections. The good news is that the majority of SSIs are preventable. Mafraq Hospital performs a range of surgical procedures that covers 14 surgical specialties. The infection prevention and control team performs surveillance for SSI for all patients who undergo operative procedure included in Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN) Operative Procedure Category (40 surgical procedures). Out of the 40 CDC NHSN listed, 33 operative procedures were performed at Mafraq Hospital, of which 17 were reported with SSI for 2013 and 2014. Surgical site infection has implicated an increase average length of stay from seven to 10 additional postoperative hospital days and additional costs of AED 10,000 to AED 100,000/SSI depending on procedure and pathogen. A multidisciplinary team was formed to develop and implement measures to reduce/eliminate surgical site infection, as well as evaluate and monitor compliance. Hence a group of multidisciplinary teams were initiated to analyse the results, find out the gaps, and implement a quality improvement project to correct the deficits. Recommendations for appropriate improvement measures were formed on evidence-based international guidelines from the Institute for Healthcare Improvement (IHI) and CDC. Evidence based practice supports that many of the causes of surgical site infection can be prevented with proper medical attention and care. PMID- 26732803 TI - The V81M variant of tyrosine hydroxylase is associated with more severe freezing of gait in Parkinson's disease. AB - INTRODUCTION: Many of the symptoms and signs of Parkinson's disease (PD) arise from the death of midbrain dopamine neurons that utilize tyrosine hydroxylase (TH) as the rate-limiting enzyme in catecholamine biosynthesis. METHODS: We investigated whether the presence of a common TH polymorphism affects the clinical outcomes in 101 PD subjects. We further examined the effect of this polymorphism on the purified recombinant enzyme. RESULTS: PD subjects homozygous for the common V81M polymorphism, have higher overall freezing of gait scores after controlling for disease duration, although this polymorphism does not associate with the occurrence of PD or FOG. In vitro functional assays on pure recombinant wild type TH and V81M TH revealed that the Km of the mutant enzyme for tyrosine was twice that of the wild-type. This polymorphism, however, did not change the stability of the enzyme, nor did it affect the Vmax or Km for the co substrate BH4. CONCLUSION: The data suggest that presence of a homozygous V81M polymorphism is associated with more severe FOG, possibly due to lower catecholamine synthetic capacity. Further studies are warranted to investigate the role of subtle changes in catecholamine availability in the development of FOG. PMID- 26732805 TI - omega-Imidazolyl- and omega-Tetrazolylalkylcarbamates as Inhibitors of Fatty Acid Amide Hydrolase: Biological Activity and in vitro Metabolic Stability. AB - Fatty acid amide hydrolase (FAAH) is a serine hydrolase that terminates the analgesic and anti-inflammatory effects of endocannabinoids such as anandamide. Herein, structure-activity relationship studies on a new series of aryl N-(omega imidazolyl- and omega-tetrazolylalkyl)carbamate inhibitors of FAAH were investigated. As one result, a pronounced increase in inhibitory potency was observed if a phenyl residue attached to the carbamate oxygen atom was replaced by a pyridin-3-yl moiety. The most active compounds exhibited IC50 values in the low nanomolar range. In addition, investigations on the metabolic properties of these inhibitors were performed. In rat liver homogenate and in porcine plasma, the extent of their degradation was shown to be strongly dependent on the kind of aryl residue bound to the carbamate as well as on the length and type of the alkyl spacer connecting the carbamate group with the heterocyclic system. With the aid of esterase inhibitors it was shown that in porcine plasma, carboxylesterase-like enzymes and paraoxonase are involved in carbamate cleavage. Moreover, it was found that highly active pyridin-3-yl carbamates reacted with albumin, which led to covalent albumin adducts. PMID- 26732806 TI - Assessment of dehydrothermally cross-linked collagen membrane for guided bone regeneration around peri-implant dehiscence defects: a randomized single-blinded clinical trial. AB - PURPOSE: The aim of this study was to determine the clinical feasibility of using dehydrothermally cross-linked collagen membrane (DCM) for bone regeneration around peri-implant dehiscence defects, and compare it with non-cross-linked native collagen membrane (NCM). METHODS: Dehiscence defects were investigated in twenty-eight patients. Defect width and height were measured by periodontal probe immediately following implant placement (baseline) and 16 weeks afterward. Membrane manipulation and maintenance were clinically assessed by means of the visual analogue scale score at baseline. Changes in horizontal thickness at 1 mm, 2 mm, and 3 mm below the top of the implant platform and the average bone density were assessed by cone-beam computed tomography at 16 weeks. Degradation of membrane was histologically observed in the soft tissue around the implant prior to re-entry surgery. RESULTS: Five defect sites (two sites in the NCM group and three sites in the DCM group) showed soft-tissue dehiscence defects and membrane exposure during the early healing period, but there were no symptoms or signs of severe complications during the experimental postoperative period. Significant clinical and radiological improvements were found in all parameters with both types of collagen membrane. Partially resorbed membrane leaflets were only observed histologically in the DCM group. CONCLUSIONS: These findings suggest that, compared with NCM, DCM has a similar clinical expediency and possesses more stable maintenance properties. Therefore, it could be used effectively in guided bone regeneration around dehiscence-type defects. PMID- 26732808 TI - Chickenpox-Related Multiple Pulmonary Granulomas: A Poorly Recognized Entity. PMID- 26732807 TI - Syndrome Evaluation System (SES) versus Blood Culture (BACTEC) in the Diagnosis and Management of Neonatal Sepsis--A Randomized Controlled Trial. AB - OBJECTIVE: To compare the clinical outcome of a multiplex polymerase chain reaction (PCR) based molecular diagnostic method -- Syndrome Evaluation System (SES) directed treatment strategy vs. standard of care (blood culture) directed treatment strategy for neonatal sepsis. METHODS: This randomized controlled trial (RCT) included 385 neonates with sepsis who were randomized into two groups -- SES and control (BACTEC). Both tests were performed for all the neonates. However, in the SES group, the results of SES test were revealed to the treating clinicians, while in the control group, SES results were withheld. Two ml of blood was drawn from each baby. One aliquot was sent for blood culture, whereas the remaining aliquot was sent for SES. Babies were then administered empirical IV antibiotics and given supportive care. Further antibiotic changes, if required were done in SES and control groups based on their respective reports. The microbiological profile, immediate outcome, duration of hospital stay, number of antibiotics used and readmission within a month in both groups were compared. RESULTS: SES was better than BACTEC in identifying the causative organism in both the groups (68 % vs. 18 % in SES group and 72 % vs. 18 % in control group). SES had 100 % concordance with blood culture by BACTEC. Detection of bacteria and fungi were four and ten-fold higher respectively with SES when compared to BACTEC culture. Microbiological diagnosis was rapid with SES compared to BACTEC (7 h vs. 72 h). Treatment based on SES resulted in significantly less mortality (3 % vs. 18 %). Readmission rate, duration of hospital stay and change in antibiotics were also significantly less in SES group. CONCLUSIONS: This new molecular based diagnostic system (SES) helps in rapid and accurate diagnosis of neonatal sepsis and reduces mortality and morbidity in affected neonates. PMID- 26732810 TI - The Muscle Metabolome Differs between Healthy and Frail Older Adults. AB - Populations around the world are aging rapidly. Age-related loss of physiological functions negatively affects quality of life. A major contributor to the frailty syndrome of aging is loss of skeletal muscle. In this study we assessed the skeletal muscle biopsy metabolome of healthy young, healthy older and frail older subjects to determine the effect of age and frailty on the metabolic signature of skeletal muscle tissue. In addition, the effects of prolonged whole-body resistance-type exercise training on the muscle metabolome of older subjects were examined. The baseline metabolome was measured in muscle biopsies collected from 30 young, 66 healthy older subjects, and 43 frail older subjects. Follow-up samples from frail older (24 samples) and healthy older subjects (38 samples) were collected after 6 months of prolonged resistance-type exercise training. Young subjects were included as a reference group. Primary differences in skeletal muscle metabolite levels between young and healthy older subjects were related to mitochondrial function, muscle fiber type, and tissue turnover. Similar differences were observed when comparing frail older subjects with healthy older subjects at baseline. Prolonged resistance-type exercise training resulted in an adaptive response of amino acid metabolism, especially reflected in branched chain amino acids and genes related to tissue remodeling. The effect of exercise training on branched-chain amino acid-derived acylcarnitines in older subjects points to a downward shift in branched-chain amino acid catabolism upon training. We observed only modest correlations between muscle and plasma metabolite levels, which pleads against the use of plasma metabolites as a direct read-out of muscle metabolism and stresses the need for direct assessment of metabolites in muscle tissue biopsies. PMID- 26732809 TI - Innate Immunity: Orchestrating Inflammation and Resolution of Otitis Media. AB - Otitis media (OM) is a common disease in young children, accounting for more office visits and surgeries than any other pediatric condition. It is associated with an estimated cost of five billion dollars annually in the USA. Moreover, chronic and recurrent middle ear (ME) disease leads to hearing loss during critical periods of language acquisition and learning leading to delays in reaching developmental milestones and risking permanent damage to the ME and inner ear in severe cases. Therefore, research to understand the disease pathogenesis and identify new therapeutics is important. Although OM is a multifactorial disease, targeting the molecular mechanisms that drive inflammation and OM resolution is critical. In this review, we discuss the current evidence suggesting that innate immune receptors and effectors play key roles in OM by mediating both the ME inflammatory responses and recovery. PMID- 26732811 TI - Initiating maize pre-breeding programs using genomic selection to harness polygenic variation from landrace populations. AB - BACKGROUND: The limited genetic diversity of elite maize germplasms raises concerns about the potential to breed for new challenges. Initiatives have been formed over the years to identify and utilize useful diversity from landraces to overcome this issue. The aim of this study was to evaluate the proposed designs to initiate a pre-breeding program within the Seeds of Discovery (SeeD) initiative with emphasis on harnessing polygenic variation from landraces using genomic selection. We evaluated these designs with stochastic simulation to provide decision support about the effect of several design factors on the quality of resulting (pre-bridging) germplasm. The evaluated design factors were: i) the approach to initiate a pre-breeding program from the selected landraces, doubled haploids of the selected landraces, or testcrosses of the elite hybrid and selected landraces, ii) the genetic parameters of landraces and phenotypes, and iii) logistical factors related to the size and management of a pre-breeding program. RESULTS: The results suggest a pre-breeding program should be initiated directly from landraces. Initiating from testcrosses leads to a rapid reconstruction of the elite donor genome during further improvement of the pre bridging germplasm. The analysis of accuracy of genomic predictions across the various design factors indicate the power of genomic selection for pre-breeding programs with large genetic diversity and constrained resources for data recording. The joint effect of design factors was summarized with decision trees with easy to follow guidelines to optimize pre-breeding efforts of SeeD and similar initiatives. CONCLUSIONS: Results of this study provide guidelines for SeeD and similar initiatives on how to initiate pre-breeding programs that aim to harness polygenic variation from landraces. PMID- 26732812 TI - NIR Electrofluorochromic Properties of Aza-Boron-dipyrromethene Dyes. AB - The photophysical properties of near-infrared (NIR) emissive aza-boron dipyrromethene (aza-BDP) dyes incorporating nitrofluorene and alkoxy decorations were intensively investigated. Their highly reversible one-electron reduction process showed characteristic electrofluorochromic (EF) properties in the NIR range, depending on the substituents. The nitrofluorene ethynyl-substituted (Type I) dyes showed smaller EF effects than the alkoxy-containing (Type II) dyes because of the difference in their intrinsic fluorescence contrast between the neutral and reduced states (radical anion). In addition, the Type II chromophores showed a larger diffusion coefficient for ion transport, which enhanced the EF contrast and the response time for the fluorescence change at a given step potential. With an optimized condition, the NIR EF ON/OFF ratio reached a value of 6.1 and a long cyclability over 1000 EF cycles between -0.4 V and +0.4 V switching potentials, with approximately 20% loss of the initial ON/OFF switching ratio. The NIR EF switching was visually observed through a visible light cut-off filter, featuring high fluorescence contrast. PMID- 26732813 TI - Chronic traumatic encephalopathy is reported in 25 year old former American football player. PMID- 26732814 TI - Natural and synthetic vocalizations of brown rat pups, Rattus norvegicus, enhance attractiveness of bait boxes in laboratory and field experiments. AB - BACKGROUND: Rats are often neophobic and thus do not readily enter trap boxes which are mandated in rodent management to help reduce the risk of accidental poisoning or capture of non-target animals. Working with brown rats, Rattus norvegicus, as a model species, our overall objective was to test whether sound cues from pups could be developed as a means to enhance captures of rats in trap boxes. RESULTS: Recording vocalizations from three-day-old pups after removal from their natal nest with both sonic and ultrasonic microphones revealed frequency components in the sonic range (1.8-7.5 kHz) and ultrasonic range (18-24 kHz, 33-55 kHz, 60-96 kHz). In two-choice laboratory bioassays, playback recordings of these vocalizations induced significant phonotactic and arrestment responses by juvenile, subadult and adult female and male rats. The effectiveness of engineered 'synthetic' rat pup sounds was dependent upon their frequency components, sound durations and the sound delivery system. Unlike other speakers, a piezoelectric transducer emitting sound bursts of 21 kHz with a 63-KHz harmonic, and persisting for 20-300 ms, proved highly effective in attracting and arresting adult female rats. In a field experiment, a battery-powered electronic device fitted with a piezoelectric transducer and driven by an algorithm that randomly generated sound cues resembling those recorded from rat pups and varying in fundamental frequency (19-23 kHz), duration (20-300 ms) and intermittent silence (300-5000 ms) significantly enhanced captures of rats in trap boxes baited with a food lure and soiled bedding material of adult female rats. CONCLUSION: Our study provides proof of concept that rat-specific sound cues or signals can be effectively reproduced and deployed as a means to enhance capture of wild rats. (c) 2016 Society of Chemical Industry. PMID- 26732815 TI - Gene-Environment Interplay in Adulthood. PMID- 26732816 TI - A closer look at prototypes: similarity, favourability, and the prototype willingness model. A response to the commentary of Gibbons and Gerrard. PMID- 26732817 TI - G-395A polymorphism in the promoter region of the KLOTHO gene associates with reduced cognitive impairment among the oldest old. AB - This study aimed to examine the possible association between G-395A polymorphism in the promoter region of the KLOTHO gene and cognitive impairment among Chinese nonagenarians and centenarians. This study is a secondary analysis of the Project of Longevity and Aging in Dujiangyan (PLAD) study. Community-dwelling Chinese people aged 90 years or older were included. G-395A (rs1207568) genotyping in the promoter region of the KLOTHO gene was performed using the TaqMan allelic discrimination assay. Cognitive function was assessed with the mini-mental status examination (MMSE). A total of 706 participants (68.0 % female; mean age 93.5 +/- 3.6 years) were included. The KLOTHO G-395A polymorphism genotype frequencies for the whole sample were 2.0 % AA, 30.3 % GA, and 67.7 % GG. The GG genotype frequencies for the cognitive impairment and control groups were 70.2 and 62.7 %, respectively. Cognitive impairment prevalence was significantly lower in the GA+AA group than in the GG genotype group (61.4 vs. 69.0 %, p = 0.044). GA+AA genotype subjects had a significantly lower risk of cognitive impairment (odds ratio 0.66; 95 % confidence interval 0.44 to 0.98) than GG genotype individuals after adjusting for age, gender, and other relevant risk factors. KLOTHO G-395A polymorphism associates with reduced cognitive impairment in a sample of Chinese nonagenarians and centenarians. PMID- 26732819 TI - Mycobacterium abscessus Complex - a Particular Challenge in the Setting of Lung Transplantation. AB - Mycobacterium abscessus complex is an emerging pathogen in lung transplant candidates and recipients. M. abscessus complex is widespread in the environment and can cause pulmonary, skin and soft tissue, and disseminated infection, particularly in lung transplant recipients. It is innately resistant to many antibiotics making it difficult to treat. Herein we describe the epidemiology, clinical manifestations, diagnosis and treatment of M. abscessus with an emphasis on lung transplant candidates and recipients. We also outline the areas where data are lacking and the areas where further research is urgently needed. PMID- 26732821 TI - Trends in OSHA Compliance Monitoring Data 1979-2011: Statistical Modeling of Ancillary Information across 77 Chemicals. AB - OBJECTIVES: The Integrated Management Information System (IMIS) is the largest multi-industry source of exposure measurements available in North America. However, many have suspected that the criteria through which worksites are selected for inspection are related to exposure levels. We investigated associations between exposure levels and ancillary variables in IMIS in order to understand the predictors of high exposure within an enforcement context. METHODS: We analyzed the association between nine variables (reason for inspection, establishment size, total amount of penalty, Occupational Safety and Health Administration (OSHA) plan, OSHA region, union status, inspection scope, year, and industry) and exposure levels in IMIS using multimodel inference for 77 agents. For each agent, we used two different types of models: (i) logistic models were used for the odds ratio (OR) of exposure being above the threshold limit value (TLV) and (ii) linear models were used for exposure concentrations restricted to detected results to estimate percent increase in exposure level, i.e. relative index of exposure (RIE). Meta-analytic methods were used to combine results for each variable across agents. RESULTS: A total of 511,047 exposure measurements were modeled for logistic models and 299,791 for linear models. Higher exposures were measured during follow-up inspections than planned inspections [meta-OR = 1.61, 95% confidence interval (CI): 1.44-1.81; meta-RIE = 1.06, 95% CI: 1.03-1.09]. Lower exposures were observed for measurements collected under state OSHA plans compared to measurements collected under federal OSHA (meta-OR = 0.82, 95% CI: 0.73-0.92; meta-RIE = 0.86, 95% CI: 0.81-0.91). A 'high' total historical amount of penalty relative to none was associated with higher exposures (meta-OR = 1.54, 95% CI: 1.40-1.71; meta-RIE = 1.18, 95% CI: 1.13-1.23). CONCLUSIONS: The relationships observed between exposure levels and ancillary variables across a vast majority of agents suggest that certain elements of OSHA's process of selecting worksites for inspection influence the exposure levels that OSHA inspectors encounter. Nonetheless, given the paucity of other sources of exposure data and the lack of a more demonstrably representative data source, our study considers the use of IMIS data for the estimation of exposures in the broader universe of worksites in the USA. PMID- 26732820 TI - Combining Decision Rules from Classification Tree Models and Expert Assessment to Estimate Occupational Exposure to Diesel Exhaust for a Case-Control Study. AB - OBJECTIVES: To efficiently and reproducibly assess occupational diesel exhaust exposure in a Spanish case-control study, we examined the utility of applying decision rules that had been extracted from expert estimates and questionnaire response patterns using classification tree (CT) models from a similar US study. METHODS: First, previously extracted CT decision rules were used to obtain initial ordinal (0-3) estimates of the probability, intensity, and frequency of occupational exposure to diesel exhaust for the 10 182 jobs reported in a Spanish case-control study of bladder cancer. Second, two experts reviewed the CT estimates for 350 jobs randomly selected from strata based on each CT rule's agreement with the expert ratings in the original study [agreement rate, from 0 (no agreement) to 1 (perfect agreement)]. Their agreement with each other and with the CT estimates was calculated using weighted kappa (kappa w) and guided our choice of jobs for subsequent expert review. Third, an expert review comprised all jobs with lower confidence (low-to-moderate agreement rates or discordant assignments, n = 931) and a subset of jobs with a moderate to high CT probability rating and with moderately high agreement rates (n = 511). Logistic regression was used to examine the likelihood that an expert provided a different estimate than the CT estimate based on the CT rule agreement rates, the CT ordinal rating, and the availability of a module with diesel-related questions. RESULTS: Agreement between estimates made by two experts and between estimates made by each of the experts and the CT estimates was very high for jobs with estimates that were determined by rules with high CT agreement rates (kappa w: 0.81-0.90). For jobs with estimates based on rules with lower agreement rates, moderate agreement was observed between the two experts (kappa w: 0.42-0.67) and poor-to-moderate agreement was observed between the experts and the CT estimates (kappa w: 0.09-0.57). In total, the expert review of 1442 jobs changed 156 probability estimates, 128 intensity estimates, and 614 frequency estimates. The expert was more likely to provide a different estimate when the CT rule agreement rate was <0.8, when the CT ordinal ratings were low to moderate, or when a module with diesel questions was available. CONCLUSIONS: Our reliability assessment provided important insight into where to prioritize additional expert review; as a result, only 14% of the jobs underwent expert review, substantially reducing the exposure assessment burden. Overall, we found that we could efficiently, reproducibly, and reliably apply CT decision rules from one study to assess exposure in another study. PMID- 26732822 TI - Coherence and resonance effects in the ultra-intense laser-induced ultrafast response of complex atoms. AB - Both coherent pumping and energy relaxation play important roles in understanding physical processes of ultra-intense coherent light-matter interactions. Here, using a large-scale quantum master equation approach, we describe dynamical processes of practical open quantum systems driven by both coherent and stochastic interactions. As examples, two typical cases of light-matter interactions are studied. First, we investigate coherent dynamics of inner-shell electrons of a neon gas irradiated by a high-intensity X-ray laser along with vast number of decaying channels. In these single-photon dominated processes, we find that, due to coherence-induced Rabi oscillations and power broadening effects, the photon absorptions of a neon gas can be suppressed resulting in differences in ionization processes and final ion-stage distributions. Second, we take helium as an example of multiphoton and multichannel interference dominated electron dynamics, by investigating the transient absorption of an isolated attosecond pulse in the presence of a femtosecond infrared laser pulse. PMID- 26732824 TI - Female genital mutilation/cutting type IV in Cambodia: a case report. AB - Nontherapeutic female genital modifications can cause short- and long-term consequences. Caregivers should promote women's self knowledge on genitals' anatomy and physiology, and psychophysical and sexual health. They should also inform on possible negative consequences of vulvar nontherapeutic alterations requested and avoid the medicalization of female genital mutilation. PMID- 26732825 TI - A newly discovered muscle: The tensor of the vastus intermedius. AB - The quadriceps femoris is traditionally described as a muscle group composed of the rectus femoris and the three vasti. However, clinical experience and investigations of anatomical specimens are not consistent with the textbook description. We have found a second tensor-like muscle between the vastus lateralis (VL) and the vastus intermedius (VI), hereafter named the tensor VI (TVI). The aim of this study was to clarify whether this intervening muscle was a variation of the VL or the VI, or a separate head of the extensor apparatus. Twenty-six cadaveric lower limbs were investigated. The architecture of the quadriceps femoris was examined with special attention to innervation and vascularization patterns. All muscle components were traced from origin to insertion and their affiliations were determined. A TVI was found in all dissections. It was supplied by independent muscular and vascular branches of the femoral nerve and lateral circumflex femoral artery. Further distally, the TVI combined with an aponeurosis merging separately into the quadriceps tendon and inserting on the medial aspect of the patella. Four morphological types of TVI were distinguished: Independent-type (11/26), VI-type (6/26), VL-type (5/26), and Common-type (4/26). This study demonstrated that the quadriceps femoris is architecturally different from previous descriptions: there is an additional muscle belly between the VI and VL, which cannot be clearly assigned to the former or the latter. Distal exposure shows that this muscle belly becomes its own aponeurosis, which continues distally as part of the quadriceps tendon. PMID- 26732823 TI - Rice phytochrome-interacting factor protein OsPIF14 represses OsDREB1B gene expression through an extended N-box and interacts preferentially with the active form of phytochrome B. AB - DREB1/CBF genes, known as major regulators of plant stress responses, are rapidly and transiently induced by low temperatures. Using a yeast one-hybrid screening, we identified a putative Phytochrome-Interacting bHLH Factor (OsPIF14), as binding to the OsDREB1B promoter. bHLH proteins are able to bind to hexameric E box (CANNTG) or N-box (CACG(A/C)G) motifs, depending on transcriptional activity. We have shown that OsPIF14 binds to the OsDREB1B promoter through two N-boxes and that the flanking regions of the hexameric core are essential for protein-DNA interaction and stability. We also showed that OsPIF14 down-regulates OsDREB1B gene expression in rice protoplasts, corroborating the OsPIF14 repressor activity observed in the transactivation assays using Arabidopsis protoplasts. In addition, we showed that OsPIF14 is indeed a phytochrome interacting factor, which preferentially binds to the active form (Pfr) of rice phytochrome B. This raises the possibility that OsPIF14 activity might be modulated by light. However, we did not observe any regulation of the OsDREB1B gene expression by light under control conditions. Moreover, OsPIF14 gene expression was shown to be modulated by different treatments, such as drought, salt, cold and ABA. Interestingly, OsPIF14 showed also a specific cold-induced alternative splicing. All together, these results suggest the possibility that OsPIF14 is involved in cross-talk between light and stress signaling through interaction with the OsDREB1B promoter. Although in the absence of stress, OsDREB1B gene expression was not regulated by light, given previous reports, it remains possible that OsPIF14 has a role in light modulation of stress responses. PMID- 26732826 TI - Xenograft of human umbilical mesenchymal stem cells from Wharton's jelly as a potential therapy for rat pilocarpine-induced epilepsy. AB - We evaluated the effects of intra-hippocampal transplantation of human umbilical mesenchymal stem cells (HUMSCs) on pilocarpine-treated rats. Sprague-Dawley rats were divided into the following three groups: (1) a normal group of rats receiving only PBS, (2) a status epilepticus (SE) group of rats with pilocarpine induced SE and PBS injected into the hippocampi, and (3) a SE+HUMSC group of SE rats with HUMSC transplantation. Spontaneous recurrent motor seizures (SRMS) were monitored using simultaneous video and electroencephalographic recordings at two to four weeks after SE induction. The results showed that the number of SRMS within two to four weeks after SE was significantly decreased in SE+HUMSCs rats compared with SE rats. All of the rats were sacrificed on Day 29 after SE. Hippocampal morphology and volume were evaluated using Nissl staining and magnetic resonance imaging. The results showed that the volume of the dorsal hippocampus was smaller in SE rats compared with normal and SE+HUMSCs rats. The pyramidal neuron loss in CA1 and CA3 regions was more severe in the SE rats than in normal and SE+HUMSCs rats. No significant differences were found in the hippocampal neuronal loss or in the number of dentate GABAergic neurons between normal and SE+HUMSCs rats. Compared with the SE rats, the SE+HUMSCs rats exhibited a suppression of astrocyte activity and aberrant mossy fiber sprouting. Implanted HUMSCs survived in the hippocampus and released cytokines, including FGF-6, amphiregulin, glucocorticoid-induced tumor necrosis factors receptor (GITR), MIP-3beta, and osteoprotegerin. In an in vitro study, exposure of cortical neurons to glutamate showed a significant decrease in cell viability, which was preventable by co-culturing with HUMSCs. Above all, the expression of human osteoprotegerin and amphiregulin were significantly increased in the media of the co-culture of neurons and HUMSCs. Our results demonstrate the therapeutic benefits of HUMSC transplantation for the development of epilepsy, which are likely due to the ability of the cells to produce neuroprotective and anti inflammatory cytokines. Thus, HUMSC transplantation may be an effective therapy in the future. PMID- 26732827 TI - Intrinsic functional connectivity of insular cortex and symptoms of sickness during acute experimental inflammation. AB - Task-based fMRI has been used to study the effects of experimental inflammation on the human brain, but it remains unknown whether intrinsic connectivity in the brain at rest changes during a sickness response. Here, we investigated the effect of experimental inflammation on connectivity between areas relevant for monitoring of bodily states, motivation, and subjective symptoms of sickness. In a double-blind randomized controlled experiment, 52 healthy volunteers were injected with 0.6ng/kg LPS (lipopolysaccharide) or placebo, and participated in a resting state fMRI experiment after approximately 2h 45min. Resting state fMRI data were available from 48 participants, of which 28 received LPS and 20 received placebo. Bilateral anterior and bilateral posterior insula sections were used as seed regions and connectivity with bilateral orbitofrontal and cingulate (anterior and middle) cortices was investigated. Back pain, headache and global sickness increased significantly after as compared to before LPS, while a non significant trend was shown for increased nausea. Compared to placebo, LPS was followed by increased connectivity between left anterior insula and left midcingulate cortex. This connectivity was significantly correlated to increase in back pain after LPS and tended to be related to increased global sickness, but was not related to increased headache or nausea. LPS did not affect the connectivity from other insular seeds. In conclusion, the finding of increased functional connectivity between left anterior insula and middle cingulate cortex suggests a potential neurophysiological mechanism that can be further tested to understand the subjective feeling of malaise and discomfort during a sickness response. PMID- 26732828 TI - Can an Emotional Reaction Mimicking White-coat Hypertension Cause Hypertensive Crisis and Cardiac Failure? PMID- 26732829 TI - Predictors of perceptions of mental illness and averseness to help: a survey of elite football players. AB - BACKGROUND: Hypermasculinity may impact elite football players' willingness to seek help for mental health problems. AIMS: This quantitative study sought to identify what set of characteristics, including hypermasculinity, best predicts elite football players' mental health attitudes. METHOD: The Attitude Scale for Mental Illness, Inventory of Attitudes toward Seeking Mental Health Services, and Athlete's Perception of Masculinity Scale were self-administered to 112 football players from the NFLPA and the Washington, DC metro area. RESULTS: Canonical correlation analysis was used to develop a regression model that best predicts elite football players' mental health attitudes. This study found that though the athletes have high levels of hypermasculinity (x = 19.66, SD = 7.43), other factors, including marital status and sport level lessen the effects of hypermasculinity and facilitate positive perceptions of mental illness and receptivity to help. CONCLUSIONS: Predictors suggest that therapeutic efforts targeted toward family and support networks, as well as intervention strategies for decreasing mental illness stigma are essential to encourage positive mental health attitudes in elite football players. PMID- 26732831 TI - Rehabilitation nutrition for undernourished participants in nursing home and home care: Cluster randomized controlled study. PMID- 26732830 TI - Reverse transduction measured in the living cochlea by low-coherence heterodyne interferometry. AB - It is generally believed that the remarkable sensitivity and frequency selectivity of mammalian hearing depend on outer hair cell-generated force, which amplifies sound-induced vibrations inside the cochlea. This 'reverse transduction' force production has never been demonstrated experimentally, however, in the living ear. Here by directly measuring microstructure vibrations inside the cochlear partition using a custom-built interferometer, we demonstrate that electrical stimulation can evoke both fast broadband and slow sharply tuned responses of the reticular lamina, but only a slow tuned response of the basilar membrane. Our results indicate that outer hair cells can generate sufficient force to drive the reticular lamina over all audible frequencies in living cochleae. Contrary to expectations, the cellular force causes a travelling wave rather than an immediate local vibration of the basilar membrane; this travelling wave vibrates in phase with the reticular lamina at the best frequency, and results in maximal vibration at the apical ends of outer hair cells. PMID- 26732832 TI - Transient severe hypercholesterolemia following bariatric surgery treated successfully with increased food intake. AB - We describe a case of transient severe hypercholesterolemia after bariatric surgery treated successfully with increased food intake. A 25-y-old policeman who had sleeve gastrectomy for morbid obesity 10 mo previously presented with generalized weakness, constipation, and significant weight loss after severe dietary restriction. All his preoperative and prior investigations were normal. Further investigation revealed severe total and low-density lipoprotein hypercholesterolemia. After all other causes of secondary hypercholesterolemia were excluded, a diagnosis of starvation-induced hypercholesterolemia was made. The patient was therefore started on a normal mixed diet gradually increased to achieve satiation. His dietary intake, body weight, and lipid profile were monitored over a 3-mo period. Eventually his symptoms abated, weight increased, and lipid profile returned back to normal levels. Although dietary management of failed weight loss after bariatric surgery is the main priority for health professionals, this case illustrates the possible harm of severe dietary restriction after surgery and the need for judicious dietary and nutritional management. PMID- 26732833 TI - Effect of curcumin on TNFR2 and TRAF2 in unilateral ureteral obstruction in rats. AB - OBJECTIVES: Tumor necrosis factor alpha (TNF-alpha) is implicated in the pathophysiology of renal obstruction through its interactions with two TNF-alpha receptors: TNFR1 and TNFR2. Activation of TNFR1 leads to the recruitment of the adaptor TNFR-associated death domain protein (TRADD), which binds the Ser/Thr kinase receptor-interacting protein (RIP) and TNFR-associated factors 2 (TRAF2). This TRADD-RIP-TRAF complex causes activation of the antiapoptotic pathway and inhibits caspase 8 activation. Meanwhile, activation of TNFR2 leads to depletion of TRAF2 and enhancement of the apoptotic pathway. Curcumin, the major component found in turmeric spice, has been reported to possess a protective role against renal injury elicited by unilateral ureteral obstruction (UUO). The present study aimed mainly to address the cytoprotective role of curcumin-rich diet (5% w/w) on the apoptotic pathway induced by UUO in rats after 30 d of ligation. METHODS: The levels of mRNA for TNFR1, TNFR2, RIP, TRAF2, and caspase 8 were measured by reverse transcription-polymerase chain reaction. The levels of TNF-alpha was determined by ELISA. Kidney sections were exposed to histologic and morphometric studies. RESULTS: Administration of curcumin decreased TNF-alpha, TNFR2, and caspase 8 without affecting TNFR1 levels. The gene expression levels of the antiapoptotic molecules RIP and TRAF2 were increased. CONCLUSIONS: The cytoprotective role of curcumin relies on its ability to decrease the TNFR2 mRNA and enhance the antiapoptotic molecules RIP and TRAF2 to decrease the apoptotic pathway via decreasing the caspase 8. PMID- 26732834 TI - The impact of red and processed meat consumption on cardiovascular disease risk in women. AB - OBJECTIVE: Recent studies suggest that red and processed meat consumption is strongly linked to cardiovascular disease (CVD), the leading cause of death in Australian women. The aim of this study was to examine the association of red and processed meat consumption with CVD using the Framingham score. METHODS: Included in the analysis were two separate female cohorts, one from an Internet-based health survey (n = 13 509, age range 30-74) and the other from a longitudinal epidemiological study (n = 176, age range 65-74). Information was available on red and processed meat consumption, exercise, and all parameters required for calculation of the Framingham score. Binomial regression was used to examine the association within the Internet-based cohort, whereas Kruskal-Wallis H tests and a Mann-Whitney U test were employed for analysis of the data in the epidemiological study. RESULTS: Consumption of red and processed meat 3 to 4 times and >5 times per week was associated with Framingham scores 1.064 (P = 0.002) and 1.108 (P <= 0.001) times higher, respectively, compared with consuming <1 time per week (n = 13509). A similar pattern was observed in the more detailed cohort, where those in the highest quartile of processed meat consumption had a relative 28.5% increase in median Framingham scores compared with the lowest quartile, with a difference of 4.5 observed (P = 0.043). No relationship was observed when red meat was investigated exclusively. CONCLUSION: The results of our analysis support an association between red and processed meat consumption and CVD risk in women and suggest that the association is stronger for processed meat alone. PMID- 26732836 TI - Intravenous lipid emulsions in kidney transplant patients requiring parenteral nutrition. PMID- 26732835 TI - Protective effects of a grape-supplemented diet in a mouse model of retinal degeneration. AB - OBJECTIVE: Retinal degenerations are a class of devastating blinding diseases that are characterized by photoreceptor dysfunction and death. In this study, we tested whether grape consumption, in the form of freeze-dried grape powder (FDGP), improves photoreceptor survival in a mouse model of retinal degeneration. METHODS: Retinal degeneration was induced in mice by acute oxidative stress using subretinal injection of paraquat. The grape-supplemented diet was made by formulating base mouse chow with FDGP, corresponding to three daily human servings of grapes, and a control diet was formulated with equivalent sugar composition as FDGP (0.68% glucose-0.68% fructose mixture). Mice were placed on the diets at weaning for 5 wk before oxidative stress injury until analysis at 2 wk post-injection. Retinal function was measured using electroretinography, thickness of the photoreceptor layer was measured using optical coherence tomography, and rows of photoreceptor nuclei were counted on histologic sections. RESULTS: In mice fed the control diet, oxidative stress significantly reduced photoreceptor layer thickness and photoreceptor numbers. In contrast, retinal thickness and photoreceptor numbers were not reduced by oxidative stress in mice on the grape-supplemented diet, indicating significantly higher photoreceptor survival after injury than mice on the control diet. Furthermore, mice on the grape diet showed preservation of retinal function after oxidative stress injury compared with mice on the control diet. CONCLUSIONS: A diet supplemented with grapes rescued retinal structure and function in an oxidative stress-induced mouse model of retinal degeneration, which demonstrates the beneficial effect of grapes on photoreceptors. PMID- 26732837 TI - Future developments: your thoughts and our plans. PMID- 26732839 TI - The evolution of basal progenitors in the developing non-mammalian brain. AB - The amplification of distinct neural stem/progenitor cell subtypes during embryogenesis is essential for the intricate brain structures present in various vertebrate species. For example, in both mammals and birds, proliferative neuronal progenitors transiently appear on the basal side of the ventricular zone of the telencephalon (basal progenitors), where they contribute to the enlargement of the neocortex and its homologous structures. In placental mammals, this proliferative cell population can be subdivided into several groups that include Tbr2(+) intermediate progenitors and basal radial glial cells (bRGs). Here, we report that basal progenitors in the developing avian pallium show unique morphological and molecular characteristics that resemble the characteristics of bRGs, a progenitor population that is abundant in gyrencephalic mammalian neocortex. Manipulation of LGN (Leu-Gly-Asn repeat enriched protein) and Cdk4/cyclin D1, both essential regulators of neural progenitor dynamics, revealed that basal progenitors and Tbr2(+) cells are distinct cell lineages in the developing avian telencephalon. Furthermore, we identified a small population of subapical mitotic cells in the developing brains of a wide variety of amniotes and amphibians. Our results suggest that unique progenitor subtypes are amplified in mammalian and avian lineages by modifying common mechanisms of neural stem/progenitor regulation during amniote brain evolution. PMID- 26732838 TI - When stem cells grow old: phenotypes and mechanisms of stem cell aging. AB - All multicellular organisms undergo a decline in tissue and organ function as they age. An attractive theory is that a loss in stem cell number and/or activity over time causes this decline. In accordance with this theory, aging phenotypes have been described for stem cells of multiple tissues, including those of the hematopoietic system, intestine, muscle, brain, skin and germline. Here, we discuss recent advances in our understanding of why adult stem cells age and how this aging impacts diseases and lifespan. With this increased understanding, it is feasible to design and test interventions that delay stem cell aging and improve both health and lifespan. PMID- 26732840 TI - The AP-1 transcription factor component Fosl2 potentiates the rate of myocardial differentiation from the zebrafish second heart field. AB - The vertebrate heart forms through successive phases of cardiomyocyte differentiation. Initially, cardiomyocytes derived from first heart field (FHF) progenitors assemble the linear heart tube. Thereafter, second heart field (SHF) progenitors differentiate into cardiomyocytes that are accreted to the poles of the heart tube over a well-defined developmental window. Although heart tube elongation deficiencies lead to life-threatening congenital heart defects, the variables controlling the initiation, rate and duration of myocardial accretion remain obscure. Here, we demonstrate that the AP-1 transcription factor, Fos-like antigen 2 (Fosl2), potentiates the rate of myocardial accretion from the zebrafish SHF. fosl2 mutants initiate accretion appropriately, but cardiomyocyte production is sluggish, resulting in a ventricular deficit coupled with an accumulation of SHF progenitors. Surprisingly, mutant embryos eventually correct the myocardial deficit by extending the accretion window. Overexpression of Fosl2 also compromises production of SHF-derived ventricular cardiomyocytes, a phenotype that is consistent with precocious depletion of the progenitor pool. Our data implicate Fosl2 in promoting the progenitor to cardiomyocyte transition and uncover the existence of regulatory mechanisms to ensure appropriate SHF mediated cardiomyocyte contribution irrespective of embryonic stage. PMID- 26732842 TI - Resolving embryonic blood cell fate choice in Drosophila: interplay of GCM and RUNX factors. PMID- 26732843 TI - Bicaudal C1 promotes pancreatic NEUROG3+ endocrine progenitor differentiation and ductal morphogenesis. PMID- 26732841 TI - Attractant and repellent cues cooperate in guiding a subset of olfactory sensory axons to a well-defined protoglomerular target. AB - Olfactory sensory axons target well-defined intermediate targets in the zebrafish olfactory bulb called protoglomeruli well before they form odorant receptor specific glomeruli. A subset of olfactory sensory neurons are labeled by expression of the or111-7:IRES:GAL4 transgene whose axons terminate in the central zone (CZ) protoglomerulus. Previous work has shown that some of these axons misproject to the more dorsal and anterior dorsal zone (DZ) protoglomerulus in the absence of Netrin 1/Dcc signaling. In search of additional cues that guide these axons to the CZ, we found that Semaphorin 3D (Sema3D) is expressed in the anterior bulb and acts as a repellent that pushes them towards the CZ. Further analysis indicates that Sema3D signaling is mediated through Nrp1a, while Nrp2b also promotes CZ targeting but in a Sema3D-independent manner. nrp1a, nrp2b and dcc transcripts are detected in or111-7 transgene-expressing neurons early in development and both Nrp1a and Dcc act cell-autonomously in sensory neurons to promote accurate targeting to the CZ. dcc and nrp1a double mutants have significantly more DZ misprojections than either single mutant, suggesting that the two signaling systems act independently and in parallel to direct a specific subset of sensory axons to their initial protoglomerular target. PMID- 26732844 TI - Methylene Blue Injection as an Alternative to Antegrade Nephrostography to Assess Urinary Obstruction After Percutaneous Nephrolithotomy. AB - AIMS AND OBJECTIVES: Percutaneous nephrolithotomy (PCNL) remains an effective treatment for large stones. When nephrostomy tube (NT) is left post operation, antegrade urine flow is often confirmed with antegrade nephrostography (ANG) before tube removal. We compare methylene blue (MB) test combined with NT capping trial against ANG to assess antegrade urine flow after PCNL. MATERIALS AND METHODS: One hundred one consecutive patients undergoing PCNL were prospectively enrolled between 7/2014 and 4/2015. An NT cap was placed the morning of postoperative day 1 (POD1). Failure was defined as need to uncap the NT for any reason. Two hours after capping, 7cc MB was injected into the NT. Positive MB test was defined as presence of blue per bladder Foley. ANG was then performed to assess antegrade urine flow. NTs were removed before discharge home when antegrade flow was documented. Primary outcomes included presence of antegrade flow on ANG and NT removal before discharge home. Receiver operating characteristic (ROC) and areas (Area under the ROC [AUC]), as well as Cohen's kappa coefficient (kappa), were calculated comparing agreement of capping trial, MB, and ANG with NT removal. RESULTS: One hundred one subjects were included in this analysis. 52.9% were left-sided surgeries and 60.4% utilized lower pole punctures. On ROC areas evaluating tests for agreement with NT removal before discharge, MB AUC 0.71 (95% CI 0.60-0.83), capping trial AUC 0.66 (95% CI 0.57 0.75), combed capping trial and MB AUC 0.72 (95% CI 0.61-0.84), and ANG AUC 0.78 (95% CI 0.68-0.88). In predicting NT removal, ANG performed better than capping trial alone (p = 0.042), but no differences were seen between MB and ANG (p = 0.229), combining the capping trial with MB test and ANG (p = 0.266) or combined testing and MB alone (p = 0.972). CONCLUSIONS: Combining capping trial with MB injection is similarly accurate for predicting NT removal after PCNL compared to ANG. Capping trial and MB may be used in combination to obviate the need for ANG. PMID- 26732847 TI - Stacks of graphene with silicane or germanane: a first-principles study. AB - We report the results of density-functional theory calculations on the stability and properties of hybrid layered systems composed of graphene and silicane or germanane monolayers. We find that the interlayer binding energy between the sheets is comparable to that of graphite, indicating that the creation of the corresponding stacks is feasible. Moreover, we show that the hybrid systems are stable against the formation of defects caused by the transfer of hydrogen atoms from one layer to another. Finally, we find that the graphene layer of the graphene-germanane stack retains its pristine electronic properties, at least close to the Fermi level. Therefore, stacks of graphene with silicane or germanane may be utilized in graphene-based devices by combining zero-gap graphene with wide band-gap two-dimensional semiconductors. PMID- 26732846 TI - Resting and Initial Beta Amplitudes Predict Learning Ability in Beta/Theta Ratio Neurofeedback Training in Healthy Young Adults. AB - Neurofeedback (NF) training has been proved beneficial in cognitive and behavioral performance improvement in healthy individuals. Unfortunately, the NF learning ability shows large individual difference and in a number of NF studies there are even some non-learners who cannot successfully self-regulate their brain activity by NF. This study aimed to find out the neurophysiological predictor of the learning ability in up-regulating beta-1 (15-18 Hz)/theta (4-7 Hz) ratio (BTR) training in healthy young adults. Eighteen volunteers finished five training sessions in successive 5 days. We found that low beta (12-15 Hz) amplitude in a 1-min eyes-open resting baseline measured before training and the beta-1 amplitude in the first training block with 4.5-min duration could predict the BTR learning ability across sessions. The results provide a low cost, convenient and easy way to predict the learning ability in up-regulating BTR training, and would be helpful in avoiding potential frustration and adjusting training protocol for the participants with poor learning ability. PMID- 26732845 TI - Cognitive Collaborations: Bidirectional Functional Connectivity Between the Cerebellum and the Hippocampus. AB - There is a growing recognition that the utility of the cerebellum is not limited to motor control. This review focuses on the particularly novel area of hippocampal-cerebellar interactions. Recent work has illustrated that the hippocampus and cerebellum are functionally connected in a bidirectional manner such that the cerebellum can influence hippocampal activity and vice versa. This functional connectivity has important implications for physiology, including spatial navigation and timing-dependent tasks, as well as pathophysiology, including seizures. Moving forward, an improved understanding of the critical biological underpinnings of these cognitive collaborations may improve interventions for neurological disorders such as epilepsy. PMID- 26732848 TI - Self-Renewal and High Proliferative Colony Forming Capacity of Late-Outgrowth Endothelial Progenitors Is Regulated by Cyclin-Dependent Kinase Inhibitors Driven by Notch Signaling. AB - Since the discovery of endothelial colony forming cells (ECFC), there has been significant interest in their therapeutic potential to treat vascular injuries. ECFC cultures display significant heterogeneity and a hierarchy among cells able to give rise to high proliferative versus low proliferative colonies. Here we aimed to define molecularly this in vitro hierarchy. Based on flow cytometry, CD34 expression levels distinguished two populations. Only CD34 + ECFC had the capacity to reproduce high proliferative potential (HPP) colonies on replating, whereas CD34- ECFCs formed only small clusters. CD34 + ECFCs were the only ones to self-renew in stringent single-cell cultures and gave rise to both CD34 + and CD34- cells. Upon replating, CD34 + ECFCs were always found at the centre of HPP colonies and were more likely in G0/1 phase of cell cycling. Functionally, CD34 + ECFC were superior at restoring perfusion and better engrafted when injected into ischemic hind limbs. Transcriptomic analysis identified cyclin-dependent kinase (CDK) cell cycle inhibiting genes (p16, p21, and p57), the Notch signaling pathway (dll1, dll4, hes1, and hey1), and the endothelial cytokine il33 as highly expressed in CD34 + ECFC. Blocking the Notch pathway using a gamma-secretase inhibitor (DAPT) led to reduced expression of cell cycle inhibitors, increased cell proliferation followed by a loss of self-renewal, and HPP colony formation capacity reflecting progenitor exhaustion. Similarly shRNA knockdown of p57 strongly affected self-renewal of ECFC colonies. ECFC hierarchy is defined by Notch signalling driving cell cycle regulators, progenitor quiescence and self renewal potential. PMID- 26732849 TI - Predicting standard-dose PET image from low-dose PET and multimodal MR images using mapping-based sparse representation. AB - Positron emission tomography (PET) has been widely used in clinical diagnosis for diseases and disorders. To obtain high-quality PET images requires a standard dose radionuclide (tracer) injection into the human body, which inevitably increases risk of radiation exposure. One possible solution to this problem is to predict the standard-dose PET image from its low-dose counterpart and its corresponding multimodal magnetic resonance (MR) images. Inspired by the success of patch-based sparse representation (SR) in super-resolution image reconstruction, we propose a mapping-based SR (m-SR) framework for standard-dose PET image prediction. Compared with the conventional patch-based SR, our method uses a mapping strategy to ensure that the sparse coefficients, estimated from the multimodal MR images and low-dose PET image, can be applied directly to the prediction of standard-dose PET image. As the mapping between multimodal MR images (or low-dose PET image) and standard-dose PET images can be particularly complex, one step of mapping is often insufficient. To this end, an incremental refinement framework is therefore proposed. Specifically, the predicted standard dose PET image is further mapped to the target standard-dose PET image, and then the SR is performed again to predict a new standard-dose PET image. This procedure can be repeated for prediction refinement of the iterations. Also, a patch selection based dictionary construction method is further used to speed up the prediction process. The proposed method is validated on a human brain dataset. The experimental results show that our method can outperform benchmark methods in both qualitative and quantitative measures. PMID- 26732850 TI - Returning to the sacred - the importance of careful attention to patients' nutritional needs in hospital settings. PMID- 26732851 TI - Optical nanostructures in 2D for wide-diameter and broadband beam collimation. AB - Eliminating curved refracting lensing components used in conventional projection, imaging and sensing optical assemblies, is critical to enable compactness and miniaturisation of optical devices. A suitable means is replacing refracting lenses with two-dimensional optical media in flat-slab form, to achieve an equivalent optical result. One approach, which has been the focus of intense research, uses a Veselago lens which features a negative-index metamaterial. However, practical implementations rely on resonance techniques, thus broadband operation at optical frequencies imposes significant technical challenges that have been difficult to overcome. Here, we demonstrate a highly-collimated, broadband, wide-diameter beam from a compact source in flat-slab form, based on light collimation using nanomaterials ordered in patterns and embedded into flexible polymers. These provide a highly anisotropic absorption coefficient due to patterns created by vertical carbon nanotube structures grown on glass, and the anisotropic electrical conductivity of the nanotubes. We show this nanostructure strongly absorbs unwanted off-axis light rays, whilst transmitting the desired on-axis rays, to achieve the required optical effect over broadband, from visible to short-infrared, thus circumventing some technical limitations of negative-index metamaterials. We further show a low substrate-temperature system for nanotube growth, allowing direct implementation into heat-sensitive large area devices. PMID- 26732852 TI - The therapeutic alliance in internet interventions: A narrative review and suggestions for future research. AB - OBJECTIVES: Research on Internet interventions has grown rapidly over the recent years and evidence is growing that Internet-based treatments often result in similar outcomes as conventional face-to-face psychotherapy. Yet there are still unanswered concerns such as whether a therapeutic alliance can be established over the Internet and whether the alliance is important in this new treatment format. METHODS: A narrative review of studies formally assessing the therapeutic alliance in Internet interventions was conducted. It is the first review summarizing findings on the therapeutic alliance that (i) distinguishes between different forms of Internet interventions and (ii) does not restrict itself to specific Internet-based treatment formats such as guided self-help treatments, e mail or videoconferencing therapies. RESULTS: Independent of communication modalities, diagnostic groups and amount of contact between clients and therapists, client-rated alliance scores were high, roughly equivalent to alliance ratings found in studies on face-to-face therapy. Mixed results were found regarding the therapist-rated alliance and alliance-outcome associations. CONCLUSIONS: The review points to the limitations of the available evidence and identifies unanswered questions. It is concluded that one of the major tasks for future research is to identify unique characteristics of the therapeutic alliance in the different treatment formats. PMID- 26732853 TI - Marc Baldus. AB - My favorite place to spend a holiday is on the coast. When I was eighteen I wanted to be a scientist. I was impressed by a book about Max Planck. PMID- 26732854 TI - The interaction between androgen receptor and PDGF-D in the radiation response of prostate carcinoma. AB - PURPOSE: To determine the functional relationship between androgen receptor (AR) and PDGF D as it relates to the radiation response of PTEN-null prostate cancer (PCa) cells and the effect of enzalutamide on these interactions. METHODS AND MATERIALS: Using murine PTEN-null prostate epithelial cell line and human prostate carcinoma LNCaP (PTEN-mutant) models, nuclear and cytosolic AR levels were determined by immunoblot analysis and the transcriptional activity of nuclear AR was assessed by RT-PCR analysis of its target genes with or without irradiation. Cell survival was evaluated by clonogenic assay or sulforhodamine B (SRB) assay upon irradiation in the absence or presence of the AR antagonist enzalutamide. RESULTS: PTEN loss resulted in upregulation of AR expression in a PDGF-D dependent manner and irradiation selectively increased the nuclear AR protein level and its activity in a murine cell model. When the functional significance of AR in cell survival was tested, treatment with enzalutamide resulted in radiosensitization of human LNCaP cells. Similarly to the murine model, PDGF-D overexpression increased the nuclear AR level and its transcriptional activity in LNCaP cells. PDGF-D over-expression was associated with radioresistance and enzalutamide treatment effectively reversed PDGF-D mediated radioresistance in LNCaP cells. CONCLUSIONS: We have demonstrated that AR, a target of the PTEN and PDGF D-downstream signaling program, contributes to radiation resistance in human PCa cells. In addition, this study suggests that anti-androgens such as enzalutamide may serve as radiation sensitizers for the treatment of PCa patients, particularly so in patients with loss of PTEN or overexpression of PDGF-D. PMID- 26732855 TI - Distribution, function and evolution characterization of microsatellite in Sargassum thunbergii (Fucales, Phaeophyta) transcriptome and their application in marker development. AB - Using transcriptome data to mine microsatellite and develop markers has growingly become prevalent. However, characterizing the possible function of microsatellite is relatively rare. In this study, we explored microsatellites in the transcriptome of the brown alga Sargassum thunbergii and characterized the frequencies, distribution, function and evolution, and developed primers to validate these microsatellites. Our results showed that Tri-nucleotide is the most abundant, followed by di- and mono-nucleotide. The length of microsatellite was significantly affected by the repeat motif size. The density of microsatellite in the CDS region is significantly lower than that in the UTR region. The annotation of the transcripts containing microsatellite showed that 573 transcripts have GO terms and can be categorized into 42 groups. Pathways enrichment showed that microsatellites were significantly overrepresented in the genes involved in pathways such as Ubiquitin mediated proteolysis, RNA degradation, Spliceosome, etc. Primers flanking 961 microsatellite loci were designed, and among the 30 pairs of primer selected randomly for availability test, 23 were proved to be efficient. These findings provided new insight into the function and evolution of microsatellite in transcriptome, and the identified microsatellite loci within the annotated gene will be useful for developing functional markers in S. thunbergii. PMID- 26732857 TI - Soluble SEMA4D/CD100: A novel immunoregulator in infectious and inflammatory diseases. AB - SEMA4D/CD100 is a homodimeric protein belonging to the semaphorin family of axonal guidance proteins. Semaphorin family members have received increased attention lately due to their diverse functions in the immune system. SEMA4D was the first semaphorin described to have immune functions and serves important roles in T cell priming, antibody production, and cell-to-cell adhesion. Proteolytic cleavage of SEMA4D from the cell surface gives rise to a soluble fragment of SEMA4D (sSEMA4D). Similar to the transmembranal form, sSEMA4D is thought to have immunoregulatory properties. While the exact mechanisms responsible for SEMA4D shedding remain to be elucidated, emerging data have revealed associations between elevated systemic sSEMA4D levels and severity of infectious and inflammatory diseases. This review summarizes the literature concerning sSEMA4D and discusses its potential as a novel prognostic immune biomarker and potential target for immunotherapy. PMID- 26732856 TI - Lack of netrin-4 modulates pathologic neovascularization in the eye. AB - Netrins are a family of matrix-binding proteins that function as guidance signals. Netrin-4 displays pathologic roles in tumorigenesis and neovascularization. To answer the question whether netrin-4 acts either pro- or anti-angiogenic, angiogenesis in the retina was assessed in Ntn-4(-/-) mice with oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV), mimicking hypoxia-mediated neovascularization and inflammatory mediated angiogenesis. The basement membrane protein netrin-4 was found to be localised to mature retinal blood vessels. Netrin-4, but not netrin-1 mRNA expression, increased in response to relative hypoxia and recovered to normal levels at the end of blood vessel formation. No changes in the retina were found in normoxic Ntn-4(-/-) mice. In OIR, Ntn-4(-/-) mice initially displayed larger avascular areas which recovered faster to revascularization. Ganzfeld electroretinography showed faster recovery of retinal function in Ntn-4(-/-) mice. Expression of netrin receptors, Unc5H2 (Unc-5 homolog B, C. elegans) and DCC (deleted in colorectal carcinoma), was found in Muller cells and astrocytes. Laser-induced neovascularization in Nnt-4(-/-) mice did not differ to that in the controls. Our results indicate a role for netrin-4 as an angiogenesis modulating factor in O2 dependent vascular homeostasis while being less important during normal retinal developmental angiogenesis or during inflammatory neovascularization. PMID- 26732858 TI - Mast cells contribute to autoimmune diabetes by releasing interleukin-6 and failing to acquire a tolerogenic IL-10+ phenotype. AB - Mast cells (MCs) are innate immune cells that exert positive and negative immune modulatory functions capable to enhance or limit the intensity and/or duration of adaptive immune responses. Although MCs are crucial to regulate T cell immunity, their action in the pathogenesis of autoimmune diseases is still debated. Here we demonstrate that MCs play a crucial role in T1D pathogenesis so that their selective depletion in conditional MC knockout NOD mice protects them from the disease. MCs of diabetic NOD mice are overly inflammatory and secrete large amounts of IL-6 that favors differentiation of IL-17-secreting T cells at the site of autoimmunity. Moreover, while MCs of control mice acquire an IL-10+ phenotype upon interaction with FoxP3+ Treg cells, MCs of NOD mice do not undergo this tolerogenic differentiation. Our data indicate that overly inflammatory MCs unable to acquire a tolerogenic IL-10+ phenotype contribute to the pathogenesis of autoimmune T1D. PMID- 26732859 TI - Clinical heterogeneity of dominant chronic mucocutaneous candidiasis disease: presenting as treatment-resistant candidiasis and chronic lung disease. AB - In gain-of-function STAT1 mutations, chronic mucocutaneous candidiasis disease (CMCD) represents the phenotypic manifestation of a complex immunodeficiency characterized by clinical and immunological heterogeneity. We aimed to study clinical manifestations, long-term complications, molecular basis, and immune profile of patients with dominant CMCD. We identified nine patients with heterozygous mutations in STAT1, including novel amino acid substitutions (L283M, L351F, L400V). High risk of azole-resistance was observed, particularly when intermittent regimens of antifungal treatment or use of suboptimal dosage occurs. We report a case of Cryptococcosis and various bacterial and viral infections. Risk of developing bronchiectasis in early childhood or gradually evolving to chronic lung disease in adolescent or adult ages emerges. Lymphopenia is variable, likely progressing by adulthood. We conclude that continuous antifungal prophylaxis associated to drug monitoring might prevent resistance to treatment; prompt diagnosis and therapy of lung disease might control long-term progression; careful monitoring of lymphopenia-related infections might improve prognosis. PMID- 26732860 TI - The case of an APDS patient: Defects in maturation and function and decreased in vitro anti-mycobacterial activity in the myeloid compartment. AB - Activated PI3-kinase delta syndrome (APDS) was recently reported as a novel primary immunodeficiency caused by heterozygous gain-of-function mutations in PIK3CD gene. Here we describe immunological studies in a 19year old APDS patient for whom genetic diagnosis was discovered by Whole Exome Sequencing (WES) analysis. In addition to the progressive lymphopenia and defective antibody production we showed that the ability of the patient's B cells to differentiate in vitro is severely reduced. An in depth analysis of the myeloid compartment showed an increased expression of CD83 activation marker on monocytes and mono derived DC cells. Moreover, monocytes-derived macrophages (MDMs) failed to solve the Mycobacterium bovis bacillus Calmette Guerin (BCG) infection in vitro. Selective p110delta inhibitor IC87114 restored the MDM capacity to kill BCG in vitro. Our data show that the constitutive activation of Akt-mTOR pathway induces important alterations also in the myeloid compartment providing new insights in order to improve the therapeutic approach in these patients. PMID- 26732861 TI - Optimal fluoroscopic viewing angles of left-sided heart structures in patients with aortic stenosis and mitral regurgitation based on multislice computed tomography. AB - BACKGROUND: Transcatheter interventions are currently undertaken using "generic" fluoroscopic viewing angles. However, the position and orientation of heart structures may vary across patients and disease-specific remodeling processes. OBJECTIVE: This study uses multislice computed tomography to determine optimal fluoroscopic viewing angles of the aortic and mitral annuli, the left atrial appendage and the atrial septum. We explored differences between patients with severe aortic stenosis (AS) and severe mitral regurgitation (MR). METHODS AND RESULTS: The multislice computed tomographies of 28 patients with severe aortic stenosis (AS) and 32 patients with severe functional mitral regurgitation (MR) were analyzed. For each patient, we evaluated the optimal fluoroscopic viewing angles of the aortic and mitral annuli (en face, maximal and minimal diameters, aortic root with right, left and non coronary sinus in center), left atrial appendage orifice (en face, maximal and minimal diameters), and atrial septum (fossa ovalis) en face. The TAVR implantation view with right coronary sinus in center was LAO 9 - CRA 0 in the AS group and LAO 6 - CAU 5 in the MR group (p = NS). AS and MR patients differed significantly with respect to the fluoroscopic angulation of the aortic annulus en face (8.3 degrees ), the aortic annulus maximal (17.7 degrees ) and minimal (18.5 degrees ) diameters, the mitral annulus aorto-mural diameter (11.3 degrees ), and the left atrial appendage orifice en face (11.1 degrees ) (all p-values<0.05). CONCLUSION: Optimal fluoroscopic viewing angles of left-sided structures vary considerably between patients. Multislice computed tomography is a valuable tool to determine the most procedurally relevant angulations, with the potential to optimize procedural safety, efficacy and duration. PMID- 26732863 TI - Constitutively Active 5-HT Receptors: An Explanation of How 5-HT Antagonists Inhibit Gut Motility in Species Where 5-HT is Not an Enteric Neurotransmitter? AB - Antagonists of 5-Hydroxytryptamine (5-HT) receptors are well known to inhibit gastrointestinal (GI)-motility and transit in a variety of mammals, including humans. Originally, these observations had been interpreted by many investigators (including us) as evidence that endogenous 5-HT plays a major role in GI motility. This seemed a logical assumption. However, the story changed dramatically after recent studies revealed that 5-HT antagonists still blocked major GI motility patterns (peristalsis and colonic migrating motor complexes) in segments of intestine depleted of all 5-HT. Then, these results were further supported by Dr. Gershons' laboratory, which showed that genetic deletion of all genes that synthesizes 5-HT had minor, or no inhibitory effects on GI transit in vivo. If 5-HT was essential for GI motility patterns and transit, then one would expect major disruptions in motility and transit when 5-HT synthesis was genetically ablated. This does not occur. The inhibitory effects of 5-HT antagonists on GI motility clearly occur independently of any 5-HT in the gut. Evidence now suggests that 5-HT antagonists act on 5-HT receptors in the gut which are constitutively active, and don't require 5-HT for their activation. This would explain a long-standing mystery of how 5-HT antagonists inhibit gut motility in species like mice, rats, and humans where 5-HT is not an enteric neurotransmitter. Studies are now increasingly demonstrating that the presence of a neurochemical in enteric neurons does not mean they function as neurotransmitters. Caution should be exercised when interpreting any inhibitory effects of 5-HT antagonists on GI motility. PMID- 26732862 TI - 3D printing based on cardiac CT assists anatomic visualization prior to transcatheter aortic valve replacement. AB - BACKGROUND: 3D printing is a promising technique that may have applications in medicine, and there is expanding interest in the use of patient-specific 3D models to guide surgical interventions. OBJECTIVE: To determine the feasibility of using cardiac CT to print individual models of the aortic root complex for transcatheter aortic valve replacement (TAVR) planning as well as to determine the ability to predict paravalvular aortic regurgitation (PAR). METHODS: This retrospective study included 16 patients (9 with PAR identified on blinded interpretation of post-procedure trans-thoracic echocardiography and 7 age, sex, and valve size-matched controls with no PAR). 3D printed models of the aortic root were created from pre-TAVR cardiac computed tomography data. These models were fitted with printed valves and predictions regarding post-implant PAR were made using a light transmission test. RESULTS: Aortic root 3D models were highly accurate, with excellent agreement between annulus measurements made on 3D models and those made on corresponding 2D data (mean difference of -0.34 mm, 95% limits of agreement: +/- 1.3 mm). The 3D printed valve models were within 0.1 mm of their designed dimensions. Examination of the fit of valves within patient specific aortic root models correctly predicted PAR in 6 of 9 patients (6 true positive, 3 false negative) and absence of PAR in 5 of 7 patients (5 true negative, 2 false positive). CONCLUSIONS: Pre-TAVR 3D-printing based on cardiac CT provides a unique patient-specific method to assess the physical interplay of the aortic root and implanted valves. With additional optimization, 3D models may complement traditional techniques used for predicting which patients are more likely to develop PAR. PMID- 26732865 TI - Heterocyclic dithiocarbamato-iron(III) complexes: single-source precursors for aerosol-assisted chemical vapour deposition (AACVD) of iron sulfide thin films. AB - Tris-(piperidinedithiocarbamato)iron(III) (1) and tris (tetrahydroquinolinedithiocarbamato)iron(iii) (2) complexes have been synthesized and their single-crystal X-ray structures were determined. Thermogravimetric analysis (TGA) of the complexes showed decomposition to iron sulfide. Both complexes were then used as single-source precursors for the deposition of iron sulfide thin films by aerosol-assisted chemical vapour deposition (AACVD). Energy dispersive X-ray (EDX) spectroscopy confirmed the formation of iron sulfide films. The addition of tert-butyl thiol almost doubled the sulfur content in the deposited films. Scanning electron microscopy (SEM) images of the iron sulfide films from both complexes showed flakes/leaves/sheets, spherical granules and nanofibres. The sizes and shapes of these crystallites depended on the nature of the precursor, temperature, solvent and the amount of tert-butyl thiol used. The observed optical properties are dependent upon the variation of reaction parameters such as temperature and solvent. Powder X-ray diffraction (p-XRD) studies revealed that pyrrhotite, hexagonal (Fe0.975S), marcasite and smythite (Fe3S4) phases were differently deposited. PMID- 26732864 TI - A New Method to Jointly Estimate the Mortality Risk of Long-Term Exposure to Fine Particulate Matter and its Components. AB - Most studies on the association between exposure to fine particulate matter (PM2.5) and mortality have considered only total concentration of PM2.5 or individual components of PM2.5, and not the combined effects of concentration and particulate composition. We sought to develop a method to estimate the risk of death from long-term exposure to PM2.5 and the distribution of its components, namely: sulphate, nitrate, ammonium, organic mass, black carbon, and mineral dust. We decomposed PM2.5 exposure into the sum of total concentration and the proportion of each component. We estimated the risk of death due to exposure using a cohort of ~2.4 million Canadians who were followed for vital status over 16 years. Modelling the concentration of PM2.5 with the distribution of the proportions of components together was a superior predictor for mortality than either total PM2.5 concentration alone, or all component concentrations modelled together. Our new approach has the advantage of characterizing the toxicity of the atmosphere in its entirety. This is required to fully understand the health benefits associated with strategies to improve air quality that may result in complex changes not only in PM2.5 concentration, but also in the distribution of particle components. PMID- 26732866 TI - Shock Wave Mediated Plume Chemistry for Molecular Formation in Laser Ablation Plasmas. AB - Although it is relatively straightforward to measure the ionic, atomic, molecular, and particle emission features from laser ablation plumes, the associated kinetic and thermodynamic development leading to molecular and nanocluster formation remain one of the most important topics of analytical chemistry and material science. Very little is known, for instance, about the evolutionary paths of molecular and nanocluster formation and its relation to laser plume hydrodynamics. This is, to a large extent; due to the complexity of numerous physical processes that coexist in a transient laser-plasma system. Here, we report the formation mechanisms of molecules during complex interactions of a laser-produced plasma plume expanding from a high purity aluminum metal target into ambient air. It is found that the plume hydrodynamics plays a great role in redefining the plasma thermodynamics and molecular formation. Early in the plasma expansion, the generated shock wave at the plume edge acts as a barrier for the combustion process and molecular formation is prevalent after the shock wave collapse. The temporally and spatially resolved contour mapping of atoms and molecules in laser ablation plumes highlight the formation routes and persistence of species in the plasma and their relation to plume hydrodynamics. PMID- 26732867 TI - Professor Eugenio Pompeo: the present and future of minimally invasive thoracic surgery. PMID- 26732870 TI - [Evaluation of the use of antibiotics in asymptomatic bacteriuria]. PMID- 26732868 TI - Population attributable risks of modifiable reproductive factors for breast and ovarian cancers in Korea. AB - BACKGROUND: Breast and ovarian cancers are predominant female cancers with increasing prevalence. The purpose of this study was to estimate the population attributable risks (PARs) of breast and ovarian cancer occurrence based on the relative risks (RRs) of modifiable reproductive factors and population-specific exposure prevalence. METHODS: The PAR was calculated by using the 1990 standardized prevalence rates, the 2010 national cancer incidence with a 20 year lag period, the meta-analyzed RRs from studies conducted in the Korean population for breast cancer, and the meta-analyzed RRs from a Korean epithelial ovarian cancer study and a prior meta-analysis, and ovarian cancer cohort results up to 2012. For oral contraceptive and hormone replacement therapy use, we did not consider lag period. RESULTS: The summary PARs for modifiable reproductive factors were 16.7% (95% CI 15.8-17.6) for breast cancer (2404 cases) and 81.9% (95% CI 55.0-100.0) for ovarian cancer (1579 cases). The modifiable reproductive factors included pregnancy/age at first birth (8.0%), total period of breastfeeding (3.1%), oral contraceptive use (5.3%), and hormone replacement therapy use (0.3%) for breast cancer and included breastfeeding experience (2.9%), pregnancy (1.2%), tubal ligation (24.5%), and oral contraceptive use (53.3%) for ovarian cancer. CONCLUSIONS: Despite inherent uncertainties in the risk factors for breast and ovarian cancers, we suggest that appropriate long term control of modifiable reproductive factors could reduce breast and ovarian cancer incidences and their related burdens by 16.7% and 81.9%, respectively. PMID- 26732871 TI - The Proteomic Response of Arabidopsis thaliana to Cadmium Sulfide Quantum Dots, and Its Correlation with the Transcriptomic Response. AB - A fuller understanding of the interaction between plants and engineered nanomaterials is of topical relevance because the latter are beginning to find applications in agriculture and the food industry. There is a growing need to establish objective safety criteria for their use. The recognition of two independent Arabidopsis thaliana mutants displaying a greater level of tolerance than the wild type plant to exposure to cadmium sulfide quantum dots (CdS QDs) has offered the opportunity to characterize the tolerance response at the physiological, transcriptomic, and proteomic levels. Here, a proteomics-based comparison confirmed the conclusions drawn from an earlier transcriptomic analysis that the two mutants responded to CdS QD exposure differently both to the wild type and to each other. Just over half of the proteomic changes mirrored documented changes at the level of gene transcription, but a substantial number of transcript/gene product pairs were altered in the opposite direction. An interpretation of the discrepancies is given, along with some considerations regarding the use and significance of -omics when monitoring the potential toxicity of ENMs for health and environment. PMID- 26732872 TI - Cell refractive index for cell biology and disease diagnosis: past, present and future. AB - Cell refractive index is a key biophysical parameter, which has been extensively studied. It is correlated with other cell biophysical properties including mechanical, electrical and optical properties, and not only represents the intracellular mass and concentration of a cell, but also provides important insight for various biological models. Measurement techniques developed earlier only measure the effective refractive index of a cell or a cell suspension, providing only limited information on cell refractive index and hence hindering its in-depth analysis and correlation. Recently, the emergence of microfluidic, photonic and imaging technologies has enabled the manipulation of a single cell and the 3D refractive index of a single cell down to sub-micron resolution, providing powerful tools to study cells based on refractive index. In this review, we provide an overview of cell refractive index models and measurement techniques including microfluidic chip-based techniques for the last 50 years, present the applications and significance of cell refractive index in cell biology, hematology, and pathology, and discuss future research trends in the field, including 3D imaging methods, integration with microfluidics and potential applications in new and breakthrough research areas. PMID- 26732874 TI - Physiological and genetic differences amongst Rhodococcus species for using glycerol as a source for growth and triacylglycerol production. AB - We analysed the ability of five different rhodococcal species to grow and produce triacylglycerols (TAGs) from glycerol, the main byproduct of biodiesel production. Rhodococcus fascians and Rhodococcus erythropolis grew fast on glycerol, whereas Rhodococcus opacus and Rhodococcus jostii exhibited a prolonged lag phase of several days before growing. Rhodococcus equi only exhibited poor growth on glycerol. R. erythropolis DSMZ 43060 and R. fascians F7 produced 3.9 4.3 g cell biomass l(-1) and 28.4-44.6% cellular dry weight (CDW) of TAGs after 6 days of incubation; whereas R. opacus PD630 and R. jostii RHA1 produced 2.5-3.8 g cell biomass l(-1) and 28.3-38.4% CDW of TAGs after 17 days of growth on glycerol. Genomic analyses revealed two different sets of genes for glycerol uptake and degradation (here named clusters 1 and 2) amongst rhodococci. Those species that possessed cluster 1 (glpFK1D1) (R. fascians and R. erythropolis) exhibited fast growth and lipid accumulation, whereas those that possessed cluster 2 (glpK2D2) (R. opacus, R. jostii and R. equi) exhibited delayed growth and lipid accumulation during cultivation on glycerol. Three glycerol-negative strains were complemented for their ability to grow and produce TAGs by heterologous expression of glpK2 from R. opacus PD630. In addition, we significantly reduced the extension of the lag phase and improved glycerol assimilation and oil production of R. opacus PD630 when expressing glpK1D1 from R. fascians. The results demonstrated that rhodococci are a flexible and amenable biological system for further biotechnological applications based on the reutilization of glycerol. PMID- 26732873 TI - Site-specific tagging proteins with a rigid, small and stable transition metal chelator, 8-hydroxyquinoline, for paramagnetic NMR analysis. AB - Design of a paramagnetic metal binding motif in a protein is a valuable way for understanding the function, dynamics and interactions of a protein by paramagnetic NMR spectroscopy. Several strategies have been proposed to site specifically tag proteins with paramagnetic lanthanide ions. Here we report a simple approach of engineering a transition metal binding motif via site-specific labelling of a protein with 2-vinyl-8-hydroxyquinoline (2V-8HQ). The protein-2V 8HQ adduct forms a stable complex with transition metal ions, Mn(II), Co(II), Ni(II), Cu(II) and Zn(II). The paramagnetic effects generated by these transition metal ions were evaluated by NMR spectroscopy. We show that 2V-8HQ is a rigid and stable transition metal binding tag. The coordination of the metal ion can be assisted by protein sidechains. More importantly, tunable paramagnetic tensors are simply obtained in an alpha-helix that possesses solvent exposed residues in positions i and i + 3, where i is the residue to be mutated to cysteine, i + 3 is Gln or Glu or i - 4 is His. The coordination of a sidechain carboxylate/amide or imidazole to cobalt(II) results in different structural geometries, leading to different paramagnetic tensors as shown by experimental data. PMID- 26732875 TI - Proteomic and morphometric study of the in vitro interaction between Oncidium sphacelatum Lindl. (Orchidaceae) and Thanatephorus sp. RG26 (Ceratobasidiaceae). AB - Orchidaceae establish symbiotic relationships with fungi in the Rhizoctonia group, resulting in interactions beneficial to both organisms or in cell destruction in one of them (pathogenicity). Previous studies have focused mostly on terrestrial species with a few, preliminary studies, on epiphytes. To further our understanding of the molecular mechanisms involved in these symbioses, we evaluated the interaction between Oncidium sphacelatum Lindl. and the mycorrhizal fungus Thanatephorus sp. strain RG26 (isolated from a different orchid species) in vitro using morphometric and proteomic analyses. Evidence from the morphometric and microscopic analysis showed that the fungus promoted linear growth and differentiation of orchid protocorms during 98 days interaction. On day 63, protocorm development was evident, so we analyzed the physiological response of both organisms at that moment. Proteome results suggest that orchid development stimulated by the fungus apparently involves cell cycle proteins, purine recycling, ribosome biogenesis, energy metabolism, and secretion that were up-regulated in the orchid; whereas in the fungus, a high expression of proteins implicated in stress response, protein-protein interaction, and saccharides and protein biosynthesis were found in the symbiotic interaction. This is the first work reporting proteins differentially expressed in the epiphytic orchid-fungus interaction and will contribute to the search for molecular markers that will facilitate the study of this symbiosis in both wild orchids and those in danger of extinction. PMID- 26732876 TI - Risk factor analysis for involvement of resection margins in gastric and esophagogastric junction cancer: an Italian multicenter study. AB - BACKGROUND: Resection margin (RM) involvement is associated with negative prognosis after gastrectomy. Intraoperative frozen section (IFS) analysis allows radical resection to be achieved in a single operation but is time-consuming and resource-consuming. The aim of this study was to assess risk factors associated with RM involvement to identify patients who would benefit from IFS analysis. METHODS: We retrospectively analyzed patients who underwent gastrectomy with curative intent for gastric or esophagogastric junction (EGJ) cancer from 2000 to 2014 in six Italian hospitals. RM status was assessed by IFS analysis and/or definitive histopathology examination. A set of 21 potential risk factors were compared in a multivariate analysis between patients with positive RMs on IFS analysis or definitive histopathology examination and a control cohort of similar patients with negative RMs, with the samples stratified into three subgroups (T1, T2-T4 Lauren intestinal pattern, T2-T4 Lauren diffuse/mixed pattern). RESULTS: One hundred forty-five patients had positive RMs. Survival was significantly worse in positive RM patients than in negative RM patients (89.5 months vs 28.9 months). Multivariate analysis showed that in T1 cancers a margin distance of less than 2 cm is a risk factor for RM involvement (odds ratio 15.7), in T2-T4 intestinal pattern cancers, serosa invasion (odds ratio 6.0), EGJ location (odds ratio 4.1), and a margin distance of less than 3 cm (odds ratio 4.0) are independent risk factors, and in T2-T4 diffuse/mixed pattern cancers, lymphatic infiltration (odds ratio 4.2), tumor diameter greater than 4 cm (odds ratio 3.5), EGJ location (odds ratio 2.8), and serosa invasion (odds ratio 2.2) are independent risk factors. CONCLUSIONS: Survival after gastrectomy is negatively affected by positive RMs. IFS analysis should be routinely used in patients with a high risk of positive RMs, especially in diffuse pattern cancers. PMID- 26732877 TI - Comparison the sixth and seventh editions of the AJCC staging system for T1 gastric cancer: a long-term follow-up study of 2124 patients. AB - BACKGROUND/AIM: The aim of this study was to establish an appropriate TNM staging system for early gastric cancer. METHODOLOGY: We evaluated 2124 patients who had undergone gastrectomy for early gastric cancer between 1989 and 2001. RESULTS: Using the seventh edition of the American Joint Committee on Cancer (AJCC) staging system, we found no significant differences in tumor recurrence and survival between N1 and N2 cancers or between N3a and N3b cancers, whereas the survival curves for N2 and N3 cancers were quite different. Similarly, using the classification in the sixth edition of the AJCC staging system, we found no significant difference in survival between the N2 and N3 cancer groups, whereas the survival curves for N1 versus N2 or N3 cancers were quite different. CONCLUSIONS: The classifications in the sixth and seventh editions of the AJCC staging system have a limitation for T1 gastric cancer (early gastric cancer). PMID- 26732880 TI - High-throughput logPo/w determination from UHPLC measurements: Revisiting the chromatographic hydrophobicity index. AB - A fast and accurate lipophilicity determination is fundamental in the drug discovery process, as long as it is a relevant property in the absorption, distribution, metabolism, excretion and toxicity (ADMET) of a potential drug substance. In the present work, different models based on chromatographic retention values for a large set of compounds and some of their molecular descriptors (calculated by ACD/Labs or CODESSA programs) have been examined in order to establish reliable equations for logPo/w determination from fast chromatographic hydrophobicity index (CHI) measurements. This appears to be a very interesting high-throughput methodology for screening purposes, since CHI values can be measured by UHPLC in very short runs (<4min) and molecular descriptors can be easily computed from the structure of any compound. The selected final descriptors were Abraham's hydrogen-bond acidity (A) and excess molar refraction (E) from ACD/Labs, and hydrogen-bond acidity HDCA-1/TMSA and HOMO-LUMO polarizability descriptors from CODESSA software. The proposed equations allow an accurate determination of logPo/w with standard errors in the range of 0.4 units. PMID- 26732878 TI - Smooth Muscle Cell-targeted RNA Aptamer Inhibits Neointimal Formation. AB - Inhibition of vascular smooth muscle cell (VSMC) proliferation by drug eluting stents has markedly reduced intimal hyperplasia and subsequent in-stent restenosis. However, the effects of antiproliferative drugs on endothelial cells (EC) contribute to delayed re-endothelialization and late stent thrombosis. Cell targeted therapies to inhibit VSMC remodeling while maintaining EC health are necessary to allow vascular healing while preventing restenosis. We describe an RNA aptamer (Apt 14) that functions as a smart drug by preferentially targeting VSMCs as compared to ECs and other myocytes. Furthermore, Apt 14 inhibits phosphatidylinositol 3-kinase/protein kinase-B (PI3K/Akt) and VSMC migration in response to multiple agonists by a mechanism that involves inhibition of platelet derived growth factor receptor (PDGFR)-beta phosphorylation. In a murine model of carotid injury, treatment of vessels with Apt 14 reduces neointimal formation to levels similar to those observed with paclitaxel. Importantly, we confirm that Apt 14 cross-reacts with rodent and human VSMCs, exhibits a half-life of ~300 hours in human serum, and does not elicit immune activation of human peripheral blood mononuclear cells. We describe a VSMC-targeted RNA aptamer that blocks cell migration and inhibits intimal formation. These findings provide the foundation for the translation of cell-targeted RNA therapeutics to vascular disease. PMID- 26732879 TI - Sinusitis and oroantral fistula in patients with bisphosphonate-associated necrosis of the maxilla. AB - BACKGROUND: The management of bisphosphonate related necrosis of the jaw has become clinical routine. While approximately two thirds of the lesions are in the mandible, one third is located in the maxilla. In 40-50 % of maxillary necrosis the maxillary sinus is involved, leading to maxillary sinusitis and oro-antral communications. METHODS: This retrospective single center study includes all patients with diagnosis of BP-ONJ of the maxilla and concomitant maxillary sinusitis. The information collected includes age, gender, primary disease, bisphosphonate intake, involving type of bisphosphonate, route of administration and duration of BP treatment previous to surgical treatment and treatment outcome. RESULTS: A total of 12 patients fulfill the criteria of the diagnosis of maxillary sinusitis associated to maxillary necrosis, of which 6 Patients showed purulent sinusitis. All patients underwent surgical treatment with complete resection of the affected bone and a multilayer wound closure. A recurrence appeared in one patient with open bone and no sign of sinusitis and was treated conservatively. CONCLUSIONS: Purulent maxillary Sinusitis is a common complication of bisphosphonate-related necrosis of the maxilla. The surgical technique described can be suggested for the treatment of these patients. PMID- 26732881 TI - Enantioseparation of N-derivatized amino acids by micro-liquid chromatography/laser induced fluorescence detection using quinidine-based monolithic columns. AB - A novel carbamoylated quinidine based monolith, namely poly(O-9-[2 (methacryloyloxy)-ethylcarbamoyl]-10,11-dihydroquinidine-co-ethylene dimethacrylate (poly(MQD-co-EDMA)), was prepared for the micro-LC enantioseparation of N-derivatized amino acids. The influence of the mobile phase composition, including the organic modifier proportion, the apparent pH and the buffer concentration, on the enantioresolution of N-derivatized amino acids was systematically investigated. Satisfactory column performance in terms of permeability, efficiency and reproducibility was obtained in most cases. The majority of the enantiomers of the tested N-protected amino acids, including 3,5 DNB, 3,5-DClB, FMOC, 3,5-DMB, p-NB, m-ClB, p-ClB and B derivatives, could be baseline separated on the poly(MQD-co-EDMA) monolithic column within 25min. A self-assembled laser induced fluorescence (LIF) detector was employed to improve sensitivity when analyzing 7-nitro-2,1,3-benzoxadiazole (NBD) derivatives of amino acids. Ten NBD-derivatized amino acids, including arginine and histidine whose enantioseparation on quinidine carbamate based CSPs has not been reported so far, were enantioresolved on the poly(MQD-co-EDMA) monolith column. It is worth noting that the d-enantiomers of NBD-derivatized amino acids eluted first, except in the case of glutamic acid. The LOD values obtained with the LIF detector were comparable to those reported using conventional LC-FL methods. The prepared poly(MQD-co-EDMA) monolithic column coupled with the LIF detector opens up interesting perspectives to the determination of trace D-amino acids in biological samples. PMID- 26732882 TI - Chiral separations of cathinone and amphetamine-derivatives: Comparative study between capillary electrochromatography, supercritical fluid chromatography and three liquid chromatographic modes. AB - The screening part of an earlier defined chiral separation strategy in capillary electrochromatography (CEC) was used for the separation of ten cathinone- and amphetamine derivatives. They were analyzed using 4 polysaccharide-based chiral stationary phases (CSPs), containing cellulose tris(3,5-dimethylphenylcarbamate) (ODRH), amylose tris(3,5-dimethylphenylcarbamate) (ADH), amylose tris(5-chloro-2 methylphenylcarbamate) (LA2), and cellulose tris(4-chloro-3 methylphenylcarbamate) (LC4) as chiral selectors. After applying the screening to each compound, ADH and LC4 showed the highest success rate. In a second part of the study, a comparison between CEC and other analytical techniques used for chiral separations i.e., supercritical fluid chromatography (SFC), polar organic solvent chromatography (POSC), reversed-phase (RPLC) and normal-phase liquid chromatography (NPLC), was made. For this purpose, earlier defined screening approaches for each technique were applied to separate the 10 test substances. This allowed an overall comparison of the success rates of the screening steps of the 5 techniques for these compounds. The results showed that CEC had a similar enantioselectivity rate as NPLC and RPLC, producing the highest number of separations (9 out of 10 racemates). SFC resolved 7 compounds, while POSC gave only 2 separations. On the other hand, the baseline separation success rates for NPLC and RPLC was better than for CEC. For a second comparison, the same chiral stationary phases as in the CEC screening were also tested with all techniques at their specific screening conditions, which allowed a direct comparison of the performance of CEC versus the same CSPs in the other techniques. This comparison revealed that RPLC was able to separate all tested compounds, and also produced the highest number of baseline separations on the CSP that were used in the CEC screening step. CEC and NPLC showed the same success rate: nine out of ten substances were separated. When CEC and NPLC are combined, separation of the ten compounds can be achieved. SFC and POSC resolved eight and three compounds, respectively. POSC was the least attractive option as it expressed only limited enantioselectivity toward these compounds. PMID- 26732883 TI - A 20-year population-based study on the epidemiology, clinical features, treatment, and outcome of nodular lymphocyte predominant Hodgkin lymphoma. AB - Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a subtype of Hodgkin lymphoma characterized by a unique clinical and histological presentation. Because of the rare nature of this disease, few large-scale studies are available. We conducted a cohort study in which patients were identified in the Netherlands Cancer Registry in the Southeast of the Netherlands between 1990 and 2010. Of these patients, we collected all clinical characteristics and re reviewed pathologic material to confirm NLPHL diagnosis. Seventy-three histologically confirmed cases of NLPHL were analyzed with a median follow-up of 65 months (range 4-257 months). Median age at diagnosis was 43 years (range 1 87); 84.9 % of the patients were male; B symptoms were present in 5.5 %; and stage I/II disease was most common (75.4 %). Patients were primarily treated with radiotherapy (50.7 %), chemotherapy (26 %), combined modality (radiotherapy and chemotherapy) (11 %), or surgical excision with careful watch-and-wait (12.3 %). Relapses occurred in seven patients (9.6 %) after a median of 26 months (21-74 months). Six patients (8.2 %) developed histologic transformation to large cell lymphoma. Five patients (6.8 %) died during follow-up due to progression of NLPHL (n = 1), histologic transformation (n = 2) and intercurrent deaths (n = 2). The estimated 10-year overall survival was 94.0 % and the 10-year progression-free survival 75.8 %. Our study confirms the distinct characteristics of NLPHL with a relatively good long-term prognosis. It may be possible to reduce treatment intensity in early stage NLPHL without affecting long-term outcome. PMID- 26732884 TI - Clinical outcomes of primary intraocular lymphoma patients treated with front line systemic high-dose methotrexate and intravitreal methotrexate injection. AB - A standard treatment for patients with primary intraocular lymphoma (PIOL) remains unclear. This study retrospectively analyzed the clinical features and outcomes of 19 patients with PIOL who were treated with a first-line therapy comprising combined intravenous high-dose methotrexate and intravitreal methotrexate between January 2003 and December 2013. Thirteen (68.4 %) patients were female, and the median age at diagnosis was 57 (39-77 years). Diagnoses were based on the identification of abnormal lymphoid cells in vitreous fluid. Ten (52.6 %) patients had bilateral eye involvement, and six had concurrent central nervous system (CNS) involvement. All 19 patients achieved complete remission (CR) as confirmed by cytological examination of vitreous and cerebrospinal fluid and brain imaging if CNS was involved. Patients with concurrent brain involvement required a longer time to achieve CR. However, the duration of complete remission did not differ between patients with and without CNS involvement. The 5-year overall survival rate was 55.8 % for the total cohort and was higher (68.8 %) in patients with isolated PIOL than in those with concurrent CNS involvement. In all patients, methotrexate treatment was well tolerated, with manageable side effects. We conclude that combined intravitreal methotrexate and systemic high dose methotrexate treatment is effective in patients with PIOL. PMID- 26732885 TI - Multiple Sources of Ca2+ Contribute to Methylmercury-Induced Increased Frequency of Spontaneous Inhibitory Synaptic Responses in Cerebellar Slices of Rat. AB - We previously showed that elevated intracellular Ca(2+) ([Ca(2+)]i) in the molecular layer and granule cells in cerebellar slices is responsible for the initial increases in frequency of spontaneous or miniature inhibitory postsynaptic currents (sIPSCs or mIPSCs) of Purkinje cells following methylmercury (MeHg) treatment. To identify the contribution of different Ca(2+) sources to MeHg-induced stimulation of spontaneous GABA release, we examined sIPSC or mIPSC frequency of Purkinje cells in acutely prepared cerebellar slices using whole-cell patch-clamp recording techniques under conditions of lowered [Ca(2+)]o, pretreatment with caffeine, cyclopiazonic acid (CPA), thapsigargin or ruthenium red (RR) to deplete ryanodine-sensitive and insensitive intracellular Ca(2+) stores or mitochondria, or a combination of lowering [Ca(2+)]o and increased BAPTA buffering. Lowering [Ca(2+)]o significantly reduced sIPSC or mIPSC frequency and amplitudes, but failed to completely prevent MeHg-induced increase in these events frequency. Caffeine, CPA, or thapisgargin also minimized MeHg-induced increase in sIPSC frequency, yet none of them completely blocked MeHg-induced increase in sIPSC frequency. Similarly, the mitochondrial Ca(2+) transport inhibitor RR, or a combination of lowering [Ca(2+)]o and BAPTA buffering reduced but did not prevent MeHg-induced changes in mIPSC frequency. Consistently, confocal Ca(2+) imaging under low [Ca(2+)]o conditions or in the presence of caffeine or CPA exhibited a marked reduction of MeHg-induced increases in [Ca(2+)]i in both molecular and granule layers. Thus, these results verify that a combination of extracellular Ca(2+) influx and Ca(2+) release from different intracellular Ca(2+) pools all contribute to MeHg-induced increase in [Ca(2+)]i and spontaneous GABA release, although extracellular Ca(2+) appears to be the primary contributor. PMID- 26732886 TI - Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects Are Diminished in Adrenalectomized Rats. AB - Acute ozone exposure increases circulating stress hormones and induces metabolic alterations in animals. We hypothesized that the increase of adrenal-derived stress hormones is necessary for both ozone-induced metabolic effects and lung injury. Male Wistar-Kyoto rats underwent bilateral adrenal demedullation (DEMED), total bilateral adrenalectomy (ADREX), or sham surgery (SHAM). After a 4 day recovery, rats were exposed to air or ozone (1 ppm), 4 h/day for 1 or 2 days and responses assessed immediately postexposure. Circulating adrenaline levels dropped to nearly zero in DEMED and ADREX rats relative to SHAM. Corticosterone tended to be low in DEMED rats and dropped to nearly zero in ADREX rats. Adrenalectomy in air-exposed rats caused modest changes in metabolites and lung toxicity parameters. Ozone-induced hyperglycemia and glucose intolerance were markedly attenuated in DEMED rats with nearly complete reversal in ADREX rats. Ozone increased circulating epinephrine and corticosterone in SHAM but not in DEMED or ADREX rats. Free fatty acids (P = .15) and branched-chain amino acids increased after ozone exposure in SHAM but not in DEMED or ADREX rats. Lung minute volume was not affected by surgery or ozone but ozone-induced labored breathing was less pronounced in ADREX rats. Ozone-induced increases in lung protein leakage and neutrophilic inflammation were markedly reduced in DEMED and ADREX rats (ADREX > DEMED). Ozone-mediated decreases in circulating white blood cells in SHAM were not observed in DEMED and ADREX rats. We demonstrate that ozone-induced peripheral metabolic effects and lung injury/inflammation are mediated through adrenal-derived stress hormones likely via the activation of stress response pathway. PMID- 26732887 TI - Intrauterine Exposure to Paracetamol and Aniline Impairs Female Reproductive Development by Reducing Follicle Reserves and Fertility. AB - Studies report that fetal exposure to paracetamol/acetaminophen by maternal consumption can interfere with male reproductive development. Moreover, recent biomonitoring data report widespread presence of paracetamol in German and Danish populations, suggesting exposure via secondary (nonpharmaceutical) sources, such as metabolic conversion from the ubiquitous industrial compound aniline. In this study, we investigated the extent to which paracetamol and aniline can interfere with female reproductive development. Intrauterine exposure to paracetamol by gavage of pregnant dams resulted in shortening of the anogenital distance in adult offspring, suggesting that fetal hormone signaling had been disturbed. Female offspring of paracetamol-exposed mothers had ovaries with diminished follicle reserve and reduced fertility. Fetal gonads of exposed animals had also reduced gonocyte numbers, suggesting that the reduced follicle count in adults could be due to early disruption of germ cell development. However, ex vivo cultures of ovaries from 12.5 days post coitum fetuses showed no decrease in proliferation or expression following exposure to paracetamol. This suggests that the effect of paracetamol occurs prior to this developmental stage. Accordingly, using embryonic stem cells as a proxy for primordial germ cells we show that paracetamol is an inhibitor of cellular proliferation, but without cytotoxic effects. Collectively, our data show that intrauterine exposure to paracetamol at levels commonly observed in pregnant women, as well as its precursor aniline, may block primordial germ cell proliferation, ultimately leading to reduced follicle reserves and compromised reproductive capacity later in life. PMID- 26732888 TI - Differential Effects of Silver Nanoparticles and Silver Ions on Tissue Accumulation, Distribution, and Toxicity in the Sprague Dawley Rat Following Daily Oral Gavage Administration for 13 Weeks. AB - There are concerns within the regulatory and research communities regarding the health impact associated with consumer exposure to silver nanoparticles (AgNPs). This study evaluated particulate and ionic forms of silver and particle size for differences in silver accumulation, distribution, morphology, and toxicity when administered daily by oral gavage to Sprague Dawley rats for 13 weeks. Test materials and dose formulations were characterized by transmission electron microscopy (TEM), dynamic light scattering, and inductively coupled mass spectrometry (ICP-MS). Seven-week-old rats (10 rats per sex per group) were randomly assigned to treatments: AgNP (10, 75, and 110 nm) at 9, 18, and 36 mg/kg body weight (bw); silver acetate (AgOAc) at 100, 200, and 400 mg/kg bw; and controls (2 mM sodium citrate (CIT) or water). At termination, complete necropsies were conducted, histopathology, hematology, serum chemistry, micronuclei, and reproductive system analyses were performed, and silver accumulations and distributions were determined. Rats exposed to AgNP did not show significant changes in body weights or intakes of feed and water relative to controls, and blood, reproductive system, and genetic tests were similar to controls. Differences in the distributional pattern and morphology of silver deposits were observed by TEM: AgNP appeared predominantly within cells, while AgOAc had an affinity for extracellular membranes. Significant dose-dependent and AgNP size-dependent accumulations were detected in tissues by ICP-MS. In addition, sex differences in silver accumulations were noted for a number of tissues and organs, with accumulations being significantly higher in female rats, especially in the kidney, liver, jejunum, and colon. PMID- 26732889 TI - Prognostic value of negative interim 2-[18F]-fluoro-2-deoxy-d-glucose PET/CT in diffuse large B-cell lymphoma. AB - AIM: To assess the prognostic value of negative interim combined 2-[(18)F]-fluoro 2-deoxy-d-glucose ((18)F-FDG) positron-emission tomography/computed tomography (PET/CT) in patients with diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: Ninety-two patients with histologically proven DLBCL were enrolled. All of the patients underwent (18)F-FDG PET/CT at diagnosis, and interim PET/CT after the second cycle of chemotherapy with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone (R-CHOP). Negative interim PET/CT was defined as the disappearance of all abnormal (18)F-FDG uptake compared to the pretreatment PET/CT image, as determined by visual assessment. The clinical outcome of patients was estimated as progression-free survival (PFS), and the prognostic significance of clinicopathological and imaging parameters were assessed using the Cox proportional hazards model. RESULTS: Thirty-six patients (39.1%) showed lymphoma progression within a median follow-up of 30.8 months. According to univariate analysis, Ann Arbor stage, serum lactate dehydrogenase level, Eastern Cooperative Oncology Group scale, International Prognostic Index (IPI) score, and maximum standardised uptake values on initial PET/CT were significant prognostic factors for PFS (all p<0.05). Among these parameters, only the IPI score was an independent predictor for PFS (p=0.044). Survival of patients with a high IPI score (>=3) was poorer than those with a low IPI score (0-2; p<0.001). CONCLUSION: Despite a negative interim (18)F-FDG PET/CT, approximately 39% of DLBCL patients showed progression during follow-up. Although the negative PET/CT was obtained during chemotherapy, it is important to closely follow-up patients, especially those with a high IPI score. PMID- 26732891 TI - Improving the documentation of the daily review of patients in general intensive care. AB - Following the daily review of patients on the general intensive care unit (GICU), ongoing issues are addressed and a management plan formulated. Within our unit, the documentation of this daily review is freehand and should include all items covered within the local GICU daily review checklist. However, an initial audit of the daily review demonstrated an average completion rate of only 57%, with several aspects of care consistently missed, most notably: eye and mouth care in ventilated patients (44% and 40%, respectively), glucose control (33%), stress ulcer prophylaxis (54%), and inspection and need for peripheral and central lines (24%). The current system relied on doctors learning the requirements for the clerking and remembering to document them all. It is known that there is a low level of reliability in successfully applying proven medical evidence; this is partly explained by dependence on vigilance and hard work by the clinician, and absence of checklists and protocols to reduce the impact of human factors on results. The majority of doctors on the unit believe they consistently record all items of this checklist, highlighting the gap between the ideal that clinicians strive towards and the outcome. An abbreviated daily review checklist was therefore implemented in the form of a laminated bookmark into the medical notes, to act as a reminder of the items that should be considered in the daily review and prompt subsequent documentation. Bookmarks were implemented over two PDSA cycles and medical notes re-audited. Post-intervention, the documentation of the daily review improved to an overall completion rate of >77%, with notable improvements in eye and mouth care in ventilated patients (89%, 95% respectively), glucose control (67%), stress ulcer prophylaxis (100%), and inspection and need for peripheral and central lines (43%). The daily review checklist concisely summarised onto bookmarks were cheap and simple to create, durable and easy to use, and improved the overall documentation of the daily review. The effect of this outcome remains untested. PMID- 26732890 TI - Non-contrast-enhanced imaging of haemodialysis fistulas using quiescent-interval single-shot (QISS) MRA: a feasibility study. AB - AIM: To assess the efficiency of a novel quiescent-interval single-shot (QISS) technique for non-contrast-enhanced magnetic resonance angiography (MRA) of haemodialysis fistulas. MATERIALS AND METHODS: QISS MRA and colour Doppler ultrasound (CDU) images were obtained from 22 haemodialysis patients with end stage renal disease (ESRD). A radiologist with extensive experience in vascular imaging initially assessed the fistulas using CDU. Two observers analysed each QISS MRA data set in terms of image quality, using a five-point scale ranging from 0 (non-diagnostic) to 4 (excellent), and lumen diameters of all segments were measured. RESULTS: One hundred vascular segments were analysed for QISS MRA. Two anastomosis segments were considered non-diagnostic. None of the arterial or venous segments were evaluated as non-diagnostic. The image quality was poorer for the anastomosis level compared to the other segments (p<0.001 for arterial segments, and p<0.05 for venous segments), while no significant difference was determined for other vascular segments. CONCLUSION: QISS MRA has the potential to provide valuable complementary information to CDU regarding the imaging of haemodialysis fistulas. In addition, QISS non-enhanced MRA represents an alternative for assessment of haemodialysis fistulas, in which the administration of iodinated or gadolinium-based contrast agents is contraindicated. PMID- 26732892 TI - Privacy-preserving genome-wide association studies on cloud environment using fully homomorphic encryption. AB - OBJECTIVE: Developed sequencing techniques are yielding large-scale genomic data at low cost. A genome-wide association study (GWAS) targeting genetic variations that are significantly associated with a particular disease offers great potential for medical improvement. However, subjects who volunteer their genomic data expose themselves to the risk of privacy invasion; these privacy concerns prevent efficient genomic data sharing. Our goal is to presents a cryptographic solution to this problem. METHODS: To maintain the privacy of subjects, we propose encryption of all genotype and phenotype data. To allow the cloud to perform meaningful computation in relation to the encrypted data, we use a fully homomorphic encryption scheme. Noting that we can evaluate typical statistics for GWAS from a frequency table, our solution evaluates frequency tables with encrypted genomic and clinical data as input. We propose to use a packing technique for efficient evaluation of these frequency tables. RESULTS: Our solution supports evaluation of the D' measure of linkage disequilibrium, the Hardy-Weinberg Equilibrium, the chi2 test, etc. In this paper, we take chi2 test and linkage disequilibrium as examples and demonstrate how we can conduct these algorithms securely and efficiently in an outsourcing setting. We demonstrate with experimentation that secure outsourcing computation of one chi2 test with 10, 000 subjects requires about 35 ms and evaluation of one linkage disequilibrium with 10, 000 subjects requires about 80 ms. CONCLUSIONS: With appropriate encoding and packing technique, cryptographic solutions based on fully homomorphic encryption for secure computations of GWAS can be practical. PMID- 26732893 TI - Evaluation of 5-methylcytosine and 5-hydroxymethylcytosine as potential biomarkers for characterisation of chemical allergens. AB - Epigenetic regulation of gene expression plays a pivotal role in the orchestration of immune responses. Chemical allergens form two categories: skin sensitizing chemicals associated with allergic contact dermatitis, and chemicals that cause sensitization of the respiratory tract and occupational asthma. In mice these are characterized by different T helper (Th) cell responses. Changes in DNA methylation in particular have been implicated in the in vivo responses to chemical allergy. As such it was hypothesised that differentially methylated regions (DMR) may provide candidates biomarkers of chemical allergy To examine this, mice were exposed to 2,4-dinitrochlorobenzene (DNCB; a contact allergen) or trimellitic anhydride (TMA; a respiratory allergen). DNA from draining lymph nodes was processed for methylated (5mC) and hydroxymethylated (5hmC) DNA immunoprecipitation (MeDIP/hMeDIP) then selected DMR analysed by qPCR. We describe a number of DMRs which, by combined analysis of 5mC and 5hmC, differentiate between responses induced by DNCB and those by TMA. Furthermore, these changes in methylation are specific to the draining lymph node. The Gmpr DMR is suggested as a possible biomarker for contact allergen-induced immune responses; it is characterised by divergent levels of 5mC and 5hmC DNCB-treated mice only. In contrast, the Nwc DMR was characterised by divergent 5mC and 5hmC specifically in response to TMA, highlighting its possible utility as a biomarker for responses induced by chemical respiratory allergens. These data not only represent novel analysis of 5hmC in response to chemical allergy in vivo, but with further investigation, may also provide a possible basis for differentiation between classes of chemical allergens. PMID- 26732894 TI - Diverse interface effects on ferroelectricity and magnetoelectric coupling in asymmetric multiferroic tunnel junctions: the role of the interfacial bonding structure. AB - Interface and size effects on electric/magnetic orders and magnetoelectric coupling are vital in the modern application of quantum-size functional devices based on multiferroic tunnel junctions. In order to give a comprehensive study of the interface and size effects, the properties of a typical asymmetric multiferroic tunnel junction, i.e., Fe/BaTiO3/Co, have been calculated using the first-principles simulations. Most importantly, all of the eight possible structures with four combinations of electrode/ferroelectric interfaces (i.e., Fe/BaO, Fe/TiO2, Co/BaO and Co/TiO2) and a series of barrier thicknesses have been taken into account. In this work, the equilibrium configurations, polarization, charge density, spin density and magnetic moments, etc., have been completely simulated and comprehensively analyzed. It is found that the ferroelectric stability is determined as a competition outcome of the strength of short-range chemical bondings and long-range depolarization/built-in fields. M/BaO (M = magnetic metal) terminations show an extraordinary enhancement of local polarization near the interface and increase the critical thickness of ferroelectricity. The bistability of polarization is well kept at the M/TiO2 interface. At the same time, the induced magnetic moment on atoms at the interfaces is rather localized and dominated by the local interfacial configuration. Reversing electric polarization can switch the induced magnetic moments, wherein atoms in M-O-Ti and M-Ti-O chains show preference for being magnetized. In addition, the difference between the sum of the interfacial magnetic moments is also enlarged with the increase of the barrier thickness. Our study provides a comprehensive and detailed reference to the manipulation and utilization of the interface, size and magnetoelectric effects in asymmetric multiferroic tunnel junctions. PMID- 26732895 TI - C2 Arylated Benzo[b]thiophene Derivatives as Staphylococcus aureus NorA Efflux Pump Inhibitors. AB - An innovative and straightforward synthesis of second-generation 2 arylbenzo[b]thiophenes as structural analogues of INF55 and the first generation of our laboratory-made molecules was developed. The synthesis of C2-arylated benzo[b]thiophene derivatives was achieved through a method involving direct arylation, followed by simple structural modifications. Among the 34 compounds tested, two of them were potent NorA pump inhibitors, which led to a 16-fold decrease in the ciprofloxacin minimum inhibitory concentration (MIC) against the SA-1199B strain at concentrations of 0.25 and 0.5 MUg mL(-1) (1 and 1.5 MUm, respectively). This is a promising result relative to that obtained for reserpine (MIC=20 MUg mL(-1)), a reference compound amongst NorA pump inhibitors. These molecules thus represent promising candidates to be used in combination with ciprofloxacin against fluoroquinolone-resistant strains. PMID- 26732896 TI - A trend towards increasing viral load in newly diagnosed HIV-infected inpatients in southeast China. AB - Peripheral blood viral load is an important indicator of viral production and clearance. Previous studies have suggested that viral load might predict the rate of decrease in CD4+ cell count and progression to AIDS and death. Here, we conducted a retrospective analysis of the trends in HIV-1 viral load in southeast China. Among inpatients newly diagnosed with HIV infection, we found that viral load has increased over the past decade from 4.20 log10 copies/ml in 2002 to 6.61 log10 copies/ml in 2014, with a mean increase of 0.19 log10 copies/ml each year. However, the CD4+ cell count was stable and insensitive to changes in viral load. Thus, increasing viral load appears to be an emerging trend in newly diagnosed HIV-infected inpatients. PMID- 26732897 TI - Improving the preoperative care of patients with femoral neck fractures through the development and implementation of a checklist. AB - The incidence of femoral neck fractures (FNFs) is expected to rise with life expectancy. It is important to improve the safety of these patients whilst under the care of orthopaedic teams. This study aimed to increase the performance of vital preoperative tasks in patients admitted for femoral neck fracture operations by producing and implementing a checklist as an aide memoir. The checklist was designed primarily for use by senior house officers (SHOs) admitting patients from the emergency department. A list of 12 preoperative tasks was identified. A baseline audit of 10 random patients showed that the mean proportion of the 12 tasks completed was 53% (range 25% - 83%). A survey of 14 nurses and surgeons found that the majority of respondents agreed that there was a problem with the performance of most of the tasks. The tasks were incorporated into a checklist which was refined in three plan-do-study-act cycles and introduced into the femoral neck fracture pathway. In the week following the introduction of the checklist, 77% of the checklist tasks were completed, 24% more than at the baseline audit (53%). In week 3, the completion of checklist tasks rose to 88% and to 95% in week 4. In conclusion, a simple checklist can markedly improve the performance and recording of preoperative tasks by SHOs. We recommend the wider adoption of the new checklist to be produced as a sticker for patients' medical records. Further study is required to ascertain the effect of the checklist on clinical outcomes. PMID- 26732898 TI - Providing services for acute low-back pain: A survey of Australian physiotherapists. AB - OBJECTIVE: To determine whether physiotherapists avoid lumbar X-rays for acute non-specific low back pain and advise people to stay active. METHODS: We conducted a cross sectional survey of Australian physiotherapists. 880 physiotherapists were randomly sampled from Victoria (495), South Australia (158), and Western Australia (227). Physiotherapists were asked which investigations they would order and interventions they would provide for five acute low back pain (LBP) presentations described in vignettes. Four of the five vignettes represented people who would not require a plain lumbar X-ray and would benefit from advice to stay active; one described a patient with a suspected vertebral fracture and would require a plain X-ray. Participants selected from a list of response options or provided free text responses. RESULTS: Questionnaires were completed by 203 of 567 potentially eligible physiotherapists (response rate 36%). Across the four vignettes where an X-ray was not indicated, 75% (95%CI 71 78%) of physiotherapists reported they would practice concordant with the guidelines and not order an X-ray, and 62% (95%CI 57-66%) provided advice to stay active. CONCLUSIONS: Most physiotherapists report intended compliance with recommendations in Australian clinical practice guidelines (CPGs) regarding avoiding the use of X-rays and providing advice to stay active for people with simple acute low back pain, given a vignette based scenario. The majority of respondents reported that they would not advise bed rest. Possible opportunities to further enhance compliance need to be developed and tested to reinforce the role of CPGs in informing physiotherapy practice. PMID- 26732899 TI - Validity and everyday clinical applicability of lumbar muscle fatigue assessment methods in patients with chronic non-specific low back pain: a systematic review. AB - PURPOSE: This systematic literature review aimed at examining the validity and applicability in everyday clinical rehabilitation practise of methods for the assessment of back muscle fatiguability in patients with chronic non-specific low back pain (CNSLBP). METHODS: Extensive research was performed in MEDLINE, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Embase, Physiotherapy Evidence Database (PEDro) and Cochrane Central Register of Controlled Trials (CENTRAL) databases from their inception to September 2014. Potentially relevant articles were also manually looked for in the reference lists of the identified publications. Studies examining lumbar muscle fatigue in people with CNSLBP were selected. Two reviewers independently selected the articles, carried out the study quality assessment and extracted the results. A modified Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) scale was used to evaluate the scientific rigour of the selected works. RESULTS: Twenty-four studies fulfilled the selection criteria and were included in the systematic review. We found conflicting data regarding the validity of methods used to examine back muscle fatigue. The Biering-Sorensen test, performed in conjunction with surface electromyography spectral analysis, turned out to be the most widely used and comparatively, the most optimal modality currently available to assess objective back muscle fatigue in daily clinical practise, even though critical limitations are discussed. CONCLUSIONS: Future research should address the identification of an advanced method for lower back fatigue assessment in patients with CNSLBP which, eventually, might provide physical therapists with an objective and reliable test usable in everyday clinical practise. Implications for Rehabilitation Despite its limitations, the Biering Sorensen test is currently the most used, convenient and easily available fatiguing test for lumbar muscles. To increase validity and reliability of the Biering-Sorensen test, concomitant activation of synergistic muscles should be taken into account. Pooled mean frequency and half-width of the spectrum are currently the most valid electromyographic parameters to assess fatigue in chronic non-specific low back pain. Body mass index, grading of pain and level of disability of the study population should be reported to enhance research quality. PMID- 26732900 TI - Retrospective analysis of 14 cases of remote epidural hematoma as a postoperative complication after intracranial tumor resection. AB - BACKGROUND: The occurrence of remote epidural hematoma as a postoperative complication after intracranial tumor resection is rare. This study reviewed experiences treating these hematomas and speculated on the causes of this disease. This study reviewed the treatment experience of 14 such cases. METHODS: The 14 patients included 10 males and 4 females, with an age range of 19 to 65 years old. Six cases of tumors occurred in the sellar region, two cases in the lateral ventricle, one case in the fourth ventricle, one case in a cerebellar hemisphere, and four cases in other sites. Among them, five cases were complicated with supratentorial hydrocephalus. The tumors included five cases of meningioma tumors, two cases of pituitary adenomas, three cases of ependymomas, two cases of craniopharyngiomas, one case of astrocytoma, and one case of tuberculosis tumor. For the cases complicated with hydrocephalus, ventricular drainage was provided if needed, and the tumor resection was then performed, with close observation for postoperative changes. If neurological symptoms and disturbance of consciousness occurred, computed tomography (CT) examination was immediately performed. If a remote epidural hematoma was found, the hematoma was evacuated by craniotomy. The patients were followed up after surgery. In the five cases complicated with hydrocephalus, ventricular drainage was first provided for three cases. RESULTS: All of the 14 cases underwent total tumor resection, and postoperative remote epidural hematoma occurred in all cases, including eight cases on the ipsilateral side and adjacent to the supratentorial operative field; two cases occurred on the contralateral side; two cases occurred on bilateral sides; and two cases occurred in distant areas (with infratentorial surgery, the hematoma occurred on the supratentorial area). Postoperative remote epidural hematoma usually occurred 0.5-5 h after the tumor resection, when the tentorial hernia had already occurred. Following tumor resection and epidural hematoma evacuation, 13 patients were discharged with good recovery, and one patient died. CONCLUSIONS: The reduced intracranial pressure due to the intracranial tumor resection may be the cause of this hematoma. This type of epidural hematoma is acute and often occurs before hernia. Thus, the risk of remote epidural hematoma after intracranial tumor resection needs to be made known. Aggressive hematoma evacuation can often result in satisfactory outcomes for patients. PMID- 26732901 TI - The Tradeoff Between Shorter and Longer Courses of Dual Antiplatelet Therapy After Implantation of Newer Generation Drug-Eluting Stents. AB - The benefit of prolonged dual antiplatelet therapy (DAPT) after implantation of drug-eluting stents (DESs) remains uncertain. In 10 randomized controlled trials (RCTs) of 31,666 predominantly low-risk patients undergoing DES implantation, shorter courses (3-12 months) of DAPT resulted in lower mortality (odds ratio [OR] 0.83, 95 % confidence interval [CI] 0.69-0.98) and major hemorrhage (OR 0.60, 95 % CI 0.48-0.75) but increased myocardial infarction (MI, OR 1.34, 95 % CI 1.04-1.73) and stent thrombosis (ST, OR 1.75, 95 % CI 1.08-2.82) than did longer courses (12-36 months) of DAPT. A risk-benefit analysis identified 3 fewer deaths and 5 fewer bleeds but 4 more MIs and 3 more STs annually for every 1000 patients treated with the shorter courses. In the predominantly low-risk population enrolled in RCTs, limiting DAPT to 3 to 12 months after DES implantation saved lives and prevented bleeding at the expense of increased ST and MI. PMID- 26732902 TI - Backbone 1H, 15N, 13C NMR assignment of the 518-627 fragment of the androgen receptor encompassing N-terminal and DNA binding domains. AB - Androgen receptor (AR) belongs to the nuclear receptor superfamily that are ligand dependent transcription factors. This protein binds to steroid hormones such as dihydrotestosterone, to specific DNA sequences as well as to a number of co-regulatory factors. A number of these interactions involve the N-terminal domain (NTD), that is predicted to be intrinsically disordered. In order to provide functional information about possible cross-talk mechanisms between the AR NTD and its DNA binding domain (DBD), we have undertaken the NMR study of a fragment of human AR encompassing the last 37 residues of the NTD and the DBD (NTD-DBD518-627). The backbone (1)H, (15)N, (13)C NMR resonance assignments of this fragment indicate the presence of residual helical secondary structure within the AR NTD. PMID- 26732903 TI - Molecular modeling of sulfoxaflor and neonicotinoid binding in insect nicotinic acetylcholine receptors: impact of the Myzus beta1 R81T mutation. AB - BACKGROUND: Sulfoxaflor (IsoclastTM active), a new sulfoximine-class insecticide, targets sap-feeding insect pests, including those resistant to neonicotinoids. Sulfoxaflor acts on the insect nicotinic acetylcholine receptor (nAChR) in a distinct manner relative to neonicotinoids. Unlike any of the neonicotinoids, sulfoxaflor has four stereoisomers. A homology model of Myzus persicae (green peach aphid) based on the ACh binding protein from Aplysia californica, overlaid with M. persicae nAChR sequence (alpha2 and beta1 subunits) was used to investigate the interactions of the sulfoxaflor stereoisomers with WT and R81T versions of the nAChR. RESULTS: Whole-molecule van der Waals interactions are highly correlated with the binding affinity for the neonicotinoids and correctly predict the rank order of binding affinity for neonicotinoids and sulfoxaflor. The R81T mutation in M. persicae nAChR is predicted to have much less effect on binding of sulfoxaflor's stereoisomers than that of the neonicotinoids. CONCLUSION: All four stereoisomers predictably contribute to the activity of sulfoxaflor. The WT and R81T nAChR homology models suggest that changes in a whole-molecule electrostatic energy component can potentially explain the effects of this target-site mutation on the pattern of reduced efficacy for the modeled neonicotinoids, and provide a basis for the reduced effect of this mutation on sulfoxaflor. (c) 2016 Society of Chemical Industry. PMID- 26732904 TI - Dirac cone move and bandgap on/off switching of graphene superlattice. AB - Using the density functional theory with generalized gradient approximation, we have studied in detail the cooperative effects of degenerate perturbation and uniaxial strain on bandgap opening in graphene. The uniaxial strain could split pi bands into pia and piz bands with an energy interval Es to move the Dirac cone. The inversion symmetry preserved antidot would then further split the pia (piz) bands into pia1 (piz1) and pia2 (piz2) bands with an energy interval Ed, which accounts for the bandgap opening in a kind of superlattices with Dirac cone being folded to Gamma point. However, such antidot would not affect the semimetal nature of the other superlattices, showing a novel mechanism for bandstructure engineering as compared to the sublattice-equivalence breaking. For a superlattice with bandgap of ~Ed opened at Gamma point, the Es could be increased by strengthening strain to close the bandgap, suggesting a reversible switch between the high velocity properties of massless Fermions attributed to the linear dispersion relation around Dirac cone and the high on/off ratio properties associated with the sizable bandgap. Moreover, the gap width actually could be continuously tuned by controlling the strain, showing attractive application potentials. PMID- 26732905 TI - Baseline coral disease surveys within three marine parks in Sabah, Borneo. AB - Two of the most significant threats to coral reefs worldwide are bleaching and disease. However, there has been a scarcity of research on coral disease in South East Asia, despite the high biodiversity and the strong dependence of local communities on the reefs in the region. This study provides baseline data on coral disease frequencies within three national parks in Sabah, Borneo, which exhibit different levels of human impacts and management histories. High mean coral cover (55%) and variable disease frequency (mean 0.25 diseased colonies m( 2)) were found across the three sites. Highest disease frequency (0.44 diseased colonies per m(2)) was seen at the site closest to coastal population centres. Bleaching and pigmentation responses were actually higher at Sipadan, the more remote, offshore site, whereas none of the other coral diseases detected in the other two parks were detected in Sipadan. Results of this study offer a baseline dataset of disease in these parks and indicate the need for continued monitoring, and suggest that coral colonies in parks under higher anthropogenic stressors and with lower coral cover may be more susceptible to contracting disease. PMID- 26732906 TI - Does emotional reasoning change during cognitive behavioural therapy for anxiety? AB - Emotional reasoning refers to the use of subjective emotions, rather than objective evidence, to form conclusions about oneself and the world. It is a key interpretative bias in cognitive models of anxiety disorders and appears to be especially evident in individuals with anxiety disorders. However, the amenability of emotional reasoning to change during treatment has not yet been investigated. We sought to determine whether emotional reasoning tendencies change during a course of routine cognitive-behavioural therapy (CBT). Emotional reasoning tendencies were assessed in 36 individuals with a primary anxiety disorder who were seeking treatment at an outpatient clinic. Changes in anxiety and depressive symptoms as well as emotional reasoning tendencies after 12 sessions of CBT were examined in 25 individuals for whom there was complete data. Emotional reasoning tendencies were evident at pretreatment assessment. Although anxiety and depressive symptoms decreased during CBT, only one of six emotional reasoning interpretative styles (pertaining to conclusions that one is incompetent) changed significantly during the course of therapy. Attrition rates were high and there was not enough information regarding the extent to which therapy specifically focused on addressing emotional reasoning tendencies. Individuals seeking treatment for anxiety disorders appear to engage in emotional reasoning, however routine individual CBT does not appear to result in changes in emotional reasoning tendencies. PMID- 26732907 TI - Importance of Intermolecular Hydrogen Bonding for the Stereochemical Control of Allene-Enone (3+2) Annulations Catalyzed by a Bifunctional, Amino Acid Derived Phosphine Catalyst. AB - The origin of stereoselectivity in the (3+2) annulation of allenes and enones catalyzed by an amino acid derived phosphine catalyst has been investigated by the use of dispersion-corrected density functional theory. An intermolecular hydrogen bond between the intermediate zwitterion and the enone was found to be the key interaction in the two enantiomeric transition states. Additional stabilization is provided by intermolecular hydrogen-bonding interactions between acidic positions on the catalyst backbone and the substrate. Enantioselectivity occurs because the intermolecular hydrogen bond in the transition state leading to the minor enantiomer is only possible at the expense of reactant distortion. PMID- 26732908 TI - [Towards personalized medicine: implications of basic sciences and the "omics" in clinical pratice]. PMID- 26732909 TI - [Lymphocyte subsets, dendritic cells and cytokine profiles in mice with melanoma treated with Uncaria tomentosa]. AB - OBJECTIVES: To evaluate the immunomodulatory effect on lymphocyte subsets, dendritic cells (DC), Th1 / Th2 / Th17 and inflammatory cytokines on systemic level and/or in the tumor microenvironment of mice with or without melanoma. MATERIALS AND METHODS: Peripheral blood and/or primary tumors samples were obtained of mice with B16 melanoma treated or not with a hydroalcoholic extract of Uncaria tomentosa (UT) with 5.03% of pentacyclic oxindole alkaloids (UT-POA) obtained from the bark of the plant. All cell assays and cytokine measurements were performed by flow cytometry. RESULTS: UT-POA systemically increased CD4/CD8a relation while cell activation was inversely proportional; increased the proportion of DCm; induced a pro-inflammatory Th1 profile and reduced Th17 response. TNF-alpha and IL-17A positively and negatively correlated with CD4/CD8a relation. CONCLUSIONS: The increase of Th1 (TNF-alpha) may result in the increase of CD4 or M1 macrophage activation. Although UT-POA shows increased DCm, is not dose-dependent. Th17(IL-17A) decreased can support the function of CD8a lymphocytes. UT-POA shows better systemic immunomodulatory effects than intratumoral. PMID- 26732910 TI - [Immunomodulation of Uncaria tomentosa over dendritic cells, il-12 and profile TH1/TH2/TH17 in breast cancer]. AB - Objetives. This study aimed to research the in vitro immunomodulatory effects of an Uncaria tomentosa hydroalcoholic extract standardized (5.03%, pentacyclic oxindole alkaloids) (UT-POA) on the immunophenotype of dendritic cells (DC) subsets, Th1, Th2, Th17 and IL-12 cytokines from patients with stage II breast cancer (BCII) and healthy women (H). MATERIALS AND METHODS: Blood of 11 H and 7 BCII was obtained, PBMC were isolated and cultured for 2h with/without various concentrations of UT-POA and stimulated or not with LPS for 24h. PBMC were labeled with specific antibodies for DC and in the supernatant we measured Th1/Th2/Th17 cytokines, both by flow cytometry. Furthermore IL-12 was measured by ELISA. RESULTS: UT-POA did not alter DC or accessory molecules expression in BCII. However, H exhibited a decrease in the percentage of mDC (myeloid DC) and an increase in HLA-DR and CD86 expression at 1000 MUg/mL. IL-12 secretion was modified only in the H group, increasing p70 subunit and decreasing p40 subunit. UT-POA increased Th1 (IFN-gamma and IL-2), Th2 (IL-4) and Th17 (IL-17) secretion in both groups. CONCLUSIONS: UT-POA increased the production of cytokines related with anti-tumoral response at concentrations of 500-1000 MUg/mL. This positive effect should be evaluated not only systemically but also in the tumor microenvironment in further studies. UT-POA may be a useful phytochemical in chemoprevention and in the alternative use in cancer therapies. PMID- 26732911 TI - [Characterization of thrombin like enzyme FROM Bothrops pictus venom]. AB - OBJECTIVES: To perform a biochemical and molecular characterization of the coagulant principle from Bothrops pictus venom. MATERIALS AND METHODS: We amplified the genetic sequence of this enzyme from cDNA and analyzed the homology of its nucleotide sequence and its deduced protein. This enzyme was also purified for N-terminal sequencing of first 20 amino acids and for coagulation assays using human plasma and human fibrinogen. Furthermore, cleavage pattern on fibrinogen was evaluated using SDS-PAGE and defibrinogenant activity on white mice (18-22 g). Finally, associated carbohydrate content, effect of protease inhibitors and chloride ions on its enzymatic activity were analyzed. RESULTS: The Thrombin-like Enzyme from Bothrops pictus showed homology at primary level of structure with other previously reported TLEs from Viperidae family. Minimum Coagulant Dosis (MCD) on plasma and human fibrinogen were 18 and 6 ug, respectively, and its coagulant potency was 131.1 NHI Thrombin units. This TLE was stable under physiological conditions and chloride ions are not necessary for its activity. Detected associated carbohydrates were hexoses (25.76%), hexosamines (13.12%) and sialic acid (0.76%). Phenyl methyl sulphonyl fluoride (PMSF) and dithiothreitol (DTT) were the main inhibitors of its enzymatic activity, but heparin had no inhibitor effect. CONCLUSIONS: The coagulant principle of Bothrops pictus venom is a Thrombin-like enzyme. PMID- 26732912 TI - [Antimicrobial resistance of Bartonella bacilliformis strains from regions endemic to bartonellosis in Peru]. AB - OBJECTIVES: To evaluate in vitro antimicrobial susceptibility to chloramphenicol (CHL) and ciprofloxacin (CIP) in strains of Bartonella bacilliformis from areas that are endemic to Bartonellosis in Peru, through three laboratory methods. MATERIALS AND METHODS: Antimicrobial susceptibility to CHL and CIP from 100 strains of Bartonella bacilliformis isolated in patients from the regions of Ancash, Cusco, Cajamarca, Lima and La Libertad were evaluated. Strains were evaluated by: disk diffusion, E-test and agar dilution. RESULTS: 26% of the strains of Bartonella bacilliformis evaluated were resistant to CIP and 1% to CHL. Similar patterns of antimicrobial sensitivity / resistance were obtained in all three methods. CONCLUSIONS: Bartonella bacilliformis strains circulating in Peru have high levels of in vitro resistance to CIP, so it is advisable to expand research on the use of drug treatment regimens of the Bartonellosis. The methods of E-test and disk diffusion were the most suitable for assessment in vitro of antimicrobial susceptibility of the microorganism. PMID- 26732913 TI - [Knowledge, attitudes and practices ABOUT HIV/AIDS in peruvian women]. AB - OBJECTIVES: To determine the level of knowledge, proper attitudes and safe sex practices regarding the Human Immunodeficiency Virus (HIV) infection in Peruvian women ages 15 to 49 years. MATERIALS AND METHODS: We used the results of the Continuous 2004-2007 Peruvian Demographic and Health survey (DHS). The dependent variable comprised the level of knowledge and attitudes regarding the disease and safe sexual practices. Descriptive statistical analysis and logistic regression was performed to find association between variables. RESULTS: A good level of knowledge about sexually transmitted infection (including HIV infection) was found in 47.8% of women from the population surveyed; 50.7% showed proper attitudes in relation to the disease and the people affected by it, while safe sexual practices were observed in 48.8% of the persons surveyed. Higher educational level, high index of socio-economic welfare, residence in the capital city during childhood, working as professional, technical, business women or clerical position; and frequent media access, were related to greater knowledge, good attitudes and safe practices. CONCLUSIONS: The level of knowledge, attitudes and practices shown by 15 to 49 year old Peruvian women regarding sexually transmitted infections is not adequate. PMID- 26732914 TI - [Development of pneumoconiosis and outsourcing work in peruvian miners]. AB - OBJETIVES: The aim of this study is to evaluate the association between the time of outsourced work and the development of pneumoconiosis in Peruvian miners who attended the "Centro Nacional de Salud Ocupacional y Proteccion al Ambiente para la Salud" between 2008 and 2011. MATERIALS AND METHODS: Retrospective case control study. Cases were defined as workers diagnosed of pneumoconiosis under standardized criteria. Outsourced work was defined as the time (in months) of work in a company that does not own the primary mining project. The project owner company was registered in the Mining Companies Directory (Ministerio de Energia y Minas). We used multiple logistic regression with crude and adjusted ORs. RESULTS: The study comprised 391 cases and 1519 controls. In both groups, most of the study subjects had a level of education lower than complete high school and were born and currently lived in the Peruvian highlands. There was statistically significant association between more frequency of pneumoconiosis and working 10 or more years in an outsourced company (OR: 1.50; 95%CI: 1.05-1.14; p=0.026). Miners with pneumoconiosis were more likely not to have education (OR: 3.07; 95%CI: 1.55-6.08; p=0.001), be currently living at the Peruvian highlands (OR: 1.40; 95%CI: 1.10-1.78; p=0.007) and to have more than 20 years of underground work history (OR: 8.92; 95%CI: 4.53-18.25; p<0.001). CONCLUSIONS: A statistically significant association was found between pneumoconiosis and the time of outsourced work. Not having education, residing in the Peruvian highlands and the time of underground work were associated risk factors. PMID- 26732915 TI - [Characteristics of the diagnosis and treatment of pulmonary tuberculosis in patients with and without diabetes mellitus type 2]. AB - OBJECTIVES: To determine whether there are demographic, clinical and radiological differences among patients with pulmonary tuberculosis (TB) and patients with TB and type 2 diabetes mellitus (DM2 + TB). MATERIALS AND METHODS: Observational retrospective cohort study. We compared the clinical characteristics of patients according to sex, age, time to sputum conversion to negative, presence of cavitation and the cure rate, duration of treatment and the proportion of change of treatment regimen, in patients with and without DM2 served by the Tuberculosis Control Program from 2010 to 2012 in the Rebagliati Healthcare Network of Lima, Peru. RESULTS: 31 patients with TB+DM2 and 144 patients with TB were included. Differences (p<0.05) in the diagnostic method, the average of symptoms and the resistance pattern of TB among patients with and without DM2 were found. The presence of cavitation was more frequent in patients with TB + DM2. Having TB + DM2 delayed the time to sputum smear conversion to negative (RRa 4.16, 95% CI: 1.1-1.6) in the adjusted Cox regression analysis. CONCLUSIONS: There are differences in demographic, clinical and radiological characteristics in TB patients with and without DM2.The time to sputum conversion to negative is greater in patients with DM2. PMID- 26732916 TI - [Prevalence of anemia and associated factors in elderly residing in peruvian households]. AB - OBJECTIVES: To estimate the prevalence of anemia and associated factors in elderly residing in Peruvian households. MATERIALS AND METHODS: the study deals with a cross-sectional design and was conducted in 2011. The sample was probabilistic, stratified and multistage independent in department of Peru. The required sample housing was 5792, we included 2172 elderly. We asked informed consent of all elderly. The anemia was defined as hemoglobin <13.0 g / dL in men and <12.0 g / dL in women, hemoglobin was adjusted for altitude. The anthropometric measurements were performed according to methodology MINSA/INS. The Nutritional status was assessed by body mass index. The classification of nutritional status: underweight (BMI<=23,0) (BMI>23 to <28), overweight (BMI>=28 to <32.0) and obesity (BMI>=32). Statistical analysis was performed using complex samples and adjusted by the weighting factor. We Calculated means, proportions. The chi-square and regression logistic. RESULTS: The mean hemoglobin was 13.4 +/- 1.6 g / dL. The prevalence of anemia was 23,3% (mild anemia 17.1%, moderate: severe 5,7% and 0,5%). The age 70 to 79 years (OR 1.5; CI 95%:1.1; 2.0),> 80 years (OR 2.1; CI 95%: 1.4; 3.0) and thinness (OR 1.7; CI 95%: 1.2, 2.3) associated with anemia. Ayacucho, Ancash, Lambayeque and Apurimac were the departments with the highest prevalence of anemia. CONCLUSIONS: Approximately one quarter of elderly were anemic, being more prevalent in the illiterate, rural and poor. Older age and thinness are associated with anemia in elderly Peruvians. PMID- 26732917 TI - [Socio-demographics characteristics and health conditions of older homeless persons of Lima, Peru]. AB - OBJECTIVES: Determine the socio-demographics characteristics and health conditions of older homeless persons at the time of enrollment into the National Program "Vida Digna" and the probability of functional dependency by age, and stratified by gender and cognitive impairment. MATERIALS ANDE METHODS: We performed a cross sectional study, reviewing all registration forms of the program in order to identify socio-demographic variables and health conditions of older homeless persons at the time of enrollment in the program. We did a descriptive analysis of the socio-demographic variables and we also determined the frequency of health conditions. Furthermore, we determined the probability of functional dependency by age, and stratified by gender and cognitive impairment through a logistic regression model. RESULTS: The older homeless persons at the time of enrollment in the program were mostly single men, with a primary education or no education. The study subjects had a high frequency of chronic and mental diseases. 50% of them had certain level of functional impairment and roughly 70% had a certain level of cognitive impairment. The probability of functional dependency increased by age, and it was higher in women than in men. This probability increased according to the level of cognitive impairment. CONCLUSIONS: This study shows that older homeless persons are a vulnerable population not only because they live outdoors but also because they a have also for the high prevalence of chronic and mental diseases. These diseases prevent the homeless persons from living by themselves special care to overcome their situations. PMID- 26732918 TI - [Mental health in older adults of a public hospital network of Medellin, Colombia]. AB - OBJECTIVES: To determine the prevalence of poor mental health and associated factors in older adults of the Social Enterprise of the State (ESE) Metrosalud. MATERIALS AND METHODS: Cross-sectional study using two-stage sampling in hospital units and health centers in the network of the ESE Metrosalud of Medellin. Participants included 342 adults aged 65 and over (57.8% women). VARIABLES: poor mental health (measured with the GHQ12), social support (Duke-11); sociodemographic: age, sex, socioeconomic status, educational level, place of residence, marital status and occupation. Study variables were described, the overall prevalence was calculated according to sociodemographic variables. The association of poor mental health with selected variables was estimated by calculating odds ratios with 95% confidence intervals adjusted for possible confounding variables using logistic regression. RESULTS: The senior population without education in both sexes (ORa = 7.61; 95% CI: 2.49 to 23.34), widows (ORa 2.78; 95% CI: 1.21 to 6.40) and men and women with low social support (ORa 3.05; 95% CI: 1.65- 5.66), reported increased risk of poor mental health, compared to their counterparts of reference. CONCLUSIONS: We found a high prevalence of poor mental health in the population studied, with differences according to socio demographic factors, suggesting that the social vulnerability in this group impacts their health status. Health and social policies and strategies that contribute to the welfare of this population group are required. PMID- 26732919 TI - [Clinical, functional and older socio-familiar profile of the community in a district of Lima, Peru]. AB - OBJECTIVES: To determine the clinical, functional and socio-familiar profile of seniors from a community in a district of Lima, Peru. MATERIALS AND METHODS: Descriptive cross-sectional study of a sample of 501 people aged 60 and over living in the San Martin de Porres district. We used a structured questionnaire in which clinical, functional and socio-familiar variables were recorded. A physical evaluation was carried out to assess performance based measures and serum samples were taken for hematological and biochemical examination. The data were presented with descriptive statistics such as frequencies and percentages for categorical variables and means and standard deviations for the numeric variables. RESULTS: A total of 501 older adults were evaluated. The mean age was 71.5 years (+/-8.9 years). The most common chronic disease was arterial hypertension at 40.9%, followed by rheumatic diseases with 36.9%. 27.7% had some degree of partial or total dependence in activities of daily living, 16.2% had cognitive impairment, 8% lived alone, 58.5% had or were at risk of having a social problem.61% self-rated their health as normal, while 16% rated it as bad or very bad. CONCLUSIONS: Seniors in the community of San Martin de Porres in Lima have frequent problems of functional dependence, have or are at risk of social problems, chronic illness and a high frequency of geriatric syndromes and problems. PMID- 26732920 TI - [Differences in mobility, traffic accidents and associated circumstances in guatemalan and spanish university students]. AB - OBJECTIVE: The purpose of this study was to compare the frequency of involvement in risky driving circumstances between Guatemalan and Spanish university students and identify in both populations the differences between the involvement in such circumstances and road crashes. MATERIALS AND METHODS: A cross sectional study was conducted during the academic courses 2007 to 2011 on a sample of 2 130 drivers (1 016 in Guatemala and 1 114 in Spain), who completed a self administered questionnaire that assessed: mobility patterns, use of safety devices, driving styles and involvement in road traffic crashes. RESULTS: Furthermore, they were involved more frequently in almost all the risky-driving circumstances compared with Spanish students, principally in: mobile use (74.4 % versus 24.3 %), distraction (47.1 % versus 18.8 %) or not using seatbelt (23.9% vs 5.9). Finally, the adjusted analysis yields an accident rate 4.8 times higher among Guatemalans (CI 95% 3.1-7.4). CONCLUSIONS: Considering the factors more frequently associated with suffer road traffic crashes dependent on human factor, it is noted physical and social factors as well as that the car-dependent issues, must play an important role in the marked differences detected in both populations. PMID- 26732921 TI - [Development of a service on line advice and information technology management for health]. AB - OBJECTIVE: To validate an advisory service and online information technology management for health and helps to make assessment and acquisition processes an informed medical equipment according to the market and the needs of the health institutions. MATERIALS AND METHODS: Internet via a technological solution supported ona data base containing systematic and updated information on technical specifications of 25 compared medical equipment, the same reference prices, list of suppliers, agents and / or producers and technical standards are developed. The"virtual" technical assistance was made with the support of a team of specialists in Health Technology Management, the decision makers in the planning, evaluation and procurement of biomedical equipment. The validation of the service was conducted by involving specialists in the field of Health Technology Management, from different disciplines and institutions who worked in health, public and private. They used the service for a period of time to verify its feasibility of use as well as its usefulness for their planning, evaluation and procurement of biomedical equipment. To these experts we applied a survey before and after them about the software developed in this project. RESULTS: We found that it is common to use the internet to search for information on medical equipment.Also,an increase on the view that the application will help in procurement of biomedical equipment(40% to 78%) was observed, it will improve the information system(40% to 89%) and communication among physicians,nurses, planners, engineers and other professionals involved in this process(20% to 78%). CONCLUSIONS: There is a need for a technological tool available with such features contribute to technology management in Peru. PMID- 26732922 TI - [Concordance between Procam and Framingham cardiovascular risk scores among men receiving HIV treatment at a National Hospital in Lima, Peru 2013]. AB - OBJECTIVES: The aim of the study is to determine the concordance between the PROCAM (Prospective Cardiovascular Munster) and Framingham scales in patients receiving highly active antiretroviral therapy (HAART). MATERIALS AND METHODS: A cross sectional study was conducted in HIV-positive male population who use HAART in a national reference hospital located in Lima, Peru. To evaluate the concordance between the two scales the graphic method of Bland and Altman was used, for the evaluation of the correlation we used the Pearson coefficient and to measure the agreement we use the kappa coefficient. RESULTS: 111 patients were enrolled, with an average age of 47.0 years. The distribution of patients according to the risk was low, moderate and high, 81.2%, 13.6% and 5.4% respectively for PROCAM and 71.2%, 25.2% and 3.6% for Framingham. According to the graphic method of Bland and Altman, the concordance was adequate in low values and was lost as the risk score increased. Pearson?s test found a strong correlation (r=0.87 and p<0.05) and the kappa coefficient was 0.56 (p<0,001). CONCLUSIONS: The agreement we found at low risk decreases as the risk increases. Strong correlation was found between the two scales. We recommend further studies in order to know which scale of cardiovascular risk is the most optimal scale for clinical practice among HIV population who receive HAART. PMID- 26732923 TI - [Supply and nutritional composition of salads in the food courts of shopping centers of Metropolitan Lima, 2014]. AB - OBJECTIVES: To assess supply and nutritional composition of the salads offered as an entree main course in the food courts of the shopping centers in Lima, Peru. MATERIALS AND METHODS: The menus of all food franchises present in the food courts of the eleven shopping centers of Lima were reviewed. The nutritional composition of salads offered as an entree were calculated for calories, protein content, carbohydrates, fats, cholesterol, fiber and sodium, and the adequacy of intake for a dinner (30% of a diet of 2000 kcal). RESULTS: Salads as entrees accounted for 4.7% of the supply, and only 7 out of 17 franchises offered at least one salad. The average cost of the salads was higher than the other dishes ($5.3 vs $4.7; p<0.001). The average calorie content was 329 kcal and 2.7 g fiber; in relation to a dinner, we found a high percentage of adequacy for protein (172.9%), cholesterol (121.0%), and low adequacy for calories (54.8%), carbohydrates (23.1%) and fiber (36.4%). CONCLUSIONS: The salads that are offered in food courts in the shopping centers of Lima are scarce and more expensive, have little fiber content and are high in cholesterol. Strategies should be reviewed to improve the accessibility of quality salads offered in areas where only fast food is offered. PMID- 26732924 TI - [Allelic variants of the CYP2D6: *4, *6 and *10 in a sample of resident from the Aragua state, Venezuela]. AB - The aim of this study was to determine the CYP2D6: * 4, * 6 and * 10 gene variants frequency and to predict the metabolizer phenotype in a sample of 145 unrelated apparently healthy individuals residing in the state of Aragua, Venezuela. Genotypes were determined by Polymerase chain reaction assays followed by restriction endonucleases digestion. The metabolizer phenotype prediction was made based on the activity score system. The frequencies of CYP2D6 * 4, * 6 and * 10 allelic variants were 14.5%, 0.3% and 1%. A significant percentage of individuals were categorized as heterozygote-extensive/intermediate (23.5%) and poor metabolizers (4.1%), this information has potential clinical impact, because the CYP2D6 protein is involved in the metabolism of drugs frequently prescribed as: carvedilol, captopril, chloroquine, codeine, fluoxetine, fluvastatin, haloperidol, idarubicin, indinavir, imatinib, loperamide, nifedipine, ondansetron and tamoxifen. PMID- 26732925 TI - [TEM and CTX-M extended-spectrum beta-lactamase in Klebsiella spp and Escherichia coli isolates from inanimate surfaces of hospital environments]. AB - The aim of the study was to determine the genotype of 15 ESBL strains of Enterobacteriaceae resistant to beta-lactams, isolated from inanimate surfaces and phenotypically characterized as producing extended-spectrum beta-lactamase. After evaluation and screening of the bacterial strains, a PCR was conducted to amplify fragments of 1078 bp and 544 bp corresponding to type TEM and CTX-M ESBL. Eleven strains presented both fragments at the time and only three had blaCTX-M. In conclusion, the presence of ESBL genes in cultures from the environment was demonstrated, some of which may belong to more than one type. This information could serve as a basis for implementing preventive measures to prevent the transmission of multiresistant bacteria from inanimate surfaces to patients, mainly in critical hospital areas. PMID- 26732926 TI - [Factors associated with Ehrlichia canis infection in dogs infested with ticks from Huanuco, Peru]. AB - The aim of the study was to determine the frequency and associated factors of Ehrlichia canis infection in dogs. Blood samples from 150 dogs infested with ticks in 10 veterinary clinics in the city of Huanuco in Peru were collected. The dogs were randomly selected without regard to breed, age or sex. Ehrlichia canis antibodies were detected by chromatographic immunoassay.51.3% of dogs were infected with Ehrlichia canis. In the multivariate analysis, factors associated with the presence of Ehrlichia canis were: poor health of the dog (p = 0.049), a higher average of tick infestation (p = 0.018), and adult dogs (p = 0.038). The frequency of Ehrlichia canis in dogs of this city is high. Control of the brown dog tick (Rhipicephalus sanguineus) vector of Ehrlichia canis is recommended. PMID- 26732927 TI - [Traditional treatments in an endemic area of american cutaneous Leishmaniasis in Peru]. AB - In order to know the first-choice treatment by villagers of an endemic area of Cutaneous Leishmaniasis (CL) prior to medical attention in a health care center, a cross sectional study was realized in Pichupampa town. A census was made in order to collect demographic data and previous history of CL. 254 participants were surveyed. 41.7% (106/254) of the village had CL at least once in their lives and only half of them went to a health center to seek for primary care. 76/106 (71.7%) used some traditional treatment as their first choice and only 23.6% (25/106) subjects went to a health-care center without manipulation of their lesions. It's evident that a high percentage (71.7%) of people potentially infected by CL manipulate and treat their lesions with traditional treatments prior to professional health-care, actions that could interfere with the diagnosis and effectiveness of the program implemented by the Health Ministry. PMID- 26732928 TI - [Obesity as a risk factor in the development of cancer]. AB - According to the World Health Organization, every year about 3.4 million adults die of consequences related to overweight or obesity. People with a Body Mass Index above 30 are more likely to express certain diseases, including some types of cancer. In this narrative review, we assess the role of adipose tissue as a modulator of the endocrine system and facilitator of chronic subclinical inflammation. We discuss how obesity can induce a suitable micro environment for the development of tumors, mainly by enhancing the levels of oxidative stress and the concentrations of hormones such as leptin, insulin and prolactin. We conclude that all together, these factors increase the probability of cancer development. PMID- 26732929 TI - [Stem cells: limitations and opportunities in Peru]. AB - Stem cells are defined as rare cells that are characterized by asymmetric division, a process known as self-renewal, and the potential to differentiate into more than one type of terminally differentiated cell. There is a diversity of stem cells including embryonic stem cells, which exist only during the first stages of human development, and many adult stem cells depending on the specific tissues from where they derive or the ones derived from mesenchymal or stromal tissues. On the other hand, there are induced pluripotent stem cells generated by genetic engineering with similar properties to embryonic stem cells that are derived from adult tissues without the ethical and legal limitations. In all cases, there are many questions that are being addressed by research in basic sciences to better inform clinical practice. In Peru, there is much to do refining techniques and improving methodologies, which requires experience, proper facilities and highly specialized human resources. However, there are interesting efforts to place Peruvian stem cell research in the international scientific arena. PMID- 26732930 TI - [Neurogenetics in Peru, example of translational research]. AB - Neurogenetics is an emerging discipline in Peru that links basic research with clinical practice. The Neurogenetics Research Center located in Lima, Peru is the only unit dedicated to the specialized care of neurogenetic diseases in the country. From the beginning, neurogenetics research has been closely linked to the study of Huntington?s Disease (HD), from the PCR genotyping of the HTT gene, to the current haplogroup studies in HD. Research in other monogenic diseases led to the implementation of alternative methodologies for the genotyping of Fragile X and Myotonic Dystrophy Type 1. Both, national and international collaborative efforts have facilitated the discovery of new genetic variants in complex multigenic diseases such as Parkinson?s disease and Alzheimer?s disease. Additionally, multidisciplinary education and mentoring have allowed for the training of new neurogenetics specialists, supporting the sustained growth of the discipline in the country. The promotion of research in Peru has spurred the growth of neurogenetics research, although limitations in infrastructure, technology, and education remain a challenge for the further growth of research in this field. PMID- 26732931 TI - [The role of pharmacogenomics in the tuberculosis treatment regime]. AB - Tuberculosis is a health problem worldwide with one-third of the population infected with the Mycobacterium tuberculosis bacilli. The first-line of treatment for tuberculosis includes the drugs Isoniazid (INH) and Rifampicin (RIF) metabolized in the liver. Drug metabolism is directly related to the genetic variation of NAT2 and CYP2E1 (associated with INH metabolism) and AADAC (associated with RIF metabolism), and the effects produced in an individual may be a fast, intermediate or slow metobolizer. Polymorphisms in genes of people in standard tuberculosis treatment can cause effects on drug metabolism with consequences of hepatotoxicity and even drug resistance. Countries have began clinical trials focused on personalization of tuberculosis treatment to reduce the consequences for patients in treatment. In countries like Peru, where high rates of tuberculosis are recorded and therefore more people in treatment, the pharmacogenomic of individuals becomes a crucial tool for an optimum tuberculosis treatment. This review highlights the importance of having pharmacogenomic studies and having the identification of polymorphisms associated to the metabolism of the anti-tuberculosis drugs in our Peruvian population. PMID- 26732932 TI - [Differences and similarities in approach of integrated strategy for dengue prevention and control between Colombia and Peru]. AB - We analyzed and compared two Integrated Management Strategies for Dengue Prevention and Control (IMS-dengue Colombia and IMS-dengue Peru), through a narrative review of available literature, in order to identify common and dissimilar patterns in two Andean countries with epidemiological differences in the context of dengue disease. We were able to identify differences related to: formal assessment of problem, formation of groups of actors, and quantitative information provided by performance indicators. These limitations identified in IMS-dengue Colombia 2006-2010 were overcome in a new version of the strategy (IMS dengue Colombia 2012-2021). We were able to document an epidemiological impact of implementation of IMS-dengue Colombia 2006-2010. Additionally, a gradual increase was observed in incidence rates of dengue cases that could be related to the strengthening of surveillance system of IMS- dengue Peru. PMID- 26732933 TI - [Endemic kaposi's sarcoma in a HIV-Negative patient]. AB - Kaposi's sarcoma (KS) is a multicentric, inflammatory angioproliferative cancer associated with herpes virus 8 (HHV-8). It has four clinico-epidemiological types: classic, endemic, iatrogenic and epidemic, or HIV associated. Clinically it may be indolent or aggressive, mainly affecting mucocutaneous areas with eventual visceral and lymph node involvement. It is often present and in a more aggressive form in the HIV-positive population. We report a case of a 27-year-old HIV- negative male patient with a bleeding tumoral lesion in the Waldeyer ring, multiple lymphadenopathies and exophytic foot lesions that remit with anthracycline-based emergency chemotherapy. HIV-negative KS is a rare condition. It is important to consider Peru as an endemic region for HHV-8. The oral involvement of KS is a rare manifestation and of poor prognosis, however, the HIV negative factor could confer a good prognosis. PMID- 26732934 TI - [Coinfection of rhinocerebral mucormycosis and sinus aspergillosis]. AB - Mucormycosis and aspergillosis are the most frequent fungal infections caused by filamentous fungi; coinfection in the same host is rare. We present a case of a 78-year-old male patient with the debut of type 2 diabetes mellitus and ketoacidosis, with swelling of the right side of the face, right facial paralysis, ptosis and a necrotic ulcer in the right palate. Facial Computed tomography showed an abscess of the right maxillary sinus. Cultured secretions revealed Aspergillus fumigatus. The pathology result of biopsies of the palate, maxillary sinus and ethmoid bone was consistent with mucormycosis. The patient was treated with voriconazole, amphotericin B deoxycholate, and surgical debridement of the maxillary sinus. The patient died despite the treatment. The coinfection of Rhinocerebral mucormycosis and aspergillosis should be suspected in immunosuppressed patients in order to establish early management that can permit an improved prognosis of the disease. PMID- 26732935 TI - [Anemia and clefts of the lip and palate]. PMID- 26732936 TI - [New routes of administration of alcohol in teens]. PMID- 26732937 TI - [Plastination as a method of preservation of biological tissue for teaching and research in human anatomy]. PMID- 26732938 TI - [Comments to the article: The medical residency program: perceptions of residents in hospitals of Lima and Callao]. PMID- 26732939 TI - [Experience of the sentinel surveillance on the border of Peru, Colombia and Brazil]. PMID- 26732940 TI - [Increased spending from investment in the health sector: Efficiency and cost effectivenes in spending?]. PMID- 26732941 TI - The role of Sema4D/CD100 as a therapeutic target for tumor microenvironments and for autoimmune, neuroimmune and bone diseases. AB - INTRODUCTION: Semaphorin 4D (Sema4D), also known as CD100, has been implicated in physiologic roles in the immune and nervous systems. However, the interaction of Sema4D with its high affinity receptor, Plexin-B1, reveals a novel role for Sema4D produced by the tumor microenvironment in tumor angiogenesis and metastasis. AREAS COVERED: The ligation of Sema4D/CD100 with CD72 on immune and inflammatory cells is known to stimulate immune responses and regulation. Because CD100 and CD72 are expressed on lung immune and nonimmune cells, as well as on mast cells, the CD100/CD72 interaction plays another important role in allergic airway inflammation and mast cell functions. A better understanding of Sema4D mediated cell signaling in physiological and pathological processes may be crucial for crafting new Sema4D-based therapeutics for human disease and tumor microenvironments. Strategies to achieve effective management through treatment with Sema4D include special siRNAs, neutralizing antibodies and knockdown. EXPERT OPINION: This review focuses on the links between Sema4D and human diseases such as cancer, bone metabolism, immune responses and organ development. The current knowledge regarding the expression of Sema4D and its receptors and its functional roles is systemically reviewed to explore Sema4D as both a target and a therapeutic in human diseases. PMID- 26732943 TI - Radiation risk models for all solid cancers other than those types of cancer requiring individual assessments after a nuclear accident. AB - In the assessment of health risks after nuclear accidents, some health consequences require special attention. For example, in their 2013 report on health risk assessment after the Fukushima nuclear accident, the World Health Organisation (WHO) panel of experts considered risks of breast cancer, thyroid cancer and leukaemia. For these specific cancer types, use was made of already published excess relative risk (ERR) and excess absolute risk (EAR) models for radiation-related cancer incidence fitted to the epidemiological data from the Japanese A-bomb Life Span Study (LSS). However, it was also considered important to assess all other types of solid cancer together and the WHO, in their above mentioned report, stated "No model to calculate the risk for all other solid cancer excluding breast and thyroid cancer risks is available from the LSS data". Applying the LSS models for all solid cancers along with the models for the specific sites means that some cancers have an overlap in the risk evaluations. Thus, calculating the total solid cancer risk plus the breast cancer risk plus the thyroid cancer risk can overestimate the total risk by several per cent. Therefore, the purpose of this paper was to publish the required models for all other solid cancers, i.e. all solid cancers other than those types of cancer requiring special attention after a nuclear accident. The new models presented here have been fitted to the same LSS data set from which the risks provided by the WHO were derived. Although it is known already that the EAR and ERR effect modifications by sex are statistically significant for the outcome "all solid cancer", it is shown here that sex modification is not statistically significant for the outcome "all solid cancer other than thyroid and breast cancer". It is also shown here that the sex-averaged solid cancer risks with and without the sex modification are very similar once breast and thyroid cancers are factored out. Some other notable model differences between those already published for all solid cancers and those presented here for all other solid cancers are also given here. The models presented here can be used to improve on the methodology adopted by WHO after Fukushima and could contribute to emergency preparedness for future nuclear accidents. PMID- 26732942 TI - Association of pain and CNS structural changes after spinal cord injury. AB - Traumatic spinal cord injury (SCI) has been shown to trigger structural atrophic changes within the spinal cord and brain. However, the relationship between structural changes and magnitude of neuropathic pain (NP) remains incompletely understood. Voxel-wise analysis of anatomical magnetic resonance imaging data provided information on cross-sectional cervical cord area and volumetric brain changes in 30 individuals with chronic traumatic SCI and 31 healthy controls. Participants were clinically assessed including neurological examination and pain questionnaire. Compared to controls, individuals with SCI exhibited decreased cord area, reduced grey matter (GM) volumes in anterior cingulate cortex (ACC), left insula, left secondary somatosensory cortex, bilateral thalamus, and decreased white matter volumes in pyramids and left internal capsule. The presence of NP was related with smaller cord area, increased GM in left ACC and right M1, and decreased GM in right primary somatosensory cortex and thalamus. Greater GM volume in M1 was associated with amount of NP. Below-level NP associated structural changes in the spinal cord and brain can be discerned from trauma-induced consequences of SCI. The directionality of these relationships reveals specific changes across the neuroaxis (i.e., atrophic changes versus increases in volume) and may provide substrates of underlying neural mechanisms in the development of NP. PMID- 26732944 TI - Choice of study endpoint significantly impacts the results of breast cancer trials evaluating chemotherapy-induced nausea and vomiting. AB - Multiple endpoints can be used to evaluate chemotherapy-induced nausea and vomiting (CINV). These endpoints reflect the various combinations of vomiting, nausea and rescue antiemetic use in the acute (0-24 h), delayed (>24-120 h) and overall (0-120 h) periods after chemotherapy. As the choice of outcome measure could potentially change the interpretation of clinical trial results, we evaluated CINV rates using different endpoints on a single dataset from a prospective cohort. Data from 177 breast cancer patients receiving anthracycline and cyclophosphamide-based chemotherapy was used to calculate CINV control rates using the 15 most commonly reported CINV endpoints. As nausea remains such a significant symptom, we explored the frequency at which pharmaceutical and non pharmaceutical company-funded studies included measures of nausea in their primary study endpoint. CINV control rates ranged from 12.5 %, 95 % (CI 7.6-17.4 %) for total control (no vomiting, no nausea and no rescue medication) in the overall period to 77.4 %, 95 % (CI 71.2-83.6 %) for no vomiting in the overall period. Similar differences were found in the acute and delayed periods. Non pharmaceutical company-funded trials were more likely to include a measure of nausea in the primary study outcome (9/18, 50 %) than pharmaceutical-funded trials (1/12, 8.3 %). The choice of trial endpoint has an important impact on reported CINV control rates and could significantly impact on interpretation of the results. Primary endpoints of studies, including those mandated by regulatory bodies, should account for nausea to reflect patient experience. Reporting of endpoints should be more comprehensive to allow for cross-trial comparisons. PMID- 26732945 TI - Immunoproteomics-Based Analysis of the Immunocompetent Serological Response to Lomentospora prolificans. AB - The filamentous fungus Lomentospora prolificans is an emerging pathogen causing severe infections mainly among the immunocompromised population. These diseases course with high mortality rates due to great virulence of the fungus, its inherent resistance to available antifungals, and absence of specific diagnostic tools. Despite being widespread in humanized environments, L. prolificans rarely causes infections in immunocompetent individuals likely due to their developed protective immune response. In this study, conidial and hyphal immunomes against healthy human serum IgG were analyzed, identifying immunodominant antigens and establishing their prevalence among the immunocompetent population. Thirteen protein spots from each morph were detected as reactive against at least 70% of serum samples, and identified by liquid chromatography tandem mass spectrometry (LC-MS/MS). Hence, the most seroprevalent antigens were WD40 repeat 2 protein, malate dehydrogenase, and DHN1, in conidia, and heat shock protein (Hsp) 70, Hsp90, ATP synthase beta subunit, and glyceraldehyde-3-phosphate dehydrogenase, in hyphae. More interestingly, the presence of some of these seroprevalent antigens was determined on the cell surface, as Hsp70, enolase, or Hsp90. Thus, we have identified a diverse set of antigenic proteins, both in the entire proteome and cell surface subproteome, which may be used as targets to develop innovative therapeutic or diagnostic tools. PMID- 26732947 TI - Induction treatment of acute myeloid leukemia in an elderly patient with intramarrow injection/administration of cytarabine: first report of a case. AB - We have used intramarrow injection/administration of cytarabine (Ara-C) instead of conventional intravenous approach to induce remission in an elderly patient with acute myelogenous leukemia. We show for the first time that the intramarrow injection of chemotherapeutic agents such as Ara-C can be used safely and effectively. PMID- 26732946 TI - Best clinical practice guidance for management of early caries lesions in children and young adults: an EAPD policy document. AB - BACKGROUND: The European Academy of Paediatric Dentistry (EAPD) encourages prevention and arrest of active dental caries. Therefore, the present guidance provides evidence- and clinically-based recommendations for detecting and diagnosing early/non-cavitated caries lesions, risk assessment and disease management. METHODS: A search of different databases was conducted using all terms related to the subject. Relevant papers were identified after a review of their titles, abstracts or full texts. Three workshops were held during the corresponding EAPD interim seminar in Brussels in 2015. Several statements were agreed upon and, furthermore, gaps in our knowledge were identified. RESULTS: Following the systematic reviews and outcomes of the seminars, it was concluded that visual and radiographic caries detection should be utilised as a basic diagnostic approach to locate, assess and monitor non-cavitated caries lesions in primary and permanent teeth. As another important evaluation step, a caries risk assessment should be performed at a child's first dental visit, and reassessments should be performed on a regular basis. It is widely accepted that non-cavitated caries lesions can be managed non-invasively in the majority of cases. The spectrum of measures includes a low cariogenicity tooth-friendly diet, daily and appropriate management of the biofilm, home and within the dental office/surgery usage of fluorides as well as sealing techniques. CONCLUSION: The detection and management of non-cavitated caries is an essential aspect of preventive dentistry. Therefore, the EAPD encourages oral health care providers and caregivers to implement preventive practices that can arrest early caries and improve individual and public dental health. PMID- 26732948 TI - Low-Cost Interactive Image-Based Virtual Endoscopy for the Diagnosis and Surgical Planning of Suprasellar Arachnoid Cysts. AB - OBJECTIVE: To investigate the feasibility and reliability of virtual endoscopy (VE) as a rapid, low-cost, and interactive tool for the diagnosis and surgical planning of suprasellar arachnoid cysts (SACs). METHODS: Eighteen patients with SACs treated with endoscopic ventriculocystostomy were recruited, and 18 endoscopic patients treated with third ventriculostomy were randomly selected as a VE reconstruction control group. After loading their DICOM data into free 3D Slicer software, VE reconstruction was independently performed by 3 blinded clinicians and the time required for each reconstruction was recorded. Another 3 blinded senior neurosurgeons interactively graded the visibility of VE by watching video recordings of the endoscopic procedures. Based on the visibility scores, receiver operating characteristic curve analysis was used to investigate the reliability of VE to diagnose SACs, and Bland-Altman plots were used to assess the reliability of VE for surgical planning. In addition, the intraclass correlation coefficient was calculated to estimate the consistency among the results of 3 reconstruction performers. RESULTS: All 3 independent reconstructing performers successfully completed VE simulation for all cases, and the average reconstruction time was 10.2 +/- 9.7 minutes. The area under the receiver operating characteristic curve of the cyst visibility score was 0.96, implying its diagnostic value for SACs. The Bland-Altman plot indicated good agreement between VE and intraoperative viewings, suggesting the anatomic accuracy of the VE for surgical planning. In addition, the intraclass correlation coefficient was 0.81, which revealed excellent interperformer consistency of our simulation method. CONCLUSIONS: This study substantiated the feasibility and reliability of VE as a rapid, low-cost, and interactive modality for diagnosis and surgical planning of SACs. PMID- 26732949 TI - Decompressive Craniectomy for Severe Traumatic Brain Injury: A Systematic Review. AB - OBJECTIVE: Systematic review of the literature to evaluate the role of decompressive craniectomy (DC) after severe traumatic brain injury (TBI), comparing the first major randomized clinical trial on this topic (DECRA) with subsequent literature. METHODS: A systematic literature search was performed from 2011 to 2015. Citations were selected using the following inclusion criteria: closed severe TBI and DC. Exclusion criteria included most patients <=18 years old, <=20 participants, review articles, DC for reasons other than TBI, or surgical procedures other than DC. Primary outcomes included mortality and Glasgow Outcome Scale (GOS) at discharge, 6 months, and 1 year after injury. Assessment of risk of bias of the randomized controlled trials was also performed. RESULTS: Only 12 of 5528 articles satisfied the eligibility criteria; of these studies, 3 were randomized controlled trials. DC in specific populations does not offer GOS or mortality advantages compared with medical treatment; on the other hand, when DC with open dural flap was compared with an alternative means of decompression, e.g., DC with multiple dural stabs, the latter showed significant advantage in mortality and GOS. Nonrandomized studies showed decreased mortality and increased GOS in patients aged <=50 years when DC was performed <5 hours after TBI and with Glasgow Coma Scale score >5. CONCLUSIONS: Our study underscores the importance of continued international prospective data collection for assessing types of surgical interventions in addition to DC and their timing in patients who have severe TBI. In addition, in geographic areas with limited access to advanced medical treatment for severe TBI, DC is of benefit when performed <5 hours after injury in younger patients with Glasgow Coma Scale >5. PMID- 26732950 TI - Endoscopic Modified Transseptal Transsphenoidal Approach for Maximal Preservation of Sinonasal Quality of Life and Olfaction. AB - OBJECTIVE: Patients experience significant postoperative sinonasal symptoms for the first few months after endoscopic transnasal transsphenoidal approach (ETN TSA) surgery. We modified this technique by bypassing the nasal mucosa and approaching through the septum bilaterally. In this study, we analyze whether these technical modifications, which we have termed the endoscopic modified transseptal transsphenoidal approach (EMTS-TSA), decrease postoperative sinonasal morbidity after endoscopic TSA. METHODS: We retrospectively reviewed a prospectively collected database. Patients who underwent endoscopic TSA from December 2012 to June 2014 were included. Thirty patients underwent ETN-TSA, and 51 underwent EMTS-TSA. Sino-Nasal Outcome Test-20, anterior skull base nasal inventory, and visual analog scale (VAS) for subjective olfaction were evaluated before and 1 and 3 months after surgery. Cross Cultural Smell Identification Test also was measured before and 3 months after surgery. RESULTS: There was a significant difference between the preoperative and 3-month VAS for olfaction in the ETN-TSA group (from 92.5 to 81.3; P = 0.002) but not the EMTS-TSA group (from 90.6 to 88.8; P = 0.403). There was no statistical difference in Sino-Nasal Outcome Test-20 or Cross-Cultural Smell Identification Test scores between 2 groups during follow-up. The EMTS-TSA group scored better than the ETN-TSA group in the anterior skull base nasal inventory subdomain ("nasal discharge," "urge to blow," and "trouble breading") 1 month postoperatively. CONCLUSIONS: EMTS-TSA could preserve almost all nasal mucosa, including the septum and turbinates. EMTS TSA may be useful for preserving early postoperative olfactory function and some sinonasal quality of life. We believe that EMTS-TSA is a good endoscopic pituitary surgery option. PMID- 26732951 TI - Ruptured Intracranial Dermoid: Is Surgery Indispensible: 11-Year Follow-Up of a Rare Entity. AB - BACKGROUND: Dermoid cysts are rare intracranial lesions that can occasionally rupture into intraventricular and subarachnoid spaces and can present with a myriad of symptoms. The surgical intervention in such cases is demanding, because the disseminated contents are spread widely in intraventricular and subarachnoid space. CASE DESCRIPTION: A 22-year-old female patient who presented with history of seizures was diagnosed as having a left parasellar ruptured dermoid. Because there were no features of increased intracranial pressure, conservative management was considered with antiepileptic administration. At 11 years of follow-up, the patient continues to do well on 2 antiepileptics with repeat imaging showing no change in size of lesion. CONCLUSIONS: Surgical intervention may not be essential in all patients with ruptured intracranial dermoids. In a few selected patients who do not manifest increased intracranial pressure and show no change in the size of the lesion on sequential radiologic follow-up, conservative management may be attempted, especially when the ruptured intracranial dermoid is located at eloquent areas and with wide dissemination of contents. PMID- 26732952 TI - A Systematic Review of Chiari I Malformation: Techniques and Outcomes. AB - OBJECTIVE: To elucidate the most efficacious treatments of Chiari I malformation (CIM). METHODS: A literature search was performed using PubMed, CINAHL/Ovid, Cochrane library, and the Elsevier database. The key words "Chiari I malformation," "Chiari malformation type I," "surgery," and "treatment" were used for the search. Articles had to be peer reviewed and provide primary outcomes measured by clinical and radiographic outcomes after surgical treatments. Exclusion criteria included non-English-language articles, case reports, commentaries, information from textbooks and expert opinions, and articles that did not provide outcomes concerning specific surgical methods. Patients included were classified into 4 groups according the procedure: only bony decompression but not duroplasty (group I), bony decompression plus duroplasty (group II), bony decompression plus the resection of tonsils (group III), and shunt (group IV). RESULTS: Eighteen studies were identified. Groups II and III had a significantly higher improvement rate (82.25%, 86.10%, P < 0.05) of outcomes with regard to clinical signs and symptoms than the other groups. Group IV showed a statistically higher rate (30.49%, P < 0.05) of aggregating clinical signs and symptoms. In patients with syringomyelia, group III showed better clinical improvement (96.08%). Group II displayed a significantly higher rate of decrease in the size of cavities (83.33%, P < 0.05). Group IV had a statistically higher rate of increase in the size of cavities (33.87%, P < 0.05). CONCLUSIONS: Only bony decompression cannot achieve satisfactory outcomes. Bony decompression plus duroplasty showed the most favorable outcomes. Resection of tonsils was not recommended because of the high rate of side effects. Shunt may aggregate clinical signs and symptoms and increase the size of cavities. PMID- 26732953 TI - The Surgical Anatomy of the Lumbosacroiliac Triangle: A Cadaveric Study. AB - OBJECTIVE: The anatomic area delineated medially by the lateral part of the L4-L5 vertebral bodies, distally by the anterior-superior surface of the sacral wing, and laterally by an imaginary line joining the base of the L4 transverse process to the proximal part of the sacroiliac joint, is of particular interest to spine surgeons. We are referring to this area as the lumbo-sacro-iliac triangle (LSIT). Knowledge of LSIT anatomy is necessary during approaches for L5 vertebral and sacral fractures, sacral and iliac tumors, and extraforaminal decompression of the L5 nerve roots. METHODS: We performed an anatomic dissection of the LSIT in 3 embalmed cadavers (6 triangles), using an anterior and posterior approach. RESULTS: We identified 3 key tissue planes: the neurological plexus plane, constituted by L4 and L5 nerve roots; an intermediate level constituted by the ileosacral tunnel; and posteriorly, by the lumbosacral ligament, and the posterior muscular plane. CONCLUSIONS: Improving anatomic knowledge of the LSIT may help surgeons decrease the risk of possible complications. When LSIT pathology is present, a lateral approach corresponding to the tip of the L4 transverse process, medially, is suggested to decrease the risk of vessel and nerve root damage. PMID- 26732954 TI - Improved Postoperative Facial Nerve and Hearing Function in Retrosigmoid Vestibular Schwannoma Surgery Significantly Associated with Semisitting Position. AB - OBJECTIVE: The pros and cons of semisitting positioning (SSP) versus lateral, horizontal positioning (LP) during retrosigmoid vestibular schwannoma (VS) surgery, especially concerning postoperative cranial nerve and brain stem preservation, are under continuous discussion. METHODS: In a single-center retrospective cohort study, 30 VSs operated on in SSP compared with 30 operated on in LP with comparable demography were analyzed. During SSP surgery, transesophageal echocardiographic monitoring for venous air embolism was used continuously. Electrophysiologic cranial nerve monitoring was used in both groups. RESULTS: Length of surgery was significantly different between both groups: 183 minutes mean in SSP surgery versus 365 minutes mean in LP surgery (P = 0.0001). Postoperative rates of facial palsy and hearing loss were also significantly different. Six months postoperatively, 63% had normal facial nerve function after SSP surgery, whereas in LP surgery, 40% had no facial palsy (P = 0.02). Hearing preservation rate was also significantly different: 44% in SSP surgery compared with 14% in LP surgery who had preserved hearing (P = 0.006). Because of cerebrospinal fluid leaks, there were 3 operative revisions in the LP group (10%) and 1 (3.3%) in the SSP group. A clinically insignificant venous air embolism rate was found in 3.3% of patients (1/30) during SSP surgery. The neurologic outcome after 6 months was 1.2 on the Rankin Scale in the LP group and 1.0 in the SSP group, with zero mortality. CONCLUSIONS: SSP compared with LP surgery was associated with significantly shorter operation time and better facial and cochlear nerve function in VS surgery postoperatively, without differences in complication rates. PMID- 26732955 TI - Meningocele and Meningoencephalocele of the Lateral Wall of the Sphenoid Sinus. PMID- 26732956 TI - Radiosurgery for Cerebral Arteriovenous Malformations with Associated Arterial Aneurysms. AB - OBJECTIVE: The radiosurgical outcomes for cerebral arteriovenous malformations (AVM) with AVM-associated arterial aneurysms (AAA) are poorly understood, because many AAAs are embolized before nidal intervention. The aim of this retrospective case-control study is to determine the effect of AAAs on AVM radiosurgery outcomes. METHODS: We evaluated an institutional AVM radiosurgery database from 1989 to 2013. AAAs were classified as intranidal (type I) or prenidal (type II). The case cohort comprised AVMs with patent type I or II AAAs. The control cohort comprised AVMs without AAAs and matched 2:1 to the case cohort. RESULTS: The case cohort comprised 51 AVMs, including 23 with type I and 28 with type II AAAs. The control cohort comprised 102 AVMs without AAAs. The cumulative AVM obliteration, annual postradiosurgery hemorrhage, and radiologically evident radiation-induced changes rates were 67%, 3.3%, and 28%, respectively, for the case cohort, compared with 70%, 2.0%, and 35%, respectively, for the control cohort. The presence of an AAA was not significantly associated with obliteration (P = 0.293), postradiosurgery hemorrhage (P = 0.209), or radiation-induced changes (P = 0.323). The rates of type II AAA occlusion at 3, 5, and 10 years were 46%, 77%, and 95%, respectively. The type II AAA occlusion rate was significantly higher in obliterated AVMs (P = 0.002). CONCLUSIONS: Patent intranidal or prenidal AAAs do not significantly affect AVM radiosurgical outcomes. Occlusion of distal prenidal AAAs commonly occurs after radiosurgery. These findings may support a more conservative stance for embolization before radiosurgery for AVMs with AAAs. PMID- 26732957 TI - Isolated, Transient, Pneumocephalus-Induced Oculomotor Neuropathy After Microvascular Decompression of the Trigeminal Nerve. AB - BACKGROUND: Pneumocephalus is a common radiographic finding after posterior fossa craniotomy. In contrast, cranial neuropathies related to pneumocephalus are extremely rare, with only a handful of previous reports. CASE DESCRIPTION: We present the rare case of a right partial oculomotor mononeuropathy occurring in a 26-year-old woman 4 hours after a microvascular decompression of her right trigeminal nerve. Postoperative imaging revealed pneumocephalus in the interpeduncular cisterns with an air bubble close to the cisternal segment of the right oculomotor nerve, trapped by a fetal right posterior cerebral artery. The patient was placed on 100% Fio2 (fraction of inspired oxygen) and encouraged to remain in the Trendelenburg position. She was discharged with only modest improvement in her pupil-involved partial oculomotor palsy, but she improved over the course of clinical follow-up and her deficit had completely resolved at 6 months. CONCLUSIONS: Cranial neuropathy secondary to pneumocephalus is a rare and usually self-limiting condition. Although high-concentration oxygen therapy hastens resolution of pneumocephalus, recovery from pneumocephalus-related neuropathies may take weeks to months. To properly treat pneumocephalus-induced cranial neuropathies, further studies into the mechanism of injury are needed. PMID- 26732958 TI - The Trans-Visible Navigator: A See-Through Neuronavigation System Using Augmented Reality. AB - INTRODUCTION: The neuronavigator has become indispensable for brain surgery and works in the manner of point-to-point navigation. Because the positional information is indicated on a personal computer (PC) monitor, surgeons are required to rotate the dimension of the magnetic resonance imaging/computed tomography scans to match the surgical field. In addition, they must frequently alternate their gaze between the surgical field and the PC monitor. OBJECTIVE: To overcome these difficulties, we developed an augmented reality-based navigation system with whole-operation-room tracking. METHODS: A tablet PC is used for visualization. The patient's head is captured by the back-face camera of the tablet. Three-dimensional images of intracranial structures are extracted from magnetic resonance imaging/computed tomography and are superimposed on the video image of the head. When viewed from various directions around the head, intracranial structures are displayed with corresponding angles as viewed from the camera direction, thus giving the surgeon the sensation of seeing through the head. Whole-operation-room tracking is realized using a VICON tracking system with 6 cameras. RESULTS: A phantom study showed a spatial resolution of about 1 mm. The present system was evaluated in 6 patients who underwent tumor resection surgery, and we showed that the system is useful for planning skin incisions as well as craniotomy and the localization of superficial tumors. CONCLUSIONS: The main advantage of the present system is that it achieves volumetric navigation in contrast to conventional point-to-point navigation. It extends augmented reality images directly onto real surgical images, thus helping the surgeon to integrate these 2 dimensions intuitively. PMID- 26732959 TI - Testing the Reliability of BOLD-fMRI Motor Mapping in Patients with Cerebral Arteriovenous Malformations by Electric Cortical Stimulation and Surgery Outcomes. AB - OBJECTIVE: To test the reliability of blood oxygenation level-dependent functional magnetic resonance imaging (fMRI) in the primary hand motor cortex (M1) among patients with arteriovenous malformations (AVMs) by electric cortical stimulation (ECS) and surgery outcomes. METHODS: Forty-three patients with AVMs involving/adjacent to M1 underwent blood oxygen level-dependent fMRI (BOLD-fMRI) with repetitive finger-to-thumb opposition movements. The generated image sets were processed on the iPlan 3.0 workstation. A site-by-site comparison between the fMRI and ECS maps was performed with the aid of neuronavigation. Surgical outcomes were analyzed as the change between preoperative and postoperative muscle strength (MS). Finally, fMRI sensitivity was calculated, and correlations of lesion-to-activation distances (LAD) and surgery outcomes were analyzed. RESULTS: The highest activation location was found in the ipsilateral M1in 40 patients (93%). The highest activation relocated in the contralateral M1area in one patient (2.3%). No motor activation was found in the other 2 (4.7%) patients. ECS results were positive in 34 patients (85%, 34/40). The fMRI sensitivity was calculated as 85%. In total, 18 patients (41.9%) had worsened MS 1 week after surgery. Eight patients (18.6%) suffered from permanent muscle strength deterioration 6 months later. Moreover, an LAD <=5 mm was significantly associated with permanent MS deterioration (P = 0.039). CONCLUSION: BOLD-fMRI exhibits high sensitivity in motor mapping in patients with AVMs. LAD <=5 mm may be associated with permanent MS deterioration in patients with AVM close to the motor cortex. PMID- 26732960 TI - Superficial Temporal Artery to Middle Cerebral Artery Bypass via a Minimized Approach: Operative Nuances and Problem-Solving Aspects. AB - BACKGROUND: The minimized approach for superficial temporal to middle cerebral artery (STA-MCA) bypass surgery is frequently associated with unfamiliar situations and technical problems. OBJECTIVE: Description of operative nuances and evaluation of problem-solving aspects to facilitate potential limitations related with a limited exposure approach. METHODS: In patients who underwent STA MCA bypass surgery between February 2012 and August 2014, a preoperative high resolution computed tomography-angiography 3-dimensional dataset was obtained to select the optimal vessels for anastomosis. Intraoperative exposure was assessed under standard neuronavigation. Anastomoses were performed with specific instruments developed by the authors. Intraoperative video documentation and follow-up records were analyzed retrospectively. RESULTS: Seventeen STA-MCA minimally invasive bypass procedures were performed on 12 patients. In all cases, the procedure could be performed through planned craniotomy (mean diameter 2.5 cm). All cases of the procedures dealt with the limitation of surgical field during bypass surgery. The described applications facilitated microsurgical handling in the environment of a limited exposure in all procedures. Follow-up showed all bypasses remained open. CONCLUSIONS: The surgical applications, operative techniques, problem-solving aspects, and development of new instruments are described. Potentially, these suggestions may enhance the surgical confidence and convenience to perform STA-MCA bypass surgery with a minimized approach. PMID- 26732961 TI - Endoscopic Third Ventriculostomy Instead of Shunt Revision in Children Younger Than 3 Years of Age. AB - OBJECTIVE: Endoscopic third ventriculostomy (ETV) is a valuable option in the treatment of shunt failure, but no clinical data exist for young children. The aim of this study was to elucidate the role of ETV in patients younger than 3 years of age with shunt malfunction. METHODS: A cohort of 37 patients younger than 3 years of age with shunt malfunction underwent ETV instead of shunt revision. Patients' preoperative condition and medical history were studied to determine the impact of a number of variables on outcome. The Fisher exact test was used to assess differences among groups. RESULTS: Median age at ETV was 21.6 months (8-36 months). Diagnosis was obstructive hydrocephalus in 24 patients and communicating hydrocephalus in 13. Median age at initial shunt placement was 3.2 months (10 days to 30 months). The etiology of shunt malfunction was obstruction (n = 27) or infection (n = 10). Overall ETV failure rate was 40.5% (15/37). Patients whose age at initial shunt placement was <6 months and/or who had a preterm birth history had higher relative rates of ETV failure. Other variables, including type of hydrocephalus, interval between initial shunt placement and ETV, history of intraventricular bleeding and/or infection, and etiology of shunt malfunction, did not significantly affect the final outcome. CONCLUSIONS: Patients younger than 3 years with obstructive or communicating hydrocephalus may benefit from ETV in the event of shunt malfunction and have about a 60% probability of becoming shunt free. PMID- 26732962 TI - Smoking Associated with Increased Aneurysm Size in Patients with Anterior Communicating Artery Aneurysms. AB - BACKGROUND: Hypertension and smoking are risk factors for aneurysm formation or rupture. We aimed to identify differences in aneurysm morphologies associated with hypertension or smoking in patients with anterior communicating artery (AcoA) aneurysms. METHODS: Between December 2007 and February 2015, 574 consecutive patients with AcoA aneurysms were identified from the Electronic Medical Record System. We extracted data on histories of hypertension alone, smoking alone, nonhypertension and nonsmoking, and both hypertension and smoking. The morphologic parameters of aneurysms were remeasured via computed tomography angiography image reconstruction. Multivariate logistic regression analyses were used to determine the differences in morphologies in patients with hypertension or who smoked. RESULTS: In the study, 495 patients with single AcoA aneurysm were included. Age, sex, vessel size, aneurysm size and height, size ratio, A1 segment configuration, and aneurysm shape were significantly different among the groups. A larger aneurysm occurred more often in patients who only smoked compared with those without hypertension who did not smoke (adjusted odds ratio, 1.19; 95% confidence interval, 1.04-1.36; P = 0.012). Patients with hypertension who also smoked more commonly had a larger aneurysm size than those with hypertension alone (adjusted odds ratio, 0.89; 95% confidence interval, 0.79-0.99; P = 0.040). There were significant differences in age, sex, and aneurysm morphology between the smoking patients and those with hypertension alone. CONCLUSIONS: Aneurysm size was an independent morphologic parameter associated with smoking in patients with ACoA aneurysms compared with other aneurysm morphologies. Smoking may be associated independently with increased aneurysm size and should be given up in patients with AcoA aneurysms. PMID- 26732963 TI - Global Neurosurgery: The Unmet Need. AB - Globally, the lack of access to basic surgical care causes 3 times as much deaths as HIV/AIDS, tuberculosis, and malaria combined. The magnitude of this unmet need has been described recently, and the numbers are startling. Major shifts in global health agenda have highlighted access to essential and emergency surgery as a high priority. A broad examination of the current global neurosurgical efforts to improve access has revealed some strengths, particularly in the realm of training; however, the demand grossly outstrips the supply; most people in low income countries do not have access to basic surgical care, either due to lack of availability or affordability. Projects that help create a robust and resilient health system within low- and middle-income countries require urgent implementation. In this context, concurrent scale-up of human resources, investments in capacity building, local data collection, and analysis for accurate assessment are essential. In addition, through process of collaboration and consensus building within the neurosurgical community, a unified voice of neurosurgery is necessary to effectively advocate for all those who need neurosurgical care wherever, whenever. PMID- 26732964 TI - Long-Term, Continuous Intra-Arterial Nimodipine Treatment of Severe Vasospasm After Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Secondary vasospasm and disturbances in cerebrovascular autoregulation are associated with the development of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. An intra-arterial application of nimodipine has been shown to increase the vessel diameter, although this effect is transient. The feasibility of long-term, continuous, intra-arterial nimodipine treatment and its effects on macrovasospasm, autoregulation parameters, and outcome were evaluated in patients with refractory severe macrovasospasm. METHODS: Ten patients were included with refractory macrovasospasm despite bolus nimodipine application (n = 4) or with primary severe vasospasm (n = 6). The patients were assessed with continuous multimodal neuromonitoring (mean arterial pressure, intraceranial pressure, cerebral perfusion pressure, brain tissue oxygen tension probe), daily transcranial Doppler examinations, and computed tomography angiography/perfusion. Autoregulation indices, the pressure reactivity index, and oxygen reactivity index were calculated. Indwelling microcatheters were placed in the extracranial internal carotid arteries and 0.4 mg nimodipine was continuously infused at 50 mL/hour. RESULTS: The duration of continuous, intra-arterial nimodipine ranged from 9 to 15 days. During treatment intracranial pressure remained stable, transcranial Doppler flow velocity decreased, and brain tissue oxygen tension improved by 37%. Macrovasospasm, as assessed via computed tomography angiography, had improved (n = 5) or disappeared (n = 5) at the end of treatment. Cerebrovascular autoregulation according to the pressure reactivity index and oxygen reactivity index significantly worsened during treatment. All patients showed a favorable outcome (median Glasgow Outcome Scale 5) at 3 months. CONCLUSIONS: In well-selected patients with prolonged severe macrovasospasm, continuous intra-arterial nimodipine treatment can be applied as a rescue therapy with relative safety for more than 2 weeks to prevent secondary cerebral ischemia. The induced impairment of cerebrovascular autoregulation during treatment seems to have no negative effects. PMID- 26732965 TI - Outcome After Clipping of Unruptured Intracranial Aneurysms Depends on Caseload. AB - OBJECTIVE: Although most neurovascular centers currently have a coil first policy, the percentage of coiled versus clipped aneurysms, as well as treatment outcomes, varies strongly between these centers. This study evaluates the impact of an increase in clipping caseload on treatment outcome in a large single-center series. METHODS: All consecutive patients who underwent microsurgical clipping of unruptured intracranial aneurysms between January 2003 and April 2014 in our department were analyzed retrospectively. According to the change of the chairman in the neurosurgical department (1 September 2008) with a subsequent increase in the clipping volume, the entire cohort was divided into 2 groups with equal time intervals (historic and current cohorts). RESULTS: There were 94 clipped unruptured intracranial aneurysms in the historic cohort and 252 in the current cohort. Unfavorable outcome at 6 months postoperatively (defined as modified Rankin Score >2) was observed in 8 cases (8.5%) in the historic cohort and 7 cases (2.8%) in the current cohort (P < 0.0001). The surgical mortality decreased from 3.2% to 0%. Cerebral infarction on postoperative computed tomography scan was observed in 25 cases (26.6%) in the historic cohort and 19 cases (7.5%) in the current cohort (P < 0.0001). Within the current cohort, there was a progressive improvement of surgical outcome over the time. CONCLUSIONS: The improvement of the surgical outcome after increasing the clipping caseload underlines the importance of sufficient surgical volume for maintenance of competitive treatment results. PMID- 26732966 TI - Prognostic Impact of Intracranial Pressure Monitoring After Primary Decompressive Craniectomy for Traumatic Brain Injury. AB - OBJECTIVE: Decompressive craniectomy (DC) for traumatic brain injury (TBI) can be used in 2 completely different situations: primary and secondary DC. Although intracranial pressure (ICP) monitoring has proved to be helpful in guiding therapy for head injuries, its role after primary DC is not well analyzed. The aim of this study was to elucidate the relationship between ICP monitoring and outcomes in patients undergoing primary DC for TBI. METHODS: We enrolled 187 head injured patients undergoing primary DC in this retrospective study. The patients were subdivided into 2 groups based on whether postoperative ICP was monitored (n = 34) or not (n = 153). We identified the intergroup differences in clinical parameters and prognosis. Unfavorable and favorable neurologic outcomes were defined by Glasgow Outcome Scale scores of 1-3 and 4-5, respectively. RESULTS: The rate of ICP monitoring was 18.2% for our head-injured patients after primary DC. There was no difference in preoperative Glasgow Coma Score, pupil reactivity, features of computed tomography images, or other demographic variables between patients with or without ICP monitoring. The mortality at discharge was 14.7% for patients with ICP monitoring and 32.7% for patients without, which showed a statistically significant difference (P = 0.037). The neurologic outcomes did not differ between the patient groups at discharge or the end of follow-up. CONCLUSIONS: Our data suggest that ICP monitoring after primary DC for head injured patients significantly decreases in-hospital mortality and should be implemented in neurocritical care to ensure the highest chances of surviving TBI. PMID- 26732967 TI - Cross-Sectional Analysis on Racial and Economic Disparities Affecting Mortality in Preterm Infants with Posthemorrhagic Hydrocephalus. AB - BACKGROUND: Despite major advances in medicine, racial and socioeconomic disparities continue to affect health care outcomes. Higher overall infant mortality has been reported for black neonates compared with their Hispanic and white counterparts. The underlying basis for these differences remains unclear. A potential influencing factor is the management of premature neurologic complications in this disadvantaged group. This study examines racial and socioeconomic disparities on mortality in preterm infants with posthemorrhagic hydrocephalus (PHH). METHODS: Data from the Nationwide Inpatient Sample and Kids Inpatient Database were combined from 2000 to 2010. Discharges with International Classification of Diseases, Ninth Revision, Clinical Modification codes for preterm births with intraventricular hemorrhage and PHH were included. Relative risk (RR) ratios for mortality, complications, length of stay, and hospital costs were obtained with multivariate analysis after controlling for patient-level, hospital-level, and admission-level factors. RESULTS: When controlling for patient and hospital factors, black neonates had increased mortality compared with whites and Hispanics (RR = 1.47; P < 0.01). This association existed despite lower rates of congenital cardiac defects (RR = 0.84; P < 0.01), gastrointestinal complications (RR = 0.84; P < 0.01), and general complications of prematurity (RR = 0.95; P = 0.04) in the black cohort. Preterm infants insured by Medicaid had increased mortality compared with those with private insurance (RR = 1.2; P = 0.04) after adjusting for patient and hospital factors. CONCLUSIONS: Among preterm infants with intraventricular hemorrhage and resultant PHH, black infants and those insured by Medicaid have significantly increased mortality but these 2 effects are independent. Further studies are needed to fully understand the factors affecting these racial and socioeconomic disparities. PMID- 26732968 TI - Endovascular Coiling Versus Microsurgical Clipping for Patients With Ruptured Very Small Intracranial Aneurysms: Management Strategies and Clinical Outcomes of 162 Cases. AB - BACKGROUND: Treatments for intracranial aneurysms mainly include endovascular treatment and craniotomy. Most studies report on large intracranial aneurysms, yet treatments for very small intracranial aneurysms remain controversial. Our purpose was to explore management strategies for ruptured very small intracranial aneurysms. METHODS: From January 2002 to September 2010, 162 consecutive patients with ruptured very small intracranial aneurysms (<=3 mm) were retrospectively analyzed by comparing procedural data, adverse events, additional procedures, and length of hospital stay between management strategies. Modified Rankin Scale was assessed at 2 months and at 1 year by a postal questionnaire and telephone interview. RESULTS: Of the 85 patients in the microsurgical group, 79 underwent surgical clipping and 6 underwent wrapping; 77 patients underwent endovascular therapy (endovascular group), including coiling (65 cases), stent-assisted (13 cases) and balloon-assisted (7 cases) coiling, and stenting (2 cases). At 2 months, a good grade (modified Rankin Scale 0-2) was achieved in 74% of patients in the endovascular group and 69.4% of patients in the microsurgical group. At 1 year, a good grade was achieved by 84.9% in the endovascular group and 80% in the microsurgical group. Logistic regression results showed that whichever treatment option was chosen, Hunt-Hess grade, age, cerebral vasospasm, and complications contributed significantly to the prediction of outcome at 2 months. CONCLUSIONS: Endovascular therapy for ruptured very small intracranial aneurysms was not inferior to surgical clipping and showed a slight trend toward better prognosis. PMID- 26732969 TI - Steroid Use for Acute Spinal Cord Injury in Latin America: A Potentially Dangerous Practice Guided by Fear of Lawsuit. AB - BACKGROUND: Current international guidelines do not recommend the routine administration of methylprednisolone (MP) in patients with acute spinal cord injury (SCI). Its use is known to be associated with complications and death. OBJECTIVES: To identify patterns of practice and reasons for MP prescription for acute SCI in Latin America. METHODS: Portuguese- and Spanish-modified versions of a previously published questionnaire were used to evaluate opinions about the administration of MP for acute SCI in Latin America. This Internet-based survey was conducted with members of AOSpine Latin America. RESULTS: A total of 970 AOSpine Latin America members from 20 countries answered the electronic questionnaire. Of the total sample, 834 surgeons (86%) reported that they routinely treat patients with acute SCI, and 56.1% of them reported routine administration of MP for these patients. Use of MP was associated with country, specialty, length of clinical practice, and number of SCI treated yearly. Among the 468 surgeons who report routine administration of MP, 56.1% believe in the clinical benefit, 29.3% do this because of fear of litigation, 27.1% because this is a protocol in their hospital, 3.5% because they believe that MP has no major adverse effects. CONCLUSIONS: Despite increasing evidence against the routine administration of MP in patients with SCI and international guidelines that do not recommend its use, this potentially dangerous practice remains common on this continent. The Latin American medical associations need to produce guidelines to standardize practices with acute SCI. Moreover, educational campaigns might reduce practices guided mainly by misperception of legal issues instead of clinical benefit. PMID- 26732970 TI - New Target-Specific Oral Anticoagulants and Intracranial Bleeding: Management and Outcome in a Single-Center Case Series. AB - INTRODUCTION: New target-specific anticoagulants such as the direct thrombin inhibitor dabigatran and the factor Xa inhibitor rivaroxaban are used in an increasing number of patients. Several studies comparing these new oral anticoagulants with vitamin K antagonists revealed a lower risk of severe bleeding complications and reduced thromboembolic events. However, the lack of antidotes is a challenging issue in the treatment of traumatic or spontaneous intracranial hemorrhage. METHODS: A retrospective analysis of patients with intracranial bleeding under new oral anticoagulants was performed; these patients were admitted to our department between January 2011 and November 2014. Treatment, reversal management of blood coagulopathy, and outcome of the patients were analyzed. RESULTS: Seventeen patients were included. The median age was 80.4 years. Seven patients were treated with dabigatran and 10 with rivaroxaban. Eight patients had traumatic intracranial bleeding and 9 patients had spontaneous intracranial hemorrhage. Complex perioperative hematologic treatment followed. In 9 cases, the clinical outcome was devastating with severe neurologic deficits (n = 2), comatose status (n = 4), or death (n = 3). Patients with the indication for acute surgical treatment had a high risk for a critical clinical outcome. CONCLUSIONS: Only a few case reports have analyzed the clinical course and the outcome after intracranial bleeding under new target-specific oral anticoagulants. Here, one of the first larger series is presented. Because of the lack of reversibility of the anticoagulative effects and the overall risks with geriatric patients, surgical treatment should be delayed as long as possible and comorbidities have to be considered. PMID- 26732971 TI - Time-Spatial Labeling Inversion Pulse Magnetic Resonance Imaging of Cystic Lesions of the Spinal Cord. AB - BACKGROUND: Cystic lesions of the spinal cord such as spinal intradural arachnoid cysts (SIACs) and spinal extradural arachnoid cysts (SEACs) contain cerebrospinal fluid (CSF). The pathology of these lesions is often difficult to understand because it is difficult to detect abnormal CSF flow by conventional magnetic resonance imaging (MRI) or myelography. We preliminarily evaluated the usefulness of time-spatial labeling inversion pulse magnetic resonance imaging (T-SLIP MRI) of cystic lesions of the spinal cord. METHODS: T-SLIP MRI was applied to the following 6 consecutive cystic lesions of the spinal cord: 3 SEACs, 1 SIAC, 1 spinal intramedullary cyst associated with adhesive arachnoiditis, and 1 chronic pseudomeningocele. Information obtained by T-SLIP MRI was evaluated with regard to the following: 1) whether exclusive pathologic information was obtained, 2) whether this information affected the therapeutic strategy, and 3) the time required for T-SLIP MRI. RESULTS: Exclusive information was obtained in all 6 cases. In SEACs and the intramedullary cyst, pathologic CSF flow into the cyst was directly visualized, enabling us to narrow the therapeutic intervention targets. In SIAC, exclusive information involved detection of the cystic cranial wall and the absence of the caudal wall, enabling us to omit the exploration of the caudal wall. The examination required as long as 80 minutes for SIAC and <30 minutes for the other cases. CONCLUSIONS: T-SLIP MRI is useful for obtaining pathologic information about cystic lesions of the spinal cord. PMID- 26732972 TI - Lost in transition or translation? Care philosophies and transitions between child and youth and adult mental health services: a systematic review. AB - BACKGROUND: Differences in care philosophies may influence transitions from child and adolescent mental health services (CAMHS) to adult mental health services (AMHS). AIMS: To review literature about CAMHS and AMHS care philosophies and their influence on transitions. METHOD: MEDLINE, PsycINFO, Embase and CINAHL databases were searched electronically using keywords related to transitions, youth and mental disorders. Content relating to philosophies of care was searched manually. Descriptive themes were extracted and the analysis suggested four hypotheses of how care philosophies influence transitions. RESULTS: Of the 1897 identified articles, 12 met eligibility criteria. Findings reveal consistent differences in care philosophies between CAMHS (developmental approach, involving families and nurturing) and AMHS (clinical/diagnosis-focus, emphasis on client autonomy and individual responsibility). CONCLUSIONS: Better understanding of philosophical differences and collaborative planning and service delivery may foster shared approaches in CAMHS and AMHS to better meet the needs of transitioning youth. PMID- 26732973 TI - Scientific and regulatory challenges in evaluating clinical trial protocols for HIV-1/AIDS vaccines - A review from a regulatory perspective. AB - Clinical development of prophylactic HIV/AIDS vaccines presents many scientific challenges that result in challenges for regulators reviewing clinical trial applications (CTAs). The World Health Organization (WHO) has the responsibility to provide technical support to these regulators. The search for an HIV/AIDS vaccine will only succeed through well-designed, -conducted and -controlled human efficacy studies reviewed and approved by regulators in countries worldwide, particularly in countries where the epidemic has hit hardest, such as in sub Saharan Africa and Asia. This review summarizes the current candidates in development and focuses on challenges regulators face when reviewing CTAs, such as the evolving landscape of "standard of prevention," trials in adolescents, adaptive trial designs, correlates of protection and their analysis, and access to successful vaccines. There are many unknowns in the field of HIV/AIDS vaccine development and often, there is not a clear right or wrong approach because of the scientific challenges described in this review. Consequently, regulators should not feel that decisions need be made in isolation, when there are many available international collaborative efforts and opportunities to seek expert advice. The WHO provides many such opportunities and support to regulators across the globe. PMID- 26732974 TI - Biopsychosocial obstetrics and gynaecology - a perspective from Australia. AB - Prior to and throughout the twentieth century, biomedical understandings of health predominated. Australian obstetrician and gynaecologist, Professor Derek Llewellyn-Jones responded to frustrations with the limitations of this narrow approach from both within and beyond the medical profession. His pioneering research, education and writings re-conceptualised the discipline as encompassing the social and psychological contexts and profoundly influenced women's own understanding of their health and the practice of obstetrics and gynaecology. The biopsychosocial model has replaced biological determinism and is now pervasive in education and clinical practice in many parts of the world. Widespread acceptance of the model has until now been associated with under-recognition of the importance of biology. Recent findings from epigenetics and neuroscience are enabling integration of body, mind and society and enhanced understanding and practice of psychosomatic obstetrics and gynaecology. PMID- 26732975 TI - Ghrelin O-acyltransferase (GOAT) and energy metabolism. AB - Ghrelin O-acyltransferase (GOAT), a member of MBOATs family, is essential for octanoylation of ghrelin, which is required for active ghrelin to bind with and activate its receptor. GOAT is expressed mainly in the stomach, pancreas and hypothalamus. Levels of GOAT are altered by energy status. GOAT contains 11 transmembrane helices and one reentrant loop. Its invariant residue His-338 and conserved Asn-307 are located in the endoplasmic reticulum lumen and cytosol respectively. GOAT contributes to the regulation of food intake and energy expenditure, as well as glucose and lipids homeostasis. Deletion of GOAT blocks the acylation of ghrelin leading to subsequent impairment in energy homeostasis and survival when mice are challenged with high energy diet or severe caloric restriction. GO-CoA-Tat, a peptide GOAT inhibitor, attenuates acyl-ghrelin production and prevents weight gain induced by a medium-chain triglycerides-rich high fat diet. Further, GO-CoA-Tat increases glucose- induced insulin secretion. Overall, inhibition of GOAT is a novel strategy for treatment of obesity and related metabolic disorders. PMID- 26732976 TI - Comparison of normalization and differential expression analyses using RNA-Seq data from 726 individual Drosophila melanogaster. AB - BACKGROUND: A generally accepted approach to the analysis of RNA-Seq read count data does not yet exist. We sequenced the mRNA of 726 individuals from the Drosophila Genetic Reference Panel in order to quantify differences in gene expression among single flies. One of our experimental goals was to identify the optimal analysis approach for the detection of differential gene expression among the factors we varied in the experiment: genotype, environment, sex, and their interactions. Here we evaluate three different filtering strategies, eight normalization methods, and two statistical approaches using our data set. We assessed differential gene expression among factors and performed a statistical power analysis using the eight biological replicates per genotype, environment, and sex in our data set. RESULTS: We found that the most critical considerations for the analysis of RNA-Seq read count data were the normalization method, underlying data distribution assumption, and numbers of biological replicates, an observation consistent with previous RNA-Seq and microarray analysis comparisons. Some common normalization methods, such as Total Count, Quantile, and RPKM normalization, did not align the data across samples. Furthermore, analyses using the Median, Quantile, and Trimmed Mean of M-values normalization methods were sensitive to the removal of low-expressed genes from the data set. Although it is robust in many types of analysis, the normal data distribution assumption produced results vastly different than the negative binomial distribution. In addition, at least three biological replicates per condition were required in order to have sufficient statistical power to detect expression differences among the three-way interaction of genotype, environment, and sex. CONCLUSIONS: The best analysis approach to our data was to normalize the read counts using the DESeq method and apply a generalized linear model assuming a negative binomial distribution using either edgeR or DESeq software. Genes having very low read counts were removed after normalizing the data and fitting it to the negative binomial distribution. We describe the results of this evaluation and include recommended analysis strategies for RNA-Seq read count data. PMID- 26732977 TI - Reconciling diverse mammalian pigmentation patterns with a fundamental mathematical model. AB - Bands of colour extending laterally from the dorsal to ventral trunk are a common feature of mouse chimeras. These stripes were originally taken as evidence of the directed dorsoventral migration of melanoblasts (the embryonic precursors of melanocytes) as they colonize the developing skin. Depigmented 'belly spots' in mice with mutations in the receptor tyrosine kinase Kit are thought to represent a failure of this colonization, either due to impaired migration or proliferation. Tracing of single melanoblast clones, however, has revealed a diffuse distribution with high levels of axial mixing--hard to reconcile with directed migration. Here we construct an agent-based stochastic model calibrated by experimental measurements to investigate the formation of diffuse clones, chimeric stripes and belly spots. Our observations indicate that melanoblast colonization likely proceeds through a process of undirected migration, proliferation and tissue expansion, and that reduced proliferation is the cause of the belly spots in Kit mutants. PMID- 26732978 TI - High electronic couplings of single mesitylene molecular junctions. AB - We report on an experimental analysis of the charge transport properties of single mesitylene (1,3,5-trimethylbenzene) molecular junctions. The electronic conductance and the current-voltage characteristics of mesitylene molecules wired into Au electrodes were measured by a scanning tunnelling microscopy-based break junction method at room temperature in a liquid environment. We found the molecular junctions exhibited two distinct conductance states with high conductance values of ca. 10(-1) G 0 and of more than 10(-3) G 0 (G 0 = 2e (2)/h) in the electronic conductance measurements. We further performed a statistical analysis of the current-voltage characteristics of the molecular junctions in the two states. Within a single channel resonant tunnelling model, we obtained electronic couplings in the molecular junctions by fitting the current-voltage characteristics to the single channel model. The origin of the high conductance was attributed to experimentally obtained large electronic couplings of the direct pi-bonded molecular junctions (ca. 0.15 eV). Based on analysis of the stretch length of the molecular junctions and the large electronic couplings obtained from the I-V analysis, we proposed two structural models, in which (i) mesitylene binds to the Au electrode perpendicular to the charge transport direction and (ii) mesitylene has tilted from the perpendicular orientation. PMID- 26732979 TI - Glycine Cleavage Powers Photoheterotrophic Growth of Chloroflexus aurantiacus in the Absence of H 2. AB - Chloroflexus aurantiacus is an anoxygenic phototrophic bacterium. Its unique CO2 fixation pathway and primitive light-harvesting antenna complexes have attracted extensive research attentions. In this work, we investigated the photoheterotrophic growth of C. aurantiacus J-10-fl using acetate [at 55 degrees C and without H2(g)]. The results indicate that glycine can promote anaerobic biomass production in a minimal medium by threefold to fivefold. Via (13)C metabolite analysis, we observed that glycine was involved in serine synthesis. Instead of being used as a major carbon source, glycine was degraded to produce C1 units and NAD(P)H. Tracer experiments also suggest that photoheterotrophic cultures growing with a exogenous glycine source exhibited capabilities of assimilating CO2 via multiple routes (including the 3-hydroxypropionate pathway). Finally, glycylglycine, a commonly used culture buffer, also significantly enhanced photoheterotrophic growth of C. aurantiacus, probably due to its thermal or enzymatic breakdown to glycine. PMID- 26732980 TI - Arrhythmic Risk Stratification in the Emergency Department. PMID- 26732981 TI - Feasibility of the vascularized fibula bone graft for reconstruction of the mandible: a cadaveric study. AB - The aim of this study was to assess the feasibility of the unilateral single barrel vascularized fibula bone graft (VFBG) for the restoration of mandibular defects. Eighty-one dry mandibles and fibulas were used. Each mandible was marked to measure the total mandible length (TML) and maximum defect length (MDL) for each type of defect (HCH, H, L, C, HC, LC, LCL, HCL; Boyd's classification and angle to angle). The fibula length (FL) was measured. The maximum vascularized fibula length (MVFL) was calculated as FL - 12 (cm). The feasibility of the unilateral single-barrel VFBG to reconstruct the mandible for each type of defect was determined from the MVFL:MDL ratio. Descriptive statistics, the Student's t test, and Pearson's correlation coefficient were used for the statistical analysis; significance was set at P<0.05. Average TML, FL, and MVFL were 30.82+/ 1.96cm, 31.75+/-2.23cm, and 19.75+/-2.23cm, respectively. The average MVFL:MDL ratios of HCH, LCL, and HCL were all <1. There was a significant positive correlation between TML and FL (r=0.48, P<0.01). The unilateral single-barrel VFBG alone is not feasible for the reconstruction of a near-total or total mandibular defect. PMID- 26732983 TI - Give patients direct access to physiotherapy. PMID- 26732982 TI - Embelin binds to human neuroserpin and impairs its polymerisation. AB - Neuroserpin (NS) is a serpin inhibitor of tissue plasminogen activator (tPA) in the brain. The polymerisation of NS pathologic mutants is responsible for a genetic dementia known as familial encephalopathy with neuroserpin inclusion bodies (FENIB). So far, a pharmacological treatment of FENIB, i.e. an inhibitor of NS polymerisation, remains an unmet challenge. Here, we present a biophysical characterisation of the effects caused by embelin (EMB a small natural compound) on NS conformers and NS polymerisation. EMB destabilises all known NS conformers, specifically binding to NS molecules with a 1:1 NS:EMB molar ratio without unfolding the NS fold. In particular, NS polymers disaggregate in the presence of EMB, and their formation is prevented. The NS/EMB complex does not inhibit tPA proteolytic activity. Both effects are pharmacologically relevant: firstly by inhibiting the NS polymerisation associated to FENIB, and secondly by potentially antagonizing metastatic processes facilitated by NS activity in the brain. PMID- 26732984 TI - Cochliomycin A inhibits the larval settlement of Amphibalanus amphitrite by activating the NO/cGMP pathway. AB - Cochliomycin A is a compound with anti-barnacle settlement activity and low toxicity, but the molecular mechanism of the compound is unknown. Here, isobaric tags for the relative or absolute quantitation (iTRAQ) labeling proteomic method were applied to analyze changes in the proteome of Amphibalanus (=Balanus) amphitrite cyprids in response to cochliomycin A treatment. Cochliomycin A affected the cytochrome P450, glutathione S-transferase (GST) and NO/cGMP pathways, among which the NO/cGMP pathway was considered to play a key role in barnacle larval settlement, while the cytochrome P450 and the GST pathways are mainly for detoxification. The results of real-time PCR further suggested the NO/cGMP pathway was activated in response to cochliomycin A. Larval settlement assays revealed that S-methylisothiourea sulfate (SMIS) and 1H (1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) rescued cyprids from cochliomycin A-induced inhibition of larval settlement. The findings supported the hypothesis that cochliomycin A inhibited barnacle larval settlement by stimulating the NO/cGMP pathway. PMID- 26732985 TI - Adiabatically twisting a magnetic molecule to generate pure spin currents in graphene. AB - The spin-orbit effect in graphene is too muted to have any observable significance with respect to its application in spintronics. However, graphene technology is too valuable to be rendered impotent to spin transport. In this communication we look at the effect of adiabatically twisting a single-molecule magnet embedded in a graphene monolayer. Surprisingly, we see that pure spin currents (zero charge current) can be generated from the system via quantum pumping. In addition we also see that spin-selective current can be pumped from the system. The pure spin current seen is quite resilient to temperature while disorder has a limited effect. Furthermore, the direction of these spin-pumped currents can be easily and exclusively controlled by the magnetization of the single-molecule magnet, with disorder having no effect on the magnetization control of the pumped spin currents. PMID- 26732986 TI - Next-generation sequencing analysis of lager brewing yeast strains reveals the evolutionary history of interspecies hybridization. AB - The lager beer yeast Saccharomyces pastorianus is considered an allopolyploid hybrid species between S. cerevisiae and S. eubayanus. Many S. pastorianus strains have been isolated and classified into two groups according to geographical origin, but this classification remains controversial. Hybridization analyses and partial PCR-based sequence data have indicated a separate origin of these two groups, whereas a recent intertranslocation analysis suggested a single origin. To clarify the evolutionary history of this species, we analysed 10 S. pastorianus strains and the S. eubayanus type strain as a likely parent by Illumina next-generation sequencing. In addition to assembling the genomes of five of the strains, we obtained information on interchromosomal translocation, ploidy, and single-nucleotide variants (SNVs). Collectively, these results indicated that the two groups of strains share S. cerevisiae haploid chromosomes. We therefore conclude that both groups of S. pastorianus strains share at least one interspecific hybridization event and originated from a common parental species and that differences in ploidy and SNVs between the groups can be explained by chromosomal deletion or loss of heterozygosity. PMID- 26732987 TI - Qualitation and Quantitation on Microplasma Jet for Bacteria Inactivation. AB - In this work, a self-made microplasma jet system was used to conduct the qualitation and quantitation of inactivation with Escherichia coli as the target bacteria. The logarithmic concentration and the size of antimicrobial rings served as the evaluation parameters, respectively. The effect of various parameters on inactivation effect was studied. The results showed that the majority of bacteria had been inactivated in 30 s. The inactivation effect enhanced and then weakened with the increase of air flow rate, and receded as the extension of treatment distance. The effect with different carrier gases showed as follows: oxygen > air > nitrogen > argon. Meanwhile, the effect of different components of microplasma was studied in the optimum conditions (The flow rate was 5 L/min; inactivation distance was 2 cm). The results showed that electrically neutral active species was the main factor of inactivation rather than heating effect, ultraviolet radiation and charged particles. Finally the experiments of thallus change proved that microplasma jet had etching effect on cell membrane. It also found that microplasma could degrade organic material like protein. Furthermore, the images of scanning electron microscope (SEM) revealed the change of cell morphology step by step in the whole process of inactivation. PMID- 26732988 TI - Experimental determination of the influence of oxygen on the PRESAGE(r) dosimeter. AB - It is generally accepted that the PRESAGE((r)) radiochromic dosimeter is not sensitive to oxygen, however, this claim has not been supported or verified experimentally. Therefore, the aim of this study was to experimentally determine the potential influence of oxygen on dose sensitivity of the PRESAGE((r)) dosimeter and its reporting system. Batches of PRESAGE((r)) and its radical initiator-leuco dye reporting system were prepared in aerobic and anaerobic conditions. The anaerobic batches were deoxygenated by bubbling nitrogen through the dosimeter precursors or reporting system for 10 min. The dosimeters and reporting systems were prepared in spectrophotometric cuvettes and glass vials, respectively, and were irradiated with 6 MV photons to various radiation doses. Changes in optical density of the dosimeters and reporting system before and after irradiation were measured using a spectrophotometer. The overall results show that oxygen has some influence on the dosimetric characteristics of PRESAGE((r)), although the radical initiator does appear to oxidize the leucomalachite green even in the presence of oxygen. Deoxygenation of the reporting system leads to an increase in sensitivity to radiation dose by ~30% when compared to the non-deoxygenated system. A minor increase in sensitivity (~5%) was also achieved by deoxygenating the PRESAGE((r)) precursor prior to casting. In addition, dissolved oxygen measurements revealed low levels of dissolved oxygen (0.40 +/- 0.04 mg l(-1)) in the polyurethane precursor used to fabricate the PRESAGE((r)) dosimeters, as compared to water (8.60 +/- 0.03 mg l( 1)) and the reporting system alone (1.30 +/- 0.10 mg l(-1)). The results suggest that the presence of oxygen does not inhibit the radiochromic properties of the PRESAGE((r)) system. However, deoxygenation of the dosimeter precursors prior to casting improves the dosimeters dose sensitivity by ~5%, which might be particularly useful for measuring low radiation doses. Nevertheless, we believe this is not sufficient enough to recommend the deoxygenation of commercial PRESAGE((r)) precursor prior to casting. In addition, there were no observed changes in the dose linearity, absorption spectrum and post-response photofading characteristics of the PRESAGE((r)) under the conditions investigated. PMID- 26732989 TI - Source of Cooperativity in Halogen-Bonded Haloamine Tetramers. AB - Inspired by the isostructural motif in alpha-bromoacetophenone oxime crystals, we investigated halogen-halogen bonding in haloamine quartets. Our Kohn-Sham molecular orbital and energy decomposition analysis reveal a synergy that can be traced to a charge-transfer interaction in the halogen-bonded tetramers. The halogen lone-pair orbital on one monomer donates electrons into the unoccupied sigma*N-X orbital on the perpendicular N-X bond of the neighboring monomer. This interaction has local sigma symmetry. Interestingly, we discovered a second, somewhat weaker donor-acceptor interaction of local pi symmetry, which partially counteracts the aforementioned regular sigma-symmetric halogen-bonding orbital interaction. The halogen-halogen interaction in haloamines is the first known example of a halogen bond in which back donation takes place. We also find that this cooperativity in halogen bonds results from the reduction of the donor acceptor orbital-energy gap that occurs every time a monomer is added to the aggregate. PMID- 26732990 TI - Patients with acute abdominal pain describe their experiences of fundamental care across the acute care episode: a multi-stage qualitative case study. AB - AIM: To explore how patients with acute abdominal pain describe their experiences of fundamental care across the acute care episode. BACKGROUND: Acute abdominal pain is one of the most common conditions to present in the acute care setting. Little is known about how patients' fundamental care needs are managed from presentation to post discharge. DESIGN: A multi-stage qualitative case study using the Fundamentals of Care framework as the overarching theoretical and explanatory mechanism. METHODS: Repeated reflective interviews were conducted with five adult patients over a 6-month period in 2013 at a university hospital in Sweden. The interviews (n = 14) were analysed using directed content analysis. RESULTS: Patients' experiences across the acute care episode are presented as five patient narratives and synthesized into five descriptions of the entire hospital journey. The patients talked about the fundamentals of care and had vivid accounts of what they meant to them. The experiences of each of the patients were influenced by the extent to which they felt engaged with the health professionals. The ability to engage or build a rapport was identified as a central component across the fundamental care elements, but it varied in visibility. CONCLUSION: Consistent pain management, comfort, timely and accurate information, choice and dignity and relationships were identified as essential fundamental care needs of patients experiencing acute abdominal pain regardless of setting, diagnosis, or demographic variables. These were variously achieved and the patients' narratives raised areas for improvement in several areas. PMID- 26732991 TI - Annual soil CO2 efflux in a cold temperate forest in northeastern China: effects of winter snowpack and artificial nitrogen deposition. AB - We conducted a snow depth 0 cm (non-snowpack), 10 cm, 20 cm, 30 cm and natural depth) gradient experiment under four quantities of nitrogen addition (control, no added N; low-N, 5 g N m(-2) yr(-1); medium-N, 10 g N m(-2) yr(-1); and high-N, 15 g N m(-2) yr(-1)) and took an-entire-year measurements of soil respiration (Rs) in Korean pine forests in northeastern China during 2013-2014. No evidence for effects of N on Rs could be found during the growing season. On the other hand, reduction of snowpack decreased winter soil respiration due to accompanied relatively lower soil temperature. We found that winter temperature sensitivities (Q10) of Rs were significantly higher than the growing season Q10 under all the N addition treatments. Moderate quantities of N addition (low-N and medium-N) significantly increased temperature sensitivities (Q10) of Rs, but excessive (high-N) addition decreased it during winter. The Gamma empirical model predicted that winter Rs under the four N addition treatments contributed 4.8. +/- 0.3% (control), 3.6 +/- 0.6% (low-N), 4.3 +/- 0.4% (medium-N) and 6.4 +/- 0.5% (high N) to the whole year Rs. Our results demonstrate that N deposition will alter Q10 of winter Rs. Moreover, winter Rs may contribute very few to annual Rs budget. PMID- 26732993 TI - The Use of Intravenous Lidocaine for Renal Colic in the Emergency Department. PMID- 26732992 TI - Rapid selection of mesenchymal stem and progenitor cells in primary prostate stromal cultures. AB - BACKGROUND: Carcinoma-associated fibroblasts (CAFs) are a dominant component of the tumor microenvironment with pro-tumorigenic properties. Despite this knowledge, their physiologic origins remain poorly understood. Mesenchymal stem cells (MSCs) can be recruited from the bone marrow to areas of tissue damage and inflammation, including prostate cancer. MSCs can generate and have many overlapping properties with CAFs in preclinical models. METHODS: Multiparameter flow cytometry and multipotent differentiation assays used to define MSCs in primary prostate stromal cultures derived from young (<25 yrs) organ donors and prostate cancer patients compared with bone marrow-derived stromal cultures. Population doubling times, population doublings, cell size, and differentiation potential determined under multiple culture conditions, including normoxia, hypoxia, and a variety of media. TGF-beta measured by ELISA. RESULTS: MSCs and stromal progenitors are not only present in normal and malignant prostate tissue, but are quickly selected for in primary stromal cultures derived from these tissues; becoming the dominant population within just a few passages. Growth potential inversely associated with TGF-beta concentrations. All conditions generated populations with an average cell diameter >15 um. All cultures tested had the ability to undergo osteogenic and chondrogenic differentiation, but unlike bone marrow-derived MSCs, primary stromal cultures derived from normal prostate tissue lack adipogenic differentiation potential. In contrast, a subset of stromal cultures derived from prostate cancer patients retain the ability to differentiate into adipocytes; a property that is significantly suppressed under hypoxic conditions in both bone marrow- and prostate-derived MSCs. CONCLUSIONS: Primary prostate stromal cultures are highly enriched in cells with an MSC or stromal progenitor phenotype. The use of primary cultures such as these to study CAFs raises interesting implications when considering their overlapping properties. The lack of adipogenesis in stromal cultures derived from normal prostates suggests they have a lineage-restricted progenitor phenotype. The retention of adipogenic differentiation in cultures from a subset of prostate cancer patients suggests the active recruitment of less committed progenitors or MSCs from the bone marrow as a function of disease progression. This recruitment can potentially be exploited for prognostic purposes or a cell-based platform for the systemic delivery of cytotoxic agents to sites of prostate cancer. PMID- 26732995 TI - Spark, an application based on Serendipitous Knowledge Discovery. AB - Findings from information-seeking behavior research can inform application development. In this report we provide a system description of Spark, an application based on findings from Serendipitous Knowledge Discovery studies and data structures known as semantic predications. Background information and the previously published IF-SKD model (outlining Serendipitous Knowledge Discovery in online environments) illustrate the potential use of information-seeking behavior in application design. A detailed overview of the Spark system illustrates how methodologies in design and retrieval functionality enable production of semantic predication graphs tailored to evoke Serendipitous Knowledge Discovery in users. PMID- 26732994 TI - Plasma Inflammatory Factors Are Associated with Anxiety, Depression, and Cognitive Problems in Adults with and without Methamphetamine Dependence: An Exploratory Protein Array Study. AB - OBJECTIVES: It is hypothesized that immune factors influence addictive behaviors and contribute to relapse. The primary study objectives were to (1) compare neuropsychiatric symptoms across adults with active methamphetamine (MA) dependence, in early remission from MA dependence, and with no history of substance dependence, (2) determine whether active or recent MA dependence affects the expression of immune factors, and (3) evaluate the association between immune factor levels and neuropsychiatric symptoms. METHODS: A cross sectional study was conducted using between group comparisons and regression analyses to investigate associations among variables. Eighty-four adults were recruited into control (CTL) (n = 31), MA-active (n = 17), or MA-remission (n = 36) groups. Participants completed self-report measures of anxiety, depression, and memory complaints and objective tests of attention and executive function. Blood samples were collected, and a panel of immune factors was measured using multiplex technology. RESULTS: Relative to CTLs, MA-dependent adults evidenced greater anxiety and depression during active use (p < 0.001) and remission (p < 0.007), and more attention, memory, and executive problems during remission (p < 0.01) but not active dependence. Regression analyses identified 10 immune factors (putatively associated with cytokine-cytokine receptor interactions) associated with anxiety, depression, and memory problems. CONCLUSION: While psychiatric symptoms are present during active MA dependence and remission, at least some cognitive difficulties emerge only during remission. Altered expression of a network of immune factors contributes to neuropsychiatric symptom severity. PMID- 26732996 TI - Measuring the effects of computer downtime on hospital pathology processes. AB - OBJECTIVE: To introduce and evaluate a method that uses electronic medical record (EMR) data to measure the effects of computer system downtime on clinical processes associated with pathology testing and results reporting. MATERIALS AND METHODS: A matched case-control design was used to examine the effects of five downtime events over 11-months, ranging from 5 to 300min. Four indicator tests representing different laboratory workflows were selected to measure delays and errors: potassium, haemoglobon, troponin and activated partial thromboplastin time. Tests exposed to a downtime were matched to tests during unaffected control periods by test type, time of day and day of week. Measures included clinician read time (CRT), laboratory turnaround time (LTAT), and rates of missed reads, futile searches, duplicate orders, and missing test results. RESULTS: The effects of downtime varied with the type of IT problem. When clinicians could not logon to a results reporting system for 17-min, the CRT for potassium and haemoglobon tests was five (10.3 vs. 2.0days) and six times (13.4 vs. 2.1days) longer than control (p=0.01-0.04; p=0.0001-0.003). Clinician follow-up of tests was also delayed by another downtime involving a power outage with a small effect. In contrast, laboratory processing of troponin tests was unaffected by network services and routing problems. Errors including missed reads, futile searches, duplicate orders and missing test results could not be examined because the sample size of affected tests was not sufficient for statistical testing. CONCLUSION: This study demonstrates the feasibility of using routinely collected EMR data with a matched case-control design to measure the effects of downtime on clinical processes. Even brief system downtimes may impact patient care. The methodology has potential to be applied to other clinical processes with established workflows where tasks are pre-defined such as medications management. PMID- 26732997 TI - More than just tracking time: Complex measures of user engagement with an internet-based health promotion intervention. AB - BACKGROUND: There has been a rise in internet-based health interventions without a concomitant focus on new methods to measure user engagement and its effect on outcomes. We describe current user tracking methods for internet-based health interventions and offer suggestions for improvement based on the design and pilot testing of healthMpowerment.org (HMP). METHODS: HMP is a multi-component online intervention for young Black men and transgender women who have sex with men (YBMSM/TW) to reduce risky sexual behaviors, promote healthy living and build social support. The intervention is non-directive, incorporates interactive features, and utilizes a point-based reward system. Fifteen YBMSM/TW (age 20-30) participated in a one-month pilot study to test the usability and efficacy of HMP. Engagement with the intervention was tracked using a customized data capture system and validated with Google Analytics. Usage was measured in time spent (total and across sections) and points earned. RESULTS: Average total time spent on HMP was five hours per person (range 0-13). Total time spent was correlated with total points earned and overall site satisfaction. CONCLUSION: Measuring engagement in internet-based interventions is crucial to determining efficacy. Multiple methods of tracking helped derive more comprehensive user profiles. Results highlighted the limitations of measures to capture user activity and the elusiveness of the concept of engagement. PMID- 26732998 TI - Mitochondrial genome evolution and tRNA truncation in Acariformes mites: new evidence from eriophyoid mites. AB - The subclass Acari (mites and ticks) comprises two super-orders: Acariformes and Parasitiformes. Most species of the Parasitiformes known retained the ancestral pattern of mitochondrial (mt) gene arrangement of arthropods, and their mt tRNAs have the typical cloverleaf structure. All of the species of the Acariformes known, however, have rearranged mt genomes and truncated mt tRNAs. We sequenced the mt genomes of two species of Eriophyoidea: Phyllocoptes taishanensis and Epitrimerus sabinae. The mt genomes of P. taishanensis and E. sabinae are 13,475 bp and 13,531 bp, respectively, are circular and contain the 37 genes typical of animals; most mt tRNAs are highly truncated in both mites. On the other hand, these two eriophyoid mites have the least rearranged mt genomes seen in the Acariformes. Comparison between eriophyoid mites and other Aacariformes mites showed that: 1) the most recent common ancestor of Acariformes mites retained the ancestral pattern of mt gene arrangement of arthropods with slight modifications; 2) truncation of tRNAs for cysteine, phenylalanine and histidine occurred once in the most recent common ancestor of Acariformes mites whereas truncation of other tRNAs occurred multiple times; and 3) the placement of eriophyoid mites in the order Trombidiformes needs to be reviewed. PMID- 26732999 TI - Spontaneous resolution of a petrous apex cholesterol granuloma. AB - Cholesterol granuloma is the most common primary lesion of the petrous apex. Management of petrous apex cholesterol granuloma has evolved in recent years from primary surgical treatment to conservative observation. In this article, a case of spontaneous resolution of a petrous apex cholesterol granuloma is described. To the authors' knowledge, this is the first known report of spontaneous involution of a petrous apex cholesterol granuloma. Radiographic differential diagnosis of petrous apex lesions and the natural history of cholesterol granulomas are discussed. PMID- 26733000 TI - Editorial: Proton pathway paradox: Hv1 H+ channel sustains neutrophil Nox2 activity, yet suppresses HOCl formation. PMID- 26733001 TI - Editorial: White blood cells matter in neonatal white-matter injury. PMID- 26733002 TI - An indirect generation of 1D M(II)-2,5-dihydroxybenzoquinone coordination polymers, their structural rearrangements and generation of materials with a high affinity for H2, CO2 and CH4. AB - A series of solid-state structural transformations are found to accompany desolvation of relatively simple coordination polymers to yield materials that exhibit unexpected gas sorbing properties. Reaction of 1,2,4,5 tetrahydroxybenzene with M(II) salts (M = Mg, or Zn) in an alcohol/water solution in the presence of air affords cis-M(II)(C6H2O4(-II))(H2O)2.2H2O.xROH, (M = Mg, or Zn), crankshaft-like chains in which the absolute configurations of the chiral metal centres follow the pattern Delta Delta Lambda Lambda Delta Delta Lambda Lambda, and are hydrogen bonded together to generate spacious channels. When crystals of the crankshaft chain are air dried the crystals undergo a single crystal-to-powder rearrangement to form linear trans-M(II)(C6H2O4(-II))(H2O)2 chains. Further dehydration yields microporous solids that reversibly sorb H2, CH4 and CO2 with high sorption enthalpies. PMID- 26733003 TI - Integr(at)in(g) EGFR therapy in HNSCC. PMID- 26733004 TI - Maternal high-fat feeding leads to alterations of brain glucose metabolism in the offspring: positron emission tomography study in a porcine model. AB - AIMS/HYPOTHESIS: Maternal obesity negatively affects fetal development. Abnormalities in brain glucose metabolism are predictive of metabolic-cognitive disorders. METHODS: We studied the offspring (aged 0, 1, 6, 12 months) of minipigs fed a normal vs high-fat diet (HFD), by positron emission tomography (PET) to measure brain glucose metabolism, and ex vivo assessments of brain insulin receptors (IRbeta) and GLUT4. RESULTS: At birth, brain glucose metabolism and IRbeta were twice as high in the offspring of HFD-fed than control mothers. During infancy and youth, brain glucose uptake, GLUT4 and IRbeta increased in the offspring of control mothers and decreased in those of HFD-fed mothers, leading to a 40-85% difference (p < 0.05), and severe glycogen depletion, lasting until adulthood. CONCLUSIONS/INTERPRETATION: Maternal high-fat feeding leads to brain glucose overexposure during fetal development, followed by long-lasting depression in brain glucose metabolism in minipigs. These features may predispose the offspring to develop metabolic-neurodegenerative diseases. PMID- 26733005 TI - Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice. AB - AIMS/HYPOTHESIS: The mammalian target of rapamycin complex 1 (mTORC1)/p70 ribosomal S6 kinase (S6K)1 pathway is overactivated in obesity, leading to inhibition of phosphoinositide 3-kinase (PI3K)/Akt signalling and insulin resistance. However, chronic mTORC1 inhibition by rapamycin impairs glucose homeostasis because of robust induction of liver gluconeogenesis. Here, we compared the effect of rapamycin with that of the selective S6K1 inhibitor, PF 4708671, on glucose metabolism in vitro and in vivo. METHODS: We used L6 myocytes and FAO hepatocytes to explore the effect of PF-4708671 on the regulation of glucose uptake, glucose production and insulin signalling. We also treated high fat (HF)-fed obese mice for 7 days with PF-4708671 in comparison with rapamycin to assess glucose tolerance, insulin resistance and insulin signalling in vivo. RESULTS: Chronic rapamycin treatment induced insulin resistance and impaired glucose metabolism in hepatic and muscle cells. Conversely, chronic S6K1 inhibition with PF-4708671 reduced glucose production in hepatocytes and enhanced glucose uptake in myocytes. Whereas rapamycin treatment inhibited Akt phosphorylation, PF-4708671 increased Akt phosphorylation in both cell lines. These opposite effects of the mTORC1 and S6K1 inhibitors were also observed in vivo. Indeed, while rapamycin treatment induced glucose intolerance and failed to improve Akt phosphorylation in liver and muscle of HF-fed mice, PF-4708671 treatment improved glucose tolerance and increased Akt phosphorylation in metabolic tissues of these obese mice. CONCLUSIONS/INTERPRETATION: Chronic S6K1 inhibition by PF-4708671 improves glucose homeostasis in obese mice through enhanced Akt activation in liver and muscle. Our results suggest that specific S6K1 blockade is a valid pharmacological approach to improve glucose disposal in obese diabetic individuals. PMID- 26733006 TI - Serotonin (5-HT) receptor 2b activation augments glucose-stimulated insulin secretion in human and mouse islets of Langerhans. AB - AIMS/HYPOTHESIS: The Gq-coupled 5-hydroxytryptamine 2B (5-HT2B) receptor is known to regulate the proliferation of islet beta cells during pregnancy. However, the role of serotonin in the control of insulin release is still controversial. The aim of the present study was to explore the role of the 5-HT2B receptor in the regulation of insulin secretion in mouse and human islets, as well as in clonal INS-1(832/13) cells. METHODS: Expression of HTR2B mRNA and 5-HT2B protein was examined with quantitative real-time PCR, RNA sequencing and immunohistochemistry. alpha-Methyl serotonin maleate salt (AMS), a serotonin receptor agonist, was employed for robust 5-HT2B receptor activation. Htr2b was silenced with small interfering RNA in INS-1(832/13) cells. Insulin secretion, Ca(2+) response and oxygen consumption rate were determined. RESULTS: Immunohistochemistry revealed that 5-HT2B is expressed in human and mouse islet beta cells. Activation of 5-HT2B receptors by AMS enhanced glucose-stimulated insulin secretion (GSIS) in human and mouse islets as well as in INS-1(832/13) cells. Silencing Htr2b in INS-1(832/13) cells led to a 30% reduction in GSIS. 5 HT2B receptor activation produced robust, regular and sustained Ca(2+) oscillations in mouse islets with an increase in both peak distance (period) and time in the active phase as compared with control. Enhanced insulin secretion and Ca(2+) changes induced by AMS coincided with an increase in oxygen consumption in INS-1(832/13) cells. CONCLUSIONS/INTERPRETATION: Activation of 5-HT2B receptors stimulates GSIS in beta cells by triggering downstream changes in cellular Ca(2+) flux that enhance mitochondrial metabolism. Our findings suggest that serotonin and the 5-HT2B receptor stimulate insulin release. PMID- 26733009 TI - Hybrid PDMS/glass microfluidics for high resolution imaging and application to sub-wavelength particle trapping. AB - We demonstrate the fabrication of a hybrid PDMS/glass microfluidic layer that can be placed on top of non-transparent samples and allows high-resolution optical microscopy through it. The layer mimics a glass coverslip to limit optical aberrations and can be applied on the sample without the use of permanent bonding. The bonding strength can withstand to hold up to 7 bars of injected pressure in the channel without leaking or breaking. We show that this process is compatible with multilayer soft lithography for the implementation of flexible valves. The benefits of this application is illustrated by optically trapping sub wavelength particles and manipulate them around photonic nano-structures. Among others, we achieve close to diffraction limited imaging through the microfluidic assembly, full control on the flow with no dynamical deformations of the membrane and a 20-fold improvement on the stiffness of the trap at equivalent trapping power. PMID- 26733008 TI - High-Up: A Remote Reservoir of Microbial Extremophiles in Central Andean Wetlands. AB - The Central Andes region displays unexplored ecosystems of shallow lakes and salt flats at mean altitudes of 3700 m. Being isolated and hostile, these so-called "High-Altitude Andean Lakes" (HAAL) are pristine and have been exposed to little human influence. HAAL proved to be a rich source of microbes showing interesting adaptations to life in extreme settings (poly-extremophiles) such as alkalinity, high concentrations of arsenic and dissolved salts, intense dryness, large daily ambient thermal amplitude, and extreme solar radiation levels. This work reviews HAAL microbiodiversity, taking into account different microbial niches, such as plankton, benthos, microbial mats and microbialites. The modern stromatolites and other microbialites discovered recently at HAAL are highlighted, as they provide unique modern-though quite imperfect-analogs of environments proxy for an earlier time in Earth's history (volcanic setting and profuse hydrothermal activity, low atmospheric O2 pressure, thin ozone layer and high UV exposure). Likewise, we stress the importance of HAAL microbes as model poly-extremophiles in the study of the molecular mechanisms underlying their resistance ability against UV and toxic or deleterious chemicals using genome mining and functional genomics. In future research directions, it will be necessary to exploit the full potential of HAAL poly-extremophiles in terms of their biotechnological applications. Current projects heading this way have yielded detailed molecular information and functional proof on novel extremoenzymes: i.e., DNA repair enzymes and arsenic efflux pumps for which medical and bioremediation applications, respectively, are envisaged. But still, much effort is required to unravel novel functions for this and other molecules that dwell in a unique biological treasure despite its being hidden high up, in the remote Andes. PMID- 26733007 TI - Acceptability of tick control interventions to prevent Lyme disease in Switzerland and Canada: a mixed-method study. AB - BACKGROUND: Lyme disease control strategies may include tick control interventions in high risk areas. Public authorities may be interested to assess how these types of interventions are perceived by the public which may then impact their acceptability. The aims of this paper are to compare socio-cognitive factors associated with high acceptability of tick control interventions and to describe perceived issues that may explain their low acceptability in populations living in two different regions, one being an endemic region for LD since the last 30 years, the Neuchatel canton, in Switzerland, and another where the disease is emerging, the Monteregie region, in Canada. METHODS: A mixed methods' design was chosen. Quantitative data were collected using web-surveys conducted in both regions (n = 814). Multivariable logistic regressions were used to compare socio-cognitive factors associated with high acceptability of selected interventions. Qualitative data were collected using focus group's discussions to describe perceived issues relative to these interventions. RESULTS: Levels of acceptability in the studied populations were the lowest for the use of acaricides and landscaping and were under 50 % in both regions for six out of eight interventions, but were higher overall in Monteregie. High perceived efficacy of the intervention was strongly associated with high acceptability of tick control interventions. A high perceived risk about LD was also associated with a high acceptability of intervention under some models. High level of knowledge about LD was negatively associated with high acceptability of the use of acaricides in Neuchatel. Perceived issues explaining low acceptability included environmental impacts, high costs to the public system, danger of individual disempowerment and perceptions that tick control interventions were disproportionate options for the level of LD risk. CONCLUSION: This study suggests that the perceived efficacy and LD risk perception may be key factors to target to increase the acceptability of tick control interventions. Community level issues seem to be important considerations driving low acceptability of public health interventions. Results of this study highlight the importance for decision-makers to account for socio-cognitive factors and perceived issues that may affect the acceptability of public health interventions in order to maximize the efficacy of actions to prevent and control LD. PMID- 26733010 TI - High perceived social standing is associated with better health in HIV-infected Ugandan adults on highly active antiretroviral therapy. AB - Perceived social standing (PSS) was evaluated as a determinant of differences in health outcomes among Ugandan HIV-infected adults from Kampala using cross sectional study design. PSS was defined using the MacArthur scale of subjective social status translated and adapted for the study setting. Socio-demographic and psychosocial correlates of PSS ranking at enrollment were determined using linear regression models. High versus low PSS was defined based on the median PSS score and evaluated as a determinant of body mass index, hemoglobin, quality of life (QOL) and frailty-related phenotype via linear regression. A log-binomial regression model estimated the relative-risk of good, very good or excellent versus fair or poor self-rated health (SRH) in relation to PSS. Older age, increasing social support and material wealth were correlated with high PSS ranking, whereas female sex, experience of multiple stigmas and multiple depressive symptoms were correlated with low PSS ranking. High PSS participants were on average 1.1 kg/m(2) heavier, had 4.7 % lower frailty scores and 3.6 % higher QOL scores compared to low PSS patients (all p < 0.05); they were also more likely to self-classify as high SRH (RR 1.4, 95 % confidence interval 1.1, 1.7) but had comparable hemoglobin levels (p = 0.634). Low PSS correlated with poor physical and psychosocial wellbeing in HIV-positive Ugandan adults. The assessment of PSS as part of clinical management, combined with efforts to reduce stigma and improve social support, may identify and possibly reduce PSS associated health inequality in Ugandan adults with HIV. PMID- 26733011 TI - A randomized controlled pilot study of inflammatory gene expression in response to a stress management intervention for stem cell transplant caregivers. AB - Few studies have addressed whether stress-associated physiological changes in caregivers are reversible by psychological interventions mitigating distress. We report on pro-inflammatory, sympathetic, and oxidative stress gene expression in response to stress management for caregivers of allogeneic hematopoietic stem cell transplant (Allo-HSCT) patients. Following randomization by permuted block to either treatment as usual (TAU, n = 11) or a stress management intervention (PsychoEducation, Paced Respiration, and Relaxation, PEPRR, n = 13), twenty-four caregivers were selected at the conclusion of a larger trial of 149 caregivers. PEPRR was provided one-on-one beginning around transplant. Genome-wide transcriptional profiling was conducted on peripheral blood mononuclear cells collected prior to randomization and on completion of PEPRR 3 months post transplant. Bioinformatics analysis of differentially expressed genes indicated reduced activity of transcription control pathways associated with inflammation (NF-kappaB), sympathetic nervous system (CREB), and oxidative stress (NRF2) in caregivers receiving PEPRR compared to TAU aligning with reductions in stress, depression, and anxiety. This suggests that PEPRR may alter transcriptomic effects reported for distressed individuals. PMID- 26733012 TI - Bromine content and brominated flame retardants in food and animal feed from the UK. AB - Current occurrence data for polybrominated diphenyl ethers (PBDE) and hexa bromocyclododecane (HBCD) measured in most commonly consumed foods (n = 156) and animal feeds (n = 51) sampled in the UK, demonstrates an ongoing ubiquity of these contaminants in human and animal diets. PBDE concentrations for the sum of 17 measured congeners ranged from 0.02 ng/g to 8.91 ng/g whole weight for food, and 0.11 ng/g to 9.63 ng/g whole weight for animal feeds. The highest concentration ranges, and mean values were detected in fish, processed foods and fish feeds. HBCD diastereomers (alpha-HBCD was the most commonly detected) generally occurred at lower concentrations (from <0.01 ng/g to 10.1 ng/g for food and <0.01 ng/g to 0.66 ng/g for animal feed) and less frequently than PBDEs, but tetrabromobisphenol A which was also measured, was rarely detected. The total bromine content of the samples was also determined in an attempt to use a mass balance approach to investigate some of these samples for the occurrence of novel and emerging BFRs. Although the approach was further refined by measuring organic bromine content, the concentrations of bromine were too high (in most cases by orders of magnitude) to allow use of the approach. A selected sub-set of samples was screened by GC-MS, for the presence of novel/emerging brominated flame retardants (PBT, TBX, PBEB, DBHCTD, HCTBPH and OBTMPI) but these were not detected at the higher limits of detection that result from full scan (GC-MS) screening. This data will contribute to the EU wide risk assessment on these contaminants. PMID- 26733013 TI - Oxidative degradation of N-Nitrosopyrrolidine by the ozone/UV process: Kinetics and pathways. AB - N-Nitrosopyrrolidine (NPYR) is an emerging contaminant in drinking water and wastewater. The degradation kinetics and mechanisms of NPYR degradation by the O3/UV process were investigated and compared with those of UV direct photolysis and ozonation. A synergistic effect of ozone and UV was observed in the degradation of NPYR due to the accelerated production of OH* by ozone photolysis. This effect was more pronounced at higher ozone dosages. The second-order rate constants of NPYR reacting with OH* and ozone was determined to be 1.38 (+/- 0.05) * 10(9) M(-1) s(-1) and 0.31 (+/- 0.02) M(-1) s(-1), respectively. The quantum yield by direct UV photolysis was 0.3 (+/- 0.01). An empirical model using Rct (the ratio of the exposure of OH* to that of ozone) was established for NPYR degradation in treated drinking water and showed that the contributions of direct UV photolysis and OH* oxidation on NPYR degradation were both significant. As the reaction proceeded, the contribution by OH* became less important due to the exhausting of ozone. Nitrate was the major product in the O3/UV process by two possible pathways. One is through the cleavage of nitroso group to form NO* followed by hydrolysis, and the other is the oxidation of the intermediates of amines by ozonation. PMID- 26733014 TI - Remediation of phthalates in river sediment by integrated enhanced bioremediation and electrokinetic process. AB - The objective of this study was to evaluate the feasibility of enhanced bioremediation coupling with electrokinetic process for promoting the growth of intrinsic microorganisms and removing phthalate esters (PAEs) from river sediment by adding an oxygen releasing compound (ORC). Test results are given as follows: Enhanced removal of PAEs was obtained by electrokinetics, through which the electroosmotic flow would render desorption of organic pollutants from sediment particles yielding an increased bioavailability. It was also found that the ORC injected into the sediment compartment not only would alleviate the pH value variation due to acid front and base front, but would be directly utilized as the carbon source and oxygen source for microbial growth resulting in an enhanced degradation of organic pollutants. However, injection of the ORC into the anode compartment could yield a lower degree of microbial growth due to the loss of ORC during the transport by EK. Through the analysis of molecular biotechnology it was found that both addition of an ORC and application of an external electric field can be beneficial to the growth of intrinsic microbial and abundance of microflora. In addition, the sequencing result showed that PAEs could be degraded by the following four strains: Flavobacterium sp., Bacillus sp., Pseudomonas sp., and Rhodococcus sp. The above findings confirm that coupling of enhanced bioremediation and electrokinetic process could be a viable remediation technology to treat PAEs-contaminated river sediment. PMID- 26733015 TI - Vertebral body fracture after anterior cervical discectomy and fusion with zero profile anchored cages in adjacent levels: a cautionary tale. AB - BACKGROUND CONTEXT: Zero-profile (also called self-locking, anchored or stand alone cages) have been recently proposed as an interesting alternative for anterior cervical discectomy and fusion (ACDF), as they are supposed to reduce the rates of post-operative cage extrusion without necessarily incurring in the additional surgical time and increased rates of dysphagia associated with plating. Nevertheless, the exact indications of zero-profile anchored cages have not yet been established in the literature. PURPOSE: To report the first case of a vertebral body fracture between the blades of zero-profile anchored cages after ACDFs in adjacent levels and to review the available literature on hardware related complications after multi-level ACDFs with zero-profile anchored cages. STUDY DESIGN: Case report and systematic literature review. METHODS: The authors report the first case of a vertebral body fracture between the blades of zero profile anchored cages after ACDFs in adjacent levels. The patient presented with refractory mechanical neck pain at the 1-month post-operative follow-up, ultimately requiring a posterior instrumented fusion. A comprehensive systematic literature review on the available data regarding the safety, complications as well as radiological and clinical outcomes of zero-profile anchored cages is also performed. RESULTS: In the reported case, the use of zero-profile anchored cages in adjacent levels on the cervical spine led to a fracture of the vertebral body between the cages at the 1-month follow-up, with anterior avulsion of the part of the vertebral body where the blades from the two cages converged. According to the systematic literature review which included 409 patients from 10 different clinical series (with a total cumulative follow-up of approximately 535 patients year), there were only two reported hardware-related complications after ACDF with zero-profile anchored cages, none of them involving fracture at the level of convergence of blades or screws. CONCLUSIONS: Although hardware-related complications after the use of zero-profile anchored cages seem to be rare events, future biomechanical and clinical studies are warranted in order to evaluate the safety of employing such devices for the treatment of multilevel degenerative disc disease in the cervical spine. PMID- 26733016 TI - The Michel Benoist and Robert Mulholland yearly European spine journal review: a survey of the "surgical and research" articles in the European spine journal, 2015. PMID- 26733017 TI - Letter to the editor concerning "Pelvic incidence: an anatomic investigation of 880 cadaveric specimens" by Weinberg DS, Morris WZ, Gebhart JJ, Liu RW: Eur Spine J (2015), doi: 10.1007/s00586-015-4317-z. PMID- 26733018 TI - Spinal metallosis: a systematic review. AB - PURPOSE: To document a rarely reported complication associated with spinal instrumentation and to evaluate the current literature on spinal metallosis and spinal metalloma. METHODS: A local case report is presented. EBSCOhost, PubMed and ScienceDirect databases were used to conduct a systematic review for articles describing spinal metallosis and spinal metalloma. RESULTS: A total of 836 articles were identified using the terms "metalloma" or "metallosis". Exclusion of arthroplasty-related abstracts retrieved 46 articles of which 3 full text articles presenting spinal metalloma as a causative pathological finding responsible for neurological signs and symptoms in patients with previous spinal fusion instrumentation were reviewed. Our case is the first described with titanium-composed posterior instrumentation and fifth reported, demonstrating the phenomena of neurological symptoms and signs attributed directly to neural tissue compression by spinal metalloma after spinal instrumentation. CONCLUSION: Spinal metallosis can present weeks to years after spinal instrumentation surgery and is a potential cause of neural compression. This process appears to be independent of the instrument composition as metallosis has now been demonstrated in both titanium and stainless steel constructs. PMID- 26733019 TI - Muscle relaxant effect on tracheal intubation with Pentax-AWS Airwayscope: a prospective randomized controlled trial. PMID- 26733022 TI - [Experience of stroke prevention-Enlightenment for cancer research]. AB - Cancer, stroke and heart diseases are most common causes of death. This paper summarized the experience of stroke prevention, which is an enlightenment for cancer research. In addition, this paper also described the progress of cancer epidemiological research, particular the primary and second preventions in China. PMID- 26733023 TI - [Vaccine might be an important means of chronic disease prevention and control]. AB - The vaccine has played an important role in the struggle between human and infectious disease. However, with the development of society and economy, the non communicable chronic disease has become the biggest threat to human health. The occurrence and development of chronic diseases is related to various factors. Whether vaccines to prevent chronic disease can be developed remains exploratory, while evidence revealing that there exists an important relationship between infection factors and chronic diseases is increasing. Therefore, the vaccine to prevent infection might become one of the most important means to effectively prevent and control chronic diseases. PMID- 26733021 TI - Human pancreatic beta-like cells converted from fibroblasts. AB - Pancreatic beta cells are of great interest for biomedical research and regenerative medicine. Here we show the conversion of human fibroblasts towards an endodermal cell fate by employing non-integrative episomal reprogramming factors in combination with specific growth factors and chemical compounds. On initial culture, converted definitive endodermal progenitor cells (cDE cells) are specified into posterior foregut-like progenitor cells (cPF cells). The cPF cells and their derivatives, pancreatic endodermal progenitor cells (cPE cells), can be greatly expanded. A screening approach identified chemical compounds that promote the differentiation and maturation of cPE cells into functional pancreatic beta like cells (cPB cells) in vitro. Transplanted cPB cells exhibit glucose stimulated insulin secretion in vivo and protect mice from chemically induced diabetes. In summary, our study has important implications for future strategies aimed at generating high numbers of functional beta cells, which may help restoring normoglycemia in patients suffering from diabetes. PMID- 26733020 TI - Meta-analysis supporting noninferiority of oxaliplatin plus S-1 to cisplatin plus S-1 in first-line treatment of advanced gastric cancer (G-SOX study): indirect comparison with S-1 alone. AB - BACKGROUND: The Randomized Phase III Study Comparing Oxaliplatin plus S-1 with Cisplatin plus S-1 in Chemotherapy-naive Patients with Advanced Gastric Cancer (G SOX) showed the noninferiority of S-1 (an oral fluoropyrimidine-derivative dihydropyrimidine dehydrogenase inhibitor) plus oxaliplatin combination therapy (SOX) to S-1 plus cisplatin therapy (CS) in overall survival [hazard ratio (HR) from proportional hazard model 0.958, 95 % confidence interval (CI) 0.803-1.142; noninferiority margin 1.15]. To further clarify the clinical position of SOX in advanced gastric cancer (AGC), a meta-analysis including information from other reported studies was conducted. METHODS: In addition to G-SOX, Japanese phase III clinical trials including S-1 monotherapy were included in the analyses. Individual patient data for SOX (318 patients) and CS (324 patients) from G-SOX, as well as those for S-1 (160 patients) from the Randomized Phase III Study Comparing the Efficacy and Safety of Irinotecan plus S-1 with S-1 Alone as First line Treatment for Advanced Gastric Cancer (GC0301/TOP-002), were available. Published clinical information for S-1 from other studies (total 705 patients) was also collected. A Weibull distribution was assumed for overall survival time, and parameters for SOX, CS, and S-1 were estimated parametrically. Posterior HR distributions were obtained with a Bayesian approach. RESULTS: The HR of SOX to S 1 was 0.817 (95 % credible interval 0.704-0.939), and the probability of the HR <1.00 was 99.8 %. The HR of CS to S-1 was 0.871 (95 % credible interval; 0.754 0.998), and the probability of the HR <1.00 was 97.6 %. The HR of SOX to CS in G SOX was 0.942 (95 % credible interval; 0.789-1.117), and the probability of HR <1.15 was 98.9 %. CONCLUSION: This meta-analysis indicates that SOX was superior to S-1 and noninferior to CS in AGC. PMID- 26733024 TI - [Distribution of esophageal squamous cell cancer and precursor lesions in high risk areas, Linzhou in Henan province and Feicheng in Shandong province of China, 2005-2009]. AB - OBJECTIVE: To understand the distribution of esophageal squamous cell cancer and precursor lesions in high-risk areas of China, and to provide evidence for determining the reference ranges of detection rates in high-risk areas. METHODS: Endoscopy with Lugol's iodine staining was performed on 15 709 local residents aged 40 to 69 years old in Linzhou of Henan province and Feicheng of Shandong province from 2005-2009. 35 cases without accurate pathology diagnosis and 11 cases with vital disease before screening were excluded. 15 663 subjects were enrolled in this study. Compliance was calculated by the percentage of the people who had endoscopic screening among the target population. Chi-square test and trend chi-square test were used to compare the distribution differences in age, gender and areas of esophageal squamous cell cancer and precancer. 95% CI of the detection rates was then employed to represent the reference ranges of esophageal squamous cell cancer and precursor lesions. RESULTS: The compliance rate of screening endoscopy of this study was 49.36% (15 709/31 826) of all, and female's compliance (54.05%, 8 447/15 628) was much higher than that of male (44.83%, 7 262/16 198) (chi(2) = 88.14, P < 0.001). The detection rates of basal cell hyperplasia, low grade intraepithelial neoplasia, high grade intraepithelial neoplasia and esophageal squamous cell cancer of males were 4.17% (302/7 246), 17.22% (1 248/7 246), 1.67% (121/7 246), 0.83% (60/7 246), and were higher than that of females (3.45% (290/8 417), 14.82% (1 247/8 417), 1.41% (119/8 417), 0.48% (40/8 417), respectively). Except for high-grade intraepithelial neoplasia, the detection rates of male were higher than that of female (P values were 0.018, < 0.001, 0.960, 0.006). The detection rates of all grades of precursor lesions increased with age rising (all P values < 0.001), among which the detection rates of the mentioned four lesions for 40-44 years old were 2.69% (94/3 500), 8.11% (284/3 500), 0.40% (14/3 500), 0.14% (5/3 500), and that of 65-69 years old were 5.46% (46/843), 23.25% (196/843), 3.68% (31/843), 2.14% (18/843). The proportion of esophageal precursor lesion of Linzhou were higher than that of Feicheng observably except for esophageal squamous cell cancer (P values were < 0.001, < 0.001, < 0.001, 0.437). The detection rates of the four lesions of Linzhou and Feicheng were 4.90% (504/10 287), 17.37% (1 787/10 287), 1.79% (184/1 0287), 0.60% (62/10 287) and 1.64% (88/5 376), 13.17% (708/5 376), 1.04% (56/5 376), 0.71% (38/5 376). The 95% CI of detection rates of various lesions were, 3.78% (3.48%-4.08%) for basal cell hyperplasia, 15.93% (15.37%-16.50%) for low-grade intraepithelial neoplasia, 12.31% (11.79%-12.82%) for mild dysplasia and 3.62% (3.33%-3.91%) for moderate hyperplasia, 1.53% (1.34%-1.72%) for high-grade intraepithelial neoplasia and 0.64% (0.51%-0.76%) for esophageal squamous cell cancer, respectively. CONCLUSION: Up to 21.88% residents that were asymptomatic were suffered from esophageal squamous cancer or precursor lesions in high-risk areas in China. The distribution of esophageal squamous cell cancer and precursor lesions was closely related to the gender and the age, which suggested that males were supposed to be paid more attention to. PMID- 26733025 TI - [Effect of tea on oral cancer in nonsmokers and nondrinkers: a case-control study]. AB - OBJECTIVE To investigate the effect of tea on oral cancer in nonsmokers and nondrinkers. METHODS: A case-control study were performed between September 2010 and January 2015 including 203 oral cancer cases in nonsmokers and nondrinkers with pathologically confirmed and 572 community controls. The related information included socio-demographic characteristics, detailed information on tobacco smoking and alcohol and tea consumption, personal medical history, family history of cancer, and occupational history were collected from all subjects. Unconditional logistic regression analysis was used to calculate the odds ratios (OR) and 95% confidence intervals (95% CI) to examine the effect of tea on oral cancer and to assess multiplicative interactions between tea and passive smoking. We also stratified by age, sex, residence, and passive smoking to explore possible difference in association between subgroups. Additive interactions between tea and passive smoking were assessed using relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI). RESULTS: Compared with non-tea drinkers, tea consumption (OR = 0.52, 95% CI: 0.34 0.81), age of tea drinking initiation (years) >= 18 (OR = 0.54, 95% CI: 0.34 0.85), duration of tea consumption (years) < 20 (OR = 0.49, 95% CI: 0.27-0.90), duration of tea consumption (years) >= 20 (OR = 0.55, 95% CI: 0.32-0.95), average daily tea consumed < 700 ml (OR = 0.52, 95% CI: 0.32-0.86), moderate concentration of tea consumed (OR = 0.56, 95% CI: 0.32-0.96), weak concentration of tea consumed (OR = 0.35, 95% CI: 0.16-0.77), drinking green-tea (OR = 0.48, 95% CI: 0.28-0.82) and drinking moderate temperature of tea (OR = 0.55, 95% CI: 0.31-0.98) could reduce the risk of oral cancer; Stratified analysis indicated the protective effects of tea drinking on female (OR = 0.53, 95% CI: 0.30-0.94), age < 60 years old (OR = 0.53, 95% CI: 0.29-0.97), live in the urban (OR = 0.38, 95% CI: 0.20-0.69) and no passive smoking (OR = 0.47, 95% CI: 0.25-0.86) population with nonsmoking and nondrinking was more obvious; Crossover analysis showed tea and passive smoking did not exist multiplication interaction relationship (OR = 0.95, 95% CI: 0.41-2.20) and addition interaction relationship (RERI = -0.15, 95% CI: -0.92-0.62;AP = -0.16, 95% CI: -1.06-0.73; SI = -0.18, 95% CI: -1.44-0.87). CONCLUSION: Tea consumption, age of tea drinking initiation, duration of tea consumption, average daily tea consumed, concentration of tea consumed, types of tea and temperature of tea might have impact on the incidence of oral cancer in nonsmokers and nondrinkers to a certain extent. PMID- 26733026 TI - [Association between oral hygiene, chronic diseases, and oral squamous cell carcinoma]. AB - OBJECTIVE: To investigate the association between oral hygiene, chronic diseases, and oral squamous cell carcinoma. METHODS: We performed a case-control study with 414 cases and 870 controls in Fujian during September 2010 to January 2015. Patients were newly diagnosed oral squamous cell carcinoma cases according to the pathologic diagnoses, control subjects were enrolled from community population. Epidemiological data were collected by in-person interviews using a standard questionnaire. The contents of the questionnaire included demography character, history of tobacco smoking and alcohol drinking, dietary habits, oral hygiene status, family history of cancer, etc. Using unconditional logistic regression analysis to estimate adjusted odds ratios (OR) and corresponding 95% confidence intervals (CI) for oral hygiene and chronic diseases. We also stratified by sex, smoking and drinking to explore possible difference in association between subgroups. RESULTS: The multivariate logistic regression analysis indicated that number of teeth (20-27 and < 20), bad prosthesis, recurrent oral ulceration were the risk factors of oral squamous cell carcinoma, the adjusted OR (95% CI) values were 2.01 (1.49-2.73), 3.51 (2.39-5.15), 2.33 (1.79-3.04), 3.96 (2.11-7.44), respectively; brushing tooth once per bay, brushing tooth more than once per day, regular oral health examination at least 5 years per time were the protective factors of oral squamous cell carcinoma, the adjusted OR (95% CI) values were 0.24 (0.13-0.43), 0.13 (0.07-0.24), 0.37 (0.26-0.53), respectively. The stratification analysis indicated that recurrent oral ulceration could increase the risk of oral squamous cell carcinoma for non-smokers and non-drinking, the adjusted OR (95% CI) value was 5.21 (2.42-11.18) and 4.71 (2.37-9.36); and a risky effect of hypertension on risk of oral squamous cell carcinoma was observed for non-smokers and non-drinking, the adjusted OR (95% CI) values were 1.70 (1.10 2.61) and 1.58 (1.07-2.34). CONCLUSIONS: Oral hygiene and chronic diseases could affect the incidence of oral squamous cell carcinoma. PMID- 26733027 TI - [Influencing factors for oral-maxillofacial benign tumors: a case-control study]. AB - OBJECTIVE: To investigate the clinical influence factors of oral-maxillofacial benign tumors. METHODS: We conducted a case-control study with 113 cases newly diagnosed primary oral-maxillofacial benign tumors and 584 cases controls from a hospital in Fujian from September 2010 to January 2015. Epidemiological data were collected by in-person interviews using a standard questionnaire. The contents of the questionnaire included demography character, history of tobacco smoking and alcohol drinking, dietary habits, oral hygiene status, family history of cancer, etc. Unconditional logistic regression was used to research the relationship between the factors and oral-maxillofacial benign tumors. RESULTS: Multivariable analysis showed that risk factors of oral-maxillofacial benign tumors included: cigarette smoking index above 1 000, passive smoking before the age of 18, age of wearing bad prosthesis between 33 to 55 years old and high blood pressure; the corresponding OR (95% CI) values were 14.63 (3.88-55.13), 2.34 (1.19-4.62), 2.35 (1.17-4.73), 3.46 (1.71-7.00), respectively; Protective factors included: regularly intake of meat above 1 time/day, fruits, health care products and vitamin tablets, brushing teeth above 1 time per day and oral examination above 5 years/time, the corresponding OR (95% CI) values were 0.22 (0.07-0.70), 0.18 (0.08-0.41), 0.32 (0.11-0.88), 0.22 (0.07-0.73), 0.28 (0.16-0.48), 0.28 (0.13 0.60), respectively. CONCLUSION: Abstinence from tobacco smoking, reduce passive smoking before the age of 18, regularly intake of meat, fruits, health care products and vitamin tablets, and oral examination at regular time might have impact on the incidence of oral-maxillofacial benign tumors to a certain extent. PMID- 26733028 TI - [Survival analysis of the AIDS patients under 14 years of age and receiving antiretroviral treatment in Henan province from 2003 to 2014]. AB - OBJECTIVE: To analyze the survival status and influencing factors of the AIDS patients under 14 years of age and receiving antiretroviral treatment in Henan Province. METHODS: Database of children AIDS patients receiving ART were download from China information system for disease preventioin and control-AIDS, AIDS cases from January, 2003 to June, 2014 were selected to be analyzed. Demographic characteristics baseline laboratory inclusion criteria: F First time receive national free ART during study; aged 14 years or below; and with relatively complete baseline information and follow-up information. 1 037 cases were selected. Patient information about survival status, death, demographic characteristics, and baseline laboratory test results were analyzed. The accumulated survival rate of AIDS patients was calculated by life table method and the influencing factors were analyzed by COX proportional hazard model. RESULTS: A total of 1 037 AIDS children-cases ((9.52 +/- 3.56) years old) which included 628 boys and 409 girls were recruited in the study, 939 cases survived 1 to 9 years from starting ART treatment and 98 cases died. Accumulated survival rate of AIDS children receiving ART from 1 year to 9 years were 96.11%, 94.17%, 92.74%, 91.28%, 90.54%, 89.47%, 88.52%, 88.52%, 86.84%, respectively. Results of multivariate analysis showed baseline count of CD4+ T lymphocyte (HR = 0.51, 95% CI: 0.36-0.72), duration from confirmation to the initial ART time (HR = 0.85, 95% CI: 0.75-0.97) and hemoglobin level (HR = 2.26, 95% CI: 1.09-4.70) were influence factors for survival time of AIDS children patients receiving ART. CONCLUSION: Survival rate of AIDS children aged 14 years or below and receiving ART in Henan Province was relatively high. Timely surveillance of CD4+ T and the hemoglobin level of the AIDS patients so as to timely launch HARRT could extend survival time of AIDS patients. PMID- 26733029 TI - [Association between negative emotion and interpersonal sensitivity among patients in methadone maintenance treatment]. AB - OBJECTIVE: To analyze interpersonal sensitivity level and influencing factors among patients in methadone maintenance treatment. METHODS: From 2010 June to 2011 June, the research was performed in Center of Methadone Maintenance Treatment of Nanjing Baixia District Hospital. A total of 272 methadone maintenance treatment was studied using a self-designed questionnaire, interpersonal sensitivity scale in symptom check list (SCL-90), self-rating depression scale (SDS), self-rating anxiety scale (SAS). If interpersonal sensitivity level >= 2 points, it was positive. In this study, through independent sample t test, analysis of the social demographic characteristics, depression and anxiety, interpersonal sensitivity level. Non conditional logistic regression analysis was used to explore a variety of factors, and the relationship of these factors with interpersonal sensitivity. RESULTS: The depression score, the anxiety score and the level of interpersonal relationship sensitivity in 272 methadone maintenance treatment (1.65 +/- 0.51, 47.66 +/- 8.58, 42.38 +/- 9.40) was higher than the national norm (1.65 +/- 0.51, 41.88 +/- 10.57, 29.78 +/- 0.46) (t values were 8.23, 17.63 and 22.27, respectively; all P values < 0.001). In 272 methadone maintenance treatment, the percentage of men was 75.0% (204/272) and the percentage of women was 25.0% (68/272). SDS score of male and female was (48.38 +/- 8.30) and (45.90 +/- 9.34) points (t = 5.67, P = 0.037); Aged 20-29, 30-39, 40-49 and >= 50 years old group, SDS scores were (48.26 +/- 7.59), (47.73 +/- 8.38), (47.79 +/- 9.22) and (48.09 +/- 6.33) points (F = 3.90, P = 0.046); According to the drug's time, divided into 1-3, 4-6 and >= 7 years group, SDS scores were (45.92 +/- 7.47), (47.41 +/- 7.57) and (48.07 +/- 8.57) points (F = 4.49, = 0.039). SAS score of male and female was (41.21 +/- 9.53) and (42.91 +/- 9.42) points (t = 2.23, P = 0.043). The positive rate of interpersonal sensitivity was 47.1% (128/272). Multivariate analysis showed that, with SDS and SAS scores increased by 1, respectively, interpersonal sensitivity increased 23.23 (8.62-96.68) and 11.97 (6.42-19.27) points. CONCLUSION: Interpersonal sensitivity level in methadone maintenance treatment was higher than normal and depression; anxiety and depression both were the risk factors of interpersonal sensitivity level. PMID- 26733030 TI - [Research on maternal health behaviors for Yi-nationality women in poor rural areas based on the theory of reasoned action]. AB - OBJECTIVE: To analyze the status of maternal health behaviors and it's risk factors for Yi-nationality women in poor rural areas of Sichuan province. METHODS: In 2012, multi-stage stratified cluster sampling method was used to select 14 villages of two poor counties in Liangshan Yi-nationality autonomous prefecture Sichuan province. At least 10 women who have infants aged 0-12 months were selected in each simple villages, a total of 284. The structured questionnaire was developed on the basis of the theory of reasoned action. Yi nationality female college students were trained as investigators. Research indicators included prenatal care rate, hospital delivery rate, postpartum examination rate, socio-demographic characteristics, maternal health care knowledge. chi2 test was used to compare the differences of above indicators among different groups. The structural equation model were used to statistical analyze. RESULTS: In the 284 subject women, 51.7% (147/284) women owned more than 2 children, 41.6% (118/284) women were more than 30 years old, 87.3% (248/284) women were illiteracy. The prenatal care rate was 69.7% (197/284), the hospital delivery rate was 26.8% (76/284), and the postnatal check rate was 22.9% (65/284). The influence factors of maternal health behaviors included the number of children, age and education (chi2 were 10.92, 13.24, 9.58; P values were 0.027, 0.004, 0.008, respectively).The structural equation model analysis results showed that the maternal health behaviors were directly or indirectly affected by subjective norms (beta = 0.236, P < 0.001), women's cognition (beta = 0.226, P = 0.020) and women's attitudes on maternal health behavior (beta = 0.157, P = 0.001). Among subjective norms, women have high compliance to their husbands (beta = 0.850, P < 0.001), their peers (beta = 0.708, P < 0.001), and their mothers-in-law (beta = 0.636, P < 0.001). CONCLUSION: There were still serious problems in maternal health behaviors for Yi-nationality women in poor rural areas. The main factors included not only the women's cognition and attitudes for maternal health, but also the attitudes of important social relationships. PMID- 26733031 TI - [Epidemic condition and molecular subtyping of ciprofloxacin and cefotaxime co resistant Salmonella Indiana isolated from retail chicken carcasses in six provinces, China]. AB - OBJECTIVE: To elucidate the epidemic condition and molecular subtyping of ciprofloxacin and cefotaxime co-resistant Salmonella Indiana (S. Indiana) isolated from retail chicken carcasses in six provinces of China. METHODS: A total of 2 647 Salmonella strains isolated from retail chicken carcasses collected from six provinces of China were subjected to antimicrobial susceptibility testing. All Salmonella isolates co-resistant to ciprofloxacin and cefotaxime were further characterized by serotyping, extended-spectrum beta lactamases (ESBLs) producing strains screening and pulsed field gel electrophoresis (PFGE) typing. RESULTS: Among 2 629 Salmonella isolates tested, 227 (8.52%) isolates were co-resistant to ciprofloxacin and ceftazidime/cefotaxime (Beijing: 11.67% (99/874), Jilin: 8.20% (60/726), Guangdong: 1.39% (7/502), Jiangsu: 15.61% (42/260), Shaanxi: 8.56% (16/186), Inner Mongolia: 0 (0/81)), and 224 of them were identified as S. Indiana. 213 (95.10%) isolates of S. Indiana were ESBLs producing strains. All ciprofloxacin and cefotaxime co-resistant S. Indiana isolates developed a multi-drug resistant profile and 17.86% (40/224) of them were resistant to all antibiotics tested except carbapenems, and 50.89% (114/224) of them resistant to 9 antibiotics, additionally, 25.45% (57/224) of them showed multi-drug resistance to 8 antibiotics. All ciprofloxacin and cefotaxime co-resistant S. Indiana isolates were divided into 32 PFGE clusters and 150 PFGE patterns. Strains of S. Indiana from same or different sampling site and time seemed to either share the same PFGE patterns or be differential to each other in different regions. CONCLUSION: The results indicated that chicken carcasses collected from parts of China were heavily contaminated by ciprofloxacin and cefotaxime co-resistant S. Indiana and could serve as an important reservoir of ciprofloxacin and cefotaxime co resistant Salmonella. Molecular subtyping results indicated that cross contamination or common pollution source might be in these strains. PMID- 26733032 TI - [Study on the relationship between traditional bullying, cyberbullying and depression in adolescents]. AB - OBJECTIVE: To investigate the relationship between traditional bullying, cyberbullying and depression in adolescents, with the involvement frequency and different roles considered. METHODS: A stratified cluster sampling method was used to randomly select 5 726 middle school students in three cities of Anhui province in December 2013. Those students were surveyed by self-designed questionnaire of adolescent health-related behaviors in Anhui province. Self reports on the general demographic information, physical, verbal, relational bullying and cyberbullying involvement and depression were collected. Additionally, the items assessing depression were based on Self-rating Depression Scale (SDS). The chi-square test used to compare prevalent rates of bullying involvement and depression in different groups of students with different demographic features. Multinomial logistic regressions were performed to explore the relationships between all four types of bullying and depression, after controlling confounders. RESULTS: We got a final effective sample of 5 726 student. The response rate was 99.4% in this study. Among 5 726 adolescents, the prevalence rates of bullying in the last two months were 23.4% (1 339/5 726) physically, 55.0% (3 147/5 726) verbally, 34.2% (1 958/5 726) socially, and 8.9% (512/5 726) electronically. The prevalence rate of depression was 64.8% (3 711/5 726). The detection rate was higher in participants who involved in physical, verbal, relational, and cyber bullying than those who not involved in bullying. After controlling the confounding factors, the different frequency and role of verbal and relational bullying were risk factors of depression (OR = 1.42-3.71, all P values < 0.001). As for physical bullying, except for occasional bully victims (OR = 1.08, 95% CI: 0.79-1.49), others were more likely to be depressed than noninvolved students. (OR = 1.40-7.84, all P values < 0.001). Frequent involvement in cyberbullying as bullies and (or) victims were more likely to be depressed than noninvolved students (OR = 2.30-4.55, all P values < 0.001), but occasional involvement in cyberbullying as bullies and (or) victims were not the risk factors of adolescents' depression (OR = 1.39, 95% CI:0.97-1.99; OR = 1.58, 95% CI: 0.88-2.82; OR = 1.50, 95% CI:0.82-2.74). CONCLUSION: Involvement in physical, verbal, relational, and cyberbullying were risk factors for depression among adolescent students. PMID- 26733033 TI - [The impact of interaction between alcohol consumption and obesity on incident hypertension]. AB - OBJECTIVE: To investigate the combined effects of alcohol consumption and obesity hypertension risk. METHODS: Based on data from program "Prevention of multiple metabolic disorders and metabolic syndrome in Jiangsu province", Baseline data were obtained in April 1999 to Jun 2004, we conducted the follow up investigation from March 2006 to October 2007 for subjects, those follow up time meet 5 years. A total of 4 083 participants completed the follow-up survey, and 2 778 eligible participants for final analysis. In the baseline and follow up survey, participants returned a completed questionnaire with information on diet, education, occupation, lifestyle factors, and medical history. Data on demographic characteristics, physical examination and laboratory tests were also obtained. Cox proportional hazards regression model was used to investigate the association between body mass index (BMI), waist circumference (WC) and waist to height ratio (WHtR). Logistic regression model was used to examine the interaction of alcohol consumption with WC, BMI and WHtR on risk of hypertension and the relative excess risk due to interaction (RERI), the attributable proportion due to interaction (AP), and the synergy index (SI) were calculated. If the 95% CI of SI do not include 1, the 95% CI of RERI and AP do not include 0, the interactions are statistically significant. RESULTS: In the study subjects, 660 patients (254 males and 406 females) were new cases, who developed hypertension by the follow-up investigation. The mean of WC, BMI and WHtR were (23.3 +/- 3.2) kg/m(2), (77.7 +/- 9.0) cm and 0.49 +/- 0.06, were higher than that in normal subjects ((22.4 +/- 3.0) kg/m2, (74.8 +/- 8.5) cm and 0.47 +/- 0.05, all P values < 0.001). After adjustment for age, sex, smoking status, family history of hypertension, the hazard ratio of EH for participants with obesity, high WC, high WHtR and alcohol consumption were higher, the HR (95% CI) were 2.12 (1.46-3.10), 1.64 (1.32-2.03), 2.80 (1.73-4.59) and 1.65 (1.29-2.12). HR (95% CI) of subjects with both abnormal BMI and current alcohol consumption was 2.76 (2.45-3.17), SI (95% CI) was 1.60 (0.48-5.28), RERI(95%CI) was 0.66 ( 0.47-1.79) and AP was 0.24 (-0.22-0.69), HR (95% CI) of subjects with both high WC and current alcohol consumption was 4.93 (2.87-8.49), SI(95% CI) was 4.49(1.97 10.22), RERI (95%CI) was 3.06 (0.48-5.64) and AP(95% CI) was 0.62 (0.41-0.83), HR (95% CI) of subjects with both high WHtR and current alcohol consumption was 2.80 (1.73-4.59), SI (95% CI) was 2.14 (0.88-5.17), RERI was 0.96 (0.48-5.64) and AP (95% CI) was 0.34 (0.03-0.68). CONCLUSION: Both obesity, high WC, high WHtR, and alcohol consumption were strong risk factors of EH, and impact of an additive interaction of alcohol consumption and high WC on EH risk existed. PMID- 26733034 TI - [Effects of egg and milk supplementation on growth and development among children in poor rural area]. AB - OBJECTIVE: To evaluate the effects of egg and milk supplementation on growth and development and body composition among children in poor rural area in Tianyang County of Guangxi province. METHODS: Total four schools were randomly selected from four towns in Tianyang County of Guangxi province as intervention group in April, 2013. The intervention measures included that these students were given salty egg (net weight: 50 g) and ultra-high-temperature-sterilization school milk (net weight: 200 g) every school day and these schools were equipped with standard kitchens. Another four schools of familiar socio-economic level, teaching quality and size from the same town were randomly chosen as control group and none of the intervention measures were implemented. About 25 students were randomly selected and stratified by grades from grade one to grade five. The height, weight, and body composition of all students were measured in April, 2013 and one year after the intervention. A total of 978 students were measured at baseline from age 6 to 13, 552 students as intervention group and 426 as control group. t-test was used to compare the differences between groups and multivariate unconditional logistic regression was used to analyze the factors of malnutrition. RESULTS: After one year intervention, 892 students were measured randomly, with 515 students in intervention group and 377 in control one. The average weight of boys in intervention group increased (3.6 +/- 1.7) kg compared with baseline. It was significantly higher than that of control group ((2.9 +/- 1.5) kg) (t = 4.40, P < 0.001). The boy's lean body mass of intervention group increased (2.6 +/- 1.4) kg, higher than the control group ((2.0 +/- 1.2) kg) (t = 3.95, P < 0.001). The decrease of malnutrition rate of intervention schools (11.8%) was significantly higher than that of the control schools (4.7%, chi2 = 16.90, P < 0.001), and the odds ratio was 0.37 (95% CI: 0.23-0.59). The risk difference of overweight and obesity was not statistically significant between the two groups (OR = 1.68, 95% CI: 0.57-4.94). CONCLUSION: After supplementing milk and egg, the nutritional status of the poor rural pupils was improved. PMID- 26733035 TI - [Analysis of cancer incidence and mortality from cancer registries of Fujian province in 2011]. PMID- 26733036 TI - [Analysis of piloting sales of oral fluid HIV antibody self-test kits at community pharmacies, Kunming]. PMID- 26733037 TI - [The identification and multilocus sequence typing of nine Campylobacter fetus isolates from specimens of patients from 2012 to 2013]. PMID- 26733038 TI - [Reasearch progress in health economic evaluation of colorectal cancer screening in China]. AB - Burden of colorectal cancer is rising in China. More attention and financial input have been paid to it by central government that colorectal cancer screening program has been carried out recently in many areas in China. Diversity of screening strategies and limited health resources render selecting the best strategy in a population-wide program a challenging task that economy was also required to be considered except safety and efficacy. To provide a reference for the subsequent further economic evaluation, here we reviewed the evidence available on the economic evaluation of colorectal cancer screening in China. Meanwhile, information related to screening strategies, participation and mid term efficacy of screening, information and results on economic evaluation were extracted and summarized. Three of the four studies finally included evaluated strategies combining immunochemical fecel occult blood test (iFOBT) with high risk factor questionnaire as initial screening, colonoscopy as diagnostic screening. There was a consensus regarding the efficacy and effectiveness of screening compared to no screening. Whereas the lack and poor comparability between studies, multi-perspective and multi-phase economic evaluation of colorectal cancer screening is needed, relying on current population-based screening program to conduct a comprehensive cost accounting. PMID- 26733039 TI - [How to properly use the fear in AIDS intervention-the history and further of fear appeal development]. AB - The AIDS epidemic in men who have sex wlth men (MSM) in recent years showed a sharp upward trend, looking for behavioral intervention strategies should be imperative. Fear appeals by fear prompted intervention received intervention information, provide a new breakthrough to achieve better effect of propaganda and intervention. After over 70 years development, the Fear Appeal generated from the driver model that proposed the fear decided the effectiveness of behavior intervention, to the extended parallel process model theory which integrated protection motivation theory and parallel process theory, both of which believed the fear is just one of the estimators, suggested fear is the key factor. The fear appeal theory is turning to be even more comprehensive and accurate. As an important theoretical basement, the fear appeal is still developing, and need more work to make it perfection. PMID- 26733040 TI - [Role of vaccination in chronic disease prevention and control]. AB - Chronic non-communicable disease is a major public health problem affecting the health of residents in china. Evidence shows that, in addition to four major risk factors, i.e. unreasonable dietary, lack of physical activity, smoking and drinking, epidemic and severe outcome of chronic disease is associated with many infectious diseases. Increasingly cancers have been shown to have an infectious etiology. There is also a significantly increased risk of infectious disease such as influenza, pneumonia and other infectious disease in people with pre-existing chronic non-communicable diseases like diabetes, heart disease, and lung diseases. And more than that, there is a high risk of susceptibility to death and severe outcomes among them. Epidemiological studies has confirmed, that through targeted vaccine inoculation, liver cancer, cervical cancer can be effectively prevented, while influenza or pneumonia vaccine are related to reduced risk of hospitalization or death and hospitalization expenses regarding with a variety of chronic diseases. World Health Organization and several other professional organizations have put forward recommendations on vaccine inoculation of chronic disease patients. Programs targeting infectious factors are also an important aspect of chronic diseases prevention and control, therefore, related researches need to be strengthened in the future. PMID- 26733041 TI - Decreasing high postprandial stearic acid in impaired fasting glucose by dietary regulation. AB - BACKGROUND/OBJECTIVES: The objective of this study was to determine the postprandial change in free fatty acid (FFA) profiles in subjects with impaired fasting glucose (IFG), and to evaluate the effect of low glycemic index (GI) load on postprandial FFA profiles and inflammation. SUBJECTS/METHODS: First, 50 IFG and 50 healthy subjects were recruited; and 2 -h postprandial changes in FFA profiles were determined. Second, the 50 IFG subjects then received three different loads: glucose load (GL), high glycemic index (HGI) load and low glycemic index (LGI) load, respectively. FFA profile, glucose, insulin, glucagon like peptide 1 (GLP-1) and inflammatory biomarkers were assayed at 0, 30, 60, 90 and 120 min. RESULTS: Postprandial stearic acid (C18:0) increased compared with baseline in all subjects, whereas the change in postprandial C18:0 was more marked in IFG subjects than in healthy subjects. Compared with subjects who received the GL and HGI load, the area under the curve for insulin, GLP-1, C18:0 and tumor necrosis factor-alpha significantly decreased and adiponectin increased in subjects who received the LGI load. CONCLUSIONS: The rise in postprandial C18:0 in IFG subjects was inhibited by LGI load. PMID- 26733042 TI - Childhood stunting and the metabolic syndrome components in young adults from a Brazilian birth cohort study. AB - BACKGROUND/OBJECTIVES: The aim of this study was to investigate the association between stunting in the second year of life and metabolic syndrome components in early adulthood among subjects who have been prospectively followed-up since birth, in a city in Southern Brazil. SUBJECTS/METHODS: In 1984, we attempted to follow-up the entire cohort; the subjects were examined and their mothers interviewed. Stunting was defined by a length-for-age Z-score 2 s.d. or more below the mean, in accordance with the World Health Organization reference. Between 2004 and 2005, we again tried to follow the entire cohort; during this period the subjects were evaluated for the following metabolic syndrome components: high-density lipoprotein (HDL) cholesterol, triglycerides, random blood glucose, waist circumference and systolic and diastolic blood pressure. Family income at the time of the baby's birth, asset index, mother's education, mother's smoking during pregnancy and duration of breastfeeding were considered possible confounders. Linear regression was used in the unadjusted and adjusted analyses. RESULTS: Among men, stunting was inversely associated with triglycerides (beta=-11.90, confidence interval (CI)=-22.33 to -1.48) and waist circumference (beta=-4.29, CI=-5.62 to -2.97), whereas for women stunting was negatively related to HDL-cholesterol (beta=-4.50, CI=-6.47 to -2.52), triglycerides (beta=-9.61, CI=-17.66 to -1.56) and waist circumference (beta= 1.14, CI=-4.22 to -1.02). However, after controlling for confounding variables, these associations vanished. CONCLUSIONS: The findings suggest that stunting in childhood is not associated with metabolic syndrome components in young adults. PMID- 26733043 TI - Inability to access addiction treatment predicts injection initiation among street-involved youth in a Canadian setting. AB - BACKGROUND: Preventing injection drug use among vulnerable youth is critical for reducing serious drug-related harms. Addiction treatment is one evidence-based intervention to decrease problematic substance use; however, youth frequently report being unable to access treatment services and the impact of this on drug use trajectories remains largely unexplored. This study examines the relationship between being unable to access addiction treatment and injection initiation among street-involved youth. METHODS: Data were derived from the At-Risk Youth Study (ARYS), a prospective cohort of street-involved youth aged 14-26 who use illicit drugs, from September 2005 to May 2014. An extended Cox model with time-dependent variables was used to identify factors independently associated with injection initiation. RESULTS: Among 462 participants who were injection naive at baseline, 97 (21 %) initiated injection drug use over study follow-up and 129 (28 %) reported trying but being unable to access addiction treatment in the previous 6 months at some point during the study period. The most frequently reported reason for being unable to access treatment was being put on a wait list. In a multivariable Cox regression analysis, being unable to access addiction treatment remained independently associated with a more rapid rate of injection initiation (Adjusted Hazard Ratio =2.02; 95 % Confidence Interval: 1.12-3.62), after adjusting for potential confounders. CONCLUSION: Inability to access addiction treatment was common among our sample and associated with injection initiation. Findings highlight the need for easily accessible, evidence-based addiction treatment for high-risk youth as a means to prevent injection initiation and subsequent serious drug-related harms. PMID- 26733045 TI - Privacy-preserving GWAS analysis on federated genomic datasets. AB - BACKGROUND: The biomedical community benefits from the increasing availability of genomic data to support meaningful scientific research, e.g., Genome-Wide Association Studies (GWAS). However, high quality GWAS usually requires a large amount of samples, which can grow beyond the capability of a single institution. Federated genomic data analysis holds the promise of enabling cross-institution collaboration for effective GWAS, but it raises concerns about patient privacy and medical information confidentiality (as data are being exchanged across institutional boundaries), which becomes an inhibiting factor for the practical use. METHODS: We present a privacy-preserving GWAS framework on federated genomic datasets. Our method is to layer the GWAS computations on top of secure multi party computation (MPC) systems. This approach allows two parties in a distributed system to mutually perform secure GWAS computations, but without exposing their private data outside. RESULTS: We demonstrate our technique by implementing a framework for minor allele frequency counting and chi2 statistics calculation, one of typical computations used in GWAS. For efficient prototyping, we use a state-of-the-art MPC framework, i.e., Portable Circuit Format (PCF) 1. Our experimental results show promise in realizing both efficient and secure cross-institution GWAS computations. PMID- 26733046 TI - Molecular recognition of naphthalene diimide ligands by telomeric quadruplex-DNA: the importance of the protonation state and mediated hydrogen bonds. AB - In depth Monte Carlo conformational scans in combination with molecular dynamics (MD) simulations and electronic structure calculations were applied in order to study the molecular recognition process between tetrasubstituted naphthalene diimide (ND) guests and G-quadruplex (G4) DNA receptors. ND guests are a promising class of telomere stabilizers due to which they are used in novel anticancer therapeutics. Though several ND guests have been studied experimentally in the past, the protonation state under physiological conditions is still unclear. Based on chemical intuition, in the case of N-methyl-piperazine substitution, different protonation states are possible and might play a crucial role in the molecular recognition process by G4-DNA. Depending on the proton concentration, different nitrogen atoms of the N-methyl-piperazine might (or might not) be protonated. This fact was considered in our simulation in terms of a case by case analysis, since the process of molecular recognition is determined by possible donor or acceptor positions. The results of our simulations show that the electrostatic interactions between the ND ligands and the G4 receptor are maximized in the case of the protonation of the terminal nitrogen atoms, forming compact ND G4 complexes inside the grooves. The influence of different protonation states in terms of the ability to form hydrogen bonds with the sugar phosphate backbone, as well as the importance of mediated vs. direct hydrogen bonding, was analyzed in detail by MD and relaxed force constant (compliance constant) simulations. PMID- 26733047 TI - Monoclonal antibody 1.6.1 against human MPL receptor allows HSC enrichment of CB and BM CD34(+)CD38(-) populations. AB - Thrombopoietin (TPO) and its receptor Mpl (CD110) play a crucial role in the regulation of hematopoietic stem cells (HSCs). Functional study of Mpl-expressing HSCs has, however, been hampered by the lack of efficient monoclonal antibodies, explaining the very few data available on Mpl(+) HSCs during human embryonic development and after birth. Investigating the main monoclonal antibodies used so far to sort CD110(+) cells from cord blood (CB) and adult bone marrow (BM), we found that only the recent monoclonal antibody 1.6.1 engineered by Immunex Corporation was specific. Using in vitro functional assays, we found that this antibody can be used to sort a CD34(+)CD38(-)CD110(+) population enriched in hematopoietic progenitor stem cells, both in CB and in adult BM. In vivo injection into NSG mice further indicated that the CB CD34(+)CD38(-)CD110(+) population is highly enriched in HSCs compared with both CD34(+)CD38(-)CD110(-) and CD34(+)CD38(-) populations. Together our results validate MAb1.6.1 as an important tool, which has so far been lacking, in the HSC field. PMID- 26733044 TI - A genetic perspective on granulomatous diseases with an emphasis on mycobacterial infections. AB - Identification of the genetic factors predisposing to mycobacterial infections has been a subject of intense research activities. Current knowledge of the genetic and immunological basis of susceptibility to mycobacteria largely comes from natural human and experimental models of Bacille Calmette Guerin (BCG) and nontuberculous mycobacterial infections. These observations support the central role of the IL-12/IFN-gamma pathway in controlling mycobacterial infection. In this review, we discuss the knowledge that associates both simple and complex inheritance with susceptibility to mycobacterial diseases. We place a special emphasis on monogenic disorders, since these clearly pinpoint pathways and can adduce mechanism. We also describe the clinical, immunological, and pathological features that may steer clinical investigation in the appropriate directions. PMID- 26733048 TI - Isoxazolines: A Novel Chemotype Highly Effective on Ectoparasites. AB - Efficient control of arthropod ectoparasite infestations has a long-standing history in the agriculture and veterinary sectors, aiming to decrease the parasite burden of affected crops and animals. Ligand-gated chloride channels (LGCCs) modulated by gamma-aminobutyric acid (GABA) and glutamate have been identified as suitable molecular targets, and several classes of potent parasiticides have been devised. Due to the increase in cross-resistance and decreased development of new chemical entities, an urgent need for new parasiticides or prevention schemes has emerged. In the last decade, an innovative isoxazoline chemotype appears to offer promise for inhibiting LGCCs with a new mode of action and distinct binding site from that of historical agents. Considerable efforts have focused on optimizing the antiparasitic activity of isoxazolines and may provide the potential for future human use. PMID- 26733049 TI - Health and health-related quality of life in pig farmers carrying livestock associated methicillin-resistant Staphylococcus aureus. AB - There is limited knowledge about the effect of livestock-associated methicillin resistant Staphylococcus aureus (LA-MRSA) carriage on health-related quality of life (QoL). With this study, we explored whether LA-MRSA causes infections or affects health-related QoL in pig farmers. This prospective cohort study surveyed persons working on 49 farrowing pig farms in The Netherlands for 1 year (2010 2011). On six sampling moments, nasal swabs, environmental samples and questionnaires on activities and infections were collected. At the end of the study year, persons were asked about their QoL using the validated SF-36 and EQ 5D questionnaires. Of 120 persons, 44 (37%) were persistent MRSA carriers. MRSA carriage was not associated with infections, use of antimicrobials, healthcare contact and health-related QoL items in univariate or multivariate analysis, most likely due to the 'healthy worker effect'. Despite high carriage rates, the impact of LA-MRSA carriage in this population of relatively healthy pig farmers on health and health-related QoL appears limited; more research is needed for confirmation. PMID- 26733050 TI - Data selection in EEG signals classification. AB - The alcoholism can be detected by analyzing electroencephalogram (EEG) signals. However, analyzing multi-channel EEG signals is a challenging task, which often requires complicated calculations and long execution time. This paper proposes three data selection methods to extract representative data from the EEG signals of alcoholics. The methods are the principal component analysis based on graph entropy (PCA-GE), the channel selection based on graph entropy (GE) difference, and the mathematic combinations channel selection, respectively. For comparison purposes, the selected data from the three methods are then classified by three classifiers: the J48 decision tree, the K-nearest neighbor and the Kstar, separately. The experimental results show that the proposed methods are successful in selecting data without compromising the classification accuracy in discriminating the EEG signals from alcoholics and non-alcoholics. Among them, the proposed PCA-GE method uses only 29.69% of the whole data and 29.5% of the computation time but achieves a 94.5% classification accuracy. The channel selection method based on the GE difference also gains a 91.67% classification accuracy by using only 29.69% of the full size of the original data. Using as little data as possible without sacrificing the final classification accuracy is useful for online EEG analysis and classification application design. PMID- 26733051 TI - Further evaluation and validation of a commercially available competitive ELISA (cELISA) for the detection of antibodies specific to equine arteritis virus (EAV). AB - The purpose of this study was to further evaluate and validate two commercially available equine arteritis virus (EAV) competitive ELISAs (original and enhanced cELISAs) using archived equine sera from experimentally inoculated animals and field sera submitted for laboratory diagnosis. First, the original and subsequently enhanced cELISAs were compared with the virus neutralisation test (VNT) using a panel of archived serum samples from experimentally inoculated animals. Then, the enhanced cELISA was compared with the VNT using a large panel of archived serum samples. The total number of equine sera tested was 3255, which included sera against 25 different EAV strains. The study confirmed that the enhanced cELISA was more sensitive than the original cELISA. Based on testing sera from experimentally inoculated animals and field sera, the enhanced cELISA had an estimated sensitivity (98.9 percent and 99.6 percent, respectively) and specificity (98.3 percent and 98.7 percent, respectively). The currently marketed enhanced VMRD EAV antibody cELISA test kit (VMRD Inc., Pullman, Washington, USA) has high sensitivity and specificity relative to the VNT. Based on the findings of this study, the authors would propose that the enhanced cELISA should be considered as an alternative approved method to the VNT for the detection of antibodies to EAV. PMID- 26733052 TI - A qualitative exploration of self-reported unmet need one year after stroke. AB - PURPOSE: Stroke survivors consistently report longer-term problems after stroke, suggesting their needs are not being met. We developed a questionnaire to identify stroke-survivor unmet needs. Preliminary questionnaire testing showed that despite residual impairment, nearly one third of respondents reported no/low unmet need. This qualitative study aims to gain insight into why stroke survivors report low/no unmet needs. METHOD: People who self-reported zero or one unmet need were purposively sampled and semi-structured interviews were conducted with 10 participants. Identification and management of current problems were discussed and thematic analysis was undertaken. RESULTS: Participants did not report having unmet need. Despite this, all participants identified current issues or problems. Living with problems while reporting no/low unmet need is explained through: acceptance of changed circumstances; making comparisons with other people and circumstances; valuing pride, determination or independence; and viewing issues in the context of their expectations and experiences of services. Additionally, all participants were receiving some support. CONCLUSIONS: Self-identification of unmet needs is complex. Further investigation could explore the factors which enable stroke survivors to appropriately identify and experience no unmet needs, and whether these could be applied to reduce unmet needs of others. Implications for Rehabilitation Despite self-reporting no/low unmet need, survivors of stroke may still be experiencing difficulties in their daily lives. Stroke-survivor identified low unmet need is influenced by complex factors including: acceptance; expectations of services; and comparisons with other people, which Health and Social Care professionals have a role in understanding. Health professionals could assess unmet need by using tools as a guide, supported by individual conversation. Factors which enable some stroke survivors to appropriately identify and experience no/low unmet need could be further explored, and considered as strategies to reduce unmet needs of others. PMID- 26733053 TI - Microwave decontamination of eyelid warming devices for the treatment of meibomian gland dysfunction. AB - PURPOSE: The role of bacteria in meibomian gland dysfunction is unclear, yet contamination of compresses used as treatment may exacerbate this condition. This study therefore determined the effect of heating on bacteria on two forms of compress. METHODS: Cotton flannels and MGDRx EyeBags (eyebags) were inoculated by adding experimental inoculum (Staphylococcus aureus, Streptococcus pyogenes, Pseudomonas aeruginosa; one species for each set of 3 eyebags and flannels). One of each were then randomised in to 3 groups: no heating (control); therapeutic (47.4+/-0.7 degrees C); or sanitisation (68+/-1.1 degrees C). After treatment, bacteria cell numbers were calculated. The experiment was repeated in triplicate. RESULTS: There was a statistically significant difference between each treatment with the eyebag for S. aureus (control=7.15+/-0.11logC/ml, therapeutic heating=5.24+/-0.59logC/ml, sanitisation heating=3.48+/-1.43logC/ml; P<0.001) and S. pyogenes (7.36+/-0.13, 5.73+/-0.26, 4.75+/-0.54; P<0.001). P. aeruginosa also showed a significant reduction (P<0.001) from control (6.39+/-0.34) to therapeutic (0.33+/-0.26) and sanitisation (0.33+/-0.21), but the latter were similar (P=1.000). For the flannels, there was significant difference between each treatment for S. aureus (6.89+/-0.46, 3.96+/-1.76, 0.42+/-0.90; P<0.001). For S. pyogenes, there was a significant reduction (P<0.001) from control (7.51+/ 0.10) to therapeutic (5.91+/-0.62) and sanitisation (5.18+/-0.8), but the latter were similar (P=0.07). For P. aeruginosa, there was a significant difference (P<0.001) from control (7.15+/-0.36) to sanitisation (5.83+/-0.44); but not to therapeutic (6.84+/-0.31) temperatures (P=0.07). CONCLUSIONS: Therapeutic heating produces a significant reduction in bacteria on the eyebags, but only sanitisation heating appears effective for flannels. However, patients should be advised to heat the eyebag to sanitisation temperatures on initial use. PMID- 26733054 TI - Can the accuracy of multifocal intraocular lens power calculation be improved to make patients spectacle free? AB - PURPOSE: To optimise intraocular lens (IOL) power calculation techniques for a segmental multifocal IOL, LENTISTM MPlus((r)) (Oculentis GmbH, Berlin, Germany) and assess outcomes. METHODS: A retrospective consecutive non-randomised case series of patients receiving the MPlus((r)) IOL following cataract surgery or clear lens extraction was performed at a privately owned ophthalmic hospital, Midland Eye, Solihull, UK. Analysis was undertaken of 116 eyes, with uncomplicated lens replacement surgery using the LENTISTM MPlus((r)) lenses. Pre operative biometry data were stratified into short (<22.00 mm) and long axial lengths (ALs) (>=22.00 mm). IOL power predictions were calculated with SRK/T, Holladay I, Hoffer Q, Holladay II and Haigis formulae and compared to the final manifest refraction. These were compared with the OKULIX ray tracing method and the stratification technique suggested by the Royal College of Ophthalmologists (RCOphth). RESULTS: Using SRK/T for long eyes and Hoffer Q for short eyes, 64% achieved postoperative subjective refractions of <=+/-0.25 D, 83%<=+/-0.50 D and 93%<=+/-0.75 D, with a maximum predictive error of 1.25D. No specific calculation method performed best across all ALs; however for ALs under 22 mm Hoffer Q and Holliday I methods performed best. CONCLUSIONS: Excellent but equivalent overall refractive results were found between all biometry methods used in this multifocal IOL study. For eyes with ALs under 22 mm Hoffer Q and Holliday I performed best. Current techniques mean that patients are still likely to need top up glasses for certain situations. PMID- 26733056 TI - Suicidal germination for parasitic weed control. AB - Parasitic weeds of the genera Striga and Orobanche spp. cause severe yield losses in agriculture, especially in developing countries and the Mediterranean. Seeds of these weeds germinate by a chemical signal exuded by the roots of host plants. The radicle thus produced attaches to the root of the host plant, which can then supply nutrients to the parasite. There is an urgent need to control these weeds to ensure better agricultural production. The naturally occurring chemical signals are strigolactones (SLs), e.g. strigol and orobanchol. One option to control these weeds involves the use of SLs as suicidal germination agents, where germination takes place in the absence of a host. Owing to the lack of nutrients, the germinated seeds will die. The structure of natural SLs is too complex to allow multigram synthesis. Therefore, SL analogues are developed for this purpose. Examples are GR24 and Nijmegen-1. In this paper, the SL analogues Nijmegen-1 and Nijmegen-1 Me were applied in the field as suicidal germination agents. Both SL analogues were formulated using an appropriate EC-approved emulsifier (polyoxyethylene sorbitol hexaoleate) and applied to tobacco (Nicotiana tabacum L.) fields infested by Orobanche ramosa L. (hemp broomrape), following a strict protocol. Four out of 12 trials showed a reduction in broomrape of >=95%, two trials were negative, two showed a moderate result, one was unclear and in three cases there was no Orobanche problem in the year of the trials. The trial plots were ca 2000 m2 ; half of that area was treated with stimulant emulsion, the other half was not treated. The optimal amount of stimulant was 6.25 g ha-1 . A preconditioning prior to the treatment was a prerequisite for a successful trial. In conclusion, the suicidal germination approach to reducing O. ramosa in tobacco fields using formulated SL analogues was successful. Two other options for weed control are discussed: deactivation of stimulants prior to action and biocontrol by Fusarium oxysporum. (c) 2016 Society of Chemical Industry. PMID- 26733055 TI - Genome-wide analysis of the AP2/ERF family in Musa species reveals divergence and neofunctionalisation during evolution. AB - AP2/ERF domain containing transcription factor super family is one of the important regulators in the plant kingdom. The involvement of AP2/ERF family members has been elucidated in various processes associated with plant growth, development as well as in response to hormones, biotic and abiotic stresses. In this study, we carried out genome-wide analysis to identify members of AP2/ERF family in Musa acuminata (A genome) and Musa balbisiana (B genome) and changes leading to neofunctionalisation of genes. Analysis identified 265 and 318 AP2/ERF encoding genes in M. acuminata and M. balbisiana respectively which were further classified into ERF, DREB, AP2, RAV and Soloist groups. Comparative analysis indicated that AP2/ERF family has undergone duplication, loss and divergence during evolution and speciation of the Musa A and B genomes. We identified nine genes which are up-regulated during fruit ripening and might be components of the regulatory machinery operating during ethylene-dependent ripening in banana. Tissue-specific expression analysis of the genes suggests that different regulatory mechanisms might be involved in peel and pulp ripening process through recruiting specific ERFs in these tissues. Analysis also suggests that MaRAV-6 and MaERF026 have structurally diverged from their M. balbisiana counterparts and have attained new functions during ripening. PMID- 26733058 TI - Synthesis, Separation, and Characterization of Small and Highly Fluorescent Nitrogen-Doped Carbon NanoDots. AB - A facile bottom-up approach to carbon nanodots (CNDs) is reported, using a microwave-assisted procedure under controlled conditions. The as-prepared nitrogen-doped CNDs (NCNDs) show narrow size-distribution, abundant surface traps and functional groups, resulting in tunable fluorescent emission and excellent solubility in water. Moreover, we present a general method for the separation of NCNDs by low-pressure size-exclusion chromatography, leading to an even narrower size distribution, different surface composition, and optical properties. They display among the smallest size and the highest FLQYs reported so far. (13)C enriched starting materials produced N(13) CNDs suitable for thorough NMR studies, which gave useful information on their molecular structure. Moreover, they can be easily functionalized and can be used as water-soluble carriers. This work provides an avenue to size- and surface-controllable and structurally defined NCNDs for applications in areas such as optoelectronics, biomedicine, and bioimaging. PMID- 26733057 TI - Randomized, active-controlled, comparative phase 3 efficacy and safety equivalence trial of Ovaleap(r) (recombinant human follicle-stimulating hormone) in infertile women using assisted reproduction technology (ART). AB - BACKGROUND: Pharmacokinetic studies with XM17 (Ovaleap(r)), a recombinant human follicle-stimulating hormone (r-hFSH, follitropin alfa), have demonstrated good safety and tolerability in healthy women whose endogenous FSH levels were down regulated with a long agonist protocol. In these studies, Ovaleap(r) pharmacokinetics were dose-proportional and bioequivalent to the reference follitropin alfa product (Gonal-f(r)). The objective of the present study is to determine whether Ovaleap(r) is equivalent to Gonal-f(r) with respect to the number of oocytes retrieved in infertile but ovulatory women undergoing assisted reproductive technology (ART) therapy. METHODS: This multinational, multicenter, randomized (1:1), active-controlled, assessor-blind, comparative study included infertile normally gonadotrophic women 18 to 37 years old with a body mass index of 18 to 29 kg/m(2) and regular menstrual cycles of 21 to 35 days undergoing ART therapy. During a 5-day fixed-dose phase, women received 150 IU/day of Ovaleap(r) (n = 153) or Gonal-f(r) (n = 146), followed by an up to 15-day dose-adaptation phase during which doses could be adjusted every 3 to 5 days, up to a maximum of 450 IU/day. Ovaleap(r) was to be deemed equivalent to Gonal-f(r) if the two-sided 0.95 confidence interval (CI) for the difference in the number of oocytes retrieved fell within the equivalence range of +/-3 oocytes. RESULTS: Similar numbers of oocytes were retrieved in the 2 treatment groups. The mean +/- SD number of oocytes retrieved was 12.2 +/- 6.7 in the Ovaleap(r) group and 12.1 +/- 6.7 in the Gonal-f(r) group (intent-to-treat [ITT] population). Regression analysis estimated a mean difference of 0.03 oocytes between the treatment groups (95 % CI: -0.76-0.82), which was well within the prespecified equivalence range of +/-3 oocytes. Ovaleap(r) and Gonal-f(r) showed favorable and comparable safety profiles, with no unexpected safety findings. CONCLUSIONS: Ovaleap(r) has shown the same efficacy and safety as Gonal-f(r) for stimulation of follicular development in infertile women (up to 37 years of age) who are undergoing ART therapy. TRIAL REGISTRATION: EudraCT: 2009-017674-20. Current controlled trials: ISRCTN74772901 . Date of trial registration: 19 March 2010. PMID- 26733059 TI - Does Metformin Reduce Cancer Risks? Methodologic Considerations. AB - The substantial burden of cancer and diabetes and the association between the two conditions has been a motivation for researchers to look for targeted strategies that can simultaneously affect both diseases and reduce their overlapping burden. In the absence of randomized clinical trials, researchers have taken advantage of the availability and richness of administrative databases and electronic medical records to investigate the effects of drugs on cancer risk among diabetic individuals. The majority of these studies suggest that metformin could potentially reduce cancer risk. However, the validity of this purported reduction in cancer risk is limited by several methodological flaws either in the study design or in the analysis. Whether metformin use decreases cancer risk relies heavily on the availability of valid data sources with complete information on confounders, accurate assessment of drug use, appropriate study design, and robust analytical techniques. The majority of the observational studies assessing the association between metformin and cancer risk suffer from methodological shortcomings and efforts to address these issues have been incomplete. Future investigations on the association between metformin and cancer risk should clearly address the methodological issues due to confounding by indication, prevalent user bias, and time-related biases. Although the proposed strategies do not guarantee a bias-free estimate for the association between metformin and cancer, they will reduce synthesis of and reporting of erroneous results. PMID- 26733060 TI - Development of a simple non-invasive microsphere quantification method for cerebral blood flow using I-123-IMP. AB - OBJECTIVE: In clinical practice, measurement of the rCBF has mainly been conducted by I-123-N-isopropyl-p-iodoamphetamine ((123)I-IMP) SPECT using the microsphere (MS) method, with continuous arterial blood sampling. While several non-invasive (123)I-IMP quantification methods have been developed, their accuracy has been shown to be lower than that of the MS method. Therefore, a non invasive quantification method for use in routine clinical practice is being sought. The purpose of this study was to develop a simple non-invasive (123)I-IMP quantification method (SIMS method) with a simple input function-determining protocol based on the MS method. METHOD: The input function for the SIMS method was determined using the administered dose and the integrated lung washout ratio obtained by analyzing the count-time activity curve of the pulmonary artery and lung on dynamic chest images. The mean CBF (mCBF) and input function measured in 80 patients by the SIMS method was compared with those determined using the MS method. RESULT: A good correlation was observed between the counts measured by continuous arterial blood sampling in the MS method and the estimated counts by image analysis in the new method (r = 0.94, p < 0.01). Similarly, a good correlation was observed between the mCBF values determined by the MS method and the SIMS method (r = 0.83, p < 0.01). CONCLUSION: The mCBF values determined by the SIMS method were closely consistent with the values obtained by the MS method. This finding indicates the possibility of use of the SIMS method for routine clinical study. PMID- 26733061 TI - Improvement of patient satisfaction with the neurosurgery service at a large tertiary care, London-based hospital. AB - Patient satisfaction is central to healthcare provision and the effective running of any surgical unit. Following on from both formal and informal feedback, we decided to look objectively at patient satisfaction with the neurosurgery service at a large tertiary care hospital in London and identify areas that needed improvement within the unit. Patient satisfaction was looked at with respect to four different aspects of the neurosurgery service: the surgeons, ward doctors, nurses, and hospital services. A questionnaire-based cross-sectional study was conducted and once the data were collected a plan of action to improve service provision was put into place. Data were collected from 150 patients over a 3 month period from September to November 2012. Interventions were made and data re collected from 150 patients from January to March 2013. With regards to satisfaction with the neurosurgery service, 76.7% (n=115) were satisfied; following implementation of our measures for improvement, which included staff education, meetings and posters, this figure increased to 90.6% (n=136, p<0.001 on Chi-square testing). In conclusion, patient satisfaction should be at the crux of patient care, with a strong focus on effective communication skills, and can be improved by identification of issues by direct patient feedback and subsequent action based on this. PMID- 26733062 TI - Vitamin D supplementation in neonates. AB - Vitamin D deficiency may lead to the development of rickets. In our paediatrics department in a major London hospital, we audited the number of babies with low vitamin D levels attending our prolonged jaundice clinic. Prior to our newly designed intervention, those babies with low vitamin D levels would be given a letter to encourage collection of supplementation from their GP. The GP would receive a letter which included a 14-page guideline on vitamin D supplementation. For this project, we included all breastfed babies that attended our prolonged jaundice clinic between August 2012 and December 2012. Those babies that were either vitamin D deficient or insufficient were identified. We then followed up these patients and asked them whether they were being prescribed the correct supplementation after being identified as vitamin deficient. For our intervention, we designed a leaflet to simplify guidelines that was then distributed to mothers and their GPs. Following this intervention, we re-audited the new cohort of patients who received the leaflet between August and November 2013. The study found 71% of babies to be vitamin D deficient. Moreover, almost two in five mothers had less than the recommended six months of vitamin supplementation during pregnancy. After identifying a deficiency, one would expect that uptake of vitamin supplementation would increase dramatically. However, only four in 10 babies went on to receive the correct dose and preparation of supplements. A marked increase in uptake was seen during the re audit post intervention, with 71% of babies receiving correct supplementation. While an increase in government advertising would have contributed to the rise in uptake of vitamin D supplementation, a leaflet proved to be a simple yet effective intervention in improving vitamin uptake in babies. As a result, this was then implemented as part of trust guidelines. PMID- 26733065 TI - Characterization of a Pathogenic Full-Length cDNA Clone and Transmission Model for Porcine Epidemic Diarrhea Virus Strain PC22A. AB - Porcine epidemic diarrhea virus (PEDV) is a highly pathogenic alphacoronavirus. In the United States, highly virulent PEDV strains cause between 80 and 100% mortality in suckling piglets and are rapidly transmitted between animals and farms. To study the genetic factors that regulate pathogenesis and transmission, we developed a molecular clone of PEDV strain PC22A. The infectious-clone-derived PEDV (icPEDV) replicated as efficiently as the parental virus in cell culture and in pigs, resulting in lethal disease in vivo. Importantly, recombinant PEDV was rapidly transmitted to uninoculated pigs via indirect contact, demonstrating virulence and efficient transmission while replicating phenotypes seen in the wild-type virus. Using reverse genetics, we removed open reading frame 3 (ORF3) and replaced this region with a red fluorescent protein (RFP) gene to generate icPEDV-DeltaORF3-RFP. icPEDV-DeltaORF3-RFP replicated efficiently in vitro and in vivo, was efficiently transmitted among pigs, and produced lethal disease outcomes. However, the diarrheic scores in icPEDV-DeltaORF3-RFP-infected pigs were lower than those in wild-type-virus- or icPEDV-infected pigs, and the virus formed smaller plaques than those of PC22A. Together, these data describe the development of a robust reverse-genetics platform for identifying genetic factors that regulate pathogenic outcomes and transmission efficiency in vivo, providing key infrastructural developments for developing and evaluating the efficacy of live attenuated vaccines and therapeutics in a clinical setting. IMPORTANCE: Porcine epidemic diarrhea virus (PEDV) emerged in the United States in 2013 and has since killed 10% of U.S. farm pigs. Though the disease has been circulating internationally for decades, the lack of a rapid reverse-genetics platform for manipulating PEDV and identifying genetic factors that impact transmission and virulence has hindered the study of this important agricultural disease. Here, we present a DNA-based infectious-clone system that replicates the pathogenesis of circulating U.S. strain PC22A both in vitro and in piglets. This infectious clone can be used both to study the genetics, virulence, and transmission of PEDV coronavirus and to inform the creation of a live attenuated PEDV vaccine. PMID- 26733067 TI - Improved Diagnosis of Prosthetic Joint Infection by Culturing Periprosthetic Tissue Specimens in Blood Culture Bottles. AB - Despite known low sensitivity, culture of periprosthetic tissue specimens on agars and in broths is routine. Culture of periprosthetic tissue samples in blood culture bottles (BCBs) is potentially more convenient, but it has been evaluated in a limited way and has not been widely adopted. The aim of this study was to compare the sensitivity and specificity of inoculation of periprosthetic tissue specimens into blood culture bottles with standard agar and thioglycolate broth culture, applying Bayesian latent class modeling (LCM) in addition to applying the Infectious Diseases Society of America (IDSA) criteria for prosthetic joint infection. This prospective cohort study was conducted over a 9-month period (August 2013 to April 2014) at the Mayo Clinic, Rochester, MN, and included all consecutive patients undergoing revision arthroplasty. Overall, 369 subjects were studied; 117 (32%) met IDSA criteria for prosthetic joint infection, and 82% had late chronic infection. Applying LCM, inoculation of tissues into BCBs was associated with a 47% improvement in sensitivity compared to the sensitivity of conventional agar and broth cultures (92.1 versus 62.6%, respectively); this magnitude of change was similar when IDSA criteria were applied (60.7 versus 44.4%, respectively; P = 0.003). The time to microorganism detection was shorter with BCBs than with standard media (P < 0.0001), with aerobic and anaerobic BCBs yielding positive results within a median of 21 and 23 h, respectively. Results of our study demonstrate that the semiautomated method of periprosthetic tissue culture in blood culture bottles is more sensitive than and as specific as agar and thioglycolate broth cultures and yields results faster. IMPORTANCE: Prosthetic joint infections are a devastating complication of arthroplasty surgery. Despite this, current microbiological techniques to detect and diagnose infections are imperfect. This study examined a new approach to diagnosing infections, through the inoculation of tissue samples from around the prosthetic joint into blood culture bottles. This study demonstrated that, compared to current laboratory practices, this new technique increased the detection of infection. These findings are important for patient care to allow timely and accurate diagnosis of infection. PMID- 26733066 TI - Corynebacterium accolens Releases Antipneumococcal Free Fatty Acids from Human Nostril and Skin Surface Triacylglycerols. AB - Bacterial interspecies interactions play clinically important roles in shaping microbial community composition. We observed that Corynebacterium spp. are overrepresented in children free of Streptococcus pneumoniae (pneumococcus), a common pediatric nasal colonizer and an important infectious agent. Corynebacterium accolens, a benign lipid-requiring species, inhibits pneumococcal growth during in vitro cocultivation on medium supplemented with human skin surface triacylglycerols (TAGs) that are likely present in the nostrils. This inhibition depends on LipS1, a TAG lipase necessary for C. accolens growth on TAGs such as triolein. We determined that C. accolens hydrolysis of triolein releases oleic acid, which inhibits pneumococcus, as do other free fatty acids (FFAs) that might be released by LipS1 from human skin surface TAGs. Our results support a model in which C. accolens hydrolyzes skin surface TAGS in vivo releasing antipneumococcal FFAs. These data indicate that C. accolens may play a beneficial role in sculpting the human microbiome. IMPORTANCE: Little is known about how harmless Corynebacterium species that colonize the human nose and skin might impact pathogen colonization and proliferation at these sites. We show that Corynebacterium accolens, a common benign nasal bacterium, modifies its local habitat in vitro as it inhibits growth of Streptococcus pneumoniae by releasing antibacterial free fatty acids from host skin surface triacylglycerols. We further identify the primary C. accolens lipase required for this activity. We postulate a model in which higher numbers of C. accolens cells deter/limit S. pneumoniae nostril colonization, which might partly explain why children without S. pneumoniae colonization have higher levels of nasal Corynebacterium. This work narrows the gap between descriptive studies and the needed in-depth understanding of the molecular mechanisms of microbe-microbe interactions that help shape the human microbiome. It also lays the foundation for future in vivo studies to determine whether habitat modification by C. accolens could be promoted to control pathogen colonization. PMID- 26733068 TI - An Unexpected Route to an Essential Cofactor: Escherichia coli Relies on Threonine for Thiamine Biosynthesis. AB - Metabolism consists of biochemical reactions that are combined to generate a robust metabolic network that can respond to perturbations and also adapt to changing environmental conditions. Escherichia coli and Salmonella enterica are closely related enterobacteria that share metabolic components, pathway structures, and regulatory strategies. The synthesis of thiamine in S. enterica has been used to define a node of the metabolic network by analyzing alternative inputs to thiamine synthesis from diverse metabolic pathways. To assess the conservation of metabolic networks in organisms with highly conserved components, metabolic contributions to thiamine synthesis in E. coli were investigated. Unexpectedly, we found that, unlike S. enterica, E. coli does not use the phosphoribosylpyrophosphate (PRPP) amidotransferase (PurF) as the primary enzyme for synthesis of phosphoribosylamine (PRA). In fact, our data showed that up to 50% of the PRA used by E. coli to make thiamine requires the activities of threonine dehydratase (IlvA) and anthranilate synthase component II (TrpD). Significantly, the IlvA- and TrpD-dependent pathway to PRA functions in S. enterica only in the absence of a functional reactive intermediate deaminase (RidA) enzyme, bringing into focus how these closely related bacteria have distinct metabolic networks. IMPORTANCE: In most bacteria, including Salmonella strains and Escherichia coli, synthesis of the pyrimidine moiety of the essential coenzyme, thiamine pyrophosphate (TPP), shares enzymes with the purine biosynthetic pathway. Phosphoribosylpyrophosphate amidotransferase, encoded by the purF gene, generates phosphoribosylamine (PRA) and is considered the first enzyme in the biosynthesis of purines and the pyrimidine moiety of TPP. We show here that, unlike Salmonella, E. coli synthesizes significant thiamine from PRA derived from threonine using enzymes from the isoleucine and tryptophan biosynthetic pathways. These data show that two closely related organisms can have distinct metabolic network structures despite having similar enzyme components, thus emphasizing caveats associated with predicting metabolic potential from genome content. PMID- 26733069 TI - Identification of Proteins Bound to Dengue Viral RNA In Vivo Reveals New Host Proteins Important for Virus Replication. AB - Dengue virus is the most prevalent cause of arthropod-borne infection worldwide. Due to the limited coding capacity of the viral genome and the complexity of the viral life cycle, host cell proteins play essential roles throughout the course of viral infection. Host RNA-binding proteins mediate various aspects of virus replication through their physical interactions with viral RNA. Here we describe a technique designed to identify such interactions in the context of infected cells using UV cross-linking followed by antisense-mediated affinity purification and mass spectrometry. Using this approach, we identified interactions, several of them novel, between host proteins and dengue viral RNA in infected Huh7 cells. Most of these interactions were subsequently validated using RNA immunoprecipitation. Using small interfering RNA (siRNA)-mediated gene silencing, we showed that more than half of these host proteins are likely involved in regulating virus replication, demonstrating the utility of this method in identifying biologically relevant interactions that may not be identified using traditional in vitro approaches. IMPORTANCE: Dengue virus is the most prevalent cause of arthropod-borne infection worldwide. Viral RNA molecules physically interact with cellular RNA-binding proteins (RBPs) throughout the course of infection; the identification of such interactions will lead to the elucidation of the molecular mechanisms of virus replication. Until now, the identification of host proteins bound to dengue viral RNA has been accomplished using in vitro strategies. Here, we used a method for the specific purification of dengue viral ribonucleoprotein (RNP) complexes from infected cells and subsequently identified the associated proteins by mass spectrometry. We then validated a functional role for the majority of these proteins in mediating efficient virus replication. This approach has broad relevance to virology and RNA biology, as it could theoretically be used to purify any viral RNP complex of interest. PMID- 26733070 TI - Coagulase and Efb of Staphylococcus aureus Have a Common Fibrinogen Binding Motif. AB - Coagulase (Coa) and Efb, secreted Staphylococcus aureus proteins, are important virulence factors in staphylococcal infections. Coa interacts with fibrinogen (Fg) and induces the formation of fibrin(ogen) clots through activation of prothrombin. Efb attracts Fg to the bacterial surface and forms a shield to protect the bacteria from phagocytic clearance. This communication describes the use of an array of synthetic peptides to identify variants of a linear Fg binding motif present in Coa and Efb which are responsible for the Fg binding activities of these proteins. This motif represents the first Fg binding motif identified for any microbial protein. We initially located the Fg binding sites to Coa's C terminal disordered segment containing tandem repeats by using recombinant fragments of Coa in enzyme-linked immunosorbent assay-type binding experiments. Sequence analyses revealed that this Coa region contained shorter segments with sequences similar to the Fg binding segments in Efb. An alanine scanning approach allowed us to identify the residues in Coa and Efb that are critical for Fg binding and to define the Fg binding motifs in the two proteins. In these motifs, the residues required for Fg binding are largely conserved, and they therefore constitute variants of a common Fg binding motif which binds to Fg with high affinity. Defining a specific motif also allowed us to identify a functional Fg binding register for the Coa repeats that is different from the repeat unit previously proposed. IMPORTANCE: Staphylococcus aureus infections are a major health problem that affects an estimated 50 million people globally and causes the death of about 20,000 Americans each year. A number of experimental vaccines have been developed during the past years. However, these vaccines have all failed in clinical trials. The ability of S. aureus to form an Fg shield surrounding and protecting bacterial cells from clearance may explain why the vaccines are failing. Furthermore, S. aureus coagulase can induce the formation of a fibrin(ogen) shield in experimental abscess models which surrounds and protects bacteria in the microcolony from clearance. In this study, we identified for the first time a microbial Fg binding motif. Variants of this motif are present in coagulase and Efb. Our results provide a molecular basis for the rational design of inhibitors that could potentially prevent the formation of the obstructing Fg shield. PMID- 26733071 TI - Basal cell adenoma in the deep portion of the parotid gland: a case report. AB - Basal cell adenoma (BCA) is a rare, benign neoplasm that most frequently arises in the parotid gland. We treated a 54-year-old female patient with BCA that had developed in the deep portion of the left parotid gland. The patient presented with gradual facial swelling with no other symptoms. We performed a total parotidectomy to excise the mass, but we preserved the facial nerve. Histopathology revealed a well-encapsulated mass. The tumor was composed of islands of comparatively uniform, small, dark, basaloid epithelial cells in the stroma. Histologic and immunohistochemical studies concluded that the BCA tumors were mostly trabecular. Postoperatively, there was no facial nerve weakness, and the tumor did not recur during the 24-month follow-up period. PMID- 26733072 TI - Norfloxacin-loaded collagen/chitosan scaffolds for skin reconstruction: Preparation, evaluation and in-vivo wound healing assessment. AB - Biomaterial scaffolds are versatile tools as drug carrier for treatment of wounds. A series of norfloxacin-loaded scaffolds were synthesized for treatment of wounds by combining collagen with two different types of chitosan using freeze drying technique. Subsequently, scaffolds were screened in terms of morphology, water absorption and retention capacity, biodegradation, ex-vivo bioadhesive strength, in-vitro drug release biological compatibility, X-ray diffractometry, differential scanning calorimetry as well as in-vivo evaluation. The results indicate that the scaffold mechanical strength is dependent on the type of used chitosan. The prepared scaffolds contained interconnected porous architecture. The scaffolds had high water uptake and retention capacity with extended biodegradation rate. Scaffolds prepared with chitosan HCl showed superior bioadhesive strength compared to those prepared with low molecular weight chitosan. All scaffolds showed almost 100% drug release within 24h. As identified by the terahertz pulsed imaging measurements, there is single scaffold area with the same concentration. After 28 days of wound dressing with selected norfoloxacin-loaded or unloaded collagen/chitosan scaffolds in Albino rats, it was found that the tissue regeneration time was fast compared to non-treated wounds. Furthermore, the drug-loaded scaffolds showed normal structure of an intact epidermal layer as well as the underlying dermis as revealed by histopathological studies. The obtained results suggest that the investigated norfloxacin-loaded collagen/chitosan scaffold is a potential candidate for skin regeneration application. PMID- 26733073 TI - Induction of intrinsic and extrinsic apoptosis through oxidative stress in drug resistant cancer by a newly synthesized Schiff base copper chelate. AB - Multidrug resistance (MDR) in cancer represents a variety of strategies employed by tumor cells to evade the beneficial cytotoxic effects of structurally different anticancer drugs and thus confers impediments to the successful treatment of cancers. Efflux of drugs by MDR protein-1, functional P-glycoprotein and elevated level of reduced glutathione confer resistance to cell death or apoptosis and thus provide a possible therapeutic target for overcoming MDR in cancer. Previously, we reported that a Schiff base ligand, potassium-N-(2-hydroxy 3-methoxy-benzaldehyde)-alaninate (PHMBA) overcomes MDR in both in vivo and in vitro by targeting intrinsic apoptotic/necrotic pathway through induction of reactive oxygen species (ROS). The present study describes the synthesis and spectroscopic characterization of a copper chelate of Schiff base, viz., copper (II)-N-(2-hydroxy-3-methoxy-benzaldehyde)-alaninate (CuPHMBA) and the underlying mechanism of cell death induced by CuPHMBA in vitro. CuPHMBA kills both the drug resistant and sensitive cell types irrespective of their drug resistance phenotype. The cell death induced by CuPHMBA follows apoptotic pathway and moreover, the cell death is associated with intrinsic mitochondrial and extrinsic receptor-mediated pathways. Oxidative stress plays a pivotal role in the process as proved by the fact that antioxidant enzyme; polyethylene glycol conjugated catalase completely blocked CuPHMBA-induced ROS generation and abrogated cell death. To summarize, the present work provides a compelling rationale for the future clinical use of CuPHMBA, a redox active copper chelate in the treatment of cancer patients, irrespective of their drug-resistance status. PMID- 26733074 TI - Over-indebtedness and chronic disease: a linked register-based study of Finnish men and women during 1995-2010. AB - OBJECTIVES: More knowledge of the associations between over-indebtedness and health is needed. This study is the first longitudinal register-based study analysing long-term health consequences of severe over-indebtedness. METHODS: Adult Finnish persons, identified in 2010 as having been over-indebted for at least 15 years, were compared with matched controls (total N = 48,778). The analyses utilized register data on socio-demographic and health-related factors. Incidence of chronic disease during 1995-2010 was measured with entitlements to special reimbursement for medicines for treatment of severe and chronic diseases. Incidence of all diseases was examined, as well as incidence of hypertension, diabetes, bronchial asthma and COPD, coronary heart disease, and psychoses. Multivariate analyses were conducted with the Cox proportional hazards method. RESULTS: Severe over-indebtedness was associated with increased incidence of any chronic disease, and most notably with increased risk of psychoses and diabetes. The associations were stronger among women than among men. CONCLUSIONS: Over indebtedness is associated with harmful health conditions. Policy makers should consider taking steps to prevent over-indebtedness and to increase the awareness of social and health service professionals of the problems associated with over indebtedness. PMID- 26733075 TI - Unveiling the Mechanism for the Split Hysteresis Loop in Epitaxial Co2Fe1-xMnxAl Full-Heusler Alloy Films. AB - Utilizing epitaxial Co2Fe1-xMnxAl full-Heusler alloy films on GaAs (001), we address the controversy over the analysis for the split hysteresis loop which is commonly found in systems consisting of both uniaxial and fourfold anisotropies. Quantitative comparisons are carried out on the values of the twofold and fourfold anisotropy fields obtained with ferromagnetic resonance and vibrating sample magnetometer measurements. The most suitable model for describing the split hysteresis loop is identified. In combination with the component resolved magnetization measurements, these results provide compelling evidences that the switching is caused by the domain wall nucleation and movements with the switching fields centered at the point where the energy landscape shows equal minima for magnetization orienting near the easy axis and the field supported hard axis. PMID- 26733076 TI - New Method for Joint Network Analysis Reveals Common and Different Coexpression Patterns among Genes and Proteins in Breast Cancer. AB - We focus on characterizing common and different coexpression patterns among RNAs and proteins in breast cancer tumors. To address this problem, we introduce Joint Random Forest (JRF), a novel nonparametric algorithm to simultaneously estimate multiple coexpression networks by effectively borrowing information across protein and gene expression data. The performance of JRF was evaluated through extensive simulation studies using different network topologies and data distribution functions. Advantages of JRF over other algorithms that estimate class-specific networks separately were observed across all simulation settings. JRF also outperformed a competing method based on Gaussian graphic models. We then applied JRF to simultaneously construct gene and protein coexpression networks based on protein and RNAseq data from CPTAC-TCGA breast cancer study. We identified interesting common and differential coexpression patterns among genes and proteins. This information can help to cast light on the potential disease mechanisms of breast cancer. PMID- 26733077 TI - Megapinocytosis: a novel endocytic pathway. AB - M2 macrophages showed large endocytotic structures, very different from classical macropinosomes that we named megapinosomes. As observed in the scanning electron microscope, megapinosome formation started with a large (diameter of several micrometers) invagination of the plasma membrane. When the invagination was almost completed, the remaining opening was closed by an actinomorphous centripetal arrangement of many (about 50-100) microvilli-like structures. In transmission electron microscopy using high-pressure freezing, we observed that the megapinosome was filled with a trabecular meshwork that originated from the highly structured plasma membrane. The trabecular meshwork was topologically part of the cytosol and separated from the extracellular fluid by a lipid bilayer. According to ultrastructural features, we could define different phases of megapinosome formation and decay. Megapinosomes became more frequent when M2 macrophages were inoculated with human cytomegalovirus. We did not find megapinosome formation in M1 macrophages. PMID- 26733078 TI - Straight and Curved Path Walking Among Older Adults in Primary Care: Associations With Fall-Related Outcomes. AB - BACKGROUND: Most falls among community-dwelling older adults occur while walking. Simple walking tests that require little resources and can be interpreted quickly are advocated as useful screening tools for fall prone patients. OBJECTIVE: To investigate 2 clinically feasible walking tests consisting of straight- and curved-path walking and examine their associations with history of previous falls and fall-related outcomes among community-living older adults. DESIGN: A cross sectional analysis was performed on baseline data from a longitudinal cohort study. SETTING: Participants were recruited through primary care practices. PARTICIPANTS: Participants included 428 primary care patients >=65 years of age at risk for mobility decline. Participants had a median age of 76.5 years, 67.8% were women, and 82.5% were white. METHODS: Straight-path walking performance was measured as the time needed to walk a 4-meter straight path at usual pace from standstill using a stopwatch (timed to 0.1 second). Curved-path walking performance was timed while participants walked from standstill in a figure-of-8 pattern around two cones placed 5 feet apart. MAIN OUTCOME MEASUREMENTS: Multivariable negative binomial regression analyses were performed to assess the relationship between straight-path walking or curved-path walking and self reported history of number of falls. For fall-related injuries, and fall-related hospitalizations, logistic regression models were used. RESULTS: In the fully adjusted model, an increase of 1 second in straight path walking time was associated with 26% greater rate of falls (rate ratio 1.26, 95% confidence interval 1.10-1.45). An increase in curved-path walking time was associated with 8% greater rate of falls (rate ratio 1.08, 95% confidence interval = 1.03-1.14). Neither walk test was associated with history of fall-related injuries or hospitalizations. CONCLUSIONS: Poor performance on straight- and curved-path walking performance was associated with a history of greater fall rates in the previous year but not with a history of fall-related injuries or hospitalizations. This information helps inform how previous fall history is related to performance on walking tests in the primary care setting. PMID- 26733079 TI - Impact on the individual: what do patients and carers gain, lose and expect from being involved in research? AB - BACKGROUND: Study feasibility and deliverability can benefit from involving patients and carers in the research process, known as patient and public involvement (PPI). There is less evidence on the experiences of patients and carers themselves and we require more information across a range of studies, health conditions and research stages. AIMS: This study explored how patients and carers in eight diagnostic research specialties have been involved in research, their motivations and the impact involvement had on them. METHOD: 143 patients and carers across the Clinical Research Network (CRN) responded to an online semi structured questionnaire (developed using participatory methodology). Quantitative and qualitative data were analysed. RESULTS: A range of benefits were reported, including providing a life focus and an improved relationship with illness. Less positive experiences regarding time and money and lack of acknowledgement were also reported, along with suggestions for improvement. CONCLUSIONS: PPI confers many benefits on patients and carers which could increase PPI recruitment if made explicit. More involvement in study recruitment and dissemination would increase the effectiveness of PPI input. Involving a more varied socioeconomic demographic and at an earlier stage is vital. Financial support for lower earners and greater feedback following involvement should also be explored. PMID- 26733080 TI - Late appearance of left ventricular non-compaction in a patient with aortic coarctation and bicuspid aortic valve. PMID- 26733081 TI - Demographic, risk factor, and provider characteristics associated with confirmatory hepatitis C testing. PMID- 26733082 TI - Depressive symptoms among Dutch pregnant women after the crash of flight MH17: the PRIDE Study. PMID- 26733083 TI - Translating exercise interventions to an in-home setting for seniors: preliminary impact on physical activity and function. AB - AIMS: The purpose of this study is to investigate whether an in-home, individually tailored intervention is efficacious in promoting increases in physical activity (PA) and improvements in physical functioning (PF) in low active older adults. METHODS: Participants were randomized to two groups for the 8-week intervention. The enhanced physical activity (EPA) group received individualized exercise programming, including personalized step goals and a resistance band training program, and the standard of care (SoC) group received a general activity goal. Pre- and post-intervention PF measures included choice step reaction time, knee extension/flexion strength, hand grip strength, and 8 ft up and go test completion time. RESULTS: Thirty-nine subjects completed this study (74.6 +/- 6.4 years). Significant increases in steps/day were observed for both the EPA and SoC groups, although the improvements in the EPA group were significantly higher when including only those who adhered to weekly step goals. Both groups experienced significant PF improvements, albeit greater in the EPA group for the 8 ft up and go test and knee extension strength. CONCLUSION: A low cost, in-home intervention elicited improvements in both PA and PF. Future research is warranted to expand upon the size and scope of this study, exploring dose thresholds (and time frames) for PA to improve PF and strategies to further bolster adherence rates to maximize intervention benefits. PMID- 26733084 TI - Examining the stability of dual-task posture and reaction time measures in older adults over five sessions: a pilot study. AB - BACKGROUND AND AIM: Improved performance may be inherent due to repeated exposure to a testing protocol. However, limited research has examined this phenomenon in postural control. The aim was to determine the influence of repeated administration of a dual-task testing protocol once per week for 5 weeks on postural sway and reaction time. METHODS: Ten healthy older adults (67.0 +/- 6.9 years) stood on a force plate for 30 s in feet apart and semi-tandem positions while completing simple reaction time (SRT) and choice reaction time (CRT) tasks. They were instructed to stand as still as possible while verbally responding as fast as possible to the stimuli. RESULTS: No significant differences in postural sway were shown over time (p > 0.05). A plateau in average CRT emerged as the time effect revealed longer CRT during session 1 compared to sessions 3-5 (p < 0.05). Furthermore, the time effect for within-subject variability of CRT uncovered no plateaus as it was less variable in session 5 than sessions 1-4 (p < 0.05). DISCUSSION: The lack of a plateau in variability of CRT may have emerged as older adults may require longer to reach optimal performance potential in a dual-task context. CONCLUSION: Postural sway and SRT were stable over the 5 testing sessions, but variability of CRT continued to improve over time. These findings form a basis for future studies to examine performance-related improvements due to repeated exposure to a testing protocol in a dual-task setting. PMID- 26733085 TI - Spontaneous seromuscular laceration of the sigmoid colon: a case report. AB - Injury to bowel can result in high morbidity and death. Bowel injuries typically occur after external trauma to the abdomen. Bowel injury in the absence of external trauma is rare. Here, we report a 36-year-old male presenting with a sigmoid colon laceration likely due to long-standing constipation. PMID- 26733086 TI - Nanoscale rippling on polymer surfaces induced by AFM manipulation. AB - Nanoscale rippling induced by an atomic force microscope (AFM) tip can be observed after performing one or many scans over the same area on a range of materials, namely ionic salts, metals, and semiconductors. However, it is for the case of polymer films that this phenomenon has been widely explored and studied. Due to the possibility of varying and controlling various parameters, this phenomenon has recently gained a great interest for some technological applications. The advent of AFM cantilevers with integrated heaters has promoted further advances in the field. An alternative method to heating up the tip is based on solvent-assisted viscoplastic deformations, where the ripples develop upon the application of a relatively low force to a solvent-rich film. An ensemble of AFM-based procedures can thus produce nanoripples on polymeric surfaces quickly, efficiently, and with an unprecedented order and control. However, even if nanorippling has been observed in various distinct modes and many theoretical models have been since proposed, a full understanding of this phenomenon is still far from being achieved. This review aims at summarizing the current state of the art in the perspective of achieving control over the rippling process on polymers at a nanoscale level. PMID- 26733087 TI - Contexts as Shared Commitments. AB - Contemporary semantics assumes two influential notions of context: one coming from Kaplan (1989), on which contexts are sets of predetermined parameters, and another originating in Stalnaker (1978), on which contexts are sets of propositions that are "common ground." The latter is deservedly more popular, given its flexibility in accounting for context-dependent aspects of language beyond manifest indexicals, such as epistemic modals, predicates of taste, and so on and so forth; in fact, properly dealing with demonstratives (perhaps ultimately all indexicals) requires that further flexibility. Even if we acknowledge Lewis (1980)'s point that, in a sense, Kaplanian contexts already include common ground contexts, it is better to be clear and explicit about what contexts constitutively are. Now, Stalnaker (1978, 2002, 2014) defines context-as common-ground as a set of propositions, but recent work shows that this is not an accurate conception. The paper explains why, and provides an alternative. The main reason is that several phenomena (presuppositional treatments of pejoratives and predicates of taste, forces other than assertion) require that the common ground includes non-doxastic attitudes such as appraisals, emotions, etc. Hence the common ground should not be taken to include merely contents (propositions), but those together with attitudes concerning them: shared commitments, as I will defend. PMID- 26733088 TI - Pyruvate Dehydrogenase Activity Is Decreased in Emergency Department Patients With Diabetic Ketoacidosis. AB - OBJECTIVES: The pyruvate dehydrogenase complex (PDH) is an essential enzyme in aerobic metabolism. Ketones are known to inhibit PDH activity, but the extent of this inhibition is unknown in patients with diabetic ketoacidosis (DKA). METHODS: We enrolled adult patients presenting to the emergency department in hyperglycemic crisis. Patients were classified as DKA or hyperglycemia without ketoacidosis based on laboratory criteria. Healthy controls were also enrolled. PDH activity and quantity were measured in isolated peripheral blood mononuclear cells. We compared PDH values between groups and measured the relationship of PDH values to measures of acid-base status. RESULTS: Twenty-seven patients (17 with DKA) and 31 controls were enrolled. Patients with DKA had lower PDH activity and quantity compared to the two other groups. PDH activity was significantly correlated with serum bicarbonate and pH and inversely correlated with the anion gap. CONCLUSIONS: DKA is associated with greater suppression of PDH activity than hyperglycemia without ketoacidosis, and this is correlated with measures of acid base status. Future studies may determine whether PDH depression plays a role in the pathophysiology of DKA and whether modification of PDH could decrease time to DKA resolution. PMID- 26733089 TI - A fast time-difference inverse solver for 3D EIT with application to lung imaging. AB - A class of sparse optimization techniques that require solely matrix-vector products, rather than an explicit access to the forward matrix and its transpose, has been paid much attention in the recent decade for dealing with large-scale inverse problems. This study tailors application of the so-called Gradient Projection for Sparse Reconstruction (GPSR) to large-scale time-difference three dimensional electrical impedance tomography (3D EIT). 3D EIT typically suffers from the need for a large number of voxels to cover the whole domain, so its application to real-time imaging, for example monitoring of lung function, remains scarce since the large number of degrees of freedom of the problem extremely increases storage space and reconstruction time. This study shows the great potential of the GPSR for large-size time-difference 3D EIT. Further studies are needed to improve its accuracy for imaging small-size anomalies. PMID- 26733090 TI - Structural and functional analysis of four non-coding Y RNAs from Chinese hamster cells: identification, molecular dynamics simulations and DNA replication initiation assays. AB - BACKGROUND: The genes coding for Y RNAs are evolutionarily conserved in vertebrates. These non-coding RNAs are essential for the initiation of chromosomal DNA replication in vertebrate cells. However thus far, no information is available about Y RNAs in Chinese hamster cells, which have already been used to detect replication origins and alternative DNA structures around these sites. Here, we report the gene sequences and predicted structural characteristics of the Chinese hamster Y RNAs, and analyze their ability to support the initiation of chromosomal DNA replication in vitro. RESULTS: We identified DNA sequences in the Chinese hamster genome of four Y RNAs (chY1, chY3, chY4 and chY5) with upstream promoter sequences, which are homologous to the four main types of vertebrate Y RNAs. The chY1, chY3 and chY5 genes were highly conserved with their vertebrate counterparts, whilst the chY4 gene showed a relatively high degree of diversification from the other vertebrate Y4 genes. Molecular dynamics simulations suggest that chY4 RNA is structurally stable despite its evolutionarily divergent predicted stem structure. Of the four Y RNA genes present in the hamster genome, we found that only the chY1 and chY3 RNA were strongly expressed in the Chinese hamster GMA32 cell line, while expression of the chY4 and chY5 RNA genes was five orders of magnitude lower, suggesting that they may in fact not be expressed. We synthesized all four chY RNAs and showed that any of these four could support the initiation of DNA replication in an established human cell-free system. CONCLUSIONS: These data therefore establish that non-coding chY RNAs are stable structures and can substitute for human Y RNAs in a reconstituted cell-free DNA replication initiation system. The pattern of Y RNA expression and functionality is consistent with Y RNAs of other rodents, including mouse and rat. PMID- 26733091 TI - A GC-MS urinary quantitative metabolomics analysis in depressed patients treated with TCM formula of Xiaoyaosan. AB - Xiaoyaosan, one of the best-known traditional Chinese medicine prescriptions, has been widely used in China for the treatment of mental disorders such as depression. Although both clinical application and animal experiments indicate that Xiaoyaosan has an obvious antidepressant effect, the mechanism still remains unclarified, and there are few studies quantitatively measured the biomarkers of Xiaoyaosan treatment by metabolomics to determination. In this study, 25 depressed patients and 33 healthy volunteers were recruited. A GC-MS based metabolomics approach and the multivariate statistical methods were used for analyzing the urine metabolites of depressed patients before and after treatment compared with healthy controls. Then the biomakers through metabolomics determination were carried out the quantitative analysis. In total, 5 metabolites were identified as the potential diseased and therapeutic biomarkers of depression and Xiaoyaosan. Alanine, citrate and hippurate levels were significantly increased in the urine samples from depressed patients compared with healthy controls, while phenylalanie and tyrosine levels were significantly decreased. However, after Xiaoyaosan treatment for 6 weeks, phenylalanie and tyrosine levels were significantly increased (p<0.05) and alanine, citrate and hippurate levels significantly decreased (p<0.05). Xiaoyaosan has a good priority on the treatment of depression and the ability to adjust the neurotransmitters to obtain the best treated response and also could regulate the metabolism of amino acids and promote to produce energy meet the needs of the body. PMID- 26733093 TI - Pressure-induced phase transformation in zircon-type orthovanadate SmVO4 from experiment and theory. AB - The compression behavior of zircon-type samarium orthovanadate, SmVO4, has been investigated using synchrotron-based powder x-ray diffraction and ab initio calculations of up to 21 GPa. The results indicate the instability of ambient zircon phase at around 6 GPa, which transforms to a high-density scheelite-type phase. The high-pressure phase remains stable up to 21 GPa, the highest pressure reached in the present investigations. On pressure release, the scheelite phase is recovered. The crystal structure of the high-pressure phase and the equations of state for the zircon- and scheelite-type phases have been determined. Various compressibilities, such as the bulk, axial and bond compressibilities, estimated from the experimental data are found to be in good agreement with the results obtained from theoretical calculations. The calculated elastic constants show that the zircon structure becomes mechanically unstable beyond the transition pressure. Overall there is good agreement between the experimental and theoretical findings. PMID- 26733094 TI - Fixation of a human rib by an intramedullary telescoping splint anchored by bone cement. AB - A novel concept for rib fixation is presented that involves the use of a bioresorbable polymer intramedullary telescoping splint. Bone cement is used to anchor each end of the splint inside the medullary canal on each side of the fracture site. In this manner, rib fixation is achieved without fixation device protrusion from the rib, making the splint completely intramedullary. Finite element analysis is used to demonstrate that such a splint/cement composite can preserve rib fixation subjected to cough-intensity force loadings. Computational fluid dynamics and porcine rib experiments were used to study the anchor formation process required to complete the fixation. PMID- 26733092 TI - Testis-enriched heat shock protein A2 (HSPA2): Adaptive advantages of the birds with internal testes over the mammals with testicular descent. AB - The molecular chaperone heat shock protein A2 (HSPA2), a member of the 70 kDa heat shock protein (HSP70) family, plays an important role in spermatogenesis and male fertility. Although HSPA2 is evolutionarily highly conserved across the metazoan lineages, the observation of striking differences in temperature sensitive expressions, testicular physiology, spermatogenesis, as well as its role in male fertility indicates that avian and mammalian HSPA2 may exhibit distinct evolutionary trajectory. The present study reports that while mammalian HSPA2 is constrained by intense purifying selection, avian HSPA2 has been subjected to positive selection. The majority of the positively selected amino acid residues fall on the alpha-helix and beta-sheets of the peptide-binding domain located at the carboxyl-terminal region of the avian HSPA2. The detection of positively selected sites at the helix and beta-sheets, which are less tolerant to molecular adaptation, indicates an important functional consequence and contribution to the structural and functional diversification of the avian HSPA2. Collectively, avian HSPA2 may have an adaptive advantage over the mammals in response to heat stress, and therefore, mammals with testicular descent may be at a greater risk in the event of scrotal temperature rise. PMID- 26733095 TI - Editorial. PMID- 26733103 TI - Perceptions of crisis care in populations who self-referred to a telephone-based mental health triage service. AB - Although psychiatric crises are very common in people with mental illness, little is known about consumer perceptions of mental health crisis care. Given the current emphasis on recovery-oriented approaches, shared decision-making, and partnering with consumers in planning and delivering care, this knowledge gap is significant. Since the late 1990s, access to Australian mental health services has been facilitated by 24/7 telephone-based mental health triage systems, which provide initial psychiatric assessment, referral, support, and advice. A significant proportion of consumers access telephone-based mental health triage services in a state of crisis, but to date, there has been no published studies that specifically report on consumer perceptions on the quality and effectiveness of the care provided by these services. This article reports on a study that investigated consumer perceptions of accessing telephone-based mental health triage services. Seventy-five mental health consumers participated in a telephone interview about their triage service use experience. An eight-item survey designed to measure the responsiveness of mental health services was used for data collection. The findings reported here focus on the qualitative data produced in the study. Consumer participants shared a range of perspectives on telephone-based mental health triage that provide invaluable insights into the needs, expectations, and service use experiences of consumers seeking assistance with a mental health problem. Consumer perceptions of crisis care have important implications for practice. Approaches and interventions identified as important to quality care can be used to inform educational and practice initiatives that promote person-centred, collaborative crisis care. PMID- 26733102 TI - Enhancement of hepatocyte differentiation from human embryonic stem cells by Chinese medicine Fuzhenghuayu. AB - Chinese medicine, Fuzhenghuayu (FZHY), appears to prevent fibrosis progression and improve liver function in humans. Here we found that FZHY enhanced hepatocyte differentiation from human embryonic stem cells (hESC). After treatment with FZHY, albumin expression was consistently increased during differentiation and maturation process, and expression of metabolizing enzymes and transporter were also increased. Importantly, expression of mesenchymal cell and cholangiocyte marker was significantly reduced by treatment with FZHY, indicating that one possible mechanism of FZHY's role is to inhibit the formation of mesenchymal cells and cholangiocytes. Edu-labelled flow cytometric analysis showed that the percentage of the Edu positive cells was increased in the treated cells. These results indicate that the enhanced proliferation involved hepatocytes rather than another cell type. Our investigations further revealed that these enhancements by FZHY are mediated through activation of canonical Wnt and ERK pathways and inhibition of Notch pathway. Thus, FZHY not only promoted hepatocyte differentiation and maturation, but also enhanced hepatocyte proliferation. These results demonstrate that FZHY appears to represent an excellent therapeutic agent for the treatment of liver fibrosis, and that FZHY treatment can enhance our efforts to generate mature hepatocytes with proliferative capacity for cell-based therapeutics and for pharmacological and toxicological studies. PMID- 26733104 TI - Experimental investigation of irregular motion impact on 4D PET-based particle therapy monitoring. AB - Particle therapy positron emission tomography (PT-PET) is an in vivo and non invasive imaging technique to monitor treatment delivery in particle therapy. The inevitable patient respiratory motion during irradiation causes artefacts and inaccurate activity distribution in PET images. Four-dimensional (4D) maximum likelihood expectation maximisation (4D MLEM) allows for a compensation of these effects, but has up to now been restricted to regular motion for PT-PET investigations. However, intra-fractional motion during treatment might differ from that during acquisition of the 4D-planning CT (e.g. amplitude variation, baseline drift) and therefore might induce inaccurate 4D PET reconstruction results. This study investigates the impact of different irregular analytical one dimensional (1D) motion patterns on PT-PET imaging by means of experiments with a radioactive source and irradiated moving phantoms. Three sorting methods, namely phase sorting, equal amplitude sorting and event-based amplitude sorting, were applied to manage the PET list-mode data. The influence of these sorting methods on the motion compensating algorithm has been analysed. The event-based amplitude sorting showed a superior performance and it is applicable for irregular motions with ? 4 mm amplitude elongation and drift. For motion with 10 mm baseline drift, the normalised root mean square error was as high as 10.5% and a 10 mm range deviation was observed. PMID- 26733105 TI - Transforming practice into clinical scholarship. AB - AIM: The aims of this paper were to explicate clinical scholarship as synonymous with the scholarship of application and to explore the evolution of scholarly practice to clinical scholarship. BACKGROUND: Boyer contributed an expanded view of scholarship that recognized various approaches to knowledge production beyond pure research (discovery) to include the scholarship of integration, application and teaching. There is growing interest in using Boyer's framework to advance knowledge production in nursing but the discussion of clinical scholarship in relation to Boyer's framework is sparse. DESIGN: Discussion paper. DATA SOURCES: Literature from 1983-2015 and Boyer's framework. IMPLICATIONS FOR NURSING: When clinical scholarship is viewed as a synonym for Boyer's scholarship of application, it can be aligned to this well established framework to support knowledge generated in clinical practice. For instance, applying the three criteria for scholarship (documentation, peer review and dissemination) can ensure that the knowledge produced is rigorous, available for critique and used by others to advance nursing practice and patient care. Understanding the differences between scholarly practice and clinical scholarship can promote the development of clinical scholarship. Supporting clinical leaders to identify issues confronting nursing practice can enable scholarly practice to be transformed into clinical scholarship. CONCLUSION: Expanding the understanding of clinical scholarship and linking it to Boyer's scholarship of application can assist nurses to generate knowledge that addresses clinical concerns. Further dialogue about how clinical scholarship can address the theory-practice gap and how publication of clinical scholarship could be expanded given the goals of clinical scholarship is warranted. PMID- 26733107 TI - Cautionary tales about DNACPR. PMID- 26733106 TI - Indirect excitation of ultrafast demagnetization. AB - Does the excitation of ultrafast magnetization require direct interaction between the photons of the optical pump pulse and the magnetic layer? Here, we demonstrate unambiguously that this is not the case. For this we have studied the magnetization dynamics of a ferromagnetic cobalt/palladium multilayer capped by an IR-opaque aluminum layer. Upon excitation with an intense femtosecond-short IR laser pulse, the film exhibits the classical ultrafast demagnetization phenomenon although only a negligible number of IR photons penetrate the aluminum layer. In comparison with an uncapped cobalt/palladium reference film, the initial demagnetization of the capped film occurs with a delayed onset and at a slower rate. Both observations are qualitatively in line with energy transport from the aluminum layer into the underlying magnetic film by the excited, hot electrons of the aluminum film. Our data thus confirm recent theoretical predictions. PMID- 26733108 TI - A Journal of Biomedical Science: Of Its Practitioners, by Its Practitioners, and for Its Practitioners. PMID- 26733109 TI - Increasing children's time spent outdoors reduces the incidence of myopia. PMID- 26733111 TI - Economic and Humanistic Burden of Dry Eye Disease in Europe, North America, and Asia: A Systematic Literature Review. AB - Dry eye disease (DED) is a chronic and progressive multifactorial disorder of the tears and ocular surface, which results in symptoms of discomfort and visual disturbance. The aim of this systematic literature review was to evaluate the burden of DED and its components from an economic and health-related quality of life (HRQoL) perspective, and to compare the evidence across France, Germany, Italy, Spain, UK, USA, Japan, and China. PubMed, Embase, and six other resources were searched for literature published from January 1998 to July 2013. Of 76 titles/abstracts reviewed on the economic burden of DED and 263 on the HRQoL burden, 12 and 20 articles, respectively, were included in the review. The available literature suggests that DED has a substantial economic burden, with indirect costs making up the largest proportion of the overall cost due to a substantial loss of work productivity. In addition, DED has a substantial negative impact on physical, and potentially psychological, function and HRQoL across the countries examined. A number of studies also indicated that HRQoL burden increases with the severity of disease. Additional data are needed, particularly in Asia, in order to gain a better understanding of the burden of DED and help inform future health care resource utilization. PMID- 26733112 TI - Highly efficient light management for perovskite solar cells. AB - Organic-inorganic halide perovskite solar cells have enormous potential to impact the existing photovoltaic industry. As realizing a higher conversion efficiency of the solar cell is still the most crucial task, a great number of schemes were proposed to minimize the carrier loss by optimizing the electrical properties of the perovskite solar cells. Here, we focus on another significant aspect that is to minimize the light loss by optimizing the light management to gain a high efficiency for perovskite solar cells. In our scheme, the slotted and inverted prism structured SiO2 layers are adopted to trap more light into the solar cells, and a better transparent conducting oxide layer is employed to reduce the parasitic absorption. For such an implementation, the efficiency and the serviceable angle of the perovskite solar cell can be promoted impressively. This proposal would shed new light on developing the high-performance perovskite solar cells. PMID- 26733110 TI - Comparison of adding tocilizumab to methotrexate with switching to tocilizumab in patients with rheumatoid arthritis with inadequate response to methotrexate: 52 week results from a prospective, randomised, controlled study (SURPRISE study). AB - OBJECTIVE: To compare the efficacy and safety between tocilizumab added to methotrexate and tocilizumab switched from methotrexate in patients with active rheumatoid arthritis (RA). METHODS: This is a 2-year randomised, controlled study. RA patients with moderate or high disease activity despite methotrexate were randomly assigned either to tocilizumab added to methotrexate (add-on) or tocilizumab switched from methotrexate (switch). The primary endpoint was the DAS28 remission rate at week 24. Secondary objectives included other clinical efficacy indices, radiological outcomes assessed with the van der Heijde-modified total Sharp scoring system (mTSS), and safety. RESULTS: Of 223 randomised patients, 83% completed 52 weeks. DAS28 remission rates at week 24 were 70% for add-on and 55% for switch (p=0.02), but they became comparable at week 52 (72% vs 70%, p=0.86). Structural remission rates (mTSS<=0.5) at week 52 were not different (66% vs 64%, p=0.92). However, clinically relevant radiographic progression rates (CRRP; mTSS>=3) tended to be higher with the switch than with the add-on (15% vs 7%, p=0.07). Radiographic progression in the CRRP patients was larger with the switch than with the add-on (9.0/year vs 5.0/year, p=0.04). The difference in the mean C-reactive protein of the CRRP patients was significant for the first 24 weeks (1.56 vs 0.49, p=0.001) but not for the following 28 weeks (0.10 vs 0.04, p=0.1). Overall safety was preferable in the switch group. CONCLUSIONS: In RA patients with inadequate response to methotrexate, tocilizumab added to methotrexate more rapidly suppressed inflammation than tocilizumab switched from methotrexate, leading to superior clinical efficacy and prevention of joint destruction. TRIAL REGISTRATION NUMBER: NCT01120366. PMID- 26733113 TI - Defects in metal-organic frameworks: a compromise between adsorption and stability? AB - Defect engineering has arisen as a promising approach to tune and optimise the adsorptive performance of metal-organic frameworks. However, the balance between enhanced adsorption and structural stability remains an open question. Here both CO2 adsorption capacity and mechanical stability are calculated for the zirconium based UiO-66, which is subject to systematic variations of defect scenarios. Modulator-dependence, defect concentration and heterogeneity are explored in isolation. Mechanical stability is shown to be compromised at high pressures where uptake is enhanced with an increase in defect concentration. Nonetheless this reduction in stability is minimised for reo type defects and defects with trifluoroacetate substitution. Finally, heterogeneity and auxeticity may also play a role in overcoming the compromise between adsorption and stability. PMID- 26733114 TI - Complexity Matters: On Gender Agreement in Heritage Scandinavian. AB - This paper investigates aspects of the noun phrase from a Scandinavian heritage language perspective, with an emphasis on noun phrase-internal gender agreement and noun declension. Our results are somewhat surprising compared with earlier research: We find that noun phrase-internal agreement for the most part is rather stable. To the extent that we find attrition, it affects agreement in the noun phrase, but not the declension of the noun. We discuss whether this means that gender is lost and has been reduced to a pure declension class, or whether gender is retained. We argue that gender is actually retained in these heritage speakers. One argument for this is that the speakers who lack agreement in complex noun phrases, have agreement intact in simpler phrases. We have thus found that the complexity of the noun phrase is crucial for some speakers. However, among the heritage speakers we also find considerable inter-individual variation, and different speakers can have partly different systems. PMID- 26733115 TI - Gender Inequalities in Noncommunicable Disease Risk Factors Among Indonesian Urban Population. AB - Gender is an important determinant of health. We conducted a study to examine hypertension, obesity, hypercholesterolemia, and smoking behavior among adults aged >15 years in urban Indonesia. We compared the prevalence, predicted socioeconomic factors, the gender inequalities, and the contributing factors to the inequalities. Women had a higher risk of obesity and hypercholesterolemia and raised blood pressure in later life (P< .001). In contrast, men had a higher risk of being a current smoker and raised blood pressure at younger age (P< .001). The gender inequalities in hypertension, obesity, and hypercholesterolemia can be accounted for by disparities in socioeconomic factors between men and women, particularly involvement in paid work. However, the inequalities were also accounted for by different effects of the socioeconomic factors in men and women. Gender is interlinked with socioeconomic and biological factors in determining health. This emphasizes the need of gender responsive policies to control and prevent chronic disease. PMID- 26733116 TI - Blocking the rectus sheath guided by ultrasound in an 8-year-old patient with cystic fibrosis: reporting a case. AB - Cystic fibrosis (CF) is a severe disease that is transmitted with an autosomal recessive inheritance pattern, and is the commonest disease among Caucasian populations (1/2,500). There are many clinical manifestations that derive from its multiorgan dysfunctions, mainly in the respiratory and digestive tract. In addition, lung disease injury is principally responsible for morbidity and mortality in CF patients. Blocking the rectus sheath, first described by Schleich in 1899, is a loco-regional technique that provides adequate analgesia in those surgical procedures with midline or umbilical incisions. PMID- 26733118 TI - Moving beyond flexible to stretchable conductive electrodes using metal nanowires and graphenes. AB - Stretchable and/or flexible electrodes and their associated electronic devices have attracted great interest because of their possible applications in high-end technologies such as lightweight, large area, wearable, and biointegrated devices. In particular, metal nanowires and graphene derivatives are chosen for electrodes because they show low resistance and high mechanical stability. Here, we review stretchable and flexible soft electrodes by discussing in depth the intrinsic properties of metal NWs and graphenes that are driven by their dimensionality. We investigate these properties with respect to electronics, optics, and mechanics from a chemistry perspective and discuss currently unsolved issues, such as how to maintain high conductivity and simultaneous high mechanical stability. Possible applications of stretchable and/or flexible electrodes using these nanodimensional materials are summarized at the end of this review. PMID- 26733117 TI - Faustovirus-Like Asfarvirus in Hematophagous Biting Midges and Their Vertebrate Hosts. AB - Faustovirus, a new Asfarviridae-related giant virus, was recently isolated in Vermamoeba vermiformis, a protist found in sewage water in various geographical locations and occasionally reported in human eye infection cases. As part of a global metagenomic analysis of viral communities existing in biting midges, we report here for the first time the identification and isolation of a Faustovirus like virus in hematophagous arthropods and its detection in their animal hosts. The DNA virome analysis of three pools of Culicoides sp., engorged female Culicoides imicola and non-engorged male/female C. imicola biting midges collected in Senegal, revealed the presence of amoeba-infecting giant viruses and, among them, a majority of sequences related to Faustovirus. Phylogenetic analyses conducted on several structural genes of Faustovirus confirmed the clustering of the arthropod-borne Faustovirus with sewage-borne Faustoviruses, with a distinct geographical clustering of Senegalese Faustovirus strains. Transmission electron microscopy identified viral particles with morphologies and diameters which were compatible with Faustovirus. The presence of infectious arthropod-borne Faustovirus was finally confirmed by successful isolation on V. vermiformis amoeba. Global proteomic analysis of biting midges identified that arthropods' blood meal originating from cattle, rodents and humans. Further screening of cattle sera and rodent tissue resulted in prevalence of Faustovirus being estimated at 38% in rodents and 14% in cattle, suggesting a possible origin of Faustovirus presence in arthropods via the ingestion of contaminated blood meal. Viral loads were the highest in rodents' urine and kidney samples, suggesting a possible excretion of viral particles into the environment. Faustovirus DNA polymerase-related sequences were also detected in more than 9 and 11% of febrile patients and healthy Senegalese human sera, respectively. Our study thus, highlights the need to investigate the role of arthropods, wildlife, and domestic animals in the lifecycle of amoeba-infecting giant viruses and, in particular, the environmental cycle of Faustovirus. PMID- 26733119 TI - Addition of L-arginine to the fertilization medium enhances subsequent bovine embryo development rates. AB - Although L-Arginine (ARG) has been reported as a promising bovine sperm capacitation agent, its effects on embryo development are still poorly understood. Herein, we compared the effects of ARG and/or heparin (HEP) addition to the fertilization medium for bovine oocytes on sperm capacitation and embryo development. We chose 10 mM ARG based on blastocyst development rates in a titration experiment. Addition of ARG and/or HEP to the fertilization medium resulted in similar rates of blastocyst development (P > 0.05). However, when ARG, but not HEP, was combined with a nitric oxide (NO) synthase inhibitor (N Nitro-L-ARG-methyl ester, 10 mM) blastocyst development was decreased (P < 0.05). To assess the effects on capacitation, bovine sperm were incubated for 0, 3, and 6 hours in fertilization medium containing ARG and/or HEP and/or N-Nitro-L-ARG methyl esterand acrosomal exocytosis rates were evaluated using fluorescein isothiocyanate conjugated Pisum sativum lectin (FITC-PSA) staining and flow cytometry. With HEP, acrosomal exocytosis rates were highest by 3 hours of incubation; however, by 6 hours, rates were similar for HEP and/or ARG (P > 0.05) and higher than those in control media (P < 0.05). Although both ARG and HEP increased sperm NO production (P < 0.05), combination with L-NAME only precluded acrosomal exocytosis when ARG added alone in the medium (P > 0.05). These results suggest that although both ARG and HEP supported sperm capacitation, only the effects of the former were driven via NO production. Moreover, ARG was also as effective as HEP at improving blastocyst development rates. Therefore, ARG may be used as a low-cost alternative sperm capacitation agent for bovine in vitro embryo production. PMID- 26733120 TI - Thyroxin and progesterone concentrations in pregnant, nonpregnant bitches, and bitches during abortion. AB - Serum progesterone and thyroxin concentrations were measured weekly until 61 to 62 days after ovulation in 24 pregnant bitches and in the control group of nine nonpregnant bitches in the luteal phase. Fourteen of the 24 dogs had a normal pregnancy and parturition. Ten of the 24 dogs showed mucinous or colored vaginal discharge, decreased appetite, or lethargy. These initial signs of abortion or fetal resorption were noted during the fourth week of pregnancy, and the process occurred over the next 2 weeks. Progesterone and thyroxin concentrations were measured by quantitative ELISAs validated to dog serum. The serum progesterone concentrations of the group going through abortions differed significantly from the third week until the end of the eighth week. The mean serum thyroxin concentrations of healthy pregnant and nonpregnant groups significantly exceeded the reference range (20-45 nmol/L). The serum thyroxin concentrations in the abortion group were between 16.15 +/- 3.17 and 40.78 +/- 8.97 nmol/L. The values in this group were significantly different from the other two groups at the third week of the luteal phase. Clinical signs of abortion or fetus resorption manifested in midpregnancy. The clinical signs of abortion coincided in each case with a low serum progesterone concentration (<10 ng/mL). This phenomenon indicated, in contrast with other studies, that the decrease of serum progesterone below 10 ng/mL at the fourth week of pregnancy may signal impending abortion. In the second half of pregnancy, the thyroid gland was not able to respond adequately to the elevated requirement in thyroid hormone, although in other periods of the ovarian cycle, there were no clinical signs of hypothyroidism. PMID- 26733121 TI - [Pearls and pitfalls for the treatment of tibial head fractures]. AB - BACKGROUND: Tibial plateau fractures requiring surgery are severe injuries of the lower extremity. Depending on the fracture pattern, the age of the patient, the range of activity and the bone quality there is a broad variation in adequate treatment. In the last decade we have had a tremendous development, might it be the angular stable anatomical plates as well as new approaches to the proximal tibia. Nevertheless in the recent literature there are still many complications reported. Not only for sports professionals, recreational athletes or heavy load workers tibial plateau fractures affect leisure, all day activity and professional life. This article reports the treatment algorithm showing different cases, outlines the pitfalls and explains treatment strategies with a detailed x ray follow-up. CONCLUSION: After a tibial plateau fracture patients are affected in their sporting activity due to an impaired knee function. Despite a long rehabilitation time and programs, physical activity changes to lower impact sports. Among the usual perioperative complications there are the specific complications of postoperative malalignment, implant infections, osteitis of the tibial head, compartment syndrome, secondary loss of reduction, avascular tibial head necrosis, secondary varus or valgus deformity, post-traumatic arthrosis and lesions of the peroneal nerve. In the literature in up to 43% of the cases complications have been noted. Despite surgery the majority of patients cannot return to their previous level of activity. However, overall about 70% of the patients return to sports after a tibial plateau fracture. For a beneficial outcome a detailed fracture analysis with CT scan and precise planning of the surgical strategies and approaches is mandatory. PMID- 26733122 TI - Five years after the accident, whiplash casualties still have poorer quality of life in the physical domain than other mildly injured casualties: analysis of the ESPARR cohort. AB - BACKGROUND: This study aims to compare health status and quality of life five years after a road accident between casualties with whiplash versus other mild injuries, to compare evolution of quality of life at 1 and 5 years after the accident, and to explore the relation between initial injury (whiplash vs. other) and quality of life. METHODS: The study used data from the ESPARR cohort (a representative cohort of road accident casualties) and included 167 casualties with "pure" whiplash and a population of 185 casualties with other mild injuries (MAIS-1). All subjects with lesions classified as cervical contusion (AIS code 310402) or neck sprain (AIS code 640278) were considered as whiplash casualties. Diagnosis was made by physicians, at the outset of hospital care, based on interview, clinical findings and X-ray. Whiplash injuries were then classified following the Quebec classification (grades 1 and 2). Quality of life was assessed on the WHOQoL-Bref questionnaire. Correlations between explanatory variables and quality of life were explored by Poisson regression and variance analysis. RESULTS: Between 1 and 5 years, global QoL improved for both whiplash and non-whiplash casualties; but, considering the two whiplash groups separately, improvement in grade 2 was much less than in grade 1. At 5 years, grade-2 whiplash casualties were more dissatisfied with their health (39.4%; p < 0.05) than non-whiplash (24.3%) or grade-1 whiplash casualties (27.0%). Deteriorated quality of life in the mental, social and environmental domains was mainly related to psychological and socioeconomic factors for both whiplash and other mildly injured road-accident casualties. While PTSD was a major factor for the physical domain, whiplash remained a predictive factor after adjustment on PTSD; unsatisfactory health at 5 years, with deteriorated quality of life in the physical domain, was observed specifically in the whiplash group, pain playing a predominant intermediate role. CONCLUSIONS: Deteriorated quality of life in the physical domain remained 5 years after the accident, specifically in the grade-2 whiplash group, pain playing a predominant intermediate role, which may be in line with the hypothesis of neuropathic pain. PMID- 26733123 TI - DREADD in parvalbumin interneurons of the dentate gyrus modulates anxiety, social interaction and memory extinction. AB - Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in which co-transfection of the hM3D-Gq-mCherry vector with a Cre plasmid resulted in a cellular response to hM3Dq ligand clozapine-N-oxide (CNO) stimulation. In addition, the dentate gyrus (DG) of PV-Cre mice received bilateral injection of control lentivirus or lentivirus expressing double floxed hM3D-Gq-mCherry. Selective activation of PV-positive interneurons in the DG did not affect locomotor activity or depression-related behavior in mice. Interestingly, stimulation of PV-positive interneurons induced an anxiolytic effect. Activation of PVpositive interneurons appears to impair social interaction to novelty, but has no effect on social motivation. However, this defect is likely due to the anxiolytic effect as the exploratory behavior of mice expressing hM3DGq is significantly increased. Mice expressing hM3D-Gq did not affect novel object recognition. Activation of PV-positive interneurons in the DG maintains intact cued and contextual fear memory but facilitates fear extinction. Collectively, our results demonstrated that proper control of PV interneurons activity in the DG is critical for regulation of the anxiety, social interaction and fear extinction. These results improve our fundamental understanding of the physiological role of PV-positive interneurons in the hippocampus. PMID- 26733124 TI - Agenda-setting revisited: When and how do primary-care physicians solicit patients' additional concerns? AB - OBJECTIVE: Soliciting patients' complete agendas of concerns (aka. 'agenda setting') can improve patients' health outcomes and satisfaction, and physicians' time management. We assess the distribution, content, and effectiveness of physicians' post-chief-complaint, agenda-setting questions. METHODS: We coded videotapes/transcripts of 407 primary-, acute-care visits between adults and 85 general-practice physicians operating in 46 community-based clinics in two states representing urban and rural care. Measures are the incidence of physicians' questions, their linguistic format, position within visits, likelihood of being responded to, and the nature of such responses. RESULTS: Physicians' questions designed to solicit concerns additional to chief concerns occurred in only 32% of visits (p<.001). Compared to questions whose communication format explicitly solicited 'questions' (e.g., "Do you have any questions?"), those that were formatted so as to allow for 'concerns' (e.g., "Any other concerns?") were significantly more likely to generate some type of agenda item (Chi(2) (1, N=131)=11.96, p=.001), and to do so more frequently when positioned 'early' vs. 'late' during visits (Chi(2) (1, N=73)=4.99, p=.025). CONCLUSIONS: Agenda setting is comparatively infrequent. The communication format and position of physicians' questions affects patients' provision of additional concerns/questions. PRACTICE IMPLICATIONS: Physicians should increase use of optimized forms of agenda setting. PMID- 26733125 TI - Response to 'Not all participatory styles are created equal' by Kathryn I. Pollak, Ph.D. PMID- 26733126 TI - "Clip first" policy in management of intracranial MCA aneurysms: Single-centre experience with a systematic review of literature. AB - BACKGROUND: The results of microsurgical treatment for middle cerebral artery (MCA) aneurysms (ANs) have been highly satisfying for decades, notoriously posing a challenge for interventional neuroradiologists. Following the International Subarachnoid Aneurysm Trial (ISAT) study results, most centres across Europe and the USA switched to a "coil first" policy. The purpose of this study is to evaluate and critically review the substantiation of this change. METHODS: The authors conducted a single-institution retrospective study of MCA AN treatment between January 2000 and December 2013 maintaining a "clip first" policy. The results are supplied with a literature review. RESULTS: A total of 315 MCA ANs were treated in 288 consecutive patients (209 females, 79 males). Microsurgical treatment was performed for 238 AN patients (116 ruptured, 122 unruptured) and 77 AN patients (46 ruptured, 31 unruptured) who underwent a coiling procedure. Treatment-related morbidity and mortality (MM) for unruptured ANs was 2.8 % in the microsurgical group and 10.3 % in the endovascular group. The percentage of patients with no/minor permanent neurological deficits after SAH in a good initial clinical state (HH 1-2) was 93 % in the microsurgical and 76 % in the endovascular group. A literature review identified 21 studies concerning MCA AN treatment with a specified decision-making algorithm. Microsurgery seemed superior to endovascular management regarding both clinical and radiological outcomes, although several aspects of the analysed reports might appear questionable. CONCLUSION: Although this study has its inherent limitations, the effect brought about by microsurgical clipping of MCA ANs remains superior to that of endovascular embolisation and it should be sustained as the first treatment choice. The decision about the treatment strategy should be made by a multi-disciplinary team consisting of specialists from both teams, bearing in mind the higher occlusion rate and longevity of the surgical treatment. PMID- 26733127 TI - Large-diameter compression arteries as a possible facilitating factor for trigeminal neuralgia: analysis of axial and radial diffusivity. AB - BACKGROUND: Neurovascular compression (NVC) of the trigeminal nerve is associated with trigeminal neuralgia (TN). Some arteries that compress the trigeminal nerve are large, while others are small. This study evaluated the influence of diameter of compression arteries (DCA) on NVC with and without TN using axial diffusivity (AD) and radial diffusivity (RD) of magnetic resonance (MR) imaging. METHODS: Fifty TN patients with unilateral NVC, 50 asymptomatic patients with unilateral NVC, and 50 healthy controls (HC) were divided into three groups (NVC with TN, NVC without TN, and HC). The three groups were imaged with a 3.0-T MR system using three-dimensional fast imaging employing steady-state acquisition (3D FIESTA) and diffusion tensor imaging (DTI). We compared the mean size of DCA between NVC with and without TN. The mean values of AD and RD at the site of NVC were compared between the three groups. Correlation analyses were performed between the DCA and the diffusion metrics (AD and RD) in NVC patients with and without TN. RESULTS: The mean DCA in NVC patients with TN (1.58 +/- 0.34 mm) was larger than that without TN (0.89 +/- 0.29 mm). Compared with NVC without TN and HC, the mean values of RD at the site of NVC with TN were significantly increased; however, no significant changes of AD were found between the groups. Correlation analysis showed that DCA positively correlated with RD in NVC patients with and without TN (r = 0.830, p = 0.000). No significant correlation was found between DCA and AD (r = 0.178, p = 0.077). CONCLUSIONS: Larger-diameter compression arteries may increase the chances of TN, and may be a possible facilitating factor for TN. PMID- 26733128 TI - Identification of cranial nerves around trigeminal schwannomas using diffusion tensor tractography: a technical note and report of 3 cases. AB - BACKGROUND: There are no large series studies identifying the locations of cranial nerves (CNs) around trigeminal schwannomas (TSs); however, surgically induced cranial neuropathies are commonly observed after surgeries to remove TSs. In this study, we preoperatively identified the location of CNs near TSs using diffusion tensor tractography (DTT). METHODS: An observational study of the DTT results and intraoperative findings was performed. We preoperatively completed tractography from images of patients with TSs who received surgical therapy. The result was later validated during tumorectomy. RESULTS: A total of three consecutive patients were involved in this study. The locations of CNs V-VIII in relation to the tumor was clearly revealed in all cases, except for CN VI in case 3.The predicted fiber tracts were in agreement with intraoperative observations. CONCLUSIONS: In this study, preoperative DTT accurately predicted the location of the majority of the nerves of interest. This technique can be applied by surgeons to preoperatively visualize nerve arrangements. PMID- 26733129 TI - Long-term follow-up of cryopreservation with glycerol of autologous bone flaps for cranioplasty after decompressive craniectomy. AB - BACKGROUND: Autologous bone flaps adequately preserved can be used successfully for repair of cranial bone defects with biological and economic advantages. However, the effect or advantages of cryopreservation of autologous bone flaps using cryoprotectant solutions have not been investigated. The aim of this study was to investigate the utility of autologous bone flaps frozen with glycerol in cranioplasty after decompressive craniectomy. METHODS: We evaluated postoperative complications and clinical and aesthetic results in 40 consecutive patients who underwent delayed cranioplasty using autologous bone flaps frozen with glycerol following decompressive craniectomy between 2001 and 2010. Bone flaps removed at the time of external decompression were dipped in 20 % glycerol solution with a sterilized plastic vessel and stored at -84 degrees C in an ultra-low temperature freezer. The bone flaps were thawed in the vessel at room temperature for 12 h. The bone flaps were taken out of melting glycerol, replaced in their original positions, and fixed with silk sutures or titanium plates. Follow-up periods ranged from 35 to 3745 days (median, 558 days). RESULTS: Mild resorption of the bone flap occurred in one case. However, there were no cases with local infection and no cases requiring reoperation for complications during the follow up period. CONCLUSIONS: Cryopreservation with glycerol is a simple and safe method for preservation of autologous bone grafts. The clinical and aesthetic results of delayed cranioplasty using autologous bone flaps frozen with glycerol solution were satisfactory. PMID- 26733131 TI - [Biological safety of nanomaterials: the opportunity and challenge of preventive medicine]. AB - Nanotechnology, as a newly arisen technology, does not only benefit people, but also become one of the inevitable threats to public health due to the widely application of nanomaterials. The safety evaluation of nanomaterials has become one of the hottest research topics in the 21st century, which provides opportunities and challenges in the field of preventive medicine once in a blue moon. Although the history of development in the safety assessment of nanomaterials is just over twenty years, the achievements could not be underestimated. This paper summarized the research of nano biological, predicted the directions for future research, and proposed several recommendations, based on which, we hope it can promote the sustainable development safety in China. PMID- 26733130 TI - Sequence variants in the PTCH1 gene associate with spine bone mineral density and osteoporotic fractures. AB - Bone mineral density (BMD) is a measure of osteoporosis and is useful in evaluating the risk of fracture. In a genome-wide association study of BMD among 20,100 Icelanders, with follow-up in 10,091 subjects of European and East-Asian descent, we found a new BMD locus that harbours the PTCH1 gene, represented by rs28377268 (freq. 11.4-22.6%) that associates with reduced spine BMD (P=1.0 * 10( 11), beta=-0.09). We also identified a new spine BMD signal in RSPO3, rs577721086 (freq. 6.8%), that associates with increased spine BMD (P=6.6 * 10(-10), beta=0.14). Importantly, both variants associate with osteoporotic fractures and affect expression of the PTCH1 and RSPO3 genes that is in line with their influence on BMD and known biological function of these genes. Additional new BMD signals were also found at the AXIN1 and SOST loci and a new lead SNP at the EN1 locus. PMID- 26733132 TI - [Analysis of the hepatitis B report data on pilot surveillance in 200 counties in China, 2013]. AB - OBJECTIVE: To analyze the information of the supplementary card for hepatitis B and the laboratory confirmed result of immunoglobulin M antibody to hepatitis B virus (HBV) Core Antigen (anti-HBc IgM) for the suspected acute hepatitis B to evaluate the hepatitis B report data on pilot surveillance. METHODS: 200 counties were established in China for hepatitis B pilot surveillance and 63 641 cases were reported. We added a supplementary card in National Notificable Disease Reporting System (NNDRS) and all the reported hepatitis B cases in NNDRS were required to fill the supplementary card. Venous blood 5 ml was collected and a confirmed test of anti-HBc IgM was made for suspected acute hepatitis B. We made confirmed diagnosis for the suspected acute hepatitis B according to the supplementary card information of the reporting card and the confirmed test result of anti-HBc IgM. RESULTS: 63 641 hepatitis B cases were reported in 200 hepatitis B pilot surveillance counties in 2013. Among 1 723 cases which were filled with the HBsAg positive within six months in supplementary card, 735 cases were reported as chronic hepatitis B, the proportion was 42.66%. Among 4 582 cases which were filled with anti-HBc IgM positive in supplementary card, 2 436 cases were reported as acute hepatitis B, the proportion was 53.16%. 1 829 cases were reported as chronic hepatitis B, the proportion was 39.92%. The validity cases of the information for liver puncture and the HBV surface antigen (HBsAg) transform during the recovery period in supplementary cards for all the reporting cases were 579 and 4 961, and the rate were 0.91% and 7.80%, respectively. 4 302 suspected acute cases were made confirmed diagnosis, and 1 197 cases (27.82%) were confirmed acute and 2 590 cases (60.20%) were confirmed chronic. CONCLUSION: Clinical doctors failed to make full use of the information of supplementary cards to make classification diagnose for hepatitis B. Suspected acute hepatitis B with anti-HBc IgM positive should be pay attention to follow up and further distinguish acute or chronic hepatitis B according to the HBsAg transform. PMID- 26733133 TI - [Present situation and influencing factors of discrimination against hepatitis B patients and carriers among rural adults in three eastern provinces in China]. AB - OBJECTIVE: To analyze the present situation and influencing factors of discrimination against hepatitis B patients and carriers among rural adults in three eastern provinces in China. METHODS: By using the method of probability proportionate to size (PPS), we involved a sample of 9 269 rural adults aged above 18 years old from 22 villages of 7 counties in Beijing, Hebei, Shandong in 2011 and 2012. We used a self-designed interview questionnaire with questions about the individual and household characteristics, attitudes toward hepatitis B patients and carriers, individual HBV vaccination history, etc. We analyzed the hepatitis B discrimination score and its distribution, and we also created a multinomial logistic regression model to analyze the influencing factors of discrimination. RESULTS: Of all the participants, 51.15% (4 741) were afraid of being infected with HBV when getting on with hepatitis B patients or carriers; 51.29% (4 754), 61.14% (5 667) and 52.22% (4 841) of them were not willing to accept gifts from hepatitis B patients or carriers, have dinner with them, or hug and shake hands with them, respectively; 73.92% (6 852) were unwilling to their children's playing with kids whose parents were hepatitis B patients or carriers, and 86.68% (8 034) were unwilling to their children's marrying hepatitis B patients or carriers. Of all the participants, only 0.88% (82) were totally discrimination-free (discrimination score = 0); mild or without discrimination (< 0 discrimination score <= 5) accounted for 23.70% (2 197/9 269); severe discrimination (discrimination score >= 6) accounted for 76.30% (7 072). The multiple multinomial logistic regression showed that migratory workers, other occupations like technician, civil servants and village doctors were less likely to show severe HBV-related discrimination compared with farmers, with OR (95% CI) 0.86 (0.75-0.98), 0.77 (0.67-0.87), 0.57 (0.41-0.79), respectively. Compared with the lowest income group (< 10 000 RMB/year per person), and the highest income group (> 40 000 RMB/year per person) had an OR (95% CI) of 0.57 (0.46-0.70). People with higher education tended to show less severe discrimination. The high education group had an OR (95% CI) of 0.64 (0.51-0.80) based on the low education group. And compared with people whose self-assessment of health status was very good, those who assessed their health status as very poor showed less severe discrimination, with an OR (95% CI) of 0.41 (0.25-0.67). CONCLUSION: The situation of discrimination against hepatitis B patients and carriers among rural adults in three eastern provinces was serious. It is of great urgency to eliminate the discrimination. Work on eliminating hepatitis B discrimination should focus on farmers, people with low incomes, and people with low educational level. PMID- 26733134 TI - [Seroepidemiological analysis of hepatitis B among children aged 1-14 in 3 counties of Guangdong province in 2013]. AB - OBJECTIVE: To investigate the epidemic status of Hepatitis B in children aged 1 14 in 3 counties of Guangdong province in 2013, and to evaluate the effect of hepatitis control in children aged 1-14 after hepatitis B vaccine was integrated into the national immunization program in 2002 and catch-up vaccination was conducted from 2009 to 2011. METHODS: A multi-stage stratified random sampling was designed to survey 1 621 children aged 1-14 in rural area of Nanxiong county, Haifeng county and Xinxing county by questionnaires including general information, medical history and risk factors. The samples were tested with chemiluminescence method to detect hepatitis B virus (HBV) surface antigen (HBsAg), antibody to HbsAg (anti-HBs) and antibody to HBV core antigen (anti HBc). Chi-square test was used to compare the positive rate of HBV serum markers in different age groups, vaccine histories, birth weight and HBV infection status of mother. RESULTS: Among the children aged 1-14 in 3 counties rural regions of Guangdong province, the positive rate of HBsAg, anti-HBs, and anti-HBc was 1.11% (18/1 621), 60.69% (982/1 618) and 1.92% (31/1 617), respectively. The HBsAg positive rate of vaccinated children (0.84%, 13/1 547) was lower than that of unvaccinated children (1/13) or children with unknown vaccination status (6.56%, 4/61) (chi2 = 22.64, P < 0.001). The HBsAg positive rate (0.45%, 5/1 118) of the children with birth-dose given within 24 hours was lower than those that of children given beyond 24 hours (2.63%, 61/190) (chi2 = 10.21, P < 0.001). The HBsAg positive rate (5/18) of children with birth weight under 2 kilogram was higher than that of children with birth weight above 2 kilogram (0.78%, 12/1 548) (chi2 = 120.8, P < 0.001). The HBsAg positive rate of children born to HBsAg positive mothers (2.80%, 3/107) was higher than that of children born to HBsAg negative mothers (0.21%, 1/470) (chi2 = 8.50, P = 0.004). With the age increasing, the coverage and timely birth-dose coverage of Hepatitis B vaccine (HepB) decreased, and the positive rate of anti-HBs gradually decreased. CONCLUSION: After the catch-up vaccination was conducted in unvaccinated children aged 1-14 years from 2009 to 2011, the HBsAg and anti-HBc positive rate decreased, while the anti-HBs positive rate increased significantly. PMID- 26733135 TI - [Anti-HBs persistence after revaccination with three doses of hepatitis B vaccines among non-responsive adults: 24-month of follow-up]. AB - OBJECTIVE: To access the antibody persistence 24-month after revaccination with 3 dose of hepatitis B vaccine (HepB) among non-response adults. METHODS: A total of 24 237 healthy adults who had no histories of hepatitis B infection and hepatitis B vaccination, resided in the local area for more than six months and were aged 18-49 years were selected from 79 villages of Zhangqiu county, Shandong province, China in 2009. Blood samples were obtained and hepatitis B surface antigen (HBsAg), antibody against hepatitis B surface antigen (anti-HBs) and antibody against hepatitis B core antigen (anti-HBc) were detected using ELISA method. A total of 11 590 persons who were negative for all of these indicators were divided into four groups by cluster sampling methods. Each group was vaccinated with one of the following four types of HepB at 0-, 1-, 6-months schedule: 20 ug HepB derived in Saccharomyces Cerevisiae (HepB-SC), 20 ug HepB derived in Chinese hamster ovary cell (HepB-CHO), 10 ug HepB-SC and 10 ug HepB derived in Hansenula Polymorpha (HepB-HP). Blood samples were collected one month after the third dose of primary immunization and tested for anti-HBs using chemiluminescence microparticle immunoassay (CMIA). The non-responders were revaccinated with three doses of HepB at 0-, 1-, 6-months schedule and the type of HepB was the same as which was used for primary immunization. Blood samples were collected one month (T1) and two years (T24) after revaccination and anti-HBs, antibody against hepatitis B core antigen (anti-HBc) and hepatitis B surface angtigen (HBsAg) (if anti-HBs < 10 mU/ml) were detected by CMIA. chi(2) test was used to compared age, gender and body mass index (BMI) between different groups and the anti-HBs positive rate at T1 and T24; analysis of variance (ANOVA) was used to compare the geometric mean concentration (GMC) of anti-HBs between difference groups. The risk factors associated with positive rate of anti-HBs and GMC of anti-HBs were identified by multiple logistic regression analysis and multifactor linear regression model analysis respectively. RESULTS: A total of 900 non-responders were identified and 71.7% (645/900) of them completed three-dose revaccination and blood collection after revaccination. 467 (72.4%) non-responsive adults were followed up at T24. The anti-HBs positive rate decreased from 85.65% (95% CI: 82.14%-88.71%) at T1 to 60.60% (95% CI: 56.01%-65.06%) at T24 and the corresponding GMC decreased from 175.62 (95% CI: 139.03-221.84) mU/ml to 21.43 (95% CI: 17.62-26.06) mU/ml. Multivariate analysis showed that positive rate of anti-HBs at T24 was associated with gender, HepB type for revaccination and anti HBs level at T1, but only anti-HBs level at T1 was associated with the anti-HBs titer at T24. No subject showed HBsAg seroconversion and anti-HBc conversion rate was 3.64% (17/467) at T24. CONCLUSION: Anti-HBs titer decreases rapidly two years after HepB revaccination among non-responsive adults, but more than half non responderd still kept anti-HBs above protective level. The immunity durability after revaccination was associated with gender, HepB type for revaccination and anti-HBs titer one month after revaccination. PMID- 26733136 TI - [Molecular typing of 12 Brucella strains isolated in Guizhou province in 2010 2013]. AB - OBJECTIVE: To identify and characterize the Brucella strains from Guizhou province in 2010-2013. METHODS: A total of 12 strains of Brucella suspicious bacteria were isolated in Guizhou province from 2010 to 2013. Four strains (GZLL3, GZLL4, GZLL11 and SH2) were isolated from goat blood samples and eight strains (SH4, GZZY, GZSQ, GZZA, BR13001, BR13004, BR13005 and BR13006) were isolated from blood samples of patient 12 Brucella suspicious strains were identified and characterized using conventional methods. Brucella genus specific gene BCSP31-based PCR (BCSP31-PCR) was used to identify the genus of Brucella and IS711 insert sequence-based PCR (AMOS-PCR) was applied to identify the species of Brucella strains. Goats and patients originated Brucella strains were comparatively analysed using Pulse-field Gel Electrophoresis (PFGE). RESULTS: Both of conventional methods and PCR identified the 12 Brucella suspicious strains as B. melitensis biotype 3. BCSP31-PCR identification results showed that a specific DNA bands (223 bp) were detected in all the 12 strains and positive control samples with no DNA band in negative samples. AMOS-PCR amplified a 731 bp DNA bands in all the 12 strains, with 731 bp, 498 bp and 275 bp in M5, S2 and A19 strains, respectively, and no DNA band was detected in the negative control samples. PFGE analysis showed that 12 Brucella isolates from patients and goats showed consistent PFGE patterns with the digestion of restriction enzyme Xba I. CONCLUSION: The epidemic species/type of Brucella in both human and animal in Guizhou province was B. melitensis biotype 3 and goat was the main animal source of infection of brucellosis in Guizhou province. PMID- 26733137 TI - [Relationship between risk of childhood acute leukemia and children's and parents' lifestyles and household environment exposure]. AB - OBJECTIVE: To investigate the association between children's and their parents' lifestyles, household environmental exposures and risk of childhood acute leukemia (AL). METHODS: A 1:2 matched case-control study of childhood AL was conducted in Shanghai between April 2011 and January 2014. The study enrolled 66 cases aged < 15, diagnosed with AL and 132 controls matched by age, gender and residence. All of the controls had no hematological diseases or previous history of malignancy. Children who had been adopted and had congenital genetic syndromes such as Down's syndrome or a positive HIV test result were not eligible as either cases or controls. Information was obtained from standardized face-to-face interviews of their parents/guardians with detailed questions on demographic characteristics, lifestyle, and household environment. Conditional logistic regression models were used to analyze effecting factors of childhood AL, odds ratios (OR) and their 95% confidence intervals (CI) were calculated. RESULTS: Among 198 cases, 66 cases were aged (5.0 +/- 3.7) years old, and 132 controls were aged (6.0 +/- 3.8) years old (t = 0.48, P = 0.523). The paternal drink frequencies of cases and controls were 57.6% (38/66), and 31.1% (41/132), respectively (chi2 = 4.91, P = 0.027). And the frequencies of household insecticides usage in the last year in the two groups were 78.8% (52/66), and 65.2% (86/132) (chi2 = 3.87, P = 0.049). Chemical exposure during childhood (OR = 4.76, 95% CI: 1.34-16.89), maternal exposure to chemicals (OR = 4.51, 95% CI: 1.65-12.33), household insecticides use during 0-3 years of child (OR = 2.90, 95% CI: 1.31-6.39), and renovating after their children's birth (OR = 3.12, 95% CI: 1.26-7.74) were associated with an increased risk of childhood AL and these differences between the cases and the controls have statistical significance. Besides, we found that frequent contaction with other children during 0-3 years old (OR = 0.32, 95% CI: 0.15-0.69) and ventilation during sleeping in summer (OR = 0.43, 95% CI: 0.18-0.98) were associated with a decreased risk of childhood AL. CONCLUSION: Our results support the association between children's and their parents' lifestyles, household environmental exposures and childhood AL. PMID- 26733138 TI - [Chemical exposure, leukemia related DNA methylation changes and childhood acute leukemia]. AB - OBJECTIVE: To evaluate the association between chemical exposure, DNA methylation status and gene-environment interactions in the development of childhood acute leukemia (AL). METHODS: From January 1st 2009 to December 31st 2010, an exploratory case-control study was conducted on childhood AL among children who were less than 15 years of age in Shanghai, China. A total of 131 patients with newly diagnosed AL were recruited from 3 Shanghai children hospitals. The controls selected from the same hospital were healthy children who attended the physical check-up held by the department of Children's Healthcare, or who visited the clinic of developmental pediatrics or orthopedics (excluding blood diseases and malignant tumors). 140 controls matched with cases in gender and age were included in this study. Chemical exposure were investigated by questionnaires, methylation specific polymerase chain reaction (MSP) was adopted to analyze the methylation or deletion status of 8 genes, and gene-environment interactions were analyzed by relative excess risk of interaction (RERI), attributable proportion of interaction (API) and synergy index (S). RESULTS: There were 131 and 140 subjects in case and control group, who were aged (6.9 +/- 3.8) and (6.9 +/- 3.9) years old (t = 0.01, P = 0.911), respectively. After adjusting age and other potential confounding factors, chemical substances' exposure of children/mother/father were all significantly higher in cases than that in controls (Children: OR = 3.90, 95% CI: 1.69-9.02; Mother: OR = 2.71, 95% CI: 1.12 6.52; Father: OR = 1.91, 95% CI: 1.05-3.47). For the 8 genes analyzed, the methylation status of DAPK and PTEN and P73 in case group were significantly higher than that in control group (cases: 3.1% (4 cases), 16.0% (21 cases), 7.6% (10 cases); controls: 0.7% (1 case), 2.9% (4 cases), 0.7% (1 case); chi2: 7.11, 16.90, 11.38; P value: 0.029, 0.000, 0.003). The methylation status of P16 in case group was significantly lower than that in control group (cases: 3.8% (5 cases); controls: 8.6% (12 cases), chi2 = 10.33, P = 0.007). The interactions of children chemical substances' exposure and 3 genes' (PTEN, P16 and P73) methylation status were probably existed after adjusted for confounding factors (PTEN: RERI = -7.01, API = -2.14, S = 0.24; P16: RERI = 4.08, API = 0.53, S = 2.59; P73: RERI = 4.32, API = 0.48, S = 2.19), we also found the potential interaction between maternal chemical substances' exposure and PTEN, P16 gene methylation status (PTEN: RERI = -1.30, API = -0.38, S = 0.65; P16: RERI = 1.70, API = 0.38, S = 1.97). CONCLUSION: The study suggested the strong combined effects of chemical substances exposure of children and abnormal methylation status were risk factors of childhood AL, and there existed different interaction between them, which may indicate the important role in the pathogenesis process of childhood AL. PMID- 26733139 TI - [Effects of family and peer support upon the stages of health-related behavior in adolescent]. AB - OBJECTIVE: To investigate the stages of health-related behaviors, family and peer support situation about adolescent in Wuhan, and to provide evidence for health intervention and health promotion. METHODS: Based on the principle of multi-stage stratified cluster sampling, extracted two junior middle school and two high school in two cities in Wuhan from March 2012 to May. A total of 1 200 students, which were part of the first and second grade class in middle school and high school, toke as the investigation object. The study surveyed following content, including the demographic situation, adolescent health-related behavior (physical activity, sedentary behavior, high-fat diet behavior, fruit and vegetable intaking behavior), stages of adolescent health related behavior (precontemplation, contemplation, preparation, action, maintenance) and adolescent support got from family and peer. The questionnaire was distributed in 1 200 copies, the valid questionnaires were 1 052 and the effective rate was 87.67%. Using chi2 test to compare the different stages of change in health related behavior, t test was used to compare different groups of social support and using analysis of variance and post test to analyze social support of the four types behavior. RESULTS: In 1 052 students, there was 555 (52.8%) middle school students, 497 (47.2%) high school students, and 553 (52.6%) boys, 499 (47.4%) girls. In physical exercise and sedentary behavior, numbers of precontemplation was respectively accounting for 42.2% (444/1 200) and 28.4% (299/1 200). In high-fat diet behavior, the stages of preparation and maintain was occupied 46.7% (492/1 200). In fruit and vegetable intake behavior, there was 32.9% (346/1200) students in contemplation. Numbers in action stage was both less in the above four behavior, accounting for 6.2% (65/1 200), 8.9% (94/1 200), 14.0% (147/1 200) and 6.3% (66/1 200) separately. Adolescent peer support score respectively (2.9 +/- 0.7), (2.8 +/- 0.8) and (2.9 +/- 0.9), which was higher than the family support scores ((2.7 +/- 1.1), (2.5 +/- 1.2) and (2.9 +/- 1.2)) (t values were -8.72, -11.22 and -2.59, respectively. All P values were < 0.001) in physical exercise, sedentary behavior and high fat diet, but in the intake of fruits and vegetables behavior, family support score was higher than peer support (score was respectively (3.3 +/- 0.9) and (3.5 +/- 1.2); t < 9.97, P < 0.001). ANOVA and post hoc comparison showed that the score of family and peer support in the after-action stage was significantly higher than that the before-action stage in physical exercise, high-fat diet and fruit and vegetable intake behavior, while the differences in sedentary behavior was not significant. CONCLUSION: Youth health-related behaviors remained in its infancy, there was a certain impact on its stages which showed that the higher social support the more advanced stages of behavior. PMID- 26733140 TI - [Association between ambient inhalable particle pollution and mortality due to circulatory disease in Nanjing: a case-crossover study]. AB - OBJECTIVE: To explore the short-term effects of ambient PM10 pollution on mortality due to circulatory diseases, and to study the modifying effect of season on the association between ambient PM10 concentration and mortality in Nanjing. METHODS: Daily mortality, air pollution, and meteorological data from 1 January 2009 to 31 December 2013 in Nanjing were collected; Time-stratified case crossover design was used to analyze the associations between daily average concentration of inhalable particle (PM10) and mortality due to circulatory diseases; Odds ratios (OR) and 95% confidence intervals (CI) were calculated; And stratified analysis was conducted to compare the mortality risks of circulatory diseases exposed to outdoor PM10 in warm season (May-October) with that in cool season (November-April). RESULTS: The mean daily average concentrations of PM10, NO2, and SO2 from 2009 to 2013 in Nanjing were 109.1, 51.5, and 35.4 ug/m(3), respectively. During our study period, a total of 78 299 circulatory disease deaths were recorded. On average, there were approximately 43 circulatory disease deaths per day; and deaths due to cardiac diseases, ischemic heart disease and cerebrovascular diseases were 19, 10 and 24 per day, respectively. After adjusting for the meteorological variables such as daily temperature, relative humidity and air pressure, a10 ug/m(3) increment of PM10 was associated with the mortality on values of (OR) 1.002 4 (95% CI: 1.000 1-1.004 8) for total circulatory diseases, 1.004 8 (95% CI: 1.001 3-1.008 3) for cardiac diseases, 1.007 3 (95% CI: 1.002 4-1.012 3) for ischemic heart disease and 1.000 5 (95% CI: 0.998 5-1.002 4) for cerebrovascular diseases, respectively. In summer season, the OR values of daily mortality for total circulatory diseases and cerebrovascular diseases were 1.008 0 (95% CI: 1.003 9-1.012 2) and 1.005 7 (95% CI: 1.002 0-1.009 4), respectively, the corresponding OR values in cool season were 1.001 4 (95% CI: 0.998 5-1.004 2) and 0.998 8 (95% CI: 0.996 4-1.001 2), respectively; The effect estimates in warm season were higher than that in cool season. CONCLUSION: The elevated levels of ambient PM10 were positively associated with the increase of mortality due to circulatory diseases, and season may modify the effects of outdoor PM10 pollution on mortality. PMID- 26733141 TI - [Effect of cadmium on TET enzymes and DNA methylation changes in human embryonic kidney cell]. AB - OBJECTIVE: To detect the expression changes of the demethylase TETs (Ten-eleven translocation enzymes) in human embryonic kidney cell (HEK293) exposed to high dose cadmium chloride (CdCl2), and to investigate the regulation effects of TETs on global genomic methylation. METHODS: HEK293 cells were exposed to CdCl2 for 24 h, 48 h and 72 h, the survival rate was tested by CCK-8 (cell counting kit-8) method, and the cell morphology was observed. The levels of TETs mRNA and protein were detected by fluorescence quantitative PCR and Western blot, respectively. The genomic DNA methylation level was detectedby pyro sequencing assay. RESULTS: CdCl2 had toxic effects on HEK293 cells, and the half inhibitory concentration (IC50) was 1.78 umol/L. After exposure of CdCl2 for 24 h, 48 h and 72 h, the morphology of HEK293 cells was altered, and the high dose group (2.0 umol/L) showed vacuolar changes and fuzzy appearance. The level of TET1 mRNA in groups of 0.0, 0.5, 1.0, 2.0 umol/L were 0.23 +/- 0.13, 0.48 +/- 0.12, 0.59 +/- 0.16 and 0.95 +/- 0.39, respectively (F = 182.89, P = 0.002); The level of TET2 mRNA in groups of 0.0, 0.5, 1.0, 2.0 umol/L were 0.23 +/- 0.12, 0.32 +/- 0.02,0.31 +/- 0.10 and 0.34 +/- 0.07, respectively (F = 27.94, P < 0.001); The level of TET3 mRNA in groups of 0.0, 0.5, 1.0, 2.0 umol/L were 0.26 +/- 0.10, 0.27 +/- 0.11, 0.25 +/- 0.11 and 0.28 +/- 0.09, respectively (F = 1.76, P = 0.036). The interaction effect existed between exposure time and doses of TET1 mRNA, TET2 mRNA and TET3 mRNA (F values were 32.94, 23.04 and 13.78, respectively; P values were < 0.001, 0.041 and < 0.001, respectively). Western blot showed that in different exposure time and dose, the protein expression levels of TETs had the similar trend as mRNA levels. In 24 h (55.01 +/- 3.62)%, 48 h (48.31 +/- 8.99)%, 72 h (48.76 +/- 6.60)%, the DNA methylation had significant differences (F = 18.50, P < 0.001); In groups of 0.0 umol/L (55.29 +/- 2.83)%, 0.5 umol/L (55.35 +/- 3.11)%, 1.0 umol/L (48.58 +/- 6.40)% and 2.0 umol/L (43.56 +/- 7.89)%, the differences of DNA methylation had significant differences (F = 7.03, P = 0.048); the effect of interaction was also existed (F = 2.73, P = 0.043). CONCLUSION: In the short term exposure to CdCl2, the levels of TETs mRNA and protein showed a trend of increase according to the exposure time and dose, and the methylation level of whole genomic DNA was also altered. The demethylase TETs may play a role in regulating the genomic methylation level of HEK293 exposed to cadmium. PMID- 26733142 TI - [Investigation on knowledge, attitude and practice on salt and health among students of primary and secondary school in four provincial capital cities]. PMID- 26733143 TI - [The genetic toxicity and toxicology mechanism of metal nano materials]. AB - Although metal nano materials have been widely used in various fields, the potential risks of it still could not be neglected. In this paper, the effects and mechanisms of genotoxicity caused by different nano materials were discussed. Human body can be exposed to metal nano materials through multiple pathways, metals nano follow the blood stream in circulatory system and distribute to organs. Metal nano particles are mainly uptaken into cells by endocytosis, and direct or indirect damages to genes can be induced by these particles after metabolism in cells. These damages would affect the course of cell cycle and the stability of the genome, resulting in gene mutation or chromosome aberration, and even leading to the death or malignant transformation of cells. PMID- 26733144 TI - [Research on advance of health effects of nanoparticles on air pollution in China]. AB - The adverse health effects of fine particles in the air pollution has been confirmed, and health consequences induced by ultrafine particles (mass media aerodynamic diameter < 0.1 micrometer), which was also known as nanoparticles, was drawing an increasing attention by researchers. Firstly, this review discussed the sources and physicochemical characteristics of nanoparticles in the atmosphere in China. And then we focused on the biological effects and potential toxicity mechanisms of some common nanoparticles in the atmosphere on the major tissues and organs. Finally, the research focus of the nano particles in air pollutants was also presented. PMID- 26733145 TI - [The advance of model of action in low-dose chronic benzene exposure induced hematotoxicity]. AB - Benzene is classified as Group 1 carcinogen by IARC. It has been found that benzene induces hematotoxicity even in low dose exposure. The identification of key events during benzene induced hematotoxicty leads to adjustment of occupational exposure limits of benzene. In this review, we focus on the exposure, metabolism, target organs, key epigenetic changes, toxicty effects and end points of low-dose chronic benzene exposure induced hematotoxicity and finally discuss the perspectives on the future study of this area. PMID- 26733146 TI - [Advances in non-carcinogenic toxicity of trichloroethylene]. AB - Trichloroethylene (TCE) is a widely used organic solvent and an important industrial material. Due to mass production and use, and improper waste disposal, TCE has become a common environmental contaminant, so there is a wide range of occupationally and environmentally exposed population. Occupational and environmental exposure to TCE can produce toxic effects on multiple organs and systems. This paper is a review of the immunotoxicity, reproductive toxicity, neurotoxicity, teratogenic effect and other non-carcinogenic toxic effects of TCE from the aspects of epidemiological study, experimental evidence on animals and toxic mechanisms. PMID- 26733147 TI - Evaluation of plasma cholestane-3beta,5alpha,6beta-triol and 7-ketocholesterol in inherited disorders related to cholesterol metabolism. AB - Oxysterols are intermediates of cholesterol metabolism and are generated from cholesterol via either enzymatic or nonenzymatic pathways under oxidative stress conditions. Cholestan-3beta,5alpha,6beta-triol (C-triol) and 7-ketocholesterol (7 KC) have been proposed as new biomarkers for the diagnosis of Niemann-Pick type C (NP-C) disease, representing an alternative tool to the invasive and time consuming method of fibroblast filipin test. To test the efficacy of plasma oxysterol determination for the diagnosis of NP-C, we systematically screened oxysterol levels in patients affected by different inherited disorders related with cholesterol metabolism, which included Niemann-Pick type B (NP-B) disease, lysosomal acid lipase (LAL) deficiency, Smith-Lemli-Opitz syndrome (SLOS), congenital familial hypercholesterolemia (FH), and sitosterolemia (SITO). As expected, NP-C patients showed significant increase of both C-triol and 7-KC. Strong increase of both oxysterols was observed in NP-B and less pronounced in LAL deficiency. In SLOS, only 7-KC was markedly increased, whereas in both FH and in SITO, oxysterol concentrations were normal. Interestingly, in NP-C alone, we observed that plasma oxysterols correlate negatively with patient's age and positively with serum total bilirubin, suggesting the potential relationship between oxysterol levels and hepatic disease status. Our results indicate that oxysterols are reliable and sensitive biomarkers of NP-C. PMID- 26733148 TI - Characterization and relative quantification of phospholipids based on methylation and stable isotopic labeling. AB - Phospholipids (PLs), one of the lipid categories, are not only the primary building blocks of cellular membranes, but also can be split to produce products that function as second messengers in signal transduction and play a pivotal role in numerous cellular processes, including cell growth, survival, and motility. Here, we present an integrated novel method that combines a fast and robust TMS diazomethane-based phosphate derivatization and isotopic labeling strategy, which enables simultaneous profiling and relative quantification of PLs from biological samples. Our results showed that phosphate methylation allows fast and sensitive identification of the six major PL classes, including their lysophospholipid counterparts, under positive ionization mode. The isotopic labeling of endogenous PLs was achieved by deuterated diazomethane, which was generated through acid catalyzed hydrogen/deuterium (H/D) exchange and methanolysis of TMS-diazomethane during the process of phosphate derivatization. The measured H/D ratios of unlabeled and labeled PLs, which were mixed in known proportions, indicated that the isotopic labeling strategy is capable of providing relative quantitation with adequate accuracy, reproducibility, and a coefficient of variation of 9.1%, on average. This novel method offers unique advantages over existing approaches and presents a powerful tool for research of PL metabolism and signaling. PMID- 26733149 TI - Identification of mesenteric lymph nodes in robotic complete mesocolic excision by near-infrared fluorescence imaging. PMID- 26733150 TI - Increased IGFBP-1 phosphorylation in response to leucine deprivation is mediated by CK2 and PKC. AB - Insulin-like growth factor binding protein-1 (IGFBP-1), secreted by fetal liver, is a key regulator of IGF-I bioavailability and fetal growth. IGFBP-1 phosphorylation decreases IGF-I bioavailability and diminishes its growth promoting effects. Growth-restricted fetuses have decreased levels of circulating essential amino acids. We recently showed that IGFBP-1 hyperphosphorylation (pSer101/119/169) in response to leucine deprivation is regulated via activation of the amino acid response (AAR) in HepG2 cells. Here we investigated nutrient sensitive protein kinases CK2/PKC/PKA in mediating IGFBP-1 phosphorylation in leucine deprivation. We demonstrated that leucine deprivation stimulated CK2 activity (enzymatic assay) and induced IGFBP-1 phosphorylation (immunoblotting/MRM-MS). Inhibition (pharmacological/siRNA) of CK2/PKC, but not PKA, prevented IGFBP-1 hyperphosphorylation in leucine deprivation. PKC inhibition also prevented leucine deprivation-stimulated CK2 activity. Functionally, leucine deprivation decreased IGF-I-induced-IGF-1R autophosphorylation when CK2/PKC were not inhibited. Our data strongly support that PKC promotes leucine deprivation-induced IGFBP-1 hyperphosphorylation via CK2 activation, mechanistically linking decreased amino acid availability and reduced fetal growth. PMID- 26733152 TI - Private genome analysis through homomorphic encryption. AB - BACKGROUND: The rapid development of genome sequencing technology allows researchers to access large genome datasets. However, outsourcing the data processing o the cloud poses high risks for personal privacy. The aim of this paper is to give a practical solution for this problem using homomorphic encryption. In our approach, all the computations can be performed in an untrusted cloud without requiring the decryption key or any interaction with the data owner, which preserves the privacy of genome data. METHODS: We present evaluation algorithms for secure computation of the minor allele frequencies and chi2 statistic in a genome-wide association studies setting. We also describe how to privately compute the Hamming distance and approximate Edit distance between encrypted DNA sequences. Finally, we compare performance details of using two practical homomorphic encryption schemes--the BGV scheme by Gentry, Halevi and Smart and the YASHE scheme by Bos, Lauter, Loftus and Naehrig. RESULTS: The approach with the YASHE scheme analyzes data from 400 people within about 2 seconds and picks a variant associated with disease from 311 spots. For another task, using the BGV scheme, it took about 65 seconds to securely compute the approximate Edit distance for DNA sequences of size 5K and figure out the differences between them. CONCLUSIONS: The performance numbers for BGV are better than YASHE when homomorphically evaluating deep circuits (like the Hamming distance algorithm or approximate Edit distance algorithm). On the other hand, it is more efficient to use the YASHE scheme for a low-degree computation, such as minor allele frequencies or chi2 test statistic in a case-control study. PMID- 26733151 TI - MicroRNA-26a suppresses epithelial-mesenchymal transition in human hepatocellular carcinoma by repressing enhancer of zeste homolog 2. AB - BACKGROUND: Our previous study reported that microRNA-26a (miR-26a) inhibited tumor progression by inhibiting tumor angiogenesis and intratumoral macrophage infiltration in hepatocellular carcinoma (HCC). The direct roles of miR-26a on tumor cell invasion remain poorly understood. In this study, we aim to explore the mechanism of miR-26a in modulating epithelial-mesenchymal transition (EMT) in HCC. METHODS: In vitro cell morphology and cell migration were compared between the hepatoma cell lines HCCLM3 and HepG2, which were established in the previous study. Overexpression and down-regulation of miR-26a were induced in these cell lines, and Western blot and immunofluorescence assays were used to detect the expression of EMT markers. Xenograft nude mouse models were used to observe tumor growth and pulmonary metastasis. Immunohistochemical assays were conducted to study the relationships between miR-26a expression and enhancer of zeste homolog 2 (EZH2) and E-cadherin expression in human HCC samples. RESULTS: Down-regulation of miR-26a in HCCLM3 and HepG2 cells resulted in an EMT-like cell morphology and high motility in vitro and increased in tumor growth and pulmonary metastasis in vivo. Through down-regulation of EZH2 expression and up-regulation of E-cadherin expression, miR-26a inhibited the EMT process in vitro and in vivo. Luciferase reporter assay showed that miR-26a directly interacted with EZH2 messenger RNA (mRNA). Furthermore, the expression of miR-26a was positively correlated with E cadherin expression and inversely correlated with EZH2 expression in human HCC tissue. CONCLUSIONS: miR-26a inhibited the EMT process in HCC by down-regulating EZH2 expression. PMID- 26733153 TI - Dental wear patterns in early modern humans from Skhul and Qafzeh: A response to Luca Fiorenza and Ottmar Kullmer. AB - It is common knowledge, that in archaic populations teeth could have been used as tools, such behavior can be studied by evaluating occlusal attrition patterns. Fiorenza and Kullmer suggested a digital approach to distinguish between masticatory and non-masticatory wear facets in archaic and modern populations. In their last response to our letter (Fiorenza and Kullmer, 2015), they used comparative modern samples to demonstrate that described para-facets in Skhul and Qafzeh individuals could not have been produced by dental occlusal anomalies and also since they claimed that more than 50% of the sample analyzed in their study are characterized by para-facets, it is highly unlikely to be the result of dental pathologies. What the authors neglected to mention is that misalignment of teeth and/or malocclusion features in the Qafzeh specimens for example are present in 55.5% of the individuals, and therefore, malocclusions should be at least reconsidered as a possible cause for the para-facets formation. Also, dental cross-bite may involve functional shift and mandibular deflection and therefore, should also be considered as a possible cause for untypical occlusal contacts. In the current reply, we indicate the disadvantages of the occlusal fingerprints analysis in archaic fragmented samples. PMID- 26733154 TI - Enhanced photocatalytic performance of an Ag3PO4 photocatalyst via fullerene modification: first-principles study. AB - The coupling of carbon nanomaterials with semiconductor photocatalysts is a promising route to improve their photocatalytic performance. Herein, density functional theory was used to investigate the electronic structure, charge transfer, photocatalytic activity, and stability in a series of hybrid fullerene (C20, Li@C20, C26, Li@C26)/Ag3PO4(100) composites. When a Li atom is incorporated in fullerene, the adsorption energies significantly increase, although the change of interface distance is negligibly small due to the weak interface interaction. The charge transfer between constituents decreases with the C atom number of fullerene. Compared to pure Ag3PO4, the band gap of the composites is smaller, which enhances the visible-light absorption and photoinduced electron transfer. Most importantly, a type-II, staggered band alignment could be obtained in the C26-Ag3PO4(Li@C26-Ag3PO4) interface, leading to significantly reduced charge recombination and thus enhanced photocatalytic activity. These results reveal that fullerene modification would be an effective strategy to improve the photocatalytic performance of Ag3PO4 semiconductor photocatalysts. PMID- 26733155 TI - Nationwide prevalence and risk factors for faecal carriage of Escherichia coli O157 and O26 in very young calves and adult cattle at slaughter in New Zealand. AB - Nationwide prevalence and risk factors for faecal carriage of Escherichia coli O157 and O26 in cattle were assessed in a 2-year cross-sectional study at four large slaughter plants in New Zealand. Recto-anal mucosal swab samples from a total of 695 young (aged 4-7 days) calves and 895 adult cattle were collected post-slaughter and screened with real-time polymerase chain reaction (PCR) for the presence of E. coli O157 and O26 [Shiga toxin-producing E. coli (STEC) and non-STEC]. Co-infection with either serogroup of E. coli (O157 or O26) was identified as a risk factor in both calves and adult cattle for being tested real time PCR-positive for E. coli O157 or O26. As confirmed by culture isolation and molecular analysis, the overall prevalence of STEC (STEC O157 and STEC O26 combined) was significantly higher in calves [6.0% (42/695), 95% confidence interval (CI) 4.4-8.1] than in adult cattle [1.8% (16/895), 95% CI 1.1-3.0] (P < 0.001). This study is the first of its kind in New Zealand to assess the relative importance of cattle as a reservoir of STEC O157 and O26 at a national level. Epidemiological data collected will be used in the development of a risk management strategy for STEC in New Zealand. PMID- 26733156 TI - Measuring the robustness of link prediction algorithms under noisy environment. AB - Link prediction in complex networks is to estimate the likelihood of two nodes to interact with each other in the future. As this problem has applications in a large number of real systems, many link prediction methods have been proposed. However, the validation of these methods is so far mainly conducted in the assumed noise-free networks. Therefore, we still miss a clear understanding of how the prediction results would be affected if the observed network data is no longer accurate. In this paper, we comprehensively study the robustness of the existing link prediction algorithms in the real networks where some links are missing, fake or swapped with other links. We find that missing links are more destructive than fake and swapped links for prediction accuracy. An index is proposed to quantify the robustness of the link prediction methods. Among the twenty-two studied link prediction methods, we find that though some methods have low prediction accuracy, they tend to perform reliably in the "noisy" environment. PMID- 26733157 TI - Ectopic overexpression of Nanog induces tumorigenesis in non-tumorous fibroblasts. AB - Key regulatory genes in pluripotent stem cells are of interest not only as reprogramming factors but also as regulators driving tumorigenesis. Nanog is a transcription factor involved in the maintenance of embryonic stem cells and is one of the reprogramming factors along with Oct4, Sox2, and Lin28. Nanog expression has been detected in different types of tumors, and its expression is a poor prognosis for cancer patients. However, there is no clear evidence that Nanog is functionally involved in tumorigenesis. In this study, we induced overexpression of Nanog in mouse embryonic fibroblast cells and subsequently assessed their morphological changes, proliferation rate, and tumor formation ability. We found that Nanog overexpression induced immortalization of mouse embryonic fibroblast cells (MEFs) and increased their proliferation rate in vitro. We also found that formation of tumors after subcutaneous injection of retroviral-Nanog infected MEFs (N-MEFs) into athymic mouse. Cancer-related genes such as Bmi1 were expressed at high levels in N-MEFs. Hence, our results demonstrate that Nanog is able to transform normal somatic cells into tumor cells. PMID- 26733158 TI - Functional organization of human SAMHD1 and mechanisms of HIV-1 restriction. AB - Sterile alpha motif and histidine-aspartate domain containing protein 1 (SAMHD1) is a triphosphohydrolase that catalyzes the conversion of deoxyribonucleoside triphosphate to deoxyribonucleoside and triphosphate. SAMHD1 has been a recent focus of study since it was identified as a potent human immunodeficiency virus-1 (HIV-1) restriction factor in the intrinsic antiviral immune system. Recent biochemical and biological studies have suggested that SAMHD1 restricts HIV-1 infection in non-cycling cells by limiting the pool of deoxyribonucleoside triphosphates, thereby interfering with HIV-1 reverse transcription. SAMHD1 also possesses single-stranded DNA and RNA binding activity, with reported nuclease activity, conferring additional HIV-1 restriction function. This review summarizes current knowledge regarding the structure of SAMHD1 and the regulation of its function in HIV-1 restriction. PMID- 26733159 TI - Chemopreventive and hepatoprotective roles of adiponectin (SULF2 inhibitor) in hepatocelluar carcinoma. AB - Sulfatase 2 (SULF2) is an extracellular enzyme that catalyzes the removal of 6-O sulfate groups from the heparan sulfate (HS). As elevated SULF2 activity has been correlated with hepatocellular carcinoma (HCC), this study was conducted to evaluate the chemoprotective and the hepatoprotective roles of adiponectin, as a SULF2 inhibitor, against hepatocellular carcinoma both in vivo and in vitro. HCC was induced in rats using thioacetamide (200 mg/kg). Treated rats received adiponectin (5 MUg/kg) once a week. Moreover, human hepatocellular carcinoma (HepG2) cell line was used as an in-vitro model. In both in-vivo and in-vitro models, adiponectin completely blocked HCC-induced SULF2 elevation. The antitumor activity of adiponectin was confirmed by 80% increased the survival rate, 73% reduction in the average number of nodules per nodule-bearing liver and 46% reduction in serum AFP. In addition, adiponectin ameliorated HCC-induced expression of tumor invasion markers, MMP9, syndecan-1 and FGF-2. Moreover, adiponectin attenuated HCC-induced elevation of nfkappab and TNF-alpha levels. Moreover, treatment of HepG2 cell line with adiponectin showed dose-dependent reduction of HepG2 cell viability and elevation of cellular cytotoxicity. Besides, Adiponectin yielded the same results in HepG2 cells in a dose-dependent manner. Adiponectin achieved both hepatoprotective and chemoprotective effects against HCC through blocking of SULF2. PMID- 26733161 TI - Synthesis of gamma-Valerolactone from Carbohydrates and its Applications. AB - gamma-Valerolactone (GVL) is a valuable chemical intermediate that can be obtained by catalytic reduction of levulinic acid (LA) or alkyl levulinates (AL). There are many reports on the synthesis of GVL from LA or AL. However, the demand for the large-scale synthesis of GVL requires more environmentally friendly and cost-effective production processes. This article focuses on the recent advance in the synthesis of GVL from carbohydrates or lignocellulosic biomass. In addition, application of GVL as the reaction solvents, fuel additives, and as precursor for the synthesis of jet fuel and polymer monomers is also discussed. PMID- 26733160 TI - Role of chitinase-like proteins in cancer. AB - Chitinase-like proteins (CLPs) are lectins combining properties of cytokines and growth factors. Human CLPs include YKL-40, YKL-39 and SI-CLP that are secreted by cancer cells, macrophages, neutrophils, synoviocytes, chondrocytes and other cells. The best investigated CLP in cancer is YKL-40. Serum and plasma levels of YKL-40 correlate with poor prognosis in breast, lung, prostate, liver, bladder, colon and other types of cancers. In combination with other circulating factors YKL-40 can be used as a predictive biomarker of cancer outcome. In experimental models YKL-40 supports tumor initiation through binding to RAGE, and is able to induce cancer cell proliferation via ERK1/2-MAPK pathway. YKL-40 supports tumor angiogenesis by interaction with syndecan-1 on endothelial cells and metastatic spread by stimulating production of pro-inflammatory and pro-invasive factors MMP9, CCL2 and CXCL2. CLPs induce production of pro- and anti-inflammatory cytokines and chemokines, and are potential modulators of inflammatory tumor microenvironment. Targeting YKL-40 using neutralizing antibodies exerts anti cancer effect in preclinical animal models. Multifunctional role of CLPs in regulation of inflammation and intratumoral processes makes them attractive candidates for tumor therapy and immunomodulation. In this review we comprehensively analyze recent data about expression pattern, and involvement of human CLPs in cancer. PMID- 26733162 TI - Human epididymis protein 4 expression positively correlated with miR-21 and served as a prognostic indicator in ovarian cancer. AB - Ovarian cancer is the most common cause of gynecological malignancy-related mortality. Human epididymis protein 4 (HE4) is a useful biomarker for ovarian cancer when either used alone or in combination with carbohydrate antigen 125 (CA125). What is more, aberrant expression of microRNA-21 (miR-21) has been shown to be involved in oncogenesis, but the relationship between miR-21 and HE4 in ovarian cancer is not clear. Tumor and adjacent tumor tissues from 43 patients with ovarian cancer were examined. Real-time polymerase chain reaction (RT-PCR) was used to detect the expression of HE4 in the carcinoma and adjacent tissues. The associations between HE4 and tumor biological characters were discussed. TaqMan((r)) MicroRNA (miRNA) assays were employed to detect the expression of miR 21 in the ovarian carcinoma. In ovarian cancer, the expression of HE4 messenger RNA (mRNA) in cancer tissues was higher than adjacent tumor tissues (P < 0.0001), which was 1.299-fold of adjacent tumor tissues. And, the expression of miR-21 was also up-regulated which was significantly different in the ovarian cancer (the positive rate was 76.74 %). There was a significantly positive correlation between miR-21 and HE4 expression (r = 0.283 and P = 0.066 for HE4 mRNA, r = 0.663 and P < 0.0001 for serum HE4). There was also a significant correlation between miR-21 and tumor grade (r = 0.608, P < 0.0001). Significantly, patients with recent recurrence (less than 6 months, n = 17) have a higher miR-21 expression than those with no recent recurrence. Therefore, HE4 and miR-21 may play an important role in the development and progression of ovarian cancer and they may serve as prognostic indicators in ovarian cancer. PMID- 26733163 TI - Overexpression of ABCC3 promotes cell proliferation, drug resistance, and aerobic glycolysis and is associated with poor prognosis in urinary bladder cancer patients. AB - Human urinary bladder cancer (UBC) is the one of the most common malignancies worldwide and occurs at a higher frequency in male individuals. ATP-binding cassette, subfamily C, member 3 (ABCC3), a member of the ABC transporter family, is highly expressed in tumor cells, where it actively effluxes a broad spectrum of metabolites. However, the expression and role of ABCC3 in human UBC remains unclear. Our study aimed to identify the expression status of ABCC3 in UBC cases and investigate the biological effects on UBC in cells. We found that both mRNA and protein levels of ABCC3 were significantly higher in UBC tissues than normal tissues. Immunochemistry evaluation of ABCC3 expression in 122 UBC clinical specimens showed that high expression of ABCC3 had a positive correlation with UBC tumor size, advanced tumor node metastasis stage, and malignant histology. Moreover, high ABCC3 expression was linked to poor overall survival in UBC. ABCC3 effects on cell proliferation and drug resistance were measured by colony formation and methylthiazolyldiphenyl-tetrazolium bromide (MTT) assays. ABCC3 knockdown cells showed a significant decrease in cell growth and drug resistance. RNA interference of ABCC3 also caused downregulation of lactate dehydrogenase A (LDHA), which positively correlated with ABCC3 expression in UBC specimens. In addition, cancer cell glycolytic ability was decreased upon ABCC3 knockdown. The activity of LDHA was also abrogated in ABCC3-deficient UBC cells, and the blockade of LDHA increased UBC cells sensitivity to Cis-diamine dichloroplatinum (CDDP). In summary, our study suggests ABCC3 is an important oncoprotein involved in glycolysis and drug resistance. These data also indicates that ABCC3 could be a potential prognostic marker and promising therapeutic target in UBC. PMID- 26733164 TI - ABCE1 plays an essential role in lung cancer progression and metastasis. AB - ATP-binding cassette E1 (ABCE1) is a member of the ATP-binding cassette transporters and regulates a broad range of biological functions including viral infection, cell proliferation, and anti-apoptosis. We have previously shown that ABCE1 is a prognostic indicator for lung cancer, although the underlying mechanisms remain unclear. To investigate whether the ABCE1 gene contributes to the malignancy of lung tumors, we introduced ABCE1 into LTEP-a-2 lung adenocarcinoma cells. Ectopic ABCE1 expression promoted clonogenicity and anchorage-independent growth of LTEP-a-2 cells, while in a mouse xenograft tumor model, it had an augmentative effect on tumor growth and metastasis and reduced the expression of the tumor-suppressor gene growth arrest and DNA damage inducible 45alpha (GADD45alpha). Moreover, apoptosis was not significantly influenced by ABCE1 in vitro. In summary, we have provided evidence that ABCE1 plays an essential role in the progression and metastasis of lung cancers and may represent a valuable therapeutic target for the management of lung tumor. PMID- 26733165 TI - Relationship of body mass index with BRAF (V600E) mutation in papillary thyroid cancer. AB - Current evidences suggest an influence of overweight body mass index (BMI) on the carcinogenesis in malignancies. However, the role of BMI is unclear in papillary thyroid cancer (PTC). The aim of the present study is to investigate the relationship between BMI and BRAF (V600E) mutation status in PTC. BRAF (V600E) mutation in 108 patients with PTC was analyzed by Sanger sequencing. The cutoff point of BMI was identified by X-tile for predicting mutation by overweight. Odds ratios (OR) and 95 % confidence interval (CI) of BRAF (V600E) mutation according to BMI and clinicopathologic variables were calculated using logistic regression models. Fifty-one patients were positive for BRAF (V600E) mutation. A positive relationship existed between BRAF (V600E) mutation and BMI (p = 0.039). A 24.3 kg/m(2) was identified as cutoff point for differentiating greater than 52.0 % observed probability of mutation for BRAF (V600E) in entire cohort, which was similar to the midpoint between the upper limit of normal BMI and overweight defined by WHO (>=24 kg/m(2)). Multivariate analysis confirmed the association between BRAF (V600E) mutation with overweight BMI range (OR 7.645, 95 % CI 1.275 45.831, p = 0.026). This study suggests an influence of overweight BMI on the status of BRAF (V600E) in patients with PTC, whereas the underlying mechanism need to be further investigated. PMID- 26733166 TI - A novel and selective inhibitor of PKC zeta potently inhibits human breast cancer metastasis in vitro and in mice. AB - Cell motility and chemotaxis play pivotal roles in the process of tumor development and metastasis. Protein kinase C zeta (PKC zeta) mediates epidermal growth factor (EGF)-stimulated chemotactic signaling pathway through regulating cytoskeleton rearrangement and cell adhesion. The purpose of this study was to develop anti-PKC zeta therapeutics for breast cancer metastasis. In this study, a novel and high-efficient PKC zeta inhibitor named PKCZI195.17 was screened out through a substrate-specific strategy. MTT assay was used to determine the cell viability of human breast cancer MDA-MB-231, MDA-MB-435, and MCF-7 cells while under PKCZI195.17 treatment. Wound-healing, chemotaxis, and Matrigel invasion assays were performed to detect the effects of PKCZI195.17 on breast cancer cells migration and invasion. Adhesion, actin polymerization, and Western blotting were performed to detect the effects of PKCZI195.17 on cells adhesion and actin polymerization, and explore the downsteam signaling mechanisms involved in PKC zeta inhibition. MDA-MB-231 xenograft was used to measure the in vivo anti metastasis efficacy of PKCZI195.17. The compound PKCZI195.17 selectively inhibited PKC zeta kinase activity since it failed to inhibit PKC alpha, PKC beta, PKC delta, PKC eta, AKT2, as well as FGFR2 activity. PKCZI195.17 significantly impaired spontaneous migration, chemotaxis, and invasion of human breast cancer MDA-MB-231, MDA-MB-435, and MCF-7 cells, while PKCZI195.17 did not obviously inhibited cells viability. PKCZI195.17 also inhibited cells adhesion and actin polymerization through attenuating the phosphorylations of integrin beta1, LIMK, and cofilin, which might be the downstream effectors of PKC zeta mediated chemotaxis in MDA-MB-231 cells. Furthermore, PKCZI195.17 suppressed the breast cancer metastasis and increased the survival time of breast tumor-bearing mice. In summary, PKCZI195.17 was a PKC zeta-specific inhibitor which dampened cancer cell migration and metastasis and may serve as a novel therapeutic drug for breast cancer metastasis. PMID- 26733167 TI - Downregulation of CD73 in 4T1 breast cancer cells through siRNA-loaded chitosan lactate nanoparticles. AB - The immunosuppressive factors in tumor microenvironment enhance tumor growth and suppress anti-tumor immune responses. Adenosine is an important immunosuppressive factor which can be secreted by both tumor and immune cells trough action of two cell surface ecto-nucleotidase molecules CD39 and CD73. Blocking the adenosine generating molecules has emerged as an effective immunotherapeutic approach for treatment of cancer. In this study, CD73-siRNA encapsulated into chitosan-lactate (ChLa) nanoparticles (NPs) was employed to suppress the expression of CD73 molecule on 4T1 breast tumor cells, in vitro. ChLa NPs were generated through ionic gelation of ChLa by tripolyphosphate (TPP). Small interfering RNA (SiRNA) loaded NPs had about 100 nm size with a polydispersive index below 0.3 and a zeta potential about 13. Our results showed that ChLa NPs with Ch 50 kDa exhibit the best physicochemical features with the high siRNA encapsulation capacity. Synthesized NPs were able to fully bind with siRNA, protect them against serum and heparin degradation, and promote the transfection process. While the NPs exhibited low toxicity during 72 h cell culture, the transfection of Ch-plasmid expressing green fluorescent protein (pEGFP) NPs was efficient in 4T1 cells with a transfection rate of 53.6 % as detected by flow cytometry. In addition, CD73 siRNA-loaded ChLa NPs could efficiently suppress the expression of CD73 as assayed by real-time polymerase chain reaction and flow cytometry. As a conclusion, CD73-siRNA-loaded ChLa NPs may be considered as a promising therapeutic tool for cancer therapy; however, further in vivo investigations are necessary. PMID- 26733168 TI - Reactive oxygen species mediate oxaliplatin-induced epithelial-mesenchymal transition and invasive potential in colon cancer. AB - Therapeutic benefits offered by common chemotherapy drugs, such as oxaliplatin, are limited due to the development of resistance, which contributes to treatment failure and metastasis. The epithelial-mesenchymal transition (EMT) is a key event contributing to the development of resistance to chemotherapeutics. Although the relationship between oxaliplatin and chemotherapy resistance has been described for decades, the molecular mechanisms have remained elusive. The aim of the present study was to investigate the underlying mechanisms of oxaliplatin-mediated metastasis. Here, we identify reactive oxygen species (ROS) as mediators that promote the oxaliplatin-induced EMT. Following oxaliplatin treatment, the messenger RNA (mRNA) levels of most peroxiredoxin family genes, except for peroxiredoxin 1 (prdx1) gene, were constant or even decreased, resulting in ROS abundance. And the antioxidant guardian Nrf2 was unconspicuously raised both transcriptionally and translationally with oxaliplatin treatment as compared to those induced by topotecan treatment, which has been proved with no induced metastasis. In addition, the study evaluated high levels of ROS leading to EMT via activation of the known oncogenes Akt and Snail. Using the Akt inhibitor LY294002 or knocking down Snail expression via RNA interference (RNAi) reversed the effects of oxaliplatin on the EMT and metastasis. Our studies establish a role for the ROS-Akt-Snail axis as a mechanism by which chemotherapeutics induce EMT and cancer metastasis. PMID- 26733169 TI - Human umbilical cord mesenchymal stem cells delivering sTRAIL home to lung cancer mediated by MCP-1/CCR2 axis and exhibit antitumor effects. AB - Mesenchymal stem cells (MSCs) are believed to be a potential vehicle delivering antitumor agents for their tumor-homing capacity, while the underlying mechanism is yet to be explored. The apoptotic ligand TNF-related apoptosis-inducing ligand (TRAIL) has been suggested as a promising candidate for cancer gene therapy owing to its advantage of selectively inducing apoptosis in cancer cells while sparing normal cells. An isoleucine zipper (ISZ) added to the N-terminal of secretable soluble TRAIL (sTRAIL) can generate the trimeric form of TRAIL (ISZ-sTRAIL) and increase its antitumor potential. However, the inefficient delivery and toxicity are still obstacles for its use. In this study, the migration of human umbilical cord mesenchymal stem cells (HUMSCs) to lung cancer was observed through transwell migration assay and animal bioluminescent imaging both in vitro and in vivo. We found that the homing ability of HUMSCs was suppressed after either knocking down the expression of monocyte chemoattractant protein-1(MCP-1) in lung cancer cells or blocking CCR2 expressed on the surface of HUMSCs, indicating the important role of MCP-1/CCR2 axis in the tropism of HUMSCs to lung cancer. Furthermore, we genetically modified HUMSCs to deliver ISZ-sTRAIL to tumor sites specifically. This targeted therapeutic system exhibited promising apoptotic induction and antitumor potential in a xenograft mouse model without obvious side effects. In conclusion, HUMSCs expressing ISZ-sTRAIL might be an efficient therapeutic approach against lung cancer and MCP-1/CCR2 axis is essential for the tumor tropism of HUMSCs. PMID- 26733170 TI - Solanum tuberosum lectin inhibits Ehrlich ascites carcinoma cells growth by inducing apoptosis and G2/M cell cycle arrest. AB - Recently, a lectin was purified from the potato cultivated in Bangladesh locally known as Sheel. In the present study cytotoxicity of the lectin against Ehrlich ascites carcinoma (EAC) cells was studied by MTT assay in vitro in RPMI-1640 medium and 8.0-36.0 % cell growth inhibition was observed at the range of 2.5-160 MUg/ml protein concentration when incubated for 24 h. The lectin-induced apoptosis in EAC cells was confirmed by fluorescence and optical microscope. The apoptotic cell death was also confirmed by using caspase inhibitors. Cells growth inhibition caused by the lectin (36 %) was remarkably decreased to 7.6 and 22.3 % respectively in the presence of caspase-3 and -8 inhibitors. RT-PCR was used to evaluate the expression of apoptosis-related genes Bcl-X, p53, and Bax. An intensive expression of Bcl-X gene was observed in untreated control EAC cells with the disappeared of the gene in Sheel-treated EAC cells. At the same time, Bax gene expression appeared only in Sheel-treated EAC cells and the expression level of the p53 gene was increased remarkable after the treatment of EAC cells with the lectin. The lectin showed strong agglutination activity against EAC cells. Flow cytometry was used to study the cell cycle phases of EAC cells and it was observed that the lectin arrested the G2/M phase. In conclusion, Sheel lectin inhibited EAC cells growth by inducing apoptosis. PMID- 26733171 TI - Sphingosine kinase 2 promotes colorectal cancer cell proliferation and invasion by enhancing MYC expression. AB - Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and causes of cancer death in developed countries. SphK2 is overexpressed in a number of aggressive human carcinomas; however, the expression profile and potential function of SphK2 in CRC are still unknown. In this study, we investigated the SphK2 expression in tumoral tissue and the matched normal mucosae using quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemistry. We also evaluated the impact of SphK2 knockdown on CRC cell proliferation and metastasis in vitro. SphK2 was significantly upregulated in CRC tissue as compared to the matched normal mucosae, and significant overexpression was found in the LoVo CRC cell line. SphK2 depletion by specific small interfering RNA (siRNA) in the CRC cell line was found to affect cell proliferation and cell migration. Our data suggest that the pathogenesis of CRC maybe mediated by SphK2, and SphK2 could represent a selective target for the molecularly targeted treatments of CRC. PMID- 26733172 TI - Number of negative lymph nodes as a prognostic factor for ypN0-N1 breast cancer patients undergoing neoadjuvant chemotherapy. AB - Some of node-positive patients could have a pathologically complete response in terms of lymph nodes. For these patients, the number of negative lymph nodes (NLNs) may be higher than that in the same-stage patients who initially received mastectomy. After neoadjuvant chemotherapy (NAC), the following treatment especially the postmastectomy radiotherapy (PMRT) is controversial for ypN1 (with one to three positive lymph nodes after NAC) patients. A total of 289 patients who received NAC from 2006 to 2009 were included in the investigation. The prognostic value of the number of NLNs on these patients was analyzed. Besides, we analyzed if the number of NLNs would give some indications on PMRT in ypN1 patients. The follow-up of all the patients began the first chemotherapy on 15 March 2015. The 5-year disease-free survival (DFS) and overall survival (OS) rates were determined as 67.2 and 81.1 %, respectively. The number of NLNs was associated with primary stage (p < 0.001), pathological tumor size (p < 0.05), pathological nodal stage (p < 0.001), and pathological stage after NAC (p < 0.001). The univariate and multivariate analyses revealed that the number of NLNs is an independent prognostic factor in both DFS and OS. In ypN0-N1 stage, patients with >13 NLNs had better DFS (p < 0.001) and OS (p < 0.001) than the patients with <=13 NLNs. Although the fact patients in ypN2-N3 stage with >13 NLNs had better DFS and OS than the others, there were no significant statistical difference. In the subgroup analysis, PMRT improved the OS (p < 0.05) and DFS (p < 0.05) of ypN1 patients with <=13 NLNs. The number of NLNs is a prognostic indicator in ypN0-N1 patients. Patients in ypN1 stage with less number of NLNs will benefit from PMRT. PMID- 26733173 TI - The green tea polyphenol EGCG potentiates the antiproliferative activity of sunitinib in human cancer cells. AB - Sunitinib is a promising drug for clinical applications; however, the efficacy is reduced by the feedback activation of many signaling cascades. In this study, we investigated the ability of (-)-epigallocatechin-3-gallate (EGCG) to synergize with sunitinib and inhibit insulin receptor substrate (IRS)/mitogen-activated protein kinase (MAPK) pathway activation. MCF-7, H460, and H1975 cell lines with PIK3CA mutations were treated with sunitinib or mock treated 0-24 h and then pulsed with 0-50 MUM EGCG for another 12 h; cell proliferation and vascular endothelial growth factor (VEGF) secretion were then evaluated. To analyze angiogenesis and VEGF levels in vivo, MCF-7 and H460 xenograft tumors were established. Cell growth signaling cascades were assessed via western blotting in vitro, and tumors were subjected to immunohistochemical analyses to evaluate signaling cascades in vivo. EGCG enhanced the antiproliferation and VEGF secretion-reducing effects of sunitinib in the three tested cell lines. In vivo, EGCG administration at 4 h after sunitinib treatment resulted in greater tumor shrinkage and antiangiogenesis than with sunitinib alone. We further demonstrated that sunitinib exposure induces insulin receptor substrate-1 (IRS-1) upregulation and activation of MAPK signaling. More strikingly, EGCG treatment downregulated IRS-1 levels and suppressed mitogenic effects. In vivo, immunohistochemical analyses demonstrated marked suppression of the IRS/MAPK/p-S6K1 signaling cascade by EGCG, especially after sunitinib treatment. EGCG potentially synergizes with sunitinib due to its ability to suppress the IRS/MAPK signaling induced by sunitinib. We conclude that administration of EGCG after sunitinib treatment represents a promising strategy for the treatment of cancer. PMID- 26733175 TI - FOXC2 is up-regulated in pancreatic ductal adenocarcinoma and promotes the growth and migration of cancer cells. AB - The transcriptional factor Forkhead box protein C2 (FOXC2) was recently demonstrated to be up-regulated in various cancer types. However, its expression profile and the biological functions in pancreatic cancer remain unknown. In this study, we examined the expression pattern of FOXC2 in pancreatic ductal adenocarcinoma (PDAC) tissues and investigated the functions of FOXC2 in the progression of PDAC. It was found that the expression of FOXC2 was up-regulated in PDAC samples. Forced expression of FOXC2 promoted the growth and migration of the PDAC cells, while knocking down the expression of FOXC2 inhibited the growth and migration of the PDAC cells. Moreover, FOXC2 was found to interact with beta catenin and promote cell growth by activating beta-catenin/TCF signaling. Taken together, this study demonstrated the oncogenic roles of FOXC2 in PDAC, and FOXC2 might be a therapeutic target for PDAC. PMID- 26733174 TI - Predictable factors for lymph node metastasis in early gastric cancer analysis of clinicopathologic factors and biological markers. AB - Predicting lymph node metastasis (LNM) accurately is very important to decide treatment strategies preoperatively. The aim of this study was to explore risk factors that predict the presence of LNM in early gastric cancer (EGC). A total of 230 patients with EGC who underwent curative gastrectomy with lymph adenectomy at Xinhua Hospital from January 2006 to July 2014 were retrospectively reviewed. We studied the relationship between clinicopathological factors, biological markers (p53, ki67, nm23, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), E-cadherin (E-cad), beta-catenin (b-catenin), glutathione S-transferase (GST), and topoisomerase II (Topo II)), and LNM of EGC patients by chi-square test and logistic regression analysis. Meta-analyses were further conducted to review the effects of the proteins (P53, ki67, E-cad, and b catenin) on LNM in ECG patients. LNM was detected in 42 (18.3 %) of 230 patients. Incidences of LNM was distinct in different tumor size (p = 0.044), depth of submucosal invasion (p < 0.0001), and P53 overexpression (p = 0.004). Multivariate analysis further indentified that large tumor size (>=20 mm, odds ratio (OR) = 2.168, p = 0.041), submucosa (OR = 4.000, p = 0.0005), and P53 overexpression (OR = 3.010, p = 0.022) were independent risk factors of LNM in EGC patients. The meta-analysis revealed a significantly statistical association of P53, ki67, and b-catenin with an increased risk of LNM in EGC patients (P53, OR = 1.81, p = 0.017; ki67, OR = 2.53, p = 0.0003; b-catenin, OR = 0.53, p = 0.01). Tumor size (>=20 mm), the depth of invasion (submucosa), and P53 overexpression may be helpful predictors of LNM in EGC patients. Furthermore, the results of meta-analysis revealed that P53, ki67 overexpression, and abnormal expression of b-catenin may be associated with LNM in EGC. The results need further validation in single large studies. PMID- 26733176 TI - Targeting P-glycoprotein expression and cancer cell energy metabolism: combination of metformin and 2-deoxyglucose reverses the multidrug resistance of K562/Dox cells to doxorubicin. AB - P-glycoprotein (P-gp) is one of the major obstacles to efficiency of cancer chemotherapy. Here, we investigated whether combination of metformin and 2 deoxyglucose reverses the multidrug resistance (MDR) of K562/Dox cells and tried to elucidate the possible mechanisms. The combination of metformin and 2 deoxyglucose selectively enhanced the cytotoxicity of doxorubicin against K562/Dox cells. Metformin was not a substrate of P-gp but suppressed the elevated level of P-gp in K562/Dox cells. The downregulation of P-gp may be partly attributed to the inhibition of extracellular signal-regulated kinase pathway. The addition of 2-deoxyglucose to metformin initiated a strong metabolic stress in both K562 and K562/Dox cells. Combination of metformin and 2-deoxyglucose inhibited glucose uptake and lactate production in K562 and K562/Dox cells leading to a severe depletion in ATP and a enhanced autophagy. Above all, P-gp substrate selectively aggravated this ATP depletion effect and increased cell apoptosis in K562/Dox cells. In conclusion, metformin decreases P-gp expression in K562/Dox cells via blocking phosphorylation of extracellular signal-regulated kinase. P-gp substrate increases K562/Dox cell apoptosis via aggravating ATP depletion induced by combination of metformin and 2-deoxyglucose. Our observations highlight the importance of combination of metformin and 2 deoxyglucose in reversing multidrug resistance. PMID- 26733177 TI - MiR-145 promotes TNF-alpha-induced apoptosis by facilitating the formation of RIP1-FADDcaspase-8 complex in triple-negative breast cancer. AB - Researches indicate that the dysregulation of microRNA (miRNA) is involved in tumorigenesis. Among such dysregulated miRNAs in cancer, miR-145 is reported to be downregulated in multiple cancers. In this study, we demonstrated the downregulation of miR-145 in triple-negative breast cancer (TNBC) tissues and TNBC cell lines by quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis. Furthermore, we found that the tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis was expanded by the transfection of miR-145 in MDA MB-231 which belongs to the TNBC cell lines. We then indicated that the mechanism by which miR-145 promotes the TNF-alpha-induced apoptosis is dependent on the formation of RIP1-FADD-caspase-8 complex. The cellular inhibitor of apoptosis (cIAP1), which is the inhibitor of apoptosis protein, was found to be a target of miR-145 in MDA-MB-231 cells. As a result of cIAP1 overexpression, the promotion of miR-145 on TNF-alpha-induced apoptosis was inhibited in MDA-MB-231 cells. Therefore, our results indicate that miR-145 acts as a tumor suppressor in TNBC, suggesting that the miR-145-cIAP1 axis might be a potential therapeutic target for TNBC. PMID- 26733178 TI - A novel dual-targeted ultrasound contrast agent provides improvement of gene delivery efficiency in vitro. AB - Ultrasound-targeted microbubble destruction (UTMD) has become a novel gene/drug delivery method in cancer therapeutic application. However, the gene transfection efficiency mediated by UTMD is still unsatisfactory. Here, we introduced iRGD/CCR2 dual-targeted cationic microbubbles (MBiRGD/CCR2) which was modified with PEI-600 and coated with iRGD peptides and anti-CCR-2 antibodies. It showed that MBiRGD/CCR2 had a 25.83 +/- 1.57 mV surface zeta potential and good stability. The experiments in vitro showed MBiRGD/CCR2 had higher binding efficiency with both bEnd.3 cells and MCF-7 cells than that of iRGD or CCR2 single-targeted cationic microbubbles (MBiRGD or MBCCR2) (P < 0.05 for both). Agarose gel electrophoresis assay showed that MBiRGD/CCR2 can effectively load pGPU6/GFP/Neo-shAKT2 plasmid DNA. Compared with the plain MBs (MBcontrol) or single-targeted cationic MBs including MBiRGD and MBCCR2 (P < 0.05 for all), the dual-targeted cationic MBiRGD/CCR2 groups had higher gene transfection efficiency under US exposure. It showed that the dual-targeted cationic MBiRGD/CCR2 has a potential value to be used as an ultrasound imaging probe for ultrasound image guided tumor gene therapy. PMID- 26733179 TI - Upregulation of p-Smad2 contributes to FAT10-induced oncogenic activities in glioma. AB - The human leukocyte antigen f-associated transcript 10 (FAT10) has a similar structure and function with ubiquitin, which efficiently mediate proteasome degradation in an ubiquitin-independent manner. FAT10 expression is upregulated in many tumor tissues and plays a vital role in cell cycle regulation and tumor genesis. However, its role in glioma has not been illuminated. The aim of this study was to evaluate the prognostic value of FAT10 and investigate its functional roles in glioma. The expression of FAT10 in glioma patient samples was examined using quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry methods. Glioma cell lines with either FAT10 overexpression or knockdown were created. The effect of FAT10 on glioma cell migration and invasion was investigated using these cells. In the present study, we had shown that FAT10 was elevated significantly in glioma samples and correlated with tumor pathological grade. FAT10 high expression glioma is associated with a poor clinical prognosis. Overexpression of FAT10 promoted proliferation, invasion, migration, and sphere formation of glioma cells, whereas downregulation of FAT10 had an opposite effect. Overexpression of FAT10 also promoted the growth of glioma cells in vivo. Moreover, FAT10 enhanced the phosphorylation of Smad2, which contributes to FAT10-induced oncogenic activities in glioma. In conclusion, these findings indicate that FAT10 is a critical regulator potential therapeutic target of glioma. PMID- 26733180 TI - The attenuation of epithelial to mesenchymal transition and induction of anoikis by gigantol in human lung cancer H460 cells. AB - Lung cancer has been the major cause of death within patients due to the high metastatic rate. One of the most essential processes of metastasis is the ability of cancer cells to resist the programmed cell death in a detached condition called anoikis. The discoveries of new natural compound that is able to sensitize anoikis in cancer cells have garnered the most interest in cancer pharmaceutical science. Gigantol, a bibenzyl compound extracted from Dendrobium draconis, has been a promising natural derived compound for cancer therapy due to several cytotoxic effects in cancer cells. This study has demonstrated for the first time that gigantol significantly decreases lung cancer cells' viability in a detached condition through anoikis and anchorage-independent assays. Western blotting analysis reveals that gigantol greatly decreases epithelial to mesenchymal transition (EMT) markers including N-cadherin, vimentin, and Slug leading to a significant suppression of protein kinase B (AKT), extracellular signal-regulated kinase (ERK), and caveolin-1 (cav-1) survival pathways during the detached condition. Therefore, gigantol could be a potential cancer therapeutic compound suggesting for further development for cancer therapy. PMID- 26733181 TI - Transcriptional profiling revealed the anti-proliferative effect of MFN2 deficiency and identified risk factors in lung adenocarcinoma. AB - Mitofusin-2 (MFN2) was initially identified as a hyperplasia suppressor in hyper proliferative vascular smooth muscle cells (VSMCs) of hypertensive rat arteries, which has also been implicated in various cancers. There exists a controversy in whether it is an oncogene or exerting anti-proliferative effect on tumor cells. Our previous cell cycle analysis and MTT assay showed that cell proliferation was inhibited in MFN2 deficient A549 human lung adenocarcinoma cells, without investigating the changes in regulatory network or addressing the underlying mechanisms. Here, we performed expression profiling in MFN2 knockdown A549 cells and found that cancer-related pathways were among the most susceptible pathways to MFN2 deficiency. Through comparison with expression profiling of a cohort consisting of 61 pairs of tumor-normal matched samples from The Cancer Genome Atlas (TCGA), we teased out the specific pathways to address the impact that MFN2 ablation had on A549 cells, as well as identified a few genes whose expression level associated with clinicopathologic parameters. In addition, transcriptional factor target enrichment analysis identified E2F as a potential transcription factor that was deregulated in response to MFN2 deficiency. Although bioinformatics analysis usually entail further verification, our study provided considerable information for future scientific inquiries in related areas as well as a paradigm for characterizing perturbation in regulatory network. PMID- 26733182 TI - Selection and characterization of resistance to the Vip3Aa20 protein from Bacillus thuringiensis in Spodoptera frugiperda. AB - BACKGROUND: Spodoptera frugiperda is one the main target pests of maize events expressing Vip3Aa20 protein from Bacillus thuringiensis (Bt) in Brazil. In this study, we selected a resistant strain of S. frugiperda on Bt maize expressing Vip3Aa20 protein and characterized the inheritance and fitness costs of the resistance. RESULTS: The resistance ratio of the Vip3Aa20-resistant strain of S. frugiperda was >3200-fold. Neonates of the Vip3Aa20-resistant strain were able to survive and emerge as fertile adults on Vip3Aa20 maize, while larvae from susceptible and heterozygous strains did not survive. The inheritance of Vip3Aa20 resistance was autosomal recessive and monogenic. Life history studies to investigate fitness cost revealed an 11% reduction in the survival rate until adult stage and a ~50% lower reproductive rate of the Vip3Aa20-resistant strain compared with susceptible and heterozygous strains. CONCLUSION: This is the first characterization of S. frugiperda resistance to Vip3Aa protein. Our results provide useful information for resistance management programs designed to prevent or delay resistance evolution to Vip3Aa proteins in S. frugiperda. (c) 2016 Society of Chemical Industry. PMID- 26733184 TI - Brewing Painkillers: A Yeast Cell Factory for the Production of Opioids from Sugar. PMID- 26733183 TI - The STAT3 pathway as a therapeutic target in head and neck cancer: Barriers and innovations. AB - Proteins of the signal transducer and activator of transcription (STAT) family mediate cellular responses to cytokines and growth factors. Aberrant regulation of the STAT3 oncogene contributes to tumor formation and progression in many cancers, including head and neck squamous cell carcinoma (HNSCC), where hyperactivation of STAT3 is implicated in both treatment resistance and immune escape. There are no oncogenic gain-of-function mutations in HNSCC. Rather, aberrant STAT3 signaling is primarily driven by upstream growth factor receptors, such as Janus kinase (JAK) and epidermal growth factor receptor (EGFR). Moreover, genomic silencing of select protein tyrosine phosphatase receptors (PTPRs), tumor suppressors that dephosphorylate STAT3, may lead to prolonged phosphorylation and activation of STAT3. This review will summarize current knowledge of the STAT3 pathway and its contribution to HNSCC growth, survival, and resistance to standard therapies, and discuss STAT3-targeting agents in various phases of clinical development. PMID- 26733185 TI - Coping strategies used by traumatic spinal cord injury patients in Sri Lanka: a focus group study. AB - PURPOSE: Psychosocial consequences of traumatic spinal cord injury (SCI) have been well documented in Western populations, but there is no published literature on such incidence in the Sri Lankan population. The purpose of this study was to explore the psychosocial impact of SCI in a Sri Lankan population and to examine this population's coping mechanisms. METHODS: Participants were recruited purposively at the Ragama Rheumatology and Rehabilitation Hospital, the sole rehabilitation facility for SCI patients in Sri Lanka. Focus groups were conducted with 23 consenting individuals. Interview transcripts were analysed using descriptive thematic analysis. RESULTS: Four domains of life impact, three types of active coping strategies and four types of external supports were identified. Decreased ambulation and burden on family life were significant concerns for male and female participants alike. Religious practices were reported most frequently as active coping strategies, followed by positive reframing and goal-setting. Reported external supports included guided physiotherapy, informational workshops, social support and peer networks. CONCLUSION: Rehabilitation efforts for Sri Lankan SCI patients should be sensitive to psychosocial concerns in addition to physical concerns in order to help patients re-integrate into their family lives and community. Furthermore, religious practices should be respected as possible aids to rehabilitation. Implications for Rehabilitation Rehabilitative efforts should be conscientious of patients' psychosocial well-being in addition to their physical well-being. Hospital-based rehabilitative efforts for traumatic spinal cord injury patients should promote functional independence and community re-integration. Spiritual and/or religious practices should be respected as ways by which traumatic spinal cord injury patients may confront personal challenges that arise following injury. PMID- 26733187 TI - Molecular dynamics of sialic acid analogues complex with cholera toxin and DFT optimization of ethylene glycol-mediated zinc nanocluster conjugation. AB - Cholera is an infectious disease caused by cholera toxin (CT) protein of bacterium Vibrio cholerae. A sequence of sialic acid (N-acetylneuraminic acid, NeuNAc or Neu5Ac) analogues modified in its C-5 position is modelled using molecular modelling techniques and docked against the CT followed by molecular dynamics simulations. Docking results suggest better binding affinity of NeuNAc analogue towards the binding site of CT. The NeuNAc analogues interact with the active site residues GLU:11, TYR:12, HIS:13, GLY:33, LYS:34, GLU:51, GLN:56, HIE:57, ILE:58, GLN:61, TRP:88, ASN:90 and LYS:91 through intermolecular hydrogen bonding. Analogues N-glycolyl-NeuNAc, N-Pentanoyl-NeuNAc and N-Propanoyl-NeuNAc show the least XPGscore (docking score) of -9.90, -9.16, and -8.91, respectively, and glide energy of -45.99, -42.14 and -41.66 kcal/mol, respectively. Stable nature of CT-N-glycolyl-NeuNAc, CT-N-Pentanoyl-NeuNAc and CT-N-Propanoyl-NeuNAc complexes was verified through molecular dynamics simulations, each for 40 ns using the software Desmond. All the nine NeuNAc analogues show better score for drug-like properties, so could be considered as suitable candidates for drug development for cholera infection. To improve the enhanced binding mode of NeuNAc analogues towards CT, the nine NeuNAc analogues are conjugated with Zn nanoclusters through ethylene glycol (EG) as carriers. The NeuNAc analogues conjugated with EG-Zn nanoclusters show better binding energy towards CT than the unconjugated nine NeuNAc analogues. The electronic structural optimization of EG Zn nanoclusters was carried out for optimizing their performance as better delivery vehicles for NeuNAc analogues through density functional theory calculations. These sialic acid analogues may be considered as novel leads for the design of drug against cholera and the EG-Zn nanocluster may be a suitable carrier for sialic acid analogues. PMID- 26733188 TI - Improving the quality of weekend handover at Yeovil District Hospital. AB - "Handover of care is one of the most perilous procedures in medicine" (British Medical Association, Safe Handover, Safe Patients). The system in place for weekend handover at YDH was deemed disorganised, unstructured and frequently missing key pieces of information, leaving the on-call Foundation Year 1 (FY1) doctor with only vague jobs and management plans. Baseline surveys demonstrated that junior doctors felt the system was inadequate, potentially compromised patient safety and increased their stress levels. In order to improve this problem a structured weekend handover proforma was created, comparable with the "Out of hours handover record keeping standards: template" from the Royal College of Physicians. This was made readily accessible on the local intranet. Education sessions were organised for the FY1 and FY2 doctors. The impact of the newly introduced proforma was measured using feedback surveys each week from the FY1 on ward cover for six months. A further change implemented was the introduction of a Friday Ward Round proforma. The aim was to reduce the time required to review notes by the on-call doctor, to minimise avoidable weekend jobs and to improve compliance with the management plans. The results demonstrated 100% compliance with the new proformas. There were notable improvements in the presence of a plan (37.5% to 91.7%, max. 100%), a minimum of two patient identifiers (68.8% to 100%) and relevant background information (62.5% to 100%). Qualitative data showed a much higher level of satisfaction with the new system. Future plans include rolling out electronic handover to improve problems such as illegible handwriting and missing data (enable 'compulsory' fields), and also for this system to be implemented Trust-wide. PMID- 26733186 TI - The effect of a cluster randomised control trial on objectively measured sedentary time and parental reports of time spent in sedentary activities in Belgian preschoolers: the ToyBox-study. AB - BACKGROUND: In preschoolers, high levels of sedentary behaviour are associated with several adverse health outcomes. The purpose of this study is to report the effects of the ToyBox-intervention (a European 24-week cluster randomised controlled trial) on sedentary behaviour in preschoolers. METHODS: In Belgium, 859 preschoolers from 27 kindergartens (15 intervention and 12 control) wore an accelerometer to objectively measure their sedentary time and 1715 parents/caregivers completed a questionnaire to assess sedentary activities in which preschoolers participate at home. Main outcomes were objectively measured sedentary time, time spent watching TV, using the computer and time spent in quiet play. Multilevel repeated measures analyses were conducted to take clustering into account. Intention to treat analysis was used to handle missing data. RESULTS: A sample of 859 (29.5% of all contacted children) preschoolers (4.4 +/- 0.6 years, 54.4% boys) provided valid accelerometer data at either baseline or follow-up and parents of 1715 (58.9% of all contacted children) preschoolers (4.4 +/- 0.5 years, 52.5% boys) completed a questionnaire at either baseline or follow-up. No intervention effects were found on objectively and subjectively measured total sedentary time in the total sample. However, some effects on objectively and subjectively measured sedentary time were found in specific subgroups. Preschoolers from the intervention group from high SES kindergartens and preschoolers with high levels of sedentary time at baseline decreased their sedentary time, while preschoolers from the control group increased their sedentary time. Girls in the intervention group decreased their TV viewing time during weekend days (-5.83 min/day), while girls' &TV viewing in the control group increased (+4.15 min/day). In low SES kindergartens, a smaller increase for computer time during weekend days was found in preschoolers in intervention kindergartens (+6.06 min/day) than in control kindergartens (+12.49 min/day). CONCLUSION: While some small positive effects were found in some sub groups, the ToyBox-intervention had no effect on objectively and subjectively measured sedentary time in the total sample. A longer period to implement the intervention and a more active involvement of parents/caregivers might enhance intervention effects. The ToyBox-study is registered with the clinical trials registry clinicaltrials.gov, ID: NCT02116296. PMID- 26733190 TI - Gambling and problem gambling in Switzerland. AB - AIMS: To provide an overview of gambling and problem gambling in Switzerland, including historical aspects, past and current legislation and policies, treatment options and the research base. METHODS: A literature search was conducted on two databases (PubMed and PsycINFO), and official government and statistical reports selected from the official websites of four sources (Federal Office of Justice; Federal Gambling Board; Federal Office of Statistics; Swiss Lottery and Betting Board). RESULTS: After a history of banning or partial banning, Swiss gambling became regulated at the beginning of the 20th century through successive laws. The current system is characterized by important differences in the law and policies for casinos and lotteries, and contradictions in the regulation of these two areas are still under debate in order to develop new legislation. Gambling is widespread in Switzerland, and the prevalence of problem gambling in this country was comparable to that in other European countries in 2014. Most gambling treatment facilities are integrated into mental health treatment services that have out-patient programmes, and treatment for problem gambling is covered by a universal compulsory Swiss health insurance system. The availability of public funding for gambling research is still limited. CONCLUSIONS: Switzerland needs to develop a more coherent regulatory and prevention policy approach to gambling, overcoming conflicts in the current dual system of federal and cantonal regulation. Recent efforts to enhance funding for gambling research are promising, and could lead to a more systematic analysis of the efficacy of prevention and treatment programmes. PMID- 26733189 TI - Pulmonary Arterial Stiffness: Toward a New Paradigm in Pulmonary Arterial Hypertension Pathophysiology and Assessment. AB - Stiffening of the pulmonary arterial bed with the subsequent increased load on the right ventricle is a paramount feature of pulmonary hypertension (PH). The pathophysiology of vascular stiffening is a complex and self-reinforcing function of extracellular matrix remodeling, driven by recruitment of circulating inflammatory cells and their interactions with resident vascular cells, and mechanotransduction of altered hemodynamic forces throughout the ventricular vascular axis. New approaches to understanding the cell and molecular determinants of the pathophysiology combine novel biopolymer substrates, controlled flow conditions, and defined cell types to recapitulate the biomechanical environment in vitro. Simultaneously, advances are occurring to assess novel parameters of stiffness in vivo. In this comprehensive state-of-art review, we describe clinical hemodynamic markers, together with the newest translational echocardiographic and cardiac magnetic resonance imaging methods, to assess vascular stiffness and ventricular-vascular coupling. Finally, fluid tissue interactions appear to offer a novel route of investigating the mechanotransduction processes and disease progression. PMID- 26733191 TI - Body Mass and Physical Activity Uniquely Predict Change in Cognition for Aging Adults. AB - BACKGROUND: Physical activity and body mass predict cognition in the elderly. However, mixed evidence suggests that obesity is associated with poorer cognition, while also protecting against cognitive decline in older age. PURPOSE: We investigated whether body mass independently predicted cognition in older age and whether these associations changed over time. METHODS: A latent curve structural equation modeling approach was used to analyze data from a sample of aging adults (N = 8442) split into two independent subsamples, collected over 6 years. RESULTS: Lower baseline Body Mass Index (BMI) and higher physical activity independently predicted greater baseline cognition (p < 0.001). Decreases in BMI and physical activity independently predicted greater decline in the slope of cognition (p < 0.001). CONCLUSIONS: Our results support the obesity paradox in cognitive aging, with lower baseline body mass predicting better cognition, but less decline over time protecting against cognitive decline. We discuss how weight loss in the elderly may serve as a useful indicator of co-occurring cognitive decline, and we discuss implications for health care professionals. PMID- 26733192 TI - Chest pain symptom scoring can improve the quality of referrals to Rapid Access Chest Pain Clinic. AB - Typical stable angina is a clinical diagnosis based on history. The challenge for GPs in primary care is to identify those patients who are presenting with either possible or typical angina symptoms and refer onwards for specialist assessment in the local Rapid Access Chest Pain Clinic (RACPC). Our initial information gathering study suggested that referring GPs may be cautiously overdiagnosing angina in primary care, potentially resulting in avoidable or unnecessary referrals to RACPC. We sought a practical and cost effective solution to reducing avoidable referrals by assisting GPs with chest pain discrimination. We tested a change of referral form incorporating chest pain symptom scoring to see whether GP referral quality could be improved and then assessed its impact post implementation. GPs that used the chest pain symptom scoring questionnaire were more than twice as likely to correctly discriminate non-cardiac chest pain. Our post implementation study of the new referral form showed that the proportion of referrals to RACPC with diagnosis of non-cardiac chest pain reduced by almost 19%, and there was a statistically significant 30% fall in the total number of referrals to RACPC. This was likely to be driven by the deterrent effect of the novel referral form on avoidable referrals. Fewer avoidable referrals results in shorter wait times for specialist review, reduces the risk of waiting time breach, and improves RACPC efficiency. In summary, chest pain symptom scoring resulted in improved GP discrimination of chest pain, improved referral quality, fewer overall referrals to RACPC and shorter patient wait times. These benefits were achieved without using additional financial resources and without the time or capital expense of training GPs. These findings could assist GPs and Clinical Commisioning Groups to achieve cost savings by reducing avoidable secondary care referrals. PMID- 26733193 TI - Mandibular osteonecrosis following herpes zoster infection in the mandibular branch of the trigeminal nerve: a case report and literature review. AB - Herpes zoster virus (HZV) infections are caused by reactivation of the varicella zoster virus. Reactivation symptoms commonly affect the thoracolumbar trunk, and rarely affect the mandibular branches of the trigeminal nerve. When the mandibular branches are involved, lesions appear proximal to the innervation area. This condition may be associated with exfoliation of the teeth and osteonecrosis of the jawbone. We report a case of mandibular osteomyelitis after herpes zoster infection and we present a review of the literature on mandibular branch involvement of HZV-related osteonecrosis. PMID- 26733194 TI - Yeast Helicase Pif1 Unwinds RNA:DNA Hybrids with Higher Processivity than DNA:DNA Duplexes. AB - Saccharomyces cerevisiae Pif1, an SF1B helicase, has been implicated in both mitochondrial and nuclear functions. Here we have characterized the preference of Pif1 for RNA:DNA heteroduplexes in vitro by investigating several kinetic parameters associated with unwinding. We show that the preferential unwinding of RNA:DNA hybrids is due to neither specific binding nor differences in the rate of strand separation. Instead, Pif1 is capable of unwinding RNA:DNA heteroduplexes with moderately greater processivity compared with its duplex DNA:DNA counterparts. This higher processivity of Pif1 is attributed to slower dissociation from RNA:DNA hybrids. Biologically, this preferential role of the helicase may contribute to its functions at both telomeric and nontelomeric sites. PMID- 26733195 TI - Experimental Data in Support of a Direct Displacement Mechanism for Type I/II L Asparaginases. AB - Bacterial L-asparaginases play an important role in the treatment of certain types of blood cancers. We are exploring the guinea pig L-asparaginase (gpASNase1) as a potential replacement of the immunogenic bacterial enzymes. The exact mechanism used by L-asparaginases to catalyze the hydrolysis of asparagine into aspartic acid and ammonia has been recently put into question. Earlier experimental data suggested that the reaction proceeds via a covalent intermediate using a ping-pong mechanism, whereas recent computational work advocates the direct displacement of the amine by an activated water. To shed light on this controversy, we generated gpASNase1 mutants of conserved active site residues (T19A, T116A, T19A/T116A, K188M, and Y308F) suspected to play a role in hydrolysis. Using x-ray crystallography, we determined the crystal structures of the T19A, T116A, and K188M mutants soaked in asparagine. We also characterized their steady-state kinetic properties and analyzed the conversion of asparagine to aspartate using NMR. Our structures reveal bound asparagine in the active site that has unambiguously not formed a covalent intermediate. Kinetic and NMR assays detect significant residual activity for all of the mutants. Furthermore, no burst of ammonia production was observed that would indicate covalent intermediate formation and the presence of a ping-pong mechanism. Hence, despite using a variety of techniques, we were unable to obtain experimental evidence that would support the formation of a covalent intermediate. Consequently, our observations support a direct displacement rather than a ping-pong mechanism for l-asparaginases. PMID- 26733196 TI - KCNQ Potassium Channels Modulate Sensitivity of Skin Down-hair (D-hair) Mechanoreceptors. AB - M-current-mediating KCNQ (Kv7) channels play an important role in regulating the excitability of neuronal cells, as highlighted by mutations in Kcnq2 and Kcnq3 that underlie certain forms of epilepsy. In addition to their expression in brain, KCNQ2 and -3 are also found in the somatosensory system. We have now detected both KCNQ2 and KCNQ3 in a subset of dorsal root ganglia neurons that correspond to D-hair Adelta-fibers and demonstrate KCNQ3 expression in peripheral nerve endings of cutaneous D-hair follicles. Electrophysiological recordings from single D-hair afferents from Kcnq3(-/-) mice showed increased firing frequencies in response to mechanical ramp-and-hold stimuli. This effect was particularly pronounced at slow indentation velocities. Additional reduction of KCNQ2 expression further increased D-hair sensitivity. Together with previous work on the specific role of KCNQ4 in rapidly adapting skin mechanoreceptors, our results show that different KCNQ isoforms are specifically expressed in particular subsets of mechanosensory neurons and modulate their sensitivity directly in sensory nerve endings. PMID- 26733198 TI - Selective Exo-Enzymatic Labeling Detects Increased Cell Surface Sialoglycoprotein Expression upon Megakaryocytic Differentiation. AB - Selective exo-enzymatic labeling (or SEEL) uses recombinant glycosyltransferases and nucleotide-sugar analogues to allow efficient labeling of cell surface glycans. SEEL can circumvent many of the possible issues associated with metabolic labeling, including low incorporation of sugar precursors, and allows for sugars to be added selectively to different types of glycans by virtue of the inherent specificity of the glycosyltransferases. Here we compare the labeling of sialoglycoproteins in undifferentiated and differentiated human erythroleukemia cells (HEL) using SEEL using the sialyltransferases ST6Gal1 and ST3Gal1, which label N- and O-glycans, respectively. Our results show that the profile of glycoproteins detected varies between undifferentiated HEL cells and those differentiated to megakaryocytes, with a shift to more N-linked sialoglycoproteins in the differentiated cells. The efficiency of SEEL for both sialyltransferases in HEL cells was greatly increased with prior neuraminidase treatment highlighting the necessity for the presence of available acceptors with this labeling method. Following metabolic labeling or SEEL, tagged glycoproteins were enriched by immunoprecipitation and identified using mass spectrometry. The proteomic findings demonstrated that the detection of many glycoproteins is markedly improved by SEEL labeling, and that unique glycoproteins can be identified using either ST6Gal1 or ST3Gal1. Furthermore, this analysis enabled the identification of increased surface expression of several sialylated cell adhesion molecules, including the known megakaryocytic markers integrinbeta3 and CD44, upon differentiation of HEL cells to adherent megakaryocytes. PMID- 26733197 TI - Base and Nucleotide Excision Repair of Oxidatively Generated Guanine Lesions in DNA. AB - The well known biomarker of oxidative stress, 8-oxo-7,8-dihydroguanine, is more susceptible to further oxidation than the parent guanine base and can be oxidatively transformed to the genotoxic spiroiminodihydantoin (Sp) and 5 guanidinohydantoin (Gh) lesions. Incubation of 135-mer duplexes with single Sp or Gh lesions in human cell extracts yields a characteristic nucleotide excision repair (NER)-induced ladder of short dual incision oligonucleotide fragments in addition to base excision repair (BER) incision products. The ladders were not observed when NER was inhibited either by mouse monoclonal antibody (5F12) to human XPA or in XPC(-/-) fibroblast cell extracts. However, normal NER activity appeared when the XPC(-/-) cell extracts were complemented with XPC-RAD23B proteins. The Sp and Gh lesions are excellent substrates of both BER and NER. In contrast, 5-guanidino-4-nitroimidazole, a product of the oxidation of guanine in DNA by peroxynitrite, is an excellent substrate of BER only. In the case of mouse embryonic fibroblasts, BER of the Sp lesion is strongly reduced in NEIL1(-/-) relative to NEIL1(+/+) extracts. In summary, in human cell extracts, BER and NER activities co-exist and excise Gh and Sp DNA lesions, suggesting that the relative NER/BER product ratios may depend on competitive BER and NER protein binding to these lesions. PMID- 26733199 TI - HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA. AB - HIV-1 depends on host-cell-encoded factors to complete its life cycle. A comprehensive understanding of how HIV-1 manipulates host machineries during viral infection can facilitate the identification of host targets for antiviral drugs or gene therapy. The cellular protein Naf1 (HIV-1 Nef-associated factor 1) is a CRM1-dependent nucleo-cytoplasmic shuttling protein, and has been identified to regulate multiple receptor-mediated signal pathways in inflammation. The cytoplasm-located Naf1 can inhibit NF-kappaB activation through binding to A20, and the loss of Naf1 controlled NF-kappaB activation is associated with multiple autoimmune diseases. However, the effect of Naf1 on HIV-1 mRNA expression has not been characterized. In this study we found that the nucleus-located Naf1 could promote nuclear export of unspliced HIV-1 gag mRNA. We demonstrated that the association between Naf1 and CRM1 was required for this function as the inhibition or knockdown of CRM1 expression significantly impaired Naf1-promoted HIV-1 production. The mutation of Naf1 nuclear export signals (NESs) that account for CRM1 recruitment for nuclear export decreased Naf1 function. Additionally, the mutation of the nuclear localization signal (NLS) of Naf1 diminished its ability to promote HIV-1 production, demonstrating that the shuttling property of Naf1 is required for this function. Our results reveal a novel role of Naf1 in enhancing HIV-1 production, and provide a potential therapeutic target for controlling HIV-1 infection. PMID- 26733200 TI - The Transcription Factor p8 Regulates Autophagy in Response to Palmitic Acid Stress via a Mammalian Target of Rapamycin (mTOR)-independent Signaling Pathway. AB - Autophagy is an evolutionarily conserved degradative process that allows cells to maintain homoeostasis in numerous physiological situations. This process also functions as an essential protective response to endoplasmic reticulum (ER) stress, which promotes the removal and degradation of unfolded proteins. However, little is known regarding the mechanism by which autophagy is initiated and regulated in response to ER stress. In this study, different types of autophagy were identified in human gastric cancer MKN45 cells in response to the stress induced by nutrient starvation or lipotoxicity in which the regulation of these pathways is mammalian target of rapamycin (mTOR)-dependent or -independent, respectively. Interestingly, we found that p8, a stress-inducible transcription factor, was enhanced in MKN45 cells treated with palmitic acid to induce lipotoxicity. Furthermore, an increase in autophagy was observed in MKN45 cells stably overexpressing p8 using a lentivirus system, and autophagy induced by palmitic acid was blocked by p8 RNAi compared with the control. Western blotting analyses showed that autophagy was regulated by p8 or mTOR in response to the protein kinase-like endoplasmic reticulum kinase/activating transcription factor 6-mediated ER stress of lipotoxicity or the parkin-mediated mitochondrial stress of nutrient starvation, respectively. Furthermore, our results indicated that autophagy induced by palmitic acid is mTOR-independent, but this autophagy pathway was regulated by p8 via p53- and PKCalpha-mediated signaling in MKN45 cells. Our findings provide insights into the role of p8 in regulating autophagy induced by the lipotoxic effects of excess fat accumulation in cells. PMID- 26733201 TI - Histone Deacetylase 1 (HDAC1) Negatively Regulates Thermogenic Program in Brown Adipocytes via Coordinated Regulation of Histone H3 Lysine 27 (H3K27) Deacetylation and Methylation. AB - Inhibiting class I histone deacetylases (HDACs) increases energy expenditure, reduces adiposity, and improves insulin sensitivity in obese mice. However, the precise mechanism is poorly understood. Here, we demonstrate that HDAC1 is a negative regulator of the brown adipocyte thermogenic program. The Hdac1 level is lower in mouse brown fat (BAT) than white fat, is suppressed in mouse BAT during cold exposure or beta3-adrenergic stimulation, and is down-regulated during brown adipocyte differentiation. Remarkably, overexpressing Hdac1 profoundly blocks, whereas deleting Hdac1 significantly enhances, beta-adrenergic activation-induced BAT-specific gene expression in brown adipocytes. beta-Adrenergic activation in brown adipocytes results in a dissociation of HDAC1 from promoters of BAT specific genes, including uncoupling protein 1 (Ucp1) and peroxisome proliferator activated receptor gamma co-activator 1alpha (Pgc1alpha), leading to increased acetylation of histone H3 lysine 27 (H3K27), an epigenetic mark of gene activation. This is followed by dissociation of the polycomb repressive complexes, including the H3K27 methyltransferase enhancer of zeste homologue (EZH2), suppressor of zeste 12 (SUZ12), and ring finger protein 2 (RNF2) from (and concomitant recruitment of H3K27 demethylase ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) to) Ucp1 and Pgc1alpha promoters, leading to decreased H3K27 trimethylation, a histone transcriptional repression mark. Thus, HDAC1 negatively regulates the brown adipocyte thermogenic program, and inhibiting Hdac1 promotes BAT-specific gene expression through a coordinated control of increased acetylation and decreased methylation of H3K27, thereby switching the transcriptional repressive state to the active state at the promoters of Ucp1 and Pgc1alpha. Targeting HDAC1 may be beneficial in prevention and treatment of obesity by enhancing BAT thermogenesis. PMID- 26733202 TI - A Porphyromonas gingivalis Periplasmic Novel Exopeptidase, Acylpeptidyl Oligopeptidase, Releases N-Acylated Di- and Tripeptides from Oligopeptides. AB - Exopeptidases, including dipeptidyl- and tripeptidylpeptidase, are crucial for the growth of Porphyromonas gingivalis, a periodontopathic asaccharolytic bacterium that incorporates amino acids mainly as di- and tripeptides. In this study, we identified a novel exopeptidase, designated acylpeptidyl oligopeptidase (AOP), composed of 759 amino acid residues with active Ser(615) and encoded by PGN_1349 in P. gingivalis ATCC 33277. AOP is currently listed as an unassigned S9 family peptidase or prolyl oligopeptidase. Recombinant AOP did not hydrolyze a Pro-Xaa bond. In addition, although sequence similarities to human and archaea type acylaminoacyl peptidase sequences were observed, its enzymatic properties were apparently distinct from those, because AOP scarcely released an N-acyl amino acid as compared with di- and tripeptides, especially with N-terminal modification. The kcat/Km value against benzyloxycarbonyl-Val-Lys-Met-4 methycoumaryl-7-amide, the most potent substrate, was 123.3 +/- 17.3 MUm(-1) s( 1), optimal pH was 7-8.5, and the activity was decreased with increased NaCl concentrations. AOP existed predominantly in the periplasmic fraction as a monomer, whereas equilibrium between monomers and oligomers was observed with a recombinant molecule, suggesting a tendency of oligomerization mediated by the N terminal region (Met(16)-Glu(101)). Three-dimensional modeling revealed the three domain structures (residues Met(16)-Ala(126), which has no similar homologue with known structure; residues Leu(127)-Met(495) (beta-propeller domain); and residues Ala(496)-Phe(736) (alpha/beta-hydrolase domain)) and further indicated the hydrophobic S1 site of AOP in accord with its hydrophobic P1 preference. AOP orthologues are widely distributed in bacteria, archaea, and eukaryotes, suggesting its importance for processing of nutritional and/or bioactive oligopeptides. PMID- 26733203 TI - Differential Roles of Cell Death-inducing DNA Fragmentation Factor-alpha-like Effector (CIDE) Proteins in Promoting Lipid Droplet Fusion and Growth in Subpopulations of Hepatocytes. AB - Lipid droplets (LDs) are dynamic subcellular organelles whose growth is closely linked to obesity and hepatic steatosis. Cell death-inducing DNA fragmentation factor-alpha-like effector (CIDE) proteins, including Cidea, Cideb, and Cidec (also called Fsp27), play important roles in lipid metabolism. Cidea and Cidec are LD-associated proteins that promote atypical LD fusion in adipocytes. Here, we find that CIDE proteins are all localized to LD-LD contact sites (LDCSs) and promote lipid transfer, LD fusion, and growth in hepatocytes. We have identified two types of hepatocytes, one with small LDs (small LD-containing hepatocytes, SLHs) and one with large LDs (large LD-containing hepatocytes, LLHs) in the liver. Cideb is localized to LDCSs and promotes lipid exchange and LD fusion in both SLHs and LLHs, whereas Cidea and Cidec are specifically localized to the LDCSs and promote lipid exchange and LD fusion in LLHs. Cideb-deficient SLHs have reduced LD sizes and lower lipid exchange activities. Fasting dramatically induces the expression of Cidea/Cidec and increases the percentage of LLHs in the liver. The majority of the hepatocytes from the liver of obese mice are Cidea/Cidec-positive LLHs. Knocking down Cidea or Cidec significantly reduced lipid storage in the livers of obese animals. Our data reveal that CIDE proteins play differential roles in promoting LD fusion and lipid storage; Cideb promotes lipid storage under normal diet conditions, whereas Cidea and Cidec are responsible for liver steatosis under fasting and obese conditions. PMID- 26733205 TI - Plant sterols, cholesterol precursors and oxysterols: Minute concentrations-Major physiological effects. AB - Non-cholesterol sterols are present in our body at very low concentrations as compared to cholesterol. Small changes in the structure of sterol molecules confer them highly distinct biological activities. The best-known example are steroid hormones derived from cholesterol. During the past decade, our knowledge of also other biomolecules related to or derived from cholesterol, particularly plant sterols, biosynthetic precursors of cholesterol, and oxysterols, has expanded rapidly. In this review article we recapitulate the latest insights into the properties and physiological activities of these non-cholesterol sterols, as well as their importance in disease processes and potential as diagnostic biomarkers. PMID- 26733204 TI - Interleukin-17A Promotes Aortic Endothelial Cell Activation via Transcriptionally and Post-translationally Activating p38 Mitogen-activated Protein Kinase (MAPK) Pathway. AB - Interleukin-17 (IL-17)-secreting T helper 17 cells were recently identified as a CD4(+) T helper subset and implicated in various inflammatory and autoimmune diseases. The issues of whether and by what mechanism hyperlipidemic stress induces IL-17A to activate aortic endothelial cells (ECs) and enhance monocyte adhesion remained largely unknown. Using biochemical, immunological, microarray, experimental data mining analysis, and pathological approaches focused on primary human and mouse aortic ECs (HAECs and MAECs) and our newly generated apolipoprotein E (ApoE)(-/-)/IL-17A(-/-) mice, we report the following new findings. 1) The hyperlipidemia stimulus oxidized low density lipoprotein up regulated IL-17 receptor(s) in HAECs and MAECs. 2) IL-17A activated HAECs and increased human monocyte adhesion in vitro. 3) A deficiency of IL-17A reduced leukocyte adhesion to endothelium in vivo. 3) IL-17A activated HAECs and MAECs via up-regulation of proinflammatory cytokines IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), chemokine CXC motif ligand 1 (CXCL1), and CXCL2. 4) IL-17A activated ECs specifically via the p38 mitogen-activated protein kinases (MAPK) pathway; the inhibition of p38 MAPK in ECs attenuated IL-17A mediated activation by ameliorating the expression of the aforementioned proinflammatory cytokines, chemokines, and EC adhesion molecules including intercellular adhesion molecule 1. Taken together, our results demonstrate for the first time that IL-17A activates aortic ECs specifically via p38 MAPK pathway. PMID- 26733206 TI - VIP treatment prevents embryo resorption by modulating efferocytosis and activation profile of maternal macrophages in the CBAxDBA resorption prone model. AB - Successful embryo implantation occurs followed by a local pro-inflammatory response subsequently shifted toward a tolerogenic one. VIP (vasoactive intestinal peptide) has embryotrofic, anti-inflammatory and tolerogenic effects. In this sense, we investigated whether the in vivo treatment with VIP contributes to an immunosuppressant local microenvironment associated with an improved pregnancy outcome in the CBA/J * DBA/2 resorption prone model. Pregnancy induced the expression of VIP, VPAC1 and VPAC2 in the uterus from CBA/J * DBA/2 mating females on day 8.5 of gestation compared with non-pregnant mice. VIP treatment (2 nmol/mouse i.p.) on day 6.5 significantly increased the number of viable implantation sites and improved the asymmetric distribution of implanted embryos. This effect was accompanied by a decrease in RORgammat and an increase in TGF beta and PPARgamma expression at the implantation sites. Moreover, VIP modulated the maternal peritoneal macrophages efferocytosis ability, tested using latex beads-FITC or apoptotic thymocytes, displaying an increased frequency of IL-10 producer F4/80 cells while did not modulate TNF-alpha and IL-12 secretion. The present data suggest that VIP treatment increases the number of viable embryos associated with an increase in the efferocytic ability of maternal macrophages which is related to an immunosuppressant microenvironment. PMID- 26733210 TI - Do Therapists Google Their Patients? A Survey Among Psychotherapists. AB - BACKGROUND: The increasing use of the Internet and its array of social networks brings new ways for psychotherapists to find out information about their patients, often referred to as patient-targeted googling (PTG). However, this topic has been subject to little empirical research; there has been hardly any attention given to it in Germany and the rest of Europe and it has not been included in ethical guidelines for psychotherapy despite the complex ethical issues it raises. OBJECTIVE: This study explored German psychotherapists' behavior and experiences related to PTG, investigated how these vary with sociodemographic factors and therapeutic background, and explored the circumstances in which psychotherapists considered PTG to be appropriate or not. METHODS: A total of 207 psychotherapists responded to a newly developed questionnaire that assessed their experience of and views on PTG. The study sample was a nonrepresentative convenience sample recruited online via several German-speaking professional therapy platforms. RESULTS: Most therapists (84.5%, 174/207) stated that they had not actively considered the topic of PTG. However, 39.6% (82/207) said that they had already looked for patient information online (eg, when they suspected a patient may have been lying) and 39.3% (81/207) knew colleagues or supervisors who had done so. Only 2.4% (5/207) of therapists had come across PTG during their education and training. CONCLUSIONS: It is essential to provide PTG as a part of therapists' education and training. Furthermore, the complex problems concerning PTG should be introduced into codes of ethics to provide explicit guidance for psychotherapists in practice. This report provides initial suggestions to open up debate on this topic. PMID- 26733211 TI - Suppression of displacement detection in the presence and absence of eye movements: a neuro-computational perspective. AB - Understanding the subjective experience of a visually stable world during eye movements has been an important research topic for many years. Various studies were conducted to reveal fundamental mechanisms of this phenomenon. For example, in the paradigm saccadic suppression of displacement (SSD), it has been observed that a small displacement of a saccade target could not easily be reported if this displacement took place during a saccade. New results from Zimmermann et al. (J Neurophysiol 112(12):3066-3076, 2014) show that the effect of being oblivious to small displacements occurs not only during saccades, but also if a mask is introduced while the target is displaced. We address the question of how neurons in the parietal cortex may be connected to each other to account for the SSD effect in experiments involving a saccade and equally well in the absence of an eye movement while perception is disrupted by a mask. PMID- 26733209 TI - A Synthesis of Reading and Spelling Interventions and Their Effects on Spelling Outcomes for Students With Learning Disabilities. AB - Spelling is one of the most challenging areas for students with learning disabilities (LD), and improving spelling outcomes for these students is of high importance. In this synthesis, we examined the effects of spelling and reading interventions on spelling outcomes for students with LD in Grades K through 12. A systematic search of peer-reviewed literature published between 2004 and 2014 was conducted using electronic databases and hand searches of relevant journals. To be eligible for inclusion, studies had to meet the following criteria: (a) Participants were identified with LD and were in Grades K through 12, (b) designs were either treatment/comparison or single case, (c) a reading or spelling intervention was implemented, (d) at least one spelling outcome was measured, and (e) instruction was in English. Ten studies met criteria for inclusion in the synthesis, and effectiveness ranged from ineffective to highly effective. Findings demonstrated that spelling outcomes for taught words were improved for students with LD with the use of explicit instruction or self-correction strategies. PMID- 26733207 TI - Global Epitranscriptomics Profiling of RNA Post-Transcriptional Modifications as an Effective Tool for Investigating the Epitranscriptomics of Stress Response. AB - The simultaneous detection of all the post-transcriptional modifications (PTMs) that decorate cellular RNA can provide comprehensive information on the effects of changing environmental conditions on the entire epitranscriptome. To capture this type of information, we performed the analysis of ribonucleotide mixtures produced by hydrolysis of total RNA extracts from S. cerevisiae that was grown under hyperosmotic and heat shock conditions. Their global PTM profiles clearly indicated that the cellular responses to these types of stresses involved profound changes in the production of specific PTMs. The observed changes involved not only up-/down-regulation of typical PTMs, but also the outright induction of new ones that were absent under normal conditions, or the elimination of others that were normally present. Pointing toward the broad involvement of different classes of RNAs, many of the newly observed PTMs differed from those engaged in the known tRNA-based mechanism of translational recoding, which is induced by oxidative stress. Some of the expression effects were stress-specific, whereas others were not, thus suggesting that RNA PTMs may perform multifaceted activities in stress response, which are subjected to distinctive regulatory pathways. To explore their signaling networks, we implemented a strategy based on the systematic deletion of genes that connect established response genes with PTM biogenetic enzymes in a putative interactomic map. The results clearly identified PTMs that were under direct HOG control, a well-known protein kinase pathway involved in stress response in eukaryotes. Activation of this signaling pathway has been shown to result in the stabilization of numerous mRNAs and the induction of selected lncRNAs involved in chromatin remodeling. The fact that PTMs are capable of altering the activity of the parent RNAs suggest their possible participation in feedback mechanisms aimed at modulating the regulatory functions of such RNAs. This tantalizing hypothesis will be the object of future studies. PMID- 26733212 TI - Pituitary apoplexy: considerations on a single center experience and review of the literature. AB - PURPOSE: To present a single-center experience on pituitary tumor apoplexy and a review of literature focusing on predisposing and precipitating factors. METHODS: Clinical presentation of our series of cases. Contemporary published literature is also reviewed. RESULTS: The definition of this syndrome has not been consistent although now the majority of authors agree to definite it as an acute condition caused by hemorrhage or infarction of a pre-existing pituitary adenoma. Different predisposing and precipitating factors have been described in literature; among these antithrombotic and anticoagulant drugs, seem to play relevant roles. The clinical cases observed in our clinic confirm these data and suggest a probable association between elderly patients taking anticoagulant therapy and pituitary apoplexy adenoma. CONCLUSION: Pituitary tumor apoplexy remains a challenging disease in relation to difficulties in correct diagnosis and thus in appropriate treatment. Antithrombotic/anticoagulant therapy may have an important role as precipitating factor. When a pituitary disorder is known, great care should be taken in the prescription of anticoagulant therapy. PMID- 26733213 TI - How to define hypogonadism? Results from a population of men consulting for sexual dysfunction. AB - PURPOSE: The thresholds for testost erone (T) and the symptoms required for defining late onset hypogonadism (LOH) are under debate. The aims of the study are: (1) to verify the association between total and calculated free T (cfT) and sexual symptoms and (2) to identify thresholds for total and calculated free T to discriminate symptomatic from asymptomatic men. METHODS: A consecutive series of 4890 men attending the outpatient clinic for sexual dysfunction was retrospectively studied. Biochemical parameters were collected. The relationships between symptoms and total or calculated free T were evaluated as LOESS curves. RESULTS: Severe impairment in morning erections, low libido and ED were reported by 14.6, 2.7 and 60.2 %, respectively. Simultaneous presence of severe ED and impaired morning erections or low desire was reported by 12.7 and 1.9 %, respectively. Severely reduced desire and morning erections were complained of by 1.0 %. The simultaneous presence of the three severe sexual symptoms was reported by 0.8 %. Receiver operating characteristic (ROC) curve analysis showed that the highest accuracy for total T and cfT in detecting subjects with two symptoms was observed for reduced morning erections and desire (area under the ROC curve [AUC] = 0.670 +/- 0.04 and 0.747 +/- 0.04, for total T and cfT, respectively, both p < 0.0001). The addition of the third symptom, ED, further improved the accuracy (AUC = 0.681 +/- 0.05 and 0.784 +/- 0.04, for total T and cfT, respectively, both p < 0.0001). The assessment of the Youden index showed that the best thresholds for detecting men with androgen deficiency-related symptoms are 10.4 nmol/L for total T and ranges 225-260 pmol/L for cfT. CONCLUSIONS: The simultaneous presence of reduced morning erections and desire is the cluster of symptoms that, along with total T < 10.4 nmol/L or cfT <225 pmol/L, defines LOH in a specific, evidence-based manner. PMID- 26733214 TI - The Development of an HIV Training Program for Nurse Practitioners. AB - Responding to a national need for a new workforce of HIV care providers as the first generation of providers decrease their practices or retire, the Duke University School of Nursing, with funding from the Health Resources and Services Administration, developed and implemented a program to train nurse practitioners (NP) to assume the full spectrum of primary care services needed by people living with HIV infection and various co-morbidities. The 12-credit program includes course work in HIV-related epidemiology; pathogenesis; psychosocial, political, ethical, and legal issues; and pharmacology and clinical management. Students complete 392 hours of HIV-specific clinical practice in addition to clinical hours required of all NP students. The program is the only distance-based program of its kind in the United States. Online didactic instruction is complemented by campus-based sessions with interprofessional faculty. We describe the 5 overarching goals that frame the program, and challenges and progress toward achieving those goals. PMID- 26733215 TI - Sub-monolayer film growth of a volatile lanthanide complex on metallic surfaces. AB - We deposited a volatile lanthanide complex, tris(2,2,6,6-tetramethyl-3,5 heptanedionato)terbium(III), onto metal surfaces of Cu(111), Ag(111) and Au(111) in vacuum and observed well-ordered sub-monolayer films with low temperature (5 K) scanning tunneling microscopy. The films show a distorted three-fold symmetry with a commensurate structure. Scanning tunneling spectroscopy reveals molecular orbitals delocalized on the ligands of the molecule. Our results imply that this complex can be transferred onto the metal substrates without molecular decomposition or contamination of the surface. This new rare-earth-based class of molecules broadens the choice of molecular magnets to study with scanning tunneling microscopy. PMID- 26733216 TI - NuSAP modulates the dynamics of kinetochore microtubules by attenuating MCAK depolymerisation activity. AB - Nucleolar and spindle-associated protein (NuSAP) is a microtubule-associated protein that functions as a microtubule stabiliser. Depletion of NuSAP leads to severe mitotic defects, however the mechanism by which NuSAP regulates mitosis remains elusive. In this study, we identify the microtubule depolymeriser, mitotic centromere-associated kinesin (MCAK), as a novel binding partner of NuSAP. We show that NuSAP regulates the dynamics and depolymerisation activity of MCAK. Phosphorylation of MCAK by Aurora B kinase, a component of the chromosomal passenger complex, significantly enhances the interaction of NuSAP with MCAK and modulates the effects of NuSAP on the depolymerisation activity of MCAK. Our results reveal an underlying mechanism by which NuSAP controls kinetochore microtubule dynamics spatially and temporally by modulating the depolymerisation function of MCAK in an Aurora B kinase-dependent manner. Hence, this study provides new insights into the function of NuSAP in spindle formation during mitosis. PMID- 26733217 TI - Reappraising the effects of artemisinin on the ATPase activity of PfATP6 and SERCA1a E255L expressed in Xenopus laevis oocytes. PMID- 26733218 TI - Motoring toward pre-60S-ribosome export. PMID- 26733219 TI - The mystery of the fusion pore. PMID- 26733221 TI - Corrigendum: Structural characterization of human heparanase reveals insights into substrate recognition. PMID- 26733220 TI - Ribosome-associated protein quality control. AB - Protein synthesis by the ribosome can fail for numerous reasons including faulty mRNA, insufficient availability of charged tRNAs and genetic errors. All organisms have evolved mechanisms to recognize stalled ribosomes and initiate pathways for recycling, quality control and stress signaling. Here we review the discovery and molecular dissection of the eukaryotic ribosome-associated quality control pathway for degradation of nascent polypeptides arising from interrupted translation. PMID- 26733222 TI - Zoonotic Transmission of Waterborne Disease: A Mathematical Model. AB - Waterborne parasites that infect both humans and animals are common causes of diarrhoeal illness, but the relative importance of transmission between humans and animals and vice versa remains poorly understood. Transmission of infection from animals to humans via environmental reservoirs, such as water sources, has attracted attention as a potential source of endemic and epidemic infections, but existing mathematical models of waterborne disease transmission have limitations for studying this phenomenon, as they only consider contamination of environmental reservoirs by humans. This paper develops a mathematical model that represents the transmission of waterborne parasites within and between both animal and human populations. It also improves upon existing models by including animal contamination of water sources explicitly. Linear stability analysis and simulation results, using realistic parameter values to describe Giardia transmission in rural Australia, show that endemic infection of an animal host with zoonotic protozoa can result in endemic infection in human hosts, even in the absence of person-to-person transmission. These results imply that zoonotic transmission via environmental reservoirs is important. PMID- 26733223 TI - Objective pulsatile tinnitus. AB - Tinnitus is the usually unwanted perception of sound, in most cases there is no genuine physical source of sound. Less than 10% of tinnitus patients suffer from pulsatile tinnitus. Objective Pulsatile tinnitus can also be the first indication of dural arteriovenous fistula, so examination for such vascular origin must be performed. PMID- 26733224 TI - Cytotoxicity of an unprecedented brominated oleanolide and a new furoceramide from the Cameroonian spice, Echinops giganteus. AB - A preliminary study on Echinops giganteus (Asteraceae) showed that the methanolic extract has interesting cytotoxicities against a panel of cancer cell lines. From this extract, a lignan, a flavonoid and a polyacetylenic thiophene identified were three times less cytotoxic than the extract. In the search of the metabolites responsible for the bioactivity, a new harvested E. giganteus was subjected to a phytochemical study using chromatographic methods. In the course of the work, two new compounds: a brominated oleanolide (1) and a tetrahydrofurano-ceramide (2) were obtained along with beta-amyrin acetate (3), 2 (penta-1,3-diynyl)-5-(4-hydroxybut-1-ynyl)-thiophene (4), 2-(penta-1,3-diynyl)-5 (3,4-dihydroxybut-1-ynyl)-thiophene (5) and 4-hydroxy-2,6-di-(3',4' dimethoxyphenyl)-3,7-dioxabicyclo-(3.3.0)octane (6). Their structures were determined on the basis of NMR spectroscopy and mass spectrometry data in conjunction with those reported in the literature. The cytotoxicity of 1, 2 and 5 was evaluated by employing resazurin assay against a panel of cancer cell lines with IC50 values in range 6.12 +/- 0.46-46.96 +/- 3.61 MUM. PMID- 26733225 TI - The vulnerability of thalamocortical circuitry to hypoxic-ischemic injury in a mouse model of periventricular leukomalacia. AB - BACKGROUND: Periventricular leukomalacia (PVL) is the leading cause of neurological disabilities including motor and cognitive deficits in premature infants. Periventricular leukomalacia is characterized by damage to the white matter in the immature brain, but the mechanisms by which damage to immature white matter results in widespread deficits of cognitive and motor function are unclear. The thalamocortical system is crucial for human consciousness and cognitive functions, and impaired development of the cortico-thalamic projections in the neonatal period is implicated to contribute importantly to abnormalities of cognitive function in children with PVL. RESULTS: In this study, using a mouse model of PVL, we sought to test the hypothesis that PVL-like injury affects the different components of the thalamocortical circuitry that can be defined by vesicular glutamate transporters 1 and 2 (vGluT1 and vGluT2), both of which are required for glutamatergic synaptic transmission in the central nervous system. We combined immunocytochemistry and immuno-electron microscopy to investigate changes in cortico-thalamic synapses which were specifically identified by vGluT1 immunolabeling. We found that a drastic reduction in the density of vGluT1 labeled profiles in the somatosensory thalamus, with a reduction of 72-74 % in ventroposterior (VP) nucleus and a reduction of 42-82 % in thalamic reticular nucleus (RTN) in the ipsilateral side of PVL mice. We further examined these terminals at the electron microscopic level and revealed onefold-twofold decrease in the sizes of vGluT1 labeled corticothalamic terminals in VP and RTN. The present study provides anatomical and ultrastructural evidence to elucidate the cellular mechanisms underlying alteration of thalamic circuitry in a mouse model of PVL, and reveals that PVL-like injury has a direct impact on the corticothalamic projection system. CONCLUSIONS: Our findings provide the first set of evidence showing that the thalamocortical circuitry is affected and vulnerable in PVL mice, supporting a working model in which vGluT1 defined corticothalamic synapses are altered in PVL mice, and vGluT2 defined thalamocortical synapses are associated with such changes, leading to the compromised thalamocortical circuitry in the PVL mice. Our study demonstrates that the thalamocortical circuitry is highly vulnerable to hypoxia-ischemia in the PVL model, thus identifying a novel target site in PVL pathology. PMID- 26733226 TI - beta-Carotene Induces Apoptosis in Human Esophageal Squamous Cell Carcinoma Cell Lines via the Cav-1/AKT/NF-kappaB Signaling Pathway. AB - beta-carotene, a type of terpenoid, has many metabolic and physiological functions. In particular, beta-carotene has an antitumor effect. However, the efficacy of beta-carotene against esophageal squamous cell carcinoma (ESCC) remains unclear. In our study, beta-carotene inhibited the growth of ESCC cells and downregulated expression of the Caveolin-1 (Cav-1) protein. Cav-1 protein was expressed only in ESCC cells, not in Het-1A cells. Moreover, beta-carotene triggered apoptosis, induced cell cycle G0/G1 phase arrest, and inhibited cell migration. To explore the mechanism involved in these processes, we further examined the effect of beta-carotene on the Cav-1-mediated AKT/NF-kappaB pathway. The results showed that the level of AKT and NF-kappaB phosphorylation was dramatically inhibited, which led to an increase in the Bax/Bcl-2 ratio. Correspondingly, the activity of Caspase-3 was also enhanced. These data suggest that beta-carotene has an antiproliferative role in ESCC cells and may be a promising chemotherapeutic agent for use against ESCC cells. PMID- 26733227 TI - The use of mechanical ventilation in patients with idiopathic pulmonary fibrosis in the United States: A nationwide retrospective cohort analysis. AB - OBJECTIVE: To investigate the mortality of patients with Idiopathic Pulmonary Fibrosis (IPF) who undergo mechanical ventilation (MV) and non-invasive mechanical ventilation (NIMV) in the United States. METHODS: We performed a retrospective cohort study using data from the Nationwide Inpatient Sample, isolating patients with a diagnosis of IPF who underwent MV and NIMV between 2006 and 2012. RESULTS: We analyzed 55,208,382 hospitalizations and identified 17,770 patients with IPF, of whom 1703 received MV and 778 received NIMV. Those receiving MV had higher mortality (51.6 vs. 30.9%, p < 0.0001), were younger (66.3 years, SD 12.8 vs. 70.2 years, SD 12.9) and had longer hospital stays (13.3 days, IQR 16 vs. 6.5 days, IQR 7, p < 0.0001), compared to those receiving NIMV. The mortality of IPF patients treated with MV decreased from 58.4% in 2006 to 49.3% in 2012 (p = 0.03). There were 149 (8.7%) patients in the mechanical ventilation group who were also receiving home oxygen therapy. They experienced an overall mortality of 48.1%, which was not significantly different than patients who did not rely on home oxygen (p = 0.35). CONCLUSIONS: In a large national cohort, the in-hospital mortality of patients with IPF who are mechanically ventilated is approximately 50%. PMID- 26733228 TI - The diagnosis of COPD in primary care; gender differences and the role of spirometry. AB - BACKGROUND: Females with exacerbations of Chronic Obstructive Pulmonary Disease now account for one half of all hospital admissions for that condition and rates have been increasing over the last few decades. Differences in presentations of disease between genders have been shown in several conditions and this study explores whether there are inter gender biases in probable diagnoses in those suspected to have COPD. METHODS: 445 individuals with a provisional diagnosis by their General Practitioner of "suspected COPD" or "definite COPD" were referred to a community Respiratory Assessment unit (CRAU) for tests including spirometry. Gender, demographics, respiratory symptoms and respiratory medical history were recorded. The provisional diagnoses were compared with the final diagnosis made after spirometry and respiratory specialist nurse review and the provisional diagnosis was either confirmed as correct or refuted as unlikely. RESULTS: Significantly more men (87.5%) had their diagnosis of "definite COPD" confirmed compared to 73.9% of women (p = 0.021). When the GP suggested a provisional diagnosis of "suspected COPD" (n = 265) at referral, this was confirmed in 60.9% of men and only 43.2% of women (p = 0.004). There was a different symptom pattern between genders with women being more likely to report allergies, symptoms starting earlier in life, and being less likely than men to report breathlessness as the main symptom. CONCLUSIONS: These results may suggest a difference between genders in some of the clinical features of COPD and a difference in likelihood of a GPs provisional diagnosis of COPD being correct. The study reiterates the absolute importance of spirometry in the diagnosis of COPD. PMID- 26733229 TI - Aberrant small airways function relates to asthma severity in young children. AB - BACKGROUND: Frequency dependence of resistance (R5-20) assessed by impulse oscillometry (IOS) is suggested to be a measure of small airways. Small airways involvement during induced bronchoconstriction has been shown to reflect severity of asthma in adults. OBJECTIVE: Our aim was to evaluate if methacholine (Mch) induced changes in R5-20 are associated with the severity of exercise induced bronchoconstriction (EIB) in young children. METHODS: A total of 109 children aged 3-8 years were studied, 95 with obstructive symptoms and 14 in good health, to assess small airways function during a Mch challenge. R5-20 and other IOS resistance and reactance parameters were measured at baseline and after the Mch challenge. In a standardized exercise test, the children were grouped according to the severity of EIB expressed as the percentage increase in resistance at 5 Hz (DeltaR5) after exercise, indicating either no EIB (DeltaR5 < 40%, n = 84), moderate EIB (DeltaR5 40-80%, n = 13) and severe EIB (DeltaR5 > 80%, n = 12). RESULTS: The baseline R5-20 was not associated with the severity of EIB, but during Mch induced bronchoconstriction the change in R5-20 was significantly higher in children with severe EIB (2.61 fold increase) than in children with moderate EIB (1.48) or no EIB (1.74, p = 0.036). No significant associations were found in changes of other IOS parameters. The children with severe EIB also used more short-acting beta-agonists during the past two months than the other two groups (p < 0.001). CONCLUSION: Frequency dependence of resistance (R5-20) measured by IOS during the Mch induced bronchoconstriction and more frequent use of beta-agonists are associated with severe EIB in young children. PMID- 26733230 TI - Systemic inflammation and lung function: A longitudinal analysis. AB - BACKGROUND: Systemic inflammation is associated with impaired lung function in healthy adults as well as in patients with lung disease. The mechanism for this association is unknown and it is unclear if systemic inflammation leads to impaired lung function or if poor lung function leads to inflammation. We explored the temporal associations between blood C-reactive protein (CRP), fibrinogen, and white blood cells, and lung function in young adults. METHODS: Spirometry, plethysmography, and diffusion capacity were measured in a population based cohort at ages 32 and 38 years. High-sensitivity CRP, fibrinogen, and white blood cells were measured at the same ages. RESULTS: Higher levels of CRP and, to a lesser extent, fibrinogen were associated with lower lung volumes in cross sectional analyses at both ages 32 and 38 years. Higher CRP and fibrinogen at age 32 were associated with higher FEV1 and FEV1/FVC at age 38, but not other measures of lung function. Lower lung volumes (total lung capacity, functional residual capacity, and residual volume) but not airflow obstruction (FEV1/FVC) at age 32 were associated with higher CRP at age 38. Associations between age 32 lung function and fibrinogen at follow-up were weaker, but consistent. There were no longitudinal associations between white blood cells and lung function. CONCLUSIONS: We found no evidence that systemic inflammation causes a decline in lung function. However, lower lung volumes were associated with higher CRP and fibrinogen at follow-up indicating that pulmonary restriction may be a risk factor for systemic inflammation. The mechanism for this association remains unclear. PMID- 26733231 TI - Description of focal liver lesions with Gd-EOB-DTPA enhanced MRI. AB - Imaging procedures play a fundamental role in the therapeutic management of focal liver lesions. The goals of imaging are to detect and correctly characterize focal liver lesions. This review highlights the performances of newer, liver specific, contrast media in the diagnosis of focal liver lesions, particularly Gd EOB-DTPA (Primovist), the most frequently used liver specific contrast media. It has been shown, in different papers, that Gd-EOB-DTPA has better performances compared to either triphasic contrast enhanced computed tomography or dynamic MRI in both detection and characterization of hepatocellular carcinoma on the cirrhotic liver. Therefore liver MRI with Primovist is considered, in many centers, the "state-of-the-art" imaging examination of the liver before surgery or liver transplantation. Gd-EOB-DTPA is also useful in the differential diagnosis of benign hypervascular focal liver lesions such as adenomas or focal nodular hyperplasias. PMID- 26733233 TI - Phase transformations and indications for acoustic mode softening in Tb-Gd orthophosphate. AB - At ambient conditions the anhydrous rare earth orthophosphates assume either the xenotime (zircon) or the monazite structure, with the latter favored for the heavier rare earths and by increasing pressure. Tb0.5Gd0.5PO4 assumes the xenotime structure at ambient conditions but is at the border between the xenotime and monazite structures. Here we show that, at high pressure, Tb0.5Gd0.5PO4 does not transform directly to monazite but through an intermediate anhydrite-type structure. Axial deformation of the unit cell near the anhydrite- to monazite-type transition indicates softening of the (c1133 + c1313) combined elastic moduli. Stress response of rare-earth orthophosphate ceramics can be affected by both formation of the anhydrite-type phase and the elastic softening in the vicinity of the monazite-phase. We report the first structural data for an anhydrite-type rare earth orthophosphate. PMID- 26733234 TI - Comparison of two bupivacaine delivery methods to control postoperative pain after enucleation in dogs. AB - In Chow et al.[1] the dose of bupivacaine used in this study was incorrectly reported as 1mL/kg. The correct dose that was used was 1mL/10kg. We apologize for this error and thank the readers that brought it to our attention. PMID- 26733232 TI - AGR2 oncoprotein inhibits p38 MAPK and p53 activation through a DUSP10-mediated regulatory pathway. AB - The tumor suppressor p53 plays a key role in malignant transformation and tumor development. However, the frequency of p53 mutations within individual types of cancer is different, suggesting the existence of other mechanisms attenuating p53 tumor suppressor activity. Changes in upstream regulators of p53 such as MDM2 amplification and overexpression, expression of viral oncoproteins, estrogen receptor signaling, or changes in p53 transcriptional target genes were previously described in wild-type p53 tumors. We identified a novel pathway responsible for attenuation of p53 activity in human cancers. We demonstrate that AGR2, which is overexpressed in a variety of human cancers and provides a poor prognosis, up-regulates DUSP10 which subsequently inhibits p38 MAPK and prevents p53 activation by phosphorylation. Analysis of human breast cancers reveals that AGR2 specifically provides a poor prognosis in ER+ breast cancers with wild-type p53 but not ER- or mutant p53 breast cancers, and analysis of independent data sets show that DUSP10 levels also have prognostic significance in this specific sub-group of patients. These data not only reveal a novel pro-oncogenic signaling pathway mediating resistance to DNA damaging agents in human tumors, but also has implications for designing alternative strategies for modulation of wild-type p53 activity in cancer therapy. PMID- 26733235 TI - Reducing radiation dose by application of optimized low-energy x-ray filters to K edge imaging with a photon counting detector. AB - K-edge imaging with photon counting x-ray detectors (PCXDs) can improve image quality compared with conventional energy integrating detectors. However, low energy x-ray photons below the K-edge absorption energy of a target material do not contribute to image formation in the K-edge imaging and are likely to be completely absorbed by an object. In this study, we applied x-ray filters to the K-edge imaging with a PCXD based on cadmium zinc telluride for reducing radiation dose induced by low-energy x-ray photons. We used aluminum (Al) filters with different thicknesses as the low-energy x-ray filters and implemented the iodine K-edge imaging with an energy bin of 34-48 keV at the tube voltages of 50, 70 and 90 kVp. The effects of the low-energy x-ray filters on the K-edge imaging were investigated with respect to signal-difference-to-noise ratio (SDNR), entrance surface air kerma (ESAK) and figure of merit (FOM). The highest value of SDNR was observed in the K-edge imaging with a 2 mm Al filter, and the SDNR decreased as a function of the filter thicknesses. Compared to the K-edge imaging with a 2 mm Al filter, the ESAK was reduced by 66%, 48% and 39% in the K-edge imaging with a 12 mm Al filter for 50 kVp, 70 kVp and 90 kVp, respectively. The FOM values, which took into account the ESAK and SDNR, were maximized for 8, 6 to 8 and 4 mm Al filters at 50 kVp, 70 kVp and 90 kVp, respectively. We concluded that the use of an optimal low-energy filter thickness, which was determined by maximizing the FOM, could significantly reduce radiation dose while maintaining image quality in the K-edge imaging with the PCXD. PMID- 26733236 TI - Measurement of Electron-Ion Relaxation in Warm Dense Copper. AB - Experimental investigation of electron-ion coupling and electron heat capacity of copper in warm and dense states are presented. From time-resolved x-ray absorption spectroscopy, the temporal evolution of electron temperature is obtained for non-equilibrium warm dense copper heated by an intense femtosecond laser pulse. Electron heat capacity and electron-ion coupling are inferred from the initial electron temperature and its decrease over 10 ps. Data are compared with various theoretical models. PMID- 26733237 TI - Genome-wide identification of calcium-dependent protein kinases in soybean and analyses of their transcriptional responses to insect herbivory and drought stress. AB - Calcium-dependent protein kinases (CDPKs) are plant-specific calcium sensors that play important roles in various aspects of plant physiology. Here, we investigated phylogenic relationships, chromosomal locations, gene structures, and tissue-specific, herbivory- and drought-induced expression profiles of soybean (Glycine max) GmCDPKs. Fifty GmCDPK genes were identified, which phylogenetically grouped into 4 distinct clusters and distributed across 13 sub clusters. Individual classes of GmCDPKs harbor highly conserved mRNA splicing sites, and their exon numbers and lengths were consistent with the phylogenetic relationships, suggesting that at least 13 ancestral CDPK genes had emerged before the split of monocots and eudicots. Gene expression analysis indicated that several GmCDPKs were tissue-specific expressed. GmCDPKs' transcript levels changed after wounding, exhibited specific expression patterns after simulated Spodoptera exigua feeding or soybean aphid (Aphis glycines) herbivory, and were largely independent of the phytohormones jasmonic acid and salicylic acid. The most pronounced transcriptional responses were detected after drought and abscisic acid treatments with more than half of all GmCDPKs being upregulated, suggesting their important roles during abiotic stress responses in soybean. Our data provide an important foundation for further functional dissection of GmCDPKs, especially in the context of soybean-insect interactions and drought stress adaptation. PMID- 26733239 TI - The prevalence of structural pituitary abnormalities by MRI scanning in men presenting with isolated hypogonadotrophic hypogonadism. AB - OBJECTIVE: Hypogonadotrophic hypogonadism (HH) is commonly associated with ageing, obesity and type 2 diabetes. The indications for pituitary imaging are controversial, and current guidelines are based on small case series. DESIGN: Retrospective case series from a secondary/tertiary endocrinology referral centre. PATIENTS: All men presenting to the Edinburgh Centre for Endocrinology and Diabetes with hypogonadotrophic hypogonadism (testosterone <10 nmol/l and normal prolactin) from 2006 to 2013, in whom pituitary MRI was performed (n = 281). All HH patients referred in 2011 (n = 86) were reviewed to assess differences between those selected for pituitary MRI and those who were not scanned. RESULTS: Pituitary MRI was normal in 235 men (83.6%), with 24 microadenomas (8.5%), 5 macroadenomas (1.8%) and 1 craniopharyngioma (0.4%) identified. The remaining 16 (5.7%) comprised a range of minor pituitary abnormalities including small cysts and empty sella. All men with abnormal imaging studies had otherwise normal pituitary function. Imaging abnormalities were associated with a significantly lower age at presentation (50 vs 54 years, P = 0.02), but no differences in testosterone or gonadotrophin levels were observed. Current Endocrine Society guidelines would have prompted imaging in only three of six patients with significant pituitary pathology. CONCLUSIONS: Structural pituitary disease is more common in isolated HH than in the general population, and current guidelines do not accurately identify 'at-risk' individuals. Full anterior pituitary function testing has a low yield in patients presenting with hypogonadism. The optimal strategy for determining the need for pituitary imaging remains uncertain. PMID- 26733238 TI - Common variation in atrial fibrillation: navigating the path from genetic association to mechanism. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia with well established clinical and genetic risk components. Genome-wide association studies (GWAS) have identified 17 independent susceptibility signals for AF at 14 genomic regions, but the mechanisms through which these loci confer risk to AF remain largely undefined. This problem is not unique to AF, as the field of functional genomics, which attempts to bridge this gap from genotype to phenotype, has only uncovered the mechanisms for a handful of GWAS loci. Recent functional genomic studies have made great strides towards translating genetic discoveries to an underlying mechanism, but the large-scale application of these techniques to AF has remain limited. These advances, as well as the continued unresolved challenges for both common variation in AF and the functional genomics field in general, will be the subject of the following review. PMID- 26733241 TI - Mitochondrial respiratory inhibition by 2,3-butanedione monoxime (BDM): implications for culturing isolated mouse ventricular cardiomyocytes. AB - Experiments in isolated ventricular cardiomyocytes have greatly facilitated the study of cellular and subcellular physiology in the heart. However, the isolation and culture of high-quality adult murine ventricular cardiomyocytes can be technically challenging. In most experimental protocols, the culture of viable adult murine cardiomyocytes for prolonged time periods is achieved with the addition of the myosin II ATPase inhibitors blebbistatin and/or 2,3-butanedione monoxime (BDM). These drugs are added to increase cell viability and life span by inhibiting spontaneous cardiomyocyte contraction, thereby preventing calcium overload, cell hypercontracture, and cell death. While the addition of BDM has been reported to prolong the life span of isolated adult murine cardiomyocytes, it is also associated with several off-target effects. Here, we report a novel off-target effect, in which BDM inhibits mitochondrial respiration by acting directly on the electron transport chain to reduce cell viability. In contrast, when cells were cultured with blebbistatin alone, cells survived for longer, and no metabolic off-target effects were observed. Based on these novel observations, we recommend that culture media for isolated mouse ventricular cardiomyocytes should be supplemented with blebbistatin alone, as BDM has the potential to affect mitochondrial respiration and cell viability, effects which may impact adversely on subsequent experiments. PMID- 26733242 TI - Gestational hypoxia modulates expression of corticotropin-releasing hormone and arginine vasopressin in the paraventricular nucleus in the ovine fetus. AB - Maturation of the fetal hypothalamo-pituitary-adrenocortical (HPA) axis is critical for organ maturation necessary for the fetus to transition to the ex utero environment. Intrauterine stressors can hasten maturation of the HPA axis leading to fetal growth restriction and in sheep, premature birth. We have previously reported that high-altitude mediated, long-term-moderate gestational hypoxia (LTH) during gestation has a significant impact on the fetal HPA axis. Significant effects were observed at the level of both the anterior pituitary and adrenal cortex resulting in elevated plasma ACTH during late gestation with decreased adrenocortical expression of enzymes rate limiting for cortisol synthesis. As such, these fetuses exhibited the normal ontogenic rise in fetal plasma cortisol but an exaggerated cortisol response to acute stress. This study extended these findings to ACTH secretagogue expression in the PVN using in situ hybridization. We report that the expression of AVP but not CRH was increased in the medial parvocellular PVN (mpPVN) in the LTH fetus. This represented an increase in both AVP mRNA per neuron as well as an increase in AVP hybridizing neurons with no increase in mpPVN CRH neurons. LTH had no effect on PVN volume, area of CRH or AVP hybridization, thus LTH did not have a trophic effect on the size of the nucleus. In conclusion, there appears to be a switch from CRH to AVP as a primary ACTH secretagogue in response to LTH, supporting our previous findings of increased anterior pituitary sensitivity to AVP over CRH in the LTH fetus. PMID- 26733243 TI - Analysis of metabolic effects of menthol on WFS1-deficient mice. AB - In this study, we investigated the physiological regulation of energy metabolism in wild-type (WT) and WFS1-deficient (Wfs1KO) mice by measuring the effects of menthol treatment on the O2 consumption, CO2 production, rectal body temperature, and heat production. The basal metabolism and behavior was different between these genotypes as well as TRP family gene expressions. Wfs1KO mice had a shorter life span and weighed less than WT mice. The food and water intake of Wfs1KO mice was lower as well as the body temperature when compared to their WT littermates. Furthermore, Wfs1KO mice had higher basal O2 consumption, and CO2 and heat production than WT mice. In addition, Wfs1KO mice showed a higher response to menthol administration in comparison to WT mice. The strongest menthol effect was seen on different physiological measures 12 h after oral administration. The highest metabolic response of Wfs1KO mice was seen at the menthol dose of 10 mg/kg. Menthol increased O2 consumption, and CO2 and heat production in Wfs1KO mice when compared to their WT littermates. In addition, the expression of Trpm8 gene was increased. In conclusion, our results show that the Wfs1KO mice develop a metabolic phenotype characterized with several physiological dysfunctions. PMID- 26733245 TI - Immunofluorescence microscopy of SNAP23 in human skeletal muscle reveals colocalization with plasma membrane, lipid droplets, and mitochondria. AB - Synaptosomal-associated protein 23 (SNAP23) is a SNARE protein expressed abundantly in human skeletal muscle. Its established role is to mediate insulin stimulated docking and fusion of glucose transporter 4 (GLUT4) with the plasma membrane. Recent in vitro research has proposed that SNAP23 may also play a role in the fusion of growing lipid droplets (LDs) and the channeling of LD-derived fatty acids (FAs) into neighboring mitochondria for beta-oxidation. This study investigates the subcellular distribution of SNAP23 in human skeletal muscle using immunofluorescence microscopy to confirm that SNAP23 localization supports the three proposed metabolic roles. Percutaneous biopsies were obtained from the m. vastus lateralis of six lean, healthy males in the rested, overnight fasted state. Cryosections were stained with antibodies targeting SNAP23, the mitochondrial marker cytochrome c oxidase and the plasma membrane marker dystrophin, whereas intramuscular LDs were stained using the neutral lipid dye oil red O. SNAP23 displayed areas of intense punctate staining in the intracellular regions of all muscle fibers and continuous intense staining in peripheral regions of the cell. Quantitation of confocal microscopy images showed colocalization of SNAP23 with the plasma membrane marker dystrophin (Pearson's correlation coefficient r = 0.50 +/- 0.01). The intense punctate intracellular staining colocalized primarily with the mitochondrial marker cytochrome C oxidase (r = 0.50 +/- 0.012) and to a lesser extent with LDs (r = 0.21 +/- 0.01) visualized with oil red O. We conclude that the observed subcellular distribution of SNAP23 in human skeletal muscle supports the three aforementioned metabolic roles. PMID- 26733244 TI - Novel hepatic microRNAs upregulated in human nonalcoholic fatty liver disease. AB - MicroRNAs (miRNAs) control gene expression by reducing mRNA stability and translation. We aimed to identify alterations in human liver miRNA expression/function in nonalcoholic fatty liver disease (NAFLD). Subjects with the highest (median liver fat 30%, n = 15) and lowest (0%, n = 15) liver fat content were selected from >100 obese patients for miRNA profiling of liver biopsies on microarrays carrying probes for 1438 human miRNAs (a cross-sectional study). Target mRNAs and pathways were predicted for the miRNAs most significantly upregulated in NAFLD, their cell-type-specific expression was investigated by quantitative PCR (qPCR), and the transcriptome of immortalized human hepatocytes (IHH) transfected with the miRNA with the highest number of predicted targets, miR-576-5p, was studied. The screen revealed 42 miRNAs up- and two downregulated in the NAFLD as compared to non-NAFLD liver. The miRNAs differing most significantly between the groups, miR-103a-2*, miR-106b, miR-576 5p, miRPlus-I137*, miR-892a, miR-1282, miR-3663-5p, and miR-3924, were all upregulated in NAFLD liver. Target pathways predicted for these miRNAs included ones involved in cancer, metabolic regulation, insulin signaling, and inflammation. Consistent transcriptome changes were observed in IHH transfected with miR-576-5p, and western analysis revealed a marked reduction of the RAC1 protein belonging to several miR-576-5p target pathways. To conclude, we identified 44 miRNAs differentially expressed in NAFLD versus non-NAFLD liver, 42 of these being novel in the context of NAFLD. The study demonstrates that by applying a novel study set-up and a broad-coverage array platform one can reveal a wealth of previously undiscovered miRNA dysregulation in metabolic disease. PMID- 26733246 TI - Development and physiology of GABAergic feedback excitation in parvalbumin expressing interneurons of the mouse basolateral amygdala. AB - We have previously shown that in the basolateral amygdala (BLA), action potentials in one type of parvalbumin (PV)-expressing GABAergic interneuron can evoke a disynaptic feedback excitatory postsynaptic potential (fbEPSP) onto the same presynaptic interneuron. Here, using whole-cell recordings from PV expressing interneurons in acute brain slices we expand on this finding to show that this response is first detectable at 2-week postnatal, and is most prevalent in animals beyond 3 weeks of age (>P21). This circuit has a very high fidelity, and single action potential evoked fbEPSPs display few failures. Reconstruction of filled neurons, and electron microscopy show that interneurons that receive feedback excitation make symmetrical synapses on both the axon initial segments (AIS), as well as the soma and proximal dendrites of local pyramidal neurons, suggesting fbEPSP interneurons are morphologically distinct from the highly specialized chandelier neurons that selectively target the axon initial segment of pyramidal neurons. Single PV interneurons could trigger very large (~ 1 nA) feedback excitatory postsynaptic currents (fbEPSCs) suggesting that these neurons are heavily reciprocally connected to local glutamatergic principal cells. We conclude that in the BLA, a subpopulation of PV interneurons forms a distinct neural circuit in which a single action potential can recruit multiple pyramidal neurons to discharge near simultaneously and feed back onto the presynaptic interneuron. PMID- 26733247 TI - Overexpression of Swedish mutant APP in aged astrocytes attenuates excitatory synaptic transmission. AB - Amyloid precursor protein (APP), a type I transmembrane protein, has different aspects, namely, performs essential physiological functions and produces beta amyloid peptide (Abeta). Overexpression of neuronal APP is responsible for synaptic dysfunction. In the central nervous system, astrocytes - a major glial cell type - have an important role in the regulation of synaptic transmission. Although APP is expressed in astrocytes, it remains unclear whether astrocytic overexpression of mutant APP affects synaptic transmission. In this study, the effect of astrocytic overexpression of a mutant APP on the excitatory synaptic transmission was investigated using coculture system of the transgenic (Tg) cortical astrocytes that express the human APP695 polypeptide with the double mutation K670N + M671L found in a large Swedish family with early onset Alzheimer's disease, and wild-type hippocampal neuron. Significant secretion of Abeta 1-40 and 1-42 was observed in cultured cortical astrocytes from the Tg2576 transgenic mouse that genetically overexpresses Swedish mutant APP. Under the condition, Tg astrocytes did not affect excitatory synaptic transmission of cocultured wild-type neurons. However, aged Tg astrocytes cultured for 9 weeks elicited a significant decrease in excitatory synaptic transmission in cocultured neurons. Moreover, a reduction in the number of readily releasable synaptic vesicles accompanied a decrease in the number of excitatory synapses in neurons cocultured with aged Tg astrocytes. These observations indicate that astrocytic expression of the mutant APP is involved in the downregulation of synaptic transmission with age. PMID- 26733248 TI - The effect of current flow direction on motor hot spot allocation by transcranial magnetic stimulation. AB - The objective of this study was to investigate the significance of pulse configurations and current direction for corticospinal activation using transcranial magnetic stimulation (TMS). In 11 healthy subjects (8 female), a motor map for the motor evoked potentials (MEPs) recorded from the first dorsal interosseus (FDI), abductor digiti minimi (ADM), extensor carpi radialis, and biceps brachii (BB) muscles of the dominant side was established. Starting from a manually determined hot spot of the FDI representation, we measured MEPs at equal oriented points on an hexagonal grid, with 7 MEPs recorded at each point, using the following pulse configurations: posteriorly directed monophasic (Mo-P), anteriorly directed monophasic (Mo-A), biphasic with the more relevant second cycle oriented posteriorly (Bi-P) as well as a reversed biphasic condition (Bi A). For each pulse configuration, a hot spot was determined and a center of gravity (CoG) was calculated. We found that the factor current direction had an effect on location of the CoG-adjusted hot spot in the cranio-caudal axis but not in the latero-medial direction with anteriorly directed pulses locating the CoG more anteriorly and vice versa. In addition, the CoG for the FDI was more laterally than the cortical representations for the abductor digiti minimi (ADM) and extensor carpi radialis (ECR) which were registered as well. The results indicate that direction of the current pulse should be taken into account for determination of the motor representation of a muscle by TMS. PMID- 26733249 TI - Treatment with selectin blocking antibodies after lengthening contractions of mouse muscle blunts neutrophil accumulation but does not reduce damage. AB - P- and E-selectins are expressed on the surface of endothelial cells and may contribute to neutrophil recruitment following injurious lengthening contractions of skeletal muscle. Blunting neutrophil, but not macrophage, accumulation after lengthening contractions may provide a therapeutic benefit as neutrophils exacerbate damage to muscle fibers, while macrophages promote repair. In this study, we tested the hypothesis that P- and E-selectins contribute to neutrophil, but not macrophage, accumulation in muscles after contraction-induced injury, and that reducing neutrophil accumulation by blocking the selectins would be sufficient to reduce damage to muscle fibers. To test our hypothesis, we treated mice with antibodies to block P- and E-selectin function and assessed leukocyte accumulation and damage in muscles 2 days after lengthening contractions. Treatment with P/E-selectin blocking antibodies reduced neutrophil content by about half in muscles subjected to lengthening contractions. In spite of the reduction in neutrophil accumulation, we did not detect a decrease in damage 2 days after lengthening contractions. We conclude that P- and/or E-selectin contribute to the neutrophil accumulation associated with contraction-induced muscle damage and that only a portion of the neutrophils that typically accumulate following injurious lengthening contractions is sufficient to induce muscle fiber damage and force deficits. Thus, therapeutic interventions based on blocking the selectins or other adhesion proteins will have to reduce neutrophil numbers by more than 50% in order to provide a benefit. PMID- 26733250 TI - Effect of laparotomy on respiratory muscle activation pattern. AB - Muscular tone of the abdominal wall is important in maintaining transdiaphragmatic pressures and its loss can lead to decreased lung volumes. Patients who are status postlaparotomy are at risk of developing atelectasis. The compensatory role of respiratory muscle activity in postlaparotomy is not well studied. Normally, inspiratory muscles are active during inspiration and passive during expiration to allow for lung recoil. However, electrical activities of the inspiratory muscles continue during early expiratory phase to prevent rapid loss of lung volume. This activity is known as post-inspiratory inspiratory activity (PIIA). In this study, we hypothesized that laparotomy will elicit an increase in PIIA, which is enhanced by respiratory chemical loading. Experiments were conducted in cats under three different conditions: intact abdomen (n = 3), open abdomen (n = 10), and post abdominal closure (n = 10) during eupnea and hypercapnia (10% CO2). Electromyography (EMG) activities of the diaphragm and parasternal muscles were recorded and peak EMG amplitude, PIIA time, and area under the curve were measured. Intraesophageal pressure was also obtained. PIIA was significantly higher under open abdominal conditions in comparison to intact abdomen during eupnea. Our data indicates that PIIA is increased during open abdomen and may be an important compensatory mechanism for altered respiratory mechanics induced by laparotomy. Also, PIIA remained elevated after abdominal closure. However, under hypercapnia, PIIA was significantly higher during intact abdomen in comparison to open abdomen, which is thought to be due to respiratory muscle compensation under chemical loading. PMID- 26733252 TI - Corrigendum. PMID- 26733253 TI - Sixty seconds on . . . mindfulness. PMID- 26733251 TI - Transcriptional profiling and muscle cross-section analysis reveal signs of ischemia reperfusion injury following total knee arthroplasty with tourniquet. AB - Total knee arthroplasty (TKA) is the most common and cost-effective treatment for older adults with long-standing osteoarthritis. Projections indicate that nearly 3.5 million older adults will undergo this procedure annually by the year 2030. Thus, understanding the factors that lead to optimal outcomes is of great clinical interest. In the majority of cases, tourniquet is applied during surgery to maintain a clear surgical field, however, there is debate as to whether this intervention is completely benign. In particular, muscle atrophy is a significant factor in preventing full functional recovery following surgery, and some evidence suggests that tourniquet application and the associated ischemia reperfusion injury that results contributes to muscle atrophy. For this reason, we examined tissue level changes in muscle in TKA patients following surgery and found that there was a significant increase in cross-sectional area of muscle fibers of all types. Furthermore, to detect changes not evident at the tissue level, we performed NextSeq analysis to assess the transcriptional landscape of quadriceps muscle cells following TKA with tourniquet and found 72 genes that were significantly upregulated. A large proportion of those genes regulate cell stress pathways, suggesting that muscle cells in our cohort of older adults were capable of mounting a significant response to cell stress. Furthermore, factors related to complement were upregulated, suggesting tourniquet may play a role in priming cells to ischemia reperfusion injury. Therefore, our analysis reveals potential harms of tourniquet during TKA, thus suggesting that surgeons should consider limiting its use. PMID- 26733255 TI - Magnetic sentinel lymph node biopsy in a murine tumour model. AB - The magnetic technique for sentinel node biopsy provides a radioisotope-free alternative for staging breast cancer. It requires refinement to reduce "residual iron content" at injection sites by maximising lymphatic uptake to prevent "void artefacts" on magnetic resonance imaging (MRI), which could adversely affect clinical use. The site and timing of injection of magnetic tracer was evaluated in a murine tumour model (right hind limb) in 24 wild type mice. Right-sided intratumoural and left sided subcutaneous injection of magnetic tracer and assessment of nodal iron uptake on MRI, surgical excision and histopathological grading at time frames up to 24 hours were performed. Rapid iron uptake on MRI, smaller "void artefacts"(P<0.001) and a significant increase in iron content with time were identified in the subcutaneous injection group (r=0.937; P<0.001).Subcutaneous injection and increasing delay between tracer injection and surgery is beneficial for lymphatic iron uptake. FROM THE CLINICAL EDITOR: Sentinel lymph node biopsy (SLNB) has been the standard of care in breast cancer management for some time. Recent development has seen the introduction of magnetic tracer for SLNB. In this article, the authors investigated the refined use of magnetic tracer in determining the optimal timing of administration and the location of injection. The findings should provide more data on the future use of this new technique. PMID- 26733256 TI - Polyhydroxylated fullerenols regulate macrophage for cancer adoptive immunotherapy and greatly inhibit the tumor metastasis. AB - Adoptive immunotherapy is a highly effective approach for cancer treatment. Several potential adoptive immunotherapies have high (though reversible) toxicities with disappointing results. Polyhydroxylated fullerenols have been demonstrated as promising antitumor drugs with low toxicities. In this study, we investigate whether polyhydroxylated fullerenols (C60(OH)22 and Gd@C82(OH)22) contribute to cancer immunotherapy by regulating macrophages. Our results show that fullerenols treatment enhances mitochondrial metabolism, phagocytosis and cytokine secretion. Moreover, activated macrophages inhibit the growth of several cancer cell types. It is likely that this inhibition is dependent on an NF-kappaB mediated release of multiple cytokines. Using a lung metastasis model, we also show that autologous macrophages greatly suppress cancer cell metastasis to lung when they are activated by C60(OH)22 and Gd@C82(OH)22. More importantly, Gd@C82(OH)22 are shown to have stronger ability than C60(OH)22 to improve the macrophage function, which shed light on the rational design for nanomedicine and clinical application. FROM THE CLINICAL EDITOR: The interest in the use of immunotherapy in cancer has rekindled recently. However, many approaches have shown disappointing results. In this study, the authors investigated the effects of polyhydroxylated fullerenol nanoparticles on regulating macrophages for immunotherapy. These positive findings may point a novel way to cancer treatment. PMID- 26733257 TI - Folate-targeted nanoparticles for rheumatoid arthritis therapy. AB - Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease, affecting almost 1% of the world population. Although the cause of RA remains unknown, the complex interaction between immune mediators (cytokines and effector cells) is responsible for the joint damage that begins at the synovial membrane. Activated macrophages are critical in the pathogenesis of RA and showed specifically express a receptor for the vitamin folic acid (FA), folate receptor beta (FRbeta). This particular receptor allows internalization of FA-coupled cargo. In this review we will address the potential of nanoparticles as an effective drug delivery system for therapies that will directly target activated macrophages. Special attention will be given to stealth degree of the nanoparticles as a strategy to avoid clearance by macrophages of the mononuclear phagocytic system (MPS). This review summarizes the application of FA-target nanoparticles as drug delivery systems for RA and proposes prospective future directions. FROM THE CLINICAL EDITOR: Rheumatoid arthritis is a debilitating autoimmune disease of the joints which affects many people worldwide. Up till now, there is a lack of optimal therapy against this disease. In this review article, the authors outlined in depth the current mechanism of disease for rheumatoid arthritis and described the latest research in using folic acid targeted nanoparticles to target synovial macrophages in the fight against rheumatoid arthritis. PMID- 26733254 TI - ATNX2 is not a regulatory gene in Italian amyotrophic lateral sclerosis patients with C9ORF72 GGGGCC expansion. AB - There are indications that both familial amyotrophic lateral sclerosis (ALS) and sporadic ALS phenotype and prognosis are partly regulated by genetic and environmental factors, supporting the theory that ALS is a multifactorial disease. The aim of this article was to assess the role of ATXN2 intermediate length repeats in a large series of Italian and Sardinian ALS patients and controls carrying a pathogenetic C9ORF72 GGGGCC hexanucleotide repeat. A total of 1972 ALS cases were identified through the database of the Italian ALS Genetic consortium, a collaborative effort including 18 ALS centers throughout Italy. The study population included: (1) 276 Italian and 57 Sardinian ALS cases who carried the C9ORF72 expansion; (2) 1340 Italian and 299 Sardinian ALS cases not carrying the C9ORF72 expansion. A total of healthy 1043 controls were also assessed. Most Italian and Sardinian cases and controls were homozygous for 22/22 or 23/23 repeats or heterozygous for 22/23 repeats of the ATXN2 gene. ATXN2 intermediate length repeats alleles (>=28) were detected in 3 (0.6%) Italian ALS cases carrying the C9ORF72 expansion, in none of the Sardinian ALS cases carrying the expansion, in 60 (4.3%) Italian cases not carrying the expansion, and in 6 (2.0%) Sardinian ALS cases without C9ORF72 expansion. Intermediate length repeat alleles were found in 12 (1.5%) Italian controls and 1 (0.84%) Sardinian controls. Therefore, ALS patients with C9ORF72 expansion showed a lower frequency of ATXN2 polyQ intermediate length repeats than both controls (Italian cases, p = 0.137; Sardinian cases, p = 0.0001) and ALS patients without C9ORF72 expansion (Italian cases, p = 0.005; Sardinian cases, p = 0.178). In our large study on Italian and Sardinian ALS patients with C9ORF72 GGGGCC hexanucleotide repeat expansion, compared to age-, gender- and ethnic-matched controls, ATXN2 polyQ intermediate length does not represent a modifier of ALS risk, differently from non-C9ORF72 mutated patients. PMID- 26733258 TI - Factor H inhibits complement activation induced by liposomal and micellar drugs and the therapeutic antibody rituximab in vitro. AB - Hypersensitivity reactions to particulate drugs can partly be caused by complement activation and represent a major complication during intravenous application of nanomedicines. Several liposomal and micellar drugs and carriers, and therapeutic antibodies, were shown to activate complement and induce complement activation-related pseudoallergy (CARPA) in model animals. To explore the possible use of the natural complement inhibitor factor H (FH) against CARPA, we examined the effect of FH on complement activation induced by CARPAgenic drugs. Exogenous FH inhibited complement activation induced by the antifungal liposomal Amphotericin-B (AmBisome), the widely used solvent of anticancer drugs Cremophor EL, and the anticancer monoclonal antibody rituximab in vitro. An engineered form of FH (mini-FH) was more potent inhibitor of Ambisome-, Cremophor EL- and rituximab-induced complement activation than FH. The FH-related protein CFHR1 had no inhibitory effect. Our data suggest that FH or its derivatives may be considered in the pharmacological prevention of CARPA. FROM THE CLINICAL EDITOR: Although liposomes and micelles are already in use in the clinical setting as drug carriers, there remains the potential problem of hypersensitivity due to complement activation. In this article, the authors investigated the use of complement inhibitor factor H (FH) on complement activation and showed good efficacy. The results would therefore suggest the potential application of complement inhibitor in the future. PMID- 26733259 TI - Multi-walled nanotubes for cellular reprogramming of cancer. AB - Triple negative breast cancer is exceptionally difficult to treat due to the lack of distinguishing biomarkers for drug targeting. An alternative approach based on recent data indicates that these cells may be more susceptible to mechanical influences, such as alterations in the tumor stroma. Three dimensional collagen gels containing co-cultures of mesenchymal cells and MDA-MB-231 cancer cells were utilized to explore the effects of multi-walled nanotubes (MWNT) on cell contraction, invasion, viability, MMP-9 expression, and migration of breast cancer cells. MWNT were able to restrict each of these features for the cancer cells without impeding the associated mesenchymal cells. MWNT-collagen gels are useful tools for cellular reprogramming of cancer cells and should be considered in greater detail as a potential agent for therapeutic treatment of triple negative breast cancer. FROM THE CLINICAL EDITOR: Breast cancer is still a leading cause of death for women worldwide. One subtype of this cancer which is very aggressive is the triple negative breast cancer. The behavior of tumors may be affected by the tumor stromal environment. In this study, the authors investigated the effects of multi-walled nanotubes (MWNT) on tumor cell biology. The positive findings may point a new way in using this modality for treatment of triple-negative breast cancer in the future. PMID- 26733260 TI - Quantifying cellular mechanics and adhesion in renal tubular injury using single cell force spectroscopy. AB - Tubulointerstitial fibrosis represents the major underlying pathology of diabetic nephropathy where loss of cell-to-cell adhesion is a critical step. To date, research has predominantly focussed on the loss of cell surface molecular binding events that include altered protein ligation. In the current study, atomic force microscopy single cell force spectroscopy (AFM-SCFS) was used to quantify changes in cellular stiffness and cell adhesion in TGF-beta1 treated kidney cells of the human proximal tubule (HK2). AFM indentation of TGF-beta1 treated HK2 cells showed a significant increase (42%) in the elastic modulus (stiffness) compared to control. Fluorescence microscopy confirmed that increased cell stiffness is accompanied by reorganization of the cytoskeleton. The corresponding changes in stiffness, due to F-actin rearrangement, affected the work of detachment by changing the separation distance between two adherent cells. Overall, our novel data quantitatively demonstrate a correlation between cellular elasticity, adhesion and early morphologic/phenotypic changes associated with tubular injury. FROM THE CLINICAL EDITOR: Diabetes affects many patients worldwide. One of the long term problems is diabetic nephropathy. Here, the authors utilized atomic force microscopy single cell force spectroscopy (AFM- SCFS) to study cellular stiffness and cell adhesion after TGF1 treatment in human proximal tubule kidney cells. The findings would help further understand the overall disease mechanism in diabetic patients. PMID- 26733261 TI - Surprising lack of liposome-induced complement activation by artificial 1,3 diamidophospholipids in vitro. AB - Cardio-vascular diseases are the main cause of death, emphasizing the need to improve patient treatment and survival. One therapeutic approach is a liposome based drug carrier system specifically targeting constricted arteries. The recently discovered mechano-sensitive liposomes use hemodynamic shear-stress differences between healthy and constricted blood vessels as trigger for drug release. Liposomes are promising delivery containers but are being recognized as foreign by the immune system. Complement activation as essential factor of the recognition leads to adverse effects. Here, we tested complement activation by liposomes formulated from the artificial phospholipid Pad-PC-Pad in vitro. Surprisingly no complement activation was detected in human sera and porcine plasma. In in vivo experiments with three pigs, neither anaphylactic reactions nor other significant hemodynamic changes were observed even at comparably high liposome doses. The pilot study holds promise for an absence of complement mediated adverse effects of Pad-PC-Pad liposomes in human. FROM THE CLINICAL EDITOR: A lot of research has been done on new treatment for cardiovascular diseases. Liposome-based carrier systems have also shown promises. In this article, the authors studied the potential risks of complement activation by liposomes in in-vivo experiments. The absence of complement activation by Pad-PC Pad liposomes may indicate its use in humans. PMID- 26733262 TI - Ultrasound-responsive microbubbles for sonography-guided siRNA delivery. AB - RNA interfering is a gene therapeutic approach of great potential for cancer. However, tumor-targeted delivery of small interfering RNA (siRNA) solely based on the enhanced permeability and retention effect of nanocarriers is often insufficient. To address this challenge, siRNA encapsulated ultrasound-responsive microbubble (MB) was developed from polymeric siRNA micelles and liposomal MBs using hetero-assembling strategy. 1MHz low-frequency ultrasound exposure of the tumor site after intratumoral injection of XIAP siRNA/MBs led to enhanced permeability for much more siRNA delivery into deep tumor regions. Significant improvement of XIAP gene silencing and cleaved caspase-3 activation was achieved, resulting in good therapeutic effect on human cervical cancer xenograft model in nude mice. Moreover, real-time US monitoring of the tumor was also possible using the siRNA/MBs as a contrast agent during the therapeutic process. These results show that the multi-functional siRNA/MBs are a promising theranostic system for cancer gene therapy. PMID- 26733263 TI - Superparamagnetic iron oxide nanoparticle uptake alters M2 macrophage phenotype, iron metabolism, migration and invasion. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) have shown promise as contrast agents and nanocarriers for drug delivery. Their impact on M2-polarised macrophages has nonetheless not been well studied. Here we explored the effects of SPIONs coated with dimercaptosuccinic acid, aminopropyl silane or aminodextran in two M2 macrophage models (murine primary IL-4-activated bone marrow-derived macrophages and human M2-like differentiated THP-1 cells). All SPIONs were internalised and no cell toxicity was observed. SPION treatment produced reactive oxygen species and activated the extracellular signal-regulated kinase and AKT pathways. After 24-h SPION incubation, M2 macrophages switched their iron metabolism towards an iron-replete state. SPION treatment in both M2 macrophage models altered their M2 activation profiles, promoted IL-10 production, and stimulated protease-dependent invasion. These results highlight the need to evaluate the interactions between SPIONs and cells to take full advantage of the intrinsic properties of these nanoparticles in biological systems. FROM THE CLINICAL EDITOR: Superparamagnetic iron oxide nanoparticles (SPIONs) have been used as an MRI contrast agent in many experimental studies. The authors here investigated the effects of these nanoparticles on M2 macrophages after cellular uptake. The findings of cell activation further enhanced our current knowledge on the interaction of SPIONS with macrophages. PMID- 26733264 TI - Otoprotective properties of 6alpha-methylprednisolone-loaded nanoparticles against cisplatin: In vitro and in vivo correlation. AB - 6alpha-Methylprednisolone-loaded surfactant-free nanoparticles have been developed to palliate cisplatin ototoxicity. Nanoparticles were based on two different amphiphilic pseudo-block copolymers obtained by free radical polymerization and based on N-vinyl pyrrolidone and a methacrylic derivative of alpha-tocopheryl succinate or alpha-tocopherol. Copolymers formed spherical nanoparticles by nanoprecipitation in aqueous media that were able to encapsulate 6alpha-methylprednisolone in their inner core. The obtained nanovehicles were tested in vitro using HEI-OC1 cells and in vivo in a murine model. Unloaded nanoparticles were not able to significantly reduce the cisplatin ototoxicity. Loaded nanoparticles reduced cisplatin-ototoxicity in vitro being more active those based on the methacrylic derivative of vitamin E, due to their higher encapsulation efficiency. This formulation was able to protect hair cells in the base of the cochlea, having a positive effect in the highest frequencies tested in a murine model. A good correlation between the in vitro and the in vivo experiments was found. FROM THE CLINICAL EDITOR: Cisplatin is a commonly used chemotherapeutic agent against many cancers clinically. However, one of the significant side-effects remains ototoxicity. Here, the authors presented their data on using 6alpha-methylprednisolone-loaded nanoparticles in the reduction of ototoxicity in in-vitro and in-vivo experiments. Early promising results should enable further refinement of adopting this new approach in future experiments. PMID- 26733265 TI - Unplanned pregnancy after ultrasound-guided percutaneous microwave ablation of uterine fibroids: A follow-up study. AB - A follow-up study was performed with 169 women of childbearing age who underwent ultrasound-guided percutaneous microwave ablation (UPMWA) therapy for symptomatic uterine fibroids in the Chinese PLA General Hospital from June 2007 to December 2014. This study aimed to observe the incidence of unplanned pregnancies in these women after UPMWA treatment in order to evaluate its effect on natural conception. Ten unplanned pregnancies in nine women were occurred. Of the nine patients, six did not want the pregnancy and chose for induced abortion to end the pregnancy at an early stage. Three chose to continue with the pregnancy and gave birth to a healthy term infant delivered by cesarean section (of these three patients, two had been previously diagnosed as infertility). None of the patients had any serious obstetric complications. After UPMWA treatment for uterine fibroids, patients may conceive naturally, the impact of the procedure on fertility and pregnancy outcomes is worthy of further prospective study in larger sample. PMID- 26733266 TI - Theta and Alpha Band Modulations Reflect Error-Related Adjustments in the Auditory Condensation Task. AB - Error commission leads to adaptive adjustments in a number of brain networks that subserve goal-directed behavior, resulting in either enhanced stimulus processing or increased motor threshold depending on the nature of errors committed. Here, we studied these adjustments by analyzing post-error modulations of alpha and theta band activity in the auditory version of the two-choice condensation task, which is highly demanding for sustained attention while involves no inhibition of prepotent responses. Errors were followed by increased frontal midline theta (FMT) activity, as well as by enhanced alpha band suppression in the parietal and the left central regions; parietal alpha suppression correlated with the task performance, left central alpha suppression correlated with the post-error slowing, and FMT increase correlated with both behavioral measures. On post-error correct trials, left-central alpha band suppression started earlier before the response, and the response was followed by weaker FMT activity, as well as by enhanced alpha band suppression distributed over the entire scalp. These findings indicate that several separate neuronal networks are involved in post-error adjustments, including the midfrontal performance monitoring network, the parietal attentional network, and the sensorimotor network. Supposedly, activity within these networks is rapidly modulated after errors, resulting in optimization of their functional state on the subsequent trials, with corresponding changes in behavioral measures. PMID- 26733267 TI - Prescribing amoxicillin for babies up to 3 months of age: definitely time for change. PMID- 26733268 TI - Water oxidation by a soluble iron(III)-cyclen complex: new findings. AB - Herein, the role of iron oxide in the electrochemical water oxidation of an iron cyclen (cyclen = 1,4,7,10-tetraazacyclododecane) is considered using scanning electron microscopy, energy-dispersive spectrometry, X-ray diffraction, nuclear magnetic resonance spectroscopy, chronoamperometry, cyclic voltammetry and electrochemical impedance spectroscopy. PMID- 26733269 TI - The Anti-Factor Xa Range For Low Molecular Weight Heparin Thromboprophylaxis. AB - Low molecular weight heparins (LMWHs) are now the mainstay option in the prevention and treatment of venous thromboembolism. In some patients receiving therapeutic doses of LMWH, activity can be measured by quantifying the presence of Anti-factor Xa (AFXa) for dose adjustment. However, currently there are no guidelines for LMWH monitoring in patients on thromboprophylactic, doses, despite certain patient populations may be at risk of suboptimal dosing. This review found that while the AFXa ranges for therapeutic levels of LMWHs are relatively well defined in the literature, prophylactic ranges are much less clear, thus making it difficult to interpret current research data. From the studies published to date, we concluded that a reasonable AFXa target range for LMWH deep venous thromboses prophylaxis might be 0.2-0.5 IU/mL. PMID- 26733271 TI - Determining Good Environmental Status under the Marine Strategy Framework Directive: Case study for descriptor 8 (chemical contaminants). AB - The European Union Marine Strategy Framework Directive (MSFD) requires individual member states to develop a robust set of tools for defining eleven qualitative descriptors of Good Environmental Status (GES), such as demonstrating that "Concentrations of contaminants are at levels not giving rise to pollution effects" (GES descriptor 8). Adopting the recommendations of the ICES/OSPAR Study Group for the Integrated Monitoring of Contaminants and Biological Effects (SGIMC), we present a case study demonstrating how the proposed approach, using chemical contaminant (metals and polycyclic aromatic hydrocarbons and polychlorinated biphenyls) and biological effects (EROD, bile metabolites and pathology) data in different matrices (sediment and biota), could be used to contribute to the determination of GES in a region of the North Sea region off the east coast of the UK. PMID- 26733270 TI - Cancer Metabolism: A Modeling Perspective. AB - Tumor cells alter their metabolism to maintain unregulated cellular proliferation and survival, but this transformation leaves them reliant on constant supply of nutrients and energy. In addition to the widely studied dysregulated glucose metabolism to fuel tumor cell growth, accumulating evidences suggest that utilization of amino acids and lipids contributes significantly to cancer cell metabolism. Also recent progresses in our understanding of carcinogenesis have revealed that cancer is a complex disease and cannot be understood through simple investigation of genetic mutations of cancerous cells. Cancer cells present in complex tumor tissues communicate with the surrounding microenvironment and develop traits which promote their growth, survival, and metastasis. Decoding the full scope and targeting dysregulated metabolic pathways that support neoplastic transformations and their preservation requires both the advancement of experimental technologies for more comprehensive measurement of omics as well as the advancement of robust computational methods for accurate analysis of the generated data. Here, we review cancer-associated reprogramming of metabolism and highlight the capability of genome-scale metabolic modeling approaches in perceiving a system-level perspective of cancer metabolism and in detecting novel selective drug targets. PMID- 26733272 TI - The art of being mentally healthy: a study to quantify the relationship between recreational arts engagement and mental well-being in the general population. AB - BACKGROUND: Little is known about the dose-response relationship between recreational arts engagement (for enjoyment, entertainment or as a hobby, rather than therapy) and mental well-being in the general population. The quantification of this relationship is of value to: (1) health professionals, clinicians and researchers interested in utilising the arts as a method for improving mental health; (2) to health promoters and policy makers in the development of population based health messages, policy and practice; and (3) to members of the general public in maintaining or improving their own well-being. As guided by theories of social epidemiology and the biopsychosocial model of health, the first aim of this study was to determine if there was a relationship between arts engagement (hours per year) and mental well-being in the general population. If an association was demonstrated, the second aim was to quantify this relationship. METHODS: A random sample of 702 Western Australian adults aged 18+ years (response rate = 71%) were invited to take part in a telephone survey. The survey took 15 min to complete and included questions about arts engagement, mental well-being, demographics and potential confounders/effect modifiers. The dependent variable was subjective mental well-being (Warwick-Edinburgh Mental Well-being Scale, WEMWBS). The independent variable was hours engaged in the arts in the last 12 months. RESULTS: Respondent engagement in the arts ranged from zero to 1572 hours/year (mean = 100.8 hours/year, SD = 206.0). The prevalence of engagement was 83 %. The average WEMWBS score was 53 (SD = 7.4). After adjustment for demographics (i.e. sex, age group, location, income, education, marital status, children), general health, sports engagement, religious activities and holidays, respondents with high levels of arts engagement (100 or more hours/year, WEMWBS score = 55) had significantly better mental well-being than those with none (0 hours/year, WEMWBS score = 53), low (0.1-22.9 hours/year, WEMWBS score = 52) and medium (23-99.9 hours/year, WEMWBS score = 53) levels of engagement (p = 0.003). Respondents with none, low and medium arts engagement had similar WEMWBS scores (p = 0.358). The relationship between arts engagement and WEMWBS was nonlinear with evidence of a minimum threshold at 100 or more hours/year (p = 0.0006). CONCLUSION: Evidence of an arts-mental health relationship was found in this study. Those who engaged in 100 or more hours/year of arts engagement (i.e. two or more hours/week) reported significantly better mental well-being than other levels of engagement. The suitability of the arts as a population based strategy to influence the mental well-being of the general population should be investigated further. PMID- 26733273 TI - Achilles tendon Total Rupture Score at 3 months can predict patients' ability to return to sport 1 year after injury. AB - PURPOSE: To investigate how the Achilles tendon Total Rupture Score (ATRS) at 3 months and 1 year after injury is associated with a patient's ability to return to work and sports as well as to investigate whether sex and age influence ATRS after 3 months and 1 year. METHOD: This is a retrospective study analysing the data from the Danish Achilles tendon Database. A total of 366 patients were included. Logistic regression was conducted to describe the effect of ATRS on return to work and sports. The effect of age and sex on ATRS was analysed by linear regression. RESULTS: Three months after injury patients had a significantly increased chance of return to sport after 1 year with an increased ATRS (OR 1.06, p = 0.001) but a non-significant effect on return to work. After 1 year, patients had a significantly increased probability of having returned to sport (OR 1.11, p < 0.001) and also having returned to work (OR 1.05, p = 0.007) with an increased ATRS. Men had an average 7 (p = 0.006) points higher ATRS at 3 months and an average 22 (p = 0.006) points higher at 1 year. CONCLUSION: ATRS is associated with patients' ability to return to sports and work. ATRS at 3 months can be used as a predictor of the patient's ability to return to sports after 1 year. Hereby, ATRS might help to individualise rehabilitation by identifying patients who do not respond adequately to the chosen treatment. LEVEL OF EVIDENCE: II. PMID- 26733274 TI - Blind suprascapular and axillary nerve block for post-operative pain in arthroscopic rotator cuff surgery. AB - PURPOSE: The goal of the study was to evaluate the efficacy of additional axillary nerve block (ANB) with suprascapular nerve block (SSNB) and patient controlled anaesthesia (PCA) with no device assistance after arthroscopic rotator cuff repair. The hypothesis is that patients with intravenous (IV) PCA and the blockade of the two main nerves (SSNB + ANB) experienced lesser pain than patients with IV PCA or IV PCA + SSNB. METHODS: The 114 patients undergoing arthroscopic rotator cuff repair were allocated randomly to three groups as follows: group I, intravenous PCA pumps (only PCA); group II, IV PCA + SSNB using a blind technique (PCA + SSNB); and group III, IV PCA + SSNB + ANB using a blind technique (PCA + SSNB + ANB). Pain visual analogue scale (VAS) scores were evaluated at 1, 6, 12, 24, 36, and 48 post-operative hours. Furthermore, the degree of pain was compared according to cuff tear size. RESULTS: The pain VAS score of group III was lower than that of the other two groups and was significantly lower at post-operative hours 1, 6, and 12. In addition, the larger cuff tear tended to be indicative of greater pain. However, all groups experienced rebound pain. CONCLUSION: PCA + SSNB + ANB using a blind technique is a better pain control method than PCA + SSNB and only PCA during the initial 12 post-operative hours. PCA + SSNB + ANB is a cost-effective, time-saving, and easily performed method for post-operative pain control as an axis of multimodal pain control strategy. LEVEL OF EVIDENCE: II. PMID- 26733275 TI - Intraoperative factors affecting conversion from cruciate retaining to cruciate substituting in total knee arthroplasty. AB - PURPOSE: The purpose of this study was to analyse the factors affecting the conversion from posterior cruciate ligament (PCL)-retaining (CR) to PCL substituting (PS) prostheses during total knee arthroplasty (TKA). METHODS: A total of 920 TKAs, which had been preoperatively planned to undergo implantation of CR-type prostheses, were reviewed retrospectively. Of these, 83 knees (9.0 %) were converted intraoperatively to PS prostheses. The clinical and radiological factors of the non-converted (CR) and converted (PS) groups were compared. Clinically, age, gender, body mass index, angle of flexion contracture, size of the femoral component, and thickness of the polyethylene insert were compared between the CR and PS groups. Radiologically, the severity of the varus deformity and the posterior tibial slope angle (PSA) were compared between the CR and PS groups. RESULTS: No significant differences in age, gender, body mass index, range of motion, thickness of the polyethylene insert, or severity of varus deformity were identified. The average preoperative angle of flexion contracture was 5.9 degrees +/- 7.4 degrees in the CR group and 8.1 degrees +/- 9.1 degrees in the PS group (p = 0.002). The average preoperative PSA was 9.6 degrees +/- 4.0 degrees in the CR group and 11.0 degrees +/- 5.0 degrees in the PS group (p = 0.018). The conversion rates to a PS-type femoral component of size C, D, and E were 13.1, 7.0, and 6.3 %, respectively (p = 0.004). CONCLUSION: The conversion rate from CR- to PS-type prostheses was high in patients with severe flexion contracture, steep posterior slope, and a small femoral component size. These factors should be carefully considered for appropriate selection of prosthesis type. LEVEL OF EVIDENCE: IV. PMID- 26733276 TI - Predictive Validity of Addiction Treatment Clinicians' Post-Training Contingency Management Skills for Subsequent Clinical Outcomes. AB - In the context of a contingency management (CM) implementation/effectiveness hybrid trial, the post-training implementation domains of direct-care clinicians (N=19) were examined in relation to a targeted clinical outcome of subsequently CM-exposed clients. Clinicians' CM skillfulness, a behavioral measure of their capability to skillfully deliver the intended CM intervention, was found to be a robust and specific predictor of their subsequent client outcomes. Analyses also revealed CM skillfulness to: (1) fully mediate an association between a general therapeutic effectiveness and client outcome, (2) partially mediate an association of in-training exposure to CM and client outcome, and (3) be composed of six component clinical practice behaviors that each contributed meaningfully to this behavior fidelity index. Study findings offer preliminary evidence of the predictive validity of post-training CM skillfulness for subsequent client outcomes, and inform suggestions for the design and delivery of skills-focused CM training curricula for the addiction treatment workforce. PMID- 26733277 TI - Aripiprazole and Risperidone for Treatment of Methamphetamine-Associated Psychosis in Chinese Patients. AB - We evaluated tolerability and efficacy of aripiprazole and risperidone for treatment of methamphetamine (METH) associated psychotic symptoms in China. Patients with acute METH-associated psychotic symptoms (N=42) and with Positive and Negative Syndrome Scale (PANSS) total score between 60 and 120 were randomized to aripiprazole (initial dose 5-10mg per day followed by flexible doses 5-15 mg per day) or risperidone (initial dose 2-4 mg per day followed by flexible doses 4-6 mg per day) from day 3 to 25 of inpatient hospital stay. Outcome measures included PANSS and Clinical Global Impressions-Severity of Illness scale (CGI-S), METH craving Visual Analogue Scale (VAS), Simpson Angus Scale (SAS), Barnes Assessments Akathasia Rating Scale (BARS), and self-reported adverse effects evaluated during treatment. Retention was evaluated using Kaplan Meier survival analysis and the MIXED models procedure was used to compare the groups on measures of psychotic and extra-pyramidal symptoms. Patients in both aripiprazole and risperidone groups showed statistically significant reductions in psychotic symptomatology from baseline during treatment (p<0.001) with no statistically significant differences between the treatment groups (p=0.73 and p=0.15, respectively). Risperidone-treated patients reported significantly greater METH craving reductions (p<0.001). Overall, 71% of patients completed the entire study, but the aripiprazole group had a significantly lower retention than the risperidone group (p=0.007), primarily due to medication related adverse effects. Aripiprazole-treated patients also had significantly more akathisia (p=0.03) and agitation (p=0.02) than risperidone-treated patients. Patients in both groups who tolerated their medications and completed the entire study achieved comparable reductions of psychotic symptoms. PMID- 26733278 TI - Lopinavir Resistance Classification with Imbalanced Data Using Probabilistic Neural Networks. AB - Resistance to antiretroviral drugs has been a major obstacle for long-lasting treatment of HIV-infected patients. The development of models to predict drug resistance is recognized as useful for helping the decision of the best therapy for each HIV+ individual. The aim of this study was to develop classifiers for predicting resistance to the HIV protease inhibitor lopinavir using a probabilistic neural network (PNN). The data were provided by the Molecular Virology Laboratory of the Health Sciences Center, Federal University of Rio de Janeiro (CCS-UFRJ/Brazil). Using bootstrap and stepwise techniques, ten features were selected by logistic regression (LR) to be used as inputs to the network. Bootstrap and cross-validation were used to define the smoothing parameter of the PNN networks. Four balanced models were designed and evaluated using a separate test set. The accuracies of the classifiers with the test set ranged from 0.89 to 0.94, and the area under the receiver operating characteristic (ROC) curve (AUC) ranged from 0.96 to 0.97. The sensitivity ranged from 0.94 to 1.00, and the specificity was between 0.88 and 0.92. Four classifiers showed performances very close to three existing expert-based interpretation systems, the HIVdb, the Rega and the ANRS algorithms, and to a k-Nearest Neighbor. PMID- 26733279 TI - Systems Genomics Support for Immune and Inflammation Hypothesis of Depression. AB - BACKGROUND: Immune system plays an important role in brain development and function. With the discovery of increased circulating inflammatory cytokine levels in depression over two decades ago, evidence implicating immune system alterations in the disease has increasingly accumulated. OBJECTIVE: To assess the underlying etiology and pathophysiology, a brief overview of the hypothesis free genomic, transcriptomic and proteomic studies in depression is presented here in order to specifically examine if the immune and inflammation hypothesis of depression is supported. RESULTS: It is observed that genes identified in genome wide association studies, and genes showing differential expression in transcriptomic studies in human depression do separately overrepresent processes related to both development as well as functioning of the immune system, and inflammatory response. These processes are also enriched in differentially expressed genes reported in animal models of antidepressant treatment. It is further noted that some of the genes identified in genome sequencing and proteomic analyses in human depression, and transcriptomic studies in chronic social defeat stress, an established animal model of depression, relate to immune and inflammatory pathways. CONCLUSION: In conclusion, integrative genomics evidence supports the immune and inflammation hypothesis of depression. PMID- 26733281 TI - LIM kinase activity is required for microtubule organising centre positioning in mouse oocyte meiosis. AB - LIM kinase 1 (LIMK1) activity is essential for cell migration and cell cycle progression. Little is known about LIMK1 expression and function in mammalian oocytes. In the present study we assessed LIMK1 protein expression, subcellular distribution and function during mouse oocyte meiosis. Western blot analysis revealed high and stable expression of LIMK1 from the germinal vesicle (GV) to MII stage. In contrast, activated LIMK1 (i.e. LIMK1 phosphorylated at threonine 508 (pLIMK1Thr508)) was only detected after GV breakdown, with levels increasing gradually to peak at MI and MII. Immunofluorescence showed pLIMK1Thr508 was colocalised with the microtubule organising centre (MTOC) components pericentrin and gamma-tubulin at the spindle poles. A direct interaction between gamma tubulin and pLIMK1Thr508 was confirmed by co-immunoprecipitation. LIMK inhibition with 1MUM BMS3 damaged MTOC protein localisation to spindle poles, undermined the formation and positioning of functional MTOC and thus disrupted spindle formation and chromosome alignment. These effects were phenocopied by microinjection of LIMK1 antibody into mouse oocytes. In summary, the data demonstrate that LIMK activity is essential for MTOC organisation and distribution and so bipolar spindle formation and maintenance in mouse oocytes. PMID- 26733280 TI - Interferon-Related Depression: A Primer on Mechanisms, Treatment, and Prevention of a Common Clinical Problem. AB - BACKGROUND: Depression is among the commonest of psychiatric disorders, and inflammatory mechanisms have been suggested to play a role in its pathophysiology. Interferons are a superfamily of proinflammatory cytokines that play a role in host defence mechanisms. Interferons are used in the treatment of a variety of autoimmune (e.g. multiple sclerosis), viral (e.g. chronic hepatitis B and C), and malignant (e.g. malignant melanoma, hairy cell leukemia) disorders; depression, however, is a notable and clinically troublesome adverse effect. OBJECTIVE: This article seeks to present a simple explanation and update for the reader about what interferons are, how interferons are classified, the clinical conditions in which interferons are used, the occurrence of depression as a clinical adverse effect of interferon therapy, possible mechanisms that explain interferon-related depression, the treatment of interferon-related depression, and the prevention of interferon-related depression. METHODS: A qualitative literature review is presented. RESULTS AND CONCLUSIONS: Irrespective of the indication for IFN therapy, IFNs are associated with a 30- 70% risk of treatment emergent depression. This risk could be due to the IFN, or to an interaction between the IFN and the indication for which it was prescribed. Various neurohormonal, neurochemical, neurohistological, and other mechanisms have been put forth to explain IFN-related depression. Prophylactic treatment with antidepressants reduces the risk of IFN-related depression; antidepressants also effectively treat the condition. Recent alternatives to IFNs have shown to decrease the risk of treatment-emergent depression. PMID- 26733282 TI - Electrochemically driven mechanical energy harvesting. AB - Efficient mechanical energy harvesters enable various wearable devices and auxiliary energy supply. Here we report a novel class of mechanical energy harvesters via stress-voltage coupling in electrochemically alloyed electrodes. The device consists of two identical Li-alloyed Si as electrodes, separated by electrolyte-soaked polymer membranes. Bending-induced asymmetric stresses generate chemical potential difference, driving lithium ion flux from the compressed to the tensed electrode to generate electrical current. Removing the bending reverses ion flux and electrical current. Our thermodynamic analysis reveals that the ideal energy-harvesting efficiency of this device is dictated by the Poisson's ratio of the electrodes. For the thin-film-based energy harvester used in this study, the device has achieved a generating capacity of 15%. The device demonstrates a practical use of stress-composition-voltage coupling in electrochemically active alloys to harvest low-grade mechanical energies from various low-frequency motions, such as everyday human activities. PMID- 26733283 TI - Post-mortem testing; germline BRCA1/2 variant detection using archival FFPE non tumor tissue. A new paradigm in genetic counseling. AB - Accurate estimation of cancer risk in HBOC families often requires BRCA1/2 testing, but this may be impossible in deceased family members. Previous, testing archival formalin-fixed, paraffin-embedded (FFPE) tissue for germline BRCA1/2 variants was unsuccessful, except for the Jewish founder mutations. A high throughput method to systematically test for variants in all coding regions of BRCA1/2 in archival FFPE samples of non-tumor tissue is described, using HaloPlex target enrichment and next-generation sequencing. In a validation study, correct identification of variants or wild-type was possible in 25 out of 30 (83%) FFPE samples (age range 1-14 years), with a known variant status in BRCA1/2. No false positive was found. Unsuccessful identification was due to highly degraded DNA or presence of large intragenic deletions. In clinical use, a total of 201 FFPE samples (aged 0-43 years) were processed. Thirty-six samples were rejected because of highly degraded DNA or failed library preparation. Fifteen samples were investigated to search for a known variant. In the remaining 150 samples (aged 0-38 years), three variants known to affect function and one variant likely to affect function in BRCA1, six variants known to affect function and one variant likely to affect function in BRCA2, as well as four variants of unknown significance (VUS) in BRCA1 and three VUS in BRCA2 were discovered. It is now possible to test for germline BRCA1/2 variants in deceased persons, using archival FFPE samples from non-tumor tissue. Accurate genetic counseling is achievable in families where variant testing would otherwise be impossible. PMID- 26733284 TI - Duplication of PTHLH causes osteochondroplasia with a combined brachydactyly type E/A1 phenotype with disturbed bone maturation and rhizomelia. AB - Parathyroid hormone-like hormone (PTHLH, MIM 168470) plays an important role in endochondral bone development and prevents chondrocytes from differentiating. Disease-causing variants and haploinsufficiency of PTHLH are known to cause brachydactyly type E and short stature. So far, three large duplications encompassing several genes including PTHLH associating with enchondromatas and acro-osteolysis have been described in the literature. Here, we report on a three generation pedigree with short humerus, curved radius, and a specific type of severe brachydactyly with features of types E and A1 but without the enchondromatas and the acro-osteolysis. Microarray-based comparative genomic hybridization (array-CGH) revealed a 70-kb duplication on chromosome 12p11.22 encompassing only PTHLH. Our data extend the phenotypic spectrum associated with copy number variations of PTHLH, and this family is to our knowledge the first description harboring a microduplication encompassing only PTHLH. PMID- 26733286 TI - Distal acroosteolysis, poikiloderma and joint stiffness: a novel laminopathy? AB - LMNA encodes lamin A and lamin C, two major components of the nuclear lamina, and its pathogenic variants lead to a dozen distinct clinical entities collectively known as laminopathies. Most LMNA-related laminopathies are autosomal dominant but four are autosomal recessive; furthermore, some of the dominant variants have been associated with distinct phenotypes when inherited recessively, further complicating the ability to correlate genotype with phenotype. We report a consanguineous family in which the index presented with an apparently unique constellation of poikiloderma, joint motion restriction and distal acroosteolysis but lacks features of muscle weakness, lipodystrophy, or cardiac or craniofacial involvement. Molecular analysis revealed the presence of a novel homozygous LMNA missense variant (NM_170707.3:c.1774G>A; p.(Gly592Arg)) within an area of autozygome that is not shared by his unaffected siblings. The proposed causal link is further supported by in silico analysis of this variant. Our case suggests an expansion of LMNA allelic disorders to include distal acroosteolysis, poikiloderma and joint stiffness (DAPJ). PMID- 26733285 TI - The HLA-DQbeta1 insertion is a strong achalasia risk factor and displays a geospatial north-south gradient among Europeans. AB - Idiopathic achalasia is a severe motility disorder of the esophagus and is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. Most recently, we identified an eight amino-acid insertion in the cytoplasmic tail of HLA-DQbeta1 as strong achalasia risk factor in a sample set from Central Europe, Italy and Spain. Here, we tested whether the HLA-DQbeta1 insertion also confers achalasia risk in the Polish and Swedish population. We could replicate the initial findings and the insertion shows strong achalasia association in both samples (Poland P=1.84 * 10(-04), Sweden P=7.44 * 10(-05)). Combining all five European data sets - Central Europe, Italy, Spain, Poland and Sweden - the insertion is achalasia associated with Pcombined=1.67 * 10(-35). In addition, we observe that the frequency of the insertion shows a geospatial north-south gradient. The insertion is less common in northern (around 6-7% in patients and 2% in controls from Sweden and Poland) compared with southern Europeans (~16% in patients and 8% in controls from Italy) and shows a stronger attributable risk in the southern European population. Our study provides evidence that the prevalence of achalasia may differ between populations. PMID- 26733287 TI - The effect of phenotypic outliers and non-normality on rare-variant association testing. AB - Rare-variant association studies (RVAS) have made important contributions to human complex trait genetics. These studies rely on specialized statistical methods for analyzing rare-variant associations, both individually and in aggregate. We investigated the impact that phenotypic outliers and non-normality have on the performance of rare-variant association testing procedures. Ignoring outliers or non-normality can significantly inflate Type I error rates. We found that rank-based inverse normal transformation (INT) and trait winsorisation were both effective at maintaining Type I error control without sacrificing power in the presence of outliers. INT was the optimal method for non-normally distributed traits. For RVAS of quantitative traits with outliers or non-normality, we recommend using INT to transform phenotypic values before association testing. PMID- 26733288 TI - The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants. AB - Genome-wide association studies (GWAS) have long relied on proposed statistical significance thresholds to be able to differentiate true positives from false positives. Although the genome-wide significance P-value threshold of 5 * 10(-8) has become a standard for common-variant GWAS, it has not been updated to cope with the lower allele frequency spectrum used in many recent array-based GWAS studies and sequencing studies. Using a whole-genome- and -exome-sequencing data set of 2875 individuals of European ancestry from the Genetics of Type 2 Diabetes (GoT2D) project and a whole-exome-sequencing data set of 13 000 individuals from five ancestries from the GoT2D and T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples) projects, we describe guidelines for genome- and exome-wide association P-value thresholds needed to correct for multiple testing, explaining the impact of linkage disequilibrium thresholds for distinguishing independent variants, minor allele frequency and ancestry characteristics. We emphasize the advantage of studying recent genetic isolate populations when performing rare and low-frequency genetic association analyses, as the multiple testing burden is diminished due to higher genetic homogeneity. PMID- 26733289 TI - Classical galactosaemia: novel insights in IgG N-glycosylation and N-glycan biosynthesis. AB - Classical galactosaemia (OMIM #230400), a rare disorder of carbohydrate metabolism, is caused by a deficient activity of galactose-1-phosphate uridyltransferase (EC 2.7.7.12). The pathophysiology of the long-term complications, mainly cognitive, neurological and female fertility problems remains poorly understood. The lack of validated biomarkers to determine prognosis, monitor disease progression and responses to new therapies, pose a huge challenge. We report the detailed analysis of an automated robotic hydrophilic interaction ultra-performance liquid chromatography N-glycan analytical method of high glycan peak resolution applied to serum IgG. This has revealed specific N-glycan processing defects observed in 40 adult galactosaemia patients (adults and adolescents), in comparison with 81 matched healthy controls. We have identified a significant increase in core fucosylated neutral glycans (P<0.0001) and a significant decrease in core fucosylated (P<0.001), non fucosylated (P<0.0001) bisected glycans and, of specific note, decreased N-linked mannose-5 glycans (P<0.0001), in galactosaemia patients. We also report the abnormal expression of a number of related relevant N-glycan biosynthesis genes in peripheral blood mononuclear cells from 32 adult galactosaemia patients. We have noted significant dysregulation of two key N-glycan biosynthesis genes: ALG9 upregulated (P<0.001) and MGAT1 downregulated (P<0.01) in galactosaemia patients, which may contribute to its ongoing pathophysiology. Our data suggest that the use of IgG N-glycosylation analysis with matched N-glycan biosynthesis gene profiles may provide useful biomarkers for monitoring response to therapy and interventions. They also indicate potential gene modifying steps in this N-glycan biosynthesis pathway, of relevance to galactosaemia and related N-glycan biosynthesis disorders. PMID- 26733290 TI - A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability. AB - The IQSEC2 gene is located on chromosome Xp11.22 and encodes a guanine nucleotide exchange factor for the ADP-ribosylation factor family of small GTPases. This gene is known to have a significant role in cytoskeletal organization, dendritic spine morphology and synaptic organization. Variants in IQSEC2 cause moderate to severe intellectual disability in males and a variable phenotype in females because this gene escapes from X-chromosome inactivation. Here we report on the first splicing variant in IQSEC2 (g.88032_88033del; NG_021296.1) that co segregates in a family diagnosed with an X-linked form of ID. In a percentage of the cells, the variant activates an intraexonic splice acceptor site that abolishes 26 amino acids from the highly conserved PH domain of IQSEC2 and creates a premature stop codon 36 amino acids later in exon 13. Interestingly, the percentage of aberrant splicing seems to correlate with the severity of the disease in each patient. The impact of this variant in the target tissue is unknown, but we can hypothesize that these differences may be related to the amount of abnormal IQSEC2 transcript. To our knowledge, we are reporting a novel mechanism of IQSEC2 involvement in ID. Variants that affect splicing are related to many genetic diseases and the understanding of their role in disease expands potential opportunities for gene therapy. Modulation of aberrant splicing transcripts can become a potent therapeutic approach for many of these diseases. PMID- 26733292 TI - Complete genome sequence of a Chuzan virus strain isolated for the first time in mainland China. AB - Chuzan virus (CHUV) belongs to the Palyam serogroup, causes bovine congenital disease, and is prevalent in Asia. To date, only one full Palyam virus (PALV) genome sequence, that of Japanese CHUV strain K47, has been reported. Sequence analysis indicates that PALV strains isolated from different geographical regions show significant diversity, which is mainly shaped by geographically independent evolution and genetic reassortment. Our understanding of the genetic characteristics of PALV is hampered by a very limited genomic sequence database. In this study, we report the complete genome sequence of CHUV strain SZ187, which was isolated for the first time in 2012 in mainland China. Sequence alignment and phylogenetic analysis demonstrate that SZ187 is closely related to other CHUV strains isolated in Taiwan and Japan, indicating that they may share a common ancestor. This new full-length CHUV genome sequence could help in the design of broader assays for epidemiological studies and facilitate the identification of new CHUV isolates in the future. PMID- 26733291 TI - Common coding variants in the HLA-DQB1 region confer susceptibility to age related macular degeneration. AB - Age-related macular degeneration (AMD) risk variants in the complement system point to the important role of immune response and inflammation in the pathogenesis of AMD. Although the human leukocyte antigen (HLA) region has a central role in regulating immune response, previous studies of genetic variation in HLA genes and AMD have been limited by sample size or incomplete coverage of the HLA region by first-generation genotyping arrays and imputation panels. Here, we conducted a large-scale HLA fine-mapping study with 4841 AMD cases and 23 790 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohort. Genotyping was conducted using custom Affymetrix Axiom arrays, with dense coverage of the HLA region. Classic HLA polymorphisms were imputed using SNP2HLA, which utilizes a large reference panel to provide improved imputation accuracy of variants in this region. We examined a total of 6937 SNPs and 172 classical HLA alleles, conditioning on established AMD risk variants, which revealed novel associations with two non-synonymous SNPs in perfect linkage disequilibrium, rs9274390 and rs41563814 (odds ratio (OR)=1.21; P=1.4 * 10(-11)) corresponding to amino-acid changes at position 66 and 67 in HLA-DQB1, respectively, and the DQB1*02 classical HLA allele (OR=1.22; P=3.9 * 10(-10)) with the risk of AMD. We confirmed these association signals, again conditioning on established risk variants, in the MMAP data set of subjects with advanced AMD (rs9274390/rs41563814: OR=1.28; P=1.30 * 10(-3), DQB1*02: OR=1.32; P=9.00 * 10( 4)). These findings support a role of HLA class II alleles in the risk of AMD. PMID- 26733294 TI - Complete nucleotide sequence of little cherry virus 1 (LChV-1) infecting sweet cherry in China. AB - Little cherry virus 1 (LChV-1), associated with little cherry disease (LCD), has a significant impact on fruit quality of infected sweet cherry trees. We report the full genome sequence of an isolate of LChV-1 from Taian, China (LChV-1-TA), detected by small-RNA deep sequencing and amplified by overlapping RT-PCR. The LChV-1-TA genome was 16,932 nt in length and contained nine open reading frames (ORFs), with sequence identity at the overall genome level of 76%, 76%, and 78% to LChV-1 isolates Y10237 (UW2 isolate), EU715989 (ITMAR isolate) and JX669615 (V2356 isolate), respectively. Based on the phylogenetic analysis of HSP70h amino acid sequences of Closteroviridae family members, LChV-1-TA was grouped into a well-supported cluster with the members of the genus Velarivirus and was also closely related to other LChV-1 isolates. This is the first report of the complete nucleotide sequence of LChV-1 infecting sweet cherry in China. PMID- 26733293 TI - Taxonomy of prokaryotic viruses: update from the ICTV bacterial and archaeal viruses subcommittee. PMID- 26733295 TI - Serological survey of avian influenza virus infection in non-avian wildlife in Xinjiang, China. AB - We conducted a serological survey to detect antibodies against avian influenza virus (AIV) in Gazella subgutturosa, Canis lupus, Capreolus pygargus, Sus scrofa, Cervus elaphus, Capra ibex, Ovis ammon, Bos grunniens and Pseudois nayaur in Xinjiang, China. Two hundred forty-six sera collected from 2009 to 2013 were assayed for antibodies against H5, H7 and H9 AIVs using hemagglutination inhibition (HI) tests and a pan-influenza competitive ELISA. Across all tested wildlife species, 4.47 % harbored anti-AIV antibodies that were detected by the HI assay. The seroprevalence for each AIV subtype across all species evaluated was 0 % for H5 AIV, 0.81 % for H7 AIV, and 3.66 % for H9 AIV. H7-reactive antibodies were found in Canis lupus (9.09 %) and Ovis ammon (4.55 %). H9 reactive antibodies were found in Gazella subgutturosa (4.55 %), Canis lupus (27.27 %), Pseudois nayaur (23.08 %), and Ovis ammon (4.55 %). The pan-influenza competitive ELISA results closely corresponded to the cumulative prevalence of AIV exposure as measured by subtype-specific HI assays, suggesting that H7 and H9 AIV subtypes predominate in the wildlife species evaluated. These data provide evidence of prior infection with H7 and H9 AIVs in non-avian wildlife in Xinjiang, China. PMID- 26733296 TI - Identification and in silico characterisation of defective molecules associated with isolates of banana bunchy top virus. AB - Banana bunchy top virus (BBTV) is a multi-component single-stranded DNA virus. From 267 potentially infected Musa plants, 24 apparently 'defective' BBTV components have been identified. Interestingly, 23/24 of these defective molecules were apparently derived from DNA-R. All of the identified defective molecules had retained at least part of the CR-SL and CR-M but had insertions and/or deletions that in most cases resulted in open reading frame disruptions. Our detection of three monophyletic but diverse (and therefore likely circulating) defective DNA-R lineages suggests that, in many cases, defective DNA R molecules might remain associated with BBTV genomes for prolonged periods. PMID- 26733297 TI - The pseudorabies virus DNA polymerase processivity factor UL42 exists as a monomer in vitro and in vivo. AB - The processivity factors (PFs) of herpesviruses confer processivity to the DNA polymerase. Understanding whether the herpesvirus PFs function as monomers or multimers is important for clarifying the mechanism by which they provide the DNA polymerase with processivity. Herpes simplex virus type 1 UL42 is a monomer, whereas human cytomegalovirus UL44, Epstein-Barr virus BMRF1, and Kaposi's sarcoma-associated herpesvirus PF-8 exist as dimers. However, the oligomeric status of the pseudorabies virus (PRV) DNA polymerase PF UL42 has not been determined. Using fluorescence confocal microscopy and chemical crosslinking, we confirmed that UL42 is a monomer when expressed in vitro. Crosslinking of nuclear extracts from PRV-infected or uninfected PK-15 cells verified that UL42 exists as a monomer in vivo. Our demonstration that UL42 exists as a monomer in vitro and in vivo contributes to the further investigation of the mechanism used by UL42 to achieve processivity. PMID- 26733298 TI - Detection and genetic characterization of a novel parvovirus distantly related to human bufavirus in domestic pigs. AB - In this study, a novel parvovirus (strain swine/Zsana3/2013/HUN, KT965075) was detected in domestic pigs and genetically characterized by viral metagenomics and PCR methods. The novel parvovirus was distantly related to the human bufaviruses and was detected in 19 (90.5 %) of the 21 and five (33.3 %) of the 15 faecal samples collected from animals with and without cases of posterior paraplegia of unknown etiology from five affected farms and one control farm in Hungary, respectively. Swine/Zsana3/2013/HUN is highly prevalent in domestic pigs and potentially represents a novel parvovirus species in the subfamily Parvovirinae. PMID- 26733299 TI - Manganese-enhanced MR imaging of brain activation evoked by noxious peripheral electrical stimulation. AB - As imaging technology develops, magnetic resonance imaging (MRI) has furthered our understanding of brain function by clarifying the anatomical structure and generating functional imaging data related to information processing in pain conditions. Recent studies have reported that manganese (Mn(2+))-enhanced MRI (MEMRI) provides valuable information about the functions of the central nervous system. The aim of this study was to identify specific brain regions activated during noxious electric stimulation using high-resolution MEMRI. Male Sprague Dawley rats were divided into three groups: naive, sham electrical stimulation, and noxious electric stimulation. Under urethane with alpha-chloralose mixture anesthesia, a catheter was placed in the external carotid artery to administrate 20% mannitol and manganese chloride (25mM MnCl2). Noxious electric stimulation (2Hz, 10V) was applied to the hind paw with a needle electrode. Stimulation induced neuronal activation was detected using 4.7-T MRI. In response to noxious electrical stimulation, remarkable Mn(2+)-enhanced signals were observed in the agranular insular cortex, auditory cortex, primary somatosensory cortex of the hind limb, and granular and dysgranular insular cortex, which correspond to sensory tactile electric stimulus to the hindpaws. These results indicate that the combination of MEMRI with activity-induced Mn(2+)-dependent contrast can delineate functional areas in the rat brain. PMID- 26733300 TI - Clostridium butyricum pretreatment attenuates cerebral ischemia/reperfusion injury in mice via anti-oxidation and anti-apoptosis. AB - Probiotics participate actively in the neuropsychiatric disorders. However, their roles on ischemic stroke remain unclear. This study aims to determine whether Clostridium butyricum (C. butyricum) could attenuate cerebral ischemia/reperfusion (I/R) injury and its possible mechanisms. Male ICR mice were intragastrically pretreated with C. butyricum for 2 successive weeks, and then subjected to cerebral I/R injury induced by the bilateral common carotid artery occlusion (BCCAO) for 20min. After 24h of the reperfusion, neurological deficit scores were evaluated. Histopathological changes of the hippocampus neurons were observed using Hematoxylin and eosin (H&E) and TUNEL staining. Malondialdehyde (MDA) contents and superoxide dismutase (SOD) activities in the brain were detected. The expression of Caspase-3, Bax and Bcl-2 were investigated by Western blot and immunohistochemistry analysis. The butyrate contents in the brain were determined. Our results showed that cerebral I/R injury led to neurological deficit, increased levels of Caspase-3 and Bax and decreased Bcl-2/Bax ratio. C. butyricum significantly improved neurological deficit, relieved histopathologic change, decreased MDA contents and increased SOD activities in the I/R injury mice. After C. butyricum pretreatment, the expression of Caspase-3 and Bax were significantly decreased, the Bcl-2/Bax ratio was significantly increased, and butyrate contents in the brain were significantly increased. These findings suggested that C. butyricum is able to exert neuroprotective effects against I/R injury mice through anti-oxidant and anti-apoptotic mechanisms, and reversing decrease of butyrate contents in the brain might be involved in its neuroprotection. PMID- 26733301 TI - Chronic benzodiazepine treatment decreases spine density in cortical pyramidal neurons. AB - The adult brain retains a substantial capacity for synaptic reorganization, which includes a wide range of modifications from molecular to structural plasticity. Previous reports have demonstrated that the structural remodeling of excitatory neurons seems to occur in parallel to changes in GABAergic neurotransmission. The function of neuronal inhibitory networks can be modified through GABAA receptors, which have a binding site for benzodiazepines (BZ). Although BZs are among the most prescribed drugs, is not known whether they modify the structure and connectivity of pyramidal neurons. In the present study we wish to elucidate the impact of a chronic treatment of 21 days with diazepam (2mg/kg, ip), a BZ that acts as an agonist of GABAA receptors, on the structural plasticity of pyramidal neurons in the prefrontal cortex of adult mice. We have examined the density of dendritic spines and the density of axonal en passant boutons in the cingulate cortex. Although no significant changes were observed in their anxiety levels, animals treated with diazepam showed a decrease in the density of spines in the apical dendrites of pyramidal neurons. Most GFP-expressing en passant boutons in the upper layers of the cingulate cortex had an extracortical origin and no changes in their density were detected after diazepam treatment. These results indicate that the chronic potentiation of GABAergic synapses can induce the structural remodeling of postsynaptic elements in pyramidal neurons. PMID- 26733302 TI - Association study of the BIN1 and IL-6 genes on Alzheimer's disease. AB - Genome-wide association study (GWAS) has identified several novel genes associated with the risk of Alzheimer's disease (AD), which is a progressive neurodegenerative disease in elders. However, most of the novel genes have not been validated through replication in separated populations. Among them, the BIN1 gene is involved in endocytosis and intracellular trafficking as well as in the formation of beta amyloid plaques and neurofibrillary tangles, which are the main pathological hallmarks of AD. The IL-6 gene has also been frequently associated with AD; however, consistent results have not been found. IL-6, a cytokine from the immune system, is implicated in the pathogenesis of several degenerative diseases. Similar to BIN1, it is suggested that IL-6 is also involved in the formation of beta amyloid plaques. In this case-control study, we aimed to investigate whether single nucleotide polymorphisms in the BIN1 (rs744373) and IL 6 (rs1800795) genes are associated with AD. Genotype frequencies were evaluated via PCR-RFLP in 82 late-onset AD patients and 159 elderly healthy controls, who were matched by age and gender. In this study, no association was found for either polymorphism, suggesting that these genes are not implicated in the aetiology of AD in all populations. PMID- 26733303 TI - Role of HDACs in optic nerve damage-induced nuclear atrophy of retinal ganglion cells. AB - Optic neuropathies are characterized by retinal ganglion cell (RGC) death, resulting in the loss of vision. In glaucoma, the most common optic neuropathy, RGC death is initiated by axonal damage, and can be modeled by inducing acute axonal trauma through procedures such as optic nerve crush (ONC) or optic nerve axotomy. One of the early events of RGC death is nuclear atrophy, and is comprised of RGC-specific gene silencing, histone deacetylation, heterochromatin formation, and nuclear shrinkage. These early events appear to be principally regulated by epigenetic mechanisms involving histone deacetylation. Class I histone deacetylases HDACs 1, 2, and 3 are known to play important roles in the process of early nuclear atrophy in RGCs, and studies using both inhibitors and genetic ablation of Hdacs also reveal a critical role in the cell death process. Select inhibitors, such as those being developed for cancer therapy, may also provide a viable secondary treatment option for optic neuropathies. PMID- 26733305 TI - Lead tolerance mechanism in Conyza canadensis: subcellular distribution, ultrastructure, antioxidative defense system, and phytochelatins. AB - We used hydroponic experiments to examine the effects of different concentrations of lead (Pb) on the performance of the Pb-tolerable plant Conyza canadensis. In these experiments, most of the Pb was accumulated in the roots; there was very little Pb accumulated in stems and leaves. C. canadensis is able to take up significant amounts of Pb whilst greatly restricting its transportation to specific parts of the aboveground biomass. High Pb concentrations inhibited plant growth, increased membrane permeability, elevated antioxidant enzyme activity in roots, and caused a significant increase in root H2O2 and malondialdehyde content. Analysis of Pb content at the subcellular level showed that most Pb was associated with the cell wall fraction, followed by the nucleus-rich fraction, and with a minority present in the mitochondrial and soluble fractions. Furthermore, transmission electron microscopy and energy dispersive X-ray analysis of root cells revealed that the cell wall and intercellular space in C. canadensis roots are the main locations of Pb accumulation. Additionally, high Pb concentrations adversely affected the cellular structure of C. canadensis roots. The increased enzyme activity suggests that the antioxidant system may play an important role in eliminating or alleviating Pb toxicity in C. canadensis roots. However, the levels of non-protein sulfhydryl compounds, glutathione, and phytochelatin did not significantly change in either the roots or leaves under Pb contaminated treatments. Our results provide strong evidence that cell walls restrict Pb uptake into the root and act as an important barrier protecting root cells, while demonstrating that antioxidant enzyme levels are correlated with Pb exposure. These findings demonstrate the roles played by these detoxification mechanisms in supporting Pb tolerance in C. canadensis. PMID- 26733304 TI - Uncovering the roles of long noncoding RNAs in neural development and glioma progression. AB - In the past decade, thousands of long noncoding RNAs (lncRNAs) have been identified, and emerging data indicate that lncRNAs can have important biological functions and roles in human diseases including cancer. Many lncRNAs appear to be expressed specifically in the brain, and the roles of lncRNAs in neural stem cells (NSCs) and brain development are now beginning to be discovered. Here we review recent advances in understanding the diversity of lncRNA structure and functions in NSCs and brain development. NSCs in the adult mouse ventricular subventricular zone (V-SVZ) generate new neurons throughout life, and we discuss how key elements of this adult neurogenic system have facilitated the discovery and functional characterization of known and novel lncRNAs. A review of lncRNAs described in other NSC systems reveals a variety of molecular mechanisms, including binding and recruitment of transcription factors, epigenetic modifiers, and RNA-splicing factors. Finally, we review emerging evidence indicating that specific lncRNAs can be key drivers of glial tumors, and discuss next steps towards an in vivo understanding of lncRNA function in development and disease. PMID- 26733307 TI - Secure distributed genome analysis for GWAS and sequence comparison computation. AB - BACKGROUND: The rapid increase in the availability and volume of genomic data makes significant advances in biomedical research possible, but sharing of genomic data poses challenges due to the highly sensitive nature of such data. To address the challenges, a competition for secure distributed processing of genomic data was organized by the iDASH research center. METHODS: In this work we propose techniques for securing computation with real-life genomic data for minor allele frequency and chi-squared statistics computation, as well as distance computation between two genomic sequences, as specified by the iDASH competition tasks. We put forward novel optimizations, including a generalization of a version of mergesort, which might be of independent interest. RESULTS: We provide implementation results of our techniques based on secret sharing that demonstrate practicality of the suggested protocols and also report on performance improvements due to our optimization techniques. CONCLUSIONS: This work describes our techniques, findings, and experimental results developed and obtained as part of iDASH 2015 research competition to secure real-life genomic computations and shows feasibility of securely computing with genomic data in practice. PMID- 26733306 TI - Maspin enhances cisplatin chemosensitivity in bladder cancer T24 and 5637 cells and correlates with prognosis of muscle-invasive bladder cancer patients receiving cisplatin based neoadjuvant chemotherapy. AB - BACKGROUND: Maspin, a non-inhibitory member of the serine protease inhibitor superfamily, has been characterized as a tumor suppressor gene in multiple cancer types. Chemotherapeutic insensitivity is one of major obstacles to effectively treating muscle invasive bladder cancer (MIBC). This study was conducted to investigate the role and probable mechanism of Maspin enhancing cisplatin chemosensitivity of bladder cancer in vitro and MIBC patients. METHODS: Maspin expression was quantified by qRT-PCR in two MIBC cell lines (T24 and 5637). After successful established Maspin overexpression model by lipidosome transfection, MTT and cell apoptosis assay were used to assess the MIBC's cisplatin sensitivity. Western blot method was used to test PI3K/ AKT/mTOR signal passway and apoptosis related molecules Caspase3 and Bcl-2. Additionally, we evaluated Maspin expression and prognosis in 62 MIBC cases who underwent cisplatin based neoadjuvant chemotherapy (NACT) using immunohistochemistry. RESULT: Upregulate Maspin expression could enhance the chemosensitivity induced by cisplatin in T24 and 5637 cell lines. The cell viability, cloning ability and IC50 were reduced while apoptosis rate was upregulated when cells were transfected Maspin. Phospho(p)-AKT, PI3K, mTOR, and Bcl-2 expression were significantly decreased, whereas Caspase3 was greatly increased in the Maspin group. In the clinic study, there was significant correlation between Maspin expression and overall survival (OS) and progression-free survival (PFS) rate in MIBC patients who received cisplatin based NACT. CONCLUSION: Maspin could enhance cisplatin chemosensitivity in T24 and 5637 cell lines. Its expression correlated with prognosis of MIBC patients who received cisplatin based neoadjuvant chemotherapy. PMID- 26733308 TI - Psychopathic Traits in Early Childhood: Further Validation of the Child Problematic Traits Inventory. AB - The aim was to further test the reliability and validity of a newly developed instrument designed to assess psychopathic personality traits in children, the Child Problematic Traits Inventory (CPTI). Data from the Preschool Twin Study in Sweden were used, a national general population study of 5-year-old twins ( n = 1,188, 50.3% girls). Both preschool teachers and parents were used as informants. Confirmatory factor analysis replicated the intended three-factorial structure of the 28 items of the CPTI. Overall, our findings demonstrated good internal consistency and convergent validity, with all the teacher-rated CPTI scores being associated with teacher and parent ratings of externalizing psychopathology, aggressive behavior, fearlessness, and prosocial peer involvement. In conclusion, the CPTI hold promise as a teacher-rated tool for assessing psychopathic traits in childhood, though more research is needed to see if these findings can be generalized to other countries, settings, and older children. PMID- 26733309 TI - Isolating Trait and Method Variance in the Measurement of Callous and Unemotional Traits. AB - To examine hypothesized influence of method variance from negatively keyed items in measurement of callous-unemotional (CU) traits, nine a priori confirmatory factor analysis model comparisons of the Inventory of Callous-Unemotional Traits were evaluated on multiple fit indices and theoretical coherence. Tested models included a unidimensional model, a three-factor model, a three-bifactor model, an item response theory-shortened model, two item-parceled models, and three correlated trait-correlated method minus one models (unidimensional, correlated three-factor, and bifactor). Data were self-reports of 234 adolescents (191 juvenile offenders, 43 high school students; 63% male; ages 11-17 years). Consistent with hypotheses, models accounting for method variance substantially improved fit to the data. Additionally, bifactor models with a general CU factor better fit the data compared with correlated factor models, suggesting a general CU factor is important to understanding the construct of CU traits. Future Inventory of Callous-Unemotional Traits analyses should account for method variance from item keying and response bias to isolate trait variance. PMID- 26733311 TI - Singularity theory of fitness functions under dimorphism equivalence. AB - We apply singularity theory to classify monomorphic singular points as they occur in adaptive dynamics. Our approach is based on a new equivalence relation called dimorphism equivalence, which is the largest equivalence relation on strategy functions that preserves ESS singularities, CvSS singularities, and dimorphisms. Specifically, we classify singularities up to topological codimension two and compute their normal forms and universal unfoldings. These calculations lead to the classification of local mutual invasibility plots that can be seen generically in systems with two parameters. PMID- 26733310 TI - Inferring average generation via division-linked labeling. AB - For proliferating cells subject to both division and death, how can one estimate the average generation number of the living population without continuous observation or a division-diluting dye? In this paper we provide a method for cell systems such that at each division there is an unlikely, heritable one-way label change that has no impact other than to serve as a distinguishing marker. If the probability of label change per cell generation can be determined and the proportion of labeled cells at a given time point can be measured, we establish that the average generation number of living cells can be estimated. Crucially, the estimator does not depend on knowledge of the statistics of cell cycle, death rates or total cell numbers. We explore the estimator's features through comparison with physiologically parameterized stochastic simulations and extrapolations from published data, using it to suggest new experimental designs. PMID- 26733312 TI - The nature of chemical bonding in actinide and lanthanide ferrocyanides determined by X-ray absorption spectroscopy and density functional theory. AB - The electronic properties of actinide cations are of fundamental interest to describe intramolecular interactions and chemical bonding in the context of nuclear waste reprocessing or direct storage. The 5f and 6d orbitals are the first partially or totally vacant states in these elements, and the nature of the actinide ligand bonds is related to their ability to overlap with ligand orbitals. Because of its chemical and orbital selectivities, X-ray absorption spectroscopy (XAS) is an effective probe of actinide species frontier orbitals and for understanding actinide cation reactivity toward chelating ligands. The soft X-ray probes of the light elements provide better resolution than actinide L3-edges to obtain electronic information from the ligand. Thus coupling simulations to experimental soft X-ray spectral measurements and complementary quantum chemical calculations yields quantitative information on chemical bonding. In this study, soft X-ray XAS at the K-edges of C and N, and the L2,3 edges of Fe was used to investigate the electronic structures of the well-known ferrocyanide complexes K4Fe(II)(CN)6, thorium hexacyanoferrate Th(IV)Fe(II)(CN)6, and neodymium hexacyanoferrate KNd(III)Fe(II)(CN)6. The soft X-ray spectra were simulated based on quantum chemical calculations. Our results highlight the orbital overlapping effects and atomic effective charges in the Fe(II)(CN)6 building block. In addition to providing a detailed description of the electronic structure of the ferrocyanide complex (K4Fe(II)(CN)6), the results strongly contribute to confirming the actinide 5f and 6d orbital oddity in comparison to lanthanide 4f and 5d. PMID- 26733313 TI - Interaction of steroid receptor coactivators and estrogen receptors in the human placenta. AB - Female sex steroid hormones such as estrogen and progesterone have a pivotal role in maintaining pregnancy in human and animals. Especially, estrogen exerts specific effects on the cardiovascular system and angiogenesis, and thus affects significantly on placentation. Although the functions of estrogen have been emphasized during pregnancy, their signaling pathways in the placenta have not been fully understood. In this study, estrogen signaling was evaluated according to gestational age. Human placenta samples were collected and divided into early preterm (n=10), late preterm (n=18), and term (n=20) groups. First, serum estrogen concentration and corticotropin-releasing hormone (CRH) mRNA expression, which is known as gestation clock gene, were increased following gestation age in our experimental condition, as we expected. Next, the expression of estrogen receptors (ERs) and steroid receptor coactivators (SRCs) in the placenta was evaluated. ERalpha (ESR1) and ERbeta (ESR2) were expressed highly at term period compared with early preterm. In addition, SRC family including SRC1, SRC2, and SRC3 was expressed in the human placenta, and the levels of SRC1, SRC2, and SRC3 were increased in the placenta at the late stage of gestation. The interaction of ERs with SRCs was also examined, which was significantly enhanced at term period. In the immunostaining results, it was indicated that ERs and SRCs were all dominantly expressed in syncytiotrophoblast cells. These results suggested that SRC1, SRC2, and SRC3 were expressed and interact with ERs highly at the late stage of gestation, and may amplify the signaling of estrogen in the placenta to maintain pregnancy. PMID- 26733314 TI - Photocatalytic Water Oxidation over Metal Oxide Nanosheets Having a Three-Layer Perovskite Structure. AB - Metal oxide nanosheets having a three-layer perovskite structure were studied as photocatalysts for water oxidation in the presence of IO3 (-) as a reversible electron acceptor. This work examined the effects of the lateral dimensions and composition of the nanosheets as well as metal oxide co-catalysts deposited on the restacked nanosheets. Depositing metal oxides capable of promoting reduction reactions on the nanosheets were found to promote the water oxidation activity. In contrast, the lateral dimensions and the degree of crystallinity of the nanosheets had little effect on the activity. Experimental results demonstrated that the reduction of IO3 (-) is the rate-limiting step in this reaction and that nanosheets with less distorted structures are advantageous with regard to increasing both light absorption and the mobility of photoexcited charge carriers. PMID- 26733315 TI - Rubber-like Quasi-thermosetting Polyetheramine-cured Epoxy Asphalt Composites Capable of Being Opened to Traffic Immediately. AB - This paper reports the facile preparation, mechanical performance and linear viscoelasticity of polyetheramine-cured rubber-like epoxy asphalt composites (EACs) with different asphalt contents. Compared with previous EACs prepared via complex chemical reactions and time-consuming high-temperature curing, the EACs reported here were obtained by using a compatible, bi-functional polyetheramine and a simple physical co-blend process, which make the EACs feasibly scalable for production at a lower cost. The EACs were cured for 1 h at 160 degrees C and 3 d at 60 degrees C; therefore, these composites can be opened to traffic immediately. The EACs have a much greater temperature stability than common thermoplastic polymer-modified asphalt composites from -30 degrees C to 120 degrees C, but their complex shear moduli at higher temperatures slightly decrease instead of remaining constant when temperatures are greater than 80 degrees C, especially for the higher asphalt content composites; that is, these composites are quasi-thermosetting. Wicket plots illustrate that the EACs reported here are thermorheological simple materials, and the master curves are constructed and well-fitted by generalized logistic sigmoidal model functions. This research provides a facile, low-cost method for the preparation of polyetheramine-cured EACs that can be opened to traffic immediately, and the concept of quasi-thermosetting may facilitate the development of cheaper EACs for advanced applications. PMID- 26733316 TI - Inverted Wedding Cake Growth Operated by the Ehrlich-Schwoebel Barrier in Two Dimensional Nanocrystal Evolution. AB - Wedding cake growth is a layer-by-layer growth model commonly observed in epitaxial growth of metal films, featured by repeated nucleation of new atomic layers on the topmost surface owing to the confinement of the Ehrlich-Schwoebel (ES) barrier. Herein, we report an inverted wedding cake growth phenomenon observed in two-dimensional nanostructure evolution. Through a dynamically controlled vapor-solid deposition process of ZnO, a unique basin-shaped crown was formed on the tip of each nanowire, featured with concentric steps. The atomic steps were nucleated along the edge and propagated toward the center. This is an opposite growth behavior compared to the conventional wedding cake growth, and is thus denoted as inverted wedding cake growth. Through the relation between the crown expansion rate and the temperature, the ES barrier of ZnO was determined to be 0.88 eV. The discovery of inverted wedding cake growth provided insight into the developing nanostructure growth mechanisms. PMID- 26733317 TI - Diagnosis of tuberculosis in groups of badgers: an exploration of the impact of trapping efficiency, infection prevalence and the use of multiple tests. AB - Accurate detection of infection with Mycobacterium bovis in live badgers would enable targeted tuberculosis control. Practical challenges in sampling wild badger populations mean that diagnosis of infection at the group (rather than the individual) level is attractive. We modelled data spanning 7 years containing over 2000 sampling events from a population of wild badgers in southwest England to quantify the ability to correctly identify the infection status of badgers at the group level. We explored the effects of variations in: (1) trapping efficiency; (2) prevalence of M. bovis; (3) using three diagnostic tests singly and in combination with one another; and (4) the number of badgers required to test positive in order to classify groups as infected. No single test was able to reliably identify infected badger groups if 80% sensitive, at least 94% specific, and able to be performed rapidly in the field. PMID- 26733318 TI - The psychometric properties of an Arabic numeric pain rating scale for measuring osteoarthritis knee pain. AB - PURPOSE: The aims of this study were to translate the numeric rating scale (NRS) into Arabic and to evaluate the test-retest reliability and convergent validity of an Arabic Numeric Pain Rating Scale (ANPRS) for measuring pain in osteoarthritis (OA) of the knee. METHODS: The English version of the NRS was translated into Arabic as per the translation process guidelines for patient rated outcome scales. One hundred twenty-one consecutive patients with OA of the knee who had experienced pain for more than 6 months were asked to report their pain levels on the ANPRS, visual analogue scale (VAS), and verbal rating scale (VRS). A second assessment was performed 48 h after the first to assess test retest reliability. The test-retest reliability was calculated using the intraclass correlation coefficient (ICC2,1). The convergent validity was assessed using Spearman rank correlation coefficient. In addition, the minimum detectable change (MDC) and standard error of measurement (SEM) were also assessed. RESULTS: The repeatability of ANPRS was good to excellent (ICC 0.89). The SEM and MDC were 0.71 and 1.96, respectively. Significant correlations were found with the VAS and VRS scores (p <0.01). CONCLUSIONS: The Arabic numeric pain rating scale is a valid and reliable scale for measuring pain levels in OA of the knee. Implications for Rehabilitation The Arabic Numeric Pain Rating Scale (ANPRS) is a reliable and valid instrument for measuring pain in osteoarthritis (OA) of the knee, with psychometric properties in agreement with other widely used scales. The ANPRS is well correlated with the VAS and NRS scores in patients with OA of the knee. The ANPRS appears to measure pain intensity similar to the VAS, NRS, and VRS and may provide additional advantages to Arab populations, as Arabic numbers are easily understood by this population. PMID- 26733319 TI - The large-scale removal of mammalian invasive alien species in Northern Europe. AB - Numerous examples exist of successful mammalian invasive alien species (IAS) eradications from small islands (<10 km2 ), but few from more extensive areas. We review 15 large-scale removals (mean area 2627 km2 ) from Northern Europe since 1900, including edible dormouse, muskrat, coypu, Himalayan porcupine, Pallas' and grey squirrels and American mink, each primarily based on daily checking of static traps. Objectives included true eradication or complete removal to a buffer zone, as distinct from other programmes that involved local control to limit damage or spread. Twelve eradication/removal programmes (80%) were successful. Cost increased with and was best predicted by area, while the cost per unit area decreased; the number of individual animals removed did not add significantly to the model. Doubling the area controlled reduced cost per unit area by 10%, but there was no evidence that cost effectiveness had increased through time. Compared with small islands, larger-scale programmes followed similar patterns of effort in relation to area. However, they brought challenges when defining boundaries and consequent uncertainties around costs, the definition of their objectives, confirmation of success and different considerations for managing recolonisation. Novel technologies or increased use of volunteers may reduce costs. Rapid response to new incursions is recommended as best practice rather than large-scale control to reduce the environmental, financial and welfare costs. (c) 2016 Crown copyright. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 26733320 TI - Musculoskeletal (MSK) and Sport and Exercise Medicine (SEM) in General Practice (GP): A Novel GP-based MSK and SEM Clinic for Managing Musculoskeletal symptoms in a GP. AB - Musculoskeletal (MSK) complaints are common within primary care (1) (2) (3) but some General Practitioners (GPs)/family physicians do not feel comfortable managing these symptoms (3), preferring to refer onto hospital specialists or Integrated Clinical Assessment and Treatment Services (ICATs). Long waiting times for hospital outpatient reviews are a major cause of patient inconvenience and complaints (4). We therefore aimed to establish a GP-ran MSK and sport and exercise medicine (SEM) clinic based within a Belfast GP surgery that would contribute to a sustainable improvement in managing these common conditions within primary care as well as reducing waiting times for patients with these conditions to see a specialist. This shift from hospital-based to community-based management is in-keeping with recent policy changes within the UK health-system, including Transforming Your Care within Northern Ireland (NI) (5). The GP-ran MSK and SEM clinic was held monthly within a Belfast GP practice, staffed by one GP with a specialist interest in MSK and SEM conditions and its performance was reviewed over a three month period. Parameters audited included cases seen, orthopaedic and x-ray referral rates and secondary care referrals comparing the GP practice's performance to the same time period in the previous year as well as patient satisfaction questionnaires. PMID- 26733321 TI - Early event related fields during visually evoked pain anticipation. AB - OBJECTIVE: Pain experience is not only a function of somatosensory inputs. Rather, it is strongly influenced by cognitive and affective pathways. Pain anticipatory phenomena, an important limitation to rehabilitative efforts in the chronic state, are processed by associative and limbic networks, along with primary sensory cortices. Characterization of neurophysiological correlates of pain anticipation, particularly during very early stages of neural processing is critical for development of therapeutic interventions. METHODS: Here, we utilized magnetoencephalography to study early event-related fields (ERFs) in healthy subjects exposed to a 3 s visual countdown task that preceded a painful stimulus, a non-painful stimulus or no stimulus. RESULTS: We found that the first countdown cue, but not the last cue, evoked critical ERFs signaling anticipation, attention and alertness to the noxious stimuli. Further, we found that P2 and N2 components were significantly different in response to first-cues that signaled incoming painful stimuli when compared to non-painful or no stimuli. CONCLUSIONS: The findings indicate that early ERFs are relevant neural substrates of pain anticipatory phenomena and could be potentially serve as biomarkers. SIGNIFICANCE: These measures could assist in the development of neurostimulation approaches aimed at curbing the negative effects of pain anticipation during rehabilitation. PMID- 26733322 TI - One of society's most vulnerable groups? A systematically conducted literature review exploring the vulnerability of deafblind people. AB - The vulnerability of deafblind people is considered axiomatic; they are seen not only as a vulnerable group but also as one of the most vulnerable. This paper aims to synthesise existing knowledge to determine what is known about such vulnerability. A comprehensive literature search was undertaken between April 2013 and May 2014. The review method was informed by systematic review principles. An approach based on a 'hierarchy of evidence' would have reduced the amount of literature reviewed significantly, to the point where synthesis would not be possible. Included material was appraised and an interpretative rather than aggregative approach to synthesis adopted. Drawing on principles of critical interpretive synthesis, rather than being a determiner of whether material should be included or excluded, a critique of the literature is offered within the synthesis. Twenty-eight references were identified for inclusion, originating from the UK, USA, Australia, Continental Europe and the Nordic Countries. No empirical studies specifically examining the experience of vulnerability of deafblind people were found. However, deafblind people describe feelings of vulnerability in studies exploring their experiences more generally, and in personal accounts of living with the impairment. Literature produced by practitioners and specialist organisations also explores the topic. Deafblind people are identified as a population 'at risk' of various adverse outcomes, particularly when compared to the non-deafblind majority, and deafblind people describe being and feeling vulnerable in various situations. The literature largely relates to negative outcomes and includes significantly less exploration of positive risk taking, coping capacity and resilience. Deafblind people do not appear to describe themselves as being vulnerable as a permanent state, suggesting a need for greater exploration of the experience among all sections of this heterogeneous population, with consideration of the concepts of resilience and coping capacity. PMID- 26733324 TI - Withdrawing Benzodiazepines in Patients With Anxiety Disorders. AB - The large class of CNS-depressant medications-the benzodiazepines-have been extensively used for over 50 years, anxiety disorders being one of the main indications. A substantial proportion (perhaps up to 20-30 %) of long-term users becomes physically dependent on them. Problems with their use became manifest, and dependence, withdrawal difficulties and abuse were documented by the 1980s. Many such users experience physical and psychological withdrawal symptoms on attempted cessation and may develop clinically troublesome syndromes even during slow tapering. Few studies have been conducted to establish the optimal withdrawal schedules. The usual management comprises slow withdrawal over weeks or months together with psychotherapy of various modalities. Pharmacological aids include antidepressants such as the SSRIs especially if depressive symptoms supervene. Other pharmacological agents such as the benzodiazepine antagonist, flumazenil, and the hormonal agent, melatonin, remain largely experimental. The purpose of this review is to analyse the evidence for the efficacy of the usual withdrawal regimes and the newer agents. It is concluded that little evidence exists outside the usual principles of drug withdrawal but there are some promising leads. PMID- 26733325 TI - Kinetics of human myeloid-derived suppressor cells after blood draw. AB - BACKGROUND: Human myeloid-derived suppressor cells (MDSC) have been described as a group of immature myeloid cells which exert immunosuppressive action by inhibiting function of T lymphocytes. While there is a huge scientific interest to study these cells in multiple human diseases, the methodological approach varies substantially between published studies. This is problematic as human MDSC seem to be a sensible cell type concerning not only cryopreservation but also time point after blood draw. To date data on delayed blood processing influencing cell numbers and phenotype is missing. We therefore evaluated the kinetics of granulocytic MDSC (gMDSC) and monocytic MDSC (mMDSC) frequencies after blood draw in order to determine the best time point for analysis of this recently defined cell type. METHODS: In this study, we isolated peripheral blood mononuclear cells (PBMC) of patients with HIV infection or solid tumors directly after blood draw. We then analyzed the frequencies of gMDSC and mMDSC 2, 4 and 6 h after blood draw and after an overnight rest by FACS analysis using the standard phenotypic markers. In addition, part of the cells was frozen directly after PBMC preparation and was measured after thawing. RESULTS: gMDSC levels showed no significant difference using fresh PBMC over time with a limitation for the overnight sample. However they were massively diminished after freezing (p = 0.0001 for all subjects). In contrast, frequencies of fresh mMDSC varied over time with no difference between time point 2 and 4 h but a significantly reduction after 6 h and overnight rest (p = 0.0005 and p = 0.005 respectively). Freezing of PBMC decreased the yield of mMDSC reaching statistical significance (p = 0.04). For both MDSC subgroups, FACS analysis became more difficult over time due to less sharp divisions between populations. CONCLUSIONS: According to our data human MDSC need to be studied on fresh PBMC. gMDSC can be studied with delay, mMDSC however should be studied no later than 4 h after blood draw. These results are crucial as an increasing number of clinical trials aim at analyzing MDSC nowadays and the logistics of blood processing implies delayed sample processing in some cases. PMID- 26733323 TI - Hypocretins, Neural Systems, Physiology, and Psychiatric Disorders. AB - The hypocretins (Hcrts), also known as orexins, have been among the most intensely studied neuropeptide systems since their discovery about two decades ago. Anatomical evidence shows that the hypothalamic neurons that produce hypocretins/orexins project widely throughout the entire brain, innervating the noradrenergic locus coeruleus, the cholinergic basal forebrain, the dopaminergic ventral tegmental area, the serotonergic raphe nuclei, the histaminergic tuberomammillary nucleus, and many other brain regions. By interacting with other neural systems, the Hcrt system profoundly modulates versatile physiological processes including arousal, food intake, emotion, attention, and reward. Importantly, interruption of the interactions between these systems has the potential to cause neurological and psychiatric diseases. Here, we review the modulation of diverse neural systems by Hcrts and summarize potential therapeutic strategies based on our understanding of the Hcrt system's role in physiology and pathophysiological processes. PMID- 26733326 TI - Targeted Inhibition of Pregnancy-Associated Plasma Protein-A Activity Reduces Atherosclerotic Plaque Burden in Mice. AB - The metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A), has been implicated in the development of cardiovascular disease in humans and mouse models. In the latter, genetic deletion or overexpression of PAPP-A confirmed a major role for PAPP-A in atherosclerosis. In this study, we tested the hypothesis that targeting PAPP-A proteolytic activity by an inhibitory monoclonal antibody (mAb-PA) reduces atherosclerotic plaque progression. Apolipoprotein E knock-out mice on high-fat diet were treated with mAb-PA or isotype control. Control mice had a 10-fold increase in aortic plaque after 10 weeks. Aortic plaque burden was reduced by ~ 70% in mice treated with mAb-PA (P = 0.0002). Treatment was efficacious even in the face of elevated cholesterol and triglycerides. This study demonstrates proof-of-principle and provides feasibility for a novel therapeutic strategy to inhibit atherosclerotic plaque burden by selective targeting of PAPP-A. PMID- 26733329 TI - 14th Trinational Meeting of the German Surgical Working Group for Minimally Invasive Surgery (CAMIC), the Austrian Working Group for Minimally Invasive Surgery (AMIC) and the Swiss Association for Laparoscopic and Thoracoscopic Surgery (SALTS). PMID- 26733328 TI - The harm threshold and parents' obligation to benefit their children. AB - In an earlier paper entitled Harm is all you need?, I used an analysis of English law to claim that the harm threshold was an unsuitable mediator of the best interests test when deciding if parental decisions should be overruled. In this paper I respond to a number of commentaries of that paper, and extend my discussion to consider the claim that the harm threshold gives appropriate normative weight to the interests of parents. While I accept that parents have some rights over their children, I argue these are dependent on parents' duties to benefit their children. While many such benefits are understood pluralistically, and are thus within parents' ambit to decide, I claim that health benefits are ordinally different, because they play a foundational role in the flourishing of an individual. In the light of this, clinicians have the moral authority to override parental refusals, although in some cases abstaining from exercising this authority may be a pragmatic way to maintain parental engagement and ensure our ability to benefit the child in future. PMID- 26733327 TI - Absence of a Primary Role for SCN10A Mutations in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. AB - Prior reports have identified associations between SCN10A and cardiac disorders, such as atrial fibrillation and Brugada syndrome. We evaluated SCN10A in 151 probands with ARVD/C. In this cohort, 10 putatively pathogenic SCN10A variants were identified, including a novel frameshift insertion. Despite a known role for the encoded protein in peripheral nerve function, the proband with the frameshift variant had no discernible neurological abnormalities. Arrhythmic phenotypes were not different between those with a rare variant in SCN10A and those without. The prevalence of rare variants in SCN10A was similar among ARVD/C probands with and without a desmosome mutation and similar among healthy Caucasian controls. These results indicate the absence of a primary role for SCN10A mutations in ARVD/C. PMID- 26733330 TI - Unseen but present danger: improving the safe prescribing of anti-embolism stockings (AES). AB - A strong evidence base exists supporting thromboprophylaxis for venous thromboembolism (VTE) in surgical patients. Given the ageing population, obesity epidemic, and rise in type 2 diabetes, VTE and peripheral vascular disease (PAD) are likely to become an escalating problem. PAD is a contraindication to the use of anti-embolism stockings (AES). Half of those patients diagnosed with PAD report no symptoms, potentially underestimating its prevalence. Implementation of guidelines for thromboprophylaxis, including the safe prescribing of AES, is therefore imperative. The aims of this project were to establish whether thromboprophylaxis was being prescribed correctly, and appropriately, to all surgical inpatients. This included documented evidence that peripheral pulses had been examined - and, in the case of diabetic patients, that there was documentation of full peripheral neurovascular examination - before AES were prescribed. Data were collected from case notes of all surgical inpatients. Foundation year 1 doctors (FY1s) completed a questionnaire assessing their knowledge of local guidelines. Teaching sessions and posters summarising local guidelines were delivered to FY1s. Appropriate pharmacological prescribing improved from 57.69% to 100%. AES were appropriately prescribed for 65.38% of patients. Post intervention this increased to 79.17%. 0% had documented peripheral neurovascular examination. This increased to 50% post intervention. PMID- 26733331 TI - Preparation and characterization of electrospun in-situ cross-linked gelatin graphite oxide nanofibers. AB - Electrospun gelatin(Gel) nanofibers scaffold has such defects as poor mechanical property and quick degradation due to high solubility. In this study, the in situ cross-linked electrospinning technique was used for the production of gelatin nanofibers. Deionized water was chosen as the spinning solvent and graphite oxide (GO) was chosen as the enhancer. The morphological structure, porosity, thermal property, moisture absorption, and moisture retention performance, hydrolysis resistance, mechanical property, and biocompatibility of the produced nanofibers were investigated. Compared with in situ cross-linked gelatin nanofibers scaffold, in situ cross-linked Gel-GO nanofibers scaffold has the following features: (1) the hydrophilicity, moisture absorption, and moisture retention performance slightly reduce, while the hydrolysis resistance is improved; (2) the breaking strength, breaking elongation, and Young's modulus are significantly improved; (3) the porosity slightly reduces while the biocompatibility considerably increases. The in situ cross-linked Gel-GO nanofibers scaffold is likely to be applied in such fields as drug delivery and scaffold for skin tissue engineering. PMID- 26733333 TI - The roles of sepsis-induced myeloid derived suppressor cells in mice corneal, skin and combined transplantation. AB - PURPOSE: To explore the effects of adoptive transferring sepsis induced myeloid derived suppressor cells (iMDSCs) in mice corneal, skin, and combined corneal skin survival. METHODS: Allogeneic full-thickness corneal transplantation, fully mismatched skin transplantation, and corneal-skin combined transplantation (donor C57BL/6 to recipient Balb/c mice) were performed. Sepsis-induced infectious-MDSCs (iMDSCs), were purified from bone marrow of cecal ligated and punctured (CLP) Balb/c mice. Recipient-derived iMDSCs were adoptively transferred into different recipient groups by retro-orbital injection after surgeries. Corneal and skin grafts were examined and photographed routinely for a period of 45days. Histopathology was performed to evaluate corneal-graft inflammation. Bone marrow and/or corneal grafts in each group were harvested from executed recipients on postoperative days 15, 25, 35. Corneal cells and bone marrow cells were stained with CD11b-PE and Gr1-FITC, analyzed by FACS. RESULTS: iMDSCs were able to significantly prolong allograft survival in both corneal and corneal-skin combined transplant groups. A substantial expansion of MDSCs was observed in recipients' bone marrow, particularly in combined groups at an early stage postoperatively, and accordingly the concentration of MDSCs in corneal grafts increased significantly in adoptive transferred groups. CONCLUSIONS: Sepsis induced MDSCs may suggest a novel cellular therapeutic approach for preventing various types of allograft rejection. PMID- 26733332 TI - Metformin modulates apoptosis and cell signaling of human podocytes under high glucose conditions. AB - Diabetic nephropathy, which is associated with loss of human (h) podocytes (PC), is a major complication in diabetes mellitus. High-glucose modulates AMP activated protein kinase (AMPK) signaling and cell apoptosis. Metformin has been demonstrated to reduce apoptosis and albuminuria in type 2 diabetes. Here, we examined the effect of metformin on cell apoptosis and on pro-/anti-apoptotic signaling in hPC. Expression analyses were done by real-time polymerase chain reaction and western blotting. Moreover, a functional apoptosis assay was performed in hPC. Determination of kinase activation by phosphorylation was done via immunodetection analyses and digital quantification. We found that hPC express organic cation transporter 1 which is the major uptake transporter of metformin. High-glucose reduced AMPK phosphorylation and induced mammalian target of rapamycin (mTOR) activation in podocytes, which was abolished and reversed by pre-treatment with metformin. Furthermore, metformin reduced high-glucose-induced podocytes apoptosis in a concentration-dependent manner. In summary, metformin exhibits an anti-apoptotic impact on podocytes under high-glucose conditions via activation of AMPK and inhibition of mTOR signaling. These data support a beneficial effect of metformin in diabetic nephropathy. PMID- 26733334 TI - A death due to ecstasy - a case report. AB - Drug addicts face the dangers of accidental overdose, fatal intoxication, reduced tolerance and carelessness in consuming drugs. There is an increasing use of designer drugs in many cities. The body of a 29 year-old male, an event manager by profession with an alleged history of consumption of ecstasy tablets, was subjected to autopsy. The cause of death was found to be disseminated intravascular coagulation consequent upon consumption of methylenedioxymethamphetamine. This was based on the brief history, autopsy features and a chemical analysis report. This case is discussed with the background of the existing literature about the interplay of the actions of methylenedioxymethamphetamine, the hyperthermia that would result from physical exertion as in dancing in rave parties leading to hyponatremia and the causes of disseminated intravascular coagulation. PMID- 26733335 TI - Utilization of Professional Mental Health Services Related to Population-Level Screening for Anxiety, Depression, and Post-traumatic Stress Disorder Among Public High School Students. AB - This study examines results from three mental health screening measures in a cohort of adolescent public school students in seven public schools in Southeast Texas affiliated with the Dating it Safe study. We estimated the odds of receiving professional mental health treatment in the previous year given results from different mental health screening batteries: the CES-D 10 battery for depression screening, the Screen for Child Anxiety Related Disorders, and the Primary Care Posttraumatic Stress Disorder screen. Overall, students with higher scores on screening instruments for depression, posttraumatic stress disorder, and combinations of screening instruments were more likely to have sought past year professional mental health treatment than non-symptomatic youth. However, the proportion of students screening positive and receiving professional treatment was low, ranging from 11 to 16 %. This study emphasizes the need for broader evaluation of population-based mental health screening among adolescents. PMID- 26733336 TI - Stigma in Male Depression and Suicide: A Canadian Sex Comparison Study. AB - Stigma in men's depression and suicide can restrict help-seeking, reduce treatment compliance and deter individuals from confiding in friends and family. In this article we report sex comparison findings from a national survey of English-speaking adult Canadians about stigmatized beliefs concerning male depression and suicide. Among respondents without direct experience of depression or suicide (n = 541) more than a third endorsed the view that men with depression are unpredictable. Overall, a greater proportion of males endorsed stigmatizing views about male depression compared to female respondents. A greater proportion of female respondents endorsed items indicating that men who suicide are disconnected, lost and lonely. Male and female respondents with direct personal experience of depression or suicide (n = 360) strongly endorsed stigmatizing attitudes toward themselves and a greater proportion of male respondents indicated that they would be embarrassed about seeking help for depression. PMID- 26733337 TI - Six upper incisors: what's next? AB - BACKGROUND: This case report describes our therapeutic approach taken in a girl with eruption disturbance of the upper anterior teeth. Two supernumerary teeth were involved, which required a combination of orthodontic and surgical treatment. DIAGNOSIS: The initial situation in the upper anterior segment was characterized by two supernumerary mesial incisors, ectopic eruption of the distally located lateral incisors, and crowded tooth buds in the canine areas. Key decisions had to be made as to whether any teeth needed to be extracted and, if so, regarding the timing and sites of extraction. Removing teeth too early would have preempted a complete assessment of tooth quality, whereas late extraction would have carried a risk of eruption disturbance. TREATMENT: Once the distal lateral incisors had erupted, the supernumerary mesial incisors were extracted and the central incisors (initially located in between) mesialized with a bracket appliance. Following space closure and mesialization of the lateral incisors, a functional appliance was used. Tooth 13 was erupting, while tooth 23 was displaced and subsequently aligned as part of the final bracket treatment. CONCLUSION: To successfully treat eruption disturbances, a careful diagnostic workup is essential, including informative radiographs, personalized treatment planning, and correct decision-making as to whether teeth need to be extracted and regarding the timing and sites of extraction. Finally, the eruption of the canines should be monitored. PMID- 26733338 TI - Plasmonic phase modulator based on novel loss-overcompensated coupling between nanoresonator and waveguide. AB - We present that surface plasmon polariton, side-coupled to a gain-assisted nanoresonator where the absorption is overcompensated, exhibits a prominent phase shift up to pi maintaining the flat unity transmission across the whole broad spectra. Bandwidth of this plasmonic phase shift can be controlled by adjusting the distance between the plasmonic waveguide and the nanoresonator. For a moderate distance, within bandwidth of 100 GHz, the phase shift and transmission are constantly maintained. The plasmonic phase can be shift-keying-modulated by a pumping signal in the gain-assisted nanoresonator. A needed length in our approach is of nanoscale while already suggested types of plasmonic phase modulator are of micrometer scale in length. The energy consumption per bit, which benefits from the nano size of this device, is ideally low on the order of 10 fJ/bit. The controllable plasmonic phase shift can find applications in nanoscale Mach-Zehnder interferometers and other phase-sensitive devices as well as directly in plasmonic phase shift keying modulators. PMID- 26733339 TI - Optimizing Social Network Support to Families Living With Parental Cancer: Research Protocol for the Cancer-PEPSONE Study. AB - BACKGROUND: Parental cancer can have a significant impact on a family's psychosocial functioning and quality of life, whereby the children's situation is strongly related to parental coping and capacity. Such parents ask for more help in order to increase their care capacity, while the network is often insecure about how to help and thereby withdraw. They ask for guidance and training to be able to support cancer families. Based on this, the Cancer- Psycho-Educational Program for the SOcial NEtwork (PEPSONE) study was developed. OBJECTIVE: To optimize social network support through a psycho-educational program for families living with parental cancer and their network members in order to increase parental capacity and thereby secure the children's safety and quality of life. METHODS: A randomized controlled trial (RCT) in which families (N=60) living with parental cancer will be randomized to either an intervention group or a control group. The intervention will last for 3 hours and includes (1) introduction, (2) psycho-education (living with cancer in the family and the importance of social network support), and (3) discussion (this family's need for social support). Primary outcomes are social support, mental health, and quality of life, and secondary outcomes are resilience and parental capacity. Data will be collected by a set of questionnaires distributed to healthy parents (N=60) living with a partner with cancer, one child in the family between 8-18 years of age (N=60), and network members (N=210) of the intervention families at inclusion, and after 3 and 6 months. Comparing differences between the intervention group (n=30) and the control group (n=30), the power analysis shows that P<.05 and a statistical power = .80 would detect effect sizes of clinical interest. RESULTS: This paper presents the Cancer-PEPSON study's protocol to provide a broader understanding of the background and content of the program. The study is ongoing until August 2016 and the first results are anticipated to be finished by November 2015. CONCLUSIONS: To our knowledge, this will be the first RCT study to optimize social network support through a psycho-educational program for families living with parental cancer and their network members, as well as provide an evidence basis for social network support. The results may provide important knowledge that is useful for clinical practice and further research. The trial is reported according to the CONSORT checklist. CLINICALTRIAL: International Standard Randomized Controlled Trial Number (ISRCTN): 15982171; http://www.controlled trials.com/ISRCTN15982171/15982171 (Archived by WebCite at http://www.webcitation.org/6cg9zunS0). PMID- 26733340 TI - Present and future role of FDG-PET/CT imaging in the management of breast cancer. AB - Integrated positron emission tomography/computed tomography (PET/CT) with 2 [18F]fluoro-2-deoxy-D-glucose (FDG) is a useful tool for acquisition of both glucose metabolic and anatomic imaging data using a single device in a single diagnostic session, and has opened a new field in clinical oncologic imaging. FDG PET/CT has been used successfully for the diagnosis, initial staging, restaging, early treatment response assessment, evaluation of metastatic disease response, and prognostication of breast cancer as well as various malignant tumors. We herein review the current place and role of FDG-PET/CT in the management of breast cancer, focusing on its usefulness and limitations in the imaging of these patients. PMID- 26733342 TI - Emergency General Surgery: evolution of a subspecialty by stealth. AB - BACKGROUND: Emergency surgical patients account for around half of all NHS surgical workload and 80 % of surgical deaths. Few trainees opt to CCT in General Surgery, and there is no recognised subspecialty training program in Emergency General Surgery (EGS). Despite this lack of training and relevant assessment by examination, there appears to be an increasing number of EGS posts advertised. This study aims to provide information about potential future employment opportunities for surgical trainees. METHODS: All consultant surgeon posts, advertised in the British Medical Journal between January 2009 and December 2014 were included. Data collected included specialty, region and institute of advertised post. For the purposes of statistical analysis, data was divided into two separate year bands: 2009-2011 and 2012-2014. Statistical analysis was by Chi squared test; p <0.01 was considered statistically significant. An online tool was also used to determine experience and attitudes towards EGS amongst Consultant members of the ASGBI and all UK trainees in national training number (NTN) posts. RESULTS: Over the six-year study period, there were 1240 consultant job adverts in a general surgical specialty. Nine hundred and 75 were substantive posts; the region with the most jobs was London and the South East (n = 278). There were 55 jobs advertised in EGS, either with (20) or without (35) another subspecialty. The number of EGS adverts increased significantly in 2012-14 compared to 2009-11 (p = 0.008). 229 (28 %) Consultants and 309 (22 %) trainees responded to the survey. 16 % of consultants work in NHS institutions with Emergency General Surgeons. Only 21 % of trainees believe EGS will be delivered by EGS consultants in the future whilst 8.2 % of trainees stated EGS as their career plan. Less than half of all UK consultant surgeons see EGS as a subspecialty. CONCLUSIONS: This data demonstrates increasing societal need for EGS consultants over the last six years and the emergence of Emergency Surgery as a new subspecialty. In order to meet the EGS needs of the NHS, general surgical training and the examination system need to be revised. PMID- 26733341 TI - Identification and functional analysis of the geranylgeranyl pyrophosphate synthase gene (crtE) and phytoene synthase gene (crtB) for carotenoid biosynthesis in Euglena gracilis. AB - BACKGROUND: Euglena gracilis, a unicellular phytoflagellate within Euglenida, has attracted much attention as a potential feedstock for renewable energy production. In outdoor open-pond cultivation for biofuel production, excess direct sunlight can inhibit photosynthesis in this alga and decrease its productivity. Carotenoids play important roles in light harvesting during photosynthesis and offer photoprotection for certain non-photosynthetic and photosynthetic organisms including cyanobacteria, algae, and higher plants. Although, Euglenida contains beta-carotene and xanthophylls (such as zeaxanthin, diatoxanthin, diadinoxanthin and 9'-cis neoxanthin), the pathway of carotenoid biosynthesis has not been elucidated. RESULTS: To clarify the carotenoid biosynthetic pathway in E. gracilis, we searched for the putative E. gracilis geranylgeranyl pyrophosphate (GGPP) synthase gene (crtE) and phytoene synthase gene (crtB) by tblastn searches from RNA-seq data and obtained their cDNAs. Complementation experiments in Escherichia coli with carotenoid biosynthetic genes of Pantoea ananatis showed that E. gracilis crtE (EgcrtE) and EgcrtB cDNAs encode GGPP synthase and phytoene synthase, respectively. Phylogenetic analyses indicated that the predicted proteins of EgcrtE and EgcrtB belong to a clade distinct from a group of GGPP synthase and phytoene synthase proteins, respectively, of algae and higher plants. In addition, we investigated the effects of light stress on the expression of crtE and crtB in E. gracilis. Continuous illumination at 460 or 920 MUmol m(-2) s(-1) at 25 degrees C decreased the E. gracilis cell concentration by 28-40 % and 13-91 %, respectively, relative to the control light intensity (55 MUmol m(-2) s(-1)). When grown under continuous light at 920 MUmol m(-2) s(-1), the algal cells turned reddish-orange and showed a 1.3-fold increase in the crtB expression. In contrast, EgcrtE expression was not significantly affected by the light-stress treatments examined. CONCLUSIONS: We identified genes encoding CrtE and CrtB in E. gracilis and found that their protein products catalyze the early steps of carotenoid biosynthesis. Further, we found that the response of the carotenoid biosynthetic pathway to light stress in E. gracilis is controlled, at least in part, by the level of crtB transcription. This is the first functional analysis of crtE and crtB in Euglena. PMID- 26733344 TI - Factors controlling soil organic carbon stability along a temperate forest altitudinal gradient. AB - Changes in soil organic carbon (SOC) stability may alter carbon release from the soil and, consequently, atmospheric CO2 concentration. The mean annual temperature (MAT) can change the soil physico-chemical characteristics and alter the quality and quantity of litter input into the soil that regulate SOC stability. However, the relationship between climate and SOC stability remains unclear. A 500-day incubation experiment was carried out on soils from an 11 degrees C-gradient mountainous system on Changbai Mountain in northeast China. Soil respiration during the incubation fitted well to a three-pool (labile, intermediate and stable) SOC decomposition model. A correlation analysis revealed that the MAT only influenced the labile carbon pool size and not the SOC stability. The intermediate carbon pool contributed dominantly to cumulative carbon release. The size of the intermediate pool was strongly related to the percentage of sand particle. The decomposition rate of the intermediate pool was negatively related to soil nitrogen availability. Because both soil texture and nitrogen availability are temperature independent, the stability of SOC was not associated with the MAT, but was heavily influenced by the intrinsic processes of SOC formation and the nutrient status. PMID- 26733343 TI - Altered expression of mRNA profiles in blood of early-onset schizophrenia. AB - To identify gene expression abnormalities in schizophrenia (SZ), we generated whole-genome gene expression profiles using microarrays on peripheral blood mononuclear cells (PBMCs) from 18 early-onset SZ cases and 12 controls. We detected 84 transcripts differentially expressed by diagnostic status, with 82 genes being upregulated and 2 downregulated. We identified two SZ associated gene coexpression modules (green and red), including 446 genes . The green module is positively correlated with SZ, encompassing predominantly up-regulated genes in SZ; while the red module was negatively correlated with disease status, involving mostly nominally down-regulated genes in SZ. The olfactory transduction pathway was the most enriched pathways for the genes within the two modules. The expression levels of several hub genes, including AKT1, BRCA1, CCDC134, UBD, and ZIC2 were validated using real-time quantitative PCR. Our findings indicate that mRNA coexpression abnormalities may serve as a promising mechanism underlying the development of SZ. PMID- 26733345 TI - Size-controlled and redox-responsive supramolecular nanoparticles. AB - Control over the assembly and disassembly of nanoparticles is pivotal for their use as drug delivery vehicles. Here, we aim to form supramolecular nanoparticles (SNPs) by combining advantages of the reversible assembly properties of SNPs using host-guest interactions and of a stimulus-responsive moiety. The SNPs are composed of a core of positively charged poly(ethylene imine) grafted with beta cyclodextrin (CD) and a positively charged ferrocene (Fc)-terminated poly(amidoamine) dendrimer, with a monovalent stabilizer at the surface. Fc was chosen for its loss of CD-binding properties when oxidizing it to the ferrocenium cation. The ionic strength was shown to play an important role in controlling the aggregate growth. The attractive supramolecular and repulsive electrostatic interactions constitute a balance of forces in this system at low ionic strengths. At higher ionic strengths, the increased charge screening led to a loss of electrostatic repulsion and therefore to faster aggregate growth. A Job plot showed that a 1:1 stoichiometry of host and guest moieties gave the most efficient aggregate growth. Different stabilizers were used to find the optimal stopper to limit the growth. A weaker guest moiety was shown to be less efficient in stabilizing the SNPs. Also steric repulsion is important for achieving SNP stability. SNPs of controlled particle size and good stability (up to seven days) were prepared by fine-tuning the ratio of multivalent and monovalent interactions. Finally, reversibility of the SNPs was confirmed by oxidizing the Fc guest moieties in the core of the SNPs. PMID- 26733346 TI - Omega-3 prevents myelin degeneration in rat foetuses exposed to radiation. AB - The aim of this study is to investigate the protective effect of antioxidant omega-3 fatty acid (FA) on demyelinisation and degeneration of nerves in central and peripheral nervous systems (CNS and PNS) of rat foetuses. 38 pregnant rats weighing 140-155 g were used. Rats were divided into five groups. Group 1: 7 rats exposed to radiation treatment (RT) for 1 hour/day only; Group 2: 7 rats exposed to RT + Omega-3 FA (p.o.) for 1 hour/day; Group 3: 7 rats exposed to RT for 4 hours/day; Group 4: 7 rats exposed to RT + Omega-3 FA (p.o.) for 4 hours/day; and Group 5: 10 rats with no treatment. Nerve injury was induced by whole-body exposure to 20-MUT magnetic field. Omega-3 FA was given orally at a dose of 50 mg/kg. After 18 days, foetuses were delivered by the milking method; CNS and PNS were taken out for pathological examination. The degeneration scores of Group 2 were significantly lower than those of Group 1, whereas the degeneration scores of Group 4 were significantly higher than those of Groups 1 and 3. In conclusion, radiation increases demyelinisation and degeneration of nerves in the rat foetuses' CNS and PNS. Omega-3 FA prevents myelin and nerve degeneration in rat foetuses in low-dose radiation exposure. PMID- 26733347 TI - Urinary heme oxygenase-1 as a potential biomarker for early diabetic nephropathy. AB - BACKGROUND: Our previous study showed that increases of urinary heme oxygenase-1 (uHO-1) could be a potential biomarker indicating evaluating intrarenal oxidative damage in obstructive nephropathy. Activation of oxidative stress is an important mediator of diabetic nephropathy (DN). The aim of this study was to investigate the clinical implications of uHO-1 levels in patients with type 2 diabetes. METHODS: Eighty-four type 2 diabetic patients with normoalbuminuria (n=28), microalbuminuria (n=28), and macroalbuminuria (n=28) were included in this study. Control samples were collected from healthy volunteers (n=28) who had normal albuminuria and renal function. Urine HO-1 levels were evaluated by enzyme-linked immunosorbent assay. RESULTS: Urinary HO-1/creatinine (cr.) levels were significantly elevated in diabetic patients with microalbuminuria and macroalbuminuria compared to those in diabetic patients with normoalbuminuria (P<0.001) and control subjects (all P<0.001). In diabetic patients with normoalbuminuria, uHO-1/cr. levels were also higher than those in controls (P<0.001). Multivariate regression analyses revealed that uHO-1/cr. levels were positively correlated to urinary albumin/creatinine ratio and inversely correlated to glomerular filtration rate. Receiver operating characteristic (ROC) curve analysis of uHO-1/cr. levels for early diagnosis and detection of DN revealed that the cut-off value of uHO-1/cr. was 4.59 ng/mg (sensitivity 75%, specificity 78.6%). CONCLUSIONS: The findings of this study indicate that increases of urine HO-1 levels can be detected in patients with type 2 diabetes before the onset of significant albuminuria, and associated with renal derangement in patients with established diabetic nephropathy. Urinary HO-1 may be used as an early biomarker for diabetic renal injury. PMID- 26733348 TI - Using magnetic resonance imaging to quantify the inflammatory response following allergen challenge in allergic rhinitis. AB - Current rhinometric and flow assessments measure nasal patency and are often poorly correlated with rhinitis symptoms. To evaluate magnetic resonance imaging (MRI) as a new method to measure inflammatory changes in nasal and sinus mucosa following nasal allergen challenge. A pilot study (n = 6) determined the optimal technical settings for MRI to measure inflammatory change which were then adopted for the main study. This study was a single blind, placebo-controlled, three-way crossover trial in 14 subjects with seasonal allergic rhinitis. Effects of cetirizine, cetirizine and pseudoephedrine (Cet+PE), or placebo on total nasal symptom scores (TNSS), peak nasal inspiratory flow (PNIF), nasal nitric oxide (nNO), acoustic rhinometry, and MRI end points following nasal intranasal allergen challenge were measured. There were significant changes in all parameters after allergen challenge (P < 0.01), except for nNO. MRI end points were less variable and more consistent than PNIF and acoustic rhinometry in detecting changes after allergen challenge. Total nasal airspace volume was the most sensitive and reproducible MRI measurement, with a mean reduction from -5.37 cm(3) (95%CI -7.35, -3.38; P < 0.001), which was maximal 60 min after allergen challenge. A change of one in TNSS corresponded to a change in MRI volume of 0.57 cm(3). There was an improvement in all parameters (except nNO) in subjects taking Cet+PE compared with placebo, however this did not achieve significance probably because of the small study size (overall analysis P > 0.07; comparison of active versus placebo P > 0.09). MRI provides novel insights into the anatomical inflammatory changes post allergen challenge and provides a new method for assessment of nasal patency and objective measurement of inflammatory responses. PMID- 26733349 TI - A review of biomechanically informed breast image registration. AB - Breast radiology encompasses the full range of imaging modalities from routine imaging via x-ray mammography, magnetic resonance imaging and ultrasound (both two- and three-dimensional), to more recent technologies such as digital breast tomosynthesis, and dedicated breast imaging systems for positron emission mammography and ultrasound tomography. In addition new and experimental modalities, such as Photoacoustics, Near Infrared Spectroscopy and Electrical Impedance Tomography etc, are emerging. The breast is a highly deformable structure however, and this greatly complicates visual comparison of imaging modalities for the purposes of breast screening, cancer diagnosis (including image guided biopsy), tumour staging, treatment monitoring, surgical planning and simulation of the effects of surgery and wound healing etc. Due primarily to the challenges posed by these gross, non-rigid deformations, development of automated methods which enable registration, and hence fusion, of information within and across breast imaging modalities, and between the images and the physical space of the breast during interventions, remains an active research field which has yet to translate suitable methods into clinical practice. This review describes current research in the field of breast biomechanical modelling and identifies relevant publications where the resulting models have been incorporated into breast image registration and simulation algorithms. Despite these developments there remain a number of issues that limit clinical application of biomechanical modelling. These include the accuracy of constitutive modelling, implementation of representative boundary conditions, failure to meet clinically acceptable levels of computational cost, challenges associated with automating patient specific model generation (i.e. robust image segmentation and mesh generation) and the complexity of applying biomechanical modelling methods in routine clinical practice. PMID- 26733350 TI - Vertebral tuberculosis complicated with retropharyngeal, parathoracic, and huge iliopsoas abscess, successfully treated with image-guided percutaneous drainage. PMID- 26733351 TI - Evaluation of efficacy and safety of Lactobacillus rhamnosus in children aged 4 48 months with atopic dermatitis: An 8-week, double-blind, randomized, placebo controlled study. AB - OBJECTIVE: The main objective of this study was to evaluate the efficacy and safety of Lactobacillus rhamnosus in children aged 4-48 months with atopic dermatitis. METHODS: The design of this study was a two-center, double-blind, randomized, and placebo-controlled study with two parallel groups to evaluate the efficacy and safety profile of L. rhamnosus in children aged 4-48 months with atopic dermatitis diagnosed using Hanifin and Rajka criteria and with a Scoring of Atopic Dermatitis (SCORAD) >= 15 at enrollment. The duration of this study was 8 weeks with a total of five visits. The enrolled patients were allocated into either a treatment group (one ComProbi capsule containing L. rhamnosus a day) or a control group (one capsule of placebo a day) at a ratio of 1:1. The primary endpoint was to compare the mean change from baseline in SCORAD after 8 weeks of treatment. The other secondary end points were to compare the following: the mean changes from baseline in SCORAD at postbaseline visits, the frequency and total amount of the use of corticosteroids during the 8-week treatment, the frequency of atopic dermatitis and the symptom-free duration, the mean changes from baseline in Infant Dermatitis Quality of Life Questionnaire at Week 4 and Week 8, and the mean changes from baseline in the Dermatitis Family Impact Questionnaire at Week 4 and Week 8. RESULTS: The mean changes in SCORAD from baseline at Week 8 was -21.69 +/- 16.56 in the L. rhamnosus group and -12.35 +/- 12.82 in the placebo group for the intent-to-treat population (p = 0.014). For the per protocol population, the mean change of SCORAD from baseline was -23.20 +/- 15.24 in the L. rhamnosus group and -12.35 +/- 12.82 in the placebo group (p = 0.003). Significant differences were demonstrated between groups at Week 8 in intensity in the intent-to-treat population and per-protocol population. Throughout the period, the amount of topical corticosteroids used showed no difference between groups. No significant difference was noted in the overall symptom-free durations compared with the placebo group. Infant Dermatitis Quality of Life Questionnaires and Dermatitis Family Impact Questionnaires scores improved significantly at Week 4 and Week 8 but did not reach statistical significance. Adverse events were documented in 14/33 patients in the L. rhamnosus group (42.42%, 35 events) and in 15/33 placebo patients (45.45%, 37 events). CONCLUSIONS: The results of this study indicated that L. rhamnosus was effective in decreasing symptoms of atopic dermatitis after an 8-week treatment by comparing the mean change of SCORAD from baseline with a placebo (p < 0.05). The reduction in SCORAD resulted from a consistent decrease in all components of SCORAD. Patients who took L. rhamnosus for 8 weeks expressed less SCORAD in the three components: area of affected skin, intensity of atopic dermatitis, and patient symptoms, with a significant decrease in the mean change of intensity from baseline compared with placebo. PMID- 26733352 TI - Response to Commentary on 'Remote Ischemic Preconditioning to Reduce Contrast Induced Nephropathy: A Randomized Controlled Trial'. PMID- 26733355 TI - Improved Li storage performance in SnO2 nanocrystals by a synergetic doping. AB - Tin dioxide (SnO2) is a widely investigated lithium (Li) storage material because of its easy preparation, two-step storage mechanism and high specific capacity for lithium-ion batteries (LIBs). In this contribution, a phase-pure cobalt-doped SnO2 (Co/SnO2) and a cobalt and nitrogen co-doped SnO2 (Co-N/SnO2) nanocrystals are prepared to explore their Li storage behaviors. It is found that the morphology, specific surface area, and electrochemical properties could be largely modulated in the doped and co-doped SnO2 nanocrystals. Gavalnostatic cycling results indicate that the Co-N/SnO2 electrode delivers a specific capacity as high as 716 mAh g(-1) after 50 cycles, and the same outstanding rate performance can be observed in subsequent cycles due to the ionic/electronic conductivity enhancement by co-doping effect. Further, microstructure observation indicates the existence of intermediate phase of Li3N with high ionic conductivity upon cycling, which probably accounts for the improvements of Co N/SnO2 electrodes. The method of synergetic doping into SnO2 with Co and N, with which the electrochemical performances is enhanced remarkably, undoubtedly, will have an important influence on the material itself and community of LIBs as well. PMID- 26733354 TI - PYCR1 and PYCR2 Interact and Collaborate with RRM2B to Protect Cells from Overt Oxidative Stress. AB - Ribonucleotide reductase small subunit B (RRM2B) is a stress response protein that protects normal human fibroblasts from oxidative stress. However, the underlying mechanism that governs this function is not entirely understood. To identify factors that interact with RRM2B and mediate anti-oxidation function, large-scale purification of human Flag-tagged RRM2B complexes was performed. Pyrroline-5-carboxylate reductase 1 and 2 (PYCR1, PYCR2) were identified by mass spectrometry analysis as components of RRM2B complexes. Silencing of both PYCR1 and PYCR2 by expressing short hairpin RNAs induced defects in cell proliferation, partial fragmentation of the mitochondrial network, and hypersensitivity to oxidative stress in hTERT-immortalized human foreskin fibroblasts (HFF-hTERT). Moderate overexpression of RRM2B, comparable to stress-induced level, protected cells from oxidative stress. Silencing of both PYCR1 and PYCR2 completely abolished anti-oxidation activity of RRM2B, demonstrating a functional collaboration of these metabolic enzymes in response to oxidative stress. PMID- 26733356 TI - Pasireotide induced adrenal insufficiency. PMID- 26733357 TI - Reciprocity in group-living animals: partner control versus partner choice. AB - Reciprocity is probably the most debated of the evolutionary explanations for cooperation. Part of the confusion surrounding this debate stems from a failure to note that two different processes can result in reciprocity: partner control and partner choice. We suggest that the common observation that group-living animals direct their cooperative behaviours preferentially to those individuals from which they receive most cooperation is to be interpreted as the result of the sum of the two separate processes of partner control and partner choice. We review evidence that partner choice is the prevalent process in primates and propose explanations for this pattern. We make predictions that highlight the need for studies that separate the effects of partner control and partner choice in a broader variety of group-living taxa. PMID- 26733358 TI - ZnO gap engineering by doping with III-V compounds. AB - Gap engineering of ZnO by codoping it with III-V materials is investigated using model and ab initio calculation. Our results show that the codoped materials (ZnO)1-x (III-V)x , where (III-V) stands for GaN, AlN, AlP, BN, BP exhibit energy band gaps that get smaller as the dopant concentrations x is increased. Even at a very small dopant concentration the obtained band gaps are found to be much smaller than that of ZnO making the studied (ZnO)1-x(III-V)x materials promising candidates for photoelectrochemical water splitting. PMID- 26733359 TI - The synergistic effect of antiglycating agents (MB-92) on inhibition of protein glycation, misfolding and diabetic complications in diabetic-atherosclerotic rat. AB - Protein glycation due to hyperglycemia resulting in misfolding and aggregation, which is known as one of the most important reasons of diabetes complications. We previously showed the beneficial effects of some antiglycating agents in diabetic rats. Here, the effect of MB-92, a combination of some amino acids and crocetin (Crt, a saffron carotenoid), was studied in the prevention of diabetic complications in diabetic-atherosclerotic rats. In addition, the inhibitory effect of these treatments on glycation intermediates, aggregation and misfolding of proteins was investigated both in vivo and in vitro. Thus, the streptozotocin induced diabetic rats that underwent an atherogenic diet were treated with Crt, N acetylcyctein and MB-92. Then, glycated products and markers of oxidation and inflammation, in addition to other markers of diabetes complications were studied. The results of the in vivo study indicated that the mentioned treatments prevented the atheromatos formation, reduced the increased blood glucose; inhibited the formation of various glycation products, induced glyoxalase system (I and II), diminished oxidation and inflammatory markers, and improved lipid profile and atherosclerotic index in the diabetic-atherosclerotic rats; but MB-92 was the most effective treatment. In vitro results also confirmed that MB-92 was the most effective treatment to inhibit protein glycation and misfolding in comparison with the other treatments. In conclusion, MB-92 showed the greatest potential for inhibition of glycation and oxidation products, atheromatose plaque formation and inflammation in diabetic-atherosclerotic rats, and to control protein glycation, misfolding and aggregation in high glucose concentration; thus, it can be suggested as a new drug to prevent diabetic complications. PMID- 26733360 TI - Evaluating the treatment of obstructive sleep apnea comorbid with insomnia disorder using an incomplete factorial design. AB - Chronic insomnia disorder is a prevalent condition and a significant proportion of these individuals also have obstructive sleep apnea (OSA). These two sleep disorders have distinct pathophysiology and are managed with different treatment approaches. High comorbidity rates have been a catalyst for emerging studies examining multidisciplinary treatment for OSA comorbid with insomnia disorder. In this article, we describe a randomized clinical trial of cognitive behavioral treatment for insomnia (CBT-I) and positive airway pressure (PAP) for OSA. Participants are randomized to receive one of three treatment combinations. Individuals randomized to treatment Arm A receive sequential treatment beginning with CBT-I followed by PAP, in treatment Arm B CBT-I and PAP are administered concurrently. These treatment arms are compared to a control condition, treatment Arm C, where individuals receive PAP alone. Adopting an incomplete factorial study design will allow us to evaluate the efficacy of multidisciplinary treatment (Arms A & B) versus standard treatment alone (Arm C). In addition, the random allocation of individuals to the two different combined treatment sequences (Arm A and Arm B) will allow us to understand the benefits of the sequential administration of CBT-I and PAP relative to concurrent treatment of PAP and CBT-I. These findings will provide evidence of the clinical benefits of treating insomnia disorder in the context of OSA. PMID- 26733362 TI - A new nanocrystalline inorganic-organic hybrid exhibiting semiconducting properties and applications. AB - A new nanocrystalline inorganic-organic hybrid semiconductor [(BV)2(Ag5Br9)]n (1) with an intriguing windmill-like 1-D [Ag5Br9]n(n-) polymeric chain was assembled. Great efforts were devoted to investigate its semiconducting properties and applications, such as photoluminescence, emission decay lifetime, waste water purification, electrochemistry behavior and dielectric properties. PMID- 26733363 TI - Self referral to physiotherapy and other services would empower patients and doctors. PMID- 26733361 TI - NAADP-Dependent Ca(2+) Signaling Controls Melanoma Progression, Metastatic Dissemination and Neoangiogenesis. AB - A novel transduction pathway for the powerful angiogenic factor VEGF has been recently shown in endothelial cells to operate through NAADP-controlled intracellular release of Ca(2+). In the present report the possible involvement of NAADP-controlled Ca(2+) signaling in tumor vascularization, growth and metastatic dissemination was investigated in a murine model of VEGF-secreting melanoma. Mice implanted with B16 melanoma cells were treated with NAADP inhibitor Ned-19 every second day for 4 weeks and tumor growth, vascularization and metastatization were evaluated. Control specimens developed well vascularized tumors and lung metastases, whereas in Ned-19-treated mice tumor growth and vascularization as well as lung metastases were strongly inhibited. In vitro experiments showed that Ned-19 treatment controls the growth of B16 cells in vitro, their migratory ability, adhesive properties and VEGFR2 expression, indicating NAADP involvement in intercellular autocrine signaling. To this regard, Ca(2+) imaging experiments showed that the response of B16 cells to VEGF stimulation is NAADP-dependent. The whole of these observations indicate that NAADP-controlled Ca(2+) signaling can be relevant not only for neoangiogenesis but also for direct control of tumor cells. PMID- 26733364 TI - Conformational Insights into the Mechanism of Acetylaminofluorene-dG-Induced Frameshift Mutations in the NarI Mutational Hotspot. AB - Frameshift mutagenesis encompasses the gain or loss of DNA base pairs, resulting in altered genetic outcomes. The NarI restriction site sequence 5'-G1G2CG3CX-3' in Escherichia coli is a well-known mutational hotspot, in which lesioning of acetylaminofluorene (AAF) at G3* induces a greater -2 deletion frequency than that at other guanine sites. Its mutational efficiency is modulated by the nature of the nucleotide in the X position (C ~ A > G ? T). Here, we conducted a series of polymerase-free solution experiments that examine the conformational and thermodynamic basis underlying the propensity of adducted G3 to form a slipped mutagenic intermediate (SMI) and its sequence dependence during translesion synthesis (TLS). Instability of the AAF-dG3:dC pair at the replication fork promoted slippage to form a G*C bulge-out SMI structure, consisting of S- ("lesion stacked") and B-SMI ("lesion exposed") conformations, with conformational rigidity increasing as a function of primer elongation. We found greater stability of the S- compared to the B-SMI conformer throughout TLS. The dependence of their population ratios was determined by the 3'-next flanking base X at fully elongated bulge structures, with 59% B/41% S and 86% B/14% S for the dC and dT series, respectively. These results indicate the importance of direct interactions of the hydrophobic AAF lesion with the 3'-next flanking base pair and its stacking fit within the -2 bulge structure. A detailed conformational understanding of the SMI structures and their sequence dependence may provide a useful model for DNA polymerase complexes. PMID- 26733366 TI - Weak antilocalization and electron-electron interaction in coupled multiple channel transport in a Bi2Se3 thin film. AB - The electron transport properties of a topological insulator Bi2Se3 thin film are studied in Hall-bar geometry. The film with a thickness of 10 nm is grown by van der Waals epitaxy on fluorophlogopite mica and Hall-bar devices are fabricated from the as-grown film directly on the mica substrate. Weak antilocalization and electron-electron interaction effects are observed and analyzed at low temperatures. The phase-coherence length extracted from the measured weak antilocalization characteristics shows a strong power-law increase with decreasing temperature and the transport in the film is shown to occur via coupled multiple (topological surface and bulk states) channels. The conductivity of the film shows a logarithmical decrease with decreasing temperature and thus the electron-electron interaction plays a dominant role in quantum corrections to the conductivity of the film at low temperatures. PMID- 26733365 TI - IFPA meeting 2015 workshop report II: mechanistic role of the placenta in fetal programming; biomarkers of placental function and complications of pregnancy. AB - Workshops are an integral component of the annual International Federation of Placenta Association (IFPA) meeting, allowing for networking and focused discussion related to specialized topics on the placenta. At the 2015 IFPA meeting (Brisbane, Australia) twelve themed workshops were held, three of which are summarized in this report. These workshops focused on various aspects of placental function, particularly in cases of placenta-mediated disease. Collectively, these inter-connected workshops highlighted the role of the placenta in fetal programming, the use of various biomarkers to monitor placental function across pregnancy, and the clinical impact of novel diagnostic and surveillance modalities in instances of late onset fetal growth restriction (FGR). PMID- 26733367 TI - Safety and benefit of curative surgical resection for esophageal squamous cell cancer associated with multiple primary cancers. AB - BACKGROUND: Enhancements in surgical techniques have led to improved outcomes for esophageal cancer. Recent findings have showed that esophageal cancer is frequently associated with multiple primary cancers, and surgical resection is usually complicated in such cases. The aim of this study was to clarify the clinical significance of surgery for patients with esophageal squamous cell cancer associated with multiple primary cancers. METHODS: The clinical outcomes of surgical resection for esophageal cancer were compared among 79 patients with antecedent and/or synchronous cancers (Multiple cancer group) and 194 patients without antecedent and/or synchronous cancers (Single cancer group). RESULTS: The most common site of multiple primary cancers was the pharynx (36 patients; 29.7%), followed by the stomach (24 patients; 19.8%). The reconstruction method was more complicated in the Multiple cancer group as a result of the prolonged surgery time and increased blood loss. However, postoperative morbidity and overall survival (OS) did not differ between the two groups. After esophagectomy, metachronous cancers were observed in 26 patients, with 30 regions in total, and 93.1% were found to be curable. Sex was the only independent risk factors for developing metachronous cancer after esophagectomy. CONCLUSIONS: The presence of antecedent and synchronous cancers complicates the surgical resection of esophageal cancer; however, no differences were found in the OS and postoperative morbidity between the two groups. Therefore, surgical intervention should be selected as a first-line treatment. Because second primary cancers are often observed in esophageal cancer, we recommend a close follow-up using esophagogastroduodenoscopy and contrast-enhanced computed tomography. PMID- 26733368 TI - Colorectal cancer with synchronous hepatic metastases: Systematic review of reports comparing synchronous surgery with sequential bowel-first or liver-first approaches. AB - BACKGROUND: The management of colorectal cancer with synchronous liver-limited metastases currently lacks randomised trial evidence to inform case selection for any of the bowel-first, liver-first or synchronous surgery routes. We examine the literature to report outcome data from reports utilising all three approaches. METHODS: A systematic review was conducted using OvidSP (including Embase, EBM Reviews and MEDLINE databases) to find articles reporting discrete peri-operative and long-term outcomes for patients undergoing sequential bowel-first, liver first surgery or synchronous liver and bowel surgery. RESULTS: Of 223 unique citations, 3 cohort studies were identified comprising a pooled population of 1203 patients who completed treatment protocols between 1982 and 2011. Patients were allocated to bowel-first surgery (748 patients, 62.2%), liver-first surgery (75, 6.2%) or synchronous liver/bowel surgery (380, 31.6%). Minor complications were similar between procedures. Major complications were consistent with a pooled fixed estimate of 9.1% (95%CI: 7.6%-10.8%, I(2) = 48%). Post-operative death was rare and consistent with a pooled fixed effect estimate of 3.1% (95%CI: 2.2%-4.3%, I(2) = 0%). Median follow-up ranged from 25.1 to 40.0 months, with a pooled underlying 5-year survival fixed effect estimate of 44% (I(2) = 39%). CONCLUSION: This review assesses outcomes of patients with colorectal cancer with synchronous liver metastases managed by either synchronous, sequential liver first or bowel-first surgery. Overall treatment-related mortality is low and survival is similar among the three groups. These findings provide support for the continued use of all three pathways until better evidence to guide selection of an individual treatment option is available. PMID- 26733369 TI - Development and Implementation of a Catheter Associated Urinary Tract Infection (CAUTI) 'Toolkit'. AB - Indwelling urinary catheters are a commonly used invasive medical device within acute and non-acute settings in NHS Scotland. The second National Survey of the Prevalence of Hospital Acquired Infection (HAI) in Scotland 2011 identified that 19.2% of patients surveyed had an indwelling urinary catheter. In this survey, Urinary Tract Infections (UTI) were identified as the most prevalent type of HAI at 22.6% in acute settings and 39% in non-acute settings [1]. In September 2013 the Scottish Government released a Chief Executive Letter (CEL 19) which identified Catheter Associated Urinary Tract Infection (CAUTI) as one of the nine Points of Care Priorities within the Scottish Patient Safety Programme, with the aim of reducing CAUTI by 30% by end of December 2015 measured against a national definition [2]. This quality improvement project saw the development, testing and introduction within NHS Tayside of an evidenced based bundle of care. This was to standardise and drive quality care delivery for the insertion and maintenance of urethral urinary catheters with the intention of reducing catheter associated urinary tract infections in our patients. Data collection tools and data reporting mechanisms were also developed, tested and introduced using a national CAUTI definition to capture data for improvement and local and national reporting of progress. PMID- 26733370 TI - Moving to the Beat and Singing are Linked in Humans. AB - The abilities to sing and to move to the beat of a rhythmic auditory stimulus emerge early during development, and both engage perceptual, motor, and sensorimotor processes. These similarities between singing and synchronization to a beat may be rooted in biology. Patel (2008) has suggested that motor synchronization to auditory rhythms may have emerged during evolution as a byproduct of selection for vocal learning ("vocal learning and synchronization hypothesis"). This view predicts a strong link between vocal performance and synchronization skills in humans. Here, we tested this prediction by asking occasional singers to tap along with auditory pulse trains and to imitate familiar melodies. Both vocal imitation and synchronization skills were measured in terms of accuracy and precision or consistency. Accurate and precise singers tapped more in the vicinity of the pacing stimuli (i.e., they were more accurate) than less accurate and less precise singers. Moreover, accurate singers were more consistent when tapping to the beat. These differences cannot be ascribed to basic motor skills or to motivational factors. Individual differences in terms of singing proficiency and synchronization skills may reflect the variability of a shared sensorimotor translation mechanism. PMID- 26733372 TI - Achieving the protection of high peak bone mass. PMID- 26733371 TI - A shear gradient-activated microfluidic device for automated monitoring of whole blood haemostasis and platelet function. AB - Accurate assessment of blood haemostasis is essential for the management of patients who use extracorporeal devices, receive anticoagulation therapy or experience coagulopathies. However, current monitoring devices do not measure effects of haemodynamic forces that contribute significantly to platelet function and thrombus formation. Here we describe a microfluidic device that mimics a network of stenosed arteriolar vessels, permitting evaluation of blood clotting within small sample volumes under pathophysiological flow. By applying a clotting time analysis based on a phenomenological mathematical model of thrombus formation, coagulation and platelet function can be accurately measured in vitro in patient blood samples. When the device is integrated into an extracorporeal circuit in pig endotoxemia or heparin therapy models, it produces real-time readouts of alterations in coagulation ex vivo that are more reliable than standard clotting assays. Thus, this disposable device may be useful for personalized diagnostics and for real-time surveillance of antithrombotic therapy in clinic. PMID- 26733373 TI - Establishment of a normal reference value of parathyroid hormone in a large healthy Chinese population and evaluation of its relation to bone turnover and bone mineral density. AB - A normal reference value of parathyroid hormone (PTH) was established for the first time in a large sample of healthy Chinese subjects by completely excluding interference of vitamin D deficiency. A high PTH level correlated significantly with an elevated bone turnover and a reduced bone mineral density (BMD). INTRODUCTION: The aims of this study are to establish a normal reference value for serum PTH and to evaluate the effect of parathyroid gland status on bone turnover and BMD. METHODS: Our cross-sectional study included 1436 healthy individuals from 5 different Chinese cities. Concentrations of serum PTH, 25 hydroxyvitamin D (25OHD), procollagen I N-terminal peptide (P1NP, a bone formation marker), and carboxyl-terminal telopeptide of type I collagen (beta CTX, a bone resorption marker) were measured by electrochemiluminescence immunoassay. BMD was measured by dual-energy X-ray absorptiometry. The relation of PTH concentration to age, gender, height, and weight was examined. Reference values of PTH were established for all subjects and for subjects categorized by serum 25OHD concentrations. Correlations of PTH levels with bone turnover biomarkers and BMD were statistically analyzed. RESULTS: Reference values of PTH were 8.84-69.95 pg/mL in all the subjects and 7.48-60.73 and 5.83-56.78 pg/mL in the subjects with serum 25OHD concentrations of >=20 and >=30 ng/mL, respectively. Serum PTH showed a negative linear correlation with 25OHD, and the breakpoint was 18.21 ng/mL, below which the PTH level rapidly increased. The increase in PTH levels with age showed a positive linear correlation with P1NP and beta-CTX concentrations and a negative linear correlation with BMD at the lumbar spines and the femoral neck. CONCLUSIONS: A reference value of PTH was established in a large sample of healthy Chinese subjects according to 25OHD status, gender, and age. A high PTH level correlated significantly with an elevated bone turnover and a reduced BMD. PMID- 26733374 TI - Determinants of vitamin D supplementation prescription in nursing homes: a survey among general practitioners. AB - SUMMARY: A total of 119 GPs participated to a survey aimed to assess the profile and determinants of vitamin D supplementation prescription in nursing homes. Among the respondent GPs, 65 (54.6%) systematically prescribe vitamin D to their institutionalized patients and the 54 (45.4%) others prescribe only sometimes. INTRODUCTION: The aim of this study is to assess the profile and determinants of vitamin D supplementation prescription in nursing homes. METHODS: General practitioners (GPs) having at least one patient in a nursing home in Liege, Belgium, were asked to complete the survey. RESULTS: A total of 119 GPs participated in the survey. Among the respondent GPs, 65 (54.6 %) systematically prescribe vitamin D to their institutionalized patients and the 54 (45.4%) others prescribe only sometimes. The main reasons for prescribing vitamin D cited by GPs who do so systematically are as follows: because they believe nursing home residents are mostly deficient in vitamin D status (92.1%), because they believe that vitamin D supplementation prevents osteoporotic fractures (77.8%), and because vitamin D supplementation is recommended by various scientific societies (38.1%). GPs who only prescribe vitamin D supplementation in some patients mainly do so following a diagnosis of osteoporosis (82.4%), on the basis the 25(OH)D level (78.4%), in the case of history of fracture (54.9%) or after a recent fracture (43.4%). Surprisingly, 16 physicians (31.4%) only prescribe vitamin D when they think of it. Interestingly, while 40.7% of GPs always prescribe the same dose of vitamin D, the remaining 59.3% prescribe a dose that will mainly depend on the results of the 25(OH)D level (94.0%), the patient's bone health (49.3%), or history of fracture (43.3%). CONCLUSIONS: More than half of GPs systematically prescribe vitamin D to their patients living in nursing homes. The other GPs usually prescribe vitamin D following the result of the vitamin D status or after a diagnosis of osteoporosis. PMID- 26733375 TI - Pre-fracture quality of life predicts 1-year survival in elderly patients with hip fracture-development of a new scoring system. AB - Hip fractures are common in elderly people. Despite great progress in surgical care, the outcome of patients with hip fracture remains disappointing. This study determined four prognostic factors (lower ASA score, higher pre-fracture EQ-5D index, higher MMSE score, and female gender) to predict 1-year survival in patients with hip fracture. INTRODUCTION: This study determined the prognostic factors for 1-year survival in patients with hip fracture. Based on these predictors, a scoring system was developed for use upon patients' admission to the hospital. METHODS: Hip fracture patients, aged >=60 years, were prospectively enrolled. Upon admission, patients' sociodemographic data, type of fracture, American Society of Anesthesiologists (ASA) score, health-related quality of life scores (EQ-5D index) and Mini-Mental State Examination (MMSE) scores were recorded, among other parameters. Correlational analysis was performed on all potential variables to identify relevant predictor variables of 1-year survival. Univariate regression analysis was performed on all selected variables, followed by a multivariate analysis for variables that were significant in the univariate analysis. The final score was developed by converting the beta-coefficients of each variable from the multivariate analysis into a scoring system. RESULTS: For 391 hip fracture patients, complete data were available at the time of the 1-year follow-up. In multivariate regression analysis, independent predictors of 1-year survival were lower ASA score, higher pre-fracture EQ-5D index, higher MMSE score, and female gender. The different variables were weighted according to their beta-coefficient to build the prognostic score, which ranged from 0 to 10 points. The ROC curve for 1-year mortality after hip fracture showed an area under the curve of 0.74 (R (2) = 0.272; 95 % CI 0.68-0.79; p < 0.001). CONCLUSIONS: With only four instruments, the new score represents a useful tool for estimating 1-year survival in elderly patients with hip fractures. At present, the score is limited due to a lack of validation. A validation study is currently underway to prove its reliability. PMID- 26733376 TI - Hip fracture incidence in Japan: Estimates of new patients in 2012 and 25-year trends. AB - We estimated the number of hip fracture patients in 2012 in Japan and investigated the trends in incidence during a 25-year period from 1987 to 2012. Despite the increasing number of patients, the incidence of hip fracture in both men and women aged 70-79 years showed the possibility of decline. INTRODUCTION: The objectives of this study were to estimate the number of hip fracture patients in 2012, to investigate the trends in incidence during a 25-year period from 1987 to 2012, and to determine the regional differences in Japan. METHODS: Data were collected through a nationwide survey based on hospitals by a mail-in survey. Hip fracture incidences by sex and age and standardized incidence ratios by region were calculated. RESULTS: The estimated numbers of new hip fracture patients in 2012 were 175,700 in total (95 % CI 170,300-181,100), 37,600 (36,600-38,600) for men and 138,100 (134,300-141,900) for women. The incidence rates in both men and women aged 70-79 years were the lowest in the 20-year period from 1992 to 2012. The incidence was higher in western areas of Japan than that in eastern areas in both men and women; however, the difference in the incidence of hip fracture between western and eastern areas is becoming smaller. CONCLUSIONS: Despite the increasing number of new patients, the incidence of hip fracture in both men and women aged 70-79 years showed the possibility of decline. The exact reasons for this are unknown, but various drugs for improving bone mineral density or preventing hip fracture might have influenced the results. A decrease in the differences in nutrient intake levels might explain some of the change in regional differences in Japan. PMID- 26733377 TI - Bisphosphonates for prevention of osteopenia in kidney-transplant recipients: a systematic review of randomized controlled trials. AB - We conducted a systematic review of randomized controlled trials (RCTs) of bisphosphonates for the prevention of osteopenia in kidney-transplant recipients. Bisphosphonates improved bone mineral density at the lumbar spine and femoral neck after 12 months. However, additional well-designed RCTs are required to determine the optimal treatment strategy. Osteopenic-osteoporotic syndrome is a bone complication of renal transplantation. Bisphosphonates, calcitonin, and vitamin D analogs may be used to prevent or treat osteoporosis or bone loss after renal transplantation. However, there is currently no widely recognized strategy for the prevention of corticosteroid-induced osteoporosis. This study aims to assess the available evidence to guide the targeted use of bisphosphonates for reducing osteoporosis and bone loss in renal-transplant recipients. We searched the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE for randomized controlled trials of bisphosphonates for osteoporosis or bone loss after renal transplantation. A total of 352 abstracts were identified, of which 55 were considered for evaluation and 9 were included in the final analysis. The primary outcome measure was change in the bone mineral density (BMD) of the lumbar spine and femoral neck after 12 months. Data extraction was performed independently by two investigators. BMD at the lumbar spine was improved after treatment with bisphosphonates [9 trials; 418 patients; weighted mean difference (WMD), 0.61; 95 % confidence interval (CI), 0.16-1.06]. Eight trials (406 patients) that reported changes in BMD at the femoral neck also showed improved outcomes after treatment with bisphosphonates (WMD, 0.06; 95 % CI, 0.03-0.09). Bisphosphonates improve BMD at the lumbar spine and femoral neck after 12 months in renal-transplant recipients. PMID- 26733378 TI - Mechanisms of vasodilation to PTH 1-84, PTH 1-34, and PTHrP 1-34 in rat bone resistance arteries. AB - Parathyroid hormone (PTH) augments bone metabolism and bone mass when given intermittently. Enhanced blood flow is requisite to support high tissue metabolism. The bone arteries are responsive to all three PTH analogs, which may serve to augment skeletal blood flow during intermittent PTH administration. INTRODUCTION: PTH augments bone metabolism. Yet, mechanisms by which PTH regulates bone blood vessels are unknown. We deciphered (1) endothelium-dependent and endothelium-independent vasodilation to PTH 1-84, PTH 1-34, and PTHrP 1-34, (2) the signaling pathways (i.e., endothelial nitric oxide synthase [eNOS], cyclooxygenase [COX], protein kinase C [PKC], and protein kinase A [PKA]), and (3) receptor activation. METHODS: Femoral principal nutrient arteries (PNAs) were given cumulative doses (10(-13)-10(-8) M) of PTH 1-84, PTH 1-34, and PTHrP 1-34 with and without signaling pathway blockade. Vasodilation was also determined following endothelial cell removal (i.e., denudation), PTH 1 receptor (PTH1R) inhibition and to sodium nitroprusside (SNP; a nitric oxide [NO] donor). RESULTS: Vasodilation was lowest to PTH 1-34, and maximal dilation was highest to PTHrP 1 34. Inhibition of eNOS reduced vasodilation to PTH 1-84 (-80 %), PTH 1-34 (-66 %), and PTHrP 1-34 (-48 %), evidencing the contribution of NO. Vasodilation following denudation was eliminated (PTH 1-84 and PTHrP 1-34) and impaired (PTH 1 34, 17 % of maximum), highlighting the importance of endothelial cells for PTH signaling. Denuded and intact PNAs responded similarly to SNP. Both PKA and PKC inhibition diminished vasodilation in all three analogs to varying degrees. PTH1R blockade reduced vasodilation to 1, 12, and 12 % to PTH 1-84, PTH 1-34, and PTHrP 1-34, respectively. CONCLUSIONS: Vasodilation of femoral PNAs to the PTH analogs occurred via activation of the endothelial cell PTH1R for NO-mediated events. PTH 1-84 and PTHrP 1-34 primarily stimulated PKA signaling, and PTH 1-34 equally stimulated PKA and PKC signaling. PMID- 26733379 TI - Polymorphisms in Wnt signaling pathway genes are associated with peak bone mineral density, lean mass, and fat mass in Chinese male nuclear families. AB - Our objective was to investigate the associations between polymorphisms in Wnt pathway genes and peak bone mineral density (BMD) and body composition in young Chinese men. Our study identified that WNT5B and CTNNBL1 for both BMD and body composition, and WNT4 and CTNNB1 gene polymorphisms contribute to the variation in BMD and body composition in young Chinese men, respectively. INTRODUCTION: Our objective was to investigate the associations between polymorphisms in WNT4, WNT5B, WNT10B, WNT16, CTNNB1, and CTNNBL1 genes and peak bone mineral density (BMD), lean mass (LM), and fat mass (FM) in young Chinese men. METHODS: Using SNPscan(TM) kits, 51 single-nucleotide polymorphisms (SNPs) located in the 6 genes were genotyped in a total of 1214 subjects from 399 Chinese nuclear families. BMD, total lean mass (TLM), and total fat mass (TFM) were measured using dual energy X-ray absorptiometry (DXA). The associations between the 51 SNPs and peak BMD and body composition [including the TLM, percentage lean mass (PLM), TFM, percentage fat mass (PFM), and the body mass index (BMI)] were analyzed through quantitative transmission disequilibrium tests (QTDTs). RESULTS: For peak BMD, we found significant within-family associations of rs2240506, rs7308793, and rs4765830 in the WNT5B gene and rs10917157 in the WNT4 gene with the lumbar spine BMD (all P < 0.05). We detected an association of rs11830202, rs3809269, rs1029628, and rs6489301 in the WNT5B gene and rs2293303 in the CTNNB1 gene with body composition (all P < 0.05). For the CTNNBL1 gene, six SNPs (rs6126098, rs6091103, rs238303, rs6067647, rs8126174, and rs4811144) were associated with peak BMD of the lumbar spine, femoral neck, or total hip (all P < 0.05). Furthermore, two of the six SNPs (rs8126174 and rs4811144) were associated with body composition. CONCLUSIONS: This study identified WNT5B and CTNNBL1 for peak BMD and body composition in males from the Han Chinese ethnic group, and the results suggest a site-specific gene regulation. The WNT4 and CTNNB1 gene polymorphisms contribute to the variation in peak BMD and body composition, respectively. PMID- 26733380 TI - Prevalence and characteristics of hypoxic hepatitis in the largest single-centre cohort of avian influenza A(H7N9) virus-infected patients with severe liver impairment in the intensive care unit. AB - Avian influenza A(H7N9) virus (A(H7N9)) emerged in February 2013. Liver impairment of unknown cause is present in 29% of patients with A(H7N9) infection, some of whom experience severe liver injury. Hypoxic hepatitis (HH) is a type of acute severe liver injury characterized by an abrupt, massive increase in serum aminotransferases resulting from anoxic centrilobular necrosis of liver cells. In the intensive care unit (ICU), the prevalence of HH is ~1%-2%. Here, we report a 1.8% (2/112) incidence of HH in the largest single-centre cohort of ICU patients with A(H7N9) infection. Both HH patients presented with multiple organ failure (MOF) involving respiratory, cardiac, circulatory and renal failure and had a history of chronic heart disease. On admission, severe liver impairment was found. Peak alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values were 937 and 1281 U/L, and 3117 and 3029 U/L, respectively, in the two patients. Unfortunately, both patients died due to deterioration of MOF. A post mortem biopsy in case 1 confirmed the presence of centrilobular necrosis of the liver, and real-time reverse transcription polymerase chain reaction of A(H7N9) specific genes was negative, which excluded A(H7N9)-related hepatitis. The incidence of HH in A(H7N9) patients is similar to that in ICU patients with other aetiologies. It seems that patients with A(H7N9) infection and a history of chronic heart disease with a low left ventricular ejection fraction on admission are susceptible to HH, which presents as a marked elevation in ALT at the time of admission. PMID- 26733381 TI - Entry inhibitors: New advances in HCV treatment. AB - Hepatitis C virus (HCV) infection affects approximately 3% of the world's population and causes chronic liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although current antiviral therapy comprising direct-acting antivirals (DAAs) can achieve a quite satisfying sustained virological response (SVR) rate, it is still limited by viral resistance, long treatment duration, combined adverse reactions, and high costs. Moreover, the currently marketed antivirals fail to prevent graft reinfections in HCV patients who receive liver transplantations, probably due to the cell-to-cell transmission of the virus, which is also one of the main reasons behind treatment failure. HCV entry is a highly orchestrated process involving initial attachment and binding, post-binding interactions with host cell factors, internalization, and fusion between the virion and the host cell membrane. Together, these processes provide multiple novel and promising targets for antiviral therapy. Most entry inhibitors target host cell components with high genetic barriers and eliminate viral infection from the very beginning of the viral life cycle. In future, the addition of entry inhibitors to a combination of treatment regimens might optimize and widen the prevention and treatment of HCV infection. This review summarizes the molecular mechanisms and prospects of the current preclinical and clinical development of antiviral agents targeting HCV entry. PMID- 26733382 TI - Space, body, time and relationship experiences of recess physical activity: a qualitative case study among the least physical active schoolchildren. AB - BACKGROUND: Increasing recess physical activity has been the aim of several interventions, as this setting can provide numerous physical activity opportunities. However, it is unclear if these interventions are equally effective for all children, or if they only appeal to children who are already physically active. This study was conducted to explore the least physically active children's "lived experiences" within four existential lifeworlds linked to physical activity during recess: space, body, time, and relations. METHODS: The study builds on ethnographic fieldwork in a public school in Denmark using a combination of participatory photo interviews and participant observation. Thirty seven grade five children (11-12 years old) were grouped in quartiles based on their objectively measured daily physical activity levels. Eight children in the lowest activity quartile (six girls) were selected to participate in the study. To avoid stigmatising and to make generalisations more reliable we further recruited eight children from the two highest activity quartiles (four girls) to participate. RESULTS: An analysis of the least physically active children's "lived experiences" of space, body, time and relations revealed several key factors influencing their recess physical activity: perceived classroom safety, indoor cosiness, lack of attractive outdoor facilities, bodily dissatisfaction, bodily complaints, tiredness, feeling bored, and peer influence. CONCLUSION: We found that the four existential lifeworlds provided an in-depth understanding of the least physically active children's "lived experiences" of recess physical activity. Our findings imply that specific intervention strategies might be needed to increase the least physically active children's physical activity level. For example, rethinking the classroom as a space for physical activity, designing schoolyards with smaller secluded spaces and varied facilities, improving children's self-esteem and body image, e.g., during physical education, and creating teacher organised play activities during recess. PMID- 26733384 TI - Culturally Grounded Prevention for Minority Youth Populations: A Systematic Review of the Literature. AB - Contemporary prevention science has focused on the application of cultural adaptations of evidence-based prevention programs for minority youth populations. Far less is known about culturally grounded methods that are intended to organically develop prevention programs within specific populations and communities. This article systematically reviews recent literature on culturally grounded interventions used to prevent health disparities in ethnic minority youth populations. In this review, we assessed 31 peer-reviewed articles published in 2003 or later that fit inclusionary criteria pertaining to the development and evaluation of culturally grounded prevention programs. The evaluated studies indicated different approaches toward cultural grounding, as well as specific populations, geographic regions, and health issues that have been targeted. Specifically, the findings indicated that most of the studies focused on the development and evaluation of culturally grounded HIV/STI and substance abuse prevention programs for Mexican-American, African American, and American Indian/Alaska Native youth residing in the South or Southwestern US. These studies largely relied on community-based participatory or qualitative research methods to develop programs from the "ground up." This review has implications for the development of future culturally grounded and culturally adapted prevention programs targeting underserved minority youth populations and geographic regions. Specifically, it identifies populations and regions where culturally grounded prevention efforts are underdeveloped or non-existent, providing some scientific direction for the future development of these types of programs. PMID- 26733385 TI - Adolescent mice show anxiety- and aggressive-like behavior and the reduction of long-term potentiation in mossy fiber-CA3 synapses after neonatal maternal separation. AB - Exposure to maternal separation (MS) during early life is an identified risk factor for emotional disorders such as anxiety and depression later in life. This study investigated the effects of neonatal MS on the behavior and long-term potentiation (LTP) as well as basic synaptic transmission at hippocampal CA3-CA1 and mossy fiber (MF)-CA3 synapses in adolescent mice for 19days. When mice were adolescents, we measured depression, learning, memory, anxious and aggressive behavior using the forced swimming test (FST), Y-maze, Morris water maze (MWM), elevated plus maze (EPM), three consecutive days of the open field test, the social interaction test, the tube-dominance test and the resident-intruder test. The results showed that there was no difference in FST, Y-maze, and MWM performance. However, MS mice showed more anxiety-like behavior in the EPM test and aggressive-like behavior in the tube-dominance and resident-intruder tests. In addition, the magnitude of LTP and release probability in the MF-CA3 synapses was reduced in the MS group but not in the CA3-CA1 synapse. Our results indicate that early life stress due to MS may induce anxiety- and aggressive-like behavior during adolescence, and these effects are associated with synaptic plasticity at the hippocampal MF-CA3 synapses. PMID- 26733387 TI - Imiquimod Increases Cutaneous VEGF Expression in Imiquimod-induced Psoriatic Mouse Model. AB - Psoriasis is a chronic skin disease of unknown aetiology but increasing evidence suggests that cutaneous angiogenesis plays an important role. Vascular endothelial growth factor (VEGF) is one of the pro-angiogenic cytokines which is related to the pathogenesis of psoriasis. Our study evaluated the influence of imiquimod (IMQ) on VEGF in IMQ-induced mouse model. Balb/c female mice (n=16) 8 12 weeks of age were randomly divided into an experimental group (5% IMQ cream) and the control group (Vaseline cream). Serum levels of circulating VEGF-A were quantified by enzyme-linked immunosorbent assay. VEGF protein expression in tested skin was measured by western blotting and immunohistochemical staining. The tested skin in the experimental group expressed higher levels of VEGF protein than in the control group (p=0.012); immunohistochemical staining revealed that the cells over-expressing VEGF localized predominantly in the epidermis and vascular endothelium. Circulating VEGF-A levels showed no significant difference between the experimental and control groups (p=0.445). The IMQ-induced mouse psoriatic model showed an upregulation of VEGF in the skin lesions mimicking human psoriasis but the circulating VEGF-A levels showed no difference. This model may be useful to investigate the role of angiogenesis in psoriasis. PMID- 26733389 TI - Erratum to: Molecular mechanisms of gravity perception and signal transduction in plants. PMID- 26733388 TI - Lipid-Lowering Therapy in HIV-Infected Patients: Relationship with Antiretroviral Agents and Impact of Substance-Related Disorders. AB - BACKGROUND: The use of combination antiretroviral therapy (cART) has significantly decreased the morbidity and mortality associated with human immunodeficiency virus (HIV) infection. Lipid disorders, including lipodystrophy, hypertriglyceridemia, and hypercholesterolemia, remain the most commonly reported metabolic disorders among those treated with long-term cART. Mounting evidence suggests an association between drug abuse and poor glycemic control and diabetes complications. Substance related disorders (SRD) may increase the risk of metabolic syndrome. MATERIALS AND METHODS: The aim of this retrospective cohort study was to examine the relationship between SRD, cART, and lipid-lowering agent use in an HIV infected population. Patients received efavirenz or protease inhibitor-based cART for at least 6 months. Prescription information was retrieved from the medical records. The primary outcome was the use of lipid lowering agents including statins, fibrates and fish oil. The impact of SRD and cART was assessed on the lipid-lowering agent use. RESULTS: A total of 276 subjects with HIV infection were included, 90 (33%) received lipid-lowering agents, and 31 (34%) had SRD. Smoking was prevalent among subjects with SRD (84 vs 15%, p<0.001). Statins were the mainstay for the management of dyslipidemia (66%), followed by the fibrates (24%), omega-3 fatty acids (5%), nicotinic acid (3%) and the cholesterol absorption inhibitors (3%). Use of statins or fibrates was significantly higher among subjects without SRD than those with (40 vs 23%, p=0.005). The type of cART, including efavirenz and protease inhibitors, appeared to have no significant impact on the use pattern of lipid-lowering agents. Lopinavir/ritonavir (lopinavir/r) was mostly prescribed for subjects with SRD (25 vs 8%, p=0.02). CONCLUSION: Among HIV-infected patients, statins remain the mainstay for the management of dyslipidemia in routine clinical care, followed by fibrates. A significant high risk of metabolic disorders among patients with SRD is implicated by heavy tobacco use and prevalent lopinavir/r-based treatment. Significantly low rate of lipid-lowering agent use in this population underscores the importance of lipid disorder scrutiny and cART treatment optimization for HIV infected patients with SRD. PMID- 26733386 TI - Monogenic mouse models of autism spectrum disorders: Common mechanisms and missing links. AB - Autism spectrum disorders (ASDs) present unique challenges in the fields of genetics and neurobiology because of the clinical and molecular heterogeneity underlying these disorders. Genetic mutations found in ASD patients provide opportunities to dissect the molecular and circuit mechanisms underlying autistic behaviors using animal models. Ongoing studies of genetically modified models have offered critical insight into possible common mechanisms arising from different mutations, but links between molecular abnormalities and behavioral phenotypes remain elusive. The challenges encountered in modeling autism in mice demand a new analytic paradigm that integrates behavioral assessment with circuit level analysis in genetically modified models with strong construct validity. PMID- 26733390 TI - Comparative whole-transcriptome analysis in Podophyllum species identifies key transcription factors contributing to biosynthesis of podophyllotoxin in P. hexandrum. AB - Podophyllum species (Podophyllum hexandrum Royle and Podophyllum peltatum) are a major source of deriving anticancer drugs from their major chemical constituent, podophyllotoxin. However, information lacks on regulatory components of podophyllotoxin biosynthesis; therefore, different classes of transcription factors were identified through mining transcriptomes of Podophyllum species and validated through qRT-PCR analysis vis-a-vis podophyllotoxin contents in different tissues/organs of Podophyllum hexandrum. A total of 82, 278, 70, and 90 transcripts were identified in shoots and 89, 273, 72, and 91 transcripts in rhizomes of P. hexandrum transcriptome; 70, 268, 48, and 92 transcripts were in shoots and 58, 245, 41, and 85 transcripts in rhizomes of P. peltatum transcriptome corresponding to bZIP, MYB, WRKY, and bHLH families of transcription factors, which have been shown in regulating biosynthesis of secondary metabolites. Two unique transcripts encoding bHLH and MYB/SANT TFs in shoots of P. peltatum (medp_podpe_41091 and medp_podpe_2547) and bZIP and MYB TFs in rhizomes of P. hexandrum (medp_podhe_163581 and medp_podhe_147614) correlated with podophyllotoxin content. Quantification of podophyllotoxin and comparative expression analysis between high (2.51 %) versus low (0.59) podophyllotoxin content accessions revealed 0.04 to ~16-folds increase in transcripts of transcription factors, thereby further supporting the association of identified transcription factors with podophyllotoxin content. bZIP TF showed the highest transcript abundance (19.60-folds) in P. hexandrum rhizomes (2.51 % podophyllotoxin) compared to shoots (0.01 %). In silico analysis of putative promoter regions of pathway genes in other plant species revealed the presence of sequence elements for MYB and WRKY transcription factors, thereby suggesting their role in controlling the production of podophyllotoxin. A repertoire of additional transcription factors has been provided, which can be functionally validated and used in designing a suitable genetic intervention strategy towards enhanced production of podophyllotoxin. PMID- 26733391 TI - FORESEE: Fully Outsourced secuRe gEnome Study basEd on homomorphic Encryption. AB - BACKGROUND: The increasing availability of genome data motivates massive research studies in personalized treatment and precision medicine. Public cloud services provide a flexible way to mitigate the storage and computation burden in conducting genome-wide association studies (GWAS). However, data privacy has been widely concerned when sharing the sensitive information in a cloud environment. METHODS: We presented a novel framework (FORESEE: Fully Outsourced secuRe gEnome Study basEd on homomorphic Encryption) to fully outsource GWAS (i.e., chi-square statistic computation) using homomorphic encryption. The proposed framework enables secure divisions over encrypted data. We introduced two division protocols (i.e., secure errorless division and secure approximation division) with a trade-off between complexity and accuracy in computing chi-square statistics. RESULTS: The proposed framework was evaluated for the task of chi square statistic computation with two case-control datasets from the 2015 iDASH genome privacy protection challenge. Experimental results show that the performance of FORESEE can be significantly improved through algorithmic optimization and parallel computation. Remarkably, the secure approximation division provides significant performance gain, but without missing any significance SNPs in the chi-square association test using the aforementioned datasets. CONCLUSIONS: Unlike many existing HME based studies, in which final results need to be computed by the data owner due to the lack of the secure division operation, the proposed FORESEE framework support complete outsourcing to the cloud and output the final encrypted chi-square statistics. PMID- 26733392 TI - A strategy for the targeted metabolomics analysis of 11 gut microbiota-host co metabolites in rat serum, urine and feces by ultra high performance liquid chromatography-tandem mass spectrometry. AB - Microbiota-host co-metabolites are well-known to play important physiological roles, and their dysregulation has been found to be closely related to various diseases, including but not limited to inflammatory disorders. We developed herein an original and feasible method using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The method developed enables rapid quantification of 11 key gut microbiota-host co-metabolites spanning the succinate, phenylacetylglutamine, hippurate and trimethylamine metabolic pathways within 10 min. With this method, we were able to simultaneously monitor inflammation-induced alterations of these metabolites in rat serum, urine and feces matrices. The measured levels for this panel of endogenous metabolites ranged from 0.001 to 172.8 MUg m L(-1). The intra- and inter-day precision of three analytes was less than 13.1% and the accuracy was between -13.0 to 11.2% for all QC levels. The extraction recoveries in serum ranged from 85.4 to 103.2%, while the RSD was 9.0% or less for all recoveries. In addition, extraction recoveries of 11 analytes in urine and feces samples were between 85.7% and 102.0% and RSD was less than 9.5%. The method developed here has been successfully applied to the analysis of real samples from 2,4,6 trinitrobenzenesulfonic acid-induced Crohn's disease in rats. All of these results suggest that the presently developed method is sufficiently sensitive and robust to simultaneously monitor co-metabolites with diverse properties and a range of different concentrations. Therefore, this method will be expected to be useful for comprehensive studies of the pathophysiological roles and mechanisms of these key microbiota-host co-metabolites, which reflect the function of the intestine, consequently offering novel opportunities for evaluating the occurrence, development and therapeutic effects of diseases related to microbiota disturbances. PMID- 26733393 TI - Conventional and enantioselective gas chromatography with microfabricated planar columns for analysis of real-world samples of plant volatile fraction. AB - Within a project exploring the application of lab-on-chip GC to in-field analysis of the plant volatile fraction, this study evaluated the performance of a set of planar columns (also known as microchannels, MEMS columns, or microfabricated columns) of different dimensions installed in a conventional GC unit. Circular double-spiral-shaped-channel planar columns with different square/rectangular sections up to 2m long were applied to the analysis of both essential oils and headspace samples of a group of medicinal and aromatic plants (chamomile, peppermint, sage, rosemary, lavender and bergamot) and of standard mixtures of related compounds; the results were compared to those obtained with reference narrow-bore columns (l:5m, dc:0.1mm, df:0.1 MUm). The above essential oils and headspaces were first analyzed quali-and quantitatively with planar columns statically coated with conventional stationary phases (5%-phenyl polymethylsiloxane and auto-bondable nitroterephthalic-acid-modified polyethylene glycol), and then submitted to chiral recognition of their diagnostic markers, by enantioselective GC with a planar columns coated with a cyclodextrin derivative (30% 6(I-VII)-O-TBDMS-3(I-VII)-O-ethyl-2(I-VII)-O-ethyl-beta-cyclodextrin in PS 086). Column characteristics and analysis conditions were first optimized to obtain suitable retention and efficiency for the samples investigated. The planar columns tested showed performances close to the reference conventional narrow bore columns, with theoretical plate numbers per meter (N/m) ranging from 6100 to 7200 for those coated with the conventional stationary phases, and above 5600 for those with the chiral selector. PMID- 26733394 TI - Improved pinocembrin production in Escherichia coli by engineering fatty acid synthesis. AB - The development of efficient microbial processes for pinocembrin production has attracted considerable attention. However, pinocembrin biosynthetic efficiency is greatly limited by the low availability of the malonyl-CoA cofactor in Escherichia coli. Fatty acid biosynthesis is the only metabolic process in E. coli that consumes malonyl-CoA; therefore, we overexpressed the fatty acid biosynthetic pathway enzymes beta-ketoacyl-ACP synthase III (FabH) and beta ketoacyl-ACP synthase II (FabF) alone and in combination, and investigated the effect on malonyl-CoA. Interestingly, overexpressing FabH, FabF or both enzymes in E. coli BL21 (DE3) decreased fatty acid synthesis and increased cellular malonyl-CoA levels 1.4-, 1.6-, and 1.2-fold, respectively. Furthermore, pinocembrin production was increased 10.6-, 31.8-, and 5.87-fold in recombinant strains overexpressing FabH, FabF and both enzymes, respectively. Overexpression of FabF, therefore, triggered the highest pinocembrin production and malonyl-CoA levels. The addition of cerulenin further increased pinocembrin production in the FabF-overexpressing strain, from 25.8 to 29.9 mg/L. These results demonstrated that overexpressing fatty acid synthases can increase malonyl-CoA availability and improve pinocembrin production in a recombinant E. coli host. This strategy may hold promise for the production of other important natural products in which cellular malonyl-CoA is rate limiting. PMID- 26733395 TI - Longer time to antibiotics and higher mortality among septic patients with non specific presentations--a cross sectional study of Emergency Department patients indicating that a screening tool may improve identification. AB - BACKGROUND: The presentation of sepsis is varied and our hypotheses were that septic patients with non-specific presentations such as decreased general condition (DGC) have a less favourable outcome, and that a screening tool could increase identification of these patients. We aimed to: 1) assess time to antibiotics and in-hospital mortality among septic patients with ED chief complaint DGC, as compared with septic patients with other ED chief complaints, and 2) determine whether a screening tool could improve identification of septic patients with non-specific presentations such as DGC. METHODS: Cross sectional study comparing time to antibiotics (Mann Whitney and Kaplan-Meier tests), and in hospital mortality (logistic regression), between 61 septic patients with ED chief complaint DGC and 516 septic patients with other ED chief complaints. The sensitivity and specificity of the modified Robson screening tool was compared with that of ED doctor clinical judgment (McNemar's two related samples test) among 122 patients presenting to the ED with chief complaint DGC, of which 61 were discharged with ICD code sepsis. RESULTS: Septic patients presenting to the ED with the chief complaint DGC had a longer median time to antibiotics (05:26 h:minutes; IQR 4:00-10:40, vs. 03:56 h:minutes; IQR 2:21-7:32) and an increased in-hospital mortality (crude OR = 4.01; 95% CI, 2.19-7.32), compared to septic patients with other ED chief complaints. This association remained significant when adjusting for sex, age, priority, comorbidity and fulfilment of the Robson score (OR 4.31; 95% CI, 2.12-8.77). The modified Robson screening tool had a higher sensitivity (63.0 vs. 24.6%, p < 0.001), but a lower specificity (68.3 vs. 100.0%, p < 0.001), as compared to clinical judgment. DISCUSSION: This is, to the best of our knowledge, the first study comparing outcome of septic patients according to ED chief complaint. Septic patients presenting with a non-specific ED presentation, here exemplified as the chief complaint DGC, have a less favourable outcome. Our results indicate that implementation of a screening tool may increase the identification of septic patients. CONCLUSIONS: The results indicate that septic patients presenting with ED chief complaint DGC constitute a vulnerable patient group with delayed time to antibiotics and high in-hospital mortality. Furthermore, the results support that implementation of a screening tool may be beneficial to improve identification of these patients. PMID- 26733396 TI - Intensified effects of multi-Cu modification on the electronic properties of the modified base pairs containing hetero-ring-expanded pyrimidine bases. AB - Novel DNA base pair derivatives (A2CunU, A2CunC, G3CunU, and G3CunC) are designed by aromatic expansion of pyrimidine bases with four kinds of hetero-rings (denoted by nC and nU, n = 1, 2, 3, and 4) and metal-decoration through Cu replacement of hydrogens in the Watson-Crick hydrogen bond region. Their structures and properties are calculated for examining the cooperative effects of the two modification ways. The calculated results reveal that multiple Cu decoration makes up the deficiencies of size-expansion, and exhibits not only increase of structural stability and reduction of ionization potentials, but also ideal shrink of the HOMO-LUMO gaps, notable enhancement of interbase coupling as well as remarkable redshifts of pi -> pi* transitions for all M-x modified base pairs. The decrease extents of the gaps and ionization potentials follow the same order G3CunU > G3CunC > A2CunU > A2CunC, and in each series (denoted by different n), the gaps, ionization potentials and first pi -> pi* transition energies have an order of 4 < 1 < 2 < 3. The Cu d orbitals function as bridges for pi electron delocalization on the conjugated aromatic rings of two bases, leading to an enhancement of transverse electronic communication, as verified by spin density delocalization, orbital composition changes, redshift of the pi -> pi* transition and also advocated by the electron-sharing indexes such as delocalization index, Mayer bond orders and multicenter bonding. Electron localization function ELF-pi isosurfaces above the molecular plane further suggested that effective longitudinal conduction is closely relevant with the bicyclic domain involving good electron delocalization and strong pi-pi stacking between layers. This work presents theoretical evidence for the cooperative effects of metal decoration and ring-expansion modifications on the electronic properties of the modified base pairs and also proves that the base pairs designed here could be competent building blocks for the DNA-based nanowires with improved electron activity and excellent conductivity. PMID- 26733398 TI - The body comes to family therapy: Treatment of a school-aged boy with hyperventilation-induced non-epileptic seizures. AB - We present the case of a 10-year-old boy, Evan, where a knock to the head activated memories of past bullying, causing intense distress, activation of the body's stress-regulation systems and recurrent hospital presentations with hyperventilation-induced non-epileptic seizures. We describe the initial assessment session that enabled Evan and his family to understand the context for Evan's non-epileptic seizures, to engage with the therapeutic team and to collaborate in the implementation of a mind-body multimodal family-based intervention. Once the physical symptoms had been addressed therapeutically, we explored possible dangers within the family and school systems and we worked with Evan and his family to increase his ability to access comfort and protection from his parents. Our short hospital intervention highlighted the importance of ongoing therapeutic work with Evan and the family and laid the foundation stones for the next part of the family's therapeutic journey. PMID- 26733397 TI - The effects of acute cold exposure on morphology and gene expression in the heart of neonatal chicks. AB - Cold exposure induces an increase in blood flow and blood pressure, and long-term exposure to cold causes cardiac hypertrophy. Neonatal chicks (Gallus gallus domesticus) are highly sensitive to cold exposure, because their capacity for thermogenesis is immature until 1 week after hatching. Hence, we hypothesized that the heart of chicks at around 1 week of age acutely responds to cold environment. To investigate the effect of acute (24 h) and long-term (2 weeks) cold on the heart of chicks, 7-day-old chicks were exposed to cold temperature (4 degrees C) or kept warm (30 degrees C). Chicks exposed to the cold showed cardiac hypertrophy with marked left ventricular (LV) chamber dilation and wall thickening. On the other hand, long-term cold exposure (2 weeks from 7-day-old) induced an increase in total ventricular mass, but not in LV morphological parameters. Then, we investigated the details of acute cardiac hypertrophy in chicks. Electron microscopy revealed that cardiomyocytes in the hypertrophied LV had enlarged mitochondria with less dense cristae. Although the mRNA expression of lipoprotein lipase in the LV of the cold-exposed chicks significantly increased, the mRNA expression of genes involved in fatty acid beta-oxidation did not change in response to cold exposure. In addition, the mRNA expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha, which enhances mitochondrial biogenesis and function under physiological cardiac hypertrophy, increased in LV of cold-exposed chicks. The study found that acute cold exposure to neonatal chicks induces LV hypertrophy. However, these results suggest that acute cold exposure to chicks might induce both adaptive and maladaptive responses of the LV. PMID- 26733399 TI - Onset of main Phanerozoic marine radiation sparked by emerging Mid Ordovician icehouse. AB - The Great Ordovician Biodiversification Event (GOBE) was the most rapid and sustained increase in marine Phanerozoic biodiversity. What generated this biotic response across Palaeozoic seascapes is a matter of debate; several intrinsic and extrinsic drivers have been suggested. One is Ordovician climate, which in recent years has undergone a paradigm shift from a text-book example of an extended greenhouse to an interval with transient cooling intervals - at least during the Late Ordovician. Here, we show the first unambiguous evidence for a sudden Mid Ordovician icehouse, comparable in magnitude to the Quaternary glaciations. We further demonstrate the initiation of this icehouse to coincide with the onset of the GOBE. This finding is based on both abiotic and biotic proxies obtained from the most comprehensive geochemical and palaeobiological dataset yet collected through this interval. We argue that the icehouse conditions increased latitudinal and bathymetrical temperature and oxygen gradients initiating an Early Palaeozoic Great Ocean Conveyor Belt. This fuelled the GOBE, as upwelling zones created new ecospace for the primary producers. A subsequent rise in delta(13)C ratios known as the Middle Darriwilian Isotopic Carbon Excursion (MDICE) may reflect a global response to increased bioproductivity encouraged by the onset of the GOBE. PMID- 26733401 TI - Emerging drugs for the treatment of perennial allergic rhinitis. AB - INTRODUCTION: Allergic rhinitis is a worldwide health problem, currently affecting up to 40% of the general population, and characterized by the following symptoms in a variable degree of severity and duration: nasal congestion/obstruction, rhinorrhea, itchy nose and/or eyes, and/or sneezing. General symptoms like fatigue, reduced quality of sleep, impaired concentration and reduced productivity, if left untreated, may significantly affect quality of life. In addition, of being associated to various comorbidities, allergic rhinitis is also an independent risk factor for the development and worsening of asthma. Perennial allergic rhinitis is caused by allergens present around the year. AREAS COVERED: Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines currently recommend a stepwise therapeutic approach that combines patient education with specific allergen avoidance, symptomatic pharmacotherapy and allergen immunotherapy. The available treatment strategies provide suboptimal symptom relief in patients with moderate-to-severe disease who continue to experience symptoms while treated, even on multiple therapies. EXPERT OPINION: New insights into current therapy have been provided with the development of new symptomatic drugs with improved pharmacokinetics and safety. However, the ultimate research goal is beyond symptomatic treatment, and is mainly directed at modifying the immune response to allergens and prevent the progression of allergic rhinitis towards asthma. In this direction, promising advances are expected in the fields of allergen immunotherapy and biological drugs, such as omalizumab. Finally, significant research efforts are also focused on the growing number of new specific molecular targets involved in the Th2 pathway inflammation of allergic diseases. PMID- 26733402 TI - Aedes albopictus (Diptera: Culicidae) Oviposition Preference as Influenced by Container Size and Buddleja davidii Plants. AB - Aedes albopictus (Skuse) is a container-breeding mosquito commonly found in residential areas of its range in the United States. Mosquitoes are known to utilize flowering plants for sugar acquisition. Limited information is known about the influences on oviposition site selection, outside of container size. Residential areas are often landscaped with a variety of flowering plants and are known to provide numerous sizes of potential larval developmental sites for container-breeding mosqutioes. Through screened enclosure and field studies, the oviposition preference of Ae. albopictus for containers of three selected sizes (473, 946 and 1,892 ml) and the influence of flowering butterfly bush (Buddleja davidii Franchett cultivar 'Guinevere') plants were examined. Our results document that significantly more eggs were oviposited in the largest containers. Additionally, significantly more eggs were oviposited in containers adjacent to flowering butterfly bushes than in those without a flowering butterfly bush. Finally, our results document that flowering butterfly bushes exerted greater influence over Ae. albopictus oviposition decisions than did container size. Our findings can be applied to several aspects of Ae. albopictus surveillance and control. PMID- 26733400 TI - Herpes simplex virus encephalitis in Peru: a multicentre prospective study. AB - Herpes simplex virus (HSV) is one of the most commonly identified infectious aetiologies of encephalitis in North America and Europe. The epidemiology of encephalitis beyond these regions, however, is poorly defined. During 2009-2012 we enrolled 313 patients in a multicentre prospective study of encephalitis in Peru, 45 (14.4%) of whom had confirmed HSV infection. Of 38 patients with known HSV type, 84% had HSV-1 and 16% had HSV-2. Patients with HSV infection were significantly more likely to present in the summer months (44.4% vs. 20.0%, P = 0.003) and have nausea (60.0% vs. 39.8%, P = 0.01) and rash (15.6% vs. 5.3%, P = 0.01) compared to patients without HSV infection. These findings highlight differences in the epidemiology and clinical presentation of HSV encephalitis outside of the Northern Hemisphere that warrant further investigation. Furthermore, there is an urgent need for improved HSV diagnostic capacity and availability of intravenous acyclovir in Peru. PMID- 26733403 TI - Improving the Peri-operative care of Patients by instituting a 'Block Room' for Regional Anaesthesia. AB - Regional anaesthesia has multiple known benefits over general anaesthesia alone, but requires time and expertise for its application. This study aimed to decrease anaesthetic time and increase total surgical operative time by instituting a 'block room' where regional anaesthesia nerve blocks could be provided by expert anaesthetists in regular scheduled sessions. A baseline audit showed that 2 hours per day was spent on performing nerve blocks. Development of the block room allowed nerve blocks to be performed in parallel to surgical operations, reducing the mean anaesthetic control time from 44 mins to 27 mins. This freed time for an extra operative case per day. In addition, pooling of expertise to one site has allowed excellent teaching opportunities for anaesthetic trainees, and a specific training programme for regional anaesthesia is being produced. In conclusion, instituting a block room has improved the efficiency of our theatre complex, and improved the service deliverable to our patients. PMID- 26733404 TI - Antigen Presentation of Vacuolated Apicomplexans--Two Gateways to a Vaccine Antigen. AB - For parasites that sequester themselves within a vacuole, new rules governing antigen presentation are coming into focus. Components of the host's autophagy machinery and the parasite's membranous nanotubular network within the parasitophorous vacuole play a major role in determining antigenicity of Toxoplasma proteins. As such, both parasite and vaccinologist may exploit these pathways to regulate the ever important CD8 T cell response to apicomplexan parasites. PMID- 26733405 TI - Analysis and Quantitation of Glycated Hemoglobin by Matrix Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry. AB - Measurement of glycated hemoglobin is widely used for the diagnosis and monitoring of diabetes mellitus. Matrix assisted laser desorption/ionization (MALDI) time of flight (TOF) mass spectrometry (MS) analysis of patient samples is used to demonstrate a method for quantitation of total glycation on the beta subunit of hemoglobin. The approach is accurate and calibrated with commercially available reference materials. Measurements were linear (R(2) > 0.99) across the clinically relevant range of 4% to 20% glycation with coefficients of variation of <= 2.5%. Additional and independent measurements of glycation of the alpha subunit of hemoglobin are used to validate beta-subunit glycation measurements and distinguish hemoglobin variants. Results obtained by MALDI-TOF MS were compared with those obtained in a clinical laboratory using validated HPLC methodology. MALDI-TOF MS sample preparation was minimal and analysis times were rapid making the method an attractive alternative to methodologies currently in practice. PMID- 26733406 TI - Healthcare Utilisation and Drug Treatment in a Large Cohort of Patients with Inflammatory Bowel Disease. AB - BACKGROUND AND AIMS: Crohn's disease [CD] and ulcerative colitis [UC] are chronic diseases associated with a substantial utilisation of healthcare resources. We aimed to estimate the prevalence of inflammatory bowel disease [IBD], CD, and UC and to describe and compare healthcare utilisation and drug treatment in CD and UC patients. METHODS: This was a cross-sectional study of all patients with a recorded IBD diagnosis in Stockholm County, Sweden. Data on outpatient visits, hospitalisations, surgeries, and drug treatment during 2013 were analysed. RESULTS: A total of 13 916 patients with IBD were identified, corresponding to an overall IBD prevalence of 0.65% [CD 0.27%, UC 0.35%, inflammatory bowel disease unclassified 0.04%]; 49% of all IBD patients were treated with IBD-related drugs. Only 3.6% of the patients received high-dose corticosteroids, whereas 32.4% were treated with aminosalicylates [CD 21.2%, UC 41.0%, p < 0.0001]. More CD patients were treated with biologicals compared with UC patients [CD 9.6%, UC 2.9%, p < 0.0001] and surgery was significantly more common among CD patients [CD 3.0%, UC 0.8%, p < 0.0001]. CONCLUSIONS: This study indicates that patients with CD are the group with the highest medical needs. Patients with CD utilised significantly more healthcare resources [including outpatient visits, hospitalisations, and surgeries] than UC patients. Twice as many CD patients received immunomodulators compared with UC patients and CD patients were treated with biologicals three times more often. These results highlight that CD remains a challenge and further efforts are needed to improve care in these patients. PMID- 26733408 TI - Strategies for Teaching Professional Ethics to IT Engineering Degree Students and Evaluating the Result. AB - This paper presents an experience in developing professional ethics by an approach that integrates knowledge, teaching methodologies and assessment coherently. It has been implemented for students in both the Software Engineering and Computer Engineering degree programs of the Technical University of Madrid, in which professional ethics is studied as a part of a required course. Our contribution of this paper is a model for formative assessment that clarifies the learning goals, enhances the results, simplifies the scoring and can be replicated in other contexts. A quasi-experimental study that involves many of the students of the required course has been developed. To test the effectiveness of the teaching process, the analysis of ethical dilemmas and the use of deontological codes have been integrated, and a scoring rubric has been designed. Currently, this model is also being used to develop skills related to social responsibility and sustainability for undergraduate and postgraduate students of diverse academic context. PMID- 26733407 TI - Serum Hepcidin and Iron Absorption in Paediatric Inflammatory Bowel Disease. AB - BACKGROUND AND AIMS: We sought to correlate hepcidin levels in inflammatory bowel disease [IBD] children with disease activity, inflammatory markers, and iron load test [ILT] and to compare IBD patients with coeliac and healthy patients. METHODS: Between December 2012 and June 2013, 145 subjects [50 IBD patients, 45 coeliac patients and 50 healthy controls] were included in the study. All patients underwent the following examinations: blood count, iron status, erythropoiesis parameters, serum hepcidin, C-reactive protein [CRP], and erythrocyte sedimentation rate [ESR]. In order to evaluate the efficacy of iron absorption, ILT was performed in IBD patients. Disease activity indexes and IBD duration, localisation, and therapy were also evaluated, and a faecal sample for calprotectin collected. RESULTS: Serum hepcidin was significantly higher in IBD patients with active disease compared with both coeliac and healthy patients [p = 0.005, p = 0.003 respectively]. In a multivariate logistic regression model, having a Paediatric Crohn's Disease Activity Index [PCDAI] / Paediatric Ulcerative Colitis Activity Index [PUCAI] >= 30 resulted in the only variable independently associated with a positive serum hepcidin (odds ratio [OR] = 6.87; 95% confidence interval [CI] 1.4-33, p = 0.01]]. Patients with iron malabsorption [IM] showed higher values of ESR, CRP, and hepcidin [p = 0.02, p = 0.001, and p = 0.06, respectively]. Eight out of 12 [66.7%] children with IM showed an active disease compared with 6/31 [19.3%] children with normal ILT [p = 0.01]. Hepcidin levels correlated negatively with ILT [r = -0.451, p = 0.002], and positively with ferritin and CRP [r = 0.442, p = 0.0001; r = 0.243, p = 0.009, respectively] CONCLUSIONS: Our study demonstrates that serum hepcidin is increased in IBD children with active disease and it is responsible for IM. PMID- 26733409 TI - Toxicity and Pharmacokinetics of Sustained-Release Dexamethasone in Beagle Dogs. AB - INTRODUCTION: The purpose of the present study was to examine the potential ocular and systemic toxicity and toxicokinetics/pharmacokinetics of sustained release dexamethasone in canines. METHODS: In this non-randomized study, intracanalicular depots (dexamethasone-loaded or placebo vehicle) were inserted into both eyes of 33 beagles. Tear fluid and plasma were collected for toxicokinetic/pharmacokinetic analysis of dexamethasone, ophthalmic examinations were performed for signs of toxicity, and urine and blood samples were collected for urinalysis, hematology, clinical chemistry, and coagulation analysis. Animals were observed daily for signs of toxicity. Macroscopic and microscopic evaluations were performed. RESULTS: Mean dexamethasone tear fluid concentration from the dexamethasone group decreased from 4245 ng/mL 6-h post-insertion to 1044 ng/mL on Day 35. All plasma dexamethasone levels were below the limit of quantitation. No systemic or ocular toxicities were attributed to the dexamethasone depot. CONCLUSION: Sustained-release dexamethasone produced no identifiable ocular or systemic toxicity in this animal model, and pharmacokinetics demonstrated a tapered, sustained drug release. FUNDING: Ocular Therapeutix. PMID- 26733410 TI - SkQ1 Ophthalmic Solution for Dry Eye Treatment: Results of a Phase 2 Safety and Efficacy Clinical Study in the Environment and During Challenge in the Controlled Adverse Environment Model. AB - INTRODUCTION: This Phase 2 clinical trial assessed the efficacy and safety of the novel antioxidative, renewable compound SkQ1 for topical treatment of dry eye signs and symptoms. METHODS: In a single-center, randomized, double-masked, placebo-controlled, 29-day study, 91 subjects with mild to moderate dry eye instilled the study drug twice daily and recorded dry eye symptoms daily. Subjects were randomized 1:1:1 into one of three ophthalmic solution treatment groups: SkQ1 1.55 ug/mL, SkQ1 0.155 ug/mL, or 0.0 ug/mL (placebo). Subjects were exposed to a controlled adverse environment chamber at 3 of the 4 study visits (Day -7, Day 1, and Day 29). Investigator assessments occurred at all study visits. RESULTS: SkQ1 was safe and efficacious in treating dry eye signs and symptoms. Statistically significant improvements with SkQ1 compared to placebo occurred for the dry eye signs of corneal fluorescein staining and lissamine green staining in the central region and lid margin redness, and for the dry eye symptoms of ocular discomfort, dryness, and grittiness. In addition, SkQ1 demonstrated greater efficacy compared to placebo, although the differences were not statistically significant, for corneal fluorescein staining in other regions and/or time points (total staining score, central region, corneal sum score, and temporal region), lissamine green staining for the central and nasal regions, and blink rate scores. CONCLUSIONS: This Phase 2 study indicated that SkQ1 is safe and efficacious for the treatment of dry eye signs and symptoms and supported previous study results. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02121301. FUNDING: Miotech S.A. PMID- 26733415 TI - Growth/differentiation factor-15 deficiency compromises dopaminergic neuron survival and microglial response in the 6-hydroxydopamine mouse model of Parkinson's disease. AB - Growth/differentiation factor-15 (Gdf-15) is a member of the TGF-beta superfamily and a pleiotropic, widely distributed cytokine, which has been shown to play roles in various pathologies, including inflammation. Analysis of Gdf-15(-/-) mice has revealed that it serves the postnatal maintenance of spinal cord motor neurons and sensory neurons. In a previous study, exogenous Gdf-15 rescued 6 hydroxydopamine (6-OHDA) lesioned Gdf-15(+/+) nigrostriatal dopaminergic (DAergic) neurons in vitro and in vivo. Whether endogenous Gdf-15 serves the physiological maintenance of nigrostriatal DAergic neurons in health and disease is not known and was addressed in the present study. Stereotactic injection of 6 OHDA into the medial forebrain bundle (MFB) led to a significant decline in the numbers of DAergic neurons in both Gdf-15(+/+) and Gdf-15(-/-) mice over a time period of 14days. However, this decrease was exacerbated in the Gdf-15(-/-) mice, with only 5.5% surviving neurons as compared to 24% in the Gdf-15(+/+) mice. Furthermore, the microglial response to the 6-OHDA lesion was reduced in Gdf-15( /-) mice, with significantly lower numbers of total and activated microglia and a differential cytokine expression as compared to the Gdf-15(+/+) mice. Using in vitro models, we could demonstrate the importance of endogenous Gdf-15 in promoting DAergic neuron survival thus highlighting its relevance in a direct neurotrophic supportive role. Taken together, these results indicate the importance of Gdf-15 in promoting survival of DAergic neurons and regulating the inflammatory response post 6-OHDA lesion. PMID- 26733414 TI - The neuromuscular impact of symptomatic SMN restoration in a mouse model of spinal muscular atrophy. AB - BACKGROUND: Significant advances in the development of SMN-restoring therapeutics have occurred since 2010 when very effective biological treatments were reported in mouse models of spinal muscular atrophy. As these treatments are applied in human clinical trials, there is pressing need to define quantitative assessments of disease progression, treatment stratification, and therapeutic efficacy. The electrophysiological measures Compound Muscle Action Potential and Motor Unit Number Estimation are reliable measures of nerve function. In both the SMN?7 mouse and a pig model of spinal muscular atrophy, early SMN restoration results in preservation of electrophysiological measures. Currently, clinical trials are underway in patients at post-symptomatic stages of disease progression. In this study, we present results from both early and delayed SMN restoration using clinically-relevant measures including electrical impedance myography, compound muscle action potential, and motor unit number estimation to quantify the efficacy and time-sensitivity of SMN-restoring therapy. METHODS: SMA?7 mice were treated via intracerebroventricular injection with antisense oligonucleotides targeting ISS-N1 to increase SMN protein from the SMN2 gene on postnatal day 2, 4, or 6 and compared with sham-treated spinal muscular atrophy and control mice. Compound muscle action potential and motor unit number estimation of the triceps surae muscles were performed at day 12, 21, and 30 by a single evaluator blinded to genotype and treatment. Similarly, electrical impedance myography was measured on the biceps femoris muscle at 12days for comparison. RESULTS: Electrophysiological measures and electrical impedance myography detected significant differences at 12days between control and late-treated (4 or 6days) and sham-treated spinal muscular atrophy mice, but not in mice treated at 2days (p<0.01). EIM findings paralleled and correlated with compound muscle action potential and motor unit number estimation (r=0.61 and r=0.50, respectively, p<0.01). Longitudinal measures at 21 and 30days show that symptomatic therapy results in reduced motor unit number estimation associated with delayed normalization of compound muscle action potential. CONCLUSIONS: The incomplete effect of symptomatic treatment is accurately identified by both electrophysiological measures and electrical impedance myography. There is strong correlation between these measures and with weight and righting reflex. This study predicts that measures of compound muscle action potential, motor unit number estimation, and electrical impedance myography are promising biomarkers of treatment stratification and effect for future spinal muscular atrophy trials. The ease of application and simplicity of electrical impedance myography compared with standard electrophysiological measures may be particularly valuable in future pediatric clinical trials. PMID- 26733413 TI - The properties, functions, and pathophysiology of maxi-anion channels. AB - The maxi-anion channels (MACs) with a unitary conductance of 200-500 pS are detected in virtually every part of the whole body and found in cells from mammals to amphibia. The channels are normally silent but can be activated by physiologically/pathophysiologically relevant stimuli, such as osmotic, salt, metabolic, oxidative, and mechanical stresses, receptor activation, serum, heat, and intracellular Ca(2+) rise. In some MACs, protein dephosphorylation is associated with channel activation. Among MACs so far studied, around 60 % (designated here as Maxi-Cl) possess, in common, the following phenotypical biophysical properties: (1) unitary conductance of 300-400 pS, (2) a linear current-voltage relationship, (3) high anion-to-cation selectivity with PCl/Pcation of >8, and (4) inactivation at positive and negative potentials over a certain level (usually +/-20 mV). The pore configuration of the Maxi-Cl is asymmetrical with extracellular and intracellular radii of ~1.42 and ~1.16 nm, respectively, and a medial constriction down to ~0.55-0.75 nm. The classical function of MACs is control of membrane potential and fluid movement. Permeability to ATP and glutamate turns MACs to signaling channels in purinergic and glutamatergic signal transduction defining them as a perspective target for drug discovery. The molecular identification is an urgent task that would greatly promote the developments in this field. A possible relationship between these channels and some transporters is discussed. PMID- 26733417 TI - Estimation of deepwater temperature and hydrogeochemistry of springs in the Takab geothermal field, West Azerbaijan, Iran. AB - Chemical analyses of water samples from 19 hot and cold springs are used to characterize Takab geothermal field, west of Iran. The springs are divided into two main groups based on temperature, host rock, total dissolved solids (TDS), and major and minor elements. TDS, electrical conductivity (EC), Cl(-), and SO4 (2-) concentrations of hot springs are all higher than in cold springs. Higher TDS in hot springs probably reflect longer circulation and residence time. The high Si, B, and Sr contents in thermal waters are probably the result of extended water-rock interaction and reflect flow paths and residence time. Binary, ternary, and Giggenbach diagrams were used to understand the deeper mixing conditions and locations of springs in the model system. It is believed that the springs are heated either by mixing of deep geothermal fluid with cold groundwater or low conductive heat flow. Mixing ratios are evaluated using Cl, Na, and B concentrations and a mass balance approach. Calculated quartz and chalcedony geothermometer give lower reservoir temperatures than cation geothermometers. The silica-enthalpy mixing model predicts a subsurface reservoir temperature between 62 and 90 degrees C. The delta(18)O and deltaD (delta(2)H) are used to trace and determine the origin and movement of water. Both hot and cold waters plot close to the local meteoric line, indicating local meteoric origin. PMID- 26733416 TI - RPS23RG1 reduces Abeta oligomer-induced synaptic and cognitive deficits. AB - Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is generally believed that beta-amyloidogenesis, tau-hyperphosphorylation, and synaptic loss underlie cognitive decline in AD. Rps23rg1, a functional retroposed mouse gene, has been shown to reduce Alzheimer's beta-amyloid (Abeta) production and tau phosphorylation. In this study, we have identified its human homolog, and demonstrated that RPS23RG1 regulates synaptic plasticity, thus counteracting Abeta oligomer (oAbeta)-induced cognitive deficits in mice. The level of RPS23RG1 mRNA is significantly lower in the brains of AD compared to non-AD patients, suggesting its potential role in the pathogenesis of the disease. Similar to its mouse counterpart, human RPS23RG1 interacts with adenylate cyclase, activating PKA/CREB, and inhibiting GSK-3. Furthermore, we show that human RPS23RG1 promotes synaptic plasticity and offsets oAbeta-induced synaptic loss in a PKA-dependent manner in cultured primary neurons. Overexpression of Rps23rg1 in transgenic mice consistently prevented oAbeta-induced PKA inactivation, synaptic deficits, suppression of long-term potentiation, and cognitive impairment as compared to wild type littermates. Our study demonstrates that RPS23RG1 may reduce the occurrence of key elements of AD pathology and enhance synaptic functions to counteract oAbeta-induced synaptic and cognitive deficits in AD. PMID- 26733418 TI - Understanding Psychosocial and High-Risk Sexual Behaviors Among Detained Juveniles: A Descriptive Study Protocol. AB - BACKGROUND: African American women are disproportionately impacted by sexually transmitted infections (STIs), such as chlamydia and gonorrhea, which are known risk factors for human immunodeficiency virus (HIV) infection. STIs, particularly chlamydia and gonorrhea, are even more prevalent among young African American women with a juvenile detention history. The population with experiences with the criminal justice system has greater rates of STIs and is diagnosed more often with mental health issues, often related to sexual abuse or intimate partner violence, compared to peers who have not been detained by law enforcement. Psychosocial factors, especially those related to intimate relationships (ie, the imperativeness of being in a relationship and the power one has in their relationship), have emerged as important explanatory factors for acquiring STIs, including HIV, and a component of risk reduction interventions. OBJECTIVE: To investigate more comprehensively the relationship between psychosocial risk factors and STIs, including HIV, as it relates to reduction and prevention of these diseases. The long-term goal is to improve the effectiveness of evidence based interventions with a major focus on intimate relationship dynamics. METHODS: This descriptive study surveys young women (ages 13-17) who have been detained (incarcerated) by a department of juvenile justice. In addition to being female and detained, eligibility criteria include being detained longer than 30 days and being free of cognitive impairments. This study will include young women from one juvenile detention center. The primary outcomes to be measured are STI knowledge, intimate relationship dynamics (ie, imperativeness and power), and high-risk sexual behaviors. High-risk sexual behaviors will be assessed using data extracted from health records. RESULTS: Preliminarily, we have received assent from 26 primarily young African American women. The majority of participants (81%) had inadequate knowledge about STIs, 52% perceived a lack of power in their relationship, 56% were fearful of negotiating condom use, and 60% were not comfortable refusing sex. Interestingly, a majority of participants (68%) did not perceive a relationship as imperative. CONCLUSIONS: When enrollment and data collection are completed, it is expected that the primary outcome of intimate relationship dynamics (ie, imperativeness and power) will be associated with high-risk sexual behaviors and having an STI. Further, the findings are expected to provide guidance in developing a risk reduction intervention, for the population in which psychosocial factors related to intimate relationships will be central. PMID- 26733412 TI - Insulin-like growth factor-1 deficiency and metabolic syndrome. AB - Consistent evidence associates IGF-1 deficiency and metabolic syndrome. In this review, we will focus on the metabolic effects of IGF-1, the concept of metabolic syndrome and its clinical manifestations (impaired lipid profile, insulin resistance, increased glucose levels, obesity, and cardiovascular disease), discussing whether IGF-1 replacement therapy could be a beneficial strategy for these patients. The search plan was made in Medline for Pubmed with the following mesh terms: IGF-1 and "metabolism, carbohydrate, lipids, proteins, amino acids, metabolic syndrome, cardiovascular disease, diabetes" between the years 1963 2015. The search includes animal and human protocols. In this review we discuss the relevant actions of IGF-1 on metabolism and the implication of IGF-1 deficiency in the establishment of metabolic syndrome. Multiple studies (in vitro and in vivo) demonstrate the association between IGF-1 deficit and deregulated lipid metabolism, cardiovascular disease, diabetes, and an altered metabolic profile of diabetic patients. Based on the available data we propose IGF-1 as a key hormone in the pathophysiology of metabolic syndrome; due to its implications in the metabolism of carbohydrates and lipids. Previous data demonstrates how IGF 1 can be an effective option in the treatment of this worldwide increasing condition. It has to distinguished that the replacement therapy should be only undertaken to restore the physiological levels, never to exceed physiological ranges. PMID- 26733419 TI - The Clinicopathological Features and Long-Term Survival Outcomes of Mucinous Gastric Carcinoma: a Consecutive Series of 244 Cases from a Single Institute. AB - BACKGROUND AND OBJECTIVES: Mucinous gastric carcinoma (MGC) is a rare kind of malignancy with unclear prognosis. This study aims to assess the clinicopathological features and prognosis of MGC. METHODS: We retrospectively analyzed a consecutive series of 244 MGC patients who underwent radical gastrectomy with D2 lymphadenectomy, and compared the data with 260 gastric signet ring cell carcinoma (SRC) patients. RESULTS: The univariate survival analysis showed that the surgical types, diameter of the primary tumor, the Borrmann type, pathological depth of tumor invasion (pT), pathological number of metastatic lymph node (pN), pathological tumor lymph metastasis (pTNM), and vascular invasion were all significant predictors of survival (all P < 0.05). The multivariate survival analysis revealed that the diameter of the tumor, the Borrmann type, pT, pTNM stage, and vascular invasion as an independent predictive factor of survival (all P < 0.05). Compared with the SRC group, the MGC group had more male patients, more elder patients, larger tumor diameter, more T3 and T4 invasion to the gastric wall, more patients with metastatic lymph nodes, more pTNM stage III, and less Borrmann type 1. The overall survival rate of patients with MGC was significantly lower than that of patients with SRC (P < 0.001). CONCLUSIONS: MGC was an aggressive malignancy which had unique clinicopathological features. PMID- 26733421 TI - Post-Surgical Language Reorganization Occurs in Tumors of the Dominant and Non Dominant Hemisphere. AB - PURPOSE: Surgical resection of brain tumors may shift the location of cortical language areas. Studies of language reorganization primarily investigated left hemispheric tumors irrespective of hemispheric language dominance. We used functional magnetic resonance imaging (fMRI) to investigate how tumors influence post-surgical language reorganization in relation to the dominant language areas. METHODS: A total of, 17 patients with brain tumors (16 gliomas, one metastasis) in the frontotemporal and lower parietal lobes planned for awake surgery underwent pre-surgical and post-surgical language fMRI. Language activation post to-pre surgery was evaluated visually and quantitatively on the statistically thresholded images on patient-by-patient basis. Results were qualitatively compared between three patient groups: temporal, with tumors in the dominant temporal lobe, frontal, with tumors in the dominant frontal lobe and remote, with tumors in the non-dominant hemisphere. RESULTS: Post-to-pre-surgical distributions of activated voxels changed in all except the one patient with metastasis. Changes were more pronounced in the dominant hemisphere for all three groups, showing increased number of activated voxels and also new activation areas. Tumor resection in the dominant hemisphere (frontal and temporal) shifted the activation from frontal towards temporal, whereas tumor resection in the non dominant hemisphere shifted the activation from temporal towards frontal dominant areas. CONCLUSION: Resection of gliomas in the dominant and in the non-dominant hemisphere induces postsurgical shifts and increase in language activation, indicating that infiltrating gliomas have a widespread influence on the language network. The dominant hemisphere gained most of the language activation irrespective of tumor localization, possibly reflecting recovery of pre-surgical tumor-induced suppression of these activations. PMID- 26733420 TI - Expression profiling of genes involved in drought stress and leaf senescence in juvenile barley. AB - BACKGROUND: Drought stress in juvenile stages of crop development and premature leaf senescence induced by drought stress have an impact on biomass production and yield formation of barley (Hordeum vulgare L.). Therefore, in order to get information of regulatory processes involved in the adaptation to drought stress and leaf senescence expression analyses of candidate genes were conducted on a set of 156 barley genotypes in early developmental stages, and expression quantitative trait loci (eQTL) were identified by a genome wide association study. RESULTS: Significant effects of genotype and treatment were detected for leaf colour measured at BBCH 25 as an indicator of leaf senescence and for the expression level of the genes analysed. Furthermore, significant correlations were detected within the group of genes involved in drought stress (r = 0.84) and those acting in leaf senescence (r = 0.64), as well as between leaf senescence genes and the leaf colour (r = 0.34). Based on these expression data and 3,212 polymorphic single nucleotide polymorphisms (SNP) with a minor allele frequency >5% derived from the Illumina 9 k iSelect SNP Chip, eight cis eQTL and seven trans eQTL were found. Out of these an eQTL located on chromosome 3H at 142.1 cM is of special interest harbouring two drought stress genes (GAD3 and P5CS2) and one leaf senescence gene (Contig7437), as well as an eQTL on chromosome 5H at 44.5 cM in which two genes (TRIUR3 and AVP1) were identified to be associated to drought stress tolerance in a previous study. CONCLUSION: With respect to the expression of genes involved in drought stress and early leaf senescence, genotypic differences exist in barley. Major eQTL for the expression of these genes are located on barley chromosome 3H and 5H. Respective markers may be used in future barley breeding programmes for improving tolerance to drought stress and leaf senescence. PMID- 26733422 TI - RANTES correlates with inflammatory activity and synaptic excitability in multiple sclerosis. AB - BACKGROUND: Alterations of synaptic transmission induced by inflammatory activity have been linked to the pathogenic mechanisms of multiple sclerosis (MS). Regulated upon activation, normal T-cell expressed, and secreted (RANTES) is a pro-inflammatory chemokine involved in MS pathophysiology, potentially able to regulate glutamate release and plasticity in MS brains, with relevant consequences on the clinical manifestations of the disease. OBJECTIVE: To assess the role of RANTES in the regulation of cortical excitability. METHODS: We explored the association of RANTES levels in the cerebrospinal fluid (CSF) of newly diagnosed MS patients with magnetic resonance imaging (MRI) and laboratory measures of inflammatory activity, as well its role in the control of cortical excitability and plasticity explored by means of transcranial magnetic stimulation (TMS), and in hippocampal mouse slices in vitro. RESULTS: CSF levels of RANTES were remarkably high only in active MS patients and were correlated with the concentrations of interleukin-1beta. RANTES levels were associated with TMS measures of cortical synaptic excitability, but not with long-term potentiation (LTP)-like plasticity. Similar findings were obtained in mouse hippocampal slices in vitro, where we observed that RANTES enhanced basal excitatory synaptic transmission with no effect on LTP. CONCLUSION: RANTES correlates with inflammation and synaptic excitability in MS brains. PMID- 26733423 TI - White matter tract abnormalities are associated with cognitive dysfunction in secondary progressive multiple sclerosis. AB - BACKGROUND: While our knowledge of white matter (WM) pathology underlying cognitive impairment in relapsing remitting multiple sclerosis (MS) is increasing, equivalent understanding in those with secondary progressive (SP) MS lags behind. OBJECTIVE: The aim of this study is to examine whether the extent and severity of WM tract damage differ between cognitively impaired (CI) and cognitively preserved (CP) secondary progressive multiple sclerosis (SPMS) patients. METHODS: Conventional magnetic resonance imaging (MRI) and diffusion MRI were acquired from 30 SPMS patients and 32 healthy controls (HC). Cognitive domains commonly affected in MS patients were assessed. Linear regression was used to predict cognition. Diffusion measures were compared between groups using tract-based spatial statistics (TBSS). RESULTS: A total of 12 patients were classified as CI, and processing speed was the most commonly affected domain. The final regression model including demographic variables and radial diffusivity explained the greatest variance of cognitive performance (R2 = 0.48, p = 0.002). SPMS patients showed widespread loss of WM integrity throughout the WM skeleton when compared with HC. When compared with CP patients, CI patients showed more extensive and severe damage of several WM tracts, including the fornix, superior longitudinal fasciculus and forceps major. CONCLUSION: Loss of WM integrity assessed using TBSS helps to explain cognitive decline in SPMS patients. PMID- 26733424 TI - Professional patienthood and mortality: Sean O Riordain's diaries 1974-1977. AB - Unwieldy by nature, unsolicited diaries and their study, this article contends, have the potential to offer deeper insights into the experience of illness but only if they receive due consideration from scholars. This article uses a series of historic diaries to examine the concept of 'professional patienthood' or being a full-time patient, and, while it found the narrative medicine approach to be very useful, it also found it limiting. The recent methodological trends in biomedicine and social sciences towards structured mechanisms like questionnaires surveying and evaluating performance, satisfaction and experience-can only go so far. This article makes a case for the unsolicited, the unorthodox and the unstructured. PMID- 26733425 TI - Searching for the patient's voice in the Irish asylums. AB - The history of mental healthcare in Ireland ends to focus on the histories of institutions and development of mental health legislation. Attention has also been devoted to clinical records, with all of their interpretative and narrative complexities. In both the historiography and archives, however, patients themselves remain remarkably elusive, their voices astonishingly distant. In countries other than Ireland, there have been more extensive analyses of patients' letters, journals and first-person accounts of hospitalisation and treatment. In Ireland, there is real difficulty accessing such accounts, if they exist, especially from the 1800s. Asylum and hospital records offer some assistance in understanding patients' concerns and, arguably, the symptoms recorded in asylum records (eg, delusions) provide further windows into patients' minds. Methodological challenges abound, but while patients' voices may remain largely unknown at present, they are certainly not unknowable. This paper posits that we just need to listen harder and, perhaps, listen better. PMID- 26733426 TI - Twin-Induced InSb Nanosails: A Convenient High Mobility Quantum System. AB - Ultra narrow bandgap III-V semiconductor nanomaterials provide a unique platform for realizing advanced nanoelectronics, thermoelectrics, infrared photodetection, and quantum transport physics. In this work we employ molecular beam epitaxy to synthesize novel nanosheet-like InSb nanostructures exhibiting superior electronic performance. Through careful morphological and crystallographic characterization we show how this unique geometry is the result of a single twinning event in an otherwise pure zinc blende structure. Four-terminal electrical measurements performed in both the Hall and van der Pauw configurations reveal a room temperature electron mobility greater than 12,000 cm(2).V(-1).s(-1). Quantized conductance in a quantum point contact processed with a split-gate configuration is also demonstrated. We thus introduce InSb "nanosails" as a versatile and convenient platform for realizing new device and physics experiments with a strong interplay between electronic and spin degrees of freedom. PMID- 26733427 TI - Does consumption of platelet-derived microparticles in the fibrin clot explain the decrease in their percentage during pregnancy? PMID- 26733428 TI - Care erosion in hospitals: Problems in reflective nursing practice and the role of cognitive dissonance. AB - Care erosion - gradual decline in care level - is an important problem in health care today. Unfortunately, the mechanism whereby it occurs is complex and poorly understood. This paper seeks to address this by emphasising problems in reflective nursing practice. Critical reflection on quality of care which should drive good care instead spawns justifications, denial, and trivialisation of deficient care. This perpetuates increasingly poor care levels. We argue that cognitive dissonance theory provides a highly effective understanding of this process and suggest for this approach to be incorporated in all efforts to address care erosion. The paper includes a detailed discussion of examples and implications for practice, in particular the need to restore critical reflection in nursing, the importance of embracing strong values and standards, and the need for increased awareness of signs of care erosion. PMID- 26733429 TI - Pyelonephritis and obstructive uropathy: a case of acute kidney injury. AB - We present a case of a man in his late 50s with a history of metastatic prostate carcinoma requiring bilateral ureteric stenting. He was admitted with increasing confusion and lethargy. He was diagnosed with sepsis and an acute kidney injury (AKI). Clinical suspicions of an obstructive component to his AKI were not confirmed by an ultrasound scan, which showed a unilateral hydronephrosis unchanged from a scan 1 month previously. A nephrostomy was performed, and frank pus aspirated. The patient's clinical state improved steadily thereafter. Patients who are dehydrated, or who have suffered from malignant or fibrotic processes affecting the retroperitoneum, may present with urinary obstruction without a corresponding increase in urinary tract dilation. Additionally, there must be a suspicion of pyonephrosis in a symptomatic patient with known hydronephrosis. Clinicians should be aware that clinical suspicions of urinary obstruction not demonstrated on ultrasound scanning require further investigation. PMID- 26733430 TI - Bloom's syndrome in an Indian man in the UK. AB - A 17-year-old Indian man was diagnosed with Bloom's syndrome at the age of 3 years. This is the first reported case of Bloom's in an Indian from the UK and the third case report from the British Isles. Bloom's is typically characterised by short stature, photosensitivity, telangiectatic erythema, learning difficulties, immunodeficiency and malignancy. He was born below the 0.4th centile and failed to gain weight as an infant. He presented in clinic with short stature, prominent facial features and hyperpigmented skin patches, which are all defining characteristics of Bloom's syndrome. Other case reports have documented early neoplasms, photosensitivity and learning difficulties in these patients; however, our patient is different, and currently attends a mainstream college, demonstrating little difficulty in coping with the work. To date, he has not presented with any malignancy or characteristic malar rash. PMID- 26733431 TI - Challenging ipsilateral hip and segmental diaphyseal femur fractures with a severely osteoarthritic hip joint: lessons learnt. PMID- 26733432 TI - Omental torsion, a rare cause of acute abdomen. AB - Omental torsion is a rare cause of acute abdominal pain. We report a case of omental torsion in a 7-year-old girl, who presented with right iliac fossa pain. The patient underwent an open appendicectomy, during which a normal appendix was identified and a diagnosis of omental torsion was made. The affected segment of omentum was resected along with the appendix. The patient made an uncomplicated recovery and was discharged on day 1 postoperatively. A normal appendix in the presence of omental torsion is found in 0.1% of all appendicectomies in children. We suggest routine visualisation of the omentum in the presence of a normal appendix during appendicectomy. PMID- 26733433 TI - PAN's labyrinth: a multidisciplinary delayed diagnosis and patient's perspective. AB - Polyarteritis nodosa (PAN) is a rare, severe form of vasculitis affecting medium sized vessels. It manifests as a multisystem syndrome, and may be associated with hepatitis B virus-associated PAN (HBV-PAN) although the incidence of this is declining with better vaccination strategies and awareness of bloodborne virus screening. We report a case in which a patient displayed many classical features of the disease, occurring separately over a period of months and leading to contact with various medical specialties. Managing each symptom in isolation led to a number of misdiagnoses (including testicular cancer) and the patient experienced considerable psychological stress and morbidity as a result. The case was complicated by acute pancreatitis developing after an initial treatment response. This may have been iatrogenic (as a consequence of either entecavir or steroids) or secondary to PAN. For our patient, this led to a protracted clinical course but eventual complete resolution of both pathologies. PMID- 26733434 TI - Subcutaneous emphysema and pneumomediastinum as rare complications of transbronchial biopsy. PMID- 26733435 TI - Novel mechanism for lung cyst formation. PMID- 26733436 TI - Nivolumab causing painless thyroiditis in a patient with adenocarcinoma of the lung. AB - Thyroiditis is characterised by transient hyperthyroidism, followed sometimes by hypothyroidism, and then recovery. We report a case of painless drug-induced thyroiditis-in a patient with no history of any thyroid disorder-treated with Nivolumab (an IgG4 monoclonal antibody against Programmed Death Receptor 1). The purpose of this case report is to increase awareness among clinicians regarding this possible adverse effect from Nivolumab, and discuss the possible pathophysiology and management strategies in such patients. PMID- 26733437 TI - Substituent directed selectivity in anion recognition by a new class of simple osmium-pyrazole derived receptors. AB - The present article deals with the structurally, spectroscopically and electrochemically characterised osmium-bipyridyl derived complexes [(bpy)2Os(II)(HL1)Cl]ClO4 [1]ClO4 and [(bpy)2Os(II)(HL2)Cl]ClO4 [2]ClO4 incorporating neutral and monodentate pyrazole derivatives (HL) with one free NH function (bpy = 2,2'-bipyridine, HL1 = pyrazole, HL2 = 3,5-dimethylpyrazole). The crystal structures of [1]ClO4 and [2]ClO4 reveal intramolecular hydrogen bonding interactions between the free NH proton of HL and the equatorially placed Cl(-) ligand (N-HCl) with donor-acceptor distances of 3.114(7) A and 3.153(6) A as well as intermolecular hydrogen bonding interactions between the NH proton and one of the oxygen atoms of ClO4(-) (N-HO) with donor-acceptor distances of 2.870(10) A and 3.024(8) A, respectively. The effect of hydrogen bonding interactions has translated into the less acidic nature of the NH proton of the coordinated HL with estimated pKa > 12. 1(+) and 2(+) exhibit reversible Os(II)/(III) and irreversible Os(III)/(IV) processes in CH3CN within +/- 2.0 V versus SCE. The effect of 3,5-dimethyl substituted HL2 on 2(+) has been reflected in the appreciable lowering (40 mV) of the Os(II/III) potential, along with the further decrease in the acidity of the NH proton (pKa > 13.0) with regard to HL1 coordinated 1(+) (pKa: ~ 12.3). The electronic spectral features of Os(ii) (1(+)/2(+)) and electrochemically generated Os(III) (1(2+)/2(2+)) derived complexes have been analysed by TD-DFT calculations. The efficacy of the 1(+) and 2(+) encompassing free NH proton towards the anion recognition process has been evaluated by different experimental investigations using a wide variety of anions. It however establishes that receptor 1(+) can recognise both F(-) and OAc(-) in acetonitrile solution, while 2(+) is exclusively selective for the F(-) ion. PMID- 26733439 TI - Bioflocculation of the oceanic microalga Dunaliella salina by the bloom-forming dinoflagellate Heterocapsa circularisquama, and its effect on biodiesel properties of the biomass. AB - The aim of this work was to evaluate the flocculation by the dinoflagellate Heterocapsa circularisquama as a means for harvesting three Chlorophyta species, Chlorella vulgaris, Nannochloropsis granulata, and Dunaliella salina. Relative fluorescence of D. salina culture significantly decreased along with 9.3-fold increased flocculation activity within 24 h when mixed with H. circularisquama. Lipid content of bioflocculated D. salina increased about 40%, while fatty acid methyl ester (FAME) profiles exhibited higher levels of C16:0, C18:0, and C18:1, compared to harvest by centrifugation, suggesting higher energy content. Furthermore, bioflocculated D. salina biomass had more suitable biodiesel properties relative to both EN14214 and ASTMD6751, with a cetane number of 49.0 and an iodine value of 95.9. These results suggest that H. circularisquama induced bioflocculation is applicable for the sustainable and qualitative production of algal biodiesel. PMID- 26733440 TI - Effect of organic loading rate during anaerobic digestion of municipal solid waste. AB - The effect of chemical oxygen demand (COD) and volatile solids (VS) on subsequent methane (CH4) production during anaerobic digestion (AD) of organic fraction of municipal solid waste (OFMSW) was studied in a laboratory-scale digester. The experiment was performed in 2L anaerobic digester under different experimental conditions using different input mass co-digested with inoculum and organic loading rate (OLR) for 27days at 38+/-2 degrees C. Three digesters (digesters 1, 2 and 3) were operated at initial loading of 5.1, 10.4 and 15.2g/L CODS per batch which were reduced to 77.9% and 84.2%, respectively. Cumulative biogas productions were 9.3, 10.7 and 17.7L in which CH4 yields were 84.3, 101.0 and 168.4mL/gVS removal in digesters 1, 2, and 3, respectively. The observed COD removal was found to be influenced on variation in CH4 production. Co-efficient of determination (R(2)) was 0.67 and 0.74 in digesters 1 and 2, respectively. PMID- 26733441 TI - Prevalence of antimicrobial resistant Streptococcus pneumoniae serotype 11A isolates in Korea, during 2004-2013, due to the increase of multidrug-resistant clone, CC166. AB - Since the introduction of the pneumococcal conjugate vaccine (PCV7) in Korea in 2003, the proportion of non-vaccine serotypes has increased. Among non-vaccine serotypes, serotype 11A is highly prevalent in Korea. We investigated the prevalence and characteristics of Streptococcus pneumoniae serotype 11A isolates in a Korean tertiary-care hospital, during 2004-2013. A total of 1579 non duplicate clinical S. pneumoniae isolates, collected from 2004 to 2013, were included in this study. Serotype was determined by the capsular Quellung method, and in vitro susceptibility testing was performed by broth microdilution method. Multilocus sequence typing was performed to determine the genotypes of the S. pneumoniae isolates. We identified 90 serotype 11A isolates (5.7%). During this period, the proportion of serotype 11A has increased from 3.2% up to 13.2% (in 2012). Among the serotype 11A isolates, two main clonal complexes (CCs), CC166 and CC99, were identified. The increase of serotype 11A was mainly due to the increase of CC166 isolates, which have high antimicrobial resistance rates. In addition, we identified that 14 isolates, belonging to ST8279, ST9875, and ST3598 of CC166, were non-susceptible to all antimicrobial agents tested in this study. We identified the increase of S. pneumoniae serotype 11A in Korea, which mainly due to the expansion of a resistant clonal group, CC166. PMID- 26733442 TI - Multiregion deep sequencing of hepatitis C virus: An improved approach for genetic relatedness studies. AB - Hepatitis C virus (HCV) is a major public health problem that affects more than 180 million people worldwide. Identification of HCV transmission networks is of critical importance for disease control. HCV related cases are often difficult to identify due to the characteristic long incubation period and lack of symptoms during the acute phase of the disease, making it challenging to link related cases to a common source of infection. Additionally, HCV transmission chains are difficult to trace back since viral variants from epidemiologically linked cases are genetically related but rarely identical. Genetic relatedness studies primarily rely on information obtained from the rapidly evolving HCV hypervariable region 1 (HVR1). However, in some instances, the rapid divergence of this region can lead to loss of genetic links between related isolates, which represents an important challenge for outbreak investigations and genetic relatedness studies. Sequencing of multiple and longer sub-genomic regions has been proposed as an alternative to overcome the limitations imposed by the rapid molecular evolution of the HCV HVR1. Additionally, conventional molecular approaches required to characterize the HCV intra-host genetic variation are laborious, time-consuming, and expensive while providing limited information about the composition of the viral population. Next generation sequencing (NGS) approaches enormously facilitate the characterization of the HCV intra-host population by detecting rare variants at much lower frequencies. Thus, NGS approaches using multiple sub-genomic regions should improve the characterization of the HCV intra-host population. Here, we explore the usefulness of multiregion sequencing using a NGS platform for genetic relatedness studies among HCV cases. PMID- 26733443 TI - Fludarabine-IV busulfan, dose-intensity and progression-free survival: Are we finally finding the way to reach a consensus opinion?: Higher busulfan dose intensity appears to improve leukemia-free and overall survival in AML allografted in CR2: An analysis from the acute leukemia working party of the European group for blood and marrow transplantation. PMID- 26733444 TI - Brief Report: Competence, Value and Enjoyment of Childcare Activities Undertaken by Parents of Children With Complex Needs. AB - Parents combine many roles when caring for a child with complex needs, but few studies measure parental value and enjoyment of childcare related activities. This study aimed to describe parental competence, enjoyment and value of childcare related activities, particularly healthcare related activities, when parenting a child with complex needs. DESIGN AND METHODS: This was a pilot cross sectional study. Ten mothers of children with complex needs rated their competence, value and enjoyment of 156 childcare related activities using the Occupational Questionnaire (Smith, Kielhofner, & Hawkins Watts, 1986). RESULTS: The mothers rated childcare related activities as important and rated themselves as competent to undertake them. Mothers disliked performing healthcare related activities, but enjoyed emotional care activities. CONCLUSION: This study extends the current knowledge regarding the role tension described by parents of children with complex needs. The finding that parents dislike performing healthcare related activities despite self-reporting high levels of competence warrants further investigation. PRACTICE IMPLICATIONS: Gaining a better understanding of the role tension described by parents of children with complex needs may enable pediatric nurses to better understand the impact of home based care provision on parents and assist them to find ways to support families so this care can continue to be provided. PMID- 26733445 TI - Design of antibody-functionalized carbon nanotubes filled with radioactivable metals towards a targeted anticancer therapy. AB - In the present work we have devised the synthesis of a novel promising carbon nanotube carrier for the targeted delivery of radioactivity, through a combination of endohedral and exohedral functionalization. Steam-purified single walled carbon nanotubes (SWCNTs) have been initially filled with radioactive analogues (i.e. metal halides) and sealed by high temperature treatment, affording closed-ended CNTs with the filling material confined in the inner cavity. The external functionalization of these filled CNTs was then achieved by nitrene cycloaddition and followed by the derivatization with a monoclonal antibody (Cetuximab) targeting the epidermal growth factor receptor (EGFR), overexpressed by several cancer cells. The targeting efficiency of the so obtained conjugate was evaluated by immunostaining with a secondary antibody and by incubation of the CNTs with EGFR positive cells (U87-EGFR+), followed by flow cytometry, confocal microscopy or elemental analyses. We demonstrated that our filled and functionalized CNTs can internalize more efficiently in EGFR positive cancer cells. PMID- 26733447 TI - WHO calls for efforts to prevent newborn deaths in South East Asia. PMID- 26733446 TI - Assessment of individual differences in the rat nucleus accumbens transcriptome following taste-heroin extended access. AB - Heroin addiction is a disease of chronic relapse that harms the individual through devaluation of personal responsibilities in favor of finding and using drugs. Only some recreational heroin users devolve into addiction but the basis of these individual differences is not known. We have shown in rats that avoidance of a heroin-paired taste cue reliably identifies individual animals with greater addiction-like behavior for heroin. Here rats received 5min access to a 0.15% saccharin solution followed by the opportunity to self-administer either saline or heroin for 6h. Large Suppressors of the heroin-paired taste cue displayed increased drug escalation, motivation for drug, and drug loading behavior compared with Small Suppressors. Little is known about the molecular mechanisms of these individual differences in addiction-like behavior. We examined the individual differences in mRNA expression in the nucleus accumbens (NAc) of rats that were behaviorally stratified by addiction-like behavior using next-generation sequencing. We hypothesized that based on the avoidance of the drug-paired cue there will be a unique mRNA profile in the NAc. Analysis of strand-specific whole genome RNA-Seq data revealed a number of genes differentially regulated in NAc based on the suppression of the natural saccharine reward. Large Suppressors exhibited a unique mRNA prolife compared to Saline controls and Small Suppressors. Genes related to immunity, neuronal activity, and behavior were differentially expressed among the 3 groups. In total, individual differences in avoidance of a heroin-paired taste cue are associated with addiction-like behavior along with differential NAc gene expression. PMID- 26733448 TI - The Impact of Education on Views of Homosexuality in the Senior Clergy of Hidalgo County, Texas. AB - This study explores clergy perspectives on homosexuality and mental health. Interviews were conducted with 245 senior clergy of faith-based organizations in Hidalgo County, Texas. Analyses revealed that the less education the individual had, the more likely he or she viewed homosexuals as being more psychologically disturbed than heterosexuals. Clergy also expressed uncertainty in their views and actions regarding referral practices. A need for clergy education on views of homosexuality is documented. Suggestions are made for future research and education. PMID- 26733449 TI - The relationship between recurrent aphthous stomatitis, and periodontal disease and Helicobacter Pylori infection. AB - OBJECTIVE: Recurrent aphthous stomatitis (RAS) is a common oral mucosal disease with unknown etiology. This cross-sectional study aimed to test the hypothesis that Helicobacter pylori and periodontal disease might play an etiological role in RAS. METHODS: Dental plaque samples obtained from 38 patients with RAS and 43 healthy individuals via periodontal examinations were examined for H. pylori colonization. H. pylori was identified using the rapid urease test (RUT). The periodontal status of the patients and controls was based on the following periodontal parameters: periodontal pocket depth (PPD), the plaque index (PI), the gingival index (GI), and clinical attachment loss (CAL). RESULTS: RUT results were positive in 34 (89.5 %) of the 38 patients and 24 (55.8 %) of the 43 controls (P = 0.002). There were not any significant differences in mean PPD, PI, GI, or CAL between the patient and control groups (P > 0.05). Mean PPD, PI, GI, and CAL were higher in the RUT-positive RAS patients than in the RUT-negative patients (P > 0.05, for all). CONCLUSIONS: The present findings show that H. pylori might have played an etiological role in RAS and might have caused periodontal disease, but RAS was not associated with any of the periodontal parameters examined in this study. CLINICAL RELEVANCE: The present study indicates that H. pylori plays a role in the development of RAS, but periodontal diseases have no effect on it. Eradicating H. pylori might be useful to prevent RAS. PMID- 26733450 TI - Does the public receive and adhere to boil water advisory recommendations? A cross-sectional study in Newfoundland and Labrador, Canada. AB - BACKGROUND: Highly publicized water supply problems highlight the importance of safe drinking water to the public. Boil water advisories (BWAs) are an important precautionary measure meant to protect public health by ensuring drinking water safety. Newfoundland and Labrador, Canada is a prime location for exploring public notification practices and adherence to recommendations as there were a total of 215 BWAs, affecting 6 % of the provincial population, in 145 communities between April 2006 and March 2007 when data for the present study were collected. METHODS: Residents who received household water from a public water supply were randomly selected for a telephone interview. Collected data included participants' notification of boil water advisory, satisfaction with information provided, and their adherence to recommendations. RESULTS: Most participants learned that a BWA had been issued or lifted in their community through radio, television, or word of mouth. BWAs were issued for a range of operational reasons. Almost all participants who had experienced a BWA reported wanting more information about the reasons a BWA had been issued. Low adherence to water use recommendations during a BWA was common. CONCLUSIONS: This study is first to report on public adherence to boil water advisory recommendations in Canada. The findings raise public health concerns, particularly given the high number of BWAs issued each year. Further studies in partnership with community stakeholders and government decision-makers responsible for overseeing public water systems are needed to assess the perceptions of BWAs, the reasons for non-adherence, and to identify information dissemination methods to increase information uptake and public adherence with acceptable uses of public drinking water during a BWA. PMID- 26733451 TI - VIRALpro: a tool to identify viral capsid and tail sequences. AB - MOTIVATION: Not only sequence data continue to outpace annotation information, but also the problem is further exacerbated when organisms are underrepresented in the annotation databases. This is the case with non-human-pathogenic viruses which occur frequently in metagenomic projects. Thus, there is a need for tools capable of detecting and classifying viral sequences. RESULTS: We describe VIRALpro a new effective tool for identifying capsid and tail protein sequences, which are the cornerstones toward viral sequence annotation and viral genome classification. AVAILABILITY AND IMPLEMENTATION: The data, software and corresponding web server are available from http://scratch.proteomics.ics.uci.edu as part of the SCRATCH suite. CONTACT: clovis.galiez@inria.fr or pfbaldi@uci.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26733452 TI - Path2PPI: an R package to predict protein-protein interaction networks for a set of proteins. AB - : We introduce Path2PPI, a new R package to identify protein-protein interaction (PPI) networks for fully sequenced organisms for which nearly none PPI are known. Path2PPI predicts PPI networks based on sets of proteins from well-established model organisms, providing an intuitive visualization and usability. It can be used to combine and transfer information of a certain pathway or biological process from several reference organisms to one target organism. AVAILABILITY AND IMPLEMENTATION: Path2PPI is an open-source tool implemented in R. It can be obtained from the Bioconductor project: http://bioconductor.org/packages/Path2PPI/ CONTACT: : ina.koch@bioinformatik.uni frankfurt.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26733453 TI - ProQ2: estimation of model accuracy implemented in Rosetta. AB - MOTIVATION: Model quality assessment programs are used to predict the quality of modeled protein structures. They can be divided into two groups depending on the information they are using: ensemble methods using consensus of many alternative models and methods only using a single model to do its prediction. The consensus methods excel in achieving high correlations between prediction and true quality measures. However, they frequently fail to pick out the best possible model, nor can they be used to generate and score new structures. Single-model methods on the other hand do not have these inherent shortcomings and can be used both to sample new structures and to improve existing consensus methods. RESULTS: Here, we present an implementation of the ProQ2 program to estimate both local and global model accuracy as part of the Rosetta modeling suite. The current implementation does not only make it possible to run large batch runs locally, but it also opens up a whole new arena for conformational sampling using machine learned scoring functions and to incorporate model accuracy estimation in to various existing modeling schemes. ProQ2 participated in CASP11 and results from CASP11 are used to benchmark the current implementation. Based on results from CASP11 and CAMEO-QE, a continuous benchmark of quality estimation methods, it is clear that ProQ2 is the single-model method that performs best in both local and global model accuracy. AVAILABILITY AND IMPLEMENTATION: https://github.com/bjornwallner/ProQ_scripts CONTACT: bjornw@ifm.liu.se SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26733454 TI - Prediction of missing sequences and branch lengths in phylogenomic data. AB - MOTIVATION: The presence of missing data in large-scale phylogenomic datasets has negative effects on the phylogenetic inference process. One effect that is caused by alignments with missing per-gene or per-partition sequences is that the inferred phylogenies may exhibit extremely long branch lengths. We investigate if statistically predicting missing sequences for organisms by using information from genes/partitions that have data for these organisms alleviates the problem and improves phylogenetic accuracy. RESULTS: We present several algorithms for correcting excessively long branch lengths induced by missing data. We also present methods for predicting/imputing missing sequence data. We evaluate our algorithms by systematically removing sequence data from three empirical and 100 simulated alignments. We then compare the Maximum Likelihood trees inferred from the gappy alignments and on the alignments with predicted sequence data to the trees inferred from the original, complete datasets. The datasets with predicted sequences showed one to two orders of magnitude more accurate branch lengths compared to the branch lengths of the trees inferred from the alignments with missing data. However, prediction did not affect the RF distances between the trees. AVAILABILITY AND IMPLEMENTATION: https://github.com/ddarriba/ForeSeqs CONTACT: : diego.darriba@h-its.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26733455 TI - Erratum To: Virtual house calls for Parkinson disease (Connect.Parkinson): study protocol for a randomized, controlled trial. PMID- 26733456 TI - The strategic role of the tail in maintaining balance while carrying a load bipedally in wild capuchins (Sapajus libidinosus): a pilot study. AB - The ability to carry objects has been considered an important selective pressure favoring the evolution of bipedal locomotion in early hominins. Comparable behaviors by extant primates have been studied very little, as few primates habitually carry objects bipedally. However, wild bearded capuchins living at Fazenda Boa Vista spontaneously and habitually transport stone tools by walking bipedally, allowing us to examine the characteristics of bipedal locomotion during object transport by a generalized primate. In this pilot study, we investigated the mechanical aspects of position and velocity of the center of mass, trunk inclination, and forelimb postures, and the torque of the forces applied on each anatomical segment in wild bearded capuchin monkeys during the transport of objects, with particular attention to the tail and its role in balancing the body. Our results indicate that body mass strongly affects the posture of transport and that capuchins are able to carry heavy loads bipedally with a bent-hip-bent-knee posture, thanks to the "strategic" use of their extendable tail; in fact, without this anatomical structure, constituting only 5 % of their body mass, they would be unable to transport the loads that they habitually carry. PMID- 26733458 TI - Production of Rebaudioside A from Stevioside Catalyzed by the Engineered Saccharomyces cerevisiae. AB - Rebaudioside A has superior taste quality among the steviol glycosides extracted from Stevia rebaudiana leaves. Given its high purity as a general-purpose sweetener, rebaudioside A has received significant attention and has been widely applied in food and beverages in recent decades. Stevioside is one of the major steviol glycosides and can be converted to rebaudioside A by the uridine diphosphate dependent glucosyltransferase UGT76G1 in S. rebaudiana. To explore the applicability of and limits in producing rebaudioside A from stevioside through whole-cell biocatalysis, the engineered Saccharomyces cerevisiae expressing UGT76G1, using a newly constructed constitutive expression vector, was used as the whole-cell biocatalyst. Citrate was added to the reaction mixture to allow metabolic regulation when glucose was fed to provide the activated sugar donor UDP-glucose for glycosylation of stevioside in vivo. In an evaluation of the whole-cell reaction parameters involving cell permeability, temperature, pH, citrate and Mg(2+) concentrations, and glucose feeding, production of 1160.5 mg/L rebaudioside A from 2 g/L stevioside was achieved after 48 h without supplementation of extracellular UDP-glucose. PMID- 26733457 TI - International neurocognitive normative study: neurocognitive comparison data in diverse resource-limited settings: AIDS Clinical Trials Group A5271. AB - Infrastructure for conducting neurological research in resource-limited settings (RLS) is limited. The lack of neurological and neuropsychological (NP) assessment and normative data needed for clinical interpretation impedes research and clinical care. Here, we report on ACTG 5271, which provided neurological training of clinical site personnel and collected neurocognitive normative comparison data in diverse settings. At ten sites in seven RLS countries, we provided training for NP assessments. We collected normative comparison data on HIV- participants from Brazil (n = 240), India (n = 480), Malawi (n = 481), Peru (n = 239), South Africa (480), Thailand (n = 240), and Zimbabwe (n = 240). Participants had a negative HIV test within 30 days before standardized NP exams were administered at baseline and 770 at 6 months. Participants were enrolled in eight strata, gender (female and male), education (<10 and >=10 years), and age (<35 and >=35 years). Of 2400 enrolled, 770 completed the 6-month follow-up. As expected, significant between-country differences were evident in all the neurocognitive test scores (p < 0.0001). There was variation between the age, gender, and education strata on the neurocognitive tests. Age and education were important variables for all tests; older participants had poorer performance, and those with higher education had better performance. Women had better performance on verbal learning/memory and speed of processing tests, while men performed better on motor tests. This study provides the necessary neurocognitive normative data needed to build infrastructure for future neurological and neurocognitive studies in diverse RLS. These normative data are a much-needed resource for both clinicians and researchers. PMID- 26733459 TI - The impact of left atrial pressure on filtered P-wave duration in patients with atrial fibrillation. AB - The cause of prolonged filtered P-wave duration (FPD) remains unclear in atrial fibrillation (AF) patients with normal left atrial size. We investigated whether FPD is associated with left atrial pressure (LAP) in AF patients without prominent LA enlargement. This study included 80 patients (48 men, age 65 +/- 9 years, 25 persistent AF) with non-valvular AF who underwent catheter ablation (CA) for AF. LAP was measured in sinus rhythm during CA and signal-averaged electrocardiogram was recorded after CA. We retrospectively assessed the clinical and echocardiographic variables. Prolonged FPD was defined as FPD > 120 ms. Prolonged FPD (FPD > 120 ms) was detected in 23/80 patients (29 %). According to univariate analysis, higher mean LAP (14.9 +/- 4.4 vs. 10.8 +/- 3.5 mmHg, p < 0.0001), higher prevalence of persistent arrhythmia, higher BNP, larger LAD, higher E wave, and lower LVEF were associated with Prolonged FPD. According to multivariate analysis, higher mean LAP was the only factor associated with Prolonged FPD (p = 0.0058, OR 1.256 for each 1 mmHg increase in mean LAP, 95 % CI 1.068-1.476). Moreover, a significant correlation was observed between FPD and mean LAP (r = 0.503, p < 0.0001). Prolonged FPD is associated with high LAP in AF patients without prominent left atrial enlargement. Pressure overload of the left atria might cause slowing of atrial electrical activation. PMID- 26733460 TI - Interprofessional education in practice: Evaluation of a work integrated aged care program. AB - Health professional clinical education is commonly conducted in single discipline modes, thus limiting student collaboration skills. Aged care residential facilities, due to the chronic and complex health care needs of residents, provide an ideal placement to provide a collaborative experience. Interprofessional education is widely acknowledged as the pedagogical framework through which to facilitate collaboration. The aim of the evaluation was to assess student attitudes towards collaboration after active involvement in an interprofessional education program. Students studying nursing, occupational therapy, and aged care were invited to complete a version of the Readiness for Interprofessional Learning Scale before and after participating in a three-week pilot interprofessional program. A positive change in student attitudes towards other health professionals and the importance of working in interprofessional teams was reported with significant differences between two statements indicated: Learning with health-care students before qualifications would improve relationships after qualifications; and I learned a lot from the students from the other disciplines. The innovative pilot project was found to enhance student learning in interprofessional teams and the aged care environment. Further development of this and similar interprofessional programs is required to develop sustainable student projects that have health benefits for residents in aged care residential facilities. PMID- 26733461 TI - Methotrexate-related lymphoproliferative disorder of the stomach in a patient with rheumatoid arthritis: a case of disease regression after methotrexate cessation. AB - We report the case of a 78-year-old woman with methotrexate-related gastric lymphoproliferative disorder (LPD). The patient had a history of rheumatoid arthritis (RA) and had been treated with methotrexate (MTX). Endoscopic examination revealed round elevated lesions in the stomach, and a biopsy specimen showed atypical lymphoid cell proliferation. Immunohistological study found these atypical cells to be positive for L-26 but not for CD3 or EBER. Therefore, we made a diagnosis of MTX-related LPD showing features of diffuse large B-cell lymphoma. Combined positron emission tomography-computed tomography (PET-CT) using 18F-fluorodeoxyglucose (FDG) showed increased avidity in the stomach in addition to slightly increased FDG-avidity in the mediastinum and left chest wall. We decided not to start chemotherapy but to discontinue administration of MTX, with follow-up using endoscopy and PET-CT. The endoscopic examinations after cessation of MTX demonstrated gradual regression of the elevated lesions. PET-CT 6 months after cessation showed no increased FDG avidity in the stomach. While disease regression was observed in the stomach, the other FDG-avid spots remained unchanged on PET-CT. Therefore, we performed chemotherapy as additional therapy. On PET-CT after chemotherapy, the FDG-avid spots remained unchanged for more than 1 year, and we eventually concluded that they were RA-related inflammatory lesions. In patients with MTX-related LPD, cessation of MTX may be a therapeutic option, but careful follow-up and chemotherapy in accordance with the clinical course are essential. PMID- 26733462 TI - Evaluation of a Coping Effectiveness Training intervention in patients with chronic heart failure - a randomized controlled trial. AB - BACKGROUND: Impaired emotional well-being has detrimental effects on health outcomes in patients with chronic heart failure (CHF). AIMS: To evaluate a nurse led Coping Effectiveness Training (CET) group intervention for patients with CHF. It was hypothesized that CET would increase emotional well-being (primary outcome) and health-related quality (HRQoL) of life and improve clinical outcomes. Furthermore, changes in appraisal and coping as mediators of the intervention effect were examined. METHODS: Participants were randomized to either control group (n=51) receiving standard health care or CET intervention group (n=52). Self-assessments of positive affect, negative affect, depression, anxiety, HRQoL, illness perception, coping strategies and social support were performed pre- and post-intervention and after six weeks, six months and 12 months. Time to death and hospitalizations were measured during the entire follow up (median 35 months, interquartile range 11 months). RESULTS: No significant improvements for emotional well-being and HRQoL in the intervention group compared with the control group were found. After excluding patients with clinical anxiety and depression at baseline the intervention group had significantly lower negative affect (p = 0.022). There were no significant differences regarding cardiovascular events between the groups. The intervention group had greater sense of control over their illness in the short-term (p = 0.036). CONCLUSION: CET intervention was found to increase sense of control over the illness in the short term. Psychosocial support programmes, like CET, for patients with CHF is currently lacking evidence for implementing in clinical practice. However, the results provide a basis for future studies with a modified CET intervention design and increased study size. PMID- 26733463 TI - Deficiency of the myogenic factor MyoD causes a perinatally lethal fetal akinesia. AB - BACKGROUND: Lethal fetal akinesia deformation sequence (FADS) describes a clinically and genetically heterogeneous phenotype that includes fetal akinesia, intrauterine growth retardation, arthrogryposis and developmental anomalies. Affected babies die as a result of pulmonary hypoplasia. We aimed to identify the underlying genetic cause of this disorder in a family in which there were three affected individuals from two sibships. METHODS: Autosomal-recessive inheritance was suggested by a family history of consanguinity and by recurrence of the phenotype between the two sibships. We performed exome sequencing of the affected individuals and their unaffected mother, followed by autozygosity mapping and variant filtering to identify the causative gene. RESULTS: Five autozygous regions were identified, spanning 31.7 Mb of genomic sequence and including 211 genes. Using standard variant filtering criteria, we excluded all variants as being the likely pathogenic cause, apart from a single novel nonsense mutation, c.188C>A p.(Ser63*) (NM_002478.4), in MYOD1. This gene encodes an extensively studied transcription factor involved in muscle development, which has nonetheless not hitherto been associated with a hereditary human disease phenotype. CONCLUSIONS: We provide the first description of a human phenotype that appears to result from MYOD1 mutation. The presentation with FADS is consistent with a large body of data demonstrating that in the mouse, MyoD is a major controller of precursor cell commitment to the myogenic differentiation programme. PMID- 26733464 TI - Resistance to glufosinate is proportional to phosphinothricin acetyltransferase expression and activity in LibertyLink((r)) and WideStrike((r)) cotton. AB - MAIN CONCLUSION: Insertion of the gene encoding phosphinothricin acetyltransferase (PAT) has resulted in cotton plants resistant to the herbicide glufosinate. However, the lower expression and commensurate reduction in PAT activity is a key factor in the low level of injury observed in the WideStrike((r)) cotton and relatively high level of resistance observed in LibertyLink((r)) cotton. LibertyLink((r)) cotton cultivars are engineered for glufosinate resistance by overexpressing the bar gene that encodes phosphinothricin acetyltransferase (PAT), whereas the insect-resistant WideStrike((r)) cultivars were obtained using the similar pat gene as a selectable marker. The latter cultivars carry some level of resistance to glufosinate which enticed certain farmers to select this herbicide for weed control with WideStrike((r)) cotton. The potency of glufosinate on conventional FM 993, insect-resistant FM 975WS, and glufosinate-resistant IMACD 6001LL cotton cultivars was evaluated and contrasted to the relative levels of PAT expression and activity. Conventional cotton was sensitive to glufosinate. The single copy of the pat gene present in the insect-resistant cultivar resulted in very low RNA expression of the gene and undetectable PAT activity in in vitro assays. Nonetheless, the presence of this gene provided a good level of resistance to glufosinate in terms of visual injury and effect on photosynthetic electron transport. The injury is proportional to the amount of ammonia accumulation. The strong promoter associated with bar expression in the glufosinate-resistant cultivar led to high RNA expression levels and PAT activity which protected this cultivar from glufosinate injury. While the insect-resistant cultivar demonstrated a good level of resistance to glufosinate, its safety margin is lower than that of the glufosinate-resistant cultivar. Therefore, farmers should be extremely careful in using glufosinate on cultivars not expressly designed and commercialized as resistant to this herbicide. PMID- 26733465 TI - Raman imaging of changes in the polysaccharides distribution in the cell wall during apple fruit development and senescence. AB - MAIN CONCLUSION: Du ring on-tree ripening, the pectin distribution changed from polydispersed in cell wall to cumulated in cell wall corners. During apple storage, the pectin distribution returned to evenly dispersed along the cell wall. The plant cell wall influences the texture properties of fruit tissue for example apples become softer during ripening and postharvest storage. This softening process is believed to be mainly connected with changes in the cell wall composition due to polysaccharides undergoing an enzymatic degradation. These changes in polysaccharides are currently mainly investigated via chemical analysis or monoclonal labeling. Here, we propose the application of Raman microscopy for evaluating the changes in the polysaccharide distribution in the cell wall of apples during both ripening and postharvest storage. The apples were harvested 1 month and 2 weeks before optimal harvest date as well as at the optimal harvest date. The apples harvested at optimal harvest date were stored for 3 months. The Raman maps, as well as the chemical analysis were obtained for each harvest date and after 1, 2 and 3 months of storage, respectively. The analysis of the Raman maps showed that the pectins in the middle lamella and primary cell wall undergo a degradation. The changes in cellulose and hemicellulose were less pronounced. These findings were confirmed by the chemical analysis results. During development changes of pectins from a polydispersed form in the cell walls to a cumulated form in cell wall corners could be observed. In contrast after 3 months of apple storage we could observe an substantial pectin decrease. The obtained results demonstrate that Raman chemical imaging might be a very useful tool for a first identification of compositional changes in plant tissue during their development. The great advantage Raman microspectroscopy offers is the simultaneous localization and identification of polysaccharides within the cell wall and plant tissue. PMID- 26733466 TI - Activation-induced regulation of GABAA receptors: Is there a link with the molecular basis of benzodiazepine tolerance? AB - Benzodiazepines have been used clinically for more than 50 years to treat disorders such as insomnia, anxiety, and epilepsy, as well as to aid muscle relaxation and anesthesia. The therapeutic index for benzodiazepines if very high and the toxicity is low. However, their usefulness is limited by the development of either or both tolerance to most of their pharmacological actions and dependence. Tolerance develops at different rates depending on the pharmacological action, suggesting the existence of distinct mechanisms for each behavioral parameter. Alternatively, multiple mechanisms could coexist depending on the subtype of GABAA receptor expressed and the brain region involved. Because most of the pharmacological actions of benzodiazepines are mediated through GABAA receptor binding, adaptive alterations in the number, structure, and/or functions of these receptors may play an important role in the development of tolerance. This review is focused on the regulation of GABAA receptors induced by long-term benzodiazepine exposure and its relationship with the development of tolerance. Understanding the mechanisms behind benzodiazepine tolerance is critical for designing drugs that could maintain their efficacy during long-term treatments. PMID- 26733467 TI - Physical and chemical parameter correlations with technical and technological characteristics of heating systems and the presence of Legionella spp. in the hot water supply. AB - The purpose of this study was to evaluate the prevalence of Legionella spp. and compare the quality of hot water between four facilities for accommodation located in Southern Croatia (the Split-Dalmatian County). The research included data collection on the technical and technological characteristics in the period from 2009 to 2012. The survey included a type of construction material for the distribution and internal networks, heating system water heater type, and water consumption. Changes in water quality were monitored by determination of the physical and chemical parameters (temperature, pH, free chlorine residual concentrations, iron, zinc, copper and manganese) in the samples, as well as the presence and concentration of bacteria Legionella spp. The temperature is an important factor for the development of biofilms, and it is in negative correlation with the appearance of Legionella spp. Positive correlations between the Fe and Zn concentrations and Legionella spp. were established, while the inhibitory effect of a higher Cu concentration on the Legionella spp. concentration was proven. Legionella spp. were identified in 38/126 (30.2%) of the water samples from the heating system with zinc-coated pipes, as well as in 78/299 (26.1%) of the samples from systems with plastic pipes. A similar number of Legionella spp. positive samples were established regardless of the type of the water heating system (central or independent). The study confirms the necessity of regular microbial contamination monitoring of the drinking water distribution systems (DWDSs). PMID- 26733468 TI - Water balance analysis of the Morava River floodplain in the Kostice-Lanzhot transect using the WBCM-7 model. AB - The study area of the Morava River floodplain is situated between the rivers Morava and Kyjovka in the reach from Hodonin to Lanzhot. This experimental area was chosen because during the last 30 years, there has been a serious problem with the frequent occurrence of hydrological extremes, such as floods and droughts. Dry seasons have a very negative impact on the floodplain forest and have been caused mainly by regulation of the Morava River channel in the 1970s. Since flooding in the catastrophic year 1977, a part of this area has served as a polder for flood impact mitigation of the urbanised area of the town of Lanzhot. Management and farming practices have been heavily affected by the enormous economic and ecological damage due to long-term flooding of agricultural land. The purpose of this study is to assess the extent to which the precipitation in the growing season of the dry years 2003 and 2011 was deficient, in comparison with the normal year 2009, through a study of the actual evapotranspiration caused by the significant drought in the Morava floodplain. A similar but converse situation in the wet year 2010 was also analysed, with the aim to show the differences in the components of the water balance equation in the growing seasons of all the extreme years tested here. The daily data from the Kostice climatological station were processed using the WBCM-7 model, where the input parameters were calibrated by the fluctuation of the groundwater table in the control borehole. PMID- 26733469 TI - Heavy metal distribution in Laportea peduncularis and growth soil from the eastern parts of KwaZulu-Natal, South Africa. AB - Laportea peduncularis is a medicinal plant consumed by the native communities in South Africa. Due to its oral consumption, its potential for harming the human health and the distribution of metals in the leaves of L. peduncularis as a function of soil characteristics were evaluated. Broadly, the concentrations of metals in the soil were in decreasing order of Fe > Ca > Mg > Mn > Zn > Cr > Cu > Ni > As > Co > Cd > Pb. Low-molecular-weight organic acid, calcium chloride, and ethylenediaminetetraacetic acid extraction methods were employed to assess for exchangeable forms of metals in the soil. Geoaccumulation indices and enrichment factors showed no contamination or enrichment for most of the heavy metals studied except for Cd, which showed moderate contamination and significant enrichment at Mona, KwaZulu-Natal. Principal component and cluster analyses revealed that As, Cd, Fe, and Ni in the soil came from the same source, whilst Cu, Pb, and Zn in the soil were from a common origin. Correlation analysis showed significantly positive correlation between heavy metals As, Cd, Fe, and Ni in the soil, as well as between Cu, Pb, and Zn, confirming the metals' common origin. Concentrations of metals in plants and soil were influenced by site, but the availability and uptake of the metals solely depended on the plant's inherent controls. PMID- 26733470 TI - Fast eutrophication assessment for stormwater wet detention ponds via fuzzy probit regression analysis under uncertainty. AB - Stormwater wet detention ponds have been a commonly employed best management practice for stormwater management throughout the world for many years. In the past, the trophic state index values have been used to evaluate seasonal changes in water quality and rank lakes within a region or between several regions; yet, to date, there is no similar index for stormwater wet detention ponds. This study aimed to develop a new multivariate trophic state index (MTSI) suitable for conducting a rapid eutrophication assessment of stormwater wet detention ponds under uncertainty with respect to three typical physical and chemical properties. Six stormwater wet detention ponds in Florida were selected for demonstration of the new MTSI with respect to total phosphorus (TP), total nitrogen (TN), and Secchi disk depth (SDD) as cognitive assessment metrics to sense eutrophication potential collectively and inform the environmental impact holistically. Due to the involvement of multiple endogenous variables (i.e., TN, TP, and SDD) for the eutrophication assessment simultaneously under uncertainty, fuzzy synthetic evaluation was applied to first standardize and synchronize the sources of uncertainty in the decision analysis. The ordered probit regression model was then formulated for assessment based on the concept of MTSI with the inputs from the fuzzy synthetic evaluation. It is indicative that the severe eutrophication condition is present during fall, which might be due to frequent heavy summer storm events contributing to high-nutrient inputs in these six ponds. PMID- 26733471 TI - Estimating time-varying exposure-outcome associations using case-control data: logistic and case-cohort analyses. AB - BACKGROUND: Traditional analyses of standard case-control studies using logistic regression do not allow estimation of time-varying associations between exposures and the outcome. We present two approaches which allow this. The motivation is a study of vaccine efficacy as a function of time since vaccination. METHODS: Our first approach is to estimate time-varying exposure-outcome associations by fitting a series of logistic regressions within successive time periods, reusing controls across periods. Our second approach treats the case-control sample as a case-cohort study, with the controls forming the subcohort. In the case-cohort analysis, controls contribute information at all times they are at risk. Extensions allow left truncation, frequency matching and, using the case-cohort analysis, time-varying exposures. Simulations are used to investigate the methods. RESULTS: The simulation results show that both methods give correct estimates of time-varying effects of exposures using standard case-control data. Using the logistic approach there are efficiency gains by reusing controls over time and care should be taken over the definition of controls within time periods. However, using the case-cohort analysis there is no ambiguity over the definition of controls. The performance of the two analyses is very similar when controls are used most efficiently under the logistic approach. CONCLUSIONS: Using our methods, case-control studies can be used to estimate time-varying exposure-outcome associations where they may not previously have been considered. The case-cohort analysis has several advantages, including that it allows estimation of time-varying associations as a continuous function of time, while the logistic regression approach is restricted to assuming a step function form for the time-varying association. PMID- 26733472 TI - The dynamic limits of hop height: Biological actuator capabilities and mechanical requirements of task produce incongruity between one- and two-legged performance. AB - The maximum hop height attainable for a given hop frequency falls well below the theoretical limit dictated by gravity, h = g/8f(2). However, maximum hop height is proportional to 1/f(2), suggesting that ground reaction force and, hence, force production capabilities of the leg muscles limit human hopping performance. Curiously, during one-legged hopping, subjects were able to produce substantially more than 50% the ground reaction force produced during two-legged maximum height hopping-66% on average and as much as 90% the total force produced during two legged hopping. This implies that two legs together should be able to produce an average of 1.32 times and as much as 1.8 times the force actually measured during two-legged maximum height hopping. Why were our subjects unable to access this extra force capacity when hopping on two legs? Here, we show that this apparent bilateral deficit and other features of maximum height hopping can be explained by the interaction of the mechanical requirements of hopping with the force velocity and force-length relationships that dictate the force production capacity of the leg muscles. Identifying the factors that limit performance in hopping provides an opportunity to understand how functional limits are determined in more complex activities such as running and jumping. PMID- 26733473 TI - Three-dimensional QSAR analysis and design of new 1,2,4-oxadiazole antibacterials. AB - The oxadiazole antibacterials, a class of newly discovered compounds that are active against Gram-positive bacteria, target bacterial cell-wall biosynthesis by inhibition of a family of essential enzymes, the penicillin-binding proteins. Ligand-based 3D-QSAR analyses by comparative molecular field analysis (CoMFA), comparative molecular shape indices analysis (CoMSIA) and Field-Based 3D-QSAR evaluated a series of 102 members of this class. This series included inactive compounds as well as compounds that were moderately to strongly antibacterial against Staphylococcus aureus. Multiple models were constructed using different types of energy minimization and charge calculations. CoMFA derived contour maps successfully defined favored and disfavored regions of the molecules in terms of steric and electrostatic properties for substitution. PMID- 26733474 TI - Identification of allosteric ERK2 inhibitors through in silico biased screening and competitive binding assay. AB - Extracellular signal-regulated kinase 2 (ERK2) is a drug target for type 2 diabetes mellitus. A peptide-type ERK2 inhibitor (PEP) was discovered in the previous study through the knowledge-based method and showed physiological effects on the db/db mice model of type 2 diabetes. Here, the crystal structure showed that PEP bound to the allosteric site without the interruption of the ATP competitive inhibitor binding to ERK2. An in silico biased-screening using the focused library rendered three compounds with inhibitory activity of IC50 <100 MUM. Among them, two compounds revealed the concentration-dependent competition with PEP and could be lead compounds for antidiabetic medicine. PMID- 26733475 TI - Synthesis and evaluation of a radioiodinated 4,6-diaryl-3-cyano-2-pyridinone derivative as a survivin targeting SPECT probe for tumor imaging. AB - Survivin is overexpressed in most of the cancerous tissues but not in terminally differentiated normal tissues, making it an attractive target for diagnosis and therapy of various types of cancers. In this study, we aimed to develop 4,6 diaryl-3-cyano-2-pyridinone (DCP) derivatives, as novel cancer imaging probes that target survivin. Chloro and iodo analogs of DCP (CDCP and IDCP, respectively) were successfully synthesized by using a previously unreported carbon monoxide-free procedure. IDCP exhibited a slightly higher binding affinity for recombinant human survivin (Kd=34 nM) than that of CDCP (Kd=44 nM). Fluorescence staining indicated that both CDCP and IDCP showed high signals in MDA-MB-231 cells with high levels of survivin expression. Significantly low fluorescent signals were observed in MCF-10A cells, which showed low levels of survivin expression. [(125)I]IDCP was synthesized for the application of IDCP to single photon emission computed tomography (SPECT) imaging. Quantitative in vitro binding of [(125)I]IDCP in cell cultures showed results consistent to those observed after fluorescent staining. In vivo biodistribution studies in tumor bearing mice demonstrated that the tumor uptake of [(125)I]IDCP increased gradually with time and was 0.65% injected dose per gram (% ID/g) at 180 min. The maximum tumor/blood and tumor/muscle ratio at 60 min were 0.87 and 2.27, respectively, indicating inadequate [(125)I]IDCP accumulation in tumors necessary for in vivo imaging. Although further structural modifications are necessary to improve pharmacokinetic properties of IDCP, this study demonstrates the feasibility of using the DCP backbone as a scaffold for the development of survivin-targeting tumor imaging probes. PMID- 26733476 TI - Salicylates are interference compounds in TR-FRET assays. AB - Given the importance of high-throughput screening in drug discovery, the identification of compounds that interfere with assay readouts is crucial. The pursuit of false positives wastes time and money, while distracting development teams from more promising leads. In the context of TR-FRET assays, most interfering compounds are dyes or aggregators. In the course of our studies on the PD1-PDL2 interaction, we discovered that salicylic acids, an extremely common compound subclass in screening libraries, interfere with TR-FRET assays. While the precise mechanism of interference was not established, our data suggest that interaction of the salicylate with the cryptand-ligated europium FRET donor is responsible for the change in assay signal. PMID- 26733477 TI - Novel carbocyclic nucleoside analogs suppress glomerular mesangial cells proliferation and matrix protein accumulation through ROS-dependent mechanism in the diabetic milieu. II. Acylhydrazone-functionalized pyrimidines. AB - We report herein the synthesis of a novel series of carbocyclic acylhydrazone derivatives of uracil, thymine and cytosine from the corresponding nucleic bases and their biological activity to treat diabetic nephropathy. Intriguingly, five derivatives significantly reduced high-glucose induced glomerular mesangial cells proliferation and matrix protein accumulation in vitro. The anti-oxidative effects displayed by these molecules suggest that their activity might involve a ROS-dependent mechanism. PMID- 26733478 TI - Adiponectin, markers of subclinical inflammation and nerve conduction in individuals with recently diagnosed type 1 and type 2 diabetes. AB - OBJECTIVE: Subclinical inflammation has been implicated in the development of diabetic sensorimotor polyneuropathy (DSPN), but studies using electrophysiological assessment as outcomes are scarce. Therefore, we aimed to investigate associations of biomarkers reflecting different aspects of subclinical inflammation with motor and sensory nerve conduction velocity (NCV) in individuals with diabetes. DESIGN AND METHODS: Motor and sensory NCV was assessed in individuals with recently diagnosed type 2 (n=352) or type 1 diabetes (n=161) from the baseline cohort of the observational German Diabetes Study. NCV sum scores were calculated for median, ulnar and peroneal motor as well as median, ulnar and sural sensory nerves. Associations between inflammation-related biomarkers, DSPN and NCV sum scores were estimated using multiple regression models. RESULTS: In type 2 diabetes, high serum interleukin (IL)-6 was associated with the presence of DSPN and reduced motor NCV. Moreover, higher levels of high molecular weight (HMW) adiponectin, total adiponectin and their ratio were associated with prevalent DSPN and both diminished motor and sensory NCV, whereas no consistent associations were observed for C-reactive protein, IL18, soluble intercellular adhesion molecule-1 and E-selectin. In type 1 diabetes, only HMW and total adiponectin showed positive associations with motor NCV. CONCLUSIONS: Our results point to a link between IL6 and both DSPN and slowed motor NCV in recently diagnosed type 2 diabetes. The reverse associations between adiponectin and NCV in type 1 and type 2 diabetes are intriguing, and further studies should explore whether they may reflect differences in the pathogenesis of DSPN in both diabetes types. PMID- 26733479 TI - Effects of vitamin D binding protein phenotypes and vitamin D supplementation on serum total 25(OH)D and directly measured free 25(OH)D. AB - OBJECTIVE: To determine the relationship between serum total 25-hydroxyvitamin D (25(OH)D), directly measured free 25(OH)D and calculated free 25(OH)D with regard to vitamin D-binding protein (DBP) phenotypes, sex, BMI, age and season, and their interrelationship to vitamin D supplementation. DESIGN, PATIENTS AND INTERVENTIONS: A randomized controlled trial with 20 000 IU of vitamin D3 per week or placebo for 12 months was designed. A total of 472 subjects, 236 in each of the intervention groups, were included in the analyses. MAIN OUTCOME MEASURES: Baseline serum concentrations and increases in serum total 25(OH)D, directly measured free 25(OH)D, calculated free 25(OH)D and DBP. RESULTS: Serum total 25(OH)D and DBP concentrations were significantly lower in subjects with the phenotype Gc2/Gc2 compared to phenotypes with the Gc1S allele, and lower in males compared to females. When using directly measured free 25(OH)D, the differences related to DBP phenotypes and sexes were clearly diminished. All calculated free 25(OH)D concentrations were overestimated compared to the directly measured free 25(OH)D. Serum parathyroid hormone showed an inverse correlation with all vitamin D parameters analyzed. The increases after 12 months of vitamin D supplementation were not significantly different for any of the vitamin D parameters regardless of DBP phenotype, sex or age. Supplementation with vitamin D did not affect serum DBP. CONCLUSION: Direct measurements of free 25(OH)D reduce the differences seen in total 25(OH)D between DBP phenotype groups and sexes, probably caused by differences in DBP concentrations. With conditions affecting serum DBP concentrations, direct measurements of free 25(OH)D should be considered. PMID- 26733480 TI - MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency. AB - Over the last 5 years, new actors involved in the pathogenesis of combined pituitary hormone deficiency in humans have been reported: they included a member of the immunoglobulin superfamily glycoprotein and ciliary G protein-coupled receptors, as well as new transcription factors and signalling molecules. New modes of inheritance for alterations of genes encoding transcription factors have also been described. Finally, actors known to be involved in a very specific phenotype (hypogonadotroph hypogonadism for instance) have been identified in a wider range of phenotypes. These data thus suggest that new mechanisms could explain the low rate of aetiological identification in this heterogeneous group of diseases. Taking into account the fact that several reviews have been published in recent years on classical aetiologies of CPHD such as mutations of POU1F1 or PROP1, we focused the present overview on the data published in the last 5 years, to provide the reader with an updated review on this rapidly evolving field of knowledge. PMID- 26733482 TI - Parents' Depressive Symptoms and Gun, Fire, and Motor Vehicle Safety Practices. AB - OBJECTIVE: This study examined associations between mothers' and fathers' depressive symptoms and their parenting practices relating to gun, fire, and motor vehicle safety. METHODS: Using data from the Early Childhood Longitudinal Study-Birth Cohort (ECLS-B), a nationally representative sample of children birth to age five, linear probability models were used to examine associations between measures of parents' depressive symptoms and their use of firearms, smoke detectors, and motor vehicle restraints. Parents reported use of smoke detectors, motor vehicle restraints, and firearm ownership and storage. RESULTS: Results suggest mothers with moderate or severe depressive symptoms were 2 % points less likely to report that their child always sat in the back seat of the car, and 3 % points less likely to have at least one working smoke detector in the home. Fathers' depressive symptoms were associated with a lower likelihood of both owning a gun and of it being stored locked. Fathers' depressive symptoms amplified associations between mothers' depressive symptoms and owning a gun, such that having both parents exhibit depressive symptoms was associated with an increased likelihood of gun ownership of between 2 and 6 % points. CONCLUSIONS: Interventions that identify and treat parental depression early may be effective in promoting appropriate safety behaviors among families with young children. PMID- 26733481 TI - The TIM Barrel Architecture Facilitated the Early Evolution of Protein-Mediated Metabolism. AB - The triosephosphate isomerase (TIM) barrel protein fold is a structurally repetitive architecture that is present in approximately 10% of all enzymes. It is generally assumed that this ubiquity in modern proteomes reflects an essential historical role in early protein-mediated metabolism. Here, we provide quantitative and comparative analyses to support several hypotheses about the early importance of the TIM barrel architecture. An information theoretical analysis of protein structures supports the hypothesis that the TIM barrel architecture could arise more easily by duplication and recombination compared to other mixed alpha/beta structures. We show that TIM barrel enzymes corresponding to the most taxonomically broad superfamilies also have the broadest range of functions, often aided by metal and nucleotide-derived cofactors that are thought to reflect an earlier stage of metabolic evolution. By comparison to other putatively ancient protein architectures, we find that the functional diversity of TIM barrel proteins cannot be explained simply by their antiquity. Instead, the breadth of TIM barrel functions can be explained, in part, by the incorporation of a broad range of cofactors, a trend that does not appear to be shared by proteins in general. These results support the hypothesis that the simple and functionally general TIM barrel architecture may have arisen early in the evolution of protein biosynthesis and provided an ideal scaffold to facilitate the metabolic transition from ribozymes, peptides, and geochemical catalysts to modern protein enzymes. PMID- 26733483 TI - Conformational space of clindamycin studied by ab initio and full-atom molecular dynamics. AB - Molecular dynamics (MD) simulations allow determining internal flexibility of molecules at atomic level. Using ab initio Born-Oppenheimer molecular dynamics (BOMD), one can simulate in a reasonable time frame small systems with hundreds of atoms, usually in vacuum. With quantum mechanics/molecular mechanics (QM/MM) or full-atom molecular dynamics (FAMD), the influence of the environment can also be simulated. Here, we compare three types of MD calculations: ab initio BOMD, hybrid QM/MM, and classical FAMD. As a model system, we use a small antibiotic molecule, clindamycin, which is one of the lincosamide antibiotics. Clindamycin acquires two energetically stable forms and we investigated the transition between these two experimentally known conformers. We performed 60-ps BOMD simulations in vacuum, 50-ps QM/MM, and 100-ns FAMD in explicit water. The transition between two antibiotic conformers was observed using both BOMD and FAMD methods but was not noted in the QM/MM simulations. PMID- 26733484 TI - The effect of Li doping on the nonlinear optical properties of [2.2]paracyclophane. AB - The similar molecules [2.2]paracyclophane (22PCP) and 1,1,2,2,9,9,10,10 octafluoro[2.2]paracyclophane (8F22PCP) have both generated considerable synthetic interest since they were first prepared. In this work, the nonlinear optical properties of 22PCP, 8F22PCP, and the related Li-doped systems 22PCP-Li and 8F22PCP-Li (which have a Li atom above 22PCP and 8F22PCP, respectively) were investigated. An analysis of natural bond orbital charges showed that there is greater charge transfer from the Li atom to the benzene rings in 8F22PCP-Li than in 22PCP-Li. The variation in the calculated nucleus independent chemical shift (NICS) value as a function of the distance from the lower benzene ring towards the upper benzene ring was found to be W-shaped for both 22PCP and 22PCP-Li. Moreover, whereas all of the NICS values of 22PCP and 22PCP-Li were markedly negative, all of the NICS values of 8F22PCP and 8F22PCP-Li were either positive or only moderately negative. Calculations of the electro-optical properties of these systems showed that the first hyperpolarizability of 22PCP-Li was noticeably larger than that of 8F22PCP-Li. According to the two-level model, the larger first hyperpolarizability of 22PCP-Li is due to its smaller transition energy. PMID- 26733485 TI - Pore diameter effects on phase behavior of a gas condensate in graphitic one-and two-dimensional nanopores. AB - Molecular dynamics (MD) simulations were performed on a hydrocarbon mixture representing a typical gas condensate composed mostly of methane and other small molecules with small fractions of heavier hydrocarbons, representative of mixtures found in tight shale reservoirs. The fluid was examined both in bulk and confined to graphitic nano-scale slits and pores. Numerous widths and diameters of slits and pores respectively were examined under variable pressures at 300 K in order to find conditions in which the fluid at the center of the apertures would not be affected by capillary condensation due to the oil-wet walls. For the bulk fluid, retrograde phase behavior was verified by liquid volumes obtained from Voronoi tessellations. In cases of both one and two-dimensional confinement, for the smallest apertures, heavy molecules aggregated inside the pore space and compression of the gas outside the solid structure lead to decreases in density of the confined fluid. Normal density/pressure relationships were observed for slits having gaps of above 3 nm and pores having diameters above 6 nm. At 70 bar, the minimum gap width at which the fluid could pass through the center of slits without condensation effects was predicted to be 6 nm and the corresponding diameter in pores was predicted to be 8 nm. The models suggest that in nanoscale networks involving pores smaller than these limiting dimensions, capillary condensation should significantly impede transmission of natural gases with similar composition. PMID- 26733486 TI - Theoretical studies of the role of C-terminal cysteines in the process of S nitrosylation of human Src kinases. AB - Src tyrosine kinases are a family of non-receptor proteins that are responsible for the growth process, cellular proliferation, differentiation and survival. Lack of Src kinase control has been associated with the development of certain human cancers. This family of proteins is constituted of four domains, with SH1 being the kinase or catalytic domain. SH1 also presents three important regulatory sites. Two residues, Tyr416 and Tyr527, are responsible for important phosphorylation processes that lead to, respectively, activation and deactivation of these kinases. More recently, however, a set of four cysteine residues located near the C-terminus-Cys483, Cys487, Cys496 and Cys498-has been associated with the activation of the Src kinases through S-nitrosylation reactions. Particularly, the Cys498 has been specified as a fundamental residue when considering this regulatory mechanism. Aiming to understand the role of these four cysteines in S-nitrosylation, theoretical studies of electrostatic, steric and hydrophobic properties were performed with a sequence of 20 amino acids, enclosing the four cysteine residues under study, extracted from the PDB coordinates of the crystal obtained from the inactive state of Src kinase. Results indicate that Cys498 is buried deeply in the protein, in hydrophobic surroundings in which NO is more likely to suffer decomposition into the electrophilic intermediates known to be responsible for S-nitrosylation reactions. Electronic calculated properties, such as punctual atomic charges, electrostatic potentials and molecular orbital energy, also demonstrated the good nucleophilic potential of Cys498. Graphical Abstract Structure of Src kinase with zoomed area representing the 20 amino acids comprising the CC motif extracted from the whole protein structure. Right upper panel Electrostatic potential map, right lower panel hydrophilic map in anterior view. PMID- 26733487 TI - Review and meta-analysis of ab-interno trabeculectomy outcomes. AB - We analysed all of the PubMed publications on ab-interno trabeculectomy (AIT) with the Trabectome (Neomedix, Irvine, California, USA) to determine the reduction in intraocular pressure (IOP) and medications following the procedure. For IOP outcomes, PubMed was searched for 'trabectome', 'ab interno trabeculotomy' and 'ab interno trabeculectomy' and all available papers retrieved. The meta-analysis used a random-effects model to achieve conservative estimates and assess statistical heterogeneity. To investigate complications, we included all abstracts from the American Glaucoma Society, American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery and the Association for Research in Vision and Ophthalmology. The overall arithmetic mean baseline IOP for standalone Trabectome was 26.71+/-1.34 mm Hg and decreased by 10.5+/-1.9 mm Hg (39% decrease) on 0.99+/-0.54 fewer medications. Defining success as IOP <=21 with a 20% decrease while avoiding reoperation, the overall average success rate after 2 years was 46+/-34%. For combined phacoemulsification Trabectome, the baseline IOP of 21+/-1.31 mm Hg decreased by 6.24+/-1.98 mm Hg (27% decrease) on 0.76+/-0.35 fewer medications. The success rate using the same definition at 2 years was 85+/-7%. The weighted mean IOP difference from baseline to study endpoint was 9.77 mm Hg (95% CI 8.90 to 10.64) standalone and 6.04 mm Hg (95% CI 4.95 to 7.13) for combined cases. Despite heterogeneity, meta-analysis showed significant and consistent decrease in IOP and medications from baseline to end point in AIT and phaco-AIT. The rate of visually threatening complications was <1%. On average, trabectome lowers the IOP by approximately 31% to a final IOP near 15 mm Hg while decreasing the number of medications by less than one, with a low rate of serious complications. After 2 years, the overall average success rate is 66%. PMID- 26733488 TI - Perspectives on Stress, Parenting, and Children's Obesity-Related Behaviors in Black Families. AB - Objective In an effort to develop targets for childhood obesity interventions in non-Hispanic-Black (Black) families, this study examined parental perceptions of stress and identified potential links among parental stress and children's eating patterns, physical activity, and screen-time. Method Thirty-three self-identified Black parents or grandparents of a child aged 3 to 7 years were recruited from a large, urban Black church to participate in semistructured interviews. Interviews were audio-recorded, transcribed, and analyzed using thematic analysis. Results Parents/grandparents described a pathway between how stress affected them personally and their child's eating, structured (sports/dance) and unstructured (free-play) physical activity, and screen-time usage, as well as strategies to prevent this association. Five themes emerged: stress affects parent behaviors related to food and physical activity variably; try to be healthy even with stress; parent/grandparent stress eating and parenting; stress influences family cooking, food choices, and child free-play; and screen-time use to decrease parent stress. Negative parent/grandparent response to their personal stress adversely influenced food purchases and parenting related to child eating, free play, and screen-time. Children of parents/grandparents who ate high-fat/high sugar foods when stressed requested these foods. In addition to structured physical activity, cooking ahead and keeping food in the house were perceived to guard against the effects of stress except during parent cravings. Parent/child screen-time helped decrease parent stress. Conclusion Parents/grandparents responded variably to stress which affected the child eating environment, free play, and screen-time. Family-based interventions to decrease obesity in Black children should consider how stress influences parents. Targeting parent cravings and coping strategies that utilize structure in eating and physical activity may be useful intervention strategies. PMID- 26733489 TI - Adaptive Genetic Robustness of Escherichia coli Metabolic Fluxes. AB - Genetic robustness refers to phenotypic invariance in the face of mutation and is a common characteristic of life, but its evolutionary origin is highly controversial. Genetic robustness could be an intrinsic property of biological systems, a result of direct natural selection, or a byproduct of selection for environmental robustness. To differentiate among these hypotheses, we analyze the metabolic network of Escherichia coli and comparable functional random networks. Treating the flux of each reaction as a trait and computationally predicting trait values upon mutations or environmental shifts, we discover that 1) genetic robustness is greater for the actual network than the random networks, 2) the genetic robustness of a trait increases with trait importance and this correlation is stronger in the actual network than in the random networks, and 3) the above result holds even after the control of environmental robustness. These findings demonstrate an adaptive origin of genetic robustness, consistent with the theoretical prediction that, under certain conditions, direct selection is sufficiently powerful to promote genetic robustness in cellular organisms. PMID- 26733490 TI - Cross-Study Comparison Reveals Common Genomic, Network, and Functional Signatures of Desiccation Resistance in Drosophila melanogaster. AB - Repeated attempts to map the genomic basis of complex traits often yield different outcomes because of the influence of genetic background, gene-by environment interactions, and/or statistical limitations. However, where repeatability is low at the level of individual genes, overlap often occurs in gene ontology categories, genetic pathways, and interaction networks. Here we report on the genomic overlap for natural desiccation resistance from a Pool genome-wide association study experiment and a selection experiment in flies collected from the same region in southeastern Australia in different years. We identified over 600 single nucleotide polymorphisms associated with desiccation resistance in flies derived from almost 1,000 wild-caught genotypes, a similar number of loci to that observed in our previous genomic study of selected lines, demonstrating the genetic complexity of this ecologically important trait. By harnessing the power of cross-study comparison, we narrowed the candidates from almost 400 genes in each study to a core set of 45 genes, enriched for stimulus, stress, and defense responses. In addition to gene-level overlap, there was higher order congruence at the network and functional levels, suggesting genetic redundancy in key stress sensing, stress response, immunity, signaling, and gene expression pathways. We also identified variants linked to different molecular aspects of desiccation physiology previously verified from functional experiments. Our approach provides insight into the genomic basis of a complex and ecologically important trait and predicts candidate genetic pathways to explore in multiple genetic backgrounds and related species within a functional framework. PMID- 26733493 TI - The diagnostic dartboard: is the bullseye a correct pathoanatomical diagnosis or to guide treatment? PMID- 26733492 TI - The Transmission of Gun and Other Weapon-Involved Violence Within Social Networks. AB - Fatal and nonfatal injuries resulting from gun violence remain a persistent problem in the United States. The available research suggests that gun violence diffuses among people and across places through social relationships. Understanding the relationship between gun violence within social networks and individual gun violence risk is critical in preventing the spread of gun violence within populations. This systematic review examines the existing scientific evidence on the transmission of gun and other weapon-related violence in household, intimate partner, peer, and co-offending networks. Our review identified 16 studies published between 1996 and 2015 that suggest that exposure to a victim or perpetrator of violence in one's interpersonal relationships and social networks increases the risk of individual victimization and perpetration. Formal network analyses find high concentrations of gun violence in small networks and that exposure to gun violence in one's networks is highly correlated with one's own probability of being a gunshot victim. Physical violence by parents and weapon use by intimate partners also increase risk for victimization and perpetration. Additional work is needed to better characterize the mechanisms through which network exposures increase individual risk for violence and to evaluate interventions aimed at disrupting the spread of gun and other weapon violence in high-risk social networks. PMID- 26733491 TI - The ascidian natural product eusynstyelamide B is a novel topoisomerase II poison that induces DNA damage and growth arrest in prostate and breast cancer cells. AB - As part of an anti-cancer natural product drug discovery program, we recently identified eusynstyelamide B (EB), which displayed cytotoxicity against MDA-MB 231 breast cancer cells (IC50 = 5 MUM) and induced apoptosis. Here, we investigated the mechanism of action of EB in cancer cell lines of the prostate (LNCaP) and breast (MDA-MB-231). EB inhibited cell growth (IC50 = 5 MUM) and induced a G2 cell cycle arrest, as shown by a significant increase in the G2/M cell population in the absence of elevated levels of the mitotic marker phospho histone H3. In contrast to MDA-MB-231 cells, EB did not induce cell death in LNCaP cells when treated for up to 10 days. Transcript profiling and Ingenuity Pathway Analysis suggested that EB activated DNA damage pathways in LNCaP cells. Consistent with this, CHK2 phosphorylation was increased, p21CIP1/WAF1 was up regulated and CDC2 expression strongly reduced by EB. Importantly, EB caused DNA double-strand breaks, yet did not directly interact with DNA. Analysis of topoisomerase II-mediated decatenation discovered that EB is a novel topoisomerase II poison. PMID- 26733494 TI - Two-Wave Dyadic Analysis of Marital Quality and Loneliness in Later Life: Results From the Irish Longitudinal Study on Ageing. AB - This study examines dyadic reports of marital quality and loneliness over a two year period among 932 older married couples resident in Ireland. Data from the first two waves of The Irish Longitudinal Study on Ageing (2009-2013) were analyzed to determine whether husbands' and wives' marital quality and loneliness at baseline predicted both spouses' loneliness 2 years later. Two-wave lagged models tested the cognitive perspective on loneliness, the induction hypothesis, and actor-partner interdependence. Results indicated that perceptions of negative marital quality at baseline were related with greater loneliness 2 years later, supporting the cognitive perspective. Further, both spouses' reports of loneliness at baseline were related with loneliness 2 years later, supporting the induction hypothesis. Partners' reports of marital quality were not related with future loneliness, failing to support actor-partner interdependence. I discuss the implications of these findings for theory, practice, and future research concerning intimate relationships and loneliness in later life. PMID- 26733495 TI - The Impact of Caring for Grandchildren on Grandparents' Physical Health Outcomes: The Role of Intergenerational Support. AB - Little longitudinal data exist on grandparent caregivers and few studies have examined their physical health outcomes. This study examined the effect of caring for grandchildren on grandparents' physical health and the role of intergenerational support from adult children. Longitudinal data derived from a survey on the well-being of older adults in China were used to conduct path analysis of previous grandparent caregivers (vs. noncaregivers) and repeated grandparent caregivers (vs. noncaregivers). The final sample was 799 grandparents aged 60 or older living in rural China. Three aspects of intergenerational support were measured: financial, emotional, and instrumental support. Repeated grandparent caregivers had better self-rated health (SRH) and fewer limitations than noncaregivers. Previous grandparent caregivers had better SRH compared to noncaregivers. Emotional support mediated the relationship between caregiving and SRH among repeated caregivers. Findings suggest that any caregiving experience (previous or repeated) provides health benefits to grandparents. PMID- 26733496 TI - Effect of cytokine level variations in individuals on the progression and outcome of bacterial urogenital infections--a meta-analysis. AB - Bacterial urogenital infections such as chlamydia, gonorrhoea and syphilis are widespread inflammatory diseases, which may be accompanied by severe complications. These complications can range from basic inflammation to tubal pathology, infertility and neurological dysfunction, though infections go unnoticed in the majority of cases. Cytokines in the host play a vital role in both the initial and long-term immune response and inflammation. However, levels of cytokine expression vary between individuals. A meta-analysis was performed to evaluate the effect of cytokine expression differences on severity of infections with these pathogens. Studies comparing expression of cytokines in humans with inflammation or inflammation-based complications were identified using NCBI, Google Scholar and Cochrane databases. Only studies into human cytokine expressions were included, and three articles per subject were required to be suitably analysed during meta-analysis. A total of 52 articles were included for meta-analysis. It was shown that differences in IL-1, IL-6, IL-8, IL-10, TNFalpha and IFNgamma affect the clinical outcome of Chlamydia trachomatis infection significantly. Similarly, IL-1 and IL-8 expression during Neisseria gonorrhoeae infection significantly affects the outcome of the disease. For Treponema pallidum infection, it was shown that IFNgamma variation in hosts could be linked to severity of disease. However, a lack of studies to use in the meta-analysis and fluctuation in the resulting data depending on the adjustments makes adequate evaluation difficult. PMID- 26733497 TI - Novel epidermal growth factor receptor pathway mediates release of human beta defensin 3 from Helicobacter pylori-infected gastric epithelial cells. AB - Persistent Helicobacter pylori (H. pylori) infection in hostile gastric mucosa can result in gastric diseases. Helicobacter pylori induces to express antimicrobial peptides from gastric epithelial cells, especially human beta defensin 3 (hBD3), as an innate immune response, and this expression of hBD3 is mediated by epidermal growth factor receptor (EGFR) activation. In this study, we found that phosphorylation of a serine residue of EGFR via transforming growth factor beta-activated kinase-1 (TAK1), and subsequent p38alpha activation is essential for H. pylori-induced hBD3 release from gastric epithelial cells. We showed that this pathway was dependent on H. pylori type IV secretion system and was independent of H. pylori-derived CagA or peptidoglycan. H. pylori infection induced phosphorylation of serine residue of EGFR, and this phosphorylation was followed by internalization of EGFR; consequently, hBD3 was released at an early phase of the infection. In the presence of TAK1 or p38alpha inhibitors, synthesis of hBD3 was completely inhibited. Similar results were observed in EGFR-, TAK1- or p38alpha-knockdown cells. However, NOD1 knockdown in gastric epithelial cells did not inhibit hBD3 induction. Our study has firstly demonstrated that this novel EGFR activating pathway functioned to induce hBD3 at an early phase of H. pylori infection. PMID- 26733498 TI - Secretome profile analysis of hypervirulent Mycobacterium tuberculosis CPT31 reveals increased production of EsxB and proteins involved in adaptation to intracellular lifestyle. AB - Epidemiological information and animal models have shown various Mycobacterium tuberculosis phenotypes ranging from hyper- to hypovirulent forms. Recent genomic and proteomic studies suggest that the outcome of infection depends on the M. tuberculosis fitness, which is a direct consequence of its phenotype. However, little is known about the molecular and cellular mechanisms used by mycobacteria to survive, replicate and persist during infection. The aim of this study was to perform a comprehensive proteomic analysis of culture filtrate from hypo- (CPT23) and hypervirulent (CPT31) M. tuberculosis isolates. Using two-dimensional electrophoresis we observed that 70 proteins were unique, or more abundant in culture filtrate of CPT31, and 15 of these were identified by mass spectrometry. Our analysis of protein expression showed that most of the proteins identified are involved in lipid metabolism (FadA3, FbpB and EchA3), detoxification and adaptation (GroEL2, SodB and HspX) and cell wall processes (LprA, Tig and EsxB). These results suggest that overrepresented proteins in M. tuberculosis CPT31 secretome could facilitate mycobacterial infection and persistence. PMID- 26733499 TI - Detection of Chlamydia infection in Peromyscus species rodents from sylvatic and laboratory sources. AB - To determine if Chlamydia muridarum, or other chlamydiae, are enzootic in rodents, we probed a serum bank of wild Peromyscus spp. mice for immunoglobulin G antibody reactivity to ultraviolet light-inactivated C. muridarum elementary bodies (EBs) using an enzyme-linked immunoassay. Applying a cut-off for a positive reaction of OD(405) nm = 0.1 at a 1:20 dilution, we found titratable antibody reactivity in 190 of 247 specimens surveyed (77%, mean OD(405) = 0.33 +/ 0.26, range = 0.11-1.81, median = 0.25). In addition, serum samples were obtained from a colony of specific pathogen-free Peromyscus spp. maintained at the University of South Carolina and six of 12 samples were reactive (50%, mean OD(405) = 0.19 +/- 0.08, range = 0.1-0.32, median = 0.18). Lastly, 40 additional wild Peromyscus spp. were captured in a disparate region of Midwestern USA and 22 serum specimens were reactive (55%, mean OD(405) = 0.22 +/- 0.11, range = 0.1 0.48, median = 0.2). Specificity of selected reactive sera for chlamydial antigen was confirmed on Western blot using resolved purified EBs as the detecting antigen. From tissues removed from several mice at necropsy, the gene for chlamydial 16S ribosomal ribonucleic acid (rRNA) was amplified by polymerase chain reaction (PCR). Positive samples of 16S rRNA were subjected to additional PCR for the major outer membrane protein gene (ompA). The amplicons of three select ompA positive samples were sequenced with >=99% homology with C. muridarum. Our findings indicate that chlamydial infection is enzootic for Peromyscus spp., and that C. muridarum, or a closely related species or strain, is likely the agent in the tested rodent species. PMID- 26733500 TI - Levonorgestrel-Releasing Intrauterine System for Women With Polycystic Ovary Syndrome: Metabolic and Clinical Effects. AB - Polycystic ovary syndrome (PCOS) is related to clinical and metabolic comorbidities that may limit the prescription of combined hormonal contraceptives, with consequent need to use progestogen-only contraceptives (POCs). Thus, the objective of the present study was to evaluate the clinical and metabolic effects of a POC, the levonorgestrel-releasing intrauterine system (LNG IUS), in women with PCOS followed up over a period of 6 months compared to baseline and to women without PCOS. Thus, an observational, prospective, controlled study was conducted on 30 women with a diagnosis of PCOS who presented adverse effect secondary to the use of combined oral contraceptives (nausea, headache, mastalgia or vomiting; PCOS group) paired with 30 ovulatory women without PCOS (control group), both groups being free of comorbidities and having chosen the LNG-IUS as contraceptive. Clinical, laboratory, and ultrasonographic variables were evaluated immediately before LNG-IUS insertion and 6 months after the use of this method. Before LNG-IUS insertion, the PCOS group had higher total testosterone levels (P = .04), lower HDL levels (P = .04), and greater ovarian volume (P < .01) than the control group. Six months after LNG-IUS insertion, there was a 2.3% increase in abdominal circumference (P = .04) and a 3.4% increase in fasting glycemia (P = .02). On the other hand, mean ovarian volume was 10% smaller compared to the volume found before LNG-IUS insertion (P = .04), LDL levels were reduced by 5.2% (P = .03), and total cholesterol levels were reduced by 6.7% (P < .01) compared to baseline evaluation in the PCOS group. The remaining variables did not differ significantly during the 6 months of observation. The control group did not show significant changes compared to the period before LNG-IUS insertion. When the groups were compared after the 6-month follow-up, only glycemia showed a statistically significant variation between the groups, with glycemia levels increasing by 3.4% in the PCOS group and decreasing by 2.6% in the control group (P = .008). In conclusion, the use of the LNG-IUS for 6 months was not associated with relevant changes in clinical or metabolic variables of women with no comorbidities regardless of the presence of PCOS. PMID- 26733501 TI - TERT promoter mutations in thyroid cancer. AB - The 2013 discovery of Telomerase reverse transcriptase (TERT) promoter mutations chr5, 1,295,228 C>T (C228T) and 1,295,250 C>T (C250T) in thyroid cancer represents an important event in the thyroid cancer field and much progress has occurred since then. This article provides a comprehensive review of this exciting new thyroid cancer field. The oncogenic role of TERT promoter mutations involves their creation of consensus binding sites for E-twenty-six transcriptional factors. TERT C228T is far more common than TERT C250T and their collective prevalence is, on average, 0, 11.3, 17.1, 43.2 and 40.1% in benign thyroid tumors, papillary thyroid cancer (PTC), follicular thyroid cancer, poorly differentiated thyroid cancer and anaplastic thyroid cancer, respectively, displaying an association with aggressive types of thyroid cancer. TERT promoter mutations are associated with aggressive thyroid tumor characteristics, tumor recurrence and patient mortality as well as BRAF V600E mutation. Coexisting BRAF V600E and TERT promoter mutations have a robust synergistic impact on the aggressiveness of PTC, including a sharply increased tumor recurrence and patient mortality, while either mutation alone has a modest impact. Thus, TERT with promoter mutations represents a prominent new oncogene in thyroid cancer and the mutations are promising new diagnostic and prognostic genetic markers for thyroid cancer, which, in combination with BRAF V600E mutation or other genetic markers (e.g. RAS mutations), are proving to be clinically useful for the management of thyroid cancer. Future studies will specifically define such clinical utilities, elucidate the biological mechanisms and explore the potential as therapeutic targets of TERT promoter mutations in thyroid cancer. PMID- 26733502 TI - Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours. AB - Somatostatin receptor type 2 (SST2) is the main pharmacological target of somatostatin (SS) analogues widely used in patients with pancreatic neuroendocrine tumours (P-NETs), this treatment being ineffective in a subset of patients. Since it has been demonstrated that Filamin A (FLNA) is involved in mediating GPCR expression, membrane anchoring and signalling, we investigated the role of this cytoskeleton protein in SST2 expression and signalling, angiogenesis, cell adhesion and cell migration in human P-NETs and in QGP1 cell line. We demonstrated that FLNA silencing was not able to affect SST2 expression in P-NET cells in basal conditions. Conversely, a significant reduction in SST2 expression (-43 +/- 21%, P < 0.05 vs untreated cells) was observed in FLNA silenced QGP1 cells after long term SST2 activation with BIM23120. Moreover, the inhibitory effect of BIM23120 on cyclin D1 expression (-46 +/- 18%, P < 0.05 vs untreated cells), P-ERK1/2 levels (-42 +/- 14%; P < 0.05 vs untreated cells), cAMP accumulation (-24 +/- 3%, P < 0.05 vs untreated cells), VEGF expression (-31 +/- 5%, P < 0.01 vs untreated cells) and in vitro release (-40 +/- 24%, P < 0.05 vs untreated cells) was completely lost after FLNA silencing. Interestingly, BIM23120 promoted cell adhesion (+86 +/- 45%, P < 0.05 vs untreated cells) and inhibited cell migration (-24 +/- 2%, P < 0.00001 vs untreated cells) in P-NETs cells and these effects were abolished in FLNA silenced cells. In conclusion, we demonstrated that FLNA plays a crucial role in SST2 expression and signalling, angiogenesis, cell adhesion and cell migration in P-NETs and in QGP1 cell line, suggesting a possible role of FLNA in determining the different responsiveness to SS analogues observed in P-NET patients. PMID- 26733503 TI - Genomic structural variation contributes to phenotypic change of industrial bioethanol yeast Saccharomyces cerevisiae. AB - Genomic structural variation (GSV) is a ubiquitous phenomenon observed in the genomes of Saccharomyces cerevisiae strains with different genetic backgrounds; however, the physiological and phenotypic effects of GSV are not well understood. Here, we first revealed the genetic characteristics of a widely used industrial S. cerevisiae strain, ZTW1, by whole genome sequencing. ZTW1 was identified as an aneuploidy strain and a large-scale GSV was observed in the ZTW1 genome compared with the genome of a diploid strain YJS329. These GSV events led to copy number variations (CNVs) in many chromosomal segments as well as one whole chromosome in the ZTW1 genome. Changes in the DNA dosage of certain functional genes directly affected their expression levels and the resultant ZTW1 phenotypes. Moreover, CNVs of large chromosomal regions triggered an aneuploidy stress in ZTW1. This stress decreased the proliferation ability and tolerance of ZTW1 to various stresses, while aneuploidy response stress may also provide some benefits to the fermentation performance of the yeast, including increased fermentation rates and decreased byproduct generation. This work reveals genomic characters of the bioethanol S. cerevisiae strain ZTW1 and suggests that GSV is an important kind of mutation that changes the traits of industrial S. cerevisiae strains. PMID- 26733504 TI - New Daily Persistent Headache Is Most Likely to Begin at the Start of School. AB - This study was performed to determine if there were a time of year that children were more likely to transition into a chronic daily headache. We retrospectively reviewed records of 103 patients with chronic migraine and 104 patients with new daily persistent headache. Of these, 56 chronic migraine and 92 new daily persistent headache patients were able to identify the specific month in which they began to experience daily headaches. Thirty-nine percent of new daily persistent headache patients had an onset of daily headache in either September or January, months traditionally associated with the start of the school semester in the United States. Only a single patient reported onset in May or June. Data for the transition from episodic to chronic migraine also showed higher rates in September and January, but did not reach statistical significance. These data demonstrate the higher rates of new daily persistent headache onset during school start months and question what factors may be responsible for this association. PMID- 26733505 TI - The Effects of Walking Surface on the Gait Pattern of Children With Idiopathic Toe Walking. AB - Idiopathic toe walking treatments are not conclusively effective. This study investigated the effects of walking surface on gait parameters in children with idiopathic toe walking. Fifteen children with idiopathic toe walking and 15 typically developing children aged 4 to 10 years completed the study, which included a barefoot gait exam over three 4-m walkways. Each of the walkways was covered with a different surface: vinyl tile, carpet, and pea gravel. Temporal spatial parameters were recorded along with a measure of early heel rise (HR32). Children with idiopathic toe walking and typically developing children shared similarly changed gait patterns on each surfaces. Only HR32 was significantly different between the groups (P < .001). Children with idiopathic toe walking showed significantly less toe-walking on the gravel walkway (P < .001). Walking surface plays a significant role in altering gait patterns in both children with idiopathic toe walking and typically developing children. Walking on a gravel surface should be further explored for idiopathic toe walking. PMID- 26733506 TI - Prevalence of Autism Spectrum Disorders in Siblings of Indian Children With Autism Spectrum Disorders. AB - This study determined the prevalence of autism spectrum disorders in 201 siblings of children with autism spectrum disorders. Siblings were screened using Modified Checklist for Autism in Toddlers and Social Responsiveness Scale, parent version. Screen-positive siblings were assessed using Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria. The risk of autism spectrum disorder in siblings was correlated with various familial and disease characteristics of the index case. Prevalence of autism spectrum disorder in siblings was 4.97%. There was a significant effect of the presence of aggressive behavior, externalizing problems and total problems in the proband, assessed using Childhood Behavior Checklist, and the young age of the father at conception on sibling risk of autism spectrum disorder. Results of our study are in line with previous studies reporting similar prevalence but have also brought up the association with behavioral problems as a possible risk factor. Siblings of children with autism spectrum disorder should be routinely screened, and genetic counseling for this increased risk should be explained to the family. PMID- 26733507 TI - Publication of surgeon level data from registers: who benefits? PMID- 26733508 TI - Thoracolumbar spinal treatment without screws: examples of clinical proficiency. PMID- 26733509 TI - Systemic cobalt toxicity from total hip arthroplasties: review of a rare condition Part 1 - history, mechanism, measurements, and pathophysiology. AB - Recently, the use of metal-on-metal articulations in total hip arthroplasty (THA) has led to an increase in adverse events owing to local soft-tissue reactions from metal ions and wear debris. While the majority of these implants perform well, it has been increasingly recognised that a small proportion of patients may develop complications secondary to systemic cobalt toxicity when these implants fail. However, distinguishing true toxicity from benign elevations in cobalt ion levels can be challenging. The purpose of this two part series is to review the use of cobalt alloys in THA and to highlight the following related topics of interest: mechanisms of cobalt ion release and their measurement, definitions of pathological cobalt ion levels, and the pathophysiology, risk factors and treatment of cobalt toxicity. Historically, these metal-on-metal arthroplasties are composed of a chromium-cobalt articulation. The release of cobalt is due to the mechanical and oxidative stresses placed on the prosthetic joint. It exerts its pathological effects through direct cellular toxicity. This manuscript will highlight the pathophysiology of cobalt toxicity in patients with metal-on-metal hip arthroplasties. TAKE HOME MESSAGE: Patients with new or evolving hip symptoms with a prior history of THA warrant orthopaedic surgical evaluation. Increased awareness of the range of systemic symptoms associated with cobalt toxicity, coupled with prompt orthopaedic intervention, may forestall the development of further complications. PMID- 26733510 TI - Systemic cobalt toxicity from total hip arthroplasties: review of a rare condition Part 2. measurement, risk factors, and step-wise approach to treatment. AB - As adverse events related to metal on metal hip arthroplasty have been better understood, there has been increased interest in toxicity related to the high circulating levels of cobalt ions. However, distinguishing true toxicity from benign elevations in cobalt levels can be challenging. The purpose of this review is to examine the use of cobalt alloys in total hip arthroplasty, to review the methods of measuring circulating cobalt levels, to define a level of cobalt which is considered pathological and to review the pathophysiology, risk factors and treatment of cobalt toxicity. To the best of our knowledge, there are 18 published cases where cobalt metal ion toxicity has been attributed to the use of cobalt-chromium alloys in hip arthroplasty. Of these cases, the great majority reported systemic toxic reactions at serum cobalt levels more than 100 MUg/L. This review highlights some of the clinical features of cobalt toxicity, with the goal that early awareness may decrease the risk factors for the development of cobalt toxicity and/or reduce its severity. TAKE HOME MESSAGE: Severe adverse events can arise from the release of cobalt from metal-on-metal arthroplasties, and as such, orthopaedic surgeons should not only be aware of the presenting problems, but also have the knowledge to treat appropriately. PMID- 26733511 TI - Arthroscopic treatment of femoroacetabular impingement following slipped capital femoral epiphysis. AB - Slipped capital femoral epiphysis (SCFE) may lead to symptomatic femoroacetabular impingement (FAI). We report our experience of arthroscopic treatment, including osteochondroplasty, for the sequelae of SCFE. Data were prospectively collected on patients undergoing arthroscopy of the hip for the sequelae of SCFE between March 2007 and February 2013, including demographic data, radiological assessment of the deformity and other factors that may influence outcome, such as the presence of established avascular necrosis. Patients completed the modified Harris hip score (mHHS) and the non-arthritic hip score (NAHS) before and after surgery. In total, 18 patients with a mean age of 19 years (13 to 42), were included in the study. All patients presented with pain in the hip and mechanical symptoms, and had evidence of FAI (cam or mixed impingement) on plain radiographs. The patients underwent arthroscopic osteoplasty of the femoral neck. The mean follow-up was 29 months (23 to 56). The mean mHHS and NAHS scores improved from 56.2 (27.5 to 100.1) and 52.1 (12.5 to 97.5) pre-operatively to 75.1 (33.8 to 96.8, p = 0.01) and 73.6 (18.8 to 100, p = 0.02) at final follow up, respectively. Linear regression analysis demonstrated a significant association between poorer outcome scores and increased time to surgery following SCFE (p < 0.05 for all parameters except baseline MHHS). Symptomatic FAI following (SCFE) may be addressed using arthroscopic techniques, and should be treated promptly to minimise progressive functional impairment and chondrolabral degeneration. TAKE HOME MESSAGE: Arthroscopy of the hip can be used to treat femoroacetabular impingement successfully following SCFE. However, this should be performed promptly after presentation in order to prevent irreversible progression and poorer clinical outcomes. PMID- 26733512 TI - Highly cross-linked polyethylene decreases the rate of revision of total hip arthroplasty compared with conventional polyethylene at 13 years' follow-up. AB - AIMS: The purpose of this study was to compare the long-term results of primary total hip arthroplasty (THA) in young patients using either a conventional (CPE) or a highly cross-linked (HXLPE) polyethylene liner in terms of functional outcome, incidence of osteolysis, radiological wear and rate of revision. METHODS: We included all patients between the ages of 45 and 65 years who, between January 2000 and December 2001, had undergone a primary THA for osteoarthritis at our hospital using a CPE or HXLPE acetabular liner and a 28 mm cobalt-chrome femoral head. From a total of 160 patients, 158 (177 hips) were available for review (CPE 89; XLPE 88). The mean age, body mass index (BMI) and follow-up in each group were: CPE: 56.8 years (46 to 65); 30.7 kg/m(2) (19 to 58); 13.2 years (2.1 to 14.7) and HXLPE: 55.6 years (45 to 65); BMI: 30 kg/m(2) (18 to 51); 13.1 years (5.7 to 14.4). RESULTS: The mean Harris hip score (HHS) at final follow-up was 89.3 for the CPE group and 90.9 for the HXLPE group (p = 0.078). Osteolysis was present around 15 acetabular (17%) and 16 femoral (18%) components in the CPE hips compared with none (0%) in the HXLPE hips. The mean radiological linear wear of the CPE liners was 0.11 mm/year compared with 0.035 mm/year for the HXLPE liners (p = 0.006). The cumulative implant survival, with revision for polyethylene wear as the endpoint, was 86% (95% confidence interval 78 to 94) in the CPE group and 100% in the HXLPE group at 13 years (numbers at risk at 13 years - CPE: 65, XLPE: 61). DISCUSSION: This study shows that HXLPE liners are associated with significantly less osteolysis and a lower rate of revision THA than CPE liners at long-term follow-up. TAKE HOME MESSAGE: The findings of this study highlight the clinical benefits of using HXLPE liners in THA and support the routine use of the material in order to improve implant longevity and to decrease the number of patients needing revision for aseptic osteolysis. PMID- 26733513 TI - Are all metal-on-metal hip revision operations contributing to the National Joint Registry implant survival curves? : a study comparing the London Implant Retrieval Centre and National Joint Registry datasets. AB - AIMS: The National Joint Registry for England, Wales and Northern Ireland (NJR) has extended its scope to report on hospital, surgeon and implant performance. Data linkage of the NJR to the London Implant Retrieval Centre (LIRC) has previously evaluated data quality for hip primary procedures, but did not assess revision records. METHODS: We analysed metal-on-metal hip revision procedures performed between 2003 and 2013. A total of 69 929 revision procedures from the NJR and 929 revised pairs of components from the LIRC were included. RESULTS: We were able to link 716 (77.1%) revision procedures on the NJR to the LIRC. This meant that 213 (22.9%) revision procedures at the LIRC could not be identified on the NJR. We found that 349 (37.6%) explants at the LIRC completed the full linkage process to both NJR primary and revision databases. Data completion was excellent (> 99.9%) for revision procedures reported to the NJR. DISCUSSION: This study has shown that only approximately one third of retrieved components at the LIRC, contributed to survival curves on the NJR. We recommend prospective registry-retrieval linkage as a tool to feedback missing and erroneous data to the NJR and improve data quality. TAKE HOME MESSAGE: Prospective Registry - retrieval linkage is a simple tool to evaluate and improve data quality on the NJR. PMID- 26733514 TI - Which imaging modality is most effective for identifying pseudotumours in metal on-metal hip resurfacings requiring revision: ultrasound or MARS-MRI or both? AB - AIMS: The aims of this study were to compare the diagnostic test characteristics of ultrasound alone, metal artefact reduction sequence MRI (MARS-MRI) alone, and ultrasound combined with MARS-MRI for identifying intra-operative pseudotumours in metal-on-metal hip resurfacing (MoMHR) patients undergoing revision surgery. METHODS: This retrospective diagnostic accuracy study involved 39 patients (40 MoMHRs). The time between imaging modalities was a mean of 14.6 days (0 to 90), with imaging performed at a mean of 5.3 months (0.06 to 12) before revision. The prevalence of intra-operative pseudotumours was 82.5% (n = 33). RESULTS: Agreement with the intra-operative findings was 82.5% (n = 33) for ultrasound alone, 87.5% (n = 35) for MARS-MRI alone, and 92.5% (n = 37) for ultrasound and MARS-MRI combined. The diagnostic characteristics for ultrasound alone and MARS MRI alone reached similar sensitivities (90.9% vs 93.9%) and positive predictive values (PPVs; 88.2% vs 91.2%), but higher specificities (57.1% vs 42.9%) and negative predictive values (NPVs; 66.7% vs 50.0%) were achieved with MARS-MRI. Ultrasound and MARS-MRI combined produced 100% sensitivity and 100% NPV, whilst maintaining both specificity (57.1%) and PPV (91.7%). For the identification of a pseudotumour, which was confirmed at revision surgery, agreement was substantial for ultrasound and MARS-MRI combined (kappa = 0.69), moderate for MARS-MRI alone (kappa = 0.54), and fair for ultrasound alone (kappa = 0.36). DISCUSSION: These findings suggest that ultrasound and/or MARS-MRI have a role when assessing patients with a MoMHR, with the choice dependent on local financial constraints and the availability of ultrasound expertise. However in patients with a MoMHR who require revision, combined imaging was most effective. TAKE HOME MESSAGE: Combined imaging with ultrasound and MARS-MRI always identified intra-operative pseudotumours if present. Furthermore, if neither imaging modality showed a pseudotumour, one was not found intra-operatively. PMID- 26733515 TI - Morphometric analysis of the distal femur in total knee arthroplasty and native knees. AB - AIMS: Analysis of the morphology of the distal femur, and by extension of the femoral components in total knee arthroplasty (TKA), has largely been related to the aspect ratio, which represents the width of the femur. Little is known about variations in trapezoidicity (i.e. whether the femur is more rectangular or more trapezoidal). This study aimed to quantify additional morphological characteristics of the distal femur and identify anatomical features associated with higher risks of over- or under-sizing of components in TKA. METHODS: We analysed the shape of 114 arthritic knees at the time of primary TKA using the pre-operative CT scans. The aspect ratio and trapezoidicity ratio were quantified, and the post-operative prosthetic overhang was calculated. We compared the morphological characteristics with those of 12 TKA models. RESULTS: There was significant variation in both the aspect ratio and trapezoidicity ratio between individuals. Femoral trapezoidicity was mostly due to an inward curve of the medial cortex. Overhang was correlated with the aspect ratio (with a greater chance of overhang in narrow femurs), trapezoidicity ratio (with a greater chance in trapezoidal femurs), and the tibio-femoral angle (with a greater chance in valgus knees). DISCUSSION: This study shows that rectangular/trapezoidal variability of the distal femur cannot be ignored. Most of the femoral components which were tested appeared to be excessively rectangular when compared with the bony contours of the distal femur. These findings suggest that the design of TKA should be more concerned with matching the trapezoidal/rectangular shape of the native femur. TAKE HOME MESSAGE: The distal femur is considerably more trapezoidal than most femoral components, and therefore, care must be taken to avoid anterior prosthetic overhang in TKA PMID- 26733516 TI - Total knee arthroplasty with an oxidised zirconium femoral component: ten-year survivorship analysis. AB - AIMS: Oxidised zirconium was introduced as a material for femoral components in total knee arthroplasty (TKA) as an attempt to reduce polyethylene wear. However, the long-term survival of this component is not known. METHODS: We performed a retrospective review of a prospectively collected database to assess the ten year survival and clinical and radiological outcomes of an oxidised zirconium total knee arthroplasty with the Genesis II prosthesis. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS) and a patient satisfaction scale were used to assess outcome. RESULTS: A total of 303 consecutive TKAs were performed in 278 patients with a mean age of 68 years (45 to 89). The rate of survival ten years post-operatively as assessed using Kaplan-Meier analysis was 97% (95% confidence interval 94 to 99) with revision for any reason as the endpoint. There were no revisions for loosening, osteolysis or failure of the implant. There was a significant improvement in all components of the WOMAC score at final follow-up (p < 0.001). The mean individual components of the KOOS score for symptoms (82.4 points; 36 to 100), pain (87.5 points; 6 to 100), activities of daily life (84.9 points; 15 to 100) and quality of life (71.4 points; 6 to 100) were all at higher end of the scale. DISCUSSION: This study provides further supportive evidence that the oxidised zirconium TKA gives comparable rates of survival with other implants and excellent functional outcomes ten years post-operatively. TAKE HOME MESSAGE: Total knee arthroplasty with an oxidised zirconium femoral component gives comparable long-term rates of survival and functional outcomes with conventional implants. PMID- 26733517 TI - Cemented or cementless humeral fixation in reverse total shoulder arthroplasty? a systematic review. AB - AIMS: To date, there is insufficient evidence available to compare the outcome of cemented and uncemented fixation of the humeral stem in reverse shoulder arthroplasty (RSA). METHODS: A systemic review comprising 41 clinical studies was performed to compare the functional outcome and rate of complications of cemented and uncemented stems in RSA. These included 1455 cemented and 329 uncemented shoulders. The clinical characteristics of the two groups were similar. Variables were compared using pooled frequency-weighted means and relative risk ratios (RR). RESULTS: Uncemented stems had a significantly higher incidence of early humeral stem migration (p < 0.001, RR 18.1, 95% confidence interval (CI) 5.0 to 65.2) and non-progressive radiolucent lines (p < 0.001, RR 2.4, 95% CI 1.7 to 3.4), but a significantly lower incidence of post-operative fractures of the acromion compared with cemented stems (p = 0.004, RR 14.3, 95% CI 0.9 to 232.8). There was no difference in the risk of stem loosening or revision between the groups. The cemented stems had a greater relative risk of infection (RR 3.3, 95% CI 0.8 to 13.7), nerve injury (RR 5.7, 95% CI 0.7 to 41.5) and thromboembolism (RR 3.9, 95% CI 0.2 to 66.6). The functional outcome and range of movement were equivalent in the two groups. DISCUSSION: RSA performed with an uncemented stem gives them equivalent functional outcome and a better complication profile than with a cemented stem. The natural history and clinical relevance of early stem migration and radiolucent lines found with uncemented stems requires further long term study. TAKE HOME MESSAGE: This study demonstrates that uncemented stems have at least equivalent clinical and radiographic outcomes compared with cemented stems when used for reverse total shoulder arthroplasty. PMID- 26733518 TI - Total shoulder arthroplasty with a second-generation tantalum trabecular metal backed glenoid component: Clinical and radiographic outcomes at a mean follow-up of 38 months. AB - AIMS: We evaluated clinical and radiographic outcomes of total shoulder arthroplasty (TSA) using the second-generation Trabecular Metal (TM) Glenoid component. The first generation component was withdrawn in 2005 after a series of failures were reported. Between 2009 and 2012, 40 consecutive patients with unilateral TSA using the second-generation component were enrolled in this clinical study. The mean age of the patients was 63.8 years (40 to 75) and the mean follow-up was 38 months (24 to 42). METHODS: Patients were evaluated using the Constant score (CS), the American Shoulder and Elbow Surgeons (ASES) score and routine radiographs. RESULTS: Significant differences were found between the pre- and post-operative CS (p = 0.003), ASES (p = 0.009) scores and CS subscores of pain (p < 0.001), strength (p < 0.001) and mobility items (p < 0.05). No glenoid or humeral components migrated. Posterior thinning of the keel and slight wear at the polyethylene-TM interface was observed in one patient but was asymptomatic. Radiolucent lines were found around three humeral (< 1.5 mm) and two glenoid components (< 1 mm) and all were asymptomatic. DISCUSSION: TSA with the second-generation TM Glenoid component results in satisfactory to excellent clinical performance, function, and subjective satisfaction at a mean follow-up of about three years. Radiographic changes were few and did not affect the outcome. TAKE HOME MESSAGE: This paper highlights that the second generation Trabecular Metal Glenoid has better outcomes than those reported with the first generation component. PMID- 26733519 TI - Treatment of nonunions in fractures of the humeral shaft according to the Diamond Concept. AB - METHODS: Between 2005 and 2012, 50 patients (23 female, 27 male) with nonunion of the humeral shaft were included in this retrospective study. The mean age was 51.3 years (14 to 88). The patients had a mean of 1.5 prior operations (sd 1.2;1 to 8). All patients were assessed according to a specific risk score in order to devise an optimal and individual therapy plan consistent with the Diamond Concept. In 32 cases (64%), a change in the osteosynthesis to an angular stable locking compression plate was performed. According to the individual risk an additional bone graft and/or bone morphogenetic protein-7 (BMP-7) were applied. RESULTS: A successful consolidation of the nonunion was observed in 37 cases (80.4%) with a median healing time of six months (IQR 6). Younger patients showed significantly better consolidation. Four patients were lost to follow-up. Revision was necessary in a total of eight (16%) cases. In the initial treatment, intramedullary nailing was most common. DISCUSSION: The use of locking compression plates in combination with autologous cancellous bone graft has been shown to be a safe and effective treatment. In more complex cases, the use of the Masquelet technique and BMP-7 may be indicated at the first revision operation. TAKE HOME MESSAGE: Our results suggest the Diamond Concept is a successful treatment strategy for nonunions of the humeral shaft. PMID- 26733520 TI - Radiographic and functional outcome of posterolateral lumbosacral fusion for low grade isthmic spondylolisthesis in children and adolescents. AB - AIMS: We reviewed 34 consecutive patients (18 female-16 male) with isthmic spondylolysis and grade I to II lumbosacral spondylolisthesis who underwent in situ posterolateral arthodesis between the L5 transverse processes and the sacral ala with the use of iliac crest autograft. Ten patients had an associated scoliosis which required surgical correction at a later stage only in two patients with idiopathic curves unrelated to the spondylolisthesis. METHODS: No patient underwent spinal decompression or instrumentation placement. Mean surgical time was 1.5 hours (1 to 1.8) and intra-operative blood loss 200 ml (150 to 340). There was one wound infection treated with antibiotics but no other complication. Radiological assessment included standing posteroanterior and lateral, Ferguson and lateral flexion/extension views, as well as CT scans. RESULTS: A solid posterolateral fusion was confirmed in all patients at mean latest follow-up of 4.7 years (3.4 to 9.8) beyond skeletal maturity into early adult life. Fusion of the isthmic lesion was documented in nine patients bilaterally and eight patients unilaterally. The poor fusion rate across the spondylolysis has not affected the excellent functional results of the procedure, which in our series depended on achieving a stable lumbosacral junction. CONCLUSION: Quality of life assessment demonstrated significant improvement in all functional scores and high patient satisfaction with 28 patients returning to previous sports activities at an elite competitive level. TAKE HOME MESSAGE: Posterolateral arthrodesis in situ with autologous iliac crest bone without instrumentation has achieved a solid fusion between the L5 transverse processes and the sacral ala in patients with grade I to II isthmic lumbosacral spondylolisthesis and this has produced excellent clinical outcomes and high patient satisfaction. PMID- 26733521 TI - Early mobilisation of thoracolumbar burst fractures without neurology: a natural history observation. AB - AIMS: The authors present the results of a cohort study of 60 adult patients presenting sequentially over a period of 15 years from 1997 to 2012 to our hospital for treatment of thoracic and/or lumbar vertebral burst fractures, but without neurological deficit. METHOD: All patients were treated by early mobilisation within the limits of pain, early bracing for patient confidence and all progress in mobilisation was recorded on video. Initial hospital stay was one week. Subsequent reviews were made on an outpatient basis. RESULTS: The mean duration from admission to final follow-up was three months, and longer follow-up was undertaken telephonically. The mean kyphosis deformity on arrival was 17.4 degrees (5 degrees to 29 degrees ); mean kyphosis at final discharge three months later was 19.5 degrees (1 degrees to 28 degrees ). Spinal canal encroachment had no influence on successful functional recovery. DISCUSSION: Pain has not been a significant problem for any patient, irrespective of the degree of kyphosis and no patient has a self-perception of clinical deformity. In all, 11 patients took occasional analgesia. All patients returned to their original work level or better. Two patients died 2.5 years after treatment, from unrelated causes. TAKE HOME MESSAGE: The natural history of thoracolumbar burst fractures without neurology would appear to be benign. PMID- 26733522 TI - The outcomes of instrumented posterolateral lumbar fusion in patients with rheumatoid arthritis. AB - AIMS: The aims of this study were to evaluate the clinical and radiological outcomes of instrumented posterolateral fusion (PLF) performed in patients with rheumatoid arthritis (RA). METHODS: A total of 40 patients with RA and 134 patients without RA underwent instrumented PLF for spinal stenosis between January 2003 and December 2011. The two groups were matched for age, gender, bone mineral density, the history of smoking and diabetes, and number of fusion segments. The clinical outcomes measures included the visual analogue scale (VAS) and the Korean Oswestry Disability Index (KODI), scored before surgery, one year and two years after surgery. Radiological outcomes were evaluated for problems of fixation, nonunion, and adjacent segment disease (ASD). The mean follow-up was 36.4 months in the RA group and 39.1 months in the non-RA group. RESULTS: Both groups had significant improvement in symptoms one year after surgery, while the RA group showed some deterioration of outcome scores owing to complications during the second year after surgery. Complications occurred at a higher rate in the group with RA (19 patients, 47.5%) than in those without RA (23 patients, 17.1%) (p < 0.001). A total of 15 patients in the RA group (37.5%) required revision surgery, mainly for implant failure and post-operative infection. DISCUSSION: Multimodal approaches should be considered when performing instrumented PLF in patients with RA to reduce the rate of complications, such as problems of fixation, post-operative infection and nonunion. TAKE HOME MESSAGE: Specific strategies should be undertaken in order to optimise outcomes in patients with rheumatoid arthritis. PMID- 26733523 TI - Is removal of the implants needed after fixation of burst fractures of the thoracolumbar and lumbar spine without fusion? a retrospective evaluation of radiological and functional outcomes. AB - METHODS: In this study of patients who underwent internal fixation without fusion for a burst thoracolumbar or lumbar fracture, we compared the serial changes in the injured disc height (DH), and the fractured vertebral body height (VBH) and kyphotic angle between patients in whom the implants were removed and those in whom they were not. Radiological parameters such as injured DH, fractured VBH and kyphotic angle were measured. Functional outcomes were evaluated using the Greenough low back outcome scale and a VAS scale for pain. RESULTS: Between June 1996 and May 2012, 69 patients were analysed retrospectively; 47 were included in the implant removal group and 22 in the implant retention group. After a mean follow-up of 66 months (48 to 107), eight patients (36.3%) in the implant retention group had screw breakage. There was no screw breakage in the implant removal group. All radiological and functional outcomes were similar between these two groups. Although solid union of the fractured vertebrae was achieved, the kyphotic angle and the anterior third of the injured DH changed significantly with time (p < 0.05). DISCUSSION: The radiological and functional outcomes of both implant removal and retention were similar. Although screw breakage may occur, the implants may not need to be removed. TAKE HOME MESSAGE: Implant removal may not be needed for patients with burst fractures of the thoracolumbar and lumbar spine after fixation without fusion. However, information should be provided beforehand regarding the possibility of screw breakage. PMID- 26733524 TI - Significant reduction in the incidence of C5 palsy after cervical laminoplasty using chilled irrigation water. AB - AIMS: The aim of this study was to determine whether chilled irrigation saline decreases the incidence of clinical upper limb palsy (ULP; a reduction of one grade or more on manual muscle testing; MMT), based on the idea that ULP results from thermal damage to the nerve roots by heat generated by friction during bone drilling. METHODS: Irrigation saline for drilling was used at room temperature (RT, 25.6 degrees C) in open-door laminoplasty in 400 patients (RT group) and chilled to a mean temperature of 12.1 degrees C during operations for 400 patients (low-temperature (LT) group). We assessed deltoid, biceps, and triceps brachii muscle strength by MMT. ULP occurring within two days post-operatively was categorised as early-onset palsy. RESULTS: The incidence of ULP (4.0% vs 9.5%, p = 0.003), especially early-onset palsy (1.0% vs 5.5%, p < 0.001), was significantly lower for the LT group than for the RT group. Multivariate analysis indicated that RT irrigation saline use, concomitant foraminotomy, and opened side were significant predictors for ULP. DISCUSSION: Using chilled irrigation saline during bone drilling significantly decreased the ULP incidence, particularly the early-onset type, and shortened the recovery period for ULP. Chilled irrigation saline can thus be recommended as a simple method for preventing ULP. TAKE HOME MESSAGE: Chilled irrigation during laminoplasty reduces C5 palsy. PMID- 26733525 TI - Smoking status and the Disabilities of the Arm Shoulder and Hand score are early predictors of symptomatic nonunion of displaced midshaft fractures of the clavicle. AB - AIMS: This study identifies early risk factors for symptomatic nonunion of displaced midshaft fractures of the clavicle that aid identification of an at risk group who may benefit from surgery. METHODS: We performed a retrospective study of 88 patients aged between 16 and 60 years that were managed non operatively. RESULTS: The rate of symptomatic nonunion requiring surgery was 14% (n = 13). Smoking (odds ratio (OR) 40.76, 95% confidence intervals (CI) 1.38 to 120.30) and the six week Disabilities of the Arm Shoulder and Hand (DASH) score (OR 1.11, 95% CI 1.01 to 1.22, for each point increase) were independent predictors of nonunion. A six week DASH score of 35 or more was identified as a threshold value to predict nonunion using receiver operating characteristic curve analysis. Smoking and the threshold value in the DASH and were additive risk factors for nonunion, when neither were present the risk of nonunion was 2%, if one or the other were present the nonunion rate was between 17% to 20%, and if both were present the rate increased to 44%. DISCUSSION: Patients with either of these risk factors, which include approximately half of all patients sustaining displaced midshaft fractures of the clavicle, are at an increased risk of developing a symptomatic non-union. TAKE HOME MESSAGE: Smoking and failure of functional return at six weeks are significant predictors of nonunion of the midshaft of the clavicle. Such patients warrant further investigation as to whether they would benefit from early surgical fixation in order to avoid the morbidity of a nonunion. PMID- 26733526 TI - Manipulation and reduction of paediatric fractures of the distal radius and forearm using intranasal diamorphine and 50% oxygen and nitrous oxide in the emergency department: a 2.5-year study. AB - A retrospective study was performed in 100 children aged between two and 16 years, with a dorsally angulated stable fracture of the distal radius or forearm, who were treated with manipulation in the emergency department (ED) using intranasal diamorphine and 50% oxygen and nitrous oxide. Pre- and post manipulation radiographs, the final radiographs and the clinical notes were reviewed. A successful reduction was achieved in 90 fractures (90%) and only three children (3%) required remanipulation and Kirschner wire fixation or internal fixation. The use of Entonox and intranasal diamorphine is safe and effective for the closed reduction of a stable paediatric fracture of the distal radius and forearm in the ED. By facilitating discharge on the same day, there is a substantial cost benefit to families and the NHS and we recommend this method. TAKE HOME MESSAGE: Simple easily reducible fractures of the distal radius and forearm in children can be successfully and safely treated in the ED using this approach, thus avoiding theatre admission and costly hospital stay. PMID- 26733527 TI - Salvage procedures for the painful chronically dislocated hip in cerebral palsy. AB - The aims of this study were to report functional outcomes of salvage procedures for patients with cerebral palsy (CP) who have chronic dislocation of the hip using validated scoring systems, and to compare the results of three surgical techniques. We reviewed 37 patients retrospectively. The mean age at the time of surgery was 12.2 years (8 to 22) and the mean follow-up was 56 months (24 to 114). Patients were divided into three groups: 14 who underwent proximal femoral resection arthroplasty (PFRA group 1), ten who underwent subtrochanteric valgus osteotomy (SVO group 2), and 13 who underwent subtrochanteric valgus osteotomy with resection of the femoral head (SVO with FHR group 3). All patients were evaluated using the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) and the Pediatric Quality of Life Inventory (PedsQL). Significant improvements occurred in most CPCHILD and PedsQL subsection scores following surgery in all patients, without significant differences between the groups. There were 12 post-operative complications. Less severe complications were seen in group 1 than in groups 2 and 3. Salvage surgery appears to provide pain relief in patients with CP who have painful chronic dislocation of the hip. The three salvage procedures produced similar results, however, we recommend the use of PFRA as the complications are less severe. TAKE HOME MESSAGE: Salvage surgery can be of benefit to patients with CP with chronic painful hip dislocation, but should be limited to selected patients considering complications. PMID- 26733528 TI - Frank Horan (1933 to 2015). PMID- 26733529 TI - Disrupted Cortical State Regulation in a Rat Model of Fragile X Syndrome. AB - Children with Fragile X syndrome (FXS) have deficits of attention and arousal. To begin to identify the neural causes of these deficits, we examined juvenile rats lacking the Fragile X mental retardation protein (FMR-KO) for disruption of cortical activity related to attention and arousal. Specifically, we examined the switching of visual cortex between activated and inactivated states that normally occurs during movement and quiet rest, respectively. In both wild-type and FMR-KO rats, during the third and fourth postnatal weeks cortical activity during periods of movement was dominated by an activated state with prominent 18-52 Hz activity. However, during quiet rest, when activity in wild-type rats became dominated by the inactivated state (3-9 Hz activity), FMR-KO rat cortex abnormally remained activated, resulting in increased high-frequency and reduced low-frequency power during rest. Firing rate correlations revealed reduced synchronization in FMR-KO rats, particularly between fast-spiking interneurons, that developmentally precede cortical state defects. Together our data suggest that disrupted inhibitory connectivity impairs the ability of visual cortex to regulate exit from the activated state in a behaviorally appropriate manner, potentially contributing to disrupted attention and sensory processing observed in children with FXS by making it more difficult to decrease cortical drive by unattended stimuli. PMID- 26733530 TI - Genetic Variation in S100B Modulates Neural Processing of Visual Scenes in Han Chinese. AB - Spatial navigation is a crucial ability for living. Previous animal studies have shown that the S100B gene is causally related to spatial navigation performance in mice. However, the genetic factors influencing human navigation and its neural substrates remain unclear. Here, we provided the first evidence that the S100B gene modulates neural processing of navigationally relevant scenes in humans. First, with a novel protocol, we demonstrated that the spatial pattern of S100B gene expression in postmortem brains was associated with brain activation pattern for spatial navigation in general, and for scene processing in particular. Further, in a large fMRI cohort of healthy adults of Han Chinese (N = 202), we found that S100B gene polymorphisms modulated scene selectivity in the retrosplenial cortex (RSC) and parahippocampal place area. Finally, the serum levels of S100B protein mediated the association between S100B gene polymorphism and scene selectivity in the RSC. Our study takes the first step toward understanding the neurogenetic mechanism of human spatial navigation and suggests a novel approach to discover candidate genes modulating cognitive functions. PMID- 26733531 TI - Adaptive Engagement of Cognitive Control in Context-Dependent Decision Making. AB - Many decisions require a context-dependent mapping from sensory evidence to action. The capacity for flexible information processing of this sort is thought to depend on a cognitive control system in frontoparietal cortex, but the costs and limitations of control entail that its engagement should be minimized. Here, we show that humans reduce demands on control by exploiting statistical structure in their environment. Using a context-dependent perceptual discrimination task and model-based analyses of behavioral and neuroimaging data, we found that predictions about task context facilitated decision making and that a quantitative measure of context prediction error accounted for graded engagement of the frontoparietal control network. Within this network, multivariate analyses further showed that context prediction error enhanced the representation of task context. These results indicate that decision making is adaptively tuned by experience to minimize costs while maintaining flexibility. PMID- 26733532 TI - Neural Processing of Second-Order Motion in the Suprasylvian Cortex of the Cat. AB - Neuronal responses to second-order motion, that is, to spatiotemporal variations of texture or contrast, have been reported in several cortical areas of mammals, including the middle-temporal (MT) area in primates. In this study, we investigated whether second-order responses are present in the cat posteromedial lateral suprasylvian (PMLS) cortex, a possible homolog of the primate area MT. The stimuli used were luminance-based sine-wave gratings (first-order) and contrast-modulated carrier stimuli (second-order), which consisted of a high spatial-frequency static grating (carrier) whose contrast was modulated by a low spatial-frequency drifting grating (envelope). Results indicate that most PMLS neurons responded to second-order motion and for the vast majority of cells, first- and second-order preferred directions were conserved. However, responses to second-order stimuli were significantly reduced when compared to those evoked by first-order gratings. Circular variance was increased for second-order stimuli, indicating that PMLS direction selectivity was weaker for this type of stimulus. Finally, carrier orientation selectivity was either absent or very broad and had no influence on the envelope's orientation selectivity. In conclusion, our data show that PMLS neurons exhibit similar first- and second order response profiles and that, akin primate area MT cells, they perform a form cue invariant analysis of motion signals. PMID- 26733533 TI - Rap1 GTPases Are Master Regulators of Neural Cell Polarity in the Developing Neocortex. AB - During the development of the mammalian neocortex, the generation of neurons by neural progenitors and their migration to the final position are closely coordinated. The highly polarized radial glial cells (RGCs) serve both as progenitor cells to generate neurons and as support for the migration of these neurons. After their generation, neurons transiently assume a multipolar morphology before they polarize and begin their migration along the RGCs. Here, we show that Rap1 GTPases perform essential functions for cortical organization as master regulators of cell polarity. Conditional deletion of Rap1 GTPases leads to a complete loss of cortical lamination. In RGCs, Rap1 GTPases are required to maintain their polarized organization. In newborn neurons, the loss of Rap1 GTPases prevents the formation of axons and leading processes and thereby interferes with radial migration. Taken together, the loss of RGC and neuronal polarity results in the disruption of cortical organization. PMID- 26733534 TI - Adolescent Cannabinoid Exposure Induces a Persistent Sub-Cortical Hyper Dopaminergic State and Associated Molecular Adaptations in the Prefrontal Cortex. AB - Considerable evidence suggests that adolescent exposure to delta-9 tetrahydrocanabinol (THC), the psychoactive component in marijuana, increases the risk of developing schizophrenia-related symptoms in early adulthood. In the present study, we used a combination of behavioral and molecular analyses with in vivo neuronal electrophysiology to compare the long-term effects of adolescent versus adulthood THC exposure in rats. We report that adolescent, but not adult, THC exposure induces long-term neuropsychiatric-like phenotypes similar to those observed in clinical populations. Thus, adolescent THC exposure induced behavioral abnormalities resembling positive and negative schizophrenia-related endophenotypes and a state of neuronal hyperactivity in the mesocorticolimbic dopamine (DA) pathway. Furthermore, we observed profound alterations in several prefrontal cortical molecular pathways consistent with sub-cortical DAergic dysregulation. Our findings demonstrate a profound dissociation in relative risk profiles for adolescent versus adulthood exposure to THC in terms of neuronal, behavioral, and molecular markers resembling neuropsychiatric pathology. PMID- 26733535 TI - Protracted Development of the Proprioceptive Brain Network During and Beyond Adolescence. AB - Proprioceptive processing is important for appropriate motor control, providing error-feedback and internal representation of movement for adjusting the motor command. Although proprioceptive functioning improves during childhood and adolescence, we still have few clues about how the proprioceptive brain network develops. Here, we investigated developmental changes in the functional organization of this network in early adolescents (n = 18, 12 +/- 1 years), late adolescents (n = 18, 15 +/- 1), and young adults (n = 18, 32 +/- 4), by examining task-evoked univariate activity and patterns of functional connectivity (FC) associated with seeds placed in cortical (supramarginal gyrus) and subcortical (dorsal rostral putamen) regions. We found that although the network is already well established in early adolescence both in terms of topology and functioning principles (e.g., long-distance communication and economy in wiring cost), it is still undergoing refinement during adolescence, including a shift from diffuse to focal FC and a decreased FC strength. This developmental effect was particularly pronounced for fronto-striatal connections. Furthermore, changes in FC features continued beyond adolescence, although to a much lower extent. Altogether, these findings point to a protracted developmental time course for the proprioceptive network, which breaks with the relatively early functional maturation often associated with sensorimotor networks. PMID- 26733536 TI - Mechanisms of Neuronal Silencing After Cortical Spreading Depression. AB - Cortical spreading depression (CSD) is associated with migraine, stroke, and traumatic brain injury, but its mechanisms remain poorly understood. One of the major features of CSD is an hour-long silencing of neuronal activity. Though this silencing has clear ramifications for CSD-associated disease, it has not been fully explained. We used in vivo whole-cell recordings to examine the effects of CSD on layer 2/3 pyramidal neurons in mouse somatosensory cortex and used in vitro recordings to examine their mechanism. We found that CSD caused a reduction in spontaneous synaptic activity and action potential (AP) firing that lasted over an hour. Both pre- and postsynaptic mechanisms contributed to this silencing. Reductions in frequency of postsynaptic potentials were due to a reduction in presynaptic transmitter release probability as well as reduced AP activity. Decreases in postsynaptic potential amplitude were due to an inhibitory shift in the ratio of excitatory and inhibitory postsynaptic currents. This inhibitory shift in turn contributed to the reduced frequency of APs. Thus, distinct but complementary mechanisms generate the long neuronal silence that follows CSD. These cellular changes could contribute to wider network dysfunction in CSD-associated disease, while the pre- and postsynaptic mechanisms offer separate targets for therapy. PMID- 26733537 TI - Auditory to Visual Cross-Modal Adaptation for Emotion: Psychophysical and Neural Correlates. AB - Adaptation is fundamental in sensory processing and has been studied extensively within the same sensory modality. However, little is known about adaptation across sensory modalities, especially in the context of high-level processing, such as the perception of emotion. Previous studies have shown that prolonged exposure to a face exhibiting one emotion, such as happiness, leads to contrastive biases in the perception of subsequently presented faces toward the opposite emotion, such as sadness. Such work has shown the importance of adaptation in calibrating face perception based on prior visual exposure. In the present study, we showed for the first time that emotion-laden sounds, like laughter, adapt the visual perception of emotional faces, that is, subjects more frequently perceived faces as sad after listening to a happy sound. Furthermore, via electroencephalography recordings and event-related potential analysis, we showed that there was a neural correlate underlying the perceptual bias: There was an attenuated response occurring at ~ 400 ms to happy test faces and a quickened response to sad test faces, after exposure to a happy sound. Our results provide the first direct evidence for a behavioral cross-modal adaptation effect on the perception of facial emotion, and its neural correlate. PMID- 26733538 TI - Socio-Cognitive Phenotypes Differentially Modulate Large-Scale Structural Covariance Networks. AB - Functional neuroimaging studies have suggested the existence of 2 largely distinct social cognition networks, one for theory of mind (taking others' cognitive perspective) and another for empathy (sharing others' affective states). To address whether these networks can also be dissociated at the level of brain structure, we combined behavioral phenotyping across multiple socio cognitive tasks with 3-Tesla MRI cortical thickness and structural covariance analysis in 270 healthy adults, recruited across 2 sites. Regional thickness mapping only provided partial support for divergent substrates, highlighting that individual differences in empathy relate to left insular-opercular thickness while no correlation between thickness and mentalizing scores was found. Conversely, structural covariance analysis showed clearly divergent network modulations by socio-cognitive and -affective phenotypes. Specifically, individual differences in theory of mind related to structural integration between temporo-parietal and dorsomedial prefrontal regions while empathy modulated the strength of dorsal anterior insula networks. Findings were robust across both recruitment sites, suggesting generalizability. At the level of structural network embedding, our study provides a double dissociation between empathy and mentalizing. Moreover, our findings suggest that structural substrates of higher-order social cognition are reflected rather in interregional networks than in the the local anatomical markup of specific regions per se. PMID- 26733539 TI - Reliability of a Simple Method for Determining Salt Taste Detection and Recognition Thresholds. AB - The aim of this study was to assess the reliability of a rapid analytical method to determine salt taste detection and recognition thresholds based on the ASTM E679 method. Reliability was evaluated according to criterion of temporal stability with a 1-week interval test-retest, with 29 participants. Thresholds were assessed by using the 3-AFC technique with 15 ascending concentrations of salt solution (1-292 mM, 1.5-fold steps) and estimated by 2 approaches: individual (geometric means) and group (graphical) thresholds. The proportion of agreement between the test and retest results was estimated using intraclass coefficient correlations. The detection and recognition thresholds calculated by the geometric mean were 2.8 and 18.6mM at session 1 and 2.3 and 14.5mM at session 2 and according to the graphical approach, 2.7 and 18.6mM at session 1 and 1.7 and 16.3mM at session 2. The proportion of agreement between test and retest for the detection and recognition thresholds was 0.430 (95% CI: 0.080-0.680) and 0.660 (95% CI: 0.400-0.830). This fast and simple method to assess salt taste detection and recognition thresholds demonstrated satisfactory evidence of reliability and it could be useful for large population studies. PMID- 26733540 TI - Effects of indomethacin prophylaxis timing on intraventricular haemorrhage and patent ductus arteriosus in extremely low birth weight infants. AB - OBJECTIVE: Indomethacin prophylaxis (IP) reduces the risk of intraventricular haemorrhage (IVH) and patent ductus arteriosus (PDA) in preterm infants. However, the optimal time to administer IP has not been determined. We hypothesised that IP at <=6 h is associated with a lower incidence of IVH or death than if administered at >6-24 h of age. METHODS: We performed a retrospective cohort study of extremely low birth weight infants (<=1000 g birth weight) treated in the neonatal intensive care units in the Neonatal Research Network from 2003 to 2010 and who received IP in the first 24 h of age. Infants were dichotomised based upon receipt of IP at <=6 or >6-24 h of age. The primary outcomes were IVH alone and IVH or death. Secondary outcomes were PDA alone and PDA or death. We used multivariable analyses to determine associations between the age of IP and the study outcomes expressed as an OR and 95% CI. RESULTS: IP was given at <=6 h to 2340 infants and at >6-24 h to 1915 infants. Infants given IP at <=6 h had more antenatal steroid exposure, more inborn and less cardiopulmonary resuscitation (p<0.01). After multivariable analyses, age of IP receipt was not associated with IVH, and IVH or death but PDA receiving treatment/ligation or death was lower among IP at <=6 h compared with IP at >6-24 h (OR 0.83, 95% CI 0.71 to 0.98). CONCLUSIONS: IP at <=6 h of age is not associated with less IVH or death, but is associated with less PDA receiving treatment/ligation or death. PMID- 26733541 TI - Stabilisation of premature infants in the delivery room with nasal high flow. AB - OBJECTIVE: This was a pilot study to determine the feasibility of using nasal high flow (nHF) (also known as heated humidified high-flow nasal cannula) for stabilisation of babies born at <30 weeks gestation in the delivery room (DR) and transfer to the neonatal intensive care unit (NICU). DESIGN: Observational study. SETTING: Single-centre NICU. PATIENTS: Infants born at <30 weeks gestation. INTERVENTIONS: Stabilisation and transfer to NICU using nHF. MAIN OUTCOME MEASURES: Feasibility of stabilisation as defined by successful transfer and clinical measures of stability at admission to NICU including oxygen requirement, temperature, requirement for surfactant and inotrope use within 72 h of delivery. RESULTS: Twenty-eight babies were enrolled after written parental consent had been obtained. 25/28 were successfully stabilised in the DR and transferred to the NICU on nHF. The average admission temperature for babies transferred on nHF was 36.9 degrees C and the average inspired oxygen at admission was 29%. Less than half (48%) required surfactant and 60% were still on nHF 72 h after admission. 1 baby received inotropes. CONCLUSIONS: Our study suggests that using nHF for stabilisation of premature infants in the DR and subsequent transfer to NICU is feasible. CLINICAL TRIAL REGISTRATION NUMBER: NCT01991886. PMID- 26733542 TI - Copper metabolism domain-containing 1 represses the mediators involved in the terminal effector pathways of human labour and delivery. AB - STUDY HYPOTHESIS: Does Copper Metabolism MURR1 Domain 1 (COMMD1) play a role in regulating the mediators involved in the terminal processes of human labour and delivery? STUDY FINDING: COMMD1 plays a critical role in the termination of nuclear factor-kappaB (NF-kappaB) activity and the control of pro-inflammatory and pro-labour mediators. WHAT IS KNOWN ALREADY: Inflammation and infection are the biggest aetiological factors associated with preterm birth. NF-kappaB drives the transcription of pro-inflammatory mediators involved in the terminal effector pathways of human labour and delivery. In non-gestational tissues, COMMD1 is a negative regulator of NF-kappaB-induced inflammation. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: The mRNA and/or protein level of COMMD1 was assessed in myometrium (n = 8 per group) and fetal membranes (n = 8 per group) obtained from term non-labouring and labouring women at term, and fetal membranes (n = 8 per group) at preterm with and without histological chorioamnionitis. Primary human myometrial cells were used to determine the effect of pro-inflammatory mediators on COMMD1 level, and the effect of COMMD1 small interfering RNA (siRNA) on pro-labour mediators. Statistical significance was ascribed to a P < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE: COMMD1 expression was significantly decreased with spontaneous term labour in myometrium; in fetal membranes with histologically confirmed chorioamnionitis and in myometrial cells treated with pro-inflammatory cytokines interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha, the bacterial product fibroblast-stimulating lipopeptide and the viral double stranded RNA analogue polyinosinic polycytidilic acid. Loss-of function studies revealed an increase in inflammation- and infection-induced TNF alpha, IL-1alpha, IL-1beta, IL-6, IL-8 and/or monocyte chemoattractant protein-1 mRNA abundance and/or release; and cyclo-oxygenase-2 mRNA level, release of prostaglandin (PG) F2alpha and mRNA level of the PGF2alpha receptor FP. In addition, siRNA knockdown of COMMD1 was associated with significantly increased NF-kappaB activation as evidenced by increased IL-1beta-induced IkappaB-alpha protein degradation and NF-kappaB DNA binding activity. LIMITATIONS, REASONS FOR CAUTION: The conclusions are based on in vitro experiments with cells isolated from myometrium. Animal models, however, will be required to establish whether COMMD1 activators can prevent spontaneous preterm birth in vivo. WIDER IMPLICATIONS OF THE FINDINGS: The control of COMMD1 activation may provide an alternative therapeutic strategy for reducing the release of pro-labour mediators in spontaneous preterm labour. LARGE SCALE DATA: Not applicable. STUDY FUNDING AND COMPETING INTERESTS: Associate Professor Martha Lappas is supported by a Career Development Fellowship from the National Health and Medical Research Council (NHMRC; grant no. 1047025). Additional funding was provided by the Medical Research Foundation for Women and Babies and the Mercy Research Foundation. The author has no conflict of interest. PMID- 26733544 TI - Think about how you think about cases. PMID- 26733543 TI - Screening of Transient Receptor Potential Canonical Channel Activators Identifies Novel Neurotrophic Piperazine Compounds. AB - Transient receptor potential canonical (TRPC) proteins form Ca(2+)-permeable cation channels activated upon stimulation of metabotropic receptors coupled to phospholipase C. Among the TRPC subfamily, TRPC3 and TRPC6 channels activated directly by diacylglycerol (DAG) play important roles in brain-derived neurotrophic factor (BDNF) signaling, promoting neuronal development and survival. In various disease models, BDNF restores neurologic deficits, but its therapeutic potential is limited by its poor pharmacokinetic profile. Elucidation of a framework for designing small molecules, which elicit BDNF-like activity via TRPC3 and TRPC6, establishes a solid basis to overcome this limitation. We discovered, through library screening, a group of piperazine-derived compounds that activate DAG-activated TRPC3/TRPC6/TRPC7 channels. The compounds [4-(5 chloro-2-methylphenyl)piperazin-1-yl](3-fluorophenyl)methanone (PPZ1) and 2-[4 (2,3-dimethylphenyl)piperazin-1-yl]-N-(2-ethoxyphenyl)acetamide (PPZ2) activated, in a dose-dependent manner, recombinant TRPC3/TRPC6/TRPC7 channels, but not other TRPCs, in human embryonic kidney cells. PPZ2 activated native TRPC6-like channels in smooth muscle cells isolated from rabbit portal vein. Also, PPZ2 evoked cation currents and Ca(2+) influx in rat cultured central neurons. Strikingly, both compounds induced BDNF-like neurite growth and neuroprotection, which were abolished by a knockdown or inhibition of TRPC3/TRPC6/TRPC7 in cultured neurons. Inhibitors of Ca(2+) signaling pathways, except calcineurin, impaired neurite outgrowth promotion induced by PPZ compounds. PPZ2 increased activation of the Ca(2+)-dependent transcription factor, cAMP response element-binding protein. These findings suggest that Ca(2+) signaling mediated by activation of DAG activated TRPC channels underlies neurotrophic effects of PPZ compounds. Thus, piperazine-derived activators of DAG-activated TRPC channels provide important insights for future development of a new class of synthetic neurotrophic drugs. PMID- 26733545 TI - Diagnosis and management of lungworm infections in cats: Cornerstones, dilemmas and new avenues. AB - PRACTICAL RELEVANCE: Respiratory parasites infecting domestic cats are attracting increased attention in feline clinical practice. In addition to the most commonly recognised 'cat lungworm' Aelurostrongylus abstrusus, Troglostrongylus brevior and Capillaria aerophila are now considered important pathogens of the respiratory tract of cats. GLOBAL IMPORTANCE: These parasites are being increasingly diagnosed in several regions of the world and a continuous update on epidemiological changes and advances in diagnosis and control is of practical importance. AIMS: This article reviews current knowledge of lungworms affecting cats, with a special focus on recent insights into diagnosis and management of the diseases they cause. The article also explores some potential new avenues for control of feline parasitic respiratory diseases, and highlights some key areas requiring further research. PMID- 26733546 TI - Pyometra in the queen: To spay or not to spay? AB - PRACTICAL RELEVANCE: Pyometra is a commonly occurring uterine disease in cats that often leads to loss of breeding potential and, in some cases, can be life threatening. An increased incidence of cystic endometrial hyperplasia (CEH) and pyometra is seen with age. Most queens present with uterine lesions after 5-7 years of age (average 7.6 years, range 1-20 years). Clinical signs most commonly occur within 4 weeks of the onset of oestrus in queens that are either mated, spontaneously ovulate or are induced to ovulate (mechanical stimulation or hormone induction). The disease is most often observed in dioestrus. CLINICAL CHALLENGES: Queens with pyometra often go undiagnosed as there may be few or only very mild clinical signs and laboratory changes. For example, the classic sign of mucopurulent bloody vulvar discharge often goes unnoticed. Abdominal ultrasound is the best tool for diagnosis of pyometra and for monitoring response to therapy. PATIENT GROUP: Classically, middle-aged/older nulliparous intact queens present with pyometra. However, so-called 'stump pyometra' can occur if ovarian tissue is left behind during ovariectomy or ovariohysterectomy (ovarian remnant syndrome). Queens treated with exogenous steroid hormones such as high doses of megestrol acetate or medroxyprogesterone acetate for oestrus prevention can also develop CEH and pyometra. EVIDENCE BASE: There has been little published to date on CEH, endometritis and pyometra in the queen and most of the currently available information has been extrapolated from studies carried out in the bitch. The queen and the bitch have very different reproductive physiology; thus, further research and investigation into the precise aetiopathogenesis of these disease processes of the uterus in the queen is warranted. AUDIENCE: This review is aimed at clinicians working in small animal practice, especially those in countries where surgical sterilisation is not practised as commonly as in the United States, Canada or Australasia, and who will therefore see a greater proportion of intact queens. PMID- 26733547 TI - Case-based clinical reasoning in feline medicine: 1: Intuitive and analytical systems. AB - AIM: This is Article 1 of a three-part series on clinical reasoning that encourages practitioners to explore and understand how they think and make case based decisions. It is hoped that, in the process, they will learn to trust their intuition but, at the same time, put in place safeguards to diminish the impact of bias and misguided logic on their diagnostic decision-making. SERIES OUTLINE: This first article discusses the relative merits and shortcomings of System 1 thinking (immediate and unconscious) and System 2 thinking (effortful and analytical). Articles 2 and 3, to appear in the March and May 2016 issues of JFMS, respectively, will examine managing cognitive error, and use of heuristics (mental short cuts) and illness scripts in diagnostic reasoning. PMID- 26733549 TI - Bringing Biosimilars to the Clinic: What's the Fuss? PMID- 26733550 TI - Are Advanced Radiation Therapy Technologies Required for Treating Patients With Hodgkin Lymphoma? PMID- 26733552 TI - Prostate Cancer, Version 1.2016. AB - The NCCN Guidelines for Prostate Cancer address staging and risk assessment after an initial diagnosis of prostate cancer and management options for localized, regional, and metastatic disease. Recommendations for disease monitoring, treatment of recurrent disease, and systemic therapy for metastatic castration recurrent prostate cancer also are included. This article summarizes the NCCN Prostate Cancer Panel's most significant discussions for the 2016 update of the guidelines, which include refinement of risk stratification methods and new options for the treatment of men with high-risk and very-high-risk disease and progressive castration-naive disease. PMID- 26733553 TI - Implementation of a Voice Messaging System is Associated With Improved Time-to Treatment and Overall Survival in Patients With Hepatocellular Carcinoma. AB - BACKGROUND: The diagnosis and treatment of cancer is a continuum, with multiple steps and interfaces between patients and providers allowing for potential delays in cancer recognition and subsequent treatment. The diagnosis and treatment of hepatocellular carcinoma (HCC) is especially prone to missteps along the continuum, leading to treatment delays due to non-tissue-based diagnosis and multiprovider treatments. The aim of this study was to evaluate outcome measures after implementation of a voice messaging system (VMS) designed to streamline patient referrals to downstream treatment physicians and ultimately reduce delays in HCC treatment, thereby improving outcome measures. METHODS: A retrospective study of outpatients with HCC was conducted in a safety net hospital between February 2008 and January 2012. In February 2010, VMS notification of HCC to the ordering physician and downstream treating physicians was implemented. Patients were divided into 2 groups: (1) preintervention: diagnosis 2 years before implementation or failure of notification following implementation, and (2) postintervention: diagnosis 2 years after implementation. Demographics, tumor characteristics, treatment, and survival were compared. RESULTS: This study included 96 patients diagnosed with HCC: 51 in the preintervention group and 45 in the postintervention group. The main cause of chronic liver disease was HCV infection, and no differences in symptoms, liver dysfunction, tumor characteristics, or treatment were observed between groups. The time from diagnosis to clinic contact (0.5 vs 2.9 months; P=.003) and time from detection to treatment (2.2 vs 5.5 months; P=.005) was significantly shorter after implementation of the VMS. Barcelona Clinic Liver Cancer stage A status (hazard ratio [HR], 3.1; 95% CI, 2, 6), treatment (HR, 1.9; 95% CI, 1, 4), and VMS (HR, 1.8; 95% CI, 1, 3) were independently associated with overall survival. Patients diagnosed after implementation of the VMS had a median survival of 28.5 versus 15.7 months (P=.02). CONCLUSIONS: Implementation of VMS reduces time to treatment and time to clinic visit. Reduction in time to treatment is associated with improved outcome independent of tumor stage, underlying liver function, and treatment. PMID- 26733551 TI - A Distributed Network for Intensive Longitudinal Monitoring in Metastatic Triple Negative Breast Cancer. AB - Accelerating cancer research is expected to require new types of clinical trials. This report describes the Intensive Trial of OMics in Cancer (ITOMIC) and a participant with triple-negative breast cancer metastatic to bone, who had markedly elevated circulating tumor cells (CTCs) that were monitored 48 times over 9 months. A total of 32 researchers from 14 institutions were engaged in the patient's evaluation; 20 researchers had no prior involvement in patient care and 18 were recruited specifically for this patient. Whole-exome sequencing of 3 bone marrow samples demonstrated a novel ROS1 variant that was estimated to be present in most or all tumor cells. After an initial response to cisplatin, a hypothesis of crizotinib sensitivity was disproven. Leukapheresis followed by partial CTC enrichment allowed for the development of a differential high-throughput drug screen and demonstrated sensitivity to investigational BH3-mimetic inhibitors of BCL-2 that could not be tested in the patient because requests to the pharmaceutical sponsors were denied. The number and size of CTC clusters correlated with clinical status and eventually death. Focusing the expertise of a distributed network of investigators on an intensively monitored patient with cancer can generate high-resolution views of the natural history of cancer and suggest new opportunities for therapy. Optimization requires access to investigational drugs. PMID- 26733554 TI - Use and Effectiveness of Adjuvant Chemotherapy for Stage III Colon Cancer: A Population-Based Study. AB - BACKGROUND: International guidelines recommend adjuvant chemotherapy (ACT) for patients with stage III colon cancer. Whether efficacy observed in clinical trials translates to effectiveness in routine practice is less well understood. Here we describe use and outcomes of ACT in routine practice. METHODS: All cases of colon cancer treated with surgery in Ontario 2002-2008 were identified using the population-based Ontario Cancer Registry. Linked electronic records of treatment identified surgery and ACT use. Pathology reports were obtained for a random 25% sample of all cases; patients with stage III disease were included in the study population. Modified Poisson regression was used to evaluate factors associated with ACT. Cox proportional hazards model and propensity score analysis were used to explore the association between ACT and cancer-specific survival (CSS) and overall survival (OS). RESULTS: The study population included 2,801 patients with stage III colon cancer; 66% (n=1,861) received ACT. ACT use rates varied substantially across age groups; 90% among patients aged 20 to 49 years versus 68% among those aged 70 to 79 years (P<.001). ACT use was inversely associated with comorbidity (P<.001) and socioeconomic status (P=.049). In adjusted analyses advanced age is associated with inferior CSS and OS. Use of ACT was associated with decreased risk of death from cancer (hazard ratio [HR], 0.63; 95% CI, 0.54-0.73) and decreased risk of death from any cause (HR, 0.63; 95% CI, 0.55-0.71). This result was consistent in the propensity score analysis. CONCLUSIONS: One-third of patients with stage III colon cancer in the general population do not receive ACT. Use of ACT in routine practice is associated with a substantial improvement in CSS and OS. PMID- 26733555 TI - Prevalence and Safety of Off-Label Use of Chemotherapeutic Agents in Older Patients With Breast Cancer: Estimates From SEER-Medicare Data. AB - BACKGROUND: Prescribing drugs outside of the label indication is legal and may reflect standard practice; however, some off-label use may be inappropriate. This study measured the prevalence and safety of off-label use both in accordance with practice guidelines and inconsistent with practice guidelines in older patients with breast cancer. PATIENTS AND METHODS: The SEER-Medicare data set was used to identify women diagnosed with breast cancer. Intravenous chemotherapy was identified using Medicare claims and classified as either on-label, off-label but included in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer ("off-label/supported"), or off-label and not included in the NCCN Guidelines ("off-label/unsupported"). Hospitalization/emergency department (ED) admission rates were compared. RESULTS: A total of 13,347 women were treated with 16,127 regimens (12% of women switched regimen); 64% of regimens were off label/supported, 25% were on-label, and 11% were off-label/unsupported, and hospitalization/ED admission occurred in 27%, 25%, and 32% of regimens, respectively (P<.0001). Drugs never included in the NCCN Guidelines for Breast Cancer accounted for 19% of off-label/unsupported use (1% of total use). CONCLUSIONS: Off-label use without scientific support was not common, whereas 64% of use was off-label/supported, reflecting the fact that widely accepted indications are often not tested in registration trials. Off-label/supported use will likely increase as more drugs are expected to have activity across cancer sites, and therefore understanding the implications of such use is critical. PMID- 26733557 TI - Palliative Care Version 1.2016. AB - The NCCN Guidelines for Palliative Care provide interdisciplinary recommendations on palliative care for patients with cancer. The NCCN Guidelines are intended to provide guidance to the primary oncology team on the integration of palliative care into oncology. The NCCN Palliative Care Panel's recommendations seek to ensure that each patient experiences the best quality of life possible throughout the illness trajectory. Accordingly, the NCCN Guidelines outline best practices for screening, assessment, palliative care interventions, reassessment, and after death care. PMID- 26733556 TI - Agreement in Metastatic Spinal Cord Compression. AB - BACKGROUND: Metastatic epidural spinal cord compression (ESCC) is a devastating medical emergency. The purpose of this study was to determine the reliability of the 6-point ESCC scoring system and the identification of the spinal level presenting ESCC. METHODS: Clinical data and imaging from 90 patients with biopsy proven spinal metastases were provided to 83 specialists from 44 hospitals. The spinal levels presenting metastases and the ESCC scores for each case were calculated twice by each clinician, with a minimum of 6 weeks' interval. Clinicians were blinded to assessments made by other specialists and their own previous assessment. Fleiss kappa (kappa) statistic was used to assess intraobserver and interobserver agreement. Subgroup analyses were performed according to clinicians' specialty (medical oncology, neurosurgery, radiology, orthopedic surgery, and radiation oncology), years of experience, and type of hospital. RESULTS: Intraobserver and interobserver agreement on the location of ESCC was substantial (kappa>0.61). Intraobserver agreement on the ESCC score was "excellent" (kappa=0.82), whereas interobserver agreement was substantial (kappa=0.64). Overall agreement with the tumor board classification was substantial (kappa=0.71). Results were similar across specialties, years of experience and hospital category. CONCLUSIONS: The ESCC score can help improve communication among clinicians involved in oncology care. PMID- 26733558 TI - Enhancing Value for Patients With Cancer: Time to Treatment as a Surrogate for Integrated Cancer Care. PMID- 26733559 TI - Re: "Putting an End to It!". PMID- 26733561 TI - Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1-3 D4Z4 reduced alleles: experience of the FSHD Italian National Registry. AB - OBJECTIVES: Facioscapulohumeral muscular dystrophy type 1 (FSHD1) has been genetically linked to reduced numbers (<= 8) of D4Z4 repeats at 4q35. Particularly severe FSHD cases, characterised by an infantile onset and presence of additional extra-muscular features, have been associated with the shortest D4Z4 reduced alleles with 1-3 repeats (1-3 DRA). We searched for signs of perinatal onset and evaluated disease outcome through the systematic collection of clinical and anamnestic records of de novo and familial index cases and their relatives, carrying 1-3 DRA. SETTING: Italy. PARTICIPANTS: 66 index cases and 33 relatives carrying 1-3 DRA. OUTCOMES: The clinical examination was performed using the standardised FSHD evaluation form with validated inter-rater reliability. To investigate the earliest signs of disease, we designed the Infantile Anamnestic Questionnaire (IAQ). Comparison of age at onset was performed using the non-parametric Wilcoxon rank-sum or Kruskal-Wallis test. Comparison of the FSHD score was performed using a general linear model and Wald test. Kaplan-Meier survival analysis was used to estimate the age-specific cumulative motor impairment risk. RESULTS: No patients had perinatal onset. Among index cases, 36 (54.5%) showed the first signs by 10 years of age. The large majority of patients with early disease onset (26 out of 36, 72.2%) were de novo; whereas the majority of patients with disease onset after 10 years of age were familial (16, 53.3%). Comparison of the disease severity outcome between index cases with age at onset before and over 10 years of age, failed to detect statistical significance (Wald test p value=0.064). Of 61 index cases, only 17 (27.9%) presented extra-muscular conditions. Relatives carrying 1-3 DRA showed a large clinical variability ranging from healthy subjects, to patients with severe motor impairment. CONCLUSIONS: The size of the D4Z4 allele is not always predictive of severe clinical outcome. The high degree of clinical variability suggests that additional factors contribute to the phenotype complexity. PMID- 26733562 TI - The efficacy and safety of complete pericardial drainage by means of intrapericardial fibrinolysis for the prevention of complications of pericardial effusion: a systematic review protocol. AB - INTRODUCTION: Intrapericardial fibrinolysis has been proposed as a means of preventing complications of pericardial effusion such as cardiac tamponade, persistent and recurrent pericardial effusion, and pericardial constriction. There is a need to understand the efficacy and safety of this procedure because it shows promise. METHODS AND ANALYSIS: We aim to assess the effects of intrapericardial fibrinolysis in the treatment of pericardial effusion. We will search PubMed, the Cochrane Library, African Journals online, Cumulative Index to Nursing and Allied Health Literature, Trip database, Clinical trials.gov and the WHO International Clinical Trials Registry Platform for studies that evaluate the efficacy and/or safety of complete pericardial fluid drainage by intrapericardial fibrinolysis irrespective of study design, geographical location, language, age of participants, aetiology of pericarditis or types of fibrinolytics. Two authors will do the search independently, screen the search outputs for potentially eligible studies and assess whether the studies meet the inclusion criteria. Discrepancies between the two authors will be resolved through discussion and arbitration by a third author. Data from the selected studies shall be extracted using a standardised data collection form which will be piloted before use. The methodological quality of studies will be assessed using the Cochrane Collaboration's tools for assessing risk of bias for experimental studies and non randomised studies, respectively. The primary meta-analysis will use random effects models due to expected interstudy heterogeneity. Dichotomous data will be analysed using relative risk and continuous with data mean differences, both with 95% CIs. ETHICS AND DISSEMINATION: Approval by an ethics committee is not required for this study as it is a protocol for a systematic review of published studies. The results will be disseminated through a conference presentation and peer-reviewed publication. REVIEW REGISTRATION NUMBER: PROSPERO, CRD42014015238. PMID- 26733563 TI - Acupuncture point injection treatment of primary dysmenorrhoea: a randomised, double blind, controlled study. AB - OBJECTIVE: To determine if injection of vitamin K3 in an acupuncture point is optimal for the treatment of primary dysmenorrhoea, when compared with 2 other injection treatments. SETTING: A Menstrual Disorder Centre at a public hospital in Shanghai, China. PARTICIPANTS: Chinese women aged 14-25 years with severe primary dysmenorrhoea for at least 6 months not relieved by any other treatment were recruited. Exclusion criteria were the use of oral contraceptives, intrauterine devices or anticoagulant drugs, pregnancy, history of abdominal surgery, participation in other therapies for pain and diagnosis of secondary dysmenorrhoea. Eighty patients with primary dysmenorrhoea, as defined on a 4 grade scale, completed the study. Two patients withdrew after randomisation. INTERVENTIONS: A double-blind, double-dummy, randomised controlled trial compared vitamin K3 acupuncture point injection to saline acupuncture point injection and vitamin K3 deep muscle injection. Patients in each group received 3 injections at a single treatment visit. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the difference in subjective perception of pain as measured by an 11 unit Numeric Rating Scale (NRS). Secondary measurements were Cox Pain Intensity and Duration scales and the consumption of analgesic tablets before and after treatment and during 6 following cycles. RESULTS: Patients in all 3 groups experienced pain relief from the injection treatments. Differences in NRS measured mean pain scores between the 2 active control groups were less than 1 unit (-0.71, CI -1.37 to -0.05) and not significant, but the differences in average scores between the treatment hypothesised to be optimal and both active control groups (1.11, CI 0.45 to 1.78) and (1.82, CI 1.45 to 2.49) were statistically significant in adjusted mixed-effects models. Menstrual distress and use of analgesics were diminished for 6 months post-treatment. CONCLUSIONS: Acupuncture point injection of vitamin K3 relieves menstrual pain rapidly and is a useful treatment in an urban outpatient clinic. TRIAL REGISTRATION NUMBER: NCT00104546; Results. PMID- 26733564 TI - Diffusion-weighted MRI in differentiating malignant from benign thyroid nodules: a meta-analysis. AB - OBJECTIVES: To perform a meta-analysis to evaluate the diagnostic efficacy of diffusion-weighted imaging (DWI) in differentiating malignant from benign thyroid nodules. DESIGN: A meta-analysis. DATA SOURCES AND STUDY SELECTION: Medical and scientific literature databases were searched for original articles published up to August 2015. Studies were selected if they (1) included diagnostic DWI for differentiating malignant from benign thyroid lesions, (2) included patients who later underwent biopsy and (3) presented sufficient data to enable the construction of contingency tables. DATA SYNTHESIS: For each study, the true positive, false-positive, true-negative and false-negative values were extracted or derived, and 2*2 contingency tables were constructed. Methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) instrument. The heterogeneity test, threshold effect test, subgroup analyses and publication bias analyses were performed. RESULTS: From the 113 identified search results, 15 studies, representing a total of 765 lesions, were included in the meta-analysis. We detected heterogeneity between studies but found no evidence of publication bias. The methodological quality was moderate. The pooled weighted sensitivity was 0.90 (95% CI 0.85 to 0.93); the specificity was 0.95 (95% CI 0.88 to 0.98); the positive likelihood ratio was 16.49 (95% CI 7.37 to 36.86); the negative likelihood ratio was 0.11 (95% CI 0.08 to 0.16); and the diagnostic OR was 150.73 (95% CI 64.96 to 349.75). The area under the receiver operator characteristic curve was 0.95 (95% CI 0.93 to 0.97). CONCLUSIONS: Quantitative DWI may be a non-invasive, non-radiative and accurate method of distinguishing malignant from benign thyroid nodules. Nevertheless, large-scale trials are necessary to assess its clinical value and to establish standards regarding b values and cut-off values for DWI-based diagnosis. PMID- 26733565 TI - Association of the consumption of common food groups and beverages with mortality from cancer, ischaemic heart disease and diabetes mellitus in Serbia, 1991-2010: an ecological study. AB - OBJECTIVES: This paper reports association between mortality rates from cancer, ischaemic heart disease and diabetes mellitus and the consumption of common food groups and beverages in Serbia. DESIGN: In this ecological study, data on both mortality and the average annual consumption of common food groups and beverages per household's member were obtained from official data-collection sources. The multivariate linear regression analysis was used to determine the strength of the associations between consumption of common food groups and beverages and mortality rates. RESULTS: Markedly increasing trends of cancer, ischaemic heart disease and diabetes mellitus mortality rates were observed in Serbia in the period 1991-2010. Mortality rates from cancer were negatively associated with consumption of vegetable oil (p=0.005) and grains (p=0.001), and same was found for ischaemic heart disease (p=0.002 and 0.021, respectively), while consumption of other dairy products showed a significant positive association (p<0.001 and p=0.032, respectively). In men and women, mortality rates from diabetes mellitus showed a significant positive association with consumption of poultry (p=0.014 and 0.004, respectively). Consumption of beef and grains showed a significant negative association with cancer mortality rates in both genders (p=0.002 and p<0.001 in men, and p<0.001 and p=0.014 in women, respectively), while consumption of cheese was negatively associated only in men (p<0.001). Mortality from diabetes mellitus showed a significant positive association with consumption of animal fat and other dairy products only in women (p=0.003 and 0.046, respectively). CONCLUSIONS: Association between unfavourable mortality trends from cancer, ischaemic heart disease and diabetes mellitus, and common food groups and beverages consumption was observed and should be assessed in future analytical epidemiological studies. Promotion of healthy diet is sorely needed in Serbia. PMID- 26733566 TI - Admission to psychiatric hospital in the early and late postpartum periods: Scottish national linkage study. AB - OBJECTIVE: To describe weekly admission rates for affective and non-affective psychosis, major depression and other psychiatric disorders in the early and late postpartum periods. To assess the impact of socioeconomic status, age and parity on admission rates. METHODS: Scottish maternity records were linked to psychiatric hospital admissions. 3290 pregnancy-related psychiatric admissions were assessed. Weekly admission rates were calculated for the pregnancy period, early postpartum period (6 weeks after birth) and late postpartum period (up to 2 years after birth), and compared with pre-pregnancy rates (up to 2 years before pregnancy). Admission rates were generated by calculating the total number of admissions for each time period divided by the number of weeks in the period. Incidence rate ratios (IRRs) were generated for each time period, using deprivation, age, parity and record of previous psychiatric hospital care adjusted Poisson regression models. RESULTS: Women from more deprived social quintiles accounted for the largest proportion of admissions across all time periods. Compared with pre-pregnancy period, admission rates fell during pregnancy, increased markedly during the early postpartum period, and remained elevated for 2 years after childbirth. Within the most affluent quintile, admission IRRs were higher in the early postpartum period (IRR=1.29, 95% CI 1.02 to 1.59) than in the late postpartum period (IRR=0.87, 95% CI 0.74 to 0.98). For the late postpartum period, there was a positive association between higher maternal age and admission IRRs (ages 20-35 years, IRR=1.35, 95% CI 1.16 to 1.54 and age>40 years IRR=1.72, 95% CI 1.41 to 2.09). CONCLUSIONS: Rates of psychiatric admission fell during pregnancy and increased in the early postpartum period (particularly during the first 2 weeks after birth), and remained elevated above baseline during the 2-year late postpartum period. An understanding of how social deprivation, age and parity might influence risk of psychiatric admission at different time points could help to target perinatal mental health services more effectively. PMID- 26733567 TI - Trends of vital signs with gestational age in normal pregnancies: a systematic review protocol. AB - INTRODUCTION: Vital signs (blood pressure, heart rate, temperature, oxygen saturation and respiratory rate) are thought to undergo changes during and immediately after pregnancy. However, these physiological changes are not taken into account in the normal ranges, which themselves are not evidence-based, used in routine and acute care monitoring. We aim to synthesise the existing evidence base for changes in vital signs during pregnancy, in order to derive new centile charts for each stage of pregnancy and the immediate postpartum period. METHODS AND ANALYSIS: We will search the MEDLINE, EMBASE and CINAHL databases from their inception to April 2015 for vital signs from pregnant, intrapartum or postpartum women who were recruited as 'healthy'. Assessment of bias will be conducted using a predefined set of independently agreed methodological criteria, which assigns an overall quality score to each study. We will record whether the vital sign measurements were made with measurement devices validated for use in pregnancy and in a standard posture. We will use regression methods to construct centile charts of vital signs across pregnancy and the immediate postpartum period for each vital sign. We will compare existing reference ranges to those derived from our centile charts. DISSEMINATION: The systematic review will be published in a peer-reviewed journal and disseminated electronically and in print. PROSPERO REFERENCE: CRD42014009673. PMID- 26733568 TI - Implementation of the guidelines for targeted temperature management after cardiac arrest: a longitudinal qualitative study of barriers and facilitators perceived by hospital resuscitation champions. AB - OBJECTIVES: To identify the barriers to and facilitators of implementing guidelines for targeted temperature management (TTM) after cardiac arrest perceived by hospital resuscitation champions and to investigate the changes in their perceptions over the early implementation period. DESIGN: A longitudinal qualitative study (up to 2 serial semistructured interviews over 1 year and focus groups). The individual interviews and focus groups were transcribed and coded by 2 independent assessors. Contents were analysed thematically; group interaction was also examined. SETTING: 21 hospitals, including community and tertiary care centres in South Korea. PARTICIPANTS: 21 hospital champions (14 acting champions and 7 managerial champions). RESULTS: The final data set included 40 interviews and 2 focus groups. The identified barriers and facilitators could be classified into 3 major themes: (1) healthcare professionals' perceptions of the guidelines and protocols, (2) interdisciplinary and interprofessional collaboration and (3) organisational resources. Lack of resources was the most commonly agreed on barrier for the acting champions, whereas lack of interdisciplinary collaboration was the most common barrier for the managerial champions. Educational activities and sharing successfully treated cases were the most frequently identified facilitators. Most of the participants identified and agreed that cooling equipment was an important barrier as well as a facilitator of successful TTM implementation. Perception of the guidelines and protocols has improved with the accumulation of clinical experience over the study period. CONCLUSIONS: Healthcare professionals' internal barriers to TTM implementation may be influenced by new guidelines and can be changed with the accumulation of successful clinical experiences during the early implementation period. Promoting interprofessional and interdisciplinary collaboration through educational activities and the use of cooling equipment with an automated feedback function can improve adherence to guidelines in hospitals with limited human resources in critical care. PMID- 26733569 TI - Analysis of health service amenable and non-amenable mortality before and since China's expansion of health coverage in 2009. AB - OBJECTIVE: To explore early impacts of China's health reforms in 2009 on mortality. METHODS: Annual mortality counts were obtained from 161 counties across all 31 provinces of mainland China between 2006 and 2012. We examined time series of health service amenable mortality counts, including separate analyses for deaths from stroke and ischaemic heart diseases (IHD). Non-amenable mortality counts, including separate models for oesophageal and pancreatic cancers, were also analysed as part of a negative-outcome strategy to provide stronger foundations for falsification. Deaths due to amenable causes were hypothesised to decrease, whereas non-amenable causes of mortality would remain uninfluenced. All analyses were conducted using multilevel negative binomial regression. RESULTS: Geographical variation was observed for each mortality indicator, especially for IHD, oesophageal and pancreatic cancers. Negative covariances in all models indicated slight degrees of convergence in these geographic variations over time (but not significantly for deaths from oesophageal and pancreatic cancers). Linear and square functions of time indicated a curvilinear inverted parabolic trend between 2006 and 2012 for stroke and IHD mortality. Reduction in health service amenable mortality over time was observed, but also for health service non-amenable mortality, including deaths from oesophageal cancer. Pancreatic cancer was found to increase across the study period. In counties where residents had more years of education, mortality from stroke was lower and reducing faster over time. A similar spatiotemporal patterning was observed for deaths from oesophageal cancer, and health service amenable and non-amenable causes. Counties with higher mean education years had higher mortality from IHD and pancreatic cancer, but also larger reductions in mortality were evident in areas with greater years of education. CONCLUSIONS: Although there was no clear evidence of an early impact of China's health reform on mortality, this does not rule out potentially important contributions to reducing the burden of disease in the longer term. PMID- 26733570 TI - Active play exercise intervention in children with asthma: a PILOT STUDY. AB - OBJECTIVE: Increased physical activity (PA) may be beneficial for children with asthma. Knowledge about how to intervene and encourage children with asthma to be physically active is required. In the present study, we aimed to pilot a 6-week exercise intervention designed as active play and examine attendance rate, exercise intensity and children's perceptions of participating. METHODS: 6 children with asthma (4 boys, 2 girls) aged 10-12 years, participated in 60 min of active play exercise twice weekly. A mixed-methods design was applied. The data analysed included attendance rate, exercise intensity assessed by heart rate (HR) monitoring during exercise sessions, registration and description of the active play exercise programme, 3 semistructured focus groups, field observations of 5 exercise sessions, and preintervention and postintervention testing. FINDINGS: The average attendance rate was 90%. Intensity >= 80% of maximal HR (HRmax) was recorded for a median (IQR) time of 22 (8) out of 60 min per session. Median (IQR) HR during the sessions was 146 (9; 74% of HRmax) bpm. Children reported increased health-related quality of life (HRQoL) post-test compared with baseline. Children enjoyed participating and reported no limitations by asthma or serious asthma attacks. Instead, they perceived that their asthma and fitness had improved after the programme. The instructors created an inclusive atmosphere that was characterised by easy-to-master games, fair competition, humour and mutual participation. CONCLUSIONS: The exercise intervention pilot focusing on active play had a high attendance rate, relatively high exercise intensity, and satisfaction; the children perceived that their fitness and asthma had improved, and reported increased HRQoL. A randomised controlled trial of active play exercise including children with asthma should be conducted to evaluate effect on PA level, physical fitness, asthma control and HRQoL. PMID- 26733571 TI - Psychological factors and DNA methylation of genes related to immune/inflammatory system markers: the VA Normative Aging Study. AB - OBJECTIVES: Although psychological factors have been associated with chronic diseases such as coronary heart disease (CHD), the underlying pathways for these associations have yet to be elucidated. DNA methylation has been posited as a mechanism linking psychological factors to CHD risk. In a cohort of community dwelling elderly men, we explored the associations between positive and negative psychological factors with DNA methylation in promoter regions of multiple genes involved in immune/inflammatory processes related to atherosclerosis. DESIGN: Prospective cohort study. SETTING: Greater Boston, Massachusetts area. PARTICIPANTS: Samples of 538 to 669 men participating in the Normative Aging Study cohort with psychological measures and DNA methylation measures, collected on 1-4 visits between 1999 and 2006 (mean age=72.7 years at first visit). OUTCOME MEASURES: We examined anxiety, depression, hostility and life satisfaction as predictors of leucocyte gene-specific DNA methylation. We estimated repeated measures linear mixed models, controlling for age, smoking, education, history of heart disease, stroke or diabetes, % lymphocytes, % monocytes and plasma folate. RESULTS: Psychological distress measured by anxiety, depression and hostility was positively associated, and happiness and life satisfaction were inversely associated with average Intercellular Adhesion Molecule-1 (ICAM-1) and coagulation factor III (F3) promoter methylation levels. There was some evidence that hostility was positively associated with toll-like receptor 2 (TLR-2) promoter methylation, and that life satisfaction was inversely associated with TLR-2 and inducible nitric oxide synthase (iNOS) promoter methylation. We observed less consistent and significant associations between psychological factors and average methylation for promoters of the genes for glucocorticoid receptor (NR3C1), interferon-gamma (IFN-gamma) and interleukin 6 (IL-6). CONCLUSIONS: These findings suggest that positive and negative psychological factors affect DNA methylation of selected genes involved in chronic immune/inflammatory processes and inflammation-related endothelial dysfunction. Such epigenetic changes may represent biological pathways that mediate the effects of psychological factors on CHD. PMID- 26733572 TI - Persistent spatial clusters of high body mass index in a Swiss urban population as revealed by the 5-year GeoCoLaus longitudinal study. AB - OBJECTIVE: Body mass index (BMI) may cluster in space among adults and be spatially dependent. Whether and how BMI clusters evolve over time in a population is currently unknown. We aimed to determine the spatial dependence of BMI and its 5-year evolution in a Swiss general adult urban population, taking into account the neighbourhood-level and individual-level characteristics. DESIGN: Cohort study. SETTING: Swiss general urban population. PARTICIPANTS: 6481 georeferenced individuals from the CoLaus cohort at baseline (age range 35-74 years, period=2003-2006) and 4460 at follow-up (period=2009-2012). OUTCOME MEASURES: Body weight and height were measured by trained healthcare professionals with participants standing without shoes in light indoor clothing. BMI was calculated as weight (kg) divided by height squared (m(2)). Participants were geocoded using their postal address (geographic coordinates of the place of residence). Getis-Ord Gi statistic was used to measure the spatial dependence of BMI values at baseline and its evolution at follow-up. RESULTS: BMI was not randomly distributed across the city. At baseline and at follow-up, significant clusters of high versus low BMIs were identified and remained stable during the two periods. These clusters were meaningfully attenuated after adjustment for neighbourhood-level income but not individual-level characteristics. Similar results were observed among participants who showed a significant weight gain. CONCLUSIONS: To the best of our knowledge, this is the first study to report longitudinal changes in BMI clusters in adults from a general population. Spatial clusters of high BMI persisted over a 5-year period and were mainly influenced by neighbourhood-level income. PMID- 26733573 TI - Antimicrobial lock solutions for the prevention of catheter-related infection in patients undergoing haemodialysis: study protocol for network meta-analysis of randomised controlled trials. AB - INTRODUCTION: Catheter-related infection (CRI) is a difficult clinical problem in renal medicine, with blood stream infections occurring in up to 40% of patients with haemodialysis (HD) catheters, conferring significant rates of morbidity and mortality. Several approaches have been assessed as a means to prevent CRI. Currently, an intervention that is the source of much discussion is the use of antimicrobial lock solutions (ALS). A number of past conventional meta-analyses have compared different ALS with heparin. However, there is no consensus recommendation regarding which type of ALS is best. The purpose of our study is to carry out a network meta-analysis comparing the efficacy of different ALS for prevention of CRI in patients with HD and ranking these ALS for practical consideration. METHODS AND ANALYSIS: We will search six electronic databases, earlier relevant meta-analyses and reference lists of included studies for randomised controlled trials (RCTs) that compared ALS for preventing episodes of CRI in patients with HD either head-to-head or against control interventions using non-ALS. Study selection and data collection will be performed by two reviewers independently. The Cochrane Risk of Bias Tool will be used to assess the quality of included studies. The primary outcome of efficacy will be catheter related bloodstream infection (CRBSI). We will perform a Bayesian network meta analysis to compare the relative efficacy of different ALS by WinBUGS (V.1.4.3) and STATA (V.13.0). The quality of evidence will be assessed by GRADE. ETHICS AND DISSEMINATION: Ethical approval is not required given that this study includes no confidential personal data and no data on interventions on patients. The results of this study will be submitted to a peer-review journal for publication. TRIAL REGISTRATION NUMBER: CRD42015027010. PMID- 26733575 TI - The Interrelationships of Placental Mammals and the Limits of Phylogenetic Inference. AB - Placental mammals comprise three principal clades: Afrotheria (e.g., elephants and tenrecs), Xenarthra (e.g., armadillos and sloths), and Boreoeutheria (all other placental mammals), the relationships among which are the subject of controversy and a touchstone for debate on the limits of phylogenetic inference. Previous analyses have found support for all three hypotheses, leading some to conclude that this phylogenetic problem might be impossible to resolve due to the compounded effects of incomplete lineage sorting (ILS) and a rapid radiation. Here we show, using a genome scale nucleotide data set, microRNAs, and the reanalysis of the three largest previously published amino acid data sets, that the root of Placentalia lies between Atlantogenata and Boreoeutheria. Although we found evidence for ILS in early placental evolution, we are able to reject previous conclusions that the placental root is a hard polytomy that cannot be resolved. Reanalyses of previous data sets recover Atlantogenata + Boreoeutheria and show that contradictory results are a consequence of poorly fitting evolutionary models; instead, when the evolutionary process is better-modeled, all data sets converge on Atlantogenata. Our Bayesian molecular clock analysis estimates that marsupials diverged from placentals 157-170 Ma, crown Placentalia diverged 86-100 Ma, and crown Atlantogenata diverged 84-97 Ma. Our results are compatible with placental diversification being driven by dispersal rather than vicariance mechanisms, postdating early phases in the protracted opening of the Atlantic Ocean. PMID- 26733574 TI - Neighbourhood environment, physical activity, quality of life and depressive symptoms in Hong Kong older adults: a protocol for an observational study. AB - INTRODUCTION: The neighbourhood environment can assist the adoption and maintenance of an active lifestyle and affect the physical and mental well-being of older adults. The psychosocial and behavioural mechanisms through which the environment may affect physical and mental well-being are currently poorly understood. AIM: This observational study aims to examine associations between the physical and social neighbourhood environments, physical activity, quality of life and depressive symptoms in Chinese Hong Kong older adults. METHODS AND ANALYSES: An observational study of the associations of measures of the physical and social neighbourhood environment, and psychosocial factors, with physical activity, quality of life and depressive symptoms in 900 Hong Kong older adults aged 65+ years is being conducted in 2012-2016. The study involves two assessments taken 6 months apart. Neighbourhood walkability and access to destinations are objectively measured using Geographic Information Systems and environmental audits. Demographics, socioeconomic status, walking for different purposes, perceived neighbourhood and home environments, psychosocial factors, health status, social networks, depressive symptoms and quality of life are being assessed using validated interviewer-administered self-report measures and medical records. Physical functionality is being assessed using the Short Physical Performance Battery. Physical activity and sedentary behaviours are also being objectively measured in approximately 45% of participants using accelerometers over a week. Physical activity, sedentary behaviours, quality of life and depressive symptoms are being assessed twice (6 months apart) to examine seasonality effects on behaviours and their associations with quality of life and depressive symptoms. ETHICS AND DISSEMINATION: The study received ethical approval from the University of Hong Kong Human Research Ethics Committee for Non Clinical Faculties (EA270211) and the Department of Health (Hong Kong SAR). Data are stored in a password-protected secure database for 10 years, accessible only to the named researchers. Findings will be submitted for publication in peer reviewed journals. PMID- 26733576 TI - Effects of Gene Duplication, Positive Selection, and Shifts in Gene Expression on the Evolution of the Venom Gland Transcriptome in Widow Spiders. AB - Gene duplication and positive selection can be important determinants of the evolution of venom, a protein-rich secretion used in prey capture and defense. In a typical model of venom evolution, gene duplicates switch to venom gland expression and change function under the action of positive selection, which together with further duplication produces large gene families encoding diverse toxins. Although these processes have been demonstrated for individual toxin families, high-throughput multitissue sequencing of closely related venomous species can provide insights into evolutionary dynamics at the scale of the entire venom gland transcriptome. By assembling and analyzing multitissue transcriptomes from the Western black widow spider and two closely related species with distinct venom toxicity phenotypes, we do not find that gene duplication and duplicate retention is greater in gene families with venom gland biased expression in comparison with broadly expressed families. Positive selection has acted on some venom toxin families, but does not appear to be in excess for families with venom gland biased expression. Moreover, we find 309 distinct gene families that have single transcripts with venom gland biased expression, suggesting that the switching of genes to venom gland expression in numerous unrelated gene families has been a dominant mode of evolution. We also find ample variation in protein sequences of venom gland-specific transcripts, lineage-specific family sizes, and ortholog expression among species. This variation might contribute to the variable venom toxicity of these species. PMID- 26733577 TI - Whole-Genome Sequencing and Intraspecific Analysis of the Yeast Species Lachancea quebecensis. AB - The gold standard in yeast population genomics has been the model organism Saccharomyces cerevisiae. However, the exploration of yeast species outside the Saccharomyces genus is essential to broaden the understanding of genome evolution. Here, we report the analyses of whole-genome sequences of nineisolates from the recently described yeast species Lachancea quebecensis. The genome of one isolate was assembled and annotated, and the intraspecific variability within L. quebecensis was surveyed by comparing the sequences from the eight other isolates to this reference sequence. Our study revealed that these strains harbor genomes with an average nucleotide diversity of pi = 2 * 10(-3) which is slightly lower, although on the same order of magnitude, as that previously determined for S. cerevisiae (pi = 4 * 10(-3)). Our results show that even though these isolates were all obtained from a relatively isolated geographic location, the same ecological source, and represent a smaller sample size than is available for S. cerevisiae, the levels of divergence are similar to those observed in this model species. This divergence is essentially linked to the presence of two distinct clusters delineated according to geographic location. However, even with relatively similar ranges of genome divergence, L. quebecensis has an extremely low global phenotypic variance of 0.062 compared with 0.59 previously determined in S. cerevisiae. PMID- 26733578 TI - Inappropriate prescribing of preventative medication in patients with life limiting illness: a systematic review. AB - OBJECTIVES: To systematically review the literature to examine the methods used to identify inappropriate prescribing of preventative medication in patients with life-limiting illness and to detail the nature of medications prescribed. METHODS: A systematic literature search of 4 databases was undertaken (MEDLINE, EMBASE, CINAHL, PsycINFO) from inception to April 2015 to identify peer-reviewed, observational studies assessing inappropriate prescribing of preventative medication in patients with life-limiting illness. Inclusion criteria were: participants had a life-limiting illness; prescribed/dispensed/using preventative medication; medication appropriateness assessed as a specific study aim or outcome. RESULTS: We found 19 studies meeting our eligibility criteria. The methods used to assess medication appropriateness included criteria developed for the elderly such as the Beers Criteria, and Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP) criteria, Delphi consensus and expert clinical opinion. Lipid-regulating drugs (12 studies), antihypertensive (11 studies) and antidiabetic medications (9 studies) were the most common classes of inappropriate medication identified. CONCLUSIONS: Patients with life limiting illnesses are prescribed preventative medications considered inappropriate in the context of diminished life expectancy. The way in which preventative medication appropriateness is assessed in patients with life limiting illness varies considerably-with some methodologies utilising criteria previously developed for elderly populations. Given this lack of standardisation, improving the prescribing in this context requires an approach that is specifically designed and validated for populations with life-limiting illness. PMID- 26733579 TI - The conserved GTPase HflX is a ribosome splitting factor that binds to the E-site of the bacterial ribosome. AB - Using a combination of biochemical, structural probing and rapid kinetics techniques we reveal for the first time that the universally conserved translational GTPase (trGTPase) HflX binds to the E-site of the 70S ribosome and that its GTPase activity is modulated by peptidyl transferase centre (PTC) and peptide exit tunnel (PET) binding antibiotics, suggesting a previously undescribed mode of action for these antibiotics. Our rapid kinetics studies reveal that HflX functions as a ribosome splitting factor that disassembles the 70S ribosomes into its subunits in a nucleotide dependent manner. Furthermore, our probing and hydrolysis studies show that the ribosome is able to activate trGTPases bound to its E-site. This is, to our knowledge, the first case in which the hydrolytic activity of a translational GTPase is not activated by the GTPase activating centre (GAC) in the ribosomal A-site. Furthermore, we provide evidence that the bound state of the PTC is able to regulate the GTPase activity of E-site bound HflX. PMID- 26733580 TI - 3CAPS - a structural AP-site analogue as a tool to investigate DNA base excision repair. AB - Abasic sites (AP-sites) are frequent DNA lesions, arising by spontaneous base hydrolysis or as intermediates of base excision repair (BER). The hemiacetal at the anomeric centre renders them chemically reactive, which presents a challenge to biochemical and structural investigation. Chemically more stable AP-site analogues have been used to avoid spontaneous decay, but these do not fully recapitulate the features of natural AP-sites. With its 3'-phosphate replaced by methylene, the abasic site analogue 3CAPS was suggested to circumvent some of these limitations. Here, we evaluated the properties of 3CAPS in biochemical BER assays with mammalian proteins. 3CAPS-containing DNA substrates were processed by APE1, albeit with comparably poor efficiency. APE1-cleaved 3CAPS can be extended by DNA polymerase beta but repaired only by strand displacement as the 5' deoxyribophosphate (dRP) cannot be removed. DNA glycosylases physically and functionally interact with 3CAPS substrates, underlining its structural integrity and biochemical reactivity. The AP lyase activity of bifunctional DNA glycosylases (NTH1, NEIL1, FPG), however, was fully inhibited. Notably, 3CAPS containing DNA also effectively inhibited the activity of bifunctional glycosylases on authentic substrates. Hence, the chemically stable 3CAPS with its preserved hemiacetal functionality is a potent tool for BER research and a potential inhibitor of bifunctional DNA glycosylases. PMID- 26733581 TI - Lineage-specific variations in the trigger loop modulate RNA proofreading by bacterial RNA polymerases. AB - RNA cleavage by bacterial RNA polymerase (RNAP) has been implicated in transcriptional proofreading and reactivation of arrested transcription elongation complexes but its molecular mechanism is less understood than the mechanism of nucleotide addition, despite both reactions taking place in the same active site. RNAP from the radioresistant bacterium Deinococcus radiodurans is characterized by highly efficient intrinsic RNA cleavage in comparison with Escherichia coli RNAP. We find that the enhanced RNA cleavage activity largely derives from amino acid substitutions in the trigger loop (TL), a mobile element of the active site involved in various RNAP activities. The differences in RNA cleavage between these RNAPs disappear when the TL is deleted, or in the presence of GreA cleavage factors, which replace the TL in the active site. We propose that the TL substitutions modulate the RNA cleavage activity by altering the TL folding and its contacts with substrate RNA and that the resulting differences in transcriptional proofreading may play a role in bacterial stress adaptation. PMID- 26733583 TI - Comparison of outcomes of patients with inpatient or outpatient onset ischemic stroke. AB - BACKGROUND: Reperfusion times for ischemic stroke occurring in the outpatient setting have improved significantly in recent years. However, quality improvement efforts have largely ignored ischemic stroke occurring in patients hospitalized for unrelated indications. METHODS: We performed a cohort study involving patients with ischemic stroke (with inpatient or outpatient onset) from 2009 to 2013 who were registered in the Statewide Planning and Research Cooperative System (SPARCS) database. A propensity score-adjusted regression analysis was used to assess the association of location of onset and outcomes. Mixed effects methods were employed to control for clustering at the hospital level. RESULTS: Of the 176 571 ischemic strokes, 160 157 (90.7%) occurred outside of a hospital and 16 414 (9.3%) occurred in patients hospitalized for unrelated indications. Using a logistic regression model with propensity score adjustment, we demonstrated that inpatient stroke onset was associated with increased inpatient mortality (OR 3.09; 95% CI 2.81 to 3.38), rate of discharge to rehabilitation (OR 2.57; 95% CI 2.37 to 2.79), and length of stay (LOS) (beta=11.58; 95% CI 10.73 to 12.42). In addition, it was associated with lower odds (OR 0.69; 95% CI 0.62 to 0.77) of undergoing stroke-related interventions (mechanical thrombectomy and intravenous tissue plasminogen activator) compared with outpatient stroke onset. CONCLUSIONS: Using a comprehensive all-payer cohort of patients with ischemic stroke in New York State, we identified an association of inpatient stroke onset with fewer stroke-related interventions and increased mortality, rate of discharge to rehabilitation, and LOS. PMID- 26733582 TI - Atrial Fibrillation Is Associated With Increased Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement: Insights From the Placement of Aortic Transcatheter Valve (PARTNER) Trial. AB - BACKGROUND: This study sought to evaluate the impact of atrial fibrillation (AF) on clinical outcomes in patients undergoing transcatheter aortic valve replacement. METHODS AND RESULTS: Data were evaluated in 1879 patients with baseline and discharge ECGs who underwent transcatheter aortic valve replacement in the Placement of AoRTic TraNscathetER Valve (PARTNER) trial. A total of 1262 patients manifested sinus rhythm (SR) at baseline/SR at discharge, 113 SR baseline/AF discharge, and 470 AF baseline/AF discharge. Patients who converted from SR to AF by discharge had the highest rates of all-cause mortality at 30 days (P<0.0001 across all groups; 14.2% SR/AF versus 2.6% SR/SR; adjusted hazard ratio [HR]=3.41; P=0.0002) and over 2-fold difference at 1 year (P<0.0001 across all groups; 35.7% SR/AF versus 15.8% SR/SR; adjusted HR=2.14; P<0.0001). The presence of AF on baseline or discharge ECG was a predictor of 1-year mortality (adjusted HR=2.14 for SR/AF group and HR=1.88 for AF/AF groups; P<0.0001 for both groups versus SR/SR). For patients discharged in AF, those with lower ventricular response (ie, <90 bpm) experienced less 1-year all-cause mortality (HR=0.74; P=0.04). CONCLUSIONS: After transcatheter aortic valve replacement, the presence of AF at discharge, and particularly, the conversion to AF by discharge and higher ventricular response are associated with increased mortality. These data underscore the deleterious impact of AF, as well as the need for targeted interventions to improve clinical outcomes, in patients undergoing transcatheter aortic valve replacement. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00530894. PMID- 26733584 TI - Cylindrical Spirals in Skeletal Muscles Originate From the Longitudinal Sarcoplasmic Reticulum. AB - Cylindrical spirals (CSs) are rare but distinct subsarcolemmal accumulations in skeletal muscle fibers. To date, CSs have been reported in only 16 patients with a variety of neuromuscular conditions. The origin and composition of CSs are unknown, although there are some morphologic similarities between CSs and tubular aggregates (TAs). To clarify the nature of CSs, we characterized the sarcoplasmic reticulum (SR) and other intracellular membrane system proteins in CSs of muscle biopsies from 2 adult Chinese siblings. Immunohistochemical studies revealed subsarcolemmal immunoreactivity for sarco/endoplasmic reticulum Ca2p-ATPase 1 (SERCA 1) in the longitudinal SR, but no immunoreactivity for calsequestrin in the terminal cisternae or type 1 ryanodine receptor (RYR1) in the junctional SR. Muscles biopsied from 2 patients with TAs showed immunoreactivity not only for SERCA1 but also for other SR proteins, including calsequestrin and RYR1. CSs exhibited no immunoreactivity for the Golgi apparatus marker GM130, the nuclear membrane emerin, desmin, the autophagosome marker LC3, the lysosomal membrane marker LAMP2, dystrophin, or myosin. Our results suggest CSs may originate only from the longitudinal SR, whereas TAs are composed of both the junctional and longitudinal SR. Immunochemical staining with antibodies against calsequestrin and RYR1 help to distinguish these 2 pathological alterations. PMID- 26733585 TI - Prognostic and Therapeutic Markers in Chordomas: A Study of 287 Tumors. AB - Chordomas are slow-growing malignant neoplasms. Determination of histopathologic prognostic factors using a large cohort study has been limited by their low incidence. In this retrospective study, we investigated the clinical, histopathologic, and immunohistochemical prognostic factors in 287 chordomas from 111 patients assessed by central pathologic review. Expression patterns of a variety of markers, including vascular endothelial growth factor (VEGF), mTOR pathway, c-kit, HER2, epidermal growth factor receptor (EGFR) and STAT3, and KRAS, BRAF, EGFR, and PIK3CA mutations were analyzed. On univariate analysis, the results confirm surgery as the best treatment, as judged by patient progression free survival (PFS) and overall survival (OS). Proton therapy, the presence of a dedifferentiated component, mitotic figures, and Ki67 and p53 labeling indices correlated with PFS . Necrosis and apoptosis correlated with OS. Based on these findings, we propose a histopathologic grading system that correlates with PFS and OS. On multivariate analysis, extent of resection, tumor grade, and proton therapy were independent prognostic factors of PFS; extent of resection, tumor location, and grade were independent prognostic factors of OS. Based on the expression of EGFR, pSTAT3, VEGF, and mTOR pathway proteins, (in 85.9%, 79.1%, 85.7%, and 46% of chordomas, respectively), and 2 new mutations in the PIK3CA gene, we also provide evidence for potential therapeutic targets. PMID- 26733586 TI - Limited Unfolded Protein Response and Inflammation in Neuroserpinopathy. AB - Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare disease characterized by the deposition of multiple intracytoplasmic neuronal inclusions that contain mutated neuroserpin. Tg-Syracuse (Tg-Syr) mice express Ser49Pro mutated neuroserpin and develop clinical and neuropathological features of human FENIB. We used 8-, 34-, 45- and 80-week-old Tg-Syr mice to characterize neuroinflammation and the unfolded protein response (UPR) in a neurodegenerative disease in which abnormal protein aggregates accumulate within the endoplasmic reticulum (ER). There were scattered neuroserpin inclusions in Tg-Syr mice at 8 weeks of age; the numbers of neurons involved and the amount of neuroserpin per neuron increased with age throughout the CNS to 80 weeks of age; no similar inclusions were found in wild type (Tg-WT) mice at any age. Increases in numbers of astrocytes and microglia occurred at advanced disease stages. Among 22 markers in 80-week-old Tg-Syr mice, only II1b and II10rb mRNAs in the somatosensory cortex and CxCl10 and Il10rb mRNAs in the olfactory bulb were upregulated when compared with Tg-WT mice indicating a limited relationship between neuroserpin inclusions and inflammatory responses. The changes were accompanied by a transient increase in expression of Xbp1 spliced at 45 weeks and increased ERdJ4 mRNAs at 80 weeks. The sequestration of UPR activators GRP78 and GRP94 in neuroserpin inclusions might explain the limited UPR responses despite the accumulation of neuroserpin in the ER in this FENIB mouse model. PMID- 26733587 TI - Quality Improvement Interventions to Improve Appropriateness of Imaging Studies: Necessary, But Are They Sufficient? PMID- 26733588 TI - Effectiveness of Quality Improvement Interventions at Reducing Inappropriate Cardiac Imaging: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Between 5% and 25% of cardiac imaging tests are performed for inappropriate indications. Studies have examined the impact of appropriate use criteria-based quality improvement initiatives on inappropriate testing, but they have not been systematically evaluated. METHODS AND RESULTS: We performed a systematic review of studies evaluating quality improvement initiatives aimed at reducing inappropriate cardiac imaging. The primary outcome was the proportion of inappropriate tests based on appropriate use criteria. Studies were analyzed using a random effects meta-analysis model, and heterogeneity was examined using subgroup analyses. We identified 6 observational studies and 1 randomized control trial. Most interventions (n=6) had a formal education component, and 5 included a mechanism for physician audit and feedback. Although these interventions were associated with lower odds of inappropriate testing (odds ratio, 0.44 [95% confidence interval, 0.32-0.61]; P<0.001), significant heterogeneity was observed (I(2)=70%), which was best explained by the utilization of physician audit and feedback. Interventions that employed physician audit and feedback were associated with significantly lower odds of inappropriate testing (odds ratio, 0.36 [95% confidence interval, 0.31-0.41]; P<0.001; I(2)=0%), whereas those that did not had no effect (odds ratio, 0.89 [95% confidence interval, 0.61-1.29]; P=0.51; I(2)=0%; P value for difference <0.001). All studies had potential sources of bias that could have affected the observed estimates. CONCLUSIONS: Interventions using physician audit and feedback are associated with lower odds of inappropriate cardiac testing. Further research is needed to evaluate a greater diversity of intervention types, with improved study designs. PMID- 26733589 TI - Concussion Dilemma. PMID- 26733590 TI - Imaging in Chronic Traumatic Encephalopathy and Traumatic Brain Injury. AB - CONTEXT: The diagnosis of chronic traumatic encephalopathy (CTE) can only be made pathologically, and there is no concordance of defined clinical criteria for premorbid diagnosis. The absence of established criteria and the insufficient imaging findings to detect this disease in a living athlete are of growing concern. EVIDENCE ACQUISITION: The article is a review of the current literature on CTE. Databases searched include Medline, PubMed, JAMA evidence, and evidence based medicine guidelines Cochrane Library, Hospital for Special Surgery, and Cornell Library databases. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Chronic traumatic encephalopathy cannot be diagnosed on imaging. Examples of imaging findings in common types of head trauma are discussed. CONCLUSION: Further study is necessary to correlate the clinical and imaging findings of repetitive head injuries with the pathologic diagnosis of CTE. PMID- 26733591 TI - Physicians' Management Practices and Perceived Health Risks When Postconcussion Symptoms Persist. AB - BACKGROUND: Concussion guidelines recommend physical and cognitive rest until all postconcussion symptoms resolve, in part because of potential health risks, including catastrophic injury related to a second impact. However, when postconcussion symptoms persist for weeks or months, these risks are poorly characterized. HYPOTHESIS: Physicians' perceived health risks and management strategies for patients with persistent postconcussion symptoms will vary. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 3. METHODS: A survey of the physician members of the American College of Sports Medicine assessed the perceived health risks related to advancing activity, the indications for neuroimaging, and the referral patterns for patients with persistent postconcussion symptoms. RESULTS: A total of 572 physicians completed the survey (response rate, 27.2%). The majority of physicians recommended physical rest (97.4%) and cognitive rest (93.8%) within the first week of injury. Perceived health risks related to advancing activity in the symptomatic patient differed at 2 weeks versus 3 months after injury (P < 0.001 for all comparisons). Respondents from the United States were more likely to list second impact syndrome as a potential health risk at 2 weeks compared with respondents from other countries (P = 0.04). The majority (56%) responded that the risk of second impact syndrome remains until all symptoms resolve. When postconcussion symptoms persist beyond 1 month, 61.9% of physicians responded that neuroimaging is indicated. Approximately 60% of respondents had access to a multidisciplinary concussion clinic within 60 miles of their practice. CONCLUSION: When postconcussion symptoms persist, the perceived health risks, management practices, and access to multidisciplinary care vary among physicians. PMID- 26733592 TI - Spontaneous Bilateral Vertebral Artery Dissection During a Basketball Game: A Case Report. AB - Spontaneous vertebral artery dissection accounts for 2% of all ischemic strokes and can occur as a consequence of sports events. We present an unusual case of spontaneous bilateral vertebral artery dissection in a 30-year-old male patient during a basketball game. He developed severe dysphagia, right hemiparesis, and balance dysfunction. We also present a review of the pathology, diagnosis, symptomatology, treatment, prognosis, and occurrence of this entity in sports. PMID- 26733594 TI - Wearable Performance Devices in Sports Medicine. AB - CONTEXT: Wearable performance devices and sensors are becoming more readily available to the general population and athletic teams. Advances in technology have allowed individual endurance athletes, sports teams, and physicians to monitor functional movements, workloads, and biometric markers to maximize performance and minimize injury. Movement sensors include pedometers, accelerometers/gyroscopes, and global positioning satellite (GPS) devices. Physiologic sensors include heart rate monitors, sleep monitors, temperature sensors, and integrated sensors. The purpose of this review is to familiarize health care professionals and team physicians with the various available types of wearable sensors, discuss their current utilization, and present future applications in sports medicine. EVIDENCE ACQUISITION: Data were obtained from peer-reviewed literature through a search of the PubMed database. Included studies searched development, outcomes, and validation of wearable performance devices such as GPS, accelerometers, and physiologic monitors in sports. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Wearable sensors provide a method of monitoring real-time physiologic and movement parameters during training and competitive sports. These parameters can be used to detect position-specific patterns in movement, design more efficient sports-specific training programs for performance optimization, and screen for potential causes of injury. More recent advances in movement sensors have improved accuracy in detecting high-acceleration movements during competitive sports. CONCLUSION: Wearable devices are valuable instruments for the improvement of sports performance. Evidence for use of these devices in professional sports is still limited. Future developments are needed to establish training protocols using data from wearable devices. PMID- 26733593 TI - Current Concepts in Hip Preservation Surgery: Part II--Rehabilitation. AB - CONTEXT: Successful treatment of nonarthritic hip pain in young athletic individuals remains a challenge. A growing fund of clinical knowledge has paralleled technical innovations that have enabled hip preservation surgeons to address a multitude of structural variations of the proximal femur and acetabulum and concomitant intra-articular joint pathology. Often, a combination of open and arthroscopic techniques are necessary to treat more complex pathomorphologies. Peri- and postoperative recovery after such procedures can pose a substantial challenge to the patient, and a dedicated, thoughtful approach may reduce setbacks, limit morbidity, and help optimize functional outcomes. EVIDENCE ACQUISITION: PubMed and CINAHL databases were searched to identify relevant scientific and review articles through December 2014 using the search terms hip preservation, labrum, surgical dislocation, femoroacetabular impingement, postoperative rehabilitation, peri-acetabular osteotomy, and rotational osteotomy. Reference lists of included articles were reviewed to locate additional references of interest. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Hip preservation procedures and appropriate rehabilitation have allowed individuals to return to a physically active lifestyle. CONCLUSION: Effective postoperative rehabilitation must consider modifications and precautions specific to the particular surgical techniques used. Proper postoperative rehabilitation after hip preservation surgery may help optimize functional recovery and maximize clinical success and patient satisfaction. PMID- 26733595 TI - How to Deal With Chronic Patellar Instability: What Does the Literature Tell Us? AB - CONTEXT: Patellar instability is a common clinical problem, affecting between 7 and 49 people per 100,000. However, not all patellar instabilities are equal, the etiology of the disorder is multifactorial, and a clear understanding of the cause of instability is crucial for appropriate surgical treatment. The goal of this article is to identify how to best treat patellar instability to provide good outcomes and hopefully prevent future osteoarthritis. EVIDENCE ACQUISITION: A PubMed search from 1983 through May 2015. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Several subpopulations of patients with chronic patellar instability exist: (1) lateral patellar instability during the early arc of knee flexion (0 degrees -30 degrees ), (2) lateral patellar instability persisting beyond 30 degrees of knee flexion, (3) lateral patellar instability in greater knee flexion, and (4) medial patellar instability. In patients with lateral instability during the early arc of knee flexion, the medial patellofemoral deficiency is the essential lesion. Persistent instability beyond 30 degrees of knee flexion suggests an unusually high patella, severe trochlear dysplasia, pathologic increment of the tibial tuberosity-trochlear groove distance, or a combination of these factors. In patients with lateral instability in greater knee flexion, increasing and unbalanced tension in the extensors pulls the patella out of the groove as the knee is flexed. Finally, medial patellar instability is an objective iatrogenic condition that appears after realignment surgery in the vast majority of cases. CONCLUSION: The etiology of chronic patellar instability is multifactorial, and its treatment must therefore be personalized. STRENGTH OF RECOMMENDATION TAXONOMY SORT: B. PMID- 26733598 TI - Comparative impact of implementing the 2013 or 2014 cholesterol guideline on vascular events in a quality improvement network. AB - OBJECTIVES: The Quality and Care Model Committee for a clinically integrated network requested a comparative analysis on the projected cardiovascular benefits of implementing either the 2013 and 2014 cholesterol guideline in a South Carolina patient population. A secondary request was to assess the relative risk of the two guidelines based on the literature. METHODS: Electronic health data were obtained on 1,580,860 adults aged 21-80 years who had had one or more visits from January 2013 to June 2015; 566,688 had data to calculate 10-year atherosclerotic cardiovascular disease (ASCVD10) risk. Adults with end-stage renal disease (n = 7852), congestive heart failure (n = 19,818), alcohol or drug abuse (n = 68,547), or currently on statins (n = 154,964) were excluded leaving 315,508 for analysis. Estimated reduction in ASCVD10 assumed that: (a) moderate intensity statins lowered low-density lipoprotein cholesterol (LDL-C) by 35% and high-intensity statins by 50%; (b) ASCVD events declined 22% for each 1 mmol/l fall in LDL-C. RESULTS: Among the 315,508 adults in the analysis, 131,289 (41.6%) were eligible for statins according to the 2013 guideline and 137,375 (43.5%) to the 2014 guideline. The 2013 and 2014 guidelines were estimated to prevent 6780 and 5915 ASCVD events over 10 years with: (a) relative risk reductions of 29.0% and 21.8%; (b) absolute risk reductions of 5.2% and 4.3%; (c) number needed-to treat (NNT) of 19 and 23, respectively. The greater projected cardiovascular protection with the 2013 guideline was largely related to greater use of high dose statins, which carry a greater risk for adverse events. The literature indicates that the NNT for benefit with high-intensity versus moderate-intensity statins is 31 in high-risk patients with a number needed-to-harm of 47. CONCLUSIONS: The 2013 guideline is projected to prevent more clinical ASCVD events and with lower NNTs than the 2014 guideline, yet both have substantial benefit. The 2013 guideline is also expected to generate more adverse events, but the risk-benefit profile appears favor . PMID- 26733599 TI - A novel use of arterial spin labelling MRI to demonstrate focal hypoperfusion in individuals with posterior cortical atrophy: a multimodal imaging study. PMID- 26733600 TI - Migraine and its psychiatric comorbidities. AB - Migraine is a highly prevalent and disabling neurological disorder associated with a wide range of psychiatric comorbidities. In this manuscript, we provide an overview of the link between migraine and several comorbid psychiatric disorders, including depression, anxiety and post-traumatic stress disorder. We present data on psychiatric risk factors for migraine chronification. We discuss the evidence, theories and methods, such as brain functional imaging, to explain the pathophysiological links between migraine and psychiatric disorders. Finally, we provide an overview of the treatment considerations for treating migraine with psychiatric comorbidities. In conclusion, a review of the literature demonstrates the wide variety of psychiatric comorbidities with migraine. However, more research is needed to elucidate the neurocircuitry underlying the association between migraine and the comorbid psychiatric conditions and to determine the most effective treatment for migraine with psychiatric comorbidity. PMID- 26733601 TI - Increased functional connectivity common to symptomatic amyotrophic lateral sclerosis and those at genetic risk. AB - OBJECTIVE: To discern presymptomatic changes in brain structure or function using advanced MRI in carriers of mutations predisposing to amyotrophic lateral sclerosis (ALS). METHODS: T1-weighted, diffusion weighted and resting state functional MRI data were acquired at 3 T for 12 asymptomatic mutation carriers (psALS), 12 age-matched controls and affected patients with ALS. Cortical thickness analysis, voxel-based morphometry, volumetric and shape analyses of subcortical structures, tract-based spatial statistics of metrics derived from the diffusion tensor, and resting state functional connectivity (FC) analyses were performed. RESULTS: Grey matter cortical thickness and shape analysis revealed significant atrophy in patients with ALS (but not psALS) compared with controls in the right primary motor cortex and right caudate. Comparison of diffusion tensor metrics showed widespread fractional anisotropy and radial diffusivity differences in patients with ALS compared to controls and the psALS group, encompassing parts of the corpus callosum, corticospinal tracts and superior longitudinal fasciculus. While FC in the resting-state sensorimotor network was similar in psALS and controls, FC between the cerebellum and a network comprising the precuneus, cingulate & middle frontal lobe was significantly higher in psALS and affected ALS compared to controls. CONCLUSIONS: Rather than structural brain changes, increased FC may be among the earliest detectable brain abnormalities in asymptomatic carriers of ALS-causing gene mutations. With replication and significant refinement, this technique has potential in the future assessment of neuroprotective strategies. PMID- 26733602 TI - Drug-induced Liver Fibrosis: Testing Nevirapine in a Viral-like Liver Setting Using Histopathology, MALDI IMS, and Gene Expression. AB - Nevirapine (NVP) is associated with hepatotoxicity in 1-5% of patients. In rodent studies, NVP has been shown to cause hepatic enzyme induction, centrilobular hypertrophy, and skin rash in various rat strains but not liver toxicity. In an effort to understand whether NVP is metabolized differently in a transiently inflamed liver and whether a heightened immune response alters NVP-induced hepatic responses, female brown Norway rats were dosed with either vehicle or NVP alone (75 mg/kg/day for 15 days) or galactosamine alone (single intraperitoneal [ip] injection on day 7 to mimic viral hepatitis) or a combination of NVP (75/100/150 mg/kg/day for 15 days) and galactosamine (single 750 mg/kg ip on day 7). Livers were collected at necropsy for histopathology, matrix-assisted laser desorption/ionization imaging mass spectrometry and gene expression. Eight days after galactosamine, hepatic fibrosis was noted in rats dosed with the combination of NVP and galactosamine. No fibrosis occurred with NVP alone or galactosamine alone. Gene expression data suggested a viral-like response initiated by galactosamine via RNA sensors leading to apoptosis, toll-like receptor, and dendritic cell responses. These were exacerbated by NVP-induced growth factor, retinol, apoptosis, and periostin effects. This finding supports clinical reports warning against exacerbation of fibrosis by NVP in patients with hepatitis C. PMID- 26733603 TI - The role of bile acids in metabolic regulation. AB - Bile acids (BA), long believed to only have lipid-digestive functions, have emerged as novel metabolic modulators. They have important endocrine effects through multiple cytoplasmic as well as nuclear receptors in various organs and tissues. BA affect multiple functions to control energy homeostasis, as well as glucose and lipid metabolism, predominantly by activating the nuclear farnesoid X receptor and the cytoplasmic G protein-coupled BA receptor TGR5 in a variety of tissues. However, BA also are aimed at many other cellular targets in a wide array of organs and cell compartments. Their role in the pathogenesis of diabetes, obesity and other 'diseases of civilization' becomes even more clear. They also interact with the gut microbiome, with important clinical implications, further extending the complexity of their biological functions. Therefore, it is not surprising that BA metabolism is substantially modulated by bariatric surgery, a phenomenon contributing favorably to the therapeutic effects of these surgical procedures. Based on these data, several therapeutic approaches to ameliorate obesity and diabetes have been proposed to affect the cellular targets of BA. PMID- 26733604 TI - Activin A and follistatin during the oestrous cycle and early pregnancy in ewes. AB - The activin pathway has been postulated to be involved in regulation of multiple reproductive processes important for survival of the conceptus. These processes include luteinisation of the follicular cells and thus function of the corpus luteum, early embryo development and uterine function including implantation of the conceptus. Therefore, the aim of the current study was to determine whether the concentrations of activin A and follistatin (FST), an activin-binding protein, differed between ewes with a lifetime history of enhanced or reduced embryonic survival (ES). The mRNAs encoding FST and activin A (inhibin beta A subunit; INHBA) were present in the uterus and abundant in the uterine luminal or glandular epithelia by day 18 of gestation. A peak of activin A was observed in the systemic circulation around the time of oestrus, and activin A concentrations were elevated in animals with reduced ES during the oestrous cycle and early gestation. Concentrations of activin A in uterine fluid were approximately twofold greater on day 16 of gestation in ewes with reduced ES compared to those with enhanced ES. No consistent differences in FST were observed between these groups. Treatment of luteinising ovine granulosa cells with activin A in vitro suppressed progesterone secretion providing evidence of a potential pathway whereby increased concentrations of activin A may decrease ES. PMID- 26733605 TI - Relation of Nailfold Capillaries and Autoantibodies to Mortality in Patients With Raynaud Phenomenon. AB - BACKGROUND: In incipient Raynaud phenomenon, nailfold capillaroscopy and autoantibody tests are obtained to screen for an emerging connective tissue disease. Whether the presence of abnormal nailfold capillaries and autoantibodies are related to mortality in patients with incipient Raynaud phenomenon is not known. METHODS AND RESULTS: In 2958 consecutive patients (78% women, median age 45 years) with incipient Raynaud phenomenon without previously known connective tissue disease, nailfold capillaroscopy and laboratory tests for antinuclear antibodies (ANA) and ANA subsets were obtained at initial presentation. During a median follow-up period of 9.3 years, 227 women (9.9% of female patients) and 129 men (20% of male patients) with Raynaud phenomenon died. In comparison with a demographically matched standard population, survival was poorer in patients with Raynaud phenomenon (log-rank test P<0.0001). In patients with Raynaud phenomenon, mortality was higher in men than in women (P<0.0001, Cox proportional hazards model). In women, the presence of abnormal nailfold capillaries, ANA, and anti Scl-70 antibodies were related to an increase in all-cause mortality. The conjoint presence of abnormal nailfold capillaries and autoantibodies was associated with the highest mortality rates. In men, abnormal nailfold capillaries, and ANA and ANA subsets, as well, were not related to survival. In both sexes, patients' age and serum creatinine were associated with mortality. CONCLUSIONS: In Raynaud phenomenon, male sex, age, and serum creatinine are related to mortality. Abnormal nailfold capillaries and autoantibodies are associated with an increase in all-cause mortality in female patients, but not in male patients with Raynaud phenomenon. PMID- 26733606 TI - Isoproterenol Promotes Rapid Ryanodine Receptor Movement to Bridging Integrator 1 (BIN1)-Organized Dyads. AB - BACKGROUND: The key pathophysiology of human acquired heart failure is impaired calcium transient, which is initiated at dyads consisting of ryanodine receptors (RyRs) at sarcoplasmic reticulum apposing CaV1.2 channels at t-tubules. Sympathetic tone regulates myocardial calcium transients through beta-adrenergic receptor (beta-AR)-mediated phosphorylation of dyadic proteins. Phosphorylated RyRs (P-RyR) have increased calcium sensitivity and open probability, amplifying calcium transient at a cost of receptor instability. Given that bridging integrator 1 (BIN1) organizes t-tubule microfolds and facilitates CaV1.2 delivery, we explored whether beta-AR-regulated RyRs are also affected by BIN1. METHODS AND RESULTS: Isolated adult mouse hearts or cardiomyocytes were perfused for 5 minutes with the beta-AR agonist isoproterenol (1 umol/L) or the blockers CGP+ICI (baseline). Using biochemistry and superresolution fluorescent imaging, we identified that BIN1 clusters P-RyR and CaV1.2. Acute beta-AR activation increases coimmunoprecipitation between P-RyR and cardiac spliced BIN1+13+17 (with exons 13 and 17). Isoproterenol redistributes BIN1 to t-tubules, recruiting P-RyRs and improving the calcium transient. In cardiac-specific Bin1 heterozygote mice, isoproterenol fails to concentrate BIN1 to t-tubules, impairing P-RyR recruitment. The resultant accumulation of uncoupled P-RyRs increases the incidence of spontaneous calcium release. In human hearts with end-stage ischemic cardiomyopathy, we find that BIN1 is also 50% reduced, with diminished P-RyR association with BIN1. CONCLUSIONS: On beta-AR activation, reorganization of BIN1 induced microdomains recruits P-RyR into dyads, increasing the calcium transient while preserving electric stability. When BIN1 is reduced as in human acquired heart failure, acute stress impairs microdomain formation, limiting contractility and promoting arrhythmias. PMID- 26733607 TI - Significance of Intermediate Values of Fractional Flow Reserve in Patients With Coronary Artery Disease. AB - BACKGROUND: The fractional flow reserve (FFR) value of 0.75 has been validated against ischemic testing, whereas the FFR value of 0.80 has been widely accepted to guide clinical decision making. However, revascularization when FFR is 0.76 to 0.80, within the so-called gray zone, is still debatable. METHODS AND RESULTS: From February 1997 to June 2013, all patients with single-segment disease and an FFR value within the gray zone or within the 2 neighboring FFR strata (0.70-0.75 and 0.81-0.85) were included. Study end points consisted of major adverse cardiovascular events (death, myocardial infarction, and any revascularization) up to 5 years. Of 17 380 FFR measurements, 1459 patients were included. Of them, 449 patients were treated with revascularization and 1010 patients were treated with medical therapy. In the gray zone, the major adverse cardiovascular events rate was similar (37 [13.9%] versus 21 [11.2%], respectively; P=0.3) between medical therapy and revascularization, whereas a strong trend toward a higher rate of death or myocardial infarction (25 [9.4] versus 9 [4.8], P=0.06) and overall death (20 [7.5] versus 6 [3.2], P=0.059) was observed in the medical therapy group. Among medical therapy patients, a significant step-up increase in major adverse cardiovascular events rate was observed across the 3 FFR strata, especially with proximal lesion location. In revascularization patients, the major adverse cardiovascular events rate was not different across the 3 FFR strata. CONCLUSIONS: FFR in and around the gray zone bears a major prognostic value, especially in proximal lesions. These data confirm that FFR<=0.80 is valid to guide clinical decision making. PMID- 26733608 TI - Exercise Training and Atrial Fibrillation: Further Evidence for the Importance of Lifestyle Change. PMID- 26733609 TI - Aerobic Interval Training Reduces the Burden of Atrial Fibrillation in the Short Term: A Randomized Trial. AB - BACKGROUND: Exercise training is an effective treatment for important atrial fibrillation (AF) comorbidities. However, a high level of endurance exercise is associated with an increased AF prevalence. We assessed the effects of aerobic interval training (AIT) on time in AF, AF symptoms, cardiovascular health, and quality of life in AF patients. METHODS AND RESULTS: Fifty-one patients with nonpermanent AF were randomized to AIT (n=26) consisting of four 4-minute intervals at 85% to 95% of peak heart rate 3 times a week for 12 weeks or to a control group (n=25) continuing their regular exercise habits. An implanted loop recorder measured time in AF continuously from 4 weeks before to 4 weeks after the intervention period. Cardiac function, peak oxygen uptake (o2peak), lipid status, quality of life, and AF symptoms were evaluated before and after the 12 week intervention period. Mean time in AF increased from 10.4% to 14.6% in the control group and was reduced from 8.1% to 4.8% in the exercise group (P=0.001 between groups). AF symptom frequency (P=0.006) and AF symptom severity (P=0.009) were reduced after AIT. AIT improved o2peak, left atrial and ventricular ejection fraction, quality-of-life measures of general health and vitality, and lipid values compared with the control group. There was a trend toward fewer cardioversions and hospital admissions after AIT. CONCLUSIONS: AIT for 12 weeks reduces the time in AF in patients with nonpermanent AF. This is followed by a significant improvement in AF symptoms, o2peak, left atrial and ventricular function, lipid levels, and QoL. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01325675. PMID- 26733610 TI - Ofatumumab and Lenalidomide for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: Correlation between Responses and Immune Characteristics. AB - PURPOSE: We evaluated efficacy and tolerability of the combination of ofatumumab and lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), and explored whether immune system characteristics could influence the response to treatment. EXPERIMENTAL DESIGN: Thirty-four patients were enrolled in this phase II study. Ofatumumab was administered at a dose of 300 mg on day 1, 1,000 mg on days 8, 15, and 22 during course 1, 1,000 mg on day 1 during courses 3-6, and once every other course during courses 7-24 (28-day courses). Oral lenalidomide (10 mg daily) was started on day 9 and continued for as long as a clinical benefit was observed. RESULTS: The overall response rate was 71%. Eight patients (24%) achieved a complete remission (CR) or CR with incomplete recovery of blood counts, including 9% with minimal residual disease negative CR. The median progression-free survival was 16 months, and the estimated 5-year survival was 53%. The most common treatment-related toxicity was neutropenia (grade >2 in 18% of the 574 patient courses). The most frequent infectious complications were pneumonia and neutropenic fever (24% and 9% of patients, respectively). We observed that patients who achieved a CR had at baseline higher numbers and a better preserved function of T cells and natural killer cells compared with non-responders. CONCLUSIONS: The combination of ofatumumab and lenalidomide is a well-tolerated regimen that induces durable responses in the majority of patients with relapsed/refractory CLL. Our correlative data suggest a role of competent immune system in supporting the efficacy of this treatment. Clin Cancer Res; 22(10); 2359-67. (c)2016 AACR. PMID- 26733611 TI - The Expression Quantitative Trait Loci in Immune Pathways and their Effect on Cutaneous Melanoma Prognosis. AB - PURPOSE: The identification of personalized germline markers with biologic relevance for the prediction of cutaneous melanoma prognosis is highly demanded but to date, it has been largely unsuccessful. As melanoma progression is controlled by host immunity, here we present a novel approach interrogating immunoregulatory pathways using the genome-wide maps of expression quantitative trait loci (eQTL) to reveal biologically relevant germline variants modulating cutaneous melanoma outcomes. EXPERIMENTAL DESIGN: Using whole genome eQTL data from a healthy population, we identified 385 variants significantly impacting the expression of 268 immune-relevant genes. The 40 most significant eQTLs were tested in a prospective cohort of 1,221 patients with cutaneous melanoma for their association with overall (OS) and recurrence-free survival using Cox regression models. RESULTS: We identified highly significant associations with better melanoma OS for rs6673928, impacting IL19 expression (HR, 0.56; 95% CI, 0.41-0.77; P = 0.0002) and rs6695772, controlling the expression of BATF3 (HR, 1.64; 95% CI, 1.19-2.24; P = 0.0019). Both associations map in the previously suspected melanoma prognostic locus at 1q32. Furthermore, we show that their combined effect on melanoma OS is substantially enhanced reaching the level of clinical applicability (HR, 1.92; 95% CI, 1.43-2.60; P = 2.38e-5). CONCLUSIONS: Our unique approach of interrogating lymphocyte-specific eQTLs reveals novel and biologically relevant immunomodulatory eQTL predictors of cutaneous melanoma prognosis that are independent of current histopathologic markers. The significantly enhanced combined effect of identified eQTLs suggests the personalized utilization of both SNPs in a clinical setting, strongly indicating the promise of the proposed design for the discovery of prognostic or risk germline markers in other cancers. Clin Cancer Res; 22(13); 3268-80. (c)2016 AACR. PMID- 26733612 TI - Strategically Timing Inhibition of Phosphatidylinositol 3-Kinase to Maximize Therapeutic Index in Estrogen Receptor Alpha-Positive, PIK3CA-Mutant Breast Cancer. AB - PURPOSE: Phosphatidylinositol 3-kinase (PI3K) inhibitors are being developed for the treatment of estrogen receptor alpha (ER)-positive breast cancer in combination with antiestrogens. Understanding the temporal response and pharmacodynamic effects of PI3K inhibition in ER(+) breast cancer will provide a rationale for treatment scheduling to maximize therapeutic index. EXPERIMENTAL DESIGN: Antiestrogen-sensitive and antiestrogen-resistant ER(+) human breast cancer cell lines and mice bearing PIK3CA-mutant xenografts were treated with the antiestrogen fulvestrant, the PI3K inhibitor GDC-0941 (pictilisib; varied doses/schedules that provided similar amounts of drug each week), or combinations. Cell viability, signaling pathway inhibition, proliferation, apoptosis, tumor volume, and GDC-0941 concentrations in plasma and tumors were temporally measured. RESULTS: Treatment with the combination of fulvestrant and GDC-0941, regardless of dose/schedule, was significantly more effective than that with single-agent treatments in fulvestrant-resistant tumors. Short-term, complete PI3K inhibition blocked cell growth in vitro more effectively than chronic, incomplete inhibition. Longer-term PI3K inhibition hypersensitized cells to growth factor signaling upon drug withdrawal. Different schedules of GDC-0941 elicited similar tumor responses. While weekly high-dose GDC-0941 with fulvestrant continuously suppressed PI3K signaling for 72 hours, inducing a bolus of apoptosis and inhibiting proliferation, PI3K reactivation upon GDC-0941 washout induced a proliferative burst. Fulvestrant with daily low-dose GDC-0941 metronomically suppressed PI3K for 6 to 9 hours/day, repeatedly inducing small amounts of apoptosis and temporarily inhibiting proliferation, followed by proliferative rebound compared with fulvestrant alone. CONCLUSIONS: Continuous and metronomic PI3K inhibition elicits robust anticancer effects in ER(+), PIK3CA mutant breast cancer. Clinical exploration of alternate treatment schedules of PI3K inhibitors with antiestrogens is warranted. Clin Cancer Res; 22(9); 2250-60. (c)2016 AACRSee related commentary by Toska and Baselga, p. 2099. PMID- 26733613 TI - A Validated Prognostic Multigene Expression Assay for Overall Survival in Resected Colorectal Cancer Liver Metastases. AB - PURPOSE: Risk stratification after surgery for colorectal cancer liver metastases (CRLM) is achieved using clinicopathologic variables, however, is of limited accuracy. We sought to derive and externally validate a multigene expression assay prognostic of overall survival (OS) that is superior to clinicopathologic variables in patients with surgically resected CRLM. EXPERIMENTAL DESIGN: We measured mRNA expression in prospectively collected frozen tumor from 96 patients with surgically resected CRLM at Memorial Sloan Kettering Cancer Center (MSKCC, New York, NY). We retrospectively generated a 20-gene molecular risk score (MRS) and compared its prognostic utility for OS and recurrence-free survival (RFS) with three common clinical risk scores (CRS). We then tested the prognostic ability of the MRS in an external validation cohort (European) of 119 patients with surgically resected CRLM at the University Medical Center Utrecht (Utrecht, the Netherlands) and Paul Brousse Hospital (Villejuif, France). RESULTS: For OS in the MSKCC cohort, MRS was the strongest independent prognosticator (HR, 3.7 4.9; P < 0.001) followed by adjuvant chemotherapy (HR, 0.3; P <= 0.001). For OS in the European cohort, MRS was the only independent prognosticator (HR, 3.5; P = 0.007). For RFS, MRS was also independently prognostic in the MSKCC cohort (HR, 2.4-2.6; P <= 0.001) and the European cohort (HR, 1.6-2.5; P <= 0.05). CONCLUSIONS: Compared with CRSs, the MRS is more accurate, broadly applicable, and an independent prognostic biomarker of OS in resected CRLM. This MRS is the first externally validated prognostic multigene expression assay after metastasectomy for CRLM and warrants prospective validation. Clin Cancer Res; 22(10); 2575-82. (c)2016 AACR. PMID- 26733614 TI - Pooled Analysis of the Prognostic Relevance of Circulating Tumor Cells in Primary Breast Cancer. AB - PURPOSE: Although unequivocal evidence has shown the prognostic relevance of circulating tumor cells (CTC) in the peripheral blood of patients with metastatic breast cancer, less evidence is available for the prognostic relevance of CTCs at the time of primary diagnosis. EXPERIMENTAL DESIGN: We conducted a pooled analysis of individual data from 3,173 patients with nonmetastatic (stage I-III) breast cancer from five breast cancer institutions. The prevalence and numbers of CTCs were assessed at the time of primary diagnosis with the FDA-cleared CellSearch System (Janssen Diagnostics, LLC). Patient outcomes were analyzed using meta-analytic procedures, univariate log-rank tests, and multivariate Cox proportional hazard regression analyses. The median follow-up duration was 62.8 months. RESULTS: One or more CTCs were detected in 20.2% of the patients. CTC positive patients had larger tumors, increased lymph node involvement, and a higher histologic tumor grade than did CTC-negative patients (all P < 0.002). Multivariate Cox regressions, which included tumor size, nodal status, histologic tumor grade, and hormone receptor and HER2 status, confirmed that the presence of CTCs was an independent prognostic factor for disease-free survival [HR, 1.82; 95% confidence interval (CI), 1.47-2.26], distant disease-free survival (HR, 1.89; 95% CI, 1.49-2.40), breast cancer-specific survival (HR, 2.04; 95% CI, 1.52 2.75), and overall survival (HR, 1.97; 95% CI, 1.51-2.59). CONCLUSIONS: In patients with primary breast cancer, the presence of CTCs was an independent predictor of poor disease-free, overall, breast cancer-specific, and distant disease-free survival. Clin Cancer Res; 22(10); 2583-93. (c)2016 AACR. PMID- 26733615 TI - The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects. AB - PURPOSE: Patients with neuroblastoma associated with MYCN oncogene amplification experience a very poor prognosis. BET bromodomain inhibitors are among the most promising novel anticancer agents as they block BRD3 and BRD4 from activating oncogene transcription. However, treatment with BET bromodomain inhibitors alone does not result in cancer remission in many murine models. EXPERIMENTAL DESIGN: MYCN-amplified neuroblastoma cells were treated with vehicle control, the BET bromodomain inhibitor JQ1, the histone deacetylase inhibitor panobinostat, or the combination of JQ1 and panobinostat. Genes modulated by JQ1, panobinostat, or the combination therapy were identified by Affymetrix microarray, and cell proliferation and apoptosis were examined by Alamar blue assays and flow cytometry analysis. Modulation of LIN28B promoter activity by BRD3 and BRD4 was examined by chromatin immunoprecipitation and luciferase assays. In addition, neuroblastoma-bearing mice were treated with vehicle control, JQ1, and/or panobinostat. RESULTS: LIN28B was one of the top genes synergistically reduced by JQ1 and panobinostat. BRD3 and BRD4 directly bound to the LIN28B gene promoter and activated LIN28B gene transcription, and knocking down LIN28B reduced the expression of N-Myc protein, but not N-Myc mRNA. JQ1 and panobinostat synergistically reduced LIN28B gene and N-Myc protein expression, and synergistically induced growth inhibition and apoptosis in neuroblastoma cells, but not normal nonmalignant cells in vitro In neuroblastoma-bearing mice, JQ1 and panobinostat synergistically and considerably reduced N-Myc protein expression in tumor tissues and blocked tumor progression. CONCLUSIONS: Our findings have identified a novel strategy to reduce the N-Myc oncoprotein expression and a novel therapeutic approach for the treatment of aggressive neuroblastoma. Clin Cancer Res; 22(10); 2534-44. (c)2016 AACR. PMID- 26733618 TI - Evolution. PMID- 26733616 TI - HMGB1 and Its Hyperacetylated Isoform are Sensitive and Specific Serum Biomarkers to Detect Asbestos Exposure and to Identify Mesothelioma Patients. AB - PURPOSE: To determine whether serum levels of high mobility group box protein 1 (HMGB1) could differentiate malignant mesothelioma patients, asbestos-exposed individuals, and unexposed controls. EXPERIMENTAL DESIGN: Hyperacetylated and nonacetylated HMGB1 (together referred to as total HMGB1) were blindly measured in blood collected from malignant mesothelioma patients (n = 22), individuals with verified chronic asbestos exposure (n = 20), patients with benign pleural effusions (n = 13) or malignant pleural effusions not due to malignant mesothelioma (n = 25), and healthy controls (n = 20). Blood levels of previously proposed malignant mesothelioma biomarkers fibulin-3, mesothelin, and osteopontin were also measured in nonhealthy individuals. RESULTS: HMGB1 serum levels reliably distinguished malignant mesothelioma patients, asbestos-exposed individuals, and unexposed controls. Total HMGB1 was significantly higher in malignant mesothelioma patients and asbestos-exposed individuals compared with healthy controls. Hyperacetylated HMGB1 was significantly higher in malignant mesothelioma patients compared with asbestos-exposed individuals and healthy controls, and did not vary with tumor stage. At the cut-off value of 2.00 ng/mL, the sensitivity and specificity of serum hyperacetylated HMGB1 in differentiating malignant mesothelioma patients from asbestos-exposed individuals and healthy controls was 100%, outperforming other previously proposed biomarkers. Combining HMGB1 and fibulin-3 provided increased sensitivity and specificity in differentiating malignant mesothelioma patients from patients with cytologically benign or malignant non-mesothelioma pleural effusion. CONCLUSIONS: Our results are significant and clinically relevant as they provide the first biomarker of asbestos exposure and indicate that hyperacetylated HMGB1 is an accurate biomarker to differentiate malignant mesothelioma patients from individuals occupationally exposed to asbestos and unexposed controls. A trial to independently validate these findings will start soon. Clin Cancer Res; 22(12); 3087-96. (c)2016 AACR. PMID- 26733617 TI - Management of atrial fibrillation in patients with chronic kidney disease in Europe Results of the European Heart Rhythm Association Survey. AB - The purpose of this European Heart Rhythm (EHRA) Scientific Initiatives Committee EP Wire Survey was to assess 'real-world' practice in the management of patients with atrial fibrillation (AF) and chronic kidney disease (CKD) in the European Eelectrophysiology centres. Of 41 responding centres, 39 (95.1%) and 37 (90.2%) routinely evaluated renal function in AF patients at first presentation and during follow-up, respectively, but 13 centres (31.7%) re-assessed advanced CKD only at >=1-year intervals. While the use of oral anticoagulants (OACs) in mild to-moderate CKD patients was mostly guided by individual patient stroke risk, 31% of the centres used no therapy, or aspirin or the left appendage occlusion in patients with advanced CKD and HAS-BLED >= 3. Vitamin K antagonists (VKAs) were preferred in patients with severe CKD or under renal replacement therapy (RRT), any non-VKA in patients with mild CKD, and apixaban in patients with moderate CKD. Rhythm control was preferred in patients with mild-to-moderate CKD (48.7% of centres), and rate control in patients with severe CKD (51.2% of centres). In 20 centres (48.8%), AF ablation was not performed in advanced CKD patients. Most centres performed AF ablation on OAC, but heparin bridging was still used in >10% of centres. Our survey has shown that the importance of renal function monitoring in AF patients is well recognized in clinical practice. In patients with mild-to moderate CKD, AF is mostly managed according to the guideline recommendations, but more data are needed to guide the management of AF in patients with severe CKD or RRT. PMID- 26733620 TI - The Farid Fata Medicare Fraud Case and Misplaced Incentives in Oncology Care. PMID- 26733621 TI - The Branding of Palliative Care. PMID- 26733624 TI - Improving Chemotherapy Ordering Process. AB - PURPOSE: Chemotherapy is a high-risk medication and is the second most common cause of fatal medication errors. The ordering process can be unsafe and inefficient, putting patients at risk for medication errors. The aim of this project was to decrease the number of chemotherapy order forms with at least one deviation by 50% within 5 months. METHODS: A multidisciplinary team identified causes for variance in form completion, deficits in knowledge of ordering processes, and acceptance of incomplete orders by the staff. The Plan, Do, Study, Act improvement methodology evaluated the chemotherapy ordering process and found different types of deviations on order forms. Interventions consisted of educating physicians on entering complete information on orders, instituting same day laboratory work on the day of the physician's visit, standardizing laboratory parameters, performing audits of the order forms manually, and educating nurses on not accepting orders with deviations. RESULTS: All order forms were reviewed, and data were collected on different types of deviations. The following deviations were identified: laboratory test results were not being entered into the order form within 7 days, physicians were not providing their name and pager number, and the days of the chemotherapy cycle were missing from the order forms. Before the intervention, 70.1% of the chemotherapy order forms had at least one deviation. After 5 months of interventions, there was a reduction of 19% in the number of order forms with at least one deviation. Follow-up at 6 months and 1 year showed continuing reductions in the number of chemotherapy orders with at least one deviation. CONCLUSION: Improvement was a result of collaboration between interdisciplinary departments. The original goal was surpassed as a result of educating physicians and staff and standardizing the ordering process. If the number of deviations in chemotherapy order forms is decreased, oncology patients will receive safe, efficient, and quality care. PMID- 26733625 TI - Pharmaceutical Industry Influence on Duplicate Abstracts at National Oncology and Hematology Meetings. PMID- 26733626 TI - Impact of a Palliative Care Checklist on Clinical Documentation. AB - PURPOSE: Checklists are used in many different settings for the purpose of standardization and reduction of preventable errors in practice. Our group sought to determine whether a palliative care checklist (PCC) would improve the clinical documentation of key patient information. METHODS: An initial review of 110 randomly selected medical records dictated by 10 physicians was performed. The authors identified portions of the dictated medical records that were included regularly, as well as those that were frequently missed. A PCC was drafted after final approval was obtained from the 13 faculty members. Dictations from 13 clinical faculties in the supportive care center were reviewed. A chi(2) test or Fisher's exact test was applied to assess the difference in overall checked rates before and after checklist use. A paired t test was used to examine the difference in the average complete rate and checked rates before and after checklist use. RESULTS: There were improvements in the documentation before and after the checklist for scores on the Cut-down, Annoyed, Guilty, Eye-opener questionnaire for alcoholism (79% v 94%; P <= .0001), psychosocial history (69% v 95%; P <= .0001), Eastern Cooperative Oncology Group performance status (38% v 81%; P <= .0001), advance care planning (28% v 41%; P = .0008), and overall (78% v 95%; P <= .0001). There was no significant improvement in the documentation for opioid-induced neurotoxicity (37% v 37%; P = .9492) or the Edmonton Symptom Assessment Scale (98% v 99%; P = .4511). CONCLUSION: Our study showed that the use of a PCC improved the quality of the documentation of a patient visit in an outpatient clinical setting. PMID- 26733627 TI - Improving the Safety of Oral Chemotherapy at an Academic Medical Center. AB - PURPOSE: Over the last decade, the use of oral chemotherapy (OC) for the treatment of cancer has dramatically increased. Despite their route of administration, OCs pose many of the same risks as intravenous agents. In this quality improvement project, we sought to examine our current process for the prescription of OC at the Abramson Cancer Center of the University of Pennsylvania and to improve on its safety. METHODS: A multidisciplinary team that included oncologists, advanced-practice providers, and pharmacists was formed to analyze the current state of our OC practice. Using Lean Six Sigma quality improvement tools, we identified a lack of pharmacist review of the OC prescription as an area for improvement. To address these deficiencies, we used our electronic medical system to route OC orders placed by treating providers to an oncology-specific outpatient pharmacist at the Abramson Cancer Center for review. RESULTS: Over 7 months, 63 orders for OC were placed for 45 individual patients. Of the 63 orders, all were reviewed by pharmacists, and, as a result, 22 interventions were made (35%). Types of interventions included dosage adjustment (one of 22), identification of an interacting drug (nine of 22), and recommendations for additional drug monitoring (12 of 22). CONCLUSION: OC poses many of the same risks as intravenous chemotherapy and should be prescribed and reviewed with the same oversight. At our institution, involvement of an oncology trained pharmacist in the review of OC led to meaningful interventions in one third of the orders. PMID- 26733628 TI - An epidemiological surveillance network of lumbar disc surgery to help prevention of and compensation for low back pain. AB - BACKGROUND: In the context of the establishment of a new surveillance system, the aim was to assess the proportion of cases of lumbar disc surgery (LDS) attributable to work according to occupation category and industry sector. METHODS: The sociodemographic and socioeconomic data of 3150 inpatients living in a French region discharged in 2007-2008 from spine centers of the region following LDS were compared with those of the regional population. Occupational history was gathered using a mailed questionnaire. The attributable fraction of risk for exposed individuals (AFE) and population attributable fraction of risk (PAF) were calculated in relation to occupations and industries. RESULTS: Three occupational subcategories presented an AFE >50% for men (police and armed forces, unskilled agricultural and skilled craft blue-collar workers). There were eight subcategories for women, including material handlers and related equipment workers, and skilled industrial and unskilled agricultural blue-collar workers. The PAF for men was highest for construction and for women it was highest for wholesale and retail trades. CONCLUSION: The AFE and PAF are valuable for public policy. Although PAF could be used to help public health policy makers to implement preventive measures, the AFE could assist expert tribunals who take decisions about compensation for occupational diseases. PMID- 26733630 TI - CCJR - a learning continuum. PMID- 26733629 TI - Clinical effectiveness of cancer screening biomarker tests offered as self-pay health service: a systematic review. AB - BACKGROUND: Biomarker tests are increasingly being offered by laboratories and clinicians as self-pay health services to screen asymptomatic individuals; however, sufficient evidence may not be available to support this practice. We investigated the benefit-harm tradeoffs associated with 11 biomarkers currently offered in Germany as self-pay tests to screen for cancer. METHODS: We systematically searched bibliographic databases for health technology assessments, systematic reviews and randomized-controlled trials (RCTs) through September 2015. We included publications that analysed cancer screening biomarkers and reported patient-relevant outcomes (mortality, morbidity, quality of life), and potential harms of screening, among asymptomatic individuals in screening and non-screening arms. Language was restricted to English and German. Two reviewers independently screened references; data were extracted and quality of included studies was evaluated by a reviewer and validated by a second reviewer. RESULTS: Six publications of secondary literature and four publications reporting results from two RCTs were included. For 10 cancer screening biomarkers, no direct evidence on patient-relevant outcomes was available. Only one trial, which simultaneously assessed cancer antigen 125 (CA125) and vaginal ultrasound for ovarian cancer screening, provided the outcome of interest. Screening compared with usual care did not reduce ovarian cancer mortality. Patient harms included overdiagnosis and false-positive results. CONCLUSION: Although ovarian cancer screening with CA125 showed no benefit, false-positive tests, overdiagnosis and overtreatment were reported. Physicians and laboratories should provide patients with comprehensive information about the lack of evidence and potential harms caused by biomarker screening tests offered as a self-pay health service. PMID- 26733631 TI - The obese patient: a problem of larger consequence. AB - Obesity is a worldwide epidemic that has both economic and health implications of enormous consequence. The obese patients tend to have earlier symptoms related to osteoarthritis, more peri-operative medical problems, higher rates of infection and more technical difficulties intra-operatively following hip and knee arthroplasty. Nevertheless, these patients have good long-term clinical outcomes and implant survival rates and are often some of the most satisfied patients after joint arthroplasty. Therefore, obese patients should not be denied surgery based on their weight alone. PMID- 26733632 TI - Bone grafts and their substitutes. AB - The continual cycle of bone formation and resorption is carried out by osteoblasts, osteocytes, and osteoclasts under the direction of the bone signaling pathway. In certain situations the host cycle of bone repair is insufficient and requires the assistance of bone grafts and their substitutes. The fundamental properties of a bone graft are osteoconduction, osteoinduction, osteogenesis, and structural support. Options for bone grafting include autogenous and allograft bone and the various isolated or combined substitutes of calcium sulphate, calcium phosphate, tricalcium phosphate, and coralline hydroxyapatite. Not all bone grafts will have the same properties. As a result, understanding the requirements of the clinical situation and specific properties of the various types of bone grafts is necessary to identify the ideal graft. We present a review of the bone repair process and properties of bone grafts and their substitutes to help guide the clinician in the decision making process. PMID- 26733633 TI - Hip resurfacing: a large, US single-surgeon series. AB - Hip resurfacing has been proposed as an alternative to traditional total hip arthroplasty in young, active patients. Much has been learned following the introduction of metal-on-metal resurfacing devices in the 1990s. The triad of a well-designed device, implanted accurately, in the correct patient has never been more critical than with these implants. Following Food and Drug Administration approval in 2006, we studied the safety and effectiveness of one hip resurfacing device (Birmingham Hip Resurfacing) at our hospital in a large, single-surgeon series. We report our early to mid-term results in 1333 cases followed for a mean of 4.3 years (2 to 5.7) using a prospective, observational registry. The mean patient age was 53.1 years (12 to 84); 70% were male and 91% had osteoarthritis. Complications were few, including no dislocations, no femoral component loosening, two femoral neck fractures (0.15%), one socket loosening (0.08%), three deep infections (0.23%), and three cases of metallosis (0.23%). There were no destructive pseudotumours. Overall survivorship at up to 5.7 years was 99.2%. Aseptic survivorship in males under the age of 50 was 100%. We believe this is the largest United States series of a single surgeon using a single resurfacing system. PMID- 26733634 TI - Ceramic on ceramic arthroplasty of the hip: new materials confirm appropriate use in young patients. AB - The leading indication for revision total hip arthroplasty (THA) remains aseptic loosening owing to wear. The younger, more active patients currently undergoing THA present unprecedented demands on the bearings. Ceramic-on-ceramic (CoC) bearings have consistently shown the lowest rates of wear. The recent advances, especially involving alumina/zirconia composite ceramic, have led to substantial improvements and good results in vitro. Alumina/zirconia composite ceramics are extremely hard, scratch resistant and biocompatible. They offer a low co efficient of friction and superior lubrication and lower rates of wear compared with other bearings. The major disadvantage is the risk of fracture of the ceramic. The new composite ceramic has reduced the risk of fracture of the femoral head to 0.002%. The risk of fracture of the liner is slightly higher (0.02%). Assuming that the components are introduced without impingement, CoC bearings have major advantages over other bearings. Owing to the superior hardness, they produce less third body wear and are less vulnerable to intra operative damage. The improved tribology means that CoC bearings are an excellent choice for young, active patients requiring THA. PMID- 26733635 TI - Minimising the risk of infection: a peri-operative checklist. AB - The purpose of this article is to provide the reader with a seven-step checklist that could help in minimising the risk of PJI. The check list includes strategies that can be implemented pre-operatively such as medical optimisation, and reduction of the bioburden by effective skin preparation or actions taking during surgery such as administration of timely and appropriate antibiotics or blood conservation, and finally implementation of post-operative protocols such as efforts to minimise wound drainage and haematoma formation. PMID- 26733636 TI - Prophylactic peri-operative local antibiotic irrigation. AB - An extensive review of the spinal and arthroplasty literature was undertaken to evaluate the effectiveness of local antibiotic irrigation during surgery. The efficacy of antibiotic irrigation for the prevention of acute post-operative infection after total joint arthroplasty was evaluated retrospectively in 2293 arthroplasties (1990 patients) between January 2004 and December 2013. The mean follow-up was 73 months (20 to 139). One surgeon performed all the procedures with minimal post-operative infection. The intra-operative protocol included an irrigation solution of normal saline with vancomycin 1000 mg/l and polymyxin 250,000 units/l at the rate of 2 l per hour. No patient required re-admission for primary infection or further antibiotic treatment. Two morbidly obese patients (two total hip arthroplasties) developed subcutaneous fat necrosis requiring debridement and one was revised because the deep capsular sutures were contaminated by the draining subcutaneous haematoma. One patient who had undergone total knee arthroplasty had unrecognised damage to the lateral superior geniculate artery and developed a haematoma that became infected secondarily four months after the surgery and underwent revision. The use of antibiotic irrigation during arthroplasty surgery has been highly effective for the prevention of infection in the author's practice. However, it should be understood that any routine prophylactic use of antibiotics may result in resistant organisms, and the wise stewardship of the use of antibiotics is an important part of surgical practice. PMID- 26733637 TI - Deep infection after hip arthroplasty: staying current with change. AB - Periprosthetic joint infection (PJI) complicates between 0.5% and 1.2% primary total hip arthroplasties (THAs) and may have devastating consequences. The traditional assessment of patients suffering from PJI has involved the serological study of inflammatory markers and microbiological analysis of samples obtained from the joint space. Treatment has involved debridement and revision arthroplasty performed in either one or two stages. We present an update on the burden of PJI, strategies for its diagnosis and treatment, the challenge of resistant organisms and the need for definitive evidence to guide the treatment of PJI after THA. PMID- 26733638 TI - Intra-articular infusion: a direct approach to treatment of infected total knee arthroplasty. AB - Bactericidal levels of antibiotics are difficult to achieve in infected total joint arthroplasty when intravenous antibiotics or antibiotic-loaded cement spacers are used, but intra-articular (IA) delivery of antibiotics has been effective in several studies. This paper describes a protocol for IA delivery of antibiotics in infected knee arthroplasty, and summarises the results of a pharmacokinetic study and two clinical follow-up studies of especially difficult groups: methicillin-resistant Staphylococcus aureus and failed two-stage revision. In the pharmacokinetic study, the mean synovial vancomycin peak level was 9242 (3956 to 32 150; sd 7608 MUg/mL) among the 11 patients studied. Serum trough level ranged from 4.2 to 25.2 MUg/mL (mean, 12.3 MUg/mL; average of 9.6% of the joint trough value), which exceeded minimal inhibitory concentration. The success rate exceeded 95% in the two clinical groups. IA delivery of antibiotics is shown to be safe and effective, and is now the first option for treatment of infected total joint arthroplasty in our institution. PMID- 26733639 TI - Placement of the acetabular component. AB - Ideal placement of the acetabular component remains elusive both in terms of defining and achieving a target. Our aim is to help restore original anatomy by using the transverse acetabular ligament (TAL) to control the height, depth and version of the component. In the normal hip the TAL and labrum extend beyond the equator of the femoral head and therefore, if the definitive acetabular component is positioned such that it is cradled by and just deep to the plane of the TAL and labrum and is no more than 4mm larger than the original femoral head, the centre of the hip should be restored. If the face of the component is positioned parallel to the TAL and psoas groove the patient specific version should be restored. We still use the TAL for controlling version in the dysplastic hip because we believe that the TAL and labrum compensate for any underlying bony abnormality. The TAL should not be used as an aid to inclination. Worldwide, > 75% of surgeons operate with the patient in the lateral decubitus position and we have shown that errors in post-operative radiographic inclination (RI) of > 50 degrees are generally caused by errors in patient positioning. Consequently, great care needs to be taken when positioning the patient. We also recommend 35 degrees of apparent operative inclination (AOI) during surgery, as opposed to the traditional 45 degrees . PMID- 26733640 TI - Evaluation and management of chronic total hip instability. AB - Given the increasing number of total hip arthroplasty procedures being performed annually, it is imperative that orthopaedic surgeons understand factors responsible for instability. In order to treat this potentially complex problem, we recommend correctly classifying the type of instability present based on component position, abductor function, impingement, and polyethylene wear. Correct classification allows the treating surgeon to choose the appropriate revision option that ultimately will allow for the best potential outcome. PMID- 26733641 TI - Modular tapered titanium stems in revision arthroplasty of the hip: The Risk and Causes of Stem Fracture. AB - Tapered fluted titanium stems are increasingly used for femoral revision arthroplasty. They are available in modular and non-modular forms. Modularity has advantages when the bone loss is severe, the proximal femur is mis shapen or the surgeon is unfamiliar with the implant, but it introduces the risk of fracture of the stem at the junction between it and the proximal body segment. For that reason, and while awaiting intermediate-term results of more recently introduced designs of this junction, non-modularity has attracted attention, at least for straightforward revision cases. We review the risks and causes of fracture of tapered titanium modular revision stems and present an argument in favour of the more selective use of modular designs. PMID- 26733642 TI - The modern, hybrid total hip arthroplasty for primary osteoarthritis at the Hospital for Special Surgery. AB - We describe our technique and rationale using hybrid fixation for primary total hip arthroplasty (THA) at the Hospital for Special Surgery. Modern uncemented acetabular components have few screw holes, or no holes, polished inner surfaces, improved locking mechanisms, and maximised thickness and shell-liner conformity. Uncemented sockets can be combined with highly cross-linked polyethylene liners, which have demonstrated very low wear and osteolysis rates after ten to 15 years of implantation. The results of cement fixation with a smooth or polished surface finished stem have been excellent, virtually eliminating complications seen with cementless fixation like peri-operative femoral fractures and thigh pain. Although mid-term results of modern cementless stems are encouraging, the long term data do not show reduced revision rates for cementless stems compared with cemented smooth stems. In this paper we review the conduct of a hybrid THA, with emphasis on pre-operative planning, surgical technique, hypotensive epidural anaesthesia, and intra-operative physiology. PMID- 26733643 TI - The dual mobility cup: what problems does it solve? AB - Dual mobility cups have two points of articulation, one between the shell and the polyethylene (external bearing) and one between the polyethylene and the femoral head (internal bearing). Movement occurs at the inner bearing; the outer bearing only moves at extremes of movement. Dislocation after total hip arthroplasty (THA) is a cause of much morbidity and its treatment has significant cost implications. Dual mobility cups provide an increased range of movement and a may reduce the risk of dislocation. This paper reviews the use of these cups in THA, particularly where stability is an issue. Dual mobility cups may be of benefit in primary THA in patients at a high risk of dislocation, such as those who are older with increased comorbidities and a higher American Association of Anesthesiology grade and those with a neuromuscular disease. They may be used at revision surgery where the risk of dislocation is high, such as in patients with many prior dislocations, or those with abductor deficiency. They may also be used in THA for displaced fractures of the femoral neck, which has a notoriously high rate of dislocation. PMID- 26733644 TI - The jumbo acetabular component for acetabular revision: Curtain Calls and Caveats. AB - The 'jumbo' acetabular component is now commonly used in acetabular revision surgery where there is extensive bone loss. It offers high surface contact, permits weight bearing over a large area of the pelvis, the need for bone grafting is reduced and it is usually possible to restore centre of rotation of the hip. Disadvantages of its use include a technique in which bone structure may not be restored, a risk of excessive posterior bone loss during reaming, an obligation to employ screw fixation, limited bone ingrowth with late failure and high hip centre, leading to increased risk of dislocation. Contraindications include unaddressed pelvic dissociation, inability to implant the component with a rim fit, and an inability to achieve screw fixation. Use in acetabulae with < 50% bone stock has also been questioned. Published results have been encouraging in the first decade, with late failures predominantly because of polyethylene wear and aseptic loosening. Dislocation is the most common complication of jumbo acetabular revisions, with an incidence of approximately 10%, and often mandates revision. Based on published results, a hemispherical component with an enhanced porous coating, highly cross-linked polyethylene, and a large femoral head appears to represent the optimum tribology for jumbo acetabular revisions. PMID- 26733645 TI - The custom triflange cup: build it and they will come. AB - The custom triflange is a patient-specific implant for the treatment of severe bone loss in revision total hip arthroplasty (THA). Through a process of three dimensional modelling and prototyping, a hydroxyapatite-coated component is created for acetabular reconstruction. There are seven level IV studies describing the clinical results of triflange components. The most common complications include dislocation and infection, although the rates of implant removal are low. Clinical results are promising given the challenging problem. We describe the design, manufacture and implantation process and review the clinical results, contrasting them to other methods of acetabular reconstruction in revision THA. PMID- 26733646 TI - The role of cages in the management of severe acetabular bone defects at revision arthroplasty. AB - An uncemented hemispherical acetabular component is the mainstay of acetabular revision and gives excellent long-term results. Occasionally, the degree of acetabular bone loss means that a hemispherical component will be unstable when sited in the correct anatomical location or there is minimal bleeding host bone left for biological fixation. On these occasions an alternative method of reconstruction has to be used. A major column structural allograft has been shown to restore the deficient bone stock to some degree, but it needs to be off-loaded with a reconstruction cage to prevent collapse of the graft. The use of porous metal augments is a promising method of overcoming some of the problems associated with structural allograft. If the defect is large, the augment needs to be protected by a cage to allow ingrowth to occur. Cup-cage reconstruction is an effective method of treating chronic pelvic discontinuity and large contained or uncontained bone defects. This paper presents the indications, surgical techniques and outcomes of various methods which use acetabular reconstruction cages for revision total hip arthroplasty. PMID- 26733647 TI - Patient-specific cutting blocks: Of Unproven Value. AB - Patient specific instrumentation (PSI) uses advanced imaging of the knee (CT or MRI) to generate individualised cutting blocks aimed to make the procedure of total knee arthroplasty (TKA) more accurate and efficient. However, in this era of healthcare cost consciousness, the value of new technologies needs to be critically evaluated. There have been several comparative studies looking at PSI versus standard instrumentation. Most compare PSI with conventional instrumentation in terms of alignment in the coronal plane, operative time and surgical efficiency, cost effectiveness and short-term outcomes. Several systematic reviews and meta-analyses have also been published. PSI has not been shown to be superior compared with conventional instrumentation in its ability to restore traditional mechanical alignment in primary TKA. Most studies show comparative efficacy and no decrease in the number of outliers in either group. In terms of operative time and efficiency, PSI tended towards decreasing operative time, saving a mean of five minutes per patient (0 to 20). Furthermore, while some cost savings could be realised with less operative time and reduced instrumentation per patient, these savings were overcome by the cost of the CT/MRI and the cutting blocks. Finally, there was no evidence that PSI positively affected clinical outcomes at two days, two months, or two years. Consequently, current evidence does not support routine use of PSI in routine primary TKA. PMID- 26733648 TI - Neutral mechanical alignment: Is it Necessary? AB - The cause of dissatisfaction following total knee arthroplasty (TKA) remains elusive. Much attention has been focused on static mechanical alignment as a basis for surgical success and optimising outcomes. More recently, research on both normal and osteoarthritic knees, as well as kinematically aligned TKAs, has suggested that other specific and dynamic factors may be more important than a generic target of 0 +/- 3o of a neutral axis. Consideration of these other variables is necessary to understand ideal targets and move beyond generic results. PMID- 26733649 TI - Mid-flexion instability after total knee arthroplasty: woolly thinking or a real concern? AB - The term mid-flexion instability has entered the orthopaedic literature as a concept, but has not been confirmed as a distinct clinical entity. The term is used freely, sometimes as a synonym for flexion instability. However, the terms need to be clearly separated. A cadaver study published in 1990 associated joint line elevation with decreased stability at many angles of flexion, but that model was not typical of clinical scenarios. The literature is considered and it is proposed that the more common entity of an uncorrected flexion contracture after a measured resection arthroplasty technique is more likely to produce clinical findings that suggest instability mid-flexion. It is proposed that the clinical scenario encountered is generalised instability, with the appearance of stability in full extension from tight posterior structures. This paper seeks to clarify whether mid-flexion instability exists as an entity distinct from other commonly recognised forms of instability. PMID- 26733650 TI - The effects of various physical non-operative modalities on the pain in osteoarthritis of the knee. AB - The purpose of this study was to evaluate the effect of various non-operative modalities of treatment (transcutaneous electrical nerve stimulation (TENS); neuromuscular electrical stimulation (NMES); insoles and bracing) on the pain of osteoarthritis (OA) of the knee. We conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify the therapeutic options which are commonly adopted for the management of osteoarthritis (OA) of the knee. The outcome measurement tools used in the different studies were the visual analogue scale and The Western Ontario and McMaster Universities Arthritis Index pain index: all pain scores were converted to a 100-point scale. A total of 30 studies met our inclusion criteria: 13 on insoles, seven on TENS, six on NMES, and four on bracing. The standardised mean difference (SMD) in pain after treatment with TENS was 1.796, which represented a significant reduction in pain. The significant overall effect estimate for NMES on pain was similar to that of TENS, with a SMD of 1.924. The overall effect estimate of insoles on pain was a SMD of 0.992. The overall effect of bracing showed a significant reduction in pain of 1.34. Overall, all four non-operative modalities of treatment were found to have a significant effect on the reduction of pain in OA of the knee. This study shows that non-operative physical modalities of treatment are of benefit when treating OA of the knee. However, much of the literature reviewed evaluates studies with follow-up of less than six months: future work should aim to evaluate patients with longer follow-up. PMID- 26733651 TI - Defining high activity in arthroplasty patients. AB - There is evidence that high levels of physical activity following arthroplasty of the hip or knee can lead to early revision. However, the term 'highly active' is not well defined. A validated ankle accelerometer was used to quantify activity in 13 patients, who had undergone a total of 20 arthroplasties of the lower limbs and who had active lifestyles. The assessments were taken at a mean of 8.7 years post-operatively (1.8 to 15.8). The mean gait cycles per day was 8273 (5964 to 12,557), which extrapolates to 3.0 million cycles per year (cpy) (2.2 to 4.6). The mean percentage of time spent in high activity mode was 4.3%, or about one hour per day. The mean percentage of cycles in high activity was 40%. Based on these data, we propose the following definitions of high activity: > 3 million cpy; one hour per day in high activity mode; 40% of cycles in high activity mode. Extrapolating the sample of activity over the time since operation, the mean cycles per arthroplasty was 25.2 million, with a maximum of 44.1 million. No joint has been revised, or shows evidence of impending failure. PMID- 26733652 TI - Strategies for reducing peri-operative blood loss in total knee arthroplasty. AB - During the last ten years, greater attention has been given to the management of peri-operative blood loss after total knee arthroplasty (TKA), as it is a modifiable outcome that has a significant effect on the rate of complications, the recovery, and the economic burden. Blood loss after TKA has been greatly reduced during this time, thereby dramatically reducing the rates of allogeneic transfusion. This has significantly reduced the complications associated with transfusion, such as fluid overload, infection, and increased length of stay. The greatest advent in lowering peri-operative blood loss after TKA has been the introduction of tranexamic acid, which reduces blood loss without increasing the risk of thromboembolic events. This paper discusses the ways of reducing blood loss after TKA, for which a multimodal algorithm, with pre-, intra- and post operative measures, has been adopted at our institution. PMID- 26733653 TI - Correcting deformity in total knee arthroplasty: Techniques to avoid the release of collateral ligaments in severely deformed knees. AB - Collateral ligament release is advocated in total knee arthroplasty (TKA) to deal with significant coronal plane deformities, but is also associated with significant disadvantages. We describe steps to avoid release of the collateral (superficial medial and lateral collateral) ligaments during TKA in severely deformed knees, while correcting deformity and balancing the knee. PMID- 26733654 TI - The epidemiology of failure in total knee arthroplasty: avoiding your next revision. AB - Total knee arthroplasty (TKA) is a cost effective and extremely successful operation. As longevity increases, the demand for primary TKA will continue to rise. The success and survivorship of TKAs are dependent on the demographics of the patient, surgical technique and implant-related factors. Currently the risk of failure of a TKA requiring revision surgery ten years post-operatively is 5%. The most common indications for revision include aseptic loosening (29.8%), infection (14.8%), and pain (9.5%). Revision surgery poses considerable clinical burdens on patients and financial burdens on healthcare systems. We present a current concepts review on the epidemiology of failed TKAs using data from worldwide National Joint Registries. PMID- 26733655 TI - The surgical approach for revision total knee arthroplasty. AB - A key to the success of revision total knee arthroplasty (TKA) is a safe surgical approach using an exposure that minimises complications. In most patients, a medial parapatellar arthrotomy with complete synovectomy is sufficient. If additional exposure is needed, a quadriceps snip performed through the quadriceps tendon often provides the additional exposure required. It is simple to perform and does not alter the post-operative rehabilitative protocol. In rare cases, in which additional exposure is needed, or when removal of a cemented long-stemmed tibial component is required, a tibial tubercle osteotomy (TTO) may be used. Given the risk of post-operative extensor lag, a V-Y quadricepsplasty is rarely indicated and usually considered only if TTO is not possible. PMID- 26733656 TI - Instability in total knee arthroplasty : assessment and solutions. AB - Instability is a common indication for early revision after both primary and revision total knee arthroplasty (TKA), accounting for up to 20% in the literature. The number of TKAs performed annually continues to climb exponentially, thus having an effective algorithm for treatment is essential. This relies on a thorough pre- and intra-operative assessment of the patient. The underlying cause of the instability must be identified initially and subsequently, the surgeon must be able to balance the flexion and extension gaps and be comfortable using a variety of constrained implants. This review describes the assessment of the unstable TKA, and the authors' preferred form of treatment for these difficult cases where the source of instability is often multifactorial. PMID- 26733657 TI - The management of bone loss in revision total knee arthroplasty: rebuild, reinforce, and augment. AB - The treatment of bone loss in revision total knee arthroplasty has evolved over the past decade. While the management of small to moderate sized defects has demonstrated good results with a variety of traditional techniques (cement and screws, small metal augments, impaction bone grafting or modular stems), the treatment of severe defects continues to be problematic. The use of a structural allograft has declined in recent years due to an increased failure rate with long term follow-up and with the introduction of highly porous metal augments that emphasise biological metaphyseal fixation. Recently published mid-term results on the use of tantalum cones in patients with severe bone loss has reaffirmed the success of this treatment strategy. PMID- 26733658 TI - Reasons to quit and barriers to quitting smoking in US young adults. AB - BACKGROUND: Young adulthood provides an enormous opportunity to alter trajectories of smoking behaviour for a large public health impact. OBJECTIVE: The purpose of this study was to examine correlates of perceived barriers to quitting smoking and reasons to quit in a sample of young adult current and former smokers. METHODS: This study used data from the 2011 National Young Adult Health Survey, a random-digit-dial cellphone survey. Participants were US young adult current smokers aged 18-34 (n = 699) and young adults who were either current smokers who had made a quit attempt in the past-year (n = 402) or former smokers (n = 289). Correlates of barriers to quitting smoking and reasons for quitting smoking were assessed using bivariate and multivariable analyses. RESULTS: More than half of current smokers identified 'loss of a way to handle stress' (59%) and 'cravings or withdrawal' (52%) as barriers to quitting. Female gender, daily smoking and intention to quit remained significantly associated with endorsing 'loss of a way to handle stress' as a barrier to quitting in multivariable analyses. The two most popular reasons for quitting smoking were physical fitness (64%) and the cost of tobacco (64%). CONCLUSION: These findings highlight barriers to cessation and the reasons that young smokers give for quitting. This information may be helpful to physicians as they counsel their young adult patients to quit smoking. PMID- 26733659 TI - A proposal for cellularity assessment for EGFR mutational analysis with a correlation with DNA yield and evaluation of the number of sections obtained from cell blocks for immunohistochemistry in non-small cell lung carcinoma. AB - AIMS: Different approaches have been described for reporting specimen adequacy for epidermal growth factor receptor (EGFR) mutation analysis. We aimed: (1) to conduct cellularity assessment and to investigate its association with DNA yield, (2) to compare the H&E slides taken before and after the thick sections (curls) obtained for EGFR testing and (3) to evaluate the number of ancillary studies performed. METHODS: Cell block (CB) slides of 110 non-small cell lung carcinoma cases submitted to EGFR analysis from 2010 to 2012 were reviewed for total cellularity (ranges 1-100, 100-250, 250-500, 500-750, 750-1000 and >1000 cells), tumour cellularity (ranges 1-50, 50-100, 100-300 and >300 cells) and the percentage of tumour cells. Precurl and postcurl H&E slides were compared using the three criteria. The number of immunohistochemistry (IHC) markers and special stains and DNA yield were recorded. RESULTS: DNA yield was significantly associated with the total cellularity, number and percentage of tumour cells. For 46 cases with precurl and postcurl slides, only three (6.5%) were classified as being different and in two of them the postcurl slide had greater cellularity than the precurl. IHC was performed in 83 cases, with a minimum of 1 and a maximum of 11 markers (median of 3) per case. CONCLUSIONS: An association between the total cellularity and the tumour cellularity with the DNA yield was demonstrated using the ranges described. Evaluation of a postcurl slide is an unnecessary practice. The majority of the CB had sufficient material for ancillary studies (up to 11 markers) and mutation testing. PMID- 26733660 TI - A New Century of GENETICS. PMID- 26733661 TI - Sewall Wright on Evolution in Mendelian Populations and the "Shifting Balance". PMID- 26733662 TI - Theodosius Dobzhansky on Hybrid Sterility and Speciation. PMID- 26733663 TI - Admixture Models and the Breeding Systems of H. S. Jennings: A GENETICS Connection. PMID- 26733664 TI - The Centenary of GENETICS: Bridges to the Future. PMID- 26733665 TI - Genetical Genomics of Behavior: A Novel Chicken Genomic Model for Anxiety Behavior. AB - The identification of genetic variants responsible for behavioral variation is an enduring goal in biology, with wide-scale ramifications, ranging from medical research to evolutionary theory on personality syndromes. Here, we use for the first time a large-scale genetical genomics analysis in the brains of chickens to identify genes affecting anxiety as measured by an open field test. We combine quantitative trait locus (QTL) analysis in 572 individuals and expression QTL (eQTL) analysis in 129 individuals from an advanced intercross between domestic chickens and Red Junglefowl. We identify 10 putative quantitative trait genes affecting anxiety behavior. These genes were tested for an association in the mouse Heterogeneous Stock anxiety (open field) data set and human GWAS data sets for bipolar disorder, major depressive disorder, and schizophrenia. Although comparisons between species are complex, associations were observed for four of the candidate genes in mice and three of the candidate genes in humans. Using a multimodel approach we have therefore identified a number of putative quantitative trait genes affecting anxiety behavior, principally in chickens but also with some potentially translational effects as well. This study demonstrates that chickens are an excellent model organism for the genetic dissection of behavior. PMID- 26733667 TI - Opinion: Specimen collections should have a much bigger role in infectious disease research and response. PMID- 26733669 TI - Concerted activities of Mcm4, Sld3, and Dbf4 in control of origin activation and DNA replication fork progression. AB - Eukaryotic chromosomes initiate DNA synthesis from multiple replication origins in a temporally specific manner during S phase. The replicative helicase Mcm2-7 functions in both initiation and fork progression and thus is an important target of regulation. Mcm4, a helicase subunit, possesses an unstructured regulatory domain that mediates control from multiple kinase signaling pathways, including the Dbf4-dependent Cdc7 kinase (DDK). Following replication stress in S phase, Dbf4 and Sld3, an initiation factor and essential target of Cyclin-Dependent Kinase (CDK), are targets of the checkpoint kinase Rad53 for inhibition of initiation from origins that have yet to be activated, so-called late origins. Here, whole-genome DNA replication profile analysis is used to access under various conditions the effect of mutations that alter the Mcm4 regulatory domain and the Rad53 targets, Sld3 and Dbf4. Late origin firing occurs under genotoxic stress when the controls on Mcm4, Sld3, and Dbf4 are simultaneously eliminated. The regulatory domain of Mcm4 plays an important role in the timing of late origin firing, both in an unperturbed S phase and in dNTP limitation. Furthermore, checkpoint control of Sld3 impacts fork progression under replication stress. This effect is parallel to the role of the Mcm4 regulatory domain in monitoring fork progression. Hypomorph mutations in sld3 are suppressed by a mcm4 regulatory domain mutation. Thus, in response to cellular conditions, the functions executed by Sld3, Dbf4, and the regulatory domain of Mcm4 intersect to control origin firing and replication fork progression, thereby ensuring genome stability. PMID- 26733670 TI - The prognostic value of TP53 mutations in oesophageal adenocarcinoma: a systematic review and meta-analysis. AB - OBJECTIVE: To clarify the prognostic role of tumour protein 53 (TP53) mutations in patients with oesophageal adenocarcinoma (OAC) as there is a need for biomarkers that assist in guiding management for patients with OAC. DESIGN: A systematic review was conducted using MEDLINE, Embase, PubMed and Current Contents Connect to identify studies published between January 1990 and February 2015 of oesophageal cancer populations (with OAC diagnoses >50% of cases) that measured tumoural TP53 status and reported hazard ratios (HR), or adequate data for estimation of HR for survival for TP53-defined subgroups. Risk of bias for HR estimates was assessed using prespecified criteria for the appraisal of relevant domains as defined by the Cochrane Prognosis Methods Group including adherence to Grading of Recommendations, Assessment, Development and Evaluation and REporting recommendations for tumor MARKer prognostic studies guidelines, as well as assay method used (direct TP53 mutation assessment vs immunohistochemistry) and adjustment for standard prognostic factors. A pooled HR and 95% CI were calculated using a random-effects model. RESULTS: Sixteen eligible studies (11 with OAC only and 5 mixed histology cohorts) including 888 patients were identified. TP53 mutations were associated with reduced survival (HR 1.48, 95% CI 1.16 to 1.90, I2=33%). A greater prognostic effect was observed in a sensitivity analysis of those studies that reported survival for OAC-only cohorts and were assessed at low risk of bias (HR 2.11, 95% CI 1.35 to 3.31, I2=0%). CONCLUSIONS: Patients with OAC and TP53 gene mutations have reduced overall survival compared with patients without these mutations, and this effect is independent of tumour stage. PMID- 26733671 TI - Rapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFNalpha. AB - OBJECTIVE: Chronic HCV infection is characterised by innate immune activation with increased interferon-stimulated genes (ISG) expression and by an altered phenotype of interferon-responsive natural killer (NK) cells. Here, we asked whether a rapid reduction in viremia by daclatasvir (DCV) and asunaprevir (ASV) improves the response to pegylated interferon (PegIFN) in patients who had previously failed a standard course of PegIFN/ribavirin (RBV) therapy. DESIGN: Twenty-two HCV-infected non-responders to previous PegIFN/RBV therapy were studied for IFN-responsiveness of NK cells during quadruple (QUAD) therapy with DCV, ASV, PegIFN and RBV. A direct comparison of early NK cell responses in PegIFN/RBV therapy and QUAD therapy was performed for seven patients using paired cryopreserved peripheral blood mononuclear cells (PBMC) from both treatment courses. As a validation cohort, nine DCV/ASV-treated patients were studied for their NK cell response to in vitro stimulation with IFNalpha. RESULTS: The 24 h virological response to QUAD therapy correlated with an increase in signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1 (pSTAT1) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in NK cells, and the STAT1/pSTAT1/TRAIL induction was greater during QUAD therapy than during previous PegIFN/RBV therapy. Successful QUAD therapy as well as successful IFN-free DCV/ASV regimen resulted in an improved functional NK cell response (degranulation and TRAIL expression) to in vitro stimulation with IFNalpha. CONCLUSIONS: IFN-responsiveness can be improved by inhibiting HCV replication and reducing the HCV-induced activation of the innate immune response. This may provide a rationale for clinical trials of a brief period of direct acting antiviral therapy followed by PegIFN/RBV therapy to reduce the overall treatment costs in low-income and middle-income countries. TRIAL REGISTRATION NUMBERS: NCT01888900 and NCT00718172. PMID- 26733672 TI - From cradle to grave: tracking socioeconomic inequalities in mortality in a cohort of 11 868 men and women born in Uppsala, Sweden, 1915-1929. AB - BACKGROUND: Ample evidence has shown that early-life social conditions are associated with mortality later in life. However, little attention has been given to the strength of these effects across specific age intervals from birth to old age. In this paper, we study the effect of the family's socioeconomic position and mother's marital status at birth on all-cause mortality at different age intervals in a Swedish cohort of 11 868 individuals followed across their lifespan. METHODS: Using the Uppsala Birth Cohort Multigenerational Study, we fitted Cox regression models to estimate age-varying HRs of all-cause mortality according to mother's marital status and family's socioeconomic position. RESULTS: Mother's marital status and family's socioeconomic position at birth were associated with higher mortality rates throughout life (HR 1.18 (95% CI 1.12 to 1.26) for unmarried mothers; 1.19 (95% CI 1.12 to 1.25) for low socioeconomic position). While the effect of family's socioeconomic position showed little variation across different age groups, the effect of marital status was stronger for infant mortality (HR 1.47 (95% CI 1.23 to 1.76); p=0.04 for heterogeneity). The results remained robust when early life and adult mediator variables were included. CONCLUSIONS: Family's socioeconomic position and mother's marital status involve different dimensions of social stratification with independent effects on mortality throughout life. Our findings support the importance of improving early-life conditions in order to enhance healthy ageing. PMID- 26733673 TI - How faceted liquid droplets grow tails. AB - Liquid droplets, widely encountered in everyday life, have no flat facets. Here we show that water-dispersed oil droplets can be reversibly temperature-tuned to icosahedral and other faceted shapes, hitherto unreported for liquid droplets. These shape changes are shown to originate in the interplay between interfacial tension and the elasticity of the droplet's 2-nm-thick interfacial monolayer, which crystallizes at some T = Ts above the oil's melting point, with the droplet's bulk remaining liquid. Strikingly, at still-lower temperatures, this interfacial freezing (IF) effect also causes droplets to deform, split, and grow tails. Our findings provide deep insights into molecular-scale elasticity and allow formation of emulsions of tunable stability for directed self-assembly of complex-shaped particles and other future technologies. PMID- 26733674 TI - Mice plan decision strategies based on previously learned time intervals, locations, and probabilities. AB - Animals can shape their timed behaviors based on experienced probabilistic relations in a nearly optimal fashion. On the other hand, it is not clear if they adopt these timed decisions by making computations based on previously learnt task parameters (time intervals, locations, and probabilities) or if they gradually develop their decisions based on trial and error. To address this question, we tested mice in the timed-switching task, which required them to anticipate when (after a short or long delay) and at which of the two delay locations a reward would be presented. The probability of short trials differed between test groups in two experiments. Critically, we first trained mice on relevant task parameters by signaling the active trial with a discriminative stimulus and delivered the corresponding reward after the associated delay without any response requirement (without inducing switching behavior). During the test phase, both options were presented simultaneously to characterize the emergence and temporal characteristics of the switching behavior. Mice exhibited timed-switching behavior starting from the first few test trials, and their performance remained stable throughout testing in the majority of the conditions. Furthermore, as the probability of the short trial increased, mice waited longer before switching from the short to long location (experiment 1). These behavioral adjustments were in directions predicted by reward maximization. These results suggest that rather than gradually adjusting their time-dependent choice behavior, mice abruptly adopted temporal decision strategies by directly integrating their previous knowledge of task parameters into their timed behavior, supporting the model-based representational account of temporal risk assessment. PMID- 26733675 TI - Bacterial RNA polymerase can retain sigma70 throughout transcription. AB - Production of a messenger RNA proceeds through sequential stages of transcription initiation and transcript elongation and termination. During each of these stages, RNA polymerase (RNAP) function is regulated by RNAP-associated protein factors. In bacteria, RNAP-associated sigma factors are strictly required for promoter recognition and have historically been regarded as dedicated initiation factors. However, the primary sigma factor in Escherichia coli, sigma(70), can remain associated with RNAP during the transition from initiation to elongation, influencing events that occur after initiation. Quantitative studies on the extent of sigma(70) retention have been limited to complexes halted during early elongation. Here, we used multiwavelength single-molecule fluorescence colocalization microscopy to observe the sigma(70)-RNAP complex during initiation from the lambda PR' promoter and throughout the elongation of a long (>2,000-nt) transcript. Our results provide direct measurements of the fraction of actively transcribing complexes with bound sigma(70) and the kinetics of sigma(70) release from actively transcribing complexes. sigma(70) release from mature elongation complexes was slow (0.0038 s(-1)); a substantial subpopulation of elongation complexes retained sigma(70) throughout transcript elongation, and this fraction depended on the sequence of the initially transcribed region. We also show that elongation complexes containing sigma(70) manifest enhanced recognition of a promoter-like pause element positioned hundreds of nucleotides downstream of the promoter. Together, the results provide a quantitative framework for understanding the postinitiation roles of sigma(70) during transcription. PMID- 26733676 TI - Structural basis for m7G recognition and 2'-O-methyl discrimination in capped RNAs by the innate immune receptor RIG-I. AB - RNAs with 5'-triphosphate (ppp) are detected in the cytoplasm principally by the innate immune receptor Retinoic Acid Inducible Gene-I (RIG-I), whose activation triggers a Type I IFN response. It is thought that self RNAs like mRNAs are not recognized by RIG-I because 5'ppp is capped by the addition of a 7-methyl guanosine (m7G) (Cap-0) and a 2'-O-methyl (2'-OMe) group to the 5'-end nucleotide ribose (Cap-1). Here we provide structural and mechanistic basis for exact roles of capping and 2'-O-methylation in evading RIG-I recognition. Surprisingly, Cap-0 and 5'ppp double-stranded (ds) RNAs bind to RIG-I with nearly identical Kd values and activate RIG-I's ATPase and cellular signaling response to similar extents. On the other hand, Cap-0 and 5'ppp single-stranded RNAs did not bind RIG-I and are signaling inactive. Three crystal structures of RIG-I complexes with dsRNAs bearing 5'OH, 5'ppp, and Cap-0 show that RIG-I can accommodate the m7G cap in a cavity created through conformational changes in the helicase-motif IVa without perturbing the ppp interactions. In contrast, Cap-1 modifications abrogate RIG-I signaling through a mechanism involving the H830 residue, which we show is crucial for discriminating between Cap-0 and Cap-1 RNAs. Furthermore, m7G capping works synergistically with 2'-O-methylation to weaken RNA affinity by 200-fold and lower ATPase activity. Interestingly, a single H830A mutation restores both high-affinity binding and signaling activity with 2'-O-methylated dsRNAs. Our work provides new structural insights into the mechanisms of host and viral immune evasion from RIG-I, explaining the complexity of cap structures over evolution. PMID- 26733677 TI - Growth factors and medium hyperglycemia induce Sox9+ ductal cell differentiation into beta cells in mice with reversal of diabetes. AB - We previously reported that long-term administration of a low dose of gastrin and epidermal growth factor (GE) augments beta-cell neogenesis in late-stage diabetic autoimmune mice after eliminating insulitis by induction of mixed chimerism. However, the source of beta-cell neogenesis is still unknown. SRY (sex determining region Y)-box 9(+) (Sox9(+)) ductal cells in the adult pancreas are clonogenic and can give rise to insulin-producing beta cells in an in vitro culture. Whether Sox9(+) ductal cells in the adult pancreas can give rise to beta cells in vivo remains controversial. Here, using lineage-tracing with genetic labeling of Insulin- or Sox9-expressing cells, we show that hyperglycemia (>300 mg/dL) is required for inducing Sox9(+) ductal cell differentiation into insulin producing beta cells, and medium hyperglycemia (300-450 mg/dL) in combination with long-term administration of low-dose GE synergistically augments differentiation and is associated with normalization of blood glucose in nonautoimmune diabetic C57BL/6 mice. Short-term administration of high-dose GE cannot augment differentiation, although it can augment preexisting beta-cell replication. These results indicate that medium hyperglycemia combined with long term administration of low-dose GE represents one way to induce Sox9(+) ductal cell differentiation into beta cells in adult mice. PMID- 26733678 TI - KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. AB - Rett syndrome is a severe form of autism spectrum disorder, mainly caused by mutations of a single gene methyl CpG binding protein 2 (MeCP2) on the X chromosome. Patients with Rett syndrome exhibit a period of normal development followed by regression of brain function and the emergence of autistic behaviors. However, the mechanism behind the delayed onset of symptoms is largely unknown. Here we demonstrate that neuron-specific K(+)-Cl(-) cotransporter2 (KCC2) is a critical downstream gene target of MeCP2. We found that human neurons differentiated from induced pluripotent stem cells from patients with Rett syndrome showed a significant deficit in KCC2 expression and consequently a delayed GABA functional switch from excitation to inhibition. Interestingly, overexpression of KCC2 in MeCP2-deficient neurons rescued GABA functional deficits, suggesting an important role of KCC2 in Rett syndrome. We further identified that RE1-silencing transcriptional factor, REST, a neuronal gene repressor, mediates the MeCP2 regulation of KCC2. Because KCC2 is a slow onset molecule with expression level reaching maximum later in development, the functional deficit of KCC2 may offer an explanation for the delayed onset of Rett symptoms. Our studies suggest that restoring KCC2 function in Rett neurons may lead to a potential treatment for Rett syndrome. PMID- 26733680 TI - Region effects influence local tree species diversity. AB - Global patterns of biodiversity reflect both regional and local processes, but the relative importance of local ecological limits to species coexistence, as influenced by the physical environment, in contrast to regional processes including species production, dispersal, and extinction, is poorly understood. Failure to distinguish regional influences from local effects has been due, in part, to sampling limitations at small scales, environmental heterogeneity within local or regional samples, and incomplete geographic sampling of species. Here, we use a global dataset comprising 47 forest plots to demonstrate significant region effects on diversity, beyond the influence of local climate, which together explain more than 92% of the global variation in local forest tree species richness. Significant region effects imply that large-scale processes shaping the regional diversity of forest trees exert influence down to the local scale, where they interact with local processes to determine the number of coexisting species. PMID- 26733679 TI - Sympathetic innervation controls homeostasis of neuromuscular junctions in health and disease. AB - The distribution and function of sympathetic innervation in skeletal muscle have largely remained elusive. Here we demonstrate that sympathetic neurons make close contact with neuromuscular junctions and form a network in skeletal muscle that may functionally couple different targets including blood vessels, motor neurons, and muscle fibers. Direct stimulation of sympathetic neurons led to activation of muscle postsynaptic beta2-adrenoreceptor (ADRB2), cAMP production, and import of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PPARGC1A) into myonuclei. Electrophysiological and morphological deficits of neuromuscular junctions upon sympathectomy and in myasthenic mice were rescued by sympathicomimetic treatment. In conclusion, this study identifies the neuromuscular junction as a target of the sympathetic nervous system and shows that sympathetic input is crucial for synapse maintenance and function. PMID- 26733681 TI - Structure determination of helical filaments by solid-state NMR spectroscopy. AB - The controlled formation of filamentous protein complexes plays a crucial role in many biological systems and represents an emerging paradigm in signal transduction. The mitochondrial antiviral signaling protein (MAVS) is a central signal transduction hub in innate immunity that is activated by a receptor induced conversion into helical superstructures (filaments) assembled from its globular caspase activation and recruitment domain. Solid-state NMR (ssNMR) spectroscopy has become one of the most powerful techniques for atomic resolution structures of protein fibrils. However, for helical filaments, the determination of the correct symmetry parameters has remained a significant hurdle for any structural technique and could thus far not be precisely derived from ssNMR data. Here, we solved the atomic resolution structure of helical MAVS(CARD) filaments exclusively from ssNMR data. We present a generally applicable approach that systematically explores the helical symmetry space by efficient modeling of the helical structure restrained by interprotomer ssNMR distance restraints. Together with classical automated NMR structure calculation, this allowed us to faithfully determine the symmetry that defines the entire assembly. To validate our structure, we probed the protomer arrangement by solvent paramagnetic resonance enhancement, analysis of chemical shift differences relative to the solution NMR structure of the monomer, and mutagenesis. We provide detailed information on the atomic contacts that determine filament stability and describe mechanistic details on the formation of signaling-competent MAVS filaments from inactive monomers. PMID- 26733682 TI - Highly efficient delivery of functional cargoes by the synergistic effect of GAG binding motifs and cell-penetrating peptides. AB - Protein transduction domains (PTDs) are powerful nongenetic tools that allow intracellular delivery of conjugated cargoes to modify cell behavior. Their use in biomedicine has been hampered by inefficient delivery to nuclear and cytoplasmic targets. Here we overcame this deficiency by developing a series of novel fusion proteins that couple a membrane-docking peptide to heparan sulfate glycosaminoglycans (GAGs) with a PTD. We showed that this GET (GAG-binding enhanced transduction) system could deliver enzymes (Cre, neomycin phosphotransferase), transcription factors (NANOG, MYOD), antibodies, native proteins (cytochrome C), magnetic nanoparticles (MNPs), and nucleic acids [plasmid (p)DNA, modified (mod)RNA, and small inhibitory RNA] at efficiencies of up to two orders of magnitude higher than previously reported in cell types considered hard to transduce, such as mouse embryonic stem cells (mESCs), human ESCs (hESCs), and induced pluripotent stem cells (hiPSCs). This technology represents an efficient strategy for controlling cell labeling and directing cell fate or behavior that has broad applicability for basic research, disease modeling, and clinical application. PMID- 26733683 TI - Cross-talk among flesh-eating Aeromonas hydrophila strains in mixed infection leading to necrotizing fasciitis. AB - Necrotizing fasciitis (NF) caused by flesh-eating bacteria is associated with high case fatality. In an earlier study, we reported infection of an immunocompetent individual with multiple strains of Aeromonas hydrophila (NF1 NF4), the latter three constituted a clonal group whereas NF1 was phylogenetically distinct. To understand the complex interactions of these strains in NF pathophysiology, a mouse model was used, whereby either single or mixed A. hydrophila strains were injected intramuscularly. NF2, which harbors exotoxin A (exoA) gene, was highly virulent when injected alone, but its virulence was attenuated in the presence of NF1 (exoA-minus). NF1 alone, although not lethal to animals, became highly virulent when combined with NF2, its virulence augmented by cis-exoA expression when injected alone in mice. Based on metagenomics and microbiological analyses, it was found that, in mixed infection, NF1 selectively disseminated to mouse peripheral organs, whereas the other strains (NF2, NF3, and NF4) were confined to the injection site and eventually cleared. In vitro studies showed NF2 to be more effectively phagocytized and killed by macrophages than NF1. NF1 inhibited growth of NF2 on solid media, but ExoA of NF2 augmented virulence of NF1 and the presence of NF1 facilitated clearance of NF2 from animals either by enhanced priming of host immune system or direct killing via a contact-dependent mechanism. PMID- 26733684 TI - Activation of integrin alpha5 mediated by flow requires its translocation to membrane lipid rafts in vascular endothelial cells. AB - Local flow patterns determine the uneven distribution of atherosclerotic lesions. Membrane lipid rafts and integrins are crucial for shear stress-regulated endothelial function. In this study, we investigate the role of lipid rafts and integrin alpha5 in regulating the inflammatory response in endothelial cells (ECs) under atheroprone versus atheroprotective flow. Lipid raft proteins were isolated from ECs exposed to oscillatory shear stress (OS) or pulsatile shear stress, and then analyzed by quantitative proteomics. Among 396 proteins redistributed in lipid rafts, integrin alpha5 was the most significantly elevated in lipid rafts under OS. In addition, OS increased the level of activated integrin alpha5 in lipid rafts through the regulation of membrane cholesterol and fluidity. Disruption of F-actin-based cytoskeleton and knockdown of caveolin-1 prevented the OS-induced integrin alpha5 translocation and activation. In vivo, integrin alpha5 activation and EC dysfunction were observed in the atheroprone areas of low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice, and knockdown of integrin alpha5 markedly attenuated EC dysfunction in partially ligated carotid arteries. Consistent with these findings, mice with haploinsufficency of integrin alpha5 exhibited a reduction of atherosclerotic lesions in the regions under atheroprone flow. The present study has revealed an integrin- and membrane lipid raft-dependent mechanotransduction mechanism by which atheroprone flow causes endothelial dysfunction. PMID- 26733685 TI - Opposing roles for serotonin in cholinergic neurons of the ventral and dorsal striatum. AB - Little is known about the molecular similarities and differences between neurons in the ventral (vSt) and dorsal striatum (dSt) and their physiological implications. In the vSt, serotonin [5-Hydroxytryptamine (5-HT)] modulates mood control and pleasure response, whereas in the dSt, 5-HT regulates motor behavior. Here we show that, in mice, 5-HT depolarizes cholinergic interneurons (ChIs) of the dSt whereas hyperpolarizing ChIs from the vSt by acting on different 5-HT receptor isoforms. In the vSt, 5-HT1A (a postsynaptic receptor) and 5-HT1B (a presynaptic receptor) are highly expressed, and synergistically inhibit the excitability of ChIs. The inhibitory modulation by 5-HT1B, but not that by 5 HT1A, is mediated by p11, a protein associated with major depressive disorder. Specific deletion of 5-HT1B from cholinergic neurons results in impaired inhibition of ACh release in the vSt and in anhedonic-like behavior. PMID- 26733686 TI - Luminopsins integrate opto- and chemogenetics by using physical and biological light sources for opsin activation. AB - Luminopsins are fusion proteins of luciferase and opsin that allow interrogation of neuronal circuits at different temporal and spatial resolutions by choosing either extrinsic physical or intrinsic biological light for its activation. Building on previous development of fusions of wild-type Gaussia luciferase with channelrhodopsin, here we expanded the utility of luminopsins by fusing bright Gaussia luciferase variants with either channelrhodopsin to excite neurons (luminescent opsin, LMO) or a proton pump to inhibit neurons (inhibitory LMO, iLMO). These improved LMOs could reliably activate or silence neurons in vitro and in vivo. Expression of the improved LMO in hippocampal circuits not only enabled mapping of synaptic activation of CA1 neurons with fine spatiotemporal resolution but also could drive rhythmic circuit excitation over a large spatiotemporal scale. Furthermore, virus-mediated expression of either LMO or iLMO in the substantia nigra in vivo produced not only the expected bidirectional control of single unit activity but also opposing effects on circling behavior in response to systemic injection of a luciferase substrate. Thus, although preserving the ability to be activated by external light sources, LMOs expand the use of optogenetics by making the same opsins accessible to noninvasive, chemogenetic control, thereby allowing the same probe to manipulate neuronal activity over a range of spatial and temporal scales. PMID- 26733687 TI - Integrated Patient Coordination System (IntPaCS): a bespoke tool for surgical patient management. AB - BACKGROUND: Efficient handover of patient information is fundamental for patient care and service efficiency. An audit exploring surgeons' views on written handover within a Trust's surgical specialties concluded that clear deficiencies existed. Such concerns have been echoed in the General Medical Council's guidance on safe surgical handover. AIMS: To design and implement bespoke software for surgical handover using the audit results of surgeons' perceptions of existing processes. To gain feedback from the surgical department on this new software and implement a long-term sustainability strategy. METHODS: Following an initial review, a proposal was presented for a new patient management tool. The software was designed and developed in-house to reflect the needs of our surgeons. The bespoke programme used open-source coding and was maintained on a secure server. A review of surgical handover occurred 12 and 134 weeks post-implementation of the new software. RESULTS: Integrated Patient Coordination System (IntPaCS) was successfully developed and delivered. The system is a centralised platform that enables the visualisation, handover and audit/research of surgical inpatient information in any part of the hospital. Feedback found that clinicians found it less stressful to create a post-take handover (60% vs 36%) than using a Word document. IntPaCS was found to be quicker to use too (15 min (SD 4) vs 24 min (SD 7.5)). Finally, the new system was considered safer with less reported missing/incorrect patient data (48% vs 9%). CONCLUSIONS: This study has shown that careful use of emerging technology and innovation over time has the potential to improve all aspects of clinical governance. PMID- 26733688 TI - The hinge domain of the epigenetic repressor Smchd1 adopts an unconventional homodimeric configuration. AB - The structural maintenance of chromosomes (SMC) proteins are fundamental to chromosome organization. They share a characteristic domain structure, featuring a central SMC hinge domain that is critical for forming SMC dimers and interacting with nucleic acids. The structural maintenance of chromosomes flexible hinge domain containing 1 (Smchd1) is a non-canonical member of the SMC family. Although it has been well established that Smchd1 serves crucial roles in epigenetic silencing events implicated in development and disease, much less is known about the structure and function of the Smchd1 protein. Recently, we demonstrated that the C-terminal hinge domain of Smchd1 forms a nucleic acid binding homodimer; however, it is unclear how the protomers are assembled within the hinge homodimer and how the full-length Smchd1 protein is organized with respect to the hinge region. In the present study, by employing SAXS we demonstrate that the hinge domain of Smchd1 probably adopts an unconventional homodimeric arrangement augmented by an intermolecular coiled coil formed between the two monomers. Such a dimeric structure differs markedly from that of archetypical SMC proteins, raising the possibility that Smchd1 binds chromatin in an unconventional manner. PMID- 26733689 TI - The plastidial retrograde signal methyl erythritol cyclopyrophosphate is a regulator of salicylic acid and jasmonic acid crosstalk. AB - The exquisite harmony between hormones and their corresponding signaling pathways is central to prioritizing plant responses to simultaneous and/or successive environmental trepidations. The crosstalk between jasmonic acid (JA) and salicylic acid (SA) is an established effective mechanism that optimizes and tailors plant adaptive responses. However, the underlying regulatory modules of this crosstalk are largely unknown. Global transcriptomic analyses of mutant plants (ceh1) with elevated levels of the stress-induced plastidial retrograde signaling metabolite 2-C-methyl-D-erythritol cyclopyrophosphate (MEcPP) revealed robustly induced JA marker genes, expected to be suppressed by the presence of constitutively high SA levels in the mutant background. Analyses of a range of genotypes with varying SA and MEcPP levels established the selective role of MEcPP-mediated signal(s) in induction of JA-responsive genes in the presence of elevated SA. Metabolic profiling revealed the presence of high levels of the JA precursor 12-oxo-phytodienoic acid (OPDA), but near wild type levels of JA in the ceh1 mutant plants. Analyses of coronatine-insensitive 1 (coi1)/ceh1 double mutant plants confirmed that the MEcPP-mediated induction is JA receptor COI1 dependent, potentially through elevated OPDA. These findings identify MEcPP as a previously unrecognized central regulatory module that induces JA-responsive genes in the presence of high SA, thereby staging a multifaceted plant response within the environmental context. PMID- 26733690 TI - Silicon decreases both uptake and root-to-shoot translocation of manganese in rice. AB - Silicon (Si) is known to alleviate manganese (Mn) toxicity in a number of plant species; however, the mechanisms responsible for this effect are poorly understood. Here, we investigated the interaction between Si and Mn in rice (Oryza sativa) by using a mutant defective in Si uptake. Silicon alleviated Mn toxicity in the wild-type (WT) rice, but not in the mutant exposed to high Mn. The Mn concentration in the shoots was decreased, but that in the roots was increased by Si in the WT. In contrast, the Mn concentration in the roots and shoots was unaffected by Si in the mutant. Furthermore, Si supply resulted in an increased Mn in the root cell sap, decreased Mn in the xylem sap in the WT, but these effects of Si were not observed in the mutant. A short-term labelling experiment with (54)Mn showed that the uptake of Mn was similar between plants with and without Si and between WT and the mutant. However, Si decreased root-to shoot translocation of Mn in the WT, but not in the mutant. The expression of a Mn transporter gene for uptake, OsNramp5, was unaffected by a short exposure (<1 d) to Si, but down-regulated by relatively long-term exposure to Si in WT. In contrast, the expression of OsNramp5 was unaffected by Si in the mutant. These results indicated that Si-decreased Mn accumulation results from both Si decreased root-to-shoot translocation of Mn, probably by the formation of Mn-Si complex in root cells, and uptake by down-regulating Mn transporter gene. PMID- 26733691 TI - Histone deacetylase HDA9 negatively regulates salt and drought stress responsiveness in Arabidopsis. AB - Histone modification is an important epigenetic regulation in higher plants adapting to environment changes including salt and drought stresses. In this report, we show that the Arabidopsis RPD3-type histone deacetylase HDA9 is involved in modulating plant responses to salt and drought stresses in Arabidopsis. Loss-of-function mutants of the gene displayed phenotypes (such as seedling root growth and seed germination) insensitive to NaCl and polyethylene glycol (PEG) treatments. HDA9 mutation led to up-regulation of many genes, among which those involved in response to water deprivation stress (GO: 0009414) were enriched. These genes were much more induced in the mutants than wild-type plants when treated with PEG and NaCl. In addition, we found that in the mutants, salt and drought stresses led to much higher levels of histone H3K9 acetylation at promoters of 14 genes randomly selected from those that respond to water deprivation stress than in wild-type plants. Our study suggested that HDA9 might be a novel chromatin protein that negatively regulates plant sensitivity to salt and drought stresses by regulating histone acetylation levels of a large number of stress-responsive genes in Arabidopsis. PMID- 26733692 TI - Network analysis of the metabolome and transcriptome reveals novel regulation of potato pigmentation. AB - To gain insights into the regulatory networks related to anthocyanin biosynthesis and identify key regulatory genes, we performed an integrated analysis of the transcriptome and metabolome in sprouts germinated from three colored potato cultivars: light-red Hongyoung, dark-purple Jayoung, and white Atlantic. We investigated transcriptional and metabolic changes using statistical analyses and gene-metabolite correlation networks. Transcript and metabolite profiles were generated through high-throughput RNA-sequencing data analysis and ultraperformance liquid chromatography quadrupole time-of-flight tandem mass spectrometry, respectively. The identification and quantification of changes in anthocyanin were performed using molecular formula-based mass accuracy and specific features of their MS(2) spectra. Correlation tests of anthocyanin contents and transcriptional changes showed 823 strong correlations (correlation coefficient, R (2)>0.9) between 22 compounds and 119 transcripts categorized into flavonoid metabolism, hormones, transcriptional regulation, and signaling. The connection network of anthocyanins and genes showed a regulatory system involved in the pigmentation of light-red Hongyoung and dark-purple Jayoung potatoes, suggesting that this systemic approach is powerful for investigations into novel genes that are potential targets for the breeding of new valuable potato cultivars. PMID- 26733694 TI - High-Cost Populations, The ACA, And More. PMID- 26733693 TI - Multiple Paternity in the Norway Rat, Rattus norvegicus, from Urban Slums in Salvador, Brazil. AB - The Norway rat, Rattus norvegicus, is one of the most important pest species globally and the main reservoir of leptospires causing human leptospirosis in the urban slums of tropical regions. Rodent control is a frequent strategy in those settings to prevent the disease but rapid growth from residual populations and immigration limit the long-term effectiveness of interventions. To characterize the breeding ecology of R. norvegicus and provide needed information for the level of genetic mixing, which can help identify inter-connected eradication units, we estimated the occurrence of multiple paternity, distances between mothers and sires, and inbreeding in rats from urban slum habitat in Salvador, Brazil. We genotyped 9 pregnant females, their 66 offspring, and 371 males at 16 microsatellite loci. Multiple paternity was observed in 22% (2/9) of the study litters. Of the 12 sires that contributed to the 9 litters, we identified 5 (42%) of those sires among our genotyped males. Related males were captured in close proximity to pregnant females (the mean inter-parent trapping distance per litter was 70 m, +/-58 m SD). Levels of relatedness between mother-sire pairs were higher than expected and significantly higher than relatedness between all females and non-sire males. Our findings indicate multiple paternity is common, inbreeding is apparent, and that mother-sire dyads occur in close proximity within the study area. This information is relevant to improve the spatial definition of the eradication units that may enhance the effectiveness of rodent management programs aimed at preventing human leptospirosis. High levels of inbreeding may also be a sign that eradication efforts are successful. PMID- 26733695 TI - A Critical Year For The Affordable Care Act. PMID- 26733696 TI - Understanding Patterns Of High-Cost Health Care Use Across Different Substance User Groups. AB - Substance use contributes to significant societal burdens, including high-cost health care use. However, these burdens may vary by type of substance and level of involvement. Using the 2009-13 National Surveys on Drug Use and Health, we examined all-cause hospitalizations and estimated costs across substance use profiles for alcohol, marijuana, and other illicit drugs. For each substance, we characterized differences between abstainers, nondiagnostic users (people who used the substance but did not meet diagnostic criteria for substance use disorder), and people with substance use disorders. In a multivariate analysis, we found that the odds of hospitalization were 16 percent lower for nondiagnostic marijuana users and 11 percent lower for nondiagnostic alcohol users, compared to abstainers. Neither alcohol- nor marijuana-specific substance use disorders were associated with hospitalization. In contrast, substance use disorders for other illicit drugs were strongly associated with hospitalization: People with those disorders had 2.2 times higher odds of hospitalization relative to abstainers. A more detailed understanding of health care use in different substance user groups could inform the ongoing expansion of substance use services in the United States. PMID- 26733697 TI - Formerly Homeless People Had Lower Overall Health Care Expenditures After Moving Into Supportive Housing. AB - The provision of supportive housing is often recognized as important public policy, but it also plays a role in health care reform. Health care costs for the homeless reflect both their medical complexity and psychosocial risk factors. Supportive housing attempts to moderate both by providing stable places to live along with on-site integrated health services. In this pilot study we used a mixture of survey and administrative claims data to evaluate outcomes for formerly homeless people who were living in a supportive housing facility in Oregon between 2010 and 2014. Results from the claims analysis showed significantly lower overall health care expenditures for the people after they moved into supportive housing. Expenditure changes were driven primarily by reductions in emergency and inpatient care. Survey data suggest that the savings were not at the expense of quality: Respondents reported improved access to care, stronger primary care connections, and better subjective health outcomes. Together, these results indicate a potential association between supportive housing and reduced health care costs that warrants deeper consideration as part of ongoing health care reforms. PMID- 26733698 TI - House Calls: California Program For Homebound Patients Reduces Monthly Spending, Delivers Meaningful Care. AB - In 2009 HealthCare Partners Affiliates Medical Group, based in Southern California, launched House Calls, an in-home program that provides, coordinates, and manages care primarily for recently discharged high-risk, frail, and psychosocially compromised patients. Its purpose is to reduce preventable emergency department visits and hospital readmissions. We present data over time from this well-established program to provide an example for other new programs that are being established across the United States to serve this population with complex needs. The findings show that the initial House Calls structure, staffing patterns, and processes differed across the geographic areas that it served, and that they also evolved over time in different ways. In the same time period, all areas experienced a reduction in operating costs per patient and showed substantial reductions in monthly per patient health care spending and hospital utilization after enrollment in the House Calls program, compared to the period before enrollment. Despite more than five years of experience, the program structure continues to evolve and adjust staffing and other features to accommodate the dynamic nature of this complex patient population. PMID- 26733699 TI - Patients With High Mental Health Costs Incur Over 30 Percent More Costs Than Other High-Cost Patients. AB - A small proportion of health care users, called high-cost patients, account for a disproportionately large share of health care costs. Most literature on these patients has focused on the entire population. However, high-cost patients whose use of mental health care services is substantial are likely to differ from other members of the population. We defined a mental health high-cost patient as someone for whom mental health-related services accounted for at least 50 percent of total health care costs. We examined these patients' health care utilization and costs in Ontario, Canada. We found that their average cost for health care, in 2012 Canadian dollars, was $31,611. In contrast, the cost was $23,681 for other high-cost patients. Mental health high-cost patients were younger, lived in poorer neighborhoods, and had different health care utilization patterns, compared to other high-cost patients. These findings should be considered when implementing policies or interventions to address quality of care for mental health patients so as to ensure that mental health high-cost patients receive appropriate care in a cost-effective manner. Furthermore, efforts to manage mental health patients' health care use should address their complex profile through integrated multidisciplinary health care delivery. PMID- 26733700 TI - Palliative Care Teams' Cost-Saving Effect Is Larger For Cancer Patients With Higher Numbers Of Comorbidities. AB - Patients with multiple serious conditions account for a high proportion of health care spending. Such spending is projected to continue to grow substantially as a result of increased insurance eligibility, the ever-rising cost of care, the continued use of nonbeneficial high-intensity treatments at the end of life, and demographic changes. We evaluated the impact of palliative care consultation on hospital costs for adults with advanced cancer, excluding those with dementia. We found that compared to usual care, the receipt of a palliative care consultation within two days of admission was associated with 22 percent lower costs for patients with a comorbidity score of 2-3 and with 32 percent lower costs for those with a score of 4 or higher. Earlier consultation was also found to be systematically associated with a larger cost-saving effect for all subsamples defined by multimorbidity. Given ongoing workforce shortages, targeting early specialist palliative care to hospitalized patients with advanced cancer and higher numbers of serious concurrent conditions could improve care while complementing strategies to curb the growth of health spending. PMID- 26733701 TI - For Working-Age Cancer Survivors, Medical Debt And Bankruptcy Create Financial Hardships. AB - The rising medical costs associated with cancer have led to considerable financial hardship for patients and their families in the United States. Using data from the LIVESTRONG 2012 survey of 4,719 cancer survivors ages 18-64, we examined the proportions of survivors who reported going into debt or filing for bankruptcy as a result of cancer, as well as the amount of debt incurred. Approximately one-third of the survivors had gone into debt, and 3 percent had filed for bankruptcy. Of those who had gone into debt, 55 percent incurred obligations of $10,000 or more. Cancer survivors who were younger, had lower incomes, and had public health insurance were more likely to go into debt or file for bankruptcy, compared to those who were older, had higher incomes, and had private insurance, respectively. Future longitudinal population-based studies are needed to improve understanding of financial hardship among US working-age cancer survivors throughout the cancer care trajectory and, ultimately, to help stakeholders develop evidence-based interventions and policies to reduce the financial hardship of cancer. PMID- 26733702 TI - Medicaid Tobacco Cessation: Big Gaps Remain In Efforts To Get Smokers To Quit. AB - Medicaid enrollees are about twice as likely as the general US population to smoke tobacco: 32 percent of people in the program identify themselves as smokers. This article provides the first data about the effectiveness of state Medicaid programs in promoting smoking cessation. Our analysis of Medicaid enrollees' use of cessation medications found that about 10 percent of current smokers received cessation medications in 2013. Every state Medicaid program covers cessation benefits, but the use of these medications varies widely, with the rate in Minnesota being thirty times higher than that in Texas. Most states could increase their efforts to help smokers quit, working with public health agencies, managed care plans, and others. In 2013 Medicaid spent $103 million on cessation medications-less than 0.25 percent of the estimated cost to Medicaid of smoking-related diseases. Additionally, states that have not expanded Medicaid eligibility in the wake of the Affordable Care Act have higher smoking prevalence and lower utilization rates of cessation medication, compared to expansion states. Given these factors, nonexpansion states will have a greater public health burden related to smoking. Medicaid and public health agencies should work together to make smoking cessation a priority for Medicaid beneficiaries. PMID- 26733703 TI - Premium-Based Financial Incentives Did Not Promote Workplace Weight Loss In A 2013-15 Study. AB - Employers commonly use adjustments to health insurance premiums as incentives to encourage healthy behavior, but the effectiveness of those adjustments is controversial. We gave 197 obese participants in a workplace wellness program a weight loss goal equivalent to 5 percent of their baseline weight. They were randomly assigned to a control arm, with no financial incentive for achieving the goal, or to one of three intervention arms offering an incentive valued at $550. Two intervention arms used health insurance premium adjustments, beginning the following year (delayed) or in the first pay period after achieving the goal (immediate). A third arm used a daily lottery incentive separate from premiums. At twelve months there were no statistically significant differences in mean weight change either between the control group (whose members had a mean gain of 0.1 pound) and any of the incentive groups (delayed premium adjustment, -1.2 pound; immediate premium adjustment, -1.4 pound; daily lottery incentive, -1.0 pound) or among the intervention groups. The apparent failure of the incentives to promote weight loss suggests that employers that encourage weight reduction through workplace wellness programs should test alternatives to the conventional premium adjustment approach by using alternative incentive designs, larger incentives, or both. PMID- 26733704 TI - Mexico's Seguro Popular Appears To Have Helped Reduce The Risk Of Preterm Delivery Among Women With Low Education. AB - Beginning in 2001 Mexico established Seguro Popular, a health insurance scheme aimed at providing coverage to its large population of uninsured people. While recent studies have evaluated the health benefits of Seguro Popular, evidence on perinatal health outcomes is lacking. We conducted a population-based study using Mexican birth certificate data for 2010 to assess the relationship between enrollment in Seguro Popular and preterm delivery among first-time mothers with singleton births in Mexico. Seguro Popular enrollees with no formal education had a far greater reduction in risk of preterm delivery, while enrollees with any formal education experienced only slight reduction in risk, after maternal age, marital status, education level, mode of delivery, and trimester in which prenatal care was initiated were controlled for. Seguro Popular appears to facilitate access to health services among mothers with low levels of education, reducing their risk for preterm delivery. Providing broad-scale health insurance coverage may help improve perinatal health outcomes in this vulnerable population. PMID- 26733705 TI - Homicides In Mexico Reversed Life Expectancy Gains For Men And Slowed Them For Women, 2000-10. AB - Life expectancy in Mexico increased for more than six decades but then stagnated in the period 2000-10. This decade was characterized by the enactment of a major health care reform-the implementation of the Seguro Popular de Salud (Popular Health Insurance), which was intended to provide coverage to the entire Mexican population-and by an unexpected increase in homicide mortality. We assessed the impact on life expectancy of conditions amenable to medical service-those sensitive to public health policies and changes in behaviors, homicide, and diabetes-by analyzing mortality trends at the state level. We found that life expectancy among males deteriorated from 2005 to 2010, compared to increases from 2000 to 2005. Females in most states experienced small gains in life expectancy between 2000 and 2010. The unprecedented rise in homicides after 2005 led to a reversal in life expectancy increases among males and a slowdown among females in most states in the first decade of the twenty-first century. PMID- 26733706 TI - Both The 'Private Option' And Traditional Medicaid Expansions Improved Access To Care For Low-Income Adults. AB - Under the Affordable Care Act, thirty states and the District of Columbia have expanded eligibility for Medicaid, with several states using Medicaid funds to purchase private insurance (the "private option"). Despite vigorous debate over the use of private insurance versus traditional Medicaid to provide coverage to low-income adults, there is little evidence on the relative merits of the two approaches. We compared the first-year impacts of traditional Medicaid expansion in Kentucky, the private option in Arkansas, and nonexpansion in Texas by conducting a telephone survey of two distinct waves of low-income adults (5,665 altogether) in those three states in November-December 2013 and twelve months later. Using a difference-in-differences analysis, we found that the uninsurance rate declined by 14 percentage points in the two expansion states, compared to the nonexpansion state. In the expansion states, again compared to the nonexpansion state, skipping medications because of cost and trouble paying medical bills declined significantly, and the share of individuals with chronic conditions who obtained regular care increased. Other than coverage type and trouble paying medical bills (which decreased more in Kentucky than in Arkansas), there were no significant differences between Kentucky's traditional Medicaid expansion and Arkansas's private option, which suggests that both approaches improved access among low-income adults. PMID- 26733707 TI - Affordable Care Act Medicaid Expansion Reduced Uninsured Hospital Stays In 2014. PMID- 26733708 TI - Medicaid Expansion Did Not Result In Significant Employment Changes Or Job Reductions In 2014. AB - Medicaid expansion undertaken through the Affordable Care Act (ACA) is already producing major changes in insurance coverage and access to care, but its potential impacts on the labor market are also important policy considerations. Economic theory suggests that receipt of Medicaid might benefit workers who would no longer be tied to specific jobs to receive health insurance (known as job lock), giving them more flexibility in their choice of employment, or might encourage low-income workers to reduce their hours or stop working if they no longer need employment-based insurance. Evidence on labor changes after previous Medicaid expansions is mixed. To view the impact of the ACA on current labor market participation, we analyzed labor-market participation among adults with incomes below 138 percent of the federal poverty level, comparing Medicaid expansion and nonexpansion states and Medicaid-eligible and -ineligible groups, for the pre-ACA period (2005-13) and the first fifteen months of the expansion (January 2014-March 2015). Medicaid expansion did not result in significant changes in employment, job switching, or full- versus part-time status. While we cannot exclude the possibility of small changes in these outcomes, our findings rule out the large change found in one influential pre-ACA study; furthermore, they suggest that the Medicaid expansion has had limited impact on labor-market outcomes thus far. PMID- 26733709 TI - Little Change Seen In Part-Time Employment As A Result Of The Affordable Care Act. PMID- 26733710 TI - Understanding Medicare Hospital Readmission Rates And Differing Penalties Between Safety-Net And Other Hospitals. AB - Since the implementation of Medicare's Hospital Readmissions Reduction Program in 2012, concerns have been raised about the effect its payment penalties for excess readmissions may have on safety-net hospitals. A number of policy solutions have been proposed to ensure that the program does not unfairly penalize safety-net institutions, which treat a disproportionate number of patients with low socioeconomic status. We examined the extent to which the program's current risk adjustment factors, measures of patient socioeconomic status, and hospital-level factors explain the observed differences in readmission rates between safety-net and other hospitals. Our analyses suggest that patient socioeconomic status can explain some of the difference in readmission rates but that unmeasured factors such as hospitals' performance may also play a role. We also found that safety net hospitals have experienced only slightly higher readmission penalties under the program than other hospitals have. Together, these findings suggest the need for a careful evaluation of policy alternatives that factor socioeconomic status into penalty calculations for excess readmissions to determine whether such alternatives could have a significant impact on penalties while remaining consistent with overall objectives for delivery system transformation. PMID- 26733711 TI - Health Care Spending Slowdown From 2000 To 2010 Was Driven By Lower Growth In Cost Per Case, According To A New Data Source. AB - In 2015 the Bureau of Economic Analysis released an experimental set of measures referred to as the Health Care Satellite Account, which tracks national health care spending by medical condition. These statistics improve the understanding of the health care sector by blending medical claims data and survey data to present measures of national spending and cost of treatment by condition. This article introduces key aspects of the new account and uses it to study the health spending slowdown that occurred in the period 2000-10. Our analysis of the account reveals that the slowdown was driven by a reduction of growth in cost per case but that spending trends varied greatly across conditions and differentially affected the slowdown. More than half of the overall slowdown was accounted for by a slowdown in spending on circulatory conditions. However, there were more dramatic slowdowns in spending on categories such as endocrine system and musculoskeletal conditions than in spending on other categories, such as cancers. PMID- 26733712 TI - Patient-Centered Medical Home Adoption: Results From Aligning Forces For Quality. AB - To improve health care quality within communities, increasing numbers of multistakeholder alliances-groups of payers, purchasers, providers, and consumers have been created. We used data from two rounds (conducted in July 2007-March 2009 and January 2012-November 2013) of a large nationally representative survey of small and medium-size physician practices. We examined whether the adoption of patient-centered medical home processes spread more rapidly in fourteen Robert Wood Johnson Foundation Aligning Forces for Quality communities, where multistakeholder health care alliances promoted their use, than in other communities. We found no difference in the overall growth of adoption of the processes between the two types of communities. However, improvement on a care coordination subindex was 7.17 percentage points higher in Aligning Forces for Quality communities than in others. Despite the enthusiasm for quality improvement led by multistakeholder alliances, such alliances may not be a panacea for spreading patient-centered medical home processes across a community. PMID- 26733713 TI - Bitten: A Patient With Tickborne Disease Struggles To Find The Right Provider. PMID- 26733714 TI - Foundation Funding To Improve Rural Health Care. PMID- 26733716 TI - New Guidelines For Breast Cancer Screening. PMID- 26733717 TI - Errata. PMID- 26733718 TI - TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria. AB - The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review. PMID- 26733719 TI - ESCRT-III on endosomes: new functions, new activation pathway. AB - The multivesicular body (MVB) pathway sorts ubiquitinated membrane cargo to intraluminal vesicles (ILVs) within the endosome, en route to the lysosomal lumen. The pathway involves the sequential action of conserved protein complexes [endosomal sorting complexes required for transport (ESCRTs)], culminating in the activation by ESCRT-II of ESCRT-III, a membrane-sculpting complex. Although this linear pathway of ESCRT activation is widely accepted, a study by Luzio and colleagues in a recent issue of the Biochemical Journal suggests that there is greater complexity in ESCRT-III activation, at least for some MVB cargoes. They show that ubiquitin-dependent sorting of major histocompatibility complex (MHC) class I to the MVB requires the central ESCRT-III complex but does not involve either ESCRT-II or functional links between ESCRT-II and ESCRT-III. Instead, they propose that MHC class I utilizes histidine-domain protein tyrosine phosphatase (HD-PTP), a non-canonical ESCRT interactor, to promote ESCRT-III activation. PMID- 26733720 TI - Comparing global alcohol and tobacco control efforts: network formation and evolution in international health governance. AB - Smoking and drinking constitute two risk factors contributing to the rising burden of non-communicable diseases in low- and middle-income countries. Both issues have gained increased international attention, but tobacco control has made more sustained progress in terms of international and domestic policy commitments, resources dedicated to reducing harm, and reduction of tobacco use in many high-income countries. The research presented here offers insights into why risk factors with comparable levels of harm experience different trajectories of global attention. The analysis focuses particular attention on the role of dedicated global health networks composed of individuals and organizations producing research and engaging in advocacy on a given health problem. Variation in issue characteristics and the policy environment shape the opportunities and challenges of global health networks focused on reducing the burden of disease. What sets the tobacco case apart was the ability of tobacco control advocates to create and maintain a consensus on policy solutions, expand their reach in low- and middle-income countries and combine evidence-based research with advocacy reaching beyond the public health-centered focus of the core network. In contrast, a similar network in the alcohol case struggled with expanding its reach and has yet to overcome divisions based on competing problem definitions and solutions to alcohol harm. The tobacco control network evolved from a group of dedicated individuals to a global coalition of membership-based organizations, whereas the alcohol control network remains at the stage of a collection of dedicated and like-minded individuals. PMID- 26733721 TI - Role of matrix metalloproteinase-9 in chronic kidney disease: a new biomarker of resistant albuminuria. AB - Resistant albuminuria, developed under adequate chronic blockade of the renin angiotensin system, is a clinical problem present in a small number of patients with chronic kidney disease (CKD). The mechanism underlying this resistant albuminuria remains unknown. Matrix metalloproteinases (MMPs) are involved in the pathophysiology of cardiovascular and renal diseases. In the present study we tested the role of MMPs in resistant albuminuria. First we evaluated gelatinase MMP-2 and MMP-9 activity by zymography in the Munich Wistar Fromter (MWF) rat, a model of progressive albuminuria, and subsequently in patients with resistant albuminuria. Markers of oxidative stress were observed in the kidneys of MWF rats, together with a significant increase in pro-MMP-2 and active MMP-9 forms. These changes were normalized together with reduced albuminuria in consomic MWF 8(SHR) rats, in which chromosome 8 of MWF was replaced with the respective chromosome from spontaneously hypertensive rats. The MMP-2 and MMP-9 protein levels were similar in patients with normal and resistant albuminuria; however, high circulating levels of collagen IV, a specific biomarker of tissue collagen IV degradation, were observed in patients with resistant albuminuria. These patients showed a significant increase in gelatinase MMP-2 and MMP-9 activity, but only a significant increase in the active MMP-9 form quantified by ELISA, which correlated significantly with the degree of albuminuria. Although the expression of the tissue inhibitor of MMP-9 (TIMP)-1 was similar, a novel AlphaLISA assay demonstrated that the MMP-9-TIMP-1 interaction was reduced in patients with resistant albuminuria. It is of interest that oxidized TIMP-1 expression was higher in patients with resistant albuminuria. Therefore, increased circulating MMP-9 activity is associated with resistant albuminuria and a deleterious oxidative stress environment appears to be the underlying mechanism. These changes might contribute to the progression of CKD in these patients. PMID- 26733722 TI - Mechanism of vascular dysfunction due to circulating factors in women with pre eclampsia. AB - Circulating factors have been proposed to play a major role in the pathophysiology of endothelial dysfunction in pre-eclampsia (PE), which is defined as new-onset hypertension with proteinuria after 20 weeks of gestation. However, the mechanisms leading to altered vascular reactivity remain unclear. We hypothesized that circulating factors lead to endothelial dysfunction by increasing oxidative stress and reducing nitric oxide (NO) and prostaglandin (PG) bioavailability. Pregnant rat uterine and mesenteric arteries were incubated overnight with 3% normotensive (NP) or PE plasma collected from women upon admission to hospital. Responses to methacholine (MCh) were obtained using wire myography to assess endothelial function pathways. Vascular superoxide level was measured via dihydroethidium staining and nitric oxide synthase (NOS) expression via Western blots. PE plasma significantly increased superoxide levels and impaired endothelial dysfunction in uterine arteries (Emax 79.9+/-5.6% compared with 44.9+/-6.3%, P=0.0004), which was restored in the presence of oxidant scavengers or PG synthesis inhibition. Uterine artery vasodilation was abolished in the presence of pan-NOS inhibitor (P<0.0001) in both NP- and PE-treated vessels, but inducible nitric oxide synthase (iNOS)-dependent vasodilation was present only in NP-treated arteries. Uterine arteries exposed to PE plasma exhibit an increased endothelial NOS expression and a decreased iNOS expression. PE plasma did not alter endothelial function in mesenteric arteries, suggesting that the effect of circulating factors was vascular-bed-specific. We have shown that circulating factors lead to endothelial dysfunction via altered oxidative stress and vasodilator pathways. The present study contributes to our understanding of the pathophysiology and finding a potential target for intervention in PE. PMID- 26733723 TI - Extracorporeal membrane oxygenation-related brain haemorrhages. PMID- 26733724 TI - Tongue infarction due to giant cell arteritis. PMID- 26733725 TI - Ethnography as a methodological descriptor: the editors' reply. PMID- 26733726 TI - Recast the debate about preventable readmissions. PMID- 26733727 TI - Matrix metalloproteinases 2 and 9 and MMP9/NGAL complex activity in women with PCOS. AB - It is believed that matrix metalloproteinases (MMPs) play important roles in follicular development and pathogenesis of polycystic ovary syndrome (PCOS). However, conflicting results are available about the alteration of MMP2 and MMP9 concentrations or activities in PCOS. In fact, there is no study entirely investigating both concentration and activity of these MMPs and serum levels of their tissue inhibitors TIMP2 and TIMP1, as well as lipocalin-bound form of MMP9 (MMP9/NGAL). Therefore, the thoroughness of previous studies is questionable. This study was conducted to determine circulatory concentration of MMP2, MMP9, MMP9/NGAL complex, TIMP1 and TIMP2 as well as gelatinase activities of MMP2, MMP9 and MMP9/NGAL complex in women with PCOS and controls. Mean age and BMI as well as serum levels of total cholesterol, triacylglycerol, HDL-C, LDL-C, fasting blood sugar (FBS), insulin, estradiol and sex hormone-binding globulin did not differ between groups, whereas a marked decrease in FSH and significant increases in LH, LH/FSH ratio, testosterone and free androgen index were observed. Women with PCOS and controls showed closed concentrations of MMP2, MMP9, MMP9/NGAL, TIMP1 and TIMP2. Gelatinase activity of MMP9 was found significantly higher in PCOS than in controls (64.53+/-15.32 vs 44.61+/-18.95 respectively) while patients and healthy subjects showed similar activities of MMP2 and MMP9/NGAL complex. Additionally, PCOS patients showed a higher MMP9/TIMP1 ratio compared with control women. Direct correlations were also observed between circulatory MMP9 level and the concentration and activity of MMP9/NGAL complex. In conclusion, based on the results of present study, we believe that MMP9 may be involved in the pathogenesis of PCOS. PMID- 26733728 TI - Ring test evaluation of the detection of influenza A virus in swine oral fluids by real-time reverse-transcription polymerase chain reaction and virus isolation. AB - The probability of detecting influenza A virus (IAV) in oral fluid (OF) specimens was calculated for each of 13 assays based on real-time reverse-transcription polymerase chain reaction (rRT-PCR) and 7 assays based on virus isolation (VI). The OF specimens were inoculated with H1N1 or H3N2 IAV and serially diluted 10 fold (10(-1) to 10(-8)). Eight participating laboratories received 180 randomized OF samples (10 replicates * 8 dilutions * 2 IAV subtypes plus 20 IAV-negative samples) and performed the rRT-PCR and VI procedure(s) of their choice. Analysis of the results with a mixed-effect logistic-regression model identified dilution and assay as variables significant (P < 0.0001) for IAV detection in OF by rRT PCR or VI. Virus subtype was not significant for IAV detection by either rRT-PCR (P = 0.457) or VI (P = 0.101). For rRT-PCR the cycle threshold (Ct) values increased consistently with dilution but varied widely. Therefore, it was not possible to predict VI success on the basis of Ct values. The success of VI was inversely related to the dilution of the sample; the assay was generally unsuccessful at lower virus concentrations. Successful swine health monitoring and disease surveillance require assays with consistent performance, but significant differences in reproducibility were observed among the assays evaluated. PMID- 26733729 TI - Oncolytic reovirus synergizes with chemotherapeutic agents to promote cell death in canine mammary gland tumor. AB - The oncolytic effects of reovirus in various cancers have been proven in many clinical trials in human medicine. Oncolytic virotherapy using reovirus for canine cancers is being developed in our laboratory. The objective of this study was to examine the synergistic anti-cancer effects of a combination of reovirus and low doses of various chemotherapeutic agents on mammary gland tumors (MGTs) in dogs. The first part of this study demonstrated the efficacy of reovirus in canine MGTs in vitro and in vivo. Reovirus alone exerted significant cell death by means of caspase-dependent apoptosis in canine MGT cell lines. A single injection of reovirus impeded growth of canine MGT tumors in xenografted mice, but was insufficient to induce complete tumor regression. The second part of this study highlighted the anti-tumor effects of reovirus in combination with low doses of paclitaxel, carboplatin, gemcitabine, or toceranib. Enhanced synergistic activity was observed in the MGT cell line treated concomitantly with reovirus and in all the chemotherapeutic agents except toceranib. In addition, combining reovirus with paclitaxel or gemcitabine at half dosage of half maximal inhibitory concentration (IC50) enhanced cytotoxicity by activating caspase 3. Our data suggest that the combination of reovirus and low dose chemotherapeutic agents provides an attractive option in canine cancer therapy. PMID- 26733730 TI - Effect of sample pooling and transport conditions on the clinical sensitivity of a real-time polymerase chain reaction assay for Campylobacter fetus subsp. venerealis in preputial samples from bulls. AB - The diagnosis of bovine genital campylobacteriosis (BGC) presents significant challenges, as traditional methods lack sensitivity when prolonged transport of samples is required. Assays of preputial samples by means of real-time polymerase chain reaction (PCR) provide good sensitivity and high throughput capabilities. However, there is limited information on the acceptable duration of transport and temperature during transport of samples. In addition, the use of pooled samples has proven to be a valuable strategy for the diagnosis of other venereal diseases in cattle. The objectives of the present study were to determine the effect of sample pooling and of transport time and temperature on the clinical sensitivity of a real-time quantitative PCR (qPCR) assay for Campylobacter fetus subsp. venerealis in preputial samples from beef bulls. Eight infected bulls and 176 virgin yearling bulls were used as the source of samples. The qPCR sensitivity was comparable for unpooled samples and pools of 5 samples, whereas sensitivity was decreased for pools of 10 samples. Sensitivity for the various pool sizes improved with repeated sampling. For shorter-term transport (2 and 48 h), sensitivity was greatest when the samples were stored at 4 degrees C and 30 degrees C, whereas for longer-term transport (96 h) sensitivity was greatest when the samples were stored at -20 degrees C. The creation of pools of 5 samples is therefore a good option to decrease costs when screening bulls for BGC with the qPCR assay of direct preputial samples. Ideally the samples should be stored at 4 degrees C and arrive at the laboratory within 48 h of collection, but when that is not possible freezing at -20 degrees C could minimize the loss of sensitivity. PMID- 26733731 TI - Generation of Salmonella ghost cells expressing fimbrial antigens of enterotoxigenic Escherichia coli and evaluation of their antigenicity in a murine model. AB - Salmonella Typhimurium ghost cells expressing K88ab, K88ac, K99, and FasA fimbriae of enterotoxigenic Escherichia coli (ETEC) in their envelopes were constructed. The genes encoding the fimbriae were individually cloned into an expression plasmid, pMMP81, carrying the asd gene, which was subsequently electroporated into the Deltaasd S. Typhimurium mutant. Plasmid pJHLP99, carrying the phiX174 lysis gene E, was also subsequently electroporated into the Salmonella mutant. The presence of the individual fimbriae on the ghost cells was examined by Western blot analysis. Forty BALB/c mice were equally divided into 2 groups of 20 mice each. Group A mice were intramuscularly vaccinated with a mixture of the 4 ghost cells expressing the individual fimbriae. The group B mice were inoculated with sterile phosphate-buffered saline as a control. The antigen specific serum IgG concentrations were significantly higher in group A than in group B from week 2 until week 6 after inoculation. In addition, the antigen specific IgA concentrations in fecal samples were significantly higher in group A than in group B at week 2 after inoculation. A large difference between the groups in the number of antigen-specific IgA-secreting cells in the small intestine was observed by immunohistochemical study. Also, the splenic lymphocyte proliferative responses were significantly greater in group A than in the control mice. These results suggest that vaccination with our Salmonella ghost cells can induce both humoral and cell-mediated immune responses and that the increased number of antigen-specific IgA-secreting cells in the small intestine may be correlated with the elevated fecal IgA immune response. PMID- 26733732 TI - Drug use and antimicrobial resistance among Escherichia coli and Enterococcus spp. isolates from chicken and turkey flocks slaughtered in Quebec, Canada. AB - An observational study was conducted of chicken and turkey flocks slaughtered at federal processing plants in the province of Quebec, Canada. The objectives were to estimate prevalence of drug use at hatchery and on farm and to identify antimicrobial resistance (AMR) in cecal Escherichia coli and Enterococcus spp. isolates and factors associated with AMR. Eighty-two chicken flocks and 59 turkey flocks were sampled. At the hatchery, the most used antimicrobial was ceftiofur in chickens (76% of flocks) and spectinomycin in turkeys (42% of flocks). Virginiamycin was the antimicrobial most frequently added to the feed in both chicken and turkey flocks. At least 1 E. coli isolate resistant to third generation cephalosporins was present in all chicken flocks and in a third of turkey flocks. Resistance to tetracycline, streptomycin, and sulfisoxazole was detected in > 90% of flocks for E. coli isolates. Antimicrobial resistance (AMR) was observed to bacitracin, erythromycin, lincomycin, quinupristin-dalfopristin, and tetracycline in both chicken and turkey flocks for Enterococcus spp. isolates. No resistance to vancomycin was observed. The use of ceftiofur at hatchery was significantly associated with the proportion of ceftiofur-resistant E. coli isolates in chicken flocks. In turkey flocks, ceftiofur resistance was more frequent when turkeys were placed on litter previously used by chickens. Associations between drug use and resistance were observed with tetracycline (turkey) in E. coli isolates and with bacitracin (chicken and turkey), gentamicin (turkey), and tylosin (chicken) in Enterococcus spp. isolates. Further studies are needed to provide producers and veterinarians with alternative management practices and tools in order to reduce the use of antimicrobial feed additives in poultry. PMID- 26733733 TI - Methaphylactic effect of tulathromycin treatment on rumen fluid parameters in feedlot beef cattle. AB - The aim of this study was to evaluate the effect of tulathromycin as a bovine respiratory disease (BRD) metaphylactic treatment on rumen fluid parameters in feedlot cattle in an intensive livestock production farm. One hundred beef cattle, immediately after housing, were divided in 2 equal groups: 50 animals with metaphylactic treatment against BRD (treated group; tulathromycin at 2.5 mg/kg BW) and 50 animals with placebo treatment (control group). Rumen fluid samples were collected from each animal by rumenocentesis in 3 periods: 1 d (T1), 8 d (T8), and 15 d (T15) after treatment. Rumen pH was determined by ruminal fluid using portable pH meter. Total volatile fatty acids (total VFA) were evaluated by high performance liquid chromatography (HPLC). All animals were singularly weighed at T1 and T15. Two-way analysis of variance (ANOVA) was applied to determine significant effects of treatment (treated group versus control group) and period (T1, T8, and T15) on rumen fluid parameters and body weight. No clinical signs of BRD or other related diseases were recorded during the periods of study from any animal. Statistically significant differences (P < 0.05) were found between treated group and control group for mean values of ruminal pH (6.02 versus 5.89) and total VFA (5.84 versus 5.13) at 8 d after treatment. The weight gain (Delta) showed an average increase of 8.6 kg in treated group (P < 0.05). The trends of ruminal pH and VFA values suggest an effect of tulathromycin as BRD metaphylactic treatment on the modulation of rumen fermentation, particularly 8 d after administration. PMID- 26733734 TI - Distribution and activity levels of matrix metalloproteinase 2 and 9 in canine and feline osteosarcoma. AB - Overexpression of matrix metalloproteinases (MMPs) has been associated with increased tumor aggressiveness and metastasis dissemination. We investigated whether the contrasting metastatic behavior of feline and canine osteosarcoma is related to levels and activities of MMP2 and MMP9. Zymography and immunohistochemistry were used to determine expression levels of MMP2 and MMP9 in canine and feline osteosarcoma. Using immunohistochemistry, increased MMP9 levels were identified in most canine osteosarcomas, whereas cat samples more often displayed moderate levels. High levels of pro-MMP9, pro-MMP2, and active MMP2 were detected by gelatin zymography in both species, with significantly higher values for active MMP2 in canine osteosarcoma. These findings indicate that MMP2 is probably involved in canine and feline osteosarcoma and their expression and activity could be associated with the different metastatic behavior of canine and feline osteosarcoma. PMID- 26733735 TI - Cytological analysis of bronchoalveolar lavage fluid acquired by bronchoscopy in healthy ferrets: A pilot study. AB - The objective of this study was to investigate the normal cytological evaluation of bronchoalveolar lavage (BAL) fluid in healthy adult ferrets (N = 12). These ferrets underwent bronchoscopy and BAL using sterile saline [1.5 mL/kg body weight (BW)]. Percentage of fluid recovered, total leukocyte count, differential leukocyte count, and cell count of the epithelial lining fluid (ELF) were determined. The mean percentage of lavage volume recovered from the right lung and left lung were 67.8 +/- 14.9% and 69.7 +/- 20.0%, respectively. Gender (P = 0.12) and weight (P = 0.17) did not significantly affect the mean percentage of recovered volume. The mean percentage of recovered volume (P = 0.47) and the mean leukocyte count (P = 0.17) from the right and left lung were not significantly different. Macrophages were the main leukocyte component of the lavages, followed by neutrophils, lymphocytes, and eosinophils. The mean proportion of ELF in BAL fluid was 9.3 +/- 3.7% v/v. Bronchoscopy is clinically useful for collecting good quality BAL samples for cytological analysis in ferrets. The leucocyte differential was established, which may help veterinarians to make better clinical decisions when treating respiratory disease. Further studies are required with a larger group in order to establish the healthy reference intervals for BAL values in ferrets. PMID- 26733736 TI - Prevalence and risk factors for Campylobacter spp., Salmonella spp., Coxiella burnetii, and Newcastle disease virus in feral pigeons (Columba livia) in public areas of Montreal, Canada. AB - Feral pigeons (Columbia livia) can harbor a range of zoonotic pathogens. A transversal study was undertaken to estimate the prevalence of feral pigeons infected by various pathogens in public areas in Montreal, Quebec. Cloacal swabs from captured birds were cultured for Salmonella spp. and Campylobacter spp. and tested by real-time polymerase chain reaction (RT-PCR) for the detection of Coxiella burnetii. An oropharyngeal swab was also submitted to real-time reverse transcription polymerase chain reaction (RRT-PCR) for the detection of Newcastle disease virus. Among the 187 pigeons tested from 10 public areas, 9.1% (95% CI: 3.0 to 15.2) were positive for Campylobacter spp. with all strains identified as Campylobacter jejuni. The Campylobacter status of birds was not associated with individual characteristics of birds, with the exception of body score. None of the pigeons tested positive for the other pathogens. Direct or indirect contacts with feral pigeons may constitute a potential risk for Campylobacter infection in humans. PMID- 26733737 TI - Assessment of stability of ketamine-xylazine preparations with or without acepromazine using high performance liquid chromatography-mass spectrometry. AB - The objective of this study was to evaluate the stability of 3 distinct preparations of ketamine and xylazine, with or without acepromazine, stored at room temperature or at 4 degrees C for 1, 2, and 3 mo. Drug concentrations were compared to fresh solutions, using a high performance liquid chromatography-mass spectrometry/selected-ion monitoring (HPLC-MS/SIM) assay. The concentrations of ketamine and xylazine, diluted in physiological saline, did not change over time at room temperature or at 4 degrees C. However, acepromazine concentrations decreased over time when stored at room temperature. In contrast, undiluted ketamine-xylazine preparations gradually decreased in concentration when stored at room temperature. All of the drug concentrations remained above 90% of their original concentration when stored at 4 degrees C. In conclusion, when diluted in physiological saline, ketamine-xylazine cocktails can be stored for 3 mo, whereas undiluted cocktails can lose efficacy over 3 mo at room temperature. Storage at 4 degrees C could preserve drug stability. PMID- 26733738 TI - Evaluation of growth differentiation factor 11 (GDF11) levels in dogs with chronic mitral valve insufficiency. AB - Growth differentiation factor 11 (GDF11) regulates cell growth and differentiation in both embryonic and adult tissues. Circulating GDF11 levels have recently been reported to be significantly lower in aging mice and restoration of GDF11 reversed age-related cardiac hypertrophy in old mice. Here, we evaluated the potential of serum levels of GDF11 as a circulating biomarker in dogs at different stages of heart failure, due to chronic mitral valve insufficiency (CMVI). We found no significant differences in serum GDF11 levels between dogs at different stages of CMVI-associated heart failure. Furthermore, the circulating levels of GDF11 did not correlate with age, body weight, echocardiographic variables, and the severity of CMVI-induced heart failure in dogs. PMID- 26733740 TI - Role of contrast-enhanced ultrasound (CEUS) in the diagnosis of endometrial pathology. AB - Ultrasound is the reference imaging procedure used for the exploration of endometrial pathology. As medical procedures improve and the requirements of modern medicine become more demanding, gray-scale ultrasound is insufficient in establishing gynecological diagnosis. Thus, more complex examination techniques are required: Doppler ultrasound, contrast-enhanced ultrasound (CEUS), 3D ultrasound, etc. Contrast-enhanced ultrasound is a special examination technique that gains more and more ground. This allows a detailed real-time evaluation of microcirculation in a certain territory, which is impossible to perform by Doppler ultrasound. The aim of this review is to synthesize current knowledge regarding CEUS applications in endometrial pathology, to detail the technical aspects of endometrial CEUS and the physical properties of the equipment and contrast agents used, as well as to identify the limitations of the method. PMID- 26733741 TI - Measurement of current perception thresholds using the Neurometer((r)) - applicability in diabetic neuropathy. AB - The incidence of diabetes mellitus is continuously growing worldwide, while the specific chronic complications that it induces have a negative impact on life expectancy andquality, entailing extremely high costs of healthcare services. Diabetic peripheral neuropathy is one of the most common chronic complications of diabetes, affecting almost half of diabetic people during life. This review aims at summarizing the evidence on the advantages and the usefulness of current perception threshold measurement for peripheral diabetic neuropathy assessment. Among the different methods used for the screening and diagnosis of diabetic neuropathy, measurement of current perception threshold using the Neurometer(r) has the ability to assess three sub-types of nerve fiber by producing transcutaneous electrical stimuli at frequencies of 2000, 250 and 5 Hz. Current evidence shows that this method provides a useful, noninvasive evaluation technique of patients with peripheral nervous system disorders, being able to detect neuropathy in the earliest and asymptomatic stages. PMID- 26733742 TI - MicroRNAs as non-invasive screening biomarkers of colorectal cancer. AB - Colorectal cancer is a major cause of cancer-associated deaths in the world. Early detection would be greatly enhanced if accurate and cost-effective diagnostic biomarkers for this disease were accessible. The development of such a blood test will evidently lower the screening costs in regards of colorectal cancer detection. Lately, it has been suggested that microRNA diagnostic biomarkers are feasible new screening methods for colorectal cancer. This review summarizes the diagnostic potential of circulating microRNA biomarkers in relation with colorectal cancer, as well as current methods to detect them. PMID- 26733743 TI - The role of ketamine in the treatment of chronic cancer pain. AB - BACKGROUND AND AIM: Ketamine is a drug used for the induction and maintenance of general anesthesia, for the treatment of postoperative and posttraumatic acute pain, and more recently, for the reduction of postoperative opioid requirements. The main mechanism of action of ketamine is the antagonization of N-methyl-D aspartate (NMDA) receptors that are associated with central sensitization. In the pathogenesis of chronic pain and particularly in neuropathic pain, an important role is played by the activation of NMDA receptors. Although ketamine is indicated and used for the treatment of chronic cancer pain as an adjuvant to opioids, there are few clinical studies that clearly demonstrate the effectiveness of ketamine in this type of pain. The aim of this study is to analyze evidence-based clinical data on the effectiveness and safety of ketamine administration in the treatment of chronic neoplastic pain, and to summarize the evidence-based recommendations for the use of ketamine in the treatment of chronic cancer pain. METHOD: We reviewed the literature from the electronic databases of MEDLINE, COCHRANE, PUBMED, MEDSCAPE (1998-2014), as well as chapters of specialized books (palliative care, pain management, anesthesia). RESULTS: A number of studies support the effectiveness of ketamine in the treatment of chronic cancer pain, one study does not evidence clear clinical benefits for the use of ketamine, and some studies included too few patients to be conclusive. CONCLUSIONS: Ketamine represents an option for neoplasic pain that no longer responds to conventional opioid treatment, but this drug should be used with caution, and the development of potential side effects should be carefully monitored. PMID- 26733744 TI - Considerations on assisted resilience and individualized therapy in bipolar affective disorder, with a clinical case exemplification. AB - Morbidity, mortality and economic consequences of bipolar affective disorder are very important to be evaluated because many of the costs entailed by this psychiatric disorder come from indirect costs due to inadequate diagnosis and treatment and from the characteristics of the affective symptoms itself. Psychotherapy focuses on diagnosis and the newest pharmacotherapy determines a decreasing of the morbidity of the disorder and also of its social and economic burden. However, more studies are necessary, with more heterogeneous patients, to find more predictors regarding the psychosocial consequences and to find more information about the prognosis of the bipolar disorder. In this context, in this paper we discuss the role of assisted resilience and the individualization of the therapy of bipolar affective disorder, especially that the resilience must be seen as a continuum and can be used anytime and in any situation, according to the theory of Geanellos. This idea is reflected in a case presentation of a patient with the diagnosis of bipolar disorder. PMID- 26733745 TI - The role of dental stem cells in regeneration. AB - Mesenchymal stem cells (MSCs) are adult stem cells that have the capacity of rising multiple cell types. A rich source of mesenchymal stem cells is represented by the dental tissues: the periodontal ligament, the dental pulp, the apical papilla, the dental follicle and the deciduous teeth. The aim of this review is to characterize the main dental- derived mesenchymal stem cell population, and to show their important role in tissue regeneration based on their properties : the multi-potency, the high proliferation rate, the differentiation in multiple cell lineages, the high cell viability and the positive expression for mesenchymal cell markers. Tissue regeneration or de novo' formation of craniofacial structures is the future of regenerative medicine, offering a solution for congenital malformations, traumas and other diseases. PMID- 26733746 TI - Statistical reporting in the "Clujul Medical" journal. AB - BACKGROUND AND AIM: Medical research needs statistical analyses to understand the reality of variable phenomena. There are numerous studies showing poor statistical reporting in many journals with different rankings, in different countries. Our aim was to assess the reporting of statistical analyses in original papers published in Clujul Medical journal in the year 2014. METHODS: All original articles published in Clujul Medical in the year 2014 were assessed using mainly Statistical Analyses and Methods in the Published Literature guidelines. RESULTS: The most important issues found in reporting statistical analyses were reduced reporting of: assumptions checking, difference between groups or measures of associations, confidence intervals for the primary outcomes, and errors in the statistical test choice or the descriptive statistic choice for several analyses. These results are similar with other studies assessing different journals worldwide. CONCLUSION: Statistical reporting in Clujul Medical, like in other journals, have to be improved. PMID- 26733747 TI - Non-alcoholic fatty liver disease severity, central fat mass and adinopectin: a close relationship. AB - AIM: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the general population. Overweight is a common condition in patients with NAFLD, and body composition (BC) assessment is useful to evaluate nutritional status and the efficacy of nutritional strategies. A valid tool for assessing BC is dual-energy X-ray absorptiometry (DXA). Adiponectin has been shown to be relevant to the pathogenesis of NAFLD. The aim of this observational study is to define the relationship between the severity of NAFLD, the central fat mass evaluated by DXA, and the circulating levels of adiponectin. METHODS: The study was carried out in 31 overweight patients. The degree of liver steatosis was evaluated by ultrasound (US) examination. Anthropometric parameters were measured according to standard methods. Fasting glucose and insulin level were used also to calculate insulin resistance (IR), according to the homeostasis model assessment-insulin resistance (HOMA-IR). The enzyme-linked immunosorbent assay technique was performed to dose fasting serum levels of adiponectin. RESULTS: NAFLD progression was significantly associated with increased central fat (p<0.05). Using DXA, we quantified the regional distribution of adipose tissue and found the expected association between central fat and the US severity of NAFLD. Serum levels of adiponectin, were inversely related to NAFLD progression (p<0.05). CONCLUSION: BC evaluated by anthropometry and DXA, may be used as indicator of NAFLD severity in overweight patients. The evaluation of BC in clinical practice, can improve the nutritional strategies and follow-up. In the clinical setting adiponectin may represent a potential marker for the staging of NAFLD. PMID- 26733748 TI - Investigation of thyroid nodules in the female population in Cyprus and in Romania. AB - BACKGROUND AND AIMS: The most common thyroid disorders, with an increasing detection worldwide, are the thyroid nodules and thyroiditis, which leads to an increase of thyroid cancer incidence . In two different countries with a different exposure to risk factors for thyroid cancer, such as Cyprus and Romania, the rank of thyroid cancer among other neoplasms is very different: the 3(rd) most prevalent cancer among females in Cyprus and the 12(th) in Romania, respectively. Environmental chemicals, such as bisphenol A have a proven effect on the thyroid function. However, the relation between the exposure to the endocrine disruptor and the development of thyroid nodules, with a potential of malignant transformation has not been previously studied. The aim of the study was to investigate the potential factors that lead to the difference of thyroid nodules incidence in the mentioned countries. METHODS: A pilot case-control study has been conducted in 2014-2015 in the "Prof. Dr. Ion Chiricuta" Institute of Oncology, Cluj-Napoca, Romania and the Endocrinology Department of Archbishop Makarios III Hospital, Nicosia, Cyprus. Females older than 20 years with no medical history were recruited. Cases were women with ultrasound-confirmed thyroid nodules of size >3mm. Controls were women without thyroid nodules after ultrasound confirmation. All participants provided blood samples for measurements of the thyroid stimulating hormone (TSH), free thyroxin (FT4), anti-thyroglobulin (ATg) and anti-thyroid peroxidase (ATPO); urine samples. Demographics, anthropometrics and other relevant information were provided through the administration of a questionnaire. RESULTS: In Romania we selected 51 patients with thyroid nodules (case group) and 41 without thyroid nodules (control group) and in Cyprus 57 cases, respectively 65 controls. After the statistical analysis of the data collected we observed statistically significant differences between the populations of the two countries regarding BMI and the value of the thyroid hormones and antibodies. CONCLUSIONS: Using the data observed in this study, differences were found between Cyprus and Romania among females with thyroid nodules the BMI, and the level of thyroid hormones had statistically significant differences. This study reports preliminary data, further analysis of environmental exposures to chemical factors that might have a certain influence over the thyroid in the two countries will follow. PMID- 26733749 TI - Comparative multivariate analyses of transient otoacoustic emissions and distorsion products in normal and impaired hearing. AB - BACKGROUND AND AIM: The clinical utility of otoacoustic emissions as a noninvasive objective test of cochlear function has been long studied. Both transient otoacoustic emissions and distorsion products can be used to identify hearing loss, but to what extent they can be used as predictors for hearing loss is still debated. Most studies agree that multivariate analyses have better test performances than univariate analyses. The aim of the study was to determine transient otoacoustic emissions and distorsion products performance in identifying normal and impaired hearing loss, using the pure tone audiogram as a gold standard procedure and different multivariate statistical approaches. METHODS: The study included 105 adult subjects with normal hearing and hearing loss who underwent the same test battery: pure-tone audiometry, tympanometry, otoacoustic emission tests. We chose to use the logistic regression as a multivariate statistical technique. Three logistic regression models were developed to characterize the relations between different risk factors (age, sex, tinnitus, demographic features, cochlear status defined by otoacoustic emissions) and hearing status defined by pure-tone audiometry. The multivariate analyses allow the calculation of the logistic score, which is a combination of the inputs, weighted by coefficients, calculated within the analyses. The accuracy of each model was assessed using receiver operating characteristics curve analysis. We used the logistic score to generate receivers operating curves and to estimate the areas under the curves in order to compare different multivariate analyses. RESULTS: We compared the performance of each otoacoustic emission (transient, distorsion product) using three different multivariate analyses for each ear, when multi-frequency gold standards were used. We demonstrated that all multivariate analyses provided high values of the area under the curve proving the performance of the otoacoustic emissions. Each otoacoustic emission test presented high values of area under the curve, suggesting that implementing a multivariate approach to evaluate the performances of each otoacoustic emission test would serve to increase the accuracy in identifying the normal and impaired ears. We encountered the highest area under the curve value for the combined multivariate analysis suggesting that both otoacoustic emission tests should be used in assessing hearing status. Our multivariate analyses revealed that age is a constant predictor factor of the auditory status for both ears, but the presence of tinnitus was the most important predictor for the hearing level, only for the left ear. Age presented similar coefficients, but tinnitus coefficients, by their high value, produced the highest variations of the logistic scores, only for the left ear group, thus increasing the risk of hearing loss. We did not find gender differences between ears for any otoacoustic emission tests, but studies still debate this question as the results are contradictory. Neither gender, nor environment origin had any predictive value for the hearing status, according to the results of our study. CONCLUSION: Like any other audiological test, using otoacoustic emissions to identify hearing loss is not without error. Even when applying multivariate analysis, perfect test performance is never achieved. Although most studies demonstrated the benefit of using the multivariate analysis, it has not been incorporated into clinical decisions maybe because of the idiosyncratic nature of multivariate solutions or because of the lack of the validation studies. PMID- 26733750 TI - The influence of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite. AB - BACKGROUND AND AIMS: To evaluate the effects of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite, 4-hydroxyatomoxetine-O glucuronide, after coadministration of atomoxetine and paroxetine in healthy volunteers. METHODS: 22 healthy volunteers, extensive metabolizers, took part in this open-label, non-randomized, clinical trial. The study consisted of two periods: Reference, when a single oral dose of 25 mg atomoxetine was administrated to each subject and Test, when 25 mg atomoxetine and 20 mg paroxetine were coadministered. Between the two periods, the volunteers received an oral daily dose of 20-40 mg paroxetine, for 6 days. Atomoxetine and 4 hydroxyatomoxetine-O-glucuronide plasma concentrations were determined within the first 48 hours following drug administration. The pharmacokinetic parameters of both compounds were assessed using a non-compartmental method and the analysis of variance aimed at identifying any statistical significant differences between the pharmacokinetic parameters of atomoxetine and its main metabolite, corresponding to each study period. RESULTS: Paroxetine modified the pharmacokinetic parameters of atomoxetine. Cmax increased from 221.26+/-94.93 to 372.53+/-128.28 ng/mL, while AUC0-t and AUC0-infinity also increased from 1151.19+/-686.52 to 6452.37+/ 3388.76 ng*h/mL, and from 1229.15+/-751.04 to 7111.74+/-4195.17 ng*h/mL respectively. The main metabolite pharmacokinetics was also influenced by paroxetine intake, namely Cmax, AUC0-t and AUC0-infinity decreased from 688.76+/ 270.27 to 131.01+/-100.43 ng*h/mL, and from 4810.93+/-845.06 to 2606.04+/-923.88 and from 4928.55+/-853.25 to 3029.82 +/-941.84 respectively. CONCLUSIONS: Multiple-dose paroxetine intake significantly influenced atomoxetine and its active metabolite pharmacokinetics, causing a 5.8-fold increased exposure to atomoxetine and 1.6-fold reduced exposure to 4-hydroxyatomoxetine-O-glucuronide. PMID- 26733751 TI - Synthesis, lipophilicity and antimicrobial activity evaluation of some new thiazolyl-oxadiazolines. AB - BACKGROUND AND AIMS: Synthesis of new potential antimicrobial agents and evaluation of their lipophilicity. METHODS: Ten new thiazolyl-oxadiazoline derivatives were synthesized and their structures were validated by 1H-NMR and mass spectrometry. The lipophilicity of the compounds was evaluated using the principal component analysis (PCA) method. The necessary data for applying this method were obtained by reverse-phase thin-layer chromatography (RP-TLC). The antimicrobial activities were tested in vitro against four bacterial strains and one fungal strain. RESULTS: The lipophilicity varied with the structure but could not be correlated with the antimicrobial activity, since this was modest. CONCLUSIONS: We have synthesized ten new heterocyclic compounds. After their physical and chemical characterization, we determined their lipophilicity and screened their antimicrobial activity. PMID- 26733752 TI - Romanian version of the oral health impact profile-49 questionnaire: validation and preliminary assessment of the psychometrical properties. AB - BACKGROUND AND AIMS: Oral Health Related Quality of Life (OHRQoL) represents a multidimensional structure, being measured by complex instruments, such as the Oral Health Impact Profile (OHIP). The aim of this present study is to develop and test the psychometric properties of an initial Romanian (OHIP-49Ro) version. METHODS: The original OHIP-49 version was translated using a forward-backward technique into the Romanian OHIP-49Ro, which was applied in an interview form to 150 patients of the Second Medical Clinique of Internal Medicine, Cluj-Napoca. Confirmatory Factor Analysis (CFA) was applied, in order to evaluate the factor structure and construct validity of the OHIP-49Ro. RESULTS: The correlations between the OHIP-49Ro subscales were all positive and statistically significant. Cronbach's Alpha coefficients values are above 0.7 for all subscales, providing support for the internal consistency of OHIP-49Ro scale scores. Regarding the CFA, for the seven factor model, the Bentler scaled chi-square (S-Bchi(2)) indicated a value of 2193.74 (df=1091; p=0.001), the CFI a value of 0.740, the TLI a value of 0.72 and RMSEA the value of 0.82. CONCLUSIONS: The results of this study suggest a high internal consistency of the OHIP-49Ro instrument. Due to the correlations between several sets of factors, and the multiple-factorial load for several items, the OHIP-49Ro's factorial structure requires further research on different samples and in different cultural and educational contexts. PMID- 26733753 TI - Spectrophotometric color evaluation of permanent incisors, canines and molars. A cross-sectional clinical study. AB - BACKGROUND AND AIMS: An accurate color reproduction represents the final validation level of an esthetic anterior or posterior restoration. The aim of this study was to evaluate the color of permanent maxillary incisors, canines and molars, using a clinical spectrophotometer. METHODS: The Vita Easyshade Advance 4.0((r)) intraoral spectrophotometer was used by one clinician to determine the color of 369 permanent maxillary incisors, canines and molars. The best matches to Vitapan Classical((r)) and 3D-Master((r)) shade guides were recorded. A one way analysis of variance and Kruskal-Wallis test were used to compare L*, a*, b*, c* and h* color coordinates among the 3 types of teeth. Differences between the mean values of all color coordinates were evaluated by use of Bonferroni corrections. Color difference (DeltaE*) between incisors, canines and molars was calculated from DeltaL*, Deltaa* and Deltab* data and the results were compared to DeltaE*=3.3 acceptability threshold. RESULTS: Except for Deltaa* and Deltah* between canines and molars, statistically significant differences among the mean differences of all color coordinates were found when the 3 types of teeth were compared by pairs. The most frequently measured shades were A1 (48.4%), respectively 1M1 (31.5%) for incisors, B3 (36.6%), respectively 2M3 (39.8%) for canines and B3 (44.7%), respectively 2M3 (52%) for molars. Incisors had the highest lightness values, followed by canines and molars. Molars were the most chromatic with the highest a* and b* values. CONCLUSIONS: Despite the limitations of this study, color differences among incisors, canines and molars were found to be statistically significant, above the clinical acceptability threshold established. In conclusion, successful esthetic restorations of permanent teeth of the same patient need an individual color assessment and reproduction of every type of tooth. PMID- 26733754 TI - The artery blood supply variant of the upper limb. AB - Variations of arterial patterns in the upper limb have represented the most common subject of vascular anatomy. Different types of artery branching pattern of the upper limb are very important for orthopedists in angiographic and microvascular surgical practice. The brachial artery (BA) is the most important vessel in the normal vascular anatomy of the upper limb. The classical pattern of the palmar hand region distribution shows the superficial palmar arch. Normally this arch is formed by the superficial branch of the ulnar artery and completed on the lateral side by one of these arteries: the superficial palmar branch of the radial artery, the princeps pollicis artery, the superficial palmar branch of the radial artery or the median artery. After the routine dissection of the right upper limb of an adult male cadaver, we found a very rare variant of the superficial arch artery - a division in a higher level brachial artery. We found this division at 10.4 cm from the beginning of the brachial artery. This superficial brachial artery became a radial artery and was not involved in the formation of the palm arch. In the forearm region, the artery variant was present with the median artery and the ulnar artery, which form the superficial palm arch. PMID- 26733755 TI - Challenges of thyroid cancer management in amiodarone-treated patients: a case report. AB - Thyroid carcinoma (TC) is the most common endocrine malignancy. Although the overall prognosis for patients with TC is good, up to 20-30% of patients have recurrent or persistent disease after conventional therapy by surgical resection and radioactive iodine (RAI). Amiodarone is a highly efficient anti-arrhythmic drug with a very long half-life, so it may interfere with RAI many months after the drug withdrawal. This case report mirrors the challenges of thyroid cancer management in an amiodarone-treated patient. PMID- 26733756 TI - Diagnostic use of magnetic resonance imaging (MRI) of a cervical epidural abscess and spondylodiscitis in an infant - case report. AB - Epidural abscess in infancy is very rare and has non-specific features, requiring very careful attention and early diagnosis. We present a case of a 3-month-old girl in which the diagnosis of spontaneous cervical epidural abscess developed after an initial episode of acute enterocolitis and was subsequently identified at a later visit to the emergency department for right-upper extremity hypotonia. Endoscopy revealed slightly domed retro pharynx and magnetic resonance imaging (MRI) scan showed cervical spondylodiscitis at the level of intervertebral disc C5-C6 with right-sided epidural abscess that compressed the spinal cord and right C6 nerve root, without extension into superior mediastinum. The systemic antibiotic treatment with meropenem and clindamycin solved the symptoms but the spondylodiscitis complicated with vertebral body fusion which can be symptomatic or not in the future and needs follow-up. Cervical spontaneous spondylodiscitis with abscess is very rare, especially in this age group. This case emphasizes the importance of investigating an upper extremity motor deficiency in infancy and diagnosing any potential spondylodiscitis complication. PMID- 26733757 TI - 275 years since the epidemic of plague in Cluj: Dr. Alexandru Lenghel's contribution to its investigation. AB - Plague is one of the most impressive diseases in the cultural history of mankind. Its lethality has influenced the evolution of society and it is frequently represented in fine arts and literature. The principality of Transylvania was also affected by this infection, the plague having strongly impacted both economic and social development. Between 1738 and 1739 an important plague epidemic spread in Transylvania. The authors introduce and discuss a less known work on this epidemic, with focus on its impact on the city of Cluj - a book written in 1930 by Dr. Alexandru Lenghel, who later became a target of political persecution during the Stalinist period, while his work entered a cone of shadow. PMID- 26733758 TI - A brief history of the evolution of the medical research article. AB - Given the current importance of publishing medical research articles in high impact international journals, this article briefly presents key moments in the evolution of this reporting genre for a better understanding of the diachronic changes that have shaped it into a highly useful tool for creating and spreading knowledge, as well as for establishing academic hierarchies at both individual and institutional level. Therefore, focus will be placed not only on the evolution of its structure and purpose, but also on issues such as knowledge construction, knowledge claims, writer-reader interaction and the appropriate writing conventions and rhetorical strategies required for successful scientific communication. PMID- 26733759 TI - The spirit of professor Iacob Iacobovici in the development of education in dentistry and maxillofacial surgery. AB - Founder of the Surgical Clinic in Cluj-Napoca and of Medical Education in Romanian, Rector of Dacia Superior University, Professor Iacob Iacobovici was one of the outstanding medical personalities in the first half of the twentieth century, in Romania. His scientific contributions have been recognized by the European great personalities of his time. A remarkable bright mind, with an overarching comprehension of things, Professor Iacob Iacobovici contributed, in an essential way, to the diversification of surgical education, stimulating the emergence of new specialties. This paper illustrates the contribution of Professor Iacob Iacobovici to the development of Education of Dentistry and Oral and Maxillofacial Surgery in Romania as well as his support for the Romanian Society of Dentistry. PMID- 26733760 TI - Effects of Massage Therapy and Occlusal Splint Usage on Quality of Life and Pain in Individuals with Sleep Bruxism: A Randomized Controlled Trial. AB - PURPOSE: The aim of the present study was to investigate the effects of massage therapy on the masticatory muscles and occlusal splint usage on quality of life and pain in individuals with sleep bruxism. METHOD: A randomized, controlled, blinded, clinical trial was conducted involving 78 volunteers aged 18 to 40 years with sleep bruxism. Quality of life and pain assessments were performed. RESULTS: Significant differences (p < 0.05) were found on the physical functioning, general health state, vitality, role emotional and mental health subscales. A large effect size was found for all treatment protocols with regard to pain. The largest effect was found in the combined treatment group. CONCLUSIONS: The findings of the present study reveal that the occlusal splint usage alone led to improvements in components of quality of life among individuals with sleep bruxism. Moreover, both treatments (occlusal splint usage and massage therapy on the masticatory muscles) led to a reduction in pain. PMID- 26733761 TI - Sit-to-walk Task in Hemiplegic Stroke Patients: Relationship between Movement Fluidity and the Motor Strategy in Initial Contact. AB - PURPOSE: Generally, stroke patients can walk and stand up fluidly but fulfill the sit-to-walk (STW) task with difficulty. The purpose of this study was to investigate the relationship between movement fluidity and motor strategy in the initial contact of the STW task. METHOD: Thirty stroke patients and ten healthy subjects performed the STW task from a sitting position, and their movement was measured by a motion analysis system. The differences in data between patients and healthy subjects were analyzed using the Mann-Whitney U test. The relationship between fluidity index (FI) and other indices (kinetic and kinematic data in STW, functional independence measure [FIM], and Fugl-Meyer Assessment [FMA]) were analyzed using Spearman's rank correlation coefficient. RESULTS: The stroke patients had lower FI values than the healthy subjects and exhibited shortened step length and prolonged duration from onset to the first stance leg off. FI values correlated with trunk flexure angle at initial contact, first step length, and maximum vertical floor reaction force. The independent level of the FIM of stair climbing and walking ability and the FMA of balance also correlated with FI. CONCLUSION: There is a possibility that poor balance is one of the reasons why stroke patients are unable to start walking fluently from the sitting position. To perform the STW fluidly, patients must start walking before the trunk extension is fully completed. The relationship between FI and indices of physical ability, namely stair climbing and balance, may have therapeutic benefits for coaching the STW task to stroke patients. PMID- 26733762 TI - Joint Function and Arthropathy Severity in Patients with Hemophilia. AB - BACKGROUND: The Arnold-Hilgartner classification is one of the most popular evaluation systems for the progression hemophilic arthropathy. A previous study reported an association between arthropathy severity and arc range of motion (ROM). However, associations between arthropathy severity and angular ROM and muscle strength remain unclear. AIM: The purpose of this study was to clarify the association between joint function and arthropathy severity in hemophilia. METHODS: We studied the knee, ankle, and elbow joints of 31 patients with hemophilia (PWH). The condition of the affected joints was evaluated on the basis of the interview data, joint function measurements, and roentgenography of the affected joints. In assessment of joint function, we evaluated knee strength (flexor, extensor) and grip strength as well as the passive ROM of the elbow, knee, and ankle. During the interview, all patients were asked about the history of intra-articular bleeding over the past year and pain. RESULTS: As arthropathy severity worsened, knee flexor strength, knee extensor strength, grip strength, and ROM (elbow flexion, elbow extension, knee flexion, knee extension, and ankle extension) significantly decreased. Even patients with mild arthropathies experienced knee extensor weakness and extension limitation. In addition, joint function of severe ankle arthropathy was significantly related to the history of intra-articular bleeding and pain. CONCLUSION: Our results suggest that physical therapy is necessary to improve joint function in PWH and mild or no arthropathy. Pain control and prophylactic hematological management are necessary for patients with severe arthropathy because intra-articular bleeding and pain significantly decrease joint function. PMID- 26733763 TI - CXCL14 as an emerging immune and inflammatory modulator. AB - CXCL14, a relatively novel chemokine, is a non-ELR (glutamic acid-leucine arginine) chemokine with a broad spectrum of biological activities. CXCL14 mainly contributes to the regulation of immune cell migration, also executes antimicrobial immunity. The identity of the receptor for CXCL14 still remains obscure and therefore the intracellular signaling pathway is not entirely delineated. The present review summarizes the contribution of CXCL14 in these two aspects and discusses the biological mechanisms regulating CXCL14 expression and potential CXCL14 mediated functional implications in a variety of cells. PMID- 26733764 TI - In a single-blind, matched group design: branched-chain amino acid supplementation and resistance training maintains lean body mass during a caloric restricted diet. AB - BACKGROUND: Athletes and active adults many times have the goal of improving/maintaining fitness while losing weight and this is best achieved by caloric restriction in combination with exercise. However, this poses a risk for lean tissue loss, which can limit performance. Thus, the purpose of this study was to determine the effectiveness of a branched-chain amino acid (BCAA) supplement, in conjunction with heavy resistance training and a carbohydrate caloric-restricted "cut diet" on body composition and muscle fitness. METHODS: Seventeen resistance-trained males (21-28 years of age) were randomized to a BCAA group (n = 9) or a carbohydrate (CHO) group (n = 8) who both received their respective supplement during the 8 weeks of a prescribed body building style resistance training protocol. Subjects were prescribed a hypocaloric diet (based upon pre-intervention analysis) that was to be followed during the study. RESULTS: The BCAA group lost fat mass (-0.05 +/- 0.08 kg;p < .05) and maintained lean mass, while the CHO group lost lean mass (-0.90 +/- 0.06 kg; p < .05) and body mass (-2.3 +/- 0.7 kg; p < .05). Both groups increased 1RM squat, but the increase in the BCAA group (15.1 +/- 2.2 kg; p < .05)was greater (P < 0.05) than the CHO group. The BCAA group increased 1RM bench press (7.1 +/- 1.6 kg; P < 0.05), while the CHO group decreased strength (-3.7 +/- 2.3 kg; P < 0.05). The only change in muscular endurance was an increase in repetitions to fatigue (5.3 +/- 0.2; p < .05) in the CHO group. CONCLUSION: These results show that BCAA supplementation in trained individuals performing resistance training while on a hypocaloric diet can maintain lean mass and preserve skeletal muscle performance while losing fat mass. PMID- 26733765 TI - Rapid Analysis of Inorganic Species in Herbaceous Materials Using Laser-Induced Breakdown Spectroscopy. AB - Inorganic compounds in biomass, often referred to as ash, are known to be problematic in the thermochemical conversion of biomass to bio-oil or syngas and, ultimately, hydrocarbon fuels because they negatively influence reaction pathways, contribute to fouling and corrosion, poison catalysts, and impact waste streams. The most common ash-analysis methods, such as inductively coupled plasma optical emission spectrometry/mass spectrometry (ICP-OES/MS), require considerable time and expensive reagents. Laser-induced breakdown spectroscopy (LIBS) is emerging as a technique for rapid analysis of the inorganic constituents in a wide range of biomass materials. This study compares analytical results using LIBS data to results obtained from three separate ICP-OES/MS methods for 12 samples, including six standard reference materials. Analyzed elements include aluminum, calcium, iron, magnesium, manganese, phosphorus, potassium, sodium, and silicon, and results show that concentrations can be measured with an uncertainty of approximately 100 parts per million using univariate calibration models and relatively few calibration samples. These results indicate that the accuracy of LIBS is comparable to that of ICP-OES methods and indicate that some acid-digestion methods for ICP-OES may not be reliable for Na and Al. These results also demonstrate that germanium can be used as an internal standard to improve the reliability and accuracy of measuring many elements of interest, and that LIBS can be used for rapid determination of total ash in biomass samples. Key benefits of LIBS include little sample preparation, no reagent consumption, and the generation of meaningful analytical data instantaneously. PMID- 26733767 TI - The Blood Group A Genotype Determines the Level of Expression of the Blood Group A on Platelets But Not the Anti-B Isotiter. AB - BACKGROUND: The extent of expression of the blood group A on platelets is controversial. Further, the relation between platelets' blood group A expression and the titers of isoagglutinins has not been thoroughly investigated, so far. METHODS: We evaluated the relation between the genotype with platelets' blood group A and H expression estimated by flow cytometry and the titers of isoagglutinins. RESULTS: The A expression varied between genotypes and within genotypes. However, the expression in A1 was stronger than in all other genotypes (p < 0.0001). An overlap of expression levels was apparent between homozygous A1A1 and heterozygous A1 individuals. Still, The A1A1 genotype is associated with a particularly high antigen expression (p = 0.009). Platelets' A expression in A2 versus blood group O donors was also significant (p = 0.007), but there was again an overlap of expression. The secretor status had only little influence on the expression (p = 0.18). Also, isoagglutinin titers were not associated with genotypes. CONCLUSION: To distinguish between A1 and A2 donors may reduce incompatible platelet transfusions and therefore be favorable on platelet transfusion increment. Clinical data are needed to support this notion. PMID- 26733766 TI - 14 Years of Polish Experience in Non-Invasive Prenatal Blood Group Diagnosis. AB - BACKGROUND: Blood cell antigens may cause maternal alloimmunization leading to fetal/newborn disorders. Non-invasive prenatal diagnostics (NIPD) of the blood group permits the determination of feto-maternal incompatibility. AIM: To evaluate 14 years of blood group NIPD at the Institute of Hematology and Transfusion Medicine (IHTM) in Warsaw. METHODS: Plasma DNA from 536 RhD-negative, 24 Rhc-negative, 26 RhE-negative, 43 K-negative, and 42 HPA-1a-negative pregnant women was examined by real-time PCR to detect RHD, RHCE*c, RHCE*E, RHCE*C, KEL*01 and HPA*1A, respectively. We tested for CCR5, SRY or bi-allelic polymorphisms and quantified the total or fetal DNA. RESULTS: The results of fetal antigen status prediction by NIPD in all but one case (false-positive result of KEL*01) were correct taking neonate serology as a reference. It was confirmed that all negative results of NIPD contained fetal DNA except for four cases where there was no difference between the parents' polymorphisms. CONCLUSIONS: A fetal genotype compatible with the mother was determined in 25% of all pregnancies tested at the IHTM for the fetal blood group. These cases were not at risk of disease, so it was possible to avoid invasive procedures. PMID- 26733768 TI - Insights into RHCE Molecular Analysis in Samples with Partial D Variants: the Experience of Western France. AB - BACKGROUND: Although systematic blood group genotyping of patients/donors is virtually possible, serological studies remain the gold standard to identify samples of clinical interest that may be further genotyped. In this context, we sought to identify variant D alleles that are likely to be clinically relevant in terms of other Rh antigens in a subset of population genotyped in Western France. METHODS: Samples presenting with the RHD*weak D type 4.2.2 allele (n = 47) were selected for the study. RHCE exons 1-7 were directly sequenced, and expression of Rh antigens was predicted on the basis of the molecular data. RESULTS: Of the 47 samples tested, 19 (40.4%) were predicted to be of potential clinical interest. Moreover, we could show that selecting the samples to be genotyped by the nature of their variant D allele (i.e., RHD*weak D type 4.2.2 allele) rather than by their Duffy-null status appears to increase significantly the likelihood of identifying clinically relevant individuals for Rh status. CONCLUSION: On the basis of our findings we suggest that all individuals genotyped as weak D type 4.2.2 should be systematically screened for RHCE variants by molecular analysis on a routine basis. PMID- 26733769 TI - The Glass Slide Extraction System Snap Card Improves Non-Invasive Prenatal Genotyping in Pregnancies with Antibodies. AB - BACKGROUND: Determination of fetal blood groups in maternal plasma samples critically depends on adequate pre-analytical steps for optimal amplification of fetal DNA. We compared the extraction of cell-free DNA by binding on a glass surface (BCSI SNAPTM Card) with an automated system based on bead technology (MagnaPure compactTM). METHODS: Maternal blood samples from 281 pregnancies (7th 39th week of gestation) with known antibodies were evaluated in this study. Both the SNAP card and the MagnaPure method were applied to isolate DNA in order to directly compare the amplification in a single base extension assay and/or real time PCR. RESULTS: The mean concentration of total DNA obtained by the SNAP card (33.8 ng/ul) exceeded more than twofold that of MagnaPure extraction (15.7 ng/ul). SNAP card-extracted samples allowed to detect 3.7 single nucleotide polymorphisms (SNPs) versus 2.5 SNPs in MagnaPure extracts to control for traces of fetal DNA. This difference is highest for samples from 7th-13th week of gestation. CONCLUSION: The SNAP card system improves DNA extraction efficacy for prenatal diagnosis in maternal blood samples and provides an at least eightfold higher total amount of DNA for the ensuing analysis. Its advantage is most evident for samples from early stages of pregnancy and thus especially valuable for pregnancies with antibodies. PMID- 26733770 TI - SNP Markers as Additional Information to Resolve Complex Kinship Cases. AB - BACKGROUND: DNA profiling with sets of highly polymorphic autosomal short tandem repeat (STR) markers has been applied in various aspects of human identification in forensic casework for nearly 20 years. However, in some cases of complex kinship investigation, the information provided by the conventionally used STR markers is not enough, often resulting in low likelihood ratio (LR) calculations. In these cases, it becomes necessary to increment the number of loci under analysis to reach adequate LRs. Recently, it has been proposed that single nucleotide polymorphisms (SNPs) could be used as a supportive tool to STR typing, eventually even replacing the methods/markers now employed. METHODS: In this work, we describe the results obtained in 7 revised complex paternity cases when applying a battery of STRs, as well as 52 human identification SNPs (SNPforID 52plex identification panel) using a SNaPshot methodology followed by capillary electrophoresis. RESULTS: Our results show that the analysis of SNPs, as complement to STR typing in forensic casework applications, would at least increase by a factor of 4 total PI values and correspondent Essen-Moller's W value. CONCLUSIONS: We demonstrated that SNP genotyping could be a key complement to STR information in challenging casework of disputed paternity, such as close relative individualization or complex pedigrees subject to endogamous relations. PMID- 26733771 TI - Hepcidin/Ferritin Quotient Helps to Predict Spontaneous Recovery from Iron Loss following Blood Donation. AB - BACKGROUND: Iron supplementation is generally recommended for blood donors even though there are inter-individual differences in iron homeostasis. METHODS: Ferritin levels of repeat donors were compared with first-time donors, retrospectively. Prospectively, we tested 27 male repeat donors for the following parameters at the day of blood donation as well as 1, 3, 7, 10, and 56 days thereafter: ferritin, hepcidin, transferrin, transferrin receptor, hemoglobin, erythropoietin, reticulocytes, hemoglobin in reticulocyte, twisted gastrulation protein homolog 1, and growth differentiation factor-15. RESULTS: 56 days after blood donation, donors' average ferritin dropped to 55% (range 30-100%) compared to the initial value. Of all tested parameters hepcidin showed the highest and most significant changes beginning 1 day after donation and lasting for the whole period of 56 days. Along with ferritin, there was a high variation in hepcidin levels indicating inter-individual differences in hepcidin response to iron loss. Donors with a hepcidin/ferritin quotient < 0.3 regained 60% of their initial ferritin after 56 days, while those with a quotient >= 0.3 reached less than 50%. CONCLUSION: As hepcidin appears to integrate erythropoietic and iron-loading signals, clinical measurement of hepcidin (together with the hepcidin-ferritin ratio) may become a useful indicator of erythropoiesis and iron kinetics. PMID- 26733772 TI - Absence of in vitro Procoagulant Activity in Immunoglobulin Preparations due to Activated Coagulation Factors. AB - BACKGROUND: Immunoglobulin (IG) products, including intravenous (IVIG) or subcutaneous (SCIG) immunoglobulins are considered safe and effective for medical therapy; however, a sudden and unexpected increase in thromboembolic events (TE) after administration of certain batches of IVIG products has been attributed to the presence of activated coagulation factors, mainly factor XIa. Our aims were to examine the presence of enduring procoagulant activity during the manufacturing process of IGs, with special focus on monitoring factor XIa, and to evaluate the presence of in vitro procoagulant activity attributed to coagulation factors in different lots of IVIG and SCIG. METHODS: Samples of different steps of IG purification, 19 lots of IVIG and 9 of SCIG were analyzed and compared with 1 commercial preparation of IVIG and 2 of SCIG, respectively. Factors II, VII, IX, XI and XIa and non-activated partial thromboplastin time (NAPTT) were assayed. RESULTS: The levels of factors II, VII, IX, X and XI were non quantifiable once fraction II had been re-dissolved and in all analyzed lots of IVIG and SCIG. The level of factor XIa at that point was under the detection limits of the assay, and NAPTT yielded values greater than the control during the purification process. In SCIG, we detected higher concentrations of factor XIa in the commercial products, which reached values up to 5 times higher than the average amounts found in the 9 batches produced by UNC-Hemoderivados. Factor XIa in commercial IVIG reached levels slightly higher than those of the 19 batches produced by UNC-Hemoderivados. CONCLUSION: IVIG and SCIG manufactured by UNC Hemoderivados showed a lack of thrombogenic potential, as demonstrated not only by the laboratory data obtained in this study but also by the absence of any reports of TE registered by the post marketing pharmacovigilance department. PMID- 26733773 TI - New Section: Novel Insights from Clinical Practice. PMID- 26733774 TI - Double, Double Toil and Trouble. PMID- 26733775 TI - The Diagnostic Utility of Single Long Contiguous Stretches of Homozygosity in Patients without Parental Consanguinity. AB - We present data from our clinical department's experience with chromosomal microarray analysis (CMA) regarding the diagnostic utility of 1 or 2 long contiguous stretches of homozygosity (LCSHs) in an outbred population. The study group consisted of 2,110 consecutive patients from 2011 to 2014 for whom CMA was performed. The minimum cut-off size for defining a homozygous stretch was 5 Mb. To focus on cases with no parental consanguinity, we further studied only patients in whom the total length of homozygous stretches did not exceed 28 Mb or 1% of the autosomal genome length. We identified 6 chromosomal regions where homozygous stretches appeared in at least 3 patients and excluded these from further analysis. In 2 out of 120 patients with an isolated finding of 1 or 2 non recurrent LCSHs, a plausible candidate gene associated with their phenotype was identified within the homozygous stretch. In both of these cases, a pathogenic mutation was detected, leading to diagnoses of pyruvate kinase deficiency and Marinesco-Sjogren syndrome. To clarify whether previously found homozygous stretches could be important for the interpretation of genome-wide sequencing data, we report 7 cases in which homozygous stretches not encompassing a clinically associated gene were first found on CMA, followed by the diagnostic whole-exome sequencing. The diagnostic utility of single LCSHs, unlikely to be caused by uniparental disomy, is discussed in detail. PMID- 26733776 TI - Diagnosis of D-Bifunctional Protein Deficiency through Whole-Genome Sequencing: Implications for Cost-Effective Care. AB - D-Bifunctional protein deficiency, caused by recessive mutations in HSD17B4, is a severe disorder of peroxisomal fatty acid oxidation. Nonspecific clinical features may contribute to diagnostic challenges. We describe a newborn female with infantile-onset seizures and nonspecific mild dysmorphisms who underwent extensive genetic workup that resulted in the detection of a novel homozygous mutation (c.302+1_4delGTGA) in the HSD17B4 gene, consistent with a diagnosis of D bifunctional protein deficiency. By comparing the standard clinical workup to diagnostic analysis performed through research-based whole-genome sequencing (WGS), which independently identified the causative mutation, we demonstrated the ability of genomic sequencing to serve as a timely and cost-effective diagnostic tool for the molecular diagnosis of apparent and occult newborn diseases. As genomic sequencing becomes more available and affordable, we anticipate that WGS and related omics technologies will eventually replace the traditional tiered approach to newborn diagnostic workup. PMID- 26733778 TI - Laminar Distribution of Phase-Amplitude Coupling of Spontaneous Current Sources and Sinks. AB - Although resting-state functional connectivity is a commonly used neuroimaging paradigm, the underlying mechanisms remain unknown. Thalamo-cortical and cortico cortical circuits generate oscillations at different frequencies during spontaneous activity. However, it remains unclear how the various rhythms interact and whether their interactions are lamina-specific. Here we investigated intra- and inter-laminar spontaneous phase-amplitude coupling (PAC). We recorded local-field potentials using laminar probes inserted in the forelimb representation of rat area S1. We then computed time-series of frequency-band- and lamina-specific current source density (CSD), and PACs of CSD for all possible pairs of the classical frequency bands in the range of 1-150 Hz. We observed both intra- and inter-laminar spontaneous PAC. Of 18 possible combinations, 12 showed PAC, with the highest measures of interaction obtained for the pairs of the theta/gamma and delta/gamma bands. Intra- and inter-laminar PACs involving layers 2/3-5a were higher than those involving layer 6. Current sinks (sources) in the delta band were associated with increased (decreased) amplitudes of high-frequency signals in the beta to fast gamma bands throughout layers 2/3-6. Spontaneous sinks (sources) of the theta and alpha bands in layers 2/3-4 were on average linked to dipoles completed by sources (sinks) in layer 6, associated with high (low) amplitudes of the beta to fast-gamma bands in the entire cortical column. Our findings show that during spontaneous activity, delta, theta, and alpha oscillations are associated with periodic excitability, which for the theta and alpha bands is lamina-dependent. They further emphasize the differences between the function of layer 6 and that of the superficial layers, and the role of layer 6 in controlling activity in those layers. Our study links theories on the involvement of PAC in resting-state functional connectivity with previous work that revealed lamina-specific anatomical thalamo cortico-cortical connections. PMID- 26733779 TI - Divergence and Convergence of Risky Decision Making Across Prospective Gains and Losses: Preferences and Strategies. AB - People choose differently when facing potential gains than when facing potential losses. Clear gross differences in decision making between gains and losses have been empirically demonstrated in numerous studies (e.g., framing effect, risk preference, loss aversion). However, theories maintain that there are strong underlying connections (e.g., reflection effect). We investigated the relationship between gains and losses decision making, examining risk preferences, and choice strategies (the reliance on option information) using a monetary gamble task with interleaved trials. For risk preferences, participants were on average risk averse in the gains domain and risk neutral/seeking in the losses domain. We specifically tested for a theoretically hypothesized correlation between individual risk preferences across the gains and losses domains (the reflection effect), but found no significant relationship in the predicted direction. Interestingly, despite the lack of reflected risk preferences, cross-domain risk preferences were still informative of individual choice behavior. For choice strategies, in both domains participants relied more heavily on the maximizing strategy than the satisficing strategy, with increased reliance on the maximizing strategy in the losses domain. Additionally, while there is no mathematical reliance between the risk preference and strategy metrics, within both domains there were significant relationships between risk preferences and strategies-the more participants relied upon the maximizing strategy the more risk neutral they were (equating value and utility maximization). These results demonstrate the complexity of gains and losses decision making, indicating the apparent contradiction that their underlying cognitive/neural processes are both dissociable and overlapping. PMID- 26733777 TI - Molecular Pathways Underlying Projection Neuron Production and Migration during Cerebral Cortical Development. AB - Glutamatergic neurons of the mammalian cerebral cortex originate from radial glia (RG) progenitors in the ventricular zone (VZ). During corticogenesis, neuroblasts migrate toward the pial surface using two different migration modes. One is multipolar (MP) migration with random directional movement, and the other is locomotion, which is a unidirectional movement guided by the RG fiber. After reaching their final destination, the neurons finalize their migration by terminal translocation, which is followed by maturation via dendrite extension to initiate synaptogenesis and thereby complete neural circuit formation. This switching of migration modes during cortical development is unique in mammals, which suggests that the RG-guided locomotion mode may contribute to the evolution of the mammalian neocortical 6-layer structure. Many factors have been reported to be involved in the regulation of this radial neuronal migration process. In general, the radial migration can be largely divided into four steps; (1) maintenance and departure from the VZ of neural progenitor cells, (2) MP migration and transition to bipolar cells, (3) RG-guided locomotion, and (4) terminal translocation and dendrite maturation. Among these, many different gene mutations or knockdown effects have resulted in failure of the MP to bipolar transition (step 2), suggesting that it is a critical step, particularly in radial migration. Moreover, this transition occurs at the subplate layer. In this review, we summarize recent advances in our understanding of the molecular mechanisms underlying each of these steps. Finally, we discuss the evolutionary aspects of neuronal migration in corticogenesis. PMID- 26733780 TI - Reduced Responses of Submucous Neurons from Irritable Bowel Syndrome Patients to a Cocktail Containing Histamine, Serotonin, TNFalpha, and Tryptase (IBS Cocktail). AB - BACKGROUND AND AIMS: Malfunctions of enteric neurons are believed to play an important role in the pathophysiology of irritable bowel syndrome (IBS). Our aim was to investigate whether neuronal activity in biopsies from IBS patients is altered in comparison to healthy controls (HC). METHODS: Activity of human submucous neurons in response to electrical nerve stimulation and local application of nicotine or a mixture of histamine, serotonin, tryptase, and TNF alpha (IBS-cocktail) was recorded in biopsies from 17 HC and 35 IBS patients with the calcium-sensitive-dye Fluo-4 AM. The concentrations of the mediators resembeled those found in biopsy supernatants or blood. Neuronal activity in guinea-pig submucous neurons was studied with the voltage-sensitive-dye di-8 ANEPPS. RESULTS: Activity in submucous ganglia in response to nicotine or electrical nerve stimulation was not different between HC and IBS patients (P = 0.097 or P = 0.448). However, the neuronal response after application of the IBS cocktail was significantly decreased (P = 0.039) independent of whether diarrhea (n = 12), constipation (n = 5) or bloating (n = 5) was the predominant symptom. In agreement with this we found that responses of submucous ganglia conditioned by overnight incubation with IBS mucosal biopsy supernatant to spritz application of this supernatant was significantly reduced (P = 0.019) when compared to incubation with HC supernatant. CONCLUSION: We demonstrated for the first time reduced neuronal responses in mucosal IBS biopsies to an IBS mediator cocktail. While excitability to classical stimuli of enteric neurons was comparable to HC, the activation by the IBS-cocktail was decreased. This was very likely due to desensitization to mediators constantly released by mucosal and immune cells in the gut wall of IBS patients. PMID- 26733782 TI - Investigating Human Neurovascular Coupling Using Functional Neuroimaging: A Critical Review of Dynamic Models. AB - The mechanisms that link a transient neural activity to the corresponding increase of cerebral blood flow (CBF) are termed neurovascular coupling (NVC). They are possibly impaired at early stages of small vessel or neurodegenerative diseases. Investigation of NVC in humans has been made possible with the development of various neuroimaging techniques based on variations of local hemodynamics during neural activity. Specific dynamic models are currently used for interpreting these data that can include biophysical parameters related to NVC. After a brief review of the current knowledge about possible mechanisms acting in NVC we selected seven models with explicit integration of NVC found in the literature. All these models were described using the same procedure. We compared their physiological assumptions, mathematical formalism, and validation. In particular, we pointed out their strong differences in terms of complexity. Finally, we discussed their validity and their potential applications. These models may provide key information to investigate various aspects of NVC in human pathology. PMID- 26733781 TI - Sex Differences in Kappa Opioid Receptor Function and Their Potential Impact on Addiction. AB - Behavioral, biological, and social sequelae that lead to drug addiction differ between men and women. Our efforts to understand addiction on a mechanistic level must include studies in both males and females. Stress, anxiety, and depression are tightly linked to addiction, and whether they precede or result from compulsive drug use depends on many factors, including biological sex. The neuropeptide dynorphin (DYN), an endogenous ligand at kappa opioid receptors (KORs), is necessary for stress-induced aversive states and is upregulated in the brain after chronic exposure to drugs of abuse. KOR agonists produce signs of anxiety, fear, and depression in laboratory animals and humans, findings that have led to the hypothesis that drug withdrawal-induced DYN release is instrumental in negative reinforcement processes that drive addiction. However, these studies were almost exclusively conducted in males. Only recently is evidence available that there are sex differences in the effects of KOR activation on affective state. This review focuses on sex differences in DYN and KOR systems and how these might contribute to sex differences in addictive behavior. Much of what is known about how biological sex influences KOR systems is from research on pain systems. The basic molecular and genetic mechanisms that have been discovered to underlie sex differences in KOR function in pain systems may apply to sex differences in KOR function in reward systems. Our goals are to discuss the current state of knowledge on how biological sex contributes to KOR function in the context of pain, mood, and addiction and to explore potential mechanisms for sex differences in KOR function. We will highlight evidence that the function of DYN-KOR systems is influenced in a sex-dependent manner by: polymorphisms in the prodynorphin (pDYN) gene, genetic linkage with the melanocortin-1 receptor (MC1R), heterodimerization of KORs and mu opioid receptors (MORs), and gonadal hormones. Finally, we identify several gaps in our understanding of "if" and "how" DYN and KORs modulate addictive behavior in a sex dependent manner. Future work may address these gaps by building on the mechanistic studies outlined in this review. Ultimately this will enable the development of novel and effective addiction treatments tailored to either males or females. PMID- 26733783 TI - Sign Tracking, but Not Goal Tracking, is Resistant to Outcome Devaluation. AB - During Pavlovian conditioning, a conditioned stimulus (CS) may act as a predictor of a reward to be delivered in another location. Individuals vary widely in their propensity to engage with the CS (sign tracking) or with the site of eventual reward (goal tracking). It is often assumed that sign tracking involves the association of the CS with the motivational value of the reward, resulting in the CS acquiring incentive value independent of the outcome. However, experimental evidence for this assumption is lacking. In order to test the hypothesis that sign tracking behavior does not rely on a neural representation of the outcome, we employed a reward devaluation procedure. We trained rats on a classic Pavlovian paradigm in which a lever CS was paired with a sucrose reward, then devalued the reward by pairing sucrose with illness in the absence of the CS. We found that sign tracking behavior was enhanced, rather than diminished, following reward devaluation; thus, sign tracking is clearly independent of a representation of the outcome. In contrast, goal tracking behavior was decreased by reward devaluation. Furthermore, when we divided rats into those with high propensity to engage with the lever (sign trackers) and low propensity to engage with the lever (goal trackers), we found that nearly all of the effects of devaluation could be attributed to the goal trackers. These results show that sign tracking and goal tracking behavior may be the output of different associative structures in the brain, providing insight into the mechanisms by which reward-associated stimuli-such as drug cues-come to exert control over behavior in some individuals. PMID- 26733785 TI - Ventral Midbrain NTS1 Receptors Mediate Conditioned Reward Induced by the Neurotensin Analog, D-Tyr[11]neurotensin. AB - The present study was aimed at characterizing the mechanisms by which neurotensin (NT) is acting within the ventral midbrain to induce a psychostimulant-like effect. In a first experiment, we determine which subtype(s) of NT receptors is/are involved in the reward-inducing effect of ventral midbrain microinjection of NT using the conditioned place-preference (CPP) paradigm. In a second study, we used in vitro patch clamp recording technique to characterize the NT receptor subtype(s) involved in the modulation of glutamatergic neurotransmission (excitatory post-synaptic current, EPSC) in ventral tegmental neurons that expressed ([Formula: see text]), or do not express ([Formula: see text]), a hyperpolarization-activated cationic current. Behavioral studies were performed with adult male Long-Evans rats while electrophysiological recordings were obtained from brain slices of rat pups aged between 14 and 21 days. Results show that bilateral ventral midbrain microinjections of 1.5 and 3 nmol of D Tyr[(11)]NT induced a CPP that was respectively attenuated or blocked by co injection with 1.2 nmol of the NTS1/NTS2 antagonist, SR142948, and the preferred NTS1 antagonist, SR48692. In electrophysiological experiments, D-Tyr[(11)]NT (0.01-0.5 MUM) attenuated glutamatergic EPSC in [Formula: see text] but enhanced it in [Formula: see text] neurons. The attenuation effect ([Formula: see text] neurons) was blocked by SR142948 (0.1 MUM) while the enhancement effect ([Formula: see text] neurons) was blocked by both antagonists (0.1 MUM). These findings suggest that (i) NT is acting on ventral midbrain NTS1 receptors to induce a rewarding effect and (ii) that this psychostimulant-like effect could be due to a direct action of NT on dopamine neurons and/or an enhancement of glutamatergic inputs to non-dopamine ([Formula: see text]) neurons. PMID- 26733786 TI - Inter-Individual Responses to Experimental Muscle Pain: Baseline Physiological Parameters Do Not Determine Whether Muscle Sympathetic Nerve Activity Increases or Decreases During Pain. AB - We have previously reported that there are inter-individual differences in the cardiovascular responses to experimental muscle pain, which are consistent over time: intramuscular infusion of hypertonic saline, causing pain lasting ~60 min, increases muscle sympathetic nerve activity (MSNA)-as well as blood pressure and heart rate-in certain subjects, but decrease it in others. Here, we tested the hypothesis that baseline physiological parameters (resting MSNA, heart rate, blood pressure, heart rate variability) determine the cardiovascular responses to long-lasting muscle pain. MSNA was recorded from the common peroneal nerve, together with heart rate and blood pressure, during a 45-min intramuscular infusion of hypertonic saline solution into the tibialis anterior of 50 awake human subjects (25 females and 25 males). Twenty-four subjects showed a sustained increase in mean amplitude of MSNA (160.9 +/- 7.3%), while 26 showed a sustained decrease (55.1 +/- 3.5%). Between the increasing and decreasing groups there were no differences in baseline MSNA (19.0 +/- 1.5 vs. 18.9 +/- 1.2 bursts/min), mean BP (88.1 +/- 5.2 vs. 88.0 +/- 3.8 mmHg), HR (74.7 +/- 2.0 vs. 72.8 +/- 1.8 beats/min) or heart rate variability (LF/HF 1.8 +/- 0.2 vs. 2.2 +/- 0.3). Furthermore, neither sex nor body mass index had any effect on whether MSNA increased or decreased during tonic muscle pain. We conclude that the measured baseline physiological parameters cannot account for the divergent sympathetic responses during tonic muscle pain. PMID- 26733787 TI - Identification of Voxels Confounded by Venous Signals Using Resting-State fMRI Functional Connectivity Graph Community Identification. AB - Identifying venous voxels in fMRI datasets is important to increase the specificity of fMRI analyses to microvasculature in the vicinity of the neural processes triggering the BOLD response. This is, however, difficult to achieve in particular in typical studies where magnitude images of BOLD EPI are the only data available. In this study, voxelwise functional connectivity graphs were computed on minimally preprocessed low TR (333 ms) multiband resting-state fMRI data, using both high positive and negative correlations to define edges between nodes (voxels). A high correlation threshold for binarization ensures that most edges in the resulting sparse graph reflect the high coherence of signals in medium to large veins. Graph clustering based on the optimization of modularity was then employed to identify clusters of coherent voxels in this graph, and all clusters of 50 or more voxels were then interpreted as corresponding to medium to large veins. Indeed, a comparison with SWI reveals that 75.6+/-5.9% of voxels within these large clusters overlap with veins visible in the SWI image or lie outside the brain parenchyma. Some of the remaining differences between the two modalities can be explained by imperfect alignment or geometric distortions between the two images. Overall, the graph clustering based method for identifying venous voxels has a high specificity as well as the additional advantages of being computed in the same voxel grid as the fMRI dataset itself and not needing any additional data beyond what is usually acquired (and exported) in standard fMRI experiments. PMID- 26733784 TI - Chronic Glutamate Toxicity in Neurodegenerative Diseases-What is the Evidence? AB - Together with aspartate, glutamate is the major excitatory neurotransmitter in the brain. Glutamate binds and activates both ligand-gated ion channels (ionotropic glutamate receptors) and a class of G-protein coupled receptors (metabotropic glutamate receptors). Although the intracellular glutamate concentration in the brain is in the millimolar range, the extracellular glutamate concentration is kept in the low micromolar range by the action of excitatory amino acid transporters that import glutamate and aspartate into astrocytes and neurons. Excess extracellular glutamate may lead to excitotoxicity in vitro and in vivo in acute insults like ischemic stroke via the overactivation of ionotropic glutamate receptors. In addition, chronic excitotoxicity has been hypothesized to play a role in numerous neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. Based on this hypothesis, a good deal of effort has been devoted to develop and test drugs that either inhibit glutamate receptors or decrease extracellular glutamate. In this review, we provide an overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration. In addition, we summarize the available experimental evidence for glutamate toxicity in animal models of neurodegenerative diseases. PMID- 26733788 TI - Autonomous Parameter Adjustment for SSVEP-Based BCIs with a Novel BCI Wizard. AB - Brain-Computer Interfaces (BCIs) transfer human brain activities into computer commands and enable a communication channel without requiring movement. Among other BCI approaches, steady-state visual evoked potential (SSVEP)-based BCIs have the potential to become accurate, assistive technologies for persons with severe disabilities. Those systems require customization of different kinds of parameters (e.g., stimulation frequencies). Calibration usually requires selecting predefined parameters by experienced/trained personnel, though in real life scenarios an interface allowing people with no experience in programming to set up the BCI would be desirable. Another occurring problem regarding BCI performance is BCI illiteracy (also called BCI deficiency). Many articles reported that BCI control could not be achieved by a non-negligible number of users. In order to bypass those problems we developed a SSVEP-BCI wizard, a system that automatically determines user-dependent key-parameters to customize SSVEP-based BCI systems. This wizard was tested and evaluated with 61 healthy subjects. All subjects were asked to spell the phrase "RHINE WAAL UNIVERSITY" with a spelling application after key parameters were determined by the wizard. Results show that all subjects were able to control the spelling application. A mean (SD) accuracy of 97.14 (3.73)% was reached (all subjects reached an accuracy above 85% and 25 subjects even reached 100% accuracy). PMID- 26733790 TI - Mutations and Modeling of the Chromatin Remodeler CHD8 Define an Emerging Autism Etiology. AB - Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder with a strong but complex genetic component. Recent family based exome-sequencing strategies have identified recurrent de novo mutations at specific genes, providing strong evidence for ASD risk, but also highlighting the extreme genetic heterogeneity of the disorder. However, disruptions in these genes converge on key molecular pathways early in development. In particular, functional enrichment analyses have found that there is a bias toward genes involved in transcriptional regulation, such as chromatin modifiers. Here we review recent genetic, animal model, co-expression network, and functional genomics studies relating to the high confidence ASD risk gene, CHD8. CHD8, a chromatin remodeling factor, may serve as a "master regulator" of a common ASD etiology. Individuals with a CHD8 mutation show an ASD subtype that includes similar physical characteristics, such as macrocephaly and prolonged GI problems including recurrent constipation. Similarly, animal models of CHD8 disruption exhibit enlarged head circumference and reduced gut motility phenotypes. Systems biology approaches suggest CHD8 and other candidate ASD risk genes are enriched during mid-fetal development, which may represent a critical time window in ASD etiology. Transcription and CHD8 binding site profiles from cell and primary tissue models of early development indicate that CHD8 may also positively regulate other candidate ASD risk genes through both direct and indirect means. However, continued study is needed to elucidate the mechanism of regulation as well as identify which CHD8 targets are most relevant to ASD risk. Overall, these initial studies suggest the potential for common ASD etiologies and the development of personalized treatments in the future. PMID- 26733791 TI - Functional Electrical Stimulation Alters the Postural Component of Locomotor Activity in Healthy Humans. AB - Knowledge of the effects of Functional Electrical Stimulation (FES) of different intensity on postural stability during walking in healthy subjects is necessary before these relationships in patients with postural disorders can be assessed and understood. We examined healthy subjects in Control group walking on a treadmill for 40 min and in FES group-provided with 30 min of stimulation, which intensity increased every 10 min. The main difference between Control and FES group was the progressive increase of trunk oscillations in sagittal, frontal, and horizontal planes and an increase of relative stance duration in parallel with FES intensity increase. Both Control and FES groups exhibited shank elevation angle increase as an after-effect. It is concluded, that high intensity FES significantly changes the postural component of locomotor activity, but the fatigue signs afterwards were not FES specific. PMID- 26733789 TI - Melanin-Concentrating Hormone (MCH): Role in REM Sleep and Depression. AB - The melanin-concentrating hormone (MCH) is a peptidergic neuromodulator synthesized by neurons of the lateral sector of the posterior hypothalamus and zona incerta. MCHergic neurons project throughout the central nervous system, including areas such as the dorsal (DR) and median (MR) raphe nuclei, which are involved in the control of sleep and mood. Major Depression (MD) is a prevalent psychiatric disease diagnosed on the basis of symptomatic criteria such as sadness or melancholia, guilt, irritability, and anhedonia. A short REM sleep latency (i.e., the interval between sleep onset and the first REM sleep period), as well as an increase in the duration of REM sleep and the density of rapid-eye movements during this state, are considered important biological markers of depression. The fact that the greatest firing rate of MCHergic neurons occurs during REM sleep and that optogenetic stimulation of these neurons induces sleep, tends to indicate that MCH plays a critical role in the generation and maintenance of sleep, especially REM sleep. In addition, the acute microinjection of MCH into the DR promotes REM sleep, while immunoneutralization of this peptide within the DR decreases the time spent in this state. Moreover, microinjections of MCH into either the DR or MR promote a depressive-like behavior. In the DR, this effect is prevented by the systemic administration of antidepressant drugs (either fluoxetine or nortriptyline) and blocked by the intra-DR microinjection of a specific MCH receptor antagonist. Using electrophysiological and microdialysis techniques we demonstrated also that MCH decreases the activity of serotonergic DR neurons. Therefore, there are substantive experimental data suggesting that the MCHergic system plays a role in the control of REM sleep and, in addition, in the pathophysiology of depression. Consequently, in the present report, we summarize and evaluate the current data and hypotheses related to the role of MCH in REM sleep and MD. PMID- 26733792 TI - Association Between Alzheimer's Disease and Glaucoma: A Study Based on Heidelberg Retinal Tomography and Frequency Doubling Technology Perimetry. AB - AIM: To assess the frequency of glaucoma-like alterations in Alzheimer's disease (AD) patients using Heidelberg Retinal Tomograph III (HRT-3) and Frequency Doubling Technology (FDT) perimetry. METHODS: The study included 51 eyes of 51 AD subjects and 67 eyes of 67 age- and sex-matched controls. Subjects underwent an ophthalmological examination including measurements of intraocular pressure (IOP), Matrix FDT visual field testing, optic nerve head morphology and retinal nerve fiber layer thickness (RNFLt) assessment by slit-lamp biomicroscopy and HRT 3. RESULTS: The frequency of alterations was significantly higher in the AD group (27.5 vs. 7.5%; p = 0.003; OR = 4.69). AD patients showed lower IOP (p = 0.000) despite not significantly different values of central corneal thickness (CCT) between the groups (p = 0.336). Of all the stereometric parameters measured by HRT-3, RNFLt was significantly lower in AD patients (p = 0.013). This group also had significantly worse results in terms of Moorfields Regression Analysis (p = 0.027). Matrix showed significantly worse Mean Deviation (MD) (p = 0.000) and Pattern Standard Deviation (PSD) (p = 0.000) values and more altered Glaucoma Hemifield Test (p = 0.006) in AD patients. Pearson's R correlation test showed that Mini Mental State Examination is directly correlated with MD (R = 0.349; p = 0.034) and inversely correlated with PSD (R = -0.357; p = 0.030). CONCLUSION: Patients with AD have a higher frequency of glaucoma-like alterations, as detected by the use of HRT-3. These alterations were not associated with elevated IOP or abnormal CCT values. PMID- 26733794 TI - Poker-DVS and MNIST-DVS. Their History, How They Were Made, and Other Details. AB - This article reports on two databases for event-driven object recognition using a Dynamic Vision Sensor (DVS). The first, which we call Poker-DVS and is being released together with this article, was obtained by browsing specially made poker card decks in front of a DVS camera for 2-4 s. Each card appeared on the screen for about 20-30 ms. The poker pips were tracked and isolated off-line to constitute the 131-recording Poker-DVS database. The second database, which we call MNIST-DVS and which was released in December 2013, consists of a set of 30,000 DVS camera recordings obtained by displaying 10,000 moving symbols from the standard MNIST 70,000-picture database on an LCD monitor for about 2-3 s each. Each of the 10,000 symbols was displayed at three different scales, so that event-driven object recognition algorithms could easily be tested for different object sizes. This article tells the story behind both databases, covering, among other aspects, details of how they work and the reasons for their creation. We provide not only the databases with corresponding scripts, but also the scripts and data used to generate the figures shown in this article (as Supplementary Material). PMID- 26733793 TI - Nanoparticle-Based and Bioengineered Probes and Sensors to Detect Physiological and Pathological Biomarkers in Neural Cells. AB - Nanotechnology, a rapidly evolving field, provides simple and practical tools to investigate the nervous system in health and disease. Among these tools are nanoparticle-based probes and sensors that detect biochemical and physiological properties of neurons and glia, and generate signals proportionate to physical, chemical, and/or electrical changes in these cells. In this context, quantum dots (QDs), carbon-based structures (C-dots, grapheme, and nanodiamonds) and gold nanoparticles are the most commonly used nanostructures. They can detect and measure enzymatic activities of proteases (metalloproteinases, caspases), ions, metabolites, and other biomolecules under physiological or pathological conditions in neural cells. Here, we provide some examples of nanoparticle-based and genetically engineered probes and sensors that are used to reveal changes in protease activities and calcium ion concentrations. Although significant progress in developing these tools has been made for probing neural cells, several challenges remain. We review many common hurdles in sensor development, while highlighting certain advances. In the end, we propose some future directions and ideas for developing practical tools for neural cell investigations, based on the maxim "Measure what is measurable, and make measurable what is not so" (Galileo Galilei). PMID- 26733795 TI - Imaging Multimodalities for Dissecting Alzheimer's Disease: Advanced Technologies of Positron Emission Tomography and Fluorescence Imaging. AB - The rapid progress in advanced imaging technologies has expanded our toolbox for monitoring a variety of biological aspects in living subjects including human. In vivo radiological imaging using small chemical tracers, such as with positron emission tomography, represents an especially vital breakthrough in the efforts to improve our understanding of the complicated cascade of neurodegenerative disorders including Alzheimer's disease (AD), and it has provided the most reliable visible biomarkers for enabling clinical diagnosis. At the same time, in combination with genetically modified animal model systems, the most recent innovation of fluorescence imaging is helping establish diverse applications in basic neuroscience research, from single-molecule analysis to animal behavior manipulation, suggesting the potential utility of fluorescence technology for dissecting the detailed molecular-based consequence of AD pathophysiology. In this review, our primary focus is on a current update of PET radiotracers and fluorescence indicators beneficial for understanding the AD cascade, and discussion of the utility and pitfalls of those imaging modalities for future translational research applications. We will also highlight current cutting-edge genetic approaches and discuss how to integrate individual technologies for further potential innovations. PMID- 26733797 TI - Commentary: Structural and functional features of central nervous system lymphatic vessels. PMID- 26733796 TI - Post-Translational Modifications of Histones in Vertebrate Neurogenesis. AB - The process of neurogenesis, through which the entire nervous system of an organism is formed, has attracted immense scientific attention for decades. How can a single neural stem cell give rise to astrocytes, oligodendrocytes, and neurons? Furthermore, how is a neuron led to choose between the hundreds of different neuronal subtypes that the vertebrate CNS contains? Traditionally, niche signals and transcription factors have been on the spotlight. Recent research is increasingly demonstrating that the answer may partially lie in epigenetic regulation of gene expression. In this article, we comprehensively review the role of post-translational histone modifications in neurogenesis in both the embryonic and adult CNS. PMID- 26733798 TI - A Transgenic Rat for Investigating the Anatomy and Function of Corticotrophin Releasing Factor Circuits. AB - Corticotrophin-releasing factor (CRF) is a 41 amino acid neuropeptide that coordinates adaptive responses to stress. CRF projections from neurons in the central nucleus of the amygdala (CeA) to the brainstem are of particular interest for their role in motivated behavior. To directly examine the anatomy and function of CRF neurons, we generated a BAC transgenic Crh-Cre rat in which bacterial Cre recombinase is expressed from the Crh promoter. Using Cre-dependent reporters, we found that Cre expressing neurons in these rats are immunoreactive for CRF and are clustered in the lateral CeA (CeL) and the oval nucleus of the BNST. We detected major projections from CeA CRF neurons to parabrachial nuclei and the locus coeruleus, dorsal and ventral BNST, and more minor projections to lateral portions of the substantia nigra, ventral tegmental area, and lateral hypothalamus. Optogenetic stimulation of CeA CRF neurons evoked GABA-ergic responses in 11% of non-CRF neurons in the medial CeA (CeM) and 44% of non-CRF neurons in the CeL. Chemogenetic stimulation of CeA CRF neurons induced Fos in a similar proportion of non-CRF CeM neurons but a smaller proportion of non-CRF CeL neurons. The CRF1 receptor antagonist R121919 reduced this Fos induction by two thirds in these regions. These results indicate that CeL CRF neurons provide both local inhibitory GABA and excitatory CRF signals to other CeA neurons, and demonstrate the value of the Crh-Cre rat as a tool for studying circuit function and physiology of CRF neurons. PMID- 26733800 TI - Editorial: Application of Genetically Encoded Indicators to Mammalian Central Nervous System. PMID- 26733799 TI - Ribosomal Protein S6 Phosphorylation in the Nervous System: From Regulation to Function. AB - Since the discovery of the phosphorylation of the 40S ribosomal protein S6 (rpS6) about four decades ago, much effort has been made to uncover the molecular mechanisms underlying the regulation of this post-translational modification. In the field of neuroscience, rpS6 phosphorylation is commonly used as a readout of the mammalian target of rapamycin complex 1 signaling activation or as a marker for neuronal activity. Nevertheless, its biological role in neurons still remains puzzling. Here we review the pharmacological and physiological stimuli regulating this modification in the nervous system as well as the pathways that transduce these signals into rpS6 phosphorylation. Altered rpS6 phosphorylation observed in various genetic and pathophysiological mouse models is also discussed. Finally, we examine the current state of knowledge on the physiological role of this post translational modification and highlight the questions that remain to be addressed. PMID- 26733801 TI - NF-kappaB Signaling Pathways in Neurological Inflammation: A Mini Review. AB - The NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) transcription factor family is a pleiotropic regulator of many cellular signaling pathways, providing a mechanism for the cells in response to a wide variety of stimuli linking to inflammation. The stimulated cells will be regulated by not only the canonical but also non-canonical NF-kappaB pathways. To initiate both of these pathways, IkappaB-degradation triggers NF-kappaB release and the nuclear translocated-heterodimer (or homodimer) can associate with the kappaB sites of promoter to regulate the gene transcriptions. NF-kappaB ubiquitously expresses in neurons and the constitutive NF-kappaB activation is associated with processing of neuronal information. NF-kappaB can regulate the transcription of genes such as chemokines, cytokines, proinflammatory enzymes, adhesion molecules, proinflammatory transcription factors, and other factors to modulate the neuronal survival. In neuronal insult, NF-kappaB constitutively active in neuron cell bodies can protect neurons against different injuries and regulate the neuronal inflammatory reactions. Besides neurons, NF-kappaB transcription factors are abundant in glial cells and cerebral blood vessels and the diverse functions of NF-kappaB also regulate the inflammatory reaction around the neuronal environment. NF-kappaB transcription factors are abundant in the brain and exhibit diverse functions. Several central nerve system (CNS) diseases are linked to NF-kappaB activated by inflammatory mediators. The RelA and c-Rel expression produce opposite effects on neuronal survival. Importantly, c-Rel expression in CNS plays a critical role in anti-apoptosis and reduces the age-related behaviors. Moreover, the different subunits of NF-kappaB dimer formation can modulate the neuroninflammation, neuronal protection, or neurotoxicity. The diverse functions of NF-kappaB depend on the subunits of the NF-kappaB dimer formation which enable us to develop a therapeutic approach to neuroinflammation based on a new concept of inflammation as a strategic tool in neuronal cells. However, the detail role of NF-kappaB in neuroinflammation, remains to be clarified. In the present article, we provide an updated review of the current state of our knowledge about relationship between NF-kappaB and neuroinflammation. PMID- 26733802 TI - Disturbances of Ligand Potency and Enhanced Degradation of the Human Glycine Receptor at Affected Positions G160 and T162 Originally Identified in Patients Suffering from Hyperekplexia. AB - Ligand-binding of Cys-loop receptors is determined by N-terminal extracellular loop structures from the plus as well as from the minus side of two adjacent subunits in the pentameric receptor complex. An aromatic residue in loop B of the glycine receptor (GlyR) undergoes direct interaction with the incoming ligand via a cation-pi interaction. Recently, we showed that mutated residues in loop B identified from human patients suffering from hyperekplexia disturb ligand binding. Here, we exchanged the affected human residues by amino acids found in related members of the Cys-loop receptor family to determine the effects of side chain volume for ion channel properties. GlyR variants were characterized in vitro following transfection into cell lines in order to analyze protein expression, trafficking, degradation and ion channel function. GlyR alpha1 G160 mutations significantly decrease glycine potency arguing for a positional effect on neighboring aromatic residues and consequently glycine-binding within the ligand-binding pocket. Disturbed glycinergic inhibition due to T162 alpha1 mutations is an additive effect of affected biogenesis and structural changes within the ligand-binding site. Protein trafficking from the ER toward the ER Golgi intermediate compartment, the secretory Golgi pathways and finally the cell surface is largely diminished, but still sufficient to deliver ion channels that are functional at least at high glycine concentrations. The majority of T162 mutant protein accumulates in the ER and is delivered to ER-associated proteasomal degradation. Hence, G160 is an important determinant during glycine binding. In contrast, T162 affects primarily receptor biogenesis whereas exchanges in functionality are secondary effects thereof. PMID- 26733804 TI - ErbB4 in Laminated Brain Structures: A Neurodevelopmental Approach to Schizophrenia. AB - The susceptibility genes for schizophrenia Neuregulin-1 (NRG1) and ErbB4 have critical functions during brain development and in the adult. Alterations in the ErbB4 signaling pathway cause a variety of neurodevelopmental defects including deficiencies in neuronal migration, synaptic plasticity, and myelination. I have used the ErbB4(-/-) HER4(heart) KO mice to study the neurodevelopmental insults associated to deficiencies in the NRG1-ErbB4 signaling pathway and their potential implication with brain disorders such as schizophrenia, a chronic psychiatric disease affecting 1% of the population worldwide. ErbB4 deletion results in an array of neurodevelopmental deficits that are consistent with a schizophrenic model. First, similar defects appear in multiple brain structures, from the cortex to the cerebellum. Second, these defects affect multiple aspects of brain development, from deficits in neuronal migration to impairments in excitatory/inhibitory systems, including reductions in brain volume, cortical and cerebellar heterotopias, alterations in number and distribution of specific subpopulations of interneurons, deficiencies in the astrocytic and oligodendrocytic lineages, and additional insults in major brain structures. This suggests that alterations in specific neurodevelopmental genes that play similar functions in multiple neuroanatomical structures might account for some of the symptomatology observed in schizophrenic patients, such as defects in cognition. ErbB4 mutation uncovers flaws in brain development that are compatible with a neurodevelopmental model of schizophrenia, and it establishes a comprehensive model to study the basis of the disorder before symptoms are detected in the adult. PMID- 26733806 TI - Commentary: GABA depolarizes immature neurons and inhibits network activity in the neonatal neocortex in vivo. PMID- 26733803 TI - A New Outlook on Mental Illnesses: Glial Involvement Beyond the Glue. AB - Mental illnesses have long been perceived as the exclusive consequence of abnormalities in neuronal functioning. Until recently, the role of glial cells in the pathophysiology of mental diseases has largely been overlooked. However recently, multiple lines of evidence suggest more diverse and significant functions of glia with behavior-altering effects. The newly ascribed roles of astrocytes, oligodendrocytes and microglia have led to their examination in brain pathology and mental illnesses. Indeed, abnormalities in glial function, structure and density have been observed in postmortem brain studies of subjects diagnosed with mental illnesses. In this review, we discuss the newly identified functions of glia and highlight the findings of glial abnormalities in psychiatric disorders. We discuss these preclinical and clinical findings implicating the involvement of glial cells in mental illnesses with the perspective that these cells may represent a new target for treatment. PMID- 26733807 TI - Methyl-CpG Binding Protein 2 (Mecp2) Regulates Sensory Function Through Sema5b and Robo2. AB - Mutations in the gene encoding the MECP2 underlies Rett syndrome, a neurodevelopmental disorder in young females. Although reduced pain sensitivity in Rett syndrome patients and in partial MeCP2 deficient mice had been reported, these previous studies focused predominantly on motor impairments. Therefore, it is still unknown how MeCP2 is involved in these sensory defects. In addition, the human disease manifestations where males with mutations in MECP2 gene normally do not survive and females show typical neurological symptoms only after 18 months of age, is profoundly different in MeCP2-deficient mouse where all animals survived, and males but not females displayed Rett syndrome phenotypes at an early age. Thus, the mecp2-deficient zebrafish serves as an additional animal model to aid in deciphering the role and mechanisms of Mecp2 in neurodevelopment. Here, we used two independent methods of silencing expression of Mecp2 in zebrafish to uncover a novel role of Mecp2 in trigeminal ganglion sensory neurons during the embryonic development. mecp2-null mutation and morpholino-mediated silencing of Mecp2 in the zebrafish embryos resulted in defects in peripheral innervation of trigeminal sensory neurons and consequently affecting the sensory function. These defects were demonstrated to be dependent on the expression of Sema5b and Robo2. The expression of both proteins together could better overcome the defects caused by Mecp2 deficiency as compared to the expression of either Sema5b or Robo2 alone. Sema5b and Robo2 were downregulated upon Mecp2 silencing or in mecp2-null embryos, and Chromatin immunoprecipitation (ChIP) assay using antibody against Mecp2 was able to pull down specific regions of both Sema5b and Robo2 promoters, showing interaction between Mecp2 and the promoters of both genes. In addition, cell-specific expression of Mecp2 can overcome the innervation and sensory response defects in Mecp2 morphants indicating that these MeCP2-mediated defects are cell-autonomous. The sensory deficits caused by Mecp2 deficiency mirror the diminished sensory response observed in Rett syndrome patients. This suggests that zebrafish could be an unconventional but useful model for this disorder manifesting defects that are not easily studied in full using rodent models. PMID- 26733805 TI - Neuroinflammation and Depression: Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation. AB - Patients with chronic inflammation are often associated with the emergence of depression symptoms, while diagnosed depressed patients show increased levels of circulating cytokines. Further studies revealed the activation of the brain immune cell microglia in depressed patients with a greater magnitude in individuals that committed suicide, indicating a crucial role for neuroinflammation in depression brain pathogenesis. Rapid advances in the understanding of microglial and astrocytic neurobiology were obtained in the past 15-20 years. Indeed, recent data reveal that microglia play an important role in managing neuronal cell death, neurogenesis, and synaptic interactions, besides their involvement in immune-response generating cytokines. The communication between microglia and neurons is essential to synchronize these diverse functions with brain activity. Evidence is accumulating that secreted extracellular vesicles (EVs), comprising ectosomes and exosomes with a size ranging from 0.1-1 MUm, are key players in intercellular signaling. These EVs may carry specific proteins, mRNAs and microRNAs (miRNAs). Transfer of exosomes to neurons was shown to be mediated by oligodendrocytes, microglia and astrocytes that may either be supportive to neurons, or instead disseminate the disease. Interestingly, several recent reports have identified changes in miRNAs in depressed patients, which target not only crucial pathways associated with synaptic plasticity, learning and memory but also the production of neurotrophic factors and immune cell modulation. In this article, we discuss the role of neuroinflammation in the emergence of depression, namely dynamic alterations in the status of microglia response to stimulation, and how their activation phenotypes may have an etiological role in neurodegeneneration, in particular in depressive-like behavior. We will overview the involvement of miRNAs, exosomes, ectosomes and microglia in regulating critical pathways associated with depression and how they may contribute to other brain disorders including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD), which share several neuroinflammatory-associated processes. Specific reference will be made to EVs as potential biomarkers and disease monitoring approaches, focusing on their potentialities as drug delivery vehicles, and on putative therapeutic strategies using autologous exosome-based delivery systems to treat neurodegenerative and psychiatric disorders. PMID- 26733808 TI - Emotional Distraction and Bodily Reaction: Modulation of Autonomous Responses by Anodal tDCS to the Prefrontal Cortex. AB - Prefrontal electric stimulation has been demonstrated to effectively modulate cognitive processing. Specifically, the amelioration of cognitive control (CC) over emotional distraction by transcranial direct current stimulation (tDCS) points toward targeted therapeutic applications in various psychiatric disorders. In addition to behavioral measures, autonomous nervous system (ANS) responses are fundamental bodily signatures of emotional information processing. However, interactions between the modulation of CC by tDCS and ANS responses have received limited attention. We here report on ANS data gathered in healthy subjects that performed an emotional CC task parallel to the modulation of left prefrontal cortical activity by 1 mA anodal or sham tDCS. Skin conductance responses (SCRs) to negative and neutral pictures of human scenes were reduced by anodal as compared to sham tDCS. Individual SCR amplitude variations were associated with the amount of distraction. Moreover, the stimulation-driven performance- and SCR modulations were related in form of a quadratic, inverse-U function. Thus, our results indicate that non-invasive brain stimulation (i.e., anodal tDCS) can modulate autonomous responses synchronous to behavioral improvements, but the range of possible concurrent improvements from prefrontal stimulation is limited. Interactions between cognitive, affective, neurophysiological, and vegetative responses to emotional content can shape brain stimulation effectiveness and require theory-driven integration in potential treatment protocols. PMID- 26733809 TI - Acid-Sensing Ion Channels Expression, Identity and Role in the Excitability of the Cochlear Afferent Neurons. AB - Acid-sensing ion channels (ASICs) are activated by an increase in the extracellular proton concentration. There are four genes (ASIC1-4) that encode six subunits, and they are involved in diverse neuronal functions, such as mechanosensation, learning and memory, nociception, and modulation of retinal function. In this study, we characterize the ASIC currents of spiral ganglion neurons (SGNs). These ASIC currents are primarily carried by Na(+), exhibit fast activation and desensitization, display a pH50 of 6.2 and are blocked by amiloride, indicating that these are ASIC currents. The ASIC currents were further characterized using several pharmacological tools. Gadolinium and acetylsalicylic acid reduced these currents, and FMRFamide, zinc (at high concentrations) and N,N,N',N'-tetrakis-(2-piridilmetil)-ethylenediamine increased them, indicating that functional ASICs are composed of the subunits ASIC1, ASIC2, and ASIC3. Neomycin and streptomycin reduced the desensitization rate of the ASIC current in SGNs, indicating that ASICs may contribute to the ototoxic action of aminoglycosides. RT-PCR of the spiral ganglion revealed significant expression of all ASIC subunits. By immunohistochemistry the expression of the ASIC1a, ASIC2a, ASIC2b, and ASIC3 subunits was detected in SGNs. Although only a few SGNs exhibited action potential firing in response to an acidic stimulus, protons in the extracellular solution modulated SGN activity during sinusoidal stimulation. Our results show that protons modulate the excitability of SGNs via ASICs. PMID- 26733810 TI - Astrocytes and Muller Cell Alterations During Retinal Degeneration in a Transgenic Rat Model of Retinitis Pigmentosa. AB - PURPOSE: Retinitis pigmentosa includes a group of progressive retinal degenerative diseases that affect the structure and function of photoreceptors. Secondarily to the loss of photoreceptors, there is a reduction in retinal vascularization, which seems to influence the cellular degenerative process. Retinal macroglial cells, astrocytes, and Muller cells provide support for retinal neurons and are fundamental for maintaining normal retinal function. The aim of this study was to investigate the evolution of macroglial changes during retinal degeneration in P23H rats. METHODS: Homozygous P23H line-3 rats aged from P18 to 18 months were used to study the evolution of the disease, and SD rats were used as controls. Immunolabeling with antibodies against GFAP, vimentin, and transducin were used to visualize macroglial cells and cone photoreceptors. RESULTS: In P23H rats, increased GFAP labeling in Muller cells was observed as an early indicator of retinal gliosis. At 4 and 12 months of age, the apical processes of Muller cells in P23H rats clustered in firework-like structures, which were associated with ring-like shaped areas of cone degeneration in the outer nuclear layer. These structures were not observed at 16 months of age. The number of astrocytes was higher in P23H rats than in the SD matched controls at 4 and 12 months of age, supporting the idea of astrocyte proliferation. As the disease progressed, astrocytes exhibited a deteriorated morphology and marked hypertrophy. The increase in the complexity of the astrocytic processes correlated with greater connexin 43 expression and higher density of connexin 43 immunoreactive puncta within the ganglion cell layer (GCL) of P23H vs. SD rat retinas. CONCLUSIONS: In the P23H rat model of retinitis pigmentosa, the loss of photoreceptors triggers major changes in the number and morphology of glial cells affecting the inner retina. PMID- 26733811 TI - Receptor for Advanced Glycation End Products and its Inflammatory Ligands are Upregulated in Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder of largely unknown pathogenesis. Recent studies suggest that enhanced oxidative stress and neuroinflammation contribute to the progression of the disease. Mounting evidence implicates the receptor for advanced glycation end-products (RAGE) as a significant contributor to the pathogenesis of certain neurodegenerative diseases and chronic conditions. It is hypothesized that detrimental actions of RAGE are triggered upon binding to its ligands, such as AGEs (advanced glycation end products), S100/calgranulin family members, and High Mobility Group Box-1 (HMGB1) proteins. Here, we examined the expression of RAGE and its ligands in human ALS spinal cord. Tissue samples from age-matched human control and ALS spinal cords were tested for the expression of RAGE, carboxymethyllysine (CML) AGE, S100B, and HMGB1, and intensity of the immunofluorescent and immunoblotting signals was assessed. We found that the expression of both RAGE and its ligands was significantly increased in the spinal cords of ALS patients versus age-matched control subjects. Our study is the first report describing co-expression of both RAGE and its ligands in human ALS spinal cords. These findings suggest that further probing of RAGE as a mechanism of neurodegeneration in human ALS is rational. PMID- 26733812 TI - Alterations in Kainate Receptor and TRPM1 Localization in Bipolar Cells after Retinal Photoreceptor Degeneration. AB - Photoreceptor degeneration differentially impacts glutamatergic signaling in downstream On and Off bipolar cells. In rodent models, photoreceptor degeneration leads to loss of glutamatergic signaling in On bipolar cells, whereas Off bipolar cells appear to retain glutamate sensitivity, even after extensive photoreceptor loss. The localization and identity of the receptors that mediate these residual glutamate responses in Off bipolar cells have not been determined. Recent studies show that macaque and mouse Off bipolar cells receive glutamatergic input primarily through kainate-type glutamate receptors. Here, we studied the impact of photoreceptor degeneration on glutamate receptor and their associated proteins in Off and On bipolar cells. We show that the kainate receptor subunit, GluK1, persists in remodeled Off bipolar cell dendrites of the rd10 mouse retina. However, the pattern of expression is altered and the intensity of staining is reduced compared to wild-type retina. The kainate receptor auxiliary subunit, Neto1, also remains in Off bipolar cell dendrites after extensive photoreceptor degeneration. Similar preservation of kainate receptor subunits was evident in human retina in which photoreceptors had degenerated due to serous retinal detachment. In contrast, photoreceptor degeneration leads to loss of synaptic expression of TRPM1 in mouse and human On bipolar cells, but strong somatic expression remains. These findings demonstrate that Off bipolar cells retain dendritic glutamate receptors during retinal degeneration and could thus serve as a conduit for signal transmission from transplanted or optogenetically restored photoreceptors. PMID- 26733813 TI - Gliopathy of Demyelinating and Non-Demyelinating Strains of Mouse Hepatitis Virus. AB - Demyelination in the central nervous system induced by neurovirulent strains of Mouse Hepatitis Virus (MHV) is mediated by the viral spike glycoprotein, but it is not clear whether the mechanism of this disease pathology involves direct viral infection of oligodendrocytes. Detailed studies of glial cell tropism of MHV are presented, demonstrating that direct MHV infection of oligodendrocytes differs between demyelinating (RSA59) and non-demyelinating (RSMHV2) viral strains both in vitro and in vivo. Our results indicate that direct injury of mature oligodendrocytes is an important mechanism of virus-induced demyelination. In vivo, RSA59 infection was identified in spinal cord gray and white matter, but infected oligodendrocytes were restricted to white matter. In contrast, RSMHV2 infection was restricted to gray matter neurons and was not localized to oligodendrocytes. In vitro, RSA59 can infect both oligodendrocyte precursors and differentiated oligodendrocytes, whereas RSMHV2 can infect oligodendrocyte precursors but not differentiated oligodendrocytes. Viral spreading through axonal means to white matter and release of the demyelinating strain MHV at the nerve end is critical for oligodendrocytes infection and subsequent demyelination. Understanding the mechanisms by which known viruses effect demyelination in this animal model has important therapeutic implications in the treatment of human demyelinating disease. PMID- 26733814 TI - Changes in Astroglial Markers in a Maternal Immune Activation Model of Schizophrenia in Wistar Rats are Dependent on Sex. AB - Data from epidemiological studies suggest that prenatal exposure to bacterial and viral infection is an important environmental risk factor for schizophrenia. The maternal immune activation (MIA) animal model is used to study how an insult directed at the maternal host can have adverse effects on the fetus, leading to behavioral and neurochemical changes later in life. We evaluated whether the administration of LPS to rat dams during late pregnancy affects astroglial markers (S100B and GFAP) of the offspring in later life. The frontal cortex and hippocampus were compared in male and female offspring on postnatal days (PND) 30 and 60. The S100B protein exhibited an age-dependent pattern of expression, being increased in the frontal cortex and hippocampus of the MIA group at PND 60, while at PND 30, male rats presented increased S100B levels only in the frontal cortex. Considering that S100B secretion is reduced by elevation of glutamate levels, we may hypothesize that this early increment in frontal cortex tissue of males is associated with elevated extracellular levels of glutamate and glutamatergic hypofunction, an alteration commonly associated with SCZ pathology. Moreover, we also found augmented GFAP in the frontal cortex of the LPS group at PND 30, but not in the hippocampus. Taken together data indicate that astroglial changes induced by MIA are dependent on sex and brain region and that these changes could reflect astroglial dysfunction. Such alterations may contribute to our understanding of the abnormal neuronal connectivity and developmental aspects of SCZ and other psychiatric disorders. PMID- 26733815 TI - Attenuated Levels of Hippocampal Connexin 43 and its Phosphorylation Correlate with Antidepressant- and Anxiolytic-Like Activities in Mice. AB - Clinical and preclinical studies have implicated glial anomalies in major depression. Conversely, evidence suggests that the activity of antidepressant drugs is based, at least in part, on their ability to stimulate density and/or activity of astrocytes, a major glial cell population. Despite this recent evidence, little is known about the mechanism(s) by which astrocytes regulate emotionality. Glial cells communicate with each other through gap junction channels (GJCs), while they can also directly interact with neurons by releasing gliotransmitters in the extracellular compartment via an hemichannels (HCs) dependent process. Both GJCs and HCs are formed by two main protein subunits: connexins (Cx) 30 and 43 (Cx30 and Cx43). Here we investigate the role of hippocampal Cx43 in the regulation of depression-like symptoms using genetic and pharmacological approaches. The first aim of this study was to evaluate the impact of the constitutive knock-down of Cx43 on a set of behaviors known to be affected in depression. Conversely, the expression of Cx43 was assessed in the hippocampus of mice subjected to prolonged corticosterone (CORT) exposure, given either alone or in combination with an antidepressant drug, the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that the constitutive deficiency of Cx43 resulted in the expression of some characteristic hallmarks of antidepressant-/anxiolytic-like behavioral activities along with an improvement of cognitive performances. Moreover, in a new cohort of wild-type mice, we showed that CORT exposure elicited anxiety and depression-like abnormalities that were reversed by chronic administration of fluoxetine. Remarkably, CORT also increased hippocampal amounts of phosphorylated form of Cx43 whereas fluoxetine treatment normalized this parameter. From these results, we envision that antidepressant drugs may exert their therapeutic activity by decreasing the expression and/or activity of Cx43 resulting from a lower level of phosphorylation in the hippocampus. PMID- 26733816 TI - Precocious Alterations of Brain Oscillatory Activity in Alzheimer's Disease: A Window of Opportunity for Early Diagnosis and Treatment. AB - Alzheimer's disease (AD) is the most common form of neurodegenerative dementia accounting for 50-80% of all age-related dementia. This pathology is characterized by the progressive and irreversible alteration of cognitive functions, such as memory, leading inexorably to the loss of autonomy for patients with AD. The pathology is linked with aging and occurs most commonly around 65 years old. Its prevalence (5% over 65 years of age and 20% after 80 years) constitutes an economic and social burden for AD patients and their family. At the present, there is still no cure for AD, actual treatments being moderately effective only in early stages of the pathology. A lot of efforts have been deployed with the aim of defining new AD biomarkers. Successful early detection of mild cognitive impairment (MCI) linked to AD requires the identification of biomarkers capable of distinguishing individuals with early stages of AD from other pathologies impacting cognition such as depression. In this article, we will review recent evidence suggesting that electroencephalographic (EEG) recordings, coupled with behavioral assessments, could be a useful approach and easily implementable for a precocious detection of AD. PMID- 26733817 TI - Corticotrigeminal Projections from the Insular Cortex to the Trigeminal Caudal Subnucleus Regulate Orofacial Pain after Nerve Injury via Extracellular Signal Regulated Kinase Activation in Insular Cortex Neurons. AB - Cortical neuroplasticity alterations are implicated in the pathophysiology of chronic orofacial pain. However, the relationship between critical cortex excitability and orofacial pain maintenance has not been fully elucidated. We recently demonstrated a top-down corticospinal descending pain modulation pathway from the anterior cingulate cortex (ACC) to the spinal dorsal horn that could directly regulate nociceptive transmission. Thus, we aimed to investigate possible corticotrigeminal connections that directly influence orofacial nociception in rats. Infraorbital nerve chronic constriction injury (IoN-CCI) induced significant orofacial nociceptive behaviors as well as pain-related negative emotions such as anxiety/depression in rats. By combining retrograde and anterograde tract tracing, we found powerful evidence that the trigeminal caudal subnucleus (Vc), especially the superficial laminae (I/II), received direct descending projections from granular and dysgranular parts of the insular cortex (IC). Extracellular signal-regulated kinase (ERK), an important signaling molecule involved in neuroplasticity, was significantly activated in the IC following IoN-CCI. Moreover, in IC slices from IoN-CCI rats, U0126, an inhibitor of ERK activation, decreased both the amplitude and the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and reduced the paired-pulse ratio (PPR) of Vc-projecting neurons. Additionally, U0126 also reduced the number of action potentials in the Vc-projecting neurons. Finally, intra-IC infusion of U0126 obviously decreased Fos expression in the Vc, accompanied by the alleviation of both nociceptive behavior and negative emotions. Thus, the corticotrigeminal descending pathway from the IC to the Vc could directly regulate orofacial pain, and ERK deactivation in the IC could effectively alleviate neuropathic pain as well as pain-related negative emotions in IoN-CCI rats, probably through this top-down pathway. These findings may help researchers and clinicians to better understand the underlying modulation mechanisms of orofacial neuropathic pain and indicate a novel mechanism of ERK inhibitor induced analgesia. PMID- 26733819 TI - Optogenetic Stimulation of Lateral Amygdala Input to Posterior Piriform Cortex Modulates Single-Unit and Ensemble Odor Processing. AB - Olfactory information is synthesized within the olfactory cortex to provide not only an odor percept, but also a contextual significance that supports appropriate behavioral response to specific odor cues. The piriform cortex serves as a communication hub within this circuit by sharing reciprocal connectivity with higher processing regions, such as the lateral entorhinal cortex and amygdala. The functional significance of these descending inputs on piriform cortical processing of odorants is currently not well understood. We have employed optogenetic methods to selectively stimulate lateral and basolateral amygdala (BLA) afferent fibers innervating the posterior piriform cortex (pPCX) to quantify BLA modulation of pPCX odor-evoked activity. Single unit odor-evoked activity of anesthetized BLA-infected animals was significantly modulated compared with control animal recordings, with individual cells displaying either enhancement or suppression of odor-driven spiking. In addition, BLA activation induced a decorrelation of odor-evoked pPCX ensemble activity relative to odor alone. Together these results indicate a modulatory role in pPCX odor processing for the BLA complex. This interaction could contribute to learned changes in PCX activity following associative conditioning, as well as support alternate patterns of odor processing that are state-dependent. PMID- 26733818 TI - Corticothalamic Synaptic Noise as a Mechanism for Selective Attention in Thalamic Neurons. AB - A reason why the thalamus is more than a passive gateway for sensory signals is that two-third of the synapses of thalamocortical neurons are directly or indirectly related to the activity of corticothalamic axons. While the responses of thalamocortical neurons evoked by sensory stimuli are well characterized, with ON- and OFF-center receptive field structures, the prevalence of synaptic noise resulting from neocortical feedback in intracellularly recorded thalamocortical neurons in vivo has attracted little attention. However, in vitro and modeling experiments point to its critical role for the integration of sensory signals. Here we combine our recent findings in a unified framework suggesting the hypothesis that corticothalamic synaptic activity is adapted to modulate the transfer efficiency of thalamocortical neurons during selective attention at three different levels: First, on ionic channels by interacting with intrinsic membrane properties, second at the neuron level by impacting on the input-output gain, and third even more effectively at the cell assembly level by boosting the information transfer of sensory features encoded in thalamic subnetworks. This top-down population control is achieved by tuning the correlations in subthreshold membrane potential fluctuations and is adapted to modulate the transfer of sensory features encoded by assemblies of thalamocortical relay neurons. We thus propose that cortically-controlled (de-)correlation of subthreshold noise is an efficient and swift dynamic mechanism for selective attention in the thalamus. PMID- 26733821 TI - Corrigendum: Control of Sleep by Dopaminergic Inputs to the Drosophila Mushroom Body. AB - [This corrects the article on p. 73 in vol. 9, PMID: 26617493.]. PMID- 26733820 TI - Attention Decreases Phase-Amplitude Coupling, Enhancing Stimulus Discriminability in Cortical Area MT. AB - Local field potentials (LFPs) in cortex reflect synchronous fluctuations in the synaptic activity of local populations of neurons. The power of high frequency (>30 Hz) oscillations in LFPs is locked to the phase of low frequency (<30 Hz) oscillations, an effect known as phase-amplitude coupling (PAC). While PAC has been observed in a variety of cortical regions and animal models, its functional role particularly in primate visual cortex is largely unknown. Here, we document PAC for LFPs recorded from extra-striate area MT of macaque monkeys, an area specialized for the processing of visual motion. We further show that directing spatial attention into the receptive field of MT neurons decreases the coupling between the low frequency phase and high frequency power of LFPs. This attentional suppression of PAC increases neuronal discriminability for attended visual stimuli. Therefore, we hypothesize that visual cortex uses PAC to regulate inter-neuronal correlations and thereby enhances the coding of relevant stimuli. PMID- 26733822 TI - Incomplete Hippocampal Inversion: A Comprehensive MRI Study of Over 2000 Subjects. AB - The incomplete-hippocampal-inversion (IHI), also known as malrotation, is an atypical anatomical pattern of the hippocampus, which has been reported in healthy subjects in different studies. However, extensive characterization of IHI in a large sample has not yet been performed. Furthermore, it is unclear whether IHI are restricted to the medial-temporal lobe or are associated with more extensive anatomical changes. Here, we studied the characteristics of IHI in a community-based sample of 2008 subjects of the IMAGEN database and their association with extra-hippocampal anatomical variations. The presence of IHI was assessed on T1-weighted anatomical magnetic resonance imaging (MRI) using visual criteria. We assessed the association of IHI with other anatomical changes throughout the brain using automatic morphometry of cortical sulci. We found that IHI were much more frequent in the left hippocampus (left: 17%, right: 6%, chi(2) test, p < 10(-28)). Compared to subjects without IHI, subjects with IHI displayed morphological changes in several sulci located mainly in the limbic lobe. Our results demonstrate that IHI are a common left-sided phenomenon in normal subjects and that they are associated with morphological changes outside the medial temporal lobe. PMID- 26733824 TI - Responses to Social Vocalizations in the Dorsal Cochlear Nucleus of Mice. AB - Identifying sounds is critical for an animal to make appropriate behavioral responses to environmental stimuli, including vocalizations from conspecifics. Identification of vocalizations may be supported by neuronal selectivity in the auditory pathway. The first place in the ascending auditory pathway where neuronal selectivity to vocalizations has been found is in the inferior colliculus (IC), but very few brainstem nuclei have been evaluated. Here, we tested whether selectivity to vocalizations is present in the dorsal cochlear nucleus (DCN). We recorded extracellular neural responses in the DCN of mice and found that fusiform cells responded in a heterogeneous and selective manner to mouse ultrasonic vocalizations. Most fusiform cells responded to vocalizations that contained spectral energy at much higher frequencies than the characteristic frequencies of the cells. To understand this mismatch of stimulus properties and frequency tuning of the cells, we developed a dynamic, nonlinear model of the cochlea that simulates cochlear distortion products on the basilar membrane. We preprocessed the vocalization stimuli through this model and compared responses to these distorted vocalizations with responses to the original vocalizations. We found that fusiform cells in the DCN respond in a heterogeneous manner to vocalizations, and that these neurons can use distortion products as a mechanism for encoding ultrasonic vocalizations. In addition, the selective neuronal responses were dependent on the presence of inhibitory sidebands that modulated the response depending on the temporal structure of the distortion product. These findings suggest that important processing of complex sounds occurs at a very early stage of central auditory processing and is not strictly a function of the cortex. PMID- 26733825 TI - The Role of Prefrontal Cortex in Working Memory: A Mini Review. AB - A prominent account of prefrontal cortex (PFC) function is that single neurons within the PFC maintain representations of task-relevant stimuli in working memory. Evidence for this view comes from studies in which subjects hold a stimulus across a delay lasting up to several seconds. Persistent elevated activity in the PFC has been observed in animal models as well as in humans performing these tasks. This persistent activity has been interpreted as evidence for the encoding of the stimulus itself in working memory. However, recent findings have posed a challenge to this notion. A number of recent studies have examined neural data from the PFC and posterior sensory areas, both at the single neuron level in primates, and at a larger scale in humans, and have failed to find encoding of stimulus information in the PFC during tasks with a substantial working memory component. Strong stimulus related information, however, was seen in posterior sensory areas. These results suggest that delay period activity in the PFC might be better understood not as a signature of memory storage per se, but as a top down signal that influences posterior sensory areas where the actual working memory representations are maintained. PMID- 26733826 TI - Can Optogenetic Tools Determine the Importance of Temporal Codes to Sensory Information Processing in the Brain? AB - There is no doubt that optogenetic tools caused a paradigm shift in many fields of neuroscience. These tools enable rapid and reversible intervention with a specific neuronal circuit and then the impact on the remaining circuit and/or behavior can be studied. However, so far the ability of these optogenetic tools to interfere with neuronal signal transmission in the time scale of milliseconds has been used much less frequently although they may help to answer a fundamental question of neuroscience: how important temporal codes are to information processing in the brain. This perspective paper examines why optogenetic tools were used so little to perturb or imitate temporal codes. Although some technical limitations do exist, there is a clear need for a systems approach. More research about action potential pattern formation by interactions between several brain areas is necessary in order to exploit the full potential of optogenetic methods in probing temporal codes. PMID- 26733823 TI - A Framework for Understanding the Emerging Role of Corticolimbic-Ventral Striatal Networks in OCD-Associated Repetitive Behaviors. AB - Significant interest in the mechanistic underpinnings of obsessive-compulsive disorder (OCD) has fueled research on the neural origins of compulsive behaviors. Converging clinical and preclinical evidence suggests that abnormal repetitive behaviors are driven by dysfunction in cortico-striatal-thalamic-cortical (CSTC) circuits. These findings suggest that compulsive behaviors arise, in part, from aberrant communication between lateral orbitofrontal cortex (OFC) and dorsal striatum. An important body of work focused on the role of this network in OCD has been instrumental to progress in the field. Disease models focused primarily on these regions, however, fail to capture an important aspect of the disorder: affective dysregulation. High levels of anxiety are extremely prevalent in OCD, as is comorbidity with major depressive disorder. Furthermore, deficits in processing rewards and abnormalities in processing emotional stimuli are suggestive of aberrant encoding of affective information. Accordingly, OCD can be partially characterized as a disease in which behavioral selection is corrupted by exaggerated or dysregulated emotional states. This suggests that the networks producing OCD symptoms likely expand beyond traditional lateral OFC and dorsal striatum circuit models, and highlights the need to cast a wider net in our investigation of the circuits involved in generating and sustaining OCD symptoms. Here, we address the emerging role of medial OFC, amygdala, and ventral tegmental area projections to the ventral striatum (VS) in OCD pathophysiology. The VS receives strong innervation from these affect and reward processing regions, and is therefore poised to integrate information crucial to the generation of compulsive behaviors. Though it complements functions of dorsal striatum and lateral OFC, this corticolimbic-VS network is less commonly explored as a potential source of the pathology underlying OCD. In this review, we discuss this network's potential role as a locus of OCD pathology and effective treatment. PMID- 26733827 TI - Spatiotemporal Processing in Crossmodal Interactions for Perception of the External World: A Review. AB - Research regarding crossmodal interactions has garnered much interest in the last few decades. A variety of studies have demonstrated that multisensory information (vision, audition, tactile sensation, and so on) can perceptually interact with each other in the spatial and temporal domains. Findings regarding crossmodal interactions in the spatiotemporal domain (i.e., motion processing) have also been reported, with updates in the last few years. In this review, we summarize past and recent findings on spatiotemporal processing in crossmodal interactions regarding perception of the external world. A traditional view regarding crossmodal interactions holds that vision is superior to audition in spatial processing, but audition is dominant over vision in temporal processing. Similarly, vision is considered to have dominant effects over the other sensory modalities (i.e., visual capture) in spatiotemporal processing. However, recent findings demonstrate that sound could have a driving effect on visual motion perception. Moreover, studies regarding perceptual associative learning reported that, after association is established between a sound sequence without spatial information and visual motion information, the sound sequence could trigger visual motion perception. Other sensory information, such as motor action or smell, has also exhibited similar driving effects on visual motion perception. Additionally, recent brain imaging studies demonstrate that similar activation patterns could be observed in several brain areas, including the motion processing areas, between spatiotemporal information from different sensory modalities. Based on these findings, we suggest that multimodal information could mutually interact in spatiotemporal processing in the percept of the external world and that common perceptual and neural underlying mechanisms would exist for spatiotemporal processing. PMID- 26733828 TI - Comparison of Visuospatial and Verbal Abilities in First Psychotic Episode of Schizophrenia Spectrum Disorder: Impact on Global Functioning and Quality of Life. AB - OBJECTIVES: Deficit in visuospatial functions can influence both simple and complex daily life activities. Despite the fact that visuospatial deficit was reported in schizophrenia, research on visuospatial functions as an independent entity is limited. Our study aims to elucidate the impact of visuospatial deficit in comparison with verbal deficit on global functioning and quality of life in the first psychotic episode of schizophrenia spectrum disorder (FES). The significance of clinical symptoms and antipsychotic medication was also studied. METHODS: Thirty-six FES patients and a matched group of healthy controls (HC group) were assessed with a neuropsychological battery focused on visuospatial (VIS) and verbal (VERB) functions. Using multiple regression analysis, we evaluated the cumulative effect of VERB and VIS functions, psychiatric symptoms (PANSS) and antipsychotic medication on global functioning (GAF) and quality of life (WHOQOL-BREF) in the FES group. RESULTS: The FES group demonstrated significant impairment both in VIS and VERB cognitive abilities compared to the HC group. Antipsychotic medication did not significantly affect either VIS or VERB functioning. PANSS was not related to cognitive functioning, apart from the Trail Making Test B. In the FES group, the GAF score was significantly affected by the severity of positive symptoms and VERB functioning, explaining together 60% of GAF variability. The severity of negative and positive symptoms affected only the Physical health domain of WHOQOL-BREF. The degree of VERB deficit was associated with both Physical and Psychological health. Although we did not find any relation between VIS functioning, GAF, and WHOQOL-BREF, a paradoxical finding emerged in the Environment quality domain, where a worse quality of the environment was associated with better VIS functioning. CONCLUSIONS: Our results suggest that the deficit in VIS functions is an integral part of cognitive deficit in schizophrenia spectrum disorders, rather than a side effect of symptomatology or antipsychotic medication. Moreover, VERB functioning was a better predictor of GAF and WHOQOL-BREF than VIS functioning. Given the findings of negative or missing effect of VIS deficit on WHOQOL-BREF and GAF, the accuracy of these measures in evaluating the impact of global cognitive deficit on everyday life in schizophrenia could be questioned. PMID- 26733829 TI - The Involvement of Genes in Adolescent Depression: A Systematic Review. AB - Numerous studies have reported on the roles of genetic factors in the development of depression in adolescents and young adults. However, there are few systematic reviews that update our understanding of adolescent depression with the biological findings identifying the roles of gene expression and/or polymorphism(s). This review systematically summarized the findings that clearly identified the contribution of a gene to the risk of depression in adolescents between the ages of 10 and 19 years old and young adults between the ages of 20 and 25 years old. Data were obtained through searching PubMed, Embase, and Web of Science. A total of 47 studies on early adolescence and three studies on young adults were included in the current review. Most articles studied genes in the serotonergic system (n = 26), dopaminergic system (n = 3), and the Brain-derived neurotropic factor (BDNF) gene (n = 12). 92.3% of studies (24/26) identified positive associations of 5-HTTLPR polymorphism with depressive illness or depressive symptoms. 83.3% of studies (10/12) found positive association between BDNF Val66Met genotype and adolescent depressive symptoms. More studies should be conducted on the 18 genes reported in a few studies to clarify their roles in the risk for adolescent depression. PMID- 26733831 TI - Could Stress Contribute to Pain-Related Fear in Chronic Pain? AB - Learning to predict pain based on internal or external cues constitutes a fundamental and highly adaptive process aimed at self-protection. Pain-related fear is an essential component of this response, which is formed by associative and instrumental learning processes. In chronic pain, pain-related fear may become maladaptive, drive avoidance behaviors and contribute to symptom chronicity. Pavlovian fear conditioning has proven fruitful to elucidate associative learning and extinction involving aversive stimuli, including pain, but studies in chronic pain remain scarce. Stress demonstrably exerts differential effects on emotional learning and memory processes, but this has not been transferred to pain-related fear. Within this perspective, we propose that stress could contribute to impaired pain-related associative learning and extinction processes and call for interdisciplinary research. Specifically, we suggest to test the hypotheses that: (1) extinction-related phenomena inducing a re-activation of maladaptive pain-related fear (e.g., reinstatement, renewal) likely occur in everyday life of chronic pain patients and may alter pain processing, impair perceptual discrimination and favor overgeneralization; (2) acute stress prior to or during acquisition of pain-related fear may facilitate the formation and/or consolidation of pain-related fear memories; (3) stress during or after extinction may impair extinction efficacy resulting in greater reinstatement or context-dependent renewal of pain-related fear; and (4) these effects could be amplified by chronic stress due to early adversity and/or psychiatric comorbidity such depression or anxiety in patients with chronic pain. PMID- 26733830 TI - To Act or Not to Act: Endocannabinoid/Dopamine Interactions in Decision-Making. AB - Decision-making is an ethologically adaptive construct that is impaired in multiple psychiatric disorders. Activity within the mesocorticolimbic dopamine system has been traditionally associated with decision-making. The endocannabinoid system through its actions on inhibitory and excitatory synapses modulates dopamine activity and decision-making. The aim of this brief review is to present a synopsis of available data obtained when the endocannabinoid system is manipulated and dopamine activity recorded. To this end, we review research using different behavioral paradigms to provide further insight into how this ubiquitous signaling system biases dopamine-related behaviors to regulate decision-making. PMID- 26733832 TI - Enhancing Motor Network Activity Using Real-Time Functional MRI Neurofeedback of Left Premotor Cortex. AB - Neurofeedback by functional magnetic resonance imaging (fMRI) is a technique of potential therapeutic relevance that allows individuals to be aware of their own neurophysiological responses and to voluntarily modulate the activity of specific brain regions, such as the premotor cortex (PMC), important for motor recovery after brain injury. We investigated (i) whether healthy human volunteers are able to up-regulate the activity of the left PMC during a right hand finger tapping motor imagery (MI) task while receiving continuous fMRI-neurofeedback, and (ii) whether successful modulation of brain activity influenced non-targeted motor control regions. During the MI task, participants of the neurofeedback group (NFB) received ongoing visual feedback representing the level of fMRI responses within their left PMC. Control (CTL) group participants were shown similar visual stimuli, but these were non-contingent on brain activity. Both groups showed equivalent levels of behavioral ratings on arousal and MI, before and during the fMRI protocol. In the NFB, but not in CLT group, brain activation during the last run compared to the first run revealed increased activation in the left PMC. In addition, the NFB group showed increased activation in motor control regions extending beyond the left PMC target area, including the supplementary motor area, basal ganglia and cerebellum. Moreover, in the last run, the NFB group showed stronger activation in the left PMC/inferior frontal gyrus when compared to the CTL group. Our results indicate that modulation of PMC and associated motor control areas can be achieved during a single neurofeedback-fMRI session. These results contribute to a better understanding of the underlying mechanisms of MI-based neurofeedback training, with direct implications for rehabilitation strategies in severe brain disorders, such as stroke. PMID- 26733833 TI - Implications of Epigenetic Variability within a Cell Population for "Cell Type" Classification. AB - Here, we propose a new approach to defining nerve "cell types" in reaction to recent advances in single cell analysis. Among cells previously thought to be equivalent, considerable differences in global gene expression and biased tendencies among differing developmental fates have been demonstrated within multiple lineages. The model of classifying cells into distinct types thus has to be revised to account for this intrinsic variability. A "cell type" could be a group of cells that possess similar, but not necessarily identical properties, variable within a spectrum of epigenetic adjustments that permit its developmental path toward a specific function to be achieved. Thus, the definition of a cell type is becoming more similar to the definition of a species: sharing essential properties with other members of its group, but permitting a certain amount of deviation in aspects that do not seriously impact function. This approach accommodates, even embraces the spectrum of natural variation found in various cell populations and consequently avoids the fallacy of false equivalence. For example, developing neurons will react to their microenvironments with epigenetic changes resulting in slight changes in gene expression and morphology. Addressing the new questions implied here will have significant implications for developmental neurobiology. PMID- 26733834 TI - Sky Compass Orientation in Desert Locusts-Evidence from Field and Laboratory Studies. AB - Locusts are long-range migratory insects. At high population density, immature animals form marching hopper bands while adults take off and form huge swarms of millions of animals. At low population densities animals are solitarious, but likewise migrate, mostly during the night. Numerous studies aimed at predicting locust infestations showed that migrations both as hopper bands and as adults are largely downwind following seasonal shifts of the tropical convergence zone taking the animals to areas of rainfall. Only a few studies provided evidence for active orientation mechanisms, including the involvement of a sun compass. This scarcity of evidence stands in contrast to recent neurobiological data showing sophisticated neuronal adaptations suited for sky compass navigation. These include a special dorsal eye region with photoreceptors suited to analyze the polarization pattern of the sky and a system of topographically arranged sky compass neurons in the central complex of the brain. Laboratory experiments, moreover, demonstrated polarotaxis in tethered flying animals. The discrepancy of these findings call for more rigorous field studies on active orientation mechanisms in locusts. It remains to be shown how locusts use their internal sky compass during mass migrations and what role it plays to guide solitarious locusts in their natural habitat. PMID- 26733835 TI - Corrigendum: Acute administration of MK-801 in an animal model of psychosis in rats interferes with cognitively demanding forms of behavioral flexibility on a rotating arena. AB - [This corrects the article on p. 75 in vol. 9, PMID: 25883558.]. PMID- 26733837 TI - Low-Cost Avoidance Behaviors are Resistant to Fear Extinction in Humans. AB - Elevated levels of fear and avoidance are core symptoms across the anxiety disorders. It has long been known that fear serves to motivate avoidance. Consequently, fear extinction has been the primary focus in pre-clinical anxiety research for decades, under the implicit assumption that removing the motivator of avoidance (fear) would automatically mitigate the avoidance behaviors as well. Although this assumption has intuitive appeal, it has received little scientific scrutiny. The scarce evidence from animal studies is mixed, while the assumption remains untested in humans. The current study applied an avoidance conditioning protocol in humans to investigate the effects of fear extinction on the persistence of low-cost avoidance. Online danger-safety ratings and skin conductance responses documented the dynamics of conditioned fear across avoidance and extinction phases. Anxiety- and avoidance-related questionnaires explored individual differences in rates of avoidance. Participants first learned to click a button during a predictive danger signal, in order to cancel an upcoming aversive electrical shock (avoidance conditioning). Next, fear extinction was induced by presenting the signal in the absence of shocks while button-clicks were prevented (by removing the button in Experiment 1, or by instructing not to click the button in Experiment 2). Most importantly, post extinction availability of the button caused a significant return of avoidant button-clicks. In addition, trait-anxiety levels correlated positively with rates of avoidance during a predictive safety signal, and with the rate of pre- to post extinction decrease during this signal. Fear measures gradually decreased during avoidance conditioning, as participants learned that button-clicks effectively canceled the shock. Preventing button-clicks elicited a sharp increase in fear, which subsequently extinguished. Fear remained low during avoidance testing, but danger-safety ratings increased again when button-clicks were subsequently prevented. Together, these results show that low-cost avoidance behaviors can persist following fear extinction and induce increased threat appraisal. On the other hand, fear extinction did reduce augmented rates of unnecessary avoidance during safety in trait-anxious individuals, and instruction-based response prevention was more effective than removal of response cues. More research is needed to characterize the conditions under which fear extinction might mitigate avoidance. PMID- 26733836 TI - Evidence for Enhanced Interoceptive Accuracy in Professional Musicians. AB - Interoception is defined as the perceptual activity involved in the processing of internal bodily signals. While the ability of internal perception is considered a relatively stable trait, recent data suggest that learning to integrate multisensory information can modulate it. Making music is a uniquely rich multisensory experience that has shown to alter motor, sensory, and multimodal representations in the brain of musicians. We hypothesize that musical training also heightens interoceptive accuracy comparable to other perceptual modalities. Thirteen professional singers, twelve string players, and thirteen matched non musicians were examined using a well-established heartbeat discrimination paradigm complemented by self-reported dispositional traits. Results revealed that both groups of musicians displayed higher interoceptive accuracy than non musicians, whereas no differences were found between singers and string-players. Regression analyses showed that accumulated musical practice explained about 49% variation in heartbeat perception accuracy in singers but not in string-players. Psychometric data yielded a number of psychologically plausible inter correlations in musicians related to performance anxiety. However, dispositional traits were not a confounding factor on heartbeat discrimination accuracy. Together, these data provide first evidence indicating that professional musicians show enhanced interoceptive accuracy compared to non-musicians. We argue that musical training largely accounted for this effect. PMID- 26733838 TI - Plasticity of Fear and Safety Neurons of the Amygdala in Response to Fear Extinction. AB - Fear inhibition learning induces plasticity and remodeling of circuits within the amygdala. Most studies examine these changes in nondiscriminative fear conditioning paradigms. Using a discriminative fear, safety, and reward conditioning task, Sangha et al. (2013) have previously reported several neural microcircuits within the basal amygdala (BA) which discriminate among these cues, including a subpopulation of neurons responding selectively to a safety cue and not a fear cue. Here, the hypothesis that these "safety" neurons isolated during discriminative conditioning are biased to become fear cue responsive as a result of extinction, when fear behavior diminishes, was tested. Although 41% of "safety" neurons became fear cue responsive as a result of extinction, the data revealed that there was no bias for these neurons to become preferentially responsive during fear extinction compared to the other identified subgroups. In addition to the plasticity seen in the "safety" neurons, 44% of neurons unresponsive to either the fear cue or safety cue during discriminative conditioning became fear cue responsive during extinction. Together these emergent responses to the fear cue as a result of extinction support the hypothesis that new learning underlies extinction. In contrast, 47% of neurons responsive to the fear cue during discriminative conditioning became unresponsive to the fear cue during extinction. These findings are consistent with a suppression of neural responding mediated by inhibitory learning, or, potentially, by direct unlearning. Together, the data support extinction as an active process involving both gains and losses of responses to the fear cue and suggests the final output of the integrated BA circuit in influencing fear behavior is a balance of excitation and inhibition, and perhaps reversal of learning-induced changes. PMID- 26733839 TI - Complex Living Conditions Impair Behavioral Inhibition but Improve Attention in Rats. AB - Rapid adaptation to changes, while maintaining a certain level of behavioral inhibition is an important feature in every day functioning. How environmental context and challenges in life can impact on the development of this quality is still unknown. In the present study, we examined the effect of a complex rearing environment during adolescence on attention and behavioral inhibition in adult male rats. We also tested whether these effects were affected by an adverse early life challenge, maternal deprivation (MD). We found that animals that were raised in large, two floor Marlau(TM) cages, together with 10 conspecifics, showed improved attention, but impaired behavioral inhibition in the 5-choice serial reaction time task. The early life challenge of 24 h MD on postnatal day 3 led to a decline in bodyweight during adolescence, but did not by itself influence responses in the 5-choice task in adulthood, nor did it moderate the effects of complex housing. Our data suggest that a complex rearing environment leads to a faster adaptation to changes in the environment, but at the cost of lower behavioral inhibition. PMID- 26733840 TI - Inhibitory Effect of the Melanocortin Receptor Agonist Melanotan-II (MTII) on Feeding Depends on Dietary Fat Content and not Obesity in Rats on Free-Choice Diets. AB - INTRODUCTION: Conflicting data exist on sensitivity changes of the melanocortin system during diet-induced obesity. We hypothesized that melanocortin sensitivity depends on diet composition, in particular on the fat content rather than the level of obesity. The aim of this study was to determine the influence of diet composition on feeding responses to a melanocortin receptor agonist, using free choice diets that differ in food components. METHODS: Male Wistar rats were subjected to a chow (CHOW) diet or a free-choice (fc) diet of either chow, saturated fat and liquid sugar (fcHFHS), chow and saturated fat (fcHF), or chow and liquid sugar (fcHS) for 4 weeks. Melanocortin sensitivity was tested by measuring food intake following administration of the melanocortin 3/4 receptor agonist melanotan II (MTII) or vehicle in the lateral ventricle. In a separate experiment, proopiomelanocortin (POMC) and agouti-related protein (AgRP) mRNA levels were determined in the arcuate nucleus with in situ hybridization in rats subjected to the free-choice diets for 4 weeks. RESULTS: Rats on the fcHFHS diet for 4 weeks show increased caloric intake and body weight gain compared to rats on the CHOW, fcHS and fcHF diet. Caloric intake and body weight gain was comparable between rats on the fcHF, fcHS, and CHOW diet. After 4 weeks diet, POMC and AgRP mRNA levels were not different between diet groups. MTII inhibited caloric intake to a larger extent in rats on the fcHF diet compared to rats on the CHOW, fcHFHS or fcHS diet. Moreover, the fat component was the most inhibited by MTII, and the sugar component the least. CONCLUSION: Rats on the fcHF diet show stronger food intake inhibition to the melanocortin receptor agonist MTII than rats on the CHOW, fcHS, and fcHFHS diet, which is independent of caloric intake and body weight gain. Our data point toward an important role for diet composition, particularly the dietary fat content, and not obesity in the sensitivity of the melanocortin system. PMID- 26733841 TI - Behavioral and Neural Plasticity of Ocular Motor Control: Changes in Performance and fMRI Activity Following Antisaccade Training. AB - The antisaccade task provides a model paradigm that sets the inhibition of a reflexively driven behavior against the volitional control of a goal-directed behavior. The stability and adaptability of antisaccade performance was investigated in 23 neurologically healthy individuals. Behavior and brain function were measured using functional magnetic resonance imaging (fMRI) prior to and immediately following 2 weeks of daily antisaccade training. Participants performed antisaccade trials faster with no change in directional error rate following 2 weeks of training; however this increased speed came at the cost of the spatial accuracy of the saccade (gain) which became more hypometric following training. Training on the antisaccade task resulted in increases in fMRI activity in the fronto-basal ganglia-parietal-cerebellar ocular motor network. Following training, antisaccade latency was positively associated with fMRI activity in the frontal and supplementary eye fields, anterior cingulate and intraparietal sulcus; antisaccade gain was negatively associated with fMRI activity in supplementary eye fields, anterior cingulate, intraparietal sulcus, and cerebellar vermis. In sum, the results suggest that following training, larger antisaccade latency is associated with larger activity in fronto-parietal cerebellar ocular motor regions, and smaller antisaccade gain is associated with larger activity in fronto-parietal ocular motor regions. PMID- 26733842 TI - Perceptual and Conceptual Distortions of Implicit Hand Maps. AB - Recent studies have revealed that human position sense relies on a massively distorted representation of hand size and shape. By comparing the judged location of landmarks on an occluded hand, Longo and Haggard (2010) constructed implicit perceptual maps of represented hand structure, showing large underestimation of finger length and overestimation of hand width. Here, we investigated the contribution of two potential sources of distortions to such effects: perceptual distortions reflecting spatial warping of the representation of bodily tissue itself, perhaps reflecting distortions of somatotopic cortical maps, and conceptual distortions reflecting mistaken beliefs about the locations of different landmarks within the body. In Experiment 1 we compared distorted hand maps to a task in which participants explicitly judged the location of their knuckles in a hand silhouette. The results revealed the conceptual distortions are responsible for at least part of the underestimation of finger length, but cannot explain overestimation of hand width. Experiment 2 compared distortions of the participant's own hand based on position sense with a prosthetic hand based on visual memory. Underestimation of finger length was found for both hands, providing further evidence that it reflects a conceptual distortion. In contrast, overestimation of hand width was specific to representation of the participant's own hand, confirming it reflects a perceptual distortion. Together, these results suggest that distorted body representations do not reflect a single underlying cause. Rather, both perceptual and conceptual distortions contribute to the overall configuration of the hand representation. PMID- 26733843 TI - Pleasant and Unpleasant Odors Influence Hedonic Evaluations of Human Faces: An Event-Related Potential Study. AB - Odors can alter hedonic evaluations of human faces, but the neural mechanisms of such effects are poorly understood. The present study aimed to analyze the neural underpinning of odor-induced changes in evaluations of human faces in an odor priming paradigm, using event-related potentials (ERPs). Healthy, young participants (N = 20) rated neutral faces presented after a 3 s pulse of a pleasant odor (jasmine), unpleasant odor (methylmercaptan), or no-odor control (clean air). Neutral faces presented in the pleasant odor condition were rated more pleasant than the same faces presented in the no-odor control condition, which in turn were rated more pleasant than faces in the unpleasant odor condition. Analysis of face-related potentials revealed four clusters of electrodes significantly affected by odor condition at specific time points during long-latency epochs (600-950 ms). In the 620-640 ms interval, two scalp time clusters showed greater negative potential in the right parietal electrodes in response to faces in the pleasant odor condition, compared to those in the no odor and unpleasant odor conditions. At 926 ms, face-related potentials showed greater positivity in response to faces in the pleasant and unpleasant odor conditions at the left and right lateral frontal-temporal electrodes, respectively. Our data shows that odor-induced shifts in evaluations of faces were associated with amplitude changes in the late (>600) and ultra-late (>900 ms) latency epochs. The observed amplitude changes during the ultra-late epoch are consistent with a left/right hemisphere bias towards pleasant/unpleasant odor effects. Odors alter evaluations of human faces, even when there is a temporal lag between presentation of odors and faces. Our results provide an initial understanding of the neural mechanisms underlying effects of odors on hedonic evaluations. PMID- 26733844 TI - The Future Orientation of Past Memory: The Role of BA 10 in Prospective and Retrospective Retrieval Modes. AB - Klein made the provocative suggestion that the purpose of human episodic memory is to enable individuals to plan and prepare for the future. In other words, although episodic (retrospective) memory is about the past, it is not actually for the past; it is for the future. Within this focus, a natural subject for investigation is prospective memory, or memory to do things in the future. An important theoretical construct in the fields of both retrospective memory and prospective memory is that of a retrieval mode, or a neurocognitive set or readiness to treat environmental stimuli as potential retrieval cues. This construct was originally introduced in a theory of episodic (retrospective) memory and has more recently been invoked in a theory of how some prospective memory tasks are accomplished. To our knowledge, this construct has not been explicitly compared between the two literatures, and thus this is the purpose of the present article. Although we address the behavioral evidence for each construct, our primary goal is to assess the extent to which each retrieval mode appears to rely on a common neural region. Our review highlights the fact that a particular area of prefrontal cortex (BA 10) appears to play an important role in both retrospective and prospective retrieval modes. We suggest, based on this evidence and these ideas, that prospective memory research could profit from more active exploration of the relevance of theoretical constructs from the retrospective memory literature. PMID- 26733845 TI - Commentary: The embodied brain: towards a radical embodied cognitive neuroscience. PMID- 26733846 TI - Empirical Bayes for Group (DCM) Studies: A Reproducibility Study. AB - This technical note addresses some key reproducibility issues in the dynamic causal modelling of group studies of event related potentials. Specifically, we address the reproducibility of Bayesian model comparison (and inferences about model parameters) from three important perspectives namely: (i) reproducibility with independent data (obtained by averaging over odd and even trials); (ii) reproducibility over formally distinct models (namely, classic ERP and canonical microcircuit or CMC models); and (iii) reproducibility over inversion schemes (inversion of the grand average and estimation of group effects using empirical Bayes). Our hope was to illustrate the degree of reproducibility one can expect from DCM when analysing different data, under different models with different analyses. PMID- 26733847 TI - Effect of Paired-Pulse Electrical Stimulation on the Activity of Cortical Circuits. AB - OBJECTIVE: We investigated the transient effect of short-duration paired-pulse electrical stimulation (ppES) on corticospinal excitability and the after-effect of long-duration ppES on excitability, short-latency afferent inhibition (SAI), and afferent facilitation (AF). METHODS: A total of 28 healthy subjects participated in two different experiments. In Experiment 1, motor-evoked potentials (MEPs) were measured in the abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles before and immediately after short-duration ppES (5 s) at various inter-pulse intervals (2, 3, 4, 5, 6, 7, 10, 15, 20, and 30 ms). In Experiment 2, MEPs, SAI, and AF were measured before, immediately, and 20 and 40 min after long-duration ppES (20 min, inter-pulse interval of 5 and 15 ms) and peripheral electrical stimulation (20 min, 10 and 20 Hz). RESULTS: Short duration ppES with inter-pulse intervals of 5 and 20 ms significantly increased MEP measured in APB but not in ADM. Long-duration ppES with an inter-pulse interval of 5 ms significantly decreased SAI but not MEPs in APB. In contrast, long-duration ppES did not affect ADM. CONCLUSION: The afferent inputs induced by ppES-5 ms were effective for transiently increasing MEP and sustaining SAI reduction. PMID- 26733848 TI - Awareness of Rhythm Patterns in Speech and Music in Children with Specific Language Impairments. AB - Children with specific language impairments (SLIs) show impaired perception and production of language, and also show impairments in perceiving auditory cues to rhythm [amplitude rise time (ART) and sound duration] and in tapping to a rhythmic beat. Here we explore potential links between language development and rhythm perception in 45 children with SLI and 50 age-matched controls. We administered three rhythmic tasks, a musical beat detection task, a tapping-to music task, and a novel music/speech task, which varied rhythm and pitch cues independently or together in both speech and music. Via low-pass filtering, the music sounded as though it was played from a low-quality radio and the speech sounded as though it was muffled (heard "behind the door"). We report data for all of the SLI children (N = 45, IQ varying), as well as for two independent subgroupings with intact IQ. One subgroup, "Pure SLI," had intact phonology and reading (N = 16), the other, "SLI PPR" (N = 15), had impaired phonology and reading. When IQ varied (all SLI children), we found significant group differences in all the rhythmic tasks. For the Pure SLI group, there were rhythmic impairments in the tapping task only. For children with SLI and poor phonology (SLI PPR), group differences were found in all of the filtered speech/music AXB tasks. We conclude that difficulties with rhythmic cues in both speech and music are present in children with SLIs, but that some rhythmic measures are more sensitive than others. The data are interpreted within a "prosodic phrasing" hypothesis, and we discuss the potential utility of rhythmic and musical interventions in remediating speech and language difficulties in children. PMID- 26733849 TI - Aberrant Topological Patterns of Structural Cortical Networks in Psychogenic Erectile Dysfunction. AB - Male sexual arousal (SA) has been known as a multidimensional experience involving closely interrelated and coordinated neurobehavioral components that rely on widespread brain regions. Recent functional neuroimaging studies have shown relation between abnormal/altered dynamics in these circuits and male sexual dysfunction. However, alterations in the topological organization of structural brain networks in male sexual dysfunction are still unclear. Here, we used graph theory to investigate the topological properties of large-scale structural brain networks, which were constructed using inter-regional correlations of cortical thickness between 78 cortical regions in 40 patients with psychogenic erectile dysfunction (pED) and 39 normal controls. Compared with normal controls, pED patients exhibited a less optimal global topological organization with reduced global and increased local efficiencies. Our results suggest disrupted neural integration among distant brain regions in pED patients, consistent with previous reports of impaired white matter structure and abnormal functional integrity in pED. Additionally, disrupted global network topology in pED was observed to be primarily relevant to altered subnetwork and nodal properties within the networks mediating the cognitive, motivational and inhibitory processes of male SA, possibly indicating disrupted integration of these networks in the whole brain networks and might account for pED patients' abnormal cognitive, motivational and inhibitory processes for male SA. In total, our findings provide evidence for disrupted integrity in large-scale brain networks underlying the neurobehavioral processes of male SA in pED and provide new insights into the understanding of the pathophysiological mechanisms of pED. PMID- 26733850 TI - The Role of Configural Processing in Face Classification by Race: An ERP Study. AB - The current study investigated the time course of the other-race classification advantage (ORCA) in the subordinate classification of normally configured faces and distorted faces by race. Slightly distorting the face configuration delayed the categorization of own-race faces and had no conspicuous effects on other-race faces. The N170 was sensitive neither to configural distortions nor to faces' races. The P3 was enhanced for other-race than own-race faces and reduced by configural manipulation only for own-race faces. We suggest that the source of ORCA is the configural analysis applied by default while processing own-race faces. PMID- 26733851 TI - Visual Search in the Real World: Color Vision Deficiency Affects Peripheral Guidance, but Leaves Foveal Verification Largely Unaffected. AB - BACKGROUND: People with color vision deficiencies report numerous limitations in daily life, restricting, for example, their access to some professions. However, they use basic color terms systematically and in a similar manner as people with normal color vision. We hypothesize that a possible explanation for this discrepancy between color perception and behavioral consequences might be found in the gaze behavior of people with color vision deficiency. METHODS: A group of participants with color vision deficiencies and a control group performed several search tasks in a naturalistic setting on a lawn. All participants wore a mobile eye-tracking-driven camera with a high foveal image resolution (EyeSeeCam). Search performance as well as fixations of objects of different colors were examined. RESULTS: Search performance was similar in both groups in a color unrelated search task as well as in a search for yellow targets. While searching for red targets, participants with color vision deficiencies exhibited a strongly degraded performance. This was closely matched by the number of fixations on red objects shown by the two groups. Importantly, once they fixated a target, participants with color vision deficiencies exhibited only few identification errors. CONCLUSIONS: In contrast to controls, participants with color vision deficiencies are not able to enhance their search for red targets on a (green) lawn by an efficient guiding mechanism. The data indicate that the impaired guiding is the main influence on search performance, while foveal identification (verification) is largely unaffected by the color vision deficiency. PMID- 26733853 TI - Corrigendum: Your Brain on Art: Emergent Cortical Dynamics During Aesthetic Experiences. AB - [This corrects the article on p. 626 in vol. 9, PMID: 26635579.]. PMID- 26733852 TI - The Associations between Regional Gray Matter Structural Changes and Changes of Cognitive Performance in Control Groups of Intervention Studies. AB - In intervention studies of cognitive training, the challenging cognitive tests, which were used as outcome measures, are generally completed in more than a few hours. Here, utilizing the control groups' data from three 1-week intervention studies in which young healthy adult subjects underwent a wide range of cognitive tests and T1-weighted magnetic resonance imaging (MRI) before and after the intervention period, we investigated how regional gray matter (GM) density (rGMD) of the subjects changed through voxel-based morphometry (VBM). Statistically significant increases in rGMD were observed in the anatomical cluster that mainly spread around the bilateral dorsal anterior cingulate cortex (dACC) and the right superior frontal gyrus (rSFG). Moreover, mean rGMD within this cluster changes were significantly and positively correlated with performance changes in the Stroop task, and tended to positively correlate with performance changes in a divergent thinking task. Affected regions are considered to be associated with performance monitoring (dACC) and manipulation of the maintained information including generating associations (rSFG), and both are relevant to the cognitive functions measured in the cognitive tests. Thus, the results suggest that even in the groups of the typical "control group" in intervention studies including those of the passive one, experimental or non-experimental factors can result in an increase in the regional GM structure and form the association between such neural changes and improvements related to these cognitive tests. These results suggest caution toward the experimental study designs without control groups. PMID- 26733854 TI - Response: No need to match: a comment on Bach, Nicholson, and Hudson's "Affordance-Matching Hypothesis". PMID- 26733855 TI - The Compression Flow as a Measure to Estimate the Brain Connectivity Changes in Resting State fMRI and 18FDG-PET Alzheimer's Disease Connectomes. AB - The human brain appears organized in compartments characterized by seemingly specific functional purposes on many spatial scales. A complementary functional state binds information from specialized districts to return what is called integrated information. These fundamental network dynamics undergoes to severe disarrays in diverse degenerative conditions such as Alzheimer's Diseases (AD). The AD represents a multifarious syndrome characterized by structural, functional, and metabolic landmarks. In particular, in the early stages of AD, adaptive functional modifications of the brain networks mislead initial diagnoses because cognitive abilities may result indiscernible from normal subjects. As a matter of facts, current measures of functional integration fail to catch significant differences among normal, mild cognitive impairment (MCI) and even AD subjects. The aim of this work is to introduce a new topological feature called Compression Flow (CF) to finely estimate the extent of the functional integration in the brain networks. The method uses a Monte Carlo-like estimation of the information integration flows returning the compression ratio between the size of the injected information and the size of the condensed information within the network. We analyzed the resting state connectomes of 75 subjects of the Alzheimer's Disease Neuroimaging Initiative 2 (ADNI) repository. Our analyses are focused on the 18FGD-PET and functional MRI (fMRI) acquisitions in several clinical screening conditions. Results indicated that CF effectively discriminate MCI, AD and normal subjects by showing a significant decrease of the functional integration in the AD and MCI brain connectomes. This result did not emerge by using a set of common complex network statistics. Furthermore, CF was best correlated with individual clinical scoring scales. In conclusion, we presented a novel measure to quantify the functional integration that resulted efficient to discriminate different stages of dementia and to track the individual progression of the impairments prospecting a proficient usage in a wide range of pathophysiological and physiological studies as well. PMID- 26733856 TI - A Model of In vitro Plasticity at the Parallel Fiber-Molecular Layer Interneuron Synapses. AB - Theoretical and computational models of the cerebellum typically focus on the role of parallel fiber (PF)-Purkinje cell (PKJ) synapses for learned behavior, but few emphasize the role of the molecular layer interneurons (MLIs)-the stellate and basket cells. A number of recent experimental results suggest the role of MLIs is more important than previous models put forth. We investigate learning at PF-MLI synapses and propose a mathematical model to describe plasticity at this synapse. We perform computer simulations with this form of learning using a spiking neuron model of the MLI and show that it reproduces six in vitro experimental results in addition to simulating four novel protocols. Further, we show how this plasticity model can predict the results of other experimental protocols that are not simulated. Finally, we hypothesize what the biological mechanisms are for changes in synaptic efficacy that embody the phenomenological model proposed here. PMID- 26733857 TI - A Retina Inspired Model for Enhancing Visibility of Hazy Images. AB - The mammalian retina seems far smarter than scientists have believed so far. Inspired by the visual processing mechanisms in the retina, from the layer of photoreceptors to the layer of retinal ganglion cells (RGCs), we propose a computational model for haze removal from a single input image, which is an important issue in the field of image enhancement. In particular, the bipolar cells serve to roughly remove the low-frequency of haze, and the amacrine cells modulate the output of cone bipolar cells to compensate the loss of details by increasing the image contrast. Then the RGCs with disinhibitory receptive field surround refine the local haze removal as well as the image detail enhancement. Results on a variety of real-world and synthetic hazy images show that the proposed model yields results comparative to or even better than the state-of-the art methods, having the advantage of simultaneous dehazing and enhancing of single hazy image with simple and straightforward implementation. PMID- 26733858 TI - Signal Processing in Periodically Forced Gradient Frequency Neural Networks. AB - Oscillatory instability at the Hopf bifurcation is a dynamical phenomenon that has been suggested to characterize active non-linear processes observed in the auditory system. Networks of oscillators poised near Hopf bifurcation points and tuned to tonotopically distributed frequencies have been used as models of auditory processing at various levels, but systematic investigation of the dynamical properties of such oscillatory networks is still lacking. Here we provide a dynamical systems analysis of a canonical model for gradient frequency neural networks driven by a periodic signal. We use linear stability analysis to identify various driven behaviors of canonical oscillators for all possible ranges of model and forcing parameters. The analysis shows that canonical oscillators exhibit qualitatively different sets of driven states and transitions for different regimes of model parameters. We classify the parameter regimes into four main categories based on their distinct signal processing capabilities. This analysis will lead to deeper understanding of the diverse behaviors of neural systems under periodic forcing and can inform the design of oscillatory network models of auditory signal processing. PMID- 26733859 TI - Spike Detection for Large Neural Populations Using High Density Multielectrode Arrays. AB - An emerging generation of high-density microelectrode arrays (MEAs) is now capable of recording spiking activity simultaneously from thousands of neurons with closely spaced electrodes. Reliable spike detection and analysis in such recordings is challenging due to the large amount of raw data and the dense sampling of spikes with closely spaced electrodes. Here, we present a highly efficient, online capable spike detection algorithm, and an offline method with improved detection rates, which enables estimation of spatial event locations at a resolution higher than that provided by the array by combining information from multiple electrodes. Data acquired with a 4096 channel MEA from neuronal cultures and the neonatal retina, as well as synthetic data, was used to test and validate these methods. We demonstrate that these algorithms outperform conventional methods due to a better noise estimate and an improved signal-to-noise ratio (SNR) through combining information from multiple electrodes. Finally, we present a new approach for analyzing population activity based on the characterization of the spatio-temporal event profile, which does not require the isolation of single units. Overall, we show how the improved spatial resolution provided by high density, large scale MEAs can be reliably exploited to characterize activity from large neural populations and brain circuits. PMID- 26733860 TI - Integrating Visualizations into Modeling NEST Simulations. AB - Modeling large-scale spiking neural networks showing realistic biological behavior in their dynamics is a complex and tedious task. Since these networks consist of millions of interconnected neurons, their simulation produces an immense amount of data. In recent years it has become possible to simulate even larger networks. However, solutions to assist researchers in understanding the simulation's complex emergent behavior by means of visualization are still lacking. While developing tools to partially fill this gap, we encountered the challenge to integrate these tools easily into the neuroscientists' daily workflow. To understand what makes this so challenging, we looked into the workflows of our collaborators and analyzed how they use the visualizations to solve their daily problems. We identified two major issues: first, the analysis process can rapidly change focus which requires to switch the visualization tool that assists in the current problem domain. Second, because of the heterogeneous data that results from simulations, researchers want to relate data to investigate these effectively. Since a monolithic application model, processing and visualizing all data modalities and reflecting all combinations of possible workflows in a holistic way, is most likely impossible to develop and to maintain, a software architecture that offers specialized visualization tools that run simultaneously and can be linked together to reflect the current workflow, is a more feasible approach. To this end, we have developed a software architecture that allows neuroscientists to integrate visualization tools more closely into the modeling tasks. In addition, it forms the basis for semantic linking of different visualizations to reflect the current workflow. In this paper, we present this architecture and substantiate the usefulness of our approach by common use cases we encountered in our collaborative work. PMID- 26733862 TI - Editorial: Neuropsychology and Neuropsychiatry of Neurodegenerative Disorders. PMID- 26733861 TI - Executive Dysfunctions and Event-Related Brain Potentials in Patients with Amyotrophic Lateral Sclerosis. AB - A growing body of evidence implies psychological disturbances in amyotrophic lateral sclerosis (ALS). Specifically, executive dysfunctions occur in up to 50% of ALS patients. The recently shown presence of cytoplasmic aggregates (TDP-43) in ALS patients and in patients with behavioral variants of frontotemporal dementia suggests that these two disease entities form the extremes of a spectrum. The present study aimed at investigating behavioral and electrophysiological indices of conflict processing in patients with ALS. A non verbal variant of the flanker task demanded two-choice responses to target stimuli that were surrounded by flanker stimuli which either primed the correct response or the alternative response (the latter case representing the conflict situation). Behavioral performance, event-related potentials (ERP), and lateralized readiness potentials (LRP) were analyzed in 21 ALS patients and 20 controls. In addition, relations between these measures and executive dysfunctions were examined. ALS patients performed the flanker task normally, indicating preserved conflict processing. In similar vein, ERP and LRP indices of conflict processing did not differ between groups. However, ALS patients showed enhanced posterior negative ERP waveform deflections, possibly indicating increased modulation of visual processing by frontoparietal networks in ALS. We also found that the presence of executive dysfunctions was associated with more error-prone behavior and enhanced LRP amplitudes in ALS patients, pointing to a prefrontal pathogenesis of executive dysfunctions and to a potential link between prefrontal and motor cortical functional dysregulation in ALS, respectively. PMID- 26733863 TI - Patterns of Age-Associated Degeneration Differ in Shoulder Muscles. AB - Shoulder complaints are common in the elderly and hamper daily functioning. These complaints are often caused by tears in the muscle-tendon units of the rotator cuff (RC). The four RC muscles stabilize the shoulder joint. While some RC muscles are frequently torn in shoulder complaints others remain intact. The pathological changes in RC muscles are poorly understood. We investigated changes in RC muscle pathology combining radiological and histological procedures. We measured cross sectional area (CSA) and fatty infiltration from Magnetic Resonance Imaging with Arthrography (MRA) in subjects without (N = 294) and with (N = 109) RC-tears. Normalized muscle CSA of the four RC muscles and the deltoid shoulder muscle were compared and age-associated patterns of muscle atrophy and fatty infiltration were constructed. We identified two distinct age-associated patterns: in the supraspinatus and subscapularis RC muscles CSAs continuously declined throughout adulthood, whereas in the infraspinatus and deltoid reduced CSA was prominent from midlife onwards. In the teres minor, CSA was unchanged with age. Most importantly, age-associated patterns were highly similar between subjects without RC tear and those with RC-tears. This suggests that extensive RC muscle atrophy during aging could contribute to RC pathology. We compared muscle pathology between torn infraspinatus and non-torn teres minor and the deltoid in two patients with a massive RC-tear. In the torn infraspinatus we found pronounced fatty droplets, an increase in extracellular collagen-1, a loss of myosin heavy chain-1 expression in myofibers and an increase in Pax7-positive cells. However, the adjacent intact teres minor and deltoid exhibited healthy muscle features. This suggests that satellite cells and the extracellular matrix may contribute to extensive muscle fibrosis in torn RC. We suggest that torn RC muscles display hallmarks of muscle aging whereas the teres minor could represent an aging-resilient muscle. PMID- 26733864 TI - Age-Related Changes in Inter-Network Connectivity by Component Analysis. AB - Healthy aging is associated with brain changes that reflect an alteration to a functional unit in response to the available resources and architecture. Even before the onset of noticeable cognitive decline, the neural scaffolds underlying cognitive function undergo considerable change. Prior studies have suggested a disruption of the connectivity pattern within the "default-mode" network (DMN), and more specifically a disruption of the anterio-posterior connectivity. In this study, we explored the effects of aging on within-network connectivity of three DMN subnetworks: a posterior DMN (pDMN), an anterior DMN (aDMN), and a ventral DMN (vDMN); as well as between-network connectivity during resting-state. Using groupICA on 43 young and 43 older healthy adults, we showed a reduction of network co-activation in two of the DMN subnetworks (pDMN and aDMN) and demonstrated a difference in between-component connectivity levels. The older group exhibited more numerous high-correlation pairs (Pearson's rho > 0.3, Number of comp-pairs = 46) in comparison to the young group (Number of comp-pairs = 34), suggesting a more connected/less segregated cortical system. Moreover, three component-pairs exhibited statistically significant differences between the two populations. Visual areas V2-V1 and V2-V4 were more correlated in the older adults, while aDMN-pDMN correlation decreased with aging. The increase in the number of high-correlation component-pairs and the elevated correlation in the visual areas are consistent with the prior hypothesis that aging is associated with a reduction of functional segregation. However, the aDMN-pDMN dis connectivity may be occurring under a different mechanism, a mechanism more related to a breakdown of structural integrity along the anterio-posterior axis. PMID- 26733865 TI - Differential Effects of Tango Versus Dance for PD in Parkinson Disease. AB - Over half of the general population does not achieve recommended daily levels of physical activity, and activity levels in people with Parkinson disease (PD) are lower than in healthy older adults. Dance can serve as an adjunct to traditional treatments to improve gait, balance, and quality of life in people with PD. This study directly compares a tango dance intervention and a dance intervention based on the Dance for PD model, which integrates multiple dance styles. Eleven people with PD participated in a community-based mixed styles dance intervention called Dance for Parkinson's (D4PD). Participants in the D4PD group were matched to participants in an ongoing community-based exercise study who participated in tango dance. The groups received 12 weeks of intervention, attending 1-h group classes twice a week. Participants were evaluated off anti-PD medication before and after intervention. Measures of balance, repeated sit-to-stand performance and endurance (mini-balance evaluation systems test, four square step test, five times sit to stand, 6-min walk time) improved from pre to post similarly in both groups. Motor sign severity (movement disorders society unified Parkinson disease rating scale motor subsection) and functional mobility (timed up and go) improved in the tango group and worsened in the D4PD group. Gait velocity was not affected by either intervention. Direct comparisons of different interventions are critical for developing optimal exercise interventions designed to specifically target motor impairments in PD. Tango dance interventions may preferentially improve mobility and motor signs in people with PD, compared to D4PD. PMID- 26733867 TI - Living with Fibrosis: From Diagnosis to Future Hope. PMID- 26733866 TI - Common Effects of Amnestic Mild Cognitive Impairment on Resting-State Connectivity Across Four Independent Studies. AB - Resting-state functional connectivity is a promising biomarker for Alzheimer's disease. However, previous resting-state functional magnetic resonance imaging studies in Alzheimer's disease and amnestic mild cognitive impairment (aMCI) have shown limited reproducibility as they have had small sample sizes and substantial variation in study protocol. We sought to identify functional brain networks and connections that could consistently discriminate normal aging from aMCI despite variations in scanner manufacturer, imaging protocol, and diagnostic procedure. We therefore combined four datasets collected independently, including 112 healthy controls and 143 patients with aMCI. We systematically tested multiple brain connections for associations with aMCI using a weighted average routinely used in meta-analyses. The largest effects involved the superior medial frontal cortex (including the anterior cingulate), dorsomedial prefrontal cortex, striatum, and middle temporal lobe. Compared with controls, patients with aMCI exhibited significantly decreased connectivity between default mode network nodes and between regions of the cortico-striatal-thalamic loop. Despite the heterogeneity of methods among the four datasets, we identified common aMCI related connectivity changes with small to medium effect sizes and sample size estimates recommending a minimum of 140 to upwards of 600 total subjects to achieve adequate statistical power in the context of a multisite study with 5-10 scanning sites and about 10 subjects per group and per site. If our findings can be replicated and associated with other established biomarkers of Alzheimer's disease (e.g., amyloid and tau quantification), then these functional connections may be promising candidate biomarkers for Alzheimer's disease. PMID- 26733869 TI - Mutations in the Voltage Sensors of Domains I and II of Nav1.5 that are Associated with Arrhythmias and Dilated Cardiomyopathy Generate Gating Pore Currents. AB - Voltage gated sodium channels (Nav) are transmembrane proteins responsible for action potential initiation. Mutations mainly located in the voltage sensor domain (VSD) of Nav1.5, the cardiac sodium channel, have been associated with the development of arrhythmias combined with dilated cardiomyopathy. Gating pore currents have been observed with three unrelated mutations associated with similar clinical phenotypes. However, gating pores have never been associated with mutations outside the first domain of Nav1.5. The aim of this study was to explore the possibility that gating pore currents might be caused by the Nav1.5 R225P and R814W mutations (R3, S4 in DI and DII, respectively), which are associated with rhythm disturbances and dilated cardiomyopathy. Nav1.5 WT and mutant channels were transiently expressed in tsA201 cells. The biophysical properties of the alpha pore currents and the presence of gating pore currents were investigated using the patch-clamp technique. We confirmed the previously reported gain of function of the alpha pores of the mutant channels, which mainly consisted of increased window currents mostly caused by shifts in the voltage dependence of activation. We also observed gating pore currents associated with the R225P and R814W mutations. This novel permeation pathway was open under depolarized conditions and remained temporarily open at hyperpolarized potentials after depolarization periods. Gating pore currents could represent a molecular basis for the development of uncommon electrical abnormalities and changes in cardiac morphology. We propose that this biophysical defect be routinely evaluated in the case of Nav1.5 mutations on the VSD. PMID- 26733868 TI - Strategies for Pharmacological Organoprotection during Extracorporeal Circulation Targeting Ischemia-Reperfusion Injury. AB - Surgical correction of congenital cardiac malformations or aortocoronary bypass surgery in many cases implies the use of cardiopulmonary-bypass (CPB). However, a possible negative impact of CPB on internal organs such as brain, kidney, lung and liver cannot be neglected. In general, CPB initiates a systemic inflammatory response (SIRS) which is presumably caused by contact of blood components with the surface of CPB tubing. Moreover, during CPB the heart typically undergoes a period of cold ischemia, and the other peripheral organs a global low flow hypoperfusion. As a result, a plethora of pro-inflammatory mediators and cytokines is released activating different biochemical pathways, which finally may result in the occurrence of microthrombosis, microemboli, in depletion of coagulation factors and haemorrhagic diathesis besides typical ischemia reperfusion injuries. In our review we will focus on possible pharmacological interventions in patients to decrease negative effects of CPB and to improve post operative outcome with regard to heart and other organs like brain, kidney, or lung. PMID- 26733870 TI - Mitochondrial Bioenergetics and Fiber Type Assessments in Microbiopsy vs. Bergstrom Percutaneous Sampling of Human Skeletal Muscle. AB - Microbiopsies of human skeletal muscle are increasingly adopted by physiologists for a variety of experimental assays given the reduced invasiveness of this procedure compared to the classic Bergstrom percutaneous biopsy technique. However, a recent report demonstrated lower mitochondrial respiration in saponin permeabilized muscle fiber bundles (PmFB) prepared from microbiopsies vs. Bergstrom biopsies. We hypothesized that ADP-induced contraction (rigor) of smaller length microbiopsy PmFB causes a greater reduction in maximal respiration vs. Bergstrom, such that respiration could be increased by a myosin II ATPase inhibitor (Blebbistatin; BLEB). Eleven males and females each received a 2 mm diameter percutaneous microbiopsy and a 5 mm diameter Bergstrom percutaneous biopsy in opposite legs. Glutamate/malate (5/0.5 mM)-supported respiration in microbiopsy PmFB was lower than Bergstrom at submaximal concentrations of ADP. 5 MUM BLEB reduced this impairment such that there were no differences relative to Bergstrom +/- BLEB. Surprisingly, pyruvate (5 mM)-supported respiration was not different between either biopsy technique +/-BLEB, whereas BLEB increased succinate-supported respiration in Bergstrom only. H2O2 emission was lower in microbiopsy PmFB compared to Bergstrom PmFB in the presence of BLEB. Microbiopsies contained fewer type I fibers (37 vs. 47%) and more type IIX fibers (20 vs. 8%) compared to Bergstrom possibly due to sampling site depth and/or longitudinal location. These findings suggest that smaller diameter percutaneous biopsies yield lower glutamate-supported mitochondrial respiratory kinetics which is increased by preventing ADP-induced rigor with myosin inhibition. Microbiopsies of human skeletal muscle can be utilized for assessing mitochondrial respiratory kinetics in PmFB when assay conditions are supplemented with BLEB, but fiber type differences with this method should be considered. PMID- 26733871 TI - Hypothesis on Skeletal Muscle Aging: Mitochondrial Adenine Nucleotide Translocator Decreases Reactive Oxygen Species Production While Preserving Coupling Efficiency. AB - Mitochondrial membrane potential is the major regulator of mitochondrial functions, including coupling efficiency and production of reactive oxygen species (ROS). Both functions are crucial for cell bioenergetics. We previously presented evidences for a specific modulation of adenine nucleotide translocase (ANT) appearing during aging that results in a decrease in membrane potential - and therefore ROS production-but surprisingly increases coupling efficiency under conditions of low ATP turnover. Careful study of the bioenergetic parameters (oxidation and phosphorylation rates, membrane potential) of isolated mitochondria from skeletal muscles (gastrocnemius) of aged and young rats revealed a remodeling at the level of the phosphorylation system, in the absence of alteration of the inner mitochondrial membrane (uncoupling) or respiratory chain complexes regulation. We further observed a decrease in mitochondrial affinity for ADP in aged isolated mitochondria, and higher sensitivity of ANT to its specific inhibitor atractyloside. This age-induced modification of ANT results in an increase in the ADP concentration required to sustain the same ATP turnover as compared to young muscle, and therefore in a lower membrane potential under phosphorylating-in vivo-conditions. Thus, for equivalent ATP turnover (cellular ATP demand), coupling efficiency is even higher in aged muscle mitochondria, due to the down-regulation of inner membrane proton leak caused by the decrease in membrane potential. In the framework of the radical theory of aging, these modifications in ANT function may be the result of oxidative damage caused by intra mitochondrial ROS and may appear like a virtuous circle where ROS induce a mechanism that reduces their production, without causing uncoupling, and even leading in improved efficiency. Because of the importance of ROS as therapeutic targets, this new mechanism deserves further studies. PMID- 26733872 TI - Historeceptomic Fingerprints for Drug-Like Compounds. AB - Most drugs exert their beneficial and adverse effects through their combined action on several different molecular targets (polypharmacology). The true molecular fingerprint of the direct action of a drug has two components: the ensemble of all the receptors upon which a drug acts and their level of expression in organs/tissues. Conversely, the fingerprint of the adverse effects of a drug may derive from its action in bystander tissues. The ensemble of targets is almost always only partially known. Here we describe an approach improving upon and integrating both components: in silico identification of a more comprehensive ensemble of targets for any drug weighted by the expression of those receptors in relevant tissues. Our system combines more than 300,000 experimentally determined bioactivity values from the ChEMBL database and 4.2 billion molecular docking scores. We integrated these scores with gene expression data for human receptors across a panel of human tissues to produce drug-specific tissue-receptor (historeceptomics) scores. A statistical model was designed to identify significant scores, which define an improved fingerprint representing the unique activity of any drug. These multi-dimensional historeceptomic fingerprints describe, in a novel, intuitive, and easy to interpret style, the holistic, in vivo picture of the mechanism of any drug's action. Valuable applications in drug discovery and personalized medicine, including the identification of molecular signatures for drugs with polypharmacologic modes of action, detection of tissue-specific adverse effects of drugs, matching molecular signatures of a disease to drugs, target identification for bioactive compounds with unknown receptors, and hypothesis generation for drug/compound phenotypes may be enabled by this approach. The system has been deployed at drugable.org for access through a user-friendly web site. PMID- 26733874 TI - The Role of the Paratrigeminal Nucleus in Vagal Afferent Evoked Respiratory Reflexes: A Neuroanatomical and Functional Study in Guinea Pigs. AB - The respiratory tree receives sensory innervation from the jugular and nodose vagal sensory ganglia. Neurons of these ganglia are derived from embryologically distinct origins and as such demonstrate differing molecular, neurochemical and physiological phenotypes. Furthermore, whereas nodose afferent neurons project to the nucleus of the solitary tract (nTS), recent neuroanatomical studies in rats suggest that jugular neurons have their central terminations in the paratrigeminal nucleus (Pa5). In the present study we confirm that guinea pigs demonstrate a comparable distinction between the brainstem terminations of nodose and jugular ganglia afferents. Thus, microinjection of fluorescently conjugated cholera toxin B (CT-B) neural tracers into the caudal nTS and Pa5 resulted in highly specific retrograde labeling of neurons in the nodose and jugular ganglia, respectively. Whereas, nodose neurons more often expressed 160 KD neurofilament proteins and the alpha3 subunit of Na(+)/K(+) ATPase, significantly more jugular neurons expressed the neuropeptides substance P (SP) and, especially, Calcitonin Gene-Related Peptide (CGRP). Indeed, terminal fibers in the Pa5 compared to the nTS were characterized by their significantly greater expression of CGRP, further supporting the notion that jugular afferents project to trigeminal-related brainstem regions. Electrical stimulation of the guinea pig larynx following selective surgical denervation of the nodose afferent innervation to the larynx (leaving intact the jugular innervation) resulted in stimulus dependent respiratory slowing and eventual apnea. This jugular ganglia neuron mediated response was unaffected by bilateral microinjections of the GABAA agonist muscimol into the nTS, but was abolished by muscimol injected into the Pa5. Taken together these data confirm that jugular and nodose vagal ganglia afferent neurons innervate distinct central circuits and support the notion that multiple peripheral and central pathways mediate sensory responses associated with airway irritations. PMID- 26733873 TI - Simulation of Cardiac Arrhythmias Using a 2D Heterogeneous Whole Heart Model. AB - Simulation studies of cardiac arrhythmias at the whole heart level with electrocardiogram (ECG) gives an understanding of how the underlying cell and tissue level changes manifest as rhythm disturbances in the ECG. We present a 2D whole heart model (WHM2D) which can accommodate variations at the cellular level and can generate the ECG waveform. It is shown that, by varying cellular-level parameters like the gap junction conductance (GJC), excitability, action potential duration (APD) and frequency of oscillations of the auto-rhythmic cell in WHM2D a large variety of cardiac arrhythmias can be generated including sinus tachycardia, sinus bradycardia, sinus arrhythmia, sinus pause, junctional rhythm, Wolf Parkinson White syndrome and all types of AV conduction blocks. WHM2D includes key components of the electrical conduction system of the heart like the SA (Sino atrial) node cells, fast conducting intranodal pathways, slow conducting atriovenctricular (AV) node, bundle of His cells, Purkinje network, atrial, and ventricular myocardial cells. SA nodal cells, AV nodal cells, bundle of His cells, and Purkinje cells are represented by the Fitzhugh-Nagumo (FN) model which is a reduced model of the Hodgkin-Huxley neuron model. The atrial and ventricular myocardial cells are modeled by the Aliev-Panfilov (AP) two-variable model proposed for cardiac excitation. WHM2D can prove to be a valuable clinical tool for understanding cardiac arrhythmias. PMID- 26733875 TI - Comparison Between 30-15 Intermittent Fitness Test and Multistage Field Test on Physiological Responses in Wheelchair Basketball Players. AB - The intermittent nature of wheelchair court sports suggests using a similar protocol to assess repeated shuttles and recovery abilities. This study aimed to compare performances, physiological responses and perceived rating exertion obtained from the continuous multistage field test (MFT) and the 30-15 intermittent field test (30-15IFT). Eighteen trained wheelchair basketball players (WBP) (WBP: 32.0 +/- 5.7 y, IWBF classification: 2.9 +/- 1.1 points) performed both incremental field tests in randomized order. Time to exhaustion, maximal rolling velocity (MRV), VO2peak and the peak values of minute ventilation (V Epeak), respiratory frequency (RF) and heart rate (HRpeak) were measured throughout both tests; peak and net blood lactate (Delta[Lact(-)] = peak-rest values) and perceived rating exertion (RPE) values at the end of each exercise. No significant difference in VO2peak, VEpeak, and RF was found between both tests. 30-15IFT was shorter (12.4 +/- 2.4 vs. 14.9 +/- 5.1 min, P < 0.05) but induced higher values of MRV and Delta[Lact(-)] compared to MFT (14.2 +/- 1.8 vs. 11.1 +/- 1.9 km.h(-1) and 8.3 +/- 4.2 vs. 6.9 +/- 3.3 mmol.L(-1), P < 0.05). However, HRpeak and RPE values were higher during MFT than 30-15IFT(172.8 +/- 14.0 vs. 166.8 +/- 13.8 bpm and 15.3 +/- 3.8 vs.13.8 +/- 3.5, respectively, P < 0.05). The intermittent shuttles intercepted with rest period occurred during the 30-15IFT could explain a greater anaerobic solicitation. The higher HR and overall RPE values measured at the end of MFT could be explained by its longer duration and a continuous load stress compared to 30-15IFT. In conclusion, 30 15IFT has some advantages over MFT for assess in addition physical fitness and technical performance in WBP. PMID- 26733876 TI - Immunosuppressant MPA Modulates Tight Junction through Epigenetic Activation of MLCK/MLC-2 Pathway via p38MAPK. AB - BACKGROUND: Mycophenolic acid (MPA) is an important immunosuppressive drug (ISD) prescribed to prevent graft rejection in the organ transplanted patients, however, its use is also associated with adverse side effects like sporadic gastrointestinal (GI) disturbances. Recently, we reported the MPA induced tight junctions (TJs) deregulation which involves MLCK/MLC-2 pathway. Here, we investigated the global histone acetylation as well as gene-specific chromatin signature of several genes associated with TJs regulation in Caco-2 cells after MPA treatment. RESULTS: The epigenetic analysis shows that MPA treatment increases the global histone acetylation levels as well as the enrichment for transcriptional active histone modification mark (H3K4me3) at promoter regions of p38MAPK, ATF-2, MLCK, and MLC-2. In contrast, the promoter region of occludin was enriched for transcriptional repressive histone modification mark (H3K27me3) after MPA treatment. In line with the chromatin status, MPA treatment increased the expression of p38MAPK, ATF-2, MLCK, and MLC-2 both at transcriptional and translational level, while occludin expression was negatively influenced. Interestingly, the MPA induced gene expression changes and functional properties of Caco-2 cells could be blocked by the inhibition of p38MAPK using a chemical inhibitor (SB203580). CONCLUSIONS: Collectively, our results highlight that MPA disrupts the structure of TJs via p38MAPK-dependent activation of MLCK/MLC-2 pathway that results in decreased integrity of Caco-2 monolayer. These results led us to suggest that p38MAPK-mediated lose integrity of epithelial monolayer could be the possible cause of GI disturbance (barrier dysfunction) in the intestine, leading to leaky style diarrhea observed in the organ-transplanted patients treated with MPA. PMID- 26733877 TI - Pathway Analysis: State of the Art. AB - Pathway analysis is a set of widely used tools for research in life sciences intended to give meaning to high-throughput biological data. The methodology of these tools settles in the gathering and usage of knowledge that comprise biomolecular functioning, coupled with statistical testing and other algorithms. Despite their wide employment, pathway analysis foundations and overall background may not be fully understood, leading to misinterpretation of analysis results. This review attempts to comprise the fundamental knowledge to take into consideration when using pathway analysis as a hypothesis generation tool. We discuss the key elements that are part of these methodologies, their capabilities and current deficiencies. We also present an overview of current and all-time popular methods, highlighting different classes across them. In doing so, we show the exploding diversity of methods that pathway analysis encompasses, point out commonly overlooked caveats, and direct attention to a potential new class of methods that attempt to zoom the analysis scope to the sample scale. PMID- 26733878 TI - Interaction Between Heart Rate Variability and Heart Rate in Pediatric Population. AB - BACKGROUND: Heart rate variability (HRV) is primarily heart rate (HR) dependent, and therefore, different HR may exert different impact on HRV. The objectives of the study were to evaluate the effect of HR on HRV in children and to determine whether HRV indices normalized to HR are sex- and age-related. METHODS: Short term ECG recordings were performed in 346 healthy children. Standard time and frequency domain HRV parameters and HR were analyzed in four age subgroups (6-7, 8-9, 10-11, and 12-13 years old). To investigate the HR impact on HRV, standard HRV parameters were normalized to prevailing HR. RESULTS: Standard HRV measures did not differ between age subgroups, however, HR significantly decreased with subjects age and turned out to be the strongest determinant of HRV. The normalization of HRV to prevailing HR allowed to show that sex-related differences in standard HRV resulted from differences in HR between boys and girls. The normalized HRV significantly decreased with age-before the normalization this effect was masked by age-related HR alterations. CONCLUSIONS: HR significantly impacts HRV in pediatric population and turns out to be the strongest determinant of all standard HRV indices. The differences in standard HRV between boys and girls result from differences in their HR. The normalized HRV is decreasing with age in healthy children and it is accompanied by the reduction of HR-as a net result, the standard HRV is constant in children at different ages. This may reflect the maturation of the autonomic nervous system. PMID- 26733879 TI - Molecular Mechanism Underlying the Plant NRT1.1 Dual-Affinity Nitrate Transporter. AB - Nitrate ([Formula: see text]) is one of the most important sources of mineral nitrogen, which also serves as a key signaling molecule for plant growth and development. To cope with nitrate fluctuation in soil that varies by up to four orders of magnitude, plants have evolved high- and low-affinity nitrate transporter systems, consisting of distinct families of transporters. Interestingly, the first cloned nitrate transporter in Arabidopsis, NRT1.1 functions as a dual-affinity transporter, which can change its affinity for nitrate in response to substrate availability. Phosphorylation of a threonine residue, Thr101, switches NRT1.1 from low- to high-affinity state. Recent structural studies have unveiled that the unmodified NRT1.1 transporter works as homodimers with Thr101 located in close proximity to the dimer interface. Modification on the Thr101 residue is shown to not only decouple the dimer configuration, but also increase structural flexibility, thereby, altering the substrate affinity of NRT1.1. The structure of NRT1.1 helps establish a novel paradigm in which protein oligomerzation and posttranslational modification can synergistically expand the functional capacity of the major facilitator superfamily (MFS) transporters. PMID- 26733880 TI - Preserved Microvascular Endothelial Function in Young, Obese Adults with Functional Loss of Nitric Oxide Signaling. AB - Data indicate endothelium-dependent dilation (EDD) may be preserved in the skeletal muscle microcirculation of young, obese adults. Preserved EDD might be mediated by compensatory mechanisms, impeding insight into preclinical vascular dysfunction. We aimed to determine the functional roles of nitric oxide synthase (NOS) and cyclooxygenase (COX) toward EDD in younger obese adults. We first hypothesized EDD would be preserved in young, obese adults. Further, we hypothesized a reduced contribution of NOS in young, obese adults would be replaced by increased COX signaling. Microvascular EDD was assessed with Doppler ultrasound and brachial artery infusion of acetylcholine (ACh) in younger (27 +/- 1 year) obese (n = 29) and lean (n = 46) humans. Individual and combined contributions of NOS and COX were examined with intra-arterial infusions of l NMMA and ketorolac, respectively. Vasodilation was quantified as an increase in forearm vascular conductance (DeltaFVC). Arterial endothelial cell biopsies were analyzed for protein expression of endothelial nitric oxide synthase (eNOS). DeltaFVC to ACh was similar between groups. After l-NMMA, DeltaFVC to ACh was greater in obese adults (p < 0.05). There were no group differences in DeltaFVC to ACh with ketorolac. With combined NOS-COX inhibition, DeltaFVC was greater in obese adults at the intermediate dose of ACh. Surprisingly, arterial endothelial cell eNOS and phosphorylated eNOS were similar between groups. Younger obese adults exhibit preserved EDD and eNOS expression despite functional dissociation of NOS-mediated vasodilation and similar COX signaling. Compensatory NOS- and COX independent vasodilatory mechanisms conceal reduced NOS contributions in otherwise healthy obese adults early in life, which may contribute to vascular dysfunction. PMID- 26733881 TI - Individualized Internal and External Training Load Relationships in Elite Wheelchair Rugby Players. AB - AIM: The quantification and longitudinal monitoring of athlete training load (TL) provides a scientific explanation for changes in performance and helps manage injury/illness risk. Therefore, accurate and reliable monitoring tools are essential for the optimization of athletic performance. The aim of the present study was to establish the relationship between measures of internal [heart rate (HR) and session RPE (sRPE)] and external TL specific to wheelchair rugby (WR). METHODS: Fourteen international WR athletes (age = 29 +/- 7 years; body mass = 58.9 +/- 10.9 kg) were monitored during 18 training sessions over a 3 month period during the competitive phase of the season. Activity profiles were collected during each training session using a radio-frequency based indoor tracking system (ITS). External TL was quantified by total distance (m) covered as well as time spent and distance covered in a range of classification-specific arbitrary speed zones. Banister's TRIMP, Edwards's summated HR zone (SHRZ), and Lucia's TRIMP methods were used to quantify physiological internal TL. sRPE was calculated as the product of session duration multiplied by perceived exertion using the Borg CR10 scale. Relationships between external and internal TL were examined using correlation coefficients and the 90% confidence intervals (90% CI). RESULTS: sRPE (r = 0.59) and all HR-based (r > 0.80) methods showed large and very large relationships with the total distance covered during training sessions, respectively. Large and very large correlations (r = 0.56 - 0.82) were also observed between all measures of internal TL and times spent and distances covered in low and moderate intensity speed zones. HR-based methods showed very large relationships with time (r = 0.71-0.75) and distance (r = 0.70-0.73) in the very high speed zone and a large relationship with the number of high intensity activities (HIA) performed (r = 0.56-0.62). Weaker relationships (r = 0.32-0.35) were observed between sRPE and all measures of high intensity activity. A large variation of individual correlation co-efficient was observed between sRPE and all external TL measures. CONCLUSION: The current findings suggest that sRPE and HR-based internal TL measures provide a valid tool for quantifying volume of external TL during WR training but may underestimate HIA. It is recommended that both internal and external TL measures are employed for the monitoring of overall TL during court-based training in elite WR athletes. PMID- 26733882 TI - Different Predictors of Right and Left Ventricular Metabolism in Healthy Middle Aged Men. AB - Dysfunction of the right ventricle (RV) plays a crucial role in the outcome of various cardiovascular diseases. Previous studies on RV metabolism are sparse although evidence implies it may differ from left ventricular (LV) metabolism. Therefore, the aims of this study were (1) to determine predictors of RV glucose uptake (GU) and free fatty acid uptake (FFAU) and (2) to compare them to predictors of LV metabolism in healthy middle-aged men. Altogether 28 healthy, sedentary, middle-aged (40-55 years) men were studied. Insulin-stimulated GU and fasting FFAU were measured by positron emission tomography and RV and LV structural and functional parameters by cardiac magnetic resonance. Several parameters related to whole-body health were also measured. Predictors of RV and LV metabolism were determined by pairwise correlation analysis, lasso regression models, and variable clustering using heatmap. RVGU was most strongly predicted by age and moderately by RV ejection fraction (EF). The strongest determinants of RVFFAU were exercise capacity (peak oxygen uptake), resting heart rate, LVEF, and whole-body insulin-stimulated glucose uptake rate. When considering LV metabolism, age and RVEF were associated also with LVGU. In addition, LVGU was strongly, and negatively, influenced by whole-body insulin-stimulated glucose uptake rate. LVFFAU was predicted only by LVEF. This study shows that while RV and LV metabolism have shared characteristics, they also have unique properties. Age of the subject should be taken into account when measuring myocardial glucose utilization. Ejection fraction is related to myocardial metabolism, and even so that RVEF may be more closely related to GU of both ventricles and LVEF to FFAU of both ventricles, a finding supporting the ventricular interdependence. However, only RV fatty acid utilization associates with exercise capacity so that better physical fitness in a relatively sedentary population is related with decreased RV fat metabolism. To conclude, this study highlights the need for further study designed specifically on less-known RV, as the results on LV metabolism and physiology may not be directly applicable to the RV. PMID- 26733883 TI - Concept of an Active Amplification Mechanism in the Infrared Organ of Pyrophilous Melanophila Beetles. AB - Jewel beetles of the genus Melanophila possess a pair of metathoracic infrared (IR) organs. These organs are used for forest fire detection because Melanophila larvae can only develop in fire killed trees. Several reports in the literature and a modeling of a historic oil tank fire suggest that beetles may be able to detect large fires by means of their IR organs from distances of more than 100 km. In contrast, the highest sensitivity of the IR organs, so far determined by behavioral and physiological experiments, allows a detection of large fires from distances up to 12 km only. Sensitivity thresholds, however, have always been determined in non-flying beetles. Therefore, the complete micromechanical environment of the IR organs in flying beetles has not been taken into consideration. Because the so-called photomechanic sensilla housed in the IR organs respond bimodally to mechanical as well as to IR stimuli, it is proposed that flying beetles make use of muscular energy coupled out of the flight motor to considerably increase the sensitivity of their IR sensilla during intermittent search flight sequences. In a search flight the beetle performs signal scanning with wing beat frequency while the inputs of the IR organs on both body sides are compared. By this procedure the detection of weak IR signals could be possible even if the signals are hidden in the thermal noise. If this proposed mechanism really exists in Melanophila beetles, their IR organs could even compete with cooled IR quantum detectors. The theoretical concept of an active amplification mechanism in a photon receptor innervated by highly sensitive mechanoreceptors is presented in this article. PMID- 26733884 TI - Effect of Angiotensin(1-7) on Heart Function in an Experimental Rat Model of Obesity. AB - AIM: Obesity is a risk factor for the development of cardiovascular diseases. Recently it was shown that overexpression of the Mas-receptor antagonist angiotensin(1-7) could prevent from diet-induced obesity. However, it remained unclear whether diet-induced obesity and angiotensin(1-7) overexpression might also have effects on the cardiovascular system in these rats. METHODS: Twenty three male Sprague Dawley rats were fed with standard chow (SD+chow, n = 5) or a cafeteria diet (SD+CD, n = 6) for 5 months. To investigate the effect of angiotensin(1-7) transgenic rats, expressing an angiotensin(1-7)-producing fusion protein in testis were used. These transgenic rats also received a 5 month's feeding period with either chow (TGR+chow, n = 6) or cafeteria diet (TGR+CD, n = 6), respectively. Hemodynamic measurements (pressure-volume loops) were carried out to assess cardiac function and blood pressure. Subsequently, hearts were explanted and investigated according to the Langendorff technique. Furthermore, cardiac remodeling in these animals was investigated histologically. RESULTS: After 5 months cafeteria diet feeding rats showed a significantly increased body weight, which could be prevented in transgenic rats. However, there was no effect on cardiac performance after cafeteria diet in non-transgenic and transgenic rats. Moreover, overexpression of angiotensin(1-7) deteriorated cardiac contractility as indicated by impaired dp/dt. Furthermore, histological analysis revealed that cafeteria diet led to myocardial fibrosis in both, control and transgenic rats and this was not inhibited by an overproduction of angiotensin(1 7). CONCLUSION: These results indicate that an overexpression of circulating angiotensin(1-7) prevents a cafeteria diet-induced increase in body weight, but does not affect cardiac performance in this experimental rat model of obesity. Furthermore, overexpression of angiotensin(1-7) alone resulted in an impairment of cardiac function. PMID- 26733886 TI - TNFalpha-Damaged-HUVECs Microparticles Modify Endothelial Progenitor Cell Functional Activity. AB - Endothelial progenitor cells (EPCs) have an important role in the maintenance of vascular integrity and homeostasis. While there are many studies that explain EPCs mechanisms action, there are few studies that demonstrate how they interact with other emerging physiological elements such as Endothelial Microparticles (EMPs). EMPs are membranous structures with a size between 100 and 1000 nm that act as molecular information transporter in biological systems and are known as an important elements in develop different pathologies; moreover a lot of works explains that are novel biomarkers. To elucidate these interactions, we proposed an in vitro model of endothelial damage mediated by TNFalpha, in which damaged EMPs and EPCs are in contact to assess EPCs functional effects. We have observed that damaged EMPs can modulate several EPCs classic factors as colony forming units (CFUs), contribution to repair a physically damaged endothelium (wound healing), binding to mature endothelium, and co-adjuvants to the formation of new vessels in vitro (angiogenesis). All of these in a dose-dependent manner. Damaged EMPs at a concentration of 10(3) MPs/ml have an activating effect of these capabilities, while at concentrations of 10(5) MPs/ml these effects are attenuated or reduced. This in vitro model helps explain that in diseases where there is an imbalance between these two elements (EPCs and damaged EMPs), the key cellular elements in the regeneration and maintenance of vascular homeostasis (EPCs) are not fully functional, and could explain, at least in part, endothelial dysfunction associated in various pathologies. PMID- 26733885 TI - Identification of Atypical Peri-Nuclear Multivesicular Bodies in Oxidative and Glycolytic Skeletal Muscle of Aged and Pompe's Disease Mouse Models. AB - Muscle wasting that occurs during aging or from disease pathology presents with an accumulation of lipid species termed ceroid or lipofuscin. This unique species of lipid has been characterized in various cell types but its properties and organization in skeletal muscle remains unclear. Using immunofluorescence and transmission electron microscopy, we were able to visualize and characterize an atypical lipid storing organelle in skeletal muscle. White myofibers contain two organelles at each pole of the myonuclei and red myofibers contain many of these structures in and around the perinuclear space. These organelles contain markers for late endosomes, are morphologically similar to multivesicular bodies, store lipid, and hypertrophy in aged muscle and a model of muscle wasting with an accumulation of large amounts of lipofuscin. Rapamycin treatment reduces the multivesicular body hypertrophy, restores late endosomal protein markers, and also increases the number and intensity of lipofuscin deposits. Together, these data demonstrate for the first time a perinuclear organelle in skeletal muscle that hypertrophies in muscle wasting phenotypes and is involved in endocytic lipid storage. PMID- 26733887 TI - Ion Channels in Native Chloroplast Membranes: Challenges and Potential for Direct Patch-Clamp Studies. AB - Photosynthesis without any doubt depends on the activity of the chloroplast ion channels. The thylakoid ion channels participate in the fine partitioning of the light-generated proton-motive force (p.m.f.). By regulating, therefore, luminal pH, they affect the linear electron flow and non-photochemical quenching. Stromal ion homeostasis and signaling, on the other hand, depend on the activity of both thylakoid and envelope ion channels. Experimentally, intact chloroplasts and swollen thylakoids were proven to be suitable for direct measurements of the ion channels activity via conventional patch-clamp technique; yet, such studies became infrequent, although their potential is far from being exhausted. In this paper we wish to summarize existing challenges for direct patch-clamping of native chloroplast membranes as well as present available results on the activity of thylakoid Cl(-) (ClC?) and divalent cation-permeable channels, along with their tentative roles in the p.m.f. partitioning, volume regulation, and stromal Ca(2+) and Mg(2+) dynamics. Patch-clamping of the intact envelope revealed both large-conductance porin-like channels, likely located in the outer envelope membrane and smaller conductance channels, more compatible with the inner envelope location. Possible equivalent model for the sandwich-like arrangement of the two envelope membranes within the patch electrode will be discussed, along with peculiar properties of the fast-activated cation channel in the context of the stromal pH control. PMID- 26733888 TI - Low Intensity Exercise Training Improves Skeletal Muscle Regeneration Potential. AB - PURPOSE: The aim of this study was to determine whether 12 days of low-to moderate exercise training at low altitude (598 m a.s.l.) improves skeletal muscle regeneration in sedentary adult women. METHODS: Satellite cells were obtained from the vastus lateralis skeletal muscle of seven women before and after this exercise training at low altitude. They were investigated for differentiation aspects, superoxide anion production, antioxidant enzymes, mitochondrial potential variation after a depolarizing insult, intracellular Ca(2+) concentrations, and micro (mi)RNA expression (miR-1, miR-133, miR-206). RESULTS: In these myogenic populations of adult stem cells, those obtained after exercise training, showed increased Fusion Index and intracellular Ca(2+) concentrations. This exercise training also generally reduced superoxide anion production in cells (by 12-67%), although not in two women, where there was an increase of ~15% along with a reduced superoxide dismutase activity. miRNA expression showed an exercise-induced epigenetic transcription profile that was specific according to the reduced or increased superoxide anion production of the cells. CONCLUSIONS: The present study shows that low-to-moderate exercise training at low altitude improves the regenerative capacity of skeletal muscle in adult women. The differentiation of cells was favored by increased intracellular calcium concentration and increased the fusion index. This low-to-moderate training at low altitude also depicted the epigenetic signature of cells. PMID- 26733889 TI - Sprint Acceleration Mechanics: The Major Role of Hamstrings in Horizontal Force Production. AB - Recent literature supports the importance of horizontal ground reaction force (GRF) production for sprint acceleration performance. Modeling and clinical studies have shown that the hip extensors are very likely contributors to sprint acceleration performance. We experimentally tested the role of the hip extensors in horizontal GRF production during short, maximal, treadmill sprint accelerations. Torque capabilities of the knee and hip extensors and flexors were assessed using an isokinetic dynamometer in 14 males familiar with sprint running. Then, during 6-s sprints on an instrumented motorized treadmill, horizontal and vertical GRF were synchronized with electromyographic (EMG) activity of the vastus lateralis, rectus femoris, biceps femoris, and gluteus maximus averaged over the first half of support, entire support, entire swing and end-of-swing phases. No significant correlations were found between isokinetic or EMG variables and horizontal GRF. Multiple linear regression analysis showed a significant relationship (P = 0.024) between horizontal GRF and the combination of biceps femoris EMG activity during the end of the swing and the knee flexors eccentric peak torque. In conclusion, subjects who produced the greatest amount of horizontal force were both able to highly activate their hamstring muscles just before ground contact and present high eccentric hamstring peak torque capability. PMID- 26733891 TI - The Impact of a Videogame-Based Pilot Physical Activity Program in Older Adults with Schizophrenia on Subjectively and Objectively Measured Physical Activity. AB - OBJECTIVES: The purpose of this report is to describe the impact of a videogame based pilot physical activity program using the Kinect for Xbox 360 game system (Microsoft, Redmond, WA, USA) on physical activity in older adults with schizophrenia. METHODS: In this one group pre-test, post-test pilot study, 20 participants played an active videogame for 30 min, once a week for 6 weeks. Physical activity was measured by self-report with the Yale Physical Activity Survey and objectively with the Sensewear Pro armband at enrollment and at the end of the 6-week program. RESULTS: There was a significant increase in frequency of self-reported vigorous physical activity. We did not detect a statistically significant difference in objectively measured physical activity although increase in number of steps and sedentary activity were in the desired direction. CONCLUSION: These results suggest participants' perception of physical activity intensity differs from the intensity objectively captured with a valid and reliable physical activity monitor. PMID- 26733890 TI - Eyeblink Conditioning in Schizophrenia: A Critical Review. AB - There is accruing evidence of cerebellar abnormalities in schizophrenia. The theory of cognitive dysmetria considers cerebellar dysfunction a key component of schizophrenia. Delay eyeblink conditioning (EBC), a cerebellar-dependent translational probe, is a behavioral index of cerebellar integrity. The circuitry underlying EBC has been well characterized by non-human animal research, revealing the cerebellum as the essential circuitry for the associative learning instantiated by this task. However, there have been persistent inconsistencies in EBC findings in schizophrenia. This article thoroughly reviews published studies investigating EBC in schizophrenia, with an emphasis on possible effects of antipsychotic medication and stimulus and analysis parameters on reports of EBC performance in schizophrenia. Results indicate a consistent finding of impaired EBC performance in schizophrenia, as measured by decreased rates of conditioning, and that medication or study design confounds do not account for this impairment. Results are discussed within the context of theoretical and neurochemical models of schizophrenia. PMID- 26733892 TI - Neurobiological Approach of Catatonia and Treatment Perspectives. PMID- 26733893 TI - Structure Modulates Similarity-Based Interference in Sluicing: An Eye Tracking study. AB - In cue-based content-addressable approaches to memory, a target and its competitors are retrieved in parallel from memory via a fast, associative cue matching procedure under a severely limited focus of attention. Such a parallel matching procedure could in principle ignore the serial order or hierarchical structure characteristic of linguistic relations. I present an eye tracking while reading experiment that investigates whether the sentential position of a potential antecedent modulates the strength of similarity-based interference, a well-studied effect in which increased similarity in features between a target and its competitors results in slower and less accurate retrieval overall. The manipulation trades on an independently established Locality bias in sluiced structures to associate a wh-remnant (which ones) in clausal ellipsis with the most local correlate (some wines), as in The tourists enjoyed some wines, but I don't know which ones. The findings generally support cue-based parsing models of sentence processing that are subject to similarity-based interference in retrieval, and provide additional support to the growing body of evidence that retrieval is sensitive to both the structural position of a target antecedent and its competitors, and the specificity or diagnosticity of retrieval cues. PMID- 26733894 TI - Portmanteau Constructions, Phrase Structure, and Linearization. AB - In bilingual code-switching which involves language-pairs with contrasting head complement orders (i.e., head-initial vs. head-final), a head may be lexicalized from both languages with its complement sandwiched in the middle. These so-called "portmanteau" sentences (Nishimura, 1985, 1986; Sankoff et al., 1990, etc.) have been attested for decades, but they had never received a systematic, formal analysis in terms of current syntactic theory before a few recent attempts (Hicks, 2010, 2012). Notwithstanding this lack of attention, these structures are in fact highly relevant to theories of linearization and phrase structure. More specifically, they challenge binary-branching (Kayne, 1994, 2004, 2005) as well as the Antisymmetry hypothesis (ibid.). Not explained by current grammatical models of code-switching, including the Equivalence Constraint (Poplack, 1980), the Matrix Language Frame Model (Myers-Scotton, 1993, 2002, etc.), and the Bilingual Speech Model (Muysken, 2000, 2013), the portmanteau construction indeed looks uncommon or abnormal, defying any systematic account. However, the recurrence of these structures in various datasets and constraints on them do call for an explanation. This paper suggests an account which lies with syntax and also with the psycholinguistics of bilingualism. Assuming that linearization is a process at the Sensori-Motor (SM) interface (Chomsky, 2005, 2013), this paper sees that word order is not fixed in a syntactic tree but it is set in the production process, and much information of word order rests in the processor, for instance, outputting a head before its complement (i.e., head-initial word order) or the reverse (i.e., head-final word order). As for the portmanteau construction, it is the output of bilingual speakers co-activating two sets of head-complement orders which summon the phonetic forms of the same word in both languages. Under this proposal, the underlying structure of a portmanteau construction is as simple as an XP in which a head X merges with its complement YP and projects an XP (i.e., X YP -> [XP X YP]). PMID- 26733896 TI - Entropic Movement Complexity Reflects Subjective Creativity Rankings of Visualized Hand Motion Trajectories. AB - In a previous study we have shown that human motion trajectories can be characterized by translating continuous trajectories into symbol sequences with well-defined complexity measures. Here we test the hypothesis that the motion complexity individuals generate in their movements might be correlated to the degree of creativity assigned by a human observer to the visualized motion trajectories. We asked participants to generate 55 novel hand movement patterns in virtual reality, where each pattern had to be repeated 10 times in a row to ensure reproducibility. This allowed us to estimate a probability distribution over trajectories for each pattern. We assessed motion complexity not only by the previously proposed complexity measures on symbolic sequences, but we also propose two novel complexity measures that can be directly applied to the distributions over trajectories based on the frameworks of Gaussian Processes and Probabilistic Movement Primitives. In contrast to previous studies, these new methods allow computing complexities of individual motion patterns from very few sample trajectories. We compared the different complexity measures to how a group of independent jurors rank ordered the recorded motion trajectories according to their personal creativity judgment. We found three entropic complexity measures that correlate significantly with human creativity judgment and discuss differences between the measures. We also test whether these complexity measures correlate with individual creativity in divergent thinking tasks, but do not find any consistent correlation. Our results suggest that entropic complexity measures of hand motion may reveal domain-specific individual differences in kinesthetic creativity. PMID- 26733895 TI - Implicit and Explicit Attention to Pictures and Words: An fMRI-Study of Concurrent Emotional Stimulus Processing. AB - The present study utilized functional magnetic resonance imaging (fMRI) to examine the neural processing of concurrently presented emotional stimuli under varying explicit and implicit attention demands. Specifically, in separate trials, participants indicated the category of either pictures or words. The words were placed over the center of the pictures and the picture-word compound stimuli were presented for 1500 ms in a rapid event-related design. The results reveal pronounced main effects of task and emotion: the picture categorization task prompted strong activations in visual, parietal, temporal, frontal, and subcortical regions; the word categorization task evoked increased activation only in left extrastriate cortex. Furthermore, beyond replicating key findings regarding emotional picture and word processing, the results point to a dissociation of semantic-affective and sensory-perceptual processes for words: while emotional words engaged semantic-affective networks of the left hemisphere regardless of task, the increased activity in left extrastriate cortex associated with explicitly attending to words was diminished when the word was overlaid over an erotic image. Finally, we observed a significant interaction between Picture Category and Task within dorsal visual-associative regions, inferior parietal, and dorsolateral, and medial prefrontal cortices: during the word categorization task, activation was increased in these regions when the words were overlaid over erotic as compared to romantic pictures. During the picture categorization task, activity in these areas was relatively decreased when categorizing erotic as compared to romantic pictures. Thus, the emotional intensity of the pictures strongly affected brain regions devoted to the control of task-related word or picture processing. These findings are discussed with respect to the interplay of obligatory stimulus processing with task-related attentional control mechanisms. PMID- 26733897 TI - Global Similarities and Multifaceted Differences in the Production of Partner Specific Referential Pacts by Adults with Autism Spectrum Disorders. AB - Over repeated reference conversational partners tend to converge on preferred terms or referential pacts. Autism spectrum disorders (ASD) are characterized by pragmatic difficulties that are best captured by less structured tasks. To this end we tested adults with ASD who did not have language or intellectual impairments, and neurotypical comparison participants in a referential communication task. Participants were directors, describing unlexicalized, complex novel stimuli over repeated rounds of interaction. Group comparisons with respect to referential efficiency showed that directors with ASD demonstrated typical lexical entrainment: they became faster over repeated rounds and used shortened referential forms. ASD and neurotypical groups did not differ with respect to the number of descriptors they provided or the number of exchanges needed for matchers to identify figures. Despite these similarities the ASD group was slightly slower overall. We examined partner-specific effects by manipulating the common ground shared with the matcher. As expected, neurotypical directors maintained referential precedents when speaking to the same matcher but not with a new matcher. Directors with ASD were qualitatively similar but displayed a less pronounced distinction between matchers. However, significant differences and different patterns of reference emerged over time; neurotypical directors incorporated the new matcher's contributions into descriptions, whereas directors with ASD were less likely to do so. PMID- 26733898 TI - Schooling Relates to Mental Health Problems in Adolescents with Cochlear Implants Mediation by Hearing and Family Variables. AB - Aim of this multicenter study was to investigate whether schooling relates to mental health problems of adolescents with cochlear implants (CI) and how this relationship is mediated by hearing and family variables. One hundred and forty secondary school students with CI (mean age = 14.7 years, SD = 1.5), their hearing parents and teachers completed the Strengths and Difficulties Questionnaire (SDQ). Additional audiological tests (speech comprehension tests in quiet and noise) were performed. Students of special schools for hearing impaired persons (SSHIs) showed significantly more conduct problems (p < 0.05) and a significantly higher total difficulty score (TDS) (p < 0.05) compared to students of mainstream schools. Mental health problems did not differ between SSHI students with sign language education and SSHI students with oral education. Late implanted students and those with indication for additional handicaps were equally distributed among mainstream schools and SSHIs. However, students in SSHIs were more restricted to understand speech in noise, had a lower social background and were more likely to come from single-parent families. These factors were found to be partial mediators of the differences in mental health problems between the two school types. However, no variable could explain comprehensively, why students of SSHIs have more mental health problems than mainstream pupils. PMID- 26733899 TI - Working Memory and Hearing Aid Processing: Literature Findings, Future Directions, and Clinical Applications. AB - Working memory-the ability to process and store information-has been identified as an important aspect of speech perception in difficult listening environments. Working memory can be envisioned as a limited-capacity system which is engaged when an input signal cannot be readily matched to a stored representation or template. This "mismatch" is expected to occur more frequently when the signal is degraded. Because working memory capacity varies among individuals, those with smaller capacity are expected to demonstrate poorer speech understanding when speech is degraded, such as in background noise. However, it is less clear whether (and how) working memory should influence practical decisions, such as hearing treatment. Here, we consider the relationship between working memory capacity and response to specific hearing aid processing strategies. Three types of signal processing are considered, each of which will alter the acoustic signal: fast-acting wide-dynamic range compression, which smooths the amplitude envelope of the input signal; digital noise reduction, which may inadvertently remove speech signal components as it suppresses noise; and frequency compression, which alters the relationship between spectral peaks. For fast acting wide-dynamic range compression, a growing body of data suggests that individuals with smaller working memory capacity may be more susceptible to such signal alterations, and may receive greater amplification benefit with "low alteration" processing. While the evidence for a relationship between wide dynamic range compression and working memory appears robust, the effects of working memory on perceptual response to other forms of hearing aid signal processing are less clear cut. We conclude our review with a discussion of the opportunities (and challenges) in translating information on individual working memory into clinical treatment, including clinically feasible measures of working memory. PMID- 26733900 TI - Mindfulness, Resilience, and Burnout Subtypes in Primary Care Physicians: The Possible Mediating Role of Positive and Negative Affect. AB - PURPOSE: Primary care health professionals suffer from high levels of burnout. The aim of the present study was to evaluate the associations of mindfulness and resilience with the features of the burnout types (overload, lack of development, neglect) in primary care physicians, taking into account the potential mediating role of negative and positive affect. METHODS: A cross-sectional design was used. Six hundred and twenty-two Spanish primary care physicians were recruited from an online survey. The Mindful Attention Awareness Scale (MAAS), Connor-Davidson Resilience Scale (CD-RISC), Positive and Negative Affect Schedule (PANAS), and Burnout Clinical Subtype Questionnaire (BCSQ-12) questionnaires were administered. Polychoric correlation matrices were calculated. The unweighted least squares (ULS) method was used for developing structural equation modeling. RESULTS: Mindfulness and resilience presented moderately high associations (phi = 0.46). Links were found between mindfulness and overload (gamma = -0.25); resilience and neglect (gamma = -0.44); mindfulness and resilience, and negative affect (gamma = -0.30 and gamma = -0.35, respectively); resilience and positive affect (gamma = 0.70); negative affect and overload (beta = 0.36); positive affect and lack of development (beta = -0.16). The links between the burnout types reached high and positive values between overload and lack of development (beta = 0.64), and lack of development and neglect (beta = 0.52). The model was a very good fit to the data (GFI = 0.96; AGFI = 0.96; RMSR = 0.06; NFI = 0.95; RFI = 0.95; PRATIO = 0.96). CONCLUSIONS: Interventions addressing both mindfulness and resilience can influence burnout subtypes, but their impact may occur in different ways, potentially mediated by positive and negative affect. Both sorts of trainings could constitute possible tools against burnout; however, while mindfulness seems a suitable intervention for preventing its initial stages, resilience may be more effective for treating its advanced stages. PMID- 26733902 TI - Enhancing Student Interest in Animals. Commentary: A Crisis in Comparative Psychology: Where Have All the Undergraduates Gone? PMID- 26733901 TI - Unpacking Constructs: A Network Approach for Studying War Exposure, Daily Stressors and Post-Traumatic Stress Disorder. AB - Conflict-affected populations are exposed to stressful events during and after war, and it is well established that both take a substantial toll on individuals' mental health. Exactly how exposure to events during and after war affect mental health is a topic of considerable debate. Various hypotheses have been put forward on the relation between stressful war exposure (SWE), daily stressors (DS) and the development of post-traumatic stress disorder (PTSD). This paper seeks to contribute to this debate by critically reflecting upon conventional modeling approaches and by advancing an alternative model to studying interrelationships between SWE, DS, and PTSD variables. The network model is proposed as an innovative and comprehensive modeling approach in the field of mental health in the context of war. It involves a conceptualization and representation of variables and relationships that better approach reality, hence improving methodological rigor. It also promises utility in programming and delivering mental health support for war-affected populations. PMID- 26733903 TI - Linguistic and Cognitive Skills in Sardinian-Italian Bilingual Children. AB - We report the results of a study which tested receptive Italian grammatical competence and general cognitive abilities in bilingual Italian-Sardinian children and age-matched monolingual Italian children attending the first and second year of primary school in the Nuoro province of Sardinia, where Sardinian is still widely spoken. The results show that across age groups the performance of Sardinian-Italian bilingual children is in most cases indistinguishable from that of monolingual Italian children, in terms of both Italian language skills and general cognitive abilities. However, where there are differences, these emerge gradually over time and are mostly in favor of bilingual children. PMID- 26733904 TI - The Relationship Between Personality Traits, Flow-Experience, and Different Aspects of Practice Behavior of Amateur Vocal Students. AB - Most of the existing studies on musical practice are concerned with instrumentalists only. Since singers are seldom considered in research, the present study is based on an online-sample of amateur vocal students (N = 120; 92 female, 28 male). The study investigated the correlations between personality traits, flow-experience and several aspects of practice characteristics. Personality was represented by the three personality dimensions extraversion, neuroticism and psychoticism, assessed by Eysenck's Personality Profiler as well as the trait form of the Positive and Negative Affect Schedule. 'Flow experience,' 'self-congruence' and 'fear of losing control over concentration,' assessed by the Practice Flow Inventory, served as variables for flow-experience. The practice motivation was measured by the Practice Motivation Questionnaire in four categories ('self,' 'group,' 'audience,' 'teacher'). In addition, the Practice Behavior Questionnaire was used to provide an insight into the practice situation and behavior of singing students. The results show significant correlations: participants with high extraversion-scores experience significantly more flow than less extraverted persons, whereas lesser flow-experience seems to be related to high neuroticism-scores. Nevertheless, there is no influence in flow-experience concerning singing style ('classical' or 'popular'). The longer the practicing time, the more likely students are to achieve flow-experience. However, older singers tend to have less flow-experience. Consequently, singers seem to differ in their personality and practice behavior compared to other musicians. Most of the findings show that having control over one's instrument is decisive for achieving a performance of high quality, especially for singers. On the other hand, certainty in handling an instrument is essential to arouse a flow feeling. However, flow-experience seems to be common mainly with amateur singers. In conclusion, this offers a starting point for new research on the psychology of vocalists in greater depth. PMID- 26733905 TI - Memory Recall After "Learning by Doing" and "Learning by Viewing": Boundary Conditions of an Enactment Benefit. AB - According to common sense, things one has done are remembered better than things done by others that one has observed. On first sight, findings concerning memory for actions appear in line with that preconception: Performed actions ("subject performed tasks") appear to be remembered particularly well, and better than observed actions ("experimenter-performed tasks"). A closer look, however, reveals important exceptions regarding this enactment effect. The aim of the present paper is critically evaluating the literature that compares memory for performed and observed tasks. In recognition memory, an enactment effect has regularly been observed. In free recall, however, findings depended on the experimental design: When performed and observed actions were intermixed, an enactment effect was typically found. In contrast, in designs where actions were either all performed or all observed, this was rarely the case. We discuss underlying memory processes, potential moderator variables, open questions, and implications. PMID- 26733907 TI - Commentary: Awareness of Risk Factors for Digital Game Addiction: Interviewing Players and Counselors. PMID- 26733906 TI - Altered Statistical Learning and Decision-Making in Methamphetamine Dependence: Evidence from a Two-Armed Bandit Task. AB - Understanding how humans weigh long-term and short-term goals is important for both basic cognitive science and clinical neuroscience, as substance users need to balance the appeal of an immediate high vs. the long-term goal of sobriety. We use a computational model to identify learning and decision-making abnormalities in methamphetamine-dependent individuals (MDI, n = 16) vs. healthy control subjects (HCS, n = 16), in a two-armed bandit task. In this task, subjects repeatedly choose between two arms with fixed but unknown reward rates. Each choice not only yields potential immediate reward but also information useful for long-term reward accumulation, thus pitting exploration against exploitation. We formalize the task as comprising a learning component, the updating of estimated reward rates based on ongoing observations, and a decision-making component, the choice among options based on current beliefs and uncertainties about reward rates. We model the learning component as iterative Bayesian inference (the Dynamic Belief Model), and the decision component using five competing decision policies: Win-stay/Lose-shift (WSLS), epsilon-Greedy, tau-Switch, Softmax, Knowledge Gradient. HCS and MDI significantly differ in how they learn about reward rates and use them to make decisions. HCS learn from past observations but weigh recent data more, and their decision policy is best fit as Softmax. MDI are more likely to follow the simple learning-independent policy of WSLS, and among MDI best fit by Softmax, they have more pessimistic prior beliefs about reward rates and are less likely to choose the option estimated to be most rewarding. Neurally, MDI's tendency to avoid the most rewarding option is associated with a lower gray matter volume of the thalamic dorsal lateral nucleus. More broadly, our work illustrates the ability of our computational framework to help reveal subtle learning and decision-making abnormalities in substance use. PMID- 26733908 TI - Adventure Thrills are Addictive. PMID- 26733910 TI - Editorial: Turn-Taking in Human Communicative Interaction. PMID- 26733909 TI - Emotion Understanding in Clinically Anxious Children: A Preliminary Investigation. AB - Children's understanding of the nature, origins and consequences of emotions has been intensively investigated over the last 30-40 years. However, few empirical studies have looked at the relation between emotion understanding and anxiety in children and their results are mixed. The aim of the present study was to perform a preliminary investigation of the relationships between emotion understanding, anxiety, emotion dysregulation, and attachment security in clinically anxious children. A sample of 16 clinically anxious children (age 8-12, eight girls/boys) was assessed for emotion understanding (Test of Emotion Comprehension), anxiety (Screening for Child Anxiety Related Emotional Disorders-Revised and Anxiety Disorder Interview Schedule), emotion dysregulation (Difficulties in Emotion Regulation Scale) and attachment security (Security Scale). Children who reported more overall anxiety also reported greater difficulties in regulating their emotions, and were less securely attached to their parents. The results also showed that more specific symptoms of anxiety (i.e., OCD and PTSD) correlated not only with emotion dysregulation and attachment insecurity but also with emotion understanding. Finally, there were interrelations among emotion understanding, attachment security, and emotion dysregulation. The present results provide the first comprehensive evidence for a socio-emotional framework and its relevance to childhood anxiety. PMID- 26733911 TI - The Possible Antecedents and Consequences of Matching of Food Intake: Examining the Role of Trait Self-Esteem and Interpersonal Closeness. AB - Although there is evidence that people tend to match their intake to that of others, less is known about the motives underlying this effect. The current study, therefore, examined the relationship between self-esteem, a specific factor that has been related to the likelihood of social matching. Further, we examined the effects of food matching on interpersonal closeness among eating companions. The sample included 89 female dyads. All dyads had free access to palatable snack food during a 15 min interaction. For each dyad the matching score was calculated, as well as both individual's trait self-esteem scores and interpersonal closeness with their eating partner. The overall degree of matching within dyads was high, replicating the findings of previous research. No relationship, however, was found between trait self-esteem and the degree of matching. Furthermore, there was no effect of matching on perceived interpersonal closeness with or liking of the other person. These results suggest that self esteem might not be a robust predictor of matching and that matching of food intake may not result in increased perceived interpersonal closeness or liking among eating partners. PMID- 26733912 TI - Machine Learning to Differentiate Between Positive and Negative Emotions Using Pupil Diameter. AB - Pupil diameter (PD) has been suggested as a reliable parameter for identifying an individual's emotional state. In this paper, we introduce a learning machine technique to detect and differentiate between positive and negative emotions. We presented 30 participants with positive and negative sound stimuli and recorded pupillary responses. The results showed a significant increase in pupil dilation during the processing of negative and positive sound stimuli with greater increase for negative stimuli. We also found a more sustained dilation for negative compared to positive stimuli at the end of the trial, which was utilized to differentiate between positive and negative emotions using a machine learning approach which gave an accuracy of 96.5% with sensitivity of 97.93% and specificity of 98%. The obtained results were validated using another dataset designed for a different study and which was recorded while 30 participants processed word pairs with positive and negative emotions. PMID- 26733913 TI - Young and Older Adults' Gender Stereotype in Multitasking. AB - In the present study, we investigated discrepancies between two components of stereotyping by means of the popular notion that women are better at multitasking behaviors: the cognitive structure in individuals (personal belief) and the perceived consensus regarding certain beliefs (perceived belief of groups). With focus on this notion, we examined whether there was empirical evidence for the stereotype's existence and whether and how it was shared among different age groups. Data were collected from 241 young (n = 129) and older (n = 112) German individuals. The reported perceptions of gender effects at multitasking were substantial and thus demonstrated the existence of its stereotype. Importantly, in young and older adults, this stereotype existed in the perception of attributed characteristics by members of a collective (perceived belief of groups). When contrasting this perceived belief of groups and the personal belief, older adults showed a similar level of conformation of the gender stereotype while young adults were able to differentiate between these perspectives. Thus, young adults showed a discrepancy between the stereotype's components cognitive structure in individuals and perceived consensus regarding certain beliefs. PMID- 26733915 TI - Corrigendum: Social coordination in animal vocal interactions. Is there any evidence of turn-taking? The starling as an animal model. AB - [This corrects the article on p. 1416 in vol. 6, PMID: 26441787.]. PMID- 26733914 TI - Cerebral Correlates of Automatic Associations Towards Performance Enhancing Substances. AB - The direct assessment of explicit attitudes toward performance enhancing substances, for example Neuroenhancement or doping in sports, can be affected by social desirability biases and cheating attempts. According to Dual Process Theories of cognition, indirect measures like the Implicit Association Test (IAT) measure automatic associations toward a topic (as opposed to explicit attitudes measured by self-report measures). Such automatic associations are thought to occur rapidly and to evade voluntary control. However, whether or not such indirect tests actually reflect automatic associations is difficult to validate. Electroencephalography (EEG) has a superior time resolution which can differentiate between highly automatic compared to more elaborate processing stages. We therefore used EEG to examine on which processing stages cortical differences between negative or positive attitudes to doping occur, and whether or not these differences can be related to BIAT scores. We tested 42 university students (31 females, 24.43 +/- 3.17 years old), who were requested to complete a brief doping IAT (BIAT) on attitudes toward doping. Cerebral activity during doping BIAT completion was assessed using high-density EEG. Behaviorally, participants D-scores exhibited negative attitudes toward doping, represented by faster reaction times in the doping + dislike pairing task. Event-related potentials (ERPs) revealed earliest effects between 200 and 300 ms. Here, a relatively larger occipital positivity was found for the doping + dislike pairing task. Further, in the LPP time range between 400 and 600 ms a larger late positive potential was found for the doping + dislike pairing task over central regions. These LPP amplitude differences were successfully predicting participants' BIAT D-scores. Results indicate that event-related potentials differentiate between positive and negative doping attitudes at stages of mid latency. However, it seems that IAT scores can be predicted only by the later occurring LPP. Our study is the first to investigate the cerebral correlates that contribute to test scores obtained in the indirect testing of automatic associations toward doping. The implications of our results for the broader NE concept are discussed in light of the conceptual similarity of doping and NE. PMID- 26733916 TI - Effects of Uncertainty on ERPs to Emotional Pictures Depend on Emotional Valence. AB - Uncertainty about the emotional content of an upcoming event has found to modulate neural activity to the event before its occurrence. However, it is still under debate whether the uncertainty effects occur after the occurrence of the event. To address this issue, participants were asked to view emotional pictures that were shortly after a cue, which either indicated a certain emotion of the picture or not. Both certain and uncertain cues were used by neutral symbols. The anticipatory phase (i.e., inter-trial interval, ITI) between the cue and the picture was short to enhance the effects of uncertainty. In addition, we used positive and negative pictures that differed only in valence but not in arousal to investigate whether the uncertainty effect was dependent on emotional valence. Electroencephalography (EEG) was recorded during the presentation of the pictures. Event-related potential (ERP) results showed that negative pictures evoked smaller P2 and late LPP but larger N2 in the uncertain as compared to the certain condition; whereas we did not find the uncertainty effect in early LPP. For positive pictures, the early LPP was larger in the uncertain as compared to the certain condition; however, there were no uncertainty effects in some other ERP components (e.g., P2, N2, and late LPP). The findings suggest that uncertainty modulates neural activity to emotional pictures and this modulation is altered by the valence of the pictures, indicating that individuals alter the allocation of attentional resources toward uncertain emotional pictures dependently on the valence of the pictures. PMID- 26733917 TI - Commentary: A crisis in comparative psychology: where have all the undergraduates gone? PMID- 26733918 TI - Auditory Discrimination Between Function Words in Children and Adults: A Mismatch Negativity Study. AB - Previous behavioral studies showed that it is not until around the age of seven that German children reliably use case markers for the interpretation of complex sentences. Some explanations of this late development suggested that children might have difficulties in perceptual differentiation between function words that carry case information. We tested this hypothesis by using the neurophysiological index of pre-attentive discrimination, the mismatch negativity (MMN). Our data showed that children at the age of 3 years are able to automatically discriminate between the two determiner forms der and den when presented out of sentential context. The determiner form der elicited a more mature MMN response in children than the form den. In adults, the MMN pattern also differed with der showing an earlier peak than den. These findings indicate that der is easier to process than den, which in turn is related to the occurrence frequency of the determiner forms in language. PMID- 26733919 TI - Tailoring Cognitive Behavioral Therapy to Subtypes of Voice-Hearing. AB - Cognitive behavioral therapy (CBT) for voice-hearing (i.e., auditory verbal hallucinations; AVH) has, at best, small to moderate effects. One possible reason for this limited efficacy is that current CBT approaches tend to conceptualize voice-hearing as a homogenous experience in terms of the cognitive processes involved in AVH. However, the highly heterogeneous nature of voice-hearing suggests that many different cognitive processes may be involved in the etiology of AVH. These heterogeneous voice-hearing experiences do, however, appear to cluster into a set of subtypes, opening up the possibility of tailoring treatment to the subtype of AVH that a voice-hearer reports. In this paper, we (a) outline our rationale for tailoring CBT to subtypes of voice-hearing, (b) describe CBT for three putative subtypes of AVH (inner speech-based AVH, memory-based AVH, and hypervigilance AVH), and (c) discuss potential limitations and problems with such an approach. We conclude by arguing that tailoring CBT to subtypes of voice hearing could prove to be a valuable therapeutic development, which may be especially effective when used in early intervention in psychosis services. PMID- 26733920 TI - Psychometric Properties and Validation of the Positive and Negative Suicide Ideation (PANSI) Inventory in an Outpatient Clinical Population in Malaysia. AB - The PANSI is a measure designed to assess the risk and protective factors related to suicidal behaviors. The present study evaluated the psychometric properties and factor structure of the Positive and Negative Suicide Ideation (PANSI) Inventory in a sample of clinical outpatients at a major hospital in Malaysia. In this study, 283 psychiatric patients and 200 medical (non-psychiatric) patients participated. All the patients completed the PANSI and seven other self-report instruments. Confirmative factor analysis supported the 2-factor oblique model. The internal consistency of the two subscales of PANSI-Negative and the PANSI Positive were 0.93 and 0.84, respectively. In testing construct validity, PANSI showed sizable correlation with the other seven scales. Criterion validity was supported by scores on PANSI which differentiated psychiatric patients from medical patients. Logistic regression analyses showed PANSI can be used to classify the patients into suicidal or non-suicidal. The PANSI is a reliable and valid instrument to measure the severity of suicidal ideation among clinical outpatients in Malaysia. PMID- 26733921 TI - This Place Looks Familiar-How Navigators Distinguish Places with Ambiguous Landmark Objects When Learning Novel Routes. AB - We present two experiments investigating how navigators deal with ambiguous landmark information when learning unfamiliar routes. In the experiments we presented landmark objects repeatedly along a route, which allowed us to manipulate how informative single landmarks were (1) about the navigators' location along the route and (2) about the action navigators had to take at that location. Experiment 1 demonstrated that reducing location informativeness alone did not affect route learning performance. While reducing both location and action informativeness led to decreased route learning performance, participants still performed well above chance level. This demonstrates that they used other information than just the identity of landmark objects at their current position to disambiguate their location along the route. To investigate how navigators distinguish between visually identical intersections, we systematically manipulated the identity of landmark objects and the actions required at preceding intersections in Experiment 2. Results suggest that the direction of turn at the preceding intersections was sufficient to tell two otherwise identical intersections apart. Together, results from Experiments 1 and 2 suggest that route knowledge is more complex than simple stimulus-response associations and that neighboring places are tightly linked. These links not only encompass sequence information but also directional information which is used to identify the correct direction of travel at subsequent locations, but can also be used for self-localization. PMID- 26733922 TI - The Change of Expression Configuration Affects Identity-Dependent Expression Aftereffect but Not Identity-Independent Expression Aftereffect. AB - The present study examined the influence of expression configuration on cross identity expression aftereffect. The expression configuration refers to the spatial arrangement of facial features in a face for conveying an emotion, e.g., an open-mouth smile vs. a closed-mouth smile. In the first of two experiments, the expression aftereffect is measured using a cross-identity/cross-expression configuration factorial design. The facial identities of test faces were the same or different from the adaptor, while orthogonally, the expression configurations of those facial identities were also the same or different. The results show that the change of expression configuration impaired the expression aftereffect when the facial identities of adaptor and tests were the same; however, the impairment effect disappears when facial identities were different, indicating the identity independent expression representation is more robust to the change of the expression configuration in comparison with the identity-dependent expression representation. In the second experiment, we used schematic line faces as adaptors and real faces as tests to minimize the similarity between the adaptor and tests, which is expected to exclude the contribution from the identity dependent expression representation to expression aftereffect. The second experiment yields a similar result as the identity-independent expression aftereffect observed in Experiment 1. The findings indicate the different neural sensitivities to expression configuration for identity-dependent and identity independent expression systems. PMID- 26733923 TI - An Evaluation of the Measurement Properties of the Five Cs Model of Positive Youth Development. AB - There is growing recognition of the need to develop acceptable measures of adolescent's positive attributes in diverse contexts. The current study evaluated the measurement properties of the Five Cs model of Positive Youth Development (PYD) scale (Lerner et al., 2005) using a sample of 672 Irish adolescents. Confirmatory factor analyses indicated that a five-factor model provided a good fit to the data. The internal reliability and construct validity of the Five Cs model were supported, with character the strongest predictor of contribution, while connection was the strongest predictor of risky-behaviors. Notably, confidence was significantly negatively related to contribution, and positively related to risky-behaviors. Multi-group hierarchical nested models supported measurement invariance across early- (11-14 years) and late- (15-19 years) adolescent age groups, with partial invariance found across gender. Younger adolescents evinced higher PYD, while PYD was associated with higher contribution and lower depression and risk-behaviors across all groups. The application of the PYD framework as a measure of positive functioning across adolescence is discussed. PMID- 26733924 TI - Electroencephalographic Correlates of Sensorimotor Integration and Embodiment during the Appreciation of Virtual Architectural Environments. AB - Nowadays there is the hope that neuroscientific findings will contribute to the improvement of building design in order to create environments which satisfy man's demands. This can be achieved through the understanding of neurophysiological correlates of architectural perception. To this aim, the electroencephalographic (EEG) signals of 12 healthy subjects were recorded during the perception of three immersive virtual reality environments (VEs). Afterwards, participants were asked to describe their experience in terms of Familiarity, Novelty, Comfort, Pleasantness, Arousal, and Presence using a rating scale from 1 to 9. These perceptual dimensions are hypothesized to influence the pattern of cerebral spectral activity, while Presence is used to assess the realism of the virtual stimulation. Hence, the collected scores were used to analyze the Power Spectral Density (PSD) of the EEG for each behavioral dimension in the theta, alpha and mu bands by means of time-frequency analysis and topographic statistical maps. Analysis of Presence resulted in the activation of the frontal midline theta, indicating the involvement of sensorimotor integration mechanisms when subjects expressed to feel more present in the VEs. Similar patterns also characterized the experience of familiar and comfortable VEs. In addition, pleasant VEs increased the theta power across visuomotor circuits and activated the alpha band in areas devoted to visuospatial exploration and processing of categorical spatial relations. Finally, the de-synchronization of the mu rhythm described the perception of pleasant and comfortable VEs, showing the involvement of left motor areas and embodied mechanisms for environment appreciation. Overall, these results show the possibility to measure EEG correlates of architectural perception involving the cerebral circuits of sensorimotor integration, spatial navigation, and embodiment. These observations can help testing architectural hypotheses in order to design environments matching the changing needs of humans. PMID- 26733925 TI - Adaptation Duration Dissociates Category-, Image-, and Person-Specific Processes on Face-Evoked Event-Related Potentials. AB - Several studies demonstrated that face perception is biased by the prior presentation of another face, a phenomenon termed as face-related after-effect (FAE). FAE is linked to a neural signal-reduction at occipito-temporal areas and it can be observed in the amplitude modulation of the early event-related potential (ERP) components. Recently, macaque single-cell recording studies suggested that manipulating the duration of the adaptor makes the selective adaptation of different visual motion processing steps possible. To date, however, only a few studies tested the effects of adaptor duration on the electrophysiological correlates of human face processing directly. The goal of the current study was to test the effect of adaptor duration on the image-, identity-, and generic category-specific face processing steps. To this end, in a two-alternative forced choice familiarity decision task we used five adaptor durations (ranging from 200-5000 ms) and four adaptor categories: adaptor and test were identical images-Repetition Suppression (RS); adaptor and test were different images of the Same Identity (SameID); adaptor and test images depicted Different Identities (DiffID); the adaptor was a Fourier phase-randomized image (No). Behaviorally, a strong priming effect was observed in both accuracy and response times for RS compared with both DiffID and No. The electrophysiological results suggest that rapid adaptation leads to a category-specific modulation of P100, N170, and N250. In addition, both identity and image-specific processes affected the N250 component during rapid adaptation. On the other hand, prolonged (5000 ms) adaptation enhanced, and extended category-specific adaptation processes over all tested ERP components. Additionally, prolonged adaptation led to the emergence of image-, and identity-specific modulations on the N170 and P2 components as well. In other words, there was a clear dissociation among category, identity-, and image-specific processing steps in the case of longer (3500 and 5000 ms) but not for shorter durations (< 3500 ms), reflected in the gradual reduction of N170 and enhancement of P2 in the No, DiffID, SameID, and RS conditions. Our findings imply that by manipulating adaptation duration one can dissociate the various steps of human face processing, reflected in the ERP response. PMID- 26733926 TI - How a (sub)Cellular Coincidence Detection Mechanism Featuring Layer-5 Pyramidal Cells May Help Produce Various Visual Phenomena. AB - Perceptual phenomena such as spatio-temporal illusions and masking are typically explained by psychological (cognitive) processing theories or large-scale neural theories involving inter-areal connectivity and neural circuits comprising of hundreds or more interconnected single cells. Subcellular mechanisms are hardly used for such purpose. Here, a mechanistic theoretical view is presented on how a subcellular brain mechanism of integration of presynaptic signals that arrive at different compartments of layer-5 pyramidal neurons could explain a couple of spatiotemporal visual-phenomenal effects unfolding along very brief time intervals within the range of the sub-second temporal scale. PMID- 26733927 TI - Mental Barriers and Links Connecting People of Different Cultures: Experiential vs. Conceptual Bases of Different Types of the WE-Concepts. PMID- 26733928 TI - A Multidimensional Approach to the Study of Emotion Recognition in Autism Spectrum Disorders. AB - Although deficits in emotion recognition have been widely reported in autism spectrum disorder (ASD), experiments have been restricted to either facial or vocal expressions. Here, we explored multimodal emotion processing in children with ASD (N = 19) and with typical development (TD, N = 19), considering uni (faces and voices) and multimodal (faces/voices simultaneously) stimuli and developmental comorbidities (neuro-visual, language and motor impairments). Compared to TD controls, children with ASD had rather high and heterogeneous emotion recognition scores but showed also several significant differences: lower emotion recognition scores for visual stimuli, for neutral emotion, and a greater number of saccades during visual task. Multivariate analyses showed that: (1) the difficulties they experienced with visual stimuli were partially alleviated with multimodal stimuli. (2) Developmental age was significantly associated with emotion recognition in TD children, whereas it was the case only for the multimodal task in children with ASD. (3) Language impairments tended to be associated with emotion recognition scores of ASD children in the auditory modality. Conversely, in the visual or bimodal (visuo-auditory) tasks, the impact of developmental coordination disorder or neuro-visual impairments was not found. We conclude that impaired emotion processing constitutes a dimension to explore in the field of ASD, as research has the potential to define more homogeneous subgroups and tailored interventions. However, it is clear that developmental age, the nature of the stimuli, and other developmental comorbidities must also be taken into account when studying this dimension. PMID- 26733929 TI - The Approximate Number System Acuity Redefined: A Diffusion Model Approach. AB - While all humans are capable of non-verbally representing numerical quantity using so-called the approximate number system (ANS), there exist considerable individual differences in its acuity. For example, in a non-symbolic number comparison task, some people find it easy to discriminate brief presentations of 14 dots from 16 dots while others do not. Quantifying individual ANS acuity from such a task has become an essential practice in the field, as individual differences in such a primitive number sense is thought to provide insights into individual differences in learned symbolic math abilities. However, the dominant method of characterizing ANS acuity-computing the Weber fraction (w)-only utilizes the accuracy data while ignoring response times (RT). Here, we offer a novel approach of quantifying ANS acuity by using the diffusion model, which accounts both accuracy and RT distributions. Specifically, the drift rate in the diffusion model, which indexes the quality of the stimulus information, is used to capture the precision of the internal quantity representation. Analysis of behavioral data shows that w is contaminated by speed-accuracy tradeoff, making it problematic as a measure of ANS acuity, while drift rate provides a measure more independent from speed-accuracy criterion settings. Furthermore, drift rate is a better predictor of symbolic math ability than w, suggesting a practical utility of the measure. These findings demonstrate critical limitations of the use of w and suggest clear advantages of using drift rate as a measure of primitive numerical competence. PMID- 26733931 TI - Psychometric Evaluation of the Overexcitability Questionnaire-Two Applying Bayesian Structural Equation Modeling (BSEM) and Multiple-Group BSEM-Based Alignment with Approximate Measurement Invariance. AB - The Overexcitability Questionnaire-Two (OEQ-II) measures the degree and nature of overexcitability, which assists in determining the developmental potential of an individual according to Dabrowski's Theory of Positive Disintegration. Previous validation studies using frequentist confirmatory factor analysis, which postulates exact parameter constraints, led to model rejection and a long series of model modifications. Bayesian structural equation modeling (BSEM) allows the application of zero-mean, small-variance priors for cross-loadings, residual covariances, and differences in measurement parameters across groups, better reflecting substantive theory and leading to better model fit and less overestimation of factor correlations. Our BSEM analysis with a sample of 516 students in higher education yields positive results regarding the factorial validity of the OEQ-II. Likewise, applying BSEM-based alignment with approximate measurement invariance, the absence of non-invariant factor loadings and intercepts across gender is supportive of the psychometric quality of the OEQ-II. Compared to males, females scored significantly higher on emotional and sensual overexcitability, and significantly lower on psychomotor overexcitability. PMID- 26733932 TI - When is Deceptive Message Production More Effortful than Truth-Telling? A Baker's Dozen of Moderators. AB - Deception is thought to be more effortful than telling the truth. Empirical evidence from many quarters supports this general proposition. However, there are many factors that qualify and even reverse this pattern. Guided by a communication perspective, I present a baker's dozen of moderators that may alter the degree of cognitive difficulty associated with producing deceptive messages. Among sender-related factors are memory processes, motivation, incentives, and consequences. Lying increases activation of a network of brain regions related to executive memory, suppression of unwanted behaviors, and task switching that is not observed with truth-telling. High motivation coupled with strong incentives or the risk of adverse consequences also prompts more cognitive exertion-for truth-tellers and deceivers alike-to appear credible, with associated effects on performance and message production effort, depending on the magnitude of effort, communicator skill, and experience. Factors related to message and communication context include discourse genre, type of prevarication, expected response length, communication medium, preparation, and recency of target event/issue. These factors can attenuate the degree of cognitive taxation on senders so that truth telling and deceiving are similarly effortful. Factors related to the interpersonal relationship among interlocutors include whether sender and receiver are cooperative or adversarial and how well-acquainted they are with one another. A final consideration is whether the unit of analysis is the utterance, turn at talk, episode, entire interaction, or series of interactions. Taking these factors into account should produce a more nuanced answer to the question of when deception is more difficult than truth-telling. PMID- 26733930 TI - Prosodic Structure as a Parallel to Musical Structure. AB - What structural properties do language and music share? Although early speculation identified a wide variety of possibilities, the literature has largely focused on the parallels between musical structure and syntactic structure. Here, we argue that parallels between musical structure and prosodic structure deserve more attention. We review the evidence for a link between musical and prosodic structure and find it to be strong. In fact, certain elements of prosodic structure may provide a parsimonious comparison with musical structure without sacrificing empirical findings related to the parallels between language and music. We then develop several predictions related to such a hypothesis. PMID- 26733933 TI - From Languishing Dyslexia to Thriving Dyslexia: Developing a New Conceptual Approach to Working with People with Dyslexia. AB - This is an account of personal narratives shared by several people with dyslexia. Most of these are presented in their original quotation format to provide personal accounts of the lives of people with dyslexia. In this paper the author shares her conversations with her participants. This paper provides an original conceptual model, which is currently been tested empirically. Dyslexia affects the learning process in areas as such reading, and spelling. Conversely abilities or strengths can be seen in other areas, such as developing coping strategies to manage and overcome challenges. This research aims to adapt positive psychology techniques to support individuals with dyslexia. To develop positive psychology interventions, individuals will be helped to discover their five signature strengths. The VIA (Values in Action) Strengths Survey has been hosted in a website which has been developed in the form of a dyslexia user friendly format, such as providing the ability for respondents to change fonts and font sizes, colors and a text to speech option. This paper introduces the theoretical model of 'How to move from Languishing Dyslexia to Thriving Dyslexia.' PMID- 26733935 TI - Commentary: Clinical Correlates of Raphe Serotonergic Dysfunction in Early Parkinson's Disease. PMID- 26733934 TI - Expanding the Repertoire of Biomarkers for Alzheimer's Disease: Targeted and Non targeted Approaches. AB - The first biofluid markers developed for Alzheimer's disease (AD) used targeted approaches for discovery. These initial biomarkers were directed at key protein constituents of the hallmark brain lesions in AD. Biomarkers for plaques targeted the amyloid beta protein (Abeta) and for tangles, the microtubule-associated protein tau. Cerebrospinal fluid levels of Abeta and tau have excellent diagnostic utility and can be used to monitor aspects of therapeutic development. Recent research has extended our current concepts of AD, which now include a slow buildup of pathology during a long pre-symptomatic period, a complex cascade of pathological pathways in the brain that may accelerate once symptoms develop, the potential of aggregated proteins to spread across brain pathways, and interactions with vascular and other age-associated brain pathologies. There are many potential roles for biomarkers within this landscape. A more diverse set of biomarkers would provide a better picture of the staging and state of pathological events in the brain across the stages of AD. The aim of this review is to focus on methods of biomarker discovery that may help to expand the currently accepted biomarkers. Opportunities and approaches for targeted and non targeted (or -omic) biomarker discovery are highlighted, with examples from recent studies. How biomarker discoveries can be developed and integrated to become useful tools in diagnostic and therapeutic efforts is discussed. PMID- 26733937 TI - Fifty Percent Prevalence of Extracampine Hallucinations in Parkinson's Disease Patients. AB - Extracampine hallucinations (EH), the sense of a presence or fleeting movement in the absence of an associated visual percept, have been reported in Parkinson's disease (PD) patients but their prevalence, characteristics, and temporal relationship to visual hallucinations (VH) remain unclear. Given that, VH are predictive of cognitive impairment in PD, improved understanding of EH may have significant prognostic implications. The objective of this study is to evaluate the prevalence and characteristics of EH in a large unselected population with PD and to assess the temporal relationship between EH, VH, and memory decline. Cross sectional data were collected from 414 PD patients using a questionnaire circulated via an online patient community. Data were obtained regarding the occurrence, timing, and characteristics of VH and EH and symptoms of PD, disease duration, disease severity, and medication history. About 50.4% of respondents reported EH and 15.5% reported VH. EH were typically experienced alongside, rather than behind, the individual (p < 0.001) without clear lateralization (p = 0.438) and were more likely to be of unfamiliar presences (p < 0.001). The occurrence of EH was associated with Hoehn and Yahr score (p = 0.002) but not disease duration (p = 0.158). EH onset was associated with VH onset (p = 0.046) and occurred after the onset of anosmia (p < 0.001), cognitive decline (p = 0.002), and sleep disturbance (p = 0.002). The reported prevalence of EH in PD patients was threefold greater than that of VH, with similar timings of onset, suggesting that EH are under-recognized and under-reported. Further work is needed to determine whether EH are predictive of cognitive decline. PMID- 26733936 TI - Epigenetics and Triplet-Repeat Neurological Diseases. AB - The term "junk DNA" has been reconsidered following the delineation of the functional significance of repetitive DNA regions. Typically associated with centromeres and telomeres, DNA repeats are found in nearly all organisms throughout their genomes. Repetitive regions are frequently heterochromatinized resulting in silencing of intrinsic and nearby genes. However, this is not a uniform rule, with several genes known to require such an environment to permit transcription. Repetitive regions frequently exist as dinucleotide, trinucleotide, and tetranucleotide repeats. The association between repetitive regions and disease was emphasized following the discovery of abnormal trinucleotide repeats underlying spinal and bulbar muscular atrophy (Kennedy's disease) and fragile X syndrome of mental retardation (FRAXA) in 1991. In this review, we provide a brief overview of epigenetic mechanisms and then focus on several diseases caused by DNA triplet-repeat expansions, which exhibit diverse epigenetic effects. It is clear that the emerging field of epigenetics is already generating novel potential therapeutic avenues for this group of largely incurable diseases. PMID- 26733938 TI - Glial Fibrillary Acidic Protein Is Not an Early Marker of Injury in Perinatal Asphyxia and Hypoxic-Ischemic Encephalopathy. AB - Brain-specific glial fibrillary acidic protein (GFAP) has been suggested as a potential biomarker for hypoxic ischemic encephalopathy (HIE) in newborns (1, 2). Previous studies have shown increased levels in post-natal blood samples. However, its ability to guide therapeutic intervention in HIE is unknown. Therapeutic hypothermia for HIE must be initiated within 6 h of birth, therefore a clinically useful marker of injury would have to be available immediately following delivery. The goal of our study was to examine the ability of GFAP to predict grade of encephalopathy and neurological outcome when measured in umbilical cord blood (UCB). Infants with suspected perinatal asphyxia (PA) and HIE were enrolled in a single, tertiary maternity hospital, where UCB was drawn, processed, and bio-banked at birth. Expression levels of GFAP were measured by ELISA. In total, 169 infants (83 controls, 56 PA, 30 HIE) were included in the study. GFAP levels were not increased in UCB of case infants (PA/HIE) when compared to healthy controls or when divided into specific grades of HIE. Additionally, no correlation was found between UCB levels of GFAP and outcome at 36 months. PMID- 26733939 TI - Editorial: Fatigue in Multiple Sclerosis. PMID- 26733940 TI - Prevalence of Vestibular Disorder in Older People Who Experience Dizziness. AB - Dizziness and imbalance are clinically poorly defined terms, which affect ~30% of people over 65 years of age. In these people, it is often difficult to define the primary cause of dizziness, as it can stem from cardiovascular, vestibular, psychological, and neuromuscular causes. However, identification of the primary cause is vital in determining the most effective treatment strategy for a patient. Our aim is to accurately identify the prevalence of benign paroxysmal positional vertigo (BPPV), peripheral, and central vestibular hypofunction in people aged over 50 years who had experienced dizziness within the past year. Seventy-six participants aged 51-92 (mean +/- SD = 69 +/- 9.5 years) were tested using the head thrust dynamic visual acuity (htDVA) test, dizziness handicap inventory (DHI), as well as sinusoidal and unidirectional rotational chair testing, in order to obtain data for htDVA score, DHI score, sinusoidal (whole body, 0.1-2 Hz with peak velocity at 30 degrees /s) vestibulo-ocular reflex (VOR) gain and phase, transient (whole-body, acceleration at 150 degrees /s(2) to a constant velocity rotation of 50 degrees /s) VOR gain and time constant (TC), optokinetic nystagmus (OKN) gain, and TC (whole-body, constant velocity rotation at 50 degrees /s). We found that BPPV, peripheral and central vestibular hypofunction were present in 38 and 1% of participants, respectively, suggesting a likely vestibular cause of dizziness in these people. Of those with a likely vestibular cause, 63% had BPPV; a figure higher than previously reported in dizziness clinics of ~25%. Our results indicate that htDVA, sinusoidal (particularly 0.5-1 Hz), and transient VOR testing were the most effective at detecting people with BPPV or vestibular hypofunction, whereas DHI and OKN were effective at only detecting non-BPPV vestibular hypofunction. PMID- 26733941 TI - Prolactin Promotes Breast Cancer Cell Migration through Actin Cytoskeleton Remodeling. AB - The role of prolactin on breast cancer development and progression is debated. Breast cancer progression largely depends on cell movement and on the ability to remodel the actin cytoskeleton. In this process, actin-binding proteins are requested to achieve fibrillar actin de-polymerization and relocation at the cell membrane. Kinases such as focal adhesion kinase (FAK) are later required to form actin/vinculin-enriched structures called focal adhesion complexes, which mediate firm adhesion to the extracellular matrix. These controllers are regulated by c Src, which forms multiprotein signaling complexes with membrane receptors and is regulated by a number of hormones, including -prolactin. We here show that breast cancer cells exposed to prolactin display an elevated c-Src expression and phosphorylation. In parallel, increased moesin and FAK expression and phosphorylation are found. These molecular changes are associated to relocation to the plasma membrane of cytoskeletal actin fibers and to increased horizontal cell movement. In conclusion, prolactin regulates actin remodeling and enhances breast cancer cell movement. This finding broadens the understanding of prolactin actions on breast cancer cells, highlighting new pathways that may be relevant to on breast cancer progression. PMID- 26733943 TI - Border Disease Virus: An Exceptional Driver of Chamois Populations Among Other Threats. AB - Though it is accepted that emerging infectious diseases are a threat to planet biodiversity, little information exists about their role as drivers of species extinction. Populations are also affected by natural catastrophes and other pathogens, making it difficult to estimate the particular impact of emerging infectious diseases. Border disease virus genogroup 4 (BDV-4) caused a previously unreported decrease in populations of Pyrenean chamois (Rupicapra pyrenaica pyrenaica) in Spain. Using a population viability analysis, we compared probabilities of extinction of a virtual chamois population affected by winter conditions, density dependence, keratoconjunctivitis, sarcoptic mange, and BD outbreaks. BD-affected populations showed double risk of becoming extinct in 50 years, confirming the exceptional ability of this virus to drive chamois populations. PMID- 26733942 TI - Dopamine and Somatostatin Analogues Resistance of Pituitary Tumors: Focus on Cytoskeleton Involvement. AB - Pituitary tumors, that origin from excessive proliferation of a specific subtype of pituitary cell, are mostly benign tumors, but may cause significant morbidity in affected patients, including visual and neurologic manifestations from mass effect, or endocrine syndromes caused by hormone hypersecretion. Dopamine (DA) receptor DRD2 and somatostatin (SS) receptors (SSTRs) represent the main targets of pharmacological treatment of pituitary tumors since they mediate inhibitory effects on both hormone secretion and cell proliferation, and their expression is retained by most of these tumors. Although long-acting DA and SS analogs are currently used in the treatment of prolactin (PRL)- and growth hormone (GH) secreting pituitary tumors, respectively, clinical practice indicates a great variability in the frequency and entity of favorable responses. The molecular basis of the pharmacological resistance are still poorly understood, and several potential molecular mechanisms have been proposed, including defective expression or genetic alterations of DRD2 and SSTRs, or an impaired signal transduction. Recently, a role for cytoskeleton protein filamin A (FLNA) in DRD2 and SSTRs receptors expression and signaling in PRL- and GH-secreting tumors, respectively, has been demonstrated, first revealing a link between FLNA expression and responsiveness of pituitary tumors to pharmacological therapy. This review provides an overview of the known molecular events involved in SS and DA resistance, focusing on the role played by FLNA. PMID- 26733944 TI - Helicobacter pylori ATCC 43629/NCTC 11639 Outer Membrane Vesicles (OMVs) from Biofilm and Planktonic Phase Associated with Extracellular DNA (eDNA). AB - Helicobacter pylori persistence is associated with its capacity to develop biofilms as a response to changing environmental conditions and stress. Extracellular DNA (eDNA) is a component of H. pylori biofilm matrix but the lack of DNase I activity supports the hypothesis that eDNA might be protected by other extracellular polymeric substances (EPS) and/or Outer Membrane Vesicles (OMVs), which bleb from the bacteria surface during growth. The aim of the present study was to both identify the eDNA presence on OMVs segregated from H. pylori ATCC 43629/NCTC 11639 biofilm (bOMVs) and its planktonic phase (pOMVs) and to characterize the physical-chemical properties of the OMVs. The presence of eDNA in bOMVs and pOMVs was initially carried out using DNase I-gold complex labeling and Transmission Electron Microscope analysis (TEM). bOMVs and pOMVs were further isolated and physical-chemical characterization carried out using dynamic light scattering (DLS) analysis. eDNA associated with OMVs was detected and quantified using a PicoGreen spectrophotometer assay, while its extraction was performed with a DNA Kit. TEM images showed that eDNA was mainly associated with the OMV membrane surfaces; while PicoGreen staining showed a four-fold increase of dsDNA in bOMVs compared with pOMVs. The eDNA extracted from OMVs was visualized using gel electrophoresis. DLS analysis indicated that both planktonic and biofilm H. pylori phenotypes generated vesicles, with a broad distribution of sizes on the nanometer scale. The DLS aggregation assay suggested that eDNA may play a role in the aggregation of OMVs, in the biofilm phenotype. Moreover, the eDNA associated with vesicle membrane may impede DNase I activity on H. pylori biofilms. These results suggest that OMVs derived from the H. pylori biofilm phenotype may play a structural role by preventing eDNA degradation by nucleases, providing a bridging function between eDNA strands on OMV surfaces and promoting aggregation. PMID- 26733945 TI - A Zinc-Dependent Protease AMZ-tk from a Thermophilic Archaeon is a New Member of the Archaemetzincin Protein Family. AB - A putative zinc-dependent protease (TK0512) in Thermococcus kodakarensis KOD1 shares a conserved motif with archaemetzincins, which are metalloproteases found in archaea, bacteria, and eukarya. Phylogenetic and sequence analyses showed that TK0512 and its homologues in Thermococcaceae represent new members in the archaemetzincins family, which we named AMZ-tk. We further confirmed its proteolytic activity biochemically by overexpression of the recombinant AMZ-tk in Escherichia coli and characterization of the purified enzyme. In the presence of zinc, the purified enzyme degraded casein, while adding EDTA strongly inhibited the enzyme activity. AMZ-tk also exhibited self-cleavage activity that required Zn(2+). These results demonstrated that AMZ-tk is a zinc-dependent protease within the archaemetzincin family. The enzyme displayed activity at alkaline pHs ranging from 7.0 to 10.0, with the optimal pH being 8.0. The optimum temperature for the catalytic activity of AMZ-tk was 55 degrees C. Quantitative reverse transcription-PCR revealed that transcription of AMZ-tk was also up-regulated after exposing the cells to 55 and 65 degrees C. Mutant analysis suggested that Zn(2+) binding histidine and catalytic glutamate play key roles in proteolysis. AMZ-tk was thermostable on incubation for 4 h at 70 degrees C in the presence of EDTA. AMZ-tk also retained >50% of its original activity in the presence of both laboratory surfactants and commercial laundry detergents. AMZ-tk further showed antibacterial activity against several bacteria. Therefore, AMZ-tk is of considerable interest for many purposes in view of its activity at alkaline pH, detergents, and thermostability. PMID- 26733946 TI - The Mutualistic Side of Wolbachia-Isopod Interactions: Wolbachia Mediated Protection Against Pathogenic Intracellular Bacteria. AB - Wolbachia is a vertically transmitted endosymbiont whose radiative success is mainly related to various host reproductive manipulations that led to consider this symbiont as a conflictual reproductive parasite. However, lately, some Wolbachia have been shown to act as beneficial symbionts by protecting hosts against a broad range of parasites. Still, this protection has been mostly demonstrated in artificial Wolbachia-host associations between partners that did not co-evolved together. Here, we tested in two terrestrial isopod species Armadillidium vulgare and Porcellio dilatatus whether resident Wolbachia (native or non-native) could confer protection during infections with Listeria ivanovii and Salmonella typhimurium and also during a transinfection with a Wolbachia strain that kills the recipient host (i.e., wVulC in P. dilatatus). Survival analyses showed that (i) A. vulgare lines hosting their native Wolbachia (wVulC) always exhibited higher survival than asymbiotic ones when infected with pathogenic bacteria (ii) P. dilatatus lines hosting their native wDil Wolbachia strain survived the S. typhimurium infection better, while lines hosting non native wCon Wolbachia strain survived the L. ivanovii and also the transinfection with wVulC from A. vulgare better. By studying L. ivanovii and S. typhimurium loads in the hemolymph of the different host-Wolbachia systems, we showed that (i) the difference in survival between lines after L. ivanovii infections were not linked to the difference between their pathogenic bacterial loads, and (ii) the difference in survival after S. typhimurium infections corresponds to lower loads of pathogenic bacteria. Overall, our results demonstrate a beneficial effect of Wolbachia on survival of terrestrial isopods when infected with pathogenic intracellular bacteria. This protective effect may rely on different mechanisms depending on the resident symbiont and the invasive bacteria interacting together within the hosts. PMID- 26733947 TI - The Effect of Natural Organic Matter on Mercury Methylation by Desulfobulbus propionicus 1pr3. AB - Methylation of tracer and ambient mercury ((200)Hg and (202)Hg, respectively) equilibrated with four different natural organic matter (NOM) isolates was investigated in vivo using the Hg-methylating sulfate-reducing bacterium Desulfobulbus propionicus 1pr3. Desulfobulbus cultures grown fermentatively with environmentally representative concentrations of dissolved NOM isolates, Hg[II], and HS(-) were assayed for absolute methylmercury (MeHg) concentration and conversion of Hg(II) to MeHg relative to total unfiltered Hg(II). Results showed the (200)Hg tracer was methylated more efficiently in the presence of hydrophobic NOM isolates than in the presence of transphilic NOM, or in the absence of NOM. Different NOM isolates were associated with variable methylation efficiencies for either the (202)Hg tracer or ambient (200)Hg. One hydrophobic NOM, F1 HpoA derived from dissolved organic matter from the Florida Everglades, was equilibrated for different times with Hg tracer, which resulted in different methylation rates. A 5 day equilibration with F1 HpoA resulted in more MeHg production than either the 4 h or 30 day equilibration periods, suggesting a time dependence for NOM-enhanced Hg bioavailability for methylation. PMID- 26733948 TI - Clinical Appearance of Oral Candida Infection and Therapeutic Strategies. AB - Candida species present both as commensals and opportunistic pathogens of the oral cavity. For decades, it has enthralled the clinicians to investigate its pathogenicity and to improvise newer therapeutic regimens based on the updated molecular research. Candida is readily isolated from the oral cavity, but simple carriage does not predictably result in development of an infection. Whether it remains as a commensal, or transmutes into a pathogen, is usually determined by pre-existing or associated variations in the host immune system. The candida infections may range from non-life threatening superficial mucocutaneous disorders to invasive disseminated disease involving multiple organs. In fact, with the increase in number of AIDS cases, there is a resurgence of less common forms of oral candida infections. The treatment after confirmation of the diagnosis should include recognizing and eliminating the underlying causes such as ill-fitting oral appliances, history of medications (antibiotics, corticosteroids, etc.), immunological and endocrine disorders, nutritional deficiency states and prolonged hospitalization. Treatment with appropriate topical antifungal agents such as amphotericin, nystatin, or miconazole usually resolves the symptoms of superficial infection. Occasionally, administration of systemic antifungal agents may be necessary in immunocompromised patients, the selection of which should be based upon history of recent azole exposure, a history of intolerance to an antifungal agent, the dominant Candida species and current susceptibility data. PMID- 26733949 TI - Sulfur Isotope Effects of Dissimilatory Sulfite Reductase. AB - The precise interpretation of environmental sulfur isotope records requires a quantitative understanding of the biochemical controls on sulfur isotope fractionation by the principle isotope-fractionating process within the S cycle, microbial sulfate reduction (MSR). Here we provide the only direct observation of the major ((34)S/(32)S) and minor ((33)S/(32)S, (36)S/(32)S) sulfur isotope fractionations imparted by a central enzyme in the energy metabolism of sulfate reducers, dissimilatory sulfite reductase (DsrAB). Results from in vitro sulfite reduction experiments allow us to calculate the in vitro DsrAB isotope effect in (34)S/(32)S (hereafter, [Formula: see text]) to be 15.3 +/- 20/00, 2sigma. The accompanying minor isotope effect in (33)S, described as [Formula: see text], is calculated to be 0.5150 +/- 0.0012, 2sigma. These observations facilitate a rigorous evaluation of the isotopic fractionation associated with the dissimilatory MSR pathway, as well as of the environmental variables that govern the overall magnitude of fractionation by natural communities of sulfate reducers. The isotope effect induced by DsrAB upon sulfite reduction is a factor of 0.3-0.6 times prior indirect estimates, which have ranged from 25 to 530/00 in (34)epsilonDsrAB. The minor isotope fractionation observed from DsrAB is consistent with a kinetic or equilibrium effect. Our in vitro constraints on the magnitude of [Formula: see text] is similar to the median value of experimental observations compiled from all known published work, where (34)epsilon r-p = 16.10/00 (r-p indicates reactant vs. product, n = 648). This value closely matches those of MSR operating at high sulfate reduction rates in both laboratory chemostat experiments ([Formula: see text] 17.3 +/- 1.50/00, 2sigma) and in modern marine sediments ([Formula: see text] 17.3 +/- 3.80/00). Targeting the direct isotopic consequences of a specific enzymatic processes is a fundamental step toward a biochemical foundation for reinterpreting the biogeochemical and geobiological sulfur isotope records in modern and ancient environments. PMID- 26733950 TI - Abundant Intergenic TAACTGA Direct Repeats and Putative Alternate RNA Polymerase beta' Subunits in Marine Beggiatoaceae Genomes: Possible Regulatory Roles and Origins. AB - The genome sequences of several giant marine sulfur-oxidizing bacteria present evidence of a possible post-transcriptional regulatory network that may have been transmitted to or from two distantly related bacteria lineages. The draft genome of a Cand. "Maribeggiatoa" filament from the Guaymas Basin (Gulf of California, Mexico) seafloor contains 169 sets of TAACTGA direct repeats and one indirect repeat, with two to six copies per set. Related heptamers are rarely or never found as direct repeats. TAACTGA direct repeats are also found in some other Beggiatoaceae, Thiocystis violascens, a range of Cyanobacteria, and five Bacteroidetes. This phylogenetic distribution suggests they may have been transmitted horizontally, but no mechanism is evident. There is no correlation between total TAACTGA occurrences and repeats per genome. In most species the repeat units are relatively short, but longer arrays of up to 43 copies are found in several Bacteroidetes and Cyanobacteria. The majority of TAACTGA repeats in the Cand. "Maribeggiatoa" Orange Guaymas (BOGUAY) genome are within several nucleotides upstream of a putative start codon, suggesting they may be binding sites for a post-transcriptional regulator. Candidates include members of the ribosomal protein S1, Csp (cold shock protein), and Csr (carbon storage regulator) families. No pattern was evident in the predicted functions of the open reading frames (ORFs) downstream of repeats, but some encode presumably essential products such as ribosomal proteins. Among these is an ORF encoding a possible alternate or modified RNA polymerase beta prime subunit, predicted to have the expected subunit interaction domains but lacking most catalytic residues. A similar ORF was found in the Thioploca ingrica draft genome, but in no others. In both species they are immediately upstream of putative sensor kinase genes with nearly identical domain structures. In the marine Beggiatoaceae, a role for the TAACTGA repeats in translational regulation is suggested. More speculatively, the putative alternate RNA polymerase subunit could be a negative transcriptional regulator. PMID- 26733951 TI - Evaluation of Antioxidative and Cytotoxic Activities of Streptomyces pluripotens MUSC 137 Isolated from Mangrove Soil in Malaysia. AB - Streptomyces pluripotens MUSC 137 was isolated from mangrove soil obtained from Tanjung Lumpur, Pahang, Malaysia. We investigated the phylogenetic, genomic, biochemical, and phenotypic characteristics of this strain. Uniquely adapted microorganisms from mangrove habitats have previously yielded compounds of biopharmaceutical interest. In order to examine the bioactivities possessed by the strain, fermentation extract was prepared through solvent extraction method prior to bioactivities screenings. Antioxidant activity was examined via DPPH assay while the cytotoxic effect was assessed by means of examining the activity of the extract against selected human cancer cell lines, namely colon cancer cells (HCT-116, Caco-2, SW480, and HT-29), breast cancer cell (MCF-7), lung cancer cell (A549), prostate cancer cell (DU145), and cervical cancer cell (Ca Ski). The results revealed MUSC 137 possesses significant antioxidant activity and demonstrates cytotoxic effect against several cancer cell lines tested. The results indicated MCF-7 cells were most susceptible to the extract with the lowest IC50 (61.33 +/- 17.10 MUg/mL), followed by HCT-116 and A549. Additionally, selective index (SI) showed that MUSC 137 extract was less toxic against normal cell lines when compared to MCF-7 and HCT-116 cells. The extract was further subjected to chemical analysis using GC-MS and revealed the presence of deferoxamine and pyrrolizidines related compounds which may account for the antioxidant and cytotoxic properties observed. PMID- 26733952 TI - Klebsiella pneumoniae: Development of Carbapenem Resistance due to Acquisition of bla NDM-1 During Antimicrobial Therapy in Twin Infants with Pneumonia. AB - OBJECTIVES: To identify the mechanism of in vivo development of carbapenem resistance in Klebsiella pneumoniae. METHODS: Seven sequential isolates of K. pneumoniae were obtained from twin infants with pneumonia. Antimicrobial susceptibility testing was performed by agar dilution method. Carbapenemases including KPC and MbetaL were initially screened using phenotypic methods, and carbapenemase-encoding genes were identified by polymerase chain reaction and amplicon sequencing. Plasmids of all clinical isolates and the conjugants of resistant isolates were estimated by S1 pulsed-field gel electrophoresis (PFGE). Molecular typing were conducted by PFGE of XbaI-digested genomic DNA and multilocus sequence typing. RESULTS: For old brother, the first and third isolates were susceptible to meropenem, whereas the second and fourth isolates were resistant (MICs 16 mg/L). The first and second isolates from the young brother were susceptible to meropenem whereas the third isolate was resistant. All the resistant isolates produced NDM-1 metallo-beta-lactamase. PFGE of XbaI digested DNA revealed almost identical patterns with similarity indices of above 92% for all the seven isolates. All the isolates had the same sequence type named sequence type 37 (ST37). CONCLUSION: To our knowledge, this is the first documented case of development of carbapenem resistance in vivo mediated by NDM-1 metallo-beta-lactamase in K. pneumoniae during treatment of pneumonia with meropenem. PMID- 26733953 TI - Differential Assimilation of Inorganic Carbon and Leucine by Prochlorococcus in the Oligotrophic North Pacific Subtropical Gyre. AB - The light effect on photoheterotrophic processes in Prochlorococcus, and primary and bacterial productivity in the oligotrophic North Pacific Subtropical Gyre was investigated using (14)C-bicarbonate and (3)H-leucine. Light and dark incubation experiments were conducted in situ throughout the euphotic zone (0-175 m) on nine expeditions to Station ALOHA over a 3-year period. Photosynthetrons were also used to elucidate rate responses in leucine and inorganic carbon assimilation as a function of light intensity. Taxonomic group and cell-specific rates were assessed using flow cytometric sorting. The light:dark assimilation rate ratios of leucine in the top 150 m were ~7:1 for Prochlorococcus, whereas the light:dark ratios for the non-pigmented bacteria (NPB) were not significant different from 1:1. Prochlorococcus assimilated leucine in the dark at per cell rates similar to the NPB, with a contribution to the total community bacterial production, integrated over the euphotic zone, of approximately 20% in the dark and 60% in the light. Depth-resolved primary productivity and leucine incorporation showed that the ratio of Prochlorococcus leucine:primary production peaked at 100 m then declined steeply below the deep chlorophyll maximum (DCM). The photosynthetron experiments revealed that, for Prochlorococcus at the DCM, the saturating irradiance (E k) for leucine incorporation was reached at approximately half the light intensity required for light saturation of (14)C-bicarbonate assimilation. Additionally, high and low red fluorescing Prochlorococcus populations (HRF and LRF), co-occurring at the DCM, had similar E k values for their respective substrates, however, maximum assimilation rates, for both leucine and inorganic carbon, were two times greater for HRF cells. Our results show that Prochlorococcus contributes significantly to bacterial production estimates using (3)H-leucine, whether or not the incubations are conducted in the dark or light, and this should be considered when making assessments of bacterial production in marine environments where Prochlorococcus is present. Furthermore, Prochlorococcus primary productivity showed rate to light-flux patterns that were different from its light enhanced leucine incorporation. This decoupling from autotrophic growth may indicate a separate light stimulated mechanism for leucine acquisition. PMID- 26733954 TI - Comparative Gut Microbiota of 59 Neotropical Bird Species. AB - The gut microbiota of vertebrates are essential to host health. Most non-model vertebrates, however, lack even a basic description of natural gut microbiota biodiversity. Here, we sampled 116 intestines from 59 Neotropical bird species and used the V6 region of the 16S rRNA molecule as a microbial fingerprint (average coverage per bird ~80,000 reads). A core microbiota of Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria was identified, as well as several gut-associated genera. We tested 18 categorical variables associated with each bird for significant correlation to the gut microbiota; host taxonomic categories were most frequently significant and explained the most variation. Ecological variables (e.g., diet, foraging stratum) were also frequently significant but explained less variation. Little evidence was found for a significant influence of geographic space. Finally, we suggest that microbial sampling during field collection of organisms would propel biological understanding of evolutionary history and ecological significance of host-associated microbiota. PMID- 26733955 TI - Year-Long Metagenomic Study of River Microbiomes Across Land Use and Water Quality. AB - Select bacteria, such as Escherichia coli or coliforms, have been widely used as sentinels of low water quality; however, there are concerns regarding their predictive accuracy for the protection of human and environmental health. To develop improved monitoring systems, a greater understanding of bacterial community structure, function, and variability across time is required in the context of different pollution types, such as agricultural and urban contamination. Here, we present a year-long survey of free-living bacterial DNA collected from seven sites along rivers in three watersheds with varying land use in Southwestern Canada. This is the first study to examine the bacterial metagenome in flowing freshwater (lotic) environments over such a time span, providing an opportunity to describe bacterial community variability as a function of land use and environmental conditions. Characteristics of the metagenomic data, such as sequence composition and average genome size (AGS), vary with sampling site, environmental conditions, and water chemistry. For example, AGS was correlated with hours of daylight in the agricultural watershed and, across the agriculturally and urban-affected sites, k-mer composition clustering corresponded to nutrient concentrations. In addition to indicating a community shift, this change in AGS has implications in terms of the normalization strategies required, and considerations surrounding such strategies in general are discussed. When comparing abundances of gene functional groups between high- and low-quality water samples collected from an agricultural area, the latter had a higher abundance of nutrient metabolism and bacteriophage groups, possibly reflecting an increase in agricultural runoff. This work presents a valuable dataset representing a year of monthly sampling across watersheds and an analysis targeted at establishing a foundational understanding of how bacterial lotic communities vary across time and land use. The results provide important context for future studies, including further analyses of watershed ecosystem health, and the identification and development of biomarkers for improved water quality monitoring systems. PMID- 26733956 TI - Recombinant Bivalent Fusion Protein rVE Induces CD4+ and CD8+ T-Cell Mediated Memory Immune Response for Protection Against Yersinia enterocolitica Infection. AB - Studies investigating the correlates of immune protection against Yersinia infection have established that both humoral and cell mediated immune responses are required for the comprehensive protection. In our previous study, we established that the bivalent fusion protein (rVE) comprising immunologically active regions of Y. pestis LcrV (100-270 aa) and YopE (50-213 aa) proteins conferred complete passive and active protection against lethal Y. enterocolitica 8081 challenge. In the present study, cohort of BALB/c mice immunized with rVE or its component proteins rV, rE were assessed for cell mediated immune responses and memory immune protection against Y. enterocolitica 8081. rVE immunization resulted in extensive proliferation of both CD4 and CD8 T cell subsets; significantly high antibody titer with balanced IgG1: IgG2a/IgG2b isotypes (1:1 ratio) and up-regulation of both Th1 (TNF-alpha, IFN-gamma, IL-2, and IL-12) and Th2 (IL-4) cytokines. On the other hand, rV immunization resulted in Th2 biased IgG response (11:1 ratio) and proliferation of CD4+ T-cell; rE group of mice exhibited considerably lower serum antibody titer with predominant Th1 response (1:3 ratio) and CD8+ T-cell proliferation. Comprehensive protection with superior survival (100%) was observed among rVE immunized mice when compared to the significantly lower survival rates among rE (37.5%) and rV (25%) groups when IP challenged with Y. enterocolitica 8081 after 120 days of immunization. Findings in this and our earlier studies define the bivalent fusion protein rVE as a potent candidate vaccine molecule with the capability to concurrently stimulate humoral and cell mediated immune responses and a proof of concept for developing efficient subunit vaccines against Gram negative facultative intracellular bacterial pathogens. PMID- 26733957 TI - Similar Microbial Communities Found on Two Distant Seafloor Basalts. AB - The oceanic crust forms two thirds of the Earth's surface and hosts a large phylogenetic and functional diversity of microorganisms. While advances have been made in the sedimentary realm, our understanding of the igneous rock portion as a microbial habitat has remained limited. We present the first comparative metagenomic microbial community analysis from ocean floor basalt environments at the Lo'ihi Seamount, Hawai'i, and the East Pacific Rise (EPR; 9 degrees N). Phylogenetic analysis indicates the presence of a total of 43 bacterial and archaeal mono-phyletic groups, dominated by Alpha- and Gammaproteobacteria, as well as Thaumarchaeota. Functional gene analysis suggests that these Thaumarchaeota play an important role in ammonium oxidation on seafloor basalts. In addition to ammonium oxidation, the seafloor basalt habitat reveals a wide spectrum of other metabolic potentials, including CO2 fixation, denitrification, dissimilatory sulfate reduction, and sulfur oxidation. Basalt communities from Lo'ihi and the EPR show considerable metabolic and phylogenetic overlap down to the genus level despite geographic distance and slightly different seafloor basalt mineralogy. PMID- 26733958 TI - Pyrosequencing Reveals a Core Community of Anodic Bacterial Biofilms in Bioelectrochemical Systems from China. AB - Bioelectrochemical systems (BESs) are promising technologies for energy and product recovery coupled with wastewater treatment, and the core microbial community in electrochemically active biofilm in BESs remains controversy. In the present study, 7 anodic communities from 6 bioelectrochemical systems in 4 labs in southeast, north and south-central of China are explored by 454 pyrosequencing. A total of 251,225 effective sequences are obtained for 7 electrochemically active biofilm samples at 3% cutoff level. While Alpha-, Beta-, and Gamma-proteobacteria are the most abundant classes (averaging 16.0-17.7%), Bacteroidia and Clostridia are the two sub-dominant and commonly shared classes. Six commonly shared genera i.e., Azospira, Azospirillum, Acinetobacter, Bacteroides, Geobacter, Pseudomonas, and Rhodopseudomonas dominate the electrochemically active communities and are defined as core genera. A total of 25 OTUs with average relative abundance >0.5% were selected and designated as core OTUs, and some species relating to these OTUs have been reported electrochemically active. Furthermore, cyclic voltammetry and chronoamperometry tests show that two strains from Acinetobacter guillouiae and Stappia indica, bacteria relate to two core OTUs, are electrochemically active. Using randomly selected bioelectrochemical systems, the study has presented extremely diverse bacterial communities in anodic biofilms, though, we still can suggest some potentially microbes for investigating the electrochemical mechanisms in bioelectrochemical systems. PMID- 26733959 TI - Volatiles in Inter-Specific Bacterial Interactions. AB - The importance of volatile organic compounds for functioning of microbes is receiving increased research attention. However, to date very little is known on how inter-specific bacterial interactions effect volatiles production as most studies have been focused on volatiles produced by monocultures of well-described bacterial genera. In this study we aimed to understand how inter-specific bacterial interactions affect the composition, production and activity of volatiles. Four phylogenetically different bacterial species namely: Chryseobacterium, Dyella, Janthinobacterium, and Tsukamurella were selected. Earlier results had shown that pairwise combinations of these bacteria induced antimicrobial activity in agar media whereas this was not the case for monocultures. In the current study, we examined if these observations were also reflected by the production of antimicrobial volatiles. Thus, the identity and antimicrobial activity of volatiles produced by the bacteria were determined in monoculture as well in pairwise combinations. Antimicrobial activity of the volatiles was assessed against fungal, oomycetal, and bacterial model organisms. Our results revealed that inter-specific bacterial interactions affected volatiles blend composition. Fungi and oomycetes showed high sensitivity to bacterial volatiles whereas the effect of volatiles on bacteria varied between no effects, growth inhibition to growth promotion depending on the volatile blend composition. In total 35 volatile compounds were detected most of which were sulfur-containing compounds. Two commonly produced sulfur-containing volatile compounds (dimethyl disulfide and dimethyl trisulfide) were tested for their effect on three target bacteria. Here, we display the importance of inter specific interactions on bacterial volatiles production and their antimicrobial activities. PMID- 26733960 TI - Modeling of the ComRS Signaling Pathway Reveals the Limiting Factors Controlling Competence in Streptococcus thermophilus. AB - In streptococci, entry in competence is dictated by ComX abundance. In Streptococcus thermophilus, production of ComX is transient and tightly regulated during growth: it is positively regulated by the cell-cell communication system ComRS during the activation phase and negatively regulated during the shut-off phase by unidentified late competence gene(s). Interestingly, most S. thermophilus strains are not or weakly transformable in permissive growth conditions (i.e., chemically defined medium, CDM), suggesting that some players of the ComRS regulatory pathway are limiting. Here, we combined mathematical modeling and experimental approaches to identify the components of the ComRS system which are critical for both dynamics and amplitude of ComX production in S. thermophilus. We built a deterministic, population-scaled model of the time course regulation of specific ComX production in CDM growth conditions. Strains LMD-9 and LMG18311 were respectively selected as representative of highly and weakly transformable strains. Results from in silico simulations and in vivo luciferase activities show that ComR concentration is the main limiting factor for the level of comX expression and controls the kinetics of spontaneous competence induction in strain LMD-9. In addition, the model predicts that the poor transformability of strain LMG18311 results from a 10-fold lower comR expression level compared to strain LMD-9. In agreement, comR overexpression in both strains was shown to induce higher competence levels with deregulated kinetics patterns during growth. In conclusion, we propose that the level of ComR production is one important factor that could explain competence heterogeneity among S. thermophilus strains. PMID- 26733961 TI - Ubiquitous Presence and Novel Diversity of Anaerobic Alkane Degraders in Cold Marine Sediments. AB - Alkanes are major constituents of crude oil and are released to the marine environment by natural seepage and from anthropogenic sources. Due to their chemical inertness, their removal from anoxic marine sediments is primarily controlled by the activity of anaerobic alkane-degrading microorganisms. To facilitate comprehensive cultivation-independent surveys of the diversity and distribution of anaerobic alkane degraders, we designed novel PCR primers that cover all known diversity of the 1-methylalkyl succinate synthase gene (masD/assA), which catalyzes the initial activation of alkanes. We studied masD/assA gene diversity in pristine and seepage-impacted Danish coastal sediments, as well as in sediments and alkane-degrading enrichment cultures from the Middle Valley (MV) hydrothermal vent system in the Pacific Northwest. MasD/assA genes were ubiquitously present, and the primers captured the diversity of both known and previously undiscovered masD/assA gene diversity. Seepage sediments were dominated by a single masD/assA gene cluster, which is presumably indicative of a substrate-adapted community, while pristine sediments harbored a diverse range of masD/assA phylotypes including those present in seepage sediments. This rare biosphere of anaerobic alkane degraders will likely increase in abundance in the event of seepage or accidental oil spillage. Nanomolar concentrations of short-chain alkanes (SCA) were detected in pristine and seepage sediments. Interestingly, anaerobic alkane degraders closely related to strain BuS5, the only SCA degrader in pure culture, were found in mesophilic MV enrichments, but not in cold sediments from Danish waters. We propose that the new masD/assA gene lineages in these sediments represent novel phylotypes that are either fueled by naturally occurring low levels of SCA or that metabolize medium- to long-chain alkanes. Our study highlights that masD/assA genes are a relevant diagnostic marker to identify seepage and microseepage, e.g., during prospecting for oil and gas, and may act as an indicator of anthropogenic oil spills in marine sediments. PMID- 26733962 TI - Methods for Baiting and Enriching Fungus-Feeding (Mycophagous) Rhizosphere Bacteria. AB - Mycophagous soil bacteria are able to obtain nutrients from living fungal hyphae. However, with exception of the soil bacterial genus Collimonas, occurrence of this feeding strategy has not been well examined. Evaluation of the importance of mycophagy in soil bacterial communities requires targeted isolation methods. In this study, we compared two different approaches to obtain mycophagous bacteria from rhizospheric soil. A short-term method based on baiting for bacteria that can rapidly adhere to fungal hyphae and a long-term method based on the enrichment of bacteria on fungal hyphae via repeated transfer. Hyphae-adhering bacteria were isolated, identified by 16S rDNA sequencing and tested for antifungal activity and the ability to feed on fungi as the sole source of carbon. Both methods yielded a range of potentially mycophagous bacterial isolates with little phylogenetic overlap. We also found indications for feeding preferences among the potentially mycophagous bacteria. Our results indicate that mycophagy could be an important growth strategy for rhizosphere bacteria. To our surprise, we found several potential plant pathogenic bacteria among the mycophagous isolates. We discuss the possible benefits that these bacteria might gain from colonizing fungal hyphae. PMID- 26733964 TI - Gene Expression Profiling in Viable but Nonculturable (VBNC) Cells of Pseudomonas syringae pv. syringae. AB - Pseudomonas syringae infects diverse crop plants and comprises at least 50 different pathovar strains with different host ranges. More information on the physiological and molecular effects of the host inhibitory environment on the pathogen is needed to develop resistant cultivars. Recently, we reported an in vitro model system that mimics the redox pulse associated with the oxidative burst in plant cells inoculated with Pseudomonas syringae pv. syringae. Using this system, we demonstrated that oxidation of acetosyringone, a major extracellular phenolic compound induced in some plants in response to bacteria, rendered Pseudomonas syringae pv. syringae to a "viable but nonculturable" (VBNC) state. Here we performed a large scale transcriptome profiling of P. s. pv. syringae in the VBNC state induced by acetosyringone treatment and identified bacterial genes and pathways presumably associated with this condition. The findings offer insight into what events occur when bacterial pathogens are first encountered and host defense responses are triggered. The acquired knowledge will improve our understanding of the molecular mechanisms of stress tolerance. We believe that this is the first work on global gene expression profiling of VBNC cells in plant pathogenic bacteria. PMID- 26733966 TI - Phosphorus Recycling from an Unexplored Source by Polyphosphate Accumulating Microalgae and Cyanobacteria-A Step to Phosphorus Security in Agriculture. AB - Phosphorus (P), an essential element required for crop growth has no substitute. The global food security depends on phosphorus availability in soil for crop production. World phosphorus reserves are fast depleting and with an annual increase of 2.3% in phosphorus demand, the current reserves will be exhausted in coming 50-100 years. India and other Western countries are forced to import phosphorus fertilizers at high costs to meet their agricultural demands due to uneven distribution of phosphate rocks on earth. The present study from India, aims to draw attention to an unnoticed source of phosphorus being wasted as parboiled rice mill effluent and subsequent bio-recovery of the valuable element from this unconventional source. The research was conducted in West Bengal, India, a state with the highest number of parboiled rice mills where its effluent carries on an average ~40 mg/L of soluble phosphorus. Technology to recover and recycle this wastewater P in India in a simple, inexpensive mode is yet to be optimized. Our strategy to use microalgae, Chlorella sp. and cyanobacteria, Cyanobacterium sp., Lyngbya sp., and Anabaena sp. to sequester the excess phosphorus from the effluent as polyphosphate inclusions and its subsequent recycling as slow and moderate release phosphorus biofertilizers to aid plant growth, preventing phosphorus loss and pollution, is a contemporary venture to meet the need of the hour. These polyphosphate accumulating microorganisms play a dual role of remediation and recovery of phosphorus, preliminarily validated in laboratory scale. PMID- 26733963 TI - The Prevalence and Control of Bacillus and Related Spore-Forming Bacteria in the Dairy Industry. AB - Milk produced in udder cells is sterile but due to its high nutrient content, it can be a good growth substrate for contaminating bacteria. The quality of milk is monitored via somatic cell counts and total bacterial counts, with prescribed regulatory limits to ensure quality and safety. Bacterial contaminants can cause disease, or spoilage of milk and its secondary products. Aerobic spore-forming bacteria, such as those from the genera Sporosarcina, Paenisporosarcina, Brevibacillus, Paenibacillus, Geobacillus and Bacillus, are a particular concern in this regard as they are able to survive industrial pasteurization and form biofilms within pipes and stainless steel equipment. These single or multiple species biofilms become a reservoir of spoilage microorganisms and a cycle of contamination can be initiated. Indeed, previous studies have highlighted that these microorganisms are highly prevalent in dead ends, corners, cracks, crevices, gaskets, valves and the joints of stainless steel equipment used in the dairy manufacturing plants. Hence, adequate monitoring and control measures are essential to prevent spoilage and ensure consumer safety. Common controlling approaches include specific cleaning-in-place processes, chemical and biological biocides and other novel methods. In this review, we highlight the problems caused by these microorganisms, and discuss issues relating to their prevalence, monitoring thereof and control with respect to the dairy industry. PMID- 26733965 TI - Potential Use of Phenolic Acids as Anti-Candida Agents: A Review. AB - There has been a sharp rise in the occurrence of Candida infections and associated mortality over the last few years, due to the growing body of immunocompromised population. Limited number of currently available antifungal agents, undesirable side effects and toxicity, as well as emergence of resistant strains pose a considerable clinical challenge for the treatment of candidiasis. Therefore, molecules that derived from natural sources exhibiting considerable antifungal properties are a promising source for the development of novel anti candidal therapy. Phenolic compounds isolated from natural sources possess antifungal properties of interest. Particularly, phenolic acids have shown promising in vitro and in vivo activity against Candida species. However, studies on their mechanism of action alone or in synergism with known antifungals are still scarce. This review attempts to discuss the potential use, proposed mechanisms of action and limitations of the phenolic acids in anti-candidal therapy. PMID- 26733967 TI - Role of Penicillium chrysogenum XJ-1 in the Detoxification and Bioremediation of Cadmium. AB - Microbial bioremediation is a promising technology to treat heavy metal contaminated soils. However, the efficiency of filamentous fungi as bioremediation agents remains unknown, and the detoxification mechanism of heavy metals by filamentous fungi remains unclear. Therefore, in this study, we investigated the cell morphology and antioxidant systems of Penicillium chrysogenum XJ-1 in response to different cadmium (Cd) concentrations (0-10 mM) by using physico-chemical and biochemical methods. Cd in XJ-1 was mainly bound to the cell wall. The malondialdehyde level in XJ-1 cells was increased by 14.82 94.67 times with the increase in Cd concentration. The activities of superoxide dismutase, glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G6PDH) peaked at 1 mM Cd, whereas that of catalase peaked at 5 mM Cd. Cd exposure increased the glutathione/oxidized glutathione ratio and the activities of GR and G6PDH in XJ-1. These results suggested that the Cd detoxification mechanism of XJ-1 included biosorption, cellular sequestration, and antioxidant defense. The application of XJ-1 in Cd-polluted soils (5-50 mg kg(-1)) successfully reduced bioavailable Cd and increased the plant yield, indicating that this fungus was a promising candidate for in situ bioremediation of Cd polluted soil. PMID- 26733968 TI - A Metagenomics-Based Metabolic Model of Nitrate-Dependent Anaerobic Oxidation of Methane by Methanoperedens-Like Archaea. AB - Methane oxidation is an important process to mitigate the emission of the greenhouse gas methane and further exacerbating of climate forcing. Both aerobic and anaerobic microorganisms have been reported to catalyze methane oxidation with only a few possible electron acceptors. Recently, new microorganisms were identified that could couple the oxidation of methane to nitrate or nitrite reduction. Here we investigated such an enrichment culture at the (meta) genomic level to establish a metabolic model of nitrate-driven anaerobic oxidation of methane (nitrate-AOM). Nitrate-AOM is catalyzed by an archaeon closely related to (reverse) methanogens that belongs to the ANME-2d clade, tentatively named Methanoperedens nitroreducens. Methane may be activated by methyl-CoM reductase and subsequently undergo full oxidation to carbon dioxide via reverse methanogenesis. All enzymes of this pathway were present and expressed in the investigated culture. The genome of the archaeal enrichment culture encoded a variety of enzymes involved in an electron transport chain similar to those found in Methanosarcina species with additional features not previously found in methane-converting archaea. Nitrate reduction to nitrite seems to be located in the pseudoperiplasm and may be catalyzed by an unusual Nar-like protein complex. A small part of the resulting nitrite is reduced to ammonium which may be catalyzed by a Nrf-type nitrite reductase. One of the key questions is how electrons from cytoplasmically located reverse methanogenesis reach the nitrate reductase in the pseudoperiplasm. Electron transport in M. nitroreducens probably involves cofactor F420 in the cytoplasm, quinones in the cytoplasmic membrane and cytochrome c in the pseudoperiplasm. The membrane-bound electron transport chain includes F420H2 dehydrogenase and an unusual Rieske/cytochrome b complex. Based on genome and transcriptome studies a tentative model of how central energy metabolism of nitrate-AOM could work is presented and discussed. PMID- 26733969 TI - The Hematopoietic Organ: A Cornerstone for Wolbachia Propagation Between and Within Hosts. AB - Wolbachia is an intracellular alpha-proteobacterium which is transmitted vertically from mother to offspring but also frequently switches horizontally from one host to another. Our hypothesis is based on the role of immune cells and the organs that produce them, the hematopoietic organs (HOs), as primordial niches for the propagation of Wolbachia via hemocytes both (i) within hosts: to initiate and maintain the systemic infection and (ii) between hosts: to promote both vertical and horizontal transmission of Wolbachia. Therefore, we review some fundamental ideas underlying this hypothesis and go further with new empirical data that lead to a first close-up analysis of the potential role of HOs in Wolbachia propagation. The monitoring of the first steps of Wolbachia infection in horizontally infected host organs by transmission electron microscopy and qPCR suggests that (i) HOs are colonized early and extensively as soon as they are in contact with Wolbachia which find in these cells a favorable niche to multiply and (ii) infected HOs which expel hemocytes all lifelong can generate and maintain a systemic infection that could contribute to increase both vertical and horizontal propagation of these symbionts. PMID- 26733970 TI - Type III Methyltransferase M.NgoAX from Neisseria gonorrhoeae FA1090 Regulates Biofilm Formation and Interactions with Human Cells. AB - Neisseria gonorrhoeae is the etiological factor of the sexually transmitted gonorrhea disease that may lead, under specific conditions, to systemic infections. The gonococcal genome encodes many restriction modification (RM) systems, which main biological role is to defend the pathogen from potentially harmful foreign DNA. However, RM systems seem also to be involved in several other functions. In this study, we examined the effect of inactivation the N. gonorrhoeae FA1090 ngoAXmod gene encoding M.NgoAX methyltransferase on the global gene expression, biofilm formation, interactions with human epithelial host cells and overall bacterial growth. Expression microarrays showed at least a twofold deregulation of a total of 121 genes in the NgoAX knock-out mutant compared to the wild-type (wt) strain under standard grow conditions. Genes with changed expression levels encoded mostly proteins involved in cell metabolism, DNA replication and repair or regulating cellular processes and signaling (such as cell wall/envelop biogenesis). As determined by the assay with crystal violet, the NgoAX knock-out strain formed a slightly larger biofilm biomass per cell than the wt strain. Live biofilm observations showed that the biofilm formed by the gonococcal ngoAXmod gene mutant is more relaxed, dispersed and thicker than the one formed by the wt strain. This more relaxed feature of the biofilm, in respect to adhesion and bacterial interactions, can be involved in pathogenesis. Moreover, the overall adhesion of mutant bacterial cells to human cells was lower than adhesion of the wt gonococci [adhesion index = 0.672 (+/-0.2) and 2.15 (+/ 1.53), respectively]; yet, a higher number of mutant than wt bacteria were found inside the Hec-1-B epithelial cells [invasion index = 3.38 (+/-0.93) * 10(5) for mutant and 4.67 (+/-3.09) * 10(4) for the wt strain]. These results indicate that NgoAX knock-out cells have lower ability to attach to human cells, but more easily penetrate inside the host cells. All these data suggest that the NgoAX methyltransferase, may be implicated in N. gonorrhoeae pathogenicity, involving regulation of biofilm formation, adhesion to host cells and epithelial cell invasion. PMID- 26733971 TI - Discovery, Prevalence, and Persistence of Novel Circular Single-Stranded DNA Viruses in the Ctenophores Mnemiopsis leidyi and Beroe ovata. AB - Gelatinous zooplankton, such as ctenophores and jellyfish, are important components of marine and brackish ecosystems and play critical roles in aquatic biogeochemistry. As voracious predators of plankton, ctenophores have key positions in aquatic food webs and are often successful invaders when introduced to new areas. Gelatinous zooplankton have strong impacts on ecosystem services, particularly in coastal environments. However, little is known about the factors responsible for regulating population dynamics of gelatinous organisms, including biological interactions that may contribute to bloom demise. Ctenophores are known to contain specific bacterial communities and a variety of invertebrate parasites and symbionts; however, no previous studies have examined the presence of viruses in these organisms. Building upon recent studies demonstrating a diversity of single-stranded DNA viruses that encode a replication initiator protein (Rep) in aquatic invertebrates, this study explored the presence of circular, Rep-encoding single-stranded DNA (CRESS-DNA) viruses in the ctenophores Mnemiopsis leidyi and Beroe ovata collected from the Skidaway River Estuary and Savannah River in Georgia, USA. Using rolling circle amplification followed by restriction enzyme digestion, this study provides the first evidence of viruses in ctenophores. Investigation of four CRESS-DNA viruses over an 8-month period using PCR demonstrated temporal trends in viral prevalence and indicated that some of the viruses may persist in ctenophore populations throughout the year. Although future work needs to examine the ecological roles of these ctenophore associated viruses, this study indicates that viral infection may play a role in population dynamics of gelatinous zooplankton. PMID- 26733972 TI - DNase-Sensitive and -Resistant Modes of Biofilm Formation by Listeria monocytogenes. AB - Listeria monocytogenes is able to form biofilms on various surfaces and this ability is thought to contribute to persistence in the environment and on contact surfaces in the food industry. Extracellular DNA (eDNA) is a component of the biofilm matrix of many bacterial species and was shown to play a role in biofilm establishment of L. monocytogenes. In the present study, the effect of DNaseI treatment on biofilm formation of L. monocytogenes EGD-e was investigated under static and dynamic conditions in normal or diluted complex medium at different temperatures. Biofilm formation was quantified by crystal violet staining or visualized by confocal laser scanning microscopy. Biomass of surface-attached L. monocytogenes varies depending on temperature and dilution of media. Interestingly, L. monocytogenes EGD-e forms DNase-sensitive biofilms in diluted medium whereas in full strength medium DNaseI treatment had no effect. In line with these observations, eDNA is present in the matrix of biofilms grown in diluted but not full strength medium and supernatants of biofilms grown in diluted medium contain chromosomal DNA. The DNase-sensitive phenotype could be clearly linked to reduced ionic strength in the environment since dilution of medium in PBS or saline abolished DNase sensitivity. Several other but not all species of the genus Listeria display DNase-sensitive and -resistant modes of biofilm formation. These results indicate that L. monocytogenes biofilms are DNase-sensitive especially at low ionic strength, which might favor bacterial lysis and release of chromosomal DNA. Since low nutrient concentrations with increased osmotic pressure are conditions frequently found in food processing environments, DNaseI treatment represents an option to prevent or remove Listeria biofilms in industrial settings. PMID- 26733973 TI - Modulation of Biofilm Exopolysaccharides by the Streptococcus mutans vicX Gene. AB - The cariogenic pathogen Streptococcus mutans effectively utilizes dietary sucrose for the synthesis of exopolysaccharide, which act as a scaffold for its biofilm, thus contributing to its pathogenicity, environmental stress tolerance, and antimicrobial resistance. The two-component system VicRK of S. mutans regulates a group of virulence genes that are associated with biofilm matrix synthesis. Knockout of vicX affects biofilm formation, oxidative stress tolerance, and transformation of S. mutans. However, little is known regarding the vicX modulated structural characteristics of the exopolysaccharides underlying the biofilm formation and the phenotypes of the vicX mutants. Here, we identified the role of vicX in the structural characteristics of the exopolysaccharide matrix and biofilm physiology. The vicX mutant (SmuvicX) biofilms seemingly exhibited "desertification" with architecturally impaired exopolysaccharide-enmeshed cell clusters, compared with the UA159 strain (S. mutans wild type strain). Concomitantly, SmuvicX showed a decrease in water-insoluble glucan (WIG) synthesis and in WIG/water-soluble glucan (WSG) ratio. Gel permeation chromatography (GPC) showed that the WIG isolated from the SmuvicX biofilms had a much lower molecular weight compared with the UA159 strain indicating differences in polysaccharide chain lengths. A monosaccharide composition analysis demonstrated the importance of the vicX gene in the glucose metabolism. We performed metabolite profiling via (1)H nuclear magnetic resonance spectroscopy, which showed that several chemical shifts were absent in both WSG and WIG of SmuvicX biofilms compared with the UA159 strain. Thus, the modulation of structural characteristics of exopolysaccharide by vicX provides new insights into the interaction between the exopolysaccharide structure, gene functions, and cariogenicity. Our results suggest that vicX gene modulates the structural characteristics of exopolysaccharide associated with cariogenicity, which may be explored as a potential target that contributes to dental caries management. Furthermore, the methods used to purify the EPS of S. mutans biofilms and to analyze multiple aspects of its structure (GPC, gas chromatography-mass spectrometry, and (1)H nuclear magnetic resonance spectroscopy) may be useful approaches to determine the roles of other virulence genes for dental caries prevention. PMID- 26733975 TI - Effects of Adaptation of In vitro Rumen Culture to Garlic Oil, Nitrate, and Saponin and Their Combinations on Methanogenesis, Fermentation, and Abundances and Diversity of Microbial Populations. AB - This study investigated the effects of garlic oil (0.25 g/L), nitrate (5 mM), and quillaja saponin (0.6 g/L), alone and in binary or ternary combinations, on methanogenesis, rumen fermentation, and abundances of select microbial populations using in vitro rumen cultures. Potential adaptation to these compounds was also examined by repeated transfers of the cultures on alternate days until day 18. All treatments except saponin alone significantly decreased methanogenesis. Ternary combinations of garlic oil, nitrate, and saponin additively/synergistically suppressed methane production by 65% at day 2 and by 40% at day 18. Feed digestion was not adversely affected by any of the treatments at day 2, but was decreased by the combinations (binary and ternary) of garlic oil with the other inhibitors at days 10 and 18. Saponin, alone or in combinations, and garlic oil alone lowered ammonia concentration at day 2, while nitrate increased ammonia concentration at days 10 and 18. Total volatile fatty acid concentration was decreased by garlic oil alone or garlic oil-saponin combination. Molar proportions of acetate and propionate were affected to different extents by the different treatments. The abundances of methanogens were similar among treatments at day 2; however, garlic oil and its combination with saponin and/or nitrate at day 10 and all treatments except saponin at day 18 significantly decreased the abundances of methanogens. All the inhibitors, either alone or in combinations, did not adversely affect the abundances of total bacteria or Ruminococcus flavefaciens. However, at day 18 the abundances of Fibrobacter succinogenes and Ruminococcus albus were lowered in the presence of garlic oil and saponin, respectively. The results suggest that garlic oil-nitrate saponin combination (at the doses used in this study) can effectively decreases methanogenesis in the rumen, but its efficacy may decrease while inhibition to feed digestion can increase over time. PMID- 26733976 TI - Rapid Detection of K1 Hypervirulent Klebsiella pneumoniae by MALDI-TOF MS. AB - Hypervirulent strains of Klebsiella pneumoniae (hvKP) are genetic variants of K. pneumoniae which can cause life-threatening community-acquired infection in healthy individuals. Currently, methods for efficient differentiation between classic K. pneumoniae (cKP) and hvKP strains are not available, often causing delay in diagnosis and treatment of hvKP infections. To address this issue, we devised a Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) approach for rapid identification of K1 hvKP strains. Four standard algorithms, genetic algorithm (GA), support vector machine (SVM), supervised neural network (SNN), and quick classifier (QC), were tested for their power to differentiate between K1 and non-K1 strains, among which SVM was the most reliable algorithm. Analysis of the receiver operating characteristic curves of the interest peaks generated by the SVM model was found to confer highly accurate detection sensitivity and specificity, consistently producing distinguishable profiles for K1 hvKP and non-K1 strains. Of the 43 K. pneumoniae modeling strains tested by this approach, all were correctly identified as K1 hvKP and non-K1 capsule type. Of the 20 non-K1 and 17 K1 hvKP validation isolates, the accuracy of K1 hvKP and non-K1 identification was 94.1 and 90.0%, respectively, according to the SVM model. In summary, the MALDI-TOF MS approach can be applied alongside the conventional genotyping techniques to provide rapid and accurate diagnosis, and hence prompt treatment of infections caused by hvKP. PMID- 26733974 TI - Microbial Biotransformation to Obtain New Antifungals. AB - Antifungal drugs belong to few chemical groups and such low diversity limits the therapeutic choices. The urgent need of innovative options has pushed researchers to search new bioactive molecules. Literature regarding the last 15 years reveals that different research groups have used different approaches to achieve such goal. However, the discovery of molecules with different mechanisms of action still demands considerable time and efforts. This review was conceived to present how Pharmaceutical Biotechnology might contribute to the discovery of molecules with antifungal properties by microbial biotransformation procedures. Authors present some aspects of (1) microbial biotransformation of herbal medicines and food; (2) possibility of major and minor molecular amendments in existing molecules by biocatalysis; (3) methodological improvements in processes involving whole cells and immobilized enzymes; (4) potential of endophytic fungi to produce antimicrobials by bioconversions; and (5) in silico research driving to the improvement of molecules. All these issues belong to a new conception of transformation procedures, so-called "green chemistry," which aims the highest possible efficiency with reduced production of waste and the smallest environmental impact. PMID- 26733977 TI - Transplanting Soil Microbiomes Leads to Lasting Effects on Willow Growth, but not on the Rhizosphere Microbiome. AB - Plants interact closely with microbes, which are partly responsible for plant growth, health, and adaptation to stressful environments. Engineering the plant associated microbiome could improve plant survival and performance in stressful environments such as contaminated soils. Here, willow cuttings were planted into highly petroleum-contaminated soils that had been gamma-irradiated and subjected to one of four treatments: inoculation with rhizosphere soil from a willow that grew well (LA) or sub-optimally (SM) in highly contaminated soils or with bulk soil in which the planted willow had died (DE) or no inoculation (CO). Samples were taken from the starting inoculum, at the beginning of the experiment (T0) and after 100 days of growth (TF). Short hypervariable regions of archaeal/bacterial 16S rRNA genes and the fungal ITS region were amplified from soil DNA extracts and sequenced on the Illumina MiSeq. Willow growth was monitored throughout the experiment, and plant biomass was measured at TF. CO willows were significantly smaller throughout the experiment, while DE willows were the largest at TF. Microbiomes of different treatments were divergent at T0, but for most samples, had converged on highly similar communities by TF. Willow biomass was more strongly linked to overall microbial community structure at T0 than to microbial community structure at TF, and the relative abundance of many genera at T0 was significantly correlated to final willow root and shoot biomass. Although microbial communities had mostly converged at TF, lasting differences in willow growth were observed, probably linked to differences in T0 microbial communities. PMID- 26733978 TI - Tree Plantation Systems Influence Nitrogen Retention and the Abundance of Nitrogen Functional Genes in the Solomon Islands. AB - Tree mono-plantations are susceptible to soil nutrient impoverishment and mixed species plantations have been proposed as a way of maintaining soil fertility while enhancing biodiversity. In the Solomon Islands, mixed species plantations where teak (Tectona grandis) is inter-planted with a local tree species (Flueggea flexuosa) have been used as an alternative to teak mono-plantations and are expected to increase soil microbial diversity and modify microbial biogeochemical processes. In this study, we quantified the abundance of microbial functional genes involved in the nitrogen (N) cycle from soil samples collected in teak, flueggea, and mixed species plantations. Furthermore, we measured soil properties such as pH, total carbon (C) and total N, stable N isotope composition (delta(15)N), and inorganic N pools. Soil pH and delta(15)N were higher under teak than under flueggea, which indicates that intercropping teak with flueggea may decrease bacterial activities and potential N losses. Higher C:N ratios were found under mixed species plantations than those under teak, suggesting an enhancement of N immobilization that would help preventing fast N losses. However, inorganic N pools remained unaffected by plant cover. Inter-planting teak with flueggea in mixed species plantations generally increased the relative abundance of denitrification genes and promoted the enrichment of nosZ-harboring denitrifiers. However, it reduced the abundance of bacterial amoA (ammonia monooxygenase) genes compared to teak mono-plantations. The abundance of most denitrification genes correlated with soil total N and C:N ratio, while bacterial and archeal nitrification genes correlated positively with soil NH4 (+) concentrations. Altogether, these results show that the abundance of bacterial N cycling functional guilds vary under teak and under mixed species plantations, and that inter-planting teak with flueggea may potentially alleviate N losses associated with nitrification and denitrification and favor N retention. Mixed plantations could also allow an increase in soil C and N stocks without losing the source of income that teak trees represent for local communities. PMID- 26733979 TI - Editorial: Exploring Bacterial Colonies in Solid Foods or Model Foods Using Non Destructive Techniques. PMID- 26733980 TI - A Plasmid-Transposon Hybrid Mutagenesis System Effective in a Broad Range of Enterobacteria. AB - Random transposon mutagenesis is a powerful technique used to generate libraries of genetic insertions in many different bacterial strains. Here we develop a system facilitating random transposon mutagenesis in a range of different Gram negative bacterial strains, including Pectobacterium atrosepticum, Citrobacter rodentium, Serratia sp. ATCC39006, Serratia plymuthica, Dickeya dadantii, and many more. Transposon mutagenesis was optimized in each of these strains and three studies are presented to show the efficacy of this system. Firstly, the important agricultural pathogen D. dadantii was mutagenized. Two mutants that showed reduced protease production and one mutant producing the previously cryptic pigment, indigoidine, were identified and characterized. Secondly, the enterobacterium, Serratia sp. ATCC39006 was mutagenized and mutants incapable of producing gas vesicles, proteinaceous intracellular organelles, were identified. One of these contained a beta-galactosidase transcriptional fusion within the gene gvpA1, essential for gas vesicle production. Finally, the system was used to mutate the biosynthetic gene clusters of the antifungal, anti-oomycete and anticancer polyketide, oocydin A, in the plant-associated enterobacterium, Dickeya solani MK10. The mutagenesis system was developed to allow easy identification of transposon insertion sites by sequencing, after facile generation of a replicon encompassing the transposon and adjacent DNA, post excision. Furthermore, the system can also create transcriptional fusions with either beta-galactosidase or beta-glucuronidase as reporters, and exploits a variety of drug resistance markers so that multiple selectable fusions can be generated in a single strain. This system of various transposons has wide utility and can be combined in many different ways. PMID- 26733981 TI - Differential Response of Acidobacteria Subgroups to Forest-to-Pasture Conversion and Their Biogeographic Patterns in the Western Brazilian Amazon. AB - Members of the phylum Acidobacteria are among the most abundant soil bacteria on Earth, but little is known about their response to environmental changes. We asked how the relative abundance and biogeographic patterning of this phylum and its subgroups responded to forest-to-pasture conversion in soils of the western Brazilian Amazon. Pyrosequencing of 16S rRNA genes was employed to assess the abundance and composition of the Acidobacteria community across 54 soil samples taken using a spatially nested sampling scheme at the landscape level. Numerically, Acidobacteria represented 20% of the total bacterial community in forest soils and 11% in pasture soils. Overall, 15 different Acidobacteria subgroups of the current 26 subgroups were detected, with Acidobacteria subgroups 1, 3, 5, and 6 accounting together for 87% of the total Acidobacteria community in forest soils and 75% in pasture soils. Concomitant with changes in soil chemistry after forest-to-pasture conversion-particularly an increase in properties linked to soil acidity and nutrient availability-we observed an increase in the relative abundances of Acidobacteria subgroups 4, 10, 17, and 18, and a decrease in the relative abundances of other Acidobacteria subgroups in pasture relative to forest soils. The composition of the total Acidobacteria community as well as the most abundant Acidobacteria subgroups (1, 3, 5, and 6) was significantly more similar in composition across space in pasture soils than in forest soils. These results suggest that preponderant responses of Acidobacteria subgroups, especially subgroups 1, 3, 4, 5, and 6, to forest-to pasture conversion effects in soils could be used to define management-indicators of agricultural practices in the Amazon Basin. These acidobacterial responses are at least in part through alterations on acidity- and nutrient-related properties of the Amazon soils. PMID- 26733982 TI - Acquisition of Full-Length Viral Helicase Domains by Insect Retrotransposon Encoded Polypeptides. AB - Recent metagenomic studies in insects identified many sequences unexpectedly closely related to plant virus genes. Here we describe a new example of this kind, insect R1 LINEs with an additional C-terminal domain in their open reading frame 2. This domain is similar to NTPase/helicase (SF1H) domains, which are found in replicative proteins encoded by plant viruses of the genus Tobamovirus. We hypothesize that the SF1H domain could be acquired by LINEs, directly or indirectly, upon insect feeding on virus-infected plants. Possible functions of this domain in LINE transposition and involvement in LINEs counteraction the silencing-based cell defense against retrotransposons are discussed. PMID- 26733983 TI - Engineering Bacterial Surface Displayed Human Norovirus Capsid Proteins: A Novel System to Explore Interaction Between Norovirus and Ligands. AB - Human noroviruses (HuNoVs) are major contributors to acute nonbacterial gastroenteritis outbreaks. Many aspects of HuNoVs are poorly understood due to both the current inability to culture HuNoVs, and the lack of efficient small animal models. Surrogates for HuNoVs, such as recombinant viral like particles (VLPs) expressed in eukaryotic system or P particles expressed in prokaryotic system, have been used for studies in immunology and interaction between the virus and its receptors. However, it is difficult to use VLPs or P particles to collect or isolate potential ligands binding to these recombinant capsid proteins. In this study, a new strategy was used to collect HuNoVs binding ligands through the use of ice nucleation protein (INP) to display recombinant capsid proteins of HuNoVs on bacterial surfaces. The viral protein-ligand complex could be easily separated by a low speed centrifugation step. This system was also used to explore interaction between recombinant capsid proteins of HuNoVs and their receptors. In this system, the VP1 capsid encoding gene (ORF2) and the protruding domain (P domain) encoding gene (3' terminal fragment of ORF2) of HuNoVs GI.1 and GII.4 were fused with 5' terminal fragment of INP encoding gene (inaQn). The results demonstrated that the recombinant VP1 and P domains of HuNoVs were expressed and anchored on the surface of Escherichia coli BL21 cells after the bacteria were transformed with the corresponding plasmids. Both cell surface displayed VP1 and P domains could be recognized by HuNoVs specific antibodies and interact with the viral histo-blood group antigens receptors. In both cases, displayed P domains had better binding abilities than VP1. This new strategy of using displayed HuNoVs capsid proteins on the bacterial surface could be utilized to separate HuNoVs binding components from complex samples, to investigate interaction between the virus and its receptors, as well as to develop an oral vaccine for HuNoVs. PMID- 26733984 TI - Key Factors Influencing Rates of Heterotrophic Sulfate Reduction in Active Seafloor Hydrothermal Massive Sulfide Deposits. AB - Hydrothermal vents are thermally and geochemically dynamic habitats, and the organisms therein are subject to steep gradients in temperature and chemistry. To date, the influence of these environmental dynamics on microbial sulfate reduction has not been well constrained. Here, via multivariate experiments, we evaluate the effects of key environmental variables (temperature, pH, H2S, [Formula: see text], DOC) on sulfate reduction rates and metabolic energy yields in material recovered from a hydrothermal flange from the Grotto edifice in the Main Endeavor Field, Juan de Fuca Ridge. Sulfate reduction was measured in batch reactions across a range of physico-chemical conditions. Temperature and pH were the strongest stimuli, and maximum sulfate reduction rates were observed at 50 degrees C and pH 6, suggesting that the in situ community of sulfate-reducing organisms in Grotto flanges may be most active in a slightly acidic and moderate thermal/chemical regime. At pH 4, sulfate reduction rates increased with sulfide concentrations most likely due to the mitigation of metal toxicity. While substrate concentrations also influenced sulfate reduction rates, energy-rich conditions muted the effect of metabolic energetics on sulfate reduction rates. We posit that variability in sulfate reduction rates reflect the response of the active microbial consortia to environmental constraints on in situ microbial physiology, toxicity, and the type and extent of energy limitation. These experiments help to constrain models of the spatial contribution of heterotrophic sulfate reduction within the complex gradients inherent to seafloor hydrothermal deposits. PMID- 26733985 TI - Endophytic Cultivable Bacteria of the Metal Bioaccumulator Spartina maritima Improve Plant Growth but Not Metal Uptake in Polluted Marshes Soils. AB - Endophytic bacterial population was isolated from Spartina maritima tissues, a heavy metal bioaccumulator cordgrass growing in the estuaries of Tinto, Odiel, and Piedras River (south west Spain), one of the most polluted areas in the world. Strains were identified and ability to tolerate salt and heavy metals along with plant growth promoting and enzymatic properties were analyzed. A high proportion of these bacteria were resistant toward one or several heavy metals and metalloids including As, Cu, and Zn, the most abundant in plant tissues and soil. These strains also exhibited multiple enzymatic properties as amylase, cellulase, chitinase, protease and lipase, as well as plant growth promoting properties, including nitrogen fixation, phosphates solubilization, and production of indole-3-acetic acid (IAA), siderophores and 1-aminocyclopropane-1 carboxylate (ACC) deaminase. The best performing strains (Micrococcus yunnanensis SMJ12, Vibrio sagamiensis SMJ18, and Salinicola peritrichatus SMJ30) were selected and tested as a consortium by inoculating S. maritima wild plantlets in greenhouse conditions along with wild polluted soil. After 30 days, bacterial inoculation improved plant photosynthetic traits and favored intrinsic water use efficiency. However, far from stimulating plant metal uptake, endophytic inoculation lessened metal accumulation in above and belowground tissues. These results suggest that inoculation of S. maritima with indigenous metal-resistant endophytes could mean a useful approach in order to accelerate both adaption and growth of this indigenous cordgrass in polluted estuaries in restorative operations, but may not be suitable for rhizoaccumulation purposes. PMID- 26733986 TI - Alcohol and Cannabinoids Differentially Affect HIV Infection and Function of Human Monocyte-Derived Dendritic Cells (MDDC). AB - During human immunodeficiency virus (HIV) infection, alcohol has been known to induce inflammation while cannabinoids have been shown to have an anti inflammatory role. For instance cannabinoids have been shown to reduce susceptibility to HIV-1 infection and attenuate HIV replication in macrophages. Recently, we demonstrated that alcohol induces cannabinoid receptors and regulates cytokine production by monocyte-derived dendritic cells (MDDC). However, the ability of alcohol and cannabinoids to alter MDDC function during HIV infection has not been clearly elucidated yet. In order to study the potential impact of alcohol and cannabinoids on differentiated MDDC infected with HIV, monocytes were cultured for 7 days with GM-CSF and IL-4, differentiated MDDC were infected with HIV-1Ba-L and treated with EtOH (0.1 and 0.2%), THC (5 and 10 MUM), or JWH-015 (5 and 10 MUM) for 4-7 days. HIV infection of MDDC was confirmed by p24 and Long Terminal Repeats (LTR) estimation. MDDC endocytosis assay and cytokine array profiles were measured to investigate the effects of HIV and substances of abuse on MDDC function. Our results show the HIV + EtOH treated MDDC had the highest levels of p24 production and expression when compared with the HIV positive controls and the cannabinoid treated cells. Although both cannabinoids, THC and JWH-015 had lower levels of p24 production and expression, the HIV + JWH-015 treated MDDC had the lowest levels of p24 when compared to the HIV + THC treated cells. In addition, MDDC endocytic function and cytokine production were also differentially altered after alcohol and cannabinoid treatments. Our results show a differential effect of alcohol and cannabinoids, which may provide insights into the divergent inflammatory role of alcohol and cannabinoids to modulate MDDC function in the context of HIV infection. PMID- 26733987 TI - Screening of Pharmacologically Active Small Molecule Compounds Identifies Antifungal Agents Against Candida Biofilms. AB - Candida species have emerged as important and common opportunistic human pathogens, particularly in immunocompromised individuals. The current antifungal therapies either have toxic side effects or are insufficiently effect. The aim of this study is develop new small-molecule antifungal compounds by library screening methods using Candida albicans, and to evaluate their antifungal effects on Candida biofilms and cytotoxic effects on human cells. Wild-type C. albicans strain SC5314 was used in library screening. To identify antifungal compounds, we screened a small-molecule library of 1,280 pharmacologically active compounds (LOPAC(1280TM)) using an antifungal susceptibility test (AST). To investigate the antifungal effects of the hit compounds, ASTs were conducted using Candida strains in various growth modes, including biofilms. We tested the cytotoxicity of the hit compounds using human gingival fibroblast (hGF) cells to evaluate their clinical safety. Only 35 compounds were identified by screening, which inhibited the metabolic activity of C. albicans by >50%. Of these, 26 compounds had fungistatic effects and nine compounds had fungicidal effects on C. albicans. Five compounds, BAY11-7082, BAY11-7085, sanguinarine chloride hydrate, ellipticine and CV-3988, had strong fungicidal effects and could inhibit the metabolic activity of Candida biofilms. However, BAY11-7082, BAY11-7085, sanguinarine chloride hydrate and ellipticine were cytotoxic to hGF cells at low concentrations. CV-3988 showed no cytotoxicity at a fungicidal concentration. Four of the compounds identified, BAY11-7082, BAY11-7085, sanguinarine chloride hydrate and ellipticine, had toxic effects on Candida strains and hGF cells. In contrast, CV-3988 had fungicidal effects on Candida strains, but low cytotoxic effects on hGF cells. Therefore, this screening reveals agent, CV-3988 that was previously unknown to be antifungal agent, which could be a novel therapies for superficial mucosal candidiasis. PMID- 26733988 TI - Bacterial Composition and Survival on Sahara Dust Particles Transported to the European Alps. AB - Deposition of Sahara dust (SD) particles is a frequent phenomenon in Europe, but little is known about the viability and composition of the bacterial community transported with SD. The goal of this study was to characterize SD-associated bacteria transported to the European Alps, deposited and entrapped in snow. During two distinct events in February and May 2014, SD particles were deposited and promptly covered by falling snow, thus preserving them in distinct ochre layers within the snowpack. In June 2014, we collected samples at different depths from a snow profile at the Jungfraujoch (Swiss Alps; 3621 m a.s.l.). After filtration, we performed various microbiological and physicochemical analyses of the snow and dust particles therein that originated in Algeria. Our results show that bacteria survive and are metabolically active after the transport to the European Alps. Using high throughput sequencing, we observed distinct differences in bacterial community composition and structure in SD-layers as compared to clean snow layers. Sporulating bacteria were not enriched in the SD-layers; however, phyla with low abundance such as Gemmatimonadetes and Deinococcus Thermus appeared to be specific bio-indicators for SD. Since many members of these phyla are known to be adapted to arid oligotrophic environments and UV radiation, they are well suited to survive the harsh conditions of long-range airborne transport. PMID- 26733989 TI - Evolution of 2014/15 H3N2 Influenza Viruses Circulating in US: Consequences for Vaccine Effectiveness and Possible New Pandemic. AB - A key factor in the effectiveness of the seasonal influenza vaccine is its immunological compatibility with the circulating viruses during the season. Here we propose a new bioinformatics approach for analysis of influenza viruses which could be used as an efficient tool for selection of vaccine viruses, assessment of the effectiveness of seasonal influenza vaccines, and prediction of the epidemic/pandemic potential of novel influenza viruses. PMID- 26733990 TI - Groundwater Isolation Governs Chemistry and Microbial Community Structure along Hydrologic Flowpaths. AB - This study deals with the effects of hydrodynamic functioning of hard-rock aquifers on microbial communities. In hard-rock aquifers, the heterogeneous hydrologic circulation strongly constrains groundwater residence time, hydrochemistry, and nutrient supply. Here, residence time and a wide range of environmental factors were used to test the influence of groundwater circulation on active microbial community composition, assessed by high throughput sequencing of 16S rRNA. Groundwater of different ages was sampled along hydrogeologic paths or loops, in three contrasting hard-rock aquifers in Brittany (France). Microbial community composition was driven by groundwater residence time and hydrogeologic loop position. In recent groundwater, in the upper section of the aquifers or in their recharge zone, surface water inputs caused high nitrate concentration and the predominance of putative denitrifiers. Although denitrification does not seem to fully decrease nitrate concentrations due to low dissolved organic carbon concentrations, nitrate input has a major effect on microbial communities. The occurrence of taxa possibly associated with the application of organic fertilizers was also noticed. In ancient isolated groundwater, an ecosystem based on Fe(II)/Fe(III) and S/SO4 redox cycling was observed down to several 100 of meters below the surface. In this depth section, microbial communities were dominated by iron oxidizing bacteria belonging to Gallionellaceae. The latter were associated to old groundwater with high Fe concentrations mixed to a small but not null percentage of recent groundwater inducing oxygen concentrations below 2.5 mg/L. These two types of microbial community were observed in the three sites, independently of site geology and aquifer geometry, indicating hydrogeologic circulation exercises a major control on microbial communities. PMID- 26733991 TI - The Phytohormone Ethylene Enhances Cellulose Production, Regulates CRP/FNRKx Transcription and Causes Differential Gene Expression within the Bacterial Cellulose Synthesis Operon of Komagataeibacter (Gluconacetobacter) xylinus ATCC 53582. AB - Komagataeibacter (formerly Gluconacetobacter) xylinus ATCC 53582 is a plant associated model organism for bacterial cellulose (BC) biosynthesis. This bacterium inhabits the carposphere where it interacts with fruit through the bi directional transfer of phytohormones. The majority of research regarding K. xylinus has been focused on identifying and characterizing structural and regulatory factors that control BC biosynthesis, but its ecophysiology has been generally overlooked. Ethylene is a phytohormone that regulates plant development in a variety of ways, but is most commonly known for its positive role on fruit ripening. In this study, we utilized ethephon (2-chloroethylphosphonic acid) to produce in situ ethylene to investigate the effects of this phytohormone on BC production and the expression of genes known to be involved in K. xylinus BC biosynthesis (bcsA, bcsB, bcsC, bcsD, cmcAx, ccpAx and bglAx). Using pellicle assays and reverse transcription quantitative polymerase chain reaction (RT qPCR), we demonstrate that ethephon-derived ethylene enhances BC directly in K. xylinus by up-regulating the expression of bcsA and bcsB, and indirectly though the up-regulation of cmcAx, ccpAx, and bglAx. We confirm that IAA directly decreases BC biosynthesis by showing that IAA down-regulates bcsA expression. Similarly, we confirm that ABA indirectly influences BC biosynthesis by showing it does not affect the expression of bcs operon genes. In addition, we are the first to report the ethylene and indole-3-acetic acid (IAA) induced differential expression of genes within the bacterial cellulose synthesis (bcs) operon. Using bioinformatics we have identified a novel phytohormone-regulated CRP/FNRKx transcription factor and provide evidence that it influences BC biosynthesis in K. xylinus. Lastly, utilizing current and previous data, we propose a model for the phytohormone-mediated fruit-bacteria interactions that K. xylinus experiences in nature. PMID- 26733992 TI - Complement Activation in Placental Malaria. AB - Sixty percent of all pregnancies worldwide occur in malaria endemic regions. Pregnant women are at greater risk of malaria infection than their non-pregnant counterparts and have a higher risk of adverse birth outcomes including low birth weight resulting from intrauterine growth restriction and/or preterm birth. The complement system plays an essential role in placental and fetal development as well as the host innate immune response to malaria infection. Excessive or dysregulated complement activation has been associated with the pathobiology of severe malaria and with poor pregnancy outcomes, dependent and independent of infection. Here we review the role of complement in malaria and pregnancy and discuss its part in mediating altered placental angiogenesis, malaria-induced adverse birth outcomes, and disruptions to the in utero environment with possible consequences on fetal neurodevelopment. A detailed understanding of the mechanisms underlying adverse birth outcomes, and the impact of maternal malaria infection on fetal neurodevelopment, may lead to biomarkers to identify at-risk pregnancies and novel therapeutic interventions to prevent these complications. PMID- 26733993 TI - Fungal Melanin: What do We Know About Structure? AB - The production of melanin significantly enhances the virulence of many important human pathogenic fungi. Despite fungal melanin's importance in human disease, as well as melanin's contribution to the ability of fungi to survive in diverse hostile environments, the structure of melanin remains unsolved. Nevertheless, ongoing research efforts have progressively revealed several notable structural characteristics of this enigmatic pigment, which will be the focus of this review. These compositional and organizational insights could further our ability to develop novel therapeutic approaches to combat fungal disease and enhance our understanding of how melanin is inserted into the cell wall. PMID- 26733994 TI - Plasticity of Streptomyces coelicolor Membrane Composition Under Different Growth Conditions and During Development. AB - Streptomyces coelicolor is a model actinomycete that is well known for the diversity of its secondary metabolism and its complex life cycle. As a soil inhabitant, it is exposed to heterogeneous and frequently changing environmental circumstances. In the present work, we studied the effect of diverse growth conditions and phosphate depletion on its lipid profile and the relationship between membrane lipid composition and development in S. coelicolor. The lipid profile from cultures grown on solid media, which is closer to the natural habitat of this microorganism, does not resemble the previously reported lipid composition from liquid grown cultures of S. coelicolor. Wide variations were also observed across different media, growth phases, and developmental stages indicating active membrane remodeling. Ornithine lipids (OL) are phosphorus-free polar lipids that were accumulated mainly during sporulation stages, but were also major components of the membrane under phosphorus limitation. In contrast, phosphatidylethanolamine, which had been reported as one of the major polar lipids in the genus Streptomyces, is almost absent under these conditions. We identified one of the genes responsible for the synthesis of OL (SCO0921) and found that its inactivation causes the absence of OL, precocious morphological development and actinorhodin production. Our observations indicate a remarkable plasticity of the membrane composition in this bacterial species, reveal a higher metabolic complexity than expected, and suggest a relationship between cytoplasmic membrane components and the differentiation programs in S. coelicolor. PMID- 26733995 TI - Antibacterial Activity of a Novel Peptide-Modified Lysin Against Acinetobacter baumannii and Pseudomonas aeruginosa. AB - The global emergence of multidrug-resistant (MDR) bacteria is a growing threat to public health worldwide. Natural bacteriophage lysins are promising alternatives in the treatment of infections caused by Gram-positive pathogens, but not Gram negative ones, like Acinetobacter baumannii and Pseudomonas aeruginosa, due to the barriers posed by their outer membranes. Recently, modifying a natural lysin with an antimicrobial peptide was found able to break the barriers, and to kill Gram-negative pathogens. Herein, a new peptide-modified lysin (PlyA) was constructed by fusing the cecropin A peptide residues 1-8 (KWKLFKKI) with the OBPgp279 lysin and its antibacterial activity was studied. PlyA showed good and broad antibacterial activities against logarithmic phase A. baumannii and P. aeruginosa, but much reduced activities against the cells in stationary phase. Addition of outer membrane permeabilizers (EDTA and citric acid) could enhance the antibacterial activity of PlyA against stationary phase cells. Finally, no antibacterial activity of PlyA could be observed in some bio-matrices, such as culture media, milk, and sera. In conclusion, we reported here a novel peptide modified lysin with significant antibacterial activity against both logarithmic (without OMPs) and stationary phase (with OMPs) A. baumannii and P. aeruginosa cells in buffer, but further optimization is needed to achieve broad activity in diverse bio-matrices. PMID- 26733996 TI - Rapid Reactivation of Cyanobacterial Photosynthesis and Migration upon Rehydration of Desiccated Marine Microbial Mats. AB - Desiccated cyanobacterial mats are the dominant biological feature in the Earth's arid zones. While the response of desiccated cyanobacteria to rehydration is well documented for terrestrial systems, information about the response in marine systems is lacking. We used high temporal resolution hyperspectral imaging, liquid chromatography, pulse-amplitude fluorometry, oxygen microsensors, and confocal laser microscopy to study this response in a desiccated microbial mat from Exmouth Gulf, Australia. During the initial 15 min after rehydration chlorophyll a concentrations increased 2-5 fold and cyanobacterial photosynthesis was re-established. Although the mechanism behind this rapid increase of chlorophyll a remains unknown, we hypothesize that it involves resynthesis from a precursor stored in desiccated cyanobacteria. The subsequent phase (15 min-48 h) involved migration of the reactivated cyanobacteria toward the mat surface, which led, together with a gradual increase in chlorophyll a, to a further increase in photosynthesis. We conclude that the response involving an increase in chlorophyll a and recovery of photosynthetic activity within minutes after rehydration is common for cyanobacteria from desiccated mats of both terrestrial and marine origin. However, the response of upward migration and its triggering factor appear to be mat-specific and likely linked to other factors. PMID- 26733997 TI - Importance of the Two Dissimilatory (Nar) Nitrate Reductases in the Growth and Nitrate Reduction of the Methylotrophic Marine Bacterium Methylophaga nitratireducenticrescens JAM1. AB - Methylophaga nitratireducenticrescens JAM1 is the only reported Methylophaga species capable of growing under anaerobic conditions with nitrate as electron acceptor. Its genome encodes a truncated denitrification pathway, which includes two nitrate reductases, Nar1 and Nar2; two nitric oxide reductases, Nor1 and Nor2; and one nitrous oxide reductase, Nos; but no nitrite reductase (NirK or NirS). The transcriptome of strain JAM1 cultivated with nitrate and methanol under anaerobic conditions showed the genes for these enzymes were all expressed. We investigated the importance of Nar1 and Nar2 by knocking out narG1, narG2 or both genes. Measurement of the specific growth rate and the specific nitrate reduction rate of the knockout mutants JAM1DeltanarG1 (Nar1) and JAM1DeltanarG2 (Nar2) clearly demonstrated that both Nar systems contributed to the growth of strain JAM1 under anaerobic conditions, but at different levels. The JAM1DeltanarG1 mutant exhibited an important decrease in the nitrate reduction rate that consequently impaired its growth under anaerobic conditions. In JAM1DeltanarG2, the mutation induced a 20-h lag period before nitrate reduction occurred at specific rate similar to that of strain JAM1. The disruption of narG1 did not affect the expression of narG2. However, the expression of the Nar1 system was highly downregulated in the presence of oxygen with the JAM1DeltanarG2 mutant. These results indicated that Nar1 is the major nitrate reductase in strain JAM1 but Nar2 appears to regulate the expression of Nar1. PMID- 26733998 TI - Airborne Bacterial Interactions: Functions Out of Thin Air? AB - Bacteria produce and release a large diversity of small molecules including organic and inorganic volatile compounds, hereafter referred to as bacterial volatile compounds (BVCs). Whereas BVCs were often only considered as wasted metabolic by-product sometimes perceived by animal olfactory systems, it is increasingly clear that they can also mediate cross-kingdom interactions with fungi, plants and animals. Recently, in vitro studies also reported the impact of BVCs on bacterial biology through modulation of antibiotic resistance, biofilm formation and virulence. Here, we review BVCs influence on bacterial adaptation to their environment and discuss the biological relevance of recently reported inter- and intra-species bacterial interactions mediated by BVCs. PMID- 26733999 TI - Potential Activity, Size, and Structure of Sulfate-Reducing Microbial Communities in an Exposed, Grazed and a Sheltered, Non-Grazed Mangrove Stand at the Red Sea Coast. AB - After oxygen, sulfate is the most important oxidant for the oxidation of organic matter in mangrove forest soils. As sulfate reducers are poor competitors for common electron donors, their relative success depends mostly on the surplus of carbon that is left by aerobic organisms due to oxygen depletion. We therefore hypothesized that sulfate-cycling in mangrove soils is influenced by the size of net primary production, and hence negatively affected by mangrove degradation and exploitation, as well as by carbon-exporting waves. To test this, we compared quantitative and qualitative traits of sulfate-reducing communities in two Saudi Arabian mangrove stands near Jeddah, where co-occurring differences in camel grazing pressure and tidal exposure led to a markedly different stand height and hence primary production. Potential sulfate reduction rates measured in anoxic flow-through reactors in the absence and presence of additional carbon sources were significantly higher in the samples from the non-grazed site. Near the surface (0-2 cm depth), numbers of dsrB gene copies and culturable cells also tended to be higher in the non-grazed sites, while these differences were not detected in the sub-surface (4-6 cm depth). It was concluded that sulfate reducing microbes at the surface were indeed repressed at the low-productive site as could be expected from our hypothesis. At both sites, sulfate reduction rates as well as numbers of the dsrB gene copies and viable cells increased with depth suggesting repression of sulfate reduction near the surface in both irrespective of production level. Additionally, sequence analysis of DNA bands obtained from DGGE gels based on the dsrB gene, showed a clear difference in dominance of sulfate-reducing genera belonging to the Deltaproteobacteria and the Firmicutes between sampling sites and depths. PMID- 26734000 TI - The Cultivable Surface Microbiota of the Brown Alga Ascophyllum nodosum is Enriched in Macroalgal-Polysaccharide-Degrading Bacteria. AB - Bacteria degrading algal polysaccharides are key players in the global carbon cycle and in algal biomass recycling. Yet the water column, which has been studied largely by metagenomic approaches, is poor in such bacteria and their algal-polysaccharide-degrading enzymes. Even more surprisingly, the few published studies on seaweed-associated microbiomes have revealed low abundances of such bacteria and their specific enzymes. However, as macroalgal cell-wall polysaccharides do not accumulate in nature, these bacteria and their unique polysaccharidases must not be that uncommon. We, therefore, looked at the polysaccharide-degrading activity of the cultivable bacterial subpopulation associated with Ascophyllum nodosum. From A. nodosum triplicates, 324 bacteria were isolated and taxonomically identified. Out of these isolates, 78 (~25%) were found to act on at least one tested algal polysaccharide (agar, iota- or kappa carrageenan, or alginate). The isolates "active" on algal-polysaccharides belong to 11 genera: Cellulophaga, Maribacter, Algibacter, and Zobellia in the class Flavobacteriia (41) and Pseudoalteromonas, Vibrio, Cobetia, Shewanella, Colwellia, Marinomonas, and Paraglaceciola in the class Gammaproteobacteria (37). A major part represents likely novel species. Different proportions of bacterial phyla and classes were observed between the isolated cultivable subpopulation and the total microbial community previously identified on other brown algae. Here, Bacteroidetes and Gammaproteobacteria were found to be the most abundant and some phyla (as Planctomycetes and Cyanobacteria) frequently encountered on brown algae weren't identified. At a lower taxonomic level, twelve genera, well-known to be associated with algae (with the exception for Colwellia), were consistently found on all three A. nosodum samples. Even more interesting, 9 of the 11 above mentioned genera containing polysaccharolytic isolates were predominant in this common core. The cultivable fraction of the bacterial community associated with A. nodosum is, thus, significantly enriched in macroalgal-polysaccharide degrading bacteria and these bacteria seem important for the seaweed holobiont even though they are under-represented in alga-associated microbiome studies. PMID- 26734001 TI - Nitrate Storage and Dissimilatory Nitrate Reduction by Eukaryotic Microbes. AB - The microbial nitrogen cycle is one of the most complex and environmentally important element cycles on Earth and has long been thought to be mediated exclusively by prokaryotic microbes. Rather recently, it was discovered that certain eukaryotic microbes are able to store nitrate intracellularly and use it for dissimilatory nitrate reduction in the absence of oxygen. The paradigm shift that this entailed is ecologically significant because the eukaryotes in question comprise global players like diatoms, foraminifers, and fungi. This review article provides an unprecedented overview of nitrate storage and dissimilatory nitrate reduction by diverse marine eukaryotes placed into an eco-physiological context. The advantage of intracellular nitrate storage for anaerobic energy conservation in oxygen-depleted habitats is explained and the life style enabled by this metabolic trait is described. A first compilation of intracellular nitrate inventories in various marine sediments is presented, indicating that intracellular nitrate pools vastly exceed porewater nitrate pools. The relative contribution by foraminifers to total sedimentary denitrification is estimated for different marine settings, suggesting that eukaryotes may rival prokaryotes in terms of dissimilatory nitrate reduction. Finally, this review article sketches some evolutionary perspectives of eukaryotic nitrate metabolism and identifies open questions that need to be addressed in future investigations. PMID- 26734002 TI - Intramuscular Priming and Intranasal Boosting Induce Strong Genital Immunity Through Secretory IgA in Minipigs Infected with Chlamydia trachomatis. AB - International efforts in developing a vaccine against Chlamydia trachomatis have highlighted the need for novel immunization strategies for the induction of genital immunity. In this study, we evaluated an intramuscular (IM) prime/intranasal boost vaccination strategy in a Gottingen Minipig model with a reproductive system very similar to humans. The vaccine was composed of C. trachomatis subunit antigens formulated in the Th1/Th17 promoting CAF01 adjuvant. IM priming immunizations with CAF01 induced a significant cell-mediated interferon gamma and interleukin 17A response and a significant systemic high titered neutralizing IgG response. Following genital challenge, intranasally boosted groups mounted an accelerated, highly significant genital IgA response that correlated with enhanced bacterial clearance on day 3 post infection. By detecting antigen-specific secretory component (SC), we showed that the genital IgA was locally produced in the genital mucosa. The highly significant inverse correlation between the vaginal IgA SC response and the chlamydial load suggests that IgA in the minipig model is involved in protection against C. trachomatis. This is important both for our understanding of protective immunity and future vaccination strategies against C. trachomatis and genital pathogens in general. PMID- 26734004 TI - Rapid Response of Advanced Squamous Non-Small Cell Lung Cancer with Thrombocytopenia after First-Line Treatment with Pembrolizumab Plus Autologous Cytokine-Induced Killer Cells. AB - We present the first clinical evidence of advanced squamous non-small cell lung cancer with severe thrombocytopenia showing dramatic improvement after first-line treatment with pembrolizumab plus autologous cytokine-induced killer cells. PMID- 26734003 TI - Myeloid Dendritic Cells are Potential Players in Human Neurodegenerative Diseases. AB - Alzheimer's diseases (AD) and Parkinson's diseases (PD) are devastating neurodegenerative disturbances, wherein neuroinflammation is a chronic pathogenic process with high therapeutic potential. Major mediators of AD/PD neuroimmune processes are resident immune cells, but immune cells derived from periphery may also participate and to some extent modify neuroinflammation. Specifically, blood borne myeloid cells emerge as crucial components of AD/PD progression and susceptibility. Among these, dendritic cells (DCs) are key immune orchestrators and players of brain immune surveillance; we candidate them as potential mediators of both AD and PD and as relevant cell model for unraveling myeloid cell role in neurodegeneration. Hence, we recapitulate and discuss emerging data suggesting that blood-derived DCs play a role in experimental and human neurodegenerative diseases. In humans, in particular, DCs are modified by in vitro culture with neurodegeneration-associated pathogenic factors and dysregulated in AD patients, while the levels of DC precursors are decreased in AD and PD patients' blood, possibly as an index of their recruitment to the brain. Overall, we emphasize the need to explore the impact of DCs on neurodegeneration to uncover peripheral immune mechanisms of pathogenic importance, recognize potential biomarkers, and improve therapeutic approaches for neurodegenerative diseases. PMID- 26734005 TI - Naive T Cell Homeostasis Regulated by Stress Responses and TCR Signaling. AB - The survival of naive T cells is believed to require signals from TCR-pMHC interactions and cytokines such as IL-7. In contrast, signals that negatively impact naive T cell survival are less understood. We conducted a forward genetic screening of mice and found a mutant mouse line with reduced number of naive T cells (T-Red mice). T-Red mice have a point mutation in the Kdelr1 gene, and their naive T cells show enhanced integrated stress response (ISR), which eventually induces their apoptosis. Therefore, naive T cells require a KDEL receptor-mediated mechanism that efficiently relieves cellular stress for their survival in vivo. Interestingly, naive T cells expressing TCR with higher affinity/avidity to self-antigens survive in T-Red mice, suggesting the possible link between TCR-mediated survival and ISR-induced apoptosis. In this article, we discuss the regulation of naive T cell homeostasis, keeping special attention on the ISR and TCR signal. PMID- 26734006 TI - The Treg/Th17 Axis: A Dynamic Balance Regulated by the Gut Microbiome. AB - T-helper 17 (Th17) and T-regulatory (Treg) cells are frequently found at barrier surfaces, particularly within the intestinal mucosa, where they function to protect the host from pathogenic microorganisms and to restrain excessive effector T-cell responses, respectively. Despite their differing functional properties, Th17 cells and Tregs share similar developmental requirements. In fact, the fate of antigen-naive T-cells to either Th17 or Treg lineages is finely regulated by key mediators, including TGFbeta, IL-6, and all-trans retinoic acid. Importantly, the intestinal microbiome also provides immunostimulatory signals, which can activate innate and downstream adaptive immune responses. Specific components of the gut microbiome have been implicated in the production of proinflammatory cytokines by innate immune cells, such as IL-6, IL-23, IL-1beta, and the subsequent generation and expansion of Th17 cells. Similarly, commensal bacteria and their metabolites can also promote the generation of intestinal Tregs that can actively induce mucosal tolerance. As such, dysbiosis of the gut microbiome may not solely represent a consequence of gut inflammation, but rather shape the Treg/Th17 commitment and influence susceptibility to inflammatory bowel disease. In this review, we discuss Treg and Th17 cell plasticity, its dynamic regulation by the microbiome, and highlight its impact on intestinal homeostasis and disease. PMID- 26734007 TI - Osteoimmune Interactions in Inflammatory Bowel Disease: Central Role of Bone Marrow Th17 TNFalpha Cells in Osteoclastogenesis. AB - Osteoimmunology is an interdisciplinary research field dedicated to the study of the crosstalk between the immune and bone systems. CD4(+) T cells are central players in this crosstalk. There is an emerging understanding that CD4(+) T cells play an important role in the bone marrow (BM) under physiological and pathological conditions and modulate the differentiation of bone-resorbing osteoclasts. However, identification of the mechanisms that maintain CD4(+) T cells in the BM is still a matter of investigation. This article describes the CD4(+) T cell populations of the BM and reviews their role as osteoclastogenic population in inflammatory bowel disease. PMID- 26734008 TI - Uninephrectomy in Rats on a Fixed Food Intake Potentiates Both Anorexia and Circulating Cytokine Subsets in Response to LPS. AB - Recent human studies have suggested that mild reduction in kidney function can alter immune response and increase susceptibility to infection. The role of mild reduction in kidney function in altering susceptibility to bacterial lipopolysaccharide (LPS) responses was investigated in uninephrectomized rats compared to Sham-operated controls rats 4 weeks after surgery. Throughout the 4 weeks, all rats were maintained under mild food restriction at 90% of ad libitum intake to ensure the same caloric intake in both groups. In comparison to Sham, uninephrectomy (UniNX) potentiated LPS-induced anorexia by 2.1-fold. The circulating anorexigenic cytokines granulocyte-macrophage colony stimulating factor, interferon-gamma, tumor necrosis factor-alpha, and complement-derived acylation-stimulating protein were elevated after LPS in UniNX animals compared to Sham animals. Interleukin(IL)1beta and IL6 pro-inflammatory cytokines were transiently increased. Anti-inflammatory cytokines IL4 and IL10 did not differ or had a tendency to be lower in UniNX group compared to Sham animals. LPS-induced anorexia was associated with increased anorexigenic neuropeptides mRNA for pro opiomelanocortin, corticotrophin-releasing factor, and cocaine-amphetamine regulated transcript in the hypothalamus of both Sham and UniNX groups, but at higher levels in the UniNX group. Melanocortin-4-receptor mRNA was markedly increased in the UniNX group, which may have contributed to the enhanced anorexic response to LPS of the UniNX group. In summary, UniNX potentiates pro inflammatory cytokine production, anorexia, and selected hypothalamic anorexigenic neuropeptides in response to LPS. PMID- 26734010 TI - Dickkopf-3 Contributes to the Regulation of Anti-Tumor Immune Responses by Mesenchymal Stem Cells. AB - Mesenchymal stem cells (MSCs) are known to limit immune responses in vivo by multiple soluble factors. Dickkopf-3 (DKK3), a secreted glycoprotein, has recently been identified as a novel immune modulator. Since DKK3 has been reported to be produced by MSCs, we investigated whether DKK3 contributes to the immune suppression of anti-tumor responses by MSCs. Whereas wild-type MSCs inhibited immune responses against two different transplantation tumors, DKK3 deficient MSCs did not affect the rejection process. Increased CD8(+) T cell and reduced M2-type macrophages infiltration was observed in tumors inoculated together with DKK3-deficient MSCs. Thus, DKK3 could alter the composition of the tumor stroma, thereby supporting the MSCs-mediated suppression of immune responses against these tumor transplants. PMID- 26734011 TI - Multiple Sclerosis between Genetics and Infections: Human Endogenous Retroviruses in Monocytes and Macrophages. AB - The etiology of multiple sclerosis (MS) is still unknown, but there is strong evidence that genetic predisposition associated with environmental factors can trigger the disease. An estimated 30 million years ago, exogenous retroviruses are thought to have integrated themselves into human germ line cells, becoming part of human DNA and being transmitted over generations. Usually such human endogenous retroviruses (HERVs) are silenced or expressed at low levels, but in some pathological conditions, such as MS, their expression is higher than that in the healthy population. Three HERV families have been associated with MS: HERV-H, HERV-K, and HERV-W. The envelope protein of MS-associated retrovirus (MSRV) from the HERV-W family currently has the strongest evidence as a potential trigger for MS. In addition to expression in peripheral immune cells, MSRV is expressed in monocytes and microglia in central nervous system lesions of people with MS and, through the activation of toll-like receptor 4, it has been shown to drive the production of proinflammatory cytokines, reduction of myelin protein expression, and death of oligodendrocyte precursors. In conclusion, the association between HERVs and MS is well documented and a pathological role for MSRV in MS is plausible. Further studies are required to determine whether the presence of these HERVs is a cause or an effect of immune dysregulation in MS. PMID- 26734009 TI - B Cells Are Multifunctional Players in Multiple Sclerosis Pathogenesis: Insights from Therapeutic Interventions. AB - Multiple sclerosis (MS) is a severe disease of the central nervous system (CNS) characterized by autoimmune inflammation and neurodegeneration. Historically, damage to the CNS was thought to be mediated predominantly by activated pro inflammatory T cells. B cell involvement in the pathogenesis of MS was solely attributed to autoantibody production. The first clues for the involvement of antibody-independent B cell functions in MS pathology came from positive results in clinical trials of the B cell-depleting treatment rituximab in patients with relapsing-remitting (RR) MS. The survival of antibody-secreting plasma cells and decrease in T cell numbers indicated the importance of other B cell functions in MS such as antigen presentation, costimulation, and cytokine production. Rituximab provided us with an example of how clinical trials can lead to new research opportunities concerning B cell biology. Moreover, analysis of the antibody-independent B cell functions in MS has gained interest since these trials. Limited information is present on the effects of current immunomodulatory therapies on B cell functions, although effects of both first-line (interferon, glatiramer acetate, dimethyl fumarate, and teriflunomide), second-line (fingolimod, natalizumab), and even third-line (monoclonal antibody therapies) treatments on B cell subtype distribution, expression of functional surface markers, and secretion of different cytokines by B cells have been studied to some extent. In this review, we summarize the effects of different MS-related treatments on B cell functions that have been described up to now in order to find new research opportunities and contribute to the understanding of the pathogenesis of MS. PMID- 26734013 TI - Introgression of Blast Resistance Genes (Putative Pi-b and Pi-kh) into Elite Rice Cultivar MR219 through Marker-Assisted Selection. AB - Blast is the most common biotic stress leading to the reduction of rice yield in many rice-growing areas of the world, including Malaysia. Improvement of blast resistance of rice varieties cultivated in blast endemic areas is one of the most important objectives of rice breeding programs. In this study, the marker assisted backcrossing strategy was applied to improve the blast resistance of the most popular Malaysian rice variety MR219 by introgressing blast resistance genes from the Pongsu Seribu 2 variety. Two blast resistance genes, Pi-b and Pi-kh, were pyramided into MR219. Foreground selection coupled with stringent phenotypic selection identified 15 plants homozygous for the Pi-b and Pi-kh genes, and background selection revealed more than 95% genome recovery of MR219 in advanced blast resistant lines. Phenotypic screening against blast disease indicated that advanced homozygous blast resistant lines were strongly resistant against pathotype P7.2 in the blast disease endemic areas. The morphological, yield, grain quality, and yield-contributing characteristics were significantly similar to those of MR219. The newly developed blast resistant improved lines will retain the high adoptability of MR219 by farmers. The present results will also play an important role in sustaining the rice production of Malaysia. PMID- 26734012 TI - Extensive Transcriptome Changes During Natural Onset and Release of Vegetative Bud Dormancy in Populus. AB - To survive winter, many perennial plants become endodormant, a state of suspended growth maintained even in favorable growing environments. To understand vegetative bud endodormancy, we collected paradormant, endodormant, and ecodormant axillary buds from Populus trees growing under natural conditions. Of 44,441 Populus gene models analyzed using NimbleGen microarrays, we found that 1,362 (3.1%) were differentially expressed among the three dormancy states, and 429 (1.0%) were differentially expressed during only one of the two dormancy transitions (FDR p-value < 0.05). Of all differentially expressed genes, 69% were down-regulated from paradormancy to endodormancy, which was expected given the lower metabolic activity associated with endodormancy. Dormancy transitions were accompanied by changes in genes associated with DNA methylation (via RNA-directed DNA methylation) and histone modifications (via Polycomb Repressive Complex 2), confirming and extending knowledge of chromatin modifications as major features of dormancy transitions. Among the chromatin-associated genes, two genes similar to SPT (SUPPRESSOR OF TY) were strongly up-regulated during endodormancy. Transcription factor genes and gene sets that were atypically up-regulated during endodormancy include a gene that seems to encode a trihelix transcription factor and genes associated with proteins involved in responses to ethylene, cold, and other abiotic stresses. These latter transcription factors include ETHYLENE INSENSITIVE 3 (EIN3), ETHYLENE-RESPONSIVE ELEMENT BINDING PROTEIN (EBP), ETHYLENE RESPONSE FACTOR (ERF), ZINC FINGER PROTEIN 10 (ZAT10), ZAT12, and WRKY DNA binding domain proteins. Analyses of phytohormone-associated genes suggest important changes in responses to ethylene, auxin, and brassinosteroids occur during endodormancy. We found weaker evidence for changes in genes associated with salicylic acid and jasmonic acid, and little evidence for important changes in genes associated with gibberellins, abscisic acid, and cytokinin. We identified 315 upstream sequence motifs associated with eight patterns of gene expression, including novel motifs and motifs associated with the circadian clock and responses to photoperiod, cold, dehydration, and ABA. Analogies between flowering and endodormancy suggest important roles for genes similar to SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL), DORMANCY ASSOCIATED MADS-BOX (DAM), and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1). PMID- 26734014 TI - Evaluation of a SUMO E2 Conjugating Enzyme Involved in Resistance to Clavibacter michiganensis Subsp. michiganensis in Solanum peruvianum, Through a Tomato Mottle Virus VIGS Assay. AB - Clavibacter michiganensis subsp. michiganensis (Cmm) causes bacterial wilt and canker of tomato. Currently, no Solanum lycopersicum resistant varieties are commercially available, but some degree of Cmm resistance has been identified in Solanum peruvianum. Previous research showed up-regulation of a SUMO E2 conjugating enzyme (SCEI) transcript in S. peruvianum compared to S. lycopersicum following infection with Cmm. In order to test the role of SCEI in resistance to Cmm, a fragment of SCEI from S. peruvianum was cloned into a novel virus-induced gene-silencing (VIGS) vector based on the geminivirus, Tomato Mottle Virus (ToMoV). Using biolistic inoculation, the ToMoV-based VIGS vector was shown to be effective in S. peruvianum by silencing the magnesium chelatase gene, resulting in leaf bleaching. VIGS with the ToMoV_SCEI construct resulted in ~61% silencing of SCEI in leaves of S. peruvianum as determined by quantitative RT-PCR. The SCEI silenced plants showed unilateral wilting (15 dpi) and subsequent death (20 dpi) of the entire plant after Cmm inoculation, whereas the empty vector-treated plants only showed wilting in the Cmm-inoculated leaf. The SCEI-silenced plants showed higher Cmm colonization and an average of 4.5 times more damaged tissue compared to the empty vector control plants. SCEI appears to play an important role in the innate immunity of S. peruvianum against Cmm, perhaps through the regulation of transcription factors, leading to expression of proteins involved in salicylic acid-dependent defense responses. PMID- 26734015 TI - Hydrogen Sulfide Regulates Salt Tolerance in Rice by Maintaining Na(+)/K(+) Balance, Mineral Homeostasis and Oxidative Metabolism Under Excessive Salt Stress. AB - Being a salt sensitive crop, rice growth and development are frequently affected by soil salinity. Hydrogen sulfide (H2S) has been recently explored as an important priming agent regulating diverse physiological processes of plant growth and development. Despite its enormous prospects in plant systems, the role of H2S in plant stress tolerance is still elusive. Here, a combined pharmacological, physiological and biochemical approach was executed aiming to examine the possible mechanism of H2S in enhancement of rice salt stress tolerance. We showed that pretreating rice plants with H2S donor sodium bisulfide (NaHS) clearly improved, but application of H2S scavenger hypotaurine with NaHS decreased growth and biomass-related parameters under salt stress. NaHS pretreated salt-stressed plants exhibited increased chlorophyll, carotenoid and soluble protein contents, as well as suppressed accumulation of reactive oxygen species (ROS), contributing to oxidative damage protection. The protective mechanism of H2S against oxidative stress was correlated with the elevated levels of ascorbic acid, glutathione, redox states, and the enhanced activities of ROS- and methylglyoxal-detoxifying enzymes. Notably, the ability to decrease the uptake of Na(+) and the Na(+)/K(+) ratio, as well as to balance mineral contents indicated a role of H2S in ion homeostasis under salt stress. Altogether, our results highlight that modulation of the level of endogenous H2S genetically or exogenously could be employed to attain better growth and development of rice, and perhaps other crops, under salt stress. Furthermore, our study reveals the importance of the implication of gasotransmitters like H2S for the management of salt stress, thus assisting rice plants to adapt to adverse environmental changes. PMID- 26734016 TI - Next Generation Sequencing Technologies: The Doorway to the Unexplored Genomics of Non-Model Plants. AB - Non-model plants i.e., the species which have one or all of the characters such as long life cycle, difficulty to grow in the laboratory or poor fecundity, have been schemed out of sequencing projects earlier, due to high running cost of Sanger sequencing. Consequently, the information about their genomics and key biological processes are inadequate. However, the advent of fast and cost effective next generation sequencing (NGS) platforms in the recent past has enabled the unearthing of certain characteristic gene structures unique to these species. It has also aided in gaining insight about mechanisms underlying processes of gene expression and secondary metabolism as well as facilitated development of genomic resources for diversity characterization, evolutionary analysis and marker assisted breeding even without prior availability of genomic sequence information. In this review we explore how different Next Gen Sequencing platforms, as well as recent advances in NGS based high throughput genotyping technologies are rewarding efforts on de-novo whole genome/transcriptome sequencing, development of genome wide sequence based markers resources for improvement of non-model crops that are less costly than phenotyping. PMID- 26734017 TI - The Arabidopsis COX11 Homolog is Essential for Cytochrome c Oxidase Activity. AB - Members of the ubiquitous COX11 (cytochrome c oxidase 11) protein family are involved in copper delivery to the COX complex. In this work, we characterize the Arabidopsis thaliana COX11 homolog (encoded by locus At1g02410). Western blot analyses and confocal microscopy identified Arabidopsis COX11 as an integral mitochondrial protein. Despite sharing high sequence and structural similarities, the Arabidopsis COX11 is not able to functionally replace the Saccharomyces cerevisiae COX11 homolog. Nevertheless, further analysis confirmed the hypothesis that Arabidopsis COX11 is essential for COX activity. Disturbance of COX11 expression through knockdown (KD) or overexpression (OE) affected COX activity. In KD lines, the activity was reduced by ~50%, resulting in root growth inhibition, smaller rosettes and leaf curling. In OE lines, the reduction was less pronounced (~80% of the wild type), still resulting in root growth inhibition. Additionally, pollen germination was impaired in COX11 KD and OE plants. This effect on pollen germination can only partially be attributed to COX deficiency and may indicate a possible auxiliary role of COX11 in ROS metabolism. In agreement with its role in energy production, the COX11 promoter is highly active in cells and tissues with high-energy demand for example shoot and root meristems, or vascular tissues of source and sink organs. In COX11 KD lines, the expression of the plasma-membrane copper transporter COPT2 and of several copper chaperones was altered, indicative of a retrograde signaling pathway pertinent to copper homeostasis. Based on our data, we postulate that COX11 is a mitochondrial chaperone, which plays an important role for plant growth and pollen germination as an essential COX complex assembly factor. PMID- 26734018 TI - Emerging Importance of Helicases in Plant Stress Tolerance: Characterization of Oryza sativa Repair Helicase XPB2 Promoter and Its Functional Validation in Tobacco under Multiple Stresses. AB - Genetic material always remains at the risk of spontaneous or induced damage which challenges the normal functioning of DNA molecule, thus, DNA repair is vital to protect the organisms against genetic damage. Helicases, the unique molecular motors, are emerged as prospective molecules to engineer stress tolerance in plants and are involved in nucleic acid metabolism including DNA repair. The repair helicase, XPB is an evolutionary conserved protein present in different organisms, including plants. Availability of few efficient promoters for gene expression in plants provoked us to study the promoter of XPB for better understanding of gene regulation under stress conditions. Here, we report the in silico analysis of novel stress inducible promoter of Oryza sativa XPB2 (OsXPB2). The in vivo validation of functionality/activity of OsXPB2 promoter under abiotic and hormonal stress conditions was performed by Agrobacterium-mediated transient assay in tobacco leaves using OsXPB2::GUS chimeric construct. The present research revealed that OsXPB2 promoter contains cis-elements accounting for various abiotic stresses (salt, dehydration, or cold) and hormone (Auxin, ABA, or MeJA) induced GUS expression/activity in the promoter-reporter assay. The promoter region of OsXPB2 contains CACG, GTAACG, CACGTG, CGTCA CCGCCGCGCT cis acting-elements which are reported to be salt, dehydration, cold, MeJA, or ABA responsive, respectively. Functional analysis was done by Agrobacterium-mediated transient assay using agroinfiltration in tobacco leaves, followed by GUS staining and fluorescence quantitative analyses. The results revealed high induction of GUS activity under multiple abiotic stresses as compared to mock treated control. The present findings suggest that OsXPB2 promoter is a multi stress inducible promoter and has potential applications in sustainable crop production under abiotic stresses by regulating desirable pattern of gene expression. PMID- 26734019 TI - Genome-Wide Linkage Mapping of QTL for Yield Components, Plant Height and Yield Related Physiological Traits in the Chinese Wheat Cross Zhou 8425B/Chinese Spring. AB - Identification of genes for yield components, plant height (PH), and yield related physiological traits and tightly linked molecular markers is of great importance in marker-assisted selection (MAS) in wheat breeding. In the present study, 246 F8 RILs derived from the cross of Zhou 8425B/Chinese Spring were genotyped using the high-density Illumina iSelect 90K single nucleotide polymorphism (SNP) assay. Field trials were conducted at Zhengzhou and Zhoukou of Henan Province, during the 2012-2013 and 2013-2014 cropping season under irrigated conditions, providing data for four environments. Analysis of variance (ANOVA) of agronomic and physiological traits revealed significant differences (P < 0.01) among RILs, environments, and RILs * environments interactions. Broad sense heritabilities of all traits including thousand kernel weight (TKW), PH, spike length (SL), kernel number per spike (KNS), spike number/m(2) (SN), normalized difference in vegetation index at anthesis (NDVI-A) and at 10 days post-anthesis (NDVI-10), SPAD value of chlorophyll content at anthesis (Chl-A) and at 10 days post-anthesis (Chl-10) ranged between 0.65 and 0.94. A linkage map spanning 3609.4 cM was constructed using 5636 polymorphic SNP markers, with an average chromosome length of 171.9 cM and marker density of 0.64 cM/marker. A total of 866 SNP markers were newly mapped to the hexaploid wheat linkage map. Eighty-six QTL for yield components, PH, and yield-related physiological traits were detected on 18 chromosomes except 1D, 5D, and 6D, explaining 2.3-33.2% of the phenotypic variance. Ten stable QTL were identified across four environments, viz. QTKW.caas-6A.1, QTKW.caas-7AL, QKNS.caas-4AL, QSN.caas-1AL.1, QPH.caas 4BS.2, QPH.caas-4DS.1, QSL.caas-4AS, QSL.caas-4AL.1, QChl-A.caas-5AL, and QChl 10.caas-5BL. Meanwhile, 10 QTL-rich regions were found on chromosome 1BS, 2AL (2), 3AL, 4AL (2), 4BS, 4DS, 5BL, and 7AL exhibiting pleiotropic effects. These QTL or QTL clusters are tightly linked to SNP markers, with genetic distances to the closest SNPs ranging from 0 to 1.5 cM, and could serve as target regions for fine mapping, candidate gene discovery, and MAS in wheat breeding. PMID- 26734020 TI - Dosage Sensitivity of RPL9 and Concerted Evolution of Ribosomal Protein Genes in Plants. AB - The ribosome in higher eukaryotes is a large macromolecular complex composed of four rRNAs and eighty different ribosomal proteins. In plants, each ribosomal protein is encoded by multiple genes. Duplicate genes within a family are often necessary to provide a threshold dose of a ribosomal protein but in some instances appear to have non-redundant functions. Here, we addressed whether divergent members of the RPL9 gene family are dosage sensitive or whether these genes have non-overlapping functions. The RPL9 family in Arabidopsis thaliana comprises two nearly identical members, RPL9B and RPL9C, and a more divergent member, RPL9D. Mutations in RPL9C and RPL9D genes lead to delayed growth early in development, and loss of both genes is embryo lethal, indicating that these are dosage-sensitive and redundant genes. Phylogenetic analysis of RPL9 as well as RPL4, RPL5, RPL27a, RPL36a, and RPS6 family genes in the Brassicaceae indicated that multicopy ribosomal protein genes have been largely retained following whole genome duplication. However, these gene families also show instances of tandem duplication, small scale deletion, and evidence of gene conversion. Furthermore, phylogenetic analysis of RPL9 genes in angiosperm species showed that genes within a species are more closely related to each other than to RPL9 genes in other species, suggesting ribosomal protein genes undergo convergent evolution. Our analysis indicates that ribosomal protein gene retention following whole genome duplication contributes to the number of genes in a family. However, small scale rearrangements influence copy number and likely drive concerted evolution of these dosage-sensitive genes. PMID- 26734021 TI - Loss of YABBY2-Like Gene Expression May Underlie the Evolution of the Laminar Style in Canna and Contribute to Floral Morphological Diversity in the Zingiberales. AB - The Zingiberales is an order of tropical monocots that exhibits diverse floral morphologies. The evolution of petaloid, laminar stamens, staminodes, and styles contributes to this diversity. The laminar style is a derived trait in the family Cannaceae and plays an important role in pollination as its surface is used for secondary pollen presentation. Previous work in the Zingiberales has implicated YABBY2-like genes, which function in promoting laminar outgrowth, in the evolution of stamen morphology. Here, we investigate the evolution and expression of Zingiberales YABBY2-like genes in order to understand the evolution of the laminar style in Canna. Phylogenetic analyses show that multiple duplication events have occurred in this gene lineage prior to the diversification of the Zingiberales. Reverse transcription-PCR in Canna, Costus, and Musa reveals differential expression across floral organs, taxa, and gene copies, and a role for YABBY2-like genes in the evolution of the laminar style is proposed. Selection tests indicate that almost all sites in conserved domains are under purifying selection, consistent with their functional relevance, and a motif unique to monocot YABBY2-like genes is identified. These results contribute to our understanding of the molecular mechanisms underlying the evolution of floral morphologies. PMID- 26734022 TI - Concepts and Analyses in the CT Scanning of Root Systems and Leaf Canopies: A Timely Summary. AB - Non-medical applications of computed tomography (CT) scanning have flourished in recent years, including in Plant Science. This Perspective article on CT scanning of root systems and leaf canopies is intended to be of interest to three categories of readers: those who have not yet tried plant CT scanning, and should find inspiration for new research objectives; readers who are on the learning curve with applications-here is helpful advice for them; and researchers with greater experience-the field is evolving quickly and it is easy to miss aspects. Our conclusion is that CT scanning of roots and canopies is highly demanding in terms of technology, multidisciplinarity and big-data analysis, to name a few areas of expertise, but eventually, the reward for researchers is directly proportional! PMID- 26734023 TI - WD40-Repeat Proteins in Plant Cell Wall Formation: Current Evidence and Research Prospects. AB - The metabolic complexity of living organisms relies on supramolecular protein structures which ensure vital processes, such as signal transduction, transcription, translation and cell wall synthesis. In eukaryotes WD40-repeat (WDR) proteins often function as molecular "hubs" mediating supramolecular interactions. WDR proteins may display a variety of interacting partners and participate in the assembly of complexes involved in distinct cellular functions. In plants, the formation of lignocellulosic biomass involves extensive synthesis of cell wall polysaccharides, a process that requires the assembly of large transmembrane enzyme complexes, intensive vesicle trafficking, interactions with the cytoskeleton, and coordinated gene expression. Because of their function as supramolecular hubs, WDR proteins could participate in each or any of these steps, although to date only few WDR proteins have been linked to the cell wall by experimental evidence. Nevertheless, several potential cell wall-related WDR proteins were recently identified using in silico approaches, such as analyses of co-expression, interactome and conserved gene neighborhood. Notably, some WDR genes are frequently genomic neighbors of genes coding for GT2-family polysaccharide synthases in eukaryotes, and this WDR-GT2 collinear microsynteny is detected in diverse taxa. In angiosperms, two WDR genes are collinear to cellulose synthase genes, CesAs, whereas in ascomycetous fungi several WDR genes are adjacent to chitin synthase genes, chs. In this Perspective we summarize and discuss experimental and in silico studies on the possible involvement of WDR proteins in plant cell wall formation. The prospects of biotechnological engineering for enhanced biomass production are discussed. PMID- 26734025 TI - Co-transforming bar and CsALDH Genes Enhanced Resistance to Herbicide and Drought and Salt Stress in Transgenic Alfalfa (Medicago sativa L.). AB - Drought and high salinity are two major abiotic factors that restrict the productivity of alfalfa. By application of the Agrobacterium-mediated transformation method, an oxidative responsive gene, CsALDH12A1, from the desert grass Cleistogenes songorica together with the bar gene associated with herbicide resistance, were co-transformed into alfalfa (Medicago sativa L.). From the all 90 transformants, 16 were positive as screened by spraying 1 mL L(-1) 10% Basta solution and molecularly diagnosis using PCR. Real-time PCR analysis indicated that drought and salt stress induced high CsALDH expression in the leaves of the transgenic plants. The CsALDH expression levels under drought (15 d) and salt stress (200 mM NaCl) were 6.11 and 6.87 times higher than in the control plants, respectively. In comparison to the WT plants, no abnormal phenotypes were observed among the transgenic plants, which showed significant enhancement of tolerance to 15 d of drought and 10 d of salinity treatment. Evaluation of the physiological and biochemical indices during drought and salt stress of the transgenic plants revealed relatively lower Na(+) content and higher K(+) content in the leaves relative to the WT plants, a reduction of toxic on effects and maintenance of osmotic adjustment. In addition, the transgenic plants could maintain a higher relative water content level, higher shoot biomass, fewer changes in the photosystem, decreased membrane injury, and a lower level of osmotic stress. These results indicate that the co-expression of the introduced bar and CsALDH genes enhanced the herbicide, drought and salt tolerance of alfalfa and therefore can potentially be used as a novel genetic resource for the future breeding programs to develop new cultivars. PMID- 26734024 TI - Expression of Arabidopsis Hexokinase in Citrus Guard Cells Controls Stomatal Aperture and Reduces Transpiration. AB - Hexokinase (HXK) is a sugar-phosphorylating enzyme involved in sugar-sensing. It has recently been shown that HXK in guard cells mediates stomatal closure and coordinates photosynthesis with transpiration in the annual species tomato and Arabidopsis. To examine the role of HXK in the control of the stomatal movement of perennial plants, we generated citrus plants that express Arabidopsis HXK1 (AtHXK1) under KST1, a guard cell-specific promoter. The expression of KST1 in the guard cells of citrus plants has been verified using GFP as a reporter gene. The expression of AtHXK1 in the guard cells of citrus reduced stomatal conductance and transpiration with no negative effect on the rate of photosynthesis, leading to increased water-use efficiency. The effects of light intensity and humidity on stomatal behavior were examined in rooted leaves of the citrus plants. The optimal intensity of photosynthetically active radiation and lower humidity enhanced stomatal closure of AtHXK1-expressing leaves, supporting the role of sugar in the regulation of citrus stomata. These results suggest that HXK coordinates photosynthesis and transpiration and stimulates stomatal closure not only in annual species, but also in perennial species. PMID- 26734027 TI - Gene Expression and Yeast Two-Hybrid Studies of 1R-MYB Transcription Factor Mediating Drought Stress Response in Chickpea (Cicer arietinum L.). AB - Drought stress has been one of the serious constraints affecting chickpea productivity to a great extent. Genomics-assisted breeding has a potential to accelerate breeding precisely and efficiently. In order to do so, understanding the molecular mechanisms for drought tolerance and identification of candidate genes are crucial. Transcription factors (TFs) have important roles in the regulation of plant stress related genes. In this context, quantitative real time PCR (qRT-PCR) was used to study the differential gene expression of selected TFs, identified from large-scale expressed sequence tags (ESTs) analysis, in contrasting drought responsive genotypes. Root tissues of ICC 4958 (tolerant), ICC 1882 (sensitive), JG 11 (elite), and JG 11+ (introgression line) were used for the study. Subsequently, a candidate single repeat MYB (1R-MYB) transcript that was remarkably induced in the drought tolerant genotypes under drought stress was cloned (coding sequence region for the 1R-MYB protein) and subjected to yeast two-hybrid (Y2H) analysis. The screening of a root cDNA library with Y2H using the 1R-MYB bait protein, identified three CDS encoding peptides namely, galactinol-sucrose galactosyltransferase 2, CBL (Calcineurin B-like)-interacting serine/threonine-protein kinase 25, and ABA responsive 17-like, which were confirmed by co-transformation in yeast. These findings provide preliminary insights into the ability of this 1R-MYB transcription factor to co-regulate drought tolerance mechanism in chickpea. PMID- 26734028 TI - Chromosome Doubling of Microspore-Derived Plants from Cabbage (Brassica oleracea var. capitata L.) and Broccoli (Brassica oleracea var. italica L.). AB - Chromosome doubling of microspore-derived plants is an important factor in the practical application of microspore culture technology because breeding programs require a large number of genetically stable, homozygous doubled haploid plants with a high level of fertility. In the present paper, 29 populations of microspore-derived plantlets from cabbage (Brassica oleracea var. capitata) and broccoli (Brassica oleracea var. italica) were used to study the ploidy level and spontaneous chromosome doubling of these populations, the artificial chromosome doubling induced by colchicine, and the influence of tissue culture duration on the chromosomal ploidy of the microspore-derived regenerants. Spontaneous chromosome doubling occurred randomly and was genotype dependent. In the plant populations derived from microspores, there were haploids, diploids, and even a low frequency of polyploids and mixed-ploidy plantlets. The total spontaneous doubling in the 14 cabbage populations ranged from 0 to 76.9%, compared with 52.2 to 100% in the 15 broccoli populations. To improve the rate of chromosome doubling, an efficient and reliable artificial chromosome doubling protocol (i.e., the immersion of haploid plantlet roots in a colchicine solution) was developed for cabbage and broccoli microspore-derived haploids. The optimal chromosome doubling of the haploids was obtained with a solution of 0.2% colchicine for 9-12 h or 0.4% colchicine for 3-9 h for cabbage and 0.05% colchicine for 6-12 h for broccoli. This protocol produced chromosome doubling in over 50% of the haploid genotypes for most of the populations derived from cabbage and broccoli. Notably, after 1 or more years in tissue culture, the chromosomes of the haploids were doubled, and most of the haploids turned into doubled haploid or mixed-ploidy plants. This is the first report indicating that tissue culture duration can change the chromosomal ploidy of microspore-derived regenerants. PMID- 26734029 TI - MicroRNA390-Directed TAS3 Cleavage Leads to the Production of tasiRNA-ARF3/4 During Somatic Embryogenesis in Dimocarpus longan Lour. AB - Trans-acting short-interfering RNAs (tasiRNAs) originate from TAS3 families through microRNA (miRNA) 390-guided cleavage of primary transcripts and target auxin response factors (ARF3/-4), which are involved in the normal development of lateral roots and flowers in plants. However, their roles in embryo development are still unclear. Here, the pathway miR390-TAS3-ARF3/-4 was identified systematically for the first time during somatic embryo development in Dimocarpus longan. We identified the miR390 primary transcript and promoter. The promoter contained cis-acting elements responsive to stimuli such as light, salicylic acid, anaerobic induction, fungal elicitor, circadian control, and heat stress. The longan TAS3 transcript, containing two miR390-binding sites, was isolated; the miR390- guided cleavage site located near the 3' end of the TAS3 transcript was verified. Eight TAS3-tasiRNAs with the 21-nucleotides phase were found among longan small RNA data, further confirming that miR390-directed TAS3 cleavage leads to the production of tasiRNA in longan. Among them, TAS3_5'D5+ and 5'D6+ tasiRNAs were highly abundant, and verified to target ARF3 and -4, implying that miR390-guided TAS3 cleavage with 21-nucleotides phase leading to the production of tasiRNA-ARF is conserved in plants. Pri-miR390 was highly expressed in friable embryogenic callus (EC), and less expressed in incomplete compact pro-embryogenic cultures, while miR390 showed its lowest expression in EC and highest expression in torpedo-shaped embryos (TEs). DlTAS3 and DlARF4 both exhibited their lowest expressions in EC, and reached their peaks in the globular embryos stage, which were mainly inversely proportional to the expression of miR390, especially at the globular embryos to cotyledonary embryos (CEs) stages. While DlARF3 showed little variation from the EC to TEs stages, and exhibited its lowest expression in the CEs stage. There was a general lack of correlation between the expressions of DlARF3 and miR390. In addition, pri-miR390, DlTAS3, DlARF3 and -4 were up regulated by 2,4-D in a concentration-dependent manner. They were also preferentially expressed in roots, pulp, and seeds of 'Sijimi' longan, implying their extended roles in the development of longan roots and fruit. This study provided insights into a possible role of miR390-tasiRNAs-ARF in plant somatic embryo development. PMID- 26734026 TI - Proteomics and Metabolomics: Two Emerging Areas for Legume Improvement. AB - The crop legumes such as chickpea, common bean, cowpea, peanut, pigeonpea, soybean, etc. are important sources of nutrition and contribute to a significant amount of biological nitrogen fixation (>20 million tons of fixed nitrogen) in agriculture. However, the production of legumes is constrained due to abiotic and biotic stresses. It is therefore imperative to understand the molecular mechanisms of plant response to different stresses and identify key candidate genes regulating tolerance which can be deployed in breeding programs. The information obtained from transcriptomics has facilitated the identification of candidate genes for the given trait of interest and utilizing them in crop breeding programs to improve stress tolerance. However, the mechanisms of stress tolerance are complex due to the influence of multi-genes and post transcriptional regulations. Furthermore, stress conditions greatly affect gene expression which in turn causes modifications in the composition of plant proteomes and metabolomes. Therefore, functional genomics involving various proteomics and metabolomics approaches have been obligatory for understanding plant stress tolerance. These approaches have also been found useful to unravel different pathways related to plant and seed development as well as symbiosis. Proteome and metabolome profiling using high-throughput based systems have been extensively applied in the model legume species, Medicago truncatula and Lotus japonicus, as well as in the model crop legume, soybean, to examine stress signaling pathways, cellular and developmental processes and nodule symbiosis. Moreover, the availability of protein reference maps as well as proteomics and metabolomics databases greatly support research and understanding of various biological processes in legumes. Protein-protein interaction techniques, particularly the yeast two-hybrid system have been advantageous for studying symbiosis and stress signaling in legumes. In this review, several studies on proteomics and metabolomics in model and crop legumes have been discussed. Additionally, applications of advanced proteomics and metabolomics approaches have also been included in this review for future applications in legume research. The integration of these "omics" approaches will greatly support the identification of accurate biomarkers in legume smart breeding programs. PMID- 26734030 TI - Ethylene Modulates Sphingolipid Synthesis in Arabidopsis. AB - Sphingolipids have essential structural and bioactive functions in membranes and in signaling. However, how plants regulate sphingolipid biosynthesis in the response to stress remains unclear. Here, we reveal that the plant hormone ethylene can modulate sphingolipid synthesis. The fungal toxin Fumonisin B1 (FB1) inhibits the activity of ceramide synthases, perturbing sphingolipid homeostasis, and thus inducing cell death. We used FB1 to test the role of ethylene signaling in sphingolipid synthesis in Arabidopsis thaliana. The etr1-1 and ein2 mutants, which have disrupted ethylene signaling, exhibited hypersensitivity to FB1; by contrast, the eto1-1 and ctr1-1 mutants, which have enhanced ethylene signaling, exhibited increased tolerance to FB1. Gene expression analysis showed that during FB1 treatment, transcripts of genes involved in de novo sphingolipid biosynthesis were down-regulated in ctr1-1 mutants but up-regulated in ein2 mutants. Strikingly, under normal conditions, ctr1-1 mutants contained less ceramides and hydroxyceramides, compared with wild type. After FB1 treatment, ctr1-1 and ein2 mutants showed a significant improvement in sphingolipid contents, except the ctr1-1 mutants showed little change in hydroxyceramide levels. Treatment of wild type seedlings with the ethylene precursor 1-aminocyclopropane carboxylic acid down-regulated genes involved in the sphingolipid de novo biosynthesis pathway, thus reducing sphingolipid contents and partially rescuing FB1-induced cell death. Taking these results together, we propose that ethylene modulates sphingolipids by regulating the expression of genes related to the de novo biosynthesis of sphingolipids. PMID- 26734032 TI - Differential Responses of Vanilla Accessions to Root Rot and Colonization by Fusarium oxysporum f. sp. radicis-vanillae. AB - Root and stem rot (RSR) disease caused by Fusarium oxysporum f. sp. radicis vanillae (Forv) is the most damaging disease of vanilla (Vanilla planifolia and V. * tahitensis, Orchidaceae). Breeding programs aimed at developing resistant vanilla varieties are hampered by the scarcity of sources of resistance to RSR and insufficient knowledge about the histopathology of Forv. In this work we have (i) identified new genetic resources resistant to RSR including V. planifolia inbreds and vanilla relatives, (ii) thoroughly described the colonization pattern of Forv into selected vanilla accessions, confirming its necrotic non-vascular behavior in roots, and (iii) evidenced the key role played by hypodermis, and particularly lignin deposition onto hypodermal cell walls, for resistance to Forv in two highly resistant vanilla accessions. Two hundred and fifty-four vanilla accessions were evaluated in the field under natural conditions of infection and in controlled conditions using in vitro plants root-dip inoculated by the highly pathogenic isolate Fo072. For the 26 accessions evaluated in both conditions, a high correlation was observed between field evaluation and in vitro assay. The root infection process and plant response of one susceptible and two resistant accessions challenged with Fo072 were studied using wide field and multiphoton microscopy. In susceptible V. planifolia, hyphae penetrated directly into the rhizodermis in the hairy root region then invaded the cortex through the passage cells where it induced plasmolysis, but never reached the vascular region. In the case of the resistant accessions, the penetration was stopped at the hypodermal layer. Anatomical and histochemical observations coupled with spectral analysis of the hypodermis suggested the role of lignin deposition in the resistance to Forv. The thickness of lignin constitutively deposited onto outer cell walls of hypodermis was highly correlated with the level of resistance for 21 accessions tested. The accumulation of p-coumaric and sinapic acids, two phenolic precursors of lignin, was observed in the resistant plants inoculated with Fo072, but not in the susceptible one. Altogether, our analyses enlightened the mechanisms at work in RSR resistant genotypes and should enhance the development of novel breeding strategies aimed at improving the genetic control of RSR of vanilla. PMID- 26734031 TI - Genome-Wide Transcriptional Profiling and Metabolic Analysis Uncover Multiple Molecular Responses of the Grass Species Lolium perenne Under Low-Intensity Xenobiotic Stress. AB - Lolium perenne, which is a major component of pastures, lawns, and grass strips, can be exposed to xenobiotic stresses due to diffuse and residual contaminations of soil. L. perenne was recently shown to undergo metabolic adjustments in response to sub-toxic levels of xenobiotics. To gain insight in such chemical stress responses, a de novo transcriptome analysis was carried out on leaves from plants subjected at the root level to low levels of xenobiotics, glyphosate, tebuconazole, and a combination of the two, leading to no adverse physiological effect. Chemical treatments influenced significantly the relative proportions of functional categories and of transcripts related to carbohydrate processes, to signaling, to protein-kinase cascades, such as Serine/Threonine-protein kinases, to transcriptional regulations, to responses to abiotic or biotic stimuli and to responses to phytohormones. Transcriptomics-based expressions of genes encoding different types of SNF1 (sucrose non-fermenting 1)-related kinases involved in sugar and stress signaling or encoding key metabolic enzymes were in line with specific qRT-PCR analysis or with the important metabolic and regulatory changes revealed by metabolomic analysis. The effects of pesticide treatments on metabolites and gene expression strongly suggest that pesticides at low levels, as single molecule or as mixture, affect cell signaling and functioning even in the absence of major physiological impact. This global analysis of L. perenne therefore highlighted the interactions between molecular regulation of responses to xenobiotics, and also carbohydrate dynamics, energy dysfunction, phytohormones and calcium signaling. PMID- 26734033 TI - Comparative Genomics of Pathogenic and Nonpathogenic Strains of Xanthomonas arboricola Unveil Molecular and Evolutionary Events Linked to Pathoadaptation. AB - The bacterial species Xanthomonas arboricola contains plant pathogenic and nonpathogenic strains. It includes the pathogen X. arboricola pv. juglandis, causing the bacterial blight of Juglans regia. The emergence of a new bacterial disease of J. regia in France called vertical oozing canker (VOC) was previously described and the causal agent was identified as a distinct genetic lineage within the pathovar juglandis. Symptoms on walnut leaves and fruits are similar to those of a bacterial blight but VOC includes also cankers on trunk and branches. In this work, we used comparative genomics and physiological tests to detect differences between four X. arboricola strains isolated from walnut tree: strain CFBP 2528 causing walnut blight (WB), strain CFBP 7179 causing VOC and two nonpathogenic strains, CFBP 7634 and CFBP 7651, isolated from healthy walnut buds. Whole genome sequence comparisons revealed that pathogenic strains possess a larger and wider range of mobile genetic elements than nonpathogenic strains. One pathogenic strain, CFBP 7179, possessed a specific integrative and conjugative element (ICE) of 95 kb encoding genes involved in copper resistance, transport and regulation. The type three effector repertoire was larger in pathogenic strains than in nonpathogenic strains. Moreover, CFBP 7634 strain lacked the type three secretion system encoding genes. The flagellar system appeared incomplete and nonfunctional in the pathogenic strain CFBP 2528. Differential sets of chemoreceptor and different repertoires of genes coding adhesins were identified between pathogenic and nonpathogenic strains. Besides these differences, some strain-specific differences were also observed. Altogether, this study provides valuable insights to highlight the mechanisms involved in ecology, environment perception, plant adhesion and interaction, leading to the emergence of new strains in a dynamic environment. PMID- 26734034 TI - Boosting Sensitivity in Liquid Chromatography-Fourier Transform Ion Cyclotron Resonance-Tandem Mass Spectrometry for Product Ion Analysis of Monoterpene Indole Alkaloids. AB - In metabolomics, the analysis of product ions in tandem mass spectrometry (MS/MS) is noteworthy to chemically assign structural information. However, the development of relevant analytical methods are less advanced. Here, we developed a method to boost sensitivity in liquid chromatography-Fourier transform ion cyclotron resonance-tandem mass spectrometry analysis (MS/MS boost analysis). To verify the MS/MS boost analysis, both quercetin and uniformly labeled (13)C quercetin were analyzed, revealing that the origin of the product ions is not the instrument, but the analyzed compounds resulting in sensitive product ions. Next, we applied this method to the analysis of monoterpene indole alkaloids (MIAs). The comparative analyses of MIAs having indole basic skeleton (ajmalicine, catharanthine, hirsuteine, and hirsutine) and oxindole skeleton (formosanine, isoformosanine, pteropodine, isopteropodine, rhynchophylline, isorhynchophylline, and mitraphylline) identified 86 and 73 common monoisotopic ions, respectively. The comparative analyses of the three pairs of stereoisomers showed more than 170 common monoisotopic ions in each pair. This method was also applied to the targeted analysis of MIAs in Catharanthus roseus and Uncaria rhynchophylla to profile indole and oxindole compounds using the product ions. This analysis is suitable for chemically assigning features of the metabolite groups, which contributes to targeted metabolome analysis. PMID- 26734035 TI - Insect Herbivory-Elicited GABA Accumulation in Plants is a Wound-Induced, Direct, Systemic, and Jasmonate-Independent Defense Response. AB - The non-proteinogenic amino acid gamma-aminobutyric acid (GABA) is present in all organisms analyzed so far. In invertebrates GABA acts as a neurotransmitter; in plants different functions are under discussion. Among others, its involvement in abiotic stress reactions and as a defensive compound against feeding insects is suggested. GABA is synthesized from glutamate by glutamate decarboxylases and degraded by GABA-transaminases. Here, in Arabidopsis thaliana, gad1/2 double mutants showing reduced GABA concentrations as well as GABA-enriched triple mutants (gad1/2 x pop2-5) were generated and employed for a systematic study of GABA induction, accumulation and related effects in Arabidopsis leaves upon herbivory. The results demonstrate that GABA accumulation is stimulated by insect feeding-like wounding by a robotic caterpillar, MecWorm, as well as by real insect (Spodoptera littoralis) herbivory. Higher GABA levels in both plant tissue and artificial dietary supplements in turn affect the performance of feeding larvae. GABA enrichment occurs not only in the challenged but also in adjacent leaf. This induced response is neither dependent on herbivore defense-related phytohormones, jasmonates, nor is jasmonate induction dependent on the presence of GABA. Thus, in Arabidopsis the rapid accumulation of GABA very likely represents a general, direct and systemic defense reaction against insect herbivores. PMID- 26734036 TI - Predicting Plant Performance Under Simultaneously Changing Environmental Conditions-The Interplay Between Temperature, Light, and Internode Growth. AB - Plant performance is significantly influenced by prevailing light and temperature conditions during plant growth and development. For plants exposed to natural fluctuations in abiotic environmental conditions it is however laborious and cumbersome to experimentally assign any contribution of individual environmental factors to plant responses. This study aimed at analyzing the interplay between light, temperature and internode growth based on model approaches. We extended the light-sensitive virtual plant model L-Cucumber by implementing a common Arrhenius function for appearance rates, growth rates, and growth durations. For two greenhouse experiments, the temperature-sensitive model approach resulted in a precise prediction of cucumber mean internode lengths and number of internodes, as well as in accurately predicted patterns of individual internode lengths along the main stem. In addition, a system's analysis revealed that environmental data averaged over the experimental period were not necessarily related to internode performance. Finally, the need for a species-specific parameterization of the temperature response function and related aspects in modeling temperature effects on plant development and growth is discussed. PMID- 26734037 TI - Depth Filters Containing Diatomite Achieve More Efficient Particle Retention than Filters Solely Containing Cellulose Fibers. AB - The clarification of biological feed stocks during the production of biopharmaceutical proteins is challenging when large quantities of particles must be removed, e.g., when processing crude plant extracts. Single-use depth filters are often preferred for clarification because they are simple to integrate and have a good safety profile. However, the combination of filter layers must be optimized in terms of nominal retention ratings to account for the unique particle size distribution in each feed stock. We have recently shown that predictive models can facilitate filter screening and the selection of appropriate filter layers. Here we expand our previous study by testing several filters with different retention ratings. The filters typically contain diatomite to facilitate the removal of fine particles. However, diatomite can interfere with the recovery of large biopharmaceutical molecules such as virus-like particles and aggregated proteins. Therefore, we also tested filtration devices composed solely of cellulose fibers and cohesive resin. The capacities of both filter types varied from 10 to 50 L m(-2) when challenged with tobacco leaf extracts, but the filtrate turbidity was ~500-fold lower (~3.5 NTU) when diatomite filters were used. We also tested pre-coat filtration with dispersed diatomite, which achieved capacities of up to 120 L m(-2) with turbidities of ~100 NTU using bulk plant extracts, and in contrast to the other depth filters did not require an upstream bag filter. Single pre-coat filtration devices can thus replace combinations of bag and depth filters to simplify the processing of plant extracts, potentially saving on time, labor and consumables. The protein concentrations of TSP, DsRed and antibody 2G12 were not affected by pre-coat filtration, indicating its general applicability during the manufacture of plant derived biopharmaceutical proteins. PMID- 26734038 TI - Interspecies Gene Transfer as a Method for Understanding the Genetic Basis for Evolutionary Change: Progress, Pitfalls, and Prospects. AB - The recent revolution in high throughput sequencing and associated applications provides excellent opportunities to catalog variation in DNA sequences and gene expression between species. However, understanding the astonishing diversity of the Tree of Life requires understanding the phenotypic consequences of such variation and identification of those rare genetic changes that are causal to diversity. One way to study the genetic basis for trait diversity is to apply a transgenic approach and introduce genes of interest from a donor into a recipient species. Such interspecies gene transfer (IGT) is based on the premise that if a gene is causal to the morphological divergence of the two species, the transfer will endow the recipient with properties of the donor. Extensions of this approach further allow identifying novel loci for the diversification of form and investigating cis- and trans-contributions to morphological evolution. Here we review recent examples from both plant and animal systems that have employed IGT to provide insight into the genetic basis of evolutionary change. We outline the practice of IGT, its methodological strengths and weaknesses, and consider guidelines for its application, emphasizing the importance of phylogenetic distance, character polarity, and life history. We also discuss future perspectives for exploiting IGT in the context of expanding genomic resources in emerging experimental systems and advances in genome editing. PMID- 26734039 TI - RNA-Seq Analysis of Rice Roots Reveals the Involvement of Post-Transcriptional Regulation in Response to Cadmium Stress. AB - Widely-spread cadmium (Cd) pollution in the soil threatens both crop production and human health. How plants deal with the excess Cd are largely unknown. To evaluate the molecular mechanism by which plants respond to Cd stress, rice seedlings were treated with two concentrations of Cd and subjected to deep RNA sequencing. Comprehensive RNA-Seq analysis of rice roots under two gradients of Cd treatment revealed 1169 Cd toxicity-responsive genes. These genes were involved in the reactive oxygen species scavenging system, stress response, cell wall formation, ion transport, and signal transduction. Nine out of 93 predicted long non-coding RNAs (lncRNAs) were detected as Cd-responsive lncRNAs due to their high correlation with the Cd stress response. In addition, we analyzed alternative splicing (AS) events under different Cd concentrations. Four hundred and seventy-six differential alternatively spliced genes with 542 aberrant splicing events were identified. GO analysis indicated that these genes were highly enriched in oxidation reduction and cellular response to chemical stimulus. Real-time qRT-PCR validation analysis strengthened the reliability of our RNA-Seq results. The results suggest that post-transcriptional AS regulation may also be involved in plant responses to high Cd stress. PMID- 26734041 TI - The Generation of Turnip Crinkle Virus-Like Particles in Plants by the Transient Expression of Wild-Type and Modified Forms of Its Coat Protein. AB - Turnip crinkle virus (TCV), a member of the genus carmovirus of the Tombusviridae family, has a genome consisting of a single positive-sense RNA molecule that is encapsidated in an icosahedral particle composed of 180 copies of a single type of coat protein. We have employed the CPMV-HT transient expression system to investigate the formation of TCV-like particles following the expression of the wild-type coat protein or modified forms of it that contain either deletions and/or additions. Transient expression of the coat protein in plants results in the formation of capsid structures that morphologically resemble TCV virions (T = 3 structure) but encapsidate heterogeneous cellular RNAs, rather than the specific TCV coat protein messenger RNA. Expression of an amino-terminal deleted form of the coat protein resulted in the formation of smaller T = 1 structures that are free of RNA. The possibility of utilizing TCV as a carrier for the presentation of foreign proteins on the particle surface was also explored by fusing the sequence of GFP to the C-terminus of the coat protein. The expression of coat protein-GFP hybrids permitted the formation of VLPs but the yield of particles is diminished compared to the yield obtained with unmodified coat protein. Our results confirm the importance of the N-terminus of the coat protein for the encapsidation of RNA and show that the coat protein's exterior P domain plays a key role in particle formation. PMID- 26734040 TI - Modified TMV Particles as Beneficial Scaffolds to Present Sensor Enzymes. AB - Tobacco mosaic virus (TMV) is a robust nanotubular nucleoprotein scaffold increasingly employed for the high density presentation of functional molecules such as peptides, fluorescent dyes, and antibodies. We report on its use as advantageous carrier for sensor enzymes. A TMV mutant with a cysteine residue exposed on every coat protein (CP) subunit (TMVCys) enabled the coupling of bifunctional maleimide-polyethylene glycol (PEG)-biotin linkers (TMVCys/Bio). Its surface was equipped with two streptavidin [SA]-conjugated enzymes: glucose oxidase ([SA]-GOx) and horseradish peroxidase ([SA]-HRP). At least 50% of the CPs were decorated with a linker molecule, and all thereof with active enzymes. Upon use as adapter scaffolds in conventional "high-binding" microtiter plates, TMV sticks allowed the immobilization of up to 45-fold higher catalytic activities than control samples with the same input of enzymes. Moreover, they increased storage stability and reusability in relation to enzymes applied directly to microtiter plate wells. The functionalized TMV adsorbed to solid supports showed a homogeneous distribution of the conjugated enzymes and structural integrity of the nanorods upon transmission electron and atomic force microscopy. The high surface-increase and steric accessibility of the viral scaffolds in combination with the biochemical environment provided by the plant viral coat may explain the beneficial effects. TMV can, thus, serve as a favorable multivalent nanoscale platform for the ordered presentation of bioactive proteins. PMID- 26734042 TI - Universal Stress Protein Exhibits a Redox-Dependent Chaperone Function in Arabidopsis and Enhances Plant Tolerance to Heat Shock and Oxidative Stress. AB - Although a wide range of physiological information on Universal Stress Proteins (USPs) is available from many organisms, their biochemical, and molecular functions remain unidentified. The biochemical function of AtUSP (At3g53990) from Arabidopsis thaliana was therefore investigated. Plants over-expressing AtUSP showed a strong resistance to heat shock and oxidative stress, compared with wild type and Atusp knock-out plants, confirming the crucial role of AtUSP in stress tolerance. AtUSP was present in a variety of structures including monomers, dimers, trimers, and oligomeric complexes, and switched in response to external stresses from low molecular weight (LMW) species to high molecular weight (HMW) complexes. AtUSP exhibited a strong chaperone function under stress conditions in particular, and this activity was significantly increased by heat treatment. Chaperone activity of AtUSP was critically regulated by the redox status of cells and accompanied by structural changes to the protein. Over-expression of AtUSP conferred a strong tolerance to heat shock and oxidative stress upon Arabidopsis, primarily via its chaperone function. PMID- 26734043 TI - Foxtail Millet NF-Y Families: Genome-Wide Survey and Evolution Analyses Identified Two Functional Genes Important in Abiotic Stresses. AB - It was reported that Nuclear Factor Y (NF-Y) genes were involved in abiotic stress in plants. Foxtail millet (Setaria italica), an elite stress tolerant crop, provided an impetus for the investigation of the NF-Y families in abiotic responses. In the present study, a total of 39 NF-Y genes were identified in foxtail millet. Synteny analyses suggested that foxtail millet NF-Y genes had experienced rapid expansion and strong purifying selection during the process of plant evolution. De novo transcriptome assembly of foxtail millet revealed 11 drought up-regulated NF-Y genes. SiNF-YA1 and SiNF-YB8 were highly activated in leaves and/or roots by drought and salt stresses. Abscisic acid (ABA) and H2O2 played positive roles in the induction of SiNF-YA1 and SiNF-YB8 under stress treatments. Transient luciferase (LUC) expression assays revealed that SiNF-YA1 and SiNF-YB8 could activate the LUC gene driven by the tobacco (Nicotiana tobacam) NtERD10, NtLEA5, NtCAT, NtSOD, or NtPOD promoter under normal or stress conditions. Overexpression of SiNF-YA1 enhanced drought and salt tolerance by activating stress-related genes NtERD10 and NtCAT1 and by maintaining relatively stable relative water content (RWC) and contents of chlorophyll, superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) and malondialdehyde (MDA) in transgenic lines under stresses. SiNF-YB8 regulated expression of NtSOD, NtPOD, NtLEA5, and NtERD10 and conferred relatively high RWC and chlorophyll contents and low MDA content, resulting in drought and osmotic tolerance in transgenic lines under stresses. Therefore, SiNF-YA1 and SiNF-YB8 could activate stress related genes and improve physiological traits, resulting in tolerance to abiotic stresses in plants. All these results will facilitate functional characterization of foxtail millet NF-Ys in future studies. PMID- 26734044 TI - Understanding Water-Stress Responses in Soybean Using Hydroponics System-A Systems Biology Perspective. AB - The deleterious changes in environmental conditions such as water stress bring physiological and biochemical changes in plants, which results in crop loss. Thus, combating water stress is important for crop improvement to manage the needs of growing population. Utilization of hydroponics system in growing plants is questionable to some researchers, as it does not represent an actual field condition. However, trying to address a complex problem like water stress we have to utilize a simpler growing condition like the hydroponics system wherein every input given to the plants can be controlled. With the advent of high-throughput technologies, it is still challenging to address all levels of the genetic machinery whether a gene, protein, metabolite, and promoter. Thus, using a system of reduced complexity like hydroponics can certainly direct us toward the right candidates, if not completely help us to resolve the issue. PMID- 26734045 TI - Genome-Wide Identification of Calcium Dependent Protein Kinase Gene Family in Plant Lineage Shows Presence of Novel D-x-D and D-E-L Motifs in EF-Hand Domain. AB - Calcium ions are considered ubiquitous second messengers in eukaryotic signal transduction pathways. Intracellular Ca(2+) concentration are modulated by various signals such as hormones and biotic and abiotic stresses. Modulation of Ca(2+) ion leads to stimulation of calcium dependent protein kinase genes (CPKs), which results in regulation of gene expression and therefore mediates plant growth and development as well as biotic and abiotic stresses. Here, we reported the CPK gene family of 40 different plant species (950 CPK genes) and provided a unified nomenclature system for all of them. In addition, we analyzed their genomic, biochemical and structural conserved features. Multiple sequence alignment revealed that the kinase domain, auto-inhibitory domain and EF-hands regions of regulatory domains are highly conserved in nature. Additionally, the EF-hand domains of higher plants were found to contain four D-x-D and two D-E-L motifs, while lower eukaryotic plants had two D-x-D and one D-x-E motifs in their EF-hands. Phylogenetic analysis showed that CPK genes are clustered into four different groups. By studying the CPK gene family across the plant lineage, we provide the first evidence of the presence of D-x-D motif in the calcium binding EF-hand domain of CPK proteins. PMID- 26734046 TI - RNA Sequencing Analysis of the msl2msl3, crl, and ggps1 Mutants Indicates that Diverse Sources of Plastid Dysfunction Do Not Alter Leaf Morphology Through a Common Signaling Pathway. AB - Determining whether individual genes function in the same or in different pathways is an important aspect of genetic analysis. As an alternative to the construction of higher-order mutants, we used contemporary expression profiling methods to perform pathway analysis on several Arabidopsis thaliana mutants, including the mscS-like (msl)2msl3 double mutant. MSL2 and MSL3 are implicated in plastid ion homeostasis, and msl2msl3 double mutants exhibit leaves with a lobed periphery, a rumpled surface, and disturbed mesophyll cell organization. Similar developmental phenotypes are also observed in other mutants with defects in a range of other chloroplast or mitochondrial functions, including biogenesis, gene expression, and metabolism. We wished to test the hypothesis that the common leaf morphology phenotypes of these mutants are the result of a characteristic nuclear expression pattern that is generated in response to organelle dysfunction. RNA Sequencing was performed on aerial tissue of msl2msl3 geranylgeranyl diphosphate synthase 1 (ggps1), and crumpled leaf (crl) mutants. While large groups of co expressed genes were identified in pairwise comparisons between genotypes, we were only able to identify a small set of genes that showed similar expression profiles in all three genotypes. Subsequent comparison to the previously published gene expression profiles of two other mutants, yellow variegated 2 (var2) and scabra3 (sca3), failed to reveal a common pattern of gene expression associated with superficially similar leaf morphology defects. Nor did we observe overlap between genes differentially expressed in msl2msl3, crl, and ggps1 and a previously identified retrograde core response module. These data suggest that a common retrograde signaling pathway initiated by organelle dysfunction either does not exist in these mutants or cannot be identified through transcriptomic methods. Instead, the leaf developmental defects observed in these mutants may be achieved through a number of independent pathways. PMID- 26734047 TI - Mapping of Membrane Lipid Order in Root Apex Zones of Arabidopsis thaliana. AB - In this study, we used the fluorescence probe, Di-4-ANEPPDHQ, to map the distribution of membrane lipid order in the apical region of Arabidopsis roots. The generalized polarization (GP) value of Di-4-ANEPPDHQ-stained roots indicated the highest lipid order in the root transition zone (RTZ). The cortical cells have higher lipid order than the epidermal cells in same regions, while the developing root hairs show very prominent cell polarity with high lipid order in apical region. Moreover, the endosomes had lower lipid order than that of the plasma membrane (PM). Brefeldin A (BFA) treatment decreased the lipid order in both the plasma and endosomal membranes of epidermal cells in the RTZ. The lipid order of BFA-induced compartments became higher than that of the PM after BFA treatment in epidermal cells. Meanwhile, the polarly growing tips of root hairs did not show the same behavior. The lipid order of the PM remained unchanged, with higher values than that of the endosomes. This suggests that the lipid ordering in the PM was affected by recycling of endosomal vesicles in epidermal cells of the root apex transition zone but not in the root hairs of Arabidopsis. PMID- 26734048 TI - The Role of Ethylene in Plant Responses to K(+) Deficiency. AB - Potassium is an essential macronutrient that is involved in regulating turgor, in driving plant growth, and in modulating enzyme activation. The changes in root morphology, root function, as well as cellular and molecular responses to low potassium conditions have been studied in the model plant Arabidopsis and in other plant species. In Arabidopsis ethylene plays a key role in roots in the transduction of the low potassium signal, which results in altered root function and growth. The first clues regarding the role of ethylene were detected through transcriptional profiling experiments showing changes in the expression of genes related to ethylene biosynthesis. Later it was shown that ethylene plays a foundational early role in the many responses observed in Arabidopsis. One of the most striking findings is the link between ethylene and reactive oxygen species (ROS) production, which is part of the signal transduction pathway in K(+) deprived plants. This mini-review will summarize what is known about the role ethylene plays in response to low potassium in Arabidopsis and other plant species. PMID- 26734049 TI - A Simple and Fast Kinetic Assay for the Determination of Fructan Exohydrolase Activity in Perennial Ryegrass (Lolium perenne L.). AB - Despite the fact that fructans are the main constituent of water-soluble carbohydrates in forage grasses and cereal crops of temperate climates, little knowledge is available on the regulation of the enzymes involved in fructan metabolism. The analysis of enzyme activities involved in this process has been hampered by the low affinity of the fructan enzymes for sucrose and fructans used as fructosyl donor. Further, the analysis of fructan composition and enzyme activities is restricted to specialized labs with access to suited HPLC equipment and appropriate fructan standards. The degradation of fructan polymers with high degree of polymerization (DP) by fructan exohydrolases (FEHs) to fructosyloligomers is important to liberate energy in the form of fructan, but also under conditions where the generation of low DP polymers is required. Based on published protocols employing enzyme coupled endpoint reactions in single cuvettes, we developed a simple and fast kinetic 1-FEH assay. This assay can be performed in multi-well plate format using plate readers to determine the activity of 1-FEH against 1-kestotriose, resulting in a significant time reduction. Kinetic assays allow an optimal and more precise determination of enzyme activities compared to endpoint assays, and enable to check the quality of any reaction with respect to linearity of the assay. The enzyme coupled kinetic 1 FEH assay was validated in a case study showing the expected increase in 1-FEH activity during cold treatment. This assay is cost effective and could be performed by any lab with access to a plate reader suited for kinetic measurements and readings at 340 nm, and is highly suited to assess temporal changes and relative differences in 1-FEH activities. Thus, this enzyme coupled kinetic 1-FEH assay is of high importance both to the field of basic fructan research and plant breeding. PMID- 26734050 TI - Loss-of-Function Mutations in CsMLO1 Confer Durable Powdery Mildew Resistance in Cucumber (Cucumis sativus L.). AB - Powdery mildew (PM) is a serious fungal disease of cucumber worldwide. The identification of resistance genes is very important for resistance breeding to ensure cucumber production. Here, natural loss-of-function mutations at an MLO homologous locus, CsMLO1, were found to confer durable PM resistance in cucumber. CsMLO1 encoded a cell membrane protein, was mainly expressed in leaves and cotyledons, and was up-regulated by PM at the early stage of host-pathogen interaction. Ectopic expression of CsMLO1 rescued the phenotype of the PM resistant Atmlo2 Atmlo12 double mutant to PM susceptible in Arabidopsis. Domesticated and wild resistant cucumbers originating from various geographical regions of the world were found to harbor three independent natural mutations that resulted in CsMLO1 loss of function. In addition, between the near-isogenic lines (NILs) of PM resistant and susceptible, S1003 and NIL(Pm5.1), quantitative RT-PCR revealed that there is no difference at expression levels of several genes in the pathways of ethylene, jasmonic acid or salicylic acid. Moreover, the two NILs were used for transcriptome profiling to explore the mechanism underlying the resistance. Several genes correlated with plant cell wall thickening are possibly involved in the PM resistance. This study revealed that loss of function of CsMLO1 conferred durable PM resistance, and that this loss of function is necessary but alone may not be sufficient for PM resistance in cucumber. These findings will facilitate the molecular breeding of PM resistant varieties to control this destructive disease in cucumber. PMID- 26734051 TI - Constitutive Expression of OsIAA9 Affects Starch Granules Accumulation and Root Gravitropic Response in Arabidopsis. AB - Auxin/Indole-3-Acetic Acid (Aux/IAA) genes are early auxin response genes ecoding short-lived transcriptional repressors, which regulate auxin signaling in plants by interplay with Auxin Response Factors (ARFs). Most of the Aux/IAA proteins contain four different domains, namely Domain I, Domain II, Domain III, and Domain IV. So far all Aux/IAA mutants with auxin-related phenotypes identified in both Arabidopsis and rice (Oryza sativa) are dominant gain-of-function mutants with mutations in Domain II of the corresponding Aux/IAA proteins, suggest that Aux/IAA proteins in both Arabidopsis and rice are largely functional redundantly, and they may have conserved functions. We report here the functional characterization of a rice Aux/IAA gene, OsIAA9. RT-PCR results showed that expression of OsIAA9 was induced by exogenously applied auxin, suggesting that OsIAA9 is an auxin response gene. Bioinformatic analysis showed that OsIAA9 has a repressor motif in Domain I, a degron in Domain II, and the conserved amino acid signatures for protein-protein interactions in Domain III and Domain IV. By generating transgenic plants expressing GFP-OsIAA9 and examining florescence in the transgenic plants, we found that OsIAA9 is localized in the nucleus. When transfected into protoplasts isolated from rosette leaves of Arabidopsis, OsIAA9 repressed reporter gene expression, and the repression was partially released by exogenously IAA. These results suggest that OsIAA9 is a canonical Aux/IAA protein. Protoplast transfection assays showed that OsIAA9 interacted ARF5, but not ARF6, 7, 8 and 19. Transgenic Arabidopsis plants expressing OsIAA9 have increased number of lateral roots, and reduced gravitropic response. Further analysis showed that OsIAA9 transgenic Arabidopsis plants accumulated fewer granules in their root tips and the distribution of granules was also affected. Taken together, our study showed that OsIAA9 is a transcriptional repressor, and it regulates gravitropic response when expressed in Arabidopsis by regulating granules accumulation and distribution in root tips. PMID- 26734053 TI - Comparative Transcriptome Analysis of Resistant and Susceptible Tomato Lines in Response to Infection by Xanthomonas perforans Race T3. AB - Bacterial spot, incited by several Xanthomonas sp., is a serious disease in tomato (Solanum lycopersicum L.). Although genetics of resistance has been widely investigated, the interactions between the pathogen and tomato plants remain unclear. In this study, tanscriptomes of X. perforans race T3 infected tomato lines were compared to those of controls. An average of 7 million reads were generated with approximately 21,526 genes mapped in each sample post-inoculation at 6 h (6 HPI) and 6 days (6 DPI) using RNA-sequencing technology. Overall, the numbers of differentially expressed genes (DEGs) were higher in the resistant tomato line PI 114490 than in the susceptible line OH 88119, and the numbers of DEGs were higher at 6 DPI than at 6 HPI. Fewer genes (78 in PI 114490 and 15 in OH 88119) were up-regulated and most DEGs were down-regulated, suggesting that the inducible defense response might not be fully activated at 6 HPI. Accumulation expression levels of 326 co-up regulated genes in both tomato lines at 6 DPI might be involved in basal defense, while the specific and strongly induced genes at 6 DPI might be correlated with the resistance in PI 114490. Most DEGs were involved in plant hormone signal transduction, plant-pathogen interaction and phenylalanine metabolism, and the genes significantly up regulated in PI 114490 at 6 DPI were associated with defense response pathways. DEGs containing NBS-LRR domain or defense-related WRKY transcription factors were also identified. The results will provide a valuable resource for understanding the interactions between X. perforans and tomato plants. PMID- 26734052 TI - Transcriptional Regulatory Network Analysis of MYB Transcription Factor Family Genes in Rice. AB - MYB transcription factor (TF) is one of the largest TF families and regulates defense responses to various stresses, hormone signaling as well as many metabolic and developmental processes in plants. Understanding these regulatory hierarchies of gene expression networks in response to developmental and environmental cues is a major challenge due to the complex interactions between the genetic elements. Correlation analyses are useful to unravel co-regulated gene pairs governing biological process as well as identification of new candidate hub genes in response to these complex processes. High throughput expression profiling data are highly useful for construction of co-expression networks. In the present study, we utilized transcriptome data for comprehensive regulatory network studies of MYB TFs by "top-down" and "guide-gene" approaches. More than 50% of OsMYBs were strongly correlated under 50 experimental conditions with 51 hub genes via "top-down" approach. Further, clusters were identified using Markov Clustering (MCL). To maximize the clustering performance, parameter evaluation of the MCL inflation score (I) was performed in terms of enriched GO categories by measuring F-score. Comparison of co-expressed cluster and clads analyzed from phylogenetic analysis signifies their evolutionarily conserved co regulatory role. We utilized compendium of known interaction and biological role with Gene Ontology enrichment analysis to hypothesize function of coexpressed OsMYBs. In the other part, the transcriptional regulatory network analysis by "guide-gene" approach revealed 40 putative targets of 26 OsMYB TF hubs with high correlation value utilizing 815 microarray data. The putative targets with MYB binding cis-elements enrichment in their promoter region, functional co occurrence as well as nuclear localization supports our finding. Specially, enrichment of MYB binding regions involved in drought-inducibility implying their regulatory role in drought response in rice. Thus, the co-regulatory network analysis facilitated the identification of complex OsMYB regulatory networks, and candidate target regulon genes of selected guide MYB genes. The results contribute to the candidate gene screening, and experimentally testable hypotheses for potential regulatory MYB TFs, and their targets under stress conditions. PMID- 26734054 TI - Editorial: Doubled Haploidy in Model and Recalcitrant Species. PMID- 26734056 TI - Epigenetic Control of Cell Division and Cell Differentiation in the Root Apex. AB - Epigenetics is defined as heritable changes in gene expression and genome integrity that are accompanied by no alteration in DNA sequence. Throughout plant life cycle, many processes, including genome imprinting, stress responses, and cellular differentiation, are known to be determined by epigenetic regulation. The root apex is also considered to be under the control of epigenetic regulation for optimal growth under variable environments. Recent reports reveal that epigenetic control is especially important in the stem cell niche and the meristematic zone where both cell production and cell specification occur. DNA methylation, histone methylation, and histone acetylation are well-known epigenetic modifications, and each epigenetic modification has distinct roles in roots. Here, we review the updated findings that demonstrate the significance of epigenetic regulation in root apex of Arabidopsis. PMID- 26734055 TI - A Bird's-Eye View of Molecular Changes in Plant Gravitropism Using Omics Techniques. AB - During evolution, plants have developed mechanisms to adapt to a variety of environmental stresses, including drought, high salinity, changes in carbon dioxide levels and pathogens. Central signaling hubs and pathways that are regulated in response to these stimuli have been identified. In contrast to these well studied environmental stimuli, changes in transcript, protein and metabolite levels in response to a gravitational stimulus are less well understood. Amyloplasts, localized in statocytes of the root tip, in mesophyll cells of coleoptiles and in the elongation zone of the growing internodes comprise statoliths in higher plants. Deviations of the statocytes with respect to the earthly gravity vector lead to a displacement of statoliths relative to the cell due to their inertia and thus to gravity perception. Downstream signaling events, including the conversion from the biophysical signal of sedimentation of distinct heavy mass to a biochemical signal, however, remain elusive. More recently, technical advances, including clinostats, drop towers, parabolic flights, satellites, and the International Space Station, allowed researchers to study the effect of altered gravity conditions - real and simulated micro- as well as hypergravity on plants. This allows for a unique opportunity to study plant responses to a purely anthropogenic stress for which no evolutionary program exists. Furthermore, the requirement for plants as food and oxygen sources during prolonged manned space explorations led to an increased interest in the identi fication of genes involved in the adaptation of plants to microgravity. Transcriptomic, proteomic, phosphoproteomic, and metabolomic profiling strategies provide a sensitive high-throughput approach to identify biochemical alterations in response to changes with respect to the influence of the gravitational vector and thus the acting gravitational force on the transcript, protein and metabolite level. This review aims at summarizing recent experimental approaches and discusses major observations. PMID- 26734058 TI - Differential Occurrence of Interactions and Interaction Domains in Proteins Containing Homopolymeric Amino Acid Repeats. AB - Homopolymeric amino acids repeats (AARs), which are widespread in proteomes, have often been viewed simply as spacers between protein domains, or even as "junk" sequences with no obvious function but with a potential to cause harm upon expansion as in genetic diseases associated with polyglutamine or polyalanine expansions, including Huntington disease and cleidocranial dysplasia. A growing body of evidence indicates however that at least some AARs can form organized, functional protein structures, and can regulate protein function. In particular, certain AARs can mediate protein-protein interactions, either through homotypic AAR-AAR contacts or through heterotypic contacts with other protein domains. It is still unclear however, whether AARs may have a generalized, proteome-wide role in shaping protein-protein interaction networks. Therefore, we have undertaken here a bioinformatics screening of the human proteome and interactome in search of quantitative evidence of such a role. We first identified the sets of proteins that contain repeats of any one of the 20 amino acids, as well as control sets of proteins chosen at random in the proteome. We then analyzed the connectivity between the proteins of the AAR-containing protein sets and we compared it with that observed in the corresponding control networks. We find evidence for different degrees of connectivity in the different AAR-containing protein networks. Indeed, networks of proteins containing polyglutamine, polyglutamate, polyproline, and other AARs show significantly increased levels of connectivity, whereas networks containing polyleucine and other hydrophobic repeats show lower degrees of connectivity. Furthermore, we observed that numerous protein-protein, nucleic acid, and -lipid interaction domains are significantly enriched in specific AAR protein groups. These findings support the notion of a generalized, combinatorial role of AARs, together with conventional protein interaction domains, in shaping the interaction networks of the human proteome, and define proteome-wide knowledge that may guide the informed biological exploration of the role of AARs in protein interactions. PMID- 26734057 TI - Comparing Gene Expression Profiles Between Bt and non-Bt Rice in Response to Brown Planthopper Infestation. AB - Bt proteins are the most widely used insecticidal proteins in transgenic crops for improving insect resistance. We previously observed longer nymphal developmental duration and lower fecundity in brown planthopper (BPH) fed on Bt rice line KMD2, although Bt insecticidal protein Cry1Ab could rarely concentrate in this non-target rice pest. In the present study, we performed microarray analysis in an effort to detect Bt-independent variation, which might render Bt rice more defensive and/or less nutritious to BPH. We detected 3834 and 3273 differentially expressed probe-sets in response to BPH infestation in non-Bt parent Xiushui 11 and Bt rice KMD2, respectively, only 439 of which showed significant differences in expression between rice lines. Our analysis revealed a shift from growth to defense responses in response to BPH infestation, which was also detected in many other studies of plants suffering biotic and abiotic stresses. Chlorophyll biosynthesis and basic metabolism pathways were inhibited in response to infestation. IAA and GA levels decreased as a result of the repression of biosynthesis-related genes or the induction of inactivation-related genes. In accordance with these observations, a number of IAA-, GA-, BR-signaling genes were downregulated in response to BPH. Thus, the growth of rice plants under BPH attack was reduced and defense related hormone signaling like JA, SA and ET were activated. In addition, growth-related hormone signaling pathways, such as GA, BR, and auxin signaling pathways, as well as ABA, were also found to be involved in BPH-induced defense. On the other side, 51 probe-sets (represented 50 genes) that most likely contribute to the impact of Bt rice on BPH were identified, including three early nodulin genes, four lipid metabolic genes, 14 stress response genes, three TF genes and genes with other functions. Two transcription factor genes, bHLH and MYB, together with lipid transfer protein genes LTPL65 and early nodulin gene ENOD93, are the most likely candidates for improving herbivore resistance in plants. PMID- 26734059 TI - Next-Generation Sequencing for Binary Protein-Protein Interactions. AB - The yeast two-hybrid (Y2H) system exploits host cell genetics in order to display binary protein-protein interactions (PPIs) via defined and selectable phenotypes. Numerous improvements have been made to this method, adapting the screening principle for diverse applications, including drug discovery and the scale-up for proteome wide interaction screens in human and other organisms. Here we discuss a systematic workflow and analysis scheme for screening data generated by Y2H and related assays that includes high-throughput selection procedures, readout of comprehensive results via next-generation sequencing (NGS), and the interpretation of interaction data via quantitative statistics. The novel assays and tools will serve the broader scientific community to harness the power of NGS technology to address PPI networks in health and disease. We discuss examples of how this next-generation platform can be applied to address specific questions in diverse fields of biology and medicine. PMID- 26734061 TI - Partial Least Squares Regression Can Aid in Detecting Differential Abundance of Multiple Features in Sets of Metagenomic Samples. AB - It is now feasible to examine the composition and diversity of microbial communities (i.e., "microbiomes") that populate different human organs and orifices using DNA sequencing and related technologies. To explore the potential links between changes in microbial communities and various diseases in the human body, it is essential to test associations involving different species within and across microbiomes, environmental settings and disease states. Although a number of statistical techniques exist for carrying out relevant analyses, it is unclear which of these techniques exhibit the greatest statistical power to detect associations given the complexity of most microbiome datasets. We compared the statistical power of principal component regression, partial least squares regression, regularized regression, distance-based regression, Hill's diversity measures, and a modified test implemented in the popular and widely used microbiome analysis methodology "Metastats" across a wide range of simulated scenarios involving changes in feature abundance between two sets of metagenomic samples. For this purpose, simulation studies were used to change the abundance of microbial species in a real dataset from a published study examining human hands. Each technique was applied to the same data, and its ability to detect the simulated change in abundance was assessed. We hypothesized that a small subset of methods would outperform the rest in terms of the statistical power. Indeed, we found that the Metastats technique modified to accommodate multivariate analysis and partial least squares regression yielded high power under the models and data sets we studied. The statistical power of diversity measure-based tests, distance-based regression and regularized regression was significantly lower. Our results provide insight into powerful analysis strategies that utilize information on species counts from large microbiome data sets exhibiting skewed frequency distributions obtained on a small to moderate number of samples. PMID- 26734060 TI - The Road to Metagenomics: From Microbiology to DNA Sequencing Technologies and Bioinformatics. AB - The study of microorganisms that pervade each and every part of this planet has encountered many challenges through time such as the discovery of unknown organisms and the understanding of how they interact with their environment. The aim of this review is to take the reader along the timeline and major milestones that led us to modern metagenomics. This new and thriving area is likely to be an important contributor to solve different problems. The transition from classical microbiology to modern metagenomics studies has required the development of new branches of knowledge and specialization. Here, we will review how the availability of high-throughput sequencing technologies has transformed microbiology and bioinformatics and how to tackle the inherent computational challenges that arise from the DNA sequencing revolution. New computational methods are constantly developed to collect, process, and extract useful biological information from a variety of samples and complex datasets, but metagenomics needs the integration of several of these computational methods. Despite the level of specialization needed in bioinformatics, it is important that life-scientists have a good understanding of it for a correct experimental design, which allows them to reveal the information in a metagenome. PMID- 26734062 TI - Addressing Bias in Small RNA Library Preparation for Sequencing: A New Protocol Recovers MicroRNAs that Evade Capture by Current Methods. AB - Recent advances in sequencing technology have helped unveil the unexpected complexity and diversity of small RNAs. A critical step in small RNA library preparation for sequencing is the ligation of adapter sequences to both the 5' and 3' ends of small RNAs. Studies have shown that adapter ligation introduces a significant but widely unappreciated bias in the results of high-throughput small RNA sequencing. We show that due to this bias the two widely used Illumina library preparation protocols produce strikingly different microRNA (miRNA) expression profiles in the same batch of cells. There are 102 highly expressed miRNAs that are >5-fold differentially detected and some miRNAs, such as miR-24 3p, are over 30-fold differentially detected. While some level of bias in library preparation is not surprising, the apparent massive differential bias between these two widely used adapter sets is not well appreciated. In an attempt to mitigate this bias, the new Bioo Scientific NEXTflex V2 protocol utilizes a pool of adapters with random nucleotides at the ligation boundary. We show that this protocol is able to detect robustly several miRNAs that evade capture by the Illumina-based methods. While these analyses do not indicate a definitive gold standard for small RNA library preparation, the results of the NEXTflex protocol do correlate best with RT-qPCR. As increasingly more laboratories seek to study small RNAs, researchers should be aware of the extent to which the results may differ with different protocols, and should make an informed decision about the protocol that best fits their study. PMID- 26734063 TI - The (Mathematical) Modeling Process in Biosciences. AB - In this communication, we introduce a general framework and discussion on the role of models and the modeling process in the field of biosciences. The objective is to sum up the common procedures during the formalization and analysis of a biological problem from the perspective of Systems Biology, which approaches the study of biological systems as a whole. We begin by presenting the definitions of (biological) system and model. Particular attention is given to the meaning of mathematical model within the context of biology. Then, we present the process of modeling and analysis of biological systems. Three stages are described in detail: conceptualization of the biological system into a model, mathematical formalization of the previous conceptual model and optimization and system management derived from the analysis of the mathematical model. All along this work the main features and shortcomings of the process are analyzed and a set of rules that could help in the task of modeling any biological system are presented. Special regard is given to the formative requirements and the interdisciplinary nature of this approach. We conclude with some general considerations on the challenges that modeling is posing to current biology. PMID- 26734064 TI - Editorial: Cancer-Associated Defects in the DNA Damage Response: Drivers for Malignant Transformation and Potential Therapeutic Targets. PMID- 26734065 TI - Sensitization to common aeroallergens in a population of young adults in a sub Saharan Africa setting: a cross-sectional study. AB - BACKGROUND: Sensitization to aeroallergens increases the risk of developing asthma or allergic rhinitis. Data on sensitization to airborne allergens in the general population in sub-Saharan Africa are lacking. The aim of this study was to determine the prevalence and determinants of sensitization to common aeroallergens in a population of young adults. METHODS: A cross-sectional study was conducted among students of the Faculty of Medicine and Pharmaceutical Sciences of the University of Douala between 1st February and 30th April 2014. We consecutively recruited all the students present in class or in hospital during our visit. They filled an anonymous questionnaire and underwent skin prick tests with common aeroallergens. A logistic regression model of the SPSS.20 software was used to investigate factors associated with sensitization to common aeroallergens. RESULTS: Of the 600 students included in the study, 305 (50.8 %) were female. The mean age of participants was 22.6 +/- 2.7 years. The prevalence of sensitization to aeroallergens was 42.8 % (95 % CI 38.8-46.8). Dermatophagoides pteronyssimus (24.2 %), Dermatophagoides farinae (22.8 %), Blomia tropicalis (23.3 %) and Blatella germanica (15.2 %) were the most common allergens found. Allergic rhinitis, asthma symptoms and family atopy were independently associated to sensitization to common aeroallergens. CONCLUSION: A significant proportion of young adults are sensitized to common aeroallergens. Dust mites and cockroach should be included in the panel of aeroallergens in Cameroon. PMID- 26734066 TI - Cytomegalovirus viral load within blood increases markedly in healthy people over the age of 70 years. AB - BACKGROUND: Cytomegalovirus (CMV) is a highly prevalent herpesvirus, which maintains lifelong latency and places a significant burden on host immunity. Infection is associated with increased rates of vascular disease and overall mortality in the elderly and there is an urgent need for improved understanding of the viral-host balance during ageing. CMV is extremely difficult to detect in healthy donors, however, using droplet digital PCR of DNA from peripheral blood monocytes, we obtained an absolute quantification of viral load in 44 healthy donors across a range of ages. RESULTS: Viral DNA was detected in 24 % (9/37) of donors below the age of 70 but was found in all individuals above this age. Furthermore, the mean CMV load was only 8.6 copies per 10,000 monocytes until approximately 70 years of age when it increased by almost 30 fold to 249 copies in older individuals (p < 0.0001). CMV was found within classical CD14+ monocytes and was not detectable within the CD14-CD16+ subset. The titre of CMV-specific IgG increased inexorably with age indicating that loss of humoral immunity is not a determinant of the increased viral load. In contrast, although cellular immunity to the structural late protein pp65 increased with age, the T cell response to the immediate early protein IE1 decreased in older donors. CONCLUSION: These data reveal that effective control of CMV is impaired during healthy ageing, most probably due to loss of cellular control of early viral reactivation. This information will be of value in guiding efforts to reduce CMV associated health complications in the elderly. PMID- 26734067 TI - Spectrum of false positivity for the fourth generation human immunodeficiency virus diagnostic tests. AB - Novel fourth generation screening and confirmatory human immunodeficiency virus (HIV) assays are now commercially available and incorporated into new diagnostic algorithms. We report two cases involving a total of three patients which highlight the spectrum of false positivity for both the Abbott Architect p24 antigen/antibody assay and the confirmatory Multispot antibody differentiation test. We then discuss the mechanisms for false positivity and the associated clinical conditions or laboratory scenarios that may predispose to inaccurate interpretation. PMID- 26734068 TI - Intraoperative diagnosis of solitary cecal diverticulum not requiring surgery: is appendectomy indicated? AB - AIM: To compare experience with solitary cecal diverticulum (SCD) with literature on the indication for appendectomy in cases of solitary cecal diverticulitis. METHODS: We retrospectively reviewed all cases of SCD in our institution from September 2011 to March 2013. Data on sex, age, ethnic origin, presence of pain in the right iliac fossa, duration of symptoms, diagnosis, management, intraoperative findings, histologic examination, hospital stay, complications, and follow-up were reviewed and analyzed. We compared this to related literature reported between 2000 and 2015. RESULTS: In the study period, 10 patients presented with an SCD. Male sex and Asian origin were predominant. All patients had pain in the right iliac fossa, with a duration of 2-5 days. In nine cases the diagnosis was made by clinical examination and laboratory testing. One patient who had undergone a previous appendectomy was diagnosed with SCD by computed tomography. This last patient was treated conservatively, four patients were treated with resection of the cecum "en bloc" with the last jejunal loop and appendix, and the other five patients were treated with appendectomies. Two patients had minor complications. All patients were followed up for a minimum of 12 to a maximum of 24 months. No recurrence was recorded in either the case treated conservatively or the cases treated by appendectomies. CONCLUSIONS: In cases of operative but conservative treatment for SCD, appendectomy could be justified to avoid misdiagnosis in case of future episodes of solitary cecal diverticulitis. PMID- 26734069 TI - Obese patients who fall have less injury severity but a longer hospital stay than normal-weight patients. AB - BACKGROUND: The effects of obesity on injury severity and outcome have been studied in trauma patients but not in those who have experienced a fall. The aim of this study was to compare injury patterns, injury severities, mortality rates, and in-hospital or intensive care unit (ICU) length of stay (LOS) between obese and normal-weight patients following a fall. METHODS: Detailed data were retrieved for 273 fall-related hospitalized obese adult patients with a body mass index (BMI) >=30 kg/m(2) and 2357 normal-weight patients with a BMI <25 kg/m(2) but >=18.5 kg/m(2) from the Trauma Registry System of a Level I trauma center between January 1, 2009, and December 31, 2013. We used the Pearson's chi-squared test, Fisher's exact test, the Mann Whitney U test, and independent Student's t test to analyze differences between the two groups. RESULTS: Analysis of AIS scores and AIS severity scaling from 1 to 5 revealed no significant differences in trauma regions between obese and normal-weight patients. When stratified by injury severity (Injury Severity Score [ISS] of <16, 16-24, or >=25), more obese patients had an ISS of <16 compared to normal-weight patients (90.5 % vs. 86.0 %, respectively; p = 0.041), while more normal-weight patients had an ISS between 16 and 24 (11.0 % vs. 6.6 %, respectively; p = 0.025). Obese patients who had experienced a fall had a significantly lower ISS (median (range): 9 (1-45) vs. 9 (1-50), respectively; p = 0.015) but longer in-hospital LOS than did normal weight patients (10.1 days vs. 8.9 days, respectively; p = 0.049). Even after taking account of possible differences in comorbidity and ISS, the obese patients have an average 1.54 day longer LOS than that of normal-weight patients. However, no significant differences were found between obese and normal-weight patients in terms of the New Injury Severity Score (NISS), Trauma-Injury Severity Score (TRISS), mortality, percentage of patients admitted to the ICU, or LOS in the ICU. CONCLUSION: Obese patients who had experienced a fall did not have different injured body regions than did normal-weight patients. However, they had a lower ISS but a longer in-hospital LOS than did normal-weight patients. PMID- 26734070 TI - Overview of the mental health system in Mozambique: addressing the treatment gap with a task-shifting strategy in primary care. AB - BACKGROUND: Mozambique has gradually changed its action on mental health (MH) from an asylum-centric care with long-term hospitalization to an innovative approach to community and primary care. OBJECTIVE: To collect essential information on Mozambique's MH system for decision making, to improve quality of services delivered, update MH Strategy and Action Plan. METHOD: The study used the WHO-AIMS to assess MH systems including policy and legislation, organization of services, MH in primary care, human resources, public education and link with other sectors, monitoring and research. A comparative analysis was conducted to present the evolution of relevant data from 2010 to 2014. RESULTS: There are two psychiatric hospitals in the country and beds in general hospitals. In the period, the number of beds in general hospitals remained stable (203), and the beds in psychiatric hospitals increased from 173 to 298. Mental health outpatient facilities have increased from 83 to 152. The number of psychiatrists (9 in 2010, and 10 in 2014) remained very low, with a significant increase in the number of psychologists (56-109) and occupational therapists (2-23). The number of Psychiatric Technicians has increased from 66 in 2010, to 241 in 2014. This increase allowed the mental health network to expand from 60 to 135 Districts, meaning an increase of coverage from 44 to 100 % of the country districts. CONCLUSION: The task-shifting strategy focused on services delivered in primary care by psychiatric technicians, mid-level professionals, allowed the expansion of mental health services for all the country districts and the reduction of treatment gap in Mozambique. PMID- 26734071 TI - Techno-economic evaluation of integrated first- and second-generation ethanol production from grain and straw. AB - BACKGROUND: Integration of first- and second-generation ethanol production can facilitate the introduction of second-generation lignocellulosic ethanol production. Consolidation of the second-generation with the first-generation process can potentially reduce the downstream processing cost for the second generation process as well as providing the first-generation process with energy. This study presents novel experimental results from integrated first- and second generation ethanol production from grain and wheat straw in a process development unit. The results were used in techno-economic evaluations to investigate the feasibility of the plant, in which the main co-products were distiller's dried grains with solubles and biogas. RESULTS: An overall glucose to ethanol yield, of 81 % of the theoretical, based on glucose available in the raw material, was achieved in the experiments. A positive net present value was found for all the base case scenarios and the minimal ethanol selling price varied between 0.45 and 0.53 EUR/L ethanol. The revenue increased with combined xylose and glucose fermentation and biogas upgrading to vehicle fuel quality. A decrease in the biogas yield from 80 to 60 % also largely affects the net present value. The energy efficiency for the energy content in products available for sale compared with the incoming energy content varied from 74 to 80 %. CONCLUSIONS: One of the two main configurations can be chosen when designing an integrated first- and second-generation ethanol production plant from grain and straw: that producing biogas or that producing distiller's dried grains with solubles from the xylose sugars. The choice depends mainly on the local market and prices for distiller's dried grains with solubles and biogas, since the prices for both co-products have fluctuated a great deal in recent years. In the current study, however, distiller's dried grains with solubles were found to be a more promising co product than biogas, if the biogas was not upgraded to vehicle fuel quality. It was also concluded that additional experimental data from biogas production using first- and second-generation substrates are required to obtain improved economic evaluations. PMID- 26734072 TI - A GH115 alpha-glucuronidase from Schizophyllum commune contributes to the synergistic enzymatic deconstruction of softwood glucuronoarabinoxylan. AB - BACKGROUND: Lignocellulosic biomass from softwood represents a valuable resource for the production of biofuels and bio-based materials as alternatives to traditional pulp and paper products. Hemicelluloses constitute an extremely heterogeneous fraction of the plant cell wall, as their molecular structures involve multiple monosaccharide components, glycosidic linkages, and decoration patterns. The complete enzymatic hydrolysis of wood hemicelluloses into monosaccharides is therefore a complex biochemical process that requires the activities of multiple degradative enzymes with complementary activities tailored to the structural features of a particular substrate. Glucuronoarabinoxylan (GAX) is a major hemicellulose component in softwood, and its structural complexity requires more enzyme specificities to achieve complete hydrolysis compared to glucuronoxylans from hardwood and arabinoxylans from grasses. RESULTS: We report the characterisation of a recombinant alpha-glucuronidase (Agu115) from Schizophyllum commune capable of removing (4-O-methyl)-glucuronic acid ((Me)GlcA) residues from polymeric and oligomeric xylan. The enzyme is required for the complete deconstruction of spruce glucuronoarabinoxylan (GAX) and acts synergistically with other xylan-degrading enzymes, specifically a xylanase (Xyn10C), an alpha-l-arabinofuranosidase (AbfA), and a beta-xylosidase (XynB). Each enzyme in this mixture showed varying degrees of potentiation by the other activities, likely due to increased physical access to their respective target monosaccharides. The exo-acting Agu115 and AbfA were unable to remove all of their respective target side chain decorations from GAX, but their specific activity was significantly boosted by the addition of the endo-Xyn10C xylanase. We demonstrate that the proposed enzymatic cocktail (Agu115 with AbfA, Xyn10C and XynB) achieved almost complete conversion of GAX to arabinofuranose (Araf), xylopyranose (Xylp), and MeGlcA monosaccharides. Addition of Agu115 to the enzymatic cocktail contributes specifically to 25 % of the conversion. However, traces of residual oligosaccharides resistant to this combination of enzymes were still present after deconstruction, due to steric hindrances to enzyme access to the substrate. CONCLUSIONS: Our GH115 alpha-glucuronidase is capable of finely tailoring the molecular structure of softwood GAX, and contributes to the almost complete saccharification of GAX in synergy with other exo- and endo-xylan-acting enzymes. This has great relevance for the cost-efficient production of biofuels from softwood lignocellulose. PMID- 26734073 TI - Overcoming substrate limitations for improved production of ethylene in E. coli. AB - BACKGROUND: Ethylene is an important industrial compound for the production of a wide variety of plastics and chemicals. At present, ethylene production involves steam cracking of a fossil-based feedstock, representing the highest CO2-emitting process in the chemical industry. Biological ethylene production can be achieved via expression of a single protein, the ethylene-forming enzyme (EFE), found in some bacteria and fungi; it has the potential to provide a sustainable alternative to steam cracking, provided that significant increases in productivity can be achieved. A key barrier is determining factors that influence the availability of substrates for the EFE reaction in potential microbial hosts. In the presence of O2, EFE catalyzes ethylene formation from the substrates alpha ketoglutarate (AKG) and arginine. The concentrations of AKG, a key TCA cycle intermediate, and arginine are tightly controlled by an intricate regulatory system that coordinates carbon and nitrogen metabolism. Therefore, reliably predicting which genetic changes will ultimately lead to increased AKG and arginine availability is challenging. RESULTS: We systematically explored the effects of media composition (rich versus defined), gene copy number, and the addition of exogenous substrates and other metabolites on the formation of ethylene in Escherichia coli expressing EFE. Guided by these results, we tested a number of genetic modifications predicted to improve substrate supply and ethylene production, including knockout of competing pathways and overexpression of key enzymes. Several such modifications led to higher AKG levels and higher ethylene productivity, with the best performing strain more than doubling ethylene productivity (from 81 +/- 3 to 188 +/- 13 nmol/OD600/mL). CONCLUSIONS: Both EFE activity and substrate supply can be limiting factors in ethylene production. Targeted modifications in central carbon metabolism, such as overexpression of isocitrate dehydrogenase, and deletion of glutamate synthase or the transcription regulator ArgR, can effectively enhance substrate supply and ethylene productivity. These results not only provide insight into the intricate regulatory network of the TCA cycle, but also guide future pathway and genome scale engineering efforts to further boost ethylene productivity. PMID- 26734074 TI - A call for biological data mining approaches in epidemiology. PMID- 26734075 TI - Effects of nateglinide and rosiglitazone on pancreatic alpha- and beta-cells, GLP 1 secretion and inflammatory markers in patients with type 2 diabetes: randomized crossover clinical study. AB - BACKGROUND: To compare the effects of nateglinide and rosiglitazone on inflammatory markers, GLP-1 levels and metabolic profile in patients with type 2 diabetes (DM2). METHODS: A prospective study was performed in 20 patients with DM2, mean age 51.82 +/- 8.05 years, previously treated with dietary intervention. Participants were randomized into rosiglitazone (4-8 mg/day) or nateglinide (120 mg 3 times a day) therapy. After 4 months, the patients were crossed-over with 8 weeks washout period to the alternative treatment for an additional 4-month period on similar dosage schedule. The following variables were assessed before and after 4 months of each treatment period: (1) a test with a standardized 500 calories meal for 5 h including frequent measurements of glucose, insulin, glucagon, proinsulin, GLP-1, free fat acids (FFA), and triglycerides levels was obtained. The lipid profile and HbA1 levels were measured at fasting. (2) Haemostatic and inflammatory markers: platelet aggregation, fibrinogen, PAI-1 activity, C reactive protein (CRP), IL-6, TNF-alpha, leptin, sICAM and TGFbeta levels. RESULTS: Both therapy decreased blood glucose levels under the postprandial curve but neither affected glucagon and GLP-1 levels. Nateglinide was associated with higher insulin and pro-insulin secretion, but similar pro insulin/insulin ratio when compared with rosiglitazone. Only rosiglitazone decreased Homa beta, PAI-1 activity, CRP, fibrinogen, TGFbeta, FFA and triglyceride levels. CONCLUSIONS: Nateglinide and rosiglitazone were effective in improving glucose and lipid profile and beta cell function, but rosiglitazone afforded a better anti-inflammatory effect. No drug restored alpha cell sensitivity or changed GLP-1 levels. Maintenance of haemostatic factors, inflammatory factors and glucagon levels can be related to the continuously worsening of cardiovascular function and glucose control observed in DM2. PMID- 26734076 TI - Recent developments in copper-catalyzed radical alkylations of electron-rich pi systems. AB - Recently, a number of papers have emerged demonstrating copper-catalyzed alkylation reactions of electron-rich small molecules. The processes are generally thought to be related to long established atom-transfer radical reactions. However, unlike classical reactions, these new transformations lead to simple alkylation products. This short review will highlight recent advances in alkylations of nitronate anions, alkenes and alkynes, as well as discuss current mechanistic understanding of these novel reactions. PMID- 26734077 TI - Synthesis of D-fructose-derived spirocyclic 2-substituted-2-oxazoline ribosides. AB - The TMSOTf-mediated synthesis of beta-configured spirocyclic 2-substituted-2 oxazoline ribosides was achieved using a "Ritter-like" reaction in toluene through nucleophilic addition of electron-rich nitriles to the oxacarbenium ion intermediate of 1,2;3,4-di-O-isopropylidene-beta-D-psicofuranose derivatives with concomitant intramolecular trapping of the C2 hydroxymethyl group on the electrophilic nitrilium carbon. These carbohydrate-derived spirooxazolines are stable and were obtained in good yield with high stereoselectivity due to the conformational rigidity imparted by the 3,4-isopropylidene group. PMID- 26734078 TI - Cu(I)-catalyzed N,N'-diarylation of natural diamines and polyamines with aryl iodides. AB - The Cu(I)-catalyzed N,N'-diarylation of natural diamines and polyamines such as putrescine, cadaverine, spermine, spermidine and their homologues is described. Aryl iodides bearing electron-donating and electron-withdrawing groups have been employed in the study. The CuI/2-(isobutyryl)cyclohexanone/DMF catalytic system has found to be more efficient in the diarylation of diamines and spermine while the CuI/L-proline/EtCN system proved to be preferable for the diarylation of other tri- and tetraamines like spermidine, norspermidine and norspermine. PMID- 26734079 TI - Co-solvation effect on the binding mode of the alpha-mangostin/beta-cyclodextrin inclusion complex. AB - Cyclodextrins (CDs) have been extensively utilized as host molecules to enhance the solubility, stability and bioavailability of hydrophobic drug molecules through the formation of inclusion complexes. It was previously reported that the use of co-solvents in such studies may result in ternary (host:guest:co-solvent) complex formation. The objective of this work was to investigate the effect of ethanol as a co-solvent on the inclusion complex formation between alpha mangostin (alpha-MGS) and beta-CD, using both experimental and theoretical studies. Experimental phase-solubility studies were carried out in order to assess complex formation, with the mechanism of association being probed using a mathematical model. It was found that alpha-MGS was poorly soluble at low ethanol concentrations (0-10% v/v), but higher concentrations (10-40% v/v) resulted in better alpha-MGS solubility at all beta-CD concentrations studied (0-10 mM). From the equilibrium constant calculation, the inclusion complex is still a binary complex (1:1), even in the presence of ethanol. The results from our theoretical study confirm that the binding mode is binary complex and the presence of ethanol as co-solvent enhances the solubility of alpha-MGS with some effects on the binding affinity with beta-CD, depending on the concentration employed. PMID- 26734080 TI - Efficient synthetic protocols for the preparation of common N-heterocyclic carbene precursors. AB - The one-pot condensation of glyoxal, two equivalents of cyclohexylamine, and paraformaldehyde in the presence of aqueous HBF4 provided a straightforward access to 1,3-dicyclohexylimidazolium tetrafluoroborate (ICy.HBF4). 1,3 Dibenzylimidazolium tetrafluoroborate (IBn.HBF4) was obtained along the same lines. To synthesize 1,3-diarylmidazolium salts, it was necessary to isolate the intermediate N,N'-diarylethylenediimines prior to their cyclization. Although this additional step required more time and reagents, it led to a much more efficient overall process. It also proved very convenient to carry out the synthesis of imidazolinium salts in parallel to their imidazolium counterparts via the reduction of the diimines into diammonium salts. The critical assembly of the C(2) precarbenic unit was best achieved with paraformaldehyde and chlorotrimethylsilane in the case of imidazolium derivatives, whereas the use of triethyl orthoformate under microwave irradiation was most appropriate for the fast and efficient synthesis of imidazolinium salts. This strategy was applied to the synthesis of six common N-heterocyclic carbene precursors, namely, 1,3 dimesitylimidazolium chloride (IMes.HCl), 1,3-dimesitylimidazolium tetrafluoroborate (IMes.HBF4), 1,3-dimesitylimidazolinium chloride (SIMes.HCl), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (IDip.HCl or IPr.HCl), 1,3 bis(2,6-diisopropylphenyl)imidazolinium chloride (SIDip.HCl or SIPr.HCl), and 1,3 bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazolium chloride (IDip*.HCl or IPr*.HCl). PMID- 26734081 TI - Syntheses of 2-substituted 1-amino-4-bromoanthraquinones (bromaminic acid analogues) - precursors for dyes and drugs. AB - Anthraquinone (AQ) derivatives play a prominent role in medicine and also in textile industry. Bromaminic acid (1-amino-4-bromoanthraquinone-2-sulfonic acid) is an important precursor for obtaining dyes as well as biologically active compounds through the replacement of the C4-bromo substituent with different (ar)alkylamino residues. Here we report methods for the synthesis of bromaminic acid analogues bearing different substituents at the 2-position of the anthraquinone core. 1-Aminoanthraquinone was converted to its 2-hydroxymethyl substituted derivative which, under different reaction conditions, yielded the corresponding carbaldehyde, carboxylic acid, and nitrile derivatives. The latter was further reacted to obtain 1-amino-2-tetrazolylanthraquinone. Subsequent bromination using bromine in DMF led to the corresponding bromaminic acid derivatives in excellent isolated yields (>90%) and high purities. Alternatively, 1-amino-4-bromo-2-hydroxymethylanthraquinone could be directly converted to the desired 2-substituted bromaminic acid analogues in high yields (85-100%). We additionally report the preparation of bromaminic acid sodium salt and 1-amino 2,4-dibromoanthraquinone directly from 1-aminoanthraquinone in excellent yields (94-100%) and high purities. The synthesized brominated AQs are valuable precursors for the preparation of AQ drugs and dyes. PMID- 26734082 TI - Bromotyrosine-derived alkaloids from the Caribbean sponge Aplysina lacunosa. AB - Three new bromotyrosine-derived alkaloids 14-debromo-11-deoxyfistularin-3 (1), aplysinin A (2), and aplysinin B (3), together with 15 known compounds (4-18) were isolated from the sponge Aplysina lacunosa collected from Stirrup Cay, Bahamas. The structures of the isolated compounds were identified on the basis of MS and NMR data analysis. The (13)C NMR assignment of spirocyclohexadienylisoxazoline moieties of 1 and 2 were confirmed by an 1,1 ADEQUATE experiment. Compounds 1 and 2 showed a mild to moderate cytotoxic activities against KB-31 and FS4-LTM cell lines. Only aplysinin A (2) exhibited cytotoxicity against MCF-7 cells. PMID- 26734083 TI - Urethane tetrathiafulvalene derivatives: synthesis, self-assembly and electrochemical properities. AB - This paper reports the self-assembly of two new tetrathiafulvalene (TTF) derivatives that contain one or two urethane groups. The formation of nanoribbons was evidenced by scanning electron microscopy (SEM) and X-ray diffraction (XRD), which showed that the self-assembly ability of T 1 was better than that of T 2 . The results revealed that more urethane groups in a molecule did not necessarily instigate self-assembly. UV-vis and FTIR spectra were measured to explore noncovalent interactions. The driving forces for self-assembly of TTF derivatives were mainly hydrogen bond interactions and pi-pi stacking interactions. The electronic conductivity of the T 1 and T 2 films was tested by a four-probe method. PMID- 26734084 TI - Life lessons. AB - Reminiscing about his younger self: "I mean I can't very well just 86 [in American slang, to "86" is to eject, remove, or discard someone or something, J.R.N.] this guy from my life. On the other hand, if through some as yet undeveloped technology I were to run into him today, how comfortable would I feel about lending him money, or for that matter even stepping down the street to have a beer and talk over old times?" - Thomas Pynchon, Slow Learner. PMID- 26734085 TI - Preparation of Pickering emulsions through interfacial adsorption by soft cyclodextrin nanogels. AB - BACKGROUND: Emulsions stabilized by colloidal particles are known as Pickering emulsions. To date, soft microgel particles as well as inorganic and organic particles have been utilized as Pickering emulsifiers. Although cyclodextrin (CD) works as an attractive emulsion stabilizer through the formation of a CD-oil complex at the oil-water interface, a high concentration of CD is normally required. Our research focuses on an effective Pickering emulsifier based on a soft colloidal CD polymer (CD nanogel) with a unique surface-active property. RESULTS: CD nanogels were prepared by crosslinking heptakis(2,6-di-O-methyl)-beta cyclodextrin with phenyl diisocyanate and subsequent immersion of the resulting polymer in water. A dynamic light scattering study shows that primary CD nanogels with 30-50 nm diameter assemble into larger CD nanogels with 120 nm diameter by an increase in the concentration of CD nanogel from 0.01 to 0.1 wt %. The CD nanogel has a surface-active property at the air-water interface, which reduces the surface tension of water. The CD nanogel works as an effective Pickering emulsion stabilizer even at a low concentration (0.1 wt %), forming stable oil-in water emulsions through interfacial adsorption by the CD nanogels. CONCLUSION: Soft CD nanogel particles adsorb at the oil-water interface with an effective coverage by forming a strong interconnected network and form a stable Pickering emulsion. The adsorption property of CD nanogels on the droplet surface has great potential to become new microcapsule building blocks with porous surfaces. These microcapsules may act as stimuli-responsive nanocarriers and nanocontainers. PMID- 26734086 TI - A concise and efficient synthesis of benzimidazo[1,2-c]quinazolines through CuI catalyzed intramolecular N-arylations. AB - A series of functionalized benzimidazo[1,2-c]quinazoline derivatives was obtained in excellent yields under mild conditions through a CuI-catalyzed Ullmann N arylation starting from easily available starting materials. PMID- 26734088 TI - Copper-catalyzed arylation of alkyl halides with arylaluminum reagents. AB - We report a Cu-catalyzed coupling between triarylaluminum reagents and alkyl halides to form arylalkanes. The reaction proceeds in the presence of N,N,N',N' tetramethyl-o-phenylenediamine (NN-1) as a ligand in combination with CuI as a catalyst. This catalyst system enables the coupling of primary alkyl iodides and bromides with electron-neutral and electron-rich triarylaluminum reagents and affords the cross-coupled products in good to excellent yields. PMID- 26734089 TI - Continuous formation of N-chloro-N,N-dialkylamine solutions in well-mixed meso scale flow reactors. AB - The continuous flow synthesis of a range of organic solutions of N,N-dialkyl-N chloramines is described using either a bespoke meso-scale tubular reactor with static mixers or a continuous stirred tank reactor. Both reactors promote the efficient mixing of a biphasic solution of N,N-dialkylamine in organic solvent, and aqueous sodium hypochlorite to achieve near quantitative conversions, in 72 100% in situ yields, and useful productivities of around 0.05 mol/h with residence times from 3 to 20 minutes. Initial calorimetric studies have been carried out to inform on reaction exotherms, rates and safe operation. Amines which partition mainly in the organic phase require longer reaction times, provided by the CSTR, to compensate for low mass transfer rates in the biphasic system. The green metrics of the reaction have been assessed and compared to existing procedures and have shown the continuous process is improved over previous procedures. The organic solutions of N,N-dialkyl-N-chloramines produced continuously will enable their use in tandem flow reactions with a range of nucleophilic substrates. PMID- 26734087 TI - Biocatalysis for the application of CO2 as a chemical feedstock. AB - Biocatalysts, capable of efficiently transforming CO2 into other more reduced forms of carbon, offer sustainable alternatives to current oxidative technologies that rely on diminishing natural fossil-fuel deposits. Enzymes that catalyse CO2 fixation steps in carbon assimilation pathways are promising catalysts for the sustainable transformation of this safe and renewable feedstock into central metabolites. These may be further converted into a wide range of fuels and commodity chemicals, through the multitude of known enzymatic reactions. The required reducing equivalents for the net carbon reductions may be drawn from solar energy, electricity or chemical oxidation, and delivered in vitro or through cellular mechanisms, while enzyme catalysis lowers the activation barriers of the CO2 transformations to make them more energy efficient. The development of technologies that treat CO2-transforming enzymes and other cellular components as modules that may be assembled into synthetic reaction circuits will facilitate the use of CO2 as a renewable chemical feedstock, greatly enabling a sustainable carbon bio-economy. PMID- 26734090 TI - Copper-catalyzed asymmetric conjugate addition of organometallic reagents to extended Michael acceptors. AB - The copper-catalyzed asymmetric conjugate addition (ACA) of nucleophiles onto polyenic Michael acceptors represents an attractive and powerful methodology for the synthesis of relevant chiral molecules, as it enables in a straightforward manner the sequential generation of two or more stereogenic centers. In the last decade, various chiral copper-based catalysts were evaluated in combination with different nucleophiles and Michael acceptors, and have unambiguously demonstrated their usefulness in the control of the regio- and enantioselectivity of the addition. The aim of this review is to report recent breakthroughs achieved in this challenging field. PMID- 26734091 TI - Copper-catalysed asymmetric allylic alkylation of alkylzirconocenes to racemic 3,6-dihydro-2H-pyrans. AB - Asymmetric allylic alkylation is a powerful reaction that allows the enantioselective formation of C-C bonds. Here we describe the asymmetric alkylation of alkylzirconium species to racemic 3,6-dihydro-2H-pyrans. Two systems were examined: 3-chloro-3,6-dihydro-2H-pyran using linear optimization (45-93% ee, up to 33% yield, 5 examples) and 3,6-dihydro-2H-pyran-3-yl diethyl phosphate with the assistance of a design of experiments statistical approach (83% ee, 12% yield). (1)H NMR spectroscopy was used to gain insight into the reaction mechanisms. PMID- 26734092 TI - Copper-catalyzed stereoselective conjugate addition of alkylboranes to alkynoates. AB - A copper-catalyzed conjugate addition of alkylboron compounds (alkyl-9-BBN, prepared by hydroboration of alkenes with 9-BBN-H) to alkynoates to form beta disubstituted acrylates is reported. The addition occurred in a formal syn hydroalkylation mode. The syn stereoselectivity was excellent regardless of the substrate structure. A variety of functional groups were compatible with the conjugate addition. PMID- 26734093 TI - Friedel-Crafts-type reaction of pyrene with diethyl 1 (isothiocyanato)alkylphosphonates. Efficient synthesis of highly fluorescent diethyl 1-(pyrene-1-carboxamido)alkylphosphonates and 1-(pyrene-1 carboxamido)methylphosphonic acid. AB - Friedel-Crafts-type reaction of pyrene with diethyl 1 (isothiocyanato)alkylphosphonates promoted by trifluoromethanosulfonic acid afforded diethyl 1-(pyrene-1-carbothioamido)alkylphosphonates in 83-94% yield. These compounds were transformed, in 87-94% yield, into the corresponding diethyl 1-(pyrene-1-carboxamido)alkylphosphonates by treatment with Oxone((r)). 1-(Pyrene 1-carboxamido)methylphosphonic acid was obtained in a 87% yield by treating the corresponding diethyl phosphonate with Me3Si-Br in methanol. All of the synthesized amidophosphonates were emissive in solution and in the solid state. The presence of a phosphonato group brought about an approximately two-fold increase in solution fluorescence quantum yield in comparison with that of a model N-alkyl pyrene-1-carboxamide. This effect was tentatively explained by stiffening of the amidophosphonate lateral chain which was caused by the interaction (intramolecular hydrogen bond) of phosphonate and amide groups. The synthesized phosphonic acid was soluble in a biological aqueous buffer (PBS, 0.01 M, pH 7.35) and was strongly emissive under these conditions (lambdaem = 383, 400 nm, tau = 18.7 ns, PhiF > 0.98). Solid-state emission of diethyl 1-(pyrene-1 carboxamido)methylphosphonate (lambdamax = 485 nm; PhiF = 0.25) was assigned to pi-pi aggregates, the presence of which was revealed by single-crystal X-ray diffraction analysis. PMID- 26734095 TI - N-Heterocyclic carbenes. PMID- 26734094 TI - Aggregation behaviour of amphiphilic cyclodextrins: the nucleation stage by atomistic molecular dynamics simulations. AB - Amphiphilically modified cyclodextrins may form various supramolecular aggregates. Here we report a theoretical study of the aggregation of a few amphiphilic cyclodextrins carrying hydrophobic thioalkyl groups and hydrophilic ethylene glycol moieties at opposite rims, focusing on the initial nucleation stage in an apolar solvent and in water. The study is based on atomistic molecular dynamics methods with a "bottom up" approach that can provide important information about the initial aggregates of few molecules. The focus is on the interaction pattern of amphiphilic cyclodextrin (aCD), which may interact by mutual inclusion of the substituent groups in the hydrophobic cavity of neighbouring molecules or by dispersion interactions at their lateral surface. We suggest that these aggregates can also form the nucleation stage of larger systems as well as the building blocks of micelles, vesicle, membranes, or generally nanoparticles thus opening new perspectives in the design of aggregates correlating their structures with the pharmaceutical properties. PMID- 26734096 TI - Diversity-oriented synthesis of analogues of the novel macrocyclic peptide FR 225497 through late stage functionalization. AB - A concise synthetic approach to a class of biologically interesting cyclic tetrapeptides is reported which involves a late-stage functionalization of a macrocyclic scaffold through cross metathesis in an attempt to create diversity. The utility of this protocol is demonstrated through the preparation of three structural analogues of the important naturally occurring histone deacetylase inhibitor FR-225497. PMID- 26734097 TI - Recent highlights in biosynthesis research using stable isotopes. AB - The long and successful history of isotopic labeling experiments within natural products research has both changed and deepened our understanding of biosynthesis. As demonstrated in this article, the usage of isotopes is not at all old-fashioned, but continues to give important insights into biosynthetic pathways of secondary metabolites. This review with 85 cited references is structured by separate discussions of compounds from different classes including polyketides, non-ribosomal peptides, their hybrids, terpenoids, and aromatic compounds formed via the shikimate pathway. The text does not aim at a comprehensive overview, but instead a selection of recent important examples of isotope usage within biosynthetic studies is presented, with a special emphasis on mechanistic surprises. PMID- 26734098 TI - Versatile synthesis and biological evaluation of novel 3'-fluorinated purine nucleosides. AB - A unified synthetic strategy accessing novel 3'-fluorinated purine nucleoside derivatives and their biological evaluation were achieved. Novel 3'-fluorinated analogues were constructed from a common 3'-deoxy-3'-fluororibofuranose intermediate. Employing Suzuki and Stille cross-coupling reactions, fifteen 3' fluororibose purine nucleosides 1-15 and eight 3'-fluororibose 2-chloro/2 aminopurine nucleosides 16-23 with various substituents at position 6 of the purine ring were efficiently synthesized. Furthermore, 3'-fluorine analogs of natural products nebularine and 6-methylpurine riboside were constructed via our convergent synthetic strategy. Synthesized nucleosides were tested against HT116 (colon cancer) and 143B (osteosarcoma cancer) tumor cell lines. We have demonstrated 3'-fluorine purine nucleoside analogues display potent tumor cell growth inhibition activity at sub- or low micromolar concentration. PMID- 26734099 TI - Synthesis of Xenia diterpenoids and related metabolites isolated from marine organisms. AB - This review describes strategies for the chemical synthesis of xenicane diterpenoids and structurally related metabolites. Selected members from the four different subclasses of the Xenia diterpenoid family, the xenicins, xeniolides, xeniaphyllanes and xeniaethers, are presented. The synthetic strategies are discussed with an emphasis on the individual key reactions for the construction of the uncommon nine-membered carbocycle which is the characteristic structural feature of these natural products. Additionally, the putative biosynthetic pathway of xenicanes is illustrated. PMID- 26734100 TI - Smart molecules for imaging, sensing and health (SMITH). AB - This autobiographical review provides a personal account of the author's academic journey in supramolecular chemistry, including brief summaries of research efforts in membrane transport, molecular imaging, ion-pair receptors, rotaxane synthesis, squaraine rotaxanes, and synthtavidin technology. The article concludes with a short perspective of likely future directions in biomedical supramolecular chemistry. PMID- 26734101 TI - Iron complexes of tetramine ligands catalyse allylic hydroxyamination via a nitroso-ene mechanism. AB - Iron(II) complexes of the tetradentate amines tris(2-pyridylmethyl)amine (TPA) and N,N'-bis(2-pyridylmethyl)-N,N'-dimethylethane-1,2-diamine (BPMEN) are established catalysts of C-O bond formation, oxidising hydrocarbon substrates via hydroxylation, epoxidation and dihydroxylation pathways. Herein we report the capacity of these catalysts to promote C-N bond formation, via allylic amination of alkenes. The combination of N-Boc-hydroxylamine with either FeTPA (1 mol %) or FeBPMEN (10 mol %) converts cyclohexene to the allylic hydroxylamine (tert-butyl cyclohex-2-en-1-yl(hydroxy)carbamate) in moderate yields. Spectroscopic studies and trapping experiments suggest the reaction proceeds via a nitroso-ene mechanism, with involvement of a free N-Boc-nitroso intermediate. Asymmetric induction is not observed using the chiral tetramine ligand (+)-(2R,2'R)-1,1' bis(2-pyridylmethyl)-2,2'-bipyrrolidine ((R,R')-PDP). PMID- 26734102 TI - Synthesis of bi- and bis-1,2,3-triazoles by copper-catalyzed Huisgen cycloaddition: A family of valuable products by click chemistry. AB - The Cu(I)-catalyzed azide-alkyne cycloaddition reaction, also known as click chemistry, has become a useful tool for the facile formation of 1,2,3-triazoles. Specifically, the utility of this reaction has been demonstrated by the synthesis of structurally diverse bi- and bis-1,2,3-triazoles. The present review focuses on the synthesis of such bi- and bistriazoles and the importance of using copper promoted click chemistry (CuAAC) for such transformations. In addition, the application of bitriazoles and the related CuAAAC reaction in different fields, including medicinal chemistry, coordination chemistry, biochemistry, and supramolecular chemistry, have been highlighted. PMID- 26734103 TI - Organocatalytic and enantioselective Michael reaction between alpha-nitroesters and nitroalkenes. Syn/anti-selectivity control using catalysts with the same absolute backbone chirality. AB - The asymmetric and catalytic Michael reaction between alpha-nitroesters and nitroalkenes has been studied in the presence of two bifunctional catalysts both containing the same absolute chirality at the carbon backbone. The reaction performed in similar conditions allows us to control the syn or anti selectivity of the Michael adduct obtaining good yields and high enantiocontrol in all cases. PMID- 26734104 TI - Rhodium, iridium and nickel complexes with a 1,3,5-triphenylbenzene tris-MIC ligand. Study of the electronic properties and catalytic activities. AB - The coordination versatility of a 1,3,5-triphenylbenzene-tris-mesoionic carbene ligand is illustrated by the preparation of complexes with three different metals: rhodium, iridium and nickel. The rhodium and iridium complexes contained the [MCl(COD)] fragments, while the nickel compound contained [NiCpCl]. The preparation of the tris-MIC (MIC = mesoionic carbene) complex with three [IrCl(CO)2] fragments, allowed the estimation of the Tolman electronic parameter (TEP) for the ligand, which was compared with the TEP value for a related 1,3,5 triphenylbenzene-tris-NHC ligand. The electronic properties of the tris-MIC ligand were studied by cyclic voltammetry measurements. In all cases, the tris MIC ligand showed a stronger electron-donating character than the corresponding NHC-based ligands. The catalytic activity of the tri-rhodium complex was tested in the addition reaction of arylboronic acids to alpha,beta-unsaturated ketones. PMID- 26734105 TI - Bifunctional phase-transfer catalysis in the asymmetric synthesis of biologically active isoindolinones. AB - New bifunctional chiral ammonium salts were investigated in an asymmetric cascade synthesis of a key building block for a variety of biologically relevant isoindolinones. With this chiral compound in hand, the development of further transformations allowed for the synthesis of diverse derivatives of high pharmaceutical value, such as the Belliotti (S)-PD172938 and arylated analogues with hypnotic sedative activity, obtained in good overall total yield (50%) and high enantiomeric purity (95% ee). The synthetic routes developed herein are particularly convenient in comparison with the current methods available in literature and are particularly promising for large scale applications. PMID- 26734106 TI - Recent advances in copper-catalyzed asymmetric coupling reactions. AB - Copper-catalyzed (or -mediated) asymmetric coupling reactions have received significant attention over the past few years. Especially the coupling reactions of aryl or alkyl halides with nucleophiles became a very powerful tool for the formation of C-C, C-N, C-O and other carbon-heteroatom bonds as well as for the construction of heteroatom-containing ring systems. This review summarizes the recent progress in copper-catalyzed asymmetric coupling reactions for the formation of C-C and carbon-heteroatom bonds. PMID- 26734107 TI - Inclusion complexes of 2-methoxyestradiol with dimethylated and permethylated beta-cyclodextrins: models for cyclodextrin-steroid interaction. AB - The interaction between the potent anticancer agent 2-methoxyestradiol (2ME) and a series of cyclodextrins (CDs) was investigated in the solid state using thermal analysis and X-ray diffraction, while the possibility of enhancing its poor aqueous solubility with CDs was probed by means of equilibrium solubility and dissolution rate measurements. Single crystal X-ray diffraction studies of the inclusion complexes between 2ME and the derivatised cyclodextrins heptakis(2,6-di O-methyl)-beta-CD (DIMEB) and heptakis(2,3,6-tri-O-methyl)-beta-CD (TRIMEB) revealed for the first time the nature of the encapsulation of a bioactive steroid by representative CD host molecules. Inclusion complexation invariably involves insertion of the D-ring of 2ME from the secondary side of each CD molecule, with the 17-OH group generally hydrogen bonding to a host glycosidic oxygen atom within the CD cavity, while the A-ring and part of the B-ring of 2ME protrude from the secondary side. In the case of the TRIMEB.2ME complex, there is evidence that complexation proceeds with mutual conformational adaptation of host and guest molecules. The aqueous solubility of 2ME was significantly enhanced by CDs, with DIMEB, TRIMEB, randomly methylated beta-CD and hydroxypropyl-beta-CD being the most effective hosts. The 2:1 host-guest beta-CD inclusion complex, prepared by two methods, yielded very rapid dissolution in water at 37 degrees C relative to untreated 2ME, attaining complete dissolution within 15 minutes (co precipitated complex) and 45 minutes (complex from kneading). PMID- 26734108 TI - Exploring architectures displaying multimeric presentations of a trihydroxypiperidine iminosugar. AB - The synthesis of new multivalent architectures based on a trihydroxypiperidine alpha-fucosidase inhibitor is reported herein. Tetravalent and nonavalent dendrimers were obtained by means of the click chemistry approach involving the copper azide-alkyne-catalyzed cycloaddition (CuAAC) between suitable scaffolds bearing terminal alkyne moieties and an azido-functionalized piperidine as the bioactive moiety. A preliminary biological investigation is also reported towards commercially available and human glycosidases. PMID- 26734109 TI - A novel and practical asymmetric synthesis of dapoxetine hydrochloride. AB - A novel and practical asymmetric synthesis of dapoxetine hydrochloride by using the chiral auxiliary (S)-tert-butanesulfinamide was explored. The synthesis was concise, mild, and easy to perform. The overall yield and stereoselectivity were excellent. PMID- 26734110 TI - Assembly of synthetic Abeta miniamyloids on polyol templates. AB - Covalent dynamic chemistry is used to mimic the first steps of the highly cooperative fibril formation of Abeta peptides. For that purpose, Abeta peptide pentapeptide boronic acids 1 and 2 were synthesized by solid-phase peptide synthesis and studied in esterification experiments with polyhydroxylated templates. The bis-hydroxylated dipeptide Hot=Tap serves as a template of adjustable degree of oligomerization which spontaneously forms boronic esters with peptides of type 1 and 2. Nuclear magnetic resonance can differentiate between regioisomeric boronic esters and identifies preferred sites of esterification on the dimeric template 9. 2-Formylphenylboronic acid (14) is used to link the parent pentapeptide Leu-Val-Phe-Phe-Ala to the template 16 to obtain threefold boronic ester 17. The miniamyloid 17 assembles from seven components by imine and boronic ester bonds between the peptides and the template. The relative orientation and spacing of the peptides mimic the assembly of peptides in Alzheimer beta-amyloids. PMID- 26734111 TI - Catalytic asymmetric formal synthesis of beraprost. AB - The first catalytic asymmetric synthesis of the key intermediate for beraprost has been achieved through an enantioselective intramolecular oxa-Michael reaction of an alpha,beta-unsaturated amide mediated by a newly developed benzothiadiazine catalyst. The Weinreb amide moiety and bromo substituent of the Michael adduct were utilized for the C-C bond formations to construct the scaffold. All four contiguous stereocenters of the tricyclic core were controlled via Rh-catalyzed stereoselective C-H insertion and the subsequent reduction from the convex face. PMID- 26734112 TI - Carbon-carbon bond cleavage for Cu-mediated aromatic trifluoromethylations and pentafluoroethylations. AB - This short review highlights the copper-mediated fluoroalkylation using perfluoroalkylated carboxylic acid derivatives. Carbon-carbon bond cleavage of perfluoroalkylated carboxylic acid derivatives takes place in fluoroalkylation reactions at high temperature (150-200 degrees C) or under basic conditions to generate fluoroalkyl anion sources for the formation of fluoroalkylcopper species. The fluoroalkylation reactions, which proceed through decarboxylation or tetrahedral intermediates, are useful protocols for the synthesis of fluoroalkylated aromatics. PMID- 26734113 TI - Roughness Analysis on Composite Materials (Microfilled, Nanofilled and Silorane) After Different Finishing and Polishing Procedures. AB - The finishing and polishing of composite materials affect the restoration lifespan. The market shows a variety of finishing and polishing procedures and the choice among them is conditioned by different factors such as the resulting surface roughness. In the present study, 156 samples were realized with three composite materials, -microfilled, nanofilled and silorane-, and treated with different finishing and polishing procedures. Profilometric analyses were carried out on the samples' surface, the measured roughness values were submitted to statistical analysis. A complete factorial plan was drawn up and two-way analysis of variance (ANOVA) was carried out to investigate whether the following factors affect the values of roughness: (i) material; (ii) polishing/finishing procedure. Tukey post-hoc test was also conducted to evaluate any statistically significant differences between the material/procedure combinations. The results show that the tested materials do not affect the resulting surface quality but roughness values depend on the finishing/polishing procedure adopted. The procedures that involve: (a) the finishing with medium Sof-Lex discs and (b) the finishing with two tungsten carbide multi-blade milling cutters Q series and UF series are those that allow the lowest values of roughness to be obtained. PMID- 26734114 TI - Assessment of the biocompatibility of three-dimensional-printed polymers using multispecies toxicity tests. AB - Additive manufacturing was adopted in multiple fields of life sciences. It is also becoming a popular tool for rapid prototyping of microfluidic and biomedical devices. Limited studies have been performed to investigate the biological implications of using 3D printed polymers. Here we assessed the biocompatibility of seven commercially available polymers, using a battery of standardized bioassays for chemical risk assessment. Our data show that leachates from photopolymers substrata appear to be very toxic to vertebrates and several invertebrate indicator organisms. These results demonstrate significant consequences for the use of selected photopolymers in the fabrication of bio devices. PMID- 26734115 TI - Hybrid capillary-inserted microfluidic device for sheathless particle focusing and separation in viscoelastic flow. AB - A novel microfluidic device which consists of two stages for particle focusing and separation using a viscoelastic fluid has been developed. A circular capillary tube was used for three-dimensional particle pre-alignment before the separation process, which was inserted in a polydimethylsiloxane microchannel. Particles with diameters of 5 and 10 MUm were focused at the centerline in the capillary tube, and the location of particles was initialized at the first bifurcation. Then, 5 and 10 MUm particles were successfully separated in the expansion region based on size-dependent lateral migration, with ~99% separation efficiency. The proposed device was further applied to separation of MCF-7 cells from leukocytes. Based on the cell size distribution, an approximate size cutoff for separation was determined to be 16 MUm. At 200 MUl/min, 94% of MCF-7 cells were separated with the purity of ~97%. According to the trypan blue exclusion assay, high viability (~90%) could be achieved for the separated MCF-7 cells. The use of a commercially available capillary tube enables the device to be highly versatile in dealing with particles in a wide size range by using capillary tubes with different inner diameters. PMID- 26734116 TI - Adsorption and isolation of nucleic acids on cellulose magnetic beads using a three-dimensional printed microfluidic chip. AB - While advances in genomics have enabled sensitive and highly parallel detection of nucleic acid targets, the isolation and extraction of the nucleic acids remain a critical bottleneck in the workflow. We present here a simple 3D printed microfluidic chip that allows for the vortex and centrifugation free extraction of nucleic acids. This novel microfluidic chip utilizes the presence of a water and oil interface to filter out the lysate contaminants. The pure nucleic acids, while bound on cellulose particles, are magnetically moved across the oil layer. We demonstrated efficient and rapid extraction of spiked Human Papillomavirus (HPV) 18 plasmids in specimen transport medium, in under 15 min. An overall extraction efficiency of 61% is observed across a range of HPV plasmid concentrations (5 * 10(1) to 5 * 10(6) copies/100 MUl). The magnetic, interfacial, and viscous drag forces inside the microgeometries of the chip are modeled. We have also developed a kinetics model for the adsorption of nucleic acids on cellulose functionalized superparamagnetic beads. We also clarify here the role of carrier nucleic acids in the adsorption and isolation of nucleic acids. Based on the various mechanistic insights detailed here, customized microfluidic devices can be designed to meet the range of current and emerging point of care diagnostics needs. PMID- 26734117 TI - A Head and Neck Support Device for Inducing Local Hypothermia. AB - The present work describes the design of a device/system intended to induce local mild hypothermia by simultaneously cooling a patient's head and neck. The therapeutic goal is to lower the head and neck temperatures to 33-35 degrees C, while leaving the core body temperature unchanged. The device works by circulating a cold fluid around the exterior of the head and neck. The head surface area is separated into five different cooling zones. Each zone has a cooling coil and can be independently controlled. The cooling coils are tightly wrapped concentric circles of tubing. This design allows for a dense packing of tubes in a limited space, while preventing crimping of the tubing and minimizing the fluid pressure head loss. The design in the neck region also has multiple tubes wrapping around the circumference of the patient's neck in a helix. Preliminary testing indicates that this approach is capable of achieving the design goal of cooling the brain tissue (at a depth of 2.5 cm from the scalp) to 35 degrees C within 30- 40 min, without any pharmacologic or circulatory manipulation. In a comparison with examples of current technology, the device has shown the potential for improved cooling capability. PMID- 26734118 TI - The complete genome sequence and analysis of a plasmid-bearing myxobacterial strain Myxococcus fulvus 124B02 (M 206081). AB - Myxobacteria, phylogenetically located in the delta division of the Proteobacteria, are well known for characterized social behaviors and large genomes of more than 9 Mb in size. Myxococcus fulvus is a typical species of the genus Myxococcus in the family Myxococcaceae. M. fulvus 124B02, originally isolated from a soil sample collected in Northeast China, is the one and only presently known myxobacterial strain that harbors an endogenous autonomously replicating plasmid, named pMF1. The endogenous plasmid is of importance for understanding the genome evolution of myxobacteria, as well as for the development of genetic engineering tools in myxobacteria. Here we describe the complete genome sequence of this organism. M. fulvus 124B02 consists of a circular chromosome with a total length of 11,048,835 bp and a circular plasmid of 18,634 bp. Comparative genomic analyses suggest that pMF1 has a longstanding sustention within myxobacteria, and probably contributes to the genome expansion of myxobacteria. PMID- 26734119 TI - Severity of Depression and Anxiety in Patients with Alopecia Areata in Bandar Abbas, Iran. AB - Alopecia areata (AA) is a chronic disease which esthetic outcomes may result in deep effects on mental disorders of patients. In this case-control study, we compared the mental health of 68 patients diagnosed with AA with 68 healthy individuals using Hamilton anxiety and depression rating scales. There were significant differences between the case and control groups regarding the prevalence of anxiety and depression. The means of anxiety scores in cases and control group were 12.76+/-7.21 vs 8.54+/-6.37, P=0.003. Likewise, the means of depression scores for the groups were 12.84+/-4.03 vs 6.22+/-4.95, P=0.001. Further-more, patients with AA were exposed to depression approximately five times and to anxiety about three times more than normal people. Our study revealed a high prevalence of anxiety and depression in AA patients. Dermatologists should pay more attention on psychological effect of the disease on the patients. PMID- 26734120 TI - Subclinical Onychomycosis in Patients With Type II Diabetes. AB - Fungal organisms could be present in the nail without any clinical manifestations. As onychomycosis in diabetics has more serious complications, early detection of such infection could be helpful to prevent them. We aim in this study to assess the possibility of detecting subclinical onychomycosis in type II diabetic patients and addressing possible associated neuropathy. A cross sectional, observational study included patients with type II diabetes with normal big toe nail. All were subjected to nail clipping of the big toe nail, followed by staining with Hematoxylin and Eosin and Periodic-Acid-Schiff (PAS) stains and examined microscopically. A total of 106 patients were included, fungal infection was identified in eight specimens, all were uncontrolled diabetes, and six had neuropathy. Using the nail clipping and microscopic examination with PAS stain to detect such subclinical infection could be an applicable screening test for diabetic patients, for early detection and management of onychomycosis. PMID- 26734121 TI - Giant Condyloma Acuminate Due to Human Papillomavirus Type 16 in an Infant Successfully Treated with Topical Imiquimod Therapy. AB - Anogenital warts related to human papillomavirus (HPV) have been observed in children. Definition of the transmission mode, therapy, and follow-up for long term potential complications is important. A 27-month old girl was admitted with multiple pedunculated red-purple colored cauliflower-like lesions of 1.5 years duration. Clinical/histopathological and microbiological diagnosis was condyloma acuminate due to HPV type 16. After 12 weeks of imiquimod 5% cream application (pea-sized) overnight three times per week, the perianal warts had completely disappeared. The mode of transmission of HPV 16 in our case was probably horizontal, related to the sharing of common personal hygiene items in the women's shelter. We report herein the case of an infant living in a women's shelter with giant condyloma acuminata due to HPV 16, which was successfully treated with topical imiquimod therapy. This patient should be followed up for recurrence and potential malignant lesions related to HPV type 16. PMID- 26734122 TI - Exploring Valrubicin's Effect on Propionibacterium Acnes-Induced Skin Inflammation in Vitro and in Vivo. AB - Acne is a common skin disease involving colonization with Propionibacterium acnes (P. acnes), hyperproliferation of the follicular epithelium and inflammatory events. Valrubicin is a second-generation anthracycline, non-toxic upon contact, and available in a topical formulation. Valrubicin's predecessor doxorubicin possesses antibacterial effects and previously we demonstrated that valrubicin inhibits keratinocyte proliferation and skin inflammation suggesting beneficial topical treatment of acne with valrubicin. This study aims to investigate valrubicin's possible use in acne treatment by testing valrubicin's antibacterial effects against P. acnes and P. acnes-induced skin inflammation in vitro and in vivo. Valrubicin was demonstrated not to possess antibacterial effects against P. acnes. Additionally, valrubicin was demonstrated not to reduce mRNA and protein expression levels of the inflammatory markers interleukin (IL)-1beta, IL-8, and tumor necrosis factor (TNF)-alpha in vitro in human keratinocytes co-cultured with P. acnes. Moreover, in vivo, valrubicin, applied both topically and intra dermally, was not able to reduce signs of inflammation in mouse ears intra dermally injected with P. acnes. Taken together, this study does not support beneficial antibacterial and anti inflammatory effects of topical valrubicin treatment of acne. PMID- 26734123 TI - Diagnostic Path of a Genetic Disease: A Case of Williams-Beuren Syndrome in Burkina Faso. AB - Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by a set of somatic, psychological, and behavioral abnormalities, which is caused by a deletion of several genes. Herein we report a 6 year-old boy, who presented with mental retardation and psychological disorders. The result of the first clinical examination was poor, since it didn't detect any dysmorphic feature which is a major component for the clinical diagnosis of WBS. Despite the multidisciplinary and the multicenter approaches used, the diagnosis of WBS (deletion of chromosome band 7q11. 23) was established more than 3 years after the first medical consultation. Rare partial forms of WBS have been recently described and they are both clinically and genetically difficult to diagnose. Unfortunately, this disorder is still little known by health professionals. PMID- 26734124 TI - Late-onset Rash in Patients with Group A Beta-hemolytic Streptococcal Pharyngitis Treated with Amoxicillin. AB - We observed late-onset rashes in patients with group A beta-hemolytic streptococcal (GAS) pharyngitis. Of 1028 patients with GAS pharyngitis, which was principally treated with amoxicillin, we evaluated those who developed a late onset rash and excluded those with scarlet fever alone. Twenty-one patients developed a rash (2.0%, 95% confidence interval, 1.3-3.1%), 7 to 20 days (median, 8 days) after GAS pharyngitis onset. The rashes were characterized by maculopapules, which increased in size with coalescence and some developing into plaques, with a symmetrical distribution with a propensity for the extremities, including the palms and soles. The clinical courses of the patients were good, and the rashes subsided within 14 days. A non-immediate reaction to beta-lactams, which usually manifests as a maculopapular rash, is a possible cause in our patients, however, repeated courses of amoxicillin in 3 patients did not induce the rash. The underlying mechanism of the late-onset rash after GAS pharyngitis with amoxicillin treatment remains unclear. PMID- 26734125 TI - Specific Echocardiographic Findings Useful for the Diagnosis of Common Pulmonary Vein Atresia. AB - In this paper, we report a case of common pulmonary vein atresia, which is a very rare disease characterized by cyanosis, heart failure and pulmonary hypertension. Reverse flow in the pulmonary artery at end-diastole as well as in the isthmus of the aorta from early systole to end-diastole detected by echocardiography were found to be specific features useful in diagnosing the disease. PMID- 26734126 TI - Neonatal Hemophilia: A Rare Presentation. AB - Hemophilia A is a X-linked hereditary condition that lead to decreased factor VIII activity, occurs mainly in males. Decreased factor VIII activity leads to increased risk of bleeding events. During neonatal period, diagnosis is made after post-partum bleeding complication or unexpected bleeding after medical procedures. Subgaleal hemorrhage during neonatal period is a rare, severe extracranial bleeding with high mortality and usually related to traumatic labor or coagulation disorders. Subgaleal hemorrhage complications result from massive bleeding. We present a neonate with unremarkable family history and uneventful pregnancy with a vaginal delivery with no instrumentation, presenting with severe subgaleal bleeding at 52 hours of life. Aggressive support measures were implemented and bleeding managed. The unexpected bleeding lead to a coagulation study and the diagnosis of severe hemophilia A. There were no known sequelae. This case shows a rare hemophilia presentation reflecting the importance of coagulation studies when faced with unexplained severe bleeding. PMID- 26734127 TI - The Role of PTEN in Myeloid Malignancies. AB - PTEN deletion in the mouse and in the zebrafish highlights the essential role of this tumor suppressor in the development of myeloid malignancies, in particular acute myeloid leukemia and myeloproliferative disorders. In humans, extensive genetic sequences of myeloid malignancies did not reveal recurrent PTEN mutations and deletions. However, PTEN was shown to be functionally inactivated in several acute myeloid leukemia and chronic myeloid leukemia samples, through both post trasductional modifications, changes in protein levels and cellular compartmentalization. Notably, non genomic inactivation of PTEN in myeloid malignancies could represent a challenging therapeutic opportunity for these diseases. Targeting those mechanisms that affect PTEN function could indeed promote PTEN reactivation with consequent cancer selective apoptosis induction. In this review we will describe the role of PTEN in the development of myeloid malignancies. PMID- 26734128 TI - Docosahexaenoic Acid Induces Apoptosis in Primary Chronic Lymphocytic Leukemia Cells. AB - Chronic lymphocytic leukemia is an indolent disorder with an increased infectious risk remaining one of the main causes of death. Development of therapies with higher safety profile is thus a challenging issue. Docosahexaenoic acid (DHA, 22:6) is an omega-3 fatty acid, a natural compound of normal cells, and has been shown to display antitumor potency in cancer. We evaluated the potential in vitro effect of DHA in primary CLL cells. DHA induces high level of in vitro apoptosis compared to oleic acid in a dose-dependent and time-dependent manner. Estimation of IC50 was only of 4.813 uM, which appears lower than those reported in solid cancers. DHA is highly active on CLL cells in vitro. This observation provides a rationale for further studies aiming to understand its mechanisms of action and its potent in vivo activity. PMID- 26734129 TI - Eculizumab Treatment in a Patient with Hematopoietic Stem Cell Transplantation Associated Thrombotic Microangiopathy and Steroid-Refractory Acute Graft Versus Host Disease. AB - A 30-year-old man with acquired aplastic anemia underwent an HLA-identical bone marrow transplant. He developed a grade III acute graft versus host disease (GVHD) refractory to various lines of treatment. On post-transplant day 196, he was diagnosed with stem cell transplantation-associated thrombotic micro angiopathy (HSCT-TMA) and he received treatment with eculizumab 900 mg iv weekly for 4 doses followed by a single dose of 1200 mg 2 weeks later. After the first dose of eculizumab, the patient ceased to require transfusions and a progressive improvement in analytical parameters for microangiopathy was observed until their complete normalization. Coinciding with the improved of HSCT-TMA, the patient presented a clear response to his acute GVHD with disappearance of the diarrhea and bilirubin normalization. He was discharged eight weeks after the start of treatment. Unfortunately, one month later, the patient was readmitted for a GVHD relapse and he died two weeks later by an acute respiratory distress syndrome. In our case, the rapid clinical and analytical response to early treatment with eculizumab supports the implication of the complement in HSCT-TMA and suggests that the drug has a beneficial effect when used as coadjuvant therapy in acute GVHD. PMID- 26734130 TI - Antimicrobial resistance profiles of Shiga toxin-producing Escherichia coli O157 and Non-O157 recovered from domestic farm animals in rural communities in Northwestern Mexico. AB - BACKGROUND: Antimicrobial resistance in Shiga toxin-producing Escherichia coli (STEC) O157 and non-O157 is a matter of increasing concern. The aim of the present study was to investigate the antimicrobial resistance profiles of STEC O157 and non-O157 recovered from feces of domestic farm animals in the agricultural Culiacan Valley in Northwestern Mexico. FINDINGS: All of the examined STEC strains showed susceptibility to five antimicrobials, ceftazidime, ceftriaxone, ciprofloxacin, nalidixic acid, and trimethoprim-sulfamethoxazole. However, resistance to the four antimicrobials, ampicillin, cephalothin, chloramphenicol, and kanamycin was commonly observed. Interestingly, non susceptibility to cephalothin was predominant among the examined STEC strains, corresponding to 85 % (22/26) of the O157:H7 from cattle, sheep and chicken and 73 % (24/33) of the non-O157 strains from cattle and sheep. Statistical analyses revealed that resistance to ampicillin was significantly correlated to 38 % (10/26) of STEC O157:H7 strains from multiple animal sources. Another significant correlation was found between serotype, source, and antimicrobial resistance; all of the O20:H4 strains, recovered from sheep, were highly resistant to tetracycline. Multidrug resistance profiles were identified in 42 % (22/53) of the non-susceptible STEC strains with clinically-relevant serotypes O8:H9, O75:H8, O146:H21, and O157:H7. CONCLUSIONS: STEC O157 and non-O157 strains, recovered from domestic farm animals in the Culiacan Valley, exhibited resistance to classes of antimicrobials commonly used in Mexico, such as aminoglycosides, tetracyclines, cephalosporins and penicillin but were susceptible to fluoroquinolones, quinolones, and sulfonamides. These findings provide fundamental information that would aid in the surveillance of antimicrobial resistance in an important agricultural region in Northwestern Mexico. PMID- 26734131 TI - Syncope and cardiac arrest during strenuous exercise associated with a novel mutation in LQTS1. AB - Exercise-induced syncope should alert clinicians to the possibility of LQTS and must be distinguished from other malignant causes of syncope such as hypertrophic cardiomyopathy, catecholaminergic ventricular tachycardia, and arrhythmogenic right ventricular cardiomyopathy. Emerging genotype-phenotype links have connected mutations resulting in LQTS with risk of developing atrial fibrillation and cardiomyopathy. PMID- 26734132 TI - Severe traumatic vulva hematoma in teenage girl. AB - Nonobstetric hematomas of the vulva are rare and not extensively reported in literature. There are no consensus guidelines and a paucity of literature to guide best practices with regard to management. We present a case of vulva hematoma in a teenage girl. Our experience highlights the importance of prompt surgical intervention to reduce associated morbidity and minimize hospital stay. PMID- 26734133 TI - Endobronchial mass formation after endobronchial ultrasound-transbronchial needle aspiration mimicking implantation metastasis. AB - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been widely used for diagnosing intrathoracic lymphadenopathy. Here, we present two cases of endobronchial polyp formation after an EBUS-TBNA for suspicious malignant lymph nodes. An inflammatory polyp should be considered as a possible differential diagnosis for a newly developed mass after an EBUS-TBNA. PMID- 26734134 TI - Synchronous neuroendocrine tumor and non-small-cell lung cancer in neurofibromatosis type 1. AB - Neurofibromatosis type 1 is a common cancer predisposing condition. Tumors, particularly gastrointestinal tumors, are commonly associated with NF1 but are not widely known. In addition, the relationship between lung cancer and neurofibromatosis has been controversial until recently with the discovery of oncogenes such as p53. PMID- 26734135 TI - Acute respiratory failure due to thyroid storm developing immediately after delivery. AB - Acute respiratory failure occurs in less than 0.1% of pregnancies. Thyroid storm should be included in the differential diagnosis of possible causes of acute respiratory failure occurring immediately after delivery, and delivery is a high risk factor for thyroid storm in pregnant women with thyrotoxicosis. PMID- 26734136 TI - Equine eosinophilic keratitis in horses: 28 cases (2003-2013). AB - This retrospective case series evaluates husbandry and environmental conditions in relation to eosinophilic keratitis in horses. While no associations were found between disease and husbandry practices or specific environmental factors such as humidity or temperature, an increased prevalence of presentation in summer months was identified in this population of horses. PMID- 26734137 TI - Case report: vitamin D-dependent rickets type 1 caused by a novel CYP27B1 mutation. AB - Vitamin D-dependent rickets type 1 VDDR-1 is a recessive inherited disorder with impaired activation of vitamin D, caused by mutations in CYP27B1. We present long time follow-up of a case with a novel mutation including high-resolution peripheral quantitative computed tomography of the bone. Adequate treatment resulted in a normalized phenotype. PMID- 26734138 TI - Subcutaneous fat necrosis of the newborn. AB - Subcutaneous fat necrosis (SCFN) is a rare fat tissue inflammation of the newborn. Risk factors include cord prolapse, perinatal asphyxia, therapeutic hypothermia, meconium aspiration, and sepsis. When present, hypercalcemia comes with lethargy, hypotonia, irritability, vomiting, polyuria, polydipsia, constipation, and dehydration. Kidney injury must be avoided. SCFN is often completely autoresolutive. PMID- 26734139 TI - Elderly-onset degenerative "lumbar spondylotic myelopathy" in a patient with a low-placed spinal cord successfully treated by laminotomy: a case report. AB - The authors report a rare case of elderly-onset "lumbar spondylotic myelopathy" occurred on a low-placed spinal cord compressed at multiple levels with thickened ligamenta flava. A posterior decompression surgery could alleviate neurological symptoms successfully instead of untethering of the spinal cord, a widely accepted surgery for tethered cord. PMID- 26734140 TI - A 19 year follow-up of a woman with lipoprotein lipase deficiency treated with biliopancreatic diversion. AB - We show the long-term efficacy and safety of modified biliopancreatic diversion for the treatment of LPL-deficiency. How this option compares with gene therapy is difficult to evaluate due to limited experience. Surgery may be the first option in patients in whom medical therapy is ineffective and gene therapy not applicable. PMID- 26734141 TI - Familial florid Cemento-osseous dysplasia - case report and review of literature. AB - Familial Florid cemento-osseous dysplasia is a very uncommon condition. Cemento osseous dysplasia is totally asymptomatic in many cases, in those conditions, lesions are detected in a radiograph taken for other purposes. In this report, we describe a family in which mother and daughter exhibited clinical, radiographic, and histologic features of florid cemento-osseous dysplasia. PMID- 26734142 TI - Conjunctival and pulmonary hemodynamic properties in sickle cell disease subjects with and without pulmonary hypertension. AB - Conjunctival microvascular hemodynamic alterations were reported for the first time in sickle cell subjects with and without pulmonary hypertension. Assessment of the conjunctival microcirculation using noninvasive imaging may improve understanding of microvascular hemodynamic alterations that occur due to pulmonary hypertension in sickle cell disease. PMID- 26734144 TI - Prenatal ultrasound diagnosis of cystic biliary atresia. AB - Nonvisualization of the gallbladder during the second trimester of pregnancy should prompt concern for biliary atresia. A normal-sized gallbladder with irregular and crenelated wall associated with a cyst of the extrahepatic tract should raise concern for cystic biliary atresia. PMID- 26734143 TI - Papillary reconstruction and guided tissue regeneration for combined periodontal endodontic lesions caused by palatogingival groove and additional root: a case report. AB - We described a combined periodontal-endodontic lesion, which was caused by a palatogingival groove and an additional root. An interdisciplinary approach involving endodontic therapy, mineral trioxide aggregate (MTA) filling, root resection, guided tissue regeneration, and papillary reconstruction was used for the case. The tooth presents morphologically and functionally normal except tooth discoloration caused by MTA. PMID- 26734145 TI - Unusual presentation of a distal cholangiocarcinoma. AB - We report a case of a 51-year-old male presented with abdominal pain and itching, whereas jaundice occurred afterwards. Diagnosis was made by means of CT and better assessed by MRI and endoscopic ultrasounds. Patient was treated with an open Whipple's procedure, and after an 18-month follow-up he was doing well. PMID- 26734146 TI - Spooning of the nails and webbing of the esophagus: koilonychia and Plummer Vinson Syndrome. AB - Chronic iron deficiency can be associated with nail deformities like Koilonychia and Platynychia. It can also be associated with esophageal webs (Plummer-Vinson syndrome or Patterson-Brown-Kelly syndrome) causing dysphagia in the patient. Though the pathogenesis of this association remains anecdotal and presence of these physical findings should prompt the clinician towards considering chronic iron deficiency as the cause of anemia. PMID- 26734147 TI - Hypertension presenting early in pregnancy. AB - Paraganglioma in pregnancy is an exceedingly rare and potentially life threatening diagnosis. It is important that the clinicians consider secondary causes when women present with hypertension in early pregnancy. PMID- 26734148 TI - Improving the correct prescription and dosage of gentamicin. AB - Gentamicin is an amino glycoside antibiotic, which is used predominantly in gram negative infections but also has anti-staphylococcal activity. It is commonly used because of its lack of diffogenicity. There are recognised issues with its dosing of which time is a major factor. A baseline study demonstrated that dosing was only being carried out correctly 30% of the time. This has serious consequences for the treatment of infections. This quality improvement project intervened with the use of a gentamicin calculator, which enabled users to perform three complex mathematical equations simultaneously without error. Post measurement demonstrated that correct dosing had increased to 92%, which was a significant increase. PMID- 26734149 TI - Improving patient follow-up after inpatient stay. AB - Follow-up is a vital part of ongoing patient safety. It allows for subsequent investigations to be checked and acted upon, encourages specialist review of patients and ensures that patients with chronic conditions receive the appropriate secondary care input. This study aims to highlight and quantify current problems with how follow-up arrangements are made within our hospital and provide a suitable solution to ensure that these problems are minimised. 20 sets of clinical notes were analysed for plans of follow-up and then compared with the discharge summaries produced. Hospital computer systems were used to find out which interventions happened, and when, to get the baseline data. A simple follow up prompt sheet was introduced and a further 20 sets of notes were audited to complete the study. Patient follow-up improved after the introduction of a simple follow-up prompt sheet but highlighted the need for a complete change in the way follow up is arranged at our hospital. There is a need for an online system for requesting follow-up appointments in our hospital. This is vital given the 24 hour environment that we work in with many patients being discharged out of normal working hours. This is currently being discussed with management and we hope that the introduction will be imminent to improve the future safety of all patients. PMID- 26734150 TI - Improving Medication Reconciliation on the Surgical Wards of a District General Hospital. AB - During a routine audit it was noted that the surgical wards were consistently underperforming in their rate of medicines reconciliation in comparison to other specialities. The process of medication reconciliation is usually performed by junior doctors during the admission process and can be a complex task which is usually undertaken in the midst of several other jobs. The aim of this project was to review this process and identify methods of improving patient safety. This led to the design of a surgical admissions proforma which incorporated a 'medications on admission' section, to be used for reconciliation. Over a six month period from its introduction into a pilot ward it was noted to improve medication reconciliation from 60% to 85%. The benefits were discussed with members of the trust and a standardised version of the admissions proforma has since been rolled out to all hospitals within the trust. PMID- 26734151 TI - Improving illiterate patients understanding and adherence to discharge medications. AB - Adherence to a hospital discharge medication regime is crucial for successful treatment and to avoid increasing rates of drug resistance. A patient's success in adhering to their medication regime is dependent on many social, cultural, economic, illness and therapy-related factors, and these are often more pronounced in the developing world. Anecdotal evidence in Services Hospital, Lahore (Pakistan) suggested that the relatively high levels of illiteracy in the patient population was a major factor in poor adherence. Baseline measurement revealed that 48% of all the hospital's patients were illiterate with just 5%-12% of illiterate patients being able to interpret their handwritten discharge prescription after leaving hospital. Unsurprisingly follow-up clinics reported very poor adherence. This quality improvement project intervened by designing a new discharge prescription proforma which used pictures and symbols rather than words to convey the necessary information. Repeated surveys demonstrated large relative increases in comprehension of the new proformas amongst illiterate patients with between 23%-35% of illiterate patients understanding the new proformas. PMID- 26734152 TI - A medication workshop for patients with schizophrenia living in community care homes. AB - Psychoeducation for patients with schizophrenia can improve a range of outcomes. Our aim was to test a workshop intervention enabling service users to learn more about mental illness and their medication. A Quality Improvement Project was undertaken to create a workshop for patients with a diagnosis of schizophrenia within the Haringey Community Rehabilitation Team (HCRT) . The response was tested using anonymous questionnaires after each workshop. We held ten workshops (total of 47 participants), after which 83% of patients felt that the workshop had helped them to understand more about their mental health, 77% felt they were able to understand the purpose of their medication, 79% felt they were able to understand the side effects, and 70% felt they could have a say in prescribing. Objectives for the Quality Improvement Project were met. This workshop will be used for other patients within the HCRT and is transferable to other community mental health teams. PMID- 26734153 TI - Acute Kidney Injury: It's as easy as ABCDE. AB - Acute kidney injury (AKI) is a common, serious problem which has been found to be poorly managed. Early recognition and action is critical in potentially slowing or reversing its course and facilitating timely referral to specialist services. In this quality improvement project, multidisciplinary education sessions and a simple 'ABCDE' checklist to aid AKI management were introduced in a district general hospital. The incidence of AKI (defined as 26umol/l rise in creatinine), its recognition and management were measured hospital wide. AKI recognition was improved by educating the entire multidisciplinary team to identify three key early warning signs: a rise in serum creatinine, urine output of <500mls in 24 hours and systolic blood pressure of <90mmHg. The 'ABCDE' checklist (Address drugs, Boost blood pressure, Calculate fluid balance, Dip urine, Exclude obstruction) was introduced to prompt AKI management. A four week educational programme was delivered, initially on a pilot ward, to doctors, nurses, nursing assistants and pharmacists. AKI recognition and implementation of the 'ABCDE' checklist were measured. Prior to project introduction 16% of patients developed AKI, but were recognised within 24 hours in only 31% of cases, with 80% of 'ABCDE' steps implemented in only 20%. Following multidisciplinary education, AKI recognition improved to 100%, with 80% of 'ABCDE' steps implemented in 67% of cases. These results were replicated when the project was rolled out across the surgical directorate (120 beds) and in the 40 bed medical admission unit. Prevention and treatment of AKI should be a core competency of all clinical staff. Educating and empowering the multidisciplinary team to implement simple interventions improves standards and should be the foundation of strategies targeting AKI. Through this study significant improvements have been demonstrated in AKI recognition and management, positively impacting on patient safety, quality of care and patients' and staff experience. PMID- 26734154 TI - Strengthening surgical handover: Developing and evaluating the effectiveness of a handover tool to improve patient safety. AB - The European Working Time Directive and economic challenges have led to a paradigm of shift-work becoming common, and yet the continuation of high-quality patient care remains paramount. Effective and safe transfer of clinical information is critical as emphasised by the Royal College of Surgeons document 'Safe handover: Guidance from the Working Time Directive working party (March 2007)'. The aim of this project was to design and implement a handover proforma in order to deliver a more efficient and safer system for patient care over the weekend. The surgical weekend handover proforma was designed following consultation with nursing and medical colleagues. It included a traffic light scoring system to alert the on-call team of the urgency of clinical review. An educational session was delivered to junior doctors on the surgical rotation to ensure accurate completion of the proforma. All trainee surgical doctors from Foundation Year 1 to Specialist Registrars were asked to complete a pre- and post intervention questionnaire. Improvement was noted in all categories measured. 85% of the firms were using the new surgical weekend handover sheet. 78% of junior doctors were confident in understanding the patient's condition and executing the clinical jobs faster, with ward rounds lasting less than 3 hours. On average, 20% of patients were discharged per weekend during the trial period. Robust patient handover is vital to maintain patient safety and avoid adverse events. Our findings support the use of a surgical proforma to provide a consistent and structured approach to inpatient handover during the weekend. PMID- 26734155 TI - Reducing Hospital Stay in Neonates with Suspected Sepsis. AB - 'Suspected sepsis' is one of the most commonly made diagnoses on any neonatal intensive care unit (NICU). Most neonates are discharged after 48 hours following negative blood culture results, thus inefficient analyses of these samples leads to delays in discharge. A baseline study demonstrated that, on average, discharge was delayed by four hours per neonate, with a range of up to 21 hours, with the longest delays being incurred as samples were not being analysed when they were received by the microbiology department out of hours. Furthermore, problems were due to increase, as the microbiology department was imminently moving to another hospital. In the short term, samples were couriered to another microbiology department, which incubates them overnight. The long-term solution is for the department to purchase their own in-house analyser, for which a business case was developed, presented, and agreed to by the lead neonatal consultant. Unfortunately, the Trust does not believe the venture is financially viable at present. PMID- 26734156 TI - Management of Parkinson's Disease medication in acutely admitted patients. AB - This project aimed to identify problems in the management of Parkinson's Disease (PD) medications in those acutely admitted to the medical ward. Errors in prescription of medications are due to difficulties in conversion of formulation of medications to suit different needs, lack of awareness of help available amongst junior doctors and lack of awareness of trust guidance. Drug charts were audited over two weeks on medical wards. Dosing, frequency, formulation, and any difficulties in the administration were noted. A survey of junior doctors regarding their knowledge of PD management was also undertaken. The effects of our interventions (creation of summary guidance made available on wards, advice regarding where to obtain prescription information, and teaching sessions) were evaluated using a survey and audit. There was improved accuracy in PD prescriptions, improved confidence in switching formulation, increased awareness of trust guidance and the consequences of missed doses of PD medications. However there was no improvement in knowledge about appropriate resources used to make correct prescriptions. Increased education and training is required to continue improvement in prescription accuracy and awareness of where to seek help, to improve patient safety. PMID- 26734157 TI - From Zero to Hero, the rise of the Trauma and Orthopaedic discharge summary. AB - Discharge summaries document key information after an in-patient care episode and hand back care to the GP. Locally our orthopaedic department used carbon-copy paper as a discharge document. Anecdotally, these were thought to be inaccurate, illegible and of poor quality. Complaints from GPs became a catalyst in assessing the accuracy and presenting it to the department. A baseline dataset of inaccuracies was collected. This became a good starting point to develop a new improved system of discharging orthopaedic patients. We proposed to develop a bespoke, electronic, patient centred discharge document. Our aims were to improve patient safety, quality and develop an adaptable document, which could be updated to be in line with local CQUINs. The initial challenges of the resistance to change within the department were overcome by presenting data in an open forum with an agreed trial period. A multidisciplinary team was formed, including managers, consultants, junior doctors, allied health professionals and IT personnel. This facilitated live decision making, streamlining the processes. We created an adaptable online document, which enabled regular updates. This in-turn improved the overall accuracy of the document, improved prescription of key medications and ensured we were able to fulfil local CQUINs. We highly recommend the use of subspecialty specific electronic discharge summaries. PMID- 26734158 TI - Prospective management of end-stage renal failure within a conservative care programme. AB - Progression to end-stage renal disease (ESRD) is a major issue for heath care systems both clinically and financially. Given dialysis may not prolong life, and may indeed impair quality of life, alternative options for these patients such as conservative care are urgently needed. We appointed a dialysis charge nurse who had many years of experience of working with patients on dialysis to spearhead the newly set up Conservative Care Programme (CCP) in the Edinburgh Renal Unit. The rationale was to work as part of the renal multidisciplinary team to support patients and their families to make an informed shared decision whether to opt for dialysis or to follow the CCP. From the perspective of the patients, their families and carers we have received positive feedback since starting the CCP - thank you cards; phone calls both to the CCP Nurse Specialist and the renal unit affirming the positive experience patients had during the conservative management of their renal failure. Whilst continuing to provide the best quality of care to renal patients in NHS Lothian and Borders, the number of prevalent dialysis patients in our catchment area has fallen significantly over the last few years as demonstrated by Scottish Renal Registry data. These benefits are potentially applicable to other renal units across the UK. PMID- 26734159 TI - Making the ward a more efficient place: a qualitative evaluation of the impact of the Vista 90 trolley. AB - A significant amount of professional time is wasted during a medical ward round retrieving patient notes from the ward trolley. If the efficiency of this non clinical, non-functional interaction could be improved it would save time, maintain continuity and have financial implications. One identified constraint was the structure of the traditional ward trolley; a stationary filing tray with vertical sleeves. During ward round, time is spent returning and retrieving each patients notes from outside the patient bay and additional time may be wasted if the notes are misplaced or in use elsewhere. To resolve this, the 'Vista 90' trolley with horizontal, transparent trays, is portable and has an ergonomic writing surface was selected as a potential second generation replacement. An assessment of the impact of the Vista 90 trolley over the traditional trolley in the clinical setting was carried out on Erringham (medical) Ward, Worthing Hospital, West Sussex Hospital Trust, UK. This was by way of qualitative analysis performed by semi-structured interview of 12 doctors and other healthcare professionals who regularly interacted with the Vista 90 and traditional trolley in December 2012. The audit found that those interviewed preferred using the Vista 90 trolley over its predecessor as it improved the efficiency of the ward round and subsequent clinical work. It's mobility allowed it to be easily transported with the ward round, reducing disruption during a consultation and between consecutives ones. The ergonomic writing surface was noted to improve legibility of documentation due to greater comfort and if placed appropriately, did not interfere with the doctor-patient interaction. The financial savings of this greater efficiency was found to be of significance and justify the cost of the Vista 90 within two weeks. PMID- 26734160 TI - Improving safety of sedation for transoesophageal echocardiography. AB - This project aimed to develop solutions for optimal, safe sedation, in transoesophageal echocardiagraphy (TOE). Prescription and dosage errors arise from physicians failing to approach experienced operators for assistance, and lack of familiarity with Trust TOE guidelines. We conducted a retrospective analysis of 319 patients who were referred for TOE over a nine-month period. Data was obtained from the hospital medical records and database. Midazolam doses exceeding Trust guidelines were being administered, posing unnecessary risks for under 18 and over 60 year-olds especially. This quality improvement project intervened by: 1. Adding a paediatric section with sedation dosage advice to Trust guidelines; 2. Increasing awareness of the need for lower sedation doses in over 60 year-olds, by updating the pre-procedure checklist with an age and maximum recommended midazolam dose section. These changes were accepted following presentation of the audit at the monthly Clinical Governance Meeting, and early indications reported increased confidence in midazolam dosing and awareness of the risks of not following the guidelines. Operator confidence in these changes requires re-audit, in order to confirm the findings, and continue improvement to the Trust TOE guidelines and patient safety. PMID- 26734161 TI - Reducing time spent by junior doctors on call performing routine tasks at weekends. AB - At the Northern General Hospital, there are sixteen medical wards, spread over approximately half a mile. Weekend care for inpatients on these wards is provided by a team of four junior doctors, of different levels of training. We undertook a quality improvement project to reduce the amount of time junior doctors spent performing routine tasks at weekends. This may increase their available time for direct patient care. The study was performed over a period of nine weeks on two medical wards - Diabetes & Endocrine (W1) and Care of the Elderly Rehabilitation (W2). We monitored the bleeps received by the covering junior doctors during the weekend daytime shifts from the two study wards. We noted that a proportion of bleeps were routine tasks that could have been performed during weekday working hours. We also noted that W2 recorded fewer bleeps than W1 ward. This seemed to be because W2 batched junior doctors' jobs together. Firstly, we attempted to reduce the amount of routine work left undone each weekend. We provided a poster to remind Junior Doctors to complete such work during the week. Secondly, on W1 we replicated the job-batching system already in place on W2. A Doctors' Book was introduced in which nursing staff recorded the tasks that needed doing. This saved them from having to bleep the doctor repeatedly. The two changes resulted in a reduction in the number of bleeps generated by each ward and the number of visits required by the Junior Doctors to W1. Simple changes can reduce the amount of time junior doctors spend performing routine work at weekends. We implemented two such changes and achieved a reduction in the number of bleeps experienced by junior doctors and the number of times they had to return to one ward. PMID- 26734162 TI - Implementing a Patient Safety Team to reduce serious incidents. AB - The Division were experiencing a high number of serious incidents, and the Team felt that a good safety strategy would improve the quality of care given. Through multidisciplinary engagement they wanted to learn from these, encourage reporting and focus on a fair blame culture. The ultimate aim was to increase incident reporting, decrease serious incidents and improve quality. The key aim of the project was to improve the quality of care for the woman and their babies, we reduced the incidence of serious incidents and increased the incident reporting of less serious incidents, this was based on the theory of the Heinrich Ratio which theorises that for every serious incident there will be 300 less serious / near miss incidents. The Team wanted to ensure that the multidisciplinary team were engaged and felt confident to report incidents, and would receive the appropriate feedback and support. In addition all staff involved in the incident would be involved in the investigation and be at the heart of the decision making. The key measure for improvement was the increase in incident reporting (44% increase 2011 - 2012) and the decrease in serious incidents. The figures support the theory that the increase in minor incidents being reported and managed has reduced the incidence of serious incidents. Staff engagement in the process was paramount, and this was driven by a passion to ensure the woman was at the centre of every decision or safety improvement that was made. Women and their families would be involved in the quality improvement process. PMID- 26734163 TI - Cardiovascular health monitoring in patients with psychotic illnesses: A project to investigate and improve performance in primary and secondary care. AB - Patients with psychotic illnesses are predicted to die 15 years younger than the national average. The chief cause is cardiovascular disease (1). Evidence-based guidelines including those produced by the National Institute of Health and clinical Excellence and the Quality Outcomes Framework, recommend regular monitoring of their cardiovascular risk (2,3,4). Primary health care audits were undertaken in an urban and a rural setting. These looked at the proportion of patients who had their physical health regularly monitored in line with NICE guidelines. Following an audit in general practice, it became clear that there was a group of patients that were chronic non-attenders. It was not clear whether these patients were the responsibility of the general practices or psychiatric services. An audit in secondary care then looked at the level of cardiovascular health monitoring in that setting, and the communication of results to primary care. These audits demonstrated that monitoring of cardiovascular health did not meet standards as set by NICE. Further to this, communication of findings between primary and secondary care was also poor. Primary care interventions included setting up Alert reminder boxes on the computer system and sending invitations for clinic attendance to 'at risk' patients. In secondary care interventions included redesign of the patient lists to include a way of monitoring cardiovascular health and generation of a new discharge summary to facilitate communication of cardiovascular indicators to primary care. These interventions have resulted in marked improvements in cardiovascular health monitoring in primary care, however, there is still room for considerable improvement. Discussions about further intervention strategies, and further audit cycles, are ongoing. PMID- 26734164 TI - Improving patient access at a movement disorder clinic by participating in a Process Improvement Program. AB - Our multi-disciplinary neurology team were dissatisfied with long access times for consultation for new referrals. We participated in a rapid process improvement workshop and a structured improvement process. Over a six-month period we were able to reduce our access time for initial appointment for patients with suspected movement disorders from 133 to 20 days. We implemented a 'carousel' multi-disciplinary appointment and a standardised clinic form that improved the flow of patients and that we estimate will save 150 hours of physician time and 320 hours of administrative time per year. PMID- 26734165 TI - Competence in confirming correct placement of nasogastric feeding tubes amongst FY1 doctors. AB - Foundation year one (FY1) doctors are required to confirm correct placement of nasogastric (NG) feeding tubes on chest radiography on a regular basis. Many FY1s do not receive formal training during medical school or during the FY1 year. Multiple incidents of harm to patients, including death, resulting from incorrect placement of an NG feeding tube have been reported to the National Patient Safety Agency (NPSA) since 2005. Our audit assessed the confidence and knowledge of FY1 doctors in correctly confirming NG placement using a qualitative questionnaire. The results showed that both confidence and knowledge on the topic were remarkably poor. Our intervention consisted of a teaching session to the FY1 cohort, which included information on NPSA guidelines for identifying correct NG placement. A post-teaching questionnaire was attained from the same group of FY1s. Confidence and knowledge of the criteria had significantly improved. We concluded that there is clearly a need for teaching on this subject at an undergraduate and post-graduate level. The interactive peer-led style of our teaching session was shown to be highly effective. The addition of handouts and posters in the clinical workplace acted as helpful reminders for junior doctors to use at the point of need. Our project has highlighted a gap in training which poses a serious potential risk to patient safety. We have created a simple solution which, if adopted on a local and national scale, will facilitate a reduction in avoidable harm to patients. PMID- 26734166 TI - Professional Support, London: the professional development unit supporting practitioner well-being, refreshment, remediation and revalidation. AB - London' s Professional Support Unit (PSU) was launched in April 2012 at a time when changes and financial pressures across the health service were placing considerable demand on the medical and dental workforce. At the same time the infrastructure to support medical revalidation was established. The PSU provides developmental support to clinicians across London in all career grades and specialities, to sustain and restore them to contribute effectively to health service delivery across the capital. The costs of medical training are high. Maintaining doctors at work has to be cost effective. Clinicians in multicultural London require diverse resources, as increasing numbers have trained abroad. The PSU offers a holistic, tailor-made approach to professional and personal development with a range of resources and approaches. It provides proven high quality educational interventions, creating a linked and integrated service, providing clinicians with new opportunities. Access is by self-referral with resources targeted at those going through transitions in their professional lives, as well as those who have specific developmental needs. A collaborative approach across the PSU and its education and governance communities ensured the provision of personal support to over 1300 clinicians in its first year, together with interdisciplinary group learning opportunities. Online materials were created to assist individuals, workplace groups and a broad network of support and expertise. To maximise the effectiveness of the service, learning events were also held for those working within the PSU. In commending the PSU and its positive impact, the General Medical Council has recommended the model be shared nationally. At the same time the London's three Local Education Training Boards have recommended that the PSU expand to encompass a more diverse range of professional groups. Our challenge is how to extend such flexible, responsive and values-based support across the workforce, given stringent financial pressures. PMID- 26734168 TI - How can we reduce violence and aggression in psychiatric inpatient units? AB - The inpatient environments in psychiatric units are not always conducive to patients' recovery. Male patients can easily feel bored especially when they are not interested in indoor activities like arts and crafts. Outdoor activities were little explored in our psychiatric intensive care unit and partly this may reflect a 'risk averse' approach. Like a pressure cooker, the patients' anger and frustration build up and unfortunately they may lash out on staff and other patients placing them at risk. The incidents of violence and aggression in our unit rose to 482 in 2011. The Blackpool zoo was close to our unit and it was felt that our patients may benefit a weekly trip to the zoo. Other activities like computer and gym sessions were maintained. Although there were initial reluctance and anxiety amongst staff to escort patients outside the unit, regular support and encouragement made them more confident and less risk averse. Our patients provided lots of positive feedback and felt better equipped to 'fit in' with their community after discharge. The initial discrimination against our patients at the zoo slowly transformed into partnership working and the authorities at the zoo have offered a training programme for our patients on animal care and hygiene. Over a period of 12 months, the incidence of aggression and violence in the ward reduced to 126. The average length of stay reduced by about 50%. We also discharged patients who recovered remarkably well, directly from the unit rather than stepping down to acute wards. Staff motivation and enthusiasm continued to improve and this was reflected in the reduction in staff sickness rates by more than 50%. Student nurses and doctors were able to understand the positive aspects of patients' lives and skills and felt able to boost their hope and determination. PMID- 26734167 TI - Written medical discharge communication from an acute stroke service: a project to improve content through development of a structured stroke-specific template. AB - Specific guidelines for the content of discharge summaries from acute stroke services do not currently exist. The aims of this project were to assess the strengths and weaknesses of stroke discharge communication from Imperial College Healthcare NHS Trust, to develop a structured template to guide completion, and to re-audit discharge communication following its implementation. The audit compared local performance against record standards from the Academy of Medical Royal Colleges (1), which was augmented by criteria generated from the British Association of Stroke Physicians (BASP) Stroke Service Standards (2). Discharge information was examined within the Trust's Electronic Discharge Communication (EDC) system to determine the recording of selected items for consecutively discharged patients from the hyperacute and acute stroke units. The audit was repeated following implementation of a newly developed stroke-specific discharge summary template. Fifty-one EDC summaries were examined at baseline (July 2012) and 30 summaries at re-audit (January 2013). The criteria which showed low adherence initially and which showed the most significant improvement following the introduction of the template were the guidance on blood pressure and lipids targets (increased from 2% and 0% respectively at baseline, to 93% post intervention), and the driving and flying advice (from 3% to 79%). Documentation was also seen to improve for measures of physical and cognitive function, discharge arrangements, and follow up plans. This audit cycle has demonstrated improvement in the consistency of content within written discharge communication following the introduction of a structured stroke-specific template adhering to combined criteria from identified standards. PMID- 26734169 TI - Look before you LEAPPTM: An interprofessional approach to bedside pediatric inpatient procedures. AB - The Golisano Children's Hospital at Upstate Medical University is a 71 bed children's hospital within a hospital, serving nearly two million people in Central New York. Minor procedures occur daily in all children's hospitals, yet team coordination when planning for these procedures is often overlooked. LEAPPTM is a mnemonic for: Listen, Evaluate, Anticipate, Plan, and Proceed. The "Look before You LEAPPTM" program was developed by a group of nurses, child life specialists, faculty, a chief resident and a fellow. LEAPPTM is a team-based program providing consistent care to all children undergoing inpatient procedures. It improves patient satisfaction and reduces procedural distress. Through LEAPPTM steps, teams are created at point of care - at the bedside or treatment room of inpatient units. Educational goals are linked to the practical goal of cooperation for good health care. The approach uses an online educational module for residents, students and nurses to introduce an innovative protocol and a planning tool.1 Pocket cards, promotional pens, and logo door-clings, purchased through grant funds (The Foundation for Upstate Medical University) were initially used to encourage participation. Pre/post observations of procedural planning and performance of the nurse, caregiver, physician, child-life specialist and independent observer included patient and family preparation, pain and anxiety, staffing and supplies, and satisfaction. Fifty procedures were assessed pre-implementation and 28 post implementation. Although satisfaction with procedures improved between pre and post LEAPPTM implementation, there were overall differences in satisfaction with procedural management and pain/anxiety control by physicians, caregivers, and staff that remained statistically significant. Interdisciplinary bedside teamwork can be used to support interprofessional education and this education can similarly be used to support improved patient outcomes. PMID- 26734170 TI - Emergency suction equipment: barriers to use and effective interventions. AB - Both investigators had personally experienced situations when they were let down by emergency suctioning equipment on the wards: due to either lack of, or operator inability to use, equipment. Failings in emergency suction have been highlighted in a recent National Patient Safety Agency signal. We focused on improving the usability of cardiac arrest trolley suction: a complex process involving turning a small, hidden lever. We produced three clearly visible bright labels which provided simple prompts to the operator. Two wards and two sampling periods were used in a randomised controlled design. Medical, nursing and allied healthcare staff participated. A scenario of a vomiting patient was given and staff were asked to use emergency suction. This was timed. On the control ward, 5/10 staff members were able to successfully suction on day 1 and the mean time spent trying to activate suction was 43 seconds. On the second sampling day 6 were able to successfully suction and the mean time taken was 50 seconds. On the intervention ward, 7/10 staff members were able to suction with a mean time of 53 seconds spent. Post-intervention, all 10 staff members successfully suctioned with an average time of 30 seconds. The intervention gathered strongly positive feedback. These interventions are being incorporated into sustainable systems changes. Poor equipment design is a needless distraction during an emergency in a busy ward setting. Simple, innovative solutions provide assistance in a pressured situation. Ideally these would become uniform and lead to a culture shift towards simple, intuitive design. PMID- 26734171 TI - How creation of a parent satisfaction questionnaire improved multidisciplinary service delivery in a paediatric day surgery unit. AB - Auditing patient satisfaction has become a keystone of quality patient centred healthcare. A plethora of patient satisfaction studies exist but only a few studies have been evaluated for their validity, reliability, specificity or psychometric properties. And the majority focus on adult health care. However, if validated tools are not utilised, then inaccurate results could stymie service improvement. The level of satisfaction with the paediatric day surgery service at Tayside Children's Hospital was unknown. Our objective was to measure parent satisfaction with the paediatric day surgery by creating a parent satisfaction questionnaire which has undergone satisfactory testing for validity, reliability, specificity and psychometric properties. A Likert-style questionnaire was constructed through literature review and focus group meetings with professionals, parents and patient groups to establish content validity. Statements worded in positive phrasing were re-worded in negative phrasing to ensure intra-rater reliability. A pilot study was conducted and responses analysed for construct validity and inter-rater agreement. Internal reliability was established using Chronbach's alpha analysis, which produced scores for each part of the questionnaire between 0.7 and 0.9. Overall parent satisfaction was high. 95.48% either strongly agreed or agreed with positively worded statements regarding pre-operative clinic service. In particular 100% satisfaction was reported with the pre-operative phone call which only 70% of participants received. 96.60% strongly agreed or agreed with positive statements regarding service provided on the ward and 87.50% strongly agreed or agreed with positive statements regarding the discharge process. 5% specifically requested improved information giving. In conclusion the parent satisfaction questionnaire was found to have proven validity, reliability, specificity and psychometric properties. Overall parent satisfaction was found to be high. Areas identified for improvement included delivering pre-operative phone call to all parents who have children undergoing day surgery and further exploration of sources and methods of information giving. PMID- 26734172 TI - Telephone consultations in primary care, how to improve their safety, effectiveness and quality. AB - Consultations on telephone are ever increasing especially in primary healthcare. Currently the estimated total number consultations in England rose from 224.5 million to 243.1 million in 1995/1996 to 303.9 million to 313.6 million in 2008/2009, out of which 3% of consultations in 1995/1996 were telephone consultations which increased to 12% in 2008/2009. Literature search was done on published articles on tele-healthcare which resulted in devising a telephone consultation model. An audit was carried out in urban Cambridge family practice over the period of one year after implementing this telephone consultation model. Following proposed consultation model by healthcare staff, it has improved patient satisfaction survey from 75% to 94%, face to face consultation rate was reduced by 1.6%, home visits were reduced by 2.9% however the direct economic saving could not be determined. Further research is required to assess the detailed economic analysis of using effective telephone consultation in healthcare. The data shown in this article is related to primary care in the UK, but its concept can be replicated by any country in Europe or rest of the world providing primary healthcare to public. PMID- 26734173 TI - Rapid access rather than open access leads to improved effectiveness of an ENT emergency clinic. AB - An Ear, Nose and Throat (ENT) emergency clinic provides important access to specialist care for patients referred by General Practitioners (GPs), Emergency Departments and doctors on non-ENT hospital wards. The aim is to enable the prompt diagnosis and management of acute conditions, within an optimum environment containing appropriate clinical and staff resources. Amid concerns that an open access ENT casualty service had become overburdened we performed a four week audit of all attendances. We identified 45% of patients presenting to the clinic without having evidence of first accessing primary care assessment or treatment. Waiting times were unpredictable, averaging 75 minutes and clinic numbers above those recommended to be safe in national guidelines. 60% of attendances to the department were judged to be inappropriate. Subsequently the ENT emergency service was changed to an appointment based Rapid Access Clinic, with an easily accessible and prompt triage facility provided by a trained triage nurse. Concurrently the opportunity was taken to improve record keeping and formalise post consultation communication. Re-audit confirmed a 43% reduction in the number of patients accessing the ENT emergency clinic facility, allowing individual clinic numbers to fall to safe levels. Average patient waiting times fell by 70% to 22 minutes. The number of referrals judged to be inappropriate was halved. The transformation of our service has enabled time and resources to be more effectively directed towards a smaller number of patients, whose needs are more urgent. PMID- 26734174 TI - Improving medical SHO weekend handover at a tertiary referral centre. AB - The GMC states that, 'You must be satisfied that, when you are off duty, suitable arrangements have been made for your patients' medical care...including effective hand-over procedures' [1]. The medical weekend handover system at this tertiary referral centre involved multiple pieces of paper with no clear list of tasks, and no way to identify critically unwell patients. Patients could be missed from the ward round or could be difficult to identify under pressure. The authors felt this process could pose a threat to patient safety so decided to improve it. A questionnaire was distributed to all 11 medical SHOs with 100% response rate. Results showed that 72% thought the process was unstructured, 81% did not think the process was always safe, and 100% thought it could be improved. After discussions with senior medical management and with the approval of the trust audit committee, a new weekend handover proforma was designed, taking into consideration the results and comments from the questionnaire. The new proforma is accessible through a shared drive, which can be accessed by all medical SHOs in the hospital. Each team is able to copy their patients onto the combined ward based list. There are columns for specific weekend jobs and registrar/SHO reviews. Any potentially unwell patients are highlighted in bold and discussed with the on-call SHO on Friday. All medical SHOs were given a post-implementation questionnaire after the new handover process had been in place for two months. Results of this showed that 100% of SHOs felt an improvement had been made, with 100% stating that the new system was more structured (64% always, 36% most of the time). The SHO's perception of patient safety increased from 81% generally unsafe, to 100% generally safe. The new handover has been well received and supported by the current SHO cohort. Improvements in the structure of handover have been made with perceived improvements in patient safety. Due to the success of the system, the handover proforma is being implemented in the trust's sister hospital. PMID- 26734175 TI - Checklist clerking document improves health promotion among medical admissions. AB - Health promotion, as defined by the Ottawa Charter (1) is the 'process of enabling people to increase control over, and to improve their health'. Four life style risk factors: smoking, alcohol, obesity and physical activity are recognised as leading to health inequalities. These factors have implications at an individual, community and national level and the burden of disease has large cost implications for the NHS and country as a whole. Therefore the assessment of these risk factors, and the provision of good health promotion assist to address these problems. A pilot and initial audit demonstrated that assessment for the key life style risk factors and the provision of health promotion was poor. This quality improvement audit developed an easy to use, checklist based, amended clerking document. This improved both assessment and provision of health promotion and will be carried forward to influence the designing of a new clerking document. PMID- 26734176 TI - Improving documentation of treatment escalation decisions in acute care. AB - The aim of this project was to improve the documentation of treatment escalation decisions at a district general hospital in southwest England. A pilot "Ceiling of Treatment" proforma was trialled on the care of the elderly wards at the Royal United Hospital (RUH), Bath. Successive PDSA cycles enabled revision of the proforma for use across the Trust. Data were collected on the proportion of patients with a documented treatment escalation decision. Formative feedback was collected via questionnaire from trainees and discussion with special interest groups of consultants within the hospital. This approach involved collaboration between acute medicine, intensive care, elderly care, the resuscitation department, palliative care and the legal department. Documentation of ceiling of treatment decisions rose from 30% to 90% during the study. A survey of medical trainees showed 67% (n=36) had seen the ceiling of treatment form, of which, 100% found it useful on on-call shifts. Initiating a proforma to record treatment escalation decisions and combining this with the existing 'Do not attempt cardiopulmonary resuscitation' (DNAR) paperwork, increased decision making and documentation. This intervention ensures patients receive the appropriate level of care, as indicated by their consultant, and reduces anxiety for junior doctors during on-call shifts. PMID- 26734177 TI - The Effect of 'On-Line' POCT on Patient waiting times in an Accident and Emergency Department. AB - This POCT (point of care testing) team was constructed at the start of 2012 to implement the POCT project aiming to define and test the hypothesis that interfacing POCT devices to a clinical electronic order communications system reduces patient waiting times in an NHS Accident and Emergency Department (A&E). The devices selected for evaluation initially comprised the Sysmex XS 1000i haematology analyser and the Abbott i-Stat chemistry analyser. The POCT devices were interfaced to a server (Midlynx) which in turn was connected via the hospital internal network, to the ICE system (Integrated Clinical Environment). Test orders entered on the ICE system produced a bar code label read by the individual POCT devices. Once required tests were assayed, the results were transmitted back to the ICE system, where they could be viewed by users across the hospital site. The quality of POCT analytical performance was assessed by running quality control checks as recommended by the manufacturers and by exchanging samples daily with the clinical laboratory. The I-Stat (a Chemistry analyser manufactured by 'Abbott plc') was also tested against material obtained from a national external quality assurance scheme (NEQAS). The time taken to produce POCT tests was calculated as the time elapsed (TE) between requesting tests, and the time at which completed results were returned to the ICE system. Patient waiting times were derived from the patient administration system (Symphony) used in the A&E department. To assess the true effect of POCT on patient waiting times the analysis was confined to cases associated with POCT tests only (n = 217). A control population (n=229) was randomly selected from the clinical laboratory database. The time interval between requesting a test and receiving the results for the POCT tests was 23 minutes and for the laboratory tests, 60 minutes. The patient waiting times (time of discharge - time of arrival) was 167 minutes for the POCT group and 208 for the clinical laboratory group, a difference of 31 minutes. The project confirmed that interfaced (on line) POCT has many advantages with respect to the quality and safety of data management. The benefits include reliable identification of the requesting clinician and patient and the assurance that the right result is allocated to the right patient. The study also showed that the quality of results produced by the POCT devices met the requirements of the clinical environment. PMID- 26734178 TI - Improving spinal trauma management in non-specialist centres. AB - Fractures of the vertebral column are increasing in incidence. Even though spinal trauma is increasingly being managed in specialist units, these patients often still initially present to district general hospitals. Due to lack of exposure to these patients, the attending Orthopaedic Senior House Officer may not always be aware of current best practice in the acute management of these patients beyond immediate Advance Trauma Life Support measures. There is concern that initiation of management may be delayed as a result of lack of a concise documented plan. The physiotherapy team requires specific instructions from the orthopaedic team before they can attempt to mobilise these patients. Lack thereof may lead to inappropriate prolonged immoblisation, prolonged hospital admission and, as a result, medical complications such as aspiration pneumonia, other nosocomial infections or pressure sores. An audit of departmental practice in two district general hospitals in the London and KSS deaneries demonstrated that a lack of easily accessible guidelines led to delays in definitive management of these patients with several episodes of medical concern. A proforma was devised in conjunction with the physiotherapy department and the regional spinal orthopaedic service in order to aid doctors in formulation of these management plans. These were rolled out effectively in both centres and re-audit in the first centre demonstrated marked improvement in patient care. Re-audit in the second hospital is ongoing. PMID- 26734179 TI - Improving patient discharge process using electronic medication input tool and on line guide to arranging follow-ups. AB - Complete, accurate and timely discharge summaries (TTOs) enable effective communication between hospital teams and GPs. It can prevent adverse events and reduce hospital readmission rates (1). If the discharge summary does not contain important information (e.g. follow-up arrangements, accurate discharge medication list), or if follow-up arrangements are not made, then patient care and outcome can be adversely affected (2,3). An electronic Medication Input Wizard was developed to improve the quality and reduce the error rates of TTOs. The Wizard makes entering drug information faster; prompts for reasons medication changes; provides examples for Controlled Drug (CD) prescribing; and prompts to refer patients taking warfarin to anticoagulation clinic. An on-line guide was developed which explains how to arrange investigations and appointments. Retrospective studies of TTOs were carried out before and after these interventions, analysing documentation of medication and completion of intended follow-up arrangements. A baseline audit found 65% of medication changes on TTOs were not clearly documented, and only 8% with changes documented reasons. 40% of prescriptions for CDs were incorrect delaying discharge by 4.9 hours per patient. 80% of intended follow-ups actually happened. After intervention, TTOs written using the Wizard had 100% of medication changes documented, and 75% were documented with reasons. CD errors decreased to 28% (76% of errors were done without using the Wizard). Follow-up arrangements that occurred increased to 86%. A survey showed 78% of Doctors reported the Wizard was faster than typing the details in separate textboxes, and 94% believed it was beneficial. Systems should be optimised to encourage better documentation of medication details and reduce prescribing errors. Guides that explain how to make follow-up arrangements should be accessible to Doctors, to make sure follow-ups are organised correctly. PMID- 26734180 TI - Using a proforma to improve standards of documentation of an orthopaedic post take ward round. AB - In Trauma and Orthopaedics, a daily Trauma Meeting (TM) occurs, where the previous 24-hour take is discussed and a management plan is decided by the consultant on-take. The post-take ward-round (PTWR) usually follows. In the district general hospital (DGH) where this audit was conducted, clinical incidents and root-cause analysis revealed that the TM/PTWR documentation were suboptimal. We identified gold standards. Variables included clear documentation of PTWR, date/time, consultant on-take, clinician leading the ward-round, and management plan. 50 cases were reviewed retrospectively. 72% were seen on PTWR. 47% of these were clearly labeled PTWR. 64% of the cases not seen on PTWR were weekend admissions. Documentation of the previously mentioned fields were also poor. Audit results were presented at the department meeting and a Trauma Meeting/Post-Take Ward Round Proforma was implemented. A prospective re-audit of 50 cases revealed that patients not seen on a PTWR decreased to 18%; 4% of these were weekend admissions. 88% of patients seen had a proforma completed. 18% of all cases did not have a proforma. Introduction of the proforma established a system to document discussions at the TM and improved the quality of documentation of the consultant-led plans. Such a simple tool can improve the overall care of patients and potentially protect staff. PMID- 26734181 TI - Training the Trainers of Tomorrow Today - driving excellence in medical education. AB - Training the Trainers of Tomorrow Today (T4) is a new way to deliver "Training for Trainers". Responding to local dissatisfaction with existing arrangements, T4 builds on 3 essential requirements for a future shape of training: 1. Clinical Leadership and a Collaborative Approach 2. Cross-Specialty Design and Participation 3. Local Delivery and Governance Networks Design principles also included: 3 levels of training to reflect differing needs of clinical supervisors, educational supervisors and medical education leader, mapping to GMC requirements and the London Deanery's Professional Development Framework; alignment of service, educational theory and research; recognition of challenges in delivering and ensuring attendance in busy acute and mental health settings, and the development of a faculty network. The delivery plan took into account census of professional development uptake and GMC Trainee Surveys. Strong engagement and uptake from the 11 Trusts in NW London has been achieved, with powerful penetration into all specialties. Attendance has exceeded expectations. Against an initial 12 month target of 350 attendances, 693 were achieved in the first 8 months. Evaluation of content demonstrates modules are pitched appropriately to attendees needs, with positive feedback from trainers new to the role. Delivery style has attracted high ratings of satisfaction: 87% attendees rating delivery as "good?excellent". External evaluation of impact demonstrated improved training experiences through changes in supervision, the learning environment and understanding of learning styles. We have addressed sustainability of the programme by advertising and recruiting Local Faculty Development Trainers. Volunteer consultants and higher trainees are trained to deliver the programme on a cascade model, supported by the Specialty Tutors, individual coaching and educational bursaries. The Trainers are local champions for excellence in training, provide a communication between the programme and local providers, are a repository of expertise in their service, and trouble shoot local barriers to engagement. PMID- 26734182 TI - Improving treatment provision of Wet AMD with intravitreal ranibizumab. AB - Wet age-related macular degeneration (AMD) treatment using intravitreal ranibizumab needs to be started as soon as possible and treatment must be administered based on regular review to achieve the best results. In clinical practice this tight schedule is a challenge and methods of carrying out such timely treatment is the objective of this quality improvement work. A departmental audit was carried out on the service providing treatment for patients with wet AMD in 2009. This audit identified that the appointment system did not meet the ideal standards and subsequently wet AMD patients' visual outcome were poorer than the standard set in trials where the patients were seen and treated at predetermined intervals. In order to enhance the visual benefit of the administered therapy for our patients we thought it necessary to find ways to see and treat patients sooner as well as reduce time intervals between follow-up appointments. The quality improvement was carried out through redesigning the service in the macular treatment centre of Manchester Royal Eye Hospital. Three main strategies were implemented including: changes to the appointment system, expansion of the treatment facility and employment of additional staff. Following changes made, regular re-audits were used to analyse the effectiveness of the new strategies. The changes introduced have brought appointment standards to the level of Royal College of Ophthalmologists' recommendations. Consequently visual outcomes were approaching the standards set by landmark studies. The visual improvement of treated patients seen in the 2011 audit are comparable to other reports outside clinical trials in the UK. In order to enhance the efficacy of ranibizumab for wet AMD it is essential for treatment to be initiated as soon as possible and administered to patients at the recommended time intervals. The actions we have taken were effective in helping develop a service performing to higher standards. PMID- 26734183 TI - Implementing scientific evidence to improve the quality of Child Protection. AB - In contrast to other areas of medical practice, there was a lack of a clear, concise and accessible synthesis of scientific literature to aid the recognition and investigation of suspected child abuse, and no national training program or evidence based guidelines for clinicians. The project's aim was to identify the current scientific evidence for the recognition and investigation of suspected child abuse and neglect and to disseminate and introduce this into clinical practice. Since 2003 a comprehensive program of Systematic Reviews of all aspects of physical abuse, emotional abuse, and neglect of children, has been developed. Based on NHS Centre for Reviews and Dissemination standards, methodology was devised and reviewers trained. Dissemination was via peer reviewed publications, a series of leaflets highlighting key points in a Question and Answer format, and a website. To date, 21 systematic reviews have been completed, generating 28 peer reviewed publications, and six leaflets around each theme (eg fractures, bruising). More than 250,000 have been distributed to date. Our website generates more than 10,000 hits monthly. It hosts primary reviews that are updated annually, links to all included studies, publications, and detailed methodology. The reviews have directly informed five national clinical guidelines, and the first evidence based training in Child Maltreatment. Child abuse is every health practitioner's responsibility, and it is vital that the decisions made are evidence based, as it is expected in all other fields of medicine. Although challenging, this project demonstrates that it is possible to conduct high quality systematic reviews in this field. For the first time a clear concise synthesis of up to date scientific evidence is available to all practitioners in a range of accessible formats. This has underpinned high quality national guidance and training programs. It ensures all professionals have the appropriate knowledge base in this difficult and challenging field. PMID- 26734184 TI - An inter-professional education programme for diabetes care in London. AB - Over the years there has been a steady increase in avoidable referrals from primary to secondary care for newly diagnosed diabetic patients. Audits have shown that diabetes referral rates were rising yearly. Secondary care is becoming overwhelmed with the heavy workload and increasing cost, which also led to compromising care for complex patients. This led to the design and implementation of a diabetes based inter-professional education (IPE) programme. The IPE programme was taught in cycles. Each cycle consists of 10 sessions. One session was taught for one afternoon a week over 10 weeks. On the 11th week an OSCE style end of course assessment was performed. Health care professionals (HCPs) from different professions were taught in the same classroom, using the same material. A re-audit of diabetes referral rates showed a change in referral ratio post programme. Qualitative interviews using Kirkpatrick and Barr's hierarchy were performed 2 years post-programme to assess learners' outcomes. Results show that the effects of the programme were sustained beyond 2 years and that these changes were carried into practice. There was a change in HCPs attitude and perception and more importantly it showed improvement in patient outcomes. This represents a novel IPE programme for diabetes care which has shown to be able to increase confidence, capacity and scope of care provided by HCPs in the community. PMID- 26734185 TI - Improving the transport of urgent specimens to an off-site laboratory using a novel sticker-tracker. AB - Obtaining results for urgent microbiology specimens in an efficient manner is imperative to ensure that patients receive appropriate antibiotic therapy. A previous audit carried out in the Paediatric department of a central teaching hospital and a number of clinical incidents, highlighted a delay in transport of specimens (exceeding eight hours) and 'missing' specimens. This results in empirical antibiotic treatment of infection, with delay in confirming microbiology result and unnecessary, distressing repeat investigation. As an initial step we sought staff opinion to further explore the problem. A sticker was designed for the microbiology specimen bag to assign accountability, track each step in the transport process and to raise awareness of the problem. The sticker required the member of staff responsible at each stage of the process to time, date and sign it, to allow tracking of potential delays. The new sticker tracking system was promoted and launched in the Paediatric department. Initial challenges included lack of awareness of the protocol and lack of pods for sending urgent specimens. The team met regularly and completed stickers were analysed weekly to identify on-going issues and to devise solutions. Consequently total transport time was reduced to an average of 69 minutes by September (within four hr target). Our intervention improved the efficiency and reliability of urgent specimen transport. This is likely to result in safer antibiotic use and avoid the need for repeat investigation. The system is now also used in the Neonatal department and has lead to the development of a new 'Central Specimens Reception'. PMID- 26734186 TI - Admission avoidance using intramuscular antibiotics for the treatment of borderline foot infections in people with diabetes in a tertiary care foot clinic. AB - Several international guidelines exist to help decision making for the infected 'diabetic foot'. However, none consider admissions avoidance. We wanted to develop an antibiotic foot formulary for the empirical treatment of diabetes related foot infections presenting to our service and subsequently to asses the costs associated with the introduction of our protocol. We rationalised our antibiotic protocol. The introduction of our formulary changed the average antibiotic prescribing costs for a 3 week course of treatment from L17.12 to L16.42. In addition, we adapted the Infectious Disease Society of America (IDSA) guideline by introducing a category of 'moderate infection - borderline admission' to our classification. This enabled the administration of outpatient intramuscular antibiotics. Over 22 months of follow up, 26 episodes were eligible for treatment with intramuscular antibiotics. Over the same time period, 121 people were admitted directly from the foot clinic. The costs saved as a result of avoided or delayed admission for those 26 episodes was over L76,000. For 12 people who required subsequent admission, their length of hospital stay was significantly shorter than those admitted directly (9.25 days [range 2-25] vs. 16.11 [2-64] p=0.045). In summary, by modifying the IDSA classification and adopting a protocol to administer outpatient oral and intramuscular antibiotics we have led to substantial cost savings, shorter hospital admissions and also have developed a successful admissions avoidance strategy. PMID- 26734188 TI - Using a screening tool to improve timely referral of patients from acute oncology haematology to palliative care services. AB - This project was done at specialist cancer hospital in Qatar. At a haematology oncology inpatient department most patients were not getting access to palliative care unless they were at the very end stages of life. Data collected from 2008 2011 showed significant numbers of patients were dying within one month of their transfer to palliative care. There was no standard measure to identify the prospective palliative care patients. A multidisciplinary team developed a Palliative care referral screening tool based on the National Cancer Care Network guideline. Retrospective medical record review done from January to April 2012 showed a mean of 68% of patients who scored more than five were not consulted, 32% of patients who scored more than seven were not transferred to palliative care and seven percent died without any referral. The team used various kinds of quality planning, analysis and improvement tools in the form of process mapping, value analysis, Fish Bone diagrams, stakeholders' analysis and communication, physician survey, "Pareto's principal" (80 / 20 rule, the law of vital few) and other data collection tools. The palliative care referral process was standardised by preparing and implementing an objective scoring tool based on international best practice. It changed the referral culture and helped manage the psychological barriers of patients, families and caregivers. Extensive orientation and education of all key stakeholders was implemented. Monthly auditing of patient records was carried out. The aim has been achieved, exceeded and sustained, and we reduced the percentage of patients who scored more than five without palliative consultation from a mean of 68% to 16% and those who scored more than seven without palliative care transfer from a mean of thirty two percent to three percent, after four months of the project's implementation. Standardising the referral process and creating an objective referral tool is needed to facilitate safe, collaborative, continuous and patient centered care. Timely referral of cancer patients to palliative care minimises patient and caregiver distress, ensures better quality of life, and provides an appropriate measure for end of life care. PMID- 26734187 TI - Improving transmission rates of electronic discharge summaries to GPs. AB - Discharge summaries are a vital tool to communicate information from Hospital to Primary Care teams; updating GPs about what happened during an admission, and handing over care detailing any follow up care required. Historically, Discharge Summaries have been posted to hospitals, increasing costs for hospitals, creating administrative work for GP practices receiving the letters, and resulting in some letters being lost or delayed in reaching the GP, with implications for patient safety if follow up requests are not received and acted upon. In an effort to improve patient care, the Clinical Commissioning Group in Surrey drew up a contract with Ashford and St Peter's Foundation Trust, aiming to increase the percentage of discharge summaries sent electronically from the rate of 9% sent within 24 hours, to over 75%. This contract set targets of 50% in May, 65% in June, and 80% in July. Financial penalties would be imposed if targets were not achieved, starting in June 2013. The Trust set up a working group comprising of doctors, IT personnel and ward PAs to devise a multi-pronged solution to achieve this target. The electronic discharge summary system was reviewed and improvements were designed and developed to make the process of signing off letters easier, and transmission of signed off letters became automated rather than requiring manual transmission by ward PAs. Presentations and leaflets to explain the importance of prompt completion and transmission of discharge summaries were given to Doctors to improve compliance using the revised IT system. Figures on transmission rates were automatically emailed to key stakeholders every day (Ward PAs, Divisional Leads) showing performance on each ward. This helped identify areas requiring more intervention. Areas (e.g. Day Surgery) that had not used electronic discharge summaries were engaged with, and persuaded to take part. As a result, transmission rates of Discharge Summaries within 24 hours of patient discharge increased from 9% on May 11th 2013, to 76% by June 29th 2013. This has improved communication with GPs, led to more reliable handover of care, and reduced costs for the Trust (both in processing and postage costs, and by avoiding fines). PMID- 26734189 TI - Targeting the initial investigation and management in cases of acute pulmonary embolism. AB - It was noted by consultants in our hospital that the early investigation of suspected pulmonary embolism (PE) lacked structure. This was causing delays in definitive diagnosis and early management. The resulting unnecessary use of investigation was also wasting resources. In particular, the inappropriate use of serum d-dimer tests was causing concern. The National Institute of Clinical Excellence (NICE) guidelines recommend use of the 2-level Well's score to target investigation in suspected PE. A baseline audit against the NICE guideline revealed that Well's scores were rarely used (only calculated in 12% of cases) and confirmed the suspicion that early investigation was poorly targeted. This project intervened using educational talks promoting the use of Well's scores in cases of suspected PE. Well's score proformas were placed in the emergency department and emergency assessment unit for reference. Their availability was advertised. This significantly increased the use of Well's scores (46% vs 11%, p<0.001). Fewer patients underwent unnecessary d-dimer measurements in cases of likely PE (65% vs 86%). Initial investigation was more targeted in cases where a Well's score had been calculated than in cases without a Well's score. For example, significantly fewer unnecessary d-dimer tests were performed in these cases (45% vs 100%, p<0.05). The cost of unnecessary investigation in suspected PE is not only significant financially but also in the resulting delay in definitive diagnosis and management for the patient. The simple intervention used here was effective in addressing this problem. PMID- 26734190 TI - Successful implementation of strategies to transform Emergency Department transfusion practice. AB - Blood component transfusion is an important and lifesaving Emergency Department (ED) procedure. It is not however risk-free and careful consideration of its clinical benefit for each individual patient is therefore essential. In 2008, we audited the patterns of blood component usage in 2007 within our ED. This work revealed that whilst 3209 units of blood component were ordered only 39.5% were transfused, and 9.5% were unaccounted for. This was the first and only published detailed look at ED blood transfusion practices. We had to address our poor traceability (i.e. unaccounted for units), our high blood usage, and our ordering of units which were then not transfused as this can lead to wastage. Firstly, better links between the ED and the Scottish National Blood Transfusion Service (SNBTS) were established. A set of improvement measures were then implemented including better ED medical and nursing staff education, monthly traceability reports sent to the ED clinical management teams, the introduction of an ED transfusion guideline, moving our blood fridge into the resuscitation room, having a named ED transfusion consultant and ED transfusion link nurse, ED consultant representation on the Hospital Transfusion Group and finally increasing awareness of ED emergency transfusion with a rotational thromboelastometry (ROTEM) research programme. In 2012, we re-audited our practice looking at our blood component usage in 2011. There was a 64% reduction in blood component ordering (3209 vs. 1034 units), a 39% reduction in blood component transfusion (1131 vs. 687 units), a 68% increase in the proportion of ordered units that were transfused and a 96% reduction in unaccounted units (289 vs. 9 units) between 2007 and 2011. In attempting to cost the savings resulting from our changes we showed that SNBTS spent L306,437 less in 2011 compared to 2007 on handling and issuing ED transfusion requests. Our improvements are immediately generalizable across the UK and the potential savings to the NHS are enormous. PMID- 26734191 TI - Quality improvement in Respiratory Medicine: Designing and implementing a bronchoscopy checklist at Southend University Hospital. AB - There is currently no standardised procedure checklist for bronchoscopies in the United Kingdom. Furthermore, very few hospitals appear to routinely use any form of checklist for these procedures. Conversely, the World Health Organisation surgical checklist has become standard practice in most hospitals, our own included, for all surgical procedures. Based on our own needs, we decided to create a bronchoscopy checklist which could be used at our hospital with the primary emphasis on ensuring patient safety and improving clinical outcomes. We surveyed local surgical checklists as well as endoscopic checklists used in hospitals around the world. We then created an initial draft which was sent out to consultation to all Respiratory Physicians in our hospital. Comments were also taken from the endoscopy nursing staff. After a series of consultations, a checklist was trialled over the course of two weeks. Feedback from use in the endoscopy suite resulted in further modifications and a final version of the checklist came into use in May 2013. It is now used for all bronchoscopic procedures carried out by Respiratory Physicians in the hospital. An audit is planned for later this year to monitor uptake of the checklist and to determine if it has changed outcomes. PMID- 26734192 TI - Post-acute surgical ward round proforma improves documentation. AB - In health care, record keeping of doctor-patient encounters is vital for quality patient care and medico-legal reasons. We audited the documentation of post-acute consultant ward round (PACWR) in our department before and six months after an introduction of a proforma (standard form). The clinical notes of all patients admitted acutely under General Surgery over a period of one week before and one week after the introduction of a proforma were reviewed to note whether time and date, signature, impression and dietary plan were documented after PACWR. The nurses were also surveyed on the day of the PACWR for their certainty regarding the dietary plan of their patients and whether they had to contact the surgical team for clarification. There were 108 and 103 patients eligible for the first and second study periods respectively. After the introduction of the proforma, there was a statistically significant improvement in the documentation of time and date (37% vs. 72%, p-value < 0.01) and impression (40% vs. 61%, p-value < 0.01). Improvement in the documentation of the dietary plan reached statistical significant only when the analysis was restricted to the cases where a proforma was filled out (78 out of 103 patients). Introduction of the proforma had no statistically significant impact on the nurses' certainty regarding their patients' dietary plan and the number of times they had to contact the surgical teams. In conclusion, PACWR proforma improves overall documentation. This will help in avoiding adverse effects on patient care and medico-legal ramifications. PMID- 26734193 TI - Helping children stop or avoid enteral feeding. AB - Long term enteral feeding is widely used to provides vital support for infants and children unable to feed orally, but once medically stable the transition to a normal diet can be difficult. Other children may need to commence tube feeding later in childhood because of difficulties associated with neurodisability, but recognising which children will benefit from tube feed is not straightforward. The Royal Hospital for Sick Children, Yorkhill set up a multidisciplinary feeding team in 2002 to help avoid unnecessary tube feeding. We accept only children who are either artificially fed or with severe nutritional problems and only after attempted uni-disciplinary management. The team members are a clinical psychologist, paediatric dietitian and consultant paediatrician, supported by a specialist paediatric registrar, assistant psychologist and administrative support. We can see only a small proportion of all with complex feeding problems, but aim to improve the care of such children generally. We disseminate the lessons learned within the Feeding Clinic via education locally and nationally and have an active programme of research. Over the first ten years of the clinic we have seen 222 patients of whom 67% were initially either tube or oral supplement fed, while only 29% remain so at follow up. In the first three years of the clinic tube fed children had spent a median of seven years on feeds before they were successfully weaned, but since then that has fallen to a median of 2.7 years. Of 53 other children referred for possibly tube feeding, 32 (60%) remain well on a normal diet and only ten (19%) have needed to start tube feeding. The service is highly cost effective. Salary costs are only around L65,000 per year, while weaning five children per year, reducing their years on feeds by four years, saves the NHS L130,000. PMID- 26734194 TI - Improving the management of Staphylococcus aureus bacteraemia, including MRSA. AB - Staphylococcus aureus bacteraemia is a serious infection associated with significant complications, including recurrence of bacteraemia, endocarditis and metastatic foci of infection. The management of these patients is often complex, involving appropriate source control, a thorough review and investigations to exclude metastatic foci and infective endocarditis. Additionally, a prolonged course of intravenous antibiotics is often required. As part of our quality improvement project, the following five aspects were evaluated in 56 patients with S. aureus bacteraemia at two District General Hospitals: 1) adequate and timely removal of the source of bacteraemia, 2) echocardiography to exclude endocarditis, 3) repeat blood culture to prove clearance of bacteraemia, 4) adequate duration and choice of antibiotics and 5) documentation of bacteraemia in the discharge summary. After an initial review revealed several areas for improvement, we instituted five Plan-Do-Study-Act learning cycles which involved: teaching microbiology trainees and junior doctors, improving clinical liaison and communication between the microbiology team and clinicians, as well as a clinical review of patients by the microbiology team where appropriate. The post intervention review evaluated 24 patients with S. aureus bacteraemia between November 2012 and May 2013. The proportion of patients undergoing an echocardiogram improved from 49% to 88%. Another marked improvement was seen in the timely obtaining of clearance blood cultures, with 88% of patients having clearance blood cultures within the 2-4 day window, compared to 56% pre intervention. 70% of patients with uncomplicated S. aureus bacteraemia received an appropriate antibiotic course post-intervention, compared with 59% pre intervention. Documentation of the S. aureus bacteraemia in the discharge summary improved from 65% to 75%. The support of the entire microbiology team was pivotal in the successful outcome of the quality improvement project. PMID- 26734195 TI - Improving out-of-hours intravenous fluid prescribing for junior doctors: a prescription label. AB - Junior doctors are routinely asked to prescribe intravenous fluids (IVF) out-of hours. Given time constraints and the number of unfamiliar patients, there is uncertainty about their prescription accuracy and safety, particularly in patients who have specific fluid balance requirements. An IVF prescription label was devised for the fluids section of the adult drug chart indicating important patient identifiers and diagnoses such as chronic heart/renal failure. The audit was carried out over a 16 day period, covering three weekends. A qualitative pre- and post-audit questionnaire assessed the confidence of junior doctors in out-of hours IVF prescribing. All doctors based on the ward during that specific time period were targeted for the post-audit questionnaire. Post-audit, 58% (n=7) saw the label. 86% of those seven doctors stated the label had prompted them to do the following: a) examine the patient b) check blood results and c) urine output. 100% stated that the label improved their confidence in prescribing IVF. In addition, 71% felt the label made them more cautious in prescribing IVF and 43% felt they prescribed less. Overall, all seven (100%) doctors stated that the IVF prescription label was a useful addition to the drug chart. In conclusion, pressurised junior doctors would feel more confident prescribing IVF for unfamiliar patients if crucial information was readily visible on the drug chart. This would improve the accuracy of fluid prescribing and patient safety. PMID- 26734196 TI - Decreasing the risk of iatrogenic lymphoedema after axillary surgery: a threefold intervention. AB - Procedures such as venepuncture and cannulation can precipitate Breast Cancer Related Lymphoedema (BCRL) in patients who have undergone axillary surgery. We noted that procedures were inadvertently being performed on the side of surgery at our hospital, as susceptible patients were not clearly identifiable to staff. An online anonymous staff survey at our hospital revealed that 26.9% of responders had seen procedures being performed on at risk arms in non-emergency settings. 83.3% of responders felt an intervention to allow easy identification of at risk arms would be useful. Our intervention was threefold. Firstly, we created an 'At Risk Arm' alert on the computerised records system. Secondly, we produced a warning sign for each susceptible patient's bed. The signs are displayed above beds, and returned to notes for use if the patient is re admitted. Thirdly, we informed GPs via discharge summaries of the need to perform procedures on the opposite side to surgery. A second staff survey was conducted after implementation. 46.2%of responders felt that the new interventions would decrease the chance of patients developing BCRL. 61.5% felt that susceptible patients being more identifiable to staff would decrease the likelihood of procedures being performed on at risk arms. Our project showed the importance of ensuring axillary surgery patients are clearly identifiable to hospital staff during admission. Further interventions could include wristbands or patient alert cards. This work could be extended to include primary care and outpatient settings. PMID- 26734197 TI - Facillitating diabetes care - a community approach. AB - Instigated through the vision of a local GP, the South East Hampshire Community Diabetes Team (CDT) is provided by Southern Health NHS Foundation Trust. Through taking an integrated, multidisciplinary, community based specialist approach, the team works in partnership with colleagues across primary and secondary care. The team support care of both newly diagnosed people with diabetes (PWD), and those requiring ongoing follow up, unless they fall into the 'super six' categories. The key focus of the team is to optimise the knowledge and self management of diabetes through clinician and patient education programmes. PMID- 26734198 TI - The utilisation of the MUST nutritional screening tool on vascular surgical wards. AB - Whilst malnutrition is prevalent in approximately 40% of general surgical patients, the prevalence of malnutrition and nutritional screening practices amongst vascular patients remain unknown. The Malnutrition Universal Screening Tool (MUST) is recommended for risk screening and provides 3 scores for risk classification: 0=low risk, 1=intermediate risk, 2=high risk. The aim of this preliminary study was to evaluate the use of MUST on vascular wards. This prospective study was undertaken in a tertiary referral vascular unit in the UK. Patient demographics, utilisation of MUST by nursing staff (N-MUST) and referral to nutritional support teams (NST) were studied. When MUST was not completed by nursing staff, the study team (S-MUST) performed it. Fifty-three patients, median (interquartile range, IQR) age 67 (59-75) years were initially studied. For N MUST: Overall MUST score was recorded in 18/25 (72%) patients, of whom 1 (4%) scored 2, whilst the remainder scored 0. For S-MUST: Overall MUST scores were recorded in 28 patients, MUST=0 in 75% and >=2 in 21%. An educational session on use of MUST was delivered to nursing staff, as well as a Trust-wide educational initiative to improve assessment of nutritional status and, after a 2-month period, the study was repeated. The second cohort comprised forty-two patients, median (IQR) age 72 (64-79) years. For N-MUST: Overall MUST score was recorded in 37/40 (93%) patients, of whom 3 (8%) scored >=2. For S-MUST: Overall MUST scores were recorded in 2 patients, MUST = 0 in 67% and >=2 in 33%. Despite the ease of use of MUST, it was under-utilised on vascular wards. However, following provision of a dedicated educational programme to ward nursing staff, utilisation of MUST for risk scoring patients on admission increased to over 90%. PMID- 26734199 TI - Improving e-discharge letters for Permanent pacemaker insertions at Wansbeck General Hospital. AB - 670 patients attend Wansbeck General Hospital each year for elective and emergency permanent pacemaker insertion or modification. Elective patients for new devices attend the cardiology department on the day of procedure and are clerked onto the cardiology ward after insertion. Patients are discharged home the following day with a letter typed by a junior doctor. Prior to October 2011, junior doctors were unaware of any guidelines regarding content of discharge letters due to poor accessibility. Vital information such as pacemaker model and indication for implantation were frequently absent from the typed summaries. In October 2011, the cardiology department reviewed the guidelines establishing the information required in all discharge summaries for pacemaker implantation and these guidelines were published on the ward in an easy to follow proforma for any junior doctor typing letters. Eight essential criteria should be included in each letter; date and indication for insertion, pacemaker type, make and model, access route, complications, chest x-ray and device check results, and follow-up details. Finally, a copy of the letter was to be sent to the cardiology department for clinic follow-up. Ten letters were audited prior to the proforma being issued. 0 letters contained 100% of the required information. Main criteria missing in most letters included indication for insertion (50%), make of device (0%), the route of access (10%) and cc to cardiology department (0%). 70 letters were audited in October 2012, one year following introduction of the discharge proforma.100% of letters contained all of the eight essential criteria required by the departmental guidelines. 53% of the letters were also received by the cardiology department. In conclusion, a set of easy to follow guidelines in the form of a published document on the cardiology ward has produced dramatic improvement in the quality of e-discharge letters for patients undergoing permanent pacemaker implantation. PMID- 26734200 TI - Improving Peripherally Inserted Central Catheter (PICC) care on a Trauma and Orthopaedics ward. AB - Peripherally Inserted Central Catheter (PICC) blockage rate was audited over a two month period on the Trauma & Orthopaedics ward at our District General Hospital. A 70% (five out of seven) PICC blockage rate was observed. High blockage rates lead to potential treatment complications, delays in delivery of treatment, increase in costs, and reduction in patient satisfaction. The factors contributing to the significant blockage rate include, long and contradictory PICC care guidelines, no information sheets in the patient notes, lack of training and awareness about care of, and flushing of, PICC lines, and lack of accountability for PICC flushing. Our project aimed to achieve a greater rate of PICC patency. We produced one succinct and comprehensive PICC care guideline, carried out staff training sessions, introduced a sticker reminding staff to flush the PICC line after use, and introduced a prescription of weekly heparin saline and PRN saline flushes (for monitoring and accountability). We used questionnaires to assess competency of hospital staff pre-teaching (doctors 6%, nurses 0%), and post-teaching (doctors 70%, nurses 38%). Blockage rate data post intervention is pending. Education improved awareness of guidelines amongst staff and we anticipate that the proposed interventions will translate into reduced blockage rates, improving patient outcomes and reducing costs. PMID- 26734201 TI - Reducing short-stay hospital admissions by ruling out non-ST elevation myocardial infarction and estimating coronary artery disease likelihood on an emergency department observation ward. AB - Chest pain is an important presentation in adult patients attending emergency departments (ED). The process of ruling out an acute coronary syndrome (ACS) conventionally requires a short in-patient stay. This places a significant burden on healthcare systems. Recent developments have encouraged us to explore the role of an ED observation ward in the management of these patients. We designed and implemented two proformas ('flowformas'). The first provides integrated guidance and documentation for the management of chest pain in the ED. In patients determined to be at low risk of short-term adverse outcomes the ACS rule-out process is now completed on the ED observation ward rather than on the cardio respiratory admission ward. The second proforma is used before discharge to determine the likelihood of underlying coronary artery disease (CAD), thereby allowing risk-based follow-up arrangements to be made. We collected data on all patients admitted to EDU on the NSTEMI rule-out pathway over a 12-month period. Between Feb 2012 and Feb 2013, 816 patients fulfilling the criteria were admitted on the pathway. 67 patients (8%) required admission due to ACS. 15 patients were admitted on two, and one on three occasions. In conclusion, it is possible to deliver ACS rule-out on an emergency observation ward. This reduces healthcare costs and shortens hospital stay. PMID- 26734202 TI - Bidding for and setting up a Comprehensive Stroke Unit. AB - Northwick Park is a district teaching hospital in NW London. In Jul 2009, Healthcare for London agreed to commission hyperacute stroke care in only eight units. These had to provide guaranteed minimum staffing levels, daily ward rounds including weekends and public holidays, and thrombolysis (clotbusting) treatment) 24/7. We were the only unit to bid that was not already a major neurology centre. Our successful bid had to be implemented to a very tight timetable and has now been operating for three years. Our results are audited nationally and demonstrate the success of the project. Before the project the Unit had 20 beds, one consultant and only three whole time equivalent therapists. We had thrombolysed 12 patients in two years. Patients did not go straight to the Stroke Unit from A&E. Although our rehabilitation processes were good we were limited by patients having to wait to get onto the Unit and by staff numbers. Now, there are 50 beds and over 130 staff. Performance is intensively monitored by the Stroke Network. Every patient is entered into the Royal College of Physicians continuous audit, and assessed against national standards. Our reputation is national and we have hosted teams from many units in the UK and abroad to demonstrate our processes and pathways. We conclude that with good planning, robust care pathways and a strong local management team backed by financial and Board level support, it is possible to implement a widespread change in treatment of a common and disabling condition. PMID- 26734203 TI - Introduction of 'Anaphylaxis Packs' to improve patient safety in a hospital setting. AB - Three reported episodes of anaphylaxis, where 1:1000 adrenaline was not immediately obtainable, triggered us to assess its availability on all adult wards. We found adrenaline was unavailable on 50% of audited wards. A questionnaire for doctors and nurses revealed lack of knowledge on both the management of anaphylaxis and location of emergency drugs. Given that anaphylaxis is a treatable but potentially fatal condition, we held a meeting to discuss the situation with senior pharmacists, resuscitation managers, and senior doctors. Our intervention was to advise the production of 'anaphylaxis packs' as part of the crash trolley kit. This was to be added to the laminated crash trolley check list and to include adrenaline, chlorphenamine, hydrocortisone, and the anaphylaxis algorithm. The aim was to improve ward stock, staff knowledge, and create a consistent location for emergency drugs, so minimising human error, and patient harm. With a PDSA approach we trialled the intervention on four pilot wards. The packs have now been dispersed trust-wide. Re-audit at four months showed 100% ward stock of anaphylaxis packs, more consistent drug location and improved staff knowledge. There were 17 coded incidents of anaphylaxis at this hospital in 2011, the actual figure likely being higher. We feel our project has greatly improved patient safety in this area. PMID- 26734204 TI - Oxfordshire Childrens Diabetes - The Primary Schools Intervention Programme. AB - Poorly controlled diabetes adversely affects a child's education, with concentration difficulties, alterations in mood, behaviour and fatigue associated with high or low blood glucose levels. Between years 2004-6 we started all toddlers and children on intensive insulin regimens (multiple dose injection or pump) making it imperative that they received support during the school day. This required close monitoring of blood glucose levels and counting carbohydrate intake to adjust rapid-acting insulin dose or pump bolus at every meal. We report our experience of formulating a sustainable structure of support in primary schools based on trained volunteers who partake in the daily 'Individualised Care Plan (ICP)'. After overcoming multiple barriers, an acceptable system was negotiated with our Primary Care Trust (PCT) and Local Education Authority (LEA). In 2009, the PCT confirmed 3 years funding for a Paediatric Diabetes specialist nurse (PDSN) for schools. In 2010, the first full school year with agreed protocols was in place. By July 2012, our nurses had trained a total of 342 volunteers who provide care for 132 children. The Oxfordshire Schools Intervention Programme ensures that legal obligations are met. A risk assessment allows the LEA to provide indemnity to their school staff to give injections and do blood tests, after training and competency sign-off by a PDSN. Parents, volunteers and PDSN jointly agree a comprehensive 'ICP' and utilise a hand-held communication record book. Diabetes control improved (age 4-11 years cohort from 2004 onwards: Mean (SD) HbA1c in 2001-4 = 8.38 (1.09)%; in 2005-8 = 7.74 (0.81)%; in 2009-12 = 7.58 (0.69)%; ANOVA p<0.001). This requires 500-1000 hours of DSN time to train/retrain/problem-solve annually (approximately 5-10days per month). The cost-benefits are discussed. We advocate that our programme supports each child's ICP, use of intensive insulin regimes in school-day and reassures parents that schools can deliver this safely. PMID- 26734205 TI - Improving documentation and use of ultrasound for suprapubic catheter insertions. AB - The British Association of Urological Surgeons (BAUS) published recommendations for the safe insertion of suprapubic catheters (SPCs) in January 2011. They identified a number of parameters surrounding the insertion and maintenance of catheters that should be identified, implemented and documented on each insertion. One such recommendation was the use of ultrasound, if available and appropriate, to aid insertion and improve patient safety. A previous review of our documentation showed that in 2009, ultrasound imaging was not utilised in any of the 19 SPC insertions. We retrospectively collected data for 36 SPC insertions between April 2010 and December 2011. The information collated was the same as that collected for the BAUS national SPC insertion audit. This quality improvement project identified a significant increase in the use of ultrasound during SPC insertion since 2009 with 17 out of the 36 (47%) cases using this imaging modality. Despite this increase, there was still substantial room for improvement. We also identified some areas of documentation that needed improving, particularly with regard to insertion technique and indication for insertion. As a result, a proforma was designed to be used on each SPC insertion ensuring that all required data is easily identifiable and clearly documented. This proforma is now being used as standard mandatory clinical practice within our Trust. PMID- 26734206 TI - Can a multi-factorial assessment and interventional programme decrease inpatient falls in an elderly care ward? AB - Each year approximately 282,000 inpatient falls are reported to the National Patient Safety Agency (NPSA). A significant number result in death, or moderate to severe injury. (1) Research shows that falls may be reduced by 18 to 31% through multi-factorial assessments and interventions. (4) If a fall cannot be prevented, the patient should receive a prompt and effective response to achieve the best possible recovery and avoidance of further falls. Using 'Plan-Do-Study Act' learning cycles, our aims were to decrease the inpatient falls rate in an Elderly Care ward by 20% and to improve post-fall care. A baseline audit reviewed incident report forms to establish the number of falls per 1000 patient bed days for one calendar year; the baseline falls rate was 14.70 falls per 1000 bed days between November 2010 and October 2011. A care plan to highlight at-risk patients and allow adaptation of care, a 'walking-stick' incentive poster to encourage nursing staff, and post-fall guidelines, were introduced. Feedback sessions with ward staff and a re-audit were organised subsequent to each intervention. Completion of the care plan was monitored to improve compliance. A re-audit at one year was conducted to assess impact. Feedback was positive regarding the interventions. Monthly monitoring of care plans achieved a compliance rate of 89% and highlighted up to 81% of patients were considered high-risk. The inpatient falls rate, re-audited at one year, was 12.44 falls / 1000 patient bed days, November 2011 to October 2012; a 15.4% reduction. This study demonstrates a 15.4% reduction in falls through use of a multi-factorial assessment and care plan and an incentive poster. As we are yet to obtain our initial goal of 20%, implementation and re-audit is ongoing. PMID- 26734207 TI - Development of an Integrated Subspecialist Multidisciplinary Neuro-oncology Service. AB - Traditionally, the poor outcome for patients with malignant brain tumours led to therapeutic nihilism. In turn, this resulted in lack of interest in neurosurgical oncology subspecialisation, and less than ideal patient pathways. One problem of concern was the low rate of tumour resection. Between 1997 and 2006, 685 treated glioblastomas were identified. In the first four years only 40% of patients underwent tumour resection, rising to 55% in the last four years. Before revision of the pathway, the median length of hospital stay was 8 days, and 35% of patients received the results of their histology outside of a clinic setting. A pathway of care was established, in which all patients were discussed pre operatively in an MDT meeting and then directed into a new surgical neuro oncology clinic providing first point of contact. This limited the number of surgeons operating on adult glioma patients and aided recruitment into research studies. Now, three consultant neurosurgeons run this service, easily fulfilling IOG requirement to spend >50% of programmed activities in neuro-oncology. Nursing support has been critical to provide an integrated service. This model has allowed increased recruitment to clinical trials. The introduction of this service led to an increase in patients discussed pre-operatively in an MDT (66% rising to 87%; P=0.027), an increase in the rate of surgical resection (from 40% to 80%) and more patients being admitted electively (from 25% to 80%; P<0.001). There was a reduction in the median length of stay (8 days reduced to 4.5 days; P<0.001). For the cohort of GBM patients that went on to have chemoradiotherapy we improved median survival to 18 months, with 35% of patients alive at two years, comparable to international outcomes. Implementing a specialist neurosurgical oncology service begins with understanding the patient care pathway. Our patients have benefitted from the culture of subspecialisation and the excellent inter-disciplinary working relationships that have been developed. PMID- 26734208 TI - Delivering preference for place of death in a specialist palliative care setting. AB - Over the last 10 years, one of the key themes of public policy in palliative care has been achievement of choice in place of death. In Marie Curie Hospice Edinburgh a baseline audit conducted in 2006 showed that only a small proportion (18%) of patients referred to hospice services died at home. The audit also revealed that only 31% of those who expressed a preference to die at home were able to do so, whereas 91% of those who chose a setting other than home achieved their preference. Overall achievement of preferred place of death was 56%. However a significant number of patients (29%) did not have a recorded preference. A programme of quality improvement has continued over the last 7 years to improve identification, communication and achievement of preferred place of death for all patients. The mechanisms to change practice have been: changes to documentation; changes to clinical systems to support use of documentation; support for clinical staff to recognise the value of discussing preferences; and support for clinical staff to develop new skills. In addition the programme has been incorporated into local clinical strategy and this has enabled gaps in service to be addressed with a new service to support early discharge of those patients who wish to die at home. A recent audit showed that all patients had a recorded preference or a documented reason why their preference was unclarified. One third of patients died at home - nearly double the proportion that died at home in the baseline audit. Seventy one per cent of patients who wished to die at home actually died at home - a substantial increase from 31% at baseline. Achievement of preferred place of death for patients wishing to die in the hospice remained high at 88%. The focus on assessment of preference for place of death has led to substantial improvements in the identification and achievement of preference for patients dying under the care of the hospice. Furthermore, it has been associated with an increase in the overall proportion of patients who die at home. PMID- 26734209 TI - Venous thromboembolism (VTE) risk assessment and prophylaxis in acute orthopaedic admissions: improving compliance with national guidelines. AB - "Each year over 25,000 people die from Venous Thromboembolism (VTE) contracted in hospital. This is more than the combined total of deaths from breast cancer, AIDS and traffic accidents". (1) Orthopaedic patients are at particular risk of VTE. In 2011, the project team carried out an audit into compliance with national VTE assessment guidelines on all acute trauma and orthopaedic admissions during a two week period at a District General Hospital. The study demonstrated that compliance was initially low, but showed a large improvement following the implementation of simple measures. The measures included: asking consultants to remind junior doctors, putting posters up in the trauma doctors office, asking nursing staff to check for a VTE assessment on admission to the ward, and putting reminders on the patient name board. The project team subsequently recommended an alteration to the hospital's computer system to incorporate a check of VTE assessment and prophylaxis. A second assessment using the same methodology sought to assess whether the previous improvements were sustained and the impact of this computer system alteration. Overall, compliance with national VTE guidance improved further. PMID- 26734210 TI - The F.R.I.D.A.Y.S. checklist - Preparing our patients for a safe weekend. AB - There is a higher incidence of mortality and adverse events among inpatients in UK hospitals at the weekend compared to weekdays. The high volume of routine tasks handed over by the weekday doctors on Fridays may be a contributing factor. An audit was carried out on four acute wards on a Friday evening at University Hospital Lewisham (UHL). It demonstrated that most patients had at least one outstanding task that would need completing by the on-call team over the weekend. To address this problem a concise and memorable checklist was created to ensure that routine jobs are completed by the weekday team prior to the weekend. The checklist uses the acronym "F.R.I.D.A.Y.S." to prompt doctors to hand over weekend bloods, ensure drug charts are reviewed, document a plan for IV fluids, complete discharge summaries, monitor antibiotic levels, dose warfarin, and clearly document the ceiling of care. The F.R.I.D.A.Y.S. checklist was printed onto history paper and integrated into the patient notes on a Friday ward round. The efficacy of the checklist was evaluated by reviewing the number of outstanding jobs on the wards after 17:00 on a Friday in the categories listed. F Phlebotomy R-Rewrite drug chart I-IV fluids D-Discharge summaries A-Antibiotic levels Y-Yellow book (warfarin) S-Resuscitation Status The number of outstanding jobs on a ward (A) that used F.R.I.D.A.Y.S. was 3 out of a total 132 jobs (2.3%) compared with 47 out of a total of 103 (45.6%) on a ward that did not use the checklist (B). When the F.R.I.D.A.Y.S. checklist is implemented there is an increase in the number of routine jobs that are carried out by the weekday team, and therefore a reduction in workload for the weekend on call team. Patient safety is improved as management decisions are made by a team that is familiar with the patient, and on call teams are able to prioritise emergencies. The cost saving of using the F.R.I.D.A.Y.S. checklist if implemented throughout UHL is estimated at L317,136 per annum. PMID- 26734211 TI - An implementation program targeted at non-physician, anaesthesia assistants improves the quality of laryngeal mask anaesthesia. AB - The laryngeal mask airway (LMA) is used to facilitate adequate ventilation in the majority of procedures requiring general anaesthesia in the UK. Excessive LMA cuff pressure and/or volume, generated by injection of air to form an adequate seal within the upper airway, has been associated with pharyngolaryngeal morbidity, an indicator of quality in anaesthetic practice. However, measurement of LMA cuff pressure to limit excessive cuff pressure is not routine practice, despite trial data showing this reduces adverse outcomes. Our aim was to reduce morbidity from the LMA through the implementation of an educational and interventional program targeted at anaesthetic nurses and operating department assistants (ODA), to alter their physician colleagues' practice. LMA cuff pressure measurements were made, and postoperative outcomes recorded, in an observational cohort of surgical patients over an initial 2-month period. These results, including patient morbidity and the evidence for LMA cuff pressure measurement, were presented to anaesthesia providers and their assistants. An implementation plan to adjust pressures within recommended levels was then undertaken by anaesthesia assistants. In 90 patients, >95% of LMA pressures were beyond the recommended level; higher volumes of injected air correlated with excess pressure (r=0.58; p<0.0001) and were associated with pharyngolaryngeal morbidity in 28% patients (P=0.04). There was no association with difficulty in LMA insertion, duration or type of surgical procedure. In the implementation cohort (102 patients), pharyngolaryngeal morbidity was reduced to 11% (P=0.001) in the 45 patients where LMA cuff pressure was reduced to within normal limits (absolute risk reduction: 38% (95% CI: 22-54%). LMA manometry in three patients (95% CI: 2-5) was required to prevent an episode of postoperative pharyngolaryngeal morbidity. A systematic educational and interventional program targeted at the entire perioperative anaesthesia team, but implemented by anaesthesia assistants, can improve perioperative safety and quality. PMID- 26734212 TI - A standardised storage solution for venepuncture/cannulation equipment could save an NHS hospital the equivalent of a whole junior doctor. AB - Junior doctors, nursing staff, and phlebotomists spend a large proportion of their time taking blood samples and siting (venous) cannulae. Approximately 350 blood samples are taken daily across 25 wards at the Royal United Hospital Bath NHS Trust. There is no standard storage solution for venepuncture or cannulation equipment. On-call junior doctors cover most of the hospital's wards. Time is wasted locating essential equipment on unfamiliar wards and nurses are frequently interrupted to assist. These delays can compromise patient safety in emergencies as well as contributing to a source of daily inefficiency. Junior doctors were timed collecting equipment needed for venepuncture and cannulation on unfamiliar wards. Initial results suggested large variation between timings on different wards. The medical admissions unit (MAU), which organises items for venepuncture and cannulation on a single trolley, was 4 times quicker than the mean of all other wards. MAU mean time 21.0s vs. Non-standardised wards mean time 103.0s (p<0.0001). Estimates suggest approximately 47 hours per week (the equivalent of a fulltime doctor) could be saved by implementing a standard trust-wide storage solution. We set out to introduce the MAU trolley format to all adult inpatient wards. All ward managers agreed to implement the trolley. 18 wards (72% of adult inpatient wards) already possessed the 'MAU style' trolley, which we standardised using an easy-to-follow inventory and laminated draw inlays. Feedback was very positive from doctors and ward staff alike. We repeated timings to validate the change and successfully presented a business case to senior management for a further 10 trolleys (L3623.78) for full adult inpatient ward coverage. As junior doctors, we identified a common problem, tested solutions, and made early simple affordable changes. Initial work helped us present a compelling case for patient safety and efficiency improvements, releasing money to implement modest trust wide quality improvement changes. PMID- 26734213 TI - Using routinely collected data to improve immunisation histories. AB - Immunisation is one of the most effective health interventions in existence yet outbreaks of vaccine-preventable diseases continue to occur in developed countries. High rates of cover are needed to provide adequate herd immunity and there is evidence that a significant proportion of paediatric inpatients are not up to date even in areas with high levels of community cover. A proportion of these children will have parents who consciously declined immunisation, however the remaining children represent a vulnerable cohort whose under-immunisation is not routinely identified. Two-hundred consecutive admissions to rural paediatric assessment unit had their routinely documented vaccination histories checked against their records on the regional Child Health Information System (CHIS). 30 children (15%) were not up to date on the CHIS, yet routine clerking only identified 5 of these children (17%). After introduction of a simple system whereby ward clerks and doctors were taught how to access and print full immunisation histories from the CHIS, a further 200 consecutive admissions were audited. A similar number were not up to date (29/200) but the proportion of children with missing immunisations correctly identified in the clerking documentation increased to 52% (15 children). This is a 35% improvement (95% CI; 12-58%). Access to routinely collected data can significantly improve identification of under-immunised children and contribute towards higher levels of individual and herd-immunity. PMID- 26734214 TI - Warfarin Management Pathway: A clear and safe algorithm, from admission to discharge. AB - Warfarin is the most commonly prescribed anticoagulant in the UK and the one most frequently associated with both fatal medication errors and litigation claims [1]. Its life-threatening interactions and side effects are a concern for all doctors. Identifying and implementing solutions to achieve safer prescribing and monitoring is imperative to improve patient safety. The National Patient Safety Agency (NPSA) has outlined the major risks associated with anticoagulant therapy and sought to establish safer practice [1]. The monitoring of safety indicators has been highlighted as a solution. This quality improvement project (QIP) introduces a management algorithm for oral anticoagulant therapy in hospital patients, validated through a completed audit cycle. It was completed at one district general hospital (DGH) in England and involved all inpatient wards. Doctors and pharmacists were interviewed to assess their knowledge of the correct pathways for management of patients on warfarin. The number of errors on hospital warfarin charts was audited over three weeks. These results, coupled with senior haematological advice led to the production of an algorithm illustrating the gold standard pathway for warfarin management from admission to discharge. It was emailed to all doctors in the Trust and a laminated copy attached to hospital Pneumatic Tube System (PTS) machines. The warfarin charts were re-audited over the following three weeks. The results showed a marked decrease in errors and incomplete anticoagulation referrals as well as a reduction in doctors' anxiety around prescribing warfarin. PMID- 26734215 TI - Improving the investigation of suspected deep vein thrombosis in the Emergency Department. AB - Deep vein thrombosis is an important medical condition that requires treatment to prevent further complications. However, diagnosing deep vein thrombosis is not straightforward because its symptoms can mimic a number of alternative diagnoses often leading to unnecessary investigation. The latest NICE guidance published in June 2012 provides a clear evidence-based approach to diagnosis which helps to minimise this potential loss of valuable time and resources. It was recognised that the Emergency Department was unaware of the latest guidance and demonstrated that it was often over and inadequately investigating suspected deep vein thromboses, unnecessarily using resources and putting patients at risk. To address this, a new investigation pathway and proforma were introduced into the department. It was placed onto the Trust website and incorporated into the departmental induction for new staff and trainees. Following the introduction of these changes, a re-audit demonstrated that the department's investigation of deep vein thrombosis improved significantly. In addition to increased adherence to the latest guidelines and improved documentation there was a 21% reduction in the total number of ultrasound scans performed indicating a significant impact upon both the department and patient care. PMID- 26734216 TI - Improving weekend patient handover. AB - The Royal College of Physicians state that 'handover, particularly of temporary 'on-call' responsibility, has been identified as a point at which errors are likely to occur' [1]. Working a weekend on-call covering medical wards is often busy and stressful for all junior doctors, with added pressure in trying to identify patients and tasks amongst several different pieces of paper and making important care escalation. All handover sheets from a random weekend were collected and studied. Only 57% of patients listed had the minimum expected 3 patient identifiers [2] included and just 11% had any indication of escalation planning. They were also often written on scrap pieces of paper and included varying levels of relevant patient background and information. After liaison with junior doctors and the handover committee, involving senior medical clinicians, a new handover sheet was created and uploaded onto the trust intranet, to rectify some of the problems identified. Junior doctors were also educated about the changes to weekend handover. At 2 months post-introduction, another set of weekend handover sheets were collected. All medical wards used the handover sheets for documentation of patients and tasks at a weekend and inclusion of 3 patient identifiers rose to 80%. There was also a big increase noted in clinical information and background included at weekend handover and anecdotally made weekend handover easier and less stressful. There was also increased consideration of escalation planning. The handover sheet is now being rolled out trust-wide in medicine and introduced to surgical colleagues. PMID- 26734217 TI - Improving the inpatient oncology experience through a new consultant ward round. AB - Regular consultant ward rounds have been shown to reduce the length of stay and improve the discharge planning for patients (1). To balance the competing demands of outpatient activity and inpatient oncology, it has been difficult to provide specialist care in our hospital. Previously, inpatients were managed primarily by the oncology specialist trainees, who are qualified in internal medicine, with an ad-hoc review by their named consultant. A regular consultant ward round was introduced for the first time on the 7/1/13. Each consultant was timetabled to give a twice weekly morning ward round on a rolling rota. To evaluate this intervention, a retrospective case note analysis was undertaken. This included all patients admitted under oncology for the two months preceding and succeeding the new ward round. For each patient the admission date, time to first consultant review, number of consultant reviews, time to discharge after consultant review, and discharge date was identified. A staff survey also took place. Statistical analysis was performed using Mann-Whitney U or Chi-Squared tests. 85 patient episodes met the inclusion criteria. Case notes were available for 63 episodes (74%). The average length of stay significantly decreased from 11 days to three and half days (p<0.05). The time to discharge after first consultant review also significantly decreased from six days to two days (p<0.05). The number of consultant reviews and time to first consultant review remained unchanged (p>0.05). The percentage of patients receiving a consultant review increased, from 54.3% to 71.4%, though this was not statistically significant. However it is likely such a large increase is clinically significant. Medical and nursing staff satisfaction also improved. This study suggests that a regular consultant ward round improves length of stay for patients. This is possibly because an increase in patients received a consultant review and that the treatment and discharge decisions were expedited after such a review. PMID- 26734218 TI - Improving adherence to guidelines for extended venous thromboembolism prophylaxis in patients with colorectal cancer. AB - Extended venous thromboembolism prophylaxis (EVTEP) with low-molecular weight heparin such as enoxaparin for 28 days following surgery for cancer significantly reduces venous thromboembolic events compared to a standard 6-10 day course. National Institute of Clinical Excellence (NICE) guidelines suggest EVTEP should be offered to patients undergoing colorectal cancer surgery. Local EVTEP prescribing and monitoring guidelines in a busy inner city teaching hospital colorectal surgery unit, were devised to ensure NICE guidelines are followed. Adherence to local EVTEP guidelines was recorded through a retrospective audit of patients undergoing elective colorectal cancer surgery during February 2011 (n=19). Prospective re-audit cycles were undertaken during April-May (n=17) and September-December 2012 (n=17). The first audit cycle revealed that overall standards were not being met with just 11% of 'at risk' patients being correctly identified in pre-operative assessment clinic and continued low adherence to guidelines on the ward with only 44% of patients being prescribed EVTEP at discharge. Following each audit cycle, educational interventions were directed towards the multi-disciplinary team involved in the care of patients undergoing colorectal cancer surgery. This involved education of the team members regarding EVTEP, presentation of the audit results with instruction for improvement. Results of the second and third audit cycles showed improvements in guideline adherence with 100% of patients in these cohorts having been prescribed EVTEP at discharge. Marked improvements were also seen in the correct identification of 'at risk' patients, patient education in pre-operative assessment clinic, and warning of potential side-effects. This project has shown a significant global improvement in EVTEP-related patient care and adherence to local guidelines following education of the multi-disciplinary team involved, which consequently reduced the risk of venous thromboembolism within this patient cohort. PMID- 26734219 TI - Improving management of patients with hyperemesis. AB - Hyperemesis gravidarum (HG), defined as severe nausea and vomiting resulting in dehydration, is a common reason for emergency admission in gynaecology (1). The management of HG is supportive, including the correction of dehydration and electrolyte disturbances and use of antiemetics. An audit in our unit identified that women with HG were not receiving appropriate fluid resuscitation and in particular inadequate potassium replacement. A proforma was developed by a multidiscplinary team to prompt appropriate investigations, medications, and fluid resuscitation. The proforma was introduced in paper format and electronically, accompanied by an education programme for junior doctors. This intervention has improved prescribing practice and fluid resuscitation for these patients. Length of admission has reduced. Efforts have been made to ensure this change is sustainable in the long term, through involvement of the junior doctors using the proforma at all stages of the project. PMID- 26734220 TI - The management of ureteric stones in the Accident and Emergency department. AB - Ureteric stones is a common cause for attendance to the A&E department. Active or conservative management is delivered dependent on the relevant history, clinical condition, and investigation results. The majority of patients can be treated conservatively and do not require admission. However, some cases of ureteric stones present as a urological emergency if, for example, there is an infected obstructed system. An initial audit over a two month period of A&E admissions with radiologically proven ureteric stones demonstrated there was no easily accessible, specific criteria used to guide which patients were admitted and which patients were discharged from A&E. Therefore, an admission criteria and discharge proforma was developed and implemented in the A&E department to ensure patients were appropriately discharged if they could be managed conservatively and appropriately admitted if they potentially required further observation and intervention. A repeat audit using the same methods and criteria was carried out and demonstrated fewer unnecessary admissions and fewer inappropriate discharges. PMID- 26734221 TI - Patient Satisfaction: Receiving a copy of the GP letter following fracture or elective orthopaedic clinic. AB - Following orthopaedic/fracture clinics at our hospital, patients now receive a copy of the letter summarizing an outpatient consultation that is sent to their General Practitioner. We undertook a patient satisfaction questionnaire to determine if patients found this change in practice beneficial. Of the 83 patients who had received this letter, most patients had read the letter (96%) and understood the content (90%). 13% were worried after having read the content and 86% found it helpful. Of the 40 patients who did not receive a copy, 32 (80%) specified that they would wish to in the future. The results support the new practice although it could be improved by identifying those who do not wish to be included thereby reducing costs. PMID- 26734222 TI - Early Experience with a Hepatobiliary and Pancreatic Quality Improvement Program. AB - This project aims to assess the impact of the introduction of a hepatobiliary and pancreatic (HPB) Quality Improvement Program (QIP) on postoperative complications following liver, biliary and pancreatic surgery. A prospective analysis of postoperative complications over a six month period was performed. Complications were analysed and graded according to internationally agreed definitions. Justification was sought and errors identified. Weekly meetings were performed to review each complication enabling an action plan to be created to prevent future recurrence. Rates were compared with previously audited and published results, using the chi-square test. A total of 326 procedures were performed over the six months including 30 pancreatectomies, 45 liver resections and 251 other procedures. 37 patients developed complications (11.3%) with 47 complications in total including two deaths. Using the ISGPS grading, eight complications were identified; two grade A, four grade B and two grade C. There were three grade A ISGLS complications and one grade B. 30 complications were justified as unavoidable, 16 as avoidable and one as indeterminate. Action plans included continued monitoring (n=41), formulation of new policy (n=3), individual counselling (n=4), educational offering (n=4). When compared with 2010 complication rates, 114 complications occurred in 233 liver operations during the baseline period, compared with 17 complications in 45 liver operations during the QIP period, OR=0.63 (95% CI: 0.33 to 1.22), p=0.17 and 86 complications occurred in 99 pancreatic resections during the baseline period, compared with 20 complications in 30 pancreatic resections during the QIP period OR=0.30 (95% CI: 0.12 to 0.79), p=0.01 The HPB QIP is a rigorous approach to grade every complication and death. A statistically significant reduction in pancreas related complications has already been obtained. Further work is required to determine the persistence and magnitude of this quality improvement. PMID- 26734223 TI - CSF xanthochromia analysis takes longer following centralisation of the laboratories testing samples - how can we improve the time to result? AB - Lumbar puncture is an essential tool for excluding subarachnoid haemorrhage. In August 2012, the laboratory at which cerebrospinal fluid (CSF) is analysed for xanthochromia in Lanarkshire was centralised at Hairmyres (East Kilbride, UK). Prior to this, each of the three hospitals analysed their own specimens. We aim to assess whether or not the change in xanthochromia processing has resulted in diagnostic delay at Wishaw General Hospital in the assessment of CT negative possible subarachnoid haemorrhage. We subsequently assessed the impact of a strategy to minimise any delay, i.e. increasing laboratory processing hours. Patients undergoing CSF analysis for xanthochromia were identified directly from the laboratory database. Time of lumbar puncture, and time of xanthochromia results were obtained from the hospital's laboratory computer system. Data were analysed using a commercially available statistical software programme (Microsoft Excel). Audit was repeated after the change to a centralised laboratory, and again following the increased laboratory working hours. Mean time from lumbar puncture to availability of xanthochromia result was significantly longer following the laboratory change (20.8+/-3.5 hours post [n=35] vs. 12.5+/-3.0 pre, p=0.01 [n=17]). However, following a change in the laboratory's practice, there was no improvement (19.8+/-3.4 hours post practice change [n=35]), and this remained significantly longer when compared to the original laboratory set-up (p=0.025). The change in laboratory processing CSF samples for xanthochromia in Lanarkshire resulted in a significant delay in analysing the samples. Attempts by the laboratory to extend processing hours did not make any significant improvement, but having expanded our knowledge of the issues, further measures are now planned to minimise delays in the future. Centralisation of laboratory services for CSF analysis, whilst cheaper, may impact negatively on clinical care. PMID- 26734224 TI - Reducing the risk of needlestick injuries in hospital. AB - After performing procedures involving sharps, many wards in St George's Hospital have no quick and accessible 'point of care' sharps bin for their safe disposal. Instead one must transport potentially hazardous equipment away from the bedside, risking injury and exposure to persons en route. Results from a questionnaire showed that 73% felt they were indeed poorly placed, 95% felt a portable sharps bin system was a good idea, and 95% felt their introduction would be safer. A one month trial of portable sharps bins on the Acute Medical Unit (AMU) showed that 97% felt that the portable sharps bin system reduced risk to themselves and others, 81% felt safer using them, and 90% felt safer knowing their colleagues were using them too. A recent audit in a six month period within 2012 established there were 148 reported needlestick injuries in St George's Hospital. This quality improvement project showed that a majority consensus felt that a portable sharps bin system would be safer than the system currently used and could potentially help reduce these numbers. This project also comes at a time when new EU legislation calls for safer sharps use and disposal and thus offers a solution to ultimately provide better, safer and more advanced safety practices when disposing of sharp equipment. PMID- 26734225 TI - Implementation of a combined Cardiopulmonary Resuscitation and Treatment Escalation Plan document in a District General Hospital. AB - Documentation of appropriate escalation of treatment was identified as a problem for junior doctors and Critical Care Outreach Nurses at Musgrove Park Hospital. An audit of resuscitation and escalation documentation of all wards found that of the patients who were not for Cardiopulmonary resuscitation (and therefore not for full escalation of care), 78.4% had no documentation of the appropriate level of escalation of treatment should they deteriorate. The majority of junior doctors had experienced cases where they felt that inappropriate treatment had been given, where no escalation plan was documented. Using several Plan, Do, Study, Act (PDSA) cycles, drawing tools used in other trusts and departments, and the views of clinicians, we developed a treatment escalation plan (TEP) tool, to be included in the resuscitation form. This included consideration of referral to critical care, ward based non-invasive ventilation, and appropriate use of intravenous or oral antibiotics. This then prompted the responsible clinician to consider and document appropriate escalation of treatment. The CPR-TEP form was trialed using a quasi-experiment design allowing the aim to be tested using two groups - intervention and control. All patients in the intervention group were not for CPR and therefore had their TEP-CPR form filled in fully (n=68). The control group consisted of patients who were not for CPR but who did not have a TEP form filled in (n=36). The appropriateness of OOH (out of hours) treatment in those patients who experienced clinical deterioration was judged by questionnaire based feedback from the in-hours team the following morning. Levels of inappropriate treatment between the two groups were compared to test the aim. At the end of the study period, questionnaire feedback indicated that 11.1% of patients in the group with the new CPR-TEP document had received inappropriate OOH care compared to 44.4% of patients in the group without the document. Using the TEP alongside resuscitation documentation prompts the responsible clinician to consistently consider and document the appropriate escalation of care for their patient, improving communication with the out of hours team and appropriate escalation of care in the event of patient deterioration. PMID- 26734226 TI - Improving the quality of written information available at weekends in a paediatric hospital: the TRANSMIT sheet. AB - The clinical outcomes at weekends are worse than during the week in a hospital setting. There are many potential factors which influence this. High quality communication between the weekday teams and the on call weekend staff could help improve clinical outcomes at weekends, but there are no validated forms of communication that have been established in a paediatric hospital setting. The casenotes of all medical patients (n=119) were prospectively evaluated across all medical wards in a large paediatric hospital over three weekends, to establish the quality of information available to on call teams. Following introduction of structured documentation, known as a TRANSMIT (including Tasks, Respiratory, Anticipated problems, Nutrition, Sepsis, Medication, Intravenous access, Transfer/discharge) sheet, the audit was repeated (n=111). A qualitative survey of junior doctors using TRANSMIT was carried out after introduction. Prior to the introduction of the structured documentation (TRANSMIT sheet) an accurate problem list was present in 56% (67/119), and an adequate written management plan in 63% (75/119). Following introduction, an improvement in the notes was seen, with accurate problem lists in 82% (91/111) and an adequate plan in 76% (84/111). Improvements in the quantity and quality of information available to weekend on call medical staff were noted. The use of a structured documentation (TRANSMIT sheet) can improve the quality of written information available to on-call teams in a paediatric hospital setting. A retrospective qualitative assessment of junior doctors using TRANSMIT sheets showed an improvement in both the quantity and quality of information available to on call staff at weekends. PMID- 26734227 TI - Improving neonatal mortality in an Ethiopian referral hospital. AB - Ethiopia has one of the world's poorest neonatal mortality rates (1). As a British paediatrician working for one year, the main aim was to improve neonatal care in a referral hospital's neonatal unit. An initial project looking at all admissions to the unit over the month of October 2012, revealed the death rate within the unit was 21% of all admissions. Of the 55 admissions only 43 (75%) had a temperature recorded at admission. 29 (67%) of these were hypothermic, and of these 29 initially hypothermic babies, 19 (65%) remained hypothermic or did not have another temperature documented during their stay. Only 33 (56%) had a heart rate and respiratory rate recorded on admission and only 11 (19%) had any further vital signs recorded during their stay. 19 of the admitted infants had a diagnosis of low birth weight and 10 (53%) of these either died or left against medical advice. With this information regular basic neonatal care teaching sessions for doctors and nursing staff were initiated. Vital signs charts were introduced and unit specific protocols were written. Continuous Positive Airway Pressure (CPAP) was trialled and found to be effective, and CPAP training was given to all nurses and doctors on the unit. A room was set aside to be used solely as Kangaroo Mother Care (KMC). The nurses were taken to a very effective neonatal unit as an 'experience sharing' trip to help with motivation and a grant was also obtained for basic equipment. After 6 months the project was repeated for all the admissions during February 2013. The death rate had progressively fallen and was 10% in February. 54 patients (98%) had a temperature taken on admission and of these, 27 (49%) were hypothermic. 25 (93%) of these hypothermic infants had subsequent temperatures documented which were normal. 54 (98%) had heart rate and respiratory rate recorded on admission and 50 (90%) had them recorded at least daily during their stay. Of the 22 babies with low birth weight (40%), only 4 (18%) died/left against medical advice. 4 received CPAP and 6 were treated with KMC. PMID- 26734228 TI - The Variable Rate Intravenous Insulin Infusion Protocol. AB - Insulin use among inpatients is high and associated with severe and regular medication errors. An initial baseline audit showed a wide variation in the prescription of intravenous insulin within the trust. These included variation in the choice of fluid prescribed, electrolyte levels not consistently checked, handwritten illegible prescriptions, and varying parameters set for adjustment of the prescription. A Variable Rate Intravenous Insulin Infusion protocol (VRIII)) was introduced to standardize intravenous insulin prescription throughout the trust by all members of the clinical team. We looked at and measured uptake and effects of the VRIII protocol in improving standardization of insulin prescription for inpatients on insulin at St George's NHS trust. The protocol was uploaded to the intranet to allow access 24 hours a day and the staff educated about it. The VRIII protocol was routinely used successfully throughout the trust. Any initial problems were addressed through education of clinical staff. The protocol has shown decreased prescribing and administrative errors, whilst demonstrating good glucose and electrolyte control. Use of a standardized protocol helps reduce medication errors and demonstrates good glycaemic control. Regular and continued education of clinical staff is necessary to maintain its efficacy. PMID- 26734229 TI - Electronic prescribing: Reducing delay to first dose of antibiotics for patients in intensive care. AB - Delays in antibiotic therapy in the context of severe sepsis are associated with increased mortality. One way to reduce such delays may be through modifications to electronic prescribing (EP) systems. The research team evaluated the role of one such EP system in reducing delays in antibiotic administration in an Intensive Care Unit (ICU). First, the delays in antibiotic administration in adult ICU patients was quantified. The EP system was then modified to remove deafult time settings for antibiotic doses, which ensured that all antibiotic doses were scheduled for administration within an hour of the prescription being generated. Enhanced training for clinicians and nurses was also implemented, focusing on the EP system and highlighting the importance of prompt antimicrobial prescribing and delivery to the patient. The antibiotic administration was re audited, and a significant reduction in delays (p=0.002, Mann-Whitney U test) was found. This study demonstrates how prudent use of EP systems can help to reduce delays in antibiotic administration in an ICU setting, thus potentially contributing to reducing mortality in patients with sepsis. PMID- 26734230 TI - Improving weekend handover between junior doctors on medical and surgical wards. AB - Poor weekend handover has been implicated as one of the causes of observed higher mortality rates at weekends in UK hospitals. In a large teaching hospital we, a group of junior doctors, set about improving the quality and effectiveness of weekend handover. We used the Model for Improvement to implement a weekend handover sticker through an iterative process using multiple Plan/Do/Study/Act (PDSA) cycles. Over the 16 week study period the number of completed weekend tasks increased by 30% and the number of patients with a documented weekend handover increased by nearly 50%. Junior doctors are well positioned to notice the quality and safety shortcomings within hospitals, and by using effective improvement methods they can improve these systems at little or no cost. PMID- 26734231 TI - Investigating the bundle compliance of IVIG delivery in the Greater Manchester Neuroscience centre. AB - Salford Royal Hospital is one of the largest users of IVIG for chronic neurological illnesses within the UK. The majority of patients are being treated for chronic inflammatory polyneuropathy and multifocal motor neuropathy. We hypothesised that the components of care being delivered to these patients differed to our stated standard of care (IVIG care bundle). We performed a service review exercise to identify shortcomings and improve quality of patient care. The aim was to measure overall bundle compliance being delivered to 75 patients with a view to improving the overall quality of care being delivered in the future. A retrospective case note study was carried out to measure compliance with the 17 areas of care, which constituted the IVIG bundle. Nine areas of care were being delivered to all 75 patients. This meant that all patients were receiving three monthly bloods, a documented cannula pathway, a filed prescription, a medical assessment, and the correct follow-up. Not all patients had a filed consent form, ECG or HAT assessment and an even smaller number of patients had a documented calculation for the amount of IVIG that needed to be given and few had a serum save. No patient in the group was receiving the intended complete bundle of care. The results led to the development of an electronic treatment dashboard for the delivery of chronic IVIG therapy to this group. A re-audit has shown that rates of individual areas of care being delivered has increased markedly but overall compliance has only increased a slightly due to a lack of serum saves for patients. PMID- 26734232 TI - Sharing knowledge, saving time: an online toolbox to aid junior doctors. AB - Junior doctors are too often frustrated by not being able to quickly find information for how to make referrals, book investigations and contact other professionals at hospital. To make matters worse, much of the knowledge gained by doctors throughout the year is lost during the August rotation. There is an unmet need for retaining such knowledge, in order to facilitate a smoother and safer handover. We set up the "Doctors Directory" at our trust; a website run by junior doctors, providing specific, up-to-date information relevant to other junior doctors within the trust. Whilst providing day-to-day information, it also contains a "survival guide" for each hospital firm. We surveyed junior doctors before and after the implementation of this site. 81% of FY1s surveyed have used the site. Of the doctors that had used the site, 94% found it helpful with a mean self reported time saving of 39 minutes a day. Whilst still in its infancy, the site now has mobile access, and has an average of 60 hits a day. Quality improvement projects such as this are readily scalable to other hospitals and have enabled junior doctors to waste less time finding how to do jobs and more time actually getting them done. PMID- 26734233 TI - Managing human factors in the assembly of the paediatric bronchoscope. AB - Foreign body aspiration in children is a life threatening event and prompt bronchoscopy and extraction is essential for their survival. During a recent paediatric airway emergency at Torbay hospital, Devon, the theatre staff were unable to assemble the paediatric bronchoscope. We therefore investigated methods to improve the efficiency and timeliness of the assembly of the paediatric bronchoscope. To assess the current problem we asked ten theatre staff at random to assemble the paediatric bronchoscope. 70% of the staff were not able to assemble the paediatric bronchoscope. A prompt poster was developed as a visual aid to help demonstrate how to assemble the paediatric bronchoscope. Another ten theatre staff were asked to assemble the paediatric bronchoscope. Now all of the staff were able to assemble the paediatric bronchoscope. The prompt poster enabled all the theatre staff tested to correctly assemble the paediatric bronchoscope and the average time taken was reduced. To further develop the service mandatory training sessions have been arranged to help theatre staff remain confident and continue to develop their skills and knowledge. PMID- 26734234 TI - Identity cards help patients identify their doctors. AB - Patients admitted to hospital are immediately overloaded with information from staff in A&E, to subsequent acute medical and inpatient wards. Essential details are conveyed to patients at each step, including diagnosis, management and identification of various team members involved in their care. An initial audit within our South London hospital revealed only one third of patients admitted onto a single medical ward could recall the name of a single member of their treating team, and less than 10% retained that information over 5 days. Identification (ID) cards were devised to facilitate clear transfer of information detailing the patient's treating team. These ID cards were piloted through a series of PDSA cycles on one inpatient medical ward following a consultant led ward round. Post intervention, 67% managed to recall a single member of the treating team, with 67% retaining this information 5 days later, a dramatic improvement. ID cards were then trialed on one surgical ward, demonstrating equally impressive results with over 87% of patients recalling their named consultant following ID card implementation, up from 54% initially. Similar trends were demonstrated for recalling other treating team members. This simple measure improved patients ability to recall and retain names of a least a single member of their treating team, encouraged communication between patients and medical team and ultimately improved patient satisfaction and quality of care. ID cards were quick and easy to implement and have been approved by the hospital patient safety committee to implement throughout the Trust. PMID- 26734235 TI - Pre-operative fasting - a patient centered approach. AB - Prolonged pre-operative fasting can be an unpleasant experience and result in serious medical complications. The Royal College of Nursing guidelines state a minimum fasting period of six hours for food and two hours for clear fluids, prior to elective anaesthesia or sedation in healthy patients. We audited the Moorfields South Pre-operative Assessment Unit fasting instruction policy to ensure it is clear and in accordance with national guidelines. A questionnaire assessing the clarity and accuracy of fasting instructions and patient hydration was employed to survey patients undergoing elective anaesthesia or sedation in July 2013 (first cycle) and September 2013 (second cycle). The fasting instruction policy and patient information leaflet were reviewed; they state "nothing to eat or drink from midnight" for morning surgery and "nothing to eat or drink from 7AM" for afternoon surgery. The 10 patients surveyed in the first cycle reported that the instructions they were given were clear. 70% expressed subjective dehydration and 40% showed clinical evidence of dehydration. The patients had not been encouraged to drink clear fluids up till two hours before surgery. Patients fasted for unnecessarily prolonged periods, the longest of which was 17 hours. Our interventions were: delivering a teaching session to update staff of current pre-operative fasting guidelines, producing a patient information leaflet that was correct, reader-friendly and comprehensive and displaying posters as a reminder of the updated fasting instruction policy. The 12 patients surveyed in the second cycle had been encouraged to drink clear fluids up till two hours before surgery. A dramatically reduced 25% expressed subjective dehydration and 25% showed clinical evidence of dehydration. The longest fasting period was reduced to eight hours. We encourage all hospitals to adopt a patient centered approach to pre-operative fasting, dispelling the "nil my mouth for eight hours" policy, to improve patient wellbeing and satisfaction. PMID- 26734236 TI - Bring on the weekend - Improving the quality of junior doctor weekend handover. AB - While it is widely recognised that communication and handover are a fundamental component in providing safe clinical care for hospital patients (1,2.3). The Royal College of Physicians found that the majority of hospital doctors are dissatisfied with the standard of their handovers (4). These findings were mirrored by the junior staff at the Royal United Hospital, who felt that the weekend handover was inadequate, and detrimental to patient safety. A group of eight junior doctors at the Royal United Hospital, Bath utilised The Model For Improvement to systematically analyse and improve various aspects of the weekend handover system. Handover sheets from a subset of wards were assessed to observe direct effects of staged interventions over a nine month period, allowing small scale testing prior to widespread implementation of a standardised intranet-based weekend handover. The effects of interventions were evaluated using a predesigned scoring system and data was collected continuously throughout the project. Over a nine month period the quality of handovers improved significantly from 76% to 93% (p <0.01): a success which was supported by a 100% improvement in formal feedback collected from hospital doctors and highlighted by the desire of senior staff and directors to implement the system throughout the trust. Using The Model For Improvement a group of junior doctors were able to introduce and develop a standardised weekend handover system that met their requirements. A structured, efficient and auditable system has been successfully produced which improves the quality and safety of patient care. PMID- 26734237 TI - Tonsillectomy discharge information - An improvement in both patient safety and satisfaction. AB - Approximately 20,000 adult and 25,000 paediatric tonsillectomies are performed each year in England. 0.9% of these patients return to theatre for post tonsillectomy bleeding. The Royal College of Surgeons of England (RCSEng) have produced guidelines regarding emergency surgery, with standards for tonsillectomy discharge information. We audited our compliance with these guidelines and patient satisfaction regarding the information currently provided. Theatre records identified all tonsillectomies carried out between December 2012 and February 2013. 71 patients and their electronic discharge information were reviewed for post-operative bleeding information. Each patient was contacted, with a second call made to those who did not answer. 35 patients took part in our telephone questionnaire. Only 35% of patients had post-operative bleeding information on their discharge summary. 51% received no written information either in clinic or on the day of surgery, 66% recalled a verbal explanation. Only 54% knew to go to A&E if they experienced bleeding. 40% were not satisfied with their discharge information, stating that they wanted to know about bleeding, recovery expectations, and information regarding oral intake. A focus group was formed to discuss potential solutions to the audit outcomes and a tonsillectomy leaflet was produced inline with the trust patient information template. It contained specific instructions regarding bleeding and the nearest A&E contact details. It was reviewed by three tonsillectomy patients and their feedback regarding further information on post-operative diet, throat appearance and pain expectations was incorporated. A second cycle of the audit took place between August and September 2013. Results showed improvement, with 83% receiving an information leaflet and 100% a verbal explanation. 100% of patients were satisfied with their discharge information and 100% knew what to do if they bled. As a result we now meet the standards set out by the RCSEng and have increased our patient safety and satisfaction rates. PMID- 26734238 TI - Improving the management of Acute Kidney Injury in a District General Hospital: Introduction of the DONUT bundle. AB - The NCEPOD report (2009) on Acute Kidney Injury (AKI) found 20% of post-admission AKIs were avoidable and only 50% of AKI care was considered 'good'. The DONUT bundle comprises of six interventions aimed at improving the management of AKI. Baseline data was collected prospectively using the biochemistry eAlert system, identifying 50 patients with Stage 1 AKI over a two week period. Management was assessed 24 hours after the eAlert using a standardised proforma. After data analysis, a DONUT sticker was introduced within the Emergency Admissions Unit, providing an efficient method of recording interventions in the notes. Education sessions outlining the DONUT bundle and stickers were delivered via Foundation Program teaching, along with summary flash cards. A re-audit assessed these interventions. Of the initial cohort (n=50), only 8% of cases had all components of the care bundle completed. Following introduction of the education programme and AKI sticker, re-audit showed a rise in full compliance to 17% (n=42). Only 7% of cases used the AKI sticker but where it was used, there was 100% compliance with the bundle. In conclusion, AKI management is sub-standard. An education program and the use of a simple sticker can improve management. Further education regarding AKI is needed and work is ongoing to improve compliance with sticker use. PMID- 26734239 TI - Better training, Better care: Medical Procedures Training Initiative. AB - Training in procedures has been identified as the top priority for core medical trainees (GMC trainee survey 2011). Current practice relies on each trainee being lucky enough to encounter each procedure during clinical rotations and during on calls. Where trainees are not lucky enough, they are entering their registrar years without the skills to efficiently lead the medical 'on-take'.(1) This can lead to delays in patient diagnosis or treatment. Because a single delay can easily burgeon into a lengthy series of multiple delays, this can lead to an associated prolongation of patient stay.(3) Both confidence and competence in practical procedures can be increased with a procedure bleep system. A dedicated procedure bleep, carried on a rotational basis alerts the bleep holder when a medical procedure is planned. The bleep holder then attends to observe, assist, perform, or teach the relevant procedure. This scheme shares the opportunities for procedure exposure amongst all trainees and ensures that a good breadth of experience has been gained independent of current placement. Formal evaluation revealed that 95% (19/20) of junior trainees felt more confident and competent as a result of participation. Furthermore, consultants felt this initiative reduced the burden on the medical registrars on-call. By ensuring our diagnostic and therapeutic interventions are conducted efficiently, we are actively reducing length of hospital stay and improving the standard of healthcare provided. PMID- 26734240 TI - Improving time to antibiotics and implementing the "Sepsis 6". AB - It has been shown that completion of the "Sepsis 6" within 1 hour reduces mortality (1). This project aims to assess compliance with this standard and evaluate the effectiveness of a sepsis improvement plan in a district general hospital in the UK. A baseline audit was performed, examining case notes of "septic patients" retrospectively (those on intravenous antibiotics). Compliance with each element of the sepsis six plus time to first antibiotic (TTFA) was assessed. A sepsis improvement plan was introduced consisting of staff education, reinforcing vigilance, regular multidisciplinary meetings and incorporating a standardised approach through the use of a sepsis proforma. Following the introduction of this, and after some refinement, the average time to antibiotic fell from 6 hours to 1.4 hours. In conclusion, an educational drive along with a systematic change in processes has seen reduced TTFA along with enhanced compliance with most elements of the sepsis 6. Through continued assessment and further improving upon systematic processes with continued education we would anticipate consistent improvement in the management of septic patients. PMID- 26734241 TI - Planning ahead: Improving escalation plans before the weekend. AB - Handover is the system by which responsibility for patient care is transferred between healthcare professionals. A significant aspect of handover is the existence of an escalation plan for each patient in case of deterioration over the weekend. According to the Royal College of Physicians, all patients should have a clear escalation plan documented in the notes before a weekend, since parent medical teams (Consultant team in charge of care) are best placed to make these decisions. If left to on-call teams, at a time of deterioration over a weekend, they might not have all available information, the patient might be unable to be involved in the decisions, and the family might not be consulted. With this is mind, we decided to analyse the existing handover process in a medium sized district general hospital, with the aim of improving the process and the documentation of escalation plans. The results from our retrospective analysis of the system in place revealed a significant lack of documentation of escalation plans in the medical notes. Three sample wards were selected to analyse the current handover system and test proposed measures before hospital wide implementation. After trialling of a physical handover meeting in addition to the existing intranet system and a proforma for the Friday ward round, the documentation of escalation plans in the patients' notes improved from 9.1% to 41.1%. Based on these results, as well as formal feedback from junior doctors and informal feedback from other staff, the physical handover meeting and Friday ward round proforma will be implemented throughout the Trust. Our interventions led to an improvement in the documentation of escalation plans in our hospital, thus saving precious time in the event of a patient's deterioration. This also ensures that families and patients are involved in the decision making process and kept informed, and reduces the burden for the weekend on-call teams. PMID- 26734242 TI - How complete are our clerkings? A project aimed at improving the quality of medical records by using a standardised proforma. AB - Clerking a patient is the first and most important contact that any medical team has with the patient. It provides information that may not be available later in the admission if recorded improperly, such as referral letters, collateral history, dosette boxes or prescription sheets. The quality of data recorded from this encounter was examined at a busy district general hospital surgical department. Initial measurement demonstrated that less than half of certain key parameters like dosages of medication were being recorded by clerking doctors. A clerking proforma was therefore designed to combat this problem. Over three audit cycles (n = 170, 150, 174) the proforma showed statistically significant improvements in the proportion of data that was captured at initial contact with the patient. We conclude that the introduction of proformas for clerking significantly improves the collection of data that impacts patient care during their hospital stay. PMID- 26734243 TI - Improving communication of inpatient blood transfusion events to GPs. AB - Patients who have had blood transfusions whilst in hospital must have this information communicated to their General Practitioner at discharge. Audit demonstrated that just 50% of patients (n=15) under medical specialties who had undergone a blood transfusion had this information included in their discharge letter. To improve this, a section was specifically designated on the e-discharge pro-forma for the documentation of blood transfusion events, and focused teaching was delivered to all new FY1 doctors at their induction. Post intervention, 80% of blood transfusions occurring in medical patients were documented on the e discharge, with an improvement in how detailed this documentation was (n=40). This simple intervention is an easily reproducible, cost neutral method of ensuring that more blood transfusion events are communicated to patients' GPs; improving care and reducing risk. PMID- 26734244 TI - Safe Handover : Safe Patients - The Electronic Handover System. AB - Failure of effective handover is a major preventable cause of patient harm. We aimed to promote accurate recording of high-quality clinical information using an Electronic Handover System (EHS) that would contribute to a sustainable improvement in effective patient care and safety. Within our hospital the human factors associated with poor communication were compromising patient care and unnecessarily increasing the workload of staff due to the poor quality of handovers. Only half of handovers were understood by the doctors expected to complete them, and more than half of our medical staff felt it posed a risk to patient safety. We created a standardised proforma for handovers that contained specific sub-headings, re-classified patient risk assessments, and aided escalation of care by adding prompts for verbal handover. Sources of miscommunication were removed, accountability for handovers provided, and tasks were re-organised to reduce the workload of staff. Long-term, three-month data showed that each sub-heading achieved at least 80% compliance (an average improvement of approximately 40% for the overall quality of handovers). This translated into 91% of handovers being subjectively clear to junior doctors. 87% of medical staff felt we had reduced a risk to patient safety and 80% felt it increased continuity of care. Without guidance, doctors omit key information required for effective handover. All organisations should consider implementing an electronic handover system as a viable, sustainable and safe solution to handover of care that allows patient safety to remain at the heart of the NHS. PMID- 26734245 TI - Improving the safety of remote site emergency airway management. AB - Airway management, particularly in non-theatre settings, is an area of anaesthesia and critical care associated with significant risk of morbidity & mortality, as highlighted during the 4th National Audit Project of the Royal College of Anaesthetists (NAP4). A survey of junior anaesthetists at our hospital highlighted a lack of confidence and perceived lack of safety in emergency airway management, especially in non-theatre settings. We developed and implemented a multifaceted airway package designed to improve the safety of remote site airway management. A Rapid Sequence Induction (RSI) checklist was developed; this was combined with new advanced airway equipment and drugs bags. Additionally, new carbon dioxide detector filters were procured in order to comply with NAP4 monitoring recommendations. The RSI checklists were placed in key locations throughout the hospital and the drugs and advanced airway equipment bags were centralised in the Intensive Care Unit (ICU). It was agreed with the senior nursing staff that an appropriately trained ICU nurse would attend all emergency situations with new airway resources upon request. Departmental guidelines were updated to include details of the new resources and the on-call anaesthetist's responsibilities regarding checks and maintenance. Following our intervention trainees reported higher confidence levels regarding remote site emergency airway management. Nine trusts within the Northern Region were surveyed and we found large variations in the provision of remote site airway management resources. Complications in remote site airway management due lack of available appropriate drugs, equipment or trained staff are potentially life threatening and completely avoidable. Utilising the intervention package an anaesthetist would be able to safely plan and prepare for airway management in any setting. They would subsequently have the drugs, equipment, and trained assistance required to manage any difficulties or complications. We suggest that this should be the gold standard of airway resource provision and is in line with NAP4 recommendations. PMID- 26734246 TI - Improving waiting time and operational clinic flow in a tertiary diabetes center. AB - The Singapore General Hospital Diabetes Centre (DBC) is a multidisciplinary specialist outpatient clinic which aims to provide an integrated one-stop service for diabetes. As with many tertiary academic centre clinics, DBC encounters an expanding patient load, greater patient expectations and increasingly complicated patients who require services from a multitude of health providers. Such rising demands amidst limited resources cause inefficiencies and long waiting times to consultation. This result in low patient satisfaction and an unpleasant clinic experience. A multidisciplinary team was formed to reduce the waiting time at DBC and improve communication and work processes of staff. Addressing wait-times is complicated as multiple stakeholders and operational processes are involved and interlinked. By systematically breaking down processes and identifying problem areas, targeted changes were implemented. This included a revised model of appointment scheduling, a patient reminder system, more effective communication sheets and work reassignments. The primary aim of this project was to improve the patient turn-around time (duration a patient spends at the centre for a visit). There was no documented improvement in turn-around time after project implementation (108.23 minutes versus 106.6 minutes) but other secondary aims were achieved. These included an increase in the percentage of patients seen by the doctor within 60 minutes from 80% to 84%, a reduction in wait-time for payment and reappointment at the cashier by 36.6% and a reduction in non attendances of new cases to the clinic from 30.2% to 21.3%. Staff satisfaction and communication were greatly improved. To aid sustainability, personalized reports of individual doctor's waiting times and workload were produced quarterly and tracked. As this is a first step quality improvement project, efforts to track, examine and further improve turn-around times are on-going. Future initiatives are directed at time-efficient appointment scheduling between care providers for same day appointments, a reactive SMS system for reminders and reappointments and optimization of processes and manpower allocation for clinics. PMID- 26734247 TI - Improving room layouts for venepuncture, cannulation and ABG equipment on surgical wards. AB - The Productive Ward series has effectively helped to standardise the storage of equipment in hospital ward treatment rooms; however, in our organisation equipment for venepunture and cannulation had been excluded. This resulted in clinicians having to navigate several unfamiliar environments while on-call and hence waste valuable time searching for basic equipment. We aimed to make it easier to locate and identify the basic equipment used for cannulation, venepuncture, and arterial blood gas sampling and more efficient to collect. We examined the initial layout of equipment on four surgical wards in a large teaching hospital. The time taken for junior doctors, nurses, health care assistants, and physician assistants to gather equipment on these wards was recorded along with a process map of steps involved. Our intervention was to relocate the equipment into adjacent storage and make it easily identifiable by the use of a 'red dot'. Following these changes we repeated the measurements. There was an overall reduction in the mean time taken to gather the equipment required to insert a venous cannula on an unfamiliar ward from 2 min 41 s pre intervention (range 52 s to 6 mins 58 s, n = 23) to 26 s post-intervention (range 8 s to 1 min 20 s, n = 51). Additionally, the number of steps involved in the process was reduced from 16 to five. All of the 32 junior doctors surveyed felt that faster identification improved patient safety. A significant reduction in the time wasted by clinicians searching for venepuncture equipment on surgical wards has been achieved by simplifying the storage, layout, and identification of this kit. The accumulated benefit includes increased productivity, familiarity, and safety, which is paramount when attending unwell patients on unfamiliar wards. PMID- 26734248 TI - Improving hospital weekend handover: a user-centered, standardised approach. AB - Clinical Handover remains one of the most perilous procedures in medicine (1). Weekend handover has emerged as a key area of concern with high variability in handover processes across hospitals (1,2,4, 5-10). Studying weekend handover processes within medicine at an acute teaching hospital revealed huge variability in documented content and structure. A total of 12 different pro formas were in use by the medical day-team to handover to the weekend team on-call. A Likert survey of doctors revealed 93% felt the current handover system needed improvement with 71% stating that it did not ensure patient safety (Chi-squared, p-value <0.001, n=32). Semi-structured interviews of doctors identified common themes including "a lack of consistency in approach" "poor standardization" and "high variability". Seeking to address concerns of standardization, a standardized handover pro forma was developed using Royal College of Physician (RCP) guidelines (2), with direct end-user input. Results following implementation revealed a considerable improvement in documented ceiling of care, urgency of task and team member assignment with 100% uptake of the new proforma at both 4-week and 6-month post-implementation analyses. 88% of doctors surveyed perceived that the new proforma improved patient safety (p<0.01, n=25), with 62% highlighting that it allowed doctors to work more efficiently. Results also revealed that 44% felt further improvements were needed and highlighted electronic solutions and handover training as main priorities. Handover briefing was subsequently incorporated into junior doctor induction and education modules delivered, with good feedback. Following collaboration with key stakeholders and with end-user input, integrated electronic handover software was designed and funding secured. The software is currently under final development. Introducing a standardized handover proforma can be an effective initial step in improving weekend handover. Handover education and end-user involvement are key in improving the process. Electronic handover solutions have been shown to significantly increase the quality of handover and are worth considering (9, 10). PMID- 26734249 TI - Saving the NHS one blood test at a time. AB - As a team of junior doctors our aim has been to save costs in day to day work so that money can be reallocated to improving nursing staff levels on our wards. Stem cell units have regular blood collection schedules in order to monitor organ response to chemotherapy and to look for complications in immunocompromised patients. We set out to reduce the number of biochemical investigations to a minimum that would be clinically indicated. We designed a new blood collection proforma for nursing staff to follow and audited all blood tests taken during a 2 week period before and after its introduction. The number of inappropriate blood tests were recorded as those that were not clinically indicated or not present on the collection schedule. After the introduction of the change the number of inappropriate tests were reduced by 937 over the 2 week period, with a cost saving of L1,478.42. Similar strategies for reducing unnecessary investigations and focusing on tests that will change management could help the NHS cope with a difficult financial future and provide continued safe staffing levels and quality care. PMID- 26734250 TI - The impact of nurse-led annual telephone follow-up of patients with inflammatory bowel disease. AB - Inflammatory bowel diseases (IBD) are characterised by periods of disease activity and period with disease in remission. In Denmark all patients are seen in hospital settings. The aim of this study was to introduce a nurse-led phone service for stable patients replacing annual visits. The study originated from an outpatient cohort of 1,600 patients with IBD. A research protocol was determined before the intervention was launched, which included surveys among the patients before the intervention, after the intervention, collection of longitudinal data in a three year period, and a clinical audit. Budget impact analysis (BIA) and cost-effectiveness analysis (CEA) were done. Furthermore, the staff evaluated the process. Almost 30% (n = 474) of the total cohort was enrolled in the service. Eighty-seven per cent of the patients welcomed the phone service beforehand. After implementation, 94% of the patients included were pleased with the service. The programme has shortened the waiting time for most other services, but no improvement in the workload was observed. The BIA showed limited savings. The CEA showed an annual saving of 100? per patient when using the annual phone service over routine visits. In conclusion, changing the method of contact from routine annual visits to annual phone calls from a nurse was feasible and well accepted for stable patients with IBD. The benefits of the service were most marked for the patients. PMID- 26734251 TI - Improving the surgical hot clinic. AB - Ambulatory care is an underdeveloped concept in the setting of emergency surgery, however it is recognised that many institutions will need to develop this service to cope with increased time and financial pressures.[1] There is increased emphasis on ambulatory care pathways for a variety of medical conditions.[2] Risk management is important in managing patients with acute abdominal pain in an outpatient setting and senior doctor support is essential. While the patient remains in the community, effective communication with the patient's primary care provider improves patient safety and satisfaction.[3] This quality improvement project identified current service provision of ambulatory care for surgical patients in the hot clinic at Croydon University Hospital with subsequent consultation with the surgical department to identify problems arising from the throughput of patients. Guidelines were then updated incorporating solutions to the identified issues which were then validated by the department of general surgery. Post intervention measurement identified a decrease in patients whose principal assessment and management was made by a senior house officer level doctor through the hot clinic patient journey from 26% to 9% (64% decrease), indicating an increase in registrar and/or consultant involvement in managing the hot clinic. The number of patients attending hot clinic that had effective discharge liaison (in the form of a formal letter) to the GP increased from 18% to 68% (250% increase). In conclusion, the introduction of updated guidelines effected a safer and more effective ambulatory hot clinic to perform closer to full capacity, providing improved patient care for the local population. PMID- 26734252 TI - Weight a minute - iatrogenic paracetamol toxicity is preventable by utilisation of well-designed drug charts. AB - Iatrogenic Paracetamol toxicity is a potentially life-threatening yet avoidable cause of acute liver failure. Unfortunately, several cases have recently been reported nationally (1,2). The impetus behind our project was a recent case of iatrogenic Paracetamol induced hepatotoxicity within our trust, a London-based District General Hospital. According to the British National Formulary, for adults weighing 10-50kg the intravenous (IV) dose is 15mg/kg every 4-6hours (max. 60mg/kg daily), not the usual 1 gram QDS oral dose which is applied irrespective of weight (3). We audited 100 adult patients in April 2013 and re-audited in July 2013. Both of the randomly selected samples consisted of an equal number of surgical and medical patients, with an equal gender ratio. Data of interest included whether patients were on IV Paracetamol, appropriately dosed; if and when patients had been weighed during admission; and whether the WHO pain ladder of analgesia was followed. Identified shortcomings included patient weight on admission not being recorded, and IV Paracetamol dose adjustment not being made in patients <50kg. 3 months were spent raising awareness of the importance to record patient weights and to dose-adjust IV Paracetamol when indicated. Patients weighed on admission improved from 37% to 68% (p<0.0001) and those on the inappropriate dose of Paracetamol fell from 18 (25% of the patients on Paracetamol) to 5 (5.75% of the patients on Paracetamol) p=0.0013. There was a marked improvement in the number of patients with the weight written on their drug chart from 27% to 53% post-intervention. (p=0.0003) In conclusion, every patient should be weighed on admission. In order to prevent potential hepatotoxicity, staff should document patient weights on the drug charts and be aware of the fact that patients who weigh <50 kg should be on a 15 mg/kg/dose of IV Paracetamol, not 1 gram QDS. PMID- 26734253 TI - Reducing door to needle time for stroke thrombolysis. AB - Better outcomes are obtained with stroke thrombolysis the more rapidly it is given, both in terms of the patient's level of functional ability and also mortality. Current UK performance targets (outside London) aim for a time of 45 minutes or less. Thrombolysis pathways involve multidisciplinary working across departmental boundaries as well as senior level decision making. Our system used telemedicine out of hours adding additional complexity to the pathway. The initial planning stages started by auditing current practice and mapping the existing pathway. The figures for door to needle times were held on a database on the stroke unit and collected in detail for the purposes of national reporting. The pathway was mapped by combining personal experience of working within the stroke service with the experiences of the general medical registrars who worked the system out of hours. The initial action was to present this information throughout the hospital at departmental meetings. Opinions were canvassed at these meetings on where the biggest barriers were within the pathway and how we could address them. An awareness campaign was held by advertising over the intranet. An intervention comprising the following elements was introduced over the period of a year: introduction of an ambulance pre-alert, revision of the existing pathway, and education to all those involved in thrombolysis. The cases where particularly long delays were noted were audited in more depth to identify barriers to flow through the system. This was reported in ward meetings for staff to contribute experience and to offer solutions. We went to commissioning group meetings to gain the support of the local ambulance service, and talked to A&E seniors about the project and the ways in which they could help. Median times were calculated from a stroke database. There was a fall in median door to needle time of 65.5 to 49 minutes over a period of 18 months. A complex intervention to improve door to needle time can and did produce good results with a reduction in times to within the London performance standards of care. The efficacy could be improved with an increased staffing level and provision of a formal setting within which to discuss changes and to keep up the momentum of change. PMID- 26734254 TI - Management of anaemia and blood transfusion in critical care - implementing national guidelines in ICU. AB - Anaemia in intensive care is common, with approximately 50% of patients receiving a red cell transfusion. Recognised complications from transfusion include 'transfusion associated lung injury', infection, and organ failure progression. Most cohort studies show a positive relationship between red cell transfusion and adverse outcomes. In 2012, the British Committee for Standards in Haematology issued guidelines for red cell (RBC) transfusion in critical care. They recommend a haemoglobin transfusion trigger of below 70 g/dL unless the patient is bleeding, has acute sepsis, neurological injury, or an acute coronary syndrome. RBC transfusions in a single intensive care unit (ICU) were prospectively assessed for compliance with national guidance. Each transfusion was categorised with a traffic light system: red for inappropriate, green for appropriate, and amber for those that were not clearly appropriate or inappropriate. The quality improvement project began with a clinical effectiveness audit of doctors' knowledge of critical care transfusion thresholds. Two quality improvement interventions were used: 1) a local blood transfusion guideline was produced and posters were placed in the ICU 2) this guidance was attached to the transfusion prescriptions. Data was collected after each intervention. A total of 30 random adult RBC transfusions were analysed between August 2013 and February 2014. Despite good results from the effectiveness audit an assessment of RBC transfusions demonstrated room for improvement. Prior to introduction of the guideline intervention, a total of two transfusions were green, one red and seven amber. Following both interventions there were seven green transfusions and three amber. No transfusions were classed as inappropriate. According to additional trust based ICU transfusion records, there was approximately a 50% reduction (41 to 18 RBC transfusions) in overall blood transfusions following the first intervention in October 2013. Simple interventions to raise awareness such as surveys, posters, and reminders can dramatically improve RBC prescribing in accordance to evidence based guidelines. Making prescribers aware of guidelines can dramatically reduce the total number of overall transfusions and increase transfusion appropriateness. PMID- 26734255 TI - Improving the accessibility of trust guidelines for junior doctors at North Bristol NHS Trust. AB - Medicine is becoming increasingly protocol driven. This provides a standardised format for doctors to deliver best practice, especially in the acute setting. 40 junior doctors were asked to locate three Trust guidelines: venous thromboembolism (VTE) prophylaxis; antibiotic prescribing; and management of upper gastrointestinal bleed (UGIB). For each doctor the time taken and number of mouse clicks to access each guideline was recorded. Following successful redesign of the Trust intranet we completed a re-audit. Initial results showed 48% of doctors were unable to locate the UGIB or the VTE guidelines within 5 min. For those who were able to locate the guidelines it took an average of 111 sec and 17 mouse clicks. 100% of doctors were able to locate the antibiotic guidelines in 12 sec and with two clicks. These are accessible via a single port of access. Following our redesign of the Trust intranet 100% of doctors located all three guidelines in an average time of 7.2 sec and in 2.1 clicks. Improvement in access to VTE prophylaxis and UGIB was statistically significant (p=0.001). Redesigning our Trust intranet homepage has significantly improved the accessibility of acute surgical and medical guidelines. PMID- 26734256 TI - Improving the safety and efficiency of nurse medication rounds through the introduction of an automated dispensing cabinet. AB - Information technology (IT) systems are being utilised with increasing frequency at the prescribing and dispensing stage of the medicines-use process in UK hospitals. However, much less development has taken place with regard to the implementation of IT systems at the administration stage of medicines-use. A technology that has been implemented widely at the administration stage in North American hospitals is the automated dispensing cabinet (ADC), which has been shown to reduce nurse medication administration errors and reduce the time that nurses spend administering medication. The current project was undertaken to assess whether these benefits would be realised with the introduction of an ADC on an inpatient ward in a UK mental health hospital. Nurses were observed administering medication before and after the implementation of an ADC on a ward at East London NHS Foundation Trust (ELFT). The findings from these observations showed that the use of the ADC led to a reduction in the medication administration error rate from 8.9% to 7.2%; however, this reduction was solely accounted for by a reduction in errors of negligible clinical severity. The types of administration errors noted after implementation of the ADC remained largely unchanged from beforehand. The ADC was found to reduce the amount of time that nurses spent administering medication from 2.94 min per dose to 2.37 min per dose. It is estimated that this reduction could generate around 66 min of additional free nursing time per ward per day. As a standalone device, the ADC was found to improve the efficiency of the medicines-use process, but had little meaningful effect on medication administration error rate at ELFT. However, it could be anticipated that additional benefit with regard to reducing medication administration errors may be demonstrated if the ADC was used in combination with other IT systems, such as electronic prescribing. PMID- 26734257 TI - Improving patient care over weekends by reducing on-call work load and better time management. AB - The Royal College of Physicians states that "handover, particularly of temporary 'on-call' responsibility, has been identified as a point at which errors are likely to occur."[1] Working a weekend on-call covering medical wards is often busy and stressful for all junior doctors. The high volume of routine and unplanned tasks make the situation even worse. In Nevill Hall hospital Abergavenny, we measured the workload on a junior doctor for medical ward cover on weekends by counting the number of times he/she was bleeped for routine tasks. Initial study demonstrated that on average 30-40% of time on a long day shift was spent on jobs which could have been done on the preceding Friday. The "FRIDAYS" checklist was introduced for clinical staff (particularly junior doctors) to identify these jobs. According to this model, all the junior doctors were encouraged to review: F: Phlebotomy R: Rewriting drug charts I: IV fluids D: discharge summaries A: Antibiotic review Y: Yellow book/Warfarin dose S: Status of resuscitation and escalation plans before leaving the wards on Friday afternoon. This implementation successfully showed reduction in weekend workload, allowing the ward cover to be focused on care and safety of comparatively sick patients while at the same time reducing the stress for the on-call team. PMID- 26734258 TI - Starting early: integration of self-management support into an acute stroke service. AB - Self-management support following stroke is rare, despite emerging evidence for impact on patient outcomes. The promotion of a common approach to self-management support across a stroke pathway requires collaboration between professionals. To date, the feasibility of self-management support in acute stroke settings has not been evaluated. The Bridges stroke self-management package (SMP) is based on self efficacy principles. It is delivered by professionals and supported by a patient held workbook. The aim of this project was to introduce the Bridges stroke SMP to the multidisciplinary staff of a London hyperacute and acute stroke unit. The 'Plan Do Study Act' (PDSA) cycle guided iterative stages of project development, with normalisation process theory helping to embed the intervention into existing ways of working. Questionnaires explored attitudes, beliefs and experiences of the staff who were integrating self-management support into ways of working in the acute stroke setting. Self-management support training was delivered to a total of 46 multidisciplinary stroke staff. Of the staff who attended the follow up training, 66% had implemented Bridges self-management support with patients since initial training, and 100% felt their practice had changed. Questionnaire findings demonstrated that staff attitudes and beliefs had changed following training, particularly regarding ownership and type of rehabilitation goals set, and prioritisation of self-management support within acute stroke care. Staff initiated an audit of washing and dressing practices pre- and post-training. This was designed to evaluate the number of occasions when techniques were used by staff to facilitate patients' independence and self-management. They found that the number of occasions featuring optimum practice went from 54% at baseline to 63% at three months post-training. This project demonstrated the feasibility of integrating self-management support into an acute stroke setting. Further work is required to evaluate sustainability of the Bridges stroke SMP, to understand the barriers and opportunities involved in engaging all professional groups in integrated self-management support in acute stroke settings, and to assess patient reported outcomes. PMID- 26734259 TI - Service improvement system to enhance the safety of patients admitted on long term warfarin. AB - It is common for hospital inpatients on warfarin to suffer from fluctuations in their INR (international normalised ratio). Raised INRs are potentially very dangerous and may result in acute life-threatening haemorrhages. Conversely, low INRs may increase the risk for the development of venous thromboembolism. Having observed many deranged INRs among hospital inpatients, we decided to focus our project on identifying the contributing factors to deranged INRs and ways to address this problem. We analysed the warfarin prescriptions on all drug charts and surveyed the junior doctor staff. Our results revealed poor knowledge and confidence levels on warfarin prescribing among junior doctor staff. This is likely to be reflected in the poor completion rate of warfarin prescriptions. We instituted practical changes to resolve the issue: most importantly, a change to the warfarin administration time from 6 pm to 2 pm, supported by a poster campaign to increase awareness of the problem. The objective of these changes was to reduce prescribing errors by reducing warfarin prescriptions out-of-hours, by the on-call doctors. We repeated the audit cycle twice. Although our interventions were successfully introduced as shown in our second audit cycle, the changes that were implemented were not sustained as shown in the third audit cycle. We identified a need for annual intervention to educate new junior doctor staff to ensure that the positive outcomes achieved are maintained in the long term. PMID- 26734260 TI - Improving the recognition of post-operative acute kidney injury. AB - The National Institute for Health and Care Excellence (NICE) state that acute kidney injury (AKI) is seen in 13-18% of all people being admitted to hospital and that other patients will further go on to develop AKI during their time in hospital, with around 30-40% being in the operative setting. AKI has an estimated inpatient mortality of 20-30% in the UK and can lead to long-term morbidities like chronic kidney disease.[2] AKI is under-recognised and badly managed despite its prevalence and seriousness, with NCEPOD report stating that only 50% of patients with AKI received good care, that there was poor assessment of risk factors for AKI, and there was an unacceptable delay in recognising post admission AKI in 43% of patients.[4] Baseline data collected on the urology ward in Ninewells Hospital, showed that only five of 22 (23%) patients undergoing urological surgery had post-operative creatinine measured on the ward within 48 hours (the primary method for detecting AKI). Excluding patients who were discharged the same day 5/16 (31%) received the blood test. The aim of the project was to increase the number of patients returning to ward 9 post-surgery who receive a serum creatinine measurement within two days of their urological surgery, excluding daycases. Specifically, we wanted the reliability of this measurement to be 95% or over in ward 9 by 30 July 2014. This was to be done by raising awareness around AKI on ward 9 and changing protocol so that every patient staying on ward 9 beyond their day of surgery should receive a post operative creatinine. This would be tested for a set amount of time to see if patients with AKI were being missed. Despite not being able to implement a set protocol, the percentage of patients receiving post-operative creatinine measurements on ward 9 after a urological surgery still increased significantly. By interacting with the urology team and presenting our data, the knowledge and comprehension of the problem was altered. This lead to a change in culture and a significant increase in the number of post-operative creatinine measurements being taken. Through building relationships on the ward and sharing our data and knowledge there was an increase from 27% of patients receiving post-op creatinine in our first week of collecting data, to 87% in our last week on ward 9. However, without a set tool or change in protocol this change appears to have not been sustainable as the percentage dropped to 42% two weeks later. PMID- 26734261 TI - Improving the efficiency of discharge summary completion by linking to preexisiting patient information databases. AB - The discharge summary (DS) is a document that contains the diagnosis, comorbidities, procedures, complications, and future treatment plan for a particular patient after an inpatient hospital stay. The DS is completed by junior medical staff and is delivered to the general practitioner (GP). DS completion is time consuming and tedious, and DSs are usually not completed within the recommended time frame after a patient is discharged. Time spent completing DSs correlate to junior doctor overtime, which costs the hospital money in overtime pay. Information that is required in the DS is generally already entered into numerous electronic information systems in the hospital, including the "electronic patient journey board" which lists all the patients in a given ward with their clinical information. This information is constantly updated by all staff in the hospital. A program was developed that transferred this information directly into the patient DS. Ten junior doctors in two departments kept daily records for one week of the time spent compiling DSs, the time at work and the actual overtime claimed, before and after the introduction of the intervention. The mean (+/- SD) time for DS compilation per week reduced by 2.8 (+/- 2.4) hours from 10.0 (+/-3.5) hours (p<0.01) and the mean overtime worked per week reduced by 2.8 (+/- 3.1) hours from 8.5 (+/- 4.4) hours (p<0.05). The mean overtime claimed reduced by 1.8 (+/- 2.8) hours from 5.3 (+/- 5.4) hours per week (p<0.05), resulting in reduction in mean overtime payment of $114.95 from $290.57 per doctor, per week. Extrapolating to the 60 ward based junior doctors, the potential annual savings for the hospital budget are over $350,000. Additionally, the number of DSs completed within 48 hours increased from 45% to 58%. In summary, the transfer of electronic data from the electronic patient journey board to the discharge summary program has yielded improvements in DS completion rates and overtime worked by medical staff, resulting in significant reduction in overtime costs. PMID- 26734262 TI - Improving the percentage of electronic discharge summaries completed within 24 hours of discharge. AB - EDSs are an important part of patient care and medical communication. The GWH has a financially motivated target stating that 95% of EDS are to be completed within 24 hours of patient discharge. On review of a six-week pre-intervention period, the medical ward mean weekly EDS completion rate within 24 hours was 74.3%. EDSs form a significant part of junior doctor workload. We found that on a medical ward the mean completion time for one EDS was 18.25 minutes. In January 2014, 387 EDSs were written between four medical wards. This equates to 29.25 hours per week of junior doctor time spent completing EDSs on the four main medical wards. Our aim was to improve the percentage of EDSs completed within 24 hours of discharge from medical wards in the GWH. We proposed and implemented two interventions: 1) Five day EDS summary 2) Protected EDS hour. The five day EDS summary was implemented on wards 1 and 2. The protected EDS hour on ward 3. Ward 1: mean pre-intervention EDS completion rate: 81.1% (six months pre intervention). This increased by 7.9% to 89% (four week mean EDS completion rate post-intervention) Ward 2: mean pre-intervention EDS completion rate: 75.2%. This increased by 11.6% to 86.8% Ward 3: mean pre-intervention EDS completion rate: 71%. This increased by 4.5% to 75.5% Control ward: mean pre-intervention EDS completion rate: 85.1%. This increased by 5.1% to 90.2% Our results show the five day EDS summary led to a mean 9.75% improvement and the protected EDS hour a mean 4.5% improvement in EDS completion rates. A 5.1% increase was seen on the control ward suggesting confounding factors in this data which are most likely the trust EDS working group, junior doctor experience and EDS project publicity. PMID- 26734263 TI - A persuasive intervention: improving the compliance of extended venous thromboembolism prophylaxis following cancer resections in a tertiary colorectal and hepatobiliary unit. AB - Extended venous thromboembolism (VTE) prophylaxis has been shown to reduce the incidence of VTE in patients following cancer resections.[1] However, ensuring patients are discharged with the prescription remains a challenge, with junior doctors frequently rotating throughout different specialties. We conducted an audit to assess the compliance rate in the colorectal and hepatobiliary (HPB) unit at the Queen's Medical Centre in Nottingham. Extended VTE prophylaxis was considered compliant to the guideline if it was prescribed on discharge. The baseline measurement demonstrated compliance rates of 79% and 48% in the colorectal and HPB units respectively. Following discussion with the stakeholders, several interventions that include education and visual reminders were implemented to increase awareness of the importance of extended VTE prophylaxis among junior doctors. Results of the re-audit have shown a remarkable improvement; compliance rates were increased to 93% and 72% in the colorectal and HPB units respectively. We conclude that visual reminder is a simple yet effective tool to improve awareness among junior doctors on the importance of extended VTE prophylaxis in cancer patients. Nevertheless, education remains crucial to ensure the sustainability of any intervention. PMID- 26734264 TI - Improving incident reporting among junior doctors. AB - To ensure systems in hospitals improve to make patient care safer, learning must occur when things go wrong. Incident reporting is one of the commonest mechanisms used to learn from harm events and near misses. Only a relatively small number of incidents that occur are actually reported and different groups of staff have different rates of reporting. Nationally, junior doctors are low reporters of incidents, a finding supported by our local data. We set out to explore the culture and awareness around incident reporting among our junior doctors, and to improve the incident reporting rate within this important staff group. In order to achieve this we undertook a number of work programmes focused on junior doctors, including: assessment of their knowledge, confidence and understanding of incident reporting, education on how and why to report incidents with a focus on reporting on clinical themes during a specific time period, and evaluation of the experience of those doctors who reported incidents. Junior doctors were asked to focus on incident reporting during a one week period. Before and after this focussed week, they were invited to complete a questionnaire exploring their confidence about what an incident was and how to report. Prior to "Incident Reporting Week", on average only two reports were submitted a month by junior doctors compared with an average of 15 per month following the education and awareness week. This project highlights the fact that using a focussed reporting period and/or specific clinical themes as an education tool can benefit a hospital by promoting awareness of incidents and by increasing incident reporting rates. This can only assist in improving hospital systems, and ultimately increase patient safety. PMID- 26734265 TI - Medical rota changes and venous thromboembolism prophylaxis in orthopaedic patients. AB - Efficacy of clinical guidelines to improve patient care is highly dependent on the ability of hospital teams to interpret and implement advised standards of care. Trimester and bi-annual rotation changes often see transference and loss of acquired experience and knowledge from wards with ensuing shortfalls in patient safety and care quality. Such shortfalls were noticed in the ability of our unit to adhere to national venous thromboembolism (VTE) prophylaxis measures. A prospective quality improvement audit was embarked upon to address this. An initial audit of VTE prophylaxis in 112 patients demonstrated just 71% compliance with suggested measures. Errors were predominantly medical in origin and secondary to poor understanding, interpretation, and knowledge of VTE guidelines. Errors were also noted in nursing and patient compliance to measures. Repeated re auditing demonstrated increased error (following initial improvement post audit) after periods of medical staff rotation. Through education of junior medical and nursing staff, and of patients, the unit was able to achieve 100% compliance. Rota changes often induce conflict of interest between maintaining adequate services and high levels of patient care or providing suitable and informed induction programmes for new medical staff. Emphasised education of VTE prophylaxis guidelines has now become part of induction of junior medical staff, whilst ward based measures ensure daily compliance. The success of the audit strategy has led to its use throughout other surgical units within the hospital. PMID- 26734266 TI - The Champions League - Improving the quality of in-patient antibiotic prescription in Trauma and Orthopaedics. AB - A Trust level audit demonstrated that the trauma and orthopaedic department did not reach its own standards in adhering to Trust antibiotic prescribing guidelines. Junior doctors are the main prescribers of antibiotics during inpatient stays. Local policy states that for all inpatients on antibiotics, the start date, duration, and indication for antibiotics must be documented on the drug card. Each patient drug card was reviewed by the department pharmacist and it was recorded whether the documentation was in line with Trust policy. A monthly league table, coined 'The Champions League', was created. It was published monthly and displayed in the doctors' office and other clinical areas to highlight which doctors had or had not adhered to the prescribing guidelines. In August 2012 the monthly audit for the trauma and orthopaedic department included 74 patients. The total number of antibiotic courses prescribed was 28; of these courses only 15 (53.5%) had an indication documented and 15 (53.5%) had a review/stop date documented. In December 2012, after two published league tables, 61 patients were reviewed. A total of 19 antibiotic courses were prescribed; 18 (94.7%) had the indication documented and 16 (84.2%) had the review/stop date documented. The standards of prescribing improved within the department and good prescribing practice became ingrained into each doctor's practice. The league table proved to be a novel tool that helped to raise the profile of antibiotic prescribing and change doctor prescribing habits. It created a competitive spirit within the department which improved morale. Doctors responded positively to feedback if they were not achieving the desirable standards, and enjoyed the challenge of improving the standard of prescribing. PMID- 26734267 TI - Management of transient ischaemic attacks in the emergency department: a quality improvement project. AB - The initial management of transient ischaemic attacks (TIAs) effectively triages patients into either high or low risk categories. The literature demonstrates that the identification of high risk patients significantly reduces the subsequent risk of stroke. The administration of aspirin following a TIA reduces the risk of stroke by approximately 25%. A full cycle retrospective audit which included a baseline audit with two improvement cycles was completed. The notes of every patient presenting to Croydon University Hospital's emergency department (ED), who were subsequently diagnosed with a TIA were reviewed, with the aim of identifying areas for improvement and to implement sustainable long term interventions aimed to improve patient safety. The patient's notes were compared with the guidelines for the management of TIA. The baseline audit demonstrated results requiring an immediate intervention. A teaching session was provided for new FY2 doctors starting their emergency medicine rotations, which covered the initial management of TIA and the importance of following the local guideline. The first improvement cycle saw an improvement in all outcomes measured. A statistically significant improvement (P-value = 0.05) was seen in the documentation of symptoms in the prior week and the prescription of antiplatelets in the department. Furthermore, where only 31% of TIA patients received antiplatelets at the baseline measurement, 86% received this treatment during the first improvement cycle. This means that 55% more patients received improved initial management, subsequently reducing their stroke risk by 25%. Similar results were seen in the second improvement cycle, thus demonstrating the intervention had been both successful and sustainable. In conclusion, a simple intervention can provide significant and sustainable improvements to the management of TIA in the ED. PMID- 26734268 TI - Simulation-based training improves ITU staff knowledge in the management of head injuries. AB - Traumatic brain injury (TBI) in the polytrauma situation is a phenomenon often seen at UK hospitals. Without immediate access to dedicated neurocritical care facilities, the potential for under-treatment of the underlying brain injury and serious neurological sequalae is high, especially if staff on the general intensive care units on which these patients are treated lack confidence in this area of practice, a reality confirmed by our baseline study. We found that by engaging staff by implementing a regular simulation-based team training programme, we were able to boost the skills, knowledge, and ultimately confidence levels in treating TBI amongst these groups of staff. "Buy-in" by those concerned was high, and we found that self-reported scores for the attributes described above were improved considerably and consistently by our intervention. This quality improvement project has been rolled out through several iterations to become sustainable, has significant cost-saving potential, and will hopefully lead to proven improved clinical outcomes for this group of patients. PMID- 26734269 TI - Improving Sepsis Management in the Acute Admissions Unit. AB - Sepsis is a common condition with a major impact on healthcare resources and expenditure. We therefore wanted to investigate and improve how the acute admission unit (AAU) at the Great Western Hospital (GWH) is managing patients who present directly to the unit with sepsis. In order to obtain this information, an audit was undertaken against the College of Emergency Medicine standards used by the emergency department within GWH and across the UK. Data was retrospectively collected for 30 patients with a diagnosis of severe sepsis or septic shock. The notes were scrutinized with regard to the implementation of College of Emergency Medicine standards for the management of sepsis. This meant that performance in the AAU was compared against the emergency department at GWH and national figures. The data collected shows performance is below national standards with regard to documentation of high flow oxygen use (AAU: 24%, ED 100%; national median: 50%; CEM standard 95%), crystalloid fluid boluses (AAU: 52%; ED: 90%; national median: 83%; CEM standard 100%), lactate measurements (AAU: 66%, ED: 93%; national median: 80%; CEM standard 95%), and obtainment of blood cultures (AAU: 52%; ED 73%; national median: 77%; CEM standard: 95%). Only 3% of patients received all six parts of the sepsis bundle. Since auditing in 2012/2013 we have introduced a sepsis proforma based on a current proforma being used within Severn Deanery. This proforma uses the 'Sepsis Six' bundle appropriate to ward based care. We have raised awareness of sepsis implications and management through the creation of a 'sepsis working group' to educate both junior doctors and nurses. In turn, this has led to education through the use of posters, pocket reference cards, and teaching sessions. Re-audit shows significant improvement in administering all parts of the Sepsis Six bundle and an 8% improvement in patients receiving all six of the bundle. PMID- 26734270 TI - Improving phlebotomy handover to doctors: a quality improvement project. AB - AIM: To design a hospital-standardised phlebotomy handover method to improve the communication between phlebotomists and doctors. To reduce delays in patient management and discharges which occur due to poor handover. METHOD: Qualitative data was collected to gauge junior doctors' experiences of the current handover process. Quantitative data was collected over a two-week period across two medical wards to measure the proportion of requested bloods that could not be taken by phlebotomists that were successfully handed over to doctors. Brainstorming sessions were held with junior doctors, phlebotomists and ward staff in order to design a, cheap, effective, sustainable, hospital-wide method of handover. The chosen intervention was a red ward-based phlebotomy handover folder for phlebotomists to place stickers of unbled patients in. The folder was trialled on two medical wards. Feedback obtained helped improve the intervention before implementing it hospital-wide. RESULTS: Seventeen of 23 junior doctors (74%) felt that a formalised handover process would be very useful. Baseline measurement over two weeks revealed that 24/129 blood tests ordered for phlebotomists to take were not taken. Only three (13%) of these were handed over to doctors. Post-intervention, 18/106 blood tests requested were not taken. All 18 (100%) were successfully handed over to doctors. CONCLUSIONS: Implementation of a hospital-standardised phlebotomy handover folder dramatically improved the communication and handover between phlebotomists and doctors allowing for medical teams to take prompt action on unbled patients. This intervention will help improve patient safety, reduce delays in management/discharge and reduce the number of jobs handed over to evening on-call teams. PMID- 26734271 TI - Improving access to competitive employment for service users in forensic psychiatric units. AB - Employment has been proven to be an effective recovery tool and therapeutic intervention for those with severe and enduring mental health conditions. Aside from monetary reward, employment is a means of structuring time and provides a sense of worth and achievement, which enhances self-esteem and confidence. A social identity is developed through employment, encouraging social support and increasing social networks. Securing employment can bring about improved quality of life and positive change in one's social circumstances; therefore it can reduce symptoms associated with mental illness and potentially prevent re offending, as the individual develops a sense of independence, self-efficacy, and value. Barriers to employment exist for forensic mental health service users and therefore it is imperative that employment needs are addressed at the earliest possible stage in recovery. An evaluation of employment activities across two forensic mental health units revealed a lack of appropriate employment opportunities for service users, and those roles available were not implemented in line with recommended best practice. In response to this issue several enterprises were established to offer opportunities for service users to engage in meaningful employment and develop skills that a future employer would value. Each enterprise responds to a business need within the units to ensure sustainability of services. The enterprises are essentially micro-businesses with social objectives whose surpluses are reinvested for the purpose of increasing opportunities for service users. The enterprises are underpinned by the philosophy of the Individual Placement and Support (IPS) model; empirical evidence suggests that the IPS model is the most effective intervention, based on the 'place then train' philosophy. The model recommends a focus upon rapid job search to achieve competitive employment for those who want to work; opportunities sourced should be consistent with individual preference and benefits counselling offered. Support should be time unlimited and integrated with mental health treatment. A person-centred and strengths-based approach is also adopted to support people to build on their strengths, establish goals, and encourage motivation. PMID- 26734272 TI - Improving Patient Safety of Acute Care Lumbar Punctures. AB - Lumbar puncture (LP) is a common invasive procedure in the acute medical setting but is not without its risks and complications, making best clinical practice and correct documentation important for patient safety. Previous audit revealed poor levels of consistency in technique and documentation in the acute medical setting, highlighting it as an area for improvement. This project aims to identify current levels of documentation and improve upon these through the departmental education and the introduction of a documentation tool to create a safer clinical environment for LPs. Gold standards in clinical practice were identified through literature review and national guidelines, establishing 15 key parameters as essential areas for documentation. Patient notes were retrospectively analysed after LP over a two month period to identify levels of documentation in these areas, and the clinical technique used. Results of this initial audit were presented to the department along with an education session regarding current evidence based best practice for LPs and the important aspects relating to patient safety. A documentation tool was also introduced. A re-audit was then performed of the same parameters and assessing the use of the documentation tool. Results showed a significant increase in overall documentation from 44% up to 95% after intervention, with 85% of cases using the new proforma. We can conclude that the introduction of a documentation tool and departmental education has significantly improved upon LP documentation in the acute medical setting. This is important for both the protection of medical professionals, as well as patient safety and quality of care, and could be implemented in other clinical environments. PMID- 26734273 TI - Signposting GP trainees to relevant learning opportunities in hospital posts:the Super-condensed Curriculum Guide. AB - UK three-year GP specialty training programmes consist of 18 months in hospital posts and 18 months in general practice. Within the hospital setting, clinical supervisors of GP trainees may have difficulty determining which learning opportunities available within the post are most relevant to training for a future career in general practice. Feedback from GP trainees has indicated that there is a lack of consistency in hospital posts regarding relevance of training for general practice. The aim of the project was to provide support to the hospital supervisors in order to improve the overall quality of hospital posts in GPST programmes and their relevance to General Practice training, and to provide guidance to GP trainees to target their learning most effectively within each specialty post to improve relevance to future career. The deanery set out to develop a tool, the Super Condensed Curriculum Guide (SCCG) consisting of a set of documents created for a specialty with involvement from stakeholder groups. It was intended that this guide would stand alongside the relevant part of the GP curriculum. A programme of familiarisation and initial training for clinical supervisors was delivered. Take-up of the clinical supervisor training sessions was not uniform. Following favourable initial feedback from trainee groups and clinical supervisors across the region, the guides were developed for the remaining specialties in the programme. Trainees were also informed about the guide and how it might help focus their learning in a hospital post. Feedback from trainees across the specialties was positive, but more needs to be done to engage clinical supervisors across the range of specialties. This will improve the utility of the tool, help to guide the clinical supervisor in their teaching, and make sure each post is as educationally effective as possible. PMID- 26734274 TI - Anticoagulation service: improving the referral process. AB - Oral anticoaguIants are extremely common, and it is estimated that there are between 500,000 and 1 million people prescribed them in the UK.[1] These drugs are the most frequently named medication in fatal errors and litigation claims [2] and they require the implementation of additional safety controls.[3] Warfarin is the most commonly prescribed anticoagulant and it requires regular international normalised ratio (INR) monitoring and dosage adjustment to achieve the desired therapeutic range.[4] Under-anticoagulation can cause thrombosis and over-anticoagulation can lead to haemorrhage, both of which can be fatal.[5] At St. Peter's hospital there is an anticoagulation service providing regular international normalised ratio (INR) monitoring for patients on warfarin. However, the current referral system is paper-based and a baseline audit found that only 66% of patients were successfully referred to the service on discharge from hospital. This identifies a significant patient safety issue which could result in life-threatening consequences. An electronic referral form was developed within a pre-existing computer based ordering system with the aim of improving the referral rate. The electronic referral tool streamlined the referral process, making the form quicker and easier to fill out and removed the need for faxing lengthy paper forms. Key information on the form was made mandatory. After intervention a re-audit revealed that 84% of patients discharged on warfarin were referred to the clinic, which equates to an increase of 18%. The increased referral rate will improve patient safety and prevent unnecessary hospital admissions. There should be continued promotion of the importance of referring patients to the anticoagulation clinic. This can be delivered through inductions, teaching sessions, and re-audits. Future goals include an automated referral system triggered on patient discharge. PMID- 26734275 TI - A daily huddle facilitates patient transports from a neonatal intensive care unit. AB - To improve hospital access for expectant women and newborns in the state of Maryland, a quality improvement team reviewed the patient flow characteristics of our neonatal intensive care unit. We identified inefficiencies in patient discharges, including delays in patient transports. Several patient transport delays were caused by late preparation and delivery of the patient transfer summary. Baseline data collection revealed that transfer summaries were prepared on-time by the resident or nurse practitioner only 41% of the time on average, while the same transfer summaries were signed on-time by the neonatologist 5% of the time on average. Our aim was to improve the rate of on-time transfer summaries to 50% over a four month time period. We performed two PDSA cycles based on feedback from our quality improvement team. In the first cycle, we instituted a daily huddle to increase opportunities for communication about patient transports. In the second cycle, we increased computer access for residents and nurse practitioners preparing the transfer summaries. The on-time summary preparation by residents/nurse practitioners improved to an average of 72% over a nine month period. The same summaries were signed on-time by a neonatologist 26% of the time on average over a nine month period. In conclusion, institution of a daily huddle combined with augmented computer resources significantly increased the percentage of on-time transfer summaries. Current data show a trend toward improved ability to accept patient referrals. Further data collection and analysis is needed to determine the impact of these interventions on access to hospital care for expectant women and newborns in our state. PMID- 26734276 TI - Obesity management in a Paediatric Emergency Department. AB - Increasing numbers of children are either overweight or obese, which has a significant negative impact on their current quality of life and their future health. The results of England's National Child Measurement Programme 2012-13 revealed that approximately one fifth of 4- to 5-year-olds and one third of children aged 10 to 11 years were overweight or obese. Emergency departments (EDs) see large numbers of children every year and therefore represent a potential opportunity to address the obesity issue. A pathway was devised to guide referral of overweight or obese children attending the ED to an existing local healthy living programme. Training sessions on the referral process were provided to ED staff. Audits of ED attendance records were undertaken before and after the implementation of the pathway, and the local programme uptake rate for the first 25 referrals was assessed. Of the first 25 children referred, two (8%) had participated in a programme, six (24%) were on a waiting list, and four (16%) were referred on to services in their local area, giving an overall engagement rate of 48%. Further work needs to be undertaken to increase referrals; however, addressing childhood obesity by accessing existing local services from the ED remains a valuable endeavour. PMID- 26734278 TI - Improving management of constipation in an inpatient setting using a care bundle. AB - Constipation is a common occurrence on geriatric in-patient wards. It can result in delirium and other complications including bowel obstruction. Over treatment with laxatives can result in iatrogenic diahorrea, which can lead to dehydration, delirium, and the false positive labeling and unnecessary treatment of clostridium difficile carriers. This can result in increased morbidity and mortality, and a longer stay in hospital. This means that improving the assessment and treatment of constipation should improve patient outcomes and result in significant hospital cost savings. Multidisciplinary discussion and planning resulted in the delivery of our constipation project. This aimed to encourage the early assessment and treatment of constipation of inpatients on a geriatric rehabilitation ward. The goal was to prevent significant constipation by intervening early, improving the prescription of laxatives, and titrating them when the constipation has resolved. This involved educational sessions, non pharmacological alternatives to laxatives (optimisation of hydration, exercise, and high fibre foods), laxative prescription guidance, and twice weekly laxative ward rounds. The profile of laxative prescription changed in keeping with our guidance. There was a reduction in overall laxative prescription by a third and the prescription of "PRN" laxatives was eliminated. This hopefully resulted in reduced morbidity for the patients and reduced length of stay. There was a cost savings on the laxative bill on average per day of the project, which when extrapolated to a 365 day year was L1226.40. This doesn't include potential savings gained from reduced complications of constipation and reduced length of stay, which are hard to accurately measure. PMID- 26734277 TI - How clean is clean: a new approach to assess and enhance environmental cleaning and disinfection in an acute tertiary care facility. AB - Traditional environmental cleaning monitoring through visual assessment can identify gross lapses in practice. However, in recent years the limitations underlying this need for ongoing compliance with cleaning and disinfection policies in the patient's immediate surroundings have become widely recognised. The value of objectively monitoring and improving environmental cleaning and disinfection in healthcare settings is becoming increasingly identified as a crucial element of strategies to mitigate the transmission of healthcare associated infections. Mafraq Hospital has adopted a new method using an invisible fluorescent marker system to target on surfaces in patient's immediate surroundings. Evaluation of at least 30 surfaces and objects in patient rooms revealed that only 11% of targets had been cleaned. Simulation training, educational interventions, empowerment, change involvement and acknowledgment were executed, leading to a sustained improvement of 77% in both quarter 2 and 3 of 2013 in cleaning and disinfecting of all surfaces and objects. PMID- 26734279 TI - Improving the follow-up of microbiology results: the origins of the Pink Book. AB - Failure to check microbiology results put patients at risk of prolonged infections, resulting in increased morbidity and mortality from sepsis. There are some electronic systems designed to address this risk although they are rarely used in the hospital setting. In many hospitals the follow-up of microbiology results for discharged patients is reliant upon individual doctor's vigilance or ad hoc lists. Our intervention, the 'Pink Book', provides a simple, cost effective system to follow-up microbiology results for discharged patients. This simple paper based system enables prompt, effective, efficient follow-up of microbiology results, saving our paediatric department an estimated 1.5 hours per week, L17,440 per year and helping to prevent one case of inadequately treated infection per month. This project highlights how small scale, simple interventions at the local level, born out of the frustration at existing inefficient systems, can make great improvements to patient safety and the efficiency of healthcare. PMID- 26734280 TI - Reducing time to reperfusion for ST elevation myocardial infarction patients by a simple process change in the Emergency Department. AB - Current reperfusion guidelines from the European Society of Cardiology (ESC) recommend that First Medical Contact to Balloon times (FMC-B) for ST elevation myocardial infarction (STEMI) should not exceed 120 minutes. Many factors can cause delay in door to balloon times for patients suffering from STEMI. Previous studies have found that longest times for FMC-B occur if the patient presents initially to a non-percutaneous intervention (PCI) capable hospital. As a non-PCI capable site we looked at ways of reducing FMC-B times. Audit revealed that registration to electrocardiogram (ECG) times were sometimes prolonged due to undertriage, long waiting times and lack of space and staff to record an ECG, resulting in some prolonged FMC-B times. To address this, we have changed the system so that patients bypass triage and go directly to a dedicated investigation cubicle for an ECG. The patient books on at reception with chest pain and is immediately directed to the investigation cubicle. The ECG is reviewed immediately and the patient is either kept in the department for further management or allowed back to the waiting room to await triage if the ECG is non diagnostic and history not worrying. Data on patients presenting with STEMI on the initial ECG were collected for one year pre-intervention (n=21 )and one year post-intervention (n=17). The median FMC-B time for the pre-intervention group was 108.5 minutes (IQR 96 - 143.5). Median FMC-B time for the post-intervention group was 82 minutes (IQR 66.5-93.5). This is a simple, low-cost intervention which could be transferable to other sites who have an interest in reducing FMC-B times. It is necessary to have a key person to carry out audit of all potential areas of delay, and a collaborative, multidisciplinary approach to making change to improve quality of care. PMID- 26734281 TI - Improving the management of patients with acute red eyes in a large London Emergency Department. AB - Anecdotal evidence suggested that the management of patients with eye complaints in the Emergency Department (ED) at King's College Hospital, London was suboptimal. Acute ophthalmology is often poorly covered at undergraduate level in the United Kingdom which can affect patient safety. Furthermore, it was notoriously difficult to obtain specialist advice within working hours. Contact lens (CL) wearers are prone to Pseudomonas conjunctivitis which requires certain antibiotics and mismanagement of this has led to sight-threatening consequences locally. Junior doctor surveys suggested under-confidence in managing eye problems and initial audit showed that eye assessments are frequently incomplete during ED clerkings. For example, CL status and visual acuity were documented in 63% and 77% of cases respectively; however, these were increased when a dedicated pro forma was used. To address these multiple issues, a new 'eye examination pro forma' was created, along with integrated clinical guidelines based on local expert practice. This would prompt staff to elicit key information to help guide management. A new referral pathway was also introduced to facilitate access to ophthalmology services. On re-auditing seven months later, the new pro forma was completed for only 28% of patients, though this was associated with a higher rate of documentation of all parameters. The referral pathways worked efficiently and patients with red flag features were identified and managed more appropriately than before. We learnt that it is important that someone personally drives the innovations from the outset, otherwise prolonged change is difficult. Secondly, junior doctors may not be proficient with slit lamp use, for instance, so targeted teaching is required, not simply new pathways. Full engagement with the pro forma and effective patient management should then improve simultaneously. Specific teaching is now being implemented and permanent staff have been recruited to oversee the project. We plan to re-audit in November 2014. PMID- 26734282 TI - Improving the frequency of visual infusion phlebitis (VIP) scoring on an oncology ward. AB - Phlebitis from peripheral intravenous infusions is an important potential source of oncology patient morbidity. Important factors found to determine phlebitis incidence include the kind of infusion and dwell time of intravenous cannula. Early studies showed incidence rates of between 25-70% worldwide, and association with up to 10% of S. aureus bacteraemia. The introduction of the visual infusion phlebitis (VIP) score tool for assessment of the early signs of phlebitis, along with prompt removal of peripheral intravenous cannulas, has been very successful in reducing the incidence below the acceptable rate of 5%. However, achieving this goal depends on strict compliance with guidelines for cannula insertion, documentation, and assessment using the VIP tool. This study aimed to increase the use of VIP scoring tool to 100% on an oncology ward during a four to six month period in order to maximise its utility in phlebitis prevention. Three plan do-study-act (PDSA) cycles were carried out, during which two major interventions were introduced. The first cycle aimed to improve junior doctors' awareness of VIP scoring using presentations in induction meetings and posters. The second cycle ensured that ready access to the VIP tool was provided in the form of bedside intentional rounding charts. Proportions of intravenous cannulas with proper documentation and VIP assessment were measured before intervention and at nine subsequent bi-weekly time points. Pre-intervention, under 30% of cannulas were properly documented and assessed. This proportion rose to around 80% by the end of the second PDSA cycle and achieved 100% by the end of the third cycle. PMID- 26734283 TI - Structured approach in improving weekend handovers in a medical high dependency unit. AB - Weekend admissions to hospital have been associated with adverse patient outcomes, including higher morbidity and mortality risk in general medicine and surgery. The reasons behind this are likely to be multifactorial and include reduced senior clinician-led care, decreased overall workforce, and ineffective or incomplete handover. With the advent of shift-work patterns, robust handover between medical teams is of paramount importance, particularly before weekends. This has been reflected in recent publications by Royal College of Physicians (acute care toolkit 1: handover, May 2011), that identified handover as an error prone process and issued guidelines designed to optimise its effectiveness. The aim of this project was to evaluate weekend patient mortality and success of handover on the medical high dependency unit of a large teaching hospital in the United Kingdom, before and after introduction of a structured handover tool on Friday afternoons during May 2013. This unit is registrar-led at weekends. Weekend mortality decreased from 43% in March 2013 to 22% in May 2013 (odds ratio 0.37, 95% CI 0.19-0.68, p=0.07). Documentation of resuscitation status and escalation plans increased from 75% in March 2013 to 93% in May 2013. There was universal positive feedback from registrars involved with the handover tool, who provided senior cover during the weekends in May 2013. It is hoped that structured, written handover will ultimately become commonplace in this unit and will improve patient safety at weekends. PMID- 26734284 TI - A quality improvement project to improve the effectiveness and patient centredness of management of people with mild-to-moderate kidney disease in primary care. AB - Chronic kidney disease (CKD) stages 3 to 5, affects 6-7% of the adult population and is an important risk factor for both advanced kidney disease and cardiovascular disease. This paper describes a quality improvement project that aimed to establish consistent implementation of best practice in people with stage 3-5 kidney disease who were managed in primary care. The intervention was a Care Bundle for CKD. The bundle included three evidence-based, high impact interventions based on National Institute for Care Excellence (NICE, 2008) guidance, with an additional and novel self-management element. 29 GP Practices in England and Wales began the study. They undertook training in clinical management of CKD and in facilitation of self-management, with the self management content designed and led by patients. Practices were asked to report baseline and then monthly outcome data extracted from practice computer systems. The project team provided implementation and ongoing quality improvement support for participating Practices. Ten Practices dropped out of the study following the training. Data submissions were incomplete in six Practices who continued to apply the care bundle. At the project end, a decision was taken by the study team to perform the final analysis on those thirteen Practices which completed the project and submitted at least six sets of monthly Practice-level outcome data. In these Practices the Care Bundle was applied to under 20% of the registered CKD stage 3 to 5 population in 5 Practices, 20-29% in 3 Practices, 30-49% in 2 Practices and >=50% in 3 Practices (998 patients in total). Of these, 671 patients (75%) agreed to the self-management component of the intervention. The reliability (at project end) in those who received the Bundle was 100%. The Bundle was applied to an additional 315 patients in the six Practices who completed the project but did not submit regular practice-level monthly data. In the thirteen remaining Practices, the achievement of NICE (2008) blood pressure targets at the start of the project was 74.8% in people with CKD stage 3-5 and no diabetes and 48% in people with CKD stage 3-5 and diabetes. At the project end these figures in the same Practices were 76.7% and 49.2% respectively. These improvements were achieved in spite of Practices increasing their recording of prevalence rate (that is, identifying and recording more patients with CKD on the Practice CKD Register). In conclusion, a care bundle can be implemented in primary care. However, maintaining engagement with primary care health care professionals and maximising exposure to an intervention in patients seen infrequently are significant challenges to generalisation and sustainability. PMID- 26734285 TI - MediDial cards: a quick win for service improvement. AB - One of the key roles of a junior doctor is co-ordinating the care of their patients and communicating with different departments or specialties within the hospital. To do this, junior doctors often spend a lot of time on a daily basis contacting the hospital switchboard in order to locate a required bleep/extension/fax number, or trying to navigate an intranet based directory which can be difficult to use. We aimed to improve this task for junior doctors as a pilot project for engaging junior doctors in service improvement. Our multi disciplinary team, led by junior doctors and with the support of the Trust, produced and implemented lanyard (MediDial) cards containing common and relevant (fax, bleep, and extension) numbers for use by junior doctors. Through the introduction of our MediDial cards we not only reduced the frequency junior doctors needed to contact the switchboard on a daily basis, but also the length of time spent waiting to speak to an operator. The MediDial cards were also found to be time saving and more useful than the previous intranet based database. Since the introduction of the MediDial cards, the project has been rolled out across the Trust and presented at Grand Rounds as an example of junior doctor led service improvement, aiming to encourage trainees to engage with quality improvement projects. PMID- 26734286 TI - Improving the accuracy of operation coding in surgical discharge summaries. AB - Procedural coding in surgical discharge summaries is extremely important; as well as communicating to healthcare staff which procedures have been performed, it also provides information that is used by the hospital's coding department. The OPCS code (Office of Population, Censuses and Surveys Classification of Surgical Operations and Procedures) is used to generate the tariff that allows the hospital to be reimbursed for the procedure. We felt that the OPCS coding on discharge summaries was often incorrect within our breast and endocrine surgery department. A baseline measurement over two months demonstrated that 32% of operations had been incorrectly coded, resulting in an incorrect tariff being applied and an estimated loss to the Trust of L17,000. We developed a simple but specific OPCS coding table in collaboration with the clinical coding team and breast surgeons that summarised all operations performed within our department. This table was disseminated across the team, specifically to the junior doctors who most frequently complete the discharge summaries. Re-audit showed 100% of operations were accurately coded, demonstrating the effectiveness of the coding table. We suggest that specifically designed coding tables be introduced across each surgical department to ensure accurate OPCS codes are used to produce better quality surgical discharge summaries and to ensure correct reimbursement to the Trust. PMID- 26734287 TI - Intravenous fluid prescribing: Improving prescribing practices and documentation in line with NICE CG174 guidance. AB - Intravenous (IV) fluid prescribing is a common occurrence in inpatient settings; it has been repeatedly demonstrated that high levels of mortality and morbidity are associated with inappropriate IV fluid prescribing. IV fluid prescriptions are often completed by the most junior and inexperienced members of the clinical team. In recognition of the issues surrounding IV fluid prescribing and in an effort to combat the issues surrounding current practice, the National Institute for Health and Care Excellence (NICE) published guidance in December 2013 - 'Intravenous fluid therapy in adults in hospital (CG174)'. At our hospital the approach to IV fluid prescribing amongst junior doctors was highly variable with poor awareness of the NICE guidance. We defined necessary components for the documentation of IV fluid prescriptions based upon the NICE guidance. Our initial data showed that these components were infrequently documented, with prescriptions often having no indication for IV fluid, no 24 hour plan / review, no documentation of patient weight or request for further weights, and no current or requested fluid balance charts. Lanyard cards emphasising the necessary components of an appropriate IV fluid prescription along with a copy of the NICE fluid prescribing algorithm were distributed to junior doctors on the acute admissions units. Following the introduction of the lanyard cards there was a significant increase in the documentation of the defined prescription components. Significant increases in the documentation of indication for IV fluid and patient weight, which are essential components of accurate fluid prescription, were demonstrated on both medical and surgical admissions units. Subsequently, as a result of improved documentation and consideration given to fluid prescriptions, we were able to increase the percentage of maintenance IV fluid prescriptions that conformed to NICE guidelines. As an endpoint to this intervention all new Foundation Year 1 doctors at our hospital were issued with IV fluid prescribing lanyard cards at Trust induction; the authors believe that this intervention will lead to a unified approach and a sustained improvement in IV fluid prescribing practices and prescription documentation at this hospital site. PMID- 26734288 TI - Improving the accuracy and turn-around time of controlled drug prescribing for patients being discharged home for end-of-life care. AB - Many patients approaching the end of their life express the preference to die at home,[1] although unfortunately the majority of people will still die in hospital.[2] For patients approaching the end of their life, it was noted anecdotally that often those who have expressed a preference to go home from hospital for end of life care may have their discharge delayed due to problems in the prescribing of common medications used to alleviate distressing symptoms at the end of life. An initial audit at Conquest Hospital showed an 89% error rate in these prescriptions, mostly related to prescribing controlled drugs such as morphine and midazolam. A single standardised dispensing chart for commonly prescribed medications at the end of life, in the form of both "Just in Case" medications and syringe driver medications, was created which addressed this problem by having the medications pre-written so as to meet all legal requirements for controlled drugs. The prescriber is able to choose and fill out an appropriate drug and dose by using flow-chart information overleaf and then sign the prescription to allow it to be dispensed. After an initial two month pilot period, a re-audit showed a significant fall in error rate down to 11%, as well as an improvement in turnaround time in dispensing the medications. PMID- 26734289 TI - Improving mid stream urine sampling: reducing labelling error and laboratory rejection. AB - A urine sample is vital in older patients with pyrexia or acute confusion, and commonly directs clinicians towards a source of infection. Not only can the organism be identified, but sensitivities to antibiotics can also guide prescribing. A high number of urine samples were not being processed on the medicine for older people wards at St. James's Hospital due to incomplete hand written request forms not complying with trust policy. Previous attempts to re educate staff had failed to improve acceptance rates. Rejected samples delay diagnosis, identification of organisms and subsequent sensitivities, as well as increasing staff workload. A total of 72 urine samples were audited from our wards in March 2013; 12 (17%) rejected. Clinicians were notified of rejected samples within one to four days. An electronic-requesting system was implemented in April 2013. Once implemented, a further two data collection cycles of 72 urine samples were completed from the same wards. In December 2013, 55 (76%) were electronically requested and 17 (24%) hand-written. Four (5%) samples were rejected and were all hand-written. In August 2014, 61 (85%) were electronically requested and 11 (15%) hand-written. No samples were rejected. The electronic requesting system has effectively reduced the number of rejected urine samples. No electronically requested samples were rejected, therefore 100% sample acceptance is achievable. It is more effective than re-educating staff alone and ensures requests meet trust policy. Clinicians were notified of a samples rejection after one to four days. By this time patients may have started antibiotic therapy, decreasing the likelihood of isolating the causative organism in subsequent samples. All urine samples requested must meet a high standard and comply with trust policy in order to be processed. An electronic-requesting system removes errors of omission and ensures policy compliance, ultimately leading to improved patient care. Now our processes are reliable we will go onto measure changes at patient level, e.g. confirmed diagnoses of urine infection, outcomes of earlier narrow spectrum antibiotics, and length of stay. PMID- 26734290 TI - Improving surgical inpatient ward lists in a large acute hospital: a simple yet effective process to save the time of junior house officers. AB - In order for the smooth running of a surgical firm, an effective ward list must be created, updated, and edited each day, often by junior medical personnel. Ward lists are used by various healthcare professionals including consultants, specialist nurses, and pharmacists. Over time ward inpatient lists can become increasingly difficult to use and lacking in vital information. Baseline measurement revealed the extent of the problem with junior house officers spending on average 95 minutes per day maintaining the ward list. After a period of research and learning, a bespoke inpatient list was created containing all of the vital information required. Criteria to fulfil included being straightforward to manipulate, easy to input new patients and aesthetically pleasing. After a trial period with modifications, an improved inpatient ward list was successfully implemented. Post-intervention data collection revealed a reduction of 42 minutes per day on average spent maintaining the list, with a 100% increase in satisfaction, and reduction in problems encountered from daily to weekly. Following this success, the general surgery weekend handover list was improved using the same prototype. This led to a saving of 8 minutes per day on average and increased doctor satisfaction. The process of creating an effective, easy to use, and useful inpatient ward list can lead to large amount of time saved each day for the staff responsible for its management. This time can then be reinvested on clinical duties, or education, to further improve the healthcare service we provide. PMID- 26734291 TI - Improving cardiac assessment and monitoring in methadone prescribing at an addiction service. AB - The assessment and monitoring of cardiac risk in patients prescribed methadone is important for patient safety. Although uncommon, QTc interval prolongation is potentially life-threatening. Known risk factors for QTc prolongation include methadone, particularly at doses above 100 milligrams daily. This project aimed to improve the cardiac assessment and monitoring at Barnet Drug and Alcohol Service through raising the awareness of this clinically importance issue as well as through amending the medical assessment guidance to promote the comprehensive assessment of QTc prolongation risk factors and ensure the identification of cardiac risk in patients prescribed methadone. The project also provided guidance on QTc prolongation management and monitoring (including performance of an electrocardiogram) at the service to provide a baseline measurement and arrangement of annual monitoring. Prior to the intervention, a randomised sample of 26 patients that had been prescribed methadone revealed no comprehensive cardiac risk assessments. Analysing 52 medical assessments in the month following the intervention suggested an improvement in assessment and management of QTc interval prolongation risk, with seven comprehensive cardiac risks assessments performed and one patient having QTc interval prolongation identified following an electrocardiogram and appropriately managed. This project was limited by small sample sizes and the relatively low incidence of QTc prolongation. The poor rate of attendance for requested electrocardiograms in this population was noted as a challenge that needed further consideration. PMID- 26734292 TI - Improving acute eye consultations in general practice: a practical approach. AB - There is significant evidence that patients with acute eye symptoms are poorly assessed in primary care. There is a tendency to diagnose viral or bacterial conjunctivitis in any acutely red eye. This has led to delays in treatment and in some cases, permanent loss of sight. The aim of this project was to improve acute eye consultations within the Birchwood Medical Practice. The project focused on the "red flag" findings that would identify patients who require referral for same-day ophthalmology assessment. A retrospective baseline audit was carried out on all cases read-coded "conjunctivitis" over the period of one year. Initially, only 2.8% of consultations had documented all four findings. By considering the main factors that lead to poor eye assessments, two main areas for improvement were identified. These were education (reinforced with memory aids) and improving the availability of eye examination equipment within each consultation room. An "eye examination kit" was developed with the needs of the general practitioner in mind. The practice was re-audited six weeks following the intervention. Consultations where all four red flag findings were documented rose from 2.8% to 50%. This was found to be a statistically significant difference (p < 0.01). Pain was checked 63% of the time, compared to 26% prior to intervention. Visual acuity screening had increased to from 35% to 69%. Photophobia was the most significantly increased metric, from being documented only 6% of the time to now 63% of the time. Documentation of whether the symptoms were unilateral or bilateral had also increased from 88% to 94% of consultations. The initial audit indicated that general practitioners often diagnosed conjunctivitis without screening for symptoms of sight-threatening disease. However, it was clear from the results that the doctors had made a significant change to their approach to acute eye consultations. This shows that doctors are willing to make changes to their behaviour when given the right tools and information. It was felt that a first-hand understanding of the problem and an open discussion regarding the changes required was key to the success of this project. This project has shown that significant improvements can be achieved with practical and inexpensive interventions. Therefore, general practices throughout the UK are encouraged to adopt similar strategies to improve the identification of patients needing same day Ophthalmology assessment. PMID- 26734293 TI - Report into "on the day cancellations" for plastic surgery in patients who failed to stop their medication. AB - It was noted that a number of patients were having their procedures cancelled on the day of surgery because their antiplatelet or anticoagulative medications had not been stopped preoperatively. The team recognised that this problem was leading to an unnecessary waste of the department's labour and financial resources, and more importantly was becoming a source of disappointment and anxiety to patients. A retrospective analysis of all plastic surgery cases was performed for procedures listed for the previous 12 months. All cancellations and the reasons for them were recorded, which came to 23 cases. The sum of the financial tariffs for each cancelled procedure was calculated to assess the financial impact of the identified problem: L20,000. A root cause analysis was performed to assess where this problem was arising in the patient's preoperative journey. The common theme was the lack of information for the gatekeeper regarding the patients' anticoagulant and antiplatelet medications. A new gatekeeper form was introduced to practice with a subsection specifically highlighting antiplatelet and anticoagulative medications. In addition, this issue was highlighted to the relevant staff in the department. After four months, a second PDSA cycle was performed in the same manner. Seven cases were cancelled due to anticoagulants or antiplatelets not being stopped prior to surgery. This equated to a net loss of L11,865 to the department when projected over 12 months, improving on the performance prior to the newly introduced changes. PMID- 26734294 TI - Improving surgical weekend handover. AB - Effective handovers are vital to patient safety and continuity of care, and this is recognised by several national bodies including the GMC. The existing model at Great Western Hospital (GWH) involved three general surgical teams and a urology team placing their printed patient lists, complete with weekend jobs, in a folder for the on-call team to collect at the weekend. We recognised a need to reduce time searching for patients, jobs and reviews, and to streamline weekend ward rounds. A unified weekend list ordering all surgical patients by ward and bed number was introduced. Discrepancies in the layout of each team's weekday list necessitated the design of a new weekday list to match the weekend list to facilitate the easy transfer of information between the two lists. A colour coding system was also used to highlight specific jobs. Prior to this improvement project only 7.1% of those polled were satisfied with the existing system, after a series of interventions satisfaction increased to 85.7%. The significant increase in overall satisfaction with surgical handover following the introduction of the unified weekend list is promising. Locating patients and identifying jobs is easier and weekend ward rounds can conducted in a more logical and timely fashion. It has also helped facilitate the transition to consultant ward rounds of all surgical inpatients at the weekends with promising feedback from a recent consultants meeting. PMID- 26734295 TI - Management of urinary tract infections in elderly patients: Strategies for improvement. AB - Urinary tract infection (UTI) is one of the most common infections affecting the elderly. However, UTI is overdiagnosed and overtreated in this group. This project aimed to look into strategies for improving the management of UTI in elderly medical inpatients. A retrospective audit was performed on the case notes of medical inpatients in a district general hospital from December 2012 to April 2013. The target measures for improvement include increasing adherence to SIGN guidelines in the diagnosis of UTI, increasing the frequency and timeliness of urinary culture collection in suspected UTI, and increasing use of urine culture sensitivities to tailor antimicrobial treatments. Initial baseline measurement revealed 16 patients treated for UTI. 31.3% of these fulfilled SIGN criteria for UTI. 68.5% had urine cultures performed. 60% of patients with positive urine cultures had correct antibiotic therapy after sensitivity results. The mean time from the diagnosis of UTI to urine collection for culture was 4 days. Three further cycles were performed. Following each cycle, improvement measures were implemented to raise the awareness of medical staff about the management of UTI in the elderly. These comprised presentations to junior doctors at local teaching sessions; emails to ward managers with results of the previous audit cycle broken down by ward; and prominent display of guidelines on medical wards and ensuring availability of 'Newcastle pads' for taking sterile urine cultures from incontinent patients. In the final cycle, 19 patients were diagnosed with UTI. 42.1% of these fulfilled SIGN criteria for diagnosis of UTI. 89.5% had urine cultures sent. 86.7% of patients with a positive urine culture were treated with appropriate antibiotics after sensitivities became available. Mean time from UTI diagnosis to culture collection improved to zero days. In conclusion, continuous educational measures, performance feedback, and increased availability of specialist equipment are imperative for improving management of UTIs in the elderly. PMID- 26734296 TI - A new patient information leaflet for Dermatology outpatients. AB - Lack of provision of information was the single most common cause of poor performance in the 2008/2009 NHS Patient Survey Programme of trusts in the UK. Information leaflets have been shown to improve patient satisfaction with consultations. We introduced a new patient information leaflet about the scheduled consultation in a district hospital's dermatology outpatient clinic. We then assessed in a small study its effect on the patients regarding helpfulness, preparation for and satisfaction with the out-patient consultation. Via the hospital's booking office, leaflets were sent to all patients (n=32) due to attend two outpatient clinics, accompanied by a letter about the survey. After the consultation, patients were given a short anonymous questionnaire to complete. Of the 32 patients, 12 patients did not receive the leaflet, three did not attend their consultation, and two left before they were handed the questionnaire. We gave out 15 questionnaires, and received 15 responses (100%). 46.9% of patients (n=15) answered the questionnaire. Of these 33.3% were new patients (n=5). 86.7% (n=13) found the leaflet helpful and 33% excellent (n=5). 86.7% felt well prepared for the consultation, 40% excellently (n=6). 86.7% were satisfied with the consultation, 73% rated their satisfaction as excellent (n=11). 60% of patients brought a list with their medication (n=9), 80% of the new patients (n=4). 13.3% of patients (n=2) wrote down questions prior to the consultation. Comments suggested the leaflet would be more useful for new patients. Patients scored highly for satisfaction with the consultation, whether or not they had received and information leaflet (we asked n=20 patients without leaflet). This short survey supports the idea that patients find it helpful to receive an information leaflet, and actively prepare by bringing a list of their medication, and thinking of questions. PMID- 26734297 TI - Continuity of care for orthopaedic patients in a district general hospital. AB - Continuity of care has been defined as a patient repeatedly consulting the same doctor and forming a therapeutic relationship. There is evidence that not only do patients value continuity of the care they receive but also that provider continuity is related to lower overall total healthcare costs and better healthcare outcomes. A retrospective audit was undertaken in James Paget Hospital, a district general hospital in East Anglia, England, to assess continuity of care from the preoperative clinic to surgery and subsequent postoperative follow-up in the orthopaedic department. Overall continuity of care by individual surgeon was 23% and by orthopaedic team (consultant and middle grade staff) 43% in the first audit cycle of 106 patients in 2008. In the second cycle in 2010, this improved to 24% and 56%, respectively, in a sample of 156 patients. Moreover, the continuity of care for trauma patients improved from 10% to 75%. Interventions which resulted in the improvement were change of on-call rota and the implementation of measures so that, following surgery, patients were allocated to the operating surgeon's clinic postoperatively. This completed audit cycle highlights the importance of continuity of care of patients and how efficient management led to a more patient centred delivery of healthcare. PMID- 26734298 TI - A reimagined discharge lounge as a way to an efficient discharge process. AB - Faced with inherent inefficiencies built into transfer of a patient from emergency department (ED) to an inpatient bed, we determined that the timely availability of an inpatient bed was essential to improving efficiency and flow. Lack of beds early in the day was a major cause for delays and backup in the ED, which in turn placed the ED at risk for overcrowding and diversion. Review of the discharge process revealed that only 33.4% of discharges were completed prior to noon, and on average took 126 minutes from the time a discharge order was written to the time the patient actually left their inpatient bed. To achieve our goals of improving patient flow and discharge efficiency, we proposed a new project, called the "Discharge Hospitality Center (DHC)." Our previous attempt at creating a "discharge lounge" was unsuccessful. However, we learned from that endeavor which then allowed us to completely redesign the new DHC project and incorporate ongoing feedback from all stakeholders, sharing performance metrics regularly, and collectively searching for ways to overcome barriers and improve performance together. Strict eligibility criteria were created, and every patient was screened for DHC eligibility daily at our multidisciplinary discharge planning meeting. This multidisciplinary group made the final decision about eligibility for the DHC, and took responsibility for distributing the list of eligible patients to the acute care nursing floors immediately after their early morning meeting. Using the list of patients appropriate for the DHC, the acute floor nursing teams developed standard work for prioritization of DHC eligible patients for discharge, which more reliably allowed those patients to leave their inpatient beds earlier in the day. We found there was no need for dedicated staff at our DHC, as after discharge all outpatient procedures and policies applied. Our outcomes were quite favorable. Four months after the DHC project was launched, ED stays over 6 hours decreased from 24.6 to 15.8%, discharges before noon increased from 33.4 to 41.5%, and time improved from 126 down to 84 minutes from the time a discharge order was written to the time the patients actually left their inpatient bed. We reviewed all patients who went to the DHC on the subject of readmission and found two that were unavoidable (whether or not the DHC was used), and one patient nearly missed his ride home as he sat in the wrong location for transport pickup. In conclusion, a DHC can be successfully designed through integration and collaboration with stakeholders which can be a valuable tool to improve discharge efficiency and patient flow. PMID- 26734299 TI - Improving management of severe sepsis and uptake of sepsis resuscitation bundle in an acute setting. AB - Severe sepsis still remains a major cause of morbidity and mortality, claiming between 36,000 to 64,000 lives annually in the UK, with a mortality rate of 35%.[1,2] The project aims to measure the management of severely septic patients in acute medical unit (AMU) in a district general hospital against best practice guidelines, before and after a set of interventions aiming to optimise patient management and outcomes. All new admissions who met the criteria for sepsis in AMU over a two week period were evaluated. Those who met the criteria for severe sepsis were further analysed. The criteria evaluated were time to first administration of oxygen, intravenous fluids, antibiotics, the taking of blood cultures, other relevant bloods tests (including lactate) and urine output monitoring. A re-audit was completed after the introduction of a set of interventions which included a "sepsis box." A total of 32 patients (19 Males, 13 Females) were identified in the pre-intervention group. Twenty-two of these patients met the criteria for severe sepsis. Only 15 out of 32 (47%) had their lactate measured. Ten out of 22 (45%) received fluids within an hour. Twelve out of 22 (55%) had their blood culture sample taken after administration of antibiotics and only 12 out of 22 (55%) had antibiotics administrated within an hour of medical assessment. Post-intervention the results however improved dramatically. A total of 30 patients were identified in the post-intervention group (12 Males, 18 Females). Antibiotics administration within an hour went up by 22%. Lactate was performed in 26/30 (87%) patients presented with sepsis compared to 47% in the pre-intervention group. Similarly, identification of severe sepsis, and administration of intravenous fluids also showed improvement ultimately improving patient safety. Following the initial success, the trial was repeated over three months period, which showed sustainable improvement. PMID- 26734300 TI - A simple measure to improve the rates of thromboprophylaxis prescription post surgical fixation of neck of femur fractures in a district general hospital. AB - Neck of femur (NOF) fractures are a major public health concern because of the ageing population and higher incidence of fragility fractures. NOF fractures are associated with high mortality and morbidity rates, and there is a high risk of venous thromboembolism (VTE) after hip fractures (Ref 1). Therefore thromboprophylaxis is vital. Current NICE guidelines advocate 28 - 35 days of thromboprophylaxis after NOF fractures (Ref 1, 2). It came to our attention that patients post NOF fixation were getting variable prescriptions in regards to their thromboprophylaxis. Therefore a retrospective study on prescription of thromboprophylaxis was conducted from October 2012 to February 2013 within the trauma and orthopaedics department at Queens Hospital, Romford. Data was collected on all NOF fractures from electronic discharge summaries. Basic descriptive statistics were used to analysis the data. There were 110 cases of NOF fractures during this period. 100 patients were included since two were discounted as they were already on long term anticoagulants and eight patients died in hospital. No thromboprophylaxis was prescribed for 15 patients (15%). Three patients (3%) were prescribed less than 28 days (mean 14 days, range (14 - 14 days)). 69 patients (69%) received 28 - 35 days of thromprophylaxis, whilst five patients (5%) received more than 35 days (mean 42 days, range 40 - 42 days). Formal departmental teaching and presentation of the findings was given after the initial study and a small label with the message, 'POST NOF #: 28-35 days Enoxaparin', was attached to the back of all the junior doctor work phones. After the intervention, data was collected from the period of 7th of January to 7th of February 2013. The second study showed that 50 patients were admitted with NOF fractures in this time period. Four patients died in hospital and three patients were discounted as they were on Warfarin. Two patients were not prescribed thromboprophylaxis (5%). 34 (79%) patients received 28 - 35 days, whereas seven patients (16%) received 42 days of thromboprophylaxis. The older patients with multiple co-morbidities and reduced mobility are at high risk of developing thromboembolism post NOF fixation. Our initial study identified inadequate prescription of thromboprophylaxis post NOF fractures. After introduction of simple measures such as the reminder label attached to phones, our repeat study found that there was improvement in prescription rates. Our study highlights that simple measures can increase awareness and improve patient safety. PMID- 26734301 TI - General Practice Locum Improvement Tool. AB - An improvement culture is required in the NHS. Staff members who move from one place of work to another are often best placed to see alternative methods of working that at times are more efficient - locum general practitioners (GPs) tend to be in this category. A tool was developed specifically to obtain quality improvement suggestions to the general practice from the locum GP and vice versa in a time efficient manner. A pilot study was performed in one general practice in Tayside (Grove Health Centre) in December 2013 to assess if this was possible. During this month a general practice partner provided feedback to the locum GP by completing a drop down tick box survey while reviewing three cases dealt with by the locum. The locum GP was emailed after their session with a one question survey enquiring about improvement suggestions for that practice. Five different locum GPs provided clinical cover during the month studied - of these, one opted out from the study. The other four locums performed their clinical session and completed the survey. Feedback from the practice to locums included specific clinical guidance, suggestions for improving documentation, and ways to optimise referrals; of note, unique feedback was given to each locum and this was generated using this tool. Themes from the locum suggestions to the practice included more physical resources (such as cameras in each room), different ways of handling prescriptions, and a suggestion about identifying complex patients. As a direct result of this pilot a locum box has been implemented in this practice and plans are to rerun this tool periodically. The authors would recommend utilising this tool periodically in other general practices as it has the potential to identify improvement suggestions unique for that particular practice. PMID- 26734302 TI - Everyone gets involved: fostering a high quality teaching and learning culture in the NHS. AB - The aim was to create an environment where doctors at all levels felt like an important part of the education team. Two teaching fellows were appointed to deliver teaching, encourage participation, and quality-assure teaching. An innovative electronic logbook named Teaching Log (T-Log) was developed to reliably "record and reward" teaching occurring at all career levels. A mentor scheme for medical students was established. Mentor training was provided for junior doctors. A near-peer teaching programme was developed for final year medical students on important skills required to be a safe junior doctor. Between September 2013 and January 2014, 83 doctors at our institution logged 657 teaching episodes using the electronic T-Log. 23% were F1s, 14% were F2s, 24% CT1 2s. 36% of sessions were delivered to 3rd year medical students and 36% were delivered to 5th year students. 24% were small group seminars, 26% were bedside teaching sessions, 12% were lectures, 5% were simulation sessions and 9% were clinical skills. 20% of sessions were delivered to a single student. 100% of respondents (15) agreed that T-Log was easy to use. 100% agreed that T-Log was useful. 100% agreed that they would continue to use T-Log. A survey found the mean score for usefulness of the mentor scheme to be 9.1 (1=not useful, 10=very useful). Students saw their mentors on average 6.5 times during a 10 week period. Confidence scores for all key areas of the curriculum were increased following implementation of the scheme. 100% of students would recommend this scheme to next year's final year students and 100% of mentor respondents (n=8) would participate in the scheme again. Rewarding those who contribute to teaching provides incentive to further increase the quality of education provided to students. T-Log rewards teaching activity. It also provides useful data at an individual level or at institutional level. PMID- 26734303 TI - Improving the medical 'take sheet'. AB - The GMC states that "Trainees in hospital posts must have well organised handover arrangements, ensuring continuity of patient care[1]". In the Belfast City Hospital throughout the day there can be multiple new medical admissions. These can be via the GP Unit, transfers for tertiary care, and transfers due to bed shortages in other hospitals. Over the course of 24 hours there can be up to four medical SHOs and three registrars that fill in the take sheet. Due to the variety of admission routes and number of doctors looking after the medical take information can be lost during handover between SHOs. In the current format there is little room to write and key and relevant information on the medical take sheet about new and transferring patients. I felt that this handover sheet could be improved. An initial questionnaire demonstrated that 47% found the old proforma easy to use and 28.2% felt that it allowed them to identify sick patients. 100% of SHOs and Registrars surveyed felt that it could be improved from its current form. From feedback from my colleagues I created a new template and trialled it in the hospital. A repeat questionnaire demonstrated that 92.3% of responders felt the new format had improved medical handover and that 92.6% felt that it allowed safe handover most of the time/always. The success of this new proforma resulted in it being implemented on a permanent basis for new medical admissions and transfers to the hospital. PMID- 26734304 TI - Improving the quality of patient handover on a surgical ward. AB - The European Working Time Directive means safe patient hand over is imperative. It is the responsibility of every doctor and an issue of patient safety and clinical governance [1]. The aims of this project were to improve the quality of patient handover between combined assessment unit (CAU) and surgical ward FY1 doctors. The Royal College of Surgeons England (RCSEng) guidelines on surgical patient handover [1] were used as the standard. Data was collected throughout November 2013. A handover tool was then introduced and attached to the front of patient notes when a patient was transferred from CAU to the surgical ward. The doctor handing over the patient and the ward doctor receiving the handover signed this document. Policy was also changed so that handover should take place once the patient had received senior review on the CAU and was deemed appropriate for transfer to the surgical ward. Data from the handover tool was collated and checked against the list of surgical admission for February 2014. The number of patients handed over improved from 15 % to 45%. The quality of patient handover also improved. 0 patient handovers in November 2013 included all of the information recommended by the RCSEng guidelines. 100% of the patient handovers in February 2014 contained all the recommended information. Introduction of a handover tool and formalisation of timing of patient handover helped to improve quality and number of patients being handed over. Further work needs to be done to improve safe handover of surgical patients, particularly out of hours. PMID- 26734305 TI - A clinico-ethical framework for multidisciplinary review of medication in nursing homes. AB - Residents in care homes are more likely to be prescribed multiple medicines yet often have little involvement in these prescribing decisions. Reviewing and stopping inappropriate medicines is not currently adopted across the health economy. This Health Foundation funded Shine project developed a pragmatic approach to optimising medicines in care homes while involving all residents in decision making. The pharmacist undertook a detailed medication review using primary care records. The results were discussed at a multidisciplinary team (MDT) meeting involving the care home nurse and the resident's general practitioner (GP), with input from the local psychiatry of old age service (POAS) where appropriate. Suggestions for medicines which should be stopped, changed or started, and other interventions (eg monitoring) were discussed with the resident and/or their family. Over 12 months 422 residents were reviewed, and 1346 interventions were made in 91% of residents reviewed with 15 different types of interventions. The most common intervention (52.3%) was to stop medicines; 704 medicines stopped in 298 residents (70.6%). On average, 1.7 medicines were stopped for every resident reviewed (range zero to nine medicines; SD=1.7), with a 17.4% reduction in medicines prescribed (3602 medicines prescribed before and 2975 after review). The main reasons for stopping medicines were: no current indication (401 medicines; 57%), resident not wanting medicine after risks and benefits were explained (120 medicines; 17%), and safety concerns (42 medicines; 6%). The net annualised savings against the medicines budget were L77,703 or L184 per person reviewed. The cost of delivering the intervention was L32,670 (pharmacist, GP, POAS consultant, and care home nurse time) for 422 residents; for every L1 invested, L2.38 could be released from the medicines budget. This project demonstrated that a multidisciplinary medication review with a pharmacist, doctor, and care home nurse can safely reduce inappropriate medication in elderly care home residents. PMID- 26734306 TI - Introducing a chest pain pathway in the emergency department to improve quality of care for patients with possible cardiac chest pain. AB - Chest pain is a common reason for patients to present to an emergency department (ED). It is crucial not to miss presentations of the potentially life-threatening acute coronary syndrome (ACS), although often these people present with a non diagnostic ECG. This makes recognition of a history consistent with ACS very important. We noted inconsistencies in assessment, with many admissions to cardiology beds who did not prove to have ACS and some erroneous discharges who subsequently did have an ACS. We introduced a history based risk tool as part of a chest pain pathway into the ED for use by medical staff assessing patients presenting with chest pain. The intervention involved a nurse from cardiology engaging with clerical, nursing, and medical staff in the ED to ensure success of this quality improvement project. The project showed a reduction in admissions to cardiology with suspected ACS from 29% to 15%, with a projected saving of L889 per patient who was prevented from being admitted. In addition, admissions became more appropriate, with an increase in the proportion of patients with a final diagnosis of ACS from 25% to 46% and a reduction in admissions with atypical chest pain from 75% to 54%. PMID- 26734307 TI - Ward round documentation in a major trauma centre: can we improve patient safety? AB - Our objective was to improve documentation and patient safety in a major trauma centre. A retrospective audit was undertaken in March 2014. Ward round entries for each orthopaedic patients on three dates were assessed against standards and analysed. The audit was repeated in April 2014, and again in August 2014. Thorough documentation is paramount in a major trauma centre. It forms a useful record of the patients hospital stay, is a legal document and is highlighted in national guidelines. It provides a basis for good handover, ensuring continuation of care and maintaining patient safety. Resultant poor compliance with Royal College guidelines in the initial audit led to the production of a new electronic based note keeping system. A meeting was held with all staff prior to introduction. Our initial results gained 75 entries, and none showed full compliance. Mean compliance per entry was 59% (0-81%). The second attempt gained 90 entries, with 30 from the weekend. Mean compliance per entry 97%. Third attempt received 61 entries, with 27 from the weekend. Mean compliance was 96%, meaning that the improvement was being maintained. Recent distressing reports regarding patient highlighted the importance of patient. Our initial audit proved there were many areas lacking in our documentation and improvement was necessary. Prior to introducing electronic systems, the implemented change has produced improvement in documentation, and provides a useful handover tool for staff. PMID- 26734308 TI - Compassionate Conversations. AB - Staff engagement is much more than just a bonus in any organisation. CQC data shows that it is very clearly linked to positive results in both patient and staff outcomes (fewer complaints, improved safety, reduced sickness, fewer accidents, and more as per Michael West). Staff engagement may seem nebulous but is in fact measured routinely annually in the National Staff Survey. The problem is that often Trust Boards with poor Staff Survey results may struggle to increase staff engagement as staff see management initiatives as 'management fads' or 'tick-box exercises' purely for targets, not their own benefit. Compassionate Conversations are a ground-level initiative focused primarily on supporting and motivating individual staff as the primary focus. This allows the benefits to patients and in Human Resources to be an unspoken anticipated benefit. They are led by a Psychologist and Consultant in a coaching supportive atmosphere in an open or selected group. The Conversations have been rated 9/10 or higher by 64% of participants, while 75% of all participants voluntarily provided feedback. Feedback initially was that Conversations were too clinically focused and further Conversations were more wide-ranging in topic and included departmental roadshows. PMID- 26734309 TI - A new oxygen prescription produces real improvements in therapeutic oxygen use. AB - In the UK, safe use and administration of oxygen therapy was unsatisfactory prior to the implementation of national guidelines in 2008. Each year since then the British Thoracic Society (BTS) has conducted a national audit that has demonstrated a slow but steady improvement in oxygen use across four key standards. Sandwell and West Birmingham NHS Hospitals Trust has participated in this audit process but has failed to show consistent improvements. The aim of this quality improvement project was to produce meaningful and sustained improvements in oxygen use across each of the four standards. Four interventions were developed over three PDSA cycles and included: 1. a new oxygen prescription chart, 2. oxygen 'alert' stickers for use on drug and MEWS charts, 3. point of care resources, and 4. senior led educational sessions for healthcare staff. Each intervention was tested on the Acute Medical Unit over seven days and data collected using the BTS data collection form. The QIP improved oxygen use across each of the standards: baseline measurement for standard one demonstrated that 55% of patients using oxygen had a valid oxygen prescription, improving to 94% after PDSA cycle three. For standard two, baseline measurement demonstrated that 50% of patients had a documented oxygen target saturation range, improving to 94% after PDSA cycle three. For standard three, baseline measurement demonstrated that 84% patients using oxygen had saturations documented on the MEWS chart, improving to 100% after PDSA cycle three. Finally, baseline measurement of standard four demonstrated that 0% patients with a valid oxygen prescription had it signed for at drugs rounds, improving to 18% after PDSA cycle three. Oxygen use was substantially improved during the QIP. Following engagement with stakeholders a new oxygen prescription will be rolled out within the Trust with projected annual savings of L30,400. PMID- 26734310 TI - Improving non-invasive ventilation documentation. AB - Record keeping for patients on non-invasive ventilation (NIV) at St. Georges Hospital is poor. The initial NIV prescription is often not recorded, and changes to the NIV prescription or the rationale for the changes (ABG results) are also poorly documented. This leads to confusion for nurses/doctors as to what the correct settings are, meaning patients could receive ineffective ventilation. The use of NIV is also poorly recorded by nursing staff meaning that doctors are unsure if the prescribed NIV is being achieved. This can lead to treatment being escalated unnecessarily in the event of treatment failure. Non-invasive ventilation (NIV) is the provision of ventilatory support in the form of positive pressure via the patient's upper airway using a mask or similar device. NIV is indicated for treatment of acute hypercapnic respiratory failure, of which there are many causes, though COPD is the indication in up to 70% of cases.[1] British Thoracic Society (BTS) guidelines for NIV suggest that the rationale for commencing a patient on NIV and the proposed settings should be clearly documented.[2] Clinicians cannot effectively tailor changes to the patients NIV settings if this information is not clearly recorded, which could lead to increased time requiring NIV or NIV failure. Three main areas were considered important to measure for this project. The initial prescription of the NIV, changes to the NIV settings, and nursing documentation surrounding NIV. A baseline measurement of NIV documentation for two weeks found NIV documentation to globally very poor. NIV was formally prescribed 29% of the time, full detail of intended settings were documented 57% of the time, the decision to commence NIV was discussed with the respiratory consultant/SpR just 29% of the time and on no occasion was a decision regarding escalation of treatment recorded. Eighteen changes were made to the NIV settings. These were formally prescribed 22% of the time and detail of the intended settings was recorded 44% of the time. Nursing documentation included detail on the length of NIV use just 21% of the time, and comments on the NIV use were left just 33% of the time. The intervention was a unified four page NIV prescription chart. Page 1: An area for the NIV to be initially prescribed with reminder questions for important considerations. Page 2: An area for changes to be made to the NIV settings. Page 3: An area for the most up to date NIV/respiratory plan to be documented. Page 4: Nursing documentation, with prompts for the time NIV was put on/off and for comments. The chart was printed at St Georges print services and paid for by the respiratory ward. A further two weeks of monitoring followed after implementation of the new chart. Improvements were seen in all areas of documentation surrounding NIV. The NIV was formally prescribed 86% of the time compared to 29% pre-intervention. The NIV settings were stated 100% of the time in the initial prescription. An escalation decision was recorded 71% of the time. Changes to the NIV settings improved to 92%. Nursing documentation improved greatly. The length of the NIV use was recorded for 91% of NIV days compared to 21% previously (p<0.001), and comments on the use of NIV improved from from 33% to 98% (p<0.001). Cases where the documentation remained poor were in those patients for whom the new chart had not been used. The implementation of a unified NIV prescription chart to be kept in the bedside notes on the respiratory ward greatly improved documentation surrounding NIV. Further work must be done to ensure that the chart is used 100% of the time. This will include adjusting the chart to reduce the workload to use it, rolling the chart out on the acute medical ward, and submitting the chart to the trust board for its acceptance as an official trust chart. PMID- 26734311 TI - Medication Reconciliation Improvement Through the Use of Video. AB - Accurate medication reconciliation at the time of hospital admission is vital to preventing adverse drug events. Compliance with medication reconciliation in our pediatric intensive care unit was low initially with overall medication reconciliation at 70%. Due to the high front line provider turnover in our unit, we focused on technological reminders for completion and used unique and innovative ways to motivate our supervising staff. Our goal was to reach >95% completion within 24 hours for medication reconciliation for all patients admitted to the pediatric intensive care unit. Pre-pilot discussions focused on examples of errors of medication reconciliation within our own institution resulting in patient harm via traditional power point presentation. The initial pilot phase instituted a job aid on how to add the medication reconciliation completion reminder column. Email updates on completion status began one week after initiation. During the implementation and spread phase, fun interactive videos were used to acknowledge roll out to the full unit. Compliance was monitored and humorous biweekly video updates emphasizing accountability were introduced. In the sustain phase, monthly video updates served as education and a reminder for provider staff. The use of a medication reconciliation completion column and reminder emails resulted in goal completion (>95%) by three weeks post intervention for the pilot unit. Overall medication reconciliation completion also reached goal of >95% completion within the entire unit after three weeks of implementation and spread. Compliance fell below goal so video updates were modified utilizing humor and emphasizing accountability. This resulted in sustained compliance now more than forty weeks post implementation. Unit compliance currently remains >95% completion within 24 hours now more than forty weeks post intervention. The use of the medication reconciliation reminder column resulted in improvement in compliance; however, that improvement was not sustained. The addition of humorous videos highlighting accountability allowed for sustained improvements. PMID- 26734312 TI - Naming babies "Baby-of" at birth: A project to encourage earlier naming of infants in Abu Dhabi. AB - In 2013, Sweihan Healthcare Center, one of several government clinics in Abu Dhabi, catered to 19,349 patients or an average of 52 patients in a day. During the weekdays, close to 80 patients are seen per day, a relatively huge number for a small town clinic. In 2011, the clinic only saw 16,816 patients, which amounts to a 15% increase in two years. Circumstances called for a search for gaps in the system in order to ease the workflow of a steadily increasing patient influx. The focus was mainly on patient identification due to a considerable number of patients having the same name. Data extraction was simplified by the advent of electronic medical records and, as the names of the patients were filtered, one name stood out: "Baby of". The goal of this project was to track the patients using the name "Baby of", and change their names in their respective medical records and thus be able to comply with the International Patient Safety Goals (IPSG) of both Joint Commission International [1] and the Health Authority of Abu Dhabi [2]. PMID- 26734313 TI - A novel approach to improving coagulation sample ordering in an emergency department. AB - Driven by emergency department targets, there is a need for rapid initial assessment and investigations of attendees to the department, and blood tests are often performed before full patient assessment. It has been shown that many investigations ordered in the emergency department are inappropriate. Coagulation samples are acknowledged as one the commonest blood samples requested on admission. We predicted that the majority of the routine coagulation samples performed in our ED department were unnecessary. We aimed to determine if coagulation tests sent from our department were appropriate, develop guidance for appropriate testing and to increase the percentage of appropriate tests to 90%. Criterion based audit was used. All coagulation samples sent from the ED over a one week period were reviewed and the indications for testing compared to guidance developed by consensus with ED consultants. On the first data collection, 66 of 369 (17%) samples were deemed appropriate. Feedback to clinical staff was given at educational meetings and appropriate indications discussed. In collaboration with both senior nursing and medical staff, coagulation screen request bottles were removed from the main clinical area and were only available in the resuscitation area. Following these interventions, 69 of 97 (71%) samples were deemed appropriate and a further intervention is planned to reach our standard. This improvement could lead to a L100,000 saving annually and a cross site collaborative study is planned to spread these improvements. PMID- 26734314 TI - Who gets admitted to the Chest Pain Unit (CPU) and how do we manage them? Improving the use of the CPU in Waikato DHB, New Zealand. AB - Chest pain is a commonly encountered presentation in the emergency department (ED). The chest pain unit at Waikato DHB is designed for patients with likely stable angina, who are at low risk of acute coronary syndrome (ACS), with a normal ECG and Troponin T, who have a history which is highly suggestive of coronary artery disease (CAD). Two issues were identified with patient care on the unit (1) the number of inappropriate admissions and (2) the number of inappropriate exercise tolerance tests. A baseline study showed that 73% of admissions did not fulfil the criteria and the majority of patients (72%) had an exercise tolerance test (ETT) irrespective of clinical picture. We delivered educational presentations to key stakeholders and the implementation of a new fast track chest pain pathway for discharging patients directly from the ED. There was an improvement in the number of patients inappropriately admitted, which fell to 61%. However, the number of inappropriate ETTs did not decrease, and were still performed on 76.9% of patients. PMID- 26734315 TI - Improving compliance with iron infusion therapy in the treatment of chronic anemia in haemodialysis patients with chronic kidney disease. AB - This quality improvement project was conducted at the haemodialysis unit in the paediatric nephrology department at Noah's Ark Children's Hospital, Cardiff. Stakeholders involved were the medical and nursing staff at the haemodialysis unit, responsible for the care of children with chronic kidney disease CKD. Anaemia is prevalent among children with CKD. Iron infusion is administered to such children with chronic anaemia. Children on haemodialysis attending the Children's Kidney Center receive iron infusion if they satisfy the criteria based on haemoglobin and serum ferritin values according to departmental guidelines. This involves measurement of c-reactive protein and serum ferritin prior to iron administration. High iron exposure is detrimental to end organ function and hence warrants regular monitoring in conjunction with CRP, another inflammatory marker. We suspect that some children may be receiving iron infusions despite being iron replete. Also, we may be over-investigating these children with anaemia. We identified all children receiving iron infusion in the haemodialysis unit over a four week period. We retrospectively enquired blood investigations done, prior to and after iron infusion. Blood investigations lagged on pre and post infusion times. We devised a checklist for nursing staff to follow, primarily looking at set times for measuring haemoglobin, serum ferritin, and CRP during the month (at the start of the first and third week of the month) and also tabulating the ferritin values that would trigger frequency of iron infusions. These were aimed to: 1. Prevent iron overloading in patients with chronic anemia 2. Regularise the checking of bloods in those receiving iron infusions 3. Empower the nursing staff to independently take decisions on iron infusion delivery. The strategy for change encompassed multiple PDSA cycles. Plan: empower decision making on iron infusion by haemodialysis nursing staff Do: formulate a checklist for iron infusion based on the recommended set values of ferritin, CRP and haemoglobin Study: analyse adherence to checklist in three months time Act: make appropriate changes to workplace behaviour based on findings of the PDSA cycle We analysed 13 patient episodes prior to the intervention and a total of 19 patient episodes after the improvement cycles. The checklist was improved based on feedback obtained after the first PDSA cycle. A second cycle showed that investigations done were optimised. The third cycle showed improved adherence and compliance with prevention of over-treatment with iron infusion. There was 100% adherence to the investigations done prior to infusion and complied well with the department guidelines. This meant that the required number of blood tests were done on a more regular basis and it did not exceed from those done previously. Nursing behaviour with regard to initiation and maintenance of iron infusion became more independent. This empowered nursing decision making skills and consequently freed doctor-time. It also resulted in improving team morale and ultimately patient safety by mitigating human errors. For any QI project, interventions should be carefully designed. Stakeholder buy-in and easy accessibility of the intervention improves sustainability. Multiple PDSA cycles and incorporating stakeholder feedback into the cycle are key to success. PMID- 26734316 TI - Reducing avoidable time delays in immediate medication administration - learning from a failed intervention. AB - Stat medications are regularly prescribed on hospital wards as part of the ongoing care for patients. Because they are prescribed at variable times that do not coincide with regular nursing drug administration times, they rely on good communication and vigilance on staff to ensure they are administered in a timely manner. Delays in drug administration can lengthen patient recovery times, prolong admission, and can lead to avoidable patient harm and suffering. While working on a geriatrics ward I noticed that there were often significant delays in administration of stat medications which occurred on a regular basis. I therefore investigated this by collecting data over a two week period to assess the situation based on our current practice. After root cause analysis (figure 1), it became clear that communication between staff was a significant factor in delayed administration. A solution was implemented in the form of "ward bay wall charts" to aid documentation and communication of stat medication requirements between nursing and medical staff with the intention to reduce delays by improving communication. After gaining support of medical and nursing staff, a trial was undertaken and a further two weeks of data collected to see the effect of the intervention. The results showed that there was an increase in the median time delay (1 hour 34 minutes to 2 hours 26 minutes, a 55% increase in median time delay) after the implementation of the my intervention, suggesting that it actually made communication worse, creating more delays. Subsequent feedback and analysis showed that this was due to a number of factors that led to worsened communication between staff and therefore an increase in medication delays. Early recognition allowed the intervention to be promptly withdrawn and a re-assessment of the nature of the initial problem. This project highlights the importance of measurement in determining if an intervention actually works and is an improvement on current practice. PMID- 26734317 TI - Cutting delays in reversing anticoagulation after intracerebral haemorrhage: three key changes at a UK comprehensive stroke centre. AB - Prothrombin complex concentrate (PCC) reduces the risk of early haematoma expansion after intracerebral haemorrhage in patients taking vitamin K antagonists (VKA-ICH), so must be given without delay. We sought to identify and remove key barriers to rapid administration of PCC at our centre. We describe a single UK comprehensive stroke centre cohort study with mixed retrospective (1/1/2008 to 1/12/2010) and prospective (1/12/2010 to 31/7/2014) participant identification and a survey of UK stroke physicians. Seven hundred and thirteen ICH patients were admitted during the study period. Sixty nine of these patients were VKA-ICH. Patients not admitted on the acute stroke pathway (n=8) or who had palliative care commenced immediately on admission (n=6) were excluded, leaving 55 patients in the final analysis. During 2011/12 we identified and implemented service changes to reduce delays in PCC administration. The primary outcome was the time interval between diagnostic brain scan and commencement of PCC treatment (scan-to-needle time). Secondary outcomes were the time interval between admission and commencement of PCC (door-to-needle time) and symptom onset and commencement of PCC (onset-to-needle time). Three key barriers were identified to rapid administration of PCC, including haematology consultation, collection of PCC from the transfusion laboratory, and obtaining the laboratory INR result. Our survey indicated that these barriers existed at most UK centres. We implemented point-of-care INR testing, moved PCC to the emergency department, and agreed a protocol to administer PCC autonomously. Our scan-to-needle time more than halved, from a median of 127 min (interquartile range (IQR), 111 to 208 min) prior to service changes to 58 min (IQR 50 to 91 min; p<0.001) afterwards. We have substantially reduced delays in delivering PCC to VKA-ICH patients at our centre and our simple changes could be easily implemented at centres facing similar barriers. PMID- 26734318 TI - Improving patient safety by implementing a new general surgical on-call rota for FY1 doctors. AB - Junior doctors often feel they have little control over their working environment and can feel overwhelmed by the numerous barriers to their involvement with rota design. This project aimed to overcome these barriers to change by implementing a new FY1 on-call rota, designed by junior doctors, for the surgical department at the Royal Sussex County Hospital, Brighton. A new rota was necessary since the department had recently undergone an organisational restructuring that altered the out of hours work load for FY1 doctors. To address this, the proposed new rota increased FY1 presence during weekend daytime shifts. To assess junior opinion about the old rota and the proposed new rota, a survey was sent to 32 FY1 doctors analysing their views about each rota in terms of safety, the sufficiency of cover for various shifts, and their willingness to work the rota. A direct comparison between the two rotas was also requested. A statistically significant (p<0.05, n=12, two-tailed paired T-test) increase in people agreeing with the following statements about the new rota: "The rota is safe", "This rota has sufficient FY1 cover during the weekend day shifts", and "I would be prepared to work this rota." A direct comparison revealed that FY1 doctors felt that the new rota would be safer, they would be more willing to work the new rota, and that the new rota should be implemented. Implementation occurred for the August 2014 general surgical FY1 intake and post implementation audits showed that the new FY1s felt that cover across all shifts was improved and that the new rota was safe. This project demonstrates that altering rotas can improve junior doctor's perception of patient safety, and also shows that junior team members, with departmental support, can overcome barriers to change and implement new rotas. PMID- 26734319 TI - Oxygen Delivery on Medical Wards. AB - Oxygen is used widely used on all medical wards. It is a drug and should be prescribed. There are known problems with over and under delivery of oxygen to patients. Through national audits and recording baseline data locally, compliance with prescribing is low. This has potentially serious patient safety issues. This quality improvement project attempted to improve oxygen prescribing and subsequent dose adjusting on various medical wards. Monitoring showed a transient improvement but this was not sustained. As a result of this project further research will be put into developing the electronic observation chart to set parameters for target saturations. PMID- 26734320 TI - Use of a validated screening tool for psoriatic arthritis in dermatology clinics. AB - Dermatology clinics represent a key opportunity to screen patients with psoriasis for psoriatic arthritis (PA) which often remains unrecognised. A significant proportion of adults with psoriasis develop arthropathy [5] with around two thirds having progressive arthritis.[6] NICE has recognised this by the annual use of a validated screening tool such as psoriasis epidemiological screening tool (PEST) on all psoriasis patients without PA. We introduced the PEST into our dermatology department since there was no established system of screening for PA. Twenty-one percent of patients that were identified through PEST as requiring a referral at baseline were not referred to rheumatology through the current system without PEST. This represented a significantly missed proportion of patients with possible PA. Using the PDSA cycle method, we introduced the PEST into cycle 1 and educated key staff about the tool. All eligible patients were referred appropriately. Through doctor and patient feedback, changes were adopted for cycle 2 and informative emails to all key staff about PEST were sent. We noted a drop in the number of PEST uptake in this cycle possibly due to lack of awareness on the purpose and use of PEST among staff, across the department. An educational teaching session was delivered to a wider audience and posters were placed in strategic areas of the department prior to the final cycle. This resulted in 100% PEST uptake and 100% of those with a score of >3 being referred. A total of 51 patients were studied, comprising of 30 eligible patients for PEST. Of these, 27 patients were actually screened (90%) and five with a PEST score of >= 3 were identified and referred appropriately (18.5%). We felt this represented a successful outcome in increasing PEST uptake within the department and in capturing a significant proportion of patients at risk of PA. PMID- 26734321 TI - Reducing Door to- Balloon- Time for Acute ST Elevation Myocardial Infarction In Primary Percutaneous Intervention: Transformation using Robust Performance Improvement. AB - Cardiovascular diseases (CVDs) are the leading causes of death in the UAE. Prompt reperfusion access is essential for patients who have Myocardial Infarction (MI) with ST-segment elevation as they are at a relatively high risk of death.This risk may be reduced by primary percutaneous coronary intervention (PCI), but only if it is performed in a timely manner. Guidelines recommend that the interval between arrival at the hospital and intracoronary balloon inflation (door-to balloon (D2B) time) during primary PCI should be 90 minutes or less. The earlier therapy is initiated, the better the outcome. Our aim was to decrease the door-to balloon time for patients with ST segment elevation myocardial infarction (STEMI) who come through the emergency department (ED) in Sheikh Khalifa Medical City,a tertiary hospital in UAE, to meet the standard of less than 90 minutes. A multidisciplinary team was formed including interventional cardiologists, catheterization laboratory personnel, emergency department caregivers and quality staff. The project utilized the Lean Six Sigma Methodology which provided a powerful approach to quality improvement. The process minimized waste and variation, and a decreased median door-to-balloon time from 75.9 minutes to 60.1 minutes was noted. The percentage of patients who underwent PCI within 90 minutes increased from 73% to 96%. In conclusion, implementing the Lean Six Sigma methodology resulted in having processes that are leaner, more efficient and minimally variable. While recent publication failed to provide evidence of better outcome, the lessons learned were extrapolated to other primary percutaneous coronary intervention centers in our system.This would have marked impact on patient safety, quality of care and patient experience. PMID- 26734322 TI - Smoking Cessation Interventions in the Cardiology Ward. AB - Hospital admission is a unique opportunity for a smoking cessation attempt; smokers may be more motivated to quit as they are distanced from the usual cues they face associated with nicotine consumption, and the effect of poor lifestyle habits on their health are brought to light. With most hospitals employing smoke free grounds, patients are further inclined to stop smoking. According to NICE guidance, smoking cessation support should be delivered within 1 working day of admission for inpatients, and NRT products should be recommended and offered to all people who smoke. Despite this, many smokers on the cardiology ward at the John Radcliffe Hospital fail to receive smoking cessation advice, and are unable to benefit from Nicotine Replacement Therapy. This leads to missed opportunities to stop smoking, increased morbidity in patients undergoing cardiovascular procedures, and increased costs for the NHS, with patients who continue smoking being re-admitted with more smoking-related illnesses in the future. PMID- 26734323 TI - To reduce the average length of stay of patients who are admitted for DA-EPOCH-R chemotherapy regimen. AB - Healthcare institutions are often faced with bed crunch situation. As a result, patients requiring inpatient hospital stay for cancer treatment are delayed and this could lead to compromised overall disease response. Apart from the early discharge of patients to step-down care and explore alternatives of treatment setting, one of the ways to reduce length of stay is to improve on the efficiency of work processes. A baseline study demonstrated that delays in prescribing chemotherapy orders has led to an increased inpatient stay of seven days for a five day treatment regimen. This has profound consequences in terms of costs, patient safety, and utilisation of healthcare resources. A quality improvement project was initiated to review and revise the workflow and processes involved for the entire episode of treatment. A post-implementation review of the interventions showed cost savings, a reduction of average length of stay from seven days to six days (with a total of 28 days saved over six months), and improved patient and staff experience. PMID- 26734324 TI - Quality improvement project using a care bundle approach on the management of the immediate discharge document (IDD) within a single general practice. AB - The Scottish Patient Safety Programme in Primary Care (SPSP-PC) aims to improve the medicines reconciliation process in primary care to help reduce the number of adverse events causing avoidable harm. [1] The aim of this project is to improve the process for handling Immediate Discharge Documents (IDDs) in a single practice and develop a protocol using the care bundle approach. The care bundle consisted of: 1. Medicines reconciled and repeat prescription updated 2. Follow up documented 3. Diagnosis coded 4. Were all actions completed? A baseline audit was performed followed by three PDSA cycles. Interventions included: education at each cycle, decision that all Doctors would use the Medicines Reconciliation Polypharmacy LES template and constructing an electronic checklist for the care bundle. Compliance with the care bundle rose from 20% in the baseline measurement to 100% in PDSA cycles two and three. In conclusion, a protocol was developed for the processing of IDDs utilizing the care bundle approach with an electronic checklist, resulting in an improvement in the practice management of IDDs. PMID- 26734325 TI - Improving the quality of discharge summaries: implementing updated Academy of Medical Royal Colleges standards at a district general hospital. AB - Quality of documentation is harder to quantify and incentivise, but it has a significant impact on patient care. Good discharge summaries facilitate continuity between secondary and primary care. The junior doctors' forum led this project to improve the quality of electronic discharge summaries (eDS). Baseline measurement revealed significant room for improvement. We measured the quality of 10 summaries per month (across all inpatient specialties), against 23 indicators from the revised Academy of Medical Royal Colleges (AoMRC) standards (2013) that were prioritised by GPs as a "minimum dataset". Junior doctors felt that the Trust's dual eDS systems were responsible for great variation in quality. This was confirmed by the results of a comparison audit of the systems in April 2014: one system greatly outperformed the other (57% mean compliance with iSoft clinical management (iCM) based system vs. 77% with InfoPath-based system). We recommended that the Trust move to a single eDS system, decommissioning the iCM based system, and this proposal was approved by several Trust committees. We worked with information services, junior doctors, general practitioners and hospital physicians to develop and implement a generic template to further improve compliance with AoMRC standards. In August 2014, the iCM-based system was withdrawn, the new template went live, and training was delivered, coinciding with the changeover of junior doctors to minimise disruption. Median compliance increased from 66.7% to 77.8%. Quality of discharge summaries had improved across the specialties. There was a reduction in the number of complaints and positive qualitative feedback from general practitioners and junior doctors. Completion of discharge summaries within 24 hours was not affected by this change. There is still more to be done to improve quality; average compliance with the full AoMRC standards (39 indicators) is 59.5%. With the approval of the Trust executive committee further plan, do, study, act (PDSA) cycles are underway, working to improve the remaining specialty-specific templates. PMID- 26734326 TI - Alterations to calling criteria for Between the Flags (an early warning system). AB - Early warning systems aim to detect clinical deterioration of patients at an early stage. Between the Flags was introduced in New South Wales Health for this purpose. When patients are transferred from the emergency department to the ward, there are circumstances when the calling criteria need to be altered to take into account the clinical context. It is recognised that confusion exists among junior medical staff about the process of making alterations to the Between the Flags calling criteria. A quality improvement project was implemented by undertaking a baseline survey of junior medical staff, providing education and training (to junior medical staff on the existing guidelines for making alteration to the calling criteria), and conducting a post-implementation survey. A baseline survey demonstrated that 74% of junior medical staff had received no education on making alterations and only 5% knew how long their alterations would last once the patient was transferred to the ward. This has potentially serious consequences for patient safety following transfer. After implementation of training, we found that 63% of junior medical staff were aware of the guidelines on making alterations and 50% knew how long their alterations would last once the patient was transferred to the ward. We conclude that educating junior medical staff improved knowledge on the guidelines for making alterations to calling criteria. PMID- 26734327 TI - Improving the care of children with urinary tract infection: use of a clinical decision proforma. AB - Urinary tract infection (UTI) is a common and important clinical problem in children. Follow up imaging is indicated in some cases to reduce the risk of long term harm from UTI and sometimes to help guide acute management. Overuse of imaging may be harmful due to radiation exposure, as well as increasing demand on services and budgets. On the other hand under-use of imaging may leave children vulnerable to renal damage and long-term morbidity. Accepted standards propose an imaging strategy specific to age and type of UTI. The complexity of the guideline makes compliance with the standards challenging. The aim of this project was to assess current practice for imaging of children with UTI managed at The Royal Oldham Hospital and to improve compliance with accepted standards through the use of a proforma to aid clinical decision making, supported by an education programme. A retrospective audit was performed over a 6 month period both prior to and after the intervention. The baseline audit found 57.7% of children treated for UTI (n=26) had imaging compliant with the accepted standards, which improved to 75.9% (n=29) on post-measurement. The percentage of inappropriate investigations reduced from 52.4% to 10.5%. The percentage of missed investigations reduced from 35.0% to 32.0%. The proforma was used and filed in 40% of cases where practice was in line with accepted standards. It was not used in any of the cases where practice deviated. In conclusion, a clear clinical decision aid, supported by an education programme, can significantly improve compliance with accepted standards for imaging of children with UTI. This may also be transferable to other scenarios where guidelines exist but have reduced efficacy due to complexity and/or lack of understanding. PMID- 26734328 TI - Evaluating the Quality of Medical Documentation at a University Teaching Hospital. AB - A recent joint publication by the Royal College of Physicians and Royal College of Nursing raised concern regarding the variability in the organisation and quality of documentation during ward rounds [1]. The aim of the study was to evaluate the standard of medical documentation at a University Teaching Hospital. Retrospective manual analysis of patient's paper and electronic paper records (EPR) from the different specialties. Inclusion criteria included in-patient stay of more than two days and admission after 1st July 2013. A VTE assessment was available in 100% of patients. The plan and postoperative instructions were available in 100% of patients. Notes were documented contemporaneously in 75% of cases which increased to 80% in the second following by 89.11% in the third cycle. If a consultant was present on the ward round this was documented in 80% of cases in the first cycle. This subsequently increased to 90% in the second cycle and 100% in the third cycle. Overall the quality of medical documentation was of a reasonable standard but could be improved even further if we continue to document contemporaneously and name every person present at each patient encounter. PMID- 26734329 TI - Improving venous thromboembolism (VTE) prophylaxis in acute urological admissions during out of hours through the introduction of a urological admission proforma. AB - Venous thromboembolism (VTE) kills more people than breast cancer, road traffic accidents, and AIDS combined, accounting for approximately 25,000 in-hospital deaths in England annually. The cost to the NHS is estimated at L640 million/annum. The most important element of VTE risk assessment strategy in England is to risk assess all patients for VTE on admission. The aim of our quality improvement programme (QIP) was to monitor our practice regarding VTE prophylaxis of the patients' admitted urgently in our department, and then implement a measure to increase compliance if found to be poor. Our standards were based on the National Institute for Health and Care Excellence (NICE) guidelines which state that all urgently admitted patients must have a completed VTE assessment form within 24 hours of admission and receive appropriate VTE prophylaxis including low molecular weight heparin (LMWH) and/or TED stockings. Our initial audit was conducted over a period of five weeks. All adult patients acutely admitted out of hours (5pm to 8am) were included. We then introduced a specially designed urological admissions proforma and organised several teaching sessions for junior doctors who facilitated acute admissions. Re-audit was performed using the same methods and timescale measuring improvement. Second re audit six months after the introduction of the proforma, following the induction of the new cohort of junior doctors. - Primary audit: n=44. Proportion of: completed VTE form=56%, LMWH appropriately prescribed=65%,TEDS=35%. VTE related complications=3 - 1st re-audit: n=42. Proportion of: completed VTE form=93%, LMWH appropriately prescribed=83%,TEDS=64%. VTE related complications=0 - 2nd re audit:n=43. Proportion of: completed VTE form=92%, LMWH prescribed=84%, TEDS=76%. VTE related complications=1 There has been a significant increase of compliance with the NICE guidelines regarding VTE prophylaxis within our department through introducing the specially designed urological admissions proforma and delivering teaching sessions for junior doctors. The implementation of the proforma also led to decreased prevalence of VTE related complications and their subsequent morbidity and mortality. PMID- 26734330 TI - Improving the handover and care of acute urological admissions. AB - The point at which a patient is most vulnerable during their journey through the hospital as an acute or emergency admission is the point at which they are transferred to the designated oncoming responsible team. Unsurprisingly, inadequate and incomplete clinical handovers have the potential for latter catastrophic consequences and are utterly avoidable. Recognising these facts, good clinical handover is an essential part of clinical governance and patient safety. Perhaps secondarily, clinical handover - especially when conducted with senior surgical personnel - can be a valuable learning tool for the surgical trainee. An complete audit loop was performed to assess the rate of handover and urology registrar involvement in acute urology periods in 2 month long periods as well as the rate of inadequate investigations and treatment. The interventions introduced included foundation doctor induction training in acute urology cases, an explanation of the importance of handover and a reflective look at ourselves and our approachability. As a result there were significant improvements in the rate of early registrar involvement and successful handover for patients admitted under our take. PMID- 26734331 TI - The endoscopy safety checklist: A longitudinal study of factors affecting compliance in a tertiary referral centre within the United Kingdom. AB - Gastrointestinal endoscopy is a widely used diagnostic and therapeutic procedure both within the United Kingdom and worldwide. With an increasingly older population the potential for complications is increased. The Wolfson Unit for Endoscopy at St. Mark's Hospital in London is a tertiary referral centre, which conducts over 14,000 endoscopic procedures annually. However, despite this high throughput, our baseline observations were that the procedure for safety checks was highly variable. Over a seven-day period we conducted a questionnaire-based survey to all staff members involved with endoscopy within our unit. We found that there was little consensus between team members, both in terms of essential safety checks and designating responsibility for the checks. A panel of experts was convened in order to devise a safety checklist and a strategy for increasing compliance with the checklist among all staff members. Using a combination of electronic and physical reminders and incentives, we found that there was a significant increase in completed checklist (53% to 66%, p = 0.021) and decrease in the number of checklists left blank post intervention (10% to 2%, p=0.03). We believe that post implementation validation of safety checklists is an important method to ensure their proper use. PMID- 26734332 TI - Implementation of a ward round pro-forma to improve adherence to best practice guidelines. AB - Our aim was firstly to assess adherence to best practice guidelines for the prevention of healthcare associated causes of inpatient mortality and morbidity by junior doctors. Secondly, we wanted to measure the impact of a ward round checklist on rates of adherence. The rates of correct prescribing of antibiotics, venous thrombo-embolism prophylaxis, and oxygen (pro re nata) as well as correctly completed paperwork for peripheral venous cannulas were measured in a spot audit of all medical notes of patients on a medical assessment unit. This was repeated two weeks and two months after the introduction of a specifically designed ward round checklist for junior doctors. Initial audit of 40 patient notes confirmed generally poor compliance with best practice guidelines in the prescription of antibiotics (58% correctly prescribed) and oxygen (42%), and in the use cannula care plans (39%). Venous thrombo-embolism prophylaxis prescribing on the other hand was widespread (82%). The introduction and extensive use of the ward round checklist did not have a significant impact on these figures as shown in the two following stop audits (30 and 36 notes respectively). Checklists are helpful in providing a structured and systematic approach to complex tasks and have been shown to have a measurable impact in improving patient care. Their effectiveness is however limited by their uptake and regular correct use. Obstructing issues include poor understanding of the need for change in practice, lack of individual accountability and variable involvement of clinical leaders. These issues must be addressed together in order to effect a successful change in clinical practice. PMID- 26734333 TI - Safer fluid prescribing at North Bristol Trust: Bringing practice in line with NICE Guidance with a redesign of the fluid prescription chart. AB - The National Institute of Clinical Excellence (NICE) released new fluid guidelines following data suggesting 20% of patients receiving fluids suffer adversely (2013). This quality improvement group assessed fluid prescribing in a tertiary teaching centre and introduced a new fluid- prescribing chart to align practice with NICE recommendations. Notes and corresponding fluid prescription charts were reviewed for evidence of (1) indication, (2) co-morbidities, and (3) further management as surrogate markers of safe prescribing in accordance with NICE. Overall, the data showed practice fell short and prompted a redesign of the Trust fluid prescription chart. Three different variations of the chart were issued consecutively using a PDSA method (plan, do, study, act) over a 6-month period. They all included indication, co-morbidities and further management plans as constant design features. Suggestions from interested parties were incorporated and an educational programme was implemented to promote awareness. Prior to our intervention, an indication for fluids was documented in 26% of notes, it took an average of 4.6 minutes to find co-morbidities, and further management plans were rarely documented. Following the new prescription chart, an indication was recorded in 72% of cases, co-morbidities noted on 63% of charts with 93.1% accuracy, and further management documented in 100% of cases. The new fluid prescription chart encourages prescribers to incorporate NICE recommendations when prescribing fluids. The new fluid prescription design has since been rolled out Trust wide. PMID- 26734334 TI - Giving ourselves a head start: improving the quality of documentation of referrals to neurosurgery. AB - Referrals to neurosurgical units are regularly made by doctors in the emergency department (ED), intensive care and acute medicine, following brain injuries sustained by both traumatic and non-traumatic processes. Although some centres accept electronic referrals, many still rely on telephone conversations with a specialist registrar. The flaw in this style of communication is that only information volunteered or requested is relayed. Furthermore, documentation of these dialogues is often incomplete, omitting specific and vital details. Inconsistent advice from referral centres on the management of such brain injury cases had been highlighted, prompting a review of practices at local level in order to improve quality of patient care. The aim of this project was to identify the current level of documentation and improve this through departmental education and implementation of a referral proforma. National guidelines and a literature review were used to formulate the gold standard for high quality documentation. ED patient notes were retrospectively reviewed over a three month period, assessing adequacy of referral documentation to a neurosurgical centre against the parameters previously set. Initial audit results and specific case studies were presented to ED team members at an educational meeting. A "record of telephone referral to neurosurgery" (RTRN) form was also introduced. Re-audit against the same set of standards was conducted to assess any change in level of documentation and use of the form itself. The results of this project have shown that, although departmental education improves clinical practice, following the introduction and use of a protocol such as the RTRN there was a significant improvement in the level, and therefore quality of, documentation. PMID- 26734335 TI - Improving management of gout in primary care using a customised electronic records template. AB - It is known that the management of chronic gout in relation to serum uric acid (SUA) monitoring, allopurinol dosing, and lifestyle advice is often sub-optimal in primary care.[1] A quality improvement project in the form of a criterion based audit was carried out in an urban general practice to improve the care of patients being treated for gout. Baseline searching of EMIS confirmed that management of patients with gout who were taking allopurinol was not in line with current guidance. 51(40%) had a SUA checked in the past 12 months, 88(25%) had a SUA below target level, and gout lifestyle advice was not being recorded. An audit was performed to measure and improve the following criteria: Monitoring of SUA levels in the past 12 monthsTitration of urate lowering therapy to bring the SUA below target levelLifestyle advice in the past 12 months An audit standard of 60% achievement at 2 months and 80% achievement at 4 months was set. The intervention consisted of a custom electronic template within EMIS which allowed guidance of gout management to be displayed and for data to be entered. All members of the team including GPs and administrative staff were educated regarding the intervention. This resulted in a sustained improvement over a 6 month period in all 3 components of the audit with 112(84%) having a SUA level checked, 79(51%) having a SUA below target level and 76(57%) receiving lifestyle advice. Although the improvement did not reach the audit standard in 2 of the criteria it would be expected that outcomes would continue given the systems changes which have been made. PMID- 26734336 TI - Keeping patients with epilepsy safe: a surmountable challenge? AB - This quality improvement project was inspired as an answer to a problem that intellectual disability teams have been struggling to manage whilst caring for people with epilepsy (PWE). The issue was that despite guidance to discuss the possibility of sudden unexpected death in epilepsy (SUDEP) be discussed with a newly diagnosed PWE this is rarely done. Additionally when, how, and what to discuss about SUDEP and reduce its risk is arbitrary, non-person centred, and with no structured evidence. Prior to initiating changes a discussion of SUDEP was recorded in just 10% of PWE. We introduced a check-list to help identify risk factors for SUDEP. We then modified the check-list, and then used it via telehealth, a way of contacting patients and their carers over the phone using the check-list approach. Following interventions, discussions of SUDEP are now recorded in 80% of PWE. Feedback from patients, carers and primary and secondary care professionals has been positive. We are now developing an app so that patients and carers can monitor their own risk factors, thus empowering them and increasing their knowledge and awareness of SUDEP. PMID- 26734337 TI - Improving smoking cessation policy by assessing user demand for an inpatient smoking cessation service in adult psychiatric wards. AB - Smoking rates are higher among people with mental health conditions compared to the general population. Smoking reduces physical, mental and financial well being, and interacts with psychotropic drugs. An inpatient admission provides an opportunity to engage and support smokers in smoking cessation. Compliance with Trust/NICE smoking cessation guidelines was assessed in two inpatient wards, and a questionnaire evaluated user demand for an inpatient smoking cessation service. A need for improved documentation of smoking status to identify and treat smokers routinely was revealed. A new electronic health form was designed and introduced, and a clear pathway for onward referrals was developed. This intervention preceded the introduction of the Trust-wide smoke free policy from October 2014. The intervention doubled rates of documentation of smoking status, cessation advice and offer of NRT/referral. There were large differences between the two wards, highlighting the need for a tailored approach. PMID- 26734338 TI - The use of conscious sedation in elective external direct current cardioversion: a single centre experience. AB - External direct current (DC) cardioversion is a commonly used method of terminating atrial arrhythmias. The chance of procedural success is inversely related to the duration of the arrhythmia. In many hospitals, the procedure is carried out under general anaesthesia, necessitating the presence of anaesthetic as well as medical staff. Frequently, it may be difficult to coordinate the availability of the two teams, causing delays to each patient, waste of staff time, an inefficient service and increased costs. The primary aim of the study was to determine the safety and tolerability of conscious sedation using intravenous midazolam in elective external DC cardioversion of patients with atrial flutter or atrial fibrillation attending University Hospital Limerick, Ireland. Patients who were electively admitted for DC cardioversion for atrial fibrillation or atrial flutter were recruited. A pre-defined sedation protocol using intravenous midazolam was used. The midazolam was given by the cardiology registrar without the presence of an anaesthetist. DC cardioversion was then performed according to the hospital protocol. Any complications arising during the procedure were noted. Prior to discharge, patients were given a questionnaire to determine their awareness of the procedure and if they would have the procedure done again in the future if needed. A total of 100 patients were recruited. The median number of shocks was one (highest number of shocks being four). The median dose of midazolam was 7.5 mg, with the highest dose being 20 mg. All of patients surveyed were not aware of the shock that was administered to them. All of the patients surveyed were happy with the service and would be happy to return for a repeat cardioversion in the future if required. The use of conscious sedation for DC cardioversion of patients with atrial fibrillation / atrial flutter was found to be safe and tolerable. PMID- 26734339 TI - Epilepsy emergency rescue training. AB - The NICE audit of epilepsy related deaths revealed that 1200 epilepsy deaths occur every year in the UK, with 42% potentially avoidable.[1] Convulsive status epilepticus (SE) is a life-threatening condition with over 20% mortality rate, especially if early treatment is not initiated.[2] Ten percent of all UK emergency department (ED) admissions are due to epilepsy, usually over represented by cases of SE.[3] Six out of seven epilepsy cases seen in the ED are admitted into medical care.[4] Patients with chronic and/or treatment resistant epilepsy carry a higher risk of premature death. When a seizure lasts for five minutes or more then the patient is at high risk of continuing to SE and this may result in causing brain damage or death.[2] Buccal midazolam is an emergency rescue medication prescribed on a special named patient license to reduce the duration of an epileptic seizure and prevent SE.[2,5] It should be administered by a trained person and is widely used due to its effectiveness and social acceptability. In the UK, epilepsy education and training courses are expected to be conducted by epilepsy professionals in line with the agreed training guidelines of Joint Epilepsy Council (JEC) backed up by evidence from NICE.[6,7] Training should provide an overview of epilepsy to facilitate safe care and appropriate administration of rescue medication for people with epilepsy (PWE) when experiencing a prolonged seizure. The medication is prescribed on specialist advice by the GP or specialists directly. Unfortunately the JEC guidelines are not robust enough to provide assurances of safe care. This problem had a myriad of complexities and an appropriate solution using web based resource was piloted, tested, and applied successfully using quality improvement methodology. PMID- 26734340 TI - Improving theatre efficiency and utilisation through early identification of trauma patients and enhanced communication between teams. AB - Surgical departments are increasingly put under pressure to improve services, cut waiting lists, increase efficiency and save money. At a district general hospital in the west-midlands we approached the challenge of improving efficiency and optimising the services available in our orthopaedic theatres. Data was collected on: anaesthetic start times, operation start and finish times, and reasons for delay in our trauma theatre over a period from October 2014 to January 2015. During this period a change was implemented to improve the start time of the first operation of each day in the trauma theatre. Through adaptation of a method developed by Javed S et al, a patient was pre-selected by the on-call team and given the name the "golden patient" the day before they were due to be operated upon. This nominated patient would then be fixed at the start of the trauma theatre list the following day. The list would only then change if a "life or limb threatening" case was admitted overnight. The on-call team would prioritise that this patient was optimised for theatre and the theatre staff would ensure the surgical instruments were prepared. A PDSA cycle method was used, collecting data on 80 orthopaedic trauma cases during the period, and demonstrated a 59 minute (95% CI 45-72) improvement in start times from 10:49 AM to 9:50 AM with a p-value of 0.00024 with the intervention of early allocation of the first patient on the trauma list. A relatively simple intervention tool designed to improve communication within and between health-care teams can have a significant impact on the efficiency of a complex environment such as a trauma theatre. PMID- 26734341 TI - Patient handover in orthopaedics, improving safety using Information Technology. AB - Good inpatient handover ensures patient safety and continuity of care. An adjunct to this is the patient list which is routinely managed by junior doctors. These lists are routinely created and managed within Microsoft Excel or Word. Following the merger of two orthopaedic departments into a single service in a new hospital, it was felt that a number of safety issues within the handover process needed to be addressed. This quality improvement project addressed these issues through the creation and implementation of a new patient database which spanned the department, allowing trouble free, safe, and comprehensive handover. Feedback demonstrated an improved user experience, greater reliability, continuity within the lists and a subsequent improvement in patient safety. PMID- 26734342 TI - Improving multidisciplinary communication at ward board rounds using video enhanced reflective practice. AB - The priority to ensure patient safety and use resources effectively, demands attention and innovation. Video enhanced reflective practice (VERP) provides training based upon analysis of film clips of one's professional practice to develop practical insight into the processes of communication, so that effective changes can be made to ongoing behaviour and practice. In this case the focus was on multi-disciplinary communication within daily board rounds on an acute medicine and care of the elderly ward. Baseline assessment and post intervention testing of perceptions of change by both full and core team were undertaken to establish the impact of VERP training. In addition pre and post focus group discussion and film analysis supplemented evaluation. The findings support the view that after VERP training of a core team, board rounds were seen as consistently easier to participate in, providing improved focus, were more efficient in goal setting and resulting in better care for patients as well as improved pathways to discharge. This suggests benefits to the communication "culture" of a multidisciplinary team resulting in increased benefits for the wider team. It is concluded that the use of tailored VERP training for personal, professional and team development is relevant, feasible, and worthy of further testing and investigation. PMID- 26734343 TI - Enhanced recovery clinical education programme improves quality of post-operative care. AB - Quality is the driving principle of Enhanced Recovery (ER). It improves the patient experience by getting patients better sooner and changes clinical practice to make care safer and more efficient. As a consequence of ER patients spend less time in hospital. A successful ER programme began to fail after organisational restructuring and staff changes. Patients did not meet their ER goals and length of stay (LOS) increased. An ER nurse was appointed to get the programme back on track. This involved a multidisciplinary approach to an ER clinical education programme. The programme aimed to develop knowledge of the physiology of post-operative recovery and the evidence underpinning the interventions required. This was considered crucial to secure longer term staff engagement while avoiding unthinking protocol driven compliance. Success of the education programme was measured by improved outcomes in patient LOS and readmission statistics. During the four months of the clinical education programme there were no significant changes in monthly LOS. At six months post implementation of the programme there was a reduction in LOS of 0.6 days compared to the previous six months. At 12 months there was a reduction in 1.1 days compared with previous 12 months. There was a mean reduction of 28 day readmissions for all elective gynaecology surgery of 1.1 patients per month in the 12 months post programme implementation compared to the 12 months before. Delivering a multidisciplinary participatory education programme improved overall understanding of ER, and achieved sustained improvement in ER for patient benefit. PMID- 26734344 TI - Recognition of the deteriorating patient. AB - Following Sir Bruce Keogh's review of 14 NHS Trusts, Buckinghamshire NHS Trust was found to have higher mortality rates than the England average. As part of a series of implementations and investigations to address this, a quality improvement project looking at clinical responses to the deteriorating patients was designed. Buckinghamshire NHS Trust utilises the National Early Warning Score (NEWS) metric for observations and escalation, and this was the standard used for the project. Episodes were eligible for inclusion if the NEWS score was increased to 5 or above. Data was collected by junior doctors from acute wards across the trust using notes and charts available. The initial cycle identified that in 57% of cases the high NEWS was escalated for review. Only half of cases were reviewed by a doctor; only a third were reviewed within an hour. In only 20% of cases were all criteria of the NEWS guidelines met. The first intervention was through education. After this, the project was completed on a monthly basis for 6 months with additional interventions introduced, including increased medical staff availability, grand round presentations, and increased outreach provision. Over this 6 month period, there was an increase to 87% of cases being reviewed by a doctor of appropriate seniority. Whilst this is a surrogate for reducing mortality and improving the clinical care given in the hospital, these results suggest successful interventions for improving clinical response to deteriorating patients across the trust. The project has recruited a new cohort of juniors to continue the quality improvement cycle. PMID- 26734345 TI - Dilemmas of a rota: Google's solution. AB - Doctors take many forms of leave to further career training. Many hospital rotas omit these and are not updated frequently to reflect swaps in on-call duties. As a result, confusion arises with reduced staffing levels leading to sub-optimal patient care. Using Google Sheets, rota's can be modified to be team specific, remotely accessed, and edited by any device with an internet connection and web browser. A qualitative pre and post-implementation questionnaire assessed the usefulness of the online rota. The rota was trialled on a surgical and medical team containing foundation year, core medical, core surgical, and registrar trainees. The respective surgical and medical rotas were copied, modified and pasted into a Google Sheet to contain only team specific information including all forms of leave. A link was emailed allowing teams to access and edit the rota. Post-implementation questionnaire 90% (n=10) stated they could access it remotely and 100% felt the new rota was very easy to use. Finally, 80% stated the Google Doc rota was a definite improvement on the old trust rota. The rota was then trialled on an ITU SHO rota (n=8). The results were reproducible with 88% feeling it addressed their requirements and stating it was an improvement on their old rota. As a result of the implementation appropriate staffing levels were maintained on the ward. The key advantages of the Google rota are that it included all forms of leave and helped ensure adequate staffing levels on the ward. The remote nature means easy access even if off-site and can be viewed easier on smart phones. The different privacy settings ensure security of document. The rota is updated in real-time giving an accurate representation of staffing levels - vital for service managers. The software is free to use, allowing it to work within current hospital IT framework. PMID- 26734346 TI - Nutritional assessment in elderly care: a MUST! AB - Malnutrition affects over three million people in the UK with associated health costs exceeding L13 billion annually.[1] In hospital, malnutrition has been shown to increase complication rates, morbidity, mortality, hospital readmissions, and length of hospital stay.[2] To screen for malnutrition, a reliable and validated screening tool such as the malnutrition universal screening tool (MUST) should be used.[3] We believe that improved patient outcomes and significant savings to the trust can be achieved, not only by ensuring that every patient has a MUST score documented, but that it is calculated correctly and the appropriate interventions are implemented. We have carried out the audit three times (May, July, and November 2013). The study included the patients on the elderly care ward of Watford General Hospital (n=64, 62, and 63 respectively). MUST scores documented in nursing notes for each patient were noted. We re-calculated each MUST score ourselves for comparison. We went through patient notes and nursing information and noted which recommended nutritional interventions were being implemented. Our results highlighted several issues: 1) Patients did not consistently have a MUST score documented 2) MUST scores were calculated incorrectly. This was generally due to BMIs calculated incorrectly, and patients' weights from six months ago not being known 3) High MUST scores not being acted on appropriately. Our interventions have involved liaising with various teams within the hospital to maximise the efficacy of the MUST score. This has included encouraging the trust to provide regular training to nurses because of high nursing staff turnover. Following our audit, the dietitian department agreed to undertake weekly ward rounds to screen for patients at risk of malnutrition. Our interventions so far have resulted in increased proportion of MUST scores being calculated (73 to 97%), and increased rates of patients being referred to dietitians (62 to 86% in the second audit cycle). PMID- 26734347 TI - Improving feedback from outpatient medical appointments attended by escorted psychiatric patients in the North London Forensic Service. AB - It is well established that patients with mental illness are known to have a high level of morbidity and mortality compared to the general population. This is particularly prominent in long-stay psychiatric patients, such as those in secure settings. The Royal College of Psychiatrists recommends that psychiatrists should promote the physical health of their patients and liaise with other specialties. However, there is evidence that communication between psychiatry and other specialties is poor. A survey was carried out at the North London Forensic Service in June 2014. This looked at the views of clinical staff about the frequency and quality of feedback obtained when inpatients attend outpatient hospital appointments at local general hospitals. This survey highlighted the general perception among staff that feedback is poor, with 68.43% of respondents saying that they were "very unsatisfied" or "unsatisfied" with the level and quality of feedback. Clinical staff felt that many patients who attended hospital outpatient appointments, even when escorted by staff, returned with little or no feedback. This was confirmed by a baseline audit across 3 wards showing that details of the appointment (date, time, hospital, and specialty) were only documented in 54.5% of cases and the content of the appointment documented in even fewer cases. A form was designed by junior doctors that provided a simple framework of 6 questions to be answered at the outpatient clinic about the problem, diagnosis, and further actions needed. This was introduced and its impact assessed with a 3-month and 6-month audit of electronic notes, as well as a follow-up survey after 6 months. The audit showed significant improvement in the quality of feedback about the appointment at both the 3-month and 6-month point. The follow-up survey showed that 70% of respondents were aware of the form and 100% of those who were aware of the form had used it at least once and found it helpful. The general satisfaction level improved, but remained low, with 40% of respondents saying that they were "very unsatisfied" or "unsatisfied" with the level and quality of feedback. This QIP shows that the outpatient appointment form is a useful and effective tool when staff know about it and use it. We plan to look at the barriers to using the form and consider future solutions to the need for increased engagement with nursing staff stakeholders in future PDSA cycles. PMID- 26734348 TI - Promoting vision and hearing aids use in an intensive care unit. AB - Vision and hearing impairments have long been recognised as modifiable risk factors for delirium.[1,2,3] Delirium in critically ill patients is a frequent complication (reported as high as 60% to 80% of intensive care patients), and is associated with a three-fold increase in mortality and prolonged hospital stay.[1] Guidelines by the UK Clinical Pharmacy Association recommend minimising risk factors to prevent delirium, rather than to treat it with pharmacological agents which may themselves cause delirium.[4] To address risk factors is a measure of multi-system management, such as sleep-wake cycle correction, orientation and use of vision and hearing aids, etc.[5] We designed an audit to survey the prevalence and availability of vision and hearing aids use in the intensive care unit (ICU) of one university hospital. The baseline data demonstrated a high level of prevalence and low level of availability of vision /hearing aid use. We implemented changes to the ICU Innovian assessment system, which serves to remind nursing staff performing daily checks on delirium reduction measures. This has improved practice in promoting vision and hearing aids use in ICU as shown by re-audit at six month. Further amendments to the Innovian risk assessments have increased the rate of assessment to 100% and vision aid use to near 100%. PMID- 26734349 TI - Introduction of a new electronic medical weekend handover at Tunbridge Wells Hospital. AB - Effective handover between shifts is vital to protect patient safety and assist doctors with clinical governance. Poor quality, or inadequate handover can lead to serious harm for both patients and doctors. The weekend medical handover system among junior doctors at Tunbridge Wells Hospital in Pembury, UK was cumbersome, inadequate and poor, restricting the ability to provide good patient care. 78.6% of doctors felt that the introduction of an electronic weekend handover system would address the issues in order to improve communication between the medical teams and thus improve patient care. A five week trial of an excel based electronic weekend handover system was conducted. 87.5% of the doctors surveyed felt that the new electronic weekend handover was better or significantly better than the old paper based handover system. The effectiveness rating of the weekend medical handover, with 1 (least effective) - 10 (most effective), rose from 6.14 to 7.31 after introduction of the electronic weekend medical handover system. As a result, this project has become part of the junior doctors medical induction, ensuring permanence of electronic weekend medical handover. This project takes a step towards improved patient safety as well improving the working conditions for junior doctors in a busy acute medical unit. There is always a need to refine and optimise systems and though this project is not perfect, it is a step toward electronic handover that is available now and free of cost. PMID- 26734350 TI - Improving the Quality of Assessment and Management of Hypoglycaemia in Hospitalised Patients with Diabetes Mellitus by Introducing 'Hypo Boxes' to General Medical Wards with a Specialist Interest in Diabetes. AB - Diabetes is becoming more prevalent in the UK and this is represented in the in patient cohort, such that 1 in 6 hospital patients have diabetes (1). The UK National Diabetes In-Patient Audit in 2012 estimated that 30% of patients experience one episode of hypoglycaemia during admission. Hypoglycaemia is associated with increased morbidity and mortality, and longer length of hospital stay. It is therefore important that hypoglycaemia is managed promptly and effectively to reduce associated morbidity. The Joint British Diabetes Society recommends that all wards should have access to 'Hypo Boxes' (2). We assessed all episodes of hypoglycaemia (<4.0 mmol/l) in the diabetes wards in over a 4 week period. 'Hypo Boxes' were installed to the wards and the appropriateness of treatment and time to correction of hypoglycaemia was re-assessed. Assessment of hypoglycaemia pre-intervention revealed 45 episodes of hypoglycaemia in 14 patients, and 42% (n=19) of episodes were deemed to have been treated appropriately. Only 17.8% of episodes were corrected within 30 minutes, and 33.3% were corrected within 60 minutes. A third of patients (35%) did not have a further blood glucose checked. Following intervention, there was a marked improvement in management. The proportion of appropriately managed episodes increased to 82% (n=35) and management of episodes of severe hypoglycaemia (<3.0 mmol/l) increased to 94%. The time to correction increased with 40% of episodes corrected to >4.0 mmol/l within 30 minutes, and a further 54% between 30-60 minutes. In conclusion, the introduction of 'Hypo Boxes' improved the assessment and management of hypoglycaemia. PMID- 26734351 TI - Improving patient flow in pre-operative assessment. AB - Annual patient attendances at a pre-operative assessment department increased by 24.8% from 5659 in 2009, to 7062 in 2012. The unit was staffed by administrative staff, nurses, and health care assistants (HCA). Medical review was accessed via on call medical staff, or notes were sent to anaesthetists for further review. With rising demand, patient waits increased. The average lead time for a patient (time from entering the department to leaving) was 79 minutes. 9.3% of patients attended within two weeks of their scheduled surgery date. 10% of patients were asked to return on a later day, as there was not sufficient capacity to undertake their assessment. There were nine routes of referral in to the department. Patients moved between different clinic rooms and the waiting area several times. Work patterns were uneven, as many attendances were from out-patient clinics which meant peak attendance times were linked to clinic times. There were substantial differences in the approaches of different nurses, making the HCA role difficult. Patients reported dissatisfaction with waits. Using a Lean quality improvement process with rapid PDSA cycles, the service changed to one in which patients were placed in a room, and remained there for the duration of their assessment. Standard work was developed for HCWs and nurses. Rooms were standardised using 5S processes, and set up improved to reduce time spent looking for supplies. A co-ordinator role was introduced using existing staff to monitor flow and to organise the required medical assessments and ECGs. Timing of booked appointments were altered to take account of clinic times. Routes in to the department were reduced from nine to one. Ten months after the work began, the average lead time had reduced to 59 minutes. The proportion of people attending within two weeks of their surgery decreased from 9.3% to 5.3%. Referrals for an anaesthetic opinion decreased from 30% to 20%, and in the month reviewed no one had to return to be seen as a result of limited capacity. PMID- 26734352 TI - Use of nurse-led telephone follow-up as a sole method of assessing patients after nasal surgery. AB - Patients undergoing nasal surgery have historically been routinely followed up in consultant led clinics some months after surgery. It has been noted that a significant proportion of these patients either did not attend these appointments or did not require them, impacting on the efficiency of ENT outpatient clinics. A quality improvement project was undertaken to assess this problem and to propose a new patient pathway whereby patients are contacted by ENT nursing staff by telephone three months following surgery. During these telephone conversations only 9.5% of patients requested outpatient follow-up and all of these patients were discharged upon their follow-up. The project demonstrates that nurse-led follow up is an efficient, effective and safe way of managing patient care post nasal surgery. PMID- 26734353 TI - Safer Wards: reducing violence on older people's mental health wards. AB - Through the Safer Wards project we aimed to reduce the number of incidents of physical violence on older people's mental health wards. This was done using quality improvement methods and supported by the Trust's extensive programme of quality improvement, including training provided by the Institute for Healthcare Improvement. Violence can be an indicator of unmet needs in this patient population, with a negative effect on patient care and staff morale. Reducing harm to patients and staff is a strategic aim of our Trust. We established a multi-disciplinary group who led on the project on each ward and used a Pareto diagram to establish the focus of our work. We established a dashboard of measures based on our incident reporting system Datix, including number of incidents of violence, days between incidents, days of staff sickness, days between staff injury, use of restraint, and use of rapid tranquilisation (the last two being balancing measures in the reduction of violence). Each team identified factors driving physical violence on the wards, under headings of unmet patient needs, staff needs and staff awareness, which included lack of activity and a safe and therapeutic environment. Using driver diagrams, we identified change ideas that included hourly rounding (proactive checks on patient well-being), the addition of sensory rooms, flexible leave for patients, and a structured activity programme. We also introduced exercise to music, therapeutic groups led by patients, and focused on discharge planning and pet therapy, each of which starting sequentially over the course of a one year period from late 2013 and subject to a cycle of iterative learning using PDSA methods. The specific aim was a 20% decrease in violent incidents on three wards in City and Hackney, and Newham. Following our interventions, days between violent incidents increased from an average of three to an average of six. Days between staff injury due to physical violence rose from an average of eight (one violent incident resulting in staff injury every eight days) to 22 (one incident every 22 days). Incidents of physical violence reduced from 63 in 2013 to 39 in 2014. We were also able to quantify reduced costs associated with reduction in violence. The success of this project in our view lay in the involvement of ward staff in understanding the problems and generating local solutions which were also broadly evidenced based. Patients were also closely involved in generating ideas. We are currently incorporating much of this work into routine practice in order to sustain improvement, as well as continuing to generate new ideas for further improvement while using the skills learnt in this process to address other problems. PMID- 26734354 TI - Improving inpatient care with the introduction of a hip fracture pathway. AB - A system of payment by results exists for the management of hip fractures in England and Wales. Poor performance against the national standards was noted, reflecting failure to deliver optimal care. Through the introduction of a multi disciplinary patient pathway and clerking pro forma, the proportion of patients earning the best practice tariff uplift increased from 44.4% to 91.7%. This demonstrates a significant improvement in patient care measured against the guidelines, also resulting in a substantial revenue increase for the department. PMID- 26734356 TI - Improving the quality of initial management of self harm and suicide patients in A+E at the James Paget Hospital. AB - Our objective was to improve the initial management and documentation of suicide risk assessment in the notes of patients attending A+E with a suicide attempt or self harm. An initial audit was carried out in 2012 looking at the notes of 50 patients who attended the James Paget Hospital accident and emergency (A+E) department following a suicide attempt or self harm episode. Compliance to the NICE guidelines on the initial management of self harm was assessed and was found to be low in certain areas. A significant number of these patients are discharged without evidence of a satisfactory suicide risk assessment being documented. This is dangerous practice for the patients and puts the doctor at risk medico legally. A number of interventions were introduced to raise compliance to the NICE guidelines. These changes included adaptation to the self harm pro-forma to better conform to the NICE guidelines, departmental teaching sessions, and posters of the pro-forma put up in A+E at the doctors stations. In addition, a "see and greet" nurse was involved in the triage and administration of activated charcoal. The audit was repeated in 2013 and 2014. It was found that the interventions led to an increase in compliance to the NICE guidelines and better documentation in the notes of patients who present with a suicide attempt or self harm episode. PMID- 26734355 TI - Reducing pre-operative length of stay for enterocutaneous fistula repair with a multi-disciplinary approach. AB - Pre-operative assessment of complex surgical patients can be a lengthy process, albeit essential to minimise complication rates. In a tertiary referral unit specialising in the surgical repair of entercutaneous fistulas, a baseline audit revealed an average in-patient length of stay of 30.1 days, mainly caused by poor co-ordination between specialities. After the introduction of a weekly multi disciplinary team meeting and the formalisation of a patient pathway, this admission length was reduced to 5.7 days (p<0.01), resulting in significant savings to the department. PMID- 26734357 TI - CQUIN audit for prescription of antibiotics for urinary tract infections in an acute medical assessment unit. AB - Urinary tract infections (UTI) are a common presentation in a medical assessment unit, and we wanted to check compliance with hospital guidelines for antibiotic prescribing in patients presenting to hospital with urinary tract infection. The guidelines are based on local organisms and sensitivities. A retrospective audit of 40 patient records with positive urine cultures from July to August 2013 showed that 20% of patients with culture confirmed UTI were not given antibiotics at all. Of those prescribed antibiotics, 25% were non-compliant with local policy, and nearly one in two patients received more than one antibiotic. Furthermore, stop dates were not stated on 77% of the drug charts and duration of treatment ranged from one to 11 days. Interventions were then introduced in the form of group teaching sessions, proactive checks by Trust pharmacists and widely distributed posters, and the same data sets collected for April to March 2014 to assess for efficacy of the interventions. On re-auditing, 35% patients were not prescribed any antibiotics. However, compliance with local policy was 100%, including 100% drug charts having a stop/review date stated. The overall duration of treatment now ranged from one to seven days, and fewer than one in four patients had more than one antibiotic. Our results showed that improvement was needed in antibiotic stewardship, in particular with regards to compliance with the local guidelines and documentation of prescription. We have demonstrated that it is possible to improve compliance through teaching, by displaying information prominently, and vigilance by the clinical team. The outcome of this is a decreased number and duration of antibiotics prescribed, which has benefits for the patients, the hospital, and the community as a whole. Further work would include interventions to improve the number of patients who are missing antibiotic prescriptions altogether. PMID- 26734358 TI - Improved Surgical Site Infection (SSI) rate through accurately assessed surgical wounds. AB - Sheikh Khalifa Medical City's (SKMC) Surgery Institute was identified as a high outlier in Surgical Site Infections (SSI) based on the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) - Semi-Annual Report (SAR) in January 2012. The aim of this project was to improve SSI rates through accurate wound classification. We identified SSI rate reduction as a performance improvement and safety priority at SKMC, a tertiary referral center. We used the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) best practice guidelines as a guide. ACS NSQIP is a clinical registry that provides risk-adjusted clinical outcome reports every six months. The rates of SSI are reported in an observed/expected ratio. The expected ratio is calculated based on the risk factors of the patients which include wound classification. We established a multidisciplinary SSI taskforce. The members of the SSI taskforce included the ACS NSQIP team members, quality, surgeons, nurses, infection control, IT, pharmacy, microbiology, and it was chaired by a colorectal surgeon. The taskforce focused on five areas: pre-op showering and hair removal, skin antisepsis, prophylactic antibiotics, peri-operative maintenance of glycaemia, and normothermia. We planned audits to evaluate our wound classification and our SSI rates based on the SAR. Our expected SSI rates in general surgery and the whole department were 2.52% and 1.70% respectively, while our observed SSI rates were 4.68% and 3.57% respectively, giving us a high outlier status with an odd's ratio of 1.72 and 2.03. Wound classifications were identified as an area of concern. For example, wound classifications were preoperatively selected based on the default wound classification of the booked procedure in the Electronic Medical Record (EMR) which led to under classifying wounds in many occasions. A total of 998 cases were reviewed, our rate of incorrect wound classification assignment was 36%, and the worst rates were in appendectomies (97%). Over time our incorrect wound classification decreased down to 22%, while at the same time our actual SSI wound occurrences per month and our odds ratio of SSI in the department have decreased an average of six to three per month. We followed the best practice guidelines of the ACS NSQIP. Accurate assessment of wound classification is necessary to make sure the expected SSI rates are not falsely high if wounds are under-classified. The present study shows that accurate wound classification in contaminated and dirty wounds can lead to lower odds ratio of SSI. PMID- 26734359 TI - Quality improvement in resident education: a pilot project to mitigate metabolic side effects from atypical antipsychotic medications in youth. AB - This resident physician-led quality improvement project was conducted with aims to improve the health of youth prescribed atypical antipsychotic medications by increasing physician monitoring for metabolic side effects, while simultaneously educating trainees in quality improvement methodology. The plan, do, study, act quality improvement framework was utilized. Baseline metabolic monitoring rates of patients prescribed atypical antipsychotic medications in the two psychiatry resident outpatient clinics were obtained. Rates were stratified based on time on medication (<1 year, >=1 year) and parameter monitored. Metabolic monitoring rates subsequent to targeted changes were obtained. Problem solving with residents revealed barriers to monitoring, such as limited awareness of specific guideline recommendations and lack of convenient access to medical equipment (calibrated scales). Residents received education about atypical antipsychotic monitoring guidelines and side effect treatment. Residents were provided with calibrated scales. Atypical antipsychotic monitoring templates were introduced. Online surveys using were conducted to determine self-reported baseline monitoring rates and comfort with guidelines following targeted change. The baseline metabolic monitoring rates of patients prescribed atypical antipsychotic medications was 9% (range: 0 to 17.6%) for youth in their first year taking an atypical antipsychotic medication and 58.9% (range: 29% to 100%) in subsequent years on medication. The results of relatively easy changes resulted in modest improvement in monitoring rates. The metabolic monitoring rate of a patient initiated on an atypical antipsychotic medication was 29% after targeted quality improvement measures were employed. Following quality improvement changes, residents reported increased knowledge about guidelines and increased monitoring for side effects. Use of a standardized data collection instrument to track monitoring of patients increased from 0% to 70% (range: 30% to 90%). Quality improvement projects provide an avenue with which to improve atypical antipsychotic monitoring rates. Through active participation in quality improvement projects, psychiatry residents may be taught to employ quality improvement methodology. PMID- 26734360 TI - Troponin: think before you request one. AB - Acute myocardial infarction (ACS) is one of the most common presentations in acute hospital settings. Troponin (cTn) has emerged as one of the most sensitive biochemical markers for the diagnosis of ACS. However, if used inappropriately and in the absence of true clinical context then it can be elevated in a number of non cardiac conditions and lead to false clinical diagnosis, inappropriate workup, and increased patient stay in hospital. The cost of unnecessary clinical testing is another aspect of the problem. At Royal Gwent Hospital in Newport (one of the busiest district general hospitals in Wales) we retrospectively analysed the nature of troponin requests over a random period of one week, specifically looking for the indications and final diagnostic impact. In many cases it was found that requests were made without any clinical justification. One of the main and probably unavoidable reasons for this was that requests were made from triage before patient was assessed by a clinician. However, steps were taken to clarify common clinical indications for suspected cardiac diagnosis in which troponin was useful. Additionally, the "tick box" practice for inappropriate laboratory investigations was discouraged. A repeat audit was done on similar basic principles and a measurable improvement was identified, with a potential for significant impact in future. PMID- 26734361 TI - The Handbook: an end to 'I wish I had known that before I started'. AB - The importance of an effective handover between clinicians is vital, particularly for junior doctors when commencing a new clinical rotation. When junior doctors commence a new rotation there is often a significant amount of new information and tasks that they must learn, whilst also maintaining a high level of care for patients. However, very little information is formally passed from the outgoing junior doctor to the incoming junior doctor when changing rotations, resulting in a gap in knowledge and information having to be relearned by each junior doctor for each ward. Through a junior doctor led service improvement initiative we created an intranet-based, updateable, easily accessible, and secure resource to assist junior doctors during this transition period. Our project was not only beneficial to junior doctors when starting on a new rotation but also helped them understand their role within the ward environment and become more efficient in their clinical work. The project is an example of a sustainable service improvement project implemented with no cost that due to its format and low maintenance, could be easily adapted on a wider scale in other hospitals or Trusts. PMID- 26734362 TI - The psychiatric inpatient physical health assessment sheet (PIPHAS): a useful tool to improve the speed, efficiency, and documentation of physical examination in new psychiatric inpatients. AB - There is increased morbidity and mortality among patients suffering from mental illness. This is believed to be multi-factorial. Poor access to healthcare, the stigma of mental illness, reduced clinic attendance, lifestyle factors, and side effects of medications are cited as possible contributing factors. It is therefore vital to perform a physical examination to identify previously undiagnosed conditions during the admission of a psychiatric inpatient. The Royal College of Psychiatrists recommends that all patients admitted to a psychiatric hospital should receive a full physical examination on admission, or within twenty-four hours of admission. A snapshot audit was carried out at Prospect Park Hospital in Reading, which highlighted that The Royal College of Psychiatrist's recommendation, along with Trust guidelines regarding physical examination were not being met, with only 78 out of 111 patients (70.3%) undergoing an examination during their admission. In addition to this, examinations were often poorly documented and not covering all examination domains. A psychiatric inpatient physical health assessment sheet (PIPHAS) was designed and introduced, providing a quick and standardised approach to the documentation of a physical examination. After the intervention was put into practice, its impact was assessed by performing a retrospective review of the admission clerking notes of the next 100 admissions to Prospect Park Hospital. Following the introduction of the PIPHAS form there was an increase in the number of patients undergoing physical examination on admission to hospital (75 out of 100 patients, 75%). There was also an increase in the thorough documentation of all examination domains (e.g. respiratory examination) for patients that had a completed PIPHAS form scanned within their medical records. This quality improvement project demonstrates that the PIPHAS form is a useful tool to improve the speed, efficiency, and documentation of a thorough physical examination in new psychiatric inpatients. PMID- 26734363 TI - Improving the quality of discharge summaries for elective surgical procedures at North Bristol NHS Trust. AB - Following elective surgical procedures, hospital discharge summaries are essential in the handover to primary care. The information provided varies between institutions and is highly user-dependent. Various interventions have focused on improving information transfer to patients and primary care physicians including the development of electronic templates, electronic transmission to primary care, and training initiatives for junior doctors. An evaluation of the urological patient's journey at Southmead Hospital revealed a need for improved discharge summary advice. Urology specialists developed "gold standard" templates for elective urological procedures. Following a new rotation of junior doctors, discharge summaries were audited for one week. The templates were then made available on the urology ward, a teaching session was employed to encourage compliance, and the hospital electronic discharge summary template was edited. Following each intervention, summaries for one week of urology procedures were audited to assess the quality of advice provided to patients. At baseline, 18% of discharge summaries contained sufficient patient advice, this reduced to 10% after templates were made available on the wards, increasing to 45% following the education session and 84% once the electronic discharge summary proforma was edited. We conclude that discharge summaries are an effective time point for intervening to provide patients with specific post-operative information and this may be optimised for different elective procedures via the introduction of electronically-distributed standardised templates. PMID- 26734364 TI - Improving documentation of cardiovascular disease risk in patients with diabetes attending non communicable disease clinics at West Bay Health Center in Qatar. AB - The documentation of cardiovascular disease (CVD) in medical records of patients with type 2 diabetes attending non communicable disease (NCD) clinics at West Bay Health Center in Qatar is less than ideal. Poor documentation of CVD will lead to poor preventive and management plans, with negative consequences for patients. Our aim is to improve this documentation of cardiovascular disease risk from 13% to 70% through the use of the WHO CVD risk prediction charts, which ran from September 2014 to January 2015. An intervention in the form of an education session was run on 13th November 2014 for nurses that run the NCD clinic, covering the new NCD format (including the location of risk documentation, the method used for calculation the CVD, and mandatory documentation of CVD scores). A group discussion was also held with a physician for revising the CVD risk that was documented by nurses. Posters were placed in the NCD nurse station and clinics to remind them about CVD calculation and documentation. The average percentage of complete CVD risk documentation for patients with diabetes was 7%, increasing to 59% after the intervention. Overall, our intervention improved the documentation of CVD by 52%. PMID- 26734365 TI - A tool to improve communication in the neonatal unit. AB - Frequent and sensitive communication from neonatal staff is important to alleviate parental stress and to ensure that parents understand their baby's condition and progress. It also consequently empowers and involves parents in their baby's care. A lack of regular and informative communication from neonatal staff is a common reason for parental complaint. We sought to assess whether the implementation of a baby diary used as a communication tool would improve parent staff communication and optimise the parental experience of neonatal care. In this study, parents and carers of babies on our neonatal unit were invited to complete a questionnaire to assess their level of satisfaction with communication by neonatal staff before and after the implementation of the diaries. The diary was designed to act as an aid to improve communication to parents about their baby and thereby complementing face-to face communication and encouraging parental involvement. The study design was a retrospective parental satisfaction questionnaire based on the Department of Health [1] and the National Institute for Health and Care Excellence (NICE) [2] quality standards for specialist neonatal care on communication and parental involvement (n=44, response rate 57%). Following implementation of the diary, the questionnaire was repeated on two occasions: one month post implementation (n=17, response rate 23%) and 15 months post implementation (n=44, response rate 65%). More parents in the post intervention cohort felt they were receiving regular communication from staff, that their questions and concerns were being addressed, and felt involved in their baby's care than in the pre-intervention cohort. In addition, 100% of parents said they liked reading the diary and 94% felt it added to their understanding of how their baby was doing. Our project demonstrates an improvement in parents' satisfaction with communication from neonatal staff following the implementation of individual baby diaries. The diary is a simple, practical, and cost-effective tool to enhance communication between parents and staff in a neonatal unit. PMID- 26734366 TI - Improving handover from intensive care to ward medical teams with simple changes to paperwork. AB - Medical handover has been highlighted by the General Medical Council[1] as a critical step in patient care, ensuring continuity of care, patient safety, and enabling efficient multidisciplinary functioning. Handover between doctors on the intensive care team and the ward teams in the Great Western Hospital on step down was evaluated by assessing discharge summaries and patient notes, and by following up discharged patients. Handover was found to be present only in the minority of patients and documented in none. Simple changes were made to discharge paperwork in the form of a prompt and documentation of to whom handover was made, as well as the creation of space in the daily review sheets for patients with outstanding handover to be completed. The initial audit findings were presented at a local meeting to remind staff of the importance of handover. These simple modifications brought the handover rates up to 100% (n=12). The rates of documentation of handover also rose from 0% to 100%. This quality improvement project serves to demonstrate that carefully targeted, simple changes to practice in identified critical areas can produce dramatic as well as legally and ethically required results in a very short space of time. PMID- 26734367 TI - The use of an IV to PO clinical intervention form to improve antibiotic administration in a community based hospital. AB - Antimicrobials are among the most commonly prescribed medications in acute care settings, with 50% of antimicrobial use deemed inappropriate. Antimicrobial stewardship programs (ASP) aim to optimize antibiotic use in order to improve patient clinical outcomes while minimizing unwanted effects of therapy including Clostridium difficile infection (CDI) and the emergence of resistant organisms. Antimicrobial Stewardship involves a coordinated set of interventions that ensure patients who require antimicrobial therapy receive the most appropriate agent at the correct dose, by the correct route for the correct duration. This project focused on the appropriate conversion from intravenous (IV) to oral (PO) antibiotics. The purpose of the project was to determine whether antibiotic prescribing patterns improved following the implementation of an IV to PO conversion clinical intervention form. A collaborative approach was used by an interprofessional team to review medical records and design a clinical intervention form that adheres to evidence-based guidelines to promote appropriate conversion for patients on intravenous antibiotics. Education efforts were made to inform health system staff about the goal of the intervention and to gather feedback for the improvement of the clinical intervention form. A five week pilot intervention period trial was carried out with a specific focus on the fluoroquinolone class of antibiotics, specifically ciprofloxacin, moxifloxacin, and levofloxacin. Data from the intervention phase, including overall antibiotic use, ratio of intravenous:oral antibiotic time and compliance with the clinical intervention form were assessed. The ratio of intravenous to oral fluoroquinolone use changed from 39.4% IV: 60.6% PO before the intervention, to 34.7% IV: 65.3% PO during the intervention, indicating an overall increase in the usage of oral fluoroquinolones during the intervention phase. In patients eligible to receive the clinical intervention form, physician compliance with the form was 50%. IV duration decreased by 42% in patients with physician compliance. Further refinement of this form and the process for implementation will further enhance the conversion of intravenous to oral therapy. Based on these findings and the lessons learned, this process will be considered for further refinements, spread, and sustainability. PMID- 26734369 TI - Developing a ward round checklist to improve patient safety. AB - Checklists have been shown to improve care and reduce morbidity and mortality in the healthcare setting.[1] Their application in safety-critical industries outside of medicine continues to offer a strong argument for their application to medicine.[2] The daily in-patient medical ward round is a complex process and includes multiple potential risks to patient safety. This project aims to evaluate the effectiveness of a ward round review checklist on one general medical ward in a district general hospital in the UK. A baseline audit was performed, examining case-notes for a set of pre-defined outcome measures relevant to patient safety. Compliance with documentation of each outcome measure was assessed prior to the introduction of a ward round checklist. This was followed by a quality improvement project through the use of PDSA cycles, with the aim of introducing and developing a ward round checklist over a nine month period. Following the introduction of a checklist, overall compliance with documentation of each outcome measure improved from 45% to 89%. In conclusion, a quality improvement project involving the introduction of a ward round checklist for daily use has resulted in improved documentation of outcome measures that are relevant to patient safety. Teamwork and leadership skills from clinicians committed to improving patient safety is essential to sustaining improvements in traditional ward round practice. PMID- 26734368 TI - Improving critical care discharge summaries: a collaborative quality improvement project using PDSA. AB - Around 110,000 people spend time in critical care units in England and Wales each year. The transition of care from the intensive care unit to the general ward exposes patients to potential harms from changes in healthcare providers and environment. Nurses working on general wards report anxiety and uncertainty when receiving patients from critical care. An innovative form of enhanced capability critical care outreach called 'iMobile' is being provided at King's College Hospital (KCH). Part of the remit of iMobile is to review patients who have been transferred from critical care to general wards. The iMobile team wished to improve the quality of critical care discharge summaries. A collaborative evidence-based quality improvement project was therefore undertaken by the iMobile team at KCH in conjunction with researchers from King's Improvement Science (KIS). Plan, Do, Study, Act (PDSA) methodology was used. Three PDSA cycles were undertaken. Methods adopted comprised: a scoping literature review to identify relevant guidelines and research evidence to inform all aspects of the quality improvement project; a process mapping exercise; informal focus groups / interviews with staff; patient story-telling work with people who had experienced critical care and subsequent discharge to a general ward; and regular audits of the quality of both medical and nursing critical care discharge summaries. The following behaviour change interventions were adopted, taking into account evidence of effectiveness from published systematic reviews and considering the local context: regular audit and feedback of the quality of discharge summaries, feedback of patient experience, and championing and education delivered by local opinion leaders. The audit results were mixed across the trajectory of the project, demonstrating the difficulty of sustaining positive change. This was particularly important as critical care bed occupancy and through-put fluctuates which then impacts on work-load, with new cohorts of staff regularly passing through critical care. In addition to presenting the results of this quality improvement project, we also reflect on the lessons learned and make suggestions for future projects. PMID- 26734370 TI - Reducing hospital acquired pressure ulcers in intensive care. AB - Pressure ulcers are a definite problem in our health care system and are growing in numbers. Unfortunately, it is usually the most weak and vulnerable of our culture that faces these complications, causing the patient and their families discomfort, anguish, and economic hardship due to their expensive treatment. Data collected by the tissue viability department showed high incidence of hospital acquire pressure ulcers in the intensive care unit in March 2013. An action plan was initiated and implemented by the tissue viability team, senior nursing management, pressure ulcer prevention (PUP) team and respiratory therapists (RT's) within the ICU. Our objective was to reduce hospital acquired pressure ulcers in the intensive care unit using the plan, do, check, act quality improvement process. PMID- 26734371 TI - Details behind the dots: How different intensive care units used common and contrasting methods to prevent ventilator associated pneumonia. AB - Care bundles promote delivery of effective care and improve patient outcomes. The understanding of how to improve delivery of care bundles is incomplete. The Scottish Patient Safety Programme is a national collaborative with the aim of improving the delivery of care to patients in acute hospitals in Scotland. Critical care is one of five workstreams in the programme. A programme goal is to reduce incidence of ventilator-associated pneumonia (VAP) to zero or 300 calendar days between events through use of a VAP Prevention bundle. We studied two ICUs participating in this programme. Each ICU had established infection surveillance system prior to the programme starting. Both units had an appreciable incidence of VAP. Initial VAP prevention bundle adherence was low in each ICU (35% and 41%). Comparing time periods before and after 80% bundle VAP prevention bundle adherence was achieved showed a similar reduction in VAP incidence (from 6.9 to 1.0, and from 7.8 to 1.4/1000 ventilation days). When compared each ICU used common and contrasting approaches to accomplish this improvement. We describe the five improvement knowledge systems used to improve bundle adherence to bundle elements in each hospital. The insights gained from these front-line clinical teams can be used as a template for improvement efforts in a variety of other healthcare settings. PMID- 26734372 TI - Mortality meetings in geriatric medicine: strategies for improvement. AB - A large proportion of patients who die in hospital will be under the care of geriatric medicine. Mortality reviews have traditionally used trigger tools to try and identify preventable deaths, but the majority of hospital deaths are not preventable and lapses in care are often very complex. Over a period of 14 months we performed four PDSA cycles to change the focus of mortality meetings within care of the elderly and stroke medicine at Cumberland Infirmary to look beyond preventable deaths. The aim was to maximise learning from mortality meetings to improve patient care. We used collaborative working at a trust and departmental level, moving from trigger tool preparation to a narrative approach, and we set up strategies to focus and disseminate our learning. The mean number of cases discussed per meeting and the mean number of lessons identified per case discussed increased, as did the learning levels (trust, department, individual). Maintaining multidisciplinary input and consolidating lessons learnt was difficult because of clinical commitments and natural staff turnover. PMID- 26734373 TI - Standardising the organisation of clinical equipment on surgical wards at North Bristol NHS Trust: a quality improvement initiative. AB - Poorly organised clinical equipment can waste significant amounts of time otherwise available for direct patient care. As a group of foundation year one doctors, we identified the organisation of clinical equipment across surgical wards at North Bristol NHS Trust to be poor with stocks often low and items frequently difficult to locate. Time-motion studies (n=80) were confirmatory demonstrating that the mean time to collect equipment necessary for venepuncture, cannulation, arterial blood gases, or blood cultures ranged from 121 to 174 seconds between different areas. By applying a plan-do-study-act (PDSA) methodology, surveying peers as well as working with nursing staff and senior managers, we were able to purchase and implement clinical equipment trolleys on 10 surgical wards across the trust to reduce the time-taken to locate clinical equipment to between 38 to 45 seconds (p=0.01). We feel the key factors for the success of our initiative were strong multidisciplinary engagement and a simple uniform idea. Clinical equipment trolleys organised in a standardised manner have now been rolled out hospital-wide in the new Southmead Hospital Brunel building. PMID- 26734374 TI - Hepatitis C: improving the quality of screening in a community hospital by implementing an electronic medical record intervention. AB - Both the Centers for Disease Control and Prevention (CDC) and the U.S. Preventive Services Task Force (USPSTF) have recommended that adults born between the years of 1945-1965 should receive one-time testing for Hepatitis C Virus (HCV). In fact, Governor Andrew Cuomo of the State of New York had signed a bill on October 23, 2013 which mandated NY hospitals and healthcare providers to offer HCV testing to all "Baby Boomers." For our project, we wanted to increase our community hospital's compliance with this law and improve the quality of patient care in doing so. An electronic medical record intervention was implemented in conjunction with our information technology services department. This intervention would flag eligible patients and would run them through a predetermined algorithm to see if they needed HCV testing. Multiple plan, do, study, act (PDSA) cycles were run during the length of the study and many changes were made in order to achieve maximum effect. We ended up increasing our HCV testing rate from 47.2% (pre-intervention) to 87.9% (final month of the study), which was statistically significant with a p-value of <0.0000001. We also ended up with a framework that is both generalizable to other projects and is also self sustaining, so that it can continue to run itself once all the project members have finished working there as house staff. PMID- 26734375 TI - Warfarin prescription and administration: reducing the delay, improving the safety. AB - Warfarin is frequently administered to hospital patients. The prescription and administration of this medication are particularly susceptible to error. Factors contributing to this include the narrow therapeutic index, patient-specific target range, and the need for regular INR monitoring. NICE guidelines state that warfarin should be given at the same time every day and the Bristol Royal Infirmary guidelines are warfarin to be given at 14:00. The 14:00 dosing ensures standardisation of administration; poor adherence to this recommendation may cause patient harm. We noticed that many warfarin doses were often given outside of maximal staffing hours and it was often left to the on call doctor to prescribe warfarin at erratic and inconsistent times. Our primary aim was to reduce the number of adverse outcomes associated with warfarin prescription and administration. We targeted two system measures: the proportion of warfarin administrations occurring within an hour of the 14:00 prescription and the proportion of INR results outside target range. We employed the model for improvement and carried out our project across seven acute medical wards. Baseline data showed that only 24% of doses were being given within an hour of the recommended time and 64% of doses were being given after 17:00 during minimal staffing hours. We successfully introduced a warfarin box within our trust which demonstrated an improvement in warfarin administration from 24% of patients receiving their warfarin within an hour of 14:00 to 49% and this was subsequently associated with a reduction in INRs above target range (23% to 9%). PMID- 26734376 TI - Improving the management of acute pancreatitis in a district general hospital. AB - Acute pancreatitis is a common problem seen in the United Kingdom, with an incidence of 56.6 per 100,000 population.[1,2,3] Optimising management has been shown to reduce mortality and morbidity, and the British Society of Gastroenterology (BSG) published revised guidelines in 2005 to standardise treatment for this potentially life threatening condition.[4] The aim of this quality improvement project was to investigate and improve the initial management of acute pancreatitis in patients presenting to the Great Western Hospital (GWH) in Swindon between November 2012 and July 2013. Patients presenting to the surgical team during this time with a diagnosis of acute pancreatitis were identified for the initial data collection. Notes were prospectively reviewed and data collected allowing a comparison between management in GWH against BSG guidelines. Following this stage, a pro forma based on the 2005 guidelines was created and implemented, with the aim of raising awareness and standardising care among surgical staff. Following implementation of the pro forma, data collection was repeated between May and June 2013 to assess the impact of the intervention. Results revealed an improvement from 93% to 100% of patients receiving the correct diagnosis within 24 hours of presentation. Severity stratification within 48 hours of diagnosis improved from 75% to 88% and identification of aetiology also improved from 64% to 74%. The implementation of an acute pancreatitis management protocol and education of junior surgical staff has been shown to improve compliance with BSG guidelines at the GWH, and ultimately aims to improves patient care and outcomes. PMID- 26734377 TI - Ceiling of care decisions at an older person's mental health unit in Gloucestershire. AB - This quality improvement project was inspired as an answer to a problem that many fellow psychiatric trainees had been struggling with while on-call covering the old age mental health hospital which includes a specialist dementia ward. The issue was that decisions around ceilings of care for patients were often not discussed or at least recorded in the electronic notes and as a result when reviewing deteriorating patients out of hours trainees would find themselves without any guidance on the treating medics opinion on what was in the best interests of the patient. This led to situations where unnecessary transfers to the acute hospital would occur overnight which could have been avoided with more consistent planning. Prior to initiating the changes it was recorded that nine out of 47 inpatients had documented decisions on ceiling of care of treatment in the consultant's ward round entries. Next policies from acute hospitals were reviewed, opinions were discussed in departmental meetings, and eventually there was agreed a change in procedure with the consultant on the dementia ward around resuscitation and ceiling of care status and consistent recording of this. Following the intervention there was seen an improvement in the recording of decisions around treatment and transfer of patients on the dementia ward of 80% (4/5) fully compliant with new criteria and then 71% (5/7) in successive cycles. Further communication both with relevant professionals on the old age ward and with the trainees on the on-call rota will be necessary to sustain any change but the centralised recording of resuscitation status and ceiling of care in the ward round entries have provided much more guidance than was previously available. In the future it may be possible to spread this policy throughout the entire old age mental health unit. PMID- 26734378 TI - Improving early recognition of delirium using SQiD (Single Question to identify Delirium): a hospital based quality improvement project. AB - Delirium is a serious condition associated with poor outcomes which can be prevented and treated if recognised early. Older people and people with dementia or severe illness are more at risk of delirium. SQiD is a simple prompt question which asks, "Is this patient more confused than before?" Focusing specifically on patients aged 75 and over, this project aimed to increase awareness and usage of SQiD to help improve early recognition of delirium, in accordance with the Healthcare Improvement Scotland national initiative. This project was carried out by two student nurses during an eight week clinical placement in the acute surgical receiving unit (ASRU) of Ninewells Hospital, Dundee, Scotland. Qualitative and quantitative methodology was used to establish baseline data which revealed that only 35% of the multidisciplinary team (MDT) were aware of SQiD, with only 15% using SQiD. Initial activities involved raising awareness of SQiD by means of information cards and posters. Once awareness was raised, the usage of the SQiD question by nurses was tested. Finally, the SQiD question was incorporated into the nursing care round forms and usage recorded. Following these awareness raising activities we noted an increase of 83% awareness and 20% use of SQiD. Incorporating the SQiD question into the hourly care round forms increased awareness to 100% and usage to 50%. Although this small scale project could be viewed as a success, the requirements for sustainability depend upon further implementation and spreading of the change. Sustained improvement is also dependent upon the implementation of the care rounds. As nursing students, undertaking this improvement project has provided valuable lessons in both quality improvement science and personal learning. The improved knowledge and understanding of effective communication and the intricacies of team working is transferrable and can be applied to future nursing practice. PMID- 26734379 TI - Introduction of a Venous Thromboembolism Prophylaxis Protocol for Older Adult Psychiatric Patients. AB - Hospital-Acquired venous thromboembolism (VTE) is a common cause of morbidity and mortality in older adults. In psychiatric patients these risks are increased due to multiple factors including poor mobility, restraint, catatonia, sedation, and conventional antipsychotic use. Diagnosis and treatment of psychiatric patients presenting with signs and symptoms of a VTE can be delayed due to a patient's communication difficulties, non-compliance, or attribution of symptoms to a psychosomatic cause. However, despite the increased risk, approved VTE prophylaxis protocols are infrequently used on Psychiatric wards. On one Older Adult Psychiatric Ward, two patients presented with VTE (a fatal pulmonary embolism and a symptomatic deep vein thrombosis) over a 6 month period demonstrating the necessity for prophylactic assessment. A baseline audit over 3 months showed that 63-83% of patients on the ward had received no assessment of VTE risk, on any given week, although this improved slightly following the critical incidents. A VTE prophylaxis protocol, based on NICE guidance for VTE risk assessment in Medical and Surgical patients, was developed with consideration given to additional Psychiatric risk factors. This took the form of a pro-forma with a tick-box design that included mobility assessment, VTE risk factors, bleeding risk factors, and guidance on prescribing decisions. This was implemented on an Older Adult Psychiatric ward and prophylaxis was provided to those meeting the threshold. Weekly audit of all pro-formas (including assessments completed within 48 hours of admission and prophylaxis prescription) was conducted after the pro-forma introduction from 1st February 2013 to 24th May 2013. Frequency of assessments increased after protocol implementation with between 36% and 85% of all patients being assessed for VTE risk post intervention. Fluctuations in numbers assessed may have related to ward pressures, staff changes, and practicalities of pro-forma use. After completion of the PDSA cycles the initiative was handed over to a specialist registrar for implementation across the other trust Older Adult Psychiatry wards, and further audit was planned to be conducted via junior doctors and established Quality Assurance systems. Discussion of integration of a condensed pro-forma into the trust electronic notes system is ongoing. PMID- 26734380 TI - Out of hours intravenous fluid therapy: a prompt to guide prescribing. AB - Recent NICE guidance has highlighted the importance of appropriate and safe intravenous fluid use. We aimed to improve the quality of out of hours fluid prescription in a Bristol hospital by ensuring that indications and cautions for fluid therapy were clearly documented at the time of initiation. Time-pressured on-call doctors need quick access to information regarding patients' care. A documented "fluid plan" allows doctors to undertake a more informed assessment of the patient's fluid balance, leading to safer prescriptions. Our ideal was for 100% of out of hours intravenous fluid prescriptions to be appropriate. Our process measures included the proportion of patients on intravenous fluids who had a documented fluid plan in the medical notes or on the prescription chart on Friday, prior to the weekend on call period. This was defined as mention of indications and/or cautions to fluid therapy. The introduction of a sticker to prompt fluid plan documentation did marginally improve use of fluid plans. It was notable that 96% of these were followed where plans were documented (n=23). Initiation of IV fluid with an accompanying plan is likely to make subsequent fluid prescriptions safer. Rapid turnover of staff and stationary proved significant barriers to consistent implementation of the sticker. Despite these challenges we demonstrated a "proof of concept", suggesting system modification to include fluid plans is safe and effective. PMID- 26734381 TI - Preconception counselling resource for women with diabetes. AB - Women with diabetes need to plan for pregnancy if they are to reduce their risk of poor pregnancy outcome. While care providers have focused on setting up specialist pre-pregnancy planning clinics to help women prepare for pregnancy, the majority of women do not attend, entering pregnancy unprepared. A major barrier to accessing this care, and a consequence of poor preconception counselling, is a lack of knowledge as to the need to plan and the reasons why. This project addressed an urgent need to raise awareness of the importance of planning for pregnancy among women with diabetes and among the healthcare professionals (HCPs) caring for them. Focus groups with the target groups informed the development of a preconception counselling resource for women with diabetes. Originally produced as a DVD (Diabetes UK funding), this resource has been embedded in routine care in Northern Ireland (NI) since 2010. A subsequent service evaluation of pregnancy planning indicators undertaken across all five antenatal-metabolic clinics in NI indicated that women who viewed the resource were better prepared for pregnancy. In order to increase the positive impact of the resource and to ensure longer term sustainability the DVD was converted to a website, http://www.womenwithdiabetes.net (Public Health Agency NI funding). The evaluation also highlighted that women with type 2 diabetes were a hard to reach group. As these women are often cared for outside of specialist clinics, it is pertinent that all HCPs caring for women with diabetes are aware of the importance of preconception counselling. Funding also supported the development of an e-learning continuing professional development (CPD) resource within the website. The e-learning resource has since been embedded into existing CPD programmes and is an important tool to ensure that all HCPs caring for women with diabetes are empowered to provide preconception counselling at every opportunity. PMID- 26734382 TI - Improving paediatric prescribing practice in a district general hospital through implementation of a quality improvement programme. AB - Prescribing errors are a well recognised cause of adverse incidents and have a direct effect on patients.[1] This impacts on the doctor-family relationship and results in breakdown of trust and communication.[2] This quality improvement project was carried out in the paediatric ward of a district general hospital in Northern Ireland. A retrospective analysis of paediatric prescribing errors between January and December 2013 identified two errors that were felt to be secondary to under-reporting. A baseline audit was subsequently performed that highlighted 32 errors across 12 drug charts. A driver diagram identified three components contributing to prescribing errors and relevant tests of change were developed. The three primary drivers included: education and communication, practical prescribing changes, and medicine reconciliation. Seven interventions were implemented sequentially over a six month period and their effectiveness assessed by a prospective drug chart audit. Ten drug charts were selected at random by the staff nurse allocated to medications on the day of audit. The charts were audited using a predesigned proforma and the total number of errors counted. These were subcategorised and results displayed in graphical format after each intervention. Seven audit cycles were completed in total after each intervention was put into practice. The number of errors (including percentage change following each intervention) is as follows: intervention 1: 32 (+19%); Intervention 2: 31 (+15%); Intervention 3: 17 (-37%); Intervention 4: 12 (-56%); Intervention 5: 15 (-44%); Intervention 6: 7 (-74%); Intervention 7: 10 (-63%). In conclusion, permanent and successful measures are needed to reduce prescribing errors in order to minimise the impact of staff changeover and knowledge deficits. PMID- 26734383 TI - Evaluation of an evidence based quality improvement innovation for patients with musculoskeletal low back pain in an accident and emergency setting. AB - We conducted a five stage pilot study which initially consisted of a review of 75 case notes of people attending an emergency department (ED) in an inner London Teaching Hospital with musculoskeletal (MSK) low back pain (LBP). This review highlighted inconsistencies in how they were assessed and managed across and within different staff groups. We found patient documentation was often incomplete and that a biomedical model approach to the management of these patients was common. As a result, four further stages in the project were conducted. Our primary aim was to evaluate the impact of implementing a locally developed quality improvement intervention for the assessment and treatment of MSK LBP in this ED. Secondary aims were to explore the user experience of the new pathway, measured by the patient experience questionnaire (PEQ), and any associated health economic costs of changes in practice. The quality improvement intervention consisted of an evidence based low back pain pathway (EBLBPP), a staff educational program, and a patient education booklet. We undertook a retrospective baseline audit of 100 clinical records of patients was undertaken prior to the instigation of the quality improvement intervention, and four months post implementation. The pre-defined variables of interest were: documentation of the case history, examination, classification of back pain (and if correct), prescribed management and if the documentation was compliant with medico-legal standards. All patients in the study were sent a PEQ to complete and return in a self-addressed envelope. Estimated health costs associated with each patient episode of care were calculated including re-attendance episodes for any people presenting with MSK LBP within a four week period. There was a significant improvement in all areas evaluated post implementation in all groups (simple, referred and simple, referred and serious spinal pathology combined). In particular; screening for red flags (22%) and biopsychosocial factors (29%), as well as noting the prevalence of previous symptoms (44%), observation of the painful area (57%), and analysis classification (59%) at a at 95% confidence interval (CI). In terms of management, an increase in adherence to the analgesic ladder, patients receiving reassurance and appropriate referral back to their GP's increased 45%, 23% and 44% at 95% CI respectively. Unfortunately, there was insufficient data to draw any meaningful conclusions from the patient experience data due to a low response rate. In conclusion, the introduction of the EBLBPP, patient education leaflet and teaching training for staff involved in the treatment of MSK LBP patients has improved the quality and consistency of the documented assessment and subsequent management of MSK LBP patients. PMID- 26734384 TI - Improving VTE risk assessment at point of admission to a tertiary centre cardiology ward. AB - Cardiology wards are generally high turnover units, which may receive primary PCI, high-risk NSTEMI patients, and other general cardiac admissions from a large geographical area. Many centres also provide national specialist services for rarer cardiac conditions for which admissions may be lengthy. Cardiac patients have significant risk factors for venous thromboembolism (VTE) as immobility may be due to systolic dysfunction, attachment to continuous monitoring and predisposition to chest pain, or cardiac syncope. It is recommended by NICE that an initial VTE risk assessment is undertaken at the time of patient admission, with reassessment within 24 hours. For this purpose a risk assessment tool is featured on the front of many Trust drug charts. It is noted that this risk assessment is electronic in other trusts. We undertook an audit into the drug chart documentation of VTE risk assessment on the cardiology ward and the Coronary Care Unit (CCU) at The Royal Free Hospital. It was evident that documentation of VTE risk assessment was poor. The audit interventions were; a teaching presentation to the cardiology department, an educational poster, several update emails to the department and the identification of a 'VTE risk assessment champion' to audit ongoing compliance. Following these measures the second audit round demonstrated that documentation of initial risk assessment was slightly improved, but significant improvement was seen in documentation of risk assessment at 24 hours post admission. Results from a third audit cycle indicated that the improvement in initial VTE risk assessment was sustained, and that there was a significant sustained improvement in risk assessment at 24 hours (p <0.05). Recommendations for sustained improvement included: redesigning the drug chart so that the VTE risk assessment tool was linked to the VTE prophylaxis prescription box, and designating the responsibility of the initial VTE risk assessment to the on call junior doctor who receives admissions on to the ward. PMID- 26734385 TI - Improving medical handover at the weekend: a quality improvement project. AB - In recent years medical handover has been identified as an increasingly important area for hospitals to improve upon, in light of the changes in shift patterns for doctors. Significant changes to weekday handover had recently been successfully introduced at Broomfield hospital. Weekend handover remained a concern, with an electronic and paper system being used simultaneously. Our objectives were to introduce a new electronic handover system for weekend handover at Broomfield Hospital and improve the organisation of the weekend handover meeting to promote patient safety. Doctors involved in weekend handover were surveyed using a questionnaire, to establish insufficiencies in the weekend handover process; where both the electronic ExtraMed system and paper were being used inconsistently. A new weekend handover system was introduced together with a new user-friendly electronic handover database, addressing the identified difficulties in the current system. These changes met the medical handover guidelines set by the Royal College of Physicians. Three months after the launch of the new system, doctors were re-surveyed using a modified questionnaire to assess the impact our changes had made. Before changes were implemented only 12% of doctors surveyed used the electronic system for weekend. Eighty-nine percent found sorting through jobs time consuming and 67% were handed jobs to them meant for a different grade of doctor. Only 41% were aware who to hand weekend discharges to. Subjective assessment of safety was 3.18 out of 5. The electronic system was felt to be time consuming and complicated. After execution of the new weekend handover process, 100% of doctors reported using the electronic system for weekend handover. Only 47% of doctors felt sorting through jobs was time consuming and 89% of doctors were aware who to handover weekend discharges to. Subjective assessment of the safety of weekend handover improved to 3.84 out of 5. Informal interviews on the ward revealed a high degree of satisfaction with the new weekend handover system. In conclusion we found that a structured, well organised weekend handover meeting together with an effective electronic handover system improves the quality of medical weekend handover. PMID- 26734386 TI - Going for growth: improvement in the infrastructural and management support for clinical academic research. AB - Our objective was to implement a directorate research strategy to improve and grow clinical academic capacity and capability and ensure that the organisational systems and processes enabled clinical staff and managers to increase grant capture, undertake clinically relevant research, including the adoption of NIHR portfolio sites and established a culture in which research was an accepted part of professional practice. An initial evaluation of senior and middle manager attitudes and understanding of the research infrastructure and benefits of research identified that the directorate had a deeply segmented view of research and only a partial view of how research could benefit patients and improve their services. A significant number of staff claimed to be research active but this activity was not contributing to the service knowledge or being translated into grant capture, leading to income that could be used to invest in patient facing research. Few managers had appreciated the challenge of implementing the research strategy or the potential of enabling research active staff to generate clinical academic careers. A quality improvement methodology was adopted, based on four equally important elements [1]; involving people (staff and patients) in research, developing people's research knowledge and skills, promoting an understanding of the complex systems and processes associated with research, and using an organisational research strategy with leadership to drive change. This improvement method suggests an equal and proportional range of activity to engage staff, amend and adapt processes and systems, carry out organisational change and "make it a habit". The improvement measures were selected by a number of managers who acted as "research champions" and shared these with all staff across the directorate; the focus was on delivering sustained improvements in performance targets agreed with the organisation. The interventions were introduced to assist managers in each professional group to champion research and undertake the organisational change that would be needed. The two cycles of improvement over 14 months were used to achieve "academic status" within the organisation, to include clinical staff in the delivery of the research strategy and to create a clinical academic infrastructure that incorporated a well organised public and patient involvement (PPI) panel. Additional measures included the level of participation of clinical academic staff in grant capture and the level of income from research to sustain the growth in activity. PMID- 26734387 TI - Coaching for recovery: a quality improvement project in mental healthcare. AB - Approximately one in four adults in the UK will experience a mental health difficulty at some point in their life. This figure is approximately 400 million people worldwide.[1] Depression alone is currently estimated to cost the UK 1.7% of GDP and is one of the largest causes of ill health in the world.[2] For conditions like psychosis, evidence tells us that people have poorer quality of life outcomes, are more likely to die early, become obese, smoke, be unemployed, and have long term physical conditions than average.[3] People's social situation is also likely to be more complex, with housing needs, social isolation, stigma, and poverty.[4] All of these factors can make it hard for a person with a long term mental health condition, or those supporting them, to hold onto a sense of hope that positive change is possible or that "recovery" towards a life that holds optimum meaning to them is achievable. An innovative "pop up" Recovery College model was co-produced, delivered, and evaluated by a team of people with lived experience of mental health difficulties, known as peer trainers. The Recovery College offered courses containing the best evidence-based knowledge about recovery in mental health, self-care and self-management. Each learning session included theory, personal testament from peer trainers, and volunteers and demonstrations of practical self-care skills and techniques. The courses were open to people experiencing mental health difficulties, their families, friends, and professionals. After the college course finished each student was offered up to three individual coaching sessions to help support putting the lessons learnt from the college into practice. The project aimed to test whether this innovative educational and coaching model could offer hope, knowledge and practical skills in self-management to support resilience and recovery. The project was underpinned by quality improvement methodologies to develop, deliver, and refine the model. PMID- 26734388 TI - Improving Detection of IV Infiltrates in Neonates. AB - Neonates and infants in the neonatal intensive care unit suffer significant morbidity when intravenous (IV) catheters infiltrate. The underreporting of adverse events through hospital voluntary reporting systems, such as ours, can complicate the monitoring of low incidence events, like IV infiltrates. Based on severe cases of IV infiltrates observed in our neonatal intensive care unit, we attempted to improve the detection of all infiltrates and reduce the incidence of Stage 4 infiltrates. We developed, and initiated the use of, an evidence-based guideline for the improved surveillance, prevention, and management of IV infiltrates, with corresponding educational interventions for faculty and staff. We instituted the use of a checklist for compliance with guidelines, and as a mechanism of surveillance. The baseline incidence rate of IV infiltrates, determined by the voluntary reporting system, was 5 per 1000 line days. Following initiation of the guidelines and checklist, the IV infiltrate rate increased to 9 per 1000 line days. In most months, the detection of IV infiltrates was improved by use of the checklist. During the post-intervention period the rate of Stage 4 infiltrates, as measured by usage of nitroglycerin ointment, was significantly reduced. In conclusion, the detection of IV infiltrates was improved following our quality improvement interventions. Further, use of an evidence-based guideline for managing infiltrates may reduce the most severe infiltrate injuries. PMID- 26734389 TI - Hypoglycaemia monitoring in a medical receiving ward. AB - It has been suggested that current care for diabetes inpatients remains inadequate and that greater attention is required for high quality management. In this project the aspect of hypoglycaemia was studied in a busy medical receiving ward at the Glasgow Royal Infirmary. A large proportion of inpatients have diabetes and episodes of hypoglycaemia experienced by this population can delay discharge and indeed be detrimental to health. Thus it is important from both an organisational and patient perspective to manage this population well. In this project BM machine data was analysed to identify patients who were hypoglycaemic. These patients were then tracked down to study the subsequent management and compared this against recommended guidance. Following this an intervention was made to promote identification, management, documentation, and prevention of hypoglycaemia. This was deliberately a simple intervention involving discussions with staff and provision of basic documented guidance next to every BM machine. In the first phase 17 patients were identified and in a second and third phase 16 patients each time were further identified. Patients in the study were both type 1 and type 2 diabetics. Initial results in phase I were compared to results in phase II and III respectively. This intervention produced significant improvements in management with correct monitoring of low BMs (i.e. upon identification of low BM repeat within 1 hour) improving from 47% to 100% (for Phase II and III). Also, recording of preventative measures of hypoglycaemia improved from 35% to 88% and 94% with an improvement from 24% to 69% and 75% in recording of treatment given if needed. In conclusion, the study successfully demonstrated that simple measures can significantly improve the quality care of inpatient diabetic patients in relation to hypoglycaemia management. PMID- 26734390 TI - A multifaceted approach to prevention of delirium on intensive care. AB - Delirium is a frequent complication of critical illness with an increased risk of death which is difficult to treat effectively. We describe a seven year quality improvement programme that aimed to reduce rates of delirium on intensive care (ICU). We completed two PDSA programmes with a number of changes including alterations to sedation practice and environmental changes to the ICU itself. Rates of delirium reduced from 70% to 44% after the first cycle of change. Rates of delirium were further reduced to 29% after the second cycle of change. The rates are now lower than predicted by the validated prediction tool PRE-DELIRIC. This project demonstrates that a multifaceted approach to prevention of delirium on ICU can deliver sustained reductions in rates of delirium. The impact of the second cycle of change was less than the first, suggesting that further reductions may prove more challenging. PMID- 26734391 TI - Mind the gap: Improving discharge communication between secondary and primary care. AB - Foundation year doctors (FYDs) write most hospital discharge communication, although they have minimal training in this skill. Poor quality discharge summaries increase the risk of adverse events and rehospitalisation. With a multidisciplinary team approach, we developed a list of "golden rules" for good discharge communication. Against these standards, we analysed the quality of electronic inpatient discharge documentation (eIDD) sent over two months from OUH Trust. We found one third of eIDDs were missing details of the discharging doctor. In 68%, changes to medications were not documented clearly and follow-up was not completed in 40%. To improve this suboptimal state, we implemented interactive teaching sessions for FYDs, designed an e-learning module, and suggested software changes to the current electronic discharge proforma. Early re audit one month after the first teaching sessions did not demonstrate any significant improvement. However, re-auditing after twelve months is planned. Through data collection and discussion with key stakeholders, we have identified standards for discharge communication. We developed interventions to help the trust achieve these standards, aiming to enhance patient safety in the peri discharge period. While discharge communication is delegated to less-experienced team members, they should receive clear guidance and training. PMID- 26734392 TI - Improving the availability of intra-operative images created during trauma operations - a multidisciplinary team collaboration. AB - Intraoperative x rays are regularly taken on multiple occasions during orthopaedic surgery, especially during the course of planned trauma lists where procedures are performed under x ray guidance. These images have an important role in demonstrating the nature of the operation to clinical staff and in permitting an assessment of the standard of surgery by colleagues at planned metalwork reviews. Furthermore, they represent an important medico-legal record of the fracture configuration at the time of completion of surgery. Various technologies are available for the creation, storage, and presentation of such images. In our hospital, relatively unsophisticated technology is employed to physically print such x rays before they are digitally uploaded to an electronic computer system to be stored. This system also allows the images to be viewed. Unfortunately, many opportunities existed within our systems which created opportunities for images to be lost so that they were not made available to clinical staff. We aimed to evaluate and improve this system with the aim of making all x rays taken intraoperatively available to clinical staff in a timely manner. By examining the processes through which images were handled, we were able to adopt strategies to ensure the prompt production of images. PMID- 26734393 TI - Optimising the Pre-Operative Investigative Work Up for Elective Surgical Patients. AB - Effective pre-operative assessment of patients awaiting elective surgery should entail appropriate use of scarce NHS resources, as well as underpin patient safety. The pre-operative admissions service in district general hospitals is often junior doctor led, with a new cohort of clinicians taking over its running every four months. Lack of familiarity on the part of these clinicians with the investigative work up required for certain surgical procedures often results in over investigation of patients in the pre-admission setting, wasting time and NHS resources. A retrospective audit of 53 patients who underwent laparoscopic cholecystectomy over a representative two month period demonstrated that 33% of patients received unnecessary pre-admission blood tests, including clotting screen and 'group and save'. Design and implementation of a "Pre-Admission Handbook", for use by junior doctors and nurse practitioners in the pre-operative setting, reduced the rate of over investigation to 12% in a subsequent, prospective audit cycle of 50 patients, and has improved patient care by standardising the pre-admissions process for elective surgery at Gloucester Royal Hospital. PMID- 26734394 TI - Improving the documentation of nasogastric tube insertion and adherence to local enteral nutrition guidelines. AB - Fine bore nasogastric (NG) tubes are often required for patients who have insufficient nutrition to meet their daily requirements, as well as for feeding or medications when there are difficulties with swallowing. "Death or severe harm as a result of a naso [...] gastric tubes being misplaced in the respiratory tract" is one of the Department of Health's list of "never events". Noble's Hospital, Isle of Man, has local guidelines based on the National Patient Safety Agency's 2005 guidelines and 2011 update, regarding the initial insertion and confirmation of placement of NG tubes. Retrospective baseline data looking at 13 case notes across 10 hospital wards showed that the majority of NG tube insertions took place on the stroke unit. A three-point quality of guidelines score showed that 8/13 (62%) cases were following guidelines appropriately. A seven-point quality of documentation score showed no case notes had full documentation. A teaching intervention for junior doctors and nurses was devised. However, there was no significant improvement in quality scores after 90 days (49 NG tube insertions). Therefore, an NG tube bundle, which included a pro forma for the case notes, information poster, and sticker for the nurse notes, was trialled on the stroke unit for six weeks. This showed that 10/12 (83%) cases were following guidelines appropriately. While only 2/12 (16%) of case notes had full documentation, this represented the two occasions when the pro forma was filled in and filed correctly. It is hoped that there could be a roll out of the intervention hospital-wide with identification of ways to improve usage of the NG tube bundle. PMID- 26734395 TI - Improving access to clinical guidance: redevelopment of a junior doctor intranet page. AB - Junior doctors frequently rely on electronic access to clinical guidelines to inform assessment and management, particularly whilst on-call and occasionally during emergencies. Difficulties in locating and accessing up to date guidance from different hospital intranet sites can lead to delays or errors in patient management. We used a focus group and email feedback to redesign an intranet site for junior doctors which logically organised the documents which doctors said they needed access to in one readily accessible location. A quality improvement project was carried out over six months, testing two iterations of the new junior doctors' intranet site before a third version was launched and evaluated. Their performance was measured by the number of mouse clicks and the time required for doctors to find a representative subset of five guidelines, and revisions were made at each cycle based on feedback from doctors and stakeholders. Cumulatively, we demonstrated a decrease in the total number of clicks required to access the sample of guidelines from 18 to 12 clicks, a corresponding decrease in the time required to access the sample of guidelines from 130 seconds to 22 seconds, and an increase in user satisfaction. We maintained one-click access to emergency guidance. In conclusion, we have developed and implemented an electronic resource for junior doctors which provides more immediate access to both emergency and non emergency clinical guidance. To ensure the resource remains up to date, it will be maintained by Foundation Programme representatives at our hospital on a rolling basis. PMID- 26734396 TI - Improving the provision of driving advice on discharge after abdominal surgery. AB - Ensuring the safety of patients is a vital duty of a doctor. It is their responsibility to advise patients about activity limitations on discharge from hospital. This study aims to assess the current provision of driving advice for patients after abdominal surgery and institute improvements to this provision of information in North Bristol NHS Trust. A preliminary questionnaire ascertained current doctor's knowledge regarding limitations of driving postoperatively and whether information was communicated to patients. Baseline retrospective data were collected from electronic discharge summaries to determine documentation of advice provision. Educational interventions were introduced, followed by data collection after each intervention. Initial questionnaires demonstrated poor knowledge amongst doctors and a lack of provision of driving advice postoperatively. After multiple educational interventions, the provision of driving advice on electronic discharge summaries increased from 0% (0) at baseline to 75% (9). Initially, the provision of driving advice postoperatively was poorly documented for inpatients undergoing abdominal surgery; following multiple educational interventions, the provision of written advice improved. Future plans include the introduction of prewritten sentences onto the electronic discharge summaries to facilitate ease of information provision and a reaudit in 12 months. PMID- 26734397 TI - "Speeding up the road to recovery": The Complex Recovery Assessment and Consultation (CRAC) service. AB - The number of bed closures in mental health is on the rise, creating additional pressure on services, including acute mental health services. An efficient way of working is required in order to streamline the acute care pathway and decrease unnecessary delays to length of stay, ensuring all individuals can be offered an inpatient bed when in crisis. The Complex Recovery Assessment and Consultation (CRAC) service was created in order to support acute mental health inpatient clinicians in streamlining hospital stays for service users who present with complex presentations that require lengthier admissions (over 40 days) by offering assessment, advice, and intervention from a rehabilitation perspective. The team was also created to understand why individuals may require a lengthy hospital stay. Preliminary data showed that requiring a placement on discharge proved to be the most significant factor in increased length of stay and so the team took on a new role of discharge coordinator after around a year of operating. This involved assisting in decreasing any delays out of hospital through improved communication and dedicated time to complete tasks, such as completing paperwork for placement referrals and funding panels. Since taking on this role it was found that the time taken for individuals to be discharged to a rehabilitation or specialist placement decreased; a rehabilitation placement by 13.12 days and a specialist placement by 9.22 days. Discharge to a family address also decreased by 2.9 days and a home address by 2.47 days. Those patients with complex presentations benefit from having one dedicated team to coordinate the discharge process. Their lengthier acute inpatient stay is improved through streamlining care pathways, ultimately decreasing delays in discharge. PMID- 26734398 TI - Are we meeting current standards in medicines reconciliation? A study in a District General Hospital. AB - INTRODUCTION: Inadequate medicines reconciliation on admission is often identified as a major cause of patient morbidity, with poor access to patient's regular medications often cited as a barrier to care. In the surgical admission unit of our district general hospital, drug charts are completed by junior doctors who do not have access to the Emergency Care Summary (ECS) thus making it difficult to accurately complete admission drug charts. METHODS: Our initial measurement of all acute surgical admissions revealed that 49% of patients had an accurate medicines reconciliation upon admission, increasing to 75% within 24 hours of admission. It was clear from this data that our current practice needed improvement in order to ensure patient safety. Resultantly the junior medical staff were provided with ECS accounts and teaching to aid the process of medicines reconciliation. RESULTS: Following the introduction of access to ECS and junior doctor education, a further two data cycles were completed. On the first cycle, the number of accurately completed drug charts increased to 62% on admission and 86% at 24 hours. After the second cycle 57% were complete on admission increasing to 84% at 24 hours. CONCLUSION: Our project has shown that by providing junior doctors with medicines reconciliation education and access to patients' pre-admission medications through a nationwide electronic system resulted in a considerable increase in the completion of medicine reconciliation. PMID- 26734399 TI - Improving venous thromboembolism risk assessment compliance using the electronic tool in admitted medical patients. AB - Sheikh Khalifa Medical City (SKMC) in Abu Dhabi is the main tertiary care referral hospital in the United Arab Emirates (UAE) with 560 bed capacity that is fully occupied most of the time. SKMC senior management has made a commitment to make quality and patient safety a top priority. Venous thromboembolism (VTE) risk assessment has been identified as a critical patient safety measure and key performance indicator. The electronic VTE risk assessment form a computerized decision support tool was introduced to improve adherence with deep venous thrombosis (DVT) prophylaxis recommendations. A multidisciplinary task force team was formed and led this quality improvement project. The purpose of this publication is to indicate the quality improvement interventions implemented to enhance compliance with VTE risk assessment and the outcomes of those interventions. We chose to conduct the pilot study in General Medicine as it is the busiest department in the hospital. The study period was from April 2014 till August 2015.The lessons learned were disseminated throughout the hospital. Our aim was to improve VTE risk assessment compliance by using the electronic form in order to ensure patient safety and reduce preventable harm. VTE risk assessment compliance improved in general medicine from 4% to 98%, and overall SKMC compliance from 21% to above 90%. PMID- 26734400 TI - Using a simple handover to improve the timing of gentamicin levels. AB - The aminoglycoside gentamicin is commonly used in many NHS trusts to cover gram negative organisms in intra-abdominal sepsis and sepsis of unknown origin. As a result it often forms an important part of thew "Sepsis 6" protocol on surgical wards. Despite it's effectiveness, the antibiotic is well known to have nephrotoxic and ototoxic side effects, making monitoring of serum levels vital. In Hairmyres Hospital, a busy district general hospital in Lanarkshire, levels are typically taken at six to 14 hour post-dose intervals, with the result guiding further gentamicin dosing. A baseline measurement was performed highlighting that 42.2% of these levels were taken after the 14 hour limit. This was thought to have serious implications for patient's, as levels designed to protect them from side effects whilst maintain g an effective antimicrobial action were not being performed properly. As a result, a "gentamicin handover" was introduced to the wards in order to ease the workload on junior staff and improve handover between teams. During our short project the number of late levels initially dropped to 33.3% after one week, falling further to 28.6% following the second week of intervention. From our results it is clear that while more intervention is required gentamicin prescription, this project highlights how a simple intervention to improve ward handover can create a very noticeable improvement in the quality of patient care within a small time period. PMID- 26734401 TI - "SHOUT" to improve the quality of care delivered to patients with acute kidney injury at Great Western Hospital. AB - Acute kidney injury (AKI) affects up to 20% of all patients admitted to hospital, and is associated with a higher risk of adverse clinical outcomes, increased healthcare costs, as well as long term risks of chronic kidney disease and end stage renal failure. The aim of this project was to improve the quality of care for patients with AKI admitted to the acute medical unit (AMU) at the Great Western Hospital (GWH). We assessed awareness and self reported confidence among physicians in our Trust, in addition to basic aspects of care relevant to AKI on our AMU. A multifaceted quality improvement strategy was developed, which included measures to improve awareness such as a Trust wide AKI awareness day, and reconfiguring the admission proforma on our AMU in order to enhance risk assessment, staging, and early response to AKI. Ancillary measures such as the dissemination of flashcards for lanyards containing core information were also used. Follow up assessments showed that foundation year one (FY1) doctors' self reported confidence in managing AKI increased from 2.8 to 4.2, as measured on a five point Likert scale (P=0.0003). AKI risk assessment increased from 13% to 57% (P=0.07) following a change in the admission proforma. Documentation of the diagnosis of AKI increased from 66% to 95% (P=0.038) among flagged patients. Documentation of urine dip results increased from 33% to 73% (P=0.01), in addition to a rise in appropriate referral for specialist input, although this was not statistically significant. Our results suggest that using the twin approaches of improving awareness, and small changes to systemic factors such as modification of the admission proforma, can lead to significant enhancements in the quality of care of patients with AKI. PMID- 26734402 TI - Nurse led venesection: a quality improvement project. AB - Venesection is a widely practised procedure, involving the removal of a unit of blood in order to treat haemochromatosis and polycythaemia. It is still well regarded due to a lack of better alternatives and a small side effect profile. At Barnet General Hospital, venesection has recently been a physician led service, unlike its neighbouring hospital at Chase Farm Hospital, which has a well run nurse led service. The current service being run at Barnet Hospital was beset with problems, including delays in service provision and discharge, using junior doctors who may not be comfortable with or have knowledge of pre and post procedure checks. Furthermore, the medical day treatment unit is comprised of highly skilled nurses. 100% of nursing staff felt comfortable gaining venous access, but none had any formal training. Following a practical tutorial, followed by formal teaching, the nurses now run the venesection service. This has been done at no cost to the hospital, has sped up discharges and this has subsequently led to the capacity of the unit to venesect patients to increase by 100%. PMID- 26734403 TI - Improving the management of sepsis in a district general hospital by implementing the 'Sepsis Six' recommendations. AB - Sepsis is a common condition with a major global impact on healthcare resources and expenditure. The Surviving Sepsis Campaign has been vigorous in promoting internationally recognised pathways to improve the management of septic patients and decrease mortality. However, translating recommendations into practice is a challenging and complex task that requires a multi-faceted approach with sustained engagement from local stakeholders. Whilst working at a district general hospital in New Zealand, we were concerned by the seemingly inconsistent management of septic patients, often leading to long delays in the initiation of life-saving measures such as antibiotic, fluid, and oxygen administration. In our hospital there were no clear systems, protocols or guidelines in place for identifying and managing septic patients. We therefore launched the Sepsis Six resuscitation bundle of care in our hospital in an attempt to raise awareness amongst staff and improve the management of septic patients. We introduced a number of simple low-cost interventions that included educational sessions for junior doctors and nursing staff, as well as posters and modifications to phlebotomy trolleys that acted as visual reminders to implement the Sepsis Six bundle. Overall, we found there to a be a steady improvement in the delivery of the Sepsis Six bundle in septic patients with 63% of patients receiving appropriate care within one hour, compared to 29% prior to our interventions. However this did not translate to an improvement in patient mortality. This project forms part of an on going process to instigate a fundamental culture change among local healthcare professionals regarding the management of sepsis. Whilst we have demonstrated improved implementation of the Sepsis Six bundle, the key challenge remains to ensure that momentum of this project continues and forms a platform for sustainable clinical improvement in the long term. PMID- 26734404 TI - A simple prioritisation system to improve the electronic handover. AB - The General Medical Council (GMC) states, "A well managed, thorough and organized handover is crucial for ensuring the quality and safety for patient care," and in their guidance on safe handover the British Medical Association (BMA) advised that "clinically unstable patients are known to the senior and covering clinicians; tasks should be prioritised; plans for further care are put in place; unstable patients are reviewed." The orthopaedic department at King's College Hospital, a busy major trauma centre in London, UK, has a significantly reduced workforce during the weekend. The general consensus was that the ward round was taking too long, giving the foundation year one (FY1) doctor very little time to commit to other ward jobs and reviewing unstable patients, making it a stressful and challenging environment. The electronic patient record (EPR), an electronic programme available on all Trust computers, is already a very reliable way to allow safe handover of information via a central electronic database. However it has limitations in clearly prioritising more unstable patients from those needing routine review. We created an easily identifiable traffic light coding system that could be simply incorporated into the electronic handover that was re reviewed and finalised in order to improve the ability to prioritise patients for senior review. This in turn would directly impact the efficiency of the ward round and improve patient safety. Our immediate results demonstrated the efficiency of the ward round improved in all parameters: time to complete the ward round improved from 7.1% to 50%; prioritisation and ability to highlight the clinical urgency for patient review improved from 15.4% to 100%; and more notably, the clinician's impression of patient safety improved from 38.5% to 100%. Overall the introduction of an uncomplicated traffic light system provided an effective addition to the electronic handover structure aimed to allow patient prioritisation and improved efficiency during weekend hours. PMID- 26734405 TI - Improving patient outcomes with technology and social media in paediatric diabetes. AB - The UK has the highest number of children and young people with diagnosed Type 1 diabetes mellitus (T1DM) in Europe, but the lowest numbers attaining good diabetes control (1, 2). Novel strategies and incorporation of digital strategies were identified in the team for development to improve overall patient care and outcomes in our population of children and young people with T1DM. Within a dual site integrated care organisation, 3 digital initiatives were proposed from 2012 2013 to 1) establish Facebook communications with parents/patients, 2) to implement an electronic diabetes information management system (using Twinkle.Net) and 3) to undertake routine uploading of blood glucose meters and insulin pumps (using DIASEND(r)) with the aim to improve outcomes in paediatric diabetes care. Key objectives for the three initiatives were aimed to optimise the following outcomes: * Reduce HbA1c levels * Decrease emergency admissions, reduce diabetes-related complications and minimise the length of hospital stays * Improve patient satisfaction and communication * Improve efficiencies with mandatory audit submissions * Empower patients, parents, and the multidisciplicnary team with accurate, real-time information. These digital initiatives showed effective use of technology and social media in achieving significant improvements in all the outcomes within the objectives. PMID- 26734406 TI - Improving the acute care of COPD patients across Gloucestershire: a quality improvement project. AB - Admissions for exacerbations of chronic obstructive pulmonary disease (COPD) present a significant proportion of patients in the acute medical take. The British Thoracic Society (BTS) provides guidelines for time specific interventions, that should be delivered to those with an acute exacerbation of COPD through the admission care bundle. These include correct diagnosis, correct assessment of oxygenation, early administration of treatment, recognition of respiratory failure, and specialist review. Gloucestershire Hospitals NHS Foundation Trust (GHNHSFT) chose improvement in acute COPD care to be a local Commissioning for Quality and Innovation (CQUIN) scheme, which enables commissioners to reward excellence by linking a proportion of English healthcare providers' income to the achievement of local quality improvement goals. The effects of initiatives put in place by senior clinicians had waned, and further improvements were required to meet the CQUIN target. The aim of the scheme was to improve compliance with the BTS guidelines and CQUIN scheme for patients admitted with an exacerbation of COPD. Specific bundle paperwork to be used for all patients admitted to the Trust with an exacerbation of COPD was introduced to the Trust in June 2014, with training and education of medical staff at that time. This had improved compliance rates from 10% to 63% by September 2014. Compliance with each intervention was audited through the examination of notes of patients admitted with an exacerbation of COPD. Compliance rates had plateaued over the last three months, and so a focus group involving junior medical staff met in September 2014 to try to increase awareness further, in order to drive greater improvements in care, and meet the CQUIN requirements. Their strategies were implemented, and then compliance with the CQUIN requirements was reaudited as described above. The December 2014 audit results showed a further improvement in overall COPD care, with 73% of patients receiving all elements of the COPD admission care bundle, versus 63% in September 2014. Appropriate blood gas analysis, nebuliser administration, and respiratory review also improved. Prescription of steroids and antibiotics remained static, with 96% of patients receiving these treatments within four hours in the emergency department (ED). The only criteria which showed a decline was appropriate oxygen prescription, which dipped from 97% to 87%. After the effect of initial strategies plateaued, this quality improvement project facilitated a further increase in compliance with the CQUIN targets, both improving patient care, and safeguarding continued CQUIN funding. There is further work to be done to maintain and support further improvement in standards, and to encourage use of the COPD admission bundle paperwork for documentation purposes. PMID- 26734407 TI - How safe is our "place of safety"? Clinical guidance promoting safer medical care of patients detained under section 136 of the Mental Health Act. AB - A new four-bed unit was opened in Bristol, UK, in 2014, for people detained under section 136 of the Mental Health Act. Police bring individuals posing a risk to themselves or others to a Place of Safety (PoS) in order to receive a mental health assessment. Individuals may be held for up to 72 hours, but cannot receive treatment against their will, unless assessed as lacking the capacity to refuse treatment. Issues requiring medical input arose in more than a third of patients, yet there was little guidance for trainees around the PoS. We conducted a survey which confirmed that robust clinical guidance was needed for junior doctors around medical assistance in this unique environment. We identified specific concerns around patient safety in relation to alcohol withdrawal, uncertainties around legislation and lack of clarity of who to call out of hours. Trainees felt they were working outside of their expertise. We collaborated with a variety of professionals to produce clinical guidance in line with best evidence, and made this easily accessible. We also gained a consensus that more experienced core trainees (SHOs) in Psychiatry should be the first point of contact. We then conducted a survey in June 2015, and found that doctors covering the PoS now felt there was sufficient guidance on most clinical scenarios, 100% consensus on who to contact and improved confidence in their ability to manage issues arising. In August 2015 we held an informal training session for the new intake of trainees on the rota. A subsequent survey revealed similarly positive results. Through this project, we were able to identify defects in a system, provide needed guidance to enable safer and more equitable care to a vulnerable group, and foster closer collaboration between junior doctors and managers in the design and use of services. PMID- 26734408 TI - Improving the completion of Quality Improvement projects amongst psychiatry core trainees. AB - Quality Improvement (QI) projects are seen increasingly as more valuable and effective in developing services than traditional audit. However, the development of this methodology has been slower in the mental health field and QI projects are new to most psychiatrists. This project describes a way of engaging trainees across Avon and Wiltshire Mental Health Partnership (AWP) Trust and the Severn School of Psychiatry in QI projects, using QI methodology itself. Through the implementation and development of training sessions and simple, low cost and sustainable interventions over a 10 month period, two thirds of core trainees and over a half of the advanced psychiatry trainees in the School are now participating in 28 individual QI projects and QI project methodology is to become embedded in the core psychiatry training course. As an additional positive outcome, specialty doctors, consultants, foundation doctors, GP trainees, medical students, as well as the wider multidisciplinary team, have all become engaged in QI projects alongside trainees, working with service users and their families to identify problems to tackle and ideas to test. PMID- 26734409 TI - Improving reporting of critical incidents through education and involvement. AB - Critical incident reporting involves highlighting events and near-misses which have a potential impact on patient care and patient safety. Reporting of critical incidents is a recognised tool in improving patient safety. Within the community paediatric setting in the Belfast Health & Social Care Trust (BHSCT) there is a paucity of incident report forms. The purpose of this quality improvement project was to establish the barriers to reporting critical incidents and to implement plan-do-study-act (PDSA) cycles to create a climate for change. The methodology for this project was to firstly perform a baseline audit to review all submitted critical incident reports for the Community Paediatric team in the BHSCT for a six month period. A questionnaire was distributed to staff within the multidisciplinary team to establish examples of barriers to reporting. Interventions performed included introducing an agreed definition of a critical incident, distributing/presenting questionnaire findings to senior members of the various management teams and providing feedback to healthcare workers after presentation of a critical incident presentation. A review of incident reports was performed over the subsequent six month period to assess how the interventions impacted on incident reporting. Over 12 questionnaires 28 barriers to reporting critical incidents were reported which fell into five separate categories. Staff members were twice as likely to report negativity after reporting a critical incident. Overall critical incident reporting within the BHSCT Community Paediatric team improved from 11 incident reports (1.8 per month) to 22 incident reports (3.7 per month) after completion of the quality improvement project. This represents an increase of 100%. PMID- 26734410 TI - ImERSE (Improving Experience through Regular Shadowing Events). AB - Systematic operational quality improvement strategies within the NHS are hard to find, although there are numerous published reports of sporadic departmental models and methods resulting in improvements in clinical care. We describe the experience of devising a tool to provide large data collection of patient care experiences by using medical students to shadow patient journeys. This combines patient and family centred care (PFCC) and quality improvement approaches to create a systematic organisational strategy for improving care. The ImERSE (improving experience through regular shadowing events) approach could be applied to any area of health care to generate population specific improvement priorities. It can be used to promote patient and family centred care and provide a unique medical education experience. We describe its evolution in its first year of use and suggest that using the ImERSE approach delivers beneficial characteristics to patients and their families, those undergoing a shadowing experience, and provider organisations. PMID- 26734411 TI - Improving documentation of physical health investigations in an adolescent mental health inpatient unit. AB - Physical health investigations, such as blood tests, ECGs, and appropriate radiological tests, are essential in the assessment and management of many patients in inpatient mental health settings. This project took place in a 12-bed adolescent mental health unit in Swindon, UK, where on average at least two thirds of patients have a diagnosed eating disorder. Multidisciplinary ward rounds provide an appropriate setting for discussion and documentation of physical investigations. Over a two-week period, 22 electronic ward round entries were audited for any documentation of five common investigations - blood tests, ECG, MRI head, DEXA, and ovarian ultrasound. Blood tests were documented in 2/22 (9.1%), ECG, MRI head, DEXA, and ovarian ultrasound were documented in 0/22 (0%). Modifications were made to an electronic ward round template, to include headings for each of these investigations, with free-text boxes as well as drop-down boxes for the radiological tests. Following this, re-audit of 22 ward round entries over a two-week period showed documentation had hugely improved - blood tests were documented in 21/22 (95.5%), with ECG, MRI head, DEXA, and pelvis US all documented in 22/22 (100%). A further audit a month later showed these results were largely sustained. In conclusion, use of a simple, structured ward round template can hugely improve documentation of important physical investigations within mental health settings. PMID- 26734412 TI - From many deaths to some few cases of drug-resistant tuberculosis: travelling with the systems quality improvement model in Lacs Health District, Togo. AB - The ultimate goal of every tuberculosis (TB) treatment program is a high treatment success rate. Treatment success is extremely important because, when the rate is high, it significantly contributes to declining numbers of new cases by reducing the number and period of infectious cases, TB morbidity and mortality, and prevents the emergence of resistant strains. Our aim was to decrease TB mortality by increasing pulmonary TB patients' treatment success rate to at least 85 % in Lacs Health District by end of July 2014. A systems and dialogic analysis of the public health system related to TB patients' treatment revealed that it was not performing well; we found weak coverage and quality of TB services, a poorly-functioning TB health information system, poor-performing health workforce, poor availability of HIV tests and antiretroviral for TB patients, and low degree of patients' participation in their care. We redesigned the system to correct those weaknesses. The effectiveness of these changes was monitored using plan, do, study, act (PDSA) cycles. We increased TB patient success rate from 80% to 95% between February 2012 and July 2014.The mortality rate dropped from 13% to 3% and the failure to follow-up rate dropped from 3% to 2%. In conclusion, district health systems performance depends on factors such as the closeness of services to population; skilled workforce; the ability to collect and analyze data and use information for action; population empowerment, and good management and improvement capabilities of management team especially the public health director. High TB patients' success rate depends also on the availability of antiretroviral drugs. It is highly important that every district health management team member develops improvement capabilities. PMID- 26734413 TI - Alcohol detoxification in Ysbyty Gwynedd: Two small sips or one big gulp? Two step screening more reliable for identification of alcohol dependency syndrome at risk of delirium tremens for routine care. AB - Compliance with pathways for hospitalised patients with alcohol dependency syndrome is often poor. A pathway for recognition and treatment of alcohol dependency was redesigned as part of a 12 month service improvement project in the acute medical unit using plan, do, study, act (PDSA) cycles. A needs assessment was undertaken: Audit data from 2013 showed over-prescription of chlordiazepoxide for detoxification treatment (DT) leading to prolonged hospital admissions with an average length of stay of 5.5 days in 2012/2013. Acceptability of screening tools was tested: Common screening tools (CEWA, AUDIT) were rejected by junior doctors due to the high number of questions as too cumbersome for routine practice. Compliance with usage in random samples over a three month period was persistently (n=10%. Testing of an abbreviated AUDIT questionnaire with only two questions and a specified threshold showed a AUROC of 1 (p<0.001 for correct identification). The screening tool was implemented in several PDSAs cycles. After the final cycle a random sample of 100 patients was reviewed for pathway compliance over a three months period. Eighty-six patients were screened with the two-question tool of these 18 were identified as possible risk. Of these 16 patients had the full AUDIT questionnaire, only eight with elevated values were started on DT. Overall compliance with the pathway increased to 84%. PMID- 26734414 TI - Improving referrals to the Liaison service at the Royal United Hospital in Bath. AB - Psychiatry liaison services provide the interface between mental and physical health in the acute medical hospital, however there can be logistical and operational difficulties to overcome. This quality improvement project aimed to improve the timeliness of referrals to a liaison service from an acute hospital through simple interventions of a newsletter, email to staff, and a pilot including attending post-take ward rounds on the Medical Assessment Unit (MAU) of the hospital. This resulted in a faster referral process to liaison as well as improved staff satisfaction with the liaison service, both of which will have a positive benefit on the clinical management of patients and the patients experience in hospital. There was a significant improvement in overall staff satisfaction with the referral pathway, appropriateness of referrals and working hours of the Mental Health Liaison Team - increasing from 14% at baseline to 100% at the end of the study. Referral outcomes also showed a considerable improvement, with the percentage of junior doctors successfully able to locate the referral form increasing from 60% at baseline to 100%. PMID- 26734415 TI - Improving validated depression screen among adolescent population in primary care practice using electronic health records (EHR). AB - Adolescent depression, has been identified as one of the important risk factors for adolescent safety. The American Academy of Pediatrics (AAP) recommends screening the adolescent population for depression with a validated screening tool at least once a year. Given the time constraints in primary care, many physicians tend to rely more on clinical questioning to screen depression.This has the potential to miss many adolescents who may have mild to moderate depression which may prove detrimental to their emotional and physical health. Quality measures had consistently indicated that the validated adolescent depression screening rate in our two pediatric clinics was 10-15% in the past two years starting from 2012. There was a need to increase our screening rate for adolescent depression with a validated questionnaire. The stakeholders identified were physicians, nurses and the health information team (HIT). The Patient Health Questionnaire-2 (PHQ-2) is a standardized tool and serves as a good first step rapid screening of the population. A decision was made to implement the use of PHQ-2 to all the adolescents aged 11-21. A clinic flow protocol was developed. As the patient checks in, there will be a computer pop-up reminding nurses to administer the PHQ-2. The PHQ-2 self-scores in the Electronic Health Record (EHR) and if the score is three or more the nurses would automatically administer the PHQ-9 which is also embedded and self-scored in the EHR. After 12 months of implementing this project with four PDSA cycles, the adolescent depression screening rate improved from 10-15% from the previous two years to 65% (six month period) and 82% at the end of the 12 month period. The rate of referral to mental health services had also increased in the same time period compared to the previous years. In conclusion, screening for adolescent depression with a brief validated tool in a busy primary care office is possible with the help of the EHR. PMID- 26734416 TI - Improving handover of acute orthopaedic admissions. AB - Handover is a crucial part of patient care and is a well recognized cause of patient harm if not performed well. The introduction of full shift working for doctors has placed even more emphasis on this area of patient care. We identified handover of orthopaedic admissions in our unit was substandard. A prospective audit over a one week period including the weekend was undertaken. The Royal College of Surgeons of England guidance on handovers was used as minimum criteria and we also included criteria essential for handover of orthopaedic patients. This initial audit revealed a poor standard of handover. 21 patients were included and in particular patient location (57%), responsible consultant (14%), and pending investigations (29%) were poorly performed. In addition two patient safety incidents were noted, including one admission that was not handed over. To improve the handover we created a trauma specific handover proforma. We then conducted a re-audit again over a one week period including the weekend with the proforma in use. There was a notable improvement, 17 patients were included and only 3 criteria fell below 80%. We presented our findings at the local audit meeting where the results were discussed with all members of the trauma team. We suggested that an electronic proforma, accessible from multiple computers within the hospital may improve handover further. This was created in conjunction with the IT department. Once again we reaudited handover over a one week period including the weekend with the electronic proforma in use. 23 patients were included and a further improvement was noted; only one criterion fell below 95%. In conclusion handover of acute fracture admissions within the unit has undoubtedly improved. The electronic proforma tool was a simple, cost effective, and accurate method of improving handover. PMID- 26734417 TI - Improving timely medical reviews for patients discharged from intensive care. AB - Transferring patients from the intensive care unit (ICU) to a general ward is commonly associated with error and adverse events, and is one of the most challenging and high-risk transitions of care. Patients discharged from ICUs often require sustained intensive multi-disciplinary team input, part of which can be provided by nurse or clinician-led outreach teams. Unfortunately, due to a lack of resources many institutions do not have such programmes. We work in one such hospital with no ICU outreach service for recently discharged patients. We noted that a disproportionate number of patients recently discharged from the ICU needed acute medical reviews by on-call evening and overnight junior doctors. Furthermore we noted that many of these patients had not been reviewed by their medical team after having arrived onto the general ward from the ICU. We aimed to foster a fundamental culture change within junior doctors to review patients within six hours of arrival onto a ward from the ICU. We introduced simple and low-cost interventions that included educational sessions for junior doctors and ward-based nurses, as well as posters that acted as visual reminders in relevant departments. Overall, the number of patients discharged from the ICU to general wards that were reviewed within six hours improved from 22% to 70% in the space of six months. In the same period, the number of patients requiring an acute medical review by the evening or overnight on-call junior doctor dropped from 14% to 0%. Whilst our project is not necessarily appropriate for many larger institutions that already have outreach teams in place, it is certainly applicable to other similar sized smaller hospitals. We hope that others who face the same inherent barriers are inspired to implement similar projects, to bring about positive change, and ultimately improve the safety of their patients. PMID- 26734418 TI - Improving the quality of handover by addressing handover culture and introducing a new, multi-disciplinary, team-based handover meeting. AB - Handover is a "major preventable cause of patient harm"[1] and this project aims to improve the quality of night handover within a teaching hospitals general medicine department, resulting in the safe transfer of patient care to the night team. Quality of handover was assessed both qualitatively, via structured qualitative interviews with trainees and a baseline survey assessing doctor's opinions of night handover, and quantitatively through the collection of a data set during regular observation of night handover. The initial intervention instituted a new handover meeting with a set time and new location and invited the night nurse practitioner to attend. A prompt card, standardised documentation, defined leadership, and an attendance register were also introduced. Successive PDSA cycles introduced technology to the intervention, enabled the nurse night practitioners to actually attend and re-branded the prompt card as an agenda. Results show a sustained reduction in length of handover from 70 minutes (n=7) to 34 minutes (n=13) post-intervention as well as a reduction in the number of distractions occurring during each handover from a mean of 14 to a mean of 8.5. An improved quality of handover was also demonstrated with an overall increase in the percentage of task handovers containing hospital number, an admitting diagnosis, comorbidities and a time allocated for the task to be performed of at least 10%. When trainees were surveyed post-implementation they unanimously identified the new handover system as safer than the previous handover process (n=30). This project demonstrates that replacing an ad-hoc system of handover with a multi-disciplinary, team based approach to handover improves handover quality. In addition it provides a useful guide to introducing a new handover meeting to a department and contains useful lessons on how to combat cultural barriers to change within a department. PMID- 26734419 TI - Utilisation of a trauma meeting handover proforma to improve trauma patient pathway. AB - Decision making within orthopaedic centres predominantly occurs at the trauma meeting, where all decisions are made as a part of the multidisciplinary process. This is an essential handover process. Difficulties occur when teaching and detailed case discussions detract from the actual decision making process, leading to failure in documentation and implementing treatment plans. An audit was carried out in a busy district general hospital (DGH), assessing the quality of trauma meeting documentation in patient records, and assessing whether the introduction of a proforma document would improve this. Prospective clinical reviews were performed on all patients discussed in the trauma meeting over a one month period. Following the initial audit cycle a proforma was introduced, and the audit process was repeated at a two month and six month interval. The quality of the entries were assessed and compared to the Academy of Medical Royal Colleges Standards for the clinical structure and content of patient records, and The Royal College of Surgeons (RCS) of England Guidelines for Clinicians on Medical Records and Notes. Sixty three patient records during a one month period from 1 August 2014 found that only 16% had any documentation of the trauma meeting, none of which met the standard set at the beginning of the audit. Following the introduction of the proforma, 102 patient records were reviewed from October 2014, showing 70% had documentation of the trauma meeting. This improved further to 84% in February 2015. The proforma has provided an effective means of documenting and communicating management plans, and in turn also improved the trauma patient pathway to theatre or discharge. PMID- 26734420 TI - Risk assessment and prophylaxis of venous thromboembolism in surgical inpatients: improving adherence to national guidelines. AB - In Europe, venous thromboembolism (VTE) is the third most common cause of vascular death after myocardial infarction and stroke. It is especially common during and after hospitalisation for surgery and acute medical illness though many other risk factors have now been identified. VTE is often preventable with judicious use of preventative measures in the form of thromboprophylaxis and mechanical antiembolism stockings. In 2014, a study was undertaken across all surgical wards at a teaching hospital in London to assess compliance to national guidelines for VTE risk assessment and subsequent institution of protective measures. The initial results demonstrated that performance could be improved in terms of meeting the national target of assessing 95% of surgical inpatients for risk of VTE at admission, prescribing anti-embolism stockings, ensuring that they are correctly worn, and reassessing patients 24 hours later. Utilising a multidisciplinary team approach, simple interventions were put in place such as e mail reminders, posters, and senior input during ward rounds. Three subsequent measurements demonstrated that sustained improvement was achieved with the national guideline of 95% VTE risk assessment met. Improved performance was noted across all parameters considered, highlighting that simple intervention with all team members involved can improve patient safety and care. PMID- 26734421 TI - Introduction of point of care analysis for prescribing warfarin at a Swedish primary care centre. AB - Boo Health Centre in Nacka, Sweden, manages approximately 240 patients on warfarin treatment. A risk analysis showed that testing and prescribing of warfarin involved 28 different steps and nine parties, leading to a high risk of errors. The aim of the study was to shorten and simplify the process flow for the testing and prescription of warfarin by introducing point of care analysis (POC). The aim was also to evaluate changes in time expenditure and cost related to the new processes well as the quality in form of time in therapeutic range (TTR) and number of adverse events. A study with POC was performed during six months in 2014. Time expenditure, cost, TTR, and adverse events related to warfarin treatment were recorded. An evaluation was also conducted in the form of surveys to patients and staff regarding satisfaction with the new process. The process was shortened from 28 steps and nine parties involved to nine steps and four parties involved. The patient got their test result and met with the prescribing doctor, all within the same visit, meaning that the feedback time for patients was shortened from one to three days by mail to less than 10 minutes at the medical centre. TTR did not change and the incidence of adverse events was not affected. The surveys showed that the overwhelming proportion of patients, doctors, assistant nurses, and laboratory staff were pleased with the changes and the patients would recommend others to monitor their treatment at Boo Health Centre. There was a reduction in time expenditure for the staff. The costs decreased from approximately 8 000 ?/month to about 7 000 ?/month. The introduction of the POC method enabled a shorter process flow with reduced time expenditure for both patients and staff and reduced costs. TTR did not change. Patients and staff were satisfied with the changes and the patients could take a more active role in their treatment. It is possible that POC analysis may have implications on improved compliance to warfarin treatment, if so, it will increase patient safety. PMID- 26734422 TI - Improving induction of labour - a quality improvement project addressing Caesarean section rates and length of process in women undergoing induction of labour. AB - Induction of labour (IOL) in maternity care is often not an area of priority in maternity services, which often results in protracted delays, a poor patient experience, and patient complaints. Caesarean section (CS) rates among women undergoing IOL at this inner city district general hospital were noted to be higher than other units nationwide. We collected pre and post-intervention data of the following outcome measures: time taken to administer prostaglandin after arrival, time taken to achieve established labour, mode of delivery, and user satisfaction scores. Our introduction of a dedicated IOL Suite, promotion of out patient IOL, use of a single administration prostaglandin (as opposed to traditional six hourly prostaglandin), widespread staff engagement and rolling audit has resulted in positive change in the maternity unit. CS rates for women undergoing IOL have been reduced from 29% to 22% (p=0.05), time taken to administer the induction medication has decreased from 6.3h to 2.7h (p=0.0001), and out-patient induction rates have increased from 3% to 33% (p=0.001). We have achieved a reduction in the overall length of in-patient stay. We have also received positive feedback from both staff and patients. We used a bottom-up approach, engaging frontline staff in problem identification and pathway design. Our staff engagement questionnaire showed other benefits such as increased staff morale as a result. Collection of simple performance data and sharing of this in real time with staff acts as a valuable tool for acceptance of change and continuous improvement. Communicating plans to a large body of people is important in ensuring the success of an intervention. Staff showing disengagement may require specific detailed information to allay their concerns. Following initial successes, ongoing vigilance, and collection of audit data is key to sustaining any improvement. PMID- 26734423 TI - Chest drain care bundle: Improving documentation and safety. AB - Chest drain insertion is a common advanced procedure with a significant associated risk of pain, distress, and complications. Nationally, audit and recommendations from leading bodies have highlighted a number of safety concerns around chest drain insertion. Audit work has demonstrated poor levels of documentation; particularly around use of premedication, use of ultrasound guidance and consent. This has obvious potential consequences for patient safety and thus is an important target for improvement work. This project quantifies current standards of documentation and aims to improve this through a combination of accessible and easy to read guidelines, education, and the introduction of a chest drain insertion bundle. National best practice standards were identified through review of national guidance. Drain insertion was prospectively analysed over a three month period to establish baseline standards of documentation. This initial work was presented and a bundle and clinical guidelines produced. Chest drain insertion was then reaudited and assessed for improvement. Results demonstrated an improvement in many areas of documentation, pushing local results above the national average. However, only 40% of cases used the new bundle due to a mixture of staff rotation and an unexpectedly high proportion of drains inserted in non targeted areas including the emergency department, theatre, and intensive care. Despite this, the introduction of accessible guidance and bundle has significantly improved chest drain insertion documentation to the benefit of all. PMID- 26734424 TI - Using league tables to reduce missed dose medication errors on mental healthcare of older people wards. AB - The unintentional omission of medication is one of the most commonly-reported administration errors on hospital wards throughout the world. The omission of a dose of medication can severely harm the patient affected, but to date there is limited evidence about cost-effective means for reducing the incidence of such errors. The current report describes a quality improvement project, conducted on the mental healthcare of older people (MHCOP) wards in East London NHS Foundation Trust, which led to a greater than 90% reduction in the rate of unintentionally omitted doses of medication. The project involved the publication of a fortnightly league table which ranked each of the wards by how many doses they had missed, with the ward missing the fewest doses receiving a prize. PDSA cycles were used to refine the concept, with the final incarnation of the fortnightly league table also incorporating the publication of a poster for each ward which showed how many weeks it had been since the ward missed a dose, and the ward's overall trend in missed doses. The project has resulted in the average missed dose rate on the MCHOP wards decreasing from 1.07% to 0.07%. In real terms, this represents a reduction from an estimated 2878 to 188 missed doses per year on the six MHCOP wards. By greatly reducing the risk of patients experiencing adverse drug events as a result of missed doses, this project has given rise to a potential cost-saving of around L34,000 per year across the wards studied. The use of league tables represents a simple, cost-effective means of tackling the problem of doses of medication being unintentionally omitted on hospital wards. PMID- 26734425 TI - Atrial fibrillation care improvement collaborative. AB - Atrial fibrillation (AF) is an increasingly common cardiac arrhythmia. Many patients with new onset or recurrent AF present to the emergency department and are subsequently admitted to the hospital and seen by cardiology specialists for follow up. In an attempt to address this high utilization of acute health care resources, reduce costs, and improve patient care, our institution instituted a collaborative project between the departments of emergency medicine, cardiology, family medicine, and primary care internal medicine. The project team oversaw development of a new emergency department AF order set, encouraged utilization of a new oral anticoagulant (dabigatran), improved the primary care follow up connection, and deployed a multimodal education plan for primary care providers. Between 2012 and 2014, these interventions resulted in a 17% reduction in total AF per member per month (PMPM) cost, a 28% reduction in AF PMPM inpatient cost, and a 24% reduction in inpatient admissions for AF. PMID- 26734426 TI - Inpatient Falls: Improving assessment, documentation, and management. AB - A frequently occurring job during on-call and out-of-hours shifts is reviewing a patient following a fall with this often being the responsibility of the most junior and inexperienced doctors. Following a pilot audit we identified inconsistencies in medical assessment and documentation, with 50% of expected data points not recorded. Failure to complete a thorough assessment can lead to missed injuries, prolonged length of stay, and litigation. Using the plan, do, study, act (PDSA) cycle model this project sought to address this through providing teaching to junior doctors and the development of a pro-forma. Three style cycles of data collection were performed; a formal baseline dataset, after delivering a teaching session to new junior doctors and following the trial of the new fall pro-forma. We selected 15 to 17 patient notes to review at random during a one month period for each data collection cycle and compared the medical assessment to the standards outlined by the National Patient Safety Agency (NPSA) guidelines.[1] There were two key areas of improvement identified following the teaching session and introduction of the proforma. Documentation of a fall history was improved by nearly 30% being recorded in 100% of cases after the interventions. Documentation of a thorough musculoskeletal examination was improved from being recorded in just 54% of cases to 77% of cases; it was recorded in 100% of the cases where the proforma was used. The project demonstrated the need to improve documentation and assessment of a patient who has fallen. Initial data collection has shown that assessment and documentation were improved providing teaching to junior doctors and by use of the document. The pro-forma has since been incorporated into hospital policy and now forms the compulsory documentation expected of the doctors and nurses managing patients following a fall. Ensuring easy access to the proforma and re-auditing after editing the document will be the next steps. PMID- 26734427 TI - Promoting oral health practice among patients with diabetes attending primary health care clinics. AB - The oral public health program for patients with diabetes was initiated by Saudi Arabia Ministry of Health (MoH) based on international quality standard to control the severity of oral disease in patients with diabetes through improving the accessibility of patients to dental clinics in primary health care centers (PHCC). This program intends to deliver oral health care (OHC) for each patient with diabetes at least one visit every six months. However, we found that more than 90% of patients with diabetes that visited prince Mohammed bin Saud PHCC in Riyadh do not get their regular dental check up every six months. We developed a quality improvement project (QIP) using the quality improvement model to activate MoH oral health program for patients with diabetes visiting prince Mohamed bin Saud PHCC. The aim of our QIP was to increase number of patients with diabetes receiving their regular oral health check up during the PHC visit. The quality team tested two simple improvement ideas. The first idea was having the dentist signature on appointment request. The testing of the first idea led to the second idea, that both physician and dentist should sign the referral form. After running several PDSA cycles to test these interventions ideas, we found the number of patients with diabetes seen in dental clinic had increased dramatically compared with the baseline assessment. We conclude that the idea of signing the referral form by both physician and dentist is a practical and simple strategy to be executed and has a direct impact on the patient clinical flow between clinics. PMID- 26734428 TI - Improving the quality of the surgical preoperative assessment in a district general hospital. AB - At Leicester General Hospital, England, patients are assessed by a team of junior doctors for elective colorectal and hepatobiliary procedures. After a number of same day cancellations, a large discrepancy was identified between the findings at the preoperative assessment clinic and the anaesthetic assessment on the day of surgery. After a multidisciplinary meeting was held, three interventions were decided on with an aim to bring the preoperative assessment in line with the anaesthetic assessment. Firstly, a set of guidelines was written and introduced for the junior doctors to use as a reference when assessing patients. Secondly, a proforma was designed specifically to prompt users to include essential details which were being missed in the assessment, having audited 100 patients' notes. Thirdly, a preoperative investigation "calculator" was recommended for each patient to simplify compliance with the National Institute for Health and Care Excellence (NICE) guidance for preoperative assessment. Before and after each intervention was introduced, a cohort of 50 patients were followed looking for differences in findings in the history, examination, investigations, and fitness for surgery between the preoperative assessment in clinic and the anaesthetic assessment on the day of surgery. Initially 68% of patients were compliant for details in the history, 76% for examination, 32% for choice of preoperative investigations, and 100% for fitness for surgery decision. After all three interventions had been introduced, 96% of patients were compliant for history, 94% for examination findings, 88% had the correct choice of preoperative investigations, and 100% had the same decision on fitness for surgery. The interventions described proved to be cheap and effective methods of improving the quality of the preoperative assessment, bringing it in line with the anaesthetic assessment and reducing the risk of same day cancellations. PMID- 26734429 TI - Postoperative analgesia for Enhanced recovery in Joint replacement: Audit of a new electronic prescribing order set. AB - Enhanced recovery in joint replacement has been shown to reduce length of inpatient stay, reduce re-admission rates, and can improve early functional recovery. Postoperative analgesia is an important component of the group of interventions required to form a holistic enhanced recovery protocol. The introduction of electronic prescribing provides the opportunity to introduce some standardisation, where clinically appropriate, in the prescription of an evidence based postoperative analgesia protocol. Enhanced recovery following joint replacement has been used at this institution since 2011. An order set for the postoperative analgesia protocol was introduced to the in house electronic prescribing system in August 2014 (JAC Medicines Management; JAC Computer Services Ltd., Basildon, UK). An audit was performed to follow the effect of the new system on compliance with the postoperative analgesia guidelines. Improvements were seen following introduction of the electronic prescribing protocol in all criteria of the guideline with a demonstrated improvement in overall compliance from 0% to 35% in the first loop, with subsequent audit showing further improvement to 59% compliance. Use of an embedded order set within an electronic prescribing system has demonstrated improved compliance with an enhanced recovery protocol. This ensures that the correct evidence based protocol is available to guide the junior clinician at the point of care, when the medication is being prescribed. PMID- 26734430 TI - Intensive care discharges: improving the quality of clinical handover through changes to discharge documentation. AB - Patients who have stepped down from intensive care tread a precarious clinical course, and the handover of care between clinical teams at this point should be treated as a high risk event. Poor handover can leave patients vulnerable to suboptimal care and preventable harm. Properly structured written discharge summaries have been shown to improve information transfer and quality of care. The National Institute for Health and Care Excellence (NICE) has published guidelines entitled "Acute illness in adults in hospital: recognising and responding to deterioration," which states that patients transferred from intensive care should have a formal structured handover supported by a written plan, and it provides minimum criteria for what information should be included. A retrospective audit was carried out (n=28) to identify if discharge summaries were compliant with these standards. Discharge summaries consistently lacked essential criteria, including psychosocial needs (29%), nutritional needs (50%), therapy needs (29%), ceilings of care (39%), and communication needs (18%). Less than a third of verbal handovers between the nursing and medical teams were documented. After consultation, a new summary template was developed and embedded into practice. The new design prompted trainees to ensure they completed adequate information in all domains of care. Additional sections were added to improve recording of when, and to whom, clinical handover took place, which led to improved clinical governance. The overall quality of discharge summaries was improved, with increased compliance in 11 out of 13 domains. Feedback from staff about the new discharge summaries was positive. This project is easily transferable, and has the potential to improve patient safety and quality of care. PMID- 26734431 TI - Improving documentation within the acute stroke unit: Introducing a stroke specific clerking proforma. AB - The Royal College of Physicians outline the guidelines for acute stroke management, they highlight the importance of early identification to enable prompt and effective treatment. The first contact that a clinician has with a patient is usually at the point of clerking. The information obtained and impression formed are the key factors which determine the management plan. The documentation of the information gleaned is subsequently used by all of the medical team to determine the sequence of events from admission. It is crucial in determining any progression of symptoms, of particular importance in this group of patients in whom this can signify potentially fatal consequences. The quality of clerkings of patients admitted to the acute stroke unit in the Royal Devon and Exeter hospital was analysed and subjective data was obtained from the junior doctors involved in this process to determine how well these were being completed. Baseline measurements showed that junior doctors lacked confidence in this process and the initial audit demonstrated that only half of the recommended categories were being completed. To address this issue a stroke specific admission proforma was made and piloted on the ward. Following this, a re-audit was completed which showed a significant improvement in the quality of clerkings produced. PMID- 26734432 TI - Four Simple Ward Based Initiatives to Reduce Unnecessary In-Hospital Patient Stay: A Quality Improvement Project. AB - Prolonged hospital stay not only increases financial stress on the National Health Service but also exposes patients to an unnecessarily high risk of adverse ward events. Each day accumulates approximately L225 in bed costs with additional risks of venousthromboembolism, hospital acquired infections, prescription errors, and falls. Despite being medically fit for discharge (MFFD), patients awaiting care packages with prolonged length of stay (LoS) have poorer outcomes and experience increased rates of mortality as a result. A six cycle prospective audit was carried out to investigate if four simple ward based initiatives could optimise patient flow through a medical ward and reduce LoS of inpatients awaiting social packages and placement. The four daily initiatives were: A morning board round between nurses and doctors to prioritise new or sick patients for early review.A post ward round meeting between the multidisciplinary team to expedite rehabilitation and plan discharges early.An evening board round to highlight which patients needed discharge paperwork for the next day to alleviate the wait for pharmacy.A 'computer on wheels' on ward rounds so investigations could be ordered and reviewed at the bedside allowing more time to address patient concerns. A control month in August 2013 and five intervention cycles were completed between September 2013 and January 2014. Prior to intervention, mean time taken for patients to be discharged with a package of care, once declared MFFD, was 25 days. With intervention this value dropped to 1 day. The total LoS fell from 46 days to 16 days. It was also found that the time taken from admission to MFFD status was reduced from 21 days to 15 days. In conclusion this data shows that with four simple modifications to ward behaviour unnecessary inpatient stay can be significantly reduced. PMID- 26734433 TI - Experience based co-design reduces formal complaints on an acute mental health ward. AB - An acute mental health triage ward at Oxleas NHS Foundation Trust was attracting high levels of formal service user and family complaints. The Trust used experience based co-design to examine the issues and redesign procedures. This resulted in an immediate eradication of formal complaints for a period of 23 months. This paper describes two outcomes: firstly, the successful adaptations made to the experience based co-design methodology from its origins in physical care, in order to ensure it was safe and effective in an acute mental health setting; and, secondly, the changes made to the ward as a result of this quality improvement intervention. PMID- 26734434 TI - Improving phlebotomy handover of untaken blood tests to junior doctors. AB - A lack of communication between junior doctors and phlebotomists means untaken blood tests are often not recognised until late in a junior doctor's day, resulting in additional hours worked, delays in patient management, and potentially avoidable handover of additional work to on-call doctors. We set out to improve communication, with an aim that ward doctors should be made aware of patients who have not been successfully bled by phlebotomists by 1:00pm. By introducing a formal handover clipboard in a designated ward space, we facilitated communication between phlebotomists and doctors, and minimised the potential for unrecognised "missed" blood tests. Our intervention was met with approval; 88% of junior doctors surveyed stated they found the clipboards useful, and 74% have noticed an improvement in communication, working efficiency and better patient safety. Post-intervention, junior doctors knew about 70% of booked blood tests that had not been taken by 1:00pm, compared to 26% pre-intervention. By allowing the recognition of missed blood tests to be noted early enough in the day for repeat samples to be taken, and the results to be acted upon, we feel our intervention has been a success. As a group of new foundation doctors we have felt empowered that as a result of recognising a problem, implementing simple changes, and monitoring results we have made a genuine improvement to multi disciplinary team working, workload of junior doctors, and patient safety. PMID- 26734435 TI - Improving the efficacy of elderly patients' hospital discharge through multi professional safety briefings and behavioural change. AB - At Leeds Teaching Hospitals NHS Trust doctors type an electronic discharge advice note (eDAN) which includes a prescription for discharge medication, before a patient can be discharged from hospital. In 2014 staff on the Medical Admissions Unit for Older People identified significant delays in the completion of this document, with an average completion time of 138 minutes. This caused patient harm and exacerbated bed management problems as patients remained in hospital longer than necessary to obtain their discharge medication. Ward staff wanted to improve the efficacy of older peoples' discharge by speeding up this process in as safe a manner as possible. A number of interventions were tested, led by junior doctors in a 'bottom-up' leadership strategy. Interventions included a daily discharge briefing to recap discharges and help junior doctors prioritise workload. After several months of sustained effort, the average time to complete eDANs fell by over an hour resulting in discharge medication dispensed earlier in the day and improved patient safety. PMID- 26734436 TI - Applying Quality Improvement into Systems-based Learning to Improve Diabetes Outcomes in Primary Care. AB - In the U.S., where the prevalence of type 2 diabetes has reached epidemic proportions, many patients with this disease are treated by primary care physicians in community-based systems, including accountable care organisations (ACOs). To address gaps in the quality of diabetes care, national quality measures have been established, including patient-centered measures adopted by the Centers for Medicare and Medicaid Services for its Shared Savings Program for ACOs. From a patient-centered perspective, high-quality diabetes care depends on effective communication between clinicians and patients, along with patient education and counseling about medications and lifestyle. We designed and implemented a quality improvement (QI) program for 30 primary care physicians treating patients with type 2 diabetes in three structurally similar but geographically diverse ACOs. Retrospective chart audits were conducted before (n = 300) and after (n = 300) each physician participated in accredited continuing medical education (CME) courses that focused on QI strategies. Randomly selected charts were audited to measurably assess essential interventions for improved outcomes in type 2 diabetes including the physicians' documentation of patient counseling and assessment of side effects, and patients' medication adherence status and changes in hemoglobin A1C (A1C) and body mass index (BMI). Paced educational interventions included a private performance improvement Internet live course conducted for each physician, small-group Internet live courses involving peer discussion, and a set of enduring materials, which were also multi accredited for all clinicians in the physician's practice. Continual improvement cycles were guided by analysis of the baseline chart audits, quantitative survey data, and qualitative feedback offered by participants. To extend the benefit of the education, the enduring materials were offered to the interprofessional team of clinicians throughout the U.S. who did not participate in the QI program. For brevity, this article presents outcomes of the 30 primary care physicians. Baseline to post-education improvements were observed for percentages of charts with documented assessment of medication side effects (+11%) and counseling about medication risks/benefits (+28%), medication adherence (+13%), and lifestyle modifications (+8%). Improvements were also observed for documented adherence to diabetes medications (+24%) and first-to-last visit changes in A1C (-0.16%) and BMI (-2.1). The findings indicate a positive influence of QI education on primary care physicians' performance of patient-centered quality measures and patient outcomes. PMID- 26734437 TI - Concise Care Bundles In Acute Medicine. AB - The Queen Elizabeth Hospital in King's Lynn, Norfolk is a 488 bed hospital providing services to approximately 331,000 people across 750 square miles. In 2012 a need was recognised for documentation (pathways) in a practical format to increase usage of national guidelines and facilitate adherence to best practice (gold standards of care) that could be easily version controlled, auditable and provide support in clinical decision-making by junior doctors. BMJ Action Sets[1] fulfilled the brief with expert knowledge, version control and support, though they were deemed too lengthy and unworkable in fast paced settings like the medical assessment unit; they formed the base creation of concise care bundles (CCB). CCB were introduced for 21 clinical presentations and one procedure. Outcomes were fully audited and showed significant improvement in a range of measures, including an increase in completions of CHADVASC score in atrial fibrillation, antibiotics prescribed per protocol in chronic obstructive pulmonary disease (COPD), and Blatchford score recorded for patients presenting with upper gastrointestinal bleed. PMID- 26734438 TI - Reducing turnaround time of surgical pathology reports in pathology and laboratory medicine departments. AB - Turnaround time is an important quality indicator in surgical pathology. Retrospective analysis of three data points in September 2014, January 2015, and February 2015 showed that on average, about a quarter (24%) of routine surgical pathology cases (26%, 19%, and 27% respectively) are not reported on time and do not meet the accepted level of the College of American Pathologists' (CAP) standard turnaround time, which states at least 90% of routine surgical pathology cases should be reported and verified within two days. Our daily observation supported by a root cause analysis exercise revealed that subprocesses including slide allocation and delivery to pathologists, slide review by pathologists, report editing by transcriptionists, and report verification by pathologists are where most delays occur. Thus, to tackle these process issues we developed a quality improvement project using the model of improvement methods to streamline the sample flow process and avoid unjustified reporting delay. The improvement ideas included developing a time log sheet to be attached with all pathology requests, and sending a daily reminder email followed by a phonecall to all pathologists to verify completed reports on the same day. These intervention elements were tested using multiple PDSA cycles resulting in a very noticeable improvement, with more than 94% of all routine cases reported in less than two days, meeting and exceeding the CAP standards. Such noticeable improvement in turnaround of surgical pathology reports will eventually lead to improving the quality and safety of patient care outcome, including diagnosing patients on time, developing the appropriate treatment plan, and avoiding unjustified complications resulting in morbidity and mortality due to delayed reports. PMID- 26734439 TI - Hypokalaemia: Improving the investigation, management and therapeutic monitoring of hypokalaemic medical inpatients at a district general hospital. AB - Hypokalaemia is prevalent in 20% of hospitalised patients. Furthermore, inadequate management of hypokalemia was identified in 24% of these patients. Associated with significant patient morbidity and mortality, the identification, investigation, and treatment of hypokalaemia was identified as an area for improvement in the management of medical inpatients. The project aims to measure the assessment, management, and therapeutic monitoring of medical inpatients with hypokalaemia in a district general hospital. All medical inpatients over a one week period who met the criteria for hypokalaemia (serum potassium <3.5 mmol/L on standard biochemical sample) were included in the audit. Patient's notes were located and evaluated to identify if they had mild, moderate, or severe hypokalaemia. Further data on ECG requests, repeat U&Es, serum magnesium analysis, treatment prescribed, and medication review dates was collated. A re audit was completed after the introduction of a set of interventions which included a hypokalaemia treatment algorithm. Pre-intervention analysis of all medical inpatients, who met our inclusion criteria for hypokalaemia, identified 32 patients. 25 of these patients met the criteria for mild hypokalaemia (3.1-3.4 mmol/L) and 7 met the criteria for moderate hypokalaemia (2.5-3.0 mmol/L). Only 7/32 (22 %) patients were receiving adequate treatment based on trust guidelines. Post intervention results showed marked improvement in the management of patients with hypokalaemia. A total of 30 patients were identified in this post intervention group. There were 16/30 patients who qualified as mild hypokalaemia (3.1-3.4 mmol/L) and 14/30 with moderate hypokalaemia (2.5-3.0 mmol/L). 19/30 (63%) patients in the post-intervention group were correctly prescribed appropriate medication doses consistent with the treatment algorithm. Following the initial success of the project, analysis at 3 months showed a positive trend for sustained improvement when compared to the pre-intervention results. PMID- 26734440 TI - Simple interventions can greatly improve clinical documentation: a quality improvement project of record keeping on the surgical wards at a district general hospital. AB - Clinical documentation is an integral part of the healthcare professional's job. Good record keeping is essential for patient care, accurate recording of consultations and for effective communication within the multidisciplinary team. Within the surgical department at the Great Western Hospital, Swindon, the case notes were deemed to be bulky and cumbersome, inhibiting effective record keeping, potentially putting patients' at risk. The aim of this quality improvement project was therefore to improve the standard of documentation, the labelling of notes and the overall filing. A baseline audit was firstly undertaken assessing the notes within the busiest surgical ward. A number of variables were assessed, but notably, only 12% (4/33) of the case notes were found to be without loose pages. Furthermore, less than half of the pages with entries written within the last 72 hours contained adequate patient identifiers on them. When assessing these entries further, the designation of the writer was only recorded in one third (11/33) of the cases, whilst the printed name of the writer was only recorded in 65% (21/33) of the entries. This project ran over a 10 month period, using a plan, do study, act methodology. Initial focus was on simple education. Afterwards, single admission folders were introduced, to contain only information required for that admission, in an attempt to streamline the notes and ease the filing. This saw a global improvement across all data subsets, with a sustained improvement of over 80% compliance seen. An educational poster was also created and displayed in clinical areas, to remind users to label their notes with patient identifying stickers. This saw a 4-fold increase (16% 68%) in the labelling of notes. In conclusion, simple, cost effective measures in streamlining medical notes, improves the quality of documentation, facilitates the filing and ultimately improves patient care. PMID- 26734441 TI - A multi-faceted approach to increase appropriate analgesia prescribing in the emergency department. AB - Pain is the most common presenting complaint within the emergency department. Whilst national RCEM guidelines exist, there tends to be low compliance with its use. A retrospective, cross-sectional audit, over a 24 hour period, was carried out in the emergency department of a tertiary hospital in London on all patients with abdominal pain. Pain score documentation was checked as well as: whether analgesia prescribed was compliant with guidelines, time to prescription, and if pain scores were rechecked within an hour. Cycle 1 (21 patients) showed that only 29% of patients were prescribed analgesia in accordance with guidelines, 38% of pain scores were documented at triage, and only 19% of scores were rechecked at any time. 22% of patients in severe pain were prescribed analgesia within the recommended duration from presentation (20 minutes). New guidelines, adapted from RCEM, were departmentally approved and disseminated to reflect local medication use. Monthly doctor and nurse teaching sessions were established to improve guideline compliance, objective pain score documentation, and encourage results driven performance. A nurse prescriber champion was established to encourage analgesia prescribing competence in addressing delayed administration. Finally, plans to integrate electronic pain scoring with timer prompts for rechecking are in place to help streamline the process. Following these interventions, cycle 2 (n=23) showed 87% of pain scores were documented at triage, 52% were prescribed guideline concordant analgesia, and 40% of severe pain scores were acted upon in time. Cycle 3 (n=33) demonstrated the need for monthly educational intervention to maintain high standards; as in its absence, any improvement returned to baseline. PMID- 26734442 TI - Development and evaluation of a community respiratory physiotherapy service for children with severe neurodisability. AB - Children with severe disability often have difficulties with secretion clearance leading to recurrent lower respiratory tract infections and prolonged hospital admissions. A community respiratory physiotherapy service was developed for this client group, including a rapid response for acute respiratory illness, and an evaluation was undertaken, comparing admissions and bed-days in hospital for respiratory tract infections, emergency admissions to hospital for any cause, and admission costs for each child for the 12 months before to the 12 months with the service. Thirty-four children aged 1 to 19 years (median 5) were eligible for the "before and after" evaluation at 28 months; most had severe cerebral palsy 22 (65%), and there were also eight (23%) children with neurodegenerative and four (12%) with neuromuscular conditions. Admissions for respiratory tract infection fell from 43 to 25 (p<0.05), respiratory admission bed-days fell from 383 to 236 (p<0.01), total non-elective admissions fell from 64 to 40 (p<0.01), with admission cost savings of GBP 78,155 (52%) per annum. This small study suggests that a community respiratory physiotherapy service can reduce hospital admissions and bed days for disabled children. The admissions cost savings have enabled the service to "pay for itself". PMID- 26734443 TI - Enhanced recovery programme in gynaecology: outcomes of a hysterectomy care pathway. AB - There was a wide variation in the peri-operative management of women undergoing hysterectomy for both benign and malignant disease at Southend University Hospital NHS Foundation Trust prior to 2010. The median length of stay following a hysterectomy and more radical gynaecological oncology surgery was five days and seven days respectively. The NHS East of England Strategic Health Authority commissioned the development of Enhanced Recovery Programme (ERP) in various surgical specialties including gynaecology and the pathway was implemented from 2012 onward. Dedicated specialist nurses collected data prospectively. The median length of stay was shortened to three days. This difference was statistically significant with a P value = 0.0001. We describe the successful implementation of an ERP in Southend Hospital resulting with no difference in measurable morbidity and mortality, a shorter length of stay, and a high patient satisfaction scores and outcomes. PMID- 26734444 TI - Getting Access to Toxbase for Doctors in the Avon and Wiltshire Partnership. AB - Doctors working in mental health often review patients who have taken an overdose. Having an evidence based resource which has information regarding the toxic doses of the drug taken enables informed discussions with senior doctors and decision making about whether to admit the patient to hospital. No site across the Avon and Wiltshire Partnership (AWP) Trust had access to TOXBASE, the Public Health England drug Toxicology database. A primary questionnaire (n= 39) found 97% of doctors thought that TOXBASE would be useful and 84.5% could not think of a better alternative. Through a series of Plan, Do, Study, Act cycles, TOXBASE access was gained for one site (Imber ward, Devizes) and following successful implementation this could be rolled out across all sites in the Trust. Doctors were surveyed and one month after the first site gained access, two out of seven doctors had used TOXBASE and found it useful. Further questionnaires were distributed following three months at three sites and then at six months to everyone. The final questionnaire showed that one third knew they had access and five doctors had used it in clinical context. Action was then taken by creating a TOXBASE on the Intranet site which directed doctors to their local inpatient unit for login details. By the end of the project access to TOXBASE was successfully gained at six out of the seven sites in the Trust. The surveys showed that access to the resource was highly regarded by doctors, and that it had enabled informed discussions with medical colleagues leading to reduced potentially lengthy transfers of patients to medical units. This has high cost implications of the transport of mental health patients, as well as reducing the distress caused to patients. PMID- 26734445 TI - Improving the likelihood of neurology patients being examined using patient feedback. AB - We aimed to establish whether recall of elements of the neurological examination can be improved by use of a simple patient assessment score. In a previous study we demonstrated that in-patients referred to neurology at two United Kingdom (UK) hospitals were not fully examined prior to referral; we therefore designed a larger quality improvement report with 80% power to detect a 10% increase in tendon hammer or ophthalmoscope use following an educational intervention. In patients referred to neurology over a four month period (in hospitals in the UK (10), Jordan (1), Sweden (2), and the United Arab Emirates (1)) were asked whether they recalled being examined with a tendon hammer (T), ophthalmoscope (O), and stethoscope (S) since admission. The results were disseminated to local medical teams using various techniques (including Grand Round presentations, email, posters, discounted equipment). Data were then collected for a further four month period post-intervention. Pre-intervention and post-intervention data were available for 11 centres with 407 & 391 patients in each arm respectively. Median age of patients was 51 (range 13-100) and 49 (range 16-95) years respectively, with 44.72% and 44.76% being male in each group. 264 patients (64.86%) recalled being examined with a tendon hammer in the pre-intervention arm, which significantly improved to 298 (76.21%) (p<0.001). Only 119 patients (29.24%) recollected examination with an ophthalmoscope pre-intervention, which significantly improved to 149 (38.11%)(p=0.009). The majority of patients (321 (78.87%)) pre-intervention recalled examination with a stethoscope, which significantly improved to 330 (84.4%) to a lesser extent (p=0.045). Results indicate that most patients are not fully examined prior to neurology referral yet a simple assessment score and educational intervention can improve recall of elements of the neurological examination and thus the likelihood of patients being examined neurologically. This is the largest and - to our knowledge - only study to assess this issue. This has implications for national neurological educators. PMID- 26734446 TI - Are patients with newly diagnosed breast cancer getting appropriate DEXA scans? A District General Hospital experience. AB - Breast cancer patients are often at high risk of fragility fractures partly due to adjuvant endocrine therapy such as aromatase inhibitors and chemotherapy. Baseline dual energy X-ray absorptiometry (DEXA) scanning is recommended as a standard of care in identifying patients who are at risk so they can be commenced on bone protective therapy. NICE guideline 80 - "Early and locally advanced breast cancer"[1] states that patients with early invasive breast cancer should have a baseline DEXA scan to assess BMD before the commencement of aromatase inhibitor treatment; if patients have treatment-induced menopause or are starting ovarian ablation/suppression therapy. We have audited the performance of a DGH against these guidelines with a target of 100% concordance. During a one year period (April 2012-April 2013), 100 patients with a new diagnosis of breast cancer were selected at random from the hospital coding database. 100 patients were chosen as this was a convenient sample size. We gathered information for these patients using electronic records, letters, and imaging. This showed a poor compliance of 38% against NICE guidelines. This in turn means that patients with low BMD at diagnosis of breast cancer are being under diagnosed and under treated, resulting in increased potential morbidity associated with fragility fractures. The interventions that resulted from this audit were: dissemination of these results to surgical and oncology departments, posters summarising the guidelines put up in breast clinics, and breast MDTs to discuss the need for DEXA scans for patients with breast cancer. A re-audit was performed for patients diagnosed with early, invasive breast cancer in January 2014 where a compliance of 90% was achieved. This represents a huge improvement in compliance from the baseline measure of 38%. In order to show that this improvement could be sustained, two further cycles were performed in February and March 2014, where the compliance was 92% and 100% respectively. Therefore the improvement in compliance was not only maintained but in fact the compliance increased even further during subsequent cycles. Hence we have achieved a large improvement in the quality of assessment of bone quality in breast cancer patients. Moreover, we have demonstrated the importance of the dissemination of information and education within a multidisciplinary setting. PMID- 26734447 TI - Improving emergency department flow through Rapid Medical Evaluation unit. AB - The Toronto Western Hospital is an academic hospital in Toronto, Canada, with an annual Emergency Department (ED) volume of 64,000 patients. Despite increases in patient volumes of almost six percent per annum over the last decade, there have been no commensurate increases in resources, infrastructure, and staffing. This has led to substantial increase in patient wait times, most specifically for those patients with lower acuity presentations. Despite requiring only minimal care, these patients contribute disproportionately to ED congestion, which can adversely impact resource utilization and quality of care for all patients. We undertook a retrospective evaluation of a quality improvement initiative aimed at improving wait times experienced by patients with lower acuity presentations. A rapid improvement event was organized by frontline workers to rapidly overhaul processes of care, leading to the creation of the Rapid Medical Evaluation (RME) unit - a new pathway of care for patients with lower acuity presentations. The RME unit was designed by re-purposing existing resources and re-assigning one physician and one nurse towards the specific care of these patients. We evaluated the performance of the RME unit through measurement of physician initial assessment (PIA) times and total length of stay (LOS) times for multiple groups of patients assigned to various ED care pathways, during three periods lasting three months each. Weekly measurements of mean and 90th percentile of PIA and LOS times showed special cause variation in all targeted patient groups. Of note, the patients seen in the RME unit saw their median PIA and LOS times decrease from 98min to 70min and from 165min to 130min, respectively, from baseline. Despite ever-growing numbers of patient visits, wait times for all patients with lower acuity presentations remained low, and wait times of patients with higher acuity presentations assigned to other ED care pathways were not adversely affected. By specifically re-purposing a fraction of existing staff, resources, and infrastructure for patients with lower acuity presentations, we were able to streamline their care and decrease wait times in the ED. These results were achieved through the incremental improvements afforded by rapidly cycling through PDSA cycles, with strong frontline staff involvement and continuously eliciting feedback for improvement. We believe the model to be replicable in other academic medical centres. PMID- 26734448 TI - Improving data management practices in the Portuguese HIV/AIDS surveillance system during a time of public sector austerity. AB - In a climate of public sector austerity, the demand for accurate information about disease epidemiology rises as health program managers try to align spending to health needs. A policy of case re-notification to improve HIV information quality resulted in a nine-fold increase in the number of case reports received in 2013 by the Portuguese HIV surveillance office. We used value stream mapping to introduce improvements to data processing practices, identify and reduce waste. Two cycles of improvement were trialled. Before intervention, processing time was nine minutes and 28 seconds (95%CI 8:53-10:58) per report. Two months post intervention, it was six minutes and 34 seconds (95% CI 6:25-6:43). One year after the start of the project, processing time was five minutes and 20 seconds (95% CI 1:46-8:52). PMID- 26734449 TI - Let's Talk About Sex! - Improving sexual health for patients in stroke rehabilitation. AB - Sexual health contributes greatly to quality of life. Research shows that stroke survivors want to learn and talk about sexual health, but are not given information. In keeping with the Canadian Best Practice Recommendations for Stroke Care, this project aimed to provide all stroke rehabilitation inpatients with the opportunity to discuss sexual health concerns with healthcare providers at West Park Healthcare Centre, a rehabilitation and complex continuing care centre in Toronto. Gap analysis conducted via staff member interviews and retrospective chart reviews showed that close to no patients were given the opportunity to discuss sexual health concerns at baseline. Plan-Do-Study-Act (PDSA) methodology was used as the project framework. The changes implemented included a reminder system, standardization of care processes for sexual health, patient-centred time points for the delivery of sexual health discussions, and the development of a sexual health supported conversation tool for patients with aphasia. By the end of the ten month project period and after three PDSA cycles, the percentage of patients provided with the opportunity to discuss sexual health during inpatient rehabilitation increased to 80%. This quality improvement project successfully implemented the Canadian Best Practice Recommendations for Stroke Care with respect to sexual health. Lessons learned included the importance of early baseline data collection and advance planning for tools used in QI projects. Future projects may focus on improving the discussion of sexual health concerns during outpatient stroke rehabilitation. PMID- 26734450 TI - Improving fluid balance monitoring on the wards. AB - Clinical experience and nursing metrics have consistently identified poor documentation of fluid balance monitoring at Milton Keynes University Hospital, compromising patient safety and quality of care. This project aimed to increase the percentage of fluid balance charts correctly completed on the wards. Three areas for improvement were identified: understanding the importance of good fluid balance monitoring, correct identification of patients requiring monitoring, and ease of completion of fluid balance charts. Three interventions were deployed on two acute medical awards in consecutive cycles; 1) small group education for staff, 2) creation of board magnets to aid the multidisciplinary team to identify patients requiring monitoring, 3) modification of the current fluid balance chart. Questionnaires were utilised to highlight improvements with current charts and measured staff awareness pre and post education. Each intervention was implemented for one week followed by daily surveys for four days to monitor compliance. Initial results showed a range of 6-12 charts used daily per ward. Of these 0-45% of them were correctly filled. Post education there was a reduced number of inappropriate charts. Introduction of board magnets improved correlation between doctors and nurses in identification of patients (52% before, 77% after magnets). Following modification there was a subjective improvement in the quality of chart completion. This study highlighted that understanding and use of fluid balance monitoring can be improved for nurses, health care assistants (HCAs), and doctors. These improvements allow better documentation and safer patient care. As a result, Milton Keynes University Hospital is investing in magnets and modified charts for a Trust-wide pilot. PMID- 26734451 TI - Improving efficiency management of radiopharmaceutical materials at a nuclear medicine department. AB - The cost of radiopharmaceutical materials is highly expensive compared with other resources employed in nuclear medicine department. Hence, inefficient utilization of these costly materials will lead to waste and more financial burden on the healthcare system, increasing the patient waiting list for important diagnostic procedures, especially in those with need urgent care on time. The available data for the previous 12 months about positron emission tomography / computed tomography (PET/CT) unit at nuclear medicine departments showed that over 16% of radiopharmaceutical materials were not utilized and being wasted due to increased number of cancelled or rescheduled oncology patients. The overall financial cost for the underutilized radiopharmaceutical materials due to cancelled and rescheduled procedures for 142 patient were about 39,760 US dollar. Most of these are the oncology patients with diabetes arriving at the nuclear medicine department with high blood glucose level and so are not fit for the procedure. This project aims to improve the oncology diabetic patients preparation for PET/CT procedure to avoid wasting the radiopharmaceutical materials. After implementing the PDSA cycles on 14 oncology patients we found that the quantity of not utilized radiopharmaceuticals were significantly reduced. On the other hand, majority of oncology diabetic patients became more aware about the importance of following the required preparation instruction. PMID- 26734452 TI - Improving viable low cost generic medication prescription rate in primary care pediatric practice. AB - The pediatric clinics of the Michigan State University College of Human Medicine (MSU-CHM) consist of academic pediatricians serving two clinics with a patient population of 5200. The internal quality measures published by the MSU health team had consistently indicated our generic medications prescription rate to be very low, with an average of about 21% for the years 2009, 2010, and 2011. There was an earnest need to increase our generic medication prescription rates, which is considered an indicator of good practice. The stakeholders identified were physicians, nurses, care managers, and the health information technology (HIT) team. The purpose of the project was to increase the prescribing rate of viable low cost and approved generic medications for the patients of the MSU-CHM general pediatric clinics. The stakeholders regularly met every few months to work on increasing the generic medication prescription rates based on the PDSA cycle. Help was sought from HIT to identify and acquire the top 10 brand names the group was prescribing along with individual provider data. The team reviewed the brand names most prescribed, and made a recommendation that the best group to target were the stimulant medications, allergy and asthma medications, and other psychotropics. The HIT team was then requested to add the available generics for all stimulant medications, asthma medications, and others in the electronic medical record (EMR). They were also clearly marked for ease of use, for example: amphetamine-dextroamphetamine extended release "generic for Adderall XR." It was decided that providers would prescribe all stimulants as a generic, unless not available, and nurses would change each brand name of stimulants to a generic every time they refilled a medicine, based on a protocol outlining the appropriate generic medications corresponding to the respective brand names. The physicians and nurses were also urged to discuss with the patients the substitution process and answer any questions from parents. Monthly reports were obtained from the HIT about our progress. After 12 months of implementing this project, the overall generic prescription rate increased from 20% at the end of first quarter 2012 to 53% at the end of 12 months, and 65.5% at the end of two years. This was well above the MSU health team (about six large group practices) primary care average of 34.6%. All brand name medication prescription rates were also decreased. This is a positive outcome for this project in a relatively short period of time, and a further plan will be to repeat the cycle and continue to improve on the generic prescription rate, thereby saving valuable dollars spent on health care. PMID- 26734453 TI - Improving the productivity and efficiency of vascular surgery and radiology multidisciplinary meetings. AB - Multidisciplinary team meetings are recognized as an important factor in driving quality of care. The Vascular Society of Great Britain and Northern Ireland recommend that all aspects of vascular surgery are suitable for discussion at multidisciplinary team (MDT) meetings, including carotid, peripheral, and aortic disease. The juniors doctors were tasked with preparing the patient list in our unit. This had become time consuming and somewhat unrewarding. The methods of preparation and information required on the patient list were reviewed. It was felt that typing a clinical summary for each patient on the list was the most time consuming factor. This was removed and patients were instead simply categorized into subgroups such as aneurysms, critical limb ischemia, and others. The information removed was substituted with the use on an electronic care record during the meeting to answer questions regarding comorbidities and previous interventions. Time spent preparing the meeting by the junior doctors was recorded before and after cycles of intervention. Prior to intervention this was found be a mean of 140 minutes (2.3 hours), and improved to a mean of 45 minutes (0.45 hours) with consequent cycles. The overall proportion of patients receiving definitive outcomes in each meeting after changes were implemented increased from 35 to 55%. This was not a primary outcome, but an unintended consequence of careful consideration of each cycle. In conclusion, the changes implemented have allowed junior doctors to spend more of their time with other activities such as the outpatient department (OPD) and theatre during their vascular surgery rotation. The proportion of cases discussed has increased due to more focused discussions during the MDT meeting, resulting in improved patient care. All stakeholders gave a largely positive reaction to the changes implemented. PMID- 26734454 TI - Waiting time reduction in intravitreal clinics by optimization of appointment scheduling: balancing demand and supply. AB - This study was designed guided by the Model for Improvement framework to reduce waiting times and visit duration in the intravitreal therapy clinic, while improving patient and staff experience. In our aim to provide good quality, patient-centred care and constantly improve, we optimised the appointment profile and patient flow. We involved a multidisciplinary team (one consultant, junior doctors, staff nurses, technicians, and receptionist), as well as patients and relatives, to try to understand the main delays in the clinic. Process mapping, a fishbone diagram, run charts, together with feedback from patients and staff, provided an insight on the possible roots of the delays experienced by our patients. The results of the inquiry led us to take actions focused on optimising appointment scheduling. After implementing the new scheduling profile (with a gap in the middle of the session), various cycles of plan-do-study-act and a comparative, qualitative study by interviewing 10 patients demonstrated that the waiting times decreased, and patients and staff experience improved. PMID- 26734455 TI - Monitoring of physical health parameters for inpatients on a child and adolescent mental health unit receiving regular antipsychotic therapy. AB - Physical health monitoring of patients receiving antipsychotics is vital. Overall it is estimated that individuals suffering with conditions like schizophrenia have a 20% shorter life expectancy than the average population, moreover antipsychotic use has been linked to a number of conditions including diabetes, obesity, and cardiovascular disease.[1-4] The severity of possible adverse effects to antipsychotics in adults has raised awareness of the importance of monitoring physical health in this population. However, there is little literature available as to the adverse effects of these medications in the child and adolescent community, which make physical health monitoring in this predominantly antipsychotic naive population even more important. An expert group meeting in the UK has laid down recommendations in regards to screening and management of adult patients receiving antipsychotics, however no specific guidelines have been put in place for the child and adolescent age group.[5] The aim of this audit was to establish whether in-patients receiving antipsychotics had the following investigations pre-treatment and 12 weeks after treatment initiation: body mass index, hip-waist circumference, blood pressure, ECG, urea and electrolytes, full blood count, lipid profile, random glucose level, liver function test, and prolactin. This is in addition to a pre-treatment VTE risk assessment. These standards were derived from local trust guidelines, NICE guidelines on schizophrenia [6] and The Maudsley Prescribing Guidelines.[7] We retrospectively reviewed 39 electronic case notes in total, of which 24 cases were post intervention. Intervention included the use of a prompting tool. This tool was filed in the physical health files of all patients receiving antipsychotics which was intended as a reminder to doctors regarding their patient's need for physical health monitoring. Professionals involved in the monitoring of such parameters were educated in the importance and purpose of its use. Following this intervention re-audit occurred after 6 and 16 months of the initial audit to establish whether the use of the prompting tool caused any significant change in clinical practice. Overall performance in monitoring physical health parameters was initially poor, however we were able to demonstrate that with the help of a single prompt sheet there was a significant improvement following post intervention audit for the majority of parameters being monitored. PMID- 26734456 TI - Perioperative dexamethasone administration in tonsillectomy patients: A three cycle audit showing improvement using printed theatre lists. AB - Dexamethasone administration prior to tonsillectomy has been shown to reduce morbidity and is part of SIGN guideline 117. We conducted a three-cycle audit of 149 patients to ascertain how well guidelines were being met and introduce a sustainable method to improve compliance. A 3-month audit was conducted to ascertain how many tonsillectomy patients didn't receive pre-operative dexamethasone. ENT secretaries were requested to add 'Dex Please' to tonsillectomy theatre lists. A 3-month re-audit was conducted; the intervention was only implemented in half of cases and so a reminding tool for the secretarial staff was administered before a third cycle. Initially, there was 73% compliance to SIGN guidelines, this improved to 87% in the second cycle. After the second intervention, all tonsillectomy theatre lists had the 'Dex Please' note and compliance to SIGN guidelines was 100%. There were five readmissions in the first cycle, three in the second and two in the third cycle. All readmissions were underdosed according to guidelines. Understanding there are regular staff rotations throughout many U.K. hospitals, we implemented a reliable method to increase compliance to guidelines which helped reduce post-operative readmission after tonsillectomy. This can be easily introduced to other institutions and for other perioperative requirements. PMID- 26734457 TI - CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids. AB - Inhaled corticosteroids (ICS) are the most effective controller medications for asthma, and variability in ICS response is associated with genetic variation. Despite ICS treatment, some patients with poor asthma control experience severe asthma exacerbations, defined as a hospitalization or emergency room visit. We hypothesized that some individuals may be at increased risk of asthma exacerbations, despite ICS use, due to genetic factors. A GWAS of 237,726 common, independent markers was conducted in 806 Caucasian asthmatic patients from two population-based biobanks: BioVU, at Vanderbilt University Medical Center (VUMC) in Tennessee (369 patients), and Personalized Medicine Research Project (PMRP) at the Marshfield Clinic in Wisconsin (437 patients). Using a case-control study design, the association of each SNP locus with the outcome of asthma exacerbations (defined as asthma-related emergency department visits or hospitalizations concurrent with oral corticosteroid use), was evaluated for each population by logistic regression analysis, adjusting for age, gender and the first four principal components. A meta-analysis of the results was conducted. Validation of expression of selected candidate genes was determined by evaluating an independent microarray expression data set. Our study identified six novel SNPs associated with differential risk of asthma exacerbations (P < 10(-05)). The top GWAS result, rs2395672 in CMTR1, was associated with an increased risk of exacerbations in both populations (OR = 1.07, 95% CI 1.03-1.11; joint P = 2.3 * 10(-06)). Two SNPs (rs2395672 and rs279728) were associated with increased risk of exacerbations, while the remaining four SNPs (rs4271056, rs6467778, rs2691529, and rs9303988) were associated with decreased risk. Three SNPs (rs2395672, rs6467778, and rs2691529) were present in three genes: CMTR1, TRIM24 and MAGI2. The CMTR1 mRNA transcript was significantly differentially expressed in nasal lavage samples from asthmatics during acute exacerbations, suggesting potential involvement of this gene in the development of this phenotype. We show that genetic variability may contribute to asthma exacerbations in patients taking ICS. Furthermore, our studies implicate CMTR1 as a novel candidate gene with potential roles in the pathogenesis of asthma exacerbations. PMID- 26734459 TI - TNF and regulatory T cells are critical for sepsis-induced suppression of T cells. AB - The immune system in sepsis is impaired as seen by reduced numbers and function of immune cells and impaired antigen-specific antibody responses. We studied T cell function in septic mice using cecal ligation and puncture (CLP) as a clinically relevant mouse model for sepsis. The proliferative response of CD4(+) and CD8(+) T cells was suppressed in septic mice. Adoptive transfer experiments demonstrated that the T cells were not intrinsically altered by CLP. Instead, the septic host environment was responsible for this T cell suppression. While CLP induced suppression was dependent on TNF activity, neither the activation of TNF receptors type 1 nor TNF receptor type 2 alone was sufficient to generate sepsis induced suppression showing that the two TNF receptors can substitute each other. Specific depletion of regulatory T (Treg) cells improved the impaired T cell proliferation in septic recipients demonstrating participation of Treg in sepsis induced suppression. In summary, sepsis leads to TNF-dependent suppression of T cell proliferation in vivo involving induction of Treg cells. PMID- 26734458 TI - A2B adenosine receptor activation switches differentiation of bone marrow cells to a CD11c(+)Gr-1(+) dendritic cell subset that promotes the Th17 response. AB - Adenosine is one of the major molecules associated with inflammation. We have previously reported that an adenosine receptor (AR) agonist has an enhancing effect on Th17 autoimmune responses, even though it suppressed Th1 responses. To determine the mechanism involved, we have examined the effect of AR agonists on mouse bone marrow dendritic cell (BMDC) differentiation and function. We show that mouse bone marrow cells (BMCs) differentiated into CD11c(+)Gr-1(+) dentritic cells (DCs) when cultured in granulocyte macrophage colony-stimulating factor (GM CSF)-containing medium containing an AR agonist. The non-selective AR agonist NECA and an A2BR-specific agonist had a similar effect, and the effect of NECA could be blocked by an A2BR-specific antagonist. Unlike CD11c(+)Gr-1(-) BMDCs, which have a greater stimulatory effect on Th1 T cells than Th17 cells, CD11c(+)Gr-1(+) BMDCs had a greater stimulatory effect on Th17 autoreactive T cells than on Th1 autoreactive T cells and this effect depended on gammadelta T cell activation. PMID- 26734460 TI - Bee venom phospholipase A2 suppresses allergic airway inflammation in an ovalbumin-induced asthma model through the induction of regulatory T cells. AB - Bee venom (BV) is one of the alternative medicines that have been widely used in the treatment of chronic inflammatory diseases. We previously demonstrated that BV induces immune tolerance by increasing the population of regulatory T cells (Tregs) in immune disorders. However, the major component and how it regulates the immune response have not been elucidated. We investigated whether bee venom phospholipase A2 (bvPLA2) exerts protective effects that are mediated via Tregs in OVA-induced asthma model. bvPLA2 was administered by intraperitoneal injection into control and OVA-challenged mice. The Treg population, total and differential bronchoalveolar lavage fluid (BALF) cell count, Th2 cytokines, and lung histological features were assessed. Treg depletion was used to determine the involvement of Treg migration and the reduction of asthmatic symptoms. The CD206 dependence of bvPLA2-treated suppression of airway inflammation was evaluated in OVA-challenged CD206(-/-) mice. The bvPLA2 treatment induced the Tregs and reduced the infiltration of inflammatory cells into the lung in the OVA challenged mice. Th2 cytokines in the bronchoalveolar lavage fluid (BALF) were reduced in bvPLA2-treated mice. Although bvPLA2 suppressed the number of inflammatory cells after OVA challenge, these effects were not observed in Treg depleted mice. In addition, we investigated the involvement of CD206 in bvPLA2 mediated immune tolerance in OVA-induced asthma model. We observed a significant reduction in the levels of Th2 cytokines and inflammatory cells in the BALF of bvPLA2-treated OVA-induced mice but not in bvPLA2-treated OVA-induced CD206(-/-) mice. These results demonstrated that bvPLA2 can mitigate airway inflammation by the induction of Tregs in an OVA-induced asthma model. PMID- 26734461 TI - Rhinovirus wheezing illness in infancy is associated with medically attended third year wheezing in low risk infants: results of a healthy birth cohort study. AB - Rhinoviruses may be pathogens contributing to the development of childhood wheezing. However, their role in low risk infants without an asthmatic predisposition is unknown. Knowing which healthy, low risk children are at increased risk for childhood wheezing after rhinovirus wheezing illness (RV-WI) in infancy, might help in developing prevention and treatment strategies for childhood wheezing. The aim of this study was to determine the association of medically attended wheezing at the age of three with RV-WI in the first year of life in low risk children without parental asthma. In a low risk, prospective birth cohort study, we followed 181 healthy born children from birth through the third year of life. We considered children 'low risk' if neither parent had a doctor's diagnosis of asthma. We determined infant RV-WI by parent-reported wheezing (based on daily logs) and simultaneous molecular rhinovirus detection in the first year of life. Respiratory function and blood eosinophil count were both measured in the first month of life. The primary outcome, third year wheezing, was defined as the use of prescribed inhaled asthma medications together with a doctor's visit for respiratory symptoms in the third year of life. We calculated the association of RV-WI with medically attended third year wheezing and other known possible risk factors for wheezing at the age of three. Among low risk children, third year wheezing was observed in 7 out of 18 (39%) children with versus 10 out of 163 (6%) children without infant RV-WI (OR 9.7, 95% CI 3.1-33.5, P < 0.0001). The association between RV-WI and third year wheezing was unchanged after adjustment for potential confounders such as eosinophilia and atopic eczema. RV-WI is a robust and independent risk factor for third year wheezing in low risk children without parental asthma. Future research will identify and protect those children at increased risk for RV-WI. PMID- 26734462 TI - Anaphylaxis cases presenting to primary care paramedics in Quebec. AB - Data on anaphylaxis cases in pre-hospital settings is limited. As part of the Cross Canada Anaphylaxis Registry (C-CARE), we assessed anaphylaxis cases managed by paramedics in Outaouais, Quebec. A software program was developed to prospectively record demographic and clinical characteristics as well as management of cases meeting the definition of the anaphylaxis. Univariate and multivariate logistic regressions were compared to assess factors associated with severity of reactions and epinephrine use. Among 33,788 ambulance calls of which 23,486 required transport, 104 anaphylaxis cases were identified (anaphylaxis rate of 0.31% [95%CI, 0.25%, 0.37%] among all ambulance calls and 0.44% [95%CI, 0.36%, 0.54%] among those requiring transport). The median age was 46.8 years and 41.3% were males. The common triggers included food (32.7% [95%CI, 24.0%, 42.7%]), drugs (24.0% [16.4%, 33.6%]), and venom (17.3% [10.8%, 26.2%]). Among all reactions, 37.5% (95%CI, 28.4%, 47.6%) were severe. Epinephrine was not administered in 35.6% (95%CI, 26.6%, 45.6%) of all cases. Males were more likely to have severe reactions (Odds ratio [OR]: 2.50 [95%CI, 1.03, 6.01]). Venom induced reactions and severe anaphylaxis were more likely to be managed with epinephrine (OR: 6.9 [95%CI, 1.3, 35.3] and 4.2 [95%CI, 1.5, 12.0], respectively). This is the first prospective study evaluating anaphylaxis managed by paramedics. Anaphylaxis accounts for a substantial proportion of the cases managed by paramedics in Outaouais, Quebec and exceeds prior reports of the proportion of Quebec emergency room visits attributed to anaphylaxis. Although guidelines recommend prompt use of epinephrine for all cases of anaphylaxis, more than a third of cases did not receive epinephrine. It is crucial to develop educational programs targeting paramedics to promote the use of epinephrine in all cases of anaphylaxis regardless of the specific trigger. PMID- 26734463 TI - Reduced iNKT cells numbers in type 1 diabetes patients and their first-degree relatives. AB - Type 1 diabetes (T1D) is an autoimmune disease that is characterized by the specific destruction of insulin-producing pancreatic beta cells. Invariant natural killer T (iNKT) cells have been associated with development of T1D. Class I MHC-restricted T cell-associated molecule (CRTAM) is expressed on activated iNKT, CD8(+), and CD4(+) T cells, and it is associated with the pro-inflammatory profiles of these cells. Crtam gene expression in CD3(+) lymphocytes from non obese diabetic (NOD) mice is associated with T1D onset. However, expression of CRTAM on T cells from patients with T1D has not yet been evaluated. We compared iNKT cell (CD3(+)Valpha24(+)Vbeta11(+)) numbers and CRTAM expression in a Mexican population with recent-onset T1D and their first-degree relatives with control families. Remarkably, we found lower iNKT cell numbers in T1D families, and we identified two iNKT cell populations in some of the families. One iNKT cell population expressed high iTCR levels (iNKT(hi)), whereas another expressed low levels (iNKT(lo)) and also expressed CRTAM. These findings support a probable genetic determinant of iNKT cell numbers and a possible role for these cells in T1D development. This study also suggests that CRTAM identifies recently activated iNKT lymphocytes. PMID- 26734464 TI - Loss of IL-4Ralpha-mediated PI3K signaling accelerates the progression of IgE/mast cell-mediated reactions. AB - Clinical and experimental evidence indicate that polymorphisms within the interleukin 4 (IL-4) receptor (IL-4R) chain are sufficient for altered strength of IL-4/IL-13 signaling, leading to an exaggerated allergic inflammatory response and increase susceptibility to allergic phenotypes. In the present study, we show that ablation of IL-4Ralpha-induced phosphatidylinositol 3-kinase (PI3K) activating signal by germline point mutation within the IL-4Ralpha motif (Y500F) did not alter susceptibility to IgE-mediated, food-induced experimental anaphylaxis. Moreover, diarrhea occurrence, antigen-specific IgE and intestinal mastocytosis were comparable between WT and IL-4Ralpha(Y500F) mice. However, mice unable to stimulate IL-4Ralpha-mediated PI3K signaling had accelerated disease progression. Notably, the accelerated anaphylactic response was associated with more rapid histamine-induced hypovolemia. Mechanistic in vitro and in vivo analyses revealed that endothelial IL-4Ralpha PI3K signaling negatively regulates the histamine-induced endothelial leak response. These results define an unanticipated role for IL-4Ralpha-mediated PI3K signaling in negative regulation of IgE-mediated anaphylactic reactions. PMID- 26734465 TI - Functional profile of S100A4-deficient T cells. AB - The protein S100A4 is best known for its significant role in promoting motility and invasive capacity of cancer cells. Since S100A4 expression has been reported also in T cells, we analyzed its potential role in T cell motility and inflammation. Using S100a4(+/Gfp) mice, we show here that S100A4 is exclusively expressed by memory T cells of CD4(+) or CD8(+) subpopulations, predominantly of the effector memory T cell subtype. However, the protein was not required for in vitro memory T cell migration toward gradients of the inflammatory chemokine CXCL10. Moreover, T cell memory response was normal in S100A4-deficient mice and lack of S100a4 gene expression did not induce any defect in promoting the development of protective immunity or inflammatory reactions leading to autoimmunity. Taken together, our results demonstrate that S100A4 activity is dispensable for T cell motility/migration and inflammatory potential. PMID- 26734467 TI - Activated protein C does not increase in the early phase of trauma with disseminated intravascular coagulation: comparison with acute coagulopathy of trauma-shock. AB - We hypothesized that activated protein C does not increase in disseminated intravascular coagulation (DIC) after trauma and that the same is true for acute coagulopathy of trauma-shock (ACOTS). Activated protein C levels were prospectively measured in 57 trauma patients: 30 with DIC and 27 without DIC. Normal to more decreased activated protein C levels were observed in DIC patients than in the controls and non-DIC patients. The activated protein C levels in ACOTS patients were similar to those in DIC patients. In conclusion, activated protein C does not increase in either DIC or ACOTS in the early phase of trauma. PMID- 26734466 TI - Interleukin-25 initiates Th2 differentiation of human CD4(+) T cells and influences expression of its own receptor. AB - Human CRTh2(+) Th2 cells express IL-25 receptor (IL-25R) and IL-25 has been shown to potentiate production of Th2 cytokines. However, regulation of IL-25R and whether it participates in Th2 differentiation of human cells have not been examined. We sought to characterize IL-25R expression on CD4(+) T cells and determine whether IL-25 plays a role in Th2 differentiation. Naive human CD4(+) T cells were activated in the presence of IL-25, IL-4 (Th2 conditions) or both cytokines to assess their relative influence on Th2 differentiation. For experiments with differentiated Th2 cells, CRTh2-expressing cells were isolated from differentiating cultures. IL-25R, GATA3, CRTh2 and Th2 cytokine expression were assessed by flow cytometry, qRT-PCR and ELISA. Expression of surface IL-25R was induced early during Th2 differentiation (2 days). Addition of IL-25 to naive CD4(+) T cells revealed that it induces expression of its own receptor, more strongly than IL-4. IL-25 also increased the proportions of IL-4-, GATA3- and CRTh2-expressing cells and expression of IL-5 and IL-13. Activation of differentiated CRTh2(+) Th2 cells through the TCR or by CRTh2 agonist increased surface expression of IL-25R, though re-expression of CRTh2 following TCR downregulation was impeded by IL-25. These data suggest that IL-25 may play various roles in Th2 mediated immunity. We establish here it regulates expression of its own receptor and can initiate Th2 differentiation, though not as strongly as IL-4. PMID- 26734468 TI - A novel surgical approach for the management of giant invasive prolactinoma compressing the brainstem. AB - Prolactinomas constitute the largest subsection of all secretory pituitary adenomas. Most are microprolactinomas and are satisfactorily treated by medical management alone. Giant prolactinomas, measuring more than 4 cm in diameter, are rare and usually occur more commonly in men. Macroprolatinomas tend to present with symptoms of mass effect rather than those of hyperprolactinaemia. Dopamine agonists (DA) are the treatment of choice for all prolactinomas. Surgery is usually reserved for DA resistance or if vision is threatened by the mass effects of the tumour. We describe the case of a 52 year-old woman with a giant invasive prolactinoma who required multiple surgical procedures as well as medical management with DA. One of the surgical interventions required a posterior approach via the trans cranial sub occipital transtentorial approach, a surgical technique that has not been previously described in the medical literature for this indication. The giant prolactinoma was reduced significantly with the above approach and patient symptoms from the compressing effects of the tumour were resolved. This case highlights the importance of a multidisciplinary approach to the management of such patients who present with florid neurological sequelae secondary to pressure effects. Although this presentation is uncommon, surgery via a sub occipital transtentorial approach may be considered the treatment of choice in suitable patients with giant invasive prolactinomas compressing the brainstem. LEARNING POINTS: Giant prolactinomas present with symptoms of mass effect or those of hyperprolactinaemia.Interpretation of the pituitary profile is crucial to guide further investigations and management.Treatment of giant invasive prolactinomas may involve a combination of medical management and multiple surgical interventions.Treatment with DA may cause pituitary haemorrhage or infarction in patients with these tumours.A sub occipital transtetorial approach may be considered the treatment of choice in invasive prolactinomas compressing the brainstem.Multidisciplinary approach of such patients is fundamental for a better outcome. PMID- 26734469 TI - Immunohistochemical Assessment of HER3 Expression in Odontogenic Cysts. AB - BACKGROUND: It has been demonstrated that HER3 plays an important role in some human cancers and the HER3 expression is associated with worse survival in solid tumors. OBJECTIVES: This study was conducted to compare HER3 expression in epithelial lining of radicular cysts (RCs), dentigerous cysts (DCs) and odontogenic keratocysts (OKCs). MATERIALS AND METHODS: This was a descriptive analytical study, which assessed all 57 paraffin blocks of RCs, DCs and OKCs (21 RCs, 16 DCs, 20 OKC) from pathological archive of Dentistry College of Zahedan, Iran. The HER3 expression in cytoplasm and membrane was examined by immunohistochemical method. The data collected was analyzed using SPSS16 by ANOVA and Chi-square. P < 0.05 was considered as statistically significant. RESULTS: The HER3 expression had positive results in 52.4% of OKC, 50% of DC and only 20% of RC samples. There was a significant difference between HER3 expression in OKCs and RCs. CONCLUSIONS: The HER3 expression in developmental odontogenic cysts was higher than that in inflammatory odontogenic cysts. The higher rate of HER3 expression in OKC may justify inherent growth potential, stimulation-independent proliferation capability, invasive growth and high recurrence rate of the cyst accepted today as a tumor. PMID- 26734470 TI - The Effect of Narrative Reminiscence on Happiness of Elderly Women. AB - BACKGROUND: Happiness has a considerable impact on elderly quality of life. Reminiscence therapy can be an effective intervention in increasing the positive emotions among elderly. OBJECTIVES: This study was performed to investigate the effect of reminiscence therapy on Iranian elderly women's happiness. PATIENTS AND METHODS: This randomized clinical trial conducted on 32 elderly women (census sampling) attending the jahandidegan daycare elderly center IN Gorgan city, Iran, in 2013. Happiness scores of 4 phases were measured: before, the third session, the sixth session and one month after the intervention. Three instruments were used in this study including a demographic questionnaire, the mini mental state examination test, and Oxford happiness questionnaire. The intervention group participated in six sessions of narrative group reminiscence that were held in three consecutive weeks, two sessions per week. The control group was also participated in six sessions of group discussions that were held in three consecutive weeks, two sessions per week. Data analysis was performed the chi square, independent t-test, Paired t-test. RESULTS: From a total of 32 elderly women, 29 cases completed the study. No significant differences were found between the two groups in terms of demographic characteristics. The mean happiness scores before the intervention between the two groups were not significantly different (P = 0.824). Comparison of the mean happiness scores of the intervention group in the four measurement times revealed a significant difference only after the third and sixth sessions (P = 0.03), and no significant difference was found between the mean happiness scores of the control group in the four measurement times. CONCLUSIONS: The elderly participating in the matched group sessions can be effective in increasing positive emotions. PMID- 26734471 TI - Right Atrium Myxoma After Lung Adenocarcinoma. AB - INTRODUCTION: Heart secondary tumors are much more common than primary tumors. These two types of tumors differ not only by their source but also by their symptoms and location in heart chambers. CASE PRESENTATION: This report presents a 66-year-old heavy smoker female with a history of pulmonary lobectomy due to lung adenocarcinoma, hysterectomy due to myoma, and lumpectomy due to benign breast mass, who had symptoms of right heart failure for months. Physical examinations followed by imaging showed a mass in her right atrium, which was most likely, a myxoma. After a successful surgical excision, histopathological findings confirmed the diagnosis. More studies are needed to evaluate a possible combination between these soft tissue masses. CONCLUSIONS: A right atrium myxoma in a patient with a history of multiple soft tissue tumors has been limited to only a few cases. This may suggest a genomic affinity or similarity; if so, those with multiple different type soft tissue masses should be screened for a heart mass before the mass becomes complicated. PMID- 26734472 TI - Relationship Between Job Characteristics and Organizational Commitment: A Descriptive Analytical Study. AB - BACKGROUND: Many factors influence the organizational commitment of employees. One of these factors is job designing since it affects the attitude, beliefs, and feelings of the organization employees. OBJECTIVES: We aimed to determine the relationship between job characteristics and organizational commitment among the employees of hospitals. PATIENTS AND METHODS: In this descriptive and correlational study, 152 Iranian employees of the hospitals (physicians, nurses, and administrative staff) were selected through stratified random sampling. Data gathered using 3-part questionnaire of "demographic information", "job characteristics model," and "organizational commitment," in 2011. Study data were analyzed using SPSS v. 16. RESULTS: There was significant statistical correlation between organizational commitment and variables of educational level (P = 0.001) and job category (P = 0.001). Also, a direct and significant correlation existed between motivating potential score and job feedback on one hand and organizational commitment on the other hand (P = 0.014). CONCLUSIONS: According to the results, managers of the hospitals should increase staff's commitment through paying attention to proper job designing. PMID- 26734473 TI - Nonsurgical Treatment of Hemifacial Microsomia: A Case Report. AB - INTRODUCTION: Hemifacial microsomia (HFM) is a birth defect involving craniofacial structures derived from the first and second branchial arches. Although it is a relatively uncommon malformation, it is the second most common craniofacial birth defect after cleft lip and palate (CL/P). CASE PRESENTATION: This is a case report about the successful orthodontic treatment of a patient with mild hemifacial microsomia (HFM), using a non-surgical orthopedic and orthodontic treatment approach. The aim of this approach was to make the best noninvasive modality to treat HFM. A 7-year-old boy with a mild HFM presented with a convex profile and slight chin deviation. Orthopedic treatment performed using a hybrid functional and high pulls headgear. Treatment continued by fixed orthodontic straight wire appliance to achieve perfect occlusion. CONCLUSIONS: Excellent esthetic and functional results achieved; total treatment duration was about 72 months. PMID- 26734474 TI - Stachys lavandulifolia Vahl. and its Relation With Marmazad Activities in Traditional Manuscripts. AB - CONTEXT: In modern phytotherapy, Stachys lavandulifolia Vahl., a type of Stachys also known as Mountain Tea (Chay-e-Kouhi) has been widely studied based on its botanical and therapeutic characteristics over the recent decades. EVIDENCE ACQUISITION: The present study investigated morphology, botanical characteristics, and some therapeutic activities of this plant and compares them with those of Marmazad, as the traditional equivalent of Stachys in traditional iranian medicine (TIM), to evaluate the similarities between Stachys and Marmazad. RESULTS: In this study by exploring morphology, botanical properties and therapeutic activities of Stachys from modern botany and Marmazad in TIM, comparing them and considering similarities between those botanical properties and some of therapeutic activities this outcome was drawn that what had been known as Marmazad in TIM nowadays is equal to Stachys or Chay-e-Kouhi in modern botany. CONCLUSIONS: The achieved findings from this comparison between botanical characteristics and therapeutic activities of Stachys based on modern researches and those of Marmazad by referring to traditional manuscripts revealed significant similarities between them. Also, there were some applications mentioned for Marmazad in TIM which could help new researchers in modern phytotherapy to deal with those dimensions of this herb which are not worked out yet. PMID- 26734475 TI - Comparing the Effects of Reflexology and Footbath on Sleep Quality in the Elderly: A Controlled Clinical Trial. AB - BACKGROUND: Sleep disorders are common mental disorders reported among the elderly in all countries, and with nonpharmacological interventions, they could be helped to improve their sleep quality. OBJECTIVES: The aim of this study was to compare the effects of two interventions, foot reflexology and foot bath, on sleep quality in elderly people. PATIENTS AND METHODS: This three-group randomized clinical trial (two experimental groups and a control group) was conducted on 69 elderly men. The two experimental groups had reflexology (n = 23) and foot bath (n = 23) interventions for 6 weeks. The reflexology intervention was done in the mornings, once a week for ten minutes on each foot. The participants in the foot bath group were asked to soak their feet in 41 degrees C to 42 degrees C water one hour before sleeping. The pittsburgh sleep quality index (PSQI) was completed before and after the intervention through an interview process. RESULTS: The results showed that the PSQI scores after intervention compared to before it in the reflexology and foot bath groups were statistically significant (P = 0.01 , P = 0.001); however, in the control group did not show a statistically significant difference (P = 0.14). In addition, the total score changes among the three groups were statistically significant (P = 0.01). Comparing the score changes of quality of sleep between the reflexology and foot bath groups showed that there was no significant difference in none of the components and the total score (P = 0.09). The two interventions had the same impact on the quality of sleep. CONCLUSIONS: It is suggested that the training of nonpharmacological methods to improve sleep quality such as reflexology and foot bath be included in the elderly health programs. In addition, it is recommended that the impact of these interventions on subjective sleep quality using polysomnographic recordings be explored in future research. PMID- 26734477 TI - Risk Factors of Graft Survival After Diagnosis of Post-kidney Transplant Malignancy: Using Cox Proportional Hazard Model. AB - BACKGROUND: All recipients of kidney transplantation, especially those with posttransplant malignancy, are at risk of long-term graft failure. OBJECTIVES: The purpose of our study was to evaluate the risk factors associated with graft survival after diagnosis of malignancy. PATIENTS AND METHODS: To reach this purpose, we conducted a historical cohort study in Iran and 266 cases with posttransplant malignancy were followed up from diagnosis of malignancy until long-term graft loss or the date of last visit. These patients were taken as a census from 16 Transplant Centers in Iran during 22 years follow-up period since October 1984 to December 2008. A Cox proportional hazards model was performed to determine the important independent predictors of graft survival after malignancy. RESULTS: At the end of the study, long-term graft failure was seen in 27 (10.2%) cases. One-year and 2-year graft survival after diagnosis of cancer were 93.6% and 91.7%, respectively. The univariate analysis showed that the incidence of chronic graft loss was significantly higher in male patients with solid cancers, withdrawal of immunosuppressant regimen, no response to treatment, and tumor metastasis. In continuation, the Cox model indicated that the significant risk factors associated with graft survival were type of cancer (P < 0.0001), response to treatment (P < 0.0001, HR = 0.14, 95% CI: 0.06 - 0.32), metastasis (P < 0.0001, HR = 5.68, 95% CI: 2.24 - 14.42), and treatment modality (P = 0.0001). CONCLUSIONS: By controlling the modifiable risk factors and modality of treatment in our study, physicians can reach more effective treatment. PMID- 26734476 TI - Transdermal Wound Oxygen Therapy on Pressure Ulcer Healing: A Single-Blind Multi Center Randomized Controlled Trial. AB - BACKGROUND: Although healthcare quality has considerably improved in many countries, pressure ulcer is still a major health challenge worldwide. OBJECTIVES: The current study aimed to evaluate the effects of TWOT on the healing of pressure ulcers. PATIENTS AND METHODS: This study was a randomized controlled trial, and the convenient sample including 100 patients hospitalized in two university-affiliated medical-surgical intensive care units and one neurology unit located in Qazvin, Iran were studied. Patients with stage II-IV pressure ulcer on the sacral or ischial areas were randomly assigned to either the control or the experimental groups. The experimental group received a 12-day transdermal wound oxygen therapy. Wound status was assessed seven times before the intervention, as well as two, four, six, eight, ten, and twelve days after the intervention. RESULTS: After 12 days of wound oxygen therapy, the number of patients with complete wound healing in the experimental group was significantly greater than that of the control group. Moreover, the total mean of wound area in the experimental group was significantly lower than that of the control group. CONCLUSIONS: Transdermal wound oxygen therapy can effectively promote wound healing in patients with pressure ulcers. PMID- 26734478 TI - Delayed Diagnosis of Hypothyroidism in Children: Report of 3 Cases. AB - INTRODUCTION: Hypothyroidism is the most common endocrine disorder in children and presented with various sign and symptoms; its diagnosis needs a high index of suspicion. CASE PRESENTATION: We report 3 cases with unusual presentations of hypothyroidism and with delay in diagnosis that referred to Pediatric Endocrine Outpatient Clinic in Mashhad University of Medical Sciences, Mashhad, Iran with different clinical manifestations. They had decreased Thyroxin (T4) and increased thyroid stimulating hormone (TSH) levels. One case had mental retardation and deafness, but the other two cases had normal neurodevelopment. Some additional interesting findings were as follows: short stature, delayed bone age, teeth eruption impairment, hair loss, anemia and hypercholesterolemia, persistent and long-term constipation that had led to several abdominal surgeries. After a year of hormonal replacement therapy, their growth parameters and hematological values improved. CONCLUSIONS: We recommend thyroid hormonal evaluation for any children with short stature, especially with delayed bone age, in order to detect and treat hypothyroidism at the right time. It seems that more attention to pediatric growth is necessary. PMID- 26734479 TI - Small Cell Carcinoma of the Esophagus: Clinicopathological Features and Outcome of 22 Cases. AB - BACKGROUND: Small cell esophageal carcinoma (SCEC) is a highly aggressive and rare neoplasm. OBJECTIVES: This study aimed to report the characteristics, prognostic factors, and treatment outcomes of 22 patients with SCEC. PATIENTS AND METHODS: This brief report was carried out by reviewing the medical records of 22 patients with newly histologically proven SCEC that were treated between 2000 and 2010 at 2 tertiary academic hospitals. All the potential prognostic variables, including the patients' characteristics, tumor features, and treatment modalities were analyzed to establish their influence on the patients' survival rates. RESULTS: This study was conducted on 7 males and 15 females with a median age of 61 years. Dysphagia and weight loss were the most prevalent symptoms. According to the results, 14 patients (64%) had limited diseases and 8 cases (36%) had extensive diseases. In those with extensive diseases, liver, lung, and lymph nodes (LNs) were the most metastatic sites. Besides, most tumors were located in lower (50%) and middle (32%) part of the esophagus. Most patients (91%) were treated with sequential (55%) or concurrent (36%) chemoradiation (CRT). Surgical resection was also performed for 7 patients. Chemotherapy regimen consisted of cisplatin and etoposide in 14 patients (64%). The median follow up time was 12 months. The 1, 3, and 5-year overall survival rates were 27%, 14%, and 4%, respectively. Yet, no prognostic factors were found because of the small sample size of the study. CONCLUSIONS: Primary SCEC is a rare and highly aggressive tumor. However, prognosis is poor and long-term survival is exceptional. CRT could be an appropriate alternative to operation. PMID- 26734480 TI - Intelligence Care: A Nursing Care Strategy in Respiratory Intensive Care Unit. AB - BACKGROUND: Working in respiratory intensive care unit (RICU) is multidimensional that requires nurses with special attributes to involve with the accountability of the critically ill patients. OBJECTIVES: The aim of this study was to explore the appropriate nursing care strategy in the RICU in order to unify and coordinate the nursing care in special atmosphere of the RICU. MATERIALS AND METHODS: This conventional content analysis study was conducted on 23 health care providers working in the RICU of Sina and Shariati hospitals affiliated to Tehran university of medical sciences and the RICU of Baqiyatallah university of medical sciences from August 2012 to the end of July 2013. In addition to in-depth semistructured interviews, uninterrupted observations, field notes, logs, patient's reports and documents were used. Information saturation was determined as an interview termination criterion. RESULTS: Intelligence care emerged as a main theme, has a broad spectrum of categories and subcategories with bridges and barriers, including equality of bridges and barriers (contingency care, forced oriented task); bridges are more than barriers (human-center care, innovative care, cultural care, participatory care, feedback of nursing services, therapeutic-professional communication, specialized and independent care, and independent nurse practice), and barriers are higher than bridges (personalized care, neglecting to provide proper care, ineffectiveness of supportive caring wards, futility care, nurse burnout, and nonethical-nonprofessional communications). CONCLUSIONS: Intelligence care is a comprehensive strategy that in addition to recognizing barriers and bridges of nursing care, with predisposing and precipitating forces it can convert barriers to bridges. PMID- 26734481 TI - Shear Bond Strength of Orthodontic Brackets to Tooth Enamel After Treatment With Different Tooth Bleaching Methods. AB - BACKGROUND: Bleaching treatments decrease shear bond strength between orthodontic brackets and teeth; although definite results have not been reported in this regard. OBJECTIVES: This study determined the effects of different bleaching protocols on the shear bond strength of orthodontic brackets to teeth. MATERIALS AND METHODS: This experimental study was performed in Iran. Forty-eight extracted human premolars were randomly assigned into four groups. In the control group, no bleaching treatment was performed. In groups 2 - 4, the bleaching procedures were performed using carbamide peroxide 45%, carbamide peroxide 20% and diode laser, respectively. Two weeks later, brackets were bonded to teeth and thermocycled. The shear bond strengths of the brackets to the teeth were measured. Data was analyzed by one-way ANOVA and Dunnett post-hoc test. RESULTS: Shear bond strength of the brackets to the teeth were 10.54 +/- 1.51, 6.37 +/- 0.92, 7.67 +/- 1.01 and 7.49 +/- 1.19 MPa, in groups 1 - 4, respectively. Significant differences were found between control group and all other groups (P < 0.001); and also between groups 2 and 3 (P < 0.05). No significant differences were found between the other groups. CONCLUSIONS: The bleaching procedures using 20% carbamide peroxide and 45% carbamide peroxide and diode laser significantly decreased shear bond strength of brackets to the teeth. 45% carbamide peroxide had a more significant effect on bond strength compared to 20% carbamide peroxide. The difference in bond strength was not significant between laser group and either carbamide peroxide groups. PMID- 26734483 TI - Herbal Remedies for Functional Dyspepsia and Traditional Iranian Medicine Perspective. AB - CONTEXT: Functional dyspepsia (FD) is a functional gastro-intestinal disorder with high prevalence. Among various treatment options, treatment by complementary and alternative medicines especially herbal remedies also practiced. Traditional Iranian medicine (TIM), a valuable resource of valid applied studies of ancient Iranian scholars, recommends numerous medicinal plants to treat dyspepsia symptoms. In this study, through investigation of TIM references, we aimed to identify medicinal plants for treatment of digestion insufficiency. EVIDENCE ACQUISITION: In this qualitative study, dyspepsia symptoms including fullness, early satiety, bloating, nausea, and belching were checked under reliable sources of traditional medicine. Then medicinal plants recommended for the treatment of the symptoms were extracted from the books. Likewise, for investigating the pharmacological properties of medicinal plants used for the relieving of dyspepsia symptoms, electronic databases such as PubMed, Scopus, Google Scholar and some Iranian databases like SID and IranMedex were employed. RESULTS: The study yielded 105 plants from 37 families which could treat various dyspepsia symptoms; fifty-seven plants, mainly from Apiaceae, Lamiaceae, Amaryllidaceae and Zingiberaceae had digestive effects. In this research, based on the information in TIM reference texts, we obtained 58 plants effective for bloating, 40 for nausea, 37 for appetite loss and 7 for belching. In human clinical trials conducted on medicinal plants effective for FD symptoms, 7 single plants were used. CONCLUSIONS: Finding the medicinal plants effective on digestion insufficiency based on TIM could suggest a better strategy for the relieving of dyspepsia symptoms. Traditional Iranian medicine prescribes medicinal plants based on each patient's personal characteristics and practices multiple target therapies. PMID- 26734482 TI - The Relationship of Disordered Eating Attitudes With Body Composition and Anthropometric Indices in Physical Education Students. AB - BACKGROUND: Abnormal eating behavior, unhealthy weight control methods, and eating disordered symptoms have risen among college students. OBJECTIVES: The aim of this study was to examine disordered eating attitudes and their relationship with anthropometric and body composition indices in physical education students in Tabriz, the capital of East Azerbaijan province, Iran. PATIENTS AND METHODS: This cross-sectional study was conducted on 210 physical education students, 105 males and 105 females aged 18 to 25, who were selected by systematic random sampling from physical education faculty of Tabriz University in Tabriz, Iran, in 2013. Eating attitude test (EAT-26) was used for the assessment of disordered eating attitudes. In addition, anthropometric and body composition indices were assessed. RESULTS: About 10% of the studied subject had disturbed eating attitudes; significantly more males (15.4%) reported an EAT-26 >= 20 (disordered eating attitudes) than females (4.8%) (P < 0.05). In males, the EAT-26 score was positively correlated with weist perimeter (WP) (r = 0.21, P < 0.05) and the waist-to-hip ratio (r = 0.26, P < 0.01). In females, the EAT-26 score was positively correlated with weight (r = 0.19, P < 0.05) and the WP (r = 0.28, P < 0.01). In females, weight (P < 0.05), body mass index (BMI) (P < 0.05), WP (P < 0.01), and waist-to-hip ratio (P < 0.05) were significantly different between disordered eating attitude and healthy subjects, while in males there was no significant difference between the two groups regarding the anthropometric and body composition indices. CONCLUSIONS: Abnormal eating attitude was notable among physical education students in Tabriz, Iran. It seems that some anthropometric indices such as BMI and central obesity indices were related to the increase of disordered eating attitude. PMID- 26734484 TI - Ten-year Survival and Its Associated Factors in the Patients Undergoing Pacemaker Implantation in Hospitals Affiliated to Shiraz University of Medical Sciences During 2002 - 2012. AB - BACKGROUND: Heart failure is a prevalent disease affecting about 4.9 million people in the U.S. and more than 22 million individuals worldwide. Using electric pacemaker is the most common treatment for the patients with heart conduction problems. The present study aimed to determine the factors affecting survival in the patients undergoing pacemaker implantation in the hospitals affiliated to Shiraz University of Medical Sciences. OBJECTIVES: The aim of the present study was to identify the factors affecting the survival of the patients suffering from arrhythmia. PATIENTS AND METHODS: This retrospective survival analysis was conducted on all 1207 patients with heart failure who had undergone permanent pacemaker implantation in the hospitals affiliated to Shiraz University of Medical Sciences from 2002 to 2012. The data were analyzed using non-parametric methods such as Kaplan-Meier method, life table, and Cox regression model. The risk factors of mortality were determined using multivariate Cox proportional hazards method. RESULTS: Survival data were available for 1030 (80%) patients (median age = 71 years [5th to 95th percentile range: 26 - 86 years]) and follow up was completed for 84.28% of them. According to the results, 56% of the patients had received dual-chamber systems, while 44% had been implanted by single-chamber ventricular systems. Moreover, sick sinus syndrome and pacemaker mode were independent predictors of increased mortality. CONCLUSIONS: In this study, sick sinus syndrome and pacemaker mode followed by syncope were independently associated with increased mortality. PMID- 26734485 TI - Effect of Relaxation With Guided Imagery on The Physical and Psychological Symptoms of Breast Cancer Patients Undergoing Chemotherapy. AB - BACKGROUND: Breast cancer patients frequently experience psychological distress during the chemotherapy period. OBJECTIVES: This study aimed to evaluate the effect of relaxation with guided imagery on patients with breast cancer. PATIENTS AND METHODS: A two-group, pretest-posttest, quasi-experimental design with a randomized controlled trial was conducted. Sixty-five breast cancer patients from one medical center in Taiwan were enrolled in the study. These patients were randomly assigned to the experimental group (n = 32) or to the control group (n = 33). Both groups received chemotherapy self-care education, but the experimental group also received relaxation with guided imagery training. The training on relaxation with guided imagery was conducted before chemotherapy, and the patients were supplied with a compact disc detailing the performance of relaxation with guided imagery for 20 minutes daily at home for 7 days after chemotherapy. RESULTS: The experimental group showed significant decreases in insomnia (-0.34 +/- 0.83, P < 0.05), pain (-0.28 +/- 0.58, P < 0.05), anxiety ( 3.56 +/- 2.94, P < 0.00), and depression (-2.38 +/- 2.70, P < 0.00) between the pretest and the posttest. Comparing the two groups, statistically significant differences were found in the overall symptom distress (B = 0.11, P < 0.05), insomnia (B = 0.50, P <0.05), depression (B = 0.38, P < 0.05), and numbness in physical symptoms (B = 0.38, P < 0.05), as well as in anxiety (B = 3.08, P < 0.00) and depression (B = 1.86, P < 0.00) in psychological distress. One week of relaxation with guided imagery can significantly improve the overall symptoms of distress, insomnia, depression, physical symptoms, and anxiety, and can decrease psychological distress. CONCLUSIONS: Relaxation with guided imagery had a positive effect on mediating anxiety and depression in breast cancer patients. PMID- 26734486 TI - Interventions to Reduce Drug Abuse in Pars Special Economic Energy Zone. AB - BACKGROUND: South Pars special economic energy zone is the world's second largest gas reservoir that was established two decades ago. High incidence of social harms is observed in this region due to various problems such as drug addiction which is of high prevalence. OBJECTIVES: The current study aimed at finding the strategies to prevent drug abuse and formulating policies in the region. MATERIALS AND METHODS: The research method was a combination of nested type (qualitative-quantitative) and analysis of participated stakeholders' views. The study was conducted from January 2014 to May 2015 in Bushehr province. Intentional sampling was used in qualitative section. Collected data were classified in 3 areas: recognition, directions, and implementation requirements. RESULTS: Different factors were identified affecting the prevalence of drug addiction. Various prevention and treatment interventions have been conducted in response to drug abuse in the region, though they have been often sectional, insular, inconsistent, and immeasurable in terms of impact. After the study, a combination of compulsory, facilitative, and promotional interventions was proposed to reduce drug abuse by 10% within a strategic 5-year plan. These interventions are based on 3 aspects: people, industry, and governance, which have been announced and approved based on a memorandum of understanding. CONCLUSIONS: It is necessary to implement simultaneous national interventions as soon as possible to improve the economic, social, political, technological, international, and environmental conditions. In the current study, unlike the previous attempts, national stakeholders, including ministry of petroleum, ministry of health and medical education, interior ministry, ministry of cooperatives, labor, and social welfare, and Iran drug control headquarters have played active roles. This fact is evident in their formulation of a policy document in the region and action plan after reaching a memorandum of understanding. PMID- 26734488 TI - A page is turned in the digital era. PMID- 26734487 TI - Occult HCV Infection: The Current State of Knowledge. AB - CONTEXT: Occult HCV infection (OCI) is defined as the presence of HCV-RNA in hepatocytes and the absence of HCV in the serum according to usual tests. We aimed to define OCI and provide information about the currently available diagnostic methods. Then we focus on specific groups that are at high risk of OCI and finally investigate immune responses to OCI and the available treatment approaches. EVIDENCE ACQUISITION: PubMed, Scopus and Google Scholar were comprehensively searched with combination of following keywords: "occult", "hepatitis C virus" and "occult HCV infection". The definition of OCI, diagnostic methods, specific groups that are at high risk and available treatment approaches were extract from literature. An analysis of available articles on OCI also was done based on Scopus search results. RESULTS: OCI has been reported in several high-risk groups, especially in hemodialysis patients and subjects with cryptogenic liver disease. Furthermore, some studies have proposed a specific immune response for OCI in comparison with chronic hepatitis C (CHC). CONCLUSIONS: With a clinical history of approximately 11 years, occult HCV infection can be considered an occult type of CHC. Evidences suggest that considering OCI in these high-risk groups seems to be necessary. We suggest that alternative diagnostic tests should be applied and that there is a need for the participation of all countries to determine the epidemiology of this type of HCV infection. Additionally, evaluating OCI in blood transfusion centers and in patients who receive large amounts of blood and clotting factors, such as patients with hemophilia, should be performed in future projects. PMID- 26734489 TI - A comparative study of combined periodontal and orthodontic treatment with fixed appliances and clear aligners in patients with periodontitis. AB - PURPOSE: With the increasing prevalence of orthodontic treatment in adults, clear aligner treatments are becoming more popular. The aim of this study was to evaluate the effect of orthodontic treatment on periodontal tissue and to compare orthodontic treatment with fixed appliances (FA) to clear aligner treatment (CAT) in periodontitis patients. METHODS: A total of 35 patients who underwent orthodontic treatment in the Department of Periodontology were included in this study. After periodontal treatment with meticulous oral hygiene education, patients underwent treatment with FA or CAT, and this study analyzed patient outcomes depending on the treatment strategy. Clinical parameters were assessed at baseline and after orthodontic treatment, and the duration of treatment was compared between these two groups. RESULTS: The overall plaque index, the gingival index, and probing depth improved after orthodontic treatment (P<0.01). The overall bone level also improved (P=0.045). However, the bone level changes in the FA and CAT groups were not significantly different. Significant differences were found between the FA and CAT groups in probing depth, change in probing depth, and duration of treatment (P<0.05). However, no significant differences were found between the FA and CAT groups regarding the plaque index, changes in the plaque index, the gingival index, changes in the gingival index, or changes in the alveolar bone level. The percentage of females in the CAT group (88%) was significantly greater than in the FA group (37%) (P<0.01). CONCLUSIONS: After orthodontic treatment, clinical parameters were improved in the FA and CAT groups with meticulous oral hygiene education and plaque control. Regarding plaque index and gingival index, no significant differences were found between these two groups. We suggest that combined periodontal and orthodontic treatment can improve patients' periodontal health irrespective of orthodontic techniques. PMID- 26734490 TI - Short-term improvement of masticatory function after implant restoration. AB - PURPOSE: Dental implants present several advantages over other tooth replacement options. However, there has been little research on masticatory function in relation to implant treatment. Therefore, the aim of the present study was to evaluate the improvement of masticatory function two weeks after implant restoration. METHODS: Masticatory ability was evaluated with the subjective food intake ability (FIA) and objective mixing ability index (MAI) methods. Fifty-four subjects with first and second missing molars completed the study. The subjects were asked to complete a self-reported questionnaire about 30 different food items, and to chew wax samples 10 times both before and two weeks after implant restoration. A total of 108 waxes were analyzed with an image analysis program. RESULTS: Dental implant restoration for lost molar teeth on one side increased the FIA score by 9.0% (P<0.0001). The MAI score also increased, by 14.3% after implant restoration (P<0.0001). Comparison between the good and poor mastication groups, which were subdivided based on the median MAI score before implant restoration, showed that the FIA score of the poor group was enhanced 1.1-fold while its MAI score was enhanced 2.0-fold two weeks after an implant surgery. CONCLUSIONS: Using the FIA and MAI assessment methods, this study showed that masticatory function was improved two weeks after implant restoration. In particular, the enhancement of masticatory function by implant restoration was greater in patients with relatively poor initial mastication than in those with good initial mastication. PMID- 26734491 TI - Implant success rates in full-arch rehabilitations supported by upright and tilted implants: a retrospective investigation with up to five years of follow up. AB - PURPOSE: The aim of this retrospective study was to investigate the cumulative success rate, the implant survival rate, and the occurrence of biological complications in implants supporting full-arch immediately loaded rehabilitations supported by upright and tilted implants. METHODS: The clinical records and periapical radiographs of patients who attended follow-up visits were collected, and information was recorded regarding marginal bone loss resorption, the occurrence of peri-implant infectious diseases, and the implant survival rate. Implants were classified as successful or not successful according to two distinct classifications for implant success. RESULTS: A total of 53 maxillary and mandibular restorations including 212 implants were analysed, of which 56 implants were studied over the full five-year follow-up period. After five years, the cumulative success rate was 76.04% according to the Misch classification and 56.34% according to the Albrektsson classification. The cumulative implant survival rate was 100%, although one implant was found to be affected by peri implantitis at the second follow-up visit. CONCLUSIONS: The cumulative success rate of the implants dropped over time, corresponding to the progression of marginal bone resorption. The prevalence of peri-implantitis was very low, and the implant survival rate was not found to be related to the cumulative success rate. PMID- 26734492 TI - Prediction of the alveolar bone level after the extraction of maxillary anterior teeth with severe periodontitis. AB - PURPOSE: After extraction, the alveolar bone tends to undergo atrophy in three dimensions. The amount of alveolar bone loss in the horizontal dimension has been reported to be greater than the amount of bone loss in the vertical dimension, and is most pronounced in the buccal aspect. The aim of this study was to monitor the predictive alveolar bone level following the extraction of anterior teeth seriously involved with advanced chronic periodontitis. METHODS: This study included 25 patients with advanced chronic periodontitis, whose maxillary anterior teeth had been extracted due to extensive attachment loss more than one year before the study. Periapical radiographs were analyzed to assess the vertical level of alveolar bone surrounding the edentulous area. An imaginary line connecting the mesial and the distal ends of the alveolar crest facing the adjacent tooth was arbitrarily created. Several representative coordinates were established in the horizontal direction, and the vertical distance from the imaginary line to the alveolar crest was measured at each coordinate for each patient using image analysis software. Regression functions predicting the vertical level of the alveolar bone in the maxillary anterior edentulous area were identified for each patient. RESULTS: The regression functions demonstrated a tendency to converge to parabolic shapes. The predicted maximum distance between the imaginary line and the alveolar bone calculated using the regression function was 1.43+/-0.65 mm. No significant differences were found between the expected and actual maximum distances. Likewise, the predicted and actual maximum horizontal distances did not show any significant differences. The distance from the alveolar bone crest to the imaginary lines was not influenced by the mesio distal spans of the edentulous area. CONCLUSIONS: After extraction, the vertical level of the alveolar ridge increased to become closer to the reference line connecting the mesial and distal alveolar crests. PMID- 26734493 TI - Antimicrobial susceptibility and pathogenic genes of Staphylococcus aureus isolated from the oral cavity of patients with periodontitis. AB - PURPOSE: The goal of this study was to characterize the patterns of antimicrobial resistance and virulence genes in samples of Staphylococcus aureus (S. aureus) isolated from periodontitis patients. METHODS: From July 2015 to August 2015, oral saliva was collected from a total of 112 patients diagnosed with periodontitis, including 80 outpatients in dental hospitals and 32 patients in dental clinics located in Seoul and Cheonan. The samples were subjected to a susceptibility test to evaluate the prevalence of antimicrobial resistance, and the pathogenic factors and antimicrobial resistance factors in the DNA of S. aureus were analyzed using polymerase chain reaction. RESULTS: A susceptibility test against 15 antimicrobial agents showed that 88% of cultures were resistant to ampicillin, 88% to penicillin, and 2% to oxacillin. Resistance to at least two drugs was observed in 90% of cultures, and the most common pattern of multidrug resistance was to ampicillin and penicillin. Enterotoxins were detected in 65.9% of samples. The cell hemolysin gene hld was detected in 100% of cultures and hla was detected in 97.6% of samples. All strains resistant to penicillin and ampicillin had the blaZ gene. The aph(3')IIIa gene, which encodes an aminoglycoside modifying enzyme, was detected in 46.3% of samples. CONCLUSIONS: In the treatment of oral S. aureus infections, it is important to identify the pathogenic genes and the extent of antimicrobial resistance. Furthermore, it is necessary to study patterns of antimicrobial resistance and cross-infection in the context of periodontological specialties in which antimicrobials are frequently used, such as maxillofacial surgery, where the frequency of antimicrobial use for minor procedures such as implant placement is increasing. PMID- 26734494 TI - Bone formation around rhBMP-2-coated implants in rabbit sinuses with or without absorbable collagen sponge grafting. AB - PURPOSE: The purpose of this study was to evaluate bone formation around recombinant human bone morphogenetic protein (rhBMP-2)-coated implants placed with or without absorbable collagen sponge (ACS) in rabbit maxillary sinuses. METHODS: The Schneiderian membrane was elevated and an implant was placed in 24 sinuses in 12 rabbits. The space created beneath the elevated membrane was filled with either blood (n=6) or ACS (n=6). In the rabbits in which this space was filled with blood, rhBMP-2-coated and non-coated implants were alternately placed on different sides. The resulting groups were referred to as the BC and BN groups, respectively. The AC and AN groups were produced in ACS-grafted rabbits in the same manner. Radiographic and histomorphometric analyses were performed after eight weeks of healing. RESULTS: In micro-computed tomography analysis, the total augmented volume and new bone volume were significantly greater in the ACS grafted sinuses than in the blood-filled sinuses (P<0.05). The histometric analysis showed that the areas of new bone and bone-to-implant contact were significantly larger in the AC group than in the AN group (P<0.05). In contrast, none of the parameters differed significantly between the BC and BN groups. CONCLUSIONS: The results of this pilot study indicate that the insertion of ACS after elevating the Schneiderian membrane, simultaneously with implant placement, can significantly increase the volume of the augmentation. However, in the present study, the rhBMP-2 coating exhibited limited effectiveness in enhancing the quantity and quality of regenerated bone. PMID- 26734495 TI - Role of gingival manifestation in diagnosis of granulomatosis with polyangiitis (Wegener's granulomatosis). AB - PURPOSE: This report describes a case of granulomatosis with polyangiitis (GPA) in which the gingival manifestation was crucial in both making an early diagnosis and possibly in deciding the approach to treatment. METHODS: A 57-year-old sailor presented to the Department of Dentistry at Ulsan University Hospital complaining of gingival swelling since approximately 2 months. He had orofacial granulomatous lesions and the specific gingival manifestation of strawberry gingivitis. RESULTS: The diagnosis of GPA was made on the basis of clinical symptoms and signs, and confirmed by the presence of the anti-neutrophil cytoplasmic antibody and a positive biopsy. The patient was admitted to the hospital and subsequently placed on a disease-modifying therapy regimen that included methotrexate and prednisone. CONCLUSIONS: Identification of the gingival manifestation of the disease permitted an early diagnosis and prompt therapy in a disease in which time is a crucial factor. Because of its rapid progression and potentially fatal outcome, an early diagnosis of GPA is important. Therefore, dentists should be aware of the oral signs and symptoms of such systemic diseases. PMID- 26734496 TI - Two cases of an atypical presentation of necrotizing stomatitis. AB - PURPOSE: The purpose of this report was to describe the clinical and microbiological characteristics of two rare cases of necrotizing stomatitis, and the outcomes of a non-invasive treatment protocol applied in both cases. METHODS: We report two cases of necrotizing stomatitis in a rare location in the hard palate of a 40-year-old woman and a 28-year-old man. Neither had a relevant medical history and both presented with highly painful ulceration in the palate and gingival margin that was accompanied by suppuration and necrosis. 3% hydrogen peroxide was applied to the lesions using sterile swabs, and antibiotic and anti inflammatory treatment was prescribed to both patients in addition to two daily oral rinses of 0.2% chlorhexidine. RESULTS: In both cases, radiological examination ruled out bone involvement, and exfoliative cytology revealed a large inflammatory component and the presence of forms compatible with fusobacteria and spirochetes. There was a rapid response to treatment and a major improvement was observed after 48 hours, with almost complete resolution of the ulcerated lesions and detachment of necrotic areas with partial decapitation of gingival papillae. CONCLUSIONS: Necrotizing periodontal lesions can hinder periodontal probing and the mechanical removal of plaque in some cases due to the extreme pain suffered by the patients. We present a non-invasive treatment approach that can manage these situations effectively. PMID- 26734497 TI - Pest control of aphids depends on landscape complexity and natural enemy interactions. AB - Aphids are a major concern in agricultural crops worldwide, and control by natural enemies is an essential component of the ecological intensification of agriculture. Although the complexity of agricultural landscapes is known to influence natural enemies of pests, few studies have measured the degree of pest control by different enemy guilds across gradients in landscape complexity. Here, we use multiple natural-enemy exclosures replicated in 18 fields across a gradient in landscape complexity to investigate (1) the strength of natural pest control across landscapes, measured as the difference between pest pressure in the presence and in the absence of natural enemies; (2) the differential contributions of natural enemy guilds to pest control, and the nature of their interactions across landscapes. We show that natural pest control of aphids increased up to six-fold from simple to complex landscapes. In the absence of pest control, aphid population growth was higher in complex than simple landscapes, but was reduced by natural enemies to similar growth rates across all landscapes. The effects of enemy guilds were landscape-dependent. Particularly in complex landscapes, total pest control was supplied by the combined contribution of flying insects and ground-dwellers. Birds had little overall impact on aphid control. Despite evidence for intraguild predation of flying insects by ground dwellers and birds, the overall effect of enemy guilds on aphid control was complementary. Understanding pest control services at large spatial scales is critical to increase the success of ecological intensification schemes. Our results suggest that, where aphids are the main pest of concern, interactions between natural enemies are largely complementary and lead to a strongly positive effect of landscape complexity on pest control. Increasing the availability of seminatural habitats in agricultural landscapes may thus benefit not only natural enemies, but also the effectiveness of aphid natural pest control. PMID- 26734498 TI - An experimental study of rill sediment delivery in purple soil, using the volume replacement method. AB - Experimental studies provide a basis for understanding the mechanisms of rill erosion and can provide estimates for parameter values in physical models simulating the erosion process. In this study, we investigated sediment delivery during rill erosion in purple soil. We used the volume-replacement method to measure the volume of eroded soil and hence estimate the mass of eroded soil. A 12 m artificial rill was divided into the following sections: 0-0.5 m, 0.5-1 m, 1 2 m, 2-3 m, 3-4 m, 4-5 m, 5-6 m, 6-7 m, 7-8 m, 8-10 m, and 10-12 m. Erosion trials were conducted with three flow rates (2 L/min, 4 L/min, and 8 L/min) and five slope gradients (5 degrees , 10 degrees , 15 degrees , 20 degrees , and 25 degrees ). The eroded rill sections were refilled with water to measure the eroded volume in each section and subsequently calculate the eroded sediment mass. The cumulative sediment mass was used to compute the sediment concentration along the length of the rill. The results show that purple soil sediment concentration increases with rill length before eventually reaching a maximal value; that is, the rate of increase in sediment concentration is greatest at the rill inlet and then gradually slows. Steeper slopes and higher flow rates result in sediment concentration increasing more rapidly along the rill length and the maximum sediment concentration being reached at an earlier location in the rill. Slope gradient and flow rate both result in an increase in maximal sediment concentration and accumulated eroded amount. However, slope gradient has a greater influence on rill erosion than flow rate. The results and experimental method in this study may provide a reference for future rill-erosion experiments. PMID- 26734499 TI - The Phanerozoic diversification of silica-cycling testate amoebae and its possible links to changes in terrestrial ecosystems. AB - The terrestrial cycling of Si is thought to have a large influence on the terrestrial and marine primary production, as well as the coupled biogeochemical cycles of Si and C. Biomineralization of silica is widespread among terrestrial eukaryotes such as plants, soil diatoms, freshwater sponges, silicifying flagellates and testate amoebae. Two major groups of testate (shelled) amoebae, arcellinids and euglyphids, produce their own silica particles to construct shells. The two are unrelated phylogenetically and acquired biomineralizing capabilities independently. Hyalosphenids, a group within arcellinids, are predators of euglyphids. We demonstrate that hyalosphenids can construct shells using silica scales mineralized by the euglyphids. Parsimony analyses of the current hyalosphenid phylogeny indicate that the ability to "steal" euglyphid scales is most likely ancestral in hyalosphenids, implying that euglyphids should be older than hyalosphenids. However, exactly when euglyphids arose is uncertain. Current fossil record contains unambiguous euglyphid fossils that are as old as 50 million years, but older fossils are scarce and difficult to interpret. Poor taxon sampling of euglyphids has also prevented the development of molecular clocks. Here, we present a novel molecular clock reconstruction for arcellinids and consider the uncertainties due to various previously used calibration points. The new molecular clock puts the origin of hyalosphenids in the early Carboniferous (~370 mya). Notably, this estimate coincides with the widespread colonization of land by Si-accumulating plants, suggesting possible links between the evolution of Arcellinid testate amoebae and the expansion of terrestrial habitats rich in organic matter and bioavailable Si. PMID- 26734500 TI - Enhanced susceptibility to predation in corals of compromised condition. AB - The marine gastropod, Coralliophila abbreviata, is an obligate corallivore that causes substantial mortality in Caribbean Acropora spp. Considering the imperiled status of Acropora cervicornis and A. palmata, a better understanding of ecological interactions resulting in tissue loss may enable more effective conservation strategies. We examined differences in susceptibility of A. cervicornis to C. abbreviata predation based on coral tissue condition. Coral tissue condition was a strong determinant of snail prey choice, with snails preferring A. cervicornis fragments that were diseased or mechanically damaged over healthy fragments. In addition, snails always chose fragments undergoing active predation by another snail, while showing no preference for a non-feeding snail when compared with an undisturbed prey fragment. These results indicate that the condition of A. cervicornis prey influenced foraging behavior of C. abbreviata, creating a potential feedback that may exacerbate damage from predation in coral populations compromised by other types of disturbance. PMID- 26734501 TI - The selenium content of SEPP1 versus selenium requirements in vertebrates. AB - Selenoprotein P (SEPP1) distributes selenium (Se) throughout the body via the circulatory system. For vertebrates, the Se content of SEPP1 varies from 7 to 18 Se atoms depending on the species, but the reason for this variation remains unclear. Herein we provide evidence that vertebrate SEPP1 Sec content correlates positively with Se requirements. As the Se content of full length SEPP1 is genetically determined, this presents a unique case where a nutrient requirement can be predicted based on genomic sequence information. PMID- 26734502 TI - Effects of acute levodopa challenge on resting cerebral blood flow in Parkinson's Disease patients assessed using pseudo-continuous arterial spin labeling. AB - Introduction. Levodopa is the gold-standard for treatment of Parkinson's disease (PD) related motor symptoms. In this study, we used pseudo-continuous arterial spin labeling (pCASL) to quantify changes in cerebral blood flow (CBF) after acute oral administration of levodopa in PD patients. Materials and Methods. Thirteen patients (3 females, age 66.2 +/- 8.7 years) with moderately advanced PD (Hoehn and Yahr stage >2 (median 2.5), disease duration >3 years) were scanned on a 3T Siemens MR scanner before and after oral levodopa administration. Statistical parametric mapping was used to detect drug-induced changes in CBF and its correlation to clinical severity scales. Images were normalized and flipped in order to examine effects on the more affected (left) and less affected (right) cerebral hemispheres across the cohort. Results. Levodopa did not change global CBF but increased regional CBF in dorsal midbrain, precuneus/cuneus, more affected inferior frontal pars opercularis and triangularis, bilateral pre- and postcentral gyri, more affected inferior parietal areas, as well as less affected putamen/globus pallidus by 27-74% (p < 0.05, FWE corrected for multiple comparisons). CBF change was negatively correlated with improvement in bradykinesia UPDRS-III subscore in the more affected precentral gyrus, and total predrug UPDRS-III score in the mid-cingulate region. Drug-induced CBF change in a widespread network of regions including parietal and postcentral areas was also negatively correlated with the predrug rigidity UPDRS-III subscore. Conclusion. These findings are in line with prior reports of abnormal activity in the nigrostriatal pathway of PD patients and demonstrate the feasibility of pCASL as a neuroimaging tool for investigating in vivo physiological effects of acute drug administration in PD. PMID- 26734503 TI - Alpine endemic spiders shed light on the origin and evolution of subterranean species. AB - We designed a comparative study to unravel the phylogeography of two Alpine endemic spiders characterized by a different degree of adaptation to subterranean life: Troglohyphantes vignai (Araneae, Linyphiidae) and Pimoa rupicola (Araneae, Pimoidae), the latter showing minor adaptation to hypogean life. We sampled populations of the model species in caves and other subterranean habitats across their known geographical range in the Western Alps. By combining phylogeographic inferences and Ecological Niche Modeling techniques, we inferred the biogeographic scenario that led to the present day population structure of the two species. According to our divergent time estimates and relative uncertainties, the isolation of T. vignai and P. rupicola from their northern sister groups was tracked back to Middle-Late Miocene. Furthermore, the fingerprint left by Pleistocene glaciations on the population structure revealed by the genetic data, led to the hypothesis that a progressive adaptation to subterranean habitats occurred in T. vignai, followed by strong population isolation. On the other hand, P. rupicola underwent a remarkable genetic bottleneck during the Pleistocene glaciations, that shaped its present population structure. It seems likely that such shallow population structure is both the result of the minor degree of specialization to hypogean life and the higher dispersal ability characterizing this species. The simultaneous study of overlapping spider species showing different levels of adaptation to hypogean life, disclosed a new way to clarify patterns of biological diversification and to understand the effects of past climatic shift on the subterranean biodiversity. PMID- 26734504 TI - Age, growth, and recruitment patterns of juvenile ladyfish (Elops sp) from the east coast of Florida (USA). AB - Ladyfish (Elops sp) are a common and economically valuable coastal nearshore species found along coastal beaches, bays, and estuaries of the southeastern United States, and subtropical and tropical regions worldwide. Previously, ladyfish were a substantial bycatch in Florida's commercial fisheries, but changes in regulations significantly reduced commercial landings. Today, ladyfish are still taken in commercial fisheries in Florida, but many are also taken by recreational anglers. Life-history information and research interest in ladyfish is almost non-existent, especially information on age and growth. Thus, the overarching purpose of this study was to expand our understanding of ladyfish age and growth characteristics. The specific objectives were to describe, for the first time, age, growth, and recruitment patterns of juvenile ladyfish from the east coast of Florida (USA). In the Indian River Lagoon (IRL), annual monthly length-frequency distributions were confounded because a few small individuals recruited throughout the year; monthly length-frequency data generally demonstrated a cyclical pattern. The smallest were collected in September and the largest in May. Post-hoc analysis showed no significant difference in length between August and May, or among the other months. In Volusia County (VC), annual monthly length-frequency distribution demonstrated growth generally occurred from late-winter and spring to summer. The smallest ladyfish were collected in February and the largest in August. On average, the absolute growth rate in the IRL was 36.3 mm in 60 days or 0.605 mm day(-1). Cohort-specific daily growth rates, elevations, and coincidentals were similar among sampling years. Cohort specific growth rates ranged from 1.807 in 1993 to 1.811 mm day(-1) in 1994. Overall, growth was best (i.e., goodness of fit) described by exponential regression. On average, the absolute growth rate in VC was 28 mm in 150 days or 0.1866 mm day(-1). Cohort-specific daily growth rates were significantly different among sampling years; however, the elevations and coincidentals were similar. Cohort-specific growth rates ranged from 1.741 in 1994 to 1.933 mm day( 1) in 1993. Mean ladyfish growth was best described by linear regression; however, natural growth was explained better by exponential regression. In the IRL, the corrected exponential growth equation yielded a size-at-age 1 of 156.0 mm SL, which corresponded to an estimated growth rate of 0.4356 mm day(-1). In VC, the corrected exponential growth equation yielded a size-at-age 1 of 80 mm SL corresponding to an estimated growth rate of 0.2361 mm day(-1). PMID- 26734505 TI - Non-inferiority of retrospective data collection for assessing perioperative morbidity. AB - Background. Postoperative morbidity has immediate and delayed consequences for surgical patients, including excess risk of premature death. Capturing these data objectively and routinely in large electronic databases using tools such as the Postoperative Morbidity Survey (POMS) would offer tremendous clinical and translational potential. However, POMS has thus far only utilised prospective data collection by research staff. We hypothesised that retrospective data collection from routinely collated hospital data from paper and electronic charts, medical and nursing notes was non-inferior to prospective data collection requiring research staff capturing POMS-defined morbidity in real-time. Methods. Morbidity was recorded by a trained investigator as defined by POMS prospectively on postoperative days 3 and 7. Separately, an independent investigator blinded to prospectively acquired data retrospectively assessed the same patients' morbidity as defined by POMS criteria, using medical charts, nursing summaries and electronic data. Equivalence was accepted when the confidence limits for both modes of data collection fell completely inside the equivalence bounds, with the maximum equivalence difference (i.e., the largest value of the difference in sensitivities deemed to reach a conclusion of equivalence) set a priori at 0.2. Differences for confidence limits between retrospective and prospective data collection were based on Nam's RMLE method. The relationship between morbidity on postoperative day 3 as recorded by each data collection method on time to become morbidity free and length of hospital stay was compared using the log-rank test. Results. POMS data from 85 patients undergoing elective or emergency surgery were analyzed. At postoperative day 3, POMS-defined morbidity was similar regardless of whether data were collected prospectively or retrospectively (95% CI [-0.13 0.013]; p < 0.001). Non-inferiority for sensitivity was observed for all other POMS domains and timepoints. Time to become morbidity free Kaplan-Meier plots were indistinguishable between POMS obtained prospectively or retrospectively (hazard ratio: 1.09 (95% CI [0.76-1.57]); p = 0.33, log rank test). Similarly, the mode of data collection did not alter the association between early postoperative morbidity on postoperative day 3 and delayed hospital discharge. Conclusions. Postoperative morbidity as defined by the Post Operative Morbidity Survey can be assessed retrospectively. These data may therefore be easily captured using electronic patient record systems, thereby expanding the potential for bioinformatics approaches to generate new clinical and translational insights into recovery from surgery. PMID- 26734506 TI - A quick and robust method for quantification of the hypersensitive response in plants. AB - One of the most studied defense reactions of plants against microbial pathogens is the hypersensitive response (HR). The HR is a complex multicellular process that involves programmed cell death at the site of infection. A standard method to quantify plant defense and the HR is to measure the release of cellular electrolytes into water after infiltration with pathogenic bacteria. In this type of experiment, the bacteria are typically delivered into the plant tissue through syringe infiltration. Here we report the development of a vacuum infiltration protocol that allows multiple plant lines to be infiltrated simultaneously and assayed for defense responses. Vacuum infiltration did not induce more wounding response in Arabidopsis leaf tissue than syringe inoculation, whereas throughput and reproducibility were improved. The method was used to study HR-induced electrolyte loss after treatment with the bacterium Pseudomonas syringae pv. tomato DC3000 harboring the effector AvrRpm1, AvrRpt2 or AvrRps4. Specifically, the influence of bacterial titer on AvrRpm1-induced HR was investigated. Not only the amplitude, but also the timing of the maximum rate of the HR reaction was found to be dose-dependent. Finally, using vacuum infiltration, we were able quantify induction of phospholipase D activity after AvrRpm1 recognition in leaves labeled with (33)PO4. PMID- 26734507 TI - Sound signatures and production mechanisms of three species of pipefishes (Family: Syngnathidae). AB - Background. Syngnathid fishes produce three kinds of sounds, named click, growl and purr. These sounds are generated by different mechanisms to give a consistent signal pattern or signature which is believed to play a role in intraspecific and interspecific communication. Commonly known sounds are produced when the fish feeds (click, purr) or is under duress (growl). While there are more acoustic studies on seahorses, pipefishes have not received much attention. Here we document the differences in feeding click signals between three species of pipefishes and relate them to cranial morphology and kinesis, or the sound producing mechanism. Methods. The feeding clicks of two species of freshwater pipefishes, Doryichthys martensii and Doryichthys deokhathoides and one species of estuarine pipefish, Syngnathoides biaculeatus, were recorded by a hydrophone in acoustic dampened tanks. The acoustic signals were analysed using time-scale distribution (or scalogram) based on wavelet transform. A detailed time-varying analysis of the spectral contents of the localized acoustic signal was obtained by jointly interpreting the oscillogram, scalogram and power spectrum. The heads of both Doryichthys species were prepared for microtomographical scans which were analysed using a 3D imaging software. Additionally, the cranial bones of all three species were examined using a clearing and double-staining method for histological studies. Results. The sound characteristics of the feeding click of the pipefish is species-specific, appearing to be dependent on three bones: the supraoccipital, 1st postcranial plate and 2nd postcranial plate. The sounds are generated when the head of the Dorichthyes pipefishes flexes backward during the feeding strike, as the supraoccipital slides backwards, striking and pushing the 1st postcranial plate against (and striking) the 2nd postcranial plate. In the Syngnathoides pipefish, in the absence of the 1st postcranial plate, the supraoccipital rubs against the 2nd postcranial plate twice as it is pulled backward and released on the return. Cranial morphology and kinesis produce acoustic signals consistent with the bone strikes that produce sharp energy spikes (discrete or merged), or stridulations between bones that produce repeated or multimodal sinusoidal waveforms. Discussion. The variable structure of the sound-producing mechanism explains the unique acoustic signatures of the three species of pipefish. The differences in cranial bone morphology, cranial kinesis and acoustic signatures among pipefishes (and seahorses) could be attributed to independent evolution within the Syngnathidae, which warrants further investigation. PMID- 26734508 TI - Bioactivities by a crude extract from the Greenlandic Pseudomonas sp. In5 involves the nonribosomal peptides, nunamycin and nunapeptin. AB - Background. Bioactive microbial metabolites provide a successful source of novel compounds with pharmaceutical potentials. The bacterium Pseudomonas sp. In5 is a biocontrol strain isolated from a plant disease suppressive soil in Greenland, which produces two antimicrobial nonribosomal peptides (NRPs), nunapeptin and nunamycin. Methods. In this study, we used in vitro antimicrobial and anticancer bioassays to evaluate the potential bioactivities of both a crude extract derived from Pseudomonas sp. In5 and NRPs purified from the crude extract. Results. We verified that the crude extract derived from Pseudomonas sp. In5 showed suppressive activity against the basidiomycete Rhizoctonia solani by inducing a mitochondrial stress-response. Furthermore, we confirmed suppressive activity against the oomycete Pythium aphanidermatum by the Pseudomonas sp. In5 crude extract, and that the purified nunamycin and nunapeptin displayed distinct antimicrobial activities. In addition to the antimicrobial activity, we found that treatment of the cancer cell lines, Jurkat T-cells, Granta cells, and melanoma cells, with the Pseudomonas sp. In5 crude extract increased staining with the apoptotic marker Annexin V while no staining of healthy normal cells, i.e., naive or activated CD4 T-cells, was observed. Treatment with either of the NRPs alone did not increase Annexin V staining of the Jurkat T-cells, despite individually showing robust antimicrobial activity, whereas an anticancer activity was detected when nunamycin and nunapeptin were used in combination. Discussion. Our results suggest that the bioactivity of a crude extract derived from Pseudomonas sp. In5 involves the presence of both nunamycin and nunapeptin and highlight the possibility of synergy between multiple microbial metabolites. PMID- 26734509 TI - How word-beginnings constrain the pronunciations of word-ends in the reading aloud of English: the phenomena of head- and onset-conditioning. AB - Background. A word whose body is pronounced in different ways in different words is body-inconsistent. When we take the unit that precedes the vowel into account for the calculation of body-consistency, the proportion of English words that are body-inconsistent is considerably reduced at the level of corpus analysis, prompting the question of whether humans actually use such head/onset conditioning when they read. Methods. Four metrics for head/onset-constrained body-consistency were calculated: by the last grapheme of the head, by the last phoneme of the onset, by place and manner of articulation of the last phoneme of the onset, and by manner of articulation of the last phoneme of the onset. Since these were highly correlated, principal component analysis was performed on them. Results. Two out of four resulting principal components explained significant variance in the reading-aloud reaction times, beyond regularity and body consistency. Discussion. Humans read head/onset-conditioned words faster than would be predicted based on their body-consistency and regularity only. We conclude that humans are sensitive to the dependency between word-beginnings and word-ends when they read aloud, and that this dependency is phonological in nature, rather than orthographic. PMID- 26734510 TI - A near-infrared spectroscopy routine for unambiguous identification of cryptic ant species. AB - Species identification-of importance for most biological disciplines-is not always straightforward as cryptic species hamper traditional identification. Fibre-optic near-infrared spectroscopy (NIRS) is a rapid and inexpensive method of use in various applications, including the identification of species. Despite its efficiency, NIRS has never been tested on a group of more than two cryptic species, and a working routine is still missing. Hence, we tested if the four morphologically highly similar, but genetically distinct ant species Tetramorium alpestre, T. caespitum, T. impurum, and T. sp. B, all four co-occurring above 1,300 m above sea level in the Alps, can be identified unambiguously using NIRS. Furthermore, we evaluated which of our implementations of the three analysis approaches, partial least squares regression (PLS), artificial neural networks (ANN), and random forests (RF), is most efficient in species identification with our data set. We opted for a 100% classification certainty, i.e., a residual risk of misidentification of zero within the available data, at the cost of excluding specimens from identification. Additionally, we examined which strategy among our implementations, one-vs-all, i.e., one species compared with the pooled set of the remaining species, or binary-decision strategies, worked best with our data to reduce a multi-class system to a two-class system, as is necessary for PLS. Our NIRS identification routine, based on a 100% identification certainty, was successful with up to 66.7% of unambiguously identified specimens of a species. In detail, PLS scored best over all species (36.7% of specimens), while RF was much less effective (10.0%) and ANN failed completely (0.0%) with our data and our implementations of the analyses. Moreover, we showed that the one-vs-all strategy is the only acceptable option to reduce multi-class systems because of a minimum expenditure of time. We emphasise our classification routine using fibre optic NIRS in combination with PLS and the one-vs-all strategy as a highly efficient pre-screening identification method for cryptic ant species and possibly beyond. PMID- 26734511 TI - Kelvin probe force microscopy for local characterisation of active nanoelectronic devices. AB - Frequency modulated Kelvin probe force microscopy (FM-KFM) is the method of choice for high resolution measurements of local surface potentials, yet on coarse topographic structures most researchers revert to amplitude modulated lift mode techniques for better stability. This approach inevitably translates into lower lateral resolution and pronounced capacitive averaging of the locally measured contact potential difference. Furthermore, local changes in the strength of the electrostatic interaction between tip and surface easily lead to topography crosstalk seen in the surface potential. To take full advantage of the superior resolution of FM-KFM while maintaining robust topography feedback and minimal crosstalk, we introduce a novel FM-KFM controller based on a Kalman filter and direct demodulation of sidebands. We discuss the origin of sidebands in FM-KFM irrespective of the cantilever quality factor and how direct sideband demodulation enables robust amplitude modulated topography feedback. Finally, we demonstrate our single-scan FM-KFM technique on an active nanoelectronic device consisting of a 70 nm diameter InAs nanowire contacted by a pair of 120 nm thick electrodes. PMID- 26734512 TI - Electroviscous effect on fluid drag in a microchannel with large zeta potential. AB - The electroviscous effect has been widely studied to investigate the effect of surface charge-induced electric double layers (EDL) on the pressure-driven flow in a micro/nano channel. EDL has been reported to reduce the velocity of fluid flow and increase the fluid drag. Nevertheless, the study on the combined effect of EDL with large zeta potential up to several hundred millivolts and surface charge depenedent-slip on the micro/nano flow is still needed. In this paper, the nonlinear Poisson-Boltzmann equation for electrical potential and ion distribution in non-overlapping EDL is first analytically solved. Then, the modified Navier-Stokes equation for the flow considering the effect of surface charge on the electrical conductivity of the electrolyte and slip length is analytically solved. This analysis is used to study the effect of non-overlapping EDL with large zeta potential on the pressure-driven flow in a microchannel with no-slip and charge-dependent slip conditions. The results show that the EDL leads to an increase in the fluid drag, but that slip can reduce the fluid drag. When the zeta potential is large enough, the electroviscous effect disappears for flow in the microchannel under a no-slip condition. However, the retardation of EDL on the flow and the enhancement of slip on the flow counteract each other under a slip condition. The underlying mechanisms of the effect of EDL with large zeta potential on fluid drag are the high net ionic concentration near the channel wall and the fast decay of electrical potential in the EDL when the zeta potential is large enough. PMID- 26734513 TI - Fabrication of hybrid nanocomposite scaffolds by incorporating ligand-free hydroxyapatite nanoparticles into biodegradable polymer scaffolds and release studies. AB - We report on the optical fabrication approach of preparing free-standing composite thin films of hydroxyapatite (HA) and biodegradable polymers by combining pulsed laser ablation in liquid and mask-projection excimer laser stereolithography (MPExSL). Ligand-free HA nanoparticles were prepared by ultrafast laser ablation of a HA target in a solvent, and then the nanoparticles were dispersed into the liquid polymer resin prior to the photocuring process using MPExSL. The resin is poly(propylene fumarate) (PPF), a photo-polymerizable, biodegradable material. The polymer is blended with diethyl fumarate in 7:3 w/w to adjust the resin viscosity. The evaluation of the structural and mechanical properties of the fabricated hybrid thin film was performed by means of SEM and nanoindentation, respectively, while the chemical and degradation studies were conducted through thermogravimetric analysis, and FTIR. The photocuring efficiency was found to be dependent on the nanoparticle concentration. The MPExSL process yielded PPF thin films with a stable and homogenous dispersion of the embedded HA nanoparticles. Here, it was not possible to tune the stiffness and hardness of the scaffolds by varying the laser parameters, although this was observed for regular PPF scaffolds. Finally, the gradual release of the hydroxyapatite nanoparticles over thin film biodegradation is reported. PMID- 26734514 TI - Au nanoparticle-based sensor for apomorphine detection in plasma. AB - Artificially roughened gold surfaces with controlled nanostructure produced by pulsed laser deposition have been investigated as sensors for apomorphine detection aiming at clinical application. The use of such gold surfaces has been optimized using aqueous solutions of apomorphine in the concentration range between 3.3 * 10(-4) M and 3.3 * 10(-7) M. The experimental parameters have been investigated and the dynamic concentration range of the sensor has been assessed by the selection of two apomorphine surface enhanced Raman scattering (SERS) peaks. The sensor behavior used to detect apomorphine in unfiltered human blood plasma is presented and discussed. PMID- 26734515 TI - A simple and efficient quasi 3-dimensional viscoelastic model and software for simulation of tapping-mode atomic force microscopy. AB - This paper introduces a quasi-3-dimensional (Q3D) viscoelastic model and software tool for use in atomic force microscopy (AFM) simulations. The model is based on a 2-dimensional array of standard linear solid (SLS) model elements. The well known 1-dimensional SLS model is a textbook example in viscoelastic theory but is relatively new in AFM simulation. It is the simplest model that offers a qualitatively correct description of the most fundamental viscoelastic behaviors, namely stress relaxation and creep. However, this simple model does not reflect the correct curvature in the repulsive portion of the force curve, so its application in the quantitative interpretation of AFM experiments is relatively limited. In the proposed Q3D model the use of an array of SLS elements leads to force curves that have the typical upward curvature in the repulsive region, while still offering a very low computational cost. Furthermore, the use of a multidimensional model allows for the study of AFM tips having non-ideal geometries, which can be extremely useful in practice. Examples of typical force curves are provided for single- and multifrequency tapping-mode imaging, for both of which the force curves exhibit the expected features. Finally, a software tool to simulate amplitude and phase spectroscopy curves is provided, which can be easily modified to implement other controls schemes in order to aid in the interpretation of AFM experiments. PMID- 26734516 TI - Core-level spectra and molecular deformation in adsorption: V-shaped pentacene on Al(001). AB - By first-principle simulations we study the effects of molecular deformation on the electronic and spectroscopic properties as it occurs for pentacene adsorbed on the most stable site of Al(001). The rationale for the particular V-shaped deformed structure is discussed and understood. The molecule-surface bond is made evident by mapping the charge redistribution. Upon X-ray photoelectron spectroscopy (XPS) from the molecule, the bond with the surface is destabilized by the electron density rearrangement to screen the core hole. This destabilization depends on the ionized carbon atom, inducing a narrowing of the XPS spectrum with respect to the molecules adsorbed hypothetically undistorted, in full agreement to experiments. When looking instead at the near-edge X-ray absorption fine structure (NEXAFS) spectra, individual contributions from the non equivalent C atoms provide evidence of the molecular orbital filling, hybridization, and interchange induced by distortion. The alteration of the C-C bond lengths due to the V-shaped bending decreases by a factor of two the azimuthal dichroism of NEXAFS spectra, i.e., the energy splitting of the sigma resonances measured along the two in-plane molecular axes. PMID- 26734517 TI - Influence of wide band gap oxide substrates on the photoelectrochemical properties and structural disorder of CdS nanoparticles grown by the successive ionic layer adsorption and reaction (SILAR) method. AB - The photoelectrochemical properties of nanoheterostructures based on the wide band gap oxide substrates (ZnO, TiO2, In2O3) and CdS nanoparticles deposited by the successive ionic layer adsorption and reaction (SILAR) method have been studied as a function of the CdS deposition cycle number (N). The incident photon to-current conversion efficiency (IPCE) passes through a maximum with the increase of N, which is ascribed to the competition between the increase in optical absorption and photocarrier recombination. The maximal IPCE values for the In2O3/CdS and ZnO/CdS heterostructures are attained at N ~ 20, whereas for TiO2/CdS, the appropriate N value is an order of magnitude higher. The photocurrent and Raman spectroscopy studies of CdS nanoparticles revealed the occurrence of the quantum confinement effect, demonstrating the most rapid weakening with the increase of N in ZnO/CdS heterostructures. The structural disorder of CdS nanoparticles was characterized by the Urbach energy (E U), spectral width of the CdS longitudinal optical (LO) phonon band and the relative intensity of the surface optical (SO) phonon band in the Raman spectra. Maximal values of E U (100-120 meV) correspond to SdS nanoparticles on a In2O3 surface, correlating with the fact that the CdS LO band spectral width and intensity ratio for the CdS SO and LO bands are maximal for In2O3/CdS films. A notable variation in the degree of disorder of CdS nanoparticles is observed only in the initial stages of CdS growth (several tens of deposition cycles), indicating the preservation of the nanocrystalline state of CdS over a wide range of SILAR cycles. PMID- 26734518 TI - Plasma fluorination of vertically aligned carbon nanotubes: functionalization and thermal stability. AB - Grafting of fluorine species on carbon nanostructures has attracted interest due to the effective modification of physical and chemical properties of the starting materials. Various techniques have been employed to achieve a controlled fluorination yield; however, the effect of contaminants is rarely discussed, although they are often present. In the present work, the fluorination of vertically aligned multiwalled carbon nanotubes was performed using plasma treatment in a magnetron sputtering chamber with fluorine diluted in an argon atmosphere with an Ar/F2 ratio of 95:5. The effect of heavily diluted fluorine in the precursor gas mixture is investigated by evaluating the modifications in the nanotube structure and the electronic properties upon plasma treatment. The existence of oxygen-based grafted species is associated with background oxygen species present in the plasma chamber in addition to fluorine. The thermal stability and desorption process of the fluorine species grafted on the carbon nanotubes during the fluorine plasma treatment were evaluated by combining different spectroscopic techniques. PMID- 26734519 TI - Orthogonal chemical functionalization of patterned gold on silica surfaces. AB - Single-step orthogonal chemical functionalization procedures have been developed with patterned gold on silica surfaces. Different combinations of a silane and a thiol were simultaneously deposited on a gold/silica heterogeneous substrate. The orthogonality of the functionalization (i.e., selective grafting of the thiol on the gold areas and the silane on the silica) was demonstrated by X-ray photoelectron spectroscopy (XPS) as well as time-of-flight secondary ion mass spectrometry (ToF-SIMS) mapping. The orthogonal functionalization was used to immobilize proteins onto gold nanostructures on a silica substrate, as demonstrated by atomic force microscopy (AFM). These results are especially promising in the development of future biosensors where the selective anchoring of target molecules onto nanostructured transducers (e.g., nanoplasmonic biosensors) is a major challenge. PMID- 26734520 TI - Silica-coated upconversion lanthanide nanoparticles: The effect of crystal design on morphology, structure and optical properties. AB - NaYF4:Yb(3+)/Er(3+) nanoparticles were synthesized by thermal decomposition of lanthanide trifluoroacetates using oleylamine (OM) as both solvent and surface binding ligand. The effect of reaction temperature and time on the properties of the particles was investigated. The nanoparticles were characterized by transmission electron microscopy (TEM), electron diffraction (ED), energy dispersive spectroscopy (EDX), dynamic light scattering (DLS), thermogravimetric analysis (TGA), elemental analysis and X-ray diffraction (XRD) to determine morphology, size, polydispersity, crystal structure and elemental composition of the nanocrystals. TEM microscopy revealed that the morphology of the nanoparticles could be fine-tuned by modifying of the synthetic conditions. A cubic-to-hexagonal phase transition of the NaYF4:Yb(3+)/Er(3+) nanoparticles at temperatures above 300 degrees C was confirmed by both ED and XRD. Upconversion luminescence under excitation at 980 nm was observed in the luminescence spectra of OM-NaYF4:Yb(3+)/Er(3+) nanoparticles. Finally, the OM-NaYF4:Yb(3+)/Er(3+) nanoparticles were coated with a silica shell to enable further functionalization and increase biocompatibility and stability in aqueous media, preventing particle aggregation. PMID- 26734521 TI - Fabrication of hybrid graphene oxide/polyelectrolyte capsules by means of layer by-layer assembly on erythrocyte cell templates. AB - A novel and facile method was developed to produce hybrid graphene oxide (GO) polyelectrolyte (PE) capsules using erythrocyte cells as templates. The capsules are easily produced through the layer-by-layer technique using alternating polyelectrolyte layers and GO sheets. The amount of GO and therefore its coverage in the resulting capsules can be tuned by adjusting the concentration of the GO dispersion during the assembly. The capsules retain the approximate shape and size of the erythrocyte template after the latter is totally removed by oxidation with NaOCl in water. The PE/GO capsules maintain their integrity and can be placed or located on other surfaces such as in a device. When the capsules are dried in air, they collapse to form a film that is approximately twice the thickness of the capsule membrane. AFM images in the present study suggest a film thickness of approx. 30 nm for the capsules in the collapsed state implying a thickness of approx. 15 nm for the layers in the collapsed capsule membrane. The polyelectrolytes used in the present study were polyallylamine hydrochloride (PAH) and polystyrenesulfonate sodium salt (PSS). Capsules where characterized by transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS) and Raman microscopy, the constituent layers by zeta potential and GO by TEM, XRD, and Raman and FTIR spectroscopies. PMID- 26734522 TI - Surfactant-controlled composition and crystal structure of manganese(II) sulfide nanocrystals prepared by solvothermal synthesis. AB - We investigated how the outcome of the solvothermal synthesis of manganese(II) sulfide (MnS) nanocrystals (NCs) is affected by the type and amount of long chain surfactant present in the reaction mixture. Prompted by a previous observation that a larger than stoichiometric amount of sulfur is required [Puglisi, A.; Mondini, S.; Cenedese, S.; Ferretti, A. M.; Santo, N.; Ponti A. Chem. Mater. 2010, 22, 2804-2813], we carried out a wide set of reactions using Mn(II) carboxylates and Mn2(CO)10 as precursors with varying amounts of sulfur and carboxylic acid. MnS NCs were obtained provided that the S/Mn ratio was larger than the L/Mn ratio, otherwise MnO NCs were produced. Since MnS can crystallize in three distinct phases (rock salt alpha-MnS, zincblende beta-MnS, and wurtzite gamma-MnS), we also investigated whether the surfactant affected the NC polymorphism. We found that MnS polymorphism can be controlled by appropriate selection of the surfactant. gamma-MnS nanocrystals formed when a 1:2 mixture of long chain carboxylic acid and amine was used, irrespective of the presence of carboxylic acid as a free surfactant or ligand in the metal precursor. When we used a single surfactant (carboxylic acid, alcohol, thiol, amine), alpha-MnS nanocrystals were obtained. The peculiar role of the amine seems to be related to its basicity. The nanocrystals were characterized by TEM and electron diffraction; ATR-FTIR spectroscopy provided information about the surfactants adsorbed on the NCs. PMID- 26734523 TI - Correction: A single-source precursor route to anisotropic halogen-doped zinc oxide particles as a promising candidate for new transparent conducting oxide materials. AB - [This corrects the article DOI: 10.3762/bjnano.6.222.]. PMID- 26734524 TI - Negative differential electrical resistance of a rotational organic nanomotor. AB - A robust, nanoelectromechanical switch is proposed based upon an asymmetric pendant moiety anchored to an organic backbone between two C60 fullerenes, which in turn are connected to gold electrodes. Ab initio density functional calculations are used to demonstrate that an electric field induces rotation of the pendant group, leading to a nonlinear current-voltage relation. The nonlinearity is strong enough to lead to negative differential resistance at modest source-drain voltages. PMID- 26734525 TI - Evidence for non-conservative current-induced forces in the breaking of Au and Pt atomic chains. AB - This experimental work aims at probing current-induced forces at the atomic scale. Specifically it addresses predictions in recent work regarding the appearance of run-away modes as a result of a combined effect of the non conservative wind force and a 'Berry force'. The systems we consider here are atomic chains of Au and Pt atoms, for which we investigate the distribution of break down voltage values. We observe two distinct modes of breaking for Au atomic chains. The breaking at high voltage appears to behave as expected for regular break down by thermal excitation due to Joule heating. However, there is a low-voltage breaking mode that has characteristics expected for the mechanism of current-induced forces. Although a full comparison would require more detailed information on the individual atomic configurations, the systems we consider are very similar to those considered in recent model calculations and the comparison between experiment and theory is very encouraging for the interpretation we propose. PMID- 26734526 TI - Self-organization of gold nanoparticles on silanated surfaces. AB - The self-organization of monolayer gold nanoparticles (AuNPs) on 3 aminopropyltriethoxysilane (APTES)-functionalized glass substrate is reported. The orientation of APTES molecules on glass substrates plays an important role in the interaction between AuNPs and APTES molecules on the glass substrates. Different orientations of APTES affect the self-organization of AuNps on APTES functionalized glass substrates. The as grown monolayers and films annealed in ultrahigh vacuum and air (600 degrees C) were studied by water contact angle measurements, atomic force microscopy, X-ray photoelectron spectroscopy, UV visible spectroscopy and ultraviolet photoelectron spectroscopy. Results of this study are fundamentally important and also can be applied for designing and modelling of surface plasmon resonance based sensor applications. PMID- 26734528 TI - Nanostructured surfaces by supramolecular self-assembly of linear oligosilsesquioxanes with biocompatible side groups. AB - Linear oligomeric silsesquioxanes with polar side moieties (e.g., carboxylic groups and derivatives of N-acetylcysteine, cysteine hydrochloride or glutathione) can form specific, self-assembled nanostructures when deposited on mica by dip coating. The mechanism of adsorption is based on molecule-to substrate interactions between carboxylic groups and mica. Intermolecular cross linking by hydrogen bonds was also observed due to the donor-acceptor character of the functional groups. The texture of supramolecular nanostructures formed by the studied materials on mica was analysed with atomic force microscopy and their specific surface energy was estimated by contact angle measurements. Significant differences in the surface roughness, thickness and the arrangement of macromolecules were noted depending on the kind of functional groups on the side chains. Specific changes in the morphology of the surface layer were observed when mica was primed with a monolayer of small organic compounds (e.g., N acetylcysteine, citric acid, thioglycolic or acid). The adsorption of both silsesquioxane oligomers and organic primers was confirmed with attenuated total reflectance infrared spectroscopy. The observed physiochemical and textural variations in the adsorbed materials correlate with the differences in the chemical structure of the applied oligomers and primers. PMID- 26734527 TI - Green and energy-efficient methods for the production of metallic nanoparticles. AB - In the last decade, researchers paid great attention to the concept of "Green Chemistry", which aims at development of efficient methods for the synthesis of nanoparticles (NPs) in terms of the least possible impact on human life and environment. Generally, several reagents including precursors, reducing agents, stabilizing agents and solvents are used for the production of NPs and in some cases, energy is needed to reach the optimum temperature for reduction. Therefore, to develop a green approach, researchers had the opportunity to investigate eco-friendly reagents and new energy transfer techniques. In order to substitute the harmful reagents with green ones, researchers worked on different types of saccharides, polyols, carboxylic acids, polyoxometalates and extracts of various plants that can play the role of reducers, stabilizers or solvents. Also, there are some reports on using ultraviolet (UV), gamma and microwave irradiation that are capable of reducing and provide uniform heating. According to the literature, it is possible to use green reagents and novel energy transfer techniques for production of NPs. However, these new synthesis routes should be optimized in terms of performance, cost, product quality (shape and size distribution) and scale-up capability. This paper presents a review on most of the employed green reagents and new energy transfer techniques for the production of metallic NPs. PMID- 26734529 TI - Surface-enhanced Raman scattering by colloidal CdSe nanocrystal submonolayers fabricated by the Langmuir-Blodgett technique. AB - We present the results of an investigation of surface-enhanced Raman scattering (SERS) by optical phonons in colloidal CdSe nanocrystals (NCs) homogeneously deposited on both arrays of Au nanoclusters and Au dimers using the Langmuir Blodgett technique. The coverage of the deposited NCs was less than one monolayer, as determined by transmission and scanning electron microscopy. SERS by optical phonons in CdSe nanocrystals showed a significant enhancement that depends resonantly on the Au nanocluster and dimer size, and thus on the localized surface plasmon resonance (LSPR) energy. The deposition of CdSe nanocrystals on the Au dimer nanocluster arrays enabled us to study the polarization dependence of SERS. The maximal SERS signal was observed for light polarization parallel to the dimer axis. The polarization ratio of the SERS signal parallel and perpendicular to the dimer axis was 20. The SERS signal intensity was also investigated as a function of the distance between nanoclusters in a dimer. Here the maximal SERS enhancement was observed for the minimal distance studied (about 10 nm), confirming the formation of SERS "hot spots". PMID- 26734531 TI - Two step formation of metal aggregates by surface X-ray radiolysis under Langmuir monolayers: 2D followed by 3D growth. AB - In order to form a nanostructured metallic layer below a Langmuir monolayer, radiolysis synthesis was carried out in an adapted geometry that we call surface X-ray radiolysis. In this procedure, an X-ray beam produced by a synchrotron beamline intercepts the surface of an aqueous metal-ion solution covered by a Langmuir monolayer at an angle of incidence below the critical angle for total internal reflection. Underneath the organic layer, the X-ray beam induces the radiolytic synthesis of a nanostructured metal-organic layer whose ultrathin thickness is defined by the vertical X-ray penetration depth. We have shown that increasing the X-ray flux on the surface, which considerably enhances the kinetics of the silver layer formation, results in a second growth regime of silver nanocrystals. Here the formation of the oriented thin layer is followed by the appearance of a 3D powder of silver clusters. PMID- 26734530 TI - Ultrastructural changes in methicillin-resistant Staphylococcus aureus induced by positively charged silver nanoparticles. AB - Silver nanoparticles offer a possible means of fighting antibacterial resistance. Most of their antibacterial properties are attributed to their silver ions. In the present work, we study the actions of positively charged silver nanoparticles against both methicillin-sensitive Staphylococcus aureus and methicillin resistant Staphylococcus aureus. We use aberration-corrected transmission electron microscopy to examine the bactericidal effects of silver nanoparticles and the ultrastructural changes in bacteria that are induced by silver nanoparticles. The study revealed that our 1 nm average size silver nanoparticles induced thinning and permeabilization of the cell wall, destabilization of the peptidoglycan layer, and subsequent leakage of intracellular content, causing bacterial cell lysis. We hypothesize that positively charged silver nanoparticles bind to the negatively charged polyanionic backbones of teichoic acids and the related cell wall glycopolymers of bacteria as a first target, consequently stressing the structure and permeability of the cell wall. This hypothesis provides a major mechanism to explain the antibacterial effects of silver nanoparticles on Staphylococcus aureus. Future research should focus on defining the related molecular mechanisms and their importance to the antimicrobial activity of silver nanoparticles. PMID- 26734532 TI - Vibration-mediated Kondo transport in molecular junctions: conductance evolution during mechanical stretching. AB - The vibration-mediated Kondo effect attracted considerable theoretical interest during the last decade. However, due to lack of extensive experimental demonstrations, the fine details of the phenomenon were not addressed. Here, we analyze the evolution of vibration-mediated Kondo effect in molecular junctions during mechanical stretching. The described analysis reveals the different contributions of Kondo and inelastic transport. PMID- 26734533 TI - Impact of ultrasonic dispersion on the photocatalytic activity of titania aggregates. AB - The effectiveness of photocatalytic materials increases with the specific surface area, thus nanoscale photocatalyst particles are preferred. However, such nanomaterials are frequently found in an aggregated state, which may reduce the photocatalytic activity due to internal obscuration and the extended diffusion path of the molecules to be treated. This paper investigates the effect of aggregate size on the photocatalytic activity of pyrogenic titania (Aeroxide((r)) P25, Evonik), which is widely used in fundamental photocatalysis research. Well defined and reproducible aggregate sizes were achieved by ultrasonic dispersion. The photocatalytic activity was examined by the color removal of methylene blue (MB) with a laboratory-scale setup based on a plug flow reactor (PFR) and planar UV illumination. The process parameters such as flow regime, optical path length and UV intensity are well-defined and can be varied. Our results firstly show that a complete dispersion of the P25 aggregates is not practical. Secondly, the photocatalytic activity is not further increased beyond a certain degree of dispersion, which probably corresponds to a critical size for which UV irradiation can penetrate the aggregate without significant obscuration. PMID- 26734534 TI - One-year results of cemented bipolar radial head prostheses for comminuted radial head fractures. AB - INTRODUCTION: Comminuted radial head fractures (Mason type III) continue to pose a challenge to orthopedic surgeons. When internal fixation is not possible, radial head arthroplasty has been advocated as the treatment of choice. The purpose of this retrospective study was to evaluate clinical and radiological short-term results of patients with Mason type III radial head fractures treated with a cemented bipolar radial prosthesis. METHODS: Twelve patients received cemented bipolar radial head hemiarthroplasty for comminuted radial head fractures. In all patients a CT scan was obtained prior to surgical treatment to assess all associated injuries. Postoperatively an early motion protocol was applied. All patients were evaluated clinically and radiologically at an average of 12.7 months. RESULTS: According to the Mayo Modified Wrist Score, the Mayo Elbow Performance Score, the functional rating index of Broberg and Morrey, and the DASH Score good to excellent results were obtained. Grip strength and range of motion were almost at the level of the unaffected contralateral side. Patient satisfaction was high, no instability or signs of loosening of the implant, and only mild signs of osteoarthritis were seen. CONCLUSION: Overall good to excellent short-term results for primary arthroplasty for comminuted radial head fractures were observed. These encouraging results warrant the conduction of further studies with long-term follow-up and more cases to see if these short term results can be maintained over time. PMID- 26734535 TI - Monteggia-like lesions - treatment strategies and one-year results. AB - INTRODUCTION: The eponym "Monteggia fracture" includes various patterns of complex fracture-dislocations of the proximal ulna and radius, which are not well defined yet. They are frequently described as Monteggia-like lesions or Monteggia equivalent injuries. Until today, these injury patterns have been reported rarely. The objective of this retrospective study was to better define patterns of injury and to document the short-term results of treatment with current fixation techniques. METHODS: Ten patients with a Monteggia-like lesion were included in this study and clinical and radiological follow-up examinations at an average of 12.3 months after the trauma were performed. For clinical follow-up the Mayo Modified Wrist Score, the Mayo Elbow Performance Score, the functional rating index of Broberg and Morrey, and the DASH score were utilized. RESULTS: Osteosynthesis of the ulna was performed using a proximally contoured or precontoured LCP (locking compression plate) in all patients. All patients had a fracture of the radial head. All patients with a Mason type III radial head fracture received a cemented bipolar radial head prosthesis. All Mason type II fractures were treated with open reduction and internal fixation using mini screws. In all Mason type I fractures the treatment of the radial head dislocation was by closed reduction. Associated coronoid fractures were stabilized with lag screws through the ulnar plate or with independent lag screws after reduction of the fracture. According to the aforementioned scoring systems good to excellent results could be achieved. CONCLUSIONS: Our findings demonstrate that good or excellent short-term results can be obtained if the injury is classified correctly and a standardized surgical treatment of all components of the injury is achieved. Further studies with larger patient populations and longer follow up periods are needed to evaluate long-term effectiveness of this treatment concept. PMID- 26734536 TI - Immunonutrition - the influence of early postoperative glutamine supplementation in enteral/parenteral nutrition on immune response, wound healing and length of hospital stay in multiple trauma patients and patients after extensive surgery. AB - INTRODUCTION: In the postoperative phase, the prognosis of multiple trauma patients with severe brain injuries as well as of patients with extensive head and neck surgery mainly depends on protein metabolism and the prevention of septic complications. Wound healing problems can also result in markedly longer stays in the intensive care unit and general wards. As a result, the immunostimulation of patients in the postoperative phase is expected to improve their immunological and overall health. PATIENTS AND METHODS: A study involving 15 patients with extensive ENT tumour surgery and 7 multiple-trauma patients investigated the effect of enteral glutamine supplementation on immune induction, wound healing and length of hospital stay. Half of the patients received a glutamine-supplemented diet. The control group received an isocaloric, isonitrogenous diet. RESULTS: In summary, we found that total lymphocyte counts, the percentage of activated CD4+DR+ T helper lymphocytes, the in-vitro response of lymphocytes to mitogens, as well as IL-2 plasma levels normalised faster in patients who received glutamine-supplemented diets than in patients who received isocaloric, isonitrogenous diets and that these parameters were even above normal by the end of the second postoperative week. SUMMARY: We believe that providing critically ill patients with a demand-oriented immunostimulating diet is fully justified as it reduces septic complications, accelerates wound healing, and shortens the length of ICU (intensive care unit) and general ward stays. PMID- 26734537 TI - Subcutaneous lateral brow lift ("Z-lift"). AB - Surgical eyebrow lift has been described by using many different open and endoscopic methods. Difficult techniques and only short time benefits oft lead to patients' complaints. We present a safe and simple temporal Z-incision technique for eyebrow lift in 37 patients. Besides simplicity and safety, our technique shows long lasting aesthetic results with hidden scars and a high rate of patient satisfaction. PMID- 26734539 TI - Reconstructive surgery in immunocompromised patients: evaluation and therapy. AB - BACKGROUND: An increasing number of patients undergoing reconstructive surgery are immunocompromised due to different reasons and different medical treatments. Some of the used immunosuppressive drugs may affect the process of wound healing and thereby, impair the long-term success of surgical treatment. Therefore, this retrospective analysis aimed at the evaluation of the perioperative treatment and surgical outcome of immunocompromised patients undergoing different reconstructive procedures. METHODS: A retrospective review was performed of 8 immunocompromised patients with different primary diseases who needed reconstructive surgery: 2 patients with non-Hodgkin lymphoma, 1 patient with an acute myeloid leukemia, 1 patient with colitis ulcerosa, 1 patient with liver cirrhosis, 1 patient with chronic polyarthritis, and 2 patients with malignant melanoma. RESULTS: In 7 of our 8 presented cases, multiple operations with wound debridements have been necessary to optimize the granulation of the wound bed before reconstructive surgery. 3 out of these 7 patients required further operations due to wound dehiscence or necrosis, with 2 of them as a result of increased immunosuppressive therapy. 5 out of 8 patients needed no further surgical treatment. CONCLUSIONS: Both the perioperative drug therapy and the reconstructive surgery concept need to be determined carefully in each individual case of the immunocompromised patients. Thus, the appropriate point in time of operation to achieve the best possible wound healing as well as the complexity of the procedure will require the consideration of a 'less is more' strategy in selected cases. PMID- 26734538 TI - Single incision laparoscopic liver resection (SILL) - a systematic review. AB - BACKGROUND: Today, minimally invasive liver resections for both benign and malignant tumors are routinely performed. Recently, some authors have described single incision laparoscopic liver resection (SILL) procedures. Since SILL is a relatively young branch of laparoscopy, we performed a systematic review of the current literature to collect data on feasibility, perioperative results and oncological outcome. METHODS: A literature research was performed on Medline for all studies that met the eligibility criteria. Titles and abstracts were screened by two authors independently. A study was included for review if consensus was obtained by discussion between the authors on the basis of predefined inclusion criteria. A thorough quality assessment of all included studies was performed. Data were analyzed and tabulated according to predefined outcome measures. Synthesis of the results was achieved by narrative review. RESULTS: A total of 15 eligible studies were identified among which there was one prospective cohort study and one randomized controlled trial comparing SILL to multi incision laparoscopic liver resection (MILL). The rest were retrospective case series with a maximum of 24 patients. All studies demonstrated convincing results with regards to feasibility, morbidity and mortality. The rate of wound complications and incisional hernia was low. The cosmetic results were good. CONCLUSIONS: This is the first systematic review on SILL including prospective trials. The results of the existing studies reporting on SILL are favorable. However, a large body of scientific evidence on the field of SILL is missing, further randomized controlled studies are urgently needed. PMID- 26734540 TI - Results after simple decompression of the ulnar nerve in cubital tunnel syndrome. AB - Cubital tunnel syndrome represents the second most common compression neuropathy of the upper limb. For more than four decades there has been a controversy about the best surgical treatment modality for cubital tunnel syndrome. In this study the results of 28 patients with simple ulnar nerve decompression are presented. Data analyses refers to clinical examination, personal interview, DASH questionnaire, and electrophysiological measurements, which were assessed pre- and postoperatively. 28 patients (15 females, 13 males) were included in this study. The average age at time of surgery was 47.78 years (31.68-73.10 years). The period from onset of symptoms to surgery ranged from 2 to 24 months (mean 6 months). The mean follow-up was 2.11 years (0.91-4.16 years). Postoperatively there was a significant decrease in DASH score from 52.6 points to 13.3 points (p<0.001). Also the electrophysiological findings improved significantly: motor nerve conduction velocity increased from 36.0 m/s to 44.4 m/s (p=0.008) and the motor nerve action potential reached 5,470 mV compared to 3,665 mV preoperatively (p=0.018). A significant increase of grip strength from 59% (in comparison to the healthy hand) to 80% was observed (p=0.002). Pain was indicated by means of a visual analog scale from 0 to 100. Preoperatively the median level of pain was 29 and postoperatively it was 0 (p=0.001). The decrease of the two-point discrimination of the three ulnar finger nerves was also highly significant (p<0.001) from 11.3 mm to 5.0 mm. Significant postoperative improvement was also observed in the clinical examination concerning muscle atrophy (p=0.002), clawing (p=0.008), paresthesia (p=0.004), the sign of Froment (p=0.004), the sign of Hoffmann-Tinel (p=0.021), and clumsiness (p=0.002). Overall nearly 90% of all patients were satisfied with the result of the operation. In 96.4% of all cases, surgery improved the symptoms and in one patient (3.6%) the success was noted as "poor" because the symptoms remained unchanged. In 35.7% the success was graded as "moderate", in 10.7% as "good" and in 50.0% as "very good". PMID- 26734541 TI - Phylogenetic placement of Itajahya: An unusual Jacaranda fungal associate. AB - Itajahya is a member of Phallales (Agaricomycetes), which, based on the presence of a calyptra and DNA sequence data for I. rosea, has recently been raised to generic status from a subgenus of Phallus. The type species of the genus, I. galericulata, is commonly known as the Jacaranda stinkhorn in Pretoria, South Africa, which is the only area where the fungus is known outside the Americas. The common name is derived from its association with the South American originating Jacaranda mimosifolia trees in the city. The aim of this study was to consider the unusual occurrence of the fungus in South Africa, to place it on the available Phallales phylogeny and to test whether it merits generic status. Fresh basidiomes were collected during the summer of 2015 and sequenced. Phylogenetic analyses were based on sequence data for the nuc-LSU-rDNA (LSU) and ATPase subunit 6 (ATP6) regions. The results showed that I. rosea and I. galericulata are phylogenetically related. They are also clearly distinguished from other members of Phallales such as Phallus spp. and Dictyophora spp., and so our new data supports the raising of Itajahya to the generic level. PMID- 26734542 TI - Accepted Trichoderma names in the year 2015. AB - A list of 254 names of species and two names of varieties in Trichoderma with name or names against which they are to be protected, following the ICN (Melbourne Code, Art. 14.13), is presented for consideration by the General Committee established by the Congress, which then will refer them to the Nomenclature Committee for Fungi (NCF). This list includes 252 species, one variety and one form. Two new names are proposed: T. neocrassum Samuel (syn. Hypocrea crassa P. Chaverri & Samuels), T. patellotropicum Samuels (syn. Hypocrea patella f. tropica Yoshim. Doi). The following new combinations in Trichoderma are proposed: T. brevipes (Mont.) Samuels, T. cerebriforme (Berk.) Samuels, T. latizonatum (Peck) Samuels, and T. poronioideum (A. Moller) Samuels. The following species are lectotypified: T. americanum (Canham) Jaklitsch & Voglmayr, Gliocladium flavofuscum J.H. Miller, Giddens & A.A. Foster, T. inhamatum Veerkamp & W. Gams, T. konilangbra Samuels, O. Petrini & C.P. Kubicek, T. koningii Oudem., T. pezizoides (Berk. & Broome) Jaklitsch & Voglmayr, T. sulphureum (Schwein.) Jaklitsch & Voglmayr and T. virens (J.H. Miller, Giddens & A.A. Foster) Arx. Epitypes are proposed for the following species: T. albocorneum (Yoshim. Doi) Jaklitsch & Voglmayr, T. albofulvum (Berk. & Broome) Jaklitsch & Voglmayr, T. atrogelatinosum (Dingley) Jaklitsch & Voglmayr, T. corneum (Pat.) Jaklitsch & Voglmayr, T. cornu-damae (Pat.) Z.X. Zhu & W.Y. Zhuang, T. flaviconidium (P. Chaverri, Druzhinina & Samuels) Jaklitsch & Voglmayr, T. hamatum (Bonord.) Bain., T. hunua (Dingley) Jaklitsch & Voglmayr, T. patella (Cooke & Peck) Jaklitsch & Voglmayr, Hypocrea patella f. tropica Yoshim. Doi, T. polysporum (Link) Rifai, T. poronioideum (A. Moller) Samuels T. semiorbis (Berk.) Jaklitsch & Voglmayr, T. sulphureum (Schwein.) Jaklitsch & Voglmayr, and T. tropicosinense (P.G. Liu) P.G. Liu, Z.X. Zhu & W.Y. Zhuang. PMID- 26734543 TI - Phytophthora boodjera sp. nov., a damping-off pathogen in production nurseries and from urban and natural landscapes, with an update on the status of P. alticola. AB - A new homothallic Phytophthora species, isolated in Western Australia (WA), is described as Phytophthora boodjera sp. nov. It produces persistent, papillate sporangia, oogonia with thick-walled oospores, and paragynous antheridia. Although morphologically similar to P. arenaria, phylogenetic analyses of the ITS, cox1, HSP90, beta-tubulin and enolase gene regions revealed P. boodjera as a new species. In addition, P. boodjera has a higher optimal temperature for growth and a faster growth rate. Phytophthora boodjera has only recently been found in Western Australia and has mostly been isolated from dead and dying Eucalyptus seedlings in nurseries and from urban tree plantings, and occasionally from disturbed natural ecosystems. It is found in association with declining and dying Agonis flexuosa, Banksia media, B. grandis, Corymbia calophylla, Eucalyptus spp,. and Xanthorrhoea preissii. The status of P. alticola was also reviewed. The loss of all isolates associated with the original description except one; discrepancies in both sequence data and morphology of the remaining isolate with that presented the original description, and inconclusive holotype material places the status of this species in doubt. PMID- 26734544 TI - Matsushimamyces, a new genus of keratinophilic fungi from soil in central India. AB - During a collecting trip exploring new habitats and locations for keratinophilic fungi, soil samples were collected from Bohani village in the central Indian state of Madhya Pradesh. Following isolation using a hair baiting technique, one sample yielded an interesting hyphomycetous fungus. The fungus, which could easily be observed under a dissecting microscope, formed prominently large, dark brown to opaque, fusoid conidia on horse hair after 2 mo of incubation. Single conidial colonies were cultivated on Sabouraud dextrose agar medium by direct transfer, using a fine needle under a dissecting microscope. Morphologically the fungus resembles genera such as Bahugada, Hadrosporium, Manoharachariella, Pithomyces, and Septosporiopsis, but differs with regard to its conidia and conidiogenous cells. Based on its unique morphology, the present collection is described as a new genus, Matsushimamyces, with M. bohaniensis as type species. Phylogenetic analysis of the LSU region placed Matsushimamyces in Latoruaceae (Pleosporales, Dothideomycetes). Furthermore, based on the morphological and phylogenetic similarity (ITS and LSU rDNA), a second species, Polyschema venustum, is also referred to Matsushimamyces. PMID- 26734545 TI - Phylogeny of Hirsutella species (Ophiocordycipitaceae) from the USA: remedying the paucity of Hirsutella sequence data. AB - Hirsutella (Ophiocordycipitaceae: Hypocreales) is a genus of insect, mite, and nematode pathogens with an asexual morph, which generally produce a mucilaginous cluster of one or several conidia on phialides that are basally subulate and taper to a fine neck. The generic name Hirsutella has been proposed for suppression in favour of Ophiocordyceps as a consequence of the ending of dual nomenclature for different morphs of pleomorphic fungi in 2011. Though the generic name is well established, geographically dispersed, and speciose, exceptionally few sequences are available in online databases. We examined 46 isolates of 23 Hirsutella species from the USA, curated by the USDA-ARS Collection of Entomopathogenic Fungal Cultures (ARSEF Culture Collection), that previously had not been molecularly characterized and produced a phylogeny of these organisms; we included previously published Hirsutella and Ophiocordyceps taxa. In producing the largest phylogeny of Hirsutella isolates so far, we provide: (1) context for discussing previously-hypothesized relationships; (2) evidence for revisions as taxonomic transitions move forward; and (3) available molecular data to be incorporated into further evolutionary studies of Ophiocordycipitaceae. PMID- 26734546 TI - New 1F1N Species Combinations in Ophiocordycipitaceae (Hypocreales). AB - Based on the taxonomic and nomenclatural recommendations of Quandt et al. (2014) new species combinations are made for Ophiocordycipitaceae. These new combinations are compliant with recent changes in the International Code of Nomenclature for algae, fungi, and plants (ICN) and the abolition of the dual system of nomenclature for fungi. These changes include 10 new combinations into Drechmeria, four new combinations into Harposporium, 23 new combinations and 15 synonymies in Ophiocordyceps, and one new combination into Purpureocillium. PMID- 26734547 TI - Bringing Laboulbeniales into the 21st century: enhanced techniques for extraction and PCR amplification of DNA from minute ectoparasitic fungi. AB - Laboulbeniales is one of the most peculiar orders of Ascomycota. These fungi are characterized by an ectoparasitic life-style on arthropods, determinate growth, lack of an asexual stage, high species richness, and intractability to culture. The order Laboulbeniales, sister to Pyxidiophorales, has only recently been assigned a separate class, the Laboulbeniomycetes, based on very few ribosomal DNA sequences. So far, DNA isolations and PCR amplifications have proven difficult. Here, we provide details of isolation techniques and the application of commercially available kits that enable efficient and reliable genetic analyses of these fungi. We provide 43 newly generated Laboulbeniales ribosomal DNA sequences, among which are the first published sequences for species in the genera Gloeandromyces, Herpomyces, Laboulbenia, Monoicomyces, and Polyandromyces. DNA extractions were possible using from 1 to 30 thalli from hosts preserved in ethanol (70-100 %). In two cases, we successfully isolated DNA from thalli on dried insect collections. Laboulbeniales molecular systematics could be substantially enhanced through these improved methods by allowing more complete sampling of both taxa and gene regions. PMID- 26734548 TI - Cercosporoid fungi (Mycosphaerellaceae) 4. Species on dicots (Acanthaceae to Amaranthaceae). AB - The present paper continues a series of comprehensive taxonomic treatments of cercosporoid fungi (formerly Cercospora s. lat.), belonging to the Mycosphaerellaceae (Ascomycota). The fourth contribution of this series initiates treatments of cercosporoid fungi on dicots and comprises species occurring on hosts belonging the the families Acanthaceae, Actinidiaceae, Adoxaceae, Aizoaceae, Altingiaceae, and Amaranthaceae. The species are described and illustrated in alphabetical order under the particular cercosporoid genera, supplemented by keys to the species concerned. A detailed introduction, a survey of currently recognised cercosporoid genera, a key to the genera concerned, and a discussion of taxonomically relevant characters were published in the first part of this series. The following taxonomic novelties are introduced: Cercospora blepharidicola nom. nov., C. celosiigena sp. nov., C. justiciae-adhatodae sp. nov., C. justiciigena nom. nov., C. sambucicola nom. nov., C. thunbergiigena nom. nov., Cercosporella pseudachyranthis comb. nov., Pseudocercospora cyathulae comb. nov., P. depazeoides comb. nov., P. varia var. viburni-sargentii var. nov., P. viburnicola sp. nov., P. viburni-erosi sp. nov., and P. viburni-nudi sp. nov. PMID- 26734549 TI - Knoxdaviesia proteae is not the only Knoxdaviesia-symbiont of Protea repens. AB - Two polyphyletic genera of ophiostomatoid fungi are symbionts of Proteaceae in southern Africa. One of these, Knoxdaviesia, includes two closely related species, K. proteae and K. capensis, that have overlapping geographical distributions, but are not known to share Protea host species. Knoxdaviesia capensis appears to be a generalist that occupies numerous hosts, but has never been found in P. repens, the only known host of K. proteae. In this study, extensive collections were made from P. repens and isolates were identified using DNA sequence comparisons. This led to the surprising discovery of K. capensis from P. repens for the first time. The fungus was encountered at a low frequency, suggesting that P. repens is not its preferred host, which may explain why it has not previously been found on this plant. The basis for the specialisation of K. proteae and K. capensis on different Protea species remains unknown. PMID- 26734550 TI - Microcyclic rusts of hollyhock ( Alcea rosea ). AB - Rust fungi infecting hollyhock and other plants in Malveae are frequently intercepted at ports of entry to the USA, particularly Puccinia malvacearum and P. heterogenea. These two species can be difficult to distinguish and can be further confused with other, less common species of microcyclic rust fungi infecting hollyhock: P. heterospora, P. lobata, P. platyspora, and P. sherardiana. Molecular phylogenetic analysis revealed that P. malvacearum and P. heterogenea are closely related, along with P. sherardiana and P. platyspora. A key to the six microcyclic Puccinia species infecting hollyhock is presented. PMID- 26734551 TI - Baobabopsis, a new genus of graminicolous downy mildews from tropical Australia, with an updated key to the genera of downy mildews. AB - So far 19 genera of downy mildews have been described, of which seven are parasitic to grasses. Here, we introduce a new genus, Baobabopsis, to accommodate two distinctive downy mildews, B. donbarrettii sp. nov., collected on Perotis rara in northern Australia, and B. enneapogonis sp. nov., collected on Enneapogon spp. in western and central Australia. Baobabopsis donbarrettii produced both oospores and sporangiospores that are morphologically distinct from other downy mildews on grasses. Molecular phylogenetic analyses showed that the two species of Baobabopsis occupied an isolated position among the known genera of graminicolous downy mildews. The importance of the Poaceae for the evolution of downy mildews is highlighted by the observation that more than a third of the known genera of downy mildews occur on grasses, while more than 90 % of the known species of downy mildews infect eudicots. PMID- 26734552 TI - IMA Genome-F 5: Draft genome sequences of Ceratocystis eucalypticola, Chrysoporthe cubensis, C. deuterocubensis, Davidsoniella virescens, Fusarium temperatum,Graphilbum fragrans, Penicillium nordicum, and Thielaviopsis musarum. AB - The genomes of Ceratocystis eucalypticola, Chrysoporthe cubensis, Chrysoporthe deuterocubensis, Davidsoniella virescens, Fusarium temperatum, Graphilbum fragrans, Penicillium nordicum and Thielaviopsis musarum are presented in this genome announcement. These seven genomes are from plant pathogens and otherwise economically important fungal species. The genome sizes range from 28 Mb in the case of T. musarum to 45 Mb for Fusarium temperatum. These genomes include the first reports of genomes for the genera Davidsoniella, Graphilbum and Thielaviopsis. The availability of these genome data will provide opportunities to resolve longstanding questions regarding the taxonomy of species in these genera. In addition these genome sequences through comparative studies with closely related organisms will increase our understanding of how these pathogens cause disease. PMID- 26734554 TI - Internet marketing in the medical industry; challenges and future. PMID- 26734553 TI - Recommended names for pleomorphic genera in Dothideomycetes. AB - This paper provides recommendations of one name for use among pleomorphic genera in Dothideomycetes by the Working Group on Dothideomycetes established under the auspices of the International Commission on the Taxonomy of Fungi (ICTF). A number of these generic names are proposed for protection because they do not have priority and/or the generic name selected for use is asexually typified. These include: Acrogenospora over Farlowiella; Alternaria over Allewia, Lewia, and Crivellia; Botryosphaeria over Fusicoccum; Camarosporula over Anthracostroma; Capnodium over Polychaeton; Cladosporium over Davidiella; Corynespora over Corynesporasca; Curvularia over Pseudocochliobolus; Elsinoe over Sphaceloma; Excipulariopsis over Kentingia; Exosporiella over Anomalemma; Exserohilum over Setosphaeria; Gemmamyces over Megaloseptoria; Kellermania over Planistromella; Kirschsteiniothelia over Dendryphiopsis; Lecanosticta over Eruptio; Paranectriella over Araneomyces; Phaeosphaeria over Phaeoseptoria; Phyllosticta over Guignardia; Podonectria over Tetracrium; Polythrincium over Cymadothea; Prosthemium over Pleomassaria; Ramularia over Mycosphaerella; Sphaerellopsis over Eudarluca; Sphaeropsis over Phaeobotryosphaeria; Stemphylium over Pleospora; Teratosphaeria over Kirramyces and Colletogloeopsis; Tetraploa over Tetraplosphaeria; Venturia over Fusicladium and Pollaccia; and Zeloasperisporium over Neomicrothyrium. Twenty new combinations are made: Acrogenospora carmichaeliana (Berk.) Rossman & Crous, Alternaria scrophulariae (Desm.) Rossman & Crous, Pyrenophora catenaria (Drechsler) Rossman & K.D. Hyde, P. dematioidea (Bubak & Wrobl.) Rossman & K.D. Hyde, P. fugax (Wallr.) Rossman & K.D. Hyde, P. nobleae (McKenzie & D. Matthews) Rossman & K.D. Hyde, P. triseptata (Drechsler) Rossman & K.D. Hyde, Schizothyrium cryptogamum (Batzer & Crous) Crous & Batzer, S. cylindricum (G.Y. Sun et al.) Crous & Batzer, S. emperorae (G.Y. Sun & L. Gao) Crous & Batzer, S. inaequale (G.Y. Sun & L. Gao) Crous & Batzer, S. musae (G.Y. Sun & L. Gao) Crous & Batzer, S. qianense (G.Y. Sun & Y.Q. Ma) Crous & Batzer, S. tardecrescens (Batzer & Crous) Crous & Batzer, S. wisconsinense (Batzer & Crous) Crous & Batzer, Teratosphaeria epicoccoides (Cooke & Massee) Rossman & W.C. Allen, Venturia catenospora (Butin) Rossman & Crous, V. convolvularum (Ondrej) Rossman & Crous, V. oleaginea (Castagne) Rossman & Crous, and V. phillyreae (Nicolas & Aggery) Rossman & Crous, combs. nov. Three replacement names are also proposed: Pyrenophora grahamii Rossman & K.D. Hyde, Schizothyrium sunii Crous & Batzer, and Venturia barriae Rossman & Crous noms. nov. PMID- 26734555 TI - Cervicofacial infection in a Nigerian tertiary health institution: a retrospective analysis of 77 cases. AB - OBJECTIVES: Infection involving the orbit, zygomatic space, lateral pharyngeal space, or hemifacial and oral floor phlegmon is referred to as cervicofacialvinfection (CFI). When diagnosis and/or adequate treatment are delayed, these infections can be life-threatening. Most cases are the result of odontogenic infections. We highlight our experiences in the management of this life-threatening condition. MATERIALS AND METHODS: This was a retrospective study of patients who presented with CFI from December 2005 to June 2012 at the Oral and Maxillofacial Surgery Clinic or the Accident and Emergency Unit of Ahmadu Bello University Teaching Hospital (Zaria, Nigeria). The medical records of all patients who presented with either localized or diffuse infection of the maxillofacial soft tissue spaces were retrospectively collected. Data collected was analyzed using SPSS version 13.0 and are expressed as descriptive and inferential statistics. RESULTS: Of the 77 patients, 49 patients (63.6%) were males, a male to female ratio of 1:7.5. The ages ranged from two years to 75 years with a mean of 35.0+/-19.3 years, although most patients were older than 40 years. The duration of symptoms prior to presentation ranged from 6 to 60 days, with a mean of 11.0+/-9.4 days. More than 90% of the patients presented to the clinic within the first 10 days. The most commonly involved anatomical space was the submandibular space (n=29, 37.7%), followed by hemifacial space (n=22, 28.6%) and buccal space (n=7, 9.1%). Ludwig angina accounted for about 7.8% of the cases. CONCLUSION: CFI most commonly involves the submandibular space, typically affects individuals with a low level of education, and is influenced by traditional medical practices. Despite improved health care delivery, CFI remains a significant problem in developing countries. PMID- 26734556 TI - Neck dissection for oral squamous cell carcinoma: our experience and a review of the literature. AB - OBJECTIVES: This article describes our experience with neck dissection in 10 patients with oral squamous cell carcinoma. MATERIALS AND METHODS: Between January 2007 and October 2009, 10 patients underwent primary surgery for the treatment of squamous cell carcinoma of the oral cavity. For patients with N0 disease on clinical exam, selective neck dissection (SND [I-III]) was performed. In patients with palpable cervical metastases (N+), modified radical neck dissections were performed, except in one patient in whom SND (I-III) was performed. The histopathologic reports were reviewed to assess the surgical margins, the presence of extra-capsular spread, perineural invasion, and lymphatic invasion. RESULTS: On histopathologic examination, positive soft tissue margins were found in three patients, and regional lymph node metastases were present in five of the ten patients. Perineural invasion was noted in five patients, and extra nodal spread was found in four patients. Regional recurrence was seen in two patients and loco-regional recurrence plus distant metastasis to the tibia was observed in one patient. During the study period, three patients died. Seven patients remain free of disease to date. CONCLUSION: Histopathological evaluation provides important and reliable information for disease staging, treatment planning, and prognosis. The philosophy of neck dissection is evolving rapidly with regard to the selectivity with which at-risk lymph node groups are removed. The sample size in the present study is small, thus, caution should be employed when interpreting these results. PMID- 26734557 TI - Fracture patterns in the maxillofacial region: a four-year retrospective study. AB - OBJECTIVES: The facial bones are the most noticeable area in the human body, and facial injuries can cause significant functional, aesthetic, and psychological complications. Continuous study of the patterns of facial bone fractures and changes in trends is helpful in the prevention and treatment of maxillofacial fractures. The purpose of the current clinico-statistical study is to investigate the pattern of facial fractures over a 4-year period. MATERIALS AND METHODS: A retrospective analysis of 1,824 fracture sites was carried out in 1,284 patients admitted to SMG-SNU Boramae Medical Center for facial bone fracture from January 2010 to December 2013. We evaluated the distributions of age/gender/season, fracture site, cause of injury, duration from injury to treatment, hospitalization period, and postoperative complications. RESULTS: The ratio of men to women was 3.2:1. Most fractures occurred in individuals aged between teens to 40s and were most prevalent at the middle and end of the month. Fractures occurred in the nasal bone (65.0%), orbital wall (29.2%), maxillary wall (15.3%), zygomatic arch (13.2%), zygomaticomaxillary complex (9.8%), mandibular symphysis (6.5%), mandibular angle (5.9%), mandibular condyle (4.9%), and mandibular body (1.9%). The most common etiologies were fall (32.5%) and assault (26.0%). The average duration of injury to treatment was 6 days, and the average hospitalization period was 5 days. Eighteen postoperative complications were observed in 17 patients, mainly infection and malocclusion in the mandible. CONCLUSION: This study reflects the tendency for trauma in the Seoul metropolitan region because it analyzes all facial fracture patients who visited our hospital regardless of the specific department. Distinctively, in this study, midfacial fractures had a much higher incidence than mandible fractures. PMID- 26734558 TI - Five-year retrospective radiographic follow-up study of dental implants with sandblasting with large grit, and acid etching-treated surfaces. AB - OBJECTIVES: The purpose of this study is to evaluate five-year radiographic follow-up results of the Korean sandblasting with large grit, and acid etching (SLA)-treated implant system. MATERIALS AND METHODS: The subjects of the study are 54 patients who have been followed-up to date, of the patients who underwent implant surgery from May 1, 2009 to April 30, 2011. In all, 176 implant placements were performed. Radiographs were taken before the first surgery, immediately after the first and second surgeries, immediately and six months after the final prosthesis installation, and every year after that. Bone loss was evaluated by the method suggested by Romanos and Nentwig. RESULTS: A total of 176 implant placements were performed-122 in men and 54 in women. These patients have been followed-up for an average of 4.9 years. In terms of prosthetic appliances, there were 156 bridges and 20 single prostheses. Nine implants installed in the maxillary molar area, three in the mandibular molar area and two in the maxillary premolar area were included in group M, with bone loss less than 2 mm at the crestal aspect of the implant. Of these, eight implants were single prostheses. In all, six implants failed-four in the mandible and two in the maxilla. All of these failures occurred in single-implant cases. The implant survival rate was 98.1% on the maxilla and 94.3% on the mandible, with an overall survival of 96.6%. CONCLUSION: Within the limitations of this study, implants with the SLA surface have a very superior survival rate in relatively poor bone environments such as the maxilla. PMID- 26734559 TI - Sclerotherapy using 1% sodium tetradecyl sulfate to treat a vascular malformation: a report of two cases. AB - Vascular malformations are the most common congenital and neonatal vascular anomalies in the head and neck region. The demand for simple and esthetic vascular malformation treatments have increased more recently. In this study, two patients that were diagnosed with venous malformations were treated with sodium tetradecyl sulfate as a sclerosing agent. Recurrence was not found one year after the surgery. This article gives a brief case report of sclerotherapy as an effective approach to treat vascular malformations in the oral cavity. PMID- 26734560 TI - Bisphosphonate-related osteonecrosis of the jaw in a patient with osteoporosis following treatment of testicular cancer: a case report. AB - Bisphosphonate-related osteonecrosis of the jaw (BRONJ) occurs mainly in female patients. In males the occurrence rate is low, which seems to be related to the low incidence of osteoporosis in men. Unfortunately, BRONJ tends to be ignored in general dental clinics in male patients with a history of osteoporosis treatment. BRONJ occurred in a male patient due to the clinician's lack of interest in the patient's history. In this case, the male patient was on bisphosphonate therapy because of a orchiectomy, and a dental treatment was performed without consideration of his medical history, resulting in BRONJ. We performed careful examinations and treatment with antibiotics and surgical operations. The postoperative healing was successful. In light of this particular case, we concluded that careful listening to the patient's history is very important. PMID- 26734561 TI - Chronic maxillary sinusitis and diabetes related maxillary osteonecrosis: a case report. AB - Dental infections and maxillary sinusitis are the main causes of osteomyelitis. Osteomyelitis can occur in all age groups, and is more frequently found in the lower jaw than in the upper jaw. Systemic conditions that can alter the patient's resistance to infection including diabetes mellitus, anemia, and autoimmune disorders are predisposing factors for osteomyelitis. We report a case of uncommon broad maxillary osteonecrosis precipitated by uncontrolled type 2 diabetes mellitus and chronic maxillary sinusitis in a female patient in her seventies with no history of bisphosphonate or radiation treatment. PMID- 26734562 TI - Contralateral recurrence of necrotizing sialometaplasia of the hard palate after five months: a case report. AB - Necrotizing sialometaplasia usually heals within 4 to 10 weeks with conservative treatment, and rarely recurs. When necrotizing sialometaplasia is present on the hard palate it may occur unilaterally or bilaterally. In this case, necrotizing ulceration occurred on the left hard palate of a 36-year-old woman after root canal treatment of the upper left first premolar under local anesthesia. After only saline irrigation the defect of the lesion completely healed and filled with soft tissue. After 5 months, however, a similar focal necrosis was found on the contralateral hard palate without any dental treatment having been performed on that side and progressed in similar fashion as the former lesion. We conducted an incisional biopsy and obtained a final pathological diagnosis for the palatal mass of necrotizing sialometaplasia. At the 3-year follow-up, the patient's oral mucosa of the hard palate was normal, without any signs and symptoms of the condition. We report a case of a second occurrence of necrotizing sialometaplasia on the contralateral side from the first, with a time lapse between the first and second occurrence. PMID- 26734563 TI - Adenomatoid odontogenic tumor associated with an unerupted mandibular lateral incisor: a case report. AB - Adenomatoid odontogenic tumor (AOT) is a rare, benign odontogenic tumor that predominantly appears in the second decade of life in female patients. Most AOTs occur in the anterior part of the maxilla and are usually associated with impacted anterior teeth. There are three types of AOT, follicular, extrafollicular, and peripheral, which are classified based on the location of the lesion and its association with the impacted tooth. We report a rare case of AOT associated with an impacted right mandibular lateral incisor in an 11-year old female patient. PMID- 26734564 TI - Recurrent arteriovenous malformation on palate after embolization combined surgical resection: preoperative magnetic resonance features and intraoperative angiographic findings. AB - Angiography is the gold standard for the diagnosis and complete resection of arteriovenous malformations (AVMs). The absence of residual AVM after surgery is commonly believed to reduce the risk of future hemorrhage. However, AVMs can recur after proven complete angiographic resection can occur, albeit rarely, especially in the pediatric population. We report a rare case of a recurrent AVM two years after complete resection in an adult patient. This case report shows that AVMs in adults can recur despite their rarity and despite postoperative angiography confirming complete removal. Moreover, in this case, the recurrent AVM involved a new feeding vessel that was not involved with the initial lesion. PMID- 26734565 TI - Human Papilloma Viruses and Breast Cancer. AB - PURPOSE: Human papillomaviruses (HPV) may have a role in some breast cancers. The purpose of this study is to fill important gaps in the evidence. These gaps are: (i) confirmation of the presence of high risk for cancer HPVs in breast cancers, (ii) evidence of HPV infections in benign breast tissues prior to the development of HPV-positive breast cancer in the same patients, (iii) evidence that HPVs are biologically active and not harmless passengers in breast cancer. METHODS: RNA seq data from The Cancer Genome Atlas (TCGA) was used to identify HPV RNA sequences in breast cancers. We also conducted a retrospective cohort study based on polymerase chain reaction (PCR) analyses to identify HPVs in archival specimens from Australian women with benign breast biopsies who later developed breast cancer. To assess whether HPVs in breast cancer were biologically active, the expression of the oncogenic protein HPV E7 was assessed by immunohistochemistry (IHC). RESULTS: Thirty (3.5%) low-risk and 20 (2.3%) high risk HPV types were identified in 855 breast cancers from the TCGA database. The high risk types were HPV 18 (48%), HPV 113 (24%), HPV 16 (10%), HPV 52 (10%). Data from the PCR cohort study indicated that HPV type 18 was the most common type identified in breast cancer specimens (55% of 40 breast cancer specimens) followed by HPV 16 (13%). The same HPV type was identified in both the benign and subsequent breast cancer in 15 patients. HPV E7 proteins were identified in 72% of benign breast specimens and 59% of invasive breast cancer specimens. CONCLUSION: There were four observations of particular interest: (i) confirmation by both NGS and PCR of the presence of high-risk HPV gene sequences in breast cancers, (ii) a correlation between high-risk HPV in benign breast specimens and subsequent HPV-positive breast cancer in the same patient, (iii) HPVs in breast cancer are likely to be biologically active (as shown by transcription of HPV DNA to RNA plus the expression of HPV E7 proteins), (iv) HPV oncogenic influences may occur early in the development of breast cancer. PMID- 26734566 TI - Aurora Kinase Inhibitors: Current Status and Outlook. AB - The Aurora kinase family comprises of cell cycle-regulated serine/threonine kinases important for mitosis. Their activity and protein expression are cell cycle regulated, peaking during mitosis to orchestrate important mitotic processes including centrosome maturation, chromosome alignment, chromosome segregation, and cytokinesis. In humans, the Aurora kinase family consists of three members; Aurora-A, Aurora-B, and Aurora-C, which each share a conserved C terminal catalytic domain but differ in their sub-cellular localization, substrate specificity, and function during mitosis. In addition, Aurora-A and Aurora-B have been found to be overexpressed in a wide variety of human tumors. These observations led to a number of programs among academic and pharmaceutical organizations to discovering small molecule Aurora kinase inhibitors as anti cancer drugs. This review will summarize the known Aurora kinase inhibitors currently in the clinic, and discuss the current and future directions. PMID- 26734567 TI - Fast Pencil Beam Dose Calculation for Proton Therapy Using a Double-Gaussian Beam Model. AB - The highly conformal dose distributions produced by scanned proton pencil beams (PBs) are more sensitive to motion and anatomical changes than those produced by conventional radiotherapy. The ability to calculate the dose in real-time as it is being delivered would enable, for example, online dose monitoring, and is therefore highly desirable. We have previously described an implementation of a PB algorithm running on graphics processing units (GPUs) intended specifically for online dose calculation. Here, we present an extension to the dose calculation engine employing a double-Gaussian beam model to better account for the low-dose halo. To the best of our knowledge, it is the first such PB algorithm for proton therapy running on a GPU. We employ two different parameterizations for the halo dose, one describing the distribution of secondary particles from nuclear interactions found in the literature and one relying on directly fitting the model to Monte Carlo simulations of PBs in water. Despite the large width of the halo contribution, we show how in either case the second Gaussian can be included while prolonging the calculation of the investigated plans by no more than 16%, or the calculation of the most time-consuming energy layers by about 25%. Furthermore, the calculation time is relatively unaffected by the parameterization used, which suggests that these results should hold also for different systems. Finally, since the implementation is based on an algorithm employed by a commercial treatment planning system, it is expected that with adequate tuning, it should be able to reproduce the halo dose from a general beam line with sufficient accuracy. PMID- 26734568 TI - Prediction of Cancer Drug Resistance and Implications for Personalized Medicine. AB - Drug resistance still impedes successful cancer chemotherapy. A major goal of early concepts in individualized therapy was to develop in vitro tests to predict tumors' drug responsiveness. We have developed an in vitro short-term test based on nucleic acid precursor incorporation to determine clinical drug resistance. This test detects inherent and acquired resistance in vitro and transplantable syngeneic and xenografted tumors in vivo. In several clinical trials, clinical resistance was predictable with more than 90% accuracy, while drug sensitivity was detected with less accuracy (~60%). Remarkably, clinical cross-resistance to numerous drugs (multidrug resistance, broad spectrum resistance) was detectable by a single compound, doxorubicin, due to its multifactorial modes of action. The results of this predictive test were in good agreement with predictive assays of other authors. As no predictive test has been established as yet for clinical diagnostics, the identification of sensitive drugs may not reach sufficiently high reliability for clinical routine. A meta-analysis of the literature published during the past four decades considering test results of more than 15,000 tumor patients unambiguously demonstrated that, in the majority of studies, resistance was correctly predicted with an accuracy between 80 and 100%, while drug sensitivity could only be predicted with an accuracy of 50-80%. This synopsis of the published literature impressively illustrates that prediction of drug resistance could be validated. The determination of drug resistance was reliable independent of tumor type, test assay, and drug used in these in vitro tests. By contrast, chemosensitivity could not be predicted with high reliability. Therefore, we propose a rethinking of the "chemosensitivity" concept. Instead, predictive in vitro tests may reliably identify drug-resistant tumors. The clinical consequence imply to subject resistant tumors not to chemotherapy, but to other new treatment options, such as antibody therapy, adoptive immune therapy, hyperthermia, gene therapy, etc. The high accuracy to predict resistant tumors may be exploited to develop new strategies for individualized cancer therapy. This new concept bears the potential of a revival of predictive tests for personalized medicine. PMID- 26734569 TI - Regulation of Mutant p53 Protein Expression. AB - For several decades, p53 has been detected in cancer biopsies by virtue of its high protein expression level which is considered indicative of mutation. Surprisingly, however, mouse genetic studies revealed that mutant p53 is inherently labile, similar to its wild type (wt) counterpart. Consistently, in response to stress conditions, both wt and mutant p53 accumulate in cells. While wt p53 returns to basal level following recovery from stress, mutant p53 remains stable. In part, this can be explained in mutant p53-expressing cells by the lack of an auto-regulatory loop with Mdm2 and other negative regulators, which are pivotal for wt p53 regulation. Further, additional protective mechanisms are acquired by mutant p53, largely mediated by the co-chaperones and their paralogs, the stress-induced heat shock proteins. Consequently, mutant p53 is accumulated in cancer cells in response to chronic stress and this accumulation is critical for its oncogenic gain of functions (GOF). Building on the extensive knowledge regarding wt p53, the regulation of mutant p53 is unraveling. In this review, we describe the current understanding on the major levels at which mutant p53 is regulated. These include the regulation of p53 protein levels by microRNA and by enzymes controlling p53 proteasomal degradation. PMID- 26734570 TI - Predictors of Complete Response and Disease Recurrence Following Chemoradiation for Rectal Cancer. AB - OBJECTIVE: Approximately 10-40% of rectal patients have a complete response (CR) to neoadjuvant chemoradiation (CRT), and these patients have improved survival. Thus, non-operative management ("watch-and-wait" approach) may be an option for select patients. We aimed to identify clinical predictors of CR following CRT. METHODS: Patients treated with definitive CRT for T3-T4, locally unresectable T1 T2, low-lying T2, and/or node-positive rectal cancer from August 2004 to February 2015 were retrospectively reviewed. Most patients were treated with 50.4 Gy radiation and concurrent 5-fluoruracil or capecitabine. Patients were considered to have a CR if surgical pathology revealed ypT0N0M0 (operative management), or if they had no evidence of residual disease on clinical and radiographic assessment (non-operative management). Statistical analysis was carried out to determine predictors of CR and long-term outcomes. RESULTS: Complete records were available on 138 patients. The median follow-up was 24.5 months. Thirty-six patients (26.3%) achieved a CR; 30/123 operatively managed patients (24.5%) and 6/15 (40%) non-operatively managed patients. None of the 10 patients with mucinous adenocarcinoma achieved a CR. Carcinoembryonic antigen (CEA) >=5 MUg/L at diagnosis (OR 0.190, 95% CI 0.037-0.971, p = 0.046), tumor size >=3 cm (OR 0.123, 95% CI 0.020-0.745, p = 0.023), distance of tumor from the anal verge >=3 cm (OR 0.091, 95% CI 0.013-0.613, p = 0.014), clinically node-positive disease at diagnosis (OR 0.201, 95% CI 0.045-0.895, p = 0.035), and interval from CRT to surgery >=8 weeks (OR 5.267, 95% CI 1.068-25.961, p = 0.041) were independent predictors of CR. The CR group had longer 3-year distant metastasis-free survival (DMFS) (93.7 vs. 63.7%, p = 0.016) and 3-year disease-free survival (DFS) (91.1 vs. 67.8%, p = 0.038). Three-year locoregional control (LRC) (96.6 vs. 81.3%, p = 0.103) and overall survival (97.2 vs. 87.5%, p = 0.125) were higher in the CR group but this did not achieve statistical significance. CR was not an independent predictor of LRC, DMFS, or DFS. CONCLUSION: CEA at diagnosis, tumor size, tumor distance from the anal verge, node positivity at diagnosis, and interval from CRT to surgery were predictors of CR. These clinical variables may offer insight into patient selection and timing of treatment response evaluation in the watch-and-wait approach. PMID- 26734571 TI - Mutant p53: One, No One, and One Hundred Thousand. AB - Encoded by the mutated variants of the TP53 tumor suppressor gene, mutant p53 proteins are getting an increased experimental support as active oncoproteins promoting tumor growth and metastasis. p53 missense mutant proteins are losing their wild-type tumor suppressor activity and acquire oncogenic potential, possessing diverse transforming abilities in cell and mouse models. Whether various mutant p53s differ in their oncogenic potential has been a matter of debate. Recent discoveries are starting to uncover the existence of mutant p53 downstream programs that are common to different mutant p53 variants. In this review, we discuss a number of studies on mutant p53, underlining the advantages and disadvantages of alternative experimental approaches that have been used to describe the numerous mutant p53 gain-of-function activities. Therapeutic possibilities are also discussed, taking into account targeting either individual or multiple mutant p53 proteins in human cancer. PMID- 26734572 TI - Aurora A's Functions During Mitotic Exit: The Guess Who Game. AB - Until recently, the knowledge of Aurora A kinase functions during mitosis was limited to pre-metaphase events, particularly centrosome maturation, G2/M transition, and mitotic spindle assembly. However, an involvement of Aurora A in post-metaphase events was also suspected, but not clearly demonstrated due to the technical difficulty to perform the appropriate experiments. Recent developments of both an analog-specific version of Aurora A and small molecule inhibitors have led to the first demonstration that Aurora A is required for the early steps of cytokinesis. As in pre-metaphase, Aurora A plays diverse functions during anaphase, essentially participating in astral microtubules dynamics and central spindle assembly and functioning. The present review describes the experimental systems used to decipher new functions of Aurora A during late mitosis and situate these functions into the context of cytokinesis mechanisms. PMID- 26734573 TI - Treatment Parameters Optimization to Compensate for Interfractional Anatomy Variability and Intrafractional Tumor Motion. AB - Scanned ion beam therapy of lung tumors is severely limited in its clinical applicability by intrafractional organ motion, interference effects between beam and tumor motion (interplay), as well as interfractional anatomic changes. To compensate for dose deterioration caused by intrafractional motion, motion mitigation techniques, such as gating, have been developed. However, optimization of the treatment parameters is needed to further improve target dose coverage and normal tissue sparing. The aim of this study was to determine treatment-planning parameters that permit to recover good target coverage for each fraction of lung tumor treatments. For 9 lung tumor patients from MD Anderson Cancer Center (Houston, Texas), a total of 70 weekly time-resolved computed tomography (4DCT) datasets, which depict the evolution of the patient anatomy over the several fractions of the treatment, were available. Using the GSI in-house treatment planning system TRiP4D, 4D simulations were performed on each weekly 4DCT for each patient using gating and optimization of a single treatment plan based on a planning CT acquired prior to treatment. The impact on target dose coverage (V 95%,CTV) of variations in focus size and length of the gating window, as well as different additional margins and the number of fields was analyzed. It appeared that interfractional variability could potentially have a larger impact on V 95%,CTV than intrafractional motion. However, among the investigated parameters, the use of a large beam spot size, a short gating window, additional margins, and multiple fields permitted to obtain an average V 95%,CTV of 96.5%. In the presented study, it was shown that optimized treatment parameters have an important impact on target dose coverage in the treatment of moving tumors. Indeed, intrafractional motion occurring during the treatment of lung tumors and interfractional variability were best mitigated using a large focus, a short gating window, additional margins, and three fields. PMID- 26734574 TI - Cap-Independent Translation in Hematological Malignancies. AB - Hematological malignancies are a heterogeneous group of diseases deriving from blood cells progenitors. Although many genes involved in blood cancers contain internal ribosome entry sites (IRESes), there has been only few studies focusing on the role of cap-independent translation in leukemia and lymphomas. Expression of IRES trans-acting factors can also be altered, and interestingly, BCL-ABL1 fusion protein expressed from "Philadelphia" chromosome, found in some types of leukemia, regulates several of them. A mechanism involving c-Myc IRES and cap independent translation and leading to resistance to chemotherapy in multiple myeloma emphasize the contribution of cap-independent translation in blood cancers and the need for more work to be done to clarify the roles of known IRESes in pathology and response to chemotherapeutics. PMID- 26734575 TI - Diagnostic Value of Methylated Human Telomerase Reverse Transcriptase in Human Cancers: A Meta-Analysis. AB - Human telomerase reverse transcriptase (hTERT) plays a critical role in the pathogenesis of human malignancies. Overexpression of hTERT is essential in controlling the propagation of cancer cells. The CpG island located at hTERT promoter region is subjected to methylation modification in human cancer. In this perspective article, we discussed the diagnostic value of methylated hTERT in human cancers. The definitive diagnosis of most solid tumors is based on histological and immunohistochemical features. Under certain circumstances, however, the use of methylated hTERT might be useful in overcoming the limitation of the conventional methods. Methylated hTERT showed a good diagnostic power in discriminating cancer from benign or normal tissues. Nevertheless, differences in detection method, methylation site, cancer type, and histological subtype of cancer make it difficult to evaluate the actual diagnostic accuracy of methylated hTERT. Therefore, we performed subgroup analysis to assess the effects of these factors on the diagnostic efficiency of methylated hTERT. We demonstrated that quantitative MSP (qMSP) assay offers the highest discriminative power between normal and cancer in comparison with different detection methods. In addition, the methylated sites selected by different studies had an impact on the detection performance. Moreover, the diagnostic power of methylated hTERT was affected by cancer type and histological subtype. In conclusion, the existing evidence demonstrated that methylated hTERT is effective in cancer detection. Detailed profiling of the methylation sites to local the common methylation hotspot across human cancers is warranted to maximize the diagnostic value of methylated hTERT in cancer detection. PMID- 26734576 TI - Image-Guided Ablation of Malignant Liver Tumors: Recommendations for Clinical Validation of Novel Thermal and Non-Thermal Technologies - A Western Perspective. AB - BACKGROUND: Image-guided ablation is used to treat patients with unresectable malignant hepatic tumors that are limited in number and size, especially hepatocellular carcinoma (HCC) and colorectal hepatic metastases. While radiofrequency ablation (RFA) has been the most popular technique, several alternate options for focal tissue destruction have recently attracted attention. These technologies appear to be able to overcome some specific limitations of RFA. Currently, there is no accepted algorithm for the use of the different techniques for image-guided ablation. SUMMARY: A panel of physicians practicing in North America or Europe met to develop a set of recommendations aimed at providing directions for clinical validation of energy-based, thermal and non thermal image-guided ablation technologies in the treatment of malignant liver tumors. The recommendations were developed through a critical appraisal of potential advantages and disadvantages of each ablation technology, based on experimental findings and available data, as well as on critical considerations for their clinical validation in hepatic tumor treatment from a Western perspective. KEY MESSAGES: Significant variability appears to exist among the different equipment and devices within each type of technology. A comprehensive understanding of the data and a critical appraisal of the efficacy and safety profile of each ablation system is required. Clinical practice guidelines should include specific information of the recommended techniques and protocols instead of a generic indication of the technology. PMID- 26734577 TI - Novel Imaging Diagnosis for Hepatocellular Carcinoma: Consensus from the 5th Asia Pacific Primary Liver Cancer Expert Meeting (APPLE 2014). AB - Current novel imaging techniques in the diagnosis of hepatocellular carcinoma (HCC), with the latest evidence in this field, was discussed at the Asia-Pacific Primary Liver Cancer Expert (APPLE) meeting held in Taipei, Taiwan, in July 2014. Based on their expertise in a specific area of research, the novel imaging group comprised 12 participants from Japan, South Korea, Taiwan, and China and it included 10 abdominal radiologists, one hepatologist, and one pathologist. The expert participants discussed topics related to HCC imaging that were divided into four categories: (i) detection method, (ii) diagnostic method, (iii) evaluation method, and (iv) functional method. Consensus was reached on 10 statements; specific comments on each statement were provided to explain the rationale for the voting results and to suggest future research directions. PMID- 26734578 TI - Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma with Portal Vein Thrombosis: Impact of Early Response to 4 Weeks of Treatment. AB - AIM: The aim of the study was to investigate the impact of early response (ER) to hepatic arterial infusion chemotherapy (HAIC) on outcomes of patients with advanced hepatocellular carcinoma (HCC) complicated with major portal vein tumor thrombosis (PVTT). METHODS: Thirty-nine patients receiving HAIC with low-dose cisplatin, 5-fluorouracil (5FU), and leucovorin were enrolled. One course of HAIC consisted of 5 days of treatment and 2 days rest per week for 4 consecutive weeks. ER was categorized as complete response, partial response, or minor response and was determined by World Health Organization criteria with dynamic computed tomography findings performed within 1 week after the first course of HAIC. RESULTS: Thirteen (33%) patients achieved an ER. Twelve (92.3%) of these 13 ER patients achieved a higher overall response than all but one (3.8%) of the 26 non-early responders (NERs) (p<0.001). ER was the exclusive independent favorable factor for survival (p=0.003). Downstaging of tumors was noted in 76.9% of ERs, and these patients could proceed to locoregional therapies. ER patients subsequently had a higher 1-year survival (76.9% vs. 3.8%, p<0.001) and 6-month progression-free survival (PFS) (84.6% vs. 15.4%, p<0.001) than those for NERs. Only 8% of patients experienced grade 3 or higher toxicity during the first 4 week course of HAIC. CONCLUSIONS: HAIC can yield a satisfactory ER for advanced HCC with PVTT. Moreover, achievement of ER after HAIC in advanced HCC with PVTT is strongly associated with better overall survival and PFS. PMID- 26734579 TI - Effectiveness of Sorafenib in Patients with Transcatheter Arterial Chemoembolization (TACE) Refractory and Intermediate-Stage Hepatocellular Carcinoma. AB - BACKGROUND AND AIMS: Patients with intermediate-stage hepatocellular carcinoma (HCC) refractory to transcatheter arterial chemoembolization (TACE) are considered to be candidates for sorafenib. The aim of this study was to evaluate the superiority of conversion of treatment to sorafenib on overall survival (OS) for cases refractory to TACE. METHODS: This was a retrospective cohort study carried out on 497 patients with HCC who were treated with TACE therapy at our hospital between January 2008 and December 2013. Fifty-six patients were diagnosed as refractory to TACE during their clinical course and they were divided into two cohorts, (1) those who switched from TACE to sorafenib and (2) those who continued TACE. The overall survival (OS) after the time of being refractory to TACE was evaluated between the two groups. RESULTS: After refractoriness to TACE therapy was confirmed, 24 patients continued with TACE (TACE-group) and 32 patients underwent treatment conversion to sorafenib (sorafenib-group). The median OS was 24.7 months in the sorafenib-group and 13.6 months in the TACE-group (p=0.002). CONCLUSIONS: Conversion to sorafenib significantly improves the OS in patients refractory to TACE therapy with intermediate-stage HCC. Administration of sorafenib is therefore recommended in such circumstances of TACE treatment failure. PMID- 26734580 TI - Phase I/II Study of Sorafenib in Combination with Hepatic Arterial Infusion Chemotherapy Using Low-Dose Cisplatin and 5-Fluorouracil. AB - We conducted a phase I/II study in patients with advanced hepatocellular carcinoma (HCC) to determine the recommended dose, as well as the safety and efficacy, of combination therapy of sorafenib with hepatic arterial infusion chemotherapy (HAIC) using low dose cisplatin (CDDP) and 5-fluorouracil (5FU). Cohorts consisting of 3-6 patients with HCC received an escalated dose of CDDP and 5-FU until a maximum-tolerated dose was achieved. The treatment regimen was as follows: oral administration of sorafenib (400 mg twice daily for 28 days) combined with HAIC using CDDP (14-20 mg/m(2), on days 1 and 8) and 5-FU (170-330 mg/m(2), continuously on days 1-5 and 8-12) via an implanted catheter system). Each treatment cycle consisted of 28 days and three cycles of combination therapy. At the end of the first cycle, adverse events were evaluated and future dose escalation was determined. Eighteen patients with advanced HCC were enrolled. Dose-limiting toxicity was observed in two patients from cohort 1 (erythema multiforme and grade 4 thrombocytopenia) and in one patient from cohort 2 (erythema multiforme). Seven of the 18 patients achieved a partial response, seven showed stable disease, two were diagnosed as progressive disease, and two were not assessable. The response rate was 38.9% and the disease control rate was 77.8%. The time-to-progression was 9.7 months and the 1-year survival rate was 88.2%. Oral administration of 400 mg of sorafenib twice daily, 20 mg/m(2) of intra-arterial infusion of CDDP, and 5-FU at 330 mg/m(2) are the recommended doses for combination therapy, which was well tolerated and efficacious. This combination therapy may be a promising treatment for patients with advanced HCC. A large prospective randomized multicenter study (ClinicalTrials.gov Identifier NCT01214343) is ongoing. PMID- 26734581 TI - The Gut Microbiota Reduces Colonization of the Mesenteric Lymph Nodes and IL-12 Independent IFN-gamma Production During Salmonella Infection. AB - The intestinal commensal microbiota is essential for many host physiological processes, but its impact on infectious diseases is poorly understood. Here we investigate the influence of the gut microbiota during oral Salmonella infection. We report a higher bacterial burden in mesenteric lymph nodes (MLN) of intragastrically infected germ-free (GF) mice compared to conventionally-raised (CONV-R) animals, despite similar inflammatory phagocyte recruitment. Salmonella penetration into the lamina propria of the small intestine and splenic bacterial burden were not altered in the absence of the microbiota. Intragastrically infected GF mice also displayed a higher frequency of IFN-gamma-producing NK, NKT, CD4(+), and CD8(+) T cells in the MLN despite IL-12 levels similar to infected CONV-R mice. However, infecting mice intraperitoneally abrogated the difference in MLN bacterial load and IFN-gamma-producing cells observed in intragastrically-infected animals. Moreover, mice treated with antibiotics (ABX) and intragastrically infected with Salmonella had a greater bacterial burden and frequency of IFN-gamma-producing cells in the MLN. In ABX mice the number of Salmonella correlated with the frequency of IFN-gamma-producing lymphocytes in the MLN, while no such correlation was observed in the MLN of infected GF mice. Overall, the data show that the lack of the microbiota influences pathogen colonization of the MLN, and the increased IFN-gamma in the MLN of infected GF mice is not only due to the absence of commensals at the time of infection but the lack of immune signals provided by the microbiota from birth. PMID- 26734582 TI - Genetic Variations of PTPN2 and PTPN22: Role in the Pathogenesis of Type 1 Diabetes and Crohn's Disease. AB - Genome wide association studies have identified several genes that might be associated with increase susceptibility to Type 1 Diabetes (T1D) and Crohn's disease. Both Crohn's disease and T1D have a profound impact on the lives of patients and it is pivotal to investigate the genetic role in patients acquiring these diseases. Understanding the effect of single nucleotide polymorphisms (SNP's) in key genes in patients suffering from T1D and Crohn's disease is crucial to finding an effective treatment and generating novel therapeutic drugs. This review article is focused on the impact of SNP's in PTPN2 (protein tyrosine phosphatase, non-receptor type 2) and PTPN22 (protein tyrosine phosphatase non receptor type 22) on the development of Crohn's disease and T1D. The PTPN2 gene mutation in T1D patients play a direct role in the destruction of beta cells while in Crohn's disease patients, it modulates the innate immune responses. The PTPN22 gene mutations also play a role in both diseases by modulating intracellular signaling. Examining the mechanism through which these genes increase the susceptibility to both diseases and gaining a better understanding of their structure and function is of vital importance to understand the etiology and pathogenesis of Type 1 Diabetes and Crohn's disease. PMID- 26734583 TI - Salivary Antimicrobial Peptides in Early Detection of Periodontitis. AB - In the pathogenesis of periodontitis, an infection-induced inflammatory disease of the tooth-supporting tissues, there is a complex interaction between the subgingival microbiota and host tissues. A periodontal diagnostic tool for detecting the initiation and progression of the disease, monitoring the response to therapy, or measuring the degree of susceptibility to future disease progression has been of interest for a long time. The value of various enzymes, proteins, and immunoglobulins, which are abundant constituents of saliva, as potential biomarkers has been recognized and extensively investigated for periodontal diseases. Gingival defensins and cathelicidins are small cationic antimicrobial peptides that play an important role in innate immune response. However, their applicability as salivary biomarkers is still under debate. The present review focuses on proteomic biomarkers and antimicrobial peptides, in particular, to be used at early phases of periodontitis. PMID- 26734584 TI - Natural Products for Chemoprevention of Breast Cancer. AB - Breast cancer is the primary cause of cancer death in women. Although current therapies have shown some promise against breast cancer, there is still no effective cure for the majority of patients in the advanced stages of breast cancer. Development of effective agents to slow, reduce, or reverse the incidence of breast cancer in high-risk women is necessary. Chemoprevention of breast cancer by natural products is advantageous, as these compounds have few side effects and low toxicity compared to synthetic compounds. In the present review, we summarize natural products which exert chemopreventive activities against breast cancer, such as curcumin, sauchinone, lycopene, denbinobin, genipin, capsaicin, and ursolic acid. This review examines the current knowledge about natural compounds and their mechanisms that underlie breast cancer chemopreventive activity both in vitro and in vivo. The present review may provide information on the use of these compounds for the prevention of breast cancer. PMID- 26734585 TI - An Overview of Carcinogenic Heavy Metal: Molecular Toxicity Mechanism and Prevention. AB - Almost all heavy metals are serious toxicants as carcinogens. However, due to their chemical and physiological properties, heavy metals are useful in industrial areas including alloy, smelting and production of commercial products. Such applications increase the opportunity for heavy metal exposure. Waste from industrial processes is also a major source of environmental contamination and accumulation in the human body. Arsenic, cadmium, chromium, and nickel are classified as group 1 carcinogens by the International Agency for Research on Cancer, and are utilized commercially. In this review, we used molecular pathway analysis to understand the toxicity and carcinogenic mechanisms of these metals. Our analyzed data showed that above-mentioned metallic substances induce oxidative stress, DNA damage, and cell death processes, resulting in increase the risk of cancer and cancer-related diseases. Thus, we might think phytochelatin molecules and antioxidative phytochemical substances are helpful for prevention of heavy metal-induced cancer. PMID- 26734586 TI - Anti-cancer Activity of Osmanthus matsumuranus Extract by Inducing G2/M Arrest and Apoptosis in Human Hepatocellular Carcinoma Hep G2 Cells. AB - BACKGROUND: Osmanthus matsumuranus, a species of Oleaceae, is found in East Asia and Southeast Asia. The bioactivities of O. matsumuranus have not yet been fully understood. Here, we studied on the molecular mechanisms underlying anti-cancer effect of ethanol extract of O. matsumuranus (EEOM). METHODS: Inhibitory effect of EEOM on cell growth and proliferation was determined by WST assay in various cancer cells. To investigate the mechanisms of EEOM-mediated cytotoxicity, HepG2 cells were treated with various concentration of EEOM and analyzed the cell cycle arrest and apoptosis induction by flow cytometry, Western blot analysis, 4,6 diamidino-2-phenylindole (DAPI) staining and DNA fragmentation. RESULTS: EEOM showed the cytotoxic activities in a dose-dependent manner in various cancer cell lines but not in normal cells, and HepG2 cells were most susceptible to EEOM induced cytotoxicity. EEOM induced G2/M arrest in HepG2 cells associated with decreased expression of cyclin-dependent kinase 1 (CDK1), cyclin A and cylcin B, and increased expression of phospho-checkpoint kinase 2, p53 and CDK inhibitor p21. Immunofluorescence staining showed that EEOM-treated HepG2 increased doublet nuclei and condensed actin, resulting in cell rounding. Furthermore, EEOM mediated apoptosis was determined by Annexin V staining, chromatin condensation and DNA fragmentation. EEOM caused upregulation of FAS and Bax, activation of caspase-3, -8, -9, and fragmentation of poly ADP ribose polymerase. CONCLUSIONS: These results suggest that EEOM efficiently inhibits proliferation of HepG2 cells by inducing both G2/M arrest and apoptosis via intrinsic and extrinsic pathways, and EEOM may be used as a cancer chemopreventive agent in the food or nutraceutical industry. PMID- 26734587 TI - Selective Activator of the Glucocorticoid Receptor Compound A Dissociates Therapeutic and Atrophogenic Effects of Glucocorticoid Receptor Signaling in Skin. AB - BACKGROUND: Glucocorticoids are effective anti-inflammatory drugs widely used in dermatology and for the treatment of blood cancer patients. Unfortunately, chronic treatment with glucocorticoids results in serious metabolic and atrophogenic adverse effects including skin atrophy. Glucocorticoids act via the glucocorticoid receptor (GR), a transcription factor that causes either gene transactivation (TA) or transrepression (TR). Compound A (CpdA), a novel non steroidal GR ligand, does not promote GR dimerization and TA, retains anti inflammatory potential but induces fewer metabolic side effects compared to classical glucocorticoids when used systemically. As topical effects of CpdA have not been well studied, this work goal was to compare the anti-inflammatory and side effects of topical CpdA and glucocorticoids and to assess their effect on GR TA and TR in keratinocytes. METHODS: We used murine immortalized keratinocytes and F1 C57BlxDBA mice. Effect of glucocorticoid fluocinolone acetonide (FA) and CpdA on gene expression in keratinocytes in vitro and in vivo was evaluated by reverse transcription-PCR. The anti-inflammatory effects were assessed in the model of tumor promoter 12-O-tertradecanoyl-acetate (TPA)-induced dermatitis and in croton oil-induced ear edema test. Skin atrophy was assessed by analysis of epidermal thickness, keratinocyte proliferation, subcutaneous adipose hypoplasia, and dermal changes after chronic treatment with FA and CpdA. RESULTS: In mouse keratinocytes in vitro and in vivo, CpdA did not activate GR-dependent genes but mimicked closely the inhibitory effect of glucocorticoid FA on the expression of inflammatory cytokines and matrix metalloproteinases. When applied topically, CpdA inhibited TPA-induced skin inflammation and hyperplasia. Unlike glucocorticoids, CpdA itself did not induce skin atrophy which correlated with lack of induction of atrophogene regulated in development and DNA damage response 1 (REDD1) causatively involved in skin and muscle steroid-induced atrophy. CONCLUSIONS: Overall, our results suggest that CpdA and its derivatives represent novel promising class of anti-inflammatory compounds with reduced topical side effects. PMID- 26734588 TI - Adequate Dextran Sodium Sulfate-induced Colitis Model in Mice and Effective Outcome Measurement Method. AB - BACKGROUND: Dextran sodium sulfate (DSS)-induced colitis mouse model is used for research of inflammatory bowel disease. The aim of this study was to establish the adequate conditions for DSS mice model, and to find useful tool to measure inflammation. METHODS: The 2.5% DSS was administered to six male C57BL/6 mice and 4% DSS to eight mice at 5 or 9 weeks of age. Each group was consisted of 6 mice with control group in which vehicle was administered instead of DSS. The mice were sacrificed on the 7th day after DSS or vehicle administration. Body weight, diarrhea, and hematochezia were recorded daily. Disease activity index (DAI) score which was composed of body weight change, diarrhea, and hematochezia was measured every day. Colon length was measured after sacrifice and colon mucosal level of interleukin 1 beta (IL-1beta) was measured by ELISA assay. Histological score was compared between ascending and descending colon in the DSS group. RESULTS: Colon length of five- and nine-week DSS group was significantly shorter than each control group but there was no statistical significance depending on DSS concentration or age. DAI score of 4% DSS group in nine-week was significantly higher than that five-week (P = 0.012) but there was no difference between 2.5% and 4% DSS group. The level of IL-1beta in DSS mice was much higher than control group (P < 0.01), but there was no difference among several DSS groups. The histological score was higher in the descending colon than in the ascending colon but there was no statistical difference between each pair of DSS groups. CONCLUSIONS: The 4% DSS mice in nine-week was adequate for DSS-induced colitis model. DAI score was useful tool and descending colon was more appropriate site for histological evaluation of colitis than ascending colon. PMID- 26734589 TI - The Significance of miR-34a Expression in Endometrial Carcinogenesis: Correlation With Expression of p16 and Ki-67 Proteins in Endometrial Cancers. AB - BACKGROUND: A microRNA, miR-34a, plays a key role in inhibiting cellular transformation and carcinogenesis by controlling cell cycle regulation and cell proliferation in various human tumors. However, miR-34a has rarely been reported in endometrial cancer research in Korea. This study was undertaken to analyze miR 34a expression in simple endometrial hyperplasia and endometrial cancer, and to evaluate the relationship between expression of miR-34a and p16 and Ki-67 proteins in endometrial cancers. METHODS: A retrospective study was carried out on 66 formalin-fixed, paraffin-embedded tissues with simple endometrial hyperplasia (31 cases) and endometrial cancer (35 cases) patients. These were analyzed for miR-34a expression by quantitative real-time PCR, and the expression of p16 and Ki-67 proteins in endometrial cancers was evaluated by immunohistochemistry. RESULTS: The miR-34a expression level was lower in endometrial cancer tissues (-0.71 +/- 3.90) than in simple endometrial hyperplasia tissues (2.68 +/- 8.62). The endometrial hyperplasia tissues showed underexpression of miR-34a in 13 of the 31 cases (41.9%) while the endometrial cancer tissues showed underexpression of miR-34a in 24 of 35 cases (68.6%). Thus, miR-34a was significantly underexpressed in endometrial cancer tissues when compared endometrial hyperplasia tissues (P = 0.046). Overexpression of p16 was detected in 25 (71.4%) and Ki-67 immunoreactivity was detected in 27 (77.1%) of the 35 endometrial cancers. Although not statistically significant, the frequency of p16 and Ki-67 overexpression tended to be lower in the cases with miR-34a underexpression than in cases with miR-34a overexpression. CONCLUSIONS: These findings suggest that underexpression of miR-34a might be involved in endometrial carcinogenesis. Further studies are needed to define the relationship between miR 34a expression and tissue specific protein expression. PMID- 26734590 TI - Evaluation and Comparison of the Biopathology of Collagen and Inflammation in the Extracellular Matrix of Oral Epithelial Dysplasias and Inflammatory Fibrous Hyperplasia Using Picrosirius Red Stain and Polarising Microscopy: A Preliminary Study. AB - BACKGROUND: The role of tumour inflammation and the dysplastic epithelial-stromal interactions on the nature of collagen fibres in the extracellular matrix of dysplastic epithelium is not fully understood. The present study was aimed to evaluate and compare the inflammation and pathological stromal collagen (loosely packed thin disorganized collagen) present in mild, moderate and severe epithelial dysplasias with that of inflammatory fibrous hyperplasias. The basement membrane intactness of epithelial dysplasias was also evaluated to determine if dysplastic epithelial mesenchymal interaction has any role in the integrity of stromal collagen in epithelial dysplasia. METHODS: Oral epithelial dysplasias, inflammatory fibrous hyperplasia and normal oral mucosal samples were used for the study. Packing, thickness and orientation of collagen fibres in mild, moderate and severe grades of oral epithelial dysplasias (n = 24), inflammatory fibrous hyperplasia (n = 8) and normal oral mucosal samples (n = 8) were analysed based on the polarisation of collagen fibres in picrosirius red polarising stain under polarising microscope. RESULTS: All the grades of epithelial dysplasias showed greenish yellow birefringence confirming the presence of loosely arranged pathological collagen in the presence of moderate inflammation. All the cases of inflammatory fibrous hyperplasia showed red polarisation hue and moderate inflammation. A statistically significant difference was found in the packing and orientation of collagen when epithelial dysplasias and inflammatory fibrous hyperplasia were compared (P < 0.01). When the intactness of basement membrane integrity was compared in all the groups of epithelial dysplasia, a statistically significant result was obtained (P < 0.05). CONCLUSIONS: Presence of significant amount of loosely packed thin disoriented collagen even in mild epithelial dysplasia suggests that tumourigenic factors are released to connective tissue stroma much earlier than expected. Hence we suggest considering the integrity of extracellular matrix collagen, intactness of basement membrane and inflammation associated with dysplasia along with the anaplasia of epithelial cells in the microscopic assessment of dysplastic epithelium. PMID- 26734591 TI - Isoliquiritigenin Inhibits Metastatic Breast Cancer Cell-induced Receptor Activator of Nuclear Factor Kappa-B Ligand/Osteoprotegerin Ratio in Human Osteoblastic Cells. AB - Bone destruction induced by the metastasis of breast cancer cells is a frequent complication that is caused by the interaction between cancer cells and bone cells. Receptor activator of nuclear factor kappa-B ligand (RANKL) and the endogenous soluble RANKL inhibitor, osteoprotegerin (OPG), directly play critical roles in the differentiation, activity, and survival of osteoclasts. In patients with bone metastases, osteoclastic bone resorption promotes the majority of skeletal-related events and propagates bone metastases. Therefore, blocking osteoclast activity and differentiation via RANKL inhibition can be a promising therapeutic approach for cancer-associated bone diseases. We investigated the potential of isoliquiritigenin (ISL), which has anti-proliferative, anti angiogenic, and anti-invasive effects, as a preventive and therapeutic agent for breast cancer cell-induced bone destruction. ISL at non-toxicity concentrations significantly inhibited the RANKL/OPG ratio by reducing the production of RANKL and restoring OPG production to control levels in hFOB1.19 cells stimulated with conditioned medium (CM) of MDA-MB-231 cells. In addition, ISL reduced the expression of cyclooxygenase-2 in hFOB1.19 cells stimulated by CM of MDA-MB-231 cells. Therefore, ISL may have inhibitory potential on breast cancer-induced bone destruction. PMID- 26734592 TI - Retrospective Evaluation of the Epidemiology and Practice Variation of Dexmedetomidine Use in Invasively Ventilated Pediatric Intensive Care Admissions, 2007-2013. AB - OBJECTIVES: The study assessed dexmedetomidine utilization and practice variation over time in ventilated pediatric intensive care unit (PICU) patients; and evaluated differences in hospital outcomes between high- and low-dexmedetomidine utilization hospitals. STUDY DESIGN: This serial cross-sectional analysis used administrative data from PICU admissions in the pediatric health information system (37 US tertiary care pediatric hospitals). Included admissions from 2007 to 2013 had simultaneous dexmedetomidine and invasive mechanical ventilation charges, <18 years of age, excluding neonates. Patient and hospital characteristics were compared as well as hospital-level severity-adjusted indexed length of stay (LOS), charges, and mortality. RESULTS: The utilization of dexmedetomidine increased from 6.2 to 38.2 per 100 ventilated PICU patients among pediatric hospitals. Utilization ranged from 3.8 to 62.8 per 100 in 2013. Few differences in patient demographics and no differences in hospital-level volume/severity of illness measures between high- and low-utilization hospitals occurred. No differences in hospital-level, severity-adjusted indexed outcomes (LOS, charges, and mortality) were found. CONCLUSION: Wide practice variation in utilization of dexmedetomidine for ventilated PICU patients existed even as use has increased sixfold. Higher utilization was not associated with increased hospital charges or reduced hospital LOS. Further work should define the expected outcome benefits of dexmedetomidine and its appropriate use. PMID- 26734593 TI - The Roles of Epidemiologists, Laboratorians, and Public Health Agencies in Preventing Invasive Cronobacter Infection. AB - BACKGROUND: Cronobacter can cause severe, invasive infection in very young infants. These bacteria can also colonize or cause insignificant infections in immunocompromised, elderly, and/or hospitalized adults. METHODS: This editorial review highlights key points addressed in the Frontiers Research Topic on Cronobacter, discusses the clinical presentation and epidemiology of Cronobacter infections, and examines the responses of public health agencies to this problem. RESULTS: Cronobacter is rarely isolated from hospitalized, immunocompromised and/or elderly adults and does not cause significant disease in those patients. Certain species and strains, especially of Cronobacter sakazakii, can cause invasive illness in previously healthy infants <2 months of age. Multilocus sequence type 4 and clonal complex 4 (ST4/MLST 4) C. sakazakii are the predominant cause of Cronobacter meningitis, which occurs only in infants. These infections and this strain type are strongly linked to powdered infant formulas (PIF), which can also be contaminated with other Cronobacter strains. End-product testing is not intended to guarantee the absence of these organisms. WHO has made recommendations that can help decrease but will not eliminate the risk of this infection. CONCLUSION: To further define the spectrum of Cronobacter-associated disease, all isolates should be genetically typed using every currently available method, typing results should be linked to the associated epidemiologic and clinical data, and these data should be analyzed in a scientifically sound manner. Based on currently available information, more can be done now to prevent cause invasive infection in young infants. This includes encouragement of exclusive breastfeeding and/or use of commercially sterile ready-to-feed formulas in the first 2 months of life. PMID- 26734594 TI - Work-Life Balance and Early Stage Careers: Dual Perspectives from One Household. PMID- 26734595 TI - Work-Life Balance: A Different Scale for Doctors. PMID- 26734597 TI - African-American Women's Perceptions and Experiences About Breastfeeding. AB - There are health benefits to breastfeeding for both mothers and their children. The preventive health effects of breastfeeding continue into adulthood, lowering rate of various chronic illnesses. African-American women, especially of lower socioeconomic status, are less likely to breastfeed in comparison to their racial and ethnic counterparts. The purpose of this study is to explore how African American women experience breastfeeding in the early stages of postpartum care. Two focus groups (N = 20, 10 in each group) were conducted with African-American mothers. Results revealed that participants felt that there were health benefits to breastfeeding, and organizations such as Women, Infants, and Children (WIC) provided support. However, participants stated that lack of information, negative perceptions, and unforeseen circumstances were barriers to breastfeeding. This study proposes support and interventions for this group to increase breastfeeding among this population. PMID- 26734596 TI - Health Disparities in the Immunoprevention of Human Papillomavirus Infection and Associated Malignancies. AB - Human papillomavirus (HPV) causes roughly 1.6% of the plus 1.6 million cases of cancer that are diagnosed in the United States each year. Despite the proven safety and efficacy of available vaccines, HPV remains the most common sexually transmitted infection. Underlying the high prevalence of HPV infection is the poor adherence to the Centers for Disease Control recommendation to vaccinate all 11- to 12-year-old males and females. In fact, only about 38 and 14% of eligible females and males, respectively, receive the complete, three-dose immunization. The many factors associated with missed HPV vaccination opportunities - including race, age, family income, and patient education - contribute to widespread disparities in vaccine completion and related health outcomes. Beyond patient circumstance, however, research indicates that the rigor and consistency of recommendation by primary care providers also plays a significant role in uptake of HPV immunization. Health disparities data are of vital importance to HPV vaccination campaigns because they can provide insight into how to address current problems and allocate limited resources where they are most needed. Furthermore, even modest gains in populations with low vaccination rates may yield great benefits because HPV immunization has been shown to provide herd immunity, indirect protection for non-immunized individuals achieved by limiting the spread of an infectious agent through a population. However, the impact of current HPV vaccination campaigns is hindered by stagnant immunization rates, which remain far below target levels despite a slow overall increase. Furthermore, gains in immunization are not equally distributed across gender, age, demographic, and socioeconomic divisions within the recommended group of vaccine recipients. To achieve the greatest impact, public health campaigns should focus on improving immunization coverage where it is weakest. They should also explore more subtle but potentially significant determinants of HPV vaccine initiation and completion, such as the attitudes of parents and healthcare providers and factors that exacerbate HPV-related health outcomes, including smoking and human immunodeficiency virus-mediated immunosuppression. Optimizing the efficacy of vaccination campaigns will require a health disparities approach that both identifies and remedies the underlying causes of population differences in HPV vaccination. PMID- 26734598 TI - Frequency of Victimization Experiences and Well-Being Among Online, Offline, and Combined Victims on Social Online Network Sites of German Children and Adolescents. AB - Victimization is associated with negative developmental outcomes in childhood and adolescence. However, previous studies have provided mixed results regarding the association between offline and online victimization and indicators of social, psychological, and somatic well-being. In this study, we investigated 1,890 German children and adolescents (grades 5-10, mean age = 13.9; SD = 2.1) with and without offline or online victimization experiences who participated in a social online network (SNS). Online questionnaires were used to assess previous victimization (offline, online, combined, and without), somatic and psychological symptoms, self-esteem, and social self-concept (social competence, resistance to peer influence, esteem by others). In total, 1,362 (72.1%) children and adolescents reported being a member of at least one SNS, and 377 students (28.8%) reported previous victimization. Most children and adolescents had offline victimization experiences (17.5%), whereas 2.7% reported online victimization, and 8.6% reported combined experiences. Girls reported more online and combined victimization, and boys reported more offline victimization. The type of victimization (offline, online, combined) was associated with increased reports of psychological and somatic symptoms, lower self-esteem and esteem by others, and lower resistance to peer influences. The effects were comparable for the groups with offline and online victimization. They were, however, increased in the combined group in comparison to victims with offline experiences alone. PMID- 26734599 TI - The Choice of Healthcare Providers for Febrile Children after Introducing Non professional Health Workers in a Malaria Endemic Area in Papua New Guinea. AB - BACKGROUND: Disease burden of malaria in Papua New Guinea (PNG) is the highest in Asia and the Pacific, and prompt access to effective drugs is the key strategy for controlling malaria. Despite the rapid economic growth, primary healthcare services have deteriorated in rural areas; the introduction of non-professional health workers [village health volunteers (VHVs)] is expected to improve antimalarial drug deliveries. Previous studies on PNG suggested that distance from households negatively affected the utilization of health services; however, price effect on healthcare demand decisions has not been explored. Empirical studies on household's affordability as well as accessibility of healthcare services contribute to policy implications, such as efficient introduction of out of-pocket costs and effective allocation of health facilities. Therefore, we investigate price responsiveness and other determinants of healthcare provider choice for febrile children in a malaria endemic rural area wherein VHVs were introduced. METHODS: Cross-sectional surveys were conducted using a structured questionnaire distributed in a health center's catchment area of East Sepik Province in the 2011/2012 rainy seasons. Caretakers were interviewed and data on fever episodes of their children in the preceding 2 weeks were collected. Mixed logit model was employed to estimate the determinants of healthcare provider choice. RESULTS: Among 257 fever episodes reported, the main choices of healthcare providers were limited to self-care, VHV, and a health center. Direct cost and walking distance negatively affected the choice of a VHV and the health center. An increase of VHV's direct cost or walking distance did not much affect predicted probability of the health center, but rather that of self-care, while drug availability and illness severity increased the choice probability of a VHV and the health center. CONCLUSION: The results suggest that the net healthcare demand increases with the introduction of a VHV. Allocations from the government's budget are required to sustain VHV activities because the introduction of a small user fee could impede the utilization of a VHV. A large travel cost related to the choice of the health center suggests that resource allocation is required for the expansion of formal healthcare providers to adequately operate a referral system. PMID- 26734600 TI - Interaction of Iron II Complexes with B-DNA. Insights from Molecular Modeling, Spectroscopy, and Cellular Biology. AB - We report the characterization of the interaction between B-DNA and three terpyridin iron II complexes. Relatively long time-scale molecular dynamics (MD) is used in order to characterize the stable interaction modes. By means of molecular modeling and UV-vis spectroscopy, we prove that they may lead to stable interactions with the DNA duplex. Furthermore, the presence of larger pi conjugated moieties also leads to the appearance of intercalation binding mode. Non-covalent stabilizing interactions between the iron complexes and the DNA are also characterized and evidenced by the analysis of the gradient of the electronic density. Finally, the structural deformations induced on the DNA in the different binding modes are also evidenced. The synthesis and chemical characterization of the three complexes is reported, as well as their absorption spectra in presence of DNA duplexes to prove the interaction with DNA. Finally, their effects on human cell cultures have also been evidenced to further enlighten their biological effects. PMID- 26734601 TI - Crossing the LINE Toward Genomic Instability: LINE-1 Retrotransposition in Cancer. AB - Retrotransposons are repetitive DNA sequences that are positioned throughout the human genome. Retrotransposons are capable of copying themselves and mobilizing new copies to novel genomic locations in a process called retrotransposition. While most retrotransposon sequences in the human genome are incomplete and incapable of mobilization, the LINE-1 retrotransposon, which comprises~17% of the human genome, remains active. The disruption of cellular mechanisms that suppress retrotransposon activity is linked to the generation of aneuploidy, a potential driver of tumor development. When retrotransposons insert into a novel genomic region, they have the potential to disrupt the coding sequence of endogenous genes and alter gene expression, which can lead to deleterious consequences for the organism. Additionally, increased LINE-1 copy numbers provide more chances for recombination events to occur between retrotransposons, which can lead to chromosomal breaks and rearrangements. LINE-1 activity is increased in various cancer cell lines and in patient tissues resected from primary tumors. LINE-1 activity also correlates with increased cancer metastasis. This review aims to give a brief overview of the connections between LINE-1 retrotransposition and the loss of genome stability. We will also discuss the mechanisms that repress retrotransposition in human cells and their links to cancer. PMID- 26734602 TI - Recent Advances Toward the Discovery of Drug-Like Peptides De novo. AB - Peptides are important natural molecules that possess functions as diverse as antibiotics, toxins, venoms and hormones, for example. However, whilst these peptides have useful properties, there are many targets and pathways that are not addressed through the activities of natural peptidic compounds. In these circumstances, directed evolution techniques, such as phage display, have been developed to sample the diverse chemical and structural repertoire of small peptides for useful means. In this review, we consider recent concepts that relate peptide structure to drug-like attributes and how these are incorporated within display technologies to deliver peptides de novo with valuable pharmaceutical properties. PMID- 26734603 TI - Systems Biology of Microbial Exopolysaccharides Production. AB - Exopolysaccharides (EPSs) produced by diverse group of microbial systems are rapidly emerging as new and industrially important biomaterials. Due to their unique and complex chemical structures and many interesting physicochemical and rheological properties with novel functionality, the microbial EPSs find wide range of commercial applications in various fields of the economy such as food, feed, packaging, chemical, textile, cosmetics and pharmaceutical industry, agriculture, and medicine. EPSs are mainly associated with high-value applications, and they have received considerable research attention over recent decades with their biocompatibility, biodegradability, and both environmental and human compatibility. However, only a few microbial EPSs have achieved to be used commercially due to their high production costs. The emerging need to overcome economic hurdles and the increasing significance of microbial EPSs in industrial and medical biotechnology call for the elucidation of the interrelations between metabolic pathways and EPS biosynthesis mechanism in order to control and hence enhance its microbial productivity. Moreover, a better understanding of biosynthesis mechanism is a significant issue for improvement of product quality and properties and also for the design of novel strains. Therefore, a systems based approach constitutes an important step toward understanding the interplay between metabolism and EPS biosynthesis and further enhances its metabolic performance for industrial application. In this review, primarily the microbial EPSs, their biosynthesis mechanism, and important factors for their production will be discussed. After this brief introduction, recent literature on the application of omics technologies and systems biology tools for the improvement of production yields will be critically evaluated. Special focus will be given to EPSs with high market value such as xanthan, levan, pullulan, and dextran. PMID- 26734604 TI - An Anthropometric-Based Subject-Specific Finite Element Model of the Human Breast for Predicting Large Deformations. AB - The large deformation of the human breast threatens proper nodules tracking when the subject mammograms are used as pre-planning data for biopsy. However, techniques capable of accurately supporting the surgeons during biopsy are missing. Finite element (FE) models are at the basis of currently investigated methodologies to track nodules displacement. Nonetheless, the impact of breast material modeling on the mechanical response of its tissues (e.g., tumors) is not clear. This study proposes a subject-specific FE model of the breast, obtained by anthropometric measurements, to predict breast large deformation. A healthy breast subject-specific FE parametric model was developed and validated by Cranio caudal (CC) and Medio-Lateral Oblique (MLO) mammograms. The model was successively modified, including nodules, and utilized to investigate the effect of nodules size, typology, and material modeling on nodules shift under the effect of CC, MLO, and gravity loads. Results show that a Mooney-Rivlin material model can estimate healthy breast large deformation. For a pathological breast, under CC compression, the nodules displacement is very close to zero when a linear elastic material model is used. Finally, when nodules are modeled, including tumor material properties, under CC, or MLO or gravity loads, nodules shift shows ~15% average relative difference. PMID- 26734606 TI - A Muscle Synergy-Inspired Adaptive Control Scheme for a Hybrid Walking Neuroprosthesis. AB - A hybrid neuroprosthesis that uses an electric motor-based wearable exoskeleton and functional electrical stimulation (FES) has a promising potential to restore walking in persons with paraplegia. A hybrid actuation structure introduces effector redundancy, making its automatic control a challenging task because multiple muscles and additional electric motor need to be coordinated. Inspired by the muscle synergy principle, we designed a low dimensional controller to control multiple effectors: FES of multiple muscles and electric motors. The resulting control system may be less complex and easier to control. To obtain the muscle synergy-inspired low dimensional control, a subject-specific gait model was optimized to compute optimal control signals for the multiple effectors. The optimal control signals were then dimensionally reduced by using principal component analysis to extract synergies. Then, an adaptive feedforward controller with an update law for the synergy activation was designed. In addition, feedback control was used to provide stability and robustness to the control design. The adaptive-feedforward and feedback control structure makes the low dimensional controller more robust to disturbances and variations in the model parameters and may help to compensate for other time-varying phenomena (e.g., muscle fatigue). This is proven by using a Lyapunov stability analysis, which yielded semi-global uniformly ultimately bounded tracking. Computer simulations were performed to test the new controller on a 4-degree of freedom gait model. PMID- 26734605 TI - Bioceramics and Scaffolds: A Winning Combination for Tissue Engineering. AB - In the last few decades, we have assisted to a general increase of elder population worldwide associated with age-related pathologies. Therefore, there is the need for new biomaterials that can substitute damaged tissues, stimulate the body's own regenerative mechanisms, and promote tissue healing. Porous templates referred to as "scaffolds" are thought to be required for three-dimensional tissue growth. Bioceramics, a special set of fully, partially, or non-crystalline ceramics (e.g., calcium phosphates, bioactive glasses, and glass-ceramics) that are designed for the repair and reconstruction of diseased parts of the body, have high potential as scaffold materials. Traditionally, bioceramics have been used to fill and restore bone and dental defects (repair of hard tissues). More recently, this category of biomaterials has also revealed promising applications in the field of soft-tissue engineering. Starting with an overview of the fundamental requirements for tissue engineering scaffolds, this article provides a detailed picture on recent developments of porous bioceramics and composites, including a summary of common fabrication technologies and a critical analysis of structure-property and structure-function relationships. Areas of future research are highlighted at the end of this review, with special attention to the development of multifunctional scaffolds exploiting therapeutic ion/drug release and emerging applications beyond hard tissue repair. PMID- 26734607 TI - Mechanisms and Regulation of the Mitotic Inheritance of the Golgi Complex. AB - In mammalian cells, the Golgi complex is structured in the form of a continuous membranous system composed of stacks connected by tubular bridges: the "Golgi ribbon." At the onset of mitosis, the Golgi complex undergoes a multi-step fragmentation process that is required for its correct partition into the dividing cells. Importantly, inhibition of Golgi disassembly results in cell cycle arrest at the G2 stage, which indicates that accurate inheritance of the Golgi complex is monitored by a "Golgi mitotic checkpoint." Moreover, mitotic Golgi disassembly correlates with the release of a set of Golgi-localized proteins that acquire specific functions during mitosis, such as mitotic spindle formation and regulation of the spindle checkpoint. Most of these events are regulated by small GTPases of the Arf and Rab families. Here, we review recent studies that are revealing the fundamental mechanisms, the molecular players, and the biological significance of mitotic inheritance of the Golgi complex in mammalian cells. We also briefly comment on how Golgi partitioning is coordinated with mitotic progression. PMID- 26734608 TI - The Good and Bad of beta-Catenin in Kidney Development and Renal Dysplasia. AB - Congenital renal malformations are a major cause of childhood and adult onset chronic kidney disease. Identifying the etiology of these renal defects is often challenging since disruptions in the processes that drive kidney development can result from disruptions in environmental, genetic, or epigenetic cues. beta catenin is an intracellular molecule involved in cell adhesion, cell signaling, and regulation of gene transcription. It plays essential roles in kidney development and in the pathogenesis of renal dysplasia. Here, we review the function of beta-catenin during kidney development and in the genesis of renal dysplasia. PMID- 26734609 TI - Alternative Therapies for the Prevention of Postoperative Nausea and Vomiting. AB - Postoperative nausea and vomiting (PONV) is a complication affecting between 20 and 40% of all surgery patients, with high-risk patients experiencing rates of up to 80%. Recent studies and publications have shed light on the uses of alternative treatment for PONV through their modulation of endogenous opioid neuropeptides and neurokinin ligands. In addition to reducing PONV, hypnosis was reported to be useful in attenuating postoperative pain and anxiety, and contributing to hemodynamic stability. Music therapy has been utilized to deepen the sedation level and decrease patient anxiety, antiemetic and analgesic requirements, hospital length of stay, and fatigue. Isopropyl alcohol and peppermint oil aromatherapy have both been used to reduce postoperative nausea. With correct training in traditional Chinese healing techniques, acupuncture (APu) at the P6 acupoint has also been shown to be useful in preventing early PONV, postdischarge nausea and vomiting, and alleviating of pain. Electro acupuncture (EAPu), as with APu, provided analgesic and antiemetic effects through release and modulation of opioid neuropeptides. These non-pharmacological modalities of treatment contribute to an overall patient wellbeing, assisting in physical and emotional healing. PMID- 26734610 TI - Therapeutic Efficacy of Alpha-RIT Using a (213)Bi-Anti-hCD138 Antibody in a Mouse Model of Ovarian Peritoneal Carcinomatosis. AB - PURPOSE: Ovarian peritoneal carcinomatosis is a pathology for which effective cures are currently lacking. New research protocols seek to eradicate residual micrometastases following cytoreductive surgery by using hyperthermic intraperitoneal chemotherapy (HIPEC) or radioimmunotherapy (RIT). This study aims to first develop alpha-RIT using an anti-CD138 mAb radiolabeled with an alpha emitter, bismuth-213 ((213)Bi-B-B4) and HIPEC in a nude mouse model and second to compare and combine these techniques. MATERIAL AND METHODS: A murine model of postoperative ovarian peritoneal carcinomatosis was established. A pilot group of six mice received an intraperitoneal injection of luciferase-tagged SHIN-3 cells and bioluminescence was measured every day. Cytoreductive surgery was performed at day 14 (n = 4) and 29 (n = 2). Because the residual bioluminescence signal measured after surgery was equivalent to that obtained 3 days after the graft, HIPEC or alpha-RIT treatments were applied 3 days after the graft. Ten mice were treated by HIPEC with cisplatine (37.5 mg/mL), 11 with 7.4 MBq of (213)Bi-B-B4, seven with 11.1 MBq of (213)Bi-B-B4, and 10 mice were treated with the combined therapy (HIPEC + 7.4 MBq of (213)Bi-B-B4). Eleven mice received no treatment. Bioluminescence imaging and survival were assessed. RESULTS: Alpha-RIT 7.4 MBq and 11.1 MBq significantly improved survival (p = 0.0303 and p = 0.0070, respectively), whereas HIPEC and HIPEC + alpha-RIT treatments did not significantly ameliorate survival as compared to the control group. CONCLUSION: Survival was significantly increased by alpha-RIT treatment in mice with peritoneal carcinomatosis of ovarian origin; however, HIPEC alone or in combination with alpha-RIT had no significant effect. PMID- 26734612 TI - Commentary: Rheumatoid Cachexia Revisited: A Metabolic Co-morbidity in Rheumatoid Arthritis. PMID- 26734613 TI - Eating Frequency, Food Intake, and Weight: A Systematic Review of Human and Animal Experimental Studies. AB - Eating frequently during the day, or "grazing," has been proposed to assist with managing food intake and weight. This systematic review assessed the effect of greater eating frequency (EF) on intake and anthropometrics in human and animal experimental studies. Studies were identified through the PubMed electronic database. To be included, studies needed to be conducted in controlled settings or use methods that carefully monitored food intake, and measure food intake or anthropometrics. Studies using human or animal models of disease states (i.e., conditions influencing glucose or lipid metabolism), aside from being overweight or obese, were not included. The 25 reviewed studies (15 human and 10 animal studies) contained varying study designs, EF manipulations (1-24 eating occasions per day), lengths of experimentation (230 min to 28 weeks), and sample sizes (3 56 participants/animals per condition). Studies were organized into four categories for reporting results: (1) human studies conducted in laboratory/metabolic ward settings; (2) human studies conducted in field settings; (3) animal studies with experimental periods <1 month; and (4) animal studies with experimental periods >1 month. Out of the 13 studies reporting on consumption, 8 (61.5%) found no significant effect of EF. Seventeen studies reported on anthropometrics, with 11 studies (64.7%) finding no significant effect of EF. Future, adequately powered, studies should examine if other factors (i.e., disease states, physical activity, energy balance and weight status, long term increased EF) influence the relationship between increased EF and intake and/or anthropometrics. PMID- 26734611 TI - Understanding the Impact of Infection, Inflammation, and Their Persistence in the Pathogenesis of Bronchopulmonary Dysplasia. AB - The concerted interaction of genetic and environmental factors acts on the preterm human immature lung with inflammation being the common denominator leading to the multifactorial origin of the most common chronic lung disease in infants - -bronchopulmonary dysplasia (BPD). Adverse perinatal exposure to infection/inflammation with added insults like invasive mecha nical ventilation, exposure to hyperoxia, and sepsis causes persistent immune dysregulation. In this review article, we have attempted to analyze and consolidate current knowledge about the role played by persistent prenatal and postnatal inflammation in the pathogenesis of BPD. While some parameters of the early inflammatory response (neutrophils, cytokines, etc.) may not be detectable after days to weeks of exposure to noxious stimuli, they have already initiated the signaling pathways of the inflammatory process/immune cascade and have affected permanent defects structurally and functionally in the BPD lungs. Hence, translational research aimed at prevention/amelioration of BPD needs to focus on dampening the inflammatory response at an early stage to prevent the cascade of events leading to lung injury with impaired healing resulting in the pathologic pulmonary phenotype of alveolar simplification and dysregulated vascularization characteristic of BPD. PMID- 26734614 TI - Polymorphism of Alcohol Metabolizing Gene ADH3 Predisposes to Development of Alcoholic Pancreatitis in North Indian Population. AB - BACKGROUND AND AIM: Genetic factors regulating alcohol metabolism could predispose in developing alcoholic pancreatitis (ACP). Studies revealed that alcohol could be metabolized by both ways, oxidative and non-oxidative. The main oxidative pathway includes alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and cytochrome P450 enzyme. We investigated the association of polymorphisms in these enzymes with the alcoholic pancreatitis in the north Indian population. METHOD: Patients with alcoholic pancreatitis (ACP; n = 72), tropical calcific pancreatitis (TCP; n = 75), alcoholic controls (AC; n = 40), and healthy controls (HC; n = 100) were included in the study. Blood samples were collected from the subjects in EDTA coated vials. DNA was extracted and genotyping for ADH3, ALDH2, and CYP2E1 was done by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism). The products were analyzed by gel electrophoresis. RESULT: The frequency distribution of ADH3(*)1/(*)1 genotype was significantly higher in ACP group (59.7%) compared with TCP (38.7%), HC (42%), and AC (37.5%) and was found to be associated with increased risk of alcoholic pancreatitis. There was no statistically significant difference between the frequency distribution of ADH3(*)1/(*)1, ADH3(*)1/(*)2, and ADH3(*)2/(*)2 genotypes between TCP and HC or healthy alcoholics. ALDH2 gene was monomorphic in our population, and the frequencies for CYP2E1 intron 6 Dra I polymorphism were comparable in all the four groups. CONCLUSION: This study shows that carriers of ADH3(*)1/(*)1 individuals consuming alcohol are at higher risk for alcoholic pancreatitis than those with other genotypes such as ADH3(*)1/(*)2 and ADH3(*)2/(*)2. PMID- 26734615 TI - Global Regulator IscR Positively Contributes to Antimonite Resistance and Oxidation in Comamonas testosteroni S44. AB - Antimonial compounds can be found as a toxic contaminant in the environment. Knowledge on mechanisms of microbial Sb oxidation and its role in microbial tolerance are limited. Previously, we found that Comamonas testosteroni S44 was resistant to multiple heavy metals and was able to oxidize the toxic antimonite [Sb(III)] to the much less toxic antimonate [Sb(V)]. In this study, transposon mutagenesis was performed in C. testosteroni S44 to isolate genes responsible for Sb(III) resistance and oxidation. An insertion mutation into iscR, which regulates genes involved in the biosynthesis of Fe-S clusters, generated a strain called iscR-280. This mutant strain was complemented with a plasmid carrying iscR to generate strain iscR-280C. Compared to the wild type S44 and iscR-280C, strain iscR-280 showed lower resistance to Sb(III) and a lower Sb(III) oxidation rate. Strain iscR-280 also showed lower resistance to As(III), Cd(II), Cu(II), and H2O2. In addition, intracellular gamma-glutamylcysteine ligase (gamma-GCL) activity and glutathione (GSH) content were decreased in the mutated strain iscR 280. Real-time RT-PCR and lacZ fusion expression assay indicated that transcription of iscR and iscS was induced by Sb(III). Results of electrophoretic mobility shift assay (EMSA) and bacterial one-hybrid (B1H) system demonstrated a positive interaction between IscR and its promoter region. The diverse defective phenotypes and various expression patterns suggest a role for IscR in contributing to multi-metal(loid)s resistance and Sb(III) oxidation via Fe-S cluster biogenesis and oxidative stress protection. Bacterial Sb(III) oxidation is a detoxification reaction. PMID- 26734616 TI - Structural and Functional Insights into Small, Glutamine-Rich, Tetratricopeptide Repeat Protein Alpha. AB - The small glutamine-rich, tetratricopeptide repeat-containing protein alpha (SGTA) is an emerging player in the quality control of secretory and membrane proteins mislocalized to the cytosol, with established roles in tail-anchored (TA) membrane protein biogenesis. SGTA consists of three structural domains with individual functions, an N-terminal dimerization domain that assists protein sorting pathways, a central tetratricopeptide repeat (TPR) domain that mediates interactions with heat-shock proteins, proteasomal, and hormonal receptors, and viral proteins, and a C-terminal glutamine rich region that binds hydrophobic substrates. SGTA has been linked to viral lifecycles and hormone receptor signaling, with implications in the pathogenesis of various disease states. Thus far, a range of biophysical techniques have been employed to characterize SGTA structure in some detail, and to investigate its interactions with binding partners in different biological contexts. A complete description of SGTA structure, together with further investigation into its function as a co chaperone involved quality control, could provide us with useful insights into its role in maintaining cellular proteostasis, and broaden our understanding of mechanisms underlying associated pathologies. This review describes how some structural features of SGTA have been elucidated, and what this has uncovered about its cellular functions. A brief background on the structure and function of SGTA is given, highlighting its importance to biomedicine and related fields. The current level of knowledge and what remains to be understood about the structure and function of SGTA is summarized, discussing the potential direction of future research. PMID- 26734617 TI - Stem Cell Ribonomics: RNA-Binding Proteins and Gene Networks in Stem Cell Differentiation. AB - Stem cells are undifferentiated cells with the ability to self-renew and the potential to differentiate into all body cell types. Stem cells follow a developmental genetic program and are able to respond to alterations in the environment through various signaling pathways. The mechanisms that control these processes involve the activation of transcription followed by a series of post transcriptional events. These post-transcriptional steps are mediated by the interaction of RNA-binding proteins (RBPs) with defined subpopulations of RNAs creating a regulatory gene network. Characterizing these RNA-protein networks is essential to understanding the regulatory mechanisms underlying the control of stem cell fate. Ribonomics is the combination of classical biochemical purification protocols with the high-throughput identification of transcripts applied to the functional characterization of RNA-protein complexes. Here, we describe the different approaches that can be used in a ribonomic approach and how they have contributed to understanding the function of several RBPs with central roles in stem cell biology. PMID- 26734620 TI - Laparoscopic liver resection in patients with clinically significant cirrhosis: an Eastern perspective. PMID- 26734618 TI - Steering Endogenous Butyrate Production in the Intestinal Tract of Broilers as a Tool to Improve Gut Health. AB - The ban on antimicrobial growth promoters and efforts to reduce therapeutic antibiotic usage has led to major problems of gastrointestinal dysbiosis in livestock production in Europe. Control of dysbiosis without the use of antibiotics requires a thorough understanding of the interaction between the microbiota and the host mucosa. The gut microbiota of the healthy chicken is highly diverse, producing various metabolic end products, including gases and fermentation acids. The distal gut knows an abundance of bacteria from within the Firmicutes Clostridium clusters IV and XIVa that produce butyric acid, which is one of the metabolites that are sensed by the host as a signal. The host responds by strengthening the epithelial barrier, reducing inflammation, and increasing the production of mucins and antimicrobial peptides. Stimulating the colonization and growth of butyrate-producing bacteria thus may help optimizing gut health. Various strategies are available to stimulate butyrate production in the distal gut. These include delivery of prebiotic substrates that are broken down by bacteria into smaller molecules which are then used by butyrate producers, a concept called cross-feeding. Xylo-oligosaccharides (XOS) are such compounds as they can be converted to lactate, which is further metabolized to butyrate. Probiotic lactic acid producers can be supplied to support the cross-feeding reactions. Direct feeding of butyrate-producing Clostridium cluster IV and XIVa strains are a future tool provided that large scale production of strictly anaerobic bacteria can be optimized. Current results of strategies that promote butyrate production in the gut are promising. Nevertheless, our current understanding of the intestinal ecosystem is still insufficient, and further research efforts are needed to fully exploit the capacity of these strategies. PMID- 26734619 TI - Summer-Long Grazing of High vs. Low Endophyte (Neotyphodium coenophialum) Infected Tall Fescue by Growing Beef Steers Results in Distinct Temporal Blood Analyte Response Patterns, with Poor Correlation to Serum Prolactin Levels. AB - Previously, we reported the effects of fescue toxicosis on developing Angus-cross steer growth, carcass, hepatic mRNA, and protein expression profiles of selected serum proteins, and blood clinical and chemical profiles, after summer-long grazing (85 days) of high endophyte (HE)- vs. low endophyte (LE)-infected fescue pastures. We now report the temporal development of acute, intermediate, and chronic responses of biochemical and clinical blood analytes determined at specified time intervals (period 1, day 0-36; period 2, day 37-58; and period 3, day 59-85). Throughout the trial, the alkaloid concentrations of the HE forage was consistently 19-25 times greater (P <= 0.002) than the concentration in the LE forage, and HE vs. LE steers had continuously lower (P <= 0.049) serum prolactin (85%), cholesterol (27%), and albumin (5%), but greater red blood cells (7%). The HE steers had decreased (P = 0.003) ADG only during period 1 (-0.05 vs. 0.4 kg/day). For period 1, HE steers had reduced (P <= 0.090) numbers of eosinophils (55%) and lymphocytes (18%), serum triglyceride (27%), and an albumin/globulin ratio (9%), but an increased bilirubin concentration (20%). During period 2, serum LDH activities were 18% lower (P = 0.022) for HE vs. LE steers. During period 3, serum levels of ALP (32%), ALT (16%), AST (15%), creatine kinase (35%), glucose (10%), and LDH (23%) were lower (P <= 0.040) for HE steers. Correlation analysis of serum prolactin and other blood analytes revealed that triglycerides (P = 0.042) and creatinine (P = 0.021) were moderately correlated (r <= 0.433) with HE serum prolactin. In conclusion, three HE-induced blood analyte response patterns were identified: continually altered, initially altered, and subsequently "recovered," or altered only after long-term exposure. Blood analytes affected by length of grazing HE vs. LE forages were either not or poorly correlated with serum prolactin. These data reveal important, temporal, data about how young cattle respond to the challenge of consuming HE pasture. PMID- 26734621 TI - Laparoscopic liver resection for hepatitis B and C virus-related hepatocellular carcinoma in patients with Child B or C cirrhosis. AB - BACKGROUND: The aim of this study was to evaluate the clinical and oncological outcomes after laparoscopic liver resection (LLR) in patients with hepatitis B and C virus-related hepatocellular carcinoma (HCC) with Child B or C cirrhosis. METHODS: Between January 2004 and December 2013, LLR was performed in 232 patients with HCC. Of these, 141 patients also had pathologically proven cirrhosis. Sixteen patients with hepatitis B and C virus-related HCC with Child B or C cirrhosis were included in the study. Thirteen (81.3%) patients had Child B disease and three (18.8%) patients had Child C disease. RESULTS: The median operation time was 215 min, the median estimated blood loss was 350 mL, and the median hospital stay was eight days. Three patients (18.8%) experienced complications after surgery. There was no postoperative mortality or reoperation. The mean follow-up period was 51.6 months. HCC recurred in eight (50%) patients: seven intrahepatic recurrences and one extrahepatic recurrence. The treatments for recurrence were laparoscopic reoperation in one (6.3%) patient, trans catheter arterial chemo-embolization (TACE) in one (6.3%) patient, radiofrequency ablation (RFA) in one (6.3%) patient, and combined TACE and RFA in four (25%) patients. The five-year postoperative overall survival (OS) and disease-free survival (DFS) were 84.4% and 41.7%, respectively. CONCLUSIONS: This study demonstrates that LLR can be safely used in patients with hepatitis B and C virus related HCC and Child B or C cirrhosis, with acceptable survival outcomes. PMID- 26734622 TI - Laparoscopic liver resection for posterosuperior and anterolateral lesions-a comparison experience in an Asian centre. AB - BACKGROUND: Minimally invasive surgery has been one of the recent developments in liver surgery, laparoscopic liver resection (LLR) was initially performed for benign lesions at easily accessible locations. As the surgical techniques, technology and experience improved over the past decades, LLR surgery had evolved to tackle malignant lesions, major resections and even in difficult locations without compromising safety and principles of oncology. It was also shown to be beneficial in cirrhotic patients. We describe our initial experience with LLR in a population with significant proportion having cirrhosis, emphasising our approach for lesions in the posterosuperior (PS) segments of the liver (segments 1, 4a, 7, and 8). METHODS: A review of patients undergoing LLR in single institution from 2006 to 2015 was performed from a prospective surgical database. Clinicopathological, operative and perioperative parameters were analyzed to compare outcomes in patients who underwent LLR for PS vs. anterolateral lesions (AL). RESULTS: LLR was performed in consecutive 197 patients, with a mean age of 60 years. The indications for resection were hepatocellular carcinoma (HCC) (n=105; 53%), colorectal cancer liver metastasis (n=31; 16%), other malignancies (n=19; 10%) and benign lesions (n=42; 21%). A significant proportion had liver cirrhosis (25.9%). More females underwent surgery in the AL group and indications for surgery were similar between both groups. Major liver resection was performed more frequently for the PS group than for the AL group (P<0.001) and significantly more PS resections was performed in our latter experience (P=0.02). The mean operative time and the conversion rate were significantly greater in the PS group than in the AL group (P<=0.001 and 0.03, respectively). However, the estimated blood loss (EBL), rate of blood transfusion and mean postoperative stay were similar in the two groups (P=0.04, 0.88 and 0.92, respectively). The overall 90-day morbidity and mortality rate was 21.3% and 0.5% respectively, with no differences between the two groups. Surrogates of difficulty such as operative time, blood loss, conversion and outcomes e.g., morbidity and mortality, were similar in patients who underwent PS resections with or without cirrhosis. CONCLUSIONS: LLR in selected patients is technically feasible and safe including cirrhotic patients with lesions in the PS segments. PMID- 26734623 TI - Liver cirrhosis grading Child-Pugh class B: a Goliath to challenge in laparoscopic liver resection?-prior experience and matched comparisons. AB - BACKGROUND: Laparoscopic hepatectomy (LH) is highly difficult in the background of liver cirrhosis. In this case series, we aimed to summarize our prior experience of LH in liver cirrhosis grading Child-Pugh class B. METHODS: In the LH database of Sir Run Run Shaw Hospital in Zhejiang, China, patients who were pathologically diagnosed with cirrhosis and graded as Child-Pugh class B or C were reviewed. RESULTS: Five patients grading Child B were included. There was no Child C case in our LH database. For included cases, median blood loss (BL) was 800 (range, 240-1,000) mL, median operative time was 135 (range, 80-170) minutes, and median length of hospital stay was 9 (range, 7-15) days. Forty percent (2/5) of patients was converted to open. The postoperative complication (PC) rate was 20.0% (1/5). When these Child B cases were compared with Child A cases undergoing LH, there was no statistical significance in BL, complication rate, operative time, open rate and hospital stay (HS) (P>0.05). This finding was confirmed by two ways of matched comparisons (a 1:2 comparison based on age and gender, and a 1:1 propensity score matching). CONCLUSIONS: Although relevant literatures had suggested feasibility of LH in cirrhotic cases grading Child A, this study was the first one to discuss the value of LH in Child B cases. Our prior experience showed that in selected patients, LH in Child B patients had the potential to be as safe as in Child A cases. The efficacy of LH in Child C patients needs further exploration. PMID- 26734624 TI - Laparoscopic liver resection for hepatocellular carcinoma with cirrhosis in a single institution. AB - BACKGROUND: In a statement by the second International Consensus Conference for Laparoscopic Liver Resection (LLR), minor LLR was confirmed to be a standard surgical practice, as it has become adopted by an increasing proportion of surgeons. However, it is unclear whether this applies to the more complex group of patients suffering from cirrhosis. Therefore, the aim of this retrospective study was to compare the feasibility and safety of LLR for hepatocellular carcinoma (HCC) between non-liver cirrhosis (NLC) patients and liver cirrhosis (LC) patients at a single high-volume laparoscopy center. METHODS: From the beginning of 2000 to the end of 2013, open liver resection (OLR) was performed in 99 HCC patients, and LLR was in 118. The HCC patients who underwent LLR were divided into NLC-LLR (n=60) and LC-LLR (n=58) groups, and we compare the short term outcomes between them. RESULTS: There was no significant difference in the incidence of blood loss and transfusion requirements between the NLC-LLR group and the LC-LLR group, although wedge resection was mainly performed in the LC-LLR group. There was no significant difference in the complication rate between the two groups, and the remarkable finding was that there was a significantly lower incidence of postoperative ascites in the LC-LLR group than in the NLC-LLR group. CONCLUSIONS: According to our experience, it appears that LLR for selected HCC patients with cirrhosis is a feasible and promising procedure that is associated with less blood loss and fewer postoperative complications, especially the incidence of postoperative ascites. Further investigations are clearly warranted. PMID- 26734625 TI - Laparoscopic liver resection for hepatocellular carcinoma in patients with cirrhosis. AB - Liver resection for patients with cirrhosis remains a challenging operation. The presence of thrombocytopenia and portal hypertension could lead to severe bleeding during hepatectomy. The enthusiasm of laparoscopic hepatectomy has been growing and many studies have reported their initial favorable results for patients with hepatocellular carcinoma (HCC). The advancement in technology, better understanding of the use of pneumoperitoneum pressure and more experience accumulated make laparoscopic liver resection for patients with cirrhosis possible. Favorable outcome may be achieved if the patients are carefully selected and carried out in high volume centers. PMID- 26734626 TI - Learning curve in laparoscopic liver surgery: a fellow's perspective. AB - The learning curve for laparoscopic liver surgery is infrequently addressed in current literature. In this paper, we explored the challenges faced in embarking on laparoscopic liver surgery in a unit that did predominantly open liver surgery. In setting up our laparoscopic liver surgery program, we adopted skills and practices learnt during fellowships at various high volume centers in North America and Australia, with modifications to suit our local patients' disease patterns. We started with simple minor resections in anterolateral segments to build confidence, which allowed us to train the surgical and nursing team before progressing to more difficult resections. Inter institutional collaboration and exchange of skills also enabled the synergistic development of techniques for safe progression to more complex surgeries. Multimedia resources and international guidelines for laparoscopic liver surgery are increasingly accessible, which further guide the practice of this emerging field, as evidence continues to validate the laparoscopic approach in well selected cases. PMID- 26734628 TI - Professor Daniel Cherqui: my experiences with laparoscopic liver resection. PMID- 26734627 TI - Liver resection for hepatocellular carcinoma in patients with portal hypertension: the role of laparoscopy. AB - Liver resection (LR) for hepatocellular carcinoma (HCC) in patients with chronic liver disease (CLD) is a major issue since patients are at risk of serious intraoperative and postoperative complications. The current EASL/AASLD guidelines recommend LR only in case of patients with stage A HCC with well-preserved liver function and consider the presence of portal hypertension (PHT) as a contraindication to surgery. Nevertheless, the literature on this topic is conflicting. Recently several studies reported that favorable outcomes can be achieved with a careful patients' selection in high volume centers. Laparoscopic LR, when performed by well-trained surgeons and with appropriate indications, proved to be a valid option for the surgical treatment of HCC on cirrhosis offering similar oncologic outcomes but a reduction in surgical related morbidities. Laparoscopic LR thanks to a reduction in the incidence of post operative liver failure and ascites development in comparison to standard open LR could, in selected cases challenge alternative treatments in the treatment of HCC patients with preserved liver function and clinical signs of mild PHT. PMID- 26734630 TI - Laparoscopic right hepatectomy for hepatocellular carcinoma in cirrhotic patient. AB - Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor worldwide and the most common primary liver cancer. Liver resection or liver transplantation is the therapeutic gold standards in patient with HCC related with or without underline liver disease. We present a video case of a 68-year-old woman admitted to our surgical and liver transplantation unit for HCC on liver segment VII. Patient has HCV cirrhosis. Patient underwent to previous right portal vein embolization. Model of end staged liver disease was 7. Body mass index (BMI) was 26.3 and ASA score was 2. Alpha-fetoprotein was 768. According with our multidisciplinary group, we suggest a laparoscopic right hepatectomy for the patient. Operation time was 343 min and blood loss estimation was 200 CC. No transfusion was required. Post-operative course was uneventful, grade 0 of Clavien-Dindo Classification. Patient was discharged in day 7. Pathology report describes a 17 mm * 15 mm HCC grade 4, pT2N0. Laparoscopic liver resection (LLR) for HCC should be performed by dedicated surgical teams in hepatobiliary and laparoscopic surgery. The use of LLR in cirrhotic patients is in many centers proposed as the first-line treatment for HCC or as bridge treatment before liver transplantation. PMID- 26734629 TI - Detection of carcinogenic etheno-DNA adducts in children and adolescents with non alcoholic steatohepatitis (NASH). AB - BACKGROUND: Carcinogenic exocyclic-DNA adducts like 1,N(6)-etheno-2' deoxyadenosine (epsilondA) are formed through reactive intermediates of 4 hydroxynonenal (4-HNE) or other lipid peroxidation (LPO) products with the DNA bases A, C, methyl-C and G. High levels of hepatic etheno-DNA adducts have been detected in cancer prone liver diseases including alcoholic liver disease (ALD). In ALD epsilondA levels correlated significantly with cytochrome P-450 2E1 (CYP2E1) expression which is also induced in non-alcoholic steatohepatitis (NASH). We investigated the occurrence of epsilondA adducts in children with NASH as a DNA damage marker. METHODS: Liver biopsies from 21 children/adolescents with histologically proven NASH were analysed for hepatic fat content, inflammation, and fibrosis. epsilondA levels in DNA, CYP2E1-expression and protein bound 4 hydroxynonenal (HNE) were semi-quantitatively evaluated by immunohistochemistry. RESULTS: Among 21 NASH children, epsilondA levels in the liver were high in 3, moderate in 5, weak in 9 and not elevated in 4 patients. There was a positive correlation between CYP2E1 and protein-bound 4-HNE (r=0.60; P=0.008) and a trend for a positive relationship for CYP2E1 vs. staining intensity of epsilondA (r=0.45; P=0.06). Inflammatory activity and fibrosis correlated significantly (r=0.49, P=0.023). CONCLUSIONS: Our results demonstrate for the first time the presence of elevated carcinogenic etheno-DNA lesions (epsilondA) in the majority (17/21) of liver biopsies from young NASH patients. Our data suggest that LPO derived etheno-adducts are implicated in NASH. Whether these adducts may serve as predictive risk markers in NASH children to develop hepatocellular cancer later in life remains to be investigated. PMID- 26734631 TI - Exchange makes progress: Hepatobiliary Surgery and Manuscript Writing Symposium cosponsored by HepatoBiliary Surgery and Nutrition and AME Publishing Company. PMID- 26734633 TI - Missing values in big data research: some basic skills. PMID- 26734634 TI - Association between methylenetetrahydrofolate reductase (MTHFR) polymorphism and carotid intima medial thickness progression in post ischaemic stroke patient. AB - BACKGROUND: Hyperhomocysteinemia is associated with an increased risk of atherosclerosis. The main cause of elevated levels of homocysteine is 677T allele, the gene encoded by methylenetetrahydrofolate reductase (MTHFR). Carotid atherosclerosis progression, which can be measured by examination of carotid intima-media thickness (C-IMT), is a predictor of recurrent ischemic stroke. The objective of this study was to determine a relationship between MTHFR polymorphism, homocysteine levels, and increased C-IMT in post- ischemic stroke patients. METHODS: This was an epidemiological prospective observational cohort study involving 71 patients with post-ischemic stroke subject of the first (onset 1 month) admitted in the Neurology Clinic of Kariadi Hospital during 2012 to 2013. C-IMT was examined using carotid duplex ultrasound at 1(st), 6(th), and 12(th) month after stroke onset. MTHFR gene polymorphism was examined using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). Homocysteine level was measured using Axis((r)) Homocysteine EIA. RESULTS: We found 3 categories of MTHFR gene variation, i.e., 677T/T, 677T/C, and 677C/C. The most frequent allele was MTHFR 677C (88.9%), while the MTHFR 677T allele frequency was 11.1%. The majority allele of the subject population was 677C/C, however, there were 3 subjects (4.2%) who had 677T/T allele. The 677T/T allele group had normal homocysteine level and the lowest mean C-IMT among others. CONCLUSIONS: This study supports that the MTHFR 677T allele polymorphism is not associated with hyperhomocysteinemia as well as an increase in C-IMT in post ischemic stroke patients. PMID- 26734636 TI - Spatial visualization of theoretical nanoparticle deposition in the human respiratory tract. AB - BACKGROUND: Although nanoparticles and their hazardous effects on human health are well elucidated meanwhile, inhalation and distribution of these materials in the human respiratory tract still represent partly enigmatic phenomena. Main objective of the present study was the detailed description of a mathematical method, with the help of which spatial distributions of nanoparticles deposited in the tracheobronchial tree may be visualized appropriately. METHODS: The technique is founded on a stochastic model of the bronchial network, within which inhaled particles follow individual, randomly selected trajectories. The lengths of these random paths depend on the airway-specific deposition probabilities calculated for the particles and the duration of the breath cycle. Positions of the deposited material were determined by computation of the exact lengths of individual particle trajectories and the orientation of single path segments within a Cartesian coordinate system, where the z-direction corresponds with the trachea. For a better quantification of the particle distribution and its eventual comparison with experimental data particle coordinates were fitted into a voxel grid [1 voxel = (0.467 cm)(3)]. Particle deposition is chiefly controlled by diffusive processes, whereas deposition mechanisms associated with inertia or gravity play a subordinate role. RESULTS: Deposition patterns were visualized for particles with sizes of 1, 10, and 100 nm. As clearly demonstrated by the results obtained from the modeling procedure, under normal breathing conditions 1-nm particles tend to deposit in the upper airways, whilst 10- and 100-nm particles are preferably accumulated in the airways of the central and peripheral lung. The particle dose deposited in the extrathoracic and thoracic airways within one breath cycle significantly declines with increasing particle size. CONCLUSIONS: Based on the predictions presented in this study possible consequences of nanoparticle inhalation to the health of subjects increasingly exposed to these airborne materials were discussed. PMID- 26734635 TI - Outcomes of reirradiation in the treatment of patients with multiple brain metastases of solid tumors: a retrospective analysis. AB - BACKGROUND: Patients with multiple brain metastases are often treated with whole brain radiation therapy (WBRT). Second course of WBRT is an important treatment option for patients with clinical or radiological intracranial disease progression. This study examines the outcomes in patients with multiple brain metastases who underwent reirradiation. METHODS: We examined the medical records of 34 patients with multiple brain metastases who were treated WBRT. The median dose for the first course of WBRT was 30 Gy (range, 25-30 Gy) and for the second course 25 Gy (range, 20-30 Gy). Statistical analyses were performed with using Cox regression analyses, log-rank test and Kaplan-Meier method. RESULTS: The median Karnofsky performance status (KPS) was 80 (range, 50-100) before reirradiation. Patients with KPS of >70 had a median survival of 11.4 months, compared to 2.2 months with KPS of <=70 (P=0.012) and patients who have severe symptoms at the time of reirradiation with median survival 2.2 months while those with mild symptoms had a median of 4.8 months survival (P=0.08). The median overall survival for all patients after diagnosis of metastases was 24.7 months, after the re-irradiation WBRT (re-WBRT) it was 5.3 months (95% CI, 4.08-6.62) and from the diagnosis of primary tumor was 27.1 months (95% CI, 17.75-37.04). CONCLUSIONS: In select patients who have good performance status and who do not have severe symptoms might benefit from re-WBRT and re-WBRT seems to be associated with minimal toxicity in patients treated with lower palliation doses. PMID- 26734637 TI - Cadaveric validation of porcine model suggests noninvasive positive pressure ventilation may be safe following esophagectomy. AB - BACKGROUND: We previously used a pig model to demonstrate that noninvasive positive pressure ventilation (NPPV) may be a safe alternative to endotracheal intubation (ET). We sought to validate our model by quantifying the pressure threshold of esophageal anastomoses in human cadavers as a step before a clinical trial. METHODS: We performed stapled side-to-side, functional end-to-end esophageal anastomoses in 10 cadaveric specimens from autopsy. With intraluminal pressure monitoring, we insufflated the anastomosis with air until a leak was observed, and measured the maximum tolerated pressure. RESULTS: Cadaveric esophageal anastomoses tolerated 101+/-39 cmH2O (range, 63-140 cmH2O) of pressure before leak was observed. The maximum pressure threshold ranged from 59 to 246 cmH2O. The leak was always at the anastomosis. There was no significant difference in pressure threshold between cadaveric and previously described porcine anastomoses. CONCLUSIONS: We created a human cadaveric model that in conjunction with our porcine data demonstrates that a human esophageal anastomosis can tolerate manifold higher pressures than are delivered to the esophagus by NPPV. This is the final step before a trial of NPPV in patients following esophagectomy. PMID- 26734638 TI - Relationship between serum CA19-9 and CEA levels and prognosis of pancreatic cancer. AB - BACKGROUND: To explore the relationship between preoperative serum CA19-9 and CEA levels and prognosis of pancreatic cancer (PC). METHODS: The clinicopathological data of 128 patients with pancreatic adenocarcinoma who were treated in our center between January 2012 and December 2013 were retrospectively analyzed. The relationships between serum CA19-9 and CEA levels and survival were analyzed using Kaplan-Meier method, log-rank test, and Cox regression analysis. The cut off values for serum CA19-9 and CEA levels were 39 U/mL and 4.7 ng/mL, respectively. RESULTS: Among these 128 patients, the mean age was 62 years, and median survival was 12.2 days. The positive rate of CA19-9 and CEA was 78.1% and 37.5%, respectively. Patients with increased CA19-9 or CEA level suffered a poorer prognosis than those with normal CA19-9 or CEA level (CA19-9: P=0.027; CEA: P=0.036). Cox logistic analysis revealed that lymphatic metastasis, CA19-9 >39 U/mL, and CEA >4.7 ng/mL were independent prognostic factors in patients with pancreatic carcinoma. CONCLUSIONS: Preoperative serum CA19-9 and CEA level are closely related with survival time in PC patients and therefore may be used for evaluating the prognosis for PC. PMID- 26734639 TI - MicroRNAs, signaling pathways and diseases. PMID- 26734632 TI - Chinese Guidelines on the Diagnosis and Treatment of Melanoma (2015 Edition). PMID- 26734640 TI - The critical roles of miR-21 in anti-cancer effects of curcumin. AB - Curcumin is a well-known phytochemical that has various anti-cancer effects. Although it has been demonstrated that curcumin can inhibit multiple signalling pathways, the exact mechanisms for its demonstrated anti-cancer effects are not fully understood. Recent studies have revealed that curcumin may affect cancer initiation and progression through regulating microRNAs (miRs). In this review, we focus on the roles of microRNA-21 (miR-21) in the anti-cancer effects of curcumin and regulatory mechanisms for the effects of curcumin on miR-21. MiR-21 mediates various effects of curcumin on cancer cells including proliferation, apoptosis, metastasis and anti-cancer drug resistance. Several downstream pathways of miR-21 have been identified including phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), programmed cell death protein 4 (PDCD4) and NF-kappaB pathways. Curcumin decreases miR-21 levels through both increasing miR-21 exosome exclusion from the cells and inhibiting the transcription of the miR-21 gene in the cells by binding to its promoter. PMID- 26734641 TI - HPV-p53-miR-34a axis in HPV-associated cancers. AB - Human papillomaviruses (HPVs) are known to cause many cancers by altering multiple signalling pathways through their oncogene integration into host genome and expression. Studies have shown that many microRNAs (miRs) may function as oncogenes (called as oncomiRs) to promote an oncogenic effect. MiR-34a among the reported oncomiRs is a key player in the carcinogenesis caused by infection with HPVs. In this mini-review, we summarise the roles of miR-34a in HPV-caused cancers. MiR-34a is transcriptionally regulated by tumour suppressor p53. HPV oncogene E6 inhibits expression of p53 to decrease the levels of miR-34a, leading to the increased expression of multiple genes which are targeted by miR-34a. The upregulation of these genes increases cancer cell proliferation, survival and migration in HPV-associated cancers. PMID- 26734642 TI - Role of microRNAs in chemoresistance. AB - Drug resistance is a major problem in the treatment of cancer patients. Resistance can develop after prolonged cycles of chemotherapy or can be present intrinsically in the patient. There is an emerging role of microRNAs (miRNAs) in resistance to cancer treatments. miRNAs are small non-coding RNAs that are evolutionarily conserved and also involved as regulators of gene expression through the silencing of mRNA targets. They are involved in many different cancer types and a plethora of mechanisms have been postulated for the roles that miRNAs play in the development of drug resistance. Hence, miRNA-based gene therapy may provide a novel approach for the future of cancer therapy. This review focuses on an overview of recent findings on the role of miRNAs in the resistance to chemotherapy in different tumours. PMID- 26734643 TI - MicroRNAs in congenital heart disease. AB - Congenital heart disease (CHD) is a broad term which encompasses a spectrum of pathology, the most common phenotypes include atrial septal defects (ASDs), ventricular septal defects (VSDs), patent ductus arteriosus (PAD) and tetralogy of Fallot (TOF). The impact of CHD is profound and it is estimated to be responsible for over 40% of prenatal deaths. MicroRNAs (miRs) are small, highly conserved, non-coding RNAs which have complex roles in a variety of pathophysiological states. miRs are post-transcriptional negative regulators of gene expression. Individual miRs are known to exert effects in multiple target genes, therefore the altered expression of a single miR could influence an entire gene network resulting in complex pathological states. Recent evidences suggest a role in the dysregulation of miRs in CHD. Mouse knock out models have contributed to our knowledge base revealing specific patterns of miR expression in cardiovascular physiology and pathological states. Specific miRs necessary for embryonic cardiac development have been revealed. Dysregulation of these miRs has been shown to cause structural abnormalities in the heart and vasculature, thus furthering our understanding of the processes which result in CHD. These advances have provided new insight into the signalling pathways responsible for CHD. Furthermore, this new appreciation for miRs in the development of CHD has uncovered their potential for new therapeutic targets where modulated miR activity may reduce the burden of disease. Here, we summarize current knowledge of the cause-effect relationships of miRs in CHD and consider their potential as a therapeutic targets and biomarkers in this clinical setting. PMID- 26734644 TI - MicroRNAs in multiple myeloma and related bone disease. AB - MicroRNAs (miRNAs) are short non coding RNAs aberrantly expressed in solid and hematopoietic malignancies where they play a pivotal function as post transcriptional regulators of gene expression. Recent reports have unveiled a central role of miRNAs in multiple myeloma onset and progression and preclinical findings are progressively disclosing their potential therapeutic value as drugs or targets. In this review, we provide the basic insights of miRNA biology and function, showing how these molecules are extensively dysregulated in malignant plasma cells (PC) and related microenvironment, thus favoring clone survival and proliferation. We here describe how these critical activities have recently been evaluated to design miRNA-based therapies against multiple myeloma cells and its surrounding microenvironment. PMID- 26734645 TI - Early surgical and functional outcomes comparison of the supercapsular percutaneously-assisted total hip and traditional posterior surgical techniques for total hip arthroplasty: protocol for a randomized, controlled study. AB - BACKGROUND: Total hip arthroplasty (THA) is one of the most commonly performed and successful orthopaedic surgeries. While the long-term success of THA is well documented, there is still significant room for improving patient speed of recovery and return to activities. The surgical technique used during THA has the potential to affect these early outcomes. METHODS: The described design is a single center, prospective, randomized, controlled study. Subjects will be randomized to receive THA using either the supercapsular percutaneously-assisted total hip (SuperPath) or traditional posterior surgical techniques. Subjects will be evaluated using Timed Up and Go (TUG), Timed Stair Climb (TSC), Hip Dysfunction and Osteoarthritis Outcome Score (HOOS), and Visual Analog Scale (VAS) for pain level estimation preoperatively, during the hospital stay, and at 2, 6 weeks, and 100 days post-discharge. Other endpoints to be evaluated include: length of stay (LOS); discharge status; transfusion rates; readmission rates; complication rates; operative time; date returned to work; and acetabular component anteversion and inclination angles. DISCUSSION: The described study will determine the effect of a tissue-sparing surgical technique on short term subject recovery following THA in comparison to the most commonly used technique in clinical practice. PMID- 26734647 TI - A multimodality approach to prevent catheter-related bloodstream infections: the role of chlorhexidine-alcohol as a skin antiseptic before intravascular catheter insertion. PMID- 26734646 TI - Photon, light ion, and heavy ion cancer radiotherapy: paths from physics and biology to clinical practice. AB - External beam radiotherapy has proven highly effective against a wide range of cancers, and in recent decades there have been rapid advances with traditional photon-based (X-ray) radiotherapy and the development of two particle-based techniques, proton and carbon ion radiotherapy (CIRT). There are major cost differences and both physical and biological differences among these modalities that raise important questions about relative treatment efficacy and cost effectiveness. Randomized clinical trials (RCTs) represent the gold standard for comparing treatments, but there are significant cost and ethical barriers to their wide-spread use. Meta-analysis of non-coordinated clinical trials data is another tool that can be used to compare treatments, and while this approach has recognized limitations, it is argued that meta-analysis represents an early stage of investigation that can help inform the design of future RCTs. PMID- 26734648 TI - One more brick in the wall of protective ventilation in surgical patients. AB - On June 14, 2015, Ladha and colleagues published an article in the BMJ entitled "Intraoperative protective mechanical ventilation and risk of postoperative respiratory complications: hospital based registry study", which investigated the effects of intraoperative protective ventilation on major postoperative respiratory complications. This study used data of over 69,265 patients in order to investigate patients over the age of 18 who underwent a non-cardiac surgical procedure between January 2007 and August 2014 and required general anesthesia with endotracheal intubation. The investigators found that intraoperative protective ventilation was associated with a decreased risk of postoperative respiratory complications. This study raises important questions about the ventilatory management of surgical patients. PMID- 26734649 TI - Seven times replacement of permanent cardiac pacemaker in 33 years to maintain adequate heart rate: a case report. AB - Over the past few decades, recent developments in pacemaker technology from fixed rate single-chamber pacemakers to dual chamber pacemakers with pacing algorithms have changed the therapeutic landscape resulting in better healthcare outcomes by improving rate response with minimal ventricular pacing. Here, we share our longest clinical experience with an elderly Chinese male patient who was diagnosed with third-degree atrioventricular (AV) block and was admitted in our hospital 33 years ago. An 85-year-old male patient from China was hospitalized due to dizziness and syncope, with an initial diagnosis revealing third-degree AV block with a heart rate of 35-40 beats per minute (bpm) along with Aase's syndrome and primary hypertension. A single-chamber pacemaker (VVI) was implanted immediately giving the patient symptomatic relief. However, 5-year post-surgery VVI was replaced due to battery exhaustion, while the primary electrode catheter was kept in use. Few years later, the patient again complained of dizziness and re-examination revealed VVI battery debilitation due to premature battery exhaustion. Single-chamber pacemaker was again implanted via the same position of right upper chest. However, after adjusting the frequency of stimulation of the pacemaker to 70 bpm, patient had a symptomatic relief. Considering the severity of patient's disease and knowing that cardiac dysfunction was reported previously, a tri-chamber pacemaker was chosen to take place of previous single chamber pacemaker. For 33 years, the patient underwent 7 times replacement of pacemaker for battery exhaustion or inadequacy. We successfully performed overall seven pacemaker implantations and upgradation in an elderly Chinese patient diagnosed with third-degree AV block for 33 years. A long following up till now demonstrated no major complications with normal heart rate functioning. PMID- 26734650 TI - Do we really need additional arms in thoracic surgery? PMID- 26734651 TI - Interfering with the IFN-gamma/CXCL10 pathway to develop new targeted treatments for vitiligo. PMID- 26734652 TI - International ward round: a 10-day academic visit of Professor Eugenio Pompeo in China. PMID- 26734653 TI - Etiology of Cellulitis and Clinical Prediction of Streptococcal Disease: A Prospective Study. AB - Background. The importance of bacteria other than group A streptococci (GAS) in different clinical presentations of cellulitis is unclear, commonly leading to treatment with broad-spectrum antibiotics. The aim of this study was to describe the etiological and clinical spectrum of cellulitis and identify clinical features predicting streptococcal etiology. Methods. We prospectively enrolled 216 patients hospitalized with cellulitis. Clinical details were registered. Bacterial culture was performed from blood, cutaneous or subcutaneous tissue, and/or swabs from skin lesions. Paired serum samples were analyzed for anti streptolysin O and anti-deoxyribonuclease B antibodies. Results. Serology or blood or tissue culture confirmed beta-hemolytic streptococcal (BHS) etiology in 72% (146 of 203) of cases. An additional 13% (27 of 203) of cases had probable BHS infection, indicated by penicillin response or BHS cultured from skin swabs. beta-hemolytic streptococcal etiology was predominant in all clinical subgroups, including patients without sharply demarcated erythema. beta-hemolytic group C or G streptococci (GCS/GGS) were more commonly isolated than GAS (36 vs 22 cases). This predominance was found in the lower extremity infections. Group C or G streptococci in swabs were associated with seropositivity just as often as GAS. Staphylococcus aureus was cultured from swabs as a single pathogen in 24 cases, 14 (64%) of which had confirmed BHS etiology. Individual BHS-associated clinical characteristics increased the likelihood of confirmed BHS disease only slightly; positive likelihood ratios did not exceed 2.1. Conclusions. beta-hemolytic streptococci were the dominating cause of cellulitis in all clinical subgroups and among cases with S aureus in cutaneous swabs. Group C or G streptococci were more frequently detected than GAS. No single clinical feature substantially increased the probability of confirmed BHS etiology. PMID- 26734654 TI - Interobserver agreement for neonatal seizure detection using multichannel EEG. AB - OBJECTIVE: To determine the interobserver agreement (IOA) of neonatal seizure detection using the gold standard of conventional, multichannel EEG. METHODS: A cohort of full-term neonates at risk of acute encephalopathy was included in this prospective study. The EEG recordings of these neonates were independently reviewed for seizures by three international experts. The IOA was estimated using statistical measures including Fleiss' kappa and percentage agreement assessed over seizure events (event basis) and seizure duration (temporal basis). RESULTS: A total of 4066 h of EEG recordings from 70 neonates were reviewed with an average of 2555 seizures detected. The IOA was high with temporal assessment resulting in a kappa of 0.827 (95% CI: 0.769-0.865; n = 70). The median agreement was 83.0% (interquartile range [IQR]: 76.6-89.5%; n = 33) for seizure and 99.7% (IQR: 98.9-99.8%; n = 70) for nonseizure EEG. Analysis of events showed a median agreement of 83.0% (IQR: 72.9-86.6%; n = 33) for seizures with 0.018 disagreements per hour (IQR: 0.000-0.090 per hour; n = 70). Observers were more likely to disagree when a seizure was less than 30 sec. Overall, 33 neonates were diagnosed with seizures and 28 neonates were not, by all three observers. Of the remaining nine neonates with contradictory EEG detections, seven presented with low total seizure burden. INTERPRETATION: The IOA is high among experts for the detection of neonatal seizures using conventional, multichannel EEG. Agreement is reduced when seizures are rare or have short duration. These findings support EEG based decision making in the neonatal intensive care unit, inform EEG interpretation guidelines, and provide benchmarks for seizure detection algorithms. PMID- 26734655 TI - Cervical dystonia caused by focal putaminal ischemia. AB - We describe a 48-year-old woman with putaminal gliosis and a sphenoid wing meningioma at the left, who developed dystonia restricted to cervical regions. We propose the following causal chain: the meningioma led to an occlusion of a lenticulo-striatal branch of the middle cerebral artery that caused ventral putaminal ischemia and finally resulting in symptomatic dystonia. The previously reported relevance of the infarcted regions to the pathophysiology of dystonia supports this assumption. Implications for the diagnostic procedure of dystonia will be discussed. PMID- 26734656 TI - JAML mediates monocyte and CD8 T cell migration across the brain endothelium. AB - Leukocyte transmigration into the central nervous system promotes multiple sclerosis pathogenesis, yet ambiguity remains regarding the mechanisms controlling the migration of distinct immune cell subsets. Using in vitro, ex vivo and postmortem human materials, we identified a significant upregulation of junctional adhesion molecule-like expression at the blood-brain barrier, monocytes, and CD8 T cells of multiple sclerosis patients. We also detected junctional adhesion molecule-like(+) trans-migratory cups when monocytes/CD8 T cells adhered to the blood-brain barrier, however, their migratory capacity was significantly compromised when junctional adhesion molecule-like was blocked. These findings highlight a novel role for junctional adhesion molecule-like in leukocyte transmigration and its potential as a promising therapeutic target. PMID- 26734657 TI - Hypomyelination following deletion of Tsc2 in oligodendrocyte precursors. AB - OBJECTIVE: While abnormalities in myelin in tuberous sclerosis complex (TSC) have been known for some time, recent imaging-based data suggest myelin abnormalities may be independent of the pathognomonic cortical lesions ("tubers"). Multiple mouse models of TSC exhibit myelination deficits, though the cell types responsible and the mechanisms underlying the myelin abnormalities remain unclear. METHODS: To determine the role of alterations in mTOR signaling in myelination, we generated a conditional knockout (CKO) mouse model using Cre recombinase and the Olig2 promoter to inactivate the Tsc2 gene in oligodendrocyte precursor cells. RESULTS: Characterization of myelin and myelin constituent proteins demonstrated a marked hypomyelination phenotype. Diffusion-based magnetic resonance imaging studies were likewise consistent with hypomyelination. Hypomyelination was due in part to decreased myelinated axon density and myelin thickness as well as decreased oligodendrocyte numbers. Coincident with hypomyelination, an extensive gliosis was seen in both the cortex and white matter tracks, suggesting alterations in cell fate due to changes in mTOR activity in oligodendrocyte precursors. Despite a high-frequency appendicular tremor and altered gait in CKO mice, no significant changes in activity, vocalizations, or anxiety-like phenotypes were seen. INTERPRETATION: Our findings support a known role of mTOR signaling in regulation of myelination and demonstrate that increased mTORC1 activity early in development within oligodendrocytes results in hypomyelination and not hypermyelination. Our data further support a dissociation between decreased Akt activity and increased mTORC1 activity toward hypomyelination. Thus, therapies promoting activation of Akt-dependent pathways while reducing mTORC1 activity may prove beneficial in treatment of human disease. PMID- 26734658 TI - Diazepam effect during early neonatal development correlates with neuronal Cl(.). AB - OBJECTIVE: Although benzodiazepines and other GABAA receptors allosteric modulators are used to treat neonatal seizures, their efficacy may derive from actions on subcortical structures. Side effects of benzodiazepines in nonseizing human neonates include myoclonus, seizures, and abnormal movements. Excitatory actions of GABA may underlie both side effects and reduced anticonvulsant activity of benzodiazepines. Neocortical organotypic slice cultures were used to study: (1) spontaneous cortical epileptiform activity during early development; (2) developmental changes in [Cl(-)]i and (3) whether diazepam's anticonvulsant effect correlated with neuronal [Cl(-)]i. METHODS: Epileptiform activity in neocortical organotypic slice cultures was measured by field potential recordings. Cl(-) changes during development were assessed by multiphoton imaging of neurons transgenically expressing a Cl-sensitive fluorophore. Clinically relevant concentrations of diazepam were used to test the anticonvulsant effectiveness at ages corresponding to premature neonates through early infancy. RESULTS: (1) Neocortical organotypic slices at days in vitro 5 (DIV5) exhibited spontaneous epileptiform activity. (2) Epileptiform event duration decreased with age. (3) There was a progressive decrease in [Cl(-)]i over the same age range. (4) Diazepam was ineffective in decreasing epileptiform activity at DIV5-6, but progressively more effective at older ages through DIV15. (5) At DIV5-6, diazepam worsened epileptiform activity in 50% of the slices. INTERPRETATION: The neocortical organotypic slice is a useful model to study spontaneous epileptiform activity. Decreasing [Cl(-)]i during development correlates with decreasing duration of spontaneous epileptiform activity and increasing anticonvulsant efficacy of diazepam. We provide a potential explanation for the reports of seizures and myoclonus induction by benzodiazepines in newborn human neonates and the limited electrographic efficacy of benzodiazepines for the treatment of neonatal seizures. PMID- 26734659 TI - Pioglitazone regulates myelin phagocytosis and multiple sclerosis monocytes. AB - OBJECTIVE: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Myeloid phagocytes, including blood monocytes recruited to demyelinating lesions, may play a dual role in MS: on one hand, they might enhance CNS damage after differentiating toward a proinflammatory phenotype; on the other, they promote remyelination and repair through effective phagocytosis of myelin debris. We have previously determined that the retinoid X receptor (RXR) plays an important role in monocyte phagocytosis of myelin. Peroxisome proliferator-activated receptor gamma is an RXR binding partner that plays a key role in myeloid cell biology and is targeted by the thiazolidinedione group of antidiabetics such as pioglitazone. Consequently, the purpose of this study was to determine if monocyte functions and differentiation profiles differ in MS patients compared to healthy volunteers (HV) and whether pioglitazone can reverse these differences to promote CNS recovery. METHODS: Monocytes were isolated from MS patients and HV (n >= 36/group), and their ability to phagocytose myelin and modulate inflammation in the presence/absence of 1 MUmol/L pioglitazone (the in vivo achievable concentration) was quantified by flow cytometry, transcriptional profiling, and proteomic assays. RESULTS: MS monocytes display impaired phagocytosis of myelin debris and enhanced proinflammatory differentiation. Pioglitazone treatment causes partial normalization of identified monocyte abnormalities in MS and fully reverses the deficit in myelin phagocytosis. INTERPRETATION: These findings suggest that by inhibiting proinflammatory differentiation of monocytes and enhancing their phagocytosis of myelin, pioglitazone may be a useful adjunct therapy to immunomodulatory agents that target dysregulated adaptive immunity in MS. PMID- 26734660 TI - Suppression of agrin-22 production and synaptic dysfunction in Cln1 (-/-) mice. AB - OBJECTIVE: Oxidative stress in the brain is highly prevalent in many neurodegenerative disorders including lysosomal storage disorders, in which neurodegeneration is a devastating manifestation. Despite intense studies, a precise mechanism linking oxidative stress to neuropathology in specific neurodegenerative diseases remains largely unclear. METHODS: Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative lysosomal storage disease caused by mutations in the ceroid lipofuscinosis neuronal-1 (CLN1) gene encoding palmitoyl-protein thioesterase-1. Previously, we reported that in the brain of Cln1 (-/-) mice, which mimic INCL, and in postmortem brain tissues from INCL patients, increased oxidative stress is readily detectable. We used molecular, biochemical, immunohistological, and electrophysiological analyses of brain tissues of Cln1 (-/-) mice to study the role(s) of oxidative stress in mediating neuropathology. RESULTS: Our results show that in Cln1 (-/-) mice oxidative stress in the brain via upregulation of the transcription factor, CCAAT/enhancer-binding protein-delta, stimulated expression of serpina1, which is an inhibitor of a serine protease, neurotrypsin. Moreover, in the Cln1 (-/-) mice, suppression of neurotrypsin activity by serpina1 inhibited the cleavage of agrin (a large proteoglycan), which substantially reduced the production of agrin 22, essential for synaptic homeostasis. Direct whole-cell recordings at the nerve terminals of Cln1 (-/-) mice showed inhibition of Ca(2+) currents attesting to synaptic dysfunction. Treatment of these mice with a thioesterase-mimetic small molecule, N-tert (Butyl) hydroxylamine (NtBuHA), increased agrin-22 levels. INTERPRETATION: Our findings provide insight into a novel pathway linking oxidative stress with synaptic pathology in Cln1 (-/-) mice and suggest that NtBuHA, which increased agrin-22 levels, may ameliorate synaptic dysfunction in this devastating neurodegenerative disease. PMID- 26734661 TI - Neuroprotective effects of deep hypothermia in refractory status epilepticus. AB - OBJECTIVE: Pharmacoresistance develops quickly during repetitive seizures, and refractory status epilepticus (RSE) remains a therapeutic challenge. The outcome of RSE is poor, with high mortality and morbidity. New treatments are needed. Deep hypothermia (20 degrees C) is used clinically during reconstructive cardiac surgery and neurosurgery, and has proved safe and effective in those indications. We tested the hypothesis that deep hypothermia reduces RSE and its long-term consequences. METHODS: We used a model of SE induced by lithium and pilocarpine and refractory to midazolam. Several EEG measures were recorded in both hypothermic (n = 17) and normothermic (n = 20) animals. Neuronal injury (by Fluoro-Jade B), cell-mediated inflammation, and breakdown of the blood-brain barrier (BBB) (by immunohistochemistry) were studied 48 h following SE onset. RESULTS: Normothermic rats in RSE seized for 4.1 +/- 1.1 h, and at 48 h they displayed extensive neuronal injury in many brain regions, including hippocampus, dentate gyrus, amygdala, entorhinal and pyriform cortices, thalamus, caudate/putamen, and the frontoparietal neocortex. Deep hypothermia (20 degrees C) of 30 min duration terminated RSE within 12 min of initiation of hypothermia, reduced EEG power and seizure activity upon rewarming, and eliminated SE-induced neuronal injury in most animals. Normothermic rats showed widespread breakdown of the BBB, and extensive macrophage infiltration in areas of neuronal injury, which were completely absent in animals treated with hypothermia. INTERPRETATION: These results suggest that deep hypothermia may open a new therapeutic avenue for the treatment of RSE and for the prevention of its long-term consequences. PMID- 26734662 TI - Quantified CSF antibody reactivity against myelin in multiple sclerosis. AB - BACKGROUND: Synthesis of clonal IgG is a consistent feature of patients with multiple sclerosis (MS). Whether oligoclonal bands (OCBs) represent unspecific disease bystanders or active components in MS pathology is an open question. The aim of this study was to develop a method to quantify and compare the reactivity of cerebrospinal fluid (CSF) antibodies from patients with and without MS. METHODS: We collected CSF from 262 patients from two different cohorts, which included 148 patients with MS and 114 with other neurological diseases (OND). We established a highly sensitive electrochemiluminescence (ECL)-based assay to measure CSF antibody reactivity against purified myelin particles and biotin anchored liposomes. The diagnostic value of the ECL score against myelin particles was assessed with receiver operating characteristic curves. RESULTS: CSF from patients with MS have higher reactivity toward purified myelin particles as compared to those with OND with OCBs. Using liposomes with defined lipid compositions and myelin particles from ceramide synthase 2 (CerS2) knockout mice, we find that some of the CSF antibody reactivity is directed against cerebrosides. CONCLUSION: The ECL-based assay system expands the currently available toolbox for the detection of autoantibodies in MS and related diseases. PMID- 26734664 TI - Editorial: "You could look more attractive!". PMID- 26734663 TI - Young-onset frontotemporal dementia in a homozygous tau R406W mutation carrier. AB - Microtubule-associated protein tau mutations result in 10-20% of cases of genetic frontotemporal lobar degeneration. Tau mutation carriers typically develop behavioral variant frontotemporal dementia with or without parkinsonism. Unlike most frontotemporal dementia gene mutations, heterozygous R406W tau mutation carriers most often develop clinical Alzheimer's disease. We report a homozygous tau R406W mutation carrier with behavioral variant frontotemporal dementia who developed symptoms 20 years before mean family symptom onset. Voxel-based morphometry showed frontoinsular, frontal, and mesial temporal cortical atrophy. Homozygous tau R406W mutations appear to accelerate symptom onset and drive a behavioral variant frontotemporal dementia syndrome. PMID- 26734665 TI - Virtual smile design systems: a current review. AB - In the age of digital dentistry, virtual treatment planning is becoming an increasingly important element of dental practice. Thanks to new technological advances in the computer- assisted design and computer-assisted manufacturing (CAD/CAM) of dental restorations, predictable interdisciplinary treatment using the backward planning approach appears useful and feasible. Today, a virtual smile design can be used as the basis for creating an esthetic virtual setup of the desired final result. The virtual setup, in turn, is used to plan further treatment steps in an interdisciplinary team approach, and communicate the results to the patient. The smile design concept and the esthetic analyses required for it are described in this article. We include not only a step-by-step description of the virtual smile design workflow, but also describe and compare the several available smile design options and systems. Subsequently, a brief discussion of the advantages and limitations of virtual smile design is followed by a section on different ways to integrate a two-dimensional (2D) smile design into the digital three-dimensional (3D) workflow. New technological developments are also described, such as the integration of smile designs in digital face scans, and 3D diagnostic follow-up using intraoral scanners. PMID- 26734666 TI - A three-dimensional morphometric study on the position of temporomandibular joints. AB - OBJECTIVES: To address the controversy, in which indications average value articulation is suitable or to what extent individual registrations, especially using the facebow, should be applied, a quantification of the variability of relevant anatomical landmarks is necessary. The goal of this study was to investigate the mean and natural bandwidth of the parameters describing articulation. METHODS: Significant landmarks were measured on three-dimensional (3D) cone beam computed tomography (CBCT) scans of 120 arbitrarily selected individuals. The bandwidth and mean values of the anatomical relations were calculated. RESULTS: The mean arm length of the Bonwill triangle was 103.3 mm, with a range of 90.2 mm (minimum) to 117.9 mm (maximum), and a mean base length of 99.6 mm, with a range of 85.2 mm to 112.6 mm. There was a high correlation between the length of the left and right arms, but not between the arms and the base. The mean height of the Bonwill triangle, measured between the condyles and the occlusal plane, resulted in 34.3 mm, with a range of 21.0 mm to 47.2 mm. The mean value of the Balkwill angle was 20.4 degrees, with a range of 9.0 degrees to 27.6 degrees. The angle between the Camper's line and the occlusal plane averaged around 7 degrees. CONCLUSIONS: This study presents the bandwidth of anatomical relations necessary for articulation systems. The results are specific for males and females. The relevant parameters offer a high symmetry between the right and left sides. Additionally, the results show that the Bonwill triangle is more likely to be isosceles than equilateral. CLINICAL SIGNIFICANCE: The knowledge of the anatomical bandwidth of temporomandibular joint (TMJ) positions in relation to the dentition allows the simulation of software- controlled virtual articulators and the substitution of facebows. PMID- 26734667 TI - "Anatomical simulation" of the biomechanical behavior of the human mandible. AB - INTRODUCTION: The load-carrying behavior of the human mandible can be described using finite element simulation, enabling investigations about physiological and pathological skeletal adaption. "Anatomical simulation" implies a stepwise approximation towards the anatomical reality. METHOD: The project is structured in three steps. In Step 1, the preprocessing, the simulation model is provided. Step 2 is the numerical computation. Step 3 is dedicated to the interpretation of the results. The requirements of the preprocessing are: a) realization of the organ's individual anatomy, namely its outer shape; b) the tissue's elastic properties, thus its inner consistency; and c) the organ's mechanical loads. For physiological mandibular loading, these are due to muscles, temporomandibular joints, and tooth forces. Meanwhile, the reconstruction of the macroscopic anatomy from computed tomography data is standard. The periodontal ligament is inserted ex post using an approach developed by the authors. The bone is modeled anisotropically and inhomogeneously. By the visualization of the individual fiber course, the muscular force vectors are realized. The mandibular condyle is freely mobile in a kind of simplified joint capsule. For the realization of bite forces, several approaches are available. RESULTS: An extendible software tool is provided, enabling the user - by variable input of muscle and bite forces - to examine the individual patient's biomechanics, eg, the influence of the periodontal ligament, the condition of the temporomandibular joints, atrophic processes, or the biomechanical situation of dental implants. DISCUSSION: By stepwise approximation towards the anatomical reality, the mandibular simulation will be advanced to a valuable tool for diagnosis and prognosis. PMID- 26734668 TI - Understanding dental CAD/CAM for restorations--accuracy from a mechanical engineering viewpoint. AB - As is the case in the field of medicine, as well as in most areas of daily life, digital technology is increasingly being introduced into dental practice. Computer-aided design/ computer-aided manufacturing (CAD/CAM) solutions are available not only for chairside practice but also for creating inlays, crowns, fixed partial dentures (FPDs), implant abutments, and other dental prostheses. CAD/CAM dental practice can be considered as the handling of devices and software processing for the almost automatic design and creation of dental restorations. However, dentists who want to use dental CAD/CAM systems often do not have enough information to understand the variations offered by such technology practice. Knowledge of the random and systematic errors in accuracy with CAD/CAM systems can help to achieve successful restorations with this technology, and help with the purchasing of a CAD/CAM system that meets the clinical needs of restoration. This article provides a mechanical engineering viewpoint of the accuracy of CAD/ CAM systems, to help dentists understand the impact of this technology on restoration accuracy. PMID- 26734669 TI - Monolithic bridges with inCoris TZI and inCoris TZI C. AB - Until now, the ability to fabricate definitive Cerec bridges for the posterior region was less a question of the capabilities of the Cerec software than the availability of ceramic materials with sufficient strength for these indications. With the launch of the somewhat translucent inCoris TZI zirconia, Sirona has made possible the computer-assisted design and computer- assisted manufacturing (CAD/CAM) of monolithic bridges using Cerec dental software. In this article, the possibilities and limitations of inCoris TZI, as well as inCoris TZI C (a recently introduced further development from Sirona), will be demonstrated, based on two clinical cases. PMID- 26734670 TI - Obituary: Prof. (TV) h.c. Dr. med. dent. Peter Schletter. PMID- 26734671 TI - The Importance of Citations and Citation Metrics in Science. PMID- 26734672 TI - Shear Bond Strength and Microleakage of a New Self-etching/Self-adhesive Pit and Fissure Sealant. AB - PURPOSE: To evaluate shear bond strength and microleakage of a new self etching/self-adhesive fissure sealant on prismless enamel compared with conventional fissure sealing. MATERIALS AND METHODS: A total of 90 extracted third molars were assigned to 3 main groups: group 1: self-etching/self-adhesive sealant, without acid etching; group 2: self-etching/self-adhesive sealant, with prior acid etching; group 3: conventional fissure sealing (control group). After specimen preparation, each group was divided into 3 subgroups according to storage time (1-day water storage, 3-month water storage, and 1-day water storage followed by 5000x thermocycling). The shear bond strength was determined with a universal testing machine, according to ISO standard 29022. Afterwards, the failure mode was analyzed. An additional 24 third molars were used for microleakage assessment. The fissure pattern was sealed in strict accordance with the manufacturers' instructions. After thermocycling, the dye penetration was examined. Data were analyzed using the Mann-Whitney U-Test at a significance level of 0.05. RESULTS: The shear bond strength of the self-etching/self-adhesive fissure sealant without prior acid etching was significantly lower (4.3 MPa) than that of the self-etching/self-adhesive fissure sealant with prior acid etching (17.1 MPa) and the conventional fissure sealing (19.1 MPa). Microleakage was significantly lower in the control group (1.1%) and in the group with the self etching/self-adhesive sealant with prior acid etching (0.8%) compared to the group that used the self-etching/self-adhesive material alone (49.4%). CONCLUSION: The self-etching/self-adhesive fissure sealant can be recommended for clinical use when enamel is etched with phosphoric acid. The self-etching/self adhesive sealant without prior acid etching showed significantly inferior results. PMID- 26734673 TI - Effect of Different Antioxidants on the Microtensile Bond Strength of an Adhesive System to Sodium Hypochlorite-treated Dentin. AB - PURPOSE: To evaluate the effects of different antioxidant treatments on the microtensile bond strength of an adhesive system to sodium hypochlorite (NaOCl) treated dentin. MATERIALS AND METHODS: Thirty extracted third molars were sectioned 3 mm below the occlusal surface and divided into six groups according to the antioxidant treatment received: control group: distilled water; NaOCl group: 5.25% NaOCl and distilled water; proanthocyanidin (PA) group: 5.25% NaOCl, 5% PA and distilled water; 1-week storage group: 5.25% NaOCl and storage for 1 week in distilled water; Accel group: 5.25% NaOCl, Accel, and distilled water; noni group: 5.25% NaOCl, noni fruit juice, and distilled water. NaOCl, PA, Accel, noni, and distilled water were administered for 30 s, 10 min, 30 s, 10 min, and 30 s, respectively. A self-etching adhesive system (Single Bond Universal Adhesive) was applied to each specimen and a resin composite (Filtek Z550) was built up to a height of 5 mm on the dentin surface. Each specimen was serially sectioned to obtain sticks with a cross-sectional area of 1 mm2, and their microtensile bond strength was determined. Statistical differences between groups were analyzed using one-way ANOVA and Tamhane's T2 test. RESULTS: Microtensile bond strength in the NaOCl group was significantly lower than in all other groups. However, there were no significant differences in the bond strength between the groups treated with different antioxidants. CONCLUSIONS: NaOCl significantly reduced the microtensile bond strength of the adhesive system. The application of PA, Accel, and noni fruit juice to NaOCl-treated dentin significantly improved the microtensile bond strength. PMID- 26734674 TI - Shear Bond Strength of Self-etching Adhesives to Cavities Prepared by Diamond Bur or Er,Cr:YSGG Laser and Effect of Prior Acid Etching. AB - PURPOSE: To compare and evaluate shear bond strength of self-etching adhesives bonded to cavities prepared by diamond bur or Er,Cr:YSGG laser and the effect of prior acid etching on shear bond strength. MATERIALS AND METHODS: Ninety-six caries-free human premolars were selected and divided into 2 groups depending on mode of cavity preparation (48 teeth each). Cavities were prepared with Er,Cr:YSGG laser in group 1 and diamond burs in an air-turbine handpiece in group 2. Groups 1 and 2 were further subdivided into three subgroups of 8 teeth each, which were bonded with sixth- or seventh-generation adhesives with or without prior acid etching, followed by restoration of all samples with APX Flow. These samples were subjected to shear bond strength testing. In addition, the surface morphology of 24 samples each from groups 1 and 2 was evaluated using SEM. Data were analyzed using the Shapiro-Wilk test, one- and two-way ANOVA, the t-test, and the least significant difference test, which showed that the data were normally distributed (p > 0.05). RESULTS: The shear bond strength of adhesives in cavities prepared by Er,Cr:YSGG laser was significantly higher than in diamond bur-prepared cavities (p < 0.05). SEM analysis showed a smear-layer-free anfractuous surface on laser-ablated teeth, in contrast to conventional bur prepared teeth. CONCLUSIONS: The Er,Cr:YSGG laser-ablated surface proved to be more receptive for adhesion than those prepared by diamond bur irrespective of the bonding agent used. Seventh-generation adhesives yielded higher shear bond strength than did sixth-generation adhesives. Prior acid etching decreased the shear bond strength of self-etching adhesives. PMID- 26734675 TI - Does Making An Adhesive System Radiopaque by Filler Addition Affect Its Bonding Properties? AB - PURPOSE: To evaluate the radiopacity, bond strength, and micromorphology of experimental filled dental adhesives. MATERIALS AND METHODS: Five experimental filled dental adhesives with different concentrations of radiopaque barium borosilicate glass (wt%) [0 (R0), 30 (R30), 40 (R40), 50 (R50), and 60 (R60)] and the commercial adhesive Adper Single Bond 2 were used in this study. Specimens were prepared by dispensing the uncured resin into a mold (5.0 mm x 1.0 mm). Digital radiographs (n = 5) of both 1-mm-thick adhesive specimens and tooth were taken with a CCD sensor. The gray levels of enamel, dentin, and adhesive systems were measured by histogram analysis and compared. Adhesives were applied to flat dentin surfaces of third molars (n = 7). Resin composite buildups were constructed and sectioned to obtain resin-dentin bonded sticks to test immediately or after 6 months of water storage. Three specimens for each tooth were qualitatively analyzed using scanning electron microscopy. Data on bond strength and radiopacity were evaluated by two-way and one-way ANOVA, respectively, and Tukey's test (alpha = 0.05). RESULTS: All experimental filled dental adhesives showed radiopacity similar to enamel (p > 0.05) and most yielded significant reductions of bond strength over time. However, the R30 produced a radiopaque material without jeopardizing the bonding of the material to the dentin substrate. CONCLUSIONS: The addition of 30% barium-borosilicate oxide produced radiopaque adhesives without jeopardizing the bonding to the dental substrate. PMID- 26734676 TI - Evaluation of the Effect of Different Surface Treatments on Luting CAD/CAM Composite Resin Overlay Workpieces. AB - PURPOSE: To evaluate the effect of different surface treatments on luting CAD/CAM composite resin workpieces. MATERIALS AND METHODS: One-hundred eight (108) composite CAD/CAM block sections (Lava Ultimate) 3 mm in thickness were polished up to 4000 grit and then randomly assigned to 6 experimental groups according to the applied surface treatment (no treatment, sodium bicarbonate [NaHCO3], glycine, alumina [Al2O3], CoJet, and SilJet). After standardized sandblasting procedures, 2 block sections from each group were randomly chosen for the qualitative SEM evaluation of the sandblasted surfaces. The remaining 96 CAD/CAM block sections were luted in pairs using a bonding agent (Single Bond) and a restorative composite resin (Filtek Ultimate). Specimens were aged for 2 weeks in 37 degrees C water with 3000 thermal cycles (5 degrees C/55 degrees C), the microtensile test was performed (n = 30), and the values were statistically analyzed with ANOVA and Tukey's HSD post-hoc test (p = 0.05). RESULTS: The qualitative SEM evaluation of the sandblasted surfaces showed that sodium bicarbonate and glycine had almost no conditioning effect on the CAD/CAM composite resin. In contrast, aluminum oxide, CoJet, and SilJet had a profound conditioning effect on the CAD/CAM composite resin. No treatment, sodium bicarbonate, and glycine specimens were debonded after thermal stressing (0 MPa), while aluminum oxide, CoJet, and SilJet showed high microtensile values (Al2O3: 104.45 +/- 18.76 MPa; CoJet: 105.55 +/- 11.88 MPa; SilJet: 105.02 +/- 20.84 MPa), which were not statistically significantly different from each other. CONCLUSION: Aluminum oxide-based sandblasting powders are the best choice for the surface treatment of CAD/ CAM workpieces. PMID- 26734677 TI - Transenamel and Transdentinal Penetration of H2O2 in Restored Bovine Teeth. AB - PURPOSE: To quantify hydrogen peroxide (H2O2) penetration into restored bovine teeth subjected to whitening treatment. MATERIALS AND METHODS: Seventy-five enamel/dentin disks were divided into 5 groups (n = 15): intact disks (G1); cavity preparation only (G2); conventional adhesive system and composite resin (G3); resin-modified glass-ionomer cement (G4); and self-etching adhesive only (G5). After 24 h, the disks were placed into artificial pulp chambers containing an acetate buffer solution, and the first whitening session was performed using a 35% H2O2 (hydrogen peroxide) product. The disks were submitted to 10,000 thermal cycles and then stored for 1 year in deionized water. After this period, a second whitening session was performed. After each whitening procedure, the buffer solutions were analyzed for optical density in a spectrophotometer to assess the amount of H2O2 that had diffused. ANOVA and Tukey's test were used to compare the different groups and a Student's t-test was used to compare the different times (p <= 0.05). RESULTS: Prior to aging, group 2 had the highest penetration of H2O2; the other groups showed similar, lower penetration. After thermocycling and aging, all groups showed a significant increase in H2O2 penetration. The greatest penetration of H2O2 into the pulp chamber was found in groups 2 and 5. CONCLUSION: Aged restorations allowed greater H2O2 permeation through the tooth structure. PMID- 26734678 TI - Evaluation of Microtensile Bond Strength and Microleakage of a Self-adhering Flowable Composite. AB - PURPOSE: To evaluate the microtensile bond strength (MUTBS) and marginal sealing ability of a self-adhering flowable composite between dentin and composite interfaces, as well as the microleakage of Class V restorations. MATERIALS AND METHODS: The occlusal thirds of 40 third molars were removed and randomly divided into 4 groups according to the applied adhesive: Adper Easy One (AEO, 3M ESPE), Clearfil SE Bond (CSEB, Kuraray), Prime & Bond NT (PBNT, Dentsply) and a self adhering flowable composite (Dyad Flow, DF, Kerr). Filtek Flowable (3M ESPE) resin composite crowns were then built up in the first three groups; in group DF, composite crowns were built up without the application of an adhesive. Thirty stick-shaped microspecimens were prepared per group, 10 of which were used for morphological observation of bonded interfaces by scanning electron microscopy (SEM) after decalcification. The remaining microspecimens underwent microtensile bond strength testing and the failure mode was analyzed. Microleakage evaluation was performed on 10 premolars per group in which standardized box-shaped Class V cavities were prepared. After 500 thermocycles, the premolars were immersed in 1% methylene blue for 24 h, and three slices from each tooth were observed under a stereomicroscope and scored. Statistical analysis was performed using one-way ANOVA, Student-Newman-Keuls and chi-square tests. RESULTS: The PBNT group presented the highest MUTBS values, followed by the CSEB and AEO groups, which did not differ significantly from each other. The DF group showed the lowest MUTBS values. No significant differences in microleakage were observed among these four groups. CONCLUSION: Although individual usage of the self-adhering flowable composite showed the lowest bond strength, the same marginal sealing ability was observed as that of combining self-etching and etch-and-rinse adhesives with flowable composite. PMID- 26734679 TI - Effect of Storage Temperature on the Shelf Life of Self-adhesive Resin Cements. AB - PURPOSE: To compare the bonding performance of three new self-adhesive resin cements to human dentin after storage under two different conditions. MATERIALS AND METHODS: Buccal, lingual, mesial, and distal dentin surfaces of 36 human molars were abraded to directly below the enamel with #600 SiC papers. The teeth were divided into two main test groups. In the first test group (FT), the cements were kept in a refrigerator (6 +/- 2 degrees C) for three months and then used for the test. The remainder of the cements was kept at a constant room temperature of 19 +/- 2 degrees C for an additional three months, and then used again for the second test group (ST). Each test group comprised 6 teeth and 24 dentin sections. The cements Clearfil SA (CSA), G-Cem (GC), and Bis-Cem (BC) were applied to the surfaces according to the manufacturers' recommendations. After application of the cements to the flat dentin surfaces and light curing, shear bond strengths were determined at a crosshead speed of 0.5 mm/min. Bond strengths were then calculated and expressed in MPa. Data were analyzed with Kruskal-Wallis and Wilcoxon Signed Rank tests. To investigate the cement/ dentin interfaces using SEM, the buccal surfaces of three additional teeth were used for each test group. RESULTS: The bond strength values of cement groups were significantly different for the FT and ST groups (p < 0.01). GC showed the highest bond strength values of all materials. There was a difference between the bond strength values of the two testing periods for all materials (p < 0.01). Bond strengths significantly decreased after storage at room temperature. CONCLUSION: Storage temperatures considerably affect the shelf life of self-adhesive resin cements. PMID- 26734680 TI - Zirconia Surface Treatments for Resin Bonding. AB - PURPOSE: To evaluate the bond strength of resin to zirconia treated with different surface conditioning methods. MATERIALS AND METHODS: Sintered zirconia was surface treated to create 7 groups. Ceramic liner (L) was fired onto three groups of zirconia and subsequently received the following treatments: hydrofluoric acid etching (L/ HFE), alumina particle abrasion (L/APA), and alumina particle abrasion with hydrofluoric acid etching (L/APAHFE). All three groups were silane treated immediately prior to bonding. Two other zirconia groups received alumina particle abrasion with and without silane coupling (AP-S and AP). Another group underwent selective infiltration etching, in which the specimens received porcelain powder firing, ultrasonic etching with HF for 15 min, then rinsing under running water for 15 min, followed by silane treatment (SIE). The control group was zirconia as-sintered (ZAS). Twenty composite resin cylinders were luted to each group with a resin cement. Each group was divided into two subgroups (n=10) and subjected to 2 storage conditions: 24 h water storage or 21 days with 6000 thermocycles between 5 degrees C and 55 degrees C. Shear bond strength testing (SBS) was performed, followed by statistical analysis of the results using one-way ANOVA (p < 0.05). RESULTS: After 21 days of thermocycling, AP and ZAS groups spontaneously debonded prior to testing. The remaining groups showed a decrease in mean shear bond strength between 11.7% and 58.5% after thermocycling, except the L/HFE group, which increased by 11.7%. L/HFE showed the highest bond strength at both test intervals, and at 21 days was significantly higher than that of the AP-S and L/APA-HFE groups, which in turn were higher than that of the L/APA group, which was higher than that of the SIE group (p < 0.05). CONCLUSION: The etched, fired ceramic liner with silane treatment provided the strongest and most durable bond under the conditions tested. Alumina particle abrasion degraded the durability of the ceramic liner. Alumina particle abrasion, as-sintered zirconia, and SIE did not provide durable bond strengths. PMID- 26734681 TI - Heat Treatment Influences Monomer Conversion and Bond Strength of Indirect Composite Resin Restorations. AB - PURPOSE: To assess the resin microtensile bond strength (MTBS) and the degree of conversion (DC) of indirect composite resin restorations polymerized with light and heat. MATERIALS AND METHODS: Two direct (Filtek Z100 and Premise) and one indirect (Premise Indirect) composite resins were polymerized with a combination of light and heat (138 degrees C for 20 min). For MTBS, 42 cylinders were fabricated (n = 7). After the surface treatment, cylinders were bonded to each other using adhesive resin (Optibond FL). Specimens were stored in water for 24 h. Another 15 cylinders (n = 5) were fabricated for determining degree of conversion using Fourier Transform Infrared Spectrometry immediately and at 24 h. The MTBS and the DC was submitted to two-way ANOVA. The interaction with existing data was explored with univariate ANOVA and two-way ANOVA. Tukey's HSD post-hoc test was used to detect pairwise differences (alpha = 0.05). RESULTS: The MTBS to light and heat polymerized Z100 was 75.7 MPa, significantly higher than that to Premise (58.6 MPa) and Premise Indirect (63.9 MPa). The immediate DC for Z100, Premise, and Premise Indirect were 51.0%, 68.7%, and 61.8%, respectively. The DC at 24 h ranged from 53.4% (Z100) to 72.8% (Premise Indirect) and significantly increased for Premise Indirect only. Comparison with previously published data revealed that the heat treatment increased both MTBS and DC of Premise and Premise Indirect. CONCLUSION: Z100 showed better bond strength but lower DC. Heat treatment and a 24-h delay before delivery can benefit DC of Premise Indirect. The increase in DC of Premise and Premise Indirect did not affect their bond strength. PMID- 26734682 TI - Restoring Nonvital Premolars with Composite Resin Onlays: Effect of Different Fiber-reinforced Composite Layers on Marginal Adaptation and Fracture Load. AB - PURPOSE: To evaluate the marginal adaptation and fracture load of composite resin onlays reinforced with different substructures. MATERIALS AND METHODS: Thirty-two extracted, caries-free premolars were selected for this study and endodontically treated. Group 1 was used as the control group, and the teeth were restored only with as-manufactured composite resin overlays. Group 2 teeth were restored with composite resin overlays with 3 fiber-reinforced composite (FRC) layers placed horizontally on the bottom of the restoration. Group 3 teeth were restored with composite resin overlays with 6 fiber-reinforced composite (FRC) layers placed as in group 2. Group 4 teeth were restored with composite resin overlays and FRC placed with an anatomical design. All specimens underwent SEM evaluation of their marginal adaptation before and after thermocycling and cyclic mechanical loading. All specimens were then subjected to a fracture test, recording the value for the initial (IF) and final (FF) failure. Differences in the means were compared using matched-pairs t-tests and one-way ANOVA. The level of significance was set at alpha = 0.05. RESULTS: No statistically significant difference between the four groups in terms of marginal adaptation was observed at the tooth/luting composite and luting composite/overlay interfaces before and after loading. The fracture loads of IF and FF, from most to least resistant were: group 4 (1431.8 +/- 294.3 N/1710.1 +/- 326.6 N), group 3 (1428.1 +/- 251.4 N/1467.9 +/- 242.4 N), group 2 (852.6 +/- 413.5 N/1058.1 +/- 251.5 N) and group 1 (899.8 +/- 352.7 N/923.5 +/- 318.8 N). Significant differences (p = 0.026) were observed comparing group 1 to groups 2 and 3, and group 1 to 4. Three irreparable fractures were found in group 3, four in group 2, and five in groups 1 and 4. CONCLUSIONS: The presence or absence of reinforcement and the different configuration of the reinforcement fibers affect fracture strength but only partially the failure modality. The presence or absence of reinforcement does not alter marginal adaptation. PMID- 26734684 TI - Protocol for Removal of Clinically Relevant Contaminants from Zirconium Dioxide Fixed Dental Prostheses. PMID- 26734688 TI - A ratiometric fluorescent probe for detection of biogenic primary amines with nanomolar sensitivity. AB - An ultrasensitive ratiometric fluorescent sensor made of an N,N dimethylaminonaphthalene anhydride moiety for detection of aliphatic primary amines is reported. Biogenic amines at nanomolar concentration is detected with the additional ability to discriminate between primary, secondary and tertiary amines by using both UV-Visible and fluorescence spectroscopy. PMID- 26734690 TI - The application of fluorescence-conjugated pyrrole/imidazole polyamides in the characterization of protein-DNA complex formation. AB - N-Methylpyrrole (Py)-N-methylimidazole-(Im) polyamides are sequence-specific DNA binding modules that are widely used for gene regulation, as synthetic transcriptional factors and as sequence-specific DNA alkylating agents. Recently, Py-Im polyamides have been conjugated with fluorophores, resulting in conjugates that are useful for the detection of specific DNA sequences. A Forster resonance energy transfer has been observed between Cy3- and Cy5-conjugated Py-Im polyamides on the nucleosome, indicating that fluorescence-conjugated Py-Im polyamides could possibly be used to characterise protein-DNA complexes. In this minireview, we discuss recent reports regarding fluorescence-conjugated Py-Im polyamides and their future application in the characterization of protein-DNA complex formation. PMID- 26734691 TI - The magnetic and crystal structures of Sr1-deltaFeO2-xFx, a new oxyfluoride. AB - A new quasi-two-dimensional oxyfluoride, Sr1-deltaFeO2-xFx, has been successfully synthesized by combining topotactic fluoridation and CaH2 reduction. The introduction of F through this synthesis provides a new route to introducing charge carriers into the square layered lattice through the formation of Fe(1+) ions. While the average crystal symmetry and magnetic structure remain the same as in the parent compound, the addition of F results in an enhanced buckling of the Fe(O/F)2 square plaquettes that is most likely topologically driven. PMID- 26734689 TI - Uncovering biologically significant lipid isomers with liquid chromatography, ion mobility spectrometry and mass spectrometry. AB - Understanding how biological molecules are generated, metabolized and eliminated in living systems is important for interpreting processes such as immune response and disease pathology. While genomic and proteomic studies have provided vast amounts of information over the last several decades, interest in lipidomics has also grown due to improved analytical technologies revealing altered lipid metabolism in type 2 diabetes, cancer, and lipid storage disease. Mass spectrometry (MS) measurements are currently the dominant approach for characterizing the lipidome by providing detailed information on the spatial and temporal composition of lipids. However, interpreting lipids' biological roles is challenging due to the existence of numerous structural and stereoisomers (i.e. distinct acyl chain and double-bond positions), which are often unresolvable using present approaches. Here we show that combining liquid chromatography (LC) and structurally-based ion mobility spectrometry (IMS) measurement with MS analyses distinguishes lipid isomers and allows insight into biological and disease processes. PMID- 26734692 TI - Synthesis of di-, tri- and tetracyclopropylhydrazines. AB - Previously unknown 1,1-dicyclopropylhydrazine was obtained in two steps starting from dicyclopropylamine. It serves as a convenient starting material to tri- and tetracyclopropylhydrazines, which have not been described in the literature either. Tricyclopropylhydrazine was prepared in an overall four-step sequence featuring the de Meijere-Chaplinski modification of the Kulinkovich reaction as a key step. Tetracyclopropylhydrazine was obtained by the reductive amination of the cyclopropanone ethyl trimethylsilyl acetal with 1,1-dicyclopropylhydrazine or with the parent hydrazine. Synthetic utility of these cyclopropylhydrazine building blocks is presented as well. PMID- 26734693 TI - Low threshold amplified spontaneous emission and ambipolar charge transport in non-volatile liquid fluorene derivatives. AB - Highly fluorescent non-volatile fluidic fluorene derivatives functionalized with siloxane chains were synthesized and used in monolithic solvent-free liquid organic semiconductor distributed feedback lasers. The photoluminescence quantum yield values, the amplified spontaneous emission thresholds and the ambipolar charge carrier mobilities demonstrate that this class of materials is extremely promising for organic fluidic light-emitting and lasing devices. PMID- 26734694 TI - Lab Medicine is Now Indexed in the MEDLINE Database. PMID- 26734695 TI - T-cell primary effusion lymphoma with pseudo-monoclonal rearrangements for immunoglobulin heavy chain. PMID- 26734696 TI - Cellular morphology of BRAF V600E-positive Langerhans cell histiocytosis. PMID- 26734697 TI - Oxygen as Acceptor. AB - Like most bacteria, Escherichia coli has a flexible and branched respiratory chain that enables the prokaryote to live under a variety of environmental conditions, from highly aerobic to completely anaerobic. In general, the bacterial respiratory chain is composed of dehydrogenases, a quinone pool, and reductases. Substrate-specific dehydrogenases transfer reducing equivalents from various donor substrates (NADH, succinate, glycerophosphate, formate, hydrogen, pyruvate, and lactate) to a quinone pool (menaquinone, ubiquinone, and dimethylmenoquinone). Then electrons from reduced quinones (quinols) are transferred by terminal reductases to different electron acceptors. Under aerobic growth conditions, the terminal electron acceptor is molecular oxygen. A transfer of electrons from quinol to O2 is served by two major oxidoreductases (oxidases), cytochrome bo3 encoded by cyoABCDE and cytochrome bd encoded by cydABX. Terminal oxidases of aerobic respiratory chains of bacteria, which use O2 as the final electron acceptor, can oxidize one of two alternative electron donors, either cytochrome c or quinol. This review compares the effects of different inhibitors on the respiratory activities of cytochrome bo3 and cytochrome bd in E. coli. It also presents a discussion on the genetics and the prosthetic groups of cytochrome bo3 and cytochrome bd. The E. coli membrane contains three types of quinones that all have an octaprenyl side chain (C40). It has been proposed that the bo3 oxidase can have two ubiquinone-binding sites with different affinities. "WHAT'S NEW" IN THE REVISED ARTICLE: The revised article comprises additional information about subunit composition of cytochrome bd and its role in bacterial resistance to nitrosative and oxidative stresses. Also, we present the novel data on the electrogenic function of appBCX-encoded cytochrome bd-II, a second bd-type oxidase that had been thought not to contribute to generation of a proton motive force in E. coli, although its spectral properties closely resemble those of cydABX-encoded cytochrome bd. PMID- 26734698 TI - Laurie M. Gunter (March 5, 1922-June 15, 2015). PMID- 26734699 TI - Aging and obesity: general assessment and management considerations. PMID- 26734700 TI - NICHE Solutions--fourteenth in a series: sensory changes. PMID- 26734701 TI - Advance care planning paves way for geriatrics nurses to support person-centered care for older adults. PMID- 26734702 TI - Accelerating Bioinformatics Applications via Emerging Parallel Computing Systems. PMID- 26734703 TI - Should all young children be screened for autism spectrum disorder? PMID- 26734704 TI - Identify Critical Genes in Development with Consistent H3K4me2 Patterns across Multiple Tissues. AB - Histone modification is an important epigenetic event which plays essential roles in cell differentiation and tissue development. Recent studies show that a unique dimethylation of lysine 4 residue on histone 3 (H3K4me2) distribution pattern around transcription starting sites (TSS) of genes marks tissue specific genes in human CD4 p T cells and mouse nervous tissue cells. However, existence of this pattern has not been widely tested and its implication remains unclear. In this paper, we study the H3K4me2 distribution patterns across six different cell lines from five major tissue types (including muscular tissue, nervous tissue, non blood connective tissue, blood, and epithelial tissue) as well as embryonic stem cells. We define a metric 'tail length' to quantitatively describe H3K4me2 distribution patterns around the TSS. While confirming the previous observations, we also identified a group of 217 genes with ubiquitous long-tail H3K4me2 patterns in all the tested tissues and the embryonic stem cells (ESC). Further analyses confirmed that these genes are critical for development, and highly interactive with other tissue specific genes as evinced by protein-protein interaction networks, suggesting their critical regulatory functions. Our results suggest that rich information on gene functions and epigenetic events can be revealed using pattern recognition methods. PMID- 26734705 TI - [Goodbye Carol]. PMID- 26734706 TI - [Not Available]. PMID- 26734707 TI - [Not Available]. PMID- 26734708 TI - Norman Bethune: Gifted Surgeon and a Strange Idealist. PMID- 26734711 TI - Involvement of beta adrenergic receptors in spasmolytic effect of caulerpine on guinea pig ileum. AB - Previously, we demonstrated that caulerpine has spasmolytic effect on guinea pig ileum. The aim of this study was to investigate pathways of its spasmolytic action. We test caulerpine against phasic contractions induced by carbachol in the circular layer of guinea pig ileum and this alkaloid did not inhibit these contractions, indicating that caulerpine did not interfering with the mobilisation of Ca2+ from intracellular stores. Additionally, the spasmolytic effect of caulerpine did not involve K+ channels. Furthermore, we observed that alpha2-adrenergic receptors were not involved in the spasmolytic effect of caulerpine, since the relaxation curve induced by caulerpine was not shifted in the presence of yohimbine (alpha2-adrenergic antagonist). However, in the presence of propranolol (beta-adrenergic antagonist), the relaxation curve induced by caulerpine was right-shifted, resulting in a fivefold increase in EC50. Thus, a possible mechanism for the spasmolytic action of caulerpine is the activation of beta-adrenergic receptors. PMID- 26734710 TI - Integrative review: postcraniotomy pain in the brain tumour patient. AB - AIM: To conduct an integrative review to examine evidence of pain and associated symptoms in adult (>=21 years of age), postcraniotomy, brain tumour patients hospitalized on intensive care units. BACKGROUND: Healthcare providers believe craniotomies are less painful than other surgical procedures. Understanding how postcraniotomy pain unfolds over time will help inform patient care and aid in future research and policy development. DESIGN: Systematic literature search to identify relevant literature. Information abstracted using the Theory of Unpleasant Symptoms' concepts of influencing factors, symptom clusters and patient performance. Inclusion criteria were indexed, peer-reviewed, full-length, English-language articles. Keywords were 'traumatic brain injury', 'pain, post operative', 'brain injuries', 'postoperative pain', 'craniotomy', 'decompressive craniectomy' and 'trephining'. DATA SOURCES: Medline, OVID, PubMed and CINAHL databases from 2000-2014. REVIEW METHOD: Cooper's five-stage integrative review method was used to assess and synthesize literature. RESULTS: The search yielded 115 manuscripts, with 26 meeting inclusion criteria. Most studies were randomized, controlled trials conducted outside of the United States. All tested pharmacological pain interventions. Postcraniotomy brain tumour pain was well documented and associated with nausea, vomiting and changes in blood pressure, and it impacted the patient's length of hospital stay, but there was no consensus for how best to treat such pain. CONCLUSION: The Theory of Unpleasant Symptoms provided structure to the search. Postcraniotomy pain is experienced by patients, but associated symptoms and impact on patient performance remain poorly understood. Further research is needed to improve understanding and management of postcraniotomy pain in this population. PMID- 26734709 TI - Epigenetic Alterations in Alzheimer's Disease. AB - Alzheimer's disease (AD) is the major cause of dementia in Western societies. It progresses asymptomatically during decades before being belatedly diagnosed when therapeutic strategies have become unviable. Although several genetic alterations have been associated with AD, the vast majority of AD cases do not show strong genetic underpinnings and are thus considered a consequence of non-genetic factors. Epigenetic mechanisms allow for the integration of long-lasting non genetic inputs on specific genetic backgrounds, and recently, a growing number of epigenetic alterations in AD have been described. For instance, an accumulation of dysregulated epigenetic mechanisms in aging, the predominant risk factor of AD, might facilitate the onset of the disease. Likewise, mutations in several enzymes of the epigenetic machinery have been associated with neurodegenerative processes that are altered in AD such as impaired learning and memory formation. Genome-wide and locus-specific epigenetic alterations have also been reported, and several epigenetically dysregulated genes validated by independent groups. From these studies, a picture emerges of AD as being associated with DNA hypermethylation and histone deacetylation, suggesting a general repressed chromatin state and epigenetically reduced plasticity in AD. Here we review these recent findings and discuss several technical and methodological considerations that are imperative for their correct interpretation. We also pay particular focus on potential implementations and theoretical frameworks that we expect will help to better direct future studies aimed to unravel the epigenetic participation in AD. PMID- 26734712 TI - Copper Speciation in Variably Toxic Sediments at the Ely Copper Mine, Vermont, United States. AB - At the Ely Copper Mine Superfund site, Cu concentrations exceed background values in both streamwater (160-1200 times) and sediments (15-79 times). Previously, these sediment samples were incubated with laboratory test organisms, and they exhibited variable toxicity for different stream sites. In this study we combined bulk- and microscale techniques to determine Cu speciation and distribution in these contaminated sediments on the basis of evidence from previous work that Cu was the most important stressor in this environment and that variable observed toxicity could have resulted from differences in Cu speciation. Copper speciation results were similar at microscopic and bulk scales. The major Cu species in the more toxic samples were sorbed or coprecipitated with secondary Mn (birnessite) and Fe minerals (jarosite and goethite), which together accounted for nearly 80% of the total Cu. The major Cu species in the less toxic samples were Cu sulfides (chalcopyrite and a covellite-like phase), making up about 80-95% of the total Cu, with minor amounts of Cu associated with jarosite or goethite. These Cu speciation results are consistent with the toxicity results, considering that Cu sorbed or coprecipitated with secondary phases at near-neutral pH is relatively less stable than Cu bound to sulfide at lower pH. The more toxic stream sediment sites were those that contained fewer detrital sulfides and were upstream of the major mine waste pile, suggesting that removal and consolidation of sulfide bearing waste piles on site may not eliminate all sources of bioaccessible Cu. PMID- 26734714 TI - Predictors of Long-Term Change in Adult Cognitive Performance: Systematic Review and Data from the Northern Finland Birth Cohort 1966. AB - OBJECTIVE: Several social life events and challenges have an impact on cognitive development. Our goal was to analyze the predictors of change in cognitive performance in early midlife in a general population sample. Additionally, systematic literature review was performed. METHOD: The study sample was drawn from the Northern Finland Birth Cohort 1966 at the ages of 34 and 43 years. Primary school performance, sociodemographic factors and body mass index (BMI) were used to predict change in cognitive performance measured by the California Verbal Learning Test, Visual Object Learning Test, and Abstraction Inhibition and Working Memory task. Analyses were weighted by gender and education, and p-values were corrected for multiple comparisons using Benjamini-Hochberg procedure (B-H). RESULTS: Male gender predicted decrease in episodic memory. Poor school marks of practical subjects, having no children, and increase in BMI were associated with decrease in episodic memory, though non-significantly after B-H. Better school marks, and higher occupational class were associated with preserved performance in visual object learning. Higher vocational education predicted preserved performance in visual object learning test, though non-significantly after B-H. Likewise, having children predicted decreased performance in executive functioning but non-significantly after B-H. CONCLUSIONS: Adolescent cognitive ability, change in BMI and several sociodemographic factors appear to predict cognitive changes in early midlife. The key advantage of present study is the exploration of possible predictors of change in cognitive performance among general population in the early midlife, a developmental period that has been earlier overlooked. PMID- 26734716 TI - [Management of STEMI patients from rural areas in Iceland--Is there room for improvement?[Editorial]]. PMID- 26734713 TI - Air Pollution and Lung Function in Minority Youth with Asthma in the GALA II (Genes-Environments and Admixture in Latino Americans) and SAGE II (Study of African Americans, Asthma, Genes, and Environments) Studies. AB - RATIONALE: Adverse effects of exposures to ambient air pollution on lung function are well documented, but evidence in racial/ethnic minority children is lacking. OBJECTIVES: To assess the relationship between air pollution and lung function in minority children with asthma and possible modification by global genetic ancestry. METHODS: The study population consisted of 1,449 Latino and 519 African American children with asthma from five different geographical regions in the mainland United States and Puerto Rico. We examined five pollutants (particulate matter <=10 MUm and <=2.5 MUm in diameter, ozone, nitrogen dioxide, and sulfur dioxide), derived from participant residential history and ambient air monitoring data, and assessed over several time windows. We fit generalized additive models for associations between pollutant exposures and lung function parameters and tested for interaction terms between exposures and genetic ancestry. MEASUREMENTS AND MAIN RESULTS: A 5 MUg/m(3) increase in average lifetime particulate matter less than or equal to 2.5 MUm in diameter exposure was associated with a 7.7% decrease in FEV1 (95% confidence interval = -11.8 to -3.5%) in the overall study population. Global genetic ancestry did not appear to significantly modify these associations, but percent African ancestry was a significant predictor of lung function. CONCLUSIONS: Early-life particulate exposures were associated with reduced lung function in Latino and African American children with asthma. This is the first study to report an association between exposure to particulates and reduced lung function in minority children in which racial/ethnic status was measured by ancestry-informative markers. PMID- 26734717 TI - [Icelandic primary health care in crisis [Editorial]]. PMID- 26734715 TI - Identification of Molecular Markers of Delayed Graft Function Based on the Regulation of Biological Ageing. AB - INTRODUCTION: Delayed graft function is a prevalent clinical problem in renal transplantation for which there is no objective system to predict occurrence in advance. It can result in a significant increase in the necessity for hospitalisation post-transplant and is a significant risk factor for other post transplant complications. METHODOLOGY: The importance of microRNAs (miRNAs), a specific subclass of small RNA, have been clearly demonstrated to influence many pathways in health and disease. To investigate the influence of miRNAs on renal allograft performance post-transplant, the expression of a panel of miRNAs in pre transplant renal biopsies was measured using qPCR. Expression was then related to clinical parameters and outcomes in two independent renal transplant cohorts. RESULTS: Here we demonstrate, in two independent cohorts of pre-implantation human renal allograft biopsies, that a novel pre-transplant renal performance scoring system (GRPSS), can determine the occurrence of DGF with a high sensitivity (>90%) and specificity (>60%) for donor allografts pre-transplant, using just three senescence associated microRNAs combined with donor age and type of organ donation. CONCLUSION: These results demonstrate a relationship between pre-transplant microRNA expression levels, cellular biological ageing pathways and clinical outcomes for renal transplantation. They provide for a simple, rapid quantitative molecular pre-transplant assay to determine post-transplant allograft function and scope for future intervention. Furthermore, these results demonstrate the involvement of senescence pathways in ischaemic injury during the organ transplantation process and an indication of accelerated bio-ageing as a consequence of both warm and cold ischaemia. PMID- 26734718 TI - [Transport and treatment of patients with STEMI in rural Iceland--Only a few patients receive PPCI within 120 minutes]. AB - INTRODUCTION: ST-segment Elevation Myocardial Infarction (STEMI) is a life threatening disease and good outcome depends on early restoration of coronary blood flow. Primary percutaneous coronary intervention (PPCI) is the treatment of choice if performed within 120 minutes of first medical contact (FMC) but in case of anticipated long transport or delays, pre-hospital fibrinolysis is indicated. The aim was to study transport times and adherence to clinical guidelines in patients with STEMI transported from outside of the Reykjavik area to Landspitali University Hospital in Iceland. MATERIALS AND METHODS: Retrospective chart review was conducted of all patients diagnosed with STEMI outside of the Reykjavik area and transported to Landspitali University Hospital in Reykjavik in 2011-2012. Descriptive statistical analysis and hypothesis testing was applied. RESULTS: Eighty-six patients had signs of STEMI on electrocardiogram (ECG) at FMC. In southern Iceland nine patients (21%) underwent PPCI within 120 minutes (median 157 minutes) and no patient received fibrinolysis. In northern Iceland and The Vestman Islands, where long transport times are expected, 96% of patients eligible for fibrinolysis (n=31) received appropriate therapy in a median time of 57 minutes. Significantly fewer patients received appropriate anticoagulation treatment with clopidogrel and enoxaparin in southern Iceland compared to the northern part. Mortality rate was 7% and median length of stay in hospital was 6 days. CONCLUSIONS: Time from FMC to PPCI is longer than 120 minutes in the majority of cases. Pre-hospital fibrinolysis should be considered as first line treatment in all parts of Iceland outside of the Reykjavik area. Directly electronically transmitted ECGs and contact with cardiologist could hasten diagnosis and decrease risk of unnecessary interhospital transfer. A STEMI database should be established in Iceland to facilitate quality control. PMID- 26734719 TI - [Liver transplantation in Iceland: a retrospective study of indications and results]. AB - BACKGROUND/AIMS: Liver transplantation is an important treatment option for end stage liver disease. Since liver transplantation is not performed in Iceland, patients are sent abroad for this procedure. The aim of this study was to investigate indications and results of liver transplantations for Icelandic patients. MATERIALS AND METHODS: The study was retrospective and included all patients in Iceland who had undergone liver transplantation from the first transplantation in 1984 to the end of 2012. Information was gathered from medical records. The study period was divided into three subperiods in order to evaluate changes in frequency of transplantation and survival. RESULTS: During the period, 45 liver transplantations, thereof five retransplantations, were performed. Of 40 patients 16 were males, 18 females, mean age 40 years. There were six children, 2 girls and 4 boys with an age range of 0.4-12 years. Number of transplantation per million inhabitants increased significantly (2.40 during 1984-1996; 5.18 during 1997-2006 and 8.90 during 2007-2013; p<0.01). The main indication for transplantation was cirrhosis with complications in 26 patients (65%), acute liver failure in 6 (15%), cirrhosis and hepatocellular carcinoma in three (8%), and hemangioendothelioma in two (5%). The most common underlying liver diseases were primary biliary cirrhosis in 8 (20%), autoimmune hepatitis in four (10%), alcoholic cirrhosis in three (7.5%) and primary sclerosing cholangitis in three (7.5%). The mean waiting time for transplantation was 5.9 months (median 3.2). Survial was 84% in one year and 63% in 5 years. Survival increased during the study period. CONCLUSIONS: The number of liver transplantations has increased significantly in recent years. Survival has improved and is comparable to survival in countries where liver transplantations are performed. PMID- 26734720 TI - [Change in attitude towards antibiotic prescriptions among Icelandic general practitioners]. AB - INTRODUCTION: Antibiotic use is a leading cause of antibiotic resistance and it is therefore important to reduce unnecessary prescribing in Iceland where antibiotic use is relatively high. The purpose of this study was to explore antibiotic prescribing practices among Icelandic physicians and compare the results with results of comparable studies from 1991 and 1995 conducted by the Directorate of Health, Iceland. METHODS: A descriptive cross-sectional study was carried out among all general practitioners registered in Iceland in 1991 and 1995 and all physicians registered in March 2014. Data was collected with questionnaires regarding diagnosis and treatment of simple urinary tract infection, acute otitis media and pharyngitis. A multiple logistic regression analysis was performed and level of significance p<=0.05. RESULTS: Response rates were 85% and 93% in 1991 and 1995 but 31% in 2014. Proportion of physicians who consider themselves prescribing antibiotics more than 10 times per week was 36% in 1991, 32% in 1995 and 21% in 2014. Proportion of trimethoprim-sulfamethoxazole as first choice for simple urinary tract infection reduced from 43% and 45% to 8% in 2014. In 2014, general practitioners considered themselves 87% less likely to prescribe an antibiotic for acute otitis media than in 1991 (p<0.001). They also claimed to use rapid diagnostic tests in pharyngitis five times more often in 2014 than in 1991 (p<0.001). CONCLUSION: Antibiotic prescribing practices have changed significantly in the past two decades in Iceland becoming more in line with clinical guidelines. Improvements are still needed to further reduce inappropriate antibiotic use. PMID- 26734721 TI - Sexual disruption in zebrafish (Danio rerio) exposed to mixtures of 17alpha ethinylestradiol and 17beta-trenbolone. AB - Environmental estrogens and androgens can be present simultaneously in aquatic environments and thereby interact to disturb multiple physiological systems in organisms. Studies on interaction effects in fish of androgenic and estrogenic chemicals are limited. Therefore, the aim of the present study was to evaluate feminization and masculinization effects in zebrafish (Danio rerio) exposed to combinations of two synthetic steroid hormones detected in environmental waters: the androgen 17beta-trenbolone (Tb) and the oestrogen 17alpha-ethinylestradiol (EE2). Juvenile zebrafish were exposed between days 20 and 60 post-hatch to different binary mixtures of Tb (1, 10, and 50 ng/L) and EE2 (2 and 5 ng/L). The endpoints studied were whole-body homogenate vitellogenin concentration at 40 days post-hatch, and sex ratio including gonad maturation at 60 days post-hatch. The feminizing potency of 5 ng/L of EE2, alone as well as in combination with Tb, was clear in the present study, with exposures resulting in almost all-female populations and females being sexually immature. Masculinization effects with male-biased sex ratios were observed when fish were exposed to 2 ng/L of EE2 in combination with Tb concentrations. Intersex fish were observed after exposure to mixtures of 2 ng/L EE2 with 50 ng/L Tb. Sexual maturity generally increased among males at increasing concentrations of Tb. The results of the present study show that exposure to environmentally relevant mixtures of an oestrogen and androgen affects the process of gonad differentiation in zebrafish and lead to sexual disruption. PMID- 26734722 TI - A highly enantioselective Hg(ii)-catalyzed Sakurai-Hosomi reaction of isatins with allyltrimethylsilanes. AB - A chiral complex derived from (S)-difluorophos and Hg(OTf)2 is identified as a powerful catalyst for the Sakurai-Hosomi reaction of isatins with allyltrimethylsilane, allowing the facile synthesis of valuable building blocks 3 allyl-3-hydroxyoxindoles in up to 97% ee, with only 0.5-1.0 mol% of catalyst loading. PMID- 26734723 TI - Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family. AB - Inhibition of the sodium-coupled citrate transporter (NaCT or SLC13A5) has been proposed as a new therapeutic approach for prevention and treatment of metabolic diseases. In a previous report, we discovered dicarboxylate 1a (PF-06649298) which inhibits the transport of citrate in in vitro and in vivo settings via a specific interaction with NaCT. Herein, we report the optimization of this series leading to 4a (PF-06761281), a more potent inhibitor with suitable in vivo pharmacokinetic profile for assessment of in vivo pharmacodynamics. Compound 4a was used to demonstrate dose-dependent inhibition of radioactive [(14)C]citrate uptake in liver and kidney in vivo, resulting in modest reductions in plasma glucose concentrations. PMID- 26734724 TI - Periodicity of nuclear morphology in human fibroblasts. AB - MOTIVATION: Morphology of the cell nucleus has been used as a key indicator of disease state and prognosis, but typically without quantitative rigor. It is also not well understood how nuclear morphology varies with time across different genetic backgrounds in healthy cells. To help answer these questions we measured the size and shape of nuclei in cell-cycle-synchronized primary human fibroblasts from 6 different individuals at 32 time points over a 75 hour period. RESULTS: The nucleus was modeled as an ellipsoid and its dynamics analyzed. Shape and volume changed significantly over this time. Two prominent frequencies were found in the 6 individuals: a 17 hour period consistent with the cell cycle and a 26 hour period. Our findings suggest that the shape of the nucleus changes over time and thus any time-invariant shape property may provide a misleading characterization of cellular populations at different phases of the cell cycle. The proposed methodology provides a general method to analyze morphological change using multiple time points even for non-live-cell experiments. PMID- 26734725 TI - The proximity ligation assay reveals that at DNA double-strand breaks WRAP53beta associates with gammaH2AX and controls interactions between RNF8 and MDC1. AB - We recently demonstrated that WRAP53beta acts as a key regulator of ubiquitin dependent repair of DNA double-strand breaks. Here, we applied the proximity ligation assay (PLA) to show that at such breaks WRAP53beta accumulates in close proximity to gammaH2AX and, furthermore as demonstrated by their co immunoprecipitation (IP) binds to gammaH2AX, in a manner dependent on the ATM and ATR kinases. Moreover, formation of complexes between MDC1 and both its partners RNF8 and phosphorylated ATM was visualized. The interaction of MDC1 with RNF8, but not with ATM requires WRAP53beta, suggesting that WRAP53beta facilitates the former interaction without altering phosphorylation of MDC1 by ATM. Furthermore, our findings highlight PLA as a more sensitive method for the analysis of recruitment of repair factors and complex formation at DNA breaks that are difficult to detect using conventional immunofluorescence. PMID- 26734726 TI - Nociceptive Local Field Potentials Recorded from the Human Insula Are Not Specific for Nociception. AB - The insula, particularly its posterior portion, is often regarded as a primary cortex for pain. However, this interpretation is largely based on reverse inference, and a specific involvement of the insula in pain has never been demonstrated. Taking advantage of the high spatiotemporal resolution of direct intracerebral recordings, we investigated whether the human insula exhibits local field potentials (LFPs) specific for pain. Forty-seven insular sites were investigated. Participants received brief stimuli belonging to four different modalities (nociceptive, vibrotactile, auditory, and visual). Both nociceptive stimuli and non-nociceptive vibrotactile, auditory, and visual stimuli elicited consistent LFPs in the posterior and anterior insula, with matching spatial distributions. Furthermore, a blind source separation procedure showed that nociceptive LFPs are largely explained by multimodal neural activity also contributing to non-nociceptive LFPs. By revealing that LFPs elicited by nociceptive stimuli reflect activity unrelated to nociception and pain, our results confute the widespread assumption that these brain responses are a signature for pain perception and its modulation. PMID- 26734728 TI - Pharmacological Characterization of the alphavbeta6 Integrin Binding and Internalization Kinetics of the Foot-and-Mouth Disease Virus Derived Peptide A20FMDV2. AB - A20FMDV2 is a peptide derived from the foot-and-mouth disease virus with a high affinity and selectivity for the alpha-v beta-6 (alphavbeta6) arginyl-glycinyl aspartic acid (RGD)-binding integrin. It has been shown to be an informative tool ligand in pre-clinical imaging studies for selective labelling of the alphavbeta6 integrin in a number of disease models. In a radioligand binding assay using a radiolabelled form of the peptide ([3H]A20FMDV2), its high affinity (K(D): 0.22 nmol/l) and selectivity (at least 85-fold) for alphavbeta6 over the other members of the RGD integrin family was confirmed. [3H]A20FMDV2 alphavbeta6 binding could be fully reversed only in the presence of EDTA, whereas a partial reversal was observed in the presence of excess concentrations of an RGD-mimetic small molecule (SC-68448) or unlabelled A20FMDV2. Using flow cytometry on bronchial epithelial cells, the ligand-induced internalization of alphavbeta6 by A20FMDV2 and latency-associated peptide-1 was shown to be fast (t(1/2): 1.5 and 3.1 min, respectively), concentration-dependent (EC50: values 1.1 and 3.6 nmol/l, respectively) and was followed by a moderately slow return of integrin to the surface. The results of the radioligand binding studies suggest that the binding of A20FMDV2 to the RGD-binding site on alphavbeta6 is required to maintain its engagement with the hypothesised A20FMDV2 synergy site on the integrin. In addition, there is evidence from flow cytometric studies that the RGD-ligand engagement of alphavbeta6 post-internalization plays a role in delaying recycling of the integrin to the cell surface. This mechanism may act as a homeostatic control of membrane alphavbeta6 following RGD ligand engagement. PMID- 26734727 TI - Distribution of Dehalococcoidia in the Anaerobic Deep Water of a Remote Meromictic Crater Lake and Detection of Dehalococcoidia-Derived Reductive Dehalogenase Homologous Genes. AB - Here we describe the natural occurrence of bacteria of the class Dehalococcoidia (DEH) and their diversity at different depths in anoxic waters of a remote meromictic lake (Lake Pavin) using 16S rRNA gene amplicon sequencing and quantitative PCR. Detected DEH are phylogenetically diverse and the majority of 16S rRNA sequences have less than 91% similarity to previously isolated DEH 16S rRNA sequences. To predict the metabolic potential of detected DEH subgroups and to assess if they encode genes to transform halogenated compounds, we enriched DEH-affiliated genomic DNA by using a specific-gene capture method and probes against DEH-derived 16S rRNA genes, reductive dehalogenase genes and known insertion sequences. Two reductive dehalogenase homologous sequences were identified from DEH-enriched genomic DNA, and marker genes in the direct vicinity confirm that gene fragments were derived from DEH. The low sequence similarity with known reductive dehalogenase genes suggests yet-unknown catabolic potential in the anoxic zone of Lake Pavin. PMID- 26734729 TI - Morphofunctional Analysis of the Quadrate of Spinosauridae (Dinosauria: Theropoda) and the Presence of Spinosaurus and a Second Spinosaurine Taxon in the Cenomanian of North Africa. AB - Six quadrate bones, of which two almost certainly come from the Kem Kem beds (Cenomanian, Upper Cretaceous) of south-eastern Morocco, are determined to be from juvenile and adult individuals of Spinosaurinae based on phylogenetic, geometric morphometric, and phylogenetic morphometric analyses. Their morphology indicates two morphotypes evidencing the presence of two spinosaurine taxa ascribed to Spinosaurus aegyptiacus and? Sigilmassasaurus brevicollis in the Cenomanian of North Africa, casting doubt on the accuracy of some recent skeletal reconstructions which may be based on elements from several distinct species. Morphofunctional analysis of the mandibular articulation of the quadrate has shown that the jaw mechanics was peculiar in Spinosauridae. In mature spinosaurids, the posterior parts of the two mandibular rami displaced laterally when the jaw was depressed due to a lateromedially oriented intercondylar sulcus of the quadrate. Such lateral movement of the mandibular ramus was possible due to a movable mandibular symphysis in spinosaurids, allowing the pharynx to be widened. Similar jaw mechanics also occur in some pterosaurs and living pelecanids which are both adapted to capture and swallow large prey items. Spinosauridae, which were engaged, at least partially, in a piscivorous lifestyle, were able to consume large fish and may have occasionally fed on other prey such as pterosaurs and juvenile dinosaurs. PMID- 26734730 TI - A Conserved Interaction between a C-Terminal Motif in Norovirus VPg and the HEAT 1 Domain of eIF4G Is Essential for Translation Initiation. AB - Translation initiation is a critical early step in the replication cycle of the positive-sense, single-stranded RNA genome of noroviruses, a major cause of gastroenteritis in humans. Norovirus RNA, which has neither a 5' m7G cap nor an internal ribosome entry site (IRES), adopts an unusual mechanism to initiate protein synthesis that relies on interactions between the VPg protein covalently attached to the 5'-end of the viral RNA and eukaryotic initiation factors (eIFs) in the host cell. For murine norovirus (MNV) we previously showed that VPg binds to the middle fragment of eIF4G (4GM; residues 652-1132). Here we have used pull down assays, fluorescence anisotropy, and isothermal titration calorimetry (ITC) to demonstrate that a stretch of ~20 amino acids at the C terminus of MNV VPg mediates direct and specific binding to the HEAT-1 domain within the 4GM fragment of eIF4G. Our analysis further reveals that the MNV C terminus binds to eIF4G HEAT-1 via a motif that is conserved in all known noroviruses. Fine mutagenic mapping suggests that the MNV VPg C terminus may interact with eIF4G in a helical conformation. NMR spectroscopy was used to define the VPg binding site on eIF4G HEAT-1, which was confirmed by mutagenesis and binding assays. We have found that this site is non-overlapping with the binding site for eIF4A on eIF4G HEAT-1 by demonstrating that norovirus VPg can form ternary VPg-eIF4G-eIF4A complexes. The functional significance of the VPg-eIF4G interaction was shown by the ability of fusion proteins containing the C-terminal peptide of MNV VPg to inhibit in vitro translation of norovirus RNA but not cap- or IRES-dependent translation. These observations define important structural details of a functional interaction between norovirus VPg and eIF4G and reveal a binding interface that might be exploited as a target for antiviral therapy. PMID- 26734731 TI - Flattening Filter-Free Beams in Intensity-Modulated Radiotherapy and Volumetric Modulated Arc Therapy for Sinonasal Cancer. AB - PURPOSE: To evaluate the dosimetric impacts of flattening filter-free (FFF) beams in intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) for sinonasal cancer. METHODS: For fourteen cases, IMRT and VMAT planning was performed using 6-MV photon beams with both conventional flattened and FFF modes. The four types of plans were compared in terms of target dose homogeneity and conformity, organ-at-risk (OAR) sparing, number of monitor units (MUs) per fraction, treatment time and pure beam-on time. RESULTS: FFF beams led to comparable target dose homogeneity, conformity, increased number of MUs and lower doses to the spinal cord, brainstem and normal tissue, compared with flattened beams in both IMRT and VMAT. FFF beams in IMRT resulted in improvements by up to 5.4% for sparing of the contralateral optic structures, with shortened treatment time by 9.5%. However, FFF beams provided comparable overall OAR sparing and treatment time in VMAT. With FFF mode, VMAT yielded inferior homogeneity and superior conformity compared with IMRT, with comparable overall OAR sparing and significantly shorter treatment time. CONCLUSIONS: Using FFF beams in IMRT and VMAT is feasible for the treatment of sinonasal cancer. Our results suggest that the delivery mode of FFF beams may play an encouraging role with better sparing of contralateral optic OARs and treatment efficiency in IMRT, but yield comparable results in VMAT. PMID- 26734732 TI - Marine Biodiversity in Juan Fernandez and Desventuradas Islands, Chile: Global Endemism Hotspots. AB - The Juan Fernandez and Desventuradas islands are among the few oceanic islands belonging to Chile. They possess a unique mix of tropical, subtropical, and temperate marine species, and although close to continental South America, elements of the biota have greater affinities with the central and south Pacific owing to the Humboldt Current, which creates a strong biogeographic barrier between these islands and the continent. The Juan Fernandez Archipelago has ~700 people, with the major industry being the fishery for the endemic lobster, Jasus frontalis. The Desventuradas Islands are uninhabited except for a small Chilean military garrison on San Felix Island. We compared the marine biodiversity of these islands across multiple taxonomic groups. At San Ambrosio Island (SA), in Desventuradas, the laminarian kelp (Eisenia cokeri), which is limited to Desventuradas in Chile, accounted for >50% of the benthic cover at wave exposed areas, while more sheltered sites were dominated by sea urchin barrens. The benthos at Robinson Crusoe Island (RC), in the Juan Fernandez Archipelago, comprised a diverse mix of macroalgae and invertebrates, a number of which are endemic to the region. The biomass of commercially targeted fishes was >2 times higher in remote sites around RC compared to sheltered locations closest to port, and overall biomass was 35% higher around SA compared to RC, likely reflecting fishing effects around RC. The number of endemic fish species was extremely high at both islands, with 87.5% of the species surveyed at RC and 72% at SA consisting of regional endemics. Remarkably, endemics accounted for 99% of the numerical abundance of fishes surveyed at RC and 96% at SA, which is the highest assemblage-level endemism known for any individual marine ecosystem on earth. Our results highlight the uniqueness and global significance of these biodiversity hotspots exposed to very different fishing pressures. PMID- 26734733 TI - Professional Judgment and Justice: Equal Respect for the Professional Judgment of Critical-Care Physicians. PMID- 26734734 TI - One Exemption Too Many: The Case for Mandated CCHD Screening. PMID- 26734735 TI - Medical Ethics and School Football. PMID- 26734737 TI - Letting Parents Say "No:" A Small Price to Pay for State-Mandated Critical Congenital Heart Disease (CCHD) Screening. PMID- 26734736 TI - Legal and Ethical Considerations in Allowing Parental Exemptions From Newborn Critical Congenital Heart Disease (CCHD) Screening. AB - Critical congenital heart disease (CCHD) screening is rapidly becoming the standard of care in the United States after being added to the Recommended Uniform Screening Panel (RUSP) in 2011. Newborn screens typically do not require affirmative parental consent. In fact, most states allow parents to exempt their baby from receiving the required screen on the basis of religious or personally held beliefs. There are many ethical considerations implicated with allowing parents to exempt their child from newborn screening for CCHD. Considerations include the treatment of religious exemptions in our current legal system, as well as medical and ethical principles in relation to the rights of infants. Although there are significant benefits to screening newborns for CCHD, when a parent refuses for religious or personal beliefs, in the case of CCHD screening, the parental decision should stand. PMID- 26734738 TI - Religion and Newborn Screening. PMID- 26734739 TI - The Pediatrician's Dilemma: Respecting Parental Autonomy Versus Protecting Vulnerable Children. PMID- 26734740 TI - An Accessibility Constraint on Parental Refusal of Critical Newborn Screening. PMID- 26734741 TI - Pulse Oximetry Should Be Required Without a Religious Exemption. PMID- 26734742 TI - Use of a Balanced Test to Resolve Competing Best Interest and Liberty Claims When Parents Refuse Consent for Neonatal Pulse Oximetry. PMID- 26734743 TI - Why Only Inform the Dissenters? PMID- 26734744 TI - Putting Children at Risk in the Name of Religion. PMID- 26734745 TI - Parental Refusal of Newborn Screening for Congenital Hearing Loss. PMID- 26734746 TI - Parents Do Not Always Have to Get Their Way: Why Critical Congenital Heart Disease Screening for Newborns Should Be Mandatory. PMID- 26734747 TI - Balancing Legitimate Critical-Care Interests: Setting Defensible Care Limits Through Policy Development. AB - Critical-care decision making is highly complex, given the need for health care providers and organizations to consider, and constructively respond to, the diverse interests and perspectives of a variety of legitimate stakeholders. Insights derived from an identified set of ethics-related considerations have the potential to meaningfully inform inclusive and deliberative policy development that aims to optimally balance the competing obligations that arise in this challenging, clinical decision-making domain. A potential, constructive outcome of such policy engagement is the collaborative development of an as-fair-as possible dispute resolution process that incorporates an appropriated-justified, defensible critical-care obligation threshold. PMID- 26734748 TI - Critical Care Limits: What Is the Right Balance? PMID- 26734749 TI - Health Care Organizations and the Power of Procedure. PMID- 26734750 TI - Using Professional Organization Policy Statements to Guide Hospital Policies and Bedside Recommendations. PMID- 26734751 TI - Power and Limits in Medical Decision Making. PMID- 26734752 TI - Defensible Limits in Critical Care: An Ethical Analysis of a Recent Multisociety Policy Statement. PMID- 26734753 TI - Expanding Deliberation in Critical-Care Policy Design. PMID- 26734754 TI - The "No Difference Rule". PMID- 26734756 TI - The Limits to Setting Limits on Critical-Care Delivery: Response to Open Peer Commentaries on "Balancing Legitimate Critical-Care Interests: Setting Defensible Care Limits Through Policy Development". PMID- 26734757 TI - Spousal labor market effects from government health insurance: Evidence from a veterans affairs expansion. AB - Measuring the total impact of health insurance receipt on household labor supply is important in an era of increased access to publicly provided and subsidized insurance. Although government expansion of health insurance to older workers leads to direct labor supply reductions for recipients, there may be spillover effects on the labor supply of uncovered spouses. While the most basic model predicts a decrease in overall household work hours, financial incentives such as credit constraints, target income levels, and the need for own health insurance suggest that spousal labor supply might increase. In contrast, complementarities of spousal leisure would predict a decrease in labor supply for both spouses. Utilizing a mid-1990s expansion of health insurance for U.S. veterans, we provide evidence on the effects of public insurance availability on the labor supply of spouses. Using data from the Current Population Survey and Health and Retirement Study, we employ a difference-in-differences strategy to compare the labor market behavior of the wives of older male veterans and non-veterans before and after the VA health benefits expansion. Although husbands' labor supply decreases, wives' labor supply increases, suggesting that financial incentives dominate complementarities of spousal leisure. This effect is strongest for wives with lower education levels and lower levels of household wealth and those who were not previously employed full-time. These findings have implications for government programs such as Medicare and Social Security and the Affordable Care Act. PMID- 26734758 TI - Laparoscopic Complete Mesocolic Excision versus Open Complete Mesocolic Excision for Transverse Colon Cancer: Long-Term Survival Results of a Prospective Single Centre Non-Randomized Study. AB - BACKGROUND/AIM: Laparoscopic complete mesocolic excision (CME) used in the treatment of transverse colon cancer has been questioned on the basis of the technical challenges. The aim of this study was to evaluate the medium- and long term clinical and survival outcomes after laparoscopic and open CME for transverse colon cancer and to compare the 2 approaches. METHODS: This study was a retrospective non-randomized study of patients with prospectively registered data on open and laparoscopic CME for transverse colon cancer tumour-node metastasis stages I-III operated on between 2007 and 2014. This was a single centre study in a community teaching hospital. A total of 56 patients with transverse colon cancer were included, excluding those with tumours in the colonic flexures. The outcome aims were 4-year time to recurrence (TTR) and cancer-specific survival (CSS). Morbidity was also measured. RESULTS: The 4-year TTR was 93.9% in the laparoscopic group and 91.3% in the open group (p = 0.71). The 4-year CSS was 97.0% in the laparoscopic group and 91.3% in the open group (p = 0.42). LIMITATIONS: This was a prospective single-institution study with a small sample size. CONCLUSION: Results of the study suggest that the laparoscopic CME approach might be the preferred approach for transverse colon cancer, especially regarding its benefits in terms of short-term morbidity, length of stay and oncological outcome. PMID- 26734760 TI - Structure and Function of Fusicoccadiene Synthase, a Hexameric Bifunctional Diterpene Synthase. AB - Fusicoccin A is a diterpene glucoside phytotoxin generated by the fungal pathogen Phomopsis amygdali that causes the plant disease constriction canker, first discovered in New Jersey peach orchards in the 1930s. Fusicoccin A is also an emerging new lead in cancer chemotherapy. The hydrocarbon precursor of fusicoccin A is the tricyclic diterpene fusicoccadiene, which is generated by a bifunctional terpenoid synthase. Here, we report X-ray crystal structures of the individual catalytic domains of fusicoccadiene synthase: the C-terminal domain is a chain elongation enzyme that generates geranylgeranyl diphosphate, and the N-terminal domain catalyzes the cyclization of geranylgeranyl diphosphate to form fusicoccadiene. Crystal structures of each domain complexed with bisphosphonate substrate analogues suggest that three metal ions and three positively charged amino acid side chains trigger substrate ionization in each active site. While in vitro incubations reveal that the cyclase domain can utilize farnesyl diphosphate and geranyl diphosphate as surrogate substrates, these shorter isoprenoid diphosphates are mainly converted into acyclic alcohol or hydrocarbon products. Gel filtration chromatography and analytical ultracentrifugation experiments indicate that full-length fusicoccadiene synthase adopts hexameric quaternary structure, and small-angle X-ray scattering data yield a well-defined molecular envelope illustrating a plausible model for hexamer assembly. PMID- 26734761 TI - A Biomechanical Model of the Scapulothoracic Joint to Accurately Capture Scapular Kinematics during Shoulder Movements. AB - The complexity of shoulder mechanics combined with the movement of skin relative to the scapula makes it difficult to measure shoulder kinematics with sufficient accuracy to distinguish between symptomatic and asymptomatic individuals. Multibody skeletal models can improve motion capture accuracy by reducing the space of possible joint movements, and models are used widely to improve measurement of lower limb kinematics. In this study, we developed a rigid-body model of a scapulothoracic joint to describe the kinematics of the scapula relative to the thorax. This model describes scapular kinematics with four degrees of freedom: 1) elevation and 2) abduction of the scapula on an ellipsoidal thoracic surface, 3) upward rotation of the scapula normal to the thoracic surface, and 4) internal rotation of the scapula to lift the medial border of the scapula off the surface of the thorax. The surface dimensions and joint axes can be customized to match an individual's anthropometry. We compared the model to "gold standard" bone-pin kinematics collected during three shoulder tasks and found modeled scapular kinematics to be accurate to within 2 mm root mean-squared error for individual bone-pin markers across all markers and movement tasks. As an additional test, we added random and systematic noise to the bone-pin marker data and found that the model reduced kinematic variability due to noise by 65% compared to Euler angles computed without the model. Our scapulothoracic joint model can be used for inverse and forward dynamics analyses and to compute joint reaction loads. The computational performance of the scapulothoracic joint model is well suited for real-time applications; it is freely available for use with OpenSim 3.2, and is customizable and usable with other OpenSim models. PMID- 26734762 TI - New Insights into the Pathogenesis of MDS and the rational therapeutic opportunities. AB - Myelodysplastic syndromes (MDS) include a heterogeneous group of acquired hematopoietic malignancies characterized by ineffective hematopoiesis, peripheral cytopenias, and a varying propensity for progression to acute myeloid leukemia. The clinical heterogeneity in MDS is a reflection of its molecular heterogeneity. Better understanding of aberrant epigenetics, dysregulation of immune responses, and del(5q) MDS has provided the rationale for well-established treatments in MDS. Further understanding of abnormal signal transduction and aberrant apoptosis pathways has led to development of new rational therapies that are in advanced phases of clinical translation. This review seeks to describe recent developments in our understanding of the pathogenesis of MDS and the potential therapeutic implications of these observations. PMID- 26734765 TI - Act local but don't think too global: The impact of ecological goal level on behavior. AB - Growing awareness of humanity's impact on the environment raises the question of how best to encourage pro-environmental actions. Numerous campaigns have been created to convince people to adopt environmentally friendly everyday behaviors, with varying success. The difficulty may be due, at least in part, to the huge gap between these small individual actions and the high-level goals, such as "saving the planet," often used as incentives. We tested this hypothesis via four experiments. Studies 1 and 2 showed that high-level goals were less effective than low-level goals in promoting paper- and energy-saving behaviors. Study 3 showed that high-level goals engender lower perceived outcome expectancy and higher perception of cumulative effort. Study 4 showed that outcome expectancy mediates the direct effect of goal level on intention. PMID- 26734763 TI - Resveratrol Improved Flow-Mediated Outward Arterial Remodeling in Ovariectomized Rats with Hypertrophic Effect at High Dose. AB - OBJECTIVES: Chronic increases in blood flow in resistance arteries induce outward remodeling associated with increased wall thickness and endothelium-mediated dilatation. This remodeling is essential for collateral arteries growth following occlusion of a large artery. As estrogens have a major role in this remodeling, we hypothesized that resveratrol, described as possessing phytoestrogen properties, could improve remodeling in ovariectomized rats. METHODS: Blood flow was increased in vivo in mesenteric arteries after ligation of adjacent arteries in 3-month old ovariectomized rats treated with resveratrol (5 or 37.5 mg/kg per day: RESV5 or RESV37.5) or vehicle. After 2 weeks arterial structure and function were measured in vitro in high flow (HF) and normal flow (NF) arteries isolated from each rat. RESULTS: Arterial diameter was greater in HF than in NF arteries in ovariectomized rats treated with RESV5 or RESV37.5, not in vehicle-treated rats. In mice lacking estrogen receptor alpha diameter was equivalent in HF and NF arteries whereas in mice treated with RESV5 diameter was greater in HF than in NF vessels. A compensatory increase in wall thickness and a greater phenylephrine mediated contraction were observed in HF arteries. This was more pronounced in HF arteries from RESV37.5-treated rats. ERK1/2 phosphorylation, involved in hypertrophy and contraction, were higher in RESV37.5-treated rats than in RESV5- and vehicle-treated rats. Endothelium-dependent relaxation was greater in HF than in NF arteries in RESV5-treated rats only. In HF arteries from RESV37.5-treated rats relaxation was increased by superoxide reduction and markers of oxidative stress (p67phox, GP91phox) were higher than in the 2 other groups. CONCLUSION: Resveratrol improved flow-mediated outward remodeling in ovariectomized rats thus providing a potential therapeutic tool in menopause-associated ischemic disorders. This effect seems independent of the estrogen receptor alpha. Nevertheless, caution should be taken with high doses inducing excessive contractility and hypertrophy in association with oxidative stress in HF arteries. PMID- 26734766 TI - Evaluation of in vitro antiprotozoal activity of Ajuga laxmannii and its secondary metabolites. AB - Context Some Ajuga L. (Lamiaceae) species are traditionally used for the treatment of malaria, as well as fever, which is a common symptom of many parasitic diseases. Objective In the continuation of our studies on the identification of antiprotozoal secondary metabolites of Turkish Lamiaceae species, we have investigated the aerial parts of Ajuga laxmannii. Materials and methods The aerial parts of A. laxmannii were extracted with MeOH. The H2O subextract was subjected to polyamide, C18-MPLC and SiO2 CCs to yield eight metabolites. The structures of the isolates were elucidated by NMR spectroscopy and MS analyses. The extract, subextracts as well as the isolates were tested for their in vitro antiprotozoal activities against Plasmodium falciparum, Trypanasoma brucei rhodesiense, T. cruzi and Leishmania donovani at concentrations of 90-0.123 MUg/mL. Results Two iridoid glycosides harpagide (1) and 8-O-acetylharpagide (2), three o-coumaric acid derivatives cis-melilotoside (3), trans-melilotoside (4) and dihydromelilotoside (5), two phenylethanoid glycosides verbascoside (6) and galactosylmartynoside (7) and a flavone-C glycoside, isoorientin (8) were isolated. Many compounds showed moderate to good antiparasitic activity, with isoorientin (8) displaying the most significant antimalarial potential (an IC50 value of 9.7 MUg/mL). Discussion and conclusion This is the first report on the antiprotozoal evaluation of A. laxmannii extracts and isolates. Furthermore, isoorientin and dihydromelilotoside are being reported for the first time from the genus Ajuga. PMID- 26734776 TI - Photoinduced Dedoping of Conducting Polymers: An Approach to Precise Control of the Carrier Concentration and Understanding Transport Properties. AB - Exploring the various applications of conjugated polymers requires systematic studies of their physical properties as a function of the doping density, which, consequently, calls for precise control of their doping density. In this study, we report a novel solid-state photoinduced charge-transfer reaction that dedopes highly conductive polyelectrolyte complexes such as poly(3,4 ethylenedioxythiophene)/poly(styrenesulfonate). Varying the UV-irradiation time of this material allows the carrier density inside the film to be precisely controlled over more than 3 orders of magnitude. We extract the carrier density, carrier mobility, and Seebeck coefficient at different doping levels to obtain a clear image of carrier-transport mechanisms. This approach not only leads to a better understanding of the physical properties of the conducting polymer but also is useful for developing applications requiring patterned, large-area conducting polymers. PMID- 26734764 TI - Effects of Argentilactone on the Transcriptional Profile, Cell Wall and Oxidative Stress of Paracoccidioides spp. AB - Paracoccidioides spp., a dimorphic pathogenic fungus, is the etiologic agent of paracoccidioidomycosis (PCM). PCM is an endemic disease that affects at least 10 million people in Latin America, causing severe public health problems. The drugs used against pathogenic fungi have various side effects and limited efficacy; therefore, there is an inevitable and urgent medical need for the development of new antifungal drugs. In the present study, we evaluated the transcriptional profile of Paracoccidioides lutzii exposed to argentilactone, a constituent of the essential oil of Hyptis ovalifolia. A total of 1,058 genes were identified, of which 208 were up-regulated and 850 were down-regulated. Cell rescue, defense and virulence, with a total of 26 genes, was a functional category with a large number of genes induced, including heat shock protein 90 (hsp90), cytochrome c peroxidase (ccp), the hemoglobin ligand RBT5 (rbt5) and superoxide dismutase (sod). Quantitative real-time PCR revealed an increase in the expression level of all of those genes. An enzymatic assay showed a significant increase in SOD activity. The reduced growth of Pbhsp90-aRNA, Pbccp-aRNA, Pbsod-aRNA and Pbrbt5 aRNA isolates in the presence of argentilactone indicates the importance of these genes in the response of Paracoccidioides spp. to argentilactone. The response of the P. lutzii cell wall to argentilactone treatment was also evaluated. The results showed that argentilactone caused a decrease in the levels of polymers in the cell wall. These results suggest that argentilactone is a potential candidate for antifungal therapy. PMID- 26734778 TI - Sulfide-driven autotrophic denitrification significantly reduces N2O emissions. AB - The Sulfate reduction-Autotrophic denitrification-Nitrification Integrated (SANI) process build on anaerobic carbon conversion through biological sulfate reduction and autotrophic denitrification by using the sulfide byproduct from the previous reaction. This study confirmed extra decreases in N2O emissions from the sulfide driven autotrophic denitrification by investigating N2O reduction, accumulation, and emission in the presence of different sulfide/nitrate (S/N) mass ratios at pH 7 in a long-term laboratory-scale granular sludge autotrophic denitrification reactor. The N2O reduction rate was linearly proportional to the sulfide concentration, which confirmed that no sulfide inhibition of N2O reductase occurred. At S/N = 5.0 g-S/g-N, this rate resulted by sulfide-driven autotrophic denitrifying granular sludge (average granule size = 701 MUm) was 27.7 mg-N/g VSS/h (i.e., 2 and 4 times greater than those at 2.5 and 0.8 g-S/g-N, respectively). Sulfide actually stimulates rather than inhibits N2O reduction no matter what granule size of sulfide-driven autotrophic denitrifying sludge engaged. The accumulations of N2O, nitrite and free nitrous acid (FNA) with average granule size 701 MUm of sulfide-driven autotrophic denitrifying granular sludge engaged at S/N = 5.0 g-S/g-N were 4.7%, 11.4% and 4.2% relative to those at 3.0 g-S/g-N, respectively. The accumulation of FNA can inhibit N2O reduction and increase N2O accumulation during sulfide-driven autotrophic denitrification. In addition, the N2O gas emission level from the reactor significantly increased from 14.1 +/- 0.5 ppmv (0.002% of the N load) to 3707.4 +/- 36.7 ppmv (0.405% of the N load) as the S/N mass ratio in the influent decreased from 2.1 to 1.4 g-S/g N over the course of the 120-day continuous monitoring period. Sulfide-driven autotrophic denitrification may significantly reduce greenhouse gas emissions from biological nutrient removal when sulfur conversion processes are applied. PMID- 26734777 TI - Adiposity, physical activity and neuromuscular performance in children. AB - We investigated the associations of body fat percentage (BF%), objectively assessed moderate-to-vigorous physical activity (MVPA) and different types of physical activity assessed by a questionnaire with neuromuscular performance. The participants were 404 children aged 6-8 years. BF% was assessed using dual-energy x-ray absorptiometry and physical activity by combined heart rate and movement sensing and a questionnaire. The results of 50-m shuttle run, 15-m sprint run, hand grip strength, standing long jump, sit-up, modified flamingo balance, box and-block and sit-and-reach tests were used as measures of neuromuscular performance. Children who had a combination of higher BF% and lower levels of physical activity had the poorest performance in 50-m shuttle run, 15-m sprint run and standing long jump tests. Higher BF% was associated with slower 50-m shuttle run and 15-m sprint times, shorter distance jumped in standing long jump test, fewer sit-ups, more errors in balance test and less cubes moved in box-and block test. Higher levels of physical activity and particularly MVPA assessed objectively by combined accelerometer and heart rate monitor were related to shorter 50-m shuttle run and 15-m sprint times. In conclusion, higher BF% and lower levels of physical activity and particularly the combination of these two factors were associated with worse neuromuscular performance. PMID- 26734779 TI - Use of aerobic spores as a surrogate for cryptosporidium oocysts in drinking water supplies. AB - Waterborne illnesses are a growing concern among health and regulatory agencies worldwide. The United States Environmental Protection Agency has established several rules to combat the contamination of water supplies by cryptosporidium oocysts, however, the detection and study of cryptosporidium oocysts is hampered by methodological and financial constraints. As a result, numerous surrogates for cryptosporidium oocysts have been proposed by the scientific community and efforts are underway to evaluate many of the proposed surrogates. The purpose of this review is to evaluate the suitability of aerobic bacterial spores to serve as a surrogate for cryptosporidium oocysts in identifying contaminated drinking waters. To accomplish this we present a comparison of the biology and life cycles of aerobic spores and oocysts and compare their physical properties. An analysis of their surface properties is presented along with a review of the literature in regards to the transport, survival, and prevalence of aerobic spores and oocysts in the saturated subsurface environment. Aerobic spores and oocysts share many commonalities with regard to biology and survivability, and the environmental prevalence and ease of detection make aerobic spores a promising surrogate for cryptosporidium oocysts in surface and groundwater. However, the long-term transport and release of aerobic spores still needs to be further studied, and compared with available oocyst information. In addition, the surface properties and environmental interactions of spores are known to be highly dependent on the spore taxa and purification procedures, and additional research is needed to address these issues in the context of transport. PMID- 26734780 TI - Microbiology and potential applications of aerobic methane oxidation coupled to denitrification (AME-D) process: A review. AB - Aerobic methane oxidation coupled to denitrification (AME-D) is an important link between the global methane and nitrogen cycles. This mini-review updates discoveries regarding aerobic methanotrophs and denitrifiers, as a prelude to spotlight the microbial mechanism and the potential applications of AME-D. Until recently, AME-D was thought to be accomplished by a microbial consortium where denitrifying bacteria utilize carbon intermediates, which are excreted by aerobic methanotrophs, as energy and carbon sources. Potential carbon intermediates include methanol, citrate and acetate. This mini-review presents microbial thermodynamic estimations and postulates that methanol is the ideal electron donor for denitrification, and may serve as a trophic link between methanotrophic bacteria and denitrifiers. More excitingly, new discoveries have revealed that AME-D is not only confined to the conventional synergism between methanotrophic bacteria and denitrifiers. Specifically, an obligate aerobic methanotrophic bacterium, Methylomonas denitrificans FJG1, has been demonstrated to couple partial denitrification with methane oxidation, under hypoxia conditions, releasing nitrous oxide as a terminal product. This finding not only substantially advances the understanding of AME-D mechanism, but also implies an important but unknown role of aerobic methanotrophs in global climate change through their influence on both the methane and nitrogen cycles in ecosystems. Hence, further investigation on AME-D microbiology and mechanism is essential to better understand global climate issues and to develop niche biotechnological solutions. This mini-review also presents traditional microbial techniques, such as pure cultivation and stable isotope probing, and powerful microbial techniques, such as (meta-) genomics and (meta-) transcriptomics, for deciphering linked methane oxidation and denitrification. Although AME-D has immense potential for nitrogen removal from wastewater, drinking water and groundwater, bottlenecks and potential issues are also discussed. PMID- 26734781 TI - The impact of sampling, PCR, and sequencing replication on discerning changes in drinking water bacterial community over diurnal time-scales. AB - High-throughput and deep DNA sequencing, particularly amplicon sequencing, is being increasingly utilized to reveal spatial and temporal dynamics of bacterial communities in drinking water systems. Whilst the sampling and methodological biases associated with PCR and sequencing have been studied in other environments, they have not been quantified for drinking water. These biases are likely to have the greatest effect on the ability to characterize subtle spatio temporal patterns influenced by process/environmental conditions. In such cases, intra-sample variability may swamp any underlying small, systematic variation. To evaluate this, we undertook a study with replication at multiple levels including sampling sites, sample collection, PCR amplification, and high throughput sequencing of 16S rRNA amplicons. The variability inherent to the PCR amplification and sequencing steps is significant enough to mask differences between bacterial communities from replicate samples. This was largely driven by greater variability in detection of rare bacteria (relative abundance <0.01%) across PCR/sequencing replicates as compared to replicate samples. Despite this, we captured significant changes in bacterial community over diurnal time-scales and find that the extent and pattern of diurnal changes is specific to each sampling location. Further, we find diurnal changes in bacterial community arise due to differences in the presence/absence of the low abundance bacteria and changes in the relative abundance of dominant bacteria. Finally, we show that bacterial community composition is significantly different across sampling sites for time-periods during which there are typically rapid changes in water use. This suggests hydraulic changes (driven by changes in water demand) contribute to shaping the bacterial community in bulk drinking water over diurnal time-scales. PMID- 26734782 TI - Microwave-acid pretreatment: A potential process for enhancing sludge dewaterability. AB - Activated sludge is hard to be dewatered due to the highly water bounded in sludge flocs. This study investigated the hybrid treatment of microwave irradiation and acidification on sludge dewaterability as well as its mechanism. Results showed that the combined microwave-acid treatment (T = 100 degrees C, initial pH = 2.5) was effective for improving sludge dewaterability, e.g. capillary suction time (CST) decreased from 37.7 s to 9.2 s, bound water content decreased from 1.96 +/- 0.19 g/g Dry Sludge (DS) to 0.88 +/- 0.24 g/g DS. The treated sludge showed more fluidity and less thixotropy. Both MW heating temperature and pH played important roles in improving sludge dewaterability. Higher temperature was beneficial for sludge disintegration, but the released polymers resulted in highly negative zeta potential and deteriorated sludge dewaterability. The acidification was capable of reducing the negative zeta potential, increasing flocs size and finally improving sludge dewaterability. According to the analysis of molecule weight distribution and 3D-EEM, the fractions of polymers especially protein-like substances at molecule weight of 10(4)-10(5) Da were the key organics related to sludge dewaterability, but not the humic acid-like and fulvic acid-like substances. PMID- 26734783 TI - Practical identifiability and uncertainty analysis of the one-dimensional hindered-compression continuous settling model. AB - The practical application of the one-dimension hindered-compression settling models remains a challenge, since the model calibration strongly depends on experimental observations with limited information. In this study, the identifiability of parameter subsets of the hindered-compression models is evaluated for various experimental layouts. Global sensitivity analysis is used to preliminarily select the influential parameters which can be reasonably estimated, while the identifiability analysis of parameter subsets is conducted based on the local sensitivity functions and collinearity measures. The batch settling curve observations are informative for calibrating hindered parameters, and to determine the compression parameters, the concentration profile observations may need to be collected. For different experimental layouts, at least three parameters are identifiable, and the number of identifiable parameters can potentially increase to five, if both batch settling curve and concentration observations are available. The parameter subset identifiability is sensitive to the choice of initial parameter values, and determining the initial values of hindered parameters and gel concentration by measuring the hindered settling velocities and the top concentration of the static sediment respectively allows efficient reduction of the sensitivity. Parameter subset estimates are sensitive to the values of fixed parameters, and reliable estimation of identifiable parameter subsets is possible to significantly decrease model prediction uncertainties. PMID- 26734784 TI - 'Tablet burden' in patients with metastatic breast cancer. AB - The implications for patients with cancer, of the 'tablet burden' resulting from increasing use of oral anticancer drugs and medication for co-morbidities have not previously been well explored. AIM: We sought to (i) quantify tablet burden in women with metastatic breast cancer (MBC), (ii) establish which groups of drug contribute most to this burden and (iii) gain insight into patients' attitudes towards oral anti-cancer treatment. METHODS: One hundred patients with MBC anonymously completed a questionnaire describing their medication histories and attitudes towards their tablets. RESULTS: The patients (mean age 60, range 31-95) were all female and taking a median of six tablets (range 0-31) daily; 37 patients were taking >10 tablets. Oral anticancer treatment constituted the category of treatment taken by the highest proportion of patients, followed by symptomatic cancer treatments, proton pump inhibitors and cardiovascular medication. Numerically, however, symptomatic drugs accounted for 44% of all tablets and specific anti-cancer treatment for 15%; medication not directly related to the cancer accounted for the remaining 40% of tablets. A quarter of patients reported inconvenience in taking their tablets, the main reason being tablet size and one third reported forgetting their tablets at least once a week. Nearly two thirds of patients expressing a preference favoured oral anticancer treatment, the commonest reason being greater convenience. CONCLUSION: Tablet burden is considerable for many patients with MBC and can be problematic. A significant proportion of tablets represent treatment for co-morbidities, the significance of which may be questionable in women with MBC. PMID- 26734786 TI - Aqueous Compatible Protocol to Both Alkyl and Aryl Thioamide Synthesis. AB - An efficient aqueous synthesis of thioamides through aldehydes, sodium sulfide, and N-substituted formamides has been developed. Both alkyl and aryl aldehydes are amenable to this protocol. N-Substituted formamides are essential for this transformation. Readily available inorganic salt (sodium sulfide) serves as the sulfur source in water, which makes this method much more practical and efficient. Furthermore, the late-stage modification of bioactive molecules and derivatives through this protocol has been established. PMID- 26734787 TI - I BRAZILIAN CONSENSUS FOR MULTIMODAL TREATMENT OF COLORECTAL LIVER METASTASES. PMID- 26734789 TI - ASSESSMENT OF THE GASTRO-JEJUNO-DUODENAL TRANSIT AFTER JEJUNAL POUCH INTERPOSITION. AB - BACKGROUND: The jejunal pouch interposition between the gastric body and the duodenum after the gastrectomy, although not frequent in the surgical practice today, has been successfully employed for the prevention and treatment of the postgastrectomy syndromes. In the latter, it is included the dumping syndrome, which affects 13-58% of the patients who undergo gastrectomy. AIM: Retrospective assessment of the results of this procedure for the prevention of the dumping syndrome. METHODS: Fourty patients were selected and treatetd surgically for peptic ulcer, between 1965 and 1970. Of these, 29 underwent vagotomy, antrectomy, gastrojejunalduodenostomy at the lesser curvature level, and the 11 remaining were submitted to vagotomy, antrectomy, gastrojejunal-duodenostomy at the greater curvature level. The gastro-jejuno-duodenal transit was assessed in the immediate or late postoperative with the contrasted study of the esophagus, stomach and duodenum. The clinical evolution was assessed according to the Visick grade. RESULTS: Of the 40 patients, 28 were followed with the contrast evaluation in the late postoperative. Among those who were followed until the first month (n=22), 20 (90%) had slow gastro-jejuno-duodenal transit and in two (10%) the transit was normal. Among those who were followed after the first month (n=16), three (19%) and 13 (81%) had slow and normal gastric emptying, respectively. None had the contrasted exam compatible with the dumping syndrome. Among the 40 patients, 22 underwent postoperative clinical evaluation. Of these, 19 (86,5%) had excellent and good results (Visick 1 and 2, respectively). CONCLUSIONS: The jejunal pouch interposition showed to be a very effective surgical procedure for the prevention of the dumping syndrome in gastrectomized patients. PMID- 26734790 TI - AUDIOVISUAL RESOURCES ON THE TEACHING PROCESS IN SURGICAL TECHNIQUE. AB - BACKGROUND: The development of didactic means to create opportunities to permit complete and repetitive viewing of surgical procedures is of great importance nowadays due to the increasing difficulty of doing in vivo training. Thus, audiovisual resources favor the maximization of living resources used in education, and minimize problems arising only with verbalism. AIM: To evaluate the use of digital video as a pedagogical strategy in surgical technique teaching in medical education. METHODS: Cross-sectional study with 48 students of the third year of medicine, when studying in the surgical technique discipline. They were divided into two groups with 12 in pairs, both subject to the conventional method of teaching, and one of them also exposed to alternative method (video) showing the technical details. All students did phlebotomy in the experimental laboratory, with evaluation and assistance of the teacher/monitor while running. Finally, they answered a self-administered questionnaire related to teaching method when performing the operation. RESULTS: Most of those who did not watch the video took longer time to execute the procedure, did more questions and needed more faculty assistance. The total exposed to video followed the chronology of implementation and approved the new method; 95.83% felt able to repeat the procedure by themselves, and 62.5% of those students that only had the conventional method reported having regular capacity of technique assimilation. In both groups mentioned having regular difficulty, but those who have not seen the video had more difficulty in performing the technique. CONCLUSION: The traditional method of teaching associated with the video favored the ability to understand and transmitted safety, particularly because it is activity that requires technical skill. The technique with video visualization motivated and arouse interest, facilitated the understanding and memorization of the steps for procedure implementation, benefiting the students performance. PMID- 26734788 TI - FIRST BRAZILIAN CONSENSUS ON MULTIMODAL TREATMENT OF COLORECTAL LIVER METASTASES. MODULE 1: PRE-TREATMENT EVALUATION. AB - BACKGROUND: Liver metastases of colorectal cancer are frequent and potentially fatal event in the evolution of patients with these tumors. AIM: In this module, was contextualized the clinical situations and parameterized epidemiological data and results of the various treatment modalities established. METHOD: Was realized deep discussion on detecting and staging metastatic colorectal cancer, as well as employment of imaging methods in the evaluation of response to instituted systemic therapy. RESULTS: The next step was based on the definition of which patients would have their metastases considered resectable and how to expand the amount of patients elegible for modalities with curative intent. CONCLUSION: Were presented clinical, pathological and molecular prognostic factors, validated to be taken into account in clinical practice. PMID- 26734791 TI - ASSESSMENT OF MECHANICAL AND MANUAL SUTURE IN THE SURGICAL TREATMENT OF THE PHARYNGOESOPHAGEAL DIVERTICULUM. AB - BACKGROUND: The occurrence of the pharyngoesophageal, or Zenker diverticulum is not frequent in the national scenario, and the technique of the diverticulectomy with cricomyotomy in medium and great dimension diverticula is still the most indicated. Because the resection of the diverticulum requires the suture of the pharynx, dehiscence can occur, thereafter delaying swallowing. Hence, the idea is to accomplish this surgical procedure, comparing the manual and mechanical suture, in order to evaluate the real benefit of the mechanical technique. AIM: To evaluate the results of the pharyngoesophageal diverticulectomy with cricomyotomy using manual and mechanical suture with regard to local and systemic complications. METHOD: Fifty-seven patients with pharyngoesophageal diverticula diagnosed through high digestive endoscopy and pharyngeal esophagogram were studied. The applied surgical technique was diverticulectomy with myotomy of the cricopharyngeal muscle, done in 24 patients (42.2%) the mechanical suture (group A) with the mechanical linear suture device and in 33 (57.8%) a manual closure of the pharynx (group B). RESULTS: In the postoperative period, one patient of group A (4.1%) presented fistula caused by dehiscence of the pharyngeal suture, and three of group B (15.1%) presented the same complication, with a good outcome using a conservative treatment. In the same group, three patients (9.0%) presented stenosis of the suture of the pharynx, with good outcome and with endoscopic dilatations, and no patient from group A presented such complication. Lung infection was present in five patients, being two (8.3%) of group A and three (9.0%) on B, having good outcomes after specific treatment. In the late review, done with 43 patients (94.4%) of group A and 22 (88.0%) on B, the patients declared to be pleased with the surgical procedure, because they were able to regain normal swallowing. CONCLUSION: The diverticulectomy with myotomy and pharyngeal closure using mechanical suture was proven appropriate, for having restored regular swallowing in most of the patients, and the mechanical closure of the pharynx proved to be more effective in comparison to the manual one, because it provided a lower index of local post-surgical complications. PMID- 26734792 TI - EFFECTS OF TOPICAL TREATMENT WITH EUPHORBIA TIRUCALLI LATEX ON THE SURVIVAL AND INTESTINAL ADHESIONS IN RATS WITH EXPERIMENTAL PERITONITIS. AB - BACKGROUND: The use of plants of the family Euphorbiaceae, particularly Euphorbia tirucalli (avelos) has been popularly widespread for treating a variety of diseases of infectious, tumoral, and inflammatory. AIM: To demonstrated antimicrobial and immunomodulatory effects of these extracts, evaluating the effect of a topical treatment with an aqueous solution of avelos latex on the survival and on intestinal adhesions in rats with experimental peritonitis. METHODS: Peritonitis was induced in 24 Wistar rats, that were randomized into four groups of six as follows: (1) Control group (n=6), no treatment; (2) Antibiotic group (n=6), treatment with a single intramuscular dose of antibiotic Unasyn; (3) Saline group (n=6), the abdominal cavity was washed with 0.9% saline; and (4) E.tirucalli group (n=6), the abdominal cavity was washed with E. tirucalli at a concentration of 12 mg/ml. The animals that died were necropsied, and the time of death was recorded. The survivors were killed on postoperative day 11, and necropsy was subsequently performed for evaluation of the intestinal adhesions. RESULTS: Significant differences were observed in the control and antibiotic groups (p<0.01) with respect to the survival hours when compared with the saline and E. tirucalli groups. There was no significant difference (p>0.05) in the survival of animals in the saline andE. tirucalli groups; however, one animal died in the saline group. Necropsy of the animals in the saline and E. tirucalligroups showed strong adhesions resistant to manipulation, between the intestinal loops and abdominal wall. The remaining groups did not show any adhesions. CONCLUSIONS: Topical treatment with E. tirucalli latex stimulated an increased formation of intestinal adhesions and prevented the death of all animals with peritonitis. PMID- 26734793 TI - EVALUATION OF ETHICAL IN INSTRUCTIONS TO AUTHORS OF BRAZILIAN SURGICAL JOURNALS. AB - BACKGROUND: The instructions to authors are the only means of communication between researchers and the editorial standards of a scientific journal. One of the mandatory items to be contained therein is about the ethical part, to prevent new research to carry out abuses with the enrolled on the research are published and stimulated. AIM: To verify the ethical questions on the guidelines of Brazilian surgical journals Method: Thirteen selected journals were divided into two groups: general surgery (n=3), and surgical specialty (n=10). The instructions to authors were analyzed by the quote of ethical requirements based on a specific research protocol, ranging from zero to six points. RESULTS: The average score of the general surgery group was similar than that of the surgical specialty group (3.66+/-0.57 vs 3.30+/-1.15, p=0.6154). When each ethical requirement was compared between the groups, there was no significant difference between the ethical requirements (p<0.05). CONCLUSION: There was respect for most ethical questions evaluated, with no difference between the journals of general or specialty surgery. PMID- 26734794 TI - FASTING IN ELECTIVE SURGICAL PATIENTS: COMPARISON AMONG THE TIME PRESCRIBED, PERFORMED AND RECOMMENDED ON PERIOPERATIVE CARE PROTOCOLS. AB - BACKGROUND: Prolonged preoperative fasting may impair nutritional status of the patient and their recovery. In contrast, some studies show that fasting abbreviation can improve the response to trauma and decrease the length of hospital stay. AIM: Investigate whether the prescribed perioperative fasting time and practiced by patients is in compliance with current multimodal protocols and identify the main factors associated. METHODS: Cross-sectional study with 65 patients undergoing elective surgery of the digestive tract or abdominal wall. We investigated the fasting time in the perioperative period, hunger and thirst reports, physical status, diabetes diagnosis, type of surgery and anesthesia. RESULTS: The patients were between 19 and 87 years, mostly female (73.8%). The most performed procedure was cholecystectomy (47.69%) and general anesthesia the most used (89.23%). The most common approach was to start fasting from midnight for liquids and solids, and most of the patients received grade II (64.6%) to the physical state. The real fasting average time was 16 h (9.5-41.58) was higher than prescribed (11 h, 6.58 -26.75). The patients submitted to surgery in the afternoon were in more fasting time than those who did in the morning (p<0.001). The intensity of hunger and thirst increased in postoperative fasting period (p=0.010 and 0.027). The average period of postoperative fasting was 18.25 h (3.33-91.83) and only 23.07% restarted feeding on the same day. CONCLUSION: Patients were fasted for prolonged time, higher even than the prescribed time and intensity of the signs of discomfort such as hunger and thirst increased over time. To better recovery and the patient's well-being, it is necessary to establish a preoperative fasting abbreviation protocol. PMID- 26734795 TI - ASSOCIATION AMONG HISTOLOGICAL FINDINGS SUGGESTIVE OF PAPILLOMA VIRUS ON HEMORRHOIDECTOMY SPECIMENS. AB - BACKGROUND: Many researchers studied human Papillomavirus infection in the anal area supposing it represents a risk factor for precursor lesions of anal cancer. AIM: To study the association between histological findings suggestive of injury by the virus in hemorrhoidectomy specimens. METHOD: Prevalence study was carried out based on histopathological analysis of hemorrhoidectomy specimens to find viral cytopathic effects. These findings were compared with anal condyloma acuminata that had no relationship with hemorrhoidectomy for microscopic comparison. RESULTS: Of the 91 hemorroidectomies analyzed, eight had findings suggestive of viral cytopathic effects, with the presence of irregular acanthosis in 63%, koilocytes in 50% and other indirect viral cytopathic effects, such as hyperkeratosis (38%), parakeratosis (25% ) and papillomatosis (13%). CONCLUSION: This study was unable to conclude that there is an association between these two pathologic entities. PMID- 26734796 TI - EFFECT OF OMEGA-3 FATTY ACID IN THE HEALING PROCESS OF COLONIC ANASTOMOSIS IN RATS. AB - BACKGROUND: The use of long-chain polyunsaturated fatty acids has been studied in the context of healing and tissue regeneration mainly due to its anti inflammatory, immunoregulatory and antioncogenic properties. Previous studies have demonstrated beneficial effects with the use of enteral immunonutrition containing various farmaconutrients such as L-arginine, omega-3, trace elements, but the individual action of each component in the healing of colonic anastomosis remains unclear. AIM: To evaluate the influence of preoperative supplementation with omega-3 fatty acids on the healing of colonic anastomoses of well-nourished rats. METHODS: Forty Wistar adult male rats, weighing 234.4+/-22.3 g were used. The animals were divided into two groups: the control group received for seven days olive oil rich in omega-9 oil through an orogastric tube, while the study group received isocaloric and isovolumetric omega-3 emulsion at a dose of 100 mg/kg/day, also for seven days. Both groups were submitted to two colotomies followed by anastomosis, in the right and left colon, respectively. Parameters evaluated included changes in body weight, anastomotic complications and mortality, as well as maximum tensile strength by using a tensiometer and collagen densitometry at the anastomotic site. RESULTS: There were no differences in body weight or mortality and morbidity between groups. The value of the maximum tensile strength of the control group was 1.9+/-0.3 N and the study group 1.7+/-0.2, p=0.357. There was, however, a larger amount of type I collagen deposition in the study group (p=0.0126). The collagen maturation index was 1.74+/-0.71 in the control group and 1.67+/-0.5 in the study group; p=0,719). CONCLUSIONS: Preoperative supplementation of omega-3 fatty acid in rats is associated with increased collagen deposition of type I fibers in colonic anastomoses on the 5th postoperative day. No differences were observed in the tensile strength or collagen maturation index. PMID- 26734797 TI - IMPROVED EXPERIMENTAL MODEL TO EVALUATE SUBMUCOSAL INJECTION SOLUTIONS FOR ENDOSCOPIC SUBMUCOSAL DISSECTION. AB - BACKGROUND: Endoscopic submucosal dissection carries an increased risk of bleeding and perforation. The creation of a long lasting submucosal cushion is essential for the safe and complete removal of the lesion. There is not a suitable experimental model for evaluation of the durability of the cushioning effect of different solutions. AIM: To describe an improved experimental model to evaluate submucosal injection solutions. METHODS: A total of four domestic pigs were employed to evaluate two different submucosal fluid solutions in the gastric submucosa. After midline laparotomy, the anterior gastric wall was incised from the gastric body to the antrum and its mucosal surface was exposed by flipping inside out the incised gastric wall. Two different solutions (10% mannitol and normal saline) were injected in the submucosa of the anterior wall of the distal gastric body. All submucosal cushions were injected until they reach the same size, standardized as 1.0 cm in height and 2.0 cm in diameter. A caliper and a ruler were employed to guarantee accuracy of the measurements. RESULTS: All four animal experiments were completed. All submucosal cushions had the exact same size measured with caliper and a ruler. By using the mannitol solution, the mean duration of the submucosal cushion was longer than the saline solution: 20 and 22 min (mean, 21 min) vs 5 and 6 min (mean, 5.5 min) CONCLUSIONS: This experimental model is simple and evaluate the duration, size, and effect of the submucosal cushion, making it more reliable than other models that employ resected porcine stomachs or endoscopic images in live porcine models. PMID- 26734798 TI - IMMUNOLOGICAL EVALUATION OF PATIENTS WITH TYPE 2 DIABETES MELLITUS SUBMITTED TO METABOLIC SURGERY. AB - BACKGROUND: Immunological and inflammatory mechanisms play a key role in the development and progression of type 2 diabetes mellitus. AIM: To raise the hypothesis that alterations in immunological parameters occur after duodenojejunal bypass surgery combined with ileal interposition without gastrectomy, and influences the insulin metabolism of betacells. METHODS: Seventeen patients with type 2 diabetes mellitus under clinical management were submitted to surgery and blood samples were collected before and six months after surgery for evaluation of the serum profile of proinflammatory (IFN-gamma, TNF alpha, IL-17A) and anti-inflammatory cytokines (IL-4, IL-10). In addition, anthropometric measures, glucose levels and insulin use were evaluated in each patient. RESULTS: No changes in the expression pattern of proinflammatory cytokines were observed before and after surgery. In contrast, there was a significant decrease in IL-10 expression, which coincided with a reduction in the daily insulin dose, glycemic index, and BMI of the patients. Early presentation of food to the ileum may have induced the production of incretins such as GLP-1 and PYY which, together with glycemic control, contributed to weight loss, diabetes remission and the consequent good surgical prognosis of these patients. In addition, the control of metabolic syndrome was responsible for the reduction of IL-10 expression in these patients. CONCLUSION: These findings suggest the presence of low-grade inflammation in these patients during the postoperative period, certainly as a result of adequate glycemic control and absence of obesity, contributing to a good outcome of surgery. PMID- 26734799 TI - PROFILE OF PATIENTS WHO SEEK THE BARIATRIC SURGERY. AB - BACKGROUND: Nowadays obesity is a chronic disease considered one of the greatest problems in public healthy. Showing to be effective in a short and long term, the bariatric surgery has emerged as an optional treatment for morbid obesity. AIM: Identify the profile of patients seeking bariatric surgery. METHODS: Were interviewed 100 patients in preoperative nutritional monitoring of bariatric surgery. The study was conducted by applying a questionnaire prepared according to the research objectives. RESULTS: From the individuals that were seeking bariatric surgery, 78% were female, 62% were married and 69% reported physical activity. The average age of those surveyed was 37+/-10.83 years and mean body mass index (BMI) was 43.51+/- 6.25 kg/m2. The comorbidity more prevalent in this group was high blood pressure (51%). In previous treatments for weight reduction, 92% have already done hypocaloric diet followed by anorectic drug (83%). The success of these treatments was reported by 92% of patients; however, the weight lost was recovered in less than one year of 75%. Patients with diabetes mellitus and dyslipidemia had higher BMI values. The patients with comorbidities showed lower levels of BMI. CONCLUSION: The profile of patients who sought surgical treatment for their obesity were predominantly women with a family background of obesity and obesity-related comorbidities, especially hypertension and diabetes mellitus. PMID- 26734800 TI - COMPARISON OF HEPATIC PROFILE IN PRE AND POSTOPERATIVE OF BARIATRIC SURGERY: PRIVATE VS PUBLIC NETWORK. AB - BACKGROUND: Obesity is associated to several comorbidities, including nonalcoholic fatty liver disease, which implicates in isolated steatosis to steatohepatitis. The latter may progress to severe manifestations such as liver fibrosis, cirrhosis and hepatocellular carcinoma. AIM: To compare the presence of advanced liver fibrosis before and after bariatric surgery in patients of private and public health system. METHODS: Patients from public and privative networks were studied before and after bariatric surgery. The presence or absence of advanced hepatic fibrosis was evaluated by NAFLD Fibrosis Score, a non-invasive method that uses age, BMI, AST/ALT ratio, albumin, platelet count and the presence or absence of hyperglycemia or diabetes. The characteristics of the two groups were compared. The established statistical significance criterion was p<0.05. RESULTS: Were analyzed 40 patients with a mean age of 34.6+/-9.5 years for private network and 40.6+/- 10.2 years for public. The study sample, 35% were treated at private health system and 65% in the public ones, 38% male and 62% female. Preoperatively in the private network one (7.1%) patient had advanced liver fibrosis and developed to the absence of liver fibrosis after surgery. In the public eight (30.8%) patients had advanced liver fibrosis preoperatively, and at one year after the proportion fell to six (23%). CONCLUSION: The non-alcoholic fatty liver disease in its advanced form is more prevalent in obese patients treated in the public network than in the treated at the private network and bariatric surgery may be important therapeutic option in both populations. PMID- 26734801 TI - PROPOSAL OF A REVISIONAL SURGERY TO TREAT NON-INSULINOMA HYPERINSULINEMIC HYPOGLICEMIA POSTGASTRIC BYPASS. AB - BACKGROUND: Hyperinsulinemic hypoglicemia with severe neuroglycopenic symptoms has been identified as a late and rare complication in patients submitted to Roux en-Y gastric bypass. However, the potential gravity of its manifestations requires effective treatment of this condition. The absence of treatment makes it necessary to develop more effective clinical or surgical methods. AIM: To present one surgical option to revisional surgery in the treatment of hyperinsulinemic hypoglicemia Methods : The procedure consists in reconstituting alimentary transit through the duodenum and proximal jejunum, while keeping the restrictive part of the gastric bypass. As an additional strategy to maintain weight loss, is realized gastric fundus resection, aiming to suppress ghrelin production more effectively. RESULTS: It was used in three patients with successful results in one year of follow-up. CONCLUSION: The procedure to reconstruct the food transit through the duodenum and proximal jejunum, keeping the restrictive component of gastric bypass in the treatment of hyperinsulinemic hypoglycemia showed good initial results and validated its application in other cases with this indication. PMID- 26734802 TI - REDUCE PORT LAPAROSCOPIC SPLENECTOMY FOR GIANT EPITELIAL CYST. AB - BACKGROUND: Delaitre and Maignien performed the first successful laparoscopic splenectomy in 1991. After that, laparoscopic splenectomy has become one of the most frequently performed laparoscopic solid organ procedures. AIM: To demonstrate the surgical techique of laparoscopic splenetomy with reduced portals. METHODS: A reduce port laparoscopic splenectomy was performed by using a 10 mm and two 5 mm trocars. To entered the abdomen a trans-umbilical open technique was done and a 10 mm trocar was placed. A subcostal 5 mm trocar was placed under direct vision at the level of the anterior axillary line and another 5 mm port was inserted at the mid-epigastric region. Once it was completely dissected and freed from all of its attachments the hilum, splenic artery and vein, was clipped with hem-o-lock and divided with scissors. Then an endobag was used to retrieve the spleen after being morcellated trough the umbilical incision. RESULTS: This technique was used in a 15 years old female with epigastric and left upper quadrant pain. An abdominal ultrasound demonstrated a giant cyst located in the spleen. Laboratory tests findings were normal. The CT scan was also done, and showed a giant cyst, which squeeze the stomach. The patient tolerated well the procedure, with an unremarkable postoperative. She was discharge home 72 h after the surgery. CONCLUSION: The use of reduce port minimizes abdominal trauma and has the hypothetical advantages of shorter postoperative stay, greater pain control, and better cosmesis. Laparoscopic splenectomy for giant cysts by using reduce port trocars is safe and feasible and less invasive. PMID- 26734803 TI - LIVER TRANSPLANTATION AFTER SEVERE HEPATIC TRAUMA: CURRENT INDICATIONS AND RESULTS. AB - BACKGROUND: The liver is the most injured organ in abdominal trauma. Currently, the treatment in most cases is non-operative, but surgery may be necessary in severe abdominal trauma with blunt liver damage, especially those that cause uncontrollable bleeding. Despite the damage control approaches in order to achieve hemodynamic stability, many patients develop hypovolemic shock, acute liver failure, multiple organ failure and death. In this context, liver transplantation appears as the lifesaving last resource Aim : Analyze the use of liver transplantation as a treatment option for severe liver trauma. METHODS: Were reviewed 14 articles in the PubMed, Medline and Lilacs databases, selected between 2008-2014 and 10 for this study. RESULTS: Were identified 46 cases undergoing liver transplant after liver trauma; the main trauma mechanism was closed/blunt abdominal trauma in 83%, and severe trauma (>grade IV) in 81 %. The transplant can be done, in this context, performing one-stage procedure (damaged organ removed with immediate transplantation), used in 72% of cases. When the two stage approach is performed, end-to-side temporary portacaval shunt is provided, until new organ becomes available to be transplanted. If two different periods are considered - from 1980 to 2000 and from 2000 to 2014 - the survival rate increased significantly, from 48% to 76%, while the mortality decreased from 52% to 24%. CONCLUSION: Despite with quite restricted indications, liver transplantation in hepatic injury is a therapeutic modality viable and feasible today, and can be used in cases when other therapeutic modalities in short and long term, do not provide the patient survival chances. PMID- 26734804 TI - URIC ACID AND TISSUE REPAIR. AB - Uric acid, a metabolic product of purines, may exert a role in tissue healing. In this review we will explore its role as an alarm initiating the inflammatory process that is necessary for tissue repair, as a scavenger of oxygen free radicals, as a mobilizer of progenitor endothelial cells and as supporter of adaptive immune system. PMID- 26734805 TI - VERRUCOUS CARCINOMA OF THE ESOPHAGUS INVOLVING THE ENTIRE ESOPHAGUS. PMID- 26734806 TI - LAPAROSCOPIC TREATMENT OF CELIAC AXIS COMPRESSION SYNDROME: CASE REPORT. PMID- 26734807 TI - INTRA-ABDOMINAL SEMINOMA TESTIS IN ADULT: CASE REPORT. PMID- 26734808 TI - LATE SURGICAL TREATMENT FOR SPONTANEOUS RUPTURE OF HEPATOCELLULAR ADENOMA: CASE REPORT. PMID- 26734809 TI - RIGHT-SIDED BOCHDALEK HERNIA IN ADULT ASSOCIATED WITH CHOLESTATIC SYNDROME: CASE REPORT. PMID- 26734810 TI - A New Method for Describing the Mechanism of a Chemical Reaction Based on the Unified Reaction Valley Approach. AB - The unified reaction valley approach (URVA) used for a detailed mechanistic analysis of chemical reactions is improved in three different ways: (i) Direction and curvature of path are analyzed in terms of internal coordinate components that no longer depend on local vibrational modes. In this way, the path analysis is no longer sensitive to path instabilities associated with the occurrences of imaginary frequencies. (ii) The use of third order terms of the energy for a local description of the reaction valley allows an extension of the URVA analysis into the pre- and postchemical regions of the reaction path, which are typically characterized by flat energy regions. (iii) Configurational and conformational processes of the reaction complex are made transparent even in cases where these imply energy changes far less than a kcal/mol by exploiting the topology of the potential energy surface. As examples, the rhodium-catalyzed methanol carbonization, the Diels-Alder reaction between 1,3-butadiene and ethene, and the rearrangement of HCN to CNH are discussed. PMID- 26734811 TI - A retrospective study on the clinical efficacy of the intense pulsed light source for photodamage and skin rejuvenation. AB - OBJECTIVE: The objective of this retrospective review is to investigate the long term effect of skin rejuvenation by the intense pulsed light (IPL) source for the treatment of photoaging. METHODS: From 5300 clinical cases that our department has treated with the IPL, the first 2534 were chosen for this study. Each patient received a minimum of 3 IPL treatments during this time-many were yearly treatments. Clinical photographs were taken on a yearly basis for up to 12 years and sent to a blinded independent panel to study the effects of continuous IPL treatments. RESULTS: Results showed that the effective rate for the IPL was between 88.24% and 96.45%. CONCLUSIONS: IPL therapy is an effective treatment for photoaging and can truly have an effect on reversing the signs of photodamage on skin. PMID- 26734812 TI - Experience with four consecutive BFM-based protocols for treatment of childhood with non-promyelocytic acute myeloblastic leukemia in Argentina. AB - Childhood acute myeloid leukemia (AML) achieves event-free-survival (EFS) rates of ~50%. Double induction phase has been introduced for improving these results. Four consecutive protocols for AML treatment were evaluated to assess the impact of the addition of a second induction course in our setting. From January 1990 to January 2014, 307 evaluable AML patients were accrued. They were classified into low-risk (LR) and high-risk (HR) according to cytogenetic/molecular findings and response on day 15. The first two studies administered one induction cycle while the latter two protocols administered double induction. Relapse was the most frequent event and early-deaths were reduced by 50% in the last protocol. Statistically significant differences were observed when comparing EFS in LR and HR groups. Patients from both risk-groups who received double induction achieved significantly better outcome. EFS improved in protocols with double induction and early-deaths rate was decreased. Cytogenetic/molecular features and early response were confirmed as prognostic factors. PMID- 26734813 TI - Outcomes of a Quality Improvement Initiative to Prevent Unnecessary Packed Red Blood Cell Transfusions Among Extremely Low Birth-Weight Neonates. AB - BACKGROUND: Extremely low birth-weight (ELBW) infants frequently receive packed red blood cell (PRBC) transfusions. Recent studies have shown that more restrictive PRBC transfusion guidelines limit donor exposure and reduce transfusion-related costs without any increase in adverse clinical outcomes. PURPOSE: We developed and implemented an evidence-based PRBC transfusion guideline for ELBW infants treated in our unit and then measured provider adherence to this guideline. METHODS/SEARCH STRATEGY: We performed a retrospective review of all PRBC transfusions given to ELBW infants in 2012 (preguideline) and the first half of 2014 (postguideline). We identified the indication for each transfusion by reviewing physiological/laboratory data and the daily clinical note. We then determine whether each transfusion met criteria according to our new evidence-based guideline. FINDINGS/RESULTS: When extrapolating the newly developed protocol to 2012 data, less than 15% of transfusions among ELBW infants would have met the current evidence-based standard. Conversely, during the first 6 months of 2014, 61% of transfusions were administered in adherence to the guideline (P < 001). Using current cost estimates, this represents a projected cost savings of $31,000 in that 6-month period. IMPLICATIONS FOR PRACTICE: A multidisciplinary approach to improving PRBC transfusion practices results in potentially safer, more cost-effective care for ELBW infants. IMPLICATIONS FOR RESEARCH: Given the frequency, potential harms, and costs associated with PRBC transfusions in ELBW infants, it seems both feasible and important to pursue prospective clinical trials comparing permissive and restrictive approaches to transfusion in this vulnerable population. PMID- 26734814 TI - Bronchopulmonary Dysplasia Within and Beyond the Neonatal Unit. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD), also known as chronic lung disease of prematurity or chronic neonatal lung disease, is a major cause of respiratory illness in premature babies. Newborn babies survive at gestational ages of 23 to 26 weeks, earlier than when BPD was first described. New mechanisms of lung injury have therefore emerged and the clinical and pathological characteristics of pulmonary involvement have changed. PURPOSE: Improved neonatal intensive care unit modalities have increased survival rates; the overall prevalence of the condition, however, has not changed. Management of evolving BPD aims at minimizing lung injury. Management of established, especially severe BPD, still poses significant clinical challenge as these babies need long-term oxygen therapy (LTOT) for variable length of time. We aim to give an overview of management of established BPD with particular focus on weaning home oxygen therapy at our local center in the United Kingdom. SEARCH AND RESULTS: On the basis of most recent evidence, we concluded that an integrated pathway for managing babies on LTOT is very important after discharge from neonatal unit. IMPLICATIONS FOR PRACTICE: A structured weaning pathway for premature babies on home oxygen improves outcome. IMPLICATIONS FOR RESEARCH: The management of severe BPD and related complications, particularly during the first 2 years of life, remains a continuing challenge for parents and healthcare providers. The most beneficial respiratory support strategy to minimize lung injury and/or promote lung healing remains unclear and requires further investigation. PMID- 26734815 TI - Delayed Umbilical Cord Clamping in the 21st Century: Indications for Practice. AB - BACKGROUND: Health care providers have debated the timing of umbilical cord clamping since the days of Aristotle. Delayed cord clamping was the mainstay of practice until about the 1950s when it was changed to immediate clamping on the basis of a series of blood volume studies combined with the introduction of active management of the third stage of labor. However, in recent years, several systematic reviews advise that delayed cord clamping should be used in all births for at least 30 to 60 seconds. PURPOSE: The purpose of this article is to discuss the physiology of umbilical cord clamping, the potential benefits and adverse effects of delayed cord clamping, and how this affects the advanced practice nurse. SEARCH STRATEGY: A search of PubMed, Cochrane Reviews, and Clinical Key was used to find relevant research on the topic of umbilical cord clamping. RESULTS: Potential benefits of delayed cord clamping include decreased frequency of iron-deficiency anemia in the first year of life with improved neurodevelopmental outcomes in term infants, reduced need for blood transfusions, possible autologous transfusion of stem cells, and a decreased incidence of intraventricular hemorrhage. Apprehension exists regarding the feasibility of the practice as well as the potential hindrance of immediate resuscitation. IMPLICATIONS FOR PRACTICE: There is a need to begin to look for populations for which delayed cord clamping can be implemented. IMPLICATIONS FOR FUTURE RESEARCH: Recommendations are inconsistent on the patient population and timing; therefore, further studies are needed to understand the multiple variables that affect timing of umbilical cord clamping. PMID- 26734816 TI - Evaluation of fluorine release from air deposited coal spoil piles: A case study at Yangquan city, northern China. AB - The fluorine content of coal has been well documented, while such data of coal spoil are limited. In the present paper, fluorine in coal spoils and its releasing behavior were studied via leaching and combustion tests, as well as field investigation. Fluoride pollution in groundwater and soil occurred in the air depositing areas of coal spoils. The average content of fluorine in coal spoils was 525 mg/kg with the highest value of 1885 mg/kg. The only XRD detectable inorganic fluorine phase was fluorphlogopite. The absence of major fluorine bearing minerals in coal spoils suggested that bulk fluorine, rather than trace phases, resided in the mineral matrix. The major extracted species were water soluble fluorine and exchangeable fluorine in the coal spoils. Batch leaching tests illustrated that the leachable fluoride in coal spoils was widely distributed, ranging from 2.0 to 108.4 mg/kg. Column leaching tests showed a clear pH-dependent leaching behavior of fluorine: lower pH situation led to fluorine release from the mineral matrix; the loosely bound or easily exchangeable fluorine was also flushed out of the column. The higher ion strength or alkaline bicarbonate/carbonate rich leaching solution tended to free more fluorine into the acidic aqueous solution. The leachable fluorine in coal spoils was estimated as ca. 6%, based on the results of leaching tests. Also, our research found that over 90% of fluorine in coal spoils could be released into the atmosphere as a result of spontaneous combustion, accounting for over 40% of the total atmospheric fluorine emissions in northern China. Our investigation suggests that it is urgent to conduct comprehensive studies to assist the management and control of fluorine pollution at coal spoil banks. PMID- 26734817 TI - Combination treatment of low-fluence Q-switched Nd:YAG laser and oral tranexamic acid for post-inflammatory hyperpigmentation due to allergic contact dermatitis to henna hair dye. AB - A 64-year-old female presented with facial hyperpigmentation. She had dyed her hair monthly with pure henna powder for the past seven months. After patch tests, the patient was diagnosed as post-inflammatory hyperpigmentastion due to allergic contact dermatitis to pure henna that has rarely been reported. The patient underwent Q-switched Nd:YAG laser treatment and was treated with oral tranexamic acid for 10 weeks. The hyperpigmentation on her forehead demonstrated substantial improvement. PMID- 26734818 TI - Alterations in excitatory amino acid-mediated regulation of midbrain dopaminergic neurones induced by chronic psychostimulant administration and stress: relevance to behavioural sensitization and drug addiction. AB - Repeated, intermittent administration of the psychostimulants d-amphetamine and cocaine, as well as other drugs of abuse, leads to an enduring augmentation of certain behavioural responses (e.g. locomotor activity) produced by these drugs. This behavioural sensitization has been the subject of considerable interest due to its potential relevance to drug addiction. Repeated administration of d amphetamine also leads to an enhancement in the ability of electrical stimulation of the prefrontal cortex to induce burst firing in midbrain dopaminergic (DA) neurones. This hyper-responsiveness probably reflects a potentiation of transmission at excitatory amino acid (EAA)ergic synapses on DA neurones. In addition, we have previously reported that selective activation of mineralocorticoid receptors (MRs) by corticosterone leads to a potentiation of EAA-induced burst firing in midbrain DA neurones, an effect antagonized by glucocorticoid receptor (GR) activation. In this review article, we propose a model describing how drugs of abuse and stress alter EAA function at the level of DA cells in the ventral tegmental area (VTA), which can result in a long-lasting impact on behaviour. D-amphetamine produces a transitory increase in EAA-mediated transmission at the level of DA cells in the VTA, which triggers a more long lasting change in EAAergic function resembling hippocampal long-term potentiation. Dopaminergic burst events are likely to be a critical link between enhanced EAAergic activity in afferents synapsing on DA neurones and plasticity at these synapses, by increasing calcium transport into the cell, which is known to be an important factor in synaptic plasticity. Selective MR occupation by corticosterone in the VTA facilitates the development of this plasticity. However, we hypothesize that during stress, GR-occupation also activates EAAergic afferents to DA neurones in a manner similar to that following psychostimulants. Under these circumstances, GR-occupation acts via circuitry external to the VTA, which may include the hippocampus. Thus, potentiation of EAAergic synapses on DA neurones in the VTA may represent a final common pathway by which two divserse means (psychostimulants and stress) achieve the same end (sensitization). Alterations in EAA-mediated transmission at the level of DA cells not only plays a critical role in the induction of behavioural sensitization, but probably continues to produce abnormal DA cell responses in the drug-free situation. PMID- 26734819 TI - Alcohol and the pancreas. AB - Alcoholic pancreatitis is a major, often lethal complication of alcohol abuse. Until recently it was generally accepted that alcoholic pancreatitis was a chronic disease from the outset. However, there is now emerging evidence in favour of the necrosis-fibrosis hypothesis that alcoholic pancreatitis begins as an acute process and that repeated acute attacks lead to chronic pancreatitis, resulting in exocrine and endocrine failure. Over the past 10-15 years, the focus of research into the pathogenesis of alcoholic pancreatitis has shifted from possible sphincteric and ductular abnormalities to the acinar cell itself which has increasingly been implicated as the initial site of injury. Recent studies have shown that the acinar cell can metabolize alcohol at rates comparable to those observed in hepatocytes. In addition, it has been demonstrated that alcohol and its metabolites exert direct effects on the pancreatic acinar cell which may promote premature digestive enzyme activation and oxidant stress. The challenge remains to identify predisposing and triggering factors in this disease. PMID- 26734820 TI - Association of polymorphism in the alcohol dehydrogenase 2 gene with alcohol related organ injuries, especially liver cirrhosis. AB - The class I hepatic alcohol dehydrogenases (ADHs) are primarily responsible for ethanol metabolism in humans. Genetic polymorphism at the ADH2 locus results in the inheritance of isozymes of strikingly different catalytic properties. In European and Caucasian American populations, beta1, which is encoded by ADH2(1) , is the most common form of the enzyme, while beta2, encoded by the ADH2(2) allele, is found primarily in Orientals. The beta2beta2 enzyme encoded by ADH2(2) /ADH2(2) is approximately 20 times more active in ethanol oxidation than the beta1beta1 enzyme. In vivo the kinetic differences of ADH2 isozymes may influence individual risk for the effects of ethanol. This article will review the role of polymorphisms at the ADH2 loci in genetic predisposition to alcoholism and alcohol-related organ injury, especially alcoholic cirrhosis. PMID- 26734821 TI - Neonatal withdrawal syndrome and behavioral effects produced by maternal drug use. AB - Over the last two decades, drug and alcohol abuse by pregnant women has spread to epidemic proportions. Maternal drug abuse has neurobehavioral and somatic effects which may be long-lasting and devastating to the offspring. Opiates, such as heroin and pain killers that contain a narcotic component, are widely abused today. A prominent manifestation of fetal exposure to these drugs is the neonatal withdrawal syndrome, which typically includes wakefulness, jitteriness and other symptoms of cerebral irritability. These, in turn, may interrupt early mother infant interaction, affecting the infant's long-term emotional and cognitive development. Fetal cocaine exposure may cause neonatal cerebral irritability, changes in habituation responses, reduced head circumference, poor mental development and long-lasting impairment of the brain. Benzodiazepines can cause fetal dysmorphism (including microcephaly), neurological and behavioral impairments and neonatal withdrawal symptoms. Maternal use of amphetamines may cause neonatal dysphoria and agitation, as well as long-term lassitude and drowsiness that may result in poor feeding. Fetal exposure to alcohol may cause neonatal withdrawal symptoms, maladaptive behavior in childhood and the fetal alcohol syndrome (including microcephaly). Maternal alcohol consumption is also a common cause of mental retardation. Fetal exposure to marijuana may delay maturation of the visual system and impair memory and verbal performance at 2 years of age. The inevitable conclusion is that society must seek ways not only to treat, but also to prevent this epidemic. To this end, a key factor would be to identify potential drug abusing mothers before they reach the stage of prenatal care and educate them regarding the fatal consequences of drug abuse. PMID- 26734822 TI - Butyrylcholinesterase: an enzyme antidote for cocaine intoxication. AB - Cocaine-associated toxicity is the result of effects on the cardiovascular and central nervous systems. Since the primary route of cocaine inactivation is enzymatic degradation by butyrylcholinesterase (BChE), we sought to determine if the administration of purified human enzyme would ameliorate the lethal effects of cocaine. While the cardiovascular, autonomic or central nervous systems were unaffected by BChE, the enzyme reduced the adverse effects of cocaine including hypertension, hyperactivity and convulsions. BChE decreased both the brain and blood levels of cocaine and shifted the metabolites towards the production of the inactive product ecgonine methyl ester and away from the physiologically active metabolites, norcocaine and benzoylecgonine. We conclude that BChE would appear to be an ideal antidote in the treatment of cocaine intoxication and has potential therapeutic application. PMID- 26734823 TI - Cocaine-like effects of intravenous procaine in cocaine addicts. AB - Pharmacological treatments that alter dopaminergic functioning have not lessened cocaine use in addicted patients. Non-dopaminergic mechanisms may therefore be important in the chronic use of cocaine. Procaine, like cocaine, is a local anesthetic, but has only 1% of cocaine's affinity for the dopamine reuptake receptor. In order to assess the subjective effects of procaine and its similarity to cocaine, we administered procaine to nine cocaine-dependent subjects. Patients 2-3 weeks abstinent were administered placebo, low dose procaine (0.46 mg/kg), and high dose procaine (1.84 mg/kg procaine) over a single 2-hour session. Patients were assessed for craving and similarity to cocaine experience and were administered the Symptom Checklist 90 Revised (SCL90R). High dose procaine was identified as similar to cocaine and induced significant cocaine craving. High dose procaine also induced significant elevations in somatization, obsessive-compulsive symptoms, phobic anxiety, interpersonal sensitivity, anxiety, positive symptoms and global severity (from the SCL90R). Our findings suggest that procaine shares subjective effects similar to cocaine, despite a much lower affinity for the dopamine reuptake receptor. Procaine may be a useful tool to explore non-dopaminergic mechanisms of cocaine's reinforcing and addictive properties. PMID- 26734824 TI - Ethanol alters the inhibitory effect of calcium ions on [(3) H]-inositol 1,4,5 trisphosphate binding. AB - In this study we have analysed the effects of ethanol and divalent cations on the binding of [(3) H]-inositol 1,4,5 trisphosphate to rat cerebellar membranes. Rats were injected intraperitoneally, daily, with 3g of ethanol/kg of body weight for different periods of time. Repeated in vivo administration of ethanol caused a reduction of about 30% of binding in an in vitro assay carried out in the presence of 1 mM EDTA. With an IC approximately 250 nM calcium ions produced a reduction in binding to cerebellar membranes isolated from control rats. The inhibitory effect was not observed in membranes taken from animals injected with alcohol for 21 days. Magnesium and manganese ions also lowered IP binding. The metabolic degradation of IP to IP was increased by magnesium and manganese but not by calcium and was similar in control and ethanol 2 treated rats. The results indicate that ethanol repeatedly administered to rats modifies the sensitivity of the IP receptor to calcium ion, but that it does not alter the metabolic fate of IP to IP. This supports the idea that ethanol may have preferable targets within the cell. PMID- 26734825 TI - Carbohydrate deficient transferrin in alcoholic and non-alcoholic liver disease: a comparison of two assay methods. AB - Carbohydrate-deficient transferrin (CDT) was assayed in 105 patients with non alcohol-related liver diseases, 50 patients with alcohol-induced liver disease and 40 alcohol misusers with minimal hepatic dysfunction. The patients with liver disease were hospitalized for assessment of suitability for orthotopic liver transplantation. CDT was measured by two commercially available micro anion exchange methods; CDTect (Pharmacia) and %CDT (AXIS). Additionally, total transferrin was measured to allow expression of the CDTect results as 'relative' measurements. Overall, 41/105 (39%) of patients with non-alcohol-related liver diseases had a raised CDTect result, 13/105 (12%) had a raised %CDT result and 26/105 (25%) an abnormal CDTect/total transferrin ratio. In general, patients with cholestatic liver disease, primary biliary cirrhosis or primary sclerosing cholangitis had more 'false positive' results by CDTect than did those with viral or autoimmune hepatitis. The sensitivity of the two methods for the detection of alcohol misuse was similar; CDTect 77%, %CDT 65% and CDTect/total transferrin ratio 70%. This was, however, lower than the sensitivity of the conventional marker GGT (82%). In patients with severe liver disease, where up to 30% of the serum total transferrin concentrations fall outside the reference range, 'relative' CDT methods have greater specificity than 'absolute' measurements. PMID- 26734826 TI - The prevalence of alcohol misuse in patients undergoing cataract surgery. AB - If a factor could be identified which delayed the onset of cataract by 10 years, the number of annual cataract operations worldwide has been estimated to decrease by 45%. A case-control study compared alcohol consumption in 78 patients attending for routine cataract surgery in South East London with data from a large population-based survey. Male cataract patients had a significantly greater risk of being harmful drinkers (odds ratio = 8, p = 0.007) than the controls. The harmful male drinkers were significantly younger than the non-drinkers with cataract (mean difference 15 years, p < 0.007). Female cataract patients were not more likely to be excessive drinkers than controls. The female drinkers with cataract were of a similar age to the non-drinking female patients with cataract. Haematological and biochemical indices of alcohol toxicity indicated five patients who were likely to be harmful drinkers, but who had denied this on direct questioning. Seven (26%) of the male patients had a low serum 25 hydroxycholecalciferol although the levels were normal in the female patients. These results support the view that excess alcohol consumption is related to cataract formation and suggest that alcohol causes premature cataract formation in male, but not female patients. Alcohol consumption is amenable to intervention and suggests that such intervention could have a significant impact on the need for cataract surgery. PMID- 26734828 TI - Characterization of Phosphate Species on Hydrated Anatase TiO2 Surfaces. AB - The adsorption/interaction of KH2PO4 with solvated (100) and (101) TiO2 anatase surfaces is investigated using periodic DFT calculations in combination with GIPAW NMR calculations and experimental IR and solid state (17)O, and (31)P NMR spectroscopies. A complete and realistic model has been used to simulate the solvent by individual water molecules. The most stable adsorption configurations are characterized theoretically at the atomic scale, and experimentally supported by NMR and IR spectroscopies. It is shown that H2PO4(-) chemisorbs on the (100) and (101) anatase surfaces, preferentially via a bidentate geometry. Dimer (H3P2O7(-)) and trimer (H4P3O10(-)) adsorption models are confronted with monomer adsorption models, in order to rationalize their occurrence. PMID- 26734829 TI - Sequential Mukaiyama-Michael reaction induced by carbon acids. AB - In the presence of a strong carbon acid, the sequential Mukaiyama-Michael reaction using two different Michael acceptors proceeded and the reaction of ketene silyl acetal derived from EtOAc with alpha-pyrones as primal acceptors yielded the corresponding cyclic ketene silyl acetals, which were reactive enough to undergo the following reaction with second acceptors. PMID- 26734830 TI - Myalgias and Myopathies: Foreword. PMID- 26734831 TI - Myalgias and Myopathies: Fibromyalgia. AB - Fibromyalgia is a syndrome of chronic widespread pain typically accompanied by fatigue, nonrestorative sleep, cognitive dysfunction, and mood disorders. As defined by the 2010 American College of Rheumatology criteria, fibromyalgia affects approximately 5% of the population and is the second most common disorder, after osteoarthritis, for which patients are referred to rheumatology subspecialists. These criteria provide a framework for diagnosing fibromyalgia that does not require tender points and incorporates other symptoms of the syndrome in addition to pain. Extensive laboratory tests and imaging are not required to diagnose fibromyalgia. A patient-centered, multimodal approach that includes patient education, behavioral therapy, a graded exercise program, and pharmacotherapy should be used for patients with fibromyalgia. Prescribers must be mindful of adverse drug effects and should tailor therapy to the individual patient. Strong evidence of benefit exists for tricyclic antidepressants, cyclobenzaprine, and serotonin-norepinephrine reuptake inhibitors in fibromyalgia management, whereas nonsteroidal anti-inflammatory drugs and opioids have limited proven benefit. Fibromyalgia can cause significant disability and loss of function. Family physicians are well equipped to direct the multimodal care of patients with fibromyalgia. PMID- 26734832 TI - Myalgias and Myopathies: Polymyalgia Rheumatica and Giant Cell Arteritis. AB - Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are related inflammatory disorders that often coexist. Both are most common among women, whites, and older individuals. PMR is characterized by morning stiffness, pain, and decreased range of motion in the shoulders, neck, and pelvis. Diagnosing PMR can be challenging because no standard set of criteria or single diagnostic test exists. Patients with PMR benefit rapidly from treatment with oral glucocorticoids, and full recovery is likely, although adverse effects of treatment contribute to morbidity. GCA is a subacute vasculitis in which focal, segmental inflammatory infiltrates primarily affect cranial arteries. Diagnosis of GCA is based on clinical features, such as headache, jaw pain, vision changes, and temporal artery tenderness, along with an elevated erythrocyte sedimentation rate and inflammation seen on temporal artery biopsy. Permanent vision loss can occur, so patients who may have temporal arteritis should be started on glucocorticoids promptly. If treatment for GCA is started before visual symptoms progress, the prognosis for a full recovery is good. In PMR and GCA, relapses or exacerbations necessitating changes in therapy occur in up to 60% of patients. PMID- 26734833 TI - Myalgias and Myopathies: Drug-Induced Myalgias and Myopathies. AB - Drugs can cause myalgias and myopathies through a variety of mechanisms. Most drug-induced myopathies are potentially reversible if recognized early. Prescribers should be familiar with common drug-induced myopathies and drug-drug interactions. Clinical presentations can be subacute or acute, ranging from benign muscle pain with mild elevations of serum creatine kinase to fulminant rhabdomyolysis with high creatine kinase levels and potentially life-threatening acute kidney injury. Myalgias and proximal muscle weakness are typical symptoms; onset can be weeks to months after drug exposure. Endocrine disorders and inflammatory etiologies should be excluded because their management may differ from that of drug-induced myopathies. Statin drugs are prescribed widely, and statin-induced myopathy is one of the most commonly recognized and studied myopathies. Risk factors include dose and type of statin prescribed, older age, female sex, genetic predisposition, and concomitant use of other drugs metabolized by the cytochrome P450 system. Glucocorticoids, immunologic drugs, and antimicrobials, as well as other drugs and alcohol, can cause myopathies. Management typically involves discontinuing the drug and switching to an alternative drug or considering an alternative dosing schedule. Referral to a neuromuscular subspecialist is warranted if symptoms persist. PMID- 26734834 TI - Myalgias and Myopathies: Rhabdomyolysis. AB - Rhabdomyolysis is the rapid breakdown of skeletal muscle with release of electrolytes, myoglobin, and other proteins into the circulation. The clinical presentation encompasses a spectrum of patients ranging from those with asymptomatic increases in creatine kinase (CK) levels to those with fulminant disease complicated by acute kidney injury (AKI), severe electrolyte abnormalities, compartment syndrome, and disseminated intravascular coagulation. A CK level at least 10 times the upper limit of normal typically is considered diagnostic, as is myoglobinuria. AKI is the most significant complication. Prompt recognition and management of rhabdomyolysis is crucial to preserving renal function. Management consists of rapidly initiating aggressive intravenous saline resuscitation to maintain a urine output of at least 300 mL/hour. Sodium bicarbonate can be used for patients who are acidotic, and mannitol can be used for those whose urine output is not at goal. Significant electrolyte abnormalities may be present and must be managed to avoid cardiac arrhythmias and arrest. Compartment syndrome can develop as an early or late finding and requires decompressive fasciotomy for definitive management. Intravenous fluids typically are continued until CK levels are lower than 1,000 U/L. PMID- 26734835 TI - Evaluation of Intraocular Pressure by Ocular Response Analyzer in Patients Undergoing Hemodialysis. AB - PURPOSE: The aim of this study was to compare the biomechanical parameters of the cornea and intraocular pressure (IOP) before and after hemodialysis (HD) in patients with end-stage renal disease (ESRD) and also healthy subjects. MATERIALS AND METHODS: Twenty-one patients with ESRD undergoing HD treatment (study group) and 21 healthy individuals (control group) were enrolled in this prospective study. Right eyes of each subjects were included. Central corneal thickness (CCT) were measured using Sirius Scheimpflug camera. Corneal hysteresis (CH), corneal resistance factor (CRF), corneal-compensated IOP (IOPcc), and Goldmann-related IOP (IOPg) were measured using ocular response analyzer. In the study group, measurements were taken just before HD and 30 minutes after HD. RESULTS: The mean CCT, CRF, IOPg values did not differ between pre-HD, post-HD, and controls (P > 0.05). CH was found to be significantly higher in control group (10.6 +/- 1.2 mm Hg) when compared with pre-HD (8.07 +/- 1.8 mm Hg) and post-HD (8.8 +/- 1.6 mm Hg) CH values (P = 0.0001). The mean IOPcc values did not differ pre-HD (18.5 +/- 3.5 mm Hg) and post-HD (17.8 +/- 3.9 mm Hg) (P = 0.39). The mean IOPcc values were lower significantly in control group (15.4 +/- 2.8 mm Hg) when compared with pre-HD and post-HD values (P = 0.02 and 0.02, respectively). Significant correlations were seen between post-HD CRF and post-HD CCT (r = 0.6, P = 0.03); and post-HD IOPg and post-HD CCT (r = 0.51, P = 0.01). CONCLUSIONS: ESRD may disrupt the biomechanical properties of the cornea. Changes in ocular response analyzer parameters should be kept in mind to evaluate accurate IOP measurements in patients with ESRD. PMID- 26734836 TI - Transforming Nanomedicines From Lab Scale Production to Novel Clinical Modality. AB - The use of nanoparticles as anticancer drug carriers has been studied for over 50 years. These nanoparticles that can carry drugs are now termed "nanomedicines". Since the approval of the first FDA "nanodrug", DOXIL in 1995, tremendous efforts have been made to develop hundreds of nanomedicines based on different materials. The development of drug nanocarriers (NCs) for cancer therapy is especially challenging and requires multidisciplinary approach. Not only is the translation from a lab scale production of the NCs to clinical scale a challenge, but tumor biology and its unique physiology also possess challenges that need to be overcome with cleverer approaches. Yet, with all the efforts made to develop new strategies to deliver drugs (including small molecules and biologics) for cancer therapy, the number of new NCs that are reaching clinical trials is extremely low. Here we discuss the reasons most of the NCs loaded with anticancer drugs are not likely to reach the clinic and emphasize the importance of understanding tumor physiology and heterogeneity, the use of predictive animal models, and the importance of sharing data as key denominators for potential successful translation of NCs from a bench scale into clinical modality for cancer care. PMID- 26734837 TI - Click chemistry, 3D-printing, and omics: the future of drug development. AB - Genomics is a disruptive technology, having revealed that cancers are tremendously complex and differ from patient to patient. Therefore, conventional treatment approaches fit poorly with genomic reality. Furthermore, it is likely that this type of complexity will also be observed in other illnesses. Precision medicine has been posited as a way to better target disease-related aberrations, but developing drugs and tailoring therapy to each patient's complicated problem is a major challenge. One solution would be to match patients to existing compounds based on in silico modeling. However, optimization of complex therapy will eventually require designing compounds for patients using computer modeling and just-in-time production, perhaps achievable in the future by three dimensional (3D) printing. Indeed, 3D printing is potentially transformative by virtue of its ability to rapidly generate almost limitless numbers of objects that previously required manufacturing facilities. Companies are already endeavoring to develop affordable 3D printers for home use. An attractive, but as yet scantily explored, application is to place chemical design and production under digital control. This could be accomplished by utilizing a 3D printer to initiate chemical reactions, and print the reagents and/or the final compounds directly. Of interest, the Food and Drug Administration (FDA) has recently approved a 3D printed drug-levetiracetam-indicated for seizures. Further, it is now increasingly clear that biologic materials-tissues, and eventually organs-can also be "printed." In the near future, it is plausible that high-throughput computing may be deployed to design customized drugs, which will reshape medicine. PMID- 26734838 TI - Use of a novel cytotoxic HEXIM1 peptide in the directed breast cancer therapy. AB - Hexamethylene bisacetamide-inducible protein 1 (HEXIM1) is best known as the inhibitor of positive transcription elongation factor b (P-TEFb) and is recently identified as a novel positive regulator of p53. We previously showed the basic region (BR) of HEXIM1 mediates the binding of HEXIM1 to a nucleolar protein, nucleophosmin (NPM), and can be ubiquitinated by human double minute 2 protein. Here we identify a cytotoxic peptide derived from the BR of HEXIM1. When fused with a cell-penetrating peptide, the HEXIM1 BR peptide triggers rapid cytotoxic effect independent of p53. Similarly, when the BR peptide is linked with a breast cancer cell targeting peptide, LTV, the LTV-BR fusion peptide exhibits specific killing of breast cancer cells, which is not observed with the commonly used cytotoxic peptide, KLA. Importantly, the BR peptide fails to enter cells by itself and does not induce any cytotoxic effects when it is not guided by any cell-penetrating or cancer targeting peptides. We showed that HEXIM1 BR peptide depolarizes mitochondrial membrane potential in a p53-dependent manner and its cell-killing activity is not suppressed by caspase inhibition. Furthermore, we observed an accumulation of the internalized BR peptide in the nucleoli of treated cells and an altered localization of NPM. These results illustrate a novel mechanism which the BR peptide induces cell death and can potentially be used as a novel therapeutic strategy against breast cancer. PMID- 26734839 TI - A new flavane acid from the fruits of Illicium verum. AB - A new compound, illiciumflavane acid (1), along with 13 known compounds (2-14), were isolated from the fruits of Illicium verum Hook. F. Their structures were elucidated through various spectroscopic methods, including 1D NMR ((1)H NMR, (13)C NMR), 2D NMR (HMQC, HMBC and NOESY) and HRMS. The stereochemistry at the chiral centres was determined using CD spectrum as well as analyses of coupling constants and optical rotation data. Cytotoxicity evaluation of four compounds showed that illiciumflavane acid and (E)-1,2-bis(4-methoxyphenyl)ethene exhibited potential against A549 activities with IC50 values of 4.63 MUM and 9.17 MUM, respectively. PMID- 26734840 TI - Application of risk-based multiple criteria decision analysis for selection of the best agricultural scenario for effective watershed management. AB - Effective watershed management requires the evaluation of agricultural best management practice (BMP) scenarios which carefully consider the relevant environmental, economic, and social criteria involved. In the Multiple Criteria Decision-Making (MCDM) process, scenarios are first evaluated and then ranked to determine the most desirable outcome for the particular watershed. The main challenge of this process is the accurate identification of the best solution for the watershed in question, despite the various risk attitudes presented by the associated decision-makers (DMs). This paper introduces a novel approach for implementation of the MCDM process based on a comparative neutral risk/risk-based decision analysis, which results in the selection of the most desirable scenario for use in the entire watershed. At the sub-basin level, each scenario includes multiple BMPs with scores that have been calculated using the criteria derived from two cases of neutral risk and risk-based decision-making. The simple additive weighting (SAW) operator is applied for use in neutral risk decision making, while the ordered weighted averaging (OWA) and induced OWA (IOWA) operators are effective for risk-based decision-making. At the watershed level, the BMP scores of the sub-basins are aggregated to calculate each scenarios' combined goodness measurements; the most desirable scenario for the entire watershed is then selected based on the combined goodness measurements. Our final results illustrate the type of operator and risk attitudes needed to satisfy the relevant criteria within the number of sub-basins, and how they ultimately affect the final ranking of the given scenarios. The methodology proposed here has been successfully applied to the Honeyoey Creek-Pine Creek watershed in Michigan, USA to evaluate various BMP scenarios and determine the best solution for both the stakeholders and the overall stream health. PMID- 26734841 TI - Incidence and injury characteristics of traumatic brain injury: Comparison between children, adults and seniors in Israel. AB - AIM: To assess the incidence and injury characteristics of hospitalized trauma patients diagnosed with TBI. METHODS: A retrospective study of all injured hospitalized patients recorded in the National Trauma Registry at 19 trauma centres in Israel between 2002-2011. Incidence and injury characteristics were examined among children, adults and seniors. RESULTS: The annual incidence rate of hospitalized TBI for the Israeli population in 2011 was 31.8/100,000. Age specific incidence was highest among seniors with a dramatic decrease in TBI related mortality rate among them. Adults, in comparison to children and seniors, had higher rates of severe TBI, severe and critical injuries, more admission to the intensive care unit, underwent surgery, were hospitalization for more than 2 weeks and were discharged to rehabilitation. After adjusting for age, gender, ethnicity, mechanism of injury and injury severity score, TBI-related in-hospital mortality was higher among seniors and adults compared to children. CONCLUSION: Seniors are at high risk for TBI-related in-hospital mortality, although adults had more severe and critical injuries and utilized more hospital resources. However, seniors showed the most significant reduction in mortality rate during the study period. Appropriate intervention programmes should be designed and implemented, targeted to reduce TBI among high risk groups. PMID- 26734842 TI - Surface-Functionalization of Nanostructured Cellulose Aerogels by Solid State Eumelanin Coating. AB - Bioinspired aerogel functionalization by surface modification and coating is in high demand for biomedical and technological applications. In this paper, we report an expedient three-step entry to all-natural surface-functionalized nanostructured aerogels based on (a) TEMPO/NaClO promoted synthesis of cellulose nanofibers (TOCNF); (b) freeze-drying for aerogel preparation; and (c) surface coating with a eumelanin thin film by ammonia-induced solid state polymerization (AISSP) of 5,6-dihydroxyindole (DHI) or 5,6-dihydroxyindole-2-carboxylic acid (DHICA) previously deposited from an organic solution. Scanning electron microscopy showed uniform deposition of the dark eumelanin coating on the template surface without affecting porosity, whereas solid state (13)C NMR and electron paramagnetic resonance (EPR) spectroscopy confirmed the eumelanin-type character of the coatings. DHI melanin coating was found to confer to TOCNF templates a potent antioxidant activity, as tested by the 2,2-diphenyl-1 picrylhydrazyl (DPPH) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays as well as strong dye adsorption capacity, as tested on methylene blue. The unprecedented combination of nanostructured cellulose and eumelanin thin films disclosed herein implements an original all-natural multifunctional aerogel biomaterial realized via an innovative coating methodology. PMID- 26734843 TI - Tet2 Catalyzes Stepwise 5-Methylcytosine Oxidation by an Iterative and de novo Mechanism. AB - Modification of cytosine-guanine dinucleotides (CpGs) is a key part of mammalian epigenetic regulation and helps shape cellular identity. Tet enzymes catalyze stepwise oxidation of 5-methylcytosine (mC) in CpGs to 5-hydroxymethylcytosine (hmC), or onward to 5-formylcytosine (fC) or 5-carboxylcytosine (caC). The multiple mC oxidation products, while intricately linked, are postulated to play independent epigenetic roles, making it critical to understand how the products of stepwise oxidation are established and maintained. Using highly sensitive isotope-based studies, we newly show that Tet2 can yield fC and caC by iteratively acting in a single encounter with mC-containing DNA, without release of the hmC intermediate, and that the modification state of the complementary CpG has little impact on Tet2 activity. By revealing Tet2 as an iterative, de novo mC oxygenase, our study provides insight into how features intrinsic to Tet2 shape the epigenetic landscape. PMID- 26734844 TI - Spectroscopic and Computational Investigations of The Thermodynamics of Boronate Ester and Diazaborole Self-Assembly. AB - The solution phase self-assembly of boronate esters, diazaboroles, oxathiaboroles, and dithiaboroles from the condensation of arylboronic acids with aromatic diol, diamine, hydroxythiol, and dithiol compounds in chloroform has been investigated by (1)H NMR spectroscopy and computational methods. Six arylboronic acids were included in the investigations with each boronic acid varying in the substituent at its 4-position. Both computational and experimental results show that the para-substituent of the arylboronic acid does not significantly influence the favorability of forming a condensation product with a given organic donor. The type of donor, however, greatly influences the favorability of self-assembly. (1)H NMR spectroscopy indicates that condensation reactions between arylboronic acids and catechol to give boronate esters are the most favored thermodynamically, followed by diazaborole formation. Computational investigations support this conclusion. Neither oxathiaboroles nor dithiaboroles form spontaneously at equilibrium in chloroform at room temperature. Computational results suggest that the effect of borylation on the frontier orbitals of each donor helps to explain differences in the favorability of their condensation reactions with arylboronic acids. The results can inform the use of boronic acids as they are increasingly utilized in the dynamic self-assembly of organic materials and as components in dynamic combinatorial libraries. PMID- 26734845 TI - DNA-Assisted Exfoliation of Tungsten Dichalcogenides and Their Antibacterial Effect. AB - This study reports a method for the facile and high-yield exfoliation of WX2 (X = S, Se) by sonication under aqueous conditions using single-stranded DNA (abbreviated as ssDNA) of high molecular weight. The ssDNA provided a high degree of stabilization and prevented reaggregation, and it enhanced the exfoliation efficiency of WX2 nanosheets due to adsorption on the WX2 surface and the electrostatic repulsion of sugars in the ssDNA backbone. The exfoliation yield was higher with ssDNA (80%-90%) than without (2%-4%); the yield with ssDNA was also higher than the value previously reported for aqueous exfoliation (~10%). Given that two-dimensional nanomaterials have potential health and environmental applications, we investigated antibacterial activity of exfoliated WX2-ssDNA nanosheets, relative to graphene oxide (GO), and found that WSe2-ssDNA nanosheets had higher antibacterial activity against Escherichia coli K-12 MG1655 cells than GO. Our method enables large-scale exfoliation in an aqueous environment in a single step with a short reaction time and under ambient conditions, and it can be used to produce surface-active or catalytic materials that have broad applications in biomedicine and other areas. PMID- 26734846 TI - Pyrenyl Derivative with a Four-Atom Linker That Can Probe the Local Polarity of Pyrene-Labeled Macromolecules. AB - The fluorescent probe 1-pyrenemethoxyethanol (PyMeEGOH) was designed to replace commercially available 1-pyrenebutanol (PyButOH) as an alternative fluorescent label to probe the internal dynamics and interior polarity of macromolecules by steady-state and time-resolved fluorescence. While excimer formation and sensitivity to solvent polarity are two well-recognized properties of pyrene, much less known is that these properties are often mutually exclusive when a 1 pyrenebutyl derivative is used to prepare pyrene-labeled macromolecules (PyLMs). As the sensitivity of pyrene to solvent polarity is a result of its symmetry, attaching a butyl group to pyrene breaks the symmetry of pyrene, so that the 1 pyrenebutyl derivatives are much less sensitive to the polarity of their environment compared to unmodified pyrene. This report demonstrates that replacement of a methylene group in the beta-position of PyButOH by an oxygen atom, such as in PyMeEGOH, restores the sensitivity of this pyrene derivative to the polarity of its local environment to the same level as that of molecular pyrene without impeding pyrene excimer formation upon incorporation into PyLMs. PMID- 26734847 TI - Modeling Individual Differences in Within-Person Variation of Negative and Positive Affect in a Mixed Effects Location Scale Model Using BUGS/JAGS. AB - A mixed effects location scale model was used to model and explain individual differences in within-person variability of negative and positive affect across 7 days (N=178) within a measurement burst design. The data come from undergraduate university students and are pooled from a study that was repeated at two consecutive years. Individual differences in level and change in mood was modeled with a random intercept and random slope where the residual within-person variability was allowed to vary across participants. Additionally changes in within-person variability were explained by the inclusion of a time-varying predictor indicating the severity of daily stressors. This model accounted for 2 location and 2 scale effects and provided evidence that individuals who reported higher severity in daily stressors also exhibited greater variability in affect but only for participants who showed low overall affect variability and who reported low average negative affect. Those who were more variable in their affect reports overall were less reactive to daily stressors in the sense that their high levels of affect variability remained high. We describe the utility of this model for further research on individual variation and change. PMID- 26734848 TI - Confidence Intervals for the Probability of Superiority Effect Size Measure and the Area Under a Receiver Operating Characteristic Curve. AB - It is good scientific practice to the report an appropriate estimate of effect size and a confidence interval (CI) to indicate the precision with which a population effect was estimated. For comparisons of 2 independent groups, a probability-based effect size estimator (A) that is equal to the area under a receiver operating characteristic curve and closely related to the popular Wilcoxon-Mann-Whitney nonparametric statistical tests has many appealing properties (e.g., easy to understand, robust to violations of parametric assumptions, insensitive to outliers). We performed a simulation study to compare 9 analytic and 3 empirical (bootstrap) methods for constructing a CI for A that can yield very different CIs for the same data. The experimental design crossed 6 factors to yield a total of 324 cells representing challenging but realistic data conditions. Results were examined using several criteria, with emphasis placed on the extent to which observed CI coverage probabilities approximated nominal levels. Based on the simulation study results, the bias-corrected and accelerated bootstrap method is recommended for constructing a CI for the A statistic; bootstrap methods also provided the least biased and most accurate standard error of A. An empirical illustration examining score differences on a citation-based index of scholarly impact across faculty at low-ranked versus high-ranked research universities underscores the importance of choosing an appropriate CI method. PMID- 26734849 TI - Isolating and Examining Sources of Suppression and Multicollinearity in Multiple Linear Regression. AB - The presence of suppression (and multicollinearity) in multiple regression analysis complicates interpretation of predictor-criterion relationships. The mathematical conditions that produce suppression in regression analysis have received considerable attention in the methodological literature but until now nothing in the way of an analytic strategy to isolate, examine, and remove suppression effects has been offered. In this article such an approach, rooted in confirmatory factor analysis theory and employing matrix algebra, is developed. Suppression is viewed as the result of criterion-irrelevant variance operating among predictors. Decomposition of predictor variables into criterion-relevant and criterion-irrelevant components using structural equation modeling permits derivation of regression weights with the effects of criterion-irrelevant variance omitted. Three examples with data from applied research are used to illustrate the approach: the first assesses child and parent characteristics to explain why some parents of children with obsessive-compulsive disorder accommodate their child's compulsions more so than do others, the second examines various dimensions of personal health to explain individual differences in global quality of life among patients following heart surgery, and the third deals with quantifying the relative importance of various aptitudes for explaining academic performance in a sample of nursing students. The approach is offered as an analytic tool for investigators interested in understanding predictor-criterion relationships when complex patterns of intercorrelation among predictors are present and is shown to augment dominance analysis. PMID- 26734850 TI - Multilevel Mixture Factor Models. AB - Factor analysis is a statistical method for describing the associations among sets of observed variables in terms of a small number of underlying continuous latent variables. Various authors have proposed multilevel extensions of the factor model for the analysis of data sets with a hierarchical structure. These Multilevel Factor Models (MFMs) have in common that-as in multilevel regression analysis-variation at the higher level is modeled using continuous random effects. In this article, we present an alternative multilevel extension of factor analysis which we call the Multilevel Mixture Factor Model (MMFM). It is based on the assumption that higher level units belong to latent classes that differ in terms of the parameters of the factor model specified for the lower level units. We demonstrate the added value of MMFM compared with MFM, both from a theoretical and applied perspective, and we illustrate the complementarity of the two approaches with an empirical application on students' satisfaction with the University of Florence. The multilevel aspect of this application is that students are nested within study programs, which makes it possible to cluster these programs based on their differences in students' satisfaction. PMID- 26734851 TI - Mixture Factor Analysis for Approximating a Nonnormally Distributed Continuous Latent Factor With Continuous and Dichotomous Observed Variables. AB - Mixture factor analysis is examined as a means of flexibly estimating nonnormally distributed continuous latent factors in the presence of both continuous and dichotomous observed variables. A simulation study compares mixture factor analysis with normal maximum likelihood (ML) latent factor modeling. Different results emerge for continuous versus dichotomous outcomes. For dichotomous outcomes, normal ML path estimates have bias that worsens as latent factor skew/kurtosis increases and does not diminish as sample size increases, whereas the mixture factor analysis model produces nearly unbiased estimators as sample sizes increase (500 and greater) and offers near nominal coverage probability. For continuous outcome variables, both methods produce factor loading estimates with minimal bias regardless of latent factor skew, but the mixture factor analysis is more efficient. The method is demonstrated using data motivated by a study on youth with cystic fibrosis examining predictors of treatment adherence. In summary, mixture factor analysis provides improvements over normal ML estimation in the presence of skewed/kurtotic latent factors, but due to variability in the estimator relating the latent factor to dichotomous outcomes and computational issues, the improvements were only fully realized, in this study, at larger sample sizes (500 and greater). PMID- 26734852 TI - Ordinary Least Squares Estimation of Parameters in Exploratory Factor Analysis With Ordinal Data. AB - Exploratory factor analysis (EFA) is often conducted with ordinal data (e.g., items with 5-point responses) in the social and behavioral sciences. These ordinal variables are often treated as if they were continuous in practice. An alternative strategy is to assume that a normally distributed continuous variable underlies each ordinal variable. The EFA model is specified for these underlying continuous variables rather than the observed ordinal variables. Although these underlying continuous variables are not observed directly, their correlations can be estimated from the ordinal variables. These correlations are referred to as polychoric correlations. This article is concerned with ordinary least squares (OLS) estimation of parameters in EFA with polychoric correlations. Standard errors and confidence intervals for rotated factor loadings and factor correlations are presented. OLS estimates and the associated standard error estimates and confidence intervals are illustrated using personality trait ratings from 228 college students. Statistical properties of the proposed procedure are explored using a Monte Carlo study. The empirical illustration and the Monte Carlo study showed that (a) OLS estimation of EFA is feasible with large models, (b) point estimates of rotated factor loadings are unbiased, PMID- 26734853 TI - Direct imaging of boron segregation at dislocations in B:diamond heteroepitaxial films. AB - A thin film of heavily B-doped diamond has been grown epitaxially by microwave plasma chemical vapor deposition on an undoped diamond layer, on top of a Ir/YSZ/Si(001) substrate stack, to study the boron segregation and boron environment at the dislocations present in the film. The density and nature of the dislocations were investigated by conventional and weak-beam dark-field transmission electron microscopy techniques, revealing the presence of two types of dislocations: edge and mixed-type 45 degrees dislocations. The presence and distribution of B in the sample was studied using annular dark-field scanning transmission electron microscopy and spatially resolved electron energy-loss spectroscopy. Using these techniques, a segregation of B at the dislocations in the film is evidenced, which is shown to be intermittent along the dislocation. A single edge-type dislocation was selected to study the distribution of the boron surrounding the dislocation core. By imaging this defect at atomic resolution, the boron is revealed to segregate towards the tensile strain field surrounding the edge-type dislocations. An investigation of the fine structure of the B-K edge at the dislocation core shows that the boron is partially substitutionally incorporated into the diamond lattice and partially present in a lower coordination (sp(2)-like hybridization). PMID- 26734855 TI - Characterization of the Stiffness of Multiple Particles Trapped by Dielectrophoretic Tweezers in a Microfluidic Device. AB - Characterization of the stiffness of multiple particles trapped by tweezers-based force spectroscopy is a key step in building simple, high-throughput, and robust systems that can investigate the molecular interactions in a biological process, but the technology to characterize it in a given environment simultaneously is still lacking. We first characterized the stiffness of multiple particles trapped by dielectrophoretic (DEP) tweezers inside a microfluidic device. In this characterization, we developed a method to measure the thermal fluctuations of the trapped multiple particles with DEP tweezers by varying the heights of the particles in the given environment at the same time. Using the data measured in this controlled environment, we extracted the stiffness of the trapped particles and calculated their force. This study not only provides a simple and high throughput method to measure the trap stiffness of multiple particles inside a microfluidic device using DEP tweezers but also inspires the application of the trapped multiple particles to investigate the dynamics in molecular interactions. PMID- 26734854 TI - Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B. AB - The polymyxin lipodecapeptides colistin and polymyxin B have become last resort therapies for infections caused by highly drug-resistant Gram-negative bacteria. Unfortunately, their utility is compromised by significant nephrotoxicity and polymyxin-resistant bacterial strains. We have conducted a systematic activity toxicity investigation by varying eight of the nine polymyxin amino acid free side chains, preparing over 30 analogues using a novel solid-phase synthetic route. Compounds were tested against a panel of Gram-negative bacteria and counter-screened for in vitro cell toxicity. Promising compounds underwent additional testing against primary kidney cells isolated from human kidneys to better predict their nephrotoxic potential. Many of the new compounds possessed equal or better antimicrobial potency compared to polymyxin B, and some were less toxic than polymyxin B and colistin against mammalian HepG2 cells and human primary kidney cells. These initial structure-activity and structure-toxicity studies set the stage for further improvements to the polymyxin class of antibiotics. PMID- 26734857 TI - End of the ABD administration 2009-2015. PMID- 26734858 TI - Benign follicular tumors. AB - Benign follicular tumors comprise a large and heterogeneous group of neoplasms that share a common histogenesis and display morphological features resembling one or several portions of the normal hair follicle, or recapitulate part of its embryological development. Most cases present it as clinically nondescript single lesions and essentially of dermatological relevance. Occasionally, however, these lesions be multiple and represent a cutaneous marker of complex syndromes associated with an increased risk of visceral neoplasms. In this article, the authors present the microscopic structure of the normal hair follicle as a basis to understand the type and level of differentiation of the various follicular tumors. The main clinicopathological features and differential diagnosis of benign follicular tumors are then discussed, including dilated pore of Winer, pilar sheath acanthoma, trichoadenoma, trichilemmoma, infundibuloma, proliferating trichilemmal cyst/tumor, trichoblastoma and its variants, pilomatricoma, trichodiscoma/fibrofolliculoma, neurofollicular hamartoma and trichofolliculoma. In addition, the main syndromes presenting with multiple follicular tumors are also discussed, namely Cowden, Birt-Hogg-Dube, Rombo and Bazex-Dupre-Christol syndromes, as well as multiple tumors of follicular infundibulum (infundibulomatosis) and multiple trichoepitheliomas. Although the diagnosis of follicular tumors relies on histological examination, we highlight the importance of their knowledge for the clinician, especially when in presence of patients with multiple lesions that may be the cutaneous marker of a cancer prone syndrome. The dermatologist is therefore in a privileged position to recognize these lesions, which is extremely important to provide further propedeutic, appropriate referral and genetic counseling for these patients. PMID- 26734859 TI - Epidemiological aspects of leprosy in Juazeiro-BA, from 2002 to 2012. AB - BACKGROUND: Leprosy is an infectious disease caused by Mycobacterium leprae, able to infect large numbers of people. This work is relevant to Juazeiro-BA, a hyper endemic area for leprosy, since unravel the behavior of the disease in the area, may suggest the decision making for sectors of surveillance, establishing strategies, organizing and evaluating programs and services. OBJECTIVES: To analyze the epidemiology of leprosy in Juazeiro-BA, from 2002 to 2012. METHODS: A descriptive, cross-sectional study was conducted based in data of the Diseases Notification System, assigned by the service of Epidemiology from Juazeiro-BA, between 2002 and 2012. RESULTS: 1,916 new cases of leprosy were detected between 2002 and 2012, of which 921 (48.07%) represented male sex, 995 (51.93%) female, and there was a reduction in the incidence rate of leprosy per 100,000 inhabitants. Most carriers were brown individuals, with low levels of education, living in the urban area, being more prevalent in the economically active age group. Through statistical analysis we found that there are more chances of developing sequelae among men, and multibacillary individuals older than 45 years. CONCLUSIONS: The work serves to direct efforts to control this disease, and highlights the importance of active search for new cases to achieve an early diagnosis, reducing the number of sequels and allowing breaking the chain of disease transmission. PMID- 26734861 TI - Clinical and histological study of permanent alopecia after bone marrow transplantation. AB - BACKGROUND: Permanent alopecia after bone marrow transplantation is rare, but more and more cases have been described, typically involving high doses of chemotherapeutic agents used in the conditioning regimen for the transplant. Busulfan, classically described in cases of irreversible alopecia, remains associated in recent cases. The pathogenesis involved in hair loss is not clear and there are few studies available. In addition to chemotherapeutic agents, another factor that has been implicated as a cause is chronic graft-versus-host disease. However, there are no histopathological criteria for defining this diagnosis yet. OBJECTIVE: the study aims to evaluate clinical and histological aspects in cases of permanent alopecia after bone marrow transplantation, identifying features of permanent alopecia induced by myeloablative chemotherapy and alopecia as a manifestation of chronic graft-versus-host disease. METHODS: data were collected from medical records of 7 patients, with description of the clinical features and review of slides and paraffin blocks of biopsies. RESULTS: Two distinct histological patterns were found: one similar to androgenetic alopecia, non-scarring pattern, and other similar to lichen planopilaris, scarring alopecia. CONCLUSION: The first pattern corroborates the literature cases of permanent alopecia induced by chemotherapeutic agents, and the second is compatible with manifestation of chronic graft-versus-host disease on scalp, that has never been described yet. The results contribute to the elucidation of the factors involved in these cases, including the development of therapeutic methods. PMID- 26734860 TI - Efficacy and safety of a single dose pentamidine (7mg/kg) for patients with cutaneous leishmaniasis caused by L. guyanensis: a pilot study. AB - BACKGROUND: There have been few studies on pentamidine in the Americas; and there is no consensus regarding the dose that should be applied. OBJECTIVES: To evaluate the use of pentamidine in a single dose to treat cutaneous leishmaniasis. METHODS: Clinical trial of phase II pilot study with 20 patients. Pentamidine was used at a dose of 7 mg/kg, in a single dose. Safety and adverse effects were also assessed. Patients were reviewed one, two, and six months after the end of treatments. RESULTS: there was no difference between the treatment groups in relation to gender, age, number or location of the lesions. Pentamidine, applied in a single dose, obtained an effectiveness of 55%. Mild adverse events were reported by 17 (85%) patients, mainly transient pain at the site of applications (85%), while nausea (5%), malaise (5%) and dizziness (5%) were reported in one patient. No patient had sterile abscess after taking medication at a single dose of 7mg/kg. CONCLUSIONS: Clinical studies with larger samples of patients would enable a better clinical response of pent amidine at a single dose of 7mg, allowing the application of more powerful statistical tests, thus providing more evidences of the decrease in the effectiveness of that medication. Hence, it is important to have larger studies with new diagrams and/or new medications. PMID- 26734862 TI - Clinical study of skin changes in low and high risk pregnant women. AB - BACKGROUND: During pregnancy there is immunological, metabolic, endocrine and vascular changes responsible for physiological and pathological skin changes. OBJECTIVES: determine the prevalence of specific physiological changes and pregnancy, comparing the period of gestation of their appearances and compare type of prenatal care as the skin changes. METHODS: A cross-sectional study with 905 pregnant women. RESULTS: The prevalence of physiological skin changes was 88.95% and the most common was pigment. The prevalence of specific dermatoses was 8.72% and atopic eruption was the most common. CONCLUSION: Physiological changes were seen more in the 3rd quarter, as well as the specific dermatoses. No statistical difference in prenatal low risk compared to high risk was observed, whereas the cutaneous physiological changes and specific pregnancy dermatoses. PMID- 26734863 TI - Observational descriptive study of cutaneous manifestations in patients from Mato Grosso with viral chronic hepatitis. AB - BACKGROUND: Extrahepatic manifestations are seen in association with chronic infection by hepatitis B or C virus including cutaneous disorders. The frequency of these findings seems to vary among different places and reports. There is a lack of information about this issue in Brazil. OBJECTIVES: To estimate the prevalence of cutaneous findings affecting HBV or HCV carriers from a reference outpatient unit in Mato Grosso. METHODS: A cross-sectional observational study. RESULTS: 108 patients were studied. 88.9% presented some cutaneous findings but must of them were nonrelated to chronic viral infection. Four patients had cutaneous or autoimmune syndromes that may be HBV or HCV related. CONCLUSION: In our study we found no statistical association between viral hepatitis and skin diseases. PMID- 26734864 TI - Systemic lupus erythematosus and Raynaud's phenomenon. AB - BACKGROUND: Patients with systemic lupus erythematosus seem to belong to different serological and clinical subgroups of the disease. Genetic background can cause the appearance of these subgroups. OBJECTIVE: To determine whether Brazilian patients who have systemic lupus erythematosus and Raynaud's phenomenon differ from those who do not. METHODS: Retrospective analysis of 373 medical records of systemic lupus erythematosus patients studied for demographic, clinical and serological data. A comparative analysis was performed of individuals with and without RP. RESULTS: There was a positive association between Raynaud's phenomenon and age at diagnosis (p=0.02), presence of anti-Sm (p=0.01) antibodies and anti-RNP (p<0.0001). Furthermore, a negative association was found between Raynaud's phenomenon and hemolysis (p=0.01), serositis (p=0.01), glomerulonephritis (p=0.0004) and IgM aCL (p=0.004) antibodies. CONCLUSION: Raynaud's phenomenon patients appear to belong to a systemic lupus erythematosus subset with a spectrum of clinical manifestations located in a more benign pole of the disease. PMID- 26734865 TI - Quality of life and psychosocial aspects in Greek patients with psoriasis: a cross-sectional study. AB - BACKGROUND: Psoriasis is a common, long-term skin disease associated with high levels of psychological distress and a considerable adverse impact on life. The effects of psoriasis, beyond skin affliction, are seldom recognized and often undertreated. OBJECTIVE: The aim of the study is to evaluate the quality of life, anxiety and depression, self-esteem and loneliness in patients with psoriasis. METHODS: Eighty-four patients with psoriasis were enrolled in the study. The quality of life, depression and anxiety, loneliness and self-esteem of the patient were assessed using the Dermatology Life Quality Index, Hospital Anxiety and Depression Scale, the UCLA loneliness Scale (UCLA-Version 3) and Rosenberg's Self-esteem Scale, respectively. RESULTS: The Dermatology Quality of Life Index score among psoriasis patients was 12.61 +/- 4.88. They had statistically significantly higher scores according to the Hospital Anxiety and Depression Scale -anxiety subscale (p=0.032)-compared with healthy volunteers. Moreover, a statistically significant difference was found between the two groups concerning the UCLA-scale (p=0.033) and RSES-scale (p<0.0001). Female patients presented with lower self-esteem than male patients. CONCLUSION: Psoriasis is a distressing, recurrent disorder that significantly impairs quality of life. Therefore, the recognition and future management of psoriasis may require the involvement of multi-disciplinary teams to manage the physical, psychological and social aspects of the condition, as is the case for systemic, long-term conditions. PMID- 26734866 TI - Long-term recurrence of nonmelanoma skin cancer after topical methylaminolevulinate photodynamic therapy in a dermato-oncology department. AB - BACKGROUND: Most available studies on the efficacy of topical photodynamic therapy focus on short-to medium-term results. Long-term data are scarce. OBJECTIVE: To evaluate the long-term efficacy of photodynamic therapy with topical methylaminolevulinate to treat Bowen's disease and basal cell carcinoma in the clinical practice setting of a dermato-oncology department. METHODS: The study included patients diagnosed with Bowen's disease or basal cell carcinoma, and who received photodynamic therapy from 2004 to 2008. Treatment protocol and clinical follow-up were standardized. The primary endpoint was clinically observed recurrence in a previous photodynamic therapy-treated area. Descriptive and survival analyses were performed. RESULTS: A total of 31 Bowen's disease lesions and 44 superficial basal cell carcinoma were treated, with a median follow-up of 43.5 months. Recurrence was observed in 14 Bowen's disease lesions (53.8%) and in 11 superficial basal cell carcinoma (33.3%). Significantly higher estimates for recurrence rates were found in patients with Bowen's disease (p=0.0036) or those aged under 58 years (p=0.039). The risk of recurrence was higher in patients with Bowen's disease than in those with superficial basal cell carcinoma and younger patients. CONCLUSIONS: Recurrence should be considered when choosing to treat non-melanoma skin cancer with photodynamic therapy. Younger age and Bowen's disease were independent predictors for long-term recurrence, suggesting the need to establish an extended period of follow-up for this subset of patients. PMID- 26734868 TI - Adenosine: an endogenous mediator in the pathogenesis of psoriasis. AB - It is known that inflammatory and immune responses protect us from the invasion of micro-organisms and eliminate "wastes" from the injured sites, but they may also be responsible for significant tissue damage. Adenosine, as a purine nucleoside, which is produced in inflamed or injured sites, fulfills its role in limiting tissue damage. Although, it may have a pleiotropic effect, which signals it with a proinflammatory state in certain situations, it can be considered a potent anti-inflammatory mediator. The effects of adenosine, which acts through its receptors on T cell, on mast cell and macrophages, on endothelial cells, on neutrophils and dendritic cells, as they indicate TNF-alpha and cytokines, show that this mediator has a central role in the pathogenesis of psoriasis. The way it acts in psoriasis will be reviewed in this study. PMID- 26734869 TI - Diagnostic methods to cutaneous leishmaniasis detection in domestic dogs and cats. AB - Cutaneous leishmaniasis is caused by different species of Leishmania. In domestic animals such as dogs and cats, the diagnostic consists of clinical, epidemiological and serological tests, which changes among countries all around the world. Because of this diversity in the methods selected, we propose this systematic literature review to identify the methods of laboratory diagnosis used to detect cutaneous leishmaniasis in domestic dogs and cats in the Americas. Articles published in the last 5 years were searched in PubMed, ISI Web of Science, LILACS and Scielo, and we selected 10 papers about cutaneous leishmaniasis in dogs and cats in the Americas. In Brazil, often the indirect immunofluorescence and enzyme immunoassay (ELISA) have been applied. Other countries like United States and Mexico have been using antigenic fractions for antibodies detections by Western blot. ELISA and Western blot showed a higher sensitivity and efficacy in the detection of leishmaniasis. Analysis of sensibility and specificity of the methods was rarely used. Although confirmatory to leishmaniasis, direct methods for parasites detection and polymerase chain reaction showed low positivity in disease detection. We suggested that more than one method should be used for the detection of feline and canine leishmaniasis. Serological methods such as Western blot and enzyme immunoassay have a high efficacy in the diagnosis of this disease. PMID- 26734867 TI - Guidelines of the Brazilian Dermatology Society for diagnosis, treatment and follow up of primary cutaneous melanoma--Part I. AB - The last Brazilian guidelines on melanoma were published in 2002. Development in diagnosis and treatment made updating necessary. The coordinators elaborated ten clinical questions, based on PICO system. A Medline search, according to specific MeSH terms for each of the 10 questions was performed and articles selected were classified from A to D according to level of scientific evidence. Based on the results, recommendations were defined and classified according to scientific strength. The present Guidelines were divided in two parts for editorial and publication reasons. In the first part, the following clinical questions were answered: 1) The use of dermoscopy for diagnosis of primary cutaneous melanoma brings benefits for patients when compared with clinical examination? 2) Does dermoscopy favor diagnosis of nail apparatus melanoma? 3) Is there a prognostic difference when incisional or excisional biopsies are used? 4) Does revision by a pathologist trained in melanoma contribute to diagnosis and treatment of primary cutaneous melanoma? What margins should be used to treat lentigo maligna melanoma and melanoma in situ? PMID- 26734870 TI - Nuclear morphometry and chromatin textural characteristics of basal cell carcinoma. AB - Histological subtypes of basal cell carcinoma have biological, evolutionary and distinct prognostic behavior. The analysis of characteristics of the nucleus can provide data on their cellular physiology and behavior. The authors of this study evaluated nuclear morphological parameters and textural patterns of chromatin from different subtypes of basal cell carcinoma: nodular (n=37), superficial (n=28) and sclerodermiform (n=28). The parameters were compared between neoplasms' subtypes and with unaffected adjacent basal epithelium. Nuclear area and diameter of sclerodermiform neoplasms were superior to the other subtypes. Chromatin's color intensity and fractal dimension were less intense in superficial subtypes. Nuclear roundness and chromatin's entropy presented lower values in tumors than in normal epithelium. There was significant correlation between morphological and textural variables of normal skin and tumors. Morphometric elements and textural chromatin's homogeneity of basal cell carcinomas may be related to evolutionary, biological and behavior particularities related to each histotype. PMID- 26734871 TI - Cutaneous metastasis of unknown primary presenting as massive and invasive abdominal lesion: an elective approach with electrochemotherapy. AB - We describe herein what is to our knowledge the first reported case of an invasive cutaneous metastasis with unknown primary, electively treated solely with electrochemotherapy. We describe a female patient with a large, invasive and painful lesion in her hypogastric region, extending up to the pubic area. The cutaneous biopsy and instrumental and laboratory analyses, all failed to reveal the primary site. A final diagnosis of cutaneous metastasis with unknown primary was made and treatment was performed with electrochemotherapy. Our case highlights the importance of interdisciplinary choices in clinical practice to cope with the lack of a primary site and to improve quality of life, since no standardized therapy exists for these classes of patients. PMID- 26734872 TI - Clinical exuberance of classic Kaposi's sarcoma and response to radiotherapy. AB - Kaposi's sarcoma (KS) is a multicentric vascular neoplasm, with cutaneous and extracutaneous involvement. Different clinical and epidemiological variants have been identified. The classic form is manifested mainly in elderly men with indolent and long-term evolution, with lesions localized primarily in the lower extremities. We present two cases of classic Kaposi's sarcoma (CKS) in two female patients with extensive, exuberant skin involvement and rapid evolution, with good response to radiotherapy. PMID- 26734873 TI - Epidermolytic Hyperkeratosis--case report. AB - Epidermolytic hipercetarose is a rare genodermatosis, with a prevalence of 1:100.000 to 1:300.000, with autosomal dominant inheritance. We report the case of a 5 year old girl who presented an hypertrophic verrucous plaques in the neck, under arm, buttocks, knees, pelvis, legs, dorsum of the right foot and elbows. Histological examination of the skin lesions showed typical changes of epidermolytic hyperkeratosis. Because it is an autosomal dominant disorder with complete penetrance, the individual carrying the mutation will necessarily develop the disease. However, in 50% of cases postzygotic mutation occur. The case report emphasizes early diagnosis and differential diagnoses with ichthyosis and other bullous diseases of childhood, as well as discussing the therapeutic possibilities. PMID- 26734874 TI - Granulomatous slack skin T-cell lymphoma: an important differential diagnosis with giant cell tumor of soft tissue. AB - Granulomatous slack skin is an indolent T-cell lymphoma, considered to be a variant of mycosis fungoides. Clinically it is characterized by areas of redundant skin, wrinkled, inelastic, with variable erythema and infiltration besides a poikilodermic surface. A differential diagnosis unknown to most dermatologists is the giant cell tumor of soft tissue, which is an extremely rare low-grade sarcoma. The authors report a patient who had undergone extensive surgery because of a primary diagnosis of giant cell tumor of soft tissue, but which proved to be granulomatous slack skin after a second interventional procedure with confirmatory histopathology. PMID- 26734875 TI - Clouston Syndrome: 25-year follow-up of a patient. AB - Clouston syndrome is a rare genodermatosis that affects skin and annexes. It is a form of ectodermal dysplasia characterized by generalized hypotrichosis, palmoplantar hyperkeratosis and nail dystrophy. This paper reports a 25-year follow-up of a patient with Clouston syndrome, from childhood to adulthood, monitoring diagnosis and clinical course of the disease. PMID- 26734876 TI - Syringocystadenoma papilliferum in an unusual location. AB - Syringocystadenoma papilliferum is a rare benign hamartomatous adnexal tumor of the apocrine or eccrine sweat glands. Most patients present a solitary lesion in the head and neck region. Presentation outside the head and neck region is even more uncommon. We present a case of Syringocystadenoma papilliferum with papulonodular lesion located on the vulva of an infant girl. This case illustrates the atypical location of this rare disease and adds to the differential diagnosis of lesions on the vulva. PMID- 26734877 TI - Dermoscopy and Onychomycosis: guided nail abrasion for mycological samples. AB - Mycological examination is still the cornerstone for the diagnosis of onychomycosis for many dermatologists, but sampling technique interferes on its sensitivity and specificity. Nail abrasion may be used to reach the most proximal part of the lesion and can be easily accomplished with an electric abrasor. We suggest nail plate dermoscopy to identify the best location for localized abrasion to obtain adequate samples for mycological examination. PMID- 26734878 TI - Tumoral chromoblastomycosis: a rare manifestation with typical complementary exams. AB - Chromoblastomycosis is a chronic subcutaneous fungal infection caused by traumatic implantation of dematiaceous fungi in the skin. The clinical presentation is usually a verrucous plaque lesion and the diagnosis is confirmed by the visualization of muriform bodies at direct examination or at the histologic study. This report describes a rare case of tumoral chromoblastomycosis confirmed by histologic study and whose agent was identified by culture and micromorphology. PMID- 26734879 TI - Syndrome in question. AB - Morbihan Syndrome is a rare entity with unknown etiology. It is clinically characterized by chronic erythematous edema on the face - especially in the middle and upper third of the face - and creates abnormal facial contours that are initially intermitent but become permanent with the development of the syndrome. The histopathology is nonspecific and its therapy is a major challenge due to poor response to the various treatment options. We present the case of a male patient with a five-month-history of disease. PMID- 26734880 TI - Contact dermatitis to methylisothiazolinone. AB - Methylisothiazolinone (MI) is a preservative found in cosmetic and industrial products. Contact dermatitis caused by either methylchloroisothiazolinone/methylisothiazolinone (MCI/MI or Kathon CG) or MI has shown increasing frequency. The latter is preferably detected through epicutaneous testing with aqueous MI 2000 ppm, which is not included in the Brazilian standard tray. We describe a series of 23 patients tested using it and our standard tray. A case with negative reaction to MCI/MI and positive to MI is emphasized. PMID- 26734881 TI - Sexually Transmitted Diseases: from HPV to HTLV--clinical profile and associated factors. AB - The Brazilian Ministry of Health recommends the performance of serological tests in patients with clinical signs of Sexually Transmitted Diseases. However, data are lacking to affirm the necessity of testing these patients for human T lymphotropic virus type 1 or type 2. This is a cross-sectional study with 120 patients seen at the Sexually Transmitted Diseases unit of the Sanitary Dermatology Outpatient Clinic of Rio Grande do Sul. The serum from none of the patients was positive for human T-lymphotropic virus type 1 or type 2. Viral warts were the most frequent diagnosis. Drug use was confirmed as a risk factor and high educational levels were found to be a protective factor against Sexually Transmitted Diseases. PMID- 26734882 TI - Microneedling in facial recalcitrant melasma: report of a series of 22 cases. AB - Melasma is a chronic skin disorder that results in symmetrical, blotchy, brownish facial pigmentation. It is more common in women than in men, it generally starts between 20 and 40 years, and it can lead to considerable embarrassment and distress. The aims of this article is to evaluate the treatment with the microneedling method in 18 female and 4 male with recalcitrant melasma. All patients demonstrated good results. In conclusion, microneedles appears to be a promising therapeutic method for melasma. PMID- 26734883 TI - Correlation between nutritional, hematological and infectious characteristics and classification of the type of epidermolysis bullosa of patients assisted at the Dermatology Clinic of the Hospital Universitario de Brasilia. AB - Epidermolysis bullosa comprises a group of phenotypically different genodermatosis, hereditary or acquired, characterized by skin fragility and subsequent formation of blisters in response to mechanical trauma, and which may also affect mucous membranes. This study aimed to analyze the relation between the nutritional, hematologic, infectious characteristics and the type of epidermolysis bullosa, through a descriptive case study based on data from medical records of 10 patients with epidermolysis bullosa assisted regularly at the Dermatology Clinic of the Hospital Universitario de Brasilia. The old classification of the type of epidermolysis bullosa, weight and height, blood count, white blood cell count, platelet count and description of the type and frequency of secondary infections during the service were considered. We verified a predominance of iron deficiency anemia, chronic leukocytosis, thrombocytosis, chronic malnutrition, low height for age and thinness, and people with epidermolysis bullosa simplex exhibited appropriate relation between height/age and BMI/age. The non-specific skin infection was the most prevalent in both sexes. The severity of the type of epidermolysis bullosa and frequency of secondary infections did not form a directly proportional relation. The absence of direct proportion in all cases between the type of epidermolysis bullosa and the analysis parameters suggest a possible significant interference from other aspects such as the extent of the affected skin area, extracutaneous type of engagement and specific genetic mutation. The inclusion of these factors in the new classification proposed by Fine et al can contribute significantly to a better correlation of clinical parameters and appropriate preventive and therapeutic approaches. PMID- 26734884 TI - Erythema annulare centrifugum as presenting sign of activation of breast cancer. AB - Erythema annulare centrifugum is a figurate erythema of unknown etiology. It has been associated with many different entities, including infections, food allergy, drug reactions and malignant neoplasms. Herein, we report a case of erythema annulare centrifugum as presenting sign of activation of breastcancer. PMID- 26734885 TI - Piezogenic Pedal Papules. PMID- 26734886 TI - Supramolecular Organization of Respiratory Complexes. AB - Since the discovery of the existence of superassemblies between mitochondrial respiratory complexes, such superassemblies have been the object of a passionate debate. It is accepted that respiratory supercomplexes are structures that occur in vivo, although which superstructures are naturally occurring and what could be their functional role remain open questions. The main difficulty is to make compatible the existence of superassemblies with the corpus of data that drove the field to abandon the early understanding of the physical arrangement of the mitochondrial respiratory chain as a compact physical entity (the solid model). This review provides a nonexhaustive overview of the evolution of our understanding of the structural organization of the electron transport chain from the original idea of a compact organization to a view of freely moving complexes connected by electron carriers. Today supercomplexes are viewed not as a revival of the old solid model but rather as a refined revision of the fluid model, which incorporates a new layer of structural and functional complexity. PMID- 26734887 TI - Brucella spp. Virulence Factors and Immunity. AB - Brucellosis, caused by bacteria of the genus Brucella, is an important zoonotic infection that causes reproductive disease in domestic animals and chronic debilitating disease in humans. An intriguing aspect of Brucella infection is the ability of these bacteria to evade the host immune response, leading to pathogen persistence. Conversely, in the reproductive tract of infected animals, this stealthy pathogen is able to cause an acute severe inflammatory response. In this review, we discuss the different mechanisms used by Brucella to cause disease, with emphasis on its virulence factors and the dichotomy between chronic persistence and reproductive disease. PMID- 26734888 TI - Persistent Infections and Immunity in Ruminants to Arthropod-Borne Bacteria in the Family Anaplasmataceae. AB - Tick-transmitted gram-negative bacteria in the family Anaplasmataceae in the order Rickettsiales cause persistent infection and morbidity and mortality in ruminants. Whereas Anaplasma marginale infection is restricted to ruminants, Anaplasma phagocytophilum is promiscuous and, in addition to causing disease in sheep and cattle, notably causes disease in humans, horses, and dogs. Although the two pathogens invade and replicate in distinct blood cells (erythrocytes and neutrophils, respectively), they have evolved similar mechanisms of antigenic variation in immunodominant major surface protein 2 (MSP2) and MSP2(P44) that result in immune evasion and persistent infection. Furthermore, these bacteria have evolved distinct strategies to cause immune dysfunction, characterized as an antigen-specific CD4 T-cell exhaustion for A. marginale and a generalized immune suppression for A. phagocytophilum, that also facilitate persistence. This indicates highly adapted strategies of Anaplasma spp. to both suppress protective immune responses and evade those that do develop. However, conserved subdominant antigens are potential targets for immunization. PMID- 26734889 TI - Adjustments of lipid pathways in plant adaptation to temperature stress. AB - Modulation of membrane lipid composition under varying environmental conditions is an important part of plant stress adaptation. Most notably, proportional changes of lipid composition in response to temperature changes are a major cellular response to requirements of membrane fluidity adjustment. In higher plants, synthesis of glycerolipids is accomplished by 2 major pathways, the prokaryotic and eukaryotic pathway, located in the chloroplast and the endoplasmic reticulum (ER), respectively. Recently, we systematically investigated the re-adjustments of glycerolipid pathways under temperature stress at the metabolite and transcript levels using 3 plant species with distinct lipid profiles. The relative contributions of 2 pathways and lipid channeling from the ER and chloroplast were both observed in plants under temperature stress. Potential factors controlling the lipid flux were identified through transcriptome analysis. PMID- 26734890 TI - The Influence of Intense Combined Training on Upper Extremity Function in Children With Unilateral Cerebral Palsy: Does Initial Ability Matter? AB - AIM: To examine whether level of manual ability modifies the response to an intensive program combining modified constraint and bimanual training on arm functioning children with unilateral cerebral palsy (UCP). METHODS: Thirty-four children aged 6-11 years, with Manual Ability Classification System (MACS) levels I-III (I:8, II:15, III:11), participated in a 2-week program, combining an hour of modified constraint with 5 hr of bimanual practice daily. The Assisting Hand Assessment (AHA) and the Jebsen-Taylor Test of Hand Function (JTTHF) were done pre-, post-, and 3-months post-intervention. RESULTS: Mean AHA logits unit scores increased overtime (F2;50 = 5, p = 0.01). There was no significant difference in AHA logits units change score between MACS levels (F4;56 = 1.4, p = 0.22). JTTHF scores did not change for either the affected or less-affected hand, although a significant interaction of time and MACS level was found in the less-affected side (F4;58 = 6.5, p < 0.01). Children in MACS levels I and II improved by similar degrees, in comparison to children at MACS level III who demonstrated significantly greater change over time. CONCLUSION: While a similar trend of improvement was found in the bimanual abilities of children at all MACS levels, only children at MACS level III had improved performance in unilateral abilities in the less-affected side following intervention. PMID- 26734891 TI - Impact of Mid-Life Symptoms of Alcoholism on the Health and Wellbeing of Aging Parents of Adults with Disabilities. AB - The study examined the effect of adult children's disability on parents' physical health in later life and the extent to which parents' symptoms of alcoholism in mid-life moderates the link between children's disability and later life parental health. Analyses are based on data from the Wisconsin Longitudinal Study. The analytic sample included parents of children with developmental disabilities (n = 145) or mental health problems (n = 200) and 2,432 parents of unaffected children. The results showed that the negative health consequences in later life of having a child with a developmental disability were greater for those who showed more symptoms of alcoholism in mid-life. However, symptoms of alcoholism in mid-life did not significantly moderate the impact of an adult child's mental health problems on parents' later life physical health. The findings suggest a potential area where gerontological social workers could intervene, given the negative impact of symptoms of alcoholism on the health of aging parents of children with a disability who may be significantly more susceptible to the negative health impacts of alcohol compared to their younger counterparts. PMID- 26734913 TI - Study of 1550-nm Erbium glass laser fractional non-ablative treatment of photoaging: Comparative clinical effects, histopathology, electron microscopy, and immunohistochemistry. AB - BACKGROUND: Non-ablative fractional lasers have been effectively used in skin rejuvenation. OBJECTIVES: This study evaluates the efficacy of 1550-nm Erbium glass laser for facial rejuvenation through the correlation of clinical evaluation and histopathology, immunohistochemistry, and electron microscopy analysis. METHODS: Fifteen subjects (average age: 56.4 years, skin types: I-III) with mild-to-moderate photodamage were submitted to biopsies and 3 facial treatments. Data from the photo assessments and the clinical improvement were analyzed 4 months after the treatments. The biopsy skins were fixed in neutral buffered formalin before being embedded in paraffin, and stained with hematoxylin and eosin. The histomorphometric quantification of collagen and elastic fibers; intercellular adhesion molecule 1 expression by immunohistochemistry; and analysis of cell cycle phases, the electrical potential of the mitochondrial, and interleukin (IL)-1, CD34, transforming growth factor (TGF)-beta, and caspase-3 expression by flow cytometry were analyzed. RESULTS: After 4 months of treatment, collagen fibers had increased by 6.68%, and intercellular adhesion molecule 1 (ICAM-1) had increased by 4.47% in vessel area. Significantly enhanced IL-1 and TGF-beta receptor expressions were identified after treatment. Proliferative responses and non-apoptosis-dependent caspase-3 activity were both observed in the cell after dermal treatment. CONCLUSION: The histopathology, immunohistochemistry, and electron microscopy showed an improvement compatible to the clinical effectiveness after 4 months. PMID- 26734914 TI - Remission of an extensively pre-treated relapsing/refractory ALK-positive anaplastic large cell lymphoma following metronomic therapy. PMID- 26734916 TI - Clinical and biochemical comparison of guided tissue regeneration versus guided tissue regeneration plus low-level laser therapy in the treatment of class II furcation defects: A clinical study. AB - OBJECTIVE: The present study was aimed to compare the clinical and biochemical effectiveness of guided tissue regeneration (GTR) alone and combined with low level laser therapy (LLLT) application in the treatment of furcation II periodontal defects, over a period of 6 months. MATERIAL AND METHODS: Thirty three furcation defects were included in the study. Seventeen of these defects were treated with GTR plus LLLT, and sixteen of them were treated with GTR alone. Probing pocket depth (PPD), clinical attachment level (CAL), horizontal probing depth (HPD), and alkaline phosphatase (ALP) and osteocalcin (OC) levels in the gingival crevicular fluid (GCF) were recorded at baseline and at postoperative 3rd and 6th months. RESULTS: Healing was uneventful in all cases. At the 3rd and 6th months, both treatment modalities-GTR and GTR plus LLLT--showed improved PPD, CAL, and HPD values compared to their baseline values. ALP and OC levels in GCF increased after the treatment in both groups (p < 0.05). When compared the two groups, at the 6th month, PPD, CAL, HPD, and ALP values showed significantly more improvement in laser group than non-laser group (p < 0.05). CONCLUSIONS: The results of this study showed that both treatments led to significantly favorable clinical improvements in furcation periodontal defects. LLLT plus GTR may be a more effective treatment modality compared to GTR alone. PMID- 26734917 TI - Obesity and Placental Function. AB - An increasing number of women of reproductive age are obese which affects the continuum of pregnancy and is associated with an increased incidence of adverse maternal and fetal outcomes, including preeclampsia, preterm birth, stillbirth, congenital anomalies, and macrosomia. Maternal obesity is associated with an increased incidence of metabolic and cardiovascular disease later in life in the mother and in the offspring who are developmentally programed by the obese pregnancy environment. The placenta transduces and mediates the effect of the adverse maternal environment to the fetus. The obese maternal environment is characterized by hyperlipidemia and an exaggerated state of inflammation and oxidative stress compared with normal pregnancy. Heightened inflammation and oxidative/nitrative stress are found in the placenta in association with placental dysfunction. We have described reduced mitochondrial respiration and ATP generation in trophoblast isolated from placentas of obese compared with lean women, again suggesting compromised placental function. In utero development exhibits sexual dimorphism with the male fetus at greater risk of poor outcome. We have shown dimorphism in inflammation-mediated regulation of trophoblast mitochondrial respiration. There is also increasing evidence that the obese in utero environment may cause epigenetic changes in placenta leading to altered function. PMID- 26734918 TI - Alcohol and injuries in elderly people. AB - Injuries are a common cause of morbidity and mortality among elderly people. Falls are the most common type of accident, accounting for around 40% of injuries. There is substantial evidence that heavy alcohol use is an important risk factor for injuries in younger people, but results of the few studies of alcohol and injuries among elderly people have been inconsistent. In this paper, we review the literature on the effects of alcohol on gait and balance and present reasons that a causal relationship between alcohol and injuries is biologically plausible. We review the epidemiological studies of the relationship between alcohol and falls, hip fractures and other injuries in the elderly population and discuss sources of error in these studies. Selection bias, small sample sizes, measurement error and potential confounders such as age, gender, health status and medications may have played a substantial role in negative results from several studies. Further research that will help clarify the relationship between alcohol and injuries in elderly people is sorely needed. PMID- 26734919 TI - Ethanol metabolism, toxicity and genetic polymorphism. AB - The relationships between the individual (and racial) differences in alcohol metabolism and toxicity, and the genetic polymorphism of alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and cytochrome P-4502E1(CYPIIE1) were reviewed. In recent studies involving DNA analysis, it was found that a deficiency of the ALDH2 isozyme (ALDH2*2) was responsible for the flushing symptoms as well as other vasomotor symptoms caused by a higher acetaldehyde level after alcohol consumption. Deficiency of ALDH2 activity has been found prevalently only among people of Mongoloid origin, and the deficiency of ALDH2 prevents them from developing alcohol dependence due to the unpleasant physical effects of the flushing symptom. It was reported that Mongoloids such as Japanese and Chinese people carry the enzymatically active (ALDH2*1) subunit and/or the inactive (ALDH2*2) one, and that a low proportion of ALDH2 deficiency (ALDH2*2 allele frequency) was found in alcoholics compared with healthy controls. It was also reported that polymorphism of ALDH2 and/or CYP2E1 may be associated with the susceptibility to alcohol-induced liver injury. Concerning blood ethanol elimination kinetics, it was reported that the c2 gene of CYP2E1 and the ALDH2*1 gene may have greater effects on ethanol and acetaldehyde elimination than the other genotypes, when the blood ethanol level is below 20 m M. PMID- 26734915 TI - Comparative DNA adduct formation and induction of colonic aberrant crypt foci in mice exposed to 2-amino-9H-pyrido[2,3-b]indole, 2-amino-3,4-dimethylimidazo[4,5 f]quinoline, and azoxymethane. AB - Considerable evidence suggests that environmental factors, including diet and cigarette smoke, are involved in the pathogenesis of colon cancer. Carcinogenic nitroso compounds (NOC), such as N-nitrosodimethylamine (NDMA), are present in tobacco and processed red meat, and NOC have been implicated in colon cancer. Azoxymethane (AOM), commonly used for experimental colon carcinogenesis, is an isomer of NDMA, and it produces the same DNA adducts as does NDMA. Heterocyclic aromatic amines (HAAs) formed during the combustion of tobacco and high temperature cooking of meats are also associated with an elevated risk of colon cancer. The most abundant carcinogenic HAA formed in tobacco smoke is 2-amino-9H pyrido[2,3-b]indole (AalphaC), whereas 2-amino-3,4-dimethylimidazo[4,5 f]quinoline (MeIQ) is the most potent carcinogenic HAA formed during the cooking of meat and fish. However, the comparative tumor-initiating potential of AalphaC, MeIQ, and AOM is unknown. In this report, we evaluate the formation of DNA adducts as a measure of genotoxicity, and the induction of colonic aberrant crypt foci (ACF) and dysplastic ACF, as an early measure of carcinogenic potency of these compounds in the colon of male A/J mice. Both AalphaC and AOM induced a greater number of DNA adducts than MeIQ in the liver and colon. AOM induced a greater number of ACF and dysplastic ACF than either AalphaC or MeIQ. Conversely, based on adduct levels, MeIQ-DNA adducts were more potent than AalphaC- and AOM DNA adducts at inducing ACF. Long-term feeding studies are required to relate levels of DNA adducts, induction of ACF, and colon cancer by these colon genotoxicants. PMID- 26734920 TI - Abstinent chronic crack-cocaine and crackcocaine/alcohol abusers evidence normal hippocampal volumes on MRI despite persistent cognitive impairments. AB - We measured hippocampal volumes and cognitive functioning in crack-cocaine and crack-cocaine/alcoholdependent subjects (abstinent approximately 10-12 weeks) compared to age-matched controls. Cognitive function was evaluated using the computerized MicroCog Assessment of Cognitive Functioning (which includes tests of explicit, declarative memory subserved by the hippocampus). The hippocampal volumes were quantified on T1-weighted MRIs and were expressed as a proportion of intracranial vault volume. Both subjects and controls showed the larger right versus left hippocampal volume expected in normal anatomy, but we found no differences in hippocampal volume between any of the groups. However, both abstinent cocaine-dependent subjects and abstinent cocaine/alcohol-dependent subjects showed persistent cognitive impairments, including deficits in explicit memory. Our results suggest that either: (1) the hippocampus is resistant to structural volume loss in young and middle-aged cocaine or cocaine/alcohol dependent subjects, (2) the hippocampal volume loss suffered by young and middle aged cocaine or cocaine/alcohol-dependent subjects resolves after approximately 3 months of abstinence, or (3) hippocampal atrophy is obscured by the process of gliosis. Further, the cognitive impairments persisting in these abstinent cocaine and cocaine/alcohol-dependent samples may (1) be unrelated to hippocampal function or (2) be associated with abnormal hippocampal function that is not reflected in MRI measures of overall hippocampal atrophy. PMID- 26734921 TI - The effect of ethanol and acetaldehyde on microsomal and mitochondrial membrane fatty acid profiles in cultured rat astroglia. AB - It has been shown that free radical damage may be involved in ethanol-induced cytotoxicity in cultured neural cells. Since changes in oxidative metabolism and the resulting lipid peroxidation readily modify biological membranes and alter cell functions we studied the effect of ethanol and its metabolite acetaldehyde on rat astroglial fatty acids profiles in the most common lipid classes of mitochondrial and microsomal membranes, i.e. phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Rat astroglial cells were grown for 1 week in the presence of 50 m M or 100 m M ethanol. To examine acetaldehyde effects we used a 4-day co-culture model consisting of astroglial cells and alcohol dehydrogenase transfected Chinese hamster ovary (CHO) cells. Acetaldehyde produced by these cells reached 172 mu M and 265 mu M, respectively, for ethanol concentrations of 10 and 20 m M. Mitochondrial and microsomal membranes were prepared by differential centrifugation, phosphatidylcholine and phosphatidylethanolamine were separated using thin layer chromatography and fatty acid quantitation was performed by GLC. Neither ethanol nor acetaldehyde changed the mitochondrial phosphatidylcholine or phosphatidylethanolamine profiles of total saturated, mono unsaturated or polyunsaturated fatty acids. However, some significant alterations in particular fatty acids appeared especially after acetaldehyde but also after the highest ethanol dose. In microsomal phosphatidylcholine monounsaturated fatty acids were significantly increased after both, ethanol and acetaldehyde exposure. Among polyunsaturated fatty acids, arachidonic acid was found to be especially affected by both ethanol and acetaldehyde. Similar decreases were observed in adrenic, docosapentaenoic and docosahexaenoic acids in the groups treated with ethanol. In microsomal phosphatidylethanolamine, ethanol and acetaldehyde decreased monounsaturated and some polyunsaturated fatty acids. These data support the role of peroxidative processes in cultured rat astroglia exposed to ethanol and point to the role of acetaldehyde in this mechanism. PMID- 26734922 TI - beta-Carbolines in alcohol-dependent intensive care patients during prophylactics and therapy of alcohol withdrawal syndrome. AB - The primary aim of this study was to investigate whether the naturally occurring beta-carbolines norharman and harman differed between alcohol-dependent patients who developed alcohol withdrawal syndrome (AWS) and those who did not. The secondary aim was to determine whether different treatment regimens influenced the levels of the beta-carbolines. Thirty chronic alcoholics with carcinoma of the upper digestive tract were included in this study. They were prophylactically treated by two different medical regimens: flunitrazepam and clonidine (FNZ regimen) and gamma-hydroxybutyrate and clonidine (GHB regimen). Patients exceeding the Revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar) score of 20 were assigned to the AWS therapy group and received haloperidol in addition to their prevous prophylactic treatment. Patients without AWS remained in the prophylactic group. From days 1-4 of the intensive care unit (ICU) stay norharman, but not harman, was increased in the AWS therapy group. In the FNZ regimen, six of 16 patients (38%) and in the GHB regimen, nine of 14 patients (64%) developed AWS (p= 0.14). Norharman levels did not differ between the two regimens. However, harman levels were increased in the GHB treated regimen on days 1, 2 and 4 following admission to the ICU and correlated with the severity of alcohol withdrawal syndrome. As norharman was elevated in the therapeutically treated ICU patients, this marker appears to be involved in the pathogenesis of AWS. As harman was elevated before and during hallucinations on the GHB regimen, it seems reasonable to carry out further investigations into the potential role of harman as a hallucinatory substance. PMID- 26734923 TI - dl-Fenfluramine inhibits ethanol-induced ascorbic acid release in rat striatum studied by microdialysis. AB - The effects of dl -fenfluramine, dl -5-hydroxytryptophan(5-HTP) and fluoxetine on ethanol-induced striatal ascorbic acid (AA) release in rat were studied by microdialysis coupled to high performance liquid chromatography with electrochemical detection. Ethanol (3.0 g/kg, i.p.) stimulated striatal AA release to more than 200% above the baseline. dl -Fenfluramine (20 mg/kg, i.p. or 40 mug/rat, i.c.v.), 10 min before ethanol administration, markedly inhibited ethanol-induced AA release. A similar result was also observed following dl -5 HTP (100 mg/kg, i.p.) administration. However, fluoxetine (10, 30 mg/kg, i.p.) showed no antagonistic effect on ethanol-induced AA release. The suppressing effect of dl -fenfluramine and dl -5-HTP on ethanolinduced AA release could be reversed by the 5-HT receptor antagonist cyproheptadine (10 mg/kg, s.c.). All these drugs had no effect on basal AA release. The results give a first evidence for the involvement of central serotonergic system, and suggest that differential activities may exist between dl -fenfluramine, dl -5-HTP and fluoxetine in regulating ethanol-induced AA release in rat striatum. PMID- 26734924 TI - MDMA toxicity: no evidence for a major influence of metabolic genotype at CYP2D6. AB - 3,4 Methylenedioxymethamphetamine (MDMA or ecstasy) has become a major drug of abuse over the last decade. It produces a mixture of systemic and neuropsychological effects. Animal studies show a range of short- and long-term toxic effects, both systemically and neurochemically. In humans, toxicity and death due to the drug have been attributed to a variety of causes, with 'idiosyncratic', or non-dose-related, reactions often cited. It has recently been established that MDMA is metabolized via the cytochrome P450 enzyme, debrisoquine hydroxylase. This enzyme is coded by the gene CYP2D6. This gene contains mutations which effect the function of the enzyme, and individuals homozygous for these mutations are known as poor metabolizers. Between 3 and 10% of the Caucasian population are thus affected, and therefore may be less able to metabolize MDMA. In this paper we examine the hypothesis that individuals selected on the basis of having had an adverse reaction to MDMA will be more likely than the general population to have homozygous mutations at CYP2D6. We obtained retrospectively seven cases of toxicity or death thought to be due to MDMA. DNA was extracted from these patients, and their genotype ascertained. None of this small sample was shown to be homozygous for the mutation at CYP2D6. Three possible explanations are offered for these results. (1) The non-dose-related nature of MDMA toxicity may be due, either alone or in combination, to contaminants in the drug, or ambient environmental/physiological factors. (2) Our genotyping methods may have missed one of the rare additional mutations which effect gene function at CYP2D6. (3) Our study sample may be too small to demonstrate a statistically significant result. A larger study is currently under way. PMID- 26734925 TI - Neurological aspects of opium addiction in imprisoned women. AB - The study covered 52 women, aged 19-30 years, who had previously taken home-made poppy preparations. In seven of them we diagnosed opium use (F 11.11 according to ICD-10) and 45 had opium abuse (F 11.21). All were detained in penitentiaries for 2-23 months. The control group consisted of 20 healthy females. A significant frequency of brain stem and extrapyramidal disturbances was found in the opium abuse group. Brain stem signs included tendon anisoreflexia (100-2%), nystagmus (87 5%), ataxia (87 5%) and corneal hyporeflexia (48 7%). Among the most frequent extrapyramidal disturbances were a positive pushing test (90 4%); test with pendular swinging of the legs (85 5%) and hand tremor (82 7%). Statistical analysis revealed a relationship between the degree of extrapyramidal system damage and duration of opiate dependence. PMID- 26734926 TI - Quality of life measures in alcohol dependent subjects and changes with abstinence and continued heavy drinking. AB - This study evaluates the quality of life status of 39 male and 21 female Caucasian subjects admitted to a voluntary sector community alcohol detoxification unit. Baseline data including socio-demographics, severity of alcohol dependence and alcohol problems were collected 4-5 days following admission. In addition, the following measures were obtained: Rotterdam Symptoms Checklist, the Beck Depression Inventory, the General Health Questionnaire 12, Chubon's Life Situation Survey and the Nottingham Health Profile. Subjects were followed up at 12 weeks, and subdivided into two groups: relapsers and non relapsers. A relapse was defined as drinking 21 or more units per week for men and 14 units or more per week for women over 7 consecutive days (1 unit is the equivalent of 8-10 g of absolute ethanol). Fifty-eight (97%) subjects were successfully followed-up, with 36 (62%) of the group relapsing to heavy drinking within 12 weeks. The results show that alcohol dependence is associated with a poor quality of life. Subjects rated poorly on the standardized questionnaires compared with the normative values for their reference populations. Relapsers and non-relapsers differed significantly in their life situation, depression, physical and psychological symptom total scores and the Nottingham Health Profile sub-score energy at 12 weeks compared with baseline, and these changes were investigated for each group. Within the relapse group a linear regression showed no association between any of the quality of life measures and time to relapse. Individual sub-score analysis of the Nottingham Health Profile results point to the importance of sleep, social isolation, pain, physical mobility and anergia in alcohol dependency. There was little change as a result of either not remitting or returning to heavy drinking and overall these findings confirm that alcohol dependent subjects have a poor quality of life. PMID- 26734927 TI - Predictors of relapse to heavy drinking in alcohol dependent subjects following alcohol detoxification-the role of quality of life measures, ethnicity, social class, cigarette and drug use. AB - Sixty DSM-IV alcohol dependent adults (39 males, 21 females) admitted to a voluntary sector alcohol detoxification unit in South London were studied. Socio demographic data and information on level of alcohol dependence, quality of life, family history, cigarette smoking and the use of prescription/illicit drugs were collected. The subjects were followed-up at 12 weeks and subdivided into two groups, relapse and non-relapse. A relapse was defined as drinking 21 units or more per week for males and 14 units or more per week for females. Data were analysed for baseline and 12-week follow-up comparisons. At 12 weeks, 58 (97%) subjects (38 males, 20 females) were successfully followed-up and 36/58 (62%) had relapsed. After controlling for a Type I error there were significant differences between the relapse and non-relapse subgroups at 12-week followup on the following outcome measures; depression, life situation, withdrawal symptoms, energy, emotional reactions and social isolation. There were no significant differences at baseline between the relapse and nonrelapse subgroups for most of the socio-demographic variables, but Irish nationality and membership of lower social classes (IV and V) were associated with relapse. Major predictors of relapse at baseline after a forward stepwise logistic regression were (in order of increasing statistical significance) Irish nationality, lower social class, greater number of cigarettes smoked and disturbed sleep. The findings are discussed with reference to their consistency with existing research and potential clinical implications. PMID- 26734928 TI - Nifedipine but not verapamil inhibits subjective effects of i.v. morphine in opiate-dependent patients. AB - The influence of verapamil and nifedipine after single and subchronic treatment on morphine-induced subjective responses were studied in opiate addicts. Heroin dependent subjects were injected via an antecubetal vein with 20 mg of morphine or placebo using a randomized cross-over design. In Experiment one, either verapamil 80 mg or nifedipine 60 mg or placebo was administered per os 1 hour prior morphine or placebo injection. In experiment two calcium blockers were administered weekly prior morphine administration. Administration of nifedipine (40 mg) reduced, not significantly, the subjective scaling of morphine effects and shifted the discrimination of morphine effects towards those of weak opiates. Acute treatment with verapamil (80 mg) increased, not significantly, the subjective rating of morphine effects. Pre-treatment of heroin abusers with nifedipine 60 mg daily for a week resulted in a remarkable inhibition of opiate induced effects both expression and duration in comparison with placebo and verapamil pre-treatment. Patients pre-treated with nifedipine were also unable to discriminate properly morphine from other psychotropic compounds. Thus, nifedipine but not verapamil markedly inhibited but did not reduce completely the central effects of morphine. It is concluded that nifedipine can potentially offer a new interesting approach to the treatment programmes of opiate abuse. PMID- 26734930 TI - Free Surface Command Layer for Photoswitchable Out-of-Plane Alignment Control in Liquid Crystalline Polymer Films. AB - To date, reversible alignment controls of liquid crystalline materials have widely been achieved by photoreactive layers on solid substrates. In contrast, this work demonstrates the reversible out-of-plane photocontrols of liquid crystalline polymer films by using a photoresponsive skin layer existing at the free surface. A polymethacrylate containing a cyanobiphenyl side-chain mesogen adopts the planar orientation. Upon blending a small amount of azobenzene containing side-chain polymer followed by successive annealing, segregation of the azobenzene polymer at the free surface occurs and induces a planar to homeotropic orientation transition of cyanobiphenyl mesogens underneath. By irradiation with UV light, the mesogen orientation turns into the planar orientation. The orientation reverts to the homeotropic state upon visible light irradiation or thermally, and such cyclic processes can be repeated many times. On the basis of this principle, erasable optical patterning is performed by irradiating UV light through a photomask. PMID- 26734931 TI - Synthesis, Ion Recognition Ability, and Metal-Assisted Aggregation Behavior of Dinuclear Metallohosts Having a Bis(Saloph) Macrocyclic Ligand. AB - Macrocyclic molecule 1 that has two saloph coordination sites was designed and synthesized. The macrocycle 1 was easily converted into the corresponding metallohosts 2 and 3 by the reaction with nickel(II) and palladium(II), respectively. As expected from the molecular structure of these metallohosts having an 18-crown-6-like cavity, the nickel(II) metallohost 2 showed excellent binding affinity toward Na(+), Ca(2+), and Sr(2+) to give 1:1 host-guest complexes. Preorganization effect due to the extremely rigid metal-containing macrocycle was suggested to be a major factor for the strong binding. Larger cations such as K(+), Rb(+), Cs(+), and Ba(2+) gave higher aggregated host-guest complexes such as 22M, 23M2, and 24M3. Density functional theory calculations revealed that smaller metal ions do not occupy the center of each macrocycle in the sandwich structures 22M, while larger Cs(+) simultaneously interacts with all the 12 oxygen donor atoms. On the basis of the interaction energy calculations, the preference for 2.Na over 22Na can be explained by destabilization of 22Na due to the elongated Na-O bonds and repulsive three-body interactions. When the ionic radius of the guest ion increases (K(+), Rb(+), Cs(+)), this destabilization becomes less significant and the formation of sandwich complexes 22M is favored. Such aggregation would significantly affect the physical and chemical properties of the metal complexes due to the interplane interactions between the metal centers. PMID- 26734932 TI - Controlled Payload Release by Magnetic Field Triggered Neural Stem Cell Destruction for Malignant Glioma Treatment. AB - Stem cells have recently garnered attention as drug and particle carriers to sites of tumors, due to their natural ability to track to the site of interest. Specifically, neural stem cells (NSCs) have demonstrated to be a promising candidate for delivering therapeutics to malignant glioma, a primary brain tumor that is not curable by current treatments, and inevitably fatal. In this article, we demonstrate that NSCs are able to internalize 2 MUm magnetic discs (SD), without affecting the health of the cells. The SD can then be remotely triggered in an applied 1 T rotating magnetic field to deliver a payload. Furthermore, we use this NSC-SD delivery system to deliver the SD themselves as a therapeutic agent to mechanically destroy glioma cells. NSCs were incubated with the SD overnight before treatment with a 1T rotating magnetic field to trigger the SD release. The potential timed release effects of the magnetic particles were tested with migration assays, confocal microscopy and immunohistochemistry for apoptosis. After the magnetic field triggered SD release, glioma cells were added and allowed to internalize the particles. Once internalized, another dose of the magnetic field treatment was administered to trigger mechanically induced apoptotic cell death of the glioma cells by the rotating SD. We are able to determine that NSC-SD and magnetic field treatment can achieve over 50% glioma cell death when loaded at 50 SD/cell, making this a promising therapeutic for the treatment of glioma. PMID- 26734933 TI - Implications for Welfare, Productivity and Sustainability of the Variation in Reported Levels of Mortality for Laying Hen Flocks Kept in Different Housing Systems: A Meta-Analysis of Ten Studies. AB - Data from ten sources comprising 3,851 flocks were modelled to identify variation in levels of mortality in laying hens. The predicted increase with age was curvilinear with significant variation between the seven breed categories. Mortality was higher in loose housing systems than in cages and variable within system, confirming previous reports. Cumulative mortality (CM) was higher in flocks with intact beaks (chi2 = 6.03; df 1; p = 0.014) than in those with trimmed beaks. Most data were available for free-range systems (2,823 flocks), where producer recorded CM at 60-80 weeks of age averaged 10% but with a range from 0% to 69.3%. Life cycle assessment showed that the main effect of increased levels of hen mortality is to increase the relative contribution of breeding overheads, so increasing environmental burdens per unit of production. Reducing CM to levels currently achieved by the 1st quartile could reduce flock greenhouse gas emissions by as much as 25%. Concurrently this would enhance hen welfare and better meet the expectation of egg consumers. More research to understand the genetic x environment interaction and detailed records of the causes of mortality is required so that improved genotypes can be developed for different systems and different breeds can be better managed within systems. PMID- 26734935 TI - Correction to "Auxiliary-Directed Pd-Catalyzed gamma-C(sp(3))-H Bond Activation of alpha-Aminobutanoic Acid Derivatives". PMID- 26734934 TI - Rapamycin Attenuates Splenomegaly in both Intrahepatic and Prehepatic Portal Hypertensive Rats by Blocking mTOR Signaling Pathway. AB - BACKGROUND: Spleen enlargement is often detected in patients with liver cirrhosis, but the precise pathogenetic mechanisms behind the phenomenon have not been clearly elucidated. We investigated the pathogenetic mechanisms of splenomegaly in both portal hypertensive patients and rats, and tried to identify the possible therapy for this disease. METHODS: Spleen samples were collected from portal hypertensive patients after splenectomy. Rat models of portal hypertension were induced by common bile duct ligation and partial portal vein ligation. Spleen samples from patients and rats were used to study the characteristics of splenomegaly by histological, immunohistochemical, and western blot analyses. Rapamycin or vehicle was administered to rats to determine the contribution of mTOR signaling pathway in the development of splenomegaly. RESULTS: We found that not only spleen congestion, but also increasing angiogenesis, fibrogenesis, inflammation and proliferation of splenic lymphoid tissue contributed to the development of splenomegaly in portal hypertensive patients and rats. Intriguingly, splenomegaly developed time-dependently in portal hypertensive rat that accompanied with progressive activation of mTOR signaling pathway. mTOR blockade by rapamycin profoundly ameliorated splenomegaly by limiting lymphocytes proliferation, angiogenesis, fibrogenesis and inflammation as well as decreasing portal pressure. CONCLUSIONS: This study provides compelling evidence indicating that mTOR signaling activation pathway plays a key role in the pathogenesis of splenomegaly in both portal hypertensive patients and rats. Therapeutic intervention targeting mTOR could be a promising strategy for patients with portal hypertension and splenomegaly. PMID- 26734936 TI - Text Mining the History of Medicine. AB - Historical text archives constitute a rich and diverse source of information, which is becoming increasingly readily accessible, due to large-scale digitisation efforts. However, it can be difficult for researchers to explore and search such large volumes of data in an efficient manner. Text mining (TM) methods can help, through their ability to recognise various types of semantic information automatically, e.g., instances of concepts (places, medical conditions, drugs, etc.), synonyms/variant forms of concepts, and relationships holding between concepts (which drugs are used to treat which medical conditions, etc.). TM analysis allows search systems to incorporate functionality such as automatic suggestions of synonyms of user-entered query terms, exploration of different concepts mentioned within search results or isolation of documents in which concepts are related in specific ways. However, applying TM methods to historical text can be challenging, according to differences and evolutions in vocabulary, terminology, language structure and style, compared to more modern text. In this article, we present our efforts to overcome the various challenges faced in the semantic analysis of published historical medical text dating back to the mid 19th century. Firstly, we used evidence from diverse historical medical documents from different periods to develop new resources that provide accounts of the multiple, evolving ways in which concepts, their variants and relationships amongst them may be expressed. These resources were employed to support the development of a modular processing pipeline of TM tools for the robust detection of semantic information in historical medical documents with varying characteristics. We applied the pipeline to two large-scale medical document archives covering wide temporal ranges as the basis for the development of a publicly accessible semantically-oriented search system. The novel resources are available for research purposes, while the processing pipeline and its modules may be used and configured within the Argo TM platform. PMID- 26734937 TI - Coarse-Grained Simulations of Topology-Dependent Mechanisms of Protein Unfolding and Translocation Mediated by ClpY ATPase Nanomachines. AB - Clp ATPases are powerful ring shaped nanomachines which participate in the degradation pathway of the protein quality control system, coupling the energy from ATP hydrolysis to threading substrate proteins (SP) through their narrow central pore. Repetitive cycles of sequential intra-ring ATP hydrolysis events induce axial excursions of diaphragm-forming central pore loops that effect the application of mechanical forces onto SPs to promote unfolding and translocation. We perform Langevin dynamics simulations of a coarse-grained model of the ClpY ATPase-SP system to elucidate the molecular details of unfolding and translocation of an alpha/beta model protein. We contrast this mechanism with our previous studies which used an all-alpha SP. We find conserved aspects of unfolding and translocation mechanisms by allosteric ClpY, including unfolding initiated at the tagged C-terminus and translocation via a power stroke mechanism. Topology-specific aspects include the time scales, the rate limiting steps in the degradation pathway, the effect of force directionality, and the translocase efficacy. Mechanisms of ClpY-assisted unfolding and translocation are distinct from those resulting from non-allosteric mechanical pulling. Bulk unfolding simulations, which mimic Atomic Force Microscopy-type pulling, reveal multiple unfolding pathways initiated at the C-terminus, N-terminus, or simultaneously from both termini. In a non-allosteric ClpY ATPase pore, mechanical pulling with constant velocity yields larger effective forces for SP unfolding, while pulling with constant force results in simultaneous unfolding and translocation. PMID- 26734938 TI - Efficacy and Safety of Fingolimod in an Unselected Patient Population. AB - BACKGROUND: Fingolimod is a first in class oral compound approved for the treatment of relapsing-remitting multiple sclerosis (RR-MS). The aim of this study was to evaluate clinical and neuroradiological responses to fingolimod as well as the safety and tolerability in RR-MS patients in clinical practice. In addition, a panel of pro-inflammatory serum cytokines was explored as potential biomarker for treatment response. METHODS: We conducted a retrospective, non randomized, open-label, observational study in 105 patients with RR-MS and measured cytokines in longitudinal serum samples. RESULTS: Compared to the year before fingolimod start the annualized relapse rate was reduced by 44%. Also, the percentage of patients with a worsening of the EDSS decreased. Accordingly, the fraction of patients with no evidence of disease activity (no relapse, stable EDSS, no new active lesions in MRI) increased from 11% to 38%. The efficacy and safety were comparable between highly active patients or patients with relevant comorbidities and our general patient population. CONCLUSIONS: The efficacy in reducing relapses was comparable to that observed in the phase III trials. In our cohort fingolimod was safe and efficacious irrespective of comorbidities and previous treatment. PMID- 26734939 TI - Integrating Paleodistribution Models and Phylogeography in the Grass-Cutting Ant Acromyrmex striatus (Hymenoptera: Formicidae) in Southern Lowlands of South America. AB - Past climate changes often have influenced the present distribution and intraspecific genetic diversity of organisms. The objective of this study was to investigate the phylogeography and historical demography of populations of Acromyrmex striatus (Roger, 1863), a leaf-cutting ant species restricted to the open plains of South America. Additionally, we modeled the distribution of this species to predict its contemporary and historic habitat. From the partial sequences of the mitochondrial gene cytochrome oxidase I of 128 A. striatus workers from 38 locations we estimated genetic diversity and inferred historical demography, divergence time, and population structure. The potential distribution areas of A. striatus for current and quaternary weather conditions were modeled using the maximum entropy algorithm. We identified a total of 58 haplotypes, divided into five main haplogroups. The analysis of molecular variance (AMOVA) revealed that the largest proportion of genetic variation is found among the groups of populations. Paleodistribution models suggest that the potential habitat of A. striatus may have decreased during the Last Interglacial Period (LIG) and expanded during the Last Maximum Glacial (LGM). Overall, the past potential distribution recovered by the model comprises the current potential distribution of the species. The general structuring pattern observed was consistent with isolation by distance, suggesting a balance between gene flow and drift. Analysis of historical demography showed that populations of A. striatus had remained constant throughout its evolutionary history. Although fluctuations in the area of their potential historic habitat occurred during quaternary climate changes, populations of A. striatus are strongly structured geographically. However, explicit barriers to gene flow have not been identified. These findings closely match those in Mycetophylax simplex, another ant species that in some areas occurs in sympatry with A. striatus. Ecophysiological traits of this species and isolation by distance may together have shaped the phylogeographic pattern. PMID- 26734940 TI - Tuning to the Positive: Age-Related Differences in Subjective Perception of Facial Emotion. AB - Facial expressions aid social transactions and serve as socialization tools, with smiles signaling approval and reward, and angry faces signaling disapproval and punishment. The present study examined whether the subjective experience of positive vs. negative facial expressions differs between children and adults. Specifically, we examined age-related differences in biases toward happy and angry facial expressions. Young children (5-7 years) and young adults (18-29 years) rated the intensity of happy and angry expressions as well as levels of experienced arousal. Results showed that young children-but not young adults rated happy facial expressions as both more intense and arousing than angry faces. This finding, which we replicated in two independent samples, was not due to differences in the ability to identify facial expressions, and suggests that children are more tuned to information in positive expressions. Together these studies provide evidence that children see unambiguous adult emotional expressions through rose-colored glasses, and suggest that what is emotionally relevant can shift with development. PMID- 26734941 TI - Correction: Discovery of a Novel Human Pegivirus in Blood Associated with Hepatitis C Virus Co-Infection. AB - [This corrects the article DOI: 10.1371/journal.ppat.1005325.]. PMID- 26734942 TI - Computationally Efficient Multiscale Reactive Molecular Dynamics to Describe Amino Acid Deprotonation in Proteins. AB - An important challenge in the simulation of biomolecular systems is a quantitative description of the protonation and deprotonation process of amino acid residues. Despite the seeming simplicity of adding or removing a positively charged hydrogen nucleus, simulating the actual protonation/deprotonation process is inherently difficult. It requires both the explicit treatment of the excess proton, including its charge defect delocalization and Grotthuss shuttling through inhomogeneous moieties (water and amino residues), and extensive sampling of coupled condensed phase motions. In a recent paper (J. Chem. Theory Comput. 2014, 10, 2729-2737), a multiscale approach was developed to map high-level quantum mechanics/molecular mechanics (QM/MM) data into a multiscale reactive molecular dynamics (MS-RMD) model in order to describe amino acid deprotonation in bulk water. In this article, we extend the fitting approach (called FitRMD) to create MS-RMD models for ionizable amino acids within proteins. The resulting models are shown to faithfully reproduce the free energy profiles of the reference QM/MM Hamiltonian for PT inside an example protein, the ClC-ec1 H(+)/Cl(-) antiporter. Moreover, we show that the resulting MS-RMD models are computationally efficient enough to then characterize more complex 2-dimensional free energy surfaces due to slow degrees of freedom such as water hydration of internal protein cavities that can be inherently coupled to the excess proton charge translocation. The FitRMD method is thus shown to be an effective way to map ab initio level accuracy into a much more computationally efficient reactive MD method in order to explicitly simulate and quantitatively describe amino acid protonation/deprotonation in proteins. PMID- 26734946 TI - Surveillance and Control of Aedes albopictus in the Swiss-Italian Border Region: Differences in Egg Densities between Intervention and Non-intervention Areas. AB - BACKGROUND: Aedes albopictus, the Asian tiger mosquito, originates from the tropical and subtropical regions of Southeast Asia. Over the recent decades it has been passively spread across the globe, primarily through the used tyre trade and passive transportation along major traffic routes. A. albopictus is a proven vector for many arboviruses, most notably chikungunya and dengue, with recent outbreaks also in continental Europe. In southern Switzerland, in the Canton of Ticino A. albopictus was spotted for the first time in 2003. Since then the local authorities have implemented a control programme based on larval source reduction. Despite these efforts, mosquito densities have increased over the last decade, casting doubts on the effectiveness of such larval control programmes. METHODOLOGY/PRINCIPAL FINDINGS: The Italian communities just across the Swiss Italian border lack a control programme. This motivated us to compare the intervention and the non-intervention areas side by side in an attempt to find evidence for, or against, the effectiveness of larval A. albopictus control. Using ovitraps and a randomised sampling scheme, we examined the seasonal and spatial abundance of A. albopictus in sylvatic and urban environments across the Swiss-Italian border in 2012 and 2013. In the urban environments of the non intervention area, egg densities were 2.26 times higher as compared to the intervention area. In the sylvatic environments, as compared to the urban environments, egg densities were 36% in the intervention area and 18% in the non intervention area. CONCLUSIONS/SIGNIFICANCE: Though alternative explanations are also valid, the results support the hypothesis that the Ticino intervention programme does have an impact. At the same time the data also suggest that current larval interventions fall short in gaining full control over the mosquito, calling for the evaluation of additional, or alternative, approaches. Ideally, these should also consider inclusion of the neighbouring Italian communities in the surveillance and control efforts. PMID- 26734947 TI - A comprehensive comparison of dye-sensitized NiO photocathodes for solar energy conversion. AB - We investigated a range of different mesoporous NiO electrodes prepared by different research groups and private firms in Europe to determine the parameters which influence good quality photoelectrochemical devices. This benchmarking study aims to solve some of the discrepancies in the literature regarding the performance of p-DSCs due to differences in the quality of the device fabrication. The information obtained will lay the foundation for future photocatalytic systems based on sensitized NiO so that new dyes and catalysts can be tested with a standardized material. The textural and electrochemical properties of the semiconducting material are key to the performance of photocathodes. We found that both commercial and non-commercial NiO gave promising solar cell and water-splitting devices. The NiO samples which had the two highest solar cell efficiency (0.145% and 0.089%) also gave the best overall theoretical H2 conversion. PMID- 26734948 TI - Influence of End-Stage Renal Disease on Hematoma Volume and Intraventricular Hemorrhage in Patients with Intracerebral Hemorrhage: A Cohort Study and Meta Analysis. AB - OBJECTIVE: To assess the association between end-stage renal disease (ESRD) and hematoma volume and intraventricular hemorrhage (IVH), we performed a meta analysis of all available evidence, including data from our own center. METHODS: We reviewed major literature databases to identify studies on association between ESRD and hematoma volume and IVH, and the association between ESRD and hematoma site. We then combined these data with those from our own retrospective cohort study. The relationship between ESRD and functional outcome was analyzed using logistic regression. RESULTS: Our retrospective study involved 15 patients with ESRD of 302 subjects. The results showed that patients with ESRD had larger hematoma volume (p = 0.028), higher proportion of patients with hematoma volume over 30 ml (OR 3.89, 95% CI 1.20-12.56 in model 1 and OR 3.72, 95% CI 1.15-12.06 in model 3), and higher incidence of IVH (OR 3.45, 95% CI 1.14-10.46 in model 1 and OR 3.22, 95% CI 1.07-9.66 in model 2) than patients without ESRD. The meta analysis further supported a relationship between the risk of ESRD and hematoma volume (p = 0.014), as well as IVH (OR 2.82, 95% CI 2.03-3.91). On multivariate analysis, ESRD was significantly associated with the mortality at the third month (OR 7.534, 95% CI 1.495-38.491). CONCLUSIONS: Evidence strongly suggests that ESRD is independently associated with hematoma volume and IVH, and is an independent risk factor for mortality at the third month. PMID- 26734949 TI - Compressive Myelopathy due to Osteochondroma of the Atlas and Review of the Literature. AB - We report a case of vertebral osteochondroma arising from the posterior C1 arch that presented with features of compressive myelopathy. Osteochondromas are usually found in extremities and are rarely seen in the spine. They are most commonly found in posterior elements in the spine, and intraspinal extension is uncommon. The most common presentation is incidental finding during routine imaging followed by palpation of painless swelling. Compressive myelopathy as a presentation of vertebral osteochondroma in a child is a rare entity. Surgical excision is the treatment of choice. Spinal osteochondromas should also be kept in mind as a cause of spinal cord or nerve root compression in children. PMID- 26734950 TI - Insights on the Application of the Retro Michael-Type Addition on Maleimide Functionalized Gold Nanoparticles in Biology and Nanomedicine. AB - The glutathione-mediated retro Michael-type addition reaction is demonstrated to take place at the interface of small water-soluble maleimide-functionalized gold nanoparticles (Maleimide-AuNP). The retro Michael-type addition reaction can be blocked by hydrolyzing the Michael addition thioether adduct at the nanoparticle's interface under reaction conditions that do not cause AuNP decomposition. This procedure "locks" the molecule of interest onto the Maleimide AuNP template for potential uses in medical imaging and bioconjugation, ensuring no loss of the molecular cargo from the nanocarrier. On the other hand, the glutathione-mediated retro Michael-type addition reaction can be exploited for delivering a molecular payload. As a proof of concept, a fluorogenic molecular cargo was incorporated onto a Maleimide-AuNP and delivered via the glutathione mediated retro Michael-type addition reaction. PMID- 26734951 TI - Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP. AB - PURPOSE OF REVIEW: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a highly disabling, life-threatening disease characterized by progressive sensorimotor and autonomic neuropathy. The profile of the disease across Europe is inadequately understood at present. RECENT FINDINGS: The incidence and clinical presentation of TTR-FAP varies widely within Europe, with early and late onset disease subtypes. In those regions in which the disease is endemic (Portugal, Sweden, Cyprus, and Majorca), a Val30Met substitution in the TTR gene is the predominant genetic cause, whereas in the rest of Europe, cases of TTR-FAP are mainly sporadic with genetic heterogeneity. Current management strategies lack cohesion and patients can experience years of misdiagnosis and suboptimal treatment. SUMMARY: The article aims to disseminate the findings and recommendations from two recent meetings of the European Network for TTR-FAP (ATTReuNET), a panel comprising representatives from 10 European countries (Bulgaria, Cyprus, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, and Turkey) with expertise in the diagnosis and management of TTR-FAP. We explore the epidemiology and genetic mark of TTR-FAP across Europe and assess current management strategies, with a view to developing an alternative framework - a networked approach to disease management with an emphasis on collaboration and sharing of best practice. PMID- 26734952 TI - First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. AB - PURPOSE OF REVIEW: Early and accurate diagnosis of transthyretin familial amyloid polyneuropathy (TTR-FAP) represents one of the major challenges faced by physicians when caring for patients with idiopathic progressive neuropathy. There is little consensus in diagnostic and management approaches across Europe. RECENT FINDINGS: The low prevalence of TTR-FAP across Europe and the high variation in both genotype and phenotypic expression of the disease means that recognizing symptoms can be difficult outside of a specialized diagnostic environment. The resulting delay in diagnosis and the possibility of misdiagnosis can misguide clinical decision-making and negatively impact subsequent treatment approaches and outcomes. SUMMARY: This review summarizes the findings from two meetings of the European Network for TTR-FAP (ATTReuNET). This is an emerging group comprising representatives from 10 European countries with expertise in the diagnosis and management of TTR-FAP, including nine National Reference Centres. The current review presents management strategies and a consensus on the gold standard for diagnosis of TTR-FAP as well as a structured approach to ongoing multidisciplinary care for the patient. Greater communication, not just between members of an individual patient's treatment team, but also between regional and national centres of expertise, is the key to the effective management of TTR-FAP. PMID- 26734953 TI - Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis. AB - PURPOSE OF REVIEW: These recommendations highlight recent experience in genetic counselling for the severe autosomal-dominant, late-onset transthyretin familial amyloid polyneuropathy (TTR-FAP) disease, and present a structured approach towards identification and monitoring of asymptomatic carriers of the mutated gene. RECENT FINDINGS: The effectiveness of current treatment options is still limited in patients with TTR-FAP beyond stage I. Diagnosis in the early stages of TTR-FAP is essential to prevent or delay the progression of disease. Existing legal and cultural issues differ among countries within Europe. Experts of the European Network for TTR-FAP (ATTReuNET) concluded that genetic counselling for diagnosed individuals and at-risk family members is mostly beneficial and should be carried out with care by trained professionals. Systematic and regular monitoring of an asymptomatic carrier is necessary to detect early signs of TTR FAP and maximize the effectiveness of treatment. This includes five areas of assessment: history/clinical examination, sensorimotor function, autonomic dysfunction, cardiac function, and renal function. At least two related symptoms and positive biopsy findings are required to confirm diagnosis of TTR-FAP. SUMMARY: Early detection of TTR-FAP is essential to improve the prognosis of TTR FAP. ATTReuNET recommends genetic counselling and routine monitoring for asymptomatic carriers of TTR-FAP. PMID- 26734954 TI - The effects of alcohol on ambulatory blood pressure and other cardiovascular risk factors in type 2 diabetes: a randomized intervention. AB - OBJECTIVE: Although prospective studies suggest light-to-moderate chronic alcohol intake protects against coronary artery disease in type 2 diabetic patients, the balance of effects on individual cardiovascular risk factors needs further assessment. We examined the effects of alcohol consumption on 24-h ambulatory blood pressure (BP) and heart rate (HR), high-density lipoprotein cholesterol, fibrinogen, C-reactive protein, homocysteine, and glycaemic control in well controlled type 2 diabetes. METHODS: Twenty-four participants aged 49-66 year were randomized to a three-period crossover study with women drinking red wine 230 ml/day (~24 g alcohol/day) and men drinking red wine 300 ml/day (~31 g alcohol/day), or equivalent volumes of dealcoholized red wine (DRW) or water, each for 4 weeks. Ambulatory BP and HR were monitored every 30 min for 24 h at the end of each period. Home blood glucose monitoring was carried out twice weekly throughout. RESULTS: Red wine increased awake SBP and DBP relative to water by 2.5 +/- 1.2 /1.9 +/- 0.7 mmHg (P = 0.033, P = 0.008, respectively), with a similar nonsignificant trend relative to DRW. Asleep DBP fell with red wine relative to DRW (2.0 +/- 0.8 mmHg, P = 0.016) with a similar nonsignificant trend relative to water. Red wine increased 24-h, awake and asleep HR relative to water and DRW. Relative to DRW, red wine did not affect glycaemic control or any other cardiovascular risk factor. CONCLUSION: In well controlled type 2 diabetic individuals 24-31 g alcohol/day (~2-3 standard drinks) raises awake BP and 24-h HR and lowers asleep BP but does not otherwise favourably or adversely modify cardiovascular risk factors. PMID- 26734955 TI - White-coat hypertension and cardiovascular events: a meta-analysis. AB - BACKGROUND: White-coat hypertension (WCH) is a frequent condition particularly in children and elderly individuals. The prognostic significance of WCH is still a matter of debate. METHODS: The present study was designed to systematically review cohort studies and assess the effects of WCH compared with normotension and sustained HTN on cardiovascular events and death, stroke, and all-cause mortality. We systematically searched the electronic databases, MEDLINE, PUBMED, EMBASE, and Cochrane for prospective cohort studies, which evaluated participants with office, and ambulatory, and/or home blood pressure. RESULTS: We included 14 studies with a total number of 29 100 participants (13 538 normotensive patients, 4806 with WCH and 10 756 with sustained HTN) with mean age of 59 years and follow up of 8 years. Individuals with WCH had higher rates of cardiovascular disease morbidity and mortality but not significantly different all-cause mortality and stroke risk compared with normotensive patients. Cardiovascular disease morbidity and mortality, all-cause mortality, and stroke rates were significantly increased in patients with sustained HTN compared with WCH. CONCLUSION: The cardiovascular morbidity and mortality associated with WCH may be slightly higher compared with normotension but well below the risks associated with sustained HTN. PMID- 26734956 TI - Modeling Multisystem Physiological Dysregulation. AB - OBJECTIVES: The purposes of this study were to compare the relative fit of two alternative factor models of allostatic load (AL) and physiological systems, and to test factor invariance across age and sex. METHODS: Data were from the Midlife in the United States II Biomarker Project, a large (n = 1255) multisite study of adults aged 34 to 84 years (56.8% women). Specifically, 23 biomarkers were included, representing seven physiological systems: metabolic lipids, metabolic glucose, blood pressure, parasympathetic nervous system, sympathetic nervous system, hypothalamic-pituitary-adrenal axis, and inflammation. For factor invariance tests, age was categorized into three groups (<=45, 45-60, and >60 years). RESULTS: A bifactor model where biomarkers simultaneously load onto a common AL factor and seven unique system-specific factors provided the best fit to the biomarker data (comparative fit index = 0.967, root mean square error of approximation = 0.043, standardized root mean square residual = 0.028). Results from the bifactor model were consistent with invariance across age groups and sex. CONCLUSIONS: These results support the theory that represents and operationalizes AL as multisystem physiological dysregulation and operationalizing AL as the shared variance across biomarkers. Results also demonstrate that in addition to the variance in biomarkers accounted for by AL, individual physiological systems account for unique variance in system-specific biomarkers. A bifactor model allows researchers greater precision to examine both AL and the unique effects of specific systems. PMID- 26734957 TI - Understanding the Relationship Between Incentive Design and Participation in U.S. Workplace Wellness Programs. AB - PURPOSE: We aimed to understand how employer characteristics relate to the use of incentives to promote participation in wellness programs and to explore the relationship between incentive type and participation rates. DESIGN: A cross sectional analysis of nationally representative survey data combined with an administrative business database was employed. SETTINGS/SUBJECTS: Random sampling of U.S. companies within strata based on industry and number of employees was used to determine a final sample of 3000 companies. Of these, 19% returned completed surveys. MEASURES: The survey asked about employee participation rate, incentive type, and gender composition of employees. Incentive types included any incentives, high-value rewards, and rewards plus penalties. ANALYSIS: Logistic regressions of incentive type on employer characteristics were used to determine what types of employers are more likely to offer which type of incentives. A generalized linear model of participation rate was used to determine the relationship between incentive type and participation. RESULTS: Employers located in the Northeast were 5 to 10 times more likely to offer incentives. Employers with a large number of employees, particularly female employees, were up to 1.25 times more likely to use penalties. Penalty and high-value incentives were associated with participation rates of 68% and 52%, respectively. CONCLUSION: Industry or regional characteristics are likely determinants of incentive use for wellness programs. Penalties appear to be effective, but attention should be paid to what types of employees they affect. PMID- 26734961 TI - Editor's Desk: The Well-Being Issue. PMID- 26734962 TI - "America's Healthiest Campus(r)": The OSU Well-Being Strategy Model. PMID- 26734963 TI - How Do You Spell Audacious? D-A-V-I-D space K-A-T-Z and the True Health Initiative. PMID- 26734964 TI - Ventilation and the Response to Hypercapnia after Morphine in Opioid-naive and Opioid-tolerant Rats. AB - BACKGROUND: Opioid-related deaths are a leading cause of accidental death, with most occurring in patients receiving chronic pain therapy. Respiratory arrest is the usual cause of death, but mechanisms increasing that risk with increased length of treatment remain unclear. Repeated administration produces tolerance to opioid analgesia, prompting increased dosing, but depression of ventilation may not gain tolerance to the same degree. This study addresses differences in the degree to which chronic morphine (1) produces tolerance to ventilatory depression versus analgesia and (2) alters the magnitude and time course of ventilatory depression. METHODS: Juvenile rats received subcutaneous morphine for 3 days (n = 116) or vehicle control (n = 119) and were then tested on day 4 following one of a range of morphine doses for (a) analgesia by paw withdraw from heat or (b) respiratory parameters by plethysmography-respirometry. RESULTS: Rats receiving chronic morphine showed significant tolerance to morphine sedation and analgesia (five times increased ED50). When sedation was achieved for all animals in a dose group (lowest effective doses: opioid-tolerant, 15 mg/kg; opioid-naive, 3 mg/kg), the opioid-tolerant showed similar magnitudes of depressed ventilation (-41.4 +/- 7.0%, mean +/- SD) and hypercapnic response (-80.9 +/- 15.7%) as found for morphine-naive (-35.5 +/- 16.9% and -67.7 +/- 15.1%, respectively). Ventilation recovered due to tidal volume without recovery of respiratory rate or hypercapnic sensitivity and more slowly in morphine-tolerant. CONCLUSIONS: In rats, gaining tolerance to morphine analgesia does not reduce ventilatory depression effects when sedated and may inhibit recovery of ventilation. PMID- 26734965 TI - Determining the Optimal Timing for Initiation of Adjuvant Chemotherapy After Resection for Stage II and III Colon Cancer. AB - BACKGROUND: Several reports suggest that the efficacy of adjuvant chemotherapy on survival diminishes over time for colon cancer; however, precise timing of its loss of benefit has not been established. OBJECTIVE: This study aimed to determine the relationship between time to adjuvant chemotherapy and survival and to identify a threshold for increased risk of mortality. DESIGN: This was a retrospective study. Multivariable Cox proportional hazard modeling with restricted cubic splines was used to evaluate the adjusted association between time to adjuvant chemotherapy and overall survival and to establish an optimal threshold for the initiation of therapy. SETTINGS: Data were collected from the National Cancer Data Base. PATIENTS: Adults who received adjuvant chemotherapy following resection of stage II to III colon cancers were selected. MAIN OUTCOME MEASURES: The primary outcome measured was overall survival. RESULTS: A total of 7794 patients were included. After adjusting for clinical, tumor, and treatment characteristics, our model determined a critical threshold of chemotherapy initiation at 44 days from surgery, after which there was an increase in the overall mortality. At a median follow-up of 61 months, the risk of mortality was increased in those who received adjuvant chemotherapy after 44 days from surgery (adjusted HR, 1.14; 95% CI, 1.05-1.24; p = 0.002), but not in those who received chemotherapy before 44 days from surgery (p = 0.11). Each additional week of delay was associated with a 7% decrease in survival (HR, 1.07; 95% CI, 1.04-1.10; p < 0.001). LIMITATIONS: This study was limited by selection bias and the inability to compare specific chemotherapy regimens. CONCLUSIONS: This study objectively determines the optimal timing of adjuvant chemotherapy for patients with resected colon cancer. Delay beyond 6 weeks is associated with compromised survival. These findings emphasize the importance of the timely initiation of therapy, and suggest that efforts to enhance recovery following surgery have the potential to improve survival by decreasing delay to adjuvant chemotherapy. PMID- 26734966 TI - Risk Factors for Nonclosure of a Temporary Defunctioning Ileostomy Following Anterior Resection of Rectal Cancer. AB - BACKGROUND: In patients with colorectal cancer, a defunctioning ileostomy is commonly constructed to reduce anastomotic complications. However, many patients do not undergo a subsequent procedure to have their temporary stoma closed. OBJECTIVE: This study investigated the incidence of nonclosure of ileostomies and identified factors associated with nonclosure. DESIGN: This study is a retrospective analysis of prospectively collected data. SETTING: This study was conducted at a tertiary referral cancer hospital. PATIENTS: A total of 296 patients who received anterior resection with a defunctioning ileostomy with protective intention from 2006 to 2013 were included. MAIN OUTCOME MEASURES: The primary outcomes measured were the incidence of nonclosure of ileostomy and associated risk factors. RESULTS: Patients were followed for a median time of 29 months (range, 21-100 months). At the end of the study, 51 (17.2%) patients were left with a permanent ileostomy. The median time interval from the creation of a defunctioning ileostomy to closure was 192 days (range, 14-865 days). Multivariate analyses using a logistic regression model showed that metastatic diseases (OR, 0.179, p < 0.001), Charlson Comorbidity Index score >1 (OR, 0.268; p < 0.01), and complications from the index surgery (OR, 0.391; p = 0.013) were significant independent risk factors for failing to close a defunctioning ileostomy. LIMITATIONS: Although our study has a large patient cohort, it is limited by its retrospective nature. It is difficult to fully evaluate stoma complications after hospital discharge, and the prevalence may be underestimated. CONCLUSION: One in 6 temporary ileostomies constructed during an elective anterior resection for rectal cancer was not closed. Patients should be told before the index surgery that there is a risk of nonclosure and possible complications associated with permanent ileostomy. PMID- 26734967 TI - Sigmoid Colectomy for Acute Diverticulitis in Immunosuppressed vs Immunocompetent Patients: Outcomes From the ACS-NSQIP Database. AB - BACKGROUND: The management of acute diverticulitis in immunosuppressed patients is increasingly debated. The appropriate timing and type of operation remains controversial. OBJECTIVE: This study examines the impact of immunosuppression on mortality and morbidity following colectomies for diverticulitis in the emergency and elective settings. DESIGN SETTINGS: With the use of the American College of Surgeons National Surgical Quality Improvement Program database, the outcomes of immunosuppressed compared with immunocompetent patients who underwent colectomy for acute diverticulitis were compared. PATIENTS: The multi-institutional database was queried for patients who underwent colectomy for acute diverticulitis from 2005 to 2012. MAIN OUTCOMES MEASURES: The impact of immunosuppression on mortality, major morbidity, organ space infection, infectious complications, and wound dehiscence was assessed. RESULTS: Of 26,987 patients, 1332 were immunosuppressed and 25,655 were immunocompetent; 4271 patients had emergency (596 immunosuppressed and 3675 immunocompetent) and 22,716 patients had elective (736 immunosuppressed and 21,980 immunocompetent) colectomies for diverticulitis. In both groups, mortality and major morbidity were significantly higher in the emergency (immunosuppressed 16% and 45%, immunocompetent 4% and 28%) compared with the elective setting (immunosuppressed 2% and 25%, immunocompetent 0.4% and 12%), p < 0.001. On multivariate regression for the emergency setting, immunosuppression significantly increased mortality (OR, 1.79; 95% CI, 1.17-2.75) and did not significantly increase morbidity. On multivariate regression for the elective setting, mortality was similar in immunosuppressed and immunocompetent groups; however, major morbidity (OR, 1.46; 95% CI, 1.17-1.83) and wound dehiscence (OR, 2.69; 95% CI, 1.63-4.42) were significantly increased in immunosuppressed compared with immunocompetent patients. LIMITATIONS: The retrospective design and standardized outcomes are based on heterogeneous data. CONCLUSIONS: Emergency colectomy for diverticulitis is associated with higher mortality in immunosuppressed than in immunocompetent patients, whereas elective colectomy is associated with comparable mortality. In the elective setting, immunosuppressed compared with immunocompetent patients are at increased risk of major morbidity and wound dehiscence. PMID- 26734968 TI - Smoking and the Risk of Hospitalization for Symptomatic Diverticular Disease: A Population-Based Cohort Study from Sweden. AB - BACKGROUND: Current studies reporting on the risk of smoking and development of symptomatic diverticular disease have reported conflicting results. OBJECTIVE: The aim of this study was to investigate the association between smoking and symptomatic diverticular disease. DESIGN: This is a cohort study SETTINGS: : Information was derived from the Swedish Construction Workers Cohort 1971-1993. PATIENTS: Patients were selected from construction workers in Sweden. MAIN OUTCOME MEASURES: The primary outcome measured was the development of symptomatic diverticular disease and complicated diverticular disease (abscess and perforation) as identified in the Swedish Hospital Discharge Register. Adjusted relative risks of symptomatic diverticular disease according to smoking status were estimated by using negative binomial regression analysis. RESULTS: In total, the study included 232,685 men and 14,592 women. During follow-up, 3891 men and 318 women had a diagnosis of later symptomatic diverticular disease. In men, heavy smokers (>=15 cigarettes a day) had a 1.6-fold increased risk of developing symptomatic diverticular disease compared with nonsmokers (adjusted relative risk, 1.56; 95% CI, 1.42-1.72). There was evidence of a dose-response relationship, because moderate and ex-smokers had a 1.4- and 1.2-fold increased risk compared with nonsmokers (adjusted relative risk, 1.39; 95% CI, 1.27-1.52 and adjusted relative risk, 1.14; 95% CI, 1.04-1.27). These relationships were similar in women, but the risk estimates were less precise owing to smaller numbers. Male ever-smokers had a 2.7-fold increased risk of developing complicated diverticular disease (perforation/abscess) compared with nonsmokers (adjusted relative risks, 2.73; 95% CI, 1.69-4.41). LIMITATIONS: We were unable to account for other confounding variables such as comorbidity, prescription medication, or lifestyle factors. CONCLUSIONS: Smoking is associated with symptomatic diverticular disease in both men and women and with an increased risk of developing complicated diverticular disease. PMID- 26734969 TI - Use of Biofeedback Combined With Diet for Treatment of Obstructed Defecation Associated With Paradoxical Puborectalis Contraction (Anismus): Predictive Factors and Short-term Outcome. AB - BACKGROUND: Numerous studies have described the use of biofeedback therapy for the treatment of anismus. Success rates vary widely, but few data are available regarding factors predictive of success. OBJECTIVE: Our aim was to evaluate short term results of biofeedback associated with diet in patients with obstructed defecation because of anismus and to investigate factors that may affect the results. DESIGN: Patients were identified from a single-institution prospectively maintained database. SETTINGS: This study was conducted in a tertiary hospital. PATIENTS: Consecutive patients who had obstructed defecation associated with anismus and were treated with biofeedback associated with diet were eligible. INTERVENTIONS: Each patient underwent anal manometry and/or dynamic anal ultrasound. Patients with anismus and were treated with biofeedback associated with diet. MAIN OUTCOME MEASURES: Patients classed as having a satisfactory response to therapy and those classed as having an unsatisfactory response were compared with regard to sex, age, Cleveland Clinic Florida constipation score, functional factors (anal resting and squeeze pressures and reversal of paradoxical puborectalis contraction on manometry), and anatomic factors in women (history of vaginal delivery, number of vaginal deliveries, menopause, hysterectomy, and previous anorectal surgery). RESULTS: A total of 116 patients were included (75 women and 41 men). Overall, 59% were classed as having a satisfactory response (decrease in constipation score, >50%). Patients with satisfactory responses to biofeedback plus diet did not differ from those with unsatisfactory responses with regard to clinical, anatomic, and physiological factors. LIMITATIONS: This was not a randomized controlled trial. CONCLUSIONS: Biofeedback combined with diet is a valuable treatment option for patients with obstructed defecation syndrome associated with anismus, and more than half of our patients of both sexes achieved a satisfactory response. Improvement was not related to reversal of paradoxical contraction of puborectalis muscles at manometry. Patient sex, age, previous anorectal surgery, anorectal manometry pressures, and vaginal delivery, menopause, and hysterectomy in women did not significantly affect outcome. PMID- 26734970 TI - Outcomes of Reimplantation of the Artificial Bowel Sphincter. AB - BACKGROUND: Outcomes of artificial bowel sphincter reimplantation for severe fecal incontinence remain unknown. OBJECTIVE: The purpose of this study was to evaluate the feasibility and outcomes of artificial bowel sphincter reimplantation versus implantation. DESIGN: This was a retrospective review study. SETTINGS: The study was conducted at a single institution. PATIENTS: Patients with severe incontinence who underwent de novo implantation and re implantation between January 1998 and December 2012 were included. MAIN OUTCOME MEASURES: Complications, length of functional device time, success rates (functioning device at follow-up), patient demographics, comorbidities, etiology of incontinence, operative data, postoperative complications, and outcomes of initial implantation versus reimplantation were analyzed. RESULTS: A total of 57 patients (mean age, 49.3 +/- 13.5 years; 44 women) underwent implantation. Sixteen (28%) succeeded and 41 (72%) failed, requiring explantation; 17 of 41 patients underwent reimplantation; 5 had 2 reimplantations. There were 79 implantations and 50 explantations (63.3%) in total. Implantation and reimplantation procedures had similar lengths of operation, hospital stay, postoperative complications, and explantation rate. Most common reasons for device explantation were infection/erosion (27/50 (54%)) and malfunction (19/50 (38%)). Reasons for reimplantation included device malfunction/migration (17/22 (77.3%)) and/or infection/erosion (5/22 (22.7%)). Seven (41.2%) of 17 patients for whom reimplantation was attributed to noninfectious reasons had a functioning device, whereas only 1 (20.0%) of 5 who had reimplantation because of infection/erosion had a working device. At a median follow-up of 29.5 months (range, 1.0-215.0 months), 24 patients (42%) retained a functioning device (implantation = 16; reimplantation = 8). Success rates were not significantly different between initial implantation and reimplantation procedures (p = 0.755). There were no differences in the length of functional device time between implanted and reimplanted devices (p = 0.439). LIMITATIONS: The study was limited by its retrospective nature and small sample size. CONCLUSIONS: Artificial bowel sphincter implantation has a high failure rate, requiring explantation in 72% of patients in this study. Reimplantation was often possible, with a success rate of 47%. Selected reimplantation for noninfectious complications had better outcomes than did reimplantation for septic causes. Short- and long-term outcomes are comparable to initial implantation. PMID- 26734971 TI - Impact of a Novel Vaginal Bowel Control System on Bowel Function. AB - BACKGROUND: Bowel dysfunction, including frequency, fecal urgency, stool consistency, and evacuation symptoms, contributes to fecal incontinence. OBJECTIVE: The purpose of this study was to examine the impact of a vaginal bowel control system on parameters of bowel function, including frequency, urgency, stool consistency, and evacuation. DESIGN: This was a secondary analysis of a multicenter, prospective clinical trial. SETTINGS: This study was conducted at 6 sites in the United States, including university hospitals and private practices in urogynecology and colorectal surgery. PATIENTS: A total of 56 evaluable female subjects aged 19 to 75 years with 4 or more fecal incontinence episodes on a 2 week bowel diary were included. INTERVENTIONS: The study intervention was composed of the vaginal bowel control system, consisting of a vaginal insert and pressure-regulated pump. MAIN OUTCOME MEASURES: Subjects completed a 2-week baseline diary of bowel function before and after treatment completed at 1 month. Fecal urgency, consistency of stool (Bristol score), and completeness of evacuation were recorded for all bowel movements. RESULTS: Use of the insert was associated with an improvement in bowel function across all 4 categories. Two thirds (8/12) of subjects with a high frequency of daily stools (more than 2 per day) shifted to a normal or low frequency of stools. Analysis of Bristol stool scale scores demonstrated a significant reduction in the proportion of all bowel movements reported as liquid (Bristol 6 or 7), from 36% to 21% (p = 0.0001). On average, 54% of stools were associated with urgency at baseline compared with 26% at 1 month (p < 0.0001). Incomplete evacuations with all bowel movements were reduced from 39% to 26% of subjects at 1 month (p = 0.0034). LIMITATIONS: The study follow-up period was 1 month (with an optional additional 2 months). CONCLUSIONS: The vaginal bowel control system was associated with an improvement in bowel symptoms and function, including reduced bowel movement frequency, less fecal urgency, increased solid consistency, and improved evacuation in patients with significant fecal incontinence. PMID- 26734972 TI - Transcutaneous Sacral Electrical Stimulation for Chronic Functional Constipation. AB - BACKGROUND: Transcutaneous sacral nerve stimulation is reported to improve symptoms of fecal incontinence. Chronic constipation may also respond to stimulation, but this is poorly reported in the literature. OBJECTIVE: The study assessed the efficacy of transcutaneous electrical stimulation directly over the sacral nerve roots in chronic constipation. PATIENTS: Chronic functional constipation was established in all patients using the Rome III criteria. SETTING: The therapy was self-administered at home. DESIGN/INTERVENTION: A pilot study was conducted of transcutaneous sacral stimulation given over a 4-week period for 12 hours a day. MAIN OUTCOME MEASURES: Patients were assessed using the Patient Assessment of Constipation Symptoms, the Patient Assessment of Constipation Quality of Life, and the Cleveland constipation tool. A Global Rating of Change measure and a 1-week bowel diary was kept for the final week and compared with baseline. RESULTS: Of the 20 patients recruited (16 female, median age 38.5 years), 80% (16) completed the trial. Five (31%) patients reported at least a point reduction in the Patient Assessment of Constipation Symptoms score, 4 (25%) deteriorated, and 7 (44%) improved by less than one point. Median (interquartile range) Patient Assessment of Constipation Symptoms scores were 2.33 (2.34) at baseline and 2.08 (2.58) at follow-up (p = 0.074). Median scores for the Patient Assessment of Constipation Quality of Life and Cleveland systems were 3.00 (1.64) and 17.15 (18) at baseline and 2.22 (3.04) and 15.31 (12) at follow-up (p = 0.096 and 0.111). One-third of patients reported a positive Global Rating of Change measure, although 68% required concurrent laxatives during the trial. LIMITATIONS: This is a pilot study and is limited by its small sample size. CONCLUSIONS: Continuous transcutaneous sacral stimulation in the short term appears to be ineffective for chronic constipation. Larger well-powered studies with intermittent stimulation regimens are required to investigate this further. PMID- 26734973 TI - Current State of Colorectal Surgery Training: A Survey of Program Directors, Current and Recently Matched Colorectal Residents, and Recent Colorectal Graduates. AB - BACKGROUND: Colorectal residency has become one of the more competitive postgraduate training opportunities; however, little information is available to guide potential applicants in gauging their competitiveness. OBJECTIVE: The aim of this study was to identify the current trends colorectal residency training and to identify what factors are considered most important in ranking a candidate highly. We hypothesized that there was a difference in what program directors, current and recently matched colorectal residents, and recent graduates consider most important in making a candidate competitive for a colorectal residency position. DESIGN: Three 10-question anonymous surveys were sent to 59 program directors, 87 current and recently matched colorectal residents, and 119 recent graduates in March 2015. SETTINGS: The study was conducted as an anonymous internet survey. MAIN OUTCOME MEASURES: Current trends in applying for a colorectal residency, competitiveness of recent colorectal residents, factors considered most important in ranking a candidate highly, and what future colorectal surgeons can expect after finishing their training were measured. RESULTS: The study had an overall response rate of 43%, with 28 (47%) of 59 program directors, 46 (53%) of 87 current and recently matched colorectal residents, and 39 (33%) of 119 recent graduates responding. The majority of program directors felt that a candidate's performance during the interview process was the most important factor in making a candidate competitive, followed by contact from a colleague, letters of recommendation, American Board of Surgery In-Training Exam scores, and number of publications/presentations. The majority of current and recently matched colorectal residents felt that a recommendation/telephone call from a colleague was the most important factor, whereas the majority of recent graduates favored letters of recommendation as the most important factor in ranking a candidate highly. LIMITATIONS: Limitations to the study include its small sample size, selection bias, responder bias, and misclassification bias. CONCLUSIONS: There are differences in what program directors and current/recent residents consider most important in making an applicant competitive for colorectal residency. PMID- 26734974 TI - Treatment of Locally Recurrent Rectal Carcinoma in Previously (Chemo)Irradiated Patients: A Review. AB - BACKGROUND: Local recurrence after rectal cancer treatment occurs in ~5% to 10% of patients. Neoadjuvant (chemo)radiotherapy for primary rectal cancer renders treatment of recurrent disease more difficult. OBJECTIVE: The purpose of this study was to review contemporary multimodality therapies, including their outcome, for locally recurrent rectal carcinoma after (chemo)radiotherapy and complete surgical resection of primary rectal cancer. DATA SOURCES: A comprehensive literature search of PubMed and EMBASE was performed. STUDY SELECTION: All English language articles presenting original patient data regarding treatment and the respective outcome of previously irradiated locally recurrent rectal cancer were included. INTERVENTIONS: All of the treatment modalities for locally recurrent rectal cancer were reviewed. MAIN OUTCOME MEASURES: Primary outcome parameters were local control, metastasis-free survival, and overall survival. Secondary outcome parameters were perioperative morbidity and mortality, and prognostic factors for treatment outcome. RESULTS: Of 854 studies, 9 studies and 474 patients with locally recurrent rectal carcinoma were included. Various treatment regimens were used, most with curative intent. Reirradiation was composed of (neo-)adjuvant external beam radiotherapy (with or without concurrent chemotherapy), additional intraoperative radiotherapy, or intraoperative radiotherapy only. Surgical technique highly varied, depending on the extent of the lesion. Radiation toxicity, perioperative morbidity, and mortality were generally acceptable. Outcome was better after curative intent treatment, any surgical resection, and R0 resections in particular. Moreover, reirradiation is associated with increased complete resection rates, which in turn positively affected local control and overall survival. LIMITATIONS: Most studies were retrospectively designed, with highly variable therapies, patient populations, and duration of follow-up. CONCLUSIONS: A complete resection is the most important prognostic factor and should be the goal of treatment in locally recurrent rectal carcinoma. Reirradiation seems safe and of additional value in reaching a complete resection. Considering the available evidence, at present reirradiation should be given on a case-specific basis, with all of the patients entering an international prospective database. PMID- 26734975 TI - Transanal Total Mesorectal Excision for Rectal Cancer: A Video Demonstration of Rectal Dissection. PMID- 26734976 TI - The Holy Plane: A Last Word. PMID- 26734977 TI - Is the Holy Plane the Last Word? PMID- 26734978 TI - Colonic Marking With Near-Infrared, Light-Emitting, Diode-Activated Indocyanine Green for Laparoscopic Colorectal Surgery. AB - BACKGROUND: Accurate identification of the location of colorectal lesions is crucial during laparoscopic surgery. Endoscopic marking has been used as an effective preoperative marker for tumor identification. OBJECTIVE: We investigated the feasibility and safety of an imaging method using near-infrared, light-emitting, diode-activated indocyanine green fluorescence in colorectal laparoscopic surgery. DESIGN: This was a single-institution, prospective study. SETTINGS: This study was conducted in a tertiary referral hospital. PATIENTS: We enrolled 24 patients who underwent laparoscopic surgery. MAIN OUTCOME MEASURES: Indocyanine green and India ink were injected into the same patients undergoing preoperative colonoscopy for colon cancer. During subsequent laparoscopic resection of colorectal tumors, the colon was first observed with white light. Then, indocyanine green was activated with a light-emitting diode at 760 nm as the light source. RESULTS: Near-infrared-induced fluorescence showed tumor location clearly and accurately in all 24 of the patients. All of the patients who underwent laparoscopic surgery after marking had positive indocyanine green staining at the time of surgery. Perioperative complications attributed to dye use were not observed. LIMITATIONS: This study is limited by the cost of indocyanine green detection, the timing of the colonoscopy and tattooing in relation to the operation and identification with indocyanine green, and the small size of the series. CONCLUSIONS: These data suggest that our novel method for colonic marking with fluorescence imaging of near-infrared, light-emitting, diode-activated indocyanine green is feasible and safe. This method is useful, has no adverse effects, and can be used for perioperative identification of tumor location. Near-infrared, light-emitting, diode-activated indocyanine green has potential use as a colonic marking agent. PMID- 26734979 TI - Area of Submucosal Invasion and Width of Invasion Predict Lymph Node Metastasis in pT1 Colorectal Cancers. PMID- 26734980 TI - The Authors Reply. PMID- 26734984 TI - Sustained immune control in HBeAg-positive patients who switched from entecavir therapy to pegylated interferon-alpha2a: 1 year follow-up of the OSST study. AB - BACKGROUND: In the OSST study, hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients who switched from long-term entecavir (ETV) therapy to pegylated interferon-alpha2a (PEG-IFN-alpha2a; 40 kDa) achieved higher rates of HBeAg seroconversion and hepatitis B surface antigen (HBsAg) loss than those who continued ETV. Herein we report the sustainability of serological responses during 1 year of untreated follow-up in patients who switched from ETV to PEG-IFN alpha2a therapy. METHODS: A total of 62 patients who completed 48 weeks of PEG IFN-alpha2a therapy were followed-up for 48 weeks off treatment. Primary end points were HBeAg seroconversion and maintenance of HBeAg seroconversion at 48 weeks post-treatment. Secondary end points included HBsAg loss, HBV DNA <1,000 copies/ml and alanine aminotransferase normalization (<1* upper limit of normal). RESULTS: The HBeAg seroconversion rate increased from 17.7% (11/62) at the end of treatment to 38.7% (24/62) 1 year post-treatment. Sustained HBeAg seroconversion was achieved by 63.6% (7/11) patients with end-of-treatment responses, while late HBeAg seroconversion was achieved by 33.3% (17/51) of patients who did not have end-of-treatment responses. Sustained HBsAg loss was documented in 6 of 7 patients, and sustained HBV DNA suppression was achieved in 60% (27/45) of patients with an end-of-treatment response. CONCLUSIONS: In patients who do not achieve HBeAg seroconversion during long-term ETV therapy, switching to finite treatment with PEG-IFN-alpha2a produces HBeAg seroconversion in a substantial proportion of patients at end of treatment and during 1 year of follow-up. Moreover, HBeAg seroconversion and HBsAg loss are sustained in most patients during 1 year of untreated follow-up. PMID- 26734985 TI - Ad libitum and restricted day and night sleep architecture. AB - This study represents a first controlled comparison of restricted versus unrestricted sleep in both day and night sleep categories. A repeated measures study of a homogenous group of young women without sleep disorders (n=14) found that stage 1, 2, 3 and REM sleep, as well as sleep latency were not statistically different between day ad libitum sleep (DAL) and day interrupted (DI) sleep categories, while night interrupted (NI) and ad libitum (NAL) sleep showed strikingly different architecture. PMID- 26734987 TI - Technical Note: Simple, scalable, and sensitive protocol for retrieving Bacillus anthracis (and other live bacteria) from heroin. AB - We describe a culture-based method suitable for isolating Bacillus anthracis and other live bacteria from heroin. This protocol was developed as a consequence of the bioforensic need to retrieve bacteria from batches of the drug associated with cases of injectional anthrax among heroin-consumers in Europe. This uncommon manifestation of infection with the notorious pathogen B. anthracis has resulted in 26 deaths between the years 2000 to 2013. Thus far, no life disease agent has been isolated from heroin during forensic investigations surrounding these incidences. Because of the conjectured very small number of disease-causing endospores in the contaminated drug it is likely that too few target sequences are available for molecular genetic analysis. Therefore, a direct culture-based approach was chosen here. Endospores of attenuated B. anthracis artificially spiked into heroin were successfully retrieved at 84-98% recovery rates using a wash solution consisting of 0.5% Tween 20 in water. Using this approach, 82 samples of un-cut heroin originating from the German Federal Criminal Police Office's heroin analysis program seized during the period between 2000 and 2014 were tested and found to be surprisingly poor in retrievable bacteria. Notably, while no B. anthracis was isolated from the drug batches, other bacteria were successfully cultured. The resulting methodical protocol is therefore suitable for analyzing un-cut heroin which can be anticipated to comprise the original microbiota from the drug's original source without interference from contaminations introduced by cutting. PMID- 26734988 TI - Menstrual cycle phase at the time of rape does not affect recovery of semen or amplification of STR profiles of a suspect in vaginal swabs. AB - The effect of women menstrual cycle on the forensic analysis of rapes was studied in a random group of 170 victims aged among 10 and 51 years. Participants were grouped according to the day of the menstrual cycle in which they were at the moment of the assault. From each participant, samples of vaginal fluid were taken and analyzed for sperm cells, p30 protein, total human DNA and human male DNA. Moreover, amplification of suspect's autosomal STR and Y-STR was attempted. Suspects' autosomal STR profiles were obtained from 92 of the 101 samples in which spermatozoa were found; and Y-STR haplotype was obtained in 1 of the 9 samples where autosomal STR profiles of a male were not obtained. On the other hand, Y-STR haplotypes were obtained in 2 of the 21 samples negative for sperm cells but positive for p30 protein. Y-STR haplotypes were also obtained in 11 of the 48 samples negative for sperm cells and p30 protein. It was found that groups of participants did not differ on the recovery of sperm cells from the vaginal swabs, quantification of suspect's DNA or amplification of their STR profiles. It is concluded that the menstrual cycle phase at the moment of the sexual assault does not affect the main outcomes of the forensic investigation of rapes. PMID- 26734989 TI - Longitudinal and retrospective study has demonstrated morphometric variations in the fingerprints of elderly individuals. AB - Dermatoglyphics can be found in the thick skin of both hands and feet which make the identification process possible, however morphological changes throughout life can affect identification in elderly individuals. Considering that dermatoglyphics is an important biometric method, due to it being practical and inexpensive, this longitudinal and retrospective study was aimed to evaluate the morphological variations in fingerprints obtained from men and women (n=20) during their adult and elderly stages of life; the time between obtaining the two fingerprints was 33.5+/-9.4 years. For the morphometric analysis, an area of 1 cm(2) was selected to quantify the visible friction ridges, minutiae, interpapillary and white lines, and later side-by-side confrontation was used to determine the identity of the individuals. Our results showed a reduction of friction ridges, an increase in the number of white lines for the group (men and women) and a decrease in the number of interpapillary lines in the group of women. It also showed that the selection of compatible fingerprints by the automated AFIS/VRP system allowed the identification of 23 individuals (57.5%), but when the identification was made by the automated AFIS/VRP system, followed by the analysis of archived patterns to eliminate incompatible fingerprints, determination of the identity of 28 individuals (70.0%) was possible. The dermatoglyphics of the elderly suffered morphometric changes that prevented the identification of 30% of them, probably due to the aging process, and pointed to the importance of improving the methods of obtaining fingerprints to clarify issues related to the identification of the elderly. PMID- 26734990 TI - Ways of making-sense: Local gamma synchronization reveals differences between semantic processing induced by music and language. AB - Similar to linguistic stimuli, music can also prime the meaning of a subsequent word. However, it is so far unknown what is the brain dynamics underlying the semantic priming effect induced by music, and its relation to language. To elucidate these issues, we compare the brain oscillatory response to visual words that have been semantically primed either by a musical excerpt or by an auditory sentence. We found that semantic violation between music-word pairs triggers a classical ERP N400, and induces a sustained increase of long-distance theta phase synchrony, along with a transient increase of local gamma activity. Similar results were observed after linguistic semantic violation except for gamma activity, which increased after semantic congruence between sentence-word pairs. Our findings indicate that local gamma activity is a neural marker that signals different ways of semantic processing between music and language, revealing the dynamic and self-organized nature of the semantic processing. PMID- 26734991 TI - Molecular Driving Forces behind the Tetrahydrofuran-Water Miscibility Gap. AB - The tetrahydrofuran-water binary system exhibits an unusual closed-loop miscibility gap (transitions from a miscible regime to an immiscible regime back to another miscible regime as the temperature increases). Here, using all-atom molecular dynamics simulations, we probe the structural and dynamical behavior of the binary system in the temperature regime of this gap at four different mass ratios, and we compare the behavior of bulk water and tetrahydrofuran. The changes in structure and dynamics observed in the simulations indicate that the temperature region associated with the miscibility gap is distinctive. Within the miscibility-gap temperature region, the self-diffusion of water is significantly altered and the second virial coefficients (pair-interaction strengths) show parabolic-like behavior. Overall, the results suggest that the gap is the result of differing trends with temperature of minor structural changes, which produces interaction virials with parabolic temperature dependence near the miscibility gap. PMID- 26734986 TI - Solution NMR Spectroscopy for the Study of Enzyme Allostery. AB - Allostery is a ubiquitous biological regulatory process in which distant binding sites within a protein or enzyme are functionally and thermodynamically coupled. Allosteric interactions play essential roles in many enzymological mechanisms, often facilitating formation of enzyme-substrate complexes and/or product release. Thus, elucidating the forces that drive allostery is critical to understanding the complex transformations of biomolecules. Currently, a number of models exist to describe allosteric behavior, taking into account energetics as well as conformational rearrangements and fluctuations. In the following Review, we discuss the use of solution NMR techniques designed to probe allosteric mechanisms in enzymes. NMR spectroscopy is unequaled in its ability to detect structural and dynamical changes in biomolecules, and the case studies presented herein demonstrate the range of insights to be gained from this valuable method. We also provide a detailed technical discussion of several specialized NMR experiments that are ideally suited for the study of enzymatic allostery. PMID- 26734992 TI - Triptolide induces protective autophagy through activation of the CaMKKbeta-AMPK signaling pathway in prostate cancer cells. AB - Triptolide, an active compound extracted from the Chinese herb thunder god vine (Tripterygium wilfordii Hook F.), has potent anti-tumor activity. Recently, triptolide was found to induce autophagy in cancer cells. However, the effects of triptolide on autophagy in human prostate cancer (PCa) cells have not yet been clearly elucidated. In this study, we demonstrated that triptolide induces autophagy in three PCa cell lines, PC-3, LNCaP and C4-2. Furthermore, we found that triptolide mediates intracellular accumulation of free calcium by stimulating the endoplasmic reticulum (ER) stress response. This activates the CaMKKbeta-AMPK signaling pathway, which in turn inhibits mTOR and activates both ULK1 and Beclin 1, finally resulting in autophagy. Moreover, we found that treatment with autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) enhances triptolide-induced PCa cell death and growth inhibition. Using a PC-3 xenografted mouse model, we showed that blocking autophagy with CQ significantly promoted triptolide-induced tumor growth inhibition in vivo. Overall, our results show that triptolide induces protective autophagy through the CaMKKbeta-AMPK pathway in PCa cells, implying that a combination of triptolide with autophagy inhibitors may potentially be an effective therapeutic strategy for PCa. PMID- 26734994 TI - Clinical prognostic significance and pro-metastatic activity of RANK/RANKL via the AKT pathway in endometrial cancer. AB - RANK/RANKL plays a key role in metastasis of certain malignant tumors, which makes it a promising target for developing novel therapeutic strategies for cancer. However, the prognostic value and pro-metastatic activity of RANK in endometrial cancer (EC) remain to be determined. Thus, the present study investigated the effect of RANK on the prognosis of EC patients, as well as the pro-metastatic activity of EC cells. The results indicated that those with high expression of RANK showed decreased overall survival and progression-free survival. Statistical analysis revealed the positive correlations between RANK/RANKL expression and metastasis-related factors. Additionally, RANK/RANKL significantly promoted cell migration/invasion via activating AKT/beta catenin/Snail pathway in vitro. However, RANK/RANKL-induced AKT activation could be suppressed after osteoprotegerin (OPG) treatment. Furthermore, the combination of medroxyprogesterone acetate (MPA) and RANKL could in turn attenuate the effect of RANKL alone. Similarly, MPA could partially inhibit the RANK-induced metastasis in an orthotopic mouse model via suppressing AKT/beta-catenin/Snail pathway. Therefore, therapeutic inhibition of MPA in RANK/RANKL-induced metastasis was mediated by AKT/beta-catenin/Snail pathway both in vitro and in vivo, suggesting a potential target of RANK for gene-based therapy for EC. PMID- 26734993 TI - Circulating microRNA-based screening tool for breast cancer. AB - Circulating microRNAs (miRNAs) are increasingly recognized as powerful biomarkers in several pathologies, including breast cancer. Here, their plasmatic levels were measured to be used as an alternative screening procedure to mammography for breast cancer diagnosis.A plasma miRNA profile was determined by RT-qPCR in a cohort of 378 women. A diagnostic model was designed based on the expression of 8 miRNAs measured first in a profiling cohort composed of 41 primary breast cancers and 45 controls, and further validated in diverse cohorts composed of 108 primary breast cancers, 88 controls, 35 breast cancers in remission, 31 metastatic breast cancers and 30 gynecologic tumors.A receiver operating characteristic curve derived from the 8-miRNA random forest based diagnostic tool exhibited an area under the curve of 0.81. The accuracy of the diagnostic tool remained unchanged considering age and tumor stage. The miRNA signature correctly identified patients with metastatic breast cancer. The use of the classification model on cohorts of patients with breast cancers in remission and with gynecologic cancers yielded prediction distributions similar to that of the control group.Using a multivariate supervised learning method and a set of 8 circulating miRNAs, we designed an accurate, minimally invasive screening tool for breast cancer. PMID- 26734995 TI - HDAC inhibitors suppress c-Jun/Fra-1-mediated proliferation through transcriptionally downregulating MKK7 and Raf1 in neuroblastoma cells. AB - Activator protein 1 (AP-1) is a transcriptional factor composed of the dimeric members of bZIP proteins, which are frequently deregulated in human cancer cells. In this study, we aimed to identify an oncogenic AP-1 dimer critical for the proliferation of neuroblastoma cells and to investigate whether histone deacetylase inhibitors (HDACIs), a new generation of anticancer agents, could target the AP-1 dimer. We report here that HDACIs including trichostatin A, suberoylanilidehydroxamic acid, valproic acid and M344 can transcriptionally suppress both c-Jun and Fra-1, preceding their inhibition of cell growth. c-Jun preferentially interacting with Fra-1 as a heterodimer is responsible for AP-1 activity and critical for cell growth. Mechanistically, HDACIs suppress Fra-1 expression through transcriptionally downregulating Raf1 and subsequently decreasing MEK1/2-ERK1/2 activity. Unexpectedly, HDACI treatment caused MKK7 downregulation at both the protein and mRNA levels. Deletion analysis of the 5' flanking sequence of the MKK7 gene revealed that a major element responsible for the downregulation by HDACI is located at -149 to -3 relative to the transcriptional start site. Knockdown of MKK7 but not MKK4 remarkably decreased JNK/c-Jun activity and proliferation, whereas ectopic MKK7-JNK1 reversed HDACI induced c-Jun suppression. Furthermore, suppression of both MKK-7/c-Jun and Raf 1/Fra-1 activities was involved in the tumor growth inhibitory effects induced by SAHA in SH-SY5Y xenograft mice. Collectively, these findings demonstrated that c Jun/Fra-1 dimer is critical for neuroblastoma cell growth and that HDACIs act as effective suppressors of the two oncogenes through transcriptionally downregulating MKK7 and Raf1. PMID- 26734996 TI - Targeting the Warburg effect in cancer cells through ENO1 knockdown rescues oxidative phosphorylation and induces growth arrest. AB - In the last 5 years, novel knowledge on tumor metabolism has been revealed with the identification of critical factors that fuel tumors. Alpha-enolase (ENO1) is commonly over-expressed in tumors and is a clinically relevant candidate molecular target for immunotherapy. Here, we silenced ENO1 in human cancer cell lines and evaluated its impact through proteomic, biochemical and functional approaches. ENO1 silencing increased reactive oxygen species that were mainly generated through the sorbitol and NADPH oxidase pathways, as well as autophagy and catabolic pathway adaptations, which together affect cancer cell growth and induce senescence. These findings represent the first comprehensive metabolic analysis following ENO1 silencing. Inhibition of ENO1, either alone, or in combination with other pathways which were perturbed by ENO1 silencing, opens novel avenues for future therapeutic approaches. PMID- 26734997 TI - Kaiso, a transcriptional repressor, promotes cell migration and invasion of prostate cancer cells through regulation of miR-31 expression. AB - Kaiso, a member of the BTB/POZ zinc finger protein family, functions as a transcriptional repressor by binding to sequence-specific Kaiso binding sites or to methyl-CpG dinucleotides. Previously, we demonstrated that Kaiso overexpression and nuclear localization correlated with the progression of prostate cancer (PCa). Therefore, our objective was to explore the molecular mechanisms underlying Kaiso-mediated PCa progression. Comparative analysis of miRNA arrays revealed that 13 miRNAs were significantly altered (> 1.5 fold, p < 0.05) in sh-Kaiso PC-3 compared to sh-Scr control cells. Real-time PCR validated that three miRNAs (9, 31, 636) were increased in sh-Kaiso cells similar to cells treated with 5-aza-2'-deoxycytidine. miR-31 expression negatively correlated with Kaiso expression and with methylation of the miR-31 promoter in a panel of PCa cell lines. ChIP assays revealed that Kaiso binds directly to the miR-31 promoter in a methylation-dependent manner. Over-expression of miR-31 decreased cell proliferation, migration and invasiveness of PC-3 cells, whereas cells transfected with anti-miR-31 restored proliferation, migration and invasiveness of sh-Kaiso PC-3 cells. In PCa patients, Kaiso high/miR-31 low expression correlated with worse overall survival relative to each marker individually. In conclusion, these results demonstrate that Kaiso promotes cell migration and invasiveness through regulation of miR-31 expression. PMID- 26734999 TI - Photo-induced biosynthesis of silver nanoparticles using aqueous extract of Erigeron bonariensis and its catalytic activity against Acridine Orange. AB - The green synthesis of silver nanoparticles (AgNPs) has reduced the pollution load in the environment to a greater extent by avoiding the use of hazardous chemicals. In the present work we have developed an ecofriendly and zero cost approach for the green synthesis of more stable and spherical AgNPs using aqueous extract of Erigeron bonariensis (AEE) which act as both reducing and stabilizing agent. The reaction of AEE and AgNO3 was carried out in direct sunlight for the instant biosynthesis of AgNPs within minutes. The biosynthesis was monitored by UV-vis spectroscopy which exhibited a sharp SPR band at 442 nm and 435 nm after 5 and 35 min of sunlight exposure. The optimum conditions for biosynthesis of AgNPs were found to be 2.5mM AgNO3 concentration, 1.5% (v/v) of AEE inoculum dose and 35 min of sunlight exposure. Presence of spherical AgNPs with average size 13 nm was confirmed by SEM and TEM analysis. The XRD and SAED analysis confirmed the crystalline nature of the AgNPs where the Bragg's diffraction pattern at (111), (200), (220) and (311) corresponded to face centered cubic crystal lattice of metallic silver. The average roughness of the synthesized AgNPs was 3.21 nm which was confirmed by AFM analysis. FTIR analysis was recorded between 4000 and 400 cm(-1) which confirmed the involvement of various functional groups in the synthesis of AgNPs. The AgNPs thus obtained showed catalytic activity towards degradation of Acridine Orange (AO) without involvement of any hazardous reducing agent. The concentration dependent catalytic activity of the synthesized AgNPs was also monitored using 1, 2 and 3 mL of silver colloids and was found that the degradation of AO followed pseudo first-order kinetics. PMID- 26734998 TI - Caspase inhibition impaired the neural stem/progenitor cell response after cortical ischemia in mice. AB - Cortical ischemia induces proliferation of neural stem/progenitor cells (NSPCs) in the subventricular zone (SVZ) and provokes migration of these cells toward the injured area. Despite sustained migration of NSPCs for an extended period of time after injury, they do not appear to survive. Here, we hypothesized that the anti apoptotic broad-spectrum caspase inhibitor Q-VD-OPh would increase NSPC survival in the injured cortex. However, contrary to our expectations, caspase inhibition did not promote NSPC survival and cortical neurogenesis. On the contrary, it abolished ischemia-induced proliferation and decreased the number of migrating neuroblasts in the injured cortex. Moreover, caspase inhibition decreased the levels of the chemoattractant chemokine CCL2 (MCP-1) and the pro-inflammatory cytokine IL-1beta. We hence for the first time show that caspase inhibition abrogates the response of NSPCs to an ischemic injury, presumably by inhibiting the production of pro-inflammatory factors. Thus, caution is warranted if anti apoptotic strategies are applied for neuroprotection. PMID- 26735000 TI - Photo-catalyzed and phyto-mediated rapid green synthesis of silver nanoparticles using herbal extract of Salvinia molesta and its antimicrobial efficacy. AB - Current study presents an economic, ecofriendly and simple photo-catalytic green route for the swift biosynthesis of silver nanoparticles (AgNPs) within 20s, devoid of any instrumental support or chemical reductant. Aqueous leaf-extract of an aquatic fern, Salvinia molesta (AES), was used as a bioreductant as well as a stabilizing agent. Rapid change in color of reaction mixture from yellowish green to reddish brown within 20s in direct sun light exposure was considered as the primary visual indication of AgNPs biosynthesis. The biosynthesis of AgNPs was confirmed by UV-visible spectroscopy through the presence of a characteristic surface plasmon resonance (SPR) band for AgNPs at lambdamax of 425 nm. The process parameters were optimized through one factor at a time approach. Optimal values of different process parameters for the current biosynthetic system were found as; 35 min of reaction time under sun light, 8.0mM AgNO3 concentration and 5.0% (v/v) AES inoculum dose. Field emission scanning electron microscopy (FESEM), energy dispersive X-Ray spectroscopy (EDX), high resolution transmission electron microscopy (HRTEM), atomic force microscopy (AFM) and X-ray diffraction (XRD) analysis showed that most of AgNPs were spherical in shape with average size distribution of 12.46 nm having face centered cubic (fcc) crystal lattice. IR analysis of AES and synthesized AgNPs indicated the involvement of both hydroxyl and amino groups in the biosynthesis and stabilization of AgNPs. The synthesized AgNPs were found to be an effective antibacterial agent against both Gram positive and Gram negative bacteria. On the basis of results and facts, a probable mechanism has also been proposed to explore the possible route of biosynthesis of AgNPs through AES. PMID- 26735001 TI - Photophysical characterization of anticancer drug valrubicin in rHDL nanoparticles and its use as an imaging agent. AB - Nanoparticles are target-specific drug delivery agents that are increasingly used in cancer therapy to enhance bioavailability and to reduce off target toxicity of anti-cancer agents. Valrubicin is an anti-cancer drug, currently approved only for vesicular bladder cancer treatment because of its poor water solubility. On the other hand, valrubicin carrying reconstituted high density lipoprotein (rHDL) nanoparticles appear ideally suited for extended applications, including systemic cancer chemotherapy. We determined selected fluorescence properties of the free (unencapsulated) drug vs. valrubicin incorporated into rHDL nanoparticles. We have found that upon encapsulation into rHDL nanoparticles the quantum yield of valrubicin fluorescence increased six fold while its fluorescence lifetime increased about 2 fold. Accordingly, these and potassium iodide (KI) quenching data suggest that upon incorporation, valrubicin is localized deep in the interior of the nanoparticle, inside the lipid matrix. Fluorescence anisotropy of the rHDL valrubicin nanoparticles was also found to be high along with extended rotational correlation time. The fluorescence of valrubicin could also be utilized to assess its distribution upon delivery to prostate cancer (PC3) cells. Overall the fluorescence properties of the rHDL: valrubicin complex reveal valuable novel characteristics of this drug delivery vehicle that may be particularly applicable when used in systemic (intravenous) therapy. PMID- 26735002 TI - Theoretical investigation, biological evaluation and VEGFR2 kinase studies of metal(II) complexes derived from hydrotris(methimazolyl)borate. AB - The reaction of soft tripodal scorpionate ligand, sodium hydrotris(methimazolyl)borate with M(ClO4)2.6H2O [MMn(II), Ni(II), Cu(II) or Zn(II)] in methanol leads to the cleavage of B-N bond followed by the formation of complexes of the type [M(MeimzH)4](ClO4)2.H2O (1-4), where MeimzH=methimazole. All the complexes were fully characterized by spectro-analytical techniques. The molecular structure of the zinc(II) complex (4) was determined by X-ray crystallography, which supports the observed deboronation reaction in the scorpionate ligand with tetrahedral geometry around zinc(II) ion. The electronic spectra of complexes suggested tetrahedral geometry for manganese(II) and nickel(II) complexes, and square-planar geometry for copper(II) complex. Frontier molecular orbital analysis (HOMO-LUMO) was carried out by B3LYP/6-31G(d) to understand the charge transfer occurring in the molecules. All the complexes exhibit significant antimicrobial activity against Gram (-ve) and Gram (+ve) bacterial as well as fungal strains, which are quite comparable to standard drugs streptomycin and clotrimazole. The copper(II) complex (3) showed excellent free radical scavenging activity against DPPH in all concentration with IC50 value of 30MUg/mL, when compared to the other complexes. In the molecular docking studies, all the complexes showed hydrophobic, pi-pi and hydrogen bonding interactions with BSA. The cytotoxic activity of the complexes against human hepatocellular liver carcinoma (HepG2) cells was assessed by MTT assay, which showed exponential responses toward increasing concentration of complexes. PMID- 26735003 TI - Unexpected Size Effect Observed in ZnO-Au Composite Photocatalysts. AB - Semiconductor-metal nanocomposites prepared with well-defined gold nanoclusters, such as Au25, Au144, and Au807, showed size-dependent photocatalytic activities for the reduction of nile blue and azobenzene. Whereas the photoreduction of nile blue was directly related with the charge separation and transfer rate from the photoexcited ZnO to gold nanoclusters, the photoreaction of azobenzene showed unexpected size effect with a clear threshold. Mechanistic investigations revealed that the photoreduction of azobenzene proceeded via a proton-coupled electron transfer process. The photocatalytic activity of the ZnO-Au nanocomposites was also dependent on the excitation intensity, demonstrating that the multielectron/multiproton process was controlled by the charge separation and transfer in the nanocomposites. PMID- 26735004 TI - Retention, dosing, tolerability and patient reported seizure outcome of Zonisamide as only add-on treatment under real-life conditions in adult patients with partial onset seizures: Results of the observational study ZOOM. AB - PURPOSE: Zonisamide is licensed for adjunctive therapy for partial-onset seizures with or without secondary generalisation in patients 6 years and older and as monotherapy for the treatment of partial seizures in adult patients with newly diagnosed epilepsy, and shows a favourable pharmacokinetic profile with low interaction potential with other drugs. The aim of the present study was to gather real-life data on retention and modalities of zonisamide use when administered as only add-on treatment to a current AED monotherapy in adult patients with partial-onset seizures. METHODS: This multicenter observational study was performed in 4 European countries and comprised three visits: baseline, and after 3 and 6 months. Data on patients' retention, reported efficacy, tolerability and safety, and quality of life was collected. Of 100 included patients, 93 could be evaluated. RESULTS: After 6 months, the retention rate of zonisamide add-on therapy was 82.8%. At this time, a reduction of seizure frequency of at least 50% was observed in 79.7% of patients, with 43.6% reporting seizure freedom over the last 3 months of the study period. Adverse events were reported by 19.4% of patients, with fatigue, agitation, dizziness, and headache being most frequent. Approximately 25% of patients were older than 60 years, many of whom suffered from late-onset epilepsy. Compared to younger patients, these patients showed considerable differences with regard to their antiepileptic drug regimen at baseline, and slightly higher responder and retention rates at 6 months. CONCLUSIONS: Despite limitations due to the non-interventional open-label design and the low sample size, the results show that zonisamide as only add-on therapy is well retained, indicating effectiveness in the majority of patients under real-life conditions. PMID- 26735005 TI - Scanning thermal microscopy with heat conductive nanowire probes. AB - Scanning thermal microscopy (SThM), which enables measurement of thermal transport and temperature distribution in devices and materials with nanoscale resolution is rapidly becoming a key approach in resolving heat dissipation problems in modern processors and assisting development of new thermoelectric materials. In SThM, the self-heating thermal sensor contacts the sample allowing studying of the temperature distribution and heat transport in nanoscaled materials and devices. The main factors that limit the resolution and sensitivities of SThM measurements are the low efficiency of thermal coupling and the lateral dimensions of the probed area of the surface studied. The thermal conductivity of the sample plays a key role in the sensitivity of SThM measurements. During the SThM measurements of the areas with higher thermal conductivity the heat flux via SThM probe is increased compared to the areas with lower thermal conductivity. For optimal SThM measurements of interfaces between low and high thermal conductivity materials, well defined nanoscale probes with high thermal conductivity at the probe apex are required to achieve a higher quality of the probe-sample thermal contact while preserving the lateral resolution of the system. In this paper, we consider a SThM approach that can help address these complex problems by using high thermal conductivity nanowires (NW) attached to a tip apex. We propose analytical models of such NW-SThM probes and analyse the influence of the contact resistance between the SThM probe and the sample studied. The latter becomes particularly important when both tip and sample surface have high thermal conductivities. These models were complemented by finite element analysis simulations and experimental tests using prototype probe where a multiwall carbon nanotube (MWCNT) is exploited as an excellent example of a high thermal conductivity NW. These results elucidate critical relationships between the performance of the SThM probe on one hand and thermal conductivity, geometry of the probe and its components on the other. As such, they provide a pathway for optimizing current SThM for nanothermal studies of high thermal conductivity materials. Comparison between experimental and modeling results allows us to provide direct estimates of the contact thermal resistances for various interfaces such as MWCNT-Al (5*10(-9)+/-1*10(-9)Km(2)W(-1)), Si3N4-Al (6*10(-8)+/-2.5*10(-8)Km(2)W(-1)) and Si3N4-graphene (~10(-8)Km(2)W(-1)). It was also demonstrated that the contact between the MWCNT probe and Al is relatively perfect, with a minimal contact resistance. In contrast, the thermal resistance between a standard Si3N4 SThM probe and Al is an order of magnitude higher than reported in the literature, suggesting that the contact between these materials may have a multi-asperity nature that can significantly degrade the contact resistance. PMID- 26735006 TI - Spatial Dependence and Heterogeneity in Bayesian Factor Analysis: A Cross National Investigation of Schwartz Values. AB - In this article, we present a Bayesian spatial factor analysis model. We extend previous work on confirmatory factor analysis by including geographically distributed latent variables and accounting for heterogeneity and spatial autocorrelation. The simulation study shows excellent recovery of the model parameters and demonstrates the consequences of ignoring spatial dependence. Specifically, we find inefficiency in the estimates of the factor score means and bias and inefficiency in the estimates of the corresponding covariance matrix. We apply the model to Schwartz value priority data obtained from 5 European countries. We show that the Schwartz motivational types of values, such as Conformity, Tradition, Benevolence, and Hedonism, possess high spatial autocorrelation. We identify several spatial patterns-specifically, Conformity and Hedonism have a country-specific structure, Tradition has a North-South gradient that cuts across national borders, and Benevolence has South-North cross national gradient. Finally, we show that conventional factor analysis may lead to a loss of valuable insights compared with the proposed approach. PMID- 26735007 TI - Default Bayes Factors for Model Selection in Regression. AB - In this article, we present a Bayes factor solution for inference in multiple regression. Bayes factors are principled measures of the relative evidence from data for various models or positions, including models that embed null hypotheses. In this regard, they may be used to state positive evidence for a lack of an effect, which is not possible in conventional significance testing. One obstacle to the adoption of Bayes factor in psychological science is a lack of guidance and software. Recently, Liang, Paulo, Molina, Clyde, and Berger (2008) developed computationally attractive default Bayes factors for multiple regression designs. We provide a web applet for convenient computation and guidance and context for use of these priors. We discuss the interpretation and advantages of the advocated Bayes factor evidence measures. PMID- 26735008 TI - An Investigation of the Sample Performance of Two Nonnormality Corrections for RMSEA. AB - The root mean square error of approximation (RMSEA) is a popular fit index in structural equation modeling (SEM). Typically, RMSEA is computed using the normal theory maximum likelihood (ML) fit function. Under nonnormality, the uncorrected sample estimate of the ML RMSEA tends to be inflated. Two robust corrections to the sample ML RMSEA have been proposed, but the theoretical and empirical differences between the 2 have not been explored. In this article, we investigate the behavior of these 2 corrections. We show that the virtually unknown correction due to Li and Bentler (2006) , which we label the sample-corrected robust RMSEA, is a consistent estimate of the population ML RMSEA yet drastically reduces bias due to nonnormality in small samples. On the other hand, the popular correction implemented in several SEM programs, which we label the population corrected robust RMSEA, has poor properties because it estimates a quantity that decreases with increasing nonnormality. We recommend the use of the sample corrected RMSEA with nonnormal data and its wide implementation. PMID- 26735010 TI - Recovery of Elemental Tellurium Nanoparticles by the Reduction of Tellurium Oxyanions in a Methanogenic Microbial Consortium. AB - This research focuses on the microbial recovery of elemental tellurium (Te(0)) from aqueous streams containing soluble tellurium oxyanions, tellurate (Te(VI)), and tellurite (Te(IV)). An anaerobic mixed microbial culture occurring in methanogenic granular sludge was able to biocatalyze the reduction of both Te oxyanions to produce Te(0) nanoparticles (NPs) in sulfur-free medium. Te(IV) reduction was seven times faster than that of Te(VI), such that Te(IV) did not accumulate to a great extent during Te(VI) reduction. Endogenous substrates in the granular sludge provided the electron equivalents required to reduce Te oxyanions; however, the reduction rates were modestly increased with an exogenous electron donor such as H2. The effect of four redox mediators (anthraquinone-2,6 disulfonate, hydroxocobalamin, riboflavin, and lawsone) was also tested. Riboflavin increased the rate of Te(IV) reduction eleven-fold and also enhanced the fraction Te recovered as extracellular Te(0) NPs from 21% to 64%. Lawsone increased the rate of Te(VI) reduction five-fold, and the fraction of Te recovered as extracellular material increased from 49% to 83%. The redox mediators and electron donors also impacted the morphologies and localization of Te(0) NPs, suggesting that NP production can be tailored for a particular application. PMID- 26735011 TI - Vascular biology: Transcriptional control of endothelial energy. PMID- 26735012 TI - Crystal structure of a DNA catalyst. AB - Catalysis in biology is restricted to RNA (ribozymes) and protein enzymes, but synthetic biomolecular catalysts can also be made of DNA (deoxyribozymes) or synthetic genetic polymers. In vitro selection from synthetic random DNA libraries identified DNA catalysts for various chemical reactions beyond RNA backbone cleavage. DNA-catalysed reactions include RNA and DNA ligation in various topologies, hydrolytic cleavage and photorepair of DNA, as well as reactions of peptides and small molecules. In spite of comprehensive biochemical studies of DNA catalysts for two decades, fundamental mechanistic understanding of their function is lacking in the absence of three-dimensional models at atomic resolution. Early attempts to solve the crystal structure of an RNA-cleaving deoxyribozyme resulted in a catalytically irrelevant nucleic acid fold. Here we report the crystal structure of the RNA-ligating deoxyribozyme 9DB1 (ref. 14) at 2.8 A resolution. The structure captures the ligation reaction in the post catalytic state, revealing a compact folding unit stabilized by numerous tertiary interactions, and an unanticipated organization of the catalytic centre. Structure-guided mutagenesis provided insights into the basis for regioselectivity of the ligation reaction and allowed remarkable manipulation of substrate recognition and reaction rate. Moreover, the structure highlights how the specific properties of deoxyribose are reflected in the backbone conformation of the DNA catalyst, in support of its intricate three-dimensional organization. The structural principles underlying the catalytic ability of DNA elucidate differences and similarities in DNA versus RNA catalysts, which is relevant for comprehending the privileged position of folded RNA in the prebiotic world and in current organisms. PMID- 26735013 TI - The functional diversity of retinal ganglion cells in the mouse. AB - In the vertebrate visual system, all output of the retina is carried by retinal ganglion cells. Each type encodes distinct visual features in parallel for transmission to the brain. How many such 'output channels' exist and what each encodes are areas of intense debate. In the mouse, anatomical estimates range from 15 to 20 channels, and only a handful are functionally understood. By combining two-photon calcium imaging to obtain dense retinal recordings and unsupervised clustering of the resulting sample of more than 11,000 cells, here we show that the mouse retina harbours substantially more than 30 functional output channels. These include all known and several new ganglion cell types, as verified by genetic and anatomical criteria. Therefore, information channels from the mouse eye to the mouse brain are considerably more diverse than shown thus far by anatomical studies, suggesting an encoding strategy resembling that used in state-of-the-art artificial vision systems. PMID- 26735014 TI - Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance. PMID- 26735015 TI - FOXO1 couples metabolic activity and growth state in the vascular endothelium. AB - Endothelial cells (ECs) are plastic cells that can switch between growth states with different bioenergetic and biosynthetic requirements. Although quiescent in most healthy tissues, ECs divide and migrate rapidly upon proangiogenic stimulation. Adjusting endothelial metabolism to the growth state is central to normal vessel growth and function, yet it is poorly understood at the molecular level. Here we report that the forkhead box O (FOXO) transcription factor FOXO1 is an essential regulator of vascular growth that couples metabolic and proliferative activities in ECs. Endothelial-restricted deletion of FOXO1 in mice induces a profound increase in EC proliferation that interferes with coordinated sprouting, thereby causing hyperplasia and vessel enlargement. Conversely, forced expression of FOXO1 restricts vascular expansion and leads to vessel thinning and hypobranching. We find that FOXO1 acts as a gatekeeper of endothelial quiescence, which decelerates metabolic activity by reducing glycolysis and mitochondrial respiration. Mechanistically, FOXO1 suppresses signalling by MYC (also known as c MYC), a powerful driver of anabolic metabolism and growth. MYC ablation impairs glycolysis, mitochondrial function and proliferation of ECs while its EC-specific overexpression fuels these processes. Moreover, restoration of MYC signalling in FOXO1-overexpressing endothelium normalizes metabolic activity and branching behaviour. Our findings identify FOXO1 as a critical rheostat of vascular expansion and define the FOXO1-MYC transcriptional network as a novel metabolic checkpoint during endothelial growth and proliferation. PMID- 26735017 TI - Cancer: Bet on drug resistance. PMID- 26735016 TI - High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects. AB - CRISPR-Cas9 nucleases are widely used for genome editing but can induce unwanted off-target mutations. Existing strategies for reducing genome-wide off-target effects of the widely used Streptococcus pyogenes Cas9 (SpCas9) are imperfect, possessing only partial or unproven efficacies and other limitations that constrain their use. Here we describe SpCas9-HF1, a high-fidelity variant harbouring alterations designed to reduce non-specific DNA contacts. SpCas9-HF1 retains on-target activities comparable to wild-type SpCas9 with >85% of single guide RNAs (sgRNAs) tested in human cells. Notably, with sgRNAs targeted to standard non-repetitive sequences, SpCas9-HF1 rendered all or nearly all off target events undetectable by genome-wide break capture and targeted sequencing methods. Even for atypical, repetitive target sites, the vast majority of off target mutations induced by wild-type SpCas9 were not detected with SpCas9-HF1. With its exceptional precision, SpCas9-HF1 provides an alternative to wild-type SpCas9 for research and therapeutic applications. More broadly, our results suggest a general strategy for optimizing genome-wide specificities of other CRISPR-RNA-guided nucleases. PMID- 26735019 TI - Total Syntheses of (R)-Strongylodiols C and D. AB - The first total syntheses of two marine natural products, (R)-strongylodiols C and D, with 99% ee were achieved. The key steps of the strategy include the zipper reaction of an alkyne, the asymmetric alkynylation of an unsaturated aliphatic aldehyde catalyzed with Trost's ProPhenol ligand, and the Cadiot Chodkiewicz cross-coupling reaction of a chiral propargylic alcohol with a bromoalkyne. PMID- 26735020 TI - Atomistic Molecular Dynamics Simulations of Charged Latex Particle Surfaces in Aqueous Solution. AB - Charged particles in aqueous suspension form an electrical double layer at their surfaces, which plays a key role in suspension properties. For example, binder particles in latex paint remain suspended in the can because of repulsive forces between overlapping double layers. Existing models of the double layer assume sharp interfaces bearing fixed uniform charge, and so cannot describe aqueous binder particle surfaces, which are soft and diffuse, and bear mobile charge from ionic surfactants as well as grafted multivalent oligomers. To treat this industrially important system, we use atomistic molecular dynamics simulations to investigate a structurally realistic model of commercial binder particle surfaces, informed by extensive characterization of particle synthesis and surface properties. We determine the interfacial profiles of polymer, water, bound and free ions, from which the charge density and electrostatic potential can be calculated. We extend the traditional definitions of the inner and outer Helmholtz planes to our diffuse interfaces. Beyond the Stern layer, the simulated electrostatic potential is well described by the Poisson-Boltzmann equation. The potential at the outer Helmholtz plane compares well to the experimental zeta potential. We compare particle surfaces bearing two types of charge groups, ionic surfactant and multivalent oligomers, with and without added salt. Although the bare charge density of a surface bearing multivalent oligomers is much higher than that of a surfactant-bearing surface at realistic coverage, greater counterion condensation leads to similar zeta potentials for the two systems. PMID- 26735022 TI - A Bacterial Cell Shape-Determining Inhibitor. AB - Helicobacter pylori and Campylobacter jejuni are human pathogens and causative agents of gastric ulcers/cancer and gastroenteritis, respectively. Recent studies have uncovered a series of proteases that are responsible for maintaining the helical shape of these organisms. The H. pylori metalloprotease Csd4 and its C. jejuni homologue Pgp1 cleave the amide bond between meso-diaminopimelate and iso d-glutamic acid in truncated peptidoglycan side chains. Deletion of either csd4 or pgp1 results in bacteria with a straight rod phenotype, a reduced ability to move in viscous media, and reduced pathogenicity. In this work, a phosphinic acid based pseudodipeptide inhibitor was designed to act as a tetrahedral intermediate analog against the Csd4 enzyme. The phosphinic acid was shown to inhibit the cleavage of the alternate substrate, Ac-l-Ala-iso-d-Glu-meso-Dap, with a Ki value of 1.5 MUM. Structural analysis of the Csd4-inhibitor complex shows that the phosphinic acid displaces the zinc-bound water and chelates the metal in a bidentate fashion. The phosphinate oxygens also interact with the key acid/base residue, Glu222, and the oxyanion-stabilizing residue, Arg86. The results are consistent with the "promoted-water pathway" mechanism for carboxypeptidase A catalysis. Studies on cultured bacteria showed that the inhibitor causes significant cell straightening when incubated with H. pylori at millimolar concentrations. A diminished, yet observable, effect on the morphology of C. jejuni was also apparent. Cell straightening was more pronounced with an acapsular C. jejuni mutant strain compared to the wild type, suggesting that the capsule impaired inhibitor accessibility. These studies demonstrate that a highly polar compound is capable of crossing the outer membrane and altering cell shape, presumably by inhibiting cell shape determinant proteases. Peptidoglycan proteases acting as cell shape determinants represent novel targets for the development of antimicrobials against these human pathogens. PMID- 26735024 TI - Prevalence and Characteristics of Salmonella Serotypes Isolated from Fresh Produce Marketed in the United States. AB - Salmonella continues to rank as one of the most costly foodborne pathogens, and more illnesses are now associated with the consumption of fresh produce. The U.S. Department of Agriculture Microbiological Data Program (MDP) sampled select commodities of fresh fruit and vegetables and tested them for Salmonella, pathogenic Escherichia coli, and Listeria. The Salmonella strains isolated were further characterized by serotype, antimicrobial resistance, and pulsed-field gel electrophoresis profile. This article summarizes the Salmonella data collected by the MDP between 2002 and 2012. The results show that the rates of Salmonella prevalence ranged from absent to 0.34% in cilantro. A total of 152 isolates consisting of over 50 different serotypes were isolated from the various produce types, and the top five were Salmonella enterica serotype Cubana, S. enterica subspecies arizonae (subsp. IIIa) and diarizonae (subsp. IIIb), and S. enterica serotypes Newport, Javiana, and Infantis. Among these, Salmonella serotypes Newport and Javiana are also listed among the top five Salmonella serotypes that caused most foodborne outbreaks. Other serotypes that are frequent causes of infection, such as S. enterica serotypes Typhimurium and Enteritidis, were also found in fresh produce but were not prevalent. About 25% of the MDP samples were imported produce, including 65% of green onions, 44% of tomatoes, 42% of hot peppers, and 41% of cantaloupes. However, imported produce did not show higher numbers of Salmonella-positive samples, and in some products, like cilantro, all of the Salmonella isolates were from domestic samples. About 6.5% of the Salmonella isolates were resistant to the antimicrobial compounds tested, but no single commodity or serotype was found to be the most common carrier of resistant strains or of resistance. The pulsed-field gel electrophoresis profiles of the produce isolates showed similarities with Salmonella isolates from meat samples and from outbreaks, but there were also profile diversities among the strains within some serotypes, like Salmonella Newport. PMID- 26735018 TI - An ID2-dependent mechanism for VHL inactivation in cancer. AB - Mechanisms that maintain cancer stem cells are crucial to tumour progression. The ID2 protein supports cancer hallmarks including the cancer stem cell state. HIFalpha transcription factors, most notably HIF2alpha (also known as EPAS1), are expressed in and required for maintenance of cancer stem cells (CSCs). However, the pathways that are engaged by ID2 or drive HIF2alpha accumulation in CSCs have remained unclear. Here we report that DYRK1A and DYRK1B kinases phosphorylate ID2 on threonine 27 (Thr27). Hypoxia downregulates this phosphorylation via inactivation of DYRK1A and DYRK1B. The activity of these kinases is stimulated in normoxia by the oxygen-sensing prolyl hydroxylase PHD1 (also known as EGLN2). ID2 binds to the VHL ubiquitin ligase complex, displaces VHL-associated Cullin 2, and impairs HIF2alpha ubiquitylation and degradation. Phosphorylation of Thr27 of ID2 by DYRK1 blocks ID2-VHL interaction and preserves HIF2alpha ubiquitylation. In glioblastoma, ID2 positively modulates HIF2alpha activity. Conversely, elevated expression of DYRK1 phosphorylates Thr27 of ID2, leading to HIF2alpha destabilization, loss of glioma stemness, inhibition of tumour growth, and a more favourable outcome for patients with glioblastoma. PMID- 26735025 TI - Impacts of Climate and Management Variables on the Contamination of Preharvest Leafy Greens with Escherichia coli. AB - The observed seasonality of foodborne disease suggests that climatic conditions play a role and that changes in the climate may affect the presence of pathogens. However, it is hard to determine whether this effect is direct or whether it works indirectly through other factors, such as farm management. This study aimed to identify the climate and management variables that are associated with the contamination (presence and concentration) of leafy green vegetables with E. coli. This study used data about E. coli contamination from 562 leafy green vegetables (lettuce and spinach) samples taken between 2011 and 2013 from 23 open field farms in Belgium, Brazil, Egypt, Norway, and Spain. Mixed-effect logistic and linear regression models were used to study the statistical relationship between the dependent and independent variables. Climate variables and agricultural management practices together had a systematic influence on E. coli presence and concentration. The variables important for E. coli presence included the minimum temperature of the sampling day (odds ratio = 1.47), region, and application of inorganic fertilizer. The variables important for concentration (R(2) = 0.75) were the maximum temperature during the 3 days before sampling and the region. Temperature had a stronger influence (had a significant parameter estimate and the highest R(2)) than did management practices on E. coli presence and concentration. Region was a variable that masked many management variables, including rainwater, surface water, manure, inorganic fertilizer, and spray irrigation. Climate variables had a positive relationship with E. coli presence and concentration. Temperature, irrigation water type, fertilizer type, and irrigation method should be systematically considered in future studies of fresh produce safety. PMID- 26735026 TI - Public Health Relevance of Cross-Contamination in the Fresh-Cut Vegetable Industry. AB - Although quantitative studies have revealed that cross-contamination during the washing stage of fresh produce occurs, the importance of cross-contamination in terms of public health relevance has rarely been assessed. The direct distribution of initially contaminated leafy vegetables to a multitude of servings by cutting and mixing also has not been addressed. The goal of this study was to assess the attribution of both contamination pathways to disease risk. We constructed a transparent and exploratory mathematical model that simulates the dispersion of contamination from a load of leafy greens during industrial washing. The risk of disease was subsequently calculated using a Beta Poisson dose-response relation. The results indicate that up to contamination loads of 10(6) CFU the direct contamination route is more important than the indirect route (i.e., cross-contamination) in terms of number of illnesses. We highlight that the relevance of cross-contamination decreases with more diffuse and uniform contamination, and we infer that prevention of contamination in the field is the most important risk management strategy and that disinfection of washing water can be an additional intervention to tackle potentially high (>10(6) CFU) point contamination levels. PMID- 26735027 TI - Assessing the Public Health Impact and Effectiveness of Interventions To Prevent Salmonella Contamination of Sprouts. AB - Sprouts have been a recurring public health challenge due to microbiological contamination, and Salmonella has been the major cause of sprout-associated outbreaks. Although seed treatment and microbiological testing have been applied as risk reduction measures during sprout production, the extent to which their effectiveness in reducing the public health risks associated with sprouts has not been well investigated. We conducted a quantitative risk assessment to measure the risk posed by Salmonella contamination in sprouts and to determine whether and how mitigation strategies can achieve a satisfactory risk reduction based on the assumption that the risk reduction achieved by a microbiological sampling and testing program at a given sensitivity is equivalent to that achieved by direct inactivation of pathogens. Our results indicated that if the sprouts were produced without any risk interventions, the health impact caused by sprouts contaminated with Salmonella would be very high, with a median annual estimated loss of disability-adjusted life years (DALYs) of 691,412. Seed treatment (with 20,000 ppm of calcium hypochlorite) or microbiological sampling and testing of spent irrigation water (SIW) alone could reduce the median annual impact to 734 or 4,856 DALYs, respectively. Combining seed treatment with testing of the SIW would further decrease the risk to 58 DALYs. This number could be dramatically lowered to 3.99 DALYs if sprouts were produced under conditions that included treating seeds with 20,000 ppm of calcium hypochlorite plus microbiological testing of seeds, SIW, and finished products. Our analysis shows that the public health impact due to Salmonella contamination in sprouts could be controlled if seeds are treated to reduce pathogens and microbiological sampling and testing is implemented. Future advances in intervention strategies would be important to improve sprout safety further. PMID- 26735028 TI - Microbiological Status and Food Safety Compliance of Commercial Basil Production Systems. AB - Basil has been implicated in a number of microbe-associated foodborne illnesses across the world, and the source of contamination has often been traced back to the production and/or processing stages of the supply chain. The aim of this study was to evaluate the microbiological quality of fresh basil from the point of production to the retail outlet in the Gauteng and Northwest Provinces of South Africa. A total of 463 samples were collected over a 3-month period from two large-scale commercial herb producing and processing companies and three retail outlets. The microbiological quality of the samples was assessed based on the presence or absence of Escherichia coli O157:H7 and Salmonella Typhimurium and the levels of the indicator bacteria E. coli and total coliforms. Salmonella Typhimurium was detected on four basil samples (0.9%) arriving at the processing facility and at dispatch, but no E. coli O157:H7 was detected throughout the study. Total coliform counts were 0.4 to 4.1 CFU/g for basil, 1.9 to 3.4 log CFU/ml for water, and 0.2 to 1.7 log CFU/cm(2) for contact surfaces, whereas E. coli was detected in the water samples and only once on basil. The Colilert-18 and membrane filter methods were used to analyze water samples, and a comparison of results revealed that the Colilert-18 method was more sensitive. Strong evidence suggests that high numbers of coliforms do not necessarily indicate the presence of Salmonella Typhimurium. The study results highlight the importance of effective implementation of food safety management systems in the fresh produce industry. PMID- 26735029 TI - Effect of Organic Acids on Salmonella Shedding and Colonization in Pigs on a Farm with High Salmonella Prevalence. AB - This study builds on the results of a previous study in which six commercial feed products based on organic acids were evaluated with respect to Salmonella contamination of piglets in an artificially challenged seeder model. In the present study, the efficacy of three of these commercial products was assessed for Salmonella reduction in fattening pigs on one closed farm with a natural high Salmonella prevalence. In each of four fattening compartments, one of the following feed treatments was evaluated during two consecutive fattening rounds: (i) butyric acid (active ingredients at 1.3 kg/ton of feed; supplement A1), (ii) a combination of short-chain organic acids (mixture of free acids and salts) and natural extracts (2.92 kg/ton; supplement A4), (iii) a 1:1 blend of two commercial products consisting of medium-chain fatty acids, lactic acid, and oregano oil (3.71 kg/ton; supplement A5+A6), and (iv) a control feed. On the farm, the Salmonella status of the fattening pigs was evaluated by taking fecal samples twice during the fattening period. At the slaughterhouse, samples were collected from the cecal contents and the ileocecal lymph nodes. Salmonella isolates were serotyped and characterized by pulsed-field gel electrophoresis. This farm had a particularly high number of pigs shedding Salmonella with a wide variety of sero- and pulsotypes. Only the feed blend based on the medium-chain fatty acids was able to significantly reduce Salmonella prevalence both on the farm and at the slaughterhouse. With this combined supplement, the Salmonella reduction in the feces at slaughter age, in cecal contents at slaughter, and the lymph nodes was 50, 36, and 67%, respectively, compared with the control animals. This promising finding calls for further investigation including cost-efficiency of this combined feed product and its effect on the animals. PMID- 26735030 TI - Pooling of Immunomagnetic Separation Beads Does Not Affect Detection Sensitivity of Six Major Serogroups of Shiga Toxin-Producing Escherichia coli in Cattle Feces. AB - Shiga toxin-producing Escherichia coli (STEC) of the serogroups O26, O45, O103, O111, O121, and O145, often called non-O157 STEC, are foodborne pathogens. Cattle are asymptomatic reservoirs for STEC; the organisms reside in the hindgut and are shed in the feces, which serve as the source of food product contaminations. Culture-based detection of non-O157 STEC involves an immunomagnetic separation (IMS) step to capture the specific serogroups in complex matrices, such as feces. The IMS procedure is time consuming and labor intensive because of the need to subject each fecal sample to six individual beads. Therefore, our objective was to evaluate whether pooling of IMS beads affects sensitivity of non-O157 STEC detection compared with using individual IMS beads. The evaluation was done by comparing detection of serogroups in feces spiked with pure cultures (experiments 1 and 2) and from feces (n = 384) of naturally shedding cattle (experiment 3). In spiked fecal samples, detection with pools of three, four, six, or seven beads was similar to, or at times higher than, detection with individual IMS beads. In experiment 3, the proportions of fecal samples that tested positive for the six serogroups as detected by individual or pooled beads were similar. Based on noninferiority tests, detection with pooled beads was not substantially inferior to detection with individual beads (P > 0.05). In conclusion, the pooling of IMS beads is a better option for detection of STEC serogroups in fecal samples compared with individual beads because the procedure saves time and labor and has the prospect of a higher throughput. PMID- 26735031 TI - Multiplex Quantitative PCR Assays for the Detection and Quantification of the Six Major Non-O157 Escherichia coli Serogroups in Cattle Feces. AB - Shiga toxin-producing Escherichia coli (STEC) serogroups O26, O45, O103, O111, O121, and O145, called non-O157 STEC, are important foodborne pathogens. Cattle, a major reservoir, harbor the organisms in the hindgut and shed them in the feces. Although limited data exist on fecal shedding, concentrations of non-O157 STEC in feces have not been reported. The objectives of our study were (i) to develop and validate two multiplex quantitative PCR (mqPCR) assays, targeting O antigen genes of O26, O103, and O111 (mqPCR-1) and O45, O121, and O145 (mqPCR-2); (ii) to utilize the two assays, together with a previously developed four-plex qPCR assay (mqPCR-3) targeting the O157 antigen and three virulence genes (stx1, stx2, and eae), to quantify seven serogroups and three virulence genes in cattle feces; and (iii) to compare the three mqPCR assays to a 10-plex conventional PCR (cPCR) targeting seven serogroups and three virulence genes and culture methods to detect seven E. coli serogroups in cattle feces. The two mqPCR assays (1 and 2) were shown to be specific to the target genes, and the detection limits were 4 and 2 log CFU/g of pure culture-spiked fecal samples, before and after enrichment, respectively. A total of 576 fecal samples collected from a feedlot were enriched in E. coli broth and were subjected to quantification (before enrichment) and detection (after enrichment). Of the 576 fecal samples subjected, before enrichment, to three mqPCR assays for quantification, 175 (30.4%) were quantifiable (>=4 log CFU/g) for at least one of the seven serogroups, with O157 being the most common serogroup. The three mqPCR assays detected higher proportions of postenriched fecal samples (P > 0.01) as positive for one or more serogroups compared with cPCR and culture methods. This is the first study to assess the applicability of qPCR assays to detect and quantify six non-O157 serogroups in cattle feces and to generate data on fecal concentration of the six serogroups. PMID- 26735032 TI - Prevalence and Distribution of Campylobacter jejuni in Small-Scale Broiler Operations. AB - Campylobacter jejuni has been recognized as one of the most prevalent causes of foodborne bacterial illnesses in humans. Previous studies have focused on the transmission routes of C. jejuni from commercial flock farms to the final retail product. The objective of this study was to determine the prevalence of C. jejuni and Campylobacter spp. in eggshells, live birds, feed, drinking water, and the rearing environment in a small-scale broiler operation. Broilers were raised under two different production systems: (i) environmentally controlled housing and (ii) open-air housing with two replications. Each week, samples were collected from eggshells, bird feces, feed, drinking water, enclosures (vertical walls of bird housing), and feed troughs for enumeration and isolation testing. All samples were plated on modified charcoal-cefoperazone-deoxycholate agar to determine the log CFU per gram and percent prevalence of Campylobacter spp. Isolation of C. jejuni was verified with latex agglutination and hippurate hydrolysis tests. The results from this study suggest that vertical transmission of these bacteria from egg surfaces to newly hatched chicks is not a significant risk factor. The results also suggest that the prevalence of C. jejuni at time of harvest (week 6) was significantly higher (P < 0.05) in the open-air housing broilers than in those in the environmentally controlled housing. Elevated levels of cross-contaminants, especially water and feed, may have played a role in this outcome. PMID- 26735033 TI - Prevalence and Genetic Diversity of Livestock-Associated Methicillin-Resistant Staphylococcus aureus on Belgian Pork. AB - Since the first description of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA), a high prevalence was observed in pigs. At present, questions remain about the transmission of LA-MRSA to the general human population through pork. The objectives of the present study were to determine the prevalence of LA-MRSA in Belgian pork and to determine the role of the pork production chain and butcheries in transmission of LA-MRSA to the human population. Pig meat samples (chops, bacon, minced pork, ribs, forelimbs, and ears; n = 137) originating from four butcheries (A through D) were spread plated on ChromID MRSA plates both before and after overnight enrichment culture. Suspect colonies were confirmed using a MRSA-specific triplex PCR assay and a CC398-specific PCR assay. The isolates (n = 147) were further characterized by SCCmec typing, multiple-locus variable number tandem repeat analysis, and antimicrobial susceptibility testing, a selection of isolates were subjected to pulsed-field gel electrophoresis and spa typing. Direct plating revealed a MRSA prevalence of 8%. After enrichment, MRSA was isolated from 98 (72%) of 137 samples of which the majority were from rib, ear, and forelimb. The majority (97%) of obtained isolates belonged to CC398, the main LA-MRSA type. A high level of genetic diversity was noted among the isolates from one butchery. Thirty antimicrobial susceptibility profiles were found; 13 and 9% of the isolates had Cip-Tet-Tri and Gen-Kan-Tet-Tob-Tri profiles, respectively. These results indicate the importance of enrichment for MRSA detection of pork. The observed genetic diversity of the isolates indicated that the pork production chain can be considered a source of multiple MRSA types that could be transmitted to the human population through cross-contaminated meat. PMID- 26735035 TI - Comparison of New and Traditional Culture-Dependent Media for Enumerating Foodborne Yeasts and Molds. AB - Fifty-six foods and food ingredients were analyzed for populations of naturally occurring yeasts and molds using Petrifilm rapid yeast and mold (RYM) count plates, Petrifilm yeast and mold (YM) count plates, dichloran rose bengal chloramphenicol (DRBC) agar plates, acidified potato dextrose agar (APDA) plates, and dichloran 18% glycerol (DG18) agar plates. Colonies were counted after incubating plates for 48, 72, and 120 h at 25 degrees C. Of 56 foods in which either yeasts or molds were detected on at least one medium incubated for 120 h, neither yeasts nor molds were detected in 55.4, 73.2, 21.4, 19.6, and 71.4% of foods plated on the five respective media and incubated for 48 h; 10.7, 14.3, 3.6, 1.8, and 19.6% of foods were negative after 72 h, and 3.6, 1.8, 0, 0, and 0% of foods were negative after 120 h. Considering all enumeration media, correlation coefficients were 0.03 to 0.97 at 48 h of incubation; these values increased to 0.75 to 0.99 at 120 h. Coefficients of variation for total yeasts and molds were as high as 30.0, 30.8, and 27.2% at 48, 72, and 120 h, respectively. The general order of performance was DRBC = APDA > RYM Petrifilm > YM Petrifilm >= DG18 when plates were incubated for 48 h, DRBC > APDA > RYM Petrifilm > YM Petrifilm >= DG18 when plates were incubated for 72 h, and DRBC > APDA > RYM Petrifilm > YM Petrifilm > DG18 when plates were incubated for 120 h. Differences in performance among media are attributed to the diversity of yeasts and molds likely to be present in test foods and differences in nutrient, pH, and water activity requirements for resuscitation of stressed cells and colony development. PMID- 26735034 TI - Fish Product-Borne Histamine Intoxication Outbreak and Survey of Imported Fish and Fish Products in Serbia. AB - Histamine levels in fish and fish products are regarded as a primary criterion for food safety, considering the effects of histamine on human health. The aim of this research was to describe a case of massive histamine intoxication in Serbian children and to provide relevant information regarding the presence of histamine in imported marine fish and fish products available in the Serbian market. In January 2014, an incident of foodborne illness occurred in 28 children (aged 2 to 5 years) who consumed canned sardines in a kindergarten in Vojvodina province, northern Serbia. The diagnosis was established based on anamnestic data, epidemiological data, and clinical symptoms and confirmed by positive histamine finding in the incriminated sardines. Substantially high histamine levels (>300 mg/kg) were detected in seven of the nine examined units of these canned sardines. In addition, during an official veterinary border control from January 2013 to January 2015, 273 lots in total, including 2,457 fish and fishery product units, were analyzed using enzyme-linked immunosorbent assay. Even though only nine (3.29%) of all examined lots were declared as unsafe for human consumption, the presented case of histamine intoxication strongly suggests the importance of border inspection and comprehensive control of each imported lot. PMID- 26735036 TI - Sanitizing in Dry-Processing Environments Using Isopropyl Alcohol Quaternary Ammonium Formula. AB - Dry-processing environments are particularly challenging to clean and sanitize because introduced water can favor growth and establishment of pathogenic microorganisms such as Salmonella. Our objective was to determine the efficacy of an isopropyl alcohol quaternary ammonium (IPAQuat) formula for eliminating potential Salmonella contamination on food contact surfaces. Clean stainless steel coupons and conveyor belt materials used in dry-processing environments were spot inoculated in the center of coupons (5 by 5 cm) with a six-serotype composite of Salmonella (approximately 10 log CFU/ml), subjected to IPAQuat sanitizer treatments with exposure times of 30 s, 1 min, or 5 min, and then swabbed for enumeration of posttreatment survivors. A subset of inoculated surfaces was soiled with a breadcrumb-flour blend and allowed to sit on the laboratory bench for a minimum of 16 h before sanitation. Pretreatment Salmonella populations (inoculated controls, 0 s treatment) were approximately 7.0 log CFU/25 cm(2), and posttreatment survivors were 1.31, 0.72, and < 0.7 (detection limit) log CFU/25 cm(2) after sanitizer exposure for 30 s, 1 min, or 5 min, respectively, for both clean (no added soil) and soiled surfaces. Treatment with the IPAQuat formula using 30-s sanitizer exposures resulted in 5.68-log reductions, whereas >6.0-log reductions were observed for sanitizer exposures of 1 and 5 min. Because water is not introduced into the processing environment with this approach, the IPAQuat formula could have sanitation applications in dry processing environments to eliminate potential contamination from Salmonella on food contact surfaces. PMID- 26735037 TI - Performance Assessment and Comparability of a Commercial Enzyme-Linked Immunosorbent Assay Kit with Liquid Chromatography-Tandem Mass Spectrometry for Chloramphenicol Residues in Crab and Shrimp. AB - Monitoring for chloramphenicol (CAP) in aquaculture products is primarily performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which requires expensive equipment and specialized training. Many laboratories prefer to screen samples with facile and high-throughput enzyme-linked immunosorbent assay (ELISA) kits for CAP residues before submitting samples for LC-MS/MS quantification and confirmation. We evaluated the performance of a Ridascreen (R Biopharm) ELISA kit for CAP in spiked and incurred crab and shrimp muscle at levels bracketing the minimum required performance level for analysis (0.3 ng/g). The Ridascreen ELISA kit incorporates antibody directed against CAP. Incurred CAP levels in crab and shrimp muscle were verified using LC-MS/MS. We found good repeatability (relative standard deviation) of the ELISA in spiked and incurred crab and shrimp muscle samples, with values ranging from 6.8 to 21.7%. Recoveries of CAP from tissues spiked at 0.15 to 0.60 ng/g ranged from 102 to 107%. Minimal cross-reactivity with blank crab and shrimp muscle matrix components was observed. ELISA data were highly correlated with those of LC-MS/MS for CAP in incurred muscle tissue. We believe this study to be the first evaluation of the performance and comparability of a CAP ELISA kit and LC-MS/MS for determination of CAP residues, as well as their elimination, in crab muscle. Our findings support the use of this ELISA kit for screening purposes and, when used in conjunction with validated instrumental methods, for regulatory monitoring of CAP in these species. PMID- 26735038 TI - Antioxidant Compounds in Traditional Indian Pickles May Prevent the Process Induced Formation of Benzene. AB - Pickles in the Indian market contain ascorbic acid from the raw material used and benzoate as an added preservative that are involved in the formation of benzene in soft drinks. In this work, 24 market pickle samples were surveyed for benzene content, as well as its precursors and other constituents that influence its formation. The analysis showed that pickle samples were high in acid content (low pH) and showed significant amount of ascorbic acid, minerals (Cu and Fe), and benzoic acid present in them. Also, most samples exhibited high antioxidant activity that might be attributed to the ingredients used, such as fruits and spices. The solid-phase microextraction headspace gas chromatography-mass spectrometry method was developed in-house for benzene analysis. Eleven of 24 samples had benzene, with the highest concentration of 4.36 +/- 0.82 MUg of benzene per kg of pickle for a lime pickle that was also reported to have highest benzoic acid and considerably less hydroxyl radical ((*)OH) scavenging activity. However, benzene levels for all 11 samples were considerably below the World Health Organization regulatory limit of 10 MUg/kg for benzene in mineral water. Studies on model systems revealed that the high antioxidant activity of Indian pickles may have had a strong inhibitory effect on benzene formation. PMID- 26735039 TI - Predictive Model for Growth of Staphylococcus aureus on Raw Pork, Ham, and Sausage. AB - Recent Staphylococcus aureus outbreaks linked to meat and poultry products underscore the importance of understanding the growth kinetics of S. aureus in these products at different temperatures. Raw pork, ham, and sausage (each 10 +/- 0.3 g) were inoculated with a three-strain cocktail of S. aureus, resulting in an initial level of ca. 3 log CFU/g. Samples were stored isothermally at 10, 15, 20, 25, 30, 35, and 40 degrees C, and S. aureus was enumerated at appropriate time intervals. The square root model was developed using experimental data collected from S. aureus grown on all samples (where data from raw pork, ham, and sausage were combined) so as to describe the growth rate of S. aureus as a function of temperature. The model was then compared with models for S. aureus growth on each individual sample in the experiments (raw pork, ham, or sausage) and the S. aureus ComBase models, as well as models for the growth of different types of pathogens (S. aureus, Escherichia coli O157:H7, Clostridium perfringens, Salmonella serovars, and Salmonella Typhimurium) on various types of meat and poultry products. The results show that the S. aureus model developed here based on the pooled data from all three pork products seems suitable for the prediction of S. aureus growth on different pork products under isothermal conditions from 10 to 25 degrees C, as well as for S. aureus growth on different meat and poultry products at higher temperatures between 20 and 35 degrees C. Regardless of some high deviations observed at temperatures between 25 and 40 degrees C, the developed model still seems suitable to predict the growth of other pathogens on different types of meat and poultry products over the temperature ranges used here, especially for E. coli O157:H7 and Salmonella Typhimurium. The developed model, therefore, may be useful for estimating the effects of storage temperature on the behavior of pathogens in different meat and poultry products and for microbial risk assessments evaluating meat safety. PMID- 26735040 TI - Assessment of Listeria sp. Interference Using a Molecular Assay To Detect Listeria monocytogenes in Food. AB - Detection of Listeria monocytogenes in food is currently based on enrichment methods. When L. monocytogenes is present with other Listeria species in food, the species compete during the enrichment process. Overgrowth competition of the nonpathogenic Listeria species might result in false-negative results obtained with the current reference methods. This potential issue was noted when 50 food samples artificially spiked with L. monocytogenes were tested with a real-time PCR assay and Canada's current reference method, MFHPB-30. Eleven of the samples studied were from foods naturally contaminated with Listeria species other than those used for spiking. The real-time PCR assay detected L. monocytogenes in all 11 of these samples; however, only 6 of these samples were positive by the MFHPB 30 method. To determine whether L. monocytogenes detection can be affected by other species of the same genus due to competition, an L. monocytogenes strain and a Listeria innocua strain with a faster rate of growth in the enrichment broth were artificially coinoculated at different ratios into ground pork meat samples and cultured according to the MFHPB-30 method. L. monocytogenes was detected only by the MFHPB-30 method when L. monocytogenes/L. innocua ratios were 6.0 or higher. In contrast, using the same enrichments, the real-time PCR assay detected L. monocytogenes at ratios as low as 0.6. Taken together, these findings support the hypothesis that L. monocytogenes can be outcompeted by L. innocua during the MFHPB-30 enrichment phase. However, more reliable detection of L. monocytogenes in this situation can be achieved by a PCR-based method mainly because of its sensitivity. PMID- 26735042 TI - Modeling the Effect of Water Activity, pH, and Temperature on the Probability of Enterotoxin A Production by Staphylococcus aureus. AB - The objectives of this study were to develop a probability model of Staphylococcus aureus enterotoxin A (SEA) production as affected by water activity (a(w)), pH, and temperature in broth and assess its applicability for milk. The probability of SEA production was assessed in tryptic soy broth using 24 combinations of a(w) (0.86 to 0.99), pH (5.0 to 7.0), and storage temperature (10 to 30 degrees C). The observed probabilities were fitted with a logistic regression to develop a probability model. The model had a concordant value of 97.5% and concordant index of 0.98, indicating that the model satisfactorily describes the probability of SEA production. The model showed that a(w), pH, and temperature were significant factors affecting the probability of toxin production. The model predictions were in good agreement with the observed values obtained from milk. The model may help manufacturers in selecting product pH and a(w) and storage temperatures to prevent SEA production. PMID- 26735041 TI - Molecular Serogrouping of Listeria monocytogenes from Brazil Using PCR. AB - We assessed the serotype distribution of Listeria monocytogenes isolates from clinical, beef, and environment samples using two PCR-based protocols for serogrouping. A panel of 134 isolates (22 clinical samples, 79 samples of beef cuts, and 33 samples from the beef processing environment) were subjected to conventional serology and identified as serotypes 1/2a (n = 12), 1/2b (n = 21), 1/2c (n = 71), and 4b (n = 30). Isolates from clinical samples were predominantly serotype 4b, and the most prevalent serotype among the beef cut and environment samples was 1/2c. The protocol described by M. Doumith, C. Buchrieser, P. Glaser, C. Jacquet, and P. Martin (J. Clin. Microbiol. 42:3819-3822, 2004) produced contradictory results for seven 1/2a isolates, which were positive for lmo1118 and had the profile IIc (serotypes 1/2c and 3c). Fifteen serotype 4b isolates amplified the target lmo0737, with the atypical profile IVb variant 1. The results obtained with the protocol described by M. K. Borucki and D. R. Call (J. Clin. Microbiol. 41:5537-5540, 2003) were in full agreement with those of the conventional serology. We recommend using this multiplex PCR approach by adding one pair of the reported primers to the panel to reduce total effort by one PCR while maintaining specificity. We present additional recommendations to improve the efficiency and reproducibility of this serogrouping assay. PMID- 26735043 TI - Implications of Decreased Nitrite Concentrations on Clostridium perfringens Outgrowth during Cooling of Ready-to-Eat Meats. AB - Increased popularity of natural and organic processed meats can be attributed to the growing consumer demand for preservative-free foods, including processed meats. To meet this consumer demand, meat processors have begun using celery juice concentrate in place of sodium nitrite to create products labeled as no nitrate or no-nitrite-added meat products while maintaining the characteristics unique to conventionally cured processed meats. Because of flavor limitations, natural cures with celery concentrate typically provide lower ingoing nitrite concentrations for ready-to-eat processed meats than do conventional cures, which could allow for increased growth of pathogens, such as Clostridium perfringens, during cooked product cooling such as that required by the U.S. Department of Agriculture. The objective of this study was to investigate the implications associated with reduced nitrite concentrations for preventing C. perfringens outgrowth during a typical cooling cycle used for cooked products. Nitrite treatments of 0, 50, and 100 ppm were tested in a broth system inoculated with a three-strain C. perfringens cocktail and heated with a simulated product thermal process followed by a typical cooling-stabilization process. The nitrite concentration of 50 ppm was more effective for preventing C. perfringens outgrowth than was 0 ppm but was not as effective as 100 ppm. The interaction between nitrite and temperature significantly affected (P < 0.05) C. perfringens outgrowth in both total population and number of vegetative cells. Both temperature and nitrite concentration significantly affected (P < 0.05) C. perfringens spore survival, but the interaction between nitrite and temperature did not have a significant effect (P > 0.05) on spore outgrowth. Results indicate that decreased nitrite concentrations (50 ppm) have increased potential for total C. perfringens population outgrowth during cooling and may require additional protective measures, such as faster chilling rates. PMID- 26735044 TI - Microbiological Analysis of Rice Cake Processing in Korea. AB - This study was conducted to evaluate the microbial contamination in rice cake materials and products during processing and in the operation environment in nonhazard analysis [and] critical control point factories. Furthermore, the environmental health of the processing facilities and the bacterial and fungal contamination on the workers' hands were investigated. Pour plate methods were used for enumeration of aerobic plate count (APC), yeast and molds (YM), Bacillus cereus, Staphylococcus aureus, and Clostridium perfringens, whereas Petrifilm count plates were used for enumeration of coliforms and Escherichia coli. The respective microbial levels of APC, coliforms, YM, and B. cereus were in the range of 2.6 to 4.7, 1.0 to 3.8, not detected (ND) to 2.9, and ND to 2.8 log CFU/g in the raw materials and in the range of 2.3 to 6.2, ND to 3.6, ND to 2.7, and ND to 3.7 log CFU/g during processing of the rice cake products. During the processing of rice cakes, APC, coliforms, YM, and B. cereus increased during soaking and smashing treatments and decreased after steaming treatment. E. coli, S. aureus, and C. perfringens were not detected in any of the raw materials and operating areas or during processing. B. cereus was detected on the operators' hands at microbial contamination levels of 1.9 +/- 0.19 to 2.0 +/- 0.19 log CFU/g. The results showed that B. cereus in the end product is presumably the main concern for rice cakes. In addition, the high contamination level of B. cereus during manufacturing processes, including soaking, smashing, and molding, and the absence of B. cereus from the air sampling plates indicated that the contaminated equipment showed the potential risk to cause cross-contamination. PMID- 26735045 TI - Bacterial Quality and Prevalence of Foodborne Pathogens in Edible Offal from Slaughterhouses in Korea. AB - Edible offal meats have recently received significant attention worldwide. However, studies evaluating the microbial quality of diverse edible offal and specifically investigating contamination by pathogens that cause foodborne illnesses are rare. Our study was conducted to investigate the microbiological quality of six kinds of edible offal produced from 11 pigs and 8 cattle slaughterhouses in the Republic of Korea and the prevalence of pathogenic microorganisms such as Salmonella, Clostridium perfringens, Staphylococcus aureus, and Escherichia coli O157:H7 in these products. The values for aerobic plate counts, coliform counts, and E. coli counts in red offal were 1.00 to 6.70, 0 (below 10 CFU) to 4.78, and 0 to 4.00 log CFU/g, respectively. For green offal, the values were 3.00 to 7.00, 1.48 to 6.30, and 0 to 6.00 log CFU/g, respectively. The most frequently detected foodborne pathogen was Salmonella (23.8% prevalence in pig offal and 7.1% prevalence in cattle offal), followed by C. perfringens (11.1 and 7.1%, respectively) and S. aureus (12.7 and 2.4%, respectively). None of the offal samples tested positive for E. coli O157:H7. Considering the microbial quality of offal from Korean slaughterhouses and the prevalence of foodborne pathogens in this material, more refined hygienic standards such as a hazard analysis critical control point system for processing, packing, and transporting edible offal are necessary for preventing further contamination. PMID- 26735046 TI - Safety of Street-Vended Soy Wara in Nigeria. AB - Soy wara is a common ready-to-eat food whose production and sale are currently unregulated. Microbiological sampling indicated that 21% of the samples had standard plate counts exceeding 100,000 CFU/g, and 14% had Staphylococcus aureus counts higher than 100,000 CFU/g. The occurrence of S. aureus at these levels can result in food poisoning. Listeria monocytogenes was isolated in 14.4% of the samples, although the counts were generally low, typically <1,000 CFU/g. Although counts of L. monocytogenes were low, immunocompromised individuals and children may particularly be at risk of listeriosis. All samples showed low counts of Bacillus cereus (< 10,000 CFU/g). Escherichia coli and Salmonella enterica were detected in 5.6 and 2.2% of all samples, respectively, indicating fecal contamination and possible links to gastroenteritis and enteric fever. Fungal counts were variable, ranging from 6.0 * 10(3) to 2.0 * 10(4) CFU/g, with Alternaria spp., Fusarium spp., and Rhizopus spp. being the predominant species. Aluminum content was as high as 0.776 mg of Al per g in soy wara processed with alum. Significantly higher aluminum contents were observed in alum-processed soy wara compared with those processed with lime or ogi (an acid-fermented gruel of either maize [Zea mays], sorghum [Sorghum bicolor], or millet [Pennisetum glaucum]) (P < 0.05). These results indicate the need to improve personal hygiene and environmental sanitation in the production and preparation of soy wara, and further studies are warranted for the implication of the accumulation of aluminum. PMID- 26735047 TI - Acaricidal and Insecticidal Activities of Essential Oils against a Stored-Food Mite and Stored-Grain Insects. AB - Twenty plant-derived oils were evaluated for their acaricidal and insecticidal activities against Sitotroga cerealella, Sitophilus oryzae, Sitophilus zeamais, and Tyrophagus putrescentiae adults, by using the fumigant and filter paper diffusion methods. Responses varied with bioassay systems, insect or mite species, plant oils, and exposure time. Based on the 50% lethal dose (LD50) values against S. oryzae and S. zeamais in the fumigant bioassay, Anethum graveolens oil (4.12 and 1.12 MUg/cm(3), respectively) induced the highest mortality, followed by Achillea millefolium (21.92 and 14.91 MUg/cm(3)) and Eucalyptus dives (28.02 and 24.02 MUg/cm(3)) oils, respectively. The most toxic oil based on the 50% lethal concentration values against T. putrescentiae was E. dives (3.13 MUg/cm(3)), followed by Melaleuca leucadendron (3.93 MUg/cm(3)) and Leptospermum pertersonii (4.41 MUg/cm(3)). Neroli birgard oil (1.70 MUg/cm(3)) was the most toxic based on the LD50 values against S. cerealella, followed by Citrus aurantium (1.80 MUg/cm(3)) and Artemisia vulgaris (1.81 MUg/cm(3)). The insecticidal and acaricidal activities of the plant oils in the filter paper diffusion bioassay were similar to those in the fumigant bioassay. In comparison, A. millefolium, A. graveolens, and E. dives oils were more effective against S. oryzae and S. zeamais in the fumigant bioassay than in the contact bioassay. These results indicate that the insecticidal activity of the three plant oils against S. oryzae and S. zeamais may be due to their fumigant action. Acaricidal activities of the A. millefolium, A. graveolens, and E. dives oils against T. putrescentiae were 2.62, 1.11, and 122 times higher than that of benzyl benzoate in the contact bioassay. These results indicate that A. millefolium, A. graveolens, and E. dives oils have potential for development as agents to control stored-grain insects and mites. PMID- 26735048 TI - 2,3-Naphtho-Fused BODIPYs as Near-Infrared Absorbing Dyes. AB - 2,3-Naphtho-fused boron-dipyrromethenes (BODIPYs) 1a and 1b, which absorb near infrared light at 740-770 nm with molar extinction coefficients above 10(5) M(-1) cm(-1) in THF, have been synthesized through a palladium(II)-catalyzed direct acylation of N-BOC hydrazones and subsequent Paal-Knorr pyrrole synthesis. Simple benzo-annulation of dibenzo-BODIPY caused a significant red-shift in the absorption. Subsequent intramolecular B,O-cyclization of 1b gave 2, which exhibited an intense absorption band at 830 nm. The structure-optical property relationship has been investigated using theoretical calculations and cyclic voltammetry. PMID- 26735049 TI - Action of AlGaInP laser and high frequency generator in cutaneous wound healing. A comparative study. AB - PURPOSE: To evaluate in a macroscopic, histological and histomorphometric manner the healing process of cutaneous wounds in mice. METHODS: The sample consisted of 40 male mice and was divided in four groups: 1st group (control, n=10), 2nd group (High Frequency Generator - HF, the maximum amplitude range, 120s, n=10), 3rd group (AlGaInP Laser 660 nm, 30mW power, 5 J/cm2, applying scan mode, 120s, n=10) and 4thgroup (AlGaInP Laser 660 nm, 30 mW power, 8 J/cm2, applying scan mode, n=10). The surgical incision was made with an 8 mm diameter punch perpendicularly to the back of the animal. The statistical analysis was achieved by the statistical test One Way Anova post hoc Tukey Test and significance at p<0.05 in GraphPad Prism program. RESULTS: It was observed that in the acute phase the AlGaInP Laser at 5 J/cm2 provided a greater stimulus to healing, and both lasers were effective in the remodeling phase. CONCLUSION: The AlGaInP lasers from 5 J/cm2 to 8 J/cm2 showed better biomodulatory results in the acute and remodeling phases respectively, however, the HF was less effective than the laser, providing significant benefits only in the acute phase of tissue repair. PMID- 26735050 TI - The effects of ankaferd blood stopper and microporous polysaccharide hemospheres on epidural fibrosis in rat laminectomy model. AB - PURPOSE: To investigate whether topically administered hemostatic agents ankaferd blood stopper and microporous polysaccharide hemospheres can decrease epidural fibrosis after laminectomy in rats. METHODS: Eighteen adult male Sprague-Dawley rats were equally and randomly divided into three groups. In the treatment groups, ankaferd blood stopper and microporous polysaccharide hemospheres topically administrated upon duramater surface after laminectomy. Fibroblast count, epidural fibrosis and arachnoidal involvement were evaluated and graded histopathologically. RESULTS: Our data revealed that the count of fibroblasts, the grading of epidural fibrosis and arachnoideal involvement in the rats treated with microporous polysaccharide hemospheres were significantly less than the control group. Although the arachnoideal involvement in ankaferd blood stopper group were significantly less than the control group, there were no statistical differences when comparing the grading of epidural fibrosis and the fibroblasts count between the treatment groups and the control group. CONCLUSION: The ankaferd blood stopper and microporous polysaccharide hemospheres reduced epidural fibrosis and arachnoideal involvement after laminectomy in rats. PMID- 26735051 TI - The low-level laser on acute myositis in rats. AB - PURPOSE: To analyze the effects of the low-level laser therapy in the acute myositis induced in rats. METHODS: Twelve rats were subjected to bilateral ovariectomy for inducing osteoporosis. After surgery, they were divided into two groups: Ovariectomy-control group (G1, n=6), receiving 0.5 ml distilled water by gavage for 30 days, and Ovariectomy plus mastruz group (G2, n=6), receiving 0.5 ml of the hydroalcoholic extract of mastruz at 10% concentration (50mg) daily, for the same period. Then, the blood of the animals was collected for further biochemical analysis (liver function) and tibia and liver were removed for histological and histomorphometric analyses. RESULTS: In the MT group there was a statistic significant decrease in the number of inflammatory cells, related to the MI group (p<0.05), increase in the fibroblastic proliferation, when compared to groups C and MI related to MT group (p<0.01) and statistic significant edema regression (p=0.0400) in the MT group CONCLUSION: The low-level laser therapy was efficient in the reduction of the inflammatory process, increase of the fibroblastic proliferation and the reduction of the edema. PMID- 26735052 TI - Chenopodium ambrosioides L. extract prevents bone loss. AB - PURPOSE: To evaluate the effect of the Chenopodium ambrosioides L (mastruz) extract for preventing bone loss and bone metabolism in ovariectomized rats. METHODS: Twelve rats were subjected to bilateral ovariectomy for inducing osteoporosis. After surgery, they were divided into two groups: Ovariectomy control group (G1, n=6), receiving 0.5 ml distilled water by gavage for 30 days, and Ovariectomy plus mastruz group (G2, n=6), receiving 0.5 ml of the hydroalcoholic extract of mastruz at 10% concentration (50mg) daily, for the same period. Then, the blood of the animals was collected for further biochemical analysis (liver function) and tibia and liver were removed for histological and histomorphometric analyses. RESULTS: The cortical bone was significantly larger in the G2 than G1, whereas G1 presented the highest amount of adipocytes in the bone marrow (p<0.05). The blood levels of aspartate aminotransferase, triglycerides and cholesterol were significantly higher, whereas globulin and lactate dehydrogenase were smaller in G2 than G1. CONCLUSION: The hydroalcoholic extract of mastruz has effects on bone metabolism by changing blood proteins and enzymes and preventing both bone loss and the substitution of bone marrow cells by. PMID- 26735053 TI - Development of an experimental model of neurocysticercosis-induced hydrocephalus. Pilot study. AB - PURPOSE: To develop an experimental model of neurocysticercosis-induced hydrocephalus METHODS: There were used 17 rats. Ten animals were inoculated with Taenia crassiceps cysts into the subarachnoid. Five animals were injected with 0. ml of 25% kaolin (a standard solution for the development of experimental hydrocephalus) and two animals were injected with saline. Magnetic resonance imaging (MRI) was used to evaluate enlargement of the ventricles after one or three months of inoculation. Volumetric study was used to quantify the ventricle enlargement. RESULTS: Seven of the 10 animals in the cyst group developed hydrocephalus, two of them within one month and five within three months after inoculation. Three of the five animals in the kaolin group had hydrocephalus and none in the saline group. Ventricle volumes were significantly higher in the 3 months MRI cyst subgroup than in the 1-month cyst subgroup. Differences between cyst subgroups and kaolin group did not reach statistical significance. CONCLUSION: The developed model may reproduce the human condition of neurocysticercosis-related hydrocephalus, which exhibits a slowly progressive chronic course. PMID- 26735054 TI - Experimental models of renal dysfunction in female rats. Functional and histological aspects after unilateral nephrectomy or ligation of right renal vein with kidney preservation. AB - PURPOSE: To compare renal dysfunction after right nephrectomy and ligation of the right renal vein with preservation of kidney. METHODS: Animals' weight, pH, density, protein in urine and histological samples of the kidneys were evaluated. Fifteen female rats (Wistar) were divided into three groups. In the control group, right renal vein dissections were performed. In the second group, the right nephrectomy was performed. In the third group, the right renal vein was ligated and the kidney was preserved. Urine samples were taken before, three and seven days after the procedure. On the seventh postoperative day the kidneys were removed to histopathological study. Analysis by Student's t test was performed. RESULTS: weight loss, alterations of urine pH (p<0.05), in specific gravity, proteinuria (p<0.05) were found in groups 2 and 3; hemorrhagic infarction and edema were found after ligation of the right renal vein; changes in the left kidney were also observed on the seventh day. PMID- 26735055 TI - Acupuncture and pharmacopuncture are as effective as morphine or carprofen for postoperative analgesia in bitches undergoing ovariohysterectomy. AB - PURPOSE: To investigate the analgesic effect of acupuncture (AP) or micro-dose pharmacopuncture (PA), using carprofen or morphine, in bitches undergoing ovariohysterectomy (OHE). METHODS: Thirty five dogs were randomly assigned to five groups after sedation with acepromazine IM: AP, 0.5 mg.kg(-1) of morphine subcutaneously (SC), 4 mg.kg(-1) of carprofen SC, and PA with 0.05 mg.kg(-1) of morphine or 0.4 mg.kg(-1) of carprofen. Anaesthesia was induced with propofol and maintained with isoflurane. Pain was assessed after OHE by a blind observer for 24h, by dynamic visual analogue scale (DIVAS), Glasgow (CMPS-SF), Melbourne (UMPS) and Colorado University pain scale (CSU). Animals reaching 33% of the UMPS score received rescue analgesia with morphine IM. Non parametric data were analysed by Kruskal-Wallis or Friedman tests where applicable, followed by Dunn's test. Parametric data were analysed by two way ANOVA, followed by Tukey test. RESULTS: There were no differences among groups in number of rescue analgesia. Except for the DIVAS score where animals treated with morphine had the lowest score compared with AP and carprofen, at 1h after surgery, there were no other differences among groups. CONCLUSION: Acupuncture or pharmacopuncture were equally effective as morphine or carprofen to control postoperative pain in bitches undergoing ovariohysterectomy. PMID- 26735056 TI - Enhanced cyclooxygenase-2 activity leads to intestinal dysmotility following hemorrhagic shock. AB - PURPOSE: To test whether hemorrhagic shock (HS) increases the Cyclooxygenase-2 (COX-2) expression in the intestine and whether this enhanced COX-2 expression mediates the intestinal dysmotility after HS. METHODS: Male Wistar rats were randomly divided into HS sham group and HS group. At 180 min following HS establishment, the duodenum samples were harvested to assess the motility function, protein expression of COX-2 and the downstream products of COX-2, prostaglandins. RESULTS: Examination of motility function ex vivo showed that the contractile response to acetylcholine of smooth muscle strips of rats subjected to HS was significantly suppressed. A COX-2 inhibitor, NS-398, abolished this depressed contractile response after HS. Western blotting revealed an increased protein expression of COX-2 in intestinal tissues of HS rats. Immunohistochemical examination indicated that intestine tissues of HS rats were manifested by part of villous expansion and disruption, a large amount of COX-2 positive cells appearance in lamina propria and submucosa. Furthermore, the contents of prostaglandin E2 was significantly increased in intestinal tissues of HS rats. CONCLUSION: The enhanced COX-2/ prostaglandin E2 involves in the hemorrhagic shock induced intestinal dysmotility. PMID- 26735057 TI - Repair of large incisional hernias. To drain or not to drain. Randomized clinical trial. AB - PURPOSE: To evaluate the occurrence of seroma and surgical wound infection after surgery. METHODS: A total of 42 individuals with large incisional hernias were subjected toonlay mesh repair. Following the mesh placement, the participants were randomly allocated to two groups. In group 1, closed-suction drains were placed in the subcutaneous tissue, while progressive tension sutures were performed in group 2. The participants were subjected to clinical and ultrasound assessment to detect seroma and surgical wound infection at three time-points after surgery. RESULTS: The occurrence of seroma at the early, intermediate or late assessments was respectively 19.0%, 47.6%, 52.4% in group 1 and 28.6%, 57.1%, 42.9% in group 2 and was not significantly different between groups (p 0.469; 0.631; 0.619). Surgical wound infection occurred 19% in group 1 and 23.8% in group 2, without a significant difference between the groups (p>0.999). CONCLUSION: The frequency of seroma and infection did not exhibit significant differences between individuals subjected to onlay mesh repair of large incisional hernias with drains or progressive tension sutures without drainage. PMID- 26735059 TI - [Errata]. PMID- 26735058 TI - Effects of the Low-Level Laser Therapy (LLLT) in the process of healing diabetic foot ulcers. AB - PURPOSE: To evaluate the effects of the low-level laser therapy applying Laser on the tissue repair in ulcer carriers due to diabetes. METHODS: Sixteen type II diabetic patients, ulcer carriers in the lower limbs, participated in the research from which eight were in the control group and eight were submitted to the low-level laser therapy with a pulsed wave form, visible ray, wave length of 632.8 nm, 30 mW peak power, (Laser - HTM). The application time was of 80 (4J/cm2) seconds. The application was punctual without contact (approximately 1mm of distance), the pen being held in a perpendicular position related to the wound, in equidistant points. There were 12 appointments, of which three were done weekly in alternated days. Photograph records and an application of the brief inventory of pain were done before and after 30 days of follow-up. RESULTS: There was a significant decrease in the size of the wound when compared to the control group (p<0.05). The pain was also reported as having an intense improvement in the treated group. CONCLUSION: The low-level laser treatment seems to be an efficient method, viable, painless and of low costs concerning the tissue repair ulcers in a diabetic foot. PMID- 26735060 TI - Regional and Temporal Population Structure of Pseudoperonospora cubensis in Michigan and Ontario. AB - Cucurbit downy mildew (CDM), caused by the oomycete pathogen Pseudoperonospora cubensis, is a devastating disease that affects cucurbit species worldwide. This obligate, wind-dispersed pathogen does not overwinter in Michigan or other northern regions and new isolates can enter the state throughout the growing season. To evaluate the regional and temporal population structure of P. cubensis, sporangia from CDM lesions were collected from cucurbit foliage grown in Michigan and Ontario field locations in 2011. Population structure and genetic diversity were assessed in 257 isolates using nine simple sequence repeat markers. Genetic diversity was high for isolates from Michigan and Canada (0.6627 and 0.6131, respectively). Five genetic clusters were detected and changes in population structure varied by site and sampling date within a growing season. The Michigan and Canada populations were significantly differentiated, and a unique genetic cluster was detected in Michigan. PMID- 26735061 TI - Leuconostoc spp. Associated with Root Rot in Sugar Beet and Their Interaction with Rhizoctonia solani. AB - Rhizoctonia root and crown rot is an important disease problem in sugar beet caused by Rhizoctonia solani and also shown to be associated with Leuconostoc spp. Initial Leuconostoc studies were conducted with only a few isolates and the relationship of Leuconostoc with R. solani is poorly understood; therefore, a more thorough investigation was conducted. In total, 203 Leuconostoc isolates were collected from recently harvested sugar beet roots in southern Idaho and southeastern Oregon during 2010 and 2012: 88 and 85% Leuconostoc mesenteroides, 6 and 15% L. pseudomesenteroides, 2 and 0% L. kimchi, and 4 and 0% unrecognized Leuconostoc spp., respectively. Based on 16S ribosomal RNA sequencing, haplotype 11 (L. mesenteroides isolates) comprised 68 to 70% of the isolates in both years. In pathogenicity field studies with commercial sugar beet 'B-7', all Leuconostoc isolates caused more rot (P < 0.0001; alpha = 0.05) when combined with R. solani than when inoculated alone in both years. Also, 46 of the 52 combination treatments over the 2 years had significantly more rot (P < 0.0001; alpha = 0.05) than the fungal check. The data support the conclusion that a synergistic interaction leads to more rot when both Leuconostoc spp. and R. solani are present in sugar beet roots. PMID- 26735062 TI - NDH-1 and NDH-2 Plastoquinone Reductases in Oxygenic Photosynthesis. AB - Oxygenic photosynthesis converts solar energy into chemical energy in the chloroplasts of plants and microalgae as well as in prokaryotic cyanobacteria using a complex machinery composed of two photosystems and both membrane-bound and soluble electron carriers. In addition to the major photosynthetic complexes photosystem II (PSII), cytochrome b6f, and photosystem I (PSI), chloroplasts also contain minor components, including a well-conserved type I NADH dehydrogenase (NDH-1) complex that functions in close relationship with photosynthesis and likewise originated from the endosymbiotic cyanobacterial ancestor. Some plants and many microalgal species have lost plastidial ndh genes and a functional NDH-1 complex during evolution, and studies have suggested that a plastidial type II NADH dehydrogenase (NDH-2) complex substitutes for the electron transport activity of NDH-1. However, although NDH-1 was initially thought to use NAD(P)H as an electron donor, recent research has demonstrated that both chloroplast and cyanobacterial NDH-1s oxidize reduced ferredoxin. We discuss more recent findings related to the biochemical composition and activity of NDH-1 and NDH-2 in relation to the physiology and regulation of photosynthesis, particularly focusing on their roles in cyclic electron flow around PSI, chlororespiration, and acclimation to changing environments. PMID- 26735063 TI - Learning the Languages of the Chloroplast: Retrograde Signaling and Beyond. AB - The chloroplast can act as an environmental sensor, communicating with the cell during biogenesis and operation to change the expression of thousands of proteins. This process, termed retrograde signaling, regulates expression in response to developmental cues and stresses that affect photosynthesis and yield. Recent advances have identified many signals and pathways-including carotenoid derivatives, isoprenes, phosphoadenosines, tetrapyrroles, and heme, together with reactive oxygen species and proteins-that build a communication network to regulate gene expression, RNA turnover, and splicing. However, retrograde signaling pathways have been viewed largely as a means of bilateral communication between organelles and nuclei, ignoring their potential to interact with hormone signaling and the cell as a whole to regulate plant form and function. Here, we discuss new findings on the processes by which organelle communication is initiated, transmitted, and perceived, not only to regulate chloroplastic processes but also to intersect with cellular signaling and alter physiological responses. PMID- 26735064 TI - The Regulation of Essential Amino Acid Synthesis and Accumulation in Plants. AB - Although amino acids are critical for all forms of life, only proteogenic amino acids that humans and animals cannot synthesize de novo and therefore must acquire in their diets are classified as essential. Nine amino acids-lysine, methionine, threonine, phenylalanine, tryptophan, valine, isoleucine, leucine, and histidine-fit this definition. Despite their nutritional importance, several of these amino acids are present in limiting quantities in many of the world's major crops. In recent years, a combination of reverse genetic and biochemical approaches has been used to define the genes encoding the enzymes responsible for synthesizing, degrading, and regulating these amino acids. In this review, we describe recent advances in our understanding of the metabolism of the essential amino acids, discuss approaches for enhancing their levels in plants, and appraise efforts toward their biofortification in crop plants. PMID- 26735065 TI - Pre-Meiotic Anther Development: Cell Fate Specification and Differentiation. AB - Research into anther ontogeny has been an active and developing field, transitioning from a strictly lineage-based view of cellular differentiation events to a more complex understanding of cell fate specification. Here we describe the modern interpretation of pre-meiotic anther development, from the earliest cell specifications within the anther lobes through SPL/NZZ-, MSP1-, and MEL1-dependent pathways as well as the initial setup of the abaxial and adaxial axes and outgrowth of the anther lobes. We then continue with a look at the known information regarding further differentiation of the somatic layers of the anther (the epidermis, endothecium, middle layer, and tapetum), with an emphasis on male sterile mutants identified as defective in somatic cell specification. We also describe the differences in developmental stages among species and use this information to discuss molecular studies that have analyzed transcriptome, proteome, and small-RNA information in the anther. PMID- 26735066 TI - Asymmetric Syntheses of the Flavonoid Diels-Alder Natural Products Sanggenons C and O. AB - Metal-catalyzed, double Claisen rearrangement of a bis-allyloxyflavone has been utilized to enable a concise synthesis of the hydrobenzofuro[3,2-b]chromenone core structure of the natural products sanggenon A and sanggenol F. In addition, catalytic, enantioselective [4+2] cycloadditions of 2'-hydroxychalcones have been accomplished using B(OPh)3/BINOL complexes. Asymmetric syntheses of the flavonoid Diels-Alder natural products sanggenons C and O have been achieved employing a stereodivergent reaction of a racemic mixture (stereodivergent RRM) involving [4+2] cycloaddition. PMID- 26735067 TI - Transport to Rhebpress activity. AB - The small GTPases from the rat sarcoma (Ras) superfamily are a heterogeneous group of proteins of about 21 kDa that act as molecular switches, modulating cell signaling pathways and controlling diverse cellular processes. They are active when bound to guanosine triphosphate (GTP) and inactive when bound to guanosine diphosphate (GDP). Ras homolog enriched in brain (Rheb) is a member of the Ras GTPase superfamily and a key activator of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1). We recently determined that microspherule protein 1 (MCRS1) maintains Rheb at lysosomal surfaces in an amino acid-dependent manner. MCRS1 depletion promotes the formation of the GDP-bound form of Rheb, which is then delocalized from the lysosomal platform and transported to endocytic recycling vesicles, leading to mTORC1 inactivation. During this delocalization process, Rheb-GDP remains farnesylated and associated with cellular endomembranes. These findings provide new insights into the regulation of small GTPases, whose activity depends on both their GTP/GDP switch state and their capacity to move between different cellular membrane-bound compartments. Dynamic spatial transport between compartments makes it possible to alter the proximity of small GTPases to their activatory sites depending on the prevailing physiological and cellular conditions. PMID- 26735082 TI - Power Mobility Training for Young Children with Multiple, Severe Impairments: A Case Series. AB - AIMS: Young children with neurodevelopmental conditions are often limited in their ability to explore and learn from their environment. The purposes of this case series were to (1) describe the outcomes of using an alternative power mobility device with young children who had multiple, severe impairments; (2) develop power mobility training methods for use with these children; and (3) determine the feasibility of using various outcome measures. METHODS: Three children with cerebral palsy (Gross Motor Function Classification System Levels IV, V, and V) ages 17 months to 3.5 years participated in the case series. Examination included the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT) and the Dimensions of Mastery Questionnaire (DMQ). An individualized, engaging power mobility training environment was created for each participant. Intervention was provided for 60 minutes per week over 12 weeks. RESULTS: All participants exhibited improvements in power mobility skills. Post intervention PEDI-CAT scores increased in various domains for all participants. Post-intervention DMQ scores improved in Participants 1 and 2. DISCUSSION: The participants appeared to make improvements in their beginning power mobility skills. Additional research is planned to further explore the impact of power mobility training in this unique population. PMID- 26735083 TI - Walking a mile in another's shoes: The impact of wearing an Age Suit. AB - The "Age Suit" described in this article was developed to enable future designers, business leaders, and engineers to experience navigating the world as many older adults must. Tools such as this Age Suit offer the opportunity to "walk a mile" in another's shoes to develop empathy that can result in better design of spaces, goods, and services to meet the needs of a rapidly growing older population. This work first examined, through a series of clinical tests, whether younger adults' physical capacities were reduced in a direction consistent with aging by wearing a suit developed by the MIT AgeLab. An experiential learning task was then completed with the suit to understand its impact on completion of an instrumental activity of daily living. Results showed that younger adults wearing the suit experienced changes in task performance consistent with expected changes associated with aging. Participants' self reports from the experiential learning task indicated that they were able to empathize with older adults regarding some issues they face while completing a grocery shopping task. Future research with the suit should involve a wider range of individuals from the population and examine what effect participants' levels of fitness have on the experience of wearing the suit. PMID- 26735084 TI - Unraveling the Determinants of Cancer Patients' Intention to Express Concerns. AB - Little is known about the behavioral determinants that underlie cancer patients' intention to express concerns during a consultation. This information can be relevant to developing effective interventions for cancer patients. In this study, the integrative model of behavioral prediction (IMBP) is used as a framework to unravel the determinants of patients' intention to express concerns. The objectives of this study are to examine which of the IMBP determinants (attitude, perceived social norm, and/or self-efficacy) are significantly related to intention and what content of these determinants can be targeted to effect a change in patients' intention. An online survey based on the IMBP determinants was distributed. A total of 236 cancer patients and cancer survivors participated. The results of the survey showed that patients' attitudes and perceived social norm were the most important determinants of their intention to express concerns. The largest change in patients' intention might be achieved by targeting the affective attitude, referring to the extent to which patients believe that expressing concerns is (un)pleasant, and the social norm, referring to the extent to which patients feel (un)supported by significant others in expressing concerns. PMID- 26735085 TI - The use of lasers in Becker's naevus: An evidence-based review. AB - Becker's naevus is a hamartoma that often appears during puberty. Clinically this presents with a pigmented and often hairy patch most often on the shoulders. Treatment has always been challenging and lasers are often used with mixed results. This article reviews the evidence of all the laser treatments used in Becker's naevus and analyses the findings from the published studies and trials. PMID- 26735111 TI - Editorial. PMID- 26735113 TI - New Americas Editor. PMID- 26735112 TI - Erratum. PMID- 26735114 TI - Gender differences in the pharmacology of nicotine addiction. AB - Smoking rates have declined in recent years less rapidly in women than in men. More adolescent girls than boys are currently smoking. Quitting smoking is reported in many studies to be more difficult in women than in men. These observations suggest that there may be gender differences in the nature of nicotine addiction. Gender differences in various pharmacological processes involved in nicotine addiction are reviewed. Women take in less nicotine from smoking per cigarette than men but, because of slower metabolism, nicotine levels in the body for a given number of cigarettes per day are similar in male and female smokers. Women tend to be less sensitive to the discriminative effects of nicotine and tend to regulate nicotine intake less precisely than men. On the other hand, women appear to be more sensitive to the effects of nicotine in reducing negative affect and reducing body weight. There is a strong association between depression and smoking, and this association appears to be stronger in women than in men. Women tend to respond more to environmental cues associated with smoking than do men. Thus, several lines of evidence suggest that nicotine addiction is different in women than in men. Understanding the basis for gender differences may be of utility in individualizing and optimizing smoking cessation therapy. PMID- 26735115 TI - Ethanol metabolism by macrophages: possible role in organ damage. AB - Macrophages and hepatocytes oxidize ethanol to acetate in vitro at comparable rates but by different biochemical pathways. Ethanol metabolism by macrophages is largely ADH-independent and mainly based on cytochrome P450 and on the extracellular release of superoxide anion radicals. There is also evidence that during ethanol metabolism, macrophages release more acetaldehyde extracellularly than hepatocytes; the high concentrations of acetaldehyde around macrophages may damage surrounding tissue cells. Some of this acetaldehyde forms unstable cytotoxic complexes with serum albumin and with erythrocytes. The superoxide anion radicals released by macrophages may not only oxidize ethanol to acetaldehyde but also react with and damage cells in their immediate vicinity. After exposure to ethanol, macrophage-depleted rodents show markedly reduced levels of cytotoxic acetaldehyde-albumin complexes in the blood and reduced levels of hydroxyethyl radicals in the bile compared to control animals, indicating that the generation of such potentially pathogenic molecules is, to a large extent, dependent on macrophage activity. Macrophage-depleted animals also show less early liver damage than control animals. The reduction in ethanol induced liver damage in macrophage-depleted mice and rats may be due to a reduction or elimination of the generation of various Kupffer-cell-derived hepatotoxic substances, including acetaldehyde and reactive oxygen radicals, in such animals. These data suggest that ethanol metabolism by tissue macrophages may play an important role in mediating ethanol-related tissue damage. PMID- 26735116 TI - Liver cirrhosis mortality trends in Eastern Europe, 1970-1989. Analyses of age, period and cohort effects and of latency with alcohol consumption. AB - There is evidence that in some Eastern European countries alcohol-related deaths have an important impact on mortality. In the whole European population increasing trends in mortality were observed until the second half of the 1970s, followed by a decline in the following decades. By contrast, in Eastern Europe continuously rising trends have been observed. The aim of the present study is to describe cirrhosis mortality trends in Eastern European countries between 1970 and 1989. This is a descriptive study in seven European countries, compared with Europe as a whole. A Poisson's log-linear age-period-cohort model is used to ascertain whether the recent trend in mortality represents a short-term fluctuation or an emerging long-term trend. In addition, changes in cirrhosis death rates were regressed onto changes in per capita alcohol consumption (1961 89) in order to evaluate the latency period between trends. The birth-cohort effects suggested that in Eastern Europe as a whole, and in particular in Hungary, Bulgaria and Romania, the mortality will probably increase in the next decade. Eastern European countries showed a latency period between trends in alcohol consumption and in mortality rates of many years, whereas in Europe as a whole the cirrhosis mortality rates were explained by their relationship with per capita alcohol consumption which lagged by only a few years. Further increases in cirrhosis mortality, and probably in other alcohol-related problems, are expected in several Eastern European countries. Epidemiological studies aimed to estimate the proportion of disease attributable to known risk factors of cirrhosis, and monitoring programmes of viral infections and of alcohol consumption and alcohol related problems, should be implemented to address the planning of public health programmes. PMID- 26735117 TI - Gastritis in the alcoholic: relationship to gastric alcohol metabolism and Helicobacter pylori. AB - Chronic gastritis is common in the alcoholic. It is characterized by histological inflammation of the gastric mucosa and is associated with variable symptomatology. Its etiology is still the subject of debate. Recently, a new alcohol dehydrogenase isoenzyme, called sigma ADH, absent from the liver but predominant in the upper GI tract, has been fully characterized, its gene cloned, and it appears to play a major role in gastric ethanol metabolism. Indeed, it has now been established, both in vivo in experimental animals and in vitro in cultured human gastric cells, that alcohol is metabolized in the gastric mucosa, resulting in the production of acetaldehyde, a toxic metabolite. In addition, Helicobacter pylori infection is common in the alcoholic, resulting in the breakdown of urea to ammonia, another toxic product. A number of studies carried out over the last 40 years revealed that antibiotic treatment eradicates ammonia production and results in histological and symptomatic improvement in the majority of patients with alcoholic gastritis. Non-invasive tests for the detection of H. pylori are now available which will facilitate the large scale studies needed to confirm whether, in H. pylori -positive patients, antibiotics should become routine treatment for alcoholic gastritis. PMID- 26735118 TI - Fos-like immunoreactivity in tyrosine hydroxylase and substance P-like immunoreactive neurones in guinea-pig brain following intracerebroventricular injection of morphine and U50,488H. AB - Opioid drugs such as morphine have powerful reinforcing effects which lead to drug-seeking behaviour. Both dopamine- and substance P-containing neurones have been implicated in reward. In the present study twocolour immunohistochemistry was used to investigate whether Fos protein was induced in dopaminergic (tyrosine hydroxylase) and substance P-containing neurones of guinea-pig brain following intracerebroventricular administration of the predominantly mu-receptor agonist, morphine, and the kappa-receptor agonist, U50,488H, which have been reported to produce rewarding and aversive effects, respectively. The present study has shown that of the large number of neurones showing Fos-like immunoreactivity following a single injection of morphine or U50,488H, few were tyrosine hydroxylase positive (dopaminergic) but a larger number were substance Plike immunoreactive. These results support the proposal that substance P plays a role in reward and reinforcement. PMID- 26735119 TI - Continuous cocaine treatment and monoamine transmission measured by microdialysis in the rat ventral tegmental area. AB - Rats were treated on a continuous cocaine administration schedule (85 mumol/kg/day s.c. by osmotic minipumps for 2 weeks followed by a 1-week drug-free period) that makes them tolerant to the locomotor-activating effect of cocaine. Subsequently, extracellular serotonin (5-HT) and dopamine (DA) were assayed in the ventral tegmental area (VTA) by microdialysis in the awake animal. Local infusion of the 5-HT 1A, B, D, 2, 6, 7 receptor antagonist methiothepin (50 muM for 3 hours) into the VTA caused a smaller increase in dialysate 5-HT in cocaine- than saline-pretreated rats (902+/-189 versus 1630+/-210%; area under the curve, p<0.02), whereas the increase in DA was small and unchanged (281+/-50 versus 290+/-76%; area under the curve, p=0.09). The results provide preliminary support for a cocaine-induced subsensitivity of 5-HT 1B autoreceptors in the VTA in agreement with our previous results obtained ex vivo. PMID- 26735120 TI - Effects of chronic inhalation of volatile solvents, malnutrition and their interaction on seizures induced by pentylenetetrazole in rats. AB - Chronic inhalation of volatile solvents induce severe brain damage. In humans, intense exposure to volatile solvents for recreational purposes is frequently associated with chronic malnutrition. We studied in rats the effects of chronic inhalation of volatile solvents and malnutrition, alone and combined, on the seizures induced by pentylenetetrazole. Animals were subjected to 14 months of either normal rodent diet or malnutrition induced by a diet based on corn derivatives; some animals were subjected for the last 4 months to daily inhalation of volatile solvents (paint thinner). Afterwards, a trial of pentylenetetrazole-induced seizures was conducted in all animals. When compared with controls, malnutrition, chronic inhalation of volatile solvents and their combination greatly reduced the threshold for both, the forebrain and the brain stem components of seizures. However, an expected lowering of the threshold when malnutrition and solvent inhalation were combined was not observed when compared with each condition alone. It is possible that malnutrition plus solvents exposure induce severe brain damage that interferes with the brain structures involved in the propagation of epileptic seizures. PMID- 26735121 TI - Effect of oral yohimbine on withdrawal jumping behaviour of morphine-dependent mice. AB - Acute administration of the alpha-2 adrenoceptor agonist clonidine and chronic administration of the alpha2 antagonist yohimbine both inhibit opioid withdrawal signs in experimental models of dependence and also in clinical studies with opiate abusers. There are exceptions to this general rule: restlessness or self reported abstinence in humans and withdrawal-induced escape behaviour in rodents are resistant to inhibition by acute clonidine. We have explored the effect of the alpha-2 antagonist yohimbine on morphine withdrawal-induced escape behaviour in a mouse model that we have proposed to differentiate between the urge to escape (number of jumps) and non-specific sedative/motor actions (height of jumps). Morphine dependence was induced by s.c. administration of a sustained release preparation (1 g/kg). Naloxone (1 mg/kg) was injected to precipitate withdrawal jumping 72 hours after morphine injection. Co-treatment with yohimbine dissolved in the tap water (70 mg/l) decreased the number of jumps upon naloxone challenge, an effect which did not seem to be related with a sedative or toxic effect of the drug. This result confirms previous data and suggests that yohimbine could prevent the development of opioid dependence being active to decrease withdrawal-induced escape behaviour. The mechanisms of this action are discussed. PMID- 26735122 TI - Biochemical and genetic studies of Caucasian subjects with ethanol-induced flushing reaction. AB - The prevalence of ethanol-induced flushing was investigated in three different Caucasian student populations, namely Irish, Belgian and English. Approximately 45% of all female subjects reported a flushing reaction, while 33%, 17% and 9%, respectively, of male students reported this reaction. There was a high familial incidence of flushing in all groups, suggesting that a specific gene defect might be involved. Our previous investigations had inferred normal ALDH2 in such affected individuals, but low activities of erythrocyte ALDH1.(1) Since the principal role of this cytosolic enzyme may be in the metabolism of biogenic amines, serotonin levels in platelet-rich plasma and urinary adrenaline, noradrenaline and dopamine were assayed in affected individuals after an oral ethanol challenge. No consistent pattern was evident for any of these parameters in any of the subjects at the time intervals investigated. Genotyping for ADH31 and ADH32 showed a higher frequency for ADH3(1) , 58%, than ADH3(2) , 42%. This is comparable to the Caucasian controls and to our previously published data. PMID- 26735123 TI - Additional evidence for an association between the dopamine D4 receptor (D4DR) exon III seven-repeat allele and substance abuse in opioid dependent subjects: relationship of treatment retention to genotype and personality. AB - The long form of the dopamine D4 receptor (D4DR) exon III repeat polymorphism has been linked in some but not all studies to impulsive, extravagant and novelty seeking personality traits that are prominent in affiliated behaviours such as attention deficit disorder and substance abuse. In particular, we have reported previously an increased frequency of the long seven-repeat D4DR exon III allele in a group of 141 opioiddependent subjects compared to 110 control subjects. In order to further substantiate the role of D4DR in contributing to heroin addiction we have genotyped an additional, smaller cohort of opioid-dependent subjects. In this new group of 57 opioid-dependent subjects compared to an expanded group of 143 control subjects a significant difference was observed in overall genotype frequency (p=0.04). An excess of the seven-repeat allele of the D4DR receptor gene was also observed compared to control subjects (p=0.06). The frequency of the seven-repeat allele is 15.8% in the heroin addict population vs. 8.1% in the control group, conferring a relative risk of 2.07 (95% CI: 0.98 4.38). An association between two polymorphisms considered together (D4DR and dopamine D3 receptor) and treatment retention was observed (p=0.02). In a subgroup of 38 opioid-dependent subjects, who were successfully administered the TPQ, higher Harm Avoidance (p< 0.001) and Novelty Seeking (NS3; extravagant vs. reserved, p< 0.001) scores were found. In contrast to some previous reports, no relationship was apparent between TPQ scores and treatment retention in this small group of opioid-dependent subjects. PMID- 26735124 TI - Nicotine dependency of a girl at the age of 18 months. AB - This case report describes severe nicotine dependency developing at the age of 18 months. Familial, genetic, biological aspects of the case and the therapeutic strategy are discussed. PMID- 26735125 TI - Binding of Lipopolysaccharide and Cholesterol-Modified Gelatin on Supported Lipid Bilayers: Effect of Bilayer Area Confinement and Bilayer Edge Tension. AB - Binding of amphiphilic molecules to supported lipid bilayers (SLBs) often results in lipid fibril extension from the SLBs. Previous studies proposed that amphiphiles with large and flexible hydrophilic regions trigger lipid fibril formation in SLBs by inducing membrane curvature via their hydrophilic regions. However, no experimental studies have verified this mechanism of fibril formation. In this work, we investigated the binding of lipopolysaccharide (LPS) and cholesterol-modified gelatin to SLBs using fluorescence microscopy. SLBs with restricted and unrestricted bilayer areas were employed to identify the mechanism of fibril generation. We show that the main cause of lipid fibril formation is an approximately 20% expansion in the bilayer area rather than increased membrane curvature. The data indicate that bilayer area confinement plays a critical role in morphological changes of SLBs even when bound amphiphilic molecules have a large hydrophilic domain. We also show that bilayer area change after LPS insertion is dependent on the patch shape of the SLB. When an SLB patch consists of a broad bilayer segment connected to a long thin streak, bilayer area expansion mainly occurs within the bilayer streak. The results indicate that LPS insertion causes net lipid flow from the broad bilayer region to the streak area. The differential increase in area is explained by the instability of planar bilayer streaks that originate from the large energetic contribution of line tension arising along the bilayer edge. PMID- 26735126 TI - Light-emitting diodes in photodynamic therapy in non-melanoma skin cancers--own observations and literature review. AB - Photodynamic therapy (PDT) employs light activation of tissue-localized photosensitizer in an oxygen-dependent process which initiates oxidative stress, inflammation, and cell death. There are many indications for PDT, although the main ones are still non-melanoma skin cancers. The light sources used include coherent and non-coherent ones, but we would like to focus on the use of light emitting diodes (LED) in PDT. We present four patients with skin lesions successfully treated with LED-based photodynamic therapy. The main advantage of that source is narrow emission spectrum that can correspond well with maximum absorption photosensitizers. Also, using LED source seems to be cheaper and simpler, and the field of irradiation is larger. The data showed good clinical and cosmetic outcome of LED-based PDT in actinic keratosis, basal cell carcinoma, and Bowen's disease. Since these diseases often appear on sun-exposed skin, aesthetic results are very important. The effect of LED treatment is as good or in some data even better than those in older types of PDT. PMID- 26735127 TI - Skeletally Diverse Synthesis of Indole-Fused Diazocine and Diazepine Frameworks by One-Pot, Two-Component Cascade Reaction. AB - An expeditious and novel strategy has been explored for the synthesis of structurally diverse indole-fused diazocine and diazepine derivatives. A substrate-based diversification approach of methyl-3-aminoindole/indoline benzoates coupled with the Pictet-Spengler reaction and three different reaction cascades furnished indolodiazepine and indoloquinoxalines. The formation of indolodiazocines proceeds through an initial condensation followed by intramolecular alkylation. PMID- 26735128 TI - Using Species Distribution Models to Predict Potential Landscape Restoration Effects on Puma Conservation. AB - A mosaic of intact native and human-modified vegetation use can provide important habitat for top predators such as the puma (Puma concolor), avoiding negative effects on other species and ecological processes due to cascade trophic interactions. This study investigates the effects of restoration scenarios on the puma's habitat suitability in the most developed Brazilian region (Sao Paulo State). Species Distribution Models incorporating restoration scenarios were developed using the species' occurrence information to (1) map habitat suitability of pumas in Sao Paulo State, Southeast, Brazil; (2) test the relative contribution of environmental variables ecologically relevant to the species habitat suitability and (3) project the predicted habitat suitability to future native vegetation restoration scenarios. The Maximum Entropy algorithm was used (Test AUC of 0.84 +/- 0.0228) based on seven environmental non-correlated variables and non-autocorrelated presence-only records (n = 342). The percentage of native vegetation (positive influence), elevation (positive influence) and density of roads (negative influence) were considered the most important environmental variables to the model. Model projections to restoration scenarios reflected the high positive relationship between pumas and native vegetation. These projections identified new high suitability areas for pumas (probability of presence >0.5) in highly deforested regions. High suitability areas were increased from 5.3% to 8.5% of the total State extension when the landscapes were restored for >= the minimum native vegetation cover rule (20%) established by the Brazilian Forest Code in private lands. This study highlights the importance of a landscape planning approach to improve the conservation outlook for pumas and other species, including not only the establishment and management of protected areas, but also the habitat restoration on private lands. Importantly, the results may inform environmental policies and land use planning in Sao Paulo State, Brazil. PMID- 26735131 TI - Identifying Centres of Plant Biodiversity in South Australia. AB - We aimed to identify regional centres of plant biodiversity in South Australia, a sub-continental land area of 983,482 km2, by mapping a suite of metrics. Broad brush conservation issues associated with the centres were mapped, specifically climate sensitivity, exposure to habitat fragmentation, introduced species and altered fire regimes. We compiled 727,417 plant species records from plot-based field surveys and herbarium records and mapped the following: species richness (all species; South Australian endemics; conservation-dependent species; introduced species); georeferenced weighted endemism, phylogenetic diversity, georeferenced phylogenetic endemism; and measures of beta diversity at local and state-wide scales. Associated conservation issues mapped were: climate sensitivity measured via ordination and non-linear modelling; habitat fragmentation represented by the proportion of remnant vegetation within a moving window; fire prone landscapes assessed using fire history records; invasive species assessed through diversity metrics, species distribution and literature. Compared to plots, herbarium data had higher spatial and taxonomic coverage but records were more biased towards major transport corridors. Beta diversity was influenced by sampling intensity and scale of comparison. We identified six centres of high plant biodiversity for South Australia: Western Kangaroo Island; Southern Mount Lofty Ranges; Anangu Pitjantjatjara Yankunytjatjara lands; Southern Flinders Ranges; Southern Eyre Peninsula; Lower South East. Species composition in the arid-mediterranean ecotone was the most climate sensitive. Fragmentation mapping highlighted the dichotomy between extensive land-use and high remnancy in the north and intensive land-use and low remnancy in the south. Invasive species were most species rich in agricultural areas close to population centres. Fire mapping revealed large variation in frequency across the state. Biodiversity scores were not always congruent between metrics or datasets, notably for categorical endemism to South Australia versus georeferenced weighted endemism, justifying diverse approaches and cautious interpretation. The study could be extended to high resolution assessments of biodiversity centres and cost:benefit analysis for interventions. PMID- 26735130 TI - Evaluation of Infectivity, Virulence and Transmission of FDMV Field Strains of Serotypes O and A Isolated In 2010 from Outbreaks in the Republic of Korea. AB - Since the early 2000s outbreaks of foot-and-mouth disease (FMD) have been described in several previously FMD-free Asian nations, including the Republic of Korea (South Korea). One outbreak with FMD virus (FDMV) serotype A and two with serotype O occurred in South Korea in 2010/2011. The causative viruses belonged to lineages that had been spreading in South East Asia, far East and East Asia since 2009 and presented a great threat to the countries in that region. Most FMDV strains infect ruminants and pigs, as it happened during the outbreaks of FMDV serotype O in South Korea. Contrastingly, the strain of serotype A affected only ruminants. Based upon these findings, the intention of the work described in the current report was to characterize and compare the infectivity, virulence and transmission of both strains under laboratory conditions in cattle and pigs, by direct inoculation and contact exposure. As expected, FMDV serotype O was highly virulent in both cattle and swine by contact exposure and direct inoculation. Surprisingly, FMDV serotype A was highly virulent in swine, but was less infectious in cattle by contact exposure to infected swine or cattle. Interestingly, similar quantities of aerosolized FMDV RNA were detected during experiments with viruses of serotypes O and A. Specific virus-host interaction of A/SKR/2010 could affect the transmission of this strain to cattle, and this may explain in part the limited spread of the serotype A epizootic. PMID- 26735129 TI - MicroRNA Profiles in Spontaneous Decidualized Menstrual Endometrium and Early Pregnancy Decidua with Successfully Implanted Embryos. AB - To comparatively analyze the human microRNA (miRNA) profiles between spontaneous decidualized menstrual endometrium and early pregnancy decidua by an in-depth sequencing of miRNAs. The specific miRNAs expressed at conception might be involved in pregnancy establishment and expression of let-7f-5p and let-7g-5p was experimentally up-regulated or inhibited to assess the effect on the expression of IGF2BP-1 and IGF2R in vitro, respectively. Samples of endometria and deciduas were obtained from 25 women who suffered from tubal or male factor subfertility and from 35 early pregnant women who underwent pregnancy termination at 6-8 weeks gestation were irrespectively collected and comparatively analyzed by miRNA sequencing and differential expression of known and novel miRNAs was analyzed using bioinformatics. The 2042 miRNA expression was analyzed in the study and the differential expression of six miRNAs was validated by qRT-PCR. The expression of four miRNAs in decidua samples was down-regulated (miR-34c, miR-92a, miR-181a-5p, and miR-191), whereas the expression of miR-10a-5p and let-7f-5p was significantly up-regulated. The expression of IGF2BP-1 and IGF2R declined and increased with overexpression and inhibition of let-7f-5p and let-7g-5p, respectively. Changes in the expression of particular miRNAs might play a role in the physiology of decidualization following successful embryo implantation, ultimately resulting in continuous decidualization. PMID- 26735132 TI - Follow-up of Thalidomide treatment in patients with Hereditary Haemorrhagic Telangiectasia. AB - BACKGROUND: Patients with a hereditary vascular disorder called Rendu-Osler-Weber syndrome (Hereditary Haemorrhagic Telangiectasia, HHT) haemorrhage easily due to weak-walled vessels. Haemorrhage in lungs or brain can be fatal but patients suffer most from chronic and prolonged nosebleeds (epistaxis), the frequency and intensity of which increases with age. Several years ago, it was discovered serendipitously that the drug Thalidomide had beneficial effects on the disease symptoms in several of a small group of HHT patients: epistaxis and the incidence of anaemia were reduced and patients required fewer blood transfusions. In addition, they reported a better quality of life. However, Thalidomide has significant negative side effects, including neuropathy and fatigue. METHODS: We followed up all HHT patients in the Netherlands who had been taking Thalidomide at the time the original study was completed to find out (i) how many had continued taking Thalidomide and for how long (ii) the nature and severity of any side-effects and (iii) whether side-effects had influenced their decision to continue taking Thalidomide. RESULTS: Only a minority of patients had continued taking the drug despite its beneficial effects on their symptoms and that the side effects were the primary reason to stop. CONCLUSION: Despite symptom reduction, alternative treatments are still necessary for epistaxis in HHT patients and a large-scale clinical trial is not justified although incidental use in the most severely affected patients can be considered. PMID- 26735133 TI - A brain-lesion pattern based algorithm for the diagnosis of posttraumatic olfactory loss. AB - BACKGROUND: Brain areas processing olfactory information exhibit functionally relevant morphological dynamics. This suggests the exploitation of anatomical information in the diagnosis of an olfactory dysfunction. Following previous identifications of olfactory eloquent areas such as the olfactory bulbs and tracts, we focused at a brain-morphology based algorithm for establishing the diagnosis of olfactory loss following brain injury. METHODOLOGY: Forty-one patients with a history of head trauma dated back 40 +/- 39 months, and additional 23 patients without head trauma, were assessed for damages in 11 olfaction-relevant brain areas using magnetic resonance imaging (MRI). Olfactory function was derived from the use of a standardized, reliable and validated olfactory test. An olfactory diagnostic algorithm was derived following classification and regression tree analysis of the brain lesion pattern. RESULTS: Subjects were assigned to olfactory diagnoses of anosmia, hyposmia or normosmia. These diagnoses were predictable at an accuracy of 62.3 % from the degree of damage in the olfactory bulb and in the left temporal lobe pole. The main diagnosis algorithm addressed the presence of anosmia, which could be predicted from the degree of damage in these brain areas at an accuracy of 81.3 %. CONCLUSIONS: We independently reproduced previously identified brain regions in which morphological damage is associated with olfactory loss. Based on this reproduction, an algorithm was developed for the diagnosis of anosmia from central-nervous damage. Thus, we introduce a morphological component to the olfactory diagnosis that specifically addresses clinical cases of olfactory loss following head trauma. PMID- 26735134 TI - Social Patterning in Adiposity in Adolescence: Prospective Observations from the Chinese Birth Cohort ''Children of 1997''. AB - INTRODUCTION: Low early life socio-economic position is more strongly associated with adiposity among women than men. We examined whether the sex difference of social patterning in general and central adiposity exists before adulthood. METHODS: In Hong Kong's "Children of 1997" birth cohort, we used multivariable regression to examine the association of parental education, a marker of early life socio-economic position, with body mass index (BMI) (n = 7252, 88% follow up) and waist-height ratio (n = 5636, 68% follow-up), at 14 years. RESULTS: Parental education of Grade 9 or below, compared to Grade 12 or above, was associated with higher waist-height ratio z-score particularly in girls (0.30, 95% confidence interval (CI) 0.19, 0.41) compared to boys (0.12, 95% CI 0.02, 0.22) (p for sex interaction = 0.02). Lower parental education was associated with greater BMI z-score in adolescents of locally born mothers, but not adolescents of migrant mothers, with no difference by sex. CONCLUSIONS: Different social patterning in different markers of adiposity may imply different sociological and biological mediating pathways. A stronger association between low early life socio-economic position and waist-height ratio in adolescent girls may indicate sex-specific influences of SEP related early life exposures on central adiposity. PMID- 26735137 TI - Characterization of RyDEN (C19orf66) as an Interferon-Stimulated Cellular Inhibitor against Dengue Virus Replication. AB - Dengue virus (DENV) is one of the most important arthropod-borne pathogens that cause life-threatening diseases in humans. However, no vaccine or specific antiviral is available for dengue. As seen in other RNA viruses, the innate immune system plays a key role in controlling DENV infection and disease outcome. Although the interferon (IFN) response, which is central to host protective immunity, has been reported to limit DENV replication, the molecular details of how DENV infection is modulated by IFN treatment are elusive. In this study, by employing a gain-of-function screen using a type I IFN-treated cell-derived cDNA library, we identified a previously uncharacterized gene, C19orf66, as an IFN stimulated gene (ISG) that inhibits DENV replication, which we named Repressor of yield of DENV (RyDEN). Overexpression and gene knockdown experiments revealed that expression of RyDEN confers resistance to all serotypes of DENV in human cells. RyDEN expression also limited the replication of hepatitis C virus, Kunjin virus, Chikungunya virus, herpes simplex virus type 1, and human adenovirus. Importantly, RyDEN was considered to be a crucial effector molecule in the IFN mediated anti-DENV response. When affinity purification-mass spectrometry analysis was performed, RyDEN was revealed to form a complex with cellular mRNA binding proteins, poly(A)-binding protein cytoplasmic 1 (PABPC1), and La motif related protein 1 (LARP1). Interestingly, PABPC1 and LARP1 were found to be positive modulators of DENV replication. Since RyDEN influenced intracellular events on DENV replication and, suppression of protein synthesis from DENV-based reporter construct RNA was also observed in RyDEN-expressing cells, our data suggest that RyDEN is likely to interfere with the translation of DENV via interaction with viral RNA and cellular mRNA-binding proteins, resulting in the inhibition of virus replication in infected cells. PMID- 26735135 TI - Residual Viremia in Treated HIV+ Individuals. AB - Antiretroviral therapy (ART) effectively controls HIV infection, suppressing HIV viral loads. However, some residual virus remains, below the level of detection, in HIV-infected patients on ART. The source of this viremia is an area of debate: does it derive primarily from activation of infected cells in the latent reservoir, or from ongoing viral replication? Observations seem to be contradictory: there is evidence of short term evolution, implying that there must be ongoing viral replication, and viral strains should thus evolve. However, phylogenetic analyses, and rare emergent drug resistance, suggest no long-term viral evolution, implying that virus derived from activated latent cells must dominate. We use simple deterministic and stochastic models to gain insight into residual viremia dynamics in HIV-infected patients. Our modeling relies on two underlying assumptions for patients on suppressive ART: that latent cell activation drives viral dynamics and that the reproductive ratio of treated infection is less than 1. Nonetheless, the contribution of viral replication to residual viremia in patients on ART may be non-negligible. However, even if the portion of viremia attributable to viral replication is significant, our model predicts (1) that latent reservoir re-seeding remains negligible, and (2) some short-term viral evolution is permitted, but long-term evolution can still be limited: stochastic analysis of our model shows that de novo emergence of drug resistance is rare. Thus, our simple models reconcile the seemingly contradictory observations on residual viremia and, with relatively few parameters, recapitulates HIV viral dynamics observed in patients on suppressive therapy. PMID- 26735138 TI - A Highly-Efficient Implementation of the Doktorov Recurrence Equations for Franck Condon Calculations. AB - In this paper, a new algorithm for computing Franck-Condon overlaps using the Doktorov recurrence equations is proposed. One of the major computational stresses of using the recurrence equations arises from searching data structures for overlaps that are stored in memory. The proposed algorithm alleviates this problem by tracking, throughout the algorithm, the locations in memory of overlaps that are required to use the recurrence relations. The tracking procedure helps to significantly reduce the run time of the algorithm compared to existing implementations. PMID- 26735140 TI - A mechanistic model for hydrogen activation, spillover, and its chemical reaction in a zeolite-encapsulated Pt catalyst. AB - The hydrogen (H) spillover phenomenon has attracted considerable attention in the catalysis field. Many researchers have focused on the phenomenon itself, as well as its applications for advanced catalytic systems. In particular, H spillover on non-reducible materials, such as alumina, silica, and zeolites, is a controversial issue owing to the lack of understanding regarding its mechanistic properties. In this study, we use density functional theory calculations to propose the entire mechanism of H spillover from H2 activation on a platinum to its participation in chemical reactions on the external surface of a zeolite. We determined that surface hydroxyl groups of the zeolites, such as Bronsted acid sites, play a role in initiating H spillover, and the Lewis acid sites facilitate the entire process by allowing H to be transferred as a H(+)/e(-) charge pair, as well as providing good binding sites for organic reactants. Theoretical results explain the key experimental features, and we expect that this work will help to elucidate the H spillover phenomenon on non-reducible support materials and to utilize it for catalytic systems. PMID- 26735139 TI - An Automated Summarization Assessment Algorithm for Identifying Summarizing Strategies. AB - BACKGROUND: Summarization is a process to select important information from a source text. Summarizing strategies are the core cognitive processes in summarization activity. Since summarization can be important as a tool to improve comprehension, it has attracted interest of teachers for teaching summary writing through direct instruction. To do this, they need to review and assess the students' summaries and these tasks are very time-consuming. Thus, a computer assisted assessment can be used to help teachers to conduct this task more effectively. DESIGN/RESULTS: This paper aims to propose an algorithm based on the combination of semantic relations between words and their syntactic composition to identify summarizing strategies employed by students in summary writing. An innovative aspect of our algorithm lies in its ability to identify summarizing strategies at the syntactic and semantic levels. The efficiency of the algorithm is measured in terms of Precision, Recall and F-measure. We then implemented the algorithm for the automated summarization assessment system that can be used to identify the summarizing strategies used by students in summary writing. PMID- 26735144 TI - Acute Stroke Syndromes with Isolated Hypoperfusion on MRI - A Clinical and MRI Study. AB - BACKGROUND: Acute stroke syndromes with negative diffusion-weighted imaging (DWI) but extensive perfusion deficits are rare and constitute a diagnostic challenge due to different operational definitions of penumbral hypoperfusion in acute stroke patients based on MRI criteria. METHODS: MR profiles of 19 patients presenting with acute stroke syndromes with negative DWI in the presence of an extensive area of hypoperfusion on time-to-peak (TTP) maps of dynamic susceptibility contrast perfusion-weighted imaging (PWI) were analysed. DWI and PWI lesions were quantified and interpreted with regard to the clinical course. RESULTS: Despite the large area of abnormal perfusion on TTP maps, the clinical course was benign (median National Institute of Health Stroke Scale 2 at admission, 0 at discharge). The volume of hypoperfused tissue was significantly smaller on postprocessed TTP maps with a TTP delay of >4 s than on unprocessed TTP maps with manual contrast adjustment. Semiquantitatively assessed TTP lesion volume was associated with the presence of DWI lesions on follow-up. CONCLUSION: TTP maps are highly sensitive to demonstrate even small-scale perfusion abnormalities. The additional information from TTP delay thresholds indicates critically reduced perfusion and appears to be a good prognostic indicator in combination with MR angiography and symptomatology. PMID- 26735143 TI - Effect of Metalation on Porphyrin-Based Bifunctional Agents in Tumor Imaging and Photodynamic Therapy. AB - Herein we report the syntheses and comparative photophysical, electrochemical, in vitro, and in vivo biological efficacy of 3-(1'-hexyloxy)ethyl-3 devinylpyropheophorbide-cyanine dye (HPPH-CD) and the corresponding indium (In), gallium (Ga), and palladium (Pd) conjugates. The insertion of a heavy metal in the HPPH moiety makes a significant difference in FRET (Forster resonance energy transfer) and electrochemical properties, which correlates with singlet oxygen production [a key cytotoxic agent for photodynamic therapy (PDT)] and long-term in vivo PDT efficacy. Among the metalated analogs, the In(III) HPPH-CD showed the best cancer imaging and PDT efficacy. Interestingly, in contrast to free base HPPH-CD, which requires a significantly higher therapeutic dose (2.5 MUmol/kg) than imaging dose (0.3 MUmol/kg), the corresponding In(III) HPPH-CD showed excellent imaging and therapeutic potential at a remarkably low dose (0.3 MUmol/kg) in BALB/c mice bearing Colon26 tumors. A comparative study of metalated and corresponding nonmetalated conjugates further confirmed that STAT-3 dimerization can be used as a biomarker for determining the level of photoreaction and tumor response. PMID- 26735142 TI - First Evidence of a Hybrid of Leishmania (Viannia) braziliensis/L. (V.) peruviana DNA Detected from the Phlebotomine Sand Fly Lutzomyia tejadai in Peru. AB - The natural infection of sand flies by Leishmania was examined in the Department of Huanuco of Peru, where cutaneous leishmaniasis caused by a hybrid of Leishmania (Viannia) braziliensis/L. (V.) peruviana is endemic. A total of 2,997 female sand flies were captured by CDC light traps and Shannon traps, of which 2,931 and 66 flies were identified as Lutzomyia tejadai and Lu fischeri, respectively. Using crude DNA extracted from individual sand flies as a template, Leishmania DNA was detected from one Lu. tejadai. The parasite species was identified as a hybrid of L. (V.) braziliensis/L. (V.) peruviana on the basis of cytochrome b and mannose phosphate isomerase gene analyses. The result suggested that Lu. tejadai is responsible for the transmission of the hybrid Leishmania circulating in this area. PMID- 26735145 TI - Spectrum of manifestations of monoclonal gammopathy-associated renal lesions. AB - PURPOSE OF REVIEW: Monoclonal gammopathies result from an overt malignant process, such as multiple myeloma, or a premalignant process, such as monoclonal gammopathy of undetermined significance. The kidney is often affected in the setting of a monoclonal gammopathy. The term 'monoclonal gammopathy of renal significance (MGRS)' was recently introduced to draw attention to renal diseases related to the monoclonal gammopathy. In this review, we define the pathology of these monoclonal gammopathy-associated kidney diseases. RECENT FINDINGS: Renal disease can be caused by deposition of the monoclonal immunoglobulin (direct mechanism) or by activation of the alternative pathway of complement by the monoclonal immunoglobulin (indirect mechanism). The deposition of monoclonal immunoglobulin can affect the glomeruli, tubules, and the interstitium and vessels. The glomerular diseases include proliferative glomerulonephritis with monoclonal immunoglobulin deposits, immunotactoid glomerulopathy, and, less commonly, fibrillary glomerulonephritis. Tubular lesions associated with monoclonal immunoglobulin include cast nephropathy and light-chain proximal tubulopathy. Lesions involving the glomeruli, tubules, interstitium or vessels include amyloidosis and monoclonal immunoglobulin deposition diseases. Rarely, monoclonal immunoglobulin may also cause C3 glomerulopathy or atypical hemolytic uremic syndrome by interfering with the regulation of the alternative pathway of complement. SUMMARY: Monoclonal gammopathy are associated with a variety of kidney diseases. The monoclonal gammopathy-associated renal diseases are distinct in their pathogenesis, kidney biopsy findings, clinical presentation, progression, prognosis, and treatment. The term monoclonal gammopathy of renal significance helps highlight patients who have renal disease secondary to monoclonal immunoglobulin secreted by a premalignant or malignant clone, but is not a disease or diagnosis in itself. PMID- 26735141 TI - An open-label phase 2 study of glycogen synthase kinase-3 inhibitor LY2090314 in patients with acute leukemia. AB - This open-label, Phase-2 study investigated the safety of LY2090314 (GSK-3 inhibitor) in AML patients. Twenty patients received 40-mg LY2090314 (50-mg ranitidine pretreatment) as follows: Cohort 1 - days 1, 8, and 15 of a 28-d cycle (n = 7); Cohort 2 - days 1, 5, and 9 of a 21-d cycle (n = 6); Cohort 3 - days 1, 5, 9, and 12 of a 21-d cycle (n = 7). Decreased appetite (n = 7) and nausea (n = 4) were the most frequently reported possibly drug-related non-hematologic treatment-emergent adverse events (TEAEs). Hematologic TEAEs included febrile neutropenia (n = 2), thrombocytopenia (n = 1), and anemia (n = 1). Atrial flutter (n = 1), QT interval prolongation (n = 3), and visual disturbances (n = 2) were observed, but were not clinically significant (investigator assessed). Although beta-catenin levels indicated an on-target effect, no complete or partial remissions were observed. Pharmacokinetics were consistent with a previous Phase 1 study. These data suggest that single-agent LY2090314 has acceptable safety but limited clinical benefit in AML patients at the dose/frequencies investigated. PMID- 26735146 TI - Complications and management of hyponatremia. AB - PURPOSE OF REVIEW: Hyponatremia causes significant morbidity, mortality, and disability. This review considers the literature of the past 18 months to improve understanding of these complications and to identify therapeutic strategies to prevent them. RECENT FINDINGS: Acute hyponatremia causes serious brain swelling that can lead to permanent disability or death. A 4-6 mEq/l increase in serum sodium is sufficient to reverse impending herniation. Brain swelling is minimal in chronic hyponatremia, and to avoid osmotic demyelination, correction should not exceed 8 mEq/l/day. In high-risk patients, correction should not exceed 4-6 mEq/l/day. Inadvertent overcorrection of hyponatremia is common and preventable by controlling unwanted urinary water losses with desmopressin. Even mild chronic hyponatremia is associated with increased mortality, attention deficit, gait instability, osteoporosis, and fractures, but it is not known if the correction of mild hyponatremia improves outcomes. SUMMARY: Controlled trials are needed to identify affordable treatments for hyponatremia that reduce the need for hospitalization, decrease hospital length of stay, and decrease morbidity. Such trials could also help answer the question of whether hyponatremia causes excess mortality or whether it is simply a marker for severe, lethal, underlying disease. PMID- 26735147 TI - HPV-Associated Atypical Mitotic Figures in Squamous Intraepithelial Lesions of the Lower Female Genital Tract. AB - OBJECTIVES: Atypical mitoses with rod and dot-shaped extra pieces of chromosomes separate to the main spindle are commonly seen in HPV-associated intraepithelial lesions. To determine the reproducibility and correlation of HPV-associated atypical mitoses (HAM) with histological diagnosis and p16 status, we performed a retrospective study. METHODS: A total of 100 consecutive cervical biopsies, 10 vulvar HSIL (usual VIN), 10 differentiated VIN, 10 vulvar condylomata, 5 normal proliferative endometrial, and 5 normal ovarian follicles were assessed. The first 10 mitoses were examined in the cervical biopsies, and the case recorded as positive when one HAM was identified. The first 50 mitoses in the vulvar cases and controls were examined, and the percentage of HAM was calculated. RESULTS: HAM were found in 62.5% of HSIL, 14.7% of LSIL, and 0% of benign cervical biopsies. When p16 was positive, 62.7% showed HAM, and when p16 was negative, 12.5% showed HAM. HAM were commonly found in vulvar HSIL, 12% of all mitoses, but extra dots of chromosome were also occasionally found in the mitoses of differentiated VIN (1%) and rarely in normal controls (0.2%). No HAM were found in condylomata. CONCLUSIONS: HAM was useful to confirm SIL, but the incidence was too low for absence to exclude SIL. Although HAM are more common in HSIL, they cannot be relied upon to distinguish HSIL from LSIL. The dot form of HAM is less reliable than the rod form, as extra dots of chromosomes may be occasionally seen in differentiated VIN and rarely seen in normal proliferative endometrium. PMID- 26735148 TI - Barriers to Cervical Cancer Screening in Geneva (DEPIST Study). AB - OBJECTIVES: Cervical screening is only efficient if a large part of eligible women participate. Our aim was to identify sociodemographic barriers to cervical screening and consider self-reported reasons to postpone screening. METHODS: Between September 2011 and June 2015, a questionnaire addressing reasons for nonparticipation in cervical screening was completed by 556 women who had not undergone a Pap test in the preceding 3 years. Pearson chi test was used to analyze differences between subgroups. Logistic regression was used to explore the association between sociodemographic characteristics and reasons for nonparticipation. RESULTS: The main reasons for nonparticipation in cervical cancer screening were practical barriers, such as lack of time and the cost of screening. These barriers were more likely to be reported by working women, women who were not sexually active, and those without health insurance. Younger women, non-European women living in Switzerland, and childless women were more likely to have never participated in a screening program before (adjusted odds ratio [aOR], 3.15; 95% CI, 1.41-6.98; aOR, 2.76; 95% CI, 1.48-5.16; aOR, 1.74; 95% CI, 1.03 2.99, respectively). CONCLUSIONS: Practical considerations seem to play a more important role in screening participation than emotional reasons and other beliefs. Particular attention should be paid to immigrant communities, where women seem more likely to skip cervical screening. PMID- 26735149 TI - A Cross-Sectional Study of Human Papillomavirus Vaccine Utilization Among University Women: The Role of Ethnicity, Race, and Risk Factors. AB - OBJECTIVE: We estimated the prevalence of human papillomavirus (HPV) vaccination by ethnicity and race and compared vaccination use by known risk factors. MATERIALS AND METHODS: We applied a cross-sectional design using an anonymous, online survey distributed in 2011 to female undergraduates (n = 284) between the ages of 18 and 26 years. The study was approved by the University of Arizona Institutional Review Board. RESULTS: Overall, 55% of women reported receiving the HPV vaccine. Within racial and ethnic groups, HPV vaccination was highest among American Indian/Alaska Native women with 71%, followed by Hispanic women with 68%, black/African American women with 58%, white women with 51%, and Asian/Pacific Island women with 31%. Moreover, Hispanic women were twice as likely to be vaccinated compared with white women (OR = 2.08; 95% CI = 1.14 3.78). Among unvaccinated women, 55% had discussed HPV with a provider and 56% had reported no concerns about the vaccine and/or had high levels of HPV knowledge. CONCLUSIONS: Human papillomavirus vaccine is highly acceptable among college women, particularly among Hispanic women. Efforts to vaccinate should include time of college enrollment. Such efforts are critical for the large scale prevention of cervical cancer and its precursor lesions and ultimately for preventable cervical cancer mortality. PMID- 26735150 TI - Vaginal Stenosis After Gonadotropin-Releasing Hormone Agonist Therapy During Treatment for Acute Lymphoblastic Leukemia. AB - A 26-year-old patient with a history of chemotherapy for acute lymphoblastic leukemia presented with secondary amenorrhea and cyclic abdominal pain, and she was found to have vaginal stenosis due to adhesion of vaginal wall. The cause of the adhesion was considered to be vaginal inflammation induced by anticancer agents themselves. It was also considered that poor estrogenization of vaginal mucosa as a result of gonadotropin-releasing hormone agonist therapy, conducted for ovarian protection during chemotherapy, might have exacerbated it. Because it is more likely than ever for us to encounter patients who will undertake or had undertaken chemotherapy with gonadotropin-releasing hormone agonist therapy, keen observation and proper intervention would be important. PMID- 26735151 TI - Monitoring of Lung Involvement in Rheumatologic Disease. AB - The monitoring of lung involvement in patients with connective tissue diseases is central to optimal long-term management and is directed towards: (a) the detection of supervening lung involvement not present at presentation and (b) the identification of disease progression in established lung disease. For both goals, accurate surveillance requires multi-disciplinary evaluation with the integration of symptomatic change, serial pulmonary function trends and imaging data. Evaluated in isolation, each of these monitoring domains has significant limitations. Symptomatic change may be confounded by a wide variety of systemic factors. Pulmonary function tests provide the most reliable data, but are limited by measurement variability, the heterogeneity of functional patterns and the confounding effects of non-pulmonary factors. Chest radiography is insensitive to change but may provide rapid confirmation of major disease progression or alert the clinician to respiratory co-morbidities. Although high-resolution computed tomography has a central role in assessing disease severity, it should be used very selectively as a monitoring tool due to the associated radiation burden. Ancillary tests include echocardiography and exercise testing to proactively identify cases of pulmonary hypertension and worsening of oxygenation. In summary, a multi-disciplinary approach is essential for the identification of disease progression and prompt treatment of comorbidities that severely impact on the morbidity and mortality of disease. PMID- 26735152 TI - Evidence Basis for Ultrasound Guidance for Lower-Extremity Peripheral Nerve Block: Update 2016. AB - This article reviews and summarizes randomized controlled studies that have investigated ultrasound guidance (USG) for lower-extremity peripheral nerve blocks in comparison with other peripheral nerve localization techniques and those that compared different ultrasound-guided techniques investigating optimal perineural local anesthetic distribution patterns.Thirty-four studies met the inclusion criteria (minimum Jadad score 3), and 10 additional studies directly compared USG with peripheral nerve stimulation, and 5 additional studies directly compared USG with landmark-based field blocks. Fourteen studies compared different local anesthetic distribution parameters.Analysis of the literature supports the use of USG for decreased block performance time, decreased block onset time, increased rate of complete sensory block, and increased analgesic efficacy. Ultrasound was never inferior to peripheral nerve stimulation. The research focus has evolved during the last 5 years into investigating optimal ultrasound-guided techniques. PMID- 26735153 TI - Accidental Dural Puncture Management: 10-Year Experience at an Academic Tertiary Care Center. AB - BACKGROUND AND OBJECTIVES: The use of spinal catheters for extended periods after accidental dural puncture (ADP) and administration of intrathecal saline via spinal catheters have been advocated to decrease the incidence of postdural puncture headache and the subsequent need for epidural blood patch (EBP), with mixed results observed. METHODS: We reviewed the medical records of 218 patients with ADP who either had the epidural resited or had a spinal catheter (with or without the administration of intrathecal saline). We compared the incidence of headache and the need for blood patch between these groups. We also assessed complications when a standard lidocaine epidural test dose was administered intrathecally and compared this with complications when a solution normally used for labor combined spinal epidurals was administered. RESULTS: There was no difference in the incidence of postdural puncture headache between the resited epidural group and the spinal catheter group, 68.0% versus 55.9% (odds ratio [OR], 1.7; 95% confidence interval [95% CI], 1.0-2.9; P = 0.07). Resiting the epidural catheter was associated with a significant increase in the number of EBPs when compared with using a spinal catheter, 52.0% versus 20.3% (OR, 4.2; 95% CI, 2.4-7.6; P < 0.001) and when compared with spinal catheters with intrathecal saline, 52.0% versus 8.1% (OR, 12.3; 95% CI, 4.3-35.4; P < 0.001). There was a significant difference in the number of blood patches between normal body mass index patients and morbidly obese patients, 55.2% versus 25.0% (OR, 3.7; 95% CI, 1.2-11.2; P = 0.02). Complications (hypotension prompting pressors, high spinal, and emergency cesarean delivery because of nonreassuring fetal status) occurred more frequently when a lidocaine test dose was immediately administered after ADP versus administering a labor combined spinal epidural solution. CONCLUSIONS: Insertion of spinal catheters after ADP and administration of intrathecal normal saline via spinal catheters reduce the need for EBP compared with resiting the epidural. Administration of the standard epidural test dose intrathecally is associated with frequent and significant complications. PMID- 26735156 TI - Acute Vision Loss Secondary to Epidural Blood Patch: Terson Syndrome. AB - BACKGROUND AND OBJECTIVES: Lumbar epidural blood patch (EBP) is a commonly used procedure to treat postdural puncture headache. We present a case of vision loss immediately following an EBP. CASE REPORT: A 49-year-old woman with idiopathic intracranial hypertension received an EBP for postdural puncture headache at an outside facility without fluoroscopic guidance and in the seated position. The patient experienced syncope during the procedure as 25 mL of autologous blood was rapidly injected. The patient regained consciousness and described bilateral vision loss. Brain magnetic resonance imaging was negative for hemorrhage. Dilated fundus examination revealed significant, bilateral retinal and vitreous hemorrhage consistent with Terson syndrome. CONCLUSIONS: This patient developed Terson syndrome as an immediate EBP complication. Iatrogenic Terson syndrome has been previously described with epidural space saline and anesthetic injections, but not EBP. Of 11 reported cases, 10 were female, and 9 had complete vision recovery. Previous studies have demonstrated that epidural space injection increases subarachnoid pressure in a volume- and rate-dependent fashion. An abrupt increase in subarachnoid space pressure likely led to retinal hemorrhage by compromising retinal venous drainage. This is the first known case of Terson syndrome caused by EBP. Injectate volume should be minimized, and a slow rate of injection pursued. The anesthesiologist, pain interventionist, and ophthalmologist should be aware of this rare but disabling complication and consider taking extra precautions when consenting patients for EBP with vision compromise or comorbidities concerning for elevated intracranial pressure. PMID- 26735155 TI - Combined Fascia Iliaca and Sciatic Nerve Block for Hip Surgery in the Presence of Severe Ankylosing Spondylitis: A Case-Based Literature Review. AB - BACKGROUND AND OBJECTIVES: Selecting an appropriate anesthetic technique for patients with ankylosing spondylitis undergoing hip surgery is challenging because of a potentially difficult airway, the risk of cardiovascular and respiratory complications, and the technical difficulty of performing central neuraxial blocks in patients with ankylosing spondylitis. Our objective was to report a case in which combination neural blockade was used successfully in an elderly patient with ankylosing spondylitis undergoing hip fracture surgery. In addition, a literature review of the anesthetic techniques reported for these patients was conducted. CASE REPORT: A 70-year-old man with severe ankylosing spondylitis and respiratory dysfunction was scheduled for a closed intertrochanteric fracture reduction and internal fixation. Combined fascia iliaca block and parasacral sciatic nerve block were used successfully for the surgery. Postoperative analgesia was accomplished by continuous fascia iliaca block. CONCLUSIONS: According to the literature review, general anesthesia is the most commonly performed anesthetic technique for patients with ankylosing spondylitis undergoing hip surgeries. Special intubation techniques and cautious airway management were very important for these patients. Although both general anesthesia and central neuraxial blockade pose considerable risks to the patients, this case report suggests that combined fascia iliaca block and sciatic nerve block might be a promising option. PMID- 26735154 TI - Quadratus Lumborum Block: Analgesic Effects and Chronological Ropivacaine Concentrations After Laparoscopic Surgery. AB - BACKGROUND AND OBJECTIVES: The quadratus lumborum block (QLB) is an abdominal truncal block, similar to transversus abdominis plane block (TAPB). However, the characteristics of QLB with regard to its duration and safety are not well known. The primary aim of this study was to determine the block duration and the cutaneous sensory block area. Our secondary analysis included assessment of the chronological change in arterial local anesthetic concentrations after QLB. METHODS: This study included 11 patients scheduled for laparoscopic ovarian surgery under general anesthesia. The patients received bilateral single injection QLBs (20 mL of 0.375% ropivacaine per side). Arterial blood was sampled at 10, 20, 30, 45, 60, 90, and 120 minutes after ropivacaine administration. The results were retrospectively compared with the results of our previous study on lateral TAPB. RESULTS: The median duration of analgesia after QLB exceeded 24 hours and was significantly longer than the duration of lateral TAPB (P = 0.003). Quadratus lumborum block affected the T7-T12 dermatomes, whereas TAPB affected T10-T12. Arterial ropivacaine levels after block peaked at comparable time in the QLB and lateral TAPB groups (Tmax: 35 [SD, 13] vs 35 [SD, 11] minutes; P = 0.93). Peak ropivacaine concentrations were significantly lower in QLB than in lateral TAPB (Cmax: 1.0 [SD, 0.5] vs 1.8 [SD, 0.4] MUg/mL; P = 0.0003). CONCLUSIONS: Quadratus lumborum block resulted in a widespread and long-lasting analgesic effect after laparoscopic ovarian surgery and resulted in lower peak arterial ropivacaine concentrations as compared with those of lateral TAPB after 150 mg ropivacaine injection. PMID- 26735158 TI - Effect of Helicobacter pylori infection and its eradication on the fate of gastric polyps. AB - OBJECTIVES: Western guidelines recommend Helicobacter pylori eradication in H. pylori-associated gastric polyps, but Korean medical insurance does not approve its eradication. The aim of this study is to evaluate the effect of H. pylori eradication on gastric polyps. METHODS: Participants in a large screening cohort underwent baseline and follow-up esophagogastroduodenoscopy and H. pylori testing. The association between gastric polyps and H. pylori was estimated using odds ratios (ORs) adjusted for confounding factors and 95% confidence intervals (CIs). The effect of H. pylori eradication on the fate of polyps was also evaluated. RESULTS: The screening cohort included 7603 participants (605 gastric polyps: 529 hyperplastic polyps, 63 fundic gland polyps, and 13 adenomas). H. pylori infection showed a positive association with hyperplastic polyps (OR 2.01; 95% CI 1.66-2.41), but was inversely related to fundic gland polyps (OR 0.05; 95% CI 0.02-0.17). Removed polyps by biopsy or endoscopic resection or tiny polyps less than 3 mm at baseline and positive conversion of H. pylori at follow-up were excluded. A total of 7060 persons were finally included to evaluate the effect of H. pylori eradication on the gastric polyp. Successful H. pylori eradication (OR 0.52; 95% CI 0.35-0.77) and persistent H. pylori-negative status (OR 0.59; 95% CI 0.46-0.76) reduced the risk of hyperplastic polyps compared with the persistent H. pylori-positive group. Successful H. pylori eradication markedly induced the disappearance of hyperplastic polyps compared with the persistent H. pylori positive group (85.0 vs. 29.0%, P=0.001). CONCLUSION: H. pylori infection increased the risk of hyperplastic polyps in both cross-sectional and longitudinal settings, and its eradication induced regression of hyperplastic polyps. PMID- 26735159 TI - Antibacterial gauzes are effective in preventing infections after percutaneous endoscopic gastrostomy placement: a retrospective analysis. AB - OBJECTIVES: The most common complication after percutaneous endoscopic gastrostomy (PEG) placement is peristomal wound infection (up to 40% without antibiotic prophylaxis). Single-dose parenteral prophylactic antibiotics as advised by current guidelines decrease the infection rate to 9-15%. We assume a prolonged effect of local antibiotic treatment with antibacterial gauzes. This study is the first to describe the effect of antibacterial gauzes in preventing infections in PEG without the use of antibiotics. METHODS: A retrospective data analysis was carried out of all patients with PEG insertion between January 2009 and October 2014 in the Catharina Hospital Eindhoven. Data include placement and the period of the first 2 weeks after PEG placement, and long-term follow-up. All patients received a locally applied antibacterial gauze polyhexamethylene biguanide immediately following PEG insertion for 3 days. No other antibiotics were administered. The main outcomes were wound infection, peritonitis, and necrotizing fasciitis; secondary outcomes included other complications. RESULTS: A total of 331 patients with only antibacterial gauzes were analyzed. The total number of infections 2 weeks after PEG insertion was 9.4%, including 8.2% minor and 1.2% major infections (peritonitis). No wound infection-related mortality or bacterial resistance was found. Costs are five times lower than antibiotics, and gauzes are more practical and patient friendly for use. CONCLUSION: Retrospectively, antibacterial gauzes are at least comparable with literature data on parenteral antibiotics in preventing peristomal wound infection after PEG placement, with an infection rate of 9.4%. Rates of other complications found in this study were comparable with current literature data. PMID- 26735160 TI - NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean pediatric patients with Crohn's disease. AB - PURPOSE: Thiopurine-induced leukopenia is a relatively common adverse event related to thiopurine medication in Korean pediatric Crohn's disease. In addition to the mutations of TPMT gene, the NUDT15 c.415C>T variant was recently identified to have a strong association with thiopurine-induced early leukopenia. We conducted this study to define the incidence of azathioprine (AZA)-related leukopenia and to determine the incidence and characteristics of their genetic variants in Korean pediatric Crohn's disease patients. PATIENTS AND METHODS: Patients diagnosed with pediatric Crohn's disease who had used AZA for more than 3 months were recruited. The dose and duration of medication and data regarding adverse events including leukopenia were collected. TPMT and NUDT15 gene sequencing was performed for patients who had experienced AZA-induced leukopenia. RESULTS: A total of 81 patients had used AZA as a maintenance therapy of Crohn's disease. The mean dose of AZA was 1.88+/-0.39 mg/kg/day. Nine patients (11.1%) experienced AZA-induced leukopenia, and eight patients (9.9%) experienced AZA induced early leukopenia. Among the eight early leukopenia patients, six patients (75.0%) harbored the NUDT15 c.415C>T variant and one patient (12.5%) had the TPMT c.719A>G (TPMT*3C) variant. All the three patients with NUDT15 c.415C>T homozygous variant suffered from alopecia totalis, and two of them experienced severe systemic infection. Three patients with the NUDT15 heterozygous variant are currently treated with AZA at a dose of 0.76 mg/kg/day. CONCLUSION: Mutations of the NUDT15 and TPMT gene accounted for ~88% of cases with thiopurine-induced early leukopenia. Extensive hair loss was a recognizable early symptom in patients with the homozygous NUDT15 c.415C>T variant. Sequencing of the NUDT15 genes can guide the clinicians before thiopurine medication. An alternative immunosuppressive medication is recommended for patients with homozygous NUDT15 c.415C>T variant. For those with the heterozygous variant, half the usual dose of AZA can achieve efficacy comparable to that for wild-type patients. PMID- 26735162 TI - Observation of Corneal Langerhans Cells by In Vivo Confocal Microscopy in Thyroid Associated Ophthalmopathy. AB - PURPOSE: To examine the density and morphology of Langerhans cells (LCs) in the cornea of patients with thyroid-associated ophthalmopathy (TAO). METHODS: Forty patients with TAO and 20 healthy volunteers were studied. All subjects underwent a thorough ophthalmic examination of both eyes. The ocular surface status was assessed by Ocular Surface Disease Index (OSDI) symptom questionnaires, tear break-up time (BUT), fluorescein staining and the Schirmer test. Laser scanning in vivo confocal microscopy was applied to evaluate the LC density and morphology in both central and peripheral cornea. The correlations between confocal microscopy data and clinical data were also analyzed. RESULTS: The OSDI and fluorescein staining values were significantly higher, while BUT and Schirmer test scores were lower in both active and inactive TAO patients compared to the controls. Central LC densities of patients with active TAO (76.38 +/- 67.77 cell/mm(2)) and inactive TAO (47.49 +/- 38.58 cell/mm(2)) were both significantly higher than those of the controls (21.46 +/- 21.74 cell/mm(2)). The number of LCs in the peripheral cornea was also significantly increased in the active TAO group (131.53 +/- 74.18 cell/mm(2)) compared to the control group (70.21 +/- 37.76 cell/mm(2)). Central LC morphology (LCM) values were significantly higher in both active (1.77 +/- 0.63) and inactive (1.51 +/- 0.63) TAO groups compared to the control group (1.01 +/- 0.80), whereas peripheral LCM scores of the two TAO groups were increased without statistical significance. There were significant correlations between both central LC density and central LCM scores and clinical data, including clinical activity score, OSDI and Schirmer test scores, and between peripheral LC density and OSDI and Schirmer test scores. No significant correlations were found between peripheral LCM scores and clinical data. CONCLUSIONS: The increase of corneal LCs in density and maturation in patients with TAO reflects an activated state of the local immune system, which indicates an inflammatory process in the cornea of TAO. PMID- 26735161 TI - Discrepancies between upper GI symptoms described by those who have them and their identification by conventional medical terminology: a survey of sufferers in four countries. AB - OBJECTIVE: The objective of this study was to develop a self-administered questionnaire for upper gastrointestinal (GI) symptoms using lay vocabulary uninfluenced by established medical terminology or concepts and to conduct a survey of symptom occurrence among sufferers in four countries. METHODS: The questionnaire was designed by integrating information gained from the vocabulary used by 38 upper GI symptom sufferers. There was no medical input to its development. The questionnaire was then used, after appropriate translation, in Brazil, Russia, the UK and the USA. Details of 10 659 symptom episodes were obtained from 2665 individuals. RESULTS: Nine symptoms described in lay vocabulary were identified during questionnaire development. Of these, one corresponded to regurgitation, whereas two that were distinguished by survey participants might both be interpreted as heartburn. One chest symptom for which a corresponding medical term was uncertain occurred in ~30% of the respondents. Five different 'stomach' or abdominal symptoms were identified. The predominant symptom and the pattern of concurrent symptoms often varied from one symptom episode to another. Use of the terms 'heartburn', 'reflux', 'indigestion' and 'burning stomach' to describe symptoms varied between countries. CONCLUSION: Some common upper GI symptoms described by those who suffer them have no clear counterpart in conventional medical terminology. Inadequacy of the conventional terminology in this respect deserves attention, first, to characterize it fully, and thereafter to construct enquiry that delivers more precise symptom identification. Our results suggest that improvement may require the use of vocabulary of individuals suffering the symptoms without imposing conformity with established symptom concepts. PMID- 26735163 TI - Reactive Metabolites: Current and Emerging Risk and Hazard Assessments. AB - Although idiosyncratic adverse drug reactions are rare, they are still a major concern to patient safety. Reactive metabolites are widely accepted as playing a pivotal role in the pathogenesis of idiosyncratic adverse drug reactions. While there are today well established strategies for the risk assessment of stable metabolites within the pharmaceutical industry, there is still no consensus on reactive metabolite risk assessment strategies. This is due to the complexity of the mechanisms of these toxicities as well as the difficulty in identifying and quantifying short-lived reactive intermediates such as reactive metabolites. In this review, reactive metabolite risk and hazard assessment approaches are discussed, and their pros and cons highlighted. We also discuss the nature of idiosyncratic adverse drug reactions, using acetaminophen and nefazodone to exemplify the complexity of the underlying mechanisms of reactive metabolite mediated hepatotoxicity. One of the key gaps moving forward is our understanding of and ability to predict the contribution of immune activation in idiosyncratic adverse drug reactions. Sections are included on the clinical phenotypes of immune mediated idiosyncratic adverse drug reactions and on the present understanding of immune activation by reactive metabolites. The advances being made in microphysiological systems have a great potential to transform our ability to risk assess reactive metabolites, and an overview of the key components of these systems is presented. Finally, the potential impact of systems pharmacology approaches in reactive metabolite risk assessments is highlighted. PMID- 26735165 TI - Dry deposition of O3 and SO2 estimated from gradient measurements above a temperate mixed forest. AB - Vertical profiles of O3 and SO2 concentrations were monitored at the Borden Forest site in southern Ontario, Canada from May 2008 to April 2013. A modified gradient method (MGM) was applied to estimate O3 and SO2 dry deposition fluxes using concentration gradients between a level above and a level below the canopy top. The calculated five-year mean (median) dry deposition velocity (Vd) were 0.35 (0.27) and 0.59 (0.54) cm s(-1), respectively, for O3 and SO2. Vd(O3) exhibited large seasonal variations with the highest monthly mean of 0.68 cm s( 1) in August and the lowest of 0.09 cm s(-1) in February. In contrast, seasonal variations of Vd(SO2) were smaller with monthly means ranging from 0.48 (May) to 0.81 cm s(-1) (December). The different seasonal variations between O3 and SO2 were caused by the enhanced SO2 uptake by snow surfaces in winter. Diurnal variations showed a peak value of Vd in early morning in summer months for both O3 and SO2. Canopy wetness increased the non-stomatal uptake of O3 while decreasing the stomatal uptake. This also applied to SO2, but additional factors such as surface acidity also played an important role on the overall uptake. PMID- 26735166 TI - Influences of humic acid on the bioavailability of phenanthrene and alkyl phenanthrenes to early life stages of marine medaka (Oryzias melastigma). AB - The influences of humic acid (HA) on the environmental behavior and bioavailability of parent polycyclic aromatic hydrocarbons (PAHs) and alkyl PAHs were investigated and compared using the early life stages of marine medaka (Oryzias melastigma, O. melastigma). It was demonstrated that the binding affinity of parent phenanthrene (PHE) with HA was smaller than that of 3-methyl phenanthrene (3-MP) and 9-ethyl phenanthrene (9-EP). Furthermore, the bioaccumulation of the three PAHs and the levels of lipid peroxidation (LPO) were calculated to study the changes in bioavailability of PAHs in presence of HA. The results indicated that the addition of HA significantly decreased the bioaccumulation and toxicity of PAHs by decreasing free PAHs concentrations. The bioavailable fractions of HA-bound PAHs in bioaccumulation (alpha) and toxicity (beta) were evaluated, indicating that the HA-bound 3-MP and 9-EP show higher bioavailability in bioaccumulation and lower bioavailability in toxicity relative to those of PHE. The beta/alpha values were less than 1 for all PAH treatment groups containing HA, suggesting that the fraction of HA-bound PAHs contributing to bioaccumulation was higher than that of HA-bound PAHs inducing toxic effect. In addition, we proposed that the free PAHs generated by desorption from HA in the cell were toxic by showing that the beta/alpha ratio values are correlated with the log KOW values (p = 0.007 and R(2) = 0.8355). Thus, oil spill risk assessments should consider both alkyl PAHs and the factors that influence the bioavailability and toxicity of PAHs in the natural aquatic environments. PMID- 26735164 TI - Ecotoxicity and genotoxicity of cyclophosphamide, ifosfamide, their metabolites/transformation products and their mixtures. AB - Cyclophosphamide (CP) and ifosfamide (IF) are commonly used cytostatic drugs that repress cell division by interaction with DNA. The present study investigates the ecotoxicity and genotoxicity of CP, IF, their human metabolites/transformation products (TPs) carboxy-cyclophosphamide (CPCOOH), keto-cyclophosphamide (ketoCP) and N-dechloroethyl-cyclophosphamide (NdCP) as individual compounds and as mixture. The two parent compounds (CP and IF), at concentrations up to 320 mg L( 1), were non-toxic towards the alga Pseudokirchneriella subcapitata and cyanobacterium Synecococcus leopoliensis. Further ecotoxicity studies of metabolites/TPs and a mixture of parent compounds and metabolites/TPs performed in cyanobacteria S. leopoliensis, showed that only CPCOOH (EC50 = 17.1 mg L(-1)) was toxic. The measured toxicity (EC50 = 11.5 mg L(-1)) of the mixture was lower from the toxicity predicted by concentration addition model (EC50 = 21.1 mg L( 1)) indicating potentiating effects of the CPCOOH toxicity. The SOS/umuC assay with Salmonella typhimurium revealed genotoxic activity of CP, CPCOOH and the mixture in the presence of S9 metabolic activation. Only CPCOOH was genotoxic also in the absence of metabolic activation indicating that this compound is a direct acting genotoxin. This finding is of particular importance as in the environment such compounds can directly affect DNA of non-target organisms and also explains toxicity of CPCOOH against cyanobacteria S. leopoliensis. The degradation study with UV irradiation of samples containing CP and IF showed efficient degradation of both compounds and remained non-toxic towards S. leopoliensis, suggesting that no stable TPs with adverse effects were formed. To our knowledge, this is the first study describing the ecotoxicity and genotoxicity of the commonly used cytostatics CP and IF, their known metabolites/TPs and their mixture. The results indicate the importance of toxicological evaluation and monitoring of drug metabolites as they may be for certain aquatic species more hazardous than parent compounds. PMID- 26735167 TI - Changes in column aerosol optical properties during extreme haze-fog episodes in January 2013 over urban Beijing. AB - Several dense haze-fog (HF) episodes were occurred in the North China Plain (NCP), especially over Beijing in January 2013 characterized by a long duration, a large influential region, and an extremely high PM2.5 values (>500 MUg m(-3)). In this study, we present the characteristics of aerosol optical properties and radiative forcing using Cimel sun-sky radiometer measurements during HF and no haze-fog (NHF) episodes occurred over Beijing during 1-31 January, 2013. The respective maximum values of daily mean aerosol optical depth at 440 nm (AOD440) were observed to be 1.21, 1.43, 1.52, and 2.21 occurred on 12, 14 19, and 28 January. It was found that the Angstrom exponent (AE) values were almost higher than 1.0 during all the days with its maximum on 26 January (1.53), suggests the dominance of fine-mode particles. The maximum (minimum) aerosol volume size distributions occurred during dense HF (NHF) days with larger particle volumes of fine-mode. The single scattering albedo, asymmetry parameter, and complex refractive index values during HF events suggest the abundance of fine-mode particles from anthropogenic (absorbing) activities mixed with scattering dust particles. The average shortwave direct aerosol radiative forcing (DARF) values at the bottom-of-atmosphere (BOA) during HF and NHF days were estimated to be 112.29 +/- 42.18 W m(-2) and -58.61 +/- 13.09 W m(-2), while at the top-of atmosphere (TOA) the forcing values were -45.78 +/- 22.17 W m(-2) and -18.64 +/- 5.84 W m(-2), with the corresponding heating rate of 1.61 +/- 0.48 K day(-1) and 1.12 +/- 0.31 K day(-1), respectively. The DARF values retrieved from the AERONET were in good agreement with the SBDART computed both at the TOA (r = 0.95) and the BOA (r = 0.97) over Beijing in January 2013. PMID- 26735168 TI - Repeated exposures to roadside particulate matter extracts suppresses pulmonary defense mechanisms, resulting in lipid and protein oxidative damage. AB - Exposure to particulate matter (PM) pollution in cities and urban canyons can be harmful to the exposed population. However, the underlying mechanisms that lead to health effects are not yet elucidated. It is postulated that exposure to repeated, small, environmentally relevant concentrations can affect lung homeostasis. This study examines the impact of repeated exposures to urban PM on mouse lungs with focus on inflammatory and oxidative stress parameters. Aqueous extracts from collected urban PM were administered to mice by 5 repeated intra tracheal instillations (IT). Multiple exposures, led to an increase in cytokine levels in both bronchoalveolar lavage fluid and in the blood serum, indicating a systemic reaction. Lung mRNA levels of antioxidant/phase II detoxifying enzymes decreased by exposure to the PM extract, but not when metals were removed by chelation. Finally, disruption of lung tissue oxidant-inflammatory/defense balance was evidenced by increased levels of lipid and protein oxidation. Unlike response to a single IT exposure to the same dose and source of extract, multiple exposures result in lung oxidative damage and a systemic inflammatory reaction. These could be attributed to compromised capacity to activate the protective Nrf2 tissue defense system. It is suggested that water-soluble metals present in urban PM, potentially from break and tire wear, may constitute major drivers of the pulmonary and systemic responses to multiple exposure to urban PM. PMID- 26735169 TI - OsteoMacs: Key players around bone biomaterials. AB - Osteal macrophages (OsteoMacs) are a special subtype of macrophage residing in bony tissues. Interesting findings from basic research have pointed to their vast and substantial roles in bone biology by demonstrating their key function in bone formation and remodeling. Despite these essential findings, much less information is available concerning their response to a variety of biomaterials used for bone regeneration with the majority of investigation primarily focused on their role during the foreign body reaction. With respect to biomaterials, it is well known that cells derived from the monocyte/macrophage lineage are one of the first cell types in contact with implanted biomaterials. Here they demonstrate extremely plastic phenotypes with the ability to differentiate towards classical M1 or M2 macrophages, or subsequently fuse into osteoclasts or multinucleated giant cells (MNGCs). These MNGCs have previously been characterized as foreign body giant cells and associated with biomaterial rejection, however more recently their phenotypes have been implicated with wound healing and tissue regeneration by studies demonstrating their expression of key M2 markers around biomaterials. With such contrasting hypotheses, it becomes essential to better understand their roles to improve the development of osteo-compatible and osteo-promotive biomaterials. This review article expresses the necessity to further study OsteoMacs and MNGCs to understand their function in bone biomaterial tissue integration including dental/orthopedic implants and bone grafting materials. PMID- 26735171 TI - Synthesis and Self-Aggregation of Poly(2-ethyl-2-oxazoline)-Based Photocleavable Block Copolymer: Micelle, Compound Micelle, Reverse Micelle, and Dye Encapsulation/Release. AB - We report on the synthesis of photocleavable poly(2-ethyl-2-oxazoline)-block poly(2-nitrobenzyl acrylate) (PEtOx-b-PNBA) block copolymers (BCPs) with varying compositions via combination of microwave-assisted cationic ring-opening polymerization (CROP) and atom transfer radical polymerization (ATRP) using alpha bromoisobutyryl bromide as an orthogonal initiator. The amphiphilic nature of this BCP causes them to self-assemble into primary micelles in THF/H2O, which further undergo secondary aggregation into nanostructured compound micelles as established through DLS, FESEM, and TEM. Upon UV irradiation (lambda = 350 nm), the photocleavage of the PNBA block of the PEtOx-b-PNBA BCP takes place, and that leads to the formation of the doubly hydrophilic poly(2-ethyl-2-oxazoline)-b poly(acrylic acid) (PEtOx-b-PAA) BCP causing the rupture of compound micelles as confirmed by spectroscopic and microscopic techniques. Encapsulation of a model hydrophobic guest molecule, nile red (NR), into the photocleavable BCP micellar core in aqueous solution and its UV-induced release is also investigated by fluorescence emission measurements. PEtOx-b-PNBA BCP amphiphiles are also shown to self-assemble into spherical nanostructures (~90 nm) in dichloromethane as established by DLS and TEM analysis. These are referred to as reverse micelles and are able to encapsulate anionic hydrophilic dye, Eosin B, and facilitate its solubilization in organic media. PMID- 26735170 TI - Analgesic drug delivery via recombinant tissue plasminogen activator and microRNA 183-triggered opening of the blood-nerve barrier. AB - The peripheral nerve contains three barriers which include the blood-nerve barrier consisting of endoneurial vessels and the perineurium as well as autotypic junctions in Schwann cells. The perineurium prevents diffusion of perineurally injected drugs that can be used for selective regional pain control. It is composed of a basal membrane and layers of perineurial cells sealed by tight junction proteins like claudin-1. Claudin-1 expression and barrier function are regulated via low-density lipoprotein receptor-related protein (LRP-1). Perisciatic application of recombinant tissue plasminogen activator (rtPA) or the catalytically inactive rtPAi - both agonists of LRP-1 - reduced claudin-1 mRNA and protein expression in the rat nerve. This facilitated an increase of nociceptive thresholds after local application of hydrophilic opioids or the voltage gated sodium channel blocker (NaV1.7) ProToxin-II without apparent nerve toxicity. RtPA-induced barrier opening was mediated by LRP-1 and intracellularly by Erk phosphorylation. In silico, microRNA (miR)-rno-29b-2-5p and rno-miR-183-5p were identified as potential regulators of claudin-1 transcription in the rat. RtPA application increased miR-183-5p in the sciatic nerve. MiR-183-5p mimics functionally opened the perineurium and downregulated claudin-1 expression in vivo. In vitro, hsa-miR-183-3p mimics reduced claudin-1 expression in human HT 29/B6 cells. Overall, rtPA regulates perineurial barrier tightness via LRP-1, Erk phosphorylation and miR-183-5p/3p. This mechanism might serve as a new principle to facilitate drug delivery to peripheral nerves in humans. PMID- 26735172 TI - Overexpressed EDIL3 predicts poor prognosis and promotes anchorage-independent tumor growth in human pancreatic cancer. AB - Epidermal Growth Factor-like repeats and Discoidin I-Like Domains 3 (EDIL3), an extracellular matrix (ECM) protein associated with vascular morphogenesis and remodeling, is commonly upregulated in multiple types of human cancers and correlates with tumor progression. However, its expression pattern and underlying cellular functions in pancreatic ductal adenocarcinoma (PDAC) remain largely unexplored. In current study, we observed that expression of EDIL3 was significantly up-regulated in PDAC compared with normal controls in both cell lines and clinical specimens. In addition, elevated EDIL3 expression was positively correlated with patients' TNM stage and T classification. Kaplan-Meier analysis indicated that high EDIL3 expression was significantly associated with shorter overall survival times in PDAC patients. Multivariate Cox regression analysis confirmed EDIL3 expression, age, lymph node metastasis and histological differentiation as independent prognostic factors in PDAC. Knockdown of EDIL3 showed no significant influence on cell viability, migration, invasion and starvation-induced apoptosis, but compromised anoikis resistance and anchorage independent tumor growth of PDAC cells. Meanwhile, treatment with recombinant EDIL3 protein markedly promoted anoikis resistance and anchorage independent tumor growth. Mechanistically, we demonstrated that altered protein expression of Bcl-2 family might contribute to the oncogenic activities of EDIL3. In conclusion, this study provides evidences that EDIL3 is a potential predictor and plays an important role in anchorage independent tumor growth of PDAC and EDIL3 related pathways might represent a novel therapeutic strategy for treatment of pancreatic cancer. PMID- 26735174 TI - The mitochondrial genetic landscape in neuroblastoma from tumor initiation to relapse. AB - Little is known about changes within the mitochondrial (mt) genome during tumor progression in general and during initiation and progression of neuroblastoma (NB) in particular. Whole exome sequencing of corresponding healthy tissue, primary tumor and relapsed tumor from 16 patients with NB revealed that most NB harbor tumor-specific mitochondrial variants. In relapsed tumors, the status of mt variants changed in parallel to the status of nuclear variants, as shown by increased number and spatio-temporal differences of tumor-specific variants, and by a concomitant decrease of germline variants. As mt variants are present in most NB patients, change during relapse and have a higher copy number compared to nuclear variants, they represent a promising new source of biomarkers for monitoring and phylogenetic analysis of NB. PMID- 26735173 TI - Reactivation of wild-type and mutant p53 by tryptophanolderived oxazoloisoindolinone SLMP53-1, a novel anticancer small-molecule. AB - Restoration of the p53 pathway, namely by reactivation of mutant (mut) p53, represents a valuable anticancer strategy. Herein, we report the identification of the enantiopure tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a novel reactivator of wild-type (wt) and mut p53, using a yeast-based screening strategy. SLMP53-1 has a p53-dependent anti-proliferative activity in human wt and mut p53R280K-expressing tumor cells. Additionally, SLMP53-1 enhances p53 transcriptional activity and restores wt-like DNA binding ability to mut p53R280K. In wt/mut p53-expressing tumor cells, SLMP53-1 triggers p53 transcription-dependent and mitochondrial apoptotic pathways involving BAX, and wt/mut p53 mitochondrial translocation. SLMP53-1 inhibits the migration of wt/mut p53-expressing tumor cells, and it shows promising p53-dependent synergistic effects with conventional chemotherapeutics. In xenograft mice models, SLMP53-1 inhibits the growth of wt/mut p53-expressing tumors, but not of p53-null tumors, without apparent toxicity. Collectively, besides the potential use of SLMP53-1 as anticancer drug, the tryptophanol-derived oxazoloisoindolinone scaffold represents a promissing starting point for the development of effective p53 reactivating drugs. PMID- 26735175 TI - Combating autophagy is a strategy to increase cytotoxic effects of novel ALK inhibitor entrectinib in neuroblastoma cells. AB - Neuroblastoma (NB) is a threatening childhood malignancy. Its prognosis is affected by several morphological, and biological characteristics, including the constitutive expression of ALK tyrosine kinase. In this study we examined the therapeutic potential of a novel ALK inhibitor, entrectinib, in obliterating NB tumor cells. Entrectinib showed the growth-inhibitory effects on NB cells with a 50% inhibitory concentration range of 0.03-5 MUM. In the ALK-dependent cells, entrectinib mediated G1-arrest, which was associated with modified expression of multiple cell-cycle regulators. Down-regulation of Ki-67, and attenuated phosphorylation of ERK1/2, and STAT3, correlated with observed antiproliferative capacity of entrectinib. Initial cytostatic activity of entrectinib was followed by concentration-dependent apoptotic cell death, and Caspase-3 activation. However, we delineated a reduced sensitivity of ALK mutated NB cells to entrectinib, and demonstrated strong activation of autophagy in SH-SY5YF1174L NB cell line. Abrogation of autophagy by chloroquine increased significantly the toxicity of entrectinib, as confirmed by enhanced death rate, and PARP protein cleavage in SH-SY5YF1174L cells. In aggregate, our data show that entrectinib inhibits proliferation, and induces G1-arrest, and apoptosis in NB cells. We propose entrectinib for further consideration in treatment of NB, and recommend pharmacological inhibition of autophagy to be explored for a combined therapeutic approach in NB patients that might develop resistance to entrectinib. PMID- 26735177 TI - GNA13 as a prognostic factor and mediator of gastric cancer progression. AB - Guanine nucleotide binding protein (G protein), alpha 13 (GNA13) has been implicated as an oncogenic protein in several human cancers. In this study, GNA13 was characterized for its role in gastric cancer (GC) progression and underlying molecular mechanisms. The expression dynamics of GNA13 were examined by immunohistochemistry (IHC) in two independent cohorts of GC samples. A series of in-vivo and in-vitro assays was performed to elucidate the function of GNA13 in GC and its underlying mechanisms. In both two cohorts of GC samples, we observed that GNA13 was markedly overexpressed in GC tissues and associated closely with aggressive magnitude of GC progression and poor patients' survival. Further study showed that upregulation of GNA13 expression increased the proliferation and tumorigenicity of GC cells in vitro and in vivo, by promoting cell growth rate, colony formation, and tumor formation in nude mice. By contrast, knockdown of GNA13 effectively suppressed the proliferation and tumorigenicity of GC cells in vitro and in vivo. Our results also demonstrated that the molecular mechanisms of the effect of GNA13 in GC included promotion of G1/S cell cycle transition through upregulation of c-Myc, activation of AKT and ERK activity, suppression of FOXO1 activity, upregulation of cyclin-dependent kinase (CDK) regulator cyclin D1 and downregulation of CDK inhibitor p21Cip1 and p27Kip1. Our present study illustrated that GNA13 has an important role in promoting proliferation and tumorigenicity of GC, and may represent a novel prognostic biomarker and therapeutic target for this disease. PMID- 26735176 TI - Hyperactive ERK and persistent mTOR signaling characterize vemurafenib resistance in papillary thyroid cancer cells. AB - Clinical studies evaluating targeted BRAFV600E inhibitors in advanced thyroid cancer patients are currently underway. Vemurafenib (BRAFV600E inhibitor) monotherapy has shown promising results thus far, although development of resistance is a clinical challenge. The objective of this study was to characterize development of resistance to BRAFV600E inhibition and to identify targets for effective combination therapy. We created a line of BCPAP papillary thyroid cancer cells resistant to vemurafenib by treating with increasing concentrations of the drug. The resistant BCPAP line was characterized and compared to its sensitive counterpart with respect to signaling molecules thought to be directly related to resistance. Expression and phosphorylation of several critical proteins were analyzed by Western blotting and dimerization was evaluated by immunoprecipitation. Resistance to vemurafenib in BCPAP appeared to be mediated by constitutive overexpression of phospho-ERK and by resistance to inhibition of both phospho-mTOR and phospho-S6 ribosomal protein after vemurafenib treatment. Expression of potential alternative signaling molecule, CRAF, was not increased in the resistant line, although formation of CRAF dimers appeared increased. Expression of membrane receptors HER2 and HER3 was greatly amplified in the resistant cancer cells. Papillary thyroid cancer cells were capable of overcoming targeted BRAFV600E inhibition by rewiring of cell signal pathways in response to prolonged vemurafenib therapy. Our study suggests that in vitro culture of cancer cells may be useful in assessing molecular resistance pathways. Potential therapies in advanced thyroid cancer patients may combine vemurafenib with inhibitors of CRAF, HER2/HER3, ERK, and/or mTOR to delay or abort development of resistance. PMID- 26735178 TI - Nucleus pulposus phenotypic markers to determine stem cell differentiation: fact or fiction? AB - Progress in mesenchymal stem cell (MSC) based therapies for nucleus pulposus (NP) regeneration are hampered by a lack of understanding and consensus of the normal NP cell phenotype. Despite the recent consensus paper on NP markers, there is still a need to further validate proposed markers. This study aimed to determine whether an NP phenotypic profile could be identified within a large population of mature NP samples.qRT-PCR was conducted to assess mRNA expression of 13 genes within human non-degenerate articular chondrocytes (AC) (n=10) and NP cells extracted from patients across a spectrum of histological degeneration grades (n=71). qRT-PCR results were used to select NP marker candidates for protein expression analysis.Differential expression at mRNA between AC and non-degenerate NP cells was only observed for Paired Box Protein 1 (PAX1) and Forkhead box F1 (FOXF1). In contrast no other previously suggested markers displayed differential expression between non-degenerate NP and AC at mRNA level. PAX1 and FOXF1 protein expression was significantly higher in the NP compared to annulus fibrosus (AF), cartilaginous endplate (CEP) and AC. In contrast Laminin-5 (LAM-332), Keratin-19 (KRT-19) and Hypoxia Inducible Factor 1 alpha (HIF1alpha) showed no differential expression in NP cells compared with AC cells.A marker which exclusively differentiates NP cells from AF and AC cells remains to be identified, raising the question: is the NP a heterogeneous population of cells? Or does the natural biological variation during IVD development, degeneration state and even the life cycle of cells make finding one definitive marker impossible? PMID- 26735180 TI - NG2 proteoglycan as a pericyte target for anticancer therapy by tumor vessel infarction with retargeted tissue factor. AB - tTF-TAA and tTF-LTL are fusion proteins consisting of the extracellular domain of tissue factor (TF) and the peptides TAASGVRSMH and LTLRWVGLMS, respectively. These peptides represent ligands of NG2, a surface proteoglycan expressed on angiogenic pericytes and some tumor cells. Here we have expressed the model compound tTF-NGR, tTF-TAA, and tTF-LTL with different lengths in the TF domain in E. coli and used these fusion proteins for functional studies in anticancer therapy. We aimed to retarget TF to tumor vessels leading to tumor vessel infarction with two barriers of selectivity, a) the leaky endothelial lining in tumor vessels with the target NG2 being expressed on pericytes on the abluminal side of the endothelial cell barrier and b) the preferential expression of NG2 on angiogenic vessels such as in tumors. Chromatography-purified tTF-TAA showed identical Factor X (FX)-activating procoagulatory activity as the model compound tTF-NGR with Km values of approx. 0.15 nM in Michaelis-Menten kinetics. The procoagulatory activity of tTF-LTL varied with the chosen length of the TF part of the fusion protein. Flow cytometry revealed specific binding of tTF-TAA to NG2 expressing pericytes and tumor cells with low affinity and dissociation KD in the high nM range. In vivo and ex vivo fluorescence imaging of tumor xenograft carrying animals and of the explanted tumors showed reduction of tumor blood flow upon tTF-TAA application. Therapeutic experiments showed a reproducible antitumor activity of tTF-TAA against NG2-expressing A549-tumor xenografts, however, with a rather small therapeutic window (active/toxic dose in mg/kg body weight). PMID- 26735179 TI - Snail1 is required for the maintenance of the pancreatic acinar phenotype. AB - The Snail1 transcriptional factor is required for correct embryonic development, yet its expression in adult animals is very limited and its functional roles are not evident. We have now conditionally inactivated Snail1 in adult mice and analyzed the phenotype of these animals. Snail1 ablation rapidly altered pancreas structure: one month after Snail1 depletion, acinar cells were markedly depleted, and pancreas accumulated adipose tissue. Snail1 expression was not detected in the epithelium but was in pancreatic mesenchymal cells (PMCs). Snail1 ablation in cultured PMCs downregulated the expression of several beta-catenin/Tcf-4 target genes, modified the secretome of these cells and decreased their ability to maintain acinar markers in cultured pancreas cells. Finally, Snail1 deficiency modified the phenotype of pancreatic tumors generated in transgenic mice expressing c-myc under the control of the elastase promoter. Specifically, Snail1 depletion did not significantly alter the size of the tumors but accelerated acinar-ductal metaplasia. These results demonstrate that Snail1 is expressed in PMCs and plays a pivotal role in maintaining acinar cells within the pancreas in normal and pathological conditions. PMID- 26735181 TI - Experimental research of mechanical behavior of porcine brain tissue under rotational shear stress. AB - The objective of this paper is to investigate mechanical behavior of porcine brain tissue with a series of rotational shear stress control experiments. To this end, several experiments including stress sweep tests, frequency sweep tests and quasi-static creep tests were designed and conducted with a standard rheometer (HAAKE RheoStress6000). The effects of the loading stress rates to mechanical properties of brain tissue were also studied in stress sweep tests. The results of stress sweep tests performed on the same brain showed that brain tissue had an obvious regional inhomogeneity and the mechanical damage occurred at the rotational shear stress of 10-15Pa. The experimental data from three different loading stress rates demonstrated that the mechanical behavior of porcine brain tissue was loading stress rate dependent. With the decrease of loading stress rate, a stiffer mechanical characteristic of brain tissue was observed and the occurrence of mechanical damage can be delayed to a higher stress. From the results of frequency sweep tests we found that brain tissue had almost completely elastic properties at high frequency area. The nonlinear creep response under the rotational shear stress of 1, 3, 5, 7 and 9Pa was shown in results of creep tests. A new nonlinear viscoelastic solid model was proposed for creep tests and matched well with the test data. Considering the regional differences, loading stress rates and test conditions effects, loss tangent tan delta in porcine brain tissue showed a high uniformity of 0.25-0.45. PMID- 26735182 TI - Comparative biomechanical study of using decellularized human adipose tissues for post-mastectomy and post-lumpectomy breast reconstruction. AB - Developing suitable biomaterials for post-mastectomy or post-lumpectomy breast reconstruction is highly important. This study is aimed at evaluating biomechanical suitability of decellularized adipose tissue (DAT) for this purpose. The study involves computational experiments for evaluating deformation of the breast reconstructed using DAT under loading conditions pertaining to two common body position changes of prone-to-supine and prone-to-upright. This was conducted using nonlinear finite element models where the breast geometry was obtained from MRI image of a female breast. The experiments were performed using DAT sourced from various adipose tissue depots in comparison to natural adipose tissue. Data obtained from the conducted experiments showed no contour defects with various DAT materials for simulated post-mastectomy or post-lumpectomy breast reconstruction under the loading conditions. They also demonstrated that a breast reconstructed using DAT derived from the breast or subcutaneous abdominal depots exhibit significantly closer deformation, both qualitatively and quantitatively, to that of a normal breast under the same loading conditions. Similarity of DAT deformation to that of natural breast tissue in post-surgery breast reconstruction was assessed using nonlinear finite element analysis. Our results provide evidence that DAT derived from subcutaneous abdominal and breast depots yield more analogous deformation pattern to the natural tissue in post mastectomy breast reconstruction applications. This is quite encouraging, as breast and subcutaneous adipose tissue can be readily obtained in large quantities from breast or abdominal lipo-reduction surgery procedures. Furthermore, in post-lumpectomy cases all DAT samples used in this research showed similar deformation, and thus are suitable as breast tissue substituents. PMID- 26735183 TI - Characterization, mechanical behavior and in vitro evaluation of a melt-drawn scaffold for esophageal tissue engineering. AB - Tubular esophageal scaffolds with fiber diameter ranging from 13.9+/-1.7MUm to 65.7+/-6.2MUm were fabricated from the highly elastic poly(l-lactide-co-epsilon caprolactone) (PLC) via a melt-drawing method. The morphology, crystallinity, thermal and mechanical properties of the PLC fibers were investigated. They were highly aligned and have a uniform diameter. PLC is found to be semicrystalline consisting of alpha- and beta- lactide (LA) crystals. The crystallinity increases up to 16.8% with increasing melt-drawing speeds due to strain-induced crystallization. Modulus and strength increases while ductility decreases with an increase in crystallinity of the PLC samples. Moisture will not degrade the overall tensile properties but affect its tangent modulus at the low strain. L929 cells are able to attach and proliferate on the scaffolds very well. The cells seeded on the scaffolds show normal morphology with >90% cell viability after 6 days of culture. These results demonstrate that the PLC fibrous scaffold has good potential for use in esophageal tissue engineering application. PMID- 26735184 TI - Nickel Nanoparticles Entangled in Carbon Nanotubes: Novel Ink for Nanotube Printing. AB - We report the serendipitous discovery of a rapid and inexpensive method to attach nanoscale magnetic chaperones to carbon nanotubes (CNTs). Nickel nanoparticles (NiNPs) become entangled in CNTs after both are dispersed in kerosene by sonication and form conjugates. An externally applied magnetic field manipulates the resulting CNTs-NiNP ink without NiNP separation, allowing us to print an embedded circuit in an elastomeric matrix and fabricate a strain gage and an oil sensor. The new method to print a circuit in a soft material using an NiNP-CNT ink is more rapid and inexpensive than the complex physical and chemical means typically used to magnetize CNTs. PMID- 26735186 TI - Sources identification and pollution evaluation of heavy metals in the surface sediments of Bortala River, Northwest China. AB - The current study focused on the Bortala River - a typical inland river located in an oasis of arid area in northwestern China. The sediment and soil samples were collected from the river and drainage basin. Results showed that: (1) the particle size of the sand fraction of the sediments was 78-697 um, accounting for 78.82% of the total samples; the average concentrations of eight heavy metals fell within the concentration ranges recommended by the Secondary National Standard of China, while the maximum concentrations of Pb, Cd, and Hg exceeded these standards; (2) results from multivariate statistical analysis indicated that Cu, Ni, As, and Zn originated primarily from natural geological background, while Cd, Pb, Hg and Cr in the sediments originated from human activities; (3) results of the enrichment factor analysis and the geo-accumulation index evaluation showed that Cd, Hg, and Pb were present in the surface sediments of the river at low or partial serious pollution levels, while Zn, Cr, As, Ni, and Cu existed at zero or low pollution levels; (4) calculation of the potential ecological hazards index showed that among the eight tested heavy metals, Cd, Pb, Hg, and Cr were the main potential ecological risk factors, with relative contributions of 25.43%, 22.23%, 21.16%, and 14.87%, respectively; (5) the spatial distribution of the enrichment factors (EF(S)), the Geo-accumulation index (I(geo)), and the potential ecological risk coefficient (E(r)(i)) for eight heavy metals showed that there was a greater accumulation of heavy metals Pb, Cd, and Hg in the sediments of the central and eastern parts of the river. Results of this research can be a reference for the heavy metals pollution prevention, the harmony development of the ecology protection and the economy development of the oases of inland river basin of arid regions of China, Central Asia and also other parts of the world. PMID- 26735185 TI - A cross-sectional examination of the correlates of current smoking among off reserve First Nations and Metis adults: Evidence from the 2012 Aboriginal Peoples Survey. AB - INTRODUCTION: The purpose of this study was to examine the correlates of current smoking among off-reserve First Nations and Metis adults, two Aboriginal Canadian groups that are at higher risk to smoke and more likely to suffer from chronic health conditions relative to their non-Aboriginal counterparts. A particular focus was on culturally specific factors and their associations with current smoking. METHODS: We used data from Statistics Canada's, 2012 Aboriginal Peoples Survey to investigate the correlates of smoking among 12,720 First Nations and Metis adults. Sequential binary logistic regression models were estimated to examine associations between smoking and culturally specific, demographic, geographic, socioeconomic and health-related variables. RESULTS: Overall, 39.4% were current smokers. Multivariate results found that those who had hunted, fished or trapped within the last year were more likely to be smokers. In addition, respondents who were exposed to an Aboriginal language at home or outside the home were more likely to be smokers. Current smoking was significantly associated with being aged 35 to 49 years, living in a small population center, low income, low education, unemployment, being unmarried, low ratings of self-perceived health, heavy drinking and low body mass index. Respondents aged 65 years and older and those living in British Columbia were less likely to smoke. DISCUSSION: The results of this study suggest that it may be useful to consider cultural characteristics, particularly language in efforts to reduce the prevalence of manufactured tobacco use among First Nations and Metis adults. Interventions should also consider demographic, geographic and socioeconomic variables, in addition to co-occurring health-risk behaviors. PMID- 26735187 TI - Network specific change in white matter integrity in mesial temporal lobe epilepsy. AB - OBJECTIVES: To identify the specific change of white matter integrity that occurs in the brain network related to epileptic activity in patients with mesial temporal lobe epilepsy (MTLE). METHODS: We recruited 18 patients with MTLE and 18 healthy subjects. In MTLE patients, the remote functional-deficit zone was delineated using fluorodeoxyglucose positron emission tomography as an extratemporal region showing glucose hypometabolism. Using diffusion magnetic resonance imaging tractography, we defined a seizure propagation tract (PT) as a white matter pathway that connects the focus with a remote functional deficit zone. We also used the corticospinal tract (CST) and inferior longitudinal fasciculus (ILF) as control tracts in the hemisphere ipsilateral to the focus. Fractional anisotropy (FA), mean diffusivity (MD), and volume of the tracts were compared among PT, CST, and ILF. RESULTS: Tractographic analysis identified the uncinate fasciculus, arcuate fasciculus, and fornix as PTs. A decrease in FA was found in MTLE patients compared with healthy subjects in all tracts, but PTs showed a more significant decrease in FA than did the two control tracts. Although the change in MD was also found in MTLE patients compared with healthy controls, a tract-specific change was not observed. Although white-matter damage was observed in all candidate tracts examined, the integrity of white matter was most significantly decreased in PTs in MTLE. CONCLUSION: The change in white matter integrity occurs specifically in the pathways that connect the focus and remote functional deficit zones in patients with MTLE, i.e., the pathways that are assume to be associated with seizure propagation. PMID- 26735190 TI - Simultaneous Decision on the Number of Latent Clusters and Classes for Multilevel Latent Class Models. AB - The Multilevel Latent Class Model (MLCM) proposed by Vermunt (2003) has been shown to be an excellent framework for analyzing nested data with assumed discrete latent constructs. The nonparametric version of MLCM assumes 2 levels of discrete latent components to describe the dependency observed in data. Model selection is an important step in any statistical modeling. The task of model selection for MLCM amounts to the decision on the number of discrete latent components at both higher and lower levels and is more challenging than standard Latent Class Models. In this article, simulation studies were conducted to systematically examine the effects of sample sizes, clusters/classes distinctness, and the number of latent clusters and classes on the performance of various information criteria in recovering the true latent structure. Results of the simulation studies are summarized and presented. The final section presents the remarks and recommendations about the simultaneous decision regarding the number of latent classes and clusters when applying MLCMs to analyze empirical data. PMID- 26735189 TI - Toward a Unified Framework for the Study of Between-Person and Within-Person Structures: Building a Bridge Between Two Research Paradigms. AB - The vast majority of empirical research in the behavioral sciences is based on the analysis of between-person variation. In contrast, much of applied psychology is concerned with the analysis of variation within individuals. Furthermore, the mechanisms specified by psychological theories generally operate within, rather than across, individuals. This disconnect between research practice, applied demands, and psychological theories constitutes a major threat to the conceptual integrity of the field. Following groundbreaking earlier work, we propose a conceptual framework that distinguishes within-person (WP) and between-person (BP) sources of variation in psychological constructs. By simultaneously considering both sources of variation, it is shown how to identify possible reasons for nonequivalence of BP and WP structures as well as establishing areas of convergence. For this purpose, we first introduce the concept of conditional equivalence as a way to study partial structural equivalence of BP and WP structures in the presence of unconditional nonequivalence. Second, we demonstrate the construction of likelihood planes to explore the causes of structural nonequivalence. Third, we examine 4 common causes for unconditional nonequivalence-autoregression, subgroup differences, linear trends, and cyclic trends-and demonstrate how to account for them. Fourth, we provide an empirical example on BP and WP differences in attentiveness. PMID- 26735188 TI - A denoising algorithm for projection measurements in cone-beam computed tomography. AB - The ability to reduce the radiation dose in computed tomography (CT) is limited by the excessive quantum noise present in the projection measurements. Sinogram denoising is, therefore, an essential step towards reconstructing high-quality images, especially in low-dose CT. Effective denoising requires accurate modeling of the photon statistics and of the prior knowledge about the characteristics of the projection measurements. This paper proposes an algorithm for denoising low dose sinograms in cone-beam CT. The proposed algorithm is based on minimizing a cost function that includes a measurement consistency term and two regularizations in terms of the gradient and the Hessian of the sinogram. This choice of the regularization is motivated by the nature of CT projections. We use a split Bregman algorithm to minimize the proposed cost function. We apply the algorithm on simulated and real cone-beam projections and compare the results with another algorithm based on bilateral filtering. Our experiments with simulated and real data demonstrate the effectiveness of the proposed algorithm. Denoising of the projections with the proposed algorithm leads to a significant reduction of the noise in the reconstructed images without oversmoothing the edges or introducing artifacts. PMID- 26735191 TI - Individual Pooling for Group-Based Modeling Under the Assumption of Ergodicity. AB - Psychology principally utilizes nomothetic, interindividual approaches to model phenomena of interest. However, it is the case that these approaches do not always capture the processes for each individual in the sample. If the research is focused on individual processes, confining analysis to the idiographic level may be more appropriate. One way to overcome the nomothetic inability to capture idiographic processes is to identify those participants who meet the criteria of ergodicity and restrict analysis to the resulting sample. Under these conditions it is quantitatively justifiable to create a group model without concern that it may fail to represent each member's idiographic process. In this study we explore the utility of such a method by (a) applying an ergodic pooling test to a sample of dyads (N = 128) who provided daily (T = 50) self-reports of affect, (b) applying an ergodic pooling test to samples (N = 4) of simulated ergodic time series data (T = 50, 250, and 1,000), PMID- 26735193 TI - Special MBR Section: SMEP Student Paper Competition Abstracts. PMID- 26735192 TI - Longitudinal Multi-Trait-State-Method Model Using Ordinal Data. AB - Multi-trait multi-method (MTMM) models provide a way to assess convergent and discriminant validity when multiple traits are measured by multiple methods. In recent years, longitudinal extensions of MTMM models have been proposed in the structural equation modeling framework to evaluate whether and how the trait as well as method factors change over time. We propose a novel longitudinal ordinal MTMM model that can be used to effectively distinguish volatile "state" processes from "trait" processes that tend to remain stable and invariant over time. The proposed model, termed a longitudinal multi-trait-state-method (LM-TSM) model, combines 3 key modeling components: (a) a measurement model for ordinal data, (b) a vector autoregressive moving average model at the latent level to examine changes in the state as well as the method factors over time, and (c) a second order factor-analytic model to capture time-invariant traits as shared variances among the state factors across all measurement occasions. Data from the Affective Dynamics and Individual Differences (ADID; Emotions and Dynamic Systems Laboratory, 2010 ) study was used to illustrate the proposed longitudinal LM-TSM model. Methodological issues associated with fitting the LM-TSM model are discussed. PMID- 26735194 TI - Abstract: An Investigation of Construct Validity Using Higher Order Invariance. PMID- 26735195 TI - Abstract: Estimation of the 4-Parameter Model with Marginal Maximum Likelihood. PMID- 26735196 TI - Abstract: Dynamic Mixture Modeling of a Single Simulated Case. PMID- 26735197 TI - Abstract: Exploring Crawford-Ferguson Family of Rotations Through an Interactive Visual System. PMID- 26735199 TI - Abstract: Automated Fitting of MIRT Models by a Simultaneous Perturbation Algorithm. PMID- 26735198 TI - Abstract: Generalized Fiducial Inference for Binary Logistic Item Response Models. PMID- 26735200 TI - Abstract: Using Cognitive Complexity to Measure the Psychometric Properties of Mathematics Assessment Items. PMID- 26735201 TI - Abstract: Impact of Non-Invariant Loadings and Intercepts in the LGM and AR Quasi Simplex Model. PMID- 26735202 TI - Abstract: Using Ratio Scaling to Assess Likelihood of Joint Events. PMID- 26735203 TI - Abstract: Relations Among Reexperiencing, Time, and Posttraumatic Growth: A Case of Cooperative Suppression. PMID- 26735204 TI - Abstract: Power to Detect Within- and Between-Person Effects: A Comparison of Multilevel SEM and Unit-Weighted Scale Scores. PMID- 26735205 TI - Abstract: Semiparametric Bayesian Modeling With Application in Growth Curve Analysis. PMID- 26735206 TI - Abstract: Improving Power in Genome-Wide Studies Using a Two-Stage Design. PMID- 26735207 TI - Abstract: The Role of Social Enjoyment in Daily Fatigue among Women with Fibromyalgia. PMID- 26735210 TI - Cultured Construction: Global Evidence of the Impact of National Values on Renewable Electricity Infrastructure Choice. AB - Renewable electricity is an important tool in the fight against climate change, but globally these technologies are still in the early stages of diffusion. To contribute to our understanding of the factors driving this diffusion, I study relationships between national values (measured by Hofstede's cultural dimensions) and renewable electricity adoption at the national level. Existing data for 66 nations (representing an equal number of developed and developing economies) are used to fuel the analysis. Somewhat dependent on limited available data on controls for grid reliability and the cost of electricity, I discover that three of Hofstede's dimensions (high uncertainty avoidance, low masculinity femininity, and high individualism-collectivism) have significant exponential relationships with renewable electricity adoption. The dimension of uncertainty avoidance appears particularly appropriate for practical application. Projects or organizations implementing renewable electricity policy, designs, or construction should particularly attend to this cultural dimension. In particular, as the data imply that renewable technologies are being used to manage risk in electricity supply, geographies with unreliable grids are particularly likely to be open to renewable electricity technologies. PMID- 26735208 TI - Abstract: Longitudinal Examination of Situational Temptations for Smoking in Adult Smokers. PMID- 26735209 TI - Investigation on the removal of the major cocaine metabolite (benzoylecgonine) in water matrices by UV254/H2O2 process by using a flow microcapillary film array photoreactor as an efficient experimental tool. AB - A microcapillary film reactor (MCF) was adopted to evaluate and compare the removal efficiency of benzoylecgonine (BE), an emerging micropollutant deriving from illicit drug abuse (cocaine), in different aqueous matrices: milliQ water, synthetic and real wastewater and surface water. The removal processes investigated were the direct photolysis with UV radiation at 254 nm, and the advanced oxidation process (AOP) with the same UV radiation and hydrogen peroxide. As a result of the microfluidics approach developed through an innovative experimental apparatus, full conversion of BE was reached within a few seconds or minutes of residence time in the MCF depending on the process conditions adopted. The radiation dose was estimated to be approximately 5.5 J cm(-2). The innovative MCF reactor was found to be an effective tool for photochemical studies, especially when using highly priced, uncommon, or regulated substances. The removal efficiency was affected by the nature of the aqueous matrix, due to the presence of different xenobiotics and natural compounds that act primarily as HO(*) radical scavengers and secondly as inner UV254 filters. Moreover, nano-liquid chromatography (LC)-high resolution-mass spectrometry analysis was utilized to identify the main reaction transformation products, showing the formation of hydroxylated aromatics during the photochemical treatment. PMID- 26735211 TI - Design of Polymer Networks Involving a Photoinduced Electronic Transmission Circuit toward Artificial Photosynthesis. AB - Many strategies have been explored to achieve artificial photosynthesis utilizing mediums such as liposomes and supramolecules. Because the photochemical reaction is composed of multiple functional molecules, the surrounding microenvironment is expected to be rationally integrated as observed during photosynthesis in chloroplasts. In this study, photoinduced electronic transmission surrounding the microenvironment of Ru(bpy)3(2+) in a polymer network was investigated using poly(N-isopropylacrylamide-co-Ru(bpy)3), poly(acrylamide-co-Ru(bpy)3), and Ru(bpy)3-conjugated microtubules. Photoinduced energy conversion was evaluated by investigating the effects of (i) Ru(bpy)3(2+) immobilization, (ii) polymer type, (iii) thermal energy, and (iv) cross-linking. The microenvironment surrounding copolymerized Ru(bpy)3(2+) in poly(N-isopropylacrylamide) suppressed quenching and had a higher radiative process energy than others. This finding is related to the nonradiative process, i.e., photoinduced H2 generation with significantly higher overall quantum efficiency (13%) than for the bulk solution. We envision that useful molecules will be generated by photoinduced electronic transmission in polymer networks, resulting in the development of a wide range of biomimetic functions with applications for a sustainable society. PMID- 26735214 TI - New mindset in scientific method in the health field: Design Thinking. PMID- 26735215 TI - Building a Lung Transplant Program. PMID- 26735217 TI - Addition of n-butyl cyanoacrylate to classic transarterial chemoembolization may improve the radiological response in patients with hepatocellular carcinoma. AB - OBJECTIVE: Transarterial chemoembolization is the treatment of choice for intermediate-stage hepatocellular carcinoma. However, there are no clear data supporting transarterial chemoembolization vs . transarterial embolization or regarding the best chemotherapeutic agent, which may suggest a preponderant role of ischemia over chemotherapeutic action. This study sought to evaluate the radiological response and outcome of transarterial chemoembolization modified by n-butyl cyanoacrylate addition compared to conventional transarterial chemoembolization in hepatocellular carcinoma patients. MATERIALS AND METHODS: A retrospective review identified forty-seven patients who underwent modified chemoembolization and thirty-three who underwent conventional chemoembolization between June 2006 and December 2011. The radiological response was reassessed using the modified Response Evaluation Criteria in Solid Tumors. The sustained complete response, time to progression and overall survival rates were also analyzed. RESULTS: Complete response rates were significantly higher in patients who had undergone modified chemoembolization compared to those who had undergone conventional treatment (61.7% and 24.3%, respectively; p < 0.001). The rate of sustained complete response was significantly higher in the modified chemoembolization group compared to the conventional chemoembolization group (median of 236 and 37 days, respectively; p < 0.001). Time to progression was significantly higher in the modified chemoembolization group compared to the conventional chemoembolization group (median of 424 and 201 days, respectively; p = 0.042). Overall survival rates revealed no difference between patients who received modified chemoembolization and conventional chemoembolization (median of 483 and 399 days, respectively; p = 0.316). CONCLUSION: Transarterial chemoembolization modified by n-butyl cyanoacrylate addition was superior to conventional transarterial chemoembolization in terms of the radiological response in the first imaging control. Although the sustained complete response and time to progression rates were higher for the modified chemoembolization group, no differences in overall survival rates were observed. PMID- 26735213 TI - Risk factors for cytomegalovirus DNAemia following haploidentical stem cell transplantation and its association with host hepatitis B virus serostatus. AB - BACKGROUND: The risk factors associated with CMV DNAemia are not well known after haploidentical stem cell transplantation (SCT). OBJECTIVES: This study investigated the risk factors and prognosis for CMV DNAemia among CMV seromatched donors and recipients (D+/R+). STUDY DESIGN: A retrospective study of patients undergoing haploidentical stem cell transplantation (SCT) between January 2010 and January 2012 was conducted. Cox regression analysis was performed to identify the risk factors for CMV DNAemia. These possible factors included recipient/donor age, recipient/donor gender, gender disparity, recipient HBsAg serostatus, diagnosis, risk stratification, anti-thymocyte globulin (ATG) dose (6mg/kg,10mg/kg), early neutrophil engraftment (<=12 days, >12 days), absolute lymphocyte count on day 30 (ALC30) and the occurrence of acute GVHD before CMV DNAemia. RESULTS: The total number of patients was 248 with median age of 31 years (range, 14-56). The cumulative incidence of CMV DNAemia (146/248) was 59.5%. CMV DNAemia was first detected after a median of +35 days (range,12-82). Seventeen patients (17/146, 11.6%) developed CMV disease. Multivariate analysis identified HBsAg seropositivity (P=0.002, hazard ratio (HR)=1.833; 95%CI=1.257 2.673) and the occurrence of acute GVHD before CMV DNAemia (P=0.014; HR=1.520; 95%CI=1.088-2.124) as risk factors for CMV DNAemia. CMV DNAemia was associated with subsequent II-IV acute graft-versus-host disease (GVHD) (P=0.014), III-IV aGVHD (P=0.013) and chronic GVHD (P=0.008). Totally, CMV DNAemia was found to be a poor prognostic factor in terms of non-relapse mortality (NRM) (P=0.003, HR=2.730; 95%CI=1.406-5.197), and overall survival (OS) (P=0.045, HR=1.654; 95%CI=1.012-2.701). CONCLUSIONS: Our data showed HBsAg seropositivity was associated with an increased risk of cytomegalovirus DNAemia. Detection of CMV DNAemia proved to be a poor prognostic factor for haploidentical patients. PMID- 26735219 TI - Blood flow velocity in monocular retinoblastoma assessed by color Doppler. AB - OBJECTIVE: To analyze the flow of retrobulbar vessels in retinoblastoma by color Doppler imaging. METHODS: A prospective study of monocular retinoblastoma treated by enucleation between 2010 and 2014. The examination comprised fundoscopy, magnetic resonance imaging, ultrasonography and color Doppler imaging. The peak blood velocities in the central retinal artery and central retinal vein of tumor containing eyes (tuCRAv and tuCRVv, respectively) were assessed. The velocities were compared with those for normal eyes (nlCRAv and nlCRVv) and correlated with clinical and pathological findings. Tumor dimensions in the pathological sections were compared with those in magnetic resonance imaging and ultrasonography and were correlated with tuCRAv and tuCRVv. In tumor-containing eyes, the resistivity index in the central retinal artery and the pulse index in the central retinal vein were studied in relation to all variables. RESULTS: Eighteen patients were included. Comparisons between tuCRAv and nlCRAv and between tuCRVv and nlCRVv revealed higher velocities in tumor-containing eyes (p < 0.001 for both), with a greater effect in the central retinal artery than in the central retinal vein (p = 0.024). Magnetic resonance imaging and ultrasonography measurements were as reliable as pathology assessments (p = 0.675 and p = 0.375, respectively). A positive relationship was found between tuCRAv and the tumor volume (p = 0.027). The pulse index in the central retinal vein was lower in male patients (p = 0.017) and in eyes with optic nerve invasion (p = 0.0088). CONCLUSIONS: TuCRAv and tuCRVv are higher in tumor-containing eyes than in normal eyes. Magnetic resonance imaging and ultrasonography measurements are reliable. The tumor volume is correlated with a higher tuCRAv and a reduced pulse in the central retinal vein is correlated with male sex and optic nerve invasion. PMID- 26735216 TI - Chemotherapy and prognosis in advanced thymic carcinoma patients. AB - OBJECTIVE: The role of chemotherapy in treating advanced thymic carcinoma is unclear. The purpose of the current study was to investigate the efficacy of chemotherapy and the prognostic factors for patients with advanced thymic carcinoma. METHODS: A retrospective review of the medical records of 86 patients treated with chemotherapy for advanced thymic carcinoma was conducted between 2000 and 2012 at our institution. The clinical characteristics, chemotherapy regimens and prognostic factors were analyzed. Survival curves were plotted using the Kaplan-Meier method and the Cox proportional hazard model was used for multivariate analysis. RESULTS: Of the 86 patients, 56 were male and 30 were female. The median survival time was 24.5 months. For the first-line chemotherapy treatment, the objective response rate was 47.7% and the disease control rate was 80.2%. The median progression-free survival for all patients was 6.5 months for first-line chemotherapy. No significant differences in progression-free survival were observed among the different chemotherapy regimens. Multivariate analyses revealed that the prognostic factors for overall survival included performance status (p=0.043), histology grade (p=0.048), and liver metastasis (p=0.047). CONCLUSION: Our results suggest that there is no difference in efficacy between multiagent and doublet regimens. The prognosis of patients with advanced thymic carcinoma can be predicted based on histological grade, liver metastasis and performance status. PMID- 26735221 TI - Is Doppler ultrasound useful for evaluating gestational trophoblastic disease? AB - Doppler ultrasound is a non-invasive method for evaluating vascularization and is widely used in clinical practice. Gestational trophoblastic neoplasia includes a group of highly vascularized malignancies derived from placental cells. This review summarizes data found in the literature regarding the applications of Doppler ultrasound in managing patients with gestational trophoblastic neoplasia. The PubMed/Medline, Web of Science, Cochrane and LILACS databases were searched for articles published in English until 2014 using the following keywords: "Gestational trophoblastic disease AND Ultrasonography, Doppler." Twenty-eight articles met the inclusion criteria and were separated into the 4 following groups according to the aim of the study. (1) Doppler ultrasound does not seem to be capable of differentiating partial from complete moles, but it might be useful when evaluating pregnancies in which a complete mole coexists with a normal fetus. (2) There is controversy in the role of uterine artery Doppler velocimetry in the prediction of development of gestational trophoblastic neoplasia. (3) Doppler ultrasound is a useful tool in the diagnosis of gestational trophoblastic neoplasia because abnormal myometrial vascularization and lower uterine artery Doppler indices seem to be correlated with invasive disease. (4) Lower uterine artery Doppler indices in the diagnosis of gestational trophoblastic neoplasia are associated with methotrexate resistance and might play a role in prognosis. CONCLUSION: Several studies support the importance of Doppler ultrasound in the management of patients with gestational trophoblastic neoplasia, particularly the role of Doppler velocimetry in the prediction of trophoblastic neoplasia and the chemoresistance of trophoblastic tumors. Doppler findings should be used as ancillary tools, along with human chorionic gonadotropin assessment, in the diagnosis of gestational trophoblastic neoplasia. PMID- 26735218 TI - Hepatic peroxisome proliferator-activated receptor gamma and alpha-mRNA expression in HCV-infected adults is decreased by HIV co-infection and is also affected by ethnicity. AB - OBJECTIVE: To determine peroxisome proliferator activated receptor alpha and gamma mRNA expression in liver tissue of hepatitis C virus-infected patients with and without human immunodeficiency virus and its possible contribution to an acceleration of liver disease progression. METHODS: We measured peroxisome proliferator-activated receptor alpha and gamma mRNA expression by real-time polymerase chain reaction in liver tissues from 40 subjects infected only with hepatitis C virus, 36 subjects co-infected with hepatitis C virus and human immunodeficiency virus and 11 normal adults. RESULTS: Hepatic mRNA expression of both peroxisome proliferator-activated receptors was significantly lower in hepatitis C virus-infected subjects with and without human immunodeficiency virus co-infection compared to the controls. Non-black race was also identified as a predictor of lower peroxisome receptor alpha and gamma mRNA expression. Compared to subjects infected only with hepatitis C virus, liver peroxisome receptor gamma mRNA expression was significantly lower in hepatitis C virus/human immunodeficiency virus-co-infected subjects (0.0092 in hepatitis C virus/human immunodeficiency virus-co-infection vs. 0.0120 in hepatitis C virus-only; p=0.004). Hepatic peroxisome receptor alpha mRNA expression in the hepatitis C virus-infected patients was lower in the presence of human immunodeficiency virus co-infection in non-black subjects (0.0769 vs. 0.1061; p=0.02), whereas the levels did not vary based on human immunodeficiency virus status among black subjects. CONCLUSION: mRNA expression of both peroxisome proliferator-activated receptors is impaired in hepatitis C virus-infected liver and further reduced by human immunodeficiency virus co-infection, although the suppressive effects of the viruses are substantially mitigated in black patients. PMID- 26735222 TI - Fetal growth according to different reference ranges in twin pregnancies with placental insufficiency. AB - The aim of this study was to compare different fetal growth curves in twin pregnancies with severe placental insufficiency. A retrospective cross-sectional analysis of 47 twin pregnancies with absent or reverse end diastolic flow in the umbilical artery of one fetus was performed. Pregnancies with major fetal abnormalities, twin-twin transfusion or three or more fetuses were not included. The estimated fetal weight zeta-scores were calculated for both fetuses (abnormal Doppler and co-twin) according to the following criteria: Hadlock, Liao and Araujo. The abdominal circumference zeta-scores were calculated according to Hadlock, Liao, Araujo, Ong and Stirrup. The mean estimates of the zeta-score values were calculated using generalized estimating equation regression analysis. The mean gestational age at inclusion was 27.4 +/- 4.7 weeks. The fetal sex and the interaction Doppler findings * criteria correlated significantly with the zeta-score values (p < 0.001 for both variables). The estimated fetal weight mean zeta-scores (standard error) according to each criteria were as follows: Hadlock abnormal Doppler: -2.98 (0.18), co-twin: -1.16 (0.15); Liao - abnormal Doppler: 2.89 (0.24), co-twin: -0.58 (0.19); and Araujo - abnormal Doppler: -3.05 (0.29), co-twin: -0.75 (0.18). Values for abdominal circumference were as follows: Hadlock - abnormal Doppler: -3.14 (0.26), co-twin: -1.13 (0.19); Liao - abnormal Doppler: -2.63 (0.27), co-twin: -0.42 (0.19); Araujo - abnormal Doppler: -2.44 (0.22), co-twin: -0.71 (0.14); Ong - abnormal Doppler: -3.36 (0.34), co-twin: 1.48 (0.23); and Stirrup AD -- -2.36 (0.14), co-twin: -1.18 (0.10). Sex- and plurality-specific charts should be used in the evaluation of fetal growth in twin pregnancies with placental insufficiency. PMID- 26735220 TI - Pulse pressure variation and stroke volume variation under different inhaled concentrations of isoflurane, sevoflurane and desflurane in pigs undergoing hemorrhage. AB - OBJECTIVES: Inhalant anesthesia induces dose-dependent cardiovascular depression, but whether fluid responsiveness is differentially influenced by the inhalant agent and plasma volemia remains unknown. The aim of this study was to compare the effects of isoflurane, sevoflurane and desflurane on pulse pressure variation and stroke volume variation in pigs undergoing hemorrhage. METHODS: Twenty-five pigs were randomly anesthetized with isoflurane, sevoflurane or desflurane. Hemodynamic and echocardiographic data were registered sequentially at minimum alveolar concentrations of 1.00 (M1), 1.25 (M2), and 1.00 (M3). Then, following withdrawal of 30% of the estimated blood volume, these data were registered at a minimum alveolar concentrations of 1.00 (M4) and 1.25 (M5). RESULTS: The minimum alveolar concentration increase from 1.00 to 1.25 (M2) decreased the cardiac index and increased the central venous pressure, but only modest changes in mean arterial pressure, pulse pressure variation and stroke volume variation were observed in all groups from M1 to M2. A significant decrease in mean arterial pressure was only observed with desflurane. Following blood loss (M4), pulse pressure variation, stroke volume variation and central venous pressure increased (p < 0.001) and mean arterial pressure decreased in all groups. Under hypovolemia, the cardiac index decreased with the increase of anesthesia depth in a similar manner in all groups. CONCLUSION: The effects of desflurane, sevoflurane and isoflurane on pulse pressure variation and stroke volume variation were not different during normovolemia or hypovolemia. PMID- 26735226 TI - AsMA Rings in the New Year 2016. PMID- 26735225 TI - Journal Metrics. PMID- 26735230 TI - Occupant Injury Severity and Accident Causes in Helicopter Emergency Medical Services (1983-2014). AB - BACKGROUND: Helicopter emergency medical services (HEMS) transport critically ill patients to/between emergency care facilities and operate in a hazardous environment: the destination site is often encumbered with obstacles, difficult to visualize at night, and lack instrument approaches for degraded visibility. The study objectives were to determine 1) HEMS accident rates and causes; 2) occupant injury severity profiles; and 3) whether accident aircraft were certified to the more stringent crashworthiness standards implemented two decades ago. METHODS: The National Transportation Safety Board (NTSB) aviation accident database was used to identify HEMS mishaps for the years spanning 1983-2014. Contingency tables (Pearson Chi-square or Fisher's exact test) were used to determine differences in proportions. A generalized linear model (Poisson distribution) was used to determine if accident rates differed over time. RESULTS: While the HEMS accident rate decreased by 71% across the study period, the fraction of fatal accidents (36-50%) and the injury severity profiles were unchanged. None of the accident aircraft fully satisfied the current crashworthiness standards. Failure to clear obstacles and visual-to-instrument flight, the most frequent accident causes (37 and 26%, respectively), showed a downward trend, whereas accidents ascribed to aircraft malfunction showed an upward trend over time. CONCLUSION: HEMS operators should consider updating their fleet to the current, more stringent crashworthiness standards in an attempt to reduce injury severity. Additionally, toward further mitigating accidents ascribed to inadvertent visual-to-instrument conditions, HEMS aircraft should be avionics-equipped for instrument flight rules flight. PMID- 26735227 TI - Physiological and Cognitive Effects of Acute Normobaric Hypoxia and Modulations from Oxygen Breathing. AB - INTRODUCTION: The emergence of normobaric devices for hypoxia awareness training makes crucial the study of physiological and cognitive effects induced by acute normobaric hypoxia (NH) exposure. Our study aimed to 1) investigate the effects of acute NH exposure on physiological variables and working memory; and 2) investigate the physiological and cognitive effects of oxygen breathing before and after acute NH exposure. METHODS: There were 86 healthy men who were randomized into 4 groups: the Normoxia-Air group (N = 23), whose subjects were breathing air; the Hypoxia-Air group (N = 22), where NH exposure was preceded and followed by air breathing; the Normoxia-O2group (N = 21), whose protocol was similar to the Normoxia-Air group, except with the addition of 100% O2breathing periods; and the Hypoxia-O2group (N = 20), whose participants were exposed to 100% O2before and after NH exposure. Working memory was assessed with the Paced Auditory Serial Addition Test. Peripheral oxygen saturation (Spo2), heart rate (HR), and electroencephalogram (EEG) were recorded. RESULTS: Acute NH exposure induced a classical physiological response (i.e., decreased Spo2and increased HR), but not identical to the well-described physiological response to acute hypobaric hypoxia. Acute NH also caused a strong impairment in working memory. Oxygen breathing following NH exposure induced a slowing in the EEG associated with a worsening of working memory performance. DISCUSSION: Acute NH exposure revealed a good surrogate for the classical hypobaric chamber for refresher hypoxia awareness training. Because the association between hypoxia and hyperoxia seems deleterious for the brain, we suggest that NH exposure should be surrounded by air breathing. PMID- 26735223 TI - Neonatal Near Miss: the need for a standard definition and appropriate criteria and the rationale for a prospective surveillance system. AB - In Latin American, there is currently a regional action with the main purposes of putting the concept of severe neonatal morbidity in practice and formulating proposals for interventions. A general overview of neonatal health conditions, including morbidity and mortality, is provided to update regional knowledge on the topic. An example of the development and implementation of the concept of maternal near miss is also provided, followed by results from a systematic review covering all previously published studies on Neonatal Near Miss. Finally, some proposals for building a common concept on the topic and for launching a prospective surveillance study are presented. A Neonatal Near Miss is a neonate who had a severe morbidity (organ dysfunction or failure) but who survived this condition within the first 27 days of life. The pragmatic criteria recommended to be used are as follows: birth weight below 1700 g, Apgar score below 7 at 5 minutes of life and gestational age below 33 weeks. As a proxy for organ dysfunction, the following management criteria are also confirmed: parenteral therapeutic antibiotics; nasal continuous positive airway pressure; any intubation during the first 27 days of life; phototherapy within the first 24 h of life; cardiopulmonary resuscitation; the use of vasoactive drugs, anticonvulsants, surfactants, blood products and steroids for refractory hypoglycemia and any surgical procedure. Although this study starts from a regional perspective, this topic is clearly globally relevant. All nations, especially low and middle-income countries, could benefit from the proposed standardization. PMID- 26735231 TI - Occupational Ocular UV Exposure in Civilian Aircrew. AB - INTRODUCTION: Ultraviolet radiation (UVR) increases with altitude; however, there are a number of other factors which may influence ocular exposure during flight. The aim of this study was to assess ocular UVR exposure of pilots in airline and off-shore helicopter operations on different aircraft types and to compare with exposure in a typical office environment. METHOD: In-flight data were captured on equipment including a CCD array spectroradiometer on five return sector European airline flights and one transatlantic flight from London Gatwick in addition to four helicopter flights from Aberdeen Dyce airport. Further data were collected in an office environment from three workstations during summer and winter months. RESULTS: A wide variation in ocular UVA dose was found during flights. The main factor influencing exposure was the UVR transmission of the windshield, which fell into two distinct profile types. In an aircraft with good UVA blocking properties, ocular exposure was found to be equivalent to office exposure and did not exceed international guideline limits regardless of external conditions or flight time. Most aircraft assessed had poor UVA blocking windshields which resulted in an ocular exposure to the unprotected eye in excess of international guideline limits (up to between 4.5 to 6.5 times greater during one flight). No significant UVB dose was found. DISCUSSION: Pilots should be warned of the potential high UVA exposure during flight and advised on the use of sunglasses. A windshield labeling system would allow the pilot to tailor their eye protection practices to that particular aircraft. PMID- 26735228 TI - Hypergravity Effects on the Retina and Intraocular Pressure in Mice. AB - BACKGROUND: We investigated the effect of exposure to +10.0 G for 4 h on the intraocular pressure and the retina of mice. METHODS: We exposed 10 mice to +10.0 Gz for 4 h by using a centrifugal acceleration test facility for animals. Intraocular changes were compared before and after hypergravity exposure. The eyeballs of the mice were enucleated after measuring the intraocular pressure. Tissue slides of the retina were prepared with hematoxylin and eosin (H&E) for histological examination and immunohistochemical analyses for vascular endothelial growth factor-A (VEGF-A), VEGF receptor 1 (VEGF-R1), VEGF-R2, glial fibrillary acidic protein (GFAP), and glutamine synthetase (GS). RESULTS: The average intraocular pressure was 7.7 +/- 0.86 mmHg before the hypergravity exposure and 6.65 +/- 0.67 mmHg after the exposure. No histological difference was observed between the retinas in the two groups. The levels of VEGF-A, VEGF R1, VEGF-R2, GFAP, and GS as assessed by immunohistochemistry were increased in the group exposed to hypergravity compared to the control group. DISCUSSION: Repeated exposure to a high level of hypergravity could cause elevation of intraocular pressure and hypoxic damage to the retina. PMID- 26735229 TI - Respiratory Muscle Training and Cognitive Function Exercising at Altitude. AB - BACKGROUND: Hiking and trekking often occur at altitudes up to 12,000 ft altitude. The hypoxia-induced hyperventilation at altitude paradoxically reduces arterial CO2 (Paco2). A reduction in Paco2 results in vasoconstriction of the blood vessels of the brain and thus in local hypoxia. The local hypoxia likely affects cognitive function, which may result in reduced performance and altitude accidents. Recent publications have demonstrated that voluntary isocapnic hyperventilatory training of the respiratory muscles (VIHT) can markedly enhance exercise endurance as it is associated with reduced ventilation and its energy cost. VIHT may be useful in blunting the altitude-induced hyperventilation leading to higher Paco2 and improved cognitive function. METHODS: This study examined the effects of VIHT, compared to control (C) and placebo (PVIHT) groups, on selected measures of executive functioning, including working memory and processing speed (i.e., Stroop Test, Symbol Digit Modalities Test, and Digit Span Forward) at simulated altitude up to 12,000 ft. Associated physiological parameters were also measured. RESULTS: The Digit Span Forward Test did not show improvements after VIHT in any group. The VIHT group, but not C or PVIHT groups, improved significantly (17-30%) on the Stroop Test. Similarly the VIHT group, but not the C and PVIHT groups, improved correct responses (26%) and number of attempts (24%) on the Symbol Digit Modalities Test. In addition, reaction time was also improved (16%). CONCLUSION: VIHT improved processing speed and working memory during exercise at altitude. PMID- 26735234 TI - Fitness to Fly Testing in Patients with Congenital Heart and Lung Disease. AB - BACKGROUND: During commercial air travel passengers are exposed to a low ambient cabin pressure, comparable to altitudes of 5000 to 8000 ft (1524 to 2438 m). In healthy passengers this causes a fall in partial pressure of oxygen, which results in relative hypoxemia, usually without symptoms. Patients with congenital heart or lung disease may experience more severe hypoxemia during air travel. This systematic review provides an overview of the current literature focusing on whether it is safe for patients with congenital heart or lung disease to fly. METHODS: The Pubmed database was searched and all studies carried out at an (simulated) altitude of 5000-8000 ft (1524-2438 m) for a short time period (several hours) and related to patients with congenital heart or lung disease were reviewed. RESULTS: Included were 11 studies. These studies examined patients with cystic fibrosis, neonatal (chronic) lung disease and congenital (a)cyanotic heart disease during a hypoxic challenge test, in a hypobaric chamber, during commercial air travel, or in the mountains. Peripheral/arterial saturation, blood gases, lung function, and/or the occurrence of symptoms were listed. DISCUSSION: Based on the current literature, it can be concluded that air travel is safe for most patients. However, those at risk of hypoxia can benefit from supplemental in flight oxygen. Therefore, patients with congenital heart and lung disease should be evaluated carefully prior to air travel to select the patients at risk for hypoxia using the current studies and guidelines. PMID- 26735233 TI - Posture and Helmet Load Influences on Neck Muscle Activation. AB - INTRODUCTION: Night vision goggles (NVG) are linked to increased neck muscle activation and pain. Counterweights (NVGcw) are hypothesized to mitigate these effects. The purpose of this study was to investigate the muscular response to varying helmet loads and postures. METHODS: Volunteering from a representative squadron were 16 male helicopter aviators (pilots, N = 9; flight engineers, N = 7). Subjects performed head movements to assume nine different postures (three directions: left, center, and right, at three different levels: down, level, and up) with four different head loads (no helmet; helmet only; NVG; and NVGcw) in randomized order. Subjects were provided real time visual guidance and feedback while assuming the appropriate posture in a cockpit seat in a laboratory setting. Neck muscle activation was assessed with electromyography (EMG) of four different muscle groups, bilaterally, including the sternocleidomastoid, splenius capitis, and mid and lower trapezius. RESULTS: Two- to fourfold increases in muscle activation were observed in postures to the left (down, level, and up) while subjects wore either the NVG or NVGcw as compared to the baseline of no helmet. This was most prevalent in smaller muscle groups (i.e., the sternocleidomastoid and splenius capitis) as compared to larger muscle groups (i.e., the mid and lower trapezius). DISCUSSION: The use of NVGcw did not decrease neck muscle activity as compared to NVG only, particularly when the head posture moved the field of view below the horizon. This suggests interventions to decrease neck muscle activity and fatigue in military helicopter aircrew using NVG should focus on task specific guidelines with respect to countermeasures. PMID- 26735235 TI - Equivalent Air Altitude and the Alveolar Gas Equation. AB - INTRODUCTION: It is expedient to use normobaric hypoxia (NH) as a surrogate for hypobaric hypoxia (HH) for training and research. The approach matches inspired oxygen partial pressure (P(I)o2) at the desired altitude to that at site pressure (PB) by reducing the inspired fraction of oxygen (FIo2) to <0.21 using the equation: PIo2= (PB - 47) * FIo2, where 47 mmHg is the vapor pressure of water at 37 degrees C. The investigator then has at site pressure the equivalent PIo2 as at altitude, i.e., the NH exposure is at an "equivalent air altitude." Some accepted as fact identical signs and symptoms of hypoxia for both conditions. However, those that derived the alveolar air equation showed that the coupled alveolar oxygen (PAo2) and carbon dioxide partial pressures (PAco2) for NH and HH are not identical when PIo2is equivalent. They attribute the difference in alveolar gas composition under equivalent PIo2to a nitrogen dilution effect or, more generally, to the respiratory exchange effect. Those that use NH as a convenient surrogate for HH must concede that physiological responses to NH cannot be identical to the responses to HH given only equivalent hypoxic PIo2. PMID- 26735232 TI - Pilots' Visual Scan Patterns and Attention Distribution During the Pursuit of a Dynamic Target. AB - INTRODUCTION: The current research was to investigate pilots' visual scan patterns in order to assess attention distribution during air-to-air maneuvers. METHODS: A total of 30 qualified mission-ready fighter pilots participated in this research. Eye movement data were collected by a portable head-mounted eye tracking device, combined with a jet fighter simulator. To complete the task, pilots had to search for, pursue, and lock on a moving target while performing air-to-air tasks. RESULTS: There were significant differences in pilots' saccade duration (ms) in three operating phases, including searching (M = 241, SD = 332), pursuing (M = 311, SD = 392), and lock-on (M = 191, SD = 226). Also, there were significant differences in pilots' pupil sizes (pixel(2)), of which the lock-on phase was the largest (M = 27,237, SD = 6457), followed by pursuit (M = 26,232, SD = 6070), then searching (M = 25,858, SD = 6137). Furthermore, there were significant differences between expert and novice pilots in the percentage of fixation on the head-up display (HUD), time spent looking outside the cockpit, and the performance of situational awareness (SA). DISCUSSION: Experienced pilots have better SA performance and paid more attention to the HUD, but focused less outside the cockpit when compared with novice pilots. Furthermore, pilots with better SA performance exhibited a smaller pupil size during the operational phase of lock on while pursuing a dynamic target. Understanding pilots' visual scan patterns and attention distribution are beneficial to the design of interface displays in the cockpit and in developing human factors training syllabi to improve the safety of flight operations. PMID- 26735236 TI - Biodynamic Hypothesis for the Frequency Tuning of Motion Sickness. AB - INTRODUCTION: Motion sickness is often provoked by oscillatory translational (linear) acceleration. For humans, motion frequencies around 0.2-0.3 Hz are the most provocative. A current explanation for this frequency band is that it spans a region of maximum ambiguity concerning the interpretation of vestibular signals. Below 0.2-0.3 Hz, linear accelerations are interpreted as 'tilt', whereas at higher frequencies accelerations are interpreted as 'translation', i.e., linear motion through space. This is termed the 'tilt-translation' hypothesis. However, the origin of this particular frequency range is unclear. We investigated whether the differential perceptions of oscillations at different frequencies derives from the biodynamics of active self-initiated whole body motion. METHODS: Video-films were taken of subjects running slaloms of various combinations of lengths/amplitudes to provoke a range of temporal frequencies of slalom (reciprocal of time to run a cycle). RESULTS: The usual tactic for cornering at frequencies <0.25 Hz was whole-body tilt, whereas >0.4 Hz lateropulsion of the legs with torso erect was observed. Between these frequencies subjects showed variable tactics, mixing components of both tilt and lateropulsion. CONCLUSIONS: This uncertainty in selecting the appropriate tactic for movement control around 0.2-0.3 Hz is the possible origin of 'tilt translation' ambiguity. It also follows that externally imposed motion around these frequencies would challenge both perception and motor control, with the consequence of motion sickness. PMID- 26735237 TI - Blue Laser Induced Retinal Injury in a Commercial Pilot at 1300 ft. AB - BACKGROUND: We report what may be the first evidence-based report of a retinal laser injury to a pilot during commercial flight from a laser device on the ground. Given the significant subjective (blind spot) and objective evidence of focal retinal damage, coupled with the distance involved, we suspect the laser had a radiant power of several watts, known to be injurious to the human retina. CASE REPORT: An airline pilot presented to our department complaining of a blind spot in the upper left area of his visual field in the right eye (right supero nasal scotoma) following exposure to a laser beam while performing a landing maneuver of a commercial aircraft. At around 1300 ft (396 m), a blue laser beam from the ground directly entered his right eye, with immediate flash blindness and pain. Spectral domain ocular coherence tomography highlighted a localized area of photoreceptor disruption corresponding to a well demarcated area of hypofluorescence on fundus autofluorescence, representing a focal outer retinal laser injury. Fundus examination a fortnight later revealed a clinically identifiable lesion in the pilot's right eye commensurate with a retinal-laser burn. DISCUSSION: The case reports highlights the growing threat to the ocular health of airline crew and, potentially, passenger safety due to the lack of regulatory oversight of high powered laser devices obtained from the internet. We strongly believe high powered handheld laser devices should not be in the possession of the general public. PMID- 26735238 TI - Motion Sickness Prediction in Aeromedical Evacuation of Patients with Ebola. AB - INTRODUCTION: Aeromedical evacuation of patients affected by severe infectious diseases inside an aircraft transit isolator (ATI) system is at potential risk of motion sickness (MS). A test flight was then conducted to quantify this risk during the transfer of an Ebola patient from West Africa to Italy. CASE REPORT: A mannequin was inserted inside an ATI and instrumented to provide acceleration parameters throughout the test flight. The analysis of the data predicted a MS incidence of about 2% for a 6-h flight, so the decision to use anti-MS drugs only in selected cases was taken (i.e., those with positive past history of MS, gastrointestinal disorders, or residual carsickness due to previous ambulance run). On this basis, an actual aeromedical evacuation of an Ebola patient was successfully performed without the use of any anti-MS drugs. DISCUSSION: During aeromedical evacuation with ATI systems, the patient's risk of MS should be evaluated on an individual basis and calibrated according to the specific exposure to motion evoked by the flight platform used. Due to the possible onset of untoward effects, prevention with anti-MS drugs in these patients should be limited to selected cases. PMID- 26735241 TI - This Month in Aerospace Medicine History. PMID- 26735239 TI - You're the Flight Surgeon. Popliteal artery entrapment syndrome. AB - Pearson VM. You're the flight surgeon: popliteal artery entrapment. Aerosp Med Hum Perform. 2016; 87(1):75-78. PMID- 26735240 TI - You're the Flight Surgeon. Malaria. AB - Li HL. You're the flight surgeon: malaria. Aerosp Med Hum Perform. 2016; 87(1):78 81. PMID- 26735242 TI - Structure of developmental gene regulatory networks from the perspective of cell fate-determining genes. AB - The core of gene regulatory networks (GRNs) is formed by transcription factors (TF) and cis-regulatory modules (CRMs) present in their downstream genes. GRNs have a modular structure in which complex circuitries link TFs to CRMs to generate specific transcriptional outputs. (1) Of particular interest are those GRNs including cell fate-determining genes, as they constitute developmental switches which activity is necessary and sufficient to promote particular cellular fates. Most of the genetic analysis of developmental processes deals with the composition and structure of GRNs acting upstream of cell fate determining genes, as they are best suited for genetic analysis and molecular deconstruction. More recently, the application of a variety of in vivo, computational and genome-wide approaches is allowing the identification and functional analysis of GRNs acting downstream of cell fate-determining genes. In this review we discuss several examples of GRNs acting upstream and downstream of cell fate-determining genes, including other TFs which activity pervade across both regulatory networks. PMID- 26735261 TI - Reconciling the Log-Linear and Non-Log-Linear Nature of the TSH-Free T4 Relationship: Intra-Individual Analysis of a Large Population. AB - CONTEXT: The TSH-T4 relationship was thought to be inverse log-linear, but recent cross-sectional studies report a complex, nonlinear relationship; large, intra individual studies are lacking. OBJECTIVE: Our objective was to analyze the TSH free T4 relationship within individuals. METHODS: We analyzed data from 13 379 patients, each with six or more TSH/free T4 measurements and at least a 5-fold difference between individual median TSH and minimum or maximum TSH. Linear and nonlinear regression models of log TSH on free T4 were fitted to data from individuals and goodness of fit compared by likelihood ratio testing. RESULTS: Comparing all models, the linear model achieved best fit in 31% of individuals, followed by quartic (27%), cubic (15%), null (12%), and quadratic (11%) models. After eliminating least favored models (with individuals reassigned to best fitting, available models), the linear model fit best in 42% of participants, quartic in 43%, and null model in 15%. As the number of observations per individual increased, so did the proportion of individuals in whom the linear model achieved best fit, to 66% in those with more than 20 observations. When linear models were applied to all individuals and averaged according to individual median free T4 values, variations in slope and intercept indicated a nonlinear log TSH-free T4 relationship across the population. CONCLUSIONS: The log TSH-free T4 relationship appears linear in some individuals and nonlinear in others, but is predominantly linear in those with the largest number of observations. A log-linear relationship within individuals can be reconciled with a non-log-linear relationship in a population. PMID- 26735260 TI - Polymorphism rs2274911 of GPRC6A as a Novel Risk Factor for Testis Failure. AB - CONTEXT: The G protein-coupled receptor GPRC6A is an emerging effector with multiple endocrine roles, including stimulation of T production from the testis. Recently, two men with an inactivating mutation (F464Y) of GPRC6A have been identified, and they showed primary testicular failure and deranged spermatogenesis. Furthermore, one of them also reported cryptorchidism at birth. In addition, a polymorphism (rs2274911, Pro91Ser) in GPRC6A is associated with prostate cancer, a typical androgen-sensitive cancer. OBJECTIVE: To study the possible association between rs2274911 polymorphism and male fertility and/or cryptorchidism. Design, Patients, Settings: A total of 611 subjects, including 343 infertile patients, 197 normozoospermic controls, and 71 cryptorchid newborns, were retrospectively selected. METHODS: Sequencing analysis for rs2274911 polymorphism and F464Y mutation, and serum levels of FSH, LH, and T were assessed. In vitro functional studies for rs2274911 and F464Y were also performed. RESULTS: Homozygous subjects for the risk allele A of rs2274911 had a 4.60-fold increased risk of oligozoospermia and 3.52-fold increased risk of cryptorchidism. A significant trend for increased levels of LH in the GA and AA genotypes, compared with GG homozygotes, was detected in men with azoospermia/cryptozoospermia (P for trend = .027), further supporting an association with primary testicular failure. The mutation F464Y was found in one cryptorchid child (one in 71; 1.41%). Functional studies showed that the A allele of rs2274911 and the F464Y substitution were associated with lower exposition of the receptor on the cell membrane and a reduced downstream phosphorylation of ERK1/2 with respect to wild type. CONCLUSION: Our results suggest that GPRC6A inactivation or sub-function contributes to reduced exposure to androgens, leading to cryptorchidism during fetal life and/or low sperm production in adulthood. PMID- 26735258 TI - Report on Racial Disparities in Hospitalized Patients with Hyperglycemia and Diabetes. AB - CONTEXT: A higher prevalence of diabetes-related complications is reported in minority populations; however, it is not known if there are racial disparities in diabetes care and outcomes in hospitalized patients. OBJECTIVE: Our objective was to determine the association between hyperglycemia, in patients with and without diabetes mellitus (non-DM), and complications among different racial groups. DESIGN: This observational study compared the frequency of hyperglycemia (blood glucose >= 180 mg/dL; 10 mmol/L) and DM and hospital complications between Black and White patients hospitalized patients between January 2012 and December 2013. SETTING AND PARTICIPANTS: Adults admitted to medical and surgery services in two academic hospitals were included in this study. RESULTS: Among 35 866 patients, there were 14 387 Black (40.1%) and 21 479 White patients (59.9%). Blacks had a higher prevalence of hyperglycemia (42.3% vs 36.7%, P < .0001) and DM (34.5% vs 22.8%, P < .0001) and a higher admission rate and mean daily blood glucose (P < .001). Blacks also had higher rates of complications (22.2% vs 19.2%, P < .0001), both in patients with DM (24.7 vs 22.9%, P = .0413) and non-DM with hyperglycemia (41.2% vs 37.2%, P = .0019). Using sequential modelling adjusted for age, gender, body mass index, comorbidities, and insurance coverage, non-DM Blacks with normoglycemia (odds ratio, 1.22; 95% confidence interval, 1.10-1.35) and non-DM Blacks with hyperglycemia (odds ratio, 1.18; 95% confidence interval, 1.04-1.33) had higher number of complications compared to Whites. CONCLUSIONS: Black patients have higher rates of hyperglycemia and diabetes, worse inpatient glycemic control, and greater frequency of hospital complications compared to Whites. Non-DM Blacks with hyperglycemia are a particularly vulnerable group. Further investigation is needed to better understand factors contributing the racial disparities in the hospital. PMID- 26735259 TI - A Novel Thyrotropin-Releasing Hormone Receptor Missense Mutation (P81R) in Central Congenital Hypothyroidism. AB - CONTEXT: Isolated central congenital hypothyroidism (CCH) is rare and evades diagnosis on TSH-based congenital hypothyroidism (CH) screening programs in the United Kingdom. Accordingly, genetic ascertainment facilitates diagnosis and treatment of familial cases. Recognized causes include TSH beta subunit (TSHB) and Ig superfamily member 1 (IGSF1) mutations, with only two previous reports of biallelic, highly disruptive mutations in the TRH receptor (TRHR) gene. CASE DESCRIPTION: A female infant presenting with prolonged neonatal jaundice was found to have isolated CCH, with TSH of 2.2 mU/L (Reference range, 0.4-3.5) and free T4 of 7.9 pmol/L (0.61 ng/dL) (Reference range, 10.7-21.8 pmol/L). Because TSHB or IGSF1 mutations are usually associated with profound or X-linked CCH, TRHR was sequenced, and a homozygous mutation (p.P81R) was identified, substituting arginine for a highly conserved proline residue in transmembrane helix 2. Functional studies demonstrated normal cell membrane expression and localization of the mutant TRHR; however, its ability to bind radio-labelled TRH and signal via Gqalpha was markedly impaired, likely due to structural distortion of transmembrane helix 2. CONCLUSIONS: Two previously reported biallelic, highly disruptive (nonsense; R17*, in-frame deletion and single amino acid substitution; p.[S115-T117del; A118T]) TRHR mutations have been associated with CCH; however, we describe the first deleterious, missense TRHR defect associated with this phenotype. Importantly, the location of the mutated amino acid (proline 81) highlights the functional importance of the second transmembrane helix in mediating hormone binding and receptor activation. Future identification of other naturally occurring TRHR mutations will likely offer important insights into the molecular basis of ligand binding and activation of TRHR, which are still poorly understood. PMID- 26735263 TI - Authenticity in Obesity Public Service Announcements: Influence of Spokesperson Type, Viewer Weight, and Source Credibility on Diet, Exercise, Information Seeking, and Electronic Word-of-Mouth Intentions. AB - This study examined the joint influence of spokesperson type in obesity public service announcements (PSAs) and viewer weight on diet intention, exercise intention, information seeking, and electronic word-of-mouth (eWoM) intention. Results of a 2 (spokesperson type: real person vs. actor) * 2 (viewer weight: overweight vs. non-overweight) between-subjects experiment indicated that overweight viewers who saw the PSA featuring the real person had the highest diet intention, exercise intention, information seeking, and eWoM intention. Parasocial interaction was also found to mediate the relationships between spokesperson type/viewer weight and two of the dependent variables: diet intention and exercise intention. In addition, viewers who saw the PSA featuring the real person rated the spokesperson as significantly higher on source credibility (trustworthiness, competence, and goodwill) than those who saw the PSA featuring the actor. PMID- 26735287 TI - ABSTRACTS FROM THE 2014 EUROPEAN VETERINARY DIAGNOSTIC IMAGING ANNUAL CONFERENCE. Utrecht, The Netherlands, August 27 - August 30, 2014. PMID- 26735262 TI - IL4 gene polymorphisms in Iranian patients with autoimmune hepatitis. AB - BACKGROUND: Autoimmune hepatitis (AIH) is a chronic long-lasting hepatocellular inflammation associated with circulating auto antibodies. In addition to the genetic component, several cytokines have been implicated to be involved in AIH. This study was performed to investigate potential associations of AIH with IL4 gene variants. METHOD: The studied alleles and genotypes included: IL4G/T allele polymorphisms at position -1098 and C/T allele polymorphisms at two positions ( 33 and -590) on the IL4 gene, in addition to the A/G allele polymorphisms at position +1902 on the IL4RA gene. RESULT: The IL4 C allele and CC genotype at position -590 and TT genotype at position -33 had a significantly higher frequency in AIH patients. CONCLUSION: This study identified the IL4 C allele and CC genotype susceptibility gene in AIH, which will provide better insights into the mechanisms of AIH and potential therapeutic interventions. PMID- 26735264 TI - Triple-combination treatment with oral alpha-lipoic acid, betamethasone injection, and NB-UVB for non-segmental progressive vitiligo. AB - BACKGROUND: Vitiligo is an acquired depigmenting disease with uncertain etiopathogenesis and the treatment modalities need to be consistently updated. AIM: To evaluate a triple-combination treatment with oral alpha-lipoic acid (ALA), betamethasone injection, and narrowband ultraviolet B (NB-UVB) on vitiligo. METHODS: Patients with non-segmental and progressive vitiligo lesions were randomly assigned to two groups. The treatment group and the control group were respectively treated with oral ALA and placebo, in combination with betamethasone injection and NB-UVB. The effectiveness and adverse events were evaluated by investigators and patients before and after treatment. RESULTS: Fifty non-segmental progressive vitiligo patients were enrolled in the study. The treatment period was 6 months. In treatment group, over 40% patients achieved > 50% improvement and >= 5 satisfaction score by 3-month therapy (M3). This percentage increased to 90% at M6. Treatment group achieved better efficacy than control group at M3, while no difference was seen at M6. CONCLUSION: The combined treatment with oral ALA, betamethasone injection, and NB-UVB was effective and safe on non-segmental progressive vitiligo. ALA could accelerate the initial response of repigmentation. PMID- 26735295 TI - Does telephone scheduling assistance increase mammography screening adherence? AB - OBJECTIVES: The 2 objectives were: 1) describe the use of a patient navigation process utilized to promote adherence to mammography screening within a primary care practice, and 2) determine the result of the navigation process and estimate the time required to increase mammography screening with this approach in a commercially insured patient population enrolled in a health maintenance organization. STUDY DESIGN: An evaluation of a nonrandomized practice improvement intervention. METHODS: Women eligible for mammography (n = 298) who did not respond to 2 reminder letters were contacted via telephone by a navigator who offered scheduling assistance for mammography screening. The patient navigator scheduled appointments, documented the number of calls, and confirmed completed mammograms in the electronic health record, as well as estimated the time for calls and chart review. RESULTS: Of the 188 participants reached by phone, 112 (59%) scheduled appointments using the patient navigator, 35 (19%) scheduled their own appointments independently prior to the call, and 41 (22%) declined. As a result of the telephone intervention, 78 of the 188 women reached (41%) received a mammogram; also, all 35 women who had independently scheduled a mammogram received one. Chart documentation confirmed that 113 (38%) of the cohort of 298 women completed a mammogram. The estimated time burden for the entire project was 55 hours and 33 minutes, including calling patients, scheduling appointments, and chart review. CONCLUSIONS: A patient navigator can increase mammography adherence in a previously nonadherent population by making the screening appointment while the patient is on the phone. PMID- 26735293 TI - Using sequence discovery to target outreach for diabetes medication adherence. AB - OBJECTIVES: To investigate exposure sequences correlated with gaps in diabetes medication refills and to identify opportunities for targeted outreach for improved adherence. STUDY DESIGN: Sequence discovery was used to identify exposures from various data sources that preceded a gap in diabetes medication refills. METHODS: Patients who refilled a diabetes medication and had 6 months of continuous refill history were included. Patients with a therapy gap between February 1, 2012, and March 31, 2013, formed the gap group; those without formed the no-gap group. Gaps were defined as a prescription refill obtained 6 days or more after the days' supply of the previous refill. Exposure sequences were explored in the 90 days before the gap, or before the date of last refill in the study period for the no-gap group. Exposures and sequences offering opportunity for health plan outreach were identified based on sequence length, confidence, number of intervention points, and higher gap group prevalence. RESULTS: Three exposure sequences with the greatest outreach opportunity to impact downstream adherence were identified within individuals taking diabetes medications who: 1) are prescribed a new medication-especially those with multiple out-of-network claims and/or visit a specialty physician after the new medication is prescribed; 2) have a prescription claim reversed by a pharmacist-particularly patients who are subsequently prescribed a new medication or visit a specialty physician; and 3) have multiple out-of-network claims and a hospitalization. CONCLUSIONS: As medication adherence is a persisting challenge, novel application of sequence discovery techniques identified unique sequences of events with opportunities for outreach. PMID- 26735289 TI - Favorable outcomes in octogenarians treated with bioresorbable polymer drug eluting stent. AB - AIM: As a result of a higher prevalence of comorbidities, elderly adults are often underrepresented in clinical trials, and more often experience complications during percutaneous coronary intervention. Our aim was to evaluate clinical outcomes of patients older than 80 years, compared with their younger counterparts, when bioresorbable polymer biolimus A9 drug-eluting stent is used for their treatment. METHODS: The prospective, observational e-Nobori registry was created to validate the safety and efficacy of bioresorbable polymer drug eluting stent in unselected patients. The primary end-point of the study was freedom from target lesion failure defined as a composite of cardiac death, target vessel-related myocardial infarction and clinically-driven target lesion revascularization at 1 year. RESULTS: There were 781 (7.8%) octogenarians, they were less frequently male (62% vs 77%; P < 0.0001) and more often presented as acute coronary syndrome (44% vs 39%; P = 0.0182). The index percutaneous coronary intervention success was lower in the elderly patients (98% vs 99%; P = 0.0398). One-year follow up was completed for 97% of the elderly patients and 99% of the younger patients. The difference in target lesion failure (3.33% vs 2.83%; log rank P = 0.0114) was mainly driven by increased mortality in octogenarians (3.73% vs 1.47%; P < 0.0001). Elderly patients had more bleeding and vascular complications (2.67% vs 1.05%; P = 0.0001). CONCLUSIONS: Despite advanced age, multiple comorbidities and complexity of treated lesions, clinical outcomes are favorable in octogenarians treated by bioresorbable polymer biolimus A9 drug eluting stent. Geriatr Gerontol Int 2016; 16: 1246-1253. PMID- 26735292 TI - Attributes common to programs that successfully treat high-need, high-cost individuals. AB - Using literature review and interviews, we have identified 8 attributes of programs, such as accountable care organizations, readmission initiatives, special needs plans, care transition programs, and patient-centered medical homes, that successfully treat high-need, high-cost patients. These 8 attributes- illustrated here with specific examples--are specific ways to target these types of individuals, promote leadership at various levels, emphasize interaction with the care coordinator, use data strategically to refine the program, update the program periodically, allow physicians to spend more time with patients, and promote interaction among clinicians and high-need, high cost patients and their families. PMID- 26735294 TI - Anticoagulation in atrial fibrillation: impact of mental illness. AB - OBJECTIVES: To characterize warfarin eligibility and receipt among Veterans Health Administration (VHA) patients with and without mental health conditions (MHCs). STUDY DESIGN: Retrospective cohort study. METHODS: This observational study identified VHA atrial fibrillation (AF) patients with and without MHCs in 2004. We examined unadjusted MHC-related differences in warfarin eligibility and warfarin receipt among warfarin-eligible patients, using logistic regression for any MHC and for specific MHCs (adjusting for sociodemographic and clinical characteristics). RESULTS: Of 125,670 patients with AF, most (96.8%) were warfarin-eligible based on a CHADS2 stroke risk score. High stroke risk and contraindications to anticoagulation were both more common in patients with MHC. Warfarin-eligible patients with MHC were less likely to receive warfarin than those without MHC (adjusted odds ratio [AOR], 0.90; 95% CI, 0.87-0.94). The association between MHC and warfarin receipt among warfarin-eligible patients varied by specific MHC. Patients with anxiety disorders (AOR, 0.86; 95% CI, 0.80 0.93), psychotic disorders (AOR, 0.77; 95% CI, 0.65-0.90), and alcohol use disorders (AOR 0.62, 95% CI 0.54-0.72) were less likely to receive warfarin than patients without these conditions, whereas patients with depressive disorders and posttraumatic stress disorder were no less likely to receive warfarin than patients without these conditions. CONCLUSIONS: Compared with patients with AF without MHCs, those with MHCs are less likely to be eligible for warfarin receipt and, among those eligible, are less likely to receive such treatment. Although patients with AF with MHC need careful assessment of bleeding risk, this finding suggests potential missed opportunities for more intensive therapy among some individuals with MHCs. PMID- 26735290 TI - Formation of Small Gold Nanoparticle Chains with High NIR Extinction through Bridging with Calcium Ions. AB - The self-assembly of citrate-capped Au nanoparticles (5 nm) resulted in branched nanochains by adding CaCl2 versus spherical nanoclusters for NaCl. These assemblies were formed between 1 s to 30 min by tuning the electrostatic repulsion and the interparticle bridging attraction between the cations and citrate ligands as a function of electrolyte concentration. For dilute Ca(2+), strong interparticle bridging favored particle attachment at chain ends. This resulted in the formation of small, branched chains with lengths as short as 20 nm, due to the large Debye length for the diffuse counterions. Furthermore, the bridging produced very small interparticle spacings and sintering, as evident in high-resolution TEM despite the low temperature. This morphology produced a large red shift in the surface plasmon resonance, as characterized by a broad extinction peak with NIR absorption out to 1000 nm, which is unusual for such small particles. Whereas these properties were seen for primary particles with partial citrate monolayers, the degrees of sintering and NIR extinction were small in the case of citrate multilayers. The ability to design the size and shape of nanoparticle clusters as well as the interparticle spacing by tuning bridging and electrostatic interactions may be expected to be quite general and of broad applicability in materials synthesis. PMID- 26735296 TI - Will preoperative smoking cessation programs generate long-term cessation? A systematic review and meta-analysis. AB - OBJECTIVES: The aim of this review was to examine published randomized controlled trials (RCTs) and quasi-experimental studies that evaluate the association between preoperative smoking cessation programs and long-term smoking cessation at a minimum of 6 months, postoperatively. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A systematic review was performed utilizing MEDLINE, EMBASE, CINAHL, PSYCHinfo, and COCHRANE databases. All eligible studies of smoking-cessation interventions initiated preoperatively, with cessation measured at a minimum of 6 months postoperatively, were identified. The effect of cessation interventions at 12 months postoperatively in RCTs was evaluated through meta-analyses using Mantel-Haenszel risk ratios (RRs) and 95% CIs. A fixed effects model was conducted initially; however, due to heterogeneity in study characteristics and patient cohorts, a more conservative random effects model was also performed. RESULTS: Four RCTs and 4 quasi-experimental studies were included. Two RCTs demonstrated an association between interventions and cessation at 12 months, and the quasi-experimental studies showed cessation rates of 48% to 56% at 12 months, postoperatively. In a fixed effects model, interventions were associated with a greater likelihood of cessation at 12 months (RR, 1.50; 95% CI, 1.05-2.15; P = .02), although this effect was not statistically significant after applying a random effects model (RR, 1.61; 95% CI, 0.88-2.96; P = .12). CONCLUSIONS: The literature suggests that preoperative smoking cessation programs will likely precipitate long-term (>=12 months) cessation. Additional studies should identify approaches that optimize preoperative cessation programs in the promotion of short-term, and long-term cessation. PMID- 26735298 TI - Sexual Motives in Heterosexual Women With and Without Sexual Difficulties. AB - Previous research indicates that women with sexual problems may have different reasons for engaging in sex than women who are not experiencing sexual problems. The current study investigated whether reasons for sex differed by women reporting high versus low overall sexual functioning, as assessed by the Female Sexual Function Index (FSFI) (Rosen et al., 2000). As low desire and inability to achieve orgasm are the two most commonly reported sexual problems for women, the study also investigated whether women with and without problems specifically related to sexual desire or orgasm cited different reasons for sex. The sample consisted of 446 heterosexual women between the ages of 18 and 61 who completed an online questionnaire assessing reasons for sex and sexual functioning. Women with low sexual functioning overall were more likely to endorse insecurity reasons for sex, while women with high sexual functioning overall were more likely to endorse physical reasons for sex. Women experiencing low desire specifically were less likely to endorse emotional and physical reasons for sex than women without desire difficulties. Women experiencing orgasm difficulties specifically were more likely to endorse insecurity reasons for sex than women without orgasm difficulties. The variance accounted for was low in all cases. This research offers insights into the important but limited role sexual functioning may play in the broader context of women's sexual motivations. PMID- 26735297 TI - Schooling, Local Knowledge and Working Memory: A Study among Three Contemporary Hunter-Gatherer Societies. AB - Researchers have analysed whether school and local knowledge complement or substitute each other, but have paid less attention to whether those two learning models use different cognitive strategies. In this study, we use data collected among three contemporary hunter-gatherer societies with relatively low levels of exposure to schooling yet with high levels of local ecological knowledge to test the association between i) schooling and ii) local ecological knowledge and verbal working memory. Participants include 94 people (24 Baka, 25 Punan, and 45 Tsimane') from whom we collected information on 1) schooling and school related skills (i.e., literacy and numeracy), 2) local knowledge and skills related to hunting and medicinal plants, and 3) working memory. To assess working memory, we applied a multi-trial free recall using words relevant to each cultural setting. People with and without schooling have similar levels of accurate and inaccurate recall, although they differ in their strategies to organize recall: people with schooling have higher results for serial clustering, suggesting better learning with repetition, whereas people without schooling have higher results for semantic clustering, suggesting they organize recall around semantically meaningful categories. Individual levels of local ecological knowledge are not related to accurate recall or organization recall, arguably due to overall high levels of local ecological knowledge. While schooling seems to favour some organization strategies this might come at the expense of some other organization strategies. PMID- 26735291 TI - The efficacy of conditioned media of adipose-derived stem cells combined with ablative carbon dioxide fractional resurfacing for atrophic acne scars and skin rejuvenation. AB - OBJECTIVE: To evaluate the effects of conditioned medium of adipose-derived stem cells (ADSC-CM) on efficacy and side effects after fractional carbon dioxide laser resurfacing (FxCR) when treating subjects with facial atrophic acne scars or with skin rejuvenation needs. MATERIALS AND METHODS: Twenty-two subjects were enrolled in the study and divided into two groups. Nine subjects were included in skin rejuvenation group and thirteen subjects were included in acne scar group, and all subjects underwent three sessions of FxCR. ADSC-CM was applied on FxCR site of one randomly selected face side. Evaluations were done at baseline, 1 week after first treatment, and 1 month after each treatment. The outcome assessments included subjective satisfaction scale; blinded clinical assessment; and the biophysical parameters of roughness, elasticity, skin hydration, transepidermal water loss (TEWL), and the erythema and melanin index. Biopsies taken from one subject in skin rejuvenation group were analyzed using hematoxylin and eosin, Masson's Trichrome, and Gomori's aldehyde fuchsin staining. RESULTS: ADSC-CM combined with FxCR increased subject satisfaction, elasticity, skin hydration, and skin elasticity and decreased TEWL, roughness, and the melanin index in both acne scars and skin rejuvenation groups. Histologic analysis showed that ADSC-CM increased dermal collagen density, elastin density, and arranged them in order. CONCLUSION: ADSC-CM with FxCR is a good combination therapy for treating atrophic acne scars and skin rejuvenation. TRIAL REGISTRATION: JSPH2012 082 - Registered 14 Feb 2012. PMID- 26735299 TI - Environmental Light Exposure Is Associated with Increased Body Mass in Children. AB - The timing, intensity, and duration of exposure to both artificial and natural light have acute metabolic and physiological effects in mammals. Recent research in human adults suggests exposure to moderate intensity light later in the day is concurrently associated with increased body mass; however, no studies have investigated the effect of light exposure on body mass in young children. We examined objectively measured light exposure and body mass of 48 preschool-aged children at baseline, and measured their body mass again 12 months later. At baseline, moderate intensity light exposure earlier in the day was associated with increased body mass index (BMI). Increased duration of light exposure at baseline predicted increased BMI 12-months later, even after controlling for baseline sleep duration, sleep timing, BMI, and activity. The findings identify that light exposure may be a contributor to the obesogenic environment during early childhood. PMID- 26735302 TI - Self-Consistent Determination of Atomic Charges of Ionic Liquid through a Combination of Molecular Dynamics Simulation and Density Functional Theory. AB - A self-consistent scheme is developed to determine the atomic partial charges of ionic liquid. Molecular dynamics (MD) simulation was conducted to sample a set of ion configurations, and these configurations were subject to density functional theory (DFT) calculations to determine the partial charges. The charges were then averaged and used as inputs for the subsequent MD simulation, and MD and DFT calculations were repeated until the MD results are not altered any more. We applied this scheme to 1,3-dimethylimidazolium bis(trifluoromethylsulfonyl) imide ([C1mim][NTf2]) and investigated its structure and dynamics as a function of temperature. At convergence, the average ionic charges were +/-0.84 e at 350 K due to charge transfer among ions, where e is the elementary charge, while the reduced ionic charges do not affect strongly the density of [C1mim][NTf2] and radial distribution function. Instead, major effects are found on the energetics and dynamics, with improvements of the overestimated heat of vaporization and the too slow motions of ions observed in MD simulations using commonly used force fields. PMID- 26735301 TI - From Bench to Bedside: Attempt to Evaluate Repositioning of Drugs in the Treatment of Metastatic Small Cell Lung Cancer (SCLC). AB - BACKGROUNDS: Based on in vitro data and results of a recent drug repositioning study, some medications approved by the FDA for the treatment of various non malignant disorders were demonstrated to have anti-SCLC activity in preclinical models. The aim of our study is to confirm whether use of these medications is associated with survival benefit. METHODS: Consecutive patients with pathologically confirmed, stage 4 SCLC were analyzed in this retrospective study. Patients that were prescribed statins, aspirin, clomipramine (tricyclic antidepressant; TCA), selective serotonin reuptake inhibitors (SSRIs), doxazosin or prazosin (alpha1-adrenergic receptor antagonists; ADRA1) were identified. RESULTS: There were a total of 876 patients. Aspirin, statins, SSRIs, ADRA1, and TCA were administered in 138, 72, 20, 28, and 5 cases, respectively. A statistically significant increase in median OS was observed only in statin treated patients when compared to those not receiving any of the aforementioned medications (OS, 8.4 vs. 6.1 months, respectively; p = 0.002). The administration of SSRIs, aspirin, and ADRA1 did not result in a statistically significant OS benefit (median OS, 8.5, 6.8, and 6.0 months, respectively). The multivariate Cox model showed that, besides age and ECOG PS, radiotherapy was an independent survival predictor (Hazard Ratio, 2.151; 95% confidence interval, 1.828-2.525; p <0.001). CONCLUSIONS: Results of drug repositioning studies using only preclinical data or small numbers of patients should be treated with caution before application in the clinic. Our data demonstrated that radiotherapy appears to be an independent survival predictor in stage 4 SCLC, therefore confirming the results of other prospective and retrospective studies. PMID- 26735300 TI - Identification of the Calmodulin-Binding Domains of Fas Death Receptor. AB - The extrinsic apoptotic pathway is initiated by binding of a Fas ligand to the ectodomain of the surface death receptor Fas protein. Subsequently, the intracellular death domain of Fas (FasDD) and that of the Fas-associated protein (FADD) interact to form the core of the death-inducing signaling complex (DISC), a crucial step for activation of caspases that induce cell death. Previous studies have shown that calmodulin (CaM) is recruited into the DISC in cholangiocarcinoma cells and specifically interacts with FasDD to regulate the apoptotic/survival signaling pathway. Inhibition of CaM activity in DISC stimulates apoptosis significantly. We have recently shown that CaM forms a ternary complex with FasDD (2:1 CaM:FasDD). However, the molecular mechanism by which CaM binds to two distinct FasDD motifs is not fully understood. Here, we employed mass spectrometry, nuclear magnetic resonance (NMR), biophysical, and biochemical methods to identify the binding regions of FasDD and provide a molecular basis for the role of CaM in Fas-mediated apoptosis. Proteolytic digestion and mass spectrometry data revealed that peptides spanning residues 209 239 (Fas-Pep1) and 251-288 (Fas-Pep2) constitute the two CaM-binding regions of FasDD. To determine the molecular mechanism of interaction, we have characterized the binding of recombinant/synthetic Fas-Pep1 and Fas-Pep2 peptides with CaM. Our data show that both peptides engage the N- and C-terminal lobes of CaM simultaneously. Binding of Fas-Pep1 to CaM is entropically driven while that of Fas-Pep2 to CaM is enthalpically driven, indicating that a combination of electrostatic and hydrophobic forces contribute to the stabilization of the FasDD CaM complex. Our data suggest that because Fas-Pep1 and Fas-Pep2 are involved in extensive intermolecular contacts with the death domain of FADD, binding of CaM to these regions may hinder its ability to bind to FADD, thus greatly inhibiting the initiation of apoptotic signaling pathway. PMID- 26735304 TI - Correction: Improving Collective Estimations Using Resistance to Social Influence. AB - [This corrects the article DOI: 10.1371/journal.pcbi.1004594.]. PMID- 26735303 TI - Molecular Evolution of the Nuclear Factor (Erythroid-Derived 2)-Like 2 Gene Nrf2 in Old World Fruit Bats (Chiroptera: Pteropodidae). AB - Mammals developed antioxidant systems to defend against oxidative damage in their daily life. Enzymatic antioxidants and low molecular weight antioxidants (LMWAs) constitute major parts of the antioxidant systems. Nuclear factor (erythroid derived 2)-like 2 (Nrf2, encoded by the Nrf2 gene) is a central transcriptional regulator, regulating transcription, of many antioxidant enzymes. Frugivorous bats eat large amounts of fruits that contain high levels of LMWAs such as vitamin C, thus, a reliance on LMWAs might greatly reduce the need for antioxidant enzymes in comparison to insectivorous bats. Therefore, it is possible that frugivorous bats have a reduced need for Nrf2 function due to their substantial intake of diet-antioxidants. To test whether the Nrf2 gene has undergone relaxed evolution in fruit-eating bats, we obtained Nrf2 sequences from 16 species of bats, including four Old World fruit bats (Pteropodidae) and one New World fruit bat (Phyllostomidae). Our molecular evolutionary analyses revealed changes in the selection pressure acting on Nrf2 gene and identified seven specific amino acid substitutions that occurred on the ancestral lineage leading to Old World fruit bats. Biochemical experiments were conducted to examine Nrf2 in Old World fruit bats and showed that the amount of catalase, which is regulated by Nrf2, was significantly lower in the brain, heart and liver of Old World fruit bats despite higher levels of Nrf2 protein in Old World fruit bats. Computational predictions suggest that three of these seven amino acid replacements might be deleterious to Nrf2 function. Therefore, the results suggest that Nrf2 gene might have experienced relaxed constraint in Old World fruit bats, however, we cannot rule out the possibility of positive selection. Our study provides the first data on the molecular adaptation of Nrf2 gene in frugivorous bats in compensation to the increased levels of LWMAs from their fruit-diet. PMID- 26735305 TI - Oxidation Effect in Octahedral Hafnium Disulfide Thin Film. AB - Atomically smooth van der Waals materials are structurally stable in a monolayer and a few layers but are susceptible to oxygen-rich environments. In particular, recently emerging materials such as black phosphorus and perovskite have revealed stronger environmental sensitivity than other two-dimensional layered materials, often obscuring the interesting intrinsic electronic and optical properties. Unleashing the true potential of these materials requires oxidation-free sample preparation that protects thin flakes from air exposure. Here, we fabricated few layer hafnium disulfide (HfS2) field effect transistors (FETs) using an integrated vacuum cluster system and study their electronic properties and stability under ambient conditions. By performing all the device fabrication and characterization procedure under an oxygen- and moisture-free environment, we found that few-layer AA-stacking HfS2-FETs display excellent field effect responses (Ion/Ioff ~ 10(7)) with reduced hysteresis compared to the FETs prepared under ambient conditions. Oxidation of HfS2 occurs uniformly over the entire area, increasing the film thickness by 250% at a prolonged oxidation time of >120 h, while defects on the surface are the preferential initial oxidation sites. We further demonstrated that the stability of the device in air is significantly improved by passivating FETs with BN in a vacuum cluster. PMID- 26735306 TI - Implications of boron doping on electrocatalytic activities of graphyne and graphdiyne families: a first principles study. AB - Dispersive force corrected density functional theory is used to map the oxygen reduction reaction (ORR) kinetics of six kinds of graphyne (Gy) and graphdiyne (Gdy) systems (namely alphaGy, betaGy, gammaGy, deltaGy, 6,6,12Gy, RGy and Gdy) with substitutional boron (B) atom doping. To this end, the most favorable sites for B doping of each structures are determined by comparing their formation energies and then the best configuration for di-oxygen (O2) adsorption is computed by analyzing the corresponding adsorption energies. Even though oxygen adsorption is found to be energetically favorable on all of these and all Gys and Gdy are found to distinctly favor the four electron pathways for ORR, a reaction scheme with monotonically exothermic DeltaG is observed only for B doped RGy. Further computations performed by varying electrode potential indicated this monotonically exothermic nature of the DeltaG of B doped RGy to persist in the range 0-0.22 V and also indicated the first (H(+) + e) transfer step to be the rate limiting step. PMID- 26735307 TI - A Shift from Cellular to Humoral Responses Contributes to Innate Immune Memory in the Vector Snail Biomphalaria glabrata. AB - Discoveries made over the past ten years have provided evidence that invertebrate antiparasitic responses may be primed in a sustainable manner, leading to the failure of a secondary encounter with the same pathogen. This phenomenon called "immune priming" or "innate immune memory" was mainly phenomenological. The demonstration of this process remains to be obtained and the underlying mechanisms remain to be discovered and exhaustively tested with rigorous functional and molecular methods, to eliminate all alternative explanations. In order to achieve this ambitious aim, the present study focuses on the Lophotrochozoan snail, Biomphalaria glabrata, in which innate immune memory was recently reported. We provide herein the first evidence that a shift from a cellular immune response (encapsulation) to a humoral immune response (biomphalysin) occurs during the development of innate memory. The molecular characterisation of this process in Biomphalaria/Schistosoma system was undertaken to reconcile mechanisms with phenomena, opening the way to a better comprehension of innate immune memory in invertebrates. This prompted us to revisit the artificial dichotomy between innate and memory immunity in invertebrate systems. PMID- 26735308 TI - Discovery of New Compounds Active against Plasmodium falciparum by High Throughput Screening of Microbial Natural Products. AB - Due to the low structural diversity within the set of antimalarial drugs currently available in the clinic and the increasing number of cases of resistance, there is an urgent need to find new compounds with novel modes of action to treat the disease. Microbial natural products are characterized by their large diversity provided in terms of the chemical complexity of the compounds and the novelty of structures. Microbial natural products extracts have been underexplored in the search for new antiparasitic drugs and even more so in the discovery of new antimalarials. Our objective was to find new druggable natural products with antimalarial properties from the MEDINA natural products collection, one of the largest natural product libraries harboring more than 130,000 microbial extracts. In this work, we describe the optimization process and the results of a phenotypic high throughput screen (HTS) based on measurements of Plasmodium lactate dehydrogenase. A subset of more than 20,000 extracts from the MEDINA microbial products collection has been explored, leading to the discovery of 3 new compounds with antimalarial activity. In addition, we report on the novel antiplasmodial activity of 4 previously described natural products. PMID- 26735310 TI - Stem cell transplantation in multiple myeloma and other plasma cell disorders (report from an EBMT preceptorship meeting). AB - The European Society for Blood and Marrow Transplantation Chronic Malignancies Working Party held a preceptorship meeting in Turin, Italy on 25-26 September 2014, to discuss the role of stem cell transplantation (SCT) in the treatment of multiple myeloma and other plasma cell disorders. Scientists and clinicians working in the field gathered to discuss a variety of topics including the results of recent clinical trials, basic research, the concept of minimal residual disease, and immune modulation. As individual presentations revealed, important advances have occurred in our understanding of the pathophysiology of myeloma and the role that SCT, along with other forms of immunotherapy, plays in treating it. Each presentation stimulated discussion and exchange of ideas among the attendants. We decided to summarize and, importantly, to update the meeting proceedings in this review to share stimulating discussions and ideas on potentially novel treatment strategies among clinicians. PMID- 26735311 TI - Low Serum Vitamin D Levels May Contribute to Gastric Dysmotility in de novo Parkinson's Disease. AB - BACKGROUND AND OBJECTIVES: Gastrointestinal dysfunction is a common non motor symptom in Parkinson's disease (PD). However, the potential association between vitamin D and gastroparesis in PD has not been previously investigated. The aim of this study was to compare vitamin D levels between drug-naive de novo PD patients with normal gastric emptying and those with delayed gastric emptying. METHODS: Fifty-one patients with drug-naive de novo PD and 20 age-matched healthy controls were enrolled in this study. Gastric emptying time (GET) was assessed by scintigraphy, and gastric emptying half-time (T1/2) was determined. The PD patients were divided into a delayed-GET group and a normal-GET group. RESULTS: The serum 25-hydroxyvitamin D3 levels were decreased in the delayed-GET group compared with the normal-GET and control groups (11.59 +/- 4.90 vs. 19.43 +/- 6.91 and 32.69 +/- 4.93, respectively, p < 0.01). In the multivariate model, the serum 25-hydroxyvitamin D3 level was independently associated with delayed gastric emptying in PD patients. CONCLUSIONS: Vitamin D status may be an independent factor for gastric dysmotility in PD. Although the underlying mechanism remains to be characterized, vitamin D status may play a role in the pathogenesis of delayed gastric emptying in drug-naive PD. PMID- 26735309 TI - Proteomic Identification of Oxidized Proteins in Entamoeba histolytica by Resin Assisted Capture: Insights into the Role of Arginase in Resistance to Oxidative Stress. AB - Entamoeba histolytica is an obligate protozoan parasite of humans, and amebiasis, an infectious disease which targets the intestine and/or liver, is the second most common cause of human death due to a protozoan after malaria. Although amebiasis is usually asymptomatic, E. histolytica has potent pathogenic potential. During host infection, the parasite is exposed to reactive oxygen species that are produced and released by cells of the innate immune system at the site of infection. The ability of the parasite to survive oxidative stress (OS) is essential for a successful invasion of the host. Although the effects of OS on the regulation of gene expression in E. histolytica and the characterization of some proteins whose function in the parasite's defense against OS have been previously studied, our knowledge of oxidized proteins in E. histolytica is lacking. In order to fill this knowledge gap, we performed a large scale identification and quantification of the oxidized proteins in oxidatively stressed E. histolytica trophozoites using resin-assisted capture coupled to mass spectrometry. We detected 154 oxidized proteins (OXs) and the functions of some of these proteins were associated with antioxidant activity, maintaining the parasite's cytoskeleton, translation, catalysis, and transport. We also found that oxidation of the Gal/GalNAc impairs its function and contributes to the inhibition of E. histolytica adherence to host cells. We also provide evidence that arginase, an enzyme which converts L-arginine into L-ornithine and urea, is involved in the protection of the parasite against OS. Collectively, these results emphasize the importance of OS as a critical regulator of E. histolytica's functions and indicate a new role for arginase in E. histolytica's resistance to OS. PMID- 26735312 TI - Updates in anterior skull base reconstruction. AB - PURPOSE OF REVIEW: This article summarizes the indications and surgical techniques for the reconstructions of anterior skull base defects. RECENT FINDINGS: There is increasing popularity of the vascularized pedicled flaps in endoscopic skull base surgery for the successful reconstruction of anterior skull base defects, compared with the use of free-tissue grafts. The location and size of the defect as well as the rate of cerebrospinal fluid (CSF) flow are important considerations for selection of the most appropriate reconstructive approach. Recent literature provides evidence suggesting that pedicled flaps may be more effective for clival defects and high-flow CSF leaks, potentially reducing the incidence of postoperative CSF leaks. Although the nasoseptal flap (NSF) continues to be the mainstay of endoscopic skull base reconstruction, alternative vascularized flaps exist when the NSF is impractical or unavailable, and new surgical approaches continue to evolve. SUMMARY: Vascularized pedicled flaps, and especially the NSF, have greatly reduced complications associated with endoscopic skull base surgery. Multiple considerations should be taken into account during closure of skull base defects, and several options are available to accommodate different needs. PMID- 26735313 TI - A Modified Antegrade Stenting Technique for Laparoscopic Pyeloplasty in Infants and Children. AB - OBJECTIVE: There are 2 critical steps of stent placement during laparoscopic pyeloplasty (LP) in children. Introduction to the ureteropelvic junction and passing through the ureterovesical junction. We aimed at overcoming those 2 steps by creating a modified technique. METHODS: Consecutive 27 children undergoing transperitoneal laparoscopic dismembered pyeloplasty by a single surgeon were prospectively enrolled into this study. The modifications of our technique are using an Amplatz dilator and a closed tip stent. RESULTS: The mean age of the children was 6.7 (range 4 months-17 years). The mean time of stent insertion was 2.7 +/- 2.0 (2-6) min and the operative time was 128.3 +/- 17.6 (90-180) min. The mean number of days of hospital stay was 2.0 +/- 0.4 (1-3). After a mean follow up period of 20.3 +/- 4.2 (14-30) months, no operative failure was detected. CONCLUSION: Our modified technique is a completion of the current armamentarium for stent placement during LP in infants and children. PMID- 26735314 TI - Synthesis of Mannosylated Lipopeptides with Receptor Targeting Properties. AB - Present on the surface of antigen presenting cells (APCs), the mannose receptor (MR) has long been recognized as a front-line receptor in pathogen recognition. During the past decade many attempts have been made to target this receptor for applications including vaccine and drug development. In the present study, a library of vaccine constructs comprising fluorescently labeled mannosylated lipid dendrimers that contained the ovalbumin CD4(+) epitope, OVA(323-339), as the model peptide antigen were synthesized using fluorenylmethyloxycarbonyl (Fmoc) solid phase peptide synthesis (SPPS). The vaccine constructs were designed with an alanine spacer between the O-linked mannose moieties to investigate the impact of distance between the mannose units on receptor-mediated uptake and/or binding in APCs. Uptake studies performed on F4/80(+) and CD11c(+) cells showed significant uptake and/or binding for lipopeptides containing mannose, and also the lipopeptide without mannose when compared to the control peptides (peptide with no lipid and peptide with no mannose and no lipid). Furthermore, mannan inhibition assays demonstrated that uptake of the mannosylated and lipidated peptides was receptor mediated. To address the specificity of receptor uptake, surface plasmon resonance studies were performed using biacore technology and confirmed high affinity of the mannosylated and lipidated vaccine constructs toward the MR. These studies confirm that both mannose and lipid moieties play significant roles in receptor-mediated uptake on APCs, potentially facilitating vaccine development. PMID- 26735315 TI - Mechanochromic Luminescence and Aggregation Induced Emission of Dinaphthoylmethane beta-Diketones and Their Boronated Counterparts. AB - Mechanochromic luminescence has been observed in many boron coordinated beta diketonate (BF2bdk) complexes. Recently, it was shown that the metal-free methoxy substituted dinaphthoylmethane beta-diketone (dnmOMe) also displayed aggregation induced emission (AIE), solvatochromism, and high contrast mechanochromic luminescence (ML) that recovered rapidly at room temperature. In order to understand how substituents and boron coordination affect solution and solid state optical properties, a series of methoxy- and bromo-substituted derivatives (dnm, dnmOMe, dnmBr, and dnmBrOMe) and their corresponding boron complexes (BF2dnm, BF2dnmOMe, BF2dnmBr, and BF2dnmBrOMe) were synthesized and their AIE, ML, and room temperature recovery properties were compared. All boron complexes exhibited red-shifted absorption and emission, in addition to larger solution and solid-state quantum yields than beta-diketones. While AIE studies show increased emission for dnmOMe and dnmBrOMe, the emission of corresponding boron complexes diminished upon aggregation. However, boron complexes were still strongly emissive in the solid state. ML properties were investigated using spin-cast films. Smearing resulted in the appearance of blue-green emission in ligands and a color change from green to yellow-orange in boron complexes. Bromide substituted derivatives showed increased room temperature recovery times compared to other dnm ligands, and boron complexes show only partial recovery over several days. PMID- 26735316 TI - Impact of a Sit-Stand Workstation on Chronic Low Back Pain: Results of a Randomized Trial. AB - OBJECTIVE: The aim of the study was to determine whether chronic low back pain (LBP) might be attenuated through the introduction of a sit-stand workstation (SSW) in office employees. METHODS: Participants were randomized to receive a SSW at the beginning or at the end of a 3-month study period. Participants responded to a short survey at the end of each workday and a comprehensive survey at weeks 1, 6, and 12. Surveys consisted of a modified brief pain inventory and the Roland Morris Disability Questionnaire. RESULTS: Forty-six university employees with self-reported chronic LBP were enrolled. Participants who were given access to a SSW reported a significant reduction in current (P = 0.02) and worst (P = 0.04) LBP over time. CONCLUSIONS: Our findings support the hypothesis that chronic LBP might be improved by the introduction of a SSW in an office environment. PMID- 26735317 TI - Economic and Environmental Considerations During Low Fresh Gas Flow Volatile Agent Administration After Change to a Nonreactive Carbon Dioxide Absorbent. AB - BACKGROUND: Reducing fresh gas flow (FGF) during general anesthesia reduces costs by decreasing the consumption of volatile anesthetics and attenuates their contribution to greenhouse gas pollution of the environment. The sevoflurane FGF recommendations in the Food and Drug Administration package insert relate to concern over potential toxicity from accumulation in the breathing circuit of compound A, a by-product of the reaction of the volatile agent with legacy carbon dioxide absorbents containing strong alkali such as sodium or potassium hydroxide. Newer, nonreactive absorbents do not produce compound A, making such restrictions moot. We evaluated 4 hypotheses for sevoflurane comparing intervals before and after converting from a legacy absorbent (soda lime) to a nonreactive absorbent (Litholyme): (1) intraoperative FGF would be reduced; (2) sevoflurane consumption per minute of volatile agent administration would be reduced; (3) cost savings due to reduced sevoflurane consumption would (modestly) exceed the incremental cost of the premium absorbent; and (4) residual wastage in discarded sevoflurane bottles would be <1%. METHODS: Inspired carbon dioxide (PICO2), expired carbon dioxide, oxygen, air, and nitrous oxide FGF, inspired volatile agent concentrations (FiAgent), and liquid volatile agent consumption were extracted from our anesthesia information management system for 8 4 week intervals before and after the absorbent conversion. Anesthesia providers were notified by e-mail and announcements at Grand Rounds about the impending change and were encouraged to reduce their average intraoperative sevoflurane FGF to 1.25 L/min. Personalized e-mail reports were sent every 4 weeks throughout the study period regarding the average intraoperative FGF (i.e., from surgery begin to surgery end) for each agent. Batch means methods were used to compare FGF, volatile agent consumption, net cost savings, and residual sevoflurane left in bottles to be discarded in the trash after filling vaporizers. The time from reaching a PICO2 = 3 mm Hg for 3 minutes until agent exhaustion (PICO2 = 5 mm Hg for 5 minutes) was evaluated. RESULTS: A total of N = 20,235 cases were analyzed (80.2% sevoflurane, 15.1% desflurane, and 4.7% isoflurane). Intraoperative FGF was reduced for cases in which sevoflurane was administered by 435 mL/min (95% confidence interval [CI], 391 to 479 mL/min; P < 10). Hypothesis 1 was accepted. Sevoflurane consumption per minute of administration decreased by 0.039 mL/min (95% CI, 0.029 to 0.049 mL/min; P < 10) after the change to the nonreactive absorbent. Hypothesis 2 was accepted. The difference in mean cost for the sum of the sevoflurane and absorbent purchases for each of the 10 4-week intervals before and after the absorbent switch was -$293 per 4-week interval (95% CI, $2853 to $2266; P = 0.81). Hypothesis 3 was rejected. The average amount of residual sevoflurane per bottle was 0.67 +/- 0.06 mL (95% CI, 0.54 to 0.81 mL per bottle; P < 10 vs 2.5 mL). Hypothesis 4 was accepted. Once the PICO2 reached 3 mm Hg for at least 3 consecutive minutes, the absorbent became exhausted within 95 minutes in most (i.e., >50%) canisters. CONCLUSIONS: We showed that an anesthesia department can transition to a premium, nonreactive carbon dioxide absorbent in a manner that is at least cost neutral by reducing FGF below the lower flow limits recommended in the sevoflurane package insert. This was achieved, in part, by electronically monitoring PICO2, automatically notifying the anesthesia technicians when to change the absorbent, and by providing personalized feedback via e-mail to the anesthesia providers. PMID- 26735318 TI - MACULAR BUCKLING WITH ANDO PLOMBE MAY INCREASE CHOROIDAL THICKNESS AND MIMIC SEROUS RETINAL DETACHMENT SEEN IN THE TILTED DISK SYNDROME. AB - PURPOSE: Serous subfoveal detachment has been described in the literature as a complication that appears at the border of the staphyloma. Macular buckling induces a postoperative inward bulge that resembles the ridge of a staphyloma. We describe three patients who developed a serous subfoveal detachment after uneventful macular buckling. To our knowledge, this complication, that shares similarities with the staphyloma ridge detachment, has not been previously reported. METHODS: The clinical records of all cases that underwent macular buckling at our clinic were reviewed. RESULTS: Three patients developed a serous subfoveal detachment that could not be explained by choroidal neovascularization or polypoidal vascular choroidopathy. Along with the development of the subfoveal detachment, we observed an increase of the choroidal thickness beneath the fovea. This thickening, that tended to progress during the follow-up, resolved spontaneously after explantation of the buckle. The decrease in foveal thickness did also lead to resolution of the subfoveal detachment. CONCLUSION: The development of the subfoveal detachment in our patients was closely associated with a focal increase of the choroidal thickness after the macular buckling. After the buckle was removed, the choroidal thickness went back to the normal prebuckling values and the detachment resolved in all three patients. This leads us to think that there is a close association between choroidal thickness and the serous subfoveal detachment. PMID- 26735319 TI - IMAGING WITH MULTIMODAL ADAPTIVE-OPTICS OPTICAL COHERENCE TOMOGRAPHY IN MULTIPLE EVANESCENT WHITE DOT SYNDROME: THE STRUCTURE AND FUNCTIONAL RELATIONSHIP. AB - PURPOSE: To elucidate the location of pathological changes in multiple evanescent white dot syndrome (MEWDS) with the use of multimodal adaptive optics (AO) imaging. METHODS: A 5-year observational case study of a 24-year-old female with recurrent MEWDS. Full examination included history, Snellen chart visual acuity, pupil assessment, intraocular pressures, slit lamp evaluation, dilated fundoscopic exam, imaging with Fourier-domain optical coherence tomography (FD OCT), blue-light fundus autofluorescence (FAF), fundus photography, fluorescein angiography, and adaptive-optics optical coherence tomography. RESULTS: Three distinct acute episodes of MEWDS occurred during the period of follow-up. Fourier domain optical coherence tomography and adaptive-optics imaging showed disturbance in the photoreceptor outer segments (PR OS) in the posterior pole with each flare. The degree of disturbance at the photoreceptor level corresponded to size and extent of the visual field changes. All findings were transient with delineation of the photoreceptor recovery from the outer edges of the lesion inward. Hyperautofluorescence was seen during acute flares. Increase in choroidal thickness did occur with each active flare but resolved. CONCLUSION: Although changes in the choroid and RPE can be observed in MEWDS, Fourier-domain optical coherence tomography, and multimodal adaptive optics imaging localized the visually significant changes seen in this disease at the level of the photoreceptors. These transient retinal changes specifically occur at the level of the inner segment ellipsoid and OS/RPE line. En face optical coherence tomography imaging provides a detailed, yet noninvasive method for following the convalescence of MEWDS and provides insight into the structural and functional relationship of this transient inflammatory retinal disease. PMID- 26735320 TI - Oxytocin, Postnatal Depression, and Parenting: A Systematic Review. AB - OBJECTIVE: To carry out a systematic review exploring the interconnections between oxytocin, postnatal depression (PND), and parenting. Questions include: (1) How does PND affect parenting? (2) How does oxytocin affect parenting? (3) How does oxytocin affect PND? METHODOLOGY: To review English articles in major medical databases. RESULTS: Compared to nondepressed controls, mothers with PND interact with their infants less sensitively, report feeling less competent, and less often choose recommended practical-parenting strategies. Psychological interventions for mothers with PND generally have positive effects on mother infant interactions. The administration of oxytocin in community samples tends to improve parental behaviors. Findings exploring the association between oxytocin and PND were inconsistent, with some evidence that oxytocin has a negative impact on mood. CONCLUSIONS: Oxytocin is potentially useful in improving parental behaviors of mothers with PND, but more research is needed to establish its safety because of the uncertain impact of OT on maternal mood. PMID- 26735321 TI - Template to Perpetrate: An Update on Violence in Autism Spectrum Disorder. AB - INTRODUCTION: For the past two decades, researchers have been using various approaches to investigate the relationship, if any, between autism spectrum disorder (ASD) and violence. The need to clarify that relationship was reinforced by the tragic mass shooting at Sandy Hook Elementary School in Newtown, Connecticut, in December 2012 by an individual diagnosed with Asperger's syndrome. The purpose of this article is (1) to provide an updated review of the literature on the association between ASD and violence, and (2) to examine implications for treating, and for preventing violence by, individuals with ASD. METHOD: A review of all published literature regarding ASD and violence from 1943 to 2014 was conducted using electronic and paper searches. RESULTS: Although some case reports have suggested an increased violence risk in individuals with ASD compared to the general population, prevalence studies have provided no conclusive evidence to support this suggestion. Among individuals with ASD, however, generative (e.g., comorbid psychopathology, social-cognition deficits, emotion-regulation problems) and associational (e.g., younger age, Asperger's syndrome diagnosis, repetitive behavior) risk factors have been identified or proposed for violent behavior. CONCLUSIONS: While no conclusive evidence indicates that individuals with ASD are more violent than those without ASD, specific generative and associational risk factors may increase violence risk among individuals with ASD. Further research would help to clarify or confirm these findings, suggest potential directions for evaluation, treatment, and prevention, and potentially provide compelling empirical support for forensic testimony regarding defendants with ASD charged with violent crimes. PMID- 26735322 TI - The Role of Temperament in the Etiopathogenesis of Bipolar Spectrum Illness. AB - Bipolar disorder constitutes a challenge for clinicians in everyday clinical practice. Our knowledge concerning this clinical entity is incomplete, and contemporary classification systems are unable to reflect the complexity of this disorder. The concept of temperament, which was first described in antiquity, provides a helpful framework for synthesizing our knowledge on how the human body works and what determines human behavior. Although the concept of temperament originally included philosophical and sociocultural approaches, the biomedical model is dominant today. It is possible that specific temperaments might constitute vulnerability factors, determine the clinical picture, or modify the course of illness. Temperaments might even act as a bridge between genes and clinical manifestations, thus giving rise to the concept of the bipolar spectrum, with major implications for mental health research and treatment. More specifically, it has been reported that the hyperthymic and the depressive temperaments are related to the more "classic" bipolar disorder, whereas cyclothymic, anxious, and irritable temperaments are related to more complex manifestations and might predict poor response to treatment, violent or suicidal behavior, and high comorbidity. Incorporating of the concept of temperament and the bipolar spectrum into the standard training of psychiatric residents might well result in an improvement of everyday clinical practice. PMID- 26735323 TI - Ambivalence About Recovery in a Case of Psychotic Illness: Diagnostic, Treatment, and Cultural Challenges. PMID- 26735324 TI - Working With Sidney Blatt: Developing Interactions. AB - This tribute to Sidney J. Blatt describes our collaboration in the study of therapy change among hospitalized patients at the Austen Riggs Center. In particular, the use of defense mechanisms by these patients, and the relation of defenses to change in personality after treatment, were examined. The unfolding of this work is described. PMID- 26735325 TI - Comment on "New Look at BTEX: Are Ambient Levels a Problem?". PMID- 26735326 TI - Angiopoietin-2 May Be Involved in the Resistance to Bevacizumab in Recurrent Glioblastoma. AB - Despite encouraging response rate of bevacizumab (BVZ) in recurrent glioblastoma, many patients do not respond to this schedule and most of the responders develop an early relapse. Plasma concentrations of VEGF, PlGF, Ang2, and sTie2 were assessed by ELISA before and during BVZ treatment in seventy patients. Baseline levels of VEGF-A, and PlGF were higher in patients than in healthy volunteers, whereas no difference was found for Ang2, and sTie2. No biomarker at baseline was associated with response, PFS or OS. At recurrence, the authors observed an increase of Ang2 suggesting that Ang2/sTie2 could be involved in the resistance to BVZ. PMID- 26735327 TI - Signal quality of endovascular electroencephalography. AB - Objective, Approach. A growing number of prototypes for diagnosing and treating neurological and psychiatric diseases are predicated on access to high-quality brain signals, which typically requires surgically opening the skull. Where endovascular navigation previously transformed the treatment of cerebral vascular malformations, we now show that it can provide access to brain signals with substantially higher signal quality than scalp recordings. MAIN RESULTS: While endovascular signals were known to be larger in amplitude than scalp signals, our analysis in rabbits borrows a standard technique from communication theory to show endovascular signals also have up to 100* better signal-to-noise ratio. SIGNIFICANCE: With a viable minimally-invasive path to high-quality brain signals, patients with brain diseases could one day receive potent electroceuticals through the bloodstream, in the course of a brief outpatient procedure. PMID- 26735328 TI - Patterns of anterior versus posterior white matter fractional anistotropy concordance in adult nonhuman primates: Effects of early life stress. AB - INTRODUCTION: Functional neuroimaging studies report global prefrontal dysconnectivity in mood disorders, supporting the notion of widespread disruptions in brain networks. Microscopic alterations in white matter (WM) tracts - which possess neuroplastic properties and play a central role in brain connectivity - are interrogated herein in the context of brain dysconnectivity. Early life stress (ELS), an antecedent to human mood disorders, induces WM alterations in volumetrics and integrity. We hypothesized that nonhuman primate infants exposed to ELS would exhibit persistent impairments in both frontal and posterior concordance of WM integrity, therefore contributing to global brain dysconnectivity. METHODS: Using a 3T MRI, diffusion tensor imaging (DTI) was performed on 21 adult male Bonnet macaques, 12 of whom had been raised under variable foraging demand (VFD) conditions and nine of whom had been raised under normative conditions (Non-VFD). As representative of anterior regions, fractional anisotropy (FA) concordance between anterior corpus callosum (ACorpusC) and anterior limb of the internal capsule (ALIC) was examined. For posterior regions, FA concordance between posterior corpus callosum (PCorpusC) and posterior limb of the internal capsule (PLICA) and between PCorpusC and occipital WM was examined. Examination of posterior FA was explored in the context of frontal markers of neuroplasticity. RESULTS: A concordant relationship for FA between left ALIC and ACorpusC was evident in Non-VFD-reared subjects, but significantly absent in VFD reared subjects. For left posterior regions, FA concordance between PLICA and PCorpusC and occipital WM and PCorpusC was evident in VFD-reared and not Non-VFD reared subjects. The posterior concordance in VFD was significantly distinguishable from the deficit in anterior concordance FA in VFD. CONCLUSIONS: The findings support the view that disrupted emotional integrity of the maternal infant attachment process affects normative synchronous development of frontal white matter tracts but creates errant posterior concordance and also disrupts an inverse relationship between posterior white matter tracts and markers of neuroplasticity. We provide preliminary evidence that a concordant relationship between capsular-callosal FA may become discordant, providing a putative mechanism for prefrontal functional brain dysconnectivity. PMID- 26735330 TI - The effects of cognitive-behavioral therapy for youth anxiety on sleep problems. AB - The present study examined (a) whether sleep related problems (SRPs) improved following cognitive-behavioral therapy (CBT) for youth with anxiety disorders, (b) whether variables that may link anxiety and SRPs (e.g., pre-sleep arousal, family accommodation, sleep hygiene) changed during treatment, and (c) whether such changes predicted SRPs at posttreatment. Youth were diagnosed with anxiety at pretreatment and received weekly CBT that targeted their principal anxiety diagnosis at one of two specialty clinics (N=69 completers, Mage=10.86). Results indicated that parent-reported SRPs improved from pre- to post-treatment and that treatment responders with regard to anxiety yielded greater SRP improvements than nonresponders. Parent report of bedtime resistance and sleep anxiety showed significant improvements. Youth reported lower rates of SRPs compared to their parents and did not demonstrate pre- to post-treatment changes in SRPs. Pre-sleep arousal and family accommodation decreased over treatment but did not predict lower SRPs at posttreatment. Higher accommodation was correlated with greater SRPs. Sleep hygiene evidenced no change and did not mediate links between accommodation and posttreatment SRPs. PMID- 26735329 TI - Lipid peroxidation biomarkers in adolescents with or at high-risk for bipolar disorder. AB - BACKGROUND: Prior work suggests that adult bipolar disorder (BD) is associated with increased oxidative stress and inflammation. This exploratory study examined markers of lipid and protein oxidation and inflammation in adolescents with and at varying risk for BD type I (BD-I). METHODS: Blood was obtained from four groups of adolescents (9-20 years of age): (1) healthy comparison subjects with no personal or family history of psychiatric disorders (n=13), (2) subjects with no psychiatric diagnosis and at least one parent with BD-I ('high-risk', n=15), (3) subjects with at least one parent with BD-I and a diagnosis of depressive disorder not-otherwise-specified ('ultra-high-risk', n=20), and (4) first-episode patients exhibiting mixed or manic symptoms that received a diagnosis of BD-I (n=16). Plasma levels of lipid peroxidation (LPH, 4-HNE, 8-ISO), protein carbonyl, and inflammation (IL-1alpha-beta, IL-6, IL-10, IFNgamma, TNFalpha) were assessed using analysis of variance and covariance models. RESULTS: LPH was lower in adolescents with fully syndromal BD than controls, while LPH levels in the at risk groups were between healthy controls and fully syndromal BD. Post-hoc analysis showed a non-significant increase in the (4-HNE+8-ISO)/LPH ratio suggesting a potential conversion of LPH into late-stage markers of lipid peroxidation. There were no significant differences among protein carbonyl content and inflammatory markers. CONCLUSIONS: In adolescents, fully syndromal BD is associated with significant reductions in LPH levels, and LPH levels decrease along the spectrum of risk for BD-I. Quantifying lipid peroxidation in longitudinal studies may help clarify the role of LPH in BD risk progression. PMID- 26735331 TI - Neoliberalism and indigenous knowledge: Maori health research and the cultural politics of New Zealand's "National Science Challenges". AB - In 2012-13 the Ministry of Business, Innovation and Employment (MBIE) in New Zealand rapidly implemented a major restructuring of national scientific research funding. The "National Science Challenges" (NSC) initiative aims to promote greater commercial applications of scientific knowledge, reflecting ongoing neoliberal reforms in New Zealand. Using the example of health research, we examine the NSC as a key moment in ongoing indigenous Maori advocacy against neoliberalization. NSC rhetoric and practice through 2013 moved to marginalize participation by Maori researchers, in part through constructing "Maori" and "science" as essentially separate arenas-yet at the same time appeared to recognize and value culturally distinctive forms of Maori knowledge. To contest this "neoliberal multiculturalism," Maori health researchers reasserted the validity of culturally distinctive knowledge, strategically appropriated NSC rhetoric, and marshalled political resources to protect Maori research infrastructure. By foregrounding scientific knowledge production as an arena of contestation over neoliberal values and priorities, and attending closely to how neoliberalizing tactics can include moves to acknowledge cultural diversity, this analysis poses new questions for social scientific study of global trends toward reconfiguring the production of knowledge about health. Study findings are drawn from textual analysis of MBIE documents about the NSC from 2012 to 2014, materials circulated by Maori researchers in the blogosphere in 2014, and ethnographic interviews conducted in 2013 with 17 Maori health researchers working at 7 sites that included university-based research centers, government agencies, and independent consultancies. PMID- 26735332 TI - Psychosocial factors and pre-abortion psychological health: The significance of stigma. AB - RATIONALE: Most research in mental health and abortion has examined factors associated with post-abortion psychological health. However, research that follows women from before to after their abortion consistently finds that depressive, anxiety, and stress symptoms are highest just before an abortion compared to any time afterwards. OBJECTIVE: This finding suggests that studies investigating psychosocial factors related to pre-abortion mental health are warranted. METHODS: The current study uses data from 353 women seeking abortions at three community reproductive health clinics to examine predictors of pre abortion psychological health. Drawing from three perspectives in the abortion and mental health literature, common risks, stress and coping, and sociocultural context, we conducted multivariable analyses to examine the contribution of important factors on depressive, anxiety, and stress symptoms just before an abortion, including sociodemographics, abortion characteristics, childhood adversities, recent adversities with an intimate partner, relationship context, future pregnancy desires, and perceived abortion stigma. RESULTS: Childhood and partner adversities, including reproductive coercion, were associated with negative mental health symptoms, as was perceived abortion stigma. Before perceived abortion stigma was entered into the model, 18.6%, 20.7%, and 16.8% of the variance in depressive, anxiety, and stress symptoms respectively, was explained. Perceived abortion stigma explained an additional 13.2%, 9.7%, and 10.7% of the variance in depressive, anxiety, and stress symptoms pre-abortion. CONCLUSION: This study, one of the first to focus on pre-abortion mental health as an outcome, suggests that addressing stigma among women seeking abortions may significantly lower their psychological distress. PMID- 26735333 TI - Does income relate to health due to psychosocial or material factors? Consistent support for the psychosocial hypothesis requires operationalization with income rank not the Yitzhaki Index. AB - Research on why income influences health has produced mixed findings. Many, but not all, studies suggest that the relationship between income and health is due to income indicating psychosocial position rather than the associated material benefits. The inconsistent findings may be partly due to the use of the Yitzhaki Index, a function which calculates the accumulated income shortfall for an individual relative to those with higher income, in order to represent the psychosocial position conferred by income. The current study tests whether an alternative specification - income rank - provides more consistent conclusions regarding the psychosocial effect of income on health. We used data from two nationally representative samples: 14,224 observations from 9,404 participants across three waves (2004, 2008, and 2012) of the English Longitudinal Study of Ageing (ELSA) and 29,237 observations from 8,441 individuals across seven waves (2007-2013) of the Longitudinal Internet Studies for the Social Sciences (LISS). Multilevel regression models indicated that income rank was a stronger and more consistent predictor than both the Yitzhaki Index and actual income of self-rated and objective health. The psychosocial hypothesis is more consistently supported when income rank is used to test it. PMID- 26735334 TI - Analysing collaboration among HIV agencies through combining network theory and relational coordination. AB - Agencies with different foci (e.g. nutrition, social, medical, housing) serve people living with HIV (PLHIV). Serving needs of PLHIV comprehensively requires a high degree of coordination among agencies which often benefits from more frequent communication. We combined Social Network theory and Relational Coordination theory to study coordination among HIV agencies in Baltimore. Social Network theory implies that actors (e.g., HIV agencies) establish linkages amongst themselves in order to access resources (e.g., information). Relational Coordination theory suggests that high quality coordination among agencies or teams relies on the seven dimensions of frequency, timeliness and accuracy of communication, problem-solving communication, knowledge of agencies' work, mutual respect and shared goals. We collected data on frequency of contact from 57 agencies using a roster method. Response options were ordinal ranging from 'not at all' to 'daily'. We analyzed data using social network measures. Next, we selected agencies with which at least one-third of the sample reported monthly or more frequent interaction. This yielded 11 agencies whom we surveyed on seven relational coordination dimensions with questions scored on a Likert scale of 1 5. Network density, defined as the proportion of existing connections to all possible connections, was 20% when considering monthly or higher interaction. Relational coordination scores from individual agencies to others ranged between 1.17 and 5.00 (maximum possible score 5). The average scores for different dimensions across all agencies ranged between 3.30 and 4.00. Shared goals (4.00) and mutual respect (3.91) scores were highest, while scores such as knowledge of each other's work and problem-solving communication were relatively lower. Combining theoretically driven analyses in this manner offers an innovative way to provide a comprehensive picture of inter-agency coordination and the quality of exchange that underlies collaborative ties. These methods together can identify areas that could be targeted to promote closer ties. PMID- 26735335 TI - Probing the Secondary Structure of Membrane Peptides Using (2)H-Labeled d(10) Leucine via Site-Directed Spin-Labeling and Electron Spin Echo Envelope Modulation Spectroscopy. AB - Previously, we reported an electron spin echo envelope modulation (ESEEM) spectroscopic approach for probing the local secondary structure of membrane proteins and peptides utilizing (2)H isotopic labeling and site-directed spin labeling (SDSL). In order to probe the secondary structure of a peptide sequence, an amino acid residue (i) side chain was (2)H-labeled, such as (2)H-labeled d10 Leucine, and a cysteine residue was strategically placed at a subsequent nearby position (denoted as i + 1 to i + 4) to which a nitroxide spin label was attached. In order to fully access and demonstrate the feasibility of this new ESEEM approach with (2)H-labeled d10-Leu, four Leu residues within the AChR M2delta peptide were fully mapped out using this ESEEM method. Unique (2)H-ESEEM patterns were observed with the (2)H-labeled d10-Leu for the AChR M2delta alpha helical model peptide. For proteins and peptides with an alpha-helical secondary structure, deuterium modulation can be clearly observed for i +/- 3 and i +/- 4 samples, but not for i +/- 2 samples. Also, a deuterium peak centered at the (2)H Larmor frequency of each i +/- 4 sample always had a significantly higher intensity than the corresponding i + 3 sample. This unique feature can be potentially used to distinguish an alpha-helix from a pi-helix or 310-helix. Moreover, (2)H modulation depth for ESEEM samples on Leu10 were significantly enhanced which was consistent with a kinked or curved structural model of the AChR M2delta peptide as suggested by previous MD simulations and NMR experiments. PMID- 26735336 TI - Wogonin inhibits multiple myeloma-stimulated angiogenesis via c-Myc/VHL/HIF 1alpha signaling axis. AB - Angiogenesis is associated with the progression of multiple myeloma (MM). Wogonin is an active mono-flavonoid with remarkable antitumor activity. However, its impact on MM-stimulated angiogenesis remains largely unknown. Here, we demonstrated that wogonin decreased expression and secretion of pro-angiogenic factors in MM cells via c-Myc/HIF-1alpha signaling axis, reducing MM-stimulated angiogenesis and MM cell proliferation in vivo. Overexpression of c-Myc in MM cells disrupted the balance between VHL SUMOylation and ubiquitination, and thus inhibited proteasome-mediated HIF-1alpha degradation. Impaired function of VHL ubiquitination complex in c-Myc-overexpressing cells was fully reversed by wogonin treatment via increasing HIF-1alpha-VHL interaction and promoting HIF 1alpha degradation. Collectively, our in vitro and in vivo studies reveal for the first time that wogonin represses MM-stimulated angiogenesis and tumor progression via c-Myc/VHL/HIF-1alpha signaling axis. PMID- 26735337 TI - Increased levels of low-density lipoprotein cholesterol within the normal range as a risk factor for nonalcoholic fatty liver disease. AB - OBJECTIVES: Dyslipidemia exists within the setting of NAFLD and the relationship of a normal level of low-density lipoprotein cholesterol (LDL-c) with NAFLD is largely unknown. This large population-based study aimed to investigate the association between LDL-c levels within the normal range and the incidence of NAFLD. METHODS: A total of 60527 subjects from 2 medical centers who had undergone liver ultrasonography were initially enrolled into this study. NAFLD was defined by ultrasonographic detection of steatosis in the absence of other liver disease. Subjects were divided into 4 groups (Q1 to Q4) by normal LDL-c quartiles : Q1: <= 2.00, Q2: 2.10-2.35, Q3: 2.36-2.68 and Q4: 2.69-3.12 mmol/L. The odds ratios (OR), hazard ratio (HR) and 95% confidence intervals (CIs) for NAFLD were calculated across each quartile of LDL-c, using the Q1 as reference. RESULTS: The prevalence rates of NAFLD in a cross-sectional population from Q1 to Q4 were 19.34%, 25.86%, 35.65% and 42.08%, respectively. The OR for NAFLD in the cross-sectional population were 1.31 (95% CI 1.14-1.54), 1.73 (95% CI 1.46-2.04), and 1.82 (95% CI 1.49-2.23), respectively, after adjusting for known confounding variables. The HR for NAFLD in the longitudinal population were 1.23 (95% CI 1.12 1.35), 1.57 (95% CI 1.44-1.72) and 2.02 (95% CI 1.86-2.21), compared with Q1. Subjects with higher LDL-c level within the normal range had an increased cumulative incidence rate of NAFLD. CONCLUSIONS: Increased levels of LDL-c within the normal range may play a significant role in the prevalence and incidence of NAFLD, independent of other confounding factors. PMID- 26735338 TI - The cytomegalovirus protein UL138 induces apoptosis of gastric cancer cells by binding to heat shock protein 70. AB - It has been hypothesized that human cytomegalovirus (HCMV) could act as a tumor promoter and play an "oncomodulatory" role in the neoplastic process of several human malignancies. However, we demonstrate for the first time that UL138, a HCMV latency-associated gene, could act as a tumor inhibitor in gastric cancer (GC). The expression of UL138 is down-regulated in HCMV positive gastric adenocarcinoma tissues, especially in poorly or none differentiated tumors. Overexpression of UL138 in several human GC cell lines inhibits cell viability and induces apoptosis, in association with the reduction of an anti-apoptotic Bcl-2 protein and the induction of cleaved caspase-3 and caspase-9. Moreover, protein array analysis reveals that UL138 interacts with a chaperone protein, heat shock protein 70 (HSP70). This interaction is confirmed by immunoprecipitation and immunostaining in situ in GC cell lines. In addition, this UL138-mediated cancer cell death could efficiently lead to suppression of human tumor growth in a xenograft animal model of GC. In conclusion, these results uncover a previously unknown role of the cytomegalovirus protein UL138 in inducing GC cells apoptosis, which might imply a general mechanism that viral proteins inhibit cancer growth in interactions with both chaperones and apoptosis-related proteins. Our findings might provide a potential target for new therapeutic strategies of GC treatment. PMID- 26735339 TI - Valproic acid potentiates the anticancer activity of capecitabine in vitro and in vivo in breast cancer models via induction of thymidine phosphorylase expression. AB - The prognosis of patients with metastatic breast cancer remains poor, and thus novel therapeutic approaches are needed. Capecitabine, which is commonly used for metastatic breast cancer in different settings, is an inactive prodrug that takes advantage of elevated levels of thymidine phosphorylase (TP), a key enzyme that is required for its conversion to 5-fluororacil, in tumors. We demonstrated that histone deacetylase inhibitors (HDACi), including low anticonvulsant dosage of VPA, induced the dose- and time-dependent up-regulation of TP transcript and protein expression in breast cancer cells, but not in the non-tumorigenic breast MCF-10A cell line. Through the use of siRNA or isoform-specific HDACi, we demonstrated that HDAC3 is the main isoform whose inhibition is involved in the modulation of TP. The combined treatment with capecitabine and HDACi, including valproic acid (VPA), resulted in synergistic/additive antiproliferative and pro apoptotic effects in breast cancer cells but not in TP-knockout cells, both in vitro and in vivo, highlighting the crucial role of TP in the synergism observed. Overall, this study suggests that the combination of HDACi (e.g., VPA) and capecitabine is an innovative antitumor strategy that warrants further clinical evaluation for the treatment of metastatic breast cancer. PMID- 26735340 TI - Metabolomic profile in pancreatic cancer patients: a consensus-based approach to identify highly discriminating metabolites. AB - PURPOSE: pancreatic adenocarcinoma is the fourth leading cause of cancer related deaths due to its aggressive behavior and poor clinical outcome. There is a considerable variability in the frequency of serum tumor markers in cancer' patients. We performed a metabolomics screening in patients diagnosed with pancreatic cancer. EXPERIMENTAL DESIGN: Two targeted metabolomic assays were conducted on 40 serum samples of patients diagnosed with pancreatic cancer and 40 healthy controls. Multivariate methods and classification trees were performed. MATERIALS AND METHODS: Sparse partial least squares discriminant analysis (SPLS DA) was used to reduce the high dimensionality of a pancreatic cancer metabolomic dataset, differentiating between pancreatic cancer (PC) patients and healthy subjects. Using Random Forest analysis palmitic acid, 1,2-dioleoyl-sn-glycero-3 phospho-rac-glycerol, lanosterol, lignoceric acid, 1-monooleoyl-rac-glycerol, cholesterol 5alpha,6alpha epoxide, erucic acid and taurolithocholic acid (T-LCA), oleoyl-L-carnitine, oleanolic acid were identified among 206 metabolites as highly discriminating between disease states. Comparison between Receiver Operating Characteristic (ROC) curves for palmitic acid and CA 19-9 showed that the area under the ROC curve (AUC) of palmitic acid (AUC=1.000; 95% confidence interval) is significantly higher than CA 19-9 (AUC=0.963; 95% confidence interval: 0.896-1.000). CONCLUSION: Mass spectrometry-based metabolomic profiling of sera from pancreatic cancer patients and normal subjects showed significant alterations in the profiles of the metabolome of PC patients as compared to controls. These findings offer an information-rich matrix for discovering novel candidate biomarkers with diagnostic or prognostic potentials. PMID- 26735341 TI - Induction of autophagy promotes the growth of early preneoplastic rat liver nodules. AB - Although inhibition of autophagy has been implicated in the onset and progression of cancer cells, it is still unclear whether its dysregulation at early stages of tumorigenesis plays an oncogenic or a tumor suppressor role. To address this question, we employed the Resistant-Hepatocyte rat model to study the very early stages of hepatocellular carcinoma (HCC) development. We detected a different autophagy-related gene expression and changes in the ultrastructural profile comparing the most aggressive preneoplastic lesions, namely those positive for the putative progenitor cell marker cytokeratin-19 (KRT-19) with the negative ones. The ultrastructural and immunohistochemical analyses of KRT-19-positive preneoplastic hepatocytes showed the presence of autophagic vacuoles which was associated with p62, Ambra1 and Beclin1 protein accumulation suggesting that a differential modulation of autophagy occurs at early stages of the oncogenesis in KRT-19-positive vs negative lesions. We observed an overall decrease of the autophagy-related genes transcripts and a strong up-regulation of miR-224 in the KRT-19-positive nodules. Interestingly, the treatment with the autophagy inducer, Amiodarone, caused a marked increase in the proliferation of KRT-19 positive preneoplastic lesions associated with a strong increase of their size; by contrast, Chloroquine, an inhibitor of the autophagic process, led to their reduction. These results show that autophagy modulation is a very early event in hepatocarcinogenesis and is restricted to a hepatocytes subset in the most aggressive preneoplastic lesions. Our findings highlight the induction of autophagy as a permissive condition favouring cancer progression indicating in its inhibition a therapeutic goal to interfere with the development of HCC. PMID- 26735343 TI - Comparative evaluation of PLGA nanoparticle delivery system for 5-fluorouracil and curcumin on squamous cell carcinoma. AB - PURPOSE: The purpose of this study is to assess the effect of 5-fluorouracil nanoparticles and curcumin naoparticles on cell proliferation and the expression of the apoptotic marker (caspase 3) in squamous cell carcinoma cell line. MATERIAL AND METHODS: PLGA 5-fluorouracil nanopartciles and PLGA curcumin nanoparticles were prepared and applied for 24 and 48h on human laryngeal squamous carcinoma cell line (Hep-2) as regard IC 50 concentration. MTT assay was used for evaluation of cytotoxicity of prepared nanoparticles. Quantitaive reverse transcriptase polymerase chain reaction (QRT-PCR) was used for the assessment of caspase-3 expression in the treated cell line. RESULTS: The drug release rate profiles was dependent upon polymer to drug ratio, noting that the higher PLGA polymer ratio to 5-fluprouracil or curcumin drug showed faster release rates. On the other hand, the least PLGA polymer ratio to 5-fluprouracil or curcumin drug showed the slowest release rates. MTT assay revelaed that 5 fluorouracil nanoparticels or curcumin nanoparticels showed a clear cytotoxic effect on Hep-2 cell line compared to non treated cancer cells. The RT-PCR assessment of caspase-3 expression revealed that there was a significant increase in caspase-3 expression in Hep-2 cell line treated with 5-fluorouracil nanoparticles or curcumin compared to non treated cancer cells. CONCLUSION: Curcumin nanoparticles could be more active in inducing apoptosis in short term assays (24h) than long term assays (48h) due to differential cellular uptake. While 5-fluorouracil nanoparticles induced higher significant apoptosis in long term (48h) compared to curcumin group. PMID- 26735344 TI - Highly CO2-Selective Gas Separation Membranes Based on Segmented Copolymers of Poly(Ethylene oxide) Reinforced with Pentiptycene-Containing Polyimide Hard Segments. AB - Poly(ethylene oxide) (PEO)-containing polymer membranes are attractive for CO2 related gas separations due to their high selectivity toward CO2. However, the development of PEO-rich membranes is frequently challenged by weak mechanical properties and a high crystallization tendency of PEO that hinders gas transport. Here we report a new series of highly CO2-selective, amorphous PEO-containing segmented copolymers prepared from commercial Jeffamine polyetheramines and pentiptycene-based polyimide. The copolymers are much more mechanically robust than the nonpentiptycene containing counterparts due to the molecular reinforcement mechanism of supramolecular chain threading and interlocking interactions induced by the pentiptycene structures, which also effectively suppresses PEO crystallization leading to a completely amorphous structure even at 60% PEO weight content. Membrane transport properties are sensitively affected by both PEO weight content and PEO chain length. A nonlinear correlation between CO2 permeability with PEO weight content was observed due to the competition between solubility and diffusivity contributions, whereby the copolymers change from being size-selective to solubility-selective when PEO content reaches 40%. CO2 selectivities over H2 and N2 increase monotonically with both PEO content and chain length, indicating strong CO2-philicity of the copolymers. The copolymer film with the longest PEO sequence (PEO2000) and highest PEO weight content (60%) showed a measured CO2 pure gas permeability of 39 Barrer, and ideal CO2/H2 and CO2/N2 selectivities of 4.1 and 46, respectively, at 35 degrees C and 3 atm, making them attractive for hydrogen purification and carbon capture. PMID- 26735342 TI - Comprehensive nucleosome mapping of the human genome in cancer progression. AB - Altered chromatin structure is a hallmark of cancer, and inappropriate regulation of chromatin structure may represent the origin of transformation. Important studies have mapped human nucleosome distributions genome wide, but the role of chromatin structure in cancer progression has not been addressed. We developed a MNase-Transcription Start Site Sequence Capture method (mTSS-seq) to map the nucleosome distribution at human transcription start sites genome-wide in primary human lung and colon adenocarcinoma tissue. Here, we confirm that nucleosome redistribution is an early, widespread event in lung (LAC) and colon (CRC) adenocarcinoma. These altered nucleosome architectures are consistent between LAC and CRC patient samples indicating that they may serve as important early adenocarcinoma markers. We demonstrate that the nucleosome alterations are driven by the underlying DNA sequence and potentiate transcription factor binding. We conclude that DNA-directed nucleosome redistributions are widespread early in cancer progression. We have proposed an entirely new hierarchical model for chromatin-mediated genome regulation. PMID- 26735346 TI - Viable Species of Flamella (Amoebozoa: Variosea) Isolated from Ancient Arctic Permafrost Sediments. AB - Six viable strains of amoebae belonging to the genus Flamella (Amoebozoa, Variosea) were isolated from permafrost sediments sampled in the Russian Arctic region. Two of them are from late Pleistocene permafrost in North-East Siberia, and four--from Holocene and late Pleistocene in North-West Siberia. Light- and electron-microscopic study and molecular phylogeny show that these isolates represent two new species belonging to the genus Flamella. Both species are cyst forming. This is a remarkable case of high resistance of protozoan cysts, allowing them to survive and recover an amoebae population after a very long, geologically significant period of rest; a "snapshot" of evolution in time. This study directly shows for the first time that amoeba cysts can be conserved not only for years and decades but for many thousand years and then recover, contributing to the formation of an active microbial community. We propose to name the new species as Flamella pleistocenica n.sp. and Flamella beringiania n.sp. Phylogenetic analysis shows that the genus Flamella is a robust and potentially species-rich group of Variosea. PMID- 26735345 TI - Systemic inflammation on postnatal days 21 and 28 and indicators of brain dysfunction 2years later among children born before the 28th week of gestation. AB - BACKGROUND: Systemic inflammation during the first two postnatal weeks in extremely preterm newborns (<28weeks gestation) has been associated with an increased risk of neurodevelopmental dysfunctions. Little is known, however, about the relationship between systemic inflammation during the third and fourth postnatal weeks and subsequent development. METHODS: We measured the concentrations of 16 inflammation-related proteins in blood spots collected on postnatal days 21 (N=749) and 28 (N=697) from infants born before the 28th week of gestation and assessed at age 2years. We then sought the developmental correlates of top quartile concentrations for gestational age and day the specimen was collected. Odds ratios and 95% confidence intervals were calculated from regular or multinomial logistic regression models (as appropriate). RESULTS: Top quartile concentrations of CRP, IL-1beta, IL-6, IL-6R, TNF-R2, IL-8, ICAM-1, and TSH on both days 21 and 28 were associated with ventriculomegaly (when in the NICU) and microcephaly at age 2years. Top quartile concentrations of CRP, SAA, IL 6, TNF-R2, IL-8, and ICAM-1 were associated with mental development index (MDI) of the Bayley-II<55, while top quartile concentrations of CRP, TNF-alpha (inversely), IL-8, and ICAM-1 were associated with psychomotor development index (PDI)<55 CONCLUSION: Extremely preterm newborns who had systemic inflammation during the third and fourth postnatal weeks were at increased risk of ventriculomegaly during the months after birth, and of microcephaly, and low Bayley Scale scores at 2years old. PMID- 26735347 TI - Identification of disinfection by-products in freshwater and seawater swimming pools and evaluation of genotoxicity. AB - Exposure to disinfection byproducts (DBPs) in swimming pools has been linked to adverse health effects. Numerous DBPs that occur in swimming pools are genotoxic and carcinogenic. This toxicity is of a greater concern in the case of brominated DBPs that have been shown to have substantially greater toxicities than their chlorinated analogs. In chlorinated seawater swimming pools, brominated DBPs are formed due to the high content of bromide. Nevertheless, very little data is reported about DBP occurrence and mutagenicity of water in these pools. In the present study, three seawater and one freshwater swimming pools located in Southeastern France were investigated to determine qualitatively and quantitatively their DBP contents. An evaluation of the genotoxic properties of water samples of the freshwater pool and a seawater pool was conducted through the Salmonella assay (Ames test). The predominant DBPs identified in the freshwater pool were chlorinated species and included trichloroacetic acid, chloral hydrate, dichloroacetonitrile, 1,1,1-trichloropropanone and chloroform. In the seawater pools, brominated DBPs were the predominant species and included dibromoacetic acid, bromoform and dibromoacetonitile. Bromal hydrate levels were also reported. In both types of pools, haloacetic acids were the most prevalent chemical class among the analyzed DBP classes. The distribution of other DBP classes varied depending on the type of pool. As to genotoxicity, the results of Ames test showed higher mutagenicity in the freshwater pool as a consequence of its considerably higher DBP contents in comparison to the tested seawater pool. PMID- 26735348 TI - Geographical variation in relative risks associated with cold waves in Spain: The need for a cold wave prevention plan. AB - In general, there are few studies that analyse the impact of low temperatures on mortality and fewer still that use cold-wave-definition thresholds based on epidemiological and non-climatological criteria. Such a threshold definition, which took into account population features such as socio-economic and demographic characteristics, made it possible for a specific threshold temperature to be obtained for each of Spain's 52 provincial capitals in this study. Using generalised linear models with the Poisson regression link, and controlling for trend, autocorrelations and seasonalities of the series, and influenza epidemics, we obtained the impact of low temperatures on mortality in each provincial capital by calculating the relative risks (RRs) and attributable risks (ARs) for natural as well as circulatory and respiratory causes. The study showed higher minimum temperature thresholds in coastal areas, and an overall impact of cold on mortality in Spain due to natural causes RR=1.13 (95% CI: 1.11 1.16), circulatory causes RR=1.18 (95% CI: 1.15-1.22) and respiratory causes RR=1.24 (95% CI: 1.20-1.29) slightly greater than that obtained to date for heat. From a public health standpoint, there is a need for specific cold wave prevention plans at a regional level which would enable mortality attributable to low temperatures to be reduced. These plans have shown themselves to be effective in decreasing heat-related mortality, and we feel that they are essential for reducing cold-related effects on morbidity and mortality. PMID- 26735350 TI - Inhalation threshold of toxicological concern (TTC) - Structural alerts discriminate high from low repeated-dose inhalation toxicity. AB - The threshold of toxicological concern (TTC) of a compound represents an exposure value below which the associated human health risk is considered negligible. As such, this approach offers assessing the risk of potential toxicants when little or no toxicological information is available. For the inhalation repeated-dose TTC, the goal was to derive structural alerts that discriminate between high- and low-toxic compounds. A further aim was to identify physicochemical parameters related to the inhalation-specific bioavailability of the compounds, and to explore their use as predictors of high vs low toxicity. 296 compounds with subacute, subchronic and chronic inhalation toxicity NOEC (no-observed effect concentration) values were subdivided into three almost equal-sized high-, medium and low-toxic (HTox, MTox, LTox) potency classes. Whereas the derived 14 HTox and 7 LTox structural alerts yield an only moderate discrimination between these three groups, the high-toxic vs low-toxic mis-classification is very low: LTox predicted compounds are not HTox to 97.5%, and HTox-predicted compounds not LTox to 88.6%. The probability of a compound being HTox vs LTox is triggered further by physicochemical properties encoding the tendency to evaporate from blood. The new structural alerts may aid in the predictive inhalation toxicity assessment of compounds as well as in designing low-toxicity chemicals, and provide a rationale for the chemistry underlying the toxicological outcome that can also be used for scoping targeted experimental studies. PMID- 26735349 TI - Newborns health in the Danube Region: Environment, biomonitoring, interventions and economic benefits in a large prospective birth cohort study. AB - BACKGROUND: The EU strategy for the Danube Region addresses numerous challenges including environment, health and socioeconomic disparities. Many old environmental burdens and heavily polluted areas in Europe are located in the Danube Region, consisting of 14 countries, with over 100 million people. Estimating the burden of environmental exposures on early-life health is a growing research area in Europe which has major public health implications, but the data from the Danube Region are largely missing. AIM: This review presents an inventory of current environmental challenges, related early-life health risks, and knowledge gaps in the Danube Region, based on publicly available databases, registers, and literature, as a rationale and incentive for a new integrated project. The review also proposes the concept for the project aiming to characterize in utero exposures to multiple environmental factors and estimate their effect on early-life health, evaluate economic impact, as well as identify interventions with a potential to harness social norms to reduce emissions, exposures and health risks in the Danube Region. METHODS: Experts in environmental epidemiology, human biomonitoring and social science in collaboration with clinicians propose to establish a new large multi-center birth cohort of mother-child pairs from Danube countries, measure biomarkers of exposure and health in biological samples at birth, collect centrally measured climate, air and water pollution data, conduct pre- and postnatal surveys on lifestyle, indoor exposures, noise, occupation, socio-economic status, risk averting behavior, and preferences; and undertake clinical examinations of children at and after birth. Birth cohort will include at least 2000 newborns per site, and a subset of at least 200 mother-child pairs per site for biomonitoring. Novel biomarkers of exposure, susceptibility, and effect will be applied, to gain better mechanistic insight. Effects of multiple environmental exposures on fetal and child growth, respiratory, allergic, immunologic, and neurodevelopmental health outcomes will be estimated. Parent's willingness to pay for reducing health risks in children will be elicited by survey, while values of cost-of illness will be gathered from literature and national statistics. Effects of risk reducing interventions will be examined. CONCLUSIONS: The proposed project would provide novel estimates of the burden of early childhood diseases attributable to environmental exposures and assess health impacts of different intervention scenarios in the Danube Region, in an integrated approach combining human biomonitoring, epidemiological and social science research. PMID- 26735351 TI - Polychlorinated biphenyls and breast cancer: A congener-specific meta-analysis. AB - The incidence of breast cancer is related to various risk factors, especially that the environmental and lifestyle factors account for major contribution at the rate of 70% to 95% over all. However, there still remains some controversy over the epidemiological evidence regarding the effects of environmental carcinogens on the risk of breast cancer. We conducted a quantitative meta analysis aiming at full evaluation of the effects of polychlorinated biphenyls (PCBs) on breast cancer in a congener-specific fashion. Four online literature databases were systematically searched before 1st January 2015, for studies stating correlation between PCB congeners and breast cancer. The Newcastle-Ottawa Scale was used to evaluate the quality of the studies that were included in our analysis. Sixteen studies were included in our final meta-analysis after screening based on the priori inclusion criteria. Nine PCB congeners were reported by more than two studies and they were presented in detail. The pooled Odds Ratios (ORs) showed a significant increase in the risk of breast cancer in individuals with higher plasma/fat levels of PCB 99 (OR: 1.36; 95% CI: 1.02 to 1.80), PCB 183 (OR: 1.56; 95% CI: 1.25 to 1.95) and PCB 187 (OR: 1.18; 95% CI: 1.01 to 1.39). Besides, the outcomes did not support a relationship between dioxin-like PCB congeners and the risk of breast cancer. The results of our meta analysis imply that PCB 99, PCB 183 and PCB 187 would increase the risk of breast cancer. The mechanism of this increased risk may be by the induction of the CYP2B family in cytochrome P450 enzymes. PMID- 26735352 TI - Transition guidelines: An important step in the future care for childhood cancer survivors. A comprehensive definition as groundwork. AB - Evidence-based clinical practice guidelines are essential to ensure that childhood cancer survivors at risk of chronic health conditions receive effective long-term follow-up care. However, adult survivors of childhood cancer are not always engaged in recommended health promotion and follow-up practices, as many centres do not have a formal transition programme that prepares survivors and their families for successful transfer from child-centred to adult-oriented healthcare. The need for a specific pan-European guideline for the transition of care for childhood cancer survivors has been recognised. The first step is to define the concept of transition of care for survivors of childhood cancer based on existing evidence. PMID- 26735353 TI - Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities. AB - Mutation of the KRAS oncogene in pancreatic cancer is responsible for permanent activation of the P21 RAS protein and the cascade of signalling pathways. Consequently, multiple cellular processes, such as transformation, proliferation, invasion, and survival are activated. The aim of this review was to present all potential clinical applications of targeting KRAS in terms of diagnosis and management of pancreatic adenocarcinoma. Quantitative polymerase chain reaction technology provides reliable assessment of KRAS mutations, both in tissues and from fine-needle aspiration biopsies. Numerous studies report that the combination of endoscopic ultrasound-guided cytopathology and a KRAS mutation assay can improve the positive and differential diagnosis of pancreatic cancer, differentiating between benign versus malignant solid pancreatic cancer, and reducing false-negative results compared to cytopathology alone. In addition, the presence of a KRAS mutation is frequently associated with a worse prognosis, both in cases of advanced and resected tumours. However, the KRAS mutation assay is not as efficient at predicting a response to both anti-epidermal growth factor receptor treatments and/or chemotherapy. Targeting of KRAS to treat pancreatic adenocarcinoma has been applied at different stages of RAS molecular intracellular processes: at the transcription level with antisense or interference RNA, at the posttranslational level with inhibitors of farnesyl transferase or anti-RAS vaccination peptides, and to target multiple signalling pathways using inhibitors of mitogen-activated protein kinase, phosphoinositide 3 kinase, AKT, mammalian target of rapamycin, RAF. Despite some encouraging results at pre-clinical and phase I stages, no significant clinical benefits have been observed. Combinatory approaches with standard chemotherapy will be welcome. PMID- 26735354 TI - Impact of surgical staging on prognosis in patients with borderline ovarian tumours: A meta-analysis. AB - BACKGROUND: To quantify the effect of complete surgical staging (CSS) on prognosis in borderline ovarian tumour (BOT) patients through a meta-analysis. METHODS: We systematically reviewed published studies comparing CSS with incomplete surgical staging (ISS) in BOT patients through April 2015. End-points were recurrence and mortality rates. Study design features that possibly affected participant selection, recurrence/death detection, and manuscript publication were assessed. For pooled estimates of the effect of CSS on recurrence/death, random- or fixed-effects meta-analytical models were used after assessing cross study heterogeneity. RESULTS: Eighteen observational studies (CSS, 1297 patients; ISS, 1473 patients) met our search criteria. Fixed-effects model-based meta analysis indicated a reduced recurrence risk among CSS patients (odds ratio [OR]=0.64; 95% confidence interval [CI]: 0.47-0.87, P < 0.05, I(2) = 25.6). However, no significant between-group difference in mortality was observed (OR = 0.98; 95% CI: 0.42-2.29, P = 0.97, I(2) = 0). In subgroup analysis by histology, CSS was associated with a reduced recurrence risk in 16 studies of all histologic types (OR = 0.66; 95% CI: 0.48-0.91, P < 0.05, I(2) = 31.9) but not in two studies of only mucinous disease (OR = 0.41; 95% CI: 0.13-1.30, P = 0.13, I(2) = 0). In subgroup analyses with four studies with recurrence data according to fertility-sparing surgery, no significant association was found (OR = 0.51; 95% CI: 0.18-1.43, P = 0.20, I(2) = 0). There was no evidence of publication bias. CONCLUSIONS: In this meta-analysis based on observational studies, CSS appeared to significantly reduce recurrence among BOT patients. No survival impact was observed. Longer-term randomised controlled trials could verify this relationship but appear infeasible for this rare tumour. PMID- 26735355 TI - Bayesian Model Averaging for Propensity Score Analysis. AB - This article considers Bayesian model averaging as a means of addressing uncertainty in the selection of variables in the propensity score equation. We investigate an approximate Bayesian model averaging approach based on the model averaged propensity score estimates produced by the R package BMA but that ignores uncertainty in the propensity score. We also provide a fully Bayesian model averaging approach via Markov chain Monte Carlo sampling (MCMC) to account for uncertainty in both parameters and models. A detailed study of our approach examines the differences in the causal estimate when incorporating noninformative versus informative priors in the model averaging stage. We examine these approaches under common methods of propensity score implementation. In addition, we evaluate the impact of changing the size of Occam's window used to narrow down the range of possible models. We also assess the predictive performance of both Bayesian model averaging propensity score approaches and compare it with the case without Bayesian model averaging. Overall, results show that both Bayesian model averaging propensity score approaches recover the treatment effect estimates well and generally provide larger uncertainty estimates, as expected. Both Bayesian model averaging approaches offer slightly better prediction of the propensity score compared with the Bayesian approach with a single propensity score equation. Covariate balance checks for the case study show that both Bayesian model averaging approaches offer good balance. The fully Bayesian model averaging approach also provides posterior probability intervals of the balance indices. PMID- 26735356 TI - Ignoring Clustering in Confirmatory Factor Analysis: Some Consequences for Model Fit and Standardized Parameter Estimates. AB - In many situations, researchers collect multilevel (clustered or nested) data yet analyze the data either ignoring the clustering (disaggregation) or averaging the micro-level units within each cluster and analyzing the aggregated data at the macro level (aggregation). In this study we investigate the effects of ignoring the nested nature of data in confirmatory factor analysis (CFA). The bias incurred by ignoring clustering is examined in terms of model fit and standardized parameter estimates, which are usually of interest to researchers who use CFA. We find that the disaggregation approach increases model misfit, especially when the intraclass correlation (ICC) is high, whereas the aggregation approach results in accurate detection of model misfit in the macro level. Standardized parameter estimates from the disaggregation and aggregation approaches are deviated toward the values of the macro- and micro-level standardized parameter estimates, respectively. The degree of deviation depends on ICC and cluster size, particularly for the aggregation method. The standard errors of standardized parameter estimates from the disaggregation approach depend on the macro-level item communalities. Those from the aggregation approach underestimate the standard errors in multilevel CFA (MCFA), especially when ICC is low. Thus, we conclude that MCFA or an alternative approach should be used if possible. PMID- 26735357 TI - Using Two-Level Factor Analysis to Test for Cluster Bias in Ordinal Data. AB - The test for cluster bias is a test of measurement invariance across clusters in 2-level data. This article examines the true positive rates (empirical power) and false positive rates of the test for cluster bias using the likelihood ratio test (LRT) and the Wald test with ordinal data. A simulation study indicates that the scaled version of the LRT that accounts for nonnormality of the data gives untrustworthy results, whereas the unscaled LRT and the Wald test have acceptable false positive rates and perform well in terms of empirical power rate if the amount of cluster bias is large. The test for cluster bias is illustrated with data from research on teacher-student relations. PMID- 26735359 TI - Graphical Data Analysis on the Circle: Wrap-Around Time Series Plots for (Interrupted) Time Series Designs. AB - Many data structures, particularly time series data, are naturally seasonal, cyclical, or otherwise circular. Past graphical methods for time series have focused on linear plots. In this article, we move graphical analysis onto the circle. We focus on 2 particular methods, one old and one new. Rose diagrams are circular histograms and can be produced in several different forms using the RRose software system. In addition, we propose, develop, illustrate, and provide software support for a new circular graphical method, called Wrap-Around Time Series Plots (WATS Plots), which is a graphical method useful to support time series analyses in general but in particular in relation to interrupted time series designs. We illustrate the use of WATS Plots with an interrupted time series design evaluating the effect of the Oklahoma City bombing on birthrates in Oklahoma County during the 10 years surrounding the bombing of the Murrah Building in Oklahoma City. We compare WATS Plots with linear time series representations and overlay them with smoothing and error bands. Each method is shown to have advantages in relation to the other; in our example, the WATS Plots more clearly show the existence and effect size of the fertility differential. PMID- 26735358 TI - Modeling Coordination in Multiple Simultaneous Latent Change Scores. AB - Coordination is a taxonomy of how processes change together through time. It depicts the changes of 2 or more variables in terms of the strength and consistency of their covariation, the directionality of their covariation (i.e., do increases in 1 variable correspond with increases [in-phase] or decreases [anti-phase] in the other variable), and the timing of their covariation (i.e., do both variables change at the same rate or does 1 variable change faster than the other). Current methods are able to characterize some, but not all, of these aspects of coordination and provide incomplete information as a result. This study addresses this limitation by demonstrating that multivariate Latent Change Score models can be used to fully differentiate all possible coordination patterns. Furthermore, one can then expand coordination beyond the 2-outcome case to test arrangements of underlying coordination mechanisms or patterns. Examples using 2 simultaneous Latent Change Score models and 4 simultaneous Latent Change Score models illustrate this approach within the context of adolescents and parents regulating Type 1 diabetes. PMID- 26735360 TI - Model Conditioned Data Elasticity in Path Analysis: Assessing the "Confoundability" of Model/Data Characteristics. AB - Much research has been directed at the validity of fit indices in Path Analysis and Structural Equation Modeling (e.g., Browne, MacCallum, Kim, Andersen, & Glaser, 2002 ; Heene, Hilbert, Draxler, Ziegler, & Buhner, 2011 ; Hu & Bentler, 1999 ; Marsh, Hau, & Wen, 2004 ). Recent developments (e.g., Preacher, 2006 ; Roberts & Pashler, 2000 , 2002 ) have encouraged researchers to investigate other criteria for comparing models, including model complexity. What has not been investigated is the inherent ability of a particular data set to be fitted with a constrained set of randomly generated linear models, which we call Model Conditioned Data Elasticity (DE). In this article we show how DE can be compared with the problem of equivalent models and a more general problem of the "confoundability" of data/model combinations (see MacCallum, Wegener, Uchino, & Fabrigar, 1993 ). Using the DE package in R, we show how DE can be assessed through automated computer searches. Finally, we discuss how DE fits within the controversy surrounding the use of fit statistics. PMID- 26735361 TI - Handling Missing Covariates in Conditional Mixture Models Under Missing at Random Assumptions. AB - Mixture modeling is a popular method that accounts for unobserved population heterogeneity using multiple latent classes that differ in response patterns. Psychologists use conditional mixture models to incorporate covariates into between-class and/or within-class regressions. Although psychologists often have missing covariate data, conditional mixtures are currently fit with a conditional likelihood, treating covariates as fixed and fully observed. Under this exogenous x approach, missing covariates are handled primarily via listwise deletion. This sacrifices efficiency and does not allow missingness to depend on observed outcomes. Here we describe a modified joint likelihood approach that (a) allows inference about parameters of the exogenous-x conditional mixture even with nonnormal covariates, unlike a conventional multivariate mixture; (b) retains all cases under missing at random assumptions; (c) yields lower bias and higher efficiency than the exogenous-x approach under a variety of conditions with missing covariates; and (d) is straightforward to implement in available commercial software. The proposed approach is illustrated with an empirical analysis predicting membership in latent classes of conduct problems. Recommendations for practice are discussed. PMID- 26735363 TI - Micro-level processes of identity development: Intra-individual relations between commitment and exploration. AB - We investigate intra-individual processes of identity at the micro level. With an intensive longitudinal design in the general context of higher education, we explore associations between changes in pivotal identity concepts: commitment and exploration and elaborate on how we conceptualize these concepts on a micro level. With our within-individual empirical approach, we revealed a large amount of variation between individuals with respect to the associations between exploration and commitment processes. At the same time, similarities were found amongst individuals, which help extend and clarify existing findings regarding identity development. Our findings highlight the necessity to, firstly, distinguish between micro- and macro-level identity processes. Secondly, and in the same vein, our findings emphasize the heterogeneous nature of micro-level identity processes, and the necessity to use a within individual approach to study these processes. PMID- 26735364 TI - Ozonation of Cylindrospermopsin (Cyanotoxin): Degradation Mechanisms and Cytotoxicity Assessments. AB - Cylindrospermopsin (CYN) is a potent toxic alkaloid produced by a number of cyanobacteria frequently found in lakes and reservoirs used as drinking water sources. We report for the first time detailed pathways for the degradation of CYN by treatment with ozone. This was accomplished by use of ultra-high performance liquid chromatography (UHPLC)-quadrupole time-of-flight mass spectrometry (QTOF MS), which revealed that CYN is readily degraded by ozone with at least 36 transformation products. Structural similarities among the major products indicated that the carbon-carbon double bond in the uracil ring of CYN was most susceptible to attack by ozone. Furthermore, the nitrogen functionality associated with the tricyclic guanidine moiety is also involved via a degradation pathway that has not been previously observed. To assess the potential toxicity of ozonation products of CYN, the cytotoxicity of CYN and the mixture of its ozonation products was measured in a human hepatoma cell line (HepG2). The IC50 for CYN at 24 and 48 h incubations was approximately 64.1 and 12.5 MUM, respectively; however, the ozonation products of CYN did not exhibit measurable cytotoxicity to human cells. The results indicate ozone is an effective and practical method for CYN attenuation in water treatment without formation of overtly toxic transformation products. PMID- 26735366 TI - On feelings, lessons, and editorial commitments. PMID- 26735367 TI - Conflicts of interest in food and nutrition. PMID- 26735368 TI - [The Brazilian National Health Conference: challenges for the country]. AB - This article was published in the context of the upcoming 15th Brazilian National Health Conference and addresses the country's health challenges based on the history of previous conferences. The authors analyze the evolution of health as a public policy agenda, highlighting the role of such institutions as the Brazilian Center for Health Studies (CEBES), the Brazilian Association of Collective Health (Abrasco), and the National Health Council in advocating and establishing the Brazilian Unified National Health System (SUS). The article also focuses on expectations concerning the 15th National Health Conference within a political and economic scenario that raises questions and challenges both for the future of health policy, exemplified by SUS, and the current capacity to mobilize stakeholders. PMID- 26735365 TI - Tunable protein synthesis by transcript isoforms in human cells. AB - Eukaryotic genes generate multiple RNA transcript isoforms though alternative transcription, splicing, and polyadenylation. However, the relationship between human transcript diversity and protein production is complex as each isoform can be translated differently. We fractionated a polysome profile and reconstructed transcript isoforms from each fraction, which we term Transcript Isoforms in Polysomes sequencing (TrIP-seq). Analysis of these data revealed regulatory features that control ribosome occupancy and translational output of each transcript isoform. We extracted a panel of 5' and 3' untranslated regions that control protein production from an unrelated gene in cells over a 100-fold range. Select 5' untranslated regions exert robust translational control between cell lines, while 3' untranslated regions can confer cell type-specific expression. These results expose the large dynamic range of transcript-isoform-specific translational control, identify isoform-specific sequences that control protein output in human cells, and demonstrate that transcript isoform diversity must be considered when relating RNA and protein levels. PMID- 26735369 TI - [Recognize and overcome the limits of institutionalized participation. Many voices, little dialogue]. PMID- 26735370 TI - [The 15th National Health Conference: do you hear the cries of the people?]. PMID- 26735371 TI - [Health conferences: challenges to participatory democracy]. PMID- 26735372 TI - [Notes on the paper by Paulo Gadelha]. PMID- 26735373 TI - [The decisive role of the 15th National Health Conference in defense of the National Health System]. PMID- 26735374 TI - [Debate]. PMID- 26735375 TI - [The author reply]. PMID- 26735376 TI - Maternal obesity and offspring body composition by indirect methods: a systematic review and meta-analysis. AB - This study reviewed the evidence that assessed the association between maternal pre-pregnancy body mass index (BMI) and/or gestational weight gain and offspring body composition in childhood. A systematic review was conducted. Cohort studies, case-control studies and randomized controlled trials measuring offspring body composition by indirect methods were included. Meta-analyses of the effect of pre pregnancy BMI on offspring fat-free mass, body fat percent, and fat mass were conducted through random-effects models. 20 studies were included, most of which reported a positive association of pre-pregnancy BMI with offspring body fat. Standardized mean differences in body fat percent, fat mass and fat-free mass between infants of women with normal pre-pregnancy BMI and those of overweight/obese women were 0.31 percent points (95%CI: 0.19; 0.42), 0.38 kg (95%CI: 0.26; 0.50), and 0.18 kg (95%CI: -0.07; 0.42), respectively. Evidence so far suggests that pre-pregnancy maternal overweight is associated with higher offspring adiposity. PMID- 26735377 TI - [Transcultural adaptation of scales for treatment adherence in hemodialysis: Renal Adherence Behaviour Questionnaire(RABQ) and Renal Adherence Attitudes Questionnaire(RAAQ)]. AB - Treatment adherence in hemodialysis is important for guaranteeing better results for patients, but Brazil still lacks validated assessment tools for this purpose. The current study aimed to perform a cross-cultural adaptation of the Renal Adherence Behaviour Questionnaire (RABQ) and the Renal Adherence Attitudes Questionnaire (RAAQ). The two questionnaires were submitted to the following cross-cultural adaptation procedures: translation, back-translation, expert panel review, and pilot study. Changes were made in the items' wording and application, which requires a face-to-face interview. It was not necessary to change the choices of answers. The Brazilian versions of the RABQ and RAAQ showed semantic and cultural equivalence to the original versions and are easy for the target population to understand. The two scales still require validity and reliability studies before use in the field. PMID- 26735378 TI - An impact assessment of the Child Growth, Development and Care Program in the Caribbean Region of Colombia. AB - This article aims to assess the impact of the Child Growth, Development and Care Program in the Caribbean region of Colombia by analyzing variables such as maternal childcare practices and indicators of the nutritional status and health of children under the age of five. To this end, the authors used the quasi experimental technique Propensity Score Matching. Positive impacts included a decrease in acute diarrheal disease, and an increase in immunization and seeking treatment for acute respiratory infection or fever symptoms. However, the program had little influence on chronic and acute malnutrition in the region. PMID- 26735379 TI - Exposure to non-ionizing electromagnetic radiation from mobile telephony and the association with psychiatric symptoms. AB - The aim of this study was to investigate the association between exposure to non ionizing electromagnetic radiation from mobile phone base stations and psychiatric symptoms. In a cross-sectional study in Salvador, Bahia State, Brazil, 440 individuals were interviewed. Psychiatric complaints and diagnoses were the dependent variables and distance from the individual's residence to the base station was considered the main independent variable. Hierarchical logistic regression analysis was conducted to assess confounding. An association was observed between psychiatric symptoms and residential proximity to the base station and different forms of mobile phone use (making calls with weak signal coverage, keeping the mobile phone close to the body, having two or more chips, and never turning off the phone while sleeping), and with the use of other electronic devices. The study concluded that exposure to electromagnetic radiation from mobile phone base stations and other electronic devices was associated with psychiatric symptoms, independently of gender, schooling, and smoking status. The adoption of precautionary measures to reduce such exposure is recommended. PMID- 26735380 TI - Study of implementation and direct cost estimates for diagnostic tests for human visceral leishmaniasis in an urban area in Brazil. AB - This work reports the process and costs of comprehensively implementing two tests to decentralize the diagnosis of visceral leishmaniasis (VL) in an endemic city in Brazil: a rapid test (IT LEISH) and a direct agglutination test (DAT-LPC). The implementation began by training health professionals to perform the tests. Estimation of the training costs considered the proportional remuneration of all professionals involved and the direct costs of the tests used for training. The study was conducted between November 2011 and November 2013. During that time, 17 training sessions were held, and 175 professionals were trained. The training cost for each professional was US$ 7.13 for the IT LEISH and US$ 9.93 for the DAT LPC. The direct costs of the IT LEISH and DAT-LPC were estimated to be US$ 6.62 and US$ 5.44, respectively. This first evaluation of the implementation of these diagnostic tests indicates the feasibility of decentralizing both methods to extend access to VL diagnosis in Brazil. PMID- 26735381 TI - [Evaluation of scientific production in different subareas of Public Health: limits of the current model and contributions to the debate]. AB - The aim of this study was to discuss the limits of the quantitative evaluation model for scientific production in Public Health. An analysis of the scientific production of professors from the various subareas of Public Health was performed for 2010-2012. Distributions of the mean annual score for professors were compared according to subareas. The study estimated the likelihood that 60% of the professors in the graduate studies programs scored P50 (Very Good) or higher in their area. Professors of Epidemiology showed a significantly higher median annual score. Graduate studies programs whose faculty included at least 60% of Epidemiology professors and fewer than 10% from the subarea Social and Human Sciences in Health were significantly more likely to achieve a "Very Good" classification. The observed inequalities in scientific production between different subareas of Public Health point to the need to rethink their evaluation in order to avoid reproducing iniquities that have harmful consequences for the field's diversity. PMID- 26735382 TI - [The Sanuma-Yanomami medical system and indigenous peoples' health policy in Brazil]. AB - The purpose of this study is to discuss how the Sanuma indigenous people, a subgroup of the Yanomami linguistic family, located in northern Roraima State, Brazil, interacts with and relates to the public policy for indigenous people's health. Missionaries and Brazilian government and non-governmental organization employees are the agents with whom the Sanuma had to deal during the implementation of a healthcare policy. The ethnography of this interrelationship, permeated by moments of epidemic outbreaks, clashes, and attempts at collaboration, raises questions on the implementation of health services in indigenous territories. PMID- 26735383 TI - Factors associated with adherence to influenza vaccination among non institutionalized elderly in Sao Paulo, Brazil. AB - The objectives of this study were to estimate influenza vaccination coverage in the elderly and identify factors associated with vaccination uptake. A cross sectional population-based study was conducted with data collected in 2006 by the Health, Well-Being, and Aging study. The sample consisted of 1,399 elderly in the city of Sao Paulo, Brazil. The association between vaccine uptake and independent variables was assessed with prevalence ratios, estimated by Poisson regression. Self-reported vaccination was 73.8%. In the final explanatory model, influenza vaccination was associated with older age, presence of chronic diseases, and use of health care in the previous year. A negative association was observed with hospitalization during the previous year. The study concludes that it is necessary to encourage vaccination of elderly less than 70 years of age and those without chronic diseases, as well as to orient health professionals to expand coverage in groups with lower uptake during vaccination campaigns. PMID- 26735384 TI - [Evolution of the burden of injuries in Brazil: a comparison between 1998 and 2008]. AB - The objective of this study was to compare estimates of external causes based on the Global Burden of Disease in Brazil Study for the years 1998 and 2008. Methods included estimation of DALYs (disability-adjusted life years) and YLL (years of life lost), based on the methodology proposed in the Global Burden of Disease Study. Calculation of YLD (years lived with disability) required applying the same methodology in both years, with the 2008 methodology as the standard. Although external causes accounted for some 10% of total DALYs in both years, their internal distribution showed marked differences between regions of Brazil, with a decrease in the Southeast and increase in the North and Northeast. There was an increase in intentional causes, and YLLs accounted for the largest share of DALYs. The results can support new policies and/or improve existing ones to address external causes. PMID- 26735385 TI - [Evaluation of the effectiveness of home-based physical activity promotion by community health workers]. AB - This study analyzed the effectiveness of physical activity promotion by community health workers (CHW) during home visits. This was a non-randomized controlled trial that lasted six months, with one group of CHW that received training to promote physical activity during home visits among users of the Brazilian Unified National Health System (SUS) and a control group. Physical activity and stages of behavior change were evaluated in 176 adults (n = 90 in the intervention group and n = 86 in the control group) assisted by the CHW. Associations, prevalence ratios, and generalized estimate equations were conducted to verify differences between groups. No evidence of differences in physical activity and stages of behavior change were observed between the two groups. CHW from the intervention group conducted more home visits promoting physical activity among elders, those with low schooling, unemployed, and those with chronic diseases. It is important to reassess the work and priorities of CHW to expand physical activity promotion under the SUS. PMID- 26735386 TI - [Prevalence of infection with Mycobacterium tuberculosis and associated factors in community health workers in Brazil based on the tuberculin skin test]. AB - This article aimed to determine the prevalence of latent Mycobacterium tuberculosis infection and associated factors in community health workers (CHW) in Brazil, using two cutoff points for the tuberculin skin test (5mm and 10mm). This was a cross-sectional study with data on gender, age, BCG scar, working in a primary care unit (PCU), having a household contact with tuberculosis (TB), alcohol consumption, previous tuberculin skin test (TST), smoking, time on the job as CHW, and comorbidities. Logistic regression was used to estimate odds ratios (OR) and to control for confounding. TST was applied and read after 48-72 hours. Prevalence rates were 57.88% and 37.3%, respectively, for the 5mm and 10mm TST cutoffs. Variables that remained associated with positive TST using the 10mm cutoff were working in a primary care unit that had implemented a Tuberculosis Control Program (TCP) and history of household contact with TB. Variables associated with the 5mm cutoff were working in a primary care unit with a TCP. Necessary actions at the local level include awareness-raising and strengthening of continuing education. PMID- 26735387 TI - [Estimated coverage of death counts and adult mortality in Mozambique based on census data]. AB - In 1997 and 2007, the questionnaire used in the Population Census in Mozambique included a question on deaths at home in the previous 12 months. This study aimed to evaluate the quality of mortality data for the country as a whole and its three major geographic regions. More specifically, based on formal demographic methods, the authors sought to evaluate the quality of information in terms of degree of coverage of death counts and mortality structure, summarized by the probability of death between 15 and 60 years of age. The 2007 census enumerated between 65% and 90% of deaths in Mozambique, suggesting that mortality estimates using direct methods underestimate mortality in the country. The study showed that there has been progress in the quality of death counts in the census, and that in the absence of high-quality vital statistics, population censuses can be a good source of mortality data in developing countries. PMID- 26735388 TI - [Working women with chronic musculoskeletal pain: a case series]. AB - This study aimed to analyze the experience of working women suffering from chronic musculoskeletal pain, using a qualitative design with a phenomenological approach. The technique drew on in-depth interviews with five working women that presented to the orthopedics and neurosurgery departments of a hospital in Guadalajara, Mexico, with a complaint of musculoskeletal pain for more than six months. The study showed that the women felt rejection, segregation, discrimination, lack of support at the workplace, and feelings of frustration and powerlessness related to their health condition. The women also perceived as a barrier the lack of efficiency in disability proceedings and job reintegration or relocation. Financial and family responsibilities were their main reason for continuing to work despite their chronic musculoskeletal pain. PMID- 26735389 TI - [Physical activity and Framingham risk score in older adults: the Bambui Health and Aging Study]. AB - This study explored the association between energy expenditure during physical activity and the Framingham risk score in the elderly. This was a cross-sectional study with a sample of 1,473 older adults. The dependent variable was level of physical activity, estimated by the metabolic equivalents in tertiles. The exploratory variables were the components of the Framingham risk score and the Framingham risk score itself. The force of associations was estimated by odds ratios and confidence intervals using ordinal logistic regression. Higher physical activity was associated with lower Framingham risk score, younger age, lower proportion of diabetes, and higher mean HDL levels. Higher energy expenditure was also associated with lower odds of smoking in men. The findings suggest that the adoption of a physically active lifestyle can reduce coronary risk, and that the promotion of physical activity is a universal strategy to fight chronic noncommunicable diseases. PMID- 26735390 TI - [Investigation of a measles outbreak in Para State, Brazil, in the age of elimination of the disease]. AB - In July 27th, 2010, witnessed the late notification of a positive test result for measles IgM antibodies in Belem, Para State, Brazil, sparking an epidemiological investigation and control and preventive measures. Two more confirmed cases were identified, both of whom were siblings of the index case, with clinical signs and symptoms and incubation period consistent with measles. We conducted a retrospective search in hospitals and laboratories for suspected cases that lived in or had visited Para State from May 1st to August 4th, 2010, and had presented fever and exanthema accompanied by cough and/or sneezing and/or conjunctivitis. All identified cases were investigated by telephone contact and/or home visits. We reviewed 183,854 consultation forms and identified 56 (0.03%) suspected cases. We applied 2,535 doses of triple viral vaccine distributed between blockades vaccination intensifications. A household measles outbreak occurred in Belem with the detection and isolation of a viral genotype imported from Europe. Timely and sensitive epidemiological surveillance is recommended for the detection of suspected cases of measles and maintenance of high immunization coverage. PMID- 26735391 TI - Is athletic really ideal? An examination of the mediating role of body dissatisfaction in predicting disordered eating and compulsive exercise. AB - BACKGROUND: Investigations into female body image have suggested that rather than thinness, preference is now being given to a female "athletic ideal" characterised by a toned abdomen, firmer lower body and muscular upper body. This study sought to investigate a) whether greater internalization of the athletic ideal is associated with higher body dissatisfaction, dieting, bulimic symptoms and compulsive exercise, and b) whether body dissatisfaction mediates the relationship between athletic-ideal internalization and the disordered eating and exercise behaviours of dieting, bulimic symptoms and compulsive exercise. METHODS: Participants were 388 females aged between 17 and 35years. Participants completed a battery of questionnaires measuring athletic-ideal internalization, body dissatisfaction, dieting, compulsive exercise and bulimic symptoms. RESULTS: Athletic-ideal internalization was not found to be associated with body dissatisfaction, but was found to predict dieting, bulimic symptoms and compulsive exercise directly. Body dissatisfaction did not mediate the relationship between athletic-ideal internalization and any of the disordered eating and exercise behaviours. LIMITATIONS: The study was limited by its cross sectional design which precluded conclusions being drawn about the direction of causality and temporal associations. CONCLUSIONS: Athletic-ideal internalization, while not associated with body dissatisfaction, was associated with a range of disordered eating and exercise behaviours. Results from the study suggest that the female athletic-ideal is an equally unrealistic and problematic ideal for women to strive towards. PMID- 26735392 TI - Contributions of cognitive inflexibility to eating disorder and social anxiety symptoms. AB - Eating disorders and social anxiety are highly co-occurring. These disorders share fears of social evaluation, possibly maintained by similar cognitive content and styles, including an inability to adapt or flexibly respond to unexpected conditions. However, the role of cognitive inflexibility in eating disorders in relation to social anxiety has not been explored. OBJECTIVE: In this study, the link between eating disorder symptoms and cognitive inflexibility, while accounting for social anxiety, is examined. METHOD: Participants (N=461) were undergraduates who completed the Detail and Flexibility Questionnaire 12 item Cognitive Rigidity subscale, the Eating Disorders Diagnostic Scale, and the Social Interaction Anxiety Scale. RESULTS: Eating disorder symptoms and social anxiety were both positively correlated with cognitive inflexibility. After controlling for social anxiety, the relationship between eating disorder symptoms and cognitive inflexibility remained robust. DISCUSSION: Further examination of cognitive inflexibility in eating disorders and comorbid social anxiety in clinical samples is warranted. We suggest future directions for examining cognitive inflexibility as a trans-diagnostic construct important to eating disorders and frequently comorbid disorders, consistent with NIMH Research Domain Criteria. PMID- 26735393 TI - Classifying symptom change in eating disorders: clinical significance metrics for the Change in Eating Disorder Symptoms Scale. AB - The purpose of this study was to determine clinically significant change criteria and change trajectories for the Change in Eating Disorder Symptoms Scale (CHEDS). Participants included non-eating disordered (n=95) and eating disordered (n=58) samples. The clinical sample was undergoing enhanced cognitive-behavior therapy (CBT-E) for eating disorders. Reliable change indices (RCI), cutscores, and change trajectories were calculated. CHEDS total score RCI was 12 points while the cutscore between eating disordered and non-eating disordered groups was 65. Trajectory models for benchmarking were successfully derived based on initial scores. The change indices and trajectories permit session-by-session analyses and benchmarking of change. These empirically-calibrated indices of patient change and progress allow for empirically-guided treatment decision-making. PMID- 26735395 TI - Take the long view. PMID- 26735396 TI - Ideas in movement: The next wave of brain-computer interfaces. PMID- 26735394 TI - Activin B Induces Noncanonical SMAD1/5/8 Signaling via BMP Type I Receptors in Hepatocytes: Evidence for a Role in Hepcidin Induction by Inflammation in Male Mice. AB - Induction of the iron regulatory hormone hepcidin contributes to the anemia of inflammation. Bone morphogenetic protein 6 (BMP6) signaling is a central regulator of hepcidin expression in the liver. Recently, the TGF-beta/BMP superfamily member activin B was implicated in hepcidin induction by inflammation via noncanonical SMAD1/5/8 signaling, but its mechanism of action and functional significance in vivo remain uncertain. Here, we show that low concentrations of activin B, but not activin A, stimulate prolonged SMAD1/5/8 signaling and hepcidin expression in liver cells to a similar degree as canonical SMAD2/3 signaling, and with similar or modestly reduced potency compared with BMP6. Activin B stimulates hepcidin via classical activin type II receptors ACVR2A and ACVR2B, noncanonical BMP type I receptors activin receptor-like kinase 2 and activin receptor-like kinase 3, and SMAD5. The coreceptor hemojuvelin binds to activin B and facilitates activin B-SMAD1/5/8 signaling. Activin B-SMAD1/5/8 signaling has some selectivity for hepatocyte-derived cells and is not enabled by hemojuvelin in other cell types. Liver activin B mRNA expression is up-regulated in multiple mouse models of inflammation associated with increased hepcidin and hypoferremia, including lipopolysaccharide, turpentine, and heat-killed Brucella abortus models. Finally, the activin inhibitor follistatin-315 blunts hepcidin induction by lipopolysaccharide or B. abortus in mice. Our data elucidate a novel mechanism for noncanonical SMAD activation and support a likely functional role for activin B in hepcidin stimulation during inflammation in vivo. PMID- 26735397 TI - Treating trisomies: Prenatal Down's syndrome therapies explored in mice. PMID- 26735398 TI - Take two: Combining immunotherapy with epigenetic drugs to tackle cancer. PMID- 26735399 TI - The road less traveled: Start-ups invest in novel approaches against neurodegeneration. PMID- 26735401 TI - Corrections. PMID- 26735402 TI - Suppressive activity of human regulatory T cells is maintained in the presence of TNF. PMID- 26735403 TI - Reply to Suppressive activity of human regulatory T cells is maintained in the presence of TNF. PMID- 26735404 TI - Targeting a regulator of protein homeostasis in myeloproliferative neoplasms. PMID- 26735405 TI - Illuminating inflammasome activity in vivo. PMID- 26735406 TI - Depleting senescent cells to combat aging. PMID- 26735407 TI - Tau toxicity feeds forward in frontotemporal dementia. PMID- 26735409 TI - Identification of Piperitone as an Aroma Compound Contributing to the Positive Mint Nuances Perceived in Aged Red Bordeaux Wines. AB - Although a sensory definition of the aging bouquet of red Bordeaux wines was recently established, its chemical transcription has only partially been elucidated. A multiple-step approach, combining sensory evaluations of red Bordeaux wines and aromatic reconstitutions of wine extract fractions, was used to identify the molecular markers involved. One wine with a high aging-bouquet score and a mint nuance has received particular attention. Various reconstitution and omission tests highlighted the contribution of two specific fractions to the intensity of the perception of mint aroma. Gas chromatography coupled to olfactometry and mass spectrometry was applied to the targeted fractions to identify molecular marker(s) responsible for the mint nuance in fine red Bordeaux wines. A similar analytical process was applied to selected fractions of essential oils presenting mint odors to characterize them and interpret the mass spectrometry data. This approach resulted in the detection of piperitone, a monoterpene ketone that, to the best of our knowledge, was reported for the first time as a contributor to the positive mint aroma of aged red Bordeaux wines. PMID- 26735408 TI - Prospects for gene-engineered T cell immunotherapy for solid cancers. AB - Adoptive transfer of receptor-engineered T cells has produced impressive results in treating patients with B cell leukemias and lymphomas. This success has captured public imagination and driven academic and industrial researchers to develop similar 'off-the-shelf' receptors targeting shared antigens on epithelial cancers, the leading cause of cancer-related deaths. However, the successful treatment of large numbers of people with solid cancers using this strategy is unlikely to be straightforward. Receptor-engineered T cells have the potential to cause lethal toxicity from on-target recognition of normal tissues, and there is a paucity of truly tumor-specific antigens shared across tumor types. Here we offer our perspective on how expanding the use of genetically redirected T cells to treat the majority of patients with solid cancers will require major technical, manufacturing and regulatory innovations centered around the development of autologous gene therapies targeting private somatic mutations. PMID- 26735427 TI - The Health Effects of Income Inequality: Averages and Disparities. AB - Much research has investigated the association of income inequality with average life expectancy, usually finding negative correlations that are not very robust. A smaller body of work has investigated socioeconomic disparities in life expectancy, which have widened in many countries since 1980. These two lines of work should be seen as complementary because changes in average life expectancy are unlikely to affect all socioeconomic groups equally. Although most theories imply long and variable lags between changes in income inequality and changes in health, empirical evidence is confined largely to short-term effects. Rising income inequality can affect individuals in two ways. Direct effects change individuals' own income. Indirect effects change other people's income, which can then change a society's politics, customs, and ideals, altering the behavior even of those whose own income remains unchanged. Indirect effects can thus change both average health and the slope of the relationship between individual income and health. PMID- 26735411 TI - A model for genesis of transcription systems. AB - Repeating sequences generated from RNA gene fusions/ligations dominate ancient life, indicating central importance of building structural complexity in evolving biological systems. A simple and coherent story of life on earth is told from tracking repeating motifs that generate alpha/beta proteins, 2-double-Psi-beta barrel (DPBB) type RNA polymerases (RNAPs), general transcription factors (GTFs), and promoters. A general rule that emerges is that biological complexity that arises through generation of repeats is often bounded by solubility and closure (i.e., to form a pseudo-dimer or a barrel). Because the first DNA genomes were replicated by DNA template-dependent RNA synthesis followed by RNA template dependent DNA synthesis via reverse transcriptase, the first DNA replication origins were initially 2-DPBB type RNAP promoters. A simplifying model for evolution of promoters/replication origins via repetition of core promoter elements is proposed. The model can explain why Pribnow boxes in bacterial transcription (i.e., (-12)TATAATG(-6)) so closely resemble TATA boxes (i.e., ( 31)TATAAAAG(-24)) in archaeal/eukaryotic transcription. The evolution of anchor DNA sequences in bacterial (i.e., (-35)TTGACA(-30)) and archaeal (BRE(up); BRE for TFB recognition element) promoters is potentially explained. The evolution of BRE(down) elements of archaeal promoters is potentially explained. PMID- 26735428 TI - The Double Disparity Facing Rural Local Health Departments. AB - Residents of rural jurisdictions face significant health challenges, including some of the highest rates of risky health behaviors and worst health outcomes of any group in the country. Rural communities are served by smaller local health departments (LHDs) that are more understaffed and underfunded than their suburban and urban peers. As a result of history and current need, rural LHDs are more likely than their urban peers to be providers of direct health services, leading to relatively lower levels of population-focused activities. This review examines the double disparity faced by rural LHDs and their constituents: pervasively poorer health behaviors and outcomes and a historical lack of investment by local, state, and federal public health entities. PMID- 26735429 TI - Cumulative Environmental Impacts: Science and Policy to Protect Communities. AB - Many communities are located near multiple sources of pollution, including current and former industrial sites, major roadways, and agricultural operations. Populations in such locations are predominantly low-income, with a large percentage of minorities and non-English speakers. These communities face challenges that can affect the health of their residents, including limited access to health care, a shortage of grocery stores, poor housing quality, and a lack of parks and open spaces. Environmental exposures may interact with social stressors, thereby worsening health outcomes. Age, genetic characteristics, and preexisting health conditions increase the risk of adverse health effects from exposure to pollutants. There are existing approaches for characterizing cumulative exposures, cumulative risks, and cumulative health impacts. Although such approaches have merit, they also have significant constraints. New developments in exposure monitoring, mapping, toxicology, and epidemiology, especially when informed by community participation, have the potential to advance the science on cumulative impacts and to improve decision making. PMID- 26735430 TI - Making Healthy Choices Easier: Regulation versus Nudging. AB - In recent years, the nudge approach to behavior change has emerged from the behavioral sciences to challenge the traditional use of regulation in public health strategies to address modifiable individual-level behaviors related to the rise of noncommunicable diseases and their treatment. However, integration and testing of the nudge approach as part of more comprehensive public health strategies aimed at making healthy choices easier are being threatened by inadequate understandings of its scientific character, its relationship with regulation, and its ethical implications. This article reviews this character and its ethical implication with a special emphasis on the compatibility of nudging with traditional regulation, special domains of experience, and the need for a more nuanced approach to the ethical debate. The aim is to advance readers' understanding and give guidance to those who have considered working with or incorporating the nudge approach into programs or policies aimed at making healthful choices easier. PMID- 26735432 TI - Rural Health Care Access and Policy in Developing Countries. AB - Compared to their urban counterparts, rural and remote inhabitants experience lower life expectancy and poorer health status. Nowhere is the worldwide shortage of health professionals more pronounced than in rural areas of developing countries. Sub-Saharan Africa (SSA) includes a disproportionately large number of developing countries; therefore, this article explores SSA in depth as an example. Using the conceptual framework of access to primary health care, sustainable rural health service models, rural health workforce supply, and policy implications, this article presents a review of the academic and gray literature as the basis for recommendations designed to achieve greater health equity. An alternative international standard for health professional education is recommended. Decision makers should draw upon the expertise of communities to identify community-specific health priorities and should build capacity to enable the recruitment and training of local students from underserviced areas to deliver quality health care in rural community settings. PMID- 26735431 TI - Latino Immigrants, Acculturation, and Health: Promising New Directions in Research. AB - This article provides an analysis of novel topics emerging in recent years in research on Latino immigrants, acculturation, and health. In the past ten years, the number of studies assessing new ways to conceptualize and understand how acculturation-related processes may influence health has grown. These new frameworks draw from integrative approaches testing new ground to acknowledge the fundamental role of context and policy. We classify the emerging body of evidence according to themes that we identify as promising directions--intrapersonal, interpersonal, social environmental, community, political, and global contexts, cross-cutting themes in life course and developmental approaches, and segmented assimilation--and discuss the challenges and opportunities each theme presents. This body of work, which considers acculturation in context, points to the emergence of a new wave of research that holds great promise in driving forward the study of Latino immigrants, acculturation, and health. We provide suggestions to further advance the ideologic and methodologic rigor of this new wave. PMID- 26735433 TI - Induction of autophagy by valproic acid enhanced lymphoma cell chemosensitivity through HDAC-independent and IP3-mediated PRKAA activation. AB - Autophagy is closely related to tumor cell sensitivity to anticancer drugs. The HDAC (histone deacetylase) inhibitor valproic acid (VPA) interacted synergistically with chemotherapeutic agents to trigger lymphoma cell autophagy, which resulted from activation of AMPK (AMP-activated protein kinase) and inhibition of downstream MTOR (mechanistic target of rapamycin [serine/threonine kinase]) signaling. In an HDAC-independent manner, VPA potentiated the effect of doxorubicin on lymphoma cell autophagy via reduction of cellular inositol 1,4,5 trisphosphate (IP3), blockade of calcium into mitochondria and modulation of PRKAA1/2-MTOR cascade. In murine xenograft models established with subcutaneous injection of lymphoma cells, dual treatment of VPA and doxorubicin initiated IP3 mediated calcium depletion and PRKAA1/2 activation, induced in situ autophagy and efficiently retarded tumor growth. Aberrant genes involving mitochondrial calcium transfer were frequently observed in primary tumors of lymphoma patients. Collectively, these findings suggested an HDAC-independent chemosensitizing activity of VPA and provided an insight into the clinical application of targeting autophagy in the treatment of lymphoma. PMID- 26735436 TI - Addiction Biology: the first year. PMID- 26735437 TI - Alcohol and heart muscle disease. AB - Ethanol consumption may induce acute and chronic effects on the myocardium. High dose acute ethanol intake may induce a decrease in myocardial contraction and produce a variety of rhythm disturbances. These effects are more relevant in patients with underlying cardiomyopathy. Chronic ethanol intake may induce the development of a dilated cardiomyopathy, which is clinically and functionally similar to idiopathic dilated cardiomyopathy. Alcoholic cardiomyopathy is potentially reversible with abstinence. The prognosis depends on the persistence or abstinence of ethanol intake. There is a positive correlation between alcoholic cardiomyopathy and the presence of other ethanol-related diseases, such as skeletal myopathy and cirrhosis. In patients with a specific ethanol-related disease, the possible presence of other complications of alcoholism should be ruled out. Although there are several factors potentially implicated in the pathogenesis of alcohol-related myocardial damage, ethanol itself may induce direct myocardial lesions, which are dose-related and independent of nutrition, protein or ionic deficiencies. The most relevant pathogenic studies on alcoholic cardiomyopathy are based on the disruption of membrane permeability and ionic fluxes mediated by ethanol, inducing a decrease in the calcium transients through the sarcolemma and interfering with the excitation-contraction coupling of myocytes. Cell energy depletion or protein-turnover disruption may contribute to the deleterious effect of ethanol on the myocardium. PMID- 26735438 TI - Alcohol and gastrointestinal cancer: pathogenic mechanisms. AB - Chronic heavy alcohol consumption leads to a significantly increased risk of cancer in the oropharynx, larynx and the oesophagus. In the liver, chronic alcohol abuse results in cirrhosis, a precursor of hepatocellular cancer. More recentepidemiologic studies also demonstrate that regular alcohol consumption, even in low amounts, has an enhanced risk for rectal cancer and cancer of the breast. Alcohol by itself is not a carcinogen. However, alcohol can increase the susceptibility of various organs to chemical carcinogens by a variety of mechanisms. Among these, increased activation of procarcinogens through microsomal enzyme induction, a change in the metabolism and/or distribution of carcinogens, interference with the system that repairs carcinogen-induced DNA alkylations, direct mucosal tissue damage with consecutive stimulation of cellular regeneration and alcohol-mediated malnutrition may be of importance. In the upper gastrointestinal tract the production of acetaldehyde and free radicals via cytochrome P450 2E1 and via alcohol dehydrogenase may lead to tissue damage and to secondary hyper-regeneration. In addition, local mechanisms may also be involved in the co-carcinogenic process. In the rectal mucosa acetaldehyde seems to be an important factor in carcinogenesis and may be predominantly produced by faecal bacteria. PMID- 26735434 TI - Evidence for autophagy-dependent pathways of rRNA turnover in Arabidopsis. AB - Ribosomes account for a majority of the cell's RNA and much of its protein and represent a significant investment of cellular resources. The turnover and degradation of ribosomes has been proposed to play a role in homeostasis and during stress conditions. Mechanisms for the turnover of rRNA and ribosomal proteins have not been fully elucidated. We show here that the RNS2 ribonuclease and autophagy participate in RNA turnover in Arabidopsis thaliana under normal growth conditions. An increase in autophagosome formation was seen in an rns2-2 mutant, and this increase was dependent on the core autophagy genes ATG9 and ATG5. Autophagosomes and autophagic bodies in rns2-2 mutants contain RNA and ribosomes, suggesting that autophagy is activated as an attempt to compensate for loss of rRNA degradation. Total RNA accumulates in rns2-2, atg9-4, atg5-1, rns2-2 atg9-4, and rns2-2 atg5-1 mutants, suggesting a parallel role for autophagy and RNS2 in RNA turnover. rRNA accumulates in the vacuole in rns2-2 mutants. Vacuolar accumulation of rRNA was blocked by disrupting autophagy via an rns2-2 atg5-1 double mutant but not by an rns2-2 atg9-4 double mutant, indicating that ATG5 and ATG9 function differently in this process. Our results suggest that autophagy and RNS2 are both involved in homeostatic degradation of rRNA in the vacuole. PMID- 26735435 TI - Epigenetic regulation of autophagy by the methyltransferase EZH2 through an MTOR dependent pathway. AB - Macroautophagy is an evolutionarily conserved cellular process involved in the clearance of proteins and organelles. Although the autophagy regulation machinery has been widely studied, the key epigenetic control of autophagy process still remains unknown. Here we report that the methyltransferase EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) epigenetically represses several negative regulators of the MTOR (mechanistic target of rapamycin [serine/threonine kinase]) pathway, such as TSC2, RHOA, DEPTOR, FKBP11, RGS16 and GPI. EZH2 was recruited to these genes promoters via MTA2 (metastasis associated 1 family, member 2), a component of the nucleosome remodeling and histone deacetylase (NuRD) complex. MTA2 was identified as a new chromatin binding protein whose association with chromatin facilitated the subsequent recruitment of EZH2 to silenced targeted genes, especially TSC2. Downregulation of TSC2 (tuberous sclerosis 2) by EZH2 elicited MTOR activation, which in turn modulated subsequent MTOR pathway-related events, including inhibition of autophagy. In human colorectal carcinoma (CRC) tissues, the expression of MTA2 and EZH2 correlated negatively with expression of TSC2, which reveals a novel link among epigenetic regulation, the MTOR pathway, autophagy induction, and tumorigenesis. PMID- 26735439 TI - Microbial metabolism of ethanol and acetaldehyde and clinical consequences. AB - Many bacteria possess marked alcohol dehydrogenase activity and in the presence of ethanol they produce reactive and toxic acetaldehyde. Acetaldehyde production mediated by microbial alcohol dehydrogenases has been demonstrated in the oropharynx and bronchopulmonary washings. Also the most important gastric pathogen, Helicobacter pylori, and many skin bacteria associating with pathological dermatological conditions, possess alcohol dehydrogenase activity and produce acetaldehyde from ethanol. The most richly colonized site of the human body, however, is the large intestine, and therefore bacterial acetaldehyde production is most important in this organ. Alcohol ingested orally is transported to the colon by blood circulation and, after the distribution phase, intracolonic ethanol levels are equal to those in the blood. In the large bowel ethanol is oxidized by a bacteriocolonic pathway. In this pathway intracolonic ethanol is at first oxidized by bacterial alcohol dehydrogenase to acetaldehyde. Then acetaldehyde is oxidized either by colonic mucosal or bacterial aldehyde dehydrogenase to acetate. Part of intracolonic acetaldehyde may also be absorbed via the portal vein and metabolized in the liver. Bacteriocolonic pathway offers a new explanation for the disappearance of a part of ethanol calories. Due to the low aldehyde dehydrogenase activity of colonic mucosa acetaldehyde accumulates in the colon. Accordingly, during ethanol oxidation highest acetaldehyde levels of the body are found in the colon and not in the liver. High intracolonic acetaldehyde may contribute to the pathogenesis of alcohol-induced diarrhoea. Acetaldehyde has been proven to be a carcinogen in experimental animals. It may therefore contribute to the increased risk of colon polyps and colon cancer found to be associated with heavy alcohol consumption in man. Intracolonic acetaldehyde may also be an important determinant of blood acetaldehyde level and a possible hepatotoxin. In addition to acetaldehyde, gut-derived endotoxin is another potential candidate in the pathogenesis of alcohol-related liver injury. PMID- 26735440 TI - YM90K, a selective-amino-3-hydroxy5-methyl-4-isoxazole propionate (AMPA) receptor antagonist, prevents induction of heat shock protein HSP -70 and hsp -70 mRNA in rat retrosplenial cortex by phencyclidine. AB - The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist such as an abused drug phencyclidine (PCP) causes the induction of heat shock protein HSP 70, a sensitive marker of neuronal injury, in the retrosplenial cortex of rat brain. The present study was undertaken to examine the role of a -amino-3- hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor in the expression of heat shock protein HSP-70 and hsp-70 mRNA in the retrosplenial cortex by PCP. Administration of PCP (50 mg/kg, i.p.) caused the induction of heat shock protein HSP-70 in the retrosplenial cortex of rat brain, whereas no HSP-70 immunoreactivity was detected in the vehicle-treated group. Pretreatment with a potent and selective AMPA receptor antagonist YM90K (1, 3 or 10 mg/kg, i.p; 15 min) inhibited in a dose dependent manner, the induction of heat shock protein HSP-70 by PCP (50 mg/kg). Furthermore, administration of PCP (50 mg/kg, i.p) caused marked expression of hsp-70 mRNA in the retrosplenial cortex of rat brain, whereas the expression of hsp-70 mRNA was NOT found in the vehicle-treated group. Pretreatment with YM90K (1, 3 or 10 mg/kg, i p; 15 min) also inhibited the expression of hsp-70 mRNA by PCP (50 mg/kg), in a dose-dependent manner. These results suggest that AMPA receptor may play a role in the expression of heat shock protein HSP-70 and heat shock gene hsp-70 mRNA in the retrosplenial cortex of rat brain by non-competitive NMDA receptor antagonists such as PCP. PMID- 26735441 TI - Brain GABA metabolism after chronic ethanol consumption and withdrawal in rats. AB - We have studied the activities of the GABA metabolizing enzymes-GABA aminotransferase (GABA-AT), succinic semialdehyde dehydrogenase (SSA-DH) and SSA reductase (SSA-R) and the levels of GABA, glutamine and glutamate in rats preferring water (WP) or ethanol (EP) after 6 months of ethanol consumption and 12 hours to 7 days after withdrawal. We showed decreased GABA levels in the brain stem, decreased GABA-AT activity in the hemispheres and brain stem, and enhanced GABA-AT activity in the striatum of EP rats compared with the control or WP animals following chronic consumption of ethanol. We found decreased activity of SSA-R and SSA-DH in the hemispheres and brain stems of alcohol-treated rats compared to the control rats. Withdrawal (0.5-7 days) induced numerous profound changes in GABA metabolism. PMID- 26735442 TI - Contractile protein synthesis rates in vivo in the rat jejunum: modulating role of adrenalectomy and thyroidectomy on ethanol-induced changes. AB - Acute ethanol toxicity has many deleterious effects on the gastrointestinal tract and, in particular, inhibits small intestinal protein synthesis. The mechanism(s) of the ethanol-induced inhibition of protein synthesis are unknown. This study was designed to investigate the role of adrenal and thyroid hormones on the ethanol-induced inhibition of whole jejunal protein synthesis in adrenalectomised and thyroidectomised male Wistar rats. Acute ethanol dosage significantly reduced protein synthesis in all subcellular protein fractions of the whole jejunum, in sham-thyroidectomized, thyroidectomized, sham-ardrenalectomized and adrenalectomized rats. Synthesis rates relative to RNA and DNA were also highly significantly reduced in all treatment groups in ethanol-dosed rats. However in most protein fractions the inhibition of protein synthesis was greater in thyroidectomized compared to sham-thyroidectomized rats, whereas the reverse was true in adrenalectomized rats. Neither adrenalectomy or thyroidectomy completely abolished ethanol-induced inhibition in protein synthesis, suggesting that ethanol or its metabolites, e.g. acetaldehyde, acts directly on the tissue. However, the ethanol-induced inhibition of protein synthesis was greater in thyroidectomized rats demonstrating that contractile and non-contractile proteins synthesis in the jejunum is under control of complex regulatory processes. PMID- 26735443 TI - Antisocial tendencies in alcohol-dependent men and their relation to harman, salsolinol and dopamine. AB - Plasma dopamine, beta-carbolines (norharman, harman) and isoquinolines ((R)- and (S)-salsolinol) were examined for their relationship to antisocial tendencies in 138 drinking men with an alcohol dependence syndrome according to ICD-10 criteria. Antisociality was assessed according to the following criteria: delinquency, involvement in fist-fights and homelessness. The personality structure was documented by the Tridimensional Personality Questionnaire of Cloninger. An early age of onset of alcohol dependence and a high degree of 'novelty seeking' were associated with antisocial tendencies. Of the beta carbolines and isoquinolines, harman and (S)-salsolinol were significantly decreased among antisocial alcoholics. Norharman, (R)-salsolinol and dopamine were not associated with antisocial personality. The contribution of endogenous alkaloids to the biological characterization of antisocial tendencies in alcoholics is described. PMID- 26735444 TI - Effects of acute ethanol on ventricular myofibrillary protein synthesis in vivo in normotensive and hypertensive rats. AB - The acute inhibitory effects of ethanol (75 mmol/kg body weight; i.p.; 2.5 hour) on the synthesis of the myofibrillary and other protein fractions in normotensive and hypertensive rats were investigated. Male Wistar rats were subjected to 30 days aortic constriction to induce hypertension. Controls were sham-operated and subjected to controlled feeding so that both groups of rats received identical food intakes. At the end of the study the left ventricles were analysed. Hypertension was associated with a significant increase in the content of myofibrillary and non-contractile proteins with slightly reduced protein synthesis. A marked decrease in the rates of contractile and non-contractile protein synthesis occurred in response to ethanol dosage in sham-operated control rats. The decline in myofibrillary protein synthesis was greater in the hypertensive animals. A reduction in the synthesis of contractile proteins will compromise the formation of new contractile elements and contribute to the impaired contractility of hypertensive ethanol misusers. PMID- 26735445 TI - Effect of cessation of drug misuse on the immune status of HIV-infected injecting drug users. AB - The effects of cessation of i.v. drug use on CD4 lymphocyte count and serum levels of beta2 -microglobulin (beta2 m) and soluble interleukin-2 receptor (sIL 2R) were prospectively investigated in 41 HIV-positive drug users enrolled in a methadone treatment programme. Fifteen HIV-positive matched non-abstainers served as controls. During the follow-up of 12 months the mean CD4 lymphocyte count remained unchanged in the methadone-treated group but fell significantly in controls. beta2 m and sIL-2R values decreased in abstainers at the beginning of the treatment but rose in non-abstaining group. We conclude that cessation of illicit drug abuse and methadone treatment in HIV-infected injecting drug users may exert a beneficial effect on the immune status. PMID- 26735447 TI - Biennal Conference of the German Research Society on Addictions, 27-30 March 1996. PMID- 26735446 TI - Alcohol consumption: a risk factor for abdominal fat accumulation in men. AB - An increased abdominal fat mass is regarded as an independent cardiovascular risk factor. In this cross-sectional study of 1099 men we found a significant positive association between alcohol intake and the waist/hip (W/H) ratio, an index for the abdominal fat mass. This relationship was independent of age and body weight. The results suggest that the risk of abdominal fat deposition could be minimized by a reduction of alcohol intake. PMID- 26735448 TI - An Effort to Increase Organ Donor Registration Through Intergroup Competition and Electronic Word of Mouth. AB - The effort to increase Web organ donation registrations in Michigan by enhancing 2 types of university campaigns with social media strategies informed by social identity theory is the focus of this research. The two campaigns focused on either ingroup or rivalry outgroup social identification, and each was enhanced with individually focused social media in the first year of the campaign and with electronic word of mouth in Year 2 of the campaign. Results indicated that individually focused social media such as Facebook ads worked well in rivalry campaigns (in which registrations increased two times over baseline) but not in ingroup identification campaigns (in which registrations decreased significantly over baseline when ads were introduced in the first year of each type of campaign). Electronic word-of-mouth strategies worked well in both ingroup identification campaigns (in which registrations increased two times over baseline) and rivalry campaigns (in which registrations rose almost eight times over baseline, when strategies were introduced in the second year of each type of campaign). PMID- 26735449 TI - Self-Assembly of X-Shaped Bolapolyphiles in Lipid Membranes: Solid-State NMR Investigations. AB - A novel class of rigid-rod bolapolyphilic molecules with three philicities (rigid aromatic core, mobile aliphatic side chains, polar end groups) has recently been demonstrated to incorporate into and span lipid membranes, and to exhibit a rich variety of self-organization modes, including macroscopically ordered snowflake structures with 6-fold symmetry. In order to support a structural model and to better understand the self-organization on a molecular scale, we here report on proton and carbon-13 high-resolution magic-angle spinning solid-state NMR investigations of two different bolapolyphiles (BPs) in model membranes of two different phospholipids (DPPC, DOPC). We elucidate the changes in molecular dynamics associated with three new phase transitions detected by calorimetry in composite membranes of different composition, namely, a change in pi-pi-packing, the melting of lipid tails associated with the superstructure, and the dissolution and onset of free rotation of the BPs. We derive dynamic order parameters associated with different H-H and C-H bond directions of the BPs, demonstrating that the aromatic cores are well packed below the final phase transition, showing only 180 degrees flips of the phenyl ring, and that they perform free rotations with additional oscillations of the long axis when dissolved in the fluid membrane. Our data suggests that BPs not only form ordered superstructures, but also rather homogeneously dispersed pi-packed filaments within the lipid gel phase, thus reducing the corrugation of large vesicles. PMID- 26735450 TI - Delayed granulomatous reactions to facial cosmetic injections of polymethylmethacrylate microspheres and liquid injectable silicone: A case series. AB - Polymethylmethacrylate microsphere (PMMA) and liquid injectable silicone (LIS) fillers are non-biodegradable, synthetic polymers utilized for long-term soft tissue augmentation. Delayed granulomatous reactions to permanent fillers are a rare yet significant event that can occur months to years post procedure and are often refractory to treatment and associated with significant cosmetic morbidity. We report a case series of 4 patients who developed granulomatous reactions to PMMA or LIS, 15 months to 5 years post injection. The etiology of granulomatous reactions to permanent fillers is still poorly understood, with foreign-body reactions and/or biofilms purported to play a role. Real-time biochemical analysis with polymerase chain reaction should be performed when the index of suspicion for the presence of a biofilm is high. PMID- 26735489 TI - Single point mutation detection in living cancer cells by far-red emitting PNA FIT probes. AB - Peptide nucleic acid bis-quinoline conjugates are reported as attractive far-red emitting probes that detect mutated mRNA in living cells at SNP resolution. PMID- 26735490 TI - Drought-Stressed Tomato Plants Trigger Bottom-Up Effects on the Invasive Tetranychus evansi. AB - Climate change will bring more drought periods that will have an impact on the irrigation practices of some crops like tomato, from standard water regime to deficit irrigation. This will promote changes in plant metabolism and alter their interactions with biotic stressors. We have tested if mild or moderate drought stressed tomato plants (simulating deficit irrigation) have an effect on the biological traits of the invasive tomato red spider mite, Tetranychus evansi. Our data reveal that T evansi caused more leaf damage to drought-stressed tomato plants (>=1.5 fold for both drought scenarios). Mite performance was also enhanced, as revealed by significant increases of eggs laid (>=2 fold) at 4 days post infestation (dpi), and of mobile forms (>=2 fold and 1.5 fold for moderate and mild drought, respectively) at 10 dpi. The levels of several essential amino acids (histidine, isoleucine, leucine, tyrosine, valine) and free sugars in tomato leaves were significantly induced by drought in combination with mites. The non-essential amino acid proline was also strongly induced, stimulating mite feeding and egg laying when added to tomato leaf disks at levels equivalent to that estimated on drought-infested tomato plants at 10 dpi. Tomato plant defense proteins were also affected by drought and/or mite infestation, but T. evansi was capable of circumventing their potential adverse effects. Altogether, our data indicate that significant increases of available free sugars and essential amino acids, jointly with their phagostimulant effect, created a favorable environment for a better T. evansi performance on drought-stressed tomato leaves. Thus, drought-stressed tomato plants, even at mild levels, may be more prone to T evansi outbreaks in a climate change scenario, which might negatively affect tomato production on area-wide scales. PMID- 26735491 TI - Vagal Activity During Physiological Sexual Arousal in Women With and Without Sexual Dysfunction. AB - Recently, heart rate variability (HRV) level has been found to be a risk factor for female sexual dysfunction. Low HRV was a significant predictor of female sexual arousal dysfunction and overall sexual dysfunction. Building upon this finding, the present study examined whether differences in vagal activity between sexually functional and sexually dysfunctional women may be driving the association between low HRV and female sexual dysfunction. Specifically, respiratory sinus arrhythmia (RSA) was assessed before, during, and after physiological sexual arousal in 84 women, aged 18 to 47, to examine potential differences in vagal activity between sexually functional and sexually dysfunctional women. Significant differences in vagal activity between these two groups were observed (p =.02). These findings provide additional specificity to the recently established relationship between HRV and female sexual function while also proposing a mechanism to target during treatments for sexual dysfunction. PMID- 26735492 TI - Olfaction Contributes to Pelagic Navigation in a Coastal Shark. AB - How animals navigate the constantly moving and visually uniform pelagic realm, often along straight paths between distant sites, is an enduring mystery. The mechanisms enabling pelagic navigation in cartilaginous fishes are particularly understudied. We used shoreward navigation by leopard sharks (Triakis semifasciata) as a model system to test whether olfaction contributes to pelagic navigation. Leopard sharks were captured alongshore, transported 9 km offshore, released, and acoustically tracked for approximately 4 h each until the transmitter released. Eleven sharks were rendered anosmic (nares occluded with cotton wool soaked in petroleum jelly); fifteen were sham controls. Mean swimming depth was 28.7 m. On average, tracks of control sharks ended 62.6% closer to shore, following relatively straight paths that were significantly directed over spatial scales exceeding 1600 m. In contrast, tracks of anosmic sharks ended 37.2% closer to shore, following significantly more tortuous paths that approximated correlated random walks. These results held after swimming paths were adjusted for current drift. This is the first study to demonstrate experimentally that olfaction contributes to pelagic navigation in sharks, likely mediated by chemical gradients as has been hypothesized for birds. Given the similarities between the fluid three-dimensional chemical atmosphere and ocean, further research comparing swimming and flying animals may lead to a unifying paradigm explaining their extraordinary navigational abilities. PMID- 26735494 TI - Exploring Chemical Bonds through Variations in Magnetic Shielding. AB - Differences in nuclear isotropic magnetic shieldings give rise to the chemical shifts measured in NMR experiments. In contrast to existing NMR experimental techniques, quantum chemical methods are capable of calculating isotropic magnetic shieldings not just at nuclei, but also at any point in the space surrounding a molecule. Using s-trans-1,3-butadiene, ethane, ethene, and ethyne as examples, we show that the variations in isotropic magnetic shielding around a molecule, represented as isosurfaces and contour plots, provide an unexpectedly clear picture of chemical bonding, which is much more detailed than the traditional description in terms of the total electron density. PMID- 26735493 TI - Conformational Sampling and Binding Site Assessment of Suppression of Tumorigenicity 2 Ectodomain. AB - Suppression of Tumorigenicity 2 (ST2), a member of the interleukin-1 receptor (IL 1R) family, activates type 2 immune responses to pathogens and tissue damage via binding to IL-33. Dysregulated responses contribute to asthma, graft-versus-host and autoinflammatory diseases and disorders. To study ST2 structure for inhibitor development, we performed the principal component (PC) analysis on the crystal structures of IL1-1R1, IL1-1R2, ST2 and the refined ST2 ectodomain (ST2ECD) models, constructed from previously reported small-angle X-ray scattering data. The analysis facilitates mapping of the ST2ECD conformations to PC subspace for characterizing structural changes. Extensive coverage of ST2ECD conformations was then obtained using the accelerated molecular dynamics simulations started with the IL-33 bound ST2ECD structure as instructed by their projected locations on the PC subspace. Cluster analysis of all conformations further determined representative conformations of ST2ECD ensemble in solution. Alignment of the representative conformations with the ST2/IL-33 structure showed that the D3 domain of ST2ECD (containing D1-D3 domains) in most conformations exhibits no clashes with IL-33 in the crystal structure. Our experimental binding data informed that the D1-D2 domain of ST2ECD contributes predominantly to the interaction between ST2ECD and IL-33 underscoring the importance of the D1-D2 domain in binding. Computational binding site assessment revealed one third of the total detected binding sites in the representative conformations may be suitable for binding to potent small molecules. Locations of these sites include the D1-D2 domain ST2ECD and modulation sites conformed to ST2ECD conformations. Our study provides structural models and analyses of ST2ECD that could be useful for inhibitor discovery. PMID- 26735495 TI - HER Specific TKIs Exert Their Antineoplastic Effects on Breast Cancer Cell Lines through the Involvement of STAT5 and JNK. AB - BACKGROUND: HER-targeted tyrosine kinase inhibitors (TKIs) have demonstrated pro apoptotic and antiproliferative effects in vitro and in vivo. The exact pathways through which TKIs exert their antineoplastic effects are, however, still not completely understood. METHODS: Using Milliplex assays, we have investigated the effects of the three panHER-TKIs lapatinib, canertinib and afatinib on signal transduction cascade activation in SKBR3, T47D and Jurkat neoplastic cell lines. The growth-inhibitory effect of blockade of HER and of JNK and STAT5 signaling was measured by proliferation- and apoptosis-assays using formazan dye labeling of viable cells, Western blotting for cleaved PARP-1 and immunolabeling for active caspase 3, respectively. RESULTS: All three HER-TKIs clearly inhibited proliferation and increased apoptosis in HER2 overexpressing SKBR3 cells, while their effect was less pronounced on HER2 moderately expressing T47D cells where they exerted only a weak antiproliferative and essentially no pro-apoptotic effect. Remarkably, phosphorylation/activation of JNK and STAT5A/B were inhibited by HER-TKIs only in the sensitive, but not in the resistant cells. In contrast, phosphorylation/activation of ERK/MAPK, STAT3, CREB, p70 S6 kinase, IkBa, and p38 were equally affected by HER-TKIs in both cell lines. Moreover, we demonstrated that direct pharmacological blockade of JNK and STAT5 abrogates cell growth in both HER-TKI-sensitive as well as -resistant breast cancer cells, respectively. CONCLUSION: We have shown that HER-TKIs exert a HER2 expression-dependent anti cancer effect in breast cancer cell lines. This involves blockade of JNK and STAT5A/B signaling, which have been found to be required for in vitro growth of these cell lines. PMID- 26735496 TI - Optogenetic Mapping of Functional Connectivity in Freely Moving Mice via Insertable Wrapping Electrode Array Beneath the Skull. AB - Spatiotemporal mapping of neural interactions through electrocorticography (ECoG) is the key to understanding brain functions and disorders. For the entire brain cortical areas, this approach has been challenging, especially in freely moving states, owing to the need for extensive craniotomy. Here, we introduce a flexible microelectrode array system, termed iWEBS, which can be inserted through a small cranial slit and stably wrap onto the curved cortical surface. Using iWEBS, we measured dynamic changes of signals across major cortical domains, namely, somatosensory, motor, visual and retrosplenial areas, in freely moving mice. iWEBS robustly displayed somatosensory evoked potentials (SEPs) in corresponding cortical areas to specific somatosensory stimuli. We also used iWEBS for mapping functional interactions between cortical areas in the propagation of spike-and wave discharges (SWDs), the neurological marker of absence seizures, triggered by optogenetic inhibition of a specific thalamic nucleus. This demonstrates that iWEBS represents a significant improvement over conventional ECoG recording methodologies and, therefore, is a competitive recording system for mapping wide range brain connectivity under various behavioral conditions. PMID- 26735498 TI - X-ray absorption spectroscopy of lithium insertion and de-insertion in copper birnessite nanoparticle electrodes. AB - The combination of ex situ X-ray diffraction (XRD) and X-ray absorption spectroscopy (XAS) measurements on 2D layered copper birnessite cathode materials for lithium ion battery applications provides detailed insight into both bulk crystalline and localized atomic structural changes resulting from electrochemically driven lithium insertion and de-insertion. Copper birnessite electrodes that had been galvanostatically discharged and charged were measured with XRD to determine the accompanying long-range crystalline structure changes, while Mn and Cu K-edge XAS measurements provided a detailed view of the Mn and Cu oxidation state changes along with variations of the local neighboring atom environments around the Mn and Cu centers. While not detectable with XRD spectra, through XAS measurements it was determined that the copper ions (Cu(2+)) are reduced to form amorphous nano-sized Cu metal, and can be oxidized back to Cu(2+). The reversible nature of the interconversion provides a rationale to the enhanced discharge capacity of copper birnessite relative to the analogous copper free birnessite materials. The manganese oxide octahedra comprising the 2D layers in the original copper birnessite crystal structure disperse during lithium insertion, and revert back close to their original orientation after lithium de insertion. During electrochemical oxidation or reduction the layered birnessite structure does not collapse, even though significant local disordering around Mn and Cu centers is directly observed. PMID- 26735497 TI - A "Pedi" Cures All: Toenail Trimming and the Treatment of Ulcerative Dermatitis in Mice. AB - Ulcerative Dermatitis (UD) is the most common cause of unplanned euthanasia in mice used in research, with prevalence rates reported between 4 and 21%. UD is characterized by a deep, ulcerative lesion that appears most commonly over the dorsal neck and is attendant with an intense pruritus. The underlying cause of UD is currently unknown, and as a consequence, there are no directed therapies that resolve lesions reliably. However, there is a growing body of evidence that suggests a behavioral component to the onset, maintenance, and progression of UD lesions. Scratching behavior in response to the intense pruritus associated with UD lesions may be an effective target for interventional therapies. We hypothesized that interfering with scratching behavior by trimming the toenails of mice with UD, would resolve UD lesions. To test this hypothesis, we first evaluated the efficacy of toenail trims with a single application of Vetericyn at the time of treatment versus our previous standard of care, topical Tresaderm applied daily. We found that toenail trims were significantly more effective at resolving lesions (n = 39 toenail trims, n = 100 Tresaderm, p<0.0001) with 93.3% of animals healing by 14 days (median time to lesion resolution). Furthermore, dorsal neck lesions did not recur by 42 days after a single toenail trim (n = 54); however, flank lesions did not resolve and the outcome of the two lesion distributions following treatment were significantly different (p<0.0001). Finally, we implemented toenail trims at an institutional level and found similar efficacies (approximately 90%) for toenail trims regardless of one-time topical supplement used (triple antibiotic ointment, Tresaderm, and Vetericyn, n = 55, 58, 18, p = 0.63). This is the first report of a highly effective treatment for one of the most serious welfare issues in laboratory mice. PMID- 26735500 TI - Summing Up Volume 36. PMID- 26735501 TI - Recovery as a Lived Experience Discipline: A Grounded Theory Study. AB - Recovery is government mandated and a core facet of mental health reform. However, Recovery implementation in this country (Australia) has been inhibited by a lack of education of, and understanding from, clinicians. A grounded theory study was undertaken to explore the potential and existing role of lived experience practitioners in assisting meaningful implementations of Recovery within the Australian mental health sector. In-depth interviews were conducted with 13 people employed to work from a lived experience perspective. The findings suggest participants have experienced and observed significant barriers to the implementation of Recovery-focused practice while operating in lived experience roles. Three main issues emerged: (1) Recovery co-opted, (2) Recovery uptake, and (3) Recovery denial. For a genuine Recovery-focused mental health system to be developed, lived experience practitioners must be enabled to take their role as Recovery experts and leaders. Lived experience practitioners are the logical leaders of Recovery implementation due to their own internal experience and understandings of Recovery and the wider lived experience movement's development and championing of the concepts. PMID- 26735499 TI - Preferential Allele Expression Analysis Identifies Shared Germline and Somatic Driver Genes in Advanced Ovarian Cancer. AB - Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients, and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those genes could lead to new therapeutic strategies. PMID- 26735502 TI - Young Victims Telling their Stories of Sexual Abuse in the Emergency Department. AB - Among young children, child sexual abuse is a common type of maltreatment. Child sexual abuse (CSA) is an important national public health problem that has a devastating impact on the emotional and psychological makeup of the child, family, and society. The purpose of this analysis is to explore the young victim's own stories of disclosure of child sexual abuse and is an exploratory case study using reported assault histories of victims of CSA between the ages of 6 and 14, taken in the immediate wake of the assault. The data were extracted from the hospital records of child victims treated in an emergency department between 2006 and 2010. This qualitative research, using thematic analysis, explored the stories of sexual abuse for children as told by them. Two themes emerged regarding the experience of sex abuse and the immediate outcomes on the children: (1) Abuse Circumstances, which included the child's level of awareness of child sexual abuse, predisposing factors, and the perpetrator's preparation (physical, behavioral, and verbal tactics), and (2) Physical/Psychological Suffering associated with disclosure. These have important implications for all service and health care providers. PMID- 26735503 TI - Who and What Does Involvement Involve? A Multi-Sited Field Study of Involvement of Relatives in Danish Psychiatry. AB - This article gives an account of aspects of a multi-sited field study of involvement of relatives in Danish psychiatry. By following metaphors of involvement across three sites of the psychiatric system-a family site, a clinical site and a policy site-the first author (J.O.) investigated how, and on what grounds, involvement of relatives is perceived in Danish psychiatry. Paradoxically, the current understanding of involvement of relatives fails to take into consideration the perspectives of the relatives per se and families that were being studied. By analyzing involvement from a discourse theoretical perspective laid out by Ernesto Laclau and Chantal Mouffe, the aim of this study is to show how the dominant discourse about involvement at the political and clinical sites is constituted by understandings of mentally ill individuals and by political objectives of involvement. The analysis elucidates how a psycho ideological discourse positions the mentally ill person as weak, incapable, and ineffective. By contrast, the supporting relative is positioned as a strong, capable, and effective co-therapist. Furthermore, the analysis considers how this dominant discourse of involvement is constituted by a broader discourse of neoliberalism and market orientation, which justifies involvement as a subtle institutionalization of social control. The article highlights that the role of the relative as a co-therapist may be contested by the families' discourse, which emphasizes issues concerning the responsibility toward the mental health of the ill individual as well as toward the psychological milieu of the family. PMID- 26735504 TI - From Resistance to Existence-Experiences of Medication-Assisted Treatment as Disclosed by People with Opioid Dependence. AB - This study aimed to describe the lived experiences of participating in a medication-assisted treatment as disclosed by individuals with opioid dependence. Eleven narrative interviews were conducted and subjected to qualitative content analysis. The experiences of participating in the programme were described as a process from resistance to existence. The participants seized the chance to claim a life lived with dignity, struggled with hidden challenges, and eventually were freed from their pasts and were grateful for an existence with dignity. The recovery process was a long-term commitment and participants asked for a more individual and flexible process based on personal needs and values. PMID- 26735505 TI - Experiences of Tenants with Serious Mental Illness Regarding Housing Support and Contextual Issues: A Meta-Synthesis. AB - This study aimed to analyze and synthesize findings from qualitative studies that explored the experiences of tenants with serious mental illness regarding housing support and contextual issues. Twenty-four articles were identified using a systematic search strategy. The total number of informants was N = 769. The reported findings were transcribed and analyzed using a systematic text condensation approach. The tenants' experiences were categorized into two main categories and subcategories (in parenthesis): Support Issues (Experience of Support Needs, Experiences with Receiving Support, Experiences with Support Approach) and Contextual Issues (Neighborhood Experiences, Community Experiences). The subcategories, with themes and subthemes, offer an in-depth understanding of the tenants' complex experiences concerning housing support and contextual issues. PMID- 26735506 TI - The Intersection of Partner Violence and Adverse Childhood Experiences: Implications for Research and Clinical Practice. AB - Violence against women continues to be a serious public health issue afflicting women worldwide. The intersection of Adverse Childhood Experiences (ACEs) and intimate partner violence is detrimental to a woman's well-being. This review aims to identify the types of ACEs reported by women who also report partner violence and the subsequent negative impact of this combination of experiences on the women's health. The evidence supports the cumulative effects of Adverse Childhood Experiences on women, particularly when coupled with experiences of intimate partner violence. Early interventions by providers have the potential to mitigate negative health outcomes of abused women and interrupt the intergenerational transmission of violence to their children. PMID- 26735507 TI - Need for Resourcefulness Training for Women Caregivers of Elders with Dementia. AB - Nearly ten million American women are caregivers of elders with dementia and may experience overwhelming stress that adversely affects their mental health. Interventions to teach them resourcefulness skills for managing stress can promote optimal mental health and facilitate continued caregiving. However, effectiveness of resourcefulness training (RT) cannot be examined until its need is established. This pilot trial with 138 women caregivers of someone with dementia examined the need for RT using subjective and objective data. Data were collected before and after RT. Data analysis focused on baseline resourcefulness scores (higher scores = lower need); scores in relation to attrition; correlations among resourcefulness, stress, and depressive symptoms; and post-RT evaluation of the need for RT. Baseline resourcefulness scores were normally distributed and showed that 74% of the caregivers had a moderate to high need for RT. Reasons for attrition were unrelated to the need for RT; however, caregivers who dropped out had resourcefulness scores that averaged two points higher than those who remained in the study. Lower resourcefulness was associated greater stress (r = -.37, p < .001) and depressive symptoms (r = -.52, p < .001). Of the 63 caregivers who received RT, 82% (n = 52) reported a felt need for RT and 94% (n = 59) believed that other caregivers need RT. The results suggest a substantial need for resourcefulness training in women dementia caregivers and support moving forward to test RT's effectiveness for reducing caregiver stress and depressive symptoms. PMID- 26735508 TI - The Cultures of Sleep. PMID- 26735509 TI - Freud Still Matters to Nursing: A Response to Sandra P. Thomas. PMID- 26735510 TI - NueDexta: A Treatment for Pseudobulbar Affect. PMID- 26735516 TI - Pulsed dye laser versus long-pulsed Nd:YAG laser in the treatment of hypertrophic scars and keloid: A comparative randomized split-scar trial. AB - INTRODUCTION: Keloids and hypertrophic scars are benign fibrous growths that occur after trauma or wounding of the skin and present a major therapeutic problem. OBJECTIVE: The purpose of this study is to evaluate and compare the effectiveness of pulsed dye laser (PDL) versus Nd:YAG laser in hypertrophic scar and keloid. METHODS: Twenty patients with hypertrophic scars and keloid were included in this prospective, randomized, split-scar study. Half of each scar was randomized to treatment with a 595-nm PDL and the contralateral half with the 1064-nm Nd:YAG. Each patient received 6 laser treatment sessions at 1-month intervals. The scars were evaluated at baseline and one month after the last laser session using the Vancouver scar scale (VSS). RESULTS: One month after the last laser treatment, final total VSS analysis of treated sites by PDL and long pulsed Nd:YAG laser revealed significant improvements (p < 0.001), whereas the average percentage of improvement in the total VSS was 55.14% for PDL and 65.44% for Nd:YAG laser. However, there were no statistically significant differences between PDL- and long-pulsed Nd:YAG laser-treated sites for total VSS (p = 0.074). LIMITATIONS: This was a single-center non-controlled trial, which included a small number of patients and subjective outcome measures. CONCLUSION: PDL and long-pulsed Nd:YAG laser treatments for keloid and hypertrophic scar provide significant improvement with insignificant difference between both modalities. PMID- 26735515 TI - Structural Based Analyses of the JC Virus T-Antigen F258L Mutant Provides Evidence for DNA Dependent Conformational Changes in the C-Termini of Polyomavirus Origin Binding Domains. AB - The replication of human polyomavirus JCV, which causes Progressive Multifocal Leukoencephalopathy, is initiated by the virally encoded T-antigen (T-ag). The structure of the JC virus T-ag origin-binding domain (OBD) was recently solved by X-ray crystallography. This structure revealed that the OBD contains a C-terminal pocket, and that residues from the multifunctional A1 and B2 motifs situated on a neighboring OBD molecule dock into the pocket. Related studies established that a mutation in a pocket residue (F258L) rendered JCV T-ag unable to support JCV DNA replication. To establish why this mutation inactivated JCV T-ag, we have solved the structure of the F258L JCV T-ag OBD mutant. Based on this structure, it is concluded that the structural consequences of the F258L mutation are limited to the pocket region. Further analyses, utilizing the available polyomavirus OBD structures, indicate that the F258 region is highly dynamic and that the relative positions of F258 are governed by DNA binding. The possible functional consequences of the DNA dependent rearrangements, including promotion of OBD cycling at the replication fork, are discussed. PMID- 26735518 TI - A comparison of college students' perceptions of older and younger tattooed women. AB - A randomly assigned sample of 376 college students responded to a survey involving a between-subjects 2 * 3 experiment designed to assess the impact of age (older versus younger) and tattoo status (i.e., no tattoo, feminine tattoo, or masculine tattoo) on three dependent measures: credibility, attractiveness, and promiscuity. Older and younger women are perceived differently depending on tattoo status. Not wearing a tattoo may lead to a more favorable perception of older women than wearing one, but wearing a feminine tattoo may engender a more favorable impression of older women than having a masculine tattoo. But not having a tattoo may not be as helpful for the perception of younger women as it is for older women. Also, while younger women may be rewarded for gender role transgression with respect to tattoo status, this is not so for older women. PMID- 26735517 TI - The Swine Plasma Metabolome Chronicles "Many Days" Biological Timing and Functions Linked to Growth. AB - The paradigm of chronobiology is based almost wholly upon the daily biological clock, or circadian rhythm, which has been the focus of intense molecular, cellular, pharmacological, and behavioral, research. However, the circadian rhythm does not explain biological timings related to fundamental aspects of life history such as rates of tissue/organ/body size development and control of the timing of life stages such as gestation length, age at maturity, and lifespan. This suggests that another biological timing mechanism is at work. Here we focus on a "many days" (multidien) chronobiological period first observed as enigmatic recurring growth lines in developing mammalian tooth enamel that is strongly associate with all adult tissue, organ, and body masses as well as life history attributes such as gestation length, age at maturity, weaning, and lifespan, particularly among the well studied primates. Yet, knowledge of the biological factors regulating the patterning of mammalian life, such as the development of body size and life history structure, does not exist. To identify underlying molecular mechanisms we performed metabolome and genome analyses from blood plasma in domestic pigs. We show that blood plasma metabolites and small non coding RNA (sncRNA) drawn from 33 domestic pigs over a two-week period strongly oscillate on a 5-day multidien rhythm, as does the pig enamel rhythm. Metabolomics and genomics pathway analyses actually reveal two 5-day rhythms, one related to growth in which biological functions include cell proliferation, apoptosis, and transcription regulation/protein synthesis, and another 5-day rhythm related to degradative pathways that follows three days later. Our results provide experimental confirmation of a 5-day multidien rhythm in the domestic pig linking the periodic growth of enamel with oscillations of the metabolome and genome. This association reveals a new class of chronobiological rhythm and a snapshot of the biological bases that regulate mammalian growth, body size, and life history. PMID- 26735519 TI - Allopurinol Resistance in Leishmania infantum from Dogs with Disease Relapse. AB - BACKGROUND: Visceral leishmaniasis caused by the protozoan Leishmania infantum is a zoonotic, life threatening parasitic disease. Domestic dogs are the main peridomestic reservoir, and allopurinol is the most frequently used drug for the control of infection, alone or in combination with other drugs. Resistance of Leishmania strains from dogs to allopurinol has not been described before in clinical studies. METHODOLOGY/PRINCIPAL FINDINGS: Following our observation of clinical disease relapse in dogs under allopurinol treatment, we tested susceptibility to allopurinol of L. infantum isolated from groups of dogs pre treatment, treated in remission, and with disease relapse during treatment. Promastigote isolates obtained from four treated relapsed dogs (TR group) showed an average half maximal inhibitory concentration (IC50) of 996 MUg/mL. A significantly lower IC50 (P = 0.01) was found for isolates from ten dogs before treatment (NT group, 200 MUg/mL), as well as for five isolates obtained from treated dogs in remission (TA group, 268 MUg/mL). Axenic amastigotes produced from isolates of the TR group also showed significantly higher (P = 0.002) IC50 compared to the NT group (1678 and 671 MUg/mL, respectively). The lower sensitivity of intracellular amastigotes from the TR group relative to those from the NT group (P = 0.002) was confirmed using an infected macrophage model (6.3% and 20% growth inhibition, respectively at 300 MUg/mL allopurinol). CONCLUSIONS: This is the first study to demonstrate allopurinol resistance in L. infantum and to associate it with disease relapse in the canine host. These findings are of concern as allopurinol is the main drug used for long term control of the disease in dogs, and resistant L. infantum strains may enhance uncontrolled transmission to humans and to other dogs. PMID- 26735520 TI - The Pediatrics Milestones Assessment Pilot: Development of Workplace-Based Assessment Content, Instruments, and Processes. AB - PURPOSE: To report on the development of content and user feedback regarding the assessment process and utility of the workplace-based assessment instruments of the Pediatrics Milestones Assessment Pilot (PMAP). METHOD: One multisource feedback instrument and two structured clinical observation instruments were developed and refined by experts in pediatrics and assessment to provide evidence for nine competencies based on the Pediatrics Milestones (PMs) and chosen to inform residency program faculty decisions about learners' readiness to serve as pediatric interns in the inpatient setting. During the 2012-2013 PMAP study, 18 U.S. pediatric residency programs enrolled interns and subinterns. Faculty, residents, nurses, and other observers used the instruments to assess learner performance through direct observation during a one-month rotation. At the end of the rotation, data were aggregated for each learner, milestone levels were assigned using a milestone classification form, and feedback was provided to learners. Learners and site leads were surveyed and/or interviewed about their experience as participants. RESULTS: Across the sites, 2,338 instruments assessing 239 learners were completed by 630 unique observers. Regarding end-of rotation feedback, 93% of learners (128/137) agreed the assessments and feedback "helped me understand how those with whom I work perceive my performance," and 85% (117/137) agreed they were "useful for constructing future goals or identifying a developmental path." Site leads identified several benefits and challenges to the assessment process. CONCLUSIONS: PM-based instruments used in workplace-based assessment provide a meaningful and acceptable approach to collecting evidence of learner competency development. Learners valued feedback provided by PM-based assessment. PMID- 26735521 TI - AM Last Page. How Can Academic Medical Centers and Teaching Hospitals Address the Social Determinants of Health? PMID- 26735522 TI - A Novel Specialty-Specific, Collaborative Faculty Development Opportunity in Education Research: Program Evaluation at Five Years. AB - PURPOSE: For the busy clinician-educator, accessing opportunities that develop the skills and knowledge necessary to perform education research can be problematic. The Medical Education Research Certification at Council of Emergency Medicine Residency Directors (MERC at CORD) Scholars' Program is a potential alternative. The current study evaluates the program's outcomes after five years. METHOD: The authors employed a quasi-experimental design in this study. The study population consisted of the initial five MERC at CORD cohorts (2009-2013). Development of a logic model informed Kirkpatrick-level outcomes. Data from annual pre/post surveys, an alumni survey (2014), and tracking of national presentations/peer-reviewed publications resulting from program projects served as outcome measurements. RESULTS: Over the first five years, 149 physicians participated in the program; 97 have completed six MERC workshops, and 63 have authored a national presentation and 30 a peer-reviewed publication based on program projects. Of the 79 participants responding to the pre- and postsurveys from the 2011-2013 cohorts, 65 (82%) reported significant improvement in skills and knowledge related to education research and would recommend the program. Of the 61 graduates completing the alumni survey, 58 (95%) indicated their new knowledge was instrumental beyond educational research, including promotion to new leadership positions, and 28 (47% of the 60 responding) reported initiating a subsequent multi-institutional education study. Of these, 57% (16/28) collaborated with one or more peers/mentors from their original program project. CONCLUSIONS: Kirkpatrick-level outcomes 1, 2, 3, and perhaps 4 demonstrate that the MERC at CORD program is successful in its intended purpose. PMID- 26735523 TI - Paradoxical Manifestation is Common in HIV-negative Tuberculous Meningitis. AB - Paradoxical manifestation is worsening of pre-existing tuberculous lesion or appearance of new lesions in patients whose condition initially improved with antituberculous treatment. Our hypothesis was that paradoxical manifestation in non-HIV tuberculous meningitis (TBM) patients was underestimated and this could contribute to patients' prognosis. This was the first systemic study of paradoxical manifestation in HIV-negative TBM patients. Between 2009 and 2014, TBM patients were studied prospectively in 2 hospitals. Clinical features, cerebrospinal fluid, and radiological findings were monitored. Paradoxical manifestation was divided into definite (4 weeks or more) and probable (between 14 and 27 d) after commencement of antituberculous treatment. Forty-one non-HIV TBM patients were recruited. Definite paradoxical manifestation occurred in 23/41 (56%) of the patients. Time to onset of paradoxical manifestation was between 28 days and 9 months, and majority was between 28 and 50 days. Neuroimaging manifestation in the brain (22/41 patients, 54%) and clinical manifestation (22/41 patients, 54%) were most commonly seen, followed by cerebrospinal fluid manifestation (7/41 patients, 17%). Neuroimaging changes most commonly seen were worsening of leptomeningeal enhancement, new infarcts, new tuberculomas, and enlargement of tuberculoma. Initial Computed Tomography Angiography/magnetic resonance angiography brain showed vasculitis in 14 patients, with 2 (12.5%) showing paradoxical vasculitis during follow-up. Recurrence of the paradoxical manifestation was seen in 7/23 (30%) of the patients. More than half (14/23, 61%) of the patients improved, 6 (26%) patients died, and 3 (13%) patients had persistent neurological deficit. Paradoxical manifestation was very common in non HIV TBM patients. Neuroimaging paradoxical manifestation of 2-4 weeks may not be paradoxical manifestation but could be delayed treatment response. PMID- 26735524 TI - Recurrent Hemolytic and Uremic Syndrome Induced by Escherichia Coli. AB - A widespread belief is that typical hemolytic and uremic syndrome (HUS) does not recur. We report the case of a patient infected twice with raw milk taken from his own cow and containing a Shiga toxin-producing Escherichia coli O174:H21 that induced recurrent HUS causing severe renal and cerebral disorders. A genomic comparison of the human and bovine Shiga toxin-producing Escherichia coli O174:H21 isolates revealed that they were identical. Typical HUS may recur. Since milk from this animal was occasionally distributed locally, thereby posing a serious threat for the whole village, this particular cow was destroyed. PMID- 26735525 TI - The Same Angiographic Factors Predict Venous and Arterial Graft Patency: A Retrospective Study. AB - To evaluate the value of angiographic factors in predicting failure of both venous and arterial coronary artery bypass graft. We retrieved from our angiographic database 148 patients who underwent venous and/or arterial CABG and for whom a control coronary angiography at more than 1 month after surgery was available. Pre-CABG and follow-up angiographies were analyzed in order to evaluate diameter stenosis (DS,%), stenosis length (mm), Bogaty score (extent index), Sullivan score, and Gensini score for the extent of coronary artery disease, and Jeopardy Duke score for the extent of myocardial area supplied by an artery. Thirty-nine patients (26%) experienced graft failure at follow-up (mean follow-up 11.3 +/- 4.6 months). Patients with venous graft failure [26 (20%)] had significantly smaller DS (P = 0.013), shorter stenosis length (P = 0.01), and lower extent index (P = 0.015), Sullivan score (P = 0.013), Gensini score (P = 0.04) as compared with those without venous graft failure. Patients with arterial graft failure [13 (11%)] had significantly lower DS (P = 0.008), shorter stenosis length (P = 0.001), and lower extent index (P = 0.03) and Sullivan score (P = 0.023) as compared with those without arterial graft failure. Venous and arterial graft failure are associated with less severe stenosis and less extensive atherosclerosis of the grafted vessel. PMID- 26735526 TI - Trends in Clinically Significant Pain Prevalence Among Hospitalized Cancer Patients at an Academic Hospital in Taiwan: A Retrospective Cohort Study. AB - Clinically significant pain (CSP) is one of the most common complaints among cancer patients during repeated hospitalizations, and the prevalence ranges from 24% to 86%. This study aimed to characterize the trends in CSP among cancer patients and examine the differences in the prevalence of CSP across repeated hospitalizations. A hospital-based, retrospective cohort study was conducted at an academic hospital. Patient-reported pain intensity was assessed and recorded in a nursing information system. We examined the differences in the prevalence of worst pain intensity (WPI) and last evaluated pain intensity (LPI) of >= 4 or >= 7 points among cancer inpatients from the 1st to the 18th hospitalization. Linear mixed models were used to determine the significant difference in the WPI and LPI (>= 4 or >= 7 points) at each hospitalization. We examined 88,133 pain scores from the 1st to the 18th hospitalization among cancer patients. The prevalence of the 4 CSP types showed a trend toward a reduction from the 1st to the 18th hospitalization. There was a robust reduction in the CSP prevalence from the 1st to the 5th hospitalization, except in the case of LPI >= 7 points. The prevalence of a WPI >= 4 points was significantly higher (0.240-fold increase) during the 1st hospitalization than during the 5th hospitalization. For the 2nd, 3rd, and 4th hospitalizations, there was a significantly higher prevalence of a WPI >= 4 points compared with the 5th hospitalization. We also observed significant reductions in the prevalence of a WPI >= 7 points during the 1st to the 4th hospitalizations, an LPI >= 4 points during the 1st to the 3rd hospitalizations, and an LPI >= 7 points during the 1st to the 2nd hospitalization. Although the prevalence of the 4 CSP types decreased gradually, it is impossible to state the causative factors on the basis of this observational and descriptive study. The next step will examine the factors that determine the CSP prevalence among cancer patients. However, based on these positive findings, we can provide feedback to nurses, physicians, and pharmacists to empower them to be more committed to pain management. PMID- 26735527 TI - Prognostic and Predictive Model for Stage II Colon Cancer Patients With Nonemergent Surgery: Who Should Receive Adjuvant Chemotherapy? AB - No ideal prognostic model has been applied to clearly identify which suitable high-risk stage II colon cancer patients with negative margins undergoing nonemergent surgery should receive adjuvant chemotherapy routinely. Clinicopathologic and prognostic data of 333 stage II colon cancer patients who underwent D2 or D3 lymphadenectomy during nonemergent surgery were retrospectively analyzed. Four pathologically determined factors, including adjacent organ involvement (RR 2.831, P = 0.001), histologic differentiation (RR 2.151, P = 0.009), lymphovascular invasion (RR 4.043, P < 0.001), and number of lymph nodes retrieved (RR 2.161, P = 0.011), were identified as independent prognostic factors on multivariate analysis. Importantly, a simple cumulative scoring system clearly categorizing prognostic risk groups was generated: risk score = ? coefficient' * status (AOI + histological differentiated + lymphovascular invasion + LNs retrieved). Our new prognostic model may provide valuable information on the impact of lymphovascular invasion, as well as powerfully and reliably predicting prognosis and recurrence for this particular cohort of patients. This model may identify suitable patients with an R0 resection who should receive routine postoperative adjuvant therapy and may help clinicians to facilitate individualized treatment. In this study, we aim to provide an ideal and quantifiable method for clinical decision making in the nonemergent surgical treatment of stage II colon cancer. Our prognostic and predictive model should be applied in multicenter, prospective studies with large sample sizes, in order to obtain a more reliable clinical recommendation. PMID- 26735528 TI - Development of a Screening Tool for Predicting Adverse Outcomes of Gestational Diabetes Mellitus: A Retrospective Cohort Study. AB - Gestational diabetes mellitus (GDM) is a common disease in pregnancy causing maternal and fetal complications. To prevent these adverse outcomes, optimal screening and diagnostic criteria must be adequate, timely, and efficient. This study suggests a novel approach that is practical, efficient, and patient- and clinician-friendly in predicting adverse outcomes of GDM. The authors conducted a retrospective cohort study via medical record review of patients admitted between March 2001 and April 2013 at the Severance Hospital, Seoul, South Korea. Patients diagnosed by a conventional 2-step method were evaluated according to the presence of adverse outcomes (neonatal hypoglycemia, hyperbilirubinemia, and hyperinsulinemia; admission to the neonatal intensive care unit; large for gestational age; gestational insulin therapy; and gestational hypertension). Of 802 women who had an abnormal 50-g, 1-hour glucose challenge test, 306 were diagnosed with GDM and 496 did not have GDM (false-positive group). In the GDM group, 218 women (71.2%) had adverse outcomes. In contrast, 240 women (48.4%) in the false-positive group had adverse outcomes. Women with adverse outcomes had a significantly higher body mass index (BMI) at entry (P = 0.03) and fasting blood glucose (FBG) (P = 0.03). Our logistic regression model derived from 2 variables, BMI at entry and FBG, predicted GDM adverse outcome with an area under the curve of 0.642, accuracy of 61.3%, sensitivity of 57.2%, and specificity of 66.9% compared with the conventional 2-step method with an area under the curve of 0.610, accuracy of 59.1%, sensitivity of 47.6%, and specificity of 74.4%. Our model performed better in predicting GDM adverse outcomes than the conventional 2 step method using only BMI at entry and FBG. Moreover, our model represents a practical, inexpensive, efficient, reproducible, easy, and patient- and clinician friendly approach. PMID- 26735529 TI - Blood Lead and Other Metal Biomarkers as Risk Factors for Cardiovascular Disease Mortality. AB - Analyses of the Third National Health and Nutrition Examination Survey (NHANES III) in 1988 to 1994 found an association of increasing blood lead levels < 10 MUg/dL with a higher risk of cardiovascular disease (CVD) mortality. The potential need to correct blood lead for hematocrit/hemoglobin and adjust for biomarkers for other metals, for example, cadmium and iron, had not been addressed in the previous NHANES III-based studies on blood lead-CVD mortality association. We analyzed 1999 to 2010 NHANES data for 18,602 participants who had a blood lead measurement, were >= 40 years of age at the baseline examination and were followed for mortality through 2011. We calculated the relative risk for CVD mortality as a function of hemoglobin- or hematocrit-corrected log-transformed blood lead through Cox proportional hazard regression analysis with adjustment for serum iron, blood cadmium, serum C-reactive protein, serum calcium, smoking, alcohol intake, race/Hispanic origin, and sex. The adjusted relative risk for CVD mortality was 1.44 (95% confidence interval = 1.05, 1.98) per 10-fold increase in hematocrit-corrected blood lead with little evidence of nonlinearity. Similar results were obtained with hemoglobin-corrected blood lead. Not correcting blood lead for hematocrit/hemoglobin resulted in underestimation of the lead-CVD mortality association while not adjusting for iron status and blood cadmium resulted in overestimation of the lead-CVD mortality association. In a nationally representative sample of U.S. adults, log-transformed blood lead was linearly associated with increased CVD mortality. Correcting blood lead for hematocrit/hemoglobin and adjustments for some biomarkers affected the association. PMID- 26735530 TI - Relationship Between 18F-Fluorodeoxyglucose Uptake and V-Ki-Ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog Mutation in Colorectal Cancer Patients: Variability Depending on C-Reactive Protein Level. AB - To evaluate clinical values of clinicopathologic and 18F-fluorodeoxyglucose (18F FDG) positron emission tomography/computed tomography (PET/CT)-related parameters for prediction of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in colorectal cancer (CRC) and to investigate their variability depending on C-reactive protein (CRP) levels. In total, 179 CRC patients who underwent PET/CT scans before curative resection and KRAS mutation evaluation following surgery were enrolled. Maximum standardized uptake value (SUV max), peak standardized uptake value (SUV peak), metabolic tumor volume, and total lesion glycolysis were determined semiquantitatively. Associations between clinicopathologic and PET/CT-related parameters and KRAS expression were analyzed. Elevated CRP (> 6.0 mg/L; n = 47) was associated with higher primary tumor size, higher SUV max, SUV peak, metabolic tumor volume, and total lesion glycolysis, compared with those for the group with a CRP lower than that the cutoff value (< 6.0 mg/L; n = 132). Interestingly, the CRC patients (having CRP < 6.0 mg/L) with KRAS mutations had significantly higher (P < 0.05) SUV max and SUV peak values than the patients expressing wild-type KRAS mutations. Multivariate analysis revealed SUV max and SUV peak to be significantly associated with KRAS mutations (odds ratio = 3.3, P = 0.005, and odds ratio = 3.9, P = 0.004), together with histologic grade and lymph node metastasis. 18F-FDG uptake was significantly higher in CRC patients with KRAS mutations and with normal CRP levels. A severe local inflammation with raised CRP levels, however, might affect accurate 18F-FDG quantification in CRC tumors. Positron emission tomography/computed tomography-related parameters could supplement genomic analysis to determine KRAS expression in CRC; however, care should be exercised to guarantee proper patient selection. PMID- 26735531 TI - Effects of a Foot Pump on the Incidence of Deep Vein Thrombosis After Total Knee Arthroplasty in Patients Given Edoxaban: A Randomized Controlled Study. AB - We conducted a randomized clinical trial to compare the effectiveness of the A-V Impulse System foot pump for reducing the incidence of deep-vein thrombosis (DVT) after total knee arthroplasty (TKA) in patients under edoxaban thromboprophylaxis. Patients undergoing primary TKA at our institution between September 2013 and March 2015 were enrolled after obtaining informed consent. The patients were randomized to use the foot pump (n = 58) and not to use the foot pump (n = 62). Both groups were given prophylactic edoxaban. Primary outcomes were any DVT as detected by bilateral ultrasonography up to postoperative day 10 (POD10) and pulmonary embolism (PE) up to POD28. The safety outcomes were bleeding and death of any cause up to POD28. Plasma D-dimer levels were measured before TKA and on POD10 after TKA. Immunoglobulin G (IgG)-class anti-PF4/heparin antibodies were measured using an IgG-specific enzyme-linked immunosorbent assay. The incidences of any DVT up to POD28 were 31.0% and 17.7% in patients with or without the foot pump, respectively. The incidences of major bleeding up to POD28 were 5.1% and 4.8% in patients with or without the foot pump, respectively. Foot pump use did not significantly reduce the incidence of DVTs in patients undergoing TKA under edoxaban thromboprophylaxis. Although seroconversion of anti PF4/heparin antibodies was confirmed in one-fourth of patients, the seroconversion rates did not differ between patients with (20.7%) or without (25.8%) foot pump use. This study shows that the A-V Impulse system foot pump did not affect the incidence of DVT under edoxaban thromboprophylaxis in patients undergoing TKA. Seroconversion of anti-PF4/heparin antibodies was detected in a significant number of patients who underwent TKA under antithrombotic prophylaxis using edoxaban. PMID- 26735532 TI - Association of Body Mass Index With Tuberculosis Mortality: A Population-Based Follow-Up Study. AB - Evidence regarding the association between body mass index (BMI) and mortality in TB patients is limited and inconsistent. We investigated the effect of BMI on TB specific and non-TB-specific mortality in TB patients. All adult Taiwanese with TB in Taipei, Taiwan, during 2011 to 2012 were included in this retrospective cohort study. Multinomial logistic regression was used to evaluate associations of BMI with cause of death in TB patients. Of the 1608 eligible patients, 83.6% (1345) were successfully treated, 3.3% (53) died of TB-specific causes, and 13.1% (210) died of non-TB-specific causes. Mean age was 64.6 years, and 67.5% of patients were male. After controlling for potential confounders, underweight was significantly associated with higher risks of all-cause mortality (adjusted odds ratio [AOR], 1.66; 95% confidence interval [CI], 1.21-2.30), TB-specific mortality (AOR, 2.14; 95% CI, 1.18-3.89), and non-TB-specific mortality (AOR, 1.58; 95% CI, 1.11-2.25) during TB treatment, while overweight was not. When gender differences on the association of BMI with mortality were considered, underweight only significantly increased risks of TB-specific (AOR, 2.37; 95% CI, 1.19-4.72) and non-TB-specific mortality (AOR, 1.58; 95% CI, 1.05-2.37) during treatment in male patients, but not female subjects.T he present findings indicate that underweight was associated with higher risks of TB-specific and non TB-specific mortality during TB treatment, particularly in male patients. PMID- 26735533 TI - The Changes of Ethical Dilemmas in Palliative Care. A Lesson Learned from Comparison Between 1998 and 2013 in Taiwan. AB - The current ethical dilemmas met by healthcare professionals were never compared with those 15 years ago when the palliative care system was newly developing in Taiwan. The aim of the study was to investigate the ethical dilemmas met by palliative care physicians and nurses in 2013 and compare the results with the survey in 1998. This cross-sectional study surveyed 213 physicians and nurses recruited from 9 representative palliative care units across Taiwan in 2013. The compared survey in 1998 studied 102 physicians and nurses from the same palliative care units. All participants took a questionnaire to survey the "frequency" and "difficulty" of 20 frequently encountered ethical dilemmas, which were grouped into 4 domains by factor analysis. The "ethical dilemma" scores were calculated and then compared across 15 years by Student's t tests. A general linear model analysis was used to identify significant factors relating to a high average "ethical dilemma" score in each domain. All of the highest-ranking ethical dilemmas in 2013 were related to insufficient resources. Physicians with less clinical experience had a higher average "ethical dilemma" score in clinical management. Physicians with dissatisfaction in providing palliative care were associated a higher average "ethical dilemma" score in communication. Nurses reported higher "ethical dilemma" scores in all items of resource allocation in 2013. Further analysis confirmed that, in 2013, nurses had a higher average "ethical dilemma" score in resource allocation after adjustment for other relating factors. Palliative care nursing staff in Taiwan are more troubled by ethical dilemmas related to insufficient resources than they were 15 years ago. Training of decision making in nurses under the framework of ethical principles and community palliative care programs may improve the problems. To promote the dignity of terminal cancer patients, long-term fundraising plans are recommended for countries in which the palliative care system is in its early stages of development. PMID- 26735534 TI - Characteristics and Outcome of Patients Diagnosed With HIV at Older Age. AB - To characterize the clinical, virological, and immunological status at presentation as well as the outcome of patients diagnosed with HIV above the age of 50. A retrospective study of 418 patients newly diagnosed with HIV in 1 Israeli center, between the years 2004 and 2013. Patients with new HIV diagnosis >= 50 years of age defined as "older' and < 50 defined as "younger.' Patients were evaluated every 1 to 3 months (mean follow-up 53 +/- 33 months). Patients with < 2 CD4/viral-load measurements or with < 1 year of follow-up were excluded. Time of HIV infection was estimated by HIV sequence ambiguity assay. Ambiguity index <= 0.43 indicated recent (<= 1 year) HIV infection. Eighty nine (21%) patients were diagnosed with HIV at an older age. Those older patients presented with significant lower CD4 cell counts and higher viral-load compared with the younger patients. At the end of the study, the older patients had higher mortality rate (21% vs 3.5%; P < 0.001) and lower CD4 cell counts (381 +/- 228 vs 483 +/- 26 cells/MUL; P < 0.001) compared with the younger patients. This difference was also observed between older and younger patients with similar CD4 cell counts and viral load at the time of HIV diagnosis and among patients with a recent (<= 1 year) HIV infection. One-fifth of HIV patients are diagnosed at older age (>= 50 years). Those older patients have less favorable outcome compared with the younger patients. This point to the need of educational and screening programs within older populations and for a closer follow-up of older HIV patients. PMID- 26735536 TI - Treatment of Severely Displaced Radial Neck Fractures in Children With Percutaneous K-wire Leverage and Closed Intramedullary Pinning. AB - To evaluate the efficacy and safety of percutaneous K-wire leverage (PKWL) reduction and closed intramedullary pinning (CIMP) for the treatment of pediatric radial neck fractures. From June 2010 to December 2013, a total of 50 children with Judet III and IV radial neck fractures were treated at our hospital. Manual closed reduction was first attempted to reduce the radial neck fractures. Upon successful closed reduction or the radial neck-shaft angle was reduced to <45 degrees , radial intramedullary pinning or CIMP was performed for fixation. Unsuccessful manual reduction was corrected using percutaneous K-wire leverage and CIMP. The injured arm was fixed at the functional position using plaster for 4 to 6 weeks. Sixteen patients were treated with manual closed reduction and CIMP (group A). Percutaneous K-wire leverage and CIMP were performed for 30 patients (group B). Another 4 patients were treated with open reduction and CIMP (group C). Groups B and C showed no significant difference in the radial neck-shaft angle, fracture displacement, and angle/displace ratio (P > 0.05), but were significantly larger than group A in the radial neck-shaft angle and fracture displacement (P < 0.05). Group A and B had significantly shorter operation time than group C (58.4 +/- 14.5 minutes, 55.2 +/- 11.2 minutes, versus 81.4 +/- 7.5 minutes, P < 0.05). Forty-five patients were followed up for a mean of 2 years. Bone union was achieved in all patients within a mean time of 4.1 months. The patients treated with manual reduction or percutaneous leverage reduction showed excellent results. Three patients, however, treated with open reduction showed 10 to 20 degrees limitation in range of motion of the elbow. No other complications were seen. Percutaneous K-wire leverage and CIMP are safe and effective for the treatment of pediatric Judet III and IV radial neck fractures. PMID- 26735537 TI - Intraventricular Silicone Oil: A Case Report. AB - Intracranial silicone oil is a rare complication of intraocular endotamponade with silicone oil. We describe a case of intraventricular silicone oil fortuitously observed 38 months after an intraocular tamponade for a complicated retinal detachment in an 82 year-old woman admitted in the Department of Neurology for a stroke. We confirm the migration of silicone oil along the optic nerve. We discuss this rare entity with a review of the few other cases reported in the medical literature. Intraventricular migration of silicone oil after intraocular endotamponade is usually asymptomatic but have to be known of the neurologists and the radiologists because of its differential diagnosis that are intraventricular hemorrhage and tumor. PMID- 26735538 TI - Analysis of Postsurgical Health-Related Quality of Life and Quality of Voice of Patients With Laryngeal Carcinoma. AB - This study aims to analyze the postsurgical health-related quality of life (HRQOL) and quality of voice (QOV) of patients with laryngeal carcinoma with an expectation of improving the treatment and HRQOL of these patients. Based on the collection of information of patients with laryngeal carcinoma regarding clinical characteristics (age, TNM stage, with or without laryngeal preservation and/or neck dissection, with or without postoperative irradiation and/or chemotherapy, etc.), QOV using Voice Handicap Index (VIH) scale and HRQOL using EORTC QLQ-C30 and EORTCQLQ-H&N35 scales, the differences of postsurgical HRQOL related to their clinical characteristics were analyzed using univariate nonparametric tests, the main factors impacting the postsurgical HRQOL were analyzed using regression analyses (generalized linear models) and the correlation between QOV and HRQOL analyzed using spearman correlation analysis. A total of 92 patients were enrolled in this study, on whom the use of EORTC QLQ-C30, EORTC QLQ-H&N35 and VHI scales revealed that: the differences of HRQOL were significant among patients with different ages, TNM stages, and treatment modalities; the main factors impacting the postsurgical HRQOL were pain, speech disorder, and dry mouth; and QOV was significantly correlated with HRQOL. For the patients with laryngeal carcinoma included in our study, the quality of life after open surgeries were impacted by many factors predominated by pain, speech disorder, and dry mouth. It is suggested that doctors in China do more efforts on the patients' postoperative pain and xerostomia management and speech rehabilitation with the hope of improving the patients' quality of life. PMID- 26735539 TI - Eosinophilic Cholangitis--A Challenging Diagnosis of Benign Biliary Stricture: A Case Report. AB - When confronting a biliary stricture, both benign and malignant etiologies must be carefully considered as a variety of benign biliary strictures can masquerade as hilar cholangiocarcinoma (CCA). Therefore, patients could undergo a major surgery despite the possibility of a benign biliary disease. Approximately 15% to 24% of patients undergoing surgical resection for suspected biliary malignancy will have benign pathology. Eosinophilic cholangitis (EC) is a rare benign disorder of the biliary tract, which can cause obstructive jaundice and can pose a difficult diagnostic task. We present a rare case of a young woman who was referred to our hospital with obstructive painless jaundice due to a biliary stricture at the confluence of the hepatic bile ducts, with a provisional diagnosis of cholangiocarcinoma. Though, during her work up she was found to have EC, an extremely rare benign cause of biliary stricture, which is characterized by a dense eosinophilic infiltration of the biliary tree causing stricturing, fibrosis, and obstruction and which is reversible with short-term high-dose steroids. Despite its rarity, EC should be taken into consideration when imaging modalities demonstrate a biliary stricture, especially if preoperative diagnosis of malignancy cannot be made, in the setting of peripheral eosinophilia and the absence of cardinal symptoms of malignancy. PMID- 26735535 TI - Secondhand Smoking and the Risk of Esophageal Squamous Cell Carcinoma in a High Incidence Region, Kashmir, India: A Case-control-observational Study. AB - Studies have associated secondhand smoking (SHS) with cancers of the lung, larynx, and pharynx. Only a few studies have examined the association between SHS and esophageal squamous cell carcinoma (ESCC) and the findings are inconclusive. We aimed to investigate the association between SHS and risk of ESCC in a case control study in Kashmir, where the incidence of ESCC is high. We recruited 703 histopathologically confirmed ESCC cases and 1664 hospital-based controls individually matched to the cases for age, sex, and district of residence. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using conditional logistic regression models. Among never-tobacco users, the ORs for the association between SHS and ESCC risk were above unity with ever exposure to SHS (OR = 1.32; 95% CI, 0.43-4.02) and exposure to SHS for > 14 h/wk (median value) (OR = 2.69; 95% CI, 0.75-20.65). In the analysis of data from all participants, the OR (95% CI) for the association between SHS and ESCC was (OR = 1.02; 95% CI, 0.53-1.93) for SHS <= 14 h/wk and (OR = 1.91; 95% CI, 0.75-4.89) for SHS >14 h/wk in the models adjusted for tobacco use and several other potential confounding factors. We found an indication of increased risk of ESCC associated with exposure to SHS. Studies with larger numbers of SHS-exposed never tobacco users are required to further examine this association. PMID- 26735540 TI - Adrenomedullin for Risk Stratification of Emergency Patients With Nonspecific Complaints: An Interventional Multicenter Pilot Study. AB - Patients with nonspecific complaints (NSC) presenting to the emergency department (ED) are at risk of life-threatening conditions. New stress biomarkers such as the midregional portion of adrenomedullin (MR-proADM) promise to support decision making. This study tested the following hypotheses: biomarker-assisted disposition of patients with NSC will not increase mortality. Second, discharge from the ED will increase if clinical risk assessment is combined with low MR proADM levels. Third, inappropriate disposition to a lower level of care will decrease, if clinical assessment is combined with high MR-proADM levels, and fourth that this algorithm is feasible in the ED setting. Prospective, multicenter, randomized, controlled interventional feasibility study with a 30 day follow-up, including patients with NSC. Patients were randomly assigned to either the standard group (decision-making solely based on clinical assessment) or the Novum group (biomarker-assisted). Regarding disposition, patients were assigned to 1 of 3 risk classes: high-risk (admission to hospital), intermediate risk (community geriatric hospital), and low-risk patients (discharge). In the Novum group, in addition to clinical risk assessment, the information of the MR proADM level was used. Unless there were overruling criteria, patients were transferred or discharged according to the risk assessment. Primary endpoint was 30-day mortality. Secondary endpoints were comparisons of patient disposition and related mortality rates, ED, and hospital length of stay and readmission. The final study cohort consisted of 398 patients (210 in the Standard group and 188 in the Novum group). Overruling, that is, disposition not according to the result of the proposed algorithm occurred in 51 cases. Baseline characteristics between Standard and Novum groups were similar. The mortality rate in the Novum group was 4.3%, as compared to the Standard group mortality of 6.2%, which was not significantly different (intention-to treat analysis). This was confirmed by the perprotocol analysis as well as by sensitivity analysis. For the secondary endpoints, no significant differences were detected. Biomarker-assisted disposition is safe in patients with NSC. Discharge rates did not increase. Feasibility could only partly be shown due to an unexpectedly high overruling rate. Inappropriate disposition to lower levels of care did not change. ClinicalTrials. gov Identifier: NCT00920491. PMID- 26735541 TI - Hyper Expression of Mucin 5ac Indicates Poor Cancer Prognoses: A Meta-Analysis. AB - The aim of the study was to explore the association between mucin 5ac expression and cancer prognosis. A systematically comprehensive search was performed through PubMed, the Web of Science, and the China National Knowledge Infrastructure (CNKI). The prognostic value of mucin 5ac expression in cancer patients was evaluated. The overexpression of mucin 5ac was found to be significantly associated with a poor prognosis in cancer patients (pooled HR: 1.53, 95%CI: 1.158-2.028, P = 0.003). This association was also detected in a biliary subgroup (pooled HR: 1.83, 95%CI: 1.269-2.639, P = 0.001) and a gastrointestinal subgroup (pooled HR: 1.44, 95%CI: 1.069-1.949 P = 0.017). In the geography subgroup analysis, a statistical association was found in the Asian subgroup (pooled HR: 1.69, 95%CI: 1.200-2.384, P = 0.003). In the clinical characteristics analysis, a statistical association was found between the hyper expression of mucin 5ac and lymphatic metastasis. We indicated that mucin 5ac is a promising prognostic predictor for cancer, especially for biliary and gastrointestinal cancer, and is more suitable for predicting cancer prognoses in Asians. PMID- 26735542 TI - Risk Factors for Renal Functional Decline in Chronic Hepatitis B Patients Receiving Oral Antiviral Agents. AB - Renal functional decline that is frequently seen during chronic hepatitis B (CHB) treatment can exert adverse effects on overall prognosis. It, however, is difficult to distinguish vulnerable patients who may experience renal dysfunction because most previous CHB studies were conducted in relatively healthy individuals. In this retrospective observational study, renal functional decline in CHB patients receiving oral antiviral agents for more than 6 months was analyzed and risk factors of chronic kidney disease (CKD) progression were determined. Renal functional decline was defined when the estimated glomerular filtration rate (eGFR) decreased by more than 25% from baseline and rapid CKD progression was defined as eGFR decreased by more than 5 mL/min/1.73 m2/y among patients who experienced renal functional decline. A total of 4178 patients were followed up for a median 23 months. Antiviral agents included lamivudine (17.0%), adefovir (3.7%), entecavir (70.4%), telbivudine (0.6%), tenofovir (4.0%), or clevudine (4.3%). Renal functional decline occurred in 706 (16.9%) patients. Based on multivariate Cox regression analysis, age, hypertension, diabetes, history of liver or kidney transplantation, underlying underlying CKD, and simultaneous administration of diuretics increased the hazard ratio for renal functional decline; however, clevudine reduced risk. The eGFR significantly increased over time in patients receiving telbivudine or clevudine compared with lamivudine. Among the 3175 patients followed up for more than 1 year, 407 (12.8%) patients experienced rapid CKD progression. Patients with rapid CKD progression showed lower serum albumin, higher total bilirubin, and prolonged prothrombin time compared with patients with stable renal function, but hepatitis B envelope antigen positivity and hepatitis B virus deoxyribonucleic acid level did not differ between the control and rapid CKD progression groups. Age, diabetes, kidney transplantation, underlying CKD, and simultaneous administration of diuretics were identified as risk factors for rapid CKD progression, and clevudine showed a beneficial effect. Age, hypertension, diabetes, liver or kidney transplantation, underlying CKD, and diuretics were identified as risk factors for renal functional decline. This study suggests that close monitoring of renal function and adequate management are required for CHB patients receiving antiviral agents with these risk factors. PMID- 26735543 TI - Computer Tomography Imaging Findings of Abdominal Follicular Dendritic Cell Sarcoma: A Report of 5 Cases. AB - Follicular dendritic cell sarcoma (FDCS) is a neoplasm that arises from follicular dendritic cells. FDCSs originating in the abdomen are extremely rare. Clinically, they often mimic a wide variety of other abdominal tumors, and correct preoperative diagnosis is often a challenging task. To date, only scattered cases of abdominal FDCS have been reported and few data are available on their radiological features. Here we present the computer tomography imaging findings of 5 patients with surgically and pathologically demonstrated abdominal FDCS. An abdominal FDCS should be included in the differential diagnosis when single or multiple masses with relatively large size, well- or ill-defined borders, complex internal architecture with marked internal necrosis and/or focal calcification, and heterogeneous enhancement with "rapid wash-in and slow wash out" or "progressive enhancement" enhancement patterns in the solid component are seen. PMID- 26735544 TI - Chinese Herbal Medicine for Improving Quality of Life Among Nonsmall Cell Lung Cancer Patients: Overview of Systematic Reviews and Network Meta-Analysis. AB - For patients with nonsmall cell lung cancer (NSCLC) receiving chemotherapy, current clinical evidence has indicated add-on benefit of Chinese herbal medicine (CHM) in improving quality of life (QoL). However, the relative performance among different CHM is unknown. The aim of this overview of systematic reviews (SRs) and network meta-analyses (NMA) is to evaluate the comparative effectiveness of different CHM. Seven electronic databases including both international databases and Chinese databases were searched. SRs focus on randomized controlled trials (RCTs) with comparison of CHM plus chemotherapy against chemotherapy alone on QoL among NSCLC patients were considered eligible. Data from RCTs were extracted for random effect pairwise meta-analyses. Pooled relative risk (RR) with 95% confidence interval (CI) was used to quantify the impact of CHM on QoL. NMA was used to explore the most effective CHM for improving QoL when used with chemotherapy. From 14 SRs, 61 RCTs (n = 4247) assessing 11 different CHM were included. Result from pairwise meta-analyses showed 6 CHM (Kang-lai-te injection, Shei-qi-fu-zheng injection, Compound ku-shen injection, Kang-ai injection, Zi-jin long tablet, and Shen-fu injection) has significant beneficial effect on QoL among NSCLC patients when used with chemotherapy, even after adjustment for publication bias. Pooled RR varied from 1.38 (95% CI: 1.11-1.72, I2 = 0.0%, Kang lai-te injection) to 3.36 (95% CI: 1.30-8.66, I2 = 0.0%, Zi-jin-long tablet). One trial comparing Hai-shen-su (a protein extract from Tegillarca granosa L.) plus chemotherapy with chemotherapy also demonstrated beneficial effect of combined treatment (RR = 3.13, 95% CI: 1.41-6.98). Results from NMA showed no differences on the comparative effectiveness among CHM, but Hai-shen-su plus chemotherapy has the highest probability (62.3%) of being the best option for improving QoL. Use of CHM on top of chemotherapy can significantly improve QoL in NSCLC patients. Although Hai-shen-su showed the highest probability of being the best add-on to chemotherapy, the effectiveness of all 11 CHM reviewed appeared to be similar. In the future, rigorous placebo controlled trials with proper blinding are needed to confirm the effectiveness of CHM. PMID- 26735545 TI - Patients With Carbon Monoxide Poisoning and Subsequent Dementia: A Population Based Cohort Study. AB - The present study evaluated the dementia risk after carbon monoxide poisoning (CO poisoning). Using the National Health Insurance Research Database of Taiwan, a total of 9041 adults newly diagnosed with CO poisoning from 2000 to 2011 were identified as the CO poisoning cohort. Four-fold (N = 36,160) of non-CO poisoning insured people were randomly selected as controls, frequency-matched by age, sex, and hospitalization year. Incidence and hazard ratio (HR) of dementia were measured by the end 2011. The dementia incidence was 1.6-fold higher in the CO exposed cohort than in the non-exposed cohort (15.2 vs 9.76 per 10,000 person years; n = 62 vs 174) with an adjusted HR of 1.50 (95% CI = 1.11-2.04). The sex- and age-specific hazards were higher in male patients (adjusted HR = 1.74, 95% CI = 1.20-2.54), and those aged <= 49 years (adjusted HR = 2.62, 95% CI = 1.38 4.99). CO exposed patients with 7-day or longer hospital stay had an adjusted HR of 2.18 (95% CI = 1.42, 3.36). The CO poisoning patients on hyperbaric oxygen (HBO2) therapy had an adjusted HR of 1.80 (95% CI = 0.96-3.37). This study suggests that CO poisoning may have association with the risk of developing dementia, which is significant for severe cases. The effectiveness of HBO2 therapy remains unclear in preventing dementia. Patients with CO poisoning are more prevalent with depression. PMID- 26735546 TI - Early Local Recurrence Presents Adverse Effect on Outcomes of Primary Breast Sarcoma: A Retrospective Study From Single Institute in China. AB - Primary breast sarcomas (PBSs) are spectrum heterogeneous sarcomas in breast and the optimal treatment for them is still under discussion. Our study was to investigate clinical characteristics and identify potential prognostic factors for this rare malignancy. The authors retrospectively reviewed 38 patients with PBSs between October 2000 and February 2014 in FuDan University Shanghai Cancer Center. Local control rate and overall survival (OS) were determined by Kaplan Meier actuarial method. Univariate analysis and Cox proportional hazards model were applied to identify potential prognostic factors. With median follow-up of 40.19 months, 14 patients (14/38) were found with local recurrence. Extensive operation like mastectomy was not superior to local resection (P = 0.167). Three year recurrence-free survival and OS rate were 61.9% and 89%, respectively. Larger tumor size and local recurrence were indicated as unfavorable prognostic factors in univariate analysis. Cox model identified narrow interval of recurrence free survival as an unfavorable factor (P = 0.048). Surgery remains crucial treatment for PBSs. Mastectomy, however, is not routinely necessary if clear margin could be achieved by local excision. Early recurrence indicates a poor OS. PMID- 26735547 TI - Regime for Bowel Preparation in Patients Scheduled to Colonoscopy: Low-Residue Diet or Clear Liquid Diet? Evidence From Systematic Review With Power Analysis. AB - Clear liquid diet (CLD) is used to perform bowel preparation before colonoscopy traditionally, but several clinical studies indicated that low-residue diet (LRD) generates equal effects to CLD and a conclusive conclusion has not yet been yielded. The systematic review was performed to address this conflict and facilitate informed decision-making eventually. To capture randomized controlled trials (RCTs) comparing LRD with CLD in terms of bowel preparation, a search was performed in PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Science Direct, recent conference abstracts, Google Scholar, and Clinicaltrials.gov through May 2015. We performed all meta-analyses based on fixed- or random-effects model, which is generated from clinical characteristics and methodology. Moreover, the G*Power software was adopted to achieve statistical power for each outcome. In total, we captured 109 potential citations at initial search stage and 2 topic-related articles were included through other sources. After critical appraisal, 7 RCTs were eligible for our inclusion criteria. Meta-analyses generated similar effects in bowel preparation quality, efficacy of colon cleansing, and compliance with recommended dietary regime when LRD versus CLD regime, but patients who were prescribed to receive LRD have slightly better tolerance (RR, 1.06; 95% CI, 1.02-1.11) and tended to repeat the same preparation regime in future (RR, 1.17; 95% CI, 1.09-1.26) relative to patients in CLD. Importantly, both regimes resulted in similar adverse events (AEs). With the best available evidence, LRD could be recommended to be as standard regime for bowel preparation prior to colonoscopy. PMID- 26735548 TI - Short-term Follow-up US Leads to Higher False-positive Results Without Detection of Structural Recurrences in PTMC. AB - To investigate the value of the annual follow-up neck ultrasonography (US) for postoperative surveillance in patients with papillary thyroid microcarcinoma (PTMC). This retrospective study has been approved by our institutional review board (IRB) with waiver for informed consent. A total of 375 patients diagnosed as PTMCs, who underwent total thyroidectomy with radioiodine remnant ablation were included, to identify the recurrence rate and the false-positive rate of annual ultrasound. The number, interval, and the results of follow-up US or fine needle aspiration were obtained from electronic medical records. Four (1.1%, 4/375) recurrences were found 3 years after the initial treatment, and only 1 patient (0.3%, 1/375) had a metastatic lymph node larger than 8 mm in the shortest diameter on US found 7.6 years after initial treatment with biochemical abnormalities. Cumulative risk of having at least 1 false-positive exam was 8.3% by the 8th US, and 8.1% by the 8-9 year follow-up. Cox multivariate regression showed shorter interval of follow-up US and presence of lymph node metastasis at initial surgery are independent predictors affecting the cumulative false positive results (hazard ratio [HR], 0.60; 95% confidence interval [CI]: 0.49 0.73; P < 0.001 and HR, 2.19; 95% CI: 1.01-4.75; P = 0.048, respectively). Short term follow-up US can result in higher cumulative false-positive results without detection of meaningful recurrences in patients with PTMCs who do not have biochemical abnormalities. PMID- 26735549 TI - Misdiagnosis and Mistherapy of Crohn's Disease as Intestinal Tuberculosis: Case Report and Literature Review. AB - The differential diagnosis of Crohn's disease (CD) and intestinal tuberculosis (ITB) remains difficult as the clinical symptoms of the 2 digestive diseases are so similar. Here we report a case where a patient was initially misdiagnosed with ITB prior to the correct CD diagnosis. The 46-year-old male patient was hospitalized elsewhere for pain in the right lower abdomen and underwent an appendectomy. The pathological diagnosis was ITB and the patient was administered antituberculosis therapy for 1 year. Afterward, the patient was readmitted to the hospital for a right lower abdominal mass. A computed tomography scan revealed intestinal gas, fistula, and abdominal mass. We performed a right hemicolectomy on the patient. Postoperatively, we diagnosed the patient with CD, based on patient history and pathological examination. According to the CD active index (CDAI), the patient was at high risk and began treatment with infliximab. The patient has remained in complete remission and made a good recovery after 8 months follow-up. We compared this case with the results of a literature review on the misdiagnosis between CD and ITB (26 previously reported cases) to determine the characteristics of misdiagnosed cases. We found that distinguishing between ITB and CD is difficult because of their varied clinical presentation, nonspecific investigative tools, and profound similarities even in pathological specimens. Although a CT scan to determine the morphology of the bowel wall is a key for correct diagnosis, each case still poses challenges for diagnosis and administrating the appropriate treatment. PMID- 26735550 TI - Recurrent Acute Liver Failure Because of Acute Hepatitis Induced by Organic Solvents: A Case Report. AB - The authors present a case of recurrent acute liver failure because of occupational exposure to organic solvents. A 35-year-old man with a 3-week history of worsening jaundice and flu-like symptoms was admitted to our hospital. Viral hepatitis serology and autoimmune factors were negative. The authors considered liver transplantation, but the patient's liver function spontaneously recovered. Liver biopsy revealed massive infiltration of neutrophils, but the cause of the acute hepatitis was not identified. Four months after discharge, the patient's liver function worsened again. The authors considered the possibility of antinuclear antibody-negative autoimmune hepatitis and initiated steroid treatment, which was effective. Four months after discharge, the patient was admitted for repeated liver injury. The authors started him on steroid pulse therapy, but this time it was not effective. Just before the first admission, he had started his own construction company where he was highly exposed to organic solvents, and thus the authors considered organic solvent-induced hepatitis. Although urine test results for organic solvents were negative, a second liver biopsy revealed severe infiltration of neutrophils, compatible with toxic hepatitis. Again, his liver function spontaneously improved. Based on the pathology and detailed clinical course, including the patient's high exposure to organic solvents since just before the first admission, and the spontaneous recovery of his liver damage in the absence of the exposure, he was diagnosed with toxic hepatitis. The authors strongly advised him to avoid organic solvents. Since then, he has been in good health without recurrence. This is the first report of recurrent acute liver failure because of exposure to organic solvents, which was eventually diagnosed through a meticulous medical history and successfully recovered by avoiding the causative agents. In acute liver failure with an undetermined etiology, clinicians should rule out organic solvent-induced hepatitis. PMID- 26735551 TI - Effects and Safety of Magnesium Sulfate on Neuroprotection: A Meta-analysis Based on PRISMA Guidelines. AB - To evaluate the evidence of effects and safety of magnesium sulfate on neuroprotection for preterm infants who had exposure in uteri. We searched electronic databases and bibliographies of relevant papers to identify studies comparing magnesium sulfate (MgSO4) with placebo or other treatments in patients at high risk of preterm labor and reporting effects and safety of MgSO4 for antenatal infants. Then, we did this meta-analysis based on PRISMA guideline. The primary outcomes included fatal death, cerebral palsy (CP), intraventricular hemorrhage, and periventricular leukomalacia. Secondary outcomes included various neonatal and maternal outcomes. Ten studies including 6 randomized controlled trials and 5 cohort studies, and involving 18,655 preterm infants were analyzed. For the rate of moderate to severe CP, MgSO4 showed the ability to reduce the risk and achieved statistically significant difference (odd ratio [OR] 0.61, 95% confidence interval [CI] 0.42-0.89, P = 0.01). The comparison of mortality rate between the MgSO4 group and the placebo group only presented small difference clinically, but reached no statistical significance (OR 0.92, 95% CI 0.77-1.11, P = 0.39). Summarily, the analysis of adverse effects on babies showed no margin (P > 0.05). Yet for mothers, MgSO4 exhibited obvious side-effects, such as respiratory depression, nausea and so forth, but there exited great heterogeneity. MgSO4 administered to women at high risk of preterm labor could reduce the risk of moderate to severe CP, without obvious adverse effects on babies. Although there exit many unfavorable effects on mothers, yet they may be lessened through reduction of the dose of MgSO4 and could be tolerable for mothers. So MgSO4 is both beneficial and safety to be used as a neuroprotective agent for premature infants before a valid alternative was discovered. PMID- 26735552 TI - Effects of Cold Water Immersion on Muscle Oxygenation During Repeated Bouts of Fatiguing Exercise: A Randomized Controlled Study. AB - Postexercise cold water immersion has been advocated to athletes as a means of accelerating recovery and improving performance. Given the effects of cold water immersion on blood flow, evaluating in vivo changes in tissue oxygenation during cold water immersion may help further our understanding of this recovery modality. This study aimed to investigate the effects of cold water immersion on muscle oxygenation and performance during repeated bouts of fatiguing exercise in a group of healthy young adults. Twenty healthy subjects performed 2 fatiguing bouts of maximal dynamic knee extension and flexion contractions both concentrically on an isokinetic dynamometer with a 10-min recovery period in between. Subjects were randomly assigned to either a cold water immersion (treatment) or passive recovery (control) group. Changes in muscle oxygenation were monitored continuously using near-infrared spectroscopy. Muscle performance was measured with isokinetic dynamometry during each fatiguing bout. Skin temperature, heart rate, blood pressure, and muscle soreness ratings were also assessed. Repeated measures ANOVA analysis was used to evaluate treatment effects. The treatment group had a significantly lower mean heart rate and lower skin temperature compared to the control group (P < 0.05). Cold water immersion attenuated a reduction in tissue oxygenation in the second fatiguing bout by 4% when compared with control. Muscle soreness was rated lower 1 day post-testing (P < 0.05). However, cold water immersion had no significant effect on muscle performance in subsequent exercise. As the results show that cold water immersion attenuated decreased tissue oxygenation in subsequent exercise performance, the metabolic response to exercise after cold water immersion is worthy of further exploration. PMID- 26735553 TI - Sleep Duration in Relation to Cognitive Function among Older Adults: A Systematic Review of Observational Studies. AB - CONTEXT: Increasing evidence suggests that circadian and sleep parameters influence cognitive function with aging. OBJECTIVE: To evaluate observational studies of sleep duration and cognition in older adults. DATA SOURCES: A systematic review of OVID Medline and PsycINFO through September 2015, and review of bibliographies from studies identified. STUDY SELECTION: English-language articles reporting observational studies of sleep duration and cognitive function in older populations. DATA EXTRACTION: Data extraction by 2 authors using predefined categories of desired information. RESULTS: Thirty-two studies met our inclusion criteria, with nearly two-thirds published in the past 4 years. One third of studies indicated that extreme sleep durations were associated with worse cognition in older adults. More studies favored an association with long vs. short sleep durations (35 vs. 26% of studies, respectively). Four studies found that greater changes in sleep duration over time were related to lower cognition. Study design and analytic methods were very heterogeneous across studies; therefore, meta-analysis was not undertaken. LIMITATIONS: We reviewed English-language manuscripts only, with a qualitative summary of studies identified. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Observational studies of sleep duration and cognitive function in older adults have produced mixed results, with more studies suggesting that long (rather than short) sleep durations are related to worse cognition. Studies more consistently indicate that greater changes in sleep duration are associated with poor cognition. Future studies should be prospectively designed, with objective sleep assessment and longer follow-up periods; intervention studies are also needed to identify strategies for promoting cognitive health with aging. PMID- 26735554 TI - Assessing Consequences of Intraaortic Balloon Counterpulsation Versus Left Ventricular Assist Devices at the Time of Heart Transplantation. AB - The proportion of heart transplant recipients bridged with durable, intracorporeal left ventricular assist devices (dLVADs) has dramatically increased; however, concern exists regarding obligate repeat sternotomy, increased bleeding risk because of anticoagulation and acquired von Willebrand disease, and increased rates of allosensitization. Whether dLVAD patients have impaired posttransplant outcomes compared with equivalent patients with less invasive intraaortic balloon pump counterpulsation (IABP) at the time of transplant is unknown. Therefore, we analyzed adult, first time, heart-only transplant procedures with dLVAD (n = 2,636) compared with IABP (n = 571) at the time of transplant based on data from the United Network for Organ Sharing (UNOS) July 2004 to December 2011. There was clear geographic variation in IABP and dLVAD at transplant. Multivariable analysis demonstrated equivalent cumulative risk of death (adjusted Cox proportional hazard ratio, 1.08; 95% confidence interval, 0.87-1.33; p = 0.51). There was no significant difference in adjusted comparison of perioperative morality, length of stay, postoperative renal failure requiring dialysis, or early acute rejection (p >= 0.14 for all). Therefore, data from UNOS suggest that the presence of dLVAD at the time of heart transplantation does not have a detrimental effect on postoperative outcomes compared with IABP, which must be considered in the context of pretransplant mortality and locoregional organ availability. PMID- 26735555 TI - Early Experience with a Novel Cannulation Strategy for Left Ventricular Decompression during Nonpostcardiotomy Venoarterial ECMO. AB - Advances in technology for the delivery of venoarterial extracorporeal membrane oxygenation (VA-ECMO) have allowed for its expanded utilization in the treatment of patients with advanced cardiogenic shock, particularly through the use of peripheral cannulation strategies. However, peripheral VA-ECMO continues to be hampered by several major limitations including inadequate decompression of the left ventricle, lower limb ischemia, and the inability to mobilize patients. Here, we present a case series of three patients who were treated with a hybrid peripheral-central cannulation strategy accompanied by direct decompression of the left ventricle through a right anterior mini-thoracotomy. This novel approach ameliorates several of the current limitations to peripheral VA-ECMO therapy and thereby holds potential for improving outcomes in VA-ECMO patients. PMID- 26735556 TI - Rapid Development and Implementation of an ECMO Program. AB - Extracorporeal membrane oxygenation (ECMO) is an established therapy in the management of patients with refractory cardiogenic shock or acute respiratory failure. In this report, we describe the rapid development and implementation of an organized ECMO program at a facility that previously provided ad hoc support. The program provides care for patients within the Emory Healthcare system and throughout the Southeastern United States. From September 2014 to February 2015, 16 patients were treated with either venovenous or venoarterial ECMO with a survival to decannulation of 53.3% and survival to intensive care unit discharge of 40%. Of the 16 patients, 10 were transfers from outside facilities of which 2 were remotely cannulated and initiated on ECMO support by our ECMO transport team. Complications included intracerebral hemorrhage, bleeding from other sites, and limb ischemia. The results suggest that a rapidly developed ECMO program can provide safe transport services and provide outcomes similar to those in the existing literature. Key components appear to be an institutional commitment, a physician champion, multidisciplinary leadership, and organized training. Further study is required to determine whether outcomes will continue to improve. PMID- 26735557 TI - A Method for Creating Artificial Thrombi In Vitro Using a Rotating Mechanical Surface. AB - Thromboembolism is a common concern in ventricular assist device (VAD) therapy. Precise VAD response to pass-through thromboembolism needs to be studied in a controlled in vitro setting where specific pump parameters (i.e., power consumption, flow rates, impeller RPM) can be monitored while various types of thrombi are introduced. In this article, we describe a method for creating standardized fibrin thrombi that could be introduced into a mock circulatory loop for testing VAD response to thromboembolism. Donor equine blood collected using a sodium citrate was allowed to clot by adding calcium chloride (CaCl2) while a rotating component applied shear forces to the blood. This rotating force was applied at various speeds and at various distances into the blood. Resulting clots showed similar microscopic features to thrombi taken from explanted clinical VADs. Higher RPM of the rotating component and smaller clearances between the rotating component and the blood created clots that closely resembled ante-explant clots found within VADs in vivo. This method is an effective way to create artificial fibrin clots for use in in vitro experiments to test thromboembolism in VADs. PMID- 26735558 TI - Outcomes in Patients with Severe Preexisting Renal Dysfunction After Continuous Flow Left Ventricular Assist Device Implantation. AB - The aim of this study was to evaluate clinical outcomes after left ventricular assist device (LVAD) implantation in patients with severe pre-LVAD renal dysfunction (RD). The cohort of 165 consecutive patients implanted with HeartMate II LVADs was divided into two groups: 1) baseline glomerular filtration rate (bGFR) <= 40 ml/min/1.73 m (n = 30), and 2) GFR > 40 ml/min/1.73 m (n = 135). In both groups, GFR increased significantly at 1 month and then declined, remaining higher than the pre-LVAD level in the bGFR <= 40 group and returning back to the pre-LVAD level in the bGFR > 40 group by 1 year post-LVAD follow-up. Post-LVAD dialysis was used in 20% of the bGFR <= 40 patients and 7% of the bGFR > 40 patients (p = 0.02). By 3 months, 14% patients had GFR <= 40 ml/min/1.73 m. Grade >=2 tricuspid regurgitation (TR) (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.23-10.28; p = 0.02) and model for end-stage liver disease-XI score >= 17 (OR, 4.2; 95% CI, 1.45-12.24; p = 0.01) were risk factors for severe RD at 3 months after LVAD implantation. Eight bGFR <= 40 patients underwent heart transplantation. Carefully selected patients with advanced heart dysfunction and bGFR <= 40 ml/min/1.73 m can improve kidney function with LVAD support and be able to bridge to isolated heart transplantation. Additional research is needed to refine patient selection for LVAD. PMID- 26735559 TI - Ventricular Recovery and Pump Explantation in Patients Supported by Left Ventricular Assist Devices: A Systematic Review. AB - Several studies have reported that a portion of patients who exhibit cardiac recovery during left ventricular assist device (LVAD) support can have their device explanted with reasonable long-term survival. The aim of this systematic review is to assess the survival and cardiac function in patients with explanted LVADs from the current literature. Electronic search was performed to identify all studies in English literature assessing LVAD explantation. All identified articles were systematically assessed using the inclusion and exclusion criteria. Selected studies were subjected to quantitative assessment. From 5 electronic databases, 11 studies (213 patients) were included. Pooled mean perioperative mortality rate of those explanted was 9.2% (95% CI, 5.0-14.5%; I = 0). Pooled mean late mortality rate was 15% (95% CI, 9.0-22.1%; I = 31%). The pooled 1, 5, and 10 year survival postexplant was 91, 76, and 65.7%, respectively. Pooled postweaning freedom from heart failure (HF) recurrence reached 81.3%. Subset analysis demonstrated that patients explanted from a continuous-flow LVAD versus pulsatile LVAD had a lower rate of HF recurrence (6.6 vs. 28.3%, p = 0.03) and LVAD reimplantation (7.5 vs. 37%, p = 0.001). Before LVAD explantation, overall mean left ventricular ejection fraction (LVEF) was 49%. Weighted pooled early and late postexplantation mean LVEF was 47.3 and 41.2%, respectively. Late postexplantation LVEF was significantly higher in the continuous-flow versus pulsatile LVAD subgroup (41.5 vs. 24%, p = 0.001). This review shows encouraging safety and 10 year survival outcomes after explantation of LVADs in carefully selected patients, with rates better than expected after a heart transplant. Recovery of the native heart is the most desirable clinical outcome in patients supported with LVADs and should be actively sought. PMID- 26735560 TI - Saved Lives at Risk in the Middle East. AB - In the Middle East, heart failure prevalence seems to be high as the rest of the world. Few countries in the region recently have started implanting left ventricular assist devices (LVADs), basically as destination therapy. Terrorism and terrorist activities have been expanded worldwide especially in this part of the world. We present a case that highlights the relation between suicide bombers and LVAD patients. PMID- 26735561 TI - Diagnostic and Therapeutic Challenges. PMID- 26735562 TI - INCIDENCE OF AND RISK FACTORS FOR DISSOCIATED OPTIC NERVE FIBER LAYER AFTER EPIRETINAL MEMBRANE SURGERY. AB - PURPOSE: To investigate the incidence of and risk factors for a dissociated optic nerve fiber layer (DONFL) after epiretinal membrane surgery. METHODS: Two hundred and ninety-six primary pars plana vitrectomy operations for epiretinal membrane that were eligible for inclusion in the study. All patients received a complete ophthalmologic examination and color fundus photography, optical coherence tomography preoperatively and postoperatively. DONFL group and non-DONFL group was compared. Univariate and multivariate analyses were performed to establish the risk factors for DONFL. RESULTS: A DONFL developed in 30 of the 296 eyes (incidence, 10.1%). Internal limiting membrane (ILM) peeling was performed in 29 of 30 eyes (96.7%) in the DONFL group and 126 of 266 eyes (47.4%) in the control group (P < 0.001). Intravitreal gas tamponade was performed in 21 eyes (70.0%) in the DONFL group and 133 eyes (50.0%) in the control group (P = 0.038). The ILM peeling (odds ratio, 32.22 [4.33-240.0]; P = 0.001) and intravitreal gas tamponade (odds ratio, 2.33 [1.03-5.28]; P = 0.042) were significantly associated with DONFL. CONCLUSION: It was found that ILM peeling and intravitreal gas tamponade were correlated with postoperative DONFL. The ILM peeling with intravitreal gas tamponade was more strongly correlated with postoperative DONFL formation than was ILM peeling alone. PMID- 26735563 TI - RETINAL LAYER RESPONSE TO RANIBIZUMAB DURING TREATMENT OF DIABETIC MACULAR EDEMA: Thinner is Not Always Better. AB - PURPOSE: To identify individual retinal layer thickness changes associated with visual acuity gain in diabetic macular edema treated with ranibizumab using layer segmentation on high-resolution optical coherence tomography scans. METHODS: Retrospective observational case series. Thirty-three treatment-naive eyes with diabetic macular edema were imaged by spectral domain optical coherence tomography at monthly visits while receiving intravitreal ranibizumab treatment as needed, guided by visual acuity. Thickness changes of individual layers after 1 year were quantitatively analyzed and correlated with visual acuity gain. RESULTS: The mean best-corrected visual acuity improvement at 1 year was 6.2 (SEM +/- 1.5) Early Treatment Diabetic Retinopathy Study letters, and central retinal thickness decreased by 66 +/- 18 MUm. In the central subfield, there was a significant decrease of thickness for all layers (P < 0.05) except the outer nuclear layer. Multiple linear regression analysis revealed that thickness decrease of the inner retina was associated with better visual acuity, whereas for the outer retina the opposite was true. The best estimate of final visual acuity (R = 0.817, P < 0.001) was obtained, by including baseline visual acuity and thickness change of the inner and outer plexiform layers in the model. CONCLUSION: Whereas thickness decrease of the inner retina was positively associated with visual acuity gain, the opposite was found for the outer retina. This might be indirect evidence for recovery of the outer retina during ranibizumab treatment. PMID- 26735564 TI - CHOROIDAL THICKNESS CHANGE AFTER INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT IN RETINAL ANGIOMATOUS PROLIFERATION AND ITS RECURRENCE. AB - PURPOSE: To investigate choroidal thickness changes after anti-vascular endothelial growth factor (VEGF) treatment in retinal angiomatous proliferation (RAP) and correlate choroidal thickness with disease recurrence. METHODS: Twenty six eyes from 21 patients with RAP were treated with 3 monthly intravitreal anti VEGF injections and additional injections as needed. RAP was divided according to the component of pigment epithelial detachment. The subfoveal choroidal thickness and choroidal thickness under the RAP lesion were measured using spectral-domain optical coherence tomography and compared between recurrence and nonrecurrence groups during the first year. RESULTS: The subfoveal choroidal thickness and choroidal thickness under the RAP lesion showed a significant decrease during the first 3 months; however, this was not maintained for the first year. The recurrence group showed a significantly thicker subfoveal choroidal thickness (P = 0.021) and choroidal thickness under the RAP lesion (P = 0.020) during the first year in those with only drusen or drusenoid pigment epithelial detachment without serous component. A significant increase and decrease in choroidal thickness was observed during the recurrence and remission period. CONCLUSION: Increased choroidal thickness was associated with a higher rate of recurrence after anti-VEGF treatment in RAP with only drusen or drusenoid pigment epithelial detachment. Choroidal thickness could also reflect disease activity, even before manifestation of retinal disease activity. PMID- 26735565 TI - SCLERAL AND CHOROIDAL THICKNESS IN SECONDARY HIGH AXIAL MYOPIA. AB - PURPOSE: To assess differences in scleral and choroidal thickness between eyes with secondary high axial myopia caused by congenital glaucoma, eyes with primary high axial myopia, and nonhighly myopic eyes. METHODS: The study consisted of 301 Chinese individuals with a mean age of 23.9 +/- 22.6 years and mean axial length of 24.8 +/- 4.2 mm. It included the "secondary highly myopic group" (SHMG) because of congenital glaucoma (n = 20 eyes; axial length >26.0 mm), the "primary highly myopic group" (PHMG) (n = 73; axial length >26.0 mm), and the remaining nonhighly myopic group (NHMG). RESULTS: The secondary highly myopic group versus the primary highly myopic group had significantly thinner sclera in the pars plana region (343 +/- 71 MUm versus 398 +/- 83 MUm; P = 0.006), whereas scleral thickness in other regions did not differ significantly between both highly myopic groups and was significantly thinner in both highly myopic groups than in the NHMG. Mean total scleral volume did not differ significantly (P > 0.20) between any group (SHMG: 659 +/- 106 MUm; PHMG: 667 +/- 128 MUm; NHMG: 626 +/- 135 MUm). Choroidal thickness was significantly thinner in both highly myopic groups than in the NHMG, with no significant differences between both highly myopic groups. Choroidal volume did not differ significantly (P > 0.40) between any of the groups (SHMG: 43 +/- 12 MUm; PHMG: 43 +/- 13 MUm; NHMG: 46 +/- 17 MUm). CONCLUSION: In secondary high axial myopia, the sclera gets thinner anterior and posterior to the equator; whereas in primary high axial myopia, scleral thinning is predominantly found posterior to the equator. Because volume of sclera and choroid did not differ between any group, scleral and choroidal thinning in myopia may be due to a rearrangement of tissue and not due to the new formation of tissue. PMID- 26735566 TI - PARS PLANA VITRECTOMY THROUGH A CUSTOM FLEXIBLE IRIS PROSTHESIS. AB - PURPOSE: To demonstrate the outcomes of pars plana vitrectomy in patients with custom flexible iris prosthesis (CFIP). METHODS: The medical records of patients who underwent CFIP placement were retrospectively reviewed. Patients who underwent pars plana vitrectomy concurrent with or after placement of CFIP were identified. Preoperative, intraoperative, and postoperative parameters were analyzed. Surgeons were surveyed regarding the technical aspects of the vitreoretinal surgery. Outcome measures included: anatomic success, complications, surgeon-rated ease of visualization through CFIP during pars plana vitrectomy, and Snellen best-corrected visual acuity. RESULTS: Twenty-four surgeries were performed in 20 eyes of 20 patients. Postoperative best-corrected visual acuity improved in 11 eyes (55%), remained unchanged in 5 eyes (25%), and declined in 4 eyes (20%) after a mean follow-up of 16.1 +/- 16.?nths (range: 3-53 months). No intraoperative complications were noted. Short-term anatomical success was 100%. Postoperative complications occurred in five eyes (recurrent retinal detachment in three eyes, recurrent epiretinal membrane in 1 eye, and CFIP and intraocular lens subluxation in 1 eye). CONCLUSION: Visualization for pars plana vitrectomy with the assistance of both direct and wide angle viewing systems through the 3.35 mm pseudopupil of a CFIP is viable in the surgical management of complex vitreoretinal diseases. PMID- 26735567 TI - Best practice nursing care for ICU patients with incontinence-associated dermatitis and skin complications resulting from faecal incontinence and diarrhoea. AB - AIMS: Incontinence-associated dermatitis (IAD), resulting from diarrhoea and/or faecal incontinence, is a common problem in intensive care, occurring in 7-50% of the patients, with an estimated 10 million dollars spent annually on continence skin care. This project aimed to evaluate and improve the staff knowledge on IAD and also improve practice in the identification, prevention and treatment of IAD in the ICU. METHODS: A pre/post-audit framework was used to implement the best practice recommendations between August 2013 and March 2014. Nursing staff were surveyed and a chart review was conducted to audit baselines of knowledge and nursing practice regarding IAD. Education and product standardization were used to implement the best practice recommendations and a post-audit was conducted to evaluate changes in knowledge and practice. RESULTS: Thirty-one (pre implementation) and 27 (post-implementation) nurses were surveyed to evaluate knowledge on IAD identification, care and documentation practices. No IAD policy or IAD-specific skin assessment tool for use existed in the ICU. After implementation, there was a 40% increase in the ability of the staff to distinguish between IAD and pressure injuries, an increase from 87% to 100% in the use of skin-protectant and an improvement from 25 to 66% in the correct application of skin-protectants. An encouraging 70% of the nurses were using a single standard skin-protectant after implementation as opposed to audit 1, where 100% of the nurses were using multiple products before implementation. There was a 16% increase in the staff surveyed post-audit who said they reported on the perineal skin in patients with IAD. However, IAD documentation in both audit 1 and audit 2, as evidenced by chart review, remained poor. CONCLUSION: The project had created an awareness of IAD in the ICU. There was clear knowledge improvement and nursing staff were able to differentiate IAD from pressure injuries. The skin cleansing and protection regime is now more clear and consistent, and a single standardized product is being used to prevent and treat IAD. There was a small improvement in consistently documenting the condition of the perineal skin of patients with IAD; however, it was beyond the scope of this project to develop a policy and implement an IAD-specific skin assessment tool in the ICU, as this would have improved documentation of IAD in the ICU. PMID- 26735568 TI - Design, development, and evaluation of printed educational materials for evidence based practice dissemination. AB - AIM: Printed educational materials (PEMs) are one of the most common dissemination strategies for communicating information about evidence-based practices (EBPs) to healthcare professionals and organizations; however, evidence is conflicting regarding the conditions and circumstances in which PEMs are effective in achieving desired outcomes. The effectiveness of PEMs is largely dependent on the manner in which they are developed. This article reports on the findings from a comprehensive review of the literature regarding best practices for creating PEMs for health professionals and illustrates how these practices were used to design, develop, and evaluate an informational packet to disseminate information about motivational interviewing. METHODS: The informational packet was disseminated to 92 community health organizations not currently implementing motivational interviewing. Evaluation surveys were completed by 212 healthcare directors and providers to examine quality and perceived helpfulness of the packets, intention to use information from the packet, and sharing of the packet with others. Associations between these and individual and organizational characteristics were also assessed. RESULTS: Overall, the packet was perceived as appropriate and helpful in making a decision to implement motivational interviewing. For example, 84.9% of participants stated that the content was 'about right'. Three-quarters (75.9%) of participants reported plans to use the information in the packet and almost half (46.7%) reported talking about the packet with others in the organizations. Higher levels of baseline interest in motivational interviewing adoption were significantly related to packet use and wanting to utilize additional resources presented in the packet. Positive attitudes toward EBPs were also significantly related to the desire to obtain resources in the packet. Perceptions of the packet did not differ by type of community health organization (i.e., community health center, community behavioral health organization) or whether the individual was a director or provider. CONCLUSION: Results indicated that PEMs can be a useful tool to disseminate EBP information to healthcare professionals particularly if they have a prior interest in the EBP and have general attitudes supportive of EBPs. Recommendations for the improvement of future PEMs are discussed. PMID- 26735569 TI - Early discharge with home support of gavage feeding for stable preterm infants who have not established full oral feeds. PMID- 26735570 TI - Response to Comment on "New Look at BTEX: Are Ambient Levels a Problem?". PMID- 26735571 TI - Extrapyramidal effects of acute organophosphate poisoning. AB - BACKGROUND: There is limited information on extrapyramidal symptoms in acute organophosphate (OP) poisoning. We describe the course and outcome of severely poisoned patients who develop extrapyramidal manifestations. METHODS: In this prospective observational study, spanning 8 months (Apr-Nov 2013) adult patients (>18 years) admitted with OP poisoning were enrolled. Patients on anti-psychotic therapy, those refusing consent or presenting with co-ingestions were excluded. Treatment included atropine and supportive care (e.g. ventilation and inotropes as indicated); oximes were not administered. The presence of rigidity, tremors, dystonia and chorea were assessed daily till discharge using modifications of the Unified Parkinson's Disease rating scale and the Tremor rating scale. The presence of extrapyramidal manifestations was correlated with length of ventilation and hospital stay and mortality. RESULTS: Of the 77 patients admitted with OP poisoning, 32 were enrolled; 17 (53.1%) developed extrapyramidal manifestations which included rigidity (94.1%), tremors (58.8%) and dystonia (58.8%). None developed chorea. The median (inter-quartile range) time of symptom onset was 8 (5-11) days; extrapyramidal features resolved in 11 (6-17) days. The median duration of intensive care stay in patients not developing extrapyramidal symptoms was 6 (2-8) days, indicating that most of these patients had recovered even before symptom onset in patients who developed extrapyramidal manifestations. Overall, 27/32 (84%) were ventilated. Hospital mortality was 6.25% (2/32). When compared with patients not developing extrapyramidal signs, those with extrapyramidal manifestations had significantly prolonged ventilation (5 versus 16 median days; p = 0.001) and hospitalization (8 versus 21 days; p < 0.001), reduced ventilator-free days (23 versus 12 days; p = 0.023) and increased infections (p = 0.03). The need for ventilation and mortality were not significantly different (p > 0.6). Extrapyramidal symptoms were not observed in non-OP poisoned patients with prolonged ICU stay. CONCLUSION: In this small series of acute OP poisoning, extrapyramidal manifestations were common after 1 week of intensive care but self-limiting. They are significantly associated with longer duration of ventilation and hospital stay. PMID- 26735572 TI - Retinal ganglion cells: mechanisms underlying depolarization block and differential responses to high frequency electrical stimulation of ON and OFF cells. AB - OBJECTIVE: ON and OFF retinal ganglion cells (RGCs) are known to have non monotonic responses to increasing amplitudes of high frequency (2 kHz) biphasic electrical stimulation. That is, an increase in stimulation amplitude causes an increase in the cell's spike rate up to a peak value above which further increases in stimulation amplitude cause the cell to decrease its activity. The peak response for ON and OFF cells occurs at different stimulation amplitudes, which allows differential stimulation of these functional cell types. In this study, we investigate the mechanisms underlying the non-monotonic responses of ON and OFF brisk-transient RGCs and the mechanisms underlying their differential responses. APPROACH: Using in vitro patch-clamp recordings from rat RGCs, together with simulations of single and multiple compartment Hodgkin-Huxley models, we show that the non-monotonic response to increasing amplitudes of stimulation is due to depolarization block, a change in the membrane potential that prevents the cell from generating action potentials. MAIN RESULTS: We show that the onset for depolarization block depends on the amplitude and frequency of stimulation and reveal the biophysical mechanisms that lead to depolarization block during high frequency stimulation. Our results indicate that differences in transmembrane potassium conductance lead to shifts of the stimulus currents that generate peak spike rates, suggesting that the differential responses of ON and OFF cells may be due to differences in the expression of this current type. We also show that the length of the axon's high sodium channel band (SOCB) affects non-monotonic responses and the stimulation amplitude that leads to the peak spike rate, suggesting that the length of the SOCB is shorter in ON cells. SIGNIFICANCE: This may have important implications for stimulation strategies in visual prostheses. PMID- 26735573 TI - The effects of mandatory HACCP implementation on microbiological indicators of process hygiene in meat processing and retail establishments in Serbia. AB - A total of 48,246 microbiological test results were collected from 130 meat processing plants and 220 meat retail facilities over a seven year period: 41 months before and 43 months after HACCP implementation. Our results confirm a strong positive effect of mandatory HACCP implementation on process hygiene indicators in meat establishments. Significant reductions were observed in the number of hygiene indicator organisms on all types of surfaces examined and types of meat establishments investigated. The improvement of process hygiene was articulated as aerobic colony count reduction of at least 1.0 log10 CFU/cm(2) for food contact surfaces and over 2 log10 CFU/cm(2) for cooling facilities (refrigerators, freezers and other meat cooling devices). Meat handlers' hands hygiene was least positively affected. The period after mandatory HACCP implementation was also marked by a steady decline of positive Enterobacteriaceae and Staphylococcus samples. Process hygiene advances for meat processing plants and meat retail facilities were similar. PMID- 26735574 TI - Valorization of indigenous dairy cattle breed through salami production. AB - The aim of the research was to produce salami manufactured with meat of three different commercial categories of bovine breed: cow on retirement, beef and young bull. A total of six experimental productions, at small-scale plant, were carried out with and without starter culture inoculums. The evolution of physico chemical parameters in all trials followed the trend already registered for other fermented meat products. Several LAB species were found during process with different levels of species diversity and frequency of isolation among inoculated (mainly Pediococcus pentosaceus and Staphylococcus xylosus) and uninoculated (mainly Enterococcus devriesei, Lactobacillus curvatus and Lactobacillus sakei) trials. Enterobacteriaceae were found at very low levels during the entire ripening period and no pathogenic bacteria were found in any samples. The multivariate analysis showed that starter inoculums and meat affected significantly the physico-chemical and the microbiological composition of salami. The sensory analysis evidenced the highest overall acceptability was displayed by salami produced with meat from cow on retirement. PMID- 26735575 TI - Stability and Characteristics of the Halogen Bonding Interaction in an Anion Anion Complex: A Computational Chemistry Study. AB - Halogen bonding is the noncovalent interaction between the positively charged sigma-hole of organohalogens and nucleophiles. In reality, both the organohalogen and nucleophile could be deprotonated to form anions, which may lead to the vanishing of the sigma-hole and possible repulsion between the two anions. However, our database survey in this study revealed that there are halogen bonding-like interactions between two anions. Quantum mechanics calculations with small model complexes composed of halobenzoates and propiolate indicated that the anion-anion halogen bonding is unstable in vacuum but attractive in solvents. Impressively, the QM optimized halogen bonding distance between the two anions is shorter than that in a neutral system, indicating a possibly stronger halogen bonding interaction, which is verified by the calculated binding energies. Furthermore, natural bond orbital and quantum theory of atoms in molecule analyses also suggested stronger anion-anion halogen bonding than that of the neutral one. Energy decomposition by symmetry adapted perturbation theory revealed that the strong binding might be attributed to large induction energy. The calculations on 4 protein-ligand complexes from PDB by the QM/MM method demonstrated that the anion-anion halogen bonding could contribute to the ligands' binding affinity up to ~3 kcal/mol. Therefore, anion-anion halogen bonding is stable and applicable in reality. PMID- 26735577 TI - Notch and Wnt/beta-catenin signaling pathway play important roles in activating liver cancer stem cells. AB - Human hepatocellular carcinoma (HCC) is driven and maintained by liver cancer stem cells (LCSCs) that display stem cell properties. These LCSCs are promoted by the intersecting of Notch and Wnt/beta-Catenin signaling pathways. In this study, we demonstrate that LCSCs with markers CD90, CD24, CD13, and CD133 possess stem properties of self-renewal and tumorigenicity in NOD/SCID mice. The increased expression of these markers was correlated with advanced disease stage, larger tumors, and worse overall survival in 61 HCC cases. We also found that both Notch and Wnt/beta-catenin signaling pathways played important roles in increasing the stem-ness characteristics of LCSCs. Our data suggested that Notch1 was downstream of Wnt/beta-catenin. The active form of Notch1 intracellular domain (NICD) expression depended on Wnt/beta-catenin pathway activation. Moreover, Notch1 negatively contributed to Wnt/beta-catenin signaling modulation. Knock down of Notch1 with lentivirus N1ShRNA up-regulated the active form of beta-catenin. Ectopic expression of NICD with LV-Notch1 in LCSCs attenuated beta-catenin/TCF dependent luciferase activity significantly. In addition, there was a non proteasome mediated feedback loop between Notch1 and Wnt/beta-catenin signaling in LCSCs. The central role of Notch and the Wnt/beta-catenin signaling pathway in LCSCs may provide an attractive therapeutic strategy against HCC. PMID- 26735576 TI - Double-strand break repair and colorectal cancer: gene variants within 3' UTRs and microRNAs binding as modulators of cancer risk and clinical outcome. AB - Genetic variations in 3' untranslated regions of target genes may affect microRNA binding, resulting in differential protein expression. microRNAs regulate DNA repair, and single-nucleotide polymorphisms in miRNA binding sites (miRSNPs) may account for interindividual differences in the DNA repair capacity. Our hypothesis is that miRSNPs in relevant DNA repair genes may ultimately affect cancer susceptibility and impact prognosis.In the present study, we analysed the association of polymorphisms in predicted microRNA target sites of double-strand breaks (DSBs) repair genes with colorectal cancer (CRC) risk and clinical outcome. Twenty-one miRSNPs in non-homologous end-joining and homologous recombination pathways were assessed in 1111 cases and 1469 controls. The variant CC genotype of rs2155209 in MRE11A was strongly associated with decreased cancer risk when compared with the other genotypes (OR 0.54, 95% CI 0.38-0.76, p = 0.0004). A reduced expression of the reporter gene was observed for the C allele of this polymorphism by in vitro assay, suggesting a more efficient interaction with potentially binding miRNAs. In colon cancer patients, the rs2155209 CC genotype was associated with shorter survival while the TT genotype of RAD52 rs11226 with longer survival when both compared with their respective more frequent genotypes (HR 1.63, 95% CI 1.06-2.51, p = 0.03 HR 0.60, 95% CI 0.41 0.89, p = 0.01, respectively).miRSNPs in DSB repair genes involved in the maintenance of genomic stability may have a role on CRC susceptibility and clinical outcome. PMID- 26735578 TI - A MALAT1/HIF-2alpha feedback loop contributes to arsenite carcinogenesis. AB - Arsenic is well established as a human carcinogen, but the molecular mechanisms leading to arsenic-induced carcinogenesis are complex and elusive. It is also not known if lncRNAs are involved in arsenic-induced liver carcinogenesis. We have found that MALAT1, a non-coding RNA, is over-expressed in the sera of people exposed to arsenite and in hepatocellular carcinomas (HCCs), and MALAT1 has a close relation with the clinicopathological characteristics of HCC. In addition, hypoxia-inducible factor (HIF)-2alpha is up-regulated in HCCs, and MALAT1 and HIF 2alpha have a positive correlation in HCC tissues. During the malignant transformation of human hepatic epithelial (L-02) cells induced by a low concentration (2.0 MUM) of arsenite, MALAT1 and HIF-2alpha are increased. In addition, arsenite-induced MALAT1 causes disassociation of the von Hippel-Lindau (VHL) protein from HIF-2alpha, therefore, alleviating VHL-mediated HIF-2alpha ubiquitination, which causes HIF-2alpha accumulation. In turn, HIF-2alpha transcriptionally regulates MALAT1, thus forming a positive feedback loop to ensure expression of arsenite-induced MALAT1 and HIF-2alpha, which are involved in malignant transformation. Moreover, MALAT1 and HIF-2alpha promote the invasive and metastatic capacities of arsenite-induced transformed L-02 cells and in HCC LM3 cells. The capacities of MALAT1 and HIF-2alpha to promote tumor growth are validated in mouse xenograft models. In mice, arsenite induces an inflammatory response, and MALAT1 and HIF-2alpha are over-expressed. Together, these findings suggest that the MALAT1/HIF-2alpha feedback loop is involved in regulation of arsenite-induced malignant transformation. Our results not only confirm a novel mechanism involving reciprocal regulation between MALAT1 and HIF-2alpha, but also expand the understanding of the carcinogenic potential of arsenite. PMID- 26735579 TI - RPS7 inhibits colorectal cancer growth via decreasing HIF-1alpha-mediated glycolysis. AB - Ribosomal protein S7 (RPS7) acts as a tumor suppressor in primary tumorigenesis but its role in cancer metabolism remains unclear. In this study, we demonstrate that RPS7 inhibits the colorectal cancer (CRC) cell glycolysis by suppressing the expression of hypoxia-inducible transcription factor-1alpha (HIF-1alpha) and the metabolic promoting proteins glucose transporter 4 (GLUT4) and lactate dehydrogenase B (LDHB). Further study found that the enhanced expression of HIF 1alpha abrogates the overexpression effects of RPS7 on CRC. In vivo assays also demonstrate that RPS7 suppresses colorectal cancer tumorigenesis and glycolysis. Clinically, the tissue microarray (TMA) analysis discloses the negative regulatory association between RPS7 and HIF-1alpha in colorectal cancer. Meanwhile, overexpression of RPS7 in colorectal cancer tissues predicts good overall survival and progression-free survival, but high expression level of HIF 1alpha indicates poor overall survival and progression-free survival. Overall, we reveal that RPS7 inhibits colorectal cancer glycolysis through HIF-1alpha associated signaling and may be a promising biomarker for prognosis prediction and a potential target for therapeutic treatment. PMID- 26735580 TI - Comprehensive mapping of the human papillomavirus (HPV) DNA integration sites in cervical carcinomas by HPV capture technology. AB - Integration of human papillomavirus (HPV) DNA into the host genome can be a driver mutation in cervical carcinoma. Identification of HPV integration at base resolution has been a longstanding technical challenge, largely due to sensitivity masking by HPV in episomes or concatenated forms. The aim was to enhance the understanding of the precise localization of HPV integration sites using an innovative strategy. Using HPV capture technology combined with next generation sequencing, HPV prevalence and the exact integration sites of the HPV DNA in 47 primary cervical cancer samples and 2 cell lines were investigated. A total of 117 unique HPV integration sites were identified, including HPV16 (n = 101), HPV18 (n = 7), and HPV58 (n = 9). We observed that the HPV16 integration sites were broadly located across the whole viral genome. In addition, either single or multiple integration events could occur frequently for HPV16, ranging from 1 to 19 per sample. The viral integration sites were distributed across almost all the chromosomes, except chromosome 22. All the cervical cancer cases harboring more than four HPV16 integration sites showed clinical diagnosis of stage III carcinoma. A significant enrichment of overlapping nucleotides shared between the human genome and HPV genome at integration breakpoints was observed, indicating that it may play an important role in the HPV integration process. The results expand on knowledge from previous findings on HPV16 and HPV18 integration sites and allow a better understanding of the molecular basis of the pathogenesis of cervical carcinoma. PMID- 26735581 TI - Chicoric acid binds to two sites and decreases the activity of the YopH bacterial virulence factor. AB - Chicoric acid (CA) is a phenolic compound present in dietary supplements with a large spectrum of biological properties reported ranging from antioxidant, to antiviral, to immunostimulatory properties. Due to the fact that chicoric acid promotes phagocytic activity and was reported as an allosteric inhibitor of the PTP1B phosphatase, we examined the effect of CA on YopH phosphatase from pathogenic bacteria, which block phagocytic processes of a host cell. We performed computational studies of chicoric acid binding to YopH as well as validation experiments with recombinant enzymes. In addition, we performed similar studies for caffeic and chlorogenic acids to compare the results. Docking experiments demonstrated that, from the tested compounds, only CA binds to both catalytic and secondary binding sites of YopH. Our experimental results showed that CA reduces activity of recombinant YopH phosphatase from Yersinia enterocolitica and human CD45 phosphatase. The inhibition caused by CA was irreversible and did not induce oxidation of catalytic cysteine. We proposed that inactivation of YopH induced by CA is involved with allosteric inhibition by interacting with essential regions responsible for ligand binding. PMID- 26735583 TI - The Vanishing Ball Illusion: A new perspective on the perception of dynamic events. AB - Our perceptual experience is largely based on prediction, and as such can be influenced by knowledge of forthcoming events. This susceptibility is commonly exploited by magicians. In the Vanishing Ball Illusion, for example, a magician tosses a ball in the air a few times and then pretends to throw the ball again, whilst secretly concealing it in his hand. Most people claim to see the ball moving upwards and then vanishing, even though it did not leave the magician's hand (Kuhn & Land, 2006; Triplett, 1900). But what exactly can such illusions tell us? We investigated here whether seeing a real action before the pretend one was necessary for the Vanishing Ball Illusion. Participants either saw a real action immediately before the fake one, or only a fake action. Nearly one third of participants experienced the illusion with the fake action alone, while seeing the real action beforehand enhanced this effect even further. Our results therefore suggest that perceptual experience relies both on long-term knowledge of what an action should look like, as well as exemplars from the immediate past. In addition, whilst there was a forward displacement of perceived location in perceptual experience, this was not found for oculomotor responses, consistent with the proposal that two separate systems are involved in visual perception. PMID- 26735582 TI - RASSF1A inhibits gastric cancer cell proliferation by miR-711- mediated downregulation of CDK4 expression. AB - Although interaction with DNA repair proteins has demonstrated that RASSF1A is a tumour suppressor gene, much attention has been directed in recent years towards its roles in regulating the cell cycle. However, the precise mechanism remains unclear. Uncovering how RASSF1A participates in regulating the cell cycle is critical to exploring effective therapeutic targets for gastric cancer. Here we show that RASSF1A could regulate 14 miRNAs' expression in the typical human gastric cancer line SGC-7901, of which miR-711 was upregulated the most. Moreover, for SGC-7901 cells, miR-711 was found to downregulate CDK4 expression, and to arrest the cell cycle in the G1 phase. Our results suggest that RASSF1A inhibits the proliferation of gastric cancer cells by upregulating the expression of miR-711, which arrested gastric cancer cells in the G1 phase by downregulating expression of CDK4. This finding might provide us with a novel therapeutic target for gastric cancer by increasing RASSF1A expression via miR-711 regulation. PMID- 26735584 TI - Segmental Dynamics and Dielectric Constant of Polysiloxane Polar Copolymers as Plasticizers for Polymer Electrolytes. AB - Dielectric relaxation spectroscopy was used to investigate the segmental dynamics of a series of siloxane-based polar copolymers combining pendant cyclic carbonates and short poly(ethylene oxide) (PEO) chains. The homopolymer with cyclic carbonate as the only side chain exhibits higher glass transition temperature T(g) and dielectric constant epsilon(s) than the one with only PEO side chains. For their copolymers the observed T(g) (agreeing well with the predicted values from the Fox equation) and epsilon(s) decrease with increasing PEO side chain content. These polar polymers exhibit a glassy beta relaxation with Arrhenius character, attributed to local chain motions of side groups attached to the main chain, and a segmental alpha relaxation, associated with the glass transition with a Vogel temperature dependence. As PEO side chain content increases, narrowing of the local glassy beta relaxation was observed in the copolymers. The segmental alpha dynamics were observed to be faster, with an increase in breadth and decrease in strength with increasing PEO side chain content. Owing to the trade-off between T(g) and epsilon(s), copolymers of intermediate composition result in the highest ionic conductivity when these copolymers are used to plasticize Li single-ion conducting ionomers. PMID- 26735585 TI - Early death among head and neck cancer patients. AB - PURPOSE OF REVIEW: Management of advanced head and neck cancer (HNC) is characterized by high mortality. Furthermore, the treatment involves significant burden to patients and high costs to healthcare systems. Recognizing the risks of early death in patients with a high probability of noncurable disease is important for each individual treatment decision-making. It is thus critical to consider the benefits and side-effects of the planned treatment in relation to the expected survival and to discuss these factors with the patient. However, only few studies have documented early death in HNC patients, that is, during the first posttreatment 6 months. We performed a systematic literature review to find the incidence of this phenomenon and to outline the probable cause. RECENT FINDINGS: Early mortality in patients with HNC can be explained either by direct effect of malignant disease, may be related to comorbidities, or secondary to the treatment. These factors act together resulting in expected or unexpected early death. SUMMARY: The present review provides information on the mechanisms leading to early phase mortality (<6 months) after management of HNC. It also reports the incidence of this phenomenon among Finnish and Swedish patient populations. PMID- 26735586 TI - Endogenous hormone levels affect the regeneration ability of callus derived from different organs in barley. AB - Hordeum vulgare (barley) is an important agricultural crop worldwide. A simple and efficient transformation system is needed to analyze the functions of barley genes and generate lines with improved agronomic traits. Currently, Golden Promise and Igri are the most amenable barley cultivars for stable transformation. Here we evaluated the regeneration ratios and endogenous hormone levels of calli derived from various malting barley cultivars, including Golden Promise, Haruna Nijo, and Morex. We harvested samples not only from immature embryos, but also from different explants of juvenile plants, cotyledons, coleoptiles, and roots. The callus properties differed among genotypes and explant types. Calli derived from the immature embryos of Golden Promise, which showed the highest ratio of regeneration of green shoots, had the highest contents of indoleacetic acid, trans-zeatin, and cis-zeatin. By contrast, calli derived from the cotyledons of Morex and the immature embryos of Haruna Nijo had elevated levels of salicylic acid and abscisic acid, respectively. We thus propose that the former phytohormones are positively associated with the regeneration ability of callus but the later phytohormones are negatively associated. PMID- 26735587 TI - Experience of complementary and alternative medicine in patients with amyotrophic lateral sclerosis and their families: A qualitative study. AB - The purpose of this study was to explore the life experience related to complementary and alternative medicine (CAM) use among patients with amyotrophic lateral sclerosis (ALS). Data were collected though semi-structured interviews of nine patients with ALS and seven family members, who have used CAM. Audio recordings of the interviews were transcribed verbatim and checked for accuracy. The Giorgi's method of phenomenology was used for data analysis. Five constituents forming the units of meaning were: facing the limits of conventional medicine; getting to know CAM; recognizing the ineffectiveness of CAM; using CAM for symptomatic treatment; and seeking new CAM endlessly for complete cure. The study results provide an in-depth understanding of experience with CAM among patients with ALS and their family members. Healthcare providers must give accurate information about the efficacy of CAM as well as its safety and possible adverse effects and should offer patient-centred treatment through active communication throughout the process of diagnosis and treatment. PMID- 26735588 TI - The paradoxical association of adiponectin with mortality rate in patients with type 2 diabetes: evidence of synergism with kidney function. AB - BACKGROUND: The paradoxical relationship between high adiponectin and increased mortality, described in several clinical subsets, has been reported only once in type 2 diabetes (T2D) and only in selected elderly patients. We investigated this relationship in unselected patients with T2D and, then, addressed its possible modulation by several demographic and clinical conditions, known to affect per se mortality rate. METHODS: Patients from the Gargano Mortality Study (GMS; N = 897, follow-up = 10.5 +/- 3.7 years; 290 events) and the Foggia Mortality Study (FMS; N = 529, follow-up = 7.1 +/- 2.5 years; 143 events), were investigated. RESULTS: For each SD adiponectin increase, HRs (95% CI) for all-cause mortality were 1.30 (1.19-1.43) in GMS, 1.43 (1.26-1.64) in FMS and 1.34 (1.24-1.45) in the combined studies. This association was independent of the possible confounding effect of demographics, adiposity measures, diabetes-related features, kidney function related parameters and medications (p = 9.34 * 10(-9)). While no interaction was observed between adiponectin and sex, age, smoking habits, BMI, waist circumference, HbA1c, diabetes duration, micro-/macro-albuminuria and medications, a strong interaction was observed with GFR, with a significant adiponectin-mortality association observed in individuals with GFR >= but not those with GFR < 60 ml/min/1.73 m(2); p for adiponectin-by-GFR status interaction = 2.13 * 10(-6)). CONCLUSION: This is the first study reporting a paradoxical association of adiponectin with all-cause mortality in a large sample of unselected diabetic patients and indicating that such counterintuitive effect is observed only among patients with preserved kidney function. Further studies are needed to address if the strong interwoven effect of adiponectin and GFR turns to be useful in improving previously validated tools for predicting mortality in T2D. PMID- 26735589 TI - Fine motor skill proficiency in typically developing children: On or off the maturation track? AB - Fine motor skill proficiency is an essential component of numerous daily living activities such as dressing, feeding or playing. Poor fine motor skills can lead to difficulties in academic achievement, increased anxiety and poor self-esteem. Recent findings have shown that children's gross motor skill proficiency tends to fall below established developmental norms. A question remains: do fine motor skill proficiency levels also fall below developmental norms? The aim of this study was to examine the current level of fine motor skill in Irish children. Children (N=253) from 2nd, 4th and 6th grades (mean age=7.12, 9.11 and 11.02 respectively) completed the Fine Motor Composite of the Bruininks Oseretsky Test of Motor Proficiency 2nd Edition (BOT-2). Analysis revealed that only 2nd grade children met the expected level of fine motor skill proficiency. It was also found that despite children's raw scores improving with age, children's fine motor skill proficiency was not progressing at the expected rate given by normative data. This leads us to question the role and impact of modern society on fine motor skills development over the past number of decades. PMID- 26735590 TI - Molecular Mechanisms of Ultrafiltration Membrane Fouling in Polymer-Flooding Wastewater Treatment: Role of Ions in Polymeric Fouling. AB - Polymer (i.e., anionic polyacrylamide (APAM)) fouling of polyvinylidene fluoride (PVDF) ultrafiltration (UF) membranes and its relationships to intermolecular interactions were investigated using atomic force microscopy (AFM). Distinct relations were obtained between the AFM force spectroscopy measurements and calculated fouling resistance over the concentration polarization layer (CPL) and gel layer (GL). The measured maximum adhesion forces (Fad,max) were closely correlated with the CPL resistance (Rp), and the proposed molecular packing property (largely based on the shape of AFM force spectroscopy curve) of the APAM chains was related to the GL resistance (Rg). Calcium ions (Ca(2+)) and sodium ions (Na(+)) caused more severe fouling. In the presence of Ca(2+), the large Rp corresponded to high foulant-foulant Fad,max, resulting in high flux loss. In addition, the Rg with Ca(2+) was minor, but the flux recovery rate after chemical cleaning was the lowest, indicating that Ca(2+) created more challenges in GL cleaning. With Na(+), the fouling behavior was complicated and concentration dependent. The GL structures with Na(+), which might correspond to the proposed molecular packing states among APAM chains, played essential roles in membrane fouling and GL cleaning. PMID- 26735591 TI - Estimating and Visualizing Nonlinear Relations Among Latent Variables: A Semiparametric Approach. AB - The graphical presentation of any scientific finding enhances its description, interpretation, and evaluation. Research involving latent variables is no exception, especially when potential nonlinear effects are suspect. This article has multiple aims. First, it provides a nontechnical overview of a semiparametric approach to modeling nonlinear relationships among latent variables using mixtures of linear structural equations. Second, it provides several examples showing how the method works and how it is implemented and interpreted in practical applications. In particular, this article examines the potentially nonlinear relationships between positive and negative affect and cognitive processing. Third, a recommended display format for illustrating latent bivariate relationships is demonstrated. Finally, the article describes an R package and an online utility that generate these displays automatically. PMID- 26735592 TI - Sequential Temporal Dependencies in Associations Between Symptoms of Depression and Posttraumatic Stress Disorder: An Application of Bivariate Latent Difference Score Structural Equation Modeling. AB - Depression and posttraumatic stress disorder (PTSD) are highly comorbid conditions that may arise following exposure to psychological trauma. This study examined their temporal sequencing and mutual influence using bivariate latent difference score structural equation modeling. Longitudinal data from 182 emergency room patients revealed level of depression symptom severity to be positively associated with changes in PTSD intrusion, avoidance, and hyperarousal over 3 time intervals, beginning shortly after the traumatic event. Higher scores on depression anticipated increases (or worsening) in PTSD symptom severity. The pattern of influence from PTSD symptom severity to change in depression symptom severity simply followed the general trend toward health and well-being. Results are discussed in terms of the dynamic interplay and associated mechanisms of posttrauma depression and PTSD symptom severity. PMID- 26735593 TI - Using Innovative Outliers to Detect Discrete Shifts in Dynamics in Group-Based State-Space Models. AB - Outliers are typically regarded as data anomalies that should be discarded. However, dynamic or "innovative" outliers can be appropriately utilized to capture unusual but substantively meaningful shifts in a system's dynamics. We extend De Jong and Penzer's 1998 approach for representing outliers in single subject state-space models to a group-based framework. The group-based model enables model predictions concerning the group as a whole while individualized change points are incorporated to capture discrete shifts in each individual's trajectory. An illustrative example using cognitive performance data from N = 38 older adults over 60 days is presented. Results indicated that a subset of older adults showed sudden shifts in learning dynamics in several forms, including sudden jumps in level, slope, and linkage between perceived control and actual performance level. The broader implications of incorporating innovative outliers into studies of intraindividual change are discussed. PMID- 26735594 TI - Assessing the Impact of Faking on Binary Personality Measures: An IRT-Based Multiple-Group Factor Analytic Procedure. AB - This article proposes a model-based multiple-group procedure for assessing the impact of faking on personality measures and the scores derived from these measures. The assessment is at the item level and the base model, which is intended for binary items, can be parameterized both as an Item Response Theory (IRT) model and as an Item Factor-Analytic (FA) model. The specific solution proposed is bidimensional, and the propensity to fake is specifically modeled as a second factor. The approach we propose allows (a) previous separate results obtained either from IRT-based or from FA-based studies to be related and (b) some hypotheses on measurement invariance and structural changes to be assessed in more detail. The procedure was used in a study based on 2 personality scales that were administered in 1 group under standard instructions and in another group under faking-good instructions. For both scales, results suggested that strong measurement invariance was attained. Also, for both scales substantial mean changes were obtained in the propensity-to-fake factor but not in the content factors. The implications of the results and future research directions are discussed. PMID- 26735595 TI - Consistent Small-Sample Variances for Six Gamma-Family Measures of Ordinal Association. AB - Gamma-family measures are bivariate ordinal correlation measures that form a family because they all reduce to Goodman and Kruskal's gamma in the absence of ties (1954) . For several gamma-family indices, more than one variance estimator has been introduced. In previous research, the "consistent" variance estimator described by Cliff and colleagues produced more accurate confidence intervals (CIs) than 3 other types of variances. However, the Cliff consistent (CC) variance is available for only 4 of 10 gamma-family measures. In the present research, a CC variance is derived for the remaining 6 gamma-family measures, and CIs constructed with the CC variance are compared with CIs constructed using other available variance estimators. The CIs are evaluated and compared in simulations and illustrated with scores on the Disinhibition and Avoidance scales of the Schedule for Nonadaptive and Adaptive Personality. Computer code for calculating all 10 gamma-family measures and their CC variances (using the R program) is available on a Web site ( http://www.artsci.wustl.edu/~cwoods/CCvarR.html ). PMID- 26735596 TI - Nucleic Acid Engineering: RNA Following the Trail of DNA. AB - The self-assembly feature of the naturally occurring biopolymer, DNA, has fascinated researchers in the fields of materials science and bioengineering. With the improved understanding of the chemical and structural nature of DNA, DNA based constructs have been designed and fabricated from two-dimensional arbitrary shapes to reconfigurable three-dimensional nanodevices. Although DNA has been used successfully as a building block in a finely organized and controlled manner, its applications need to be explored. Hence, with the myriad of biological functions, RNA has recently attracted considerable attention to further the application of nucleic acid-based structures. This Review categorizes different approaches of engineering nucleic acid-based structures and introduces the concepts, principles, and applications of each technique, focusing on how DNA engineering is applied as a guide to RNA engineering. PMID- 26735597 TI - Experimental Study and Early Clinical Application Of a Sutureless Aortic Bioprosthesis. AB - INTRODUCTION: The conventional aortic valve replacement is the treatment of choice for symptomatic severe aortic stenosis. Transcatheter technique is a viable alternative with promising results for inoperable patients. Sutureless bioprostheses have shown benefits in high-risk patients, such as reduction of aortic clamping and cardiopulmonary bypass, decreasing risks and adverse effects. OBJECTIVE: The objective of this study was to experimentally evaluate the implantation of a novel balloon-expandable aortic valve with sutureless bioprosthesis in sheep and report the early clinical application. METHODS: The bioprosthesis is made of a metal frame and bovine pericardium leaflets, encapsulated in a catheter. The animals underwent left thoracotomy and the cardiopulmonary bypass was established. The sutureless bioprosthesis was deployed to the aortic valve, with 1/3 of the structure on the left ventricular face. Cardiopulmonary bypass, aortic clamping and deployment times were recorded. Echocardiograms were performed before, during and after the surgery. The bioprosthesis was initially implanted in an 85 year-old patient with aortic stenosis and high risk for conventional surgery, EuroSCORE 40 and multiple comorbidities. RESULTS: The sutureless bioprosthesis was rapidly deployed (50-170 seconds; average=95 seconds). The aortic clamping time ranged from 6-10 minutes, average of 7 minutes; the mean cardiopulmonary bypass time was 71 minutes. Bioprostheses were properly positioned without perivalvar leak. In the first operated patient the aortic clamp time was 39 minutes and the patient had good postoperative course. CONCLUSION: The deployment of the sutureless bioprosthesis was safe and effective, thereby representing a new alternative to conventional surgery or transcatheter in moderate- to high-risk patients with severe aortic stenosis. PMID- 26735599 TI - Evaluation of Pulmonary Reperfusion Injury in Rats Undergoing Mesenteric Ischemia and Reperfusion and Protective Effect of Postconditioning on this Process. AB - INTRODUCTION: Some publications have demonstrated the presence of lung reperfusion injury in mesenteric ischemia and reperfusion (I/R), but under to diverse methods. Postconditioning has been recognized as effective in preventing reperfusion injury in various organs and tissues. However, its effectiveness has not been evaluated in the prevention of lung reperfusion injury after mesenteric ischemia and reperfusion. OBJECTIVE: To evaluate the presence of pulmonary reperfusion injury and the protective effect of ischemic postconditioning on lung parenchyma in rats submitted to mesenteric ischemia and reperfusion. METHODS: Thirty Wistar rats were distributed into three groups: group A (10 rats), which was held mesenteric ischemia (30 minutes) and reperfusion (60 minutes); group B (10 rats), ischemia and reperfusion, interspersed by postconditioning with two alternating cycles of reperfusion and reocclusion, for two minutes each; and group C (10 rats), ischemia and reperfusion interleaved by postconditioning with four alternating cycles of reperfusion and reocclusion of 30 seconds each. Finally, it was resected the upper lung lobe for histological analysis. RESULTS: There were mild lung lesions (grade 1) in all samples. There was no statistical difference between groups 1 and 2 (P >0.05). CONCLUSION: The mesenteric ischemia and reperfusion in rats for thirty and sixty minutes, respectively, caused mild reperfusion injury in lung. Postconditioning was not able to minimize the remote reperfusion injury and there was no difference comparing two cycles of two minutes with four cycles of 30 seconds. PMID- 26735598 TI - Atrial Fibrillation, Neurocognitive Decline and Gene Expression After Cardiopulmonary Bypass. AB - OBJECTIVE: Atrial fibrillation and neurocognitive decline are common complications after cardiopulmonary bypass. By utilizing genomic microarrays we investigate whether gene expression is associated with postoperative atrial fibrillation and neurocognitive decline. METHODS: Twenty one cardiac surgery patients were prospectively matched and underwent neurocognitive assessments pre operatively and four days postoperatively. The whole blood collected in the pre cardiopulmonary bypass, 6 hours after-cardiopulmonary bypass, and on the 4th postoperative day was hybridized to Affymetrix Gene Chip U133 Plus 2.0 Microarrays. Gene expression in patients who developed postoperative atrial fibrillation and neurocognitive decline (n=6; POAF+NCD) was compared with gene expression in patients with postoperative atrial fibrillation and normal cognitive function (n=5; POAF+NORM) and patients with sinus rhythm and normal cognitive function (n=10; SR+NORM). Regulated genes were identified using JMP Genomics 4.0 with a false discovery rate of 0.05 and fold change of >1.5 or < 1.5. RESULTS: Eleven patients developed postoperative atrial fibrillation. Six of these also developed neurocognitive decline. Of the 12 patients with sinus rhythm, only 2 developed neurocognitive decline. POAF+NCD patients had unique regulation of 17 named genes preoperatively, 60 named genes six hours after cardiopulmonary bypass, and 34 named genes four days postoperatively (P<0.05) compared with normal patients. Pathway analysis demonstrated that these genes are involved in cell death, inflammation, cardiac remodeling and nervous system function. CONCLUSION: Patients who developed postoperative atrial fibrillation and neurocognitive decline after cardiopulmonary bypass may have differential genomic responses compared to normal patients and patients with only postoperative atrial fibrillation, suggesting common pathophysiology for these conditions. Further exploration of these genes may provide insight into the etiology and improvements of these morbid outcomes. PMID- 26735601 TI - Patient's Perception About Coronary Artery Bypass Grafting. AB - OBJECTIVE: The diagnosis of coronary artery disease referred for heart surgery has an important psychological component. The purpose of this study was to access the difficulties experienced by individuals awaiting coronary artery bypass grafting and to determine strategies that facilitate adaptation to a new lifestyle, modified by the disease. METHODS: A qualitative, exploratory study involving patients admitted to a university teaching hospital in the city of Salvador, Bahia, Brazil, awaiting coronary artery bypass grafting. Semi structured interviews were performed in accordance with a previously defined script based on the study objective. Each transcription was read in its entirety to verify the representativeness, homogeneity and pertinence of the data obtained (pre-analysis), followed by separation of categories of analysis. RESULTS: The descriptions of this study show that patients admitted to the completion of coronary artery bypass grafting experience a wide range of psychological difficulties, considering that surgery acquires interpretations that vary according to individuals' subjectivity. The patients recognized the benefit of being able to discuss their feelings as a means of diminishing their fear and anxiety. CONCLUSION: Helping patients find resources to confront more positively the daily hospitalization is an important aspect for the health care professionals who assist them. This goal can be achieved through modification of the biomedical model of care for a biopsychosocial view. The investment of time and attention is of fundamental importance and aims to overcome existing deficiencies that interfere with the outcome of patients after cardiac surgery. PMID- 26735600 TI - Adjunctive Hyperbaric Oxygen Therapy or Alone Antibiotherapy? Methicillin Resistant Staphylococcus aureus Mediastinitis in a Rat Model. AB - OBJECTIVE: In the post-sternotomy mediastinitis patients, Staphylococcus aureus is the pathogenic microorganism encountered most often. In our study, we aimed to determine the efficacy of antibiotic treatment with vancomycin and tigecycline, alone or in combination with hyperbaric oxygen treatment, on bacterial elimination in experimental S. aureus mediastinitis. METHODS: Forty-nine adult female Wistar rats were used. They were randomly divided into seven groups, as follows: non-contaminated, contaminated control, vancomycin, tigecycline, hyperbaric oxygen, hyperbaric oxygen + vancomycin and hyperbaric oxygen + tigecycline. The vancomycin rat group received 10 mg/kg/day of vancomycin twice a day through intramuscular injection. The tigecycline group rats received 7 mg/kg/day of tigecycline twice a day through intraperitoneal injection. The hyperbaric oxygen group underwent 90 min sessions of 100% oxygen at 2.5 atm pressure. Treatment continued for 7 days. Twelve hours after the end of treatment, tissue samples were obtained from the upper part of the sternum for bacterial count assessment. RESULTS: When the quantitative bacterial counts of the untreated contaminated group were compared with those of the treated groups, a significant decrease was observed. However, comparing the antibiotic groups with the same antibiotic combined with hyperbaric oxygen, there was a significant reduction in microorganisms identified (P<0.05). Comparing hyperbaric oxygen used alone with the vancomycin and tigecycline groups, it was seen that the effect was not significant (P<0.05). CONCLUSION: We believe that the combination of hyperbaric oxygen with antibiotics had a significant effect on mediastinitis resulting from methicillin-resistant Staphylococcus aureus. Methicillin-resistant Staphylococcus aureus mediastinitis can be treated without requiring a multidrug combination, thereby reducing the medication dose and concomitantly decreasing the side effects. PMID- 26735602 TI - Factors Associated With the Development of Chronic Post-Sternotomy Pain: a Case Control Study. AB - OBJECTIVE: The aim of the present study was to investigate the factors associated with chronic post-sternotomy pain in heart surgery patients. METHODS: Between January 2013 and February 2014, we evaluated 453 patients with >6 months post sternotomy for cardiac surgery at a surgical outpatient clinic. The patients were allocated into a group with chronic post-sternotomy pain (n=178) and a control group without pain (n=275). The groups were compared for potential predictors of chronic post-sternotomy pain. We used Cox proportional hazards regression to determine which independent variables were associated with the development of chronic post-sternotomy pain. RESULTS: In total, 39.29% of the patients had chronic poststernotomy pain. The following factors were significantly associated with chronic post-sternotomy pain: (a) use of the internal thoracic artery in coronary bypass grafting (P =0.009; HR=1.39; 95% CI, 1.08 to 1.80); (b) a history of antidepressant use (P =0.0001; HR=2.40; 95% CI, 1.74 to 3.32); (c) hypothyroidism (P =0.01; HR=1.27; 95% CI, 1.03 to 1.56); (d) surgical wound complication (P =0.01; HR=1.69; 95% CI, 1.08 to 2.63), and (e) patients on disability benefits or scheduled for a consultative medical examination for retirement (P =0.0002; HR=2.05; 95% CI, 1.40 to 3.02). CONCLUSION: The factors associated with chronic poststernotomy pain were: use of the internal thoracic artery; use of antidepressants; hypothyroidism; surgical wound complication, and patients on disability benefits or scheduled for a consultative examination. PMID- 26735603 TI - Association of Angiotensin-Converting Enzyme Genotype, Insertion/Deletion Polymorphism and Saphenous Vein Graft Atherosclerosis in Iranian Patients. AB - OBJECTIVE: The aim of this study was to evaluate possible interactions among Angiotensin-I converting enzyme genotype, insertion/deletion polymorphism and atherosclerosis of vein grafts in Iranian patients, and characterize their clinical and demographic profile. METHODS: In this cross-sectional study, patients who underwent coronary artery bypass graft surgery more than five years ago, were included for angiographic analysis. Atherosclerosis was determined by quantitative angiography and adjusted Gensini score. The gene angiotensin converting enzyme I/D polymorphism was detected by polymerase chain reaction. RESULTS: A total of 102 patients participated in this study. Eighty-four patients were male. The frequency distribution of DD, ID and II polymorphism were 23.6%, 62.7% and 13.7% respectively. There were no differences among genotypic groups in age, sex, number of risk factors, number of vein grafts and months since bypass surgery. According to adjusted Gensini score [0.18+/-0.12 (II) vs. 0.11+/-0.09 (ID) and 0.1+/-0.09 (DD) P=0.021] the II genotype was associated with severity of vein graft atherosclerosis. CONCLUSION: Although there are conflicting results about gene angiotensin converting enzyme I/D polymorphism and the degree of venous bypass graft degeneration, this study suggests an association between ACE genotype II and atherosclerosis of saphenous vein grafts, however, large samples considering clinical, demographic and ethnic profile are necessary to confirm these results. PMID- 26735604 TI - Cardiovascular Surgery Residency Program: Training Coronary Anastomosis Using the Arroyo Simulator and UNIFESP Models. AB - OBJECTIVE: Engage the UNIFESP Cardiovascular Surgery residents in coronary anastomosis, assess their skills and certify results, using the Arroyo Anastomosis Simulator and UNIFESP surgical models. METHODS: First to 6th year residents attended a weekly program of technical training in coronary anastomosis, using 4 simulation models: 1. Arroyo simulator; 2. Dummy with a plastic heart; 3. Dummy with a bovine heart; and 4. Dummy with a beating pig heart. The assessment test was comprised of 10 items, using a scale from 1 to 5 points in each of them, creating a global score of 50 points maximum. RESULTS: The technical performance of the candidate showed improvement in all items, especially manual skill and technical progress, critical sense of the work performed, confidence in the procedure and reduction of the time needed to perform the anastomosis after 12 weeks practice. In response to the multiplicity of factors that currently influence the cardiovascular surgeon training, there have been combined efforts to reform the practices of surgical medical training. CONCLUSION: 1 - The four models of simulators offer a considerable contribution to the field of cardiovascular surgery, improving the skill and dexterity of the surgeon in training. 2 - Residents have shown interest in training and cooperate in the development of innovative procedures for surgical medical training in the art. PMID- 26735605 TI - Infected Cardiac Myxoma: an Updated Review. AB - OBJECTIVE: This study aims to present an updated clinical picture of the infected cardiac myxoma. Revankar & Clark made a systematic review of infected cardiac myxoma based on the literature before 1998. Since then, there has not been any updated information describing its recent changing trends. METHODS: A comprehensive literature search of infected cardiac myxoma was conducted on MEDLINE, Highwire Press and Google between 1998 and 2014. RESULTS: In comparison with Revankar & Clark's series, the present series disclosed a significantly decreased overall mortality. It is believed that refinement of the prompt diagnosis and timely management (use of sensitive antibiotics and surgical resection of the infected myxoma) have resulted in better outcomes of such patients. CONCLUSION: The present series of infected cardiac myxoma illustrated some aggravated clinical manifestations (relative more occasions of high-grade fever, multiple embolic events and the presence of refractory microorganisms), which should draw enough attention to careful diagnosis and treatment. In general, the prognosis of infected cardiac myxoma is relatively benign and the long-term survival is always promising. PMID- 26735607 TI - Overcoming Obstacles. PMID- 26735606 TI - Partial Left Ventriculectomy: Have Well-Succeeded Cases and Innovations in the Procedure Been Observed in the Last 12 Years? AB - OBJECTIVE: In 1996, the Brazilian cardiovascular surgeon, Dr. Randas Batista, introduced a surgical technique called partial left ventriculectomy, where he admitted the possibility of reducing the diameter of the left ventricle through the sectioning of one section of its wall. After the publication of this study, thousands of case reports and procedure analysis have been published, and due to several disappointing results, many doctors and institutions failed to execute it. As the main objective of this study, stands out the search for success cases of ventriculectomy in the last 12 years and if during this period it was achieved some significant development in this procedure that allows obtaining lower mortality rate postoperatively. METHODS: Systematic review of indexed scientific literature over the past 12 years and the term "Partial Left Ventriculectomy". RESULTS: There has been a considerable number of reported successful cases and highly significant findings in regard to determining the most suitable region for the section, proper selection of the patients indicated to the procedure, including the influence of the coronary artery anatomy in the nomination procedure and the need for preservation of ventricular geometry to ensure better quality of ventricular contractions after the sectioning. CONCLUSION: This surgical procedure has been successfully performed, mainly in Japan, improvements in its efficiency were found and the need for a mathematical modeling of the slice to be severed is a prominent factor in many studies. PMID- 26735608 TI - Bilateral Internal Thoracic Artery and Optimal Revascularization Strategy in Insulin-Dependent Diabetic Patients. PMID- 26735609 TI - Effect of FOXP3 polymorphism on the clinical outcomes after allogeneic hematopoietic stem cell transplantation in pediatric acute leukemia patients. AB - Forkhead BOX P3 (FOXP3) polymorphisms have recently been investigated as candidate risk factors in several tumors and autoimmune diseases. This study aims to evaluate the potential influence of FOXP3 rs3761548 polymorphism in the donor on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 171 patients were enrolled for this study and genotyped using direct sequencing. Patients with rs3761548 CC genotype had higher incidence of hepatic veno-occlusive disease (HVOD) and cytomegalovirus (CMV) infection than that of the individuals with AA or AC genotype (P=0.011, P=0.023). Treatment-related mortality (TRM) rate of patients with AA or AC genotype was lower than that of the patients with CC genotype (P=0.044) resulting in a difference in overall survival (OS). However, there was no difference in graft-versus-host disease (GVHD) relapse or blood stream infection (BSI), depending on the genotype at rs3761548 locus. In multivariate analysis, CC genotype showed as a risk factor in the development of HVOD and CMV infection, with low OS. In conclusion, this is the first report on FOXP3 rs3761548 SNP in allo-HSCT and we suggest that this SNP be considered a candidate marker for predicting the development of HVOD and CMV infection after allo-HSCT. PMID- 26735610 TI - Nordihydroguaiaretic acid (NDGA) and alpha-mangostin inhibit the growth of Mycobacterium tuberculosis by inducing autophagy. AB - Tuberculosis (TB) remains as a global health problem. The prevalence of this infection is related to the association with other diseases, such as HIV, neglect treatment and misuse of antibiotics. Hence, the identification of new drugs is required to eradicate TB. Possible alternatives to existing antibiotics include pure compounds extracted from medicinal plants, which are an important source of antimicrobial agents. The aim of this study was to evaluate the effect of nordihydroguaiaretic acid (NDGA) and alpha-mangostin on Mycobacterium tuberculosis growth and bacterial survival in infected macrophages derived from the human THP-1 cell line and monocytes. Our results show that both compounds directly inhibit M. tuberculosis growth in liquid medium with Minimal Inhibitory Concentrations (MIC) of 250 and 62 MUg/mL respectively, likely through preventing bacterial replication. In addition, NDGA and alpha-mangostin were able to induce autophagy in human cells at lower concentrations (7 and 6 MUg/mL, respectively) and contributed to the elimination of intracellular bacteria. NDGA and alpha mangostin could be candidates for coadjuvant therapy in cases of drug-resistant TB, and their ability to enhance the immune response by promoting autophagy might contribute to TB treatment. PMID- 26735611 TI - Potent antigen-specific immune response induced by infusion of spleen cells coupled with succinimidyl-4-(N-maleimidomethyl cyclohexane)-1-carboxylate (SMCC) conjugated antigens. AB - In the present study, we report our recently developed new approach to inducing antigen-specific immune response. We use two nucleophilic substitution "click" chemistry processes to successfully couple protein antigens or peptides to mouse spleen cells or T cells by a heterobifunctional crosslinker, succinimidyl-4-(N maleimidomethyl cyclohexane)-1-carboxylate (SMCC) or sulfo-SMCC. SMCC and its water-soluble analog sulfo-SMCC contain N-hydroxysuccinimide (NHS) ester and maleimide groups, which allow stable covalent conjugation of amine- and sulfhydryl-containing molecules in trans. Protein coupling to cells relies on the free sulfhydryls (thiols) on cell surfaces and the free amines on protein antigens. Although the amount of protein coupled to cells is limited due to the limited number of cell surface thiols, the injection of spleen cells coupled with antigenic proteins, such as keyhole limpet hemocyanin (KLH) or ovalbumin (OVA), induces a potent antigen-specific immune response in vivo, which is even stronger than that induced by the injection of a large dose of protein plus adjuvants. In addition, short peptides coupled to purified splenic T cells also potently elicit peptide-specific T cell proliferation in vivo after injection. Further studies show that antigen-coupled spleen cell treatment leads to augmented IFN-gamma producing T cells. Our study provides a unique antigen delivery method that efficiently distributes antigen to the entire immune system, subsequently eliciting a potent antigen-specific immune response with enhanced IFN-gamma production. The findings in the present study suggest that this antigen-cell coupling strategy could be employed in immunotherapy for cancers, infectious diseases as well as immune-mediated disorders. PMID- 26735613 TI - Oxidative Cleavage of the beta-O-4 Linkage of Lignin by Transition Metals: Catalytic Properties and the Performance of Density Functionals. AB - The catalytic degradation of lignin is of considerable interest because the depolymerization of lignin to small molecules is the initial step for the conversion of lignin to biofuels and other useful chemicals. Because of the complex structure of lignin, methoxyethane was used in this study as a representative model of the most common linkage within lignin, the beta-O-4 linkage. The completely renormalized coupled cluster with singles, doubles, and perturbative triples [CR-CCSD(T)] method was used to calculate the energetics of the C-O bond cleavage in methoxyethane by late 3d, 4d, and 5d transition metal atoms and to evaluate the performance of a set of density functionals (BLYP, B97D, TPSS, M06L, B3LYP, PBE0, M06, TPSSh, and B2PLYP) in predicting the reaction energetics. PMID- 26735612 TI - Melatonin enhances interleukin-10 expression and suppresses chemotaxis to inhibit inflammation in situ and reduce the severity of experimental autoimmune encephalomyelitis. AB - Melatonin is the major product secreted by the pineal gland at night and displays multifunctional properties, including immunomodulatory functions. In this study, we investigated the therapeutic effect of melatonin in experimental autoimmune encephalomyelitis (EAE). We demonstrated that melatonin exhibits a therapeutic role by ameliorating the clinical severity and restricting the infiltration of inflammatory Th17 cells into the CNS of mice with myelin oligodendrocyte glycoprotein (MOG)-induced EAE. Furthermore, melatonin enhances splenic interleukin (IL)-10 expression in regulatory T cells by inducing IL-27 expression in the splenic DC; it also suppresses the expression of IFN-gamma, IL-17, IL-6, and CCL20 in the CNS and inhibits antigen-specific T cell proliferation. However, there were no significant differences in the percentage of splenic regulatory T cells. These data provide the first evidence that the therapeutic administration of melatonin is effective in mice with EAE and modulates adaptive immunity centrally and peripherally. Thus, we suggest that melatonin could play an adjunct therapeutic role in treating human CNS autoimmune diseases such as multiple sclerosis. Melatonin merits further studies in animals and humans. PMID- 26735616 TI - Localizing non-palpable breast lesions: the subtleties of selecting the right method. PMID- 26735615 TI - Greater memory impairment in dementing females than males relative to sex-matched healthy controls. AB - Previously we demonstrated sex differences in episodic memory in healthy elderly and suggested that normative data be separated by sex. The present study extended the exploration of sex differences on memory measures into two clinical populations, mild cognitive impairment (MCI) and Alzheimer's disease (AD). Seventy-six subjects with MCI and 101 subjects with AD diagnosed by a multidisciplinary team were included. These two groups were also compared to a group of 177 healthy elderly control participants. Sex differences on the Rey Auditory Verbal Learning Test (RAVLT; total and delayed recall) raw scores and Brief Visuospatial Memory Test-Revised (BVMT-R) were demonstrated within the healthy but not the MCI or AD groups. Calculating z scores by sex for both dementing groups based on the healthy controls suggested a larger performance gap between healthy and dementing women than between healthy and dementing men. MCI females were on average 0.48 standard deviations lower for total verbal learning compared to healthy female controls than were MCI males when compared to healthy male controls. For verbal delayed recall the gap was even larger (SD = 1.09). Similarly, on the BVMT-R, a measure of visual memory, the difference was 0.60 standard deviations for total visual learning and 0.99 standard deviations for delayed recall. This same sex difference, with females showing greater impairment compared to the controls group than did the males, was also present within the AD group. The greater memory impairment in dementing females rather than males when compared to sex-matched healthy controls was unlikely to be due to more severe illness since females performed equivalently to males on the Clinical Dementia Rating Scale, Mini-Mental Status Examination, and Dementia Rating Scale, and were also similar for age, education, and apolipoprotein status. The present study suggested relatively greater memory impairment in females with MCI or AD than in controls. PMID- 26735617 TI - Bullying and harassment and 'the looking glass self'. PMID- 26735619 TI - Re: Preparing surgeons for rural Australia: the RACS Rural Surgical Training Program. PMID- 26735618 TI - Surgical face masks: an old wives' tale? PMID- 26735620 TI - Intrafocal light-emitting diode operating lighting: perspectives in trauma surgery. PMID- 26735621 TI - Paediatric fractures in suburban Australia: a warning about monkey bars. PMID- 26735622 TI - Colonic-type appendiceal adenocarcinoma: an intermediate prognosis between mucinous and signet ring cell adenocarcinoma. PMID- 26735623 TI - Alvarado scoring in primary health care: managing acute surgical workload at the source. PMID- 26735624 TI - Role of Enterobius vermicularis in appendicitis in children. PMID- 26735625 TI - Re: Mortality from acute appendicitis is associated with complex disease and co morbidity. PMID- 26735626 TI - Psoriatic arthritis: complexities, comorbidities and implications for the clinic. AB - Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory disease that affects peripheral joints, entheses and axial sites in addition to both skin and nails. There is considerable evidence to support the assertion that PsA is actually a multisystem disease. Contrary to earlier beliefs, PsA is not only common but also a potentially deforming and disabling disease. In addition to the characteristic extra-articular features, such as uveitis and inflammatory bowel disease, patients with PsA may also suffer from co-existing diseases, referred to as comorbidities. The presence of both extra-articular manifestations and comorbidities may have consequences for the treatment, prognosis and outcome of the disease, which frequently go unrecognized or undertreated. The following review article describes the complexities and comorbidities of PsA as well as their implications for the clinic. PMID- 26735629 TI - CSL-p53: From senescence to CAF activation. PMID- 26735631 TI - Alcohol, auditory functioning and deafness. AB - This paper reviews studies of alcohol and auditory impairment and the treatment of deaf people with alcohol problems and concludes that: (a) alcohol affects auditory functioning, (b) prenatal exposure to alcohol is a risk factor for hearing impairment in FAS children, PMID- 26735630 TI - Feasibility and usability of a wearable orthotic for stroke survivors with hand impairment. AB - PURPOSE: The concept of a vibrating wristband, to improve dextrous hand function of stroke survivors, was recently proposed with clinical results and is referred to as 'TheraBracelet' in this paper. The purpose of this study was to demonstrate feasibility of a portable, wearable TheraBracelet, and to apply usability evaluation techniques to assess potential demands of TheraBracelet and to identify critical improvement needs of the prototype. METHOD: A prototype was developed with a vibrating element housed in an elastic wristband and connected to a wearable electronics box via a cable. Expectation for TheraBracelet and evaluation of the prototype were obtained from 10 chronic stroke survivors using surveys before and after using the prototype and House of Quality analysis. RESULTS: The survey for expectation showed stroke survivors' willingness to try out TheraBracelet at a low cost. The survey evaluating the prototype showed that the current prototype was overall satisfactory with a mean rating of 3.7 out of 5. The House of Quality analysis revealed that the priority improvement needs for the prototype are to improve clinical knowledge on long-term effectiveness, reduce cost, ease donning/doffing and waterproof. CONCLUSIONS: This study presents a potential for a low-cost wearable hand orthotic likable by stroke survivors. Implications for Rehabilitation Feasibility for a portable wearable wristband-type hand orthotic was demonstrated. The survey showed stroke survivors are willing to try such an orthotic at low cost. The current prototype was rated overall satisfactory by stroke survivors. This study provides a potential for a low-cost wearable hand orthotic likable by stroke survivors. PMID- 26735632 TI - Sleep, alcohol and alcohol abuse. AB - Use and abuse of alcohol is extremely common in many countries. Sometimes alcohol may be used to self-treat insomnia. However, alcohol consumption for any reason will affect an individual's sleep quality. The effects of alcohol use and abuse on sleep are complex and interactive. Anyone who consumes alcohol is likely to observe them, although the particular pattern and severity of the sleep impairment will differ with both the amount and duration of alcohol consumption. The fact that alcohol is a sedative and can induce rapid onset of sleep may contribute to its use, while the resultant disturbance of night-time sleep quality and of respiration may possibly result in post-consumptive daytime impairment. The persistent sleep disturbance that accompanies both acute and chronic alcohol abstinence syndromes may contribute to the continued craving and urge to resume drinking seen among chronic alcoholics. This review broadly examines the interaction of alcohol consumption and sleep disturbance. Beginning with a brief overview of normal sleep it examines the effects of modest acute alcohol consumption on sleep, sleepiness, night-time respiration and cognitive function; examines the sleep patterns of chronic alcoholics both while drinking and during acute and chronic alcohol withdrawal; reviews what is known of the relationship between alcohol use and night-time respiratory dysfunction; and concludes with some reflections on the implications of this information for drinking practices. PMID- 26735627 TI - Incidence and Risk Factors for Intensive Care Unit-related Post-traumatic Stress Disorder in Veterans and Civilians. AB - RATIONALE: The incidence and risk factors of post-traumatic stress disorder (PTSD) related to the intensive care unit (ICU) experience have not been reported in a mixed veteran and civilian cohort. OBJECTIVES: To describe the incidence and risk factors for ICU-related PTSD in veterans and civilians. METHODS: This is a prospective, observational, multicenter cohort enrolling adult survivors of critical illness after respiratory failure and/or shock from three Veterans Affairs and one civilian hospital. After classifying those with/without preexisting PTSD (i.e., PTSD before hospitalization), we then assessed all subjects for ICU-related PTSD at 3 and 12 months post hospitalization. MEASUREMENTS AND MAIN RESULTS: Of 255 survivors, 181 and 160 subjects were assessed for ICU-related PTSD at 3- and 12-month follow-up, respectively. A high probability of ICU-related PTSD was found in up to 10% of patients at either follow-up time point, whether assessed by PTSD Checklist Event-Specific Version (score >= 50) or item mapping using the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV). In the multivariable regression, preexisting PTSD was independently associated with ICU-related PTSD at both 3 and 12 months (P < 0.001), as was preexisting depression (P < 0.03), but veteran status was not a consistent independent risk factor for ICU-related PTSD (3-month P = 0.01, 12 month P = 0.48). CONCLUSIONS: This study found around 1 in 10 ICU survivors experienced ICU-related PTSD (i.e., PTSD anchored to their critical illness) in the year after hospitalization. Preexisting PTSD and depression were strongly associated with ICU-related PTSD. PMID- 26735633 TI - Alcohol, hypertension and the cardiovascular system: a critical appraisal. AB - Cross-sectional and longitudinal population studies have provided a considerable corpus of evidence for an inverse association between light to moderate alcohol intake and both coronary artery disease and stroke. The formulation of balanced public health advice on the basis of such studies, however, needs to take into account the full spectrum of the effects of alcohol on the cardiovascular system, particularly its equally well documented effect to increase level of blood pressure and prevalence of hypertension. In this review, the broader implications of the association of alcohol with hypertension are discussed, principally in the context of the effect of higher levels of alcohol consumption to increase ischaemic and haemorrhagic stroke, left ventricular hypertrophy, congestive cardiomyopathy, cardiac arrhythmia and sudden cardiac death. PMID- 26735634 TI - Platelet monoamine oxidase (MAO) activity and alcoholism: is there a genuine association? AB - Monoamine oxidase (MAO) is a particle-bound flavoenzyme principally located in the outer mitochondrial membrane, which catalyzes the oxidative deamination of a variety of the amine transmitters in the central nervous system. There have been many reports from different groups around the world over the last 20 years that indicated a lower platelet MAO activity was associated with alcoholism. As there are multiple influences upon measured MAO activity, this article attempts to address each of the issues in turn for potential confounding of the reported association. These issues include: the duration of abstinence from alcohol, the substrate used for analysis, gender issues, association with different subtypes of alcoholics, the influence of other psychopathology, personality traits of alcoholics, the question of smoking, and proposed modes of transmission of MAO activity. The initial promise about MAO activity being a possible marker for alcoholism or a least a genetically predisposed subgroup has receded as the number of negative typology-based studies increases. The failure to account for a major confounding variable, e.g. smoking and other minor but possibly vital confounds in almost all these studies leaves the whole hypothesis open to criticism. However, the possible association between personality traits that might predispose to some if not all substances of addiction to low MAO activity may make it possible to reframe the hypothesized association in the setting of a generalized predisposition to addictions in particular, and to psychopathology in general. Nonetheless the association remains of great interest and may yet yield vital genetic and clinical information. PMID- 26735635 TI - T2 relaxometry in the central nervous system of solvent misusers. AB - The purpose of this study was to investigate T2 changes in the central nervous system of solvent misusers and to validate a classification of white matter changes (restricted, intermediate and diffuse) proposed in our previous study by visual inspection of magnetic resonance images. T2 values were calculated from the intensity measurements at nine regions in the brain of eight solvent misusers, six of whom showed white matter changes on MRI (two patients for each type), compared with age and gender-matched controls. The misusers with white matter changes on MRI showed significantly prolonged T2 in the centrum semiovale (p= 0.002), periventricular white matter (p= 0.016), internal capsule (p= 0.040), and cerebellar white matter surrounding the dentate nucleus (p= 0.001) and shortened T2 in the thalamus (p= 0.025) compared to controls by ANOVA with post hoc comparison of Scheffe. In addition, each type of white matter changes showed different distribution of T2 changes corresponding to the findings from visual inspection. These results confirmed T2 prolongation in the white matter with T2 shortening in the thalamus of solvent misusers with white matter changes, and provided further support for our classification of white matter changes. PMID- 26735636 TI - The feasibility of abrupt methadone-buprenorphine transfer in British opiate addicts in an outpatient setting. AB - A study of 13 male opiate addicts was undertaken to investigate the feasibility of transferring abruptly from methadone maintenance treatment to buprenorphine in an outpatient setting. The mean age of subjects was 30 years (range 18-45) and all fulfilled DSM-III-R criteria for opioid dependence. All were maintained on a methadone dose of 20-30 mg mixture daily and were transferred for 3 days to 4 mg buprenorphine sublingually 24-26 hours after their last dose of methadone. On day 1 repeated measures of drug effects were performed, including agonist and withdrawal effects, and this was complemented by saccadic eye movements, a potential new measure of central opioid effects. These recordings were repeated once on days 2 and 3 and the subjects returned to their previous dose of methadone on day 4. Buprenorphine caused no detectable agonist effects or drug "high", but had "good" effects, was "liked" and well tolerated, suggesting that subjects would comply with buprenorphine treatment despite the lack of reinforcing effects. A mild increase in subjective withdrawal symptoms, which was not clinically significant, was seen in association with an increase in saccadic peak velocity on day 2 of the study but no withdrawal occurred on the other days, indicating that the abrupt transfer technique was acceptable. PMID- 26735637 TI - Effects of age, gender, duration of drug use and infection with viral hepatitis B and C on lymphocyte subsets in a population of HIV-negative injecting drug users in Italy. AB - A series of 716 HIV-negative IDUs entering a large drug treatment centre in central Italy was studied to evaluate the pattern of T-lymphocyte subsets among IDUs and to determine the effects of individual variables such as age, gender, duration of drug use and infection with viral hepatitis B and C. To this end, white cell count, total lymphocyte count and absolute number of lymphocyte subsets (i.e. CD3+, CD4+ and CD8+), HBV markers and HCV serology, were determined. For each individual, information on age, gender and duration of drug use was collected. To evaluate the association between level of lymphocyte subsets and phases of HBV infection, participants were stratified into three groups: (A) negative for all markers; (B) HBsAg-positive, with or without HBeAg, and HBsAb-negative; and (C) HBsAg and HBeAg-negative, positive for any other serological marker. The median absolute number of CD3+, CD4+ and CD8+ was 1909, 1080 and 770 cells/mm3, respectively, and did not vary across age bands. The CD8+ count was higher in males than in females. There was a tendency for CD3+ lymphocyte counts (mainly due to CD8+ counts) to be higher in individuals with 6 8 years of drug use compared to those who started injecting 4 years before or less. There was no evidence of increasing counts for a duration of drug use of more than 8 years. With regard to HBV, there was a general tendency for individuals in group "C" to have higher CD3+ and CD8+ counts than those in group "A". Finally, there was no difference in absolute lymphocyte count subsets between HCV-positive and HCV-negative IDUs. In conclusion, demographic and behavioural factors such as long-term heroin use or infection with HCV do not seem to influence the level of lymphocyte subsets among HIV-negative IDUs, nor does the infection with HBV seem to determine dramatic changes in CD4+ counts. PMID- 26735638 TI - Frequency of the A1/A2 alleles of the D2 dopamine receptor (DRD2) gene in a British, Caucasian control group screened to exclude alcoholism and heavy drinking. AB - Recent reports of a genetic association between restriction fragment length polymorphisms at the D2 dopamine receptor locus (DRD2) on chromosome 11q and alcoholism have suggested involvement of the D2 receptor protein in the aetiology of alcoholism, smoking and possibly other disorders. These allelic association findings have been criticized on the basis of the possible confounding of ethnic with disease differences, between allele frequencies of subjects and controls, and the fact that some of the control groups were not screened to exclude alcoholism or heavy drinking. We have observed the frequency of the A1 and A2 alleles in a population of 307 Caucasian British individuals screened for alcohol consumption of less than the UK Royal College of Psychiatrists' recommended sensible drinking limits for males and females and who also failed to qualify for a diagnosis of alcoholism according to the Research Diagnostic Criteria (RDC). The frequency of the A1 allele was found to be 0.20, which is slightly higher than most of the other screened Caucasian control groups from Europe and the United States. The allele and genotype frequencies in our sample are a resource for comparison with samples of alcoholics from the United Kingdom which have been selected on the basis of British ancestry and for residence in London. When we combined our new control data with that of the previous Caucasian control samples we found a significantly higher frequency of A1A1 homozygotes among the unscreened than the screened controls, suggesting that the DRD2 locus may be involved in drinking variation among the general population. PMID- 26735639 TI - Involvement of CNS cholinergic systems in alcohol drinking of P rats. AB - Experiments were undertaken to determine if CNS muscarinic- and nicotinic cholinergic receptors are involved in regulating alcohol drinking of rats from the selectively-bred alcohol-preferring P line. Intracerebroventricular (i.c.v.) drug infusions were administered into the lateral ventricle of female P rats 15 minutes before ethanol access. The muscarinic antagonists pirenzepine and scopolamine were tested on limited access (4 hours/day) to a 10% (v/v) ethanol solution. Food and water were available ad libitum. Nicotine and the nicotinic antagonist mecamylamine were tested on limited access (4 hours/day) to 10% (v/v) ethanol and 0.0125% saccharin solutions. Food was available ad libitum and water was available during the remaining 20 hours. The baseline ethanol intakes ranged between an average of 3.0 +/- 0.3 g/kg/4 hours and 3.4 +/- 0.3 g/kg/4 hours. Administration of 40-100 m g pirenzepine (M1-selective antagonist) had no effect on ethanol, food or water consumption. However, 20-80 m g scopolamine, a non selective muscarinic antagonist, dosedependently decreased ethanol intake as much as 60% (p < 0.05) without altering food or water consumption. The nicotinic antagonist mecamylamine (20-120 m g) did not alter ethanol intake, but nicotine (40-80 m g) dose-dependently decreased ethanol drinking as much as 60% within the first 30 minutes (p < 0.05) without an effect on saccharin intake. The results suggest that: (a), muscarinic receptors, with the possible exception of the M1 subtype, are involved in regulating alcohol drinking and (b), activation of nicotinic receptors can reduce alcohol drinking of the P line of rats. PMID- 26735640 TI - How useful is aminolevulinic acid dehydratase as a marker of recent alcohol intake? AB - Erythroycte delta aminolevulinic acid dehydratase (ALAD) has been suggested as a marker for detecting recent alcohol intake. Unlike other markers, ALAD activity decreases after alcohol intake. Review of the literature suggests that the main interest in this marker is because it increases rapidly after withdrawal. The present study investigated the changes in erythrocyte ALAD and serum gamma glutamyltransferase activities after alcohol withdrawal in 120 alcoholics. Our data showed that ALAD is less sensitive than GGT as an indicator of recent alcohol intake (56% and 84% abnormal, respectively). The increase in ALAD activity was greater between day 12 and 18 after withdrawal (11%) than between day 1 and 12 after withdrawal (5%). There were as many patients returning to normal values 12 and 18 days after withdrawal, for GGT as for ALAD. Thus, our results contradict the claim that ALAD rises rapidly after withdrawal. ALAD shows no advantage over GGT as a marker of recent alcohol intake. PMID- 26735641 TI - Units, mg/l or % CDT for detection of harmful alcohol consumption? AB - Recent studies have demonstrated that the diagnostic performance of CDT measurements is influenced by variations in total transferrin concentration. Improved specificity is obtained with relative values, either %CDT or units CDT per total transferrin concentration. Whether relative or absolute values are used, confirmatory methods by HPLC or IEF should be available, and definition of the CDT values and correlation to HPLC or IEF should be given. PMID- 26735644 TI - Taxonomy, Ecology, and Management of Native and Exotic Fruit Fly Species in Africa. AB - Horticulture is one of the most important agricultural subsectors in Africa, providing income, creating employment opportunities, and enhancing food and nutritional security. However, tephritid fruit flies are responsible for both direct and indirect losses, with alien invasive species often having the most severe ecological and economic impact. In the past 20 years, systematic analysis of tephritids has provided comparative information on taxonomy, synonymy, and character-state differentiation. New molecular techniques are now available for identifying species, reconstructing phylogenies, and studying population genetic structures. Research on biology, host range and shifts, thermotolerance, and demography has provided useful information for developing predictive and ecological niche models to guide management methods. In recent years, the responses of various species to attractants have been documented. Several suppression methods, including the release of coevolved parasitoid species targeting invasives, have been promoted within the context of integrated pest management, leading to improvement in the quality and quantity of fruits and vegetables produced. However, there is still the need for wide-scale availability of these technologies to smallholder growers across Africa. PMID- 26735645 TI - Biology, Ecology, and Management of an Invasive Stink Bug, Bagrada hilaris, in North America. AB - The painted bug, Bagrada hilaris, native to eastern and southern Africa and Asia, was detected in California in 2008, and it has spread rapidly throughout several southwestern US states. A polyphagous insect, it is particularly damaging to the billion dollar cole crop industry. B. hilaris frequently causes damage when it migrates to newly planted crops from weedy hosts. Feeding produces circular or star-shaped chlorotic lesions that become necrotic, and infested plants may be distorted. Currently, no reliable sampling methods for B. hilaris exist, nor are there effective natural enemies in the United States. Therefore, management has relied on multiple applications of insecticides and cultural practices such as removal of weedy hosts, destruction of crop residues, timing of planting, and use of transplants. Several pyrethroid and neonicotinoid insecticides are most effective for controlling the insect. Reliable sampling methods and further development of integrated pest management strategies to manage this invasive pest are urgently needed as its range continues to expand. PMID- 26735647 TI - Follow-up of melanocytic nevi after depilation techniques. PMID- 26735646 TI - Family Ties: The Role of Family Context in Family Health History Communication About Cancer. AB - Family health history about cancer is an important prevention and health promotion tool. Yet few studies have identified family context factors that promote such discussions. We explored relations among family context (cohesion, flexibility, and openness), self-efficacy, and cancer communication (gathering family history, sharing cancer risk information, and frequency) in a diverse group of women enrolled in a randomized control trial. Baseline survey data for 472 women were analyzed. The women's average age was 34 years, 59% identified as Black, 31% had graduated high school, and 75% reported a family history of any cancer. Results showed that greater family cohesion and flexibility were related to higher communication frequency and sharing cancer information. Women who reported greater self-efficacy were more likely to have gathered family history, shared cancer risk information, and communicated more frequently with relatives. Openness was not associated with communication but was related to greater family cohesion and flexibility. Adjusting for demographic variables, self-efficacy, and family cohesion significantly predicted communication frequency. Women with higher self-efficacy were also more likely to have gathered family health history about cancer and shared cancer risk information. Future research may benefit from considering family organization and self-efficacy when developing psychosocial theories that in turn inform cancer prevention interventions. PMID- 26735684 TI - Nanoelectrodes reveal the electrochemistry of single nickelhydroxide nanoparticles. AB - Individual Ni(OH)2 nanoparticles deposited on carbon nanoelectrodes are investigated in non-ensemble measurements with respect to their energy storage properties and electrocatalysis for the oxygen evolution reaction (OER). Charging by oxidation of Ni(OH)2 is limited by the diffusion of protons into the particle bulk and the OER activity is independent of the particle size. PMID- 26735683 TI - Women's Sex-Related Dissociation: The Effects of Alcohol Intoxication, Attentional Control Instructions, and History of Childhood Sexual Abuse. AB - This study examined influences of alcohol intoxication, attentional control, and childhood sexual abuse (CSA) severity on sex-related dissociation. Sex-related dissociation is defined here as dissociation (e.g., feeling as if the world is unreal and feeling disconnected from one's body) during sexual activity or in the presence of sexual stimuli. Women (N = 70) were randomized to a 2 (alcohol condition: none,.10% peak breath alcohol concentration) X 2 (attentional control instructions: none, "relax and maximize" sexual arousal) experiment and exposed to sexual stimuli. Alcohol intoxication was positively associated with sex related dissociation. CSA severity and sex-related dissociation were positively associated in the no-instruction condition but not in the "relax and maximize" condition. For some women, efforts to relax and maximize sexual arousal may buffer the association between CSA and sex-related dissociation. PMID- 26735685 TI - Efficient Temperature-Dependent Green's Functions Methods for Realistic Systems: Compact Grids for Orthogonal Polynomial Transforms. AB - The Matsubara Green's function that is used to describe temperature-dependent behavior is expressed on a numerical grid. While such a grid usually has a couple of hundred points for low-energy model systems, for realistic systems with large basis sets the size of an accurate grid can be tens of thousands of points, constituting a severe computational and memory bottleneck. In this paper, we determine efficient imaginary time grids for the temperature-dependent Matsubara Green's function formalism that can be used for calculations on realistic systems. We show that, because of the use of an orthogonal polynomial transform, we can restrict the imaginary time grid to a few hundred points and reach micro Hartree accuracy in the electronic energy evaluation. Moreover, we show that only a limited number of orthogonal polynomial expansion coefficients are necessary to preserve accuracy when working with a dual representation of the Green's function or self-energy and transforming between the imaginary time and frequency domain. PMID- 26735687 TI - Atomic-Scale Picture of the Composition, Decay, and Oxidation of Two-Dimensional Radioactive Films. AB - Two-dimensional radioactive (125)I monolayers are a recent development that combines the fields of radiochemistry and nanoscience. These Au-supported monolayers show great promise for understanding the local interaction of radiation with 2D molecular layers, offer different directions for surface patterning, and enhance the emission of chemically and biologically relevant low energy electrons. However, the elemental composition of these monolayers is in constant flux due to the nuclear transmutation of (125)I to (125)Te, and their precise composition and stability under ambient conditions has yet to be elucidated. Unlike I, which is stable and unreactive when bound to Au, the newly formed Te atoms would be expected to be more reactive. We have used electron emission and X-ray photoelectron spectroscopy (XPS) to quantify the emitted electron energies and to track the film composition in vacuum and the effect of exposure to ambient conditions. Our results reveal that the Auger electrons emitted during the ultrafast radioactive decay process have a kinetic energy corresponding to neutral Te. By combining XPS and scanning tunneling microscopy experiments with density functional theory, we are able to identify the reaction of newly formed Te to TeO2 and its subsequent dimerization. The fact that the Te2O4 units stay intact during major lateral rearrangement of the monolayer illustrates their stability. These results provide an atomic-scale picture of the composition and mobility of surface species in a radioactive monolayer as well as an understanding of the stability of the films under ambient conditions, which is a critical aspect in their future applications. PMID- 26735686 TI - Conversion from Tacrolimus to Cyclosporine A Improves Glucose Tolerance in HCV Positive Renal Transplant Recipients. AB - BACKGROUND: Calcineurin-inhibitors and hepatitis C virus (HCV) infection increase the risk of post-transplant diabetes mellitus. Chronic HCV infection promotes insulin resistance rather than beta-cell dysfunction. The objective was to elucidate whether a conversion from tacrolimus to cyclosporine A affects fasting and/or dynamic insulin sensitivity, insulin secretion or all in HCV-positive renal transplant recipients. METHODS: In this prospective, single-center study 10 HCV-positive renal transplant recipients underwent 2h-75g-oral glucose tolerance tests before and three months after the conversion of immunosuppression from tacrolimus to cyclosporine A. Established oral glucose tolerance test-based parameters of fasting and dynamic insulin sensitivity and insulin secretion were calculated. Data are expressed as median (IQR). RESULTS: After conversion, both fasting and challenged glucose levels decreased significantly. This was mainly attributable to a significant amelioration of post-prandial dynamic glucose sensitivity as measured by the oral glucose sensitivity-index OGIS [422.17 (370.82-441.92) vs. 468.80 (414.27-488.57) mL/min/m2, p = 0.005), which also resulted in significant improvements of the disposition index (p = 0.017) and adaptation index (p = 0.017) as markers of overall glucose tolerance and beta cell function. Fasting insulin sensitivity (p = 0.721), insulinogenic index as marker of first-phase insulin secretion [0.064 (0.032-0.106) vs. 0.083 (0.054 0.144) nmol/mmol, p = 0.093) and hepatic insulin extraction (p = 0.646) remained unaltered. No changes of plasma HCV-RNA levels (p = 0.285) or liver stiffness (hepatic fibrosis and necroinflammation, p = 0.463) were observed after the conversion of immunosuppression. CONCLUSIONS: HCV-positive renal transplant recipients show significantly improved glucose-stimulated insulin sensitivity and overall glucose tolerance after conversion from tacrolimus to cyclosporine A. Considering the HCV-induced insulin resistance, HCV-positive renal transplant recipients may benefit from a cyclosporine A-based immunosuppressive regimen. TRIAL REGISTRATION: ClinicalTrials.gov NCT02108301. PMID- 26735688 TI - Spatial Biodiversity Patterns of Madagascar's Amphibians and Reptiles. AB - Madagascar has become a model region for testing hypotheses of species diversification and biogeography, and many studies have focused on its diverse and highly endemic herpetofauna. Here we combine species distribution models of a near-complete set of species of reptiles and amphibians known from the island with body size data and a tabulation of herpetofaunal communities from field surveys, compiled up to 2008. Though taxonomic revisions and novel distributional records arose since compilation, we are confident that the data are appropriate for inferring and comparing biogeographic patterns among these groups of organisms. We observed species richness of both amphibians and reptiles was highest in the humid rainforest biome of eastern Madagascar, but reptiles also show areas of high richness in the dry and subarid western biomes. In several amphibian subclades, especially within the Mantellidae, species richness peaks in the central eastern geographic regions while in reptiles different subclades differ distinctly in their richness centers. A high proportion of clades and subclades of both amphibians and reptiles have a peak of local endemism in the topographically and bioclimatically diverse northern geographic regions. This northern area is roughly delimited by a diagonal spanning from 15.5 degrees S on the east coast to ca. 15.0 degrees S on the west coast. Amphibian diversity is highest at altitudes between 800-1200 m above sea-level whereas reptiles have their highest richness at low elevations, probably reflecting the comparatively large number of species specialized to the extended low-elevation areas in the dry and subarid biomes. We found that the range sizes of both amphibians and reptiles strongly correlated with body size, and differences between the two groups are explained by the larger body sizes of reptiles. However, snakes have larger range sizes than lizards which cannot be readily explained by their larger body sizes alone. Range filling, i.e., the amount of suitable habitat occupied by a species, is less expressed in amphibians than in reptiles, possibly reflecting their lower dispersal capacity. Taxonomic composition of communities assessed by field surveys is largely explained by bioclimatic regions, with communities from the dry and especially subarid biomes distinctly differing from humid and subhumid biomes. PMID- 26735689 TI - Do Amplitudes of Water Level Fluctuations Affect the Growth and Community Structure of Submerged Macrophytes? AB - Submerged macrophytes are subjected to potential mechanical stresses associated with fluctuating water levels in natural conditions. However, few experimental studies have been conducted to further understand the effects of water level fluctuating amplitude on submerged macrophyte species and their assemblages or communities. We designed a controlled experiment to investigate the responses of three submerged macrophyte species (Hydrilla verticillata, Ceratophyllum demersum and Elodea nuttallii) and their combinations in communities to three amplitudes (static, +/- 30 cm, +/- 60 cm) of water level fluctuations. Results showed that water level fluctuating amplitude had little effects on the community performance and the three tested species responded differently. H. verticillata exhibited more growth in static water and it was negatively affected by either of the water level fluctuations amplitude, however, growth parameters of H. verticillata in two fluctuating water level treatments (i.e., +/- 30 cm, +/- 60 cm) were not significantly different. On the other hand, the growth of C. demersum was not significantly correlated with different amplitude treatments. However, it became more abundant when water levels fluctuated. E. nuttallii was inhibited by the two fluctuating water level treatments, and was less in growth parameters compared to the other species especially in water level fluctuating conditions. The inherent differences in the adaptive capabilities of the tested species indicate that C. demersum or other species with similar responses may be dominant species to restore submerged macrophyte communities with great fluctuating water levels. Otherwise, H. verticillata, E. nuttallii or other species with similar responses could be considered for constructing the community in static water conditions. PMID- 26735692 TI - Correction: IBR5 Modulates Temperature-Dependent, R Protein CHS3-Mediated Defense Responses in Arabidopsis. AB - [This corrects the article DOI: 10.1371/journal.pgen.1005584.]. PMID- 26735690 TI - Interferon Alpha Signalling and Its Relevance for the Upregulatory Effect of Transporter Proteins Associated with Antigen Processing (TAP) in Patients with Malignant Melanoma. AB - INTRODUCTION: Interferon alpha (IFNalpha) is routinely used in the clinical practice for adjuvant systemic melanoma therapy. Understanding the molecular mechanism of IFNalpha effects and prediction of response in the IFNalpha therapy regime allows initiation and continuation of IFNalpha treatment for responder and exclusion of non-responder to avoid therapy inefficacy and side-effects. The transporter protein associated with antigen processing-1 (TAP1) is part of the MHC class I peptide-loading complex, and important for antigen presentation in tumor and antigen presenting cells. In the context of personalized medicine, we address this potential biomarker TAP1 as a target of IFNalpha signalling. RESULTS: We could show that IFNalpha upregulates TAP1 expression in peripheral blood mononuclear cells (PBMCs) of patients with malignant melanoma receiving adjuvant high-dose immunotherapy. IFNalpha also induced expression of TAP1 in mouse blood and tumor tissue and suppressed the formation of melanoma metastasis in an in vivo B16 tumor model. Besides its expression, TAP binding affinity and transport activity is induced by IFNalpha in human monocytic THP1 cells. Furthermore, our data revealed that IFNalpha clearly activates phosphorylation of STAT1 and STAT3 in THP1 and A375 melanoma cells. Inhibition of Janus kinases abrogates the IFNalpha-induced TAP1 expression. These results suggest that the JAK/STAT pathway is a crucial mediator for TAP1 expression elicited by IFNalpha treatment. CONCLUSION: We suppose that silencing of TAP1 expression provides tumor cells with a mechanism to escape cytotoxic T-lymphocyte recognition. The observed benefit of IFNalpha treatment could be mediated by the shown dual effect of TAP1 upregulation in antigen presenting cells on the one hand, and of TAP1 upregulation in 'silent' metastatic melanoma cells on the other hand. In conclusion, this work contributes to a better understanding of the mode of action of IFNalpha which is essential to identify markers to predict, assess and monitor therapeutic response of IFNalpha treatment in the future. PMID- 26735691 TI - Validation of a Low-Cost Paper-Based Screening Test for Sickle Cell Anemia. AB - BACKGROUND: The high childhood mortality and life-long complications associated with sickle cell anemia (SCA) in developing countries could be significantly reduced with effective prophylaxis and education if SCA is diagnosed early in life. However, conventional laboratory methods used for diagnosing SCA remain prohibitively expensive and impractical in this setting. This study describes the clinical validation of a low-cost paper-based test for SCA that can accurately identify sickle trait carriers (HbAS) and individuals with SCA (HbSS) among adults and children over 1 year of age. METHODS AND FINDINGS: In a population of healthy volunteers and SCA patients in the United States (n = 55) the test identified individuals whose blood contained any HbS (HbAS and HbSS) with 100% sensitivity and 100% specificity for both visual evaluation and automated analysis, and detected SCA (HbSS) with 93% sensitivity and 94% specificity for visual evaluation and 100% sensitivity and 97% specificity for automated analysis. In a population of post-partum women (with a previously unknown SCA status) at a primary obstetric hospital in Cabinda, Angola (n = 226) the test identified sickle cell trait carriers with 94% sensitivity and 97% specificity using visual evaluation (none of the women had SCA). Notably, our test permits instrument- and electricity-free visual diagnostics, requires minimal training to be performed, can be completed within 30 minutes, and costs about $0.07 in test specific consumable materials. CONCLUSIONS: Our results validate the paper-based SCA test as a useful low-cost tool for screening adults and children for sickle trait and disease and demonstrate its practicality in resource-limited clinical settings. PMID- 26735693 TI - Lyn Delivers Bacteria to Lysosomes for Eradication through TLR2-Initiated Autophagy Related Phagocytosis. AB - Extracellular bacteria, such as Pseudomonas aeruginosa and Klebsiella pneumoniae, have been reported to induce autophagy; however, the role and machinery of infection-induced autophagy remain elusive. We show that the pleiotropic Src kinase Lyn mediates phagocytosis and autophagosome maturation in alveolar macrophages (AM), which facilitates eventual bacterial eradication. We report that Lyn is required for bacterial infection-induced recruitment of autophagic components to pathogen-containing phagosomes. When we blocked autophagy with 3 methyladenine (3-MA) or by depleting Lyn, we observed less phagocytosis and subsequent bacterial clearance by AM. Both morphological and biological evidence demonstrated that Lyn delivered bacteria to lysosomes through xenophagy. TLR2 initiated the phagocytic process and activated Lyn following infection. Cytoskeletal trafficking proteins, such as Rab5 and Rab7, critically facilitated early phagosome formation, autophagosome maturation, and eventual autophagy mediated bacterial degradation. These findings reveal that Lyn, TLR2 and Rab modulate autophagy related phagocytosis and augment bactericidal activity, which may offer insight into novel therapeutic strategies to control lung infection. PMID- 26735694 TI - Molecular Epidemiology of Methicillin-Resistant Staphylococcus aureus Isolated from Australian Veterinarians. AB - This work investigated the molecular epidemiology and antimicrobial resistance of methicillin-resistant Staphylococcus aureus (MRSA) isolated from veterinarians in Australia in 2009. The collection (n = 44) was subjected to extensive molecular typing (MLST, spa, SCCmec, dru, PFGE, virulence and antimicrobial resistance genotyping) and antimicrobial resistance phenotyping by disk diffusion. MRSA was isolated from Australian veterinarians representing various occupational emphases. The isolate collection was dominated by MRSA strains belonging to clonal complex (CC) 8 and multilocus sequence type (ST) 22. CC8 MRSA (ST8-IV [2B], spa t064; and ST612-IV [2B], spa variable,) were strongly associated with equine practice veterinarians (OR = 17.5, 95% CI = 3.3-92.5, P < 0.001) and were often resistant to gentamicin and rifampicin. ST22-IV [2B], spa variable, were strongly associated with companion animal practice veterinarians (OR = 52.5, 95% CI = 5.2-532.7, P < 0.001) and were resistant to ciprofloxacin. A single pig practice veterinarian carried ST398-V [5C2], spa t1451. Equine practice and companion animal practice veterinarians frequently carried multiresistant-CC8 and ST22 MRSA, respectively, whereas only a single swine specialist carried MRSA ST398. The presence of these strains in veterinarians may be associated with specific antimicrobial administration practices in each animal species. PMID- 26735695 TI - A Comparative Study of Lipid-Lowering Effects of Guggul and Atorvastatin Monotherapy in Comparison to Their Combination in High Cholesterol Diet-Induced Hyperlipidemia in Rabbits. AB - BACKGROUND: Hypolipidemic activity of gugulipid has been widely described in traditional literature. OBJECTIVE: This study was done to evaluate hypolipidemic activity of guggul and atorvaststin monotherapy in comparison to their combination in rabbits. MATERIALS AND METHODS: Male New Zealand White rabbits (body weight 1.3-1.8 kg and age 8-10 weeks) were made hyperlipidemic by feeding cholesterol (0.5 g/kg) for three weeks and randomly divided into a control and three treatment groups receiving: atorvastatin (3.7 mg/kg), guggul (3.5 mg/kg) and their combination (same dose) for the next three weeks. Body weight measurements, estimation of serum lipid profile were done at the beginning, after three and six weeks, respectively. Histopathological examination of liver, heart and aorta was done after six weeks. Statistical analysis was done with SPSS version 16.0 using one-way and repeated measures analysis of variance (ANOVA) followed by post-hoc multiple comparison test with two tailed P value < 0.05 as significant. RESULTS: All treated groups had significant reduction in cholesterol, triglyceride, low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) in comparison to pre-treatment values and control group, and had significant increase in high-density lipoprotein (HDL) in comparison to pre treatment values. CONCLUSION: Combination of atorvastatin and guggul was comparable to their monotherapies in improving lipid profile. PMID- 26735696 TI - The Ecological Dynamics of Fecal Contamination and Salmonella Typhi and Salmonella Paratyphi A in Municipal Kathmandu Drinking Water. AB - One of the UN sustainable development goals is to achieve universal access to safe and affordable drinking water by 2030. It is locations like Kathmandu, Nepal, a densely populated city in South Asia with endemic typhoid fever, where this goal is most pertinent. Aiming to understand the public health implications of water quality in Kathmandu we subjected weekly water samples from 10 sources for one year to a range of chemical and bacteriological analyses. We additionally aimed to detect the etiological agents of typhoid fever and longitudinally assess microbial diversity by 16S rRNA gene surveying. We found that the majority of water sources exhibited chemical and bacterial contamination exceeding WHO guidelines. Further analysis of the chemical and bacterial data indicated site specific pollution, symptomatic of highly localized fecal contamination. Rainfall was found to be a key driver of this fecal contamination, correlating with nitrates and evidence of S. Typhi and S. Paratyphi A, for which DNA was detectable in 333 (77%) and 303 (70%) of 432 water samples, respectively. 16S rRNA gene surveying outlined a spectrum of fecal bacteria in the contaminated water, forming complex communities again displaying location-specific temporal signatures. Our data signify that the municipal water in Kathmandu is a predominant vehicle for the transmission of S. Typhi and S. Paratyphi A. This study represents the first extensive spatiotemporal investigation of water pollution in an endemic typhoid fever setting and implicates highly localized human waste as the major contributor to poor water quality in the Kathmandu Valley. PMID- 26735699 TI - Women's perspectives toward menopause: A phenomenological study in Iran. AB - This study explores the attitude and feelings toward menopause among Azeri menopausal women using hermeneutic phenomenology based on Van Manen's approach. A total of 18 menopausal women who were attended in urban health centers of Tabriz, Iran, were recruited using a purposive sampling method. Data were gathered through semistructured interviews. Each interview was transcribed verbatim and analyzed simultaneously. Data analysis led to the emergence of five main themes: positive attitude, neutral attitude, negative attitude, positive feelings, and negative feelings. Participants had different feelings and attitude. Acceptance of menopause as a natural process helps women to have a neutral attitude toward menopause. PMID- 26735701 TI - Spatial synchronization of visual stimulus-evoked gamma frequency oscillations in the rat superior colliculus. AB - In the superior colliculus, visual stimuli can induce gamma frequency oscillations of neuronal activity. It has been shown that in cats, these oscillations are synchronized over distances of greater than 300 MUm that may contribute toward visual information processing. We investigated the spatial properties of such oscillations in a rodent because the availability of molecular tools could enable future studies on the role of these oscillations in visual information processing. Using extracellular electrode array recordings in anesthetized rats, we found that visual stimuli-induced gamma and eta frequency (30-115 Hz) oscillations of the local field potential that were synchronized over distances of ~ 600 MUm. Multiple-unit events were phase locked to the local field potential signal and showed prominent oscillations during OFF responses. The rate of lower than 5 ms cross-electrode coincidences was in line with the response corrected predictions for each electrode. These data suggest that the synchronized superior colliculus neuronal activity is largely network driven, whereas common synaptic inputs play a minor role. PMID- 26735700 TI - Sequential Morphological Changes in the CNV Net after Intravitreal Anti-VEGF Evaluated with OCT Angiography. AB - PURPOSE: To assess and describe sequential morphological changes in the choroidal neovascularization (CNV) net using optical coherence tomography angiography (OCTA) in patients undergoing treatment with intravitreal antivascular endothelial growth factor (VEGF). METHODS: Prospective cohort study. OCTA was performed sequentially: before (t0), 1 h (t1), 1 week (t2) and 1 month after the injection (t3), using Avanti RTVue XR equipped with the AngioVue(r) software (Optovue, Calif., USA). All images were classified by two independent graders. RESULTS: Ten eyes of 10 patients, with a mean age of 72.4 +/- 10.5 years, were included. CNV morphology was described as tree-like in 5 eyes, glomerular in 1 and fragmented in 4. A fibrovascular capsule surrounding the CNV net was found in 4 eyes and a feeder trunk was noticed in 6. No changes were observed at t1. Loss of peripheral capillaries, vessel fragmentation and decreased vessel density were evident in 8 eyes at t2. The CNV capillary density and the peripheral anastomosis increased in all of these at t3. Two eyes remained unchanged through the whole length of follow-up. CONCLUSIONS: Significant changes in the CNV net can be observable in OCTA at least 1 week after intravitreal anti-VEGF. The safety of frequent examinations may provide a method of gauging treatment effects. PMID- 26735698 TI - Genomics of Immune Diseases and New Therapies. AB - Genomic DNA sequencing technologies have been one of the great advances of the 21st century, having decreased in cost by seven orders of magnitude and opening up new fields of investigation throughout research and clinical medicine. Genomics coupled with biochemical investigation has allowed the molecular definition of a growing number of new genetic diseases that reveal new concepts of immune regulation. Also, defining the genetic pathogenesis of these diseases has led to improved diagnosis, prognosis, genetic counseling, and, most importantly, new therapies. We highlight the investigational journey from patient phenotype to treatment using the newly defined XMEN disease, caused by the genetic loss of the MAGT1 magnesium transporter, as an example. This disease illustrates how genomics yields new fundamental immunoregulatory insights as well as how research genomics is integrated into clinical immunology. At the end, we discuss two other recently described diseases, CHAI/LATAIE (CTLA-4 deficiency) and PASLI (PI3K dysregulation), as additional examples of the journey from unknown immunological diseases to new precision medicine treatments using genomics. PMID- 26735697 TI - Transcriptional Control of Dendritic Cell Development. AB - The dendritic cells (DCs) of the immune system function in innate and adaptive responses by directing activity of various effector cells rather than serving as effectors themselves. DCs and closely related myeloid lineages share expression of many surface receptors, presenting a challenge in distinguishing their unique in vivo functions. Recent work has taken advantage of unique transcriptional programs to identify and manipulate murine DCs in vivo. This work has assigned several nonredundant in vivo functions to distinct DC lineages, consisting of plasmacytoid DCs and several subsets of classical DCs that promote different immune effector modules in response to pathogens. In parallel, a correspondence between human and murine DC subsets has emerged, underlying structural similarities for the DC lineages between these species. Recent work has begun to unravel the transcriptional circuitry that controls the development and diversification of DCs from common progenitors in the bone marrow. PMID- 26735702 TI - Dabigatran deliberate overdose: two cases and suggestions for laboratory monitoring. AB - CONTEXT: Dabigatran etexilate (dabigatran) is a direct thrombin inhibitor anticoagulant agent. There is limited information about the changes in coagulation profile and outcomes in overdose. A monoclonal antibody has been developed to neutralize the anticoagulant effect of dabigatran. Case reports describe enhanced clearance of dabigatran by haemodialysis as an intervention to prevent haemorrhagic complications - however, the threshold for initiating haemodialysis is not well defined in an asymptomatic patient with normal renal function. CASE DETAILS: Two patients presented following deliberate dabigatran overdoses. A 55-year-old woman ingested 10 * 150 mg dabigatran. A 21-year-old woman with a history of systemic lupus erythematosus and pulmonary embolus ingested 100 * 110 mg dabigatran. Both were admitted to the intensive care unit and managed expectantly. Serial coagulation tests normalized over 60 h. The half life of dabigatran was not prolonged following overdose, being calculated between 7 and 11 h in each case. There was positive correlation between international normalized ratio (INR), prothrombin time (PT) and activated partial thromboplastin time (aPTT) with plasma dabigatran levels. CONCLUSION: There is limited experience with dabigatran overdoses. Normal aPTT, PT and INR assays 12 h following deliberate ingestion indicate that the drug concentration is not high. Individual risk assessment of bleeding risk needs to be formulated for each patient and expectant management is reasonable in the presence of normal renal function and absent risk factors for bleeding. PMID- 26735703 TI - Management of Pediatric Supracondylar Humerus Fractures With Vascular Injury. AB - The American Academy of Orthopaedic Surgeons has developed the Appropriate Use Criteria (AUC) document Management of Pediatric Supracondylar Humerus Fractures With Vascular Injury. Evidence-based information, in conjunction with the clinical expertise of physicians, was used to develop the criteria to improve patient care and obtain the best outcomes while considering the subtleties and distinctions necessary in making clinical decisions. The AUC clinical patient scenarios were derived from patient indications that generally accompany a pediatric supracondylar humerus fracture with vascular injury, as well as from current evidence-based clinical practice guidelines and supporting literature. The 6 patient scenarios and 18 treatments were developed by the Writing Panel, a group of clinicians who are specialists in this AUC topic. Next, the Review Panel, a separate group of volunteer physicians, independently reviewed these materials to ensure that they were representative of patient scenarios that clinicians are likely to encounter in daily practice. Finally, the multidisciplinary Voting Panel (made up of specialists and nonspecialists) rated the appropriateness of treatment of each patient scenario using a 9-point scale to designate a treatment as Appropriate (median rating, 7 to 9), May Be Appropriate (median rating, 4 to 6), or Rarely Appropriate (median rating, 1 to 3). PMID- 26735704 TI - Vitamin D levels in white coat and sustained hypertension. AB - OBJECTIVE: The plasma levels of vitamin D in patients with white coat hypertension (WCHT) have not been studied previously. The aim of this study was to evaluate vitamin D levels in WCHT and compare with sustained hypertension (SHT) and with normotension (NT). PATIENTS AND METHODS: Fifty-three normotensive, 42 WCHT, and 59 SHT patients were recruited in this study. The participants were matched for age, sex, and BMI. The vitamin D levels were determined using the electrochemiluminescence immunoassay method. RESULTS: Plasma vitamin D levels were significantly lower in SHT than in the WCHT and NT groups (26.4+/-4.9, 34.3+/-3.6, and 36+/-5 ng/ml, respectively), and were similar in the WCHT and NT groups. There was a negative correlation between vitamin D levels and blood pressure parameters such as clinic systolic blood pressure (SBP), clinic diastolic blood pressure (DBP), 24-h SBP, 24-h DBP, daytime SBP, daytime DBP, night-time SBP, and night-time DBP (r=-0.554, -0.419, -0.629, -0.427, -0.559, 0.534, -0.607, -0.462, respectively, and all P<0.001) in the entire study group. Clinic SBP (B+/-SE=-0.97+/-0.037, P=0.009) and 24-h SBP (B+/-SE=-0.138+/-0.055, P=0.013) were identified as predictors for vitamin D levels in the entire study group. CONCLUSION: Our data show that sustained hypertensive patients have lower vitamin D levels than white coat hypertensive and normotensive individuals. White coat hypertensive patients without other cardiovascular risk factors have higher vitamin D levels than sustained hypertensive patients, suggesting that they have a lower cardiovascular risk. PMID- 26735705 TI - Asynchronous detection of kinesthetic attention during mobilization of lower limbs using EEG measurements. AB - OBJECTIVE: Attention is known to modulate the plasticity of the motor cortex, and plasticity is crucial for recovery in motor rehabilitation. This study addresses the possibility of using an EEG-based brain-computer interface (BCI) to detect kinesthetic attention to movement. APPROACH: A novel experiment emulating physical rehabilitation was designed to study kinesthetic attention. The protocol involved continuous mobilization of lower limbs during which participants reported levels of attention to movement-from focused kinesthetic attention to mind wandering. For this protocol an asynchronous BCI detector of kinesthetic attention and deliberate mind wandering was designed. MAIN RESULTS: EEG analysis showed significant differences in theta, alpha, and beta bands, related to the attentional state. These changes were further pinpointed to bands relative to the frequency of the individual alpha peak. The accuracy of the designed BCI ranged between 60.8% and 68.4% (significantly above chance level), depending on the used analysis window length, i.e. acceptable detection delay. SIGNIFICANCE: This study shows it is possible to use self-reporting to study attention-related changes in EEG during continuous mobilization. Such a protocol is used to develop an asynchronous BCI detector of kinesthetic attention, with potential applications to motor rehabilitation. PMID- 26735706 TI - Photosensitivity in a patient with C9orf72 repeat expansion. AB - The phenotype of C9ORF72 repeat expansions is rapidly expanding. Originally found to be the major genetic cause of familial frontotemporal dementia with amyotrophic lateral sclerosis, several other clinical characteristics have been described more recently. Here, we report on a family diagnosed with 'degenerative schizophrenia' and harbouring a C9ORF72 repeat expansion, in which at least the index patient and an uncle showed a photoparoxysmal response during electroencephalography. Whereas epilepsy has been described in several repeat expansion disorders, photosensitivity has thus far only been reported in dentatorubral-pallidoluysian atrophy. The photoparoxysmal response may therefore be a new clinical feature of C9ORF72 repeat expansion related disease. Our observation learns that a repeat expansion disorder like C9ORF72 should be considered in patients with a combination of young-onset dementia, psychiatric symptoms and/or photosensitive epilepsy. We advocate the occasional use of EEG in the dementia workup and in particular urge to consider provocative tests such as photic stimulation. PMID- 26735707 TI - Prevalence and correlates of bullying perpetration and victimization among school aged youth with intellectual disabilities: A systematic review. AB - Recent literature reviews show that bullying perpetration and victimization are major public health concerns for typically developing (TD) youth. Nevertheless, the magnitude of this phenomenon among youth with intellectual disabilities (ID) remains unclear. Therefore, the purpose of this review is to provide a synthesis of the empirical studies examining the prevalence and correlates of bullying perpetration and victimization among youth with ID. A systematic literature search was performed and 11 studies met the inclusion criteria. The findings from these studies showed weighted mean prevalence rates of general bullying perpetration, bullying victimization and both of 15.1%, 36.3%, and 25.2%, respectively. Weighted mean prevalence rates of bullying perpetration and victimization differed according to the characteristics of the studies (e.g., assessment context, school setting, information source, type of measures, time frame). Additionally, high weighted mean prevalence rates of physical (33.3%), verbal (50.2%), relational (37.4%), and cyber (38.3%) victimization were found among youth with ID. When youth with ID were compared to youth with other disabilities or TD peers, no clear differences were found. Finally, the present review shows that correlates of bullying perpetration and victimization in this population remain understudied. PMID- 26735708 TI - Differences in autonomic functions as related to induced stress between children with and without cerebral palsy while performing a virtual meal-making task. AB - BACKGROUND: Efforts to improve the participation and performance of children with cerebral palsy (CP) are often related to the adaptation of environmental conditions to meet their cognitive and motor abilities. However, the influence of affective stimuli within the environment on emotion and performance, and their ability to improve or impede the children's participation has not been investigated in any systematic way although the emerging evidence suggests that it affects the individuals in many levels. OBJECTIVES: (1) To measure autonomic responses to affective stimuli during a simulated Meal-Maker task in children with CP in comparison to children who are typically developing, and (2) to examine the interactions between autonomic functions, subjective reports of stress, and task performance among children with and without CP. METHODS: Fifteen children with CP and 19 typically developing peers (6 to 12 years) participated. After completing behavioral questionnaires (e.g., State and Trait Anxiety Inventories), children prepared meals within a camera tracking virtual Meal-Maker environment. Either a negative, positive, or neutral visual stimulus was displayed, selected from the International Affective Picture System. Children also passively viewed the same pictures while rating their valence and arousal levels. Heart rate (HR) and skin conductance were recorded synchronously with stimulus onset. RESULTS: Significant differences in autonomic functions were found between groups, i.e., a higher "low frequency" to "high frequency" (LF:HF) ratio in the children with CP during the meals associated with a negative stimulus (p=0.011). Only children with CP had significant positive correlations between trait anxiety and LF:HF ratio during virtual meal-making associated with positive (p=0.049) and negative stimuli (p=0.003) but not during neutral stimuli. For children with CP the amplitude of skin conductance response during passive picture viewing was significantly higher for negative than for positive stimuli (p=0.017) but there were no significant changes in autonomic responses during virtual Meal-Maker task. Significant correlations between trait anxiety, autonomic activity during the calm state and Meal-Maker performance outcomes were found only for children with CP. CONCLUSIONS: In general, the Meal-Maker virtual environment was shown to be a feasible platform for the investigation of the effect of emotionally loaded stimuli on the balance of autonomic functions in children with and without CP. Anxiety level appears to play a significant role in children with CP and should be considered as a potentially important factor during clinical evaluation and intervention. Further studies are needed to develop additional measurements of emotional responses and to refine the types of affective interference. PMID- 26735709 TI - Cytoarchitecture and probability maps of the human medial orbitofrontal cortex. AB - Previous architectonical studies of human orbitofrontal cortex (OFC) provided divergent maps regarding number, location, and extent of areas. To solve this controversy, an observer-independent cytoarchitectonical mapping of medial OFC (mOFC) was performed. Borders of cortical areas were detected in histological sections of ten human post-mortem brains using a quantitative, statistically testable method, and their stereotaxic localization and intersubject variability were determined. Three areas were identified: granular Fo1 mainly on the rostral Gyrus rectus and medial of the olfactory sulcus; granular to dysgranular Fo2, mainly on the posterior part of the ventromedial Gyrus rectus and the medial and lateral banks of the olfactory sulcus; granular Fo3 between the olfactory and medial or intermediate orbital sulci. Fo3 was bordered medially by Fo1 and Fo2 and laterally by the lateral OFC (lOFC). A cluster analysis of the cytoarchitectonical features of Fo1-Fo3, subgenual cingulate areas, BA12, lateral and medial areas of the frontopolar cortex, lOFC and areas of Broca's region demonstrated the cytoarchitectonical similarity between the mOFC areas in contrast to all other frontal areas. Probabilistic maps of mOFC areas show a considerable intersubject variability in extent and position in stereotaxic space, and provide spatial templates for anatomical localization of in vivo neuroimaging data via the JuBrain atlas and the Anatomy Toolbox. PMID- 26735710 TI - Simultaneous quantification of cardiovascular disease related metabolic risk factors using liquid chromatography tandem mass spectrometry in human serum. AB - Recent observations from metabonomic studies have consistently found that branched-chain amino acids (BCAAs), aromatic amino acids (AAAs), glutamine (Gln), glutamic acid (Glu), Gln/Glu ratio, carnitine, and several species of acylcarnitines and lysophosphatidylcholines (LPCs) are possible risk factors for metabolic diseases such as diabetes mellitus (DM) and cardiovascular diseases (CVD). We described here a simple and reliable method for simultaneous quantification of these metabolic risk factors by liquid chromatography tandem mass spectrometry (LC-MS/MS). Serum samples were extracted with isopropanol, and the extracted metabolites were separated by hydrophilic interaction liquid chromatography (HILIC) and detected with electrospary ionization (ESI) inpositive ion mode with multiple reaction monitor (MRM) mode. All the metabolites were effectively separated within 5.5min. Analytical recoveries were in the range of 92.8-106.9%, with an average of 100.6%. The intra- run and total imprecisions for the measurement of these metabolites were 1.2-3.8% and 1.5-7.4%, respectively. Serum concentrations of the metabolites were analyzed in 123 apparently healthy volunteers. Significant associations between the metabolites and traditional CVD risk factors were observed. The newly developed LC-MS/MS method was simple, precise, and accurate and can be used as an efficient tool in CVD research and studies. PMID- 26735712 TI - Job Performance as Multivariate Dynamic Criteria: Experience Sampling and Multiway Component Analysis. AB - Questions about the dynamic processes that drive behavior at work have been the focus of increasing attention in recent years. Models describing behavior at work and research on momentary behavior indicate that substantial variation exists within individuals. This article examines the rationale behind this body of work and explores a method of analyzing momentary work behavior using experience sampling methods. The article also examines a previously unused set of methods for analyzing data produced by experience sampling. These methods are known collectively as multiway component analysis. Two archetypal techniques of multimode factor analysis, the Parallel factor analysis and the Tucker3 models, are used to analyze data from Miner, Glomb, and Hulin's (2010) experience sampling study of work behavior. The efficacy of these techniques for analyzing experience sampling data is discussed as are the substantive multimode component models obtained. PMID- 26735711 TI - Characterization of odor-active compounds of various Chrysanthemum essential oils by gas chromatography-olfactometry, gas chromatography-mass spectrometry and their correlation with sensory attributes. AB - Volatiles of five kinds of Chrysanthemum essential oils with different manufactures were characterized by descriptive sensory analysis, gas chromatography-olfactometry (GC-O), gas chromatography-mass spectrometry (GC-MS) and statistics analysis. Six sensory attributes (floral, woody, grassy, fruity, sour and minty) were selected to assess Chrysanthemum essential oils. A total of 38 volatile compounds were detected and quantified using standard substances by GC-O and GC-MS. Terpenes constituted the largest chemical group among the volatiles of the essential oils. Then partial least squares regression (PLSR) was used to elucidate the relationship between sensory attributes and aroma compounds. The result showed that alpha-pinene, beta-thujene, alpha-terpinolen, beta-cubebene, caryophyllene, (Z)beta-farnesene, (-)-spathulenol, linalool, camphor, camphene, 4-terpineol, Z-citral and 4-isopropyltoluene were typical aroma compounds covaried with characteristic aroma of Chrysanthemum essential oils. PMID- 26735713 TI - Quantifying and Testing Indirect Effects in Simple Mediation Models When the Constituent Paths Are Nonlinear. AB - Most treatments of indirect effects and mediation in the statistical methods literature and the corresponding methods used by behavioral scientists have assumed linear relationships between variables in the causal system. Here we describe and extend a method first introduced by Stolzenberg (1980) for estimating indirect effects in models of mediators and outcomes that are nonlinear functions but linear in their parameters. We introduce the concept of the instantaneous indirect effect of X on Y through M and illustrate its computation and describe a bootstrapping procedure for inference. Mplus code as well as SPSS and SAS macros are provided to facilitate the adoption of this approach and ease the computational burden on the researcher. PMID- 26735714 TI - Assessing Mediational Models: Testing and Interval Estimation for Indirect Effects. AB - Theoretical models specifying indirect or mediated effects are common in the social sciences. An indirect effect exists when an independent variable's influence on the dependent variable is mediated through an intervening variable. Classic approaches to assessing such mediational hypotheses ( Baron & Kenny, 1986 ; Sobel, 1982 ) have in recent years been supplemented by computationally intensive methods such as bootstrapping, the distribution of the product methods, and hierarchical Bayesian Markov chain Monte Carlo (MCMC) methods. These different approaches for assessing mediation are illustrated using data from Dunn, Biesanz, Human, and Finn (2007). However, little is known about how these methods perform relative to each other, particularly in more challenging situations, such as with data that are incomplete and/or nonnormal. This article presents an extensive Monte Carlo simulation evaluating a host of approaches for assessing mediation. We examine Type I error rates, power, and coverage. We study normal and nonnormal data as well as complete and incomplete data. In addition, we adapt a method, recently proposed in statistical literature, that does not rely on confidence intervals (CIs) to test the null hypothesis of no indirect effect. The results suggest that the new inferential method-the partial posterior p value-slightly outperforms existing ones in terms of maintaining Type I error rates while maximizing power, especially with incomplete data. Among confidence interval approaches, the bias-corrected accelerated (BC a ) bootstrapping approach often has inflated Type I error rates and inconsistent coverage and is not recommended; In contrast, the bootstrapped percentile confidence interval and the hierarchical Bayesian MCMC method perform best overall, maintaining Type I error rates, exhibiting reasonable power, and producing stable and accurate coverage rates. PMID- 26735715 TI - Revisiting Interpretation of Canonical Correlation Analysis: A Tutorial and Demonstration of Canonical Commonality Analysis. AB - In the face of multicollinearity, researchers face challenges interpreting canonical correlation analysis (CCA) results. Although standardized function and structure coefficients provide insight into the canonical variates produced, they fall short when researchers want to fully report canonical effects. This article revisits the interpretation of CCA results, providing a tutorial and demonstrating canonical commonalty analysis. Commonality analysis fully explains the canonical effects produced by using the variables in a given canonical set to partition the variance of canonical variates produced from the other canonical set. Conducting canonical commonality analysis without the aid of software is laborious and may be untenable, depending on the number of noteworthy canonical functions and variables in either canonical set. Commonality analysis software is identified for the canonical correlation case and we demonstrate its use in facilitating model interpretation. Data from Holzinger and Swineford (1939) are employed to test a hypothetical theory that problem-solving skills are predicted by fundamental math ability. PMID- 26735716 TI - Estimating Dynamical Systems: Derivative Estimation Hints From Sir Ronald A. Fisher. AB - The fitting of dynamical systems to psychological data offers the promise of addressing new and innovative questions about how people change over time. One method of fitting dynamical systems is to estimate the derivatives of a time series and then examine the relationships between derivatives using a differential equation model. One common approach for estimating derivatives, Local Linear Approximation (LLA), produces estimates with correlated errors. Depending on the specific differential equation model used, such correlated errors can lead to severely biased estimates of differential equation model parameters. This article shows that the fitting of dynamical systems can be improved by estimating derivatives in a manner similar to that used to fit orthogonal polynomials. Two applications using simulated data compare the proposed method and a generalized form of LLA when used to estimate derivatives and when used to estimate differential equation model parameters. A third application estimates the frequency of oscillation in observations of the monthly deaths from bronchitis, emphysema, and asthma in the United Kingdom. These data are publicly available in the statistical program R, and functions in R for the method presented are provided. PMID- 26735717 TI - Recent progress and new challenges in pediatric infectious disease. PMID- 26735719 TI - Genotoxic and carcinogenic products arising from reductive transformations of the azo dye, Disperse Yellow 7. AB - Selected aromatic azo and benzidine based dyes are priority compounds under the Government of Canada's Chemical Management Plan (CMP) for environmental risk assessments. Organic compounds undergo chemical and biological transformations when they interact with environmental matrices and biotic species; identifying the transformation products is thus a critical component of the risk assessment process. Here, we used zero valent iron (ZVI) to initiate the reduction of the diazo compound dye Disperse Yellow 7 (DY 7). Using state-of-the-art accurate mass Liquid Chromatography-Quadrupole Time of Flight-Mass Spectroscopy (LC-QToF-MS), four transformation products were conclusively identified, while a fifth product was tentatively ascertained. The conclusively established transformation products included p-phenylenediamine (p-PDA, a known genotoxin), 4-aminoazobenzene (4-AAB, a category 2 carcinogen) and 4-aminobiphenyl (4-ABP, a category 1 human carcinogen). 4-ABP is thought to form via a benzidine rearrangement; this is the first report of DY 7 undergoing a benzidine rearrangement. Given the importance of reduction processes in the metabolism of organic contaminants by aquatic species, we used LC-MS/MS to analyze sediment samples that had been generated previously upon exposure of Western clawed frogs (Silurana tropicalis) to DY 7 (at exposure levels where cellular stress was observed in S. tropicalis). We found p-PDA, 4-AAB, and 4-ABP were present in all exposures, but not in any of the sediment controls, demonstrating that upon release of DY 7 to the aquatic environment, sediment dwelling organisms will metabolize DY 7 to generate known (and suspected) human carcinogens, including through a previously unreported in vivo benzidine rearrangement to produce 4-ABP. PMID- 26735720 TI - Sonophotocatalytic mineralization of Norflurazon in aqueous environment. AB - Norflurazon (4-chloro-5-(methylamino)-2-[3-(trifluoromethyl)phenyl]pyridazin 3(2H)-one; C12H9ClF3N3O) is an excellent weed controlling agent being practiced in the agricultural lands. The excessive addition or the undissolved Norflurazon (maximum solubility 28 mg/L at 25 degrees C) enters into the aquatic environment and causes the adverse effects associated with its high concentration. To avoid the perilous effects, visible light assisted photocatalysis set-up coupled with the 42 kHz ultrasound producing bath type sonicator is used to completely mineralize the Norflurazon. TiO2, ZnO and gold loaded zinc oxide nanocatalysts were utilized to study the mineralization of Norflurazon. Au-ZnO shows the greater efficiency for the sonophotocatalytic removal of Norflurazon among the various nanocatalysts employed to study the mineralization. The order of Norflurazon mineralization was sonophotocatalysis > sonocatalysis > photocatalysis. The additive effect was achieved for the sonophotocatalytic degradation. The high performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometric (LCMS) analyses were employed to identify the various intermediates produced during the mineralization. The identification of four pseudo molecular ions and various intermediates using the LCMS analysis evidently suggests the sonophotocatalytic degradation was preceded in various decay pathways. A suitable mechanism has been proposed for the sonophotocatalytic mineralization of Norflurazon. PMID- 26735722 TI - The numerical model of biosorption of Zn2+ and its application to the bio-electro tower reactor (BETR). AB - A 2-D numerical kinetic model considering flow velocity and adsorption is developed to simulate the bio-electro tower reactor (BETR). This new model considers the adsorbed amount when equilibrium qe as transient variable, which is superior to the old pseudo-first-order and the pseudo-second-order model which regards qe as a constant. We did research on the intensifying effect of electric field upon heavy metal ions adsorption process. The calculation result matches well with the experimental data. BETR is a coupling technique whose mechanism is that outer electric field can enhance the mass transfer rate when the solute is metal ions. Two kinds of carriers, pottery ball and 3-dimensional electrode (3DE), were used to support the biofilm layer; and organic wastewater that contains Zn(2+) is selected as a sample to validate the model. The 3DE carriers can be polarized by outer electric field, but pottery ball cannot. It is found that Zn(2+) transfers faster in 3DE carriers than in pottery ball (insulation materials); and an intensifying coefficienteta is introduced to describe this effect in BETR. PMID- 26735721 TI - Toxicological responses following short-term exposure through gavage feeding or water-borne exposure to Dechlorane Plus in zebrafish (Danio rerio). AB - Dechlorane Plus (DP) is a chlorinated flame retardant widely used worldwide, and has been reported in environment and humans. However, only limited information is currently available on its toxicity on aquatic organisms. In this study, we employed zebrafish to evaluate possible toxicological responses including oxidative stress and endocrine disruption following exposure to DP. DP was dissolved in corn oil and was delivered to adult male zebrafish via gavage feeding. Delivery of DP was carried out twice on days 0 and 2, at up to 3 MUg/g fish wet weight. Body residue level of DP in the fish at day 6 was within a range that has been reported in hot spot areas of China. On day 6, blood, liver, testis, and brain were collected and were evaluated for oxidative damage and endocrine disruption. Following DP exposure, hepatic catalase activity significantly increased, implying its oxidative damage potential. In addition, plasma thyroxine (T4) concentrations increased along with up-regulation of corticotropin releasing hormone and thyroid stimulating hormone beta genes in brain. Following DP exposure, transcriptional responses of sex hormone related genes in brain were observed, suggesting possible sex hormone disrupting potentials of DP. However, water-borne exposure to DP up to 267 MUg/L among the embryo and larval fish did not show any adverse effects on hatching time and transcription of thyroid hormone related genes. Our observations indicate for the first time that DP disrupts thyroid hormone balance of zebrafish by altering regulatory pathways in the brain. Handling editor: David Volz. PMID- 26735723 TI - Seasonal variation of carbonaceous pollutants in PM2.5 at an urban 'supersite' in Shanghai, China. AB - Multiple PM2.5 samples collected through different seasons from October 2011 to August 2012 at an urban site in Shanghai, China were analyzed for carbonaceous pollutants. Data from this site, a 'super' air quality monitoring station at Fudan University, has been used by researchers to investigate the formation mechanism of haze episodes. The characteristics and concentrations of organic carbon (OC), elemental carbon (EC), n-alkanes, as well as relative abundances of hopanes, in these samples were determined. The concentrations showed a pronounced annual cycle with higher values in cold seasons (spring and winter, mean: 8.6 MUg/m(3), 3.3 MUg/m(3) and 136.4 ng/m(3) for OC, EC and n-alkanes, respectively) and lower values in warm seasons (fall and summer, mean: 6.6 MUg/m(3), 2.6 MUg/m(3) and 73.8 ng/m(3) for OC, EC and n-alkanes, respectively). EC generally displayed a common source with that of OC in all seasons. Petroleum residue was the major source of n-alkanes, contributing 71.4% to the targeted C14-C33n alkanes over four seasons. Principal components analysis and the composition of hopanes showed that emissions from vehicle exhaust contributed more carbonaceous aerosols than coal combustion. These data could provide important information for measures to reduce carbonaceous pollutant emissions and improve air quality in Shanghai, and other urban centers across China. PMID- 26735724 TI - Investigation of acid red 88 oxidation in water by means of electro-Fenton method for water purification. AB - In this study, electro-Fenton method was applied to acid red 88 (AR88) containing aqueous solutions for the removal of it from water. The mineralization of AR88 has been achieved by oxidation with hydroxyl radicals. These radicals were produced simultaneously by the electro-Fenton method using an electrochemical cell including a carbon felt cathode and a platinum anode. Applied current and concentrations of catalyst and supporting electrolyte were optimized to obtain the best effective parameters of 500 mA, 0.1 mM and 75 mM, respectively. The absolute rate constant for the oxidation reaction of AR88 with hydroxyl radical was determined as (1.57 +/- 0.06) x 10(10) M(-1) s(-1). Total organic carbon (TOC) analysis was performed to determine whether the organics were converted to carbon dioxide or not. A two-hour electrolysis at 500 mA is enough to remove 87% of initial TOC values of 0.25 mM AR88 solution. Electro-Fenton treatment of AR88 led to the formation of five aromatic intermediates, five short-chain carboxylic acids and three inorganic ions. Identified intermediates and complete mineralization of AR88 allowed us to propose a mineralization pathway for first time in the literature. PMID- 26735725 TI - Low-cost nanoparticles sorbent from modified rice husk and a copolymer for efficient removal of Pb(II) and crystal violet from water. AB - In this work, preparation of adsorbent nanoparticles based on treated low-value agricultural by-product rice husk (TARH), and poly(methylmethacrylate-co-maleic anhydride), poly(MMA-co-MA), is reported for the removal of Pb(II) ion and Crystal violet dye from water. The prepared adsorbent was characterized by FT-IR, SEM, AFM, DLS, BET and Zeta potential. The metal ion adsorption capability was determined for rice husk (RH), TARH, crosslinked poly(MMA-co-MA) (CNR), and CNR@TARH nanoparticles. Different factors affecting the adsorption of Pb(II) such as pH, contact time, initial metal ion concentration and also temperature were studied to investigate adsorption isotherms, kinetics and thermodynamics. For the four tested adsorption isotherm models, the equilibrium sorption data for CNR@TARH nanoparticles obeyed the Langmuir isotherm equation with maximum sorption capacity of 93.45 mg g(-1). The kinetic adsorption data fitted best the Lagergren pseudo-second order model. Regeneration of adsorbent was easily performed by adsorption/desorption experiments followed for 4 cycles. Finally, the ability of the nanoparticles to remove Crystal violet dye from aqueous solution was also investigated by varying the initial dye concentration, pH and immersion time and the adsorption mechanism followed the second-order kinetic model. PMID- 26735726 TI - The mercury species and their association with carbonaceous compositions, bromine and iodine in PM2.5 in Shanghai. AB - PM2.5 samples were collected in south Shanghai from November 2013 to October 2014. The species of particulate bounded mercury (PBM), including hydrochloric soluble particle-phase mercury (HPM), element soluble particle-phase mercury (EPM) and residual soluble particle-phase mercury (RPM), were determined in PM2.5. The chemical composition of PM2.5 including organic carbon (OC) and elemental carbon (EC), total bromine and iodine were also analyzed. The results showed that the annual average concentration of PBM was 0.30 +/- 0.31 ng m(-3) and 0.34 +/- 0.32 ng m(-3) in winter, 0.31 +/- 0.19 ng m(-3) in spring, 0.30 +/- 0.45 ng m(-3) in fall and 0.28 +/- 0.17 ng m(-3) in summer. HPM took the highest fraction 51.2% in PBM, followed by RPM 27.7% and EPM 21.1%. EC positively correlated to particle mercury, especially in winter (r = 0.70), the same for OC in winter (r = 0.72), which indicated that the carbonaceous composition may affect the transformation of Hg in the atmosphere. Mercury species showed different correlations with bromine and iodine in the four seasons. The strongest correlation between bromine, iodine and mercury was found in spring and fall, respectively. Bromine showed the stronger correlation with total mercury and speciated particle mercury than iodine. In addition, the days were classified into haze and non-haze days based on the visibility and relative humidity, while the ratio of HPM in haze days was much higher than that in non-haze days. EC strongly correlated with PBM during haze and non-haze days while OC only positively correlated with PBM in non-haze days, this may indicate that the different carbonaceous part may affect PBM differently. PMID- 26735727 TI - Persistence of polycyclic aromatic hydrocarbons (PAHs) in biochar-amended soil. AB - In the present study the persistence of polycyclic aromatic hydrocarbons (PAHs) applied with biochar to acidic soil (loamy sand) was studied in two and half year field experiment. An experiment was carried out in three experimental plots (15 m(2) each). The biochar was introduced in the following doses: soil without fertilization - control (C-BC00), soil with 30 t ha(-1) (B-BC30) and soil with 45 t ha(-1) (A-BC45) of biochar. Biochar addition to soils resulted in an increase in the PAHs content from 0.239 MUg g(-1) in control soil to 0.526 MUg g(-1) and 1.310 MUg g(-1) in 30 and 45 t ha(-1) biochar-amended soil respectively. However during the experimental period the PAHs content decreased to a level characteristic for the control soil. The highest losses of PAHs were observed during the first 105 days of the experiment. Three and four rings PAHs were the most susceptible for degradation and leaching. Migration of PAHs from 0-10 cm to 10-20 cm soil horizon was also observed. PMID- 26735728 TI - Degradation of herbicide 2,4-dichlorophenoxybutanoic acid in the photolysis of [FeOH]2+ and [Fe(Ox)3]3- complexes: A mechanistic study. AB - In the present work the Fe(III)-assisted photodegradation of the herbicide 2,4 dichlorophenoxybutanoic acid (2,4-DB) has been studied by means of stationary (308 nm) and laser flash (355 nm) photolysis. The initial quantum yield of 2,4-DB photodegradation in [FeOH](2+) and [Fe(Ox)3](3-) systems was evaluated to be 0.11 and 0.17 upon 308 nm exposure, respectively. The prolonged photolysis of [FeOH](2+) and [Fe(Ox)3](3-) systems results in the complete degradation of 2,4 DB with almost complete mineralization of herbicide and its aromatic products in the case of [FeOH](2+) photolysis and the accumulation of some persistent aromatic products in the case of [Fe(Ox)3](3-) photolysis. For both systems the main primary products of 2,4-DB photolysis determined by liquid chromatography - mass spectrometry are products of the hydroxylation, the substitution of chlorine atom to OH group, the loss of aliphatic tail and the opening of benzene ring. The obtained results indicate ROS species (mainly OH radical) to be responsible for the herbicide photodegradation. PMID- 26735729 TI - Restoration of manufactured gas plant site soil through combined ultrasound assisted soil washing and bioaugmentation. AB - An effective ex situ soil remediation technology was developed in this study to remove polycyclic aromatic hydrocarbons (PAHs) and heavy metals in a mixed contaminated site. Ultrasonication (20 kHz, 45 min) combined with methyl-beta cyclodextrin (75 g/L) and S,S-ethylenediaminedisuccinic acid (25 g/L) were efficient in extracting mixed pollutants from the soil. After two successive washing cycles, the removal efficiency of PAHs and heavy metals were approximately 84.5% and 81.3%, respectively. The high removal of metals remarkably reduced soil microtoxicity and thus activated biodegradation activity towards PAHs. Inoculation of PAHs-degrading bacterial strains with nutrients addition further removed 86.8% of residual PAHs in 16 weeks. These results were indicated by the significant increase in the number of PAH degraders and soil enzyme activity. After treatment, the residual levels of individual PAHs and heavy metals could meet Chinese soil quality standard for residential use. The proposed combined cleanup strategy proved to be effective and environmentally friendly for remediation of mixed-contaminated site. PMID- 26735730 TI - Effect of electric field on the performance of soil electro-bioremediation with a periodic polarity reversal strategy. AB - In this work, it is studied the effect of the electric fields (within the range 0.0-1.5 V cm(-1)) on the performance of electrobioremediation with polarity reversal, using a bench scale plant with diesel-spiked kaolinite with 14-d long tests. Results obtained show that the periodic changes in the polarity of the electric field results in a more efficient treatment as compared with the single electro-bioremediation process, and it does not require the addition of a buffer to keep the pH within a suitable range. The soil heating was not very important and it did not cause a change in the temperature of the soil up to values incompatible with the life of microorganisms. Low values of water transported by the electro-osmosis process were attained with this strategy. After only 14 d of treatment, by using the highest electric field studied in this work (1.5 V cm( 1)), up to 35.40% of the diesel added at the beginning of the test was removed, value much higher than the 10.5% obtained by the single bioremediation technology in the same period. PMID- 26735731 TI - Novel iron metal matrix composite reinforced by quartz sand for the effective dechlorination of aqueous 2-chlorophenol. AB - In this work, we tested a novel iron metal matrix composite (MMC) synthesized by mechanically introducing quartz sand (SiO2) into an iron matrix (denoted as SiO2 Fe MMC). The pseudo-first-order reaction rate constant of the SiO2-Fe MMC (initial pH 5.0) for 20 mg/L of 2-chlorophenol (2-CP) was 0.051 * 10(-3) L/m(2)/min, which was even higher than that of some reported Pd/Fe bimetals. This extraordinary high activity was promoted by the quick iron dissolution rate, which was caused by the formation of Fe-C internal electrolysis from carbonization of process control agent (PCA) and the active reinforcement/metal interfaces during the milling process. In addition, pH has slight effect on the dechlorination rate. The SiO2-Fe MMC retained relatively stable activity, still achieving 71% removal efficiency for 2-CP after six consecutive cycles. The decrease in dechlorination efficiency can be attributed to the rapid consumption of Fe(0). A dechlorination mechanism using the SiO2-Fe MMC was proposed by a direct electron transfer from Fe(0) to 2-CP at the quartz sand/iron interface. PMID- 26735732 TI - Enantioselective degradation and chiral stability of the herbicide fluazifop butyl in soil and water. AB - The stereoselective degradation and transformation of the enantiomers of the herbicide fluazifop-butyl in soil and water were studied to investigate the environmental behavior and chiral stability of the optical pure product. Its main chiral metabolite fluazifop was also monitored. LC/MS/MS with Chiralpak IC chiral column was used to separate the enantiomers of fluazifop-butyl and fluazifop. Validated enantioselective residue analysis methods were established with recoveries ranging from 77.1 to 115.4% and RSDs from 0.85 to 8.9% for the enantiomers. It was found the dissipation of fluazifop-butyl was rapid in the three studied soils (Beijing, Harbin and Anhui soil), and the degradation half lives of the enantiomers ranged from 0.136 to 2.7 d. Enantioselective degradations were found in two soils. In Beijing soil, R-fluazifop-butyl was preferentially degraded leading to relative enrichment of S-enantiomer, but in Anhui soil, S-fluazifop-butyl dissipated faster. There was no conversion of the R fluazifop-butyl into S-fluazifop-butyl or vice versa in the soils. The formation of fluazifop in the soils was rapidly accompanied with the fast degradation of fluazifop-butyl, and the enantioselectivity and the transformation of S-fluazifop to R-fluazifop were found. The degradation of fluazifop-butyl in water was also quick, with half-lives of the enantiomers ranging from 0.34 to 2.52 d, and there was no significant enantioselectivity of the degradation of fluazifop-butyl and the formation of fluazifop. The effects of pH on the degradation showed fluazifop butyl enantiomers degraded faster in alkaline conditions. This study showed an evidence of enantioselective behavior and enantiomerization of the chiral herbicide fluazifop-butyl. PMID- 26735733 TI - Regression models to estimate the total concentration of polycyclic aromatic hydrocarbon metabolites in urine. AB - Polycyclic aromatic hydrocarbons (PAH) are potentially mutagenic and carcinogenic and as such their exposure is of serious concern. Regression models to estimate the total concentration of polycyclic aromatic hydrocarbon metabolites (?PAH) in urine were developed. Using data from National Health and Nutrition Examination Survey for the years 2003-2008 and 2011-2012, regression models were developed to estimate ?PAH in urine. The performance of the fitted models were computed by comparing percent predicted values located between 0 and 5%, 5-10%, 15-20% and >20% of the observed values. While data for 2003-2008 were used to fit the regression models, the data for 2011-2012 were solely used to evaluate the performance of the fitted models. R(2) of the fitted model was 94.7%. About 46% of the predicted values for the 2003-2008 data and over 48% of the predicted values for the 2011-2012 data were found to be between 0 and 10% of the observed values. In order to use these models, in addition to age, gender, and smoking status, and optionally race/ethnicity, the knowledge of the levels of only 1 hydroxynaphthalene, 2-hydroxynaphthalene, and 9-hydroxyfluorene is necessary. Models that optionally require the knowledge of the levels of urine creatinine were also developed. PMID- 26735734 TI - Immobilization of Ochrobactrum tritici As5 on PTFE thin films for arsenite biofiltration. AB - Ochrobactrum tritici SCII24T bacteria is an environmental strain with high capacity to resist to arsenic (As) toxicity, which makes it able to grow in the presence of As(III). The inactivation of the two functional arsenite efflux pumps, ArsB and ACR3_1, resulted in the mutant O. tritici As5 exhibiting a high accumulation of arsenite. This work describes a method for the immobilization of the mutant cells O. tritici As5, on a commercial polymeric net after sputtered modified by the deposition of poly(tetrafluoroethylene) (PTFE) thin films, and demonstrates the capacity of immobilized cells to accumulate arsenic from solutions. Six different set of deposition parameters for PTFE thin films were developed and tested in vitro regarding their ability to immobilize the bacterial cells. The surface that exhibited a mild zeta potential value, hydrophobic characteristics, the lowest surface free energy but with a high polar component and the appropriate ratio of chemical reactive groups allowed cells to proliferate and to grow as a biofilm. These immobilized cells maintained their ability to accumulate the surrounding arsenite, making it a great arsenic biofilter to be used in bioremediation processes. PMID- 26735735 TI - Structural incorporation of As5+ into rhomboclase ((H5O2)Fe3+(SO4)2 . 2H2O) and (H3O)Fe(SO4)2. AB - Iron sulfates represent an essential sink for the toxic element arsenic in arid and semi-arid mining areas with high evaporation rates. Information about the structural incorporation of As(5+) in iron sulfates, however, remains scarce. Here we present evidence for the heterogeneous substitution of S(6+) by As(5+) in the crystal structure of rhomboclase ((H5O2)Fe(3+)(SO4)2 . 2H2O) and its dehydration product (H3O)Fe(SO4)2. Rhomboclase (Rhc) was synthesized in the presence of As(5+) with molar As/Fe ratios of 0, 0.25, 0.5, 0.75 and 1.0, resulting in As loads of 0.0, 0.93, 1.44, 1.69 and 1.87 wt.%, respectively. The unit cell parameters of Rhc increase from 9.729(6), 18.303(2), and 5.432(1) A for a, b, and c, to 9.745(9), 18.332(5), and 5.436(8) A when Rhc is crystallized at a molar As/Fe ratio of 1. Simultaneously, the crystallite size decreased from 304 to 176 nm. In situ dehydration of Rhc to (H3O)Fe(SO4)2, investigated by powder X ray diffraction, shows that Rhc starts to dehydrate at 76 degrees C, which is completed at 86 degrees C. The presence of As(5+) does not impact the start or end temperatures of Rhc dehydration but does accelerate the dehydration. X-ray absorption fine structure spectroscopy (EXAFS) reveals that S(6+), in the Rhc and (H3O)Fe(SO4)2 structure, is replaced by As(5+), while the polymerization of AsO4 tetrahedra and FeO6-octahedra during the formation of (H3O)Fe(SO4)2 results in a strong distortion of the AsO4-tetrahedron. PMID- 26735736 TI - Polybrominated diphenyl ethers and polychlorinated biphenyls in dust from cars, homes, and offices in Lagos, Nigeria. AB - Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) were measured in dust from 16 cars, 12 homes, and 18 offices in Lagos, Nigeria. These represent the first and second reports respectively of contamination of Nigerian indoor dust with these contaminants, and the second report on PCBs in car dust worldwide. Concentrations of BDE-47 and BDE-99 in two car dust samples (9300 and 3700 ng g(-1) for BDE-47 and 4200 and 19,000 ng g(-1) for BDE-99), are amongst the highest ever reported in car dust. ANOVA comparison with Canada, New Zealand, the UK, and the USA; reveals concentrations of BDEs-28, 49, 47, 66, 100, 99, 154, and 153 in Nigerian house dust, to be significantly lower than in Canada and the USA, with those of BDE-49 and 154 significantly lower than in New Zealand and the UK. Concentrations of BDE-209 in Nigeria were significantly lower than concentrations in the UK and the USA; while concentrations of PCB-180 were significantly greater than those in New Zealand, the UK, and the USA. Median concentrations of PCBs in cars were substantially higher than in the only previous study (in Kuwait and Pakistan). While median concentrations of PBDEs in cars generally exceeded those in homes, this was significant only for BDEs-49, 154, and 197, with concentrations in cars significantly greater than those in offices for BDEs-49 and 154. Contrastingly, concentrations of all target PCBs in offices exceeded significantly those in cars. This study underlines the truly global distribution of indoor contamination with PBDEs and PCBs. PMID- 26735737 TI - Persistent organic pollutant levels in eggs of leatherback turtles (Dermochelys coriacea) point to a decrease in hatching success. AB - Sea turtles are susceptible to environmental pollution, since many harmful effects have been reported for different chemicals over the last two decades. In this context, persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are of particular concern due to their endocrine-disrupting nature. The aims of this study were to provide additional baseline data on PCB and PBDE concentrations in eggs of Dermochelys coriacea; and to investigate whether any of the congeners could compromise reproductive success in this species. A total of 18 nests from different females were studied during the nesting season of 2008 at Reserva Pacuare Beach, in the Caribbean side of Costa Rica. Reproductive parameters (viability, fertility and hatching rates) were calculated for all nests and hatchling morphometrics were successfully measured in 8 of them. Two to three fresh eggs per nest were taken for contaminant study. Different congeners of POPs were purified and identified using gas chromatography (GC) coupled to an ion trap detector (GC-ITD MS/MS), as described below. Mean +/- SD concentrations were calculated for POP congeners within each nest and clustering was also evaluated. Correlations were performed searching for potential relationships with reproductive parameters. POP levels were similar to those reported in French Guiana populations and slightly lower than those associated to Florida populations. Sum of PBDEs showed a negative correlation to the hatching success, suggesting potential harmful effects of these contaminants on the reproduction of leatherbacks. PMID- 26735738 TI - Determining the effect of oil sands process-affected water on grazing behaviour of Daphnia magna, long-term consequences, and mechanism. AB - Oil sands process-affected water (OSPW) is a byproduct of the extraction of bitumen in the surface-mining oil sands industry and is currently stored in on site tailings ponds. OSPW from three oil sands companies were studied to capture some of the variability associated with OSPW characteristics. To investigate the effect and mechanism(s) of effect of OSPW on feeding behaviour, Daphnia magna were exposed to low OSPW concentrations for 24 h and monitored for their feeding rate, olfactory response and swimming activity. The Al and Si content, which are indicators of suspended particulate matter in D. magna exposed to OSPW were investigated using energy-dispersive X-ray (EDX) spectroscopy. In long-term experiments, effects of exposure to OSPW for 21 days on feeding behaviour, growth, and reproduction of D. magna were evaluated. Feeding rates were similar among the three exposure populations, yielding a 24 h IC50 of 5.3% OSPW. Results of behavioural assays suggest that OSPW impairs the chemosensory function and reduces the total activity of D. magna. In EDX spectroscopy, Al and Si were detected in the body of the exposed D. magna, suggesting that D. magna filter clay particles from the OSPW solution. Results of the long-term exposure showed that OSPW significantly inhibits feeding behaviour, suppresses growth, and reduces reproductive output of D. magna. There were no differences in the toxicity of the three samples of OSPW, which was in agreement with the fact that there were no differences in the species of dissolved organic compounds in the OSPW samples. PMID- 26735741 TI - The Development of an Information Criterion for Change-Point Analysis. AB - Change-point analysis is a flexible and computationally tractable tool for the analysis of times series data from systems that transition between discrete states and whose observables are corrupted by noise. The change point algorithm is used to identify the time indices (change points) at which the system transitions between these discrete states. We present a unified information-based approach to testing for the existence of change points. This new approach reconciles two previously disparate approaches to change-point analysis (frequentist and information based) for testing transitions between states. The resulting method is statistically principled, parameter and prior free, and widely applicable to a wide range of change-point problems. PMID- 26735739 TI - Flexible High-Performance Lead-Free Na0.47K0.47Li0.06NbO3 Microcube-Structure Based Piezoelectric Energy Harvester. AB - Lead-free piezoelectric nano- and microstructure-based generators have recently attracted much attention due to the continuous demand of self-powered body implantable devices. We report the fabrication of a high-performance flexible piezoelectric microgenerator based on lead-free inorganic piezoelectric Na0.47K0.47Li0.06NbO3 (NKLN) microcubes for the first time. The composite generator is fabricated using NKLN microcubes and polydimethylsiloxane (PDMS) polymer on a flexible substrate. The flexible device exhibits excellent performance with a large recordable piezoelectric output voltage of 48 V and output current density of 0.43 MUA/cm(2) under vertical compressive force of 2 kgf, for which an energy conversion efficiency of about 11% has been achieved. Piezoresponse and ferroelectric studies reveal that NKLN microcubes exhibited high piezoelectric charge coefficient (d33) as high as 460 pC/N and a well defined hysteresis loops with remnant polarization and coercive field of 13.66 MUC/cm(2) and 19.45 kV/cm, respectively. The piezoelectric charge generation mechanism from NKLN microgenerator are discussed in the light of the high d33 and alignment of electric dipoles in polymer matrix and dielectric constant of NKLN microcubes. It has been demonstrated that the developed power generator has the potential to generate high electric output power under mechanical vibration for powering biomedical devices in the near future. PMID- 26735740 TI - Development and Characterization of Ultrafiltration TiO2 Magneli Phase Reactive Electrochemical Membranes. AB - This research focused on the synthesis, characterization, and performance testing of a novel Magneli phase (TinO2n-1), n = 4 to 6, reactive electrochemical membrane (REM) for water treatment. The REMs were synthesized from tubular asymmetric TiO2 ultrafiltration membranes, and optimal reactivity was achieved for REMs composed of high purity Ti4O7. Probe molecules were used to assess outer sphere charge transfer (Fe(CN)6(4-)) and organic compound oxidation through both direct oxidation (oxalic acid) and formation of OH(*) (coumarin, terephthalic acid). High membrane fluxes (3208 L m(-2) h(-1) bar(-1) (LMH bar(-1))) were achieved and resulted in a convection-enhanced rate constant for Fe(CN)6(4-) oxidation of 1.4 * 10(-4) m s(-1), which is the highest reported in an electrochemical flow-through reactor and approached the kinetic limit. The optimal removal rate for oxalic acid was 401.5 +/- 18.1 mmol h(-1) m(-2) at 793 LMH, with approximately 84% current efficiency. Experiments indicate OH(*) were produced only on the Ti4O7 REM and not on less reduced phases (e.g., Ti6O11). REMs were also tested for oxyanion separation. Approximately 67% removal of a 1 mM NO3(-) solution was achieved at 58 LMH, with energy consumption of 0.22 kWh m( 3). These results demonstrate the extreme promise of REMs for water treatment applications. PMID- 26735742 TI - An Online Policy Gradient Algorithm for Markov Decision Processes with Continuous States and Actions. AB - We consider the learning problem under an online Markov decision process (MDP) aimed at learning the time-dependent decision-making policy of an agent that minimizes the regret-the difference from the best fixed policy. The difficulty of online MDP learning is that the reward function changes over time. In this letter, we show that a simple online policy gradient algorithm achieves regret O(?T) for T steps under a certain concavity assumption and O(log T) under a strong concavity assumption. To the best of our knowledge, this is the first work to present an online MDP algorithm that can handle continuous state, action, and parameter spaces with guarantee. We also illustrate the behavior of the proposed online policy gradient method through experiments. PMID- 26735743 TI - A Block Successive Lower-Bound Maximization Algorithm for the Maximum Pseudo Likelihood Estimation of Fully Visible Boltzmann Machines. AB - Maximum pseudo-likelihood estimation (MPLE) is an attractive method for training fully visible Boltzmann machines (FVBMs) due to its computational scalability and the desirable statistical properties of the MPLE. No published algorithms for MPLE have been proven to be convergent or monotonic. In this note, we present an algorithm for the MPLE of FVBMs based on the block successive lower-bound maximization (BSLM) principle. We show that the BSLM algorithm monotonically increases the pseudo-likelihood values and that the sequence of BSLM estimates converges to the unique global maximizer of the pseudo-likelihood function. The relationship between the BSLM algorithm and the gradient ascent (GA) algorithm for MPLE of FVBMs is also discussed, and a convergence criterion for the GA algorithm is given. PMID- 26735744 TI - Kernelized Elastic Net Regularization: Generalization Bounds, and Sparse Recovery. AB - Kernelized elastic net regularization (KENReg) is a kernelization of the well known elastic net regularization (Zou & Hastie, 2005). The kernel in KENReg is not required to be a Mercer kernel since it learns from a kernelized dictionary in the coefficient space. Feng, Yang, Zhao, Lv, and Suykens (2014) showed that KENReg has some nice properties including stability, sparseness, and generalization. In this letter, we continue our study on KENReg by conducting a refined learning theory analysis. This letter makes the following three main contributions. First, we present refined error analysis on the generalization performance of KENReg. The main difficulty of analyzing the generalization error of KENReg lies in characterizing the population version of its empirical target function. We overcome this by introducing a weighted Banach space associated with the elastic net regularization. We are then able to conduct elaborated learning theory analysis and obtain fast convergence rates under proper complexity and regularity assumptions. Second, we study the sparse recovery problem in KENReg with fixed design and show that the kernelization may improve the sparse recovery ability compared to the classical elastic net regularization. Finally, we discuss the interplay among different properties of KENReg that include sparseness, stability, and generalization. We show that the stability of KENReg leads to generalization, and its sparseness confidence can be derived from generalization. Moreover, KENReg is stable and can be simultaneously sparse, which makes it attractive theoretically and practically. PMID- 26735745 TI - Microdomain [Ca(2+)] Fluctuations Alter Temporal Dynamics in Models of Ca(2+) Dependent Signaling Cascades and Synaptic Vesicle Release. AB - Ca(2+)-dependent signaling is often localized in spatially restricted microdomains and may involve only 1 to 100 Ca(2+) ions. Fluctuations in the microdomain Ca(2+) concentration (Ca(2+)) can arise from a wide range of elementary processes, including diffusion, Ca(2+) influx, and association/dissociation with Ca(2+) binding proteins or buffers. However, it is unclear to what extent these fluctuations alter Ca(2+)-dependent signaling. We construct Markov models of a general Ca(2+)-dependent signaling cascade and Ca(2+)-triggered synaptic vesicle release. We compare the hitting (release) time distribution and statistics for models that account for [Ca(2+)] fluctuations with the corresponding models that neglect these fluctuations. In general, when Ca(2+) fluctuations are much faster than the characteristic time for the signaling event, the hitting time distributions and statistics for the models with and without Ca(2+) fluctuation are similar. However, when the timescale of Ca(2+) fluctuations is on the same order as the signaling cascade or slower, the hitting time mean and variability are typically increased, in particular when the average number of microdomain Ca(2+) ions is small, a consequence of a long tailed hitting time distribution. In a model of Ca(2+)-triggered synaptic vesicle release, we demonstrate the conditions for which [Ca(2+)] fluctuations do and do not alter the distribution, mean, and variability of release timing. We find that both the release time mean and variability can be increased, demonstrating that Ca(2+) fluctuations are an important aspect of microdomain Ca(2+) signaling and further suggesting that Ca(2+) fluctuations in the presynaptic terminal may contribute to variability in synaptic vesicle release and thus variability in neuronal spiking. PMID- 26735746 TI - Orthogonal Connectivity Factorization: Interpretable Decomposition of Variability in Correlation Matrices. AB - In many multivariate time series, the correlation structure is nonstationary, that is, it changes over time. The correlation structure may also change as a function of other cofactors, for example, the identity of the subject in biomedical data. A fundamental approach for the analysis of such data is to estimate the correlation structure (connectivities) separately in short time windows or for different subjects and use existing machine learning methods, such as principal component analysis (PCA), to summarize or visualize the changes in connectivity. However, the visualization of such a straightforward PCA is problematic because the ensuing connectivity patterns are much more complex objects than, say, spatial patterns. Here, we develop a new framework for analyzing variability in connectivities using the PCA approach as the starting point. First, we show how to analyze and visualize the principal components of connectivity matrices by a tailor-made rank-two matrix approximation in which we use the outer product of two orthogonal vectors. This leads to a new kind of transformation of eigenvectors that is particularly suited for this purpose and often enables interpretation of the principal component as connectivity between two groups of variables. Second, we show how to incorporate the orthogonality and the rank-two constraint in the estimation of PCA itself to improve the results. We further provide an interpretation of these methods in terms of estimation of a probabilistic generative model related to blind separation of dependent sources. Experiments on brain imaging data give very promising results. PMID- 26735747 TI - Synthesis and biological evaluation of novel dioxa-bicycle C-aryl glucosides as SGLT2 inhibitors. AB - A series of novel C-aryl glucosides containing dioxa-bicycle were synthesized and evaluated for inhibition activity against hSGLT2. Among the compounds tested, compound 6a showed moderate SGLT2 inhibition activities at 700 nM. The results could benefit the discovery of new SGLT2 inhibitors. PMID- 26735748 TI - General Copper-Catalyzed Coupling of Alkyl-, Aryl-, and Alkynylaluminum Reagents with Organohalides. AB - We report the first example of a very general Cu-catalyzed cross-coupling of organoaluminum reagents with organohalides. The reactions proceed for the couplings of alkyl-, aryl-, and alkynylaluminum reagents with aryl and heteroaryl halides and vinyl bromides, affording the cross-coupled products in good to excellent yields. Both primary and secondary alkylaluminum reagents can be utilized as organometallic coupling partners. These reactions are not complicated by beta-hydride elimination, and as a result rearranged products are not observed with secondary alkylaluminum reagents even for couplings with heteroaryl halides under "ligand-free" conditions. Radical clock experiment with a radical probe and relative reactivity study of Ph3Al with two haloarenes, 1-bromonaphthalene and 4 chlorobenzonitrile, having two different redox potentials indicates that the reaction does not involve free aryl radicals and radical anions as intermediates. These results combined with the result of the Hammett plot obtained by reacting Ph3Al with iodoarenes containing p-H, p-Me, p-F, and p-CF3 substituents, which shows a linear curve (R(2) = 0.99) with a rho value of +1.06, suggest that the current transformation follows an oxidative addition-reductive elimination pathway. PMID- 26735749 TI - Regulation of cell wall remodeling in grapevine (Vitis vinifera L.) callus under individual mineral stress deficiency. AB - Cell wall (CW) is a dynamic structure that determines the plant form, growth and response to environmental conditions. Vitis vinifera callus grown under nitrogen (-N), phosphorous (-P) and sulfur (-S) deficiency were used as a model system to address the influence of mineral stress in CW remodeling. Callus cells morphology was altered, mostly under -N, resulting in changes in cell length and width compared with the control. CW composition ascertained with specific staining and immuno-detection showed a decrease in cellulose and altered pattern of pectin methylesterification. Under mineral stress genes expression from candidate families disclosed mainly a downregulation of a glycosyl hydrolase family 9C (GH9C), xyloglucan transglycosylase/hydrolases (XTHs) with predicted hydrolytic activity and pectin methylesterases (PMEs). Conversely, upregulation of PMEs inhibitors (PMEIs) was observed. While methylesterification patterns can be associated to PME/PMEI gene expression, the lower cellulose content cannot be attributed to altered cellulose synthase (CesA) gene expression suggesting the involvement of other gene families. Salt extracts from -N and -P callus tissues increased plastic deformation in cucumber hypocotyls while no effect was observed with -S extracts. The lower endo-acting glycosyl hydrolase activity of -N callus extracts pinpoints a more expressive impact of -N on CW-remodeling. PMID- 26735750 TI - Quantum Dynamics with Gaussian Bases Defined by the Quantum Trajectories. AB - Development of a general approach to construction of efficient high-dimensional bases is an outstanding challenge in quantum dynamics describing large amplitude motion of molecules and fragments. A number of approaches, proposed over the years, utilize Gaussian bases whose parameters are somehow-usually by propagating classical trajectories or by solving coupled variational equations-tailored to the shape of a wave function evolving in time. In this paper we define the time dependent Gaussian bases through an ensemble of quantum or Bohmian trajectories, known to provide a very compact representation of a wave function due to conservation of the probability density associated with each trajectory. Though the exact numerical implementation of the quantum trajectory dynamics itself is, generally, impractical, the quantum trajectories can be obtained from the wave function expanded in a basis. The resulting trajectories are used to guide compact Gaussian bases, as illustrated on several model problems. PMID- 26735752 TI - Mixed methods: open yourself to new opportunities. PMID- 26735753 TI - [Adherence to the use of the surgical checklist for patient safety]. AB - OBJECTIVE: Evaluate adherence to the checklist of the Programa Cirurgias Seguras (safe surgery programme) at a teaching hospital. METHODS: Evaluative study conducted at a teaching hospital in the south of Brazil in 2012. Data were collected by means of non-participant observation in 20 hip and knee replacement surgeries and an instrument that was created for research based on the checklist and used by the institution. RESULTS: In the observed procedures (n=20) there was significant adhesion (p<0.05) to the instrument in relation to the verification of documentation, fasting, hair removal in the surgical site, absence of nail varnish and accessories, identification of the patient and surgical site on admission to the surgical unit, availability of blood and functionality of materials. However, there was no significant adherence to the checklist in the operating room in relation to patient identification, procedure and laterality, team introduction, surgical break and materials count. CONCLUSION: The results showed that the items on the checklist were verified nonverbally and there was no significant adherence to the instrument. PMID- 26735754 TI - [Adherence to the five moments for hand hygiene among intensive care professionals]. AB - OBJECTIVE: To identify the adherence of health professionals of an intensive care unit to the five moments for hand hygiene. METHOD: Cross-sectional analytical study with a quantitative approach, based on secondary data from a database of a hospital infection control service at an institution in southern Brazil. A total of 793 observations were analyzed from July to December 2012. RESULTS: Hand washing was not performed in 446 (56.2%) of the observations, and the adherence rate was 43.7%. The greatest adherence to hand hygiene was among the physiotherapists (53.5%) and the lowest adherence was among the nursing staff (29.2%). The indications with the lowest adherence rates to hand hygiene were "before touching the patient" (18.4%) and "before aseptic procedure" (20.9%). CONCLUSION: We conclude that adherence to hand washing does not comply with the national and international guidelines, especially when we consider the current scenario of growing infections caused by multidrug-resistant microorganisms. PMID- 26735755 TI - [Nurses leadership evaluation by nursing aides and technicians according to the 360-degree feedback method]. AB - OBJECTIVE: to assess the leadership of nurses of a maternity hospital according to the nursing aides and technicians and the 360-degree feedback method. METHOD: a descriptive, cross-sectional study. The population was 19 nurses and 96 nursing aides and assistants. Data were collected from May 2010 to July 2011 using a questionnaire based on the 360-degree method. RESULTS: the nurses mentioned having a favourable performance in the four studied categories. The nursing aides and technicians disagreed with the recorded leadership performance of the nurses in the category "Communication" and "Support environment." The responses for the category "Role Model" were favourable in all items, especially PAPEL18. In "Management Style", the highest favourable rating was 79% for GESTAO16. CONCLUSION: the categories "Communication" and "Support Environment" revealed a greater fragility of the nurses in comparison to the categories "Role Model" and "Management Style". PMID- 26735756 TI - [Characterization and functional capacity in women with breast cancer, gynaecological cancer and gestational trophoblastic disease]. AB - OBJECTIVE: To describe the social, demographic and clinical profile, and functional capacity of women diagnosed with gynecological cancer, breast cancer and gestational trophoblastic disease during chemotherapy. METHOD: Longitudinal retrospective study that evaluated the records of women treated in hospital clinics from January 2000 to December 2012. RESULTS: They evaluated the records of 438 women. The analysis showed that were not able to perform their daily activities, limited to the activities of self-care. Older patients had greater functional impairment during therapy. CONCLUSIONS: The sample was women 41 to 50 years, diagnosed with breast cancer (50.9%) and made use of anthracycline based protocols (47%); the scores of the functional capacity of the sample fell from 78.22 to 73.57. It is evident that nursing care should focus on the control of signs and symptoms that impact the functional capacity of women under chemotherapy. PMID- 26735757 TI - [Educational strategies to improve adherence to patient identification]. AB - OBJECTIVE: The aim of this study was to analyze the impact of educational actions on the results of an adherence indicator while checking patient identification wristbands before high-risk care. METHODS: This is a descriptive and exploratory study that was conducted in a large university hospital between January 2013 and December 2014, where 6,201 patients were interviewed. Data were analyzed by descriptive statistics. RESULTS: The analysis and monitoring of the adherence indicator in patient identification wristbands showed a tendency to increased percentage along the study period, from 42.9% to 57.8% between January and April 2013,and from 81.38% to 94.37% between September and December 2014. CONCLUSIONS: Teaching strategies based on staff awareness improved the professionals' adherence to checking patient ID wristbands. In addition, this result can contribute to strengthening the safety culture within the institution. PMID- 26735758 TI - [Longitudinality in childcare provided through Family Health Strategy]. AB - OBJECTIVE: To evaluate the longitudinality attribute in childcare provided through the Family Health Strategy. METHOD: Quantitative survey performed with 344 caregivers of children below 10 years old, registered in the family health strategy of Distrito Sanitario III in Joao Pessoa, Paraiba. Data were collected from July to December, 2012, from the Brazil PCATool child version form and analyzed using descriptive statistics. RESULTS: Among the aspects evaluated, it is highlighted that 89.5% of caregivers said they were consulted by the same professionals, and 81.9% felt good talking to the professional. The average score for the longitudinality component was satisfactory, with a 6.6 value. CONCLUSION: The health facilities assessed are guided towards the longitudinality attribute, however, the target mean score was exactly the cutoff value, implying the need for a thoughtful look at the improvement of the attribute in the care of children under ten years. PMID- 26735759 TI - [Digital learning object for diagnostic reasoning in nursing applied to the integumentary system]. AB - OBJECTIVE: To describe the creation of a digital learning object for diagnostic reasoning in nursing applied to the integumentary system at a public university of Piaui. METHOD: A methodological study applied to technological production based on the pedagogical framework of problem-based learning. The methodology for creating the learning object observed the stages of analysis, design, development, implementation and evaluation recommended for contextualized instructional design. The revised taxonomy of Bloom was used to list the educational goals. RESULTS: The four modules of the developed learning object were inserted into the educational platform Moodle. The theoretical assumptions allowed the design of an important online resource that promotes effective learning in the scope of nursing education. CONCLUSION: This study should add value to nursing teaching practices through the use of digital learning objects for teaching diagnostic reasoning applied to skin and skin appendages. PMID- 26735760 TI - [Perceptions about the hospital environment from the perspective of high-risk puerperal women based on Florence Nightingale's theory]. AB - OBJECTIVE: to understand the perceptions of high-risk puerperal women about the hospital environment based on Florence Nightingale's theory. High-risk postpartum period is the period of time when post-partum women care for their babies in the neonatal ICU, and experience high stress levels. METHODS: it is a qualitative study with narrative approach based on Florence Nightingale's theory, conducted at a public institution in southern Brazil, from January to March 2010. Seven mothers over 18 years with newborns admitted to the neonatal ICU were the research subjects. RESULTS: the contextualization of their narratives, the caring environment in which they experienced this particular stage in their lives, indicates that high-risk puerperal women seek ties and support. CONCLUSIONS: the challenge of spending an indefinite period of time in a strange environment, away from home, with their babies under the care of health professionals, while apart from their relatives, highlights the need for nursing care during this stage. PMID- 26735761 TI - [Preventive practices in the elderly and vulnerability to HIV]. AB - OBJECTIVE: To know the vulnerability of the elderly to the HIV infection in the context of preventive practices. METHOD: Exploratory qualitative study, lead from December 2012 to May 2013, with 37 nursing Coexistence Groups in Joao Pessoa- Paraiba. The Focus Group was elected as the research technique, and the empirical material obtained was subjected to a Content Analysis Technique, thematic modality. RESULTS: The elderly recognize the importance of preventive practices, but they face difficulties in its use when their emotional relationships with their partners do not favor preventive behavior, resulting in vulnerability. The elderly showed the population groups most vulnerable to HIV and do not recognize themselves as such. CONCLUSION: The complexity of the various contexts experienced by the elderlies of this study indicate the need for more research that allows advances in the understanding of subjectivity imposed in relations that underlie the aging process and the experience of sexuality in this age group. PMID- 26735762 TI - [Risk of developing diabetes mellitus in primary care health users: a cross sectional study]. AB - OBJECTIVE: to identify the risk of developing diabetes mellitus among primary care users in a municipality of the Southern Brazil. METHOD: data were collected from October 2013 to April 2014 by applying the Finnish Diabetes Risk Score questionnaire on 189 users. RESULTS: the majority of the interviewees presented a slight moderate to moderate risk of developing diabetes mellitus (63.5%). There was a greater prevalence of high risk among the men. The variables with a significant prevalence ratio for high risk were age, obesity, abdominal circumference, sedentarism and family history of diabetes mellitus. CONCLUSION: the identified risk factors for diabetes reveal the importance of the health team and how it can intervene to prevent disease. PMID- 26735763 TI - [Late-onset neonatal sepsis in preterm infants with birth weight under 1.500 g]. AB - OBJECTIVE: The research objective was to characterize preterm infants with birth weight under 1500 g, and to identify the incidence of late-onset neonatal sepsis among this population. METHODS: A prospective cohort study with a sample of 30 preterm newborns that weighed under 1500 g and were hospitalized in the NICU of the university hospital. Data were collected from January to December 2013 using a structured instrument. RESULTS: Of the 30 neonates included in the study, 14 developed late-onset neonatal sepsis with a prevalence of coagulase-negative staphylococci. CONCLUSIONS: The incidence of late-onset neonatal sepsis indicates a vulnerability in preterm infants due to immunological immaturity. These results reveal that knowledge of the profile of newborn infants admitted to the NICU and the risk factors to which they are exposed are central to the planning of nursing care for these patients. Future studies should address strategies for preventing nosocomial infection. PMID- 26735764 TI - [Suffering and pleasure in the process of forming multidisciplinary health residents]. AB - OBJECTIVE: to identify situations of pleasure and suffering in the process of training multidisciplinary health resident. METHOD: qualitative research, developed in the Multiprofessional Residence Program in Health at a university from the south of Brazil. Data was collected in 2013 through focus groups with nine residents, and analyzed according to a thematic analysis. RESULTS: The situations of suffering were stimulated by negative situations undergone by the health workers such as difficulties in participating in other professional training activities, excessive number of activities the residents commit to as health workers, lack of knowledge and hindered integration in the areas of Residency. The situations of pleasure were a result of the multiprofessional activities developed and the resident's larning possibility. CONCLUSION: The situations of pleasure and suffering identified can help in the planning of institutional actions that contribute to a professional training process and the overall wellbeing of the residents. PMID- 26735765 TI - [Feeding tube placement: auscultatory method and x-ray agreement]. AB - OBJECTIVE: to evaluate the correlation between the auscultation test and X-ray when detecting the position of an enteral feeding tube. METHODS: cross-sectional study in an intensive care unit in southern Brazil, in 2011. Clinical nurse and nurse researcher performed auscultation test recording the impressions regarding the placement of an enteral feeding tube in 80 patients. A doctor evaluated the X ray. Kappa coefficient and PABAK reviewed the agreements. RESULTS: The X-ray showed that 70% of the enteral tubes were in the stomach, 27.4% in the duodenum, 1.3% in the esophagus, and 1.3% in the right lung. There was a weak correlation between clinical nurses and nurse researchers (PABAK=0.054; P=0.103), clinical nurses and X-rays (PABAK=0.188; P=0.111) and nurse researchers and X-rays (PABAK=0.128; P=0.107) . The auscultation test did not detect two risk conditions, enteral feeding tube in the esophagus and the bronchus. CONCLUSION: the auscultation test showed little agreement with the X-ray on the enteral feeding tube location. PMID- 26735766 TI - [Knowledge produced from the outcomes of the "Nursing Outcomes Classification- NOC": integrative review]. AB - OBJECTIVE: To identify the knowledge produced from the outcomes of the Nursing Outcomes Classification (NOC). METHOD: A literature review using the integrative databases: Latin American and Caribbean Health Sciences (LILACS), US National Library of Medicine (PubMed), Cumulative Index to Nursing & Allied Health Literature (CINAHL) and Scopus Info Site (SCOPUS), during the months of August and September 2014. RESULTS: The review consisted of 21 articles that addressed different issues: Translation and Cultural adaptation (4.77%); Applicability in clinical practice (33.33%); and, Validation (63.90%). Analysis of these articles showed that the knowledge produced from the Nursing Outcomes Classification includes translation and cultural adaptation, evaluation of applicability and validation of its items. CONCLUSION: Considering the continuous evolution of this classification, periodic reviews should be carried out to identify the knowledge, use and effects of the NOC. PMID- 26735767 TI - [Conscientious objection: reflections for nursing in Portugal]. AB - OBJECTIVE: To discuss conscientious objection in nursing, identifying the ethic and legal basis for this decision-making. METHODOLOGY: Qualitative study in which the methodology used was ethical reflection based on a legal analysis of the laws in question, proceeding to a bibliographical and documentary research CONCLUSIONS: Portuguese law and ethical pillars that form the basis of the Code of Ethics of nurses in Portugal defend the freedom of conscience as a professional practice. However, the obligation to protect human life, which imposes the need for coordination between this protection and the exercise of the right to conscientious objection on the part of the nurse, is also clear. PMID- 26735769 TI - The development, evaluation and performance of molecular diagnostics for detection of Mycobacterium tuberculosis. AB - The unique pathogenesis of tuberculosis (TB) poses several barriers to the development of accurate diagnostics: a) the establishment of life-long latency by Mycobacterium tuberculosis (M.tb) after primary infection confounds the development of classical antibody or antigen based assays; b) our poor understanding of the molecular pathways that influence progression from latent to active disease; c) the intracellular nature of M.tb infection in tissues means that M.tb and/or its components, are not readily detectable in peripheral specimens; and d) the variable presence of M.tb bacilli in specimens from patients with extrapulmonary TB or children. The literature on the current portfolio of molecular diagnostics tests for TB is reviewed here and the developmental pipeline is summarized. Also reviewed are data from recently published operational research on the GeneXpert MTB/RIF assay and discussed are the lessons that can be taken forward for the design of studies to evaluate the impact of TB diagnostics. PMID- 26735770 TI - Network Analysis of Lung Transcriptomics Reveals a Distinct B-Cell Signature in Emphysema. AB - RATIONALE: Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation caused by a combination of airways disease (bronchiolitis) and parenchymal destruction (emphysema), whose relative proportion varies from patient to patient. OBJECTIVES: To explore and contrast the molecular pathogenesis of emphysema and bronchiolitis in COPD. METHODS: We used network analysis of lung transcriptomics (Affymetrix arrays) in 70 former smokers with COPD to compare differential expression and gene coexpression in bronchiolitis and emphysema. MEASUREMENTS AND MAIN RESULTS: We observed that in emphysema (but not in bronchiolitis) (1) up-regulated genes were enriched in ontologies related to B-cell homing and activation; (2) the immune coexpression network had a central core of B cell-related genes; (3) B-cell recruitment and immunoglobulin transcription genes (CXCL13, CCL19, and POU2AF1) correlated with emphysema severity; (4) there were lymphoid follicles (CD20(+)IgM(+)) with active B cells (phosphorylated nuclear factor-kappaB p65(+)), proliferation markers (Ki 67(+)), and class-switched B cells (IgG(+)); and (5) both TNFRSF17 mRNA and B cell-activating factor protein were up-regulated. These findings were by and large reproduced in a group of patients with incipient emphysema and when patients with emphysema were matched for the severity of airflow limitation of those with bronchiolitis. CONCLUSIONS: Our study identifies enrichment in B cell related genes in patients with COPD with emphysema that is absent in bronchiolitis. These observations contribute to a better understanding of COPD pathobiology and may open new therapeutic opportunities for patients with COPD. PMID- 26735768 TI - Ionizing radiation modulates human macrophages towards a pro-inflammatory phenotype preserving their pro-invasive and pro-angiogenic capacities. AB - In order to improve the efficacy of conventional radiotherapy, attention has been paid to immune cells, which not only modulate cancer cell response to therapy but are also highly recruited to tumours after irradiation. Particularly, the effect of ionizing radiation on macrophages, using therapeutically relevant doses, is not well understood. To evaluate how radiotherapy affects macrophage behaviour and macrophage-mediated cancer cell activity, human monocyte derived-macrophages were subjected, for a week, to cumulative ionizing radiation doses, as used during cancer treatment (2 Gy/fraction/day). Irradiated macrophages remained viable and metabolically active, despite DNA damage. NF-kappaB transcription activation and increased Bcl-xL expression evidenced the promotion of pro survival activity. A significant increase of pro-inflammatory macrophage markers CD80, CD86 and HLA-DR, but not CCR7, TNF and IL1B was observed after 10 Gy cumulative doses, while anti-inflammatory markers CD163, MRC1, VCAN and IL-10 expression decreased, suggesting the modulation towards a more pro-inflammatory phenotype. Moreover, ionizing radiation induced macrophage morphological alterations and increased their phagocytic rate, without affecting matrix metalloproteases (MMP)2 and MMP9 activity. Importantly, irradiated macrophages promoted cancer cell-invasion and cancer cell-induced angiogenesis. Our work highlights macrophage ability to sustain cancer cell activities as a major concern that needs to be addressed to improve radiotherapy efficacy. PMID- 26735773 TI - 'There is no such thing as alternative medicine'. PMID- 26735771 TI - Mental health consumers' with medical co-morbidity experience of the transition through tertiary medical services to primary care. AB - Medical comorbidity in people with long-term mental illness is common and often undetected; however, these consumers frequently experience problems accessing and receiving appropriate treatment in public health-care services. The aim of the present study was to understand the lived experience of mental health consumers with medical comorbidity and their carers transitioning through tertiary medical to primary care services. An interpretative, phenomenological analysis approach was used, and semistructured, video-recorded, qualitative interviews were used with 12 consumers and four primary caregivers. Four main themes and related subthemes were abstracted from the data, highlighting consumer's and carers' experience of transition through tertiary medical to primary care services: (i) accessing tertiary services is difficult and time consuming; (ii) contrasting experiences of clinician engagement and support; (iii) lack of continuity between tertiary medical and primary care services; and (iv) Mental Health Hospital Admission Reduction Programme (MH HARP) clinicians facilitating transition. Our findings have implications for organisational change, expanding the role of MH HARP clinicians (whose primary role is to provide consumers with intensive support and care coordination to prevent avoidable tertiary medical hospital use), and the employment of consumer and carer consultants in tertiary medical settings, especially emergency departments. PMID- 26735774 TI - Our time is now - how companion animal veterinarians can transform biomedical science. AB - Over the past decade, there has been growing interest in the "One Health" agenda, defined by the One Health Initiative to be "a worldwide strategy for expanding interdisciplinary collaborations and communications in all aspects of health care for humans, animals and the environment." The concept has spawned numerous conferences, under- and post-graduate courses and has been the topic of dozens of articles that have discussed how medical doctors, scientists and veterinarians can work together to improve the health of both animals and humans. Although there is widespread agreement about the potential benefits of medical doctors and veterinarians working more closely together, this is far from routine practice for most companion animal veterinarians. This article reflects on why the topic of "One Health" is attracting such interest at the moment and discusses some of the reasons why the "One Health" agenda offers companion animal veterinarians a chance to be centre stage in the global drive to improve the health of both animals and humans. PMID- 26735775 TI - Chiropractic abnormalities of the lumbar spine significantly associated with urinary incontinence and retention in dogs. AB - OBJECTIVES: To retrospectively summarise chiropractic findings in dogs presented in a veterinary practice with urinary incontinence and urinary retention over a 6 year period, and compare these to non-urinary patients presented during the same time period. METHODS: Twenty-two cases were included in the study. They all first underwent a standard clinical examination to rule out or treat other possible causes of their urinary problems. They then underwent chiropractic examination and hypomobility findings were recorded using Gonstead listings. Odds ratios (ORs) were calculated for the occurrence of chiropractic findings in urinary versus non-urinary patients for each vertebra in the lumbar, sacral and ilial regions. RESULTS: All patients had chiropractic findings in the lumbar region that differed from non-urinary patients. The urinary patients were significantly more likely to have chiropractic findings in L3 (OR=4 . 81; 95%CI: 2 . 02 to 11 . 44; P = 0 . 0004), L4 (OR=6 . 85; 95%CI: 2 . 63 to 17 . 84; P = 0 . 0001) and L5 (OR=3 . 98; 95%CI: 1 . 64 to 9 . 69; P = 0 . 0023). In addition, urinary patients were significantly less likely to have chiropractic findings associated with the ilium (OR=0 . 26; 95%CI: 0 . 11 to 0 . 66; P = 0 . 0043). CLINICAL SIGNIFICANCE: This is the first report of an association between chiropractic findings in the lumbar vertebrae and urinary incontinence and retention in dogs. PMID- 26735776 TI - Inter- and intraobserver agreement in interpretation of CT features of medial coronoid process disease. AB - OBJECTIVES: To evaluate inter- and intraobserver reliability of the assessment of computed tomography features commonly used in the identification and classification of medial coronoid process disease and to assess inter- and intraobserver variability in the identification of the percentage ulna sclerosis from single transverse computed tomography images. METHODS: Eight observers, on two occasions, reviewed 84 standardised single transverse computed tomography images acquired at the level of the apex of the medial coronoid process. Observers assessed: medial coronoid process disease, coronoid process fragmentation, osteophytes, sclerosis grade and sclerosis delineation with normal bone defined using a sclerometer. Cohen's kappa and intraclass correlation coefficient were calculated. RESULTS: Inter-observer agreement was fair to moderate for identification of computed tomography changes consistent with medial coronoid process disease, moderate to almost perfect for fragmentation, and moderate for osteophyte detection. Agreement was poor for sclerosis grading. Percentage sclerosis measured with a sclerometer had moderate to almost perfect inter- and intraobserver agreement. CLINICAL SIGNIFICANCE: These findings suggest that subjective assessment of computed tomography images is less repeatable than more quantitative methods. PMID- 26735777 TI - Straelensiosis in two cats and ten dogs from Israel. AB - Straelensiosis is uncommonly described outside Europe. This report describes straelensiosis in two cats and in ten dogs diagnosed with the disease outside Europe. Both cats displayed erythematous macules or nodules on the abdominal skin. One cat was extremely pruritic, while in the other the lesions were incidental findings when the cat was presented for neutering. The mites were noted in skin scrapings in both cats and histopathologically in one cat. All dogs showed a general distribution of papules, and intense pruritus was noted in six dogs. The diagnosis in all dogs was based on histopathology. Treatment of the animals in this study varied, and among the various administrated treatments, amitraz showed promising results. PMID- 26735778 TI - Coagulation status in dogs with naturally occurring Angiostrongylus vasorum infection and primary hyperfibrinolysis. PMID- 26735779 TI - Reply. PMID- 26735780 TI - Circadian disruption-induced breast cancer--knowns and unknowns. PMID- 26735781 TI - Developments in Addiction Biology. PMID- 26735782 TI - Combined effects of nicotine and alcohol on subjective, behavioral and physiological responses in humans. AB - Nicotine and alcohol have each been widely studied in humans, but there has been relatively little attention paid to their combined effects. This is surprising, given the high frequency with which they are consumed together. The limited literature on these combined effects is murky, partly because of failure to recognize that alcohol can have contrasting subjective mood effects depending on whether blood alcohol level is ascending or descending. However, in general, nicotine and alcohol (when blood alcohol level is descending) tend to have contrasting effects on mood ("stimulating" vs. "sedating", respectively), behavioral performance (slightly improving vs. impairing, respectively), and selected physiological responses (e.g. increased beta EEG vs. increased alpha EEG, respectively), but similar effects on other physiological responses (e.g. heart rate). Thus, when consumed together, mood, performance, and EEG responses are often intermediate between those due to alcohol alone or nicotine alone. Responses influenced in the same direction by either, such as cardiovascular effects, are exacerbated beyond effects due to either alone. Since mood and behavioral effects are likely to reinforce drug use, the attenuating influence of nicotine on alcohol's sedative effects could explain the frequently observed increase in smoking after alcohol consumption. At the same time, nicotine plus alcohol may exacerbate some physiological responses (e.g. cardiovascular) that can impact negatively on health. Limitations of this research and possible mechanisms of interaction between nicotine and alcohol are briefly noted. The need to consider the modulating influences of environmental and baseline-relevant factors is also emphasized. PMID- 26735783 TI - Alcoholic beverages and lipid peroxidation: relevance to cardiovascular disease. AB - Overall there is good evidence that alcohol consumption induces oxidative stress, and leads to lipid peroxidation, effects which have been linked to alcohol related toxicity and disease and may be relevant to alcoholatherosclerosis interrelationships. On the other hand, a protective effect of light to moderate alcohol consumption against cardiovascular disease is well recognized, with the further hypothesis that red wine offers extra cardiovascular protection due to its rich content of antioxidant phenolic compounds. Although this hypothesis is given some credence from in vitro data, controlled studies in humans have produced conflicting results. Clearly, the equally well described pro-oxidant effects of alcohol and its metabolism have been insufficiently considered in the pursuit of what to many is an intuitively attractive hypothesis. Further studies are required to determine if red wine phenolics are actually absorbed from the gut and whether they offer any overall antioxidant protection in vivo. The hypothesis that red wine offers extra cardiovascular protection compared to other alcoholic beverages is not proven and must await the outcome of studies in which the full spectrum of the pro-oxidant and antioxidant effects of alcoholic beverages are duly considered. In the absence of such studies, there are no grounds at present for the promotion of the consumption of alcoholic beverages on the basis of their putative "antioxidant" properties. PMID- 26735784 TI - Catalase and the production of brain acetaldehyde: a possible mediator of the psychopharmacological effects of ethanol. AB - This review represents an attempt to assess the available data on the role of catalase in the mediation of the behavioral actions of ethanol and the regulation of voluntary ethanol consumption. It is argued that acetaldehyde may be formed in brain through the peroxidatic activity of catalase. Furthermore, acetaldehyde formed centrally through the activity of this enzyme, may be responsible, at least in part, for some of the motivational, behavioral and neurotoxic effects of ethanol. PMID- 26735785 TI - Ultra-rapid, antagonist-precipitated opiate detoxification under general anaesthesia or sedation. AB - Ultra-rapid opiate withdrawal precipitated by naloxone or naltrexone during general anaesthesia or varying degrees of sedation, usually with the addition of alpha-2 adrenergic agonists, is an increasingly popular technique. As with anaesthesia or effective analgesia for dentistry or obstetrics, it can be justified on general humane principles. It also simplifies and speeds the transition to treatment programmes involving naltrexone. This paper reviews its development and the current range of techniques, including the use of octreotide to prevent diarrhoea. The prospect of avoiding or shortening the worst discomforts of withdrawal may encourage more opiate addicts to attempt detoxification and opiate-free management, including patients who have been successfully rehabilitated on long-term methadone maintenance treatment (MMT). Despite good motivation and preparation, a significant minority of MMT patients consistently fail to complete conventional withdrawal programmes because of increasing physical discomfort. It is emphasized that there is usually more to the treatment of opiate dependence than withdrawal. PMID- 26735786 TI - Human mu opioid receptor gene polymorphisms and vulnerability to substance abuse. AB - Two polymorphisms of the human mu opioid receptor gene are described. A non coding region polymorphism (G to T) occurs at nucleotide 175 preceding the initiation of translation. A coding polymorphism in exon 1 (C to T) at nucleotide 229 changes an alanine residue to a valine residue. Frequencies of these polymorphisms were examined in groups of cocaine and/or opioid dependent individuals and matched controls. There were no significant differences between groups, although a trend (p= 0.05) towards a higher frequency of the 229 valine allele was observed in the substance abuse group, suggesting a need for large, well-controlled studies of this polymorphism in severe substance abusers. PMID- 26735787 TI - No allelic association of an exon 13 polymorphism of the Gsalpha gene to alcohol and/or drug dependence. AB - The adenylyl cyclase signal transduction system, a ubiquitous second messenger system, has been identified as a potential marker for genetic risk of alcohol and drug dependence. Using the polymerase chain reaction (PCR) to amplify exon 13 of the Gsalpha gene, two alleles were distinguished by denaturing gradient gel electrophoresis. One allele, designed A, contained the previously published C in the codon for asparagine 371, while the second allele, designated A, contains a C T transition that conserves the asparagine residue at codon 371. The neutral polymorphism eliminates a Fok I restriction enzyme cleavage site, allowing use of restriction fragment length polymorphisms of PCR products to determine allelic frequency in 235 subjects with alcohol and/or drug dependence and in 85 control subjects. Since allele frequencies differ significantly by race, comparisons between affected individuals and controls were conducted separately for white and black groups. Within race, there were no significant differences in the frequency of the A allele among alcoholics, subjects dependent on cocaine or opioids, subjects dependent on these drugs and alcohol, and controls. We conclude that there is no association between alcohol and/or drug dependence and alleles of an exon 13 polymorphism of the Gsalpha gene in either black or white individuals. PMID- 26735788 TI - Induction of Fos protein by 3,4- methylenedioxymethamphetamine (Ecstasy) in rat brain: regional differences in pharmacological manipulation. AB - Psychostimulant drugs have been reported to increase the expression of some immediate-early genes in the brain. In the present study, immunohistochemical techniques were used to assess the pattern of Fos protein produced by 3,4 methylenedioxymethamphetamine (MDMA) in several brain regions. Furthermore, we also studied the role of the dopamine D and D receptors and the N-methyl- D aspartate (NMDA) receptor in the induction of Fos protein by MDMA. A single administration of MDMA (5, 10 or 20 mg/kg) caused marked induction of Fos immunoreactivity in several regions including frontal cortex, striatum and olfactory tubercle of rat brain, in a dose-dependent manner. However, in the hippocampus and cerebellum, there were few or no Fos immunoreactive cells induced by MDMA. Furthermore, the induction of Fos protein in the striatum and olfactory tubercle after administration of MDMA (10 mg/kg) was blocked by pre-treatment with the dopamine D receptor antagonist SCH 23390 (1 mg/kg) or the NMDA receptor antagonist dizocilpine (1 mg/kg), but not by the dopamine D receptor antagonist ( )-sulpiride (100 mg/kg). However, the induction of Fos protein in the frontal cortex and hippocampus by MDMA was unaltered by pretreatment with SCH 23390 (1 mg/kg) or (-)-sulpiride (100 mg/kg). These results suggest that MDMA induces the expression of Fos protein in several regions of rat brain, and that the expression of Fos protein by MDMA in the striatum and olfactory tubercle appears to be mediated at least in part by the dopamine D and NMDA receptors. PMID- 26735789 TI - Ethanol-induced osmolality changes and lymphocyte proliferation. AB - While there have been reports on the in vitro effects of ethanol on mitogen stimulated lymphocyte proliferation, little attention has been paid to whether these effects are mediated by the ethanol molecule per se or the associated hyperosmolality. There is controversy whether ethanol at high concentrations inhibits or has no effect on mitogen-stimulated proliferation of T cells. In this study we sought to distinguish between effects due to ethanol and those related to increased osmolality. Rat splenocytes were cultured in vitro in hypertonic (320 mOsm) or isotonic (320 mOsm) ethanol solutions (up to 400 mg/dL), or in corresponding hypertonic solutions without ethanol. Proliferative responses to the B cell mitogen lipopolysaccharide and the T cell mitogen concanavalin A were measured by mitochondrial dimethylthiazole diphenyl tetrazolium metabolism and [(3) H]-thymidine incorporation into DNA. B cell response was not significantly affected by ethanol under any conditions. By contrast, T cell proliferative responses were significantly inhibited by isotonic ethanol solutions or hypertonic solutions in the absence of ethanol, but not by hypertonic ethanol solutions. These results indicate that, while high osmolality is normally inhibitory to lymphocyte function, the increase in osmolality caused by ethanol is protective against the otherwise detrimental effects of ethanol. PMID- 26735790 TI - Concentrations of transferrin and carbohydrate-deficient transferrin in postmortem human brain from alcoholics. AB - Transferrin (T f) and its carbohydrate-deficient isoform (CDT) were measured by radioimmunoassay in phosphate-buffered saline extracts of two informative areas of cerebral cortex tissue obtained at autopsy from alcoholics without other associated disease (n = 4); alcoholics with cirrhosis of the liver (n = 4) and agematched controls (n = 4). Total T f was also measured in two informative cortical areas from five dementia cases. All cases were male. Total immunoreactive T f was assayed directly in the extract, CDT immunoreactivity in the concentrated eluate after the sialylated form was removed by passing through DEAE-Sephacel at pH 5.65. Brain CDT averaged 10% of total T f overall. Although replicate extractions of individual samples gave consistent assays for both substances, there was wide variation both between different cortical areas from a given case and between cases within groups. There were no significant differences between total T f levels in uncomplicated alcoholics, dementia cases and controls, but cirrhotic alcoholics gave significantly higher values. The CDT: T f ratio was not increased in the brains of either group of alcoholics compared to controls. Whereas the serum CDT: T f ratio is an excellent marker of recent alcohol consumption, brain T f and CDT concentrations do not mark alcoholism nor dementia, and their biological variability diminishes their usefulness as disease indices. However, brain T f may be a marker of cirrhosis-induced changes. PMID- 26735791 TI - The effect of acetaldehyde on human brain transketolase activity. AB - Chronic alcoholism and thiamine deficiency are well documented factors in the aetiology of Wernicke-Korsakoff Syndrome. More recently, acetaldehyde (ACH) has been implicated as a possible aetiological factor. In the present investigation the direct effect of ACH was studied on the activity of transketolase, a thiaminedependent enzyme, as well as two non-thiamine-dependent enzymes (aspartate aminotransferase and lactate dehydrogenase), isolated from five control human brains. The concentration of ACH required to inhibit 50% activity of holo- and apo-transketolase was 80 mM and 60 mM, respectively, whereas that for aspartate aminotransferase and lactate dehydrogenase was 14 mM and 10 mM, respectively. None of the enzymes were completely inhibited by the range of ACH concentrations used in the study. It was concluded that the thiamineindependent enzymes were markedly affected by the concentrations of ACH which did not affect the thiaminedependent enzyme, transketolase. In vitro studies with homogenates pre-treated with ACH in the presence of various concentrations of glutathione showed that the latter had a protective effect against loss of transketolase activity. PMID- 26735793 TI - Successful treatment of isolated venous malformation with 1444-nm fiberoptic Nd YAG laser. AB - Two patients with isolated venous malformations on the face were treated with fiberoptic Nd-YAG laser (Lutronic laser company, South Korea). After nerve block anesthesia, the laser tip was pushed into the lesions either through a hole made by a 16 gauge needle or directly by inserting and triggering the laser tip few millimeters away from the lesions. The laser tip was pushed from one or few directions and moved back and forth, while triggering, in a fan pattern to cover the whole lesion. The procedure was continued till complete flattening of the lesions. The parameters used were pulse rate = 30 hertz, pulse energy = 300 mJoules, power = 6.0 watt, and total energy used for the first patient was 1000 Joules and for the second patient was 800 joules. RESULTS: The lesions flattened completely after whole tissue coagulation. Moderate redness disappeared in the first 48 hours. No persistent discoloration and no sign of cutaneous burning appeared after the procedures. No antibiotic or analgesic was prescribed after the procedure. The patients were followed for more than 2 years with no recurrence and good cosmetic results. CONCLUSION: The fiberoptic Nd-YAG laser can be used as an effective procedure for venous malformations. PMID- 26735794 TI - High-Molecular-Weight Proanthocyanidins in Foods: Overcoming Analytical Challenges in Pursuit of Novel Dietary Bioactive Components. AB - Proanthocyanidins (PACs) are an abundant but complex class of polyphenols found in foods and botanicals. PACs are polymeric flavanols with a variety of linkages and subunits. Connectivity and degree of polymerization (DP) determine PAC bioavailability and bioactivity. Current quantitative and qualitative methods may ignore a large percentage of dietary PACs. Subsequent correlations between intake and activity are hindered by a lack of understanding of the true PAC complexity in many foods. Additionally, estimates of dietary intakes are likely inaccurate, as nutrient databank values are largely based on standards from cocoa (monomers to decamers) and blueberries (mean DP of 36). Improved analytical methodologies are needed to increase our understanding of the biological roles of these complex compounds. PMID- 26735795 TI - High-Intensity Ultrasound to Improve Physical and Functional Properties of Lipids. AB - High-intensity ultrasound (HIU) has been used in recent years to change the crystallization behavior of edible lipids. This technique can be used in combination with other processing technologies to tailor lipids' functional properties and broaden their application for various food products. In general, sonication induces crystallization, increases crystallization rate, and generates a harder and more elastic crystalline network characterized by smaller crystals with a sharper melting profile. An important application of HIU is to improve the hardness and elasticity of shortenings that have a low content of saturated fatty acids and are free of trans-fats. This review summarizes recent research that used HIU to change the physical and functional properties of edible lipids and focuses on the importance of controlling processing variables such as sonication power level and duration and crystallization temperature. PMID- 26735796 TI - Conjugated Linoleic Acid: Potential Health Benefits as a Functional Food Ingredient. AB - Conjugated linoleic acid (CLA) has drawn significant attention since the 1980s for its various biological activities. CLA consists mainly of two isomers, cis 9,trans-11 and trans-10,cis-12, and the mixture of these two (CLA mix or 50:50) has been approved for food as GRAS (generally recognized as safe) in the United States since 2008. Along with its original discovery as an anticancer component, CLA has been shown to prevent the development of atherosclerosis, reduce body fat while improving lean body mass, and modulate immune and/or inflammatory responses. This review summarizes the clinical trials involving CLA since 2012; additional uses of CLA for age-associated health issues are discussed; and CLA's potential health concerns, including glucose homeostasis, oxidative stress, hepatic steatosis, and milk-fat depression, are examined. With ongoing applications to food products, CLA consumption is expected to rise and close monitoring of not only its efficacy but also its known and unknown consequences are required to ensure proper applications of CLA. PMID- 26735797 TI - Organic Nanoparticles in Foods: Fabrication, Characterization, and Utilization. AB - In the context of food systems, organic nanoparticles (ONPs) are fabricated from proteins, carbohydrates, lipids, and other organic compounds to a characteristic dimension, such as a radius smaller than 100 nm. ONPs can be fabricated with bottom-up and top-down approaches, or a combination of both, on the basis of the physicochemical properties of the source materials and the fundamental principles of physical chemistry, colloidal and polymer sciences, and materials science and engineering. ONPs are characterized for dimension, morphology, surface properties, internal structures, and biological properties to understand structure-function correlations and to explore their applications. These potential applications include modifying physical properties, improving sensory attributes and food quality, protecting labile compounds, and delivering encapsulated bioactive compounds for improved bioactivity and bioavailability. Because ONPs can have digestion and absorption properties different from conventional materials, the eventual applications of ONPs require in vitro and in vivo studies to guide the development of safe food products that utilize the unique functionalities of ONPs. PMID- 26735798 TI - Phage-Host Interactions of Cheese-Making Lactic Acid Bacteria. AB - Cheese production is a global biotechnological practice that is reliant on robust and technologically appropriate starter and adjunct starter cultures to acidify the milk and impart particular flavor and textural properties to specific cheeses. To this end, lactic acid bacteria, including Lactococcus lactis, Streptococcus thermophilus, and Lactobacillus and Leuconostoc spp., are routinely employed. However, these bacteria are susceptible to infection by (bacterio)phages. Over the past decade in particular, significant advances have been achieved in defining the receptor molecules presented by lactococcal host bacteria and in the structural analysis of corresponding phage-encoded receptor binding proteins. These lactococcal model systems are expanding toward understanding phage-host interactions of other LAB species. Ultimately, such scientific efforts will uncover the mechanistic (dis)similarities among these phages and define how these phages recognize and infect their hosts. This review presents the current status of the LAB-phage interactome, highlighting the most recent and significant developments in this active research field. PMID- 26735799 TI - Development, Characterization, and Utilization of Food-Grade Polymer Oleogels. AB - The potential of organogels (oleogels) for oil structuring has been identified and investigated extensively using different gelator-oil systems in recent years. This review provides a comprehensive summary of all oil-structuring systems found in the literature, with an emphasis on ethyl-cellulose (EC), the only direct food grade polymer oleogelator. EC is a semicrystalline material that undergoes a thermoreversible sol-gel transition in the presence of liquid oil. This unique behavior is based on the polymer's ability to associate through physical bonds. These interactions are strongly affected by external fields such as shear and temperature, as well as by solvent chemistry, which in turn strongly affect final gel properties. Recently, EC-based oleogels have been used as a replacement for fats in foods, as heat-resistance agents in chocolate, as oil-binding agents in bakery products, and as the basis for cosmetic pastes. Understanding the characteristics of the EC oleogel is essential for the development of new applications. PMID- 26735800 TI - Caffeine: Friend or Foe? AB - The debate on the safety of and regulatory approaches for caffeine continues among various stakeholders and regulatory authorities. This decision-making process comes with significant challenges, particularly when considering the complexities of the available scientific data, making the formulation of clear science-based regulatory guidance more difficult. To allow for discussions of a number of key issues, the North American Branch of the International Life Sciences Institute (ILSI) convened a panel of subject matter experts for a caffeine-focused session entitled "Caffeine: Friend or Foe?," which was held during the 2015 ILSI Annual Meeting. The panelists' expertise covered topics ranging from the natural occurrence of caffeine in plants and interindividual metabolism of caffeine in humans to specific behavioral, reproductive, and cardiovascular effects related to caffeine consumption. Each presentation highlighted the potential risks, benefits, and challenges that inform whether caffeine exposure warrants concern. This paper aims to summarize the key topics discussed during the session. PMID- 26735801 TI - A Critical Look at Prebiotics Within the Dietary Fiber Concept. AB - This article reviews the current knowledge of the health effects of dietary fiber and prebiotics and establishes the position of prebiotics within the broader context of dietary fiber. Although the positive health effects of specific fibers on defecation, reduction of postprandial glycemic response, and maintenance of normal blood cholesterol levels are generally accepted, other presumed health benefits of dietary fibers are still debated. There is evidence that specific dietary fibers improve the integrity of the epithelial layer of the intestines, increase the resistance against pathogenic colonization, reduce the risk of developing colorectal cancer, increase mineral absorption, and have a positive impact on the immune system, but these effects are neither generally acknowledged nor completely understood. Many of the latter effects are thought to be particularly elicited by prebiotics. Although the prebiotic concept evolved significantly during the past two decades, the line between prebiotics and nonprebiotic dietary fiber remains vague. Nevertheless, scientific evidence demonstrating the health-promoting potential of prebiotics continues to accumulate and suggests that prebiotic fibers have their rightful place in a healthy diet. PMID- 26735802 TI - Career Paths of Recipients of a Master's Degree in Health Communication: Understanding Employment Opportunities, Responsibilities, and Choices. AB - A growing number of institutions offer a master's degree in health communication to prepare individuals for applied work in the field, but there is very little literature on the career paths graduates pursue. The current study reports the results of a national survey that targeted the alumni of five institutions that offer the degree. Of the 522 total graduates to whom the survey was sent, 398 responded (76.2% response rate). Results show that the degree recipients have found employment in a wide variety of organizations across the country, including jobs within very prestigious organizations, such as the National Cancer Institute. Common job titles include manager, coordinator, communication associate/specialist, and program/project director. The most common job responsibilities include research activities, the development of health communication materials, project/program management, communication management, and social media/website management. The results also include stories of graduates across programs that illustrate details of career paths. The discussion of the findings addresses implications for career preparation, curriculum development, and advising. PMID- 26735803 TI - Non-invasive cryolipolysis to reduce subcutaneous fat in the arms. AB - BACKGROUND: Cryolipolysis received U.S. Food and Drug Administration clearance for reducing fat from the flanks, abdomen, and thighs. The upper arms are an off label indication for cryolipolysis, and outcome data on reducing fat from the arms using a cryolipolytic device has rarely been published. OBJECTIVE: This pilot study evaluated cryolipolysis to reduce upper arm fat. MATERIALS AND METHODS: A flat vacuum applicator was used to treat seven subjects in a single side study. The patients underwent one cycle of upper-arm cryolipolysis treatment, and the contralateral arm served as a control. Follow-up was conducted at 8 weeks. Equalization treatments were delivered subsequently to the opposite arm. Efficacy was evaluated by ultrasound imaging, physician's assessment, and patient satisfaction. Side effects and adverse events were monitored. RESULTS: Ultrasound measurements showed a decrease in the fat layer at 83.3% of the 12 measured sites. The mean reduction in fat layer thickness was 15.3%, corresponding to 2.03 mm. A significant difference was detected between baseline and 8-week assessments (p = 0.001). CONCLUSION: One treatment using a flat vacuum cryolipolysis applicator was safe and effective to reduce arm fat. PMID- 26735804 TI - Sexual Excitation and Sexual Inhibition as Predictors of Sexual Function in Women: A Cross-Sectional and Longitudinal Study. AB - To date, no longitudinal studies have evaluated the predictive value of the two factors of the dual control model-sexual excitation (SE) and sexual inhibition (SI)-for future sexual function. The aims of the present study were to investigate the associations between SE/SI and sexual function and estimate their predictive value for future sexual function in a sample of women. Overall, 2,214 women participated in a web-based survey that assessed SE, SI, and sexual function as well as symptoms of depression. The one- and two-year follow-up surveys included 396 and 382 participants, respectively. Correlational analyses and hierarchical regression analyses were conducted to analyze the relationships between predictor and outcome variables. Four factors of SE (Arousability, Partner Characteristics, Sexual Power Dynamics, and Setting) and two factors of SI (Concerns about Sexual Function and Arousal Contingency), as well as symptoms of depression and partnership status, were significant predictors of concurrent and future sexual function. Several subscales of SE and SI contributed to the prediction of future sexual function above and beyond prior sexual function levels. Our study provides the first supportive evidence for the assumptions of the dual control model that propensities for low SE and high SI influence future sexual function. PMID- 26735805 TI - Novel hollow and yolk-shell structured periodic mesoporous polymer nanoparticles. AB - The pioneered construction of novel monodisperse hollow and yolk-shell structured periodic mesoporous polymer nanoparticles was reported by the development of an efficient reactive interface-guided co-assembly approach. PMID- 26735843 TI - Significant Enhancement of the Chiral Correlation Length in Nematic Liquid Crystals by Gold Nanoparticle Surfaces Featuring Axially Chiral Binaphthyl Ligands. AB - Chirality is a fundamental scientific concept best described by the absence of mirror symmetry and the inability to superimpose an object onto its mirror image by translation and rotation. Chirality is expressed at almost all molecular levels, from single molecules to supramolecular systems, and present virtually everywhere in nature. Here, to explore how chirality propagates from a chiral nanoscale surface, we study gold nanoparticles functionalized with axially chiral binaphthyl molecules. In particular, we synthesized three enantiomeric pairs of chiral ligand-capped gold nanoparticles differing in size, curvature, and ligand density to tune the chirality transfer from nanoscale solid surfaces to a bulk anisotropic liquid crystal medium. Ultimately, we are examining how far the chirality from a nanoparticle surface reaches into a bulk material. Circular dichroism spectra of the gold nanoparticles decorated with binaphthyl thiols confirmed that the binaphthyl moieties form a cisoid conformation in isotropic organic solvents. In the chiral nematic liquid crystal phase, induced by dispersing the gold nanoparticles into an achiral anisotropic nematic liquid crystal solvent, the binaphthyl moieties on the nanoparticle surface form a transoid conformation as determined by imaging the helical twist direction of the induced cholesteric phase. This suggests that the ligand density on the nanoscale metal surfaces provides a dynamic space to alter and adjust the helicity of binaphthyl derivatives in response to the ordering of the surrounding medium. The helical pitch values of the induced chiral nematic phase were determined, and the helical twisting power (HTP) of the chiral gold nanoparticles calculated to elucidate the chirality transfer efficiency of the binaphthyl ligand capped gold nanoparticles. Remarkably, the HTP increases with increasing diameter of the particles, that is, the efficiency of the chirality transfer of the binaphthyl units bound to the nanoparticle surface is diminished as the size of the particle is reduced. However, in comparison to the free ligands, per chiral molecule all tested gold nanoparticles induce helical distortions in a 10- to 50-fold larger number of liquid crystal host molecules surrounding each particle, indicating a significantly enhanced chiral correlation length. We propose that both the helicity and the chirality transfer efficiency of axially chiral binaphthyl derivatives can be controlled at metal nanoparticle surfaces by adjusting the particle size and curvature as well as the number and density of the chiral ligands to ultimately measure and tune the chiral correlation length. PMID- 26735842 TI - Exploring Selective Inhibition of the First Bromodomain of the Human Bromodomain and Extra-terminal Domain (BET) Proteins. AB - A midthroughput screening follow-up program targeting the first bromodomain of the human BRD4 protein, BRD4(BD1), identified an acetylated-mimic xanthine derivative inhibitor. This compound binds with an affinity in the low micromolar range yet exerts suitable unexpected selectivity in vitro against the other members of the bromodomain and extra-terminal domain (BET) family. A structure based program pinpointed a role of the ZA loop, paving the way for the development of potent and selective BET-BRDi probes. PMID- 26735844 TI - The economic burden of brain metastasis among lung cancer patients in the United States. AB - OBJECTIVE: Brain metastases among lung cancer patients can impair cognitive and functional ability, complicate care, and reduce survival. This study focuses on the economic burden of brain metastasis in lung cancer-direct healthcare costs to payers and indirect costs to patients, payers, and employers-in the US. METHODS: Retrospective study using claims data from over 60 self-insured Fortune 500 companies across all US census regions (January 1999-March 2013). Adult, non elderly lung cancer patients with brain metastasis were evaluated over two study periods: (1) pre-diagnosis (<=30 days prior to first observed lung cancer diagnosis to <=30 days prior to first-observed brain metastasis diagnosis) and (2) post-diagnosis (<=30 days prior to first observed brain metastasis diagnosis to end of continuous eligibility or observation). OUTCOME MEASURES: Healthcare costs to payers and resource utilization, salary loss to patients, disability payouts for payers, and productivity loss to employers. RESULTS: A total of 132 patients were followed for a median of 8.4 and 6.6 months in the pre- and post diagnosis periods, respectively. At diagnosis of brain metastasis, 21.2% of patients were on leave of absence and 6.1% on long-term disability leave. Substantial differences were observed in the pre- vs post-diagnosis periods. Specifically, patients incurred much greater healthcare utilization in the post diagnosis period, resulting in $25,579 higher medical costs per-patient-per-6 months (PPP6M). During this period, patients missed significantly more work days, generating an incremental burden of $2853 PPP6M in salary loss for patients, $2557 PPP6M in disability payments for payers, and $4570 PPP6M in productivity loss for employers. LIMITATIONS: Type of primary lung cancer and extent of brain metastasis could not be assessed in the data. The analysis was also limited to patients with comprehensive disability coverage. CONCLUSIONS: Development of brain metastasis among lung cancer patients is associated with a substantial economic burden to payers, patients, and employers. PMID- 26735846 TI - Failure to Respond to Food Resource Decline Has Catastrophic Consequences for Koalas in a High-Density Population in Southern Australia. AB - Understanding the ability of koalas to respond to changes in their environment is critical for conservation of the species and their habitat. We monitored the behavioural response of koalas to declining food resources in manna gum (Eucalyptus viminalis) woodland at Cape Otway, Victoria, Australia, from September 2011 to November 2013. Over this period, koala population density increased from 10.1 to 18.4 koalas.ha-1. As a result of the high browsing pressure of this population, manna gum canopy condition declined with 71.4% manna gum being completely or highly defoliated in September 2013. Despite declining food resources, radio collared koalas (N = 30) exhibited high fidelity to small ranges (0.4-1.2 ha). When trees became severely defoliated in September 2013, koalas moved relatively short distances from their former ranges (mean predicted change in range centroid = 144 m) and remained in areas of 0.9 to 1.0 ha. This was despite the high connectivity of most manna gum woodland, and close proximity of the study site (< 3 km) to the contiguous mixed forest of the Great Otway National Park. Limited movement had catastrophic consequences for koalas with 71% (15/21) of radio collared koalas dying from starvation or being euthanased due to their poor condition between September and November 2013. PMID- 26735845 TI - Micronutrient-Fortified Rice Can Increase Hookworm Infection Risk: A Cluster Randomized Trial. AB - BACKGROUND: Fortification of staple foods is considered an effective and safe strategy to combat micronutrient deficiencies, thereby improving health. While improving micronutrient status might be expected to have positive effects on immunity, some studies have reported increases in infections or inflammation after iron supplementation. OBJECTIVE: To study effects of micronutrient fortified rice on hookworm infection in Cambodian schoolchildren. METHODS: A double-blinded, cluster-randomized trial was conducted in 16 Cambodian primary schools partaking in the World Food Program school meal program. Three types of multi-micronutrient fortified rice were tested against placebo rice within the school meal program: UltraRice_original, UltraRice_improved and NutriRice. Four schools were randomly assigned to each study group (placebo n = 492, UltraRice_original n = 479, UltraRice_improved n = 500, NutriRice n = 506). Intestinal parasite infection was measured in fecal samples by Kato-Katz method at baseline and after three and seven months. In a subgroup (N = 330), fecal calprotectin was measured by ELISA as a marker for intestinal inflammation. RESULTS: Baseline prevalence of hookworm infection was 18.6%, but differed considerably among schools (range 0%- 48.1%).Micronutrient-fortified rice significantly increased risk of new hookworm infection. This effect was modified by baseline hookworm prevalence at the school; hookworm infection risk was increased by all three types of fortified rice in schools where baseline prevalence was high (>15%), and only by UltraRice_original in schools with low baseline prevalence. Neither hookworm infection nor fortified rice was related to fecal calprotectin. CONCLUSIONS: Consumption of rice fortified with micronutrients can increase hookworm prevalence, especially in environments with high infection pressure. When considering fortification of staple foods, a careful risk-benefit analysis is warranted, taking into account severity of micronutrient deficiencies and local prevalence of parasitic infections. TRIAL REGISTRATION: ClinicalTrials.gov NCT01706419. PMID- 26735847 TI - Empirical Study of User Preferences Based on Rating Data of Movies. AB - User preference plays a prominent role in many fields, including electronic commerce, social opinion, and Internet search engines. Particularly in recommender systems, it directly influences the accuracy of the recommendation. Though many methods have been presented, most of these have only focused on how to improve the recommendation results. In this paper, we introduce an empirical study of user preferences based on a set of rating data about movies. We develop a simple statistical method to investigate the characteristics of user preferences. We find that the movies have potential characteristics of closure, which results in the formation of numerous cliques with a power-law size distribution. We also find that a user related to a small clique always has similar opinions on the movies in this clique. Then, we suggest a user preference model, which can eliminate the predictions that are considered to be impracticable. Numerical results show that the model can reflect user preference with remarkable accuracy when data elimination is allowed, and random factors in the rating data make prediction error inevitable. In further research, we will investigate many other rating data sets to examine the universality of our findings. PMID- 26735848 TI - Role of Ultra-Wide Field Imaging in the Management of Tubercular Posterior Uveitis. AB - PURPOSE: To assess the utility of ultra-wide field (UWF) versus conventional fundus imaging in the management of tubercular (TB) posterior uveitis. METHODS: Twenty-two consecutive patients (33 eyes) diagnosed with TB posterior uveitis in a tertiary care center who underwent UWF fundus photography and fluorescein angiography (FA) between July 2014 and March 2015 were included. Complete clinical and imaging records of the patients were retrospectively reviewed. A circle simulating the central 75-degree field was drawn on UWF pseudocolor and fluorescein angiography images. Findings within the circle were compared with the information yielded by the complete image and its impact on patient management was noted. RESULTS: The clinical manifestations of posterior tubercular uveitis included retinal vasculitis (17 eyes), multifocal serpiginoid choroiditis (13 eyes), choroidal granulomas (2 eyes) and intermediate uveitis (1 eye). UWF imaging revealed additional capillary non-perfusion areas, neovascularization, active vasculitis, and peripheral choroiditis lesions in 30/33 eyes (90.9%), which influenced treatment decision in 15 eyes (45.5%). CONCLUSIONS: UWF imaging is useful in the detection of peripheral pathologies in tubercular posterior uveitis that may influence management decisions, such as addition of immunosuppressive therapy or scatter laser photocoagulation. PMID- 26735849 TI - Estimation of a Killer Whale (Orcinus orca) Population's Diet Using Sequencing Analysis of DNA from Feces. AB - Estimating diet composition is important for understanding interactions between predators and prey and thus illuminating ecosystem function. The diet of many species, however, is difficult to observe directly. Genetic analysis of fecal material collected in the field is therefore a useful tool for gaining insight into wild animal diets. In this study, we used high-throughput DNA sequencing to quantitatively estimate the diet composition of an endangered population of wild killer whales (Orcinus orca) in their summer range in the Salish Sea. We combined 175 fecal samples collected between May and September from five years between 2006 and 2011 into 13 sample groups. Two known DNA composition control groups were also created. Each group was sequenced at a ~330bp segment of the 16s gene in the mitochondrial genome using an Illumina MiSeq sequencing system. After several quality controls steps, 4,987,107 individual sequences were aligned to a custom sequence database containing 19 potential fish prey species and the most likely species of each fecal-derived sequence was determined. Based on these alignments, salmonids made up >98.6% of the total sequences and thus of the inferred diet. Of the six salmonid species, Chinook salmon made up 79.5% of the sequences, followed by coho salmon (15%). Over all years, a clear pattern emerged with Chinook salmon dominating the estimated diet early in the summer, and coho salmon contributing an average of >40% of the diet in late summer. Sockeye salmon appeared to be occasionally important, at >18% in some sample groups. Non salmonids were rarely observed. Our results are consistent with earlier results based on surface prey remains, and confirm the importance of Chinook salmon in this population's summer diet. PMID- 26735850 TI - An Audit of Protocol Deviations Submitted to an Institutional Ethics Committee of a Tertiary Care Hospital. AB - Protocol deviations (PDs) may jeopardize safety, rights, and welfare of subjects and data integrity. There is scarce literature and no guidelines for Institutional Ethics Committees (IECs) to process PD reports. The PD reports submitted to IECs from Jan 2011 to August 2014 were analyzed retrospectively. Types of studies reporting PDs, category and type of PDs, PD rate per participant, time of reporting PD since its occurrence and corrective actions stated by principal investigator (PI) for major deviations were noted. Out of 447 PDs from 73/1387 total studies received during study period, 402 were from 126 pharma studies. Investigator initiated studies and dissertations reported negligible PDs. Median number of PDs was 4 per protocol. Out of 447 PDs, 304 were related to study procedure, 87, 47 and 9 were from safety, informed consent document (ICD) and eligibility category respectively. The most common reason for PDs was incomplete ICD (22/47). Maximum study procedure related PDs were due to patient visiting outside window period (126/304). Thirty five of 87 PDs were due to missed safety assessment. The overall PD reporting rate per participant was 0.08. In 90% of reports, date of occurrence of PD was not specified. The median delay for reporting PDs after occurrence was 94 days. PDs classified as Major were 73% (323/447). The most common corrective actions stated by PI were participant counseling (85/323) and caution in future (70/323). The study findings emphasize the need for GCP training at regular interval of study team members. IEC have to be vigilant and visit sites frequently, take initiative and formulate guidelines regarding PD reporting. PMID- 26735853 TI - Long-Term Evolution of Email Networks: Statistical Regularities, Predictability and Stability of Social Behaviors. AB - In social networks, individuals constantly drop ties and replace them by new ones in a highly unpredictable fashion. This highly dynamical nature of social ties has important implications for processes such as the spread of information or of epidemics. Several studies have demonstrated the influence of a number of factors on the intricate microscopic process of tie replacement, but the macroscopic long term effects of such changes remain largely unexplored. Here we investigate whether, despite the inherent randomness at the microscopic level, there are macroscopic statistical regularities in the long-term evolution of social networks. In particular, we analyze the email network of a large organization with over 1,000 individuals throughout four consecutive years. We find that, although the evolution of individual ties is highly unpredictable, the macro evolution of social communication networks follows well-defined statistical patterns, characterized by exponentially decaying log-variations of the weight of social ties and of individuals' social strength. At the same time, we find that individuals have social signatures and communication strategies that are remarkably stable over the scale of several years. PMID- 26735854 TI - Abdominal wall reconstruction: Enhancing outcomes for patients with ventral incisional hernias. PMID- 26735851 TI - A Multilayer Network Approach for Guiding Drug Repositioning in Neglected Diseases. AB - Drug development for neglected diseases has been historically hampered due to lack of market incentives. The advent of public domain resources containing chemical information from high throughput screenings is changing the landscape of drug discovery for these diseases. In this work we took advantage of data from extensively studied organisms like human, mouse, E. coli and yeast, among others, to develop a novel integrative network model to prioritize and identify candidate drug targets in neglected pathogen proteomes, and bioactive drug-like molecules. We modeled genomic (proteins) and chemical (bioactive compounds) data as a multilayer weighted network graph that takes advantage of bioactivity data across 221 species, chemical similarities between 1.7 105 compounds and several functional relations among 1.67 105 proteins. These relations comprised orthology, sharing of protein domains, and shared participation in defined biochemical pathways. We showcase the application of this network graph to the problem of prioritization of new candidate targets, based on the information available in the graph for known compound-target associations. We validated this strategy by performing a cross validation procedure for known mouse and Trypanosoma cruzi targets and showed that our approach outperforms classic alignment-based approaches. Moreover, our model provides additional flexibility as two different network definitions could be considered, finding in both cases qualitatively different but sensible candidate targets. We also showcase the application of the network to suggest targets for orphan compounds that are active against Plasmodium falciparum in high-throughput screens. In this case our approach provided a reduced prioritization list of target proteins for the query molecules and showed the ability to propose new testable hypotheses for each compound. Moreover, we found that some predictions highlighted by our network model were supported by independent experimental validations as found post-facto in the literature. PMID- 26735852 TI - IL-17A Promotes Pulmonary B-1a Cell Differentiation via Induction of Blimp-1 Expression during Influenza Virus Infection. AB - B-1 cells play a critical role in early protection during influenza infections by producing natural IgM antibodies. However, the underlying mechanisms involved in regulating this process are largely unknown. Here we found that during influenza infection pleural cavity B-1a cells rapidly infiltrated lungs, where they underwent plasmacytic differentiation with enhanced IgM production. This process was promoted by IL-17A signaling via induction of Blimp-1 expression and NF kappaB activation in B-1a cells. Deficiency of IL-17A led to severely impaired B 1a-derived antibody production in the respiratory tract, resulting in a deficiency in viral clearance. Transfer of B-1a-derived natural antibodies rescued Il17a-/- mice from otherwise lethal infections. Together, we identify a critical function of IL-17A in promoting the plasmacytic differentiation of B-1a cells. Our findings provide new insights into the mechanisms underlying the regulation of pulmonary B-1a cell response against influenza infection. PMID- 26735855 TI - Trypanosoma brucei gambiense Infections in Mice Lead to Tropism to the Reproductive Organs, and Horizontal and Vertical Transmission. AB - Trypanosoma brucei gambiense, transmitted by the tsetse fly, is the main causative agent of Human African trypanosomosis in West Africa and poses a significant health risk to 70 million people. Disease progression varies depending on host immunity, but usually begins with a haemo-lymphatic phase, followed by parasite invasion of the central nervous system. In the current study, the tropism of T. b. gambiense 1135, causing a low level chronic 'silent' infection, was monitored in a murine model using bioluminescence imaging and PCR. A tropism to the reproductive organs, in addition to the central nervous system, after 12-18 months of infection was observed. Bioluminescent analysis of healthy females crossed with infected males showed that 50%, 62.5% and 37.5% of the female mice were subsequently positive for parasites in their ovaries, uteri and brain respectively. Although PCR confirmed the presence of parasites in the uterus of one of these mice, the blood of all mice was negative by PCR and LAMP. Subsequently, bioluminescent imaging of the offspring of infected female mice crossed with healthy males indicated parasites were present in the reproductive organs of both male (80%) and female (60%) offspring. These findings imply that transmission of T. b. gambiense 1135 occurs horizontally, most probably via sexual contact, and vertically in a murine model, which raises the possibility of a similar transmission in humans. This has wide reaching implications. Firstly, the observations made in this study are likely to be valid for wild animals acting as a reservoir for T. b. gambiense. Also, the reproductive organs may act as a refuge for parasites during drug treatment in a similar manner to the central nervous system. This could leave patients at risk of a relapse, ultimately allowing them to act as a reservoir for subsequent transmission by tsetse and possibly, horizontally and vertically. PMID- 26735856 TI - Clinicopathologic Characteristics of Hepatocellular Carcinoma With Reactive Ductule-like Components, a Subset of Liver Cancer Currently Classified as Combined Hepatocellular-Cholangiocarcinoma With Stem-Cell Features, Typical Subtype. AB - The aim of this study was to elucidate the clinicopathologic characteristics of hepatocellular carcinoma with reactive ductule-like components (HCC-RD), corresponding to combined hepatocellular-cholangiocarcinoma (CHC) with stem cell features, typical subtype. Retrospective clinicopathologic analysis was performed on HCCs surgically treated at the University of Tokyo Hospital between 1995 and 2013. RD components were defined as neoplastic ductular structures composed of small "stem/progenitor-like" cells. There were 46 HCC-RDs, comprising about 3% of all HCCs. Thirty-eight cases of CHC, classical type (classical CHC), were identified during the study period. When compared with conventional HCC, HCC-RD was characterized by younger patient age (P=0.016), higher frequency of female patients (P<0.001), and higher serum alpha-fetoprotein levels (P=0.005). Serum carbohydrate antigen 19-9 elevation was also more frequently observed in HCC-RD than in conventional HCC (P=0.002). Histologically, clear cell constituents and interstitial fibrosis were more frequent in HCC-RD than in conventional HCC (P=0.003 and <0.001, respectively). When compared with HCC-RD and conventional HCC, classical CHC was characterized by a poorly differentiated HCC component, frequent vascular invasion, and lymph node metastasis (P<0.05). There was little prognostic difference between HCC-RD and conventional HCC, whereas overall and disease-free survival in classical CHC was significantly worse than in conventional HCC. In conclusion, although HCC-RDs do have some unique clinicopathologic characteristics, they have no prognostic significance, and it is not reasonable to include these tumors in the CHC category. PMID- 26735858 TI - Evaluation for High-risk HPV in Squamous Cell Carcinomas and Precursor Lesions Arising in the Conjunctiva and Lacrimal Sac. AB - High-risk human papilloma virus (HR-HPV) is a well-established causative agent of oropharyngeal squamous cell carcinoma (SCC). In addition, HR-HPV has occasionally been reported to be present in dysplastic and malignant lesions of the conjunctiva and lacrimal sac, although its overall incidence and etiological role in periocular SCC are controversial. Sequential surgical samples of 52 combined cases of invasive SCC (I-SCC) and SCC in situ (SCCIS) from 2 periocular sites (conjunctiva and lacrimal sac) diagnosed over a 14-year period (2000 to 2014) were selected for evaluation, and relevant patient characteristics were documented. p16 immunohistochemistry was performed as a screening test. All p16 positive cases were further evaluated for HR-HPV using DNA in situ hybridization (DNA ISH), and a subset was also analyzed by polymerase chain reaction (PCR). Of 43 ocular surface squamous neoplasias (OSSNs), 30% (n=13; 8 SCCIS and 5 I-SCC cases) were positive for HR-HPV. HPV-positive OSSNs occurred in 8 men and 5 women with a mean age of 60 years (range, 39 to 94 y). HPV type-16 was detected in all conjunctival cases evaluated by PCR. All 5 conjunctival I-SCCs were nonkeratinizing (n=4) or partially keratinizing (n=1) and managed by simple excision. In contrast, HPV-negative conjunctival I-SCCs were predominantly keratinizing (11 keratinizing and 2 nonkeratinizing). Of 9 lacrimal sac I-SCCs (LSSCCs), 66.7% (n=6) were positive for HR-HPV by p16 and DNA ISH; HPV subtypes were HPV-16 (n=5) and HPV-58 (n=1). In addition, 2 p16-positive cases with negative DNA ISH results were HR-HPV positive (HPV-16 and HPV-33) when evaluated by PCR, suggesting that the rate of HR-HPV positivity among the LSSCCs may be as high as 89% (n=8). The combined group of HR-HPV-positive LSSCCs was seen in 4 men and 4 women with a mean age of 60 years (range, 34 to 71 y). Seven of the 8 HPV positive LSSCCs (87.5%) had a nonkeratinizing or partially keratinizing histomorphology, whereas 1 case (12.5%) was predominantly keratinizing. The presence of HR-HPV in 30% of OSSNs and at least 66.7% of LSSCCs suggests the possibility of an etiologic role for HR-HPV at these sites. PMID- 26735857 TI - Large Cell Neuroendocrine Carcinoma of the Head and Neck: A Clinicopathologic Series of 10 Cases With an Emphasis on HPV Status. AB - Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine neoplasm first described in the lung and subsequently well documented in many other anatomic sites. It has only recently been recognized that LCNEC can also occasionally arise in the head and neck. The role of human papillomavirus (HPV), which is associated with some small cell carcinomas of the head and neck, has not been investigated for LCNEC. We sought to further characterize the histologic, immunophenotypic, and clinical features of LCNEC and also investigate the role of HPV in this newly described group of tumors. The surgical pathology archives of 2 large academic institutions were searched for cases of LCNEC arising in the head and neck. p16 immunohistochemistry and HPV in situ hybridization were performed, and clinical information was obtained from electronic medical records. Ten cases of head and neck LCNEC were identified. The tumors arose in 6 men and 4 women ranging in age from 14 to 70 years (median, 63.5 y). The primary tumor sites were the oropharynx (n=4), the sinonasal tract (n=3), and the larynx (n=3). The LCNECs consisted of nests and trabeculae of medium-large cells with abundant cytoplasm, coarse chromatin, and prominent nucleoli with very high mitotic rates. The tumor nests were often associated with necrosis, peripheral palisading, and rosette formations. The LCNECs were positive for pan-cytokeratin and at least 1 neuroendocrine marker (most often synaptophysin) and were largely negative for p63 (focal staining in 2/10) and CK5/6 (staining in 1/10). The LCNECs demonstrated aggressive clinical behavior: 8 of 10 presented with advanced disease, 5 of 10 died, with 4 more living but with persistent tumor. Three of 10 LCNECs were HPV-related (HPV-LCNEC); they arose in the oropharynx (n=2) and sinonasal tract (n=1). The HPV-LCNECs did not differ from the HPV-negative tumors in histologic appearance or behavior: 2 patients with HPV-LCNEC have died because of their disease and 1 remains alive but with widespread metastases. LCNEC is a rare but distinct form of head and neck carcinoma that exhibits aggressive clinical behavior. A subset of oropharyngeal and sinonasal LCNEC is HPV related, but the presence of HPV may not impart a more favorable prognosis. Because of its aggressive behavior, LCNEC should be distinguished from moderately differentiated neuroendocrine carcinoma and squamous cell carcinoma. The morphology of LCNEC overlaps considerably with the nonkeratinizing appearance of HPV-related squamous cell carcinoma, and as a result a high index of suspicion is needed to identify LCNEC. Immunohistochemical studies for synaptophysin and p63 are helpful tools for making this distinction. PMID- 26735859 TI - Recurrent CIC Gene Abnormalities in Angiosarcomas: A Molecular Study of 120 Cases With Concurrent Investigation of PLCG1, KDR, MYC, and FLT4 Gene Alterations. AB - Angiosarcoma (AS) is a rare sarcoma subtype showing considerable clinicopathologic and genetic heterogeneity. Most radiation-induced AS show MYC gene amplifications, with a subset of cases harboring KDR, PTPRB, and PLCG1 mutations. Despite recent advances, the genetic abnormalities of most primary AS remain undefined. Whole-transcriptome sequencing was initiated in 2 index cases of primary soft tissue AS with epithelioid morphology occurring in young adults for novel gene discovery. The candidate abnormalities were validated and then screened by targeted sequencing and fluorescence in situ hybridization in a large cohort of 120 well-characterized AS cases. Findings were subsequently correlated with the status of KDR, PLCG1, MYC, and FLT4 gene abnormalities. The clinicopathologic relevance and prognostic significance of these genetic changes were analyzed by statistical methods. Concurrent CIC mutations and CIC rearrangements were identified in both index cases, with a CIC-LEUTX fusion detected in 1 case. Upon screening, an additional visceral AS in a young adult had a complex CIC rearrangement, whereas 6 others harbored only CIC mutations. All 3 CIC-rearranged AS cases lacked vasoformation and had a solid growth of round, epithelioid to rhabdoid cells, showing immunoreactivity for CD31 and Ets related gene and sharing a transcriptional signature with other round cell sarcomas, including CIC-rearranged tumors. Overall, CIC abnormalities occurred in 9% (9/98) of cases, affecting younger patients with primary AS, with an inferior disease-free survival. In contrast, PLCG1 and KDR mutations occurred in both primary and secondary AS cases, accounting for 9.5% and 7%, respectively, with a predilection for breast and bone/viscera location, regardless of MYC status. MYC amplification was present in most secondary AS related to breast cancer (91%) compared with other causes (25%) or primary AS (7%). FLT4-amplified AS lacked PLCG1/KDR mutations, occurring predominantly in MYC-amplified population, and showed poor prognosis. PMID- 26735860 TI - BSEP and MDR3: Useful Immunohistochemical Markers to Discriminate Hepatocellular Carcinomas From Intrahepatic Cholangiocarcinomas and Hepatoid Carcinomas. AB - We herein examined the immunohistochemical expression of 2 hepatocyte-specific transporters (bile salt export pump [BSEP] and multidrug-resistance protein 3 [MDR3]) in hepatocellular carcinomas (HCCs, n=54), intrahepatic cholangiocarcinomas (n=34), combined hepatocellular and cholangiocarcinomas (n=23), and hepatoid carcinomas originated from extrahepatic organs (n=27) to compare their diagnostic values with those of arginase-1 (ARG1) and hepatocyte paraffin-1 (HepPar-1). BSEP was expressed in 91% of HCCs and MDR3 in 83%. Although their sensitivities were slightly lower than those of ARG1 (96%) and HepPar-1 (93%), the 2 transporters appeared to be more specific for HCCs. ARG1 and HepPar-1 were expressed in intrahepatic cholangiocarcinomas (9% and 6%) and hepatoid carcinomas (22% and 44%, respectively), whereas BSEP and MDR3 were entirely negative in these neoplasms, except for 1 case of BSEP-positive hepatoid carcinoma of the esophagus. The highly specific expression of BSEP and MDR3 in hepatocytes was recapitulated in additional examinations of combined hepatocellular and cholangiocarcinomas, in which the expression of the transporters was restricted to morphologically hepatocellular areas. In contrast, ARG1 and HepPar-1 were also variably positive in areas of biliary or indeterminate differentiation. We also applied BSEP and MDR3 immunohistochemistry to 8 biopsy cases of poorly differentiated primary liver cancer, in which the original diagnosis was not conclusive. The diagnosis of HCC was retrospectively suggested in 2 cases expressing both BSEP and MDR3. In conclusion, given the highly specific expression of BSEP and MDR3 in HCCs, immunohistochemistry for these transporters will be useful not only for determining hepatocellular differentiation in primary liver cancers but also for discriminating HCCs from hepatoid carcinomas. PMID- 26735862 TI - An interesting case of left-to-right shunt: clues from noninvasive imaging. PMID- 26735863 TI - Use of Anti-Noxa Antibody for Differential Diagnosis between Epithelioid Mesothelioma and Reactive Mesothelial Hyperplasia. AB - OBJECTIVES: The histological differential diagnosis between epithelioid mesothelioma (EM) and reactive mesothelial hyperplasia (RMH) is not always straightforward. The aim of the present study was to search for new immunohistochemical markers to distinguish EM from RMH. METHODS: We evaluated and compared the expression of apoptosis-related genes in EM and RMH by real-time RT PCR array analysis followed by clustering of significant gene expression. Immunohistochemical staining and statistical analysis of Noxa expression in 81 cases of EM and 55 cases of RMH were performed and compared with the utility of other previously reported antibodies such as Desmin, EMA, GLUT-1, IMP-3 and CD146. RESULTS: Noxa mRNA expression levels were found to be increased in EM when compared to RMH by RT-PCR array analysis. In the immunohistochemical analysis, Noxa showed sensitivity of 69.0%, specificity of 93.6% and positive predictive value of 93.0% as a positive marker of EM in distinguishing it from RMH, and these values were almost similar to IMP-3. CONCLUSION: Noxa is a marker with relatively high specificity, and can be used to distinguish EM from RMH. It would be a valuable addition to the current antibody panel used for the differential diagnosis of EM and RMH. PMID- 26735864 TI - Do Pain-related Beliefs Influence Adherence to Multidisciplinary Rehabilitation?: A Systematic Review. AB - OBJECTIVES: To understand how pain-related cognitions predict and influence treatment retention and adherence during and after a multidisciplinary rehabilitation program. METHODS: Electronic databases including Medline, CINAHL, PsycINFO, Academic Search Complete, and Scopus were used to search 3 combinations of key words: chronic pain, beliefs, and treatment adherence. RESULTS: The search strategy yielded 591 results, with an additional 12 studies identified through reference screening. Eighty-one full-text papers were assessed for eligibility and 10 papers met the inclusion and exclusion criteria for this review. The pain related beliefs that have been measured in relation to treatment adherence include: pain-specific self-efficacy, perceived disability, catastrophizing, control beliefs, fear-avoidance beliefs, perceived benefits and barriers, and other less commonly measured beliefs. The most common pain-related belief investigated in relation to treatment adherence was pain-related self-efficacy. Findings for the pain-related beliefs investigated among the studies were mixed. Collectively, all of the aforementioned pain-related beliefs, excluding control beliefs, were found to influence treatment adherence behaviors. DISCUSSION: The findings suggest that treatment adherence is determined by a combination of pain related beliefs either supporting or inhibiting chronic pain patients' ability to adhere to treatment recommendations over time. In the studies reviewed, self efficacy appears to be the most commonly researched predictor of treatment adherence, its effects also influencing other pain-related beliefs. More refined and standardized methodologies, consistent descriptions of pain-related beliefs, and methods of measurement will improve our understanding of adherence behaviors. PMID- 26735861 TI - Progress and perspective of inorganic nanoparticle-based siRNA delivery systems. AB - INTRODUCTION: Small interfering RNA (siRNA) is an effective method for regulating the expression of proteins, even "undruggable" ones that are nearly impossible to target through traditional small molecule therapeutics. Delivery to the cell and then to the cytosol is the primary requirement for realization of therapeutic potential of siRNA. AREAS COVERED: We summarize recent advances in the design of inorganic nanoparticle with surface functionality and physicochemical properties engineered for siRNA delivery. Specifically, we discuss the main approaches developed so far to load siRNA into/onto NPs, and NP surface chemistry engineered for enhanced intracellular siRNA delivery, endosomal escape, and targeted delivery of siRNA to disease cells and tissues. EXPERT OPINION: Several challenges remain in developing inorganic NPs for efficient and effective siRNA delivery. Getting the material to the chosen site is important, however the greatest hurdle may well be delivery into the cytosol, either through efficient endosomal escape or by direct cytosolic siRNA delivery. Effective delivery at the organismic and cellular level coupled with biocompatible vehicles with low immunogenic response will facilitate the clinical translation of RNAi for the treatment of genetic diseases. PMID- 26735865 TI - Maintenance measures for preservation and recovery of permeable pavement surface infiltration rate--The effects of street sweeping, vacuum cleaning, high pressure washing, and milling. AB - The surface infiltration rates (SIR) of permeable pavements decline with time as sediment and debris clog pore spaces. Effective maintenance techniques are needed to ensure the hydraulic functionality and water quality benefits of this stormwater control. Eight different small-scale and full-scale maintenance techniques aimed at recovering pavement permeability were evaluated at ten different permeable pavement sites in the USA and Sweden. Maintenance techniques included manual removal of the upper 2 cm of fill material, mechanical street sweeping, regenerative-air street sweeping, vacuum street sweeping, hand-held vacuuming, high pressure washing, and milling of porous asphalt. The removal of the upper 2 cm of clogging material did not significantly improve the SIR of concrete grid paves (CGP) and permeable interlocking concrete pavers (PICP) due to the inclusion of fines in the joint and bedding stone during construction, suggesting routine maintenance cannot overcome improper construction. For porous asphalt maintenance, industrial hand-held vacuum cleaning, pressure washing, and milling were increasingly successful at recovering the SIR. Milling to a depth of 2.5 cm nearly restored the SIR for a 21-year old porous asphalt pavement to like new conditions. For PICP, street sweepers employing suction were shown to be preferable to mechanical sweepers; additionally, maintenance efforts may become more intensive over time to maintain a threshold SIR, as maintenance was not 100% effective at removing clogging material. PMID- 26735866 TI - Application of controlled nutrient release to permeable reactive barriers. AB - The application of controlled release nutrient (CRN) materials to permeable reactive barriers to promote biodegradation of petroleum hydrocarbons in groundwater was investigated. The longevity of release, influence of flow velocity and petroleum hydrocarbon concentration on nutrient release was assessed using soluble and ion exchange CRN materials; namely PolyonTM and ZeoproTM. Both CRN materials, assessed at 4 degrees C and 23 degrees C, demonstrated continuing release of nitrogen, phosphorus and potassium (N-P-K) at 3500 bed volumes passing, with longer timeframes of N-P-K release at 4 degrees C. ZeoproTM-activated carbon mixtures demonstrated depletion of N-P-K prior to 3500 bed volumes passing. Increased flow velocity was shown to lower nutrient concentrations in PolyonTM flow cells while nutrient release from ZeoproTM was largely unchanged. The presence of petroleum hydrocarbons, at 1.08 mmol/L and 3.25 mmol/L toluene, were not shown to alter nutrient release from PolyonTM and ZeoproTM across 14 days. These findings suggest that PolyonTM and ZeoproTM may be suitable CRN materials for application to PRBs in low nutrient environments. PMID- 26735868 TI - Label-free detection of liver cancer cells by aptamer-based microcantilever biosensor. AB - Liver cancer is one of the most common and highly malignant cancers in the world. There are no effective therapeutic options if an early liver cancer diagnosis is not achieved. In this work, detection of HepG2 cells by label-free microcantilever array aptasensor was developed. The sensing microcantilevers were functionalized by HepG2 cells-specific aptamers. Meanwhile, to eliminate the interferences induced by the environment, the reference microcantilevers were modified with 6-mercapto-1-hexanol self-assembled monolayers. The aptasensor exhibits high specificity over not only human liver normal cells, but also other cancer cells of breast, bladder, and cervix tumors. The linear relation ranges from 1*10(3) to 1*10(5)cells/mL, with a detection limit of 300 cells/mL (S/N=3). Our work provides a simple method for detection of liver cancer cells with advantages in terms of simplicity and stability. PMID- 26735867 TI - Rehabilitation following cerebral anoxia: An assessment of 27 patients. AB - OBJECTIVES: (1) To evaluate cognitive and emotional impairments, disability and quality-of-life for adults with cerebral anoxia institutionalized in residential care facilities. (2) To evaluate the efficacy of medication, psychotherapy, support group and therapeutic activities. METHODS: Twenty-seven persons with cerebral anoxia were recruited, on average 8 years post-injury. Only 20 went through the whole study. Over three consecutive 2-month periods, they were assessed four times to evaluate: baseline observations (T1-T2), adjustment of their medication (T2-T3); and the effect of psychotherapy, support group and therapeutic activities such as physical and artistic or cultural activities usually proposed in the facilities involved (T3-T4). Examined variables at all time points were cognitive status, anxiety and depression, anosognosia, alexithymia, disability and quality-of-life. RESULTS: All participants exhibited cognitive and emotional impairments comparable to those reported in the literature. Statistical analyses revealed good baseline stability of their condition and no significant effects of changes in medication (between T2 and T3). Conversely, following implementation of psychotherapy, support group and therapeutic activities (between T3 and T4), quality-of-life and social participation were significantly improved. CONCLUSION: Social participation and quality-of-life for persons instutionalized several years after cerebral anoxia were improved by psychotherapeutic and therapeutic activities. PMID- 26735869 TI - Metal-organic frameworks supported surface-imprinted nanoparticles for the sensitive detection of metolcarb. AB - A novel approach to synthesize molecularly imprinted polymer (MIP) nanoparticles using a MIL-101 support (a type of metal-organic framework) is reported herein for the first time; the sample is referred as MIL@MIP. The nanoparticles were well distributed within the polymer film, and exhibit an octahedral shape, satisfied thermal stability, and a high specific surface area (SSA) of 1579.43 m(2)g(-1). The adsorption behavior of MIL@MIP toward metolcarb in aqueous solution was subsequently examined. The synthesized MIL@MIP displayed satisfactory high transfer mass rates and a high selective adsorption affinity for metolcarb. Based on these results, a quartz crystal microbalance (QCM) sensor based on MIL@MIP was subsequently constructed and examined for the sensitive detection of metolcarb. Under optimal conditions, the detection limit of the system assessed in pear juice was 0.0689 mg L(-1) within a linear concentration range of 0.1-0.9 mg L(-1). MIL@MIP-QCM system combines the advantages of MIL-101 and molecularly imprinted technology (MIT), thereby achieving high detection sensitivity and selectivity. The current findings suggest the potential of MIL@MIP for detecting trace level pesticides and veterinary drugs for food safety and environmental control. PMID- 26735870 TI - A novel electrochemical immunosensor based on the rGO-TEPA-PTC-NH2 and AuPt modified C60 bimetallic nanoclusters for the detection of Vangl1, a potential biomarker for dysontogenesis. AB - The aberrant expression of Vangl1 is highly correlated with dysontogenesis, especially for neural tube defects. Therefore, the ultrasensitive detection of Vangl1 would provide a new approach for the specific early diagnostics in dysembryoplasia. However, no quantitative detection method is currently available. Herein, we describe the development of a new approach to fill this assay gap. We utilized C60-templated AuPt bimetallic nanoclusters for signal amplification because the promising C60 nanomaterial provides a large surface area for the in site reduction of bimetallic nanocomposites as well as excellent conductivity. To further amplify the electrochemical signal, reduced graphene oxide-tetraethylene pentamine (rGO-TEPA) and a derivative of 3,4,9,10 perylenetetracarboxylicdianhydride (PTC-NH2) were selected for modification of the electrode to provide more amino groups for the immobilization of antibodies and to enhance the conductivity. The electrochemical signal was primarily derived from the catalysis of H2O2 by C60-AuPt. Chronoamperometry was applied to record the electrochemical signals. Under optimal conditions, the prepared immunosensor exhibited a wide linear range from 0.1 pg mL(-1) to 450 pg mL(-1) and a low detection limit of 0.03 pg mL(-1). Moreover, the proposed method exhibited good stability and recovery, suggesting its potential for use in clinical research. PMID- 26735871 TI - Microfluidic hydrogel arrays for direct genotyping of clinical samples. AB - A microfluidic hydrogel DNA microarray is developed to overcome the limitations of conventional planar microarrays such as low sensitivity, long overnight hybridization time, lack of a melting verification of proper hybrid, and complicated sample preparation process for genotyping of clinical samples. Unlike our previous prototype hydrogel array which can analyze only single-stranded DNA (ssDNA) targets, the device is the first of its type to allow direct multiplexed single nucleotide polymorphism (SNP) detection of human clinical samples comprising double-stranded DNA (dsDNA). This advance is made possible by incorporating a streptavidin (SA) hydrogel capture/purification element in a double T-junction at the start of the linear hydrogel array structure and fabricating ten different probe DNAs-entrapped hydrogels in microfluidic channels. The purified or unpurified polymerase chain reaction (PCR) products labeled with a fluorophore and a biotin are electrophoresed through the SA hydrogel for binding and purification. After electrophoretic washing, the fluorophore-labeled DNA strand is then thermally released for hybridization capture by its complementary probe gel element. We demonstrate the precise and rapid discrimination of the genotypes of five different clinical targets by melting curve analysis based on temperature-gradient electrophoresis within 3h, which is at least 3-fold decrease in incubation time compared to conventional microarrays. In addition, a 1.7 pg (0.024 femtomoles) limit of detection for clinical samples is achieved which is ~100-fold better sensitivity than planar microarrays. PMID- 26735872 TI - Electrochemiluminescent immunosensing of prostate-specific antigen based on silver nanoparticles-doped Pb (II) metal-organic framework. AB - In this work, silver nanoparticles-doped Pb (II) metal-organic framework (Ag-MOF) was prepared and exploited as a luminescence probe for the development of label free electrochemiluminescence (ECL) immunosensing scheme for prostate-specific antigen (PSA). The beta-cyclodextrin based MOF, Pb-beta-cyclodextrin (Pb(II)-beta CD) shows excellent ECL behavior and unexpected reducing capacity towards silver ions. Silver nanoparticles could massively form on the surface of Pb(II)-beta-CD (Ag@Pb(II)-beta-CD) without use any additional reducing agent, while the ECL behavior of Pb(II)-beta-CD still was well retained. The Ag@Pb(II)-beta-CD was used as a substrate material to modify glass carbon electrodes and formed a sensing platform for the fabricating ECL immunosensor. The presence of silver nanoparticles enables the facile immobilization of capturing antibody of PSA. The specific binding of PSA onto the electrode surface induces the decrease of ECL signals. A linear range of 0.001-50 ng mL(-1) with a detection limit of 0.34 pg mL(-1) (S/N=3) was obtained after the optimization of experimental conditions. This simply fabricated immunosensor exhibits good stability, accuracy and acceptable reproducibility, which suggesting its potential applications in clinical diagnostics. PMID- 26735873 TI - Recent advances on developing 3rd generation enzyme electrode for biosensor applications. AB - The electrochemical biosensor with enzyme as biorecognition element is traditionally pursued as an attractive research topic owing to their high commercial perspective in healthcare and environmental sectors. The research interest on the subject is sharply increased since the beginning of 21st century primarily, due to the concomitant increase in knowledge in the field of material science. The remarkable effects of many advance materials such as, conductive polymers and nanomaterials, were acknowledged in the developing efficient 3rd generation enzyme bioelectrodes which offer superior selectivity, sensitivity, reagent less detection, and label free fabrication of biosensors. The present review article compiles the major knowledge surfaced on the subject since its inception incorporating the key review and experimental papers published during the last decade which extensively cover the development on the redox enzyme based 3rd generation electrochemical biosensors. The tenet involved in the function of these direct electrochemistry based enzyme electrodes, their characterizations and various strategies reported so far for their development such as, nanofabrication, polymer based and reconstitution approaches are elucidated. In addition, the possible challenges and the future prospects in the development of efficient biosensors following this direct electrochemistry based principle are discussed. A comparative account on the design strategies and critical performance factors involved in the 3rd generation biosensors among some selected prominent works published on the subject during last decade have also been included in a tabular form for ready reference to the readers. PMID- 26735874 TI - Hybrid microarray based on double biomolecular markers of DNA and carbohydrate for simultaneous genotypic and phenotypic detection of cholera toxin-producing Vibrio cholerae. AB - Life-threatening diarrheal cholera is usually caused by water or food contaminated with cholera toxin-producing Vibrio cholerae. For the prevention and surveillance of cholera, it is crucial to rapidly and precisely detect and identify the etiological causes, such as V. cholerae and/or its toxin. In the present work, we propose the use of a hybrid double biomolecular marker (DBM) microarray containing 16S rRNA-based DNA capture probe to genotypically identify V. cholerae and GM1 pentasaccharide capture probe to phenotypically detect cholera toxin. We employed a simple sample preparation method to directly obtain genomic DNA and secreted cholera toxin as target materials from bacterial cells. By utilizing the constructed DBM microarray and prepared samples, V. cholerae and cholera toxin were detected successfully, selectively, and simultaneously; the DBM microarray was able to analyze the pathogenicity of the identified V. cholerae regardless of whether the bacteria produces toxin. Therefore, our proposed DBM microarray is a new effective platform for identifying bacteria and analyzing bacterial pathogenicity simultaneously. PMID- 26735875 TI - Enhanced biofilm distribution and cell performance of microfluidic microbial fuel cells with multiple anolyte inlets. AB - A laminar-flow controlled microfluidic microbial fuel cell (MMFC) is considered as a promising approach to be a bio-electrochemical system (BES). But poor bacterial colonization and low power generation are two severe bottlenecks to restrict its development. In this study, we reported a MMFC with multiple anolyte inlets (MMFC-MI) to enhance the biofilm formation and promote the power density of MMFCs. Voltage profiles during the inoculation process demonstrated MMFC-MI had a faster start-up process than the conventional microfluidic microbial fuel cell with one inlet (MMFC-OI). Meanwhile, benefited from the periodical replenishment of boundary layer near the electrode, a more densely-packed bacterial aggregation was observed along the flow direction and also the substantially low internal resistance for MMFC-MI. Most importantly, the output power density of MMFC-MI was the highest value among the reported ul-scale MFCs to our best knowledge. The presented MMFC-MI appears promising for bio-chip technology and extends the scope of microfluidic energy. PMID- 26735876 TI - Microfluidic paper-based analytical device for photoelectrochemical immunoassay with multiplex signal amplification using multibranched hybridization chain reaction and PdAu enzyme mimetics. AB - Combining multibranched hybridization chain reaction (mHCR), the photoelectrochemical (PEC) immunosensor was fabricated with a microfluidic paper based analytical devices using different sizes of CdTe quantum dots (QDs) sensitized flower-like 3D ZnO superstructures as photoactive materials. Firstly, 4-aminothiophenol (PATP) functioned ZnO was anchored on gold-paper working electrode. With the aid of PATP, large-sized CdTe-COOH QDs (QDs1) were conjugated onto the ZnO surface because of the formation of a strong bond (Zn-S) between the thiol of PATP molecule and the ZnO, and the remaining amino group formed an amide bond with carboxylic acid group capping CdTe. Then the small-sized CdTe-NH2 QDs (QDs2) were modified on the QDs1 by forming amide bond, which leaded to a very strong photocurrent response because of the formation of cosensitized structure. The designed mHCR produced long products with multiple branched arms, which could attached multiple PdAu nanoparticles and catalyze the oxidation of hydroquinone (HQ) using H2O2 as anoxidant. Double strands DNA with multiple branched arms (mdsDNA) was formed by mHCR. In the presence of carcinoembryonic antigen (CEA), PdAu-mdsDNA conjugates-labeled CEA antibody was captured. The concentrations of CEA were measured through the decrease in photocurrent intensity resulting from the increase in steric hindrance of the immunocomplex and the polymeric oxidation product of HQ. In addition, the oxidation product of HQ deposited on the as obtained electrode, which could efficiently inhibit the photoinduced electron transfer. Under optimal conditions, the PEC immunosensor exhibited excellent analytical performance: the detection range of CEA was from 0.001 to 90 ng mL(-1) with low detection limit of 0.33 pg mL(-1). The as-obtained immunosensor exhibited excellent precision, prominent specificity, acceptable stability and reproducibility, and could be used for the detection of CEA in real samples. The proposed assay opens a promising platform of clinical immunoassay for other biomolecules. PMID- 26735877 TI - Hydrothermal liquefaction of freshwater and marine algal biomass: A novel approach to produce distillate fuel fractions through blending and co-processing of biocrude with petrocrude. AB - Biocrude was produced from Tetraselmis sp. - a marine alga and Arthrospira platensis - a fresh water alga using hydrothermal liquefaction (HTL) process. Considering the constraints in cultivating algae for replacing 100% petrocrude, this study evaluated the option of blending and co-processing algal biocrude with petrocrude. Biocrudes obtained from algal strains cultivated in fresh water and sea water were blended with petrocrude at 10% concentration and the characteristics were studied using FT-IR and CNS SIMDIST. True Boiling Point (TBP) distillation was carried out to assess yields and properties of distillates of blended biocrudes. Biocrudes obtained from both algae were light crudes and the blended crudes recorded distillate yields of 76-77 wt%. The yield of light naphtha fraction of biocrude blends was 29-30%; whereas the yield of diesel fraction was about 18%. This study proposes blending and co-processing of algal biocrude with petrocrude to produce drop-in biofuels. PMID- 26735878 TI - Biodiesel production from Nannochloropsis gaditana lipids through transesterification catalyzed by Rhizopus oryzae lipase. AB - Biodiesel (fatty acid methyl esters, FAMEs) was produced from saponifiable lipids (SLs) extracted from wet Nannochloropsis gaditana biomass using methanolysis catalyzed by Rhizopus oryzae intracellular lipase. SLs were firstly extracted with ethanol to obtain 31 wt% pure SLs. But this low SL purity also gave a low biodiesel conversion (58%). This conversion increased up to 80% using SLs purified by crystallization in acetone (95 wt% purity). Polar lipids play an important role in decreasing the reaction velocity - using SLs extracted with hexane, which have lower polar lipid content (37.4% versus 49.0% using ethanol), we obtained higher reaction velocities and less FAME conversion decrease when the same lipase batch was reused. 83% of SLs were transformed to biodiesel using a 70 wt% lipase/SL ratio, 11:1 methanol/SL molar ratio, 10 mL t-butanol/g SLs after 72 h. The FAME conversion decreased to 71% after catalyzing three reactions with the same lipase batch. PMID- 26735879 TI - High-effective denitrification of low C/N wastewater by combined constructed wetland and biofilm-electrode reactor (CW-BER). AB - The low denitrification effect on constructed wetlands (CWs) treating low carbon to nitrogen ratio (C/N) wastewater was a problem. In this study, a novel coupled system by installing CW and biofilm-electrode reactor (CW-BER) was developed. In this system, the heterotrophic and autotrophic denitrifying bacteria all played their roles in denitrification process. The system was investigated systematically with simulated wastewater at different C/Ns, electric current intensities (I), hydraulic retention times (HRTs), and pH. Results showed that the optimum running conditions were C/N=0.75-1, I=15 mA, HRT=12 h, and pH=7.5. The highest removal efficiency of NO3-N and TN at the best conditions was respectively 63.03% and 98.11% for CW-BER. Also, the TN and NO3-N enhancive removal efficiency of CW-BER was 23.26% and 24.20%, respectively. No residual organic carbon source was detected in final effluent at the best parameters. PMID- 26735880 TI - Pilot-scale steam explosion for xylose production from oil palm empty fruit bunches and the use of xylose for ethanol production. AB - Pilot-scale steam explosion equipments were designed and constructed, to experimentally solubilize xylose from oil palm empty fruit bunches (OPEFB) and also to enhance an enzyme accessibility of the residual cellulose pulp. The OPEFB was chemically pretreated prior to steam explosion at saturated steam (SS) and superheated steam (SHS) conditions. The acid pretreated OPEFB gave the highest xylose recovery of 87.58 +/- 0.21 g/kg dried OPEFB in the liquid fraction after explosion at SHS condition. These conditions also gave the residual cellulose pulp with high enzymatic accessibility of 73.54 +/- 0.41%, which is approximately threefold that of untreated OPEFB. This study has shown that the acid pretreatment prior to SHS explosion is an effective method to enhance both xylose extraction and enzyme accessibility of the exploded OPEFB. Moreover, the xylose solution obtained in this manner could directly be fermented by Candida shehatae TISTR 5843 giving high ethanol yield of 0.30 +/- 0.08 g/g xylose. PMID- 26735881 TI - Influence of the gas composition on the efficiency of ammonia stripping of biogas digestate. AB - Impact of strip gas composition on side stream ammonia stripping, a technology aiming at the reduction of high ammonia levels in anaerobic reactors, was investigated. Evaluation of the effect of oxygen contact during air stripping showed a distinct, though lower than perceived, inhibition of anaerobic microflora. To circumvent, the feasibility and possible constraints of biogas and flue gas as alternatives in side stream stripping were studied. Experiments, with ammonia bicarbonate model solution and digestate, were conducted. It was demonstrated that the stripping performance is negatively correlated to the CO2 level in the strip gas with a progressive performance loss towards higher concentrations. In contrast to biogas with its high CO2 content, the efficiency reduction observed for flue gas was significantly less pronounced. The later provides the additional benefit that its high thermal energy can be re-utilized in the stripping unit and it is therefore considered a viable alternative for air. PMID- 26735882 TI - Introduction to the Special Issue on Propensity Score Methods in Behavioral Research. AB - This issue includes six articles that present logic, methods, and models for causal analyses of observational data, in particular those based on propensity score (PS) methods. The articles include a general introduction to propensity score analysis (PSA), uses of PSA in mediation studies, issues involved in choosing covariates, challenges that often arise in PSA applications, hierarchical data issues and models, and an application in an educational testing context. In this editorial I briefly summarize each article and make a few recommendations that relate to future applications in this field: the first pertains to how propensity score (PS) work could profit by connecting it with stronger forms of randomized experiments, not just simple randomization; the second to how and why graphical methods could be used to greater advantage in PSA studies; then why it might be helpful to reconsider the meaning of the term "treatments" in observational studies and why conventional usage might be modified; and finally, to the distinction between retrospective and prospective approaches to observational study design, noting the advantages, when feasible, of the latter approach. PMID- 26735883 TI - Covariate Selection in Propensity Scores Using Outcome Proxies. AB - This study examined the practical problem of covariate selection in propensity scores (PSs) given a predetermined set of covariates. Because the bias reduction capacity of a confounding covariate is proportional to the concurrent relationships it has with the outcome and treatment, particular focus is set on how we might approximate covariate-outcome relationships while retaining the PS as a design tool (i.e., without using the observed outcomes). To make this approach tractable, I examined the extent to which alternative measures of the outcome might inform covariate-outcome empirical relationships and corresponding covariate selection. Specifically, two such measures were examined: proximal pretreatment measures of the outcome and cross validation. Further, because the implications of covariate choice reach beyond the properties of the treatment effect estimator, I reason that the primary objective of PS covariate selection is to effectively and efficiently reduce bias while forming a scientific basis for inference through, for example, covariate balance. By using outcome proxies or cross validation, substantive knowledge is augmented with empirical evidence of covariates' bias reduction/amplification capacities to better inform covariate selection, improve estimation, and form an evidentiary basis for inference. PMID- 26735884 TI - Challenges With Propensity Score Strategies in a High-Dimensional Setting and a Potential Alternative. AB - This article explores some of the challenges that arise when trying to implement propensity score strategies to answer a causal question using data with a large number of covariates. We discuss choices in propensity score estimation strategies, matching and weighting implementation strategies, balance diagnostics, and final analysis models. We demonstrate the wide range of estimates that can result from different combinations of these choices. Finally, an alternative estimation strategy is presented that may have benefits in terms of simplicity and reliability. These issues are explored in the context of an empirical example that uses data from the Early Childhood Longitudinal Study, Kindergarten Cohort to investigate the potential effect of grade retention after the 1st-grade year on subsequent cognitive outcomes. PMID- 26735885 TI - The Use of Propensity Scores for Nonrandomized Designs With Clustered Data. AB - In this article we propose several modeling choices to extend propensity score analysis to clustered data. We describe different possible model specifications for estimation of the propensity score: single-level model, fixed effects model, and two random effects models. We also consider both conditioning within clusters and conditioning across clusters. We examine the underlying assumptions of these modeling choices and the type of randomized experiment approximated by each approach. Using a simulation study, we compare the relative performance of these modeling and conditioning choices in reducing bias due to confounding variables at both the person and cluster levels. An applied example based on a study by Hughes, Chen, Thoemmes, and Kwok (2010) is provided in which the effect of retention in Grade 1 on passing an achievement test in Grade 3 is evaluated. We find that models that consider the clustered nature of the data both in estimation of the propensity score and conditioning on the propensity score performed best in our simulation study; however, other modeling choices also performed well. The applied example illustrates practical limitations of these models when cluster sizes are small. PMID- 26735886 TI - A Comparison of Paper and Online Tests Using a Within-Subjects Design and Propensity Score Matching Study. AB - This inquiry had 2 components: (1) the first was substantive and focused on the comparability of paper-based and computer-based test forms and (2) the second was a within-study comparison wherein a quasi-experimental method, propensity score matching, was compared with a credible benchmark method, a within-subjects design. The tests used in the comparison of online tests and paper-based tests were End-of-Course tests in Algebra and English, in a statewide high school testing program. Students were tested in Grades 8 and 9. In general, the substantive studies suggested that the online and paper tests appeared to be measuring the same underlying constructs with the same level of reliability. The within-study portion of the investigation indicated that propensity score matching study yielded results that were virtually identical to the outcome of the more conventional within-subjects experimental design. Both the methodological and substantive aspects of this investigation yielded outcomes that should be of interest to investigators in both of these areas. PMID- 26735887 TI - RUNX1 and FOXP3 interplay regulates expression of breast cancer related genes. AB - Runx1 participation in epithelial mammary cells is still under review. Emerging data indicates that Runx1 could be relevant for breast tumor promotion. However, to date no studies have specifically evaluated the functional contribution of Runx1 to control gene expression in mammary epithelial tumor cells. It has been described that Runx1 activity is defined by protein context interaction. Interestingly, Foxp3 is a breast tumor suppressor gene. Here we show that endogenous Runx1 and Foxp3 physically interact in normal mammary cells and this interaction blocks Runx1 transcriptional activity. Furthermore we demonstrate that Runx1 is able to bind to R-spondin 3 (RSPO3) and Gap Junction protein Alpha 1 (GJA1) promoters. This binding upregulates Rspo3 oncogene expression and downregulates GJA1 tumor suppressor gene expression in a Foxp3-dependent manner. Moreover, reduced Runx1 transcriptional activity decreases tumor cell migration properties. Collectively, these data provide evidence of a new mechanism for breast tumor gene expression regulation, in which Runx1 and Foxp3 physically interact to control mammary epithelial cell gene expression fate. Our work suggests for the first time that Runx1 could be involved in breast tumor progression depending on Foxp3 availability. PMID- 26735888 TI - Identification and validation of the dopamine agonist bromocriptine as a novel therapy for high-risk myelodysplastic syndromes and secondary acute myeloid leukemia. AB - Myelodysplastic syndromes (MDS) represent a broad spectrum of diseases characterized by their clinical manifestation as one or more cytopenias, or a reduction in circulating blood cells. MDS is predominantly a disease of the elderly, with a median age in the UK of around 75. Approximately one third of MDS patients will develop secondary acute myeloid leukemia (sAML) that has a very poor prognosis. Unfortunately, most standard cytotoxic agents are often too toxic for older patients. This means there is a pressing unmet need for novel therapies that have fewer side effects to assist this vulnerable group. This challenge was tackled using bioinformatic analysis of available transcriptomic data to establish a gene-based signature of the development and progression of MDS. This signature was then used to identify novel therapeutic compounds via statistically significant connectivity mapping. This approach suggested re-purposing an existing and widely-prescribed drug, bromocriptine as a novel potential therapy in these disease settings. This drug has shown selectivity for leukemic cells as well as synergy with current therapies. PMID- 26735889 TI - Identification of ovarian cancer subtype-specific network modules and candidate drivers through an integrative genomics approach. AB - Identification of cancer subtypes and associated molecular drivers is critically important for understanding tumor heterogeneity and seeking effective clinical treatment. In this study, we introduced a simple but efficient multistep procedure to define ovarian cancer types and identify core networks/pathways and driver genes for each subtype by integrating multiple data sources, including mRNA expression, microRNA expression, copy number variation, and protein-protein interaction data. Applying similarity network fusion approach to a patient cohort with 379 ovarian cancer samples, we found two distinct integrated cancer subtypes with different survival profiles. For each ovarian cancer subtype, we explored the candidate oncogenic processes and driver genes by using a network-based approach. Our analysis revealed that alterations in DLST module involved in metabolism pathway and NDRG1 module were common between the two subtypes. However, alterations in the RB signaling pathway drove distinct molecular and clinical phenotypes in different ovarian cancer subtypes. This study provides a computational framework to harness the full potential of large-scale genomic data for discovering ovarian cancer subtype-specific network modules and candidate drivers. The framework may also be used to identify new therapeutic targets in a subset of ovarian cancers, for which limited therapeutic opportunities currently exist. PMID- 26735890 TI - Effect of pravastatin on the survival of patients with advanced gastric cancer. AB - OBJECTIVES: A fluoropyrimidine plus cisplatin combined with surgery is standard first-line treatment for advanced gastric cancer. We evaluated the effect of pravastatin on overall survival in patients with advanced gastric cancer in a prospective cohort study. METHODS: At the time of surgery, we assigned 60 patients with advanced gastric cancer (stage III or IV) to receive standard first line treatment (control group) or standard first-line treatment plus pravastatin at a dose of 40 mg once daily (pravastatin group). The minimum follow-up period was 4 years and the maximum of 6 years. RESULTS: The mean of age was 66 years and the TNM stage was III and IV in 65% and 35% of patients, respectively. There was no significant difference between the two groups (control vs pravastatin) in median overall survival (15 vs 14 months; P = 0.8). Predictors of survival were the stage (hazard ratio of death stage IV (III stage as reference): 4.4; 95% CI: 2-9.7; p < 0.05) and older age (hazard ratio of death >= 65 years (< 65 years as reference): 2.8; 95% CI: 1.3-6; p < 0.05). CONCLUSIONS: Pravastatin did not improve outcome in patients with advanced gastric cancer. PMID- 26735891 TI - Safety and efficacy of sorafenib therapy in patients with hepatocellular carcinoma: final outcome from the Chinese patient subset of the GIDEON study. AB - We report data from the final analysis of the Chinese subset of the GIDEON (the Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) study, which evaluated the safety and efficacy of sorafenib in Child-Pugh A, B and C patients with unresectable hepatocellular carcinoma (uHCC) in real-life clinical practice. Patient demographics, disease characteristics and treatment history were recorded at enrollment; dose, adverse events (AEs) and efficacy were recorded at follow-up. Of the 338 evaluable patients, 98.5% started on 800 mg/day sorafenib, regardless of their Child-Pugh status. The median treatment duration (21.1 vs. 18.8 weeks) and median overall survival (322 vs 240 days) were longer in patients with Child-Pugh A compared with the Child-Pugh B, progression-free survival were 183 vs. 208 days, respectively). AEs (all grades) were comparable in the Child-Pugh B vs A group (56.3% vs. 50.4%, respectively), moreover, the Child-Pugh B group also had comparable rates of drug-related AEs (35.4% vs. 27.2%, respectively) and serious AEs (25.0% vs. 23.0%, respectively) compared with the Child-Pugh A group. The overall dosing strategy was consistent in Chinese patients across Child-Pugh subgroups. Tolerability and safety data suggest that Child-Pugh B patients might be safely treated with sorafenib. The findings from our study showed that safety profile of sorafenib in terms of rate and type of AEs is similar to the global international GIDEON study as well as other pivotal studies. PMID- 26735893 TI - Protein corona as a proteome fingerprint: The example of hidden biomarkers for cow mastitis. AB - Proteome modifications in a biological fluid can potentially indicate the occurrence of pathologies, even if the identification of a proteome fingerprint correlated to a specific disease represents a very difficult task. When a nanomaterial is introduced into a biological fluid, macromolecules compete to form a protein corona on the nanoparticle surface, and depending on the specific proteome, different patterns of proteins will form the final protein corona shell depending on their affinity for the nanoparticle surface. Novel surface active maghemite nanoparticles (SAMNs) display a remarkable selectivity toward protein corona formation, and they are able to concentrate proteins and peptides presenting high affinities for their surface even if they are present in very low amounts. Thus, SAMNs may confer visibility to hidden biomarkers correlated to the occurrence of a pathology. In the present report, SAMNs were introduced into milk samples from healthy cows and from animals affected by mastitis, and the selectively bound protein corona shell was easily analyzed and quantified by gel electrophoresis and characterized by mass spectrometry. Upon incubation in mastitic milk, SAMNs were able to selectively bind alphas2-casein fragments containing the FALPQYLK sequence, as part of the larger casocidin-1 peptide with strong antibacterial activity, which were not present in healthy samples. Thus, SAMNs can be used as a future candidate for the rapid diagnosis of mastitis in bovine milk. The present report proposes protein competition for SAMN protein corona formation as a means of mirroring proteome modifications. Thus, the selected protein shell on the nanoparticles results in a fingerprint of the specific pathology. PMID- 26735892 TI - Drug-induced acute kidney injury in neonates. AB - PURPOSE OF REVIEW: Acute kidney injury (AKI) is an independent risk factor for morbidity and mortality in critically ill neonates. Nephrotoxic medication exposure is common in neonates. Nephrotoxicity represents the most potentially avoidable cause of AKI in this population. RECENT FINDINGS: Recent studies in critically ill children revealed the importance of recognizing AKI and potentially modifiable risk factors for the development of AKI such as nephrotoxic medication exposures. Data from critically ill children who have AKI suggest that survivors are at risk for the development of chronic kidney disease. Premature infants are born with incomplete nephrogenesis and are at risk for chronic kidney disease. The use of nephrotoxic medications in the neonatal intensive care unit is very common; yet the effects of medication nephrotoxicity on the short and long-term outcomes remains highly understudied. SUMMARY: The neonatal kidney is predisposed to nephrotoxic AKI. Our ability to improve outcomes for this vulnerable group depends on a heightened awareness of this issue. It is important for clinicians to develop methods to minimize and prevent nephrotoxic AKI in neonates through a multidisciplinary approach aiming at earlier recognition and close monitoring of nephrotoxin-induced AKI. PMID- 26735894 TI - Facile preparation of biphasic-induced magnetic icariin-loaded composite microcapsules by automated in situ click technology. AB - This research aims to prepare the biphasic-induced magnetic composite microcapsules (BIMCM) as a promising environmental stimuli-responsive delivery vehicle to dispose the problem of drug burst effect. The paper presented a novel automated in situ click technology of magnetic chitosan/nano hydroxyapatite (CS/nHA) microcapsules. Fe3O4 magnetic nanoparticles (MNP) and nHA were simultaneously in situ crystallized by one-step process. Icariin (ICA), a plant derived flavonol glycoside, was combined to study drug release properties of BIMCM. BIMCM were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and Thermal gravimetric analysis/Differential Scanning Calorimetry(TGA/DSC) in order to reveal their component and surface morphology as well as the role of the in situ generated Fe3O4 MNP and nHA. The magnetic test showed the BIMCM were super-paramagnetic. Both in situ generated Fe3O4 MNP and nHA serve as stable inorganic crosslinkers in BIMCM to form many intermolecular crosslinkages for the movability of the CS chains. This makes ICA loaded microcapsules take on a sustained release behavior and results in the self adjusting of surface morphology, decreasing of swelling and degradation rates. In addition, in vitro tests were systematically carried out to examine the biocompatibility of the microcapsules by MTT test, Wright-Giemsa dying assay and AO/EB fluorescent staining method. These results demonstrated that successful introduction of the in situ click Fe3O4 MNP provided an alternative strategy because of magnetic sensitivity and sustained release. As such, the novel ICA loaded biphasic-induced magnetic CS/nHA/MNP microcapsules are expected to find potential applications in drug delivery system for bone repair. PMID- 26735895 TI - Ellipsometric study of molecular orientations of Thermomyces lanuginosus lipase at the air-water interface by simultaneous determination of refractive index and thickness. AB - Ellipsometric studies of very thin organic films suffer from the low refractive index contrast between layer and bulk substrate. We demonstrate that null ellipsometry can not only provide detailed information about the adsorption kinetics and surface excess values, but in addition on layer thicknesses with submonolayer resolution of a lipase from Thermomyces lanuginosus at the air-water interface. While measuring very close to the Brewster angle, refractive indices and layer-thicknesses can both be determined with a precision that is sufficiently high to make conclusions on the density and orientation of the molecules at the interface. The orientation was found to be concentration- and pH value-dependent. At the isoelectric point, the lipase was almost vertically oriented with respect to the surface, while for pure distilled water and low lipase concentration a rather horizontal alignment was found. Further experiments, varying the size of the interfacial area in a Langmuir trough, confirm the different layer structures. PMID- 26735896 TI - Interference of 1:1 and 2:1 layered phyllosilicates as excipients with ranitidine. AB - As natural ingredients and excipients, kaolinite and talc were frequently studied for their interactions with drugs in pharmaceutical formulations. In this study, the uptake of ranitidine (RT) on these two minerals was studied under different physic-chemical conditions and the mechanism of RT uptake on these two minerals contrasted. Although the thermodynamic and kinetic RT uptake on these two minerals was similar and the RT uptake on both minerals were limited to the external surfaces only, drastic difference in RT uptake was found under different equilibrium solution pH and ionic strength conditions. As cation exchange process was strongly affected by solution pH and ionic strength, the RT uptake on kaolinite was dominated by cation exchange and electrostatic interactions, while the RT uptake on talc was more controlled by inter- and intra- molecular hydrogen bonding interactions. For kaolinite, the limiting factor for RT uptake was the specific surface area due to monolayer RT adsorption. In contract, multilayer RT uptake was found on talc surfaces. No matter which mechanism dominated RT uptake on these minerals, the interaction should not be neglected in pharmaceutical formulations should these minerals be used as additives and/or excipients. PMID- 26735897 TI - Pulmonary macrophages activity in CO intoxication. AB - The presence of macrophages and their activation on the pulmonary tissues of 21 subjects deceased after CO intoxication has been studied. A notable number of activated macrophages, especially in the interstitial level, have been evidenced, and such phenomenon supports the hypothesis of a possible association between CO intoxication and pulmonary macrophages activity. The highlighted association could be mediated by changes of the surfactant, by impairing of mitochondrial respiration and by release of pro-inflammatory cytokines. PMID- 26735898 TI - Postmortem diagnosis of anaphylaxis in presence of decompositional changes. AB - Eosinophil and activated mast cell identification in the spleen combined with mast cell tryptase determination in postmortem serum may diagnose fatal anaphylaxis with a high degree of certainty. Mast cell tryptase measurement and significance in corpses with decompositional changes remains however an issue of controversy. Analogously, immunohistochemistry in corpses with decompositional changes may be influenced by several mechanisms, including protein alteration, antigen diffusion and unspecific antibody binding to disrupted protein structures. The authors present an autopsy case involving a 55-year-old woman who unintentionally received clarithromycin. Due to difficult in administrative procedures, the postmortem examination was performed 96 h after death. Mast cell tryptase was measured in postmortem serum from femoral, aortic and right heart blood. The obtained results were consistent with mast cell activation. Histochemistry (Pagoda Red) and immunohistochemistry (anti-tryptase antibodies) allowed splenic eosinophils and mast cells to be detected. Based on the results of all postmortem investigations, the hypothesis of anaphylaxis following accidental clarithromycin administration was formulated. PMID- 26735899 TI - Anthropogenic Sulfur Perturbations on Biogenic Oxidation: SO2 Additions Impact Gas-Phase OH Oxidation Products of alpha- and beta-Pinene. AB - In order to probe how anthropogenic pollutants can impact the atmospheric oxidation of biogenic emissions, we investigated how sulfur dioxide (SO2) perturbations impact the oxidation of two monoterpenes, alpha-and beta-pinene. We used chemical ionization mass spectrometry to examine changes in both individual molecules and gas-phase bulk properties of oxidation products as a function of SO2 addition. SO2 perturbations impacted the oxidation systems of alpha-and beta pinene, leading to an ensemble of products with a lesser degree of oxygenation than unperturbed systems. These changes may be due to shifts in the OH:HO2 ratio from SO2 oxidation and/or to SO3 reacting directly with organic molecules. Van Krevelen diagrams suggest a shift from gas-phase functionalization by alcohol/peroxide groups to functionalization by carboxylic acid or carbonyl groups, consistent with a decreased OH:HO2 ratio. Increasing relative humidity dampens the impact of the perturbation. This decrease in oxygenation may impact secondary organic aerosol formation in regions dominated by biogenic emissions with nearby SO2 sources. We observed sulfur-containing organic compounds following SO2 perturbations of monoterpene oxidation; whether these are the result of photochemistry or an instrumental artifact from ion-molecule clustering remains uncertain. However, our results demonstrate that the two monoterpene isomers produce unique suites of oxidation products. PMID- 26735900 TI - Tuning Mesenchymal Stem Cell Response onto Titanium-Niobium-Hafnium Alloy by Recombinant Fibronectin Fragments. AB - Since metallic biomaterials used for bone replacement possess low bioactivity, the use of cell adhesive moieties is a common strategy to improve cellular response onto these surfaces. In recent years, the use of recombinant proteins has emerged as an alternative to native proteins and short peptides owing to the fact that they retain the biological potency of native proteins, while improving their stability. In the present study, we investigated the biological effect of two different recombinant fragments of fibronectin, spanning the 8-10th and 12 14th type III repeats, covalently attached to a new TiNbHf alloy using APTES silanization. The fragments were studied separately and mixed at different concentrations and compared to a linear RGD, a cyclic RGD and the full-length fibronectin protein. Cell culture studies using rat mesenchymal stem cells demonstrated that low to medium concentrations (30% and 50%) of type III 8-10th fragment mixed with type III 12-14th fragment stimulated cell spreading and proliferation compared to RGD peptides and the fragments separately. On the other hand, type III 12-14th fragment alone or mixed at low volume percentages <=50% with type III 8-10th fragment increased alkaline phosphatase levels compared to the other molecules. These results are significant for the understanding of the role of fibronectin recombinant fragments in cell responses and thus to design bioactive coatings for biomedical applications. PMID- 26735902 TI - A French Approach to Test Fetuses with Ultrasound Abnormalities Using a Customized Microarray as First-Tier Genetic Test. AB - Cytogenetic microarray analysis is now the first-tier genetic test used in a postnatal clinical setting to explore genomic imbalances in individuals with developmental disability and/or birth defects. However, in a prenatal setting, this technique is not widely implemented, largely because the clinical impact of some copy number variants (CNVs) remains difficult to assess. This limitation is especially true in France where termination of pregnancy for medical reasons may be performed at any stage of gestation. During a period of 15 months, we investigated 382 fetuses presenting with ultrasound anomalies, using a customized microarray designed to avoid the detection of CNVs raising challenges for genetic counseling. After excluding common aneuploidies, 20/374 (5.3%) fetuses had a pathogenic CNV, among which 12/374 (3.2%) could have been detected by karyotyping, whereas 8/374 (2.1%) were cryptic. Within these 374 cases, 300 were ongoing pregnancies at the time of array comparative genomic hybridization (aCGH) testing. For these pregnancies, we detected 18/300 (6%) pathogenic CNVs, among which 6/300 (2%) were cryptic. Using this approach, only 2/300 (0.6%) of the detected CNVs raised difficulties for genetic counseling. This study confirms the added value of this strategy in a prenatal clinical setting to minimize ethical issues for genetic counseling while enhancing the detection of genomic imbalances. PMID- 26735903 TI - Identification and Visualization of Kinase-Specific Subpockets. AB - The identification and design of selective compounds is important for the reduction of unwanted side effects as well as for the development of tool compounds for target validation studies. This is, in particular, true for therapeutically important protein families that possess conserved folds and have numerous members such as kinases. To support the design of selective kinase inhibitors, we developed a novel approach that allows identification of specificity determining subpockets between closely related kinases solely based on their three-dimensional structures. To account for the intrinsic flexibility of the proteins, multiple X-ray structures of the target protein of interest as well as of unwanted off-target(s) are taken into account. The binding pockets of these protein structures are calculated and fused to a combined target and off target pocket, respectively. Subsequently, shape differences between these two combined pockets are identified via fusion rules. The approach provides a user friendly visualization of target-specific areas in a binding pocket which should be explored when designing selective compounds. Furthermore, the approach can be easily combined with in silico alanine mutation studies to identify selectivity determining residues. The potential impact of the approach is demonstrated in four retrospective experiments on closely related kinases, i.e., p38alpha vs Erk2, PAK1 vs PAK4, ITK vs AurA, and BRAF vs VEGFR2. Overall, the presented approach does not require any profiling data for training purposes, provides an intuitive visualization of a large number of protein structures at once, and could also be applied to other target classes. PMID- 26735905 TI - Increased Dead Space Ventilation Mediates Reduced Exercise Capacity in Systolic Heart Failure. AB - RATIONALE: Patients with chronic heart failure have limited exercise capacity, which cannot be completely explained by markers of cardiac dysfunction. Reduced pulmonary diffusing capacity at rest and excessively high ventilation during exercise are common in heart failure. We hypothesized that the reduced pulmonary diffusing capacity in patients with heart failure would predict greater dead space ventilation during exercise and that this would lead to impairment in exercise capacity. OBJECTIVES: To determine the relationship between pulmonary diffusing capacity at rest and dead space ventilation during exercise, and to examine the influence of dead space ventilation on exercise in heart failure. METHODS: We analyzed detailed cardiac and pulmonary data at rest and during maximal incremental cardiopulmonary exercise testing from 87 consecutive heart transplant assessment patients and 18 healthy control subjects. Dead space ventilation was calculated using the Bohr equation. MEASUREMENTS AND MAIN RESULTS: Pulmonary diffusing capacity at rest was a significant predictor of dead space ventilation at maximal exercise (r = -0.524, P < 0.001) in heart failure but not in control subjects. Dead space at maximal exercise also correlated inversely with peak oxygen consumption (r = -0.598, P < 0.001), peak oxygen consumption per kilogram (r = -0.474, P < 0.001), and 6-minute-walk distance (r = -0.317, P = 0.021) in the heart failure group but not in control subjects. CONCLUSIONS: Low resting pulmonary diffusing capacity in heart failure is indicative of high dead space ventilation during exercise, leading to excessive and inefficient ventilation. These findings would support the concept of pulmonary vasculopathy leading to altered ventilation perfusion matching (increased dead space) and resultant dyspnea, independent of markers of cardiac function. PMID- 26735901 TI - Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies. AB - Background Peripartum cardiomyopathy shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in more than 40 genes, including TTN, which encodes the sarcomere protein titin. Methods In 172 women with peripartum cardiomyopathy, we sequenced 43 genes with variants that have been associated with dilated cardiomyopathy. We compared the prevalence of different variant types (nonsense, frameshift, and splicing) in these women with the prevalence of such variants in persons with dilated cardiomyopathy and with population controls. Results We identified 26 distinct, rare truncating variants in eight genes among women with peripartum cardiomyopathy. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than that in a reference population of 60,706 persons (4.7%, P=1.3*10(-7)) but was similar to that in a cohort of patients with dilated cardiomyopathy (55 of 332 patients [17%], P=0.81). Two thirds of identified truncating variants were in TTN, as seen in 10% of the patients and in 1.4% of the reference population (P=2.7*10(-10)); almost all TTN variants were located in the titin A-band. Seven of the TTN truncating variants were previously reported in patients with idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of 83 women with peripartum cardiomyopathy, the presence of TTN truncating variants was significantly correlated with a lower ejection fraction at 1-year follow-up (P=0.005). Conclusions The distribution of truncating variants in a large series of women with peripartum cardiomyopathy was remarkably similar to that found in patients with idiopathic dilated cardiomyopathy. TTN truncating variants were the most prevalent genetic predisposition in each disorder. PMID- 26735904 TI - ALS-Causing Mutations Significantly Perturb the Self-Assembly and Interaction with Nucleic Acid of the Intrinsically Disordered Prion-Like Domain of TDP-43. AB - TAR-DNA-binding protein-43 (TDP-43) C-terminus encodes a prion-like domain widely presented in RNA-binding proteins, which functions to form dynamic oligomers and also, amazingly, hosts most amyotrophic lateral sclerosis (ALS)-causing mutations. Here, as facilitated by our previous discovery, by circular dichroism (CD), fluorescence and nuclear magnetic resonance (NMR) spectroscopy, we have successfully determined conformations, dynamics, and self-associations of the full-length prion-like domains of the wild type and three ALS-causing mutants (A315E, Q331K, and M337V) in both aqueous solutions and membrane environments. The study decodes the following: (1) The TDP-43 prion-like domain is intrinsically disordered only with some nascent secondary structures in aqueous solutions, but owns the capacity to assemble into dynamic oligomers rich in beta sheet structures. By contrast, despite having highly similar conformations, three mutants gained the ability to form amyloid oligomers. The wild type and three mutants all formed amyloid fibrils after incubation as imaged by electron microscopy. (2) The interaction with nucleic acid enhances the self-assembly for the wild type but triggers quick aggregation for three mutants. (3) A membrane interacting subdomain has been identified over residues Met311-Gln343 indispensable for TDP-43 neurotoxicity, which transforms into a well-folded Omega loop-helix structure in membrane environments. Furthermore, despite having very similar membrane-embedded conformations, three mutants will undergo further self association in the membrane environment. Our study implies that the TDP-43 prion like domain appears to have an energy landscape, which allows the assembly of the wild-type sequence into dynamic oligomers only under very limited condition sets, and ALS-causing point mutations are sufficient to remodel it to more favor the amyloid formation or irreversible aggregation, thus supporting the emerging view that the pathologic aggregation may occur via the exaggeration of functionally important assemblies. Furthermore, the coupled capacity of TDP-43 in aggregation and membrane interaction may critically account for its high neurotoxicity, and therefore its decoupling may represent a promising therapeutic strategy to treat TDP-43 causing neurodegenerative diseases. PMID- 26735906 TI - Breaking the Symmetry in Molecular Nanorings. AB - Because of their unique electronic properties, cyclic molecular structures ranging from benzene to natural light-harvesting complexes have received much attention. Rigid pi-conjugated templated porphyrin nanorings serve as excellent model systems here because they possess well-defined structures that can readily be controlled and because they support highly delocalized excitations. In this study, we have deliberately modified a series of six-porphyrin nanorings to examine the impact of lowering the rotational symmetry on their photophysical properties. We reveal that as symmetry distortions increase in severity along the series of structures, spectral changes and an enhancement of radiative emission strength occur, which derive from a transfer of oscillator strength into the lowest (k = 0) state. We find that concomitantly, the degeneracy of the dipole allowed first excited (k = +/-1) state is lifted, leading to an ultrafast polarization switching effect in the emission from strongly symmetry-broken nanorings. PMID- 26735907 TI - Ultrafast Photodissociation Dynamics of Nitromethane. AB - Nitromethane (NM), a high explosive (HE) with low sensitivity, is known to undergo photolysis upon ultraviolet (UV) irradiation. The optical transparency, homogeneity, and extensive study of NM make it an ideal system for studying photodissociation mechanisms in conventional HE materials. The photochemical processes involved in the decomposition of NM could be applied to the future design of controllable photoactive HE materials. In this study, the photodecomposition of NM from the npi* state excited at 266 nm is being investigated on the femtosecond time scale. UV femtosecond transient absorption (TA) spectroscopy and excited state femtosecond stimulated Raman spectroscopy (FSRS) are combined with nonadiabatic excited state molecular dynamics (NA-ESMD) simulations to provide a unified picture of NM photodecomposition. The FSRS spectrum of the photoproduct exhibits peaks in the NO2 region and slightly shifted C-N vibrational peaks pointing to methyl nitrite formation as the dominant photoproduct. A total photolysis quantum yield of 0.27 and an npi* state lifetime of ~20 fs were predicted from NA-ESMD simulations. Predicted time scales revealed that NO2 dissociation occurs in 81 +/- 4 fs and methyl nitrite formation is much slower having a time scale of 452 +/- 9 fs corresponding to the excited state absorption feature with a decay of 480 +/- 17 fs observed in the TA spectrum. Although simulations predict C-N bond cleavage as the primary photochemical process, the relative time scales are consistent with isomerization occurring via NO2 dissociation and subsequent rebinding of the methyl radical and nitrogen dioxide. PMID- 26735908 TI - Synthesis, vasorelaxant activity and 2D-QSAR study of some novel pyridazine derivatives. AB - Novel 3,6-disubstituted pyridazines were synthesized by facile method and screened for their vasorelaxant properties utilizing isolated thoracic rat aortic rings. Compounds 8a and 11a exerted potent vasorelaxant activity (IC50 = 198 and 177 MUM, respectively) relative to doxazosin mesylate (used reference standard, IC50 = 226 MUM), that, they may represent promising hits for treatment of cardiovascular disorders. The observed activity was validated by a statistically significant QSAR model (N = 32, n = 6, R(2) = 0.811782, R(2)cvOO = 0.7153, R(2)cvMO = 0.7209, F = 17.9708, s(2) = 9.65226 * 10(-8)) that was obtained employing CODESSA-Pro software. PMID- 26735909 TI - Synthesis and biological evaluation of 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin 11-one structural derivatives as anti-cancer and apoptosis inducing agents. AB - A series of thirteen 5H-dibenzo [b,e][1,4]diazepin-11(10H)-one structural derivatives has been synthesized and evaluated for anti-proliferative activity against five human cancer cell lines. Compound 9a exhibited potent tumour growth inhibition in all cell lines with IC50 values in the range of 0.71-7.29 MUM. Experiments on lung (A549) and breast (MDAMB-231) cancer cell lines to investigate the mechanisms of growth inhibition and apoptosis inducing effects of 9a showed that it arrested both cancer cell lines in the G2/M phase of cell cycle in a dose dependent manner. Hoechst staining analysis revealed that 9a inhibited tumour cell proliferation through apoptosis induction. Additionally, the mitochondrial membrane potential (DeltaPsim) was affected and the levels of reactive oxygen species (ROS) were raised. The simple synthetic preparation and their biological properties make these dibenzodiazepinone-triazole scaffolds promising new entities for the development of cancer therapeutics. PMID- 26735911 TI - Recyclable Earth-Abundant Metal Nanoparticle Catalysts for Selective Transfer Hydrogenation of Levulinic Acid to Produce gamma-Valerolactone. AB - Nanoparticles (NPs) derived from earth-abundant metal(0) carbonyls catalyze conversion of bio-derived levulinic acid into gamma-valerolactone in up to 93% isolated yield. This sustainable and green route uses non-precious metal catalysts and can be performed in aqueous or ethanol solution without using hydrogen gas as the hydrogen source. Generation of metal NPs using microwave irradiation greatly enhances the rate of the conversion, enables the use of ethanol as both solvent and hydrogen source without forming the undesired ethyl levulinate, and affords recyclable polymer-stabilized NPs. PMID- 26735910 TI - Cardanol-derived AChE inhibitors: Towards the development of dual binding derivatives for Alzheimer's disease. AB - Cardanol is a phenolic lipid component of cashew nut shell liquid (CNSL), obtained as the byproduct of cashew nut food processing. Being a waste product, it has attracted much attention as a precursor for the production of high-value chemicals, including drugs. On the basis of these findings and in connection with our previous studies on cardanol derivatives as acetylcholinesterase (AChE) inhibitors, we designed a novel series of analogues by including a protonable amino moiety belonging to different systems. Properly addressed docking studies suggested that the proposed structural modifications would allow the new molecules to interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, thus being able to act as dual binding inhibitors. To disclose whether the new molecules showed the desired profile, they were first tested for their cholinesterase inhibitory activity towards EeAChE and eqBuChE. Compound 26, bearing an N-ethyl-N-(2-methoxybenzyl)amine moiety, showed the highest inhibitory activity against EeAChE, with a promising IC50 of 6.6 MUM, and a similar inhibition profile of the human isoform (IC50 = 5.7 MUM). As another positive feature, most of the derivatives did not show appreciable toxicity against HT-29 cells, up to a concentration of 100 MUM, which indicates drug-conform behavior. Also, compound 26 is capable of crossing the blood-brain barrier (BBB), as predicted by a PAMPA-BBB assay. Collectively, the data suggest that the approach to obtain potential anti-Alzheimer drugs from CNSL is worth of further pursuit and development. PMID- 26735912 TI - Drinking, abstinence, and academic motives: Relationships among multiple motivational domains and alcohol use in college students. AB - BACKGROUND: Drinking, abstinence, and academic motives have been previously linked with alcohol consumption in high school and college students; however, little research has examined the impact of such sources of motivations concurrently. OBJECTIVE: Drawing from self-determination theory (SDT; Ryan & Deci, 2000), the current study tested the hypothesis that alcohol-related and academic motives would be associated with one another along internal vs. external focused dimensions. We also examined the relative influence of these motives on alcohol consumption. METHODS: College students (N=226) completed self-report measures assessing drinking motives, abstinence motives, academic motives, and alcohol-related outcomes. RESULTS: Findings suggest that drinking motives are related to abstinence motives but not academic motives. Both forms of alcohol related motives were related to alcohol use and consequences; no associations between academic motives and alcohol variables were observed. CONCLUSIONS/IMPORTANCE: The lack of associations among academic motives, alcohol related motives, and alcohol variables departs from previous findings suggesting that academic motives impact alcohol use. The current findings indicate a greater understanding of the interplay of motivational sets related to salient issues for youth, such as academics, is needed in order to expand intervention models for alcohol use in such populations. PMID- 26735913 TI - The moderating role of dysphoria in the relationship between intrusions and alcohol use. AB - Posttraumatic Stress Disorder (PTSD) is frequently comorbid with alcohol use disorders (AUD; Calabrese et al., 2011; McFall, Mackay, & Donovan, 1992). Among several explanations for this comorbidity, the most empirically supported is the self-medication theory which postulates that substances are used to medicate PTSD related distress (Keane & Wolfe, 1990; Khantzian, 1985; Stewart, 1996). The current study examines the effects of trauma-related distress on alcohol use (total drinking days, drinks per drinking day, heavy drinking days) in a sample of 127 trauma-exposed Veterans following deployment to Iraq or Afghanistan. The dysphoria symptoms of PTSD were used as an indicator of distress, and examined as a moderator in the relationship between intrusion symptoms of PTSD and alcohol use. The proposed moderation model was tested using cross-sectional data from the first month following return from deployment, and at 6 months and at 12 months post-deployment. Results showed that dysphoria symptoms significantly moderated relations between intrusions and total drinking days and heavy drinking days at one month post-deployment; however, a significant pattern was not demonstrated at 6 months and 12 months. Further, dysphoria did not moderate the relation between intrusion symptoms and drinks per drinking day at the three time points. Theoretical and clinical implications are subsequently discussed. PMID- 26735914 TI - The relationship between temporal profiles and alcohol-related problems in University undergraduates: Results from the United Kingdom. AB - Time perspective is an individual difference variable which assesses the extent to which orientation to the past, present and future affects current behaviors. The present study investigated the viability of temporal profiles and the degree (if any) to which these predict meaningful differences in alcohol-related problems. Participants were undergraduates recruited from a University in the North West of England. Full survey data were available for 455 individuals (aged 18-25; 49.7% male) on (a) time perspective, and (b) alcohol-related problems. Four profiles emerged and were labeled Future-Positive, Present, Past Negative Future, and Ambivalent. As hypothesized, the Future-Positive profile was associated with the best alcohol-related outcomes. The Present profile was associated with the worst outcomes. This study demonstrates that temporal profiles are associated with alcohol-related problems. PMID- 26735915 TI - Cross-Regulation between the phz1 and phz2 Operons Maintain a Balanced Level of Phenazine Biosynthesis in Pseudomonas aeruginosa PAO1. AB - Gene duplication often provides selective advantages for the survival of microorganisms in adapting to varying environmental conditions. P. aeruginosa PAO1 possesses two seven-gene operons [phz1 (phzA1B1C1D1E1F1G1) and phz2 (phzA2B2C2D2E2F2G2)] that are involved in the biosynthesis of phenazine-1 carboxylic acid and its derivatives. Although the two operons are highly homologous and their functions are well known, it is unclear how the two phz operons coordinate their expressions to maintain the phenazine biosynthesis. By constructing single and double deletion mutants of the two phz operons, we found that the phz1-deletion mutant produced the same or less amount of phenazine-1 carboxylic acid and pyocyanin in GA medium than the phz2-knockout mutant while the phz1-phz2 double knockout mutant did not produce any phenazines. By generating phzA1 and phzA2 translational and transcriptional fusions with a truncated lacZ reporter, we found that the expression of the phz1 operon increased significantly at the post-transcriptional level and did not alter at the transcriptional level in the absence of the phz2 operon. Surprisingly, the expression the phz2 operon increased significantly at the post-transcriptional level and only moderately at the transcriptional level in the absence of the phz1 operon. Our findings suggested that a complex cross-regulation existed between the phz1 and phz2 operons. By mediating the upregulation of one phz operon expression while the other was deleted, this crosstalk would maintain the homeostatic balance of phenazine biosynthesis in P. aeruginosa PAO1. PMID- 26735916 TI - Functions of the SLC36 transporter Pathetic in growth control. AB - Neurons exhibit extreme diversity in size, but whether large neurons have specialized mechanisms to support their growth is largely unknown. Recently, we identified the SLC36 transporter Pathetic (Path) as a factor required for extreme dendrite growth in neurons. Path is broadly expressed, but only neurons with large dendrite arbors or small neurons that are forced to grow large require path for their growth. To gain insight into the basis of growth control by path, we generated additional alleles of path and further examined the apparent specificity of growth defects in path mutants. Here, we confirm our prior finding that loss of path function imposes an upper limit on neuron growth, and additionally report that path likely limits overall neurite length rather than dendrite length alone. Using a GFP knock-in allele of path, we identify additional tissues where path likely functions in nutrient sensing and possibly growth control. Finally, we demonstrate that path regulates translational capacity in a cell type that does not normally require path for growth, suggesting that path may confer robustness on growth programs by buffering translational output. Altogether, these studies suggest that Path is a nutrient sensor with widespread function in Drosophila. PMID- 26735917 TI - Comprehension of Co-Speech Gestures in Aphasic Patients: An Eye Movement Study. AB - BACKGROUND: Co-speech gestures are omnipresent and a crucial element of human interaction by facilitating language comprehension. However, it is unclear whether gestures also support language comprehension in aphasic patients. Using visual exploration behavior analysis, the present study aimed to investigate the influence of congruence between speech and co-speech gestures on comprehension in terms of accuracy in a decision task. METHOD: Twenty aphasic patients and 30 healthy controls watched videos in which speech was either combined with meaningless (baseline condition), congruent, or incongruent gestures. Comprehension was assessed with a decision task, while remote eye-tracking allowed analysis of visual exploration. RESULTS: In aphasic patients, the incongruent condition resulted in a significant decrease of accuracy, while the congruent condition led to a significant increase in accuracy compared to baseline accuracy. In the control group, the incongruent condition resulted in a decrease in accuracy, while the congruent condition did not significantly increase the accuracy. Visual exploration analysis showed that patients fixated significantly less on the face and tended to fixate more on the gesturing hands compared to controls. CONCLUSION: Co-speech gestures play an important role for aphasic patients as they modulate comprehension. Incongruent gestures evoke significant interference and deteriorate patients' comprehension. In contrast, congruent gestures enhance comprehension in aphasic patients, which might be valuable for clinical and therapeutic purposes. PMID- 26735918 TI - Road Traffic Injury Prevention Initiatives: A Systematic Review and Metasummary of Effectiveness in Low and Middle Income Countries. AB - BACKGROUND: Road traffic injuries (RTIs) are a growing but neglected global health crisis, requiring effective prevention to promote sustainable safety. Low- and middle-income countries (LMICs) share a disproportionately high burden with 90% of the world's road traffic deaths, and where RTIs are escalating due to rapid urbanization and motorization. Although several studies have assessed the effectiveness of a specific intervention, no systematic reviews have been conducted summarizing the effectiveness of RTI prevention initiatives specifically performed in LMIC settings; this study will help fill this gap. METHODS: In accordance with PRISMA guidelines we searched the electronic databases MEDLINE, EMBASE, Scopus, Web of Science, TRID, Lilacs, Scielo and Global Health. Articles were eligible if they considered RTI prevention in LMICs by evaluating a prevention-related intervention with outcome measures of crash, RTI, or death. In addition, a reference and citation analysis was conducted as well as a data quality assessment. A qualitative metasummary approach was used for data analysis and effect sizes were calculated to quantify the magnitude of emerging themes. RESULTS: Of the 8560 articles from the literature search, 18 articles from 11 LMICs fit the eligibility and inclusion criteria. Of these studies, four were from Sub-Saharan Africa, ten from Latin America and the Caribbean, one from the Middle East, and three from Asia. Half of the studies focused specifically on legislation, while the others focused on speed control measures, educational interventions, enforcement, road improvement, community programs, or a multifaceted intervention. CONCLUSION: Legislation was the most common intervention evaluated with the best outcomes when combined with strong enforcement initiatives or as part of a multifaceted approach. Because speed control is crucial to crash and injury prevention, road improvement interventions in LMIC settings should carefully consider how the impact of improvements will affect speed and traffic flow. Further road traffic injury prevention interventions should be performed in LMICs with patient-centered outcomes in order to guide injury prevention in these complex settings. PMID- 26735919 TI - Two-Arm Randomized Pilot Intervention Trial to Decrease Sitting Time and Increase Sit-To-Stand Transitions in Working and Non-Working Older Adults. AB - BACKGROUND: Excessive sitting has been linked to poor health. It is unknown whether reducing total sitting time or increasing brief sit-to-stand transitions is more beneficial. We conducted a randomized pilot study to assess whether it is feasible for working and non-working older adults to reduce these two different behavioral targets. METHODS: Thirty adults (15 workers and 15 non-workers) age 50 70 years were randomized to one of two conditions (a 2-hour reduction in daily sitting or accumulating 30 additional brief sit-to-stand transitions per day). Sitting time, standing time, sit-to-stand transitions and stepping were assessed by a thigh worn inclinometer (activPAL). Participants were assessed for 7 days at baseline and followed while the intervention was delivered (2 weeks). Mixed effects regression analyses adjusted for days within participants, device wear time, and employment status. Time by condition interactions were investigated. RESULTS: Recruitment, assessments, and intervention delivery were feasible. The 'reduce sitting' group reduced their sitting by two hours, the 'increase sit-to stand' group had no change in sitting time (p < .001). The sit-to-stand transition group increased their sit-to-stand transitions, the sitting group did not (p < .001). CONCLUSIONS: This study was the first to demonstrate the feasibility and preliminary efficacy of specific sedentary behavioral goals. TRIAL REGISTRATION: clinicaltrials.gov NCT02544867. PMID- 26735920 TI - Antimony to Cure Visceral Leishmaniasis Unresponsive to Liposomal Amphotericin B. AB - We report on 4 patients (1 immunocompetent, 3 immunosuppressed) in whom visceral leishmaniasis had become unresponsive to (or had relapsed after) treatment with appropriate doses of liposomal amphotericin B. Under close follow-up, full courses of pentavalent antimony were administered without life-threatening adverse events and resulted in rapid and sustained clinical and parasitological cure. PMID- 26735921 TI - UIS2: A Unique Phosphatase Required for the Development of Plasmodium Liver Stages. AB - Plasmodium salivary sporozoites are the infectious form of the malaria parasite and are dormant inside salivary glands of Anopheles mosquitoes. During dormancy, protein translation is inhibited by the kinase UIS1 that phosphorylates serine 59 in the eukaryotic initiation factor 2alpha (eIF2alpha). De-phosphorylation of eIF2alpha-P is required for the transformation of sporozoites into the liver stage. In mammalian cells, the de-phosphorylation of eIF2alpha-P is mediated by the protein phosphatase 1 (PP1). Using a series of genetically knockout parasites we showed that in malaria sporozoites, contrary to mammalian cells, the eIF2alpha P phosphatase is a member of the PP2C/PPM phosphatase family termed UIS2. We found that eIF2alpha was highly phosphorylated in uis2 conditional knockout sporozoites. These mutant sporozoites maintained the crescent shape after delivery into mammalian host and lost their infectivity. Both uis1 and uis2 were highly transcribed in the salivary gland sporozoites but uis2 expression was inhibited by the Pumilio protein Puf2. The repression of uis2 expression was alleviated when sporozoites developed into liver stage. While most eukaryotic phosphatases interact transiently with their substrates, UIS2 stably bound to phosphorylated eIF2alpha, raising the possibility that high-throughput searches may identify chemicals that disrupt this interaction and prevent malaria infection. PMID- 26735924 TI - Tandem Mass Spectrometry Multiplex Analysis of Glucosylceramide and Galactosylceramide Isoforms in Brain Tissues at Different Stages of Parkinson Disease. AB - Previous studies demonstrated that Parkinson disease (PD) is associated with a decreased activity of the glucocerebrosidase (GCase) enzyme in brain tissues. The objective of this study was to determine if GCase deficiency is associated with the accumulation of its glucosylceramide (GluCer) substrate in PD brain tissues. An ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed, optimized, and validated for the multiplex analysis of GluCer isoforms (C18:0, C20:0, C22:0, C24:1, and C24:0) in brain tissue samples. These molecules were chromatographically separated from their isobaric galactosylceramide (GalCer) counterparts using normal phase chromatography. The analysis was performed by tandem mass spectrometry in the multiple reaction monitoring (MRM) acquisition mode. Limits of detection ranging from 0.4 to 1.1 nmol/g brain tissue were established for the different GluCer isoforms analyzed. For the first time, GluCer isoform levels were analyzed in temporal cortex brain tissue samples from 26 PD patients who were divided into three PD disease stages (IIa, III, and IV) according to the Unified Staging System for Lewy Body Disorders. These specimens were compared with brain tissue samples from 12 controls and 6 patients with Incidental Lewy Body Disease. No significant GluCer concentration differences were observed between the 5 sample groups. The GluCer isoform levels were also normalized with their matching GalCer isoforms. The normalized results showed a trend for GluCer levels which increased with PD severity. However, the differences observed between the groups were not significant, owing likely to the high standard deviations measured. PMID- 26735925 TI - Pd-Catalyzed Synthesis of Aryl and Heteroaryl Triflones from Reactions of Sodium Triflinate with Aryl (Heteroaryl) Triflates. AB - A novel method for Pd-catalyzed triflination of aryl and heteroaryl triflates using NaSO2CF3 as the nucleophile is described. The combination of Pd2(dba)3 and RockPhos formed the most effective catalyst. A broad range of functional groups and heteroaromatic compounds were tolerated under the neutral reaction conditions. The order of reactivity ArOTf >= ArCl >= ArBr is consistent with transmetalation being a slow step of the reaction. PMID- 26735922 TI - Meta-Analysis of a Complex Network of Non-Pharmacological Interventions: The Example of Femoral Neck Fracture. AB - BACKGROUND: Surgical interventions raise specific methodological issues in network meta-analysis (NMA). They are usually multi-component interventions resulting in complex networks of randomized controlled trials (RCTs), with multiple groups and sparse connections. PURPOSE: To illustrate the applicability of the NMA in a complex network of surgical interventions and to prioritize the available interventions according to a clinically relevant outcome. METHODS: We considered RCTs of treatments for femoral neck fracture in adults. We searched CENTRAL, MEDLINE, EMBASE and ClinicalTrials.gov up to November 2015. Two reviewers independently selected trials, extracted data and used the Cochrane Collaboration's tool for assessing the risk of bias. A group of orthopedic surgeons grouped similar but not identical interventions under the same node. We synthesized the network using a Bayesian network meta-analysis model. We derived posterior odds ratios (ORs) and 95% credible intervals (95% CrIs) for all possible pairwise comparisons. The primary outcome was all-cause revision surgery. RESULTS: Data from 27 trials were combined, for 4,186 participants (72% women, mean age 80 years, 95% displaced fractures). The median follow-up was 2 years. With hemiarthroplasty (HA) and total hip arthroplasty (THA) as a comparison, risk of surgical revision was significantly higher with the treatments unthreaded cervical osteosynthesis (OR 8.0 [95% CrI 3.6-15.5] and 5.9 [2.4-12.0], respectively), screw (9.4 [6.0-16.5] and 6.7 [3.9-13.6]) and plate (12.5 [5.8-23.8] and 7.8 [3.8-19.4]). CONCLUSIONS: In older women with displaced femoral neck fractures, arthroplasty (HA and THA) is the most effective treatment in terms of risk of revision surgery. SYSTEMATIC REVIEW REGISTRATION: PROSPERO no. CRD42013004218. LEVEL OF EVIDENCE: Network Meta-Analysis, Level 1. PMID- 26735923 TI - Influence of Familial Renal Glycosuria Due to Mutations in the SLC5A2 Gene on Changes in Glucose Tolerance over Time. AB - Familial renal glycosuria is an inherited disorder resulting in glucose excretion in the urine despite normal blood glucose concentrations. It is most commonly due to mutations in the SLC5A2 gene coding for the glucose transporter SGLT2 in the proximal tubule. Several drugs have been introduced as means to lower glucose in patients with type 2 diabetes targeting SGLT2 resulting in renal glycosuria, but no studies have addressed the potential effects of decreased renal glucose reabsorption and chronic glycosuria on the prevention of glucose intolerance. Here we present data on a large pedigree with renal glycosuria due to two mutations (c.300-303+2del and p.A343V) in the SLC5A2 gene. The mutations, which in vitro affected glucose transport in a cell line model, and the ensuing glycosuria were not associated with better glycemic control during a follow-up period of more than 10 years. One individual, who was compound heterozygous for mutations in the SLC5A2 gene suffered from severe urogenital candida infections and postprandial hypoglycemia. In conclusion, in this family with familial glycosuria we did not find any evidence that chronic loss of glucose in the urine would protect from deterioration of the glucose tolerance over time. PMID- 26735926 TI - Current laser applications in reconstructive microsurgery: A review of the literature. AB - BACKGROUND: Microvascular surgery has become an important method for reconstructing surgical defects following trauma, tumor resection, or burns. Laser-assisted microanastomoses (LAMA) were introduced by Jain in 1979 in order to help the microsurgeon reduce both operating time and complications. This article reviews the literature on clinical applications of LAMA. METHODS: A Medline literature search was performed and cross-referenced. Articles between 1979 and 2014 were included. Keywords used were laser, laser microanastomoses, laser microanastomosis, LAMA, and microsurgery. RESULTS: Only seven clinical studies using three different wavelengths were found in the literature: 1,064 nm (Nd: YAG), 10,600 nm (CO2), 514 nm (Argon), and 1,950 nm (Diode). Clinical outcomes, type of procedures, laser wavelength and parameters, and possible wider applications in the operating room are discussed in each case. CONCLUSIONS: The success rate for reconstructive free flap surgery and hand surgery achieved with LAMA appears promising. In particular, use of the 1950-nm diode laser for microsurgery is likely to increase in the near future. PMID- 26735928 TI - Correction: Depletion of UDP-Glucose and UDP-Galactose Using a Degron System Leads to Growth Cessation of Leishmania major. AB - [This corrects the article DOI: 10.1371/journal.pntd.0004205.]. PMID- 26735927 TI - "I'm Not Telling": The Effects of Racial Disparities Communications on Task Persistence Among Blacks. AB - Research suggests that communications about racial health disparities may adversely affect Blacks. In this study, we varied the message content (Black White cardiovascular-related disparities + neutral health topics vs. neutral health topics only) embedded in public service announcements given to Black and White participants (N = 86) and had them complete a purported health self assessment. We used the number of items completed as a measure of task persistence. Our results showed that participants in the disparities condition completed fewer items on average than participants in the neutral condition (p < .01). Planned contrasts revealed that this effect was driven by the responses of Blacks who completed fewer items in the disparities condition (p < .01), though Whites evinced a comparable condition-based trend (p = .12). We found no Black White differences in the number of items completed in either of our experimental conditions (ps >= .53). Although preliminary, our findings suggest that Blacks and Whites exposed to comparative racial disparities messaging about cardiovascular diseases could experience reduced task persistence. Research implications and study limitations are also discussed. PMID- 26735929 TI - Perceptual-cognitive expertise of handball coaches in their young and middle adult years. AB - There is little research investigating the maintenance of perceptual-cognitive expertise in general and even less comparing coaches of different ages. The aim of this study was to test for perceptual-cognitive differences between age groups, licence levels, and their interaction. This study investigated differences in skilled performance between young and middle-aged coaches of three different skill levels. Participants performed an accuracy-oriented pattern recall (mean distance in pixel) and a time-oriented flicker test (mean detection time in ms). There were some significant differences between age groups and between skill groups for both tests, but no interactions. For the pattern recall test, the effect sizes were larger for skill level differences, while for the flicker test effects were larger for ageing. These results suggest coaches are able to maintain accuracy skills better than reaction timed tasks. This is in line with findings on speeded performance in general populations, which show declines with age. Moreover, results also support findings on perceptual expertise in skills where accuracy was important. PMID- 26735930 TI - Insider trading: Extracellular matrix proteins and their non-canonical intracellular roles. AB - In metazoans, the extracellular matrix (ECM) provides a dynamic, heterogeneous microenvironment that has important supportive and instructive roles. Although the primary site of action of ECM proteins is extracellular, evidence is emerging for non-canonical intracellular roles. Examples include osteopontin, thrombospondins, IGF-binding protein 3 and biglycan, and relate to roles in transcription, cell-stress responses, autophagy and cancer. These findings pose conceptual problems on how proteins signalled for secretion can be routed to the cytosol or nucleus, or can function in environments with diverse redox, pH and ionic conditions. We review evidence for intracellular locations and functions of ECM proteins, and current knowledge of the mechanisms by which they may enter intracellular compartments. We evaluate the experimental methods that are appropriate to obtain rigorous evidence for intracellular localisation and function. Better insight into this under-researched topic is needed to decipher the complete spectrum of physiological and pathological roles of ECM proteins. PMID- 26735931 TI - Pluripotency and the endogenous retrovirus HERVH: Conflict or serendipity? AB - Remnants of ancient retroviral infections during evolution litter all mammalian genomes. In modern humans, such endogenous retroviral (ERV) sequences comprise at least 8% of the genome. While ERVs and other types of transposable elements undoubtedly contribute to the genomic "junk yard", functions for some ERV sequences have been demonstrated, with growing evidence that ERVs can be important players in gene regulatory processes. Here we focus on one particular large family of human ERVs, termed HERVH, which several recent studies suggest has a key regulatory role in human pluripotent stem cells. Remarkably, this is not the first instance of an ERV controlling pluripotency. We speculate as to why this convergent evolution might have come about, suggesting that it may reflect selection on the virus to extend the time available for transposition. Alternatively it may reflect serendipity alone. PMID- 26735934 TI - Molecular Dissection of the Homotrimeric Sliding Clamp of T4 Phage: Two Domains of a Subunit Display Asymmetric Characteristics. AB - Sliding clamp proteins are circular dimers or trimers that encircle DNA and serve as processivity factors during DNA replication. Their presence in all the three domains of life and in bacteriophages clearly indicates their high level of significance. T4 gp45, besides functioning as the DNA polymerase processivity factor, also moonlights as the late promoter transcription determinant. Here we report a detailed biophysical analysis of gp45. The chemical denaturation of gp45 probed by circular dichroism spectroscopy, tryptophan fluorescence anisotropy, and blue-native polyacrylamide gel electrophoresis suggests that the protein follows a three-state denaturation profile and displays an intermediate molten globule-like state. The three-state transition was found to be the result of the sequential unfolding of the two domains, the N-terminal domain (NTD) and the C terminal domain (CTD), of gp45. The experiments involving Trp fluorescence quenching by acrylamide demonstrate that the CTD undergoes substantial changes in conformation during formation of the intermediate state. Further biophysical dissection of the individual domain reveals contrasting properties of the two domains. The NTD unfolds at low urea concentrations and is also susceptible to protease cleavage, whereas the CTD resists urea-mediated denaturation and is not amenable to protease digestion even at higher urea concentrations. These experiments allow us to conclude that the two domains of gp45 differ in their dynamics. While the CTD shows stability and rigidity, we find that the NTD is unstable and flexible. We believe that the asymmetric characteristics of the two domains and the interface they form hold significance in gp45 structure and function. PMID- 26735933 TI - Effects of Methoxychlor and Its Metabolite Hydroxychlor on Human Placental 3beta Hydroxysteroid Dehydrogenase 1 and Aromatase in JEG-3 Cells. AB - Progesterone and estradiol produced by the human placenta are critical for maintenance of pregnancy and fetal development. In the human placenta, 3beta hydroxysteroid dehydrogenase 1 (HSD3B1) is responsible for the formation of progesterone from pregnenolone and aromatase (CYP19A1) for the production of estradiol from androgen. Insecticide methoxychlor (MXC) and its metabolite hydroxychlor (HPTE) may disrupt the activities of these 2 enzymes. In this study, we investigated the effects of MXC and HPTE on steroid production in human placental JEG-3 cells and on HSD3B1 and CYP19A1 activities. MXC and HPTE inhibited progesterone and estradiol production in JEG-3 cells. MXC and HPTE were potent HSD3B1 inhibitors with the half maximal inhibitory concentration (IC50) values of 2.339 +/- 0.096 and 1.918 +/- 0.078 MUmol/l, respectively. MXC had no inhibition on CYP19A1 at 100 MUmol/l, while HPTE was a weak inhibitor with IC50 of 97.16 +/- 0.10 MUmol/l. When pregnenolone was used to determine the inhibitory mode, MXC and HPTE were found to be competitive inhibitors of HSD3B1. When cofactor NAD+ was used, MXC and HPTE were the noncompetitive inhibitors of HSD3B1. When testosterone was used, HPTE was a mixed inhibitor of CYP19A1. In conclusion, MXC and HPTE are potent inhibitors of human HSD3B1, and HPTE is a weak CYP19A1 inhibitor. PMID- 26735935 TI - Ferrocene-containing non-interlocked molecular machines. AB - Ferrocene is the prototypical organometallic sandwich complex and despite over 60 years passing since the discovery and elucidation of ferrocene's structure, research into ferrocene-containing compounds continues to grow as potential new applications in catalysis, biology and the material sciences are found. Ferrocene is chemically robust and readily functionalized which enables its facile incorporation into more complex molecular systems. This coupled with ferrocene's reversible redox properties and ability function as a "molecular ball bearing" has led to the use of ferrocene as a component in wide range of interlocked and non-interlocked synthetic molecular machine systems. This review will focus on the exploitation of ferrocene (and related sandwich complexes) for the development of non-interlocked synthetic molecular machines. PMID- 26735936 TI - Deducing the functional characteristics of the human selenoprotein SELK from the structural properties of its intrinsically disordered C-terminal domain. AB - The intrinsically disordered proteins (IDPs) cannot be described by a single structural representation but, due to their high structural fluctuation, through conformational ensembles. Certainly, molecular dynamics (MD) simulations represent a useful tool to study their different conformations capturing the conformational distribution. Our group is focusing on the structural characterization of proteins belonging to the seleno-proteome due to their involvement in cancer. They present disordered domains central for their biological function, and, in particular, SELK is a single-pass transmembrane protein that resides in the endoplasmic reticulum membrane (ER) with a C-terminal domain exposed to the cytoplasm that is known to interact with different components of the endoplasmic reticulum associated to the protein degradation (ERAD) pathway. This protein is found to be up-expressed in hepatocellular carcinoma and in other cancers. In this work we performed a detailed analysis of the C-terminal domain sequence of SELK and discovered that it is characterized by many prolines, and four negatively and eleven positively charged residues, which are crucial for its biological activity. This region can be considered as a weak polyelectrolyte and, specifically, a polycation, with high disordered propensity and different phosphorylation sites dislocated along the sequence. Then, we modeled its three-dimensional structure by performing MD simulations in water at neutral pH to analyze the structural stability as well as to identify the presence of HUB residues that play a key structural role as evidenced by the residue-residue interaction network analysis. Through this approach, we demonstrate that the C-terminal domain of SELK (i) presents a poor content of regular secondary structure elements, (ii) is dynamically stabilized by a network of intra-molecular H-bonds and H-bonds with water molecules, (iii) is highly fluctuating and, therefore, can be described only through a conformational ensemble, where we evidenced a distribution of equilibrium conformers which continuously inter-change their conformations. Finally to verify the specific role played by the negative charges, we also performed MD simulations at acidic pH. Overall, all the obtained results evidenced that SELK has the dynamic structural features to be defined as a HUB protein able to interact with multiple members. Therefore, considering the possible role that this protein can have in cancer development and progression, it can represent a target for drug design studies. PMID- 26735937 TI - Efficacy and Safety of Methotrexate Combined with Low- to Moderate-Dose Corticosteroids for Severe Alopecia Areata. AB - BACKGROUND: In severe alopecia areata (AA), spontaneous recovery is unlikely, and treatment is not standardized. OBJECTIVE: To evaluate the efficacy and safety of methotrexate (MTX) used alone or combined with low- to moderate-dose oral corticosteroids (OC) for treating severe AA (totalis, universalis and severe multifocal). METHODS: Retrospective monocentric study of all consecutive patients receiving this treatment between 2006 and 2012. Efficacy was defined as achieving a total regrowth of terminal hair. RESULTS: 26 patients were included (17 with AA universalis or totalis and 9 with severe multifocal AA). Total regrowth was noted in 15/26 patients. After 3 months of treatment, hair regrowth >80% was associated with further complete regrowth, and hair regrowth <30% was associated with later treatment failure (p = 0.0014). When treatment was tapered, 11/15 patients with initial complete efficacy experienced AA relapse. CONCLUSION: MTX combined with low- to moderate-dose OC may be an efficient and well-tolerated treatment for severe AA. However, long-term maintenance treatment is usually required. PMID- 26735938 TI - Steroid atrophy scarring treated with fat grafting in a patient with complex regional pain syndrome: A case report. AB - Subcutaneous atrophy is a known complication of steroid injections. Excellent results with fat grafting for the treatment of steroid atrophy have been documented. However, the benefit of treating steroid-induced subcutaneous atrophy in an extremity diagnosed with complex regional pain syndrome (CRPS) has not been described. CRPS, known formerly as reflex sympathetic dystrophy or RSD, causalgia, or reflex neurovascular dystrophy, is a severe, progressive musculoskeletal pain syndrome characterized by pain which is disproportionate to the severity of the inciting event, edema, or skin changes. Common treatment modalities include pharmacotherapy, physical therapy, and nerve blocks-each therapy producing varying results. We present a literature review of CRPS and the case of a 15-year-old female who developed CRPS of the left lower leg after arthroscopic debridement with retrograde drilling of an osteochondral lesion. Steroid atrophy of the involved area following a saphenous nerve block complicated the patient's treatment course. The area of atrophy was treated with autologous fat grafting. Following the adipose injection procedure, the patient experienced almost complete resolution of her CPRS-associated pain symptoms, along with improved cosmetic appearance of the area. PMID- 26735939 TI - Pyrrolizidine alkaloids from Solenanthus lanatus DC. with acetylcholinesterase inhibitory activity. AB - The whole plant ethanolic extract of Solenanthus lanatus was used for the isolation of acetylcholinesterase inhibitors. A new pyrrolizidine alkaloid, 7-O angeloylechinatine N-oxide, 1, was isolated together with three known compounds of the same class (3'-O-acetylheliosupine N-oxide, 2, heliosupine N-oxide, 3, and heliosupine, 4), by bioassay-guided approach. Their structures were elucidated by spectroscopic methods. All the isolated compounds showed inhibition activity against the AChE, with IC50 0.53-0.60 mM. PMID- 26735941 TI - Liquor, tobacco and editorial independence. PMID- 26735942 TI - The Farmington Consensus. PMID- 26735943 TI - Acute reactions to alcohol. AB - Where the experience of alcohol is unpleasant because of adverse reactions to small amounts, alcohol consumption is likely to be low and alcohol dependence rare. This is shown by many studies of Asian subjects who experience the alcohol flush reaction (AFR) due to inherited aldehyde dehydrogenase (ALDH) deficiency. Alcohol reactions are less common and on average less severe in non-Asian subjects, but they do occur and can affect alcohol consumption. Information about alcohol reactions and their consequences in Europeans is reviewed, and such reactions are compared with those caused by mitochondrial ALDH deficiency in Asians. PMID- 26735944 TI - Ethanol metabolism in the brain. AB - Acetaldehyde is suspected of being involved in the central mechanism of central nervous system depression and addiction to ethanol, but in contrast to ethanol, it can not penetrate easily from blood into the brain because of metabolic barriers. Therefore, the possibility of ethanol metabolism and acetaldehyde formation inside the brain has been one of the crucial questions in biomedical research of alcoholism. This article reviews the recent progress in this area and summarizes the evidence on the first stage of ethanol oxidation in the brain and the specific enzyme systems involved. The brain alcohol dehydrogenase and microsomal ethanol oxidizing systems, including cytochrome P450 II E1 and catalase are considered. Their physicochemical properties, the isoform composition, substrate specificity, the regional and subcellular distribution in CNS structures, their contribution to brain ethanol metabolism, induction under ethanol administration and the role in the neurochemical mechanisms of psychopharmacological and neurotoxic effects of ethanol are discussed. In addition, the nonoxidative pathway of ethanol metabolism with the formation of fatty acid ethyl esters and phosphatidylethanol in the brain is described. PMID- 26735940 TI - High-Throughput Genetic Screens Identify a Large and Diverse Collection of New Sporulation Genes in Bacillus subtilis. AB - The differentiation of the bacterium Bacillus subtilis into a dormant spore is among the most well-characterized developmental pathways in biology. Classical genetic screens performed over the past half century identified scores of factors involved in every step of this morphological process. More recently, transcriptional profiling uncovered additional sporulation-induced genes required for successful spore development. Here, we used transposon-sequencing (Tn-seq) to assess whether there were any sporulation genes left to be discovered. Our screen identified 133 out of the 148 genes with known sporulation defects. Surprisingly, we discovered 24 additional genes that had not been previously implicated in spore formation. To investigate their functions, we used fluorescence microscopy to survey early, middle, and late stages of differentiation of null mutants from the B. subtilis ordered knockout collection. This analysis identified mutants that are delayed in the initiation of sporulation, defective in membrane remodeling, and impaired in spore maturation. Several mutants had novel sporulation phenotypes. We performed in-depth characterization of two new factors that participate in cell-cell signaling pathways during sporulation. One (SpoIIT) functions in the activation of sigmaE in the mother cell; the other (SpoIIIL) is required for sigmaG activity in the forespore. Our analysis also revealed that as many as 36 sporulation-induced genes with no previously reported mutant phenotypes are required for timely spore maturation. Finally, we discovered a large set of transposon insertions that trigger premature initiation of sporulation. Our results highlight the power of Tn-seq for the discovery of new genes and novel pathways in sporulation and, combined with the recently completed null mutant collection, open the door for similar screens in other, less well characterized processes. PMID- 26735945 TI - Cerebrospinal fluid neuroendocrinology of alcohol misusers. AB - Cerebrospinal fluid (CSF) neurohumors reflect central nervous system physiology in a way that peripheral indices can not. We reviewed clinical studies of CSF biogenic amines and neurohormones in alcohol misusers during various stages of withdrawal or abstinence and found them difficult to compare because of highly variable experimental methods, reliance on single time collections (lumbar punctures) that fail to control for potential stress-induced effects of the procedure, lack of control for tobacco use, and a paucity of non-alcoholmisusing controls. However, taken together, the data thus far show that a variety of neuroactive substances are reduced in concentration in the CSF of some alcohol misusers. Low CSF levels of corticotropinreleasing hormone, beta-endorphin, norepinephrine, diazepam-binding inhibitor, 5-hydroxyindoleacetic acid and somatostatin have all been reported. Whether the decreased CSF levels of these neurohormones and neurotransmitters are a cause or consequence of alcoholism has not been determined. In fact, further studies using serial or continuous CSF sampling techniques with homogeneous, better-characterized patients and normal volunteers are still needed to establish the precise CSF neurochemical abnormalities in alcohol misusers. PMID- 26735946 TI - Hepatitis in alcohol and drug misusers: practical issues. AB - Viral hepatitis, particularly that due to HBV or HCV, is a significant problem in the UK population of IVDUs and alcohol misusers. Patients attending drug rehabilitation clinics should be screened for HBV and HCV infection. All those found to be HBcAb negative should be vaccinated against HBV. Those found to be HBsAg or HCV antibody positive should have their liver function tests (LFTs) checked and be referred to a specialist liver clinic for further evaluation. Interferon treatment of HBV or HCV infection is effective in a proportion of cases but it is an expensive agent that requires careful monitoring. Current management regimes are centred around the modification of risk behaviour and the identification of those most in need of, and most likely to respond to, anti viral treatment. Several new anti-viral agents are currently undergoing clinical evaluation and this together with the prospect of vaccines designed to clear an established infection means that the next few years are likely to see some major advances in the treatment of chronic viral hepatitis. PMID- 26735947 TI - SIV infection of macaques: a model for studying AIDS and drug abuse. AB - Rhesus monkeys (Macaca mulatta) and the simian immunodeficiency virus (SIV) were used as an animal model system to evaluate longitudinally the effects of opioid dependence on the development of AIDS. Results have shown that in addition to weakening the host's T cell and PMN functions, chronic opioid treatment of SIVmac239-infected animals caused (a) an increased virus replication rate, (b) an increased rate of viral mutation, (c) a nascent humoral (antibody) response against mutated autologous strains of virus, (d) an alteration of CD8 + cell mediated immunity toward the mutant virus, (e) an increased tolerance of AZT among the infectious virus and (f) a shorter life span for the infected animals. These results suggest that chronic administration of opioids alters general fundamental aspects of the AIDS viremia. PMID- 26735948 TI - A study of event-related potential-P3 characteristics in children of alcoholics. AB - Auditory P3 characteristics were studied in children (aged 8-14 years) of male alcoholics without psychiatric problems and children of normal parents employing an oddball auditory paradigm. All the children of alcoholics were from families with multiple cases of alcoholism (each child had an average of 4.3 first- and second-degree relatives including the father, meeting criteria for alcoholism). Subjects were presented with high and low pitched tones with global probabilities of 25% and 75% of total trials, respectively. The amplitude of P3 component was significantly reduced in high-risk children (p < 0.001). Implications of the findings, including the role of P3 as biologi cal marker of risk for alcoholism, are discussed. PMID- 26735949 TI - Effect of captopril on voluntary consumption of ethanol, water and solid food by UChA and UChB rats. AB - Angiotensin converting enzyme inhibitors (ACEI) have been reported to reduce ethanol consumption in rats, but it is unclear whether this effect is specific for ethanol or secondary to effects on appetite or satiation for calories or water. In the present study we assessed the effect of captopril, an ACEI, on the voluntary consumption of 10% ethanol solution, water and solid food in our strain of rats genetically selected for their voluntary consumption of ethanol, namely UChA (low consumer) and UChB (high consumer). Captopril (30 mg/kg) was injected intraperitoneally for 3 consecutive days to UChA and UChB rats and ethanol, water and food intake were measured before, during and after captopril treatment; these results were compared with those produced by a control saline solution. Results showed that captopril produced a significant reduction of alcohol voluntary consumption in UChB but not in UChA rats. However, this effect was not specific for ethanol since captopril also induced a significant decrease in food intake leading to a loss of weight in both rat strains, suggesting that it seems to be secondary to changes in appetite for calories. PMID- 26735950 TI - Hepatic haemodynamics and reticuloendothelial function in the rat in response to chronic ethanol administration. AB - This study investigated the effects of chronic ethanol intake on hepatic haemodynamics and reticuloendothelial system function in the rat. Comparisons were also made with blood flow to pancreas, kidney, spleen, lung and skin. Male Wistar rats, approximately 0.15 kg initial body weight, were fed a diet containing 35% of the total calories as ethanol. Controls were pair-fed identical amounts of the same diet in which ethanol was replaced by isocaloric glucose. The hepatic perfusion index and reticuloendothelial function was determined with [(99m) Tc]-labelled sulphur colloid [(99m) Tc]-SC) and blood flow with radiolabelled microspheres under anaesthesia. After 4-5 weeks the weights of liver and skin of alcohol fed rats decreased by 10% (p= 0.040) and 23% (p= 0.024), respectively, compared to controls and there was a small increase in kidney weight (15%, p = 0.001). Blood flow to liver, pancreas, kidney, spleen, lung and skin was not altered significantly by chronic alcohol administration, irrespective of whether the data were expressed as a percentage of cardiac output, blood flow per minute per organ or blood flow per minute per g tissue weight (p > 0.113 in all instances). However, there was a significant increase in splenic reticuloendothelial system activity (+ 121%, p = 0.018). Hepatic reticuloendothelial system activity was also increased (+ 22%, p = 0.061). Chronic alcohol administration resulted in significant increases in portal pressure (+ 55%, p = 0.042) and portal venous resistance (+ 66%, p = 0.001), but portal venous inflow and hepatic perfusion index were not altered compared to controls The results of this study indicated that chronic alcohol administration did not alter visceral blood flow significantly, but did increase portal pressure, portal vascular resistance and reticuloendothelial system activity. PMID- 26735951 TI - Modulation of the decrease in the seizure threshold of pentylenetetrazole in diazepam withdrawn mice by the neurosteroid 5alphapregnan-3alpha,21-diol-20-one (alloTHDOC). AB - The effect of the neurosteroid 5alpha-pregnan-3alpha,21-diol-20-one (alloTHDOC) on pentylenetetrazole (PTZ)induced diazepam-withdrawal seizure was examined in mice. The threshold for PTZ-induced seizure was markedly decreased by discontinuation of chronic diazepam treatment. The decrease in the seizure threshold of PTZ during diazepam withdrawal was significantly attenuated by pretreatment with alloTHDOC (10 and 20 mug/mouse, i.c.v.), which did not affect the seizure threshold of PTZ in chronically vehicle-treated mice. However, the loss of the righting reflex (LRR) induced by other GABAA receptor activators (pentobarbital and propofol) did not differ between control and diazepam withdrawn mice. These findings provide the first demonstration that alloTHDOC may be able to suppress diazepam withdrawal signs, and that the sensitivity to the pharmacological effect of alloTHDOC via GABAA receptor may be enhanced in diazepam-with- drawn mice. PMID- 26735952 TI - Tropisetron and hangover. PMID- 26735953 TI - Distribution and Numbers of Pygmies in Central African Forests. AB - Pygmy populations occupy a vast territory extending west-to-east along the central African belt from the Congo Basin to Lake Victoria. However, their numbers and actual distribution is not known precisely. Here, we undertake this task by using locational data and population sizes for an unprecedented number of known Pygmy camps and settlements (n = 654) in five of the nine countries where currently distributed. With these data we develop spatial distribution models based on the favourability function, which distinguish areas with favourable environmental conditions from those less suitable for Pygmy presence. Highly favourable areas were significantly explained by presence of tropical forests, and by lower human pressure variables. For documented Pygmy settlements, we use the relationship between observed population sizes and predicted favourability values to estimate the total Pygmy population throughout Central Africa. We estimate that around 920,000 Pygmies (over 60% in DRC) is possible within favourable forest areas in Central Africa. We argue that fragmentation of the existing Pygmy populations, alongside pressure from extractive industries and sometimes conflict with conservation areas, endanger their future. There is an urgent need to inform policies that can mitigate against future external threats to these indigenous peoples' culture and lifestyles. PMID- 26735954 TI - Normal and Fibrotic Rat Livers Demonstrate Shear Strain Softening and Compression Stiffening: A Model for Soft Tissue Mechanics. AB - Tissues including liver stiffen and acquire more extracellular matrix with fibrosis. The relationship between matrix content and stiffness, however, is non linear, and stiffness is only one component of tissue mechanics. The mechanical response of tissues such as liver to physiological stresses is not well described, and models of tissue mechanics are limited. To better understand the mechanics of the normal and fibrotic rat liver, we carried out a series of studies using parallel plate rheometry, measuring the response to compressive, extensional, and shear strains. We found that the shear storage and loss moduli G' and G" and the apparent Young's moduli measured by uniaxial strain orthogonal to the shear direction increased markedly with both progressive fibrosis and increasing compression, that livers shear strain softened, and that significant increases in shear modulus with compressional stress occurred within a range consistent with increased sinusoidal pressures in liver disease. Proteoglycan content and integrin-matrix interactions were significant determinants of liver mechanics, particularly in compression. We propose a new non-linear constitutive model of the liver. A key feature of this model is that, while it assumes overall liver incompressibility, it takes into account water flow and solid phase compressibility. In sum, we report a detailed study of non-linear liver mechanics under physiological strains in the normal state, early fibrosis, and late fibrosis. We propose a constitutive model that captures compression stiffening, tension softening, and shear softening, and can be understood in terms of the cellular and matrix components of the liver. PMID- 26735955 TI - Ten Years after the International Committee of Medical Journal Editors' Clinical Trial Registration Initiative, One Quarter of Phase 3 Pediatric Epilepsy Clinical Trials Still Remain Unpublished: A Cross Sectional Analysis. AB - INTRODUCTION: Although selective reporting of clinical trial results introduces bias into evidence based clinical decision making, publication bias in pediatric epilepsy is unknown today. Since there is a considerable ambiguity in the treatment of an important and common clinical problem, pediatric seizures, we assessed the public availability of results of phase 3 clinical trials that evaluated treatments of seizures in children and adolescents as a surrogate for the extent of publication bias in pediatric epilepsy. METHODS: We determined the proportion of published and unpublished study results of phase 3 clinical trials that were registered as completed on ClinicalTrials.gov. We searched ClinicalTrials.gov, PubMed, and Google Scholar for publications and contacted principal investigators or sponsors. The analysis was performed according to STROBE criteria. RESULTS: Considering studies that were completed before 2014 (N = 99), 75 (76%) pediatric phase 3 clinical trials were published but 24 (24%) remained unpublished. The unpublished studies concealed evidence from 4,437 patients. Mean time-to-publication was 25 SD +/- 15.6 months, more than twice as long as mandated. CONCLUSION: Ten years after the ICMJE's clinical trials registration initiative there is still a considerable amount of selective reporting and delay of publication that potentially distorts the body of evidence in the treatment of pediatric seizures. PMID- 26735956 TI - Re: "Proprioceptive Phenomenon With Involutional Ptosis: Evidential Findings in Anophthalmic Ptosis". PMID- 26735957 TI - Reply re: "Proprioceptive Phenomenon With Involutional Ptosis: Evidential Findings in Anophthalmic Ptosis". PMID- 26735958 TI - Re: "Treating Buccinator with Botulinum Toxin in Patients with Facial Synkinesis: A Previously Overlooked Target". PMID- 26735959 TI - Reply re: "Treating Buccinator with Botulinum Toxin in Patients with Facial Synkinesis: A Previously Overlooked Target". PMID- 26735960 TI - Re: "Cosmetic Microdroplet Botulinum Toxin A Forehead Lift: A New Treatment Paradigm". PMID- 26735961 TI - Reply re: "Cosmetic Microdroplet Botulinum Toxin A Forehead Lift: A New Treatment Paradigm". PMID- 26735962 TI - Re: "Orbital Fat Decompression for Thyroid Eye Disease: Retrospective Case Review and Criteria for Optimal Case Selection". PMID- 26735963 TI - Re: "Evolving Minimally Invasive Techniques for Tear Trough Enhancement". PMID- 26735964 TI - Pigs Can Be Used as a Large Animal Model for Autologous Fat Grafting. PMID- 26735965 TI - Hemorrhagic Complications of Rivaroxaban After Eyelid Surgery. PMID- 26735966 TI - Re: "Tumescent Anesthesia for Muller's Muscle-Conjunctival Resection". PMID- 26735967 TI - Probing Electric Field Effect on Covalent Interactions at a Molecule Semiconductor Interface. AB - Fundamental understanding of the energetic coupling properties of a molecule semiconductor interface is of great importance. The changes in molecular conformations and vibrational modes can have significant impact on the interfacial charge transfer reactions. Here, we have probed the change in the interface properties of alizarin-TiO2 system as a result of the externally applied electric field using single-hot spot microscopic surface-enhanced Raman spectroscopy (SMSERS) and provided a theoretical understanding of our experimental results by density functional theory (DFT) calculations. The perturbation, caused by the external potential, has been observed as a shift and splitting of the 648 cm(-1) peak, typical indicator of the strong coupling between alizarin and TiO2, at SMSERS. On the basis of our experimental results and DFT calculations, we suggest that electric field has significant effects on vibrational coupling at the molecule-TiO2 interface. The presence of perturbed alizarin-TiO2 coupling under interfacial electric potential may lead to changes in the interfacial electron transfer dynamics. Additionally, heterogeneously distributed dye molecules at the interface on nanometer length scale and different chromophore-semiconductor binding interactions under charge accumulation associated interfacial electric field changes create intrinsically inhomogeneous interfacial ET dynamics associated with both static and dynamic disorders. PMID- 26735968 TI - Implication of the myokine irisin in maternal energy homeostasis in pregnancies with abnormal fetal growth. AB - OBJECTIVE: To prospectively investigate maternal concentrations of the myokine irisin in large for gestational age (LGA) and intrauterine growth restricted (IUGR) versus appropriate for gestational age (AGA) normal pregnancies and associate them with various perinatal parameters. METHODS: Plasma irisin and insulin concentrations were measured by enzyme-linked immunosorbent assay (ELISA) and immunoradiometric assay (IRMA), respectively, in a cohort of 80 mothers delivering LGA (n = 30), IUGR (n = 30) and AGA (n = 20) singleton full-term infants. RESULTS: Maternal irisin concentrations were similar among LGA, IUGR and AGA groups and did not correlate with respective insulin ones or maternal body mass index. In a combined group, maternal irisin concentrations decreased with advancing gestational age (p < 0.001) and were lower in multi-, compared to nulliparous women (p = 0.004). In the IUGR group, maternal irisin concentrations were higher in cases of smoking (p = 0.006). CONCLUSIONS: Irisin may not be differentially regulated in insulin resistance-associated pregnancy disorders resulting in fetal macrosomia and IUGR. Maternal irisin down-regulation with advancing gestation could possibly contribute to the observed maternal fat accumulation and progressive insulin resistance towards term. Similarly, lower maternal irisin concentrations in multiparous women may reflect the documented positive association between parity and fat deposition. Irisin up-regulation in cases of smoking may indicate the need for enhanced oxygen consumption to maintain energy production under conditions of hypoxia. PMID- 26735969 TI - Evaluation in Cameroon of a Novel, Simplified Methodology to Assist Molecular Microbiological Analysis of V. cholerae in Resource-Limited Settings. AB - BACKGROUND: Vibrio cholerae is endemic in South Asia and Africa where outbreaks of cholera occur widely and are particularly associated with poverty and poor sanitation. Knowledge of the genetic diversity of toxigenic V. cholerae isolates, particularly in Africa, remains scarce. The constraints in improving this understanding is not only the lack of regular cholera disease surveillance, but also the lack of laboratory capabilities in endemic countries to preserve, store and ship isolates in a timely manner. We evaluated the use of simplified sample preservation methods for molecular characterization using multi-locus variable number tandem-repeat analysis (MLVA) for differentiation of Vibrio cholerae genotypes. METHODS AND FINDINGS: Forty-seven V. cholerae isolates and 18 enriched clinical specimens (e.g. stool specimens after enrichment in broth) from cholera outbreaks in Cameroon were preserved on Whatman filter paper for DNA extraction. The samples were collected from two geographically distinct outbreaks in the Far North of Cameroon (FNC) in June 2014 and October 2014. In addition, a convenience sample of 14 isolates from the Philippines and 8 from Mozambique were analyzed. All 87 DNAs were successfully analyzed including 16 paired samples, one a cultured isolate and the other the enriched specimen from which the isolate was collected. Genotypic results were identical between 15 enriched specimens and their culture isolates and the other pair differed at single locus. Two closely related, but distinct clonal complexes were identified among the Cameroonian specimens from 2014. CONCLUSIONS: Collecting V. cholerae using simplified laboratory methods in remote and low-resource settings allows for subsequent advanced molecular characterization of V. cholerae O1. These simplified DNA preservation methods identify V. cholerae and make possible timely information regarding the genetic diversity of V. cholerae; our results set the stage for continued molecular epidemiological research to better understand the transmission and dissemination of V. cholerae in Africa and elsewhere worldwide. PMID- 26735970 TI - Tissue plasminogen activator followed by antioxidant-loaded nanoparticle delivery promotes activation/mobilization of progenitor cells in infarcted rat brain. AB - Inherent neuronal and circulating progenitor cells play important roles in facilitating neuronal and functional recovery post stroke. However, this endogenous repair process is rather limited, primarily due to unfavorable conditions in the infarcted brain involving reactive oxygen species (ROS) mediated oxidative stress and inflammation following ischemia/reperfusion injury. We hypothesized that during reperfusion, effective delivery of antioxidants to ischemic brain would create an environment without such oxidative stress and inflammation, thus promoting activation and mobilization of progenitor cells in the infarcted brain. We administered recombinant human tissue-type plasminogen activator (tPA) via carotid artery at 3 h post stroke in a thromboembolic rat model, followed by sequential administration of the antioxidants catalase (CAT) and superoxide dismutase (SOD), encapsulated in biodegradable nanoparticles (nano CAT/SOD). Brains were harvested at 48 h post stroke for immunohistochemical analysis. Ipsilateral brain slices from animals that had received tPA + nano CAT/SOD showed a widespread distribution of glial fibrillary acidic protein positive cells (with morphology resembling radial glia-like neural precursor cells) and nestin-positive cells (indicating the presence of immature neurons); such cells were considerably fewer in untreated animals or those treated with tPA alone. Brain sections from animals receiving tPA + nano-CAT/SOD also showed much greater numbers of SOX2- and nestin-positive progenitor cells migrating from subventricular zone of the lateral ventricle and entering the rostral migratory stream than in t-PA alone treated group or untreated control. Further, animals treated with tPA + nano-CAT/SOD showed far fewer caspase-positive cells and fewer neutrophils than did other groups, as well as an inhibition of hippocampal swelling. These results suggest that the antioxidants mitigated the inflammatory response, protected neuronal cells from undergoing apoptosis, and inhibited edema formation by protecting the blood-brain barrier from ROS-mediated reperfusion injury. A longer-term study would enable us to determine if our approach would assist progenitor cells to undergo neurogenesis and to facilitate neurological and functional recovery following stroke and reperfusion injury. PMID- 26735971 TI - HTLV-1 bZIP Factor Impairs Anti-viral Immunity by Inducing Co-inhibitory Molecule, T Cell Immunoglobulin and ITIM Domain (TIGIT). AB - Human T-cell leukemia virus type 1 (HTLV-1) infects CD4+ T cells and induces proliferation of infected cells in vivo, which leads to the onset of adult T-cell leukemia (ATL) in some infected individuals. The HTLV-1 bZIP factor (HBZ) gene, which is encoded in the minus strand of HTLV-1, plays critical roles in pathogenesis. In this study, RNA-seq and ChIP-seq analyses using HBZ transduced T cells revealed that HBZ upregulates the expression and promoter acetylation levels of a co-inhibitory molecule, T cell immunoglobulin and ITIM domain (TIGIT), in addition to those of regulatory T cells related genes, Foxp3 and Ccr4. TIGIT was expressed on CD4+ T cells from HBZ-transgenic (HBZ-Tg) mice, and on ATL cells and HTLV-1 infected CD4+ T cells of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in vivo. Expression of Blimp1 and IL-10 was upregulated in TIGIT+CD4+ cells of HBZ-Tg mice compared with TIGIT CD4+ T cells, suggesting the correlation between TIGIT expression and IL-10 production. When CD4+ T cells from HBZ-Tg mice were stimulated with TIGIT's ligand, CD155, their production of the inhibitory cytokine IL-10 was enhanced. Furthermore, dendritic cells from HBZ-Tg mice produced high levels of IL-10 after stimulation. These data suggest that HBZ alters immune system to suppressive state via TIGIT and IL-10. Importantly, TIGIT suppressed T-cell responses to another HTLV-1 virus protein, Tax, in vitro. Blocking of TIGIT and PD-1 slightly increased anti-Tax T-cell activity in some HAM/TSP patients. These results suggest that HBZ-induced TIGIT on HTLV-1 infected cells impairs T-cell responses to viral antigens. This study shows that HBZ-induced TIGIT plays a pivotal role in attenuating host immune responses and shaping a microenvironment favorable to HTLV-1. PMID- 26735972 TI - A Clinical, Neuropathological and Genetic Study of Homozygous A467T POLG-Related Mitochondrial Disease. AB - Mutations in the nuclear gene POLG (encoding the catalytic subunit of DNA polymerase gamma) are an important cause of mitochondrial disease. The most common POLG mutation, A467T, appears to exhibit considerable phenotypic heterogeneity. The mechanism by which this single genetic defect results in such clinical diversity remains unclear. In this study we evaluate the clinical, neuropathological and mitochondrial genetic features of four unrelated patients with homozygous A467T mutations. One patient presented with the severe and lethal Alpers-Huttenlocher syndrome, which was confirmed on neuropathology, and was found to have a depletion of mitochondrial DNA (mtDNA). Of the remaining three patients, one presented with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), one with a phenotype in the Myoclonic Epilepsy, Myopathy and Sensory Ataxia (MEMSA) spectrum and one with Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO). All three had secondary accumulation of multiple mtDNA deletions. Complete sequence analysis of muscle mtDNA using the MitoChip resequencing chip in all four cases demonstrated significant variation in mtDNA, including a pathogenic MT-ND5 mutation in one patient. These data highlight the variable and overlapping clinical and neuropathological phenotypes and downstream molecular defects caused by the A467T mutation, which may result from factors such as the mtDNA genetic background, nuclear genetic modifiers and environmental stressors. PMID- 26735974 TI - Knowledge, Attitudes and Behaviors on Child Passenger Safety among Expectant Mothers and Parents of Newborns: A Qualitative and Quantitative Approach. AB - OBJECTIVE: To investigate the knowledge, attitudes, and intended behaviors about use of child safety seats among parents of newborns and explore expectant mothers' views and decisions regarding child safety seats use. METHODS: A cross sectional survey and semi-structured interview were conducted in the maternity departments of two hospitals in China. Parents of newborns were recruited after delivery and surveyed on their knowledge, attitudes and behaviors regarding child safety seats use. Pregnant women were also interviewed to learn about their views and decisions regarding child safety seats use. Both quantitative and qualitative methods were used to analyze the data collected. RESULTS: Of a total of 242 parents of newborns recruited in the quantitative survey, 202 (83.5%) parents had heard of child safety seats and 149 (61.6%) parents reported they would use child safety seats for their babies. Parents' knowledge, car ownership, occupation, and income were significantly associated with their decision regarding use of child safety seats. Three themes were identified from the qualitative interview of 30 pregnant women: (1) the pregnant women perceived child passenger safety as important; (2) the car ownership and price and quality of child safety seats were major influencing factors of their decisions on use of child safety seats; and (3) lack of awareness and lack of laws requiring use were perceived to contribute to low use of child safety seats in China. CONCLUSION: Lack of knowledge and awareness on child passenger safety were found to be two most important factors associated with low use of child safety seats. Effective interventions are urgently needed to improve parents' knowledge before laws are enacted and implemented. PMID- 26735975 TI - Relationship Between Short Umbilical Cord Length and Adverse Pregnancy Outcomes. AB - To investigate how umbilical cord length relates to pregnancy outcomes, we retrospectively analyzed data from 89,042 deliveries recorded in the Japan Society of Obstetrics and Gynecology Successive Pregnancy Birth Registry System. We included term deliveries in which vaginal birth was attempted. Umbilical cord length was categorized into four groups: less than the first percentile, from the first percentile to less than the 10th percentile, from the 10th percentile to less than 25th percentile, and from the 25th percentile to less than the 75th percentile, which constituted the control group. Cord lengths of 33, 43, 48, 63 cm corresponded to the first, 10th, 25th, and 75th percentile values of the cord length distribution, respectively. Statistically significant differences were observed in the rate of unplanned cesarean delivery for all three short cord groups compared to control. There was a higher odds ratio for unplanned cesarean delivery as the umbilical cord became shorter. PMID- 26735973 TI - Identification of Aphis gossypii Glover (Hemiptera: Aphididae) Biotypes from Different Host Plants in North China. AB - BACKGROUND: The cotton-melon aphid, Aphis gossypii Glover (Hemiptera: Aphididae), is a polyphagous species with a worldwide distribution and a variety of biotypes. North China is a traditional agricultural area with abundant winter and summer hosts of A. gossypii. While the life cycles of A. gossypii on different plants have been well studied, those of the biotypes of North China are still unclear. RESULTS: Host transfer experiments showed that A. gossypii from North China has two host-specialized biotypes: cotton and cucumber. Based on complete mitochondrial sequences, we identified a molecular marker with five single nucleotide polymorphisms to distinguish the biotypes. Using this marker, a large scale study of biotypes on primary winter and summer hosts was conducted. All A. gossypii collected from three primary hosts-hibiscus, pomegranate, and Chinese prickly ash-were cotton biotypes, with more cotton-melon aphids found on hibiscus than the other two species. In May, alate cotton and cucumber biotypes coexisted on cotton and cucumber seedlings, but each preferred its natal host. Both biotypes existed on zucchini, although the cucumber biotype was more numerous. Aphids on muskmelon were all cucumber biotypes, whereas most aphids on kidney bean were cotton biotypes. Aphids on seedlings of potato and cowpea belong to other species. In August, aphids on cotton and cucumber were the respective biotypes, with zucchini still hosting both biotypes as before. Thus, the biotypes had different fitnesses on different host plants. CONCLUSIONS: Two host specialized biotypes (cotton and cucumber) are present in North China. Hibiscus, pomegranate, and Chinese prickly ash can serve as winter hosts for the cotton biotype but not the cucumber biotype in North China. The fitnesses of the two host-specialized biotypes differ on various summer hosts. When alate aphids migrate to summer hosts, they cannot accurately land on the corresponding plant. PMID- 26735976 TI - The influence of labels and facts on children's and adults' categorization. AB - Language has been assumed to influence categorization for both adults and children but the precise role and potency of linguistic labels in category formation remains open. Here we explore how linguistic labels help fit objects into categories when relevant perceptual information is either ambiguous or inconsistent with the labels. We also ask how the effects of labels compare to those of other types of information such as facts. We presented 4-year-old children and adults with tasks in which they had to categorize a perceptually ambiguous natural-kind stimulus with one of two equidistant standards (Exp. 1 and 2) or group an ambiguous natural-kind stimulus into a category with a perceptually dissimilar standard (Exp. 3). Participants had access to labels (e.g., "This one is a lorp/pim"), observable facts (e.g., "This one has a long/short beak"), or unobservable facts (e.g., "This one drinks water/milk") that grouped the ambiguous stimulus with one of the standards. Both children and adults followed label- and fact-driven category boundaries for perceptually ambiguous stimuli (Exp. 1 and 2), and continued to do so even when the labels or facts pointed to perceptually incongruent categories (Exp. 3). These findings suggest a strong causal role for both labels and facts in categorization and have implications about theories of how categorization develops in children. PMID- 26735989 TI - Innovation and Change in the Chilean Health System. PMID- 26735990 TI - Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia. AB - BACKGROUND: The ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) is elevated in pregnant women before the clinical onset of preeclampsia, but its predictive value in women with suspected preeclampsia is unclear. METHODS: We performed a prospective, multicenter, observational study to derive and validate a ratio of serum sFlt-1 to PlGF that would be predictive of the absence or presence of preeclampsia in the short term in women with singleton pregnancies in whom preeclampsia was suspected (24 weeks 0 days to 36 weeks 6 days of gestation). Primary objectives were to assess whether low sFlt-1:PlGF ratios (at or below a derived cutoff) predict the absence of preeclampsia within 1 week after the first visit and whether high ratios (above the cutoff) predict the presence of preeclampsia within 4 weeks. RESULTS: In the development cohort (500 women), we identified an sFlt-1:PlGF ratio cutoff of 38 as having important predictive value. In a subsequent validation study among an additional 550 women, an sFlt-1:PlGF ratio of 38 or lower had a negative predictive value (i.e., no preeclampsia in the subsequent week) of 99.3% (95% confidence interval [CI], 97.9 to 99.9), with 80.0% sensitivity (95% CI, 51.9 to 95.7) and 78.3% specificity (95% CI, 74.6 to 81.7). The positive predictive value of an sFlt-1:PlGF ratio above 38 for a diagnosis of preeclampsia within 4 weeks was 36.7% (95% CI, 28.4 to 45.7), with 66.2% sensitivity (95% CI, 54.0 to 77.0) and 83.1% specificity (95% CI, 79.4 to 86.3). CONCLUSIONS: An sFlt-1:PlGF ratio of 38 or lower can be used to predict the short-term absence of preeclampsia in women in whom the syndrome is suspected clinically. (Funded by Roche Diagnostics.). PMID- 26735991 TI - Effect of Artesunate-Amodiaquine on Mortality Related to Ebola Virus Disease. AB - BACKGROUND: Malaria treatment is recommended for patients with suspected Ebola virus disease (EVD) in West Africa, whether systeomatically or based on confirmed malaria diagnosis. At the Ebola treatment center in Foya, Lofa County, Liberia, the supply of artemether-lumefantrine, a first-line antimalarial combination drug, ran out for a 12-day period in August 2014. During this time, patients received the combination drug artesunate-amodiaquine; amodiaquine is a compound with anti-Ebola virus activity in vitro. No other obvious change in the care of patients occurred during this period. METHODS: We fit unadjusted and adjusted regression models to standardized patient-level data to estimate the risk ratio for death among patients with confirmed EVD who were prescribed artesunate amodiaquine (artesunate-amodiaquine group), as compared with those who were prescribed artemether-lumefantrine (artemether-lumefantrine group) and those who were not prescribed any antimalarial drug (no-antimalarial group). RESULTS: Between June 5 and October 24, 2014, a total of 382 patients with confirmed EVD were admitted to the Ebola treatment center in Foya. At admission, 194 patients were prescribed artemether-lumefantrine and 71 were prescribed artesunate amodiaquine. The characteristics of the patients in the artesunate-amodiaquine group were similar to those in the artemether-lumefantrine group and those in the no-antimalarial group. A total of 125 of the 194 patients in the artemether lumefantrine group (64.4%) died, as compared with 36 of the 71 patients in the artesunate-amodiaquine group (50.7%). In adjusted analyses, the artesunate amodiaquine group had a 31% lower risk of death than the artemether-lumefantrine group (risk ratio, 0.69; 95% confidence interval, 0.54 to 0.89), with a stronger effect observed among patients without malaria. CONCLUSIONS: Patients who were prescribed artesunate-amodiaquine had a lower risk of death from EVD than did patients who were prescribed artemether-lumefantrine. However, our analyses cannot exclude the possibility that artemether-lumefantrine is associated with an increased risk of death or that the use of artesunate-amodiaquine was associated with unmeasured patient characteristics that directly altered the risk of death. PMID- 26735992 TI - Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea. AB - BACKGROUND: In the wake of the recent outbreak of Ebola virus disease (EVD) in several African countries, the World Health Organization prioritized the evaluation of treatment with convalescent plasma derived from patients who have recovered from the disease. We evaluated the safety and efficacy of convalescent plasma for the treatment of EVD in Guinea. METHODS: In this nonrandomized, comparative study, 99 patients of various ages (including pregnant women) with confirmed EVD received two consecutive transfusions of 200 to 250 ml of ABO compatible convalescent plasma, with each unit of plasma obtained from a separate convalescent donor. The transfusions were initiated on the day of diagnosis or up to 2 days later. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration. The control group was 418 patients who had been treated at the same center during the previous 5 months. The primary outcome was the risk of death during the period from 3 to 16 days after diagnosis with adjustments for age and the baseline cycle-threshold value on polymerase-chain-reaction assay; patients who had died before day 3 were excluded. The clinically important difference was defined as an absolute reduction in mortality of 20 percentage points in the convalescent-plasma group as compared with the control group. RESULTS: A total of 84 patients who were treated with plasma were included in the primary analysis. At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, -7 percentage points; 95% confidence interval [CI], -18 to 4). The difference was reduced after adjustment for age and cycle threshold value (adjusted risk difference, -3 percentage points; 95% CI, -13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed. CONCLUSIONS: The transfusion of up to 500 ml of convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. (Funded by the European Union's Horizon 2020 Research and Innovation Program and others; ClinicalTrials.gov number, NCT02342171.). PMID- 26735994 TI - Viral Bronchiolitis in Children. PMID- 26735993 TI - Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease. AB - BACKGROUND: Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling. METHODS: We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease. RESULTS: After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P=0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P=0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P=0.005). CONCLUSIONS: The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275.). PMID- 26735995 TI - IMAGES IN CLINICAL MEDICINE. Hyperviscosity-Related Retinopathy in Waldenstrom's Macroglobulinemia. PMID- 26735996 TI - CLINICAL PROBLEM-SOLVING. A Complementary Affair. PMID- 26735997 TI - Improving the Prediction of Preeclampsia. PMID- 26735998 TI - Cardiac Repair after Myocardial Infarction. PMID- 26735999 TI - Cyclosporine before PCI in Acute Myocardial Infarction. PMID- 26736000 TI - Cyclosporine before PCI in Acute Myocardial Infarction. PMID- 26736001 TI - Cyclosporine before PCI in Acute Myocardial Infarction. PMID- 26736002 TI - Cyclosporine before PCI in Acute Myocardial Infarction. PMID- 26736003 TI - Cyclosporine before PCI in Acute Myocardial Infarction. PMID- 26736004 TI - Bridging Anticoagulation in Patients with Atrial Fibrillation. PMID- 26736005 TI - Bridging Anticoagulation in Patients with Atrial Fibrillation. PMID- 26736006 TI - Bridging Anticoagulation in Patients with Atrial Fibrillation. PMID- 26736007 TI - Bridging Anticoagulation in Patients with Atrial Fibrillation. PMID- 26736008 TI - Bridging Anticoagulation in Patients with Atrial Fibrillation. PMID- 26736009 TI - Bridging Anticoagulation in Patients with Atrial Fibrillation. PMID- 26736010 TI - Abrupt Relapse of ALK-Positive Lymphoma after Discontinuation of Crizotinib. PMID- 26736011 TI - Ebola Virus Disease among Male and Female Persons in West Africa. PMID- 26736012 TI - IMAGES IN CLINICAL MEDICINE. Percutaneous Rotational Pulmonary Thrombectomy. PMID- 26736014 TI - Correction: Cholera Transmission in Ouest Department of Haiti: Dynamic Modeling and the Future of the Epidemic. AB - [This corrects the article DOI: 10.1371/journal.pntd.0004153.]. PMID- 26736013 TI - Dye-Sensitized Core/Active Shell Upconversion Nanoparticles for Optogenetics and Bioimaging Applications. AB - Near-infrared (NIR) dye-sensitized upconversion nanoparticles (UCNPs) can broaden the absorption range and boost upconversion efficiency of UCNPs. Here, we achieved significantly enhanced upconversion luminescence in dye-sensitized core/active shell UCNPs via the doping of ytterbium ions (Yb(3+)) in the UCNP shell, which bridged the energy transfer from the dye to the UCNP core. As a result, we synergized the two most practical upconversion booster effectors (dye sensitizing and core/shell enhancement) to amplify upconversion efficiency. We demonstrated two biomedical applications using these UCNPs. By using dye sensitized core/active shell UCNP embedded poly(methyl methacrylate) polymer implantable systems, we successfully shifted the optogenetic neuron excitation window to a biocompatible and deep tissue penetrable 800 nm wavelength. Furthermore, UCNPs were water-solubilized with Pluronic F127 with high upconversion efficiency and can be imaged in a mouse model. PMID- 26736015 TI - Pharmacologic Prophylaxis for Venous Thromboembolism Among Patients With Total Joint Replacement: An Electronic Medical Records Study. AB - Patients who have total hip (THR) or knee (TKR) replacement have an elevated risk of venous thromboembolism (VTE). The American College of Chest Physicians guidelines recommend prophylactic anticoagulation. The aim of the study was to examine pharmacologic prophylaxis against VTE among patients with THR or TKR and to assess demographic and clinical correlates related to VTE prophylaxis. Using 15 years of data (1995-2009) from an electronic medical record system for an inner-city public hospital in the United States, we examined pharmacologic prophylaxis against VTE and associated factors in patients after THR (n = 242) and TKR (n = 317). Before the early 2000s, aspirin was the most common prophylaxis agent (THR, 61% and TKR, 65%), and 26% of patients with THR and 19% of patients with TKR did not receive prophylaxis. Enoxaparin use has increased since 2000, and warfarin is now the most common prophylaxis agent (THR, 70% and TKR, 61%). After controlling for time period, factors associated with prophylaxis pattern included obesity, hip fracture, and the surgeon's number of years in practice. VTE prophylaxis medications in patients with total joint replacement have changed over 15 years, in trends generally consistent with the evolution of guidelines. Obesity, history of hip fracture, and physician's experience are associated with the prescription of VTE prophylaxis medications. PMID- 26736016 TI - A Water-Withdrawal Input-Output Model of the Indian Economy. AB - Managing freshwater allocation for a highly populated and growing economy like India can benefit from knowledge about the effect of economic activities. This study transforms the 2003-2004 economic input-output (IO) table of India into a water withdrawal input-output model to quantify direct and indirect flows. This unique model is based on a comprehensive database compiled from diverse public sources, and estimates direct and indirect water withdrawal of all economic sectors. It distinguishes between green (rainfall), blue (surface and ground), and scarce groundwater. Results indicate that the total direct water withdrawal is nearly 3052 billion cubic meter (BCM) and 96% of this is used in agriculture sectors with the contribution of direct green water being about 1145 BCM, excluding forestry. Apart from 727 BCM direct blue water withdrawal for agricultural, other significant users include "Electricity" with 64 BCM, "Water supply" with 44 BCM and other industrial sectors with nearly 14 BCM. "Construction", "miscellaneous food products"; "Hotels and restaurants"; "Paper, paper products, and newsprint" are other significant indirect withdrawers. The net virtual water import is found to be insignificant compared to direct water used in agriculture nationally, while scarce ground water associated with crops is largely contributed by northern states. PMID- 26736017 TI - Cytomegalovirus Infection in Pediatric Renal Transplantation and the Impact of Chemoprophylaxis With (Val-)Ganciclovir. AB - BACKGROUND: Cytomegalovirus (CMV) replication and disease, with its associated morbidity and poor transplant outcome, represents a serious threat to transplant recipients. The pediatric kidney transplant population is at a particularly increased risk of CMV infection. METHODS: We therefore analyzed CMV epidemiology in a large cohort of pediatric renal transplant recipients (n = 242) and assessed the impact of antiviral chemoprophylaxis with valganciclovir (VGCV) or ganciclovir (GCV) on CMV replication and morbidity. RESULTS: While antiviral chemoprophylaxis with VGCV or GCV in patients with a high (D+/R-) or intermediate (D+/R+) CMV risk (n = 82) compared to preemptive therapy (n = 47) had no significant effect on the incidence of CMV syndrome or tissue-invasive disease, chemoprophylaxis was associated with a better preservation of transplant function at 3 years posttransplant (loss of estimated glomerular filtration rate in the chemoprophylaxis cohort, 16.0 +/- 3.4 vs. 30.1 +/- 4.7 mL/min per 1.73 m(2) in the preemptive therapy cohort, P < 0.05).CMV replication was associated with a more pronounced decline of graft function (difference in estimated glomerular filtration rate of 9.6 mL/min per 1.73 m(2) at 3 years) compared to patients without CMV replication. However, patients undergoing VGCV or GCV chemoprophylaxis had more leukocytopenia. CONCLUSION: Antiviral chemoprophylaxis with VGCV or GCV in recipients with a high or moderate CMV risk is associated with a better preservation of transplant function. Hence, the prevention of CMV replication in this patient population has the potential to improve transplant outcome. PMID- 26736018 TI - Population Pharmacokinetics of Bisoprolol in Hemodialysis Patients with Hypertension. AB - The aim of our study was to estimate clearance of bisoprolol and reveal the factors that could influence its pharmacokinetic (PK) variability in hypertensive patients on hemodialysis, using the population PK analysis. Parameters associated with plasma concentration of bisoprolol at steady state were analyzed in 63 patients (mean age 62.12 years, mean total weight 69.63 kg) who were hypertensive and on hemodialysis due to severe renal failure using non-linear mixed-effect modeling with ADVAN1 subroutine. The final regression model for the clearance of the drug included only creatinine clearance (CLcr) out of 12 tested covariates. The equation that describes CL of bisoprolol is the following: CL (l/h) = 0.12 + 6.33 * CLcr. These findings suggest that the routine measuring of serum creatinine level may be used to facilitate administration of bisoprolol in patients on hemodialysis. PMID- 26736019 TI - Microparticle derived proteins as potential biomarkers for cerebral vasospasm post subarachnoid hemorrhage. A preliminary study. AB - OBJECTIVE: Cerebral vasospasm (CV) and associated secondary brain injury are major contributors to death and disability after aneurysmal subarachnoid hemorrhage (aSAH). Microparticles (MP) are small vesicular micro-molecules released by red and white blood cells, platelets and endothelial cells that can change rapidly and specifically depending on the type of cellular insult. They may serve as useful tools to target a specific pool of proteins associated with the development of CV post aSAH. In these studies, our goal was to use targeted MP-derived protein isolation to find reliable biomarkers indicating increased risk for the development of CV. We hypothesize that there are specific early changes in MP-derived protein expression in CV patients. These proteins may be useful as biomarkers for CV and may help us to further understand the mechanism for the development of CV. Patients Adult male and female patients with angiographically confirmed aSAH and an external ventricular drain (EVD) placed for medical or surgical needs were included in this study. Patients were closely monitored for CV development. Cerebrospinal fluid (CSF) was collected daily until EVD was removed. METHODS: Microparticles were isolated using serial ultra centrifugation. Differential protein expression in CSF microparticles was analyzed by a mass spectroscopy based system using isotopically-tagged peptides to profile proteins and determine their relative concentrations in individual patient samples. These proteins were correlated with the patient's clinical data and used to identify candidates for biomarkers predictive of CV. RESULTS: Over 140 proteins were isolated from CSF microparticles. Proteomic and molecular pathways analysis revealed marked differential expression of proteins in patients with CV. We identified specific candidate proteins that could potentially serve as early biomarkers for CV. ApoE, ApoD, synaptic nuclear envelope protein 1, clusterin, alpha-1-acid glycoprotein, plasma protease C1 inhibitor, and prostaglandin H2 D isomerase were downregulated in patients who developed CV post aSAH. Haptoglobin, fibrinogen alpha and gamma chain, synaptic nuclear envelope protein 2, and hemoglobin subunits alpha and beta were upregulated. Some of these proteins are associated with immune and metabolic processes and some have been specifically associated with cerebrovascular disease states. CONCLUSIONS: This is the first preliminary demonstration that there is differential protein expression in CSF microparticles from CV patients. Alone or in combination, these and other proteins may be useful as reliable biomarkers to guide in stratifying patients into categories of risk to develop CV post aSAH. These results will deepen our understanding of the mechanisms of cerebral vasospasm and potentially facilitate the development of safer and more effective therapies therapies for cerebral vasospasm. PMID- 26736020 TI - Correlating subcortical interhemispheric connectivity and cortical hemispheric dominance in brain tumor patients: A repetitive navigated transcranial magnetic stimulation study. AB - OBJECTIVE: The present study aims to investigate the relationship between transcallosal interhemispheric connectivity (IC) and hemispheric language lateralization by using a novel approach including repetitive navigated transcranial magnetic stimulation (rTMS), hemispheric dominance ratio (HDR) calculation, and rTMS-based diffusion tensor imaging fiber tracking (DTI FT). METHODS: 31 patients with left-sided perisylvian brain lesions underwent diffusion tensor imaging (DTI) and rTMS language mapping. Cortical language positive rTMS spots were used to calculate HDRs (HDR: quotient of the left-sided divided by right-sided naming error rates for corresponding left- and right-sided cortical regions) and to create regions of interest (ROIs) for DTI FT. Then, fibers connecting the rTMS-based ROIs of both hemispheres were tracked, and the correlation of IC to HDRs was calculated via Spearman's rank correlation coefficient (rs). RESULTS: Fibers connecting rTMS-based ROIs of both hemispheres were detected in 12 patients (38.7%). Within the patients in which IC was detected, the mean number of subcortical IC fibers +/- standard deviation (SD) was 138.0 +/- 346.5 (median: 7.5; range: 1-1,217 fibers). Regarding rs for the correlation of HDRs and fiber numbers of patients that showed IC, only moderate correlation was revealed. CONCLUSION: Our approach might be beneficial and technically feasible for further investigation of the relationship between IC and language lateralization. However, only moderate correlation was revealed in the present study. PMID- 26736021 TI - Modeling the Detection of Organic and Inorganic Compounds Using Iodide-Based Chemical Ionization. AB - Iodide-based chemical ionization mass spectrometry (CIMS) has been used to detect and measure concentrations of several atmospherically relevant organic and inorganic compounds. The significant electronegativity of iodide and the strong acidity of hydroiodic acid makes electron transfer and proton abstraction essentially negligible, and the soft nature of the adduct formation ionization technique reduces the chances of sample fragmentation. In addition, iodide has a large negative mass defect, which, when combined with the high resolving power of a high resolution time-of-flight chemical ionization mass spectrometer (HR-ToF CIMS), provides good selectivity. In this work, we use quantum chemical methods to calculate the binding energies, enthalpies and free energies for clusters of an iodide ion with a number of atmospherically relevant organic and inorganic compounds. Systematic configurational sampling of the free molecules and clusters was carried out at the B3LYP/6-31G* level, followed by subsequent calculations at the PBE/SDD and DLPNO-CCSD(T)/def2-QZVPP//PBE/aug-cc-pVTZ-PP levels. The binding energies, enthalpies, and free energies thus obtained were then compared to the iodide-based University of Washington HR-ToF-CIMS (UW-CIMS) instrument sensitivities for these molecules. We observed a reasonably linear relationship between the cluster binding enthalpies and logarithmic instrument sensitivities already at the PBE/SDD level, which indicates that relatively simple quantum chemical methods can predict the sensitivity of an iodide-based CIMS instrument toward most molecules. However, higher level calculations were needed to treat some outlier molecules, most notably oxalic acid and methylerythritol. Our calculations also corroborated the recent experimental findings that the molecules that the UW-CIMS detects at maximum sensitivity usually have binding enthalpies to iodide which are higher than about 26 kcal/mol, depending slightly on the level of theory. PMID- 26736023 TI - Development and Validation of the Behavioral Avoidance Test-Back Pain (BAT-Back) for Patients With Chronic Low Back Pain. AB - OBJECTIVES: Pain-related fear and avoidance of physical activities are central elements of the fear-avoidance model of musculoskeletal pain. Pain-related fear has typically been measured by self-report instruments. In this study, we developed and validated a Behavioral Avoidance Test (BAT) for chronic low back pain (CLBP) patients with the aim of assessing pain-related avoidance behavior by direct observation. MATERIALS AND METHODS: The BAT-Back was administered to a group of CLBP patients (N=97) and pain-free controls (N=31). Furthermore, pain, pain-related fear, disability, catastrophizing, and avoidance behavior were measured using self-report instruments. Reliability was assessed with intraclass correlation coefficient and Cronbach alpha. Validity was assessed by examining correlation and regression analysis. RESULTS: The intraclass correlation coefficient for the BAT-Back avoidance score was r=0.76. Internal consistency was alpha=0.95. CLBP patients and controls differed significantly on BAT-Back avoidance scores as well as self-report measures. BAT-Back avoidance scores were significantly correlated with scores on each of the self-report measures (rs=0.27 to 0.54). They were not significantly correlated with general anxiety and depression, age, body mass index, and pain duration. The BAT-Back avoidance score was able to capture unique variance in disability after controlling for other variables (eg, pain intensity and pain-related fear). DISCUSSION: Results indicate that the BAT-Back is a reliable and valid measure of pain-related avoidance behavior. It may be useful for clinicians in tailoring treatments for chronic pain as well as an outcome measure for exposure treatments. PMID- 26736022 TI - Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development. AB - Effective translation of breakthrough discoveries into innovative products in the clinic requires proactive mitigation or elimination of several drug development challenges. These challenges can vary depending upon the type of drug molecule. In the case of therapeutic antibody candidates, a commonly encountered challenge is high viscosity of the concentrated antibody solutions. Concentration-dependent viscosity behaviors of mAbs and other biologic entities may depend on pairwise and higher-order intermolecular interactions, non-native aggregation, and concentration-dependent fluctuations of various antibody regions. This article reviews our current understanding of molecular origins of viscosity behaviors of antibody solutions. We discuss general strategies and guidelines to select low viscosity candidates or optimize lead candidates for lower viscosity at early drug discovery stages. Moreover, strategies for formulation optimization and excipient design are also presented for candidates already in advanced product development stages. Potential future directions for research in this field are also explored. PMID- 26736024 TI - Trunk Muscle Training Augmented With Neuromuscular Electrical Stimulation Appears to Improve Function in Older Adults With Chronic Low Back Pain: A Randomized Preliminary Trial. AB - OBJECTIVES: To assess the feasibility of a trial to evaluate a trunk muscle training program augmented with neuromuscular electrical stimulation (TMT+NMES) for the rehabilitation of older adults with chronic low back pain (LBP) and to preliminarily investigate whether TMT+NMES could improve physical function and pain compared with a passive control intervention. MATERIALS AND METHODS: We conducted a single-blind, randomized feasibility trial. Patients aged 60 to 85 years were allocated to TMT+NMES (n=31) or a passive control intervention (n=33), consisting of passive treatments, that is, heat, ultrasound, and massage. Outcomes assessed 3- and 6-month postrandomization included Timed Up and Go Test, gait speed, pain, and LBP-related functional limitation. RESULTS: Feasibility was established by acceptable adherence (>=80%) and attrition (<20%) rates for both interventions. Both groups had similar, clinically important reductions in pain of >2 points on a numeric pain rating scale during the course of the trial. But, only the TMT+NMES group had clinically important improvements in both performance based and self-reported measures of function. In terms of the participants' global rating of functional improvement at 6 months, the TMT+NMES group improved by 73.9% and the passive control group improved by 56.7% compared with baseline. The between-group difference was 17.2% (95% confidence interval, 5.87-28.60) in favor of TMT+NMES. DISCUSSION: It seems that a larger randomized trial investigating the efficacy of TMT+NMES for the purpose of improving physical function in older adults with chronic LBP is warranted. PMID- 26736025 TI - Acute Low Back Pain: Differential Somatosensory Function and Gene Expression Compared With Healthy No-Pain Controls. AB - OBJECTIVES: Low back pain (LBP) is the second most frequently diagnosed pain condition in the United States, and although a majority of individuals have resolution of pain during the acute period, an estimated 40% of individuals will experience persistent pain. Given the heterogenous nature of LBP, this study sought to describe and compare somatosensory and molecular (gene expression) profiles between individuals with acute LBP and healthy no-pain controls. METHODS: Using a previously established protocol, we comprehensively assessed somatosensory parameters among 31 no-pain control participants and 31 participants with acute LBP. Samples of whole blood were drawn to examine mRNA expression of candidate genes involved in the transduction, maintenance, and modulation of pain. RESULTS: The acute LBP group exhibited increased pain sensitivity to cold stimuli, mechanical stimuli, including mechanical temporal summation at both the painful back area and remote location suggesting a mechanism of enhanced central nervous system excitability. In addition, deep tissue-specific peripheral sensitization was suggested due to significant differences in pressure pain threshold of the painful back area, but not the remote body site. Several genes that were differentially expressed were significantly associated with somatosensory alterations identified in the acute LBP group. DISCUSSION: Acute LBP participants showed selective pain sensitivity enhancement and differential gene expression profiles compared with pain-free controls. Further research to characterize pain-associated somatosensory changes in the context of altered mRNA expression levels may provide insight on the molecular underpinnings of maladaptive chronic pain. PMID- 26736026 TI - Characterizing the Pain Narratives of Parents of Youth With Chronic Pain. AB - OBJECTIVES: Questionnaire-based research has shown that parents exert a powerful influence on and are profoundly influenced by living with a child with chronic pain. Examination of parents' pain narratives through an observational lens offers an alternative approach to understanding the complexity of pediatric chronic pain; however, the narratives of parents of youth with chronic pain have been largely overlooked. The present study aimed to characterize the vulnerability-based and resilience-based aspects of the pain narratives of parents of youth with chronic pain. METHODS: Pain narratives of 46 parents were recorded during the baseline session as part of 2 clinical trials evaluating a behavioral intervention for parents of youth with chronic pain. The narratives were coded for aspects of pain-related vulnerability and resilience. RESULTS: Using exploratory cluster analysis, 2 styles of parents' pain narratives were identified. Distress narratives were characterized by more negative affect and an exclusively unresolved orientation toward the child's diagnosis of chronic pain, whereas resilience narratives were characterized by positive affect and a predominantly resolved orientation toward the child's diagnosis. Preliminary support for the validity of these clusters was provided through our finding of differences between clusters in parental pain catastrophizing about child pain (helplessness). DISCUSSION: Findings highlight the multidimensional nature of parents' experience of their child's pain problem. Clinical implications in terms of assessment and treatment are discussed. PMID- 26736027 TI - Alcohol use and craving among Veterans with mental health disorders and mild traumatic brain injury. AB - Mental health disorders (MHDs), mild traumatic brain injury (mTBI), and alcohol use disorder (AUD) are endemic among recent Veterans, resulting in a population with heterogeneous, co-occurring conditions. While alcohol craving negatively affects rehabilitation and leads to relapse, no studies have examined alcohol craving among Veterans with co-occurring MHDs and mTBI. The purpose of this preliminary cohort study is to describe alcohol craving in a convenience sample of Iraq and Afghanistan Veterans (n = 48), including those exposed to traumatic events and experiencing active symptoms. Veterans completed weekly telephone interviews that included the Alcohol Use Disorder Identification Test, consumption questions (AUDIT-C) (week 1) and the Penn Alcohol Craving Scale (PACS) (weeks 1-6). Sixty percent of the sample screened positive on the AUDIT-C for probable AUD. Using Rasch analysis, the person separation reliability of the PACS was strong (0.87) among AUDIT-C positive Veterans. Higher PACS scores were reported among AUDIT-C positive versus AUDIT-C negative Veterans (mixed effects analysis, p < 0.001). PACS scores were higher among AUDIT-C positive Veterans with MHDs with and without mTBI versus AUDIT-C positive combat comparison Veterans (pairwise comparison, p < 0.001). Rates of hazardous alcohol use are high among Iraq and Afghanistan conflict Veterans and suggest that alcohol craving is elevated among those with MHDs with and without mTBI. PMID- 26736028 TI - Novel p-Type Conductive Semiconductor Nanocrystalline Film as the Back Electrode for High-Performance Thin Film Solar Cells. AB - Thin film solar cells, due to the low cost, high efficiency, long-term stability, and consumer applications, have been widely applied for harvesting green energy. All of these thin film solar cells generally adopt various metal thin films as the back electrode, like Mo, Au, Ni, Ag, Al, graphite, and so forth. When they contact with p-type layer, it always produces a Schottky contact with a high contact potential barrier, which greatly affects the cell performance. In this work, we report for the first time to find an appropriate p-type conductive semiconductor film, digenite Cu9S5 nanocrystalline film, as the back electrode for CdTe solar cells as the model device. Its low sheet resistance (16.6 Omega/sq) could compare to that of the commercial TCO films (6-30 Omega/sq), like FTO, ITO, and AZO. Different from the traditonal metal back electrode, it produces a successive gradient-doping region by the controllable Cu diffusion, which greatly reduces the contact potential barrier. Remarkably, it achieved a comparable power conversion efficiency (PCE, 11.3%) with the traditional metal back electrode (Cu/Au thin films, 11.4%) in CdTe cells and a higher PCE (13.8%) with the help of the Au assistant film. We believe it could also act as the back electrode for other thin film solar cells (alpha-Si, CuInS2, CIGSe, CZTS, etc.), for their performance improvement. PMID- 26736029 TI - Electrophoretic Deposition of Dexamethasone-Loaded Mesoporous Silica Nanoparticles onto Poly(L-Lactic Acid)/Poly(epsilon-Caprolactone) Composite Scaffold for Bone Tissue Engineering. AB - The incorporation of microcarriers as drug delivery vehicles into polymeric scaffold for bone regeneration has aroused increasing interest. In this study, the aminated mesoporous silica nanoparticles (MSNs-NH2) were prepared and used as microcarriers for dexamethasone (DEX) loading. Poly(l-lactic acid)/poly(epsilon caprolactone) (PLLA/PCL) nanofibrous scaffold was fabricated via thermally induced phase separation (TIPS) and served as template, onto which the drug loaded MSNs-NH2 nanoparticles were deposited by electrophoretic deposition (EPD). The physicochemical and release properties of the prepared scaffolds (DEX@MSNs NH2/PLLA/PCL) were examined, and their osteogenic activities were also evaluated through in vitro and in vivo studies. The release of DEX from the scaffolds revealed an initial rapid release followed by a slower and sustained one. The in vitro results indicated that the DEX@MSNs-NH2/PLLA/PCL scaffold exhibited good biocompatibility to rat bone marrow-derived mesenchymal stem cells (BMSCs). Also, BMSCs cultured on the DEX@MSNs-NH2/PLLA/PCL scaffold exhibited a higher degree of osteogenic differentiation than those cultured on PLLA/PCL and MSNs-NH2/PLLA/PCL scaffolds, in terms of alkaline phosphatase (ALP) activity, mineralized matrix formation, and osteocalcin (OCN) expression. Furthermore, the in vivo results in a calvarial defect model of Sprague-Dawley (SD) rats demonstrated that the DEX@MSNs-NH2/PLLA/PCL scaffold could significantly promote calvarial defect healing compared with the PLLA/PCL scaffold. Thus, the EPD technique provides a convenient way to incorporate osteogenic agents-containing microcarriers to polymer scaffold, and thus, prepared composite scaffold could be a potential candidate for bone tissue engineering application due to its capacity for delivery of osteogenic agents. PMID- 26736030 TI - Juvenile Adamantiades-Behcet Disease. AB - Adamantiades-Behcet disease (ABD) is a chronic, multisystemic, recurrent, inflammatory vascular disorder of unknown etiology. Patients with symptoms initially appearing at the age of 16 or less are considered as cases of juvenile onset ABD (JABD). JABD is relatively rare compared to ABD of adults, and only case reports and case studies have been published regarding this subtype of the disease. Epidemiology, clinical features, diagnosis and treatment of JABD are discussed in this review. PMID- 26736032 TI - A case study of the neuropsychological outcomes following microsurgery, conventional radiotherapy and stereotactic radiotherapy for an adult's recurrent craniopharyngioma. AB - OBJECTIVE: To examine the neuropsychological outcomes for an adult patient, 2 years after receiving microsurgery and conventional radiotherapy for a recurrent craniopharyngioma; and the impact of a further intervention, stereotactic radiotherapy, on this level of neuropsychological functioning. PARTICIPANT: JD, a 30 year old male whose recurrent craniopharyngioma had 2 years earlier been treated with two operations and conventional radiotherapy. DESIGN: JD was assessed (using standardized clinical tests) before and after a course of stereotactic radiotherapy. RESULTS: Prior to stereotactic radiotherapy (and 2 years after microsurgery and conventional radiotherapy) JD's IQ was intact, but considerable impairments were present in executive functioning, memory, theory of mind and processing speed. Fifteen months after stereotactic radiotherapy, all neuropsychological domains remained largely static or improved, supporting the utility of this treatment option in the neuropsychological domain. However, deficits in executive functioning, memory and processing speed remained. CONCLUSION: These findings suggest that, even after multiple treatments, substantial cognitive impairments can be present in an adult patient with a recurrent craniopharyngioma. This profile of deficits underlines the inadequacy of relying purely on IQ as a marker for cognitive health in this population and emphasizes the need to include neuropsychological impairments as a focus of rehabilitation with these patients. PMID- 26736033 TI - LC-MS/MS method development for quantification of busulfan in human plasma and its application in pharmacokinetic study. AB - A simple, rapid, specific and precise liquid chromatography-tandem mass spectrophotometric (LC-MS/MS) method was developed and validated for quantification of busulfan, in human plasma. busulfan d8 was used as internal standard, added to plasma sample prior to extraction using acetonitrile as a precipitating agent. Chromatographic separation was achieved on phenomenex kinetex C18 column (50mm*2.1mm, 2.6MUm) with acteonitrile: 10mM ammonium formate buffer (80:20v/v) as an isocratic mobile phase with a flow rate of 0.5mLmin(-1). Quantitation was performed by transition of 264.1->151.1 (m/z) for busulfan and 272.1->159.1 (m/z) for busulfan d8. The lower limit of quantitation was 0.2ngmL( 1) with a 100MUL plasma sample. The concentrations of nine working standards showed linearity between 0.2 and 100ngmL(-1) (r(2)>=0.9986). Chromatographic separation was achieved within 2.0min. The average extraction recoveries of 3quality control concentrations were 92.52% for busulfan and 90.75% for busulfan d8. The coefficient of variation was <=15% for intra- and inter-batch assays. The developed method was successfully applied for the determination of Busulfan pharmacokinetics after oral administration. PMID- 26736034 TI - Psychosocial treatments for tic disorders: A meta-analysis. PMID- 26736035 TI - Potential involvement of the interleukin-18 pathway in schizophrenia. AB - OBJECTIVE: Accumulating evidence implicates inflammatory cytokines in the development of psychiatric disorders, including schizophrenia (SZ). IL-18 is one of cytokines that plays a crucial role in immune response and neurodevelopment. We aimed to investigate potential genetic alterations of the cytokine system underpinning SZ. METHODS: We tested the association of genetic variants within the cytokine-cytokine receptor interaction (CCRI) pathway with SZ, using GWAS derived data involving 768 adult SZ patients and 1348 controls, and replicated the association of IL18R1 rs1035130 with SZ in an independent sample of 1957 adult patients and 1509 controls. We compared expression levels of IL18, IL18R1 and IL18RAP in peripheral blood of a cohort of adolescent participants (<18 years), including 14 early-onset SZ patients and 13 healthy controls. Furthermore, we carried out a cis-eQTL (expression Quantitative Trait Loci) and a cis-mQTL (Methylation Quantitative Trait Loci) analysis for IL18R1 rs1035130. RESULTS: In the discovery stage, we detected association signals within two IL18 pathway genes, IL18R1 and IL18RAP, with the most significant marker being IL18R1 rs1035130 (P = 1.84E-7, OR = 0.70). In the validation stage, we found rs1035130 was associated with SZ (P = 0.028, OR = 0.89). Expressions of IL18 and IL18R1 were altered in blood of SZ patients compared with 13 controls. Furthermore, cis QTL analyses indicated that rs1035130 was associated with an eQTL and 5 mQTLs. CONCLUSION: Our findings suggest the alteration of IL18 pathway may contribute to the psychopathology of SZ. PMID- 26736036 TI - Sedation mediates part of Citalopram's effect on agitation in Alzheimer's disease. AB - BACKGROUND: We found a benefit of citalopram for agitation in the Citalopram for Agitation in Alzheimer's Disease study (CitAD), and wondered if this was mediated by a sedative effect. CitAD was a randomized, placebo-controlled, double-blind, parallel group trial conducted at 8 academic centers in the United States and Canada from August 2009 to January 2013. One hundred sixty-two participants with probable Alzheimer's disease (AD) and clinically significant agitation were analyzed in this study. Participants received a psychosocial intervention and were randomized to receive either citalopram or placebo (approximately half assigned to each group). Participants were rated on the Neurobehavioral Rating Scale Agitation subscale and measures of sedation (i.e., fatigue and somnolence). METHODS: Using the MacArthur Foundation procedures for documenting a mediator effect, we performed a secondary analysis examining whether sedation mediates the effect of treatment on agitation outcome. RESULTS: We found a statistically significant mediating effect of sedation on agitation outcomes, but the magnitude of the effect was small, only explaining 11% of the variance in agitation, with a significant, but modest effect size of 0.16 (95% CI: 0.08 to 0.22). CONCLUSIONS: The benefit of citalopram was partly due to sedation but largely due to other mechanisms of action. PMID- 26736038 TI - The associations between state veteran population rates, handgun legislation, and statewide suicide rates. AB - BACKGROUND: Within the US, veterans exhibit an elevated suicide rate, with firearms serving as the most common method. Research has demonstrated that several state laws regulating handgun ownership are associated with lower suicide rates. METHOD: Publically available databases were utilized to extract relevant data. RESULTS: Statewide veteran population rates (per 100,000) predicted overall suicide rates, firearm suicide rates, and the proportion of suicides by firearms. Furthermore, the association between veteran population and overall suicide rate was largely explained by the elevated proportion of suicides by firearms in states with higher veteran populations. Lastly, results demonstrated states without handgun legislation in place exhibited higher veteran populations. CONCLUSIONS: Findings indicate veterans may impact statewide suicide rates through their propensity to use firearms as their method and that the tendency for veterans to live in states without handgun legislation may exacerbate this phenomenon. PMID- 26736037 TI - Single nucleotide polymorphism near CREB1, rs7591784, is associated with pretreatment methamphetamine use frequency and outcome of outpatient treatment for methamphetamine use disorder. AB - Although stimulant dependence is highly heritable, few studies have examined genetic influences on methamphetamine dependence. We performed a candidate gene study of 52 SNPs and pretreatment methamphetamine use frequency among 263 methamphetamine dependent Hispanic and Non-Hispanic White participants of several methamphetamine outpatient clinical trials in Los Angeles. One SNP, rs7591784 was significantly associated with pretreatment methamphetamine use frequency following Bonferroni correction (p < 0.001) in males but not females. We then examined rs7591784 and methamphetamine urine drug screen results during 12 weeks of outpatient treatment among males with treatment outcome data available (N = 94) and found rs7591784 was significantly associated with methamphetamine use during treatment controlling for pretreatment methamphetamine use. rs7591784 is near CREB1 and in a linkage disequilibrium block with rs2952768, previously shown to influence CREB1 expression. The CREB signaling pathway is involved in gene expression changes related to chronic use of multiple drugs of abuse including methamphetamine and these results suggest that variability in CREB signaling may influence pretreatment frequency of methamphetamine use as well as outcomes of outpatient treatment. Medications targeting the CREB pathway, including phosphodiesterase inhibitors, warrant investigation as pharmacotherapies for methamphetamine use disorders. PMID- 26736039 TI - Further evidence of behavioral interventions for tic disorders: A reply to Theule and colleagues. AB - We were delighted to read the letter by Dr. Theule and colleagues (Theule et al., 2016) commenting on our meta-analysis of behavior therapy for Tourette Syndrome (TS)(McGuire et al., 2014). We welcome this discussion, and were interested to learn of their related meta-analysis on psychosocial treatments for tic disorders. This commentary addresses the similarities and distinctions between these two meta-analytic investigations, and concludes with recommendations regarding the future of treatment research for TS. PMID- 26736040 TI - Relationship between placebo response rate and clinical trial outcome in bipolar depression. AB - The aim of this work is to investigate the impact of placebo response rates on the relative risk of response to drug versus placebo in randomized, double-blind, placebo-controlled clinical trials of pharmacological therapy in Bipolar Depression (BPD). Medline/PubMed publication databases were searched for randomized, double-blind, placebo-controlled trials of oral drugs used as monotherapy for the treatment of BPD. The search was limited to articles published between January 1980 and September 2015. Data extracted from 12 manuscripts and one poster with yet unpublished results, representing a total of 17 clinical trials were pooled (n = 6578). Pooled response rates for drug and placebo were 55.1% and 39.2%, corresponding to a risk ratio (RR) for responding to active treatment versus placebo of 1.29 (p < 0.001). Clinical response was defined as a 50% or greater reduction in depression scores, baseline to endpoint. A higher placebo response rate correlated with a significantly lower RR of responding to pharmacotherapy versus placebo (p = 0.002). The pooled drug and placebo response rates for studies with a placebo response rate <= 30% were 50.5% versus 26.6%, while corresponding values from studies with a placebo response rate >30 were 55.0% versus 41.6%. These results suggest that the relative efficacy of the active drug compared to placebo in clinical trials for BPD is highly heterogeneous across studies with different placebo response rates, with a worse performance in showing a superiority of the drug versus placebo for studies with placebo response rates >30%. It is important to maintain placebo response rates below this critical threshold, since this is one of the most challenging obstacles for new treatment development in BPD. PMID- 26736042 TI - Pacing, packing and sex-based differences in Olympic and IAAF World Championship marathons. AB - The aim of this study was to describe pacing profiles and packing behaviours of athletes in Olympic and World Championship marathons. Finishing and split times were collated for 673 men and 549 women across nine competitions. The mean speeds for each intermediate 5 km and end 2.2 km segments were calculated. Medallists of both sexes maintained even-paced running from 10 km onwards whereas slower finishers dropped off the lead pack at approximately half-distance. Athletes who ran with the same opponents throughout slowed the least in the second half (P < 0.001, men: ES >= 1.19; women: ES >= 1.06), whereas other strategies such as moving between packs or running alone were less successful. Overall, women slowed less (P < 0.001, ES = 0.44) and were more likely to run a negative split (P < 0.001), and their more conservative start meant fewer women dropped out (P < 0.001). This also meant that women medallists sped up in the final 2.2 km, which might have decided the medal positions. Marathon runners are advised to identify rivals with similar abilities and ambitions to run alongside provided they start conservatively. Coaches should note important sex-based differences in tactics adopted and design training programmes accordingly. PMID- 26736043 TI - Identification of Differential Item Functioning in Multiple-Group Settings: A Multivariate Outlier Detection Approach. AB - We focus on the identification of differential item functioning (DIF) when more than two groups of examinees are considered. We propose to consider items as elements of a multivariate space, where DIF items are outlying elements. Following this approach, the situation of multiple groups is a quite natural case. A robust statistics technique is proposed to identify DIF items as outliers in the multivariate space. For low dimensionalities, up to 2-3 groups, a simple graphical tool is derived. We illustrate our approach with a reanalysis of data from Kim, Cohen, and Park (1995) on using calculators for a mathematics test. PMID- 26736041 TI - A Novel Platform for the Potentiation of Therapeutic Antibodies Based on Antigen Dependent Formation of IgG Hexamers at the Cell Surface. AB - IgG antibodies can organize into ordered hexamers on cell surfaces after binding their antigen. These hexamers bind the first component of complement C1 inducing complement-dependent target cell killing. Here, we translated this natural concept into a novel technology platform (HexaBody technology) for therapeutic antibody potentiation. We identified mutations that enhanced hexamer formation and complement activation by IgG1 antibodies against a range of targets on cells from hematological and solid tumor indications. IgG1 backbones with preferred mutations E345K or E430G conveyed a strong ability to induce conditional complement-dependent cytotoxicity (CDC) of cell lines and chronic lymphocytic leukemia (CLL) patient tumor cells, while retaining regular pharmacokinetics and biopharmaceutical developability. Both mutations potently enhanced CDC- and antibody-dependent cellular cytotoxicity (ADCC) of a type II CD20 antibody that was ineffective in complement activation, while retaining its ability to induce apoptosis. The identified IgG1 Fc backbones provide a novel platform for the generation of therapeutics with enhanced effector functions that only become activated upon binding to target cell-expressed antigen. PMID- 26736044 TI - Estimating Independent Locally Shifted Random Utility Models for Ranking Data. AB - We consider the estimation of probabilistic ranking models in the context of conjoint experiments. By using approximate rather than exact ranking probabilities, we avoided the computation of high-dimensional integrals. We extended the approximation technique proposed by Henery (1981) in the context of the Thurstone-Mosteller-Daniels model to any independent locally shifted random utility model. In particular, this allowed us to estimate any independent random utility model with common shape (e.g., normal, logistic) and scale. Moreover, our approach also allows for the analysis of any partial ranking. Partial rankings are essential in practical conjoint analysis to collect data efficiently to relieve respondents' task burden. We applied the approach to the reanalysis of the career preference data set described in Maydeu-Olivares and Bockenholt (2005) , and to a holiday preferences data set. PMID- 26736045 TI - Comparison of Methods for Collecting and Modeling Dissimilarity Data: Applications to Complex Sound Stimuli. AB - Sorting procedures are frequently adopted as an alternative to dissimilarity ratings to measure the dissimilarity of large sets of stimuli in a comparatively short time. However, systematic empirical research on the consequences of this experiment-design choice is lacking. We carried out a behavioral experiment to assess the extent to which sorting procedures compare to dissimilarity ratings in terms of efficiency, reliability, and accuracy, and the extent to which data from different data-collection methods are redundant and are better fit by different distance models. Participants estimated the dissimilarity of either semantically charged environmental sounds or semantically neutral synthetic sounds. We considered free and hierarchical sorting and derived indications concerning the properties of constrained and truncated hierarchical sorting methods from hierarchical sorting data. Results show that the higher efficiency of sorting methods comes at a considerable cost in terms of data reliability and accuracy. This loss appears to be minimized with truncated hierarchical sorting methods that start from a relatively low number of groups of stimuli. Finally, variations in data-collection method differentially affect the fit of various distance models at the group-average and individual levels. On the basis of these results, we suggest adopting sorting as an alternative to dissimilarity-rating methods only when strictly necessary. We also suggest analyzing the raw behavioral dissimilarities, and avoiding modeling them with one single distance model. PMID- 26736046 TI - Editorial: Introduction to the Special Section on Causal Inference in Cross Sectional and Longitudinal Mediational Models. PMID- 26736047 TI - Bias in Cross-Sectional Analyses of Longitudinal Mediation: Partial and Complete Mediation Under an Autoregressive Model. AB - Maxwell and Cole (2007) showed that cross-sectional approaches to mediation typically generate substantially biased estimates of longitudinal parameters in the special case of complete mediation. However, their results did not apply to the more typical case of partial mediation. We extend their previous work by showing that substantial bias can also occur with partial mediation. In particular, cross-sectional analyses can imply the existence of a substantial indirect effect even when the true longitudinal indirect effect is zero. Thus, a variable that is found to be a strong mediator in a cross-sectional analysis may not be a mediator at all in a longitudinal analysis. In addition, we show that very different combinations of longitudinal parameter values can lead to essentially identical cross-sectional correlations, raising serious questions about the interpretability of cross-sectional mediation data. More generally, researchers are encouraged to consider a wide variety of possible mediation models beyond simple cross-sectional models, including but not restricted to autoregressive models of change. PMID- 26736048 TI - Commentary: Are Three Waves of Data Sufficient for Assessing Mediation? AB - Maxwell, Cole, and Mitchell (2011) demonstrated that simple structural equation models, when used with cross-sectional data, generally produce biased estimates of meditated effects. I extend those results by showing how simple structural equation models can produce biased estimates of meditated effects when used even with longitudinal data. Even with longitudinal data, simple autoregressive structural equation models can imply the existence of indirect effects when only direct effects exist and the existence of direct effects when only indirect effects exist. PMID- 26736049 TI - Commentary: Mediation Analysis, Causal Process, and Cross-Sectional Data. AB - Maxwell, Cole, and Mitchell (2011) extended the work of Maxwell and Cole (2007) , which raised important questions about whether mediation analyses based on cross sectional data can shed light on longitudinal mediation process. The latest article considers longitudinal processes that can only be partially explained by an intervening variable, and Maxwell et al. showed that the same general conclusions are obtained, namely that analyses of cross-sectional data will not reveal the longitudinal mediation process. While applauding the advances of the target article, this comment encourages the detailed exploration of alternate causal models in psychology beyond the autoregressive model considered by Maxwell et al. When inferences based on cross-sectional analyses are compared to alternate models, different patterns of bias are likely to be observed. I illustrate how different models of the causal process can be derived using examples from research on psychopathology. PMID- 26736050 TI - Metagenomic analysis revealed highly diverse microbial arsenic metabolism genes in paddy soils with low-arsenic contents. AB - Microbe-mediated arsenic (As) metabolism plays a critical role in global As cycle, and As metabolism involves different types of genes encoding proteins facilitating its biotransformation and transportation processes. Here, we used metagenomic analysis based on high-throughput sequencing and constructed As metabolism protein databases to analyze As metabolism genes in five paddy soils with low-As contents. The results showed that highly diverse As metabolism genes were present in these paddy soils, with varied abundances and distribution for different types and subtypes of these genes. Arsenate reduction genes (ars) dominated in all soil samples, and significant correlation existed between the abundance of arr (arsenate respiration), aio (arsenite oxidation), and arsM (arsenite methylation) genes, indicating the co-existence and close-relation of different As resistance systems of microbes in wetland environments similar to these paddy soils after long-term evolution. Among all soil parameters, pH was an important factor controlling the distribution of As metabolism gene in five paddy soils (p = 0.018). To the best of our knowledge, this is the first study using high-throughput sequencing and metagenomics approach in characterizing As metabolism genes in the five paddy soil, showing their great potential in As biotransformation, and therefore in mitigating arsenic risk to humans. PMID- 26736051 TI - In vivo and In vitro neurochemical-based assessments of wastewater effluents from the Maumee River area of concern. AB - Wastewater treatment plant (WWTP) effluents contain potentially neuroactive chemicals though few methods are available to screen for the presence of such agents. Here, two parallel approaches (in vivo and in vitro) were used to assess WWTP exposure-related changes to neurochemistry. First, fathead minnows (FHM, Pimephales promelas) were caged for four days along a WWTP discharge zone into the Maumee River (Ohio, USA). Grab water samples were collected and extracts obtained for the detection of alkylphenols, bisphenol A (BPA) and steroid hormones. Second, the extracts were then used as a source of in vitro exposure to brain tissues from FHM and four additional species relevant to the Great Lakes ecosystem (rainbow trout (RT), river otter (RO), bald eagle (BE) and human (HU)). The ability of the wastewater (in vivo) or extracts (in vitro) to interact with enzymes (monoamine oxidase (MAO) and glutamine synthetase (GS)) and receptors (dopamine (D2) and N-methyl-D-aspartate receptor (NMDA)) involved in dopamine and glutamate-dependent neurotransmission were examined on brain homogenates. In vivo exposure of FHM led to significant decreases of NMDA receptor binding in females (24-42%), and increases of MAO activity in males (2.8- to 3.2-fold). In vitro, alkylphenol-targeted extracts significantly inhibited D2 (66% in FHM) and NMDA (24-54% in HU and RT) receptor binding, and induced MAO activity in RT, RO, and BE brains. Steroid hormone-targeted extracts inhibited GS activity in all species except FHM. BPA-targeted extracts caused a MAO inhibition in FHM, RT and BE brains. Using both in vivo and in vitro approaches, this study shows that WWTP effluents contain agents that can interact with neurochemicals important in reproduction and other neurological functions. Additional work is needed to better resolve in vitro to in vivo extrapolations (IVIVE) as well as cross species differences. PMID- 26736052 TI - Tracking the conversion of nitrogen during pyrolysis of antibiotic mycelial fermentation residues using XPS and TG-FTIR-MS technology. AB - Antibiotic mycelial fermentation residues (AMFRs), which are emerging solid pollutants, have been recognized as hazardous waste in China since 2008. Nitrogen (N), which is an environmental sensitivity element, is largely retained in AMFR samples derived from fermentation substrates. Pyrolysis is a promising technology for the treatment of solid waste. However, the outcomes of N element during the pyrolysis of AMFRs are still unknown. In this study, the conversion of N element during the pyrolysis of AMFRs was tracked using XPS (X-ray photoelectron spectroscopy) and online TG-FTIR-MS (Thermogravimetry-Fourier transform infrared Mass spectrometry) technology. In the AMFR sample, organic amine-N, pyrrolic-N, protein-N, pyridinic-N, was the main N-containing species. XPS results indicated that pyrrolic-N and pyridinic-N were retained in the AMFR-derived pyrolysis char. More stable species, such as N-oxide and quaternary-N, were also produced in the char. TG-FTIR-MS results indicated that NH3 and HCN were the main gaseous species, and their contents were closely related to the contents of amine-N and protein-N, and pyrrolic-N and pyridinic-N of AMFRs, respectively. Increases in heating rate enhanced the amounts of NH3 and HCN, but had less of an effect on the degradation degree of AMFRs. N-containing organic compounds, including amine N, nitrile-N and heterocyclic-N, were discerned from the AMFR pyrolysis process. Their release range was extended with increasing of heating rate and carbon content of AMFR sample. This work will help to take appropriate measure to reduce secondary pollution from the treatment of AMFRs. PMID- 26736053 TI - Source apportionment of trace metals in river sediments: A comparison of three methods. AB - Increasing trace metal pollution in river sediment poses a significant threat to watershed ecosystem health. Identifying potential sources of sediment metals and apportioning their contributions are of key importance for proposing prevention and control strategies of river pollution. In this study, three advanced multivariate receptor models, factor analysis with nonnegative constraints (FA NNC), positive matrix factorization (PMF), and multivariate curve resolution weighted-alternating least-squares (MCR-WALS), were comparatively employed for source apportionment of trace metals in river sediments and applied to the Le'an River, a main tributary of Poyang Lake which is the largest freshwater lake in China. The pollution assessment with contamination factor and geoaccumulation index suggested that the river sediments in Le'an River were contaminated severely by trace metals due to human activities. With the three apportionment tools, similar source profiles of trace metals in sediments were extracted. Especially, the MCR-WALS and PMF models produced essentially the same results. Comparatively speaking, the weighted schemes might give better solutions than the unweighted FA-NNC because the uncertainty information of environmental data was considered by PMF and MCR-WALS. Anthropogenic sources were apportioned as the most important pollution sources influencing the sediment metals in Le'an River with contributions of about 90%. Among them, copper tailings occupied the largest contribution (38.4-42.2%), followed by mining wastewater (29.0-33.5%), and agricultural activities (18.2-18.7%). To protect the ecosystem of Le'an River and Poyang Lake, special attention should be paid to the discharges of mining wastewater and the leachates of copper tailing ponds in that region. PMID- 26736054 TI - The associations between birth weight and exposure to fine particulate matter (PM2.5) and its chemical constituents during pregnancy: A meta-analysis. AB - We performed this meta-analysis to estimate the associations of maternal exposure to PM2.5 and its chemical constituents with birth weight and to explore the sources of heterogeneity in regard to the findings of these associations. A total of 32 studies were identified by searching the MEDLINE, PUBMED, Embase, China Biological Medicine and Wanfang electronic databases before April 2015. We estimated the statistically significant associations of reduced birth weight (beta = -15.9 g, 95% CI: -26.8, -5.0) and LBW (OR = 1.090, 95% CI: 1.032, 1.150) with PM2.5 exposure (per 10 MUg/m(3) increment) during the entire pregnancy. Trimester-specific analyses showed negative associations between birth weight and PM2.5 exposure during the second (beta = -12.6 g) and third (beta = -10.0 g) trimesters. Other subgroup analyses indicated significantly different pooled effect estimates of PM2.5 exposure on birth weight in studies with different exposure assessment methods, study designs and study settings. We further observed large differences in the pooled effect estimates of the PM2.5 chemical constituents for birth weight decrease and LBW. We concluded that PM2.5 exposure during pregnancy was associated with lower birth weight, and late pregnancy might be the critical window. Some specific PM2.5 constituents may have larger toxic effects on fetal weight. Exposure assessment methods, study designs and study settings might be important sources of the heterogeneity among the included studies. PMID- 26736055 TI - Impacts of reclaimed water irrigation on soil antibiotic resistome in urban parks of Victoria, Australia. AB - The effluents from wastewater treatment plants have been recognized as a significant environmental reservoir of antibiotics and antibiotic resistance genes (ARGs). Reclaimed water irrigation (RWI) is increasingly used as a practical solution for combating water scarcity in arid and semiarid regions, however, impacts of RWI on the patterns of ARGs and the soil bacterial community remain unclear. Here, we used high-throughput quantitative PCR and terminal restriction fragment length polymorphism techniques to compare the diversity, abundance and composition of a broad-spectrum of ARGs and total bacteria in 12 urban parks with and without RWI in Victoria, Australia. A total of 40 unique ARGs were detected across all park soils, with genes conferring resistance to beta-lactam being the most prevalent ARG type. The total numbers and the fold changes of the detected ARGs were significantly increased by RWI, and marked shifts in ARG patterns were also observed in urban parks with RWI compared to those without RWI. The changes in ARG patterns were paralleled by a significant effect of RWI on the bacterial community structure and a co-occurrence pattern of the detected ARG types. There were significant and positive correlations between the fold changes of the integrase intI1 gene and two beta-lactam resistance genes (KPC and IMP-2 groups), but no significant impacts of RWI on the abundances of intI1 and the transposase tnpA gene were found, indicating that RWI did not improve the potential for horizontal gene transfer of soil ARGs. Taken together, our findings suggested that irrigation of urban parks with reclaimed water could influence the abundance, diversity, and compositions of a wide variety of soil ARGs of clinical relevance. ONE-SENTENCE SUMMARY: Irrigation of urban parks with treated wastewater significantly increased the abundance and diversity of various antibiotic resistance genes, but did not significantly enhance their potential for horizontal gene transfer. PMID- 26736056 TI - Partitions and vertical profiles of 9 endocrine disrupting chemicals in an estuarine environment: Effect of tide, particle size and salinity. AB - Phenolic endocrine disrupting chemicals (EDCs) in an estuarine water column in a depth profile of five water layers (0.05 D, 0.20 D, 0.60 D, 0.80 D and 0.90 D, D = Depth, 10.7 +/- 0.7 m) and their corresponding environmental parameters (tide, salinity and particle size) were investigated over a year. Water sample from each layer was further separated into three fractions, which were dissolved, coarse (SPM-D, Phi >= 2.7 MUm) and fine (SPM-F, 2.7 MUm > Phi >= 0.7 MUm) suspended particulate matters. Most of EDCs in the water column were presented in the dissolved fraction. Vertical profiles of salinity fluctuations showed that the upper water layer was most influenced by upstream flow. Estriol (E3), mestranol (Mes) and 17alpha-ethynylestradiol (EE2) concentrations were significantly higher in ebb tide than in flood tide, indicating that EDCs mainly came from terrestrial source, the upstream flow. Dissolved EDCs also exhibited high levels in the surface layer (0.05 D) due to the upstream source and atmosphere deposition, followed by the bottom layer (0.90 D) owing to the re-suspension of EDCs containing sediment. Compared to the dissolved phase, the contents of BPA, Mes and EE2 in the solid phase were affected by particle size and exhibited a trend of SPM-F > SPM-D > sediment. On the other hand, the concentrations of octylphenol (OP) and t-nonylphenol (NP), the degradation products from common nonionic surfactants, in sediment were higher than those in suspended particles, and NP concentration was higher in flood tide than that in ebb tide. For both SPM-D and SPM-F, their corresponding EDCs concentrations were negatively related to SPM concentrations due to particle concentration effect (PCE). Owing to the "salting out effect", salinity pushed EDCs from dissolved fraction to particulate or sedimentary phase. PMID- 26736057 TI - Effects of prenatal exposure to cadmium on neurodevelopment of infants in Shandong, China. AB - Although animal studies suggested that prenatal cadmium exposure can cause neurodevelopmental deficits, little is explored in human populations, or its mechanism. We investigated the association between prenatal cadmium exposures and infants' developmental quotients (DQs) based on the Gesell Developmental Schedules (gross motor, fine motor, adaptive, language, and social domains) at 12 months of age and explored the role of brain-derived neurotrophic factor (BDNF) in prenatal cadmium-induced neurodevelopmental deficits in Shandong, China, by enrolling 300 mothers between September 2010 and December 2011. Maternal blood cadmium concentration (median, 1.24 MUg/L) was negatively associated with social domain DQs and BDNF levels in cord serum. A 10-fold increase in maternal cadmium levels was associated with a 5.70-point decrease in social domain DQs, a 4.31 point decrease in BDNF levels. BDNF levels were positively associated with social domain DQs. These data suggest that prenatal low-level cadmium exposure has adverse effects on neurodevelopment. BDNF may play an important role in the decline of social domain DQs induced by prenatal low-level cadmium exposure. PMID- 26736058 TI - Reconstructing temporal variation of fluoride uptake in eastern grey kangaroos (Macropus giganteus) from a high-fluoride area by analysis of fluoride distribution in dentine. AB - Trace element profiling in the incrementally formed dentine of mammalian teeth can be applied to reconstruct temporal variation of incorporation of these elements into the tissue. Using an electron microprobe, this study analysed fluoride distribution in dentine of first and third mandibular molars of free ranging eastern grey kangaroos inhabiting a high-fluoride area, to assess temporal variation in fluoride uptake of the animals. Fluoride content in the early-formed dentine of first molars was significantly lower than in the late formed dentine of these teeth, and was also lower than in both, the early and the late-formed dentine of third molars. As early dentine formation in M1 takes place prior to weaning, this finding indicates a lower dentinal fluoride uptake during the pre-weaning compared to the post-weaning period. This is hypothetically attributed to the action of a partial barrier to fluoride transfer from blood to milk in lactating females and a low bioavailability of fluoride ingested together with milk. Another factor contributing to lower plasma fluoride levels in juveniles compared to adults is the rapid clearance of fluoride from blood plasma in the former due to their intense skeletal growth. The combined action of these mechanisms is considered to explain why in kangaroos from high-fluoride areas, the (early-formed) first molars are not affected by dental fluorosis while the (later-formed) third and fourth molars regularly exhibit marked to severe fluorotic lesions. PMID- 26736059 TI - Reading from computer screen versus reading from paper: does it still make a difference? AB - Four experiments were conducted to test whether recent developments in display technology would suffice to eliminate the well-known disadvantages in reading from screen as compared with paper. Proofreading speed and performance were equal for a TFT-LCD and a paper display, but there were more symptoms of eyestrain in the screen condition accompanied by a strong preference for paper (Experiment 1). These results were replicated using a longer reading duration (Experiment 2). Additional experiments were conducted to test hypotheses about the reasons for the higher amount of eyestrain associated with reading from screen. Reduced screen luminance did not change the pattern of results (Experiment 3), but positioning both displays in equal inclination angles eliminated the differences in eyestrain symptoms and increased proofreading speed in the screen condition (Experiment 4). A paper-like positioning of TFT-LCDs seems to enable unimpaired reading without evidence of increased physical strain. Practitioner Summary: Given the developments in screen technology, a re-assessment of the differences in proofreading speed and performance, well-being, and preference between computer screen and paper was conducted. State-of-the-art TFT-LCDs enable unimpaired reading, but a book-like positioning of screens seems necessary to minimise eyestrain symptoms. PMID- 26736060 TI - Extensive angiokeratoma circumscriptum - successful treatment with 595-nm variable-pulse pulsed dye laser and 755-nm long-pulse pulsed alexandrite laser. AB - Angiokeratomas are rare vascular mucocutaneous lesions characterized by small vessel ectasias in the upper dermis with reactive epidermal changes. Angiokeratoma circumscriptum (AC) is the rarest among the five types in the current classification of angiokeratoma. We present a case of an extensive AC in 19-year-old women with Fitzpatrick skin type I of the left lower extremity, characterized by a significant morphological heterogeneity of the lesions, intermittent bleeding, and negative psychological impact. Histopathological examination after deep biopsy was consistent with that of angiokeratoma. The association with metabolic diseases (Fabry disease) was excluded by ophthalmological, biochemical, and genetic examinations. Nuclear magnetic resonance imaging has not detected deep vascular hyperplasia pathognomic for verrucous hemangioma. The combined treatment with 595-nm variable-pulse pulsed dye laser (VPPDL) and 755-nm long-pulse pulsed alexandrite laser (LPPAL) with dynamic cooling device led to significant removal of the pathological vascular tissue of AC. Only a slight degree of secondary reactions (dyspigmentations and texture changes) occurred. No recurrence was observed after postoperative interval of 9 months. We recommend VPPDL and LPPAL for the treatment of extensive AC. PMID- 26736061 TI - Synergistic Effect of the TiCl4/p-TsOH Promoter System on the Aza-Prins Cyclization. AB - A novel aza-Prins cyclization promoted by a synergistic combination between a Lewis acid and a Bronsted acid to efficiently afford piperidines is described. Contrary to what has been previously reported in the literature, the generality of the reaction employing N-alkyl, N-aryl, and nonprotected homoallylamines has been demonstrated. The reaction is highly diastereoselective depending on the homoallylic amine used, N-PMP homoallyl amine leading preferentially to the trans diastereomer, and free homoallylamine affording the deprotected piperidine as single cis diastereomer. PMID- 26736063 TI - Significant effects of sex, strain, and anesthesia in the intrahippocampal kainate mouse model of mesial temporal lobe epilepsy. AB - The intrahippocampal kainate mouse model of mesial temporal lobe epilepsy is increasingly being used for studies on epileptogenesis and antiepileptogenesis. Almost all previous studies used male mice for this purpose, and no study is available in this or other models of acquired epilepsy that directly compared epileptogenesis in female and male rodents. Epidemiological studies suggest that gender may affect susceptibility to epilepsy and its prognosis; therefore, one goal of this study was to investigate whether sex has an influence on latent period and epileptogenesis in the intrahippocampal kainate model in mice. Another aspect that was examined in the present study was whether mouse strain differences in epileptogenesis exist. Finally, we examined the effects of different types of anesthesia (chloral hydrate, isoflurane) on kainate-induced status epilepticus (SE) and epileptogenesis. Continuous (24/7) video-EEG monitoring was used during SE and the 2 weeks following SE as well as 4-6 weeks after SE. In male NMRI mice with chloral hydrate anesthesia during kainate injection, SE was followed by a seizure-free latent period of 10-14 days if hippocampal paroxysmal discharges (HPDs) recorded from the kainate focus were considered the onset of epilepsy. Anesthesia with isoflurane led to a more rapid onset and higher severity of SE, and not all male NMRI mice exhibited a seizure free latent period. Female NMRI mice differed from male animals in the lack of any clear latent period, independently of anesthesia type. Furthermore, HPDs were only rarely observed. These problems were not resolved by decreasing the dose of kainate or using other strains (C57BL/6, FVB/N) of female mice. The present data are the first to demonstrate marked sex-related differences in the latent period following brain injury in a rodent model of acquired epilepsy. Furthermore, our data demonstrate that the choice of anesthestic agent during kainate administration affects SE severity and as a consequence, the latent period, which may explain some of the differences reported for this model in the literature. PMID- 26736065 TI - Bacterial diversity of Grenache and Carignan grape surface from different vineyards at Priorat wine region (Catalonia, Spain). AB - Epiphytic bacteria on grape berries play a critical role in grape health and quality, which decisively influence the winemaking process. Despite their importance, the bacteria related with grape berry surface remain understudied and most previous work has been based on culture-dependent methods, which offer a limited view of the actual diversity. Herein, we used high-throughput sequencing to investigate the bacterial diversity on the surface from two grape varieties, Grenache and Carignan, and compared them across five vineyards included within the Priorat region (Spain). We could detect up to 14 bacterial phyla with Firmicutes (37.6% Bacillales and 14% Lactobacillales), Proteobacteria (16.8% Pseudomonadales and 11.6% Enterobacteriales) and Actinobacteria (3.4% Actinomycetales) being the most abundant. Bacterial community was different at each vineyard being grape varietal, geographical situation and orientation related with changes in bacterial populations. The most abundant bacterial taxa and those driving differences between the vineyards and grape varietals were identified. This study indicates that bacterial community heterogeneities can be influenced by geographic factors like orientation. PMID- 26736064 TI - Exome Sequencing Analysis in Severe, Early-Onset Chronic Obstructive Pulmonary Disease. AB - RATIONALE: Genomic regions identified by genome-wide association studies explain only a small fraction of heritability for chronic obstructive pulmonary disease (COPD). Alpha-1 antitrypsin deficiency shows that rare coding variants of large effect also influence COPD susceptibility. We hypothesized that exome sequencing in families identified through a proband with severe, early-onset COPD would identify additional rare genetic determinants of large effect. OBJECTIVES: To identify rare genetic determinants of severe COPD. METHODS: We applied filtering approaches to identify potential causal variants for COPD in whole exomes from 347 subjects in 49 extended pedigrees from the Boston Early-Onset COPD Study. We assessed the power of this approach under different levels of genetic heterogeneity using simulations. We tested genes identified in these families using gene-based association tests in exomes of 204 cases with severe COPD and 195 resistant smokers from the COPDGene study. In addition, we examined previously described loci associated with COPD using these datasets. MEASUREMENTS AND MAIN RESULTS: We identified 69 genes with predicted deleterious nonsynonymous, stop, or splice variants that segregated with severe COPD in at least two pedigrees. Four genes (DNAH8, ALCAM, RARS, and GBF1) also demonstrated an increase in rare nonsynonymous, stop, and/or splice mutations in cases compared with resistant smokers from the COPDGene study; however, these results were not statistically significant. We demonstrate the limitations of the power of this approach under genetic heterogeneity through simulation. CONCLUSIONS: Rare deleterious coding variants may increase risk for COPD, but multiple genes likely contribute to COPD susceptibility. PMID- 26736066 TI - Evaluation of detection methods for non-O157 Shiga toxin-producing Escherichia coli from food. AB - Shiga toxin-producing Escherichia coli (STEC) remains a major foodborne pathogen of concern across the globe. Rapid detection and isolation of this pathogen is of great importance for public health reasons. In this study the detection and isolation of four non-O157 STEC strains (O26, O103, O111, O145) from different artificially contaminated matrices, namely ground (minced) beef, cattle carcass swab, lettuce mix and sprouted soy beans, were evaluated. Low amounts of STEC were used (0.25-1.40 cfu/g) to spike the samples. All samples were enriched in parallel in Buffered Peptone Water (BPW) and Brila broth. After enrichment, detection was performed using real-time PCR (qPCR), and isolation using two chromogenic agar media, CHROMagarTM STEC and ChromIDTM EHEC. Inoculation on the agar media was performed either directly after enrichment or after the use of an acid treatment procedure. Furthermore, the use of this procedure was also tested on naturally contaminated food products, using 150 stx-positive samples. Although the qPCR Cycle Threshold (Ct) values were lower after enrichment in Brila broth, no significant differences in recovery were observed between both enrichment broths. Both agar media were equally suitable for the isolation of STEC, although a significantly higher recovery was obtained when using both agar media in parallel. For samples with a Ct value above 25, an acid treatment step prior to isolation ensured a significant improvement in the recovery of STEC due to the reduction in background microbiota. This acid treatment procedure proved especially useful for the isolation of STEC from sprouted soy bean samples. PMID- 26736067 TI - Vascular Repair by Circumferential Cell Therapy Using Magnetic Nanoparticles and Tailored Magnets. AB - Cardiovascular disease is often caused by endothelial cell (EC) dysfunction and atherosclerotic plaque formation at predilection sites. Also surgical procedures of plaque removal cause irreversible damage to the EC layer, inducing impairment of vascular function and restenosis. In the current study we have examined a potentially curative approach by radially symmetric re-endothelialization of vessels after their mechanical denudation. For this purpose a combination of nanotechnology with gene and cell therapy was applied to site-specifically re endothelialize and restore vascular function. We have used complexes of lentiviral vectors and magnetic nanoparticles (MNPs) to overexpress the vasoprotective gene endothelial nitric oxide synthase (eNOS) in ECs. The MNP loaded and eNOS-overexpressing cells were magnetic, and by magnetic fields they could be positioned at the vascular wall in a radially symmetric fashion even under flow conditions. We demonstrate that the treated vessels displayed enhanced eNOS expression and activity. Moreover, isometric force measurements revealed that EC replacement with eNOS-overexpressing cells restored endothelial function after vascular injury in eNOS(-/-) mice ex and in vivo. Thus, the combination of MNP-based gene and cell therapy with custom-made magnetic fields enables circumferential re-endothelialization of vessels and improvement of vascular function. PMID- 26736069 TI - Photoorganocatalysed and visible light photoredox catalysed trifluoromethylation of olefins and (hetero)aromatics in batch and continuous flow. AB - Trifluoromethylation of olefins and (hetero)aromatics with sodium triflinate as CF3 source and readily accessible benzophenone derivatives as photosensitisers has been developed in batch and flow. The use of an iridium-based photocatalyst enables the trifluoromethylation to proceed under visible light irradiation. PMID- 26736068 TI - Quantitative Secretomic Analysis Identifies Extracellular Protein Factors That Modulate the Metastatic Phenotype of Non-Small Cell Lung Cancer. AB - Lung cancer is the leading cause of cancer-related deaths for men and women in the United States, with non-small cell lung cancer (NSCLC) representing 85% of all diagnoses. Late stage detection, metastatic disease and lack of actionable biomarkers contribute to the high mortality rate. Proteins in the extracellular space are known to be critically involved in regulating every stage of the pathogenesis of lung cancer. To investigate the mechanism by which secreted proteins contribute to the pathogenesis of NSCLC, we performed quantitative secretomic analysis of two isogenic NSCLC cell lines (NCI-H1993 and NCI-H2073) and an immortalized human bronchial epithelial cell line (HBEC3-KT) as control. H1993 was derived from a chemo-naive metastatic tumor, while H2073 was derived from the primary tumor after etoposide/cisplatin therapy. From the conditioned media of these three cell lines, we identified and quantified 2713 proteins, including a series of proteins involved in regulating inflammatory response, programmed cell death and cell motion. Gene Ontology (GO) analysis indicates that a number of proteins overexpressed in H1993 media are involved in biological processes related to cancer metastasis, including cell motion, cell-cell adhesion and cell migration. RNA interference (RNAi)-mediated knock down of a number of these proteins, including SULT2B1, CEACAM5, SPRR3, AGR2, S100P, and S100A14, leads to dramatically reduced migration of these cells. In addition, meta analysis of survival data indicates NSCLC patients whose tumors express higher levels of several of these secreted proteins, including SULT2B1, CEACAM5, SPRR3, S100P, and S100A14, have a worse prognosis. Collectively, our results provide a potential molecular link between deregulated secretome and NSCLC cell migration/metastasis. In addition, the identification of these aberrantly secreted proteins might facilitate the development of biomarkers for early detection of this devastating disease. PMID- 26736070 TI - Rhodamine intense pulsed light versus conventional intense pulsed light for facial telangiectasias. AB - Facial telangiectasias represent the major aesthetic alterations of several chronic inflammatory disorders arising on facial skin. We herein report on relevant clinical results of a new subtype of intense pulsed light treatments, the so-called rhodamine intense pulsed light (r-IPL), in comparison with conventional IPL (c-IPL) treatments on forty-five patients affected by facial telangiectasias. The aim of this study is to determinate whether r-IPL represents an effective and safe treatment for the most common superficial vascular alterations and could be advised as a first choice therapy for facial telangiectasias. PMID- 26736071 TI - Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure-Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin 6-yl)pyridin-2(1H)-one Derivatives. AB - Aiming to discover melanin-concentrating hormone receptor 1 (MCHR1) antagonists with improved safety profiles, we hypothesized that the aliphatic amine employed in most antagonists reported to date could be removed if the bicyclic motif of the compound scaffold interacted with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from our compound designs, with a cutoff value of pK(a) < 8, and explored aliphatic amine-free MCHR1 antagonists in a CNS-oriented chemical space limited by four descriptors (TPSA, ClogP, MW, and HBD count). Screening of novel bicyclic motifs with high intrinsic binding affinity for MCHR1 identified the imidazo[1,2-a]pyridine ring (represented in compounds 6a and 6b), and subsequent cyclization of the central aliphatic amide linkage led to the discovery of a potent, orally bioavailable MCHR1 antagonist 4-[(4-chlorobenzyl)oxy]-1-(2 cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one 10a. It exhibited low potential for hERG inhibition and phospholipidosis induction as well as sufficient brain concentration to exert antiobesity effects in diet induced obese rats. PMID- 26736072 TI - Thermoresponsive and Mechanical Properties of Poly(L-proline) Gels. AB - Gelation of the left helical N-substituted homopolypeptide poly(L-proline) (PLP) in water was explored, employing rheological and small-angle scattering studies at different temperatures and concentrations in order to investigate the network structure and its mechanical properties. Stiff gels were obtained at 10 wt % or higher at 5 degrees C, the first time gelation has been observed for homopolypeptides. The secondary structure and helical rigidity of PLP has large structural similarities to gelatin but as gels the two materials show contrasting trends with temperature. With increasing temperature in D2O, the network stiffens, with broad scattering features of similar correlation length for all concentrations and molar masses of PLP. A thermoresponsive transition was also achieved between 5 and 35 degrees C, with moduli at 35 degrees C higher than gelatin at 5 degrees C. The brittle gels could tolerate strains of 1% before yielding with a frequency-independent modulus over the observed range, similar to natural proline-rich proteins, suggesting the potential for thermoresponsive or biomaterial-based applications. PMID- 26736073 TI - The social mentality theory of self-compassion and self-reassurance: The interactive effect of care-seeking and caregiving. AB - The aim of this study was to test social mentality theory, which views self compassion/reassurance as a form of intrapersonal relating in which the interpersonal mentalities of care-seeking and caregiving are activated. Self report measures of motivations, cognitions, and behaviors related to seeking and receiving care from others were administered to 195 students. Self compassion/reassurance was predicted by the interaction of care-seeking and caregiving, with the positive effect of care-seeking intensified at high caregiving. As hypothesized, the combination of high care-seeking and high caregiving predicted the highest level of self-compassion/reassurance. The lowest level of self-compassion/reassurance was predicted by the combination of low care seeking and high caregiving consistent with the concept of compulsive caregiving. Findings suggest that fostering a kinder way of relating to oneself may be achieved through more effective care-seeking and caregiving with others. PMID- 26736074 TI - Innate lymphoid cells: parallel checkpoints and coordinate interactions with T cells. AB - Protection of epithelial and mucosal surfaces is required for survival. The recent discovery of a diverse array of innate lymphoid cells that lie immediately beneath these surfaces has unexpectedly uncovered an entire defense system distinct from the adaptive system essential to protect these barriers. This multilayered design provides a robust system through coupling of two highly complementary networks to ensure immune protection. Here, we discuss the similarities in the hardwiring and diversification of innate lymphoid cells and T cells during mammalian immune responses. PMID- 26736075 TI - Production of a highly potent epoxide through the microbial metabolism of 3beta acetoxyurs-11-en-13beta,28-olide by Aspergillus niger culture. AB - Context 3beta-Acetoxyurs-11-en-13beta,28-olide (I), a triterpenoid, is found in most plant species. Pharmacologically triterpenes are very effective compounds with potent anticancer, anti-HIV and antimicrobial activities. Objectives Microbial transformation of 3beta-acetoxyurs-11-en-13beta,28-olide (I) was performed in order to obtain derivatives with improved pharmacological potential. Materials and methods Compound (I, 100 mg) was incubated with Aspergillus niger culture for 12 d. The metabolite formed was purified through column chromatography. Structure elucidation was performed through extensive spectroscopy (IR, MS and NMR). In vitro alpha- and beta-glucosidase inhibitory, and antiglycation potentials of both substrate and metabolite were evaluated. Results Structure of metabolite II was characterized as 3beta-acetoxyurs-11,12 epoxy-13beta,28-olide (II). Metabolite II was found to be an oxidized product of compound I. In vitro alpha- and beta-glucosidases revealed that metabolite II was a potent and selective inhibitor of alpha-glucosidase (IC50 value = 3.56 +/- 0.38 MUM), showing that the inhibitory effect of metabolite II was far better than compound I (IC50 value = 14.7 +/- 1.3 MUM) as well as acarbose (IC50 value = 545 +/- 7.9 MUM). Antiglycation potential of compound II was also high with 82.51 +/- 1.2% inhibition. Thus, through oxidation, the biological potential of the substrate molecule can be enhanced. Conclusion Biotransformation can be used as a potential tool for the production of biologically potent molecules. PMID- 26736076 TI - Fatty acid ethyl esters: nonoxidative metabolites of ethanol. AB - The story of fatty acid ethyl (FAEE) encompasses nearly 40 years of research. For more than half of this time, the investigation was limited to documenting the presence of ethyl ester synthesis in different cells and tissues. In the last three years, increasing evidence has emerged that FAEE contribute to ethanol induced organ damage, with a variety of different mechanisms proposed for mediation of this toxic effect. In addition, multiple enzymatic activities associated with FAEE formation have been described. Independent of their role in mediating cell injury, it has very recently been shown that FAEE are useful short term and long-term serum markers of ethanol intake, given their appearance in the blood rapidly after ethanol ingestion and their presence when ethanol is no longer detectable. PMID- 26736077 TI - Central nervous system impairment caused by chronic solvent abuse-a review of Japanese studies on the clinical and neuroimaging aspects. AB - Organic solvents are some of the most frequently abused substances in Japan. Abuse is especially prevalent among young people. In this article, we review Japanese studies, along with those of other countries, on central nervous system impairment caused by chronic solvent abuse. Neuroimaging studies provided valuable information on this problem. Magnetic resonance imaging revealed T2 prolonged lesions in diffuse white matter which were related to neurological symptoms and cognitive dysfunction. Clinical observations indicated that neurological symptoms and their reversibility differed among patients. Histopathological studies similarly revealed variation in severity of brain damage reflected by demyelination and neuronal damage. The basis of these variations are yet to be elucidated along with their causes such as severity of dependence, composition of solvents, individual predispositions and starting age of abuse. Cerebral perfusion analyses revealed some regional decreases in blood flow. These decreases may occur earlier than white matter changes and may relate to psychiatric symptoms such as apathy and lack of initiative. PMID- 26736078 TI - Substance misuse in Aboriginal Australians. AB - Australia's Aborigines lived in isolation from the rest of humanity as successful hunter-gatherers for tens of thousands of years. That isolation ended abruptly with British colonization in the late 18th century and was followed by a traumatic 200 years for Aborigines who are now seriously disadvantaged, socio economically and in terms of their health standards. It has often been assumed that the Aborigines had no access to psychotropic substances before permanent European contact but several pieces of evidence dispute this view. The history of Aboriginal contact with and usage of intoxicating substances, including alcohol, is extremely complex and affected by a maze of restrictive government policies. These interact with a wide range of other Federal and State policies which have changed rapidly since the late 1960s when Aborigines were first granted the franchise; access to unrestricted drinking followed soon afterwards. Today Aborigines suffer disproportionately to other Australians from the physical and social consequences of excess alcohol consumption, tobacco usage, petrol and other solvent sniffing, usage of marijuana, amphetamines, cocaine and heroin, as well as other drugs. The Aboriginal population is dispersed in cities, towns, fringe settlements, rural and remote areas over this vast continent and there are different patterns of drug usage from place to place. This review attempts to synthesize some of this information in order to give an overview to the history, background, current status of substance misuse by Aborigines as well as some strategies being used to try to overcome this serious problem. PMID- 26736079 TI - Liver disease due to illicit substance use. AB - While the adverse neurological, cardiovascular, renal, haematologic and musculoskeletal consequences of the use of various illicit substances are widely appreciated, less attention has been directed to possible hepatotoxic effects. This is an important issue in view of increasing evidence in both experimental animals and humans that the use of some illicit substances may be associated with substantial liver damage, leading on occasion to acute liver failure. This manuscript reviews the effects on the liver of some of the most commonly used illicit substances, including ecstasy (3,4-methylenedioxymethamphetamine), other amphetamines, cocaine, heroin, angel dust (phencyclidine), lysergic acid diethylamide and marijuana. Additional causes of liver damage in those using illicit substances are discussed. PMID- 26736080 TI - NMDA-receptor antagonists block the development of rapid tolerance to ethanol in mice. AB - Several studies have emphasized the role of learning in the development of rapid and chronic tolerances. Recently, it was shown that the NMDA antagonists MK 801(dizocilpine) and ketamine block the development of tolerance to ethanol in rats submitted to tilt-plane apparatus. The present study examines the generality of this inhibition using mice submitted to the rota-rod test. Mice were tested in the rota-rod apparatus at 5, 10 and 15 minutes after intraperitoneal ethanol injections. The first experiment evaluated the time course of acute effects of different doses of ethanol (1.0-2.25 g/kg) in the rota-rod test. In the second experiment, the most effective dose of ethanol to produce rapid tolerance (RT) was determined. Mice were injected on day 1 with ethanol or saline and tested on the rota-rod. After 24 hours, all groups were injected with the same doses of ethanol and tested. The third experiment investigated whether ketamine (1.0-5.0 mg/kg) injected before ethanol on day 1 influenced the development of RT to ethanol. The last experiment compared the actions of the (+) and (-)MK-801 isomers (0.015-0.060 mg/kg) on RT to ethanol. Maximum motor impairment was obtained 5 minutes after ethanol injections. Pretreatment of animals with ketamine (2.5 and 5 mg/kg) or with (+)MK-801 (0.030 and 0.060 mg/kg) significantly blocked the development of RT. The (-)MK-801 isomer did not affect RT, suggesting that the blockade by MK-801 is stereospecific. These results confirm and extend previous studies showing that NMDA receptor antagonists block RT to the motor impairment produced by ethanol in other animals tested in different models. PMID- 26736081 TI - Effect of polyunsaturated phosphatidyl-choline on lipid transport system in alcoholic liver injury. AB - The aim of this study was to determine whether serum lipid composition and lipolytic activities in alcoholinduced liver dystrophy were modified by the co administration of polyunsaturated phosphatidylcholine (PPC). Chronic alcohol intoxication was induced in rats by intragastric ethanol administration of 3.5 g/kg body weight per day over 56 days. Aqueous PPC suspension was given intragastrally in doses of 100 and 300 mg/kg body weight. Chronic alcohol intoxication led to the development of protein and lipid dystrophy of hepatocytes. PPC partially prevented alcoholic injury of the liver cells and had a normalizing effect on cholesterol esterification, lipolysis of lipoproteins and on the fatty acid composition of the main lipoprotein classes. PMID- 26736082 TI - Tryptophan pyrrolase gene expression in an alcohol preferring and non-preferring mouse strain. AB - There is considerable evidence that the level of cerebral serotonin plays a key role in the volitional consumption of ethanol in both man and animals. Naive alcohol-preferring C57BL/6J mice have been shown to have a lower cerebral serotonin content compared to the non-preferring CBA/Ca mouse strain. This has been attributed to the enhancement of hepatic tryptophan pyrrolase activity in C57 mice. Activity and/or expression of tryptophan pyrrolase may be an important biological determinant of alcohol preference. We have investigated the possible mechanism/s underlying this strain difference in tryptophan pyrrolase activity by assaying both mRNA levels encoding for the tryptophan pyrrolase gene and by mutational analysis of tryptophan pyrrolase cDNA. We were unable to demonstrate any difference in tryptophan pyrrolase mRNA levels between naive C57 and CBA mice. Tryptophan pyrrolase mRNA levels were increased following starvation in C57 mice and following glucocorticoid administration in both C57 and CBA mice. Heteroduplex mutational analysis failed to detect any tryptophan pyrrolase cDNA sequence heterogeneity between these mice strains. PMID- 26736083 TI - Expression of brain-derived neurotrophic factor (BDNF) mRNA in rat retrosplenial cortex following administration of phencyclidine. AB - The non-competitive NMDA receptor antagonists such as phencyclidine (PCP) cause neurotoxicity in the retrosplenial cortex of rat brain. However, the precise mechanism(s) underlying the neurotoxicity of NMDA receptor antagonists is currently unclear. Using an in situ hybridization technique, we studied the effects of PCP on expression of brain-derived neurotrophic factor (BDNF) mRNA in the rat brain. No expression of BDNA mRNA was observed in the retrosplenial cortex of rats treated with vehicle, although a high basal level of BDNF mRNA was detected in the hippocampus of control rats. Administration of PCP (12.5, 25 or 50 mg/kg, i.p., 6 hours) caused marked induction of BDNF mRNA in the retrosplenial cortex, in a dosedependent manner. These results suggest that the expression of BDNF mRNA may occur as a trophic response to the neurotoxicity of NMDA receptor antagonists such as PCP. PMID- 26736084 TI - Effects of acute and chronic ethanol exposure on fatty acid ethyl ester synthases in mouse cerebellar membranes. AB - Fatty acid ethyl esters (FAEE), the products of esterification of fatty acids with ethanol (EtOH), are shown to cause organ injury in chronic alcohol abusers. Their formation is catalysed by the enzyme FAEE synthase which is present in both animal and human brain. In the present study, we investigated the effects of acute and chronic EtOH exposure on FAEE synthase activity in crude cerebellar membrane preparation of mice, using oleic, linoleic and arachidonic acids as substrates. The results indicate that FAEE synthase activity exists in synaptosomal membranes and the activity of this enzyme varied with various fatty acid substrates. The synthase activity was optimal in the membranes from the animals exposed acutely to EtOH when oleic acid was used as a substrate. A 14% increase in the incorporation of oleic acid was observed in the membranes from animals exposed to acute dose of EtOH. However, there was a 10% reduction in the synthase activity when arachidonic acid was used as a substrate in the membrane preparations from mice exposed chronically to EtOH. The results suggest that substrate specificity for FAEE synthase varied with the duration of exposure to EtOH. PMID- 26736086 TI - Two novel prenylated kaempferol derivatives from fresh bud's fur of Platanus acerifolia and their anti-proliferative activities. AB - Two novel prenylated kaempferol derivatives (1, 2), together with seven known metabolites were isolated from ethanol extract of fresh Platanus acerifolia bud's fur by multistep chromatographic processing. Structure of compounds 1 and 2 was confirmed by 1D, 2D NMR spectra and HR-ESI-MS. In addition, compound 1 was further analysed by X-ray crystallography. Anti-proliferative activities in vitro against human breast carcinoma (MCF-7) and human hepatocellular carcinoma (Hep G2) cell lines for compound 1, 2 and 8 were evaluated. Compound 1 exhibited cytotoxic activity towards MCF-7 and Hep-G2 cell lines with the IC50 values 38.2 and 39.5 MUM, respectively. Moreover, compound 2 showed weak cytotoxic activities against the two cell lines. PMID- 26736087 TI - PGRNseq: a targeted capture sequencing panel for pharmacogenetic research and implementation. AB - OBJECTIVES: Although the costs associated with whole-genome and whole-exome next generation sequencing continue to decline, they remain prohibitively expensive for large-scale studies of genetic variation. As an alternative, custom-target sequencing has become a common methodology on the basis of its favorable balance between cost, throughput, and deep coverage. METHODS: We have developed PGRNseq, a custom-capture panel of 84 genes with associations to pharmacogenetic phenotypes, as a tool to explore the relationship between drug response and genetic variation, both common and rare. We utilized a set of 32 diverse HapMap trios and two clinical cohorts to assess platform performance, accuracy, and ability to discover novel variation. RESULTS: We found that PGRNseq generates ultra-deep coverage data (mean=496*) that are over 99.8% concordant with orthogonal datasets. In addition, in our testing sets, PGRNseq identified many novel, rare variants of interest, underscoring its value in both research and clinical settings. CONCLUSION: PGRNseq is an ideal platform for carrying out sequencing-based analyses of pharmacogenetic variation in large cohorts. In addition, the high accuracy associated with genotypes from PGRNseq highlight its utility as a clinical test. PMID- 26736088 TI - Tissue plasminogen activator deficiency preserves neurological function and protects against murine acute ischemic stroke. AB - BACKGROUND: We tested the hypothesis that tissue plasminogen activator (tPA) deficiency protected against acute ischemic stroke (AIS)-induced brain injury. METHODS AND RESULTS: Wild-type mice (n=54) were categorized into group 1 (sham control, n=18) and group 3 [AIS by permanent ligation of left common carotid artery (CCA) and cramping right CCA for 1h and then reperfusion followed by hypoxia (11% of oxygen supply for 2h), n=36]. Similarly, tPA knockout (tPA(-/-)) mice (n=54) were randomized into group 2 (sham control, n=18) and group 4 (AIS, n=36). By day 28 after AIS procedure, mortality rate was higher in group 3 (77.8%) than in group 4 (38.9%) and lowest in groups 1 (0%) and 2 (0%) (p<0.001). By days 3 and 28, MRI demonstrated a pattern of changes in brain-infarct volume identical to that of mortality among four groups (p<0.001). By day 28, protein expressions of inflammatory (MMP-9, TNF-alpha, NF-kappaB, iNOS, PAI-1, RANTES), oxidative (NOX-1, NOX-2, oxidized protein), apoptotic (cleaved caspase-3 & PARP, Bax), and fibrotic (Smad3, TGF-beta) biomarkers and cellular expressions of inflammation (CD11, F4/80, GFAP), DNA-damage (gamma-H2AX) and brain-edema (AQP4) markers exhibited an identical pattern compared to that of mortality (all p<0.001), whereas protein expressions of endothelial (eNOS, CD31), anti-fibrotic (Smad1/5, BMP-2) biomarkers, and number of small vessels displayed an opposite pattern (all p<0.001) among four groups. Expressions of protein and cellular angiogenesis markers (VEGF, SDF-1alpha, CXCR4) were progressively increased from groups 1 and 2 to group 4 (all p<0.0001). CONCLUSION: tPA deficiency protected the brain from AIS injury. PMID- 26736089 TI - Database evaluation of the association between serum magnesium levels and the risk of atrial fibrillation in the community. AB - BACKGROUND: In population studies, mild hypomagnesemia, determined by a single measurement, was associated with incident atrial fibrillation, over ~20 years of follow-up. We sought to determine whether mild (<= 1.7 mg/dL) and moderate (<= 1.5mg/dL) hypomagnesemia are temporally associated with increased incidence of atrial fibrillation (AF) in the community. METHODS: Health Maintenance Organization (HMO) database cohort study including beneficiaries with >= 1 serum magnesium measurement between 2004 and 2013. The follow-up period was defined from the first magnesium measurement to first listing in an AF registry (for cases) and December 2013 or date of death or loss to follow-up (for controls). We analyzed the association between serum magnesium quintiles, as well as the above clinically relevant hypomagnesemia thresholds, and incident AF using Cox proportional hazard regression analysis, adjusting for confounders. The association between serum magnesium and AF occurring within 3 months was also examined. RESULTS: Among 162,162 subjects, 2228 (1.4%) developed AF over a median follow-up of 25.3 months. Compared to the middle quintile the lowest magnesium quintile (<= 1.9 mg/dL) had a significantly higher risk of AF (HR, 1.21; 95% CI: 1.07-1.37). Increased AF risk was also associated with mild (HR, 1.44; 95% CI: 1.20-1.73) and moderate hypomagnesemia (HR, 1.57; 95% CI: 1.14-2.15). No association was found when limiting the follow-up period to 3 months. CONCLUSIONS: In our study, hypomagnesemia was associated with incident AF over prolonged but not short-term follow-up periods, suggesting that this association may not be causal. PMID- 26736091 TI - A parametric study of inflammatory effects on plaque mechanical stress. PMID- 26736090 TI - Effectiveness of fixed dose combination medication ('polypills') compared with usual care in patients with cardiovascular disease or at high risk: A prospective, individual patient data meta-analysis of 3140 patients in six countries. AB - AIMS: To conduct a prospective, individual participant data (IPD) meta-analysis of randomised controlled trials comparing a polypill-based approach with usual care in high risk individuals. METHODS AND RESULTS: Three trials comparing polypill-based care with usual care in individuals with CVD or high calculated cardiovascular risk contributed IPD. Primary outcomes were self-reported adherence to combination therapy (anti-platelet, statin and >= two blood pressure (BP) lowering agents), and difference in mean systolic BP (SBP) and LDL cholesterol at 12 months. Analyses used random effects models. Among 3140 patients from Australia, England, India, Ireland, New Zealand and The Netherlands (75% male, mean age 62 years), median follow-up was 15 months. At baseline, 84%, 87% and 61% respectively were taking a statin, anti-platelet agent and at least two BP lowering agents. At 12 months, compared to usual care, participants in the polypill arm had higher adherence to combination therapy (80% vs. 50%, RR 1.58; 95% CI, 1.32 to 1.90; p < 0.001), lower SBP (-2.5 mmHg; 95% CI, -4.5 to -0.4; p = 0.02) and lower LDL-cholesterol (-0.1 mmol/L; 95% CI, -0.2 to 0.0; p = 0.04). Baseline treatment levels were a major effect modifier for adherence and SBP (p homog < 0.0001 and 0.02 respectively) with greatest improvements seen among those under-treated at baseline. CONCLUSIONS: Polypill therapy significantly improved adherence, SBP and LDL-cholesterol in high risk patients compared with usual care, especially among those who were under-treated at baseline. PMID- 26736092 TI - Ischemia-induced Brugada Phenocopy during balloon angioplasty. PMID- 26736093 TI - Diagnostic impact of genetic testing in hypertrophic cardiomyopathy: The story of two families. PMID- 26736095 TI - Men's health and quality of life. PMID- 26736094 TI - Andersen-Tawil syndrome. A diagnostic challenge. PMID- 26736096 TI - Diastereoselective Synthesis of 3,4-Benzomorphan Derivatives via Tandem [5 + 1]/Hemiaminalization of (2-Aminoaryl)divinyl Ketones. AB - A novel tandem formal [5 + 1]/hemiaminalization reaction based on the readily available (2-aminoaryl)divinyl ketones and various nucleophiles has been developed. The reaction represents a highly efficient and convenient methodology for the synthesis of 3,4-benzomorphan derivatives with high diastereoselectivity, and three new bonds and two rings are successively formed in one step under mild, metal-free conditions. PMID- 26736116 TI - Hemidystonia - hemiatrophy syndrome in Domenico Morone's Madonna with child. AB - The authors present an image of the Madonna and Child painted by one of the less well-known Italian artists of the Renaissance. The appearance of the child in this work raises the question of whether his obvious physical deformities were deliberately portrayed as an empathic gesture toward children with disabilities. Various retrospective diagnoses of the child's condition are enumerated, one of which is considered more probable. PMID- 26736117 TI - Comparison of Modern Methods for Analyzing Repeated Measures Data With Missing Values. AB - Missing data are a pervasive problem in many psychological applications in the real world. In this article we study the impact of dropout on the operational characteristics of several approaches that can be easily implemented with commercially available software. These approaches include the covariance pattern model based on an unstructured covariance matrix (CPM-U) and the true covariance matrix (CPM-T), multiple imputation-based generalized estimating equations (MI GEE), and weighted generalized estimating equations (WGEE). Under the missing at random mechanism, the MI-GEE approach was always robust. The CPM-T and CPM-U methods were also able to control the error rates provided that certain minimum sample size requirements were met, whereas the WGEE was more prone to inflated error rates. In contrast, under the missing not at random mechanism, all evaluated approaches were generally invalid. Our results also indicate that the CPM methods were more powerful than the MI-GEE and WGEE methods and their superiority was often substantial. Furthermore, we note that little or no power was sacrificed by using CPM-U method in place of CPM-T, although both methods have less power in situations where some participants have incomplete data. Some aspects of the CPM-U and MI-GEE methods are illustrated using real data from 2 previously published data sets. The first data set comes from a randomized study of AIDS patients with advanced immune suppression, the second from a cohort of patients with schizotypal personality disorder enrolled in a prevention program for psychosis. PMID- 26736118 TI - Scaling Variances of Latent Variables by Standardizing Loadings: Applications to Working Memory and the Position Effect. AB - The standardization of loadings gives a metric to the corresponding latent variable and thus scales the variance of this latent variable. By assigning an appropriately estimated weight to all the loadings on the same latent variable it can be achieved that the average squared loading is 1 as the result of standardization. As a consequence, there is comparability of the variances of the latent variables of a confirmatory factor model. A precondition of comparability is that the latent variables must have loadings of the same manifest variables and that the variances are estimated with respect to the same covariance matrix. The usefulness of this standardization method is demonstrated by applying it for the evaluation of the sources of performance in a working memory task and for the evaluation of the impact of the position effect on performance in completing a reasoning measure. In these examples the scaled variances of the latent variables provided useful information. PMID- 26736119 TI - Latent Differential Equation Modeling of Self-Regulatory and Coregulatory Affective Processes. AB - We examine emotion self-regulation and coregulation in romantic couples using daily self-reports of positive and negative affect. We fit these data using a damped linear oscillator model specified as a latent differential equation to investigate affect dynamics at the individual level and coupled influences for the 2 partners in each couple. Results indicate an absence of damping of relationship-specific affect within individuals in the sample. When both positive and negative affect are modeled at the individual level, the influence of positive affect is greater than that of negative affect. At the dyad level, the findings indicate coupled influences in both positive and negative affect between partners. With regard to positive affect, females are sensitive to their partners' overall displacement from average as well as their rate of change; males are sensitive only to their partners' displacement from average. For negative affect both partners are sensitive to each other's displacement from average, yet there are no coupled influences for rates of change in this dimension. We interpret the influence of the parameters on the system by examining the expected behavior of the system as a function of varying parameter values. PMID- 26736120 TI - Reply to Steele & Ferrer: Modeling Oscillation, Approximately or Exactly? AB - This article addresses modeling oscillation in continuous time. It criticizes Steele and Ferrer's article "Latent Differential Equation Modeling of Self Regulatory and Coregulatory Affective Processes" (2011), particularly the approximate estimation procedure applied. This procedure is the latent version of the local linear approximation procedure based on Boker (2001) and Boker, Neale, and Rausch (2004). It furthermore presents two exact alternative estimation procedures, one using filter techniques and the other using structural equation modeling. PMID- 26736121 TI - Response to Oud & Folmer: Randomness and Residuals. AB - This article presents our response to Oud and Folmer's "Modeling Oscillation, Approximately or Exactly?" (2011), which criticizes aspects of our article, "Latent Differential Equation Modeling of Self-Regulatory and Coregulatory Affective Processes" (2011). In this response, we present a conceptual explanation of the derivative-based estimation that we implemented in our original article, as well as the exact discrete model promoted by Oud & Folmer. We describe relevant differences between each of the two methods, highlight some of their benefits and limitations, and offer justifications for our choice. PMID- 26736122 TI - Special MBR Section: SMEP Student Paper Competition Abstracts, 2011. PMID- 26736123 TI - Abstract: Identifying Longitudinal Patterns of Adherence to Treatment for Obstructive Sleep Apnea. AB - Increasing adherence to medical recommendations is crucial for improving health outcomes and reducing costs of health care. To improve adherence, we have to better understand behavior change over time. The focus of this study was adherence to treatment for obstructive sleep apnea (OSA). Adherence to positive airway pressure (PAP), the most common treatment for OSA, is poor. This study involved an international sample of 161 participants, each with approximately 180 nights of data, and had three phases. First, a separate time series analysis was performed for each individual. Time series parameters included the mean (average hours of use per night), level (the intercept), slope (the rate of change over time), variance (variability in use), and autocorrelation (a measure of dependency). Second, a dynamic cluster analysis was performed to find homogenous subgroups of individuals with similar adherence patterns. A four-cluster solution was found, and the subgroups were labeled (see Figure 1 ): Great Users (17.2%; high mean and level, no slope), Good Users (32.8%; moderate mean and level, no slope), Poor Users (22.7%; low mean and level, negative slope), and Slow Decliners (moderate mean and level, negative slope, high variance). Third, participants in the identified subgroups were compared on a number of variables that were not involved in the clustering to establish external validity. Some notable findings at later time points include the following: Great Users reported the most self-efficacy (confidence to use PAP), Poor Users reported the most sleepiness, and Great Users reported the highest quality of sleep. Combining time series analysis and dynamic cluster analysis is a useful way to evaluate adherence patterns at both the individual level and subgroup level. Psychological variables relevant to adherence patterns, such as self-efficacy, could be the focus of interventions to increase PAP usage. PMID- 26736124 TI - Abstract: Comparing Semiparametric and Parametric Methods for Modeling Interactions Among Latent Variables. AB - Many approaches have been proposed to estimate interactions among latent variables. These methods often assume a specific functional form for the interaction, such as a bilinear interaction. Theory is seldom specific enough to provide a functional form for an interaction, however, so a more exploratory, diagnostic approach may often be required. Bauer (2005) proposed a semiparametric approach that allows for the estimation of interaction effects of unknown functional form among latent variables. A structural equation mixture model (SEMM) is first fit to the data. Then an approximation of the interaction is obtained by aggregating over the mixing components. A simulation study is used to examine the performance of this semiparametric approach to two parametric approaches: the latent moderated structures approach (Klein & Moosbrugger, 2000) and the unconstrained product-indicator approach (Marsh, Wen, & Hau, 2004). Data were generated from four functional forms: main effects only, quadratic trend, bilinear interaction, and exponential interaction. Estimates of bias and root mean squared error of approximation were calculated by comparing the surface used to generate the data and the model-implied surface constructed from each approach. As expected, the parametric approaches were more efficient than the SEMM. For the main effects model, bias was similar for both the SEMM and parametric approaches. For the bilinear interaction, the parametric approaches provided nearly identical results, although the SEMM approach was slightly more biased. When the parametric approaches assumed a bilinear interaction and the data were generated from a quadratic trend or an exponential interaction, the parametric approaches generated biased estimates of the true surface. The SEMM approach approximated the true data generation surface with a similarly low level of bias for all the nonlinear surfaces. For example, Figure 1 shows the true surface for the bilinear interaction along with the SEMM estimated average surface. The results suggest that the SEMM approach can provide a relatively unbiased approximation to variety of nonlinear relationships among latent variables. PMID- 26736125 TI - Abstract: A Meta-Analysis of the Autocorrelation in Single Case Designs. AB - Single case design (SCD) experiments in the behavioral sciences utilize just one participant from whom data is collected over time. This design permits causal inferences to be made regarding various intervention effects, often in clinical or educational settings, and is especially valuable when between-participant designs are not feasible or when interest lies in the effects of an individualized treatment. Regression techniques are the most common quantitative practice for analyzing time series data and provide parameter estimates for both treatment and trend effects. However, the presence of serially correlated residuals, known as autocorrelation, can severely bias inferences made regarding these parameter estimates. Despite the severity of the issue, few researchers test or correct for the autocorrelation in their analyses. Shadish and Sullivan (in press) recently conducted a meta-analysis of over 100 studies in order to assess the prevalence of the autocorrelation in the SCD literature. Although they found that the meta-analytic weighted average of the autocorrelation was close to zero, the distribution of autocorrelations was found to be highly heterogeneous. Using the same set of SCDs, the current study investigates various factors that may be related to the variation in autocorrelation estimates (e.g., study and outcome characteristics). Multiple moderator variables were coded for each study and then used in a metaregression in order to estimate the impact these predictor variables have on the autocorrelation. This current study investigates the autocorrelation using a multilevel meta-analytic framework. Although meta analyses involve nested data structures (e.g., effect sizes nested within studies nested within journals), there are few instances of meta-analysts utilizing multilevel frameworks with more than two levels. This is likely attributable to the fact that very few software packages allow for meta-analyses to be conducted with more than two levels and those that do allow this provide sparse documentation on how to implement these models. The proposed presentation discusses methods for carrying out a multilevel meta-analysis. The presentation also discusses the findings from the metaregression on the autocorrelation and the implications these findings have on SCDs. PMID- 26736126 TI - Abstract: An International Comparison of Private and Public Schools Using Multilevel Propensity Score Methods and Graphics. AB - As can be seen from the recent Special Issue of MBR on propensity score analysis (PSA) methods, the use of PSA has gained increasing popularity for estimating causal effects in observational studies. However, PSA use with multilevel or clustered data has been limited, and to date there seems to have been no development of specialized graphics for such data. This paper introduces the multilevelPSA ( http://multilevelPSA.r-forge.r-project.org ) package for R that provides cluster-based functions for estimating propensity scores as well as graphics to exhibit results for multilevel data. This work extends to the multilevel case the framework for visualizing propensity score analysis introduced by Helmreich and Pruzek (2009). International data from the Programme for International Student Assessment (Organization for Economic Co-operation and Development, 2009) are comprehensively examined to compare private with public schools on reading, mathematics, and science outcomes after adjusting for covariate differences in the multilevel context. Particularly for analyses of large data sets, focusing on statistical significance is limiting. As can readily be seen, overall results favor "private" over "public" schools, at least for end of secondary school math achievement. But the graphics provide a more nuanced understanding of the nature and magnitude of adjusted differences for countries. Furthermore, the graphics are readily interpreted by a nontechnical audience. Broadly speaking, it is seen that modern graphics can enhance and extend conventional numerical summaries by focusing on details of what data have to say for multilevel comparisons of many countries based on propensity score methods. PMID- 26736127 TI - Abstract: Inference and Interval Estimation for Indirect Effects With Latent Variable Models. AB - Models specifying indirect effects (or mediation) and structural equation modeling are both popular in the social sciences. Yet relatively little research has compared methods that test for indirect effects among latent variables and provided precise estimates of the effectiveness of different methods. This simulation study provides an extensive comparison of methods for constructing confidence intervals and for making inferences about indirect effects with latent variables. We compared the percentile (PC) bootstrap, bias-corrected (BC) bootstrap, bias-corrected accelerated (BC a ) bootstrap, likelihood-based confidence intervals (Neale & Miller, 1997), partial posterior predictive (Biesanz, Falk, and Savalei, 2010), and joint significance tests based on Wald tests or likelihood ratio tests. All models included three reflective latent variables representing the independent, dependent, and mediating variables. The design included the following fully crossed conditions: (a) sample size: 100, 200, and 500; (b) number of indicators per latent variable: 3 versus 5; (c) reliability per set of indicators: .7 versus .9; (d) and 16 different path combinations for the indirect effect (alpha = 0, .14, .39, or .59; and beta = 0, .14, .39, or .59). Simulations were performed using a WestGrid cluster of 1680 3.06GHz Intel Xeon processors running R and OpenMx. Results based on 1,000 replications per cell and 2,000 resamples per bootstrap method indicated that the BC and BC a bootstrap methods have inflated Type I error rates. Likelihood-based confidence intervals and the PC bootstrap emerged as methods that adequately control Type I error and have good coverage rates. PMID- 26736128 TI - Abstract: Sample Size Planning for Latent Curve Models. AB - When designing a study that uses structural equation modeling (SEM), an important task is to decide an appropriate sample size. Historically, this task is approached from the power analytic perspective, where the goal is to obtain sufficient power to reject a false null hypothesis. However, hypothesis testing only tells if a population effect is zero and fails to address the question about the population effect size. Moreover, significance tests in the SEM context often reject the null hypothesis too easily, and therefore the problem in practice is having too much power instead of not enough power. An alternative means to infer the population effect is forming confidence intervals (CIs). A CI is more informative than hypothesis testing because a CI provides a range of plausible values for the population effect size of interest. Given the close relationship between CI and sample size, the sample size for an SEM study can be planned with the goal to obtain sufficiently narrow CIs for the population model parameters of interest. Latent curve models (LCMs) is an application of SEM with mean structure to studying change over time. The sample size planning method for LCM from the CI perspective is based on maximum likelihood and expected information matrix. Given a sample, to form a CI for the model parameter of interest in LCM, it requires the sample covariance matrix S, sample mean vector [Formula: see text], and sample size N. Therefore, the width (w) of the resulting CI can be considered a function of S, [Formula: see text], and N. Inverting the CI formation process gives the sample size planning process. The inverted process requires a proxy for the population covariance matrix Sigma, population mean vector MU, and the desired width omega as input, and it returns N as output. The specification of the input information for sample size planning needs to be performed based on a systematic literature review. In the context of covariance structure analysis, Lai and Kelley (2011) discussed several practical methods to facilitate specifying Sigma and omega for the sample size planning procedure. PMID- 26736129 TI - Abstract: Within-Person Processes Leading to Quarrelsome Behavior in Interactions Between Romantic Partners. AB - This study used multilevel structural equation modeling (MSEM; Preacher, Zyphur, & Zhang, 2010) to examine within-person processes that give rise to quarrelsome behavior in interactions between romantic partners. Based on Interpersonal Theory and Adult Attachment Theory, we hypothesized that a person's quarrelsome behavior would be predicted by (a) the direct effect of the partner's quarrelsome behavior, (b) an indirect effect mediated by the person's perceptions of the partner's quarrelsome behavior, and (c) an indirect effect mediated by the person's felt security. Using an event-contingent recording methodology, both partners in 93 cohabiting community couples reported independently on their quarrelsome behavior, felt security, and perceptions of the partner's quarrelsome behavior in interactions with each other during a 20-day period. Findings (see Figure 1 ) supported a direct effect of partner's increases in quarrelsome behavior on person's increases in quarrelsome behavior. This association was partly accounted for by perceptions of partner's behavior and felt security following these perceptions. The more a person perceived the partner as engaging in quarrelsome behavior, the more the person engaged in quarrelsome behavior [indirect effect = .016, 95% CI (.009 - .022)]. Furthermore, the person's perception of greater quarrelsomeness in the partner's behavior was associated with decreases in the person's felt security, which in turn were related to increases in a person's quarrelsome behavior [indirect effect = .009, 95% CI (.005 - .013)]. No gender differences were found. Findings indicate that a partner's increase in quarrelsome behavior is partly related to a person's increase in quarrelsome behavior in part to the extent that the person perceives the behavior as quarrelsome and consequently feels insecure during the interaction. Findings illustrate an application of MSEM for assessing multilevel mediation in the dyadic context. Moreover, the results suggest that theory and therapeutic interventions should consider interpersonal perceptions as the first link in the chain of affective and behavioral reactions to the interpersonal behaviors of others. PMID- 26736130 TI - Abstract: Evaluation of Test Statistics for Robust Structural Equation Modeling With Nonnormal Missing Data. AB - Traditional structural equation modeling (SEM) techniques have trouble dealing with incomplete and/or nonnormal data that are often encountered in practice. Yuan and Zhang (2011a) developed a two-stage procedure for SEM to handle nonnormal missing data and proposed four test statistics for overall model evaluation. Although these statistics have been shown to work well with complete data, their performance for incomplete data has not been investigated in the context of robust statistics. Focusing on a linear growth curve model, a systematic simulation study is conducted to evaluate the accuracy of the parameter estimates and the performance of five test statistics including the naive statistic derived from normal distribution based maximum likelihood (ML), the Satorra-Bentler scaled chi-square statistic (RML), the mean- and variance adjusted chi-square statistic (AML), Yuan-Bentler residual-based test statistic (CRADF), and Yuan-Bentler residual-based F statistic (RF). Data are generated and analyzed in R using the package rsem (Yuan & Zhang, 2011b). Based on the simulation study, we can observe the following: (a) The traditional normal distribution-based method cannot yield accurate parameter estimates for nonnormal data, whereas the robust method obtains much more accurate model parameter estimates for nonnormal data and performs almost as well as the normal distribution based method for normal distributed data. (b) With the increase of sample size, or the decrease of missing rate or the number of outliers, the parameter estimates are less biased and the empirical distributions of test statistics are closer to their nominal distributions. (c) The ML test statistic does not work well for nonnormal or missing data. (d) For nonnormal complete data, CRADF and RF work relatively better than RML and AML. (e) For missing completely at random (MCAR) missing data, in almost all the cases, RML and AML work better than CRADF and RF. (f) For nonnormal missing at random (MAR) missing data, CRADF and RF work better than AML. (g) The performance of the robust method does not seem to be influenced by the symmetry of outliers. PMID- 26736132 TI - Controlled Fabrication of Silk Protein Sericin Mediated Hierarchical Hybrid Flowers and Their Excellent Adsorption Capability of Heavy Metal Ions of Pb(II), Cd(II) and Hg(II). AB - Fabrication of protein-inorganic hybrid materials of innumerable hierarchical patterns plays a major role in the development of multifunctional advanced materials with their improved features in synergistic way. However, effective fabrication and applications of the hybrid structures is limited due to the difficulty in control and production cost. Here, we report the controlled fabrication of complex hybrid flowers with hierarchical porosity through a green and facile coprecipitation method by using industrial waste natural silk protein sericin. The large surface areas and porosity of the microsize hybrid flowers enable water purification through adsorption of different heavy metal ions. The high adsorption capacity depends on their morphology, which is changed largely by sericin concentration in their fabrication. Superior adsorption and greater selectivity of the Pb(II) ions have been confirmed by the characteristic growth of needle-shaped nanowires on the hierarchical surface of the hybrid flowers. These hybrid flowers show excellent thermal stability even after complete evaporation of the protein molecules, significantly increasing the porosity of the flower petals. A simple, cost-effective and environmental friendly fabrication method of the porous flowers will lead to a new solution to water pollution required in the modern industrial society. PMID- 26736133 TI - Catalytic Promiscuity of Ancestral Esterases and Hydroxynitrile Lyases. AB - Catalytic promiscuity is a useful, but accidental, enzyme property, so finding catalytically promiscuous enzymes in nature is inefficient. Some ancestral enzymes were branch points in the evolution of new enzymes and are hypothesized to have been promiscuous. To test the hypothesis that ancestral enzymes were more promiscuous than their modern descendants, we reconstructed ancestral enzymes at four branch points in the divergence hydroxynitrile lyases (HNL's) from esterases ~ 100 million years ago. Both enzyme types are alpha/beta-hydrolase-fold enzymes and have the same catalytic triad, but differ in reaction type and mechanism. Esterases catalyze hydrolysis via an acyl enzyme intermediate, while lyases catalyze an elimination without an intermediate. Screening ancestral enzymes and their modern descendants with six esterase substrates and six lyase substrates found higher catalytic promiscuity among the ancestral enzymes (P < 0.01). Ancestral esterases were more likely to catalyze a lyase reaction than modern esterases, and the ancestral HNL was more likely to catalyze ester hydrolysis than modern HNL's. One ancestral enzyme (HNL1) along the path from esterase to hydroxynitrile lyases was especially promiscuous and catalyzed both hydrolysis and lyase reactions with many substrates. A broader screen tested mechanistically related reactions that were not selected for by evolution: decarboxylation, Michael addition, gamma-lactam hydrolysis and 1,5-diketone hydrolysis. The ancestral enzymes were more promiscuous than their modern descendants (P = 0.04). Thus, these reconstructed ancestral enzymes are catalytically promiscuous, but HNL1 is especially so. PMID- 26736134 TI - Relationship Between Near-Infrared Spectroscopy and Transabdominal Ultrasonography: Noninvasive Monitoring of Intestinal Function in Neonates. AB - BACKGROUND: Near-infrared spectroscopy (NIRS) has the potential to continuously and noninvasively monitor intestinal function. This technology may be valuable because among neonates, intestinal maturity is highly variable and difficult to assess based solely on clinical signs. The aim of this study was to determine if there is an association between NIRS-based StO2 measurements and peristaltic activity assessed by transabdominal ultrasonography (US). MATERIAL/METHODS: Nineteen neonates of gestational age >32 weeks were categorized according to "no/low" versus "normal/hyperactive" motility levels, based on blinded US scan results. StO2 was recorded every 2 s for 24 h, following the ultrasound recording. Differences between the resulting estimates of average StO2 (bias of fits) and goodness-of-fit (residuals) were evaluated. RESULTS: Newborns with normal/hyperactive motility had higher mean StO2 than newborns with no/low motility (72.3+/-4.4 vs. 65.5+/-7.9, p<0.05, F=5.65). Residual errors were not significantly different between the 2 groups (p=0.213, F=0.213). A multivariate linear regression model using the means, residuals, and pairwise products of both, demonstrated more significant separation (0.47+/-0.26 vs. -0.24+/-0.33, p<0.01, F=27.4). A non-linear variant of the multivariate linear regression model demonstrated greatest separation (0.68+/-0.24 vs. -0.49+/-0.53, p<0.01, F=41.9). CONCLUSIONS: This is the first study to demonstrate an association between NIRS based StO2 measurements and peristaltic activity visualized by ultrasound imaging. NIRS may offer a continuous, noninvasive method to assess motility. This may have significant implications in premature infants at risk for feeding intolerance or necrotizing enterocolitis. PMID- 26736135 TI - Metastatic testicular cancer presenting with liver and kidney dysfunction treated with modified BEP chemotherapy combined with continuous hemodiafiltration and rasburicase. AB - A 25-year-old man was admitted to our hospital complaining of right scrotal pain and upper abdominal pain. A computed tomographic scan indicated a right scrotal mass, a huge liver mass, and multiple lung masses, although there was no enlarged retroperitoneal lymph node swelling. Laboratory tests showed severe liver and kidney dysfunction and high levels of serum alpha-fetoprotein (11,997 ng/ml). Although needle biopsies of the testicular and liver masses were performed, the tissues were insufficient for a pathological diagnosis. As liver and kidney function worsened, we started chemotherapy with bleomycin, etoposide, and cisplatin (BEP chemotherapy), which was modified because of the liver and renal dysfunction. We also used continuous hemodiafiltration and rasburicase to prevent tumor lysis syndrome. After induction of chemotherapy, the liver and kidney dysfunction improved immediately and the high orchiectomy was performed on day 8 after chemotherapy. The pathological diagnosis was a yolk sac tumor. He underwent four courses of the BEP regimen and five courses of the TIN regimen (paclitaxel, ifosphamide, and nedaplatin), followed by the resection of liver metastases. There was no evidence of viable cells in the resected liver and no recurrence was evident at 1 year postoperatively. PMID- 26736136 TI - Efficacy and safety of vinorelbine in heavily pretreated recurrent/metastatic head and neck squamous cell carcinoma patients. AB - The aim of this study was to evaluate the efficacy and tolerance of vinorelbine as a single agent in the treatment of recurrent/metastatic head and neck squamous cell carcinoma. Patients were treated with oral or intravenous vinorelbine according to the pluridisciplinary tumor board's decision. Efficacy and safety outcomes were analyzed retrospectively. Twenty-three patients were included in the study. Sixteen patients (69%) had received at least two previous lines of chemotherapy. The disease control rate was 19%. The median progression-free survival was 2.6 months and the median overall survival was 3.4 months. The rate of grade 3-4 side effects was low (13%). Only one patient discontinued treatment because of side effects. Vinorelbine seems to be a well-tolerated regimen in heavily pretreated patients. However, this regimen does not seem to be efficient enough to be recommended. PMID- 26736137 TI - Incorporating Sulfur Inside the Pores of Carbons for Advanced Lithium-Sulfur Batteries: An Electrolysis Approach. AB - We have developed an electrolysis approach that allows effective and uniform incorporation of sulfur inside the micropores of carbon nanosheets for advanced lithium-sulfur batteries. The sulfur-carbon hybrid can be prepared with a 70 wt % sulfur loading, in which no nonconductive sulfur agglomerations are formed. Because the incorporated sulfur is electrically connected to the carbon matrix in nature, the hybrid cathode shows excellent electrochemical performance, including a high reversible capacity, good rate capability, and good cycling stability, as compared to one prepared using the popular melt-diffusion method. PMID- 26736138 TI - Analysis of Y-chromosome STRs in Chile confirms an extensive introgression of European male lineages in urban populations. AB - We analyzed the Y chromosome haplotypes (Yfiler) of 978 non-related Chilean males grouped in five sampling regions (Iquique, Santiago de Chile, Concepcion, Temuco and Punta Arenas) covering main geo-political regions. Overall, 803 different haplotypes and 688 singletons were observed. Molecular diversity was moderately lower than in other neighboring countries (e.g. Argentina); and AMOVA analysis on Y-STR haplotypes showed that among variation within Chile accounted for only 0.25% of the total variation. Punta Arenas, in the southern cone, showed the lowest haplotype diversity, and discrimination capacity, and also the highest matching probability of the five Chilean samples, probably reflecting its more marked geographic isolation compared to the other regions. Multidimensional scaling (MDS) analysis based on RST genetic distances suggested a close proximity of Chilean Y-chromosome profiles to European ones. Consistently, haplogroups inferred from Y-STR profiles revealed that the Native American component constituted only 8% of all the haplotypes, and this component ranged from 5% in the Centre of the country to 9-10% in the South and 13% in the North, which is in good agreement with the distribution of Native American communities in these regions. AMOVA computed on inferred haplogroups confirmed the very low among variation observed in Chilean populations. The present project provides the first Chilean dataset to the international Y-chromosome STR Haplotype Reference Database (YHRD) and it is also the first reference database for Y-chromosome forensic casework of the country. PMID- 26736140 TI - Evaluating the Operative Note: A Reanalysis of SAFE-OR. PMID- 26736139 TI - Prevalence of human cell material: DNA and RNA profiling of public and private objects and after activity scenarios. AB - Especially when minute evidentiary traces are analysed, background cell material unrelated to the crime may contribute to detectable levels in the genetic analyses. To gain understanding on the composition of human cell material residing on surfaces contributing to background traces, we performed DNA and mRNA profiling on samplings of various items. Samples were selected by considering events contributing to cell material deposits in exemplary activities (e.g. dragging a person by the trouser ankles), and can be grouped as public objects, private samples, transfer-related samples and washing machine experiments. Results show that high DNA yields do not necessarily relate to an increased number of contributors or to the detection of other cell types than skin. Background cellular material may be found on any type of public or private item. When a major contributor can be deduced in DNA profiles from private items, this can be a different person than the owner of the item. Also when a specific activity is performed and the areas of physical contact are analysed, the "perpetrator" does not necessarily represent the major contributor in the STR profile. Washing machine experiments show that transfer and persistence during laundry is limited for DNA and cell type dependent for RNA. Skin conditions such as the presence of sebum or sweat can promote DNA transfer. Results of this study, which encompasses 549 samples, increase our understanding regarding the prevalence of human cell material in background and activity scenarios. PMID- 26736141 TI - Back-to-Front Hemicorporectomy With Double-barreled Wet Colostomy for Treatment of Squamous Cell Carcinoma of a Pressure Ulcer. PMID- 26736142 TI - Developing an Algorithm for Reconstruction of Full Thickness Cheek Defect by Submental Flap. PMID- 26736143 TI - Iatrogenic Parahiatal Hernia With Gastric Herniation and Necrosis after Robotic Hiatal Hernia Repair. PMID- 26736144 TI - The Painful Diversity of Proctitis in the Modern Era. PMID- 26736145 TI - Surgical Attending Practice Patterns Regarding the Timing of Tracheostomy. PMID- 26736146 TI - The Effect of Statin Use on Outcomes after Trauma. PMID- 26736147 TI - Nontraumatic Splenic Rupture: A Surgical Emergency. PMID- 26736148 TI - Conservative Management of Pneumoperitonitis after Percutaneous Transhepatic Insertion of Metallic Biliary Stents. PMID- 26736149 TI - Massive Duodenal Bleeding Secondary to Vena Cava Interruption and Azygos Vein Continuation. PMID- 26736150 TI - An Unusual Case of Lymphadenopathy Due to Traumatic Foreign-Body-Associated Granulomatous Lymphadenitis. PMID- 26736151 TI - Occult Sternal Fractures Identified by Bone Scintigraphy Occult Sternal Fractures. PMID- 26736152 TI - Recalcitrant Hypocalcemia after Thyroidectomy in Patients Post Sleeve Gastrectomy -Challenges in Management. PMID- 26736153 TI - Rate of Sentinel Lymph Node Biopsy for T2 and T3 Cutaneous Melanoma at an Independent Academic Medical Center: Observations and Lessons Learned as Part of a Quality Improvement Project. PMID- 26736154 TI - Repair of Large Sliding Inguinal Hernias. AB - Sliding inguinal hernias are often unexpected intra-operative findings, and repair of which can be technically challenging. A number of repair techniques have been described. The author modified a technique based on an approach described by Bevan. The purpose of our study is to describe this modified Bevan technique for repair of sliding inguinal hernias and report its efficacy in a series of patients. We retrospectively reviewed all patients with open inguinal hernia repairs performed by a single surgeon from August 2007 to April 2013 for sliding indirect hernias using the modified Bevan technique. Patient records were reviewed for demographics, hernia characteristics, complications, admission status, length of stay, and complications. There were 25 patients eligible for our review (male = 25, mean age = 49 years). All sliding hernias were indirect, none were bilateral, and two were incarcerated. The sliding component involved the bladder and perivesical fat (n = 12), sigmoid colon (n = 10), and the cecum and appendix (n = 3). Eighteen patients were treated as outpatients; seven patients were admitted with a mean stay of 2.2 days. Complications included intra operative bleeding (n = 1), subcutaneous wound hematoma (n = 1), scrotal seroma (n = 1), transient orchialgia (n = 1), and ileus (n = 1). All patients were seen postoperatively for short-term follow-up with no hernia recurrences. Thirteen patients were available for long-term follow-up (mean = 13.6 months); all had no hernia recurrences. The modification of Bevan's technique for repair of large sliding hernias worked well in our series. PMID- 26736155 TI - Role of Elevated Aminotransferases in ICU Patients with Rhabdomyolysis. AB - To evaluate whether patients with rhabdomyolysis and serum alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) higher than 1000 IU/L had higher mortality that patients with low aminotransferases. Retrospective analysis of intensive care unit patients with rhabdomyolysis [creatine kinase (CK) higher than 5000 IU/L]. Patients were classified in two groups: low aminotransferases group, when AST and ALT were equal or lower to 1000 IU/L, and elevated aminotransferases group, when AST or ALT was above 1000 IU/L. Forty-six out of 189 patients included in the analysis (24.3%) had elevated aminotransferases. The mortality of patients with rhabdomyolysis was 25.9 per cent, being higher in patients with elevated aminotransferases compared with patients with low aminotransferases (60.9% vs 14.7%; P < 0.001). Mortality stratified by quartiles of CK in patients with low aminotransferases was independent of the level of CK (P = 0.67). Logistic regression analysis showed that the independent variables associated with mortality were Simplified Acute Physiology Score II [1.11 (1.07-1.16) for each point of increase, P < 0.001], the international normalized ratio value [4.2 (1.6-10.7) for each point of increase, P = 0.003], and the need of renal replacement therapy [5.4 (1.7-17.2), P = 0.004]. Patients with rhabdomyolysis with elevated serum aminotransferases had higher mortality than patients with low serum aminotransferase levels. PMID- 26736156 TI - Impact of Postoperative Venous Thromboembolism on Postoperative Morbidity, Mortality, and Resource Utilization after Hepatectomy. AB - The impact of venous thromboembolism (VTE) after hepatectomy on patient morbidity, mortality, and resource usage remains poorly defined. Better understanding of thromboembolic complications is needed to improve perioperative management and overall outcomes. About 3973 patients underwent hepatectomy within NSQIP between 2005 and 2008. Patient characteristics, operative features, and postoperative correlates of VTE were compared with identify risk factors for VTE and to assess its overall impact on postoperative outcomes. Overall incidence of postoperative VTE was 2.4 per cent. Risk factors for postoperative VTE included older age, male gender, compromised functional status, degree of intraoperative blood transfusion, preoperative albumin level (all P < 0.05), and extent of hepatectomy (P = 0.004). Importantly, major postoperative complications, including acute renal failure, pneumonia, sepsis, septic shock, reintubation, prolonged ventilation, cardiac arrest, and reoperation were all associated with higher rates of VTE (all P < 0.05). Operative mortality was increased among patients with VTE (6.5% vs 2.4%, P = 0.03), and patients with VTE had a 2-fold increase in hospital length of stay (12.0 vs 6.0 days, P < 0.001). Postoperative VTE remains a significant source of morbidity, mortality, and increased resource usage after hepatectomy in the United States. Routine aggressive VTE prophylaxis measures are imperative to avoid development of VTE among patients requiring hepatectomy. PMID- 26736157 TI - Is 6-Month Radiologic Imaging Necessary after Benign Breast Biopsy? Review of Literature and Multicenter Experience. AB - A retrospective study of 786 patients was conducted to determine the necessity of a 6-month interval study after a benign stereotactic or ultrasound-guided breast biopsy. These results were compared with those of other centers. After reviewing the data, we found few patients developed cancer after their original biopsy, and for those that did, the 6-month study did not contribute to an earlier diagnosis. Those short-term interval radiologic studies that were interpreted as concerning were all benign when biopsied. A 6-month study contributes to higher costs of health care and can be inconvenient, painful, and anxiety producing to patients. Short-interval follow-up was found to be unnecessary. PMID- 26736158 TI - Postoperative Morbidity in Curative Resection of Gastroesophageal Carcinoma Does Not Impact Long-term Survival. AB - Significant morbidity and mortality have historically been reported for surgical resection of gastric and gastroesophageal junction tumors. We evaluated our experience to determine morbidity and mortality and evaluated demographic and pathologic risk factors associated with postoperative outcome and long-term survival. A retrospective, Institutional Review Board-approved, single institution database identified 102 patients who underwent resection with curative intent for gastroesophageal junction or gastric carcinoma from 2004 to 2012. The method of Kaplan and Meier was used to describe overall survival and estimate median survival. Of 102 patients, 74 were male and 28 were female. Of these, 24 patients were > 70 years of age at surgery (median = 62.9). Forty esophagectomies, 25 total gastrectomies, and 37 subtotal gastrectomies were performed. Two patients died (one esophagectomy and one gastrectomy). Forty-one developed a complication: 17 minor and 35 major, including six anastomotic leaks. Patients with low preoperative albumin (P = 0.01) and increased age (P = 0.05) were associated with having a postoperative complication; extent of nodal dissection (P = 0.48), jejunostomy (0.24), performance status (P = 0.77), type of surgery (P = 0.74), and neoadjuvant therapy (P = 0.24) were not associated. More extensive nodal dissection was associated with a decreased risk of death (P = 0.007). Having any complication (P = 0.20), an anastomotic leak (P = 0.17), worse grade of complication (P = 0.15), presence of feeding jejunostomy tube (P = 0.17), and neoadjuvant therapy (P = 0.30) were not associated with changes in overall survival. Thorough lymph node dissection improves survival without increasing postoperative morbidity. The data advocate for increased lymph node yield and close attention to nutritional support in gastroesophageal carcinoma patients. PMID- 26736159 TI - Does Transumbilical Incision Influence Surgical Site Infection Rates of the Laparoscopic Sigmoidectomy and Anterior Resection? AB - Laparoscopic surgery is widespread and is safe and effective for the management of patients with colorectal cancer. However, surgical site infection (SSI) remains an unresolved complication. The present study investigated the comparative effect of supraumbilical incision versus transumbilical incision (TU) on the incidence of SSI in patients undergoing laparoscopic surgery for colon cancer. Medical records from patients with colorectal cancer who underwent laparoscopic sigmoid and rectosigmoid colon surgeries with either supraumbilical incision (n = 150) or TU (n = 150) were retrospectively reviewed. There was no difference in demographics, comorbidities, or operative variables between the two groups. The transumbilical group and the supraumbilical group were comparable with regards to overall SSI (6.0% vs 4.0%; P = 0.4062), superficial SSI (6.0% vs 3.3%; P = 0.2704), and deep SSI (0% vs 0.7%; P = 0.2385). SSI developed after laparoscopic sigmoid and rectosigmoid colon cancer surgery in 15 (5.0%) of the 300 patients. Of these superficial SSI, all wounds were in the left lower quadrant incision, and the transumbilical port sites did not become infected. Univariate analysis failed to identify any risk factors for SSI. Avoidance of the umbilicus offers no benefit with regard to SSI compared with TU. PMID- 26736160 TI - Incidence and Operative Excision of Presacral Masses: An Institutional Analysis. AB - Presacral masses are rare lesions that encompass a broad range of pathologic findings. Most presacral masses are benign. The aim of this study was to analyze the clinical presentation, pathology, and surgical treatment of presacral masses at a single academic institution over a decade. In this retrospective study, we reviewed all surgically excised presacral tumors between 2003 and 2013. Clinical and pathologic data were recorded. Thirteen patients had surgical excision of a presacral mass. The median age was 42 years (standard deviation +/- 19.7) and average follow-up was 11.9 months (standard deviation +/- 17.5). The majority of patients were symptomatic. Forty-six per cent (6/13) had sacral or rectal pain. Thirty-eight per cent (5/13) of patients had a palpable mass on digital rectal examination. Sixty-nine per cent of patients had an MRI, 84.6 per cent a CT, and 61.5 per cent multimodality imaging. Most presacral masses were benign (10/13, 77%). Twenty-three per cent (3/13) were malignant. A majority were excised via posterior approach (9/13, 69%), but 31 per cent (4/13) required an anterior or combined approach. Presacral masses are rare, even at a high-volume tertiary care center. They are commonly evaluated with a multiple imaging modalities, are most likely benign, and can be excised via posterior approach. PMID- 26736161 TI - The Influence of Resected Gastric Weight upon Weight Loss after Sleeve Gastrectomy. AB - Bariatric surgery is an effective and enduring treatment for obesity. Sleeve gastrectomy (SG) has emerged as an increasingly prevalent surgical intervention. Further investigation is required to determine optimal standardization of SG. Data were collected prospectively for 64 patients who underwent a laparoscopic vertical SG between December 2010 and February 2013 at a single academic institution. Demographic, intraoperative, and postoperative (postop) data were collected for all patients including weighing each resected stomach. The total resected gastric weight varied widely. Preoperatively, patients in the upper tercile for resected gastric weight were more likely to be male (lower 10%, middle 23%, upper 52%, P = 0.006) and had greater initial weights (lower 255.9%, middle 245.1%, upper 280.0%, P = 0.019). The resected gastric weight (g) varied by tercile (mean of all, 131.24 +/- 39.8; lower, 93.9 +/- 10.9; middle, 127.4 +/- 11.7; upper 172.7 +/- 37.9, P = 0.000). Patients were followed for 1-year postop with follow-up data for 94 per cent (60/64) of participants. Per cent excess weight loss (EWL) was obtained at three, six, and 12 months postop. At 12 months, there was a trend toward increased per cent EWL in the upper tercile (lower 61.1%, middle 54.1%, upper 90.5%, P = 0.057). In conclusion, while the amount of gastric sleeve resected can vary, this study shows that intraoperative assessment of resected sleeve weight can help evaluate adequacy of resection. Improved 12 month per cent EWL in patients with greater resected tissue demonstrate potentially improved outcomes. PMID- 26736162 TI - Incidence of Ostomy Site Incisional Hernias after Stoma Closure. AB - This study sought to evaluate the incidence of ostomy site incisional hernias after stoma reversal at a single institution. This is a retrospective analysis from 2001 to 2011 evaluating the following demographics: age, gender, indication for stoma, urgent versus elective operation, time to closure, total follow-up time, the incidence of and reoperation for stoma incisional hernia, diabetes, postoperative wound infection, smoking status within six months of surgery, body mass index, and any immunosuppressive medications. A total of 365 patients were evaluated. The median follow-up time was 30 months. The clinical hernia rate was 19 percent. Significant risk factors for hernia development were age, diabetes, end colostomies, loop colostomies, body mass index >30, and undergoing an urgent operation. The median time to clinical hernia detection was 32 months. Sixty-four percent of patients required surgical repair of their stoma incisional hernia. A significant number of patients undergoing stoma closure developed an incisional hernia at the prior stoma site with the majority requiring definitive repair. These hernias are a late complication after stoma closure and likely why they are under-reported in the literature. PMID- 26736163 TI - Left-sided Gallbladder in the Era of Laparoscopic Cholecystectomy: A Single center Experience. AB - The malposition of gallbladder under the liver segment III, defined as left-sided gallbladder (LSG), is an unexpected situation for the laparoscopic surgeon. The purpose of this study is to present our experience in treating patients with cholecystitis and LSG discovered incidentally during laparoscopic surgical procedure. Between 1993 and 2009, 5569 patients underwent laparoscopic cholecystectomy in our surgical department. Their records were reviewed and seven patients revealed having LSG (0.12%). Analysis parameters included demographic data, diagnostic methods, mode of surgery, and postoperative outcome. Mean follow up was 140 months. Of the seven patients, five were women. Mean patient age was 56.7 years. All patients were referred to our department with clinical symptoms of classic cholelithiasis and the diagnosis was established in all of them during surgery. Laparoscopic cholecystectomy was successful in five patients, while in two patients, a conversion to open procedure was needed. A postoperative complication, i.e., biliary leakage was registered in one patient, which was treated successfully. Laparoscopic cholecystectomy is safe even in LSG, but the surgeon must consider the possibility for more anatomical anomalies, adjust the technique of dissection, and must not hesitate, if in doubt, to strive for conversion to open procedure to avoid serious complications. PMID- 26736164 TI - Outcomes of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Mesothelioma: Experience of a Peritoneal Surface Malignancy Center. AB - Diffuse malignant peritoneal mesothelioma (DMPM) is an uncommon malignancy, which can be difficult to treat. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have evolved as the treatment of choice when complete cytoreduction is to be achieved. This study reports the outcomes of CRS/HIPEC for peritoneal mesothelioma performed in a center for peritoneal surface malignancy. A retrospective analysis of a prospective database of 389 CRS/HIPEC procedures identified 23 patients who underwent CRS/HIPEC for DMPM from 1999 to 2014. Gender, age at diagnosis, age at surgery, previous surgeries, follow-up time, peritoneal cancer index (PCI) score, completeness of cytoreduction (CC), pathology, and overall survival (OS) were analyzed. The univariate analysis was used to determine the prognostic value of age, gender, neoadjuvant chemotherapy, histopathology of the tumor, PCI, CC, and lymph node status on survival. Mean follow-up time from surgery was 31 months (range = 0.5 124). The median PCI score was 28, and 77 per cent had PCI >=20. CC 0-1 was achieved in 65 per cent of cases. One- and 5-year actuarial OS rates from diagnosis were 86 per cent and 60 per cent, respectively. One- and 5-year actuarial OS from HIPEC was 70 per cent and 64 per cent, respectively. The univariate analysis showed that the CC was the only significant prognostic factor. Patients with DMPM may achieve long-term survival when treated with CRS/HIPEC. The CC is the most significant prognostic factor for long-term survival. PMID- 26736165 TI - Two-center Analysis of Long-term Outcomes after High Ligation Inguinal Hernia Repair in Adolescents. AB - High ligation of the inguinal hernia sac is standard practice for many pediatric surgeons in postpubertal adolescents. Most adult surgeons do not use this technique to repair indirect inguinal hernias because of concerns for higher recurrence rates compared with mesh repairs. Therefore, we examined long-term outcomes of adolescent high ligation hernia repair performed by pediatric surgeons. Telephone surveys were conducted on children over 12 years old at the time of repair, and patients and/or their parents were contacted 18 months postrepair. Patients were identified from two institutions between 1998 and 2010. The incidences of reoperation, recurrence, presence of bulge, chronic pain, or numbness were determined. A total of 210 patients (40.7% response rate) were available for phone interviews at 18.6 to 159.5 months postrepair. Mean age was 14.6 +/- 1.8 (range: 12.0-19.0 years). Fourteen patients had pain (6.7%) and five had numbness (2.4%). There were four (1.9%) patients with a second operation, two of which confirmed a recurrent hernia. Three patients expressed concern about possible recurrence. Two report a bulge, but have not been evaluated. Pediatric hernia repair with high sac ligation appears effective in patients anatomically similar to adults with low recurrence rate and low incidence of chronic symptoms. These data suggest that prospective trials on the adequacy of high ligation in adults are warranted. PMID- 26736166 TI - Lymph Node Size Alone Is Not an Accurate Predictor of Metastases in Rectal Cancer: A Node-for-Node Comparative Study of Specimens and Histology. AB - Although size criteria have been proposed to identify lymph node metastases in patients with rectal cancer, size may not be an accurate predictor. Specimens from consecutive rectal cancer patients who underwent curative-intent radical surgery were examined. The long and short axes of lymph nodes were measured on the glass slides using micrometer calipers. The pathologic diagnosis was used as the reference. The diagnostic accuracy of metastatic status according to lymph node size was evaluated. Overall, 1283 lymph nodes from 78 patients were reviewed. The metastatic rate correlates with the length of both the long and short axes. However, metastases were present even in 1-mm lymph nodes, and the metastatic rate exceeds 5 per cent in lymph nodes measuring 3 mm along both axes. Cutoff values of >=4 mm and >=3 mm for the long and short axes result in a sensitivity of 76 per cent and 79 per cent, and a specificity of 36 per cent and 33 per cent, respectively, for each axis. Size criteria alone do not accurately predict the N-stage of rectal cancer. Diminutive lymph nodes, which are not seen on imaging studies, can contain metastatic disease. PMID- 26736167 TI - Evaluation of Microvascular Perfusion and Resuscitation after Severe Injury. AB - Achieving adequate perfusion is a key goal of treatment in severe trauma; however, tissue perfusion has classically been measured by indirect means. Direct visualization of capillary flow has been applied in sepsis, but application of this technology to the trauma population has been limited. The purpose of this investigation was to compare the efficacy of standard indirect measures of perfusion to direct imaging of the sublingual microcirculatory flow during trauma resuscitation. Patients with injury severity scores >15 were serially examined using a handheld sidestream dark-field video microscope. In addition, measurements were also made from healthy volunteers. The De Backer score, a morphometric capillary density score, and total vessel density (TVD) as cumulative vessel area within the image, were calculated using Automated Vascular Analysis (AVA3.0) software. These indices were compared against clinical and laboratory parameters of organ function and systemic metabolic status as well as mortality. Twenty severely injured patients had lower TVD (X = 14.6 +/- 0.22 vs 17.66 +/- 0.51) and De Backer scores (X = 9.62 +/- 0.16 vs 11.55 +/- 0.37) compared with healthy controls. These scores best correlated with serum lactate (TVD R(2) = 0.525, De Backer R(2) = 0.576, P < 0.05). Mean arterial pressure, heart rate, oxygen saturation, pH, bicarbonate, base deficit, hematocrit, and coagulation parameters correlated poorly with both TVD and De Backer score. Direct measurement of sublingual microvascular perfusion is technically feasible in trauma patients, and seems to provide real-time assessment of microcirculatory perfusion. This study suggests that in severe trauma, many indirect measurements of perfusion do not correlate with microvascular perfusion. However, visualized perfusion deficiencies do reflect a shift toward anaerobic metabolism. PMID- 26736168 TI - An Innovative Approach for Decreasing Fall Trauma Admissions from Geriatric Living Facilities: Preliminary Investigation. AB - Geriatric living facilities have been associated with a high rate of falls. We sought to develop an innovative intervention approach targeting geriatric living facilities that would reduce geriatric fall admissions to our Level II trauma center. In 2011, a Trauma Prevention Taskforce visited 5 of 28 local geriatric living facilities to present a fall prevention protocol composed of three sections: fall education, risk factor identification, and fall prevention strategies. To determine the impact of the intervention, the trauma registry was queried for all geriatric fall admissions attributed to patients living at local geriatric living facilities. The fall admission rate (total fall admissions/total beds) of the pre-intervention period (2010-2011) was compared with that of the postintervention period (2012-2013) at the 5 intervention and 23 control facilities. A P value < 0.05 was considered statistically significant. From 2010 to 2013, there were 487 fall admissions attributed to local geriatric living facilities (intervention: 179 fall admissions; control: 308 fall admissions). The unadjusted fall rate decreased at intervention facilities from 8.9 fall admissions/bed pre-intervention to 8.1 fall admissions/bed postintervention, whereas fall admission rates increased at control sites from 5.9 to 7.7 fall admissions/bed during the same period [control/intervention odds ratio (OR), 95% confidence interval (CI) = 1.32, 1.05-1.67; period OR, 95%CI = 1.55, 1.18-2.04, P = 0.002; interaction of control/intervention group and period OR 95% CI = 0.68, 0.46-1.00, P = 0.047]. An aggressive intervention program targeting high-risk geriatric living facilities resulted in a statistically significant decrease in geriatric fall admissions to our Level II trauma center. PMID- 26736169 TI - Decision-making framework for the application of in-situ activated carbon amendment to sediment. AB - This study provides a decision-support framework and a design methodology for preliminary evaluation of field application of in-situ activated carbon (AC) amendment to sediment to control the (bio)availability of hydrophobic organic contaminants. The decision-making framework comprises four sequential steps: screening assessment, input parameter determination, model prediction, and evaluation for process optimization. The framework allows the application of state-of-the-art experimental and modeling techniques to assess the effectiveness of the treatment under different field conditions and is designed for application as a part of a feasibility study. Through a stepwise process it is possible to assess the effectiveness of in-situ AC amendment with a proper consideration of different site conditions and application scenarios possible in the field. The methodology incorporates the effect of various parameters on performance including: site-specific kinetic coefficients, varied AC dose and particle size, sediment and AC sorption parameters, and pore-water velocity. The modeling framework allows comparison of design alternatives for treatment optimization and estimation of long-term effectiveness over a period of 10-20 years under slow mass transfer in the field. PMID- 26736170 TI - Genotoxic and cell-transformation effects of multi-walled carbon nanotubes (MWCNT) following in vitro sub-chronic exposures. AB - BEAS-2B cells were sub-chronically exposed (up to 4 weeks) to low doses of multi walled carbon nanotubes (MWCNT, NM403). Genotoxic effects were evaluated using the comet and the micronucleus (MN) assays at three different time-points. The expression of different interleukins (IL) such as IL-1B, IL-6 and IL-8, as well as HO-1 as stress marker, was assessed after 3 weeks treatments. As a hallmark biomarker of cell-transforming ability we used the soft-agar assay, which detects anchorage-independent cell growth. Our results show high levels of intracellular reactive oxygen species (ROS) associated to MWCNT exposure. Nevertheless, an important proportion of these ROS levels seems to be associated to solubilized metals contaminants present in NM403, more than to the internalized MWCNT. No primary DNA damage was obtained in the Comet assay although significant levels of chromosome damage were detected using the micronucleus assay. A significant decrease in the expression of the studied cytokines was observed and significant increases in the number of induced colonies were obtained when the ability of induce anchorage-independent growth was determined. These results show that chromosome damage and reducing inflammatory signalling correlated with an increase in attachment-independent growth associated with sub-chronic MWCNT exposure. PMID- 26736171 TI - Chromium(VI) transport and fate in unsaturated zone and aquifer: 3D Sandbox results. AB - The simulation of Cr(VI) behavior in an unsaturated zone and aquifer, using a 3D experimental set-up were performed to illustrate the distribution, transport and transformation of Cr(VI), and further to reveal the potential harm of Cr(VI) after entering the groundwater. The result indicated that chromium(VI) was transported in the vertical direction, meanwhile, was transported in the horizontal direction under the influence of groundwater flow. The direction and distance away from the pollution source zone had great effect on the chromium(VI) concentration. At the sampling sites near the pollution source zone, there was a sudden increase of chromium(VI) concentration. The concentration of chromium(III) concentration in some random effluent samples was not detected. Chromium had not only transported but also had fraction and specie transformation in the unsaturated zone and aquifer. The relative concentration of residue fraction chromium was decreased with time. The content of Fe-Mn oxide fraction chromium was increased with time. The relative content of exchangeable and carbonate-bound fraction chromium was lower and the content variations were not obvious. Chromium(VI) (91-98%) was first reduced to chromium(III) rapidly. The oxidation reaction occurred later and the relative content of chromium(VI) was increased again. The presence of manganese oxides under favorable soil conditions can promote the reoxidation of Cr(III) to Cr(VI). PMID- 26736172 TI - Facile preparation of highly hydrophilic, recyclable high-performance polyimide adsorbents for the removal of heavy metal ions. AB - To obtain high-performance adsorbents that combine excellent adsorption ability, thermal stability, service life and recycling ability, polyimide (PI)/silica powders were prepared via a facile one-pot coprecipitation process. A benzimidazole unit was introduced into the PI backbone as the adsorption site. The benzimidazole unit induced more hydroxyls onto the silica, which provided hydrophilic sites for access by heavy metal ions. By comprehensively analyzing the effect of hydrophilcity, agglomeration, silica polycondensation, specific surface area and PI crystallinity, 10% was demonstrated to be the most proper feed silica content. The equilibrium adsorption amount (Qe) for Cu(2+) of PI/silica adsorbents was 77 times higher than that of pure PI. Hydrogen chloride (HCl) was used as a desorbent for heavy metal ions and could be decomplexed with benzimidazole unit at around 300 degrees C, which was lower than the glass transition temperature of PI. The complexation and decomplexation process of HCl made PI/silica adsorbents recyclable, and the adsorption ability remained steady for more than 50 recycling processes. As PI/silica adsorbents possess excellent thermal stability, chemical resistance and radiation resistance and hydrophilicity, they have potential as superior recyclable adsorbents for collecting heavy metal ions from waste water in extreme environments. PMID- 26736173 TI - A novel hydrothermal method to convert incineration ash into pollucite for the immobilization of a simulant radioactive cesium. AB - The Fukushima nuclear accident in Japan on March 11, 2011 produced huge amounts of Cs-polluted incineration ashes; conventional solidification methods seem unsuitable for the treatment of large amounts of Cs-polluted ashes. A novel hydrothermal method was developed to directly convert Cs-polluted incineration ash (rice husk ash) into pollucite to immobilize Cs in its crystal structure in situ. Results revealed that pollucite could be synthesized readily over a wide range of added Cs (Cs/Si=0.2-0.6); the addition of more Cs (Cs/Si>=0.5) caused the formation of a small amount of cesium aluminosilicate (CsAlSiO4), which exhibits poor immobilization behavior for Cs. Pollucite could be formed even for a short curing time (1h) or at a low curing temperature (150 degrees C). However, a high curing temperature or a long curing time favored the formation of a pure pollucite. With the added calcium hydroxide, a tough specimen with a flexural strength of approximately 22MPa could be obtained, which suggested that this technology may be applied directly to the solidification of Cs-polluted incineration ashes. Hydrogarnet and tobermorite formations enhanced the strength of the solidified specimens, and meanwhile the formed pollucite was present in a matrix steadily. Leaching test demonstrated that the amount of Cs that leached from the synthesized specimens was very low (0.49*10(-5)-2.31*10(-5)) and even lower than that from the reference hollandite-rich synroc (2.0*10(-2)), although a higher content of Cs was found in the synthesized pollucite specimens (6.0 31.7%) than in the reference (3.7%). Therefore, the hydrothermal conversion of Cs polluted incineration ash into pollucite can be applied to immobilize Cs directly. PMID- 26736174 TI - Metabolism of oxybenzone in a hairy root culture: Perspectives for phytoremediation of a widely used sunscreen agent. AB - Oxybenzone (OBZ), known as Benzophenone-3, is a commonly used UV filter in sun tans and skin protectants, entering aquatic systems either directly during recreational activities or indirectly through wastewater treatment plants discharge. To study the potential degradation capacity of plants for OBZ in phytotreatment, a well-established hairy root culture (Armoracia rusticana) was treated with OBZ. More than 20% of spiked OBZ (100MUM) was eliminated from the medium by hairy roots after 3h of exposure. Two metabolites were identified as oxybenzone-glucoside (OBZ-Glu) and oxybenzone-(6-O-malonyl)-glucoside (OBZ-Mal Glu) by LC-MS/MS and TOF-MS. Formation of these metabolites was confirmed by enzymatic synthesis, as well as enzymatic and alkaline hydrolysis. Incubation with O-glucosyltransferase (O-GT) extracted from roots formed OBZ-Glu; whereas beta-d-Glucosidase hydrolyzed OBZ-Glu. However, alkaline hydrolysis led to cleavage of OBZ-Mal-Glu and yielded OBZ-Glu. In the hairy root culture, an excretion of OBZ-Glu into the growth medium was observed while the corresponding OBZ-Mal-Glu remained stored in root cells over the incubation time. We propose that metabolism of oxybenzone in plants involves initial conjugation with glucose to form OBZ-Glu followed by malonylation to yield OBZ-Mal-Glu. To our best knowledge this first finding presenting the potential of plants to degrade benzophenone type UV filters by phytoremediation. PMID- 26736175 TI - Basilar dolichoectasia and the spontaneous intradural vertebral artery dissection. AB - OBJECT: Basilar dolichoectasia (BD) is an atherosclerotic, a distinct arteriopathy or a chronic-phase dissection characterized by elongation and dilation of the basilar artery. Spontaneous intradural vertebral artery dissection (siVAD) is an important cause of stroke in young and middle-aged people. It is hypothesized that the BD and the siVAD might partially share aetiologies and this study aimed to examine the relationship. METHODS: This study compared clinical and radiological characteristics in 93 patients with siVAD with 93 controls. Ectasia was defined as basilar artery diameter >4.5 mm and dolichosis, as either basilar artery bifurcation above the suprasellar cistern or lateral to the margin of the clivus or dorsum sellae. The BD was defined if both ectasia and dolichosis were simultaneously observed. Multivariate logistic regression analysis was performed using variables that were marginally or significantly associated with siVAD on univariate analysis (p < 0.20). RESULTS: Multivariate analysis showed siVAD patients have higher proportions of hypertension (OR = 2.4; 95% CI = 1.3-4.6; p = 0.007) and BD (OR = 3.7; 95% CI = 1.1-12; p = 0.036). CONCLUSIONS: The present study suggested that BD was related to the siVAD. A randomized study from multi-institutions with an adequate sample size is needed to make a strong argument about the association between BD and siVAD. PMID- 26736176 TI - Performance enhancement of epoxy based sandwich composites using multiwalled carbon nanotubes for the application of sockets in trans-femoral amputees. AB - A socket plays a vital role in giving the comfort to the amputees. However, the accumulation of heat inside the socket and its weight led to increase their metabolic cost. Hence, an attempt was made to increase the performance of the epoxy based sandwich composites to be used for the socket by reinforcing multiwalled carbon nanotubes (MWCNT), which was varied from 0.1 to 0.5wt%. It was homogeneously dispersed in epoxy to obtain the desired properties, where the enhancement of thermal conductivity, compressive strength and modulus of epoxy was observed to be 76.7%, 62.6% and 20.2%, respectively at 0.3wt% of MWCNT concentration beyond which the mechanical properties were found to be decreased. Hence, the epoxy, E-glass plain fabric, 2-10 layers of stockinet and 0.3wt% of MWCNT were used to prepare the sandwich composites. The flexural strength and thermal conductivity of 0.3wt% of MWCNT reinforced sandwich composites were found to be improved by 11.38+/-1.5% and 29.8+/-1.3% for the 4-10 layers and up to 10 layers of stockinet, respectively compared to unreinforced sandwich composites, which helped to reduce the weight of the socket and decrease the heat accumulation inside the socket. Thus, it is suggested to be explored for the application of socket in trans-femoral amputees to increase their comfort level by decreasing the metabolic cost. PMID- 26736177 TI - Alternative Mechanism for White Adipose Tissue Lipolysis after Thermal Injury. AB - Extensively burned patients often suffer from sepsis, a complication that enhances postburn hypermetabolism and contributes to increased incidence of multiple organ failure, morbidity and mortality. Despite the clinical importance of burn sepsis, the molecular and cellular mechanisms of such infection-related metabolic derangements and organ dysfunction are still largely unknown. We recently found that upon endoplasmic reticulum (ER) stress, the white adipose tissue (WAT) interacts with the liver via inflammatory and metabolic signals leading to profound hepatic alterations, including hepatocyte apoptosis and hepatic fatty infiltration. We therefore hypothesized that burn plus infection causes an increase in lipolysis of WAT after major burn, partially through induction of ER stress, contributing to hyperlipidemia and profound hepatic lipid infiltration. We used a two-hit rat model of 60% total body surface area scald burn, followed by intraperitoneal (IP) injection of Pseudomonas Aeruginosa derived lipopolysaccharide (LPS) 3 d postburn. One day later, animals were euthanized and liver and epididymal WAT (EWAT) samples were collected for gene expression, protein analysis and histological study of inflammasome activation, ER stress, apoptosis and lipid metabolism. Our results showed that burn plus LPS profoundly increased lipolysis in WAT associated with significantly increased hepatic lipid infiltration. Burn plus LPS augmented ER stress by upregulating CHOP and activating ATF6, inducing NLRP3 inflammasome activation and leading to increased apoptosis and lipolysis in WAT with a distinct enzymatic mechanism related to inhibition of AMPK signaling. In conclusion, burn sepsis causes profound alterations in WAT and liver that are associated with changes in organ function and structure. PMID- 26736178 TI - HMGB1 Mediates Anemia of Inflammation in Murine Sepsis Survivors. AB - Patients surviving sepsis develop anemia, but the molecular mechanism is unknown. Here we observed that mice surviving polymicrobial gram-negative sepsis develop hypochromic, microcytic anemia with reticulocytosis. The bone marrow of sepsis survivors accumulates polychromatophilic and orthochromatic erythroblasts. Compensatory extramedullary erythropoiesis in the spleen is defective during terminal differentiation. Circulating tumor necrosis factor (TNF) and interleukin (IL)-6 are elevated for 5 d after the onset of sepsis, and serum high-mobility group box 1 (HMGB1) levels are increased from d 7 until at least d 28. Administration of recombinant HMGB1 to healthy mice mediates anemia with extramedullary erythropoiesis and significantly elevated reticulocyte counts. Moreover, administration of anti-HMGB1 monoclonal antibodies after sepsis significantly ameliorates the development of anemia (hematocrit 48.5 +/- 9.0% versus 37.4 +/- 6.1%, p < 0.01; hemoglobin 14.0 +/- 1.7 versus 11.7 +/- 1.2 g/dL, p < 0.01). Together, these results indicate that HMGB1 mediates anemia by interfering with erythropoiesis, suggesting a potential therapeutic strategy for anemia in sepsis. PMID- 26736179 TI - ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto Kakizaki Rats. AB - Effects of ARA290 on glucose homeostasis were studied in type 2 diabetic Goto Kakizaki (GK) rats. In GK rats receiving ARA290 daily for up to 4 wks, plasma glucose concentrations were lower after 3 and 4 wks, and hemoglobin A1c (Hb A1c) was reduced by ~20% without changes in whole body and hepatic insulin sensitivity. Glucose-stimulated insulin secretion was increased in islets from ARA290-treated rats. Additionally, in response to glucose, carbachol and KCl, islet cytoplasmic free Ca2+ concentrations, [Ca2+]i, were higher and the frequency of [Ca2+]i oscillations enhanced compared with placebo. ARA290 also improved stimulus-secretion coupling for glucose in GK rat islets, as shown by an improved glucose oxidation rate, ATP production and acutely enhanced glucose stimulated insulin secretion. ARA290 also exerted an effect distal to the ATP sensitive potassium (KATP) channel on the insulin exocytotic pathway, since the insulin response was improved following islet depolarization by KCl when KATP channels were kept open by diazoxide. Finally, inhibition of protein kinase A completely abolished effects of ARA290 on insulin secretion. In conclusion, ARA290 improved glucose tolerance without affecting hematocrit in diabetic GK rats. This effect appears to be due to improved gamma-cell glucose metabolism and [Ca2+]i handling, and thereby enhanced glucose-induced insulin release. PMID- 26736180 TI - Estimation of (41)Ar activity concentration and release rate from the TRIGA Mark II research reactor. AB - The BAEC TRIGA research reactor (BTRR) is the only nuclear reactor in Bangladesh. Bangladesh Atomic Energy Regulatory Authority (BAERA) regulations require that nuclear reactor licensees undertake all reasonable precautions to protect the environment and the health and safety of persons, including identifying, controlling and monitoring the release of nuclear substances to the environment. The primary activation product of interest in terms of airborne release from the reactor is (41)Ar. (41)Ar is a noble gas readily released from the reactor stacks and most has not decayed by the time it moves offsite with normal wind speed. Initially (41)Ar is produced from irradiation of dissolved air in the primary water which eventually transfers into the air in the reactor bay. In this study, the airborne radioisotope (41)Ar generation concentration, ground level concentration and release rate from the BTRR bay region are evaluated theoretically during the normal reactor operation condition by several governing equations. This theoretical calculation eventually minimizes the doubt about radiological safety to determine the radiation level for (41)Ar activity whether it is below the permissible limit or not. Results show that the estimated activity for (41)Ar is well below the maximum permissible concentration limit set by the regulatory body, which is an assurance for the reactor operating personnel and general public. Thus the analysis performed within this paper is so much effective in the sense of ensuring radiological safety for working personnel and the environment. PMID- 26736181 TI - Ultra-trace determination of (90)Sr, (137)Cs, (238)Pu, (239)Pu, and (240)Pu by triple quadruple collision/reaction cell-ICP-MS/MS: Establishing a baseline for global fallout in Qatar soil and sediments. AB - The development of practical, fast, and reliable methods for the ultra-trace determination of anthropogenic radionuclides (90)Sr, (137)Cs, (238)Pu, (239)Pu, and (240)Pu by triple quadruple collision/reaction cell inductively coupled plasma mass spectrometry (CRC-ICP-MS/MS) were investigated in term of its accuracy and precision for producing reliable results. The radionuclides were extracted from 1 kg of the environmental soil samples by concentrated nitric and hydrochloric acids. The leachate solutions were measured directly by triple quadrupole CRC-ICP-MS/MS. For quality assurance, a chemical separation of the concerned radionuclides was conducted and then measured by single quadrupole-ICP MS. The developed methods were next applied to measure the anthropogenic radionuclides (90)Sr, (137)Cs, (238)Pu, (239)Pu, and (240)Pu in soil samples collected throughout the State of Qatar. The average concentrations of (90)Sr, (137)Cs, (238)Pu, (239)Pu, and (240)Pu were 0.606 fg/g (3.364 Bq/kg), 0.619 fg/g (2.038 Bq/kg), 0.034 fg/g (0.0195 Bq/kg), 65.59 fg/g (0.150 Bq/kg), and 12.06 fg/g (0.103 Bq/kg), respectively. PMID- 26736182 TI - Like a bridge over troubled water--Opening pathways for integrating social sciences and humanities into nuclear research. AB - Research on nuclear technologies has been largely driven by a detachment of the 'technical content' from the 'social context'. However, social studies of science and technology--also for the nuclear domain--emphasize that 'the social' and 'the technical' dimensions of technology development are inter-related and co produced. In an effort to create links between nuclear research and innovation and society in mutually beneficial ways, the Belgian Nuclear Research Centre started fifteen years ago a 'Programme of Integration of Social Aspects into nuclear research' (PISA). In line with broader science-policy agendas (responsible research and innovation and technology assessment), this paper argues that the importance of such programmes is threefold. First, their multi disciplinary basis and participatory character contribute to a better understanding of the interactions between science, technology and society, in general, and the complexity of nuclear technology assessment in particular. Second, their functioning as (self -)critical policy supportive research with outreach to society is an essential prerequisite for policies aiming at generating societal trust in the context of controversial issues related to nuclear technologies and exposure to ionising radiation. Third, such programmes create an enriching dynamic in the organisation itself, stimulating collective learning and transdisciplinarity. The paper illustrates with concrete examples these claims and concludes by discussing some key challenges that researchers face while engaging in work of this kind. PMID- 26736183 TI - Characterizing the interaction between uranyl ion and fulvic acid using regional integration analysis (RIA) and fluorescence quenching. AB - The development of chemometric methods has substantially improved the quantitative usefulness of the fluorescence excitation-emission matrix (EEM) in the analysis of dissolved organic matter (DOM). In this study, Regional Integration Analysis (RIA) was used to quantitatively interpret EEMs and assess fluorescence quenching behavior in order to study the binding between uranyl ion and fulvic acid. Three fulvic acids including soil fulvic acid (SFA), Oyster River fulvic acid (ORFA) and Suwannee River fulvic acid (SRFA) were used and investigated by the spectroscopic techniques. The EEM spectra obtained were divided into five regions according to fluorescence structural features and two distinct peaks were observed in region III and region V. Fluorescence quenching analysis was conducted for these two regions with the stability constants, ligand concentrations and residual fluorescence values calculated using the Ryan-Weber model. Results indicated a relatively strong binding ability between uranyl ion and fulvic acid samples at low pH (log K value varies from 4.11 to 4.67 at pH 3.50). Fluorophores in region III showed a higher binding ability with fewer binding sites than in region V. Stability constants followed the order, SFA > ORFA > SRFA, while ligand concentrations followed the reverse order, SRFA > ORFA > SFA. A comparison between RIA and Parallel Factor Analysis (PARAFAC) data treatment methods was also performed and good agreement between these two methods (less than 4% difference in log K values) demonstrates the reliability of the RIA method in this study. PMID- 26736184 TI - Keynotes. AB - Provides an abstract for each of the keynote presentations and a brief professional biography of each presenter. The complete presentations were not made available for publication as part of the conference proceedings. PMID- 26736186 TI - Force-feedback sensory substitution using supervised recurrent learning for robotic-assisted surgery. AB - The lack of force feedback is considered one of the major limitations in Robot Assisted Minimally Invasive Surgeries. Since add-on sensors are not a practical solution for clinical environments, in this paper we present a force estimation approach that starts with the reconstruction of a 3D deformation structure of the tissue surface by minimizing an energy functional. A Recurrent Neural Network Long Short Term Memory (RNN-LSTM) based architecture is then presented to accurately estimate the applied forces. According to the results, our solution offers long-term stability and shows a significant percentage of accuracy improvement, ranging from about 54% to 78%, over existing approaches. PMID- 26736187 TI - Development of the dual SMART micro-surgical system using common-path swept source optical coherence tomography. AB - Manual micro-surgical tasks are fundamentally divided into grasping, cutting and injecting maneuvers performed on biological tissues. Efficient dissection of fibrous tissue from the surface of the retina often requires grasping and cutting maneuvers carried out simultaneously. True bimanual surgery requires that the surgeon contend with the innate hand tremor of two hands at once as well as unpredicted patient's movement. In this study, we develop and test a dual SMART micro-surgical system to suppress bimanual hand tremor during micro-surgical dissection. PMID- 26736188 TI - Intra-operative 3D imaging system for robot-assisted fracture manipulation. AB - Reduction is a crucial step in the treatment of broken bones. Achieving precise anatomical alignment of bone fragments is essential for a good fast healing process. Percutaneous techniques are associated with faster recovery time and lower infection risk. However, deducing intra-operatively the desired reduction position is quite challenging due to the currently available technology. The 2D nature of this technology (i.e. the image intensifier) doesn't provide enough information to the surgeon regarding the fracture alignment and rotation, which is actually a three-dimensional problem. This paper describes the design and development of a 3D imaging system for the intra-operative virtual reduction of joint fractures. The proposed imaging system is able to receive and segment CT scan data of the fracture, to generate the 3D models of the bone fragments, and display them on a GUI. A commercial optical tracker was included into the system to track the actual pose of the bone fragments in the physical space, and generate the corresponding pose relations in the virtual environment of the imaging system. The surgeon virtually reduces the fracture in the 3D virtual environment, and a robotic manipulator connected to the fracture through an orthopedic pin executes the physical reductions accordingly. The system is here evaluated through fracture reduction experiments, demonstrating a reduction accuracy of 1.04 +/- 0.69 mm (translational RMSE) and 0.89 +/- 0.71 degrees (rotational RMSE). PMID- 26736189 TI - FBG-based sensorized light pipe for robotic intraocular illumination facilitates bimanual retinal microsurgery. AB - In retinal surgery, microsurgical instruments such as micro forceps, scissors and picks are inserted through the eye wall via sclerotomies. A handheld intraocular light source is typically used to visualize the tools during the procedure. Retinal surgery requires precise and stable tool maneuvers as the surgical targets are micro scale, fragile and critical to function. Retinal surgeons typically control an active surgical tool with one hand and an illumination source with the other. In this paper, we present a "smart" light pipe that enables true bimanual surgery via utilization of an active, robot-assisted source of targeted illumination. The novel sensorized smart light pipe measures the contact force between the sclerotomy and its own shaft, thereby accommodating the motion of the patient's eye. Forces at the point of contact with the sclera are detected by fiber Bragg grating (FBG) sensors on the light pipe. Our calibration and validation results demonstrate reliable measurement of the contact force as well as location of the sclerotomy. Preliminary experiments have been conducted to functionally evaluate robotic intraocular illumination. PMID- 26736190 TI - Visual and somatic sensory feedback of brain activity for intuitive surgical robot manipulation. AB - This paper presents a method to evaluate the hand-eye coordination of the master slave surgical robot by measuring the activation of the intraparietal sulcus in users brain activity during controlling virtual manipulation. The objective is to examine the changes in activity of the intraparietal sulcus when the user's visual or somatic feedback is passed through or intercepted. The hypothesis is that the intraparietal sulcus activates significantly when both the visual and somatic sense pass feedback, but deactivates when either visual or somatic is intercepted. The brain activity of three subjects was measured by the functional near-infrared spectroscopic-topography brain imaging while they used a hand controller to move a virtual arm of a surgical simulator. The experiment was performed several times with three conditions: (i) the user controlled the virtual arm naturally under both visual and somatic feedback passed, (ii) the user moved with closed eyes under only somatic feedback passed, (iii) the user only gazed at the screen under only visual feedback passed. Brain activity showed significantly better control of the virtual arm naturally (p<;0.05) when compared with moving with closed eyes or only gazing among all participants. In conclusion, the brain can activate according to visual and somatic sensory feedback agreement. PMID- 26736191 TI - Hand-eye calibration of a robot--UltraSound probe system without any 3D localizers. AB - 3D UltraSound (US) probes are used in clinical applications for their ease of use and ability to obtain intra-operative volumes. In surgical navigation applications a calibration step is needed to localize the probe in a general coordinate system. This paper presents a new hand-eye calibration method using directly the kinematic model of a robot and US volume registration data that does not require any 3D localizers. First results show a targeting error of 2.34 mm on an experimental setup using manual segmentation of five beads in ten US volumes. PMID- 26736192 TI - A gap junction-based cardiac electromechanics model. AB - Action potential propagation in cardiac tissue is mainly governed by highly resistive gap junctions, which causes the tissue to behave as a network of active cell nodes interconnected by resistors. This property causes the action potential propagation to be less dependent on the level of mechanical deformation. This study proposes that the electrical conductivity in cardiac electromechanical simulations should be held fixed relative to the material frame, reproducing the dominant effect of intercellular gap junctions on the tissue electrical resistance instead of the more commonly employed spatial frame. Our simulations showed that the implementation of gap junction-based conductivity resulted in similar activation times at given material point, irrespective of the level of deformation. In contrast, the activation time of a given material point using spatial-based conductivity was dependent on the deformation experienced by the tissue. These findings have implication on more complex electromechanical simulations such as spiral wave since gap junction-based conductivity is independent of contraction, in contrast to spatial-based conductivity. Therefore, selection of the appropriate electrical conductivity assumption is highly crucial in electromechanics models of cardiac tissue. PMID- 26736193 TI - Modelling the effect of thickness on the electromechanical properties of in vitro cardiac cultures: A simulation study. AB - Nowadays, in vitro cardiac cultures offer a valid tool to study the bioelectrical activity and the biomechanics of the heart tissue. Modelling their properties could be helpful for researchers involved in this field. In this paper, we develop a three-dimensional electromechanical model to study how thickness affects the bioelectrical and biomechanical performances of an in vitro culture made of ventricular cells. In particular, by our in silico simulations we want to verify if thickness variations can be a key factor in modifying the response of the whole culture when this one is grown to become a cardiac patch. Therefore, for this parameter we choose three increasing values while keeping a fiber architecture among layers that is similar to the one of the in vivo heart but it is randomly stated at the beginning of each simulation. We prove that, independently from the selected architectures, the more thickness increases the more mechanical improvements are attained, but the more electrical problems may arise too. PMID- 26736194 TI - From the Purkinje fibres to the ventricle: One dimensional computer simulation for the healthy and failing heart. AB - This study used one-dimensional computer simulation to investigate the influence of heart failure on action potential conduction through the left Purkinje fibres to the left ventricle. The study was based on a rabbit model of left ventricular heart failure caused by volume and pressure overload. To simulate the effect of heart failure, we began with models of the healthy rabbit Purkinje fibre action potential and healthy left ventricular (endocardial) action potential. In the absence of ionic current measurements from failing rabbit Purkinje fibres, we assumed that changes in ionic currents mirrored changes in ion channel expression (measured at the messenger RNA level): ionic conductances were adjusted based on changes in expression of the relevant ion channels. Ionic currents in the left ventricle were adjusted in the same way, but in addition, changes in ionic currents measured in the failing rabbit left ventricle by Ruijter et al. and Powizd et al. were used in simulations. The simulations predict a gradient in action potential duration from the Purkinje fibres to the ventricle and this gradient is exacerbated in heart failure. The predicted changes in the Purkinje fibre and left ventricular action potential were compared to actual changes measured using sharp microelectrodes. PMID- 26736195 TI - In silico modelling and analysis of the electrical and mechanical properties of in vitro cardiac cultures with different fiber architectures. AB - Today, in vitro cardiac cultures are widely exploited to investigate several aspects of the electromechanical behavior of the cardiac tissue. Thus, new forecasts may derive from modelling their properties. In particular, in this paper, we focus on the fiber architecture of cultures, i.e. on the way cellular sarcomeres are locally oriented, when they are designed to be cardiac patches. We employ a three-dimensional model to simulate the bioelectrical activity and the biomechanics of a multilayered culture made of ventricular cells and with four possible architectures consisting of: i) random fibers in all cells; ii) randomly rotating fibers among layers; iii) structurally rotating fibers from the bottom layer to the top one; iv) parallel fibers among layers. Our results suggest that the best configuration for a patch may be the architecture with structurally rotating fibers, which is the one that most approaches the anisotropic structure of the in vivo heart, thanks to its better electrical and mechanical performances. PMID- 26736196 TI - Autonomic nervous system regulation of the sinoatrial cell depolarization rate: Unifying computational models. AB - In the last years different computational models have been proposed to simulate the sinoatrial node cell (SANC) action potential. Also, there has been a great effort to model the heart regulation mechanism by the autonomic nervous system (ANS) through the sympathetic and parasympathetic pathways. Both computational models have tried to fit the rabbit and/or the guinea-pig experimental heart rate data with an increasing success. Thus, the aim of this work was to unify the available models that have been reported to study the heart rate behavior when the SANC is stimulated by using different frequency patterns. Our results contribute to the unification of part of the Scepanovic's model [1] (involved with second messengers dynamics and its influence over specific SANC ionic channels), and the SANC ionic channels computational model proposed by Severi et al. [2] in 2012. In this model unification we did refit some parameters, particularly, those related to the Hill functions in the dynamic modeling of phosphokinase and its effect on the ionic channels currents If and ICaL, and over the Pup, parameter that is related to the Ca(++) uptake by the sarcoplasmic reticulum. Also, we eliminated the neurotransmitter effect over the ionic current IKr that is not presented in the Severi's model. These modifications were enough to successfully reproduce the heart rate experimental recordings under acetylcholine (Ach) or norepinephrine (NE) for independent stimulation: Ach 10 nM stimulation showed a 21.54% action potential shift compared with the 20% reported for experimental recordings; Isoprenaline 1 MUM, also displayed a depolarization increased rate of 29.3%, compared with the experimental data of 28.2%. Furthermore, we were able to reproduce the guinea-pig experimental heart rate recordings, when the SANC model was vagal stimulated by using a 2 Hz, 10 Hz and 20 Hz frequency for 10 seconds and the experimental heart rate data for a sympathetic stimulation of 10 Hz frequency for 10 seconds. PMID- 26736197 TI - Role of atrium in automaticity of the sinus node. AB - As the electrical source of hearts, sino-atrial node cells (SANCs) play significant roles in rhythmic firings. Due to the complex structure and function of SANCs, electrical interactions of SAN and its surrounding atrium has not yet been fully understood. The aim of the present study is to investigate effects of coupling conductance between SAN and atrial cells as well as the ectopic beats in atrium on automaticity of the SAN by computer simulation methods. On the basis of a dynamic mathematical single cell model considering the heterogeneity of central and peripheral SANCs, a two-dimensional inhomogeneous tissue slice including SAN and atrium was developed. The operator splitting method was used to integrate the tissue model. The results demonstrated that the coupling conductance between SAN and atrium had effects on the direction of spontaneous action potential conduction in SAN. Weak coupling resulted in a shift of the earliest pacemaker site from central to peripheral SANCs. Additionally, the ectopic beat-induced excitation in atrium was found to be able to enter into and overdrive suppress the automaticity of SAN. Even if the ectopic beat was delivered after the spontaneous firing had started in central SANCs, the spontaneous conduction toward the periphery could also be suppressed by the retrograde activation from the entering atrial depolarization wave. These findings suggested a direct link between sinus node dysfunction and atrial arrhythmias, and therefore were helpful in explaining the role of atrium in sinus node dysfunction. PMID- 26736198 TI - A bidirectional brain-machine interface connecting alert rodents to a dynamical system. AB - We present a novel experimental framework that implements a bidirectional brain machine interface inspired by the operation of the spinal cord in vertebrates that generates a control policy in the form of a force field. The proposed experimental set-up allows connecting the brain of freely moving rats to an external device. We tested this apparatus in a preliminary experiment with an alert rat that used the interface for acquiring a food reward. The goal of this approach to bidirectional interfaces is to explore the role of voluntary neural commands in controlling a dynamical system represented by a small cart moving on vertical plane and connected to a water/pellet dispenser. PMID- 26736199 TI - Phase locking of beta oscillation in electrocorticography (ECoG) in the monkey motor cortex at the onset of EMGs and 3D reaching movements. AB - beta oscillations in local field potentials, electrocorticography (ECoG), and electroencephalograms (EEG) are ubiquitous in the motor cortex of monkeys and humans. However, relations between their dynamical properties and behavior have not been well studied. Here, we used ECoG grids to cover large areas of motor cortex and some somatosensory cortex in monkeys while they performed an unconstrained reaching and a lever pulling task in three dimensional space with or without go cue. We used percentage of phase locking (PPL) as a dynamical property of beta oscillations aligned to behaviorally relevant events, reaching onsets (RO), lever onset (LO), and holding onset (HO) as well as multiple peaks of electromyography (EMG) recorded from various upper limb muscles. We showed that relative strength of PPL aligned to RO and LO were reserved with or without the external go cues. Furthermore, among the muscles that we recorded EMGs from, beta oscillations were not closely phase locked to any of EMG onsets. Therefore, phase locking of beta oscillations is related more to the attentive state and external cues as opposed to detailed muscle activities. PMID- 26736200 TI - Causal network in a deafferented non-human primate brain. AB - De-afferented/efferented neural ensembles can undergo causal changes when interfaced to neuroprosthetic devices. These changes occur via recruitment or isolation of neurons, alterations in functional connectivity within the ensemble and/or changes in the role of neurons, i.e., excitatory/inhibitory. In this work, emergence of a causal network and changes in the dynamics are demonstrated for a deafferented brain region exposed to BMI (brain-machine interface) learning. The BMI was controlling a robot for reach-and-grasp behavior. And, the motor cortical regions used for the BMI were deafferented due to chronic amputation, and ensembles of neurons were decoded for velocity control of the multi-DOF robot. A generalized linear model-framework based Granger causality (GLM-GC) technique was used in estimating the ensemble connectivity. Model selection was based on the AIC (Akaike Information Criterion). PMID- 26736201 TI - Preliminary study for extraction of P300 and SSVEP by stimulus presentation using phase inversion technique in hybrid BCI. AB - In this study, we propose a novel stimulation presentation method for the hybrid BCI of the P300 and steady state visual evoked potential (SSVEP) to separate the two components efficiently. The method produces the separation by generating the P300 at two time points whose phase difference is pi radians in the SSVEP component corresponding to stimulus frequency. Assuming that the consecutive two P300 responses are identical and the SSVEP is sinusoidal, the P300 can be extracted as a summation of the above two responses by suppressing the SSVEP. Also, the SSVEP can be detected by the subtraction of the above two responses. Accordingly, this method is realized by a stimulus pair consisting of the above two stimuli. In an EEG experiment, we used a checkerboard stimulus and character presentation for obtaining the SSVEP and P300, respectively. The stimulus frequencies of the checkerboard were assigned to 5 Hz and 3 Hz to classify the target character from the two given characters. The results showed the appearance of a prominent P300 component from only one pair of stimuli, even though the fundamental and harmonic frequency components of the SSVEP for lower stimulus frequencies are not very stable. This is because of the asymmetry of the positive and negative potentials for the SSVEP. It is a good idea to use a stimulus frequency that overlaps with the P300 frequency band, because this method does not separate the P300 and SSVEP by EEG frequency difference. Moreover, it reduces the measurement time (i.e., it shortens the number of averagings required for P300 estimation) because the SSVEP cancels out if it is sinusoidal. We consider that this will be a useful method to estimate the P300 and SSVEP simultaneously from these aspects. PMID- 26736202 TI - A 3D learning playground for potential attention training in ADHD: A brain computer interface approach. AB - This paper presents a novel brain-computer-interface (BCI) system that could potentially be used for enhancing the attention ability of subjects with attention deficit hyperactivity disorder (ADHD). It employs the steady state visual evoked potential (SSVEP) paradigm. The developed system consists of a 3D classroom environment with active 3D distractions and 2D games executed on the blackboard. The system is concealed as a game (with stages of varying difficulty) with an underlying story to motivate the subjects. It was tested on eleven healthy subjects and the results undeniably establish that by moving to a higher stage in the game where the 2D environment is changed to 3D along with the added 3D distractions, the difficulty level in keeping attention on the main task increases for the subjects. Results also show a mean accuracy of 92.26 +/- 7.97% and a mean average selection time of 3.07 +/- 1.09 seconds. PMID- 26736203 TI - Auto-deleting brain machine interface: Error detection using spiking neural activity in the motor cortex. AB - Brain machine interfaces (BMIs) aim to assist people with paralysis by increasing their independence and ability to communicate, e.g., by using a cursor-based virtual keyboard. Current BMI clinical trials are hampered by modest performance that causes selection of wrong characters (errors) and thus reduces achieved typing rate. If it were possible to detect these errors without explicit knowledge of the task goal, this could be used to automatically "undo" wrong selections or even prevent upcoming wrong selections. We decoded imminent or recent errors during closed-loop BMI control from intracortical spiking neural activity. In our experiment, a non-human primate controlled a neurally-driven BMI cursor to acquire targets on a grid, which simulates a virtual keyboard. In offline analyses of this closed-loop BMI control data, we identified motor cortical neural signals indicative of task error occurrence. We were able to detect task outcomes (97% accuracy) and even predict upcoming task outcomes (86% accuracy) using neural activity alone. This novel strategy may help increase the performance and clinical viability of BMIs. PMID- 26736204 TI - Accuracy of measurements derived from intracardiac unipolar electrograms: A simulation study. AB - The ventricular action potential duration (APD) is a fundamental determinant of cardiac electrical stability and can be estimated by measuring the activation recovery interval (ARI) from the unipolar electrogram (UEG), which represents the electrical activity of the heart at the tissue level. Under experimental conditions, automatic estimation of ARIs is challenging due to non-related interferences and low signal-to-noise ratios (SNRs). In this simulation study, we investigated how the reliability of ARI estimates is affected by noise and artefacts in the UEG. Real-like electrograms were generated using a 257-node whole heart model to synthesize 20 real-like UEGs exhibiting constant and dynamic ARI patterns. Controlled degrees of noise and contamination (ectopic beats) were added to obtain a range of signal qualities. The generated recordings were automatically analyzed using a proposed standard method to estimate the ARI. The performance was compared with two improvements of the standard method including a narrow search window and a correlation filter. The results show that the robustness of automatic ARI analysis was dramatically improved by using the proposed improvement methods. For typical recordings with a SNR of 10dB and filtered with often used cutoff frequency of 30Hz to measure repolarization, the average mean absolute error of the estimations was reduced from 16.2ms (range:12.2-29.0ms) for the standard method to 11.6ms (range:6.0-13.4ms) for the improved method. The standard deviation was reduced from 38.2ms (range:26.8- 58.5ms) to 14.6ms (range:7.6-16.9ms). Detection of cyclical variation of ARI was also improved by using the improvement strategy: for 0.2Hz ARI oscillations with an amplitude of 5ms, the highest average detection rate increased from 41% for the standard method to 100% using the improved method for recordings with a SNR of 10dB. PMID- 26736205 TI - A novel statistical model for arterial blood pressure signals. AB - This paper introduces a novel arterial blood pressure (ABP) signal model that generates statistically accurate synthetic signals with known characteristics. Using parameter identification from real ABP signals to form base parameter templates, our model applies stochastic processes to modulate cardiac cycle period and shape. A real-time control component modulates model parameters between cycle boundaries to emulate properties of real cardiovascular signals, such as arrhythmia, ectopic beats, resonances in the heart-rate variability spectrum, and respiratory cycle modulation of ABP signal amplitude. We present several examples to illustrate the capability of the proposed model. PMID- 26736206 TI - Gaussian mixture model based identification of arterial wall movement for computation of distension waveform. AB - This work proposes a novel Gaussian Mixture Model (GMM) based approach for accurate tracking of the arterial wall and subsequent computation of the distension waveform using Radio Frequency (RF) ultrasound signal. The approach was evaluated on ultrasound RF data acquired using a prototype ultrasound system from an artery mimicking flow phantom. The effectiveness of the proposed algorithm is demonstrated by comparing with existing wall tracking algorithms. The experimental results show that the proposed method provides 20% reduction in the error margin compared to the existing approaches in tracking the arterial wall movement. This approach coupled with ultrasound system can be used to estimate the arterial compliance parameters required for screening of cardiovascular related disorders. PMID- 26736207 TI - Detecting breast cancer using microwave imaging and stochastic optimization. AB - Breast cancer detection is one of the most important problems in health care as it is second most frequent cancer according to WHO. Breast cancer is among cancers which are most probably curable, only if it is diagnosed at early stages. To this purpose it has been recently proposed that microwave imaging could be used as a cheaper and safer alternative to the commonly used combination of mammography. From a physical standpoint breast cancer can be modelled as a scatterer with a significantly (tenfold) larger conductivity than a healthy tissue. In our previous work we proposed a maximum likelihood based method for detection of cancer which estimates the unknown parameters by minimizing the residual error vector assuming that the error can be modelled as a multivariate (multiple antennas) random variable. In this paper we utilize stochastic optimization technique and evaluate its applicability to the detection of cancer using numerical models. Although these models have significant limitations they are potentially useful as they provide insight in required levels of noise in order to achieve desirable detection rates. PMID- 26736208 TI - An analytical model for regular respiratory signals derived from the probability density function of Rayleigh distribution. AB - Regular respiratory signals (RRSs) acquired with physiological sensing systems (e.g., the life-detection radar system) can be used to locate survivors trapped in debris in disaster rescue, or predict the breathing motion to allow beam delivery under free breathing conditions in external beam radiotherapy. Among the existing analytical models for RRSs, the harmonic-based random model (HRM) is shown to be the most accurate, which, however, is found to be subject to considerable error if the RRS has a slowly descending end-of-exhale (EOE) phase. The defect of the HRM motivates us to construct a more accurate analytical model for the RRS. In this paper, we derive a new analytical RRS model from the probability density function of Rayleigh distribution. We evaluate the derived RRS model by using it to fit a real-life RRS in the sense of least squares, and the evaluation result shows that, our presented model exhibits lower error and fits the slowly descending EOE phases of the real-life RRS better than the HRM. PMID- 26736209 TI - Tri-axial telecoil hearing aid for improved connection to public induction loops. AB - Telecoils in hearing aids serve a dual purpose: to enhance telephone conversation and enable hearing aids to serve as a wireless interface for public audio broadcasts. When broadcasting audio signals, the signal is transmitted to the telecoil sensor (a magnetic field sensor located in the hearing aid) via magnetic energy from an induction wire loop located near the listener. This induction loop can be a small assembly located in the handset of the telephone or a large wire loop within a public venue like a theatre. Current hearing aids detect the magnetic signal using a single telecoil. If the telecoil is not aligned with the magnetic field, the strength of the detected signal is diminished. Unfortunately, public induction loops and telephone handsets seldom share a common alignment to the hearing aid, leading to sub-optimal performance by one or both in hearing aids available today. In this research, a prototype behind-the-ear (BTE) hearing aid with tri-axial telecoils was developed and DSP algorithms to process and combine the three signals were developed. The resulting hearing aid was evaluated in a human trial and provided better performance than a similar quality conventional telecoil hearing aid. PMID- 26736210 TI - Combination of signal segmentation approaches using fuzzy decision making. AB - Segmentation is an important stage in signal analysis, and its performance plays a significant role in the efficiency of the subsequent steps, such as extraction of descriptive features and classification. There are a large number of approaches to segment signals. The performance of each of them remarkably varies when the signal changes. In this present study, two novel algorithms, which use the probability and fuzzy concepts, are proposed to combine several well-known existing signal segmentation approaches. The simulation results confirm the efficiency of the proposed approaches using the synthetic and real electroencephalogram signals. PMID- 26736211 TI - Empirical mode decomposition of multiple ECG leads for catheter ablation long term outcome prediction in persistent atrial fibrillation. AB - Predictive models arouse increasing interest in clinical practice, not only to improve successful intervention rates but also to extract information of diverse physiological disorders. This is the case of persistent atrial fibrillation (AF), the most common cardiac arrhythmia in adults. Currently, catheter ablation (CA) is one of the preferred therapies to face this disease. However, selecting the best responders to CA by standard noninvasive techniques such as the electrocardiogram (ECG) remains a challenge. This work presents different predictive models for determining long-term CA outcome based on the dominant frequency (DF) of atrial activity measured in the ECG. The ensemble empirical mode decomposition (EEMD) is employed to obtain the intrinsic mode functions (IMFs) composing the ECG signal in each lead. The IMF DFs computed in multiple leads are then combined into a logistic regression (LR) model. The IMF DF features are discriminant enough to reach 79% accuracy for long-term CA outcome prediction, outperforming other methods based on DF computation. Our study shows EEMD as a valuable alternative to extract clinically relevant spectral information from AF ECGs and confirms the advantage of LR to build multivariate predictive models as compared with univariate analysis. PMID- 26736212 TI - Empirical mode decomposition of digital mammograms for the statistical based characterization of architectural distortion. AB - Among the different and common mammographic signs of the early-stage breast cancer, the architectural distortion is the most difficult to be identified. In this paper, we propose a new multiscale statistical texture analysis to characterize the presence of architectural distortion by distinguishing between textural patterns of architectural distortion and normal breast parenchyma. The proposed approach, firstly, applies the bidimensional empirical mode decomposition algorithm to decompose each mammographic region of interest into a set of adaptive and data-driven two-dimensional intrinsic mode functions (IMF) layers that capture details or high-frequency oscillations of the input image. Then, a model-based approach is applied to IMF histograms to acquire the first order statistics. The normalized entropy measure is also computed from each IMF and used as a complementary textural feature for the recognition of architectural distortion patterns. For evaluating the proposed AD characterization approach, we used a mammographic dataset of 187 true positive regions (i.e. depicting architectural distortion) and 887 true negative (normal parenchyma) regions, extracted from the DDSM database. Using the proposed multiscale textural features and the nonlinear support vector machine classifier, the best classification performance, in terms of the area under the receiver operating characteristic curve (or Az value), achieved was 0.88. PMID- 26736213 TI - Localization of brain activities using multiway analysis of EEG tensor via EMD and reassigned TF representation. AB - Electroencephalogram (EEG) is widely used for monitoring, diagnosis purposes and also for study of brain's physiological, mental and functional abnormalities. Processing of information by the brain is reflected in dynamical changes of the electrical activity in time, frequency, and space. EEG signal processing tends to describe and quantify these variations in such a way that they are localized in temporal, spectral and spatial domain. Here we use multi-way (Tensor) analysis for localizing the EEG events. We used EMD process for decomposing EEG into distinct oscillatory modes, which are then mapped to TF plane using the near optimal Reassigned Spectrogram. Temporal, Spatial and Spectral information of the Multichannel EEG are then used to generate a three-way Frequency-Time-Space EEG tensor. Exploiting EMD also enables us to detrend the EEG recordings. Simulation results on both synthetic and real EEG data show that tensor analysis greatly improve separation and localization of overlapping events in EEG and it could be effectively exploited for detecting and characterizing the evoked potentials. PMID- 26736214 TI - Assessing EEG slow wave activity during anesthesia using Hilbert-Huang Transform. AB - Slow waves (<; 1 Hz) are considered to be the most important electroencephalogram (EEG) signature of non-rapid eye movement sleep and have substantial physiological importance. In addition to natural sleep, slow waves can be seen in the EEG during general anesthesia offering great potential for depth of anesthesia monitoring. In this paper, Hilbert-Huang Transform, an adaptive data driven method designed for the analysis on non-stationary data, was used to investigate the dynamical changes in the EEG slow wave activity during induction of anesthesia with propofol. The method was found to be able to extract stable signal components representing slow wave activity that were consistent between patients. The signal analysis revealed a possible specific structure between different components dependent on the depth of anesthesia on which further studies are needed. PMID- 26736215 TI - Eye blink artifact rejection in single-channel electroencephalographic signals by complete ensemble empirical mode decomposition and independent component analysis. AB - To study an eye blink artifact rejection scheme from single-channel electroencephalographic (EEG) signals has been now a major challenge in the field of EEG signal processing. High removal performance is still needed to more strictly investigate pattern of EEG features. This paper proposes a new eye blink artifact rejection scheme from single-channel EEG signals by combining complete ensemble empirical mode decomposition (CEEMD) and independent component analysis (ICA). We compare the separation performance of our proposed scheme with existing schemes (wavelet-ICA, EMD-ICA, and EEMD-ICA) though real-life data by using signal-to-noise ratio. As a result, CEEMD-ICA showed high performance (11.86 dB) than all other schemes (10.78, 10.59, and 11.30 dB) in the ability of eye blink artifact removal. PMID- 26736216 TI - Mutual cineMR/RT3DUS cardiac segmentation. AB - We present a new method to segment a cardiac RT3D ultrasound volume by integrating the registered segmentation of a cardiac cine-MR series in short axis of the same patient. The motivation behind our method is to improve the ultrasound segmentation process by integrating a reference shape built using the cine-MR segmentation on the same patient. As a side effect we obtain a close registration of the cine MR short axis slices with respect to the ultrasound volume. We use the level set framework with a functional including a region-based and a shape-based term. The reference shape is iteratively registered onto the contour during the ultrasound segmentation process and using an affine transform. The proposed method is demonstrated on the MICCAI11 Motion Tracking Challenge database. PMID- 26736218 TI - The polydisperse acoustic signature of rigid microbubbles. AB - Microbubbles are used in medical ultrasound imaging as contrast agents to image the vascular bed under the mode of Ultrasound Contrast Imaging (UCI). The microbubble shell determines the acoustic response and hence the signal that is utilized to form the images in UCI. Single microbubble signals from BiSphereTM (POINT Biomedical, San Carlos, CA, USA) microbubbles were captured using a clinical ultrasound system. Three main typical responses of microbubbles were identified, a) full duration echo, b) echo with duration shorter than the incident pulse and c) echo that in part resembles that in (b) and in addition prior to that another short duration initial lower amplitude signal. These data corroborate that the shell structural and nanomechanical property provide the different responses at different microbubble sizes. These different signals present an opportunity for tracking the movement of well differentiated single microbubbles particularly with novel super-resolution imaging methods that require sparse microbubble populations. PMID- 26736217 TI - Continuous ultrasound speckle tracking with Gaussian mixtures. AB - Speckle tracking echocardiography (STE) is now widely used for measuring strain, deformations, and motion in cardiology. STE involves three successive steps: acquisition of individual frames, speckle detection, and image registration using speckles as landmarks. This work proposes to avoid explicit detection and registration by representing dynamic ultrasound images as sparse collections of moving Gaussian elements in the continuous joint space-time space. Individual speckles or local clusters of speckles are approximated by a single multivariate Gaussian kernel with associated linear trajectory over a short time span. A hierarchical tree-structured model is fitted to sampled input data such that predicted image estimates can be retrieved by regression after reconstruction, allowing a (bias-variance) trade-off between model complexity and image resolution. The inverse image reconstruction problem is solved with an online Bayesian statistical estimation algorithm. Experiments on clinical data could estimate subtle sub-pixel accurate motion that is difficult to capture with frame to-frame elastic image registration techniques. PMID- 26736219 TI - Ultrasound Synthetic Aperture Focusing with the Delay Multiply and sum beamforming algorithm. AB - The Delay Multiply and Sum (DMAS) beamforming algorithm was originally conceived for microwave imaging of breast cancer. In a previous work, we demonstrated that, by properly modifying and improving the algorithm processing steps, DMAS can be successfully applied to ultrasound signals for B-mode image formation and that it outperforms standard Delay and Sum (DAS) beamforming in terms of contrast resolution. As previously pointed out, however, DMAS-beamformed B-mode images, in which fixed and dynamic focusing are applied respectively during transmit and receive operations, show an intensity drop away from the transmit focal depth compared to DAS images. This could be due to the fact that DMAS beamforming is based on a measure of backscattered signal coherence, which reaches its maximum only at the transmit focus, where signals are perfectly realigned. The preliminary results presented in this work show that, by employing Synthetic Aperture Focusing (SAF), which allows to achieve dynamic focusing both on transmission and reception, this intensity loss is compensated, as DAS and DMAS images have almost the same maximum amplitude level at all depths. PMID- 26736220 TI - Robust deformable registration of pre- and post-resection ultrasound volumes for visualization of residual tumor in neurosurgery. AB - The brain tissue deforms significantly during neurosurgery, which has led to the use of intra-operative ultrasound in many sites to provide updated ultrasound images of tumor and critical parts of the brain. Several factors degrade the quality of post-resection ultrasound images such as hemorrhage, air bubbles in tumor cavity and the application of blood-clotting agent around the edges of the resection. As a result, registration of post- and pre-resection ultrasound is of significant clinical importance. In this paper, we propose a nonrigid symmetric registration (NSR) framework for accurate alignment of pre- and post-resection volumetric ultrasound images in near real-time. We first formulate registration as the minimization of a regularized cost function, and analytically derive its derivative to efficiently optimize the cost function. We use Efficient Second order Minimization (ESM) method for fast and robust optimization. Furthermore, we use inverse-consistent deformation method to generate realistic deformation fields. The results show that NSR significantly improves the quality of alignment between pre- and post-resection ultrasound images. PMID- 26736221 TI - A hierarchical model for automated breast lesion detection from ultrasound 3D data. AB - Ultrasound imaging plays an important role in breast cancer screening for which early and accurate lesion detection is crucial for clinical practice. Many researches were performed on supporting the breast lesion detection based on ultrasound data. In the paper, a novel hierarchical model is proposed to automatically detect breast lesion from ultrasound 3D data. The model simultaneously considers the data information from low-level to high-level for the detection by processing with a joint probability. For each layer of the model, the corresponding algorithm is performed to denote the certain level image information. A dynamic programming approach is applied to efficiently obtain the optimal solution. With a preliminary dataset, the superior performance of the proposed model has been demonstrated for the automated detection of breast lesion with 0.375 false positive per case at 91.7% sensitivity. PMID- 26736222 TI - Characterization of the central sulcus in the brain in early childhood. AB - Characterization of the developing brain during early childhood is of interest for both neuroscience and medicine, and in particular, is key to understanding what goes wrong in neurodevelopmental disorders. In particular, the cortex grows rapidly in the first 3 years of life, and creating a normative atlas can provide a comparison tool to diagnose disorders at an early stage, thereby empowering early interventional therapies. Zooming in on specific sulci may provide additional targeted information, and notably, an understanding of central sulcus growth can provide important insight on the development of laterality. However, there currently do not exist any atlases of specific changes in sulci as the brain grows. In this pilot study, we explore regional differences in the depth of the central sulcus between two and three year old infants using brain magnetic resonance images. PMID- 26736223 TI - Fully-automated identification and segmentation of aortic lumen from fetal ultrasound images. AB - Intrauterine growth restriction (IUGR) is a fetal condition that has been linked to an increase in cardiovascular mortality in the adult life. IUGR induces cardiovascular remodeling, including a decrease in aortic intima-media thickness (aIMT) which can be evaluated using fetal ultrasound imaging, potentially improving IUGR assessment and cardiovascular risk management. A necessary step for aIMT quantification is the identification of a region-of-interest (ROI) containing the lumen. This step is usually performed manually, even within the few semi-automated approaches to aIMT estimation. The aims of this study were to develop and test a fully-automated technique for lumen identification and segmentation from ultrasound images as a basis for aIMT quantification. The technique relies on convolution with a set of discriminative kernels learned from a training dataset using an AdaBoost classifier followed by segmentation based on anisotropic filtering and level-set methods. This approach was tested on 50 images acquired from 5 subjects: automatically extracted mean lumen width values were compared to reference ones manually obtained by an experienced interpreter. Results (R = 0.97) show that the proposed technique is accurate, suggesting that it could serve as a basis for fully-automated approaches to aIMT quantification. PMID- 26736224 TI - Quantification of kidneys from 3D ultrasound in pediatric hydronephrosis. AB - This paper introduces a complete framework for the quantification of renal structures (parenchyma, and collecting system) in 3D ultrasound (US) images. First, the segmentation of the kidney is performed using Gabor-based appearance models (GAM), a variant of the popular active shape models, properly tailored to the imaging physics of US image data. The framework also includes a new graph-cut based method for the segmentation of the collecting system, including brightness and contrast normalization, and positional prior information. The significant advantage (p = 0.03) of the new method over previous approaches in terms of segmentation accuracy has been successfully verified on clinical 3DUS data from pediatric cases with hydronephrosis. The promising results obtained in the estimation of the volumetric hydronephrosis index demonstrate the potential of our new framework to quantify anatomy in US and asses the severity of hydronephrosis. PMID- 26736225 TI - Automatic fetal measurements for low-cost settings by using Local Phase Bone detection. AB - The estimation of gestational age is done mostly by measurements of fetal anatomical structures such as the head and femur. These measurement are also used in diagnosis and growth assessment. Manual measurements is operator dependent and hence subject to variability. PMID- 26736226 TI - Severity quantification of pediatric viral respiratory illnesses in chest X-ray images. AB - Accurate assessment of severity of viral respiratory illnesses (VRIs) allows early interventions to prevent morbidity and mortality in young children. This paper proposes a novel imaging biomarker framework with chest X-ray image for assessing VRI's severity in infants, developed specifically to meet the distinct challenges for pediatric population. The proposed framework integrates three novel technical contributions: a) lung segmentation using weighted partitioned active shape model, b) obtrusive object removal using graph cut segmentation with asymmetry constraint, and c) severity quantification using information-theoretic heterogeneity measures. This paper presents our pilot experimental results with a dataset of 148 images and the ground-truth severity scores given by a board certified pediatric pulmonologist, demonstrating the effectiveness and clinical relevance of the presented framework. PMID- 26736227 TI - Landmark detection from 3D mesh facial models for image-based analysis of dysmorphology. AB - Facial landmark detection is a task of interest for facial dysmorphology, an important factor in the diagnosis of genetic conditions. In this paper, we propose a framework for feature points detection from 3D face images. The method is based on 3D Constrained Local Model (CLM) which learns both global variations in the 3D facial scan and local changes around every vertex landmark. Compared to state of the art methods our framework is distinguished by the following novel aspects: 1) It operates on facial surfaces, 2) It allows fusion of shape and color information on the mesh surface, 3) It introduces the use of LBP descriptors on the mesh. We showcase our landmarks detection framework on a set of scans including down syndrome and control cases. We also validate our method through a series of quantitative experiments conducted with the publicly available Bosphorus database. PMID- 26736228 TI - Adaptive emergency scenery video communications using HEVC for responsive decision support in disaster incidents. AB - This study proposes a unifying framework for m-Health video communication systems that provides for the joint optimization of video quality, bitrate demands, and encoding time. The framework is video modality and infrastructure independent and facilitates adaptation to the best available encoding mode that satisfies underlying technology and application imposed constraints. The scalability of the proposed algorithm is demonstrated using different HEVC encoding configurations and realistic modelling of 802.11* wireless infrastructure for emergency scenery and response videos. Extensive experimentation shows that a jointly optimal solution in the encoding time, bitrate, and video quality space is feasible. PMID- 26736229 TI - The development of an obstetric tele-monitoring system. AB - Fetal growth restriction and preterm uterine contractions can turn a normal pregnancy into a problematic one. In previous work, we have developed a system for electrophysiological measurement of fetal heart rate (fHR), fetal electrocardiogram (fECG) and (premature) uterine contractions to enable early detection of foetal problems. In this work we have expanded this system into a tele-monitoring system for measurement at home. In order to permit home monitoring, the communication chain of the data has to be designed such that home measured signals (fHR, fECG, uterine activities) are available in the hospital in real-time. Furthermore, the data must be transferred wirelessly to any location (worldwide) for interpretation by gynaecologists. A web application helps the gynaecologist or midwife to access the signals everywhere, provided that internet access is available. We developed a webserver as the heart of the entire system; it manages the patient database, transforms the signals in a graphical representation similar to that of the cardiotocography and manages the data communication with the proper data security policy. This tele-monitoring system can be used also during home deliveries enabling prompt transfer and proper intervention in the hospital when complications occur. PMID- 26736230 TI - Synchronizing physiological data and video in a telemedicine application: A multimedia approach. AB - Several medical examinations require that multiple modalities of exams are stored in a synchronized manner. For instance, an EEG exam needs that several physiological signals along with video of the exam are acquired synchronously to aid the neurophysiologists to perform their diagnostics. Furthermore support for telemedicine for such exams have become important in recent years. The existing EDF standard that is used for physiological signals makes it difficult to provide integrated support of adding video and compressed component data, however due to widespread use of EDF standard in the domain, cross compatibility with EDF standard for physiological data is also essential. We present in this work a novel idea to solve these issues. Our approach uses standard multimedia containers in which physiological data are embedded alongside video and audio. This paper provides our analyses of the state of the art of multimedia containers EDF, AVI, ASF, MPEG and MKV and their potentials for a telemedicine application and outlines how MKV stands out as an interesting option in this regard, allowing also capability of compression of physiological data if needed. PMID- 26736231 TI - The study on a telemedicine interaction mode for Deep Brain Stimulation postoperative follow-up. AB - Since the development of information technology, telemedicine has been increasingly important in various medical activities. However, telemedicine application for Deep Brain Stimulation (DBS) has not been sufficiently perceived by the public. In this study, we first made a primary exploration to identify the DBS tele-health requirements. According to our questionnaires, 31 participants (22 patients, 9 neurosurgeons) reported an urgent remote adjustment demand. Tele program combined with video communication were a preferred communication pattern. Based on the requirements discovery, this paper proposed an appropriate interaction mode for DBS remote follow-up. System details were illustrated. Four clinical cases were done in China to test the functionality of the remote monitoring system. The results shows the interaction mode is feasible and efficient for DBS postoperative follow-up. PMID- 26736232 TI - Development and preliminary validation of an interactive remote physical therapy system. AB - In this paper, we present an interactive physical therapy system (IPTS) for remote quantitative assessment of clients in the home. The system consists of two different interactive interfaces connected through a network, for a real-time low latency video conference using audio, video, skeletal, and depth data streams from a Microsoft Kinect. To test the potential of IPTS, experiments were conducted with 5 independent living senior subjects in Kansas City, MO. Also, experiments were conducted in the lab to validate the real-time biomechanical measures calculated using the skeletal data from the Microsoft Xbox 360 Kinect and Microsoft Xbox One Kinect, with ground truth data from a Vicon motion capture system. Good agreements were found in the validation tests. The results show potential capabilities of the IPTS system to provide remote physical therapy to clients, especially older adults, who may find it difficult to visit the clinic. PMID- 26736233 TI - Psycho-physiological tele-monitoring of human operators in commercial diving: The Life Support System in the SUONO project. AB - Sea-diving operations for monitoring or intervention are carried out by highly specialized divers called Certified Commercial Divers (CCD). CCDs operate under highly demanding working conditions in extreme and hazardous environments. Every day consists of an 8 hours' shift. To avoid decompression problems the remaining 16 hours are spent in a hyperbaric environment located aboard the surface vessel or on the platform. These operating conditions require the design of a technologically-advanced device for tele-monitoring, to maximize CCDs' safety. Here we describe a proposal for monitoring and supporting CCDs during operations. We design a dedicated Life Support System (LSS), that captures real-time, vital (heart rate, respiratory rate, accelerometry, etc) and stress-related (heart-rate variability) signals from operators to transmit them to dedicated servers via telematic protocols. LSS is equipped with protocols for tele-medicine/tele consultation. Our system is being developed within the research project SUONO (Safe Underwater OperatioNs in Oceans). PMID- 26736234 TI - Influence of the surrounded tissue in the detection of microcalcifications using wavelets. AB - Breast cancer is the most common cancer in women. Many clinical decision support systems aimed to help in the diagnosis of breast cancer have been developed because an early diagnosis is fundamental to improve the results of the treatment. Most of the developments are aimed to detect microcalcifications using the same system and parameters for all the mammograms without considering any other characteristic of the breast. In this paper we introduce the type of tissue in the breast as an element that can affect the selection of the right algorithm to improve the detection rates. We adapt the system setup depending on the type of tissue improving the results of the aid system. PMID- 26736235 TI - Implementation of machine learning for classifying prosthesis type through conventional gait analysis. AB - Current forecasts imply a significant increase in the quantity of lower limb amputations. Synergizing the capabilities of a conventional gait analysis system and machine learning facilitates the capacity to classify disparate types of transtibial prostheses. Automated classification of prosthesis type may eventually advance rehabilitative acuity for selecting an appropriate prosthesis for a given aspect of the rehabilitation process. The presented research utilized a force plate as a conventional gait analysis device to acquire a feature set for two types of prosthesis: passive Solid Ankle Cushioned Heel (SACH) and the iWalk BiOM powered prosthesis. The feature set consists of both temporal and kinetic data with respect to the force plate signal during stance. Intuitively a passive prosthesis and powered prosthesis generate distinctively different force plate recordings. A support vector machine, which is type of machine learning application, achieves 100% classification between a passive prosthesis and powered prosthesis regarding the feature set derived from force plate recordings. PMID- 26736236 TI - ChRIS--A web-based neuroimaging and informatics system for collecting, organizing, processing, visualizing and sharing of medical data. AB - The utility of web browsers for general purpose computing, long anticipated, is only now coming into fruition. In this paper we present a web-based medical image data and information management software platform called ChRIS ([Boston] Children's Research Integration System). ChRIS' deep functionality allows for easy retrieval of medical image data from resources typically found in hospitals, organizes and presents information in a modern feed-like interface, provides access to a growing library of plugins that process these data - typically on a connected High Performance Compute Cluster, allows for easy data sharing between users and instances of ChRIS and provides powerful 3D visualization and real time collaboration. PMID- 26736237 TI - A semi-supervised method for predicting cancer survival using incomplete clinical data. AB - Prediction of survival for cancer patients is an open area of research. However, many of these studies focus on datasets with a large number of patients. We present a novel method that is specifically designed to address the challenge of data scarcity, which is often the case for cancer datasets. Our method is able to use unlabeled data to improve classification by adopting a semi-supervised training approach to learn an ensemble classifier. The results of applying our method to three cancer datasets show the promise of semi-supervised learning for prediction of cancer survival. PMID- 26736238 TI - Swarm intelligence applied to the risk evaluation for congenital heart surgery. AB - Particle Swarm Optimization is an optimization technique based on the positions of several particles created to find the best solution to a problem. In this work we analyze the accuracy of a modification of this algorithm to classify the levels of risk for a surgery, used as a treatment to correct children malformations that imply congenital heart diseases. PMID- 26736239 TI - An artificial system for selecting the optimal surgical team. AB - We introduce an intelligent system to optimize a team composition based on the team's historical outcomes and apply this system to compose a surgical team. The system relies on a record of the procedures performed in the past. The optimal team composition is the one with the lowest probability of unfavorable outcome. We use the theory of probability and the inclusion exclusion principle to model the probability of team outcome for a given composition. A probability value is assigned to each person of database and the probability of a team composition is calculated from them. The model allows to determine the probability of all possible team compositions even if there is no recoded procedure for some team compositions. From an analytical perspective, assembling an optimal team is equivalent to minimizing the overlap of team members who have a recurring tendency to be involved with procedures of unfavorable results. A conceptual example shows the accuracy of the proposed system on obtaining the optimal team. PMID- 26736240 TI - Field modeling for transcranial magnetic stimulation: A useful tool to understand the physiological effects of TMS? AB - Electric field calculations based on numerical methods and increasingly realistic head models are more and more used in research on Transcranial Magnetic Stimulation (TMS). However, they are still far from being established as standard tools for the planning and analysis in practical applications of TMS. Here, we start by delineating three main challenges that need to be addressed to unravel their full potential. This comprises (i) identifying and dealing with the model uncertainties, (ii) establishing a clear link between the induced fields and the physiological stimulation effects, and (iii) improving the usability of the tools for field calculation to the level that they can be easily used by non-experts. We then introduce a new version of our pipeline for field calculations (www.simnibs.org) that substantially simplifies setting up and running TMS and tDCS simulations based on Finite-Element Methods (FEM). We conclude with a brief outlook on how the new version of SimNIBS can help to target the above identified challenges. PMID- 26736241 TI - Quiet transcranial magnetic stimulation: Status and future directions. AB - A significant limitation of transcranial magnetic stimulation (TMS) is that the magnetic pulse delivery is associated with a loud clicking sound as high as 140 dB resulting from electromagnetic forces. The loud noise significantly impedes both basic research and clinical applications of TMS. It effectively makes TMS less focal since every click activates auditory cortex, brainstem, and other connected regions, synchronously with the magnetic pulse. The repetitive clicking sound can induce neuromodulation that can interfere with and confound the intended effects at the TMS target. As well, there are known concerns regarding blinding of TMS studies, hearing loss, induction of tinnitus, as well as tolerability. Addressing this need, we are developing a quiet TMS (qTMS) device that incorporates two key concepts: First, the dominant frequency components of the TMS pulse sound (typically 2-5 kHz) are shifted to higher frequencies that are above the human hearing upper threshold of about 20 kHz. Second, the TMS coil is designed electrically and mechanically to generate suprathreshold electric field pulses while minimizing the sound emitted at audible frequencies (<; 20 kHz). The enhanced acoustic properties of the coil are accomplished with a novel, layered coil design. We summarize a proof-of-concept qTMS prototype demonstrating noise loudness reduction by 19 dB(A) with ultrabrief pulses at conventional amplitudes. Further, we outline next steps to accomplish further sound reduction and suprathreshold pulse amplitudes. PMID- 26736242 TI - Dealing with artifacts in TMS-evoked EEG. AB - The artifact problem in TMS-evoked EEG is analyzed in an attempt to clarify the nature of the problem and to present solutions. The best way to deal with artifacts is to avoid them; the removal or suppression of the unavoidable artifacts should be based on accurate information about their characteristics and the properties of the signal of interest. PMID- 26736243 TI - Transcranial Direct Current Stimulation: Personalizing the neuromodulation. AB - The beneficial effects of transcranial direct current stimulation (tDCS) has been demonstrated, but the neuroscientific community is working to increase its efficiency. A promising line of advancement may be reducing the inter-individual variability of the response through the personalization of the stimulation, adapted to fit the structural and functional features of individual subjects. In this paper, we approach the personalization of stimulation parameters using modeling, a powerful tool to test montages enabling the optimization of brain's targeting. PMID- 26736244 TI - Modulation of motor performance by a monetary incentive: A pilot study. AB - It is commonly acknowledged that movement performance is determined by a trade off between accuracy requirements and energetic expenditure. However, their relative weights are subjective and depend on the perceived benefit (or cost) associated to successful movement completion. A deeper knowledge on how this trade-off affects motor behavior may suggest ways to manipulate it in pathologies, like Parkinson's disease, in which the mechanisms underlying the selection of motor response are believed to be defective. In this preliminary study, we associate a monetary incentive to successful completion of a full-body reaching task and look at the determinants of motor performance. Our preliminary results suggest that motor performance (measured as the absolute average acceleration of hand movements) increases with movement amplitude/target elevation. Overall, performance also increases with the amount of monetary incentive and with the average reward experienced in previous trials. In addition, subjects with a greater sensitivity to incentive exhibit a low sensitivity to the average reward. In contrast, subjects with a negative sensitivity to incentive exhibit a smaller sensitivity to the average reward. These results suggest that motor performance has a complex relation with its perceived benefits, and this relation is probably subject-dependent. PMID- 26736245 TI - Recruitment of small synergistic movement makes a good pianist. AB - Time-varying synergies from kinematic data can be used to discern fundamental patterns of movement. We show through simultaneous extraction of synergies from both novice and experienced pianists that movement common to both groups can be identified. The extracted synergies successfully allow for the majority of the variability of the data to be accounted for by a limited number of components. Furthermore, classification of the weightings representing the recruitment of each of the synergies accurately distinguishes between the piano playing of the two groups of subjects. However, the major differences between the two groups lie not in the synergies representing the majority of the variance of the data but in the recruitment of smaller synergies. PMID- 26736246 TI - Neuro-mechanics of muscle coordination during recumbent pedaling in post-acute stroke patients. AB - Motor impairment after stroke has been hypothesized to be related, among others, to impairments in the modular control of movement. In this study we analyzed muscle coordination and pedal forces during a recumbent pedaling exercise from a sample of post-acute stroke patients (n=5) and a population of age-matched healthy individuals (n=4). Healthy subjects and the less impaired patients showed a shared modular organization of pedaling based on 4 similar muscle synergies. The most impaired patient, characterized by a Motricity Index of 52/100, showed a reduced complexity (only 2 muscle synergies for the affected side). Differences between healthy subjects and post-stroke patients in the execution of the task were identified in terms of unbalance in mechanical work production, which well corresponded to the level of impairment. This pedaling unbalance could be traced back to different activation strategies of the 4 identified modules. Investigation on a more representative sample will provide a full characterization of the neuro-mechanics of pedaling after stroke, helping our understandings of the disruption of motor coordination at central level after stroke and of the most effective solutions for functional recovery. PMID- 26736247 TI - Agonist-to-antagonist dependency during target-directed isometric elbow flexion and extension. AB - Muscle coordination during isometric elbow contraction was investigated in this study in order to understand the agonist-to-antagonist dependency. 15 healthy subjects were recruited and instructed to perform target-directed isometric elbow flexion and extension. Electromyography (EMG) signals from both biceps and triceps were captured. Root mean square (RMS) of the EMG signals was applied to reflect the muscle activation level and fuzzy approximate entropy (fApEn) was utilized to represent the complexity of EMG signals. Mutual information (MI) was applied to analyze the inter-dependency between biceps brachii and triceps brachii. The differences in RMS and fApEn between elbow flexion and extension were non-significant. And the MI between the biceps and triceps during isometric extension was significantly higher than that during isometric flexion. Our results suggested that the lack of proficiency in using triceps may result in more dependency towards the use of antagonist during isometric elbow extension than elbow flexion. PMID- 26736248 TI - Theoretical Model and Experimental Validation of the estimated proportions of common and independent input to motor neurons. AB - Motor neurons in the spinal cord receive synaptic input that comprises common and independent components. The part of synaptic input that is common to all motor neurons is the one regulating the production of force. Therefore, its quantification is important to assess the strategy used by Central Nervous System (CNS) to control and regulate movements, especially in physiological conditions such as fatigue. In this study we present and validate a method to estimate the ratio between strengths of common and independent inputs to motor neurons and we apply this method to investigate its changes during fatigue. By means of coherence analysis we estimated the level of correlation between motor unit spike trains at the beginning and at the end of fatiguing contractions of the Tibialis Anterior muscle at three different force targets. Combining theoretical modeling and experimental data we estimated the strength of the common synaptic input with respect to the independent one. We observed a consistent increase in the proportion of the shared input to motor neurons during fatigue. This may be interpreted as a strategy used by the CNS to counteract the occurrence of fatigue and the concurrent decrease of generated force. PMID- 26736249 TI - Robot-assisted training to improve proprioception does benefit from added vibro tactile feedback. AB - Proprioception is central for motor control and its role must also be taken into account when designing motor rehabilitation training protocols. This is particularly important when dealing with motor deficits due to proprioceptive impairment such as peripheral sensory neuropathy. In these cases substituting or augmenting diminished proprioceptive sensory information might be beneficial for improving motor function. However it still remains to be understood how proprioceptive senses can be improved by training, how this would translate into motor improvement and whether additional sensory modalities during motor training contribute to the sensorimotor training process. This preliminary study investigated how proprioceptive/haptic training can be augmented by providing additional sensory information in the form of vibro-tactile feedback. We tested the acuity of the wrist proprioceptive position sense before and after robotic training in two groups of healthy subjects, one trained only with haptic feedback and one with haptic and vibro-tactile feedback. We found that only the group receiving the multimodal feedback significantly improved proprioceptive acuity. This study demonstrates that non-proprioceptive position feedback derived from another somatosensory modality is easily interpretable for humans and can contribute to an increased precision of joint position. The clinical implications of this finding will be outlined. PMID- 26736250 TI - The platelet hammer: In vitro platelet activation under repetitive hypershear. AB - Mechanical circulatory support (MCS) devices, such as ventricular assist devices and the total artificial heart, have emerged as a vital therapy for advanced and end-stage heart failure. However, MCS patients face life-long antiplatelet and anticoagulant therapy to minimize thrombotic complications resulting from the dynamic and supraphysiologic device-associated shear stress conditions, whose effect on platelet activation is poorly understood. We repeatedly exposed platelets to average shear stresses up to 1000 dyne/cm(2) for as short as 25 ms in the "platelet hammer," a syringe-capillary viscometer. Platelet activation state was measured using a modified prothrombinase assay and morphological changes analyzed using scanning electron microscopy. An increase in stress accumulation (SA), the product of shear stress and exposure time, led to an increase in the platelet activation state and post-high shear platelet activation rate, or sensitization. A significant increase in platelet activation state was observed beyond an SA of 1500 dyne-s/cm(2), with a marked increase in pseudopod length visible beyond an SA of 1000 dyne-s/cm(2). The platelet hammer may be used to study other shear-dependent pathologies and may ultimately enhance the safety and effectiveness of MCS devices and objective antithrombotic pharmacotherapy management. PMID- 26736251 TI - Modulation of platelet membrane function via exogenous lipid moiety exposure alters platelet responsiveness to shear. AB - Shear-induced platelet activation may cause life-threatening thrombosis, particularly in patients with mechanical support devices or coronary atherosclerosis. The majority of present anti-platelet agents target or interfere with biochemical, rather than physical mechanisms of platelet activation. Less data and understanding exists with regard to pharmacologic modulation of shear mediated platelet activation. In this work, we hypothesized that modulating cell membrane properties, via alteration of membrane composition through addition of exogenous lipid moieties, would alter platelet responsiveness to shear. Here we tested fatty acids, lecithin and cholesterol as additive lipid compounds. We demonstrated that incorporation of fatty acids (DHA/EPA) or lecithin into the platelet membrane triggered enhanced sensitivity of platelets to shear-mediated activation. On the other hand, cholesterol incorporation provides significant protection, limiting the effect of shear on platelet activation. These findings provide valuable insight for the development of therapeutic strategies that can modulate shear-mediated platelet activation. PMID- 26736252 TI - Evaluation of erythrocyte flow at a bearing gap in a hydrodynamically levitated centrifugal blood pump. AB - We have developed a hydrodynamically levitated centrifugal blood pump for extracorporeal circulatory support. In the blood pump, a spiral groove bearing was adopted for a thrust bearing. In the spiral groove bearing, separation of erythrocytes and plasma by plasma skimming has been postulated to occur. However, it is not clarified that plasma skimming occurs in a spiral groove bearing. The purpose of this study is to verify whether plasma skimming occurs in the spiral groove bearing of a hydrodynamically levitated centrifugal blood pump. For evaluation of plasma skimming in the spiral groove bearing, an impeller levitation performance test using a laser focus displacement meter and a microscopic visualization test of erythrocyte flow using a high-speed microscope were conducted. Bovine blood diluted with autologous plasma to adjust hematocrit to 1.0% was used as a working fluid. Hematocrit on the ridge region in the spiral groove bearing was estimated using image analysis. As a result, hematocrits on the ridge region with gaps of 45 MUm, 31 MUm, and 25 MUm were calculated as 1.0%, 0.6%, and 0.3%, respectively. Maximum skimming efficiency in this study was calculated as 70% with a gap of 25 MUm. We confirmed that separation of erythrocyte and plasma occurred in the spiral groove bearing with decrease in bearing gap in a hydrodynamically levitated centrifugal blood pump. PMID- 26736253 TI - In vitro study of an intra-aortic VAD: Effect of reverse-rotating mode on ventricular recovery. AB - Cardiac recovery has been observed in end-stage heart failure patients with mechanical circulatory support. An intra-aortic ventricular assist device (IntraVAD) is a novel rotary blood pump designed to operate in the ascending aorta behind the aortic valve, working in series with the compromised left ventricle (LV). Such a device requires optimal motion control in order to enhance the myocardial perfusion and thus promote cardiac recovery. Therefore, a reverse rotating control (RRc) mode has been proposed to increase the mean arterial pressure (MAP) in diastole where the most coronary flow occurs. The RRc mode consists of two motions - forward rotating speed (FS) and reversely rotating speed (RS). The capability of cardiac recovery of three control modes, including 'continuous', 'on/off ' and 'RRc' modes, was evaluated in vitro. Stroke work (SW), ventricular volume, coronary perfusion pressure (CPP), and arterial pulsatility index (API) were used to evaluate LV unloading, myocardial perfusion and arterial pulsatility. The results show that, all three modes increased the LV stroke work (0.98W vs 1.00W vs 1.01W for continuous, on/off and RRc, respectively; baseline 0.9W) and decreased both end-diastolic volume (EDV) and end-systolic volume (ESV). The "RRc" mode improved CPP significantly (78.4 mm Hg compared to 66.4 mmHg and 70.9 mm Hg for continuous and on/off modes; baseline 71 mm Hg). The arterial pulsatility was higher in 'RRc' mode (0.84 compared to 0.43 and 0.59; baseline 0.48). In summary, the IntraVAD operating in the RRc mode can successfully unload the LV, enhance the myocardial perfusion, and restore the arterial pulsatility; therefore, it could be a promising therapeutic option to bridge heart failure patients to recovery. PMID- 26736254 TI - Effect of valsalva in the pulmonary prosthetic conduit valve on hemodynamic function in a mock circulatory system. AB - Pulmonary conduit valves are used as one of the surgical treatment methods of congenital heart diseases. We have been designing a sophisticated pulmonary conduit valve for the right ventricular outflow tract reconstruction in pediatric patients. In this study, two types of polyester grafts with or without bulging structures for the conduit valves were used and evaluated from the hemodynamic point of view focusing on the application of these conduit valves in the grown-up congenital heart failure patients. We examined valvular function in the originally developed pulmonary mock circulatory system, which consisted of a pneumatic driven right ventricular model, a pulmonary valve chamber, and an elastic pulmonary compliance model with peripheral vascular resistance units. Prior to the measurement, a bileaflet valve was sutured in each conduit. Each conduit valve was installed in the mock right ventricular outflow portion, and its leaflet motion was obtained by using a high-speed camera synchronously with pressure and flow waveforms. As a result, we could obtain hemodynamic changes in two different types of conduits for pulmonary valves, and it was indicated that the presence of the Valsalva shape might be effective for promoting valvular response in the low cardiac output condition. PMID- 26736255 TI - Simulation of Transcatheter Aortic Valve Replacement in patient-specific aortic roots: Effect of crimping and positioning on device performance. AB - Calcific aortic valve disease (CAVD) is a cardiovascular condition that causes the progressive narrowing of the aortic valve (AV) opening, due to the growth of bone-like deposits all over the aortic root (AR). Transcatheter aortic valve replacement (TAVR), a minimally invasive procedure, has recently become the only lifesaving solution for patients that cannot tolerate the standard surgical valve replacement. However, adverse effects, such as AR injury or paravalvular leakage (PVL), may occur as a consequence of a sub-optimal procedure, due to the presence of calcifications in situ. Additionally, the crimping required for delivering the valve via stenting may damage the valve. The aim of the present study is to comparatively assess the crimping mechanics of the commercialized Edwards SAPIEN valve and an alternative polymeric valve (Polynova, Inc) and to evaluate the effect of different TAVR deployment positions using patient-specific numerical models. The optimal deployment location for achieving better patient outcomes was calculated and based on the interactions between the TAVR stent and the native AR. Results demonstrated that the Polynova valve withstands the crimping process better than the SAPIEN valve. Furthermore, deployment simulations showed the role that calcifications deposits may play in the TAVR sub-optimal valve anchoring to the AV wall, leading to the presence of gaps that result in PVL. PMID- 26736256 TI - A percentile-based coarse graining approach is helpful in symbolizing heart rate variability during graded head-up tilt. AB - Coarse graining of physiological time series such as the cardiac interbeat interval series by means of a symbolic transformation retains information about dynamical properties of the underlying system and complements standard measures of heart rate variability. The transformations of the original time series to the coarse grained symbolic series usually lead to a non-uniform occurrence of the different symbols, i.e. some symbols appear more often than others influencing the results of the subsequent symbolic series analysis. Here, we defined a transformation procedure to assure that each symbol appears with equal probability using a short alphabet {0,1,2,3} and a long alphabet {0,1,2,3,4,5}. The procedure was applied to the cardiac interbeat interval series RRi of 17 healthy subjects obtained during graded head-up tilt testing. The symbolic dynamics is analyzed by means of the occurrence of short sequences ('words') of length 3. The occurrence of words is grouped according to words without variations of the symbols (0V%), one variation (1V%), two like variations (2LV%) and two unlike variations (2UV%). Linear regression analysis with respect to tilt angle showed that for the short alphabet 0V% increased with increasing tilt angle whereas 1V%, 2LV% and 2UV% decreased. For the long alphabet 0V%, and 1V% increased with increasing tilt angle whereas 2LV% and 2UV% decreased. These results were slightly better compared to the results from non-uniform symbolic transformations reflecting the deviation from the mean. In conclusion, the symbolic transformation assuring the appearance of symbols with equal probability is capable of reflecting changes of the cardiac autonomic nervous system during graded head-up tilt. Furthermore, the transformation is independent of the time series' distribution. PMID- 26736257 TI - The fractal structure of cardiovascular beat-to-beat series described over a broad range of scales: Differences between blood pressure and heart rate, and the effect of gender. AB - The fractal characteristics of heart rate variability are usually assessed by estimating short- and long-term scale coefficients, alpha1 and alpha2, by detrended fluctuation analysis. Recently we extended this approach introducing a temporal spectrum of scale coefficients, alpha(tau), that describes the deviations of self-similarity from the bi-fractal model at each scale tau. Until now relatively short recordings were considered and alpha(tau) was characterized only for scales tau<;100 s. Aim of this work is to describe alpha(tau) of cardiovascular signals extending the range tau by an order of magnitude with respect to previous studies. We considered 2-hour recordings of systolic and diastolic blood pressure (SBP and DBP) and of pulse interval (PI) in 68 volunteers (26 males, 42 females) sitting at rest. The alpha(tau) spectra were estimated for 5s <=tau <=1000s and compared. We found important differences between alpha(tau) of SBP, DBP and PI. In particular, alpha(tau) of PI was lower than alpha(tau) of SBP at all the scales tau, with a relative maximum at tau =26 s and a minimum at tau =300 s that were completely missing in alpha(tau) of DBP. Significant differences were also found between alpha(tau) of males and females, probably linked to gender differences in the cardiovascular autonomic tone. PMID- 26736258 TI - Time, frequency and information domain analysis of heart period and QT variability in asymptomatic long QT syndrome type 2 patients. AB - This study was designed to characterize in time, frequency and information domains heart period (HP) and QT interval variabilities in asymptomatic (ASYMP) long QT syndrome type 2 (LQT2) subjects. HP, approximated as the temporal distance between two consecutive R-wave peaks, and QT, approximated as the temporal distance between the R-wave peak and the T-wave offset, were automatically derived from 24h Holter recordings in 10 ASYMP LQT2 patients and 13 healthy non mutation carriers (NMC) subjects. All analyses were carried out during DAY (from 2 to 6 PM) and NIGHT (from 12 to 4 AM). Mean, variance, spectral power and complexity indices at short, medium and long time scales were assessed over HP and QT beat-to-beat series. Circadian rhythmicity was evident in both NMC and ASYMP LQT2 but ASYMP LQT2 subjects were characterized by higher HP, QT interval and HP variability during both DAY and NIGHT. In addition, multiscale complexity analysis was able to differentiate the groups by showing a higher HP complexity and a lower QT complexity at long time scales in ASYMP LQT2 during DAY. ASYMP LQT2 exhibited a different autonomic control compared to NMC and such a differentiation could be protective and assure them a lower risk profile. PMID- 26736259 TI - Gender-specific velocity recognition of caress-like stimuli through nonlinear analysis of Heart Rate Variability. AB - This study reports on the development of a gender-specific classification system able to discern between two levels of velocity of a caress-like stimulus, through information gathered from Autonomic Nervous System (ANS) linear and nonlinear dynamics. Specifically, caress-like stimuli were administered to 32 healthy volunteers (16 males) while monitoring electrocardiogram signal to extract Heart Rate Variability (HRV) series. Caressing stimuli were administered to the forearm at a fixed force level (6 N) and two levels of velocity, 9.4 mm/s and 37 mm/s. Standard HRV measures, defined in the time and frequency domain, as well as HRV nonlinear measures were extracted during the pre- and post-stimulus sessions, and given as an input to a Support Vector Machine (SVM) classifier implementing a leave-one-subject-out procedure. Results show an accuracy of velocity recognition of 70% for the men, and 84.38% for the women, when both standard and nonlinear HRV measures were taken into account. Conversely, non-significant results were achieved considering standard measures only, or a gender-aspecific classification. We can conclude that caress-like stimuli elicitation significantly affect HRV nonlinear dynamics with a highly specific gender dependency. PMID- 26736260 TI - Influence of sleep state and position on cardio-respiratory regulation in newborn babies. AB - The paper presents results of a sleep study on 60 newborn infants and 22 one month infants, in quiet and active sleep and in prone and supine position. During the study, HRV and respiration were acquired and then analyzed with a multi parametric approach. Time, Frequency Domain and Non-Linear parameters were calculated, also encompassing indices from the adult and fetal field. The novelty of this study is the introduction of innovative measurements in a thorough investigation to characterize the effect of sleep state and position on the cardio-respiratory control in newborns. Results show that most parameters succeed in classifying different sleep states, while differences between positions were found in the one-month population only. This study comes as a continuation of previous analysis with the addition of respiratory signal. These results are encouraging for the aim of defining a set of parameters that could help characterizing the autonomic control of infants and early detect the onset of distress or particular pathologies. PMID- 26736261 TI - Cardiorespiratory and cardiovascular interactions in cardiomyopathy patients using joint symbolic dynamic analysis. AB - Cardiovascular diseases are the first cause of death in developed countries. Using electrocardiographic (ECG), blood pressure (BP) and respiratory flow signals, we obtained parameters for classifying cardiomyopathy patients. 42 patients with ischemic (ICM) and dilated (DCM) cardiomyopathies were studied. The left ventricular ejection fraction (LVEF) was used to stratify patients with low risk (LR: LVEF>35%, 14 patients) and high risk (HR: LVEF<= 35%, 28 patients) of heart attack. RR, SBP and TTot time series were extracted from the ECG, BP and respiratory flow signals, respectively. The time series were transformed to a binary space and then analyzed using Joint Symbolic Dynamic with a word length of three, characterizing them by the probability of occurrence of the words. Extracted parameters were then reduced using correlation and statistical analysis. Principal component analysis and support vector machines methods were applied to characterize the cardiorespiratory and cardiovascular interactions in ICM and DCM cardiomyopathies, obtaining an accuracy of 85.7%. PMID- 26736262 TI - Structured prediction for differentiating between normal rhythms, ventricular tachycardia, and ventricular fibrillation in the ECG. AB - Recent studies have been performed on feature selection for diagnostics between non-ventricular rhythms and ventricular arrhythmias, or between non-ventricular fibrillation and ventricular fibrillation. However they did not assess classification directly between non-ventricular rhythms, ventricular tachycardia and ventricular fibrillation, which is important in both a clinical setting and preclinical drug discovery. In this study it is shown that in a direct multiclass setting, the selected features from these studies are not capable at differentiating between ventricular tachycardia and ventricular fibrillation. A high dimensional feature space, Fourier magnitude spectra, is proposed for classification, in combination with the structured prediction method conditional random fields. An improvement in overall accuracy, and sensitivity of every category under investigation is achieved. PMID- 26736263 TI - Live ECG readings using Google Glass in emergency situations. AB - Most sudden cardiac problems require rapid treatment to preserve life. In this regard, electrocardiograms (ECG) shown on vital parameter monitoring systems help medical staff to detect problems. In some situations, such monitoring systems may display information in a less than convenient way for medical staff. For example, vital parameters are displayed on large screens outside the field of view of a surgeon during cardiac surgery. This may lead to losing time and to mistakes when problems occur during cardiac operations. In this paper we present a novel approach to display vital parameters such as the second derivative of the ECG rhythm and heart rate close to the field of view of a surgeon using Google Glass. As a preliminary assessment, we run an experimental study to verify the possibility for medical staff to identify abnormal ECG rhythms from Google Glass. This study compares 6 ECG rhythms readings from a 13.3 inch laptop screen and from the prism of Google Glass. Seven medical residents in internal medicine participated in the study. The preliminary results show that there is no difference between identifying these 6 ECG rhythms from the laptop screen versus Google Glass. Both allow close to perfect identification of the 6 common ECG rhythms. This shows the potential of connected glasses such as Google Glass to be useful in selected medical applications. PMID- 26736264 TI - Novel method for atrioventricular motion assessment from three-dimensional cine magnetic resonance imaging. AB - This study was carried out to (i) track the motion of six atrioventricular junction (AVJ) sites from the two-, three-, and four-chamber cardiovascular magnetic resonance (CMR) views in 27 healthy subjects, (ii) extract four clinically most useful AVJ velocities (i.e., myocardial systolic velocities Sm1 and Sm2, early diastolic velocity Em, and late diastolic velocity Am) for each AVJ site, and (iii) assess the relationship between CMR measurements to age and gender, and set up preliminary normal reference ranges for CMR derived AVJ velocites stratified by age and gender. The data obtained by CMR based method demonstrated that men had significant higher Sm1 (10.5+/-3.7 cm/s vs. 7.8+/-2.5 cm/s, P<;0.05) and Am (10.5+/-4.5 cm/s vs. 7.7+/-2.6 cm/s, P<;0.05), but comparable Sm2 (6.6+/-2.2 cm/s vs. 6.9+/-1.6 cm/s, P>0.05) and Em (11.2+/-3.3 cm/s vs. 11.5+/-4.3 cm/s, P>0.05) than women. There was no significant correlation between Sm1, Sm2 and age, while Em and Am strongly or moderately correlated with age. The lateral, posterolateral and posterior AVJ velocities were significant higher than the ones in septal, anteroseptal and anterior locations. Atrioventricular motion and derived velocities are independent of imaging reference frames, and thereby computationally light-weight. They can be derived by post-processing three-dimensional routine CMR images without additional image acquisition. This shall potentially extend routine CMR's capability for left ventricular (LV) systolic and diastolic function assessment. PMID- 26736265 TI - Cardiac fibrillation risks with TASER conducted electrical weapons. AB - The TASER((r)) conducted electrical weapon (CEW) delivers electrical pulses that can temporarily incapacitate subjects. We analyzed the cardiac fibrillation risk with TASER CEWs. Our risk model accounted for realistic body mass index distributions, used a new model of effects of partial or oblique dart penetration and used recent epidemiological CEW statics. PMID- 26736266 TI - Comparing twelve-lead electrocardiography with close-to-heart patch based electrocardiography. AB - Electrocardiographic (ECG) recording using adhesive patch-type ECG monitors (PEMs) has several advantages over conventional ECG recorders. However, due to the unconventional electrode locations used in PEM systems, the morphology of the acquired ECG signals may differ from conventional ECG leads used in the clinic impeding clinical interpretation. In this study, recordings from an ePatch(r) lead system involving three torso sites are compared with concurrently recorded standard 12-lead ECG. Pearson's correlation coefficients (CC) of -0.90 and 0.91 is found between two of the PEM signals and the standard 12-lead ECG signals aVR and V2, respectively. Deriving the 12-lead ECG from the PEM leads through linear transforms on a subject-specific basis yield CC values ranging from 0.78 to 0.96 between measured and derived leads. The corresponding CC values for the PEM ECG leads range from 0.88 to 0.95. It is found that the PEM lead system captures "residual" information not contained in the standard 12-lead ECG and i.a. a negative deflection after the T-wave is discovered in the PEM signals. PMID- 26736267 TI - Prediction of the time period of stroke based on ultrasound image analysis of initially asymptomatic carotid plaques. AB - Non-invasive ultrasound imaging of carotid plaques can provide information on the characteristics of the arterial wall including the size, morphology and texture of the atherosclerotic plaques. Several studies were carried out that demonstrated the usefulness of these feature sets for differentiating between asymptomatic and symptomatic plaques and their corresponding cerebrovascular risk stratification. The aim of this study was to develop predictive modelling for estimating the time period of a stroke event by determining the risk for short term (less or equal to three years) or long term (more than three years) events. Data from 108 patients that had a stroke event have been used. The information collected included clinical and ultrasound imaging data. The prediction was performed at base line where patients were still asymptomatic. Several image texture analysis and clinical features were used in order to create a classification model. The different features were statistically analyzed and we conclude that image texture analysis features extracted using Spatial Gray Level Dependencies method had the best statistical significance. Several predictive models were derived based on Binary Logistic Regression (BLR) and Support Vector Machines (SVM) modelling. The best results were obtained with the SVM modelling models with an average correct classifications score of 77+/-7% for differentiating between stroke event occurrences within 3 years versus more than 3 years. Further work is needed in investigating additional multiscale texture analysis features as well as more modelling techniques on more subjects. PMID- 26736268 TI - Modeling the Blood-Brain Barrier in a 3D triple co-culture microfluidic system. AB - The need for a blood-brain barrier (BBB) model that accurately mimics the physiological characteristics of the in-vivo situation is well-recognized by researchers in academia and industry. However, there is currently no in-vitro model allowing studies of neuronal growth and/or function influenced by factors from the blood that cross through the BBB. Therefore, we established a 3D triple co-culture microfluidic system using human umbilical vein endothelial cells (HUVEC) together with primary rat astrocytes and neurons. Immunostaining confirmed the successful triple co-culture system consisting of an intact BBB with tight intercellular junctions in the endothelial monolayer. The BBB selective permeability was determined by a fluorescent-based assay using dextrans of different molecular weights. Finally, neuron functionality was demonstrated by calcium imaging. PMID- 26736269 TI - Regulation of nuclear morphology by actomyosin components and cell geometry. AB - Extracellular microenvironmental signals modulate the coupling between cytoskeleton to nuclear links to regulate gene expression profiles. However the influence of actomyosin assembly on the morphology of the nucleus is not well understood. In this paper, we quantitatively demonstrate the role of cell geometry and specific actomyosin molecular components in their control of nuclear morphology. PMID- 26736270 TI - Novel culturing platform for brain slices and neuronal cells. AB - In this paper we demonstrate a novel culturing system for brain slices and neuronal cells, which can control the concentration of nutrients and the waste removal from the culture by adjusting the fluid flow within the device. The entire system can be placed in an incubator. The system has been tested successfully with brain slices and PC12 cells. The culture substrate can be modified using metal electrodes and/or nanostructures for conducting electrical measurements while culturing and for better mimicking the in vivo conditions. PMID- 26736271 TI - Construction of stable capillary networks using a microfluidic device. AB - Construction of stable capillary networks is required to provide sufficient oxygen and nutrients to the deep region of thick tissues, which is important in the context of 3D tissue engineering. Although conventional in vitro culture models have been used to investigate the mechanism of capillary formation, recent advances in microfluidics technologies allowed us to control biophysical and biochemical culture environments more precisely, which led to the construction of functional and stable capillary networks. In this study, endothelial cells and mesenchymal stem cells were co-cultured in microfluidic devices to construct stable capillary networks, which resulted in the construction of luminal structures covered by pericytes. Interactions between endothelial cells and mesenchymal stem cells are also discussed in the context of capillary formation. PMID- 26736272 TI - Microgrooved ultra-thin films as building blocks of future bio-hybrid actuators. AB - This paper aims to demonstrate the possibility of exploiting poly-L-lactic acid (PLLA) ultra-thin films as platforms for bio-hybrid actuation. Firstly, flat PLLA nanofilms at different concentrations (15 and 25 mg/ml in dichloromethane) were tested with contractile cardiomyocytes. The results obtained using motion vector analysis, a non-invasive method capable of estimating flow velocities on recorded videos, demonstrated that PLLA nanofilms were able to move under the contraction of muscle cells. Immunofluorescence images reflected good cell spreading, thus confirming that these films are promising matrices for bio-hybrid actuation. Subsequently, microgrooved PLLA nanofilms were fabricated, in order to drive muscle cell distribution on an anisotropic surface, thus optimizing the system's efficiency. After matrix characterization, in terms of AFM and SEM imaging, we investigated the viability and morphology of C2C12 skeletal muscle cells (a more controllable muscle cell type), 24 h after cell seeding as well as at the 7-day differentiation state. PMID- 26736273 TI - Sleep stage classification based on respiratory signal. AB - One of the research tasks, which should be solved to develop a sleep monitor, is sleep stages classification. This paper presents an algorithm for wakefulness, rapid eye movement sleep (REM) and non-REM sleep detection based on a set of 33 features, extracted from respiratory inductive plethysmography signal, and bagging classifier. Furthermore, a few heuristics based on knowledge about normal sleep structure are suggested. We used the data from 29 subjects without sleep related breathing disorders who underwent a PSG study at a sleep laboratory. Subjects were directed to the PSG study due to suspected sleep disorders. A leave one-subject-out cross-validation procedure was used for testing the classification performance. The accuracy of 77.85 +/- 6.63 and Cohen's kappa of 0.59 +/- 0.11 were achieved for the classifier. Using heuristics we increased the accuracy to 80.38 +/- 8.32 and the kappa to 0.65 +/- 0.13. We conclude that heuristics may improve the automated sleep structure detection based on the analysis of indirect information such as respiration signal and are useful for the development of home sleep monitoring system. PMID- 26736274 TI - Sleep stage classification based on bioradiolocation signals. AB - This paper presents an algorithm for the detection of wakeful state, rapid eye movement sleep (REM) and non-REM sleep based on the analysis of respiratory movements acquired through a bioradar. We used the data from 29 subjects without sleep-related breathing disorders who underwent a polysomnography study at a sleep laboratory. A leave-one-subject-out cross-validation procedure was used for testing the classification performance. Cohen's kappa of 0.56 +/- 0.16 and accuracy of 75.13 +/- 9.81 % were achieved when compared to polysomnography results. The results of our work contribute to the development of home sleep monitoring systems. PMID- 26736275 TI - Characterising insomnia: A graph spectral theory approach. AB - This paper introduces a computational approach to characterise healthy controls and insomniacs based on graph spectral theory. Based upon expert-generated hypnograms of sleep onset periods, a network of sleep stages transitions is derived to compute four similarity distances amongst subjects' sleeping patterns. A subsequent statistical analysis is performed to differentiate the 16-subject healthy group from a 16-patient disordered cohort. Our findings demonstrated that the similarity distances based on eigenvalues determination, i.e. d1 and d4 were the most reliable and robust measures to characterise insomniacs, discriminating 93% and 87% of the affected population, respectively. PMID- 26736276 TI - A Classification method for eye movements direction during REM sleep trained on wake electro-oculographic recordings. AB - Rapid eye movements (REMs) are a peculiar and intriguing aspect of REM sleep, even if their physiological function still remains unclear. During this work, a new automatic tool was developed, aimed at a complete description of REMs activity during the night, both in terms of their timing of occurrence that in term of their directional properties. A classification stage of each singular movement detected during the night according to its main direction, was in fact added to our procedure of REMs detection and ocular artifact removal. A supervised classifier was constructed, using as training and validation set EOG data recorded during voluntary saccades of five healthy volunteers. Different classification methods were tested and compared. The further information about REMs directional characteristic provided by the procedure would represent a valuable tool for a deeper investigation into REMs physiological origin and functional meaning. PMID- 26736277 TI - Improving sleep/wake detection via boundary adaptation for respiratory spectral features. AB - In previous work, respiratory spectral features have been successfully used for sleep/wake detection. They are usually extracted from several frequency bands. However, these traditional bands with fixed frequency boundaries might not be the most appropriate to optimize the sleep and wake separation. This is caused by the between-subject variability in physiology, or more specifically, in respiration during sleep. Since the optimal boundaries may relate to mean respiratory frequency over the entire night. Therefore, we propose to adapt these boundaries for each subject in terms of his/her mean respiratory frequency. The adaptive boundaries were considered as those being able to maximize the separation between sleep and wake states by means of their mean power spectral density (PSD) curves overnight. Linear regression models were used to address the association between the adaptive boundaries and mean respiratory frequency based on training data. This was then in turn used to estimate the adaptive boundaries of each test subject. Experiments were conducted on the data from 15 healthy subjects using a linear discriminant classifier with a leave-one-subject-out cross-validation. We reveal that the spectral boundary adaptation can help improve the performance of sleep/wake detection when actigraphy is absent. PMID- 26736278 TI - Automatic sleep staging using state machine-controlled decision trees. AB - Automatic sleep staging from a reduced number of channels is desirable to save time, reduce costs and make sleep monitoring more accessible by providing home based polysomnography. This paper introduces a novel algorithm for automatic scoring of sleep stages using a combination of small decision trees driven by a state machine. The algorithm uses two channels of EEG for feature extraction and has a state machine that selects a suitable decision tree for classification based on the prevailing sleep stage. Its performance has been evaluated using the complete dataset of 61 recordings from PhysioNet Sleep EDF Expanded database achieving an overall accuracy of 82% and 79% on training and test sets respectively. The algorithm has been developed with a very small number of decision tree nodes that are active at any given time making it suitable for use in resource-constrained wearable systems. PMID- 26736279 TI - A new multi-window detection approach for P-wave boundary points in electrocardiograms based on bilateral accumulative area. AB - This study presented an efficient and robust multi-window detection method for P wave boundary points in electrocardiograms on the basis of bilateral accumulative area. Through mathematical analysis, the local extreme points of bilateral accumulative area curves were respectively found in a fitting parabola, which might be regarded as a significant indicator for the morphological characteristic of boundary points. And, bilateral accumulative area curves of different window lengths had different sensitivities to the details and contours of signals. With combination of the multi-window and 12-lead synchronous detection, the proposed method could screen the optimal boundary points from all extreme points of different window lengths, and adaptively match the P-wave location. The results of the proposed method were evaluated on the dataset-3 of the standard CSE database. As a result, the value of sensitivity Se = 97.8% was obtained for the detection of P-wave, with the standard deviations of 3.9 ms and 4.8 ms respectively for the onset and offset of P-wave. PMID- 26736280 TI - A new algorithm for estimating the nu-index using sinusoidal basis functions. AB - Recently it was shown that the spatial dispersion of ventricular repolarization (SHVR) can be assessed from the surface ECG using a metric termed nu-index. In this paper, a new algorithm is presented for estimating the nu-index, allowing the inclusion of higher order terms with ease, even in the presence of noise, leading to more accurate estimates. We first introduced a new analytical model for the derivative of the average transmembrane potentials during repolarization (the dominant T-wave) based on trigonometric functions. This functional set is closed under the operation of derivation. Therefore, the nonlinear iterative optimization required by previous methods is no longer necessary. Then, we suggested an iterative linear matrix factorization method to properly estimate the leads factors and the nu-index. Several synthetic SHVR (in the range 20 to 70 ms) were simulated, employing a publicly-available forward electrophysiological model (ECGSIM), leading to a total of 240 synthetic 8-lead electrocardiographical recordings (ECG), each composed of 128 beats. Then the nu-index was estimated with the newly introduced method and compared (root mean square error, RMSE) with the theoretical values, available for each series. The simulation results confirmed the theoretical expectations and indeed showed that the nu-index estimates were improved by increasing the number of lead factors included (RMSE=0:295+/-0:037 vs 0:280+/-0:038 for 2 and 8 lead factors respectively). PMID- 26736281 TI - Visualization of multivariate physiological data for cardiorespiratory fitness assessment through ECG (R-peak) analysis. AB - The recent rise and popularization of wearable and ubiquitous fitness sensors has increased our ability to generate large amounts of multivariate data for cardiorespiratory fitness (CRF) assessment. Consequently, there is a need to find new methods to visualize and interpret CRF data without overwhelming users. Current visualizations of CRF data are mainly tabular or in the form of stacked univariate plots. Moreover, normative data differs significantly between gender, age and activity, making data interpretation yet more challenging. Here we present a CRF assessment tool based on radar plots that provides a way to represent multivariate cardiorespiratory data from electrocardiographic (ECG) signals within its normative context. To that end, 5 parameters are extracted from raw ECG data using R-peak information: mean HR, SDNN, RMSSD, HRVI and the maximal oxygen uptake, VO2max. Our tool processes ECG data and produces a visualization of the data in a way that it is easy to compare between the performance of the user and normative data. This type of representation can assist both health professionals and non-expert users in the interpretation of CRF data. PMID- 26736282 TI - Towards numerical temporal-frequency system modelling of associations between electrocardiogram and ballistocardiogram. AB - Ballistocardiogram (BCG) is a vital sign of ballistic forces generated by each heartbeat. With the advancements in related sensor and computing technologies in recent years, BCG has become far more accessible and thus regained its interest in both research and industry fields. Here we would like to promote the system modelling approach to BCG computing that allows to explore the underlying association between BCG and other physiological signals such as electrocardiogram (ECG). This is in contrast to most of the existing works in the related signal processing domain, which focus on detecting heart rate only. The system modelling approach may eventually improve the clinical significance of the BCG by extracting deeply embedded information. Towards this goal, here we present our preliminary study where we design a Wavelet-based temporal-frequency system model for associating BCG and ECG. To validate the model, we also collect simultaneous BCG and ECG recordings from 4 healthy subjects. We use the system model to build a BCG to ECG predicting algorithm. We demonstrate that this temporal-frequency model and algorithm is far superior, in terms of accuracy, to the naive method of linear modelling. PMID- 26736283 TI - Photoplethysmogram intensity ratio: A potential indicator for improving the accuracy of PTT-based cuffless blood pressure estimation. AB - The most commonly used method for cuffless blood pressure (BP) measurement is using pulse transit time (PTT), which is based on Moens-Korteweg (M-K) equation underlying the assumption that arterial geometries such as the arterial diameter keep unchanged. However, the arterial diameter is dynamic which varies over the cardiac cycle, and it is regulated through the contraction or relaxation of the vascular smooth muscle innervated primarily by the sympathetic nervous system. This may be one of the main reasons that impair the BP estimation accuracy. In this paper, we propose a novel indicator, the photoplethysmogram (PPG) intensity ratio (PIR), to evaluate the arterial diameter change. The deep breathing (DB) maneuver and Valsalva maneuver (VM) were performed on five healthy subjects for assessing parasympathetic and sympathetic nervous activities, respectively. Heart rate (HR), PTT, PIR and BP were measured from the simultaneously recorded electrocardiogram (ECG), PPG, and continuous BP. It was found that PIR increased significantly from inspiration to expiration during DB, whilst BP dipped correspondingly. Nevertheless, PIR changed positively with BP during VM. In addition, the spectral analysis revealed that the dominant frequency component of PIR, HR and SBP, shifted significantly from high frequency (HF) to low frequency (LF), but not obvious in that of PTT. These results demonstrated that PIR can be potentially used to evaluate the smooth muscle tone which modulates arterial BP in the LF range. The PTT-based BP measurement that take into account the PIR could therefore improve its estimation accuracy. PMID- 26736284 TI - Analysis of T-wave Alternans in ambulatory recordings using the ADTWA index. AB - Implantable cardioverter defibrillators (ICD) are the most effective way of preventing sudden cardiac death (SCD). However, the implantation of an ICD is an invasive procedure with associated risks and a high cost. Therefore, it is necessary to determine non-invasive risk markers that identify patients at a higher risk of suffering malignant arrhytmias. One of the most promising non invasive indices is T-wave alternans (TWA). This work assesses T-wave alternans using the Amplitude of Dominant T-Wave Alternans (ADTWA), that is derived from the dominant T wave associated to a number of consecutive beats. Data from 650 patients with heart failure enrolled in the MUSIC study were analyzed. ADTWA have higher values increasing heart rate. ADTWA was also significantly higher in SCD patients than in survivors (survivors vs. SCD: 6.60+/-1.98 vs. 7.55+/-2.53, p=0.01). ADTWA seems a promising index to identify patients with heart failure at higher risk of SCD. PMID- 26736285 TI - Improved spherical deconvolution to solve fiber crossing in diffusion-weighted MR Imaging. AB - An improved spherical deconvolution algorithm to solve fiber crossing in diffusion magnetic resonance imaging is here presented. The introduction of a regularization parameter on the reconstruction of the fibers directions allows to consider the deconvolution as a constrained least squares problem and enforces the normalization of the reconstructed directions. Moreover a new automatic stopping criterion is implemented which allows to push the algorithm to convergence. These modifications improve significantly the performance of the algorithm, decreasing the resolution limit and reconstructing better profiles of the fibers. PMID- 26736286 TI - Theoretical analysis of phantom rotations in BSD-DTI. AB - A novel method of improving accuracy of diffusion tensor imaging (DTI), called BSD-DTI (B-spatial distribution in DTI), has been recently proposed. Determination of the b matrix components using an anisotropic phantom, and derivation of the spatial distribution are of the essence in this approach. So far, a sufficient uniformity of the diffusion properties across the entire phantom has been assumed. Nevertheless, BSD-DTI is not limited only to highly homogeneous phantoms. This study describes a procedure which allows to use basically any anisotropic phantom of a precisely defined structure. PMID- 26736287 TI - Anisotropic phantoms in Magnetic Resonance Imaging. AB - Even though Magnetic Resonance Imaging (MRI) gives possibility to obtain qualitatively very good images, most quantitative results obtained by means of MRI are biased with high dependence on particular hardware parameters, imaging sequence used, and properties of analysed sample. Thus to enable comparison between results obtained on different scanners a calibration is needed. In one of the approaches to Diffusion Tensor Imaging (DTI), a B-matrix Spatial Distribution DTI (BSD-DTI) anisotropic phantoms are crucial in precise determination of the diffusion tensor. Anisotropic phantoms can be also useful as a porosity models or rock models in geology. The paper focuses on characterization of several anisotropic phantoms and describes their applications in DTI, and other domains related to MRI. PMID- 26736288 TI - The b matrix calculation using the anisotropic phantoms for DWI and DTI experiments. AB - B-matrix Spatial Distribution Diffusion Tensor Imaging (BSD-DTI) is a novel approach to imaging of the diffusion tensor. By means of the method a spatial distribution of the b matrices is determined and subsequently incorporated into diffusion tensor calculation. This paper presents experimental verification of the method. Statistical analysis of the results shows significant variation of the b matrix components through the slices and spatial b matrix maps depict inhomogeneity of the gradient distribution for MRI scanners equipped with wide bore magnets. The accuracy of the diffusion tensor determination was improved by the factor of about 3 for the isotropic phantom using the Spin Echo Diffusion sequence. PMID- 26736289 TI - The relationships between the identified critical nodes within DTI-based brain structural network using hub measurements and vulnerability measurement. AB - Network analysis of human brain connectivity based on graph theory has consistently identified sets of regions that are critically important for enabling efficient information integration and communication, especially for the understanding of cognitive functions, the discoveries of aging effects and the network change due to brain diseases. Two major approaches, hub measurement (HM) and vulnerability measurement (VM), have been proposed to detect these 'important nodes' within brain network organization. However, the relationship between the spatial localization and the number of these identified nodes found using HM and VM approaches respectively is still unknown. In this study, we aim to figure out the relationships between the identified critical nodes of brain network based on various HM and VM methods with DTI-based structural brain network. Two factors of parcellation atlases and level of scale are also considered to address the effects in the definition of these nodes. From the results, the great consistency is existed between the node identification using HM and VM approaches in the same atlases, but the divergence between different atlases and level of node scale. PMID- 26736290 TI - Automatic segmentation of short association bundles using a new multi-subject atlas of the left hemisphere fronto-parietal brain connections. AB - Human brain connection map is far from being complete. In particular the study of the superficial white matter (SWM) is an unachieved task. Its description is essential for the understanding of human brain function and the study of the pathogenesis associated to it. In this work we developed a method for the automatic creation of a SWM bundle multi-subject atlas. The atlas generation method is based on a cortical parcellation for the extraction of fibers connecting two different gyri. Then, an intra-subject fiber clustering is applied, in order to divide each bundle into sub-bundles with similar shape. After that, a two-step inter-subject fiber clustering is used in order to find the correspondence between the sub-bundles across the subjects, fuse similar clusters and discard the outliers. The method was applied to 40 subjects of a high quality HARDI database, focused on the left hemisphere fronto-parietal and insula brain regions. We obtained an atlas composed of 44 bundles connecting 22 pair of ROIs. Then the atlas was used to automatically segment 39 new subjects from the database. PMID- 26736291 TI - Evaluation of accuracy and reliability of PulseOn optical heart rate monitoring device. AB - PulseOn is a wrist-worn optical heart rate (HR) monitor based on photoplethysmography. It utilizes multi-wavelength technology and optimized sensor geometry to monitor blood flow at different depths of skin tissue, and it dynamically adapts to an optimal measurement depth in different conditions. Movement artefacts are reduced by adaptive movement-cancellation algorithms and optimized mechanics, which stabilize the sensor-to-skin contact. In this paper, we evaluated the accuracy and reliability of PulseOn technology against ECG derived HR in laboratory conditions during a wide range of physical activities and also during outdoor sports. In addition, we compared the performance to another on-the-shelf wrist-worn consumer product Mio LINK((r)). The results showed PulseOn reliability (% of time with error <;10bpm) of 94.5% with accuracy (100% - mean absolute percentage error) 96.6% as compared to ECG (vs 86.6% and 94.4% for Mio LINK((r)), correspondingly) during laboratory protocol. Similar or better reliability and accuracy was seen during normal outdoor sports activities. The results show that PulseOn provides reliability and accuracy similar to traditional chest strap ECG HR monitors during cardiovascular exercise. PMID- 26736292 TI - Pulse detection with a single accelerometer placed at the carotid artery: Performance in a real-life diagnostic test during acute hypotension. AB - Pulse detection via palpation is a basic and essential procedure in daily medical practice. We have been investigating the performance of a single accelerometer placed above the carotid artery, which is one of the recommended locations for manual palpation. A low-cost sensor attached by an adhesive measures accelerations due to carotid dilatations and whole body vibrations. A real-time demonstrator has been developed to classify 10 second- windows in "Pulse", "Motion" and "No Pulse" and to infer pulse rate. Data were obtained during a scheduled head-up tilt table test (HUTT). Our results show for a subgroup of 10 patients with acute hypotension a wide spread of "good" signal coverage ranging from as low as 37% up to 100%. Key factors compromising the performance in HUTT are motion artifacts, arrhythmias, sensor placement and sensor-skin coupling. In conclusion, pulse detection with a single accelerometer is sufficiently accurate, if good signal coverage can be achieved. PMID- 26736293 TI - Congestive heart failure patient monitoring using wearable Bio-impedance sensor technology. AB - A new technique to monitor the fluid status of congestive heart failure (CHF) patients in the hospital is proposed and verified in a clinical trial with 8 patients. A wearable Bio-impedance (BioZ) sensor allows a continuous localized measurement which can be complement clinical tools in the hospital. Thanks to the multi-parametric approach and correlation analysis with clinical reference, BioZ is successfully shown as a promising parameter for continuous and wearable CHF patient monitoring application. PMID- 26736294 TI - Wearable sensor network to study laterality of brain functions. AB - In the last decade researches on laterality of brain functions have been reinvigorated. New models of lateralization of brain functions were proposed and new methods for understanding mechanisms of asymmetry between right and left brain functions were described. We design a system to study laterality of motor and autonomic nervous system based on wearable sensors network. A mobile application was developed for analysis of upper and lower limbs movements, cardiac and respiratory function. The functionalities and experience gained with deployment of the system are described. PMID- 26736295 TI - From the design to real e-textile platforms for Rehabilitation and chronic obstructive pulmonary diseases care. AB - In this paper is described the work done to move from the concept of a monitoring system based on a sensing textile platform to the working prototype, in the frame of two different European projects: INTERACTION and WELCOME. PMID- 26736296 TI - A preliminary health technology assessment of a guidance system for interventional radiology. AB - Disruptive innovation in biomedical devices have to be carefully assessed in order to be included in the clinical practice, especially when these new systems interact with the human body. In this scenario the guidance devices for interventional radiology represent an area of great interest. In this paper a CT navigation system, SIRIO, used for percutaneous interventions such as biopsy, thermal ablation, percutaneous interventional, is tested and assessed. The technical features of the system in terms of efficacy and safety and the comparison with the traditional CT-guided biopsy are analyzed. According to the clinical evidences, biopsies carried out with SIRIO show an important reduction of number of CT scans, procedure's time and radiation dose absorbed by the patients. The analysis of the technology costs, the social impact related to the benefits to clinicians and patients are also reported. Although SIRIO does not have an appropriate reimbursement procedure, short- and long-term benefits introduced by this device are discussed. PMID- 26736297 TI - Safety-preserving closed-loop control of anesthesia. AB - In safety-critical control systems, such as closed-loop control of anesthesia, it is of utmost importance to guarantee the ability of a control approach to maintain states of the systems within a safe region. In this paper, we address the problem by applying a safety-preserving control technique to anesthesia control. The approach relies on a conservative approximation of the viability set. The set specifies initial states for which there exists an input that keeps the trajectory emanating from those states within the safe region. This approach can be applied to any type of controller which satisfies the performance criteria. Furthermore, it prevents the performance controller from taking the states out of the safe region. PMID- 26736298 TI - Validation of clinical activity tracking system in Intensive Care Unit to assess nurse workload distribution. AB - Therapeutic Intervention Score System (TISS-28) and the Nursing Activities Score (NAS) are common used to evaluate nursing workload in the Intensive Care Unit (ICU). However, they require experienced researchers to perform, are subject to user bias and experience, and are labor intensive, which all exclude regular use. A Clinical Activities Tracking System (CATS) was developed to evaluate bedside nursing activities automatically. This paper presents the validation of this system in quantifying bedside nursing activities. A total of 30 hours (1 hour/day) of nursing activities were manually recorded by trained researcher. The manually recorded total time spent on bedside nursing activities (Atime) was compared with time recorded using CATS (Ctime). A high correlation was found between Atime and Ctime with R = 0.882, and thus the actual time spent in nursing activity can be estimated using a first order polynomial function. In this study, it was found that the median Atime between 7 am-10 pm is 1.4-1.5 times higher than nursing activities at 10 pm-7 am. Results showed that CATS was able to provide unique and high information on patient bedside nursing activities. PMID- 26736299 TI - Smartphone derived movement profiles to detect changes in health status in COPD patients - A preliminary investigation. AB - Over 3.2 million people in the UK alone have the lung disease Chronic Obstructive Pulmonary Disease. Identifying when COPD patients are at risk of an exacerbation is a major problem and there is a need for smart solutions that provide us with a means of tracking patient health status. Smart-phone sensor technology provides us with an opportunity to automatically monitor patients. With sensors providing the ability to measure aspects of a patient's daily life, such a motion, methods to interpret these signals and infer health related information are needed. In this work we aim to investigate the feasibility of utilizing motion sensors, built within smartphones, to measure patient movement and to infer the health related information about the patient. We perform experiments, based on 7 COPD patients using data collected over a 12 week period for each patient, and identify a measure to distinguish between periods when a patient feels well Vs periods when a patient feels unwell. PMID- 26736300 TI - Can virtual reality trainers improve the compliance discrimination abilities of trainee surgeons? AB - The assessment of tissue compliance using a handheld tool is an important skill in medical areas such as laparoscopic and dental surgery. The increasing prevalence of virtual reality devices raises the question of whether we can exploit these systems to accelerate the training of compliance discrimination in trainee surgeons. We used a haptic feedback device and stylus to assess the abilities of naive participants to detect compliance differences with and without knowledge of results (KR) (groups 1 and 2), as well as the abilities of participants who had undergone repetitive training over several days (group 3). Kinematic analyses were carried out to objectively measure the probing action. Untrained participants had poor detection thresholds (mean just noticeable difference, JND = 33%), and we found no effect of KR (provided after each trial) on performance (mean JND = 35%). Intensive training dramatically improved group performance (mean JND = 12%). Probing action (in particular, slower movement execution) was associated with better detection thresholds, but training did not lead to systematic changes in probing behaviour. These findings set a benchmark for training systems that act to increase perceptual sensitivity and guide the learner toward optimal movement strategies to improve discrimination. PMID- 26736301 TI - Parametric estimation of sample entropy for physical activity recognition. AB - Insufficient amount of physical activity, and hence storage of calories may lead depression, obesity, cardiovascular diseases, and diabetes. The amount of consumed calorie depends on the type of activity. The recognition of physical activity is very important to estimate the amount of calories spent by a subject every day. There are some research works already published in the literature for activity recognition through accelerometers (body worn sensors). The accuracy of any recognition system depends on the robustness of selected features and classifiers. The typical features reported for most physical activities recognitions are autoregressive coefficients (ARcoeffs), signal magnitude area (SMA), tilt angle (TA), and standard deviation (STD). In this study, we have studied the feasibility of using single value of sample entropy estimated parametrically (SETH) of an AR model instead of ARcoeffs. After feasibility study, we also compared the recognition accuracies between two popular classifiers i.e. artificial neural network (ANN) and support vector machines (SVM). The recognition accuracies using linear structure (where all types of activities are classified using a single classifier) and hierarchical structure (where activities are first divided into static and dynamic events, and then activities of each event are classified in the second stage). The study showed that the use of SETH provides similar recognition accuracy (69.82%) as provided by ARcoeffs (67.67%) using ANN. The linear structure of SVM performs better (average accuracy of SVM: 98.22%) than linear ANN (average accuracy with ANN: 94.78%). The use of hierarchical structure of ANN increases the average recognition accuracy of static activities to about 100%. However, no significant changes are observed using hierarchical SVM than the linear one. PMID- 26736302 TI - A Two-stage model for inference of target identity during 2D cursor control from natural gaze trajectories. AB - We describe a two stage hidden Markov model based algorithm for inferring target identity in a 2D cursor control task where subjects are instructed to use a joystick to steer a cursor towards a target while avoiding obstacles. The first stage of the model converts a regularly sampled gaze trajectory into a sequence of fixations. The second stage then makes a determination of the end target in the cursor control task based on this sequence of fixations. In contrast to prior work, this two stage model allows for more accurate modelling of the natural eye gaze behavior of subjects, which in turn leads to increased accuracy and speed of target identification. This work demonstrates the importance of accurate gaze modelling, and paves the way for more natural and reliable hybrid Brain Computer Interfaces. PMID- 26736303 TI - Task discrimination for non-weight-bearing movements using muscle synergies. AB - Myoelectric control of lower limb prostheses requires discrimination of task specific muscle patterns. In this paper we present a method based on the notion of muscle synergies to discriminate between various non-weight-bearing movements such as knee extension/flexion, femur rotation in/out, tibia rotation in/out and ankle dorsiflexion/plantarflexion. Data is recorded from eight targeted muscle sites on the thigh. Non-negative matrix factorization is used to identify the muscle synergies using multiple features and estimation of electromyographic (EMG) patterns is done using non-negative least squares (NNLS). Classification accuracy for the movements involving the knee joint was higher than the movements involving the ankle joint. The proposed algorithm performs at par with the common machine learning algorithm Linear Discriminant Analysis (LDA) in offline analysis. PMID- 26736304 TI - Automatic misclassification rejection for LDA classifier using ROC curves. AB - This paper presents a technique to improve the performance of an LDA classifier by determining if the predicted classification output is a misclassification and thereby rejecting it. This is achieved by automatically computing a class specific threshold with the help of ROC curves. If the posterior probability of a prediction is below the threshold, the classification result is discarded. This method of minimizing false positives is beneficial in the control of electromyography (EMG) based upper-limb prosthetic devices. It is hypothesized that a unique EMG pattern is associated with a specific hand gesture. In reality, however, EMG signals are difficult to distinguish, particularly in the case of multiple finger motions, and hence classifiers are trained to recognize a set of individual gestures. However, it is imperative that misclassifications be avoided because they result in unwanted prosthetic arm motions which are detrimental to device controllability. This warrants the need for the proposed technique wherein a misclassified gesture prediction is rejected resulting in no motion of the prosthetic arm. The technique was tested using surface EMG data recorded from thirteen amputees performing seven hand gestures. Results show the number of misclassifications was effectively reduced, particularly in cases with low original classification accuracy. PMID- 26736305 TI - Upper-limb movement classification based on sEMG signal validation with continuous channel selection. AB - This paper aims to provide an efficient, automatic and auto-adaptive approach to establish a continuous electromyography (EMG) signal monitoring, to constantly identify an optimal electrode assortment to use as input of a pattern recognition method through time. The average classification accuracy for the adaptive input selection method was 83,96+/-5,79% against 72,06+/-7,15% in a non-adaptive system. Both systems make use of a neural network to classify 9 distinguish upper limb movements. PMID- 26736306 TI - Real-time motion discrimination considering variation of EMG signals associated with lapse of time. AB - This study proposes a motion discrimination method that considers the variation of electromyogram (EMG) signals associated with a lapse of time. In a previous study, we proposed a real-time discrimination method based on EMG signals of the forearm. Our method uses a hypersphere model as a discriminator. In motion discrimination using EMG signals, one problem is to maintain high discrimination accuracy over time because EMG signals change with a lapse of time. This study analyzed the effect of changes in EMG signals on our method. Based on analysis results, adding a relearning system of the decision criteria to the discrimination system was expected to be effective. We created a new motion discrimination method that contains the relearning system and experimentally verified its effectiveness. The motion discrimination system discriminated three hand motions, open, grasp, and pinch with discrimination accuracy above 90% in real-time (processing time below 300 ms) even after time elapsed. PMID- 26736307 TI - Muscular fatigue detection using sEMG in dynamic contractions. AB - In this work we have studied different indicators of muscle fatigue from the electrical signal produced by the muscles when contract (sEMG or EMG: surface electromyography): Mean Frequency of the power spectrum (MNF), Median Frequency (Fmed), Dimitrov Spectral Index (FInsm5), Root Mean Square (RMS), and Zerocrossing (ZC). The most reliable features are selected to develop a detection algorithm that estimates muscle fatigue. The approach used in the algorithm is probabilistic and is based on the technique of Gaussian Mixture Model (GMM). The system is divided into two stages: training and validation. During training, the algorithm learns the distribution of data regarding fatigue evolution; after that, the algorithm is validated with data that have not been used to train. Therefore, two experimental sessions have been performed with 6 healthy subjects for biceps. PMID- 26736308 TI - Intersession adaptation of the EEG-based detector of self-paced walking intention in stroke patients. AB - Brain-computer interfaces (BCIs) have been used in patients with motor impairments as a rehabilitation tool, allowing the control of prosthetic devices with their brain signals. Typically, before each rehabilitation session a calibration phase is recorded to account for session-specific signal changes. Calibration is often an inconvenient process due to its length and patients' fatigue-proneness. This paper focuses on improving the performance of an EEG based detector of walking intention for intersession transfer. Nine stroke subjects executed a self-paced walking task during three sessions, with one week between sessions. We performed an intersession adaptation by using 80% of one session's data and an additional 20% of a next session for training, and then we tested the detection model on the remaining part of the next session. In practice, this would constitute a longer initial calibration (40 minutes) and a shorter recalibration in subsequent sessions (10 minutes). After training set adaption we attain an average increase in performance of 13.5% over non-adaptive training. Furthermore, we used an approximation of Kullback-Leibler (KL) divergence to quantify the difference between training and testing sets for the non-adaptive and adaptive transfer. As a potential explanation for the improvement of intersession performance, we found a significant decrease in KL divergence in the case of adaptive transfer. PMID- 26736309 TI - Fitness activity classification by using multiclass support vector machines on head-worn sensors. AB - Fitness activity classification on wearable devices can provide activity-specific information and generate more accurate performance metrics. Recently, optical head-mounted displays (OHMD) like Google Glass, Sony SmartEyeglass and Recon Jet have emerged. This paper presents a novel method to classify fitness activities using head-worn accelerometer, barometric pressure sensor and GPS, with comparisons to other common mounting locations on the body. Using multiclass SVM on head-worn sensors, we obtained an average F-score of 96.66% for classifying standing, walking, running, ascending/descending stairs and cycling. The best sensor location combinations were found to be on the ankle plus another upper body location. Using three or more sensors did not show a notable improvement over the best two-sensor combinations. PMID- 26736310 TI - Towards increasing the number of commands in a hybrid brain-computer interface with combination of gaze and motor imagery. AB - Non-invasive brain-computer interface (BCI) provides a novel means of communication. This can be achieved by measuring electroencephalogram (EEG) signal over the sensory motor cortex of a person performing motor imagery (MI) tasks. However, the performance of BCI remains currently too low to be of wide practical use. A hybrid BCI system could improve the performance by combining two or more modalities such as eye tracking, and the detection of brain activity responses. In this paper, first, we propose a simultaneous hybrid BCI that combines an event-related de-synchronization (ERD) BCI and an eye tracker. Second, we aim to further improve performance by increasing the number of commands (i.e., the number of choices accessible to the user). In particular, we show a significant improvement in performance for a simultaneous gaze-MI system using a total of eight commands. The experimental task requires subjects to search for spatially located items using gaze, and select an item using MI signals. This experimental task studied visuomotor compatible and incompatible conditions. As incorporating incompatible conditions between gaze direction and MI can increase the number of choices in the hybrid BCI, our experimental task includes single-trial detection for average, compatible and incompatible conditions, using seven different classification methods. The mean accuracy for MI, and the information transfer rate (ITR) for the compatible condition is found to be higher than the average and the incompatible conditions. The results suggest that gaze-MI hybrid BCI systems can increase the number of commands, and the location of the items should be taken into account for designing the system. PMID- 26736311 TI - Physical activity group classification algorithm using triaxial acceleration and heart rate. AB - As described in this paper, a physical activity classification algorithm is proposed for energy expenditure estimation. The proposed algorithm can improve the classification accuracy using both the triaxial acceleration and heart rate. The optimal classification also contributes to improvement of the accuracy of the energy expenditures estimation. The proposed algorithm employs three indices: the heart rate reserve (%HRreserve), the filtered triaxial acceleration, and the ratio of filtered and unfiltered acceleration. The percentage HRreserve is calculated using the heart rate at rest condition and the maximum heart rate, which is calculated using Karvonen Formula. Using these three indices, a decision tree is constructed to classify physical activities into five classes: sedentary, household, moderate (excluding locomotive), locomotive, and vigorous. Evaluation results show that the average classification accuracy for 21 activities is 91%. PMID- 26736312 TI - Classification of driver fatigue in an electroencephalography-based countermeasure system with source separation module. AB - An electroencephalography (EEG)-based counter measure device could be used for fatigue detection during driving. This paper explores the classification of fatigue and alert states using power spectral density (PSD) as a feature extractor and fuzzy swarm based-artificial neural network (ANN) as a classifier. An independent component analysis of entropy rate bound minimization (ICA-ERBM) is investigated as a novel source separation technique for fatigue classification using EEG analysis. A comparison of the classification accuracy of source separator versus no source separator is presented. Classification performance based on 43 participants without the inclusion of the source separator resulted in an overall sensitivity of 71.67%, a specificity of 75.63% and an accuracy of 73.65%. However, these results were improved after the inclusion of a source separator module, resulting in an overall sensitivity of 78.16%, a specificity of 79.60% and an accuracy of 78.88% (p <; 0.05). PMID- 26736313 TI - A one-class approach to cardiotocogram assessment. AB - Cardiotocogram (CTG) is the most widely used means for the assessment of fetal condition. CTG consists of two traces one depicting the Fetal Heart Rate (FHR), and the other the Uterine Contractions (UC) activity. Many automatic methods have been proposed for the interpretation of the CTG. Most of them rely either on a binary classification approach or on a multiclass approach to come up with a decision about the class that the tracing belongs to. This work investigates the use of a one-class approach to the assessment of CTGs building a model only for the healthy data. The preliminary results are promising indicating that normal traces could be used as part of an automatic system that can detect deviations from normality. PMID- 26736314 TI - Temporal correction of detected R-peaks in ECG signals: A crucial step to improve QRS detection algorithms. AB - In the last decade the interest for heart rate variability analysis has increased tremendously. Related algorithms depend on accurate temporal localization of the heartbeat, e.g. the R-peak in electrocardiogram signals, especially in the presence of arrhythmia. This localization can be delivered by numerous solutions found in the literature which all lack an exact specification of their temporal precision. We implemented three different state-of-the-art algorithms and evaluated the precision of their R-peak localization. We suggest a method to estimate the overall R-peak temporal inaccuracy-dubbed beat slackness-of QRS detectors with respect to normal and abnormal beats. We also propose a simple algorithm that can complement existing detectors to reduce this slackness. Furthermore we define improvements to one of the three detectors allowing it to be used in real-time on mobile devices or embedded hardware. Across the entire MIT-BIH Arrhythmia Database, the average slackness of all the tested algorithms was 9ms for normal beats and 13ms for abnormal beats. Using our complementing algorithm this could be reduced to 4ms for normal beats and to 7ms for abnormal beats. The presented methods can be used to significantly improve the precision of R-peak detection and provide an additional measurement for QRS detector performance. PMID- 26736315 TI - Dry contact fingertip ECG-based authentication system using time, frequency domain features and support vector machine. AB - Acquiring fingertip ECG (electrocardiogram) signal using dry contact electrodes is challenging due to the presence of noise and interference by EMG (electromyogram) potentials. In this paper, we propose a method for using the fingertip ECG signal for biometric authentication. The noisy segments of the signal are segmented out using a variance-based heuristic and the clean signal is used for subsequent processing. By applying baseline correction and band pass filtering, the filtered signal is used for beat feature extraction. The features are used to train a support vector machine (SVM) classifier. Experimental results are presented to show the optimum filter parameters and feature sets for best classification performance. The performance of the proposed method with the optimum parameters was evaluated on a public domain CYBHi dataset with 126 subjects and the beat level EER of 3.4% was obtained. PMID- 26736316 TI - Automatic sleep staging based on ECG signals using hidden Markov models. AB - This study is designed to investigate the feasibility of automatic sleep staging using features only derived from electrocardiography (ECG) signal. The study was carried out using the framework of hidden Markov models (HMMs). The mean, and SD values of heart rates (HRs) computed from each 30-second epoch served as the features. The two feature sequences were first detrended by ensemble empirical mode decomposition (EEMD), formed as a two-dimensional feature vector, and then converted into code vectors by vector quantization (VQ) method. The output VQ indexes were utilized to estimate parameters for HMMs. The proposed model was tested and evaluated on a group of healthy individuals using leave-one-out cross validation. The automatic sleep staging results were compared with PSG estimated ones. Results showed accuracies of 82.2%, 76.0%, 76.1% and 85.5% for deep, light, REM and wake sleep, respectively. The findings proved that HRs-based HMM approach is feasible for automatic sleep staging and can pave a way for developing more efficient, robust, and simple sleep staging system suitable for home application. PMID- 26736317 TI - An enhanced cerebral recovery index for coma prognostication following cardiac arrest. AB - Prognostication of coma outcomes following cardiac arrest is both qualitative and poorly understood in current practice. Existing quantitative metrics are powerful, but lack rigorous approaches to classification. This is due, in part, to a lack of available data on the population of interest. In this paper we describe a novel retrospective data set of 167 cardiac arrest patients (spanning three institutions) who received electroencephalography (EEG) monitoring. We utilized a subset of the collected data to generate features that measured the connectivity, complexity and category of EEG activity. A subset of these features was included in a logistic regression model to estimate a dichotomized cerebral performance category score at discharge. We compared the predictive performance of our method against an established EEG-based alternative, the Cerebral Recovery Index (CRI) and show that our approach more reliably classifies patient outcomes, with an average increase in AUC of 0.27. PMID- 26736318 TI - Emotion state identification based on heart rate variability and genetic algorithm. AB - The objective of this study is to develop an effective emotion recognition system based on ECG. The proposed emotion recognition system is capable of differentiating four kinds of emotions, namely neutral, happiness, stress, and sadness, based on the heart rate variability (HRV). Ten male subjects were involved in the study. Both visual and auditory stimuli were used to stimulate the emotions. Four categories of HRV features, namely time-domain, frequency domain, Poincare plot, and differential features, were exploited to characterize the physiological changes during the affective stimuli. The support vector machine (SVM) was employed as the classifier. The genetic algorithm (GA) was exploited as feature selector. Without feature selector, only 52.2% recognition rate was achieved. However, with the GA feature selector, an optimal recognition rate of 90% was achieved. Compared with other user-independent systems published in the literature, the proposed method achieves an accuracy of 90% which is demonstrated to be the most effective for discriminating four kinds of emotions with user-independent design policy. PMID- 26736319 TI - Early mastitis diagnosis through topological analysis of biosignals from low voltage alternate current electrokinetics. AB - Mastitis is the most economically important disease of dairy cows worldwide, and it constantly plagues the dairy industry. A reliable biosensing method is thus imperative to detect this disease at its early stage and accurately identify the pathogen concentration level in order to better control the disease and consequently improve the quality of milk. Recent research indicates that shorter assay time and/or higher sensitivity can be achieved by integrating alternate current electrokinetics (ACEK) with biosensing. However, most existing ACEK devices use voltage levels around 10V at the risk of electrochemical reactions because a lower voltage may not effectively trigger the ACEK effect. Currently, there are no related works that can efficiently tackle the dilemma between avoiding electrochemical reaction and accelerating assay process. This paper adopts low-voltage (40~135mV) ACEK, which is safe but yields ambiguous biosignals within a short assay time, presenting great challenge to high-fidelity identification of pathogen concentration levels. This paper makes two distinctive contributions to the field of biosignal analysis. First, moving away from the traditional signal analysis in the time or spectral domain, we exploit the possibility of representing the biosignal through topological analysis that would reveal the intrinsic topological structure of point clouds generated from the biosignal. Second, in order to tackle another common challenge of biosignal analysis, i.e., limited sample size, we propose a so-called Gaussian-based decision tree (GDT), which can efficiently classify the biosignals even when the sample size is extremely small. Experimental results on the classification of five pathogen concentration levels using only 10 samples taken under various voltage levels demonstrate the robustness of the topological features as well as the advantage of GDT over some other conventional classifiers in handling small dataset. Our method reduces the voltage of ACEK to a safe level and still yields high-fidelity results in a short time. PMID- 26736320 TI - The respiration pattern as an indicator of the anaerobic threshold. AB - The anaerobic threshold (AT) is a good index of personal endurance but needs a laboratory setting to be determined. It is important to develop easy AT field measurements techniques in order to rapidly adapt training programs. In the present study, it is postulated that the variability of the respiratory parameters decreases with exercise intensity (especially at the AT level). The aim of this work was to assess, on healthy trained subjects, the putative relationships between the variability of some respiration parameters and the AT. The heart rate and respiratory variables (volume, rate) were measured during an incremental exercise performed on a treadmill by healthy moderately trained subjects. Results show a decrease in the variance of 1/tidal volume with the intensity of exercise. Consequently, the cumulated variance (sum of the variance measured at each level of the exercise) follows an exponential relationship with respect to the intensity to reach eventually a plateau. The amplitude of this plateau is closely related to the AT (r=-0.8). It is concluded that the AT is related to the variability of the respiration. PMID- 26736321 TI - Age group classification and gender detection based on forced expiratory spirometry. AB - This paper investigates the utility of forced expiratory spirometry (FES) test with efficient machine learning algorithms for the purpose of gender detection and age group classification. The proposed method has three main stages: feature extraction, training of the models and detection. In the first stage, some features are extracted from volume-time curve and expiratory flow-volume loop obtained from FES test. In the second stage, the probabilistic models for each gender and age group are constructed by training Gaussian mixture models (GMMs) and Support vector machine (SVM) algorithm. In the final stage, the gender (or age group) of test subject is estimated by using the trained GMM (or SVM) model. Experiments have been evaluated on a large database from 4571 subjects. The experimental results show that average correct classification rate performance of both GMM and SVM methods based on the FES test is more than 99.3 % and 96.8 % for gender and age group classification, respectively. PMID- 26736322 TI - An application of Gaussian processes on ocular artifact removal from EEG. AB - Consequences of eye movements are one of the main interferences that distort the brain EEG recordings. In this paper, a multi-modal approach is used to estimate the ocular artifacts in the EEG: both vertical and horizontal eye movement signals recorded by an eye tracker are used as a reference to denoise the EEG. A Gaussian process, i.e. a second order statistics method, is assumed to model the link between the eye tracker signals and the EEG signals. The proposed method is thus a non-linear extension of the well-known adaptive filtering and can be applied with a single EEG signal contrary to independent component analysis (ICA) which is extensively used. The results show the applicability and the efficiency of this model on the ocular artifact removal. PMID- 26736323 TI - Global EEG segmentation using singular value decomposition. AB - In this paper, we propose a method based on singular value decomposition (SVD) for segmenting multichannel electroencephalography (EEG) data into temporal blocks during which the spatial distributions of the underlying active neuronal generators stay fixed. We locate segment boundaries by statistically comparing the residual error resulting from projecting the data under a reference window, on one hand, and a sliding window, on the other hand, onto a feature subspace. The basis of this subspace is the most significant left eigenvectors of the data block under the reference window. The statistical testing is performed using the Kolmogorov-Smirnov (K-S) test. To enhance the reliability of the K-S test, the consecutive K-S decisions are aggregated under a given decision window. Simulation results confirm that the proposed algorithm can successfully detect segment boundaries under a wide range of different conditions. PMID- 26736324 TI - Reliability-based automatic repeat request for short code modulation visual evoked potentials in brain computer interfaces. AB - We propose two methods to improve code modulation visual evoked potential brain computer interfaces (cVEP BCIs). Most of BCIs average brain signals from several trials in order to improve the classification performance. The number of averaging defines the trade-off between input speed and accuracy, and the optimal averaging number depends on individual, signal acquisition system, and so forth. Firstly, we propose a novel dynamic method to estimate the averaging number for cVEP BCIs. The proposed method is based on the automatic repeat request (ARQ) that is used in communication systems. The existing cVEP BCIs employ rather longer code, such as 63-bit M-sequence. The code length also defines the trade off between input speed and accuracy. Since the reliability of the proposed BCI can be controlled by the proposed ARQ method, we introduce shorter codes, 32-bit M-sequence and the Kasami-sequence. Thanks to combine the dynamic averaging number estimation method and the shorter codes, the proposed system exhibited higher information transfer rate compared to existing cVEP BCIs. PMID- 26736325 TI - The portable P300 dialing system based on tablet and Emotiv Epoc headset. AB - A Brain-computer interface (BCI) is a novel communication system that translates brain signals into a control signal. Now with the appearance of the commercial EEG headsets and mobile smart platforms (tablet, smartphone), it is possible to develop the mobile BCI system, which can greatly improve the life quality of patients suffering from motor disease, such as amyotrophic lateral scleroses (ALS), multiple sclerosis, cerebral palsy and head trauma. This study adopted a 14-channel Emotiv EPOC headset and Microsoft surface pro 3 to realize a dialing system, which was represented by 4*3 matrices of alphanumeric characters. The performance of the online portable dialing system based on P300 is satisfying. The average classification accuracy reaches 88.75+/-10.57% in lab and 73.75+/ 16.94% in metro, while the information transfer rate (ITR) reaches 7.17+/-1.80 and 5.05+/-2.17 bits/min respectively. This means the commercial EEG headset and tablet has good prospect in developing real time BCI system in realistic environments. PMID- 26736326 TI - Using robust principal component analysis to alleviate day-to-day variability in EEG based emotion classification. AB - An emerging challenge for emotion classification using electroencephalography (EEG) is how to effectively alleviate day-to-day variability in raw data. This study employed the robust principal component analysis (RPCA) to address the problem with a posed hypothesis that background or emotion-irrelevant EEG perturbations lead to certain variability across days and somehow submerge emotion-related EEG dynamics. The empirical results of this study evidently validated our hypothesis and demonstrated the RPCA's feasibility through the analysis of a five-day dataset of 12 subjects. The RPCA allowed tackling the sparse emotion-relevant EEG dynamics from the accompanied background perturbations across days. Sequentially, leveraging the RPCA-purified EEG trials from more days appeared to improve the emotion-classification performance steadily, which was not found in the case using the raw EEG features. Therefore, incorporating the RPCA with existing emotion-aware machine-learning frameworks on a longitudinal dataset of each individual may shed light on the development of a robust affective brain-computer interface (ABCI) that can alleviate ecological inter-day variability. PMID- 26736327 TI - Classification of high frequency oscillations in epileptic intracerebral EEG. AB - High Frequency Oscillations (HFOs 40-500 Hz), recorded from intracerebral electroencephalography (iEEG) in epileptic patients, are categorized into four distinct sub-bands (Gamma, High-Gamma, Ripples and Fast Ripples). They have recently been used as a reliable biomarker of epileptogenic zones. The objective of this paper is to investigate the possibility of discriminating between the different classes of HFOs which physiological/pathological value is critical for diagnostic but remains to be clarified. The proposed method is based on the definition of a relevant feature vector built from energy ratios (computed using Wavelet Transform-WT) in a-priori-defined frequency bands. It makes use of a multiclass Linear Discriminant Analysis (LDA) and is applied to iEEG signals recorded in patients candidate to epilepsy surgery. Results obtained from bootstrap on training/test datasets indicate high performances in terms of sensitivity and specificity. PMID- 26736328 TI - Epileptic seizure detection on patients with mental retardation based on EEG features: A pilot study. AB - Mental retardation (MR) is one of the most common secondary disabilities in people with Epilepsy. However, to our knowledge there are no reliable seizure detection methods specified for MR-patients. In this paper we performed a pilot study on a group of six patients with mental retardation to assess what EEG features potentially work well on this group. A group of EEG features on the time, frequency and spatio-temporal domain were extracted, the modified wrapper approach was then employed as an improved feature subset selection method. Results show high variance on obtained features subset across this group, meanwhile there exist some common features which characterize the high-frequency components of epileptic EEG signals. PMID- 26736329 TI - Classification of convulsive psychogenic non-epileptic seizures using muscle transforms obtained from accelerometry signal. AB - Convulsive psychogenic non-epileptic seizure (PNES) can be characterized as events which mimics epileptic seizures but do not show any characteristic changes on electroencephalogram (EEG). Correct diagnosis requires video electroencephalography monitoring (VEM) as the diagnosis of PNES is extremely difficult in primary health care. Recent work has demonstrated the usefulness of accelerometry signal taken during a seizure in classification of PNES. In this work, a new direction has been explored to understand the role of different muscles in PNES. This is achieved by modeling the muscle activity of ten different upper limb muscles as a resultant function of accelerometer signal. Using these models, the accelerometer signals recorded from convulsive epileptic patients were transformed into individual muscle components. Based on this, an automated algorithm for classification of convulsive PNES is proposed. The algorithm calculates four wavelet domain features based on signal power, approximate entropy, kurtosis and signal skewness. These features were then used to build a classification model using support vector machines (SVM) classifier. It was found that the transforms corresponding to anterior deltoid and brachioradialis results in good PNES classification accuracy. The algorithm showed a high sensitivity of 93.33% and an overall PNES classification accuracy of 89% with the transform corresponding to anterior deltoid. PMID- 26736330 TI - Classification of convulsive psychogenic non-epileptic seizures using histogram of oriented motion of accelerometry signals. AB - A seizure is caused due to sudden surge of electrical activity within the brain. There is another class of seizures called psychogenic non-epileptic seizure (PNES) that mimics epilepsy, but is caused due to underlying psychology. The diagnosis of PNES is done using video-electroencephalography monitoring (VEM), which is a resource intensive process. Recently, accelerometers have been shown to be effective in classification of epileptic and non-epileptic seizures. In this work, we propose a novel feature called histogram of oriented motion (HOOM) extracted from accelerometer signals for classification of convulsive PNES. An automated algorithm based on HOOM is proposed. The algorithm showed a high sensitivity of (93.33%) and an overall accuracy of (80%) in classifying convulsive PNES. PMID- 26736331 TI - Joint collaborative representation based sleep stage classification with multi channel EEG signals. AB - Multi-channel electroencephalography (EEG) signals have been effectively used for sleet staging. However, it is still a challenge to effectively fuse and represent multi-channel EEG features. The coding based feature representation methods, such as sparse representation (SR), have achieved great success in computer vision and pattern recognition. Collaborative representation (CR) is a new coding method, which effectively works as a classifier. In this work, we first employ CR as a feature representation method. Moreover, a new joint CR (JCR) model is proposed for fusing multi-view data, which can represent not only the individual view information, but also the inner-correlative information between multi-views. JCR method is then applied to fuse and represent the features of multi-channel EEG signals for the classification of sleep stages. The experimental results indicate that CR feature outperforms SR feature, and JCR achieves best performance for sleep stage classification by effectively fusing multi-channel EEG signals. PMID- 26736332 TI - Pattern recognition with adaptive-thresholds for sleep spindle in high density EEG signals. AB - Medicine and Surgery, University of Pisa, via Savi 10, 56126, Pisa, Italy Sleep spindles are electroencephalographic oscillations peculiar of non-REM sleep, related to neuronal mechanisms underlying sleep restoration and learning consolidation. Based on their very singular morphology, sleep spindles can be visually recognized and detected, even though this approach can lead to significant mis-detections. For this reason, many efforts have been put in developing a reliable algorithm for spindle automatic detection, and a number of methods, based on different techniques, have been tested via visual validation. This work aims at improving current pattern recognition procedures for sleep spindles detection by taking into account their physiological sources of variability. We provide a method as a synthesis of the current state of art that, improving dynamic threshold adaptation, is able to follow modification of spindle characteristics as a function of sleep depth and inter-subjects variability. The algorithm has been applied to physiological data recorded by a high density EEG in order to perform a validation based on visual inspection and on evaluation of expected results from normal night sleep in healthy subjects. PMID- 26736333 TI - Sleep-stage scoring in mice: The influence of data pre-processing on a system's performance. AB - Sleep-stage analysis in mice and rats has received growing attention in recent years, due to the fact that mice display electrical activity during sleep which has underlying similarities with that of human sleep. Both conventional manual and automatic sleep-wakefulness scoring are rule based tasks which use brain waves measured by Electroencephalogram (EEG) and activity detected by Electromyography (EMG) of skeletal muscles. Several works have been conducted trying to provide an automatic sleep-scoring system on the basis of machine learning methods. In this study we try to understand the reasons behind the complexity of this problem and we emphasize the importance of normalization procedure that leads to a better stage discrimination comparing different classification methods. PMID- 26736334 TI - A brain computer interface for robust wheelchair control application based on pseudorandom code modulated Visual Evoked Potential. AB - In this pilot study, a novel and minimalistic Brain Computer Interface (BCI) based wheelchair control application was developed. The system was based on pseudorandom code modulated Visual Evoked Potentials (c-VEPs). The visual stimuli in the scheme were generated based on the Gold code, and the VEPs were recognized and classified using subject-specific algorithms. The system provided the ability of controlling a wheelchair model (LEGO((r)) MINDSTORM((r)) EV3 robot) in 4 different directions based on the elicited c-VEPs. Ten healthy subjects were evaluated in testing the system where an average accuracy of 97% was achieved. The promising results illustrate the potential of this approach when considering a real wheelchair application. PMID- 26736335 TI - EEG recordings as a source for the detection of IRBD. AB - The purpose of this pilot study was to develop a supportive algorithm for the detection of idiopathic Rapid Eye-Movement (REM) sleep Behaviour Disorder (iRBD) from EEG recordings. iRBD is defined as REM sleep without atonia with no current sign of neurodegenerative disease, and is one of the earliest known biomarkers of Parkinson's Disease (PD). It is currently diagnosed by polysomnography (PSG), primarily based on EMG recordings during REM sleep. The algorithm was developed using data collected from 42 control subjects and 34 iRBD subjects. A feature was developed to represent high amplitude contents of the EEG and a semi-automatic signal reduction method was introduced. The reduced feature set was used for a subject-based classification. With a subject specific re-scaling of the feature set and the use of an outlier detection classifier the algorithm reached an accuracy of 0.78. The result shows that EEG recordings contain valid information for a supportive algorithm for the detection of iRBD. Further investigation could lead to promising application of EEG recordings as a supportive source for the detection of iRBD. PMID- 26736336 TI - Automated sleep spindle detection using IIR filters and a Gaussian Mixture Model. AB - Sleep spindle detection using modern signal processing techniques such as the Short-Time Fourier Transform and Wavelet Analysis are common research methods. These methods are computationally intensive, especially when analysing data from overnight sleep recordings. The authors of this paper propose an alternative using pre-designed IIR filters and a multivariate Gaussian Mixture Model. Features extracted with IIR filters are clustered using a Gaussian Mixture Model without the use of any subject independent thresholds. The Algorithm was tested on a database consisting of overnight sleep PSG of 5 subjects and an online public spindles database consisting of six 30 minute sleep excerpts. An overall sensitivity of 57% and a specificity of 98.24% was achieved in the overnight database group and a sensitivity of 65.19% at a 16.9% False Positive proportion for the 6 sleep excerpts. PMID- 26736337 TI - Experimental realization of induced current magnetic resonance current density imaging. AB - In this paper, recently proposed Induced Current Magnetic Resonance Current Density Imaging (ICMRCDI) is experimentally realized. The reconstructed current density images from the simulated measurements and from the physical measurements are in agreement. The proposed method is promising in reconstructing images of electrical conductivity as well as images of induced current density distribution within the body. PMID- 26736338 TI - Event-related brain potential signaling unexpected timing of feedback: A source localization analysis. AB - Mediofrontal event-related potential (ERP) components have been extensively reported following performance error or unexpected feedback, and could reflect dopaminergic phasic changes conveyed to medial prefrontal cortex. Recent studies suggest a role for medial prefrontal cortex not only in signaling unexpected feedback but also unexpected timing of expected feedback. However, analyses of this aspect are still scarce. In this study, a task creating a condition of unexpected (anticipated) timing of a predicted feedback was designed and the associated ERP analyzed. Both an aversive and a neutral feedback were considered. ERP analysis evidenced frontocentral component elicited by unexpected, relative to expected, timing of feedback, more significant for aversive than neutral feedback. Cortical generators of this ERP component were estimated using sLORETA source localization method: we found that some regions in the frontal and prefrontal cortex may be responsive to unexpected timing of feedback, to a larger extent in case of aversive than neutral feedback. Results are discussed with respect to findings of previous works. This study can contribute to inform current theories of performance monitoring in frontal/prefrontal cortex and to drive future investigations. PMID- 26736339 TI - Tackling modelling error in the application of electrical impedance tomography to the head. AB - In the head application of Electrical Impedance Tomography (EIT), reconstruction of voltage measurements for a conductivity distribution image using an ordinary method, the absolute imaging approach, is impossible due to the traditional ignorance of modelling error. The modelling error comes from the inaccuracy of geometry and structure, which are unable to be known accurately in practice, and are usually large in head application of EIT. Difference imaging is an alternative approach which is able to reduce the size of this error, but it introduces other kinds of error. In this work, we demonstrate that in situations like head EIT, the nonlinear difference imaging approach can reconstruct difference conductivity effectively: the reduced modelling error and the new errors arising are able to be ignored, because they are much smaller than the original modelling error. The magnitude of conductivity change in the head-like situation is also investigated, and a selection scheme for the initial guess in the reconstruction process is also proposed. PMID- 26736340 TI - Mapping of language brain areas in patients with brain tumors. AB - Language cortex in the human brain shows high variability among normal individuals and may exhibit a considerable shift from its original position due to tumor growth. Mapping the precise location of language areas is important before surgery to avoid postoperative language deficits. In this paper, the Magnetoencephalography (MEG) recording and the MRI scanning of six brain tumorous subjects are used to localize the language specific areas. MEG recordings were performed during two silent reading tasks; silent word reading and silent picture naming. MEG source imaging is performed using distributed source modeling technique called CLARA ("Classical LORETA Analysis Recursively Applied"). Estimated MEG sources are overlaid on individual MRI of each patient to improve interpretation of MEG source imaging results. The results show successful identification of the essential language areas and clear definition of the time course of neural activation connecting them. PMID- 26736341 TI - EEG source localization constrained by time varying fMRI. AB - A novel approach for Electroencephalogram (EEG) and functional Magnetic Resonance Imaging (fMRI) integration analysis was developed, specifically designed to explore the spatial and temporal details of the "sequential multi-event-related potential" type of neural activities. The approach utilizes the high temporal resolution nature of EEG to compute a current density mapping of the cortical activity, informed by the high spatial resolution fMRI in a time-variant, spatially selective manner. This method was implemented in the analysis of an EEG/fMRI study on motor activation in responses to a visual stimulus that evoked an emotional response. The processed windowed EEG signals were analyzed to select the temporally relevant partial fMRI mapping, which in turn was used to inform EEG source localization calculation. The results were compared against traditional fMRI-informed EEG approaches to demonstrate the spatiotemporal variant fMRI constraints feature as well as the performance of the developed method. PMID- 26736342 TI - Estimating underlying neuronal activity from EEG using an iterative sparse technique. AB - In this paper a novel technique for solving the bio-electromagnetic inverse problem is proposed. This method provides information about the location and extent of underlying neuronal activity. This is essential for the presurgical planning for partial epilepsy patients who are resistant to anti-epileptic drugs. The proposed algorithm takes advantage of the fact that neuronal activity transparent to EEG, arises from a spatially extended brain region. This spatial coherence is modeled within the framework of sparse signal processing techniques and makes better use of the limited number of EEG recordings. An iterative data driven weighting is also introduced to better the extent estimation as well as eliminating the need to threshold estimated solutions. PMID- 26736343 TI - Voxel seed coherent source analysis on transient global amnesia patients. AB - Transient global amnesia (TGA) is a rare neurological disorder with a sudden, temporary episode of memory loss which usually occurs in old age. The episodic loss of memory becomes normal after a stipulated time of approximately 24 hours. The precise pathology is not yet completely understood. Moreover, there is no proper neuroimaging method to assess this condition. In this study, the EEG was measured at two time points one with the occurrence of the episode (acute) and the second time point after the patient returns to the normal memory condition (follow-up). The aim of the study was to look at the pathological network involved during the acute phase and the follow up phase in these patients for the five frequency bands, namely, delta, theta, alpha, beta, and gamma. The method used for the source analyses was a beamforming approach called dynamic imaging of coherent sources in the frequency domain. The seed voxel was the lesion area taken from the anatomical MRI of each patient. The cortical and subcortical network comprised of the caudate and cerebellum in case of the delta band frequency. Two temporal sources in case of the theta band. Temporal, medial frontal, parietal, putamen, and thalamus sources were found in case of the alpha band. Prefrontal, parietal, and thalamus sources were found in case of the beta band. Temporal and thalamus in case of the gamma band frequency. All these sources were involved in the acute phase. Moreover, in the follow-up phase the motor area, in all frequency bands except gamma band, was additionally active followed by parietal and occipital regions in alpha and gamma frequencies. The differences involved in the network of sources between the two phases gives us better understanding of this neurological disorder. PMID- 26736344 TI - Combining bayesian source imaging with equivalent dipole approach to solve the intracranial EEG source localization problem. AB - The brain source localization problem has been extensively studied in the past years, yielding a large panel of methodologies, each bringing their own strengths and weaknesses. Combining several of these approaches might help in enhancing their respective performance. Our study is carried out in the particular context of intracranial recordings, with the objective to explain the measurements based on a reduced number of dipolar activities. We take benefit of the sparse nature of the Bayesian approaches to separate the noise from the source space, and to distinguish between several source contributions on the electrodes. This first step provides accurate estimates of the dipole projections, which can be used as an entry to an equivalent current dipole fitting procedure. We demonstrate on simulations that the localization results are significantly enhanced by this post processing step when up to five dipoles are activated simultaneously. PMID- 26736345 TI - Impedance based automatic electrode positioning. AB - The position of electrodes in electrical imaging and stimulation of the human brain is an important variable with vast influences on the precision in modeling approaches. Nevertheless, the exact position is obscured by many factors. 3-D Digitization devices can measure the distribution over the scalp surface but remain uncomfortable in application and often imprecise. We demonstrate a new approach that uses solely the impedance information between the electrodes to determine the geometric position. The algorithm involves multidimensional scaling to create a 3 dimensional space based on these impedances. The success is demonstrated in a simulation study. An average electrode position error of 1.67cm over all 6 subjects could be achieved. PMID- 26736346 TI - Contactless vision-based pulse rate detection of Infants Under Neurological Examinations. AB - In this paper, we propose a method for detecting variations in the Pulse Rate (PR) of infants undergoing the Hammersmith Infant Neurological Examinations (HINE) using video data. As in every other medical examination the measurement of the PR is critical to underpin the physiological state of living beings. During HINE, measuring the infant's PR is important as its variations against physical conditions, age and other factors must be studied and correlated against developmental scores. However, this becomes highly complicated with active infants where their movements often lead to inconsistent PR estimation. We propose the use of a non-linear dimensionality reduction technique, called Laplacian Eigenmap (LE), to uncover the pulse information encapsulated within the high dimensional visual manifold characterized by normalized RGB feature vectors. Furthermore, low-level image filtering is applied to accurately detect PR within a chosen region-of-interest (ROI) from different parts of the infant's body. For validation and analysis, a set of 14 video sequences of infants undergoing five important tests of HINE have been chosen. Experimental results suggest that a bi parametrized combination of color features from the RG and GB channels provide more valuable information in comparison to the RB and RGB channels. Results have demonstrated that this contactless method of PR detection has promising prospects for its future use in other clinical examinations of infants. PMID- 26736347 TI - Speeding up the file access of large compressed NIfTI neuroimaging data. AB - A method and implementation are presented to achieve a thousand fold speed-up for seeking of large files in a commonly used compressed neuroimaging data format NIfTI. Such technologies are not currently available in this research field while they would make the everyday work for hundreds of researchers and experts much smoother and faster. The method includes the creation of a novel index structure for the compressed data in order to achieve the speed-up. With random seek simulations, we demonstrate that a speed-up of over hundred up to even five thousand can be reached compared to the currently available implementations. By configuring the index structure properly, one can set an operating point which optimizes the efficiency as speed-up versus index size according to the requirements by the user. For example, a thousand fold speed-up can be achieved with an index size of only about two percent of the original compressed data. PMID- 26736348 TI - Brain tumor image segmentation using kernel dictionary learning. AB - Automated brain tumor image segmentation with high accuracy and reproducibility holds a big potential to enhance the current clinical practice. Dictionary learning (DL) techniques have been applied successfully to various image processing tasks recently. In this work, kernel extensions of the DL approach are adopted. Both reconstructive and discriminative versions of the kernel DL technique are considered, which can efficiently incorporate multi-modal nonlinear feature mappings based on the kernel trick. Our novel discriminative kernel DL formulation allows joint learning of a task-driven kernel-based dictionary and a linear classifier using a K-SVD-type algorithm. The proposed approaches were tested using real brain magnetic resonance (MR) images of patients with high grade glioma. The obtained preliminary performances are competitive with the state of the art. The discriminative kernel DL approach is seen to reduce computational burden without much sacrifice in performance. PMID- 26736349 TI - Symbolic representation of brain vascular network with Arteriovenous Malformations from 3DRA images. AB - Vascular imaging is crucial in the treatment of many diseases. In the case of cerebral ArterioVenous Malformation (AVM), where the vascular network can be deeply altered, an accurate knowledge of its topology is required. For this purpose, after a vessels segmentation and skeletization applied on 3D rotational angiographic images (3DRA), we build a symbolic tree representation of the vascular network thanks to topological descriptors, such as end points, junctions and branches. This leads to an efficient tool to assist the neuroradiologist to understand the feeding and the draining of the AVM and to apprehend its complex architecture in order to determine the best therapeutic strategy before and during embolization interventions. PMID- 26736350 TI - An age estimation method using brain local features for T1-weighted images. AB - Previous statistical analysis studies using large-scale brain magnetic resonance (MR) image databases have examined that brain tissues have age-related morphological changes. This fact indicates that one can estimate the age of a subject from his/her brain MR image by evaluating morphological changes with healthy aging. This paper proposes an age estimation method using local features extracted from T1-weighted MR images. The brain local features are defined by volumes of brain tissues parcellated into local regions defined by the automated anatomical labeling atlas. The proposed method selects optimal local regions to improve the performance of age estimation. We evaluate performance of the proposed method using 1,146 T1-weighted images from a Japanese MR image database. We also discuss the medical implication of selected optimal local regions. PMID- 26736351 TI - Exploring influence of subliminal interoception on whole-brain functional network connectivity dynamics. AB - Recent fMRI studies have highlighted a dynamic relation across large-scale intrinsic connectivity networks (ICNs) of human brain. The origin of such temporal variations in functional connectivity especially during the task-free (resting-state) fMRI is still a matter of debate and ongoing investigation. In this exploratory study, we sought to determine whether subliminal differences in interoception (e.g., distention pressure on the viscera) can influence the dynamics of whole-brain functional network connectivity. A group of healthy right handed female subjects, close in age (n = 15, mean age +/- SD = 30.33 +/- 8.7 years) underwent a series of eyes-open resting-state fMRI scans under different interoceptive conditions including catheterization and partial bladder filling. Using a high-dimensional independent component analysis, the functional imaging data were parcellated into 75 components, out of which 33 were identified as non artifactual ICNs. Changes in dynamic functional network connectivity (dFNC) were evaluated using the sliding-time window approach and k-means clustering algorithm. We used subject medians for each cluster state and compared differences in dFNC correlations using a paired t-test. Following a false discovery rate multiple comparison correction threshold of p<;0.05, no significant differences in dFNC were found. However, different dwell times for each (pseudo-)resting-state were observed. More liberal statistical criteria (uncorrected p<;0.005) also indicated differences in dFNC between ICN pairs especially involving the salience, subcortical, sensorimotor, cerebellar and brainstem networks. Further investigations of the effect of internal (bodily) sensations on the time-varying aspects of functional connectivity can improve our understanding of the nature of temporal fluctuations in interrelations between intrinsic brain networks. PMID- 26736352 TI - Automatic and robust single-camera specular highlight removal in cardiac images. AB - In computer-assisted beating heart surgeries, accurate tracking of the heart's motion is of huge importance and there is a continuous need to eliminate any source of error that might disturb the tracking process. One source of error is the specular reflection that appears on the glossy surface of the heart. In this paper, we propose a robust solution for the detection and removal of specular highlights. A hybrid color attributes and wavelet based edge projection approach is applied to accurately identify the affected regions. These regions are then recovered using a dynamic search-based inpainting with adaptive windowing. Experimental results demonstrate the precision and efficiency of the proposed method. Moreover, it has a real-time performance and can be generalized to various other applications. PMID- 26736353 TI - Creating shape templates for patient specific biventricular modeling in congenital heart disease. AB - Survival rates for infants with congenital heart disease (CHD) are improving, resulting in a growing population of adults with CHD. However, the analysis of left and right ventricular function is very time-consuming owing to the variety of congenital morphologies. Efficient customization of patient geometry and function depends on high quality shape templates specifically designed for the application. In this paper, we combine a method for creating finite element shape templates with an interactive template customization to patient MRI examinations. This enables different templates to be chosen depending on patient morphology. To demonstrate this pipeline, a new biventricular template with 162 elements was created and tested in place of an existing 82-element template. The method was able to provide fast interactive biventricular analysis with 0.31 sec per edit response time. The new template was customized to 13 CHD patients with similar biventricular topology, showing improved performance over the previous template and good agreement with clinical indices. PMID- 26736354 TI - Automatic localization of the left ventricle in cardiac MRI images using deep learning. AB - Automatic localization of the left ventricle (LV) in cardiac MRI images is an essential step for automatic segmentation, functional analysis, and content based retrieval of cardiac images. In this paper, we introduce a new approach based on deep Convolutional Neural Network (CNN) to localize the LV in cardiac MRI in short axis views. A six-layer CNN with different kernel sizes was employed for feature extraction, followed by Softmax fully connected layer for classification. The pyramids of scales analysis was introduced in order to take account of the different sizes of the heart. A publically-available database of 33 patients was used for learning and testing. The proposed method was able it localize the LV with 98.66%, 83.91% and 99.07% for accuracy, sensitivity and specificity respectively. PMID- 26736355 TI - Relationship between cardiac quiescent periods derived from seismocardiography and echocardiography. AB - The seismocardiogram (SCG) is a measure of chest wall acceleration due to cardiac motion that could potentially supplement the electrocardiogram (ECG) to more reliably predict cardiac quiescence. Accurate prediction is critical for modalities requiring minimal motion during imaging data acquisition, such as cardiac computed tomography (CT) and magnetic resonance imaging (MRI). For seven healthy subjects, SCG and B-mode echocardiography were used to identify quiescent periods on a beat-by-beat basis. Quiescent periods were detected as time intervals when the magnitude of the velocity signals calculated from SCG and echocardiography were less than a specified threshold. The quiescent periods detected from SCG were compared to those detected from B-mode echocardiography. The quiescent periods of the SCG were found to occur before those detected by echocardiography. A linear relationship between the delay from SCG- to echocardiography-detected phases with respect to heart rate was found. This delay could potentially be used to predict cardiac quiescence from SCG-observed quiescence for use with cardiac imaging modalities such as CT and MRI. PMID- 26736356 TI - Identification of left ventricular systolic dysfunction and contraction inhomogeneity in post-infarction patients using a segmental two-parameter empirical deformable model. AB - Various computational models have been developed with an objective to mimic the left ventricular (LV) wall motion and establishing global and regional parameters for evaluating cardiac performance. Recently, a segmental two-parameter empirical deformable model was introduced which performs a non-rigid registration to derive contraction and rotational parameters describing the LV motion. In this work, we assessed the capability of the segmental model in identifying the impairment of the LV contraction in the post-infarction patients. The correlation between the contraction parameter, alpha/repi defined in this work and the total percentage of infarct was investigated. The temporal pattern of the contraction parameter in each LV segment at the mid ventricular slice was also analyzed throughout the systolic cardiac phases. Our results demonstrated that mean alpha/repi decreased exponentially with an increase in the infarct percentage. While normal subjects showed synchronous contraction for all LV segments, the presence of infarct regions caused LV dyssynchrony, with the infarcted segments demonstrated abnormal contraction patterns. PMID- 26736357 TI - Quantification of coronary artery Stenosis by Area Stenosis from cardiac CT angiography. AB - Non-invasive cardiac computed tomography angiography (CTA) is widely used to assess coronary artery stenosis and give clinical decision-making support to clinicians. The severity of stenosis lesion is commonly graded by a range of percent Diameter Stenosis (DS), which can introduce false positive diagnoses or over-estimation, triggering unnecessary further procedures. In this paper, a system and the associate methods to quantify stenosis by the percent Area Stenosis (AS) from cardiac CTA is presented. In the process, coronary artery tree is segmented and the centerline is extracted by Hessian filtering and the minimal path method. After a serial of 2D cross-sectional artery images along the artery centerline are obtained, lumen areas are segmented by ellipse-fitting with deformable models, and consequently to compute the lesion's AS. Experimental results on 5 CTA data sets show that compared to DS, AS better correlates to the reference standard for stenosis quantification, suggesting the efficacy of the proposed system. PMID- 26736358 TI - Brain tumor grading based on Neural Networks and Convolutional Neural Networks. AB - This paper studies brain tumor grading using multiphase MRI images and compares the results with various configurations of deep learning structure and baseline Neural Networks. The MRI images are used directly into the learning machine, with some combination operations between multiphase MRIs. Compared to other researches, which involve additional effort to design and choose feature sets, the approach used in this paper leverages the learning capability of deep learning machine. We present the grading performance on the testing data measured by the sensitivity and specificity. The results show a maximum improvement of 18% on grading performance of Convolutional Neural Networks based on sensitivity and specificity compared to Neural Networks. We also visualize the kernels trained in different layers and display some self-learned features obtained from Convolutional Neural Networks. PMID- 26736359 TI - Measurement of body joint angles for physical therapy based on mean shift tracking using two low cost Kinect images. AB - Range of motion (ROM) is commonly used to assess a patient's joint function in physical therapy. Because motion capture systems are generally very expensive, physical therapists mostly use simple rulers to measure patients' joint angles in clinical diagnosis, which will suffer from low accuracy, low reliability, and subjective. In this study we used color and depth image feature from two sets of low-cost Microsoft Kinect to reconstruct 3D joint positions, and then calculate moveable joint angles to assess the ROM. A Gaussian background model is first used to segment the human body from the depth images. The 3D coordinates of the joints are reconstructed from both color and depth images. To track the location of joints throughout the sequence more precisely, we adopt the mean shift algorithm to find out the center of voxels upon the joints. The two sets of Kinect are placed three meters away from each other and facing to the subject. The joint moveable angles and the motion data are calculated from the position of joints frame by frame. To verify the results of our system, we take the results from a motion capture system called VICON as golden standard. Our 150 test results showed that the deviation of joint moveable angles between those obtained by VICON and our system is about 4 to 8 degree in six different upper limb exercises, which are acceptable in clinical environment. PMID- 26736360 TI - Multiscale edge detection and parametric shape modeling for boundary delineation in optoacoustic images. AB - In this article, we present a novel scheme for segmenting the image boundary (with the background) in optoacoustic small animal in vivo imaging systems. The method utilizes a multiscale edge detection algorithm to generate a binary edge map. A scale dependent morphological operation is employed to clean spurious edges. Thereafter, an ellipse is fitted to the edge map through constrained parametric transformations and iterative goodness of fit calculations. The method delimits the tissue edges through the curve fitting model, which has shown high levels of accuracy. Thus, this method enables segmentation of optoacoutic images with minimal human intervention, by eliminating need of scale selection for multiscale processing and seed point determination for contour mapping. PMID- 26736361 TI - Transfer representation learning for medical image analysis. AB - There are two major challenges to overcome when developing a classifier to perform automatic disease diagnosis. First, the amount of labeled medical data is typically very limited, and a classifier cannot be effectively trained to attain high disease-detection accuracy. Second, medical domain knowledge is required to identify representative features in data for detecting a target disease. Most computer scientists and statisticians do not have such domain knowledge. In this work, we show that employing transfer learning can remedy both problems. We use Otitis Media (OM) to conduct our case study. Instead of using domain knowledge to extract features from labeled OM images, we construct features based on a dataset entirely OM-irrelevant. More specifically, we first learn a codebook in an unsupervised way from 15 million images collected from ImageNet. The codebook gives us what the encoders consider being the fundamental elements of those 15 million images. We then encode OM images using the codebook and obtain a weighting vector for each OM image. Using the resulting weighting vectors as the feature vectors of the OM images, we employ a traditional supervised learning algorithm to train an OM classifier. The achieved detection accuracy is 88.5% (89.63% in sensitivity and 86.9% in specificity), markedly higher than all previous attempts, which relied on domain experts to help extract features. PMID- 26736362 TI - Glaucoma detection based on deep convolutional neural network. AB - Glaucoma is a chronic and irreversible eye disease, which leads to deterioration in vision and quality of life. In this paper, we develop a deep learning (DL) architecture with convolutional neural network for automated glaucoma diagnosis. Deep learning systems, such as convolutional neural networks (CNNs), can infer a hierarchical representation of images to discriminate between glaucoma and non glaucoma patterns for diagnostic decisions. The proposed DL architecture contains six learned layers: four convolutional layers and two fully-connected layers. Dropout and data augmentation strategies are adopted to further boost the performance of glaucoma diagnosis. Extensive experiments are performed on the ORIGA and SCES datasets. The results show area under curve (AUC) of the receiver operating characteristic curve in glaucoma detection at 0.831 and 0.887 in the two databases, much better than state-of-the-art algorithms. The method could be used for glaucoma detection. PMID- 26736363 TI - Fuzzy membership functions for analysis of high-resolution CT images of diffuse pulmonary diseases. AB - We propose the use of fuzzy membership functions to analyze images of diffuse pulmonary diseases (DPDs) based on fractal and texture features. The features were extracted from preprocessed regions of interest (ROIs) selected from high resolution computed tomography images. The ROIs represent five different patterns of DPDs and normal lung tissue. A Gaussian mixture model (GMM) was constructed for each feature, with six Gaussians modeling the six patterns. Feature selection was performed and the GMMs of the five significant features were used. From the GMMs, fuzzy membership functions were obtained by a probability-possibility transformation and further statistical analysis was performed. An average classification accuracy of 63.5% was obtained for the six classes. For four of the six classes, the classification accuracy was superior to 65%, and the best classification accuracy was 75.5% for one class. The use of fuzzy membership functions to assist in pattern classification is an alternative to deterministic approaches to explore strategies for medical diagnosis. PMID- 26736364 TI - Classification of vertebral compression fractures in magnetic resonance images using spectral and fractal analysis. AB - Fractures with partial collapse of vertebral bodies are generically referred to as "vertebral compression fractures" or VCFs. VCFs can have different etiologies comprising trauma, bone failure related to osteoporosis, or metastatic cancer affecting bone. VCFs related to osteoporosis (benign fractures) and to cancer (malignant fractures) are commonly found in the elderly population. In the clinical setting, the differentiation between benign and malignant fractures is complex and difficult. This paper presents a study aimed at developing a system for computer-aided diagnosis to help in the differentiation between malignant and benign VCFs in magnetic resonance imaging (MRI). We used T1-weighted MRI of the lumbar spine in the sagittal plane. Images from 47 consecutive patients (31 women, 16 men, mean age 63 years) were studied, including 19 malignant fractures and 54 benign fractures. Spectral and fractal features were extracted from manually segmented images of 73 vertebral bodies with VCFs. The classification of malignant vs. benign VCFs was performed using the k-nearest neighbor classifier with the Euclidean distance. Results obtained show that combinations of features derived from Fourier and wavelet transforms, together with the fractal dimension, were able to obtain correct classification rate up to 94.7% with area under the receiver operating characteristic curve up to 0.95. PMID- 26736365 TI - Detection of blur artifacts in histopathological whole-slide images of endomyocardial biopsies. AB - Histopathological whole-slide images (WSIs) have emerged as an objective and quantitative means for image-based disease diagnosis. However, WSIs may contain acquisition artifacts that affect downstream image feature extraction and quantitative disease diagnosis. We develop a method for detecting blur artifacts in WSIs using distributions of local blur metrics. As features, these distributions enable accurate classification of WSI regions as sharp or blurry. We evaluate our method using over 1000 portions of an endomyocardial biopsy (EMB) WSI. Results indicate that local blur metrics accurately detect blurry image regions. PMID- 26736366 TI - Blood detection in wireless capsule endoscope images based on salient superpixels. AB - Wireless capsule endoscopy (WCE) enables screening of the gastrointestinal (GI) tract with a miniature, optical endoscope packed within a small swallowable capsule, wirelessly transmitting color images. In this paper we propose a novel method for automatic blood detection in contemporary WCE images. Blood is an alarming indication for the presence of pathologies requiring further treatment. The proposed method is based on a new definition of superpixel saliency. The saliency of superpixels is assessed upon their color, enabling the identification of image regions that are likely to contain blood. The blood patterns are recognized by their color features using a supervised learning machine. Experiments performed on a public dataset using automatically selected first order statistical features from various color components indicate that the proposed method outperforms state-of-the-art methods. PMID- 26736367 TI - Voice pathology classification based on High-Speed Videoendoscopy. AB - This work presents a method for automatical and objective classification of patients with healthy and pathological vocal fold vibration impairments using High-Speed Videoendoscopy of the larynx. We used an image segmentation and extraction of a novel set of numerical parameters describing the spatio-temporal dynamics of vocal folds to classification according to the normal and pathological cases and achieved 73,3% cross-validation classification accuracy. This approach is promising to develop an automatic diagnosis tool of voice disorders. PMID- 26736368 TI - Automatic segmentation of the rima glottidis in 4D laryngeal CT scans in Parkinson's disease. AB - Parkinson's disease (PD) is a progressive, incurable neuro-degenerative disease. Symptoms appear when approximately 70% of mid-brain dopaminergic neurons have died. Temporal analysis of the calculated area of the rima glottidis may give an indication of vocal impairment. In this paper, we present an automatic segmentation algorithm to segment the rima glottidis from 4D CT images using texture features and support vector machines (SVM). Automatic two dimensional region growing is then applied as a post processing step to segment the area accurately. The proposed segmentation algorithm resulted in accurate segmentation and we demonstrate a high correlation between the manually segmented area and automatic segmentation. PMID- 26736369 TI - Automatic detection of cell divisions (mitosis) in live-imaging microscopy images using Convolutional Neural Networks. AB - We propose a semi-automated pipeline for the detection of possible cell divisions in live-imaging microscopy and the classification of these mitosis candidates using a Convolutional Neural Network (CNN). We use time-lapse images of NIH3T3 scratch assay cultures, extract patches around bright candidate regions that then undergo segmentation and binarization, followed by a classification of the binary patches into either containing or not containing cell division. The classification is performed by training a Convolutional Neural Network on a specially constructed database. We show strong results of AUC = 0.91 and F-score = 0.89, competitive with state-of-the-art methods in this field. PMID- 26736370 TI - A multi-environment dataset for activity of daily living recognition in video streams. AB - Public datasets played a key role in the increasing level of interest that vision based human action recognition has attracted in last years. While the production of such datasets has been influenced by the variability introduced by various actors performing the actions, the different modalities of interactions with the environment introduced by the variation of the scenes around the actors has been scarcely took into account. As a consequence, public datasets do not provide a proper test-bed for recognition algorithms that aim at achieving high accuracy, irrespective of the environment where actions are performed. This is all the more so, when systems are designed to recognize activities of daily living (ADL), which are characterized by a high level of human-environment interaction. For that reason, we present in this manuscript the MEA dataset, a new multi environment ADL dataset, which permitted us to show how the change of scenario can affect the performances of state-of-the-art approaches for action recognition. PMID- 26736371 TI - Estimating flow rate and total volume of simulated urine flow noninvasively from a monocular camera. AB - Urodynamics measurement tools in practical use carry the risk of nosocomial infection and invasiveness. Our study proposes a new method for urinary flow estimation. We propose multiple cylindrical model to estimate the amount of liquid volume from images taken by a monocular camera. This model is based on the idea of calculating the total volume of cylinder extracted from each image. First, images of liquid simulating male urination are binarized to derive features for the model. Each volume of cylinder is calculated by the initial velocity and diameter of liquid in each image. We conducted experiments to evaluate the model by comparing our estimated volume and flow rate to the data acquired from uroflowmeter in practical use. As a result, estimation was within the accuracy of +/-10% which is enough accuracy of actual uroflowmeter being used in Japanese hospitals for practical use. PMID- 26736372 TI - Follow-me: A new start-and-stop method for visual animal tracking in biology research. AB - Very frequently, research in biology and ethology requires visual tracking of live animals, such as insects, rodents and fish. The challenge is particularly difficult in the aquatic environment because of the light scattering effect of water: reflections and refractions, low contrast and resolution images, noise, and also due to the unpredictable animal behavior. This paper describes a new tracking method that is based in start and stop detection. When the animals stop or move very slowly, a precise tracker based on AdaBoost classifiers is applied. Otherwise, when they move faster, a more efficient process based on background detection is used. A control system is responsible for deciding which method should be used in each instant. The experimental results using sea cucumbers (Echinodermata, Holothuroidea), zebrafish and rodents, show the efficiency and accuracy of the proposed method, which is able to deal with complex situations. PMID- 26736373 TI - Hyperspectral image acquisition and analysis of cultured bacteria for the discrimination of urinary tract infections. AB - Because of their widespread diffusion and impact on human health, early identification of pathogens responsible for urinary tract infections (UTI) is one of the main challenges of clinical microbiology. Currently, bacteria culturing on Chromogenic plates is widely adopted for UTI detection for its readily interpretable visual outcomes. However, the search of alternate solutions can be highly attractive, especially in the rapidly developing context of bacteriology laboratory automation and digitization, as long as they can improve cost effectiveness or allow early discrimination. In this work, we consider and develop hyperspectral image acquisition and analysis solutions to verify the feasibility of a "virtual chromogenic agar" approach, based on the acquisition of spectral signatures from bacterial colonies growing on blood agar plates, and their interpretation by means of machine learning solutions. We implemented and tested two classification approaches (PCA+SVM and RSIMCA) that evidenced good capability to discriminate among five selected UTI bacteria. For its better performance, robustness and attitude to work with an expanding set of pathogens, we conclude that the RSIMCA-based approach is worth to be further investigated in a clinical usage perspective. PMID- 26736374 TI - A tool for the quantification of radial neo-vessels in chick chorioallantoic membrane angiogenic assays. AB - Angiogenesis, the process of new blood vessels formation, plays a key role in different physiological and pathological conditions and it is considered a promising target for the development of new anti-inflammatory and anti-tumor therapies. Several assays have been developed to mimic the angiogenic process in vitro and in vivo. Here we propose a technique for the quantification of the pro angiogenic or anti-angiogenic responses induced by different molecules when implanted in vivo on the chick embryo chorioallantoic membrane (CAM). At day 11 of development CAM is completely vascularized and neo-vessels induced by exogenous molecules converge radially to the implant. Our algorithm is an effective and rapid tool to characterize molecules endowed with proor anti angiogenic effects by means of the quantification of the vessels present in the CAM macroscopic images. Based on conventional and dedicated image morphology tools, the proposed technique is able to discriminate radial from non-radial vessels, excluding the last ones from the count. PMID- 26736375 TI - Eigenfoot decomposition of plantar pressure images and case study of feature prediction of two modalities. AB - The registration of plantar pressure images is a widely used technique to support human gait analysis. In plantar pressure images, most of the time conventionally derived features are used for further processing. Recently, automatic feature extraction based on PCA and kPCA is being used, to increase the information that can be extracted from this data. In this paper, we describe our work flow and a case study on the application of predicting two pressure features and a non pressure feature out of the automatically derived PCA features. This includes the normalization of the pressure images, the PCA based feature extraction, and building and testing the regression model based on a linear and kernel SVM. PMID- 26736376 TI - Moddicom: a complete and easily accessible library for prognostic evaluations relying on image features. AB - Decision Support Systems (DSSs) are increasingly exploited in the area of prognostic evaluations. For predicting the effect of therapies on patients, the trend is now to use image features, i.e. information that can be automatically computed by considering images resulting by analysis. The DSSs application as predictive tools is particularly suitable for cancer treatment, given the peculiarities of the disease -which is highly localised and lead to significant social costs- and the large number of images that are available for each patient. At the state of the art, there exists tools that allow to handle image features for prognostic evaluations, but they are not designed for medical experts. They require either a strong engineering or computer science background since they do not integrate all the required functions, such as image retrieval and storage. In this paper we fill this gap by proposing Moddicom, a user-friendly complete library specifically designed to be exploited by physicians. A preliminary experimental analysis, performed by a medical expert that used the tool, demonstrates the efficiency and the effectiveness of Moddicom. PMID- 26736377 TI - A 3D sparse motion field filtering for quantitative analysis of fascial layers mobility based on 3D ultrasound scans. AB - In the last few years, there has been an increasing interest in the role of deep fascia mobility in musculoskeletal dynamics and chronic pain mechanisms. In a previous paper we presented an innovative semiautomatic approach to evaluate the 3D motion of the fascia using ultrasound (US) imaging, generating a sparse deformation vector field. This paper presents an improvement of our original method, focusing on the filtering of the sparse vector field and its validation. Moreover, in order to evaluate the performance of the algorithm, a method is proposed to generate synthetic deformation vector fields, including: expansion, rotation, horizontal shear, and oblique shear components. Preliminary tests on the final synthetic deformation vector fields showed promising results. Further experiments are required in order to optimize the tuning of the algorithm. PMID- 26736378 TI - Differential evolution based advised SVM for histopathalogical image analysis for skin cancer detection. AB - Automated detection of cancerous tissue in histopathological images is a big challenge. This work proposed a new pattern recognition method for histopathological image analysis for identification of cancerous tissues. It comprised of feature extraction using a combination of wavelet and intensity based statistical features and autoregressive parameters. Moreover, differential evolution based feature selection is used for dimensionality reduction and an efficient self-advised version of support vector machine is used for evaluation of selected features and for the classification of images. The proposed system is trained and tested using a dataset of 150 histopathological images and showed promising comparative results with an average diagnostic accuracy of 89.1%. PMID- 26736379 TI - Transfer learning for Bag-of-Visual words approach to NBI endoscopic image classification. AB - We address a problem of endoscopic image classification taken by different (e.g., old and new) endoscopies. Our proposed method formulates the problem as a constraint optimization that estimates a linear transformation between feature vectors (or Bag-of-Visual words histograms) in a framework of transfer learning. Experimental results show that the proposed method works much better than the case without feature transformation. PMID- 26736380 TI - Preprocessing with image denoising and histogram equalization for endoscopy image analysis using texture analysis. AB - A preprocessing method for endoscopy image analysis using texture analysis is proposed. In a previous study, we proposed a feature value that combines a co occurrence matrix and a run-length matrix to analyze the extent of early gastric cancer from images taken with narrow-band imaging endoscopy. However, the obtained feature value does not identify lesion zones correctly due to the influence of noise and halation. Therefore, we propose a new preprocessing method with a non-local means filter for de-noising and contrast limited adaptive histogram equalization. We have confirmed that the pattern of gastric mucosa in images can be improved by the proposed method. Furthermore, the lesion zone is shown more correctly by the obtained color map. PMID- 26736381 TI - Segmentation of ultrasound images of fetal anatomic structures using random forest for low-cost settings. AB - In ultrasound imaging, manual extraction of contours of fetal anatomic structures from echographic images have been found to be very challenging due to speckles and low contrast characteristic features. Contours extracted are therefore associated with variability of human observers. In this case, the contours that are extracted are not reproducible and hence not reliable. This challenge has called for the need to develop a method that can accurately segment the fetal anatomic structures. This will help to estimate and measure the contours of the structures of fetal bodies such as the head circumference, femur length, etc. Most recent methods are able to integrate global shape and appearance. The drawback to most of these methods is that, they are not able to handle localized appearance variations. They only rely on an assumption of Gaussian gray value distribution and also require initialization near the optimal solution. In this manuscript random forest is used to segment head contour in fetal ultrasound scans acquired in low-cost settings, such as acquisition performed in rural areas of low-income countries using low-cost portable machines. PMID- 26736382 TI - Convolutional neural networks for mammography mass lesion classification. AB - Feature extraction is a fundamental step when mammography image analysis is addressed using learning based approaches. Traditionally, problem dependent handcrafted features are used to represent the content of images. An alternative approach successfully applied in other domains is the use of neural networks to automatically discover good features. This work presents an evaluation of convolutional neural networks to learn features for mammography mass lesions before feeding them to a classification stage. Experimental results showed that this approach is a suitable strategy outperforming the state-of-the-art representation from 79.9% to 86% in terms of area under the ROC curve. PMID- 26736384 TI - Development of a multichannel implantable connector. AB - Further development of active implantable medical devices (AIMDs) coming along with higher channel counts and improved maintainability raises the requirements for implantable connectors in such systems. We developed a concept for an implantable multichannel connector. Contact pads manufactured by laser structuring that are embedded into a silicone substrate serve as contact partners. Processing features specific to two laser technologies were exploited not only to cut the materials but also to 3D-shape the surfaces of the contact pads. First tests for the long-term behavior show stable contact and isolation properties during 6 weeks of soaking at elevated temperature. PMID- 26736385 TI - Non-hermetic encapsulation for implantable electronic devices based on epoxy. AB - Hermetic and non-hermetic implant packaging are the two strategies to protect electronic systems from the humid conditions inside the human body. Within the scope of this work twelve different material combinations for a non-hermetic, high-reliable epoxy based encapsulation technique were characterized. Three EPO TEK (ET) epoxies and one low budget epoxy were chosen for studies with respect to their processability, water vapor transmission rate (WVTR) and adhesion to two different ceramic-based substrates as well as to one standard FR4-substrate. Setups were built to analyze the mentioned properties for at least 30 days using an aging test in a moist environment. As secondary test subjects, commercially available USB flash drives (UFD) were successfully encapsulated inside the epoxies, soaked in phosphate buffered saline (PBS, pH=7.4), stored in an incubator (37 degrees C) and tested for 256 days without failure. By means of epoxy WVTR (0.0278 g/day/m(2)) and degrease of adhesion (24.59 %) during 30 days in PBS, the combination of the standard FR4-substrate and the epoxy ET 301-2 was found to feature the best encapsulation properties. If a ceramic-based electronic system has to be used, the most promising combination consists of the alumina substrate and the epoxy ET 302-3M (WVTR: 0.0588 g/day/m(2); adhesion drop: 49.58 %). PMID- 26736386 TI - On the use of test gases of various radii to investigate molecular sieving in leak channels. AB - Evidence of the effect of molecule size (molecular sieving) was discovered in leak channels similar to those found in hermetically sealed implantable bionics. A range of test gases of different molecular sizes was used to investigate the relative leak rates of several different samples. A contemporary model of molecular sieving is shown to be in partial agreement with our data. PMID- 26736387 TI - Safe inductive power transmission to millimeter-sized implantable microelectronics devices. AB - Power transfer efficiency (PTE) and power delivered to the load (PDL) are key inductive link design parameters for powering millimeter-sized implants. While several groups have suggested increasing the power carrier frequency (fp) of inductive links to 100s of MHz to maximize PTE, we have demonstrated that operating at 10s of MHz offers higher allowable PDL under the safety absorption rate (SAR) constraints. We have proposed a closed-form power function that relates maximum power levels that can safely be transferred at different frequencies under the SAR constraints. Three sets of inductive links at different frequencies of 50 MHz, 200 MHz, and 400 MHz have been optimized for powering a 1 mm(3)-sized implant. We have shown in simulations that reducing fp from 200 MHz to 50 MHz along with shrinking the size of the transmitter coil results in ~7.8 times higher PDL under SAR constraints, at the cost of only 52% drop in PTE. PMID- 26736388 TI - Deep tissue targeted near-infrared optogenetic stimulation using fully implantable upconverting light bulbs. AB - We demonstrate for the first time, the possibility of targeted optogenetic stimulation of neurons deep into brain tissue (>2 mm) in a minimally-invasive way by sending near-infrared light through tissue to excite passive lanthanide-doped blue-emitting upconverting nanocrystals (UCNPs) encapsulated in Parylene C microstructure light bulbs that emit visible (blue) light and locally excite opsins with high spatial resolution. PMID- 26736389 TI - Adaptive Kalman filter for indoor localization using Bluetooth Low Energy and inertial measurement unit. AB - This paper proposes a novel indoor localization method using the Bluetooth Low Energy (BLE) and an inertial measurement unit (IMU). The multipath and non-line of-sight errors from low-power wireless localization systems commonly result in outliers, affecting the positioning accuracy. We address this problem by adaptively weighting the estimates from the IMU and BLE in our proposed cascaded Kalman filter (KF). The positioning accuracy is further improved with the Rauch Tung-Striebel smoother. The performance of the proposed algorithm is compared against that of the standard KF experimentally. The results show that the proposed algorithm can maintain high accuracy for position tracking the sensor in the presence of the outliers. PMID- 26736390 TI - A wireless monitoring system for Hydrocephalus shunts. AB - Patients with Hydrocephalus are usually treated by diverting the excess Cerebrospinal Fluid (CSF) to other parts of the body using shunts. More than 40 percentage of shunts implanted fail within the first two years. Obstruction in the shunts is one of the major causes of failure (45 percent) and the detection of obstruction reduces the complexity of the revision surgery. This paper describes a proposed wireless monitoring system for clog detection and flow measurement in shunts. A prototype was built using multiple pressure sensors along the shunt catheters for sensing the location of clog and flow rate. Regular monitoring of flow rates can be used to adjust the valve in the shunt to prevent over drainage or under drainage of CSF. The accuracy of the flow measurement is more than 90 percent. PMID- 26736391 TI - A reconfigurable medically cohesive biomedical front-end with SigmaDelta ADC in 0.18um CMOS. AB - This paper presents a generic programmable analog front-end (AFE) for acquisition and digitization of various biopotential signals. This includes a lead-off detection circuit, an ultra-low current capacitively coupled signal conditioning stage with programmable gain and bandwidth, a new mixed signal automatic gain control (AGC) mechanism and a medically cohesive reconfigurable SigmaDelta ADC. The full system is designed in UMC 0.18MUm CMOS. The AFE achieves an overall linearity of more 10 bits with 0.47MUW power consumption. The ADC provides 2(nd) order noise-shaping while using single integrator and an ENOB of ~11 bits with 5MUW power consumption. The system was successfully verified for various ECG signals from PTB database. This system is intended for portable batteryless u Healthcare devices. PMID- 26736392 TI - A 0.5-V multi-channel low-noise readout front-end for portable EEG acquisition. AB - This article presents a low-noise readout front-end suitable for Electroencephalogram (EEG) acquisition. The chip includes 8-channel fully differential instrumentation amplifiers, utilizing chopper stabilization technique for reducing the flicker noise, each amplifier with a small Gm-C low pass filter, a programmable gain amplifier, and a 10-bit successive approximation register (SAR) ADC with a detect logic for DAC switching. The chip is fabricated with the TSMC 90nm CMOS process. The low-noise readout front-end has simulated frequency response from 0.57 Hz to 213 Hz, programmable gain from 54.4 dB to 87.6 dB, integrated input-referred noise of 0.358 MUVrms within EEG bandwidth, a noise efficiency factor (NEF) of 2.43, and a power efficiency factor (PEF) of 2.95. The overall system consumes 32.08 MUW under 0.5-V supply. PMID- 26736393 TI - Estimating direction and depth of visual fixation using electrooculography. AB - Eye tracking is a useful method of human-computer interaction and of interest to scientific studies on cognition. An electrooculogram (EOG), measuring the changes caused by the angular rotation of the dipole moment of the eyes, contains information on the direction of each eye's movement. A known target stimulus moving in 3D space was used to calibrate an 8-channel EOG to resolve the target position and fixation depth. Linear estimations of target position, valid for small-angle deflections from center, resulted in average azimuth (horizontal) and elevation (vertical) angle errors of 2.9+/-2.1 and 4.4+/-3.3 degrees, respectively, and average fixation distance errors of 13.4+/-11.8%(7.5+/-5.6 cm). Accounting for nonlinearities from wider angles and closer fixations, estimations by a single layer, feedforward neural network, resulted in average errors for azimuth and elevation angle of 2.3+/-1.6 and 3.2+/-2.6 degrees, and average fixation distance error of 10.3+/-10.0% (5.7+/-4.7 cm). This work is the first apparent demonstration of EOG signals as a basis for eye tracking in 3D. PMID- 26736394 TI - On the identification and interpretation of human skin spectral responses under adverse environmental conditions. AB - The identification and interpretation of skin spectral responses play a central role in a wide range of biomedical engineering applications, from the noninvasive assessment of human health parameters to the location of individuals in distress during search and rescue operations. In this paper, we investigate the sensitivity of these responses to physiological changes triggered by adverse environmental conditions. Our findings, which are supported by predictive computer simulations and experimental observations reported in the scientific literature, indicate that the resulting variations of skin reflectance can be substantial. Accordingly, if not properly taken into account, they may considerably impair the efficacy of systems designed for the detection and analysis of skin signatures within and outside the visible spectral region. PMID- 26736395 TI - A non-contact capacitance based electrocardiograph and associated heart-rate detection using enhanced Fourier interpolation method. AB - Cardio-vascular health monitoring has gained considerable attention in the recent years. Principle of non-contact capacitive electrocardiograph (ECG) and its applicability as a valuable, low-cost, easy-to-use scheme for cardio-vascular health monitoring has been demonstrated in some recent research papers. In this paper, we develop a complete non-contact ECG system using a suitable front-end electronic circuit and a heart-rate (HR) measurement unit using enhanced Fourier interpolation technique. The front-end electronic circuit is realized using low cost, readily available components and the proposed HR measurement unit is designed to achieve fairly accurate results. The entire system has been extensively tested to verify its efficacy and test results show that the developed system can estimate HR with an accuracy of +/-2 beats. Detailed tests have been conducted to validate the performance of the system for different cloth thicknesses of the subject. Some basic tests which illustrate the application of the proposed system for heart-rate variability estimation has been conducted and results reported. The developed system can be used as a portable, reliable, long term cardiac health monitoring device and can be extended to human drowsiness detection. PMID- 26736396 TI - Estimating respiratory rate from FBG optical sensors by using signal quality measurement. AB - Non-intrusiveness is one of the advantages of in-bed optical sensor device for monitoring vital signs, including heart rate and respiratory rate. Estimating respiratory rate reliably using such sensors, however, is challenging, due to body movement, signal variation according to different subjects or body positions, etc. This paper presents a method for reliable respiratory rate estimation for FBG optical sensors by introducing signal quality estimation. The method estimates the quality of the signal waveform by detecting regularly repetitive patterns using proposed spectrum and cepstrum analysis. Multiple window sizes are used to cater for a wide range of target respiratory rates. Furthermore, the readings of multiple sensors are fused to derive a final respiratory rate. Experiments with 12 subjects and 2 body positions were conducted using polysomnography belt signal as groundtruth. The results demonstrated the effectiveness of the method. PMID- 26736397 TI - An ultra low power ECG signal processor design for cardiovascular disease detection. AB - This paper presents an ultra low power ASIC design based on a new cardiovascular disease diagnostic algorithm. This new algorithm based on forward search is designed for real time ECG signal processing. The algorithm is evaluated for Physionet PTB database from the point of view of cardiovascular disease diagnosis. The failed detection rate of QRS complex peak detection of our algorithm ranges from 0.07% to 0.26% for multi lead ECG signal. The ASIC is designed using 130-nm CMOS low leakage process technology. The area of ASIC is 1.21 mm(2). This ASIC consumes only 96 nW at an operating frequency of 1 kHz with a supply voltage of 0.9 V. Due to ultra low power consumption, our proposed ASIC design is most suitable for energy efficient wearable ECG monitoring devices. PMID- 26736398 TI - Accuracy of reflectance photoplethysmography on detecting cuff-induced vascular occlusions. AB - Photoplethysmography (PPG) is a noninvasive optical technique, which can also be used to derive important parameters other than arterial oxygen saturation (SpO2). In this work, the accuracy of the technique on detecting changes in blood perfusion during different levels of vascular occlusions has been explored. A dual-wavelength, reflectance PPG probe was applied on the left forearm of 10 healthy volunteers and raw PPG signals were acquired by a research PPG processing system. The raw PPG signals were separated into pulsatile AC and continuous DC PPG components. The signals were used to estimate SpO2 and changes in concentration of oxygenated, deoxygenated, and total haemoglobin. Different levels of occlusions, from 20 mmHg to total occlusion were induced by a pressure cuff on the left arm. The system was able to indicate all the occlusions. In particular, the haemoglobin concentration changes estimated from PPG were in high agreement with Near Infrared Spectroscopy measurements. PMID- 26736399 TI - Preliminary analysis of the use of smartwatches for longitudinal health monitoring. AB - New generations of smartwatches feature continuous measurement of physiological parameters, such as heart rate, galvanic skin resistance (GSR), and temperature. In this paper we present the results of preliminary analysis of the use of Basis Peak smartwatch for longitudinal health monitoring during a 4 month period. Physiological measurements during sleep are validated using Zephyr Bioharness 3 monitor and SOMNOscreen+ polysomnographic monitoring system from SOMNOmedics. Average duration of sequences with no missed data was 49.9 minutes, with maximum length of 17 hours, and they represent 88.88% of recording time. Average duration of the charging event was 221.9 min, and average time between charges was 54 hours, with maximum duration of the charging event of 16.3 hours. Preliminary results indicate that the physiological monitoring performance of existing smartwatches provides sufficient performance for longitudinal monitoring of health status and analysis of health and wellness trends. PMID- 26736400 TI - A hand-held micro surgical device for contact force regulation against involuntary movements. AB - Involuntary movements such as heart beating in surgical environment and surgeon's tremor disturb a micro surgical manipulation and cause a risk of patient wound. Although the delicate operation is performed by a skilled surgeon, the sensitivity of the surgeon is limited to quantify the range of safe contact forces. In this paper, we developed a compact hand-held surgical device to maintain a required contact force to maintain a required contact force using a custom force sensor and a linear delta mechanism. The custom optical force sensor measured the contact force of the device tip and the linear delta mechanism compensated undesired forces to maintain a consistent contact force. The proposed device is consisted of force sensing unit and actuating unit. The device was improved from our previous Linear Delta mechanism based prototype in terms of size, weight, and force sensing capability. The developed device was validated by investigation of contact force accuracy in a fixed condition and a hand-held condition. In hand-held condition, the visual feedback of the current contact force was provided, and the performance of the contact force regulation was investigated by comparing the root mean square (RMS) contact force errors and standard deviation in with and without control cases. The fluctuation (less than 50 mN) of the force regulation control of the device showed the feasibility of the device for the use in delicate operations. PMID- 26736401 TI - Electronic cages for living cells. AB - Design and construction of an electronic cage is described which enables real time manipulation of live and dead eukaryotic cells. Non-uniform, radio frequency (RF) AC electric fields are used to enable translational and rotational movement of cells, known as dielectrophoresis (DEP) and electro-rotation (EROT), and distinguish their state as viable and non-viable. A concentric multilayered mathematical model, applicable for eukaryotic cells, is also developed, coded and implemented. The simulations predict three dielectric dispersions in the DEP and EROT spectra, though in practice the third is very small so that two are observed. The cage is part of a multi-staged project incorporating controller and DEP/EROT digital signal generator and image processing. PMID- 26736402 TI - A 512-channels, whole array readout, CMOS implantable probe for acute recordings from the brain. AB - The integration of implantable CMOS neural probes with thousands of simultaneously recording microelectrodes is a promising approach for neuroscience and might allow to literally image electrophysiological neuronal activity in multiple brain circuits as we have previously shown in vitro. Here, we present a complete system based on a fully multiplexed CMOS neural probe that was designed for in-vivo acute recordings with a scalable circuit architecture. In particular, a first prototype of a single-shaft probe with 512 electrodes was realized in a standard CMOS 0.18MUm technology and post-processed to structure the shaft with a wedge-like geometry of 30MUm in thickness at the tip and 80MUm at the base. The design of the system and of the probe as well as the post-processing techniques are discussed. Finally, preliminary results on electrical, mechanical and implantation tests are presented to demonstrate the feasibility of our approach. PMID- 26736403 TI - Automated navigation of a glass micropipette on a high-density microelectrode array. AB - High-density microelectrode arrays (HDMEAs) provide the capability to monitor the extracellular electric potential of multiple neurons at subcellular resolution over extended periods of time. In contrast, patch clamp allows for intracellular, sub-threshold recordings from a single patched neuron for very limited time on the order of an hour. Therefore, it will be beneficial to combine HDMEA and patch clamp for simultaneous intra- and extracellular recording of neuronal activity. Previously, it has been shown that the HDMEA can be used to localize and steer a glass micropipette towards a target location without using an optical microscope [1]. Here, we present an automated system, implemented in LabVIEW, which automatically locates and moves the glass micropipette towards a user-defined target. The presented system constitutes a first step towards developing an automated system to navigate a pipette to patch a neuron in vitro. PMID- 26736404 TI - Design of a wideband CMOS impedance spectroscopy ASIC analog front-end for multichannel biosensor interfaces. AB - This paper presents the preliminary design and simulation of a flexible and programmable analog front-end (AFE) circuit with current and voltage readout capabilities for electric impedance spectroscopy (EIS). The AFE is part of a fully integrated multifrequency EIS platform. The current readout comprises of a transimpedance stage and an automatic gain control (AGC) unit designed to accommodate impedance changes larger than 3 order of magnitude. The AGC is based on a dynamic peak detector that tracks changes in the input current over time and regulates the gain of a programmable gain amplifier in order to optimise the signal-to-noise ratio. The system works up to 1 MHz. The voltage readout consists of a 2 stages of fully differential current-feedback instrumentation amplifier which provide 100 dB of CMRR and a programmable gain up to 20 V/V per stage with a bandwidth in excess of 10MHz. PMID- 26736405 TI - A 1.04uW wireless integrated MEMS interface in UMC 0.18um CMOS. AB - This paper presents an ultra low-power integrated interface for capacitive and resistive MEMS and sensors, intended for use in biomedical applications. The interface encodes the sensed data in the time between transmitted UWB pulses: this reduces the number of transmitted bits and benefits the power consumption. The interface was designed and fabricated in the UMC 0.18MUm CMOS process: the power consumption of the system was measured to be 1.04MUW at a sample rate of 37Hz. PMID- 26736406 TI - High-intensity static magnetic field exposure devices for in vitro experiments on biopharmaceutical plant factories in aerospace environments. AB - Three high-intensity static magnetic field (SMF) exposure devices have been designed and realized for application to in vitro experimental research on hairy root cultures, supposed to grow in extreme environments- as those of space aircrafts- for producing biopharmaceutical molecules. The devices allow the exposure at two different levels of induction magnetic (B) field (250 mT and 500 mT) plus sham for blind exposure. The exposure levels can be considered representative of possible B-fields experienced within the habitat of a spacecraft in presence of active magnetic shielding systems. Each device can house a single 85-mm diameter Petri dish. Numerical simulations have been performed to accurately evaluate the B-field distribution in the biological target. Numerical results have been confirmed by measured data, proving that designed setups allows exposure to SMFs with a homogeneity better than 90%. The exposure devices will be employed for experiments scheduled within BIOxTREME research project, funded by the Italian Space Agency (ASI). PMID- 26736407 TI - Design optimization of the sensor spatial arrangement in a direct magnetic field based localization system for medical applications. AB - Motivated by the need for developing a neuronavigation system to improve efficacy of intracranial surgical procedures, a localization system using passive magnetic fields for real-time monitoring of the insertion process of an external ventricular drain (EVD) catheter is conceived and developed. This system operates on the principle of measuring the static magnetic field of a magnetic marker using an array of magnetic sensors. An artificial neural network (ANN) is directly used for solving the inverse problem of magnetic dipole localization for improved efficiency and precision. As the accuracy of localization system is highly dependent on the sensor spatial location, an optimization framework, based on understanding and classification of experimental sensor characteristics as well as prior knowledge of the general trajectory of the localization pathway, for design of such sensing assemblies is described and investigated in this paper. Both optimized and non-optimized sensor configurations were experimentally evaluated and results show superior performance from the optimized configuration. While the approach presented here utilizes ventriculostomy as an illustrative platform, it can be extended to other medical applications that require localization inside the body. PMID- 26736408 TI - Inferring intra-cellular mechanics using geometric metamorphosis: A preliminary study. AB - Mechanotransduction plays an important role in sub-cellular processes and is an active area of research. Determining the forces/strains that the intra-cellular structures experience is vital for developing quantitative models of cellular behavior. Established techniques such as traction force microscopy, digital image correlation etc. track surface forces and kinematics of intra-cellular structures. However, difficulties arise when cells cannot be seeded on micro patterned substrates or the intra-cellular structures vary (unstable landmarks). Here, we applied geometric metamorphosis, a global image registration method, to determine the kinematic profile of a cell during cell division. The method does not require stable landmarks, the registration is non-local in nature and constraints such as volume conservation can be enforced. The cell wall was tracked over time and a sequence of transformations relating the cell wall at the start of cytokinesis to the configuration prior to the daughters completely separate was determined. These transformations are associated with a scalar metric and a statistical atlas describing the wall kinematics from multiple tracking's of the wall shape is constructed. Using these transformations, the cellular kinematics can be described using a Lagrangian frame of reference and the evolution of a material point property can be easily modeled. To demonstrate this, we use the kinematic data derived from the atlas along with a model of stress-fiber (de)formation dynamics to simulate the stress-fiber configuration as the cell domain deforms. PMID- 26736409 TI - Stiffness matrix representation of hyper-elasticity for surgical simulation and navigation. AB - Nowadays, physics-based simulation plays an important role in industries and clinical fields thanks to the outstanding progress of computer technologies and numerical simulation. One of the demands for the applied technology of physics based simulation, is the surgical simulation of organ tissue not only for surgical training but also for intra-operative navigation. Although linear Finite Element Method (FEM) is capable of real-time simulation, the conventional FEM analysis does not satisfy the accuracy of non-linear response and interactivity at the same time. The aim of this study is to establish the surgical simulation and navigation to consider hyper-elasticity (HE), which represents the organ's non-linear response material better than the conventional linear material. In this paper, we propose a novel method to decompose the stress-strain relationship of HE, and construct the stiffness matrix for real-time and interactive simulation by extending the linear FEM, which is capable of efficient simulation. The experimental results showed that the proposed method is able to simulate non linear FEM deformation accurately almost equivalent to the existing non-linear FEM analysis by shorter calculation time. In addition, the deformation with the kidney model was demonstrated. PMID- 26736410 TI - Development of a finite element model of a finger pad for biomechanics of human tactile sensations. AB - The aim of ongoing research is to develop a multi-scale multi-physics computational framework for modelling of human touch in order to provide understanding of fundamental biophysical mechanisms responsible for tactile sensation. The paper presents the development of a macro-scale global finite element model of the finger pad and calibration of applied material models against experimental results using inverse method. The developed macro model serves as a basis for down-scaling to micro finite element models of mechanoreceptors and further implementations and applications as a virtual tool in scientific or industrial applications related to neuroscience, haptics, prosthetics, virtual touch and packaging. PMID- 26736411 TI - Combined approach for the biomechanical characterization of skin lesions. AB - Melanocytic nevi are common benign skin lesions, known as moles, due to proliferation of melanocytes, the pigmented skin cells. The uncontrolled growth of these cells leads instead to cutaneous malignant melanoma, an aggressive tumour whose rate of survival dramatically increases if early diagnosis is provided. Alteration on the mechanical properties of the skin in presence of lesions has been assessed. In this context, we aim at developing a combined approach consisting of an experimental and a computational study to biomechanically characterize the skin and both malign and benign skin lesions (i.e., nevi and malignant melanoma). In particular, the former study is performed to evaluate the biomechanical response of the different skin layers after the application of a displacement field and relies on a multi-scale strategy, ranging from the tissue level to the cellular level. Computational models will be tuned against experimental data (e.g., confocal laser scanning microscopy data) to estimate the mechanical properties of the different layers of the skin and the skin lesions. In particular, the confocal laser scanning microscopy is able to provide non-invasive histomorphological analysis of skin in vivo. The integration of the experimental and the computational results will allow the evaluation of possible alterations of the local mechanical properties occurring in case of pathological condition. PMID- 26736412 TI - Implementation of a 3D porcine lumbar finite element model for the simulation of monolithic spinal rods with variable flexural stiffness. AB - Monolithic superelastic-elastoplastic spinal rods (MSER) are promising candidates to provide (i) dynamic stabilisation in spinal segments prone to mechanical stress concentration and adjacent segment disease and (ii) to provide fusion ready stabilization in spinal segments at risk of implant failure. However, the stiffness distributions along the rod's longitudinal axis that best meet clinical requirements remain unknown. The present study is part of a mixed numerical experimental research project and aims at the implementation of a 3D finite element model of the porcine lumbar spine to study the role of MSER material properties and stiffness distributions on the intradiscal pressure distribution in the adjacent segment. In this paper, preliminary intradiscal pressure predictions obtained at one functional spinal unit are presented. Due to a lack of porcine material property data, these predictions were obtained on the basis of uncalibrated human vertebral disc data which were taken from the literature. The results indicate that human annulus and nucleus data predict experimental porcine in vivo and in vitro data reasonably well for the compressive forces of varying magnitudes. PMID- 26736413 TI - A mechano-regulatory model for bone healing predictions under the influence of ultrasound. AB - The bone healing process involves a sequence of cellular action and interaction, regulated by biochemical and mechanical signals. Experimental studies have shown that ultrasound accelerates bone solidification and enhances the underlying healing mechanisms. An integrated computational model is presented for deriving predictions of bone healing under the presence of ultrasound. PMID- 26736414 TI - Effect of modeling parameters on the frequency response of the middle ear by means of finite element analysis. AB - A 3D finite element model of the human middle ear was developed for the investigation of the modeling parameters' effect on the frequency response. In this study, we incorporated realistic reconstructed geometries from microCT imaging data. The geometric representation of the stapedial annular ligament provided additional damping and the Rayleigh parameter beta was adjusted to lower values in comparison to previous computational studies. The maximum displacement of the stapes footplate, equal to 0.168 MUm, was observed at a frequency of 1050 Hz. The computational results were validated with experimental measurements. Good agreement is observed between our results and the experimental data and other finite element studies. PMID- 26736415 TI - Compliance boundary conditions for simulating deformations in a limited target region. AB - Patient-specific models in medical procedures are often limited to a relatively small region of interest due either to computational concerns or to the fact that only a part of anatomy could be observed in the input medical images. Thus, for deformable planning or training simulations, boundary conditions at the borders of such models are necessitated. Zero-displacement or -force constraints at outer boundaries are commonly used, with the assumption that the selected region is large enough to minimize effects on the deformable behavior inside the region of interest. This may, however, still result in errors and does require superfluous elements to extend models. In this work, a mixed boundary condition type, called compliance boundary condition, is proposed to constrain model boundaries. Different techniques to define and estimate these boundary constraints are studied with simulation experiments. Results are presented for palpation on 2D and 3D phantoms and needle insertion to a male pelvic anatomical model. PMID- 26736416 TI - Recovering the mechanical properties of denatured intervertebral discs through Platelet-Rich Plasma therapy. AB - Degenerative disc disease is one of the most common causes of low back pain instigating huge socioeconomic costs and posing an immense burden on healthcare systems worldwide. New therapeutic approaches to damaged intervertebral discs are therefore of great interest. Platelet-Rich Plasma (PRP) has been proposed for the repair and regeneration of degenerated discs, but there remains a knowledge gap regarding its effectiveness and influence on disc material properties. The objective of this study was to investigate and quantify the material properties of intact, denatured, and PRP treated discs. A systematic methodology was established in the process, where ex-vivo experiments were conducted and material properties were extracted using an inverse finite element approach. The results showed that PRP is able to recover the mechanical properties of denatured discs, thereby providing a promising effective therapeutic modality. PMID- 26736417 TI - Reconfigurable neuromorphic computation in biochemical systems. AB - Implementing application-specific computation and control tasks within a biochemical system has been an important pursuit in synthetic biology. Most synthetic designs to date have focused on realizing systems of fixed functions using specifically engineered components, thus lacking flexibility to adapt to uncertain and dynamically-changing environments. To remedy this limitation, an analog and modularized approach to realize reconfigurable neuromorphic computation with biochemical reactions is presented. We propose a biochemical neural network consisting of neuronal modules and interconnects that are both reconfigurable through external or internal control over the concentrations of certain molecular species. Case studies on classification and machine learning applications using the DNA strain displacement technology demonstrate the effectiveness of our design in both reconfiguration and autonomous adaptation. PMID- 26736418 TI - Retroactivity analysis of a chemical reaction network module for the subtraction of molecular fluxes. AB - The availability of a well-characterised subtraction module is a key step towards the realisation of modular embedded feedback controllers in synthetic biological systems. A well-known problem when dealing with complex biosystems is represented by the retroactivity effect, which can significantly modify the dynamics of interconnected subsystem, with respect to the behaviour they exhibit when disconnected from each other. In this paper, we illustrate a minimal CRN that implements a subtraction operation between two input molecular fluxes. In order to assess its effectiveness as a module of a more complex system, we analyse its retroactivity upon interconnection. More specifically, we connect the subtraction module with an upstream module, which determines the dynamics of the inputs species, and with a downstream transcriptional module, which acts as a load. By comparing the dynamics of the loaded and unloaded subtractor, we show that the retroactivity can be attenuated when the dynamics of the subtractor and of the load system evolve over different timescales. This result, obtained through a singular perturbation analysis, is confirmed by means of numerical simulations. PMID- 26736419 TI - Development and experimental validation of a mechanistic model of in vitro DNA recombination. AB - Engineering cellular memory is a key area of research in which Synthetic Biology has already begun to make significant impacts. Recent work elucidating transcriptional memory devices has paved the way for the creation of bistable genetic switches based on DNA recombination. Attempts to experimentally design and build synthetic systems using recombinases have thus far been hindered by a lack of validated computational models that capture the mechanistic basis of DNA recombination. The predictive capabilities of such models could be exploited by Synthetic Biologists to reduce the number of iterative cycles required to align experimental results with design performance requirements. Here, we develop and validate the first detailed mechanistic model of DNA recombination, with a focus on how efficiently recombination can occur, and the model features required to replicate and predict experimental data. PMID- 26736420 TI - Biomolecular implementation of a quasi sliding mode feedback controller based on DNA strand displacement reactions. AB - A fundamental aim of synthetic biology is to achieve the capability to design and implement robust embedded biomolecular feedback control circuits. An approach to realize this objective is to use abstract chemical reaction networks (CRNs) as a programming language for the design of complex circuits and networks. Here, we employ this approach to facilitate the implementation of a class of nonlinear feedback controllers based on sliding mode control theory. We show how a set of two-step irreversible reactions with ultrasensitive response dynamics can provide a biomolecular implementation of a nonlinear quasi sliding mode (QSM) controller. We implement our controller in closed-loop with a prototype of a biological pathway and demonstrate that the nonlinear QSM controller outperforms a traditional linear controller by facilitating faster tracking response dynamics without introducing overshoots in the transient response. PMID- 26736421 TI - Methods for genetic optimization of biocatalysts for biofuel production from dairy waste through synthetic biology. AB - Whey is an abundant by-product of cheese production process and it is considered a special waste due to its high nutritional load and hypertrophic potential. Technologies for whey valorization are available. They can convert such waste into high-value products, like whey proteins. However, the remaining liquid (called permeate) is still considered as a polluting waste due to its high lactose concentration. The alcoholic fermentation of lactose into ethanol will simultaneously achieve two important goals: safe disposal of a pollutant waste and green energy production. This methodology paper illustrates the workflow carried out to design and realize an optimized microorganism that can efficiently perform the lactose-to-ethanol conversion, engineered via synthetic biology experimental and computational approaches. PMID- 26736422 TI - Changes in inflammatory response during and after cardiopulmonary bypass using a rat extracorporeal circulation model. AB - Cardiopulmonary bypass (CPB) is indispensable for cardiac surgery. Since the ethical and technical difficulties associated with clinical research limit the acquisition of new knowledge, it is desirable to have a miniature extracorporeal circulation (ECC) system for small animals. We aimed to establish a miniature ECC system and apply the system to the rat for investigating systemic inflammatory response changes during and after CPB. The ECC system consisted of a membranous oxygenator (polypropylene, 0.03 m(2)), tubing line (polyvinyl chloride) and a roller pump. Priming volume of this system is only 7 ml. Rats were divided into the SHAM (received surgical preparation only without CPB) group and the CPB group. ECC pump flow was initiated and maintained at 70 ml/kg/min. We measured the serum cytokine levels of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-10, and biochemical markers (lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase) before, 30, and 60 min after the initiation of CPB, in addition, 30, 60, and 120 min after the CPB weaning. During CPB, blood pressure and hemoglobin were maintained around 80 mmHg and 10g/dl, the serum cytokine levels and biochemical markers were significantly elevated in the CPB group compared with the SHAM group. These data suggest that CPB promotes organ damage and a systemic inflammatory response. This rat ECC model is considered to be equivalent to the already established human CPB and useful for studying the mechanism of pathophysiological changes during and after CPB. PMID- 26736423 TI - Effect of in vivo flow dynamics on angiogenesis by computational modeling. AB - This work represents the role that flow dynamics play in the process of angiogenesis during vascular remodeling. We have developed a method to simultaneously image blood flow dynamics and vascular morphology over a period of 12-16 hours in the remodeling vasculature of avian embryos. The data is combined in a computational model that allows us to calculate parameters such as shear stress, pressure and vorticity in real time and during the entire cardiac cycle. We find that sprouts always form from a vessel at lower pressure towards a vessel at higher pressure. PMID- 26736424 TI - GPU-accelerated model for fast, three-dimensional fluid-structure interaction computations. AB - In this paper we introduce a methodology for performing one-way Fluid-Structure interaction (FSI), i.e. where the motion of the wall boundaries is imposed. We use a Graphics Processing Unit (GPU) accelerated Lattice-Boltzmann Method (LBM) implementation and present an efficient workflow for embedding the moving geometry, given as a set of polygonal meshes, in the LBM computation. The proposed method is first validated in a synthetic experiment: a vessel which is periodically expanding and contracting. Next, the evaluation focuses on the 3D Peristaltic flow problem: a fluid flows inside a flexible tube, where a periodic wave-like deformation produces a fluid motion along the centerline of the tube. Different geometry configurations are used and results are compared against previously published solutions. The efficient approach leads to an average execution time of approx. one hour per computation, whereas 50% of it is required for the geometry update operations. Finally, we also analyse the effect of changing the Reynolds number on the flow streamlines: the flow regime is significantly affected by the Reynolds number. PMID- 26736425 TI - CFD analysis of unsteady flow through conjoining Aorta and aortic isthmus. AB - The initial stages of fetal development require that blood oxygenation occur through the placenta rather than the non functioning lungs. As a result the fetal circulatory system develops a temporary shunt between the aorta and pulmonary artery, known as the ductus arteriosis (DA). This study utilizes CFD techniques to analyze the flow behavior in the aortic isthmus neighboring the DA. The geometry used to represent these structures is equivalent to that of a 25 week old fetus. The effect of aortic and pulmonary pressure pulse wave delay is examined for producing flow disturbances in the fetal circulatory system. This is accomplished by analyzing both axial and tangential flow fields downstream of the DA. The study demonstrates that there exist different swirl profiles that are related to the timing of pulse contributions from both the left and right ventricles. PMID- 26736426 TI - Validation study of a 3D-QCA coronary reconstruction method using a hybrid intravascular ultrasound and angiography reconstruction method and patient specific Fractional Flow Reserve data. AB - The estimation of the severity of coronary lesions is of utmost importance in today's clinical practice, since Cardiovascular diseases often have fatal consequences. The most efficient method to estimate the severity of a lesion is the calculation of the Fractional Flow Reserve. The necessary use of a pressure wire, however, makes this method invasive and strenuous for the patient. In this work, we present a novel 3-Dimensional Quantitative Coronary Analysis coronary reconstruction method and a framework for the computation of the virtual Functional Assessment Index (vFAI). In a dataset of 5 coronary arterial segments, we use the aforementioned method to reconstruct them in 3D, and compare them to the respective 3D models reconstructed from our already validated hybrid IVUS angiography reconstruction method [2]. The obtained results indicate a high correlation between the two methods in terms of the calculated FFR values, presenting a difference of 3.19% in the worst case scenario. Furthermore, when compared to the actual FFR values that derive from a pressure wire, the differences were statistically insignificant. PMID- 26736427 TI - Numerical analysis of the hemodynamics of an abdominal aortic aneurysm repaired using the endovascular chimney technique. AB - This paper presents a numerical analysis of the hemodynamics in an abdominal aorta (AA) with an aneurysm repaired by a stent graft (SG) system using the chimney technique. Computational fluid dynamics (CFD) simulations were conducted in a model of an AA repaired with a chimney stent graft (CSG) inserted into a renal artery parallel to an aortic SG and a model of a healthy AA. Comparing the simulation results of these two cases suggests that the presence of the CSG in the AA causes changes in average wall shear stress (WSS), potentially damaging recirculation zones, and additional changes in flow patterns. PMID- 26736428 TI - Computational analysis of stenosis geometry effects on right coronary hemodynamics. AB - Coronary artery disease (CAD) is one of the most frequent causes of death in western countries. It is characterized by the presence of coronary artery stenosis that can be flow-limiting or susceptible to rupture, triggering intracoronary thrombosis and -consequently- an acute myocardial infarction. For these reasons, hemodynamic alterations associated to the presence of coronary stenosis are of large relevance. Aim of this study was to numerically investigate the effect of stenosis geometry on hemodynamics, comparing three different shapes with an equivalent stenotic lumen. A right coronary artery (RCA) was reconstructed from the angiogram of a patient. Flow pattern analyses were performed using the computational fluid dynamic (CFD) approach, showing that the worst stenosis geometry is the elliptical one, characterized by areas with stasis, multidirectional velocity and high wall shear stress (WSS). On the other hand, the least dangerous stenosis is the parabolic one. However, the strongest predictor of pressure drop is not geometry but the minimal lumen area. In conclusion, while the minimal lumen area is associated to the trans-stenotic pressure drop, stenosis geometry has a significant impact on translesional flow pattern and WSS. PMID- 26736429 TI - Predicting hyperlactatemia in the MIMIC II database. AB - Sepsis, which occurs when an infection leads to a systemic inflammatory response, is believed to contribute to one in two to three hospital deaths in the United States. Using the Multiparameter Intelligent Monitoring in Intensive Care (MIMIC II) database of electronic medical records from Boston's Beth Israel Deaconess Medical Center (BIDMC), we worked to characterize sepsis at BIDMC's intensive care units. Additionally, we developed a real-time algorithm to stratify patients with infectious complaints into different risk categories for progressing to septic shock. From time series of heart rate and arterial blood pressure, as well as estimates of cardiac output and total peripheral resistance, we developed a variety of classifiers to predict high serum lactate levels, a proxy for hypoperfusion and imminent circulatory shock. The records from 146 patients met our selection criteria. In discriminating patients whose measured serum lactate stays below 2.5 mmol/L from those whose value drifts above, the best of our classifiers perform with area under the receiver operating characteristic exceeding 0.8 on test data. PMID- 26736430 TI - Intraoperative hemodynamics predict postoperative mortality in orthotopic liver transplantation. AB - Liver transplantation remains the only curative treatment option for a variety of end-stage liver diseases. Prediction of major adverse events following surgery has traditionally focused on static predictors that are known prior to surgery. The effects of intraoperative management can now be explored due to the archiving of high-resolution monitoring data. We extracted intraoperative hemodynamic trend data of 55 patients undergoing orthotopic liver transplantation (OLT) and computed 12 features from the systolic arterial blood pressure (ABP), cardiac index, central venous pressure (CVP), and stroke volume variation (SVV) signals. Using a logistic regression classifier with a leave-one-out cross-validation procedure, we selected subsets of these features to predict mortality up to 180 days after surgery. Best performance was achieved with a combination of 3 features - median absolute deviation (MAD) of ABP, median CVP, and time spent with SVV <; 10% - reaching an area under the receiver-operating characteristic (or c-statistic) of 0.808. Odds ratios (OR) computed from the coefficients of the multivariate logistic regression model constructed from these features showed that greater time spent with SVV <; 10% (OR = 0.981 min(-1), p = 0.001) and greater MAD of systolic ABP (OR = 0.696 mmHg(-1), p = 0.026) were significantly associated with survival. Adding preoperative measures such as age and serum concentrations of albumin, bilirubin, and creatinine failed to improve performance of the prediction model. These results show that the course of intraoperative hemodynamics can predict 180-day mortality after OLT. PMID- 26736431 TI - Investigation of the composition of arterial plaques based on arterial waveforms and material properties. AB - Stroke is mainly caused by a narrowing of the carotid artery from a build-up of plaque. The risk of plaque rupture and subsequent stroke is dependent on plaque composition. Advances in imaging modalities offer a non-invasive means to assess the health of blood vessels and detect damage. However, the current diagnosis fails to identify patients with soft lipid plaque that are more susceptible to fissure, resulting in stroke. The aim of this study was to use waveform analysis to identify plaque composition and the risk of rupture. We have investigated pressure and flow by combining an artificial blood flow circuit with tubing containing different materials, to simulate plaques in a blood vessel. We used fat and bone to model lipid and calcification respectively to determine if the composition of plaques can be identified by arterial waveforms. We demonstrate that the arterial plaque models with different percentages of calcification and fat, results in significantly different arterial waveforms. These findings imply that arterial waveform analysis has the potential for further development to identify the vulnerable plaques prone to rupture. These findings could have implications for improved patient prognosis by speed of detection and a more appropriate treatment strategy. PMID- 26736432 TI - Cardiovascular system identification: Simulation study using arterial and central venous pressures. AB - The paper presents a study of the identifiability of a lumped model of the cardiovascular system. The significance of this work from the existing literature is in the potential advantage of using both arterial and central venous (CVP) pressures, two signals that are frequently monitored in the critical care unit. The analysis is done on the system's state-space representation via control theory and system identification techniques. Non-parametric state-space identification is preferred over other identification techniques as it optimally assesses the order of a model, which best describes the input-output data, without any prior knowledge about the system. In particular, a recent system identification algorithm, namely Observer Kalman Filter Identification with Deterministic Projection, is used to identify a simplified version of an existing cardiopulmonary model. The outcome of the study highlights the following two facts. In the deterministic (noiseless) case, the theoretical indicators report that the model is fully identifiable, whereas the stochastic case reveals the difficulty in determining the complete system's dynamics. This suggests that even with the use of CVP as an additional pressure signal, the identification of a more detailed (high order) model of the circulatory system remains a challenging task. PMID- 26736433 TI - An Assessment of the relationship between dicrotic notch timing and cardiac preload. AB - Cardiovascular disease (CVD) patient outcomes can be improved by extracting and synthesizing as much useful information as possible from a limited number of available measurements. An important metric in assessing the pathological state of CVD patients is cardiac preload. Left ventricular preload can be estimated through the surrogate measurement of left ventricular end diastolic volume (LVEDV). However, cardiac volumes are difficult to measure, clinically. This study develops a 3 parameter model relating the location of the dicrotic notch in the aortic waveform to LVEDV. This model was constructed using data from porcine experiments (N = 5 pietrain pigs, weights 20-28kg). The median difference between the observed LVEDV and modelled LVEDV was 5.4%, with a 100% range of 3.0% to 15.1%. Model parameters varied between individuals as well as contractile states. The median correlation was rho = 0.77, with a minimum of 0.58 and maximum of 0.95. This model could be used to estimate prseload from the commonly measured aortic pressure waveform. PMID- 26736434 TI - Stroke Volume estimation using aortic pressure measurements and aortic cross sectional area: Proof of concept. AB - Accurate Stroke Volume (SV) monitoring is essential for patient with cardiovascular dysfunction patients. However, direct SV measurements are not clinically feasible due to the highly invasive nature of measurement devices. Current devices for indirect monitoring of SV are shown to be inaccurate during sudden hemodynamic changes. This paper presents a novel SV estimation using readily available aortic pressure measurements and aortic cross sectional area, using data from a porcine experiment where medical interventions such as fluid replacement, dobutamine infusions, and recruitment maneuvers induced SV changes in a pig with circulatory shock. Measurement of left ventricular volume, proximal aortic pressure, and descending aortic pressure waveforms were made simultaneously during the experiment. From measured data, proximal aortic pressure was separated into reservoir and excess pressures. Beat-to-beat aortic characteristic impedance values were calculated using both aortic pressure measurements and an estimate of the aortic cross sectional area. SV was estimated using the calculated aortic characteristic impedance and excess component of the proximal aorta. The median difference between directly measured SV and estimated SV was -1.4ml with 95% limit of agreement +/- 6.6ml. This method demonstrates that SV can be accurately captured beat-to-beat during sudden changes in hemodynamic state. This novel SV estimation could enable improved cardiac and circulatory treatment in the critical care environment by titrating treatment to the effect on SV. PMID- 26736435 TI - Wave speed and reflections proximal to aneurism and stenosis of flexible tubes. AB - Arterial aneurism and stenosis are disorders that lead to circulation malfunction. Stenosis often leads to hypoxia of the organ depending on the affected artery, whilst aneurism can lead to dissection with known lethal consequences. On both cases, the pulse wave produced by the contracting heart is reflected at these discontinuities, and estimating the size of these reflected waves using wave intensity analysis (WIA) is the main aim of this work. We also aim to measure wave speed, or pulse wave velocity (PWV) as more commonly known within the discontinuities. We manufactured 4 stenosis and 4 aneurism silicon sections, connected one at a time to a mother tube, and tested in vitro. Pressure and flow were measured proximal to the discontinuity and were used to calculate WIA. PWV was calculated using the foot to foot technique and also the classical Moens-Korteweg and Bramwell-Hill equations. Wave speed in an aneurism decreases, whereas it increases in a stenosis, all compared to the values determined in a standard mother tube. Presence of aneurisms resulted in a backward expansion whilst the presence of stenosis resulted in a backward compression wave, which related linearly to the size of the discontinuity. Larger aneurisms and smaller stenosis cause an increase in wave reflection. PMID- 26736436 TI - Chronic and low charge injection wireless intraneural stimulation in vivo. AB - Functional stability and in-vivo reliability are significant factors determining the longevity of a neural interface. In this ongoing study, we test the performance of a wireless floating microelectrode array (WFMA) over a period of 143 days. The topography of the microelectrodes has allowed for selective stimulation of different fascicles of the rat sciatic nerve. We confirmed that motor evoked thresholds remain stable over time and that the nerve stimulation charges were within tissue safety limits. Importantly, motor evoked responses were elicited at threshold currents in fully awake animals without causing pain or discomfort. These data validate the use of the WFMA system for intraneural interfacing of peripheral nerves for neuroprosthetic and bioelectronics medical applications. PMID- 26736437 TI - Chronic in-vivo testing of a 16-channel implantable wireless neural stimulator. AB - Here, we report on chronic in-vivo testing of a 16-channel wireless floating microelectrode array (WFMA) in a rat sciatic nerve model. Muscle threshold currents, charge injection levels, and charge density were monitored for electrodes of two WFMA devices implanted into animal subjects over a five month period. This type of wireless stimulation device could eliminate problems associated with percutaneous connectors for a variety of neural prostheses and other medical devices. PMID- 26736439 TI - Towards out-of-the-lab EEG in uncontrolled environments: Feasibility study of dry EEG recordings during exercise bike riding. AB - Conventional EEG (electroencephalography) has relied on wet electrodes which require conductive gel to help the electrodes make contact with the scalp. In recent years many dry electrode EEG systems have become available that do not require this gel. As a result they are quicker and easier to set up, with the potential to record the the EEG in situations and environments where it has not previously been possible. This paper investigates the practicality of using dry EEG in new non-conventional recording situations. In particular it uses a dry EEG recording system to monitor the EEG while a subject is riding an exercise bike. The results show that good-quality EEG, free from high-amplitude motion artefacts, can be collected in this challenging motion rich environment. In the frequency domain a peak of activity is seen over the motor cortex (C4) at 23 Hz starting five minutes after the start of the exercise task, giving initial insights into the on-going operation of the brain during exercise. PMID- 26736438 TI - Design of mechanical interface to re-distribute excess pressure to prevent the formation of decubitus ulcers in bed ridden patients. AB - Pressure ulcers are the major problem in the stroke management and rehabilitation. Prevention of pressure ulcer is of keen interest and is achieved by frequently changing the position of patient on the mattress. However, the care needs to be intensive to address this issue; else it would lead to pressure ulcer or bed sores formation. Skin surface over the bony prominences provide comparatively more pressure than the other regions. Therefore they are called as pressure vulnerable regions. Skin over these regions is more susceptible for formation of ulcers. An engineering approach is needed to shift the accumulating pressure from the pressure vulnerable regions. Although pressure sensed in these region would be more than that of which sensed in other regions, shifting protocol has to be designed to channelize or to grade the pressure shift in order to avoid any injuries to the non pressure vulnerable region. This paper aims at devising one such protocol using MATLab and thereby designing the layout of mattress using Pro/Engineer: the number of partitions needed to cover the entire surface of the skin that is in contact with the mattress. PMID- 26736440 TI - KDI: A wireless ECoG recording platform with impedance spectroscopy, electrical stimulation and real-time, lossless data compression. AB - A power-efficient modular wireless platform has been designed for prototyping and pre-clinical evaluations of neural recording implants. This Kit for Designing Implants (KDI) is separated in function specific modules of 34*34mm which can be assembled as needed. This paper presents the design of new modules for this existing wireless KDI platform. These modules cover the functionalities of electrical stimulation for BCI neurofeedback, impedance spectroscopy for monitoring tissue reaction around implanted electrodes and a real-time lossless data compression algorithm for ECoG signals. This algorithm has been implemented using two different hardware solutions and its performances compared. The design and evaluation of these modules are a first step towards the inclusion of these functionalities into the next generation of WIMAGINE((r)) implants. PMID- 26736441 TI - An implantable wireless optogenetic stimulation system for peripheral nerve control. AB - An implantable wireless optogenetic stimulation system with an LED-based optical stimulation cuff electrode was developed for peripheral nerve control. The proposed system consisted of a battery-powered optical cuff electrode, optical stimulation controller, and wireless communication system. The optical cuff electrode had a polydimethylsiloxane (PDMS) structure was designed to illuminate the entire sciatic nerve. The wireless communication system was designed to comply with medical implant communication service (MICS) regulations. To evaluate the proposed system, optogenetic stimulation was performed in optogenetic transgenic mice (Thy1::ChR2). The optical cuff electrode was implanted on the sciatic nerve, and movement was elicited during optical stimulation. The experimental results show that ankle movement can be generated wirelessly using optical stimulation pulse parameters. PMID- 26736442 TI - A current-excited triple-time-voltage oversampling method for bio-impedance model for cost-efficient circuit system. AB - This paper presents a mathematic method and a cost-efficient circuit to measure the value of each component of the bio-impedance model at electrode-electrolyte interface. The proposed current excited triple-time-voltage oversampling (TTVO) method deduces the component values by solving triple simultaneous electric equation (TSEE) at different time nodes during a current excitation, which are the voltage functions of time. The proposed triple simultaneous electric equations (TSEEs) allows random selections of the time nodes, hence numerous solutions can be obtained during a single current excitation. Following that, the oversampling approach is engaged by averaging all solutions of multiple TSEEs acquired after a single current excitation, which increases the practical measurement accuracy through the improvement of the signal-to-noise ratio (SNR). In addition, a print circuit board (PCB) that consists a switched current exciter and an analog-to-digital converter (ADC) is designed for signal acquisition. This presents a great cost reduction when compared against other instrument-based measurement data reported [1]. Through testing, the measured values of this work is proven to be in superb agreements on the true component values of the electrode-electrolyte interface model. This work is most suited and also useful for biological and biomedical applications, to perform tasks such as stimulations, recordings, impedance characterizations, etc. PMID- 26736443 TI - Restoration of vision using wireless cortical implants: The Monash Vision Group project. AB - Monash Vision Group is developing a bionic vision system based on implanting several small tiles in the V1 region of the visual cortex. This cortical approach could benefit a greater proportion of people with total blindness than other approaches, as it bypasses the eyes and optic nerve. Each tile has 43 active electrodes on its base, and a wirelessly powered electronic system to decode control signals and drive the electrodes with biphasic pulses. The tiles are fed with power and data using a common transmitting coil at the back of the patient's head. Sophisticated image processing, described in a companion paper, ensures that the user experiences maximum benefit from the small number of electrodes. This paper describes key features of this system. PMID- 26736444 TI - Mechanical deformation of thin film platinum under electrical stimulation. AB - Thin-film-based electrodes used to interact with nervous tissue often fail quickly if used for electrical stimulation, impairing their translation into long term clinical applications. We initiated investigations about the mechanical load on thin-film electrodes caused by the fact of electrical stimulation. Platinum electrodes of O 300MUm on a polyimide carrier were subjected to approximately 50 000 asymmetrical, biphasic stimulation pulses in vitro. The electrode's surface was investigated optically by means of white-light interferometry. The structural expansion for the metallic surface subjected to stimulation was measured to reach roughly 30%. The study points towards a failure mechanism of thin-films being of mechanical nature, inherent to the unavoidable electrochemical processes involved (change in lattice constants) during electrical stimulation at the electrode's surface. Based on further scientific facts, we set 3 hypotheses for the exact mechanisms involved in the failure of thin-films used for electrical stimulation, opening a new door for research and improvement of novel neuroprosthetic devices. PMID- 26736445 TI - A co-adaptive sensory motor rhythms Brain-Computer Interface based on common spatial patterns and Random Forest. AB - Sensorimotor rhythm (SMR) based Brain-Computer Interfaces (BCI) typically require lengthy user training. This can be exhausting and fatiguing for the user as data collection may be monotonous and typically without any feedback for user motivation. Hence new ways to reduce user training and improve performance are needed. We recently introduced a two class motor imagery BCI system which continuously adapted with increasing run-time to the brain patterns of the user. The system was designed to provide visual feedback to the user after just five minutes. The aim of the current work was to improve user-specific online adaptation, which was expected to lead to higher performances. To maximize SMR discrimination, the method of filter-bank common spatial patterns (fbCSP) and Random Forest (RF) classifier were combined. In a supporting online study, all volunteers performed significantly better than chance. Overall peak accuracy of 88.6 +/- 6.1 (SD) % was reached, which significantly exceeded the performance of our previous system by 13%. Therefore, we consider this system the next step towards fully auto-calibrating motor imagery BCIs. PMID- 26736446 TI - Sheet music by mind: Towards a brain-computer interface for composing. AB - Providing brain-computer interface (BCI) users engaging applications should be one of the main targets in BCI research. A painting application, a web browser and other applications can already be controlled via BCI. Another engaging application would be a music composer for self-expression. In this work, we describe Brain Composing: A BCI controlled music composing software. We tested and evaluated the implemented brain composing system with five volunteers. Using a tap water-based electrode biosignal amplifier further improved the usability of the system. Three participants reached accuracies above 77% and were able to copy compose a given melody. Results of questionnaires support that our brain composing system is an attractive and easy way to compose music via a BCI. PMID- 26736447 TI - A dynamic stopping method for improving performance of steady-state visual evoked potential based brain-computer interfaces. AB - The performance of steady-state visual evoked potential (SSVEP)-based brain computer interfaces (BCIs) has been drastically improved in the past few years. In conventional SSVEP-based BCIs, the speed of a selection is fixed towards high performance based on preliminary offline analysis. However, due to inter-trial variability, the optimal selection time to achieve sufficient accuracy is different for each trial. To optimize the performance of SSVEP-based BCIs, this study proposed a dynamic stopping method that can adaptively determine a selection time in each trial by applying a threshold to the probability of detecting a target. A 12-class SSVEP dataset recorded from 10 subjects was used to evaluate the performance of the proposed method. Compared to the conventional method with a fixed selection time towards the highest accuracy, the proposed method could significantly reduce the averaged selection time (0.84+/-0.39 s vs. 1.44+/-0.63 s, p<;0.05) with comparable accuracy (99.44+/-1.57 % vs. 99.55+/-1.22 %). As a result, the simulated online information transfer rate (ITR) with the dynamic stopping method achieved a significant improvement compared to the conventional method (125.30+/-21.55 bits/min vs. 92.75+/-23.77 bits/min). These results suggest that the proposed dynamic stopping method is effective for improving the performance of SSVEP-based BCI systems. PMID- 26736448 TI - Leveraging historical knowledge of neural dynamics to rescue decoder performance as neural channels are lost: "Decoder hysteresis". AB - An intracortical brain-machine interface (BMI) decodes spiking activity recorded from motor cortical neurons to drive a prosthetic device (e.g., a computer cursor or robotic arm). As the number of recorded neurons decreases over time due to decay in recording quality, the performance of a BMI decreases. We asked: can degrading BMI performance be rescued by using prior information from when more neurons were observed? This would entail augmenting a decoder by using previously learned knowledge about motor cortex (at an earlier point in the array lifetime). We implemented this idea by modeling low-dimensional dynamics of the neural population, which describe how the population evolves through time. We posit that if the neural dynamics accurately reflect properties of motor cortex, then having a better estimate of these dynamics should result in a better decoder. Using previously collected (offline) experimental data, we found that a decoder using dynamics inferred in the past (when more neural channels were available) outperformed the same decoder using dynamics inferred from the (fewer) remaining neural channels. These results suggest that neural dynamics capture important features of the neural population responses in motor cortex, and that knowledge of these dynamics may rescue BMI performance even as array signal quality degrades. PMID- 26736449 TI - Multimodal 2D Brain Computer Interface. AB - In this work we used multimodal, non-invasive brain signal recording systems, namely Near Infrared Spectroscopy (NIRS), disc electrode electroencephalography (EEG) and tripolar concentric ring electrodes (TCRE) electroencephalography (tEEG). 7 healthy subjects participated in our experiments to control a 2-D Brain Computer Interface (BCI). Four motor imagery task were performed, imagery motion of the left hand, the right hand, both hands and both feet. The signal slope (SS) of the change in oxygenated hemoglobin concentration measured by NIRS was used for feature extraction while the power spectrum density (PSD) of both EEG and tEEG in the frequency band 8-30Hz was used for feature extraction. Linear Discriminant Analysis (LDA) was used to classify different combinations of the aforementioned features. The highest classification accuracy (85.2%) was achieved by using features from all the three brain signals recording modules. The improvement in classification accuracy was highly significant (p = 0.0033) when using the multimodal signals features as compared to pure EEG features. PMID- 26736450 TI - Head-related impulse response cues for spatial auditory brain-computer interface. AB - This study provides a comprehensive test of a head-related impulse response (HRIR) cues for a spatial auditory brain-computer interface (saBCI) speller paradigm. We present a comparison with the conventional virtual sound headphone based spatial auditory modality. We propose and optimize the three types of sound spatialization settings using a variable elevation in order to evaluate the HRIR efficacy for the saBCI. Three experienced and seven naive BCI users participated in the three experimental setups based on ten presented Japanese syllables. The obtained EEG auditory evoked potentials (AEP) resulted with encouragingly good and stable P300 responses in online BCI experiments. Our case study indicated that users could perceive elevation in the saBCI experiments generated using the HRIR measured from a general head model. The saBCI accuracy and information transfer rate (ITR) scores have been improved comparing to the classical horizontal plane-based virtual spatial sound reproduction modality, as far as the healthy users in the current pilot study are concerned. PMID- 26736451 TI - Region based Brain Computer Interface for a home control application. AB - Environment control is one of the important challenges for disabled people who suffer from neuromuscular diseases. Brain Computer Interface (BCI) provides a communication channel between the human brain and the environment without requiring any muscular activation. The most important expectation for a home control application is high accuracy and reliable control. Region-based paradigm is a stimulus paradigm based on oddball principle and requires selection of a target at two levels. This paper presents an application of region based paradigm for a smart home control application for people with neuromuscular diseases. In this study, a region based stimulus interface containing 49 commands was designed. Five non-disabled subjects were attended to the experiments. Offline analysis results of the experiments yielded 95% accuracy for five flashes. This result showed that region based paradigm can be used to select commands of a smart home control application with high accuracy in the low number of repetitions successfully. Furthermore, a statistically significant difference was not observed between the level accuracies. PMID- 26736452 TI - Is breathing rate a confounding variable in brain-computer interfaces (BCIs) based on EEG spectral power? AB - Brain-computer interfaces (BCIs) enable paralyzed patients to interact with the world by directly decoding brain activity. We investigated if systematic changes in breathing rate affect EEG bandpower features that are commonly used in BCIs. This is of particular interest for the development of cognitive BCIs for patients with artificial ventilation, e.g. for those in late stages of amyotrophic lateral sclerosis (ALS). If subjects can alter the spectrum of the EEG by changing their breathing rate, decoding results obtained with healthy subjects may not generalize to this patient population. We recorded a high-density EEG from twelve healthy subjects, who were instructed to alternate between fast and slow breathing. We do not find any statistically significant modulation of EEG bandpower. As such, changes in breathing rate are unlikely to substantially bias the performance of BCIs based on EEG bandpower features. PMID- 26736453 TI - Comparing metrics to evaluate performance of regression methods for decoding of neural signals. AB - The use of regression methods for decoding of neural signals has become popular, with its main applications in the field of Brain-Machine Interfaces (BMIs) for control of prosthetic devices or in the area of Brain-Computer Interfaces (BCIs) for cursor control. When new methods for decoding are being developed or the parameters for existing methods should be optimized to increase performance, a metric is needed that gives an accurate estimate of the prediction error. In this paper, we evaluate different performance metrics regarding their robustness for assessing prediction errors. Using simulated data, we show that different kinds of prediction error (noise, scaling error, bias) have different effects on the different metrics and evaluate which methods are best to assess the overall prediction error, as well as the individual types of error. Based on the obtained results we can conclude that the most commonly used metrics correlation coefficient (CC) and normalized root-mean-squared error (NRMSE) are well suited for evaluation of cross-validated results, but should not be used as sole criterion for cross-subject or cross-session evaluations. PMID- 26736454 TI - A Brain-Computer Interface (BCI) system to use arbitrary Windows applications by directly controlling mouse and keyboard. AB - A Brain-Computer Interface (BCI) allows to control a computer by brain activity only, without the need for muscle control. In this paper, we present an EEG-based BCI system based on code-modulated visual evoked potentials (c-VEPs) that enables the user to work with arbitrary Windows applications. Other BCI systems, like the P300 speller or BCI-based browsers, allow control of one dedicated application designed for use with a BCI. In contrast, the system presented in this paper does not consist of one dedicated application, but enables the user to control mouse cursor and keyboard input on the level of the operating system, thereby making it possible to use arbitrary applications. As the c-VEP BCI method was shown to enable very fast communication speeds (writing more than 20 error-free characters per minute), the presented system is the next step in replacing the traditional mouse and keyboard and enabling complete brain-based control of a computer. PMID- 26736455 TI - Combining firing rate and spike-train synchrony features in the decoding of motor cortical activity. AB - Decoding of directional information in the motor cortex traditionally utilizes only firing rate information. However, information from other features could be extracted and combined with firing rate in order to increase classification accuracy. This study proposes the combination of firing rate and spike-train synchrony information in the decoding of motor cortical activity. Synchrony measures used are Event Synchronization (ES), SPIKE-Distance, and ISI-Distance. All data used for analyses were obtained from implanted electrode recordings of the primary motor cortex of a monkey that was trained to manipulate a motorized vehicle with 4 degrees of freedom (left, right, front and stop) via joystick control. Firstly, synchrony features could decode time periods, which were otherwise incorrectly decoded by firing rate alone, above chance levels. Secondly, using an ensemble classifier design for offline analysis, combining firing rate and ISI-distance information increases overall decoding accuracy by 1.1%. These results show that synchrony features in spike-trains do contain information not carried in firing rate. In addition, these results also demonstrate the feasibility of combining synchrony and firing rate for improving the classification accuracy of invasive brain-machine interface (BMI) in the control of neural prosthetics. PMID- 26736456 TI - Towards SSVEP-based, portable, responsive Brain-Computer Interface. AB - A Brain-Computer Interface in motion control application requires high system responsiveness and accuracy. SSVEP interface consisted of 2-8 stimuli and 2 channel EEG amplifier was presented in this paper. The observed stimulus is recognized based on a canonical correlation calculated in 1 second window, ensuring high interface responsiveness. A threshold classifier with hysteresis (T H) was proposed for recognition purposes. Obtained results suggest that T-H classifier enables to significantly increase classifier performance (resulting in accuracy of 76%, while maintaining average false positive detection rate of stimulus different then observed one between 2-13%, depending on stimulus frequency). It was shown that the parameters of T-H classifier, maximizing true positive rate, can be estimated by gradient-based search since the single maximum was observed. Moreover the preliminary results, performed on a test group (N=4), suggest that for T-H classifier exists a certain set of parameters for which the system accuracy is similar to accuracy obtained for user-trained classifier. PMID- 26736457 TI - A generalizable adaptive brain-machine interface design for control of anesthesia. AB - Brain-machine interfaces (BMIs) for closed-loop control of anesthesia have the potential to automatically monitor and control brain states under anesthesia. Since a variety of anesthetic states are needed in different clinical scenarios, designing a generalizable BMI architecture that can control a wide range of anesthetic states is essential. In addition, drug dynamics are non-stationary over time and could change with the depth of anesthesia. Hence for precise control, a BMI needs to track these non-stationarities online. Here we design a BMI architecture that generalizes to control of various anesthetic states and their associated neural signatures, and is adaptive to time-varying drug dynamics. We provide a systematic approach to build general parametric models that quantify the anesthetic state and describe the drug dynamics. Based on these models, we develop an adaptive closed-loop controller within the framework of stochastic optimal feedback control. This controller tracks the non stationarities in drug dynamics, achieves tight control in a time-varying environment, and removes the need for an offline system identification session. For robustness, the BMI also ensures small drug infusion rate variations at steady state. We test the BMI architecture for control of two common anesthetic states, i.e., burst suppression in medically-induced coma and unconsciousness in general anesthesia. Using numerical experiments, we find that the BMI generalizes to control of both these anesthetic states; in a time-varying environment, even without initial knowledge of model parameters, the BMI accurately controls these two different anesthetic states, reducing bias and error more than 70 times and 9 times, respectively, compared with a non-adaptive system. PMID- 26736458 TI - Immersive BCI with SSVEP in VR head-mounted display. AB - In this paper we present an immersive brain computer interface (BCI) where we use a virtual reality head-mounted display (VRHMD) to invoke SSVEP responses. Compared to visual stimuli in monitor display, we demonstrate that visual stimuli in VRHMD indeed improve the user engagement for BCI. To this end, we validate our method with experiments on a VR maze game, the goal of which is to guide a ball into the destination in a 2D grid map in a 3D space, successively choosing one of four neighboring cells using SSVEP evoked by visual stimuli on neighboring cells. Experiments indicate that the averaged information transfer rate is improved by 10% for VRHMD, compared to the case in monitor display and the users feel easier to play the game with the proposed system. PMID- 26736459 TI - Brain-machine interfaces for assistive smart homes: A feasibility study with wearable near-infrared spectroscopy. AB - Smart houses for elderly or physically challenged people need a method to understand residents' intentions during their daily-living behaviors. To explore a new possibility, we here developed a novel brain-machine interface (BMI) system integrated with an experimental smart house, based on a prototype of a wearable near-infrared spectroscopy (NIRS) device, and verified the system in a specific task of controlling of the house's equipments with BMI. We recorded NIRS signals of three participants during typical daily-living actions (DLAs), and classified them by linear support vector machine. In our off-line analysis, four DLAs were classified at about 70% mean accuracy, significantly above the chance level of 25%, in every participant. In an online demonstration in the real smart house, one participant successfully controlled three target appliances by BMI at 81.3% accuracy. Thus we successfully demonstrated the feasibility of using NIRS-BMI in real smart houses, which will possibly enhance new assistive smart-home technologies. PMID- 26736460 TI - Decoding fast-paced error-related potentials in monitoring protocols. AB - Error-related EEG potentials (ErrP) can be used for brain-machine interfacing (BMI). Decoding of these signals, indicating subject's perception of erroneous system decisions or actions can be used to correct these actions or to improve the overall interfacing system. Multiple studies have shown the feasibility of decoding these potentials in single-trial using different types of experimental protocols and feedback modalities. However, previously reported approaches are limited by the use of long inter-stimulus intervals (ISI > 2 s). In this work we assess if it is possible to overcome this limitation. Our results show that it is possible to decode error-related potentials elicited by stimuli presented with ISIs lower than 1 s without decrease in performance. Furthermore, the increase in the presentation rate did not increase the subject workload. This suggests that the presentation rate for ErrP-based BMI protocols using serial monitoring paradigms can be substantially increased with respect to previous works. PMID- 26736461 TI - Detecting intention to grasp during reaching movements from EEG. AB - Brain-computer interfaces (BCI) have been shown to be a promising tool in rehabilitation and assistive scenarios. Within these contexts, brain signals can be decoded and used as commands for a robotic device, allowing to translate user's intentions into motor actions in order to support the user's impaired neuro-muscular system. Recently, it has been suggested that slow cortical potentials (SCPs), negative deflections in the electroencephalographic (EEG) signals peaking around one second before the initiation of movements, might be of interest because they offer an accurate time resolution for the provided feedback. Many state-of-the-art studies exploiting SCPs have focused on decoding intention of movements related to walking and arm reaching, but up to now few studies have focused on decoding the intention to grasp, which is of fundamental importance in upper-limb tasks. In this work, we present a technique that exploits EEG to decode grasping correlates during reaching movements. Results obtained with four subjects show the existence of SCPs prior to the execution of grasping movements and how they can be used to classify, with accuracy rates greater than 70% across all subjects, the intention to grasp. Using a sliding window approach, we have also demonstrated how this intention can be decoded on average around 400 ms before the grasp movements for two out of four subjects, and after the onset of grasp itself for the two other subjects. PMID- 26736462 TI - Real-time simultaneous myoelectric control by transradial amputees using linear and probability-weighted regression. AB - Regression-based prosthesis control using surface electromyography (EMG) has demonstrated real-time simultaneous control of multiple degrees of freedom (DOFs) in transradial amputees. However, these systems have been limited to control of wrist DOFs. Use of intramuscular EMG has shown promise for both wrist and hand control in able-bodied subjects, but to date has not been evaluated in amputee subjects. The objective of this study was to evaluate two regression-based simultaneous control methods using intramuscular EMG in transradial amputees and compare their performance to able-bodied subjects. Two transradial amputees and sixteen able-bodied subjects used fine wire EMG recorded from six forearm muscles to control three wrist/hand DOFs: wrist rotation, wrist flexion/extension, and hand open/close. Both linear regression and probability-weighted regression systems were evaluated in a virtual Fitts' Law test. Though both amputee subjects initially produced worse performance metrics than the able-bodied subjects, the amputee subject who completed multiple experimental blocks of the Fitts' law task demonstrated substantial learning. This subject's performance was within the range of able-bodied subjects by the end of the experiment. Both amputee subjects also showed improved performance when using probability-weighted regression for targets requiring use of only one DOF, and mirrored statistically significant differences observed with able-bodied subjects. These results indicate that amputee subjects may require more learning to achieve similar performance metrics as able-bodied subjects. These results also demonstrate that comparative findings between linear and probability-weighted regression with able-bodied subjects reflect performance differences when used by the amputee population. PMID- 26736463 TI - Iron 'ElectriRx' man: Overground stepping in an exoskeleton combined with noninvasive spinal cord stimulation after paralysis. AB - We asked whether coordinated voluntary movement of the lower limbs could be regained in an individual having been completely paralyzed (>4 yr) and completely absent of vision (>15 yr) using a novel strategy - transcutaneous spinal cord stimulation at selected sites over the spinal vertebrae with just one week of training. We also asked whether this stimulation strategy could facilitate stepping assisted by an exoskeleton (EKSO, EKSO Bionics) that is designed so that the subject can voluntarily complement the work being performed by the exoskeleton. We found that spinal cord stimulation enhanced the level of effort that the subject could generate while stepping in the exoskeleton. In addition, stimulation improved the coordination patterns of the lower limb muscles resulting in a more continuous, smooth stepping motion in the exoskeleton. These stepping sessions in the presence of stimulation were accompanied by greater cardiac responses and sweating than could be attained without the stimulation. Based on the data from this case study it appears that there is considerable potential for positive synergistic effects after complete paralysis by combining the overground stepping in an exoskeleton, a novel transcutaneous spinal cord stimulation paradigm, and daily training. PMID- 26736464 TI - Detection of critical errors of locomotion mode recognition for volitional control of powered transfemoral prostheses. AB - Combination of intrinsic control and volitional control that recognizes the user's locomotion mode (LM) has been applied to powered prosthetic legs, which enables lower limb amputees to adapt to varying terrains seamlessly. However, errors in volitional control may disrupt the user's walking balance. This study aimed to determine whether the critical errors in volitional control could be detected before they disturbed the user's walking. The positive answer might lead to more robust volitional control for powered prosthetic legs. To achieve this goal, volitional control and intrinsic control were connected hierarchically to operate a powered transfemoral prosthesis. Critical errors for recognizing the user's LM were introduced artificially when transfemoral amputees walked with the powered prosthesis. Intrinsic measurements from the prosthesis were explored first in order to select effective data sources for error detection. Then a phase dependent outlier detector was designed and offline evaluated. The results demonstrated that the designed detector can detect the tested critical errors with a high sensitivity and a low false alarm ratio before the errors disrupted the amputees' balance. Additional engineering efforts were still necessary to test the detector on more error types and design a control strategy that can make volitional control of powered lower limb prosthesis robust and safe to use. PMID- 26736465 TI - Musculoskeletal model predicts multi-joint wrist and hand movement from limited EMG control signals. AB - Electromyography (EMG)-driven human-machine systems permit volitional control of external devices, including powered prosthetic arms. However, current control schemes are either non-intuitive to operate or lack robustness across different arm postures and dynamics, partly because these methods did not incorporate the full knowledge of biological movement production. In this study, we developed and evaluated a new musculoskeletal model to predict hand and wrist motion based on surface EMG signals. Kinematic and EMG data were collected from an able-bodied subject while performing wrist and metacarpophalangeal (MCP) joint movements with either a fixed or random speed in two static upper limb postures. A part of data collected in one posture was used to develop the model with four virtual muscles. Four parameters were optimized for each of four muscles in one posture. The model kinematic predictions were evaluated offline using the other part of the data recorded from both postures. Mean (+/-SD) RMS errors in predicting the joint movement were significantly lower at the MCP joint (10.1+/-2.5 degrees ) than at the wrist (23.5+/-5.2 degrees ) (p<;0.05). At both the wrist and MCP joints, the model predicted the timing and trend of joint movements reasonably well across postures and for both simple (fixed speed, single joint) and complex (random speed, simultaneous, multi-joint) movements. The results implied that our EMG driven musculoskeletal model was promising for predicting simultaneous joint motions without significant posture and dynamics dependency. Additional engineering efforts are still needed to improve the musculoskeletal model for various human-machine interfacing applications. PMID- 26736466 TI - Muscle synergies for reliable classification of arm motions using myoelectric interface. AB - Synergistic activation of muscles are considered to be the phenomenon by which the central nervous system simplifies its control strategy. Muscle synergies are neurally encoded and considered robust to be able to adapt for various external dynamics. This paper presents a myoelectric-based interface to identify and classify motions of the upper arm involving the shoulder and elbow. We contrast performance of the decoder while using time domain and synergy features. The decoder is trained using extreme learning machine algorithm, and online testing is performed in a virtual environment. Better classification accuracy for online control is obtained while using muscle synergy features. The results indicate better online performance compared to offline performance while using synergy features to classify movements, indicating generalization to dynamic situations and robustness of control. PMID- 26736467 TI - Offline accuracy: A potentially misleading metric in myoelectric pattern recognition for prosthetic control. AB - Offline accuracy has been the preferred performance measure in myoelectric pattern recognition (MPR) for the prediction of motion volition. In this study, different metrics relating the fundamental binary prediction outcomes were analyzed. Our results indicate that global accuracy is biased by 1) the unbalanced number of possible true positive and negative outcomes, and 2) the almost perfect specificity and negative predicted value, which were consistently found across algorithms, topologies, and movements (individual and simultaneous). Therefore, class-specific accuracy is advisable instead. Additionally, we propose the use of precision (positive predictive value) and sensitivity (recall) as a complement to accuracy to better describe the discrimination capabilities of MPR algorithms, as these consider the effect of false predictions. However, all the studied offline metrics failed to predict real-time decoding, and therefore real time testing continue to be necessary to truly evaluate the clinical usability of MPR. PMID- 26736468 TI - A comparison of open-loop and closed-loop adaptive calibration for pattern recognition based myoelectric control. AB - This study presented a closed-loop adaptive calibration (CLAC) scheme where subjects could get instantaneous feedback of their movements and alter their motions immediately to update the model parameters to enhance its ability. The real-time performance was compared between the conventional open-loop calibration (OLC) and the presented CLAC based on three metrics (motion-selection time, motion-completion time and motion-completion rate). The CLAC performed slightly better than the OLC, but the difference was not significant. This was the first study designed to investigate the effects of CLAC for pattern recognition-based myoelectric control (discrete movement). The CLAC could be potentially applied in the multiuser interface to make the adaptation of the common model to a novel user efficiently and flexibly. PMID- 26736469 TI - Evaluation of touch-sensitive screen tablet terminal button size and spacing accounting for effect of fingertip contact angle. AB - Touch-sensitive screen terminals enabling intuitive operation are used as input interfaces in a wide range of fields. Tablet terminals are one of the most common devices with a touch-sensitive screen. They have a feature of good portability, enabling use under various conditions. On the other hand, they require a GUI designed to prevent decrease of usability under various conditions. For example, the angle of fingertip contact with the display changes according to finger posture during operation and how the case is held. When a human fingertip makes contact with an object, the contact area between the fingertip and contact object increases or decreases as the contact angle changes. A touch-sensitive screen detects positions using the change in capacitance of the area touched by the fingertip; hence, differences in contact area between the touch-sensitive screen and fingertip resulting from different forefinger angles during operation could possibly affect operability. However, this effect has never been studied. We therefore conducted an experiment to investigate the relationship between size/spacing and operability, while taking the effect of fingertip contact angle into account. As a result, we have been able to specify the button size and spacing conditions that enable accurate and fast operation regardless of the forefinger contact angle. PMID- 26736470 TI - An online hybrid brain-computer interface combining multiple physiological signals for webpage browse. AB - The hybrid brain computer interface (hBCI) could provide higher information transfer rate than did the classical BCIs. It included more than one brain computer or human-machine interact paradigms, such as the combination of the P300 and SSVEP paradigms. Research firstly constructed independent subsystems of three different paradigms and tested each of them with online experiments. Then we constructed a serial hybrid BCI system which combined these paradigms to achieve the functions of typing letters, moving and clicking cursor, and switching among them for the purpose of browsing webpages. Five subjects were involved in this study. They all successfully realized these functions in the online tests. The subjects could achieve an accuracy above 90% after training, which met the requirement in operating the system efficiently. The results demonstrated that it was an efficient system capable of robustness, which provided an approach for the clinic application. PMID- 26736471 TI - Development of a haptic interface for motor rehabilitation therapy using augmented reality. AB - In this paper, a robot-assisted therapy system is presented, mainly focused on the improvement of fine movements of patients with motor deficits of upper limbs. This system combines the use of a haptic device with an augmented reality environment, where a kind of occupational therapy exercises are implemented. The main goal of the system is to provide an extra motivation to patients, who are stimulated visually and tactilely into a scene that mixes elements of real and virtual worlds. Additionally, using the norm of tracking error, it is possible to quantitatively measure the performance of the patient during a therapy session, likewise, it is possible to obtain information such as runtime and the followed path. PMID- 26736472 TI - Operation assistance for the Bio-Remote environmental control system using a Bayesian Network-based prediction model. AB - This paper proposes a Bayesian Network (BN) based prediction model for a layer based selection and its application to an operation assistance for the environmental control system Bio-Remote (BR). In the proposed method, each node of the BN model is involved in the layer-based selection function, which corresponds to an individual operation command, appliance, etc., and previous logs of operation commands and time division are used as input factors to predict the user's intended operation. The prediction results are displayed on the layer based selection for the BR, and the number of times of operations and time taken for the operations can be reduced with the proposed prediction model. In the experiments, life-logs were collected from a cervical spinal injury patient who used the BR in daily life, and the proposed model was trained based on these recorded life-logs. The prediction accuracy for control devices of the BR system using the proposed model was 84.3 +/- 6.5 %. The results indicated that the proposed prediction model could be useful for the operation assistance of the BR system. PMID- 26736473 TI - Displaying shape haptically using MRF-based device. AB - Smart materials such as magnetorheological fluids (MRF) offer an interesting medium to present viscoelastic cues in haptic displays as changes in the magnetic field are rapid, reversible and controllable. These interfaces have been evaluated in a number of medical and surgical simulators where they can provide cues regarding the viscoelastic properties of tissues. The present experiment determined whether eight different shapes could be identified reliably with a MRF haptic display and compared the information transfer (IT) associated with this type of display with that achieved by other forms of haptic communication. The overall performance of participants at identifying the shapes was good with a mean score of 70% correct and an IT of 2.13 bits. This type of display shows promise as a training tool for simulating tissue properties. PMID- 26736474 TI - A dual-user teleoperation system with Online Authority Adjustment for haptic training. AB - This paper introduces a dual-user teleoperation system for hands-on medical training. A shared control based architecture is presented for authority management. In this structure, the combination of control signals is obtained using a dominance factor. Its main improvement is Online Authority Adjustment (OAA): the authority can be adjusted manually/automatically during the training progress. Experimental results are provided to validate the performances of the system. PMID- 26736476 TI - A multi-stage design framework for the development of task-specific robotic exoskeletons. AB - This work presents a multi-stage design framework for developing robotic exoskeletons suited for specific tasks, such as individualized exercises that meet the needs of patients undergoing physical therapy. The framework systematically develops the exoskeleton based on the required task space, represented by a set of limb poses which may be defined directly, or indirectly using means such as motion capture. The design process seeks to maximize the poses inside and surrounding the defined task space whilst ensuring additional criteria required to perform the task are satisfied. A case study demonstrates the framework applied to develop two variations of shoulder exoskeleton suited for two specific upper limb activities. Prototype exoskeletons based on the framework's outcomes were constructed, and their suitability for use in their intended tasks were evaluated. PMID- 26736475 TI - Large displacement haptic stimulus actuator using piezoelectric pump for wearable devices. AB - Recently, given Japan's aging society background, wearable healthcare devices have increasingly attracted attention. Many devices have been developed, but most devices have only a sensing function. To expand the application area of wearable healthcare devices, an interactive communication function with the human body is required using an actuator. For example, a device must be useful for medication assistance, predictive alerts of a disease such as arrhythmia, and exercise. In this work, a haptic stimulus actuator using a piezoelectric pump is proposed to realize a large displacement in wearable devices. The proposed actuator drives tactile sensation of the human body. The measurement results obtained using a sensory examination demonstrate that the proposed actuator can generate sufficient stimuli even if adhered to the chest, which has fewer tactile receptors than either the fingertip or wrist. PMID- 26736477 TI - A novel holding mechanism for next generation active wireless capsule endoscopy. AB - This paper proposes that next generation wireless capsule endoscopy (WCE) technology will feature active mechanical components (i.e. actuated) as opposed to current systems that are predominantly passive (e.g. for imaging purposes). Future systems will integrate microsystems that use micro-actuators to, for example, perform micro-surgery, take tissue samples, deliver medication, etc. In this paper we detail a novel, ultra-compact integrated mechanism for resisting peristalsis and describe how this can be fabricated in Nylon 6 using CNC milling. The holding action is achieved by extending an "anchor" spanning an effective 60.4mm circumference, for a 11.0mm diameter WCE. This function is achieved by a mechanism that occupies only 347.0mm(3) volume, including mechanics and actuator. This shows how exploiting conventional manufacturing processes can result in a radical change in the capabilities of WCE systems and empower the next generation of active devices. PMID- 26736478 TI - Development of an MRI-powered robotic system for cryoablation. AB - This study proposes a novel MRI-powered robotic system controlled with the magnetic field generated by a magnetic resonance imaging (MRI) scanner. In the proposed system, we use an MRI-powered actuator unit proposed in the previous study and a spherical positioning mechanism. The actuator unit contains a ferromagnetic sphere, which acts as a power source and is used to control the positioning unit inside the MRI environment. These elements enable the development of a remote needle tip positioning system for use within the MRI scanner. Potential applications of the developed system include the automation of procedures during under MRI inspections, especially the cryoablation of breast cancer. In this paper, we report on the performance evaluation and the MR-safety of the proposed system and describe the newly developed spherical positioning mechanism, which can be activated by the actuator units. PMID- 26736479 TI - Kinematic reconstruction of the human arm joints in robot-aided therapies with Hermes robot. AB - This paper presents a kinematic reconstruction algorithm for the variables of the human arm joints in robot-aided neurorehabilitation therapies. The presented algorithm uses the end effector of a rehabilitation robot and an accelerometer placed onto the upper arm to compute accurate values of the human arm chain. The goal of this algorithm is to obtain the joint values of the patient's arm to provide objective information to the therapist about the progress of the patient and to study the effectiveness of these kind of therapies. PMID- 26736480 TI - Development of implantable hemodialysis system using PES membranes with high water-permeability. AB - This paper presents development of high water-permeable dialysis membranes. We proposed the system that does not use dialysis fluid for the implantable micro dialysis treatment and development of such membranes is crucial. We developed micro dialysis system composed by nanoporous membranes and microfluidic channels in our prior work. The membranes were made of nanoporous polyethersulfone (PES), which was not water-permeable. By not using dialysate, our device can be simplified because the pumps and storage tanks for the dialysis fluid are not necessary. This treatment is termed as hemofiltration. We measured the water permeability of PES membrane with respect to the concentrations of the PES, the additives, and the solvents in the casting solution. We could find the membranes with sufficiently high water permeability through in vitro experiments using a syringe pomp and whole cow blood, and the membrane had enough mechanical strength. We conducted experiments with multi-layered device in in vitro and in vivo using rats, where the system was connected to the vein and artery. We successfully collected the filtrate beyond target line, which was set by a medical doctor, without any leakage of blood from the device. The results verified that the filtration device can be scaled-up by increasing a number of the layer. We connected the device to a rat for 5h. It was verified the device maintained almost constant water permeability beyond our target line. PMID- 26736481 TI - Development and integration of a Surveillance Monitoring solution to provide earlier detection of the deteriorating patient. AB - This paper presents recent improvement of a Wi-Fi based vital signs monitor used for in-hospital monitoring in medium-risk settings. Valuable insight into design strengths and weaknesses has been gained and device improvements have been confirmed with real-world use. Integration with intuitive central station software is considered with respect to balancing functionality and performance. Practical use of the early warning system in challenging clinical environments has enabled further understanding of the potential impact of the system. A tool to provide a convenient method of tracking patient condition and alerting on deterioration is offered. PMID- 26736482 TI - Determining the variability in O(2) saturation measurements in devices of the "Dr. Guillermo Rawson" hospital. AB - Measurement of oxygen saturation is a noninvasive monitoring method that has had a major impact on patient care in both emergency and ambulatory situations. It is an important parameter in neonatology field, especially in newborn preterm births, and in anesthetic and surgical procedures. PMID- 26736483 TI - Sleep state classification using pressure sensor mats. AB - Sleep state detection is valuable in assessing patient's sleep quality and in-bed general behavior. In this paper, a novel classification approach of sleep states (sleep, pre-wake, wake) is proposed that uses only surface pressure sensors. In our method, a mobility metric is defined based on successive pressure body maps. Then, suitable statistical features are computed based on the mobility metric. Finally, a customized random forest classifier is employed to identify various classes including a new class for pre-wake state. Our algorithm achieves 96.1% and 88% accuracies for two (sleep, wake) and three (sleep, pre-wake, wake) class identification, respectively. PMID- 26736484 TI - The dimensioning and development of hospital electric installations to guarantee the continuity of use of the therapeutic and diagnostic system. AB - The Technical Services and the Medical Administration of the Hospitals of Trieste have been working for years to ensure the optimal functioning of the Medicine, Surgery, Diagnostics and Research services offered to the Patients and to the University in an 800-bed hospital complex, transforming and innovating the buildings and support installations. We have dedicated special attention to the technologies necessary to guarantee the continuity of the power supply to the electromedical devices, increasingly numerous in highly specialized hospitals. We report our electricity consumption and the power of the generator sets and the UPS and our opinion that their power must be related to the overall consumption of the Hospital, with a reserve margin. PMID- 26736485 TI - Tablet-based patient monitoring and decision support systems in hospital care. AB - Remote patient monitoring with evidence-based decision support is revolutionizing healthcare. This novel approach could enable both patients and healthcare providers to improve quality of care and reduce costs. Clinicians can also view patients' data within the hospital network on tablet computers as well as other ubiquitous devices. Today, a wide range of applications are available on tablet computers which are increasingly integrating into the healthcare mainstream as clinical decision support systems. Despite the benefits of tablet-based healthcare applications, there are concerns around the accuracy, security and stability of such applications. In this study, we developed five tablet-based application screens for remote patient monitoring at hospital care settings and identified related issues and challenges. The ultimate aim of this research is to integrate decision support algorithms into the monitoring system in order to improve inpatient care and the effectiveness of such applications. PMID- 26736486 TI - Integrated vital signs monitoring system using ubiquitous devices: Multiple physical signs detection and decision support for hospitalized older adults. AB - Vital signs monitoring systems are rapidly becoming the core of today's healthcare deliveries. The paradigm has shifted from traditional and manual recording to computer based electronic records and further to handheld devices as versatile and innovative healthcare monitoring systems. Interpretation of vital signs to early detect multiple physical signs using a multifactorial and holistic approach is presented. A total of 30 patient data have been collected under local and national ethics approvals in New Zealand Hospitals. Ultimately, this system achieved a high level of agreement with clinicians' interpretation when assessing specific physical signs such as bradycardia, tachycardia, hypertension, hypotension, hypoxaemia, fever and hypothermia. The proposed vital signs interpretation system was validated through off-line as well as real-time tests with a high level of agreement between the system and the physician. The system achieved an accuracy of 95.83%, sensitivity of 100%, specificity of 93.15%, and predictability of 90.38% in compare with a clinician assessment for tachycardia, hypertension, hypotension, hypoxaemia and hypothermia. PMID- 26736487 TI - Image based quantitative reader for Lateral flow immunofluorescence assay. AB - Fluorescence Lateral flow immunoassays (LFIA) have wide range of applications in point-of-care testing (POCT). An integrated, motion-free, accurate, reliable reader that performs automated quantitative analysis of LFIA is essential for POCT diagnosis. We demonstrate an image based quantitative method to read the lateral flow immunofluorescence test strips. The developed reader uses line laser diode module to illuminate the LFIA test strip having fluorescent dye. Fluorescence light coming from the region of interest (ROI) of the LFIA test strip was filtered using an emission filter and imaged using a camera following which images were processed in computer. A dedicated control program was developed that automated the entire process including illumination of the test strip using laser diode, capturing the ROI of the test strip, processing and analyzing the images and displaying of results. Reproducibility of the reader has been evaluated using few reference cartridges and HbA1c (Glycated haemoglobin) test cartridges. The proposed system can be upgraded to a compact reader for widespread testing of LFIA test strips. PMID- 26736488 TI - Comprehensive framework for preventive maintenance priority of medical equipment. AB - Throughout the medical equipment life cycle, preventive maintenance is considered one of the most important stages that should be managed properly. However, the need for better management and control by giving a reasonable prioritization for preventive maintenance becomes essential. The purpose of this study is to develop a comprehensive framework for preventive maintenance priority of medical equipment using Quality Function Deployment (QFD) and Fuzzy Logic (FL). The quality function deployment is proposed in order to identify the most important criteria that could impact preventive maintenance priority decision; meanwhile the role of the fuzzy logic is to generate a priority index of the list of equipment considering those criteria. The model validation was carried out on 140 pieces of medical equipment belonging to two hospitals. In application, we propose to classify the priority index into five classes. The results indicate that the strong correlation existence between risk-based criteria and preventive maintenance priority decision. PMID- 26736489 TI - Organizational principles of cloud storage to support collaborative biomedical research. AB - This paper describes organizational guidelines and an anonymization protocol for the management of sensitive information in interdisciplinary, multi-institutional studies with multiple collaborators. This protocol is flexible, automated, and suitable for use in cloud-based projects as well as for publication of supplementary information in journal papers. A sample implementation of the anonymization protocol is illustrated for an ongoing study dealing with Automated Prediction of EXtubation readiness (APEX). PMID- 26736490 TI - A preliminary study of the relation between back-pain and plantar-pressure evolution during pregnancy. AB - This work presents the dynamic study of the plantar pressure in a group of 15 pregnant women. An instrumented insoles (ECnsole) developed by the research group were used in order to measure the plantar pressure distribution. A questionnaire that described their perception of the back pain were filled by the participants. This test were repeated in weeks 12, 20 and 32 of pregnancy. From our preliminary results, the centre pressure in the Y-axis in both foot were slightly displaced towards the heel in week test 20 and 32, and it agrees with the onset of back pain in pregnant women. PMID- 26736491 TI - Anterior temporal artery tap to identify systemic interference using short separation NIRS measurements: A NIRS/EEG-tDCS study. AB - Transcranial direct current stimulation (tDCS) has been shown to modulate neural activity. Neural activity has been shown to be closely related, spatially and temporally, to cerebral blood flow (CBF) that supplies glucose via neurovascular coupling. Therefore, noninvasive and continuous monitoring of neural activity is possible with a measure of cerebral hemoglobin oxygenation using near-infrared spectroscopy (NIRS). In principal accordance, NIRS can capture the hemodynamic response to tDCS but the challenge remains in removing the systemic interference occurring in the superficial layers of the head that are also affected by tDCS. An approach may be to use short optode separations to measure systemic hemodynamic fluctuations occurring in the superficial layers which can then be used as regressors to remove the systemic contamination. Here, we demonstrate that temporal artery tap may be used to better identify systemic interference using this short-separation NIRS. Moreover, NIRS-EEG joint-imaging during anodal tDCS was used to measure changes in mean cerebral haemoglobin oxygen saturation (rSO2) along with changes in the log-transformed mean-power of EEG within 0.5 Hz 11.25 Hz. We found that percent change in the mean rSO2 better correlated with the corresponding percent change in log-transformed mean-power of EEG within 0.5 Hz-11.25 Hz frequency band after removing the systemic contamination using the temporal artery tap method. Based on our findings, we propose that anterior temporal artery tap technique presented in this paper may be able to classify carotid stenosis, external carotid artery stenosis, and internal carotid artery stenosis patients using the laterality in the hemodynamic response evoked by anodal tDCS both at the brain as well as at the superficial layers. These findings may have important implications for both prognosis and rehabilitation of patients with intracranial stenosis. PMID- 26736492 TI - Towards a full-field strain sensor for guiding hernia repairs. AB - Each year, approximately 400,000 ventral hernia repairs are performed in the United States [1], [2]. Large ventral hernias (hernias that occur in the abdominal wall) are typically treated by suturing in a surgical mesh to cover and overlap the hernia defect. However, in 10-20% of patients, the hernia repair fails, resulting in recurrence of the hernia, along with other complications including infection and intestinal obstruction [3], [4]. One potential cause of hernia recurrence is the unequal distribution of stress across the mesh resulting in high stress concentrations at the tissue-mesh interface, particularly at the site of mesh fixation to the abdominal wall muscles[5], [6]. Strain across the mesh can be used as an indicator for how evenly stress is distributed across the surface of the mesh. To this end, we have built a full-field, 3D strain measurement system to enable physicians to actively identify and address areas of high strain during the surgery, thus decreasing the rate of hernia recurrence. The strain sensor uses an optical technique, called the grid method, in conjunction with the defocused particle image velocimetry (DPIV) technique to measure the 3D strain distribution across the mesh. The system can achieve a limit of detection down to 0.4% strain and across a 50 cm range z-axis displacement using a Canon EOS 7D camera with a pinhole aperture mask. PMID- 26736493 TI - Non-invasive estimation of cardiovascular parameters using ballistocardiography. AB - Ballistocardiography is a non-invasive technique to estimate heart function and relative changes in cardiac output. The goal of this study was to establish the relationship between ballistocardiogram (BCG) parameters and changes in cardiovascular parameters. A group of 20 subjects performed three different exercises on a force plate. In this study, we have characterized the significant differences induced by static and dynamic squats, and controlled respiration exercises on BCG parameters such as IJ-amplitude and RJ-time. The dynamic squat exercise induced the largest changes in IJ-amplitude (107-123% higher) and the RJ time (21-23% lower). Furthermore, the IJ-amplitude of the BCG signal was found to be positively related to the cardiac output. PMID- 26736494 TI - A smart phone-based robust correction algorithm for the colorimetric detection of Urinary Tract Infection. AB - This paper presents the preliminary work of developing a smart phone based application for colorimetric detection of Urinary Tract Infection. The purpose is to make a smart phone function as a practical point-of-care device for nurses or medical personnel without access to strip readers. The main challenge is the constancy of camera color perception across different illuminations and devices, which is the first step towards a practical solution without additional equipment. A reported black and white reference correction and a comprehensive color image normalization have been utilized in this work. Comprehensive color image normalization appears to be quite effective at correcting the difference in perceived color due to different illumination, and is therefore a candidate for inclusion in the further work. PMID- 26736495 TI - Shear-mediated platelet activation in patients implanted with continuous flow LVADs: A preliminary study utilizing the platelet activity state (PAS) assay. AB - Left ventricular assist devices (LVADs) have emerged as vital life-saving therapeutic systems for patients with advanced and end-stage heart failure (HF). Despite their efficacy, VAD systems remain limited by post-implantation thrombotic complications. Shear-mediated platelet activation is the major driver of such complications in these devices. Nowadays few platelet function assays are routinely utilized in assessing the degree of platelet activation in VAD implanted patients. No assays exist that specifically target shear-mediated platelet activation. The platelet activity state (PAS) is a novel assay that has been well validated in vitro, measuring thrombin release as a surrogate for shear mediated platelet activation. To date limited data exist as to the utility of this assay in the clinical setting. In the present study we evaluated eight LVAD patients' platelet activation level using the PAS assay. Simultaneous measurements of conventional prothrombotic and hemolysis markers, - i.e. fibrinogen and lactate dehydrogenase (LDH) - were also performed. Trends as to alteration from baseline were studied. We observed that the PAS assay allowed detection of an abnormal level of platelet activation in one patient in our series who suffered from an overt thrombosis. Interestingly in the same patient no signal of major abnormality in fibrinogen or LDH was detected. Further for 7/8 patients who were free of thrombosis, no significant level of platelet activation was detected via PAS assay, while elevation in fibrinogen and LDH were observed. As such, from our observational series it appears that the PAS assay is a sensitive and specific indicator of shear-mediated platelet activation. Further patients' experience will help elucidate the role of this promising assay in the management of LVAD implanted patients. PMID- 26736496 TI - Evaluation of the variation in sensory test results using Semmes-Weinstein monofilaments. AB - The purpose of this study is to examine the variability in sensory test of tactile results using Semmes-Weinstein monofilament (SWM). At present, several methods for measuring the tactile sensitivity are clinically used in diabetic peripheral neuropathy screening. One of these methods is a touch test that uses a device with nylon SWMs, i.e., SWMs embedded in a plastic handle. A small pushing force is applied at the handle to bow the filaments. Because of its ease and simplicity, the SWM test is conducted at the patient's bedside in a hospital. However, previous studies have reported some problems with this test. Studies have shown variations in the measured data, and it is uncertain whether these variations are caused by mechanical properties of the nylon fiber or by the motion of the operator's hands. We carried out two experiments to examine the effect of (1) the variability caused by the human operator conducting the SWM test on the test results and (2) the number of compressions of the SWM on the test results. In experiment 1, we measured the velocity of the operator's hand motion and the buckling force of the SWMs. The results showed variability in the hand motion of the operator conducting the SWM tests. In experiment 2, we measured the buckling force of the SWMs under a controlled velocity. We compared the buckling force of the SWMs through a number of trials. These results showed that the buckling force gradually decreases as the number of test cycles increase. In conclusion, we find that the accuracy of the SWM tests is a factor of the number of test cycles. Additionally, manual training for standardizing skills of medical staff members needs to be developed. Furthermore, the characteristics of the SWMs deteriorated over time. In future work, we aimto find a solution to minimize the variability in the SWM test results and develop a new testing system that uses tactile sensibility for diabetic peripheral neuropathy screening. PMID- 26736497 TI - A multimodal stress monitoring system with canonical correlation analysis. AB - The multimodal stress monitoring headband is proposed for mobile stress management system. It is composed of headband and earplugs. Electroencephalography (EEG), hemoencephalography (HEG) and heart-rate variability (HRV) can be achieved simultaneously in the proposed system for user status estimation. With canonical correlation analysis (CCA) and temporal-kernel CCA (tkCCA) algorithm, those different signals can be combined for maximum correlation. Thanks to the proposed combination algorithm, the accuracy of the proposed system increased up to 19 percentage points than unimodal monitoring system in n-back task. PMID- 26736498 TI - Behavior of long-period measurements using a small-sized photoacoustic cell for aqueous glucose monitoring. AB - Reliable, noninvasive glucose-monitoring devices are not currently available. From the patient's point of view, it is necessary that glucose-monitoring devices are portable as well as noninvasive. In photoacoustic spectroscopy (PAS), the PA signal induced by the irradiation of the sample with modulated light depends on the optical absorption coefficient of the sample. Unlike the sensitivity of conventional absorption spectroscopy, the sensitivity of PAS scales inversely with the dimensions. An external laser (wavelength of 1550 nm) and a PA cell with a volume of only 4.0 mm(3) were used for monitoring a glucose solution contained in a special sample reservoir. We present PA measurements of glucose in aqueous solutions using a sample reservoir that is suitable for investigations of liquid samples, such as native capillary blood, by performing a long-period measurement. PMID- 26736499 TI - Development of a diagnostic dehydration screening sensor based on infrared spectrometry. AB - The clinical assessment of dehydration is highly subjective and requires experienced and highly trained clinical personnel. At present no objective method for quantitatively determining an individual's dehydration status exists. The aim of this study is to address this deficiency by presenting the development and testing of a novel diagnostic tool for dehydration detection based on infrared spectrometry. Laboratory testing and two clinical studies were conducted to evaluate the efficacy of the device in both adults and infants. The results were promising for the infant study with a clear trend exhibited. However, a number of challenges must be overcome before this sensor can be applied in a clinical setting. PMID- 26736500 TI - Head ballistocardiogram based on wireless multi-location sensors. AB - Recently a wearable BCG monitoring technique based on an accelerometer worn at the ear was demonstrated to replace a conventional bulky BCG acquisition system. In this work, a multi-location wireless vital signs monitor was developed, and at least two common acceleration vectors correlating to sitting-BCG were found in the supine position by using head PPG signal as a reference for eight healthy human subjects. The head side amplitude in the supine position is roughly proportional to the sitting amplitude that is in turn proportional to the stroke volume. Signal processing techniques to identify J-waves in a subject having small amplitude was also developed based on the two common vectors at the head side and top. PMID- 26736501 TI - Kinect v2 based system for Parkinson's disease assessment. AB - Human motion analysis can provide valuable information for supporting the clinical assessment of movement disorders, such as Parkinson's disease (PD). In this contribution, we study the suitability of a Kinect v2 based system for supporting PD assessment in a clinical environment, in comparison to the original Kinect (v1). In this study, 3-D body joint data were acquired from both normal subjects, and PD patients treated with deep brain stimulation (DBS). Then, several gait parameters were extracted from the gathered data. The obtained results show that 96% of the considered parameters are appropriate for distinguishing between non-PD subjects, PD patients with DBS stimulator switched on, and PD patients with stimulator switched off (p-value <; 0.001, Kruskal Wallis test). These results are markedly better than the ones obtained using Kinect v1, where only 73% of the parameters are considered appropriate (p-value <; 0.001). PMID- 26736502 TI - Goniometric measurement for the estimation of anisotropy coefficient of human and animal pancreas. AB - Estimation of optical properties of biologic tissues is determinant for laser dosimetry in medical applications. Tissues highly absorb and scatter the light in near infrared spectrum, where the laser provides therapeutic effects. Novel frontiers of clinical practice, e.g., the employment of laser light for the treatment of pancreatic cancer, require information about pancreas-laser interaction, which are crucial for therapy management. The property of biological tissues to scatter the light traveling through is described by the anisotropy coefficient (g). The relationship between g and the angular distribution of the scattered light is described by Henyey-Greenstein phase function. The measurement of angular distribution of scattered light is performed by the goniometric technique. This paper describes the estimation of g of ex vivo pancreas at 1064 nm, performed by a goniometric-based system, where a photodetector measures intensities of scattered light at fixed angles between -120 degrees and 120 degrees . A two-term Henyey-Greenstein phase function has been employed to estimate anisotropy coefficient for forward (gfs) and backward scattering (gbs). Experimental trails were performed to assess the repeatability of measurement system: percentage value of standard deviation is generally lower than 8% for angles higher (lower) than 13 degrees (13 degrees ). Measurements were performed for the first time on healthy swine pancreas, aiming to investigate the influence of coagulation temperature: gfs decreases from 0.94 (at 25 degrees C) to 0.93 (at 80 degrees C). Afterwards, the same set up has been employed for the estimation of g of human pancreas affected by neuroendocrine tumor, which presented an estimated values for gfs of 0.89. PMID- 26736503 TI - Magnetic Resonance-compatible needle-like probe based on Bragg grating technology for measuring temperature during Laser Ablation. AB - Temperature monitoring in tissue undergone Laser Ablation (LA) may be particularly beneficial to optimize treatment outcome. Among many techniques, fiber Bragg grating (FBG) sensors show valuable characteristics for temperature monitoring in this medical scenario: good sensitivity and accuracy, and immunity from electromagnetic interferences. Their main drawback is the sensitivity to strain, which can entail measurement error for respiratory and patient movements. The aims of this work are the design, the manufacturing and the characterization of a needle-like probe which houses 4 FBGs. Three FBGs have sensitive length of 1 mm and are used as temperature sensors; one FBG with length of 10 mm is used as reference and to sense eventual strain. The optical fiber housing the FBGs was encapsulated within a needle routinely used in clinical practice to perform MRI guided biopsy. Two materials were used for the encapsulation: i) thermal paste for the 3 FBGs used for temperature monitoring, to maximize the thermal exchange with the needle; ii) epoxy resin for the reference FBG, to improve its sensitivity to strain. The static calibration of the needle-like probe was performed to estimate the thermal sensitivity of each FBG; the step response was investigated to estimate the response time. FBGs 1 mm long have thermal sensitivity of 0.01 nm. degrees C(-1), whereas the reference FBG presents 0.02 nm. degrees C(-1). For all FBGs, the response time was in the order of 100 ms. Lastly, experiments were performed on ex vivo swine liver undergoing LA to i) evaluate the possible presence of measurement artifact, due to the direct absorption of laser light by the needle and ii) assess the feasibility of the probe in a quasi clinical scenario. PMID- 26736504 TI - Evaluation of optoelectronic Plethysmography accuracy and precision in recording displacements during quiet breathing simulation. AB - Opto-electronic Plethysmography (OEP) is a motion analysis system used to measure chest wall kinematics and to indirectly evaluate respiratory volumes during breathing. Its working principle is based on the computation of marker displacements placed on the chest wall. This work aims at evaluating the accuracy and precision of OEP in measuring displacement in the range of human chest wall displacement during quiet breathing. OEP performances were investigated by the use of a fully programmable chest wall simulator (CWS). CWS was programmed to move 10 times its eight shafts in the range of physiological displacement (i.e., between 1 mm and 8 mm) at three different frequencies (i.e., 0.17 Hz, 0.25 Hz, 0.33 Hz). Experiments were performed with the aim to: (i) evaluate OEP accuracy and precision error in recording displacement in the overall calibrated volume and in three sub-volumes, (ii) evaluate the OEP volume measurement accuracy due to the measurement accuracy of linear displacements. OEP showed an accuracy better than 0.08 mm in all trials, considering the whole 2m(3) calibrated volume. The mean measurement discrepancy was 0.017 mm. The precision error, expressed as the ratio between measurement uncertainty and the recorded displacement by OEP, was always lower than 0.55%. Volume overestimation due to OEP linear measurement accuracy was always <; 12 mL (<; 3.2% of total volume), considering all settings. PMID- 26736505 TI - Talaporfin sodium binding and photocytotoxicity of photosensitization reaction on myocardial cell under various albumin concentrations and temperature. AB - To understand the efficiency change of the extracellular photosensitization reaction by the external factor in myocardium interstitial space, we studied the efficiency change of the extracellular photosensitization reaction caused by talaporfin sodium binding with serum proteins under various serum proteins concentrations and temperature conditions. Talaporfin sodium Q band absorbance was measured with various albumin concentrations and the cell survival rate was measured by WST assay in the same conditions. The talaporfin sodium binding ratio with albumin, high-density lipoprotein, and low-density lipoprotein were measured by talaporfin sodium absorbance measurement after the ultrafiltration. The albumin concentration affects the photocytotoxicity strongly when the albumin concentration was over 2.1 mg/ml in the case of the extracellular photosensitization reaction. It would be useful to measure the peak wavelength in Q band absorbance was suggested to know the albumin concentration and the photocytotoxicity efficiency to realize the safety treatment. The binding ratios with high-density lipoprotein and low-density lipoprotein were decreased with the solution temperature rise from 17 degrees C to 37 degrees C and the photocytotoxicity was increased with temperature rise from 17 degrees C to 37 degrees C involving this binding ratio change. It would be important to maintain the target organ temperature during the photosensitization reaction to keep the photosensitization reaction efficiency. PMID- 26736506 TI - Drug delivery of anti-restenosis agent by 40 - 60 degrees C heating to porcine aortic smooth muscle cells in vitro. AB - We investigated the uptake of anti-restenosis agent in vascular smooth muscle cells with heating observing the fluorescence intensity of Oregon green labeled paclitaxel in vitro. The heating temperature to porcine aortic smooth muscle cells was varied from 40 to 60 degrees C in 5 s in order to simulate laser mediated short-duration heating balloon. The cells were contacted with the agent from 1 to 30 min in 37 degrees C after the heating. We measured the agent uptake characteristics on agent concentration and duration in 37 degrees C as a reference. The uptake of the agent in the cells increased with increasing of both the concentration around the cells and contact duration in the case of 37 degrees C. When the cells were heated with 40 degrees C in 5 s and then contacted with the agent in 30 minutes, the uptake of the agent in the cells significantly increased. The uptake of the agent with 50 degrees C or 60 degrees C in 5 s did not show any increasing. We prospected that 40 degrees C heating to the smooth muscle cells would promote the agent uptake ability of the cells because of homeostasis of the cells. PMID- 26736507 TI - An RF device for effective thermal treatment of atherosclerosis. AB - There is a high rate of restenosis after current treatment of atherosclerosis, which is often associated to the damage of the vascular endothelial cell layer during therapeutic process. Lately, it was found that the plaque was related to the local proliferation of vascular smooth muscle cells (VSMCs) [1, 2]. An RF angioplasty balloon is designed to selectively treat the proliferated region while keeping the intima layer intact. Micro-electrodes are integrated onto the balloon surface, and cooling agent circulates inside to lower the temperature of the vascular endothelium. A controlled thin layer thermal treatment region has been achieved using this device through theoretical modeling and experimental validation. The penetration of RF energy heats up to ablate the plaque and also suppress the proliferation of VSMCs. PMID- 26736508 TI - Different responses of the skin temperature to physical exercise: Systematic review. AB - Studies suggest that skin temperature behavior varies according to the type of exercise, intensity, duration, muscle mass and subcutaneous fat layer. In this sense, the aim of this study was to investigate the skin temperature behavior in the active muscles and other body segments, during and after exercise, according to the type and intensity of the exercise. A systematic literature review was conducted between November 2014 and March 2015 in the Web of Science database, using the terms "thermography" and "exercise" and "muscle" to achieve the objective of this study. During the research were found 55 scientific articles which were subjected to a selection process. Inclusion criteria were: Studies in human beings and original research. The exclusion criterion was the presence of subjects with some kind of disease. The seven papers that make up the present review are dated between 2008 and 2015. From all analyzed studies, it was possible to understand the general behavior of the active muscle skin temperature during the exercise, immediately after and in the 48h after exercise, according to the type and intensity of the exercise performed, which are illustrated in two figures. It can be concluded that the skin temperature over active muscles increases during high intensity anaerobic exercise, decreases slowly after exercise and increases again in the days after the exercise. On the other hand, during low intensity aerobic exercise, skin temperature over active muscles decreases, returning to normal values a few minutes after it and present a small rise in the following days. With regard to the skin temperature over non-active muscles, it can be seen that it decreases during exercise, returning to normal values a few minutes after it and rise similarly to the skin temperature over active muscles in the following days, in all types of exercises studied. PMID- 26736509 TI - A computer-assisted robotic platform for Focused Ultrasound Surgery: Assessment of high intensity focused ultrasound delivery. AB - In the last century, medicine showed considerable advancements in terms of new technologies, devices and diagnostic/therapeutic strategies. Those advantages led to a significant reduction of invasiveness and an improvement of surgical outcomes. In this framework, a computer-assisted surgical robotic platform able to perform non-invasive Focused Ultrasound Surgery (FUS) - the FUTURA platform - has the ambitious goal to improve accuracy, safety and flexibility of the treatment, with respect to current FUS procedures. Aim of this work is to present the current implementation of the robotic platform and the preliminary results about high intensity focused ultrasound (HIFU) delivery in in-vitro conditions, under 3D ultrasound identification and monitoring. Tests demonstrated that the average accuracy of the HIFU delivery is lower than 0.7 mm in both X and Y radial directions and 3.7 mm in the axial direction (Z) with respect to the HIFU transducer active surface. PMID- 26736510 TI - Treatment for neuropathic pain and chronic inflammation using LASER in animal models. AB - The ST36 (Zusanli) acupuncture point is used to treat inflammatory processes, pain and gastrointestinal disturbs. For this reason, the aim of the present study was to evaluate the antinociceptive effect of Low-level Laser Treatment (LLLT) on ST36 acupoint using models of chronic nociception and inflammation. Male Swiss mice were treated with LLLT on ST36 30 minutes before the mechanical allodynia (von Frey) performed on the partial sciatic nerve ligation (PSNL) method and Complete Freund's Adjuvant (CFA). The results demonstrated that application of LLLT on ST36 inhibited the mechanical allodynia response induced by PSNL and CFA, with total reversion at 30 minutes after application. Long-term treatment of animals with LLLT on the same acupoint, once a day, also reduced the PNSL and CFA induced mechanical allodynia response during 8 days of treatment. As conclusion, the results demonstrated that photonic stimulus on ST36 with LLLT produces antinociceptive effect in chronic models of nociception and inflammation. These findings suggest that LLLT may constitute an important therapeutic alternative to control chronic pain. PMID- 26736511 TI - Fundamental analysis and development of the current and voltage control method by changing the driving frequency for the transcutaneous energy transmission system. AB - We have been developing transcutaneous energy transmission system (TETS) for a ventricular assist device, shape memory alloy (SMA) fibered artificial organs and so on, the system has high efficiency and a compact size. In this paper, we summarize the development, design method and characteristics of the TETS. New control methods for stabilizing output voltage or current of the TETS are proposed. These methods are primary side, are outside of the body, not depending on a communication system from the inside the body. Basically, the TETS operates at the fixed frequency with a suitable compensation capacitor so that the internal impedance is minimalized and a flat load characteristic is obtained. However, when the coil shifted from the optimal position, the coupling factor changes and the output is fluctuated. TETS has a resonant property; its output can be controlled by changing the driving frequency. The continuous current to continuous voltage driving method was implemented by changing driving frequency and setting of limitation of low side frequency. This method is useful for battery charging system for electrically driven artificial hearts and also useful for SMA fibered artificial organs which need intermittent high peak power comsumption. In this system, the internal storage capacitor is charged slowly while the fibers are turned off and discharge the energy when the fibers are turned on. We examined the effect of the system. It was found that the size and maximum output of the TETS would able to be reduced. PMID- 26736512 TI - Design and simulation of a 800 Mbit/s data link for magnetic resonance imaging wearables. AB - This paper presents the optimization of electronic circuitry for operation in the harsh electro magnetic (EM) environment during a magnetic resonance imaging (MRI) scan. As demonstrator, a device small enough to be worn during the scan is optimized. Based on finite element method (FEM) simulations, the induced current densities due to magnetic field changes of 200 T s(-1) were reduced from 1 * 10(10) A m(-2) by one order of magnitude, predicting error-free operation of the 1.8V logic employed. The simulations were validated using a bit error rate test, which showed no bit errors during a MRI scan sequence. Therefore, neither the logic, nor the utilized 800 Mbit s(-1) low voltage differential swing (LVDS) data link of the optimized wearable device were significantly influenced by the EM interference. Next, the influence of ferro-magnetic components on the static magnetic field and consequently the image quality was simulated showing a MRI image loss with approximately 2 cm radius around a commercial integrated circuit of 1*1 cm(2). This was successively validated by a conventional MRI scan. PMID- 26736513 TI - Combining qualitative and quantitative methods to analyze serious games outcomes: A pilot study for a new cognitive screening tool. AB - Computer games for a serious purpose - so called serious games can provide additional information for the screening and diagnosis of cognitive impairment. Moreover, they have the advantage of being an ecological tool by involving daily living tasks. However, there is a need for better comprehensive designs regarding the acceptance of this technology, as the target population is older adults that are not used to interact with novel technologies. Moreover given the complexity of the diagnosis and the need for precise assessment, an evaluation of the best approach to analyze the performance data is required. The present study examines the usability of a new screening tool and proposes several new outlines for data analysis. PMID- 26736514 TI - Developing medical device software in compliance with regulations. AB - In the last decade, the use of information technology (IT) in healthcare has taken a growing role. In fact, the adoption of an increasing number of computer tools has led to several benefits related to the process of patient care and allowed easier access to social and health care resources. At the same time this trend gave rise to new challenges related to the implementation of these new technologies. Software used in healthcare can be classified as medical devices depending on the way they are used and on their functional characteristics. If they are classified as medical devices they must satisfy specific regulations. The aim of this work is to present a software development framework that can allow the production of safe and high quality medical device software and to highlight the correspondence between each software development phase and the appropriate standard and/or regulation. PMID- 26736515 TI - Development and validation of a bioartificial liver device with fluidized bed bioreactors hosting alginate-encapsulated hepatocyte spheroids. AB - Acute and acute-on-chronic liver failure are associated to high mortality when transplantation is not possible. The lack of donors has resulted in an important demand for liver support devices. This paper describes the design and validation of a new bioartificial liver (BAL) device including fluidized bed bioreactors hosting alginate-encapsulated hepatocytes spheroids. To ensure the efficacy of the BAL and the safety of the patients, a complex extracorporeal circulation was designed to be compatible with a commercial medical device, the Prismaflex((r)) monitor, already used in intensive care units. Preclinical studies on large animal show that the treatment was well tolerated in terms of hemodynamics considerations. A method using non adhesive coating in petri dish led to the production of large amount of viable spheroids in vitro that were further encapsulated to follow up bioartificial liver activity during four days. PMID- 26736516 TI - A 128-ch Delta-Sigma ADC based mixed signal IC for full digital beamforming Wireless handheld Ultrasound imaging system. AB - This paper reports a massively integrated Delta-Sigma ADC based mixed signal chipset for a handheld Wireless Ultrasound imaging system. The IC has been fabricated in a standard 0.13 MUm 1.5V 7M2F CMOS process with 128 parallel channels containing Delta-Sigma (Delta-Sigma) ADCs, Anti-aliasing filter, Decimation filters, Serializers and LVDS drivers. The entire chip is SPI controlled and allows group-level power control through an FPGA. The IC measures 15 * 15 mm and dissipates around ~ 4.6 W of power, with 12-bit resolution at 20 Msps sample rate. The chip was packaged in a thermally stable BGA package and demonstrated in a handheld ultrasound battery operated system with complete digital beamforming. PMID- 26736517 TI - Electric fence standards comport with human data and AC limits. AB - INTRODUCTION: The ubiquitous electric fence is essential to modern agriculture and has saved lives by reducing the number of livestock automobile collisions. Modern safety standards such as IEC 60335-2-76 and UL 69 have played a role in this positive result. However, these standards are essentially based on energy and power (RMS current), which have limited direct relationship to cardiac effects. We compared these standards to bioelectrically more relevant units of charge and average current in view of recent work on VF (ventricular fibrillation) induction and to existing IEC AC current limits. METHODS AND RESULTS: There are 3 limits for normal (low) pulsing rate: IEC energy limit, IEC current limit, and UL current limit. Wethen calculated the delivered charge allowed for each pulse duration for these limits and then compared them to a charge-based safety model derived from published human ventricular-fibrillation induction data. Both the IEC and UL also allow for rapid pulsing for up to 3 minutes. We calculated maximum outputs for various pulse durations assuming pulsing at 10, 20, and 30 pulses per second. These were then compared to standard utility power safety (AC) limits via the conversion factor of 7.4 to convert average current to RMS current for VF risk. The outputs of TASER electrical weapons (typically < 100 MUC and ~100 MUs duration) were also compared. CONCLUSIONS: The IEC and UL electric fence energizer normal rate standards are conservative in comparison with actual human laboratory experiments. The IEC and UL electric fence energizer rapid-pulsing standards are consistent with accepted IEC AC current limits for commercially used pulse durations. PMID- 26736518 TI - In-vitro testing of RF-enabled low force mechanical thrombectomy for ischemic stroke. AB - Mechanical thrombectomy for ischemic stroke has high recanalization rate, long treatment time window and low hemorrhage risk. However, the clot engagement approach of caging the clot against the vessel wall can cause vessel stenosis and stroke recurrence. A device with reduced radial stenting force that reduces vessel wall friction would minimize stenosis and damage. The use of localized Radio Frequency (RF) to enable clot engagement and retrieval with minimal stenting force is explored in this study. New mechanical thrombectomy devices enabled with RF (Patent No.: US 62/172,043) were built and tested on human blood clots in vessels ex vivo. Test results showed that the RF-mechanical thrombectomy successfully and reproducibly captured and retrieved the clots without relying on stent caging of the clot against the vessel wall. Further work will be conducted on animals to compare vessel wall damage between conventional and RF-mechanical thrombectomy. PMID- 26736519 TI - Feasibility examination of isolated zonal thrombolysis using Raman spectroscopy. AB - Intravenous thrombolysis for the treatment of ischemic stroke requires long treatment time and high drug dosage which increases the risk of hemorrhage. Localized zonal dosage of urokinase between 100 - 500 International Units (IU), i.e., less than 5% of typical systemic dosage (60,000 - 120,000 IU) at the thrombus can shorten the treatment time to less than 30 minutes while reducing the risk of hemorrhage. The effect of zonal-delivered urokinase on the molecular changes in a 100 MUm thick by 20 mm diameter blood clot was quantified using Raman spectroscopy. In situ Raman spectra showed that the fibrin concentration in the clot decreased with time. The results verified that a zonal-delivered urokinase can dissolve the clot and reduce the treatment time. Further trials on animals will be conducted to examine the potential of zonal-delivery to accelerate clot dissolution for ischemic stroke while minimizing the risk of hemorrhage. PMID- 26736520 TI - Creating eye closure in patients with facial nerve paralysis using an implantable solenoid actuator. AB - This paper proposes the use of an implantable solenoid actuator to create a more natural eyelid closure over current lid loading therapies in patients with facial nerve paralysis (FNP). The actuator works by moving a magnet when a solenoid is activated. This is used to tension a sling applied to the upper eyelid which closes the eye. The sling design has been described elsewhere and creating eye closure using it requires a force of 627 (+/- 128) mN over a movement of approximately 6 mm. The actuator described here was able to successfully achieve these parameters and repeatedly perform eyelid closure in a cadaveric rabbit model. Device limitations and future improvements have also been identified and discussed. PMID- 26736522 TI - Fabrication of SU-8 based Capacitive Micromachined Ultrasonic Transducer for low frequency therapeutic applications. AB - In this paper we present a simple post-CMOS compatible sacrificial release method of fabricating SU-8 based Capacitive Micromachined Ultrasonic Transducer (CMUT) for low frequency therapeutic applications. CMUTs fabricated with Silicon Nitride and Silicon Dioxide lay constraints in terms of area and power consumption especially in the low frequency range. Fabrication of these devices need complex high temperature processes that makes them incompatible for post-CMOS processing. Analytical modeling shows that SU-8 based CMUT consumes less area (below 25%) and power compared to Silicon Nitride and Silicon Dioxide based CMUTs. The proposed fabrication method overcomes inherent disadvantages of sacrificial release method by providing uniformity in air gap and reducing the possibility of stiction. PMID- 26736521 TI - A smart pill for drug delivery with sensing capabilities. AB - In this paper a novel system for local drug delivery is described. The actuation principle of the micropump used for drug delivery relies on the electrolysis of a water-based solution, which is separated from a drug reservoir by an elastic membrane. The electrolytically produced gases pressurize the electrolytic solution reservoir, causing the deflection of the elastic membrane. Such deflection, in turn, forces the drug out of its reservoir through a nozzle. The proposed system is integrated in a swallowable capsule, equipped with an impedance sensor useful to acquire information on the physiological conditions of the tissue. Such information can be used to control pump activation. PMID- 26736523 TI - Active induction of in vivo microbubbles by acoustic radiation force at the bifurcation of blood vessel and its evaluation. AB - Alhough the development of drug delivery system using microbubbles and ultrasound is expected, because microbubbles diffuse in bloodstream, we have so far reported our attempts for active control of the microbubbles in flow by acoustic radiation force in order to increase local concentration of the microbubbles. However, there was no evidence that in vivo microbubbles act as similar as in vitro experiments, because there were limitations for reproduction of in vivo conditions. In this study, we have elucidated the relationship between brightness variation and microbubbles concentration in the suspension to estimate the absolute concentration in an invisible condition considering in vivo experiment. Then we conducted an experiment of active induction of microbubbles in a Y-form bifurcation of artificial blood vessel, where experimental conditions were with focused ultrasound, the central frequency of 5 MHz, flow velocity of 30 mm/s, and maximum sound pressure of 300 kPa-pp, respectively. Then we applied the conditions for active induction of in vivo microbubbles to compare with in vitro experiments. We used a bifurcation of blood vessel in an ear of a rabbit because the bifurcation shape in its blood vessel is visible. As the results of the experiment, the microbubbles concentration in the induced path was almost two times higher than that in the other path, which agrees with the results from in vitro experiments. PMID- 26736524 TI - A semantically-aided architecture for a web-based monitoring system for carotid atherosclerosis. AB - Carotid atherosclerosis is a multifactorial disease and its clinical diagnosis depends on the evaluation of heterogeneous clinical data, such as imaging exams, biochemical tests and the patient's clinical history. The lack of interoperability between Health Information Systems (HIS) does not allow the physicians to acquire all the necessary data for the diagnostic process. In this paper, a semantically-aided architecture is proposed for a web-based monitoring system for carotid atherosclerosis that is able to gather and unify heterogeneous data with the use of an ontology and to create a common interface for data access enhancing the interoperability of HIS. The architecture is based on an application ontology of carotid atherosclerosis that is used to (a) integrate heterogeneous data sources on the basis of semantic representation and ontological reasoning and (b) access the critical information using SPARQL query rewriting and ontology-based data access services. The architecture was tested over a carotid atherosclerosis dataset consisting of the imaging exams and the clinical profile of 233 patients, using a set of complex queries, constructed by the physicians. The proposed architecture was evaluated with respect to the complexity of the queries that the physicians could make and the retrieval speed. The proposed architecture gave promising results in terms of interoperability, data integration of heterogeneous sources with an ontological way and expanded capabilities of query and retrieval in HIS. PMID- 26736525 TI - A new femtocaching file placement algorithm for Telemedicine. AB - A new femtocaching file placement algorithm is designed for Telemedicine to improve transmission of medical scan images via wireless networks. The experiments show that the proposed algorithm drops the delay compared to the Greedy algorithm and the baseline case. The experimental results also show that the proposed algorithm improves the capacity of the caching helpers and reduces the total delay of the daily operations in healthcare facilities. PMID- 26736526 TI - A machine learning methodology for medical imaging anonymization. AB - Privacy protection is a major requirement for the complete success of EHR systems, becoming even more critical in collaborative scenarios, where data is shared among institutions and practitioners. While textual data can be easily de identified, patient data in medical images implies a more elaborate approach. In this work we present a solution for sensitive word identification in medical images based on a combination of two machine-learning models, achieving a F1 score of 0.94. Three experts evaluated the system performance. They analyzed the output of the present methodology and categorized the studies in three groups: studies that had their sensitive words removed (true positive), studies with complete patient identity (false negative) and studies with mistakenly removed data (false positive). The experts were unanimous regarding the relevance of the present tool in collaborative medical environments, as it may improve the exchange of anonymized patient data between institutions. PMID- 26736527 TI - CPDI: An Index for measuring deviations in Clinical Pathways. AB - Clinical Pathways (CPs) are evidence-based recommendation for treating a diagnosis and an effective instrument to decrease undesired practice variability and improve clinician performance. Deviations from CPs might just as well reduce quality of care. Moreover they can be associated to possible adverse events. In this perspective, we developed and tested a system for comparing a patient trajectory (PT) with the corresponding CP in order to recognize significant variations. To measure adherence, a Clinical Pathway Deviation Index (CPDI) was constructed as the weighted-sum of five indicators. To build the indicators three different tools for CPs modeling have been tested. Only two of them proved suitable for our system. A preliminary analysis has been carried out using data of 24 real PTs. The aim of this paper is to present the system and to characterize CPDI performances. PMID- 26736528 TI - Technical solutions for mitigating security threats caused by health professionals in clinical settings. AB - The objective of this paper is to present a brief description of technical solutions for health information system security threats caused by inadequate security and privacy practices in healthcare professionals. A literature search was carried out in ScienceDirect, ACM Digital Library and IEEE Digital Library to find papers reporting technical solutions for certain security problems in information systems used in clinical settings. A total of 17 technical solutions were identified: measures for password security, the secure use of e-mail, the Internet, portable storage devices, printers and screens. Although technical safeguards are essential to the security of healthcare organization's information systems, good training, awareness programs and adopting a proper information security policy are particularly important to prevent insiders from causing security incidents. PMID- 26736529 TI - Real-time medical collaboration services over the web. AB - The gradual shift in modern medical practice, from working alone clinical doctors to MDTs (Multi-Disciplinary Teams), raises the need of online real-time collaboration among geographically distributed medical personnel. The paper presents a Web-based platform, featuring an efficient medical data management and exchange, for hosting real-time collaborative services. The presented work leverages state-of-the-art features of the web (technologies and APIs) to support client-side medical data processing. Moreover, to address the typical bandwidth bottleneck and known scalability issues of centralized data sharing, an indirect RPC (Remote Process Call) scheme is introduced through object synchronization over the WebRTC paradigm. PMID- 26736530 TI - Digital patient: Personalized and translational data management through the MyHealthAvatar EU project. AB - The advancements in healthcare practice have brought to the fore the need for flexible access to health-related information and created an ever-growing demand for the design and the development of data management infrastructures for translational and personalized medicine. In this paper, we present the data management solution implemented for the MyHealthAvatar EU research project, a project that attempts to create a digital representation of a patient's health status. The platform is capable of aggregating several knowledge sources relevant for the provision of individualized personal services. To this end, state of the art technologies are exploited, such as ontologies to model all available information, semantic integration to enable data and query translation and a variety of linking services to allow connecting to external sources. All original information is stored in a NoSQL database for reasons of efficiency and fault tolerance. Then it is semantically uplifted through a semantic warehouse which enables efficient access to it. All different technologies are combined to create a novel web-based platform allowing seamless user interaction through APIs that support personalized, granular and secure access to the relevant information. PMID- 26736531 TI - Electronic Health Record Application Support Service Enablers. AB - There is a huge need for open source software solutions in the healthcare domain, given the flexibility, interoperability and resource savings characteristics they offer. In this context, this paper presents the development of three open source libraries - Specific Enablers (SEs) for eHealth applications that were developed under the European project titled "Future Internet Social and Technological Alignment Research" (FI-STAR) funded under the "Future Internet Public Private Partnership" (FI-PPP) program. The three SEs developed under the Electronic Health Record Application Support Service Enablers (EHR-EN) correspond to: a) an Electronic Health Record enabler (EHR SE), b) a patient summary enabler based on the EU project "European patient Summary Open Source services" (epSOS SE) supporting patient mobility and the offering of interoperable services, and c) a Picture Archiving and Communications System (PACS) enabler (PACS SE) based on the dcm4che open source system for the support of medical imaging functionality. The EHR SE follows the HL7 Clinical Document Architecture (CDA) V2.0 and supports the Integrating the Healthcare Enterprise (IHE) profiles (recently awarded in Connectathon 2015). These three FI-STAR platform enablers are designed to facilitate the deployment of innovative applications and value added services in the health care sector. They can be downloaded from the FI-STAR cataloque website. Work in progress focuses in the validation and evaluation scenarios for the proving and demonstration of the usability, applicability and adaptability of the proposed enablers. PMID- 26736532 TI - A Trust Assessment mechanism for Ubiquitous Healthcare environment employing cloud theory. AB - Mental healthcare domain highlights the significance of trustworthiness between patient and psychiatrist for treatment process. In this paper, the issue of assessing psychiatrist trustworthiness from patient perspective, within a Ubiquitous Healthcare (UH) environment, is addressed. To meet that challenge, a Trust Assessment mechanism mimicking human cognitive judgment, is proposed. The exploitation of innovative fuzzy-probabilistic transformation model, denoted as cloud, for mechanism deployment enables fuzziness as well as adhered randomness of cognitive perception and assessment to be captured. A set of simulations within MATLAB software environment verify the introduced mechanism efficiency. PMID- 26736533 TI - Steganography in arrhythmic electrocardiogram signal. AB - Security and privacy of patient data is a vital requirement during exchange/storage of medical information over communication network. Steganography method hides patient data into a cover signal to prevent unauthenticated accesses during data transfer. This study evaluates the performance of ECG steganography to ensure secured transmission of patient data where an abnormal ECG signal is used as cover signal. The novelty of this work is to hide patient data into two dimensional matrix of an abnormal ECG signal using Discrete Wavelet Transform and Singular Value Decomposition based steganography method. A 2D ECG is constructed according to Tompkins QRS detection algorithm. The missed R peaks are computed using RR interval during 2D conversion. The abnormal ECG signals are obtained from the MIT-BIH arrhythmia database. Metrics such as Peak Signal to Noise Ratio, Percentage Residual Difference, Kullback-Leibler distance and Bit Error Rate are used to evaluate the performance of the proposed approach. PMID- 26736534 TI - Development of health diagnostics based on personalized medical models. AB - Due to rapid evolution of new technologies the concept of personalized medicine has evolved. Components include molecular biology, proteomics, metabolomic analysis, genetic testing, and molecular medicine for diagnostics. In addition to diagnostics these methods can be used to determine individual susceptibility to diseases and conditions. In conjunction with new diagnostic methods, new therapies can be tailored to the individual. These new technologies present a challenge in terms of the expansion of the medical record as well as the development of new methods for creating disease profiles. This article focuses on a computer-aided support for personalized medicine. Specific approaches are explored that permit automated data analysis for prognosis and treatment based on analysis methods for numeric and pictorial data. Although personalized medicine based on the genome of the patient are occasionally performed, because of the large amount of data new methods are needed to form general disease models as well as specific profiles of the individual patient. PMID- 26736535 TI - Dealing with instability in bimanual and collaborative tasks. AB - In the context of unstable tasks, whenever the dynamics of the interaction are unknown, our ability to control an object depends on the predictability of the sensory feedback generated from the physical coupling at the interface with the object. In the case of physical human-human interaction, the haptic sensory feedback plays a primary role in the construction of a shared motor plan, being the channel for the mutual sharing of intentions. The present work addresses the issue of strategy selection in contexts in which instability is arising both from the environment, i.e. controlling a compliant object subject to nonlinear forces, and from the interaction with a partner, i.e. carrying out a bimanual balancing task in the presence of disturbing force-fields. PMID- 26736536 TI - Impedance control: Learning stability in human sensorimotor control. AB - The human sensorimotor control system generates movement by adapting and controlling the mechanics of the musculoskeletal system. To generate skilful movements the sensorimotor control system must be able to predict and compensate for any disturbances generated either in our own body or in the external environment. While stable and repeatable perturbations can be easily adapted through iterative learning, instability and unpredictability require a different approach: impedance control. Here I outline the arguments for impedance control as a fundamental process of human adaptation as well as describe evidence suggesting the manner in which such impedance can be learned in order to ensure the stability of the neuro-mechanical system. PMID- 26736537 TI - Multivariate outcomes in a three week bimanual self-telerehabilitation with error augmentation post-stroke. AB - We present the outcomes of a study on stroke patients in a 3-week intervention of bimanual self-telerehabilitation. This training is similar to an upper-extremity treadmill in that patients can make use of their healthy arm to provide a cue for the more impaired arm. We further inspected a cohort that covertly received error augmentation training while they practiced. Finally, we focused here on the many quantitative measures available from the robotic device, testing if these measures collectively can predict outcome on the final day. We found in a cross validation study that predictions are possible, yielding median r-squared values over 99%. Several particular measures were found to dominate their contribution to the prediction of recoverability. These results show that interactive self rehabilitation may be a viable method for motor restoration, and the quantitative metrics available can be used to predict the eventual state of recovery. PMID- 26736538 TI - Non-actively controlled double-inverted-pendulum-like dynamics can minimize center of mass acceleration during human quiet standing. AB - Multiple joint movements during human quiet standing exhibit characteristic inter joint coordination, shortly referred to as reciprocal relationship, in which angular acceleration of the hip joint is linearly and negatively correlated with that of the ankle joint (antiphase coordination) and, moreover, acceleration of the center of mass (CoM) of the double-inverted-pendulum (DIP) model of the human body is close to zero constantly. A question considered in this study is whether the reciprocal relationship is established by active neural control of the posture, or rather it is a biomechanical consequence of non-actively controlled body dynamics. To answer this question, we consider a DIP model of quiet standing, and show that the reciprocal relationship always holds by Newton's second law applied to the DIP model with human anthropometric dimensions, regardless of passive and active joint torque patterns acting on the ankle and hip joints. We then show that characteristic frequencies included in experimental sway trajectories with the reciprocal relationship match with harmonics of the eigenfrequency of the stable antiphase eigenmode of the non-actively controlled DIP-like unstable body dynamics. The results suggest that non-actively controlled DIP-like mechanical dynamics is a major cause of the minimization of the CoM acceleration during quiet standing, which is consistent with a type of control strategy that allows switching off active neural control intermittently for suitable periods of time during quiet standing. PMID- 26736539 TI - Intermittent control of unstable multivariate systems. AB - A sensorimotor architecture inspired from biological, vertebrate control should (i) explain the interface between high dimensional sensory analysis, low dimensional goals and high dimensional motor mechanisms and (ii) provide both stability and flexibility. Our interest concerns whether single-input-single output intermittent control (SISO_IC) generalized to multivariable intermittent control (MIC) can meet these requirements.We base MIC on the continuous-time observer-predictorstate-feedback architecture. MIC uses event detection. A system matched hold (SMH), using the underlying continuoustime optimal control design, generates multivariate open-loop control signals between samples of the predicted state. Combined, this serial process provides a single-channel of control with optimised sensor fusion and motor synergies. Quadratic programming provides constrained, optimised equilibrium control design to handle unphysical configurations, redundancy and provides minimum, necessary reduction of open loop instability through optimised joint impedance. In this multivariate form, dimensionality is linked to goals rather than neuromuscular or sensory degrees of freedom. The biological and engineering rationale for intermittent rather than continuous multivariate control, is that the generalised hold sustains open loop predictive control while the open loop interval provides time within the feedback loop for online centralised, state dependent optimisation and selection. PMID- 26736540 TI - Structure of the set of feasible neural commands for complex motor tasks. AB - The brain must select its control strategies among an infinite set of possibilities; researchers believe that it must be solving an optimization problem. While this set of feasible solutions is infinite and lies in high dimensions, it is bounded by kinematic, neuromuscular, and anatomical constraints, within which the brain must select optimal solutions. That is, the set of feasible activations is well structured. However, to date there is no method to describe and quantify the structure of these high-dimensional solution spaces. Bounding boxes or dimensionality reduction algorithms do not capture their detailed structure. We present a novel approach based on the well-known Hit and-Run algorithm in computational geometry to extract the structure of the feasible activations capable of producing 50% of maximal fingertip force in a specific direction. We use a realistic model of a human index finger with 7 muscles, and 4 DOFs. For a given static force vector at the endpoint, the feasible activation space is a 3D convex polytope, embedded in the 7D unit cube. It is known that explicitly computing the volume of this polytope can become too computationally complex in many instances. However, our algorithm was able to sample 1,000,000 uniform at random points from the feasible activation space. The computed distribution of activation across muscles sheds light onto the structure of these solution spaces-rather than simply exploring their maximal and minimal values. Although this paper presents a 7 dimensional case of the index finger, our methods extend to systems with at least 40 muscles. This will allow our motor control community to understand the distributions of feasible muscle activations, providing important contextual information into learning, optimization and adaptation of motor patterns in future research. PMID- 26736541 TI - A modeling approach to study the normal mammary gland growth process. AB - Terminal end buds (TEBs) are bulb-like structures at the growing tips of elongating mammary ducts, and the growth of a TEB is a complex, organized biological process. In this paper, we present a hybrid continuum-discrete agent based model to provide quantitative insight into the properties of cell symmetric and asymmetric division on the spatial and developing cell rearrangement within the TEB during ductal elongation. An interplay of endocrine-paracrine signaling and cell lineage has been implemented in the model. Our results show that higher symmetric division rates resulted in more progenitor cells remaining in the TEB, while lower rates resulted in more differentiated cells in the TEB. Moreover, pure proliferation alone was enough to result in ductal elongation in the absence of any cellular migration, a result consistent with current experimental data. This model can also serve as a platform to study how mutation-induced phenotypic changes contribute to developmental defects in mammary gland development. PMID- 26736542 TI - Determining the efficient inter-electrode distance for high-resolution mapping using a mathematical model of human gastric dysrhythmias. AB - Motility of the stomach is in part coordinated by an electrophysiological event called slow waves, which are generated by pacemaker cells called the interstitial cells of Cajal (ICC). In functional motility disorders, which can be associated with a reduction of ICC, dynamic slow wave dysrhythmias can occur. In recent years, high-resolution (HR) mapping techniques have been applied to describe both normal and dysrhythmic slow wave patterns. The main aim of this study was to inform gastric HR mapping array design by determining the efficient inter electrode distance required to accurately capture normal and dysrhythmic gastric slow wave activity. A two-dimensional mathematical model was used to simulate normal activity and four types of reported slow wave dysrhythmias in human patients: ectopic activation, retrograde propagation, slow conduction, conduction block. For each case, the simulated data were re-sampled at 4, 6, 10, 12, 20 and 30mm inter-electrode distances. The accuracy of each distance was compared to a reference set sampled at 2mm inter-electrode distance, in terms of accuracy of velocity, using an ANOVA. Manual groupings were also conducted to test the ability of the human markers to distinguish separate cycles of slow waves as inter-electrode distance increases. The largest interelectrode distance for human gastric slow wave analysis, which produced both accurate grouping and velocity, was 10mm (CI [0.3 2.4]mms(-1); p<;0.05). Therefore an inter-electrode distance of less than 10mm was required to accurately describe the types of baseline and dysrhythmic activities reported in this study. However, it is likely that more spatially complex dysrhythmias, such as re-entry, may require finer inter electrode distances. PMID- 26736543 TI - A comparison of solver performance for complex gastric electrophysiology models. AB - Computational techniques for solving systems of equations arising in gastric electrophysiology have not been studied for efficient solution process. We present a computationally challenging problem of simulating gastric electrophysiology in anatomically realistic stomach geometries with multiple intracellular and extracellular domains. The multiscale nature of the problem and mesh resolution required to capture geometric and functional features necessitates efficient solution methods if the problem is to be tractable. In this study, we investigated and compared several parallel preconditioners for the linear systems arising from tetrahedral discretisation of electrically isotropic and anisotropic problems, with and without stimuli. The results showed that the isotropic problem was computationally less challenging than the anisotropic problem and that the application of extracellular stimuli increased workload considerably. Preconditioning based on block Jacobi and algebraic multigrid solvers were found to have the best overall solution times and least iteration counts, respectively. The algebraic multigrid preconditioner would be expected to perform better on large problems. PMID- 26736544 TI - Ultrasound propagation in cortical bone: Axial transmission and backscattering simulations. AB - Cortical bone is a heterogeneous, composite medium with a porosity from 5-10%. The characterization of cortical bone using ultrasonic techniques is a complicated procedure especially in numerical studies as several assumptions must be made to describe the concentration and size of pores. This study presents numerical simulations of ultrasound propagation in two-dimensional numerical models of cortical bone to investigate the effect of porosity on: a) the propagation of the first arriving signal (FAS) velocity using the axial transmission method, and b) the displacement and scattering amplitude in the backward direction. The excitation frequency 1 MHz was used and different receiving positions were examined to provide a variation profile of the examined parameters along cortical bone. Cortical porosity was simulated using ellipsoid scatterers and the concentrations of 0-10% were examined. The results indicate that the backscattering method is more appropriate for the evaluation of cortical porosity in comparison to the axial transmission method. PMID- 26736545 TI - Computational modeling of ultrasonic backscattering to evaluate fracture healing. AB - Fracture healing is a complex, regenerative procedure including several phases of recovery as the original mechanical and geometrical features of bone are gradually restored. Ultrasonic evaluation of bone pathologies such as osteoporosis and fracture healing has recently gained significant interest due to the non-invasive and non-radiating nature of the method. In this study, we present numerical simulations of ultrasonic backscattering in simple, two dimensional geometries of healing long bones to investigate the monitoring capacity of the acoustic pressure in the backward direction. The fracture process was modeled as a 7-stage procedure and the results were compared to the acoustic pressure derived for the case of intact bone. A 100 kHz plane wave was used as the excitation frequency and multiple receivers were placed at a distance of 20 mm from the cortical cortex. It was found that the acoustic pressure profile is gradually restored at the final healing stages approaching the values of intact bone. PMID- 26736546 TI - Physiomodel - an integrative physiology in Modelica. AB - Physiomodel (http://www.physiomodel.org) is our reimplementation and extension of an integrative physiological model called HumMod 1.6 (http://www.hummod.org) using our Physiolibrary (http://www.physiolibrary.org). The computer language Modelica is well-suited to exactly formalize integrative physiology. Modelica is an equation-based, and object-oriented language for hybrid ordinary differential equations (http:// www.modelica.org). Almost every physiological term can be defined as a class in this language and can be instantiated as many times as it occurs in the body. Each class has a graphical icon for use in diagrams. These diagrams are self-describing; the Modelica code generated from them is the full representation of the underlying mathematical model. Special Modelica constructs of physical connectors from Physiolibrary allow us to create diagrams that are analogies of electrical circuits with Kirchhoff's laws. As electric currents and electric potentials are connected in electrical domain, so are molar flows and concentrations in the chemical domain; volumetric flows and pressures in the hydraulic domain; flows of heat energy and temperatures in the thermal domain; and changes and amounts of members in the population domain. PMID- 26736547 TI - Movement target decoding from EEG and the corresponding discriminative sources: A preliminary study. AB - Brain-computer interfaces (BCIs) can detect movement imaginations (MI) which can act as a control signal for a neuroprosthesis of a paralyzed person. However, today's non-invasive BCIs can only detect simply qualities of MI, like what body part is subjected to MI. More advanced future non-invasive BCIs should be able to detect many qualities of MI to allow a natural control of a neuroprosthesis. In this preliminary study, we decoded movement targets during a self-paced center out reaching task, and calculated corresponding spatial patterns in the source space. We were able to decode the movement targets with significant classification accuracy from one out of three subjects during the movement planning phase. This subject showed a distinct spatial pattern over the central motor area. PMID- 26736548 TI - The detection and classification of the mental state elicited by humor from EEG patterns. AB - In this paper we investigate the use of EEG to detect the affective state of humor. The EEG of five subjects was recorded while they recalled humorous videos. Extracted frequency features were compared to a control state in which users where asked to remain in a neutral mental state. An ANOVA test performed on the two groups: neutral and humor recall found a statistically significant difference in the frequency range 28-32 Hz for a number of channels including T7 and P7. Both of which presented the greatest statistically significant results with p values of 0.009 and 0.0 respectively Furthermore, we demonstrate that these mental states can be classified using Principal Component Analysis followed by a 3 features Linear Discriminant Analysis resulting in a leave one out classification accuracy of 95%. PMID- 26736549 TI - Hybrid gaze/EEG brain computer interface for robot arm control on a pick and place task. AB - We describe a hybrid brain computer interface that integrates gaze information from an eye tracker with brain activity information measured by electroencephalography (EEG). Users explicitly control the end effector of a robot arm to move in one of four directions using motor imagery to perform a pick and place task. Measurements of the natural eye gaze behavior of subjects is used to infer the instantaneous intent of the users based on the past gaze trajectory. This information is integrated with the output of the EEG classifier and contextual information about the environment probabilistically using Bayesian inference. Our experiments demonstrate that subjects can achieve 100% task completion within three minutes and that the integration of EEG and gaze information significantly improves performance over either cue in isolation. PMID- 26736550 TI - Towards perception awareness: Perceptual event detection for Brain computer interfaces. AB - Brain computer interface (BCI) technology is becoming increasingly popular in many domains such as entertainment, mental state analysis, and rehabilitation. For robust performance in these domains, detecting perceptual events would be a vital ability, enabling adaptation to and act on the basis of user's perception of the environment. Here we present a framework to automatically mine spatiotemporal characteristics of a given perceptual event. As this "signature" is derived directly from subject's neural behavior, it can serve as a representation of the subject's perception of the targeted scenario, which in turn allows a BCI system to gain a new level of context awareness: perception awareness. As a proof of concept, we show the application of the proposed framework on MEG signal recordings from a face perception study, and the resulting temporal and spatial characteristics of the derived neural signature, as well as it's compatibility with the neuroscientific literature on face perception. PMID- 26736551 TI - Neural indicators of the depth of cognitive processing for user-adaptive neurotechnological applications. AB - The ability to infer implicit user variables in realtime and in an unobtrusive way would open a broad variety of applications such as adapting the user interface in human-computer interaction or developing safety assistance systems in industrial workplaces. Such information may be extracted from behavior, peripheral physiology and brain activity. Each of these sensors has its advantages and disadvantages suggesting that finally all available features should be fused. While in Brain-Computer Interface (BCI) research powerful methods for the real-time extraction of information from brain signals have been developed, comparatively little effort was spent on the extraction of hidden user states. As a further step in this direction, we propose a novel experimental paradigm to study the feasibility of quantifying how deeply presented information is processed in the brain. An investigation of event-related potentials (ERPs) demonstrates the effectiveness of our task in inducing different levels of cognitive processing and shows which features of brain activity provide discriminative information. PMID- 26736552 TI - Goal-directed or aimless? EEG differences during the preparation of a reach-and touch task. AB - The natural control of neuroprostheses is currently a challenge in both rehabilitation engineering and brain-computer interfaces (BCIs) research. One of the recurrent problems is to know exactly when to activate such devices. For the execution of the most common activities of daily living, these devices only need to be active when in the presence of a goal. Therefore, we believe that the distinction between the planning of goal-directed and aimless movements, using non-invasive recordings, can be useful for the implementation of a simple and effective activation method for these devices. We investigated whether those differences are detectable during a reach-and-touch task, using electroencephalography (EEG). Event-related potentials and oscillatory activity changes were studied. Our results show that there are statistically significant differences between both types of movement. Combining this information with movement decoding would allow a natural control strategy for BCIs, exclusively relying on the cognitive processes behind movement preparation and execution. PMID- 26736553 TI - Data-driven metric representing the maturation of preterm EEG. AB - Essential information about early brain maturation can be retrieved from the preterm human electroencephalogram (EEG). This study proposes a new set of quantitative features that correlate with early maturation. We exploit the known early trend in EEG content from intermittent to continuous activity, which changes the line length content of the EEG. The developmental shift can be captured in the line length histogram, which we use to obtain 28 features; 20 histogram bins and 8 other statistical measurements. Using the mutual information, we select 6 features with high correlation to the infant's age. This subset appears promising to detect deviances from normal brain maturation. The presented data-driven index holds promise for developing into a computational EEG index of maturation that is highly needed for overall assessment in the Neonatal Intensive Care Units. PMID- 26736554 TI - L0-regularized time-varying sparse inverse covariance estimation for tracking dynamic fMRI brain networks. AB - Exploration of time-varying functional brain connectivity based on functional Magnetic Resonance Imaging (fMRI) data is important for understanding dynamic brain mechanisms. l1-penalized inverse covariance is a common measure for the inference of sparse structure of functional brain networks, and it has been recently extended to estimate time-varying sparse brain networks by using a sliding window and incorporating a smoothing constraint on temporal variation. However, l1 penalty cannot induce maximum sparsity, as compared with l0 penalty, so l0 penalty is supposed to have superior quality on inverse covariance estimation. This paper introduces a novel time-varying sparse inverse covariance estimation method based on dual l0-penalties (DLP). The new DLP method estimates the sparse inverse covariance by minimizing an l0-penalized log-likelihood function and an extra l0 penalty on temporal homogeneity. A cyclic descent optimization algorithm is further developed to localize the minimum of the objective function. Experiment results on simulated signals show that the proposed DLP method can achieve better performance than conventional l1-penalized methods in estimating time-varying sparse network structures under different scenarios. PMID- 26736555 TI - Estimation of heart rate from photoplethysmography during physical exercise using Wiener filtering and the phase vocoder. AB - A system for estimation of the heart rate (HR) from the photoplethysmographic (PPG) signal during intensive physical exercises is presented. The Wiener filter is used to attenuate the noise introduced by the motion artifacts in the PPG signals. The frequency with the highest magnitude estimated using Fourier transformation is selected from the resultant de-noised signal. The phase vocoder technique is exploited to refine the frequency estimate, from which the HR in beats per minute (BPM) is finally calculated. On a publically available database of twenty three PPG recordings, the proposed technique obtains an error of 2.28 BPM. A relative error rate reduction of 18% is obtained when comparing with the state-of-the art PPG-based HR estimation methods. The proposed system is shown to be robust to strong motion artifact, produces high accuracy results and has very few free parameters, in contrast to other available approaches. The algorithm has low computational cost and can be used for fitness tracking and health monitoring in wearable devices. PMID- 26736556 TI - Robust monitoring of hypovolemia in intensive care patients using photoplethysmogram signals. AB - The paper presents a fingertip photoplethysmography based technique to assess patient fluid status that is robust to waveform artifacts and health variability in the underlying patient population. The technique is intended for use in intensive care units, where patients are at risk for hypovolemia, and signal artifacts and inter-patient variations in health are common. Input signals are preprocessed to remove artifact, then a parameter-invariant statistic is calculated to remove effects of patient-specific physiology. Patient data from the Physionet MIMICII database was used to evaluate the performance of this technique. The proposed method was able to detect hypovolemia within 24 hours of onset in all hypovolemic patients tested, while producing minimal false alarms over non-hypovolemic patients. PMID- 26736557 TI - Attenuation of the influence of cardiolocomotor coupling in heart rate variability interpretation during exercise test. AB - During exercise test, cardiolocomotor coupling related components appear in heart rate variability (HRV), blurring its interpretation as autonomic nervous system (ANS) marker. These cardiolocomotor coupling related components are centered at the pedalling and running stride frequency, as well as at their aliases, and may overlap with the low frequency (LF) and high frequency (HF) components of HRV. In this work cardiolocomotor-related HRV components are studied during maximal exercise test on treadmill and cycle ergometer. Power in the bands related to cardiolocomotor coupling increases with exercise intensity in cycle ergometer but not in treadmill exercise test, where it displays higher values for all exercise intensities. A method is proposed to reduce the effect of this coupling in the interpretation of HRV. Evolution of the power in the low frequency (LF) and high frequency (HF) bands are studied after the proposed reduction of cardiolocomotor coupling, showing more significant changes with exercise intensity than before the method is applied. PMID- 26736558 TI - EEG-based index for engagement level monitoring during sustained attention. AB - This paper investigates the relation between mental engagement level and sustained attention in 9 healthy adults performing a Conners' "not-X" continuous performance test (CPT), while their electroencephalographic (EEG) activity was simultaneously acquired. Spectral powers were estimated and extracted in the classical EEG frequency bands. The engagement index (beta/alpha) was calculated employing four different cortical montages suggested by the literature. Results show the efficacy of the estimated measures in detecting changes in mental state and its correlation with subject reaction times throughout the test. Moreover, the influence of the recording sites was proved underling the role of frontal cortex in maintaining a constant sustained attention level. PMID- 26736559 TI - A feature design framework for hardware efficient neural spike sorting. AB - We propose a feature design framework that considers simultaneously performance and computational complexity. In particular, we incorporate these two metrics, which are very important to many low-energy on-chip applications such as implantable neural interfaces, onto an optimization problem. This allows us to strike a balance between the performance of the signal processing task and the computational complexity of the feature extraction process. Simulation results for neural spike sorting demonstrate that by leveraging proposed design framework, we can construct features that outperform other state-of-the-art, low complexity feature designs, both in terms of classification error and complexity. PMID- 26736560 TI - Automated analysis of local field potentials evoked by mechanical whisker stimulation in rat barrel cortex. AB - Local field potentials (LFPs) recorded in the barrel cortex in rats and mice are important to investigate somatosensory systems, the final aim being to start to understand mechanisms of brain representation of sensory stimuli in humans. Parameters extracted from LFP of particular interest include spike timing and transmembrane current flow. Recent improvements in microelectrodes technology have enabled neuroscientists to acquire a great amount of LFP signals during the same experimental session, calling for the development of algorithms for their quantitative automatic analysis. In the present work, an algorithm based on Phillips-Tikhonov regularization is presented to automatically detect the main features (in terms of amplitude and latency) of LFP waveforms recorded after whisker stimulation in rat. The accuracy of the algorithm is first assessed in a Monte Carlo simulation mimicking the acquisition of LFP in three different conditions of SNR. Then, the algorithm is tested by analyzing a set of 100 LFP recorded in the primary somatosensory (S1) cortex, i.e., the region involved in the cortical representation of touch in mammals. PMID- 26736561 TI - Supervised segmentation of microelectrode recording artifacts using power spectral density. AB - Appropriate detection of clean signal segments in extracellular microelectrode recordings (MER) is vital for maintaining high signal-to-noise ratio in MER studies. Existing alternatives to manual signal inspection are based on unsupervised change-point detection. We present a method of supervised MER artifact classification, based on power spectral density (PSD) and evaluate its performance on a database of 95 labelled MER signals. The proposed method yielded test-set accuracy of 90%, which was close to the accuracy of annotation (94%). The unsupervised methods achieved accuracy of about 77% on both training and testing data. PMID- 26736562 TI - Patient specific Parkinson's disease detection for adaptive deep brain stimulation. AB - Continuous deep brain stimulation for Parkinson's disease (PD) patients results in side effects and shortening of the pacemaker battery life. This can be remedied using adaptive stimulation. To achieve adaptive DBS, patient customized PD detection is required due to the inconsistency associated with biomarkers across patients and time. This paper proposes the use of patient specific feature extraction together with adaptive support vector machine (SVM) classifiers to create a patient customized detector for PD. The patient specific feature extraction is obtained using the extrema of the ratio between the PD and non-PD spectra bands of each patient as features, while the adaptive SVM classifier adjusts its decision boundary until a suitable model is obtained. This yields individualised features and classifier pairs for each patient. Datasets containing local field potentials of PD patients were used to validate the method. Six of the nine patient datasets tested achieved a classification accuracy greater than 98%. The adaptive detector is suitable for realization on chip. PMID- 26736563 TI - Prediction of outcome in traumatic brain injury patients using long-term qEEG features. AB - Treatment of patients suffering from severe traumatic brain injury (TBI) commonly involves sedation and mechanical ventilation during prolonged stay in the intensive care unit. Continuous EEG is often monitored in these patients to detect epileptic seizures. It has also been suggested that EEG has prognostic value regarding the outcome of the treatment. In this study the ability of 186 qEEG features to predict the outcome of the treatment of TBI patients is assessed. The features are based on the power spectrum of the EEG. The data underlying the study contains long term (over 24 h) recordings from 20 patients treated in the postoperative intensive care unit of the North Estonian Medical Center. 12 qEEG features were found to have predictive value when evaluated by calculating the area under the receiver operating curve constructed from feature probabilities. PMID- 26736564 TI - Relationship between inter-stimulus-intervals and intervals of autonomous activities in a neuronal network. AB - To investigate relationships between neuronal network activity and electrical stimulus, we analyzed autonomous activity before and after electrical stimulus. Recordings of autonomous activity were performed using dissociated culture of rat hippocampal neurons on a multi-electrodes array (MEA) dish. Single stimulus and pared stimuli were applied to a cultured neuronal network. Single stimulus was applied every 1 min, and paired stimuli was performed by two sequential stimuli every 1 min. As a result, the patterns of synchronized activities of a neuronal network were changed after stimulus. Especially, long range synchronous activities were induced by paired stimuli. When 1 s inter-stimulus-intervals (ISI) and 1.5 s ISI paired stimuli are applied to a neuronal network, relatively long range synchronous activities expressed in case of 1.5 s ISI. Temporal synchronous activity of neuronal network is changed according to inter-stimulus intervals (ISI) of electrical stimulus. In other words, dissociated neuronal network can maintain given information in temporal pattern and a certain type of an information maintenance mechanism was considered to be implemented in a semi artificial dissociated neuronal network. The result is useful toward manipulation technology of neuronal activity in a brain system. PMID- 26736565 TI - 3D ultrasound imaging method to assess the true spinal deformity. AB - Spinal deformity is a three-dimensional (3D) spinal disorder with a lateral deviation and coupled with axial vertebral rotation (AVR). The current clinical practice only measures its severity on postero-anterior (PA) radiographs, which may underestimate the deformity. The actual severity should be obtained on the plane of maximal curvature (PMC), which requires a 3D spinal image. There are many approaches to reconstruct 3D spinal images; however, ultrasound is one of the promising techniques with its non-ionizing characteristic. This study proposed an image processing method using the voxel-based bilinear interpolation to reconstruct a 3D spinal image from ultrasound data, from which the AVR was measured and the spinal curvature on the PMC was determined. In-vitro and in-vivo experiments were performed to determine the accuracy of the measurements from the ultrasound method. The results showed that the 3D ultrasound spinal image could be reconstructed. The curvature angle on the PA and the PMC planes could also be determined. The tilt angle of each individual vertebra in in-vitro study showed high accuracy and correlation (MAD <; 0.9 degrees +/- 0.2 degrees and r(2) > 0.87) when comparing the measurements from CT with ultrasound. In in-vivo study, the curvature angles measured on the PA radiographs and ultrasound images yielded a small difference (MAD 3.4 degrees +/- 1.0 degrees ) and a strong correlation (r(2) = 0.63) within a clinical accepted error of 5 degrees . PMID- 26736566 TI - Using rotation for steerable needle detection in 3D color-Doppler ultrasound images. AB - This paper demonstrates a new way to detect needles in 3D color-Doppler volumes of biological tissues. It uses rotation to generate vibrations of a needle using an existing robotic brachytherapy system. The results of our detection for color Doppler and B-Mode ultrasound are compared to a needle location reference given by robot odometry and robot ultrasound calibration. Average errors between detection and reference are 5.8 mm on needle tip for B-Mode images and 2.17 mm for color-Doppler images. These results show that color-Doppler imaging leads to more robust needle detection in noisy environment with poor needle visibility or when needle interacts with other objects. PMID- 26736568 TI - Compressed sensing for high frame rate, high resolution and high contrast ultrasound imaging. AB - Compressed sensing (CS) or compressive sampling allows much lower sampling frequency than the Nyquist sampling frequency. In this paper, we propose a novel technique, named compressed sensing based synthetic transmit aperture (CS-STA), to speed up the acquisition of ultrasound imaging. Ultrasound transducer transmits plane wave with random apodizations for several times and receives the corresponding echoes. The full dataset of STA is then recovered from the recorded echoes using a CS reconstruction algorithm. Finally, a standard STA beamforming is performed on the dataset to form a B-mode image. When the number of CS-STA firings is smaller than the number of STA firings, higher frame rate is achieved. In addition, CS-STA maintains the high resolution of STA because of the CS recovered full dataset of STA, and improves the contrast due to plane wave firings. Computer simulations and phantom experiments are carried out to investigate the feasibility and performance of the proposed CS-STA method. The CS STA method is proven to be capable of obtaining simultaneously high frame rate, high solution and high contrast ultrasound imaging. PMID- 26736567 TI - Co-located haptic interaction for virtual USG exploration. AB - Ultrasonography is a widespread diagnostic technique that can take advantage of virtual reality for the purpose of training and rehearsal. The placement, orientation and body interaction of the probe is fundamental for the execution of the exploration. This paper introduces a virtual reality setup that employs visuo haptic feedback for virtual ultrasonography. The haptic feedback is provided by desktop delta-like haptic interface with a 3D printed ultrasonography probe, and features haptic point-cloud rendering with implicit surface rendering. The visual feedback is provided by a Head Mounted Display that displays the virtual body, the probe and the operator's hand while not in contact with the probe. The system provides a co-located experience by means of precise calibration of the reference system allowing to synchronize the display of the hand and the probe with the location of the corresponding physical entities. PMID- 26736569 TI - 2D simulations based on general time-dependent reciprocal relation for LFEIT. AB - Lorentz field electrical impedance tomography (LFEIT) is a newly proposed technique for imaging the conductivity of the tissues by measuring the electromagnetic induction under the ultrasound pressure field. In this paper, the theory and numerical simulations of the LFEIT are reported based on the general time dependent formulation. In LFEIT, a phased array ultrasound probe is used to introduce a current distribution inside a conductive body. The velocity current occurs, due to the movement of the conductive particles under a static magnetic field. In order to sense this current, a receiver coil configuration that surrounds the volume conductor is utilized. Finite Element Method (FEM) is used to carry out the simulations of LFEIT. It is shown that, LFEIT can be used to reconstruct the conductivity even up to 50% perturbation in the initial conductivity distribution. PMID- 26736570 TI - Evaluation of a frequency-domain ultrasonic imaging attenuation compensation technique. AB - Ultrasound attenuation is typically compensated for in clinical scanners by using time gain compensation (TGC). However, TGC operates in a frequency-independent fashion and therefore the spatial resolution of the echographic images degrades as the examination depth increases. In the current study, the capability of a multi-band attenuation compensation (MBAC) TGC technique to recover both magnitude and spatial resolution in lossy media was evaluated. Simulations were performed using a 5-MHz transducer for imaging point targets embedded in a medium with attenuation coefficient slope (ACS) of 0.5 dB/(cm.MHz). For performance assessment, the magnitude and spatial resolution of the reflected point spread functions (PSFs) were compared to the ones obtained from point targets embedded in a lossless medium. The results showed a complete recovery of the spectral content when using MBAC for all depths when compared to the lossless case. Both the magnitude and spatial resolution of the compensated PSFs were in agreement with the lossless result (i.e., less than 1 dB and 3 % difference in PSF magnitude and spatial resolution, respectively). The MBAC was then applied to in vivo liver imaging using a scanner equipped with a 5-MHz linear array. Attenuation compensation was performed using ACSs reported in the literature for skin, fat and muscle, and experimentally estimated ACS using the spectral log difference technique for the liver. The lateral and axial extent of the autocorrelation function was estimated in the liver tissue. The experimental MBAC image exhibited only 6 % and 11 % variation in speckle magnitude and lateral autocorrelation length for depths between 2.5 and 4 cm. These results suggest that MBAC technique may enhance speckle uniformity in homogeneous tissue regions. PMID- 26736571 TI - A frequency translation approach for multichannel (13)C spectroscopy. AB - Multi-channel receivers are commonplace in MRI, but very few of these receivers are capable of operating over a broad enough bandwidth to accommodate nuclei other than (1)H. While this is fine for imaging, the recent surge in interest in in vivo NMR has created a need for receive arrays to improve the often-poor sensitivity of other nuclei. However, the development of these arrays has been slowed by the scarcity of multi-channel, multinuclear receivers. Frequency translation is a method to solve this by using radiofrequency mixers to convert signals received from multinuclear arrays to the proton frequency, adapting narrow-band receivers to multinuclear use. This method works with a wide variety of nuclei and easily accommodates proton decoupling, a necessity for working with (13)C. PMID- 26736572 TI - High-resolution dynamic speech imaging with deformation estimation. AB - Dynamic speech magnetic resonance imaging (DSMRI) is a promising technique for visualizing articulatory motion in real time. However, many existing applications of DSMRI have been limited by slow imaging speed and the lack of quantitative motion analysis. In this paper, we present a novel DS-MRI technique to simultaneously estimate dynamic image sequence of speech and the associated deformation field. Extending on our previous Partial Separability (PS) model based methods, the proposed technique visualizes both speech motion and deformation with a spatial resolution of 2.2 * 2.2 mm(2) and a nominal frame rate of 100 fps. Also, the technique enables direct analysis of articulatory motion through the deformation fields. Effectiveness of the method is systematically examined via in vivo experiments. Utilizing the obtained high-resolution images and deformation fields, we also performed a phonetics study on Brazilian Portuguese to show the method's practical utility. PMID- 26736573 TI - Even-odd mode excitation for stability investigation of Cartesian feedback amplifier used in parallel transmit array. AB - A 7 Tesla Magnetic Resonance Imaging (MRI) system with parallel transmission (pTx) for 32 near-magnet Cartesian feedback loop power amplifiers (PA) with output power of 1kW is under construction at Erwin L. Hahn Institute for Magnetic Resonance Imaging. Variation of load impedance due to mutual coupling of neighborhood coils in the array may lead to instability of the Cartesian feedback loop amplifier. MRI safety requires unconditional stability of the PAs at any load. In order to avoid instability in the pTx system, conditions and limits of stability have to be investigated for every possible excitation mode for the coil array. In this work, an efficient method of stability check for an array of two transmit channels (Tx) with Cartesian feedback loop amplifier and a selective excitation mode for the coil array is proposed which allows extension of stability investigations to a large pTx array with any arbitrary excitation mode for the coil array. PMID- 26736574 TI - MRI of biopsy needles by susceptibility mapping based on Wiener filter F and L1 regularization. AB - Biopsy needles are devices that have been used for intravenous therapy. However, the high susceptibility of needles results in signal loss and distortion which makes the location of needles hard to identify in the MRI images. A variety of approaches has been proposed to quantify the susceptibility of the materials being imaged because susceptibility is an intrinsic property that can be used to make a good contrast between different materials. Although previous techniques on susceptibility mapping seem quite effective, they usually consume too much time due to the iterations. In this paper, a method based on Wiener filter is developed to improve the speed of susceptibility mapping. Simulation and phantom experiment demonstrate the effectiveness and high efficiency of the proposed method. PMID- 26736575 TI - Resistive tapered striplines design for MR conditional implants. AB - Despite its remarkable success, one of the significant limitations of Deep Brain Stimulation (DBS) and other types of active medical implants is their incompatibility with magnetic resonance imaging (MRI). This work presents in detail the theory behind a novel MR conditional leads based on resistive tapered stripline technology. The innovative high-resistance technology was shown to allow for decreased Specific Absorption Rate while maintaining low lead resistivity for continuous current injection. The final goal is the development of an active implant systems compatible with MRI and using a more effective stimulation, with significant benefits to patients that may require neural implantation in pathological conditions such as Parkinson's disease, epilepsy, and stroke. PMID- 26736576 TI - Magnetic resonance microimaging of a swine infarcted heart: Performing cardiac virtual histologies. AB - The aim of this study is to develop a computer-aided intuitive software tool based on MATLAB to reproduce the functions of a virtual histology over Magnetic Resonance (MR) microimages of small samples of swine's infarcted hearts. The basic characterization consists of selecting regions of interest (ROIs) of that MR microimage and extracting the most important information of these regions. The software tool will implement intuitive and sophisticated tools that allow the user to define ROIs on the different types of images provided by the MR scanner. The final purpose of this tool will be to analyze the acquired data in order to characterize some aspects of the later possible events after a myocardial infarction in swine's hearts and expand the study to human cases. PMID- 26736577 TI - Model based methods for the analysis of non-stationary effects of telemonitoring as an intervention for the management of chronic conditions at home. AB - The monitoring of vital signs for the management of chronic conditions at home have been demonstrated in numerous trials to have a positive impact on the patient's healthcare outcomes as well as to reduce hospitalization and improve quality of life. The CSIRO has just completed a two year clinical trial designed to evaluate a large number of qualitative and quantitative outcomes of at home telemonitoring. As preliminary data demonstrates that before and after data is not stationary, a model based BACI (Before-After-Control-Impact) design frequently used in environmental and agricultural yield studies, but rarely in clinical trials, has been developed to model the effects of the intervention on healthcare outcomes over time as well as possible secondary effects associate with environmental and seasonal conditions. PMID- 26736578 TI - Data correction for seven activity trackers based on regression models. AB - Using an activity tracker for measuring activity-related parameters, e.g. steps and energy expenditure (EE), can be very helpful in assisting a person's fitness improvement. Unlike the measuring of number of steps, an accurate EE estimation requires additional personal information as well as accurate velocity of movement, which is hard to achieve due to inaccuracy of sensors. In this paper, we have evaluated regression-based models to improve the precision for both steps and EE estimation. For this purpose, data of seven activity trackers and two reference devices was collected from 20 young adult volunteers wearing all devices at once in three different tests, namely 60-minute office work, 6-hour overall activity and 60-minute walking. Reference data is used to create regression models for each device and relative percentage errors of adjusted values are then statistically compared to that of original values. The effectiveness of regression models are determined based on the result of a statistical test. During a walking period, EE measurement was improved in all devices. The step measurement was also improved in five of them. The results show that improvement of EE estimation is possible only with low-cost implementation of fitting model over the collected data e.g. in the app or in corresponding service back-end. PMID- 26736579 TI - A cloud-based system for automatic glaucoma screening. AB - In recent years, there has been increasing interest in the use of automatic computer-based systems for the detection of eye diseases including glaucoma. However, these systems are usually standalone software with basic functions only, limiting their usage in a large scale. In this paper, we introduce an online cloud-based system for automatic glaucoma screening through the use of medical image-based pattern classification technologies. It is designed in a hybrid cloud pattern to offer both accessibility and enhanced security. Raw data including patient's medical condition and fundus image, and resultant medical reports are collected and distributed through the public cloud tier. In the private cloud tier, automatic analysis and assessment of colour retinal fundus images are performed. The ubiquitous anywhere access nature of the system through the cloud platform facilitates a more efficient and cost-effective means of glaucoma screening, allowing the disease to be detected earlier and enabling early intervention for more efficient intervention and disease management. PMID- 26736580 TI - Visualization-based medical expenditure analysis support system. AB - Japanese municipalities have recently been required to decrease their medical expenditure, which has been expanding as a result of an increasing number of patients with chronic diseases. We attempted to visualize insurance claim data to support medical expenditure analysis for insurers or local government (e.g. cities, towns and villages). We introduce two perspectives for the visualization of medical expenditure data: the general perspective approach to understanding overall medical expenditure and the specific perspective approach focused on particular issues such as lifestyle-related diseases. We have created the visual primitives, which enables interactive visualization for very large datasets, from raw insurance claim data. This system uses hypertext markup language and Data driven Documents and provides analysis support for a comprehensive understanding of overall medical expenditure and comparisons between municipalities over time. PMID- 26736581 TI - Septic safe interactions with smart glasses in health care. AB - In this paper, septic safe methods of interaction with smart glasses, due to the health care environment applications consideration, are presented. The main focus is on capabilities of an optical, proximity-based gesture sensor and eye-tracker input systems. The design of both interfaces is being adapted to the open smart glasses platform that is being developed under the eGlasses project. Preliminary results obtained from the proximity sensor show that the recognition of different static and dynamic hand gestures is promising. The experiments performed for the eye-tracker module shown the possibility of interaction with simple Graphical User Interface provided by the near-to-eye display. Research leads to the conclusion of attractiveness of collaborative interfaces for interaction with smart glasses. PMID- 26736582 TI - Establishing an indigenous tele-eye care service. AB - We describe the establishment of a new tele-eye care solution over a Broadband Satellite service, connecting metropolitan-based ophthalmologists to patients with eye conditions in rural and remote Australia. A trial of the service demonstrates the ability of the telehealth system to close the gap in access to eye care services for adult Australians living in under-served rural and remote communities, preventing needless blindness. PMID- 26736583 TI - Investigating correlation between verbal interactions and perceived stress. AB - While moderate exposure to stress at work can act as productivity booster, prolonged exposure not only decreases productivity, but it can also lead to an array of health related problems. Therefore, monitoring stress levels and more importantly correlated stressors, becomes prerequisite for a productive workforce. Considering that verbal interaction is an integral part of workplace environments, we report the results of our study that investigates correlation between perceived stress levels and verbal interaction. 28 workers were monitored over 6 weeks through their smartphones during their daily, real-world behaviour, capturing both verbal interaction and perceived stress levels. Results show that more than half of participants show correlation between perceived stress levels and verbal interaction, while this correlation is observed for over 90% of highly stressed participants. PMID- 26736584 TI - Time-series modeling of long-term weight self-monitoring data. AB - Long-term self-monitoring of weight is beneficial for weight maintenance, especially after weight loss. Connected weight scales accumulate time series information over long term and hence enable time series analysis of the data. The analysis can reveal individual patterns, provide more sensitive detection of significant weight trends, and enable more accurate and timely prediction of weight outcomes. However, long term self-weighing data has several challenges which complicate the analysis. Especially, irregular sampling, missing data, and existence of periodic (e.g. diurnal and weekly) patterns are common. In this study, we apply time series modeling approach on daily weight time series from two individuals and describe information that can be extracted from this kind of data. We study the properties of weight time series data, missing data and its link to individuals behavior, periodic patterns and weight series segmentation. Being able to understand behavior through weight data and give relevant feedback is desired to lead to positive intervention on health behaviors. PMID- 26736585 TI - Annotation and prediction of stress and workload from physiological and inertial signals. AB - Continuous daily stress and high workload can have negative effects on individuals' physical and mental well-being. It has been shown that physiological signals may support the prediction of stress and workload. However, previous research is limited by the low diversity of signals concurring to such predictive tasks and controlled experimental design. In this paper we present 1) a pipeline for continuous and real-life acquisition of physiological and inertial signals 2) a mobile agent application for on-the-go event annotation and 3) an end-to-end signal processing and classification system for stress and workload from diverse signal streams. We study physiological signals such as Galvanic Skin Response (GSR), Skin Temperature (ST), Inter Beat Interval (IBI) and Blood Volume Pulse (BVP) collected using a non-invasive wearable device; and inertial signals collected from accelerometer and gyroscope sensors. We combine them with subjects' inputs (e.g. event tagging) acquired using the agent application, and their emotion regulation scores. In our experiments we explore signal combination and selection techniques for stress and workload prediction from subjects whose signals have been recorded continuously during their daily life. The end-to-end classification system is described for feature extraction, signal artifact removal, and classification. We show that a combination of physiological, inertial and user event signals provides accurate prediction of stress for real life users and signals. PMID- 26736587 TI - A smart spirometry device for asthma diagnosis. AB - In this paper an innovative prototype for smart asthma spirometry device to be used by doctors and asthma patients is presented. The novelty in this prototype relies in the fact that it is destined to subtend not only adults but offers an efficient and attractive manner to accommodate children patients as well thus, making it efficient for doctors, patients and parents to detect and monitor such intricate cases at stages as early as six years old. Moreover, the apparatus used enables us to integrate a vital parameter representing the Forced Expiratory Volume to the final diagnosis. Besides, the presented device will automatically diagnose those patients, assess their asthma condition, and schedule their medication process without excessive visits to medical centers whilst providing doctors with accurate and pertinent and comprehensive medical data in a chronological fashion. Zooming into under the hood of the device, a fully reliable hardware digital system lies along with a flowmeter detector and a Bluetooth emitter to interface with a user-friendly GUI-based application installed on smartphones which incorporates appealing animated graphics to encourage children to take the test. Furthermore, the device offers the capability of storing chronological data and a relevant resourceful display for accurate tracking of patients' medical record, the evolvement of their asthma condition, and the administered medication. Finally, the entire device is aligned with the medical requirements as per doctors' and telemedicine specialists' recommendations; the experiments carried out demonstrated the effectiveness and sustainable use of such device. PMID- 26736586 TI - Modeling perceived stress via HRV and accelerometer sensor streams. AB - Discovering and modeling of stress patterns of human beings is a key step towards achieving automatic stress monitoring, stress management and healthy lifestyle. As various wearable sensors become popular, it becomes possible for individuals to acquire their own relevant sensory data and to automatically assess their stress level on the go. Previous studies for stress analysis were conducted in the controlled laboratory and clinic settings. These studies are not suitable for stress monitoring in one's daily life as various physical activities may affect the physiological signals. In this paper, we address such issue by integrating two modalities of sensors, i.e., HRV sensors and accelerometers, to monitor the perceived stress levels in daily life. We gathered both the heart and the motion data from 8 participants continuously for about 2 weeks. We then extracted features from both sensory data and compared the existing machine learning methods for learning personalized models to interpret the perceived stress levels. Experimental results showed that Bagging classifier with feature selection is able to achieve a prediction accuracy 85.7%, indicating our stress monitoring on daily basis is fairly practical. PMID- 26736588 TI - Quantifiable fitness tracking using wearable devices. AB - Monitoring health and fitness is emerging as an important benefit that smartphone users could expect from their mobile devices today. Rule of thumb calorie tracking and recommendation based on selective activity monitoring is widely available today, as both on-device and server based solutions. What is surprisingly not available to the users is a simple application geared towards quantitative fitness tracking. Such an application potentially can be a direct indicator of one's cardio-vascular performance and associated long term health risks. Since wearable devices with various inbuilt sensors like accelerometer, gyroscope, SPO2 and heart rate are increasingly becoming available, it is vital that the enormous data coming from these sensors be used to perform analytics to uncover hidden health and fitness associated facts. A continuous estimation of fitness level employing these wearable devices can potentially help users in setting personalized short and long-term exercise goals leading to positive impact on one's overall health. The present work describes a step in this direction. This work involves an unobtrusive method to track an individual's physical activity seamlessly, estimate calorie consumption during a day by mapping the activity to the calories spent and assess fitness level using heart rate data from wearable sensors. We employ a heart rate based parameter called Endurance to quantitatively estimate cardio-respiratory fitness of a person. This opens up avenues for personalization and adaptiveness by dynamically using individual's personal fitness data towards building robust modeling based on analytical principles. PMID- 26736589 TI - Assistive peripheral prosthetic vision aids perception and mobility in outdoor environments: A virtual-reality simulation study. AB - Retinitis pigmentosa (RP) causes visual field (VF) constriction due to progressive loss of photoreceptors, typically from the retinal periphery to the fovea. Retinal prostheses offer vision restoration via electrode implantation and stimulation near the fovea, thereby eliciting articifial percepts, so-called phosphenes in the center VF. Although foveal photoreceptors can persist for prolonged periods of time, bionic therapy is usually restricted to stages of RP with complete vision loss. However, persons with RP experience mobility impairment from peripherally restricted VFs much earlier. Consequently, the amount of visual scanning necessary for navigation is increased, and maintaining a steady pace is challenging. Receiving a retinal implant at this early stage might be feasible. We investigated the potential of a peripheral visual prosthesis coexisting with central residual vision to facilitate scene perception and mobility. Simulating prosthetic and residual vision in a virtual mobility environment, we found that assistive phosphene layouts were associated with reductions in visual scanning-related head movements of up to 42.1%, body rotations of up to 30%, and up to 45% lower frequency of stopping when circumventing low-lying obstacles, pedestrians and following a path. Further research on early implantation of retinal prostheses for the peripheral VF is therefore advised. PMID- 26736590 TI - Cortical neural excitations in rats in vivo with using a prototype of a wireless multi-channel microstimulation system. AB - Understanding neural responses to multi-site electrical stimuli would be of essential importance for developing cortical neural prostheses. In order to provide a tool for such studies in experimental animals, we recently constructed a prototype of a wireless multi-channel microstimulation system, consisting of a stimulator chip, wireless data/power transmitters and receivers, and microcomputers. The proper operations of the system in cortical neural excitations were examined in anesthetized rats in vivo, with utilizing the voltage-sensitive dye imaging technique. PMID- 26736591 TI - Impact of monaural frequency compression on binaural fusion at the brainstem level. AB - A classical objective measure for binaural fusion at the brainstem level is the so-called beta-wave of the binaural interaction component (BIC) in the auditory brainstem response (ABR). However, in some cases it appeared that a reliable detection of this component still remains a challenge. In this study, we investigate the wavelet phase synchronization stability (WPSS) of ABR data for the analysis of binaural fusion and compare it to the BIC. In particular, we examine the impact of monaural nonlinear frequency compression on binaural fusion. As the auditory system is tonotopically organized, an interaural frequency mismatch caused by monaural frequency compression could negatively effect binaural fusion. In this study, only few subjects showed a detectable beta wave and in most cases only for low ITDs. However, we present a novel objective measure for binaural fusion that outperforms the current state-of-the-art technique (BIC): the WPSS analysis showed a significant difference between the phase stability of the sum of the monaurally evoked responses and the phase stability of the binaurally evoked ABR. This difference could be an indicator for binaural fusion in the brainstem. Furthermore, we observed that monaural frequency compression could indeed effect binaural fusion, as the WPSS results for this condition vary strongly from the results obtained without frequency compression. PMID- 26736592 TI - Resistivity profiles of wild-type, rd1, and rd10 mouse retina. AB - Electrical impedance of the retina is a critical factor in retinal prostheses, determining the intraretinal current flow and potential distribution of electrical stimulation. Previous resistivity measurements in retina were limited to healthy retina, and didn't include mouse models, a common and important animal model in retinal research. This experimental study measured the resistivity profiles of wild-type, rd1, and rd10 mice, providing basis for computational simulations and predictive modeling studies. The peak resistance frequency method has been utilized to measure the resistivity profiles of the retina cross section, and the results show agreement with previous studies in retina of normal rats and embryonic chicks. Retinal degeneration affects the width of the profile, which is in agreement with histological measurements. Degeneration also results in lower peak resistivity. The results indicate that, on the mesoscopic scale, resistivity is dominated by spatial factors, while influence of remodeling on the cellular level is not apparent under such scale. PMID- 26736593 TI - Mental workload estimations in unilateral deafened children. AB - Despite of technological innovations, noisy environments still constitute a challenging and stressful situation for words recognition by hearing impaired subjects. The evaluation of the mental workload imposed by the noisy environments for the recognition of the words in prelingually deaf children is then of paramount importance since it could affect the speed of the learning process during scholar period.The aim of the present study was to investigate different electroencephalographic (EEG) power spectral density (PSD) components (in theta 4 8 Hz - and alpha - 8-12 Hz - frequency bands) to estimate the mental workload index in different noise conditions during a word recognition task in prelingually deaf children, a population not yet investigated in relation to the workload index during auditory tasks. A pilot study involving a small group of prelingually deaf children was then subjected to EEG recordings during an auditory task composed by a listening and a successive recognition of words with different noise conditions. Results showed that in the pre-word listening phase frontal EEG PSD in theta band and the ratio of the frontal EEG PSD in theta band and the parietal EEG PSD in alpha band (workload index; IWL) reported highest values in the most demanding noise condition. In addition, in the phase preceding the word forced-choice task the highest parietal EEG PSD in alpha band and IWL values were reported at the presumably simplest condition (noise emitted in correspondence of the subject's deaf ear). These results could suggest the prominence of EEG PSD theta component activity in the pre-word listening phase. In addition, a more challenging noise situation in the pre-choice phase would be so "over-demanding" to fail to enhance both the alpha power and the IWL in comparison to the already demanding "simple" condition. PMID- 26736594 TI - Motion sensitivity analysis of retinal ganglion cells in mouse retina using natural visual stimuli. AB - One of the major objectives in functional studies of the retina is the understanding of neural circuits and identification of the function of involved nerve cells. Instead of stimulating the retina with light patterns of simple geometrical shapes, we analyze the response of retinal ganglion cells of mouse retina to a black and white movie containing a natural scenery. By correlating measured spike trains with a metric for the velocity of a visual scene, PV0 cells were found to be direction selective, whereas PV5 cells did not show any sensitivity to motion. PMID- 26736595 TI - Classification of hand and wrist tasks of unknown force levels using muscle synergies. AB - Muscle synergies have been proposed as a way for the central nervous system (CNS) to simplify the generation of motor commands and they have been shown to explain a large portion of the variation in the muscle patterns across a variety of conditions. However, whether human subjects are able to control prostheses proportionally with a small set of synergies has not been tested directly. Here we investigated if muscle synergies can be used to identify different wrist and hand motions. We recorded electromyographic (EMG) activity from eight arm muscles while the subjects exerted seven different intensity levels during the motions when performing seven classes of hand and wrist motion. From these data we extracted the muscle synergies and classified the tasks associated to each contraction intensity profile by linear discriminant analysis (LDA). We compared the performance obtained using muscle synergies with the performance of using the mean absolute values (MAV) as a feature. Also, the consistency of extracted muscle synergies was studied across intensity variations. While the synergies showed relative consistency particularly across closer intensity levels, average classification results generated with the synergies were less accurate than MAVs. These results indicate that although the performance of muscle synergies was very close to MAVs, they do not provide additional information for task identification across different exerted intensity levels. PMID- 26736596 TI - Optimal calibration of the learning rate in closed-loop adaptive brain-machine interfaces. AB - Closed-loop decoder adaptation (CLDA) can improve brain-machine interface (BMI) performance. CLDA methods use batches of data to refit the decoder parameters in closed-loop operation. Recently, dynamic state-space algorithms have also been designed to fit the parameters of a point process decoder (PPF). A main design parameter that needs to be selected in any CLDA algorithm is the learning rate, i.e., how fast should the decoder parameters be updated on the basis of new neural observations. So far, the learning rate of CLDA algorithms has been selected empirically using ad-hoc methods. Here we develop a principled framework to calibrate the learning rate in adaptive state-space algorithms. The learning rate introduces a trade-off between the convergence rate and the steady-state error covariance of the estimated decoder parameters. Hence our algorithm first finds an analytical upper-bound on the steady-state error covariance as a function of the learning rate. It then finds the inverse mapping to select the optimal learning rate based on the maximum allowable steady-state error. Using numerical BMI experiments, we show that the calibration algorithm selects the optimal learning rate that meets the requirement on steady-state error level while achieving the fastest convergence rate possible corresponding to this steady-state level. PMID- 26736597 TI - Design of a pulse-triggered four-channel functional electrical stimulator using complementary current source and time division multiplexing output method. AB - In this paper, a four-channel pulse-triggered functional electrical stimulator using complementary current source and time division output method is proposed for the research and application of functional electrical stimulation (FES). The high-voltage compliance and output impedance is increased by adopting the complementary current source, which can also realize the linear voltage-to current conversion and high channel isolation. A high-voltage analog switch chip MAX14803, combined with a FIFO queue algorithm in the microprocessor, is used to setup the H-bridge and multiplexers for the four-channel time division multiplexing output. With this method, the size and cost of the key components are reduced greatly. The stimulating core circuit area is 30 * 50 mm(2). According to the experiments, the stimulator can achieve the four-channel charge balanced biphasic stimulation with a current range between 0 and 60 mA and a single-phase pulse amplitude up to 60 V. PMID- 26736598 TI - Nonlinear mappings between discrete and simultaneous motions to decrease training burden of simultaneous pattern recognition myoelectric control. AB - Real-time simultaneous pattern recognition (PR) control of multiple degrees of freedom (DOF) has been demonstrated using a set of parallel linear discriminant analysis (LDA) classifiers trained with both discrete (1-DOF) and simultaneous (2 DOF) motion data. However, this training method presents a clinical challenge, requiring large amounts of data necessary to re-train the system. This study presents a parallel classifier training method that aims to reduce the training burden. Artificial neural networks (ANNs) were used to determine a nonlinear mapping between surface EMG features of 2-DOF motions and their 1-DOF motion components. The mapping was then used to transform experimentally collected features of 1-DOF motions into simulated features of 2-DOF motions. A set of parallel LDA classifiers were trained using the novel training method and two previously reported training methods. The training methods evaluated were (1) using experimentally collected 1-DOF data and ANN-simulated 2-DOF data, (2) using only experimentally collected 1-DOF data and (3) using experimentally collected 1 and 2-DOF data. Using the novel training method resulted in significantly lower classification error overall (p<;0.01) and in predicting 2-DOF motions (p<;0.01) compared to training with experimental 1-DOF data only. These findings demonstrate that using a set of ANNs to predict 2-DOF data from 1-DOF data can improve system performance when only discrete training data are available, thus reducing the training burden of simultaneous PR control. PMID- 26736599 TI - Influence of multiple dynamic factors on the performance of myoelectric pattern recognition. AB - Hand motion classification using surface Electromyogram (EMG) signals has been widely studied for the control of powered prosthetics in laboratory conditions. However, clinical applicability has been limited, as imposed by factors like electrodes shift, variations in the contraction force levels, forearm rotation angles, change of limb position and many other factors that all affect the EMG pattern recognition performance. While the impact of several of these factors on EMG parameter estimation and pattern recognition has been considered individually in previous studies, a minimum number of experiments were reported to study the influence of multiple dynamic factors. In this paper, we investigate the combined effect of varying forearm rotation angles and contraction force levels on the robustness of EMG pattern recognition, while utilizing different time-and frequency based feature extraction methods. The EMG pattern recognition system has been validated on a set of 11 subjects (ten intact-limbed and one bilateral transradial amputee) performing six classes of hand motions, each with three different force levels, each at three different forearm rotation angles, with six EMG electrodes plus an accelerometer on the subjects' forearm. Our results suggest that the performance of the learning algorithms can be improved with the Time-Dependent Power Spectrum Descriptors (TD-PSD) utilized in our experiments, with average classification accuracies of up to 90% across all subjects, force levels, and forearm rotation angles. PMID- 26736600 TI - Design and preliminary testing of the RIC hybrid knee prosthesis. AB - We present a novel hybrid knee prosthesis that uses a motor, transmission and control system only for active dynamics tasks, while relying on a spring/damper system for passive dynamics activities. Active dynamics tasks require higher torque, lower speed, and occur less frequently than passive dynamic activities. By designing the actuation system around active tasks alone, we achieved a lightweight design (1.7 Kg w/o battery) without sacrificing peak torque (85Nm repetitive). Preliminary tests performed by an able-bodied person using a bypass orthosis show that the hybrid knee can support reciprocal stairs ambulation with low electrical energy consumption. PMID- 26736601 TI - Model-based estimation of pulmonary compliance and resistance parameters from time-based capnography. AB - We propose a highly-simplified single-alveolus mechanistic model of lung mechanics and gas mixing that leads to an analytical solution for carbon dioxide partial pressure in exhaled breath, as measured by time-based capnography. Using this solution, we estimate physiological parameters of the lungs on a continuous, breath-by-breath basis. We validate our model with capnograms from 15 subjects responding positively (>20% FEV1 drop from baseline) to methacholine challenge, and subsequently recovering with bronchodilator treatment. Our results suggest that parameter estimates from capnography may provide discriminatory value for lung function comparable to spirometry, thus warranting more detailed study. PMID- 26736602 TI - Design and characterization of a measurement system for monitoring pressure exerted by bronchial blockers: In vitro trials. AB - Bronchial blockers (BBs) allow occluding the bronchial duct and collapsing the "dependent" lung in a number of thoracic surgery. The occlusion is obtained through a cuff that, inflated with a proper air volume, exerts a pressure, Pe, on the inner wall of the mainstem bronchus. In this work a measurement chain, based on two piezorestistive force sensors, was developed and calibrated to measure Pe exerted by six BBs, as a function of inflated volume on in vitro models (two latex ducts with diameters similar to the ones of the adult mainstem bronchi: 12 mm and 15 mm). Pe showed wide changes considering different BBs, and significantly increases with the decrease of the model's diameter, at the same inflated volume. Lastly, the minimum occlusive volume (MOV) to sail the two models was estimated for each BB. These experiments were performed by applying a pressure difference across the cuff of 25 cmH2O, in order to simulate the worst condition in a clinical scenario. Results show that MOV depends on both the type of BB and the duct diameter. The knowledge of this volume allows estimating the minimum value of Pe exerted by BBs to avoid air leakage. PMID- 26736603 TI - Liquid ventilator for ultrafast hypothermia induction in juvenile lambs: Preliminary results. AB - Total liquid ventilation (TLV) is an emerging mechanical ventilation technique. In this technique, the lungs are filled with liquid perfluorocarbons (PFC) and a liquid ventilator assures ventilation by periodically renewing a volume of oxygenated, CO2 freed and temperature controlled PFC. A huge difference between conventional mechanical ventilation and TLV relates to the fact that PFCs are about 1500 times denser than air. Thus, the PFCs filled lungs turn into an efficient heat exchanger with the circulating blood. One of the most appealing utilization of the lungs as a heat exchanger in TLV is for ultrafast induction of mild therapeutic hypothermia (MTH) for neuroprotection and cardioprotection after ischemia-reperfusion injuries. This study aimed to perform ultrafast MTH induction by TLV in animals up to 25 kg, then perform a fast post-hypothermic rewarming while maintaining proper ventilation. A thermal model of the lamb and liquid ventilator was developed to predict the dynamic and the control strategy to adopt for MTH induction. Two juvenile lambs were instrumented with temperature sensors in the femoral artery, pulmonary artery, oesophagus, right eardrum and rectum. After stabilization in conventional mechanical ventilation, TLV was initiated with ultrafast MTH induction, followed by posthypothermic rewarming. Preliminary results in the two juvenile lambs reveal that the liquid ventilator Inolivent-6.0 can induce MTH by TLV in less than 2.5 min for systemic arterial blood and in less than 10 min for venous return, esophagus and eardrum. Rectal temperature reached MTH in respectively 19.4 and 17.0 min for both lambs. Experimental results were consistent with the model predictions. Moreover, blood gas analysis exhibited that the gas exchange in the lungs was maintained adequately for the entire experiments. PMID- 26736604 TI - Clustering of capnogram features to track state transitions during procedural sedation. AB - Procedural sedation has allowed many painful interventions to be conducted outside the operating room. During such procedures, it is important to maintain an appropriate level of sedation to minimize the risk of respiratory depression if patients are over-sedated and added pain or anxiety if under-sedated. However, there is currently no objective way to measure the patient's evolving level of sedation during a procedure. We investigated the use of capnography-derived features as an objective measure of sedation level. Time-based capnograms were recorded from 30 patients during sedation for cardioversion. Through causal k means clustering of selected features, we sequentially assigned each exhalation to one of three distinct clusters, or states. Transitions between these states correlated to events during sedation (drug administration, procedure start and end, and clinical interventions). Similar clustering of capnogram recordings from 26 healthy, non-sedated subjects did not reveal distinctly separated states. PMID- 26736605 TI - EMG-Derived Respiration Signal Using the Fixed Sample Entropy during an Inspiratory Load Protocol. AB - Extracting clinical information from one single measurement represents a step forward in the assessment of the respiratory muscle function. This attracting idea entails the reduction of the instrumentation and fosters to develop new medical integrated technologies. We present the use of the fixed sample entropy (fSampEn) as a more direct method to non-invasively derive the breathing activity from the diaphragm electromyographic (EMGdi) signal, and thus to extract the respiratory rate, an important vital sign which is cumbersome and time-consuming to be measured by clinicians. fSampEn is a method to evaluate the EMGdi activity that is less sensitive to the cardiac activity (ECG) and its application has proven to be useful to evaluate the load of the respiratory muscles. The behavior of the proposed method was tested in signals from two subjects that performed an inspiratory load protocol, which consists of increments in the inspiratory mouth pressure (P mouth). Two respiratory signals were derived and compared to the P mouth signal: the ECG-derived respiration (EDR) signal from the lead-I configuration, and the EMG-derived respiration (EMGDR) signal by applying the fSampEn method over the EMGdi signal. The similitude and the lag between signals were calculated through the cross-correlation between each derived respiratory signal and the P mouth. The EMGDR signal showed higher correlation and lower lag values (>= 0.91 and <= 0.70 s, respectively) than the EDR signal (>= 0.83 and <= 0.99 s, respectively). Additionally, the respiratory rate was estimated with the P mouth, EDR and EMGDR signals showing very similar values. The results from this preliminary work suggest that the fSampEn method can be used to derive the respiration waveform from the respiratory muscle electrical activity. PMID- 26736606 TI - Wearable lung-health monitoring system with electrical impedance tomography. AB - The wearable lung-health monitoring system is proposed with an electrical impedance tomography (EIT). The proposed system has light belt-type form factor which is implemented with the EIT integrated circuit (IC) on the planar fashionable circuit board (P-FCB) technology. The EIT IC provides programmable current stimulation which is optimally controlled by the results of contact impedance monitoring. The measured data is transmitted to the mobile device and the lung EIT images are reconstructed and displayed with up to 20 frames/s real time. From the lung EIT image, the measured lung air volume ratio can be used as an indicator of the lung-health, and other various parameters can be extracted to monitor lung status. The proposed wearable system achieves the user convenience for lung-health monitoring which can be used personally at home. The proposed system is fully implemented and verified on both in-vitro and in-vivo tests. PMID- 26736607 TI - Communication patterns for interconnecting and composing medical systems. AB - This paper proposes a set of communication patterns to enable the construction of medical systems by composing devices and apps in Integrated Clinical Environments (ICE). These patterns abstract away the details of communication tasks, reduce engineering overhead, and ease compositional reasoning of the system. The proposed patterns have been successfully implemented on top of two distinct platforms (i.e., RTI Connext and Vert.x) to allow for experimentation. PMID- 26736608 TI - Dynamic DICOM configuration in a service-oriented medical device architecture. AB - A surgical intervention raises additional requirements to a medical device network, be it security concerns or the demand for just-in-time integration of an additional devices. The German national flagship project OR.NET aims to satisfy these requirements by defining, implementing and validating an integration solution for safe and dynamic networking. This work presents an approach to incorporate imaging related medical devices into a dynamic plug and play operating room (OR) network utilizing the existing Digital Imaging and Communications in Medicine (DICOM) protocol. The presented approach was created as part of the OR.NET project to realize the integration of DICOM devices into the developed infrastructure, both in regard to newly created DICOM devices with direct support of the OR.NET protocol and the integration of existing DICOM devices (e.g. image archives) employing a gateway. Preliminary evaluation results indicate that the approach is viable and that no critical transmission delays are introduced by the prototypical gateway implementation. PMID- 26736609 TI - New IEEE 11073 Standards for interoperable, networked Point-of-Care Medical Devices. AB - Surgical procedures become more and more complex and the number of medical devices in an operating room (OR) increases continuously. Today's vendor dependent solutions for integrated ORs are not able to handle this complexity. They can only form isolated solutions. Furthermore, high costs are a result of vendor-dependent approaches. Thus we present a service-oriented device communication for distributed medical systems that enables the integration and interconnection between medical devices among each other and to (medical) information systems, including plug-and-play functionality. This system will improve patient's safety by making technical complexity of a comprehensive integration manageable. It will be available as open standards that are part of the IEEE 11073 family of standards. The solution consists of a service-oriented communication technology, the so called Medical Devices Profile for Web Services (MDPWS), a Domain Information & Service Model, and a binding between the first two mechanisms. A proof of this concept has been done with demonstrators of real world OR devices. PMID- 26736611 TI - Regulatory science based approach in development of novel medical devices. AB - For development rational evaluation method for medical devices' safety and efficacy, regulatory science studies are important. Studies on regulatory affairs related to a medical device under development should be conducted as well as its technological development. Clinical performance of a medical device is influenced by performance of the device, medical doctors' skill, pathological condition of a patient, and so on. Thus it is sometimes difficult to demonstrate superiority of the device in terms of clinical outcome although its efficacy as a medical device is accepted. Setting of appropriate end points is required to evaluate a medical device appropriately. Risk assessment and risk management are the basis of medical device safety assurance. In case of medical device software, there are difficulties in identifying the risk due to its complexity of user environment and different design and manufacturing procedure compared with conventional hardware based medical devices. Recent technological advancement such as information and communication technologies (ICT) for medical devices and wireless network has raised new issue on risk management: cybersecurity. We have to watch closely the progress of safety standard development. PMID- 26736610 TI - Reporting Device Observations for semantic interoperability of surgical devices and clinical information systems. AB - Service-oriented medical device architectures make the progress from interdisciplinary research projects to international standardisation: A new set of IEEE 11073 proposals shall pave the way to industry acceptance. This expected availability of device observations in a standardised representation enables secondary usage if interoperability with clinical information systems can be achieved. The Device Observation Reporter (DOR) described in this work is a gateway that connects these realms. After a user chooses a selection of signals from different devices in the digital operating room, the DOR records these semantically described values for a specified duration. Upon completion, the signals descriptions and values are transformed to Health Level Seven version 2 messages and sent to a hospital information system/electronic health record system within the clinical IT network. The successful integration of device data for documentation and usage in clinical information systems can further leverage the novel device communication standard proposals. Complementing these, an Integrating the Healthcare Enterprise profile will aid commercial implementers in achieving interoperability. Their solutions could incorporate clinical knowledge to autonomously select signal combinations and generate reports of diagnostic and interventional procedures, thus saving time and effort for surgical documentation. PMID- 26736612 TI - Rule-based medical device adaptation for the digital operating room. AB - A workflow-driven cooperative operating room needs to be established in order to successfully unburden the surgeon and the operating room staff very time consuming information-seeking and configuration tasks. We propose an approach towards the integration of intraoperative surgical workflow management and integration technologies. The concept of rule-based behavior is adapted to situation-aware medical devices. A prototype was implemented and experiments with sixty recorded brain tumor removal procedures were conducted to test the proposed approach. An analysis of the recordings indicated numerous applications, such as automatic display configuration, room light adaptation and pre-configuration of medical devices and systems. PMID- 26736613 TI - Bioengineered cell-instructive 3D matrices as vehicles for cellular therapies. AB - The delivery of cells, namely of stem cells, from biomaterial-based vehicles has been used to promote and accelerate functional tissue regeneration. Carrier materials can transport and localize cells into target sites, increase their survival and engraftment, and provide a supportive matrix to assist cellular assembly into a newly formed tissue. Hydrogels are amongst the most widely used carrier materials, as they can entrap and protect cells within a real three dimensional (3D) microenvironment, and intrinsically present many structural properties of the natural extracellular matrix (ECM). To recreate important features of the native ECM, hydrogels may be bio-functionalized with specific cell-instructive moieties for improved biomimetic properties. The biophysical properties of hydrogels can also be tuned, increasing their versatility, as it is currently recognized that stem cells respond to their biomechanical environment. Here, an overview of some strategies commonly employed in the preparation of biomimetic matrices is presented, using alginate as a model hydrogel. PMID- 26736614 TI - A novel 3-dimensional approach for cardiac regeneration. AB - Ischemic heart diseases, such as coronary artery disease and microvascular disease, are cardiovascular pathologies that cause reduced blood supply to the heart muscle. Acute and chronic ischemia cause cardiomyocytes to die, and these cells are not naturally replaced as part of the wound healing process in the heart. To promote neovascularization in the wound bed and in implanted engineered tissues, we have developed a collagen-alginate microspheres scaffold intended for local release of drugs and growth factors in order to recruit host endothelial cells to the area and provide them with geometrical cues to form new vessels. Optimization of alginate microspheres included modulation of nitrogen pressure, alginate and CaCl2 concentrations, nozzle size, and velocity of extrusion to achieve monodisperse populations of 100 MUm diameter microspheres with protein release over 3 days. In vitro incorporation of fibroblasts in the bulk collagen demonstrated cellular compatibility with embedded alginate microspheres. An in vitro vessel formation assay, performed with human umbilical vein endothelial cells (HUVECs) immobilized in the collagen phase of the collagen-alginate microspheres scaffolds, showed that HUVECs formed networks following the 3 dimensional pattern of the microspheres even in the absence of growth factor. Implantation of acellular collagen-alginate microspheres scaffolds onto healthy rat hearts confirmed the invasion of host cells at one week. Together, these results suggest that the collagen-alginate microspheres scaffold is a viable, tunable therapeutic approach for directing neovascularization in engineered tissues and in the heart after ischemic events. PMID- 26736615 TI - Biofunctionalization of polymeric surfaces. AB - Most of the synthetic polymeric biomaterials used for biomedical applications lack of functional groups able to specifically instruct cells to unlock their potential for tissue regeneration. Surface modification strategies are able to overcome this limitation by introducing bioactive cues. In this study, several functionalization approaches are analyzed. Wet chemical methods such as controlled hydrolysis of polyesters followed by biomolecules grafting by carbodiimide chemistry are simple and versatile approaches, able to succesfully improve the bioactivity of devices with virtually any architecture. Grafting of short peptides, extracellular matrix proteins (ECM) or engineered protein-like recombinamers are promising techniques to improve cell adhesion to biomaterials, including polylactic acid (PLA) and its derivatives. ECM molecules and recombinamers can present more effectively bioactive signals, even in presence of competing, nonadhesive serum proteins. Besides adhesion, surface modifications intended to improve cell attachment, play a role on other cell responses, such as migratory potential. Collagen coating were shown to enhance the expression of the migratory receptor CXCR4 in mesenchymal stromal cells, when compared to short RGD peptides, while the modality of functionalization (covalent vs. physisorbed) tuned the rate of cell migration from PLA-based microcarriers. This multiple effects have to be taken into account when designing biomaterials for cell delivery and tissue engineering. Furthermore, as we aim to recapitulate in vitro the complexity of native tissues, alternative strategies based on the generation of decellularized polymer scaffold rich in cell-deposited ECM are proposed. PMID- 26736616 TI - Molecular mechanisms orchestrating the stem cell response to translational scaffolds. AB - A 2013 Perspective in Science titled "Deconstructing Dimensionality" noted the importance of fiber morphology on cell phenotype, concluding with the statement "Identifying the mechanisms by which cells assess the nature of their environment will advance basic cell biology and facilitate the development of synthetic matrices for specific tissue engineering applications." Nanofibers have revolutionized scaffold-based approaches for musculoskeletal tissues; demonstrating surprising efficacy over promoting mesenchymal stem cell, MSC, differentiation down multiple musculoskeletal lineages. Understanding the fundamental mechanisms involved will allow the future design of nanofiber-based scaffolds to target a lineage with specificity. This article focuses on how three geometry sensors: focal adhesions, membrane associated vesicle stabilizing and trafficking proteins, and adherens junctions; potentially regulate MSC lineage commitment in response to bio-instructive nanofibers. PMID- 26736617 TI - Biomimetic hybrid scaffolds for osteo-chondral tissue repair: Design and osteogenic differentiation of human placenta-derived cells (hPDC). AB - A novel functionally-graded hybrid (FGHY) scaffold was designed and developed with a load-bearing structure represented by a PU foam loaded with a graded composition of CaPs (biomimetic component) and pectin gel as cell carrier. hPDC populations encapsulated in pectin gels and injected into the FGHY scaffolds demonstrated the ability to differentiate toward the osteogenic lineage. The ability of these biomimetic hybrid scaffolds to stimulate cell adhesion and proliferation and to support differentiation of hPDCs make these scaffolds excellent candidates for an use in bone regeneration. PMID- 26736618 TI - Time-varying and simultaneous frequency stimulation for multi-class SSVEP-based brain-computer interface. AB - In recent years, there has been increasing interest in using steady-state visual evoked potentials (SSVEP) in brain-computer interface (BCI) systems for their high signal to noise ratio. However, due to the limitations of brain physiology and the refresh rate of the display devices, the available stimulation frequencies that evoke strong SSVEPs are limited. The goal of this paper is to investigate time-varying and simultaneous frequency stimulation in order to increase the number of visual stimuli with a fixed number of stimulation frequencies in multiclass SSVEP-based BCI systems. This study analyzes the SSVEPs induced by groups of light-emitting diodes (LEDs). The proposed method produces more selections than the number of stimulation frequencies through an efficient combination of time-varying and simultaneous frequencies for stimulation. The feasibility and effectiveness of our proposed method was confirmed by a set of experiments conducted on six subjects. The results confirmed that our proposed stimulation is a promising method to increase the number of stimuli using a fixed number of frequencies for multi-class SSVEP-based BCI tasks. PMID- 26736619 TI - EEG error potentials detection and classification using time-frequency features for robot reinforcement learning. AB - In thought-based steering of robots, error potentials (ErrP) can appear when the action resulting from the brain-machine interface (BMI) classifier/controller does not correspond to the user's thought. Using the Steady State Visual Evoked Potentials (SSVEP) techniques, ErrP, which appear when a classification error occurs, are not easily recognizable by only examining the temporal or frequency characteristics of EEG signals. A supplementary classification process is therefore needed to identify them in order to stop the course of the action and back up to a recovery state. This paper presents a set of time-frequency (t-f) features for the detection and classification of EEG ErrP in extra-brain activities due to misclassification observed by a user exploiting non-invasive BMI and robot control in the task space. The proposed features are able to characterize and detect ErrP activities in the t-f domain. These features are derived from the information embedded in the t-f representation of EEG signals, and include the Instantaneous Frequency (IF), t-f information complexity, SVD information, energy concentration and sub-bands' energies. The experiment results on real EEG data show that the use of the proposed t-f features for detecting and classifying EEG ErrP achieved an overall classification accuracy up to 97% for 50 EEG segments using 2-class SVM classifier. PMID- 26736620 TI - Online control of a humanoid robot through hand movement imagination using CSP and ECoG based features. AB - Intention recognition through decoding brain activity could lead to a powerful and independent Brain-Computer-Interface (BCI) allowing for intuitive control of devices like robots. A common strategy for realizing such a system is the motor imagery (MI) BCI using electroencephalography (EEG). Changing to invasive recordings like electrocorticography (ECoG) allows extracting very robust features and easy introduction of an idle state, which might simplify the mental task and allow the subject to focus on the environment. Especially for multi channel recordings like ECoG, common spatial patterns (CSP) provide a powerful tool for feature optimization and dimensionality reduction. This work focuses on an invasive and independent MI BCI that allows triggering from an idle state, and therefore facilitates tele-operation of a humanoid robot. The task was to lift a can with the robot's hand. One subject participated and reached 95.4 % mean online accuracy after six runs of 40 trials. To our knowledge, this is the first online experiment with a MI BCI using CSPs from ECoG signals. PMID- 26736621 TI - Single-Trial Classification of Multi-User P300-Based Brain-Computer Interface Using Riemannian Geometry. AB - The classification of electroencephalographic (EEG) data recorded from multiple users simultaneously is an important challenge in the field of Brain-Computer Interface (BCI). In this paper we compare different approaches for classification of single-trials Event-Related Potential (ERP) on two subjects playing a collaborative BCI game. The minimum distance to mean (MDM) classifier in a Riemannian framework is extended to use the diversity of the inter-subjects spatio-temporal statistics (MDM-hyper) or to merge multiple classifiers (MDM multi). We show that both these classifiers outperform significantly the mean performance of the two users and analogous classifiers based on the step-wise linear discriminant analysis. More importantly, the MDM-multi outperforms the performance of the best player within the pair. PMID- 26736622 TI - Feature Extraction for BCIs Based on Electromagnetic Source Localization and Multiclass Filter Bank Common Spatial Patterns. AB - Brain-Computer Interfaces (BCIs) provide means for communication and control without muscular movement and, therefore, can offer significant clinical benefits. Electrical brain activity recorded by electroencephalography (EEG) can be interpreted into software commands by various classification algorithms according to the descriptive features of the signal. In this paper we propose a novel EEG BCI feature extraction method employing EEG source reconstruction and Filter Bank Common Spatial Patterns (FBCSP) based on Joint Approximate Diagonalization (JAD). The proposed method is evaluated by the commonly used reference EEG dataset yielding an average classification accuracy of 77.1 +/- 10.1 %. It is shown that FBCSP feature extraction applied to reconstructed source components outperforms conventional CSP and FBCSP feature extraction methods applied to signals in the sensor domain. PMID- 26736623 TI - Classifying the auditory P300 using mobile EEG recordings without calibration phase. AB - One of the major drawbacks in mobile EEG Brain Computer Interfaces (BCI) is the need for subject specific training data to train a classifier. By removing the need for supervised classification and calibration phase, new users could start immediate interaction with a BCI. We propose a solution to exploit the structural difference by means of canonical polyadic decomposition (CPD) for three-class auditory oddball data without the need for subject-specific information. We achieve this by adding average event-related-potential (ERP) templates to the CPD model. This constitutes a novel similarity measure between single-trial pairs and known-templates, which results in a fast and interpretable classifier. These results have similar accuracy to those of the supervised and cross-validated stepwise LDA approach but without the need for having subject-dependent data. Therefore the described CPD method has a significant practical advantage over the traditional and widely used approach. PMID- 26736624 TI - Wiener-Granger causality in QT-HP variability interactions. AB - The study exploits a Wiener-Granger causality (WGC) approach in the time domain to assess directionality of the dynamical interactions between QT interval and heart period (HP) during a graded head-up tilt protocol challenging the cardiovascular control as a function of the tilt table inclination. QT interval and HP are approximated from the surface ECG as the temporal distance between the R-wave apex and T-wave offset and between two consecutive R-wave peaks respectively. The adopted WGC approach accounts for the confounding effect of respiration (RESP) affecting both QT and HP. Causality ratios (CRs) from HP to QT given RESP (CRHP->QT|RESP) and from QT to HP given RESP (CRQT->HP|RESP) were computed and their significance was tested via F-test. We found that, regardless of the tilt table angle, CRHP->QT|RESP is significant, while CRQT->HP|RESP is negligible. CRHP->QT|RESP showed a trend towards a decrease with tilt table angle. These findings suggested that the causal direction from HP over QT is dominant compared to the reverse one and sympathetic activation induced a QT-HP uncoupling. PMID- 26736625 TI - Assessing cerebral blood flow control from variability in blood pressure and arterial CO2 levels. AB - Blood flow to the brain is controlled by a number of physiological mechanisms that respond to changes in arterial blood pressure, arterial CO2 levels and many other factors. Assessing the integrity of this control system is a major challenge. We report on repeatability of measures based on single and multiple input models during spontaneous and enhanced fluctuations in blood pressure. PMID- 26736626 TI - Algorithms for the inference of causality in dynamic processes: Application to cardiovascular and cerebrovascular variability. AB - This study faces the problem of causal inference in multivariate dynamic processes, with specific regard to the detection of instantaneous and time-lagged directed interactions. We point out the limitations of the traditional Granger causality analysis, showing that it leads to false detection of causality when instantaneous and time-lagged effects coexist in the process structure. Then, we propose an improved algorithm for causal inference that combines the Granger framework with the approach proposed by Pearl for the study of causality among multiple random variables. This new approach is compared with the traditional one in theoretical and simulated examples of interacting processes, showing its ability to retrieve the correct structure of instantaneous and time-lagged interactions. These approaches for causal inference are then tested on the physiological variability series of heart period, arterial pressure and cerebral blood flow variability obtained in subjects with postural-related syncope during a tilt-test protocol. PMID- 26736627 TI - Causal coherence analysis of cardiovascular variables in obese preadolescents and adolescents. AB - Obesity during adulthood has been associated with cardiovascular disease, but its adverse effects during adolescence are less well established. The aim of this study was to probe cardiovascular control in obese adolescence by studying causal coherence between cardiovascular variables. Sixty minutes of resting ECG and finger blood pressure were recorded in 19 obese and 19 non-obese subjects in the supine position to measure pair-wise spectral coherence in the low frequency band between heart rate, systolic and diastolic blood pressure, pulse pressure, total peripheral resistance and left ventricular ejection time. We observed that causal coherences in {systolic blood pressure -> total peripheral resistance} and {left ventricular ejection time -> systolic blood pressure} directions were significantly decreased in obese preadolescents and adolescents when compared to the healthy control group, despite the lack of difference in the magnitude of oscillations of cardiovascular variables. In conclusion, causal coherence analysis of cardiovascular variables may give new insight into cardiovascular dysregulation in young obese subjects. PMID- 26736628 TI - Measuring heart rate variability by means of information entropies based on Choi Williams distribution. AB - The Shannon entropy theory was applied to the Choi-Williams time-frequency distribution (CWD) of cardiac time series (RR series) in order to extract entropy information in both time and frequency domains. From this distribution, four indexes were defined: (1) instantaneous partial entropy; (2) spectral partial entropy; (3) instantaneous complete entropy; (4) spectral complete entropy. These indexes were used for analyzing the heart rate variability of ischemic cardiomyopathy patients (ICM) with different sudden cardiac death risk. The results have shown that the values of these indexes tend to decrease, with different proportion, when the severity of pathological condition increases. Statistical differences (p-value < 0.0005) of these indexes were found comparing low risk and high risk of cardiac death during night and between daytime and nighttime periods of ICM patients. Finally, these indexes have demonstrated to be useful tools to quantify the different complex components of the cardiac time series. PMID- 26736629 TI - Symbolic dynamics of pulse transit time and heart period in children with upper airway obstruction. AB - Upper airway obstruction (UAO) is a relatively common condition during childhood that is characterized by periods of partial or complete upper airway closure, resulting in restless sleep. It has also been suggested that UAO triggers early cardiovascular changes that may predispose to an increased risk of developing cardiovascular diseases later in life. The aim of this study was to assess the temporal dynamics of heart period (HP) and pulse transit time (PTT) during quite, event-free periods of sleep in children with UAO (n = 40) and matched healthy controls. The dynamics of HP and PTT were symbolized based on the sextiles of their distribution and words of length three were formed and classified into four types based on their patterns. Joint symbolic dynamics represent the concomitant occurrence of words in HP and PTT. Children with UAO showed a significantly increased frequency in word types of monotonously increasing and decreasing HP and PTT as well as joint dynamics across all stages of sleep. The dynamics of HP showed a marked sleep stage dependence, while PTT dynamics appeared to be relatively unaffected. In conclusion, cardiovascular dynamics are altered in children with UAO during scored event-free sleep, indicative of frequent bursts in sympathetic nervous system activity, possibly reflecting subcortical arousal responses to brief and subtle increases in UAO. PMID- 26736630 TI - Evaluation of performance to detect default mode network among some algorithms applied to resting-state fMRI data. AB - Significant correlation exists in the blood-oxygen-level-dependent (BOLD) signals of resting-state fMRI across different regions in the brain. These regions form the default mode network (DMN), salience network (SN), sensory networks, and others. Among these, the DMN is widely investigated in relation to various mental diseases. Several analytic methods are available for obtaining the DMN activity from individuals' fMRI time-series signals, but a fully effective method has not yet been established. In the present study, we examined a functional connectivity analysis and three algorithms of blind source separation including independent component analysis, second-order blind identification, and non-negative matrix factorization using a set of resting-state fMRI data measured for twelve young participants. Results showed that the second-order blind identification yielded superior performance for the DMN detection, indicating significant activation in all DMN regions based on statistical parametric maps. PMID- 26736631 TI - Arterial CO2 effects modulate dynamic functional connectivity in resting-state fMRI. AB - It is well known that the blood-oxygen level dependent (BOLD) signal measured by functional magnetic resonance imaging (fMRI) is influenced - in addition to neuronal activity - by fluctuations in physiological signals, including arterial CO2. For instance, even spontaneous CO2 fluctuations have been shown to influence the BOLD fMRI signal regionally. Related to this, studies of functional connectivity between different brain regions, performed when the subject is at rest, may be confounded by the effects of physiological noise. Moreover, resting functional connectivity has been shown to vary with respect to time (dynamic functional connectivity), with the sources of this variation not fully understood at present. In this context, in the present paper we examine the relation between dynamic functional connectivity patterns and the properties of the end-tidal CO2 signal (PETCO2) using resting-state fMRI measurements from 12 healthy subjects. The results demonstrate that there exists a modulatory effect of the correlation strength between PETCO2 and the BOLD signal on dynamic resting functional connectivity. The extent to which this effect was observed was found to be strongly dependent on the data analysis methodology. PMID- 26736632 TI - Effects of acute electromagnetic fields exposure on the interhemispheric homotopic functional connectivity during resting state. AB - In this paper, we aimed to investigate the possible effects of acute radiofrequency electromagnetic fields (EMF) on the interhemispheric homotopic functional connectivity with resting state functional magnetic resonance imaging (fMRI) technique. We designed a controllable LTE-related EMF exposure environment at 2.573 GHz and performed the 30 min real/sham exposure experiments on human brain under the safety limits. The resting state fMRI signals were collected before and after EMF exposure. Then voxel-mirrored homotopic connectivity method was utilized to evaluate the acute effects of LTE EMF exposure on the homotopic functional connectivity between two human hemispheres. Based on our previous research, we further demonstrated that the 30 min short-term LTE EMF exposure would modulate the interhemispheric homotopic functional connectivity in resting state around the medial frontal gyrus and the paracentral lobule during the real exposure. PMID- 26736633 TI - Independent Component versus Local Sparse Component Analysis in Resting State fMRI. AB - Independent Component Analysis (ICA) algorithms are potentially powerful ways of localizing sources of cerebral activity in resting state functional Magnetic Resonance Imaging (fMRI). But the assumptions underling the nature of identified sources limits this tool. By creating local one-dimensional approximations, Local Sparse Component Analysis (LSCA) can separate contiguous sources on the basis of their sparse representation into smoothness spaces via the 3D wavelet transformation. In this paper we systematically compare Probabilistic ICA (PICA) and LSCA for analyzing resting state fMRI across healthy participants. We show that the PICA sources usually representing biologically plausible components can in fact be decomposed into several LSCA sources that are not necessarily independent from each other. In addition, we show that LSCA identifies sources that approximate much better the local variations of the blood oxygenation level dependent (BOLD) signal than PICA sources. PMID- 26736634 TI - Emergence of the default-mode network from resting-state to activation-state in reciprocal social interaction via eye contact. AB - The default-mode network has been identified as a resting state BOLD response that is often associated with self-referential or sensory task-passive processes. Many recent studies reveal that this vaguely defined network often plays an essential role in many pervasive mental diseases. By taking advantage of the recent development of dyadic fMRI, this study presents the initial experimental evidence that the default-mode network emerges from resting-state to activation state in social interaction during live eye contact. Moreover, by comparing the BOLD responses between dyadic fMRI and monadic fMRI, it suggests that live eye contact excites empathy networks in the exogenous system which further activates the default mode network in endogenous system; whereas seeing eyes in face pictures activates completely different brain responses in which the default-mode network remains in resting-state. PMID- 26736635 TI - Object categories specific brain activity classification with simultaneous EEG fMRI. AB - Any kind of visual information is encoded in terms of patterns of neural activity occurring inside the brain. Decoding neural patterns or its classification is a challenging task. Functional magnetic resonance imaging (fMRI) and Electroencephalography (EEG) are non-invasive neuroimaging modalities to capture the brain activity pattern in term of images and electric potential respectively. To get higher spatiotemporal resolution of human brain from these two complementary neuroimaging modalities, simultaneous EEG-fMRI can be helpful. In this paper, we proposed a framework for classifying the brain activity patterns with simultaneous EEG-fMRI. We have acquired five human participants' data with simultaneous EEG-fMRI by showing different object categories. Further, combined analysis of EEG and fMRI data was carried out. Extracted information through combine analysis is passed to support vector machine (SVM) classifier for classification purpose. We have achieved better classification accuracy using simultaneous EEG-fMRI i.e., 81.8% as compared to fMRI data standalone. This shows that multimodal neuroimaging can improve the classification accuracy of brain activity patterns as compared to individual modalities reported in literature. PMID- 26736636 TI - Smart helmet: Monitoring brain, cardiac and respiratory activity. AB - The timing of the assessment of the injuries following a road-traffic accident involving motorcyclists is absolutely crucial, particularly in the events with head trauma. Standard apparatus for monitoring cardiac activity is usually attached to the limbs or the torso, while the brain function is routinely measured with a separate unit connected to the head-mounted sensors. In stark contrast to these, we propose an integrated system which incorporates the two functionalities inside an ordinary motorcycle helmet. Multiple fabric electrodes were mounted inside the helmet at positions featuring good contact with the skin at different sections of the head. The experimental results demonstrate that the R-peaks (and therefore the heart rate) can be reliably extracted from potentials measured with electrodes on the mastoids and the lower jaw, while the electrodes on the forehead enable the observation of neural signals. We conclude that various vital sings and brain activity can be readily recorded from the inside of a helmet in a comfortable and inconspicuous way, requiring only a negligible setup effort. PMID- 26736637 TI - Accelerometer body sensor network improves systolic time interval assessment with wearable ballistocardiography. AB - Systolic time intervals (STI) are non-invasive measures of cardiac function. Due to the fact that STI can be measured noninvasively outside the clinic, STI are a promising method for long-term monitoring of patients with cardiovascular disease. In particular, the pre-ejection period (PEP) has been measured successfully from body vibrations of the beating heart, a technique called ballistocardiography (BCG), using a weighing scale. Similar measurements can be made with on-body accelerometers, however these wearable BCG signals are typically more challenging to interpret than whole-body BCG. In this paper, we conducted a small pilot study with four subjects to investigate whether a body sensor network of four accelerometers positioned on the wrist, arm, sternum, and head could improve beat-by-beat PEP prediction beyond that of each sensor alone. Linear models were fitted from the R-J and R-I intervals of the four BCG signals to PEP measured with impedance cardiography from 5-minute recordings after isometric lower-body exercise. Specifically, we found that (i) the RMS error of PEP estimation from the wearable BCG sensors can be reduced by using double integration, (ii) the standard deviation of PEP estimates from R-I intervals was smaller than from R-J intervals, and (iii) linear models combining both R-J and R I measurements from all sensors resulted in the best average correlation (r(2) = 0.96 +/- 0.01) and lowest average root mean square error (2.5 +/- 0.8 ms) from 5*2-fold cross validation. PMID- 26736638 TI - Periodic leg movement (PLM) monitoring using a distributed body sensor network. AB - Wireless sensors networks represent the architecture of choice for distributed monitoring due to the ease of deployment and configuration. We developed a distributed sleep monitoring system which combines wireless inertial sensors SP 10C by Sensoplex controlled by a custom smartphone application as an extension of the polysomnographic (PSG) monitor SOMNOscreen plus from Somnomedics. While existing activity monitors are wired to the SOMNOscreen, our system allows the use of wireless inertial sensors to improve user's comfort during sleep. The system is intended for monitoring of periodic leg movements (PLM) and user's activity during sleep. Wireless sensors are placed on ankle and toes of the foot in a customized sock. An Android app communicates with wireless sensors over Bluetooth Smart (BTS) link and streams 3D accelerometer values, 4D unit quaternion values and timestamps. In this paper we present a novel method of synchronization of data streams from PSG and inertial sensors, and original method of detection of PLM events. The system was tested using five experiments of simulated PLM, and achieved 96.51% of PLM detection accuracy. PMID- 26736639 TI - Magnetic human body communication. AB - This paper presents a new human body communication (HBC) technique that employs magnetic resonance for data transfer in wireless body-area networks (BANs). Unlike electric field HBC (eHBC) links, which do not necessarily travel well through many biological tissues, the proposed magnetic HBC (mHBC) link easily travels through tissue, offering significantly reduced path loss and, as a result, reduced transceiver power consumption. In this paper the proposed mHBC concept is validated via finite element method simulations and measurements. It is demonstrated that path loss across the body under various postures varies from 10-20 dB, which is significantly lower than alternative BAN techniques. PMID- 26736640 TI - Human body and head characteristics as a communication medium for Body Area Network. AB - An in-depth investigation of the Body Channel Communication (BCC) under the environment set according to the IEEE 802.15.6 Body Area Network (BAN) standard is conducted to observe and characterize the human body as a communication medium. A thorough measurement of the human head as part of the human channel is also carried out. Human forehead, head to limb, and ear to ear channel is characterized. The channel gain of the human head follows the same bandpass profile of the human torso and limbs with the maximum channel gain occurring at 35MHz. The human body channel gain distribution histogram at given frequencies, while all the other parameters are held constant, exhibits a maximum variation of 2.2dB in the channel gain at the center frequency of the bandpass channel gain profile. PMID- 26736641 TI - Smart photoplethysmographic sensor for pulse wave registration at different vascular depths. AB - The aim of this paper is to propose a smart optical sensor for cardiovascular activity monitoring at different tissue layers. Photoplethysmography (PPG) is a noninvasive optical technique for monitoring mainly blood volume changes in the examined tissue. However, different important physiological parameters, such as oxygen saturation, heart and breathing rate, dynamics of skin micro-circulation, vasomotion activity etc., can be extracted from the registered PPG signal. The developed sensor consists of 32 light emitting sources with four different wavelengths, which are located to the four different distances from four photo detectors. Compared to the existing sensors, the system enables to select the optimal LED (light emitting diode) and photo detector couple in order to obtain the pulse wave signal from the interested blood vessels with the highest possible signal to noise ratio. In this study, the designed PPG sensor was tested for the pulse wave registration from radial artery. The highest efficiency and signal to noise ratio was achieved using infrared LED (940 nm) and photo-diode pair. PMID- 26736642 TI - Using microfluidics to investigate tumor cell extravasation and T-cell immunotherapies. AB - Understanding the mechanism of tumor cell extravasation, cell migration and the role of the immunosystem is crucial in creating targeted and patient-specific cancer therapies. We created an in-vitro microfluidic cell extravasation assay, incorporating a microvascular network and demonstrated its use to study cancer cells extravasation. Separately, we developed an assay for screening T-cell migration and cytotoxicity as a means to evaluate the efficiency of adoptive immunotherapies against cancer. Similar devices using a similar platform can be used to recreate a tumor liver microenvironment, taking in consideration the hypoxic and inflammatory conditions in the liver. These platforms show considerable potential as efficient pre-clinical models for testing the efficiency of cancer drugs and engineered T-cell functionality for personalized medicine. PMID- 26736643 TI - A strain-dependent diffusivity model to study the nuclear import of mechanobiological transcription factors. AB - Nuclear spreading plays a crucial role in stem cell fate determination. In previous works, we reported evidence of multipotency maintenance of mesenchymal stromal cells cultured on three-dimensional engineered niche substrates fabricated via two-photon laser polymerization (2PP). We correlated multipotency maintenance to a more roundish nuclear morphology of cells cultured in the 2PP fabricated niches, with respect to those on flat substrates. To interpret these findings, here we present a multiphysics model coupling nuclear strains induced by cell adhesion to diffusive transport across the cell nucleus. We reconstructed the cell nuclear geometry from confocal Z-stack images of 2PP-cultured cells, and we estimated the volume, surface and shape factors. The levels of nuclear spreading significantly varied depending on the cell localization within the niche architecture. We assumed the cell diffusivity as a function of the local volumetric strain. The computational model also indicate that the larger the nuclear deformation (e.g. in spread nuclei), the higher the nuclear flux of small solutes such as transcription factors through the nuclear membrane. Our results point towards nuclear deformation as a primary mechanism by which the stem cell translates its shape into a fate decision, i.e. through a strain-dependent amplification of the diffusive flow of signaling molecules into the nucleus. PMID- 26736644 TI - Real-time deformability cytometry as a label-free indicator of cell function. AB - The mechanical properties of cells are known to be a label-free, inherent marker of biological function in health and disease. Wide-spread utilization has so far been impeded by the lack of a convenient measurement technique with sufficient throughput. To address this unmet need, we have recently introduced real-time deformability cytometry (RT-DC) for continuous mechanical single-cell classification of heterogeneous cell populations at rates of several hundred cells per second. Cells are driven through the constriction zone of a microfluidic chip leading to cell deformations due to hydrodynamic stresses only. Our custom-built image processing software performs image acquisition, image analysis and data storage on the fly. The ensuing deformations can be quantified and an analytical model enables the derivation of cell material properties. Performing RT-DC we highlight its potential to identify rare objects in heterogeneous suspensions and to track drug-induced changes in cells. In summary, RT-DC enables marker-free, quantitative phenotyping of heterogeneous cell populations with a throughput comparable to standard flow cytometry. PMID- 26736645 TI - Modulation of cellular responses: The two-photon polymerization approach in the control of the physical micro/nanoenvironment. AB - Cells and tissues are extremely sensitive to their physico-chemical surroundings: in regenerative medicine, as an example, the maintenance of culture conditions resembling the in vivo environment is essential for a correct tissue development. In this review, we summarize our results concerning the preparation and testing of micro/nanostructures for fostering peculiar cellular behavior, prepared by exploiting an innovative technique of high resolution 3D photolithography, the two-photon polymerization (2pp). PMID- 26736646 TI - Theory and application of arterial tissue in-host remodelling. AB - A central therapeutic goal in many applications of modern Biomedicine is the reconstruction of the diseased arterial sections via robust and viable tissue equivalents. In-host remodelling is an emerging technology that exploits the remodelling ability of the host to regenerate tissue. We develop a general theoretical framework of growth and remodeling of arterial tissue starting from a synthetic, degradable, acellularized graft and we demonstrate the potential of mechanistic models to guide the development and assisting in the design of arterial tissue engineered constructs. PMID- 26736647 TI - Tissue motion due to needle deflection. AB - Various concepts of steerable needles have been developed in order to reduce placement errors during insertions and to enable complex procedures through curved trajectories in minimally invasive surgery. When inserted into soft tissue, motion of the targeted location ahead of the needle tip has to be taken into account for controlling such tools. This paper investigates the motion caused by flexible bending needles in comparison to rigid straight ones when inserted into a homogeneous tissue phantom. A laser based experimental setup is used to measure displacements of the substrate around the needles. Displacements are transformed into the local frame in order to quantify the relative substrate motion. It is shown that the radial contribution of the displacements is higher for bending needles and that this effect increases with higher path curvatures. This motion must be taken into account for controlling steerable needles along curved trajectories to reduce placement errors in applications such as multi targeting or reinsertions in soft tissue. PMID- 26736648 TI - Modeling of blood flow through sutured micro-vascular anastomoses. AB - Microanastomosis is a surgical procedure used to reconnect two blood vessels using sutures. The optimal microanastomosis may be predicted by assessing the factors that influence this invasive procedure. Blood flow and hemodynamics following microanastomosis are important factors for the successful longevity of this operation. How is the blood flow affected by the presence of sutures? Computational Fluid Dynamics (CFD) is a powerful tool that permits the estimation of specific quantities, such as fluid stresses, that are hardly measurable in vivo. In this study, we propose a methodology which evaluates the alterations in the hemodynamic status due to microanastomosis. A CFD model of a reconstructed artery has been developed, based on anatomical information provided by intravascular ultrasound and angiography, and was used to simulate blood flow after microanastomosis. The 3D reconstructed arterial segments are modeled as non compliant 1.24 - 1.47 mm diameter ducts, with approximately 0.1 mm arterial thickness. The blood flow is considered laminar and the no-slip condition is imposed on the boundary wall, which is assumed to be rigid. In analyzing the results, the distribution of the wall shear stress (WSS) is presented in the region of interest, near the sutures. The results indicate that high values of WSS appear in the vicinity of sutures. Such regions may promote thrombus formation and subsequently anastomotic failure, therefore their meticulous study is of high importance. PMID- 26736649 TI - Simulation of aortic valve dynamics during ventricular support. AB - Existing commercially-used left ventricular assist devices (LVADs) make no attempt to automatically detect the aortic valve condition in their control methods to optimize ventricular assistance. An important design goal for LVADs is the ability to reliably and accurately detect aortic valve (AV) states during heart pump support that can cause harmful effects on AV structure and function. In this paper, we have investigated the correlation between AV performance and LVAD motor current as well as speed set points, simulating aortic valve blood flow, pressure, pump flow and LV mechanics using a simplified two-dimensional fluid-structure interaction finite-element model of AV dynamics. PMID- 26736650 TI - Modeling of neonatal hemodynamics during PDA closure. AB - The transition of the fetus at birth to extrauterine life is an extremely complex process. As part of the hemodynamic transition, the closure of ductus arteriosus, a fetal shunt, is among the key steps to achieve normal postnatal cardiovascular function. However, significant gaps remain in our knowledge pertaining to the hemodynamics of normal ductal closure, and in case of failure of closure, to the hemodynamic consequences and treatment of the patent ductus arteriosus (PDA) in preterm infants. This paper presents a mathematical model of a newborn's cardiovascular system with five peripheral organ systems, the ductus arteriosus, and the baroreceptor reflex. We present the hemodynamic findings during simulation of sudden ductal closure, an event seen in real life when the PDA is closed surgically. The results of our model match the clinical data. PMID- 26736651 TI - Development of a cerebral circulation model for the automatic control of brain physiology. AB - In various clinical guidelines of brain injury, intracranial pressure (ICP), cerebral blood flow (CBF) and brain temperature (BT) are essential targets for precise management for brain resuscitation. In addition, the integrated automatic control of BT, ICP, and CBF is required for improving therapeutic effects and reducing medical costs and staff burden. Thus, a new model of cerebral circulation was developed in this study for integrative automatic control. With this model, the CBF and cerebral perfusion pressure of a normal adult male were regionally calculated according to cerebrovascular structure, blood viscosity, blood distribution, CBF autoregulation, and ICP. The analysis results were consistent with physiological knowledge already obtained with conventional studies. Therefore, the developed model is potentially available for the integrative control of the physiological state of the brain as a reference model of an automatic control system, or as a controlled object in various control simulations. PMID- 26736652 TI - Morphological analysis of pressure wave in the arterial tree with stenosis - a modeling approach. AB - This paper describes the morphological changes in peripheral signals due to arterial diseases with various severity conditions and site of stenosis using modeling approaches, and its effect in the morphological parameters of radial artery. As stenosis induces abrupt change in geometry and elastic properties of arterial tree (constitutes major reflection sites), hybrid model is well suited for studying the changes in shape of the pressure and flow wave transmitted through the stenosis. These morphological changes in wave shape of peripheral signal have significant diagnostic value in both modern and traditional medicine systems. It can be used for the quantitative assessment of the severity of the arterial diseases. PMID- 26736653 TI - A method for localized computation of Pulse Wave Velocity in carotid structure. AB - Pulse Wave Velocity (PWV) promises to be a useful clinical marker for noninvasive diagnosis of atherosclerosis. This work demonstrates the ability to perform localized carotid PWV measurements from the distention waveform derived from the Radio Frequency (RF) ultrasound signal using a carotid phantom setup. The proposed system consists of low cost custom-built ultrasound probe and algorithms for envelope detection, arterial wall identification, echo tracking, distension waveform computation and PWV estimation. The method is proposed on a phantom data acquired using custom-built prototype non-imaging probe. The proposed approach is non-image based and can be seamlessly integrated into existing clinical ultrasound scanners. PMID- 26736654 TI - Improved concept and first results of an auditory single-switch BCI for the future use in disorders of consciousness patients. AB - A promising approach to establish basic communication for disorders of consciousness (DOC) patients, is the application of Brain-Computer Interface (BCI) systems, especially the use of single-switch BCIs (ssBCIs). Recently we proposed the concept of a novel auditory ssBCI paradigm and presented first classification results. In this study we report on the evaluation of four different modifications of the original paradigm with the intention to increase the suitability. Therefore we investigated different sound types and the inclusion of additional spatial information. Finally, the classification investigation with the most encouraging modifications shows an enhancement compared to our original paradigm, within healthy subjects, implicating better results for the future use in DOC patients. PMID- 26736655 TI - Chromatic and high-frequency cVEP-based BCI paradigm. AB - We present results of an approach to a code-modulated visual evoked potential (cVEP) based brain-computer interface (BCI) paradigm using four high-frequency flashing stimuli. To generate higher frequency stimulation compared to the state of-the-art cVEP-based BCIs, we propose to use the light-emitting diodes (LEDs) driven from a small micro-controller board hardware generator designed by our team. The high-frequency and green-blue chromatic flashing stimuli are used in the study in order to minimize a danger of a photosensitive epilepsy (PSE). We compare the the green-blue chromatic cVEP-based BCI accuracies with the conventional white-black flicker based interface. The high-frequency cVEP responses are identified using a canonical correlation analysis (CCA) method. PMID- 26736656 TI - Inter-stimulus interval study for the tactile point-pressure brain-computer interface. AB - The paper presents a study of an inter-stimulus interval (ISI) influence on a tactile point-pressure stimulus-based brain-computer interface's (tpBCI) classification accuracy. A novel tactile pressure generating tpBCI stimulator is also discussed, which is based on a three-by-three pins' matrix prototype. The six pin-linear patterns are presented to the user's palm during the online tpBCI experiments in an oddball style paradigm allowing for "the aha-responses" elucidation, within the event related potential (ERP). A subsequent classification accuracies' comparison is discussed based on two ISI settings in an online tpBCI application. A research hypothesis of classification accuracies' non-significant differences with various ISIs is confirmed based on the two settings of 120 ms and 300 ms, as well as with various numbers of ERP response averaging scenarios. PMID- 26736657 TI - Accurate single-trial detection of movement intention made possible using adaptive wavelet transform. AB - The outlook of brain-computer interfacing (BCI) is very bright. The real-time, accurate detection of a motor movement task is critical in BCI systems. The poor signal-to-noise-ratio (SNR) of EEG signals and the ambiguity of noise generator sources in brain renders this task quite challenging. In this paper, we demonstrate a novel algorithm for precise detection of the onset of a motor movement through identification of event-related-desynchronization (ERD) patterns. Using an adaptive matched filter technique implemented based on an optimized continues Wavelet transform by selecting an appropriate basis, we can detect single-trial ERDs. Moreover, we use a maximum-likelihood (ML), electrooculography (EOG) artifact removal method to remove eye-related artifacts to significantly improve the detection performance. We have applied this technique to our locally recorded Emotiv((r)) data set of 6 healthy subjects, where an average detection selectivity of 85 +/- 6% and sensitivity of 88 +/- 7.7% is achieved with a temporal precision in the range of -1250 to 367 ms in onset detections of single-trials. PMID- 26736658 TI - Event-related modulation of steady-state visual evoked potentials for eyes-closed brain computer interface. AB - Brain computer interfaces (BCIs), also be referred to be as brain machine interfaces, transform modulations of electroencephalogram (EEG) into user's intents to communicate with others without voice and physical movement. BCIs have been studied and developed as one of the important means for communication-aid between disabled with severe motor disabilities such as amyotrophic lateral sclerosis and muscular dystrophy patients and their caregivers. State-of-art BCIs have achieved the outstanding performance in information transfer rate and classification accuracy. However, most of conventional BCIs are still unavailable for patients with impaired oculomotor control due to requirement of visual modality. The present study aimed at developing a novel 2-class BCI which was independent of oculomotor control including eye-opening using event-related modulation of steady state visual evoked potential (SSVEP) associated with mental tasks under eyes-closed condition. Eleven healthy subjects aged 21-24 years old were recruited and directed to perform each of two mental tasks under an eyes closed condition; mental focus on flicker stimuli and image recall of their favorite animals, respectively. The magnitudes of SSVEP in the posterior regions of almost all the subjects were seen to be modulated by performing the mental tasks under the conditions of the flickering frequency of 10 Hz and stimulus intensity of 3-5 lx, which was used to express a user's binary intent, namely, performing one of the mental tasks or not (rest). The classification performance on the mental focus, 80 %, was larger than that on the image recall, 75 %, in average across all the subjects. Shortening of the data length used for classification would improve the information transfer rate of the proposed BCI. PMID- 26736659 TI - Towards decoding of functional movements from the same limb using EEG. AB - In recent years, there has been an increasing interest in using electroencephalographic (EEG) activity to close the loop between brain oscillations and movement to induce functional motor rehabilitation. Rehabilitation robots or exoskeletons have been controlled using EEG activity. However, all studies have used a 2-class or one-dimensional decoding scheme. In this study we investigated EEG decoding of 5 functional movements of the same limb towards an online scenario. Six healthy participants performed a three dimensional center-out reaching task based on direction movements (four directions and rest) wearing a 32-channel EEG cap. A BCI design based on multiclass extensions of Spectrally Weighted Common Spatial Patterns (Spec-CSP) and a linear discriminant analysis (LDA) classifier was developed and tested offline. The decoding accuracy was 5-fold cross-validated. A decoding accuracy of 39.5% on average for all the six subjects was obtained (chance level being 20%). The results of the current study demonstrate multiple functional movements decoding (significantly higher than chance level) from the same limb using EEG data. This study represents first steps towards a same limb multi degree of freedom (DOF) online EEG based BCI for motor restoration. PMID- 26736660 TI - Comparison of three ICA algorithms for ocular artifact removal from TMS-EEG recordings. AB - The combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) is a powerful tool to investigate brain excitability and information processing in brain networks. However, EEG-TMS recordings are challenging because EEG is contaminated by powerful TMS-related artifacts. Because of these artifacts, different EEG-driven analyses (for instance, source analysis and analysis of information flow on the sensors and source level) reveal incorrect results. The aim of this study was to remove ocular artifacts from TMS EEG recordings following stimulation of motor cortex using three independent component analysis (ICA) algorithms and to evaluate the effectiveness of these algorithms. We showed that the temporal ICA algorithm better separates those components that contain time-locked eye blink artifacts. PMID- 26736661 TI - Artifact removal algorithms for stroke detection using a multistatic MIST beamforming algorithm. AB - Microwave imaging (MWI) has been recently proved as a promising imaging modality for low-complexity, low-cost and fast brain imaging tools, which could play a fundamental role to efficiently manage emergencies related to stroke and hemorrhages. This paper focuses on the UWB radar imaging approach and in particular on the processing algorithms of the backscattered signals. Assuming the use of the multistatic version of the MIST (Microwave Imaging Space-Time) beamforming algorithm, developed by Hagness et al. for the early detection of breast cancer, the paper proposes and compares two artifact removal algorithms. Artifacts removal is an essential step of any UWB radar imaging system and currently considered artifact removal algorithms have been shown not to be effective in the specific scenario of brain imaging. First of all, the paper proposes modifications of a known artifact removal algorithm. These modifications are shown to be effective to achieve good localization accuracy and lower false positives. However, the main contribution is the proposal of an artifact removal algorithm based on statistical methods, which allows to achieve even better performance but with much lower computational complexity. PMID- 26736662 TI - Automatic identification of artifacts in electrodermal activity data. AB - Recently, wearable devices have allowed for long term, ambulatory measurement of electrodermal activity (EDA). Despite the fact that ambulatory recording can be noisy, and recording artifacts can easily be mistaken for a physiological response during analysis, to date there is no automatic method for detecting artifacts. This paper describes the development of a machine learning algorithm for automatically detecting EDA artifacts, and provides an empirical evaluation of classification performance. We have encoded our results into a freely available web-based tool for artifact and peak detection. PMID- 26736663 TI - Extending the automated gastrointestinal analysis pipeline: Removal of invalid slow wave marks in gastric serosal recordings. AB - Gastric contractions are governed by a bioelectrical event known as slow waves. High-resolution electrical mapping has recently been applied to study complex gastric slow wave spatiotemporal propagations in detail. As these methods are translated to clinical and experimental applications, it is evident that efficient and automated methods are a necessity for analysis. Despite automated methods to detect slow wave events, manual review and correction remains necessary due to the presence of experimental noise in the recordings. Manual deletion of invalid slow wave events is time consuming and inefficient. We have therefore developed an algorithm to eliminate invalid markers of slow waves, via the use of frequency and morphological analysis. The techniques were validated with experimental data using serosal gastric slow wave recordings from animals and humans with a sensitivity of 90% and specificity of 85%. It is anticipated these methods will facilitate analyzing high-resolution slow wave mapping data and accelerate clinical translation of electrical mapping to clinical and diagnostic gastroentrology. PMID- 26736664 TI - Investigating effects of different artefact types on motor imagery BCI. AB - Artefacts in recordings of the electroencephalogram (EEG) are a common problem in Brain-Computer Interfaces (BCIs). Artefacts make it difficult to calibrate from training sessions, resulting in low test performance, or lead to artificially high performance when unintentionally used for BCI control. We investigate different artefacts' effects on motor-imagery based BCI relying on Common Spatial Patterns (CSP). Data stem from an 80-subject BCI study. We use the recently developed classifier IC_MARC to classify independent components of EEG data into neural and five classes of artefacts. We find that muscle, but not ocular, artefacts adversely affect BCI performance when all 119 EEG channels are used. Artefacts have little influence when using 48 centrally located EEG channels in a configuration previously found to be optimal. PMID- 26736665 TI - Automatic detection and removal of muscle artifacts from scalp EEG recordings in patients with epilepsy. AB - Automatic detection and removal of muscle artifacts plays an important role in long-term scalp electroencephalography (EEG) monitoring, and muscle artifact detection algorithms have been intensively investigated. This paper proposes an algorithm for automatic muscle artifacts detection and removal using canonical correlation analysis (CCA) and wavelet transform (WT) in epochs from long-term EEG recordings. The proposed method first performs CCA analysis and then conducts wavelet decomposition on the canonical components within a specific frequency range and selects a subset of the wavelet coefficients for subsequent processing. A set of features, including the mean of wavelet coefficients and the canonical component autocorrelation values, are extracted from the above analysis and subsequently used as input in a random forest (RF) classifier. The RF classifier produces a similarity measure between observations and selects a subset of the most important features by comparing the original data with a set of synthetic data that is constructed based on the latter. The RF predictor output is finally used in combination with unsupervised clustering algorithms to discriminate between contaminated and non-contaminated EEG epochs. The proposed method is evaluated in epochs of 30 min from scalp EEG recordings obtained from three patients with epilepsy and yields a sensitivity of 71% and 80%, as well as a specificity of 81% and 85% for k-means and spectral clustering, respectively. PMID- 26736666 TI - Point-process high-resolution representations of heartbeat dynamics for multiscale analysis: A CHF survivor prediction study. AB - Multiscale analysis of human heartbeat dynamics has been proved effective in characterizeing cardiovascular control physiology in health and disease. However, estimation of multiscale properties can be affected by the interpolation procedure used to preprocess the unevenly sampled R-R intervals derived from the ECG. To this extent, in this study we propose the estimation of wavelet coefficients and wavelet leaders on the output of inhomogeneous point process models of heartbeat dynamics. The RR interval series is modeled using probability density functions (pdfs) characterizing and predicting the time until the next heartbeat event occurs, as a linear function of the past history. Multiscale analysis is then applied to the pdfs' instantaneous first order moment. The proposed approach is tested on experimental data gathered from 57 congestive heart failure (CHF) patients by evaluating the recognition accuracy in predicting survivor and non-survivor patients, and by comparing performances from the informative point-process based interpolation and non-informative spline-based interpolation. Results demonstrate that multiscale analysis of point-process high resolution representations achieves the highest prediction accuracy of 65.45%, proving our method as a promising tool to assess risk prediction in CHF patients. PMID- 26736667 TI - Removing movement artifacts from equine ECG recordings acquired with textile electrodes. AB - This study reports on the implementation of a novel system to detect and reduce movement artifact (MA) contribution in electrocardiogram (ECG) recordings acquired from horses in free movement conditions. The system comprises both integrated textile electrodes for ECG acquisition and one triaxial accelerometer for movement monitoring. Here, ECG and physical activity are continuously acquired from seven horses through the wearable system and a model that integrates cardiovascular and movement information to estimate the MA contribution is implemented. Moreover, in this study we propose a new algorithm where the Stationary Wavelet Transform (SWT) decomposition algorithm is employed to identify and remove movement artifacts from ECG recodigns. Achieved results showed a reduction of MA percentage greater than 40% between before- and after- the application of the proposed algorithm to seven hours of recordings. PMID- 26736668 TI - Primary study for detection of arterial blood pressure waveform components. AB - The paper presents a technique to detect significant systolic peaks, the percussion (P) and tidal peak (T) and diastolic peak (D) from the arterial blood pressure (ABP) waveform. The technique is aimed at robust detection even in presence of significant noise. Singular Value Decomposition (SVD) based dominant period extraction of the ABP waveform followed by wavelet transform and local peak detection is applied to detect the points of interest. MIMIC-II ABP databse serves as a training dataset to select SVD and wavelet transform parameters and CSL Benchmark database is used to analyze the technique. Salient systolic peak detection for the CSL dataset was performed with positive predictive value and sensitivity figures of 98.48% and 99.24% respectively. PMID- 26736669 TI - Ineffective efforts in ICU assisted ventilation: Exploring causalities via multiscale analysis. AB - Intensive Care Unit (ICU) is a data intensive environment, requiring continuous monitoring of patient's physiology and response to treatment. In assisted ventilation, where patient effort that triggers the ventilator and there is need for patient-ventilator coupling, attention is required in cases where patient's effort that doesn't trigger the ventilator at all. When synchronization between the patient's attempt to breath and the assisted ventilation event is lost, an ineffective effort (IE) event takes place. A series of relevant bioparameters continuously monitored, are meant to guide the medical professionals in appropriately adapting the operation and treatment, in order to minimize IEs. The purpose of this work is to investigate the causal relations between physiological or ventilation parameters and IE events. A multiscale approach is proposed, based on wavelet similarity and localized phase relationship. The proposed method indicates the existence of distinct frequency zones correlated with the IE experienced by the patient. PMID- 26736670 TI - Dysfunctional long term habituation to exogeneous tinnitus-matched sounds in patients with high tinnitus distress. AB - During the last years, the demand of accurate diagnostic tools for individualized tinnitus treatment gradually increased. Today several different psychometric instruments for the estimation of the patients degree of decompensation with clinical relevance have emerged. All of these tools are questionnaires for a subjective self-assessment and have deficits in comparability due to severe differences in their factor structure in the anamnesis. Those questionnaires thus they are only of limited value in the design of an individualized therapeutic approach. Objective diagnostic tools for the categorization of the patients' distress level are lacking in clinical routine. Scientific approaches yet demonstrated the feasibility of individual distress assessment by objective markers in the EEG. In this article we present the preliminary results of our study of a use of habituation correlates as objective indicator for the decompensation degree in high-distress tinnitus patients. PMID- 26736671 TI - P-leader multifractal analysis and sparse SVM for intrapartum fetal acidosis detection. AB - Interpretation and analysis of intrapartum fetal heart rate, enabling early detection of fetal acidosis, remains a challenging signal processing task. Among the many strategies that were used to tackle this problem, scale-invariance and multifractal analysis stand out. Recently, a new and promising variant of multifractal analysis, based on p-leaders, has been proposed. In this contribution, we use sparse support vector machines applied to p-leader multifractal features with a double aim: Assessment of the features actually contributing to classification; Assessment of the contribution of non linear features (as opposed to linear ones) to classification performance. We observe and interpret that the classification rate improves when small values of the tunable parameter p are used. PMID- 26736672 TI - Image registration robust to sparse large errors. AB - Registration is difficult when images to be registered contain sparse but large valued differences. We present a method for robust registration that ignores some fraction of large differences, while constraining the sparseness of these errors. We apply the method to stabilize microscopy videos of C. elegans tissues, in which bright moving filaments and tissue wounding appear as sparse large-valued differences. We demonstrate the advantage of the method on both synthetic and real data compared to state-of-the-art methods. PMID- 26736673 TI - Optical flow with structure information for epithelial image mosaicing. AB - Mosaicing of biological tissue surfaces is challenging due to the weak image textures. This contribution presents a mosaicing algorithm based on a robust and accurate variational optical flow scheme. A Riesz pyramid based multiscale approach aims at overcoming the "flattening-out" problem at coarser levels. Moreover, the structure information present in images of epithelial surfaces is incorporated into the data-term to improve the algorithm robustness. The algorithm accuracy is first assessed with simulated sequences and then used for mosaicing standard clinical endoscopic data. PMID- 26736674 TI - Automatic mitral annulus tracking in volumetric ultrasound using non-rigid image registration. AB - Analysis of mitral annular dynamics plays an important role in the diagnosis and selection of optimal valve repair strategies, but remains cumbersome and time consuming if performed manually. In this paper we propose non-rigid image registration to automatically track the annulus in 3D ultrasound images for both normal and pathological valves, and compare the performance against manual tracing. Relevant clinical properties such as annular area, circumference and excursion could be extracted reliably by the tracking algorithm. The root-mean square error, calculated as the difference between the manually traced landmarks (18 in total) and the automatic tracking, was 1.96 +/- 0.46 mm over 10 valves (5 healthy and 5 diseased) which is within the clinically acceptable error range. PMID- 26736675 TI - Automated fiducial point selection for reducing registration error in the co localisation of left atrium electroanatomic and imaging data. AB - Registration of electroanatomic surfaces and segmented images for the co localisation of structural and functional data typically requires the manual selection of fiducial points, which are used to initialise automated surface registration. The identification of equivalent points on geometric features by the human eye is heavily subjective, and error in their selection may lead to distortion of the transformed surface and subsequently limit the accuracy of data co-localisation. We propose that the manual trimming of the pulmonary veins through the region of greatest geometrical curvature, coupled with an automated angle-based fiducial-point selection algorithm, significantly reduces target registration error compared with direct manual selection of fiducial points. PMID- 26736676 TI - Registration of coronary arteries in computed tomography angiography images using Hidden Markov Model. AB - Computed tomography angiography (CTA) allows for not only diagnosis of coronary artery disease (CAD) with high spatial resolution but also monitoring the remodeling of vessel walls in the progression of CAD. Alignment of coronary arteries in CTA images acquired at different times (with a 3-7 years interval) is required to visualize and analyze the geometric and structural changes quantitatively. Previous work in image registration primarily focused on large anatomical structures and leads to suboptimal results when applying to registration of coronary arteries. In this paper, we develop a novel method to directly align the straightened coronary arteries in the cylindrical coordinate system guided by the extracted centerlines. By using a Hidden Markov Model (HMM), image intensity information from CTA and geometric information of extracted coronary arteries are combined to align coronary arteries. After registration, the pathological features in two straightened coronary arteries can be directly visualized side by side by synchronizing the corresponding cross-sectional slices and circumferential rotation angles. By evaluating with manually labeled landmarks, the average distance error is 1.6 mm. PMID- 26736677 TI - Non-rigid registration of cervical spine MRI volumes. AB - Whiplash is the colloquial term for neck injuries caused by sudden extension of the cervical spine. Patients with chronic whiplash associated disorder (WAD) can experience neck pain for many years after the original injury. Researchers have found some evidence to suggest that chronic whiplash is related to the amount of intra-muscular fat in the cervical spine muscles. Hence, an important step towards developing a treatment for chronic WAD is a technique to accurately and efficiently measure the amount of intra-muscular fat in the muscles of the cervical spine. Our proposed technique for making this measurement is to automatically segment the cervical spine muscles using a fused volume created from multi-modal MRI volumes of the cervical spine. Multiple modes are required to enhance the boundaries between the different muscles to assist the following automatic segmentation process. However, before these multiple modes can be fused it is first necessary to accurately register these volumes. Hence, in this paper, we have proposed a new non-rigid multi-modal registration algorithm using the sum of conditional variance (SCV) with partial volume interpolation (PVI) similarity measure and Gauss-Newton (GN) optimization for the accurate registration of multi modal cervical spine MRI volumes. The performance of the proposed approach is compared with the existing SCV based registration algorithm and the sum of the conditional squared deviation from the mode (SCSDM) method. The experimental results demonstrate that the proposed approach provides superior performance than the best existing approaches. PMID- 26736678 TI - Atlas-based segmentation of abdominal organs in 3D ultrasound, and its application in automated kidney segmentation. AB - Automated segmentation of abdominal organs in 3D ultrasound images is an important and challenging task toward computer assisted emergency diagnosis. However, speckle noise, low-contrast organ tissues, intensity-profile inhomogeneity, and partial organ visibility are some ultrasound challenges which limits the utility of the automated diagnosis solutions. In this paper, an atlas based method to automatically segment an organ of interest in abdominal 3D ultrasound images is proposed. The atlas model contains texture information and shape knowledge of the organ, which facilitates an accurate discrimination of organ from non-organ voxels in input 3D ultrasound images. The proposed method offers a mechanism to automatically detect the organ, and therefore, it eliminates the need of manual initialization of organ segmentation. The proposed method is applied to automatically segment the right kidney in 3D ultrasound images. The experimental results indicate that the proposed method provides a higher detection and segmentation accuracy compared to state-of-the-art. PMID- 26736679 TI - A fully-automatic locally adaptive thresholding algorithm for blood vessel segmentation in 3D digital subtraction angiography. AB - Subarachnoid hemorrhage due to a ruptured cerebral aneurysm is still a devastating disease. Planning of endovascular aneurysm therapy is increasingly based on hemodynamic simulations necessitating reliable vessel segmentation and accurate assessment of vessel diameters. In this work, we propose a fully automatic, locally adaptive, gradient-based thresholding algorithm. Our approach consists of two steps. First, we estimate the parameters of a global thresholding algorithm using an iterative process. Then, a locally adaptive version of the approach is applied using the estimated parameters. We evaluated both methods on 8 clinical 3D DSA cases. Additionally, we propose a way to select a reference segmentation based on 2D DSA measurements. For large vessels such as the internal carotid artery, our results show very high sensitivity (97.4%), precision (98.7%) and Dice-coefficient (98.0%) with our reference segmentation. Similar results (sensitivity: 95.7%, precision: 88.9% and Dice-coefficient: 90.7%) are achieved for smaller vessels of approximately 1mm diameter. PMID- 26736680 TI - Emphasizing mesenteric blood vessels in laparoscopic colon cancer surgery video images. AB - This study aims to reduce surgeon burden by emphasising mesenteric blood vessels buried in the mesentery using image processing techniques.We have developed an image processing system that can be connected to a laparoscope. The first step of the method is superficial vessel deletion using an opening process. Next, the mesenteric blood vessels are extracted by multiple regression analysis using hue, saturation, and value color space information in the image. Finally, the enhanced regions are determined by areas obtained by a labeling process. Although examples with both true and false positives are observed, the proposed technique demonstrates sufficient accuracy. PMID- 26736681 TI - Automatic segmentation of the spine by means of a probabilistic atlas with a special focus on ribs suppression. Preliminary results. AB - Spine is a structure commonly involved in several prevalent diseases. In clinical diagnosis, therapy, and surgical intervention, the identification and segmentation of the vertebral bodies are crucial steps. However, automatic and detailed segmentation of vertebrae is a challenging task, especially due to the proximity of the vertebrae to the corresponding ribs and other structures such as blood vessels. In this study, to overcome these problems, a probabilistic atlas of the spine, including cervical, thoracic and lumbar vertebrae has been built to introduce anatomical knowledge in the segmentation process, aiming to deal with overlapping gray levels and the proximity to other structures. From a set of 3D images manually segmented by a physician (training data), a 3D volume indicating the probability of each voxel of belonging to the spine has been developed, being necessary the generation of a probability map and its deformation to adapt to each patient. To validate the improvement of the segmentation using the atlas developed in the testing data, we computed the Hausdorff distance between the manually-segmented ground truth and an automatic segmentation and also between the ground truth and the automatic segmentation refined with the atlas. The results are promising, obtaining a higher improvement especially in the thoracic region, where the ribs can be found and appropriately eliminated. PMID- 26736682 TI - A Markov Random Field orientation prior for electronic cleansing in CT Colonography. AB - Tagging of the bowel content with an oral contrast facilitates CT Colonography with limited bowel preparation. Electronic colon cleansing (ECC) reconstructs the colon lumen, devoid of feces from a CT scan acquired with fecal fluid tagging. A popular method to estimate the stool composition in an image (with the purpose of removing it) is the well-established Expectation Maximization (EM) method. The tagged fluid residue appears as a contrast enhanced region with a largely horizontal interface with air above it. One of the issues is the partial volume (PV) effect that creates voxels with attenuations similar to that of the colon wall at the boundary of air and tagged fluid. We present here, a novel orientation prior formulated as a Markov Random Field that is included as part of the EM tissue segmentation framework to mitigate this PV effect at the air and tagged fluid layer. We show quantitative results on a simple synthetic dataset and qualitative results on patient data that highlight improvements due to the inclusion of the orientation prior. PMID- 26736683 TI - Semi-automated breast cancer tumor detection with thermographic video imaging. AB - Screening for breast cancer enables early detection by which curative treatment can be possible. While mammography is the current gold standard for screening, it has low sensitivity in younger women and its harmful X-rays in frequent screening can increase the risk of cancer. Incidence rates are rising in younger women, causing a relook at thermography for low cost and non-harmful screening. In this paper, thermography is compared to mammography correlated with sono-mammography in 65 FNAC/biopsy proven cancer subjects in India. Thermography is comparable to mammography correlated with sono-mammography, having 94% and 95% sensitivity, respectively. A novel semi-automated thermographic tumor detection and location algorithm used in this paper also provides 97% sensitivity. This shows the promise of automated thermographic screening for reaching large populations in a cost effective manner in low resource settings in countries like India. Further studies in a large scale need to be done to evaluate the specificity to enable such solutions. PMID- 26736684 TI - Motion artifact cancellation and outlier rejection for clip-type ppg-based heart rate sensor. AB - Heart rate sensing can be used to not only understand exercise intensity but also detect life-critical condition during sports activities. To reduce stress during exercise and attach heart rate sensor easily, we developed a clip-type photoplethysmography (PPG)-based heart rate sensor. The sensor can be attached just by hanging it to the waist part of undershorts, and furthermore, it employs the motion artifact (MA) cancellation technique. However, due to its low contact pressure, sudden jumps and drops, which are called "outliers," are often observed in the sensed heart rate, so we also developed a simple outlier rejection technique. By an experiment using five male subjects (4 sets per subject), we confirmed the MA cancellation and outlier rejection capabilities. PMID- 26736685 TI - SEEQTM MCT wearable sensor performance correlated to skin irritation and temperature. AB - The Medtronic SEEQ(TM) Mobile Cardiac Telemetry System provides continuous monitoring of symptomatic and asymptomatic cardiac arrhythmias. Deployed across disparate geographies, the device and the patients wearing it are subject to a wide range of weather conditions, specifically differing temperatures. We hypothesized that extremes of temperature would result in degradation of SEEQ system performance due to patient discomfort, perspiration, and other factors. Towards that end, we investigated data from over 5000 devices worldwide, including those linked to patient complaints for discomfort. We found that the data does not show a degradation of wearable performance as defined by artifact or event rate with temperature. However, there was a correlation between patient complaints of discomfort and degraded performance as well as a weak correlation with reduced system longevity at temperatures above 80 degrees F. PMID- 26736686 TI - Automatic detection, extraction and analysis of unrestrained gait using a wearable sensor system. AB - Within this paper we demonstrate the effectiveness of a novel body-worn gait monitoring and analysis framework to both accurately and automatically assess gait during 'free-living' conditions. Key features of the system include the ability to automatically identify individual steps within specific gait conditions, and the implementation of continuous waveform analysis within an automated system for the generation of temporally normalized data and their statistical comparison across subjects. PMID- 26736687 TI - A programmable low power current source for bioimpedance measurement: Towards a wearable personalized health assistant. AB - Bioimpedance is a noninvasive measurement method that facilitates body composition analysis, besides being indicative of many other health parameters. In this work a novel programmable, low complexity, high output impedance, high voltage compliance and wideband current source for bioimpedance applications is presented. Previously, we designed, fabricated and tested in vivo a bio-patch for acquisition of multiple bio-signals. Upon integration with our previous work, this circuit is envisioned to constitute part of a personalized health assistant. Simulation at worst case corners and real operation conditions was carried out using UMC-180 nm 1 poly 6 metal CMOS process. Full duty cycle, shortened or stepped square waves can be generated. Amplitude control of 8 different current levels is supported. Frequency can be tuned up to 1 MHz and an output impedance of 2.8 MO @ 250 KHz is achieved at full current capacity. Total current consumption is comparable to the injected current, making the circuit highly efficient. PMID- 26736688 TI - Design and implementation of an intelligent belt system using accelerometer. AB - Activity monitor systems are increasing used recently. They are important for athletes and casual users to manage physical activity during daily exercises. In this paper, we use a triaxial accelerometer to design and implement an intelligent belt system, which can detect the user's step and flapping motion. In our system, a wearable intelligent belt is worn on the user's waist to collect activity acceleration signals. We present a step detection algorithm to detect real-time human step, which has high accuracy and low complexity. In our system, an Android App is developed to manage the intelligent belt. We also propose a protocol, which can guarantee data transmission between smartphones and wearable belt effectively and efficiently. In addition, when users flap the belt in emergency, the smartphone will receive alarm signal sending by the belt, and then notifies the emergency contact person, which can be really helpful for users in danger. Our experiment results show our system can detect physical activities with high accuracy (overall accuracy of our algorithm is above 95%) and has an effective alarm subsystem, which is significant for the practical use. PMID- 26736689 TI - The effect of fluid overload by saline infusion on heart rate variability in men during sleep. AB - Fluid shift from the legs and into the neck during sleep has been shown to increase tissue pressure around the upper airway and increase sleep apnea severity. Recently, acute fluid overload via saline infusion during sleep was shown to increase sleep apnea severity in an older men (>= 40 years of age) but not the younger men (<;40 years of age). The purpose of this study was to estimate the changes in the autonomic nervous system response to saline infusion in the younger and older men using well studied time- and frequency domain heart rate variability metrics (HRV). Eighteen healthy men (10 in the younger group and 8 in the older group) slept for up to 3 hours during the day while ~ 2L of saline was intravenously injected during sleep. An electrocardiogram was collected continuously during the sleep period. Two five minute segments of stage 1 or 2 sleep were selected for analysis of HRV: one before saline infusion and one after completion of saline infusion. Time- and frequency domain metrics of HRV were used to characterize autonomic nervous system response. Results generally showed increased HRV as measured by time-domain statistical measures in the younger men after saline infusion. In the frequency domain, the change in high frequency power from pre- to post-saline infusion was significantly greater in the younger compared to the older men. In addition, there was a borderline significant trend showing an increase in HF power from pre- to post-saline infusion in the younger, but not the older men. These results suggest that only in the younger men and not the older men, parasympathetic nervous activity increased in response to acute fluid overload. This might be one of the mechanisms that increased the severity of OSA in older and not the younger men. PMID- 26736690 TI - Hemodynamics changes with acute carotid baroreceptor field stimulation are age dependent in normotensive rats. AB - Carotid baroreceptor stimulation can treat resistant hypertension with possible effects on the vasculature beyond the decrease in arterial pressure. This study aims to characterize age-dependency of vascular hemodynamics changes with unilateral field stimulation of carotid baroreceptors in normotensive rats to infer underlying hemodynamic mechanisms. Anesthetized Wistar-Kyoto rats divided into two groups (young: n=10, 13-33 weeks; old: n=6, 52-58 weeks) were instrumented to measure heart rate (HR) and mean arterial pressure (MAP), and flow in the abdominal aorta and renal artery. Measures of aortic and renal artery stiffness and resistance were calculated. Baroreceptor stimulation caused a consistent reduction in MAP, HR, pulse pressure and aortic pulse wave velocity. In young rats reduced MAP (77 +/- 10 to 64 +/- 13 mmHg, p<;0.001) was concomitant with reduced mean aortic (40 +/- 15 to 32 +/- 11 ml/min, p<;0.05) and renal flow (3.0 +/- 1.6 2.2 +/- 1.1 ml/min, p<;0.001). However, in old rats reduced MAP (76 +/- 14 to 64 +/- 10 mmHg, p<;0.05) occurred with a reduced aortic resistance (1.8 +/- 0.9 to 1.6 +/- 0.9 mmHg.min/ml, p<;0.05), renal artery resistance (17.4 +/- 2.4 to 16.5 +/- 2.3 mmHg.min/ml, p<;0.05) and mean renal flow (4.5 +/- 1.2 to 4.0 +/- 1.1 ml/min, p<;0.05). This was consistent with reduced characteristic impedance in older rats in both the aorta (0.17 +/- 0.08 to 0.13 +/- 0.08 mmHg.min/ml, p<;0.05) and renal artery (4.97 +/- 1.16 to 3.97 +/- 1.08 mmHg.min/ml, p<;0.05). Stimulation caused a leftward shift in renal impedance phase frequency spectrum in both age groups indicating changes in wave reflection from the renal bed. Findings show that the reduction in MAP due to carotid barostimulation is associated with different hemodynamic mechanisms that depend on age. PMID- 26736691 TI - Cardiovascular control indexes in amyotrophic lateral sclerosis patients and their relation with clinical markers. AB - We studied the autonomic response to an orthostatic challenge (i.e. head-up tilt) in 52 amyotrophic lateral sclerosis (ALS) patients and 16 healthy subjects by means of power spectral analysis of heart period (HP) and systolic arterial pressure (SAP) variability. In addition, we verified the correlation of spectral indexes with clinical features of the ALS patients. Results showed that cardiovascular control of the ALS patients was impaired and this impairment was more evident from SAP series. While the revised Functional Rating Scale score, its bulbar subscore, and disease duration were uncorrelated with spectral indexes, the rate of the disease progression was positively correlated with the absolute low frequency power of SAP variability at rest and negatively correlated with the normalized high frequency power of HP variability during head-up tilt. We conclude that: i) spectral analysis of HP and SAP variability provides indexes helpful to quantify the impairment of the cardiovascular neural control in ALS patients; ii) patients with a faster disease progression are characterized by a higher vascular sympathetic drive and/or a depressed vagal cardiac regulation. PMID- 26736692 TI - Cardioinhibitory Carotid Sinus Syndrome - a mathematical model. AB - Carotid sinus massage (CSM) is a simple clinical test for stimulating the carotid sinus reflex. During CSM, firm longitudinal massage is applied at the point of maximal pulsation over the carotid bifurcation resulting in relative bradycardia. CSM is used to diagnose Cardioinhibitory Carotid Sinus Syndrome (CICSS). CICSS is an age-related disorder, characterized by profound symptomatic cardioinhibition (> 3 seconds pause) following CSM. CICSS prevalence increases with age and is responsible for 1 to 20% of all pacemaker implantations per year. Treatment options for CSS are limited and much debate still remains around its underlying etiology. In this paper we present a first computer simulation of carotid sinus massage (CSM) in older adults and demonstrate its ability to simulate normal heart rate responses to CSM. Importantly we demonstrate that our mathematical model requires inclusion of model elements to simulate autonomic control of perinodal T-cell activity in order to replicate the profound cardioinhibitory response observed in CICSS. Our model findings implicate CSS as a candidate biomarker of biological aging and frailty. PMID- 26736693 TI - Evaluation of the correlation between cardiac and sympathetic baroreflex sensitivity before orthostatic syncope. AB - The study investigates the two different aspects of the baroreflex control resulting in two baroreflex sensitivity (BRS) indexes: i) sympathetic BRS (sBRS); ii) cardiac BRS (cBRS). sBRS was assessed as the slope of the regression line of the conditional probability of detecting a burst on the integrated muscle nerve sympathetic activity (MSNA) given an assigned diastolic arterial pressure (DAP) on DAP. cBRS was estimated from spontaneous heart period (HP) and systolic arterial pressure (SAP) via a spectral approach in the low (0.04-0-15 Hz) and high (0.15-0.5 Hz) frequency bands respectively. Both sBRS and cBRS were assessed in eight healthy subjects undergoing three experimental sessions: supine resting position (REST), 80 degrees head-up tilt test (TILT) and before the occurrence of pre-syncope symptoms (TILT_PRE). Results showed a decrease of both sBRS and cBRS during TILT and a baroreflex impairment during TILT_PRE. sBRS and cBRS were linearly correlated during TILT but became uncorrelated during TILT_PRE. Findings suggest a failure of both "baroreflexes" and their disassociation during TILT_PRE. PMID- 26736694 TI - Temporal analysis of cardiac autonomic regulation during orthostatic challenge by short-term symbolic dynamics. AB - The gradual shift of cardiac autonomic regulation toward sympathetic predominance and vagal withdrawal during graded head-up tilt test in young controls has been demonstrated by parameters from symbolic dynamics obtained from short-term heart rate variability (HRV) analysis. In this study, the influence of gender and vasovagal syncope (VVS) on the autonomic response to an orthostatic challenge was investigated by HRV analysis using short-term symbolic dynamics (STSD). This study included 24 healthy young subjects (12 males; 12 age-matched females) and 16 female patients diagnosed with VVS. All subjects were enrolled in a head-up tilt (HUT) test, breathing normally, including 5 minutes of supine position (baseline) and 20-40 minutes of 70 degrees orthostatic phase. The STSD parameters were obtained following their behavior at different times during the HUT test, i.e., at baseline, early and middle orthostatic phases. Gender differences including increased sympathetic activity in men were already present in baseline and in the middle tilt phase. In baseline there were no differences between female controls and female patients, but parameters from STSD showed highly significantly (p=0.0007) reduced heart rate variability due to increased sympathetic activity in female patients in the middle tilt phase. Furthermore a new nonlinear index for the estimation of sympatho-vagal balance was introduced. PMID- 26736695 TI - Gender effect on discrimination of location and frequency in surface electrical stimulation. AB - This work investigated the gender effect on discrimination of surface electrical stimulation applied on the human forearm. Three experiments were conducted to examine the abilty of discriminating stimulation frequency, location, or both parameters in 14 healthy subjects. The results indicated a statistically significant impact of gender on the discrimination performance in all the three experiments (p <; 0.01, p <; 0.01, and p <; 0.001, respectively). The female group performed noticeably better than the male group (i.e., mean difference 15.4%, 11.9%, and 16.7% in repective experiment). The findings may provide evidence of gender difference in perceiving and interpreting electrical stimulation. Considering the gender difference may improve the efficacy of electrically evoked sensory feedback in applications such as prosthetic use and pain relief. PMID- 26736696 TI - A figure of merit for neural electrical stimulation circuits. AB - Electrical stimulators are widely used in neuro-prostheses. Many different implementations exist. However, no quantitative ranking criterion is available to allow meaningful comparison of the various stimulation circuits and systems to aid the designer. This paper presents a novel Figure of Merit (FOM) dedicated to stimulation circuits and systems. The proposed optimization performance metric takes into account tissue safety conditions and energy efficiency which can be evaluated by measurement. The FOM is used to rank several stimulator circuits and systems. PMID- 26736697 TI - A theoretical framework for studying the electromagnetic stimulation of nervous tissue. AB - In this paper we present a model for calculating the electric field, and its spatial derivatives, produced by arbitrarily shaped, oriented and placed coils carrying time-varying currents. The model has been validated by comparing its results with those obtained using FEM simulations. The model provides a simple and fast computation framework to investigate the electromagnetic stimulation of neural tissues. Some example applications are also provided. PMID- 26736698 TI - Subject-specific optimization of channel currents for multichannel transcranial magnetic stimulation. AB - The goal of this work is to develop a focal transcranial magnetic stimulation (TMS) system using a multichannel coil array for high-resolution neuromodulation. We proposed a novel spatially-distributed stimulation strategy to significantly improve the focality of TMS. Computer simulations were conducted to evaluate the proposed approach and test the merits of multichannel TMS. Three different multichannel coil arrays were modeled in addition to a conventional figure-8 coil for comparison. Simulations were performed on finite element head models of six subjects constructed from anatomical MR images via an automated pipeline. Multichannel TMS arrays exhibited significantly more focal induced electric field magnitudes compared to the figure-8 coil. Additionally, electrical steering of stimulation sites without physical movement of the coil array was demonstrated. PMID- 26736699 TI - A framework for identification of brain network dynamics using a novel binary noise modulated electrical stimulation pattern. AB - Modeling and identification of brain network dynamics is of great importance both for understanding brain function and for closed-loop control of brain states. In this work, we present a multi-input-multi-output (MIMO) linear state-space model (LSSM) to describe the brain network dynamics in response to electrical stimulation. The LSSM maps the parameters of electrical stimulation, such as frequency, amplitude and pulse-width to recorded brain signals such as electrocorticography (ECoG) and electroencephalography (EEG). Effective identification of the LSSM in open-loop stimulation experiments, however, is strongly dependent on the open-loop input stimulation design. We propose a novel input design to accurately identify the LSSM by integrating the concept of binary noise (BN) with practical constraints on stimulation waveforms. The designed input pattern is a pulse train modulated by stochastic BN parameters. We show that this input pattern both satisfies the necessary spectral condition for accurate system identification and can incorporate any desired pulse shape. Using numerical experiments, we show that the quality of identification depends heavily on the input signal pattern and the proposed binary noise modulated pattern achieves satisfactory identification results, reducing the relative estimation error more than 300 times compared with step sequence modulated, single-sinusoid modulated and multi-sinusoids modulated input patterns. PMID- 26736700 TI - Multi-electrode neurostimulation system for treatment of cognitive impairments. AB - Peculiarities of neurostimulation organization by a multi-electrode system are considered. The system forms the spatially distributed field of current pulses that impact the nerve centers of the neck. An example is given for technical implementation of such a system in device SYMPATHOCOR and the method of its application: the dynamic correction of activity of the sympathetic nervous system. Results of its clinic application to treating the children with the attention deficit syndrome are given. It is shown that taking into account pathophysiological peculiarities of such a syndrome, it could be considered as a general model of cognitive impairments. PMID- 26736701 TI - Modeling dynamic high-DOF finger postures from surface EMG using nonlinear synergies in latent space representation. AB - Accurate proportional myoelectric control of the hand is important in replicating dexterous manipulation in robot prostheses and orthoses. However, this is still difficult to achieve due to the complex and high degree-of-freedom (DOF) nature present in the governing musculoskeletal system. To address this problem, we suggest using a low dimensional encoding based on nonlinear synergies to represent both the high-DOF finger joint kinematics and the coordination of muscle activities taken from surface electromyographic (EMG) signals. Generating smooth multi-finger movements using EMG inputs is then done by using a shared Gaussian Process latent variable model that learns a dynamical model between both the kinematic and EMG data represented in a shared latent space. The experimental results show that the method is able to synthesize continuous movements of a full five-finger hand model, with total dimensions as large as 69 (although highly redundant and correlated). Finally, by comparing the estimation performances when the number of EMG latent dimensions are varied, we show that these synergistic features can capture the variance, shared and specific to the observed kinematics. PMID- 26736702 TI - Muscle synergies in children with dystonia capture "healthy" patterns regardless the altered motor performance. AB - Muscle synergies are hypothesized to represent motor modules recruited by the nervous system to flexibly perform subtasks necessary to achieve movement. Muscle synergy analysis may offer a better view of the neural structure underlying motor behaviors and how they change in motor deficits and rehabilitation. The aim of this study is to investigate if muscle synergies are able to encode regularities in the musculoskeletal system organization and dynamic behavior of patients with dystonia, or if they are altered as a consequence of the nervous system dysfunction in dystonia. To do so, we applied muscle synergies analysis to muscle activity recorded during the execution of upper limb writing tasks in 10 children with dystonia and 9 age-matched healthy controls. We show that, although children with dystonia present movement abnormalities compared to control subjects, the muscle synergies extracted from the two groups are very similar, and that the two groups share a significant number of motor modules. Our finding therefore suggests that a regular modular organization of upper limb muscle coordination is preserved for childhood dystonia. PMID- 26736703 TI - An analysis of physiological signals as a measure of task engagement in a multi limb-coordination motor-learning task. AB - There is widespread agreement in the physical rehabilitation community that task engagement is essential to effective neuromuscular recovery. Despite this, there are no clear measures of such task engagement. This paper assesses the extent to which certain physiological measurements might provide a measure of task engagement. In previous studies, correlations between mental focus and certain physiological measurements have been observed in subjects performing tasks requiring mental effort. In this study, the authors analyzed whether these signals showed similar correlation when subjects performed a multi-limb coordination motor-learning task. Subjects played a video game which required the use of both arms and one leg to play a simplified electronic drum set with varying difficulty. Heart rate (HR), skin conductance level (SCL), and facial electromyogram (EMG) were recorded while the subjects played. Analysis of the recordings showed statistically significant correlations relating task difficulty to SCL, HR and EMG amplitude in corrugator supercilii. No statistically significant correlation was observed between task difficulty and EMG in frontalis. PMID- 26736704 TI - Processing of surface EMG through pattern recognition techniques aimed at classifying shoulder joint movements. AB - Artificial arms for shoulder disarticulation need a high number of degrees of freedom to be controlled. In order to control a prosthetic shoulder joint, an intention detection system based on surface electromyography (sEMG) pattern recognition methods was proposed and experimentally investigated. Signals from eight trunk muscles that are generally preserved after shoulder disarticulation were recorded from a group of eight normal subjects in nine shoulder positions. After data segmentation, four different features were extracted (sample entropy, cepstral coefficients of the 4th order, root mean square and waveform length) and classified by means of linear discriminant analysis. The classification accuracy was 92.1% and this performance reached 97.9% after reducing the positions considered to five classes. To reduce the computational cost, the two channels with the least discriminating information were neglected yielding to a classification accuracy diminished by just 4.08%. PMID- 26736705 TI - Analog Front-Ends comparison in the way of a portable, low-power and low-cost EMG controller based on pattern recognition EMBC 2015. AB - Compact and low-noise Analog Front-Ends (AFEs) are becoming increasingly important for the acquisition of bioelectric signals in portable system. In this work, we compare two popular AFEs available on the market, namely the ADS1299 (Texas Instruments) and the RHA2216 (Intan Technologies). This work develops towards the identification of suitable acquisition modules to design an affordable, reliable and portable device for electromyography (EMG) acquisition and prosthetic control. Device features such as Common Mode Rejection (CMR), Input Referred Noise (IRN) and Signal to Noise Ratio (SNR) were evaluated, as well as the resulting accuracy in myoelectric pattern recognition (MPR) for the decoding of motion intention. Results reported better noise performances and higher MPR accuracy for the ADS1299 and similar SNR values for both devices. PMID- 26736706 TI - Antagonist muscle co-activation of limbs in human infant crawling: A pilot study. AB - Muscle Co-activation (MCo) is the simultaneous muscular activation of agonist and antagonist muscle groups, which provides adequate joint stability, movement accuracy during movement. Infant crawling is an important stage of motor function development that manifests non-synchronization growth and development of upper and lower limbs due to the well-known gross motor development principle of head to toe. However, the effect of MCo level for agonist and antagonist muscle groups on motor function development of limbs has not been previously reported. In this paper, sEMG signals were collected from triceps brachii (TB) and biceps brachii (BB), quadriceps femoris (QF) and hamstrings (HS) of limbs when fourteen infants were crawling at their self-selected speed. Antagonist muscle co-activation was evaluated by measuring two common indexes (co-activation index and Pearson's correlation coefficient).A significant difference was observed between upper limbs and lower limbs, but the relationship between MCo and speed of crawling was poor. This study is an opening for further investigation including a longitudinal study and compare against infant with CNS disorders. PMID- 26736707 TI - A Bayesian Network analysis of the probabilistic relations between risk factors in the predisposition to type 2 diabetes. AB - In order to better understand the relations between different risk factors in the predisposition to type 2 diabetes, we present a Bayesian Network analysis of a large dataset, composed of three European population studies. Our results show, together with a key role of metabolic syndrome and of glucose after 2 hours of an Oral Glucose Tolerance Test, the importance of education, measured as the number of years of study, in the predisposition to type 2 diabetes. PMID- 26736708 TI - Template for preparation of papers for IEEE sponsored conferences & symposia. AB - To improve the access to medical information is necessary to design and implement integrated informatics techniques aimed to gather data from different and heterogeneous sources. This paper describes the technologies used to integrate data coming from the electronic medical record of the IRCCS Fondazione Maugeri (FSM) hospital of Pavia, Italy, and combines them with administrative, pharmacy drugs purchase coming from the local healthcare agency (ASL) of the Pavia area and environmental open data of the same region. The integration process is focused on data coming from a cohort of one thousand patients diagnosed with Type 2 Diabetes Mellitus (T2DM). Data analysis and temporal data mining techniques have been integrated to enhance the initial dataset allowing the possibility to stratify patients using further information coming from the mined data like behavioral patterns of prescription-related drug purchases and other frequent clinical temporal patterns, through the use of an intuitive dashboard controlled system. PMID- 26736709 TI - Diabetes care related process modelling using Process Mining techniques. Lessons learned in the application of Interactive Pattern Recognition: coping with the Spaghetti Effect. AB - Diabetes is one of the metabolic disorders with more growth expectations in next decades. The literature points to a correct self-management, to an appropriate treatment and to an adequate healthy lifestyle as a way to dramatically improve the quality of life of patients with diabetes. The implementation of a holistic diabetes care system, using rising information technologies for deploying cares based on the thesis of the Evidence-Based Medicine can be a effective solution to provide an adequate and continuous care to patients. However, the design and deployment of computer readable careflows is not a easy task. In this paper, we propose the use of Interactive Pattern Recognition techniques for the iterative design of those protocols and we analyze the problems of using Process Mining to infer careflows and how to how to cope with the resulting Spaghetti Effect. PMID- 26736710 TI - Improving risk-stratification of Diabetes complications using temporal data mining. AB - To understand which factor trigger worsened disease control is a crucial step in Type 2 Diabetes (T2D) patient management. The MOSAIC project, funded by the European Commission under the FP7 program, has been designed to integrate heterogeneous data sources and provide decision support in chronic T2D management through patients' continuous stratification. In this work we show how temporal data mining can be fruitfully exploited to improve risk stratification. In particular, we exploit administrative data on drug purchases to divide patients in meaningful groups. The detection of drug consumption patterns allows stratifying the population on the basis of subjects' purchasing attitude. Merging these findings with clinical values indicates the relevance of the applied methods while showing significant differences in the identified groups. This extensive approach emphasized the exploitation of administrative data to identify patterns able to explain clinical conditions. PMID- 26736711 TI - Social media for empowering people with diabetes: Current status and future trends. AB - The use of social media has become commonplace in society. Consequently, many people living with chronic conditions are turning to social media applications to support self-management. This paper presents a formative non-exhaustive review of research literature regarding the role of social media for diabetes type II empowerment. In our review, we identified several major areas for diabetes health social media research, namely: a) social network data analytics, b) mHealth and diabetes, c) gamification for diabetes, c) wearable, and d) MOOCs (Massive Open Online Courses). In all these areas, we analyzed how social media is being used and the challenges emerging from its application in the diabetes domain. PMID- 26736712 TI - Use of an holistic approach for effective adoption of User-Centred-Design techniques in diabetes disease management: Experiences in user need elicitation. AB - One of the most important challenges of designing eHealth tools for Chronic Disease Management is to understand how transforming cutting-edge innovations in something that can impact the current clinical practice and improve the performance of the health care systems. The adoption of User Centered Design techniques is fundamental in order to integrate these systems in an effective and successful way. The work presented in this paper describe the methodologies used in the context of two multidisciplinary research projects, METABO and MOSAIC. The adoption of the methodologies have been driven by the CeHRes Roamap, a holistic framework that support participatory development of eHealth. The work reported in this paper describes the results of the first two (out of the five) phases in eliciting user needs. PMID- 26736713 TI - An ingestible, NIR-fluorometric, cancer-screening capsule. AB - Asymptomatic, early-stage, cancer detection is a problem in the small intestine, that is largely inaccessible. This paper presents a cost-effective screening capsule prototype, which is able to detect infrared (IR) fluorescence emitted by indocyanine green (ICG) fluorophore dye. The presented mixed-signal system has a small size, consumes little power and works as a high-sensitivity fluorometer that records fluorescence levels throughout the small intestine, rather than collecting images that need labour intensive video analysis. Ex-vivo experiments, on ICG-impregnated swine intestine, have shown that the prototype system is able to detect low concentrations of ICG in the nanomolar and micromolar region, which is required to detect early cancer in the small intestine. PMID- 26736714 TI - 3D-printed wearable backpack stimulator for chronic in vivo aquatic stimulation. AB - The neural mechanisms underlying changes in gene expression in the interconversion between skeletal muscle and the non-contractile electrogenic cells of the electric organ in electric fishes require several days to be manifested. It is extremely challenging to study these non-immediate forms of plasticity in reduced preparations in cell culture due to the time requirements. To address this experimental obstacle we developed a 3D-printed wearable backpack that allows chronic electrical stimulation of aquatic teleost fish. The backpack holds a biphasic simulator using a full H-bridge driver structure. Stimulation amplitude is adjusted with a current source controlled by a micro potentiometer whereas the stimulation waveform is reconfigurable through a micro-controller. A 3.7 V Lithium Ion Polymer battery powers the entire circuit. This backpack system will allow underwater chronic stimulation experiments aimed to study the role that neuronal input exerts on cell phenotypes in a vertebrate species with high tissue regeneration and cell trans-differentiation capabilities. PMID- 26736715 TI - Pulsed ultrasound for enhancing vaccine production. AB - Hepatitis B is an infectious liver disease and vaccination is an effective way to protect individuals. We have applied mechanical wave stimulation to increase protein production. To validate our design, we used Sf9 insect cells to increase antigen fragment fusion protein expression for hepatitis B virus (HBV S1/S2). We discovered that stimulation at a frequency of 1.5 MHz, intensity of 60 mW/cm(2), for a duration of 10 minutes per day increased HBV S1/S2 production by 15%. This finding is very significant for shortening vaccine production time or increasing the yield of proteins for use as vaccines. PMID- 26736716 TI - Efficient microstimulation of the brain: A parametric approach. AB - Microstimulation of brain tissue plays a key role in a variety of sensory prosthetics, clinical therapies and research applications. At present, tailoring the parameters of a stimulation signal to a specific goal relies heavily on parameters from literature. Optimization methods seek to improve tried and tested waveforms developed for specific purposes, however the fundamental understanding of how stimulation parameters interact and the effects these interactions have on brain tissue remains widely unknown. This study explores the interactions between parameters of the constant-current, biphasic square waveform with the intention of developing a stimulation efficient strategy. We find that, the traditional premise of a waveform's effectiveness being dominated by its amplitude does apply, however exceptions are noted which may be of essential importance to the development of electrical stimuli in restrictive paradigms. PMID- 26736717 TI - Cortical control of intraspinal microstimulation: Toward a new approach for restoration of function after spinal cord injury. AB - Approximately 6 million people in the United States are currently living with paralysis in which 23% of the cases are related to spinal cord injury (SCI). Miniaturized closed-loop neural interfaces have the potential for restoring function and mobility lost to debilitating neural injuries such as SCI by leveraging recent advancements in bioelectronics and a better understanding of the processes that underlie functional and anatomical reorganization in an injured nervous system. This paper describes our current progress toward developing a miniaturized brain-machine-spinal cord interface (BMSI) that converts in real time the neural command signals recorded from the cortical motor regions to electrical stimuli delivered to the spinal cord below the injury level. Using a combination of custom integrated circuit (IC) technology for corticospinal interfacing and field-programmable gate array (FPGA)-based technology for embedded signal processing, we demonstrate proof-of-concept of distinct muscle pattern activation via intraspinal microstimulation (ISMS) controlled in real time by intracortical neural spikes in an anesthetized laboratory rat. PMID- 26736718 TI - VLSI circuits for bidirectional interface to peripheral and visceral nerves. AB - This paper presents an architecture for sensing nerve signals and delivering functional electrical stimulation to peripheral and visceral nerves. The design is based on the very large scale integration (VLSI) technology and amenable to interface to microelectrodes and building a fully implantable system. The proposed stimulator was tested on the vagus nerve and is under further evaluation and testing of various visceral nerves and their functional effects on the innervated organs. PMID- 26736719 TI - Low-power adaptive spike detector based on a sigma-delta control loop. AB - This paper presents a resources-optimized digital action potential (AP) detector featuring an adaptive threshold based on a new Sigma-delta control loop. The proposed AP detector is optimized for utilizing low hardware resources, which makes it suitable for implementation on most popular low-power microcontrollers units (MCU). The adaptive threshold is calculated using a digital control loop based on a Sigma-delta modulator that precisely estimates the standard deviation of the amplitude of the neuronal signal. The detector was implemented on a popular low-power MCU and fully characterized experimentally using previously recorded neural signals with different signal-to-noise ratios. A comparison of the obtained results with other thresholding approaches shows that the proposed method can compete with high performance and highly resources demanding spike detection approaches while achieving up to 100% of true positive detection rate at high SNR, and up to 63% for an SNR as low as 0 dB, while necessitating an execution time as low as 11 MUs with the MCU operating at 8 MHz. PMID- 26736720 TI - Microfluidic platform for neurotransmitter sensing based on cyclic voltammetry and dielectrophoresis for in vitro experiments. AB - This paper presents a new microfluidic platform that can simultaneously measure and locally modulate neurotransmitter concentration in a neuron network. This work focuses on the development of a first prototype including a potentiostat and electrode functionalization to detect several neurotransmitter's simultaneously. We tested dopamine as proof of concept to validate functionality. The system is based on 320 bidirectional electrode array for dielectrophoretic manipulation and cyclic voltammetry. Each electrode is connected to a mechanical multiplexer in order to reduce noise interference and fully isolate the electrode. The multiplexing rate is 476 kHz and each electrode can drive a signal with an amplitude of 60 V pp for dielectrophoretic manipulation. PMID- 26736721 TI - An automated microphysiological assay for toxicity evaluation. AB - Screening a newly developed drug, food additive or cosmetic ingredient for toxicity is a critical preliminary step before it can move forward in the development pipeline. Due to the sometimes dire consequences when a harmful agent is overlooked, toxicologists work under strict guidelines to effectively catalogue and classify new chemical agents. Conventional assays involve long experimental hours and many manual steps that increase the probability of user error; errors that can potentially manifest as inaccurate toxicology results. Automated assays can overcome many potential mistakes that arise due to human error. In the presented work, we created and validated a novel, automated platform for a microphysiological assay that can examine cellular attributes with sensors measuring changes in cellular metabolic rate, oxygen consumption, and vitality mediated by exposure to a potentially toxic agent. The system was validated with low buffer culture medium with varied conductivities that caused changes in the measured impedance on integrated impedance electrodes. PMID- 26736722 TI - High-speed event detector for embedded nanopore bio-systems. AB - Biological measurements of microscopic phenomena often deal with discrete-event signals. The ability to automatically carry out such measurements at high-speed in a miniature embedded system is desirable but compromised by high-frequency noise along with practical constraints on filter quality and sampler resolution. This paper presents a real-time event-detection method in the context of nanopore sensing that helps to mitigate these drawbacks and allows accurate signal processing in an embedded system. Simulations show at least a 10* improvement over existing on-line detection methods. PMID- 26736723 TI - Robotic printing and drug testing of 384-well tumor spheroids. AB - A major impediment to anti-cancer drug development is the lack of a reliable and inexpensive tumor model to test the efficacy of candidate compounds. This need has emerged due to the insufficiency of widely-used monolayer cultures to predict drug efficacy in vivo. Spheroids, 3D compact clusters of cancer cells, mimic important characteristics of tumors and provide a tissue analog for drug testing. Here we present a novel spheroid formation microtechnology that is simple to use and allows high throughput drug screening in 384-microwell plates. This approach is based on a polymeric aqueous two-phase system. The denser aqueous phase is mixed with cancer cells at a desired density. Using a robotic liquid handler, a drop of this cell suspension is dispensed into each well of a 384-microwell plate containing the second, immersion aqueous phase. Cancer cells remain contained in the drop, which rests on the well bottom, and form a spheroid during incubation. The use of liquid handling robotics ensures precise dispensing of a single drop, resulting in a single spheroid per well and homogenously sized spheroids within each plate. We confirmed the consistency of production of spheroids and demonstrated their biological relevance to tumors. A proof of concept study with spheroids of triple negative breast cancer cells treated with a standard chemotherapeutic compound, doxorubicin, showed the potential of this method for drug testing. This spheroid culture microtechnology presents key advantages over existing methods such as the ease of drug and viability reagent addition, ability to analyze spheroids without transferring them to a new plate, and the elimination of the need for specialized plates or devices to form spheroids. Incorporating this technology in anti-cancer drug development pipeline will help examine the efficacy of drug candidates more effectively and expedite discovery of novel drugs. PMID- 26736724 TI - Affordable techniques for fabricating large array of functional nanowires: From DNA to micellar systems. AB - Large arrays of aligned DNA and polymeric nanowires ranging from 20 to 100 nm in diameter are fabricated by de-wetting of patterned surfaces. Compared to other nanofabrication techniques, our approach is robust, fast and low cost. In addition, arrays of functionalized nanowires for bio/chemical applications can be simply produced at large scale. PMID- 26736725 TI - Connectivity of epileptic brain regions in wake and sleep. AB - Focal epileptic brain is characterized by a region of pathological tissue seizure onset zone (SOZ) - the pathologic tissue generating seizures. During the interictal period (nonseizure) the SOZ is characterized by epileptiform activity interictal spikes & high-frequency oscillations (HFO). The SOZ also exhibits hyper-synchrony and functional disconnection from the surrounding areas. Recent studies have described the synchrony inside the SOZ and surrounding tissue for just small sets of patients (2-4) and without any distinction in behavioral states. Wake and sleep cycles can, however, have a significant influence on SOZ activity. Here we show the results of connectivity analysis in three fundamental areas of the epileptic brain - inside SOZ, outside SOZ and bridging areas in 7 patients during wake and sleep. We observed increased synchrony inside SOZ and decreased synchrony on its edges (bridging areas) in specific frequency bands. We also detected significant differences of synchrony levels between wake and sleep periods in HFO frequencies. Our results provide additional insight into the properties of SOZ connectivity. Knowledge of these principles may prove useful for SOZ localization and understanding epileptic brain function in general. PMID- 26736726 TI - Detecting labor using graph theory on connectivity matrices of uterine EMG. AB - Premature labor is one of the most serious health problems in the developed world. One of the main reasons for this is that no good way exists to distinguish true labor from normal pregnancy contractions. The aim of this paper is to investigate if the application of graph theory techniques to multi-electrode uterine EMG signals can improve the discrimination between pregnancy contractions and labor. To test our methods we first applied them to synthetic graphs where we detected some differences in the parameters results and changes in the graph model from pregnancy-like graphs to labor-like graphs. Then, we applied the same methods to real signals. We obtained the best differentiation between pregnancy and labor through the same parameters. Major improvements in differentiating between pregnancy and labor were obtained using a low pass windowing preprocessing step. Results show that real graphs generally became more organized when moving from pregnancy, where the graph showed random characteristics, to labor where the graph became a more small-world like graph. PMID- 26736727 TI - Comparison of different Kalman filter approaches in deriving time varying connectivity from EEG data. AB - Kalman filter approaches are widely applied to derive time varying effective connectivity from electroencephalographic (EEG) data. For multi-trial data, a classical Kalman filter (CKF) designed for the estimation of single trial data, can be implemented by trial-averaging the data or by averaging single trial estimates. A general linear Kalman filter (GLKF) provides an extension for multi trial data. In this work, we studied the performance of the different Kalman filtering approaches for different values of signal-to-noise ratio (SNR), number of trials and number of EEG channels. We used a simulated model from which we calculated scalp recordings. From these recordings, we estimated cortical sources. Multivariate autoregressive model parameters and partial directed coherence was calculated for these estimated sources and compared with the ground truth. The results showed an overall superior performance of GLKF except for low levels of SNR and number of trials. PMID- 26736729 TI - Comparison of network analysis approaches on EEG connectivity in beta during Visual Short-term Memory binding tasks. AB - We analyse the electroencephalogram signals in the beta band of working memory representation recorded from young healthy volunteers performing several different Visual Short-Term Memory (VSTM) tasks which have proven useful in the assessment of clinical and preclinical Alzheimer's disease. We compare network analysis using Maximum Spanning Trees (MSTs) with network analysis obtained using 20% and 25% connection thresholds on the VSTM data. MSTs are a promising method of network analysis negating the more classical use of thresholds which are so far chosen arbitrarily. However, we find that the threshold analyses outperforms MSTs for detection of functional network differences. Particularly, MSTs fail to find any significant differences. Further, the thresholds detect significant differences between shape and shape-colour binding tasks when these are tested in the left side of the display screen, but no such differences are detected when these tasks are tested for in the right side of the display screen. This provides evidence that contralateral activity is a significant factor in sensitivity for detection of cognitive task differences. PMID- 26736728 TI - Brain network properties in depressed patients receiving seizure therapy: A graph theoretical analysis of peri-treatment resting EEG. AB - Electroconvulsive therapy (ECT), the most efficacious antidepressant therapy for treatment-resistant depression, has been reported to alter functional brain network architecture by down-regulating connectivity in frontotemporal circuitry. Magnetic seizure therapy (MST), which induces therapeutic seizures with high dose repetitive transcranial magnetic stimulation, has been introduced to improve the seizure therapy risk/benefit ratio. Unfortunately, there is limited understanding of seizure therapy's underlying mechanisms of action. In this study, we apply graph theory-based connectivity analysis to peri-treatment, resting-state, topographical electroencephalography (EEG) in patients with depression receiving seizure therapy. Functional connectivity was assessed using the de-biased weighted phase lag index, a measure of EEG phase synchronization. Brain network structure was quantified using graph theory metrics, including betweenness centrality, clustering coefficient, network density, and characteristic path length. We found a significant reduction in the phase synchronization and aberration of the small-world architecture in the beta frequency band, which could be related to acute clinical and cognitive effects of seizure therapy. PMID- 26736730 TI - Graph theory in brain-to-brain connectivity: A simulation study and an application to an EEG hyperscanning experiment. AB - Hyperscanning consists in the simultaneous recording of hemodynamic or neuroelectrical signals from two or more subjects acting in a social context. Well-established methodologies for connectivity estimation have already been adapted to hyperscanning purposes. The extension of graph theory approach to multi-subjects case is still a challenging issue. In the present work we aim to test the ability of the currently used graph theory global indices in describing the properties of a network given by two interacting subjects. The testing was conducted first on surrogate brain-to-brain networks reproducing typical social scenarios and then on real EEG hyperscanning data recorded during a Joint Action task. The results of the simulation study highlighted the ability of all the investigated indexes in modulating their values according to the level of interaction between subjects. However, only global efficiency and path length indexes demonstrated to be sensitive to an asymmetry in the communication between the two subjects. Such results were, then, confirmed by the application on real EEG data. Global efficiency modulated, in fact, their values according to the inter-brain density, assuming higher values in the social condition with respect to the non-social condition. PMID- 26736731 TI - Can home-monitoring of sleep predict depressive episodes in bipolar patients? AB - The aim of this study is the evaluation of the autonomic regulations during depressive stages in bipolar patients in order to test new quantitative and objective measures to detect such events. A sensorized T-shirt was used to record ECG signal and body movements during the night, from which HRV data and sleep macrostructure were estimated and analyzed. 9 out of 20 features extracted resulted to be significant (p<;0.05) in discriminating among depressive and non depressive states. Such features are representation of HRV dynamics in both linear and non-linear domain and parameters linked to sleep modulations. PMID- 26736732 TI - An online algorithm for least-square spectral analysis: Applied to time-frequency analysis of heart rate. AB - We propose a novel online algorithm for computing least-square based periodograms, otherwise known as the Lomb-Scargle Periodogram. Our spectral analysis technique has been shown to be superior to traditional discrete Fourier transform (DFT) based methods, and we introduce an algorithm which has O(N) time complexity per input sample. The technique is suitable for real-time embedded implementations and its utility is demonstrated through an application to the high resolution time-frequency domain analysis of heart rate variability (HRV). PMID- 26736733 TI - Dependence of cardiac spectrum on the spatial resolution of the electrode systems in a realistic model of the canine ventricles. AB - Body-surface dominant frequency (DF) mapping has been proposed as a technique for non-invasively identifying high-frequency cardiac sources during fibrillation. However, previous studies indicate that volume conduction could distort the spectrum of body-surface cardiac signals and hence, affect body-surface DF maps. In this study, we analyze the effects of volume conduction on the spectrum of cardiac signals in a realistic computer model of the canine ventricles. We simulate complex cardiac dynamics on the ventricular model and analyze the dependence of the bandwidth (BW) of simulated unipolar cardiac signals on the spatial resolution of the corresponding unipolar electrode, which we quantify with the lead equivalent volume (LEV). Our analysis shows that the BW decreases for increasing LEV values and saturates for high LEV values. Our results also indicate that the LEV saturation value is low for low degrees of spatiotemporal correlation. We conclude that the spectral effects of volume conduction might limit our ability to accurately identify high-frequency sources in body-surface DF maps during cardiac fibrillation. PMID- 26736734 TI - Influences of gender and anthropometric features on inspiratory inhaler acoustics and peak inspiratory flow rate. AB - Inhalers are hand-held devices used to treat chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Medication is delivered from an inhaler to the user through an inhalation maneuver. It is unclear whether gender and anthropometric features such as age, height, weight and body mass index (BMI) influence the acoustic properties of inspiratory inhaler sounds and peak inspiratory flow rate (PIFR) in inhalers. In this study, healthy male (n=9) and female (n=7) participants were asked to inhale at an inspiratory flow rate (IFR) of 60 L/min in four commonly used inhalers (Turbuhaler(TM), Diskus(TM), Ellipta(TM) and Evohaler(TM)). Ambient inspiratory sounds were recorded from the mouthpiece of each inhaler and over the trachea of each participant. Each participant's PIFR was also recorded for each of the four inhalers. Results showed that gender and anthropometric features have the potential to influence the spectral properties of ambient and tracheal inspiratory inhaler sounds. It was also observed that males achieved statistically significantly higher PIFRs in each inhaler in comparison to females (p<;0.05). Acoustic features were found to be significantly different across inhalers suggesting that acoustic features are modulated by the inhaler design and its internal resistance to airflow. PMID- 26736735 TI - Upper airway resistance changes from inspiration to expiration during wakefulness is a predictor of sleep apnea: A pilot study. AB - Upper airway structure is known to be affected in individuals with obstructive sleep apnea (OSA). In this pilot study, we investigated whether the changes of upper airway resistance (UAR) within a breathing phase, estimated from tracheal breathing sounds and airflow, is a predictor of OSA severity. Tracheal breathing sounds and airflow of 15 individuals in three groups of mild, moderate and severe OSA during wakefulness, recorded in supine position, were used in this study. The grouping of the study subjects were done based on their apnea/hypopnea index (AHI) per hour, prospectively. The breathing sounds and airflow were recorded simultaneously with full overnight polysomnography (PSG) assessment. The sounds of 3 noise-free breathing cycles were extracted and sequestered into inspiratory and expiratory phase segments manually for each study subject. The power spectra of the sound signals of each respiratory phase were calculated in 15ms windows with 50% overlap between adjacent windows. The UAR was then estimated as the ratio of the energy of power spectrum of each window within 100 to 2500 Hz, and its corresponding airflow. Then, the variance of the short-time windows' UAR, Var(UAR) during each respiratory phase was calculated. The ratio of the Var(UAR) in logarithmic scale between inspiration and expiration was found to be significantly different (p<;0.01) between the three OSA groups; also it was found to be highly correlated with AHI. These results are congruent with the hypothesis that the upper airway patency is not kept constant in OSA population, and suggest the change in acoustic UAR during wakefulness maybe considered as a predictor of OSA. PMID- 26736736 TI - Effects of changing in the neck circumference during sleep on snoring sound characteristics. AB - Rostral fluid shift during sleep from the lower body part into the neck can increase neck circumference (NC) and narrow the upper airway. Such narrowing in the upper airway may increase turbulence of airflow passing through the upper airway; thus, induce snoring. The objective of this study was to investigate the effects of changes in NC during sleep on snoring sound characteristics. Fifteen non-obese men slept supine, and their sleep was monitored by a regular polysomnography. Snoring sounds were recorded with a microphone attached to the neck. NC was measured before and after sleep with a measuring tape. Snoring sounds' average power was calculated in different frequency ranges of 100 - 4000 Hz, 100 - 150 Hz, 150 - 450 Hz, 450 - 600 Hz, 600 - 1200 Hz, 1200 - 1800 Hz, 1800 - 2500 Hz and 2500 - 4000 Hz. Statistical analysis showed that increases in NC after sleep were strongly correlated with higher average power of the snoring sounds in the frequency ranges of 100-4000 Hz (r=0.74, P=0.004), 100-150 Hz (r=0.70, P=0.008), 150-450 Hz (r=0.73, P=0.005), and 450 - 600 Hz (r= 0.65, P=0.025). These results encourage the use of snoring sound analysis for monitoring the effects of fluid accumulation in the neck in relation to sleep apnea. PMID- 26736737 TI - Weighted quantification of 18F-FDG tumor metabolism activity using fuzzy thresholding to predict post-treatment tumor recurrence. AB - Cervical cancer is one of the most common cancer to affect women worldwide. Despite the efficiency of radiotherapy treatment, some patients present post treatment tumor recurrence which increases the risk of death. Early outcome prediction could help oncologists to adapt the treatment. Several studies suggest that quantification of tumor activity using (18)FFDG PET imaging could be used to predict post-treatment tumor recurrence. In this paper we study the predictive value of weighted quantification of tumor metabolism extracted by fuzzy thresholding for tumor recurrence of locally advanced cervical cancer. Fifty three patients with locally advanced cervical cancer treated by chemo radiotherapy were considered in our study. For each patient, a coregistered (18)F FDG PET/CT scan was acquired before the treatment and was segmented using different hard and fuzzy segmentations methods. The tumor activity was extracted through the total lesion glycolysis and through a weighted analog of the total lesion glycolysis using the probability maps provided by the fuzzy segmentations. Outcomes prediction was performed using the area under the receiver operating characteristic curve (AUC) and the Harrell's C-index. Results suggest that weighted quantification of tumor activity seems to be strongly informative and could be used to predict post-treatment tumor recurrence in cervical cancer. PMID- 26736738 TI - Non-invasive quantification of brain [18F]-FDG uptake by combining medical health records and dynamic PET imaging data. AB - Quantification of regional cerebral metabolic rate of glucose (rCMRglu) via positron emission tomography (PET) imaging requires measuring the arterial input function (AIF) via invasive arterial blood sampling. In this study we describe a non-invasive approach, the non-invasive simultaneous estimation (nSIME), for the estimation of rCMRglu that considers a pharmacokinetic input function model and constraints derived from machine learning applied to a fusion of individual medical health records and dynamic [(18)F]-FDG-PET brain images data. The results obtained with our data indicate potential for future clinical application of nSIME, with correlation measures of 0.87 for rCMRglu compared to quantification with full arterial blood sampling. PMID- 26736739 TI - Modelling arterial input functions in positron emission tomography dynamic studies. AB - The quantification of dynamic positron emission tomography (PET) images often requires the invasive measures of the arterial plasma tracer concentration to be used as arterial input function (AIF). In several situations, a mathematical model is fit to the hematic data to obtain a continuous and noise-free description of the AIF. In common practice, the tri-exponential and Feng's models are generally adopted. Despite their general applicability, often these approximations of blood tracer activity do not properly describe the complex behavior of the AIF (e.g. different clearance rates of the tracers) as well as they do not account for the length of the radiotracer injection. Here we propose two models able to include the injection duration as additional information in the AIF modeling and we compare their performances in eight different datasets acquired from different PET facilities. PMID- 26736740 TI - Semi-supervised manifold learning with affinity regularization for Alzheimer's disease identification using positron emission tomography imaging. AB - Dementia, Alzheimer's disease (AD) in particular is a global problem and big threat to the aging population. An image based computer-aided dementia diagnosis method is needed to providing doctors help during medical image examination. Many machine learning based dementia classification methods using medical imaging have been proposed and most of them achieve accurate results. However, most of these methods make use of supervised learning requiring fully labeled image dataset, which usually is not practical in real clinical environment. Using large amount of unlabeled images can improve the dementia classification performance. In this study we propose a new semi-supervised dementia classification method based on random manifold learning with affinity regularization. Three groups of spatial features are extracted from positron emission tomography (PET) images to construct an unsupervised random forest which is then used to regularize the manifold learning objective function. The proposed method, stat-of-the-art Laplacian support vector machine (LapSVM) and supervised SVM are applied to classify AD and normal controls (NC). The experiment results show that learning with unlabeled images indeed improves the classification performance. And our method outperforms LapSVM on the same dataset. PMID- 26736741 TI - A statistical method for lung tumor segmentation uncertainty in PET images based on user inference. AB - PET has been widely accepted as an effective imaging modality for lung tumor diagnosis and treatment. However, standard criteria for delineating tumor boundary from PET are yet to develop largely due to relatively low quality of PET images, uncertain tumor boundary definition, and variety of tumor characteristics. In this paper, we propose a statistical solution to segmentation uncertainty on the basis of user inference. We firstly define the uncertainty segmentation band on the basis of segmentation probability map constructed from Random Walks (RW) algorithm; and then based on the extracted features of the user inference, we use Principle Component Analysis (PCA) to formulate the statistical model for labeling the uncertainty band. We validated our method on 10 lung PET CT phantom studies from the public RIDER collections [1] and 16 clinical PET studies where tumors were manually delineated by two experienced radiologists. The methods were validated using Dice similarity coefficient (DSC) to measure the spatial volume overlap. Our method achieved an average DSC of 0.878 +/- 0.078 on phantom studies and 0.835 +/- 0.039 on clinical studies. PMID- 26736742 TI - Iterative reconstruction for pet scanners with continuous scintillators. AB - Several technical developments have led to a comeback of the continuous scintillators in positron emission tomography (PET). Important differences exist between the resurgent continuous scintillators and the prevailing pixelated devices, which can translate into certain advantages of the former over the latter. However, if the peculiarities of the continuous scintillators are not considered in the iterative reconstruction in which the measured data is converted to images, these advantages will not be fully exploited. In this paper, we review which those peculiarities are and how they have been considered in the literature of PET reconstruction. In light of this review, we propose a new method to compute one of the key elements of the iterative schemes, the system matrix. Specifically, we substitute the traditional Gaussian approach to the so called uncertainty term by a more general Monte Carlo estimation, and account for the effect of the optical photons, which cannot be neglected in continuous scintillators devices. Finally, we gather in a single scheme all the elements of the iterative reconstruction that have been individually reformulated, in this or previous works, for continuous scintillators, providing the first reconstruction framework fully adapted to this type of detectors. The preliminary images obtained for a commercially available PET scanner show the benefits of adjusting the reconstruction to the nature of the scintillators. PMID- 26736743 TI - Performance evaluation of power transmission coils for powering endoscopic wireless capsules. AB - This paper presents an analysis of H-field generated by a simple solenoid, pair of solenoids, pair of double-layer solenoids, segmented-solenoid, and Helmholtz power transmission coils (PTCs) to power an endoscopic wireless capsule (WC). The H-fields were computed using finite element analysis based on partial differential equations. Three parameters were considered in the analysis: i) the maximum level of H-field (Hmax) to which the patient's body would be exposed, ii) the minimum level of H-field (Hmin) effective for power transmission, and iii) uniformity of H-field. We validated our analysis by comparing the computed data with data measured from a fabricated Helmholtz PTC. This analysis disclosed that at the same excitation power, all the PTCs are able to transfer same amount of minimum usable power since they generated almost equal value of Hmin. The level of electromagnetic exposure and power transfer stability across all the PTCs would vary significantly which is mainly due to the different level of Hmax and H field uniformity. The segmented solenoid PTC would cause the lowest exposure and this PTC can transfer the maximum amount of power. The Helmholtz PTC would be able to transfer the most stable power with a moderate level of exposure. PMID- 26736744 TI - Development of an eyewear to measure eye and body movements. AB - To enable precise detection of mental and physical states of users in a daily life, we have been developing an eyewear to measure eye and body movement in a unrestricted way. The horizontal and vertical EOG (electrooculogram) signals are measured and amplified with three metal dry electrodes placed near nasion and both sides of rhinion, of which positions correspond to the bridge and nose pads of eyewear, respectively. The user's mental states like drowsiness, sleepiness, fatigue, or interest to objects can be identified by the movements and blinking of the eyes extracted from the measured EOG. And the six-axis motion sensor (three-axis accelerometer and three-axis gyroscope) mounted in the eyewear measures the body motion. As the sensor located near the head is on the body axis, this eyewear is suitable to measure user's movement or shift of center of gravity during physical exercise with a high precision. The measured signals are used to extract various events of eye and body movement by the mounted microcontroller chip, or can be transmitted to the external devices via Bluetooth communication. This device can enable you to look into "yourself", as well as outer scenes. In this presentation, the outline of the eyewear is introduced and some possible applications are shown. PMID- 26736745 TI - Developing an online steady-state visual evoked potential-based brain-computer interface system using EarEEG. AB - The purpose of this study is to demonstrate an online steady-state visual evoked potential (SSVEP)-based BCI system using EarEEG. EarEEG is a novel recording concept where electrodes are embedded on the surface of earpieces customized to the individual anatomical shape of users' ear. It has been shown that the EarEEG can be used to record SSVEPs in previous studies. However, a long distance between the visual cortex and the ear makes the signal-to-noise ratio (SNR) of SSVEPs acquired by the EarEEG relatively low. Recently, filter bank- and training data-based canonical correlation analysis algorithms have shown significant performance improvement in terms of accuracy of target detection and information transfer rate (ITR). This study implemented an online four-class SSVEP-based BCI system using EarEEG. Four subjects participated in offline and online BCI experiments. For the offline classification, an average accuracy of 82.71+/-11.83 % was obtained using 4 sec-long SSVEPs acquired from earpieces. In the online experiment, all subjects successfully completed the tasks with an average accuracy of 87.92+/-12.10 %, leading to an average ITR of 16.60+/-6.55 bits/min. The results suggest that EarEEG can be used to perform practical BCI applications. The EarEEG has the potential to be used as a portable EEG recordings platform, that could enable real-world BCI applications. PMID- 26736746 TI - Energy-aware embedded classifier design for real-time emotion analysis. AB - Detection and classification of human emotions from multiple bio-signals has a wide variety of applications. Though electronic devices are available in the market today that acquire multiple body signals, the classification of human emotions in real-time, adapted to the tight energy budgets of wearable embedded systems is a big challenge. In this paper we present an embedded classifier for real-time emotion classification. We propose a system that operates at different energy budgeted modes, depending on the available energy, where each mode is constrained by an operating energy bound. The classifier has an offline training phase where feature selection is performed for each operating mode, with an energy-budget aware algorithm that we propose. Across the different operating modes, the classification accuracy ranges from 95% - 75% and 89% - 70% for arousal and valence respectively. The accuracy is traded off for less power consumption, which results in an increased battery life of up to 7.7 times (from 146.1 to 1126.9 hours). PMID- 26736747 TI - A wireless patch for sleep respiratory disorders applications. AB - This paper presents a conformable wireless patch and its mobile application for physical activity, spO2 and pCO2 recording associated to digital biomarkers that aim at providing the clinicians with a reliable computer-aided diagnosis tool for rapid and continuous monitoring of sleep respiratory disorders. Each part of the system is described and results are presented and discussed. The reflectance sp02 sensor has been tested in vivo on several body sites and several subjects then compared to a reference device. The electrochemical tcpO2 sensor has been validated in vitro. Based on these physiological parameters, the proposed algorithms to automatically identifying sleep respiratory events are compared to a reference index. PMID- 26736748 TI - On the tridimensional estimation of the gaze point by a stereoscopic wearable eye tracker. AB - This paper reports a novel stereo-vision-method (binocular system-geometrical mapped (BS-GM)) to estimate the depth coordinates of the eye gaze point in a controlled 3D space of vision. The method outcomes were compared in both 2D and 3D visual targets with both mono- and stereo-vision algorithms in order to estimate accuracy of results. More specifically, we compared BS-GM with a monocular method and with two stereo-vision methodologies which were different in order to the mapping functions. All of the methods were implemented in the same head mounted eye tracking system able to acquire both eyes. In 2D visual space (i.e. plane of vision) we compared BS-GM with a monocular method, a binocular system-linear mapped (BS-LM) and a binocular system-quadratic mapped (BS-QM). In the 3D space estimation all of the binocular systems were compared each other. Thirteen enrolled subjects observed 31 targets of known coordinates in a controlled environment. Results achieved on 2D comparison showed no statistical significant difference among the four methods, while the comparison on 3D space of vision showed that BS-GM method achieved a significant better accuracy than BS LM and BS-QM method. Specifically, BS-GM showed and average percentage error obit of 3.47%. PMID- 26736749 TI - A model of electrical stimulation of a retinal cell population using a multi electrode array. AB - A novel computational modelling approach is employed to investigate the response of a population of retinal ganglion cells (RGCs) to external electrical stimulation. Current is delivered via a multi-electrode array design that would be employed in a future retinal prosthesis device being developed by our group. The RGCs are morphologically realistic and allow examination of the biophysical responses of intracellular compartments to externally applied currents. A number of stimulation paradigms are simulated including the use of monopolar, hexapolar and quasi-monopolar return paths. The model provides a powerful simulation tool to test and optimize electrical stimulation strategies for future retinal prosthesis devices. PMID- 26736750 TI - A 3D-continuum bidomain model of retinal electrical stimulation using an anatomically detailed mesh. AB - A continuum bidomain model of sub-retinal electrical stimulation on an anatomically detailed mesh of retina is presented. The underlying geometry is made up of 256 B-scans of optical coherence tomography (OCT) images of a healthy human retina, covering approximately 6*2 mm(2) centered on the macula. The OCT images are initially segmented and digitized into five major retinal layers comprising passive and active retinal cell types. This computational mesh is then used to model a subretinal hexapolar biphasic electrical stimulation. Our results indicate that the ultra-structure of the retina results in an asymmetric spatial extracellular potential distribution, leading to an irregular pattern of retinal ganglion cell activation. This finding is in contrast to focal circular activation previously reported in retinal electrical stimulation modeling with a uniform mesh. PMID- 26736751 TI - A 3-D admittance-level computational model of a rat hippocampus for improving prosthetic design. AB - Hippocampal prosthetic devices have been developed to bridge the gap between functioning portions of the hippocampus, in order to restore lost memory functionality in those suffering from brain injury or diseases. One approach taken in recent neuroprosthetic design is to use a multi-input, multi-output device that reads data from the CA3 in the hippocampus and electrically stimulates the CA1 in an attempt to mimic the appropriate firing pattern that would occur naturally between the two areas. However, further study needs to be conducted in order to optimize electrode placement, pulse magnitude, and shape for creating the appropriate firing pattern. This paper describes the creation and implementation of an anatomically correct 3D model of the hippocampus to simulate the electric field patterns and axonal activation from electrical stimulation due to an implanted electrode array. The activating function was applied to the voltage results to determine the firing patterns in possible axon locations within the CA1. PMID- 26736752 TI - Analysis of bipolar external excitation of spherical tissue by spatially opposed current source and sink points. AB - The recently increasing role in medical imaging that electrophysiology plays has spurned the need for its quantitative analysis at all scales-ions, cells, tissues, organs, etc.; so, here is presented a model of nerve tissue in a spherical volume excited by a point current source at one pole and a point current sink at the opposite pole. The sphere of tissue is described as an isotropic bidomain, consisting of the intra- and extra-cellular regions and the membrane that separates them, and is immersed in an infinite isotropic conductive bath. The system of coupled differential equations is solved by redefining the domains to be in terms of a monodomain and a membrane. The solution takes the form of an infinite sum of the product of certain transcendental functions. The study concludes with a numeric example in which the boundary conditions are shown to be satisfied, validating this analysis, paving the way for more sophisticated models of excitable tissue. PMID- 26736753 TI - External current application in a bidomain model of active neural tissue. AB - The formal treatment of tissue as two coupled continua is referred to as a bidomain model. Bidomain models have recently been used to describe the properties of neural tissue and nerve fiber bundles [1, 2]. By adapting the Hodgkin Huxley equations in COMSOL Multiphysics, we have investigated the propagation of an action potential through neural tissue by external current stimulation. PMID- 26736754 TI - Reactive near field electromagnetic axonal communication channels and their role in neurodegenerative diseases. AB - Research focus is on the micron-scale subsystem of the human nervous system known as the axon, or nerve fibre. In studying what has been traditionally treated as an electrochemical subsystem, we find that the axon is both an electrochemical and electromagnetic link in an intricately designed network. This work offers a game changing look at phenomena which enable interaction among millions of fibres tightly packed in bundles and tracts in the human peripheral and central nervous systems, respectively. We maintain that these fibres do not act independently as generally believed, but form intricate spatial and temporal near-field networks. An understanding of these networks will lead to improved diagnostics and therapeutics for neurodegenerative diseases. PMID- 26736755 TI - Spatial filter and feature selection optimization based on EA for multi-channel EEG. AB - The EEG signals employed for BCI systems are generally band-limited. The band limited multiple Fourier linear combiner (BMFLC) with Kalman filter was developed to obtain amplitude estimates of the EEG signal in a pre-fixed frequency band in real-time. However, the high-dimensionality of the feature vector caused by the application of BMFLC to multi-channel EEG based BCI deteriorates the performance of the classifier. In this work, we apply evolutionary algorithm (EA) to tackle this problem. The real-valued EA encodes both the spatial filter and the feature selection into its solution and optimizes it with respect to the classification error. Three BMFLC based BCI configurations are proposed. Our results show that the BMFLC-KF with covariance matrix adaptation evolution strategy (CMAES) has the best overall performance. PMID- 26736756 TI - Effects of feedback latency on P300-based brain-computer interface. AB - Feedback has been shown to affect performance when using a Brain-Computer Interface (BCI) based on sensorimotor rhythms. In contrast, little is known about the influence of feedback on P300-based BCIs. There is still an open question whether feedback affects the regulation of P300 and consequently the operation of P300-based BCIs. In this paper, for the first time, the influence of feedback on the P300-based BCI speller task is systematically assessed. For this purpose, 24 healthy participants performed the classic P300-based BCI speller task, while only half of them received feedback. Importantly, the number of flashes per letter was reduced on a regular basis in order to increase the frequency of providing feedback. Experimental results showed that feedback could significantly improve the P300-based BCI speller performance, if it was provided in short time intervals (e.g. in sequences as short as 4 to 6 flashes per row/column). Moreover, our offline analysis showed that providing feedback remarkably enhanced the relevant ERP patterns and attenuated the irrelevant ERP patterns, such that the discrimination between target and non-target EEG trials increased. PMID- 26736757 TI - Modulation of the inter-hemispheric asymmetry of motor-related brain activity using brain-computer interfaces. AB - Non-invasive brain stimulation has shown promising results in neurorehabilitation for motor-impaired stroke patients, by rebalancing the relative involvement of each hemisphere in movement generation. Similarly, brain-computer interfaces have been used to successfully facilitate movement-related brain activity spared by the infarct. We propose to merge both approaches by using BCI to train stroke patients to rebalance their motor-related brain activity during motor tasks, through the use of online feedback. In this pilot study, we report results showing that some healthy subjects were able to learn to spontaneously up- and/or down-regulate their ipsilateral brain activity during a single session. PMID- 26736758 TI - Bring mental activity into action! An enhanced online co-adaptive brain-computer interface training protocol. AB - Non-stationarity and inherent variability of the noninvasive electroencephalogram (EEG) makes robust recognition of spontaneous EEG patterns challenging. Reliable modulation of EEG patterns that a BCI can robustly detect is a skill that users must learn. In this paper, we present a novel online co-adaptive BCI training paradigm. The system autonomously screens users for their ability to modulate EEG patterns in a predictive way and adapts its model parameters online. Results of a supporting study in seven first-time BCI users with disability are very encouraging. Three of 7 users achieved online accuracy > 70% for 2-class BCI control after 24 minutes of training. Online performance in 6 of 7 users was significantly higher than chance level. Online control was based on one single bipolar EEG channel. Beta band activity carried most discriminant information. Our fully automatic co-adaptive online approach allows to evaluate whether user benefit from current BCI technology within a reasonable timescale. PMID- 26736759 TI - Orientation-modulated attention effect on visual evoked potential: Application for PIN system using brain-computer interface. AB - This research demonstrates the orientation-modulated attention effect on visual evoked potential. We combined this finding with our previous findings about the motion-modulated attention effect and used the result to develop novel visual stimuli for a personal identification number (PIN) application based on a brain computer interface (BCI) framework. An electroencephalography amplifier with a single electrode channel was sufficient for our application. A computationally inexpensive algorithm and small datasets were used in processing. Seven healthy volunteers participated in experiments to measure offline performance. Mean accuracy was 83.3% at 13.9 bits/min. Encouraged by these results, we plan to continue developing the BCI-based personal identification application toward real time systems. PMID- 26736760 TI - Classification of unconscious like/dislike decisions: First results towards a novel application for BCI technology. AB - More and more applications for BCI technology emerge that are not restricted to communication or control, like gaming, rehabilitation, Neuro-IS research, neuro economics or security. In this context a so called passive BCI, a system that derives its outputs from arbitrary brain activity for enriching a human-machine interaction with implicit information on the actual user state will be used. Concretely EEG-based BCI technology enables the use of signals related to attention, intentions and mental state, without relying on indirect measures based on overt behavior or other physiological signals which is an important point e.g. in Neuromarketing research. The scope of this pilot EEG-study was to detect like/dislike decisions on car stimuli just by means of ERP analysis. Concretely to define user preferences concerning different car designs by implementing an offline BCI based on shrinkage LDA classification. Although classification failed in the majority of participants the elicited early (sub) conscious ERP components reflect user preferences for cars. In a broader sense this study should pave the way towards a "product design BCI" suitable for neuromarketing research. PMID- 26736762 TI - Exploratory analysis of associations between individual lifestyles and heart rate variability -based recovery during sleep. AB - Sleep is the most important period for recovering from daily stress and load. Assessment of the stress recovery during sleep is therefore, an important metric for care and quality of life. Heart rate variability (HRV) is a non-invasive marker of autonomic nervous system (ANS) activity, and HRV-based methods can be used to assess physiological recovery, characterized by parasympathetic domination of the ANS. HRV is affected by multiple factors of which some are unmodifiable (such as age and gender) but many are related to daily lifestyle choices (e.g. alcohol consumption, physical activity, sleeping times). The purpose of this study was to investigate the association of these aforementioned factors on HRV-based recovery during sleep on a large sample. Variable importance measures yielded by random forest were used for identifying the most relevant predictors of sleep-time recovery. The results emphasize the disturbing effects of alcohol consumption on sleep-time recovery. Good physical fitness is associated to good recovery, but acute physical activity seems to challenge or delay the recovery process for the next night. Longer sleeping time enables more recovery minutes, but the proportion of recovery (i.e. recovery efficiency) seems to peak around 7.0-7.25 hours of sleep. PMID- 26736761 TI - Intrapartum fetal heart rate classification from trajectory in Sparse SVM feature space. AB - Intrapartum fetal heart rate (FHR) constitutes a prominent source of information for the assessment of fetal reactions to stress events during delivery. Yet, early detection of fetal acidosis remains a challenging signal processing task. The originality of the present contribution are three-fold: multiscale representations and wavelet leader based multifractal analysis are used to quantify FHR variability ; Supervised classification is achieved by means of Sparse-SVM that aim jointly to achieve optimal detection performance and to select relevant features in a multivariate setting ; Trajectories in the feature space accounting for the evolution along time of features while labor progresses are involved in the construction of indices quantifying fetal health. The classification performance permitted by this combination of tools are quantified on a intrapartum FHR large database (? 1250 subjects) collected at a French academic public hospital. PMID- 26736763 TI - Time-dependent sleep stage transition model based on heart rate variability. AB - A new model is proposed to automatically classify sleep stages using heart rate variability (HRV). The generative model, based on the characteristics that the distribution and the transition probabilities of sleep stages depend on the elapsed time from the beginning of sleep, infers the sleep stage with a Gibbs sampler. Experiments were conducted using a public data set consisting of 45 healthy subjects and the model's classification accuracy was evaluated for three sleep stages: wake state, rapid eye movement (REM) sleep, and non-REM sleep. Experimental results demonstrated that the model provides more accurate sleep stage classification than conventional (naive Bayes and Support Vector Machine) models that do not take the above characteristics into account. Our study contributes to improve the quality of sleep monitoring in the daily life using easy-to-wear HRV sensors. PMID- 26736764 TI - MICROST: A mixed approach for heart rate monitoring during intensive physical exercise using wrist-type PPG Signals. AB - The performance of heart rate (HR) monitoring using wrist-type photoplethysmographic (PPG) signals is strongly influenced by motion artifacts (MAs), since the intensive physical exercises are common in real world. Few works focus on this study so far because of unsatisfying quality of corrupted PPG signals. In this paper, we propose an accurate and efficient strategy, named MICROST, which estimates heart rate based on a mixed approach. The MICROST framework is designed as a MIxed algorithm which consists of acceleration Classification (AC), fiRst-frame prOcessing and heuriStic Tracking. Experimental results using recordings from 12 subjects during fast running and intensive movement showed the average absolute error of heart rate estimation was 2.58 beat per minute (BPM), and the Pearson correlation between the estimates and the ground-truth of heart rate was 0.988. We discuss our approach in real time to face the applications of wearable devices such as smart-watches in reality. PMID- 26736765 TI - Psychophysiology of disgust: ECG noise entropy as a biomarker. AB - The identification or classification of emotions allows the description of the person's state and, therefore, the inference of their preferences. The basic emotion of disgust, in particular, allows the organism to protect itself against diseases. Usually, the decrease in heart rate is associated with this emotion. As an avoidance behavior, when facing with disgust stimuli, the body reacts with movements, such as muscle contraction, etc. These reactions are evidenced in the electrocardiogram (ECG) as noise responses. In this paper, we propose the amount of ECG noise measured by the noise entropy as a new biomarker in emotion identification, which has been neglected in the literature. Our results showed that the noise entropy was able to discriminate between disgust, fear and neutral conditions in 88% (p<;0.05). It was also evidenced in this dataset that the median noise entropy in disgust was higher than in neutral and in fear conditions. PMID- 26736766 TI - Classification of hypoxic-ischemic encephalopathy using long term heart rate variability based features. AB - Hypoxic-ischemic HI injury at the time of birth could lead to severe neurological dysfunction at an older age. Therapeutic hypothermia can be used to treat HI if severity of injury is determined within 6 hours of birth. EEG is generally used to assess the brain injury but it is neither widely recorded after birth nor is the expertise to interpret it commonly available. This study presents a novel system to classify HI injury using heart rate variability. The system makes decisions based on long-term statistical features extracted from the short-term HRV features. The preliminary results show the promising performance and robustness of the proposed method given a poor quality dataset. This tool can serve as decision support system in remote maternity units to help clinical staff to initiate hypothermia. PMID- 26736767 TI - Accuracy of devices for self-monitoring of blood glucose: A stochastic error model. AB - Self-monitoring of blood glucose (SMBG) devices are portable systems that allow measuring glucose concentration in a small drop of blood obtained via finger prick. SMBG measurements are key in type 1 diabetes (T1D) management, e.g. for tuning insulin dosing. A reliable model of SMBG accuracy would be important in several applications, e.g. in in silico design and optimization of insulin therapy. In the literature, the most used model to describe SMBG error is the Gaussian distribution, which however is simplistic to properly account for the observed variability. Here, a methodology to derive a stochastic model of SMBG accuracy is presented. The method consists in dividing the glucose range into zones in which absolute/relative error presents constant standard deviation (SD) and, then, fitting by maximum-likelihood a skew-normal distribution model to absolute/relative error distribution in each zone. The method was tested on a database of SMBG measurements collected by the One Touch Ultra 2 (Lifescan Inc., Milpitas, CA). In particular, two zones were identified: zone 1 (BG<=75 mg/dl) with constant-SD absolute error and zone 2 (BG>75mg/dl) with constant-SD relative error. Mean and SD of the identified skew-normal distributions are, respectively, 2.03 and 6.51 in zone 1, 4.78% and 10.09% in zone 2. Visual predictive check validation showed that the derived two-zone model accurately reproduces SMBG measurement error distribution, performing significantly better than the single zone Gaussian model used previously in the literature. This stochastic model allows a more realistic SMBG scenario for in silico design and optimization of T1D insulin therapy. PMID- 26736768 TI - Patient decision-making of CGM sensor driven insulin therapies in type 1 diabetes: In silico assessment. AB - In type 1 diabetes (T1D) therapy, continuous glucose monitoring (CGM) sensors, which provide glucose concentration in the subcutis every 1-5 min for 7 consecutive days, should allow in principle a more efficient insulin dosing than that based on the conventional 3-4 self-monitoring of blood glucose (SMBG) measurements per day. However, CGM, at variance with SMBG, is still not approved for insulin dosing in T1D management because regulatory agencies, e.g. FDA, are looking for more factual evidence on its safety. An in silico assessment of SMBG- vs CGM-driven insulin therapy can be a first step. Here we present a simulation model of T1D patient decision-making obtained by interconnecting models of glucose-insulin dynamics, SMBG and CGM measurement errors, carbohydrates-counting errors, insulin boluses time variability and forgetfulness, and subcutaneous insulin pump delivery. Inter- and intra- patient variability of model parameters are considered. The T1D patient decision-making model allows to run realistic multi-day simulations scenarios in a population of virtual subjects. We present the first results of simulations run in 20 virtual subjects over a 7-day period, which demonstrates that additional information brought by CGM (trend and hypo/hyperglycemic warnings) with respect to SMBG produces a statistically significant increment (about of 9%) of time spent by the patient in the euglycemic range (70-180 mg/dl). PMID- 26736769 TI - Multi-lag HRV analysis discriminates disease progression of post-infarct people with no diabetes versus diabetes. AB - Diabetes mellitus is associated with multi-organ system dysfunction including the cardiovascular and autonomic nervous system. Although it is well documented that post-infarct patients are at higher risk of sudden cardiac death, diabetes adds an additional risk associated with autonomic neuropathy. However it is not known how the presence of diabetes in post-infarct patients affects cardiac rhythm. The majority of HRV algorithms for determining cardiac inter-beat interval changes describe only beat-to-beat variation determined over the whole heart rate recording and therefore do not consider the ability of a heart beat to influence a train of succeeding beats nor whether or how the temporal dynamics of the inter beat intervals changes. This study used Poincare Plot derived features and incorporated increased lag intervals to compare post-infarct patients with no history of prior infarct with or without diabetes and found that for the nondiabetic post-infarct patients only increased lag of short term correlation (SD1) predicted mortality, whereas in the diabetic post-infarct group only long term correlations (SD2) significantly predicted mortality at a follow-up period of eight years. Temporal dynamics measured as a complex correlation measure (CCM) was also a significant predictor of mortality only in the diabetic post-infarct cohort. This study highlights the different pathophysiological progression and risk profile associated with presence of diabetes in a post-infarct patient population at eight year follow-up. PMID- 26736770 TI - Assessment of beta-cell function and insulin secretion in subjects that underwent renal transplantation. AB - In this study we aimed to assess the performance of various indices of beta-cell function derived from oral glucose tolerance test (OGTT) in subjects that underwent renal transplantation. Impaired insulin secretion seems in fact central for development of new onset diabetes after transplantation, but its assessment has not been systematically evaluated. Twenty subjects underwent a 75 g 2h-OGTT for measurement of glucose, insulin, C-peptide. OGTT indices of beta-cell function were either derived by mathematical modeling (yielding the reference index: glucose sensitivity) or were empirical: insulinogenic index (IGI), IGI derived indices, whole shape C-peptide (WHOSH_CP). Indices of beta cell function, showed significant correlation with glucose sensitivity (R(2)=0.40-0.86, all P<;0.003). The majority of beta-cell function indices provided comparable results also when subjects were divided into subgroups according to sex, age, body mass index, mean glycemia. In conclusion, in transplanted subjects OGTT empirical indices are typically acceptable for the estimation of beta-cell function. PMID- 26736771 TI - Decrease of EEG Coherence during hypoglycemia in type 1 diabetic subjects. AB - Hypoglycemic events have been proven to be associated with measurable EEG changes. Several works in the literature have evaluated these changes by considering approaches at the single EEG channel level, but multivariate analyses have been scarcely investigated in Type 1 diabetes (T1D) subjects. The aim of the present work is to assess if and how hypoglycemia affects EEG coherence in a subset of EEG channels acquired in a hospital setting where eye- and muscle activation-induced artifacts are virtually absent. In particular, EEG multichannel data, acquired in 19 T1D hospitalized subjects undertaken to an insulin-induced hypoglycemia experiment, are considered. Computation of Partial Directed Coherence (PDC) through multivariate autoregressive models of P3-A1A2, P4-A1A2, C3-A1A2 and C4-A1A2 EEG channels shows that a decrease in the value of coherence, most likely related to the progressive loss of cognitive function and altered cerebral activity, occurs when passing from eu- to hypoglycemia, in both theta ([4, 8] Hz) and alpha ([8, 13] Hz) bands. PMID- 26736772 TI - Improving the prediction performance of PLSR using RReliefF and FSD for the quantitative analysis of glucose in Near Infrared spectra. AB - This paper proposes a novel pre-processing method, Fourier Self Deconvoluted RReliefF (FSDR) that is based on combining Fourier Self Deconvolution (FSD) with the Regressional Relief-F (RReliefF) processing to improve the prediction performance of the Partial Least Squares Regression (PLSR) model in Near Infrared (NIR) spectroscopy. The FSD is used to eliminate both the baseline variations and high frequency noise from the raw spectra and the RReliefF is applied as a feature weighting algorithm. The proposed FSDR-PLSR technique is validated for the determination of glucose from NIR spectra of a mixture composed of triacetin, urea and glucose in a phosphate buffer solution where the individual component concentrations are selected to be within their physiological range in blood. The results obtained confirm that the proposed pre-processing technique improved the prediction performance of the PLSR model. PMID- 26736773 TI - Detection and analysis of temperature-sensitive dermal blood perfusion dynamics and distribution by a hybrid camera system. AB - In this paper we present an application of two optical imaging modalities for non invasive assessment of dermal perfusion. This hybrid setup consists of a photo plethysmographic camera sensing in the visible spectrum and a thermal camera sensing in the infrared-C-band. This allows to combine the information of both sources complementarily: The extracted perfusion index as well as the skin surface temperature. The feasibility of the presented system is tested in two studies with local temperature stress on the forehead of a subject. In the first, a local cooling on the subject's forehead is monitored and further analyzed. In the second, skin perfusion reactions to heat are considered. For both experiments the results are compared to baseline measurements and non-affected areas in the field of view of the cameras. As results, the dependencies between temperature and perfusion change are presented. Further, influences of the stressor can be visualized in functional mappings of calculated perfusion indices. For the performed test, a linear correlation between temperature and perfusion change is obtained. PMID- 26736774 TI - Macrophage with gold nanorod visualized by optical-resolution and acoustic resolution photoacoustic microscopes. AB - Macrophages play a key role in inflammation and they are frequently observed in vulnerable atherosclerotic plaque. In the present study, macrophages phagocytosing gold nanorod (AuNR) were observed by optical-resolution (OR) and acoustic-resolution (AR) photoacoustic microscope (PAM). The OR-PAM consisted of diode laser optically focused to 60 micron and planar ultrasonic transducer with the central frequency of 8 MHz placed under the object. AR-PAM consisted of concave ultrasonic transducer with the central frequency of 20 MHz and optical fiber through the center hole of the transducer for laser irradiation. First, PA signal from gold, silver and copper wire were measured in order to determine the best metal substrate for enhancing PA contrast. Gold generated largest PA signal. AuNR with the resonance wavelength of 1064 nm was co-cultured with the macrophages for phagocytosis. PA signal was successfully detected from macrophages with AuNR by both OR-PAM and AR-PAM. PA imaging of the macrophages with AuNR indicates inflammation in the vulnerable plaque and AR-PAM method would be applicable for clinical settings. PMID- 26736775 TI - Multi-modal data fusion for Cardiac Resynchronization Therapy planning and assistance. AB - Cardiac Resynchronization Therapy (CRT) has been validated as an efficient treatment for selected patients suffering from heart failure with cardiac dyssynchrony. In case of bi-ventricular stimulation, the response to the therapy may be improved by an optimal choice of the left ventricle (LV) pacing sites. The characterization of LV properties to select the best candidate sites and to precise their access modes would be useful for the clinician in pre- and per operative stages. For that purpose, we propose a new pre-operative analysis solution integrating previously developed multi-modal data registration methods and a new segmentation process of their coronary venous access. Moreover, a novel visualization interface is proposed to help the clinician to visualize the most relevant pacing sites and their access during the implantation in the operating room. This work is illustrated on real CRT data patients. PMID- 26736776 TI - Combining 3D models with 2D infrared images for medical applications. AB - Infrared images are very useful for providing physiological information, although the representation is two-dimensional. On the other hand, a 3D scanning system is able to generate precise 3D spatial models of the area under study. This paper presents a methodology for combining both imaging modalities into a single representation. The Structure from Motion (SfM) technique is used in order to find the correct infrared camera's positioning and rotations in the space. Then, those 2D infrared images generate a 3D SfM model. Following this stage, the SfM model is replaced by an accurate 3D model from a scanning system, which is wrapped around by the infrared images. The experiments performed with a volunteer's face have shown that the proposed methodology successfully reconstruct a unique 3D surface model, which is able to deliver potential clinical applications. PMID- 26736777 TI - Prostate whole-mount histology reconstruction and registration to MRI for correlating in-vivo observations with biological findings. AB - Multi-parametric magnetic resonance imaging (mMRI) is the standard exam for prostate cancer diagnosis, staging and risk assessment in current clinical routine. Correlating mMRI in-vivo observations with biological findings from radical prostatectomy specimen would improve the optimal therapy selection. Thus, we proposed a method for reconstructing and registering the prostate whole-mount histology (WMH) to the MRI, considering a thin slicing of the prostatectomy specimen. The method was evaluated on 3 patients, included in a prospective study, for which hematein-eosinsafran and immunohistochemistry stainings were performed. The registration error was assessed by measuring the Euclidean distance between landmarks, previously identified by an expert on both mMRI and histological slices. The mean error was 4:90alpha1:34 mm. Our method demonstrated promising results for registering prostate WMH to in-vivo mMRI, thus allowing for spatial accurate correlation between radiologic observations and biological information. PMID- 26736778 TI - Automatic segmentation of lymph vessel wall using optimal surface graph cut and hidden Markov Models. AB - We present a novel method to segment the lymph vessel wall in confocal microscopy images using Optimal Surface Segmentation (OSS) and hidden Markov Models (HMM). OSS is used to preform a pre-segmentation on the images, to act as the initial state for the HMM. We utilize a steerable filter to determine edge based filters for both of these segmentations, and use these features to build Gaussian probability distributions for both the vessel walls and the background. From this we infer the emission probability for the HMM, and the transmission probability is learned using a Baum-Welch algorithm. We transform the segmentation problem into one of cost minimization, with each node in the graph corresponding to one state, and the weight for each node being defined using its emission probability. We define the inter-relations between neighboring nodes using the transmission probability. Having constructed the problem, it is solved using the Viterbi algorithm, allowing the vessel to be reconstructed. The optimal solution can be found in polynomial time. We present qualitative and quantitative analysis to show the performance of the proposed method. PMID- 26736779 TI - A custom grow-cut based scheme for 2D-gel image segmentation. AB - This work introduces a novel method for the detection and segmentation of protein spots in 2D-gel images. A multi-thresholding approach is utilized for the detection of protein spots, while a custom grow-cult algorithm combined with region growing and morphological operators is used for the segmentation process. The experimental evaluation against four state-of-the-art 2D-gel image segmentation algorithms demonstrates the superiority of the proposed approach and indicates that it constitutes an advantageous and reliable solution for 2D-gel image analysis. PMID- 26736780 TI - Unsupervised detection of liver lesions in CT images. AB - This work presents an automatic approach for liver lesions detection in CT images. In this approach, liver is first segmented using fast and reliable semi automatic technique. After liver segmentation, lesion detection is formulated as an unsupervised segmentation approach to alleviate tedious user interaction or prior learning requirements. The Meanshift clustering technique is utilized to separate different liver tissues in each CT slice. Consequently, a rule-based system is proposed to automatically and dynamically estimate healthy and unhealthy tissues distributions, and produces initial estimation of defected tissue. Finally, the graph cuts algorithm is employed to refine the initial detection and produces the finial lesions. Validation of the proposed approach using 15 patients' CT data shows high detection rate of 93%, which makes it an efficient initial opinion in the diagnosis process. PMID- 26736781 TI - A unified framework for automatic wound segmentation and analysis with deep convolutional neural networks. AB - Wound surface area changes over multiple weeks are highly predictive of the wound healing process. Furthermore, the quality and quantity of the tissue in the wound bed also offer important prognostic information. Unfortunately, accurate measurements of wound surface area changes are out of reach in the busy wound practice setting. Currently, clinicians estimate wound size by estimating wound width and length using a scalpel after wound treatment, which is highly inaccurate. To address this problem, we propose an integrated system to automatically segment wound regions and analyze wound conditions in wound images. Different from previous segmentation techniques which rely on handcrafted features or unsupervised approaches, our proposed deep learning method jointly learns task-relevant visual features and performs wound segmentation. Moreover, learned features are applied to further analysis of wounds in two ways: infection detection and healing progress prediction. To the best of our knowledge, this is the first attempt to automate long-term predictions of general wound healing progress. Our method is computationally efficient and takes less than 5 seconds per wound image (480 by 640 pixels) on a typical laptop computer. Our evaluations on a large-scale wound database demonstrate the effectiveness and reliability of the proposed system. PMID- 26736782 TI - 3-dimensional throat region segmentation from MRI data based on Fourier interpolation and 3-dimensional level set methods. AB - A new algorithm for 3D throat region segmentation from magnetic resonance imaging (MRI) is presented. The proposed algorithm initially pre-processes the MRI data to increase the contrast between the throat region and its surrounding tissues and to reduce artifacts. Isotropic 3D volume is reconstructed using the Fourier interpolation. Furthermore, a cube encompassing the throat region is evolved using level set method to form a smooth 3D boundary of the throat region. The results of the proposed algorithm on real and synthetic MRI data are used to validate the robustness and accuracy of the algorithm. PMID- 26736783 TI - RFA-cut: Semi-automatic segmentation of radiofrequency ablation zones with and without needles via optimal s-t-cuts. AB - In this contribution, we present a semi-automatic segmentation algorithm for radiofrequency ablation (RFA) zones via optimal s-t-cuts. Our interactive graph based approach builds upon a polyhedron to construct the graph and was specifically designed for computed tomography (CT) acquisitions from patients that had RFA treatments of Hepatocellular Carcinomas (HCC). For evaluation, we used twelve post-interventional CT datasets from the clinical routine and as evaluation metric we utilized the Dice Similarity Coefficient (DSC), which is commonly accepted for judging computer aided medical segmentation tasks. Compared with pure manual slice-by-slice expert segmentations from interventional radiologists, we were able to achieve a DSC of about eighty percent, which is sufficient for our clinical needs. Moreover, our approach was able to handle images containing (DSC=75.9%) and not containing (78.1%) the RFA needles still in place. Additionally, we found no statistically significant difference (p<;0.423) between the segmentation results of the subgroups for a Mann-Whitney test. Finally, to the best of our knowledge, this is the first time a segmentation approach for CT scans including the RFA needles is reported and we show why another state-of-the-art segmentation method fails for these cases. Intraoperative scans including an RFA probe are very critical in the clinical practice and need a very careful segmentation and inspection to avoid under treatment, which may result in tumor recurrence (up to 40%). If the decision can be made during the intervention, an additional ablation can be performed without removing the entire needle. This decreases the patient stress and associated risks and costs of a separate intervention at a later date. Ultimately, the segmented ablation zone containing the RFA needle can be used for a precise ablation simulation as the real needle position is known. PMID- 26736784 TI - A Finite element model of tactile flow for softness perception. AB - Touch is an extremely dynamic sense. To take into account this aspect, it has been hypothesized that there are mechanisms in the brain that specialize in processing dynamic tactile stimuli, in a way not too dissimilar from what happens for optical flow in dynamic vision. The concept of tactile flow, related to the rate of expansion of isostrain volumes in the human fingerpad, was used to explain some perceptual illusions as well as mechanisms of human softness perception. In this paper we describe a computational model of tactile flow, and apply it to a finite element model of interaction between deformable bodies. The shape and material properties of the bodies are modeled from those of a human fingertip interacting with specimens with different softness properties. Results show that the rate of expansion of isostrain volumes can be used to discriminate different materials in terms of their softness characteristics. PMID- 26736785 TI - Concurrent multibody and Finite Element analysis of the lower-limb during amputee running. AB - Lower-limb amputee athletes use Carbon fiber Energy Storage and Return (ESAR) prostheses during high impact activities such as running. The advantage provided to amputee athletes due to the energy-storing properties of ESAR prostheses is as yet uncertain. Conventional energy analysis methods for prostheses rely upon multibody models with articulating joints. Alternatively, Finite Element (FE) analysis treats bodies as a deforming continuum and can therefore calculate the energy stored without using these rigid-body mechanics assumptions. This paper presents a concurrent multibody and FE model of the femur, tibia, socket and ESAR prosthesis of a transtibial amputee athlete during sprinting. Gait analysis spatial data was used to conduct an offline simulation of the affected leg's stance phase in COMSOL Multiphysics. The calculated peak elastic strain energy of the prosthesis was 80J, with an overall RMSE of simulated marker displacement of 4.19 mm. This concurrent model presents a novel method for analyzing in vivo ESAR prosthesis behavior. PMID- 26736786 TI - Upper limb strength estimation of physically impaired persons using a musculoskeletal model: A sensitivity analysis. AB - Sensitivity of upper limb strength calculated from a musculoskeletal model was analyzed, with focus on how the sensitivity is affected when the model is adapted to represent a person with physical impairment. Sensitivity was calculated with respect to four muscle-tendon parameters: muscle peak isometric force, muscle optimal length, muscle pennation, and tendon slack length. Results obtained from a musculoskeletal model of average strength showed highest sensitivity to tendon slack length, followed by muscle optimal length and peak isometric force, which is consistent with existing studies. Muscle pennation angle was relatively insensitive. The analysis was repeated after adapting the musculoskeletal model to represent persons with varying severities of physical impairment. Results showed that utilizing the weakened model significantly increased the sensitivity of the calculated strength at the hand, with parameters previously insensitive becoming highly sensitive. This increased sensitivity presents a significant challenge in applications utilizing musculoskeletal models to represent impaired individuals. PMID- 26736787 TI - Forward dynamics simulation of human figures on assistive devices using geometric skin deformation model. AB - We present a forward dynamics (FD) simulation technique for human figures when they are supported by assistive devices. By incorporating a geometric skin deformation model, called linear blend skinning (skinning), into rigid-body skeleton dynamics, we can model a time-varying geometry of body surface plausibly and efficiently. Based on the skinning model, we also derive a Jacobian (a linear mapping) that maps contact forces exerted on the skin to joint torques, which is the main technical contribution of this paper. This algorithm allows us to efficiently simulate dynamics of human body that interacts with assistive devices. Experimental results showed that the proposed approach can generate plausible motions and can estimate pressure distribution that is roughly comparable to the tactile sensor data. PMID- 26736788 TI - Bipedal spring-damper-mass model reproduces external mechanical power of human walking. AB - Previous authors have long investigated the behavior of different models of passive walkers with stiff or compliant limbs. We investigated a model of bipedal mechanism whose limba are provided with damping and elastic elements. This model is designed for walking along an inclined plane, in order to make up the energy lost due to the damping element with that gained thanks to the lowering the CoM. The proposed model is hence able to steadily walk. In particular we investigated the stability of this model by using the Poincare return map for different dynamical configurations. Then we compared the estimated external mechanical power with experimental data from literature in order to validate the model. Results show that the model is able to reproduce the main features of the time course of the external mechanical power during the gait cycle. Accordingly, dissipative elements coupled with limbs' compliant behavior represent a suitable paradigm, to mimic human locomotion. PMID- 26736789 TI - Optimizing porous lattice structures for orthopaedic implants. AB - Porous lattice structures are increasingly used for tissue and implant device design, and require precise structural characteristics such as stiffness, porosity, volume fraction and surface area. A non-uniform distribution of these properties may be required to suit design requirements or to match in-vivo conditions. Thus, porous lattice design is complex due to competing objectives from the distributed structural properties. A lattice structural design and optimization methods is presented using global objective functions for effective stiffness, porosity, volume fraction and surface area. PMID- 26736790 TI - Feasibility of a biomechatronic EPP Upper Limb Prosthesis Controller. AB - In this paper, we examine the feasibility of an implantable topology of a Biomechatronic Extended Physiological Proprioception (EPP) Upper Limb Prosthesis Controller. Initial findings support the hypothesis that the topology is safe and feasible. This novel controller topology can maintain the advantages of EPP, but without its inherent disadvantages i.e. of the existence of unaesthetic cables, or mechanical linkages. PMID- 26736791 TI - Design and characterization of a powered elbow prosthesis. AB - This paper describes the design of a powered elbow prosthesis, which incorporates a belt and cable drive transmission with a brushless DC motor to achieve an output torque of approximately 18.4 Nm, a backdrive torque of 1.5 Nm, and a speed of up to 360 deg/s while remaining within the anthropomorphic envelope with regard to mass and size. The measured torque and speed of the prosthesis is commensurate with nominal capability of the natural limb (for purposes of performing activities of daily living). PMID- 26736792 TI - Exploiting arm posture synergies in activities of daily living to control the wrist rotation in upper limb prostheses: A feasibility study. AB - Although significant technological advances have been made in the last forty years, natural and effortless control of upper limb prostheses is still an open issue. Commercially available myoelectric prostheses present limited Degrees of Freedom (DoF) mainly because of the lack of available and reliable independent control signals from the human body. Thus, despite the crucial role that an actuated wrist could play in a transradial prosthesis in terms of avoiding compensatory movements, commercial hand prostheses present only manually adjustable passive wrists or actuated rotators controlled by (unnatural) sequential control strategies. In the present study we investigated the synergies between the humeral orientation with respect to the trunk and the forearm pronation/supination angles during the execution of a wide range of activities of daily living, in healthy subjects. Our results showed consistent postural synergies between the two selected body segments for almost the totality of the activities of daily living under investigation. This is a promising result because these postural synergies could be exploited to automatically control the wrist rotator unit in transradial prostheses improving the fluency and the dexterity of the amputee. PMID- 26736793 TI - Pinch-force-magnification mechanism of low degree of freedom EMG prosthetic hand for children. AB - EMG prosthetic hands are being extensively studied for the disabled who need them not only for cosmesis but also for the functions to help them with basic daily activities. However, most EMG prosthetic hands are developed for adults. Since the early use of prosthetic hands is important for the children to accept and adapt to them, we are developing low degrees of freedom (DoF) prosthetic hand that is suitable for children. Due to the limited size of a child's hand, the servo motor which drives the MP joint are small-sized and low-power. Hence, a pinch-force-magnification mechanism is required to improve the pinch force of the EMG prosthetic hand. In this paper we designed a wire-driven mechanism which can magnify pinch force by increasing the length of the MP joint's moment arm. Pinch force measurement experiment validated that the pinch force of the prosthetic hand with the mechanism is more than twice of that of the hand with direct drive. PMID- 26736795 TI - Design and analysis of an underactuated anthropomorphic finger for upper limb prosthetics. AB - This paper presents the design of a linkage based finger mechanism ensuring extended range of anthropomorphic gripping motions. The finger design is done using a path-point generation method based on geometrical dimensions and motion of a typical index human finger. Following the design description, and its kinematics analysis, the experimental evaluation of the finger gripping performance is presented using the finger 3D printed prototype. The finger underactuation is achieved by utilizing mechanical linkage system, consisting of two crossed four-bar linkage mechanisms. It is shown that the proposed finger design can be used to design a five-fingered anthropomorphic hand and has the potential for upper limb prostheses development. PMID- 26736794 TI - Rehand: Realistic electric prosthetic hand created with a 3D printer. AB - Myoelectric prosthetic hands provide an appearance with five fingers and a grasping function to forearm amputees. However, they have problems in weight, appearance, and cost. This paper reports on the Rehand, a realistic electric prosthetic hand created with a 3D printer. It provides a realistic appearance that is same as the cosmetic prosthetic hand and a grasping function. A simple link mechanism with one linear actuator for grasping and 3D printed parts achieve low cost, light weight, and ease of maintenance. An operating system based on a distance sensor provides a natural operability equivalent to the myoelectric control system. A supporter socket allows them to wear the prosthetic hand easily. An evaluation using the Southampton Hand Assessment Procedure (SHAP) demonstrated that an amputee was able to operate various objects and do everyday activities with the Rehand. PMID- 26736796 TI - Linking wheelchair kinetics to glenohumeral joint demand during everyday accessibility activities. AB - The aim of the study was to investigate if push-rim kinetics could be used as markers of glenohumeral joint demand during manual wheelchair accessibility activities; demonstrating a method of biomechanical analysis that could be used away from the laboratory. Propulsion forces, trunk and upper limb kinematics and surface electromyography were recorded during four propulsion tasks (level, 2.5% cross slope, 6.5% incline and 12% incline). Kinetic and kinematic data were applied to an OpenSim musculoskeletal model of the trunk and upper limb, to enable calculation of glenohumeral joint contact force. Results demonstrated a positive correlation between propulsion forces and glenohumeral joint contact forces. Both propulsion forces and joint contact forces increased as the task became more challenging. Participants demonstrated increases in trunk flexion angle as the requirement for force application increased, significantly so in the 12% incline. There were significant increases in both resultant glenohumeral joint contact forces and peak and mean normalized muscle activity levels during the incline tasks. This study demonstrated the high demand placed on the glenohumeral joint during accessibility tasks, especially as the gradient of incline increases. A lightweight instrumented wheelchair wheel has potential to guide the user to minimize upper limb demand during daily activity. PMID- 26736797 TI - Reliability of phantom pain relief in neurorehabilitation using a multimodal virtual reality system. AB - The objective of this study is to demonstrate the reliability of relief from phantom limb pain in neurore-habilitation using a multimodal virtual reality system. We have developed a virtual reality rehabilitation system with multimodal sensory feedback and applied it to six patients with brachial plexus avulsion or arm amputation. In an experiment, patients executed a reaching task using a virtual phantom limb displayed in a three-dimensional computer graphic environment manipulated by their real intact limb. The intensity of the phantom limb pain was evaluated through a short-form McGill pain questionnaire. The experiments were conducted twice on different days at more than four-week intervals for each patient. The reliability of our task's ability to relieve pain was demonstrated by the test-retest method, which checks the degree of the relative similarity between the pain reduction rates in two experiments using Fisher's intraclass correlation coefficient (ICC). The ICC was 0.737, indicating sufficient reproducibility of our task. The average of the reduction rates across participants was 50.2%, and it was significantly different from 0 (p <; 0:001). Overall, our findings indicate that neurorehabilitation using our multimodal virtual reality system reduces the phantom limb pain with sufficient reliability. PMID- 26736798 TI - A sensory feedback system for prosthetic hand based on evoked tactile sensation. AB - The lack of reliable sensory feedback has been one of the barriers in prosthetic hand development. Restoring sensory function from prosthetic hand to amputee remains a great challenge to neural engineering. In this paper, we present the development of a sensory feedback system based on the phenomenon of evoked tactile sensation (ETS) at the stump skin of residual limb induced by transcutaneous electrical nerve stimulation (TENS). The system could map a dynamic pattern of stimuli to an electrode placed on the corresponding projected finger areas on the stump skin. A pressure transducer placed at the tip of prosthetic fingers was used to sense contact pressure, and a high performance DSP processor sampled pressure signals, and calculated the amplitude of feedback stimulation in real-time. Biphasic and charge-balanced current pulses with amplitude modulation generated by a multi-channel laboratory stimulator were delivered to activate sensory nerves beneath the skin. We tested this sensory feedback system in amputee subjects. Preliminary results showed that the subjects could perceive different levels of pressure at the tip of prosthetic finger through evoked tactile sensation (ETS) with distinct grades and modalities. We demonstrated the feasibility to restore the perceptual sensation from prosthetic fingers to amputee based on the phenomenon of evoked tactile sensation (ETS) with TENS. PMID- 26736799 TI - Quantifying facial paralysis using the Kinect v2. AB - Assessment of facial paralysis (FP) and quantitative grading of facial asymmetry are essential in order to quantify the extent of the condition as well as to follow its improvement or progression. As such, there is a need for an accurate quantitative grading system that is easy to use, inexpensive and has minimal inter-observer variability. A comprehensive automated system to quantify and grade FP is the main objective of this work. An initial prototype has been presented by the authors. The present research aims to enhance the accuracy and robustness of one of this system's modules: the resting symmetry module. This is achieved by including several modifications to the computation method of the symmetry index (SI) for the eyebrows, eyes and mouth. These modifications are the gamma correction technique, the area of the eyes, and the slope of the mouth. The system was tested on normal subjects and showed promising results. The mean SI of the eyebrows decreased slightly from 98.42% to 98.04% using the modified method while the mean SI for the eyes and mouth increased from 96.93% to 99.63% and from 95.6% to 98.11% respectively while using the modified method. The system is easy to use, inexpensive, automated and fast, has no inter-observer variability and is thus well suited for clinical use. PMID- 26736800 TI - Tuning of robotic therapy controllers for stroke gait: Using isometrically constrained EMG modular structures. AB - The development of EMG based controllers for automated gait orthosis is a promising intervention for post-stroke gait rehabilitation and assistive device applications. However, the integration of stroke specific modular neuromuscular patterns for the design of active gait assistance controller is largely unexplored. To this end, this work presents preliminary evidence of the associated variability between lower limb muscle activation patterns underlying discrete isometric control objectives and the analogous dynamic subtask during treadmill gait using matrix factorization algorithms. We find that common muscle coordination patterns underlying both isometric and dynamic gait submovements can be used to reconstruct relevant spatio-temporal patterns for healthy locomotion. We propose that synergies extracted isometrically may be sufficient to tune adaptive controller assistance for disruptive linkages in the EMG control signal to impact gait dysfunction. PMID- 26736801 TI - Reconstruction of neural network topology using spike train data: Small-world features of hippocampal network. AB - As the amount of experimental data made publicly accessible has gradually increased in recent years, it is now possible to reconsider many of the longstanding questions in neuroscience. In this paper, we present an efficient frame-work for reconstructing the functional connectivity from the spike train data curated from the Collaborative Research in Computational Neuroscience (CRCNS) program. We used a modified generalized linear model (GLM) framework with L1 norm penalty to investigate 10 datasets. These datasets contain spike train data collected from the hippocampal region of rats performing various tasks. Analysis of the reconstructed network showed that the neural network in the hippocampal region of well-trained rats demonstrated significant small-world features. PMID- 26736802 TI - Characteristics of the neuronal firing patterns in the subthalamic nucleus with graded dopaminergic cell loss in the nigrostriatal pathway. AB - The aim of this study was to evaluate the neuronal firing changes in the subthalamic nucleus (STN) in a graded mouse model of Parkinson's disease. Unilateral graded dopaminergic cell loss in the substantia nigra pars compacta was achieved by injecting different concentrations of 6-hydroxydopamine (6-OHDA) in the right medial forebrain bundle. Electrophysiological analysis of neuronal firing patterns in the STN revealed an increased firing rate, burst index, and interspike interval coefficient of variation in groups treated with higher 6-OHDA concentrations. The results of this study suggest the detailed pathophysiological characteristics of Parkinson's disease in a mouse model. PMID- 26736803 TI - Healthy and pathological cerebellar Spiking Neural Networks in Vestibulo-Ocular Reflex. AB - Since the Marr-Albus model, computational neuroscientists have been developing a variety of models of the cerebellum, with different approaches and features. In this work, we developed and tested realistic artificial Spiking Neural Networks inspired to this brain region. We tested in computational simulations of the Vestibulo-Ocular Reflex protocol three different models: a network equipped with a single plasticity site, at the cortical level; a network equipped with a distributed plasticity, at both cortical and nuclear levels; a network with a pathological plasticity mechanism at the cortical level. We analyzed the learning performance of the three different models, highlighting the behavioral differences among them. We proved that the model with a distributed plasticity produces a faster and more accurate cerebellar response, especially during a second session of acquisition, compared with the single plasticity model. Furthermore, the pathological model shows an impaired learning capability in Vestibulo-Ocular Reflex acquisition, as found in neurophysiological studies. The effect of the different plasticity conditions, which change fast and slow dynamics, memory consolidation and, in general, learning capabilities of the cerebellar network, explains differences in the behavioral outcome. PMID- 26736804 TI - Analysis of EEG variables to measure the affective dimensions of arousal and valence related to the vision of emotional pictures. AB - The present work aims to investigate the electroencephalographic (EEG) activity elicited by the observation of emotional pictures selected from the International Affective Picture System (IAPS) database. We analyzed the evoked activity within time intervals of increasing duration taking into account the related ratings of Valence and Arousal. The scalp statistical maps of Power Spectral Density (PSD), related to pictures with high valence, revealed an enhanced activity across frontal areas in the theta band and the involvement of fronto-parietal circuits in the alpha band. Difference in the processing of low and high arousing pictures, however, seems to be highly dependent on the valence dimension: for low valenced pictures, the difference in arousal was processed immediately after the observation of the picture, while for the high-valenced ones the processing took part in the second part of the observation. These results appear to be congruent with the literature, while the novelty of the current study is represented by the comparison of the activity elicited in different time windows by both the Arousal and Valence dimensions. It is possible, in this way, to observe how the processing of one variable influences the other, creating a dynamic description of the Valence-Arousal space. PMID- 26736805 TI - Higher visual functions in the upper and lower visual fields: A pilot study in healthy subjects. AB - Visual perception is not identical in the upper and lower visual hemifields. The mechanisms behind this difference can be found at the retinal, cortical, or higher attentional level. In this study, a new visual test battery, that involves real-time comparisons of complex visual stimuli, such as shape of objects, and speed of moving dot patterns, in the upper and lower visual hemifields, is presented. This study represents, to our knowledge, the first to implement such a visual test battery in an immersive environment composed of a hemisphere, in order to present visual stimuli in precise regions of the visual field. Ten healthy volunteers were tested in this pilot study. The results showed a higher accuracy in the image matching when the visual test was performed in the lower visual hemifield. PMID- 26736806 TI - Estimation of a large-scale generalized Volterra model for neural ensembles with group lasso and local coordinate descent. AB - Estimation of neural models based on observed spike timing faces challenges as the amount of recorded units increases, especially when identifying detailed model features. Given that neural regions are generally sparsely connected, input selection is a critical step in model estimation but oftentimes computationally and theoretically challenging. In this paper, we detail an efficient methodology for estimating a sparse, nonlinear dynamical multiple-input, single-output model (MISO) applicable to large-scale (n > 50) single-unit recorded activity. The main contribution of this paper is the complete implementation of a principled group lasso and local coordinate descent (LCD) algorithm into a generalized Volterra model (GVM) framework to achieve efficient sparse model estimation. Input selection is achieved with group-lasso by simultaneously selecting groups of parameters that are associated with each input. LCD yields efficient computation as the amount of inputs and parameters increase. We investigate and validate the performance of this estimation procedure with the application to a 64 input simulated model. PMID- 26736807 TI - Early detection of heart failure with varying prediction windows by structured and unstructured data in electronic health records. AB - Heart failure (HF) prevalence is increasing and is among the most costly diseases to society. Early detection of HF would provide the means to test lifestyle and pharmacologic interventions that may slow disease progression and improve patient outcomes. This study used structured and unstructured data from electronic health records (EHR) to predict onset of HF with a particular focus on how prediction accuracy varied in relation to time before diagnosis. EHR data were extracted from a single health care system and used to identify incident HF among primary care patients who received care between 2001 and 2010. A total of 1,684 incident HF cases were identified and 13,525 controls were selected from the same primary care practices. Models were compared by varying the beginning of the prediction window from 60 to 720 days before HF diagnosis. As the prediction window decreased, the performance [AUC (95% CIs)] of the predictive HF models increased from 65% (63%-66%) to 74% (73%-75%) for the unstructured, from 73% (72%-75%) to 81% (80%-83%) for the structured, and from 76% (74%-77%) to 83% (77%-85%) for the combined data. PMID- 26736808 TI - A data-driven feature extraction framework for predicting the severity of condition of congestive heart failure patients. AB - In this paper, we propose a novel methodology for utilizing disease diagnostic information to predict severity of condition for Congestive Heart Failure (CHF) patients. Our methodology relies on a novel, clustering-based, feature extraction framework using disease diagnostic information. To reduce the dimensionality we identify disease clusters using cooccurence frequencies. We then utilize these clusters as features to predict patient severity of condition. We build our clustering and feature extraction algorithm using the 2012 National Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP) which contains 7 million discharge records and ICD-9-CM codes. The proposed framework is tested on Ronald Reagan UCLA Medical Center Electronic Health Records (EHR) from 3041 patients. We compare our cluster-based feature set with another that incorporates the Charlson comorbidity score as a feature and demonstrate an accuracy improvement of up to 14% in the predictability of the severity of condition. PMID- 26736809 TI - Expert knowledge integration in the data mining process with application to cardiovascular risk assessment. AB - The data mining process, when applied to clinical databases, suffers from critical data problems, from noisy acquisitions to missing or incomplete data points. Expert knowledge, in the form of practitioners' experience and clinical guidelines, is already used to manually correct some of these problems, while enhancing expert's confidence in such systems. In this work, we propose the Knowledge-Biased Tree (KB3), a knowledge biased decision tree inducer that is able to exploit IF THEN rules to guide the tree inducing process. The KB3 approach was tested against its unbiased counterpart, the C5.0 algorithm in the cardiovascular risk assessment task. Using a clinical dataset provided by the hospital of Sta Cruz (Lisbon, Portugal) the performance of the proposed algorithm is compared against the unbiased C5.0 and the state of the art risk score used in clinical practice (GRACE risk score). PMID- 26736810 TI - Prediction of health outcomes using big (health) data. AB - The vast amounts of information in the form of electronic medical records are used to develop a novel model of disease progression. The proposed model is based on the representation of a patient's medical history in the form of a binary history vector, motivated by empirical evidence from previous work and validated using a large 'real-world' data corpus. The scope for the use of the described methodology is overarching and ranges from smarter allocation of resources and discovery of novel disease progression patterns and interactions, to incentivization of patients to make lifestyle changes. PMID- 26736811 TI - A reusable ontology for primitive and complex HL7 FHIR data types. AB - HL7((r)) FHIR((r)) standard is a new standard aiming to offer more flexible interoperability mechanisms. We present a stand-alone RDF vocabulary as an OWL ontology that defines the primitive and complex data types of the FHIR framework, alongside their validation rules. We address the non-trivial questions of representing FHIR data types as RDF/OWL constructs in a coherent and complete manner. The proposed ontology can be used as a basic framework, where the complexity of a FHIR-based EHR is not required, while still maintaining semantic cohesion with an industry-based standard. It can also be the base for a complete representation of FHIR model as an ontology. PMID- 26736812 TI - An automatic method for the enrichment of DICOM metadata using biomedical ontologies. AB - This work is a novel contribution for enriching medical images using semantic annotations with a strategy for unifying different ontologies and instances of DICOM medical files. We present the L-MOM library (Library for Mapping of Ontological Metadata) as a tool for making an automatic mapping between instances of DICOM medical files and different medical ontologies (e.g., FMA, RadLex, MeSH). The main contributions are: i) the domain independent L-MOM library which is able to integrate DICOM metadata with ontologies from different domains; ii) a strategy to automatically annotate DICOM data with universally accepted medical ontologies, and provide values of similarity between ontologies and DICOM metadata; and iii) a framework to traverse ontological concepts that characterized clinical studies of patients registered in the framework catalog. PMID- 26736813 TI - Modeling Tumor Treating fields (TTFields) application within a realistic human head model. AB - Tumor Treating Fields (TTFields) are an antimitotic treatment against brain and other tumors. They are applied regionally and non-invasively by inducing intermediate frequency (100-300 kHz) alternating electric field of intensities between 1 to 3 V/cm through transducer arrays placed on the patient's skin close to the tumor. All TTFields studies predicted variability in treatment response among patients, whereas in vitro experiments indicate that the magnitude and direction of the electric field in the tumor might be crucial determinants of efficacy. Differences in the field might arise from varying tumor positions or array placement. By investigating different scenarios within a realistic human head model we hope to advance our understanding of TTFields therapy in clinical practice. We constructed a model from MRI data to calculate the electric field distribution in the brain using the Finite Element Method. An anisotropic electrical conductivity tensor was estimated using diffusion tensor imaging data. The head model contained different tissue types: scalp, skull, cerebrospinal fluid, gray and white matter. Additionally a virtual spherical tumor was included, two positions for the tumor were considered. Transducer arrays were placed on the scalp to model the commonly used device for TTFields delivery. One additional setup of the two transducer pairs was specifically adapted to the second tumor position. The results predict that the electric field strength exceeds the assumed therapeutic threshold value of 1 V/cm in both tumors for both active array pairs. For the second tumor the adapted transducer layout improved field delivery. The average field strength in the tumor further depends on tumor electrical properties. Yet a cystic and a solid tumor experience the same average field strength when treated with TTFields. As a next step towards personalized TTFields therapy, we will explore possible benefits of individualized treatment planning. PMID- 26736814 TI - FEM numerical model study of electrosurgical dispersive electrode design parameters. AB - Electrosurgical dispersive electrodes must safely carry the surgical current in monopolar procedures, such as those used in cutting, coagulation and radio frequency ablation (RFA). Of these, RFA represents the most stringent design constraint since ablation currents are often more than 1 to 2 Arms (continuous) for several minutes depending on the size of the lesion desired and local heat transfer conditions at the applicator electrode. This stands in contrast to standard surgical activations, which are intermittent, and usually less than 1 Arms, but for several seconds at a time. Dispersive electrode temperature rise is also critically determined by the sub-surface skin anatomy, thicknesses of the subcutaneous and supra-muscular fat, etc. Currently, we lack fundamental engineering design criteria that provide an estimating framework for preliminary designs of these electrodes. The lack of a fundamental design framework means that a large number of experiments must be conducted in order to establish a reasonable design. Previously, an attempt to correlate maximum temperatures in experimental work with the average current density-time product failed to yield a good match. This paper develops and applies a new measure of an electrode stress parameter that correlates well with both the previous experimental data and with numerical models of other electrode shapes. The finite element method (FEM) model work was calibrated against experimental RF lesions in porcine skin to establish the fundamental principle underlying dispersive electrode performance. The results can be used in preliminary electrode design calculations, experiment series design and performance evaluation. PMID- 26736815 TI - Internal temperature increase during photothermal tumour ablation in mice using gold nanorods. AB - Laser ablation (LA) is gaining large acceptance in the treatment of tumor. One of the main risks of this treatment is damaging the healthy tissue around the tumor. Among the solutions proposed to improve the selectivity of the LA and to localize heating to tumor tissue, the use of gold nanoparticles is one of the most promising. The aim of this work is threefold: i) to measure the temperature increase within the tumor during plasmonic photothermal therapy using gold nanorods; ii) to investigate the influence of nanorods concentration and laser settings on both the intra-tumoral temperature and the tumor surface temperature; iii) and to establish the nanorods concentrations able to cause tumor resorption at a defined laser settings. Two sets of trials were performed: i) 16 mice were divided in four groups with different treatment time (i.e., 5 min, 2 min, 1 min, and 30s), with constant gold nanorods amount (i.e., 12.5 MUg) and laser power (i.e., 3 W.cm(-2)); ii) 16 mice were divided in four groups treated with different amount of gold nanorods (i.e., control, 12.5 MUg, 25 MUg, 50 MUg) for 5 min at 2 W.cm(-2). Results show significant differences between internal and surface temperatures. We also demonstrate that this temperature difference increases with nanoparticle concentrations, decreases with laser power, and is not influenced by treatment time. This information is critical to improve the theoretical models that will guide future study designs in sensitive orthotopic tumor models. PMID- 26736816 TI - Multi-Pulse laser ablation modeling with applications to automated zona removal. AB - Laser zona drilling (LZD), the ablation of a portion of the zona pellucida (ZP) in embryos with the use of a laser, is a required step in many embryonic surgical procedures such as assisted hatching and preimplantation genetic diagnosis. The objective of LZD is to remove specific locations of the ZP while minimizing potential harmful thermal effects to important structures of the embryo, namely the blastomeres. Current thermal analyzes of lasers used in LZD only encompass the use of a single pulse, whereas LZD is typically performed using multiple pulses. In this paper we analyze the effect of multipulse LZD and introduce a linear approximation method for multi-pulse LZD. Furthermore, we describe a novel method of measuring the thermal effect of a single laser pulse using the thermosensitive fluorescent dye Rhodamine B and a high speed camera. PMID- 26736817 TI - Robotized High Intensity Focused Ultrasound (HIFU) system for treatment of mobile organs using motion tracking by ultrasound imaging: An in vitro study. AB - High Intensity Focused Ultrasound (HIFU) therapy is a very promising method for ablation of solid tumors. However, intra-abdominal organ motion, principally due to breathing, is a substantial limitation that results in incorrect tumor targeting. The objective of this work is to develop an all-in-one robotized HIFU system that can compensate motion in real-time during HIFU treatment. To this end, an ultrasound visual servoing scheme working at 20 Hz was designed. It relies on the motion estimation by using a fast ultrasonic speckle tracking algorithm and on the use of an interleaved imaging/HIFU sonication sequence for avoiding ultrasonic wave interferences. The robotized HIFU system was tested on a sample of chicken breast undergoing a vertical sinusoidal motion at 0.25 Hz. Sonications with and without motion compensation were performed in order to assess the effect of motion compensation on thermal lesions induced by HIFU. Motion was reduced by more than 80% thanks to this ultrasonic visual servoing system. PMID- 26736818 TI - Non-invasive measurement of the temperature rise in tissue surrounding a kidney stone subjected to ultrasonic propulsion. AB - Transcutaneous focused ultrasound (US) is used to propel kidney stones using acoustic radiation force. It is important to estimate the level of heating generated at the stone/tissue interface for safety assessment. An in-vitro experiment is conducted to measure the temperature rise in a tissue-mimicking phantom with an embedded artificial stone and subjected to a focused beam from an imaging US array. A novel optical-imaging-based thermometry method is described using an optically clear tissue phantom. Measurements are compared to the output from a fine wire thermocouple placed on the stone surface. The optical method has good sensitivity, and it does not suffer from artificial viscous heating typically observed with invasive probes and thermocouples. PMID- 26736819 TI - Peroxidated olive oil nanoemulsion for cancer targeted therapy. AB - A reactive oxygen species-mediated targeting system has been used to selectively kill cancer cells. Two different cell lines, normal and cancer cells, have been cultured and treated with a peroxide olive oil (K600) in simple solution and in form of nanoemulsion (N-K600). Preliminary results of both treatments have been compared. PMID- 26736820 TI - Modeling and simulation of platelet reaction and diffusion towards an electro stimulating dental implant. AB - Electrical stimulation (ES) has been used clinically to promote bone ingrowth on implant surface. The osseointegration of biomaterials in bone requires complex biological interactions between different bone cells species. At the early stages of bone healing, it is reported in literature that platelets play an important role in stimulating stem cells, osteogenic cells and osteoblasts. This work studies the coupling of the reaction-diffusion model of platelets with external ES. For this, we introduce a mathematical model framework consisting of a system of coupled partial differential equations. Platelets' migration and interaction within a realistic 3D model adapted from an electro-stimulating dental implant is studied. DC voltage of 3.1 V is applied at the electrodes. The electric field distribution around the electro-stimulating dental implant is simulated. High concentration of platelets around the implant surface is achieved after one day of healing. Based on these results, it is shown that osseointegration of dental implants in bone could be enhanced and accelerated by means of ES. PMID- 26736821 TI - A lumped-parameter approach for designing a novel pulsatile bioreactor for ex vivo studies of human saphenous vein remodeling. AB - After coronary artery bypass grafting (CABG), the hemodynamic conditions experienced by the saphenous veins are similar to those experienced by coronary arteries: pulsatile pressure (80-120 mmHg), pulsatile flow (mean flow rate of 250 ml/min), and elevated shear stress (1-7 Pa). Here we present a novel pulsatile platform for studying the human saphenous vein early remodeling events after CABG. The system was designed in order to apply CABG-like pressure/flow stimulation patterns to the hosted human saphenous vein segments, i.e. a pulsatile pressure oscillating between a diastolic minimum and a systolic maximum in counter-phase with a pulsatile flow rate. Functional tests revealed good fitting of simulated and measured tracings and the ability of the pulsatile platform to mimic the complexity of the coronary hemodynamic environment with good fidelity in comparison with state-of-the-art devices. This system will enable us to study the biological response of human saphenous veins to CABG conditioning ex vivo, in currently ongoing experiments. PMID- 26736822 TI - In-vitro assessment of Jurkat T-cells response to 1966 MHz electromagnetic fields in a GTEM cell. AB - This paper presents the experimental configuration and procedure as well as the in-vitro assessment of Jurkat T-cells response to 1966 MHz exposure of modulated and unmodulated electromagnetic signals within a Gigahertz Transverse Electro Magnetic (GTEM) cell. Different combinations of electric field intensity, exposure duration and modulation schemes were applied. Exposures at continuous wave (CW) signal at low intensity levels (3 V/m) did not induce any significant DNA damage, but a slight increase was observed for extreme stress levels (76.4 V/m). On the other hand, the results indicate that, at both, low and high electric field intensity UMTS (Universal Mobile Telecommunications System) signal could be statistically related to DNA damage in-vitro. Nevertheless, further experiments are required, increasing the statistical number of samples and recruiting more DNA damage endpoints before conclusive statements are drawn. PMID- 26736823 TI - Chitosan solutions as injectable systems for dermal filler applications: Rheological characterization and biological evidence. AB - A new generation of dermal filler for wrinkle filler based on chitosan was compared to current hyaluronic acid-based dermal fillers by using a new rheological performance criterion based on viscosity during injection related to Newtonian viscosity. In addition an in vivo evaluation was performed for preclinical evidence of chitosan use as dermal filler. In this way, biocompatibility and dermis reconstruction was evaluated on a pig model. PMID- 26736824 TI - Producing 3D neuronal networks in hydrogels for living bionic device interfaces. AB - Hydrogels hold significant promise for supporting cell based therapies in the field of bioelectrodes. It has been proposed that tissue engineering principles can be used to improve the integration of neural interfacing electrodes. Degradable hydrogels based on poly (vinyl alcohol) functionalised with tyramine (PVA-Tyr) have been shown to support covalent incorporation of non-modified tyrosine rich proteins within synthetic hydrogels. PVA-Tyr crosslinked with such proteins, were explored as a scaffold for supporting development of neural tissue in a three dimensional (3D) environment. In this study a model neural cell line (PC12) and glial accessory cell line, Schwann cell (SC) were encapsulated in PVA Tyr crosslinked with gelatin and sericin. Specifically, this study aimed to examine the growth and function of SC and PC12 co-cultures when translated from a two dimensional (2D) environment to a 3D environment. PC12 differentiation was successfully promoted in both 2D and 3D at 25 days post-culture. SC encapsulated as a single cell line and in co-culture were able to produce both laminin and collagen-IV which are required to support neuronal development. Neurite outgrowth in the 3D environment was confirmed by immunocytochemical staining. PVA Tyr/sericin/gelatin hydrogel showed mechanical properties similar to nerve tissue elastic modulus. It is suggested that the mechanical properties of the PVA-Tyr hydrogels with native protein components are providing with a compliant substrate that can be used to support the survival and differentiation of neural networks. PMID- 26736826 TI - Convolutional Neural Networks for patient-specific ECG classification. AB - We propose a fast and accurate patient-specific electrocardiogram (ECG) classification and monitoring system using an adaptive implementation of 1D Convolutional Neural Networks (CNNs) that can fuse feature extraction and classification into a unified learner. In this way, a dedicated CNN will be trained for each patient by using relatively small common and patient-specific training data and thus it can also be used to classify long ECG records such as Holter registers in a fast and accurate manner. Alternatively, such a solution can conveniently be used for real-time ECG monitoring and early alert system on a light-weight wearable device. The experimental results demonstrate that the proposed system achieves a superior classification performance for the detection of ventricular ectopic beats (VEB) and supraventricular ectopic beats (SVEB). PMID- 26736825 TI - Knee motion pattern classification from trunk muscle based on sEMG signals. AB - A prominent change is being carried out in the fields of rehabilitation and assistive exoskeletons in order to actively aid or restore legged locomotion for individuals suffering from muscular impairments, muscle weakness, neurologic injury, or disabilities that affect the lower limbs. This paper presents a characterization of knee motion patterns from Surface Electromyography (sEMG) signals, measured in the Erector spinae (ES) muscle. Feature extraction (mean absolute value, waveform length and auto-regressive model) and pattern classification methods (Linear Discrimination Analysis, K-Nearest Neighborhood and Support Vector Machine) are applied for recognition of eight-movement classes. Additionally, several channels setup are analyzed to obtain a suitable electrodes array. The results were evaluated based on signals measured from lower limb using quantitative metric such as error rate, sensitivity, specificity and predictive positive value. A high accuracy (> 95%) was obtained, which suggest that it is possible to detect the knee motion intention from ES muscle, as well as to reduce the electrode number (from 2 to 3 channels) to obtain an optimal electrodes array. This implementation can be applied for myoelectric control of lower limb active exoskeletons. PMID- 26736828 TI - Towards fully automated closed-loop Deep Brain Stimulation in Parkinson's disease patients: A LAMSTAR-based tremor predictor. AB - This paper describes the application of the LAMSTAR (LArge Memory STorage and Retrieval) neural network for prediction of onset of tremor in Parkinson's disease (PD) patients to allow for on-off adaptive control of Deep Brain Stimulation (DBS). Currently, the therapeutic treatment of PD by DBS is an open loop system where continuous stimulation is applied to a target area in the brain. This work demonstrates a fully automated closed-loop DBS system so that stimulation can be applied on-demand only when needed to treat PD symptoms. The proposed LAMSTAR network uses spectral, entropy and recurrence rate parameters for prediction of the advent of tremor after the DBS stimulation is switched off. These parameters are extracted from non-invasively collected surface electromyography and accelerometry signals. The LAMSTAR network has useful characteristics, such as fast retrieval of patterns and ability to handle large amount of data of different types, which make it attractive for medical applications. Out of 21 trials blue from one subject, the average ratio of delay in prediction of tremor to the actual delay in observed tremor from the time stimulation was switched off achieved by the proposed LAMSTAR network is 0.77. Moreover, sensitivity of 100% and overall performance better than previously proposed Back Propagation neural networks is obtained. PMID- 26736827 TI - Prediction of switching time between movement preparation and execution by neural activity in monkey premotor cortex. AB - Premotor cortex is a higher level cortex than primary motor cortex in movement controlling hierarchy, which contributes to the motor preparation and execution simultaneously during the planned movement. The mediation mechanism from movement preparation to execution has attracted many scientists' attention. Gateway hypothesis is one possible explanation that some neurons act as "gating" to release the movement intention at the "on-go" cue. We propose to utilize a local learning based feature extraction method to target the neurons in premotor cortex, which functionally contribute mostly to the discrimination between motor preparation and execution without tuning information to either target or movement trajectory. Then the support vector machine is utilized to predict the single trial switching time. With top three functional "gating" neurons, the prediction accuracy rate of the switching time is above 90%, which indicates the potential of asynchronous BMI control using premotor cortical activity. PMID- 26736829 TI - On the use of convolutional neural networks and augmented CSP features for multi class motor imagery of EEG signals classification. AB - Learning the deep structures and unknown correlations is important for the detection of motor imagery of EEG signals (MI-EEG). This study investigates the use of convolutional neural networks (CNNs) for the classification of multi-class MI-EEG signals. Augmented common spatial pattern (ACSP) features are generated based on pair-wise projection matrices, which covers various frequency ranges. We propose a frequency complementary feature map selection (FCMS) scheme by constraining the dependency among frequency bands. Experiments are conducted on BCI competition IV dataset IIa with 9 subjects. Averaged cross-validation accuracy of 68.45% and 69.27% is achieved for FCMS and all feature maps, respectively, which is significantly higher (4.53% and 5.34%) than random map selection and higher (1.44% and 2.26%) than filter-bank CSP (FBCSP). The results demonstrate that the CNNs are capable of learning discriminant, deep structure features for EEG classification without relying on the handcrafted features. PMID- 26736830 TI - Functional Mesh Model with Temporal Measurements for brain decoding. AB - We propose a method called Functional Mesh Model with Temporal Measurements (FMM TM) to estimate a functional relationship among voxels using temporal data, and employ these relationships for brain decoding. For each sample, we measure Blood Oxygenation Level Dependent (BOLD) responses from each voxel, and construct a functional mesh around each voxel (called seed voxel) with its nearest neighbors selected using distance metrics namely Pearson correlation, cosine similarity and Euclidean distance. Then, we represent the BOLD response of a seed voxel in terms of linear combination of BOLD responses of its p-nearest neighbors. The relationship between the seed voxel and its neighbors is represented using a set of weights which are estimated by employing linear regression. We train Support Vector Machine and k-Nearest Neighbor classifiers using the estimated weights as features. We test our model in an event-related design experiment, namely object recognition, and observe that our features perform better than raw voxel intensity values, features obtained using various pairwise distance metrics, and local mesh model features extracted using stationary and temporal measurements. PMID- 26736831 TI - Multimodal based classification of schizophrenia patients. AB - Schizophrenia is currently diagnosed by physicians through clinical assessment and their evaluation of patient's self-reported experiences over the longitudinal course of the illness. There is great interest in identifying biologically based markers at the onset of illness, rather than relying on the evolution of symptoms across time. Functional network connectivity shows promise in providing individual subject predictive power. The majority of previous studies considered the analysis of functional connectivity during resting-state using only fMRI. However, exclusive reliance on fMRI to generate such networks, may limit inference on dysfunctional connectivity, which is hypothesized to underlie patient symptoms. In this work, we propose a framework for classification of schizophrenia patients and healthy control subjects based on using both fMRI and band limited envelope correlation metrics in MEG to interrogate functional network components in the resting state. Our results show that the combination of these two methods provide valuable information that captures fundamental characteristics of brain network connectivity in schizophrenia. Such information is useful for prediction of schizophrenia patients. Classification accuracy performance was improved significantly (up to ~ 7%) relative to only the fMRI method and (up to ~ 21%) relative to only the MEG method. PMID- 26736832 TI - Joint source separation of simultaneous EEG-fMRI recording in two experimental conditions using common spatial patterns. AB - Simultaneous collection of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data has become increasingly popular in neuroscientific studies, because it can provide neural information with both high spatial and temporal resolution. In order to maximally utilize the information contained in simultaneous EEG-fMRI recording, many sophisticated multimodal data-mining methods, such as joint ICA, have been developed. However, these methods normally deal with data recorded in one experimental condition, and they cannot effectively extract information on activities that are distinct in two conditions. In this paper, a new data decomposition method called joint common spatial pattern (jCSP) is proposed. Compared with previous methods, the jCSP method exploits inter-conditional difference in the strength of brain source activities to achieve source separation, and is able to uncover the source activities with the strongest discriminative power. A group analysis based on clustering is further proposed to reveal distinctive jCSP patterns at group level. We applied joint CSP to a simultaneous EEG-fMRI dataset collected from 21 subjects under two different resting-state conditions (eyes-closed and eyes open). Results show a distinct dynamic pattern shared by EEG alpha power and fMRI signal during eyes-open resting-state. PMID- 26736833 TI - Spatiotemporal analysis of the appearance of gamma-band Microstates in resting state MEG. AB - Spatiotemporal analysis of EEG signal has revealed a rich set of methods to quantify neuronal activity using spatially global topographic templates, called Microstates. These methods complement more traditional spectral analysis, which uses band limited source data to determine defining differences in band power and peak characteristics. The high sampling rate and increased resistance to high frequency noise of MEG data offers an opportunity to explore the utility of spatiotemporal analysis over a wider spectrum than in EEG. In this work, we explore the utility of representing band limited MEG source data using established microstate techniques, especially in gamma frequency bands - a range yet unexplored using these techniques. We develop methods for gauging the goodness-of-fit achieved by resultant microstate templates and demonstrate sensor level dispersion characteristics across wide-band signals as well as across signals filtered by canonical bands. These analyses reveal that, while high frequency-band derived microstate templates are visually lawful, they fail to exhibit important explained variance and dispersion characteristics present in low- and full-band data necessary to meet the requirements of a microstate model. PMID- 26736834 TI - Supervised nonlinear dimension reduction of functional magnetic resonance imaging data using Sliced Inverse Regression. AB - Dimension reduction is essential for identifying a small set of discriminative features that are predictive of behavior or cognition from high-dimensional functional magnetic resonance imaging (fMRI) data. However, conventional linear dimension reduction techniques cannot reduce the dimension effectively if the relationship between imaging data and behavioral parameters are nonlinear. In the paper, we proposed a novel supervised dimension reduction technique, named PC-SIR (Principal Component - Sliced Inverse Regression), for analyzing high-dimensional fMRI data. The PC-SIR method is an important extension of the renowned SIR method, which can achieve the effective dimension reduction (e.d.r.) directions even the relationship between class labels and predictors is nonlinear but is unable to handle high-dimensional data. By using PCA prior to SIR to orthogonalize and reduce the predictors, PC-SIR can overcome the limitation of SIR and thus can be used for fMRI data. Simulation showed that PC-SIR can result in a more accurate identification of brain activation as well as better prediction than support vector regression (SVR) and partial least square regression (PLSR). Then, we applied PC-SIR on real fMRI data recorded in a pain stimulation experiment to identify pain-related brain regions and predict the pain perception. Results on 32 subjects showed that PC-SIR can lead to significantly higher prediction accuracy than SVR and PLSR. Therefore, PC-SIR could be a promising dimension reduction technique for multivariate pattern analysis of fMRI. PMID- 26736835 TI - Efficient solution methodology for calibrating the hemodynamic model using functional Magnetic Resonance Imaging (fMRI) measurements. AB - Our aim is to propose a numerical strategy for retrieving accurately and efficiently the biophysiological parameters as well as the external stimulus characteristics corresponding to the hemodynamic mathematical model that describes changes in blood flow and blood oxygenation during brain activation. The proposed method employs the TNM-CKF method developed in [1], but in a prediction/correction framework. We present numerical results using both real and synthetic functional Magnetic Resonance Imaging (fMRI) measurements to highlight the performance characteristics of this computational methodology. PMID- 26736837 TI - Melanoma detection algorithm based on feature fusion. AB - A Computer Aided-Diagnosis (CAD) System for melanoma diagnosis usually makes use of different types of features to characterize the lesions. The features are often combined into a single vector that can belong to a high dimensional space (early fusion). However, it is not clear if this is the optimal strategy and works on other fields have shown that early fusion has some limitations. In this work, we address this issue and investigate which is the best approach to combine different features comparing early and late fusion. Experiments carried on the datasets PH2 (single source) and EDRA (multi source) show that late fusion performs better, leading to classification scores of Sensitivity = 98% and Specificity = 90% (PH(2)) and Sensitivity = 83% and Specificity = 76% (EDRA). PMID- 26736836 TI - Exploring automatic prostate histopathology image Gleason grading via local structure modeling. AB - Gleason-grading of prostate cancer pathology specimens reveal the malignancy of the cancer tissues, thus provides critical guidance for prostate cancer diagnoses and treatment. Computer-aided automatic grading methods have been providing efficient and result-consistent alternative to traditional manually slide reading approach, through statistical and structural feature analysis of the digitized pathology slides. In this paper, we propose a novel automatic Gleason grading algorithm through local structure model learning and classification. We use attributed graph to represent the tissue glandular structures in histopathology images; representative sub-graphs features were learned as bags-of-words features from labeled samples of each grades. Then structural similarity between sub graphs in the unlabeled images and the representative sub-graphs were obtained using the learned codebook. Gleason grade was given based on an overall similarity score. We validated the proposed algorithm on 300 prostate histopathology images from the TCGA dataset, and the algorithm achieved average grading accuracy of 91.25%, 76.36% and 64.75% on images with Gleason grade 3, 4 and 5 respectively. PMID- 26736838 TI - A new parameter computed with independent component analysis to predict rectal toxicity following prostate cancer radiotherapy. AB - The main challenge in prostate cancer radiotherapy is to deliver the prescribed dose to the clinical target while minimizing the dose to the neighboring organs at risk and thus avoiding subsequent toxicity-related events. With the aim of improving toxicity prediction following prostate cancer radiotherapy, the goal of our work is to propose a new predictive variable computed with independent component analysis to predict late rectal toxicity, and to compare its performance to other models (logistic regression, normal tissue complication probability model and recent principal component analysis approach). Clinical data and dose-volume histograms were collected from 216 patients having received 3D conformal radiation for prostate cancer with at least two years of follow-up. Independent component analysis was trained to predict the risk of 3-year rectal bleeding Grade >= 2. The performance of all the models was assessed by computing the area under the receiving operating characteristic curve. Clinical parameters combined with the new variable were found to be predictors of rectal bleeding. The mean area under the receiving operating curve for our proposed approach was 0:75. The AUC values for the logistic regression, the Lyman-Kutcher-Burman model and the recent principal component analysis approach were 0:62, 0:53 and 0:62, respectively. Our proposed new variable may be an useful new tool in predicting late rectal toxicity. It appears as a strong predictive variable to improve classical models. PMID- 26736839 TI - An automated method for detecting architectural distortions on mammograms using direction analysis of linear structures. AB - Architectural distortion is one of the most important findings when evaluating mammograms for breast cancer. Abnormal breast architecture is characterized by the presence of spicules, which are distorted mammary structures that are not accompanied by an increased density or mass. We have been developing an automated method for detecting spiculated architectural distortions by analyzing linear structures extracted by normal curvature. However, some structures that are possibly related to distorted areas are not extracted using this method. The purpose of this study was to develop a new automated method for direction analysis of linear structures to improve detection performance in mammography. The direction of linear structures in each region of interest (ROI) was first determined using a direction filter and a background filter that can define one of eight directions (0 degrees , 22.5 degrees , 45 degrees , 67.5 degrees , 90 degrees , 112.5 degrees , 135 degrees , and 157.5 degrees ). The concentration and isotropic indexes were calculated using the determined direction of the linear structures in order to extract the candidate areas. Discriminant analysis was performed to eliminate false positives results. Our database consisted of 168 abnormal images containing 174 distorted areas and 580 normal images. The sensitivity of the new method was 81%. There were 2.6 and 4.2 false positives per image using the new and previous methods, respectively. These findings show that our new method is effective for detecting spiculated architectural distortions. PMID- 26736840 TI - Determination of border irregularity in dermoscopic color images of pigmented skin lesions. AB - Malignant melanoma, which is the most dangerous type of skin cancer, is commonly diagnosed in all people, regardless of age, gender, or race. In the last several years an increasing melanoma incidence and mortality rate has been observed worldwide. In this research we present a new approach to the detection and classification of border irregularity, one of the major parameter in a widely used diagnostic algorithm ABCD rule of dermoscopy. Accurate assessment of irregular borders is clinically important due to a significantly different occurrence in benign and malignant skin lesions. In this paper we describe a complex algorithm containing following steps: image enhancement, lesion segmentation, border irregularity detection as well as classification. The algorithm has been tested on 300 dermoscopic images and achieved a detection of 79% and classification accuracy of 90%. Compared to state-of-the-art, we obtain improved classification accuracy. PMID- 26736841 TI - Automatic polyp detection: A comparative study. AB - In this work we present a performance comparison between a set of different state of-the-art image descriptors for the automatic detection of polyps in colonoscopy videos. This set includes: Local binary patterns, 2-dimensional Gabor filters, wavelet-based texture, and histogram of oriented gradients. We use these descriptors in conjunction with support vector machine or nearest neighbor classifiers to classify candidate regions, which in turn are selected using the maximally stable extremal regions algorithm. We present performance scores on the ASU-Mayo Clinic polyp database. PMID- 26736842 TI - Ultrasonic beamforming system for interrogating multiple implantable sensors. AB - In this paper, we present an ultrasonic beamforming system capable of interrogating individual implantable sensors via backscatter in a distributed, ultrasound-based recording platform known as Neural Dust [1]. A custom ASIC drives a 7 * 2 PZT transducer array with 3 cycles of 32V square wave with a specific programmable time delay to focus the beam at the 800mm neural dust mote placed 50mm away. The measured acoustic-to-electrical conversion efficiency of the receive mote in water is 0.12% and the overall system delivers 26.3% of the power from the 1.8V power supply to the transducer drive output, consumes 0.75MUJ in each transmit phase, and has a 0.5% change in the backscatter per volt applied to the input of the backscatter circuit. Further miniaturization of both the transmit array and the receive mote can pave the way for a wearable, chronic sensing and neuromodulation system. PMID- 26736843 TI - Piezoresistive nanocomposite as an embedded stress sensor in instrumented knee prosthesis. AB - We characterize the electrical properties of a biocompatible nanocomposite which will be used as a stress sensing material in an instrumented knee implant. The composite is fabricated from multi-walled carbon nanotubes and ultra high molecular weight polyethylene. Experimental cyclic compression loading shows that the composite's resistance exponentially decreases with increasing compression stress, proving its potential for application as a piezoresistive stress sensing material. An analytical model is built to estimate the optimal depth from the tibio-femoral contact surface at which an embedded stress sensor could achieve the highest stress resolution and lowest distortion energy inside the tibial insert. PMID- 26736844 TI - Electrically induced energy transmission used for implantable medical devices deep inside the body: Measurement of received voltage in consideration of biological effect. AB - We proposed an electrically induced energy transmission method for implantable medical devices deep inside the body. This method makes it possible to transmit energy deep inside the body using only a couple of titanium electrodes attached to the surface of the implantable medical device. In this study, electromagnetic simulations in which the area and distance of the receiving electrodes were changed were conducted. Then, experimental measurements of the received voltage were conducted in which electric energy was transmitted from the surface of the human phantom to an implantable device inside it (transmitting distance: 12 cm). As a result of the electromagnetic simulation, the area and distance of the receiving electrodes were roughly proportional to the received voltage, respectively. As a result of the experimental measurement, a received voltage of 2460 mV could be obtained with a load resistance of 100 Omega. We confirmed that our energy transmission method could be a powerful method for transmitting energy to a deeply implanted medical device. PMID- 26736845 TI - Experimenting with microbial fuel cells for powering implanted biomedical devices. AB - Microbial Fuel Cell (MFC) technology has the ability to directly convert sugar into electricity by using bacteria. Such a technology could be useful for powering implanted biomedical devices that require a surgery to replace their batteries every couple of years. In steps towards this, parameters such as electrode configuration, inoculation size, stirring of the MFC and single versus dual chamber reactor configuration were tested for their effect on MFC power output. Results indicate that a Top-Bottom electrode configuration, stirring and larger amounts of bacteria in single chamber MFCs, and smaller amounts of bacteria in dual chamber MFCs give increased power outputs. Finally, overall dual chamber MFCs give several fold larger MFC power outputs. PMID- 26736846 TI - Towards a highly-scalable wireless implantable system-on-a-chip for gastric electrophysiology. AB - This paper presents the system design of a highly-scalable system-on-a-chip (SoC) to wirelessly and chronically detect the mechanisms underlying gastric dysrhythmias. The proposed wireless implantable gastric-wave recording (WIGR) SoC records gastric slow-wave and spike activities from 256 sites, and establishes transcutaneous data communication with an external reader while being inductively powered. The SoC is highly scalable by employing a modular architecture for the analog front-end (AFE), a near-field pulse-delay modulation (PDM) data transmitter (Tx) that its data rate is proportional to the power carrier frequency (fp), and an adaptive power management equipped with automatic resonance tuning (ART) that dynamically compensates for environmental and fp variations of the implant power coil. The simulation and measurement results for individual blocks have been presented. PMID- 26736847 TI - A low-noise instrumentation amplifier with DC suppression for recording ENG signals. AB - This paper presents an AC-coupled instrumentation amplifier for electroneurogram (ENG) activity recording. For this design, we evaluate gain and noise requirements based on interference sources (electrodes, power line, EMG). The circuit has been implemented in a commercially-available 0.35MUm CMOS technology with total power consumption 460MUW. The amplifier achieves CMRR 107 dB and integrated input referred noise 940 nV. The gain is 63 dB and the bandwidth is 0.5 Hz- 13 kHz. The chosen topology enables to minimise on-chip capacitance (only 27 pF), with a total chip area of 0.4mm2. PMID- 26736848 TI - Ultrasound observation of GAG content of human hip joint cartilage in different old age groups. AB - In this study, we observed the age-related changes of glycosaminoglycan (GAG) content of human hip joint cartilage based on ultrasound (US). Seventy human hip cartilage-bone samples were collected from hip-fracture patients (ages 51 to 96) and divided into 5 groups (10 years in an age group). They were firstly measured by ultrasound to obtain quantitative acoustic parameters, including the speed of sound (SOS), US amplitude attenuation coefficient (UAA) and normalized broadband US attenuation coefficient (nBUA). Then the samples were stained for GAG with toluidine blue. Results showed SOS, UAA, nBUA decreased by 5.49%, 36.67%, 25.57% from 50-80 age group (p<;0.01), but increased by 0.34%, 1.19%, 5.23% in the 90 age group compared with the 80 age group, respectively. There were linear correlations between SOS and GAG optical density (r=0.825, p<;0.01), as well as UAA and GAG optical density (r=0.708, p <; 0.01). However, nBUA showed less significant linear correlation to GAG optical density (r=0.688, p <; 0.07). In summary, GAG content of hip joint cartilage varied with aging in elderly people and conventional ultrasound can potentially be used to detect the age-related changes of acoustic parameters of human hip joint cartilage. PMID- 26736849 TI - Motion trajectory analysis for evaluating the performance of functional upper extremity tasks in daily living: a pilot study. AB - Since 1998, tele-rehabilitation has been extensively studied for its potential capacity of saving time and cost for both therapists and patients. However, one gap hindering the deployment of tele-rehabilitation service is the approach to evaluate the outcome after tele-rehabilitation exercises without the presence of professional clinicians. In this paper, we propose an approach to model jerky and jerky-free movement trajectories with hidden Markov models (HMMs). The HMMs are then utilised to identify the jerky characteristics in a motion trajectory, thereby providing the number and amplitude of jerky movements in the specific length of the trajectory. Eventually, the ability of performing functional upper extremity tasks can be evaluated by classifying the motion trajectory into one of the pre-defined ability levels by looking at the number and amplitude of jerky movements. The simulation experiment confirmed that the proposed method is able to correctly classify motion trajectories into various ability levels to a high degree. PMID- 26736850 TI - Spatially distributed surface electromyography signal simulator. AB - Electromyographic signals are of great importance to current biomedical research society since they may be used in several ways as, for example, in the diagnosis of neuromuscular diseases, the control of active prosthetic limbs as well as the test and validation of medical equipment. PMID- 26736851 TI - A wall-less poly(vinyl alcohol) cryogel flow phantom with accurate scattering properties for transcranial Doppler ultrasound propagation channels analysis. AB - Medical phantoms are frequently required to verify image and signal processing systems, and are often used to support algorithm development for a wide range of imaging and blood flow assessments. A phantom with accurate scattering properties is a crucial requirement when assessing the effects of multi-path propagation channels during the development of complex signal processing techniques for Transcranial Doppler (TCD) ultrasound. The simulation of physiological blood flow in a phantom with tissue and blood equivalence can be achieved using a variety of techniques. In this paper, poly (vinyl alcohol) cryogel (PVA-C) tissue mimicking material (TMM) is evaluated in conjunction with a number of potential scattering agents. The acoustic properties of the TMMs are assessed and an acoustic velocity of 1524ms(-1), an attenuation coefficient of (0:49) * 10(-4)fdBm(1)Hz(-1), a characteristic impedance of (1.72) * 10(6)Kgm(-2)s(-1) and a backscatter coefficient of (1.12) * 10(-28)f(4)m(-1)Hz(-4)sr(-1) were achieved using 4 freeze thaw cycles and an aluminium oxide (Al(2)O(3)) scattering agent. This TMM was used to make an anatomically realistic wall-less flow phantom for studying the effects of multipath propagation in TCD ultrasound. PMID- 26736852 TI - A novel pseudo resistor structure for biomedical front-end amplifiers. AB - This study proposes a novel pseudo resistor structure with a tunable DC bias voltage for biomedical front-end amplifiers (FEAs). In the proposed FEA, the high pass filter composed of differential difference amplifier and a pseudo resistor is implemented. The FEA is manufactured by using a standard TSMC 0.35 MUm CMOS process. In this study, three types FEAs included three different pseudo resistor are simulated, fabricated and measured for comparison and electrocorticography (ECoG) measurement, and all the results show the proposed pseudo resistor is superior to other two types in bandwidth. In chip implementation, the lower and upper cutoff frequencies of the high-pass filter with the proposed pseudo resistor are 0.15 Hz and 4.98 KHz, respectively. It also demonstrates lower total harmonic distortion performance of -58 dB at 1 kHz and higher stability with wide supply range (1.8 V and 3.3 V) and control voltage range (0.9 V and 1.65 V) than others. Moreover, the FEA with the proposed pseudo successfully recorded spike and-wave discharges of ECoG signal in in vivo experiment on rat with pentylenetetrazol-induced seizures. PMID- 26736853 TI - Interferogram-based breast tumor classification using microwave-induced thermoacoustic imaging. AB - Microwave-induced thermoacoustic (TA) imaging combines the dielectric/conductivity contrast in the microwave range with the high resolution of ultrasound imaging. Lack of ionizing radiation exposure in TA imaging makes this technique suitable for frequent screening applications, as with breast cancer screening. In this paper we demonstrate breast tumor classification based on TA imaging. The sensitivity of the signal-based classification algorithm to errors in the estimation of tumor locations is investigated. To reduce this sensitivity, we propose to use the interferogram of received pressure waves as the feature basis used for classification, and demonstrate the robustness based on a finite-difference time-domain (FDTD) simulation framework. PMID- 26736854 TI - Detection of fiducial points in ECG waves using iteration based adaptive thresholds. AB - This paper presents an algorithm for the detection of fiducial points in electrocardiogram (ECG) waves using iteration based adaptive thresholds. By setting the search range of the processing frame to the interval between two consecutive R peaks, the peaks of T and P waves are used as reference salient points (RSPs) to detect the fiducial points. The RSPs are selected from candidates whose slope variation factors are larger than iteratively defined adaptive thresholds. Considering the fact that the number of RSPs varies depending on whether the ECG wave is normal or not, the proposed algorithm proceeds with a different methodology for determining fiducial points based on the number of detected RSPs. Testing was performed using twelve records from the MIT-BIH Arrhythmia Database that were manually marked for comparison with the estimated locations of the fiducial points. The means of absolute distances between the true locations and the points estimated by the algorithm are 12.2 ms and 7.9 ms for the starting points of P and Q waves, and 9.3 ms and 13.9 ms for the ending points of S and T waves. Since the computational complexity of the proposed algorithm is very low, it is feasible for use in mobile devices. PMID- 26736855 TI - Influence of the occlusion effect over the prediction-error feedback cancellation system in hearing aids. AB - This work presents a theoretical analysis of the prediction-error method-based adaptive feedback canceller in hearing aid applications. The studied scene takes into account the occlusion effect caused by the partial or complete closing of the ventilation opening. Such a situation may occur in high gain applications to avoid undesired whistling. Deterministic recursive equations and steady-state conditions were derived for the mean weight behaviour of the predictor and the adaptive filter. The expected theoretical predictions were compared to Monte Carlo simulations, showing very accurate agreement. The simulation results suggest the steady-state performance of this feedback canceller is not affected by the occlusion effect, however the occlusion is still perceived, being annoying to the user. PMID- 26736856 TI - Automatic artifact suppression in simultaneous tDCS-EEG using adaptive filtering. AB - Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation method that can be used in cognitive and clinical protocols in order to modulate neural activity. Although some macro effects are known, the underlying mechanisms are still not clear. tDCS in combination with electroencephalography (EEG) could help to understand these mechanisms from a neural point of view. However, simultaneous tDCS-EEG still remains challenging because of the artifacts that affect the recorded signals. In this paper, an automated artifact cancellation method based on adaptive filtering is proposed. Using independent component analysis (ICA), the artifacts were characterized using data from both a phantom and a group of healthy subjects. The resulting filter can successfully remove tDCS-related artifacts during anodal and cathodal stimulations. PMID- 26736857 TI - Effects of contralateral acoustic stimulation on otoacoustic emissions induced by swept tones. AB - The medial olivocochlear complex (MOC) is an auditory nucleus that projects efferent nerve fibers to control the behaviors of both sides of the cochlea. Otoacoutsic emissions (OAEs) are by-products the activities of the outer hair cells (OHCs) in the cochlea and could be used as a noninvasive way to study the efferent control of the MOC. However, existing results regarding the efferent control are quite controversial and often restricted to a rather limited frequency range. In this study, a new method of measuring stimulus frequency otoacoustic emissions (SFOAEs) with the presence of a contralateral acoustic stimulation (CAS) was proposed to study the efferent control over the cochlea. SFOAEs were measured with swept tones with time varying frequencies so that SFOAE spectra with and without the presence of the CAS could be compared with high frequency-resolution. The results showed that there was consistent decrease in the amplitude of the swept-tone SFOAEs across a wide frequency range from 0.5 to 8 kHz when the CAS was presented, suggesting an outstanding attenuation of OHC activities by the efferent control from the MOC. The SFOAE decrease with the presence of the CAS might provide a new approach to measure the strength of the efferent control and to evaluate the functional status of the central auditory pathway. PMID- 26736858 TI - Orientation and depth estimation for femoral components using image sensor, magnetometer and inertial sensors in THR surgeries. AB - Malposition of the acetabular and femoral component has long been recognized as an important cause of dislocation after total hip replacement (THR) surgeries. In order to help surgeons improve the positioning accuracy of the components, a visual-aided system for THR surgeries that could estimate orientation and depth of femoral component is proposed. The sensors are fixed inside the femoral prosthesis trial and checkerboard patterns are printed on the internal surface of the acetabular prosthesis trial. An extended Kalman filter is designed to fuse the data from inertial sensors and the magnetometer orientation estimation. A novel image processing algorithm for depth estimation is developed. The algorithms have been evaluated under the simulation with rotation quaternion and translation vector and the experimental results shows that the root mean square error (RMSE) of the orientation estimation is less then 0.05 degree and the RMSE for depth estimation is 1mm. Finally, the femoral head is displayed in 3D graphics in real time to help surgeons with the component positioning. PMID- 26736859 TI - The performance of the spatiotemporal Kalman filter and LORETA in seizure onset localization. AB - The assumption of spatial-smoothness is often used to solve the bioelectric inverse problem during electroencephalographic (EEG) source imaging, e.g., in low resolution electromagnetic tomography (LORETA). Since the EEG data show a temporal structure, the combination of the temporal-smoothness and the spatial smoothness constraints may improve the solution of the EEG inverse problem. This study investigates the performance of the spatiotemporal Kalman filter (STKF) method, which is based on spatial and temporal smoothness, in the localization of a focal seizure's onset and compares its results to those of LORETA. The main finding of the study was that the STKF with an autoregressive model of order two significantly outperformed LORETA in the accuracy and consistency of the localization, provided that the source space consists of a whole-brain volumetric grid. In the future, these promising results will be confirmed using data from more patients and performing statistical analyses on the results. Furthermore, the effects of the temporal smoothness constraint will be studied using different types of focal seizures. PMID- 26736860 TI - The choice of the source space and the Laplacian matrix in LORETA and the spatio temporal Kalman filter EEG inverse methods. AB - The discretization of the brain and the definition of the Laplacian matrix influence the results of methods based on spatial and spatio-temporal smoothness, since the Laplacian operator is used to define the smoothness based on the neighborhood of each grid point. In this paper, the results of low resolution electromagnetic tomography (LORETA) and the spatiotemporal Kalman filter (STKF) are computed using, first, a greymatter source space with the standard definition of the Laplacian matrix and, second, using a whole-brain source space and a modified definition of the Laplacian matrix. Electroencephalographic (EEG) source imaging results of five inter-ictal spikes from a pre-surgical patient with epilepsy are used to validate the two aforementioned approaches. The results using the whole-brain source space and the modified definition of the Laplacian matrix were concentrated in a single source activation, stable, and concordant with the location of the focal cortical dysplasia (FCD) in the patient's brain compared with the results which use a grey-matter grid and the classical definition of the Laplacian matrix. This proof-of-concept study demonstrates a substantial improvement of source localization with both LORETA and STKF and constitutes a basis for further research in a large population of patients with epilepsy. PMID- 26736861 TI - Model- based filtering for artifact and noise suppression with state estimation for electrodermal activity measurements in real time. AB - Measurement of electrodermal activity (EDA) has recently made a transition from the laboratory into daily life with the emergence of wearable devices. Movement and nongelled electrodes make these devices more susceptible to noise and artifacts. In addition, real-time interpretation of the measurement is needed for user feedback. The Kalman filter approach may conveniently deal with both these issues. This paper presents a biophysical model for EDA implemented in an extended Kalman filter. Employing the filter on data from Physionet along with simulated noise and artifacts demonstrates noise and artifact suppression while implicitly providing estimates of model states and parameters such as the sudomotor nerve activation. PMID- 26736862 TI - Searching arousals: A fuzzy logic approach. AB - This paper presents a computational approach to detect spontaneous, chin tension and limb movement-related arousals by estimating neuronal and muscular activity. Features extraction is carried out by Time Varying Autoregressive Moving Average (TVARMA) models and recursive particle filtering. Classification is performed by a fuzzy inference system with rule-based decision scheme based upon the AASM scoring rules. Our approach yielded two metrics: arousal density and arousal index to comply with standardised clinical benchmarking. The obtained statistics achieved error deviation around +/-1.5 to +/-30. These results showed that our system can differentiate amongst 3 different types of arousals, subject to inter subject variability and up-to-date scoring references. PMID- 26736863 TI - Heart rate estimation from facial photoplethysmography during dynamic illuminance changes. AB - Camera-based remote photoplethysmography (rPPG) enables low-cost, non-contact cardiovascular activity monitoring. However, applying rPPG to practical use has some limitations caused from the artifacts by illuminance changes. During watching a video in a dark room, for example, watching a TV at night without illuminance, there is a high correlation between the brightness changes of a video and the illuminance variation on the skin of the viewer's face. In this study, we propose an artifact reduction method in rPPG, which is caused by the variation of the illuminance. The method subtracts the artifacts from the raw facial rPPG signal by applying multi-order curve fitting between the illuminance information from the facial rPPG signal and the brightness information from a video. On average, the results showed that signal-to-noise ratio (SNR) increased from -11.74 to -4.19 dB and from -15.27 to 7.99 dB for low-dynamic-brightness and high-dynamic-brightness video, respectively. In addition, the root-mean-square error (RMSE) of estimated heart rate decreased from 11.00 to 1.82 bpm and from 9.88 to 4.65 bpm for the videos, respectively. PMID- 26736864 TI - Robust driver heartbeat estimation: A q-Hurst exponent based automatic sensor change with interactive multi-model EKF. AB - Preventing car accidents by monitoring the driver's physiological parameters is of high importance. However, existing measurement methods are not robust to driver's body movements. In this paper, a system that estimates the heartbeat from the seat embedded piezoelectric sensors, and that is robust to strong body movements is presented. Multifractal q-Hurst exponents are used within a classifier to predict the most probable best sensor signal to be used in an Interactive Multi-Model Extended Kalman Filter pulsation estimation procedure. The car vibration noise is reduced using an autoregressive exogenous model to predict the noise on sensors. The performance of the proposed system was evaluated on real driving data up to 100 km/h and with slaloms at high speed. It is shown that this method improves by 36.7% the pulsation estimation under strong body movement compared to static sensor pulsation estimation and appears to provide reliable pulsation variability information for top-level analysis of drowsiness or other conditions. PMID- 26736865 TI - Fst-Filter: A flexible spatio-temporal filter for biomedical multichannel data denoising. AB - In this paper, we present the noise reduction method for a multichannel measurement system where the true underlying signal is spatially low-rank and contaminated by spatially correlated noise. Our proposed formulation applies generalized singular value decomposition (GSVD) with signal recovery approach to extend the conventional subspace-based methods for performing the spatio-temporal filtering. Without necessarily requiring the noise covariance data in advance, the implemented optimization scheme allows users to choose the denoising function, F(.) flexibly satisfying for different temporal noise characteristics from a variety of existing efficient temporal filters. An effectiveness of proposed method is demonstrated by yielding the better accuracy for the brain source estimation on simulated magnetoencephalography (MEG) experiments than some traditional methods, e.g., principal component analysis (PCA), robust principal component analysis (RPCA) and multivariate wavelet denoising (MWD). PMID- 26736866 TI - Measuring cervical vertebra movements using kinect sensor. AB - The incidence of cervical vertebra spondylosis is increasing with the pace of life while there is no high-efficient measurement method. This study proposed a non-contact, high-efficient, and high-precisionmethod measuring the cervical vertebra activities which obtains the cervical vertebra activities by combining the function of skeletal tracking and face tracking. A comparison study between the proposed and traditional methods has been conducted here. Statistics shows that the efficiency of the proposed measurement method at least is 6 times faster than modified square shaped goniometers that is the represent of traditional measurement, and it's angular error in average is 0.35 degrees . Moreover, the proposed measuring method has been tested in hospital clinical environment and the results show that the proposed method can be used easily and have little interference. PMID- 26736867 TI - An evaluation of EEG ocular artifact removal with a multi-channel wiener filter based on probabilistic generative model. AB - Data contamination by ocular artifacts such as eye blinks and eye movements is a major barrier that must be overcome when attempting to analyze electroencephalogram (EEG) and event-related potential (ERP) data. To handle this problem, a number of artifact removal methods has been proposed. Specifically, we focus on a method using a multi-channel Wiener filters based on a probabilistic generative model. This method assumes that the observed signal is the sum of multiple signals elicited by psychological or physical events, and separates the observed signal into each event signal using estimated model parameters. Based on this scheme, we have proposed a model parameter estimation method using prior information of each event signal. In this paper, we examine the potential of this model to deal with highly contaminated signals by collecting EEG data intentionally contaminated by eye blinks and relatively clean ERP data, and using them as prior information of each event signal. We conducted an experimental evaluation using a classical attention task. The results showed the proposed method effectively enhances the target ERP component while reducing the contamination caused by eye blinks. PMID- 26736868 TI - Eliminating pulse-induced artifacts in Urethral Pressure data. AB - Urethral Pressure Profilometry (UPP) is a tool in the diagnosis of urinary incontinence. The pressure profile along the urethra is measured by a special catheter in order to assess the contraction strength of the sphincter muscle. The use of microtip catheters with several pressure sensors and an integrated acceleration sensor enables signal reconstruction of the pressure distribution on the urethra's inside. Experimental data from minipigs exhibit artifact patterns in the pressure data. It is shown that these artifacts are caused by vascular pulsation in the sphincter structure. We therefore investigate different methods exploiting the time-correlation of the artifacts to eliminate pulse-induced artifacts in the pressure data without compromising the actual signal. Evaluation of these methods applied to experimental data conclude this work showing that both an Input-Model and Principal Component Analysis Decorrelation are effective at removing the artifacts. PMID- 26736869 TI - Reconstruction of signal in plastic scintillator of PET using Tikhonov regularization. AB - The new concept of Time of Flight Positron Emission Tomography (TOF-PET) detection system, which allows for single bed imaging of the whole human body, is currently under development at the Jagiellonian University. The Jagiellonian-PET (J-PET) detector improves the TOF resolution due to the use of fast plastic scintillators. Since registration of the waveform of signals with duration times of few nanoseconds is not feasible, a novel front-end electronics allowing for sampling in a voltage domain at four thresholds was developed. To take fully advantage of these fast signals a novel scheme of recovery of the waveform of the signal, based on idea from the Tikhonov regularization method, is presented. From the Bayes theory the properties of regularized solution, especially its covariance matrix, may be easily derived. This step is crucial to introduce and prove the formula for calculations of the signal recovery error. The method is tested using signals registered by means of the single detection module of the J PET detector built out from the 30 cm long plastic scintillator strip. It is shown that using the recovered waveform of the signals, instead of samples at four voltage levels alone, improves the spatial resolution of the hit position reconstruction from 1.05 cm to 0.94 cm. Moreover, the obtained result is only slightly worse than the one evaluated using the original raw-signal. The spatial resolution calculated under these conditions is equal to 0.93 cm. PMID- 26736870 TI - CAP waveform estimation from the measured electrical bioimpedance values: Patient's heart rate variability analysis. AB - The paper presents analysis of the generic transfer function (TF) between Electrical Bioimpedance (EBI) measured non-invasively on the wrist and Central Aortic Pressure (CAP) invasively measured at the aortic root. Influence of the Heart Rate (HR) variations on the generic TF and on reconstructed CAP waveforms is investigated. The HR variation analysis is provided on a single patient data to exclude inter-patient influences at the current research stage. A new approach for the generic TF estimating from a data ensemble is presented as well. Moreover, an influence of the cardiac period beginning point selection is analyzed and empirically optimal solution for its selection is proposed. PMID- 26736871 TI - Mortality prediction in septic shock patients: Towards new personalized models in critical care. AB - We studied the problem of mortality prediction in 23 septic shock patients selected from the public database MIMIC-II. For each patient we derived hemodynamic variables, laboratory results and clinical information of the first 48 hours after shock onset and we performed univariate and multivariate analyses to predict mortality in the following 7 days. The results show interesting features that individually identify significant differences between survivors and non survivors and features which gain importance only when considered together with the others in a multivariate regression model, such as the respiratory rate (RR). This preliminary study on a small septic shock population represents a novel contribution towards new personalized models for an integration of multi scale and multi-level patient information to improve critical care management of shock patients. PMID- 26736872 TI - A novel technique to investigate the effect of ageing on ventricular repolarization characteristics in healthy and LQTS subjects. AB - Ventricular repolarization(VR) characteristics is affected by ageing alongside several other factors like Heart rate(HR),respiration, modulation of autonomic nervous system, different drug effects, genetical factors affecting the cardiac ion channel characteristics, gender etc. Therefore, total VR variability (i.e. QT interval variability in surface ECG) consists of two components: one dependent on HR variability (HRV) and another independent of HRV. Analysis of QT interval variability (QTV) is crucial for both healthy and pathological conditions as increase in VR variability measured by QTV increases cardiac repolarization instability, which might lead to arrhythmogenesis. Analyzing the effect of ageing using a widely used measure of QTV (i.e. QTVI) is reported inconsistently in Healthy subjects whereas the same for Long QT Syndrome (LQTS) subjects is not widely reported. In this study, we propose a novel time domain measure from beat tobeat QT-RR distribution to analyze how ageing affects VR in both Healthy and a group of genotyped LQTS1 subjects. A total of 139 Healthy subjects and 134 LQTS1 subjects of three different age groups (i.e. Young: age 20-35, Middle-aged: 40-55 and Old: age<;60) were analyzed for this study. The proposed measure is also compared with other existing widely used measures of QTV like SDQT and QTVI in differentiating different age groups. The proposed measure stands out to be more discriminatory than other existing variability measures of QT interval. PMID- 26736873 TI - Automated analysis of nocturnal oximetry as screening tool for childhood obstructive sleep apnea-hypopnea syndrome. AB - Childhood obstructive sleep apnea-hypopnea syndrome (OSAHS) is a highly prevalent condition that negatively affects health, performance and quality of life of infants and young children. Early detection and treatment improves neuropsychological and cognitive deficits linked with the disease. The aim of this study was to assess the performance of automated analysis of blood oxygen saturation (SpO2) recordings as a screening tool for OSAHS. As an initial step, statistical, spectral and nonlinear features were estimated to compose an initial feature set. Then, fast correlation-based filter (FCBF) was applied to search for the optimum subset. Finally, the discrimination power (OSAHS negative vs. OSAHS positive) of three pattern recognition algorithms was assessed: linear discriminant analysis (LDA), quadratic discriminant analysis (QDA) and logistic regression (LR). Three clinical cutoff points commonly used in the literature for positive diagnosis of the disease were applied: apnea-hypopnea index (AHI) of 1, 3 and 5 events per hour (e/h). Our methodology reached 88.6% accuracy (71.4% sensitivity and 100.0% specificity, 100.0% positive predictive value, and 84.0% negative predictive value) in an independent test set using QDA for a clinical cut-off point of 5 e/h. These results suggest that SpO2 nocturnal recordings may be used to develop a reliable and efficient screening tool for childhood OSAHS. PMID- 26736874 TI - Breast Cancer classification using extracted parameters from a terahertz dielectric model of human breast tissue. AB - Our previous study proposed a dielectric model for human breast tissue and provided initial analysis of classification potential of the eight model parameters and their multiparameter combinations with the support vector machine (SVM). A combination of three model parameters could achieve a leave-one-out cross validation accuracy of 93.2%. However, the SVM approach fails to exploit the combinations of more than three model parameters for classification improvement. Thus, the Bayesian neural network (BNN) method is employed to overcome this problem based on its advantages of handling our small data and high complexity of the multiparamter combinations. The BNN successfully classifies the data using the combinations of four model parameters with an accuracy, estimated by leave-one-out cross validation, of 97.3%. Overall performance assessed by leaveone-out and repeated random-subsampling cross validations for all examined combinations is also remarkably improved by BNN. The results indicate the advance of BNN as compared to SVM in utilising the model parameters for detecting tumour from normal breast tissue. PMID- 26736875 TI - Automatic cough episode detection using a vibroacoustic sensor. AB - Cough monitoring is an important element of the diagnostics of respiratory diseases. The European Respiratory Society recommends objective assessment of cough episodes and the search for methods of automatic analysis to make obtaining the quantitative parameters possible. The cough "events" could be classified by a microphone and a sensor that measures the vibrations of the chest. Analysis of the recorded signals consists of calculating the features vectors for selected episodes and of performing automatic classification using them. The aim of the study was to assess the accuracy of classification based on an artificial neural networks using vibroacoustic signals collected from chest. Six healthy, young men and eight healthy, young women carried out an imitated cough, hand clapping, speech and shouting. Three methods of parametrization were used to prepare the vectors of episode features - time domain, time-frequency domain and spectral modeling. We obtained the accuracy of 95% using artificial neural networks. PMID- 26736876 TI - Residual analysis of ground reaction forces simulation during gait using neural networks with different configurations. AB - The aim of the study was to analyze and compare the residuals obtained from ground reaction force (GRF) models developed using two different neural network configurations (one network with three outputs; and three networks with one output each), based on accelerometer data. Seventeen healthy subjects walked along a walkway, with a force plate embedded, with a three dimensional accelerometer attached to the shank. Multilayer perceptron networks (MLP) models were developed with the 3D accelerometer data as inputs to predict the GRF. The residuals of these models were evaluated graphically and numerically to verify the fitting. A visual analysis of the simulated signals suggests the model was able to adequately predict the GRF. The errors and correlations found in the MLP models for the 3D GRF is at least similar to other studies, although some of them showed higher errors. There was not difference between the two MLP configurations. However, despite the high correlation coefficient and closeness to a normal probability distribution, the residual analysis still presented a higher kurtosis and skewness, suggesting that the inclusion of other variables and the increase of the validation sample size could increase the fitting of the simulation. PMID- 26736877 TI - Biometric identification with high frequency electrocardiogram: Unregistered user refusal method and performance evaluation. AB - As a new modality for biometric identification, electrocardiogram-based identification technique has been developed. We proposed a technique with high frequency component of electrocardiogram (HFECG) in QRS segment. In this report, an unregistered user refusal algorithm was combined with the artificial neural network based waveform classifier. The refusal function was realized by simple thresholding technique. HFECGs from twenty collaborators were used for supervised learning. Twenty HFECGs from the same collaborators were tested and false acceptance rate (FAR) and false rejection rate (FRR) were evaluated. Ten HFECGs from other collaborators were also tested to find unregistered user refusal performance. The results show that FAR and FRR in the registrants can be kept within 1%, however, unregistered user refusal performance was not acceptable under the same condition. PMID- 26736878 TI - EEG based patient emotion monitoring using relative wavelet energy feature and Back Propagation Neural Network. AB - In EEG-based emotion recognition, feature extraction is as important as the classification algorithm. A good choice of features results in higher recognition rate. However, there is no standard method for feature extraction in EEG-based emotion recognition, especially for real time monitoring, where speed of computation is crucial. In this work, we assess the use of relative wavelet energy as features and Back Propagation Neural Network (BPNN) as classifier for emotion recognition. This method was implemented in simulated real time emotion recognition by using a publicly accessible database. The results showed that relative wavelet energy and BPNN achieved an average recognition rate of 92.03%. The highest average recognition rate was achieved when the time window was 30s. PMID- 26736879 TI - Model Selection for PCA-Linear SVM for automated detection of NS1 molecule from Raman spectra of salivary mixture. AB - Of recent, detection of Non-structural Protein 1 (NS1) in saliva has become appealing, as it may lead to a noninvasive detection method for NS1-related diseases at the febrile phase, before complication developed. NS1 is found to have a molecular fingerprint with the use of SERS technique. Our work here intends to determine an optimum PCA-Linear SVM model for automated detection of NS1 molecules from Raman spectra of NS1 adulterated saliva. Raman spectra of normal saliva (n=64) and saliva adulterated with low concentration NS1 (n=64) are used. Since Raman features extracted for each spectrum numbered at 1801, ranking and selection of features in order of their contribution is important prior to classification, for efficient computation. Hence, PCA for feature selection and SVM with linear kernel for classification are integrated. It is found that the Cattel's Scree test is the best stopping criteria for PCA with a selection of 5 PCs and a box constraint of 20 is optimum for Linear SVM. Together they achieve a classification performance, [accuracy sensitivity, specificity], of [98.71% 98.97% 98.44%]. PMID- 26736880 TI - Sleep spindle detection using deep learning: A validation study based on crowdsourcing. AB - Sleep spindles are significant transient oscillations observed on the electroencephalogram (EEG) in stage 2 of non-rapid eye movement sleep. Deep belief network (DBN) gaining great successes in images and speech is still a novel method to develop sleep spindle detection system. In this paper, crowdsourcing replacing gold standard was applied to generate three different labeled samples and constructed three classes of datasets with a combination of these samples. An F1-score measure was estimated to compare the performance of DBN to other three classifiers on classifying these samples, with the DBN obtaining an result of 92.78%. Then a comparison of two feature extraction methods based on power spectrum density was made on same dataset using DBN. In addition, the DBN trained in dataset was applied to detect sleep spindle from raw EEG recordings and performed a comparable capacity to expert group consensus. PMID- 26736881 TI - A new connectivity toolbox to infer topological features of in-vitro neural networks. AB - A detailed analysis of functional connectivity of in vitro neural networks, as well as the possibility to understand the interplay between topology, structure, function and dynamics, is very important for better understanding how the nervous system represents and stores the information. Thus, we developed an informatics toolbox to infer functional connectivity in in-vitro neuronal networks. To prove the validity of the software tool and to verify its performances, we used it to estimate topological metrics on mature hippocampal assemblies coupled to Micro Electrode Arrays (MEAs). PMID- 26736882 TI - A comparative study of breast cancer diagnosis based on neural network ensemble via improved training algorithms. AB - Breast cancer is one of the most common types of cancer in women all over the world. Early diagnosis of this kind of cancer can significantly increase the chances of long-term survival. Since diagnosis of breast cancer is a complex problem, neural network (NN) approaches have been used as a promising solution. Considering the low speed of the back-propagation (BP) algorithm to train a feed forward NN, we consider a number of improved NN trainings for the Wisconsin breast cancer dataset: BP with momentum, BP with adaptive learning rate, BP with adaptive learning rate and momentum, Polak-Ribikre conjugate gradient algorithm (CGA), Fletcher-Reeves CGA, Powell-Beale CGA, scaled CGA, resilient BP (RBP), one step secant and quasi-Newton methods. An NN ensemble, which is a learning paradigm to combine a number of NN outputs, is used to improve the accuracy of the classification task. Results demonstrate that NN ensemble-based classification methods have better performance than NN-based algorithms. The highest overall average accuracy is 97.68% obtained by NN ensemble trained by RBP for 50%-50% training-test evaluation method. PMID- 26736883 TI - Cluster-span threshold: An unbiased threshold for binarising weighted complete networks in functional connectivity analysis. AB - We propose a new unbiased threshold for network analysis named the Cluster-Span Threshold (CST). This is based on the clustering coefficient, C, following logic that a balance of 'clustering' to 'spanning' triples results in a useful topology for network analysis and that the product of complementing properties has a unique value only when perfectly balanced. We threshold networks by fixing C at this balanced value, rather than fixing connection density at an arbitrary value, as has been the trend. We compare results from an electroencephalogram data set of volunteers performing visual short term memory tasks of the CST alongside other thresholds, including maximum spanning trees. We find that the CST holds as a sensitive threshold for distinguishing differences in the functional connectivity between tasks. This provides a sensitive and objective method for setting a threshold on weighted complete networks which may prove influential on the future of functional connectivity research. PMID- 26736884 TI - Investigating deep learning for fNIRS based BCI. AB - Functional Near infrared Spectroscopy (fNIRS) is a relatively young modality for measuring brain activity which has recently shown promising results for building Brain Computer Interfaces (BCI). Due to its infancy, there are still no standard approaches for meaningful features and classifiers for single trial analysis of fNIRS. Most studies are limited to established classifiers from EEG-based BCIs and very simple features. The feasibility of more complex and powerful classification approaches like Deep Neural Networks has, to the best of our knowledge, not been investigated for fNIRS based BCI. These networks have recently become increasingly popular, as they outperformed conventional machine learning methods for a variety of tasks, due in part to advances in training methods for neural networks. In this paper, we show how Deep Neural Networks can be used to classify brain activation patterns measured by fNIRS and compare them with previously used methods. PMID- 26736885 TI - Resting State EEG-based biometrics for individual identification using convolutional neural networks. AB - Biometrics is a growing field, which permits identification of individuals by means of unique physical features. Electroencephalography (EEG)-based biometrics utilizes the small intra-personal differences and large inter-personal differences between individuals' brainwave patterns. In the past, such methods have used features derived from manually-designed procedures for this purpose. Another possibility is to use convolutional neural networks (CNN) to automatically extract an individual's best and most unique neural features and conduct classification, using EEG data derived from both Resting State with Open Eyes (REO) and Resting State with Closed Eyes (REC). Results indicate that this CNN-based joint-optimized EEG-based Biometric System yields a high degree of accuracy of identification (88%) for 10-class classification. Furthermore, rich inter-personal difference can be found using a very low frequency band (0-2Hz). Additionally, results suggest that the temporal portions over which subjects can be individualized is less than 200 ms. PMID- 26736886 TI - A dynamic EMG-torque model of elbow based on neural networks. AB - In this paper, a dynamic EMG-torque model of the elbow joint is developed based on ANN, and two novel test methods are proposed to validate its generalization performance. A time-delay neural network (TDNN) model is built and proved to have less risk of overfitting than the most-used multilayer feedfoward neural network (MFNN) model for dynamic EMG-torque modeling. Both EMG and kinematic features are included in the input of ANN, but the zero-EMG test shows that the trained ANN is part of the inverse joint dynamics rather than the EMG-torque model, and some random samples for ANN training are added to overcome this problem. The single muscle test shows that an inappropriate choice of the motion type may cause the model to estimate wrong torque directions. After tuning and testing, the root mean square error (RMSE) across all subjects is 0.60+/-0.20 N.m. PMID- 26736887 TI - The segmented-beat modulation method for ECG estimation. AB - Electrocardiographic (ECG) tracings corrupted by noise with frequency components in the ECG frequency band, may result useless unless appropriately processed. The estimation of the clean ECG from such recordings, however, is quite challenging; being linear filtering inappropriate. In the common situations in which the R peaks are detectable, template-based techniques have been proposed to estimate the ECG by a template-beat concatenation. However, such techniques have the major limit of not being able to reproduce physiological heart-rate and morphological variability. Thus, the aim of the present study was to propose the segmented-beat modulation method (SBMM) as the technique that overcomes such limit. The SBMM is an improved template-based technique that provides good-quality estimations of ECG tracings characterized by some heart-rate and morphological variability. It segments the template ECG beat into QRS and TUP segments and then, before concatenation, it applies a modulation/demodulation process to the TUP-segment so that the estimated-beat duration and morphology adjust to those of the corresponding original-beat. To test its performance, the SBMM was applied to 19 ECG tracings from normal subjects. There were no errors in estimating the R peak location, and the errors in the QRS and TUP segments were low (<=65 MUV and <=30 MUV, respectively), with the former ones being significantly higher than the latter ones. Eventually, TUP errors tended to increase with increasing heart-rate variability (correlation coefficient: 0.59, P<;10(-2)). In conclusion, the new SBMM proved to be a useful tool for providing good-quality ECG estimations of tracings characterized by heart-rate and morphological variability. PMID- 26736888 TI - A basic study of activity type detection and energy expenditure estimation for children and youth in daily life using 3-axis accelerometer and 3-stage cascaded artificial neural network. AB - It is important to prevent obesity in childhood given that many obese adults have been obese since childhood. An activity monitor could provide an effective aid in preventing obesity if it records not only the calorie assessment but also activity detection to check how active a child is in daily life. The current study is for activity monitoring algorithm and we designed 3-stage cascaded artificial neural network. To develop the algorithm, we recruited 76 participants, made 3-axis accelerometer for them, and acquired activity data and calorie consumption data through them. Finally, we designed 3-stage cascaded network to classify the activities and to assess energy consumption. The 3-stage network classifies 4 activities of walking, running, stairs moving, and jumping rope with overall accuracy of 94.70%, and predicts calorie consumption with average accuracy of 81.91%, which is better than the results of the 2-stage network. Future work would include the enhancement of the network performance. PMID- 26736889 TI - Kernel-nonlinear-PDC extends Partial Directed Coherence to detecting nonlinear causal coupling. AB - Here we investigate a new concept, kernel-nonlinear-Partial Directed Coherence, whereby a kernel feature space representation of the data allows detecting nonlinear causal links that are otherwise undetectable through linear modeling. We show that adequate connectivity detection is achievable by applying asympotic decision criteria similar to the ones developed for linear models. PMID- 26736890 TI - Assessing assumptions of multivariate linear regression framework implemented for directionality analysis of fMRI. AB - Directionality analysis of time-series, recorded from task-activated regions-of interest (ROIs) during functional Magnetic Resonance Imaging (fMRI), has helped in gaining insights of complex human behavior and human brain functioning. The most widely used standard method of Granger Causality for evaluating directionality employ linear regression modeling of temporal processes. Such a parameter-driven approach rests on various underlying assumptions about the data. The short-comings can arise when misleading conclusions are reached after exploration of data for which the assumptions are getting violated. In this study, we assess assumptions of Multivariate Autoregressive (MAR) framework which is employed for evaluating directionality among fMRI time-series recorded during a Sensory-Motor (SM) task. The fMRI time-series here is an averaged time-series from a user-defined ROI of multiple voxels. The "aim" is to establish a step-by step procedure using statistical methods in conjunction with graphical methods to seek the validity of MAR models, specifically in the context of directionality analysis of fMRI data which has not been done previously to the best of our knowledge. Here, in our case of SM task (block design paradigm) there is violation of assumptions, indicating the inadequacy of MAR models to find directional interactions among different task-activated regions of brain. PMID- 26736891 TI - Induced schizophrenic like breathing pattern leads to impaired cardiorespiratory coupling in healthy subjects. AB - Schizophrenia is referred to as one of the most severe mental disorders in the world, and patients with this condition are associated with high cardiac mortality rates. However, the reasons for this high mortality rates are still under debate. One major contributing factor seems to be that a dysfunction of the autonomic nervous system (ANS) is evident in schizophrenia. Thereby, recent investigations focused on the analyses of respiration and cardiorespiratory coupling (CRC) in these patients.The objective of this study was to characterize the causal strength and direction of CRC applying the normalized short time partial directed coherence (NSTPDC) approach in healthy subjects (CON). In this study 25 healthy control subjects were enrolled matching in terms of age and gender to schizophrenic patients. CON were measured in resting condition (pre), breathing with schizophrenic like breathing pattern (stress) and resting condition for recovery (post). During stress CON were asked to breathe with a controlled fixed respiratory frequency, inspirationand expiration time. We found during induced stress significantly increased heart rate and reduced heart rate variability, increased breathing rate and reduced respiratory variability as well as impaired CRC for CON. In conclusion, during induced pathological breathing pattern CON exhibit an impaired and altered heart rate and respiratory regulation and CRC as indicators of a vagal withdrawal and sympathetic overdrive by the ANS. CRC analyses revealed impaired coupling strength and direction, with a driver responder relationship from respiration to heart rate during stress. These findings support the central role of the respiratory dysregulation in schizophrenia and the assumed suppression of higher regulatory centers of the brain stem due to arousals and permanent stress situations in acute schizophrenia. PMID- 26736892 TI - Classification of pregnancy and labor contractions using a graph theory based analysis. AB - In this paper, we propose a new framework to characterize the electrohysterographic (EHG) signals recorded during pregnancy and labor. The approach is based on the analysis of the propagation of the uterine electrical activity. The processing pipeline includes i) the estimation of the statistical dependencies between the different recorded EHG signals, ii) the characterization of the obtained connectivity matrices using network measures and iii) the use of these measures in clinical application: the classification between pregnancy and labor. Due to its robustness to volume conductor, we used the imaginary part of coherence in order to produce the connectivity matrix which is then transformed into a graph. We evaluate the performance of several graph measures. We also compare the results with the parameter mostly used in the literature: the peak frequency combined with the propagation velocity (PV +PF). Our results show that the use of the network measures is a promising tool to classify labor and pregnancy contractions with a small superiority of the graph strength over PV+PF. PMID- 26736893 TI - Prediction of motor imagery based brain computer interface performance using a reaction time test. AB - Brain computer interfaces (BCIs) enable human brains to interact directly with machines. Motor imagery based BCI (MI-BCI) encodes the motor intentions of human agents and provides feedback accordingly. However, 15-30% of people are not able to perform vivid motor imagery. To save time and monetary resources, a number of predictors have been proposed to screen for users with low BCI aptitude. While the proposed predictors provide some level of correlation with MI-BCI performance, simple, objective and accurate predictors are currently not available. Thus, in this study we have examined the utility of a simple reaction time (SRT) test for predicting MI-BCI performance. We enrolled 10 subjects and measured their motor imagery performance with either visual or proprioceptive feedback. Their reaction time was also measured using a SRT test. The results show a significant negative correlation (r ~ -0.67) between SRT and MI-BCI performance. Therefore SRT may be used as a simple and reliable predictor of MI BCI performance. PMID- 26736894 TI - An EEG coherence-based analysis approach for investigating response conflict processes in 7 and 9-year old children. AB - Understanding the development of the brain's neural networks can reveal critical insights into the cognitive changes that occur from infancy to late childhood. Behavioural metrics including: task accuracy, stimuli recognition, and reaction time show dramatic changes over childhood. In this study we investigated response control using the Erikson Flanker task. In a dataset of 45 EEG recordings, we calculated spectral coherence to measure connectivity between all possible electrode pairs. Coherence measures were performed on two different trial conditions -congruent (where there is no response conflict) and incongruent (where response conflict is induced). The increase in incongruent coherence compared to the congruent was investigated for each electrode pair over 45 healthy subjects aged seven years. The same calculation was then performed on the same group of subjects two years later when they were aged nine years. The results revealed that at age seven years, increased coherence was detected in the left prefrontal to right and left parieto-occipital - i.e. an anatomical region located between the parietal and occipital lobes - within theta band. No increase was found for the older group-at age nine years- which may indicate cognitive development in conflict processing mechanism. PMID- 26736895 TI - Seizure prediction by analyzing EEG signal based on phase correlation. AB - Epilepsy is a common neurological disorders characterized by sudden recurrent seizures. Electroencephalogram (EEG) is widely used to diagnose possible epileptic seizure. Many research works have been devoted to predict epileptic seizure by analyzing EEG signal. Seizure prediction by analyzing EEG signals are challenging task due to variations of brain signals of different patients. In this paper, we propose a new approach for feature extraction based on phase correlation in EEG signals. In phase correlation, we calculate relative change between two consecutive segments of an EEG signal and then combine the changes with neighboring signals to extract features. These features are then used to classify preictal/ictal and interictal EEG signals for seizure prediction. Experiment results show that the proposed method carries good prediction rate with greater consistence for the benchmark data set in different brain locations compared to the existing state-of-the-art methods. PMID- 26736896 TI - Long-term scalp epileptic EEG quantification with GMA dynamics. AB - The paper concerns the problem of automatic seizure detection based on scalp EEG and proposes to employ the generalized measure of association (GMA) to quantify the statistical dependencies and infer the dynamical interactions of brain regions with the focus area. The experimental results with clinical recordings show that the estimated GMA values changes dramatically before and during epileptic seizures reflecting the dynamic coupling and decoupling between brain regions, which can be an useful measure to quantify epileptic EEG signals. PMID- 26736897 TI - EEG classification of emotions using emotion-specific brain functional network. AB - The brain functional network perspective forms the basis to relate mechanisms of brain functions. This work analyzes the network mechanisms related to human emotion based on synchronization measure - phase-locking value in EEG to formulate the emotion specific brain functional network. Based on network dissimilarities between emotion and rest tasks, most reactive channel pairs and the reactive band corresponding to emotions are identified. With the identified most reactive pairs, the subject-specific functional network is formed. The identified subject-specific and emotion-specific dynamic network pattern show significant synchrony variation in line with the experiment protocol. The same network pattern are then employed for classification of emotions. With the study conducted on the 4 subjects, an average classification accuracy of 62 % was obtained with the proposed technique. PMID- 26736898 TI - Effect of age on changes in motor units functional connectivity. AB - With age, there is a change in functional connectivity of motor units in muscle. This leads to reduced muscle strength. This study has investigated the effect of age on the changes in the motor unit recruitment by measuring the mutual information between multiple channels of surface electromyogram (sEMG) of biceps brachii muscle. It is hypothesised that with ageing, there is a reduction in number of motor units, which can lead to an increase in the dependency of remaining motor units. This increase can be observed in the mutual information between the multiple channels of the muscle activity. Two channels of sEMG were recorded during the maximum level of isometric contraction. 28 healthy subjects (Young: age range 20-35years and Old: age range - 60-70years) participated in the experiments. The normalized mutual information (NMI), a measure of dependency factor, was computed for the sEMG recordings. Statistical analysis was performed to test the effect of age on NMI. The results show that the NMI among the older cohort was significantly higher when compared with the young adults. PMID- 26736899 TI - Assessing small-worldness of dynamic functional brain connectivity during complex tasks. AB - The development of network theory has introduced new approaches to understand the brain as a complex system. Currently the time-variant functional connectivity of brain networks under complex tasks is still being investigated. To explore connectivity during complex cognitive and motor tasks, this study focused on the relevance of small-worldness to human workloads using EEG signals from a dynamic analytic approach. Experiments were designed to investigate the small-worldness under two types of flight simulation tasks at two levels of difficulty - easy and hard. The results demonstrated a consistent small-world architecture of brain connectivity with time-based variance during complex tasks. We noticed an increased small-world effect especially at the alpha band when performing hard tasks compared to easy tasks, which relate to high and low workload respectively. Our results show the potential of dynamic brain network analysis in exploring time-variant and task-dependent brain connectivity during complex tasks. PMID- 26736900 TI - Patient Specific Phantom in bimodal image navigation system. AB - The paper presents the multistep methodology of bimodal Patient Specific Phantom (PSP) development. First, CT based abdominal digital model is designed. It serves as a source for designing organ moulds manufactured by means of a 3D-printer. The collagen based colloid fills the moulds yielding the organ casts. The PSP permits a bimodal navigation system to be developed that employs a realistic CT-based digital model and US imaging. Highly accurate results were achieved with mean Dice similarity coefficient value of 0.92 and Hausdorff distance 9.67 mm. PMID- 26736901 TI - Finding complete 3D vertex correspondence for statistical shape modeling. AB - A statistical shape model that accurately generalizes a family of 3D shapes requires establishing correspondences across the set of shapes. However in 3D anatomical meshes, finding a sufficient number of landmarks to accurately describe the shape can be a challenge, and often only a few points are easily identifiable due to the smooth nature of the object surface. Using a sparse set of landmarks, this paper finds a dense set of vertex correspondences across a set of 3D aortic root meshes. This is achieved by non-rigidly transforming a source mesh to a target mesh. Then, for every vertex on the target, a corresponding vertex on the deformed source is found, resulting in complete correspondence. A more accurate transformation results in better correspondence establishment, and our mesh registration experiments show an average Hausdorff distance of 3.65mm, and an average point-to-mesh distance of 0.41mm, i. e. within one voxel. PMID- 26736902 TI - Development of 2D+T tracking algorithm in ultrasound images for radiotherapy. AB - The aim of this study is to develop and validate a deformable tracking algorithm for monitoring the motion of the target volume on 2D ultrasound (US) images during a radiotherapy fraction. The proposed method is applied on images acquired with a transperineal ultrasound (TP-US) probe on 31 treatment patient's sessions, treated with a prostate or after a surgery, called a prostatectomy. The developed algorithm is based on Speeded-Up Robust Features (SURF) to find and match the corresponding salient points in the reference and moving images, and Thin Plate Spline (TPS) to warp the image. The results are promising and show that the proposed algorithm performs well with either artificial transforms, or in comparison with a rigid intensity based algorithm used in clinic. PMID- 26736903 TI - A new region descriptor for multi-modal medical image registration and region detection. AB - Establishing accurate anatomical correspondences plays a critical role in multi modal medical image registration and region detection. Although many features based registration methods have been proposed to detect these correspondences, they are mostly based on the point descriptor which leads to high memory cost and could not represent local region information. In this paper, we propose a new region descriptor which depicts the features in each region, instead of in each point, as a vector. First, feature attributes of each point are extracted by a Gabor filter bank combined with a gradient filter. Then, the region descriptor is defined as the covariance of feature attributes of each point inside the region, based on which a cost function is constructed for multi-modal image registration. Finally, our proposed region descriptor is applied to both multi-modal region detection and similarity metric measurement in multi-modal image registration. Experiments demonstrate the feasibility and effectiveness of our proposed region descriptor. PMID- 26736904 TI - Atlas to patient registration with brain tumor based on a mesh-free method. AB - Brain atlas to patient registration in the presence of tumors is a challenging task because its presence cause brain structure deformations and introduce large intensity variation between the affected areas. This large dissimilarity affects the results of traditional registration methods based on intensity or shape similarities. In order to overcome these problems, we propose a novel method that brings closer the atlas and the patient's image by simulating the mechanical behavior of brain deformation under a tumor pressure. The proposed method use a mesh-free total Lagrangian Explicit Dynamic algorithm for the simulation of atlas deformation and a data driven model of the tumor using multi-modal MRI segmentation. Experimental results look structurally very similar to the patient's image and outperform two of the top ranking algorithms. PMID- 26736905 TI - Regional assessment of lung function using thin-plate splines to align structural and functional imaging. AB - Ventilation / perfusion (VQ) Single Photon Emission Computed Tomography (SPECT) imaging provides 3D data of the regional distribution of ventilation and perfusion throughout the lung, but interpretation of the results is difficult without reference to the underlying lung anatomy. Multi-Slice Computed Tomography (MSCT) imaging is able to provide significant anatomical detail in the lung, allowing delineation of regional features such as the lobes. The purpose of this work was to develop software tools to allow the alignment of regions delineated from the MSCT scans, with the corresponding SPECT data, to allow measurements of VQ to be made for anatomically meaningful regions. The technique developed was based on the use of thin-plate splines and the results showed that it was able to provide good alignment between the MSCT and SPECT data. PMID- 26736906 TI - Markerless registration for image-guided endoscopic retrograde cholangiopancreatography (ERCP). AB - This paper proposes methods for markerless registration, which enable tracking pose of the endoscope camera in real time for implementation of the image-guided ERCP. Edge-based initialization is developed to determine the initial pose of the endoscope camera. Images of virtual endoscope are rendered from the virtual 3D organ model constructed from the patient's CT images. The similarity between edges on the image of the virtual and real endoscope is exploited for registration. An optical-flow-based tracking method is developed to track the changes starting from the initial pose of the endoscope camera in real time. The redefinition method is proposed to prevent the accumulation of the tracking error. Accuracy of the proposed methods is compared with the previous methods. The initialization method reduces 5.2 mm, 33.1 degrees, and 10.9 degrees of the position, direction, and roll angle error, on average, respectively. The tracking method reduces 3.5 degrees and 1.7 degrees of the hysteresis error in the direction angle and roll angle, respectively, with 15% faster update rate. PMID- 26736907 TI - Registration of lung CT images acquired in different respiratory ranges with 4DCT and HRCT. AB - Pulmonary image registration is challenging because of the unique structure of the lung, its high deformability and its non-uniform intensity change with breathing. In the present work we propose a new method for pulmonary image registration, based on the reconstruction and the combination of the main pulmonary structures to modify parenchyma intensity prior to the application of the registration algorithm. The algorithm has been applied to both four dimensional CT and multi-volume high resolution CT demonstrating an increased accuracy of the results with the application of the pulmonary structure enhancement, evaluated both on landmarks distance in 4DCT and structures' surface distance in HRCT. PMID- 26736908 TI - A comparative study for chest radiograph image retrieval using binary texture and deep learning classification. AB - In this work various approaches are investigated for X-ray image retrieval and specifically chest pathology retrieval. Given a query image taken from a data set of 443 images, the objective is to rank images according to similarity. Different features, including binary features, texture features, and deep learning (CNN) features are examined. In addition, two approaches are investigated for the retrieval task. One approach is based on the distance of image descriptors using the above features (hereon termed the "descriptor"-based approach); the second approach ("classification"-based approach) is based on a probability descriptor, generated by a pair-wise classification of each two classes (pathologies) and their decision values using an SVM classifier. Best results are achieved using deep learning features in a classification scheme. PMID- 26736909 TI - Content-based image retrieval in homomorphic encryption domain. AB - In this paper, we propose a secure implementation of a content-based image retrieval (CBIR) method that makes possible diagnosis aid systems to work in externalized environment and with outsourced data as in cloud computing. This one works with homomorphic encrypted images from which it extracts wavelet based image features next used for subsequent image comparison. By doing so, our system allows a physician to retrieve the most similar images to a query image in an outsourced database while preserving data confidentiality. Our Secure CBIR is the first one that proposes to work with global image features extracted from encrypted images and does not induce extra communications in-between the client and the server. Experimental results show it achieves retrieval performance as good as if images were processed non-encrypted. PMID- 26736910 TI - Ensembling brain regions for brain decoding. AB - In this study, we propose a new method which ensembles the brain regions for brain decoding. The ensemble is generated by clustering the fMRI images recorded during an experimental set-up which measures the cognitive states associated to semantic categories. Initially, voxel clusters are formed by using hierarchical agglomerative clustering with correlation as the similarity metric. Then, for each voxel cluster, a support vector machine (SVM) classifier is trained to estimate the class-posteriori probabilities. Lastly, the class-posteriori probabilities are ensembled by concatenating them under the same feature space, which are then used to train a meta-layer SVM for the final classification of the cognitive states. By using the voxel clusters, we aim to utilize the distributed, but complementing nature of the semantic representations in the brain and improve the classification accuracy. Thus, we make an existential claim that the brain regions provide a natural basis for ensemble learning which should be superior to the random clusters formed over a selected set of voxels. Our approach yields to better classification accuracies in Mitchell dataset on most of the subjects, when compared to state-of-the-art which emphasizes voxel selection and ensemble learning with random subspaces. PMID- 26736911 TI - Sparse high order potentials for extending multi-surface segmentation of OCT images with drusen. AB - Drusen quantification is important for evaluating age-related macular degeneration (AMD) progress. Most methods for retinal layers segmentation in optical coherence tomography (OCT) depend heavily on prior information. This improves robustness, but also has the downside of increasing surface rigidity. Hence, those algorithms normally smooth drusen borders, as significant local variations are not expected. In this work, we propose to integrate sparse higher order potentials (SHOPs) into a multi-surface segmentation framework to cope with local boundary variations caused by drusen. The algorithm was evaluated in a database of 20 patients with AMD. The mean unsigned error for the inner retinal pigment epithelium (IRPE) and Bruch's membrane (BM) was 5.65+/-6.26 and 4.37+/ 5.25 MUm, respectively. These results are relative to the average of two experts, whose inter-observer variability was 7.30+/-6.87 MUm for IRPE and 5.03+/-4.37 MUm for BM. The use SHOPs resulted in a successful segmentation of the IRPE. The remaining boundaries were also successfully segmented. PMID- 26736912 TI - Lossless compression of medical images using Burrows-Wheeler Transformation with Inversion Coder. AB - Medical imaging is a quickly growing industry where the need for highly efficient lossless compression algorithms is necessary in order to reduce storage space and transmission rates for the large, high resolution, medical images. Due to the fact that medical imagining cannot utilize lossy compression, in the event that vital information may be lost, it is imperative that lossless compression be used. While several authors have investigated lossless compression of medical images, the Burrows-Wheeler Transformation with an Inversion Coder (BWIC) has not been examined. Our investigation shows that BWIC runs in linear time and yields better compression rates than well-known image coders, such as JPEG-LS and JPEG 2000. PMID- 26736913 TI - Hair removal on dermoscopy images. AB - Digital Dermoscopy is a tool commonly used by dermatologists for assisting the diagnosis of skin lesions. The presence of hair in such dermoscopic images frequently occludes significant diagnostic information and reduces their value. In this work we propose algorithms that successfully identify and remove hair from the dermoscopic images. The proposed algorithms consist of two parts; the first deals with the identification of hair, while the second part concerns the image restoration using interpolation. For the evaluation of the algorithms we used ground truth images with synthetic hair and compared the results with the commonly used in the literature DullRazor tool. According to the experimental results the proposed hair removal algorithms can be used successfully in the detection and removal of both dark and light colored hair. PMID- 26736914 TI - Facial nerve image enhancement from CBCT using supervised learning technique. AB - Facial nerve segmentation plays an important role in surgical planning of cochlear implantation. Clinically available CBCT images are used for surgical planning. However, its relatively low resolution renders the identification of the facial nerve difficult. In this work, we present a supervised learning approach to enhance facial nerve image information from CBCT. A supervised learning approach based on multi-output random forest was employed to learn the mapping between CBCT and micro-CT images. Evaluation was performed qualitatively and quantitatively by using the predicted image as input for a previously published dedicated facial nerve segmentation, and cochlear implantation surgical planning software, OtoPlan. Results show the potential of the proposed approach to improve facial nerve image quality as imaged by CBCT and to leverage its segmentation using OtoPlan. PMID- 26736915 TI - Nasopharyngeal carcinoma segmentation via HMRF-EM with maximum entropy. AB - This paper presents a novel automatic nasopharyngeal carcinoma segmentation approach used in magnetic resonance images. Adaptive calculation of the nasopharyngeal region location is first performed. The contour of the tumor is determined through distance regularized level set evolution with the initial contour obtained by the nearest neighbor graph model. To further refine the segmentation, a hidden Markov random field model with maximum entropy (HMRF-EM) is introduced to model the spatial information with prior knowledge. The proposed method is tested on magnetic resonance images of 26 nasopharyngeal carcinoma patients, and achieves good results. PMID- 26736916 TI - CT image segmentation in traumatic brain injury. AB - Traumatic brain injury (TBI) is a major cause of disability and death. Speed and accuracy are vital in diagnosing TBI for which computer-aided imaging analysis may speedup and improve the efficiency of diagnosis and help reduce mortality, long-term complications, and the associated costs. However, developing such a system is challenging due to some factors such as the inherent noise associated with obtaining the images, artifacts and quality of the images. An automated system that can preliminary identify, localize and quantify the imaging features of TBI would be beneficial in guiding real-time clinical diagnosis as well as for quality assurance. In this paper we propose an automated system to segment the hematoma region from CT images. The proposed method first performs denoising and image enhancement and then by developing a Gaussian mixture model, segmentation is carried out. We show the performance of the system by comparing the results with ground truth generated by specialists. PMID- 26736917 TI - Multi-atlas label fusion using hybrid of discriminative and generative classifiers for segmentation of cardiac MR images. AB - Multi-atlas segmentation first registers each atlas image to the target image and transfers the label of atlas image to the coordinate system of the target image. The transferred labels are then combined, using a label fusion algorithm. In this paper, we propose a novel label fusion method which aggregates discriminative learning and generative modeling for segmentation of cardiac MR images. First, a probabilistic Random Forest classifier is trained as a discriminative model to obtain the prior probability of a label at the given voxel of the target image. Then, a probability distribution of image patches is modeled using Gaussian Mixture Model for each label, providing the likelihood of the voxel belonging to the label. The final label posterior is obtained by combining the classification score and the likelihood score under Bayesian rule. Comparative study performed on MICCAI 2013 SATA Segmentation Challenge demonstrates that our proposed hybrid label fusion algorithm is accurate than other five state-of-the-art label fusion methods. The proposed method obtains dice similarity coefficient of 0.94 and 0.92 in segmenting epicardium and endocardium respectively. Moreover, our label fusion method achieves more accurate segmentation results compared to four other label fusion methods. PMID- 26736918 TI - Accurate kidney surface reconstruction from 3D ultrasonography for volume assessment: First clinical evaluation. AB - An accurate, repeatable and noninvasive measurement of kidney volume is an important but difficult task for nephrologists. This paper proposes a new kidney volumetry method by reconstructing the kidney surface from three-dimensional ultrasonography (3DUS) using statistical shape model (SSM). The measurement starts with picking sparse points on the kidney contour from 3DUS images. Then an accurate 3D kidney surface mesh can be reconstructed from the input points using the SSM in a fine-tune way. The kidney volume is finally calculated from the surface using divergence theorem of Gauss. The accuracy and repeatability of the proposed method have been validated on 36 patients. The results demonstrate that the proposed method is a promising solution for clinical evaluation of the kidney volume. PMID- 26736919 TI - Determination of lung regions on chest ct images with diffuse lung diseases by use of anatomical structures and pulmonary textures. AB - To analyze diffuse lung diseases based on chest region computed tomography (CT) imaging by using a computer-aided diagnosis (CAD) system, it is necessary to first determine the lung regions subject to analysis. The lung regions can be selected relatively easily for healthy individuals, by applying a threshold. Selecting an area by using a threshold-based method can be difficult when dealing with lungs with diffuse lung diseases, owing to the abnormal opacities that characterize the diseases. Trials for determining the lung regions were conducted in this study, through texture analysis and machine learning, by narrowing down the lung regions to rough regions, and by referring to ribs and the diaphragm. This method can be used for determining lung regions for analysis of diffuse lung diseases. PMID- 26736920 TI - Echogenicity based approach to detect, segment and track the common carotid artery in 2D ultrasound images. AB - Automatic detection and segmentation of the common carotid artery in transverse ultrasound (US) images of the thyroid gland play a vital role in the success of US guided intervention procedures. We propose in this paper a novel method to accurately detect, segment and track the carotid in 2D and 2D+t US images of the thyroid gland using concepts based on tissue echogenicity and ultrasound image formation. We first segment the hypoechoic anatomical regions of interest using local phase and energy in the input image. We then make use of a Hessian based blob like analysis to detect the carotid within the segmented hypoechoic regions. The carotid artery is segmented by making use of least squares ellipse fit for the edge points around the detected carotid candidate. Experiments performed on a multivendor dataset of 41 images show that the proposed algorithm can segment the carotid artery with high sensitivity (99.6 +/-m 0.2%) and specificity (92.9 +/-m 0.1%). Further experiments on a public database containing 971 images of the carotid artery showed that the proposed algorithm can achieve a detection accuracy of 95.2% with a 2% increase in performance when compared to the state-of the-art method. PMID- 26736921 TI - A DBSCAN based approach for jointly segment and classify brain MR images. AB - In recent years a growing interest has grown in Magnetic Resonance images segmentation techniques, due to their usefulness in many applications. Within this manuscript, a novel segmentation approach is presented, based on two main innovations. First, it exploits the estimated proton density and relaxation times for each pixel, instead of its gray-level intensity. This feature makes the algorithm particularly robust and allows the classification of identified segments. Secondly, it implements a specifically evolved version of the DBSCAN approach, gaining advantages in the effectiveness of region estimation. The technique, compared to an euclidean distance based one, is able to improve the correct classification rate. The effectiveness of the approach is evaluated on a simulated case study, and will be extended to real data within next weeks. PMID- 26736922 TI - Image segmentation of pyramid style identifier based on Support Vector Machine for colorectal endoscopic images. AB - With the increase of colorectal cancer patients in recent years, the needs of quantitative evaluation of colorectal cancer are increased, and the computer aided diagnosis (CAD) system which supports doctor's diagnosis is essential. In this paper, a hardware design of type identification module in CAD system for colorectal endoscopic images with narrow band imaging (NBI) magnification is proposed for real-time processing of full high definition image (1920 * 1080 pixel). A pyramid style image segmentation with SVMs for multi-size scan windows, which can be implemented on an FPGA with small circuit area and achieve high accuracy, is proposed for actual complex colorectal endoscopic images. PMID- 26736923 TI - Segmentation of bones & MCP joint region of the hand from ultrasound images. AB - Rheumatic arthritis (RA) is an autoimmune disease that causes irreversible damage to joints and other physiological structures. The Metacarpophalangeal (MCP) joint is one of the first regions to suffer alterations. These alterations are visible with high frequency ultrasound devices, which are used to quantify inflammatory activity in the MCP due to RA. The accurate segmentation of the bone surface and the identification of the MCP capsule region remains a challenge in ultrasound image processing. In this article we aim to make a contribution to this problem by incorporating prior knowledge of the bone and joint regions anatomy into our segmentation algorithm. The log Gabor filter is used for speckle noise reduction and to extract ridge-like structures from the images, while the phase is left unchanged. After thresholding, scores are generated, based on the intensities and areas of the resulting regions, enabling the selection of the structure that best matches the bone. Finally, segmented joint bones are processed to calculate the initial seeds of joint capsule region. Experimental results demonstrate the accuracy of the proposed segmentation algorithm. The mean pixel error between the automatic segmentation and the reference images were 4.4 pixel. The bone regions not segmented were, on average, 5.4%. PMID- 26736924 TI - Image processing in biodosimetry: A proposal of a generic free software platform. AB - The scoring of chromosome aberrations is the most reliable biological method for evaluating individual exposure to ionizing radiation. However, microscopic analyses of chromosome human metaphases, generally employed to identify aberrations mainly dicentrics (chromosome with two centromeres), is a laborious task. This method is time consuming and its application in biological dosimetry would be almost impossible in case of a large scale radiation incidents. In this project, a generic software was enhanced for automatic chromosome image processing from a framework originally developed for the Framework V project Simbio, of the European Union for applications in the area of source localization from electroencephalographic signals. The platforms capability is demonstrated by a study comparing automatic segmentation strategies of chromosomes from microscopic images. PMID- 26736925 TI - Automated saliency-based lesion segmentation in dermoscopic images. AB - The segmentation of skin lesions in dermoscopic images is considered as one of the most important steps in computer-aided diagnosis (CAD) for automated melanoma diagnosis. Existing methods, however, have problems with over-segmentation and do not perform well when the contrast between the lesion and its surrounding skin is low. Hence, in this study, we propose a new automated saliency-based skin lesion segmentation (SSLS) that we designed to exploit the inherent properties of dermoscopic images, which have a focal central region and subtle contrast discrimination with the surrounding regions. The proposed method was evaluated on a public dataset of lesional dermoscopic images and was compared to established methods for lesion segmentation that included adaptive thresholding, Chan-based level set and seeded region growing. Our results show that SSLS outperformed the other methods in regard to accuracy and robustness, in particular, for difficult cases. PMID- 26736926 TI - Computer aided analysis of prostate histopathology images Gleason grading especially for Gleason score 7. AB - Clinically, prostate adenocarcinoma is diagnosed by recognizing certain morphology on histology. While the Gleason grading system has been shown to be the strongest prognostic factor for men with prostrate adenocarcinoma, there is a significant intra and interobserver variability between pathologists in assigning this grading system. In this study, we present a new method for prostate gland segmentation from which we then utilize to develop a computer aided Gleason grading. The novelty of our method is a region-based nuclei segmentation to get individual gland without using lumen as prior information. Because each gland region is surrounded by nuclei, individual gland can be segmented by using the structure features and Delaunay Triangulation. The precision, recal and F1 of this approach are 0.94+/-0.11, 0.60+/-0.23 and 0.70+/-0.19 respectively. Our method achieves a high accuracy for prostate gland segmentation with less computation time. PMID- 26736927 TI - Colon centerline extraction in fragmented segmentations. AB - In virtual colonoscopy, the clinical need is a smooth centered path from the rectum to the cecum, for interactive navigation along the colonic lumen. The primary challenge is breakages in the colon, due to fecal residue, abnormalities, poor insufflation and inadequate electronic cleansing. Here we propose a method, that is a modification of the classic energy minimized geodesic, that extracts centered paths through fragmented colons. To begin, we perform electronic cleansing, automatically localize 4 points: rectum, cecum, sphlenic and hepatic flexures; followed by region growing and heuristic approaches to generate the initial segmentation. This is followed by a daisy chaining procedure to link possibly large colon blobs that may have been missed as weaker candidate segmentations. We then perform a front propagation to extract a minimal energy path through the ordered set of points. This propagation is guided by multiple forces: (a) A strong force given by the distance to the colon segmentation surface (b) A weak force derived from the CT intensity (c) A weak force from the distance to the surface of weaker candidate colon segmentations (d) A geodesic repulsive force, where the other points exhibit an repelling force in their voronoi partition, the force proportional to the geodesic distance to the point. Our contribution is a path extraction method for the colon that is the energy minimized geodesic (a) favouring centeredness (b) punching through gaps, traversing in so far as possible through lower intensity regions and possibly centered within these gaps (c) ordered through the feature points. Results show improvements of the method over the standard minimal energy path approach. PMID- 26736928 TI - Automated colour identification in melanocytic lesions. AB - Colour information plays an important role in classifying skin lesion. However, colour identification by dermatologists can be very subjective, leading to cases of misdiagnosis. Therefore, a computer-assisted system for quantitative colour identification is highly desirable for dermatologists to use. Although numerous colour detection systems have been developed, few studies have focused on imitating the human visual perception of colours in melanoma application. In this paper we propose a new methodology based on QuadTree decomposition technique for automatic colour identification in dermoscopy images. Our approach mimics the human perception of lesion colours. The proposed method is trained on a set of 47 images from NIH dataset and applied to a test set of 190 skin lesions obtained from PH2 dataset. The results of our proposed method are compared with a recently reported colour identification method using the same dataset. The effectiveness of our method in detecting colours in dermoscopy images is vindicated by obtaining approximately 93% accuracy when the CIELab1 colour space is used. PMID- 26736929 TI - Automatic detection of small bowel tumors in endoscopic capsule images by ROI selection based on discarded lightness information. AB - This paper addresses the problem of automatic detection of tumoral frames in endoscopic capsule videos by using features directly extracted from the color space. We show that tumor can be appropriately discriminated from normal tissue by using only color information histogram measures from the Lab color space and that light saturated regions are usually classified as tumoral regions when color based discriminative procedures are used. These regions are correctly classified if lightening is discarded becoming the tissue classifier based only on the color differences a and b of the Lab color space. While current state of the art systems for small bowel tumor detection usually rely on the processing of the whole frame regarding features extraction this paper proposes the use of fully automatic segmentation in order to select regions likely to contain tumoral tissue. Classification is performed by using Support Vector Machine (SVM) and Multilayer Perceptron (MLP) by using features from color channels a and b of the Lab color space. The proposed algorithm outperforms in more than 5% a series of other algorithms based on features obtained from the higher frequency components selected from Wavelets and Curvelets transforms while saving important computational resources. In a matter of fact the proposed algorithm is more than 25 times faster than algorithms requiring wavelet/curvelet and co-occurrence computations. PMID- 26736930 TI - Deep neural network and random forest hybrid architecture for learning to detect retinal vessels in fundus images. AB - Vision impairment due to pathological damage of the retina can largely be prevented through periodic screening using fundus color imaging. However the challenge with large-scale screening is the inability to exhaustively detect fine blood vessels crucial to disease diagnosis. In this work we present a computational imaging framework using deep and ensemble learning based hybrid architecture for reliable detection of blood vessels in fundus color images. A deep neural network (DNN) is used for unsupervised learning of vesselness dictionaries using sparse trained denoising auto-encoders (DAE), followed by supervised learning of the DNN response using a random forest for detecting vessels in color fundus images. In experimental evaluation with the DRIVE database, we achieve the objective of vessel detection with max. avg. accuracy of 0.9327 and area under ROC curve of 0.9195. PMID- 26736931 TI - Correction tool for Active Shape Model based lumbar muscle segmentation. AB - In the clinical environment, accuracy and speed of the image segmentation process plays a key role in the analysis of pathological regions. Despite advances in anatomic image segmentation, time-effective correction tools are commonly needed to improve segmentation results. Therefore, these tools must provide faster corrections with a low number of interactions, and a user-independent solution. In this work we present a new interactive correction method for correcting the image segmentation. Given an initial segmentation and the original image, our tool provides a 2D/3D environment, that enables 3D shape correction through simple 2D interactions. Our scheme is based on direct manipulation of free form deformation adapted to a 2D environment. This approach enables an intuitive and natural correction of 3D segmentation results. The developed method has been implemented into a software tool and has been evaluated for the task of lumbar muscle segmentation from Magnetic Resonance Images. Experimental results show that full segmentation correction could be performed within an average correction time of 6+/-4 minutes and an average of 68+/-37 number of interactions, while maintaining the quality of the final segmentation result within an average Dice coefficient of 0.92+/-0.03. PMID- 26736932 TI - Brain Tumour Segmentation based on Extremely Randomized Forest with high-level features. AB - Gliomas are among the most common and aggressive brain tumours. Segmentation of these tumours is important for surgery and treatment planning, but also for follow-up evaluations. However, it is a difficult task, given that its size and locations are variable, and the delineation of all tumour tissue is not trivial, even with all the different modalities of the Magnetic Resonance Imaging (MRI). We propose a discriminative and fully automatic method for the segmentation of gliomas, using appearance- and context-based features to feed an Extremely Randomized Forest (Extra-Trees). Some of these features are computed over a non linear transformation of the image. The proposed method was evaluated using the publicly available Challenge database from BraTS 2013, having obtained a Dice score of 0.83, 0.78 and 0.73 for the complete tumour, and the core and the enhanced regions, respectively. Our results are competitive, when compared against other results reported using the same database. PMID- 26736933 TI - A multiparametric and multiscale approach to automated segmentation of brain veins. AB - Cerebral vein analysis provides a fundamental tool to study brain diseases such as neurodegenerative disorders or traumatic brain injuries. In order to assess the vascular anatomy, manual segmentation approaches can be used but are observer dependent and time-consuming. In the present work, a fully automated cerebral vein segmentation method is proposed, based on a multiscale and multiparametric approach. The combined investigation of the R2(*)- and a Vesselness probability map was used to obtain a fast and highly reliable classification of venous voxels. A semiquantitative analysis showed that our approach outperformed the previous state-of-the-art algorithm both in sensitivity and specificity. Inclusion of this tool within a parametric brain framework may therefore pave the way for a quantitative study of the intracranial venous system. PMID- 26736934 TI - Epidermal segmentation in high-definition optical coherence tomography. AB - Epidermis segmentation is a crucial step in many dermatological applications. Recently, high-definition optical coherence tomography (HD-OCT) has been developed and applied to imaging subsurface skin tissues. In this paper, a novel epidermis segmentation method using HD-OCT is proposed in which the epidermis is segmented by 3 steps: the weighted least square-based pre-processing, the graph based skin surface detection and the local integral projection-based dermal epidermal junction detection respectively. Using a dataset of five 3D volumes, we found that this method correlates well with the conventional method of manually marking out the epidermis. This method can therefore serve to effectively and rapidly delineate the epidermis for study and clinical management of skin diseases. PMID- 26736935 TI - A fully automated level-set based segmentation method of thoracic and lumbar vertebral bodies in Computed Tomography images. AB - Spine is a structure commonly involved in several diseases. Identification and segmentation of the vertebral structures are of relevance to many medical applications related to the spine such as diagnosis, therapy or surgical intervention. However, the development of automatic and reliable methods are an unmet need. This work presents a fully automatic segmentation method of thoracic and lumbar vertebral bodies from Computed Tomography images. The procedure can be divided into four main stages: firstly, seed points were detected in the spinal canal in order to generate initial contours in the segmentation process, automating the whole process. Secondly, a processing step is performed to improve image quality. Third step was to carry out the segmentation using the Selective Binary Gaussian Filtering Regularized Level Set method and, finally, two morphological operations were applied in order to refine the segmentation result. The method was tested in clinical data coming from 10 trauma patients. To evaluate the result the average value of the DICE coefficient was calculated, obtaining a 90.86 +/- 1.87% in the whole spine (thoracic and lumbar regions), a 86.08 +/- 1.73% in the thoracic region and a 95,61 +/-2,25% in the lumbar region. The results are highly competitive when compared to the results obtained in previous methods, especially for the lumbar region. PMID- 26736936 TI - A fast atlas pre-selection procedure for multi-atlas based brain segmentation. AB - Multi-atlas based MR image segmentation has been recognized as a quantitative analysis approach for brain. For such purpose, atlas databases keep increasing to include various anatomical characteristics of human brain. Atlas pre-selection becomes a necessary step for efficient and accurate automated segmentation of human brain images. In this study, we proposed a method of atlas pre-selection for target image segmentation on the MriCloud platform, which is a state-of-the art multi-atlas based segmentation tool. In the MRIcloud pipeline, segmentation of lateral ventricle (LV) label is generated as an additional input in the segmentation pipeline. Under this circumstance, similarity of the LV label between target image and atlases was adopted as the atlas ranking scheme. Dice overlap coefficient was calculated and taken as the quantitative measure for atlas ranking. Segmentation results based on the proposed method were compared with that based on atlas pre-selection by mutual information (MI) between images. The final segmentation results showed a comparable accuracy of the proposed method with that from MI based atlas pre-selection. However, the computation load for the atlas pre-selection was speeded up by about 20 times compared to MI based pre-selection. The proposed method provides a promising assistance for quantitative analysis of brain images. PMID- 26736937 TI - Minimum mutual information based level set clustering algorithm for fast MRI tissue segmentation. AB - Accurate and accelerated MRI tissue recognition is a crucial preprocessing for real-time 3d tissue modeling and medical diagnosis. This paper proposed an information de-correlated clustering algorithm implemented by variational level set method for fast tissue segmentation. The key idea is to design a local correlation term between original image and piecewise constant into the variational framework. The minimized correlation will then lead to de-correlated piecewise regions. Firstly, by introducing a continuous bounded variational domain describing the image, a probabilistic image restoration model is assumed to modify the distortion. Secondly, regional mutual information is introduced to measure the correlation between piecewise regions and original images. As a de correlated description of the image, piecewise constants are finally solved by numerical approximation and level set evolution. The converged piecewise constants automatically clusters image domain into discriminative regions. The segmentation results show that our algorithm performs well in terms of time consuming, accuracy, convergence and clustering capability. PMID- 26736939 TI - Speckle reduction based on Wiener filter in ultrasound images. AB - In this manuscript, a technique for speckle noise reduction in ultrasound images is presented. The method exploits Wiener filter and is able to take into account spatial correlation among noise samples. With respect to classical Wiener filter approach developed in independence hypothesis, the methodology is able to sensibly improve filtering performances, at the cost of no computational time increase. Results on realistic simulated datasets are reported, showing the effectiveness of the approach. PMID- 26736938 TI - Region of interest extraction for lossless compression of bone X-ray images. AB - For few decades digital X-ray imaging has been one of the most important tools for medical diagnosis. With the advent of distance medicine and the use of big data in this respect, the need for efficient storage and online transmission of these images is becoming an essential feature. Limited storage space and limited transmission bandwidth are the main challenges. Efficient image compression methods are lossy while the information of medical images should be preserved with no change. Hence, lossless compression methods are necessary for this purpose. In this paper, a novel method has been proposed to eliminate the non-ROI data from bone X-ray images. Background pixels do not contain any valuable medical information. The proposed method is based on the histogram dispersion method. ROI is separated from the background and it is compressed with a lossless compression method to preserve medical information of the image. Compression ratios of the implemented results show that the proposed algorithm is capable of effective reduction of the statistical and spatial redundancies. PMID- 26736940 TI - Active contour segmentation using level set function with enhanced image from prior intensity. AB - This paper presents a new active contour segmentation model using a level set function that can correctly capture both the strong and the weak boundaries of a target enclosed by bright and dark regions at the same time. We introduce an enhanced image obtained from prior information about the intensity of the target. The enhanced image emphasizes the regions where pixels have intensities close to the prior intensity. This enables a desirable segmentation of an image having a partially low contrast with the target surrounded by regions that are brighter or darker than the target. We define an edge indicator function on an original image, and local and regularization forces on an enhanced image. An edge indicator function and two forces are incorporated in order to identify the strong and weak boundaries, respectively. We established an evolution equation of contours in the level set formulation and experimented with several medical images to show the performance of the proposed method. PMID- 26736941 TI - Ground truth delineation for medical image segmentation based on Local Consistency and Distribution Map analysis. AB - Computer-aided detection (CAD) systems are being increasingly deployed for medical applications in recent years with the goal to speed up tedious tasks and improve precision. Among others, segmentation is an important component in CAD systems as a preprocessing step to help recognize patterns in medical images. In order to assess the accuracy of a CAD segmentation algorithm, comparison with ground truth data is necessary. To-date, ground truth delineation relies mainly on contours that are either manually defined by clinical experts or automatically generated by software. In this paper, we propose a systematic ground truth delineation method based on a Local Consistency Set Analysis approach, which can be used to establish an accurate ground truth representation, or if ground truth is available, to assess the accuracy of a CAD generated segmentation algorithm. We validate our computational model using medical data. Experimental results demonstrate the robustness of our approach. In contrast to current methods, our model also provides consistency information at distributed boundary pixel level, and thus is invariant to global compensation error. PMID- 26736942 TI - Segmentation of acne lesion using fuzzy C-means technique with intelligent selection of the desired cluster. AB - Segmentation is the basic and important step for digital image analysis and understanding. Segmentation of acne lesions in the visual spectrum of light is very challenging due to factors such as varying skin tones due to ethnicity, camera calibration and the lighting conditions. In this approach the color image is transformed into various color spaces. The image is decomposed into the specified number of homogeneous regions based on the similarity of color using fuzzy C-means clustering technique. Features are extracted for each cluster and average values of these features are calculated. A new objective function is defined that selects the cluster holding the lesion pixels based on the average value of cluster features. In this study segmentation results are generated in four color spaces (RGB, rgb, YIQ, I1I2I3) and two individual color components (I3, Q). The number of clusters is varied from 2 to 6. The experiment was carried out on fifty images of acne patients. The performance of the proposed technique is measured in terms of the three mostly used metrics; sensitivity, specificity, and accuracy. Best results were obtained for Q and I3 color components of YIQ and I1I2I3 color spaces with the number of clusters equal to three. These color components show robustness against non-uniform illumination and maximize the gap between the lesion and skin color. PMID- 26736943 TI - Geometry-independent assessment of renal volume in polycystic kidney disease from magnetic resonance imaging. AB - Total renal volume (TRV) is an important quantitative indicator of the progression of autosomal dominant polycystic kidney disease (ADPKD). The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease proposes a method for TRV computation based on manual tracing and geometric modeling. We developed a fast and nearly-automated technique for kidney segmentation and automatically compute TRV. In this study we aim to compare TRV estimates derived from these two different approaches. The highly-automated technique for the analysis of MR images was tested on 30 ADPKD patients. TRV was computed from both axial and coronal acquisitions, and compared to measurements based on geometric modeling by linear regression and Bland Altman analysis. In addition, to assess reproducibility, intra-observer and inter-observer variabilities were computed. The results of this study provide the feasibility of using a nearly-automated approach for accurate and fast evaluation of TRV also in markedly enlarged ADPKD kidneys. PMID- 26736944 TI - Muscle segmentation in time series images of Drosophila metamorphosis. AB - In order to study genes associated with muscular disorders, we characterize the phenotypic changes in Drosophila muscle cells during metamorphosis caused by genetic perturbations. We collect in vivo images of muscle fibers during remodeling of larval to adult muscles. In this paper, we focus on the new image processing pipeline designed to quantify the changes in shape and size of muscles. We propose a new two-step approach to muscle segmentation in time series images. First, we implement a watershed algorithm to divide the image into edge preserving regions, and then, we classify these regions into muscle and non muscle classes on the basis of shape and intensity. The advantage of our method is two-fold: First, better results are obtained because classification of regions is constrained by the shape of muscle cell from previous time point; and secondly, minimal user intervention results in faster processing time. The segmentation results are used to compare the changes in cell size between controls and reduction of the autophagy related gene Atg 9 during Drosophila metamorphosis. PMID- 26736945 TI - Automatic segmentation of nerve structures in ultrasound images using Graph Cuts and Gaussian processes. AB - Peripheral Nerve Blocking (PNB), is a procedure used for performing regional anesthesia, that comprises the administration of anesthetic in the proximity of a nerve. Several techniques have been used with the purpose of locating nerve structures when the PNB procedure is performed: anatomical surface landmarks, elicitation of paresthesia, nerve stimulation and ultrasound imaging. Among those, ultrasound imaging has gained great attention because it is not invasive and offers an accurate location of the nerve and the structures around it. However, the segmentation of nerve structures in ultrasound images is a difficult task for the specialist, since such images are affected by echo perturbations and speckle noise. The development of systems for the automatic segmentation of nerve structures can aid the specialist for locating nerve structures accurately. In this paper we present a methodology for the automatic segmentation of nerve structures in ultrasound images. An initial step is carried out using Graph Cut segmentation in order to generate regions of interest; we then use machine learning techniques with the aim of segmenting the nerve structure; here, a specific non-linear Wavelet transform is used for the feature extraction stage, and Gaussian processes for the classification step. The methodology performance is measured in terms of accuracy and the dice coefficient. Results show that the implemented methodology can be used for automatically segmenting nerve structures. PMID- 26736946 TI - Colorectal polyp segmentation using front propagation on surfaces guided by shape. AB - Polyp size is a biomarker of colon cancer. Manual size measurements are subject to a variety of sources of error. We present an automatic method for segmenting a polyp from a user clicked point. The method is based on front propagation on surface mesh, guided by features that characterize the local protrudedness, its thickness, its resemblance to wall like structures and ridge measures. These measures are designed to characterize growths in the colonic lumen and differentiate polyp growth from other protrusions such as haustral folds. These measures are aggregated and smoothed. Fast marching guided by these features extracts the polyps. Empirical observation suggests that the method successfully segments a variety of polyp shapes in less than 2 s. PMID- 26736947 TI - A clustering based method for collagen proportional area extraction in liver biopsy images. AB - Collagen Proportional Area (CPA) extraction using digital image analysis (DIA) in liver biopsies provides an effective way to estimate the liver disease staging. CPA represents accurately fibrosis expansion in liver tissue. This paper presents an automated clustering-based method for fibrosis detection and CPA computation. Initially, a k-means based approach is employed to detect the liver tissue and eliminate the background. Next, the method decides about the adequacy of current biopsy, according to the size of liver tissue. Biopsies which contain small and segmented specimens must be repeated. Since the tissue has been detected, fibrosis areas are also found in the tissue. Finally, CPA is computed. For the evaluation of the proposed method 25 images are employed and the percentage errors of CPA are computed for each image. In the majority of the cases, small variation of CPA is computed, comparing to the expert's annotation. PMID- 26736948 TI - Peripheral nerve segmentation using Nonparametric Bayesian Hierarchical Clustering. AB - Several cases related to chronic pain, due to accidents, illness or surgical interventions, depend on anesthesiology procedures. These procedures are assisted with ultrasound images. Although, the ultrasound images are a useful instrument in order to guide the specialist in anesthesiology, the lack of intelligibility due to speckle noise, makes the clinical intervention a difficult task. In a similar manner, some artifacts are introduced in the image capturing process, challenging the expertise of anesthesiologists for not confusing the true nerve structures. Accordingly, an assistance methodology using image processing can improve the accuracy in the anesthesia practice. This paper proposes a peripheral nerve segmentation method in medical ultrasound images, based on Nonparametric Bayesian Hierarchical Clustering. The experimental results show segmentation performances with a Mean Squared Error performance of 1.026 +/- 0.379 pixels for ulnar nerve, 0.704 +/- 0.233 pixels for median nerve and 1.698 +/- 0.564 pixels for peroneal nerve. Likewise, the model allows to emphasize other soft structures like muscles and aqueous tissues, that might be useful for an anesthesiologist. PMID- 26736949 TI - Estimation of vocal fold plane in 3D CT images for diagnosis of vocal fold abnormalities. AB - Vocal folds are the key body structures that are responsible for phonation and regulating air movement into and out of lungs. Various vocal fold disorders may seriously impact the quality of life. When diagnosing vocal fold disorders, CT of the neck is the commonly used imaging method. However, vocal folds do not align with the normal axial plane of a neck and the plane containing vocal cords and arytenoids does vary during phonation. It is therefore important to generate an algorithm for detecting the actual plane containing vocal folds. In this paper, we propose a method to automatically estimate the vocal fold plane using vertebral column and anterior commissure localization. Gray-level thresholding, connected component analysis, rule based segmentation and unsupervised k-means clustering were used in the proposed algorithm. The anterior commissure segmentation method achieved an accuracy of 85%, a good estimate of the expert assessment. PMID- 26736950 TI - Pull Test estimation in Parkinson's disease patients using wearable sensor technology. AB - Postural instability is one of the main motor impairment of Parkinson's disease (PD). The Pull Test is the most common clinical examination to assess postural instability in PD. However, the subjectivity and low discriminative power of this test presents as a major drawback. In this paper we propose a novel methodology to estimate the Pull Test scores from patients with PD. We capture the relationship between the Pull Test outcomes and patients' foot motion patterns, using wearable sensors mounted on their shoes. 139 idiopathic Parkinson's disease patients performed four motor function tests, including walking and repetitive foot motions, while acceleration and orientation data was recorded. A total of 684 features were extracted from the acceleration and orientation signals. Feature selection and classification algorithms were utilized to estimate the Pull Test score for each participant. Further, we estimate which motor function test would better predict the Pull Test score, depending on the patient's phenotype (i.e. bradykinetic, tremor-dominant or equivalent). When combining all phenotypes and all tests, the mean of the classification probability distribution achieved was 0.75 (CI: [0.69-0.82]). Foot circling was the best predictive test for the equivalent patients (mean = 0.79, CI: [0.69-0.87]) and the bradykinetic patients (mean: 0.75, CI: [0.64-0.85]), while 2*10 m. walk with stop-and-go proved superior for the tremor-dominant patients (mean: 0.75, CI: [0.64-0.85]). Overall, these results suggest that inertial data from patient's foot motion can be used to estimate postural instability in PD patients. PMID- 26736951 TI - Preliminary methods for wearable neuro-vascular assessment with non-invasive, active sensing. AB - In this study, a non-invasive and active sensing scheme that is ultimately aimed to be integrated in a wearable system for neuro-vascular health assessment is presented with preliminary results. With this system, vascular tone is modulated by local heating and cooling of the palm, and the resulting changes in local hemodynamics are monitored via impedance plethysmography (IPG) and photoplethysmography (PPG) sensors interfaced with custom analog electronics. Proof-of-concept measurements were conducted on three subjects using hot packs/ice bags to modulate the palmar skin temperature. From ensemble averaged and smoothed versions of pulsatile IPG and PPG signals, the effects of local changes in skin temperature on a series of parameters associated with neuro vascular mechanisms (heart rate, blood volume, blood flow rate, blood volume pulse inflection point area ratio, and local pulse transit time) have been observed. The promising experimental results suggest that, with different active temperature modulation schemes (consisting of heating/cooling cycles covering different temperature ranges at different rates), it would be possible to enhance the depth and specificity of the information associated with neuro-vascular health by using biosensors that can fit inside a wearable device (such as a sleeve). This study sets the foundation for future studies on designing and testing such a wearable neuro-vascular health assessment system employing active sensing. PMID- 26736952 TI - Objective evaluation of oral presentation skills using Inertial Measurement Units. AB - Oral presentation is considered as one of the most sought after skills by companies and professional organizations and program accreditation agencies. However, both learning process and evaluation of this skill are time demanding and complex tasks that need dedication and experience. Furthermore, the role of the instructor is fundamental during the presentation assessment. The instructor needs to consider several verbal and nonverbal communications cues sent in parallel and this kind of evaluation is often subjective. Even if there are oral presentation rubrics that try to standardize the evaluation, they are not an optimal solution because they do not provide the presenter a real-time feedback. In this paper, we describe a system for behavioral monitoring during presentations. We propose an ecological measurement system based on Inertial Measurement Units to evaluate objectively the presenter's posture through objective parameters. The system can be used to provide a real-time feedback to the presenters unobtrusively. PMID- 26736953 TI - A knitted garment using intarsia technique for Heart Rate Variability biofeedback: Evaluation of initial prototype. AB - Heart rate variability (HRV) biofeedback is a method based on paced breathing at specific rate called resonance frequency by giving online feedbacks from user respiration and its effect on HRV. Since the HRV is also influence by different factors like stress and emotions, stress related to an unfamiliar measurement device, cables and skin electrodes may cover the underling effect of such kind of intervention. Wearable systems are usually considered as intuitive solutions which are more familiar to the end-user and can help to improve usability and hence reducing the stress. In this work, a prototype of a knitted garment using intarsia technique is developed and evaluated. Results show the satisfactory level of quality for Electrocardiogram and thoracic electrical bioimpedance i.e. for respiration monitoring as a part of HRV biofeedback system. Using intarsia technique and conductive yarn for making the connection instead of cables will reduce the complexity of fabrication in textile production and hence reduce the final costs in a final commercial product. Further development of garment and Android application is ongoing and usability and efficiency of final prototype will be evaluated in detail. PMID- 26736954 TI - Clinical validation of LTMS-S: A wearable system for vital signs monitoring. AB - LTMS-S is a new wearable system for the monitoring of several physiological signals--including a two-lead electrocardiogram (ECG)--and parameters, such as the heart rate, the breathing rate, the peripheral oxygen saturation (SpO2), the core body temperature (CBT), and the physical activity. All signals are measured using only three sensors embedded within a vest. The sensors are standalone with their own rechargeable battery, memory, wireless communication and with an autonomy exceeding 24 hours. This paper presents the results of the clinical validation of the LTMS-S system. PMID- 26736955 TI - Synchronization and communication of cooperative sensors. AB - Cooperative sensors are an emerging technology consisting of autonomous sensor units working in concert to measure physiological signals requiring distant sensing points, such as biopotential (e.g., ECG) or bioimpedance (e.g., EIT). Their advantage with respect to the state-of-the-art technology is that they do not require shielded and even insulated cables to measure best quality biopotential or bioimpedance signals. Moreover, as all sensors are simply connected to a single electrical connection (which can be for instance a conductive vest) there is no connecting limitation to the miniaturization of the system or to its extension to large numbers of sensors. This results in an increase of wearability and comfort, as well as in a decrease of costs and integration challenges. However, cooperative sensors must communicate to be synchronized and to centralize the data. This paper presents possible communication strategies and focuses on the implementation of one of them that is particularly well suited for biopotential and bioimpedance measurements. PMID- 26736956 TI - Towards the development of a wearable Electrical Impedance Tomography system: A study about the suitability of a low power bioimpedance front-end. AB - Wearable systems for remote monitoring of physiological parameter are ready to evolve towards wearable imaging systems. The Electrical Impedance Tomography (EIT) allows the non-invasive investigation of the internal body structure. The characteristics of this low-resolution and low-cost technique match perfectly with the concept of a wearable imaging device. On the other hand low power consumption, which is a mandatory requirement for wearable systems, is not usually discussed for standard EIT applications. In this work a previously developed low power architecture for a wearable bioimpedance sensor is applied to EIT acquisition and reconstruction, to evaluate the impact on the image of the limited signal to noise ratio (SNR), caused by low power design. Some anatomical models of the chest, with increasing geometric complexity, were developed, in order to evaluate and calibrate, through simulations, the parameters of the reconstruction algorithms provided by Electrical Impedance Diffuse Optical Reconstruction Software (EIDORS) project. The simulation results were compared with experimental measurements taken with our bioimpedance device on a phantom reproducing chest tissues properties. The comparison was both qualitative and quantitative through the application of suitable figures of merit; in this way the impact of the noise of the low power front-end on the image quality was assessed. The comparison between simulation and measurement results demonstrated that, despite the limited SNR, the device is accurate enough to be used for the development of an EIT based imaging wearable system. PMID- 26736957 TI - Psychological acute stress measurement using a wireless adhesive biosensor. AB - Stress management is essential in this modern civilization to maintain one's stress level low and reduce health risks, since stress is one of the primary causes leading to major chronic health disorders. The present study investigates the validity of stress index (SI) metric that objectively quantifies the psychological acute stress using a disposable adhesive biosensor worn on the chest called as HealthPatch((r)). Eleven healthy volunteers (n=11) were attached with one HealthPatch sensor at left pectoralis major muscle along the cardiac axis to record modified Lead-II ECG. The subjects carried out a standard Trier Social Stress Test (TSST) protocol. During the study, the subjects filled out state anxiety form-Y1 of the State Anxiety Inventory questionnaire (sSTAI); salivary samples were obtained for salivary alpha-amylase (sAA) and salivary cortisol (sC) measurements; and the HealthPatch sensor data were wirelessly acquired. The data analyses revealed that sSTAI scores were significantly increased (P<0.001) due to TSST compared to the baseline. But, the changes in both sAA and sC measurements were not significant (P=0.281 and P=0.792, respectively). On the other hand, SI metric of HealthPatch showed significant (P<0.001) increase (~50%) during TSST, and shown to be sensitive to objectively track acute changes in psychological stress. Thus, HealthPatch biosensor can be valuable for continuous monitoring of psychological health and effective management of stress leading to healthy life. PMID- 26736958 TI - A magnetometer-free indoor human localization based on loosely coupled IMU/UWB fusion. AB - The magnetic distortions in indoor environment affects the accuracy of yaw angle estimation using magnetometer. Thus, the accuracy of indoor localization based on inertial-magnetic sensors will be affected as well. To address this issue, this paper proposes a magnetometer-free solution for indoor human localization and yaw angle estimation. The proposed algorithm fuses a wearable inertial sensor consisting of MEMS-based accelerometer and gyroscope with a portable ultra wideband (UWB) localization system in a cascaded two-step filter consisting of a tilt Kalman filter and a localization Kalman filter. By benchmarking against an optical motion capture system, the experimental results show that the proposed algorithm can accurately track position and velocity as well as the yaw angle without using magnetometer. PMID- 26736959 TI - Optimum Experimental Design applied to MEMS accelerometer calibration for 9 parameter auto-calibration model. AB - Optimum Experimental Design (OED) is an information gathering technique used to estimate parameters, which aims to minimize the variance of parameter estimation and prediction. In this paper, we further investigate an OED for MEMS accelerometer calibration of the 9-parameter auto-calibration model. Based on a linearized 9-parameter accelerometer model, we show the proposed OED is both G optimal and rotatable, which are the desired properties for the calibration of wearable sensors for which only simple calibration devices are available. The experimental design is carried out with a newly developed wearable health monitoring device and desired experimental results have been achieved. PMID- 26736960 TI - Performance assessment of an RFID system for automatic surgical sponge detection in a surgery room. AB - A retained surgical instrument is a frequent incident in medical surgery rooms all around the world, despite being considered an avoidable mistake. Hence, an automatic detection solution of the retained surgical instrument is desirable. In this paper, the use of millimeter waves at the 60 GHz band for surgical material RFID purposes is evaluated. An experimental procedure to assess the suitability of this frequency range for short distance communications with multiple obstacles was performed. Furthermore, an antenna suitable to be incorporated in surgical materials, such as sponges, is presented. The antenna's operation characteristics are evaluated as to determine if it is adequate for the studied application over the given frequency range, and under different operating conditions, such as varying sponge water content. PMID- 26736961 TI - Sensors on instrumented socks for detection of lower leg edema--An in vitro study. AB - This paper presents the design, sensing principles and in vitro evaluation of a novel instrumented sock intended for prediction and prevention of acute decompensated heart failure. The sock contains a drift-free ankle size sensor and a leg tissue elasticity sensor. Both sensors are inexpensive and developed using innovative new sensing ideas. Preliminary tests with the sensor prototypes show promising results: The ankle size sensor is capable of measuring 1 mm changes in ankle diameter and the tissue elasticity sensor can detect 0.15 MPa differences in elasticity. A low-profile instrumented sock prototype with these two sensors has been successfully fabricated and will be evaluated in the future in an IRB approved human study. PMID- 26736962 TI - Flexible and self-adaptive neural ribbon with three-dimensional electrodes for sciatic nerve recording. AB - Various peripheral nerve interfaces have been developed in the last decades and transferred into neuroscientific researches or clinical applications. In this study, we present a novel flexible neural ribbon electrode that can achieve self adaption to nerves in various diameters and have three dimensional (3D) contacts. Impedance spectroscopy of the neural ribbon electrode was carried out to determine its electrochemical characteristics during the recording. The recording capability of the neural ribbon on sciatic nerves with different diameter was demonstrated by successful signal acquisitions. PMID- 26736963 TI - Study of impedance spectra for dry and wet EarEEG electrodes. AB - EarEEG is a novel recordings concept where electrodes are embedded on the surface of an earpiece customized to the individual anatomical shape of the users ear. A key parameter for recording EEG signals of good quality is a stable and low impedance electrode-body interface. This study characterizes the impedance for dry and wet EarEEG electrodes in a study of 10 subjects. A custom made and automated setup was used to characterize the impedance spectrum from 0.1 Hz-2 kHz. The study of dry electrodes showed a mean (standard deviation) low frequency impedance of the canal electrodes of 1.2 MOmega (1.4 MOmega) and the high frequency impedance was 230 kOmega (220 kOmega). For wet electrodes the low frequency impedance was 34 kOmega (37 kOmega) and the high frequency impedance was 5.1 kOmega (4.4 kOmega). The high standard deviation of the impedance for dry electrodes imposes very high requirements for the input impedance of the amplifier in order to achieve an acceptable common-mode rejection. The wet electrode impedance was in line with what is typical for a wet electrode interface. PMID- 26736964 TI - Electroencephalogram measurement from the hairy part of the scalp using polymer based dry microneedle electrodes. AB - This paper reports a successful electroencephalogram (EEG) measurement from the hairy part of the scalp using a polymer-based dry microneedle electrode. The electrode consists of 25 pillars, each of which has a sharp microneedle on the top. Hairs are collected into the gaps of the pillars and the microneedles can reach the scalp surface. Since the microneedles can penetrate through the stratum corneum, no conductive gel is necessary to acquire high quality EEG. We experimentally investigated the pillar diameters in EEG measurement from the occipital region with hairs. The fabricated electrodes successfully measured EEG without any skin preparation or conductive gel. PMID- 26736965 TI - EEG acquisition system based on active electrodes with common-mode interference suppression by Driving Right Leg circuit. AB - We present a system for the acquisition of EEG signals based on active electrodes and implementing a Driving Right Leg circuit (DgRL). DgRL allows for single-ended amplification and analog-to-digital conversion, still guaranteeing a common mode rejection in excess of 110 dB. This allows the system to acquire high-quality EEG signals essentially removing network interference for both wet and dry-contact electrodes. The front-end amplification stage is integrated on the electrode, minimizing the system's sensitivity to electrode contact quality, cable movement and common mode interference. The A/D conversion stage can be either integrated in the remote back-end or placed on the head as well, allowing for an all-digital communication to the back-end. Noise integrated in the band from 0.5 to 100 Hz is comprised between 0.62 and 1.3 MUV, depending on the configuration. Current consumption for the amplification and A/D conversion of one channel is 390 MUA. Thanks to its low noise, the high level of interference suppression and its quick setup capabilities, the system is particularly suitable for use outside clinical environments, such as in home care, brain-computer interfaces or consumer oriented applications. PMID- 26736966 TI - An MRI-readable wireless flexible pressure sensor. AB - We developed a magnetic resonance imaging (MRI) -detectable wireless flexible pressure sensor with pressure-sensitive LC resonator fabricated on a flexible film substrate. Measuring pressures in the body such as blood vessels and cardiac ventricle are very important in making diagnoses and in postoperative observation. However, conventional wired pressure sensors have difficulty in maintaining their connections to external readout equipment, and they also increase the risk of infection during and after implantation. In this study, to read the pressure wirelessly using an MRI system, an LC resonator consisting of a spiral coil and a pressure-sensitive capacitor was designed resonate at 300 MHz which corresponds to the Larmor frequency in an external magnetic field of 7-T. In order to validate the operating principle of the fabricated device, the frequency-impedance characteristics were measured by changing the pressure. The resonance frequencies of complemented LC circuits were lower by approximately 10% than those of nonpressured conditions. After implanting these devices in a 1% agarose gel, MR images were acquired by inducing pressures close to blood pressures of 20 kPa. As a result, contrast changes in the MR images were observed around the integrated spiral coils. This result indicated that the developed flexible pressure sensor has sufficient sensitivity to measure physiological pressure such as blood pressure of 20 kPa wirelessly in the body. In the future, quantitative pressure sensing will be evaluated by comparing it to the contrast changes in MR images with flip angle mapping. PMID- 26736967 TI - Electrochemical label-free degranulation monitoring for in-situ evaluation of cellular function. AB - We fabricated a degranulation monitoring device, combining ion-sensitive field effect transistor (ISFET) and microperfusion system. The electrical properties of ISFET were maintained even after immobilization of RBL-2H3 mast cells on the sensor. We successfully demonstrated in-situ monitoring of degranulation from stimulated RBL-2H3 cells by ionomycin. Potential change was induced by the release of acid-granule contents, which result in local pH decrease on the sensor under physiological conditions. This microdevice is expected to contribute as a platform technology for evaluating induced immune responses by chemical compounds. PMID- 26736968 TI - A novel Love Wave biosensor for rapid and sensitive detection of marine toxins. AB - Marine toxins are produced by plankton and do a great harm to human through food chain by accumulating in shellfishes and fishes. It is highly required and favorable to develop novel methods for the rapid and efficient detection of marine toxins to avoid the poisoning cases that have occurred frequently in many countries. This study presents a real-time Love Wave biosensor for the rapid detection of okadaic acid (OA), which used HepG2 cell lines as the sensing elements. The results indicate that this cell-based biosensor can provide real time information of cellular activities induced by okadaic acid and has a higher sensitivity than the conventional cell-based assay. It is suggested that this cell-based biosensor can be used as a convenient and efficient method for marine toxin detection, which has a great potential to contribute to avoid the harmful effects of marine toxins on the human health. PMID- 26736969 TI - Finger motion capture from wrist-electrode contact resistance. AB - Hand motion capture is an important yet challenging topic for biomechanics and human computer interaction. We proposed a novel electrical sensing technology for capturing the finger angles from the variation of the wrist shape. The proposed device detects the signal related to the wrist-electrode contact resistances, which change according to the variation of the wrist shape accompanying finger movements. The developed sensing device consists of a wrist band, sixteen electrodes and a sensing circuit of contact resistances. We investigated the relationships between the finger angles and the system outputs by using a glove type joint angle sensor. As a result, we confirmed high correlations of the system outputs with the finger angles for several electrodes. Therefore, we conclude that the proposed system can be used for the estimation of the finger joint angles. PMID- 26736970 TI - Digitally controlled feedback for DC offset cancellation in a wearable multichannel EMG platform. AB - Wearable systems capable to capture vital signs allow the development of advanced medical applications. One notable example is the use of surface electromyography (EMG) to gather muscle activation potentials, in principle an easy input for prosthesis control. However, the acquisition of such signals is affected by high variability and ground loop problems. Moreover, the input impedance influenced in time by motion and perspiration determines an offset, which can be orders of magnitude higher than the signal of interest. We propose a wearable device equipped with a digitally controlled Analog Front End (AFE) for biopotentials acquisition with zero-offset. The proposed AFE solution has an internal Digital to Analog Converter (DAC) used to adjust independently the reference of each channel removing any DC offset. The analog integrated circuit is coupled with a microcontroller, which periodically estimates the offset and implements a closed loop feedback on the analog part. The proposed approach was tested on EMG signals acquired from 4 subjects while performing different activities and shows that the system correctly acquires signals with no DC offset. PMID- 26736971 TI - A programmable and self-adjusting class E amplifier for efficient wireless powering of biomedical implants. AB - In this paper, an enhanced approach of a class E amplifier being insensitive to coil impedance variations is presented. While state of the art class E amplifiers widely being used to supply implanted systems show a strong degradation of efficiency when powering distance, coil orientation or the implant current consumption deviate from the nominal design, the presented concept is able to detect these deviations on-line and to reconfigure the amplifier automatically. The concept is facilitated by a new approach of sensing the load impedance without interruption of the power supply to the implant, while the main components of the class E amplifier are programmable by software. Therefore, the device is able to perform dynamic impedance matching. Besides presenting the operational principle and the design equations, we show an adaptive prototype reader system which achieves a drain efficiency of up to 92% for a wide range of reflected coil impedances from 1 to 40 Omega. The integrated communication concept allows downlink data rates of up to 500 kBit/s, while the load modulation based uplink from implant to reader was verified of providing up to 1.35 MBit/s. PMID- 26736972 TI - Evaluation of novel textile electrodes for ECG signals monitoring based on PEDOT:PSS-treated woven fabrics. AB - Despite surface electrodes technology for biopotential recording is well established, different researches are aimed at overcoming the limitations exhibited by the available solutions. In this paper, a proposal for the low-cost development of textile electrodes based on woven fabrics treated with polymer poly-3,4-ethylenedioxythiophene doped with poly(styrene sulfonate) ( PEDOT: PSS), is presented. Compared to other approaches, the proposed one can be exploited on any finished fabric. An accurate analysis of the electrodes performance, based on impedance measurements and signal processing techniques, both in wet and dry conditions, reveals the virtues and vices of the proposed solution, when used for electrocardiogram recording. In particular, the potentialities of these electrodes clearly emerge, in terms of ability to work without any electrolyte, providing a valuable interface between the skin and the electrode, in some cases achieving better performance than commercial disposable electrodes. PMID- 26736973 TI - The role of micro-scale current sensing in biomedicine: A unifying view and design guidelines. AB - The electrical activity of cells is regulated by ion fluxes and chemical signaling between them is sustained by redox-reactive molecules. Consequently, current sensing represents a straightforward way to interface electronics with biology and a common detection tool in several applications spanning from patch clamp and nanopores to micro-scale impedance tracking. Reaching pA resolution at the ms timescale represents a challenge for the readout circuit and here all the criticalities involved in the optimal design of the sensing electrode are reviewed. Advantages vs. drawbacks and risks of the use of silicon as active vs. passive substrate respectively are illustrated by means of experimental examples. PMID- 26736974 TI - A miniaturized electrolytic pump sensorized with a strain gauge based on thermoplastic nanocomposite for drug delivery systems. AB - In this paper we present a miniature electrolytic pump sensorized with a novel strain sensor to be used as active component of a drug delivery system. It consists of an electrolytic solution reservoir where inert electrodes are immersed. By polarizing the electrodes, the electrolytic reaction is activated and the produced gases (i.e. oxygen and hydrogen) displace an elastic membrane delimiting the electrolytic solution reservoir. In order to measure and monitor the membrane displacement, and therefore the volume of drug ejected, a strain gauge sensor has been prepared using a conductive thermoplastic nanocomposite elastomer (CTPE). The sensor has been fixed on the deformable membrane. The conductive thermoplastic elastomer is a good candidate for this application because of its high sensitivity. Furthermore, the CTPE allows to customize the resistance of the device in order to obtain low power consumption. PMID- 26736975 TI - Long range microfluidic shear device for cellular mechanotransduction studies. AB - Cells sense external mechanical stimulus and respond to it through mechanotransduction mechanism. Fluid shear stress (FSS) has been found to be an important element among the mechanical stimuli. Recent advancements in microfluidics made mechanotransduction studies possible in near physiological conditions using microfluidic devices. FSS on human cells covers a broad range from very low level experienced due to interstitial flows (0.1 mPa) to very high level in aorta (10 Pa). In the present communication, we have designed a novel microfluidic device which can generate FSS on cells of five different orders with single inflow of fluid which can cover the whole range of physiological fluid shear stresses in one run. The dimensions of the device were calculated taking a resistance model for the micro channels. Flow velocities and wall shear stress were predicted through computer simulation. Shear stress values were analyzed for two different depths of channels and different inlet flow rates ranging from 50 to 0.5 MUl/s. FSS was found to increase linearly with inlet flow rate and the stress profile was flatter for lesser depth of channel. PMID- 26736976 TI - E. coli DH5alpha cell response to a sudden change in microfluidic chemical environment. AB - Motile bacteria respond to changing chemical environment by moving towards or away from a particular location. Bacterial migration under chemical gradient is one of the most studied areas in biomedical field. In this work we looked into how bacterial cells respond to sudden change in the microfluidic chemical environment. E. coli DH5alpha cells were subjected to an attractant gradient (0.1 mM sorbitol--attractant to E. coli cells) and after 120 min the same cells were exposed to an inhibitor (0.1 mM NiSO4) gradient in the same microfluidic device. Our studies revealed that when the E. coli DH5alpha cells were exposed to 0.1 mM sorbitol, they showed faster chemotaxis towards the attractant (0.1 mM sorbitol) and achieved steady state by 60 min. When we replaced 0.1 mM sorbitol with 0.1 mM NiSO4 in the device we found that that the E. coli DH5alpha cells started responding to change in chemical environment within 10 min and achieved steady state at the end of 60 min. This shows that the bacterial cells respond to change in local chemical environment is within few minutes. PMID- 26736977 TI - Novel localized heating technique on centrifugal microfluidic disc with wireless temperature monitoring system. AB - Recent advances in the field of centrifugal microfluidic disc suggest the need for electrical interface in the disc to perform active biomedical assays. In this paper, we have demonstrated an active application powered by the energy harvested from the rotation of the centrifugal microfluidic disc. A novel integration of power harvester disc onto centrifugal microfluidic disc to perform localized heating technique is the main idea of our paper. The power harvester disc utilizing electromagnetic induction mechanism generates electrical energy from the rotation of the disc. This contributes to the heat generation by the embedded heater on the localized heating disc. The main characteristic observed in our experiment is the heating pattern in relative to the rotation of the disc. The heating pattern is monitored wirelessly with a digital temperature sensing system also embedded on the disc. Maximum temperature achieved is 82 degrees C at rotational speed of 2000 RPM. The technique proves to be effective for continuous heating without the need to stop the centrifugal motion of the disc. PMID- 26736978 TI - Liquid density effect on burst frequency in centrifugal microfluidic platforms. AB - Centrifugal microfluidic platforms are widely used in various advanced processes such as biomedical diagnostics, chemical analysis and drug screening. This paper investigates the effect of liquid density on the burst frequency of the centrifugal microfluidic platform. This effect is experimentally investigated and compared to theoretical values. It is found that increasing the liquid density results in lower burst frequency and it is in agreement with theoretical calculations. Moreover, in this study we proposed the use of the microfluidic CD platform as an inexpensive and simple sensor for liquid density measurements. The proposed liquid sensor requires much less liquid volume (in the range of microliters) compared to conventional density meters. This study presents fundamental work which allows for future advance studies with the aim of designing and fabricating centrifugal microfluidic platforms for more complex tasks such as blood analysis. PMID- 26736979 TI - Red blood cells flows in rectilinear microfluidic chip. AB - The red blood cells flow in a controlled environment as a microfluidic chip with a rectilinear geometry was investigated. The optical monitoring performed by an automatic Particle Image Velocimetry procedure has allowed a quantitative analysis on flow features. Various parameters such as velocity, shear rate, strain rate, vorticity, divergence were extracted. The comparisons of the results obtained from the different experiments was used for the overall understanding of the RBC movements in different conditions and the establishment of the analysis procedure. PMID- 26736980 TI - Simplified fluid-structure coupled analysis of particle movement for designing of microfluidic cell sorter. AB - Recently, methods of the separation and selection of cells using a microfluidic device are receiving a lot of attention as the latest technology and those devices are called microfluidic cell sorter. Those methods have many advantages compared to conventional methods. There are a lot of researches on the microfluidic cell sorting but there isn't the automated design method of this device in spite of the necessary. To achieve the automated design of the microfluidic cell sorter, the analysis of the movement of cells in the microfluidic device and optimum design of the microfluidic cell sorter corresponding to kind of various cells are required. In the former case, the fluid-structure interaction analysis of fluid and cell movement is needed. However, it is very complex and needs a lot of computational time. Therefore, we focused on this problem in the fluid-structure interaction analysis for designing the microfluidic cell sorter. We assume cell is a sphere particle and propose the simplified fluid-structure coupled analysis which combines the CFD analysis with the motion equation of a sphere particle. PMID- 26736981 TI - Identification of dynamical biological systems based on random effects models. AB - System identification is a data-driven modeling approach more and more used in biology and biomedicine. In this application context, each assay is always repeated to estimate the response variability. The inference of the modeling conclusions to the whole population requires to account for the inter-individual variability within the modeling procedure. One solution consists in using random effects models but up to now no similar approach exists in the field of dynamical system identification. In this article, we propose a new solution based on an ARX (Auto Regressive model with eXternal inputs) structure using the EM (Expectation Maximisation) algorithm for the estimation of the model parameters. Simulations show the relevance of this solution compared with a classical procedure of system identification repeated for each subject. PMID- 26736982 TI - New VHP-Female v. 2.0 full-body computational phantom and its performance metrics using FEM simulator ANSYS HFSS. AB - Simulation of the electromagnetic response of the human body relies heavily upon efficient computational models or phantoms. The first objective of this paper is to present a new platform-independent full-body electromagnetic computational model (computational phantom), the Visible Human Project((r)) (VHP)-Female v. 2.0 and to describe its distinct features. The second objective is to report phantom simulation performance metrics using the commercial FEM electromagnetic solver ANSYS HFSS. PMID- 26736983 TI - A semi-mechanistic pharmacokinetic model of saquinavir combined with itraconazole in HIV-1-positive patients. AB - The mechanism of drug-drug interaction between saquinavir, a protease inhibitor used effectively for HIV/AIDS treatment, and itraconazole, an azole antifungal agent, is hypothesized to involve competitive inhibition at CYP3A4 enzyme, an important drug metabolizing enzyme in humans. The resulting interaction between these CYP3A4 substrates can be utilized clinically as a pharmacokinetic booster for prolonging saquinavir dosing regimen and/or decreasing saquinavir dose requirement in HIV/AIDS patients. To quantitatively describe this specific drug drug interaction, based on the existing data, we aimed to develop a mathematical model incorporated with the competitive inhibition phenomena. PlotDigitizer was used to extract data from literature. Advance Continuous Simulating Language Extreme (ACSLX), a FORTRAN-based computer program, was employed as our developing tool. Our computer model simulations could successfully describe concentration time course of saquinavir from selected pharmacokinetic studies in HIV-1-positive patients. To extend the model's utility as an aid in saquinavir dosage regimens, the developed model may be applied to other HIV/AIDS patients in genuine clinical settings. PMID- 26736984 TI - Pharmacokinetic model for the inhibition of simvastatin metabolism by itraconazole. AB - BACKGROUND: Concomitant use of simvastatin, a HMG-CoA reductase inhibitor, with a potent CYP3A4 inhibitor, itraconazole, can result in a serious drug-drug interaction induced severe adverse event, rhabdomyolysis. Even though pharmacokinetic data regarding such interaction are available, they cannot be used for quantitative prediction. For this reason, we aimed to develop a pharmacokinetic model for predicting the magnitude of inhibition of simvastatin metabolism by itraconazole. METHODS: Published data involving pharmacokinetic of simvastatin, itraconazole, and pharmacokinetic interaction between simvastatin and itraconazole were selected from PubMed search. Serum simvastatin concentrations were subsequently extracted and used for model development. Advanced Continuous Simulating Language Extreme (ACSLX) was used for modeling. RESULTS: The drug-drug interaction model between simvastatin and itraconazole was simultaneously modeled using a one compartment parent-metabolite model for simvastatin, and a two-compartment model for itraconazole. CONCLUSION: The final drug-drug interaction model can adequately describe the actual simvastatin concentrations. Model application can be of advantage for dosing adjustment to avoid serious adverse effects resulted from concomitant use of both drugs. PMID- 26736985 TI - Incorporation of inhaled insulin into the FDA accepted University of Virginia/Padova Type 1 Diabetes Simulator. AB - The University of Virginia/Padova Type 1 Diabetes (T1DM) Simulator has been extensively used in artificial pancreas research mostly for testing and design of control algorithms. However, it also offers the possibility of testing new insulin analogs and alternative routes of delivery given that subcutaneous insulin administration present significant delays & variability. Inhaled insulin appears an important candidate to improve post-prandial glucose control given its rapid appearance in plasma. In this contribution, we present the results of incorporating a pharmacokinetic model of inhaled Technosphere((r)) Insulin (TI) into the T1DM simulator. In particular, we successfully reproduced in silico the post-prandial glucose control observed in T1DM subjects treated with TI given at meal time, and the post-prandial glucose dynamics in response to different timing of TI dose. PMID- 26736986 TI - Uncovering microbial duality within human microbiomes: A novel algorithm for the analysis of host-pathogen interactions. AB - Microbial species thrive within human hosts by establishing complex associations between themselves and the host. Even though species diversity can be measured (alpha- and beta-diversity), a methodology to estimate the impact of microorganisms in human pathways is still lacking. In this work we propose a computational approach to estimate which human pathways are targeted the most by microorganisms, while also identifying which microorganisms are prominent in this targeting. Our results were consistent with literature evidence, and thus we propose this methodology as a new prospective approach to be used for screening potentially impacted pathways. PMID- 26736987 TI - An evaluation of the emergence of drug resistant virus for HIV/AIDS drug treatments. AB - HIV/AIDS drug treatment, such as highly active anti-retroviral therapy (HAART), often fails due to the emergence of drug resistant species. In this paper we investigate a new estimation method for the possibility of emergence of drug resistant mutation. To the best knowledge of the author this work is the first study to try to describe quantitatively the possibility of drug resistance emergence for HIV/AIDS drug treatments. In simulation studies we compare HIV/AIDS treatment methods, such as structured treatment interruption (STI) and improved gradual dosage reduction (iGDR), based on the proposed analysis. From the analysis we can explain why STI treatment often fails and also can show that iGDR is desirable rather than STI particularly in terms of the decrease of the possibility of emergence of drug resistant virus. PMID- 26736988 TI - Online prediction of glucose concentration in type 1 diabetes using extreme learning machines. AB - We propose an online machine-learning solution to the problem of nonlinear glucose time series prediction in type 1 diabetes. Recently, extreme learning machine (ELM) has been proposed for training single hidden layer feed-forward neural networks. The high accuracy and fast learning speed of ELM drive us to investigate its applicability to the glucose prediction problem. Given that diabetes self-monitoring data are received sequentially, we focus on online sequential ELM (OS-ELM) and online sequential ELM kernels (KOS-ELM). A multivariate feature set is utilized concerning subcutaneous glucose, insulin therapy, carbohydrates intake and physical activity. The dataset comes from the continuous multi-day recordings of 15 type 1 patients in free-living conditions. Assuming stationarity and evaluating the performance of the proposed method by 10 fold cross- validation, KOS-ELM were found to perform better than OS-ELM in terms of prediction error, temporal gain and regularity of predictions for a 30-min prediction horizon. PMID- 26736989 TI - Mathematical modeling of tumor response to radiation: radio-sensitivity correlation with BOLD, TOLD, DeltaR1 and DeltaR2* investigated in large Dunning R3327-AT1 rat prostate tumors. AB - Tumor response to radiation therapy can vary highly across patients. Several factors, both tumor- and environment-specific, can influence the radio sensitivity, one of the most well-known being hypoxia. In this work, we investigated possible correlations between the radio-sensitivity parameters determined by means of a simple mathematical model of tumor volume evolution, and the MRI-based indicators of oxygenation in Dunning R3327-AT1 rats. Prior to irradiation the rats were subjected to an oxygen-breathing challenge, which was evaluated by MRI. The tumors were administered a single irradiation dose (30 Gy), while breathing air or oxygen. Despite a poor fitting performance, the model was able to identify two different tumor volume regression patterns. Moreover, the radio-sensitivity of the oxygen-breathing group was found to correlate with the variation of the transverse relaxation rate DeltaR2* (-0.89). This suggests that MRI-based indices of tumor oxygenation may provide information about radio sensitivity. PMID- 26736990 TI - Inference of asynchronous Boolean network from biological pathways. AB - Gene regulation is a complex process with multiple levels of interactions. In order to describe this complex dynamical system with tractable parameterization, the choice of the dynamical system model is of paramount importance. The right abstraction of the modeling scheme can reduce the complexity in the inference and intervention design, both computationally and experimentally. This article proposes an asynchronous Boolean network framework to capture the transcriptional regulation as well as the protein-protein interactions in a genetic regulatory system. The inference of asynchronous Boolean network from biological pathways information and experimental evidence are explained using an algorithm. The suitability of this paradigm for the variability of several reaction rates is also discussed. This methodology and model selection open up new research challenges in understanding gene-protein interactive system in a coherent way and can be beneficial for designing effective therapeutic intervention strategy. PMID- 26736991 TI - Predicting protein function from biomedical text. AB - We propose a classifier system called PFPBT that predicts the functions of un annotated proteins. PFPBT assigns an un-annotated protein p the functional category of annotated proteins that are semantically similar to p. Each protein p is represented by a vector of weights. Each weight reflects the significance of a molecule m in the biomedical abstracts associated with p. That is, each weight quantifies the likelihood of the association between m and p. This is because all proteins bind to other molecules, which are highly predictive of the functions of the proteins. Let S be the set of proteins that is semantically similar to an un annotated protein p. p is annotated with the functional category f, if its occurrence probability in abstracts associated with S whose functional category is f is statistically significantly different than its occurrences in abstracts associated with S that belong to all other functional categories. PFPBT automatically extracts each co-occurrence of a protein-molecule pair that represents semantic relationship between the pair. We present novel semantic rules based on the syntactic structures of sentences for identifying the semantic relationships between each co-occurrence of a protein-molecule pair in a sentence. We evaluated PFPBT by comparing it experimentally with two systems. Results showed improvement. PMID- 26736992 TI - Differential pathlength factor estimation for brain-like tissue from a single layer Monte Carlo model. AB - A Monte Carlo simulation-based computational model has been developed for tracing the pathway of light within a single layer of tissue like bloodless human brain. A reflectance mode source-detector geometry is assumed to illuminate the tissue slab with an irradiation of a near infrared wavelength and to detect the re emitted light intensity. Light is considered to be attenuated within tissue by scattering and absorption. The model has been used to predict the relationship of mean optical path of photons with variable source-detector geometry and thus, to determine a differential pathlength factor (DPF) of 5.66 for incident light of wavelength 810 nm. PMID- 26736993 TI - GPU technology as a platform for accelerating physiological systems modeling based on Laguerre-Volterra networks. AB - The use of a GPGPU programming paradigm (running CUDA-enabled algorithms on GPU cards) in biomedical engineering and biology-related applications have shown promising results. GPU acceleration can be used to speedup computation-intensive models, such as the mathematical modeling of biological systems, which often requires the use of nonlinear modeling approaches with a large number of free parameters. In this context, we developed a CUDA-enabled version of a model which implements a nonlinear identification approach that combines basis expansions and polynomial-type networks, termed Laguerre-Volterra networks and can be used in diverse biological applications. The proposed software implementation uses the GPGPU programming paradigm to take advantage of the inherent parallel characteristics of the aforementioned modeling approach to execute the calculations on the GPU card of the host computer system. The initial results of the GPU-based model presented in this work, show performance improvements over the original MATLAB model. PMID- 26736994 TI - Software tools for data modelling and processing of human body temperature circadian dynamics. AB - This paper is presenting a software development for simulating and processing thermometry data. The motivation of this research is the miniaturization of actuators attached to human body which allow frequent temperature measurements and improve the medical diagnosis procedures related to circadian dynamics. PMID- 26736995 TI - The volterra functional series is a viable alternative to kinetic models for synaptic modeling--calibration and benchmarking. AB - Synaptic transmission is governed by a series of complex and highly nonlinear mechanisms and pathways in which the dynamics have a profound influence on the overall signal sent to the postsynaptic cell. In simulation, these mechanisms are often represented through kinetic models governed by state variables and rate law equations. Calculations of such ordinary differential equations (ODEs) in kinetic models can be computationally intensive, and although algorithms have been optimally developed to handle ODEs efficiently, simulation of numerous, large and complex kinetic models requires a prohibitively large amount of computational power. Here we present an alternative representation of ionotropic glutamatergic receptors AMPAr and NMDAr kinetic models consisting of input-output surrogates of the receptor models which can capture the nonlinear dynamics seen in the kinetic models. We benchmark this Input-Output (IO) synapse model and compare it with kinetic receptor models to evaluate the simulation time required when using either synapse model, as well as the number of time steps each model needs for simulation. While remaining faithful to the original dynamics of the model, our results indicate that the IO synapse model requires less simulation time than the kinetic models under conditions which elicit normal physiological responses, thereby improving computational efficiency while preserving the complex non linear dynamics of the receptors. These IO surrogates therefore constitute an appealing alternative to kinetic models in large scale networks simulations. PMID- 26736996 TI - Bearing gap adjustment for improvement of levitation performance in a hydrodynamically levitated centrifugal blood pump. AB - The purpose of the present study is to investigate a bearing gap adjustment for improvement of levitation performance in a hydrodynamically levitated centrifugal blood pump to realize a blood pump with a low hemolysis level. The impeller levitates axially by balancing a gravitational force, buoyancy, a magnetic force, and hydrodynamic forces on the top and bottom sides of the impeller. To adjust the levitation position of the impeller, the balance of acting forces on the impeller was adjusted by changing the shroud area on the bottom impeller. Three pumps having various shroud area were prepared as tested models: 817 mm(2) (HH S), 875 mm(2) (HH-M) and 931 mm(2) (HH-L). First, for evaluating the bearing gap adjustment, the bearing gap was estimated by calculating a balancing position of the acting forces on the impeller. We actually measured the gravitational force, buoyancy and the magnetic force, and numerically analyzed hydrodynamic forces on the top and bottom sides of the impeller. Second, to verify accuracy of the estimated bearing gap, the measurement test of the bearing gap was performed. Finally, an in-vitro hemolysis test was performed to evaluate a hemolysis level of the pump. As a result, bottom bearing gaps were estimated as 40 MUm (HH-S), 60 MUm (HH-M) and 238 MUm (HH-L). In the measurement test, bottom bearing gaps were measured as 63 MUm (HH-S), 219 MUm (HH-M), and 231 MUm (HH-L). The estimated bearing gaps had positively correlated with the measured bearing gaps in relation to the shroud area on the impeller. In the hemolysis test, hemolysis level in every model was almost equivalent to that of BPX-80, when the bearing gap was adjusted greater than 60 MUm. We could adjust the bearing gap by changing the shroud area on the impeller for improvement of levitation performance to realize a blood pump with a low hemolysis level. PMID- 26736997 TI - A new approach to generate arbitrary pulsatile pressure wave forms in mechanical circulatory support systems. AB - Pulsatile pressure/flow wave forms reproduction of blood in mechanical circulatory systems are still an open topic. Regarding the periodic behavior of pulsatile hemodynamics, a repetitive control algorithm was adopted as a potential methodology for rotary blood pumps. The developed algorithm was tested on a mock system including an oxygenator, a resistance, and a compliance. The post oxygenator pressure served as the feedback of the control system. Initially, a model of the whole system was developed in order to use repetitive control algorithm. Then the performance of the developed algorithm was evaluated in three different scenarios. The experimental results indicated that the proposed method was able to accurately reproduce any pattern of pulsatile pressure. Moreover, it demonstrated an acceptable robustness in terms of model uncertainty and nonlinearity. PMID- 26736998 TI - Effect of intra-aortic balloon pump on coronary blood flow during different balloon cycles support: A computer study. AB - Intra-aortic balloon pump (IABP) has been used in clinical treatment as a mechanical circulatory support device for patients with heart failure. A computer model is used to study the effect on coronary blood flow (CBF) with different balloon cycles under both normal and pathological conditions. The model of cardiovascular and IABP is developed by using MATLAB SIMULINK. The effect on coronary blood flow has been studied under both normal and pathological conditions using different balloon cycles (balloon off; 1:4; 1:2; 1:1). A pathological heart is implemented by reducing the left ventricular contractility. The result of this study shows that the rate of balloon cycles is related to the level of coronary blood flow. PMID- 26736999 TI - Hemodynamics during Rotary Blood Pump support with speed synchronization in heart failure condition: A modelling study. AB - The aim of this work is to study the hemodynamic changes in the cardiovascular system under different modes of Rotary Blood Pump (RBP) support. Continuous mode (constant pump speed) and co-pulse mode (increased pump speed in systole) are studied. Computer simulation studies have been conducted to evaluate the performances of these two modes under normal and pathological conditions. The pathological heart condition is simulated by reducing the maximum systolic elestance (Emax) in the cardiovascular system model. The model is implemented by using MATLAB Simulink. The pressure-volume loop of different heart conditions (normal heart: 100% of normal contractility, pathological heart: 30% of normal contractility) and the different modes of RBP support (8 krpm and 11 krpm in continuous mode, between 8 krpm and 11 krpm in co-pulse mode) are simulated. The results of this study show the slope of end systolic pressure volume relationship (ESPVR) changes in pathological condition. The reduction of area inside pressure volume loops depend on the increasing level of pump speed. The results indicated systolic aortic pressures in co-pulse mode are higher than in the continuous mode. In normal condition, the value of systolic aortic pressure in co-pulse mode is 113 mmHg and the values of systolic aortic pressures in continuous modes are 109 mmHg (8 k) and 95 mmHg (11 k). In pathological condition, the value of systolic aortic pressure in co pulse mode is 100 mmHg and the values of systolic aortic pressures in continuous modes are 90 mmHg (8 k) and 95 mmHg (11 k). The hemodynamics results of this study are comparable in vivo data, clinical data and other simulation studies. Therefore, this simulation enables hemodynamic studies in patients with end-stage heart failure, and patients under different modes of rotary blood pump support. PMID- 26737000 TI - Oscillometric measurement of arterial pulse pressure for patients supported by a rotary blood pump. AB - A computer model has been developed to evaluate the accuracy of an oscillometric method to measure the arterial pulse pressure from a patient with a rotary ventricular assist device (VAD). This computer model consists of three major components: the cardiovascular system, the HeartMate II VAD, and the operation of an automated cuff. Simulation was performed to mimic failure, recovery, and normal cardiac functions of a patient, supported by the HeartMate II VAD at different levels from minimum to maximum. The oscillating cuff pressure, simulating the air pressure of a deflecting cuff, was obtained from simulation under different conditions to test the accuracy of an oscillometric algorithm in determining the arterial pulse pressure. The algorithm was able to detect the systolic and diastolic arterial pressure with the error within +/-2 mmHg in most cases, except the cases when ventricular suction, induced by the VAD, occurred. The results from this study suggested that the oscillometric algorithm is capable to accurately detect the arterial pulse pressure for a rotary VAD patient if the algorithm is properly tuned. PMID- 26737001 TI - Hemodynamic performance of Edwards Intuity valve in a compliant aortic root model. AB - Numerous designs of bioprosthetic valves exist. The sutureless surgical valve is a newer design concept which combines elements of the transcatheter valve technology with surgical valves. This design aims at shorter and easier implantation. It was the aim of this study to perform hemodynamic and kinematic measurements for this type of valves to serve as a baseline for following studies which investigate the effect of the aortic root on the valve performance. To this end, the Edwards Intuity aortic valve was investigated in a new in vitro flow loop mimicking the left heart. The valve was implanted in a transparent, compliant aortic root model, and the valve kinematics was investigated using a high speed camera together with synchronized hemodynamic measurements of pressures and flows. The valve closure was asynchronous (one by one leaflet), and the valve started to close before the deceleration of the fluid. The aortic root model showed a dilation of the sinuses which was different to the ascending aorta, and the annulus was found to move towards the left ventricle during diastole and towards the aorta during systole. PMID- 26737002 TI - Design of Bioprosthetic Aortic Valves using biaxial test data. AB - Bioprosthetic Aortic Valves (BAVs) do not have the serious limitations of mechanical aortic valves in terms of thrombosis. However, the lifetime of BAVs is too short, often requiring repeated surgeries. The lifetime of BAVs might be improved by using computer simulations of the structural behavior of the leaflets. The goal of this study was to develop a numerical model applicable to the optimization of durability of BAVs. The constitutive equations were derived using biaxial tensile tests. Using a Fung model, stress and strain data were computed from biaxial test data. SolidWorks was used to develop the geometry of the leaflets, and ABAQUS finite element software package was used for finite element calculations. Results showed the model is consistent with experimental observations. Reaction forces computed by the model corresponded with experimental measurements when the biaxial test was simulated. As well, the location of maximum stresses corresponded to the locations of frequent tearing of BAV leaflets. Results suggest that BAV design can be optimized with respect to durability. PMID- 26737003 TI - Energy-efficient implantable transmitter for restenosis monitoring with intelligent-stents. AB - An analog circuit forming part of an intelligent-stent system is proposed with the aim of converting pressure-related capacitance measurements into a FM signal (around 800 MHz) to be analyzed outside of the patient body. Based on the information obtained from this signal, a reliable restenosis monitoring can be carried out. An energy-saver block controls the oscillator and reduces the power consumption of the whole circuit from 547.1 MUW in active state to 152.1 MUW in idle state, in order to comply with energy restriction imposed by inductive coupling powering. The design is implemented in TSMC 0.18 MUm CMOS technology. PMID- 26737004 TI - 3D velocity field characterization of prosthetic heart valve with two different valve testers by means of stereo-PIV. AB - BACKGROUND: Prosthetic heart valves can be associated to mechanical loading of blood, potentially linked to complications (hemolysis and thrombogenicity) which can be clinically relevant. In order to test such devices in pulsatile mode, pulse duplicators (PDs) have been designed and built according to different concepts. This study was carried out to compare anemometric measurements made on the same prosthetic device, with two widely used PDs. METHODS: The valve (a 27-mm bileaflet valve) was mounted in the aortic section of the PD. The Sheffield University PD and the RWTH Aachen PD were selected as physical models of the circulation. These two PDs differ mainly in the vertical vs horizontal realization, and in the ventricular section, which in the RWTH PD allows for storage of potential energy in the elastic walls of the ventricle. A glassblown aorta, realized according to the geometric data of the same anatomical district in healthy individuals, was positioned downstream of the valve, obtaining 1:1 geometric similarity conditions. A NaI-glycerol-water solution of suitable kinematic viscosity and, at the same time, the proper refractive index, was selected. The flow field downstream of the valve was measured by means of the stereo-PIV (Particle Image Velocimetry) technique, capable of providing the complete 3D velocity field as well as the entire Reynolds stress tensor. The measurements were carried out at the plane intersecting the valve axis. RESULTS: A three-jet profile was clearly found in the plane crossing the leaflets, with both PDs. The extent of the typical recirculation zone in the Valsalva sinus was much larger in the RWTH PD, on account of the different duration of the swirling motion in the ventricular chamber, caused by the elasticity of the ventricle and its geometry. CONCLUSION: The comparison of the hemodynamical behaviour of the same bileaflet valve tested in two PDs demonstrated the role of the mock loop in affecting the valve performance. PMID- 26737005 TI - Towards an objective measurement of emotional stress: Preliminary analysis based on heart rate variability. AB - This paper presents a study performed in 25 young healthy subjects measuring the evolution of heart rate variability (HRV) indices during emotional stress. Acute emotional stress was generated with a modified version of Trier Social Stress Test (TSST). The TSST comprises several tasks which include a memory test, anticipation of stress, public exposition, and an arithmetic task. Each task has different demanding conditions, carrying subjects' emotional stress to different states. An autogenic relaxation was done before TSST. Significant differences in HRV indices were observed in the arithmetic and memory task with respect to the relaxation stage. In particular during the arithmetic task, mean heart rate increased 22% (p-value <0.00001) the power in the very low frequency band increased 47% (p-value <0.00001 and normalized power in the low frequency (LF) band increased 19% (p-value <0.04). These results support a sympathetic activation during these tasks. PMID- 26737006 TI - Statistical assessment of performance of algorithms for detrending RR series. AB - Detrending RR series is a common processing step prior to HRV analysis. Customarily, RR series, which are inherently unevenly sampled, are interpolated and uniformly resampled, thus introducing errors in subsequent HRV analysis. We have recently proposed a novel approach to detrending unevenly sampled series, which is based on the notion of weighted quadratic variation reduction. In this paper, we extensively assess its performance on RR series through a statistical analysis. Numerical results confirm the effectiveness of the approach, which outperforms state-of-the-art methods. Furthermore, it is statistically uniformly better than competing algorithms. A sensitivity analysis shows that it is robust to variations of its controlling parameter. The algorithm is simple and favorable in terms of computational complexity, thus being suitable for long-term HRV analysis. To the best of the authors' knowledge, it is the fastest algorithm for detrending RR series. PMID- 26737007 TI - Concomitant dynamic changes in autonomic nervous system function and nasal airflow resistance during allergen provocation. AB - Allergic rhinitis is a major chronic respiratory disease which more than 500 million people suffer from around the world. It is considered to be an immuno neuronal disorder, but little is known about the part played by the neural system in nasal allergic reaction. This is due mainly to the lack of objective measurement techniques producing accurate, reliable and continuous measurement data about the dynamic changes in nasal respiratory function. Here, a method to assess the association of nasal airflow resistance and the underlying function of autonomic nervous system (ANS) is presented and used during the birch pollen provocation test. Ten allergic volunteers were challenged with allergen. Continuous nasal airflow resistance and spectral heart rate variability parameters were computed and analyzed for the dynamic changes. The derived signals show in detail the timing and intensity differences in subjects' reactions. After the provocation, the nasal airflow resistance rose gradually, whereas LF power and LF/HF ratio decreased gradually for all subjects. This implies gradually increasing sympathetic withdrawal in allergic patients during the provocation with allergen. The proposed method opens entirely new possibilities to assess accurately the dynamic and short-term changes in non stationary nasal function and could increase the accuracy and reliability of diagnostics and assessment of the effect of nasal treatments. PMID- 26737008 TI - Correlation between autonomous function and left ventricular performance after acute myocardial infarction. AB - Reduced ejection fraction (EF), possibly induced/mediated by autonomic abnormal activation, is one of the most powerful predictors of adverse outcome after acute myocardial infarction (MI). A deep understanding of the correlation between the autonomous functionality and the left ventricular performance in these patients is therefore of paramount importance. The autonomous function is reflected in the cardiac activity and, specifically, in the heart rate variability (HRV) signal. Given the cardiac activity nonlinearity, growing interest is being manifested towards nonlinear methods of analysis, which might provide more significant information than the traditional linear approaches. The aim of the present study was to investigate if non-linear HRV metrics change between MI patients with preserved EF (pEF) and MI patients with reduced EF (rEF). Data were acquired in the context of the cardioRisk project. Ten MI patients with rEF and six MI patients with pEF, admitted to Intensive Cardiac Care after a first acute MI episode, were studied. The ECG was acquired during a Holter recording and the tachogram was extracted. Sample entropy (SE) and Lempel-Ziv Complexity (LZC 1 and LZC 2) metrics were computed on five hour long tachogram portions. A significant correlation was found between LZC indices and EF in the whole population; SE, LZC 1 and LZC 2 were significantly higher in patients with pEF. Our results indicate that lower complexity characterizes the HRV of MI patients with rEF. Complexity reduction might be due to a simplification of regulatory mechanisms, which might explain why MI patients with rEF are at higher risk for subsequent non-fatal and fatal events. PMID- 26737009 TI - Alignment of R-R interval signals using the circadian heart rate rhythm. AB - R-R interval signals that come from different subjects are regularly aligned and averaged according to the horological starting time of the recordings. We argue that the horological time is a faulty alignment criterion and provide evidence in the form of a new alignment method. Our main motivation is that the human heart rate (HR) rhythm follows a circadian cycle, whose pattern can vary among different classes of people. We propose two novel alignment algorithms that consider the HR circadian rhythm, the Puzzle Piece Alignment Algorithm (PPA) and the Event Based Alignment Algorithm (EBA). First, we convert the R-R interval signal into a series of time windows and compute the mean HR per window. Then our algorithms search for matching circadian patterns to align the signals. We conduct experiments using R-R interval signals extracted from two databases in the Physionet Data Bank. Both algorithms are able to align the signals with respect to the circadian rhythmicity of HR. Furthermore, our findings confirm the presence of more than one pattern in the circadian HR rhythm. We suggest an automatic classification of signals according to the three most prominent patterns. PMID- 26737010 TI - Degeneration stage-specific response pattern of retinal ganglion cell spikes in rd10 mouse retina. AB - It is known that with retinal degeneration there is rewiring of retinal networks. Consequently, electrical stimulation of the degenerating retina produces responses that differ according to the stage of retinal degeneration. We sought to delineate a degeneration stage-specific parameter for the response pattern of retinal ganglion cell (RGC) spikes as a strategy for stage-specific electrical stimulation for perceptual efficiency of prosthetic vision devices. Electrically evoked RGC spikes were recorded at different degeneration stages in the rd10 mouse model for human retinitis pigmentosa (RP). Retinal explants mounted on an 8*8 multi-electrode array were stimulated by applying 1 Hz cathodic-phase first biphasic current pulses. RGC firing rate during the first 100 ms post-stimulus was compared to that during the 100-1000 ms period and a response ratio of 100 ms (RR100 ms) was calculated through the different postnatal weeks. Our results show that during post-stimulus 100-1000 ms, the degree of correlation between pulse amplitude and evoked RGC spikes drastically decreases at PNW 4.5. This pattern was closely matched by the RR100 ms curve at this stage. We conclude that the RR100 ms might be a good indicator of the therapeutic potential of a retinal electrical prosthesis. PMID- 26737011 TI - Fabrication and functional demonstration of a smart electrode with a built-in CMOS microchip for neural stimulation of a retinal prosthesis. AB - In this study, we propose an advanced architecture of a smart electrode for neural stimulation of a retinal prosthesis. A feature of the proposed architecture is embedding CMOS microchips into the core of the stimulus electrodes. Microchip integration without dead space on the array is possible. Additionally, higher durability can be expected because the microchips are protected by the stimulus electrodes like a metal casing. Dedicated circular shaped CMOS microchips were designed and fabricated. The microchip measured 400 MUm in diameter. Stimulus electrodes that had a microcavity for embedding the microchip were also fabricated. In the assembly process, the CMOS microchip was mounted on a flexible substrate, and then the stimulus electrode was mounted to cover the microchip. The microchip was completely built into the inside of the electrode. By performing an ex-vivo experiment using the extracted eyeball of a pig, stimulus function of the electrode was demonstrated successfully. PMID- 26737012 TI - Electrically evoked potentials in an ovine model for the evaluation of visual prosthesis efficacy. AB - Visual prostheses are becoming a reality as a therapy to restore functional vision to the blind. New stimulation strategies and novel electrode designs are contributing to accelerate the development of such devices triggering the interest of scientists, clinicians and the blind community worldwide. In this scenario, there is a need for large animal models that are suitable for preclinical testing of retinal neuroprostheses. This study presents an electrophysiology assessment of an ovine model for single and simultaneous electrode stimulation from the suprachoroidal space, using symmetric biphasic current pulses with a monopolar return configuration. Visually and electrically evoked potentials were recorded using supradural surface electrodes, showing charge thresholds comparable to those in humans. This model represents an alternative to feline or canine models with analogous activation levels and an eye anatomy similar to that of humans. PMID- 26737013 TI - Patch clamp recordings of retinal bipolar cells in response to extracellular electrical stimulation in wholemount mouse retina. AB - Retinitis pigmentosa is a family of inherited retinal diseases identified by the degeneration of photoreceptors, which leads to blindness. In efforts to restore vision lost to retinitis pigmentosa, retinal prostheses have been developed to generate visual percepts by electrically stimulating the surviving retinal bipolar and ganglion cells. The response of retinal ganglion cells to electrical stimulation has been characterized through direct measurement. However, the response of bipolar cells has only been inferred by measuring retinal ganglion cell activity. This investigation reports on a novel tissue preparation technique facilitating bipolar cell patch clamp recordings in wholemount retina. We find that bipolar cells respond to extracellular electrical stimuli with time-locked voltage spike depolarizations, which are likely mediated by voltage-gated calcium channels. PMID- 26737014 TI - Towards determining the afferent sites of perception feedback on residual arms of amputees with transcutaneous electrical stimulation. AB - The coordination and combination of motion and sensation are critical to realize a natural and precise control of prosthetic hands. Transcutaneous electrical stimulation (TES) is one of possible methods to develop an intuitive perception feedback for limb amputees. However, the perception afferent sites would be a critical issue that is still unexplored in depth. This paper reports a preliminary study on using somatosensory evoked potentials (SEP) to determine the proper afferent sites of perceptions on residual arms of transradial amputees. In this study, two transradial amputees with phantom finger perception (PFP) were recruited and SEP for the stimulation of median nerves and ulnar nerves were recorded and analyzed. PFP distribution maps on subjects' stumps were obtained by mechanical stimulations performed manually. Electrical stimulation was then applied to some selected sites on the stumps of their residual arms with surface electrodes to evoke SEP. In the experiments, SEP were successfully recorded, which means that the proposed method might be a suitable approach for localizing the afferent sites of perceptions, and could provide technique support for possible intuitive neural feedback for limb amputees in future work. PMID- 26737015 TI - A wearable mobility device for the blind using retina-inspired dynamic vision sensors. AB - Proposed is a prototype of a wearable mobility device which aims to assist the blind with navigation and object avoidance via auditory-vision-substitution. The described system uses two dynamic vision sensors and event-based information processing techniques to extract depth information. The 3D visual input is then processed using three different strategies, and converted to a 3D output sound using an individualized head-related transfer function. The performance of the device with different processing strategies is evaluated via initial tests with ten subjects. The outcome of these tests demonstrate promising performance of the system after only very short training times of a few minutes due to the minimal encoding of outputs from the vision sensors which are translated into simple sound patterns easily interpretable for the user. The envisioned system will allow for efficient real-time algorithms on a hands-free and lightweight device with exceptional battery life-time. PMID- 26737016 TI - Investigating the feasibility of EVestG assessment for screening concussion. AB - Electrovestibulography (EVestGTM) is a new technology that objectively measures the vestibular response. It has the potential to objectively, quickly and cost effectively screen concussion. EVestG signals are recorded painlessly and non invasively from the external ear in response to vestibular stimuli, and consist of brainstem and peripheral sensory oto-acoustic signals modulated by the cortical responses. In this study, we investigated the relationship between characteristic features of the extracted field potentials (FPs) of EVestG signals in people with side-impact concussion in comparison with those of control participants. 10 side-impact concussed individuals (4 Right and 6 left side impact) and 10 age-and-gender-matched controls were tested by EVestG. The participants also completed comprehensive neuropsychological assessments. Characteristic features were extracted from the FPs during side tilt, and linear discriminant analysis (LDA) classification was applied to the extracted features using a leave-one-out routine. The results show the difference between the left and right FP area was significantly (P<0.05) different. The LDA classification resulted a sensitivity of 85% and specificity of 69% for separating concussed individuals from controls. EVestG appears to have diagnostic potential in diagnosing side impact concussion. PMID- 26737017 TI - Semantic labelling to aid navigation in prosthetic vision. AB - Current and near-term implantable prosthetic vision systems offer the potential to restore some visual function, but suffer from limited resolution and dynamic range of induced visual percepts. This can make navigating complex environments difficult for users. Using semantic labelling techniques, we demonstrate that a computer system can aid in obstacle avoidance, and localizing distant objects. Our system automatically classifies each pixel in a natural image into a semantic class, then produces an image from the induced visual percepts that highlights certain classes. This technique allows the user to clearly perceive the location of different types of objects in their field of view, and can be adapted for a range of navigation tasks. PMID- 26737018 TI - Effects of electrode size and spacing on sensory modalities in the phantom thumb perception area for the forearm amputees. AB - Tactile sensory feedback plays a key role in accomplishing the dexterous manipulation of prosthetic hands for the amputees, and the non-invasive transcutaneous electrical nerve stimulation (TENS) of the phantom finger perception (PFP) area would be an effective way to realize sensory feedback clinically. In order to realize the high-spatial-resolution tactile sensory feedback in the PFP region, we investigated the effects of electrode size and spacing on the tactile sensations for potentially optimizing the surface electrode array configuration. Six forearm-amputated subjects were recruited in the psychophysical studies. With the diameter of the circular electrode increasing from 3 mm to 12 mm, the threshold current intensity was enhanced correspondingly under different sensory modalities. The smaller electrode could potentially lead to high sensation spatial resolution. Whereas, the smaller the electrode, the less the number of sensory modalities. For an Phi-3 mm electrode, it is even hard for the subject to perceive any perception modalities under normal stimulating current. In addition, the two-electrode discrimination distance (TEDD) in the phantom thumb perception area decreased with electrode size decreasing in two directions of parallel or perpendicular to the forearm. No significant difference of TEDD existed along the two directions. Studies in this paper would guide the configuration optimization of the TENS electrode array for potential high spatial-resolution sensory feedback. PMID- 26737019 TI - A new handheld electromagnetic cortical stimulator for brain mapping during open skull neurosurgery: a feasibility study. AB - Transcranial magnetic stimulations have provided invaluable tools for investigating nervous system functions in a preoperative context; in this paper we propose an innovative tool to extend the magnetic stimulation to an open skull context as a promising approach to map the brain cortex. The present gold standard for intraoperative functional mapping of the brain cortex, the direct brain stimulation, has a low spatial resolution and limited penetration and focusing capabilities. The magnetic stimulatory device that we present, is designed to overcome these limitations, while working with low currents and voltages. In the present work we propose an early study of feasibility, in which the possibility of exploiting a train of fast changing magnetic fields to reach the neuron's current thresholds is investigated. Measurements of electric field intensity at different distances from the coil, showed that the magnetic stimulator realized is capable of delivering an electric field on a loop of wire theoretically sufficient to evoke neuron's action potential, thus showing the approach' feasibility. PMID- 26737020 TI - Interfacing in silico and in vitro neuronal networks. AB - In this study, an in vitro cortical culture was stimulated according to the activity exhibited by its in silico counterpart. We connected the latter, an artificial spiking neural network (SNN), to the former, a biological network (BNN), via an open-loop (i.e. unidirectional) configuration, with the ultimate goal of establishing a closed-loop bidirectional connection in future studies. We detected network bursts in the SNN and utilized them as triggers for stimulus delivery to the BNN. We analyzed evoked BNN responses to evaluate whether the BNN activity was entrained by the SNN by correlating stimuli and BNN evoked network burst rates at different timescales. We found that this correlation was nearly constant at all timescales, but its magnitude depended on the efficacy of the stimulation source in entraining BNN activity. PMID- 26737021 TI - Optimization of a wearable pudendal nerve stimulator using computational models. AB - After spinal cord injury, lower urinary tract functions may be disrupted. Trans rectal stimulation of the pudendal nerve may enable patients to regain these functions via minimally invasive means. Using a finite element model of a wearable trans-rectal stimulator in the pelvic region, and a computational model of mammalian nerve fiber, various electrode configurations and the corresponding required current levels were studied. A configuration requiring considerably lower current level than previously reported was identified. For this configuration, the strength-duration curve was simulated and the effect of different stimulus waveforms on the required current was studied. In addition, the study examined whether a multi-electrode device could selectively activate different terminal branches of the pudendal nerve. PMID- 26737022 TI - Corticospinal excitability changes to anodal tDCS elucidated with NIRS-EEG joint imaging: An ischemic stroke study. AB - Transcranial direct current stimulation (tDCS) has been shown to modulate corticospinal excitability. We used near-infrared spectroscopy (NIRS) electroencephalography (EEG) joint-imaging during and after anodal tDCS to measure changes in mean cerebral haemoglobin oxygen saturation (rSO2) along with changes in the log-transformed mean-power of EEG within 0.5 Hz-11.25 Hz. In two separate studies, we investigated local post-tDCS alterations from baseline at the site of anodal tDCS using NIRS-EEG/tDCS joint-imaging as well as local post tDCS alterations in motor evoked potentials (MEP)-measure of corticospinal excitability. In the first study, we found that post-tDCS changes in the mean rSO2 from baseline mostly correlated with the corresponding post-tDCS change in log-transformed mean-power of EEG within 0.5 Hz-11.25 Hz. Moreover, a decrease in log-transformed mean-power of EEG within 0.5 Hz-11.25 Hz corresponded with an increase in the MEP-measure of corticospinal excitability--found in the second study. Therefore, we propose to combine NIRS-EEG/tDCS joint-imaging with corticospinal excitability investigation in a single study to confirm these finding. Furthermore, we postulate that the innovative technologies for portable NIRS-EEG neuroimaging may be leveraged to objectively quantify the progress (e.g., corticospinal excitability alterations) and dose tDCS intervention as an adjuvant treatment during neurorehabilitation. PMID- 26737023 TI - A comparison between block and smooth modeling in finite element simulations of tDCS. AB - Current density distributions in five selected structures, namely, anterior superior temporal gyrus (ASTG), hippocampus (HIP), inferior frontal gyrus (IFG), occipital lobe (OCC) and pre-central gyrus (PRC) were investigated as part of a comparison between electrostatic finite element models constructed directly from MRI-resolution data (block models), and smoothed tetrahedral finite element models (smooth models). Three electrode configurations were applied, mimicking different tDCS therapies. Smooth model simulations were found to require three times longer to complete. The percentage differences between mean and median current densities of each model type in arbitrarily chosen brain structures ranged from -33.33-48.08%. No clear relationship was found between structure volumes and current density differences between the two model types. Tissue regions nearby the electrodes demonstrated the least percentage differences between block and smooth models. Therefore, block models may be adequate to predict current density values in cortical regions presumed targeted by tDCS. PMID- 26737024 TI - Spatially distributed sequential array stimulation of tibial anterior muscle for foot drop correction. AB - Electrode arrays for the ease of electrode placement in the correction of foot drop with surface electrical stimulation have been developed in recent years. However, the configuration and identification of optimal stimulation sites with regard to time efficiency, stimulation comfort, and fatigue resistance is yet to be solved. In this study, the candidate stimulation sites were ranked and selected according to the motor thresholds induced by 1 Hz stimulation trains. Then based on the selected sites, a new stimulation configuration method termed spatially distributed sequential stimulation was tested and compared with traditional single electrode stimulation for foot drop correction in two normal subjects. The preliminary results demonstrated that the motor threshold of spatially distributed sequential stimulation was equal or less than motor thresholds of each stimulus sites. Besides, with the same stimulation parameters, the spatially distributed sequential stimulation induced larger dorsiflexion motion compared with traditional single electrode stimulation. These findings suggest that spatially distributed sequential stimulation on the selected sites might be an effective electrode array configuration method for correcting foot drop with electrical stimulation. PMID- 26737025 TI - Fiber size-selective stimulation using action potential filtering for a peripheral nerve interface: A simulation study. AB - Functional electrical stimulation is a powerful tool for restoration of function after nerve injury. However selectivity of stimulation remains an issue. This paper presents an alternative stimulation technique to obtain fiber size selective stimulation of nerves using FDA-approved electrode implants. The technique was simulated for the ventral roots of Xenopus Laevis, motivated by an application in bladder control. The technique relies on applying a high frequency alternating current to filter out action potentials in larger fibers, resulting in selective stimulation of the smaller fibers. Results predict that the technique can distinguish fibers with only a 2 MUm difference in diameter (for nerves not exceeding 2mm in diameter). The study investigates the behaviour of electrically blocked nerves in detail. Model imperfections and simplifications yielded some artefacts in the results, as well as unexpected nerve behaviour which is tentatively explained. PMID- 26737026 TI - Fabrication and characterization of stimulus nerve cuff electrode with highly roughened surface for chronic implant. AB - Nerve cuff electrodes for peripheral nerve prostheses are required chronically implanted electrodes which simultaneously stimulate and record nerve activity. It is inevitable challenge to investigate electrode material with low interfacial impedance and enhanced charge transfer capacity. In this study, stimulus nerve cuff electrodes on polyimide with Pt, conducting polymer poly(3,4 ethylenedioxythiophene) (PEDOT), black Pt, and IrOx were fabricated and characterized. The electrochemical properties were investigated using cyclic voltammetry, electrochemical impedance spectroscopy, and voltage transient measurements. From th experimental results, stimulus nerve cuff electrodes with black Pt showed the highest charge delivery capacity (80 times higher than Pt), charge injection capacity (6 times higher than Pt), and lowest interfacial impedance (3.8 times lower than Pt). PMID- 26737027 TI - Iterative electrodes increase neural recruitment for deep brain stimulation. AB - Deep brain stimulators require surgical replacement when primary cell batteries are depleted. We designed novel electrode contact geometries based on the principle of iterative element addition as a method of increasing perimeter. Our hypothesis was that these novel, high-perimeter designs would increase surface current density variation and neuronal activation, thus improving stimulation efficiency by decreasing power requirement. Finite element models of iterative electrodes displayed greater surface current density variations on the electrode surface. Subsequent analysis of their activation efficiency when 100 neurons were randomly positioned either parallel or perpendicular to the electrode yielded higher stimulation efficiencies in response to a monophasic cathodic voltage pulse with a pulse width of 100 MUs. Recruitment curves showing the percentage of activated axons as a function of stimulation intensity yielded a ~8% and ~24% reduction in threshold voltage and a ~2% and ~28% reduction in power consumption when nerve fibers were oriented parallel and perpendicular to the electrode, respectively. This heightened efficiency would reduce the frequency of surgical replacements of depleted stimulators, as well as induce fewer side effects associate with high voltage requirement for therapeutic stimulation. PMID- 26737028 TI - Wrist rigidity assessment during Deep Brain Stimulation surgery. AB - Parkinson's Disease (PD) patients often need Deep Brain Stimulation (DBS) surgery when they become intolerant to drugs or these lose efficiency. A stimulation electrode is implanted in the basal ganglia to promote the functional control of the deregulated dopaminergic motor pathways. The stimulation target is defined by medical imaging, followed by electrophysiological inspection for fine electrode position trimming and electrical stimulation tuning. Intra-operative stimulation of the target and the evaluation of wrist rigidity allows to choose the stimulation parameters which best alleviate PD symptoms without side effects. Neurologists impose a passive wrist flexion movement and qualitatively describe the perceived decrease in rigidity under different voltages, based on its experience and with subjectivity. We designed a novel, comfortable and wireless wearable motion sensor to classify the wrist rigidity by deriving a robust signal descriptor from angular speed values and a polynomial mathematical model to classify signals using a quantitative continuous scale. The descriptor significantly (p<0.05) distinguished between non-rigid and rigid states, and the classification model labelled correctly 83.9% of the evaluated signals against the blind-agreement of two specialists. Additionally, we developed a methodology to detect cogwheel rigidity from the angular speed signal with high sensitivity (0.93). Our system provides a reliable evaluation of wrist rigidity, improving upon the inherent subjective clinical evaluation while using small, simple and easy to use motion sensor. PMID- 26737029 TI - Long-term detection of Parkinsonian tremor activity from subthalamic nucleus local field potentials. AB - Current deep brain stimulation paradigms deliver continuous stimulation to deep brain structures to ameliorate the symptoms of Parkinson's disease. This continuous stimulation has undesirable side effects and decreases the lifespan of the unit's battery, necessitating earlier replacement. A closed-loop deep brain stimulator that uses brain signals to determine when to deliver stimulation based on the occurrence of symptoms could potentially address these drawbacks of current technology. Attempts to detect Parkinsonian tremor using brain signals recorded during the implantation procedure have been successful. However, the ability of these methods to accurately detect tremor over extended periods of time is unknown. Here we use local field potentials recorded during a deep brain stimulation clinical follow-up visit 1 month after initial programming to build a tremor detection algorithm and use this algorithm to detect tremor in subsequent visits up to 8 months later. Using this method, we detected the occurrence of tremor with accuracies between 68-93%. These results demonstrate the potential of tremor detection methods for efficacious closed-loop deep brain stimulation over extended periods of time. PMID- 26737030 TI - Therapeutic effects of functional electrical stimulation on motor cortex in children with spastic Cerebral Palsy. AB - In the present study we have evaluated the electroencephalogram (EEG) signal recorded during ankle dorsal and plantar flexion in children with spastic Cerebral Palsy (CP) after Functional Electrical Stimulation (FES) of the Tibialis Anterior (TA) muscles. The intervention group had 10 children with spastic diaplegic/hemiplegic CP within the age group of 5 to 14 years of age who received both FES for 30 minutes and the conventional physiotherapy for 30 minutes a day, while the control group had 5 children who received only conventional physiotherapy for 60(30 + 30) minutes a day only. Both group were treated for 5 days a week, up to 12 weeks. The EEG data were analyzed for Peak Alpha Frequency (PAF), sensorimotor rhythm (SMR), mu wave suppression and power spectral density (PSD) of all the bands. The results showed a decrease in SMR and mu wave suppression in the intervention group as compared to the control group, indicating a positive/greater improvement in performance of motor activities. Therefore, from this study we could conclude that FES combined with conventional physiotherapy improves the motor activity in children with spastic CP. PMID- 26737031 TI - Removal of Transcranial a.c. Current Stimulation artifact from simultaneous EEG recordings by superposition of moving averages. AB - Transcranial Current Stimulation (tCS) is a recent development for non-invasive brain stimulation. At present tCS introduces large artifacts into simultaneous EEG (electroencephalogram) recordings, which must be removed to enable brain changes from during the stimulation to be monitored. This paper presents a new approach for removing artifacts of transcranial Alternating Current Stimulation (tACS) from simultaneous EEG. Termed the Superposition of Moving Averages (SMA) our approach is independent of the number of EEG channels used and has a low computational complexity for use in real-time online artifact removal and data responsive stimulation. Compared to a Principal Component Analysis (PCA) approach our results show that SMA achieves superior artifact removal performance, especially with regards to the use of low channel count EEG devices. PMID- 26737032 TI - A fast stimulability screening protocol for neuronal cultures on microelectrode arrays. AB - Microelectrode arrays (MEAs) are used to study the electrical activity in brain slices and neuronal cultures. MEA experiments for the analysis of electrical stimulation responses require the tissue or culture to be prone to stimulation. For brain slices, potential stimulation sites may be directly visible in microscope, in which case the determination of stimulability at those locations is sufficient. In unstructured neuronal cultures, potential stimulation sites may not be known a priori, and spatial stimulability screening should be performed. Considering, e.g., 59 microelectrode sites, each to be stimulated several times, may result in long screening times, unacceptable with a MEA system without an integrated CO2 incubator, or in high stimulation effects on the networks. Here, we describe an implementation of a fast stimulation protocol employing pseudorandom stimulation site switching aiming at alleviating the network effects of the stimulability screening. In this paper, we show the usability of the proposed protocol by first detecting stimulable locations and subsequently apply repeated stimulation on the identified potentially stimulable locations to observe an exemplary neuronal pathway. PMID- 26737033 TI - Optimization of Parkinson Disease treatment combining anti-Parkinson drugs and deep brain stimulation using patient diaries. AB - The number of patients suffering from Parkinson's disease is increasing rapidly due to population aging. While traditional medications-based palliative therapy is successful in early stages, deep brain stimulation (DBS) may be used as an alternative treatment in later stages. After DBS implantation, the therapy typically consists of electrical stimulation and reduced medication. In order to provide good clinical outcome, a balance has to be found between medication and stimulation parameters, this is usually done as follows: First, Unified Parkinson's Disease Rating Scale (UPDRS) scoring is performed, second patients are supposed to fill subjective diaries during a specific period. This study shows that these diaries are useful as therapy progression indicator. Feel scores based on diaries and sleep time were examined with respect to DBS stimulation and medication. The results confirmed the positive effect of both therapy components- stimulation as well as medication--on patient feel scores. Furthermore, a positive correlation was observed between stimulation energy and sleep duration. PMID- 26737034 TI - Bioimpedance spectroscopy method for investigating changes to intracranial dose during transcranial direct current stimulation. AB - Tissue resistance changes upon application of DC current. We posit that in a similar fashion, that scalp and skull resistances during trancranial direct current stimulation (tDCS) are variable, resulting in changes to intracranial dose. Transcranial magnetic stimulation (TMS), electoencephelogram (EEG), functional magnetic resonance imaging (fMRI), proton magnetic resonance spectroscopy ((1)H MRS) and functional near infrared spectroscopy (fNIRS) are technologies used to measure individual neural response to tDCS. These technologies are complex and may not be directly correlated to intracranial dose. We therefore present a bioimpedance spectroscopy method of measuring changes to the intracranial dose in vivo. Scalp resistance changes are measured during tDCS. Current flow through the scalp is calculated as the ratio of voltage measured on the scalp and scalp resistance. Variation of intracranial current is indirectly calculated from changes in the current shunted through the scalp. We thus demonstrate a novel methodology of on-line monitoring of scalp resistance and current as an objective feedback of estimated individual tDCS dose. PMID- 26737035 TI - Effect of handedness on muscle synergies during upper limb planar movements. AB - Handedness is a prominent but poorly understood aspect of human motor performances. Despite it is generally accepted that it results from differences in the neural control of the arm, the mechanisms at the origin of the side difference in motor performances are still unknown. In this work, we propose to deepen this aspect by investigating muscle synergies organization. We obtained muscle synergies through the factorization of the superficial electromyographical (EMG) activity related to fifteen upper limb muscles in the dominant and non dominant side of 5 healthy young right and left dominant subjects, while executing planar wide and tight circular trajectories. Our preliminary results showed that right and left handed subjects performed the circular trajectories with a different muscle organization. Moreover, a task-related side-difference in muscle synergies was observed. Further investigations in a larger cohort of individuals are necessary to determine the neural mechanisms generating the differences in number and organization of muscle synergies between left and right handed individuals. PMID- 26737036 TI - Effects of prosthesis use on the capability to control myoelectric robotic prosthetic hands. AB - The natural control of robotic prosthetic hands with non-invasive techniques is still a challenge: myoelectric prostheses currently give some control capabilities; the application of pattern recognition techniques is promising and recently started to be applied in practice but still many questions are open in the field. In particular, the effects of clinical factors on movement classification accuracy and the capability to control myoelectric prosthetic hands are analyzed in very few studies. The effect of regularly using prostheses on movement classification accuracy has been previously studied, showing differences between users of myoelectric and cosmetic prostheses. In this paper we compare users of myoelectric and body-powered prostheses and intact subjects. 36 machine-learning methods are applied on 6 amputees and 40 intact subjects performing 40 movements. Then, statistical analyses are performed in order to highlight significant differences between the groups of subjects. The statistical analyses do not show significant differences between the two groups of amputees, while significant differences are obtained between amputees and intact subjects. These results constitute new information in the field and suggest new interpretations to previous hypotheses, thus adding precious information towards natural control of robotic prosthetic hands. PMID- 26737037 TI - High Density EMG investigation of H-reflex distribution over the soleus muscle. AB - The spatial distribution of H-reflexes over soleus muscle was investigated through High-Density EMG in five healthy subjects. The posterior tibial nerve was stimulated with a staircase current envelope with 1mA steps. The regions where the incremental responses (incremental H-reflexes) occurred were identified for each stimulation step with a validated segmentation algorithm. The average centroid of the segmented areas was located over the Achilles tendon, 5 cm below the myo-tendinous junction of the medial gastrocnemius. The average dimension of these regions corresponded to 28% of the surface covered by the grid of electrodes. The amplitude of H-reflexes recorded in the segmented areas was higher than the average amplitude computed over the entire detection system as well as the H-reflex recorded by the electrode positioned according to SENIAM guidelines. These preliminary results suggest that: i) H-reflex detected from a specific soleus region unlikely reflects the whole muscle volume and ii) H reflexes with greatest amplitude can be recorded over the Achilles tendon. PMID- 26737038 TI - Does the global temporal activation differ in triceps surae during standing balance? AB - One of the most important muscular groups which contribute to maintain standing balance is triceps surae. However, it is unclear whether the postural controllers of triceps surae, medial gastrocnemius (MG) and soleus (SOL), have different temporal patterns of activation during upright stance. This paper aimed at evaluating whether the global temporal activation in triceps surae differ among young subjects during standing balance. Nine male volunteers performed two tasks: standing quietly and with voluntary back and forward sways over their ankle. Electromyograms (EMGs) from soleus medial (MSOL) and lateral (LSOL) regions and from MG were sampled with linear arrays of surface electrodes. The percentage of muscle activation in time (i.e. temporal index) was computed for each muscle during upright standing. The results revealed that the medial portion of soleus muscle (MSOL) was activated continuously compared to the lateral portion of soleus (LSOL) and MG, which were activated intermittently. Therefore, the global temporal activation differed among the postural muscles of triceps surae during standing balance. PMID- 26737039 TI - Time to boundary function to assess upright stance in blind children. AB - The goal of this preliminary study was to assess the difference in postural stability between blind and sighted children using the Time to Boundary function (TtB). The experiment was conducted in twelve children (6-12 yrs), six of them had no visual impairment, and other six had congenital blindness. The participants stood on RotoBit force plate maintaining upright stance in static conditions. Each blind subject executed the task three times, each sighted subject executed the task six times, three with eyes closed (EC) and three with eyes open (EO). For all subjects each repetition lasted 30 s. The Centre of Pressure (CoP) coordinates, extracted directly from a force plate, are used to calculate four classical parameters (sway path, sway area, mean amplitude and mean frequency) and a predictive variable called Time to Boundary (TtB). The latter is the time it would take the CoP, given its instantaneous trajectory, to contact a stability boundary. Descriptive statistics were calculated for all parameters. Twoway ANOVA test was done considering the visual condition (EO, EC, BLIND) and the repetitions (RP) as a factor. In the first comparison (BLIND/EO) the results showed significant difference for all the parameters except for TtB. In the second comparison (BLIND/EC) the results showed significant difference only for TtB. In the third comparison (EO/EC) the results showed significant difference for all the calculated parameters. Therefore the TtB would be used to asses the postural control in children with blindness. PMID- 26737040 TI - Motor control strategies in the bimanual stabilization of an unstable virtual tool. AB - Previous works have shown that, when dealing with instabilities in a bimanual manipulation paradigm, humans modulate the stiffness of the arms according to feedforward or feedback mechanisms as a function of the dynamics of the task. The aim of this work is to complement these results getting insights on how the CNS controls the muscles to achieve the stabilization goal in the two aforementioned control strategies. Surface EMG was recorded from 13 muscles of each arm and trunk while three expert subjects performed bimanual balancing of a virtual underactuated tool immersed in an unstable force-field. Results suggest the existence of an intermittent muscle ensemble recruitment that follows two distinct activation patterns, namely synchronous co-contractions and independent activations. The observed EMG patterns were independent of the motor control strategy applied in the task. These findings therefore suggest the existence of separate control strategies for the tool stabilization and the control of hand movements at the muscular level during a bimanual postural task. PMID- 26737041 TI - Development of a method to quantify inter-limb coupling in individuals with hemiparetic stroke. AB - A common motor deficit in individuals post-stroke is altered interlimb coupling. Efforts at one extremity can cause involuntary muscle activity and movement at a different extremity. An important step in understanding interlimb coupling and developing effective treatment strategies is to have an accurate quantification of the motor behavior. This paper outlines the development of an approach to measure interlimb coupling between the upper and lower extremity. Isometric and EMG based approaches were explored before determining that the use of a haptic robotic system was ideal to quantify altered interlimb coupling. This is a novel engineering approach that can measure biomechanical parameters while avoiding confounding factors. Preliminary evidence shows that lower extremity efforts cause involuntary movement in the upper extremity in stereotypical flexion and extension patterns. PMID- 26737043 TI - fNIRS measure of transitive and intransitive gesture execution, observation and imagination in ecological setting: A pilot study. AB - To explore the presence of differential cortical hemodynamic activations related to cognitive components of actions, we performed a fNIRS (functional Near Infrared Spectroscopy) study during Observation (O), Execution (E) and Imagination (I) of complex and meaningful (transitive and intransitive) gestures in ecological setting. A pilot sample of 5 healthy adults underwent an event related study consisting of these 3 different conditions, with O set as first and followed by a randomized presentation of E or I. fNIRS measurements were performed using a 24 channel array of optodes (8 light injectors and 8 detectors) placed over the contralateral central, centro-parietal, parietal and temporal areas. Results showed that the premotor (PMC) and the sensory-motor cortices (SM1) were recruited selectively during E, with levels of oxygenated hemoglobin (oxy-Hb) higher than the other conditions, while the posterior parietal cortex (PPC) showed increased oxy-Hb levels for both E and O. These data suggest that variations in hemodynamic responses can be attributed to different neural processes underpinning these tasks, with PMC and SM1 being more involved in action preparation and performance, and PPC prevalently dedicated to attentive processes related to the execution and observation of limb movements. PMID- 26737042 TI - A wearable vibrotactile device for upper-limb bilateral motion training in stroke rehabilitation: A case study. AB - Real-time feedback is essential for motor learning. Automated feedback is especially valuable for at-home stroke rehabilitation in the absence of therapist supervision. This study examined the effect of real-time corrective vibrotactile feedback for training bilateral reaching motions. A bilateral upper-limb motor learning system, comprising a wireless wearable sleeve-armband device for providing vibrotactile feedback, a computer target game, and a customized motion tracking technology, was developed and evaluated on both hemiparetic stroke survivors and able-bodied people. This paper introduces the system and presents preliminary data for one hemiparetic stroke subject and one healthy subject performing bimanual reaching motions in the transverse plane. Vibrotactile training was found to successfully alter both subjects' original trajectories and to improve the motion symmetry of the stroke subject. These preliminary findings indicated the potential efficacy of vibrotactile cues for unsupervised motor learning in both the healthy and the stroke populations. PMID- 26737044 TI - Phantom movements from physiologically inappropriate muscles: A case study with a high transhumeral amputee. AB - Individuals with high-level amputation have a great need for functional prostheses because of their vast functional deficits. Conventional techniques are considered inappropriate for high-level amputees due to the lack of physiologically appropriate muscles. This study investigates how accurate phantom movements (PMs) can be classified from physiologically inappropriate muscles. The study involves a case study of a 42-year-old transhumeral amputee. Suitable PMs and best electrode configuration were identified using the sequential forward selection method and brute-force technique. Using linear discriminant analysis, the best PMs (elbow extension/flexion, wrist supination/pronation) and rest were classified with error ranging from 3% to 0.18% when using 3 to 8 EMG channels respectively. A completion rate of 93 % was obtained during a targeted achievement control test in a virtual reality environment. This case indicates that a proximal transhumeral amputee can generate muscle activation patterns related to distinct PMs; and these PMs can be decoded from physiologically inappropriate muscles. PMID- 26737045 TI - Muscle fatigue estimation with twitch force derived from sEMG peaks. AB - We propose a new method - twitch force - for estimation of the muscle behavior during voluntary contraction for assessing localized muscle fatigue. The proposed method uses the sEMG peaks as input and the measured force as output. The twitch force, which is a transfer function to generate force, was estimated during fatiguing contraction. We verified the estimated twitch force based on the measured results with electrical stimulation. The participants performed isometric little finger flexion until exhaustion. SEMG was recorded on the flexor digiti minimi brevis muscle for the proposed method and the electrical stimulation electrodes on the ulnar nerve induced involuntary contraction for reference. As the muscle fatigue level increased, the twitch peaks decreased in both methods. The proposed method can be widely used in the quantitative analysis of muscle fatigue during voluntary contraction. PMID- 26737046 TI - Decomposing time series data by a non-negative matrix factorization algorithm with temporally constrained coefficients. AB - The non-negative matrix factorization algorithm (NMF) decomposes a data matrix into a set of non-negative basis vectors, each scaled by a coefficient. In its original formulation, the NMF assumes the data samples and dimensions to be independently distributed, making it a less-than-ideal algorithm for the analysis of time series data with temporal correlations. Here, we seek to derive an NMF that accounts for temporal dependencies in the data by explicitly incorporating a very simple temporal constraint for the coefficients into the NMF update rules. We applied the modified algorithm to 2 multi-dimensional electromyographic data sets collected from the human upper-limb to identify muscle synergies. We found that because it reduced the number of free parameters in the model, our modified NMF made it possible to use the Akaike Information Criterion to objectively identify a model order (i.e., the number of muscle synergies composing the data) that is more functionally interpretable, and closer to the numbers previously determined using ad hoc measures. PMID- 26737047 TI - Intermittent appearances of saddle-type hyperbolic dynamics during human stick balancing on a manually controlled cart. AB - Stabilization of an inverted pendulum on a manually controlled cart (cart inverted pendulum; CIP), analogous to human fingertip stick balancing, is considered to get insights of how the human central nervous system stabilizes unstable dynamics. We explore a possibility that a type of intermittent control strategy proposed for human postural control might also be applicable to the CIP task, i.e., whether a transient contracting dynamics along a stable manifold of a saddle-type equilibrium of the non-controlled inverted pendulum is exploited intermittently. To this end, we measured task performances during CIP balancing from several experimental subjects. Intermittent appearances of hyperbolicity as typical characteristics reflecting the intermittent control strategy were examined in the recorded motion data using phase space analysis and wavelet analysis. We show that skilled subjects tend to exhibit those characteristics, suggesting that they stabilize upright posture of the stick by utilizing the intermittent control strategy. PMID- 26737048 TI - A computer vision based candidate for functional balance test. AB - Balance in humans is a motor skill based on complex multimodal sensing, processing and control. Ability to maintain balance in activities of daily living (ADL) is compromised due to aging, diseases, injuries and environmental factors. Center for Disease Control and Prevention (CDC) estimate of the costs of falls among older adults was $34 billion in 2013 and is expected to reach $54.9 billion in 2020. In this paper, we present a brief review of balance impairments followed by subjective and objective tools currently used in clinical settings for human balance assessment. We propose a novel computer vision (CV) based approach as a candidate for functional balance test. The test will take less than a minute to administer and expected to be objective, repeatable and highly discriminative in quantifying ability to maintain posture and balance. We present an informal study with preliminary data from 10 healthy volunteers, and compare performance with a balance assessment system called BTrackS Balance Assessment Board. Our results show high degree of correlation with BTrackS. The proposed system promises to be a good candidate for objective functional balance tests and warrants further investigations to assess validity in clinical settings, including acute care, long term care and assisted living care facilities. Our long term goals include non-intrusive approaches to assess balance competence during ADL in independent living environments. PMID- 26737049 TI - Analysis of neck muscle activity and comparison of head movement and body movement during rotational motion. AB - The neck is a very delicate part of the body that is highly prone to whiplash injuries, during jerk. A lot of the research relating to whiplash injuries performed to date has been tested in environments with linear motions and have mostly applied their work to car collisions. Whiplash injuries can also affect disabled individuals during falls, bed transfers, and while travelling in wheelchairs. The primary objective of this paper was to focus on neck and body behaviour during rotational motion, rather than linear motion which has been often associated with car collisions. This paper takes the current motion signal processing technique a step further by computing the differential between head and body motion. Neck electromyogram (EMG) and angular velocity data of the head and body were acquired simultaneously from 20 subjects, as they were rotated 45 degrees in the forward pitch plane, with and without visual input, in a motion simulator. The centre of rotation (COR) on the simulator was located behind the subject Results showed that neck muscle behaviour was affected by the forward rotations, as well as visual input. Anterior neck muscles were most active during forward rotations and trials including VR. Maximum effective muscle power and activity of 10.54% and 55.72 (mV/mV).s were reached respectively. Furthermore, during forward rotations the motion profiles started off with dominance in body motion, followed by dominance in head motion. PMID- 26737050 TI - The effect of light-emitting diode irradiation at different wavelengths on calcification of osteoblast-like cells in 3D culture. AB - This study aimed to investigate the effect of four different light-emitting diode (LED) wavelengths on calcification and proliferation of osteoblast-like cells in vitro. MC3T3-E1 cells were seeded within three-dimensional collagen scaffolds and irradiated daily by LED light with peak emission wavelengths of 630-, 680-, 760- and 830-nm at constant fluency of 3.1 J/cm(2) (irradiance intensity 2 mW/cm(2)). Cultures were measured for calcium content at day 0, 7, 14, 21, 28, 35 and 42. The significant enhancement in calcium content was observed at the early stage of culture (days 7 and 14) (p<;0.05). After that, the calcium content of irradiated groups was similar to that of the controls group. This suggests the transient effect of light irradiation on osteoblastic cell calcification. Only 680-nm irradiated samples revealed a significant enhancement of calcium content until the late stages of culture (from days 21 to 42) (p<;0.001). The cyclin D mRNA expression that was investigated 3 hours after stimulation at day3 also show that the 680-nm LED irradiation can enhance cyclin D expression more than others. For enhancing bone mineralization, LED irradiation at the 680-nm is more effective than those at 630-, 760- and 830-nm. Further studies should be investigated in order to obtain the most effective parameters of LLLI on bone regeneration in clinical setting. PMID- 26737051 TI - Computational tool for morphological analysis of cultured neonatal rat cardiomyocytes. AB - This study describes the development and evaluation of a semiautomatic myocyte edge-detector using digital image processing. The algorithm was developed in Matlab 6.0 using the SDC Morphology Toolbox. Its conceptual basis is the mathematical morphology theory together with the watershed and Euclidean distance transformations. The algorithm enables the user to select cells within an image for automatic detection of their borders and calculation of their surface areas; these areas are determined by adding the pixels within each myocyte's boundaries. The algorithm was applied to images of cultured ventricular myocytes from neonatal rats. The edge-detector allowed the identification and quantification of morphometric alterations in cultured isolated myocytes induced by 72 hours of exposure to a hypertrophic agent (50 MUM phenylephrine). There was a significant increase in the mean surface area of the phenylephrine-treated cells compared with the control cells (p<;0.05), corresponding to cellular hypertrophy of approximately 50%. In conclusion, this edge-detector provides a rapid, repeatable and accurate measurement of cell surface areas in a standardized manner. Other possible applications include morphologic measurement of other types of cultured cells and analysis of time-related morphometric changes in adult cardiac myocytes. PMID- 26737052 TI - Efficacy of ultrasound mediated microbubbles in diclofenac gel to enhance transdermal permeation in rheumatoid arthritis induced rat. AB - In previous study in the literature, the effect of ultrasound on the transdermal permeation of the nonsteroidal anti-inflammatory drug, diclofenac has been investigated. Therapeutic ultrasound can increase circulation in the inflamed joint and decrease arthritic pain. Recently, transdermal drug delivery has been demonstrated by ultrasound (US) combining with microbubbles (MBs) contrast agent. In this study, the efficiency of US-MBs mediated diclofenac delivery for adjuvant induced rheumatoid arthritis (RA) in rats was evaluated. RA was induced by injection of 100 MUl Freund's complete adjuvant into the ankle joint in SD male rats (250-300g) and were randomly divided into five groups: (1) control group (C); (2) penetrating diclofenac alone (D); (3) US alone (U); (4) US combined with penetrating diclofenac (DU); (5) US combined with MBs and penetrating diclofenac (DUB). The evaluations of ankle width were performed for 10 days by high frequency (40MHz) US B-mode and color Doppler mode imaging before and after treatment. Longitudinal US images of arthritis induced show synovitis and neovascularity. After treatment, only a little neovascularity has been observed. The recovery rate at 10th day in the group DUB (97.7+/-2.7 %) was significantly higher than in the group C (1.0+/-2.7 %), group D (37.5+/-4.6 %), group U (75.5+/ 4.2 %) and group DU (87.3+/-5.2 %) (p <; 0.05). Our results investigated that the treatments of US and MBs can increase skin permeability to enhance diclofenac sodium delivery and inhibit inflammation of the tissues surrounded the arthritic ankle. In color Doppler imaging, after the combination treatment, the synovial neoangiogenesis in the arthritic area was reduced quickly. PMID- 26737053 TI - Neuralization of mouse embryonic stem cells in alginate hydrogels under retinoic acid and SAG treatment. AB - This paper examines the differentiation of a mouse embryonic stem cell line (CGR8) into neurons, under retinoic acid (RA) and smoothened agonist (SAG) treatment. When stem cells underwent through an embryoid body (EB) formation stage, dissociation and seeding on glass coverslips, immunofluorescent labelling for neuronal markers (Nestin, b-Tubulin III, MAP2) revealed the presence of both immature neural progenitors and mature neurons. Undifferentiated CGR8 were also encapsulated in tubular, alginate-gelatin hydrogels and incubated in differentiation media containing retinoic acid (RA) and smoothened agonist (SAG). Cryo-sections of the hydrogel tubes were positive for Nestin, Pax6 and b-Tubulin III, verifying the presence of neurons and neural progenitors. Provided neural induction can be more precisely directed in the tubular hydrogels, these scaffolds will become a powerful model of neural tube development in embryos and will highlight potential strategies for spinal cord regeneration. PMID- 26737054 TI - Evaluation of the repairing effect of collagen type I and MaxGel on the infarcted myocardium in an animal model. AB - Nowadays and in spite of all the preventive effort made, cardiovascular diseases remain as one of the leading causes of death worldwide. Current treatments decrease the progression of the disease but fail to offer a solution where the contractile function lost due to the injury can be recovered. In response to this, regenerative medicine proposes new approaches and one of this is the use of biomaterials that can mimic the role of the extracellular matrix and provide support for new cells in the affected heart. This study evaluated the repairing effect of collagen type I and MaxGel when injected, alone or combined, into the infarcted heart of Wistar rats. Cardiac function was quantified using the ejection fraction as the main parameter and it was measured in three time points during the study: pre-infarction, post-infarction, and post-treatment. Additionally, histological samples of the hearts were taken for evaluation. The data obtained showed a marked recovery of the cardiac function in the animals were collagen type I was injected with an increase of 8.2% on the mean ejection fraction, suggesting that this biomaterial has the capacity to stop the progressive decline of the cardiac function in an infarcted heart. PMID- 26737055 TI - High pressure assessment of bilayered electrospun vascular grafts by means of an Electroforce Biodynamic System(r). AB - INTRODUCTION: Tissue engineering offers the possibility of developing a biological substitute material in vitro with the inherent properties required in vivo. However, the inadequate performance in vascular replacement of small diameter vascular grafts (VG) reduces considerably the current alternatives in this field. In this study, a bilayered tubular VG was produced, where its mechanical response was tested at high pressure ranges and compared to a native femoral artery. MATERIALS AND METHOD: The VG was obtained using sequential electrospinning technique, by means of two blends of Poly(L-lactic acid) and segmented poly(ester urethane). Mechanical testing was performed in a biodynamic system and the pressure-strain relationship was used to determine the elastic modulus. RESULTS: Elastic modulus assessed value of femoral artery at a high pressure range (33.02*106 dyn/cm(2)) was founded to be 36% the magnitude of VG modulus (91.47*106 dyn/cm(2)) at the same interval. CONCLUSION: A new circulating mock in combination with scan laser micrometry have been employed for the mechanical evaluation of bioresorbable bilayered VGs. At same pressure levels, graft elasticity showed a purely "collagenic" behavior with respect to a femoral artery response. PMID- 26737056 TI - Massively-multicellular alignment with the self-aggregate of air bubbles. AB - This study proposes a cell manipulation method with aggregated air bubbles on cell culture medium. This method requires no additional regents nor devices, except for normal cell-culture materials such as cell culture dishes and pipettes. Bubbles generated by pipetting were spontaneously aggregated with regularity on the whole surface and used as a mask for avoiding cell adhesion after cell-seeding. The diameter of bubbles was able to be controlled by the size of micro-pipette tips. Seeded cells spread to the whole area along the bubble gap. This technique is a surface-tension-driven self-assembly-based method. Using this technique, millions of living cells were successfully aligned into a hexagonal pattern within 300 MUm in pattern width on the whole surface of dish for less than 2 h. PMID- 26737057 TI - Natural magnetic nanoparticle containing droplet for smart drug delivery and heat treatment. AB - Biodegradable polymer droplet containing natural magnetic nanoparticle is composed for smart drug delivery and heat treatment. For selective and efficient drug delivery to the target tissue, direct high magnetic field will be applied near the target tissue. For drug release control and heat treatment, alternative high magnetic field will be applied. Magnetosome, natural magnetic nanoparticle, is extracted from magnetotactic bacteria, AMB-1. Mixture of magnetosome and sodium alginate composes into droplet using the microfluidic device applied Plateau-Rayleigh instability principle. The magnetosome contained droplet selected its rout at the bifurcate microchannels by direct high magnetic field. High alternative magnetic field generating circuit is designed with 18 mT and 4 Hz magnetic wave. The generated magnetic wave was applied to the extracted magnetosomes so that temperature of the magnetosomes increased from 15.2 degrees C to 17.6 degrees C. PMID- 26737058 TI - The impact of bone microstructure on the field distribution of electrostimulative implants. AB - Since the 1980s several methods of electrostimulative techniques have been developed to accelerate bone regeneration during orthopedic treatment. These techniques have proven to provide increased bone formation while curing fractures and bone diseases. The electric parameters, however, are mostly results of empiric research regarding the bone tissue as homogeneous material. Especially cancellous bone, which is the objective of a new electrostimulative total hip revision system, has a porous, inhomogeneous microstructure. The present work investigates numerically the electric field distribution within this tissue using microscopic computer tomography scans of small bone samples. The 3-dimensional X ray absorption values of these scans are correlated with conductivity values from literature applying different correlation approaches. Compared to electric fields within a homogeneous material strong elevations can be observed within the structures which include most of the bone forming cells. PMID- 26737059 TI - Controlling cell migration and adhesion into a scaffold by external electric currents. AB - Fabrication of more complex tissue-engineered structures, resembling the tissues and organs in vivo requires combining more than one cell type within the same construct. This can be achieved by designing and fabricating complex scaffolds with asymmetric properties but controlled arrangement of cells within the scaffold could also be realized by using electric current. External electric currents are able to modify cell adhesion, orientation and migration and this can be used for influencing cell location within a scaffold. In this paper we studied the effect of an electric current on cell migration and adhesion into a three dimensional scaffold through a conductive mesh. PMID- 26737060 TI - On-line tracking of living cell subjected to cyclic stretch. AB - We propose a novel system for the observation of living cell exposed to cyclic stretch under dynamic conditions. The developed system is mainly composed of a laptop PC, a stretching unit with three motorized stages, and a microscope with a CCD camera. The design of the cell tracking system is based on the deformation characteristics of the elastic chamber and its performance was confirmed through the basic experiments. Finally, we succeeded in on-line imaging of living single cells under the microscope with a high magnification ratio. We believe that the developed system is a promising platform for studying the immediate responses of cells exposed to cyclic stretch. PMID- 26737061 TI - Microengineered embryonic stem cells niche to induce neural differentiation. AB - A major challenge in therapeutic use of embryonic stem cells (ESCs) for treating neurodegenerative diseases is creating a niche in vitro for controlled neural specific differentiation of ESCs. We employ a niche microengineering approach to derive neural cells from ESCs by mimicking embryonic development in terms of direct intercellular interactions. Using a polymeric aqueous two-phase system (ATPS) microprinting technology, murine ESCs (mESCs) are precisely localized over a monolayer of supporting stromal cells to allow formation of individual mESC colonies. Polyethylene glycol (PEG) and dextran (DEX) are dissolved in culture media to form two immiscible aqueous solutions. A robotic liquid handler is used to print a nanoliter-volume drop of the denser DEX phase solution containing mESCs onto a confluent layer of supporting PA6 stromal cells submerged in the aqueous PEG phase. mESCs proliferate into isolated colonies of uniform size. For the first time, a comprehensive protein expression analysis of individual mESC colonies is performed over a two-week culture period to track temporal progression of cells from a pluripotent stage to specific neural cells. Starting from day 4, the expression of nestin, neural cell adhesion molecule (NCAM), and beta-III tubulin shows a significant increase but then levels off after the first week of culture. The expression of specific neural cell markers glial fibrillary acidic protein (GFAP), 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase), and tyrosine hydroxylase (TH) is elevated during the second week of culture. This microengineering approach to control ESCs differentiation niche combined with the time-course protein expression analysis of individual differentiating colonies facilitates understanding of evolution of specific neural cells from ESCs and identifying underlying molecular markers. PMID- 26737063 TI - Real-time transmission of panoramic images for a telepresence wheelchair. AB - This paper proposes an approach to transmit panoramic images in real-time for a telepresence wheelchair. The system can provide remote monitoring and assistive assistance for people with disabilities. This study exploits technological advancement in image processing, wireless communication networks, and healthcare systems. High resolution panoramic images are extracted from the camera which is mounted on the wheelchair. The panoramic images are streamed in real-time via a wireless network. The experimental results show that streaming speed is up to 250 KBps. The subjective quality assessments show that the received images are smooth during the streaming period. In addition, in terms of the objective image quality evaluation the average peak signal-to-noise ratio of the reconstructed images is measured to be 39.19 dB which reveals high quality of images. PMID- 26737062 TI - Mimicking biophysical stimuli within bone tumor microenvironment. AB - In vivo, cells reside in a complex environment regulating their fate and function. Most of this complexity is lacking in standard in vitro models, leading to readouts falling short of predicting the actual in vivo situation. The use of engineering tools, combined with deep biological knowledge, leads to the development and use of bioreactors providing biologically sound niches. Such bioreactors offer new tools for biological research, and are now also entering the field of cancer research. Here we present the development and validation of a modular bioreactor system providing: (i) high throughput analyses, (ii) a range of biological conditions, (iii) high degree of control, and (iv) application of physiological stimuli to the cultured samples. The bioreactor was used to engineer a three-dimensional (3D) tissue model of cancer, where the effects of mechanical stimulation on the tumor phenotype were evaluated. Mechanical stimuli applied to the engineered tumor model activated the mechanotransduction machinery and resulted in measurable changes of mRNA levels towards a more aggressive tumor phenotype. PMID- 26737064 TI - A novel target following solution for the electric powered hospital bed. AB - The paper proposes a novel target following solution for an electric powered hospital bed. First, an improved real-time decoupling multivariable control strategy is introduced to stabilize the overall system during its operation. Environment laser-based data are then collected and pre-processed before engaging a neural network classifier for target detection. Finally, a high-level control algorithm is implemented to guarantee safety condition while the hospital bed tracks its target. The proposed solution is successfully validated through real time experiments. PMID- 26737065 TI - A robotic gait training system integrating split-belt treadmill, footprint sensing and synchronous EEG recording for neuro-motor recovery. AB - This paper presents a robotic gait training system for neuro-motor rehabilitation of hemiplegic stroke survivors. The system is composed of a treadmill consisting of two separated belts, footprint array sensor attached below each belt for gait data acquisition, and an electroencephalography (EEG) device for monitoring brain activities during gait training. The split belt treadmill allow physical therapists to set different treadmill belt velocities to modify physical workload of the patients during walking, thus being able to better improve the symmetry of gait phases between affected and unaffected (sound) legs in comparison with conventional treadmills where there is only one single belt. In contrast to in shoe pressure sensors, the under-belt footprint sensor array designed in this study not only reduces the preparation complexity of gait training but also collects more gait data for motion analysis. Recorded EEG is segmented synchronously with gait-related events. The processed EEG data can be used for monitoring brain-activities during gait training, providing a neurological approach for motion assessment. One subject with simulated stroke using an ankle foot orthosis participated in this study. Preliminary results indicate the feasibility of the proposed system to improve gait function and monitor neuro motor recovery. PMID- 26737066 TI - Stiffness-based tuning of an adaptive impedance controller for robot-assisted rehabilitation of upper limbs. AB - In this paper, the tuning procedure of an adaptive impedance control approach, for upper limb rehabilitation therapies assisted by robots, is presented. The main feature of the proposed approach is a custom tuning of the impedance parameters for the controller, based on the stiffness estimation of users (patients), thus achieving a suitable robot-assisted rehabilitation system according with the different conditions of user's mobility. A set of simulation results are presented, in order to verify the suitable performance of the proposed approach in human-robot interaction tasks. PMID- 26737067 TI - Evaluation of venous return in lower limb by passive ankle exercise performed by PHARAD. AB - This paper presents evaluation of venous return, i.e., blood flow volume of vein (BF), in the lower limb after passive exercise performed by our developed "parallel link type human ankle rehabilitation assistive device (PHARAD)". The PHARAD can perform complex passive exercises (plantar flexion/dorsiflexion, inversion/eversion, adduction/abduction, and combination of these motions) by reproducing input motions of a foot plate that is attached to a sole of foot. The passive exercise can be performed for not only rehabilitation but also prevention of deep vein thrombosis (DVT). In this study, we measured the concentration of Total hemoglobin (Total-Hb) using multi-channel near infra-red spectroscopy (NIRS)-based tissue oximeters and calculated a gradient of Total-Hb during a venous occlusion. We defined the gradient as BF and evaluated BF after 3 min passive exercise performed by the PHARAD comparing to BF of resting. Seven healthy young adult people were recruited for the experiment and we assessed passive exercise, active exercise, and walking. Experimental results show that BF after the passive exercises significantly increases compare to BF of resting and this indicates that passive exercises performed by the PHARAD increases BF and has a potential to prevent DVT. PMID- 26737068 TI - A tactile handle for cane use monitoring. AB - Assistive ambulatory devices are used for gait rehabilitation and assistance. In both cases, their benefit is greater when they are used properly. As for canes, embedded sensors can be used for monitoring purposes. In this paper, a custom tactile handle equipping a cane is described. It is composed of cost-effective commercially available pressure sensors. Experimental results involving 10 subjects show that the developed handle can provide information on the cane orientation as well as on the load applied to it during assisted gait. These data can help monitoring the cane usage and misuses detection. PMID- 26737069 TI - An ecological evaluation of the metabolic benefits due to robot-assisted gait training. AB - Cerebral palsy (CP), one of the most common neurological disorders in childhood, features affected individual's motor skills and muscle actions. This results in elevated heart rate and rate of oxygen uptake during sub-maximal exercise, thus indicating a mean energy expenditure higher than healthy subjects. Rehabilitation, currently involving also robot-based devices, may have an impact also on these aspects. In this study, an ecological setting has been proposed to evaluate the energy expenditure of 4 children with CP before and after a robot assisted gait training. Even if the small sample size makes it difficult to give general indications, results presented here are promising. Indeed, children showed an increasing trend of the energy expenditure per minute and a decreasing trend of the energy expenditure per step, in accordance to the control group. These data suggest a metabolic benefit of the treatment that may increase the locomotion efficiency of disabled children. PMID- 26737070 TI - Wrist proprioceptive acuity: A comprehensive robot-aided assessment. AB - Proprioception is the sense of the body awareness. Proprioceptive deficits represent frequent consequences of several neurological conditions like stroke, Parkinson's disease and others. The assessment of such somatosensory function is crucial, although the available clinical tests are not sensitive enough. The human wrist is a crucial joint for many activities of daily living and to address the lack of its characterization in terms of proprioceptive acuity the authors in previous studies proposed a novel method that combined the use of a 3-DoF robot and a threshold haunting paradigm. Further experiments were performed to characterize the proprioceptive acuity of the dominant wrist for adduction, extension, pronation and supination by using a 2-alternative-forced-choice test. The acuity thresholds obtained from six subjects (mean values +/- standard deviation of 1.65+/-0.39 for extension, 1.13+/-0.34 for adduction, 1.90+/-0.58 for pronation and 1.70+/-0.30 for supination) were finally combined with the ones harvested in the previous studies for flexion and abduction in order to build the first comprehensive database of human wrist proprioceptive acuity. PMID- 26737071 TI - Preliminary analysis of non-dominant proprioceptive acuity and interlimb asymmetry in the human wrist. AB - Proprioception provides information about limb configuration which are essential for planning and controlling its posture and movement. Asymmetries in the way dominant and non-dominant limbs exploit proprioceptive information have been previously evaluated, with contradictory results due to the difference in the employed methodology. A measure of proprioceptive acuity that does not reflect the influence of one limb on the other consists in the evaluation of the psychophysical threshold. This metric, evaluated separately for each limb and involving only passive movements, reflects a reliable measure of proprioceptive acuity. The aim of this work is to first evaluate the proprioceptive acuity of the non-dominant wrist joint in flexion/extension and adduction/abduction and to compare these results to the acuity of the dominant wrist. Data were collected during a unidirectional 2-alternative-forcedchoice test performed by six right handed subjects. We found acuity of 1.31 degrees , 1.26 degrees , 1.33 degrees and 1.63 degrees respectively for abduction, adduction, extension and flexion of the non-dominant wrist. Acuity of the dominant wrist was assessed for five of the subjects for abduction and flexion and resulted lower (mean values were respectively 1.64 degrees and 2.14 degrees ). The preliminary results suggest a leading role of the non-dominant wrist in the processing of the proprioceptive feedback. PMID- 26737072 TI - An intelligent control framework for robot-aided resistance training using hybrid system modeling and impedance estimation. AB - This study presents a novel therapy control method for robot-assisted resistance training using the hybrid system modeling technology and the estimated patient's bio-impedance changes. A new intelligent control framework based on hybrid system theory is developed, to automatically generate the desired resistive force and to make accommodating emergency behavior, when monitoring the changes of the impaired limb's muscle strength or the unpredictable safety-related occurrences during the execution of the training task. The impaired limb's muscle strength progress is online evaluated using its bio-damping and bio-stiffness estimation results. The proposed method is verified with a custom constructed therapeutic robot system featuring a Barrett WAMTM compliant manipulator. A typical inpatient stroke subject was recruited and enrolled in a ten-week resistance training program. Preliminary results show that the proposed therapeutic strategy can enhance the impaired limb's muscle strength and has practicability for robot aided rehabilitation training. PMID- 26737073 TI - Initial investigation into the effect of an Active/Passive exoskeleton on hammer curl performance in healthy subjects. AB - Assistive robotic devices are traditionally constrained by their power source. Entirely passive devices exist, but are limited by their fixed mechanical parameters. This work introduces a new device that can provide active and passive assistance. This device provides assistance in a passive mode, but retains the actively change this passive response. This paper examines the effect different passive parameter settings have on healthy subjects performing hammer curls. Passive parameter settings to either increase or decrease the number of curls a subject could perform were found. An average increase of 84% or a decrease of 33% in curls was produced by varying the passive parameters. These effects were seen across all six subjects. This indicates that there is potential for the Active/Passive framework to provide lightweight, energy efficient assistance. PMID- 26737074 TI - Estimating EMG signals to drive neuromusculoskeletal models in cyclic rehabilitation movements. AB - A main challenge in the development of robotic rehabilitation devices is how to understand patient's intentions and adapt to his/her current neuro-physiological capabilities. A promising approach is the use of electromyographic (EMG) signals which reflect the actual activation of the muscles during the movement and, thus, are a direct representation of user's movement intention. However, EMGs acquisition is a complex procedure, requiring trained therapists and, therefore, solutions based on EMG signals are not easily integrable in devices for home rehabilitation. This work investigates the effectiveness of a subject- and task specific EMG model in estimating EMG signals in cyclic plantar-dorsiflexion movements. Then, the outputs of this model are used to drive CEINMS toolbox, a state-of-the-art EMG-driven neuromusculoskeletal model able to predict joint torques and muscle forces. Preliminary results show that the proposed methodology preserves the accuracy of the estimates values. PMID- 26737075 TI - Beyond astronaut's capabilities: The current state of the art. AB - Space agencies have developed extensive expertise with sustaining human presence in low earth orbits and microgravity. Prolonged human presence in space beyond EarthaAZs orbit presents additional, some still unsolved issues. These are linked to the distance to Earth (impossibility of effective tele-operation, psychological effects linked to remoteness from Earth, required autonomy, the handling of emergencies, long mission durations), and to the environments beyond the Earth magnetosphere (radiation levels, local environments including atmospheres, dust, gravity, day-night cycles). These issues have impacts on the spacecraft design, the mission operations, astronaut selection and preparation and required supporting/ enabling technologies. This paper builds upon previous work by Rossini et al. , in critically reviewing and updating the current state of scientific research on enhancing astronaut's capabilities to face some of these challenges. In particular, it discusses the pertinence and feasibility of two approaches aiming at enhancing the chances of success of human missions: induced hibernation state and brain-machine interfaces. PMID- 26737076 TI - Design and development of a bio-inspired, under-actuated soft gripper. AB - The development of robotic devices able to perform manipulation tasks mimicking the human hand has been assessed on large scale. This work stands in the challenging scenario where soft materials are combined with bio-inspired design in order to develop soft grippers with improved grasping and holding capabilities. We are going to show a low-cost, under-actuated and adaptable soft gripper, highlighting the design and the manufacturing process. In particular, a critical analysis is made among three versions of the gripper with same design and actuation mechanism, but based on different materials. A novel actuation principle has been implemented in both cases, in order to reduce the encumbrance of the entire system and improve its aesthetics. Grasping and holding capabilities have been tested for each device, with target objects varying in shape, size and material. Results highlight synergy between the geometry and the intrinsic properties of the soft material, showing the way to novel design principles for soft grippers. PMID- 26737077 TI - A biorobotic model of the human larynx. AB - This work focuses on a physical model of the human larynx that replicates its main components and functions. The prototype reproduces the multilayer vocal folds and the ab/adduction movements. In particular, the vocal folds prototype is made with soft materials whose mechanical properties have been obtained to be similar to the natural tissue in terms of viscoelasticity. A computational model was used to study fluid-structure interaction between vocal folds and the airflow. This tool allowed us to make a comparison between theoretical and experimental results. Measurements were performed with this prototype in an experimental platform comprising a controlled air flow, pressure sensors and a high-speed camera for measuring vocal fold vibrations. Data included oscillation frequency at the onset pressure and glottal width. Results show that the combination between vocal fold geometry, mechanical properties and dimensions exhibits an oscillation frequency close to that of the human vocal fold. Moreover, computational results show a high correlation with the experimental one. PMID- 26737078 TI - Self-entrainment to optimal gaits of an underactuated biomimetic swimming robot using adaptive frequency oscillators. AB - Underactuated compliant swimming robots are characterized by a simple mechanical structure, capable to mimic the body undulation of many fish species. One of the design issue for these robots is the generation and control of best performing swimming gaits. In this paper we propose a new controller, based on AFO oscillators, to address this issue. After analyzing the effects of the motion on the robot natural frequencies, we show that the closed loop system is able to generate self-sustained oscillations, at a characteristic frequency, while maximizing swimming velocity. PMID- 26737079 TI - Magnetically driven microrobotic system for cancer cell manipulation. AB - Lab-on-a-chip applications, such as single cell manipulation and targeted delivery of chemicals, could greatly benefit from mobile untethered microdevices able to move in fluidic environments by using magnetic fields. In this paper a magnetically driven microrobotic system enabling the controlled locomotion of objects placed at the air/liquid interface is proposed and exploited for cell manipulation. In particular authors report the design, fabrication and testing of a polymeric thin film-based magnetic microrobot (called "FilmBot") used as a support for navigating cancer cells. By finely controlling magnetic film locomotion, it is possible to navigate the cells by exploiting their adhesion to the film without affecting their integrity. Preliminary in vitro tests demonstrated that the magnetic thin film is able to act as substrate for T24 bladder cancer cells without affecting their viability and that film locomotion can be magnetically controlled (with a magnetic field and a gradient of 6 mT and 0.6 T/m, respectively) along specific directions, with a mean speed of about 3 mm/s. PMID- 26737080 TI - Anticipation of brain shift in Deep Brain Stimulation automatic planning. AB - Deep Brain Stimulation is a neurosurgery procedure consisting in implanting an electrode in a deep structure of the brain. This intervention requires a preoperative planning phase, with a millimetric accuracy, in which surgeons decide the best placement of the electrode depending on a set of surgical rules. However, brain tissues may deform during the surgery because of the brain shift phenomenon, leading the electrode to mistake the target, or moreover to damage a vital anatomical structure. In this paper, we present a patient-specific automatic planning approach for DBS procedures which accounts for brain deformation. Our approach couples an optimization algorithm with FEM based brain shift simulation. The system was tested successfully on a patient-specific 3D model, and was compared to a planning without considering brain shift. The obtained results point out the importance of performing planning in dynamic conditions. PMID- 26737081 TI - Planning screw insertion trajectory in lumbar spinal fusion using pre-operative CT images. AB - Spinal fusion permanently connects two or more vertebrae in spine to improve stability, correct a deformity or reduce pain by immobilizing the vertebrae through pedicle screw fixation. Pedicle screws should be inserted very carefully to prevent possible irrecoverable damages to the spinal cord. Surgeons use CT/fluoroscopic images to find how to insert the screws safely. However, there is still human error, as determining precise trajectory in 3D space is difficult because of asymmetric structure of pedicle. In this study we attempt to propose a shape based method to help the surgeons to find the more accurate and safe path for screw insertion that minimizes the risk or invasiveness of the surgery using pre-operative CT images. We extracted two features for insertion paths from CT images, named "safety margin" and "pedicular screw fixation strength". By using weighted k-means different paths were clustered and compared with each other. Results of comparison between those paths obtained from surgeon's pre-operative planning, intra operative and the proposed method proves a great improvement on the rate of success in reaching a suitable insertion trajectory by using our method. It is observed that the risk of damage in intra operative stage can be potentially high and it can be reduced considerably by using the proposed planning approach. PMID- 26737082 TI - Shoulder-Mounted Robot for MRI-guided arthrography: Accuracy and mounting study. AB - A new version of our compact and lightweight patient-mounted MRI-compatible 4 degree-of-freedom (DOF) robot for MRI-guided arthrography procedures is introduced. This robot could convert the traditional two-stage arthrography procedure (fluoroscopy-guided needle insertion followed by a diagnostic MRI scan) to a one-stage procedure, all in the MRI suite. The results of a recent accuracy study are reported. A new mounting technique is proposed and the mounting stability is investigated using optical and electromagnetic tracking on an anthropomorphic phantom. Five volunteer subjects including 2 radiologists were asked to conduct needle insertion in 4 different random positions and orientations within the robot's workspace and the displacement of the base of the robot was investigated during robot motion and needle insertion. Experimental results show that the proposed mounting method is stable and promising for clinical application. PMID- 26737083 TI - Enhancing professionalism among engineering students through involvements in technical societies. AB - A student chapter can be considered to be a miniature enterprise; however without the latter's major financial risks. Involvement in the student chapter of a professional society like IEEE at undergraduate level plays a pivotal role in the overall professional development of the student by keeping the students informed about the various career possibilities. A student chapter shapes the hitherto naive students into industry ready professionals and to suitable candidates for some of the best grad schools worldwide. This assertion has been discussed in depth taking the example of IEEE EMBS Student Branch chapter of VIT University. It has been described how the entire process, - starting from inception of an idea to its materialization in to an activity, has shaped the volunteers and participants into better professionals. PMID- 26737084 TI - Walking cycle control for an active ankle prosthesis with one degree of freedom monitored from a personal computer. AB - This paper proposes a fuzzy control algorithm for human walking cycle of an active ankle prosthesis for people who have suffered amputation of the lower limb, the system has one degree of freedom in the sagittal plane. Also, a biomechanical analysis of foot and ankle is shown to define the phases of plantar support and swinging. The used actuator is an intelligent servomotor, Dynamixel MX-106T which has torque, current and position feedback, among others, allowing real-time telemetry of the prototype implemented in a microcontroller system. PMID- 26737085 TI - Complete factorial design experiment for 3D load cell instrumented crank validation. AB - Developing of instrumentation systems for sport medicine is a promising area, that's why this research evaluates the design of a new instrumented crank arm prototype for a race bicycle projecting an experiment for indoor - outdoor comparison. This study investigated the viability of an instrumentation 3D load cell for force measurement crank, implementing a design of experiment. A Complete factorial design experiment was developed for data validation, with an Analysis of Variance (ANOVA) throwing significant results for controlled factors with response variables rms, mean and variance. A software routine allowed to obtained system variables metrics for Symmetry and Cadence analysis, which came out from Effective force bilateral comparing and speed computation. Characterization allowed achieving calibration curves that were used for data conversion in force projection channels with a linearity error of 0.29% (perpendicular), 0.55% (parallel) and 0.10% (lateral). Interactions of factors resulted significant mainly for indoor tests in symmetry and cadence was significant in interactions generally for outdoor tests. Implemented system was able to generate Effective Force graph for 3D plot symmetry analysis, torque and power symmetry for specialist's analysis. PMID- 26737086 TI - An assessment strategy for proposals of engineering projects in the Bachelor of Biomedical Engineering Curriculum at Universidad Autonoma Metropolitana Iztapalapa. AB - Since 1974, the Bachelor of Biomedical Engineering Program (BBME) is offered at Universidad Autonoma Metropolitana-Iztapalapa, in Mexico City. By design, it must be completed in four years (12 trimesters) and, in the latter three, the senior students work on a BME project, which is done by completing three modules: Project Seminar (PS), Project on BME I and Project on BME II. In the PS module, the student must find a problem of interest in the BME field and suggest a solution through the development of an Engineering Project Proposal (EPP). Currently, the module is being taught by two faculty members of the BBME, who instruct students on how to develop their EPPs and evaluate their progress by reviewing a number of EPPs during the trimester. This generates a huge workload for the module instructors, which makes it necessary to involve more faculty members trimester-to-trimester (i.e. every 12 weeks) and, therefore, to create a set of systematic guidelines that ease the evaluation process for new instructors. Hence, the purpose of this paper is to present an assessment strategy (in the form of an assessment matrix) for the PS module as well as some preliminary results after two trimesters of its implementation. PMID- 26737087 TI - Closed loop control of a robot assisted smart flexible needle for percutaneous intervention. AB - This paper presents the experimental evaluation of a coordinated control system for a robot and robot-driven shape memory alloy (SMA) actuated smart flexible needle capable of following a curved path for percutaneous intervention. The robot driving the needle is considered the outer loop and the non-linear SMA actuated flexible needle system comprises the inner loop. The two feedback control loops are coordinated in such a way that the robot drives the needle while monitoring the needle's actual deflection against a preplanned ideal trajectory, so that the needle tip reaches the target location within an acceptable accuracy. In air and in water experimental results are presented to validate the ability of the proposed coordinated controller to track the overall desired trajectory which includes the combined trajectory of the robot driver and the needle. PMID- 26737088 TI - Student teaching and research laboratory focusing on brain-computer interface paradigms--A creative environment for computer science students. AB - This paper presents an applied concept of a brain-computer interface (BCI) student research laboratory (BCI-LAB) at the Life Science Center of TARA, University of Tsukuba, Japan. Several successful case studies of the student projects are reviewed together with the BCI Research Award 2014 winner case. The BCI-LAB design and project-based teaching philosophy is also explained. Future teaching and research directions summarize the review. PMID- 26737089 TI - Instrumented and interactive limb models for biomechanics education: An assessment of efficacy and engagement. AB - Custom anatomical and instrumented models of the human arm and leg were designed and manufactured to complement the teaching of introductory biomechanics subjects. The models were assessed for engagement and efficacy via questionnaires and unscheduled pop-quizzes, respectively. Questionnaire results demonstrated the ability of the models to provide assistance with understanding and visualising the fundamental principles of biomechanics. Additionally, the majority of students who participated also stated that the models enhanced their motivation to learn and stimulated their interest in biomechanics. Results from the pop quizzes were ambiguous about the efficacy of the arm and leg models; only one group (out of five) showed significant improvements in pop-quiz scores following exposure to the models. Significance was not reached in the remaining groups. Further assessment is required to expose the true efficacy of the models. PMID- 26737090 TI - Italy-Japan international project-based learning for developing human resources using design of welfare equipment as a subject. AB - Project-based learning (PBL) is effective for developing human resources of young students. The design of welfare equipment, such as wheelchairs and gait assistive devices, is taken as the subject in this study because these devices must be fit to their environment, users, and method of use; students must consider the circumstances of each country concerned. The program commenced in 2012 at L'Aquila, Italy, and the Shibaura Institute of Technology, Japan and has been continuing for three years. Students were divided into four groups and discussions were held on how to adapt the equipment to the user and environment. After discussion, they designed and simulated a model of the equipment using CAD. Finally, they presented their designs to each other. Through the program, students had fruitful discussions, exchanged ideas from different cultures, and learned from each other. Furthermore, friendships among the students were nurtured. It is believed that the objective of the program was satisfactorily accomplished. PMID- 26737091 TI - Surviving sepsis--a 3D integrative educational simulator. AB - Computer technology offers greater educational possibilities, notably simulation and virtual reality. This paper presents a technology which serves to integrate multiple modalities, namely 3D virtual reality, node-based simulator, Physiomodel explorer and explanatory physiological simulators employing Modelica language and Unity3D platform. This emerging tool chain should allow the authors to concentrate more on educational content instead of application development. The technology is demonstrated through Surviving sepsis educational scenario, targeted on Microsoft Windows Store platform. PMID- 26737092 TI - Experiences in teaching of modeling and simulation with emphasize on equation based and acausal modeling techniques. AB - This work introduces experiences of teaching modeling and simulation for graduate students in the field of biomedical engineering. We emphasize the acausal and object-oriented modeling technique and we have moved from teaching block-oriented tool MATLAB Simulink to acausal and object oriented Modelica language, which can express the structure of the system rather than a process of computation. However, block-oriented approach is allowed in Modelica language too and students have tendency to express the process of computation. Usage of the exemplar acausal domains and approach allows students to understand the modeled problems much deeper. The causality of the computation is derived automatically by the simulation tool. PMID- 26737093 TI - Open Biomedical Engineering education in Africa. AB - Despite the virtual revolution, the mainstream academic community in most countries remains largely ignorant of the potential of web-based teaching resources and of the expansion of open source software, hardware and rapid prototyping. In the context of Biomedical Engineering (BME), where human safety and wellbeing is paramount, a high level of supervision and quality control is required before open source concepts can be embraced by universities and integrated into the curriculum. In the meantime, students, more than their teachers, have become attuned to continuous streams of digital information, and teaching methods need to adapt rapidly by giving them the skills to filter meaningful information and by supporting collaboration and co-construction of knowledge using open, cloud and crowd based technology. In this paper we present our experience in bringing these concepts to university education in Africa, as a way of enabling rapid development and self-sufficiency in health care. We describe the three summer schools held in sub-Saharan Africa where both students and teachers embraced the philosophy of open BME education with enthusiasm, and discuss the advantages and disadvantages of opening education in this way in the developing and developed world. PMID- 26737094 TI - Experimental and credentialing capital: an adaptable framework for facilitating science outreach for underrepresented youth. AB - Increasing the numbers of black, latino and native youth in STEM careers is both an important way to reduce poverty in low income communities, and a contribution to the diversity of thought and experience that drives STEM research. But underrepresented youth are often alienated from STEM. Two new forms of social capital have been identified that can be combined to create a learning environment in which students and researchers can meet and explore an area of shared interest. Experimental capital refers to the intrinsic motivation that students can develop when they learn inquiry techniques for exploring topics that they feel ownership over. Credentialing capital denotes a shared interest and ability between all parties engaged in the experimental endeavor. These two forms of social capital form an adaptable framework for researchers to use to create effective outreach programs. In this case study sports biomechanics was utilized as the area of shared interest and understanding the slam dunk was used as experimental capital. PMID- 26737095 TI - A virtual surgical training system that simulates cutting of soft tissue using a modified pre-computed elastic model. AB - This work presents a surgical training system that incorporates cutting operation of soft tissue simulated based on a modified pre-computed linear elastic model in the Simulation Open Framework Architecture (SOFA) environment. A precomputed linear elastic model used for the simulation of soft tissue deformation involves computing the compliance matrix a priori based on the topological information of the mesh. While this process may require a few minutes to several hours, based on the number of vertices in the mesh, it needs only to be computed once and allows real-time computation of the subsequent soft tissue deformation. However, as the compliance matrix is based on the initial topology of the mesh, it does not allow any topological changes during simulation, such as cutting or tearing of the mesh. This work proposes a way to modify the pre-computed data by correcting the topological connectivity in the compliance matrix, without re-computing the compliance matrix which is computationally expensive. PMID- 26737096 TI - Early illness recognition using frequent motif discovery. AB - Living alone in their own residence, older adults are at risk for late assessment of physical or cognitive changes due to many factors such as their impression that such changes are simply a normal part of aging or their reluctance to admit to a problem. This paper describes an early illness recognition framework using sensor network technology to identify the health trajectory of older adults reflected in patterns of day-today activities. Describing the behavior of older adults could help clinicians to identify those at the greatest risk for functional decline and adverse events. The proposed framework, denoted as Abnormal Frequent Activity Pattern (AFAP), is based on the identification of known past abnormal frequent activities in current sensor data. More specifically, AFAP declares a day abnormal when past frequent abnormal behavior patterns, not found during normal days, are discovered in the current activity data. While AFAP requires the labeling of past days as normal/abnormal, it doesn't need specific activity identification. Frequent activity patterns (FAP) are found using MEME, a bioinformatics motif detection algorithm. To validate our approach, we used data obtained from TigerPlace, an aging in place community situated in Columbia, MO, where apartments are equipped with sensor networks (motion, bed and depth sensors). A retrospective multiple case study (N=3) design was used to quantify the in-home older adult's daily routines, over a period of two weeks. Within-person variability of routine activities may be used as a new predictor in the study of health trajectories of older adults. PMID- 26737097 TI - Preliminary results of using inertial sensors to detect dementia- related wandering patterns. AB - We present a solution for detecting dementia-related travel patterns using only inertial sensors. The results and lessons learnt from the experiments on dementia and non-dementia subjects are reported. PMID- 26737098 TI - Slightly superior performance of bioimpedance spectroscopy over single frequency regression equations for assessment of total body water. AB - Electrical bioimpedance has been used for several decades to assess body fluid distribution and body composition by using single frequency and bioimpedance spectroscopic (BIS) techniques. It remains uncertain whether BIS methods have better performance compare to single frequency regression equations. In this work the performance of two BIS methods and four different 50 kHz single frequency prediction equations was studied in a data set of wrist-to-ankle tetrapolar BIS measurements (5-1000 kHz) together with reference values of total body water obtained by tritium dilution in 92 patients. Data were compared using regression techniques and Bland-Altman plots. The results of this study showed that all methods produced similarly high correlation and concordance coefficients, indicating good accuracy as a method. Limits of agreement analysis indicated that the population level performance of Sun's prediction equations was very similar to the performance of both BIS methods. However, BIS methods in practice have slightly better predictive performance than the single-frequency equations as judged by higher correlation and the limits of agreement from the Bland-Altman analysis. In any case, the authors believe that an accurate evaluation of performance of the methods cannot be done as long as the evaluation is done using Bland-Altman analysis, the commonly accepted technique for this kind of performance comparisons. PMID- 26737099 TI - Extraction of facial features as indicators of stress and anxiety. AB - Stress and anxiety heavily affect the human wellbeing and health. Under chronic stress, the human body and mind suffers by constantly mobilizing all of its resources for defense. Such a stress response can also be caused by anxiety. Moreover, excessive worrying and high anxiety can lead to depression and even suicidal thoughts. The typical tools for assessing these psycho-somatic states are questionnaires, but due to their shortcomings, by being subjective and prone to bias, new more robust methods based on facial expression analysis have emerged. Going beyond the typical detection of 6 basic emotions, this study aims to elaborate a set of facial features for the detection of stress and/or anxiety. It employs multiple methods that target each facial region individually. The features are selected and the classification performance is measured based on a dataset consisting 23 subjects. The results showed that with feature sets of 9 and 10 features an overall accuracy of 73% is reached. PMID- 26737100 TI - Extraction of traditional COP-based features from COM sway in postural stability evaluation. AB - Postural control during quiet standing is evaluated by analyzing CoP sway, easily measured using a force platform. However, recent proliferation of motion tracking systems made easily available an estimate of the CoM location. Traditional CoP based measures presented in literature provide information about age-related changes in postural stability and fall risk. We investigated, on an age-matched group of subjects, the relationship between classical CoP-based measures computed on sway path and statistical mechanics parameters on diffusion plot, with those extracted from CoM time-series. Our purpose is to understand which of these parameters, computed on CoM sway, can discriminate postural abnormalities, in order to use a video tracking system to evaluate balance in addition to motor capabilities. PMID- 26737101 TI - Continuous real-world gait monitoring in community-based older adults. AB - This paper describes the collection of real-world gait data in a cohort of 7 community living older adults, who have fallen at least once in the previous year, while they live in a smart apartment for four days. It describes the approach used to collect various gait metrics, from inertial sensors placed on the lower shanks, where gait bouts can be contextualised by smart home data. Results from this study are presented with a brief discussion into the smart-home based contextualisation of outliers in the gait data. Future work will investigate the normative ranges of various gait metrics, and how such real-world gait data may be integrated into clinical practice. PMID- 26737102 TI - FreeWalker: a smart insole for longitudinal gait analysis. AB - Gait analysis is an important diagnostic measure to investigate the pattern of walking. Traditional gait analysis is generally carried out in a gait lab, with equipped force and body tracking sensors, which needs a trained medical professional to interpret the results. This procedure is tedious, expensive, and unreliable and makes it difficult to track the progress across multiple visits. In this paper, we present a smart insole called FreeWalker, which provides quantitative gait analysis outside the confinement of traditional lab, at low- cost. The insole consists of eight pressure sensors and two motion tracking sensors, i.e. 3-axis accelerometer and 3-axis gyroscope. This enables measurement of under-foot pressure distribution and motion sequences in real-time. The insole is enabled with onboard SD card as well as wireless data transmission, which help in continuous gait-cycle analysis. The data is then sent to a gateway, for analysis and interpretation of data, using a user interface where gait features are graphically displayed. We also present validation result of a subject's left foot, who was asked to perform a specific task. Experiment results show that we could achieve a data-sampling rate of over 1 KHz, transmitting data up to a distance of 20 meter and maintain a battery life of around 24 hours. Taking advantage of these features, FreeWalker can be used in various applications, like medical diagnosis, rehabilitation, sports and entertainment. PMID- 26737103 TI - Fall-detection solution for mobile platforms using accelerometer and gyroscope data. AB - Falls are a major health risk that diminish the quality of life among elderly people. Apart from falls themselves, most dramatic consequences are usually related with long lying periods that can cause serious side effects. These findings call for pervasive long-term fall detection systems able to automatically detect falls. In this paper, we propose an effective fall detection algorithm for mobile platforms. Using data retrieved from wearable sensors, such as Inertial Measurements Units (IMUs) and/or SmartPhones (SPs), our algorithm is able to detect falls using features extracted from accelerometer and gyroscope. While mostly of the mobile-based solutions for fall management deal only with accelerometer data, in the proposed approach we combine the instantaneous acceleration magnitude vector with changes of the user's heading in a Threshold Based Algorithm (TBA). In such a way, we were able to handle falls detection with minimal computational load, increasing the overall system accuracy with respect to traditional fall management methods. Experimental results show the strong detection performance of the proposed solution in discriminating between falls and typical Activities of Daily Living (ADLs) presenting fall-like acceleration patterns. PMID- 26737104 TI - Robotic psychophysics system for assessment, diagnosis and rehabilitation of the neurological causes of falls in the elderly. AB - Falls are the leading causes of unintentional injuries in the elderly and thus a pose a major hazard to our ageing society. We present the FOHEPO (FOot HEight POsitioning) system to measure, diagnose and eventually rehabilitate ageing related neurological causes of falls. We hypothesise that both perceptual and motor variability is likely to increase with age and may lead to imprecise perception and movements causing trip overs, the major triggers of falls. Our robotic experimental system automatically measures and tracks different sources of noise in the nervous system: visual perception noise of obstacle height, proprioceptive noise of localising raising one's foot to a desired height, noise in the visual feedback of the foot movements. We developed age-appropriate psychophysical measurement protocols shorter than standard protocols for perceptual and motor accuracy. These quantify individual subjects perceptual and movement accuracy thresholds through their psychometric curves. Therefore, these platform measurements will enable us to estimate fall probabilities quantitatively, i.e. the chance that a foot will clip an obstacle because subjects did not add a sufficient safety factor when clearing it. Potentially, we can use our FOHEPO system in a game-ified setting to rehabilitate elderly users to move with larger safety factors so as to reduce their risks of trip-over. PMID- 26737105 TI - Characterization of wrist-wearable activity measurement using whole body calorimetry in semi-free living conditions. AB - Physical activity (PA) is a significant factor in a number of health conditions and monitoring PA can play a significant role in the treatment of, or research into, these conditions. For longitudinal monitoring of PA, unobtrusive devices are often used and there is a need for the development of energy expenditure (EE) estimation techniques from single-device systems. This paper presents an experiment designed to characterize the relationship between a previously described technique, the activity score (AS) and EE obtained from whole-room indirect calorimetry. The study used 8 participants over a 24-hr period with interspersed exercise periods to observe physical movement with wearable devices and EE in 5 minute epochs. Results show that AS and EE are correlated with a Spearman's rank correlation coefficient of 0.775 with p <; 0.001. PMID- 26737106 TI - Monitoring physiology and behavior using Android in phobias. AB - In this paper, we present an Android-based system Application - AWARE - for the assessment of the person's physiology and behavior outside of the laboratory. To accomplish this purpose, AWARE delivers context dependent audio-visual stimuli, embedded into the subject's real-world perception, via marker/vision-based augmented reality (AR) technology. In addition, it employs external measuring resources connected via Bluetooth, as well as the smartphone's integrated resources. It synchronously acquires the experiment's video (camera input with AR overlay), physiologic responses (with a dedicated ECG measuring device) and behavior (through movement and location, with accelerometer/gyroscope and GPS, respectively). Psychological assessment is heavily based on laboratory procedures, even though it is known that these settings disturb the subjects' natural reactions and condition. The major idea of this application is to evaluate the participant condition, mimicking his/her real life conditions. Given that phobias are rather context specific, they represent the ideal candidate for assessing the feasibility of a mobile system application. AWARE allowed presenting AR stimuli (e.g., 3D spiders) and quantifying the subjects' reactions non-intrusively (e.g., heart rate variation) - more emphatic in the phobic volunteer when presented with spider vs non phobic stimulus. Although still a proof of concept, AWARE proved to be flexible, and straightforward to setup, with the potential to support ecologically valid monitoring experiments. PMID- 26737107 TI - Novel textile systems for the continuous monitoring of vital signals: design and characterization. AB - In this article we present a smart textile system for the continuous monitoring of cardiorespiratory signals, produced and integrated with an industrial embroidery unit. The design of a T-shirt system, having embedded textile sensors and interconnects and custom designed circuit for data collection and Bluetooth transmission is presented. The performance of skin-contact textile electrodes, having distinctive electrical characteristics and surface morphologies, was characterized by measurements of signal to noise ratio, under dry and moisture conditions. The influence of the electrodes size and the wear resistance were addressed. Results of an electrocardiogram acquisition with a subject wearing the T-shirt and display on a smartphone are also shown. The presented smart textile systems exhibit good performance and versatility for custom demand production. PMID- 26737108 TI - Implementation of smart phone video plethysmography and dependence on lighting parameters. AB - The remote measurement of heart rate (HR) and heart rate variability (HRV) via a digital camera (video plethysmography) has emerged as an area of great interest for biomedical and health applications. While a few implementations of video plethysmography have been demonstrated on smart phones under controlled lighting conditions, it has been challenging to create a general scalable solution due to the large variability in smart phone hardware performance, software architecture, and the variable response to lighting parameters. In this context, we present a selfcontained smart phone implementation of video plethysmography for Android OS, which employs both stochastic and deterministic algorithms, and we use this to study the effect of lighting parameters (illuminance, color spectrum) on the accuracy of the remote HR measurement. Using two different phone models, we present the median HR error for five different video plethysmography algorithms under three different types of lighting (natural sunlight, compact fluorescent, and halogen incandescent) and variations in brightness. For most algorithms, we found the optimum light brightness to be in the range 1000-4000 lux and the optimum lighting types to be compact fluorescent and natural light. Moderate errors were found for most algorithms with some devices under conditions of low brightness (<;500 lux) and highbrightness (>4000 lux). Our analysis also identified camera frame rate jitter as a major source of variability and error across different phone models, but this can be largely corrected through non linear resampling. Based on testing with six human subjects, our real-time Android implementation successfully predicted the measured HR with a median error of -0.31 bpm, and an inter-quartile range of 2.1bpm. PMID- 26737109 TI - Unconstrained detection of freezing of Gait in Parkinson's disease patients using smartphone. AB - Freezing of gait (FOG) is a common motor impairment to suffer an inability to walk, experienced by Parkinson's disease (PD) patients. FOG interferes with daily activities and increases fall risk, which can cause severe health problems. We propose a novel smartphone-based system to detect FOG symptoms in an unconstrained way. The feasibility of single device to sense gait characteristic was tested on the various body positions such as ankle, trouser pocket, waist and chest pocket. Using measured data from accelerometer and gyroscope in the smartphone, machine learning algorithm was applied to classify freezing episodes from normal walking. The performance of AdaBoost.M1 classifier showed the best sensitivity of 86% at the waist, 84% and 81% in the trouser pocket and at the ankle respectively, which is comparable to the results of previous studies. PMID- 26737110 TI - ARTSENSTouch--A portable device for evaluation of carotid artery stiffness. AB - Arterial stiffness is recognized as an independent risk factor for cardiovascular events and has potential in vascular screening. We have developed 'ARTSENS((r))', an image free system for evaluation of vascular stiffness. Here, we present ARTSENSTouch, a portable device for evaluation of carotid artery stiffness in field settings. A technical validation of the device in comparison with reference ultrasound imaging system is presented. The validation study emulated constraints faced in evaluation of stiffness in field, such as measurement in sitting posture, use of brachial blood pressure for computations, limited time available for testing and lack of electrical power supply for instrument. The usability of the device and its accuracy, with respect to the reference ultrasound imaging system, was verified by conducting in-vivo measurements on 30 subjects. Stiffness measurements made using ARTSENS in sitting posture showed strong correlation with those obtained from the imaging system in supine posture. The repeatability of ARTSENS measurements was also found to be satisfactory. PMID- 26737111 TI - Investigating cell culture dynamics combining high density recordings with dimensional reduction techniques. AB - High density multielectrode array recordings with CMOS-MEAs allow to monitor cell culture activity with unprecedent details respect to previous recording techniques. This is clarifying how network activity develops and is motivating the development of novel data analysis tools. Here, in order to advance in the exploitation of the richness of these large-scale array recordings, we introduce a principal component analysis approach that aims at improving on existing methodologies to describe neural activity events within large networks. PMID- 26737112 TI - High-density MEA recordings unveil the dynamics of bursting events in Cell Cultures. AB - High density multielectrode arrays (MEAs) based on CMOS technology (CMOS-MEAs) can simultaneously record extracellular spiking activity in neuronal cultures from 4096 closely spaced microelectrodes. This allows for a finer investigation of neuronal network activity compared to conventional MEAs with a few tens of electrodes. However, the sensing properties of these devices differ. To highlight this aspect, here we investigate and discuss the differences observed when quantifying spontaneous synchronized bursting events (SBEs) in datasets acquired with conventional MEAs and high-density MEAs from comparable hippocampal cultures. We found that datasets acquired with high-density MEAs exhibit collective dynamics similar to conventional arrays, but are characterized by a higher percentage of random spikes, i.e. spikes that are not part of a burst, most probably resulting from the larger recording capability. Additionally, the percentage of electrodes that record a burst is remarkably small on high-density MEAs compared to what can be observed on conventional MEAs and SBEs appear to be propagating in time across the electrode array, by involving shorter sequences of spikes per electrode. Overall, these results highlight a lower level of network synchronization involved in SBEs compared to what has been debated for several decades based on conventional MEA recordings from cell cultures. PMID- 26737113 TI - A Step towards EEG-based brain computer interface for autism intervention. AB - Autism Spectrum Disorder (ASD) is a prevalent and costly neurodevelopmental disorder. Individuals with ASD often have deficits in social communication skills as well as adaptive behavior skills related to daily activities. We have recently designed a novel virtual reality (VR) based driving simulator for driving skill training for individuals with ASD. In this paper, we explored the feasibility of detecting engagement level, emotional states, and mental workload during VR-based driving using EEG as a first step towards a potential EEG-based Brain Computer Interface (BCI) for assisting autism intervention. We used spectral features of EEG signals from a 14-channel EEG neuroheadset, together with therapist ratings of behavioral engagement, enjoyment, frustration, boredom, and difficulty to train a group of classification models. Seven classification methods were applied and compared including Bayes network, naive Bayes, Support Vector Machine (SVM), multilayer perceptron, K-nearest neighbors (KNN), random forest, and J48. The classification results were promising, with over 80% accuracy in classifying engagement and mental workload, and over 75% accuracy in classifying emotional states. Such results may lead to an adaptive closed-loop VR-based skill training system for use in autism intervention. PMID- 26737114 TI - Multi-Unit Activity contains information about spatial stimulus structure in mouse primary visual cortex. AB - This study investigates the spatial and directional tuning of Multi-Unit Activity (MUA) in mouse primary visual cortex and how MUA can reflect spatiotemporal structures contained in moving gratings. Analysis of multi-shank laminar electrophysiological recordings from mouse primary visual cortex indicates a directional preference for moving gratings around 180 degrees , while preferred spatial frequency peaks around 0.02 cycles per degree, which is similar as reported in single-unit studies. Using only features from MUA, we further achieved a significant performance in decoding spatial frequency or direction of moving gratings, with average decoding performances of up to 58.54% for 8 directions, and 44% correctly identified spatial frequencies against chance level of 16.7%. PMID- 26737115 TI - Optimized echo state networks with leaky integrator neurons for EEG-based microsleep detection. AB - The performance of a microsleep detection system was calculated in terms of its ability to detect the behavioural microsleep state (1-s epochs) from spectral features derived from 16-channel EEG sampled at 256 Hz. Best performance from a single classifier model was achieved using leaky integrator neurons on an echo state network (ESN) classifier with a mean phi correlation (phi) of 0.38 and accuracy of 67.3%. A single classifier model of ESN with sigmoidal inputs achieved phi of 0.20 and accuracy of 48.5% and a single classifier model of linear discriminant analysis (LDA) achieved phi of 0.31 and accuracy of 53.6%. However, combining the output of several single classifier models (ensemble learning) via stacked generalization of the ESN with leaky integrator neurons approach led to a substantial increase in detection performance of phi of 0.51 and accuracy of 81.2%. This is a substantial improvement of our previous best result of phi = 0.39 on this data with LDA and stacked generalization. PMID- 26737116 TI - Characteristics of thalamic local field potentials in patients with disorders of consciousness. AB - A functioning thalamus is essential for treatment of patients with disorders of consciousness (DOC) using deep brain stimulation (DBS). This work aims to identify the potential biomarkers related to consciousness from the thalamic deep brain local field potentials (LFPs) in DOC patients. The frequency features of central thalamic LFPs were characterized with spectral analysis. The features were further compared to those of LFPs from the ventroposterior lateral nucleus of the thalamus (VPL) in patients with pain. There are several distinct characteristics of thalamic LFPs found in patients with DOC. The most important feature is the oscillation around 10Hz which could be relevant to the existence of residual consciousness, whereas high power below 8Hz seemed to be associated with loss of consciousness. The invasive deep brain recording tool opens a unique way to explore the brain function in consciousness, awareness and alertness and clarify the potential mechanisms of thalamic stimulation in DOC. PMID- 26737117 TI - Atrial sources identification by causality analysis during atrial fibrillation. AB - Ablation of electrical drivers during atrial fibrillation (AF) has been proved as an effective therapy to prevent recurrence of fibrillatory episodes. This study presents a new methodology based on causality analysis that is able to identify the hierarchical dominance of atrial areas driving AF. Realistic mathematical models of the atrial electrical activity during AF were used to assess the validity of our method. Identification of the dominant atrial propagation patterns was achieved by computing causal relations between multiple electrogram signals. The causal relationships between atrial areas during the fibrillatory processes were summarized into a recurrence map, highlighting the hierarchy and dominant areas. Recurrence maps computed from causality analysis allowed the identification of sites responsible for maintenance of the arrhythmia. These maps were able to locate the position of the atrial driver in fibrillatory processes with a single rotor, with 2 rotors or with several drivers. Additionally, the correspondence between the nodal values of the recurrence map and the distance to the rotor core has been established. Causal analysis consistently estimated propagation patterns and location of atrial drivers during AF. This methodology could guide ablation procedures in AF patients. PMID- 26737118 TI - A new algorithm for neural connectivity estimation of EEG event related potentials. AB - We propose a new algorithm for estimating neural connectivity during event related potentials (ERP) in EEG. It is composed of two steps: the estimation of a time-varying multivariate-autoregressive (MVAR) model and the calculation of the generalized partial directed coherence (gPDC) for assessing the connectivities between channels where MVAR estimation is done via an adapted version of the Nuttall-Strand algorithm, a multivariate generalization of Burg's spectral estimation algorithm. Successful algorithm validation was performed through simulations using toys model with physiologically ERP inspired features. PMID- 26737119 TI - Effect of inter-trials variability on the estimation of cortical connectivity by Partial Directed Coherence. AB - Partial Directed Coherence (PDC) is a powerful estimator of effective connectivity. In neuroscience it is used in different applications with the aim to investigate the communication between brain regions during the execution of different motor or cognitive tasks. When multiple trials are available, PDC can be computed over multiple realizations, provided that the assumption of stationarity across trials is verified. This allows to improve the amount of data, which is an important constraint for the estimation accuracy. However, the stationarity of the data across trials is not always guaranteed, especially when dealing with patients. In this study we investigated how the inter-trials variability of an EEG dataset affects the PDC accuracy. Effects of density variations and of changes of connectivity values across trials were first investigated with a simulation study and then tested on real EEG data collected from two post-stroke patients during a motor imagery task and characterized by different inter-trials variability. Results showed the effect of different factors on the PDC accuracy and the robustness of such estimator in a range of conditions met in practical applications. PMID- 26737120 TI - Globally conditioned causality in estimating directed brain-heart interactions through joint MRI and RR series analysis. AB - We used 7T fMRI with simultaneous physiological signals acquisitions to investigate the causal interactions from resting state brain activity to autonomic nervous system (ANS) outflow as quantified through a probabilistic heartbeat model. Given the highly redundant nature of brain-derived signals, we compare the results of traditional bivariate Granger Causality (GC) to a globally conditioned approach which evaluates the additional influence of each brain region on ANS activity while factoring out effects concomitantly mediated by other brain regions. The bivariate approach results in an unrealistically large number of spurious causal brain-heart links. In contrast, using the globally conditioned approac, we demonstrate the existence of significant selective causal links between cortical/subcortical brain regions and ANS outflow for sympathetic and parasympathetic modulation as well as sympathovagal balance, with a prominent involvement of frontal, parietal, and cerebellar regions and Sensory Motor, Default Mode, Left and Right executive networks. Provided proper conditioning is employed to eliminate spurious causalities, 7T functional imaging coupled with physiological signal acquisition and GC analysis is able to quantify directed brain-heart interactions reflecting central modulation of ANS outflow. PMID- 26737121 TI - Causal relationships in the variability of cardiovascular system evoked by orthostatic stress by transfer entropy. AB - The coupling between cardiac and vascular systems in healthy volunteers, elicited by the head-up tilt test is estimated by means of transfer entropy with non uniform embedding. The method applied to beat-to-beat recordings with heart periods and systolic blood pressure, supports the commonly accepted model, that baroreflex is the key factor in maintaining homeostatic blood distribution after tilting. However the method applied to changes of heart periods and changes of blood pressure, display switches in the driving system, from vascular in the early tilt, to cardiac just after the early tilt and back to vascular in the late tilt. PMID- 26737122 TI - Reduction of EEG artifacts in simultaneous EEG-fMRI: Reference layer adaptive filtering (RLAF). AB - Although simultaneous measurement of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) is one of the most valuable methods for studying human brain activity non-invasively, it remains challenging to measure high quality EEG inside the MRI scanner. Recently, a new approach for minimizing residual MRI scanner artifacts in the EEG was presented: reference layer artifact subtraction (RLAS). Here, reference electrodes capture only the artifacts, which are subsequently subtracted from the measurement electrodes. With the present work we demonstrate that replacing the subtraction by adaptive filtering statistically significantly outperforms RLAS. Reference layer adaptive filtering (RLAF) attenuates the average artifact root-mean-square (RMS) voltage of the passive MRI scanner to 0.7 MUV (-14.4 dB). RLAS achieves 0.78 MUV (-13.5 dB). The combination of average artifact subtraction (AAS) and RLAF reduces the residual average gradient artifact RMS voltage to 2.3 MUV (-49.2 dB). AAS alone achieves 5.7 MUV (-39.0 dB). All measurements were conducted with an MRI phantom, as the reference layer cap available to us was a prototype. PMID- 26737123 TI - Simple method for adaptive filtering of motion artifacts in E-textile wearable ECG sensors. AB - In this paper, we have developed a simple method for adaptive out-filtering of the motion artifact from the electrocardiogram (ECG) obtained by using conductive textile electrodes. The textile electrodes were placed on the left and the right wrist to measure ECG through lead-1 configuration. The motion artifact was induced by simple hand movements. The reference signal for adaptive filtering was obtained by placing additional electrodes at one hand to capture the motion of the hand. The adaptive filtering was compared to independent component analysis (ICA) algorithm. The signal-to-noise ratio (SNR) for the adaptive filtering approach was higher than independent component analysis in most cases. PMID- 26737124 TI - ECG De-noising: A comparison between EEMD-BLMS and DWT-NN algorithms. AB - Electrocardiogram (ECG) is a widely used non-invasive method to study the rhythmic activity of the heart and thereby to detect the abnormalities. However, these signals are often obscured by artifacts from various sources and minimization of these artifacts are of paramount important. This paper proposes two adaptive techniques, namely the EEMD-BLMS (Ensemble Empirical Mode Decomposition in conjunction with the Block Least Mean Square algorithm) and DWT NN (Discrete Wavelet Transform followed by Neural Network) methods in minimizing the artifacts from recorded ECG signals, and compares their performance. These methods were first compared on two types of simulated noise corrupted ECG signals: Type-I (desired ECG+noise frequencies outside the ECG frequency band) and Type-II (ECG+noise frequencies both inside and outside the ECG frequency band). Subsequently, they were tested on real ECG recordings. Results clearly show that both the methods works equally well when used on Type-I signals. However, on Type-II signals the DWT-NN performed better. In the case of real ECG data, though both methods performed similar, the DWT-NN method was a slightly better in terms of minimizing the high frequency artifacts. PMID- 26737125 TI - Estimation of heart rate and heart rate variability from pulse oximeter recordings using localized model fitting. AB - Heart rate variability is one of the key parameters for assessing the health status of a subject's cardiovascular system. This paper presents a local model fitting algorithm used for finding single heart beats in photoplethysmogram recordings. The local fit of exponentially decaying cosines of frequencies within the physiological range is used to detect the presence of a heart beat. Using 42 subjects from the CapnoBase database, the average heart rate error was 0.16 BPM and the standard deviation of the absolute estimation error was 0.24 BPM. PMID- 26737126 TI - Evaluation of adaptive PARAFAC alogorithms for tracking of simulated moving brain sources. AB - In this paper, we proposed an online 2D localization method for tracking of dynamic moving brain sources. For this purpose, we used an adaptive version of PARAllel FACtor (PARAFAC) analysis for factorization of electroencephalographic (EEG) signals. We utilized Boundary Element Method (BEM) with four layers to solve the forward problem for the simulated EEG signals caused by two moving dipoles within the brain. Then, we created an appropriate tensor built by second order statistics of EEG signals. We adopted an online method to brain source localization called the Recursive Least Squares Tracking (RLST) as an adaptive PARAFAC algorithm with two windowing schemes. Finally, we evaluated the performance of the method applied to EEG signals. PMID- 26737127 TI - Power line interference attenuation in multi-channel sEMG signals: Algorithms and analysis. AB - Electromyogram (EMG) recordings are often corrupted by power line interference (PLI) even though the skin is prepared and well-designed instruments are used. This study focuses on the analysis of some of the recent and classical existing digital signal processing approaches have been used to attenuate, if not eliminate, the power line interference from EMG signals. A comparison of the signal to interference ratio (SIR) of the output signals is presented, for four methods: classical notch filter, spectral interpolation, adaptive noise canceller with phase locked loop (ANC-PLL) and adaptive filter, applied to simulated multichannel monopolar EMG signals with different SIR. The effect of each method on the shape of the EMG signals is also analyzed. The results show that ANC-PLL method gives the best output SIR and lowest shape distortion compared to the other methods. Classical notch filtering is the simplest method but some information might be lost as it removes both the interference and the EMG signals. Thus, it is obvious that notch filter has the lowest performance and it introduces distortion into the resulting signals. PMID- 26737128 TI - Use of digital image correlation and ultrasound: analysis of thigh muscle displacement fields. AB - The understanding of the mechanical behavior of the muscle tissue is an important field of investigation with different applications in medicine, car crash and sport. Currently, few in vivo imaging techniques are able to characterize the mechanical properties of muscle. Thus, the development of an in vivo identification method is a current thematic where the displacement field measurements could be used for further interpretations. This study aims at presenting the displacement fields measured in the anterior, posterior, lateral and medial parts of the thigh muscles using ultrasound and Digital Image Correlation (DIC) techniques. The results of the displacement field measurements confirmed and are correlated with the ultrasound observations. PMID- 26737129 TI - Enabling real-time ultrasound imaging of soft tissue mechanical properties by simplification of the shear wave motion equation. AB - Ultrasound based shear wave elastography (SWE) is a technique used for non invasive characterization and imaging of soft tissue mechanical properties. Robust estimation of shear wave propagation speed is essential for imaging of soft tissue mechanical properties. In this study we propose to estimate shear wave speed by inversion of the first-order wave equation following directional filtering. This approach relies on estimation of first-order derivatives which allows for accurate estimations using smaller smoothing filters than when estimating second-order derivatives. The performance was compared to three current methods used to estimate shear wave propagation speed: direct inversion of the wave equation (DIWE), time-to-peak (TTP) and cross-correlation (CC). The shear wave speed of three homogeneous phantoms of different elastic moduli (gelatin by weight of 5%, 7%, and 9%) were measured with each method. The proposed method was shown to produce shear speed estimates comparable to the conventional methods (standard deviation of measurements being 0.13 m/s, 0.05 m/s, and 0.12 m/s), but with simpler processing and usually less time (by a factor of 1, 13, and 20 for DIWE, CC, and TTP respectively). The proposed method was able to produce a 2-D speed estimate from a single direction of wave propagation in about four seconds using an off-the-shelf PC, showing the feasibility of performing real-time or near real-time elasticity imaging with dedicated hardware. PMID- 26737130 TI - Edge-preserving ultrasonic strain imaging with uniform precision. AB - Ultrasound elastography involves measuring the mechanical properties of tissue, and has many applications in diagnostics and intervention. A common step in different elastography methods is imaging the tissue while it undergoes deformation and estimating the displacement field from the images. A popular next step is to estimate tissue strain, which gives clues into the underlying tissue elasticity modulus. To estimate the strain, one should compute the gradient of the displacement image, which amplifies the noise. The noise is commonly minimized by least square estimation of the gradient from multiple displacement measurements, which reduces the noise by sacrificing image resolution. In this work, we adaptively adjust the level and orientation of the smoothing using two different mechanisms. First, the precision of the displacement field decreases significantly in the regions with high signal decorrelation, which requires increasing the smoothness. Second, smoothing the strain field at the boundaries between different tissue types blurs the edges, which can render small targets invisible. To minimize blurring and noise, we perform anisotropic smoothing parallel to the direction of edges. The first mechanism ensures that textures/variations in the strain image reflect underlying tissue properties and are not caused by errors in the displacement estimation. The second mechanism keeps the edges between different tissue structures sharp while minimizing the noise. We validate the proposed method using phantom and in-vivo clinical data. PMID- 26737131 TI - Effects of data acquisition parameters on the quality of sonoelastographic imaging. AB - Sonoelastography is an ultrasonic technique that provides qualitative and quantitative images of tissue elasticity. Even though the Kasai variance estimator is a key part of the sonoelastographic image formation, there are no studies that demonstrate that its performance using discrete time signals and finite sized ensemble lengths is optimal. In this work, the influence of the selection of acquisition parameters (pulse repetition frequency or PRF, vibration frequency, and ensemble length) on the quality of the elastograms is studied. Simulations are carried out to define the optimal PRF and ensemble length given a vibration frequency in order to avoid artifacts which can severely degrade image quality. This empirical criterion is supported by sonoelastography experiments performed using two commercial scanners, where the variability increased from 4% to 42% at the worst selection of acquisition parameters. Although a further mathematical proof of the empirical findings is required, these results suggest that careful selection of PRF, vibration frequency and ensemble lengths is required to ensure unbiased sonoelastograms. PMID- 26737132 TI - An experimental phantom study on the effect of calcifications on ultrasound shear wave elastography. AB - In this study, we investigated the effects of single macrocalcifications and groups of microcalcifications on shear wave elastography. Supersonic shear imaging (SSI) and comb-push ultrasound shear elastography (CUSE) were performed on three sets of phantoms to investigate how calcifications of different sizes and distributions influence measured elasticity. Our results demonstrate that the presence of large isolated macrocalcifications and highly concentrated clusters of microcalcifications can introduce areas with apparent high elasticity when they are evaluated by shear wave elastography. PMID- 26737133 TI - A new shear wave imaging system for ultrasound elastography. AB - Ultrasound elastography is able to provide a non-invasive measurement of tissue elasticity properties. Shear wave imaging (SWI) technique is a quantitative method for tissue stiffness assessment. However, traditional SWI implementations cannot acquire 2D quantitative images of tissue elasticity distribution. In this study, a new shear wave imaging system is proposed and evaluated. Detailed delineation of hardware and image processing algorithms are presented. Programmable devices are selected to support flexible control of the system and the image processing algorithms. Analytic signal based cross-correlation method and a Radon transform based shear wave speed determination method are proposed with parallel computation ability. Tissue mimicking phantom imaging, and in vitro imaging measurements are conducted to demonstrate the performance of the proposed system. The system has the ability to provide a new choice for quantitative mapping of the tissue elasticity, and has good potential to be implemented into commercial ultrasound scanner. PMID- 26737134 TI - Robust supervised segmentation of neuropathology whole-slide microscopy images. AB - Alzheimer's disease is characterized by brain pathological aggregates such as Abeta plaques and neurofibrillary tangles which trigger neuroinflammation and participate to neuronal loss. Quantification of these pathological markers on histological sections is widely performed to study the disease and to evaluate new therapies. However, segmentation of neuropathology images presents difficulties inherent to histology (presence of debris, tissue folding, non specific staining) as well as specific challenges (sparse staining, irregular shape of the lesions). Here, we present a supervised classification approach for the robust pixel-level classification of large neuropathology whole slide images. We propose a weighted form of Random Forest in order to fit nonlinear decision boundaries that take into account class imbalance. Both color and texture descriptors were used as predictors and model selection was performed via a leave one-image-out cross-validation scheme. Our method showed superior results compared to the current state of the art method when applied to the segmentation of Abeta plaques and neurofibrillary tangles in a human brain sample. Furthermore, using parallel computing, our approach easily scales-up to large gigabyte-sized images. To show this, we segmented a whole brain histology dataset of a mouse model of Alzheimer's disease. This demonstrates our method relevance as a routine tool for whole slide microscopy images analysis in clinical and preclinical research settings. PMID- 26737135 TI - Efficient segmentation of skin epidermis in whole slide histopathological images. AB - Segmentation of epidermis areas is an important step towards automatic analysis of skin histopathological images. This paper presents a robust technique for epidermis segmentation in whole slide skin histopathological images. The proposed technique first performs a coarse epidermis segmentation using global thresholding and shape analysis. The epidermis thickness is then estimated by a series of line segments perpendicular to the main axis of the initially segmented epidermis mask. If the segmented epidermis mask has a thickness greater than a predefined threshold, the segmentation is suspected to be inaccurate. A second pass of fine segmentation using k-means algorithm is then carried out over these coarsely segmented result to enhance the performance. Experimental results on 64 different skin histopathological images show that the proposed technique provides a superior performance compared to the existing techniques. PMID- 26737136 TI - Automatic segmentation of zona pellucida and its application in cleavage-stage embryo biopsy position selection. AB - A very important step of Pre-implantation genetic diagnosis (PGD) is embryo biopsy, in which process the zona pellucida (ZP) is cut open partially and a part of cellular material is extracted from the embryo. Recognition of the ZP is necessary not only for embryo biopsy, but also for other applications such as zona pellucida thickness variation (ZPTV), embryo dissection, etc. The ZP opening position is closely related to the cell survival rate after the biopsy. Selection of an unsuitable position may cause blastomere lysis after the ZP opening. Normal procedures of ZP recognition and biopsy position selection involve a skilled human embryologist. In order to make the process automatic, we introduce an automatic segmentation method for ZP recognition by using edge detection and ellipse fitting with a value adjustment algorithm in this paper. An application of ZP recognition in embryo biopsy position selection is also introduced. Our ZP recognition algorithm was able to correctly segment 43 out of 45 sample embryo images, achieving a success rate of 96%. Its application in embryo biopsy position selection achieved a success rate of 93%. PMID- 26737137 TI - A multi-stage random forest classifier for phase contrast cell segmentation. AB - We present a machine learning based approach to automatically detect and segment cells in phase contrast images. The proposed method consists of a multi-stage classification scheme based on random forest (RF) classifier. Both low level and mid level image features are used to determine meaningful cell regions. Pixel wise RF classification is first carried out to categorize pixels into 4 classes (dark cell, bright cell, halo artifact, and background) and generate a probability map for cell regions. K-means clustering is then applied on the probability map to group similar pixels into candidate cell regions. Finally, cell validation is performed by another RF to verify the candidate cell regions. The proposed method has been tested on U2-OS human osteosarcoma phase contrast images. The experimental results show better performance of the proposed method with precision 92.96% and recall 96.63% compared to a state-of-the-art segmentation technique. PMID- 26737138 TI - Automated segmentation of regions of interest in whole slide skin histopathological images. AB - In the diagnosis of skin melanoma by analyzing histopathological images, the epidermis and epidermis-dermis junctional areas are regions of interest as they provide the most important histologic diagnosis features. This paper presents an automated technique for segmenting epidermis and dermis regions from whole slide skin histopathological images. The proposed technique first performs epidermis segmentation using a thresholding and thickness measurement based method. The dermis area is then segmented based on a predefined depth of segmentation from the epidermis outer boundary. Experimental results on 66 different skin images show that the proposed technique can robustly segment regions of interest as desired. PMID- 26737139 TI - Bacterial foraging based edge detection for cell image segmentation. AB - Edge detection is the most popular and common choices for cell image segmentation, in which local searching strategies are commonly used. In spite of their computational efficiency, traditional edge detectors, however, may either produce discontinued edges or rely heavily on initializations. In this paper, we propose a bacterial foraging based edge detection (BFED) algorithm for cell image segmentation. We model the gradients of intensities as the nutrient concentration and propel bacteria to forage along nutrient-rich locations via mimicking the behavior of Escherichia coli, including the chemotaxis, swarming, reproduction, elimination and dispersal. As a nature-inspired evolutionary technique, this algorithm can identify the desired edges and mark them as the tracks of bacteria. We have evaluated the proposed algorithm against the Canny, SUSAN, Verma's and an active contour model (ACM) based edge detectors on both synthetic and real cell images. Our results suggest that the BFED algorithm can identify boundaries more effectively and provide more accurate cell image segmentation. PMID- 26737140 TI - Design and performance characterization of a hand orthosis prototype to aid activities of daily living in a post-stroke population. AB - This paper presents the design of a hand orthosis prototype intended to assist persons with hand paresis, as a result of stroke, perform activities of daily living. Among its attributes, the orthosis is characterized by a low mass and small profile, while still offering the power assistance of a robotic exoskeleton. Experimental characterization of the orthosis is presented, including its mass, envelope dimensions, motion bandwidth, and joint torque characteristics. PMID- 26737141 TI - Gastrocnemius myoelectric control of a robotic hip exoskeleton. AB - In this paper we present a novel EMG-based assistive control strategy for lower limb exoskeletons. An active pelvis orthosis (APO) generates torque profiles for the hip flexion motion assistance, according to the Gastrocnemius Medialis EMG signal. The strategy has been tested on one healthy subject: experimental results show that the user is able to reduce his muscular activation when the assistance is switched on with respect to the free walking condition. PMID- 26737142 TI - Compliant gait assistance triggered by user intention. AB - An automatic gait initialization strategy based on user intention sensing in the context of rehabilitation with a lower-limb wearable robot is proposed and evaluated. The proposed strategy involves monitoring the human-orthosis interaction torques and initial position deviation to determine the gait initiation instant and to modify orthosis operation for gait assistance, when needed. During gait, the compliant control algorithm relies on the adaptation of the joints' stiffness in function of their interaction torques and their deviation from the desired trajectories, while maintaining the dynamic stability. As a reference input, the average of a set of recorded gaits obtained from healthy subjects is used. The algorithm has been tested with five healthy subjects showing its efficient behavior in initiating the gait and maintaining the equilibrium while walking in presence of external forces. The work is performed as a preliminary study to assist patients suffering from incomplete Spinal cord injury and Stroke. PMID- 26737143 TI - Modeling and design of a tendon actuated soft robotic exoskeleton for hemiparetic upper limb rehabilitation. AB - Robotic technology has recently been explored as a means to rehabilitate and assist individuals suffering from hemiparesis of their upper limbs. Robotic approaches allow for targeted rehabilitation routines which are more personalized and adaptable while providing quantitative measurements of patient outcomes. Development of these technologies into inherently safe and portable devices has the potential to extend the therapy outside of the clinical setting and into the patient's home with benefits to the cost and accessibility of care. To this end, a soft, cable actuated robotic glove and sleeve was designed, modeled, and constructed to provide assistance of finger and elbow movements in a way that mimics the biological function of the tendons. The resulting design increases safety through greater compliance as well as greater tolerance for misalignment with the user's skeletal frame over traditional rigid exoskeletons. Overall this design provides a platform to expand and study the concepts around soft robotic rehabilitation. PMID- 26737144 TI - Fuzzy-logic-based hybrid locomotion mode classification for an active pelvis orthosis: Preliminary results. AB - In this paper, we present a fuzzy-logic-based hybrid locomotion mode classification method for an active pelvis orthosis. Locomotion information measured by the onboard hip joint angle sensors and the pressure insoles is used to classify five locomotion modes, including two static modes (sitting, standing still), and three dynamic modes (level-ground walking, ascending stairs, and descending stairs). The proposed method classifies these two kinds of modes first by monitoring the variation of the relative hip joint angle between the two legs within a specific period. Static states are then classified by the time-based absolute hip joint angle. As for dynamic modes, a fuzzy-logic based method is proposed for the classification. Preliminary experimental results with three able bodied subjects achieve an off-line classification accuracy higher than 99.49%. PMID- 26737145 TI - A Wearable Virtual Chair with the Passive Stability Assist. AB - This paper introduces a wearable device which performs function of swinging chair with worn status on the legs. The users with the proposed device can sit in anyplace and experience the stable swing motion. The device is designed to maintain the stability within the stable swing region while moving back and forth by external forces or user intension. The coupled motion between ankle and knee provides the users concave swing motion in chair mode, while the joints passively follows the motion of the legs in normal gait mode. The key feature of this stable motion is a CAM-drive implemented around the ankle frame and connected to the knee joint by wires. With any directional motion of the ankle joint, the knee joint rotate only one direction to lift up the body of the user. So it can move following concave equilibrium line. We verified the payload of the device is more than 70 kg in computer-aided stress simulation as well as in experiments. PMID- 26737146 TI - Simulation of high energy vertebral fractures on complete porcine specimens. AB - This work presents a novel method creating high energy vertebral fractures on complete swine specimens to investigate realistic vertebral fracture mechanisms. An apparatus was developed to maintain a porcine specimen in an upright position and apply a caudal impact simulating a fall. Five mature minipigs were impacted with varying impact magnitude. Computed tomography scans were used to assess the resulting fracture type, fracture level, spinal canal encroachment and fractures of adjacent bony structures. Lumbar fractures were produced on four specimens: three inferior endplate burst fractures (L2) and one superior endplate burst fracture (L5). One trial resulted in a hyperextension fracture between L2 and L3 vertebrae. Spinal canal encroachment was important for three specimens. No fracture was created on the pelvis or hind limbs. The proposed method developed and the resulting swine model of high energy vertebral fractures could be used to instigate novel biomechanical studies, to validate finite element models or to investigate surgical strategies. PMID- 26737147 TI - Lumbar load estimation using a musculoskeletal model in consideration of vertebral body displacement: Lumbar load simulation under static conditions. AB - In this study, we propose an estimation model of lumbar load, which is a factor in lumbar disorders. Our proposed method uses a musculoskeletal model with elastic elements between the vertebral bodies, and simulates the inter- vertebral disk pressure and the displacement of the vertebral bodies simultaneously. PMID- 26737148 TI - Calibration method for lumbosacral dimensions in wearable sensor system of lumbar alignment. AB - Anteflexion of the spine is essential for many physical activities in everyday life. However, this motion places the lumbar disks under heavy load due to changes in the shape of the lumbar spine and can lead to low back pain. With the aim of reducing low back pain, here we developed a wearable sensor system that can estimate lumbosacral alignment and lumbar load by measuring the shape of the lumbar skin when the lumbosacral alignment changes. In addition, we used this system to measure the parameters of anteflexion and studied the change in dimensions of the lumbar spine from changes in posture. By determining the dimensions of the lumbosacral spine on an X-ray image, a lumbosacral dimensions calibration method based on body surface area and height was developed. By using this method, lumbosacral alignment and lumbar load could be accurately estimated using the wearable sensor system. PMID- 26737149 TI - In-vitro assessment of the stabilization capacity of monolithic spinal rods with variable flexural stiffness: Methodology and examples. AB - The concept of a monolithic Ti-Ni spinal rod with variable flexural stiffness is proposed to reduce the risks associated with spinal fusion. The variable stiffness is conferred to the rod using the Joule-heating local annealing technique. To assess the stabilization capacity of such a spinal rod, in vitro experiments on porcine spine models are carried out. This paper describes the methodology followed to evaluate the effect of Ti-Ni rods compared to conventional titanium rods. Validation of the methodology and examples of results obtained are also presented. PMID- 26737150 TI - A Mechanical model for flexible exercise bars to study the influence of the initial position of the bar on lumbar discs and muscles forces. AB - A single-degree-of-freedom model is considered for flexible exercise bars based on the lumped-element approach. By considering the side segment of a flexible bar as a cantilever beam with an equivalent mass at the free end, its free-vibration response, as well as the forced response under the excitation of the grip, are expressed parametrically. Experiments are performed on a particular flexible bar (FLEXI_BAR) in order to obtain numerical values for quantifying the model's parameters. The model is also computationally simulated to study the response of the flexible bar to various excitations. The results are imported into a multi segment musculoskeletal software (AnyBody), where the effect of different initial hand positions on the lumbar disc and back muscle forces is investigated (including Longissimus, Iliocostalis, and Transversus) during up-down exercises. The results show that all intervertebral discs and muscles forces are more sensitive to the horizontal position of the bar as compared to its vertical position. PMID- 26737151 TI - A simulation study on marrow fat effect on biomechanics of vertebra bone. AB - Trabecular bone and bone marrow are main components of cancellous bone. Most mechanical studies for bone mainly focus on hard tissues, while if bone marrow contributes to bone biomechanics is not clear yet. This study was proposed to investigate marrow fat effect on trabecular bone biomechanics by simulation. Finite element (FE) bone models were established based on quantitative CT images at L3 lumbar spine, from which trabecular structures with and without marrow fat were investigated respectively. Auni-static compressive test was applied on the proposed models until to the appearance of fracture. Simulation results showed that trabecular models filled with marrow fat had about 3%-9% less maximum stress in volume than models with only trabeculae. However, its average stress in volume was about 9%-56% larger than those with only trabeculae. The strain energy density of the bone model with marrow fat showed a more uniformed distribution. As a conclusion, marrow fat has contributions to the bone mechanics. It can balance the stress distribution of the bone tissue, which may reduce bone deformation under a compressive loading. The mixture of trabecular structure and marrow fat would be against higher compress load before the failure point. PMID- 26737152 TI - Assessing neuro-motor recovery in a stroke survivor with high-resolution EEG, robotics and Virtual Reality. AB - One post-stroke patient underwent neuro-motor rehabilitation of one upper limb with a novel system combining a passive robotic device, Virtual Reality training applications and high resolution electroencephalography (HR-EEG). The outcome of the clinical tests and the evaluation of the kinematic parameters recorded with the robotic device concurred to highlight an improved motor recovery of the impaired limb despite the age of the patient, his compromised motor function, and the start of rehabilitation at the 3rd week post stroke. The time frequency and functional source analysis of the HR-EEG signals permitted to quantify the functional changes occurring in the brain in association with the rehabilitation motor tasks, and to highlight the recovery of the neuro-motor function. PMID- 26737153 TI - An arm for a leg: Adapting a robotic arm for gait rehabilitation. AB - The purpose of this study was to adapt a multipurpose robotic arm for gait rehabilitation. An advantage of this approach is versatility: a robotic arm can be attached to almost any point on the body to assist with lower- and upper extremity rehabilitation. This may be more cost-effective than purchasing and training rehabilitation staff to use several specialized rehabilitation robots. Robotic arms also have a more human-like morphology, which may make them less intimidating or alien to patients. In this study a mechanical interface was developed that allows a fast, secure, and safe attachment between a robotic arm and a human limb. The effectiveness of this interface was assessed by having two healthy subjects walk on a treadmill with and without a robotic arm attached to their legs. The robot's ability to follow the subjects' swinging legs was evaluated at slow and fast walking speeds. Two different control schemes were evaluated: one using the standard manufacturer-provided control algorithm, and another using a custom algorithm that actively compensated for robot-human interaction forces. The results showed that both robot control schemes performed well for slow walking. There were negligible differences between subjects' gait kinematics with and without the robot. During fast walking with the robot, similar results were obtained for one subject; however, the second subject demonstrated noticeable gait modifications. Together, these results show the feasibility of adapting a multipurpose robotic arm for gait rehabilitation. PMID- 26737154 TI - Pediatric rehabilitation with the reachMAN's modular handle. AB - This paper presents the results of a preliminary study with one cerebral palsy child using the ReHaptic Handle, a novel robotic device for the pediatric rehabilitation of upper limb function. The device has two degrees-of-freedom to train pinching, forearm supination/pronation and wrist flexion/extension movements. Interactive computer games have been implemented to increase subjects' participation and engagement, thus promoting motor recovery. Pinching, with the index finger and thumb, forearm supination/pronation as well as wrist flexion/extension were trained two or three times a week for 15 minutes each. An increase in forearm supination/pronation movement precision and smoothness was observed with the subject, as well as a reduction in the movement duration. PMID- 26737155 TI - A model of injury potential for myelinated nerve fiber. AB - Excellent models have been described in literatures which related membrane potential to extracellular electric or magnetic stimulation and which described the formation and propagation of action potentials along the axon, for both myelinated and nonmyelinated fibers. There is not, however, an adequate model for nerve injury which allows to compute the distribution of injury potential, a direct current potential difference between intact and injured nerve, because its importance has been ignored in the shadow of the well-known action potential. This paper focus on the injury potential and presents a model of the electrical properties of myelinated nerve which describes the time course of events following injury. The time-varying current and potential at all nodes can be computed from the model, and the factors relate to the amplitude of injury potential can be determined. It is shown that the amplitude of injury potential decreased gradually with injury time, and the recession curve was exponential. Results also showed that the initial amplitude of injury potential is positively related to the grade of injury and fiber diameter. This model explained the mechanism of formation of injury potential and can provide instruction for applied electric field to prevent the formation injury potential. PMID- 26737156 TI - Monitoring game-based motor rehabilitation of patients at home for better plans of care and quality of life. AB - This paper describes the biomedical, remote monitoring infrastructure developed and currently tested in the EU REHAB@HOME project to support home rehabilitation of the upper extremity of persons post-stroke and in persons with other neurological disorders, such as Multiple Sclerosis patients, in order to track their progress over therapy and improve their Quality of Life. The paper will specifically focus on describing the initial testing of the tele-rehabilitation system's components for patients' biomedical monitoring over therapy, which support the delivery and monitoring of more personalized, engaging plans of care by rehabilitation centers and services. PMID- 26737157 TI - The impact of visual feedback on the motor control of the upper-limb. AB - Stroke is a leading cause of adult disability with upper-limb hemiparesis being one of the most frequent consequences. Given that stroke only affects the paretic arm's control structure (the set of synergies and activation vectors needed to perform a movement), we propose that the control structure of the non-affected arm can serve as a physiological reference to rehabilitate the paretic arm. However, it is unclear how rehabilitation can effectively tune the control structure of a patient. The use of Visual Feedback (VF) is recommended to boost stroke rehabilitation, as it is able to positively modify neural mechanisms and improve motor performance. Thus, in this study we investigate whether VF can effectively modify the control structure of the upper-limb. We asked six neurologically intact subjects to perform a complete upper-limb rehabilitation routine comprised of 12 movements in absence and presence of VF. Our results indicate that VF significantly increases interlimb similarity both in terms of synergies and activation coefficients. However, the magnitude of improvement depended upon each subject. In general, VF brings the control structure of the nondominant side closer to the control structure of dominant side, suggesting that VF modifies the control structure towards more optimized motor patterns. This is especially interesting because stroke mainly affects the activation coefficients of patients and because it has been shown that the control of the affected side resembles that of the nondominant side. In conclusion, VF may enhance motor performance by effectively tuning the control-structure. Notably, this finding offers new insights to design improved stroke rehabilitation. PMID- 26737158 TI - Bidirectional neural interface: Closed-loop feedback control for hybrid neural systems. AB - Closed-loop neural prostheses enable bidirectional communication between the biological and artificial components of a hybrid system. However, a major challenge in this field is the limited understanding of how these components, the two separate neural networks, interact with each other. In this paper, we propose an in vitro model of a closed-loop system that allows for easy experimental testing and modification of both biological and artificial network parameters. The interface closes the system loop in real time by stimulating each network based on recorded activity of the other network, within preset parameters. As a proof of concept we demonstrate that the bidirectional interface is able to establish and control network properties, such as synchrony, in a hybrid system of two neural networks more significantly more effectively than the same system without the interface or with unidirectional alternatives. This success holds promise for the application of closed-loop systems in neural prostheses, brain machine interfaces, and drug testing. PMID- 26737159 TI - Comparison of sensorimotor rhythms in EEG signals during simple and combined motor imageries over the contra and ipsilateral hemispheres. AB - Imaginary motor tasks cause brain oscillations that can be detected through the analysis of electroencephalographic (EEG) recordings. This article aims at studying whether or not the characteristics of the brain activity induced by the combined motor imagery (MI) of both hands can be assumed as the superposition of the activity generated during simple hand MIs. After analyzing the sensorimotor rhythms in EEG signals of five healthy subjects, results show that the imagination of both hands movement generates in each brain hemisphere similar activity as the one produced by each simple hand MI in the contralateral side. Furthermore, during simple hand MIs, brain activity over the ipsilateral hemisphere presents similar characteristics as those observed during the rest condition. Thus, it is shown that the proposed scheme is valid and promising for brain-computer interfaces (BCI) control, allowing to easily detect patterns induced by combined MIs. PMID- 26737160 TI - A large scale simulation of excitation propagation in layer 2/3 of primary and secondary visual cortices of mice. AB - Analyzing network architecture and spatio-temporal dynamics of the visual cortical areas can facilitate understanding visual information processing in the brain. Recently, several physiological experiments utilizing the fast in-vivo imaging technique have demonstrated that the primary visual cortex (V1) and the secondary visual cortex (V2) in mice exhibit complex properties of the responses to visual and electrical stimuli. In order to provide a tool for quantitatively analyzing such a complex dynamics of the cortices at the level of neurons and circuits, here, we constructed a physiologically plausible large-scale network model of the layers 2/3 of V1 and V2, composed of 14,056 multi-compartment neuron models. The Message-Passing-Interface-based parallel simulations of our network model were able to reproduce, at least quantitatively, the neural responses experimentally observed in mouse V1 and V2 with the voltage-sensitive dye imaging. PMID- 26737161 TI - Sparse generalized volterra model of human hippocampal spike train transformation for memory prostheses. AB - In order to build hippocampal prostheses for restoring memory functions, we build multi-input, multi-output (MIMO) nonlinear dynamical models of the human hippocampus. Spike trains are recorded from the hippocampal CA3 and CA1 regions of epileptic patients performing a memory-dependent delayed match-to-sample task. Using CA3 and CA1 spike trains as inputs and outputs respectively, second-order sparse generalized Laguerre-Volterra models are estimated with group lasso and local coordinate descent methods to capture the nonlinear dynamics underlying the spike train transformations. These models can accurately predict the CA1 spike trains based on the ongoing CA3 spike trains and thus will serve as the computational basis of the hippocampal memory prosthesis. PMID- 26737162 TI - Topography-dependent spatio-temporal correlations in the entorhinal-dentate-CA3 circuit in a large-scale computational model of the Rat Hippocampus. AB - The correlation due to different topographies was characterized in a large-scale, biologically-realistic, computational model of the rat hippocampus using a spatio temporal correlation analysis. The effect of the topographical projection between the following subregions of the hippocampus was investigated: the entorhinal to dentate projection, the entorhinal to CA3 projection, and the mossy fiber to CA3 projection. Through this work, analysis was performed on the individual and combined effects of these projections on the activity of the principal neurons of the dentate gyrus and CA3. The simulations show that uncorrelated input transmitted through the entorhinal-to-dentate or entorhinal-to-CA3 projection causes spatio-temporally correlated activity in the principal neurons that manifest as spike clusters. However, if the mossy fiber system provides uncorrelated input to the CA3, then the CA3 activity remains uncorrelated. When considering the transfer of correlation through the dentate, this analysis suggests that the mossy fiber system do not imbue any correlation to the activity as it propagates from the granule cells of the dentate to the CA3. With the spatio-temporal correlation analysis, the influence of each topographical projection on the transfer of correlation can be investigated as additional subregions and neuron types are added to the large-scale model. PMID- 26737163 TI - Thermo-electrical equivalents for simulating the electro-mechanical behavior of biological tissue. AB - Equivalence is one of most popular techniques to simulate the behavior of systems governed by the same type of differential equation. In this case, a thermo electrical equivalence is considered as a method for modelling the inter dependence of electrical and mechanical phenomena in biological tissue. We seek to assess this approach for multi-scale models (from micro-structure to tissue scale) of biological media, such as nerve cells and cardiac tissue, in which the electrical charge distribution is modelled as a heat distribution in an equivalent thermal system. This procedure allows for the reduction in problem complexity and it facilitates the coupling of electrical and mechanical phenomena in an efficient and practical way. Although the findings of this analysis are mainly addressed towards the electro-mechanics of tissue within the biomedical domain, the same approach could be used in other studies in which a coupled finite element analysis is required. PMID- 26737164 TI - Critical assessment and outlook for the 50 biomedical engineering undergraduate programs in Mexico. AB - Biomedical Engineering (BME) has been taught in Mexico at the undergraduate level for over forty years. The rationale for the introduction of this profession was to help manage and maintain the growing technological infrastructure in the health care system during the seventies. Owing to this, it is not surprising that early versions of the BME curricula were oriented towards clinical engineering and medical instrumentation. In the last decade the number of programs has grown from three in the seventies and eighties to fifty at present. This work is the result of the analysis of the BME programs in all the institutions that offer this degree in Mexico. Three main issues were studied: the curricula, the sub disciplines that were emphasized in the programs and the job market. Results have shown a striking resemblance in most of the programs, which are mostly dedicated to teaching aspects of medical instrumentation and clinical engineering. These results reflect an agreement with the requirements of the job market, but since most job offerings are for low-paying positions in sales, service and hospital maintenance, we question the wisdom of stressing these sub-specialties at research universities, where faculties and research labs offer a wide variety of options. An analysis of work at these centers shows that most of the results are publications, so the need to emphasize translational research and partnerships with industry are suggested. PMID- 26737165 TI - A proposal to enhance Engineering education in biology and Medicine by following the legacy of Rene Favaloro. AB - The synergy amongst Engineering, Medicine and Biology evolves as fast as these disciplines. We propose to articulate these specialties based on the premise that new professionals must face different situations or crisis due to the so-called islands of excellence. Rene Favaloro focused his work and struggles against poverty, since malnutrition and environmental degradation may increase the propensity to cardiovascular diseases. Doctor Favaloro has dedicated, throughout his career, a considerable amount of time to prepare and qualify a research group, aware of the importance that an adequate working environment has over the final results. He created a team of young students, engineers, medical doctors, physicists, mathematicians and other specialists. He centered his attention on human resources, in order to disseminate his latest advances in Biology, Medicine and Engineering. We are revising the programs of biomedical engineering education and the application of new pedagogic paradigms, where critical thinking is the key: a holistic challenge that consists of a new way of learning, innovating, communicating and shearing, with a creative attitude that represents quality of perception. PMID- 26737166 TI - Influencing the job market by the quality of graduates--a biomedical engineering example. AB - Academic teaching of a new discipline, besides its contents and formal issues, requires participation of the university in development of a target job market. This was the case of biomedical engineering in Poland ten years ago. This paper presents examples of activities, taken up by our university in cooperation with prospective employers, and evaluated with a help of our first alumni. The evaluation survey shows that despite the immature job market, the number of graduates employed accordingly to their education systematically raises each year from 72,5% in 2011 to 93,8% in 2013. Another interesting result is the distribution of job searching period: 19.2% of graduates were already employed before the graduation, further 23.1% found their job in less than one month after the diploma examination and another 28.8% in less than three months. The paper also highlights the role the former graduates play in motivating teachers and students to efforts towards a better educational outcome. PMID- 26737167 TI - Design and implementation of a flipped classroom learning environment in the biomedical engineering context. AB - The design and implementation of a learning environment that leverages on the use of various technologies is presented. The context is an undergraduate core engineering course within the biomedical engineering curriculum. The topic of the course is data analysis in biomedical engineering problems. One of the key ideas of this study is to confine the most mathematical and statistical aspects of data analysis in prerecorded video lectures. Students are asked to watch the video lectures before coming to class. Since the classroom session does not need to cover the mathematical theory, the time is spent on a selected real world scenario in the field of biomedical engineering that exposes students to an actual application of the theory. The weekly cycle is concluded with a hands-on tutorial session in the computer rooms. A potential problem would arise in such learning environment if the students do not follow the recommendation of watching the video lecture before coming to class. In an attempt to limit these occurrences, two key instruments were put in place: a set of online self assessment questions that students are asked to take before the classroom session and a simple rewards system during the classroom session. Thanks to modern learning analytics tools, we were able to show that, on average, 57.9% of students followed the recommendation of watching the video lecture before class. The efficacy of the learning environment was assessed through various means. A survey was conducted among the students and the gathered data support the view that the learning environment was well received by the students. Attempts were made to quantify the impacts on learning of the proposed measures by taking into account the results of selected questions of the final examination of the course. Although the presence of confounding factors demands caution in the interpretation, these data seem to indicate a possible positive effect of the use of video lectures in this technologically enhanced learning environment. PMID- 26737168 TI - Modeling the LPS-induced effects on transcription factor activation and gene expression in murine macrophages. AB - Macrophages within the liver are of particular importance for a functional defense against bacterial infection. They exhibit a complex response to lipopolysaccharide and secrete a variety of pro-inflammatory cytokines and chemokines that both coordinate the immune response and regulate activity of the macrophages, themselves. In this context, the dynamic of pathway activation and gene expression is important for a better understanding of the role of activated macrophages in healthy and diseased states. Therefore, we present a representative model of LPS-induced macrophage activation that covers the principle regulatory motifs. Based on that, we propose a simplified model with a reduced number of states and parameters that allows estimation of transcription factor activity from gene expression data and can be easily extended to describe the full spectrum of gene regulation in LPS-activated macrophages. PMID- 26737169 TI - Selection and mutation in X-linked recessive diseases epidemiological model. AB - To describe the epidemiology of X-linked recessive diseases we developed a discrete time, structured, non linear mathematical model. The model allows for de novo mutations (i.e. affected sibling born to unaffected parents) and selection (i.e., distinct fitness rates depending on individual's health conditions). Applying Lyapunov direct method we found the domain of attraction of model's equilibrium point and studied the convergence properties of the degenerate equilibrium where only affected individuals survive. PMID- 26737170 TI - Identifying miRNA-mediated signaling subpathways by integrating paired miRNA/mRNA expression data with pathway topology. AB - In the road for network medicine the newly emerged systems-level subpathway-based analysis methods offer new disease genes, drug targets and network-based biomarkers. In parallel, paired miRNA/mRNA expression data enable simultaneously monitoring of the micronome effect upon the signaling pathways. Towards this orientation, we present a methodological pipeline for the identification of differentially expressed subpathways along with their miRNA regulators by using KEGG signaling pathway maps, miRNA-target interactions and expression profiles from paired miRNA/mRNA experiments. Our pipeline offered new biological insights on a real application of paired miRNA/mRNA expression profiles with respect to the dynamic changes from colostrum to mature milk whey; several literature supported genes and miRNAs were recontextualized through miRNA-mediated differentially expressed subpathways. PMID- 26737171 TI - MRI-guided epilepsy detection. AB - One of the most common neurological brain disorder is epilepsy that happen as an abrupt seizure. Around 30% of patients with epilepsy resist to all forms of medical treatments and, therefore, the removal of epileptic brain tissue is the only solution to get these patients free from chronical seizures. Discovering the epileptic region is a first key into the treatment. In this paper, we introduced a method for epilepsy detection. In this method superparamagnetic nanoparticle, (SPMN) is used as a sensing material in order to investigate the epileptic area. Based on the magnetic field, first they are crossed through the Blood Brain Barrier (BBB). They can cross the blood-brain barrier into the brain by means of magnetic forces. In this study, the optimal force for crossing to the brain and nanoparticles aggregation by means of MRI magnetic field for crossing and weak magnetic field inside the brain have been considered. Nanoparticles aggregation can be used as a marker to increase the contrast of MRI images in the epileptic brain area. PMID- 26737172 TI - Electrostatic study of Alanine mutational effects on transcription: application to GATA-3:DNA interaction complex. AB - Protein-DNA interaction is of fundamental importance in molecular biology, playing roles in functions as diverse as DNA transcription, DNA structure formation, and DNA repair. Protein-DNA association is also important in medicine; understanding Protein-DNA binding kinetics can assist in identifying disease root causes which can contribute to drug development. In this perspective, this work focuses on the transcription process by the GATA Transcription Factor (TF). GATA TF binds to DNA promoter region represented by 'G,A,T,A' nucleotides sequence, and initiates transcription of target genes. When proper regulation fails due to some mutations on the GATA TF protein sequence or on the DNA promoter sequence (weak promoter), deregulation of the target genes might lead to various disorders. In this study, we aim to understand the electrostatic mechanism behind GATA TF and DNA promoter interactions, in order to predict Protein-DNA binding in the presence of mutations, while elaborating on non-covalent binding kinetics. To generate a family of mutants for the GATA:DNA complex, we replaced every charged amino acid, one at a time, with a neutral amino acid like Alanine (Ala). We then applied Poisson-Boltzmann electrostatic calculations feeding into free energy calculations, for each mutation. These calculations delineate the contribution to binding from each Ala-replaced amino acid in the GATA:DNA interaction. After analyzing the obtained data in view of a two-step model, we are able to identify potential key amino acids in binding. Finally, we applied the model to GATA-3:DNA (crystal structure with PDB-ID: 3DFV) binding complex and validated it against experimental results from the literature. PMID- 26737173 TI - Evaluation of a plasma insulin model for glycaemic control in intensive care. AB - Hyperglycaemia is a common complication in the intensive care unit (ICU), and is associated with worsened outcomes. Model-based insulin therapy protocols have been shown to be safe and effective in intensive care. Such protocols rely on correct modeling of glucose-insulin dynamics. In particular, model-based control typically relies on insulin sensitivity (SI) metrics, which are heavily influenced by plasma insulin kinetics. Plasma insulin samples were taken as part of a sepsis study and compared to modeled plasma insulin. Samples were taken in septic patients at the onset of glycaemic control, and once the patient consistently met less than two of the SIRs criteria that help define sepsis. It was found that inter-patient insulin dynamics were more variable at the onset of insulin therapy, than in the later samples after sepsis abated. Overall, the model adequately captured crucial steady state dynamics. Transient dynamics in plasma insulin following a bolus were faster than modeled, indicating greater clearance of insulin than currently modeled. PMID- 26737174 TI - Inkjet printed ECG electrodes for long term biosignal monitoring in personalized and ubiquitous healthcare. AB - This paper investigates the performance of inkjet printed electrodes for electrocardiogram (ECG) monitoring in personalized and ubiquitous healthcare. As a rapid prototyping, additive manufacturing approach, inkjet printing can allow personalization of electrode sizes and shapes and can be used with a range of substrates to achieve good long term connections to the skin. We compare the performance of two types of inkjet electrodes printed using different substrates. Results demonstrate that both new electrodes can record ECG information, with comparable signal-to-noise ratios to conventional Ag/AgCl electrodes. The time frequency decomposition of the collected signals is also explored. PMID- 26737175 TI - Real-time sensing, transmission and analysis for vital signs of persons during exercises. AB - Real-time monitoring of vital signs from persons during exercises is useful from the medical, healthcare and sports physiological points of view. In professional team sports, physical trainers or technical coaches want to manage the physical conditions of athletes during exercise training in the grounds, on the other hand, in elementary and junior high schools, teachers want to take care of schoolchildren during physical training. In realization of the vital signs monitoring, there are three technical problems to be solved. The first is how to accurately sense vital signs, the second is how to reliably transmit them by wireless, and the third is how to identify factors effective for disease screening, injury prevention, performance analysis and talent identification. In this paper, we present the necessity of real-time monitoring of vital signs from persons during exercises, introduce solutions for the problems which we have so far worked out, and point out remaining technical problems. PMID- 26737176 TI - Psychobehavioral validity of self-reported symptoms based on spontaneous physical activity. AB - A limitation of self-reports is the presence of recall biases including retrospective distortions of the respondents' experiences. To overcome this concern, ecological momentary assessment (EMA) and day reconstruction method (DRM) have recently been developed. Very recently, we reported the psychobehavioral validity of within-individual temporal variations in momentary depressive mood recorded with EMA by examining co-variant properties with spontaneous physical activity as the external criteria. However, the validity of DRM in this context has not been objectively examined yet. Therefore, in this study, we examined the psychobehavioral validity of DRM by examining temporal associations with spontaneous physical activity and then showed the difference from EMA. Twenty-two healthy undergraduates wore a watch-type computer for two consecutive days and recorded self-reported symptoms (fatigue, depressive mood, and anxious mood) by EMA. They also recorded the symptoms afterward according to the series of behavioral episodes they reconstructed (DRM) about the same days. Physical activity was also obtained using an actigraph built into the watch-type computer. Multilevel analysis showed the significant association between depressive mood recorded with EMA and local statistics (mean activity levels calculated from 60 min data length) of physical activity around EMA recordings. However, depressive mood recorded with DRM had no significant association with physical activity. As for fatigue and anxious mood, none of the methods showed significant associations with the local statistics of physical activity. These results imply that depressive mood recorded with EMA would include psychobehavioral information which cannot be captured with DRM. PMID- 26737177 TI - Wearable near-infrared spectroscopy neuroimaging and its applications. AB - Wearable near-infrared spectroscopy (NIRS) systems are expected to be applied in various fields such as health care (medical use), education (teaching), and biofeedback. An investigation on hyperscanning by using NIRS is discussed first, where multiple brains were simultaneously measured for investigating and evaluating important social interactions, such as communication. The relationship between interacting brain activities and performance in cooperation has been demonstrated. An investigation on mood-state measurements in a return-to-work program is next discussed. It has been reported that a specified index calculated using NIRS signals obtained during performance of a working memory task correlated with a mood score. Using this index, the mood states of volunteers who participated in a return-to-work program after psychiatric clinical treatment were monitored. It has been suggested that the relationship between brain activities and subjective assessment of depression mood will be useful for evaluating the recovery stage for return-to-work programs. These techniques open new applications of wearable NIRS systems in mental health care. PMID- 26737178 TI - General anesthesia reduces the information exchange between heart and circulation. AB - The study demonstrates the ability of an information-theoretic measure, such as the transfer entropy (TE), in detecting the depression of the cardiac baroreflex control and circulatory-cardio mechanical feedforward link during propofol induced general anesthesia. TE was computed from spontaneous variability of heart period (HP) and systolic arterial pressure (SAP) in patients undergoing coronary artery bypass graft (CABG). TE from SAP to HP and from HP to SAP were evaluated by accounting for the confounding effect of respiration (R) affecting both HP and SAP (i.e. TESAP->HP|R and TEHP->SAP|R respectively). Both TESAP->HP|R and TEHP >SAP|R decreased during general anesthesia, thus suggesting that the strength of the causal relation diminished over both arms of the closed loop HP-SAP control. The squared coherence function between HP and SAP confirmed the decreased HP-SAP coupling during general anesthesia, even though it could not distinguish directionality. PMID- 26737179 TI - Redundant and synergistic information transfer in cardiovascular and cardiorespiratory variability. AB - In the framework of information dynamics, new tools are emerging which allow one to quantify how the information provided by two source processes about a target process results from the contribution of each source and from the interaction between the sources. We present the first implementation of these tools in the assessment of short-term cardiovascular and cardiorespiratory variability, by introducing two strategies for the decomposition of the information transferred to heart period (HP) variability from systolic arterial pressure (SAP) and respiration flow (RF) variability. Several measures based on the notion of transfer entropy (TE) are defined to quantify joint, individual and redundant/synergistic information transfer, and are then estimated from the series of HP, SAP and RF obtained from healthy subjects during head-up tilt and paced breathing protocols. Our results show that the proposed information decomposition methods provide an enhanced view on cardiovascular and cardiorespiratory regulation. PMID- 26737180 TI - Synergy, redundancy and unnormalized Granger causality. AB - We analyze by means of Granger causality the effect of synergy and redundancy in the inference (from time series data) of the information flow between subsystems of a complex network. Whilst fully conditioned Granger causality is not affected by synergy, the pairwise analysis fails to put in evidence synergetic effects. We show that maximization of the total Granger causality to a given target, over all the possible partitions of the set of driving variables, puts in evidence redundant multiplets of variables influencing the target, provided that an unnormalized definition of Granger causality is adopted. Along the same lines we also introduce a pairwise index of synergy (w.r.t. to information flow to a third variable) which is zero when two independent sources additively influence a common target; thus, this definition differs from previous definitions of synergy. PMID- 26737181 TI - Causality networks from multivariate time series and application to epilepsy. AB - Granger causality and variants of this concept allow the study of complex dynamical systems as networks constructed from multivariate time series. In this work, a large number of Granger causality measures used to form causality networks from multivariate time series are assessed. For this, realizations on high dimensional coupled dynamical systems are considered and the performance of the Granger causality measures is evaluated, seeking for the measures that form networks closest to the true network of the dynamical system. In particular, the comparison focuses on Granger causality measures that reduce the state space dimension when many variables are observed. Further, the linear and nonlinear Granger causality measures of dimension reduction are compared to a standard Granger causality measure on electroencephalographic (EEG) recordings containing episodes of epileptiform discharges. PMID- 26737182 TI - Anesthesia-related changes in information transfer may be caused by reduction in local information generation. AB - In anesthesia research it is an open question how general anesthetics lead to loss of consciousness (LOC). It has been proposed that LOC may be caused by the disruption of cortical information processing, preventing information integration. Therefore, recent studies investigating information processing under anesthesia focused on changes in information transfer, measured by transfer entropy (TE). However, often this complex technique was not applied rigorously, using time series in symbolic representation, or using TE differences without accounting for neural conduction delays, or without accounting for signal history. Here, we used current best-practice in TE estimation to investigate information transfer under anesthesia: We conducted simultaneous recordings in primary visual cortex (V1) and prefrontal cortex (PFC) of head-fixed ferrets in a dark environment under different levels of anesthesia (awake, 0.5% isoflurane, 1.0 % isoflurane). To elucidate reasons for changes in TE, we further quantified information processing within brain areas by estimating active information storage (AIS) as an estimator of predictable information, and Lempel-Ziv complexity (LZC) as an estimator of signal entropy. Under anesthesia, we found a reduction in information transfer (TE) between PFC and V1 with a stronger reduction for the feedback direction (PFC to V1), validating previous results. Furthermore, entropy (LZC) was reduced and activity became more predictable as indicated by higher values of AIS. We conclude that higher anesthesia concentrations indeed lead to reduced inter-areal information transfer, which may be partly caused by decreases in local entropy and increases in local predictability. In revealing a possible reason for reduced TE that is potentially independent of inter-areal coupling, we demonstrate the value of directly quantifying information processing in addition to focusing on dynamic properties such as coupling strength. PMID- 26737183 TI - Quantifying spatiotemporal complexity of cardiac dynamics using ordinal patterns. AB - Analyzing the dynamics of complex excitation wave patterns in cardiac tissue plays a key role for understanding the origin of life-threatening arrhythmias and for devising novel approaches to control them. The quantification of spatiotemporal complexity, however, remains a challenging task. This holds in particular for the analysis of data from fluorescence imaging (optical mapping), which allows for the measurement of membrane potential and intracellular calcium at high spatial and temporal resolution. Hitherto methods, like dominant frequency maps and the analysis of phase singularities, address important aspects of cardiac dynamics, but they consider very specific properties of excitable media, only. This article focuses on the benchmark of spatial complexity measures over time in the context of cardiac cell cultures. Standard Shannon Entropy and Spatial Permutation Entropy, an adaption of [1], have been implemented and applied to optical mapping data from embryonic chicken cell culture experiments. We introduce spatial separation of samples when generating ordinal patterns and show its importance for Spatial Permutation Entropy. Results suggest that Spatial Permutation Entropies provide a robust and interpretable measure for detecting qualitative changes in the dynamics of this excitable medium. PMID- 26737184 TI - Source-domain spectral EEG analysis of sports-related concussion via Measure Projection Analysis. AB - Here, we investigated EEG-based source-level spectral differences between adolescents with sports-related concussions and healthy age matched controls. We transformed resting state EEG collected in both groups to the source domain using Independent Component Analysis (ICA) and computed the component process power spectra. For group-level analysis in the source domain, we used a probabilistic framework, Measure Projection Analysis (MPA), that has advantages over parametric k-means clustering of brain sources. MPA revealed that some frontal brain sources in the concussed group had significantly more power in the beta band (p<;0.005) and significantly less delta (p<;0.01) and theta band power (p<;0.05) than the healthy control group. These results suggest that a shift in spectral profile toward higher frequencies in some frontal brain regions might distinguish individuals with concussion from healthy controls. PMID- 26737185 TI - Sparse cortical source localization using spatio-temporal atoms. AB - This paper addresses the problem of sparse localization of cortical sources from scalp EEG recordings. Localization algorithms use propagation model under spatial and/or temporal constraints, but their performance highly depends on the data signal-to-noise ratio (SNR). In this work we propose a dictionary based sparse localization method which uses a data driven spatio-temporal dictionary to reconstruct the measurements using Single Best Replacement (SBR) and Continuation Single Best Replacement (CSBR) algorithms. We tested and compared our methods with the well-known MUSIC and RAP-MUSIC algorithms on simulated realistic data. Tests were carried out for different noise levels. The results show that our method has a strong advantage over MUSIC-type methods in case of synchronized sources. PMID- 26737186 TI - A novel volume integral equation for solving the Electroencephalography forward problem. AB - In this paper, a novel volume integral equation for solving the Electroencephalography forward problem is presented. Differently from other integral equation methods standardly used for the same purpose, the new formulation can handle inhomogeneous and fully anisotropic realistic head models. The new equation is obtained by a suitable use of Green's identities together with an appropriate handling of all boundary conditions for the EEG problem. The new equation is discretized with a consistent choice of volume and boundary elements. Numerical results shows validity and convergence of the approach, together with its applicability to real case models obtained from MRI data. PMID- 26737187 TI - Feature analysis for correlation studies of simultaneous EEG-fMRI data: A proof of concept for neurofeedback approaches. AB - The identification and interpretation of facial expressions is an important feature of social cognition. This characteristic is often impaired in various neurodevelopmental disorders. Recent therapeutic approaches to intervene in social communication impairments include neurofeedback (NF). In this study, we present a NF real-time functional Magnetic Resonance Imaging (rt-fMRI), combined with electroencephalography (EEG) to train social communication skills. In this sense, we defined the right Superior Temporal Sulcus as our target region-of interest. To analyze the correlation between the fMRI regions of interest and the EEG data, we transposed the sources located at the nearest cortical location to the target region. We extracted a set of 75 features from EEG segments and performed a correlation analysis with the brain activations extracted from rt fMRI in the right pSTS region. The finding of significant correlations of simultaneously measured signals in distinct modalities (EEG and fMRI) is promising. Future studies should address whether the observed correlation levels between local brain activity and scalp measures are sufficient to implement NF approaches. PMID- 26737188 TI - EIT image regularization by a new Multi-Objective Simulated Annealing algorithm. AB - Multi-Objective Optimization can be used to produce regularized Electrical Impedance Tomography (EIT) images where the weight of the regularization term is not known a priori. This paper proposes a novel Multi-Objective Optimization algorithm based on Simulated Annealing tailored for EIT image reconstruction. Images are reconstructed from experimental data and compared with images from other Multi and Single Objective optimization methods. A significant performance enhancement from traditional techniques can be inferred from the results. PMID- 26737189 TI - The ACE1 thoracic Electrical Impedance Tomography system for ventilation and perfusion. AB - Electrical Impedance Tomography (EIT) is a technique which can image the varying electrical properties of biological tissues. For clinical use of EIT, it can be advantageous to know both tissue conductivity and permittivity. Presented is the hardware design for the pairwise current injection active complex electrode (ACE1) EIT system which measures phasic voltages for conductivity and permittivity image reconstruction. In this system, alternating current is injected on electrodes on the boundary of a domain and single-ended voltage measurements are used in image reconstructions of the domain's interior and in calculating the current applied at the electrodes. PMID- 26737190 TI - An intra-body molecular communication networks framework for continuous health monitoring and diagnosis. AB - Intra-body communication networks are designed to interconnect nano- or micro sized sensors located inside the body for health monitoring and drug delivery. The most promising solutions are made of implanted nanosensors to timely monitor the body for the presence of specific diseases and pronounce a diagnosis without the intervention of a physician. In this manner, several deadly health conditions such as heart attacks are avoided through the early in vivo detection of their biomarkers. In reality, nanosensors are challenged by the individual specificities, molecular noise, limited durability, and low energy resources. In this paper, a framework is proposed for estimating and detecting diseases and localizing the nanosensors. This framework is based on molecular communication, a novel communication paradigm where information is conveyed through molecules. Through the case study of the shedding of endothelial cells as an early biomarker for heart attack, the intra-body molecular communication networks framework is shown to resolve major issues with in vivo nanosensors and lay the foundations of low-complexity biomedical signal processing algorithms for continuous disease monitoring and diagnosis. PMID- 26737191 TI - Wireless communication link for capsule endoscope at 600 MHz. AB - Simulation of a wireless communication link for a capsule endoscopy is presented for monitoring of small intestine in humans. The realized communication link includes the transmitting capsule antenna, the outside body receiving antenna and the model of the human body. The capsule antenna is designed for operating at the frequency band of 600 MHz with an impedance bandwidth of 10 MHz and omnidirectional radiation pattern. The quality of the communication link is improved by using directive antenna outside body inside matching layer for electromagnetic wave tuning to the body. The outside body antenna has circular polarization that guaranteeing the communication link for different orientations of the capsule inside intestine. It is shown that the path loss for the capsule in 60 mm from the abdomen surface varies between 37-47 dB in relation to the antenna orientation. This link can establish high data rate wireless communications for capsule endoscopy. PMID- 26737192 TI - Wireless radio channel for intramuscular electrode implants in the control of upper limb prostheses. AB - In the last few years the use of implanted devices has been considered also in the field of myoelectric hand prostheses. Wireless implanted EMG (Electromyogram) sensors can improve the functioning of the prosthesis, providing information without the disadvantage of the wires, and the usability by amputees. The solutions proposed in the literature are based on proprietary communication protocols between the implanted devices and the prosthesis controller, using frequency bands that are already assigned to other purposes. This study proposes the use of a standard communication protocol (IEEE 802.15.6), specific for wireless body area networks (WBANs), which assign a specific bandwidth to implanted devices. The propagation losses from in-to-on body were investigated by numerical simulation with a 3D human model and an electromagnetic solver. The channel model resulting from the study represents the first step towards the development of myoelectric prosthetic hands which are driven by signals acquired by implanted sensors. However these results can provide important information to researchers for further developments, and manufacturers, which can decrease the production costs for hand prostheses having a common standard of communication with assigned frequencies of operation. PMID- 26737193 TI - A more acceptable endoluminal implantation for remotely monitoring ingestible sensors anchored to the stomach wall. AB - Several types of implant devices have been proposed and introduced into healthcare and telemedicine systems for monitoring physiological parameters, sometimes for very long periods of time. To our disappointment, most of the devices are implanted invasively and by surgery. We often have to surgically remove such devices after they have finished their mission or before the battery becomes worn out. Wearable devices have the possibility to become new modalities for monitoring vital parameters less-invasively. However, for round-the-clock monitoring of data from sensors over long periods of time, it would be better to put them inside the body to avoid causing inconvenience to patients in their daily lives. This study tested a less invasive endoluminal approach and innovative tools (developed during our research into therapeutic capsule endoscopy) for remotely anchoring ingestible sensors to the stomach wall. Preliminary investigations are also described about wireless communication (NFC, ZigBee, and Bluetooth) for low power consumption and inductive extracorporeal power feeding wirelessly to the circuits in a phantom lined with swine gastric mucosa. Electrocardiogram and pH were monitored and those parameters were successfully transmitted by wireless communication ICs to the Internet via a portable device. PMID- 26737194 TI - A microwave imaging-based 3D localization algorithm for an in-body RF source as in wireless capsule endoscopes. AB - A microwave imaging-based technique for 3D localization of an in-body RF source is presented. Such a technique can be useful for localization of an RF source as in wireless capsule endoscopes for positioning of any abnormality in the gastrointestinal tract. Microwave imaging is used to determine the dielectric properties (relative permittivity and conductivity) of the tissues that are required for a precise localization. A 2D microwave imaging algorithm is used for determination of the dielectric properties. Calibration method is developed for removing any error due to the used 2D imaging algorithm on the imaging data of a 3D body. The developed method is tested on a simple 3D heterogeneous phantom through finite-difference-time-domain simulations. Additive white Gaussian noise at the signal-to-noise ratio of 30 dB is added to the simulated data to make them more realistic. The developed calibration method improves the imaging and the localization accuracy. Statistics on the localization accuracy are generated by randomly placing the RF source at various positions inside the small intestine of the phantom. The cumulative distribution function of the localization error is plotted. In 90% of the cases, the localization accuracy was found within 1.67 cm, showing the capability of the developed method for 3D localization. PMID- 26737195 TI - Multichannel neural recording with a 128 Mbps UWB wireless transmitter for implantable brain-machine interfaces. AB - To realize a low-invasive and high accuracy BMI (Brain-machine interface) system, we have already developed a fully-implantable wireless BMI system which consists of ECoG neural electrode arrays, neural recording ASICs, a Wi-Fi based wireless data transmitter and a wireless power receiver with a rechargeable battery. For accurate estimation of movement intentions, it is important for a BMI system to have a large number of recording channels. In this paper, we report a new multi channel BMI system which is able to record up to 4096-ch ECoG data by multiple connections of 64-ch ASICs and time division multiplexing of recorded data. This system has an ultra-wide-band (UWB) wireless unit for transmitting the recorded neural signals to outside the body. By preliminary experiments with a human body equivalent liquid phantom, we confirmed 4096-ch UWB wireless data transmission at 128 Mbps mode below 20 mm distance. PMID- 26737196 TI - On the influence of high-pass filtering on ICA-based artifact reduction in EEG ERP. AB - Standard artifact removal methods for electroencephalographic (EEG) signals are either based on Independent Component Analysis (ICA) or they regress out ocular activity measured at electrooculogram (EOG) channels. Successful ICA-based artifact reduction relies on suitable pre-processing. Here we systematically evaluate the effects of high-pass filtering at different frequencies. Offline analyses were based on event-related potential data from 21 participants performing a standard auditory oddball task and an automatic artifactual component classifier method (MARA). As a pre-processing step for ICA, high-pass filtering between 1-2 Hz consistently produced good results in terms of signal-to noise ratio (SNR), single-trial classification accuracy and the percentage of 'near-dipolar' ICA components. Relative to no artifact reduction, ICA-based artifact removal significantly improved SNR and classification accuracy. This was not the case for a regression-based approach to remove EOG artifacts. PMID- 26737197 TI - Tracking non-stationary EEG sources using adaptive online recursive independent component analysis. AB - Electroencephalographic (EEG) source-level analyses such as independent component analysis (ICA) have uncovered features related to human cognitive functions or artifactual activities. Among these methods, Online Recursive ICA (ORICA) has been shown to achieve fast convergence in decomposing high-density EEG data for real-time applications. However, its adaptation performance has not been fully explored due to the difficulty in choosing an appropriate forgetting factor: the weight applied to new data in a recursive update which determines the trade-off between the adaptation capability and convergence quality. This study proposes an adaptive forgetting factor for ORICA (adaptive ORICA) to learn and adapt to non stationarity in the EEG data. Using a realistically simulated non-stationary EEG dataset, we empirically show adaptive forgetting factors outperform other commonly-used non-adaptive rules when underlying source dynamics are changing. Standard offline ICA can only extract a subset of the changing sources while adaptive ORICA can recover all. Applied to actual EEG data recorded from a task switching experiments, adaptive ORICA can learn and re-learn the task-related components as they change. With an adaptive forgetting factor, adaptive ORICA can track non-stationary EEG sources, opening many new online applications in brain computer interfaces and in monitoring of brain dynamics. PMID- 26737198 TI - Automatic preprocessing of EEG signals in long time scale. AB - Electroencephalography (EEG) signals are highly affected by physiological artifacts. Establishing a robust and repeatable EEG pre-processing is fundamental to overcome this issue and be able to use fully EEG data especially in long time scale experiments. In this work, starting from the Independent Component Analysis (ICA) of the EEG data, a control feedback scheme aiming to manage the cleaning of the independent component signals in an automatic way avoiding cut-bind solutions is presented, both with and without co-registrations. The method implemented combines different approaches based on the residual artifact contents check, identification and cleaning. The results of this procedure are shown on a test dataset. This analysis tool is embedded as core module, in a platform that can manage the automatic clearing of EEG recordings for multiple-subjects studies. PMID- 26737199 TI - Real-time EEG Source-mapping Toolbox (REST): Online ICA and source localization. AB - The Electroencephalogram (EEG) is a noninvasive functional brain activity recording method that shows promise for becoming a 3-D cortical imaging modality with high temporal resolution. Currently, most of the tools developed for EEG analysis focus mainly on offline processing. This study introduces and demonstrates the Real-time EEG Source-mapping Toolbox (REST), an extension to the widely distributed EEGLAB environment. REST allows blind source separation of EEG data in real-time using Online Recursive Independent Component Analysis (ORICA), plus near real-time localization of separated sources. Two source localization methods are available to fit equivalent current dipoles or estimate spatial source distributions of selected sources. Selected measures of raw EEG data or component activations (e.g. time series of the data, spectral changes over time, equivalent current dipoles, etc.) can be visualized in near real-time. Finally, this study demonstrates the accuracy and functionality of REST with data from two experiments and discusses some relevant applications. PMID- 26737200 TI - r-principal subspace for driver cognitive state classification. AB - Using EEG signals, a novel technique for driver cognitive state assessment is presented, analyzed and experimentally verified. The proposed technique depends on the singular value decomposition (SVD) in finding the distributed energy of the EEG data matrix A in the direction of the r-principal subspace. This distribution is unique and sensitive to the changes in the cognitive state of the driver due to external stimuli, so it is used as a set of features for classification. The proposed technique is tested with 42 subjects using 128 EEG channels and the results show significant improvements in terms of accuracy, specificity, sensitivity, and false detection in comparison to other recently proposed techniques. PMID- 26737201 TI - Multiscale PCA to distinguish regular and irregular surfaces using tri axial head and trunk acceleration signals. AB - This study uses multiscale principal component analysis (MSPCA) signal processing technique in order to distinguish the two different surfaces, tiled (regular) and cobbled (irregular) using accelerometry data (recorded from MTx sensors). Two MTx sensors were placed on the head and trunk of the subject while the subject walked freely over the regular and irregular surfaces during a free walk. 3D acceleration signals, vertical, medio lateral (ML) and anterior-posterior (AP) were recorded for the head and trunk segments and compared for the free walk on a defined route. The magnitude of the ML and AP acceleration obtained from the MTx sensors (for both head & trunk) was higher when walking over the irregular (cobbled) surface as compared to the regular (tiled) surface. The accelerometry data was initially analysed using MSPCA and was later classified using naive Bayesian classifier with >86% accuracy. This research study demonstrates that MSPCA can be used to distinguish the regular and irregular surfaces. The proposed method could be very useful as an automated method for classification of the two surfaces. PMID- 26737202 TI - Automated clustering of independent components for discontinuous sounds thoracic imaging. AB - Discontinuous lung sounds (DLS), also known as crackles, are abnormal sounds produced by different pulmonary pathologies (PP) whose thoracic spatial distribution and prevalence are relevant for diagnosis purpose. Recently, DLS imaging has been proposed to help diagnose and follow-up PP where automated recognition of DLS is meaningful. The present study focuses on the automated selection of independent components (ICs) associated with DLS. Extraction of ICs information for clustering by k-means is achieved in two ways: (1) forming features vectors (FVs) containing the kurtosis, entropy and sparsity of each IC or (2) by applying mutual information (MI) or Euclidean distance (ED) to all ICs. Next, silhouette index is computed to estimate the number of necessary clusters (C). Afterward, to detect just the clusters containing ICs of DLS a selection index is proposed. Finally, to estimate the number of DLS per ICs in each selected cluster a time-variant AR modeling is applied; the estimated number is shown in conjunction with the 2D-ICs spatial distribution. The methodology is applied to simulated and real cases; DLS imaging results are also compared against clinical auscultation. The results showed that the automated selection via FVs is promising to imaging DLS. PMID- 26737203 TI - Hessian regularization based non-negative matrix factorization for gene expression data clustering. AB - Since a key step in the analysis of gene expression data is to detect groups of genes that have similar expression patterns, clustering technique is then commonly used to analyze gene expression data. Data representation plays an important role in clustering analysis. The non-negative matrix factorization (NMF) is a widely used data representation method with great success in machine learning. Although the traditional manifold regularization method, Laplacian regularization (LR), can improve the performance of NMF, LR still suffers from the problem of its weak extrapolating power. Hessian regularization (HR) is a newly developed manifold regularization method, whose natural properties make it more extrapolating, especially for small sample data. In this work, we propose the HR-based NMF (HR-NMF) algorithm, and then apply it to represent gene expression data for further clustering task. The clustering experiments are conducted on five commonly used gene datasets, and the results indicate that the proposed HR-NMF outperforms LR-based NMM and original NMF, which suggests the potential application of HR-NMF for gene expression data. PMID- 26737204 TI - Empirical mode decomposition applied for non-invasive electrohysterograhic signals denoising. AB - The electrical activity of the uterus, i.e. the electrohysterogram (EHG), is one of the most prominent tool for preterm labour. There is no standard acquisition set up and often the EHG is corrupted with different types of noise: maternal and fetal electrocardiogram (mECG, fECG), electrical activity of the skeletal muscles, movement artifacts, power line interference (PLI) etc. Moreover, some of these noises overlap in frequency domain with the EHG. Thus, simple linear filtering approaches are not adequate. In this paper the empirical mode decomposition (EMD), a simple and data driven method, is proposed for EHG denoising. The method is evaluated on simulated data having different signal to noise ratios (SNRs) obtaining promising results. PMID- 26737205 TI - Empirical Mode Decomposition for slow wave extraction from electrogastrographical signals. AB - The aim of this study was to investigate the effectiveness of Empirical Mode Decomposition (EMD) for slow wave extraction from multichannel electrogastrographical signal (EGG) the cutaneous recording of gastric myoelectrical activity. From the pacemaker region of stomach both spontaneous depolarization and repolarization occur generating the myoelectrical waves that are called the gastric pacesetter potentials, or slow waves. The 3 cycles per minute (3pcm) (0.05Hz) slow wave is fundamental electrical phenomenon in stomach responsible for the propagation and maximum frequency of stomach contractions. Appropriate spread of gastric contractions is a key for the correct stomach emptying whereas delay in this action causes various gastric disorders, such as bloating, vomiting or unexplained nausea. Unfortunately the EGG signal is not a pure one but usually a sort of mixture consisting of respiratory signals, cardiac signals, random noise and possible myoelectrical activity from other organs surrounding the stomach, such as duodenum or small intestine. Identify and removal of contaminations from different artifactual sources from the EGG recording is a major task before EGG analysis and interpretation. The use of EMD method and Hilbert spectrum combination for slow wave extraction from raw EGG signal seems to be a good choice, because this adaptive decomposition technique is unique suitable for both nolinear, no-stationary data analysis. PMID- 26737206 TI - Preliminary evaluation of Wearable Wellness System for Obstructive Sleep Apnea detection. AB - Several studies have proven how sleep deprivation has a negative impact on daily life, affecting people's psychophysical state. In this field, research is focusing on the improvement of unobtrusive sleep monitoring devices for promoting sleep hygiene and early detection of sleep disorders. This study aims to assess the use of a textile-based wearable system, with its associated apnea detection algorithm, in monitoring of Obstructive Sleep Apnea Syndrome (OSAs). The system has been compared through the simultaneous acquisition of physiological signals in parallel with polysomnograph in laboratory and home environments. Results show that such a wearable system could be successfully used for early detection of OSAs (Obstructive Sleep Apnea Syndrome) and could stimulate people to a better self healthcare looking for a specialized medic examination and eventually undergoing to proper treatment avoiding the onset of OSAs co-morbidities. PMID- 26737207 TI - Fractals properties of EEG during event-related desynchronization of motor imagery. AB - Chaos and fractal dimension are emerging modalities for the research of electroencephalogram (EEG) signal processing. The capability of measuring non linear characteristics of the fractal dimension enables new methodologies to identify distinct brain activities. Recent studies on the topic focus on utilizing various types of fractals as features in order to design better brain state classification system. However, we have little insight about the EEG signals projected in fractal dimension. In this paper, we investigate the relationship between the non-linear characteristics of ongoing EEG signals and event-related desynchronization (ERD) during motor imagery. We observed a considerable synchronization between ERD and fractal dimension. This finding suggests further usage of chaos and fractal theory in investigating brain activities. PMID- 26737208 TI - Phase-amplitude cross-frequency coupling in EEG-derived cortical time series upon an auditory perception task. AB - Recent evidence suggests that cross-frequency coupling (CFC) plays an essential role in multi-scale communication across the brain. The amplitude of the high frequency oscillations, responsible for local activity, is modulated by the phase of the lower frequency activity, in a task and region-relevant way. In this paper, we examine this phase-amplitude coupling in a two-tone oddball paradigm for the low frequency bands (delta, theta, alpha, and beta) and determine the most prominent CFCs. Data consisted of cortical time series, extracted by applying three-dimensional vector field tomography (3D-VFT) to high density (256 channels) electroencephalography (HD-EEG), and CFC analysis was based on the phase-amplitude coupling metric, namely PAC. Our findings suggest CFC spanning across all brain regions and low frequencies. Stronger coupling was observed in the delta band, that is closely linked to sensory processing. However, theta coupling was reinforced in the target tone response, revealing a task-dependent CFC and its role in brain networks communication. PMID- 26737209 TI - EEG signal features extraction based on fractal dimension. AB - The spread of electroencephalography (EEG) in countless applications has fostered the development of new techniques for extracting synthetic and informative features from EEG signals. However, the definition of an effective feature set depends on the specific problem to be addressed and is currently an active field of research. In this work, we investigated the application of features based on fractal dimension to a problem of sleep identification from EEG data. We demonstrated that features based on fractal dimension, including two novel indices defined in this work, add valuable information to standard EEG features and significantly improve sleep identification performance. PMID- 26737210 TI - Lempel-Ziv and multiscale Lempel-Ziv complexity in depression. AB - There is a high demand for objective indicators in diagnosis of depression as diagnosis of depression is still based on psychiatrist's subjective judgment. A nonlinear method Lempel Ziv Complexity (LZC) has been previously successfully used for detection of neuronal or mental disorders based on electroencephalographic (EEG) signals. However, the method overlooks the high frequency content of EEG signals. Therefore, this study is aimed to find out whether the use of Multiscale Lempel Ziv Complexity (MLZC), considering also high frequencies, could overcome the limitations of LZC and better differentiate depression. In current study the EEG recordings were carried out on the groups of depressive and healthy subjects of 11 volunteers each. The LZC and MLZC were calculated on resting EEG signals in eyes open condition from 30 channels at a length of 2 minutes. The results revealed the incapability of traditional LZC to differentiate depressive subjects from healthy controls in eyes open condition, while MLZC differentiated two groups in numerous channels at different frequencies, giving the highest classification accuracy in channel F3 (86 %) at frequencies 9 and 15.5 Hz. The results indicate that the high frequency information, which is lost in calculation of traditional LZC, has a great value in differentiating between depressive and control groups. PMID- 26737211 TI - Detrended fluctuation analysis for major depressive disorder. AB - Clinical utility of Electroencephalography (EEG) based diagnostic studies is less clear for major depressive disorder (MDD). In this paper, a novel machine learning (ML) scheme was presented to discriminate the MDD patients and healthy controls. The proposed method inherently involved feature extraction, selection, classification and validation. The EEG data acquisition involved eyes closed (EC) and eyes open (EO) conditions. At feature extraction stage, the de-trended fluctuation analysis (DFA) was performed, based on the EEG data, to achieve scaling exponents. The DFA was performed to analyzes the presence or absence of long-range temporal correlations (LRTC) in the recorded EEG data. The scaling exponents were used as input features to our proposed system. At feature selection stage, 3 different techniques were used for comparison purposes. Logistic regression (LR) classifier was employed. The method was validated by a 10-fold cross-validation. As results, we have observed that the effect of 3 different reference montages on the computed features. The proposed method employed 3 different types of feature selection techniques for comparison purposes as well. The results show that the DFA analysis performed better in LE data compared with the IR and AR data. In addition, during Wilcoxon ranking, the AR performed better than LE and IR. Based on the results, it was concluded that the DFA provided useful information to discriminate the MDD patients and with further validation can be employed in clinics for diagnosis of MDD. PMID- 26737212 TI - Tsallis entropy as a biomarker for detection of Alzheimer's disease. AB - Alzheimer's disease (AD) and other forms of dementia are one of the major public health and social challenges of our time because of the large number of people affected. Early diagnosis is important for patients and their families to get maximum benefits from access to health and social care services and to plan for the future. EEG provides useful insight into brain functions and can play a useful role as a first line of decision-support tool for early detection and diagnosis of dementia. It is non-invasive, low-cost and has a high temporal resolution. The functions of brain cells are affected by damage caused by dementia and this in turn causes changes in the features of the EEG. Information theoretic methods have emerged as a potentially useful way to quantify changes in the EEG as biomarkers of dementia. Tsallis entropy has been shown to be one of the most promising information theoretic methods for quantifying changes in the EEG. In this paper, we develop the approach further. This has yielded an enhanced performance compared to existing approaches. PMID- 26737213 TI - Distribution entropy analysis of epileptic EEG signals. AB - It is an open-ended challenge to accurately detect the epileptic seizures through electroencephalogram (EEG) signals. Recently published studies have made elaborate attempts to distinguish between the normal and epileptic EEG signals by advanced nonlinear entropy methods, such as the approximate entropy, sample entropy, fuzzy entropy, and permutation entropy, etc. Most recently, a novel distribution entropy (DistEn) has been reported to have superior performance compared with the conventional entropy methods for especially short length data. We thus aimed, in the present study, to show the potential of DistEn in the analysis of epileptic EEG signals. The publicly-accessible Bonn database which consisted of normal, interictal, and ictal EEG signals was used in this study. Three different measurement protocols were set for better understanding the performance of DistEn, which are: i) calculate the DistEn of a specific EEG signal using the full recording; ii) calculate the DistEn by averaging the results for all its possible non-overlapped 5 second segments; and iii) calculate it by averaging the DistEn values for all the possible non-overlapped segments of 1 second length, respectively. Results for all three protocols indicated a statistically significantly increased DistEn for the ictal class compared with both the normal and interictal classes. Besides, the results obtained under the third protocol, which only used very short segments (1 s) of EEG recordings showed a significantly (p <; 0.05) increased DistEn for the interictal class in compassion with the normal class, whereas both analyses using relatively long EEG signals failed in tracking this difference between them, which may be due to a nonstationarity effect on entropy algorithm. The capability of discriminating between the normal and interictal EEG signals is of great clinical relevance since it may provide helpful tools for the detection of a seizure onset. Therefore, our study suggests that the DistEn analysis of EEG signals is very promising for clinical and even portable EEG monitoring. PMID- 26737214 TI - Non-linear analysis of EEG and HRV signals during sleep. AB - The sleep phenomenon is a complex process that involves fluctuations of autonomic functions such as the blood pressure, temperature and brain function. These fluctuations change their properties through the different sleep stages with specific relations among the different systems. In order to understand the relation between the cardiovascular and central nervous system at the different sleep stages, we applied different non-linear methods to the energy of electroencephalographic signal (EEG) and the heart rate fluctuations. The EEG was divided in the Delta, Theta, Alpha and Beta frequency bands and the mean energy of these bands was computed at each heart rate interval. Thus, the non-linear relation was evaluated between the energy of the EEG bands and the heart rate fluctuations using Cross-Correlation, Cross-Sample Entropy and Recurrence Quantification Analysis in segments of 5 minutes grouped by sleep stage. The results showed that a relation exists between the changes of the energy in the Delta band and the Heart rate fluctuations. PMID- 26737215 TI - Highly scalable parallel processing of extracellular recordings of Multielectrode Arrays. AB - Technological advances of Multielectrode Arrays (MEAs) used for multisite, parallel electrophysiological recordings, lead to an ever increasing amount of raw data being generated. Arrays with hundreds up to a few thousands of electrodes are slowly seeing widespread use and the expectation is that more sophisticated arrays will become available in the near future. In order to process the large data volumes resulting from MEA recordings there is a pressing need for new software tools able to process many data channels in parallel. Here we present a new tool for processing MEA data recordings that makes use of new programming paradigms and recent technology developments to unleash the power of modern highly parallel hardware, such as multi-core CPUs with vector instruction sets or GPGPUs. Our tool builds on and complements existing MEA data analysis packages. It shows high scalability and can be used to speed up some performance critical pre-processing steps such as data filtering and spike detection, helping to make the analysis of larger data sets tractable. PMID- 26737216 TI - Effect of filtering on the classification rate of nonlinear analysis methods applied to uterine EMG signals. AB - Nonlinear time series analysis can provide useful information regarding nonlinear features of biological signals. The effect of filtering on the performance of nonlinear methods is not well-understood. In this work, we investigate the effects of signal filtering on the sensitivity of four nonlinear methods: Time reversibility, Sample Entropy, Lyapunov Exponents and Delay Vector Variance. These methods were applied to uterine EMG signals with the aim of using them to discriminate between pregnancy and labor contractions. The signals were filtered using three different band-pass filters before the application of the methods. Results showed that the sensitivity of some methods such as sample entropy was significantly improved with filtering. On the other hand, filtering had little effect on some other methods such as time reversibility. This study concludes that while filtering increases computation time, it may be necessary for some nonlinear methods particularly those with low sensitivity. PMID- 26737217 TI - Sensors' Ground Reaction Force behavior for both Normal and Parkinson subjects--A qualitative study. AB - Characterization of normal and abnormal Gait has been a major research field for decades, whether in fall prevention, sports biomechanics or even disease indication. In this paper, we assess time domain statistical properties of the Vertical Ground Reaction Force (VGRF) during moderate-pace walking, aiming eventually to create a reliable mathematical model of VGRF for normal and abnormal cases. For that endeavor, first order statistical analysis was performed upon signal segmentation in order to determine the degree of stationarity and base the model upon it. Furthermore, we performed curve fitting of the VGRF time series between present and past values, which led us to model the waveform with linear regression via Autoregressive Model for both Normal Walking Signals and Parkinson diseased patients' walking signals. However this is done only for one chosen sensor. However, it would be crucial to take the advantage of the array of sensors. Evaluating the cross-covariance between multi-sensor data of a given subject at different time lags capture the most important information. The seasonality in the values give a quite important indications of the behavior of data. The objective behind this analysis is to recommend a preliminary basis to create reliable mathematical model of normal walking signals versus pathological walking signals, that we will emphasize in a complementary work, in the simplest way available and creating fall prevention indicators for old patients. PMID- 26737218 TI - Toward lightweight biometric signal processing for wearable devices. AB - Wearable devices are becoming a natural and economic means to gather biometric data from end users. The massive amount of information that they will provide, unimaginable until a few years ago, owns an immense potential for applications such as continuous monitoring for personalized healthcare and use within fitness applications. Wearables are however heavily constrained in terms of amount of memory, transmission capability and energy reserve. This calls for dedicated, lightweight but still effective algorithms for data management. This paper is centered around lossy data compression techniques, whose aim is to minimize the amount of information that is to be stored on their onboard memory and subsequently transmitted over wireless interfaces. Specifically, we analyze selected compression techniques for biometric signals, quantifying their complexity (energy consumption) and compression performance. Hence, we propose a new class of codebook-based (CB) compression algorithms, designed to be energy efficient, online and amenable to any type of signal exhibiting recurrent patterns. Finally, the performance of the selected and the new algorithm is assessed, underlining the advantages offered by CB schemes in terms of memory savings and classification algorithms. PMID- 26737219 TI - A multi-spot exploration of the topological structures of the reconstructed phase space for the detection of cardiac murmurs. AB - Acoustic heart signals are generated by a turbulence effect created when the heart valves snap shut, and therefore carrying significant information of the underlying functionality of the cardiovascular system. In this paper, we present a method for heart murmur classification divided into three major steps: a) features are extracted from the heart sound; b) features are selected using a Backward Feature Selection algorithm; c) signals are classified using a K-nearest neighbor's classifier. A new set of fractal features are proposed, which are based on the distinct signatures of complexity and self-similarity registered on the normal and pathogenic cases. The experimental results show that fractal features are the most capable of describing the non-linear structure and the underlying dynamics of heart sounds among the all feature families tested. The classification results achieved for the mitral auscultation spot (88% of accuracy) are in agreement with the current state of the art methods for heart murmur classification. PMID- 26737220 TI - Intracranial pressure for the characterization of different types of hydrocephalus: A Permutation Entropy study. AB - Hydrocephalus is a condition characterized by altered cerebrospinal fluid (CSF) dynamics and chronic rises in intracranial pressure (ICP). However, the reason why hydrocephalic physiologies fail to inhibit dangerously high ICP levels is not known. Infusion studies are used to raise ICP and evaluate CSF circulation disorders. In this pilot study, ICP signals recorded during infusion tests from 33 patients with normal pressure hydrocephalus and 36 patients having developed a secondary form of normal pressure hydrocephalus were characterized using Permutation Entropy (PE), a symbolic non-linear method to quantify complexity. Each ICP signal was divided into four epochs--baseline (before infusion begins), infusion, plateau, and recovery (after infusion has stopped)--and the mean PE was calculated for each epoch. Statistically significant differences were found between PE for most epochs (p<;0.00833, Bonferroni-corrected Wilcoxon tests), with a significant decrease in the plateau phase. However, differences between PE for normal pressure and secondary hydrocephalus were not significant. Results suggest that the increase in ICP during infusion studies is associated with a significant decrease in PE. PE analysis of ICP signals could be useful for increasing our understanding of CSF dynamics in normal pressure hydrocephalus. PMID- 26737221 TI - Non-contact dual pulse Doppler system based respiratory and heart rates estimation for CHF patients. AB - Long term continuous patient monitoring is required in many health systems for monitoring and analytical diagnosing purposes. Most of monitoring systems had shortcomings related to their functionality or patient comfortably. Non-contact continuous monitoring systems have been developed to address some of these shortcomings. One of such systems is non-contact physiological vital signs assessments for chronic heart failure (CHF) patients. This paper presents a novel automated estimation algorithm for the non-contact physiological vital signs assessments for CHF patients based on a patented novel non-contact biomotion sensor. A database consists of twenty CHF patients with New York Heart Association (NYHA) heart failure Classification Class II & III, whose underwent full Polysomnography (PSG) analysis for the diagnosis of sleep apnea, disordered sleep, or both, were selected for the study. The patients mean age is 68.89 years, with mean body weight of 86.87 kg, mean BMI of 28.83 (obesity) and mean recorded sleep duration of 7.78 hours. The propose algorithm analyze the non contact biomotion signals and estimate the patients' respiratory and heart rates. The outputs of the algorithm are compared with gold-standard PSG recordings. Across all twenty patients' recordings, the respiratory rate estimation median accuracy achieved 92.4689% with median error of +/- 1.2398 breaths per minute. The heart rate estimation median accuracy achieved 88.0654% with median error of +/- 7.9338 beats per minute. Due to the good performance of the propose novel automated estimation algorithm, the patented novel non-contact biomotion sensor can be an excellent tool for long term continuous sleep monitoring for CHF patients in the home environment in an ultra-convenient fashion. PMID- 26737222 TI - A GPU accelerated moving mesh correspondence algorithm with applications to RV segmentation. AB - This study proposes a parallel nonrigid registration algorithm to obtain point correspondence between a sequence of images. Several recent studies have shown that computation of point correspondence is an excellent way to delineate organs from a sequence of images, for example, delineation of cardiac right ventricle (RV) from a series of magnetic resonance (MR) images. However, nonrigid registration algorithms involve optimization of similarity functions, and are therefore, computationally expensive. We propose Graphics Processing Unit (GPU) computing to accelerate the algorithm. The proposed approach consists of two parallelization components: 1) parallel Compute Unified Device Architecture (CUDA) version of the non-rigid registration algorithm; and 2) application of an image concatenation approach to further parallelize the algorithm. The proposed approach was evaluated over a data set of 16 subjects and took an average of 4.36 seconds to segment a sequence of 19 MR images, a significant performance improvement over serial image registration approach. PMID- 26737223 TI - A high-accuracy surgical augmented reality system using enhanced integral videography image overlay. AB - Image guided surgery has been used in clinic to improve the surgery safety and accuracy. Augmented reality (AR) technique, which can provide intuitive image guidance, has been greatly evolved these years. As one promising approach of surgical AR systems, integral videography (IV) autostereoscopic image overlay has achieved accurate fusion of full parallax guidance into surgical scene. This paper describes an image enhanced high-accuracy IV overlay system. A flexible optical image enhancement system (IES) is designed to increase the resolution and quality of IV image. Furthermore, we introduce a novel IV rendering algorithm to promote the spatial accuracy with the consideration of distortion introduced by micro lens array. Preliminary experiments validated that the image accuracy and resolution are improved with the proposed methods. The resolution of the IV image could be promoted to 1 mm for a micro lens array with pitch of 2.32 mm and IES magnification value of 0.5. The relative deviation of accuracy in depth and lateral directions are -4.68 +/- 0.83% and -9.01 +/- 0.42%. PMID- 26737224 TI - Adaptive stereo medical image watermarking using non-corresponding blocks. AB - Today with the advent of technology in different medical imaging fields, the use of stereoscopic images has increased. Furthermore, with the rapid growth in telemedicine for remote diagnosis, treatment, and surgery, there is a need for watermarking. This is for copyright protection and tracking of digital media. Also, the efficient use of bandwidth for transmission of such data is another concern. In this paper an adaptive watermarking scheme is proposed that considers human visual system in depth perception. Our proposed scheme modifies maximum singular values of wavelet coefficients of stereo pair for embedding watermark bits. Experimental results show high 3D visual quality of watermarked video frames. Moreover, comparison with a compatible state of the art method shows that the proposed method is highly robust against attacks such as AWGN, salt and pepper noise, and JPEG compression. PMID- 26737225 TI - Techniques for estimating blood pressure variation using video images. AB - It is important to know about a sudden blood pressure change that occurs in everyday life and may pose a danger to human health. However, monitoring the blood pressure variation in daily life is difficult because a bulky and expensive sensor is needed to measure the blood pressure continuously. In this study, a new non-contact method is proposed to estimate the blood pressure variation using video images. In this method, the pulse propagation time difference or instantaneous phase difference is calculated between two pulse waves obtained from different parts of a subject's body captured by a video camera. The forehead, left cheek, and right hand are selected as regions to obtain pulse waves. Both the pulse propagation time difference and instantaneous phase difference were calculated from the video images of 20 healthy subjects performing the Valsalva maneuver. These indices are considered to have a negative correlation with the blood pressure variation because they approximate the pulse transit time obtained from a photoplethysmograph. However, the experimental results showed that the correlation coefficients between the blood pressure and the proposed indices were approximately 0.6 for the pulse wave obtained from the right hand. This result is considered to be due to the difference in the transmission depth into the skin between the green and infrared light used as light sources for the video image and conventional photoplethysmogram, respectively. In addition, the difference in the innervation of the face and hand may be related to the results. PMID- 26737226 TI - High quality surface reconstruction in radiotherapy: Cross-sectional contours to 3D mesh using wavelets. AB - A novel approach for three-dimensional (3D) surface reconstruction of anatomical structures in radiotherapy (RT) is presented. This is obtained from manual cross sectional contours by combining both image voxel segmentation processing and implicit surface streaming methods using wavelets. 3D meshes reconstructed with the proposed approach are compared to those obtained from traditional triangulation algorithm. Qualitative and quantitative evaluations are performed in terms of mesh quality metrics. Differences in smoothness, detail and accuracy are observed in the comparison, considering three different anatomical districts and several organs at risk in radiotherapy. Overall best performances were recorded for the proposed approach, regardless the complexity of the anatomical structure. This demonstrates the efficacy of the proposed approach for the 3D surface reconstruction in radiotherapy and allows for further specific image analyses using real biomedical data. PMID- 26737227 TI - An innovative calibration based integral photography rendering algorithm for medical application and its evaluation. AB - Autostereoscopic has long been proposed to fulfill medical display in image guided surgery and clinical education to provide more intuitive position information of clinical interest zone thus improving surgery safety and accuracy. As one category of flexible autostereoscopic 3D display, computer generated integral photography (CGIP) has been studied in medical application by many researches for its convenience and cost-efficiency. However, IP still suffers from inaccurate light field reconstruction, which limits its practicality in surgery. In this paper, we propose and apply a flexible fish-eye model based micro lens array (MLA) distortion calibration method and pre-distorted retracing rendering algorithm to render elemental image array (EIA) of CGIP. Furthermore, we also evaluate light field of the proposed algorithm in depth cue, and signal noise ratio of IP images by phantom experiment. PMID- 26737228 TI - Clustering-based limb identification for pressure ulcer risk assessment. AB - Bedridden patients have a high risk of developing pressure ulcers. Risk assessment for pressure ulceration is critical for preventive care. For a reliable assessment, we need to identify and track the limbs continuously and accurately. In this paper, we propose a method to identify body limbs using a pressure mat. Three prevalent sleep postures (supine, left and right postures) are considered. Then, predefined number of limbs (body parts) are identified by applying Fuzzy C-Means (FCM) clustering on key attributes. We collected data from 10 adult subjects and achieved average accuracy of 93.2% for 10 limbs in supine and 7 limbs in left/right postures. PMID- 26737229 TI - Visualization of multiple anatomical structures with explicit isosurface manipulation. AB - In medical image analysis and surgical planning, it is an essential task to visualize and differentiate multiple anatomical structures. The traditional approaches require expensive 3D segmentation steps during pre-processing stage, which defeats the purpose of real-time interaction with the data. In this paper, we propose an interactive method for visualization of multiple anatomical structures. In our results, we show that the new method is a promising technique for visual analysis of medical datasets and a helpful tool for surgical planning. It can be very efficient for a wide range of visualization and analysis tasks. PMID- 26737230 TI - Accelerating DRR generation using Fourier slice theorem on the GPU. AB - Digitally Reconstructed Radiographs (DRRs) play a vital role in medical imaging procedures and radiotherapy applications. They allow the continuous monitoring of patient positioning during image guided therapies using multi-dimensional image registration. Conventional generation of DRRs using spatial domain algorithms such as ray casting is associated with computational complexity of O(N(3)). Fourier slice theorem is an alternative approach for generating the DRRs in the k space with reduced time complexity. In this work, we present a high performance, scalable, and optimized DRR generation pipeline on the Graphics Processing Unit (GPU). The strong scaling performance of the presented pipeline is investigated and demonstrated using two contemporary GPUs. Our pipeline is capable of generating DRRs for 512(3) volumes in less than a milli-second. PMID- 26737231 TI - GPU acceleration for digitally reconstructed radiographs using bindless texture objects and CUDA/OpenGL interoperability. AB - This paper features an advanced implementation of the X-ray rendering algorithm that harnesses the giant computing power of the current commodity graphics processors to accelerate the generation of high resolution digitally reconstructed radiographs (DRRs). The presented pipeline exploits the latest features of NVIDIA Graphics Processing Unit (GPU) architectures, mainly bindless texture objects and dynamic parallelism. The rendering throughput is substantially improved by exploiting the interoperability mechanisms between CUDA and OpenGL. The benchmarks of our optimized rendering pipeline reflect its capability of generating DRRs with resolutions of 2048(2) and 4096(2) at interactive and semi interactive frame-rates using an NVIDIA GeForce 970 GTX device. PMID- 26737232 TI - Hyperspectral imaging of vascular anastomosis associated with blood flow and hemoglobin concentration. AB - The feasibility of optical non-invasive evaluation of the graft function of vascular anastomosis was investigated in vitro using hyperspectral imaging (HSI) in the wavelength range from 500 to 600 nm. A Y-shaped vessel was made using porcine carotid arteries having an inner diameter of 3.5 to 4 mm. The graft vessel was anastomosed at a 45 degrees angle with 8-0 polypropylene suture. Fresh porcine blood at an oxygen saturation of 100% was circulated in the specially designed circuit loop and through the graft or main vessel. The vessels were then irradiated with light, and the reflected light was captured with an HSI camera. The attenuation (A) image at each wavelength (lambda) was obtained and the spectral A(lambda) image was created. The spectral A(lambda) image showed graft patency and changes in the hemoglobin concentration. The A(lambda) decreased as the flow rate increased due to the orientation of the red blood cells. The experimental results indicated that imaging of the hemoglobin concentration without distortion from blood flow is possible using two wavelengths: 625 and 770 nm. This method is able to distinguish between the blood flow and changes in hemoglobin concentration. The multispectral and hyperspectral imaging method is useful for the non-invasive evaluation of graft function. PMID- 26737233 TI - Robust remote monitoring of breathing function by using infrared thermography. AB - An abnormal breathing rate (BR) is one of the strongest markers of physiological distress. Moreover, it plays an important role in early detection of sudden infant death syndrome, as well as in the diagnosis of respiratory disorders. However, the current measuring modalities can cause discomfort to the patient, since attachment to the patient's body is required. This paper proposes a new approach based on infrared thermography to remotely monitor BR. This method allows to (1) detect automatically the nose, (2) track the associate region of interest (ROI), and (3) extract BR. To evaluate the performance of this method, thermal recording of 5 healthy subjects were acquired. Results were compared with BR obtained by capnography. The introduced approach demonstrated an excellent performance. ROIs were precisely segmented and tracked. Furthermore, a Bland Altman diagram showed a good agreement between estimated BR and gold standard. The mean correlation and mean absolute BR error are 0.92 +/- 0.07 and 0.53 bpm, respectively. In summary, infrared thermography seems to be a great, clinically relevant alternative to attached sensors, due to its outstanding characteristics and performance. PMID- 26737234 TI - Thermogram breast cancer prediction approach based on Neutrosophic sets and fuzzy c-means algorithm. AB - The early detection of breast cancer makes many women survive. In this paper, a CAD system classifying breast cancer thermograms to normal and abnormal is proposed. This approach consists of two main phases: automatic segmentation and classification. For the former phase, an improved segmentation approach based on both Neutrosophic sets (NS) and optimized Fast Fuzzy c-mean (F-FCM) algorithm was proposed. Also, post-segmentation process was suggested to segment breast parenchyma (i.e. ROI) from thermogram images. For the classification, different kernel functions of the Support Vector Machine (SVM) were used to classify breast parenchyma into normal or abnormal cases. Using benchmark database, the proposed CAD system was evaluated based on precision, recall, and accuracy as well as a comparison with related work. The experimental results showed that our system would be a very promising step toward automatic diagnosis of breast cancer using thermograms as the accuracy reached 100%. PMID- 26737235 TI - Functional connectivity analysis of brain hemodynamics during rubber hand illusion. AB - Embodied cognition has been eagerly studied in the recent neuroscience research field. In particular, hand ownership has been investigated through the rubber hand illusion (RHI). Most of the research measured the brain activities during the RHI by using EEG, fMRI, etc., however, near-infrared spectroscopy (NIRS) has not yet been utilized. Here we attempt to measure the brain activities during the RHI task with NIRS, and analyze the functional connectivity so as to understand the relationship between NIRS features and the state of embodied cognition. For the purpose, we developed a visuo-tactile stimulator in the study. As a result, we found that the subjects felt illusory experience showed significant peaks of oxy-Hb in both prefrontal and premotor cortices during RHI. Furthermore, we confirmed a reliable causality connection from right prefrontal to right premotor cortex. This result suggests that the RHI is associated with the neural circuits underlying motor control. Therefore, we considered that the RHI with the functional connectivity analysis will become an appropriate model investigating a biomarker for neurorehabilitation, and the diagnosis of the mental disorders. PMID- 26737236 TI - In vivo NIRS monitoring in pig Spinal Cord tissues. AB - Little is known about the processes occurring after Spinal Cord damage. Whether permanent or recoverable, those processes have not been precisely characterized because their mechanism is complex and information on the functioning of this organ are partial. This study demonstrates the feasibility of Spinal Cord activity monitoring using Near Infra-Red Spectroscopy in a pig animal model. This animal has been chosen because of its comparable size and its similarities with humans. In the first step, optical characterization of the Spinal Cord tissues was performed in different conditions using a spectrophotometer. Optical Density was evaluated between 3.5 and 6.5 in the [500; 950] nm range. Secondly, adapted light sources with custom probes were used to observe autonomic functions in the spine. Results on the measured haemodynamics at rest and under stimulation show in real time the impact of a global stimulus on a local section of the Spinal Cord. The photoplethysmogram signal of the Spinal Cord showed low AC-to-DC ratio (below to 1 %). PMID- 26737237 TI - High-resolution MRI of spinal cords by compressive sensing parallel imaging. AB - Spinal Cord Injury (SCI) is a common injury due to diseases or accidents. Noninvasive imaging methods play a critical role in diagnosing SCI and monitoring the response to therapy. Magnetic Resonance Imaging (MRI), by the virtue of providing excellent soft tissue contrast, is the most promising imaging method for this application. However, spinal cord has a very small cross-section, which needs high-resolution images for better visualization and diagnosis. Acquiring high-resolution spinal cord MRI images requires long acquisition time due to the physical and physiological constraints. Moreover, long acquisition time makes MRI more susceptible to motion artifacts. In this paper, we studied the application of compressive sensing (CS) and parallel imaging to achieve high-resolution imaging from sparsely sampled and reduced k-space data acquired by parallel receive arrays. In particular, the studies are limited to the effects of 2D Cartesian sampling with different subsampling schemes and reduction factors. The results show that compressive sensing parallel MRI has the potential to provide high-resolution images of the spinal cord in 1/3 of the acquisition time required by the conventional methods. PMID- 26737238 TI - The predictive power of structural MRI in Autism diagnosis. AB - Diagnosis of Autism Spectrum Disorder (ASD) using structural magnetic resonance imaging (sMRI) of the brain has been a topic of significant research interest. Previous studies using small datasets with well-matched Typically Developing Controls (TDC) report high classification accuracies (80-96%) but studies using the large heterogeneous ABIDE dataset report accuracies less than 60%. In this study we investigate the predictive power of sMRI in ASD using 373 ASD and 361 TDC male subjects from the ABIDE. Brain morphometric features were derived using FreeSurfer and classification was performed using three different techniques: Random Forest (RF), Support Vector Machine (SVM) and Gradient Boosting Machine (GBM). Although high classification accuracies were possible in individual sites (with a maximum of 97% in Caltech), the highest classification accuracy across all sites was only 60% (sensitivity = 57%, specificity = 64%). However, the accuracy across all sites improved to 67% when IQ and age information were added to morphometric features. Across all three classifiers, volume and surface area had more discriminative power. In general, important features for classification were present in the frontal and temporal regions and these regions have been implicated in ASD. This study also explores the effect of demographics and behavioral measures on the predictive power of sMRI. Results show that classification accuracy increases with autism severity and that ASD detection with sMRI is easier before the age of 10 years. PMID- 26737239 TI - Medial temporal lobe high resolution magnetic resonance images for the early diagnosis of Alzheimer's disease. AB - A challenging point in neuroimaging is the diagnosis of Alzheimer's disease (AD) during its asymptomatic phase. Among all the biomarkers proposed in the literature, a measure of the hippocampal atrophy via Magnetic Resonance Imaging (MRI) seems to be one of the most reliable. Refined image processing techniques were already proposed to automatically extract the hippocampal boxes from images acquired with the standard full brain acquisition protocol suggested by the Alzheimer's Disease Neuroimaging Initiative (ADNI). In order to enhance this approach, here we propose a high resolution (HR) MRI protocol focused on the medial temporal lobe (MTL) mainly conceived for 1.5T MRI device, hereafter referred as MTL-HR protocol. A preliminary characterization of its behavior when compared to the standard ADNI protocol is also presented. PMID- 26737240 TI - Multimodal MRI classification in vascular mild cognitive impairment. AB - Vascular mild cognitive impairment (VMCI) is a disorder in which multimodal MRI can add significant value by combining diffusion tensor imaging (DTI) with brain morphometry. In this study we implemented and compared machine learning techniques for multimodal classification between 58 VMCI patients and 29 healthy subjects as well as for discrimination (within the VMCI group) between patients with different cognitive performances. For each subject, a cortical feature vector was constructed based on cortical parcellation and cortical and subcortical volumetric segmentation and a DTI feature vector was formed by combining descriptive statistical metrics related to the distribution of DTI invariants within white matter. We employed both a sequential minimal optimization and a functional tree classifier, using feature selection and 10 fold cross-validation, and compared their performances in monomodal and multimodal classification for both classification problems (healthy subjects vs VMCI and prediction of cognitive performance). While monomodal classification resulted in satisfactory performance in most cases, turning from monomodal to multimodal classification resulted in an improvement of the performance in the discrimination between VMCI patients with low cognitive performance and healthy subjects by up to 10% in sensitivity (leaving specificity unchanged). We therefore are able to confirm the usefulness of machine learning techniques in discriminating diseased states based on neuroimaging data. PMID- 26737241 TI - Functional diffusion map: A biomarker of brain metastases response to treatment based on magnetic resonance image analysis. AB - Validated biomarkers for treatment response in patients suffering from brain metastases are needed in daily clinical practice as they may improve survival by providing reliable prognostic information and allowing alternative therapies. This work presents a new analysis tool for an early and non-invasive evaluation of treatment response in patients with brain metastases. A set of twenty-five metastases from sixteen patients were examined by T1-weighted and diffusion magnetic resonance imaging before starting radiotherapy and at least once after treatment. Diffusion MRI can show a correlation between water diffusion variation within metastasis area and its clinical evolution. Images were co-registered to pretreatment scans. Diffusion changes, resulting in spatially varying changes in apparent diffusion coefficient values of metastatic lesions, were quantified and presented as a functional diffusion map (fDM). These functional maps were compared to two traditional criteria for assessing oncological response. Of the twenty-five metastases analyzed, seven were classified as partial response (PR), eight as stable disease (SD) and nine as progressive disease (PD). Normalized volume values of the metastases for each response group were obtained, disclosing that apparent diffusion coefficient increase was a good predictor of response. Sensitivity was 88%, specificity 100%, positive predictive value 100% and negative predictive value was 94%. Outcome reveals that the implemented tool, based on functional diffusion mapping as evolution biomarker, provides a reliable prediction of metastases response to treatment. PMID- 26737242 TI - Sparse dictionary learning for fMRI analysis using autocorrelation maximization. AB - In this paper, the effect of temporal autocorrelations in functional magnetic resonance imaging (fMRI) data on sparse dictionary learning (SDL) is addressed. For sparse general linear model (sGLM), the fMRI time-series is modeled as a linear mixture of several signals such as neural dynamics, structured noise, random noise and unexplained signal variations on the basis of spatial sparseness. These signals are considered as underlying sources and SDL is used to estimate them. However, the sparse GLM model does not take into account the autocorrelations in fMRI data. To address this shortcoming, a new model is proposed to incorporate the prior knowledge about lag-1 autocorrelation into dictionary update stage. This helps improve the sensitivity and specificity of the fMRI data during statistical analysis. Using a simulation study, the effect of the proposed dictionary update on sGLM is compared to conventional sGLM by utilizing various detrending techniques. Furthermore, the proposed update is validated in an sGLM framework for real fMRI datasets, which shows its better capability to estimate neural dynamics in presence of spatiotemporal dependencies. PMID- 26737243 TI - Resting-state brain activity in the motor cortex reflects task-induced activity: A multi-voxel pattern analysis. AB - It has been suggested that resting-state brain activity reflects task-induced brain activity patterns. In this study, we examined whether neural representations of specific movements can be observed in the resting-state brain activity patterns of motor areas. First, we defined two regions of interest (ROIs) to examine brain activity associated with two different behavioral tasks. Using multi-voxel pattern analysis with regularized logistic regression, we designed a decoder to detect voxel-level neural representations corresponding to the tasks in each ROI. Next, we applied the decoder to resting-state brain activity. We found that the decoder discriminated resting-state neural activity with accuracy comparable to that associated with task-induced neural activity. The distribution of learned weighted parameters for each ROI was similar for resting-state and task-induced activities. Large weighted parameters were mainly located on conjunctive areas. Moreover, the accuracy of detection was higher than that for a decoder whose weights were randomly shuffled, indicating that the resting-state brain activity includes multi-voxel patterns similar to the neural representation for the tasks. Therefore, these results suggest that the neural representation of resting-state brain activity is more finely organized and more complex than conventionally considered. PMID- 26737244 TI - Automatic detection of local arterial input functions through Independent Component Analysis on Dynamic Contrast enhanced Magnetic Resonance Imaging. AB - Arterial Input Function (AIF) is obtained from perfusion studies as a basic parameter for the calculus of hemodynamic variables used as surrogate markers of the vascular status of tissues. However, at present, its identification is made manually leading to high subjectivity, low repeatability and considerable time consumption. We propose an alternative method to automatically identify local AIF in perfusion images using Independent Component Analysis. PMID- 26737245 TI - An MRI-compatible and quantifiable mechanical stimulator for allodynia in a rat model of neuropathic pain. AB - We developed an MRI-compatible and quantifiable mechanical stimulator for rats. Functional MRI (fMRI) was used to investigate brain activations resulting from mechanical stimulation in normal rats and in a rat model of neuropathic pain. In the previous MRI-compatible mechanical stimulator, stimulation intensity was not adjustable. In this study, the strength of mechanical stimulation was controlled by von Frey filaments, which were used for mechanical nociception assessment. It provides us to investigate correlations between behavioral sensitivities in von Frey tests and BOLD signal changes during mechanical stimulation. In order to transmit mechanical force to a stimulation site under the strong magnetic field of a 7-T MRI system, a tube-rod structure consisting of nonmagnetic materials was used. The mechanical stimulation evoked a change in blood oxygenation level dependent (BOLD) signals in normal rats. Changes in brain activation were investigated at around- and supra-threshold conditions of mechanical nociception using the filaments for 15 g and 60 g forces. The mechanical stimulation from the 60-g-force filament, which was over the mechanical nociceptive threshold, induced strong brain activation in the areas related to nociceptive pain perception. This result was consistent with that associated with strong electrical stimulation. Mechanical stimulation in the neuropathic pain model evoked brain activity even at around-threshold conditions of mechanical nociception. Higher brain activity in the neuropathic pain model compared with normal rats was considered to be associated with allodynia. PMID- 26737246 TI - Testing the effects of pre-processing on voxel based morphometry analysis. AB - Voxel based morphometry (VBM) is an automated analysis technique which allows voxel-wise comparison of mainly grey-matter volumes between two magnetic resonance images (MRI). Two main analysis processes in VBM are possible. One is cross-sectional data analysis, where one group is compared with another to depict see the regions in the brain, which show changes in their grey-matter volume. Second is longitudinal data analysis, where MRIs, taken at different time points, are compared to see the regions in the brain that show changes in their grey matter volume for one time point with respect to another time point. Both types of analyses require pre-processing steps before performing the statistical analysis. In this study, we examined grey matter differences for patients with blepharospasmus (BFS) before and after treatment, at two different time points. The main evidence base therapy for this condition is the "botulinum toxin" injection in the respective muscles. The main aim of this study was to look at the effects of different pre-processing steps, namely, normalization and smoothing on the results of the longitudinal data analysis. A second aim was to analyze structural grey-matter differences before and after the treatment. Our results showed that the DARTEL normalization and the lower width for smoothing as preprocessing steps delivered pathophysiological plausible results. The longitudinal analysis revealed significant temporal differences after the injection of the botulinum toxin injection mainly in patients with BFS. PMID- 26737247 TI - A collaborative environment for shared classification of neuroimages: The experience of the Colibri project. AB - The Colibri project is introduced, whose aim is setting up a shared database of Magnetic Resonance images concerning pediatric patients affected by neurological rare disorders. The project involves 19 Italian centers of excellence in pediatric neuro-radiology and is supported by the nationwide coordinating center for the Information and Communication Technology research infrastructure. After the first year devoted to the design and the implementation, in November 2014 the system finally went into service at the centers involved in the project. This paper illustrates the initial assessment of the user perception and provides some preliminary statistics about its use. PMID- 26737248 TI - A statistical approach in human brain connectome of Parkinson Disease in elderly people using Network Based Statistics. AB - Parkinson's Disease (PD) is a progressive neurodegenerative disorder assumed to involve different areas of CNS and PNS. Thus, Diffusion Tensor Imaging (DTI) is used to examine the areas engaged in PD neurodegeneration. In the present study, we computed average tract length and fiber volume as a measure of white matter integrity and adopted Network Based Statistics (NBS) to conduct group analyses between age- and gender-matched PD patients and healthy control connectivity matrices. NBS is a powerful statistical tool that utilizes the presence of every link in connectivity matrices and controls family wise error rates (in weak sense). The major regions with significantly reduced interconnecting fiber volume or average tract length were cingulum, temporal lobe, frontal lobe, parahippocampus, hippocampus, olfactory lobe, and occipital lobe. PMID- 26737249 TI - Testing different ICA algorithms and connectivity analyses on MS patients. AB - Multiple sclerosis (MS) is a progressive neurological disorder that affects the central nervous system. Functional magnetic resonance imaging (fMRI) has been employed to track the course and disease progression in patients with MS. The two main aims of this study were to apply in a data-driven approach the independent component analysis (ICA) in the spatial domain to depict the active sources and to look at the effective connectivity between the identified spatial sources. Several ICA algorithms have been proposed for fMRI data analysis. In this study, we aimed to test two well characterized algorithms, namely, the fast ICA and the complex infomax algorithms, followed by two effective connectivity algorithms, namely, Granger causality (GC) and generalized partial directed coherence (GPDC), to illustrate the connections between the spatial sources in patients with MS. The results obtained from the ICA analyses showed the involvement of the default mode network sources. The connectivity analyses depicted significant changes between the two applied algorithms. The significance of this study was to demonstrate the robustness of the analyzed algorithms in patients with MS and to validate them before applying them on larger datasets of patients with MS. PMID- 26737250 TI - Glaucoma classification using Regional Wavelet Features of the ONH and its surroundings. AB - Glaucoma is one of the leading cause of blindness but the detection at its earliest stage and subsequent treatment can aid patients to preserve blindness. The existing work has been focusing on global features such as texture, grayscale and wavelet energy of the Optic Nerve Head (ONH) and its surrounding to differentiate between normal and glaucoma images. In contrast to previous approaches which focus on global information only, this work proposes a new approach to automatically classify between the normal and glaucoma images based on Regional Wavelet Features of the ONH and different regions around it. These regions are usually used for diagnosis of glaucoma by clinicians through visual observation only. Our method automatically determines different clinically observed regions around the ONH and performs classification on the basis of wavelet energy at different frequency subbands. We have conducted experiments based on different global features and regional features respectively and applied it to RIMONE (An Open Retinal Image Database for Optic Nerve Evaluation) database with 158 images. The experimental evaluation demonstrated that the classification accuracy of normal and glaucoma images using Regional Wavelet Features of different regions with 93% outperforms all other feature sets. PMID- 26737251 TI - New hierarchical approach for microaneurysms detection with matched filter and machine learning. AB - Microaneurysms are regarded as the first signs of diabetic retinopathy (DR), but the microaneurysms are not clear in the color retinal images, and many researches were studied to detect and locate these lesions. In this paper, a new hierarchical computing-aided diagnosis approach is proposed for the microaneurysms detection by using the multi-scale and multi-orientation sum of matched filter (MMMF) and machine learning, where 37 dimensional features are extracted from each candidate. Furthermore, several classifiers such as the k nearest neighbor (kNN), local linear discrimination analysis (LLDA) and support vector machine (SVM) are modified to distinguish the true microaneurysms from the false ones, which is a typical unbalanced classification problem. The effectiveness of the proposed method is verified through the training set of a publicly available database, and the experiment results show that the proposed method has better detection performance including the receiver operating characteristic (ROC) curve and the free-response receiver operating characteristic (FROC) curve. Moreover, the proposed method with 37 dimensional features outperforms that with other features and has a sensitivity from 1/8 to 8 with the average of all seven points being 0.286 tested on the same database. PMID- 26737252 TI - An augmented reality assistance platform for eye laser surgery. AB - This paper presents a novel augmented reality assistance platform for eye laser surgery. The aims of the proposed system are for the application of assisting eye doctors in pre-planning as well as providing guidance and protection during laser surgery. We developed algorithms to automatically register multi-modal images, detect macula and optic disc regions, and demarcate these as protected areas from laser surgery. The doctor will then be able to plan the laser treatment pre surgery using the registered images and segmented regions. Thereafter, during live surgery, the system will automatically register and track the slit lamp video frames on the registered retina images, send appropriate warning when the laser is near protected areas, and disable the laser function when it points into the protected areas. The proposed system prototype can help doctors to speed up laser surgery with confidence without fearing that they may unintentionally fire laser in the protected areas. PMID- 26737253 TI - Computer-assisted grading of diabetic macular edema on retinal color fundus images. AB - Diabetic macular edema (DME) is one of the vision-impairing manifestations of Diabetic Retinopathy (DR). Early detection and treatment of DME can prevent permanent vision loss in people suffering from DR. However, the clinical detection through biomicroscopy is time-consuming. In this paper, a computer assisted grading method has been proposed to determine the DME severity based on the spatial distribution of exudative lesions around macula. The region around macula is classified into zonal levels and severity of the DME is graded based on the presence of exudative lesions in each zone. The proposed method has been evaluated on diverse public and local databases, and produced the sensitivity of 89.54% for 9.1 false positive per image (FPPI) for exudate detection and 98.8% accuracy for DME grading. PMID- 26737254 TI - 3-D localization of Diabetic Macular Edema using OCT thickness maps. AB - This paper presents a novel automated system that segments 3-D thickness maps of sub-retinal layers from healthy and abnormal OCT image stacks with Diabetic Macular Edema (DME). These automated thickness maps are well correlated (r > 0.7) with the manually segmented thickness maps. The thickness maps demonstrate highly irregular regions in the inner and outer nuclear layers for patients with DME when compared to the healthy images. The combined area of irregularity in the inner and outer nuclear layers can thereby be extracted as a novel metric with correlation r = 0.99 to track the severity of DME. No other existing automated algorithm has extracted inner sub-retinal layer thickness maps from OCT image stacks of DME patients. The proposed system is fast and robust in locating the sub-retinal changes caused by DME in the 3-D sub-retinal micro-structure. PMID- 26737255 TI - Computer-aided diagnosis of plus disease in retinal fundus images of preterm infants via measurement of vessel tortuosity. AB - An increase in retinal vessel tortuosity can be indicative of the presence of various diseases including retinopathy of prematurity (ROP). Accurate detection and measurement of such changes could help in computer-aided diagnosis of plus disease, which warrants treatment of ROP. We present image processing methods for detection and segmentation of retinal vessels, quantification of vessel tortuosity, and diagnostic-decision-making criteria that incorporate the clinical definition of plus-diagnosis. The obtained results using 110 retinal fundus images of preterm infants (91 without plus and 19 with plus) provide high sensitivity = 0.89 (17/19) and excellent specificity = 0.95 (86/91) in the diagnosis of plus disease. PMID- 26737256 TI - A new tool to connect blood vessels in fundus retinal images. AB - This paper presents a novel tool that allows a user to reconstruct the retinal vascular network from fundus images. The retinal vasculature consists of trees of arteries and veins. Common segmentation algorithms are not able to completely segment out the blood vessels in fundus images. This failure results in a set of disconnected or broken up vascular segments. Reconstructing the whole network has crucial importance because it can offer insight into global features not considered so far, including retinal fluid dynamics. This tool uses implicit neural cost functions to join vessel segments. Results have shown that the quality of the segmentation affects the outcome of connectivity algorithms and by enhancing the segmentation the connectivity can be improved. PMID- 26737257 TI - Interactive retinal vessel centreline extraction and boundary delineation using anisotropic fast marching and intensities consistency. AB - In this paper, we propose a new interactive retinal vessels extraction method with anisotropic fast marching (AFM) based on the observation that one vessel may have the property of local intensities consistency. Our goal is to extract both the centrelines and boundaries between two given points. The proposed method consists of two stages: the first stage aims to finding the vessel centrelines using AFM and local intensities consistency roughly, while the second stage is to refine the centrelines from the previous stage using constrained Riemannian metric based AFM, and get the boundaries of the vessels simultaneously. Experiments show that results of our method outperform the classical minimal path method [1]. PMID- 26737258 TI - Reducing the artifacts in the identification of outer retinal boundary in the SD OCT image with inherit retinal dystrophies. AB - This paper presents a new SD-OCT outer retinal boundary identification method based on the improved graph-theoretic approach in SD-OCT retinal image, which is robust to the image quality degradation and the pathological morphology variability. The performance of the proposed method was verified using the SD-OCT image database with inherit retinal dystrophies, which suffer from the artifacts most among different macular degeneration diseases. The experimental results of the subjective evaluation indicated that the identification results using the proposed method was substantially improved compared with the current built-in software in the SD-OCT devices. PMID- 26737259 TI - A mucoadhesive endoluminal wearable sensory system. AB - Bio- or muco-adhesive anchoring is a challenge for the development of advanced gastrointestinal (GI) surgical instruments, endoluminal monitoring devices and drug delivery systems. In this paper, we present a polymeric bio-adhesive film embedded with an optical sensor that can potentially be used to detect gastrointestinal bleeding. Four different formulas of mucoadhesive polymers were synthesized based on various chemical components and concentration combinations, and they were further layered with miniature photoplethymographic (PPG) sensors. The adhesive ability of the proposed mucoadhesive-sensor module was tested by attaching it to the lumen of a porcine stomach and compared amongst the four formulas. pH testing was also implemented to simulate the performance of the film in gastric cavity. To demonstrate the signal quality of this module, we also tested on the skin of five healthy subjects for hours. The observed shear detachment force between mucoadhesive film and porcine stomach tissue of all four formulations ranged from 0.09 to 1.38 N, and the performance of mucoadhesive film in pH 7 and pH 2 were similar. The module can attach firmly onto the skin for 3 10 hours with comparable PPG signal quality to traditional clip-based setup. With the advent of mucosal tissue anchoring by means of bioadhensive film, a wider extent of endoluminal procedures may become feasible. This emerging technology can also help shape the future of in-body wearable devices in the GI tract or other endoluminal cavities. PMID- 26737260 TI - Photoelectric properties in metal ion modified DNA nanostructure. AB - Due to specific or as designed self-assembly, DNA nanostructures gaining popularity in various nanoscale electronic applications. Herein, a novel divalent metal ion-DNA complex known as M-DNA have been investigated for its photoelectric characteristics. The increased conductivity of M-DNA thin films is attributed to the metal ion electrical and optical properties. The gate voltage effect along with illumination on the conductivity of M-DNA demonstrates that M-DNA can be used as an active element of a field-effect transistor. The Zn DNA shows maximum conductivity of 300MUS/cm at 480 nm light illumination suggest that M-DNA can be utilized in nano-opto-electronics and bio-sensing applications. PMID- 26737261 TI - Development of an integrated optical contact force monitoring sensor for cardiac ablation catheters. AB - Contact force monitoring technology during cardiac catheter ablation has become a major issue as both appropriate RF delivery and risk-free therapy have been more and more significant. In this study, an elastic waveguide was utilized to detect the contact force of 0 to 40 gF applied at the end of the sensor tip. The sensor showed a hysteresis between the force loading and releasing because of the elasticity of waveguide. The sensing responses were nearly linear and the sensitivity was about 0.2 mV/gF. PMID- 26737262 TI - Resistopalatography as an assistive technology for users with spinal cord injuries. AB - Translating a desired user's input using conventional methods such as a keyboard and mouse for the computer, or a joystick for a wheelchair is a major challenge faced by users whom have no limb control. This paper describes an iteration of Resistopalatography, a method using the tongue as a pointing device to emulate the use of the hand for cursor movement and wheelchair control. The system employs force sensitive sensors located within the mouth on a dental retainer plate to measure the tongue's pressure against the hard palate. The position and force of tongue against the sensors can be translated into mouse cursor or wheelchair joystick equivalents. PMID- 26737263 TI - A low power, area efficient fpga based beamforming technique for 1-D CMUT arrays. AB - A low power area efficient digital beamformer targeting low frequency (2MHz) 1-D linear Capacitive Micromachined Ultrasonic Transducer (CMUT) array is developed. While designing the beamforming logic, the symmetry of the CMUT array is well exploited to reduce the area and power consumption. The proposed method is verified in Matlab by clocking an Arbitrary Waveform Generator(AWG). The architecture is successfully implemented in Xilinx Spartan 3E FPGA kit to check its functionality. The beamforming logic is implemented for 8, 16, 32, and 64 element CMUTs targeting Application Specific Integrated Circuit (ASIC) platform at Vdd 1.62V for UMC 90nm technology. It is observed that the proposed architecture consumes significantly lesser power and area (1.2895 mW power and 47134.4 MUm(2) area for a 64 element digital beamforming circuit) compared to the conventional square root based algorithm. PMID- 26737264 TI - Unobtrusive tactile sensing based on electromechanical boundary estimation. AB - Unobtrusive tactile sensing is an important yet challenging topic for medical and robotic fields. We proposed a novel tactile sensing technology for obtaining the force of an interaction and the position at which it makes contact with an object of arbitrary shape without any mechanical obstructions. The proposed sensing method is based on electromechanical boundary estimation from the potential distribution, which is related to the contact state of the two objects with a potential applied. To evaluate the sensing method, we investigated the error of positional estimation and the relationship between force and sensor output. The experimental results indicated that the contact position can be estimated with a correctable systematic error several mm.We also confirmed a high correlation between the interacting force and the system output. PMID- 26737265 TI - A MU-biomimetic flow sensor for medical and pharmaceutical applications. AB - Flow sensing is pivotal in many medical and pharmaceutical applications. Most commercial flow sensors are either expensive, complex, or consume a lot of energy, while low cost sensors usually lack sensitivity, robustness, or long-term stability. In addition, the maintenance and sterilization of most commercial flow sensors is difficult to perform. Here, we present a new MU-biomimetic flow sensor based on the fish lateral line. It measures flow velocity and detects the transition between laminar and turbulent flow, thereby fulfilling most requirements for medical and pharmaceutical applications. Additionally, it has a modular setup featuring a screened or passive bypass configuration, enabling it not only to meter flow in medical applications but also under harsh or well defined environmental conditions, such as found in pharmaceutical applications. The sensor is robust and can be easily cleaned. Individual parts of the sensor can even be replaced or sterilized. In sum, this sensor opens up a whole new field of applications in the area of medical and pharmaceutical related flow monitoring. PMID- 26737266 TI - Effects of sensor type and sensor location on signal quality in bed mounted ballistocardiographic heart rate and respiration monitoring. AB - Sleeping is a crucial part of our circadian rhythm and the quality of sleep has substantial impact on the quality of life in general and the overall well-being of a person. That is why sleep related physiological measurements have been in the focus of many scientific studies along the years, and why a large number of different measurement methods have been developed for this purpose. The ability to monitor heart rate respiration without any sensors or electrodes being directly attached to the body is extremely useful especially in long-term monitoring and it allows automated daily measurements without any medical staff present. This is the reason why ballistocardiographic force sensors and accelerometers have been introduced alongside electrocardiography (ECG) and thermistors or respiration belts as a means to monitor the heart rate and respiration during sleep. While ECG remains as the most reliable and accurate method for heart rate monitoring, the development of unobtrusive monitoring methods has improved to the point where the commercialization of such sleep monitoring systems has been possible. In this paper, the signals of five sensors and sensor placement combinations for measuring physiological parameters from a sleeping person are evaluated and compared in terms of their measurement sensitivities and waveform quality. The sensors are accelerometer and film type force sensors made of PVDF and EMFi material placed under the mattress topper and PVDF and EMFi sensors placed under the bed posts. PMID- 26737267 TI - Comparative study on dielectric constants and conductivities of invasive ductal carcinoma tissues. AB - Measurements of dielectric constants and conductivities of invasive ductal carcinoma (IDC) tissues such as scirrhous carcinoma, solidtubular carcinoma and papillotubular carcinoma were made by use of microwave dielectric spectroscopy. Dielectric constants of inhomogeneous breast tumor tissues were analyzed by use of Bruggeman's effective medium approximation theory. It is found that the dielectric constants of scirrhous carcinoma, solidtubular carcinoma and papillotubular carcinoma of IDC tissues have correlation to the volume fractions of the cancer cells in the stroma tissues. PMID- 26737268 TI - Nanomaterial-based biosensors for a real-time detection of biological damage by UV light. AB - In this work, the design and fabrication of a miniaturized and light-weight biosensor that can be used to monitor the biological effects of hostile ultraviolet radiation in earth and space are presented. The biosensor is generated by embedding a sensitive element to UV radiation, DNA, in a hybrid carbon-based nanomaterial. In particular, we present results on the fabrication and characterization of hybrid nanostructured films containing graphene nanoplatelets (GNPs) and double-stranded DNA for the in situ and real-time detection of UV radiation damaging effects from the changes of the film electrical properties induced by exposure to UV-C radiation. The biosensor is realized by the deposition of the sensitive unit GNP/DNA on a supporting substrate made of flexible polymers or glass. PMID- 26737269 TI - Evaluation of a noninvasive deep body thermometer in measurement of specific positions. AB - This study tried to address the theoretical issue of a noninvasive deep body thermometer based on dual-heat-flux method about what depth does the thermometer measure and to what extent can it reflect the change of the real core body temperature (CBT). Authors built up two elaborate 3D models incorporated with the statistics of clinical studies and minute description of blood perfusion to mimic the situations when the thermometer was applied to forehead and thorax, respectively. The results based on finite element analysis show that the thermometer can approximate to the frontal bone and reach to the sternum. For the range from 34 to 40 degrees C, the measuring depth was stable and hardly be influenced by central thermoregulatory system. Furthermore, it is also suggested that the forehead may be suited for intensive CBT monitoring and the thorax is feasible for daily healthcare application. PMID- 26737270 TI - Intuitive wireless control of a robotic arm for people living with an upper body disability. AB - Assistive Technologies (ATs) also called extrinsic enablers are useful tools for people living with various disabilities. The key points when designing such useful devices not only concern their intended goal, but also the most suitable human-machine interface (HMI) that should be provided to users. This paper describes the design of a highly intuitive wireless controller for people living with upper body disabilities with a residual or complete control of their neck and their shoulders. Tested with JACO, a six-degree-of-freedom (6-DOF) assistive robotic arm with 3 flexible fingers on its end-effector, the system described in this article is made of low-cost commercial off-the-shelf components and allows a full emulation of JACO's standard controller, a 3 axis joystick with 7 user buttons. To do so, three nine-degree-of-freedom (9-DOF) inertial measurement units (IMUs) are connected to a microcontroller and help measuring the user's head and shoulders position, using a complementary filter approach. The results are then transmitted to a base-station via a 2.4-GHz low-power wireless transceiver and interpreted by the control algorithm running on a PC host. A dedicated software interface allows the user to quickly calibrate the controller, and translates the information into suitable commands for JACO. The proposed controller is thoroughly described, from the electronic design to implemented algorithms and user interfaces. Its performance and future improvements are discussed as well. PMID- 26737271 TI - Passive RFID tag based heart rate monitoring from an ECG signal. AB - In this paper, we propose a monitoring system that employs a passive RFID tag to transmit heart rate using an ECG signal as its source. This system operates without a battery and has been constructed with easily available commercial components. Here, an RFID tag is used as an on-off keying device, wherein it is normally transmitting, but turns off every time a heart beat is detected. Heart beats ranging from 30BPM through 300BPM are successfully measured using our device. It is shown that the system is capable of providing accurate heart rate measurements up to a distance of ten feet with a standard deviation of less than one beat per minute without a local power source. The proposed system is also found to be resilient in the presence of an additional RFID tag. PMID- 26737272 TI - An eight-legged tactile sensor to estimate coefficient of static friction. AB - It is well known that a tangential force larger than the maximum static friction force is required to initiate the sliding motion between two objects, which is governed by a material constant called the coefficient of static friction. Therefore, knowing the coefficient of static friction is of great importance for robot grippers which wish to maintain a stable and precise grip on an object during various manipulation tasks. Importantly, it is most useful if grippers can estimate the coefficient of static friction without having to explicitly explore the object first, such as lifting the object and reducing the grip force until it slips. A novel eight-legged sensor, based on simplified theoretical principles of friction is presented here to estimate the coefficient of static friction between a planar surface and the prototype sensor. Each of the sensor's eight legs are straight and rigid, and oriented at a specified angle with respect to the vertical, allowing it to estimate one of five ranges (5 = 8/2 + 1) that the coefficient of static friction can occupy. The coefficient of friction can be estimated by determining whether the legs have slipped or not when pressed against a surface. The coefficients of static friction between the sensor and five different materials were estimated and compared to a measurement from traditional methods. A least-squares linear fit of the sensor estimated coefficient showed good correlation with the reference coefficient with a gradient close to one and an r(2) value greater than 0.9. PMID- 26737273 TI - Surface deformation tracking and modeling of soft materials. AB - Characterizing the mechanical properties of skin may lead to improvements in surgical scarring, burns treatments, artificial skin science, and disease detection. We present a method of validating a phase-based crosscorrelation method of material point tracking, used to measure surface deformations in soft tissues, using a silicone gel phantom. Tracking of a high spatial-resolution speckle pattern was validated using independent fluorescent microsphere markers. A finite element mesh was deformed according to the tracked speckle pattern, and used to predict the location of the markers. Predictions of microsphere location were compared to stereo-reconstructions. Under a 2900 MUm indentation, markers under rms displacements of 125 MUm produced a discrepancy between prediction and reconstruction of 23 MUm. The same deformation conditions were used to illustrate the use of surface tracking for identifying mechanical properties. A force-driven finite element mesh, using a Neo-Hookean constitutive model, reproduced the surface deformation with an rms error of 172 MUm. PMID- 26737274 TI - Melanosome distribution patterns affecting skin reflectance: Implications for the in vivo estimation of epidermal melanin content. AB - Several techniques employed in the in vivo estimation of epidermal melanin content rely on the assumption that the effects of different distribution patterns of aggregated melanin (clustered within the melanosomes) on skin spectral responses, particularly across the 600-1350 nm range, can be ignored. Accordingly, for all practical purposes, only the non-aggregated (colloidal) form of melanin is taken into account by these techniques. In this paper, however, we demonstrate through predictive computer simulations that these responses are directly influenced by the occurrence of both forms of melanin. Our in silico findings, in turn, indicate that such an assumption may lead to inaccurate estimations of epidermal melanin content. PMID- 26737275 TI - Homology modeling of target proteins and identification novel antifungal compounds against Candida tropicalis through structure based virtual screening. AB - Candida tropicalis, the etiological agent of candidiasis evades the immune system and survive in the human host for decades. Currently there are not many drugs available in the market to treat these fungal infections. The increasing number of fungal infections necessitates the need for new drug candidates that can be used to treat fungal infections such as candida. Many natural products available in plants, animals and microorganisms exhibit potent anti-microbial activity; but they are not explored to their potential. Virtual screening of anti-microbials against known targets accelerates the process of drug discovery and development. In the present study, a total of 27 compounds of natural origin such as plants, microbes and marine sponges were evaluated for their ability to interact with four of the new targets. The study revealed the effectiveness of 3 compounds with improved binding affinity against the four target proteins; that could be used as lead compounds in designing new drug candidates. PMID- 26737276 TI - Anthropometric measurements for assessing insulin sensitivity on patients with metabolic syndrome, sedentaries and marathoners. AB - The diagnosis of low insulin sensitivity is commonly done through the HOMA-IR index, in which fasting insulin and glucose blood levels are evaluated. Insulin and blood glucose levels are used for insulin sensitivity assessment by surrogate methods (HOMA-IR, Matsuda, etc), but anthropometric measurements like body weight, height and waist circumference are not considered, even if these variables also are related to low insulin sensitivity and metabolic syndrome. In this study we evaluate the impact of anthropometric measurements on the HOMA-IR, Matsuda and Caumo indexes to estimate insulin sensitivity. Specifically, we compare insulin sensitivity indexes with and without the anthropometric measurements in their equations on three different groups: patients with metabolic syndrome, sedentaries and marathoners. Results show relationships between anthropometric variables and insulin sensitivity indexes. On the other hand, subjects are mapped differently for insulin sensitivity assessment when anthropometric variables are taken into account. In addition, subjects diagnosed with normal insulin sensitivity could be considered as having low insulin sensitivity when anthropometric variables are considered. PMID- 26737277 TI - Feature selection and oversampling in analysis of clinical data for extubation readiness in extreme preterm infants. AB - We present an approach for the analysis of clinical data from extremely preterm infants, in order to determine if they are ready to be removed from invasive endotracheal mechanical ventilation. The data includes over 100 clinical features, and the subject population is naturally quite small. To address this problem, we use feature selection, specifically mutual information, in order to choose a small subset of informative features. The other challenge we address is class imbalance, as there are many more babies that succeed extubation than those who fail. To handle this problem, we use SMOTE, an algorithm which creates synthetic examples of the minority class. PMID- 26737278 TI - Correlation of clinical parameters with cardiorespiratory behavior in successfully extubated extremely preterm infants. AB - Extremely preterm infants (gestational age <= 28 weeks) often require EndoTracheal Tube-Invasive Mechanical Ventilation (ETT-IMV) to survive. Clinicians wean infants off ETT-IMV as early as possible using their judgment and clinical information. However, assessment of extubation readiness is not accurate since 20 to 40% of preterm infants fail extubation. We extended our work in automated prediction of extubation readiness by examining correlations of automated cardiorespiratory features to clinical parameters in successfully extubated infants. Only a few features, mainly those related to variability of breathing synchrony, had any consistent correlation with clinical parameters, namely gestational age, day of life at extubation, and bicarbonate. We conclude that the automated cardiorespiratory features likely provide different information additional to clinical practice. PMID- 26737279 TI - Accuracy and optimization of a subcutaneous insulin model for less acute critical care patients. AB - Extending safe, effective glycemic control to the general wards requires a simple approach using subcutaneous (SC) insulin. However, this approach can increase relative risk compared to intravenous insulin due to the increased variability of SC insulin appearance. This paper evaluates the accuracy of a SC plasma insulin model and optimizes its parameters using measured plasma insulin data from 6 less acute critical care patients treated with SC insulin. The SC plasma insulin model used captures the dynamics of regular SC insulin well. However, there appears to be a positive bias leading to an overall median [IQR] residual error of -28.3 [ 37 - 19] mU/L. The optimized model reduced the RMS residual error by 20-70% for each patient. The distinct inter- and intra-patient, and cohort variation seen in this data highlights the importance to of understanding how SC insulin appearance dynamics may be affected by the subject condition. PMID- 26737280 TI - Procoagulant control strategies for the human blood clotting process. AB - This paper describes the comparison between two drug control strategies to hemophilia A. To emulate blood clotting and the pathological condition of hemophilia, a mathematical model composed by 14 ordinary differential equations is considered. We adopt a variable structure non-linear PID approach and a Model Predictive Control in order to control the dosage of procoagulant factor used in the treatment of hemophiliac patient. The two control actions are sampled for a practical application. Finally, we discuss and compare the results of the two control approaches, introducing a suited control index (eINR). PMID- 26737281 TI - A machine learning pipeline for multiple sclerosis course detection from clinical scales and patient reported outcomes. AB - In this work we present a machine learning pipeline for the detection of multiple sclerosis course from a collection of inexpensive and non-invasive measures such as clinical scales and patient-reported outcomes. The proposed analysis is conducted on a dataset coming from a clinical study comprising 457 patients affected by multiple sclerosis. The 91 collected variables describe patients mobility, fatigue, cognitive performance, emotional status, bladder continence and quality of life. A preliminary data exploration phase suggests that the group of patients diagnosed as Relapsing-Remitting can be isolated from other clinical courses. Supervised learning algorithms are then applied to perform feature selection and course classification. Our results confirm that clinical scales and patient-reported outcomes can be used to classify Relapsing-Remitting patients. PMID- 26737282 TI - Next generation patient monitor powered by in-silico physiology. AB - The goal of this paper is to introduce a next generation patient monitoring technology that relies on objective and continuous data analytics to alleviate the data overload in the critical care unit. The technology provides the foundation for increasing the consistency and efficacy of data use in clinical practice and improving outcomes. This paper presents results for applying the approach to the hemodynamic monitoring of infants immediately following cardiac surgery and demonstrates its efficacy of estimating the probability of inadequate systemic oxygen delivery, which is an essential risk attribute in the management of critically ill patients. PMID- 26737283 TI - Mathematical models of tumor growth using Voronoi tessellations in pathology slides of kidney cancer. AB - The impact of patient-specific spatial distribution features of cell nuclei on tumor growth characteristics was analyzed. Tumor tissues from kidney cancer patients were allowed to grow in mice to apply H&E staining and to measure tumor volume during preclinical phase of our study. Imaging the H&E stained slides under a digital light microscope, the morphological characteristics of nuclei positions were determined. Using artificial intelligence based techniques, Voronoi features were derived from diagrams, where cell nuclei were considered as distinct nodes. By identifying the effect of each Voronoi feature, tumor growth was expressed mathematically. Consistency between the computed growth curves and preclinical measurements indicates that the information obtained from the H&E slides can be used as biomarkers to build personalized mathematical models for tumor growth. PMID- 26737284 TI - Extracting reliable gene expression signatures through Stable Bootstrap Validation. AB - Identification of candidate genes responsible for specific phenotypes, such as cancer, has been a major challenge in the field of bioinformatics. Given a DNA Microarray dataset, traditional feature selection methods produce lists of candidate genes which vary significantly under variations of the training data. That instability hinders the validity of research findings and raises doubts about the reliability of such methods. In this study, we propose a framework for the extraction of stable genomic signatures. The proposed methodology enforces stability at the validation step, independent of the feature selection and classification methods used. The statistical significance of the selected gene set is also assessed. The results of this study demonstrate the importance of stability issues in genomic signatures, beyond their prediction capabilities. PMID- 26737285 TI - Rank-based miRNA signatures for blood-based diagnosis of tuberculosis. AB - We describe a new signature definition and analysis method to be used as biomarker for blood-based diagnosis of tuberculosis. Our new approach is based on the construction of a reference map of transcriptional signatures of both healthy and affected individuals using circulating miRNA from a large number of subjects. Once such a map is available, the diagnosis for a new patient can be performed by observing the relative position on the map of his/her transcriptional signature. To demonstrate its efficacy for this specific application we report the results of the application of our method to published data sets of circulating miRNA. Two crucial features make this method an ideal candidate for large scale applications such as a mass screening tool, or for point-of-care diagnostics. Specifically, our method is minimally invasive because it works well with profiles of circulating miRNA. More importantly, it is robust with respect to lab-to-lab protocol variability, measurement errors and batch effects because it requires that only the relative ranking of miRNA species in a profile be accurate, not their absolute values. PMID- 26737286 TI - Epileptic EEG visualization and sonification based on linear discriminate analysis. AB - In this paper, we first presents a high accuracy epileptic electroencephalogram (EEG) classification algorithm. EEG data of epilepsy patients are preprocessed, segmented, and decomposed to intrinsic mode functions, from which features are extracted. Two classifiers are trained based on linear discriminant analysis (LDA) to classify EEG data into three types, i.e., normal, spike, and seizure. We further in-depth investigate the changes of the decision values in LDA on continuous EEG data. An epileptic EEG visualization and sonification algorithm is proposed to provide both temporal and spatial information of spike and seizure of epilepsy patients. In the experiment, EEG data of six subjects (two normal and four seizure patients) are included. The experiment result shows the proposed epileptic EEG classification algorithm achieves high accuracy. As well, the visualization and sonification algorithm exhibits a great help in nursing seizure patients and localizing the area of seizures. PMID- 26737287 TI - Early detection of epilepsy seizures based on a weightless neural network. AB - This work introduces a new methodology for the early detection of epileptic seizure based on the WiSARD weightless neural network model and a new approach in terms of preprocessing the electroencephalogram (EEG) data. WiSARD has, among other advantages, the capacity of perform the training phase in a very fast way. This speed in training is due to the fact that WiSARD's neurons work like Random Access Memories (RAM) addressed by input patterns. Promising results were obtained in the anticipation of seizure onsets in four representative patients from the European Database on Epilepsy (EPILEPSIAE). The proposed seizure early detection WNN architecture was explored by varying the detection anticipation (delta) in the 2 to 30 seconds interval, and by adopting 2 and 3 seconds as the width of the Sliding Observation Window (SOW) input. While in the most challenging patient (A) one obtained accuracies from 99.57% (delta=2s; SOW=3s) to 72.56% (delta=30s; SOW=2s), patient D seizures could be detected in the 99.77% (delta=2s; SOW=2s) to 99.93% (delta=30s; SOW=3s) accuracy interval. PMID- 26737288 TI - Magnetocardiograms early detection of pulmonary arterial hypertension using inverse problem analysis in rat model. AB - Utilizing small animal magnetocardiograms (MCG), we have developed a diagnostic method to detect the development of pulmonary hypertension (PH) in a rat heart. We obtained multiple MCG of rats with monocrotaline-induced PH and monitored the development of pathophysiological conditions. Current dipole estimation was then applied to determine the association between abnormal propagation of the cardiac excited wavefront and disease states. The progress of right ventricular hypertrophy correlated with a decrease in the angles of the current dipoles during R and S waves. In addition, clear changes in the current dipole angles during S waves were observed 9-19 days before the availability of echocardiographic diagnosis of the PH. Our results showed, using a rat PH model, that continuous monitoring of myocardial conditions allows PH to be detected at an earlier stage than echocardiographic screening. PMID- 26737289 TI - Imaging of cardiac electrical excitation conduction. AB - We present a multiple time windows beamformer (MTWB) method of solving the inverse problem of magnetic field and non-invasively imaging the cardiac electrical excitation conduction using the magnetocardiac signals acquired by a 61-channel superconducting quantum interference device (SQUID). The MTWB constructs spatial filters for each location in source space, one for each component of the source moment based on the distributed source model, and estimates the cardiac equivalent current sources. The output of spatial filters is the source strength estimated in three-dimensional space and the weight matrix calculated with magnetocardiac signals in multiple time windows. A signal subspace projection technique is used to suppress noise. Then, the characteristics of cardiac electrical excitation conduction among two healthy subjects and two coronary vessel stenosis (CVS) patients are extracted from reconstructed current sources with maximum strength at each instant during QRS complex and ST-T segment, and a series of two-dimensional cardiac electrical excitation conduction maps (EECM) are obtained. It is demonstrated that two healthy subjects are of similar and the stronger electrical activities than those of two CVS patients. This technique can be used as an effective tool for the diagnosis of heart diseases. PMID- 26737290 TI - Computationally efficient method for localizing the spiral rotor source using synthetic intracardiac electrograms during atrial fibrillation. AB - Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is an extremely costly public health problem. Catheter-based ablation is a common minimally invasive procedure to treat AF. Contemporary mapping methods are highly dependent on the accuracy of anatomic localization of rotor sources within the atria. In this paper, using simulated atrial intracardiac electrograms (IEGMs) during AF, we propose a computationally efficient method for localizing the tip of the electrical rotor with an Archimedean/arithmetic spiral wavefront. The proposed method deploys the locations of electrodes of a catheter and their IEGMs activation times to estimate the unknown parameters of the spiral wavefront including its tip location. The proposed method is able to localize the spiral as soon as the wave hits three electrodes of the catheter. Our simulation results show that the method can efficiently localize the spiral wavefront that rotates either clockwise or counterclockwise. PMID- 26737291 TI - Calcium leak induced arrhythmias in mouse sino-atrial node and ventricle cells: A simulation study. AB - Bradycardia is found to be a complication during catecholaminergic polymorphic ventricular tachycardia in which calcium leak plays a pivotal role. In this computational study, we determined the effects of sarcoplasmic reticulum calcium leak on the function of sino-atrial node and ventricular model cells. PMID- 26737292 TI - Formation of second-degree atrioventricular blocks in the cardiac heterogeneous oscillator model. AB - We study formation of second-degree atrioventricular blocks (Wenckebach and Mobitz types) with reduction of coupling between nodes in the heterogeneous oscillator model of cardiac conduction system. We demonstrate that maximal possible number of physiological mode lock patterns in both cases appears at a particular value of coupling coefficient. For the type II atrioventricular block total conduction ratio at high sinus rates might be represented by a product of conduction ratios of atrioventricular nodal and infrahisian blocks. PMID- 26737293 TI - Performance of Dower's inverse transform and Frank lead system for Identification of Myocardial Infarction. AB - This study performs a comparison between Dower's inverse transform and Frank lead system for Myocardial Infarction (MI) identification. We have selected a set of relevant features for MI detection from the vectorcardiogram and used the lasso method after that to build a model for the Dower's inverse transform and one for the Frank leads system. Then we analyzed the performance between both models on MI detection. The proposed methods have been tested using PhysioNet PTB database that contains 550 records from which 368 are MIs. Two main conclusions are coming from this study. The first one is that Dower's inverse transform performs equally well than Frank leads in identification of MI patients. The second one is that lead positions have a large influence on the accuracy of MI patient identification. PMID- 26737294 TI - Feasibility of visualizing higher regions of Shannon entropy in atrial fibrillation patients. AB - Catheter ablation is associated with limited success rates in patients with persistent atrial fibrillation (AF), which is mostly maintained by rotors that are located outside of pulmonary veins (PV) region. None of the currently available commercial mapping systems can accurately predict the rotor location outside of PV in patients with persistent AF. Experimental verification of the feasibility of using Shannon entropy (SE) based mapping technique based on symbolic dynamics approach to identify pivotal points of rotors in isolated rabbit hearts was performed. This mapping approachwas applied to clinical intracardiac electrograms from a patient with persistent AF to construct a 3 dimensional (3D) SE map. Our results demonstrate that SE can correctly predict the pivot point of the rotor in animal model. We also demonstrated the feasibility of generating 3D SE maps using current catheter mapping methods to identify active rotor sites that may maintain AF. Higher SE areas are noted at the base of right atrial appendage. Further clinical studies are needed to validate ablation of areas with high SE with outcomes. PMID- 26737295 TI - Spiral wave classification using normalized compression distance: Towards atrial tissue spatiotemporal electrophysiological behavior characterization. AB - Analysis of electrical activation patterns such as re-entries during atrial fibrillation (Afib) is crucial in understanding arrhythmic mechanisms and assessment of diagnostic measures. Spiral waves are a phenomena that provide intuitive basis for re-entries occurring in cardiac tissue. Distinct spiral wave behaviors such as stable spiral waves, meandering spiral waves, and spiral wave break-up may have distinct electrogram manifestations on a mapping catheter. Hence, it is desirable to have an automated classification of spiral wave behavior based on catheter recordings for a qualitative characterization of spatiotemporal electrophysiological activity on atrial tissue. In this study, we propose a method for classification of spatiotemporal characteristics of simulated atrial activation patterns in terms of distinct spiral wave behaviors during Afib using two different techniques: normalized compressed distance (NCD) and normalized FFT (NFFTD). We use a phenomenological model for cardiac electrical propagation to produce various simulated spiral wave behaviors on a 2D grid and labeled them as stable, meandering, or breakup. By mimicking commonly used catheter types, a star shaped and a circular shaped both of which do the local readings from atrial wall, monopolar and bipolar intracardiac electrograms are simulated. Virtual catheters are positioned at different locations on the grid. The classification performance for different catheter locations, types and for monopolar or bipolar readings were also compared. We observed that the performance for each case differed slightly. However, we found that NCD performance is superior to NFFTD. Through the simulation study, we showed the theoretical validation of the proposed method. Our findings suggest that a qualitative wavefront activation pattern can be assessed during Afib without the need for highly invasive mapping techniques such as multisite simultaneous electrogram recordings. PMID- 26737296 TI - A multi-criteria evaluation method for assessing the defibrillation outcome of different electrode placements in swine. AB - Compared with clinical and experimental approaches, numerical modeling of defibrillation offers a great opportunity to optimize the defibrillation strategy in a more individualized way. Through numerical simulation of the shock-induce electric field distribution, the outcome of a certain defibrillation shock could be predicted according to several different metrics. In this paper, we propose a novel evaluation method, in which four defibrillation criteria are assigned with separate weighting factors to quantitatively assess the efficiency of a certain defibrillation shock. Three anatomically realistic finite element models of swine were constructed for the evaluation study of 8 electrode pairs in different placements. In addition, corresponding animal experiments were performed to determine the defibrillation threshold of 8 electrode placements. Both computational and experimental results suggest that the clinical recommended anterior-lateral position is the most efficient electrode displacement for transthoracic defibrillation in swine. In conclusion, the good agreement between stimulations and experiments indicates that the present multi-criteria evaluation method would be potentially useful for optimizations of cardiac defibrillation outcome. PMID- 26737297 TI - Rib-cage-movement measurements as a potential new trigger signal in non-invasive mechanical ventilation. AB - Non-invasive ventilation performed through an oronasal mask is a standard in clinical and homecare mechanical ventilation. Besides all its advantages, inevitable leaks through the mask cause errors in the feedback information provided by the airflow sensor and, hence, patient-ventilator asynchrony with multiple negative consequences. Here we investigate a new way to provide a trigger to the ventilator. The method is based on the measurement of rib cage movement at the onset of inspiration and during breathing by fibre-optic sensors. In a series of simultaneous measurements by a long-period fibre grating sensor and pneumotachograph we provide the statistical evidence of the 200 ms lag of the pneumo with respect the fibre-optic signal. The lag is registered consistently across three independent delay metrics. Further, we discuss exceptions from this trend and identify the needed improvements to the proposed fibre-sensing scheme. PMID- 26737298 TI - Lung assist devices influence cardio-energetic parameters: Numerical simulation study. AB - We aim at an analysis of the effects mechanical ventilators (MVs) and thoracic artificial lungs (TALs) will have on the cardiovascular system, especially on important quantities, such as left and right ventricular external work (EW), pressure-volume area (PVA) and cardiac mechanical efficiency (CME). Our analyses are based on simulation studies which were carried out by using our CARDIOSIM((c)) software simulator. At first, we carried out simulation studies of patients undergoing mechanical ventilation (MV) without a thoracic artificial lung (TAL). Subsequently, we conducted simulation studies of patients who had been provided with a TAL, but did not undergo MV. We aimed at describing the patient's physiological characteristics and their variations with time, such as EW, PVA, CME, cardiac output (CO) and mean pulmonary arterial/venous pressure (PAP/PVP). We were starting with a simulation run under well-defined initial conditions which was followed by simulation runs for a wide range of mean intrathoracic pressure settings. Our simulations of MV without TAL showed that for mean intrathoracic pressure settings from negative (-4 mmHg) to positive (+5 mmHg) values, the left and right ventricular EW and PVA, right ventricular CME and CO decreased, whereas left ventricular CME and the PAP increased. The simulation studies of patients with a TAL, comprised all the usual TAL arrangements, viz. configurations "in series" and in parallel with the natural lung and, moreover, hybrid configurations. The main objective of the simulation studies was, as before, the assessment of the hemodynamic response to the application of a TAL. We could for instance show that, in case of an "in series" configuration, a reduction (an increase) in left (right) ventricular EW and PVA values occurred, whereas the best performance in terms of CO can be achieved in the case of an in parallel configuration. PMID- 26737299 TI - Retrospective data-driven respiratory gating for PET using TOF information. AB - Traditional data-driven respiratory gating method is capable of detecting breathing cycles directly from positron emission tomography (PET) data, but usually fails at low SNR, particularly at low dose PET/CT study. Time-of-flight (TOF) PET has the potential to improve the SNR. In order for TOF information to reduce the statistical noise and boost the performance of respiratory gating, we present a robust data-driven respiratory gating method using TOF information, which retrospectively derived the respiratory signal from the acquired TOF-PET data. The PET data was acquired in list mode format and analyzed in sinogram space. The method was demonstrated with patient datasets acquired on a TOF PET/CT system. Data-driven gating methods by center of mass (COM) and principle component analysis (PCA) algorithm were successfully performed on nonTOF PET and TOF PET dataset. To assess the accuracy of the data-driven respiratory signal, a hardware-based signal was acquired for comparison. The study showed that retrospectively respiratory gating using TOF sinograms has improved the SNR, and outperforms the non-TOF gating under both COM and PCA algorithms. PMID- 26737300 TI - A novel method for non-invasive respiration monitoring. AB - In this paper we present an atypical method for measuring respiration volume. We infer heart rate variability (HRV) from an electrocardiogram (ECG) and present results from a pilot study of 6 participants to validate measuring respiration volume from HRV in comparison to the Cosmed K4b(2). We show a qualitative correlation and trend between the known respiration volume as measured by the Cosmed K4b(2) and the new method for measuring lung volume. From these results, we propose guidelines for an in-depth study of measuring respiration volumes from heart rate variability. PMID- 26737301 TI - Comparing consumption oxygen during and after squat exercise in Smith Machine and whole-body vibration. AB - Currently the physical exercise in whole body vibration platforms has become popular among people that frequenting gym and physiotherapy clinics. The objective of this study was to compare the oxygen consumption in the squat exercise performed at Smith Machine and squat performed on the vibration platform following the protocols usually referenced in both types of exercise (with load of 70% in the Smith Machine and unloaded on the vibration platform). The sample consisted of eight male subjects, with a mean age of 22.75 +/- 2.05 years, an average body mass 74.50 +/- 9.50kg, a stature of 1.79 +/- 0.63m and estimated body fat percentage of 5.01 +/- 0.94%. The volunteers performed two exercise sessions, one in the Smith Machine (AGSM) and the other on the vibration platform (AGPP). Each session consisted in 5 sets of 10 repetitions each, with a cadence of 40 beat.min(-1). The load used in the exercise AGSM performance was 70% of 1RM and in the AGPP was used a vibration frequency of 50 Hz, during 60 seconds in high amplitude. The order of the sections was randomized, with seven days apart. The AGPP session presented VO2 absolute = 0.95 +/- 0.21L/min, VO2 relative = 12.86 +/- 2.43ml/kg/min, and HR = 93.69 +/- 10.55 beats/min; and the AGSM session presented VO2 absolute = 1.33 +/- 0.29 L/min, VO2 relative = 17.91 +/- 2.70 ml/kg/min, and HR = 120.69 +/- 14.21 beats/min. The VO2 and HR values of the AGSM session were significantly higher than that found in AGPP session. PMID- 26737302 TI - A polynomial model of patient-specific breathing effort during controlled mechanical ventilation. AB - Patient breathing efforts occurring during controlled ventilation causes perturbations in pressure data, which cause erroneous parameter estimation in conventional models of respiratory mechanics. A polynomial model of patient effort can be used to capture breath-specific effort and underlying lung condition. An iterative multiple linear regression is used to identify the model in clinical volume controlled data. The polynomial model has lower fitting error and more stable estimates of respiratory elastance and resistance in the presence of patient effort than the conventional single compartment model. However, the polynomial model can converge to poor parameter estimation when patient efforts occur very early in the breath, or for long duration. The model of patient effort can provide clinical benefits by providing accurate respiratory mechanics estimation and monitoring of breath-to-breath patient effort, which can be used by clinicians to guide treatment. PMID- 26737303 TI - Identifying sleep apnea syndrome using heart rate and breathing effort variation analysis based on ballistocardiography. AB - Sleep apnea syndrome (SAS) is regarded as one of the most common sleep-related breathing disorders, which can severely affect sleep quality. Since SAS is usually accompanied with the cyclical heart rate variation (HRV), many studies have been conducted on heart rate (HR) to identify it at an earlier stage. While most related work mainly based on clinical devices or signals (e.g., polysomnography (PSG), electrocardiography (ECG)), in this paper we focus on the ballistocardiographic (BCG) signal which is obtained in a non-invasive way. Moreover, as the precision and reliability of BCG signal are not so good as PSG or ECG, we propose a fine-grained feature extraction and analysis approach in SAS recognition. Our analysis takes both the basic HRV features and the breathing effort variation into consideration during different sleep stages rather than the whole night. The breathing effort refers to the mechanical interaction between respiration and BCG signal when SAS events occur, which is independent from autonomous nervous system (ANS) modulations. Specifically, a novel method named STC-Min is presented to extract the breathing effort variation feature. The basic HRV features depict the ANS modulations on HR and Sample Entropy and Detrended Fluctuation Analysis are applied for the evaluations. All the extracted features along with personal factors are fed into the knowledge-based support vector machine (KSVM) classification model, and the prior knowledge is based on dataset distribution and domain knowledge. Experimental results on 42 subjects in 3 nights validate the effectiveness of the methods and features in identifying SAS (90.46% precision rate and 88.89% recall rate). PMID- 26737305 TI - Computer-assisted diagnosis of the Sleep Apnea-Hypopnea Syndrome: An overview of different approaches. AB - Automatic diagnosis of the Sleep Apnea-Hypopnea Syndrome (SAHS) has become an important area of research due to the growing interest in the field of sleep medicine, and the costs associated to its manual diagnosis. The increment and heterogeneity of the different techniques, however, makes somewhat difficult to adequately follow recent developments. In this paper an overview within the area of computer-assisted diagnosis of SAHS has been performed. This overview of the different methods is presented together with a critical discussion of the current state-of-the-art. PMID- 26737304 TI - Analysis and classification of oximetry recordings to predict obstructive sleep apnea severity in children. AB - Current study is focused around the potential use of oximetry to determine the obstructive sleep apnea-hypopnea syndrome (OSAHS) severity in children. Single channel SpO2 recordings from 176 children were divided into three severity groups according to the apnea-hypopnea index (AHI): AHI<;1 events per hour (e/h), 1<=AHI<;5 e/h, and AHI >=5 e/h. Spectral analysis was conducted to define and characterize a frequency band of interest in SpO2. Then we combined the spectral data with the 3% oxygen desaturation index (ODI3) by means of a multi-layer perceptron (MLP) neural network, in order to classify children into one of the three OSAHS severity groups. Following our MLP multiclass approach, a diagnostic protocol with capability to reduce the need of polysomnography tests by 46% could be derived. Moreover, our proposal can be also evaluated, in a binary classification task for two common AHI diagnostic cutoffs (AHI = 1 e/h and AHI= 5 e/h). High diagnostic ability was reached in both cases (84.7% and 85.8% accuracy, respectively) outperforming the clinical variable ODI3 as well as other measures reported in recent studies. These results suggest that the information contained in SpO2 could be helpful in pediatric OSAHS severity detection. PMID- 26737306 TI - Development of the bedridden person support system using hand gesture. AB - The purpose of this study is to support the bedridden and physically handicapped person who live independently. In this study, we developed Electric appliances control system that can be used on the bed. The subject can control Electric appliances using hand motion. Infrared sensors of a Kinect are used for the hand motion detection. Our developed system was tested with some normal subjects and results of the experiment were evaluated. In this experiment, all subjects laid on the bed and tried to control our system. As results, most of subjects were able to control our developed system perfectly. However, motion tracking of some subject's hand was reset forcibly. It was difficult for these subjects to make the system recognize his opened hand. From these results, we think if this problem will be improved our support system will be useful for the bedridden and physically handicapped persons. PMID- 26737307 TI - Preliminary evaluation of the tactile feedback system based on artificial skin and electrotactile stimulation. AB - This research is motivated by the need of integrating cutaneous sensing into a prosthetic device, enabling a bidirectional communication between the amputee and the prosthetic limb. An electronic skin based on piezoelectric polymer sensors transduces mechanical contact into electrical response which is conveyed to the human subject by electrotactile stimulation. Rectangular electrode arrays are placed on each patient's forearm and experiments are conducted on five different subjects to determine how well the orientation, position and direction of single lines are recognized. Overall, subjects discriminate the different touch modalities with acceptable success rates. In particular, the direction is identified at best and longitudinal lines on the patient's skin are recognized with the highest success rates. These preliminary results assess the feasibility of the artificial skin - electrostimulation system for prosthetic applications. PMID- 26737308 TI - Kinematic analysis of unilateral and bilateral drinking task after brain and periphery injuries. AB - In this study, we aim to understand how functional movement is affected by various physical and neurological injuries. Using a novel system known as the Bilateral Assessment System (BiAS), we tracked the wrist movement of subjects with stroke, cerebral palsy, transradial amputations, as well as healthy individuals in space and in time as they completed a drinking task. The BiAS allowed us to analyze the kinematics of the movement of subjects to describe how specific impairment types at varying levels of the nervous system affect upper limb movement. Using kinematics to provide an objective analysis, the results suggest that bilateral ability is not analogous to unilateral ability and the importance of bilateral training, in addition to unilateral training, in the rehabilitation of injured persons is highlighted. In addition, motor, sensory, and strength impairment and subsequent ADL functional ability is a function of impairment level and not just impairment type. PMID- 26737309 TI - Motor control investigation of dystonic cerebral palsy: A pilot study of passive knee trajectory. AB - The purpose of this study is to better understand dystonia in CP and be able to objectively distinguish between individuals who experience spasticity, dystonia, or a combination of these conditions while evaluating the effect of 2Hz vestibular stimulation. Selected outcome measures included knee ROM, angular velocity and acceleration and all measures increased post vestibular stimulation; these results are indications of a possible reduction in the level of disability. The current investigation also identified an unexpected and unique behavior of the knee in children with dystonic cerebral palsy (CP) that was noticed while administering the Pendulum Knee Drop test (PKD) at approximately 0.4 rad (a mid angle between full extension and zero vertical). There was a catch-like phenomenon at the described mid-angle in dystonic individuals. These results may suggest that dystonia is not a velocity dependent hypersensitivity of reflexes, but may include position dependent muscle reflexes and co-contractions. This reinforces the need for a more precise objective measure or perhaps a modified measure such as a mid-angle PKD test. Furthermore, based on the results obtained through the modified technique, beneficial alterations can be made to the form of treatment such as: robotic therapy or physical therapy that specifically accommodates the unique motor control disorder in individuals with dystonic CP. PMID- 26737310 TI - Combined robotic-aided gait training and 3D gait analysis provide objective treatment and assessment of gait in children and adolescents with Acquired Hemiplegia. AB - To evaluate the feasibility of a fully objective rehabilitative and assessment process of the gait abilities in children suffering from Acquired Hemiplegia (AH), we studied the combined employment of robotic-aided gait training (RAGT) and 3D-Gait Analysis (GA). A group of 12 patients with AH underwent 20 sessions of RAGT in addition to traditional manual physical therapy (PT). All the patients were evaluated before and after the training by using the Gross Motor Function Measures (GMFM), the Functional Assessment Questionnaire (FAQ), and the 6 Minutes Walk Test. They also received GA before and after RAGT+PT. Finally, results were compared with those obtained from a control group of 3 AH children who underwent PT only. After the training, the GMFM and FAQ showed significant improvement in patients receiving RAGT+PT. GA highlighted significant improvement in stance symmetry and step length of the affected limb. Moreover, pelvic tilt increased, and hip kinematics on the sagittal plane revealed statistically significant increase in the range of motion during the hip flex-extension. Our data suggest that the combined program RAGT+PT induces improvements in functional activities and gait pattern in children with AH, and it demonstrates that the combined employment of RAGT and 3D-GA ensures a fully objective rehabilitative program. PMID- 26737311 TI - Improving posture and sitting behavior through tactile and visual feedback in a sedentary environment. AB - This paper presents the concept Backtive: an interactive office chair with an accompanying mobile application to provide both tactile and visual feedback for the user to correct his posture and make him more aware of the sitting behavior throughout the day. The concept aims to make people unintentionally and more voluntarily aware of their sitting behavior while not interrupting their daily tasks. The concept is developed through a user centered design approach and by building a prototype to test feasibility as well as evaluating the concept. An evaluation with four persons received positive results with regard to credibility and expectancy of Backtive for posture improvement. Participants also expect that Backtive would be easy in use and are likely to integrate the system in their daily activities. PMID- 26737312 TI - Smartphone app design for the wireless control of a neuromuscular electrical stimulator device with integrated randomization allocation process for RCT applications. AB - The use of NMES has evolved over the last five decades. Technological advancements have transformed these once complex systems into user-friendly devices with enhanced control functions, leading to new applications of NMES being investigated. The use of Randomized Control Trial (RCT) methodology in evaluating the effectiveness of new and existing applications of NMES is a demanding process adding time and cost to a translation into clinical practice. Poor quality trials may result in poor evidence of NMES effectiveness. In this paper some of the key challenges encountered in NMES clinical trials are identified with the aim of purposing a solution to address these challenges through the adoption of Smartphone technology. The design and evaluation of a smartphone application to provide automatic blind randomization control and facilitating the wireless temporal control of a portable Bluetooth enabled NMES is presented. PMID- 26737313 TI - Design of small-size pouch motors for rat gait rehabilitation device. AB - Recent studies have demonstrated that active gait training can recover voluntary locomotive ability of paralyzed rats. Rehabilitation devices used for studying spinal cord injury to date are usually fixed on a treadmill, but they have been used only slightly for active training. To process active rehabilitation, a wearable, lightweight device with adequate output is needed. Pouch motors, soft pneumatic actuators, are extremely light and have other benefits such as low cost, easy fabrication, and highly customizable design. They can be used to develop active gait rehabilitation devices. However, performance details of different motor designs have not been examined. As described herein, to build a wearable gait assistive device for rat study, we specifically examine how to design small pouch motors with a good contraction ratio and force output. Results show that pouch performance decreases dramatically with size, but better output is obtainable by separation into small 0.8 length-to-width ratio rooms. We used this knowledge to produce an assistive robot suit for gait rehabilitation and to test it with paralyzed rats. Results show that these small pouches can produce sufficient power to control hip joint movements during gait training. They can reveal the potential for new pouch motor applications for spinal cord injury studies. PMID- 26737314 TI - An EEG-driven Lower Limb Rehabilitation Training System for Active and Passive Co stimulation. AB - With the advent of an aging society, stroke makes a heavy burden for our society. Stroke can damage the motor and sensory neural system and block the closed loop between the brain and the body. Due to the neural plasticity, this closed loop can be rebuilt through training. Users' actively engagement can help expedite functional recovery. Therefore, we propose an EEG-driven Lower Limb Rehabilitation Training System (LLRTS) that can achieve Active and Passive Co stimulation (APC). Virtual Reality (VR), BCI and robot are introduced into the system. When users have motor intentions, this system could automatically support corresponding visual and somatic sensory feedback. That is to say active and passive stimulations are controlled by user's mind. This paper reports the idea and construction of this rehabilitation system. Preliminary experimental results support the concept. PMID- 26737315 TI - Neural network decoupling technique and its application to a powered wheelchair system. AB - This paper proposes a neural network decoupling technique for an uncertain multivariable system. Based on a linear diagonalization technique, a reference model is designed using nominal parameters to provide training signals for a neural network decoupler. A neural network model is designed to learn the dynamics of the uncertain multivariable system in order to avoid required calculations of the plant Jacobian. To avoid overfitting problem, both neural networks are trained by the Lavenberg-Marquardt with Bayesian regulation algorithm that uses a real-time recurrent learning algorithm to obtain gradient information. Three experimental results in the powered wheelchair control application confirm that the proposed technique effectively minimises the coupling effects caused by input-output interactions even under the condition of system uncertainties. PMID- 26737316 TI - Cough detection through mechanomyographic signal in synchronized respiratory electrical stimulation systems. AB - Synchronization of transcutaneous functional electrical stimulation (TFES) with the spontaneous inspiration and expiration phases is a new approach for respiratory rehabilitation. One of the requirements for proper operation is the identification of cough events to automatically change the stimulation parameters in order to increase muscle strength during the cough. The aim of this work is to assess the viability in detection of cough events with a mechanomyographic (MMG) sensor on the abdominal region, and to evaluate if it can be used simultaneously with the synchronized TFES system. An MMG sensor was placed in contact with skin lined with the last ribs, above the rectus abdominis muscle and the linea alba. Two tests were accomplished which included quiet breathing, speaking and coughing episodes. The developed system efficiently distinguishes quiet breathing and coughing signals, but speaking is still confused with coughing episodes. The MMG sensor suffered detectable amplitude changes mainly during the forced expiration phase of the cough, but it could also detect the compression phase at lower amplitude. Therefore, the MMG system can be used for cough detection in this application. PMID- 26737317 TI - Oscillating field stimulation promotes recovery after spinal cord injury in rats: Assessment using behavioral, electrophysiological and histological evaluations. AB - OBJECTIVES: We explored whether oscillating field stimulation (OFS) could efficiently promote motor function recovery in rat model of spinal cord injury. METHODS: SD rats with spinal cord injury induced by Allen method was divided into two groups, experimental group rats received active stimulator units and control group rats received sham (inoperative) stimulator units. The electric field intensity was 600MUV/mm, and the polarity alternated every 15 min. RESULTS: The results showed that the experimental group rats had significantly better locomotor function recovery (inclined-plane testing and modified Tarlov motor grading scale) 5 weeks after the injury (P<;0.05). OFS treatment significantly decreased motor evoked potential (MEP) latency differences and amplitude differences 4 w and 8 w post injury (P<;0.05, P<;0.01). Furthermore, the number of axons was quantified by immunofluorescence staining of nerve fiber (NF), increased axon numbers were observed at 4 w and 8 w in experimental group (P<;0.05). CONCLUSIONS: These findings suggest OFS can promote motor function recovery in SCI rats, and this effect may be related to the improving axon regeneration in spinal cord. PMID- 26737318 TI - Determination of appropriate imagery task to discriminate ERD of "Pinch" and "Hold" movements in healthy participants and stroke patients. AB - Using video clips of hand movement to facilitate motor imagery and evoke strong ERD, we investigated the appropriate imagery task to discriminate ERD of "Pinch" and "Hold" movements in healthy controls and stroke patients. Participants watched 4 types of video clips that were a combination of 2 hand actions (pinch a small metal ball ("Pinch") or hold a tennis ball ("Hold")) and 2 object properties (ball rolls into the hand ("Move" condition) or stay still close to the hand ("Stop" condition)). The mean decrease in the mu band power from the baseline was 47.0+/-8.8% and 45.9+/-5.5% in healthy controls and patients, respectively, showing that all video clips evoked stable ERD. However, the relationship in ERD power between these hand actions varied across participants and object properties. We therefore calculated the absolute value of difference in ERD power between two hand actions (adERD) to further investigate the appropriate object property of the video clip stimuli. The mean adERD across participants and object properties was 22.3+/-6.0% in healthy controls and 33.9+/ 6.6% in patients, showing a good contrast between the ERD powers between 2 hand actions. The adERD was significantly larger in Move condition than Stop condition at electrode C6 in healthy participants for left hand imagery. Similar tendency was also found at electrode C3 in right paralyzed patients. The post-experiment questionnaire demonstrated that the ease in hand motor imagery was greater in Move condition compared to Stop condition in all participant groups. These results suggest that the video clip stimuli with Move object properties are appropriate to induce stable ERD for classification of Pinch and Hold movements. PMID- 26737319 TI - A new methodology for Functional Principal Component Analysis from scarce data. Application to stroke rehabilitation. AB - Functional Principal Component Analysis (FPCA) is an increasingly used methodology for analysis of biomedical data. This methodology aims to obtain Functional Principal Components (FPCs) from Functional Data (time dependent functions). However, in biomedical data, the most common scenario of this analysis is from discrete time values. Standard procedures for FPCA require obtaining the functional data from these discrete values before extracting the FPCs. The problem appears when there are missing values in a non-negligible sample of subjects, especially at the beginning or the end of the study, because this approach can compromise the analysis due to the need to extrapolate or dismiss subjects with missing values. In this paper, we present an alternative methodology extracting the FPCs directly from the sampled data, avoiding the need to have functional data before extracting them. We demonstrate the feasibility of our approach from real data obtained from the analysis of balance recovery after stroke. Finally, we demonstrate that FPCA can obtain differences between groups when these differences are more related to the dynamics of the process than data values at given points. PMID- 26737320 TI - Impaired regulation post-stroke of motor unit firing behavior during volitional relaxation of knee extensor torque assessed using high density surface EMG decomposition. AB - The purpose of this study was to use high density surface EMG recordings to quantify stroke-related abnormalities in motor unit firing behavior during repeated sub-maximal knee extensor contractions. A high density surface EMG system (sEMG) was used to record and extract single motor unit firing behavior in the vastus lateralis muscle of 6 individuals with chronic stroke and 8 controls during repeated sub-maximal isometric knee extension contractions. Paretic motor unit firing rates were increased with subsequent contractions (6.19+/-0.35 pps vs 7.89+/-0.66 pps, P <; 0.05) during task phases of torque decline as compared to controls (6.95+/-0.40 pps vs 6.68+/-0.41 pps). In addition, corresponding rates of torque decline were decreased for the paretic leg as compared to the non paretic leg. These results suggest that regulation of declining forces may be impaired post stroke due to prolonged firing of paretic motor units. PMID- 26737321 TI - A study on cortico-muscular coupling in finger motions for exoskeleton assisted neuro-rehabilitation. AB - In this paper our objective is to analyze the cortico-muscular coupling for hand finger motion and its possible use in the control of an exoskeleton based neurorehabilitation system for stroke sufferers. Cortical activity alone is often not sufficient to reliably control a device such as an exoskeleton and hence, our focus is to ascertain and analyze the connectivity between the motor cortex and forearm muscles, controlling the fingers, in terms of coherence between electroencephalogram (EEG) and electromyogram (EMG) signals. We have analyzed the signals separately for three different kinds of exercises consisting of passive motion of fingers using exoskeleton, active motion without any assistance, and motor imagery of the same movements. Four out of six healthy subjects who participated in the experiments have shown significant (p<;0.01) coherence for active finger motion which is well distinguished from the rest state. The EEG analysis resulted in average accuracy of 69.17% for passive finger motion with exoskeleton, 71.25% for active finger motion, and 67.92% for motor imagery, in detecting the volitional intention of the subjects to move their fingers. These results support that EEG-EMG coherence along with EEG analysis has the potential to make a more effective neurorehabilitation system for finger movement restoration of stroke sufferers. PMID- 26737322 TI - A shape-based helmet fitting system for concussion protection. AB - Helmets are widely used as protection against sports-related concussions. The degree of concussion protection offered by a helmet may be related to the fit between the helmet and head. This paper presents the design of a prototype helmet fitting recommendation system using shape-based helmet fitting. The shape-based helmet fitting system uses a Kinect sensor to scan a client's head and then compares the head shape to helmet shapes from a database of off-the-shelf helmets. A slice extraction method is used to compare a standard reference slice extracted from the head to a corresponding slice from the helmet. The degree to which the helmet fits the client's head is calculated and displayed to the user. The prototype system could potentially help a concussion expert make recommendations about helmet fit to clients, if more research about the effects of helmet fitting on concussion protection becomes available. PMID- 26737323 TI - Effect of viewing mode on pathfinding in immersive Virtual Reality. AB - The use of Head Mounted Displays (HMDs) to view Virtual Reality Environments (VREs) has received much attention recently. This paper reports on the difference between actual humans' navigation in a VRE viewed through an HMD compared to that in the same VRE viewed on a laptop PC display. A novel Virtual Reality (VR) Navigation input device (VRNChair), designed by our team, was paired with an Oculus Rift DK2 Head-Mounted Display (HMD). People used the VRNChair to navigate a VRE, and we analyzed their navigational trajectories with and without the HMD to investigate plausible differences in performance due to the display device. It was found that people's navigational trajectories were more accurate while wearing the HMD compared to viewing an LCD monitor; however, the duration to complete a navigation task remained the same. This implies that increased immersion in VR results in an improvement in pathfinding. In addition, motion sickness caused by using an HMD can be reduced if one uses an input device such as our VRNChair. The VRNChair paired with an HMD provides vestibular stimulation as one moves in the VRE, because movements in the VRE are synchronized with movements in the real environment. PMID- 26737324 TI - Validating ArmAssist Assessment as outcome measure in upper-limb post-stroke telerehabilitation. AB - The ArmAssist is a low-cost robotic system for post-stroke upper-limb telerehabilitation based on serious games. The system incorporates a set of games for the assessment of arm function, the ArmAssist Assessment (AAA), which allows a remote monitoring of the progress of the patient and an automatic adaptation of the therapy. In this study, different components of the AAA are compared against three widely-used clinical tests, the Fugl-Meyer Assessment (FMA) [1], the Action Research Arm Test (ARAT) [2] and the Wolf Motor Function Test (WMFT) [3] in order to select the most clinically meaningful ones for the final score provided to patients and therapist, and evaluate their capability to predict or even improve some aspects of these standard scales. All four tests were performed in 38 separate sessions in 19 post-stroke individuals in their sub-acute phase, as part of a broader study. Statistically significant correlation could be shown with the three clinical tests. These preliminary results are promising for the validation of AAA as a fast, automatic and clinically meaningful tool for remote progress assessment and therapy adaptation; however, more data and further analysis is needed to confirm this. PMID- 26737325 TI - Design and fabrication of a three dimensional printable non-assembly articulated hand exoskeleton for rehabilitation. AB - Robotic rehabilitation has proven to be cost-effective in accelerating the rehabilitation process by eliminating the constant need for supervision by a therapist. This work aimed to design and develop a novel three-dimensional (3D) printable non-assembly five-fingered robotic hand exoskeleton for rehabilitation. A single degree-of-freedom (DOF) linkage was designed to actuate each finger with 3 output links that correspond to the three phalanxes of the human finger. We used a parametric modelling approach that suits the dimensions of individual's hand. The fabrication of this dynamic model was achieved by printing the complete assembly including all the driving links, output links, and joints. We manufactured a prototype and developed real-time actuation and control. The reported unique linkage design, combined with parametric modelling and 3D printing technology, will pave the way for mass customization of active assistive and resistive hand exoskeletons. PMID- 26737326 TI - Data glove embedded with 9-axis IMU and force sensing sensors for evaluation of hand function. AB - A hand injury can greatly affect a person's daily life. Physicians must evaluate the state of recovery of a patient's injured hand. However, current manual evaluations of hand functions are imprecise and inconvenient. In this paper, a data glove embedded with 9-axis inertial sensors and force sensitive resistors is proposed. The proposed data glove system enables hand movement to be tracked in real-time. In addition, the system can be used to obtain useful parameters for physicians, is an efficient tool for evaluating the hand function of patients, and can improve the quality of hand rehabilitation. PMID- 26737327 TI - Powered exoskeleton with palm degrees of freedom for hand rehabilitation. AB - Robotic rehabilitation is a currently underutilised field with the potential to allow huge cost savings within healthcare. Existing rehabilitation exoskeletons oversimplify the importance of movement of the hand while undertaking everyday tasks. Within this study, an investigation was undertaken to establish the extent to which the degrees of freedom within the palm affect ability to undertake everyday tasks. Using a 5DT data glove, bend sensing resistors and restrictors of palm movement, 20 participants were recruited to complete tasks that required various hand shapes. Collected data was processed and palm arching trends were identified for each grasping task. It was found that the extent of utilizing arches in the palm varied with each exercise, but was extensively employed throughout. An exoskeleton was subsequently designed with consideration of the identified palm shapes. This design included a number of key features that accommodated for a variety of hand sizes, a novel thumb joint and a series of dorsally mounted servos. Initial exoskeleton testing was undertaken by having a participant complete the same exercises while wearing the exoskeleton. The angles formed by the user during this process were then compared to those recorded by 2 other participants who had completed the same tasks without exoskeleton. It was found that the exoskeleton was capable of forming the required arches for completing the tasks, with differences between participants attributed to individual ergonomic differences. PMID- 26737328 TI - Heart rate regulation during cycle-ergometer exercise via bio-feedback. AB - This paper explains our developed control system which regulates the heart rate (HR) to track a desired trajectory. The controller is indeed a non-conventional non-model-based proportional, integral and derivative (PID) controller. The controller commands are interpreted as biofeedback auditory commands. These commands can be heard and implemented by the exercising subject as a part of the control-loop. However, transmitting a feedback signal while the pedals are not in the appropriate position to efficiently exert force may lead to a cognitive disengagement of the user from the feedback controller. This note explains a novel form of control system regarding as "actuator-based event-driven control system", designed specifically for the purpose of this project. We conclude that the developed event-driven controller makes it possible to precisely regulate HR to a predetermined HR profile. PMID- 26737329 TI - Bimanual elbow exoskeleton: Force based protocol and rehabilitation quantification. AB - An aging population, along with the increase in cardiovascular disease incidence that accompanies this demographic shift, is likely to increase both the economic and medical burden associated with stroke in western societies. Rehabilitation, the standard treatment for stroke, can be expanded and augmented with state of the art technologies, such as robotic therapy. This paper expands upon a recent work involving a force-feedback master-slave bimanual exoskeleton for elbow rehabilitation, named a Bimanual Wearable Robotic Device (BWRD). Elbow force data acquired during the execution of custom tasks is analyzed to demonstrate the feasibility of tracking patient progress. Two training tasks that focus on applied forces are examined. The first is called "slave arm follow", which uses the absolute angular impulse as a metric; the second is called "conditional arm static", which uses the rise time to target as a metric, both presented here. The outcomes of these metrics are observed over three days. PMID- 26737330 TI - Evaluation of an objective listening effort measure in a selective, multi-speaker listening task using different hearing aid settings. AB - Speaker recognition in a multi-speaker environment is a complex listening task that requires effort to be solved. Especially people with hearing loss show an increased listening effort in demanding listening situations compared to normal hearing people. However, a standardized method to quantify listening effort does not exist yet. Recently we have shown a possible way to determine listening effort objectively. The aim of this study was to validate the proposed objective measure in a challenging, true-to-life listening situation, and to get an insight on the influence of different hearing aid (HA) settings on the listening effort using the proposed measure. To achieve this we investigated the influence of four different HA settings and two different listening task difficulties (LTD) on the listening effort of people with hearing loss in a selective, real-speech listening task. HA setting A, B and C all had an adaptive compression with static characteristic, but differed in the gain and compression settings (more and less gain and more and less linear). Setting D had an adaptive compression whose characteristic was situation-dependent. To quantify the listening effort the ongoing oscillatory EEG activity was recorded as the basis to calculate the objective measure (OLEosc). By way of comparison a subjective listening effort score was determined on an individual basis (SLEscr). The results show that the OLEosc maps the SLEscr well in every of the tested conditions. Furthermore, the results also suggest that OLEosc might be more sensitive to small variances in listening effort than the employed subjective rating scale. PMID- 26737331 TI - Determining inertial measurement unit placement for estimating human trunk sway while standing, walking and running. AB - Inertial measurement units (IMU) are often used to estimate medial-lateral (M/L) trunk sway for assessing and treating gait disorders, and IMU sensor placement is an important factor effecting estimation accuracy. This study tracked multi segment spine movements during standing and ambulation tasks to determine optimal IMU placement. Ten young healthy subjects, wearing markers placed along the spine, left/right acromion, and left/right posterior superior iliac spine performed standing and walking trials in a motion capture laboratory. Results showed that movement at the spine location T7-T8 most closely matched the clinical definition of M/L trunk sway for standing trials (0.5 deg error) and at the spine location T9-T10 for walking trials (1.0 deg error), while movement at the lower spine L2-L4 tended to be the least accurate for standing and ambulation tasks (1.5 deg error and 4.0 deg error, respectively). Based on these results, a second study was performed to develop and validate a trunk sway estimation algorithm during walking trials with a single optimally-placed IMU. IMU trunk sway estimation was compared to the clinical definition of trunk sway from motion capture markers and showed root-mean-square errors of 2.5 deg and peak trunk sway errors of 2.0 deg. The results of this study suggest that IMUs should be placed on the mid-back to reduce errors associated with spine movements not matching clinically-defined M/L trunk motion. PMID- 26737332 TI - MovAid- a novel device for advanced rehabilitation monitoring. AB - The present article introduces a new device "MovAid" which helps to measure and monitor rehabilitation. It has two main components- "MovAid device" and the "MovAid Smart Phone Application". The device connects wirelessly to the MovAid smart phone application via Bluetooth. It has electronic sensors to measure three important parameters of the patient- Angle of Joint Bent, Lift from the ground and Orientation of the limb. A mono-axis flex sensor to measure the degree of joint bent and a 3-axis accelerometer and gyroscope to measure the orientation of the limb and lift from the ground have been used. MovAid system bridges the gap between caretakers and patients, empowering both in ways never thought of before, by providing detailed and accurate data on every move. PMID- 26737333 TI - Injury potentials of spinal cord in ex vivo compression injury model. AB - The effect of applied electric field on neuroprotection and axonal regeneration has been studied in previous studies of acute spinal cord injury (SCI). However, due to the complexity of the microenvironment of the lesion site, the underlying mechanism of applied electric field is not yet fully understood. Thus, the injury potential, a significant index of the microenvironment change, was investigated in ex vivo spinal cords compression injury. Spinal cords isolated from rat were cultured in a double sucrose gap recording chamber. Both compound action potential (CAP) and injury potential were measured. Compression induced the decreasement of compound action potential, but the amplitude of CAP increased gradually after decompression. Compression also lead to the appearance of injury potential, represented by the voltage difference between the gap potential before and after compression, and the injury potential decreased with time logarithmicly after decompression. Intracellular Na(+) and Ca(2+) concentrations were measured and results showed that after injury these ions flowed into intracellular space. Therefore, the current approach can provide a basis for investigating the formation mechanism of the injury potential and help understand the pathophysiology of the SCI. PMID- 26737334 TI - A body-machine interface for training selective pelvis movements in stroke survivors: A pilot study. AB - The body-machine interfaces (BMIs) map the subjects' movements into the low dimensional control space of external devices to reach assistive and/or rehabilitative goals. This work is a first proof of concept of this kind of BMI as tool for rehabilitation after stroke. We designed an exercise to improve the control of selective movements of the pelvis in stroke survivors, increasing the ability to decouple the motion in the sagittal and frontal planes and decreasing compensatory adjustments at the shoulder girdle. A Kinect sensor recorded the movements of the subjects. Subjects played different games by controlling the vertical and horizontal motion of a cursor on a screen with respectively the lateral tilt and the ante/retroversion of their pelvis. We monitored also the degrees of freedom not directly involved in cursor control, thus subjects could complete the task only with a correct posture. Our preliminary results highlight significant improvement not only in cursor control, but also in the Trunk Impairment Scale (TIS) and in the Five Times Sit to Stand Test (5xSST). PMID- 26737335 TI - A wearable device for monitoring and prevention of repetitive ankle sprain. AB - This study presents the design and implementation of a wearable wireless device, connected to a smart phone, which monitors and prevents repetitive ankle sprain due to chronic ankle instability (CAI). The device prevents this common foot injury by electrical stimulation of the peroneal muscles using surface electrodes which causes dorsiflexion of the foot. This is done after measuring ankle kinematics using inertial motion sensors and predicting ankle sprain. The prototype implemented here has a fast response time of 7 msec which enables prevention of ankle sprain before ligament damage occurs. Wireless communication between the components of the device, in addition to their small size, low cost and low power consumption, makes it unobtrusive, easy to wear and not hinder normal activities. The device connects via Bluetooth to an android smart phone application for continuous data logging and reporting to keep track of the incidences of possible ankle sprain and correction. This is a significant feature of this device since it enables monitoring of patients with CAI and quantifying progression of the condition or improvement in the case of treatment. PMID- 26737336 TI - Preliminary assessment of variable geometry stair ascent and descent with a powered lower limb orthosis for individuals with paraplegia. AB - This paper describes a controller for a lower-limb exoskeleton that enables variable-geometry stair ascent and descent for persons with lower limb paralysis. The controller was evaluated on a subject with T10 complete spinal cord injury (SCI) on two staircases, one with a riser height and tread depth of 18.4 * 27.9 cm (7.25 * 11 in) and the other 17.8 * 29.8 cm (7 * 11.75 in). The controller enabled ascent and descent of both staircases without explicit tuning for each, and with an average step rate of 12.9 step/min during ascent and 14.6 step/min during descent. PMID- 26737337 TI - Comparison between the therapeutic effects of robotic-assisted locomotor training and an anti-spastic medication on spasticity. AB - We studied the effects of robotic-assisted locomotor (LOKOMAT) training or an anti-spastic medication (tizanidine) on neuromuscular abnormality associated with spasticity in persons with incomplete Spinal Cord Injury (SCI). Subjects were randomly divided to three groups: Lok, Tiz, and Cont. LOKOMAT training was performed 3 days/week for 4 weeks, with up to 45 minutes of training per session. Tizanidine (2mg) was administered (4?day), for 4 weeks. Subjects in Cont group received no intervention. The participants were evaluated before and after 4 weeks of training, and the effects of training on the intrinsic (muscular) and reflexive components of the neuromuscular properties were quantified over the ankle range-of-motion. A parallel-cascade system identification technique was used to determine the reflex and intrinsic stiffness of the ankle joint as a function of ankle position at each time point. The intercept and slope of the stiffness vs. joint angle curve were then calculated and tracked over the four week period. The number of subjects that achieved the minimally important difference (MID) for the intercepts and slopes, and levels of changes were compared. Both Lokomat and tizanidine resulted in significant reduction in both intercept and slope of reflex and intrinsic stiffness. However, a higher proportion of subjects in Lok group achieved the MID for the reflex (>90%) and intrinsic (65-78%) parameters compared with Tiz group (up to 63% and 25% for reflex and intrinsic parameters, respectively). The levels of reduction were also higher in the Lok than the Tiz group. No one in the Cont group achieved the MID. Our findings demonstrate that LOKOMAT training can be more efficient in modifying neuromuscular abnormalities associated with spasticity than tizanidine. PMID- 26737338 TI - Neural correlates of ankle movements during different motor tasks: A feasibility study. AB - This ongoing study investigates the neural correlates of ankle dorsi-plantar flexion in active, passive, and proprioceptive tasks. Specifically, we investigated two proprioceptive matching tasks that required a simple combination of active and passive ankle movements: (1) a memory-based ipsilateral matching task and (2) a contralateral concurrent matching task. As expected, during the passive tasks, subjects recruited the same brain areas involved in the correspondent active movements (primary motor cortex (M1), premotor cortex (PM) supplementary motor cortex (SMA) and primary somatosensory cortex (S1)), but the activations were lower. Instead, in both the proprioceptive matching tasks, subjects recruited more motor and sensory-motor areas of the brain and the activations were greater. PMID- 26737339 TI - Combining sudomotor nerve impulse estimation with fMRI to investigate the central sympathetic response to nausea. AB - The skin conductance (SC) signal is one of the most important non-invasive indirect measures of autonomic outflow. Several mathematical models have been proposed in the literature to characterize specific SC features. In this work, we present a method for the estimation of central control of sudomotor nerve impulse (SMI) function using SC. The method is based on a differential formulation decomposed into two first order differential equations. We validate our estimation framework by applying it on an experimental protocol where eleven motion sickness-prone subjects were exposed to a nauseogenic visual stimulus while SC and fMRI signals were recorded. Our results show an expected significant increase in the mean amplitude of SMI peaks during the highest reported nausea, as well as a decreasing trend during recovery, which was not evident for skin conductance level. Importantly, SMI/fMRI analysis found a negative association between SMI and fMRI signal in orbitofrontal, dorsolateral prefrontal, and posterior insula cortices, consistent with previous studies correlating brain fMRI and microneurographic signals. PMID- 26737340 TI - The brain responses to different frequencies of binaural beat sounds on QEEG at cortical level. AB - Beat phenomenon is occurred when two slightly different frequency waves interfere each other. The beat can also occur in the brain by providing two slightly different frequency waves separately each ear. This is called binaural beat. The brain responses to binaural beat are in discussion process whether the brain side and the brain area. Therefore, this study aims to figure out the brain responses to binaural beat by providing different binaural beat frequencies on 250 carrier tone continuously for 30 minutes to participants and using quantitative electroencephalography (QEEG) to interpret the data. The result shows that different responses appear in different beat frequency. Left hemisphere dominance occur in 3 Hz beat within 15 minutes and 15 Hz beat within 5 minutes. Right hemisphere dominance occurs in 10 Hz beat within 25 minute. 6 Hz beat enhances all area of the brain within 10 minutes. 8 Hz and 25 Hz beats have no clearly responses while 40 Hz beat enhances the responses in frontal lobe. These brain responses can be used for brain modulation application to induce the brain activity in further studies. PMID- 26737341 TI - Tendency to overestimate the explicit time interval in relation to aging and cognitive decline. AB - Age-related deficits in explicit time perception has been reported by some studies. However, the findings are inconsistent about the preference of older adults to over/underestimate the observed interval as well as the relationship between the time estimation and the participant's cognitive status. In this study, we used a verbal estimation task for the rotation time of a virtual building (40 seconds) to assess the explicit interval timing of participants. The performance of a cohort of 250 cognitively-healthy adults and 10 Alzheimer's patients was analyzed in relation to their age and cognitive scale, measured by Montreal Cognitive Assessment (MoCA) score. The participants' performances were evaluated based on three measurements: Coefficient of variation (CV) for measuring stability, Absolute Error (AE) for measuring accuracy and Directional Error (DE) for measuring the degree of over/under-estimation. A significant difference was observed between the participants who overestimated the interval and those who underestimated it in terms of age, cognitive status and Absolute Error. We also found a significant effect of time estimation, with underestimation by cognitively healthy participants to mild over-estimation by 70+ year old and low-MoCA (MoCA score <; 26) participants as well as severe overestimation by Alzheimer's disease patients. The result of regression analysis for predicting MoCA score based on the dependent variables (AE, DE and CV) support the superiority of Directional Error to Absolute Error and Coefficient of Variation that are commonly used in the time perception studies. PMID- 26737342 TI - Cooperation driven coherence: Brains working hard together. AB - The current study aims to look at the difference in coupling of EEG activity of participant pairs while they perform a cooperative, concurrent, independent yet different task at high and low difficulty levels. Participants performed the National Aeronautics and Space Administration (NASA) designed Multi-Attribute Task Battery (MATB-II) task which simulates a pilot and copilot operating an aircraft. Each participant in the pair was responsible for 2 out of 4 subtasks which were independent and different from one another while all tasks occurs concurrently in real time with difficulty levels being the frequency that adjustments are required for each subtask. We found that as the task become more difficult, there was more coupling between the pilot and copilot. PMID- 26737343 TI - 3D axonal network coupled to Microelectrode Arrays: A simulation model to study neuronal dynamics. AB - Action Potentials in a neuron are generated and propagated by exchange of ions through the membrane. The model of Hodgkin and Huxley (HH) describes these time dependent complex ion dynamics. We have implemented the FitzHugh-Nagumo model, one of the simplified versions of HH model on a pyramidal neuron with branches of axons to study the spontaneous activity of neurons. The network is then coupled to Micro-Electrode Arrays to record the extracellular potential in a neurochip environment. This in silico model is used to study the coupling of AP with the electrodes. Such a model is also a first step to investigate the morphological influence of neurons on their signaling properties. PMID- 26737344 TI - Electrical neurostimulation for chronic pain: On selective relay of sensory neural activities in myelinated nerve fibers. AB - Chronic pain affects about 100 million adults in the US. Despite their great need, neuropharmacology and neurostimulation therapies for chronic pain have been associated with suboptimal efficacy and limited long-term success, as their mechanisms of action are unclear. Yet current computational models of pain transmission suffer from several limitations. In particular, dorsal column models do not include the fundamental underlying sensory activity traveling in these nerve fibers. We developed a (simple) simulation test bed of electrical neurostimulation of myelinated nerve fibers with underlying sensory activity. This paper reports our findings so far. Interactions between stimulation-evoked and underlying activities are mainly due to collisions of action potentials and losses of excitability due to the refractory period following an action potential. In addition, intuitively, the reliability of sensory activity decreases as the stimulation frequency increases. This first step opens the door to a better understanding of pain transmission and its modulation by neurostimulation therapies. PMID- 26737345 TI - Balance of synaptic and electrotonic connections controls the excitability of networks in biophysical model of epilepsy. AB - Recent studies have implicated astrocytes in multiple active roles in neuronal networks. In particular they have been shown to be able to moderate and alter neural firing patterns both in normal and epileptic conditions. In addition, it has been proposed that one of the roles of gap junctions between astrocytes, as well as neurons is in increasing synchronization of neuronal firing and potential epileptogenic effect. In this study we build upon a model of a network that incorporates both pyramidal cells and interneurons as well as astrocytes with potassium clearance mechanisms and basic calcium dynamics. We include electrotonic connections between cells to be able to separate the effects of synaptic connections and gap junctions on neuronal hyperexcitability. Preliminary findings of this model show that under normal conditions, when gap junctions are blocked the network exists in an interictal-like state. When the system is put in a zero calcium environment (i.e. synaptic connections are disabled), the network enters spontaneous rhythmic bursting with very regular spiking. This suggests that electrotonic connections play a crucial role in the epileptogenesis within the neuronal network. PMID- 26737346 TI - A million-plus neuron model of the hippocampal dentate gyrus: Dependency of spatio-temporal network dynamics on topography. AB - This paper describes a million-plus granule cell compartmental model of the rat hippocampal dentate gyrus, including excitatory, perforant path input from the entorhinal cortex, and feedforward and feedback inhibitory input from dentate interneurons. The model includes experimentally determined morphological and biophysical properties of granule cells, together with glutamatergic AMPA-like EPSP and GABAergic GABAA-like IPSP synaptic excitatory and inhibitory inputs, respectively. Each granule cell was composed of approximately 200 compartments having passive and active conductances distributed throughout the somatic and dendritic regions. Modeling excitatory input from the entorhinal cortex was guided by axonal transport studies documenting the topographical organization of projections from subregions of the medial and lateral entorhinal cortex, plus other important details of the distribution of glutamatergic inputs to the dentate gyrus. Results showed that when medial and lateral entorhinal cortical neurons maintained Poisson random firing, dentate granule cells expressed, throughout the million-cell network, a robust, non-random pattern of spiking best described as spatiotemporal "clustering". To identify the network property or properties responsible for generating such firing "clusters", we progressively eliminated from the model key mechanisms such as feedforward and feedback inhibition, intrinsic membrane properties underlying rhythmic burst firing, and/or topographical organization of entorhinal afferents. Findings conclusively identified topographical organization of inputs as the key element responsible for generating a spatio-temporal distribution of clustered firing. These results uncover a functional organization of perforant path afferents to the dentate gyrus not previously recognized: topography-dependent clusters of granule cell activity as "functional units" that organize the processing of entorhinal signals. PMID- 26737347 TI - Classification of finger vibrotactile input using scalp EEG. AB - While there are many output brain-computer interface (output BCIs) studies, few have examined the input pathway, namely decoding the sensory input. To examine the possibility of building a BCI with sensory input using scalp electroencephalography (EEG), this study builds a classifier based on Local Fisher Discriminant Analysis (LFDA) and Gaussian Mixture Model (GMM) to classify neural activity generated by vibrotactile sensory stimuli delivered to the fingers. Small vibrators were placed on the fingertips of the participant. They vibrated one by one in a random sequence while the participant sat still with eyes closed. EEG data were recorded and later used to classify which finger was vibrated. There were two tasks: one focusing on differentiating between ipsilateral fingers, the other one focusing on differentiating contralateral fingers. Decoding accuracies were high in both tasks: 97.6% and 99.3% respectively. Event-related EEG features in both amplitude and power domain are discussed. PMID- 26737348 TI - Anesthesia effect on single local field potentials variability in rat barrel cortex: Preliminary results. AB - The rat barrel cortex is a widely used model of information processing in the somatosensory area, thanks to its precise and easily recognizable organization. However, evoked Local Field Potentials (LFPs) generated in the barrel cortex by repetitive deflections of rat whiskers show large variability in shapes and timings. Moreover, anesthetics can deeply affect the profile of evoked responses. This paper presents preliminary report on the variability and the effect of commonly used anesthetics on these signals. We studied representative signal shape characteristics (e.g., latency and amplitude of events) extracted from evoked responses acquired by means of standard Ag/AgCl electrodes from different cortical layers. As an early result, we found significant difference in the latency of the first principal peak of the responses. Under Tiletamine-Xylazine anesthetic, the responses or events of the evoked LFPs occurred later than the ones recorded while urethane was administered. Furthermore, the distributions of the peak latencies in all cortical layers were narrower in case of Urethane. This behavior should be attributed to the different effects of these two anesthetics on specific synaptic receptors and thus on the processing of neural information and the encoding of sensory input along the cortical pathway. PMID- 26737349 TI - Investigating the correlation between the neural activity and task performance in a psychomotor vigilance test. AB - Neural activity is known to correlate with decrements in task performance as individuals enter the state of mental fatigue which might lead to lowered productivity and increased safety risks. Incorporating a passive brain computer interface (BCI) technique that detects changes in subject's neural activity and predicts the behavioral performance when the subject is underperforming might be a promising approach to reduce human error in real-world situations. Here, we developed a reliable model using EEG power spectrum to estimate time-on-task performance in a psychomotor vigilance test (PVT) which can fit across individuals. High correlation between the estimated and actual reaction time was achieved. Hence, our results illustrate the feasibility for modeling time-on-task decrements in performance among different individuals from their brainwave activity, with potential applications in several domains, including traffic and industrial safety. PMID- 26737350 TI - Quantification and automatized adaptive detection of in vivo and in vitro neuronal bursts based on signal complexity. AB - In this paper, we propose employing entropy values to quantify action potential bursts in electrophysiological measurements from the brain and neuronal cultures. Conventionally in the electrophysiological signal analysis, bursts are quantified by means of conventional measures such as their durations, and number of spikes in bursts. Here our main aim is to device metrics for burst quantification to provide for enhanced burst characterization. Entropy is a widely employed measure to quantify regularity/complexity of time series. Specifically, we investigate the applicability and differences of spectral entropy and sample entropy in the quantification of bursts in in vivo rat hippocampal measurements and in in vitro dissociated rat cortical cell culture measurement done with microelectrode arrays. For the task, an automatized and adaptive burst detection method is also utilized. Whereas the employed metrics are known from other applications, they are rarely employed in the assessment of burst in electrophysiological field potential measurements. Our results show that the proposed metrics are potential for the task at hand. PMID- 26737351 TI - Electroencephalographic spectral correlates of caress-like affective haptic stimuli. AB - This paper describes how brain dynamics, as estimated through spectral analysis of electroencephalographic (EEG) oscillatory rhythms, is modified by quantifiable, affective haptic stimuli. Specifically, 32 healthy subjects (16 females) interacted with a haptic device able to convey caress-like stimuli while varying force and velocity of the device itself. More specifically, 2 values of force (i.e., "strength of the caress") and 3 velocity levels (i.e. "velocity of the caress") were combined to control the device during the experiment. Subjects were also asked to self-assess the haptic stimuli in terms of arousal (activation/ deactivation) and valence (pleasure/displeasure) scores. Results, shown in terms of p-values topographic maps, revealed a suppression of the oscillations over the controlateral somatosensory cortex, during caresses performed with the lowest force (2N) and the highest velocity (65 mm/s). This occurred in all of the frequency bands considered, alpha, beta, and gamma. Lower velocities (9.4 mm/s and 37 mm/s) did not significantly modify EEG reactivity in such bands. Concerning caresses administered at high force (6N), there was a significant decrease of EEG oscillatory activity focused on mid-frontal electrodes, in all of the considered frequency bands, when the velocity of the caresses was the lowest one. Significant sparse decrease of EEG power spectra, in all of the considered frequency bands, occurred at higher strength and velocity of the caress. PMID- 26737352 TI - Emergence of critical dynamics in large-scale in vitro cortical networks. AB - In vitro neuronal networks coupled to Micro-Electrode Arrays (MEAs) represent a valid experimental framework to study neuronal dynamics. This preparation is free of chemical or physical constraints and allows neurons to self-organize during development, creating networks that exhibit complex spatio-temporal patterns of activity. Starting from this experimental evidence, here we address the question whether a particular network architecture can drive the network dynamics towards a sub-, super-, or critical state. PMID- 26737353 TI - Beta/theta ratio neurofeedback training effects on the spectral topography of EEG. AB - Neurofeedback training (NFT) has shown positive effects on cognition and behavior enhancement as well as clinical treatment. However, little is known about the training effects in brain activity besides training location which is crucial for understanding the mechanism of neurofeedback and enhancing training efficiency. This study aimed to investigate beta/theta ratio (BTR) NFT effects on the spectral topography of electroencephalogram (EEG). Eleven healthy volunteers completed 25 sessions of NFT in consecutive five days with 5 sessions per day. The results showed that BTR NFT in occipital region did have significant effect on parietal, central and frontal regions, and the changes of BTR and theta amplitude detected in these regions were consistent with the changes at the training location. Moreover, the percentage changes of BTR and theta amplitude in parietal region were significantly greater than those in frontal region probably due to the shorter distance to the training location. PMID- 26737354 TI - Neural network based forward prediction of bladder pressure using pudendal nerve electrical activity. AB - Individuals with spinal cord injury or neurological disorders have problems in urinary bladder storage and in voiding function. In these people, the detrusor of bladder contracts at low volume and this causes incontinence. The goal of bladder control is to increase the bladder capacity by electrical stimulation of relative nerves such as pelvic nerves, sacral nerve roots or pudendal nerves. For this purpose, the bladder pressure has to be monitored continuously. In this paper, we propose a method for real-time estimating the bladder pressure using artificial neural network. The method is based upon measurements of electroneurogram (ENG) signal of pudendal nerve. This approach yields synthetic bladder pressure estimates during bladder contraction. The experiments were conducted on three rats. The results show that neural predictor can provide accurate estimation and prediction of bladder pressure with good generalization ability. The average error of 1-second and 5-second ahead prediction of bladder pressure are 9.62% and 10.54%, respectively. PMID- 26737355 TI - Filter bank common spatial patterns in mental workload estimation. AB - EEG-based workload estimation technology provides a real time means of assessing mental workload. Such technology can effectively enhance the performance of the human-machine interaction and the learning process. When designing workload estimation algorithms, a crucial signal processing component is the feature extraction step. Despite several studies on this field, the spatial properties of the EEG signals were mostly neglected. Since EEG inherently has a poor spacial resolution, features extracted individually from each EEG channel may not be sufficiently efficient. This problem becomes more pronounced when we use low-cost but convenient EEG sensors with limited stability which is the case in practical scenarios. To address this issue, in this paper, we introduce a filter bank common spatial patterns algorithm combined with a feature selection method to extract spatio-spectral features discriminating different mental workload levels. To evaluate the proposed algorithm, we carry out a comparative analysis between two representative types of working memory tasks using data recorded from an Emotiv EPOC headset which is a mobile low-cost EEG recording device. The experimental results showed that the proposed spatial filtering algorithm outperformed the state-of-the algorithms in terms of the classification accuracy. PMID- 26737356 TI - Spectra of infant EEG within the first year of life: A pilot study. AB - Rhythmic activities in electroencephalography (EEG) have been extensively studied in adults and classic rhythms are found to correlate with specific human brain functions. However, less has been investigated in infant EEG, and EEG rhythms in infants at early ages have not been well characterized in terms of their frequency ranges. In the present pilot study, we investigated rhythmic activities in infant EEG recorded weekly from 4-8 months using high-density EEG sensor nets. The developmental changes of EEG rhythms in different frequency bands along maturation were evaluated through spectral analysis. Their longitudinal scalp maps were also studied to understand their plausible functional correlates. The present study aims to enrich the sparse knowledge about the developing patterns of EEG rhythms within the first year of life from EEG recordings of high temporal and spatial resolutions. PMID- 26737357 TI - EEG-based time and spatial interpretation of activation areas for relaxation and words writing between poor and capable dyslexic children. AB - Symptoms of dyslexia such as difficulties with accurate and/or fluent word recognition, and/or poor spelling as well as decoding abilities, are easily misinterpreted as laziness and defiance amongst school children. Indeed, 37.9% of 699 school dropouts and failures are diagnosed as dyslexic. Currently, Screening for dyslexia relies heavily on therapists, whom are few and subjective, yet objective methods are still unavailable. EEG has long been a popular method to study the cognitive processes in human such as language processing and motor activity. However, its interpretation is limited to time and frequency domain, without visual information, which is still useful. Here, our research intends to illustrate an EEG-based time and spatial interpretation of activated brain areas for the poor and capable dyslexic during the state of relaxation and words writing, being the first attempt ever reported. From the 2D distribution of EEG spectral at the activation areas and its progress with time, it is observed that capable dyslexics are able to relax compared to poor dyslexics. During the state of words writing, neural activities are found higher on the right hemisphere than the left hemisphere of the capable dyslexics, which suggests a neurobiological compensation pathway in the right hemisphere, during reading and writing, which is not observed in the poor dyslexics. PMID- 26737358 TI - Impact of stimuli distribution on neural network responses. AB - In this study we investigated the relationship between stimulus regularity and observed responses in a biological neural network of dissociated cortical rat neurons plated over Micro-Electrode Arrays (MEAs). In particular, the intervals between identical stimuli in our experiments followed a 1/f(beta) distribution, and regularity increased with the value of beta (values tested were 0, 0.5, 1, 1.5, infinity). Comparisons occurred on the correlation between low-passed (rectangular window, 0.1s in length) stimulation trains and network-wide spike trains. Our results show that cultures are largely unable to synchronize network wide responses with regular stimulation at the considered stimulation rate (0.5Hz), while this occurs to a much higher degree for irregular stimulations. PMID- 26737359 TI - A computationally efficient order statistics based outlier detection technique for EEG signals. AB - Detecting artifacts in EEG data produced by muscle activity, eye blinks and electrical noise is a common and important problem in EEG applications. We present a novel outlier detection method based on order statistics. We propose a 2 step procedure comprising of detecting noisy EEG channels followed by detection of noisy epochs in the outlier channels. The performance of our method is tested systematically using simulated and real EEG data. Our technique produces significant improvement in detecting EEG artifacts over state-of-the-art outlier detection technique used in EEG applications. The proposed method can serve as a general outlier detection tool for different types of noisy signals. PMID- 26737360 TI - Classification of awake, REM, and NREM from EEG via singular spectrum analysis. AB - In this study, a single-channel electroencephalography (EEG) analysis method has been proposed for automated 3-state-sleep classification to discriminate Awake, NREM (non-rapid eye movement) and REM (rapid eye movement). For this purpose, singular spectrum analysis (SSA) is applied to automatically extract four brain rhythms: delta, theta, alpha, and beta. These subbands are then used to generate the appropriate features for sleep classification using a multi class support vector machine (M-SVM). The proposed method provided 0.79 agreement between the manual and automatic scores. PMID- 26737361 TI - Feasibility of blind source separation methods for the denoising of dense-array EEG. AB - High-density electroencephalographic recordings have recently been proved to bring useful information during the pre-surgical evaluation of patients suffering from drug-resistant epilepsy. However, these recordings can be particularly obscured by noise and artifacts. This paper focuses on the denoising of dense array EEG data (e.g. 257 channels) contaminated with muscle artifacts. In this context, we compared the efficiency of several Independent Component Analysis (ICA) methods, namely SOBI, SOBIrob, PICA, InfoMax, two different implementations of FastICA, COM2, ERICA, and SIMBEC, as well as that of Canonical Correlation Analysis (CCA). We evaluated the performance using the Normalized Mean Square Error (NMSE) criterion and calculated the numerical complexity. Quantitative results obtained on realistic simulated data show that some of the ICA methods as well as CCA can properly remove muscular artifacts from dense-array EEG. PMID- 26737362 TI - Combining human volitional control with intrinsic controller on robotic prosthesis: A case study on adaptive slope walking. AB - Affording lower-limb amputees the ability to volitionally control robotic prostheses can improve the adaptability to terrain changes as well as enhancing proprioception. However, it also increases amputees' conscious burdens for prosthesis control. Therefore, in this paper, we aim to propose a hybrid controller which combines human volitional control with the intrinsic controller on the robotic transtibial prosthesis, enabling the amputee actively controlling prosthesis with little conscious attention. In this preliminary study, a hybrid controller for adaptive slope walking was designed. A slope estimator was embedded in the intrinsic controller to estimate the ground slope of the previous step using signals measured by prosthetic sensors. And a myoelectric controller allows the amputee subject to convey slope changes to prosthetic controller by volitionally contract his residual muscles, whose electromyography signals were mapped to the slope increment. The hybrid controller combined these two results to obtain the estimated slope. One male transtibial amputee subject was recruited in this research. Experiment results showed that the intrinsic slope estimator produced satisfactory estimation results with an average absolute error of 0.70 +/- 0.54 degrees. By adding amputee's volitional control, the hybrid controller is able to predict the upcoming slope changes. PMID- 26737363 TI - Structure design for a Two-DoF myoelectric prosthetic hand to realize basic hand functions in ADLs. AB - Prosthetic hands are desired by those who have lost a hand or both hands not only for decoration but also for the functions to help them with their activities of daily living (ADL). Prosthetic robotic hands that are developed to fully realize the function of a human hand are usually too expensive to be economically available, difficult to operate and maintain, or over heavy for longtime wearing. The aim of this study is therefore to develop a simplified prosthetic hand (sim PH), which is to be controlled by myoelectric signals from the user, to realize the most important grasp motions in ADL by trading off the cost and performance. This paper reports the structure design of a two-DoF sim-PH with two motors to drive the CM joint of the thumb and the interlocked MP joints of the other four fingers. In order to optimize the structure, the model of the sim-PH was proposed based on which 7 sim-PHs with different structural parameters were manufactured and tested in a pick-and-place experiment. Correspondence analysis of the experimental results clarified the relationship between the hand functions and the shapes of fingers. PMID- 26737364 TI - Real-time gait event detection for transfemoral amputees during ramp ascending and descending. AB - Events and phases detection of the human gait are vital for controlling prosthesis, orthosis and functional electrical stimulation (FES) systems. Wearable sensors are inexpensive, portable and have fast processing capability. They are frequently used to assess spatio-temporal, kinematic and kinetic parameters of the human gait which in turn provide more details about the human voluntary control and ampute-eprosthesis interaction. This paper presents a reliable real-time gait event detection algorithm based on simple heuristics approach, applicable to signals from tri-axial gyroscope for lower limb amputees during ramp ascending and descending. Experimental validation is done by comparing the results of gyroscope signal with footswitches. For healthy subjects, the mean difference between events detected by gyroscope and footswitches is 14 ms and 10.5 ms for initial contact (IC) whereas for toe off (TO) it is -5 ms and -25 ms for ramp up and down respectively. For transfemoral amputee, the error is slightly higher either due to the placement of footswitches underneath the foot or the lack of proper knee flexion and ankle plantarflexion/dorsiflexion during ramp up and down. Finally, repeatability tests showed promising results. PMID- 26737365 TI - Application of metal hydride paper to simple pressure generator for use in soft actuator systems. AB - Metal hydride (MH) actuators have a simple structure and a number of features that make them attractive for use in rehabilitation engineering and assistive technology. The MH actuator provides a high power-to-weight ratio, high-strain actuation, human-compatible softness, and noiseless operation, while being environmentally benign. On the other hand, there remain technical challenges to be overcome to improve the MH actuator regarding its speed of operation and energy efficiency, given the low heat conductivity of the MH powder that is used as the pressure generator for soft actuation. To overcome the issues of low heat conductivity and the handling of MH powder, we developed an MH paper, which is a special paper incorporating MH powder and carbon fiber, for use as a new pressure generating element for a soft MH actuator system. In addition, the basic properties and structure of the proposed MH paper were investigated through scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), and several thermodynamic experiments. The results of these experiments showed that the hydrogen absorption and desorption rates of the MH paper were significantly higher than those of the MH powder around room temperature. PMID- 26737366 TI - Performance evaluation of the extra corporeal enteral prosthesis (ECEP) vs a By Pass. AB - Intestinal stoma constitutes a symptomatic treatment in a wide range of digestive diseases, such as rectal cancer, digestive traumatic perforation and inflammatory intestinal diseases. It affects a patient's life causing physiologic and social constraints. The stoma can lead to involution of the downstream digestive tissue, impairing his function in case of restored continuity. Some technical solutions have been developed in order to maintain intestinal continuity, reduce inflammatory risk and to increase patient's quality of life. In this paper, we describe a smart intestinal prosthesis equipped with a pump working as an intestinal segment and creating a bypass between the upstream and downstream intestinal sides. We also evaluate the performance the digestive prosthesis ECEP vs a simple digestive By-Pass. PMID- 26737367 TI - Lightweight custom composite prosthetic components using an additive manufacturing-based molding technique. AB - Additive manufacturing techniques are becoming more prominent and cost-effective as 3D printing becomes higher quality and more inexpensive. The idea of 3D printed prosthetics components promises affordable, customizable devices, but these systems currently have major shortcomings in durability and function. In this paper, we propose a fabrication method for custom composite prostheses utilizing additive manufacturing, allowing for customizability, as well the durability of professional prosthetics. The manufacturing process is completed using 3D printed molds in a multi-stage molding system, which creates a custom finger or palm with a lightweight epoxy foam core, a durable composite outer shell, and soft urethane gripping surfaces. The composite material was compared to 3D printed and aluminum materials using a three-point bending test to compare stiffness, as well as gravimetric measurements to compare weight. The composite finger demonstrates the largest stiffness with the lowest weight compared to other tested fingers, as well as having customizability and lower cost, proving to potentially be a substantial benefit to the development of upper-limb prostheses. PMID- 26737368 TI - Modification of hemiplegic compensatory gait pattern by symmetry-based motion controller of HAL. AB - As one of several characteristics of hemiplegic patients after stroke, compensatory gait caused by affected limb is often seen. The purpose of this research is to apply a symmetry-based controller of a wearable type lower limb robot, Hybrid Assistive Limb (HAL) to hemiplegic patients with compensatory gait, and to investigate improvement of gait symmetry. The controller is designed respectively for swing phase and support phase according to characteristics of hemiplegic gait pattern. The controller during swing phase stores the motion of the unaffected limb and then provides motion support on the affected limb during the subsequent swing using the stored pattern to realize symmetric gait based on spontaneous limb swing. Moreover, the controller during support phase provides motion to extend hip and knee joints to support wearer's body. Clinical tests were conducted in order to assess the modification of gait symmetry. Our case study involved participation of one chronic stroke patient who performs abnormally-compensatory gait for both of the affected and unaffected limbs. As a result, the patient's gait symmetry was improved by providing motion support during the swing phase on the affected side and motion constraint during the support phase on the unaffected side. The study showed promising basis for the effectiveness of the controller for the future clinical study. PMID- 26737369 TI - Development of Stewart platform type ankle-foot device for trip prevention support. AB - This paper presents an ankle-foot device using a Stewart platform, which is a type of parallel-link mechanism, for trip prevention support. The developed device can reproduce the input motions of the ankle joint in six degrees of freedom by controlling six pneumatic cylinders at the same time. The root mean square errors of the 3-D position and rotation angle of the reproduced motions with the input motions (dorsiflexion and plantar flexion) were 6.3 mm and 3.0 degrees , respectively. Verification experiments for trip prevention support performance were conducted by comparing motions in each walking condition measured using a motion capture system. The experimental results showed that the minimum foot clearance during mid-swing and initial swing increased significantly by the trip prevention support offered by the developed device. The developed device can perform passive exercises for ankle rehabilitation and support walking for trip prevention. PMID- 26737370 TI - Selective Linear-Regression Model for hand posture discrimination and grip force estimation using surface electromyogram signals. AB - This paper proposes the method of hand posture discrimination and grip force estimation by means of Selective Linear-Regression Model. Generally, myoelectric hands which discriminate hand posture and estimate grip force at the same time result in unsatisfying results because of complication of EMG signals. Therefore, most of myoelectric hands can control either the force or the posture. However, the proposed method is able to discriminate hand posture and to estimate grip force simultaneously while the accuracy results are achieved. In experiments, EMG signals were measured while hand posture and grip force were changing. As a result, it appears that EMG features increase monotonically with grip force. In addition, increasing forms of EMG features are different on each posture. Based on these experimental results, the authors propose the method for both discriminating hand posture and estimating grip force by means of several linear regression models which utilize the relationship between the grip force and EMG features on each posture. To evaluate the effectiveness of this method, the failure rates of discrimination and the estimation errors of the proposed method were employed. The results indicate that failure rates and estimation errors are improved significantly. PMID- 26737371 TI - Stress analysis of two craniofacial implants in implant retained auricular prostheses. AB - Implant-retained auricular prostheses require attachments to connect the implants and prostheses. Different attachments have different retention forces and hence different stress is transmitted to the implants. Splinting the implants together with a Hader bar allows the combination of different attachments with the Hader bar and allows changes in the amount and pattern of stress on the implants. However, the amount of removal force is also influenced by the retention components and the direction of removal of the prosthesis. In this paper, we studied the stress distribution around two craniofacial implants, in an auricular prosthesis, according to the removal forces, among three different attachment combinations and evaluated the stress distribution around two craniofacial implants in an auricular prosthesis with removal force at normal direction. The mean removal force was experimentally determined and the models were created using finite element software to analyze the distribution of von-Mises stress. Within the limitations of this study, the prosthodontist should place an emphasis on encouraging patients to remove the prosthesis at 90 degrees and if possible use a low retentive attachment to reduce the stress. PMID- 26737372 TI - Application of neural based estimation algorithm for gait phases of above knee prosthesis. AB - In this study, two gait phase estimation methods which utilize a rule based quantization and an artificial neural network model respectively are developed and applied for the microcontroller based semi-active knee prosthesis in order to respond user demands and adapt environmental conditions. In this context, an experimental environment in which gait data collected synchronously from both inertial and image based measurement systems has been set up. The inertial measurement system that incorporates MEM accelerometers and gyroscopes is used to perform direct motion measurement through the microcontroller, while the image based measurement system is employed for producing the verification data and assessing the success of the prosthesis. Embedded algorithms dynamically normalize the input data prior to gait phase estimation. The real time analyses of two methods revealed that embedded ANN based approach performs slightly better in comparison with the rule based algorithm and has advantage of being easily scalable, thus able to accommodate additional input parameters considering the microcontroller constraints. PMID- 26737373 TI - A bio-inspired force control for cyclic manipulation of prosthetic hands. AB - The human hand is considered as the highest example of dexterous system capable of interacting with different objects and adapting its manipulation abilities to them. The control of poliarticulated prosthetic hands represents one important research challenge, typically aiming at replicating the manipulation capabilities of the natural hand. For this reason, this paper wants to propose a bio-inspired learning architecture based on parallel force/position control for prosthetic hands, capable of learning cyclic manipulation capabilities. To this purpose, it is focused on the control of a commercial biomechatronic hand (the IH2 hand) including the main features of recent poliarticulated prosthetic hands. The training phase of the hand was carried out in simulation, the parallel force/position control was tested in simulation whereas preliminary tests were performed on the real IH2 hand. The results obtained in simulation and on the real hand provide an important evidence of the applicability of the bio-inspired neural control to real biomechatronic hand with the typical features of a hand prosthesis. PMID- 26737374 TI - Stable force-myographic control of a prosthetic hand using incremental learning. AB - Force myography has been proposed as an appealing alternative to electromyography for control of upper limb prosthesis. A limitation of this technique is the non stationary nature of the recorded force data. Force patterns vary under influence of various factors such as change in orientation and position of the prosthesis. We hereby propose an incremental learning method to overcome this limitation. We use an online sequential extreme learning machine where occasional updates allow continual adaptation to signal changes. The applicability and effectiveness of this approach is demonstrated for predicting the hand status from forearm muscle forces at various arm positions. The results show that incremental updates are indeed effective to maintain a stable level of performance, achieving an average classification accuracy of 98.75% for two subjects. PMID- 26737375 TI - Development of an eye tracking medical headlamp. AB - This study investigates a medical headlamp which is designed to adjust LED light automatically on the X axis and Y axis plane as determined a surgeon during a surgery. The needs of surgeons are determined through a CMOS camera which detects the movement of the eye. The system is composed of a mechanical actuator and an electrical control center. The LED lamp actuator (50*24*21 mm(3)) was designed to be as small as possible. The actuator can be easily attached onto typical goggles and incurs no burden during long-term use due to its light weight of 40g. To determine the movement of the eye, a limited embedded CPU was designed while considering memory, the process speed, simplicity and accuracy. The designed system was tested by exercises such as moving the eye in a zigzag direction and in random up, down, left, and right directions with adjustments for different lightings. Each was tested 100 times (total 1500), showing satisfactory results with 98.72% accuracy. PMID- 26737376 TI - Method for estimating the temperature distribution associated with the vessel cooling effect in radio frequency ablation. AB - Recently, radio frequency ablation (RFA) has become one of the most popular thermal treatments for liver cancer. RFA is minimally invasive and effective in inducing tumor coagulation, however, because use the procedure depends on the experience of the physician, consistent accuracy cannot be guaranteed. In particular, when the tumor is close to a large vessel, a suboptimal ablation margin can result in tumor recurrence. To improve the accuracy of RFA treatment, we have developed an RFA supporting system, which was constructed by using finite element method and operated by means of a model-based control method. In this study, we focused on the cooling effect of flow volume inside a large vessel during RFA, and analyzed heat transfer between the large vessel and liver tissue using a model. We derived the heat transfer parameter (the Nusselt number (Nu)) between the large vessel and liver tissue during RFA by using a finite-element method (FEM). When the Nu for FEM analysis had a value of 3, the FEM analysis model was representative of the actual ablation objective, and the maximum error between FEM analysis and the measurement results was within 2.0[ degrees C]. Thus, it was suggested that the Nu was effective for FEM analysis regarding heat transfer between a large vessel and tissue. However, according to the differences between the results of FEM analysis and measurements concerning the three livers, the heat transfer volume was determined by the Nu, which is different individually in common with other thermal properties. In conclusion, it is necessary to consider the individual differences in the heat transfer volume parameter for FEM analysis. PMID- 26737377 TI - Modelling needle forces during insertion into soft tissue. AB - Robot-assisted needle-based surgeries are sought to improve many operations, from brain surgery to spine and urological procedures. Force feedback from a needle can provide important guidance during needle insertion. This paper presents a new modelling method of needle force during insertion into soft tissue based on finite element simulation. This is achieved by analysing the results of a series of needle inserting experiments with different insertion velocities. The forces acting on the needle are then modelled based on the experimental results. A simulation is implemented to verify the designed model. PMID- 26737378 TI - Prediction of mechanical behaviour from histology in thin collagenous tissues. AB - A method of generating a rough, robust estimate of tensile modulus, elongation at break, and tear out of tissue from histology for the purpose of accelerating medical device and simulator design is presented. The known properties of the individual structural components of tissue are utilized by organizing these components according to existing histological data. This method was able to predict the elastic modulus of esophageal tissue by layer and direction with accuracy close to the standard deviation of the tissue properties, to provide a robust upper limit on tear out force for small (< 0.2mm or 3-0) sutures or clips, and predict force distribution between the layers during tear out. PMID- 26737379 TI - Master device for teleoperated needle insertion-type interventional robotic system. AB - This paper proposes a new master device for teleoperated needle insertion-type interventional robotic system. The 5-DOF master device is optimally designed based on the newly defined interventional procedures and the physicians' requirements. It comprises a 2-DOF rotational mechanism for adjustment of needle orientation, a 2-DOF translational mechanism for fine-tuning of needle entry point, and a handle assembly. The handle assembly includes a 1-DOF translational mechanism for needle insertion and buttons for operation mode selection. The passive actuation modules of the rotational mechanism and the active actuation modules of the translational mechanism are controlled appropriately for the selected mode according to the procedure phase. The needle insertion mechanism also warns the user by vibrating the shaft when the needle reaches the dangerous region. PMID- 26737380 TI - Design optimization of neuroendoscopic continuum instruments for third ventriculostomy and tumor biopsy. AB - A simulation-based approach to the design of procedure-specific dexterous neuroendoscopic continuum instruments for endoscopic third ventriculostomy and tumor biopsy is proposed. Given pre-operative CT and MRI images, the algorithm returns instrument design specifications including lengths, curvatures and alternative positions for the surgical incision while respecting anatomical boundaries. This methodology proposes a novel clinically-guided geometric representation of surgical targets specific to this indication. The additional constraints imposed by the presence of surgical trocars and endoscopes are also considered. Finally, we conclude with a clinical example to demonstrate the proposed approach. PMID- 26737381 TI - Redundancy optimization strategy for hands-on robotic surgery. AB - During hands-on cooperative surgery, the use of a redundant robot allows to address encumbrance issues in the Operating Room (OR), which can occur due to the presence of large medical instrumentation, such as the surgical microscope. This work presents a new Null Space Optimization (NSO) strategy to constraint the position of the manipulator's elbow within predefined range of motions, according to the spatial requirements of the specific procedure, also taking into account the physical joint limits of the robotic assistant. The proposed strategy was applied to the 7 degrees of freedom (dof) lightweight robot LWR4+. The performance of the NSO was compared to two state-of-the-art null space optimization strategies, i.e. damped posture and fixed optimal posture, over a pool of three non-expert users in both strict (20deg) and negligible (100deg) angular encumbrance limitations. The NSO strategy was proved versatile in providing wide elbow mobility together with safe distance from relevant continuity null space boundaries, guaranteeing smooth guidance trajectories. Future works would be performed in order to evaluate the potential feasibility of NSO in a real surgical scenario. PMID- 26737382 TI - Comfort and learnability assessment of a new soft robotic manipulator for minimally invasive surgery. AB - Laparoscopic surgeons perform precise and time consuming procedures while holding awkward poses in their upper body and arms. There is an ongoing effort to produce robotic tools for laparoscopic surgery that will simplify these tasks and reduce risk of errors to help both the surgeon and the patient. STIFF-FLOP is an ongoing EU FP7 project focusing on this by creating a stiffness controllable soft robotic manipulator. This paper reports on a study to test the soft manipulator's learnability and the effort associated with its use. The tests involved a limited prototype of the manipulator with a custom built test rig and EMG acquisition system. Task times and video recordings along with EMG waveforms from the forearm muscles of participants (n=25) were measured for objective assessment. A questionnaire was also provided to the participants for subjective assessment. The data shows that in average EMG levels were 25.9% less in RMS when using the STIFF-FLOP arm than when conventional laparoscopic tools were used. In terms of learnability, from the first to the second attempt on the STIFF-FLOP manipulator, elapsed time was reduced by an average of 32.1%. Further details and analysis of the EMG signals as well as time and questionnaire results is presented in the paper. PMID- 26737383 TI - Design and real-time control of a robotic system for fracture manipulation. AB - This paper presents the design, development and control of a new robotic system for fracture manipulation. The objective is to improve the precision, ergonomics and safety of the traditional surgical procedure to treat joint fractures. The achievements toward this direction are here reported and include the design, the real-time control architecture and the evaluation of a new robotic manipulator system. The robotic manipulator is a 6-DOF parallel robot with the struts developed as linear actuators. The control architecture is also described here. The high-level controller implements a host-target structure composed by a host computer (PC), a real-time controller, and an FPGA. A graphical user interface was designed allowing the surgeon to comfortably automate and monitor the robotic system. The real-time controller guarantees the determinism of the control algorithms adding an extra level of safety for the robotic automation. The system's positioning accuracy and repeatability have been demonstrated showing a maximum positioning RMSE of 1.18 +/- 1.14mm (translations) and 1.85 +/- 1.54 degrees (rotations). PMID- 26737384 TI - Closed-loop asymmetric-tip needle steering under continuous intraoperative MRI guidance. AB - Magnetic resonance imaging (MRI) provides excellent image contrast for various types of tissues, making it a suitable choice over other imaging modalities for various image-guided needle interventions. Furthermore, robot-assistance is maturing for surgical procedures such as percutaneous prostate and brain interventions. Although MRI-guided, robot-assisted needle interventions are approaching clinical usage, they are still typically open-loop in nature due to the lack of continuous intraoperative needle tracking. Closed-loop needle-based procedures can improve the accuracy of needle tip placement by correcting the needle trajectory during insertion. This paper proposes a system for robot assisted, flexible asymmetric-tipped needle interventions under continuous intraoperative MRI guidance. A flexible needle's insertion depth and rotation angle are manipulated by an MRI-compatible robot in the bore of the MRI scanner during continuous multi-planar image acquisition to reach a desired target location. Experiments are performed on gelatin phantoms to assess the accuracy of needle placement into the target location. The system was able to successfully utilize live MR imaging to guide the path of the needle, and results show an average total targeting error of 2.5+/-0.47mm, with an average in-plane error of 2.09+/-0.33mm. PMID- 26737385 TI - Motion prediction using dual Kalman filter for robust beating heart tracking. AB - A novel prediction method for robust beating heart tracking is proposed. The dual time-varying Fourier series is used to model the heart motion. The frequency parameters and Fourier coefficients in the model are estimated respectively by using a dual Kalman filter scheme. The instantaneous frequencies of breathing and heartbeat motion are measured online from the 3D trajectory of the point of interest using an orthogonal decomposition algorithm. The proposed method is evaluated based on both the simulated signals and the real motion signals, which are measured from the videos recorded using the da Vinci surgical system. PMID- 26737386 TI - Robot assisted stapedotomy ex vivo with an active handheld instrument. AB - Micron is a fully handheld active micromanipulator that helps to improve position accuracy and precision in microsurgery by cancelling hand tremor. This work describes adaptation, tuning, and testing of the Micron system for stapedotomy, a microsurgical procedure performed in the middle ear to restore hearing that requires accurate manipulation in narrow spaces. Two end-effectors, a handle, and a brace (or rest) were designed and prototyped. The control system was adapted for the new hardware. The system was tested ex vivo in stapedotomy procedure comparing manually-performed and Micron-assisted surgical tasks. Tremor amplitude was found to be reduced significantly. Further testing is needed in order to obtain statistically significant results regarding other parameters dealing with regularity of the fenestra shape. PMID- 26737387 TI - Design and development of magnetorheological fluid-based passive actuator. AB - We present the design and experimental validation of a magnetorheological (MR) fluid-based passive actuator for tele-robotic bone biopsy procedures. With Finite Element Method Magnet (FEMM) software, the required uniform magnetic field circuit design was simulated. An 1100 turn 24 AWG copper wire coil wrapped around a magnetic core was used to create a magnetic field. The field strength was measured with a Hall effect sensor, and compared to the simulation. The maximum magnetic field flux produced by a constant current of 1.4 A was 0.2 T, similar to the simulation results. A series of quasi-static experiments were conducted to characterize the forces generated by the MR fluid-based actuator under various currents up to 12 N. An analytical model was developed to validate the measurements from the passive actuator. PMID- 26737388 TI - Design and evaluation of a trilateral shared-control architecture for teleoperated training robots. AB - Multilateral teleoperated robots can be used to train humans to perform complex tasks that require collaborative interaction and expert supervision, such as laparoscopic surgical procedures. In this paper, we explain the design and performance evaluation of a shared-control architecture that can be used in trilateral teleoperated training robots. The architecture includes dominance and observation factors inspired by the determinants of motor learning in humans, including observational practice, focus of attention, feedback and augmented feedback, and self-controlled practice. Toward the validation of such an architecture, we (1) verify the stability of a trilateral system by applying Llewellyn's criterion on a two-port equivalent architecture, and (2) demonstrate that system transparency remains generally invariant across relevant observation factors and movement frequencies. In a preliminary experimental study, a dyad of two human users (one novice, one expert) collaborated on the control of a robot to follow a trajectory. The experiment showed that the framework can be used to modulate the efforts of the users and adjust the source and level of haptic feedback to the novice user. PMID- 26737389 TI - Enhanced position-force tracking of time-delayed teleoperation for robotic assisted surgery. AB - The advance of minimally invasive surgery has been empowered by new medical/surgical robotic systems towards achieving less invasiveness, smaller or even no scars. Wireless communication possesses great potential to be utilized in miniaturized surgical robotic system. However time delay is inevitably introduced in the control loop which causes stability issues for robotic-assisted surgeries. Wave variable based teleoperation structure provides stable force reflecting teleoperation performance but with both position and force tracking performance compromised due to conservative passivity condition. Recently, we proposed a new wave variable compensated structure to improve position and force tracking performance together with energy reservoir based regulators for stability purpose. In this paper, different energy reservoir based regulators are proposed with consideration of passivity of master and slave system to avoid uncertain compensated wave variables. Experiments are designed to evaluate the performance of proposed structure in comparison with traditional wave variable structure. Quantitative analyses of the obtained results justify the efficiency of proposed method. PMID- 26737390 TI - Preliminary study for motion scaling based control in minimally invasive vascular interventional robot. AB - Robot-assisted vascular interventions present promising trend for reducing the X ray radiation to the surgeon during the operation. However, the control methods in the current vascular interventional robots only repeat the manipulation of the surgeon. While under certain circumstances, it is necessary to scale the manipulation of the surgeon to obtain a higher precision or a shorter manipulation time. A novel control method based on motion scaling for vascular interventional robot is proposed in this paper. The main idea of the method is to change the motion speed ratios between the master and the slave side. The motion scaling based control method is implemented in the vascular interventional robot we've developed before, so the operator can deliver the interventional devices under different motion scaling factors. Experiment studies verify the effectiveness of the motion scaling based control. PMID- 26737391 TI - Preliminary analysis of force-torque measurements for robot-assisted fracture surgery. AB - Our group at Bristol Robotics Laboratory has been working on a new robotic system for fracture surgery that has been previously reported [1]. The robotic system is being developed for distal femur fractures and features a robot that manipulates the small fracture fragments through small percutaneous incisions and a robot that re-aligns the long bones. The robots controller design relies on accurate and bounded force and position parameters for which we require real surgical data. This paper reports preliminary findings of forces and torques applied during bone and soft tissue manipulation in typical orthopaedic surgery procedures. Using customised orthopaedic surgical tools we have collected data from a range of orthopaedic surgical procedures at Bristol Royal Infirmary, UK. Maximum forces and torques encountered during fracture manipulation which involved proximal femur and soft tissue distraction around it and reduction of neck of femur fractures have been recorded and further analysed in conjunction with accompanying image recordings. Using this data we are establishing a set of technical requirements for creating safe and dynamically stable minimally invasive robot-assisted fracture surgery (RAFS) systems. PMID- 26737392 TI - Haptic interface for robot-assisted ophthalmic surgery. AB - Vitreo-retinal surgery is challenging, as delicate structures have to be manipulated. Eliminating tremor caused by human motions when doing micromanipulation can therefore improve the outcome of such an intervention. An eye surgery robot has been built to overcome this problem. The contribution of this paper is the design of a telemanipulation setup for the robotic system. A telemanipulation setup using a haptic device featuring force feedback as a user interface for controlling a hybrid parallel-serial micromanipulator is designed and developed. The position error control scheme is chosen and different control modes are provided. The output forces of the haptic device are analyzed. The system allows the surgeon to perform precise and comfortable micromanipulation. Nevertheless a way to provide more meaningful force feedback still has to be found. PMID- 26737393 TI - Computer-assisted single-stage cranioplasty. AB - Cranioplasty treats and repairs cranial defects with a custom craniofacial implant (CCI). Typically, surgeons know the defect size prior to surgery. Recent efforts consider single-stage cranioplasty-performing the bony resection and fixating the CCI in a single operation. This paper develops a computer-assisted technique to perform single-stage cranioplasty. Intraoperatively, the surgeon traces the bony resection. The outline of the bony cuts is projected on a preoperatively-designed CCI to guide the surgeon during the resizing. A cadaveric case study showed good fit with minimal gaps between the implant and remaining skull. Moreover, the procedure reduced the time to resize the implant by an order of magnitude compared to manual resizing without the use of the computer-assisted technique. This approach represents the next step in quickly, effectively, and robustly performing single-stage CCI to treat craniofacial defects. PMID- 26737394 TI - Volumetric compensation of accuracy errors in a multi-robot surgical platform. AB - A multi-robot platform, made of a hybrid parallel kinematic machine and 2 KUKA LWR arms, is dedicated to open skull neuro-surgical tasks. Sub-millimeter accuracy is clearly required for both the absolute tool tracking and for good performances in motion compensation when the head is set free to move. An analysis of the sources of inaccuracies, mostly derived from the calibration phase, illustrates that errors are insufficiently reduced by stand-alone calibrations of the single robots. A method for volumetric compensation of errors is reported. A compensation transform is, in fact, computed during an offline training phase for a set of discretized subregions of the constrained head workspace. At runtime, a compensation motion is applied to robots so as to reach the desired real targets on anatomical parts. The resulting end-to-end static accuracy is distributed with median 0.75 mm and below 1 mm for the 95% of tests, with a 1:36 reduction factor from the starting conditions. The accuracy is evaluated also in dynamic tests with mild oscillatory patterns. PMID- 26737395 TI - BCI-based user training in surgical robotics. AB - Human error is a critical risk in surgery, so an important aim of surgical robotic systems is to improve the performance and the safety of surgical operations. Such systems can be potentially enhanced by a brain-computer interface (BCI) able to monitor the user's mental focus and use this information to improve the level of safety of the procedures. In order to evaluate such potential usage of BCIs, this paper describes a novel framework for training the user to regulate his/her own mental state while performing surgery-like tasks using a robotic system. This self-regulation is based on augmented reality (AR) feedback representing the BCI-monitored mental state, which helps the user's effort in maintaining a high level of mental focus during the task. A comparison between a BCI-based training and a training without a BCI highlighted a reduction of post-training trial times as a result of the enhanced training setup, without any loss in performance or in user experience. Such finding allows the identification of further improvements and novel potential applications of this training and interaction paradigm. PMID- 26737396 TI - 3D-printed soft microrobot for swimming in biological fluids. AB - Microscopic artificial swimmers hold the potential to enable novel non-invasive medical procedures. In order to ease their translation towards real biomedical applications, simpler designs as well as cheaper yet more reliable materials and fabrication processes should be adopted, provided that the functionality of the microrobots can be kept. A simple single-hinge design could already enable micro swimming in non-Newtonian fluids, which most bodily fluids are. Here, we address the fabrication of such single-hinge microrobots with a 3D-printed soft material. Firstly, a finite element model is developed to investigate the deformability of the 3D-printed microstructure under typical values of the actuating magnetic fields. Then the microstructures are fabricated by direct 3D-printing of a soft material and their swimming performances are evaluated. The speeds achieved with the 3D-printed microrobots are comparable to those obtained in previous work with complex fabrication procedures, thus showing great promise for 3D-printed microrobots to be operated in biological fluids. PMID- 26737397 TI - Requirements analysis and preliminary design of a robotic assistant for reconstructive microsurgery. AB - Microanastomosis is a microsurgical gesture that involves suturing two very small blood vessels together. This gesture is used in many operations such as avulsed member auto-grafting, pediatric surgery, reconstructive surgery - including breast reconstruction by free flap. When vessels have diameters smaller than one millimeter, hand tremors make movements difficult to control. This paper introduces our preliminary steps towards robotic assistance for helping surgeons to perform microanastomosis in optimal conditions, in order to increase gesture quality and reliability even on smaller diameters. A general needs assessment and an experimental motion analysis were performed to define the requirements of the robot. Geometric parameters of the kinematic structure were then optimized to fulfill specific objectives. A prototype of the robot is currently being designed and built in order to providing a sufficient increase in accuracy without prolonging the duration of the procedure. PMID- 26737398 TI - Preliminary assessment of the SensiumVitals(r): A low-cost wireless solution for patient surveillance in the general wards. AB - This paper presents SensiumVitals((r)) - an FDA cleared and CE marked wireless wearable vital signs monitoring system, developed for frequent surveillance of in hospital patients. A number of in-house evaluations with artificial data and healthy volunteers were carried out in different stages to assess the reliability of two crucial vital signs measured by the system - respiration and heart rate. In order to illustrate the potential of the system in hospital, a subset of data collected from acutely-ill patients during a separate clinical trial was also analyzed. In all cases the results revealed satisfactory agreement between the values reported by SensiumVitals((r)) and those recorded simultaneously by a clinically-approved bedside monitor. However, further work will be required to improve the reliability of the system under certain clinical conditions; which, although not crucial for our intended population (i.e. patients in general ward), pose interesting challenges for upgrading our technology for future use in these types of patients. PMID- 26737399 TI - ROI analysis for remote photoplethysmography on facial video. AB - As wide spreading of camera-equipped devices to the daily living environment, there are enormous opportunities to utilize the camera-based remote photoplethysmography (PPG) for daily physiological monitoring. In the camera based remote PPG (rPPG) monitoring, the region of interest (ROI) is related to the signal quality and the computational load for the signal extraction processing. Designating the best ROI on the body while minimizing its size is essential for computationally efficient rPPG extraction. In this study, we densely analyzed the face region to find the computationally efficient ROI for facial rPPG extraction. We divided the face into seven regions and evaluated the quality of the signal of each region using the area ratio of high-SNR and high correlation, and mean and standard deviation (SD) of SNR and correlation coefficient. The results show that a forehead and both cheeks especially have a potential to be a good candidates for computationally efficient ROI. On the other hand, the signal quality from a mouth and a chin was relatively low. A nasion and a nose have a limitation to be efficient ROI. PMID- 26737400 TI - Estimation of sleep posture using a patch-type accelerometer based device. AB - In this study, we developed a sleep posture estimation algorithm using 3-axis accelerometer signals measured from a patch-type sensor. Firstly, we inspected the characteristics of accelerometer signals for different sleep postures. Based on the results, we established decision rules to estimate 5 postures containing supine, left, right lateral, prone postures, and non-sleep postures such as sitting and standing. The algorithm was tested by the data from thirteen subjects during night time PSG. As a result, the algorithm estimated sleep postures with an average agreement of 99.16%, and cohen's kappa of 0.98 compared with reference sleep postures determined by position sensor and video recording. The proposed method with the device could be used as supportive purpose in routine PSG study and out-of-hospital environment. PMID- 26737401 TI - A tracking system for laboratory mice to support medical researchers in behavioral analysis. AB - The behavioral analysis of laboratory mice plays a key role in several medical and scientific research areas, such as biology, toxicology, pharmacology, and so on. Important information on mice behavior and their reaction to a particular stimulus is deduced from a careful analysis of their movements. Moreover, behavioral analysis of genetically modified mice allows obtaining important information about particular genes, phenotypes or drug effects. The techniques commonly adopted to support such analysis have many limitations, which make the related systems particularly ineffective. Currently, the engineering community is working to explore innovative identification and sensing technologies to develop new tracking systems able to guarantee benefits to animals' behavior analysis. This work presents a tracking solution based on passive Radio Frequency Identification Technology (RFID) in Ultra High Frequency (UHF) band. Much emphasis is given to the software component of the system, based on a Web oriented solution, able to process the raw tracking data coming from a hardware system, and offer 2D and 3D tracking information as well as reports and dashboards about mice behavior. The system has been widely tested using laboratory mice and compared with an automated video-tracking software (i.e., EthoVision). The obtained results have demonstrated the effectiveness and reliability of the proposed solution, which is able to correctly detect the events occurring in the animals' cage, and to offer a complete and user-friendly tool to support researchers in behavioral analysis of laboratory mice. PMID- 26737402 TI - Application of smart glasses for fast and automatic color correction in health care. AB - In recent years different applications of smart glasses in health care have been proposed. In this paper we present the experiments related to automatic color correction using smart glasses platform developed within the eGlasses project. The color pattern is proposed and tested enabling the automatic detection of the pattern and automatic correction of colors. Additionally, the method for encoding and decoding of patient ID in the color pattern is presented. This enables automatic data integration using smart glasses connected to Hospital Information System or similar systems. PMID- 26737403 TI - A dynamic control algorithm based on physiological parameters and wearable interfaces for adaptive ventricular assist devices. AB - In this work we present an innovative algorithm for the dynamic control of ventricular assist devices (VADs), based on the acquisition of continuous physiological and functional parameters such as heart rate, blood oxygenation, temperature, and patient movements. Such parameters are acquired by wearable devices (MagIC & Winpack) and sensors implanted close to the VAD. The aim of the proposed algorithm is to dynamically control the hydraulic power of the VAD as a function of the detected parameters, patient's activity and emotional status. In this way, the cardiac dynamics regulated by the proposed autoregulation control algorithm for sensorized VADs, thus providing new therapy approaches for heart failure. PMID- 26737404 TI - Relative accuracy of time and frequency domain features to quantify upper extremity coordination. AB - Upper limb coordination is necessary for the performance of activities of daily living (ADLs). This coordination is impaired in individuals suffering from motor deficits. The evolution of inter- and intra-limb coordination patterns may provide insight into mechanisms of recovery. In this paper, we investigate the ability of inertial sensors to capture measures of limb coordination in non disabled individuals during the performance of ADL inspired tasks. We evaluate limb coordination as measured by time and frequency domain features extracted from inertial sensors for a subset of upper limb tasks, and evaluate the relative sensitivity of these measures to different task types. PMID- 26737405 TI - Wearable and low-stress ambulatory blood pressure monitoring technology for hypertension diagnosis. AB - We propose a highly wearable, upper-arm type, oscillometric-based blood pressure monitoring technology with low-stress. The low-stress is realized by new developments in the hardware and software design. In the hardware design, conventional armband; cuff, is almost halved in volume thanks to a flexible plastic core and a liquid bag which enhances the fitness and pressure uniformity over the arm. Reduced air bag volume enables smaller motor pump size and battery leading to a thinner, more compact and more wearable unified device. In the software design, a new prediction algorithm enabled to apply less stress (and less pain) on arm of the patient. Proof-of-concept experiments on volunteers show a high accuracy on both technologies. This paper mainly introduces hardware developments. The system is promising for less-painful and less-stressful 24-hour blood pressure monitoring in hypertension managements and related healthcare solutions. PMID- 26737406 TI - Monitoring activities of daily living using Wireless Acoustic Sensor Networks in clean and noisy conditions. AB - This work examines the use of a Wireless Acoustic Sensor Network (WASN) for the classification of clinically relevant activities of daily living (ADL) of elderly people. The aim of this research is to automatically compile a summary report about the performed ADLs which can be easily interpreted by caregivers. In this work, the classification performance of the WASN will be evaluated in both clean and noisy conditions. Results indicate that the classification performance of the WASN is 75.3+/-4.3% on clean acoustic data selected from the node receiving with the highest SNR. By incorporating spatial information extracted by the WASN, the classification accuracy further increases to 78.6+/-1.4%. In addition, the classification performance of the WASN in noisy conditions is in absolute average 8.1% to 9.0% more accurate compared to highest obtained single microphone results. PMID- 26737407 TI - A mobile indoor positioning system based on iBeacon technology. AB - To increase the efficiency in the emergency room, the goal of this research is to implement a mobile-based indoor positioning system using mobile applications (APP) with the iBeacon solution based on the Bluetooth Low Energy (BLE) technology. We use the Received Signal Strength (RSS) based localization method to estimate the patients' locations. Our positioning algorithm achieves 97.22% (95% Confidence Interval = 95.90% - 98.55%) accuracy of classification. As the result, our mechanism is reliable enough to satisfy the need for medical staff to track the locations of their patients. PMID- 26737408 TI - Fall detection algorithm in energy efficient multistate sensor system. AB - Health issues for elderly people may lead to different injuries obtained during simple activities of daily living (ADL). Potentially the most dangerous are unintentional falls that may be critical or even lethal to some patients due to the heavy injury risk. Many fall detection systems are proposed but only recently such health care systems became available. Nevertheless sensor design, accuracy as well as energy consumption efficiency can be improved. In this paper we present a single 3-axial accelerometer energy-efficient sensor system. Power saving is achieved by selective event processing triggered by fall detection procedure. The results in our simulations show 100% accuracy when the threshold parameters are chosen correctly. Estimated energy consumption seems to extend battery life significantly. PMID- 26737409 TI - A novel ultra-wideband 80 GHz FMCW radar system for contactless monitoring of vital signs. AB - In this paper an ultra-wideband 80 GHz FMCW-radar system for contactless monitoring of respiration and heart rate is investigated and compared to a standard monitoring system with ECG and CO(2) measurements as reference. The novel FMCW-radar enables the detection of the physiological displacement of the skin surface with submillimeter accuracy. This high accuracy is achieved with a large bandwidth of 10 GHz and the combination of intermediate frequency and phase evaluation. This concept is validated with a radar system simulation and experimental measurements are performed with different radar sensor positions and orientations. PMID- 26737410 TI - Telemedicine multimedia system to support neurodegenerative diseases participatory management. AB - Parkinson's disease (PD) is a highly prevalent and disabling condition that requires a constant monitoring of patient's condition. Nevertheless, in Portugal appointments with specialist only occur every 6 months and the patient's capability to recall important past events is not always accurate besides often being a misinterpretation of their symptoms. In this paper we present a user centred process for the design of a multimedia platform for the self-management of PD. PMID- 26737411 TI - SenseMyHeart: A cloud service and API for wearable heart monitors. AB - In the era of ubiquitous computing, the growing adoption of wearable systems and body sensor networks is trailing the path for new research and software for cardiovascular intensity, energy expenditure and stress and fatigue detection through cardiovascular monitoring. Several systems have received clinical certification and provide huge amounts of reliable heart-related data in a continuous basis. PhysioNet provides equally reliable open-source software tools for ECG processing and analysis that can be combined with these devices. However, this software remains difficult to use in a mobile environment and for researchers unfamiliar with Linux-based systems. In the present paper we present an approach that aims at tackling these limitations by developing a cloud service that provides an API for a PhysioNet-based pipeline for ECG processing and Heart Rate Variability measurement. We describe the proposed solution, along with its advantages and tradeoffs. We also present some client tools (windows and Android) and several projects where the developed cloud service has been used successfully as a standard for Heart Rate and Heart Rate Variability studies in different scenarios. PMID- 26737412 TI - A fall prediction methodology for elderly based on a depth camera. AB - With the aging of society population, efficient tracking of elderly activities of daily living (ADLs) has gained interest. Advancements of assisting computing and sensor technologies have made it possible to support elderly people to perform real-time acquisition and monitoring for emergency and medical care. In an earlier study, we proposed an anatomical-plane-based human activity representation for elderly fall detection, namely, motion-pose geometric descriptor (MPGD). In this paper, we present a prediction framework that utilizes the MPGD to construct an accumulated histograms-based representation of an ongoing human activity. The accumulated histograms of MPGDs are then used to train a set of support-vector-machine classifiers with a probabilistic output to predict fall in an ongoing human activity. Evaluation results of the proposed framework, using real case scenarios, demonstrate the efficacy of the framework in providing a feasible approach towards accurately predicting elderly falls. PMID- 26737413 TI - Easy-to-use, general, and accurate multi-Kinect calibration and its application to gait monitoring for fall prediction. AB - Falls are the most-common causes of unintentional injury and death in older adults. Many clinics, hospitals, and health-care providers are urgently seeking accurate, low-cost, and easy-to-use technology to predict falls before they happen, e.g., by monitoring the human walking pattern (or "gait"). Despite the wide popularity of Microsoft's Kinect and the plethora of solutions for gait monitoring, no strategy has been proposed to date to allow non-expert users to calibrate the cameras, which is essential to accurately fuse the body motion observed by each camera in a single frame of reference. In this paper, we present a novel multi-Kinect calibration algorithm that has advanced features when compared to existing methods: 1) is easy to use, 2) it can be used in any generic Kinect arrangement, and 3) it provides accurate calibration. Extensive real-world experiments have been conducted to validate our algorithm and to compare its performance against other multi-Kinect calibration approaches, especially to show the improved estimate of gait parameters. Finally, a MATLAB Toolbox has been made publicly available for the entire research community. PMID- 26737414 TI - Person identification from gait analysis with a depth camera at home. AB - The aim of our project is to develop a markerless system to detect falls and evaluate the frailty of elderly people at home. In previous work, we developed an algorithm detecting falls and daily life activities based on depth images provided by Microsoft's Kinect sensor. We also developed another algorithm based on the same features for gait analysis. However, an ambient system installed at home for frailty evaluation should be able to identify the individuals that one wishes to monitor. This paper proposes a method to identify individuals based on the depth images of gait sequences. The gait sequences are detected using previously presented results on activity recognition based on Hidden Markov Models (HMMs). The visibility of the person in the sequence is assessed from the likelihood of the sequence. We propose to perform the identification of the person from her height and gait in sequences in which she walks being fully visible. The gait pattern of the person is modeled using a HMM built from features of the trajectory of the centre of mass. A specific HMM is built for each person to be identified. This approach also allows us to identify unknown individuals who do not correspond to any of the built HMMs. We test the algorithm with 10 known and 2 unknown individuals. The results show that the presented method differentiates accurately enough the unknown and known individuals, and in the last case identifies correctly the individuals. In other words, our algorithm is able to identify the person of interest among other known (family, caregivers) or unknown persons (occasional individuals). PMID- 26737415 TI - Characterization of a multi-user indoor positioning system based on low cost depth vision (Kinect) for monitoring human activity in a smart home. AB - An increasing number of systems use indoor positioning for many scenarios such as asset tracking, health care, games, manufacturing, logistics, shopping, and security. Many technologies are available and the use of depth cameras is becoming more and more attractive as this kind of device becomes affordable and easy to handle. This paper contributes to the effort of creating an indoor positioning system based on low cost depth cameras (Kinect). A method is proposed to optimize the calibration of the depth cameras, to describe the multi-camera data fusion and to specify a global positioning projection to maintain the compatibility with outdoor positioning systems. The monitoring of the people trajectories at home is intended for the early detection of a shift in daily activities which highlights disabilities and loss of autonomy. This system is meant to improve homecare health management at home for a better end of life at a sustainable cost for the community. PMID- 26737416 TI - Design and evaluation of a smartphone application for non-speech sound awareness for people with hearing loss. AB - Auditory cues provide people with information about events outside of their field of view and can so help detecting potential hazards. People with severe hearing loss, i.e. hard of hearing, deafened, and deaf people, often cannot or can only partially benefit from auditory cues, which can lead to a lowered quality of life. Even though hearing aids are available, not everyone can benefit from them. To provide deaf people (i.e. deaf, deafened, and hard of hearing) with auditory cues from environmental sounds different assistive devices have been introduced, usually for use at home. A flexible and mobile assistive device basing on a smartphone is presented in this contribution. It detects and recognizes acoustic events by analysing the acoustic environment of the user. By using pattern recognition algorithms the user can define the sounds that should be recognised by the device. Warning sounds occurring in road traffic were chosen as demonstrator. Interviews were conducted with deaf people to evaluate the concept and to gain more insights into the user needs and expectations. PMID- 26737417 TI - Low vision system for rapid near- and far-field magnification switching. AB - People suffering from low vision, a condition caused by a variety of eye-related diseases and/or disorders, find their ability to read greatly improved when text is magnified between 2 and 6 times. Assistive devices currently on the market are either geared towards reading text far away (~20 ft.) or very near (~2 ft.). This is a problem especially for students suffering from low vision, as they struggle to flip their focus between the chalkboard (far-field) and their notes (near- field). A solution to this problem is of high interest to eye care facilities in the developing world - no devices currently exist that have the aforementioned capabilities at an accessible price point. Through consultation with specialists at L.V. Prasad Eye Institute in India, the authors propose, design and demonstrate a device that fills this need, directed primarily at the Indian market. The device utilizes available hardware technologies to electronically capture video ahead of the user and zoom and display the image in real-time on LCD screens mounted in front of the user's eyes. This design is integrated as a wearable system in a glasses form-factor. PMID- 26737418 TI - Towards personalized smart wheelchairs: Lessons learned from discovery interviews. AB - We posit that it is necessary to investigate the personalization of smart wheelchairs in three aspects interfaces for interaction, controllers for action (top-level, middle-level, and low-level), and feedback in interaction. Our team has been selected as an Innovation Corps (I-Corps) Team by the National Science Foundation to pursue customer discovery research to explore the commercial viability of smart wheelchairs. Through the process, our team has performed more than 110 interviews with powered wheelchair users, manufacturers, therapists, policy makers, and non-profit organization staff. Our findings revealed that the acceptability of fully autonomous systems by the users is still challenging and highly-dependent on the severity of the disability. Furthermore, the cost, ease of-use and personalization are the most important factors in commercializing smart wheelchair technologies. PMID- 26737419 TI - User-centric design of a personal assistance robot (FRASIER) for active aging. AB - We present our preliminary results from the design process for developing the Worcester Polytechnic Institute's personal assistance robot, FRASIER, as an intelligent service robot for enabling active aging. The robot capabilities include vision-based object detection, tracking the user and help with carrying heavy items such as grocery bags or cafeteria trays. This work-in-progress report outlines our motivation and approach to developing the next generation of service robots for the elderly. Our main contribution in this paper is the development of a set of specifications based on the adopted user-centered design process, and realization of the prototype system designed to meet these specifications. PMID- 26737420 TI - Development and pilot testing of a kneeling ultralight wheelchair design. AB - "Dynamic wheeled mobility" offers "on the fly" seating adjustments for wheelchair users such that various activities performed throughout the day can be matched by an appropriate seat position. While this has benefits for user participation and health, the added weight in existing dynamic wheelchairs may impact the user's ability to transport the frame, e.g. into cars. Other dynamic features to enable more participation avenues are also desirable. This paper outlines the development of a "kneeling" ultralight wheelchair design that offers dynamic wheeled mobility functionality at a weight that is comparable to many existing ultralight wheelchairs. In addition, the wheelchair's kneeling function allows a lowered seat position to facilitate low-to-the-ground tasks such as floor transfers and other activities where sustained low level reaching may be required (e.g. playing with children, changing a tire, etc.). This paper also describes the development and pilot testing of an end user evaluation protocol designed to validate the wheelchair's functionality and performance. Successful realization and commercialization of the technology would offer a novel product choice for people with mobility disabilities, and that may support daily activities, health, improved quality of life, and greater participation in the community. PMID- 26737421 TI - Early detection of sit-to-stand transitions in a lower limb orthosis. AB - This paper describes a method for early detection of posture transitions in a powered orthotic brace purposed for assisting elderly people in sit-to-stand transitions. The detection system is constructed using a linear Support Vector Machine classifier that is trained from features extracted from the signals produced by the sensors mounted on the orthosis. The sensors include accelerometers, potentiometers, gyroscopes and force sensors. The data were collected from 9 healthy individuals that performed various activities, including transitions between sitting, standing and walking. The collected sensor data were processed, normalized and manually annotated to label all posture transitions. A Support Vector Machine classifier was trained and validated in a leave-one-out manner to detect early onset of sit-to-stand transitions. Use of lagged windows was examined in efforts to increase accuracy. The proposed method was to detect posture transitions with a high detection rate and a relatively low number of false positives. PMID- 26737422 TI - Promoting autonomy in a smart home environment with a smarter interface. AB - In the not too distant future, the median population age will tend towards 65; an age at which the need for dependency increases. Most older people want to remain autonomous and self-sufficient for as long as possible. As environments become smarter home automation solutions can be provided to support this aspiration. The technology discussed within this paper focuses on providing a home automation system that can be controlled by most users regardless of mobility restrictions, and hence it may be applicable to older people. It comprises a hybrid Brain Computer Interface, home automation user interface and actuators. In the first instance, our system is controlled with conventional computer input, which is then replaced with eye tracking and finally a BCI and eye tracking collaboration. The systems have been assessed in terms of information throughput; benefits and limitations are evaluated. PMID- 26737423 TI - Action tagging in a multi-user indoor environment for behavioural analysis purposes. AB - EU population is getting older, so that ICT-based solutions are expected to provide support in the challenges implied by the demographic change. At the University of Parma an AAL (Ambient Assisted Living) system, named CARDEA, has been developed. In this paper a new feature of the system is introduced, in which environmental and personal (i.e., wearable) sensors coexist, providing an accurate picture of the user's activity and needs. Environmental devices may greatly help in performing activity recognition and behavioral analysis tasks. However, in a multi-user environment, this implies the need of attributing environmental sensors outcome to a specific user, i.e., identifying the user when he performs a task detected by an environmental device. We implemented such an "action tagging" feature, based on information fusion, within the CARDEA environment, as an inexpensive, alternative solution to the problematic issue of indoor locationing. PMID- 26737424 TI - Automated walking aid detector based on indoor video recordings. AB - Due to the rapidly aging population, developing automated home care systems is a very important step in taking care of elderly people. This will enable us to automatically monitor the health of senior citizens in their own living environment and prevent problems before they happen. One of the challenging tasks is to actively monitor walking habits of elderlies, who alternate between the use of different walking aids, and to combine this with automated fall risk assessment systems. We propose a camera based system that uses object categorization techniques to robustly detect walking aids, like a walker, in order to improve the classification of the fall risk. By automatically integrating the application specific scenery knowledge like camera position and used walker type, we succeed in detecting walking aids within a single frame with an accuracy of 68% for trajectory A and 38% for trajectory B. Furthermore, compared to current state of the art detection systems, we use a rather limited set of training data to achieve this accuracy and thus create a system that is easily adaptable for other applications. Moreover, we applied spatial constraints between detections to optimize the object detection output and to limit the amount of false positive detections. Finally, we evaluate the output on a walking sequence base, leading up to a 92.3% correct classification rate of walking sequences. It can be noted that adapting this approach to other walking aids, like a walking cane, is quite straightforward and opens up the door for many future applications. PMID- 26737425 TI - Automatic detection of health changes using statistical process control techniques on measured transfer times of elderly. AB - It has been shown that gait speed and transfer times are good measures of functional ability in elderly. However, data currently acquired by systems that measure either gait speed or transfer times in the homes of elderly people require manual reviewing by healthcare workers. This reviewing process is time consuming. To alleviate this burden, this paper proposes the use of statistical process control methods to automatically detect both positive and negative changes in transfer times. Three SPC techniques: tabular CUSUM, standardized CUSUM and EWMA, known for their ability to detect small shifts in the data, are evaluated on simulated transfer times. This analysis shows that EWMA is the best suited method with a detection accuracy of 82% and an average detection time of 9.64 days. PMID- 26737426 TI - Physical activity classification meets daily life: Review on existing methodologies and open challenges. AB - Recent advances in the MEMS devices make it happen to wirelessly integrate miniature motion capturing devices with Smartphones and to use them in personal health care and physical activity monitoring in daily life. There is no ground truth, though, to measure the physical activity (PA) in daily life and because of this, there is no common validation procedure adapted by the researchers for benchmarking the performance of algorithms for PA classification. The major issue in the existing studies for PA classification is the utilization of structured protocol in a controlled setting or simulated daily environment, which limits their implementation in real life conditions where activities are unplanned and unstructured, both in occurrence and in duration. This study provides a critical review on the validation procedures used for PA classification, types of activities classified and limitations in the exiting studies to implement them in daily life settings. Only those studies are considered which classify PA based on wearable accelerometers as an objective measure. The pros and cons of existing methodologies are highlighted and future possibilities are addressed for the development of a robust PA classification system which is feasible under real life conditions. PMID- 26737427 TI - Influence of age and gender on sensor-based functional measures: A factor analysis approach. AB - The purpose of this study was to investigate the functional decline associated with aging and gender-related differences by means of a set of sensor-based measures. A actor analysis has been performed in order to classify domains of an instrumented Timed Up and Go (TUG) test in a group of community-dwelling elderly people. 239 elderly people were recruited and underwent an instrumented TUG test. Features extracted from TUG trials, were grouped by the factor analysis in six factors with a clear clinical value. Significant correlations and gender-related differences were found between age and factors associated with the global fitness, the turning ability, and the dynamics of the trunk during postural transitions. Results provide evidence that a sensor-based assessment is a feasible and effective tool for assessing functional decline in the general population. PMID- 26737428 TI - ECG synthesis from separate wearable bipolar electrodes. AB - Compared to cabled ECG devices, the use of wearable patches to reconstruct ECG offers a more comfortable alternative for continuous monitoring, especially for patients at home. In this work, we investigate the feasibility of synthesizing a 3-lead ECG signal from 3 separate wearable and wireless patches. We also investigate the effect of their orientation on the synthesized signal. We conduct an experiment on healthy subjects and show the ability of this method to provide a similar ECG signal to the reference, in terms of matching the overall signal pattern. However, a more detailed study would be needed in order to investigate the ability of this method to identify critical conditions for vulnerable subjects. PMID- 26737429 TI - Mining human behavior for health promotion. AB - The monitoring of human lifestyles has gained much attention in the recent years. This work presents a novel approach to combine multiple context-awareness technologies for the automatic analysis of people's conduct in a comprehensive and holistic manner. Activity recognition, emotion recognition, location detection, and social analysis techniques are integrated with ontological mechanisms as part of a framework to identify human behavior. Key architectural components, methods and evidences are described in this paper to illustrate the interest of the proposed approach. PMID- 26737430 TI - Modeling of human movement monitoring using Bluetooth Low Energy technology. AB - Bluetooth Low Energy (BLE) is a wireless communication technology which can be used to monitor human movements. In this monitoring system, a BLE signal scanner scans signal strength of BLE tags carried by people, to thus infer human movement patterns within its monitoring zone. However to the extent of our knowledge one main aspect of this monitoring system which has not yet been thoroughly investigated in literature is how to build a sound theoretical model, based on tunable BLE communication parameters such as scanning time interval and advertising time interval, to enable the study and design of effective and efficient movement monitoring systems. In this paper, we proposed and developed a statistical model based on Monte-Carlo simulation, which can be utilized to assess impacts of BLE technology parameters in terms of latency and efficiency, on a movement monitoring system, and can thus benefit a more efficient system design. PMID- 26737431 TI - Human motion energy harvesting using a piezoelectric MFC patch. AB - The improvements in efficiency of electronic components and miniaturization is quickly pushing wearable devices. Kinetic human energy harvesting is a way to power these components reducing the need of batteries replacement since walking or running is how humans already expend much of their daily energy. This work explores the case of kinetic energy from bending of a piezoelectric patch. For assessing the quality of the system, a testing setup has been designed and controlled by means of knee joint recordings obtained from a large motion dataset. The promising result of the chosen patch is an output power of 2.6MUW associated to a run activity. PMID- 26737432 TI - A Random Forest-based ensemble method for activity recognition. AB - This paper presents a multi-sensor ensemble approach to human physical activity (PA) recognition, using random forest. We designed an ensemble learning algorithm, which integrates several independent Random Forest classifiers based on different sensor feature sets to build a more stable, more accurate and faster classifier for human activity recognition. To evaluate the algorithm, PA data collected from the PAMAP (Physical Activity Monitoring for Aging People), which is a standard, publicly available database, was utilized to train and test. The experimental results show that the algorithm is able to correctly recognize 19 PA types with an accuracy of 93.44%, while the training is faster than others. The ensemble classifier system based on the RF (Random Forest) algorithm can achieve high recognition accuracy and fast calculation. PMID- 26737433 TI - Validation of an optimized algorithm to use Kinect in a non-structured environment for Sit-to-Stand analysis. AB - The aim of this work is to obtain reliable kinematic measures relative to the execution of the Sit-to-Stand functional evaluation test, by low-cost and widely diffused instrumentation, that even non-experienced users can adopt in non structured environments, like ambulatory or domestic settings. In particular, the paper refers to a low cost RGB-Depth sensor widely used in the gaming scenario like the Microsoft Kinect sensor. An algorithm is proposed that allows a reliable measure of human motion in a sagittal view. The performance of the proposed algorithm is compared to other two classic commercial algorithms. Results obtained by all the three algorithms have been compared to kinematic results obtained by the use of a stereophotogrammetric system that represents the gold standard for kinematic measurement of human movement. Average errors of about 4 degrees, both for the trunk/leg angle and for the knee flexion/extension angle, have been obtained by the proposed algorithm and open the way to its possible adoption in non-clinical environments and further applications. PMID- 26737434 TI - Affordable low complexity heart/brain monitoring methodology for remote health care. AB - This paper introduces a dual-mode low complex on-chip methodology for processing of ECG (Electrocardiogram) and EEG (Electroencephalography) signals, wherein based on the input switch the architecture can be dynamically configured to operate either as an ECG bio-marker or EEG signal de-noising system. In both the modes the signal processing technique depends on the output of the DWT (Discrete Wavelet Transform), hence a low complex methodology has been developed in which both ECG and EEG processing blocks sharing the same DWT block resulting in low area and low power consumption. The integrated ECG and EEG methodology has been implemented in Matlab, for verifying the ECG processing block the ECG database is taken from MIT-BIH PTBDB and IITH DB, similarly for EEG processing block the EEG signals are taken from PhysioNet database. The outcome of methodology in Matlab is equal to the results obtained from individual ECG and EEG blocks. PMID- 26737435 TI - Epileptic seizure detection using wristworn biosensors. AB - Single signal seizure detection algorithms suffer from high false positive rates. We have found a set of signals which can be easily monitored by a wristworn device and which produce a distinctive pattern during seizure for patients in an epilepsy monitoring unit (EMU). This pattern is much less likely to be reproduced by nonseizure events in the patient's daily life than are changes in heart rate alone. We collected 108 hours of data from three EMU patients who suffered a combined total of seven seizures, then developed a time series analysis/pattern recognition based algorithm which distinguishes the seizures from nonseizure events with 100% accuracy. PMID- 26737436 TI - Visualizing the brain on a mixed reality smartphone application. AB - Augmented and Virtual Reality approaches are getting more and more advanced and consequently their use in various real world areas is increasing. Medicine is one of the fields in which more practical applications are surfacing, mainly approaches that enable new forms of visualization of data obtained from real patients. Our work focuses on providing a new simple, practical and efficient way to visualize the brain of a patient, both in an Augmented Reality and in a Virtual Reality approach, through a smartphone application. PMID- 26737437 TI - Transmission of wireless neural signals through a 0.18 um CMOS low-power amplifier. AB - In the field of Brain Machine Interfaces (BMI) researchers still are not able to produce clinically viable solutions that meet the requirements of long-term operation without the use of wires or batteries. Another problem is neural compatibility with the electrode probes. One of the possible ways of approaching these problems is the use of semiconductor biocompatible materials (silicon carbide) combined with an integrated circuit designed to operate with low power consumption. This paper describes a low-power neural signal amplifier chip, named Cortex, fabricated using 0.18 MUm CMOS process technology with all electronics integrated in an area of 0.40 mm(2). The chip has 4 channels, total power consumption of only 144 MUW, and is impedance matched to silicon carbide biocompatible electrodes. PMID- 26737438 TI - New training methods based on mixed reality for interventional ultrasound: Design and validation. AB - Currently the learning model for ultrasound imaging diagnosis and intervention follows a traditional approach based on learning by doing but this model exposes the patient to the whole learning curve of the novice. In order to enable training in a safe environment without compromising patient's health we have developed and demonstrated face, content and construct validity of a hybrid simulator for ultrasound-guided biopsy. This hybrid simulator is able to provide a support to acquire skills in term of 3D perception and hand-eye coordination thanks to a mixed reality visualization that allows accurate and easy planning of probe position/orientation and needle trajectory to reach the target. PMID- 26737439 TI - Basic Endovascular Skills Trainer: A surgical simulator for the training of novice practitioners of endovascular procedures. AB - In recent years the clinical interest for structured training in endovascular procedures has increased. Such procedures respect the physical integrity of the patient and at the same time ensure good therapeutic results. This study describes the development and testing of the B.E.S.T. (Basic Endovascular Skills Trainer) simulator. The B.E.S.T is an innovative physical endovascular simulator to learn basic skills of endovascular surgery. The simulator was tested by 25 clinicians with different levels of experience: novices, intermediates, and experts. All clinicians agree on affirming the importance of training in endovascular surgery; in particular they consider the B.E.S.T a valid simulator to learn specific basic skills of vascular surgery. PMID- 26737440 TI - Development of trabecular bone surrogates for kyphoplasty-balloon dilatation training. AB - Vertebral compression fractures can limit quality of life. Cement augmentation techniques show good results in attaining pain relief. Kyphoplasty enables a better restoration of vertebra height due to a dilatable balloon tamp, which is inflated in the fractured vertebra. Surgical training of vertebral cement augmentation techniques is currently performed on patients or specimens. To enable another training possibility for surgical residents, a new hybrid patient simulator was developed. Artificial vertebrae allocate a realistic haptic feedback during needle insertion. Based on these results, new polyurethane foam recipes were developed to either enable a realistic needle insertion as well as a balloon tamp dilatation. Needle insertion forces of the newly developed foams were compared against commercially available artificial trabecular bone material and balloon tamp dilatations were performed in manufactured materials. Based on the matching needle insertion forces, two suitable material compositions for needle insertion and balloon dilatation training were found. This investigation is considered as a prior study before evaluation on human specimen. PMID- 26737441 TI - Assessment parameters for a novel simulator in minimally invasive spine surgery. AB - Surgical simulators provide a safe environment where novice surgeons can acquire their surgical skills. Although the number of patients with diseases of the musculoskeletal system is growing, the development of orthopedic simulators is still in it's infancy. The aim of this work was to identify simulation-based assessment parameters for a novel simulator in minimally invasive spine surgery. Apart from parameters targeting the duration and the surgeon's economy of motion during percutaneous bone access, parameters characterizing the movement smoothness were also examined with respect to their suitability. The results indicated, that the overall duration, the number of instrument movements, the number of velocity peaks and the Movement Arrest Period Ratio are the most promising predictors of expertise. Targeting performance improvement, the overall duration (p = 0.001), the number of instrument movements (p = 0.003) and the traveled instrument path length (p = 0.009) detected significant differences between subsequent trials. Using these parameters, a study can be designed targeting the validity and reliability of the simulation-based assessment. PMID- 26737442 TI - Comparison of oral surgery task performance in a virtual reality surgical simulator and an animal model using objective measures. AB - The use of virtual reality (VR) simulation for surgical training has gathered much interest in recent years. Despite increasing popularity and usage, limited work has been carried out in the use of automated objective measures to quantify the extent to which performance in a simulator resembles performance in the operating theatre, and the effects of simulator training on real world performance. To this end, we present a study exploring the effects of VR training on the performance of dentistry students learning a novel oral surgery task. We compare the performance of trainees in a VR simulator and in a physical setting involving ovine jaws, using a range of automated metrics derived by motion analysis. Our results suggest that simulator training improved the motion economy of trainees without adverse effects on task outcome. Comparison of surgical technique on the simulator with the ovine setting indicates that simulator technique is similar, but not identical to real world technique. PMID- 26737443 TI - A chair for cuffless real-time estimation of systolic blood pressure based on pulse transit time. AB - This study presents an unobtrusive cuffless blood pressure (BP) monitoring system for estimating beat-by-beat systolic blood pressure (SBP) in real-time based on pulse transit time (PTT). The system mainly includes an electrocardiograph with three conductive textile electrodes, a pulse monitor with a LED and a photodetector, a control circuit with a Bluetooth module, and a battery, all of which are mounted on a common armchair to measure ECG and photoplethysmography (PPG) signals from users during sitting on the armchair. The measured ECG and PPG data are transmitted to the software terminal installed on a tablet PC and are further derived to obtain a series of PTT for estimating beat-by-beat BP using Chen's method. We had 9 healthy subjects undergo the BP monitoring experiments of still sitting on a chair for 3 minutes, lying on a bed for 10 minutes, and pedaling using ergometer for 11 minutes in order to assess the accuracy of the estimated BP. A Finometer and a cuff-type BP meter were used as references in the experiments. Preliminary results showed that the mean error and mean absolute difference (MAD) of estimated BP were within -0.5 +/- 5.3 mmHg and 4.1 +/- 3.4 mmHg, respectively, compared to references. The result suggests that the proposed BP estimation system has the potential for long-term home BP monitoring. PMID- 26737444 TI - Simulation study on the effect of tissue geometries to fluence composition for non-invasive fetal pulse oximetry. AB - Transabdominal fetal pulse oximetry is a method to estimate the state of oxygenation of a fetus in-utero, utilizing the principle of reflection pulse oximetry. The extraction of fetal related information from a mixed fetal-maternal signal is elementary. Minimizing the ratio of purely maternal components of the signal at the detector side obviously facilitates signal separation. In this paper we analyze the influence of tissue geometries to the fluence composition at the surface of the abdomen. Monte-Carlo method is used to compute photon propagation in spherical layered tissue models. Spatial fluence distributions at the surface of the models are visualized and discussed. Our results show the characteristic effects of the distance between the fetus and the surface and the radius of the abdomen to the fluence composition at the detector. Further, the simulations indicate suitable source-detector configurations considering various anatomical conditions. We conclude that an adoption of the source-detector configuration to the individual tissue geometry at hand is necessary to achieve a proper signal composition and quality. Utilizing simulations for sensor design enhances the understanding of photon distributions in complex tissue geometries and supports a successful implementation of transabdominal fetal pulse oximetry. PMID- 26737445 TI - Intraoperative monitoring of intestinal viability: Evaluation of a new combined sensor. AB - A dual wavelength photoplethysmography (PPG) and laser Doppler flowmetry (LDF) sensor was developed to investigate the suitability of these techniques for monitoring bowel viability intraoperatively. Clinical measurements were obtained from thirty patients undergoing bowel surgery. Three measurements were performed at different stages of the operation. The amplitude of infrared PPG decreased from the baseline measurement to the pre-anastomosis measurement by 36% and LDF flux decreased by 21% for the same measurements. An increase of 33% in amplitude for infrared PPG was observed from the pre-anastomotic to post-anastomosis measurement; the equivalent increase was not seen for LDF flux. The results revealed that the sensor could potentially indicate changes in perfusion and blood flow at critical phases of surgery, thereby assisting in the early detection of inadequate blood supply in bowel tissue. The results also suggest that laser Doppler is more sensitive to movement artefact compared to PPG. PMID- 26737447 TI - Detection of Levodopa Induced Dyskinesia in Parkinson's Disease patients based on activity classification. AB - In this paper, we present an activity classification-based algorithm for the automatic detection of Levodopa Induced Dyskinesia in Parkinson's Disease (PD) patients. Two PD patients experiencing motor fluctuations related to chronic Levodopa therapy performed a protocol of simple daily life activities on at least two different occasions. A Random Forest classifier was able to classify the performed activities by the patients with an overall accuracy of 86%. Based on the detected activity, a K Nearest Neighbor classifier detected the presence of dyskinesia with accuracy ranging from 75% to 88%. PMID- 26737446 TI - Impedance sensing device for monitoring ulcer healing in human patients. AB - Chronic skin wounds affect millions of people each year and take billions of dollars to treat. Ulcers are a type of chronic skin wound that can be especially painful for patients and are tricky to treat because current monitoring solutions are subjective. We have developed an impedance sensing tool to objectively monitor the progression of healing in ulcers, and have begun a clinical trial to evaluate the safety and feasibility of our device to map damaged regions of skin. Impedance data has been collected on five patients with ulcers, and impedance was found to correlate with tissue health. A damage threshold was applied to effectively identify certain regions of skin as "damaged tissue". PMID- 26737448 TI - Impedance spectroscopy to monitor fracture healing. AB - An estimated 7.9 million fracture injuries occur each year in the United States, of which a substantial fraction result in delayed or non-union. Current methods of monitoring fracture healing include taking x-rays and making clinical observations. However, x-ray confirmation of bone healing typically lags behind biologic healing, and physician assessment of healing is fraught with subjectivity. No standardized methods exist to assess the extent of healing that has taken place in a fracture. Without such knowledge, interventions to aid healing and prevent fracture non-union are often delayed, leading to increased morbidity and suffering to patients. We are developing an objective measurement tool that utilizes electrical impedance spectroscopy to distinguish between the various types of tissue present during the different stages of fracture healing. Preliminary measurements of cadaveric tissues reveal adequate spread in impedance measurements and differences in frequency response among different tissue types. Electrodes implanted in a simulated fracture created in an ex vivo cadaver model yield promising results for our system's ability to differentiate between the stages of fracture healing. PMID- 26737449 TI - EC-PC spike detection for high performance brain-computer interface. AB - Spike detection is often the first step in neural signal processing. It has profound effects on subsequent steps down the signal processing pipeline. Most existing spike detection algorithms require manual setting of detection threshold, which is very inconvenient for long-term neural interface. Furthermore, these algorithms are usually only evaluated using simulated dataset. Few studies are devoted to evaluating how different spike detection algorithms affect decoding performance in brain-computer interface. We have proposed a new spike detection algorithm called "exponential component - power component" (EC PC) that offers fully automatic unsupervised spike detection. In this study, we compared the performance of a motor decoding task when different spike detection algorithms were used. EC-PC is shown to produce a higher decoding accuracy compared with other existing algorithms. Our results suggest that EC-PC can help improve motor decoding performance of brain-computer interface. PMID- 26737450 TI - Improving neural decoding in the central auditory system using bio-inspired spectro-temporal representations and a generalized bilinear model. AB - We study the impact of different encoding models and spectro-temporal representations on the accuracy of Bayesian decoding of neural activity recorded from the central auditory system. Two encoding models, a generalized linear model (GLM) and a generalized bilinear model (GBM), are compared along with three different spectro-temporal representations of the input stimuli: a spectrogram and two bio-inspired representations, i.e. a gammatone filter bank (GFB) and a spikegram. Signal to noise ratios between the reconstructed and original representations are used to evaluate the decoding, or reconstruction accuracy. We experimentally show that the reconstruction accuracy is best with the spikegram representation and worst with the spectrogram representation and, furthermore, that using a GBM instead of a GLM significantly increases the reconstruction accuracy. In fact, our results show that the spikegram reconstruction accuracy with a GBM fitting yields an SNR that is 3.3 dB better than when using the standard decoding approach of reconstructing a spectrogram with GLM fitting. PMID- 26737451 TI - FPGA implementation of principal component regression (PCR) for real-time differentiation of dopamine from interferents. AB - This paper reports on field-programmable gate array (FPGA) implementation of a digital signal processing (DSP) unit for real-time processing of neurochemical data obtained by fast-scan cyclic voltammetry (FSCV) at a carbonfiber microelectrode (CFM). The DSP unit comprises a decimation filter and two embedded processors to process the FSCV data obtained by an oversampling recording front end and differentiate the target analyte from interferents in real time with a chemometrics algorithm using principal component regression (PCR). Interfaced with an integrated, FSCV-sensing front-end, the DSP unit successfully resolves the dopamine response from that of pH change and background-current drift, two common dopamine interferents, in flow injection analysis involving bolus injection of mixed solutions, as well as in biological tests involving electrically evoked, transient dopamine release in the forebrain of an anesthetized rat. PMID- 26737452 TI - Comparison of speech envelope extraction methods for EEG-based auditory attention detection in a cocktail party scenario. AB - Recent research has shown that it is possible to detect which of two simultaneous speakers a person is attending to, using brain recordings and the temporal envelope of the separate speech signals. However, a wide range of possible methods for extracting this speech envelope exists. This paper assesses the effect of different envelope extraction methods with varying degrees of auditory modelling on the performance of auditory attention detection (AAD), and more specifically on the detection accuracy. It is found that sub-band envelope extraction with proper power-law compression yields best performance, and that the use of several more detailed auditory models does not yield a further improvement in performance. PMID- 26737453 TI - Probing meaningfulness of oscillatory EEG components with bootstrapping, label noise and reduced training sets. AB - As oscillatory components of the Electroencephalogram (EEG) and other electrophysiological signals may co-modulate in power with a target variable of interest (e.g. reaction time), data-driven supervised methods have been developed to automatically identify such components based on labeled example trials. Under conditions of challenging signal-to-noise ratio, high-dimensional data and small training sets, however, these methods may overfit to meaningless solutions. Examples are spatial filtering methods like Common Spatial Patterns (CSP) and Source Power Comodulation (SPoC). It is difficult for the practitioner to tell apart meaningful from arbitrary, random components. We propose three approaches to probe the robustness of extracted oscillatory components and show their application to both, simulated and EEG data recorded during a visually cued hand motor reaction time task. PMID- 26737454 TI - Research on multi-dimensional N-back task induced EEG variations. AB - In order to test the effectiveness of multi-dimensional N-back task for inducing deeper brain fatigue, we conducted a series of N*L-back experiments: 1*1-back, 1*2-back, 2*1-back and 2*2-back tasks. We analyzed and compared the behavioral results, EEG variations and mutual information among these four different tasks. There was no significant difference in average EEG power and power spectrum entropy (PSE) among the tasks. However, the behavioral result of N*2-back task showed significant difference compared to traditional one dimensional N-back task. Connectivity changes were observed with the addition of one more matching task in N-back. We suggest that multi-dimensional N-back task consume more brain resources and activate different brain areas. These results provide a basis for multi-dimensional N-back tasks that can be used to induce deeper mental fatigue or exert more workload. PMID- 26737455 TI - Automatic task analysis based on head movement. AB - Analysis of movement using accelerometers mounted on the torso or limbs has shown good potential for the recognition of physical activities. However many contemporary lifestyle tasks are sedentary, and less is known about how these can be automatically characterized using movement signals. This paper proposes possibly the first system that employs head movement for recognizing different levels of mental activity and for discriminating between various kinds of sedentary and non-sedentary tasks. Results from analysis of a 20-participant database show that head movement is surprisingly indicative of cognitive load and discriminative between different task types, as well as exhibiting some sensitivity to the instant of task change. Given the possibility for wearing hats or glasses with embedded inertial measurement units, this suggests a range of interesting future applications, including monitoring of sedentary daily activities, and developing rough estimates of mental exertion. PMID- 26737456 TI - Timed Up-and-Go phase segmentation in Parkinson's disease patients using unobtrusive inertial sensors. AB - A widely accepted functional motor test for measuring basic mobility capabilities is the 'Timed Up-and-Go' (TUG) test. Although several basic mobility tasks are included, only the total time is used as outcome parameter. It has been shown that timings of sub-phases can be used as relevant clinical parameters for the assessment of Parkinson's disease patients. A variety of systems and methods have been proposed for instrumenting the TUG test, but only limited information has been published regarding phase classification. In this paper an automated TUG phase classification methodology is proposed and validated in a study with 16 Parkinson's disease patients. Statistical, signal energy, chronological and gait features were extracted from acceleration and orientation signals of shoe mounted inertial measurement units. The phases 'sit to walk', 'walking', 'first turn', 'second turn' and 'turn to sit' were segmented in a two stage classifier approach. Strides were used for a separation of the walking phase and classifiers like NaiveBayes, k-Nearest-Neighbor, Support Vector Machine (SVM) and Random Forest for the final phase segmentation. SVM performed best with a mean sensitivity of 81.80% over all phases. Additionally, the impact of UPDRS and Hoehn & Yahr ratings on the phase times was assessed. The proposed methodology could be used to analyze gait parameters of sub-phases like stride length, stride time, foot clearance, heel-strike or toe-off angle for an improved assessment of Parkinson's disease patients. PMID- 26737457 TI - Estimating in-home walking speed distributions for unobtrusive detection of mild cognitive impairment in older adults. AB - Timely recognition of cognitive impairment such as Alzheimer's disease is of great significance. Many smart systems, developed to continuously monitor older adults' health and cognition, use a number of predefined measures associated with the older adults' activity in their homes. However, this approach has been demonstrated to focus on idiosyncratic nuances of the individual subjects, and thus could potentially not perform as well when tested on new subjects. In this paper, we address this problem by building proper statistical models of older adults' in-home walking speed. Using the data pertaining to 15 older adults monitored for an average period of 3 years, we used linear regression with a Gaussian likelihood to model the subjects' in-home walking speed, and we used dynamic time warping to demonstrate significant difference between the walking speed distributions of the subjects when cognitively intact and when having mild cognitive impairment (MCI). Using a simple thresholding approach of the dynamic time warping costs, we were able to detect MCI in older adults with areas under the ROC curve and the precision-recall curve of 0.906 and 0.790, respectively, using a time frame of 12 weeks. PMID- 26737458 TI - Hidden Markov model-based strategy for gait segmentation using inertial sensors: Application to elderly, hemiparetic patients and Huntington's disease patients. AB - A solution to discriminate stance and swing in both healthy and abnormal gait using inertial sensors is proposed. The method is based on a two states hidden Markov model trained in a supervised way. The proposed method can generalize across different groups of subjects, without the need of parameters tuning. Leave one-subject-out validation tests showed 20 ms and 16 ms errors on average in the determination of foot strike and toe off events across the three groups of subjects including 10 elderly, 10 hemiparetic patients and 10 Huntington's disease patients. The proposed methodology can be implemented online in portable devices to be used in clinical practice or in everyday personal health assessment. PMID- 26737459 TI - Temporal and kinematic variables for real-world falls harvested from lumbar sensors in the elderly population. AB - Automatic fall detection will reduce the consequences of falls in the elderly and promote independent living, ensuring people can confidently live safely at home. Inertial sensor technology can distinguish falls from normal activities. However, <;7% of studies have used fall data recorded from elderly people in real life. The FARSEEING project has compiled a database of real life falls from elderly people, to gain new knowledge about fall events. We have extracted temporal and kinematic parameters to further improve the development of fall detection algorithms. A total of 100 real-world falls were analysed. Subjects with a known fall history were recruited, inertial sensors were attached to L5 and a fall report, following a fall, was used to extract the fall signal. This data-set was examined, and variables were extracted that include upper and lower impact peak values, posture angle change during the fall and time of occurrence. These extracted parameters, can be used to inform the design of fall-detection algorithms for real-world falls detection in the elderly. PMID- 26737460 TI - Frequency-based features for early cerebral palsy prediction. AB - In this paper we aim at predicting cerebral palsy, the most serious and lifelong motor function disorder in children, at an early age by analysing infants' motion data. An essential step for doing so is to extract informative features with high class separability. We propose a set of features derived from frequency analysis of the motion data. Then, we evaluate the practicality of our features on one of the richest data sets collected to study this disease. In this data set, the motion data are extracted from both electromagnetic sensors as well as video camera. The proposed features are used for classifying both data sets. Using these features, we manage to achieve promising classification performance. Classification accuracy of 91% for the sensor data and 88% for the video-derived data show not only the advantage of employing these features for predicting cerebral palsy, but also that replacing electromagnetic sensors with a video camera is feasible. PMID- 26737461 TI - Arrhythmia detection using amplitude difference features based on random forest. AB - A number of promising studies have been proposed for diagnosing arrhythmia, using classification techniques based on a variety of heartbeat features by the interpretation of electrocardiogram (ECG). In this study, a new feature called amplitude difference was investigated using the random forest classifier. Evaluations conducted against the MIT-BIH arrhythmia database before and after adding the amplitude difference features obtained heartbeat classification accuracies of 98.51% and 98.68%, respectively. To validate the significance of the increased performance, the Wilcoxon signed rank test was extensively employed. By the absolute preponderance of plus ranks, we confirmed that applying an amplitude difference feature for heartbeat classification improves their performance. PMID- 26737462 TI - Arrhythmia classification based on novel distance series transform of phase space trajectories. AB - Cardiac arrhythmia is a serious disorder in heart electrical activity that may have fatal consequences especially if not detected early. This motivated the development of automated arrhythmia detection systems that can early detect and accurately recognize arrhythmias thus significantly improving the chances of patient survival. In this paper, we propose an improved arrhythmia detection system particularly designed to identify five different types based on nonlinear dynamical modeling of electrocardiogram signals. The new approach introduces a novel distance series domain derived from the reconstructed phase space as a transform space for the signals that is explored using classical features. The performance measures showed that the proposed system outperforms state of the art methods as it achieved 98.7% accuracy, 99.54% sensitivity, 99.42% specificity, 98.19% positive predictive value, and 99.85% negative predictive value. PMID- 26737463 TI - Image features of spectral correlation function for arrhythmia classification. AB - Recently, computerized arrhythmia classification tools have been intensively used to aid physicians to recognize different irregular heartbeats. In this paper, we introduce arrhythmia CAD system exploiting cyclostationary signal analysis through estimation of the spectral correlation function for 5 different beat types. Two experiments were performed. Raw spectral correlation data were used as features in the first experiment while the other experiment which dealt with the spectral correlation coefficients as image included extraction of wavelet and shape features followed by fisher score for dimensionality reduction. As for the classification task, Support Vector Machine (SVM) with linear kernel was used for both experiments. The experimental results showed that both proposed approaches are superior compared to several state of the art methods. This approach achieved sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of 99.20%, 99.70%, 98.60%, 99.90% and 97.60% respectively. PMID- 26737464 TI - Automatic cardiac arrhythmia detection and classification using vectorcardiograms and complex networks. AB - This paper intends to bring new insights in the methods for extracting features for cardiac arrhythmia detection and classification systems. We explore the possibility for utilizing vectorcardiograms (VCG) along with electrocardiograms (ECG) to get relevant informations from the heartbeats on the MIT-BIH database. For this purpose, we apply complex networks to extract features from the VCG. We follow the ANSI/AAMI EC57:1998 standard, for classifying the beats into 5 classes (N, V, S, F and Q), and de Chazal's scheme for dataset division into training and test set, with 22 folds validation setup for each set. We used the Support Vector Machinhe (SVM) classifier and the best result we chose had a global accuracy of 84.1%, while still obtaining relatively high Sensitivities and Positive Predictive Value and low False Positive Rates, when compared to other papers that follows the same evaluation methodology that we do. PMID- 26737465 TI - Distribution Entropy (DistEn): A complexity measure to detect arrhythmia from short length RR interval time series. AB - Heart rate complexity analysis is a powerful non-invasive means to diagnose several cardiac ailments. Non-linear tools of complexity measurement are indispensable in order to bring out the complete non-linear behavior of Physiological signals. The most popularly used non-linear tools to measure signal complexity are the entropy measures like Approximate entropy (ApEn) and Sample entropy (SampEn). But, these methods become unreliable and inaccurate at times, in particular, for short length data. Recently, a novel method of complexity measurement called Distribution Entropy (DistEn) was introduced, which showed reliable performance to capture complexity of both short term synthetic and short term physiologic data. This study aims to i) examine the competence of DistEn in discriminating Arrhythmia from Normal sinus rhythm (NSR) subjects, using RR interval time series data; ii) explore the level of consistency of DistEn with data length N; and iii) compare the performance of DistEn with ApEn and SampEn. Sixty six RR interval time series data belonging to two groups of cardiac conditions namely 'Arrhythmia' and 'NSR' have been used for the analysis. The data length N was varied from 50 to 1000 beats with embedding dimension m = 2 for all entropy measurements. Maximum ROC area obtained using ApEn, SampEn and DistEn were 0.83, 0.86 and 0.94 for data length 1000, 1000 and 500 beats respectively. The results show that DistEn undoubtedly exhibits a consistently high performance as a classification feature in comparison with ApEn and SampEn. Therefore, DistEn shows a promising behavior as bio marker for detecting Arrhythmia from short length RR interval data. PMID- 26737466 TI - Discriminative sparse coding of ECG during ventricular arrhythmias using LC-K-SVD approach. AB - Ventricular tachycardia (VT) and ventricular fibrillation (VF) are two major types of ventricular arrhythmias that results due to abnormalities in the electrical activation in the ventricles of the heart. VF is the lethal of the two arrhythmias, which may lead to sudden cardiac death. The treatment options for the two arrhythmias are different. Therefore, detection and characterization of the two arrhythmias is critical to choose appropriate therapy options. Due to the time-varying nature of the signal content during cardiac arrhythmias, modeling and extracting information from them using time and frequency localized functions would be ideal. To this effect, in this work, we perform discriminative sparse coding of the ECG during ventricular arrhythmia with hybrid time-frequency dictionaries using the recently introduced Label consistent K-SVD (LC-K-SVD) approach. Using 944 segments of ventricular arrhythmias extracted from 23 patients in the Malignant Ventricular Ectopy and Creighton University Tachy Arrhythmia databases, an overall classification accuracy of 71.55% was attained with a hybrid dictionary of Gabor and symlet4 atoms. In comparison, for the same database and non-trained dictionary (i.e the original dictionary) the classification accuracy was found to be 62.71%. In addition, the modeling error using the trained dictionary from LC-K-SVD approach was found to be significantly lower to the one using the non-trained dictionary. PMID- 26737467 TI - Roles of Deformable Image Registration in adaptive RT: From contour propagation to dose monitoring. AB - Adaptive radiation therapy (ART) is based on the optimization of the treatment plan during the treatment delivery to compensate for anatomical deformations. Deformable Image Registration (DIR) then constitutes a key step in order to analyze the huge amount of daily or weekly images to provide clinically usefull information. Two main applications of DIR have been developped in ART: delineation propagation and dose accumulation. If delineation propagation is well validated and transfered in the clinic, some challenges remain to address for dose accumulation. In this paper, we review the recent developments of DIR in ART, particularly in prostate and head-and-neck (H&N), with a focus on their evaluation. PMID- 26737468 TI - Texture analysis to assess structural modifications induced by radiotherapy. AB - Texture analysis is an emerging tool employed in Radiotherapy (RT) to improve tumor characterization for planning and to evaluate treatment effects. In the treatment of Head and Neck Cancer, parotid glands can receive high dose that may compromise gland functionality and structure. Texture analysis was here applied on CT images of Head and Neck to evaluate changes in parotid gland structure during RT. CT images at the beginning, at the intermediate stage and at the end of RT were considered and in each time point different features (i.e. mean intensity, variance, entropy, homogeneity, local entropy, fractal dimension and volume) were extracted within parotid volume. A general decrease in tissue complexity and heterogeneity was found, with different time trend for textural features. This is explainable by different biological mechanisms associated to the variation of each index. Volume and mean intensity variation are also correlated with some pre-treatment dosimetric parameters, indicating a relationship between the dose plan and the structural variation estimated after RT. PMID- 26737469 TI - An innovative multimodal/multispectral image registration method for medical images based on the Expectation-Maximization algorithm. AB - In this paper, we present a methodology for multimodal/ multispectral image registration of medical images. This approach is formulated by using the Expectation-Maximization (EM) methodology, such that we estimate the parameters of a geometric transformation that aligns multimodal/multispectral images. In this framework, the hidden random variables are associated to the intensity relations between the studied images, which allow to compare multispectral intensity values between images of different modalities. The methodology is basically composed by an iterative two-step procedure, where at each step, a new estimation of the joint conditional multispectral intensity distribution and the geometric transformation is computed. The proposed algorithm was tested with different kinds of medical images, and the obtained results show that the proposed methodology can be used to efficiently align multimodal/multispectral medical images. PMID- 26737470 TI - Challenges and opportunities in image guided particle therapy. AB - The application of biomedical imaging and image processing to radiation therapy with accelerated particles has unique challenges. The potential of particle therapy to precisely tailor the dose distribution around the target volume needs to account for the intrinsic sensitivity to uncertainties in dose deposition. These peculiar features motivate the use of image guided methods to consistently verify the accuracy in dose delivery. Dedicated imaging and image processing methods are required, from treatment planning to treatment verification phases, in order to reduce the effects of uncertainties. The scenario is also complicated by the lack of standardized layouts of treatment bunkers, which implies the relatively increased use of custom solutions. Conversely, imaging can be applied to verify the actual delivered dose, representing a valuable opportunity to validate specific protocols and visualize the efficacy of the intended treatment. In this contribution, challenges and opportunities in image guided particle therapy are overviewed, with a clear focus on research perspectives in biomedical imaging and image processing. PMID- 26737471 TI - Recent advancements in toxicity prediction following prostate cancer radiotherapy. AB - In external beam radiotherapy for prostate cancer limiting toxicities for dose escalation are bladder and rectum toxicities. Normal tissue complication probability models aim at quantifying the risk of developping adverse events following radiotherapy. These models, originally proposed in the context of uniform irradiation, have evolved to implementations based on the state-of-the art classification methods which are trained using empirical data. Recently, the use of image processing techniques combined with population analysis methods has led to a new generation of models to understand the risk of normal tissue complications following radiotherapy. This paper overviews those methods in the case of prostate cancer radiation therapy and propose some lines of future research. PMID- 26737472 TI - Analysis of serial CT images for studying the RT effects in head-neck cancer patients. AB - Images taken during and after RT for head and neck cancer have the potential to quantitatively assess xerostomia. Image information may be used as biomarkers of RT effects on parotid glands with significant potential to support adaptive treatment strategies. We investigated the possibility to extract information based on in-room CT images (kVCT, MVCT), acquired for daily image-guided radiotherapy treatment of head-and-neck cancer patients, in order to predict individual response in terms of toxicity. Follow-up MRI images were also used in order to investigate long term parotid gland deformation. PMID- 26737473 TI - Automated retinal vessel recognition and measurements on large datasets. AB - The characteristics of the retinal vascular network have been prospectively associated with many systemic and vascular diseases. QUARTZ is a fully automated software that has been developed to localize and quantify the morphological characteristics of blood vessels in retinal images for use in epidemiological studies. This software was used to analyse a dataset containing 16,000 retinal images from the EPIC-Norfolk cohort study. The objective of this paper is to both assess the suitability of this dataset for computational analysis and to further evaluate the QUARTZ software. PMID- 26737475 TI - Retinal image registration for eye movement estimation. AB - This paper describes a novel methodology for eye fixation measurement using a unique videoophthalmoscope setup and advanced image registration approach. The representation of the eye movements via Poincare plot is also introduced. The properties, limitations and perspective of this methodology are finally discussed. PMID- 26737474 TI - Improving the performance of an ensemble-based exudate detection system using stochastic parameter optimization. AB - In this paper, we propose an efficient way to determine the optimal parameter setting of an ensemble based system dedicated to the detection of exudates in retinal images. We show that the optimal parameter settings of an individual detector may be different, when it becomes a member of an ensemble. We consider a stochastic search algorithm to solve this optimization problem. However, since the computational demand is extremely high, we introduce a specific speed-up by sampling the test dataset in every search step. We show that this approach is equivalent to the noisy evaluation of the energy function and fits the corresponding theoretical results to our case. Experimental results showing improvement with respect to the member exudate detectors and individually optimal parameter settings are presented for publicly available datasets. PMID- 26737476 TI - Automatic Gunn and Salus sign quantification in retinal images. AB - Prolonged hypertension can lead to abnormal changes in the retinal vasculature, including sclerosis and thickening of the arteriole walls. These changes can cause compression (Gunn's sign) and deflection (Salus's sign) of the veins at arteriovenous crossings. In retinal images, Gunn's sign appears as a tapering of the vein at a crossing point, while Salus's sign presents as an S-shaped curving. This paper presents a method for the automatic quantification of these two signs once a crossover has been detected; combining segmentation, artery vein classification, and morphological feature extraction techniques to calculate vein widths and angles entering and exiting the crossover. The method was tested on a small set of crossings, graded by a set of 3 doctors who were in agreement as having or not having Gunn/Salus sign. Results show separation between the two classes and that we can reliably detect and quantify these sign under the right conditions. PMID- 26737477 TI - Evaluation of geometric features as biomarkers of diabetic retinopathy for characterizing the retinal vascular changes during the progression of diabetes. AB - Diabetic retinopathy (DR) has been widely studied and characterized. However, until now, it is unclear how different features, extracted from the retinal vasculature, can be associated with the progression of diabetes and therefore become biomarkers of DR. In this study, a comprehensive analysis is presented, in which four groups were created, using eighty fundus images from twenty patients, who have progressed to DR and they had no history of any other diseases (e.g. hypertension or glaucoma). The significance of the following features was evaluated: widths, angles, branching coefficient (BC), angle-to-BC ratio, standard deviations, means and medians of widths and angles, fractal dimension (FD), lacunarity and FD-to-lacunarity ratio, using a mixed model analysis of variance (ANOVA) design. All the features were measured from the same junctions of each patient, using an automated tool. The discriminative power of these features was evaluated, using decision trees and random forests classifiers. Cross validation and out-of-bag error were used to evaluate the classifiers' performance, calculating the area under the ROC curve (AUC) and the classification error. Widths, FD and FD-to-Lacunarity ratio were found to differ significantly. Random forests had a superior performance of 0.768 and 0.737 in the AUC for the two cases of classification, namely three-years-pre-DR/post-DR and two-years-pre-DR/post-DR respectively. PMID- 26737478 TI - Multiple ocular diseases detection based on joint sparse multi-task learning. AB - In this paper, we present a multiple ocular diseases detection scheme based on joint sparse multi-task learning. Glaucoma, Pathological Myopia (PM), and Age related Macular Degeneration (AMD) are three major causes of vision impairment and blindness worldwide. The proposed joint sparse multitask learning framework aims to reconstruct a test fundus image with multiple features from as few training subjects as possible. The linear version of this problem could be casted into a multi-task joint covariate selection model, which can be very efficiently optimized via kernelizable accelerated proximal gradient method. Extensive experiments are conducted in order to validate the proposed framework on the SiMES dataset. From the Area Under Curve (AUC) results in multiple ocular diseases classification, our method is shown to outperform the state-of-the-art algorithms. PMID- 26737479 TI - A surgical parallel continuum manipulator with a cable-driven grasper. AB - In this paper, we present the design, construction, and control of a six-degree of-freedom (DOF), 12 mm diameter, parallel continuum manipulator with a 2-DOF, cable-driven grasper. This work is a proof-of-concept first step towards miniaturization of this type of manipulator design to provide increased dexterity and stability in confined-space surgical applications, particularly for endoscopic procedures. Our robotic system consists of six superelastic NiTi (Nitinol) tubes in a standard Stewart-Gough configuration and an end effector with 180 degree motion of its two jaws. Two Kevlar cables pass through the centers of the tube legs to actuate the end effector. A computationally efficient inverse kinematics model provides low-level control inputs to ten independent linear actuators, which drive the Stewart-Gough platform and end-effector actuation cables. We demonstrate the performance and feasibility of this design by conducting open-loop range-of-motion tests for our system. PMID- 26737480 TI - Estimating the configuration of a continuum dexterous manipulator with variable curvature bending using partial shape-sensing. AB - Reliably estimating the shape of variable curvature continuum dexterous manipulators (CDMs) is necessary to use these devices in biomedical applications. Embedding shape-sensing elements have been shown to effectively measure the shape of constant curvature CDMs. This paper explores several methods for estimating the configuration of variable curvature CDMs. Experiments bent the CDM in varying configurations, applied an external load, and measured the configuration. Three methods are described that use the measurements from simulated shape-sensing elements. Analyses included varying the number and placement of the shape sensors. The results showed at least three shape-sensing elements are necessary to predict manipulator configuration, with one method demonstrating average error less than 0.35 mm for a CDM under an external load. The presented techniques offer promise for successfully predicting, tracking, and controlling CDM configuration during surgery. PMID- 26737481 TI - Markerless surgical robotic system for intracerebral hemorrhage surgery. AB - Conventional intracerebral hemorrhage (ICH) surgery uses a stereotactic frame to access an intracerebral hematoma. Using a stereotactic frame for ICH surgery requires a long preparation time. In order to resolve this problem, we propose a markerless surgical robotic system. This system uses weighted iterative closest point technology for surface registration, hand-eye calibration for needle insertion, and 3D surface scanning for registration. We need calibration to integrate the technologies: calibration of robot and needle coordinates and calibration of 3D surface scanning and needle coordinates. These calibrations are essential elements of the markerless surgical robotic system. This system has the advantages of being non-invasive, a short total operation time, and low radiation exposure compared to conventional ICH surgery. PMID- 26737482 TI - Recognition of user's activity for adaptive cooperative assistance in robotic surgery. AB - During hands-on robotic surgery it is advisable to know how and when to provide the surgeon with different assistance levels with respect to the current performed activity. Gesteme-based on-line classification requires the definition of a complete set of primitives and the observation of large signal percentage. In this work an on-line, gesteme-free activity recognition method is addressed. The algorithm models the guidance forces and the resulting trajectory of the manipulator with 26 low-level components of a Gaussian Mixture Model (GMM). Temporal switching among the components is modeled with a Hidden Markov Model (HMM). Tests are performed in a simplified scenario over a pool of 5 non-surgeon users. Classification accuracy resulted higher than 89% after the observation of a 300 ms-long signal. Future work will address the use of the current detected activity to on-line trigger different strategies to control the manipulator and adapt the level of assistance. PMID- 26737483 TI - Biometry-based concentric tubes robot for vitreoretinal surgery. AB - Vitreoretinal surgery requires dexterous manoeuvres of tiny surgical tools in the confined cavity of the human eye through incisions made on the sclera. The fulcrum effect stemming from these incisions limits the safely reachable intraocular workspace and may result in scleral stress and collision with the intraocular lens. This paper proposes a concentric tube robot for panretinal interventions without risking scleral or lens damage. The robot is designed based on biometric measurements of the human eye, the required workspace, and the ease of incorporation in the clinical workflow. Our system is suited to 23 G vitreoretinal surgery, which does not require post-operative suturing, by comprising sub-millimetre concentric tubes. The proposed design is modular and features a rapid tube-exchange mechanism. To grasp and manipulate tissue, a sub millimetre flexible gripper is fabricated. Experiments demonstrate the ability to reach peripheral retinal regions with limited motion at the incision point and no risk of lens contact. PMID- 26737484 TI - Development of the SAIT single-port surgical access robot--slave arm based on RCM mechanism. AB - An innovative single-port surgical robot has recently been developed by the Samsung Advanced Institute of Technology (SAIT). The robot can reach various surgical sites inside the abdominal cavity from a single incision on the body. It has two 7-DOF surgical tools, a 3-DOF endoscope, a flexible hyper-redundant 6-DOF guide tube, and a 6-DOF manipulator. This paper primarily focuses on the manipulator, called a slave arm, which is capable of setting the location of a Remote Center Motion (RCM) point. Because the surgical tools can explore the abdominal area through a small incision point when the RCM point is aligned with the incision area, the RCM mechanism is an integral part of the manipulator for single-port surgery. The mechanical feature, operational principle, control method, and the system architecture of the slave arm are introduced in this paper. In addition, manipulation experiments conducted validate its efficacy. PMID- 26737485 TI - Effects of aging and perturbation intensities on temporal parameters during slipping-like perturbations. AB - The aim of this study was to analyze the modifications of temporal parameters during slipping-like perturbations associated both with aging and perturbation intensities. Twelve participants equally distributed from two age groups (elderly and young) were recorded while, during steady locomotion, managing unexpected slipping-like perturbations, in forward direction, at different intensity and amplitude of foot shift. Two metrics were extrapolated from the analysis of the ground reaction force supplied by ad hoc platform aimed at destabilizing the balance control. The results indicated that the analyzed timing variables, both for elderly and young, are strongly modified by intensity of the perturbation, but only slight altered by the amplitude. Concerning the comparison about the two groups, elderly people seem to have slower reactive response than young subjects. These findings support further investigations in order to gain a better understanding of fall dynamics in elderly people. PMID- 26737486 TI - Effects of slipping-like perturbation intensity on the dynamical stability. AB - Falls are a major cause of morbidity and death in elderly people. Understanding how subjects maintain stability while walking or while being exposed to perturbations is important in order to prevent falls. Here, five healthy subjects were asked to manage unexpected slipping-like perturbations of increasing intensities (i.e., soft, medium and strong) in order to investigate the effects of the perturbation intensity on the biomechanical behavior and on the dynamical stability, described by the Margin of Stability. The lower limb kinematic (i.e., hip, knee and ankle joints angles) was computed before and after the onset of the perturbation. The compensatory time and the Margin of Stability were calculated after the onset of the perturbation. As expected, results showed that the perturbation altered the subjects' kinematic and the modulation of the perturbation intensity was reflected in the dynamical stability: the stronger was the perturbation, the lower was the Margin of Stability describing a lower balance recovery. PMID- 26737487 TI - Walking on uneven terrain with a powered ankle prosthesis: A preliminary assessment. AB - A successful walking gait with a powered prosthesis depends heavily on proper timing of power delivery, or push-off. This paper describes a control approach which provides improved walking on uneven terrain relative to previous work intended for use on even (level) terrain. This approach is motivated by an initial healthy subject study which demonstrated less variation in sagittal plane shank angle than sagittal plane ankle angle when walking on uneven terrain relative to even terrain. The latter therefore replaces the former as the control signal used to initiate push-off in the powered prosthesis described herein. The authors demonstrate improvement in consistency for several gait characteristics, relative to healthy, as well as controller characteristics with the new control approach, including a 50% improvement in the consistency of the percentage of stride at which push-off is initiated. PMID- 26737488 TI - Local dynamic stability of the trunk segments and lower extremity joints during backward walking. AB - Backward walking has become a popular training method in physical exercise and clinical rehabilitation. For the sake of safety, it is important to keep a stable gait during backward walking. However, the gait stability during backward walking was rarely studied. This study investigated the effects of walking direction on local dynamic stability of the trunk segments (neck, torso and pelvis) and lower extremity joints (hip, knee and ankle joint). The maximum Lyapunov exponents (lambda(s)) of 17 young healthy male adults were calculated while they were walking under three conditions: backward walking with preferred walking speed (BW), forward walking (FW) with the same speed determined by BW, and forward walking with normal speed (FWN). We found that compared with FW, BW showed significant higher values of lambda(s) in the trunk segments in vertical (VT) direction (p<0.05). The torso segment also displayed a higher value of lambda(s) in anterior-posterior (AP) direction (p<0.01); Higher values of lambda(s) during BW were found in the rotation (RT) motion of hip and knee joint (p=0.036, and p=0.009, respectively), and in the abduction/adduction (AB/AD) motion of knee and ankle joint (p=0.013, and p=0.021, respectively). The significant effect of walking speed was found between FW and FWN condition in VT direction (p<0.01). These findings indicate that backward walking did impair the local dynamic stability in trunk segments and lower extremity joints. Especially, the negative effect of BW on the poor gait stability in the AP direction of torso segment, and AB/AD and RT motion of knee joint should not be neglected. PMID- 26737489 TI - Metabolics of stair ascent with a powered transfemoral prosthesis. AB - This paper evaluates the effectiveness of a powered knee and ankle prosthesis for stair ascent through a metabolic assessment comparing energy expenditure of a single transfemoral amputee subject while ascending stairs with the powered prosthesis relative to his passive daily use device, as well as comparing the kinematics and kinetics obtained with the passive prosthesis to healthy biomechanics. The subject wore a portable system that measured pulmonary gaseous exchange rates of oxygen and carbon dioxide while he ascended stairs with each of the prostheses in alternating tests. The results indicated that the amputee's energy expenditure decreased by 32 percent while climbing with the powered prosthesis as compared to his passive one, and the kinematics and kinetics achieved were representative of healthy biomechanics. PMID- 26737490 TI - Measuring body sway of bipedally standing rat and quantitative evaluation of its postural control. AB - Human generates very slow (<1 Hz) body sway during standing, and the behavior of this sway is known to be changed characteristically depending on the neural ataxia. In order to investigate the sway mechanism and mechanism of neural ataxia through this sway behavior, the present research proposes an experimental environment of rats under bipedal standing. By the experiment, we succeeded the measurement of six intact rats standing for over 200 seconds without postural supports. Moreover, by comparing measured center of pressure (COP) and that of system model with nonlinear PID control model which is proposed as human standing model, control parameters of rats were numerically evaluated. Evaluated control parameters of rats were close to those of human, i.e., control strategy was considered to be comparable between rats and human. PMID- 26737491 TI - Automated logging of inspiratory and expiratory non-synchronized breathing (ALIEN) for mechanical ventilation. AB - Asynchronous Events (AEs) during mechanical ventilation (MV) result in increased work of breathing and potential poor patient outcomes. Thus, it is important to automate AE detection. In this study, an AE detection method, Automated Logging of Inspiratory and Expiratory Non-synchronized breathing (ALIEN) was developed and compared between standard manual detection in 11 MV patients. A total of 5701 breaths were analyzed (median [IQR]: 500 [469-573] per patient). The Asynchrony Index (AI) was 51% [28-78]%. The AE detection yielded sensitivity of 90.3% and specificity of 88.3%. Automated AE detection methods can potentially provide clinicians with real-time information on patient-ventilator interaction. PMID- 26737492 TI - Development of an integrated model of cardiovascular and pulmonary physiology for the evaluation of mechanical ventilation strategies. AB - We describe the development of an integrated cardiovascular and pulmonary model for use in the investigation of novel mechanical ventilation strategies in the intensive care unit. The cardiac model includes the cardiac chambers, the pulmonary circulation and the systemic circulation. The modeling of complex mechanisms for vascular segments, time varying elastance functions of cardiovascular components and the effect of vascular resistances, in health and disease under the influence of mechanical ventilation is investigated. The resulting biomedical simulator can aid in understanding the underlying pathophysiology of critically-ill patients and facilitate the development of more effective therapeutic strategies for evaluation in clinical trials. PMID- 26737493 TI - Steps towards 3D Electrical Impedance Tomography. AB - Electrical Impedance Tomography (EIT) is a promising imaging technique to visualize the dynamics of regional lung ventilation. 2D EIT has shown promise in monitoring ventilation therapy, with the drawback of only displaying a single horizontal slice of the lungs. Until now there are no generally accepted approaches available to generate meaningful 3D images in real-time. This paper describes general problems and first attempts to overcome those that may extend to a hierarchical scheme for 3D EIT imaging. PMID- 26737494 TI - Constrained optimization for noninvasive estimation of work of breathing. AB - This paper presents a technique for noninvasive estimation of respiratory muscle effort (also known as work of breathing, WOB) in mechanically ventilated patients. Continual and real-time assessment of the patient WOB is desirable, as it helps the clinician make decisions about increasing or decreasing mechanical respiratory support. The technique presented is based on a physiological model of the respiratory system, from which a cost function is constructed as the sum of squared errors between model-based airway pressure predictions and actual measurements. Quadratic programming methods are used to minimize this cost function. An experimental example on animal data shows the effectiveness of the technique. PMID- 26737495 TI - Model-based advice for mechanical ventilation: From research (INVENT) to product (Beacon Caresystem). AB - This paper describes the structure and functionality of a physiological model based system for providing advice on the settings of mechanical ventilation. Use of the system is presented with examples of patients on support and control modes of mechanical ventilation. PMID- 26737496 TI - Creating clinical decision support systems for respiratory medicine. AB - Clinical decision support systems are vital for advances in improving patient therapeutic care. We share lessons learned from creating two respiratory clinical decisions support systems for ventilating patients in a critical care setting. PMID- 26737497 TI - Decoding of articulatory gestures during word production using speech motor and premotor cortical activity. AB - Brain-machine interfaces that directly translate attempted speech from the speech motor areas could change the lives of people with complete paralysis. However, it remains uncertain exactly how speech production is encoded in cortex. Improving this understanding could greatly improve brain-machine interface design. Specifically, it is not clear to what extent the different levels of speech production (phonemes, or speech sounds, and articulatory gestures, which describe the movements of the articulator muscles) are represented in the motor cortex. Using electrocorticographic (ECoG) electrodes on the cortical surface, we recorded neural activity from speech motor and premotor areas during speech production. We decoded both gestures and phonemes using the neural signals. Overall classification accuracy was higher for gestures than phonemes. In particular, gestures were better represented in the primary sensorimotor cortices, while phonemes were better represented in more anterior areas. PMID- 26737498 TI - Recurrence network analysis of multiple local field potential bands from the orofacial portion of primary motor cortex. AB - Local field potentials (LFPs), which have been considered as aggregate signals that reflect activities of a large number of neurons in the cerebral cortex, have been observed to mediate gross functional activities of a relatively small volume of the brain tissues. Historically there have been several frequency bands observed and defined across various brain areas. However, detailed analysis, either spectral analysis or any dynamical analysis of LFPs particularly in the orofacial part of the primary motor cortex (MIo) has not been done before. Here, we recorded LFPs from MIo using an electrode array from a non-human primate during feeding behavior. Then we performed spectral analysis during the whole feeding sequences and to characterize temporal evolution of spectrum around the time of swallow cycles. The spectrogram over the beta range showed dynamical change in its power around the swallow cycle onsets. We then characterized dynamical behaviors of LFPs over multiple bands, alpha, beta, low gamma, and high gamma using two measures from the recurrence network (RN) method, network transitivity, T and average path length L. Temporal profile of T in alpha and beta indicated that there was a sudden change in the dynamical properties around the swallow cycle onsets, while temporal profile of L indicated that a range of 200 to -150 ms and 200 ms to the swallow cycle onsets exhibited large changes both in alpha and beta ranges. Therefore, to further understand the involvement of cortical oscillation to behavior, particularly swallowing, the combination of traditional spectral methods and various dynamical methods such as RN method would be essential. PMID- 26737500 TI - Infant-caregiver interactions affect the early development of vocalization. AB - Vocal communication is a unique means to bilaterally exchange messages in real time. The developmental origin of such communication is the vocal interactions between an infant and a caregiver, and one of the big mysteries is how the infant learns to vocalize the mother tongue of the caregiver. Many theories claim to explain an infant's capability to imitate a caregiver based on acoustic matching. However, the acoustic qualities of the infant and the caregiver are quite different, and, therefore, cannot fully explain the imitation. Instead, the interaction itself may have an important role, but the mechanism is still unclear. In this article, we review studies addressing this problem using constructive approaches based on cognitive developmental robotics. PMID- 26737499 TI - Semiautomatic marker tracking of tongue positions captured by videofluoroscopy during primate feeding. AB - Videofluoroscopy (VF) is one of the most commonly used tools to assess oropharyngeal dysphagia as well as to visualize musculoskeletal structures of humans and animals engaged in various behaviors, including feeding. Despite its importance in clinical and scientific use, processing VF data has historically been extremely tedious because it is performed using manual frame-by-frame methods. With recent technological advances, the frame rate for scientific use has been increasing along with the use of high speed data capture systems. In the current study, we used non-human primates as a model animal to study human feeding behaviors to capture tongue movement based on markers implanted into the tongue. Here, we introduce a semi-automatic marker tracking algorithm that yields high tracking accuracy (> 90%) and dramatic speed improvements (faster than real time labeling). Furthermore, we quantify the sources of tracking errors and the tracking performance as a function of marker speeds. Our results indicate that there is more room for methodological improvements both in detection and prediction of marker positions. Moreover, correspondingly faster frame rates will be required to capture faster kinematic behaviors such as those of mice, which are extensively used to study both control and pathological conditions. PMID- 26737501 TI - A control-theoretical approach to the identification of a commitment switch in B lymphopoiesis cell fate determination. AB - Cellular differentiation is continuously orchestrated by complex networks of transcription factors, signaling molecules and genetic and epigenetic events, a fundamental prerequisite for the design of strategies for reprogramming differentiated cells to immature stem/progenitor cells is a thorough understanding of such complex regulatory machinery. Therefore, mathematical models, along with the associated analysis and control methods, are highly needed in this research field. In the present work, we provide a first model of the genetic regulatory network driving the cellular fate determination at the stage of lymphoid lineage commitment, in particular during lineage restriction of multipotent progenitors to early B-cell committed precursors. PMID- 26737502 TI - A mathematical model of the calcium transient in urinary bladder smooth muscle cells. AB - An increase in cytoplasmic calcium (Ca(2+)) concentration ([Ca(2+)]i) is a prerequisite for the contraction of detrusor smooth muscle (DSM) cells . The increase in [Ca(2+)]i is accomplished by Ca(2+) entry mainly via voltage dependent L-type Ca(2+) channel and Ca(2+) release from intracellular stores. We report here a simulation of the processes that regulate intracellular Ca(2+) and their dependence on Ca(2+) concentration. Based on experimentally recorded data, mathematical equations for Ca(2+) current (generated mainly by L-type Ca(2+) channel) are developed along with representation of Ca(2+)ATPase pump currents. The plasma membrane Ca(2+)ATPase (PMCA) pump and sarco/endoplasmic reticulum Ca(2+)ATPase (SERCA) pump are responsible for lowering [Ca(2+)]i which leads to relaxation of smooth muscle. Our model simulates Ca(2+) current, action potential and the Ca(2+) transient response so as to reasonably mimic the experimental recordings. In novel findings, currents produced by PMCA and SERCA along with their amplitude and waveform pattern under voltage clamp condition have been predicted for DSM cells. The model has further been used to produce the Ca(2+) transient which results because of L-type Ca(2+) channel, Ca(2+) release from intracellular store, PMCA, SERCA and presence of buffer in the cytoplasm. To explore the model further, Ca(2+) transient decay rate in control condition is compared to the decay rate reached when PMCA and SERCA are inhibited. We conclude that this model can be used to describe the Ca(2+) transient response produced by the DSM cell in response to depolarization of cell membrane. PMID- 26737503 TI - Impairment of energy metabolism in cardiomyocytes caused by 5-FU catabolites can be compensated by administration of amino acids. AB - Identification of patients with increased risk of 5-fluorouracil (5-FU)-related toxicity is an important challenge for cancer treatment. Research often focus on dihydropyrimidine dehydrogenase (DPYD) deficiency in this context. However, patients with normal DPYD activity may also develop life-threatening 5-FU adverse effects. DPYD initiates the catabolic route of 5-FU generating metabolites such as fluoroacetate (FAC). The catabolite FAC is known to inhibit the TCA cycle enzyme aconitase, which is supposed to impair mitochondrial energy metabolism. Therefore, we aim for a systems understanding of the association of 5-FU-related cardiac side effects with aconitase inhibition caused by FAC. Using a mitochondrial model of cardiomyocytes we found strong depletion of ATP production and citrate accumulation as main effects of aconitase inhibition. Shadow price analysis revealed that the uptakes of valine, arginine, proline and glutamate are most effective in compensating the impairment of energy metabolism. Our findings suggest that 5-FU catabolism contributes to the occurrence of cardiac adverse effects and are the basis for further biomarker identifications and development of side effect treatment. PMID- 26737504 TI - Dynamics of cancer progression and suppression: A novel evolutionary game theory based approach. AB - In this paper, a novel mathematical approach is proposed for the dynamics of progression and suppression of cancer. We define mutant cell density, rho(MU) (MU * rho), as a primary factor in cancer dynamics, and use logistic growth model and replicator equation for defining the dynamics of total cell density (rho) and mutant fraction (MU), respectively. Furthermore, in the proposed model, we introduce an analytical expression for a control parameter D (drug), to suppress the proliferation of mutants with extra fitness level sigma. Lastly, we present a comparison of the proposed model with some existing models of tumour growth. PMID- 26737505 TI - Epithelial mesenchymal transition in lung cancer cells: A quantitative analysis. AB - Cellular auto-fluorescence along with morphological and cytoskeletal features were assessed in lung cancer cells undergoing induced epithelial mesenchymal transition (EMT). During EMT progression, significant increase was observed in cellular aspect ratio (AR), filamentous (F)-actin and green auto-fluorescence intensities while blue intensity decreased. These features were provided to a kernel classification framework. The classification accuracy were impressive, thus these features along with the classification technique can be considered as suitable tools for automated grading of lung cancer cells undergoing EMT progression. PMID- 26737506 TI - Computational studies on bladder small dorsal root ganglion neurons: Modelling BK channels. AB - The urinary bladder afferent neurons called the dorsal root ganglion (DRG) neurons carry information on diverse modalities such as stretch, pressure and nociception to the spinal cord. This information is carried in the form of electrical activity called action potentials (AP). The bladder small diameter DRG neurons that are considered to be putative nociceptors express several ion channels and active mechanisms which are responsible for generating this electrical activity. One of the channels that has been suggested to play a role in cell excitability is the large conductance calcium activated potassium channel (BK) channel. Its activation is governed by cell membrane potential and intracellular calcium concentration. Here, we present a computational model of the BK channel along with other ion channels and mechanisms present in the bladder small DRG neuron cell body. The BK channel simulations show properties that are similar to those shown by Isolectin B4 (IB4) negative cutaneous small DRG neurons. The bladder small DRG neurons have also been found to show some of these properties. Thus, we hypothesize that the bladder small DRG neurons are IB4 negative. This hypothesis is supported by experimental studies which suggest that about 80% of bladder small DRG neurons are IB4 negative. The model of bladder small DRG neuron also faithfully reproduced some of the electrical properties that have been reported experimentally. This model can thus be used to predict abnormal behaviour of the DRG neuron during pathological conditions. PMID- 26737507 TI - Identification of whole-brain network modules based on a large scale Granger Causality approach. AB - Spatially high resolved neurophysiological data commonly pose a computational and analytical problem for the identification of functional networks in the human brain. We introduce a multivariate linear Granger Causality approach with an embedded dimension reduction that enables the computation of brain networks at the large scale. In order to grasp the information about connectivity patterns contained in the resulting high-dimensional directed networks, we furthermore propose the inclusion of module detection methods from network theory that can help to identify functionally associated brain areas. As a proof of concept, the methodology is verified by means of synthetic data with known ground truth module properties. Resting state fMRI data are used to demonstrate the applicability and benefit in the case of clinical data. PMID- 26737508 TI - Investigating the neural basis of empathy by EEG hyperscanning during a Third Party Punishment. AB - The recently developed technique of hyperscanning consists of the simultaneous recording of brain activity from multiple subjects involved in social interaction. The multivariate analysis of data coming from different subjects allows to model a system made of multiple brains interacting, and to characterize it in relation with different processes at the basis of social cognition. In this study, we investigate the empathy established between two subjects during a Third Party Punishment paradigm, in terms of the properties of the multiple-brain network obtained from EEG hyperscanning. Preliminary results show that significantly different multiple-brain network structures characterize a social situation operated by a human agent with respect to a computer based condition, and that the different levels of empathy induced by a fair or unfair treatment received by one of the subjects are characterized by denser inter-subjects connectivity and lower divisibility in the two single brain networks. PMID- 26737509 TI - Partial directed coherence statistical performance characteristics in frequency domain. AB - In this work we show the asymptotic behavior of information partial directed coherence estimator via the Monte Carlo simulation of a particular toy model taken from the literature. We show that the control of false positive rate tends to the chosen significance level if detection decision is made at specific frequency values. PMID- 26737510 TI - Spectrally weighted Granger-causal modeling: Motivation and applications to data from animal models and epileptic patients. AB - In this paper we motivate and describe spectral weighting in methods based on the Granger-causal modeling framework. We show how these methods were validated in recordings from an animal model (rats) with relatively well-understood dynamic connectivity, and provide a comparison of their performances in terms of physiological interpretability and time resolution. Having shown that spectrally weighted Partial Directed Coherence (wPDC) shows good performances in real animal data, we provide an example of the application of this method to EEG data recorded from patients with left or right temporal lobe epilepsy. The result showed that wPDC correctly identified the major drivers of interictal epileptic spiking activity, in line with invasive validation and surgical outcome, and furthermore that right temporal lobe epilepsy is characterized by more inter hemispheric influence than left temporal lobe epilepsy. PMID- 26737511 TI - Investigating dynamical information transfer in the brain following a TMS pulse: Insights from structural architecture. AB - Transcranial magnetic stimulation (TMS) has been used for more than 20 years to investigate connectivity and plasticity in the human cortex. By combining TMS with high-density electroencephalography (hd-EEG), one can stimulate any cortical area and measure the effects produced by this perturbation in the rest of the cerebral cortex. The purpose of this paper is to investigate changes of information flow in the brain after TMS from a functional and structural perspective, using multimodal modeling of source reconstructed TMS/hd-EEG recordings and DTI tractography. We prove how brain dynamics induced by TMS is constrained and driven by its structure, at different spatial and temporal scales, especially when considering cross-frequency interactions. These results shed light on the function-structure organization of the brain network at the global level, and on the huge variety of information contained in it. PMID- 26737512 TI - On neural connectivity estimation problems. AB - After briefly recapping and reframing the problem of neural connectivity and its implications for today's brain mapping efforts, we argue that supplementing/replacing traditional conservative correlation based analysis methods requires active user understanding of the aims and limitations of the newly proposed multivariate analysis frameworks before the new methods can gain general acceptance and full profit can be made from the expanded descriptive opportunities they offer. PMID- 26737514 TI - Fast underdetermined BSS architecture design methodology for real time applications. AB - In this paper, we propose a high speed architecture design methodology for the Under-determined Blind Source Separation (UBSS) algorithm using our recently proposed high speed Discrete Hilbert Transform (DHT) targeting real time applications. In UBSS algorithm, unlike the typical BSS, the number of sensors are less than the number of the sources, which is of more interest in the real time applications. The DHT architecture has been implemented based on sub matrix multiplication method to compute M point DHT, which uses N point architecture recursively and where M is an integer multiples of N. The DHT architecture and state of the art architecture are coded in VHDL for 16 bit word length and ASIC implementation is carried out using UMC 90 - nm technology @V DD = 1V and @ 1MHZ clock frequency. The proposed architecture implementation and experimental comparison results show that the DHT design is two times faster than state of the art architecture. PMID- 26737513 TI - Reverse bi-orthogonal wavelets & fuzzy classifiers for the automatic detection of spike waves in the EEG of the hypoxic ischemic pre-term fetal sheep. AB - There exists a 6-8 hour window of opportunity for the treatment of perinatal Hypoxic-Ischemic Encephalopathy (HIE) following the original insult after which significant irreversible brain injury manifests leading to debilitating neurological conditions such as epilepsy and cerebral palsy. At present, there are no identified biomarkers in the electroencephalogram (EEG) that are currently being used to help classify if a HIE insult has occurred or not. However, high frequency micro-scale transients in the form of spikes, sharp waves and slow waves appear in the EEG, post insult, that could provide precursory information whether a HIE insult has occurred or not. This paper describes the superiority of using reverse bi-orthogonal wavelets (RBIO-WT), in the form of the rbio2.8 mother wavelet, in conjunction with a Type-1 Fuzzy Logic System (Type-I FLS) classifier for accurate micro-scale spike wave transient detection in the EEG of Pre-term Fetal Sheep. The algorithm performance for spike detection was assessed over the most critical time period of 25 minutes within the first 8 hours, post occlusion using an in utero fetal sheep model. Obtained results demonstrate that the suggested algorithm detected spikes with a considerably high overall performance of 99.25% using the developed RBIO-WT Type-I FLS. PMID- 26737515 TI - Feature extraction using time-frequency analysis for monophonic-polyphonic wheeze discrimination. AB - The aim of this study is monophonic-polyphonic wheeze episode discrimination rather than the conventional wheeze (versus non-wheeze) episode detection. We used two different methods for feature extraction to discriminate monophonic and polyphonic wheeze episodes. One of the methods is based on frequency analysis and the other is based on time analysis. Frequency analysis based method uses ratios of quartile frequencies to exploit the difference in the power spectrum. Time analysis based method uses mean crossing irregularity to exploit the difference in periodicity in the time domain. Both methods are applied on the data before and after an image processing based preprocessing step. Calculated features are used in classification both individually and in combinations. Support vector machine, k-nearest neighbor and Naive Bayesian classifiers are adopted in leave one-out scheme. A total of 121 monophonic and 110 polyphonic wheeze episodes are used in the experiments, where the best classification performances are 71.45% for time domain based features, 68.43% for frequency domain based features, and 75.78% for a combination of selected best features. PMID- 26737516 TI - Estimation of sleep status in sleep apnea patients using a novel head actigraphy technique. AB - Polysomnography is a comprehensive modality for diagnosing sleep apnea (SA), but it is expensive and not widely available. Several technologies have been developed for portable diagnosis of SA in the home, most of which lack the ability to detect sleep status. Wrist actigraphy (accelerometry) has been adopted to cover this limitation. However, head actigraphy has not been systematically evaluated for this purpose. Therefore, the aim of this study was to evaluate the ability of head actigraphy to detect sleep/wake status. We obtained full overnight 3-axis head accelerometry data from 75 sleep apnea patient recordings. These were split into training and validation groups (2:1). Data were preprocessed and 5 features were extracted. Different feature combinations were fed into 3 different classifiers, namely support vector machine, logistic regression, and random forests, each of which was trained and validated on a different subgroup. The random forest algorithm yielded the highest performance, with an area under the receiver operating characteristic (ROC) curve of 0.81 for detection of sleep status. This shows that this technique has a very good performance in detecting sleep status in SA patients despite the specificities in this population, such as respiration related movements. PMID- 26737517 TI - Automatic identification of Cyclic Alternating Pattern (CAP) sequences based on the Teager Energy Operator. AB - The Cyclic Alternating Pattern (CAP) is a periodic cerebral activity prevalent during Non-Rapid Eye Movement (NREM) sleep-stages. The CAP is composed by A phases that are related to a change in amplitude, frequency or both from the background activity epochs, called B-phases. Depending on the type of increase the A-phase could be classified as A1, A2 or A3 subtype. This paper proposes the usage of the Teager Energy Operator (TEO) to analyze the amplitude changes in the different frequency-bands to detect A-phases subtypes. The TEO classification performance is compared with the performance of a state-of-the art EEG feature, applied previously for CAP scoring and referred as the macro-micro structure descriptor (MMSD). In general, the TEO is the best feature and the improved results were obtained in the delta band for the A1 and A2 sub-types. More precisely, a sensitivity and specificity of 80.31% and 82.93% were obtained for the A1 subtype, respectively. A2 phases were detected with 76.96% of sensitivity and 73.22% of specificity. The two features detected A3 subtype with approximately the same sensitivity (approx. 70%) and specificity (approx. 75%), however the results were improved by considering the highest frequency band. These results are consistent with the frequency content of the different sub phases. PMID- 26737518 TI - Inertial sensor based and shoe size independent gait analysis including heel and toe clearance estimation. AB - Falls are a major cause for morbidity and mortality in the ageing society. Inertial sensor based gait assessment including the analysis of the heel and toe clearance can be an indicator for the risk of falling. This paper presents a method for calculating the continuous heel and toe clearance without the knowledge of the shoe dimensions as well as the foot angle in the sagittal plane. These gait parameters were validated using an optical motion capture system. 20 healthy subjects from 3 different age groups (young, mid age, old) performed gait trials with different stride lengths and stride velocities. We obtained low mean absolute errors, low standard deviations and high Pearson correlations (0.91 0.99) for all gait parameters. In summary, we implemented a viable algorithm for the calculation of the heel and toe clearance without knowing the shoe dimensions as well as the foot angle in sagittal plane. We conclude that the given method is applicable for a mobile and unobtrusive gait assessment for healthy subjects from all age classes. PMID- 26737519 TI - High-resolution quantitative imaging of the substantia nigra. AB - There is a growing interest in identifying neuroimaging-based biomarkers for Parkinson's disease (PD), a progressive neurodegenerative disorder in which the major pathologic substrate is the loss of pigmented dopaminergic neurons in the substantia nigra (SN). Recently, an MRI technique dubbed "neuromelanin-sensitive MRI" (NM-MRI), has been found to provide notable contrast between the SN and surrounding brain tissues with potential applications as biomarker of PD. The contrast in NM-MRI has been associated with magnetization transfer (MT) effects, and thus the goal of this study was to characterize the impact of MT on NM-MRI, and to demonstrate the feasibility of performing quantitative MT (qMT) imaging in human SN. The results of this study demonstrate that high-resolution rapid qMT imaging of the SN can be reliably obtained within reasonable scan times, thereby can be translatable into clinical practice. PMID- 26737520 TI - The impact of data preprocessing in traumatic brain injury detection using functional magnetic resonance imaging. AB - Traumatic brain injury (TBI) can adversely affect a person's thinking, memory, personality and behavior. For this reason new and better biomarkers are being investigated. Resting state functional network connectivity (rsFNC) derived from functional magnetic resonance (fMRI) imaging is emerging as a possible biomarker. One of the main concerns with this technique is the appropriateness of methods used to correct for subject movement. In this work we used 50 mild TBI patients and matched healthy controls to explore the outcomes obtained from different fMRI data preprocessing. Results suggest that correction for motion variance before spatial smoothing is the best alternative. Following this preprocessing option a significant group difference was found between cerebellum and supplementary motor area/paracentral lobule. In this case the mTBI group exhibits an increase in rsFNC. PMID- 26737521 TI - Brain tissues atrophy is not always the best structural biomarker of physiological aging: A multimodal cross-sectional study. AB - This study presents a voxel-based multiple regression analysis of different magnetic resonance image modalities, including anatomical T1-weighted, T2* relaxometry, and diffusion tensor imaging. Quantitative parameters sensitive to complementary brain tissue alterations, including morphometric atrophy, mineralization, microstructural damage, and anisotropy loss, were compared in a linear physiological aging model in 140 healthy subjects (range 20-74 years). The performance of different predictors and the identification of the best biomarker of age-induced structural variation were compared without a priori anatomical knowledge. The best quantitative predictors in several brain regions were iron deposition and microstructural damage, rather than macroscopic tissue atrophy. Age variations were best resolved with a combination of markers, suggesting that multiple predictors better capture age-induced tissue alterations. These findings highlight the importance of a combined evaluation of multimodal biomarkers for the study of aging and point to a number of novel applications for the method described. PMID- 26737522 TI - Improved partial volume correction method for detecting brain activation in disease using Arterial Spin Labeling (ASL) fMRI. AB - The insight provided by fMRI, particularly BOLD fMRI, has been critical to the understanding of human brain function. Unfortunately, the application of fMRI techniques in clinical research has been held back by several factors. In order for the clinical field to successfully apply fMRI, two main challenges posed by aging and diseased brains need to be overcome: (1) difficulties in signal measurement and interpretation, and (2) partial voluming effects (PVE). Recent work has addressed the first challenge by developing fMRI methods that, in contrast to BOLD, provide a direct measurement of a physiological correlate of function. One such method is Arterial Spin Labeling (ASL) fMRI, which provides images of cerebral blood flow (CBF) in physiologically meaningful units. Although the problems caused by PVE can be mitigated to some degree through the acquisition of high spatial resolution fMRI data, both hardware and experimental design considerations limit this solution. Our team has developed a PVE correction (PVEc) algorithm that produces CBF images that are theoretically independent of tissue content and the associated PVE. The main drawback of the current PVEc method is that it introduces an inherent smoothing of the functional data. This smoothing effect can reduce the sensitivity of the method, complicating the detection of local changes in CBF, such as those due to stroke or activation. Here, we present results from an improved PVEc algorithm (ssPVEc), which uses high-resolution structural space information to correct for the tissue driven heterogeneity in the ASL signal. We tested the ssPVEc method on ASL images obtained on patients with asymptomatic carotid occlusive disease during rest and motor activation. Our results showed that the sensitivity of the ssPVEc method (defined as the average T-value in the activated region) was at least 1.5 times greater than that of the original, functional space, fsPVEc, for all patients. PMID- 26737523 TI - Spontaneous neuronal activity in insula predicts symptom severity of unmedicated obsessive compulsive disorder adults. AB - Emerging evidence has suggested that the pathophysiology of obsessive compulsive disorder (OCD) might involve widely distributed large-scale brain systems. The dysfunction within salience network, which is comprised of dorsal anterior cingulated cortex (dACC) and bilateral insular areas, has been proposed to contribute to OCD onset. The mechanism underlying salience network abnormality remains unclear and it is worthwhile to investigate its clinical relevance using functional neuroimaging approaches. In this study, we performed the spontaneous brain activity measurement using resting-state functional magnetic resonance imaging (fMRI) on unmedicated OCD patients (n=23). Specifically, the amplitude of low frequency (0.01-0.08 Hz) fluctuations (ALFF) was calculated for regions in salience network. The voxel-based Pearson's correlative analysis was conducted to explore the relationship beween ALFF measures and symptom severity for OCD patients. The results showed that the spontaneous neuronal activity in insula was significantly correlated to OCD clinical symptoms, especially compulsive behaviors. Our findings consolidated that the salience network played an important role in the pathogenesis of OCD and the intensity of intrinsic brain activity in insula provided a predictive biomarker for OCD symptom severity. PMID- 26737524 TI - Combining EPI and motion correction for fMRI human brain images with big motion. AB - Motion correction is an important component in fMRI brain image analysis. Linear registration technique is mostly used in the process based on the assumption that there is not any shape changes of human brain during imaging process. Echo planar imaging (EPI) technique has been widely adapted in fMRI imaging to shorten encoding duration and increase temporal resolution. However, due to the magnetic field inhomogeneity caused by tissues, shape distortion and signal intensity lose are brought into fMRI images by the technique. On the other hand, subject's pose in scanner has a effect on magnetic field inhomogeneity, so the EPI distortions are subject to head movement, especially when the movement is big. As a result, most current motion correction techniques, which are based on rigid registration, cannot handle the problem. In this paper, a technique that combines EPI distortion correction and motion correction to handle the above-mentioned problem is proposed. Since it is almost impossible to obtain ground truth at present, a task-related fMRI BOLD time course image with big motion is selected as experimental material to test its performance. The image is pre-processed with the proposed EPI-motion correction scheme then analyzed by FSL feat tool. Compared with another process with only motion correction and FSL feat analysis, the experimental result using the proposed method has no false activation detection. It is suggested the proposed EPI-motion correction scheme has the ability to handle the fMRI human brain images with big motion. PMID- 26737525 TI - Wireless power transmission for biomedical implants: The role of near-zero threshold CMOS rectifiers. AB - Biomedical implants require an electronic power conditioning circuitry to provide a stable electrical power supply. The efficiency of wireless power transmission is strongly dependent on the power conditioning circuitry specifically the rectifier. A cross-connected CMOS bridge rectifier is implemented to demonstrate the impact of thresholds of rectifiers on wireless power transfer. The performance of the proposed rectifier is experimentally compared with a conventional Schottky diode full wave rectifier over 9 cm distance of air and tissue medium between the transmitter and receiver. The output voltage generated by the CMOS rectifier across a 1 KOmega resistive load is around twice as much as the Schottky rectifier. PMID- 26737526 TI - Experimental UWB frequency analysis for implant communications. AB - Implantable biomedical sensors with the ability to transmit wirelessly real-time physiological data to an external unit can enable better management of chronic diseases. The IEEE Standard 802.15.6-2012 specifies the implementation of implant communications within 402-405 MHz, which unfortunately allows low data transmission rates only. Ultra wideband (UWB) interfaces within 3.1-10.6 GHz offer a number of advantages at the expense of higher path losses. Efforts to characterize the implant UWB channel have been undertaken via computer simulations, but these may not capture completely the effects on the implant radio channel of multiple physiological functions. To overcome these limitations we provide insight into the frequency-domain behavior of the UWB implant channel within 3.1-8.5 GHz based on propagation measurements in a liquid phantom and a living swine. A thorough comparison of the relative received power in phantom based and in vivo measurements for the in-body to on-body (IB2OB) and in-body to off-body (IB2OFF) channel scenarios are presented. PMID- 26737527 TI - Investigation of in-body path loss in different human subjects for localization of capsule endoscope. AB - Recent developments in capsule endoscopy have highlighted the need for accurate techniques to estimate the location of a capsule endoscope. A highly accurate location estimation of a capsule endoscope in the gastrointestinal (GI) tract in the range of several millimeters is a challenging task. This is mainly because the radio-frequency signals encounter high loss and a highly dynamic channel propagation environment. Therefore, an accurate path-loss model is required for the development of accurate localization algorithms. This paper presents an in body path-loss model for the human abdomen region at 2.4 GHz frequency. To develop the path-loss model, electromagnetic simulations using the Finite Difference Time-Domain (FDTD) method were carried out on two different anatomical human models. A mathematical expression for the path-loss model was proposed based on analysis of the measured loss at different capsule locations inside the small intestine. The proposed path-loss model is a good approximation to model in body RF propagation, since the real measurements are quite infeasible for the capsule endoscopy subject. PMID- 26737528 TI - Reconfigurable antenna options for 2.45/5 GHz wireless body area networks in healthcare applications. AB - This paper presents electronically reconfigurable antenna options in healthcare applications. They are suitable for wireless body area network devices operating in the industrial, scientific, and medical (ISM) band at 2.45 GHz and IEEE 802.11 Wireless Local Area Network (WLAN) band at 5 GHz (5.15-5.35 GHz, 5.25-5.35 GHz). Two types of antennas are investigated: Antenna-I has a full ground plane and Antenna-II has a partial ground plane. The proposed antennas provide ISM operation in one mode while in another mode they support 5 GHz WLAN band. Their performance is assessed for body centric wireless communication using a simplified human body model. Antenna sensitivity to the gap between the antenna and the human body is investigated for both modes of each antenna. The proposed antennas exhibit a wide radiation pattern along the body surface to provide wide coverage and their small width (14 mm) makes them suitable for on-body communication in healthcare applications. PMID- 26737529 TI - Performance comparison between UWB-IR and MB-OFDM with transmit diversity in implant communications. AB - An ultra wideband (UWB) technology is a potential candidate for implant body area networks (BANs), where wireless communications are established between inside and outside of a human body. The UWB can accomplish higher data rate than the other frequency band for the implant communication. However, due to its high frequencies, the UWB signals suffer from quite large attenuation in the implant communication link, which makes it difficult to achieve reliable communications. For achieving reliable communication, it is well known that a spatial diversity technique is efficient without any frequency extension. In our previous works, we developed a transmit polarization diversity antenna for the UWB implant communication. However, optimal UWB modulation scheme for transmit diversity were rarely discussed. In this paper, in order to investigate the optimal UWB modulation schemes for implant communication with transmit diversity, we compare the communication performances of UWB-impulse radio (UWB-IR) and multiband orthogonal frequency division multiplexing (MB-OFDM). For this purpose, we first analyze the propagation characteristics in the implant UWB channel, which ranges from 3.4 GHz to 4.8 GHz, using a finite difference time domain (FDTD) numerical analysis technique. Then, we evaluate and discuss the communication performances of both modulation schemes for the transmit polarization diversity from the viewpoint of the BER and the required transmit power. PMID- 26737530 TI - Efficiency optimization of class-D biomedical inductive wireless power transfer systems by means of frequency adjustment. AB - Inductive powering for implanted medical devices is a commonly employed technique, that allows for implants to avoid more dangerous methods such as the use of transcutaneous wires or implanted batteries. However, wireless powering in this way also comes with a number of difficulties and conflicting requirements, which are often met by using designs based on compromise. In particular, one aspect common to most inductive power links is that they are driven with a fixed frequency, which may not be optimal depending on factors such as coupling and load. In this paper, a method is proposed in which an inductive power link is driven by a frequency that is maintained at an optimum value f(opt), to ensure that the link is in resonance. In order to maintain this resonance, a phase tracking technique is employed at the primary side of the link; this allows for compensation of changes in coil separation and load. The technique is shown to provide significant improvements in maintained secondary voltage and efficiency for a range of loads when the link is overcoupled. PMID- 26737531 TI - Context aware falls risk assessment: A case study comparison. AB - This paper describes three retrospective case studies to illustrate the potential clinical value of a system capable of capturing objective gait metrics and environment data from older adults with a history of falls while they go about their daily lives. Participants in this study wore an inertial sensor above each ankle and a wearable camera around their neck for seven consecutive days. Selected metrics are presented to illustrate scenarios where the data collected by the system could be of clinical value. Evidence suggests that obtaining objective gait metrics and environment data from older adults may not only allow healthcare professionals to assess gait more accurately, but also to design treatment plans and falls prevention strategies that are more specifically tailored to each individual. PMID- 26737532 TI - Multi-resident identification using device-free IR and RF fingerprinting. AB - Remote monitoring of health and mobility is critical in the support of aging-in place for seniors. However, it is challenging to passively monitor individuals in multi-resident homes. In this paper we present a new method for the identification of individuals using simple wall-mounted radio frequency (RF) transceivers and IR sensors with fingerprinting techniques. The approach is passive or device-free in that it does not require the person being identified to wear any transmitting device Classification is achieved using features derived from measuring the disruption of RF received signal strength (RSS) among 4 transceivers positioned across either a hallway or doorframe. Three IR sensors provide timing information. Results are given for 3 test subjects (1 female, 2 males). The approach achieves over 98% classification accuracy in distinguishing the female from the male subjects and over 83% in distinguishing between the males using a Gaussian Mixture Model for classification. More than 2300 labeled examples per subject were used for training. When the training data is reduced to less than 140 examples per subject, 96% and 82% classification accuracy is still achieved respectively. PMID- 26737534 TI - Preliminary study of a new home healthcare monitoring to prevent the recurrence of stroke. AB - We tested a new model that involves monitoring physiological parameters and the use of a rehabilitation training system to improve team-based healthcare. The system consisted of unobtrusive monitoring, a highly efficient database, and interventions by health professionals. This report discusses the core technologies, especially those involved in monitoring, which have been developed. The unobtrusive blood pressure (BP) estimation system, electrocardiogram (ECG), Kinect-based rehabilitation training system, and web-based care system, including its database, were designed and tested separately. BP was estimated with a cuffless BP monitor Estimated BP values were sufficiently accurate compared with noninvasive beat-by-beat BP values. The ECG was monitored with textile electrodes mounted on pajamas, and this allowed accurate calculation of heart rates. The training system was tested with four hemiplegic patients and garnered a high acceptance rate. The core technologies operated well, and the proposed system may prove useful and effective for home-based healthcare. Further studies are needed to evaluate the total care system. PMID- 26737533 TI - Remote health coaching for interactive exercise with older adults in a home environment. AB - Optimal health coaching interventions are tailored to individuals' needs, preferences, motivations, barriers, timing, and readiness to change. Technology approaches are useful in both monitoring a user's adherence to their behavior change goals and also in providing just-in-time feedback and coaching messages. User models that incorporate dynamically varying behavior change variables with algorithms that trigger tailored messages provide a framework for making health interventions more effective. These principles are applied in the described system for assisting older adults in meeting their physical exercise goals with a tailored interactive video system with just-in-time feedback and encouragement. PMID- 26737535 TI - Pervasive health monitor and analysis based on multi-parameter smart armband. AB - With the growing attention on personal health, keeping track of the health related parameters has become an important issue, which is quite useful to increase people's living quality and reduce unpredicted risks. However, conventional physical checks are discrete and transient, which is incapable for the health monitor of daily living. Dedicated to everyday physiological monitor, we have developed a multi-parameter smart armband which is able record pulse, temperature and triaxial accelerations continuously. With the wearable device and signal processing algorithm, experiments of data acquisition in the daily living have been implemented on the volunteers. The long period record of 38 hours has demonstrated its feasibility of a total record without disturbing. And both historical and cross comparisons on the parameter correlation analysis have proven the valuable health information that the armband could reveal. As an integrated sensor module, the smart armband is simple and non-obtrusive, thus opens a promising approach towards the pervasive health monitor, especially for the elder population. PMID- 26737536 TI - Unsupervised daily routine and activity discovery in smart homes. AB - The ability to accurately recognize daily activities of residents is a core premise of smart homes to assist with remote health monitoring. Most of the existing methods rely on a supervised model trained from a preselected and manually labeled set of activities, which are often time-consuming and costly to obtain in practice. In contrast, this paper presents an unsupervised method for discovering daily routines and activities for smart home residents. Our proposed method first uses a Markov chain to model a resident's locomotion patterns at different times of day and discover clusters of daily routines at the macro level. For each routine cluster, it then drills down to further discover room level activities at the micro level. The automatic identification of daily routines and activities is useful for understanding indicators of functional decline of elderly people and suggesting timely interventions. PMID- 26737537 TI - A stereophotogrammetric-based method to assess spatio-temporal gait parameters on healthy and Parkinsonian subjects. AB - Generally, the study of gait requires the detection of successive heel contacts and toe-off instants. Traditional gait analysis methods obtain these gait events using dynamometric platforms together with stereophotogrammetric data. Usually, are kept valid only those walking trials where the subjects step on each platform by only one foot. For subjects suffering from walking impairments it is very difficult or sometimes impossible to walk naturally and step properly on the dynamometric platforms. The aim of the present study is to propose a new method to identify, in an automatic manner, the initial contact (IC) and the toe-off (TO) time instants using only stereophotogrammetric data and a classic gait analysis protocol. The assessment of spatio-temporal gait variables during natural walking is also performed. The study consisted in analyzing healthy and Parkinsonian elderly subjects. The reliability of the proposed stereophotogrammetric-based method was tested by direct comparison with the IC and TO instants determined by the dynamometric platform data. The absence of any statistically significant differences between the values estimated by the two different modalities, highlights the reliability of the proposed method in the assessment of these two gait events. Results underline, as expected, the reduction of walking velocity in pathological patients during free ambulation. The present study proposes this method as a valid alternative to the traditional technique that use dynamometric platforms to identify main gait events, for subjects unable to walk naturally and to step properly on the platforms. PMID- 26737538 TI - Foot clearance estimation during overground walking and vertical obstacle passing using shank-mounted MIMUs in healthy and pathological subjects. AB - A method for assessing maximum foot clearance (maxFCl) during overground walking and obstacle passing using magnetic and inertial measurement units (MIMUs) placed above the malleoli is proposed and validated. The method precision and accuracy were evaluated using a stereo-photogrammetric system as a gold standard. The proposed method was applied to the data obtained from the gait of both healthy subjects and patients with various abnormal gaits. First, an optimally filtered direct and reverse integration (OFDRI) was used for each gait cycle to determine the gait velocity. Then, the effect of an additional OFDRI or a simple DRI approach for obtaining vertical foot displacement was explored. The results showed that the mean absolute errors associated to the maxFCl estimates were about 10% of its range of variation for the healthy and pathological subjects during overground walking. An accurate estimate of the maxFCl during obstacle passing was reached (mean absolute errors less than 5%). Additional testing on gait at various gait speed and on a greater number of subjects should be carried out to fully validate the MIMU-based maxFCl estimates. PMID- 26737539 TI - The effects of an ankle foot orthosis on cerebral palsy gait: A multiple regression analysis. AB - The aim of this study was twofold. Firstly, to develop a multiple regression normalization (MR) strategy to decorrelate physical properties and walking speed from spatiotemporal gait data in healthy children; and secondly, to use this MR approach to identify the effect of a solid ankle foot orthosis (AFO) on gait in children with cerebral palsy (CP). Spatiotemporal gait data during self-selected walking were obtained from 51 children with diplegic CP and 34 aged-matched healthy controls. Data were normalized using standard dimensionless equations (DS) and a MR approach. Stride length, stance time, swing time, and double support time were significantly different between children with CP and healthy controls using DS (p<;0.05); however, only stride length and swing time were significantly different when children with CP walked with and without an AFO. Normalizing gait data using DS demonstrated significant differences in cadence and step time in children with CP when wearing an AFO compared to the controls (p<;0.05). In contrast, MR normalization revealed significant differences in all spatiotemporal parameters between children with CP with and without an AFO, except double support time. After MR normalization, spatiotemporal parameters in children wearing an AFO became closer to those of the controls, except for double support time. The MR approach presented will assist in evaluating the effectiveness of conservative interventions such as AFOs in children with CP, as well as in surgery, and may be useful in gait classification using machine learning. PMID- 26737540 TI - Preliminary design of a new device to measure muscle function. AB - A description and early results are presented for a novel device to estimate the torque-angle and torque-angular velocity properties of the quadriceps muscle group using electrical stimulation. The device straps to the shin and is moved by the operator while pulses of stimulation are applied to the motor point of the quadriceps. During stimulation, the operator raises and lowers the leg to the desired angle, and also can oscillate the leg to generate a rich velocity profile. The resulting muscle force is measured by a load cell contained in the device. In a preliminary study using 11 healthy subjects, normalized torque-angle and torque-velocity data for the quadriceps were consistent with literature results that used maximum voluntary contraction methods. PMID- 26737541 TI - Measurement of biomechanical interactions at the stump-socket interface in lower limb prostheses. AB - This paper introduces a novel measuring approach for detecting relative movement between stump and socket in lower limb prostheses. The application of the motion capturing based measuring approach is shown at a single male trans-tibial amputee using a Patella Tendon Bearing (PTB) socket. It further investigates and assesses the feasibility of measuring the relative movement between stump and socket during level walking at different velocities and allocating it to the coinciding loads. Representative results for the two translational degrees of freedom in the sagittal plane are presented and discussed. For the proximodistal (pd) direction, a linear correlation between applied load and relative movement is found, while for the anteroposterior (ap) direction the stump movement is largely influenced by the motion sequence during the respective gait event. Additionally, the effect of walking speed is discussed. PMID- 26737542 TI - Disposable soft 3 axis force sensor for biomedical applications. AB - This paper proposes a new disposable soft 3D force sensor that can be used to calculate either force or displacement and vibrations. It uses three Hall Effect sensors orthogonally placed around a cylindrical beam made of silicon rubber. A niobium permanent magnet is inside the silicon. When a force is applied to the end of the cylinder, it is compressed and bent to the opposite side of the force displacing the magnet. This displacement causes change in the magnetic flux around the ratiomatric linear sensors (Hall Effect sensors). By analysing these changes, we calculate the force or displacement in three directions using a lookup table. This sensor can be used in minimal invasive surgery and haptic feedback applications. The cheap construction, bio-compatibility and ease of miniaturization are few advantages of this sensor. The sensor design, and its characterization are presented in this work. PMID- 26737543 TI - A blood viscosity estimation method based on pressure-flow characteristics of an oxygenator during cardiopulmonary bypass and its clinical application. AB - In this paper, we developed a model that uses pressure-flow monitoring information in the oxygenator to estimate viscosity of human blood. The comparison between estimated viscosity (etae) and measured viscosity (eta) was assessed in 16 patients who underwent cardiac surgery using mild hypothermia cardiopulmonary bypass (CPB). After initiation of CPB, etae was recorded at three periods: post-establishment of total CPB, post-aortic cross-clamp, and post declamp. During the same period, blood samples were collected from the circuit and eta was measured with a torsional oscillation viscometer. The etae was plotted as a function of eta and the systematic errors and compatibility between two methods were assessed using Bland-Altman analysis. The parameters etae and eta were very strongly correlated at all points (R(2)=0.9616, p<;0.001). The Bland-Altman analysis revealed a mean bias of -0.001 mPas, a standard deviation of 0.03 mPas, limits of agreement of -0.06 mPas to 0.06 mPas, and a percent error of 3.3%. There was no fixed bias or proportion bias for the viscosity. As this method estimates blood viscosity with good precision during CPB continuously, it may be helpful for clinical perfusion management. PMID- 26737544 TI - Seven phases of gait detected in real-time using shank attached gyroscopes. AB - A new gyroscope-based gait phase detection system (GPDS) with ability to detect all seven phases of gait was proposed in this study. Gyroscopes were attached to each shank. Shank angular velocity, about the medio-lateral axis, was streamed to a PC and a rule-based algorithm was used to identify characteristics of the signals. Five subjects were asked to walk on treadmill at their self-selected speed while using this system. All 7 phases of gait: LR, MSt, TSt, PSw, ISw, MSw, and TSw were detected in real-time using only shank angular velocities. To quantify system performance, sensor data was compared to simultaneously collected motion capture data. Average gait phase detection delays of the system were less than 40ms except TSw (74ms). The present system, consisting of minimal sensors and decreased processing, is precise, cosmetic, economical, and a good alternative for portable stand-alone applications. PMID- 26737546 TI - Development of diagnostic sensors for infant dehydration assessment using optical methods. AB - Dehydration resulting from acute diarrhea is one of the leading causes of infant mortality in the developing world. Safe assessment of an infant's hydration level is essential to determine appropriate clinical intervention strategies. However, clinical hydration scales, which are the current gold standard for non-invasive hydration assessment, are often unreliable in lower resource settings. This study presents the development and testing of non-invasive, optical sensors for the objective assessment of dehydration based on the quantitative measurement of skin recoil time, capillary refill time and skin temperature. The results obtained have demonstrated the basic feasibility of using optical sensors for the objective assessment of dehydration. However, several challenges must be overcome before these sensors can be applied in a clinical setting. PMID- 26737545 TI - Analysis of gold nanoparticles as carriers for different molecular dye type photosensitizers in Photodynamic Therapy applied to carcinomas. AB - The effect of gold nanoparticles on the depth of photodynamic treatment for different types of photosensitizers with significant potential for their application in oncology is studied by means of a predictive model. Results show differences of up to 18 % when nanoparticles are used as carriers for Cyanine based photosensitizers in a carcinoma. Therefore these results could be useful to rule out the administration of this means of delivery for certain molecular dye type photosensitizers when Photodynamic Therapy is applied to carcinomas with a given structure. PMID- 26737547 TI - A single element 3D ultrasound tomography system. AB - Over the past decade, substantial effort has been directed toward developing ultrasonic systems for medical imaging. With advances in computational power, previously theorized scanning methods such as ultrasound tomography can now be realized. In this paper, we present the design, error analysis, and initial backprojection images from a single element 3D ultrasound tomography system. The system enables volumetric pulse-echo or transmission imaging of distal limbs. The motivating clinical applications include: improving prosthetic fittings, monitoring bone density, and characterizing muscle health. The system is designed as a flexible mechanical platform for iterative development of algorithms targeting imaging of soft tissue and bone. The mechanical system independently controls movement of two single element ultrasound transducers in a cylindrical water tank. Each transducer can independently circle about the center of the tank as well as move vertically in depth. High resolution positioning feedback (~1MUm) and control enables flexible positioning of the transmitter and the receiver around the cylindrical tank; exchangeable transducers enable algorithm testing with varying transducer frequencies and beam geometries. High speed data acquisition (DAQ) through a dedicated National Instrument PXI setup streams digitized data directly to the host PC. System positioning error has been quantified and is within limits for the imaging requirements of the motivating applications. PMID- 26737548 TI - Rapid detection of E. coli cells in urine samples using a self-capacitance touchscreen device. AB - Escherichia coli is one of the main causes of urinary tract infections (UTIs). E. coli is commonly detected from urine using standard culture method. However, the urine sampling and analysis required for these methods can be costly, time consuming (requires 24 to 48 hours) and labor-intensive. This work proposes a capacitive touch screen sensor concept as possible alternative device for rapid detection of E. coli in urine samples. E. coli solutions prepared at different concentrations and urine samples (with spiked and nor spike E. coli) obtained from healthy women participants, have been analyzed using a capacitance evaluation kit. It has been demonstrated in this study that the use of this evaluation kit provides a low-cost and simple alternative system for detecting E. coli present in urine. Several experimental tests were performed to determine the optimal testing volume, the sensitivity of the sensor, limit of detection and repeatability. The optimal testing volume was 80 microliters and the analytical sensitivity was 17 counts per picofarad (pF). The lowest detectable concentration is around 3.98 * 10(5) CFU/ml. The repeatability (r) was found to be 7.2 or 6.2 % (in r%). The capacitive touch sensor gave promising results that could be used to design and realize a portable diagnostic device for early-stage detection of UTIs. PMID- 26737549 TI - Application of higher-order spectral analysis to local field potentials recorded in patients treated with deep brain stimulation. AB - Local field potentials (LFPs) recorded from implanted deep brain electrodes demonstrated the oscillatory nature of human basal ganglia. LFP rhythms were mainly characterized by means od power spectral analysis, thus loosing information related to rhythm phase synchronization and to event related phase modulations. Because the application of higher-order spectral analysis methodology can overcome such limitation, here we review the present applications of bispectral and cross-bispectral analysis to LFP recordings. The results obtained up to now showed that higher-order spectral analysis was able to clarify detect different rhythm synchronizations and interactions characterizing different pathologies and patient's states. PMID- 26737550 TI - Motor task event detection using Subthalamic Nucleus Local Field Potentials. AB - Deep Brain Stimulation (DBS) provides significant therapeutic benefit for movement disorders such as Parkinson's disease. Current DBS devices lack real time feedback (thus are open loop) and stimulation parameters are adjusted during scheduled visits with a clinician. A closed-loop DBS system may reduce power consumption and DBS side effects. In such systems, DBS parameters are adjusted based on patient's behavior, which means that behavior detection is a major step in designing such systems. Various physiological signals can be used to recognize the behaviors. Subthalamic Nucleus (STN) Local Field Potential (LFP) is a great candidate signal for the neural feedback, because it can be recorded from the stimulation lead and does not require additional sensors. A practical behavior detection method should be able to detect behaviors asynchronously meaning that it should not use any prior knowledge of behavior onsets. In this paper, we introduce a behavior detection method that is able to asynchronously detect the finger movements of Parkinson patients. As a result of this study, we learned that there is a motor-modulated inter-hemispheric connectivity between LFP signals recorded bilaterally from STN. We used non-linear regression method to measure this connectivity and use it to detect the finger movements. Performance of this method is evaluated using Receiver Operating Characteristic (ROC). PMID- 26737551 TI - Spatial distribution of nonlinear interactions in subthalamic nucleus local field potentials in Parkinson'S disease. AB - Abnormally synchronized neural oscillations within the subthalamic nucleus have been proposed as a contributor to the pathophysiology of Parkinson's disease. Recent studies have demonstrated phase-amplitude coupling between beta rhythms and high frequency oscillations in the subthalamic nucleus in unmedicated Parkinsonian patients. However, the nature of this coupling remains unclear. In this study, we first show the presence of nonlinear interactions between different frequency bands of oscillations. Then, we demonstrate that the amplitude of spatially localized high frequency activity is phase coupled with widespread beta oscillations within the subthalamic nucleus. PMID- 26737552 TI - Spatio-spectral characterization of local field potentials in the subthalamic nucleus via multitrack microelectrode recordings. AB - Deep brain stimulation of the subthalamic nucleus (STN) is a highly effective treatment for motor symptoms of Parkinson's disease. However, precise intraoperative localization of STN remains a procedural challenge. In the present study, local field potentials (LFPs) were recorded from three tracks during microelectrode recording-based (MER) targeting of STN, in five patients. The raw LFP data were preprocessed in original recording setup and then data quality was compared to data with common average derivation. The depth-frequency maps were generated according to preprocessing results for each patient and spectral characteristics of LFPs were explored at each depth across different tracks and different subjects. Spatio-spectral analysis of LFP was investigated to see whether LFP activity can be used for optimal track selection and STN border identification. Analysis show that monopolar derivation suffer from various artifacts and/or power line noise which makes the interpretation of target localization very difficult in most of the subjects. Unlikely, bipolar derivation helps to recover the neurological signals and investigation of signal characteristics. The frequency-vs-depth maps using a modified Welch periodogram with robust statistics, demonstrated that a median-based spectrum estimation approach eliminates outliers pretty well by preserving band-specific LFP activity. The results indicate that there is a clear oscillatory beta activity around 20 Hz in all subjects. 1/f normalization reveals the high frequency oscillations (HFOs) between 200-to-350 Hz in two subjects. It's noted that the optimal track selection is not consistent with the track having highest beta band oscillations in two out of five subjects. In conclusion, microelectrode-derived LFP recordings may provide an alternative approach to single unit activity (SUA) based MER, for localizing the target STN borders during DBS surgery. Despite the small number of subjects, the present study adds to existing knowledge about LFP based pathophysiology of PD and its target-based spectral activities. PMID- 26737553 TI - Time-frequency characterization of local field potential in a decision making task. AB - This study seeks to characterize the neuronal mechanisms underlying voluntary decisions to check/verify. In order to describe and potentially decode decisions from brain signals we analyzed intracortical recordings from monkey prefrontal regions obtained during a cognitive task requiring self-initiated as well as cue instructed decisions. Using local field potentials (LFP) and single units, we analyzed power spectral density, oscillatory modes, power profiles in time, single unit firing rate, and spike-phase relationships in the beta band. Our results point toward specific but variable activation patterns of oscillations in beta band from separate recordings, with task-dependent frequency preference and amplitude modulation of power. The results suggest relationships between particular LFP oscillations and functions engaged at specific time in the task. PMID- 26737554 TI - Detection of mild Alzheimer's disease and mild cognitive impairment from elderly speech: Binary discrimination using logistic regression. AB - In this research, we have developed a novel data-mining approach for detection of cognitive impairment, SPCIR (Speech Prosody-Based Cognitive Impairment Rating), which can discriminate between mild cognitive impairment and mild Alzheimer's disease from elderly using prosodic sign extracted from elderly speech during questionnaire test. This paper proposes a binary discrimination model of SPCIR using multivariate logistic regression and model selection using receiver operating characteristic (ROC) curve analysis, and reports the sensitivity and specificity of SPCIR for diagnosis (control; mild cognitive impairment/mild Alzheimer's disease). PMID- 26737555 TI - Pronunciation analysis for children with speech sound disorders. AB - Phonological disorders affect 10% of preschool and school-age children, adversely affecting their communication, academic performance, and interaction level. Effective pronunciation training requires prolonged supervised practice and interaction. Unfortunately, many children do not have access or only limited access to a speech-language pathologist. Computer-assisted pronunciation training has the potential for being a highly effective teaching aid; however, to-date such systems remain incapable of identifying pronunciation errors with sufficient accuracy. In this paper, we propose to improve accuracy by (1) learning acoustic models from a large children's speech database, (2) using an explicit model of typical pronunciation errors of children in the target age range, and (3) explicit modeling of the acoustics of distorted phonemes. PMID- 26737556 TI - Objective measures of perceptual quality for predicting speech intelligibility in sensorineural hearing loss. AB - An objective method to predict speech intelligibility in sensorineural hearing loss of different types and increasing degrees of severity is proposed and validated with experimental data. The novel approach is based on the combined use of acoustic simulations of impaired perception and objective measures of perceptual speech quality (PESQ). Acoustic simulations were obtained after degradation of the original, non distorted, speech waveforms by spectral smearing, expansive nonlinearity, and level scaling. PESQ was used to measure perceptual quality of the acoustic simulations obtained by varying the degree of the simulated hearing loss. A logistic function was applied to transform PESQ scores into predicted intelligibility scores. A set of CV and VC syllables in /a/, /u/, and /i/ contexts was used as reference test material. The method was validated with subjective measures of intelligibility of the degraded speech obtained in a group of 10 normal hearing subjects. Overall, prediction of experimental speech intelligibility through the transformed PESQ measures was good (R(2)=0.7; RMSE=0.08) revealing that the proposed approach could be a valuable aid in real clinical applications. PMID- 26737557 TI - Detection of wheezes using their signature in the spectrogram space and musical features. AB - In this work thirty features were tested in order to identify the best feature set for the robust detection of wheezes. The features include the detection of the wheezes signature in the spectrogram space (WS-SS) and twenty-nine musical features usually used in the context of Music Information Retrieval. The method proposed to detect the signature of wheezes imposes a temporal Gaussian regularization and a reduction of the false positives based on the (geodesic) morphological opening by reconstruction operator. Our dataset contains wheezes, crackles and normal breath sounds. Four selection algorithms were used to rank the features. The performance of the features was asserted having into account the Matthews correlation coefficient (MCC). All the selection algorithms ranked the WS-SS feature as the most important. A significant boost in performance was obtained by using around ten features. This improvement was independent of the selection algorithm. The use of more than ten features only allows for a small increase of the MCC value. PMID- 26737558 TI - Parameter-based binaural hearing aid algorithms to improve speech intelligibility and localization in complex environments. AB - This paper presents new binaural enhancement and noise suppression algorithms for binaural hearing aids. To enhance interaural level difference (ILD) cues at low frequencies, which are usually small, interaural time difference (ITD) cues are estimated and transformed to ILDs. The binaural noise suppression algorithm consists of adaptive beamforming and a coherence-based suppression filter. The estimated phase and signal-to-noise ratio (SNR) at each hearing aid are used to perform the processing. The performance of the proposed methods was assessed using perceptual evaluation with hearing-impaired listeners and objective evaluation. PMID- 26737559 TI - Computerised objective measurement of strain in voiced speech. AB - Voice quality assessment is required by healthcare professionals in patients suffering from voice problems. Speech and language therapists (SLTs) use a well known subjective assessment approach which is called GRBAS, to quantify voice problems. GRBAS is an acronym for a five dimensional scale of measurements of voice properties which were originally recommended by the Japanese Society of Logopeadics and Phoniatrics and the European Research for clinical and research use. The properties are 'Grade', 'Roughness', 'Breathiness', 'Asthenia' and 'Strain'. In requiring the services of trained SLTs, this subjective assessment make the GRBAS measurement expensive to administer. In this research, computerised objective measurement of 'Strain' in voice using two regression prediction models is compared with measurements produced by SLTs according to the GRBAS scale. These regression models are K Nearest Neighbor Regression (KNNR) and Multiple Linear Regression (MLR). These new approaches for prediction of Strain are based on different subsets of features, different sets of data, and different prediction models in comparison with previous approaches in the literature. The best feature subset for predicting Strain objectively was obtained amongst different feature subsets. When compared with the mean of five SLT's scores, over 102 samples, the computerised measurement was found to have a Normalized Root Mean Square Error (NRMSE) averaged over 20 trials, lower than that of each individual SLT. We have achieved a NRMSE of 14.6% and 15.1% for the MLR and KNNR respectively when the best feature subsets were used for predicting Strain objectively. PMID- 26737560 TI - Using wearable sensors for semiology-independent seizure detection - towards ambulatory monitoring of epilepsy. AB - Epilepsy is a disease of the central nervous system. Nearly 70% of people with epilepsy respond to a proper treatment, but for a successful therapy of epilepsy, physicians need to know if and when seizures occur. The gold standard diagnosis tool video-electroencephalography (vEEG) requires patients to stay at hospital for several days. A wearable sensor system, e.g. a wristband, serving as diagnostic tool or event monitor, would allow unobtrusive ambulatory long-term monitoring while reducing costs. Previous studies showed that seizures with motor symptoms such as generalized tonic-clonic seizures can be detected by measuring the electrodermal activity (EDA) and motion measuring acceleration (ACC). In this study, EDA and ACC from 8 patients were analyzed. In extension to previous studies, different types of seizures, including seizures without motor activity, were taken into account. A hierarchical classification approach was implemented in order to detect different types of epileptic seizures using data from wearable sensors. Using a k-nearest neighbor (kNN) classifier an overall sensitivity of 89.1% and an overall specificity of 93.1% were achieved, for seizures without motor activity the sensitivity was 97.1% and the specificity was 92.9%. The presented method is a first step towards a reliable ambulatory monitoring system for epileptic seizures with and without motor activity. PMID- 26737561 TI - Online detection of tonic-clonic seizures in pediatric patients using ECG and low complexity incremental novelty detection. AB - Home monitoring of refractory epilepsy patients has become of more interest the last couple of decades. A biomedical signal that can be used for online seizure detection at home is the electrocardiogram. Previous studies have shown that tonic-clonic seizures are most often accompanied with a strong heart rate increase. The main issue however is the strong patient-specific behavior of the ictal heart rate features, which makes it hard to make a patient-independent seizure detection algorithm. A patient-specific algorithm might be a solution, but existing methods require the availability of data of several seizures, which would make them inefficient in case the first seizure only occurs after a couple of days. Therefore an online method is described here that automatically converts from a patient-independent towards a patient-specific algorithm as more patient specific data become available. This is done by using online feedback from the users to previously given alarms. By using a simplified one-class classifier, no seizure training data needs to be available for a good performance. The method is already able to adapt to the patient-specific characteristics after a couple of hours, and is able to detect 23 of 24 seizures longer than 10s, with an average of 0.38 false alarms per hour. Due to its low-complexity, it can be easily used for wearable seizure detection at home. PMID- 26737562 TI - Analysis of epileptic seizure count time series by ensemble state space modelling. AB - We propose an approach for the analysis of epileptic seizure count time series within a state space framework. Time-dependent dosages of several simultaneously administered anticonvulsants are included as external inputs. The method aims at distinguishing which temporal correlations in the data are due to the medications, and which correspond to an unrelated background signal. Through this method it becomes possible to disentagle the effects of the individual anticonvulsants, i.e., to decide which anticonvulsant in a particular patient decreases or rather increases the number of seizures. PMID- 26737563 TI - Support vector machines using EEG features of cross-frequency coupling can predict treatment outcome in Mecp2-deficient mice. AB - Anti-convulsive drug treatments of epilepsy typically produce varied outcomes from one patient to the next, often necessitating patients to go through several anticonvulsive drug trials until an appropriate treatment is found. The focus of this study is to predict treatment outcome using a priori electroencephalogram (EEG) features for a rare genetic model of epilepsy seen in patients with Rett Syndrome. Previous work on Mecp2-deficient mice, exhibiting the symptoms of Rett syndrome, have revealed EEG-based biomarkers that track the pathology well. Specifically the presence of cross-frequency coupling of the delta-like (3-6 Hz) frequency range phase with the fast ripple (400 - 600 Hz) frequency range amplitude in long duration discharges was found to track seizure pathology. Support Vector Machines (SVM) were trained with features generated from phase amplitude comodulograms and tested on (n=6) Mecp2-deficient mice to predict treatment outcome to Midazolam, a commonly used anti-convulsive drug. Using SVMs it was shown that it is possible to generate a likelihood score to predict treatment outcomes on all of the animal subjects. Identifying the most appropriate treatment a priori would potentially lead to improved treatment outcomes. PMID- 26737564 TI - Identification of epileptogenic networks from dense EEG: A model-based study. AB - Epilepsy is a network disease. Identifying the epileptogenic networks from noninvasive recordings is a challenging issue. In this context, M/EEG source connectivity is a promising tool to identify brain networks with high temporal and spatial resolution. In this paper, we analyze the impact of the two main factors that intervene in EEG source connectivity processing: i) the algorithm used to solve the EEG inverse problem and ii) the method used to measure the functional connectivity. We evaluate three inverse solutions algorithms (dSPM, wMNE and cMEM) and three connectivity measures (r(2), h(2) and MI) on data simulated from a combined biophysical/physiological model able to generate realistic interictal epileptic spikes reflected in scalp EEG. The performance criterion used here is the similarity between the network identified by each of the inverse/connectivity combination and the original network used in the source model. Results show that the choice of the combination has a high impact on the identified network. Results suggest also that nonlinear methods (nonlinear correlation coefficient and mutual information) for measuring the connectivity are more efficient than the linear one (the cross correlation coefficient). The dSPM as inverse solution shows the lowest performance compared to cMEM and wMNE. PMID- 26737565 TI - A neural network based infant monitoring system to facilitate diagnosis of epileptic seizures. AB - In this paper, we propose an infant monitoring system that automatically detects epileptic seizures in domestic and hospital environments. The proposed system measures the movements and electroencephalogram (EEG) signals of an infant using a video camera and an electroencephalograph. Seizure features are then extracted from the video images and EEG signals, and the evaluation indices based on medical knowledge are calculated from the features. The system employs a probabilistic neural network for the automatic detection of seizures, thereby allowing the choice/combination of evaluation indices appropriate for the environment via network training. We tested the system in simulated domestic and hospital environments. The validity of the proposed system was reinforced by the results of comparisons with clinical diagnoses. PMID- 26737566 TI - X-ray CT image reconstruction from few-views via total generalized p-variation minimization. AB - Total variation (TV)-based CT image reconstruction, employing the image gradient sparsity, has shown to be experimentally capable of reducing the X-ray sampling rate and removing the unwanted artifacts, yet may cause unfavorable over smoothing and staircase effects by the piecewise constant assumption. In this paper, we present a total generalized p-variation (TGpV) regularization model to adaptively preserve the edge information while avoiding the staircase effect. The new model is solved by splitting variables with an efficient alternating minimization scheme. With the utilization of generalized p-shrinkage mappings and partial Fourier transform, all the subproblems have closed solutions. The proposed method shows excellent properties of edge preserving as well as the smoothness features by the consideration of high order derivatives. Experimental results indicate that the proposed method could avoid the mentioned effects and reconstruct more accurately than both the TV and TGV minimization algorithms when applied to a few-view problem. PMID- 26737567 TI - Computed tomography image source identification by discriminating CT-scanner image reconstruction process. AB - In this paper, we focus on the identification of the Computed Tomography (CT) scanner that has produced a CT image. To do so, we propose to discriminate CT Scanner systems based on their reconstruction process, the footprint or the signature of which can be established based on the way they modify the intrinsic sensor noise of X-ray detectors. After having analyzed how the sensor noise is modified in the reconstruction process, we define a set of image features so as to serve as CT acquisition system footprint. These features are used to train a SVM based classifier. Experiments conducted on images issued from 15 different CT Scanner models of 4 distinct manufacturers show it is possible to identify the origin of one CT image with high accuracy. PMID- 26737568 TI - X-ray microtomography of collagen and polylactide scaffolds in liquids. AB - Methods to image and assess the microstructure of polymer based biomaterials in liquid phase, for example cell culture medium, are well warranted. X-ray microtomography could provide a mean to visualize and analyze such structures. However, the density of such polymers is close to that of water and hence the X ray contrast is poor. Moreover, if the biomaterials contain cells and are dried, the cell morphology may be distorted. In this paper we test phosphotungstic acid (PTA) staining to improve the contrast. We imaged collagen and PLA samples with MUCT in air, water and alcohol. The methods were compared visually and with contrast to noise ratio calculated from the images. Our results demonstrate that with alcohol the PLA can be imaged also in liquid phase. PTA staining seems to be a good method to increase the contrast for collagen in MUCT imaging. PMID- 26737569 TI - Simulated imaging of atherosclerotic & radiofrequency ablation lesions using phase subtraction. AB - Cardiovascular diseases are the main cause of death worldwide. Atherosclerosis and atrial fibrillation are structural and electrical pathophysiology, respectively, that can lead to acute events such as stroke or myocardial infarction. We used particle-based Monte Carlo methods to simulate X-ray phase imaging of atherosclerotic plaque types IV-VIII in the aorta, iliac, and coronary arteries. We also assessed scar lesion development in radiofrequency catheter ablation treatment of atrial fibrillation by simulating lesions 2, 5, 10, 30, and 60 days post-procedure. For both applications, we found high signal-to-noise and contrast-to-noise ratios in all lesions. These results suggest that X-ray phase imaging is a viable technique for non-invasive quantitative cardiovascular lesion characterization. PMID- 26737570 TI - Optimization-based scatter estimation using semi-transparent beam absorber array. AB - To correct the scatter in cone beam CT, an optimization-based scatter estimation method (OPMSE) is proposed. Like the previous Fourier-based primary modulation method (FPMSE), semi-transparent beam absorber array (SBAA) is placed between the X-ray source and the imaging target, thus projection data behind the absorber can still be obtained, which is meaningful for dose saving and image quality improving. In the proposed algorithm, scatter is estimated by solving an optimization problem, which makes use of the prior information that primary and scatter are both smooth not only in each frame, but also between adjacent frames. Moreover, an edge-preserving weighting is incorporated to prevent the over smoothing of structures in the primary signal. The new algorithm is robust that various patterns of modulator can be applied. Simulation and physical experiments demonstrated the good performance of OPMSE in scatter removing. PMID- 26737571 TI - Three-dimensional reconstruction of coronary arteries and plaque morphology using CT angiography - comparison and registration using IVUS. AB - The aim of this study is to present a new method for three-dimensional (3D) reconstruction of coronary arteries and plaque morphology using Computed Tomography (CT) Angiography. The method is summarized in three steps. In the first step, image filters are applied to CT images and an initial estimation of the vessel borders is extracted. In the second step, the 3D centerline is extracted using the center of gravity of each rough artery border. Finally in the third step, the borders and the plaque are detected and placed onto the 3D centerline constructing a 3D surface. By using as gold standard the results of a recently presented Intravascular Ultrasound (IVUS) plaque characterization method, high correlation is observed for calcium objects detected by CT and IVUS. The correlation coefficients for objects' volume, surface area, length and angle are r=0.51, r=0.89, r=0.96 and r=0.93, respectively. PMID- 26737572 TI - Computer-assisted identification of proliferative diabetic retinopathy in color retinal images. AB - Advanced (proliferative) stage of diabetic retinopathy (DR) is indicated by the growth of thin, fragile and highly unregulated vessels, neovascularization (NV). In order to identify proliferative diabetic retinopathy (PDR), our approach models the micro-pattern of local variations using texture based analysis and quantifies the structural changes in vessel patterns in localized patches, to map them to the confidence score of being neovascular using supervised learning framework. Rule-based criteria on patch-level neovascularity scores in an image is used for the decision of absence or presence of PDR. Evaluated using 3 datasets, our method achieves 96% sensitivity and 92.6% specificity for localizing NV. Image-level identification of PDR achieves high sensitivity of 96.72% at 79.6% specificity and high specificity of 96.50% at 73.22% sensitivity. Our approach could have potential application in DR grading where it can localize NVE regions and identify PDR images for immediate intervention. PMID- 26737573 TI - Method for segmentation of the layers in the outer retina. AB - This paper presents a method to determine the number of visible layers in the outer retina and perform segmentation. Each layer in the outer retina is represented by a Gaussian function, and multiple models with a different number of layers are used to form the outer retina. Parameters of competing models are calculated by using maximum likelihood estimation after which the model that best describes the data is selected. Model selection is based on the goodness of fit and model complexity thereby ensuring that the model that best represents the data is chosen. The method was applied to in-vivo macular images of human retinas acquired by optical coherence tomography after conversion to attenuation coefficients. Examples of detected number of visible layers and corresponding segmentation results are shown in both normal and retinitis pigmentosa affected retinas. PMID- 26737574 TI - Retinal image registration based on keypoint correspondences, spherical eye modeling and camera pose estimation. AB - In this work, an image registration method for two retinal images is proposed. The proposed method utilizes keypoint correspondences and assumes a spherical model of the eye. Image registration is treated as a pose estimation problem, which requires estimation of the rigid transformation that relates the two images. Using this estimate, one image can be warped so that it is registered to the coordinate frame of the other. Experimental evaluation shows improved accuracy over state-of-the-art approaches as well as robustness to noise and spurious keypoint correspondences. Experiments also indicate the method's applicability to diagnostic image enhancement and comparative analysis of images from different examinations. PMID- 26737575 TI - Combining efficient hand-crafted features with learned filters for fast and accurate corneal nerve fibre centreline detection. AB - We propose a new approach to corneal nerve fibre centreline detection for in vivo confocal microscopy images. Relying on a combination of efficient hand-crafted features and learned filters, our method offers an excellent compromise between accuracy and running time. Unlike previous solutions using sparse coding to learn small filter banks, we employ K-means to efficiently learn the high amount of filters needed to cope with the multiple challenges involved, e.g., low contrast and resolution, non-uniform illumination, tortuosity and confounding non-target structures. The use of K-means for dictionary learning allows us to learn banks of 100 filters in less than 30 seconds compared to several days needed when using sparse coding. Experimental results using a dataset including 100 images show that our approach outperforms significantly state-of-the-art methods in terms of precision-recall curves. PMID- 26737576 TI - Age-related changes of the corneal speckle by Optical Coherence Tomography. AB - Ageing of the population has several consequences for the human visual system. The corneal tissue which is responsible for two thirds of the total optical power is not an exception, suffering structural and anatomical changes with the age. In this study, we have explored the usefulness of Optical Coherence Tomography (OCT) speckle to study the age-related changes in corneal stroma. The Generalized Gamma distribution has been suggested as a model for OCT corneal speckle and was used here to investigate OCT envelope statistics in three different age groups (65 subjects in total). The scaling and the two shape parameters have shown significant statistical differences (p <; 0.05) among the age groups, showing the possibility to track the corneal changes using envelope statistics. This study shows that Generalized Gamma distribution has a great potential to fit the corneal speckle and could be a helpful complement to evaluate the structure and elastic properties of the cornea in vivo. PMID- 26737577 TI - Red lesion detection in retinal fundus images using Frangi-based filters. AB - This paper presents a method to detect red lesions related to Diabetic Retinopathy (DR), namely Microaneurysms and Hemorrhages from retinal fundus images with robustness to the presence of blood vessels. Filters based on Frangi filters are used for the first time for this task. Green channel of the input image was decomposed into smaller sub images and proposed filters were applied to each sub image after initial preprocessing. Features were extracted from the filter response and used to train a Support Vector Machine classifier to predict whether a test image had lesions or not. Experiments were performed on a dataset of 143 retinal fundus and the proposed method achieved areas under the ROC curve equal to 0.97 and 0.87 for Microaneurysms and Hemorrhages respectively. Results show the effectiveness of the proposed method for detecting red lesions. This method can help significantly in automated detection of DR with fewer false positives. PMID- 26737578 TI - ICD lead failure detection in chronic soaked leads. AB - Abrasion-induced insulation breach is a common failure mode of silicone-body, transvenous, implantable cardioverter defibrillator leads. It is caused either by external compression or internal motion of conducting cables. The present method of monitoring lead integrity measures low frequency conductor impedance. It cannot detect insulation failures until both the silicone lead body and inner fluoropolymer insulation have been breached completely, exposing conductors directly to blood or tissue. Even then the resistance changes are usually swamped by the baseline values. Thus the first clinical presentation may be either failure to deliver a life-saving shock or painful, inappropriate shocks in normal rhythm. We have previously presented a method for identifying early lead failure based on high frequency transmission line impedance measurements. That work used fresh leads in a liquid simulation bath; we have now demonstrated similar effects in leads soaked for 32 days and hence with saline-saturated silicone lead bodies. PMID- 26737579 TI - Analytical description of the slope of the APD-restitution curve to assess the interacting contribution of conduction and repolarization dynamics. AB - The restitution of the action potential duration (APDR) is a mechanism whereby cardiac excitation and relaxation adapt to changes in heart rate. Several studies, mainly carried out in-vitro and in-silico, have demonstrated that a steep APDR curve is associated with increased vulnerability to fatal arrhythmias. However, the mechanisms that link the steepness of the APDR curve to arrhythmogenesis remain undetermined. Although APDR is known to interact with conduction dynamics, few studies have focused on these interactions. In this paper, an analytical expression of the slope of the APDR is derived. This expression explicitly describes the dependency of the slope of the APDR curve on the activation time and/or conduction velocity changes. The study of this expression shows that conduction dynamics are among the main determinants of the slope of the APDR curve. A small absolute increment in the steepness of the activation time restitution slope can cause the steepness of the APDR slope to dramatically increase. Theoretically, the APDR slope quickly diverges to infinity when the increase in activation time matches the decrease in the pacing interval. High density epicardial mapping performed in a patient undergoing open heart surgery, shows excellent agreement between measures of the slope of the APDR curve and its analytical prediction (linear correlation > 0.95). The in-vivo recordings suggest that activation time restitution is the main determinant of the slope of the APDR curve. PMID- 26737580 TI - On how 2?1 conduction block can induce T-wave alternans in the unipolar intracavitary electrogram: Modelling in-vivo human recordings from an ischemic heart. AB - Repolarization alternans is a marker of increased vulnerability to fatal arrhythmias. At the tissue level, in unipolar electrograms (UEGs) recorded on the myocardium, repolarization alternans is often measured as an alternating change of the T-wave, so called T-wave alternans (TWA). During ischemia, UEG-TWA is used as a marker of cardiac instability and is considered as a key parameter to assess pharmacological strategies. However, during ischemia it is not clear whether UEG TWA is a sign of repolarization alternans which may promote 2:1 conduction block, or whether it is induced by ongoing regional 2:1 conduction block. In this study, we first show in-vivo human data recorded during an ischemic event that suggest that 2:1 conduction block induces UEG-TWA beyond the region of 2:1 conduction block. We then develop an analytical forward model of the UEG by coupling an analytical description of the cardiac action potential with a theoretical expression of the UEG, where each UEG is the combination of a local and a remote component and noise. With this model, we were able to generate signals that closely resemble UEGs recorded in-vivo, with a maximum correlation rho > 0.94. Finally, we interrogate the model and demonstrate that whenever 2:1 conduction block is present, UEG-TWA arises as a consequence of alternating imbalance of both the local and remote components of the UEG. The statistical significance of UEG-TWA depends on the interactions between local and remote dynamics and noise.We conclude that in an ischemic model, UEG-TWA is likely to be a sign of 2:1 conduction block, either proximal or distal from the recording site. PMID- 26737581 TI - Far-field effect in unipolar electrograms revisited: High-density mapping of atrial fibrillation in humans. AB - Unipolar electrogram can detect local as well as remote electrical activity of the heart. Information on how the amplitude and morphology of the recorded signal changes with the distance from the source tissue undergoing depolarization can help to better understand unipolar electrograms fractionation and provide insights into the passive conduction properties of the atrial tissue. Ten second unipolar atrial fibrillation (AF) electrograms were recorded using high-density electrode array from the posterior left atrium (LA) and right atrium (RA) of 19 (8 persistent - PERS & 11 paroxysmal - PAF) AF patients undergoing cardiac surgery. Conduction along lines of conduction block was detected in the recorded activation patterns by a proposed automated algorithm. Changes of the amplitude of the unipolar electrogram with increasing distance from the conduction blocks were assessed and compared to predictions of a theoretical model. For each recording, the median far-field decay space constant (FF0.5) was calculated. Overall, we found a significant difference between FF0.5 for patients with paroxysmal and persistent AF. Estimation of maximum FF0.5 from both RA and LA resulted in a mean FF0.5 of 1.5+/-0.2 mm for PERS patients and 2.1+/-0.6 mm for PAF patients (p=0.03). Moreover, detected conduction blocks demonstrated high spatial organization and appeared in distinctive areas of the mapped area in all patients, regardless of the type of AF, while the total number of detected block lines was higher in PERS patients. PMID- 26737582 TI - Electromechanics modeling of the effects of myocardial infarction on left ventricular function. AB - Ventricular remodeling may occur following myocardial infarction of the left ventricle (LV) and such remodeling has been shown to be correlated with increased patient morbidity and mortality. It is thus important to estimate the likelihood of remodeling from the state of the infarcted LV. In this paper, we present simulations from an actively-contracting truncated ellipsoid LV model, incorporating realistic fiber orientation and electromechanical properties, to investigate the effects of infarct size and transmural extent (TME) on myofiber regional mechanics. Results showed that transmural infarcts greatly elevated both the myofiber stress and strain at the border zone during end systole, making the LV more susceptible to structural remodeling. It was found that TME rather than infarct size was more predictive of LV remodeling. PMID- 26737583 TI - Low-energy defibrillation with multi-electrodes stimulation: A simulation study. AB - The objective of this study is to explore the possible ways to reduce defibrillation energy and further reveal the mechanism of electric defibrillation. A bidomain simulation study was performed on a rabbit whole ventricle electrophysiological model and the feasibility of the defibrillation strategy with multi-electrodes stimulation was verified. Simulation results indicate that the new approach is effective in low-energy defibrillation. PMID- 26737584 TI - Carotid arterial blood pressure waveform monitoring using a portable ultrasound system. AB - This work presents a non-invasive arterial blood pressure (ABP) waveform monitoring technique using ultrasound. A portable ultrasound system to excite ultrasound transducers and acquire data is designed with off-the-shelf components. The insonation angles are identified using a vector Doppler technique based on the cosine dependency of the Doppler signals. The pulse pressure of an estimated waveform at the left common carotid artery is compared to the standard sphygmomanometer measurement in a clinical test. The estimated carotid ABP waveform shows excellent agreement to the finger ABP waveform with expected discrepancy of the systolic peak shape due to different measurement sites. The proposed method also tracks slow blood pressure fluctuations. This validation on human subjects shows potential for a noninvasive blood pressure waveform monitoring device at central arterial sites. PMID- 26737585 TI - Pulse rate variability analysis by video using face detection and tracking algorithms. AB - Heart rate variability (HRV) is a physiological parameter which has increased its importance in recent years due to its relationship with the autonomic nervous system (ANS) and cardiovascular disorders. In this work the pulse rate variability (PRV) is measured as a surrogate measurement of HRV using only a video of the face of the subject. Because of pulse rate signals obtained by video are largely affected by the person movements and the analyzed region of interest (ROI), we propose the application of face detection and tracking algorithms as a solution to the artifacts produced by these factors. We compare the obtained results of the proposed method with a pulse sensor signal of a reference system. The statistical analysis results show good agreement between both methods. PMID- 26737586 TI - Accuracy of heart rate variability estimation by photoplethysmography using an smartphone: Processing optimization and fiducial point selection. AB - This work compares several fiducial points to detect the arrival of a new pulse in a photoplethysmographic signal using the built-in camera of smartphones or a photoplethysmograph. Also, an optimization process for the signal preprocessing stage has been done. Finally we characterize the error produced when we use the best cutoff frequencies and fiducial point for smartphones and photopletysmograph and compare if the error of smartphones can be reasonably be explained by variations in pulse transit time. The results have revealed that the peak of the first derivative and the minimum of the second derivative of the pulse wave have the lowest error. Moreover, for these points, high pass filtering the signal between 0.1 to 0.8 Hz and low pass around 2.7 Hz or 3.5 Hz are the best cutoff frequencies. Finally, the error in smartphones is slightly higher than in a photoplethysmograph. PMID- 26737587 TI - Cuffless blood pressure estimation from the carotid pulse arrival time using continuous wave radar. AB - Ambulatory blood pressure monitors based on pulse transit time are limited by the challenge of changing vascular tone. This study focuses on the use of the carotid artery as an alternative location for arterial pulse acquisition. We use continuous wave radio frequency (RF) radar coupled directly to the body to detect the pulse wave signal. We have shown that the blood pressure-pulse transit time calibration using the carotid pulse is as accurate as that of the radial arterial pulse. The results of this investigation may be useful in developing wearable sensors for long-term monitoring of the pulse wave signal at the carotid artery. PMID- 26737588 TI - A simplified method for quantifying the subject-specific relationship between blood pressure and carotid-femoral pulse wave velocity. AB - Devices that estimate blood pressure from arterial pulse wave velocity (PWV) potentially provide continuous, ambulatory blood pressure monitoring. Accurate blood pressure estimation requires reliable quantification of the relationship between blood pressure and PWV. Regression to population normal values or, when using limb artery PWV, changing hydrostatic blood pressure within the limb provides a calibration index. Population lookup tables require accurate anthropometric correlates, assuming no individual variation. Only devices that measure PWV in the limb can use limb position changes. This study proposes a method for developing a calibration curve independent of lookup tables and useful for large artery PWV measurement, such as carotid-femoral PWV (PWVcf). PWVcf was measured in 27 normal subjects (15 female, 36+/-19 years) in both the supine and standing position. The change in systemic pressure was measured and hydrostatic pressure change calculated from estimated vessel path length height, measured using body surface distances. Brachial diastolic blood pressure increased for all subjects from supine to standing (supine 70+/-8 mmHg, standing 83+/-8 mmHg, p<;0.001) with an additional hydrostatic change across the carotid-femoral path length of 19+/-2 mmHg (p<;0.001). PWVcf also increased in all subjects (supine 5.2+/-1.3 m/s, standing 7.3+/-2.2 m/s, p<;0.001). The subject-specific calibration index (DeltaDP/DeltaPWVcf) varied amongst the cohort (20+/-8 mmHg/m/s), was correlated with age (-0.57, p=0.002) and seated aortic systolic pressure (-0.38, p=0.048) and was always greater than zero. Thus, this study describes a simple but novel method of measuring an individualized calibration index using blood pressure and PWV measurements in the supine and standing position. PMID- 26737589 TI - Arterial compliance probe for local blood pulse wave velocity measurement. AB - Arterial compliance and vessel wall dynamics are significant in vascular diagnosis. We present the design of arterial compliance probes for measurement of local pulse wave velocity (PWV). Two designs of compliance probe are discussed, viz (a) a magnetic plethysmograph (MPG) based probe, and (b) a photoplethysmograph (PPG) based probe. The ability of the local PWV probes to consistently capture carotid blood pulse waves is verified by in-vivo trials on few volunteers. The probes could reliably perform repeatable measurements of local PWV from carotid artery along small artery sections less than 20 mm. Further, correlation between the measured values of local PWV using probes and various measures of blood pressure (BP) was also investigated. The study indicates that such arterial compliance probes have strong potential in cuff less BP monitoring. PMID- 26737590 TI - A novel method for quantifying arm motion similarity. AB - This paper proposes a novel task-independent method for quantifying arm motion similarity that can be applied to any kinematic/dynamic variable of interest. Given two arm motions for the same task, not necessarily with the same completion time, it plots the time-normalized curves against one another and generates four real-valued features. To validate these features we apply them to quantify the relationship between healthy and paretic arm motions of chronic stroke patients. Studying both unimanual and bimanual arm motions of eight chronic stroke patients, we find that inter-arm coupling that tends to synchronize the motions of both arms in bimanual motions, has a stronger effect at task-relevant joints than at task-irrelevant joints. It also revealed that the paretic arm suppresses the shoulder flexion of the non-paretic arm, while the latter encourages the shoulder rotation of the former. PMID- 26737591 TI - Kinect One-based biomechanical assessment of upper-limb performance compared to clinical scales in post-stroke patients. AB - This paper presents a Kinect One sensor-based protocol for the evaluation of the motor-performances of the upper limb of neurological patients during rehabilitative sessions. The assessment provides evaluations of kinematic, dynamic, motor and postural control variables. A pilot study was conducted on three post-stroke neurological patients, comparing Kinect-One biomechanical assessment with the outcomes of some of the most common clinical scales for the evaluation of the upper-limb functionality. Preliminary results indicate coherency between the clinical and instrumental evaluation. Moreover, the Kinect One assessment seems to provide some complementary quantitative information, consistently integrating the clinical assessment. PMID- 26737592 TI - Development of the RT-GAIT, a Real-Time feedback device to improve Gait of individuals with stroke. AB - Regaining the ability to walk is a major rehabilitation goal after a stroke. Recent research suggests that, in people with stroke, task-oriented and intensive rehabilitation strategies can drive cortical reorganization and increase activity levels. This paper describes development and pilot testing of a novel wearable device for Real-Time Gait and Activity Improving Telerehabilitation (RT-GAIT), designed for use with such rehabilitation strategies. The RT-GAIT provides auditory or tactile feedback to the individual wearing the platform. The feedback is based on the amount of time spent in stance phase on each foot, as measured by the pressure sensors embedded into the insoles. The system was initially bench validated using sensor signals collected in a previous study. Next, a clinical case study was conducted with one post-stroke individual. The results of the case study suggest that the RT-GAIT device can potentially improve the gait parameters. Mean difference in stance times between the healthy limb and paretic limb was improved by 48% and the standard deviation for the same was improved by 87.5%, between baseline measurements and the measurements taken after the treatment with the RT-GAIT. PMID- 26737593 TI - Effect of interface type in the VR-based acquisition of pedestrian skills in persons with ASD. AB - Possession of 'social' skills is crucial for persons with autism spectrum disorders (ASD) to maintain a certain independence and a better quality of life, and interaction with virtual environments seems an effective learning aid. In a previous study, we reported that in adults with ASD interaction with a virtual environment (a virtual city) is beneficial to the acquisition of pedestrian skills (street crossing and street navigation). Interaction was based on a gesture-based interface (Microsoft Kinect). Here we compare the learning performance when the same virtual environment is operated by a gamepad interface. We used exactly the same training protocol and data analysis than the original study. We found that both interface types are effective in the acquisition of street crossing and city navigation skills. The gamepad interface seems easier to use (thus leading to faster interaction), but gesture-based interfaces are superior in terms of transfer of the learned skills to real road environments (as reported by parents and caregivers). PMID- 26737594 TI - Gait generation for powered Hip-Ankle-Linkage-Orthosis. AB - A hip-knee-ankle-foot orthotic system called 'HALO'(Hip and Ankle Linked Orthosis) for paraplegic walking has been developed in our previous study. Each ankle joint of the HALO system is linked with a medial single joint via a wire which allows both feet of the orthosis to stay always parallel to the floor during walking and assists swinging the leg. The tests of the HALO system demonstrated that it allows smoother walking and easy don/doff. In order to improve further the characteristics of the previous design, we started a new project called pHALO aiming at further reducing of the energy expenditure during walking. As a difference from the previous solution where ankle joints were restrained, the new solution will incorporate two actuators to control the ankle joints angles. As an intermediate step from the development of the pHALO system, in this study we added to the existing system a feedback PI controller to control the ankle joint angle of the right foot in the push-off phase and conducted an experiment to evaluate the effect of the new design on the walking patterns and energy efficiency. The results showed longer stride length, faster gait speed, smaller variation of the CoG, and less energy consumption. PMID- 26737595 TI - Smart Rehabilitation Garment for posture monitoring. AB - Posture monitoring and correction technologies can support prevention and treatment of spinal pain or can help detect and avoid compensatory movements during the neurological rehabilitation of upper extremities, which can be very important to ensure their effectiveness. We describe the design and development of Smart Rehabilitation Garment (SRG) a wearable system designed to support posture correction. The SRG combines a number of inertial measurement units (IMUs), controlled by an Arduino processor. It provides feedback with vibration on the garment, audible alarm signals and visual instruction through a Bluetooth connected smartphone. We discuss the placement of sensing modules, the garment design, the feedback design and the integration of smart textiles and wearable electronics which aimed at achieving wearability and ease of use. We report on the system's accuracy as compared to optical tracker method. PMID- 26737596 TI - Improved decoding of attentional selection in a cocktail party environment with EEG via automatic selection of relevant independent components. AB - Recently it has been shown to be possible to ascertain which speaker a subject is attending to in a cocktail party environment from single-trial (~60s) electroencephalography (EEG) data. The attentional selection of most of subjects could be decoded with a very high accuracy (>90%). However, the performance of many subjects fell below what would be required for a potential brain computer interface (BCI). One potential reason for this is that activity related to the stimuli may have a lower signal-to-noise ratio on the scalp for some subjects than others. Independent component analysis (ICA) is a commonly used method for denoising EEG data. However, its effective use often requires the subjective choice of the experimenter to determine which independent components (ICs) to retain and which to reject. Algorithms do exist to automatically determine the reliability of ICs, however they provide no information as to their relevance for the task at hand. Here we introduce a novel method for automatically selecting ICs which are relevant for decoding attentional selection. In doing so, we show a significant increase in classification accuracy at all test data durations from 60s to 10s. These findings have implications for the future development of naturalistic and user-friendly BCIs, as well as for smart hearing aids. PMID- 26737597 TI - A highly detailed FEM volume conductor model based on the ICBM152 average head template for EEG source imaging and TCS targeting. AB - In electroencephalographic (EEG) source imaging as well as in transcranial current stimulation (TCS), it is common to model the head using either three shell boundary element (BEM) or more accurate finite element (FEM) volume conductor models. Since building FEMs is computationally demanding and labor intensive, they are often extensively reused as templates even for subjects with mismatching anatomies. BEMs can in principle be used to efficiently build individual volume conductor models; however, the limiting factor for such individualization are the high acquisition costs of structural magnetic resonance images. Here, we build a highly detailed (0.5mm(3) resolution, 6 tissue type segmentation, 231 electrodes) FEM based on the ICBM152 template, a nonlinear average of 152 adult human heads, which we call ICBM-NY. We show that, through more realistic electrical modeling, our model is similarly accurate as individual BEMs. Moreover, through using an unbiased population average, our model is also more accurate than FEMs built from mismatching individual anatomies. Our model is made available in Matlab format. PMID- 26737598 TI - Seizure prediction using polynomial SVM classification. AB - This paper presents a novel patient-specific algorithm for prediction of seizures in epileptic patients with low hardware complexity and low power consumption. In the proposed approach, we first compute the spectrogram of the input fragmented EEG signals from a few electrodes. Each fragmented data clip is ten minutes in duration. Band powers, relative spectral powers and ratios of spectral powers are extracted as features. The features are then subjected to electrode selection and feature selection using classification and regression tree. The baseline experiment uses all features from selected electrodes and these features are then subjected to a radial basis function kernel support vector machine (RBF-SVM) classifier. The proposed method further selects a small number features from the selected electrodes and train a polynomial support vector machine (SVM) classifier with degree of 2 on these features. Prediction performances are compared between the baseline experiment and the proposed method. The algorithm is tested using intra-cranial EEG (iEEG) from the American Epilepsy Society Seizure Prediction Challenge database. The baseline experiment using a large number of features and RBF-SVM achieves a 100% sensitivity and an average AUC of 0.9985, while the proposed algorithm using only a small number of features and polynomial SVM with degree of 2 can achieve a sensitivity of 100.0%, an average area under curve (AUC) of 0.9795. For both experiments, only 10% of the available training data are used for training. PMID- 26737599 TI - MR-compatible hand exoskeleton for monitoring brain activity during active assistance. AB - This work presents the mechanical design, implementation and evaluation of an MR compatible hand exoskeleton that provides real-time monitoring of the joint angle, angular velocity and joint force produced by the MCP joint of the four fingers in an fMRI scanner. For force measurement, a novel optical type force sensor has been designed and implemented. The proposed hand exoskeleton is also capable of providing computer controlled assistive and resistive forces to the MCP joints using a non-magnetic ultrasonic motor, which allows the investigation of the brain activity during both passive (non-voluntary) and active (voluntary) movements. The MR-compatibility of the system was verified based on the analysis of SNR images of phantom tests and by the acquisition of human brain images. PMID- 26737600 TI - Recovering HRFs from overlapping ROIs in fMRI data using thresholding correlations for sparse dictionary learning. AB - Recovering region-specific hemodynamic response function (HRF) in noisy fMRI data is essential to characterize the temporal dynamics of functionally coherent brain regions during activation. Data-driven techniques not based on sparsity fails to recover sub-region HRFs from overlapping regions of interest (ROIs) in task related activations. This paper exploits spatial sparsity for recovering distinct HRFs from un-delineated overlapping ROIs in fMRI data. Spatial sparsity is realized using thresholding correlation for dictionary learning. The effectiveness of the proposed procedure is illustrated on both simulated and an experimental fMRI data obtained during a visual-task. PMID- 26737601 TI - Distinction of individual finger responses in somatosensory cortex using ECoG high-gamma activation mapping. AB - This study demonstrates the feasibility of high-gamma activity mapping for localization of somatosensory finger areas in the human brain. Identification of functional brain regions is important in surgical planning, such as for resections of epileptic foci or brain tumors. The mapping procedure is done using electrocorticography (ECoG), an invasive technique in which electrical brain signals are acquired from the cortical surface. Two epilepsy patients with implanted electrode grids participated in the study. Data were collected during a vibrotactile finger stimulation paradigm and showed significant cortical activation (p <; 0.001) in the high-gamma range over the contralateral somatosensory cortex. The results are consistent with previous studies that used fMRI in test subjects without implanted electrodes. Therefore, the results suggest that localizing the cortical representations of the fingers in clinical practice using ECoG is feasible, even without the patient's active participation. PMID- 26737602 TI - Study on the human perception of incipient and overall slippages using a 2D FE fingertip model. AB - Slippage on the fingertips is an important phenomenon that occurs constantly in our daily life. However, the mechanism behind the slippage, especially incipient slippage, which appears prior to overall slippage, has not been fully understood. In this paper, a 2D finite element (FE) model of the human fingertip was presented to study how the human fingertip perceives slippages. The 2D geometries of the fingertip were generated based on magnetic resonance (MR) images. The fingertip model consisted of four layers: epidermis, dermis, subcutaneous tissue, and distal phalanx. The microstructures of the intermediate and limiting ridges in between the epidermis and dermis layers were manually constructed to locate four types of mechanoreceptors. Simulations of pushing and sliding motions were implemented, and mechanical measures of the acceleration and strain energy density (SED) were investigated at the locations of the mechanoreceptors. We found that both incipient and overall slippages could be clearly detected using the acceleration signal captured by the FA-I and SA-I receptors. The SED measurement does not provide useful information for the slippage detection. PMID- 26737603 TI - Human precision manipulation workspace: Effects of object size and number of fingers used. AB - Precision manipulation, or moving small objects in the fingertips, is important for daily tasks such as writing and key insertion, as well as medically relevant tasks such as scalpel cuts and surgical teleoperation. While fingertip force coordination has been studied in some detail, few previous works have experimentally studied the kinematics of human precision manipulation with real objects. The present work focuses on studying the effects of varying object size and the number of fingers used on the resulting manipulation workspace, or range of motions that the object can be moved through. To study object size effects, seven bar-shaped objects ranging from 20 to 80 mm length were tested; after scaling object length to the equivalent for a 17.5 cm hand, the peak volume was obtained for 48-59 mm object length range (23% above average), and the minimum volume was obtained for the smallest 17-27 mm range (72% of average). 50 mm and 80 mm circular objects were used to study the effect of using different numbers of fingers; the five-finger manipulation volume dropped to less than half the two finger volume (p<;0.001). We anticipate these results will be useful in designing devices such as hand held tools, as well as in designing protocols for effectively testing and rehabilitating hand function. Finally, the results can provide a benchmark for the manipulation capability of prosthetic hands. PMID- 26737604 TI - An ergonomic handheld ultrasound probe providing contact forces and pose information. AB - This paper presents a handheld ultrasound probe which is integrated with sensors to measure force and pose (position/orientation) information. Using an integrated probe like this, one can relate ultrasound images to spatial location and create 3D ultrasound maps. The handheld device can be used by sonographers and also easily be integrated with robot arms for automated sonography. The handheld device is ergonomically designed; rapid attachment and removal of the ultrasound transducer itself is possible using easy-to-operate clip mechanisms. A cable locking mechanism reduces the impact that gravitational and other external forces have (originating from data and power supply cables connected to the probe) on our measurements. Gravitational errors introduced by the housing of the probe are compensated for using knowledge of the housing geometry and the integrated pose sensor that provides us with accurate orientation information. In this paper, we describe the handheld probe with its integrated force/pose sensors and our approach to gravity compensation. We carried out a set of experiments to verify the feasibility of our approach to obtain accurate spatial information of the handheld probe. PMID- 26737605 TI - Electrodermal activity analysis during affective haptic elicitation. AB - This paper investigates how the autonomic nervous system dynamics, quantified through the analysis of the electrodermal activity (EDA), is modulated according to affective haptic stimuli. Specifically, a haptic display able to convey caress like stimuli is presented to 32 healthy subjects (16 female). Each stimulus is changed according to six combinations of three velocities and two forces levels of two motors stretching a strip of fabric. Subjects were also asked to score each stimulus in terms of arousal (high/low activation) and valence (pleasant/unpleasant), in agreement with the circumplex model of affect. EDA was processed using a deconvolutive method, separating tonic and phasic components. A statistical analysis was performed in order to identify significant differences in EDA features among force and velocity levels, as well as in their valence and arousal scores. Results show that the simulated caress induced by the haptic display significantly affects the EDA. In detail, the phasic component seems to be inversely related to the valence score. This finding is new and promising, since it can be used, e.g., as an additional cue for haptics design. PMID- 26737606 TI - Micro-needle electro-tactile display. AB - Haptic feedback is strongly demanded for high-precision robot-assisted surgery and teleoperation. The haptic feedback consists of force and tactile feedback, however tactile feedback has been little studied and the size and weight of the system poses challenges for practical applications. In this paper we propose a sheet-type wearable electro-tactile display which provides tactile sensations to the user as the feedback at a low voltage and power consumption. The display possesses needle-shaped electrodes, which can penetrate through the high impedance stratum corneum. We developed the fabrication process and, as the first step, we investigated the tactile sensation that can be created to the fingertip by the display. Rough and smooth surfaces were successfully presented to the user. Then, we characterized the tactile display when used on the forearm, in particular, with respect to the spatial resolution. These tactile displays can be used to inform the user of the surface property of the parts of interest, such as tumor tissues, and to guide him in the manipulation of surgery robots. PMID- 26737607 TI - Rotational ranges of human precision manipulation when grasping objects with two to five digits. AB - The ability to move and manipulate objects within the hand is important for the overall performance of the human hand. Such movements are key for many tasks, including writing, using precision tools, turning knobs, and operating various haptic interfaces. In this work we analyze the ability of 17 unimpaired subjects to rotate objects 50 and 80 mm in diameter using 2 to 5 digits, while maintaining the initial finger-object contact locations. Subjects were asked to rotate the object with a particular number of fingers around one of three orthogonal hand axes for 30 seconds and explore their rotational range. The average rotational range achieved over all conditions was 47 degrees, with the largest rotation of 82 degrees for the 3 digit case around a distal-proximal axis. The rotations around the palmar-dorsal and the ulnar-radial axes showed similar trends, where the smaller object resulted in 1.3 and 1.2 times larger rotation workspaces than the larger object (p <; 0.001), respectively. The rotation around the distal proximal axis has a different trend, where the difference in rotation amplitude between different number of finger conditions is over 50% (p <; 0.003), but the difference in object size conditions is only 10%. The results highlight that the orientation of the rotation axis has significant influence on the rotation capabilities of the human hand. In designing handheld tools and haptic devices one should carefully consider around which axes a rotation is required. PMID- 26737608 TI - Finite-element-modeling of egg white as a substitute for tissue coagulation during bipolar radiofrequency-induced thermofusion. AB - Radiofrequency-induced thermofusion is a frequently used electrosurgical procedure for the sealing of blood vessels. A disadvantage of vessel sealing instruments is that the generated thermal energy spreads to the surrounding tissue and may irreversibly damage it. This is particularly problematic when operating close to sensitive structures such as nerves. Given their advantages, there is nonetheless a lot of interest in using bipolar vessel sealing for surgical procedures. To select instruments that may be safely used in such cases, it is important to reliably quantify the thermal spread to the surrounding tissue. Mathematical models can help to evaluate the transient behavior, that is the evolution of the thermal spread over time, more precisely. A finite element model allows for a detailed analysis of inhomogeneities in the spatial temperature distribution. As a first step towards a finite model of the bipolar vessel sealing process, a model of the coagulation of chicken egg white is presented here. Egg white has thermal and electrical properties that are very similar to tissue, making it suitable as a substitute for the analysis of the coagulation process. It has the additional advantage, that the spatial and temporal evolution of the thermal spread can be visually gauged. The presented model describes the experimentally observed spatial temperature distribution, the shape of the coagulated egg white, and the formation of hotspots. Furthermore, it is shown that the model can correctly predict the shape of the coagulated egg white in further experiments. PMID- 26737609 TI - Analysis of power deposition and temperature rise due to presence of an implant inside a 1.5 t MRI RF coil. AB - We numerically investigated power deposition and temperature rise generated due to the presence of a titanium rod placed in a phantom, located inside a 1.5 T coil. The induced power deposition and temperature rise normalized to incident tangential electric field was found to be dependent on distance to the phantom wall. The different dependence of the integral of power deposition over a box surrounded the rod and the temperature rise on American Society for Testing and Materials (ASTM) phantom medium electrical conductivity was observed. The consequences of numerical domain simplification have been analyzed. PMID- 26737610 TI - Modeling the impact of spinal cord stimulation paddle lead position on impedance, stimulation threshold, and activation region. AB - The effectiveness of spinal cord stimulation (SCS) for chronic pain treatment depends on selection of appropriate stimulation settings, which can be especially challenging following posture change or SCS lead migration. The objective of this work was to investigate the feasibility of using SCS lead impedance for determining the location of a SCS lead and for detecting lead migration, as well as the impact of axial movement and rotation of the St. Jude Medical PENTATM paddle in the dorsal-ventral or medial-lateral directions on dorsal column (DC) stimulation thresholds and neural activation regions. We used a two-stage computational model, including a finite element method model of field potentials in the spinal cord during stimulation, coupled to a biophysical cable model of mammalian, myelinated nerve fibers to calculate tissue impedance and nerve fiber activation within the DC. We found that SCS lead impedance was highly sensitive to the distance between the lead and cerebrospinal fluid (CSF) layer. In addition, among all the lead positions studied, medial-lateral movement resulted in the most substantial changes to SC activation regions. These results suggest that impedance can be used for detecting paddle position and lead migration, and therefore for guiding SCS programming. PMID- 26737611 TI - Unintentional heating at implants when using electrosurgery. AB - Electrosurgery is a commonly used device in the operating room, but it has some adverse effects, which are only partly described in literature. Interference issues are well described, but unintended heating in and around implants is not well studied. We simulated different scenarios using a Finite Element Model to investigate unintended heating caused by electrosurgery. We looked at different shapes, sizes, and active electrode placements. We found that all these factors play a role in the amount of heating. PMID- 26737612 TI - Fast and stable guidewire simulator for minimally invasive vascular surgery. AB - In recent years, minimally invasive vascular surgery is widely applied in treatment of cardiovascular diseases, and the manipulation of the guidewire is the essential skill for this surgery. Lots of time and money have to be taken to achieve the skill. In this paper, we present a multithreading guidewire simulator which can help the apprentice to gain the skill and modeling the guidewire is the core technique of the simulator. The guidewire is modeled by a fast and stable method based on the Cosserat theory of elastic rods. The method describes the behavior of the guidewire with the Lagrange equations of motion and it uses the penalty method to maintain constraints. We further propose a simplified solving procedure for the guidewire model. Finally, some experiments are conducted to evaluate the effectiveness of this model. PMID- 26737613 TI - Design of site-directed magnetic targeting system in acute spinal cord injury. AB - Effective repair immediately after spinal cord injury can improve the prognosis of the patient. Injection of membrane resealing nanomaterial is one of the most promising technique to repair the membrane. In order to improve the retention rate of membrane repair material at injury site, membrane resealing nanomaterial can be combined with magnetic nanoparticle and magnetic targeting system. In this paper, a special site directed magnetic targeting system, which contain a C shaped permanent magnet and a ferromagnetic needle, was constructed. Simulation was conducted to analyze the influence of the shape of needle on the magnetic field to provide magnetic force large enough to make the magnetic particles stay at the target site. Results showed that the appearance of ferromagnetic needle raised both the strength and the gradient of magnetic field at the target site. Moreover, with similar apex angles, longer needles with larger diameters can produced lager magnetic field, but smaller needles has better focal area at the small injury site in spinal cord injury. These results provide a basis for design and fabrication of ferromagnetic needles when the targeting system is applied in future experiments. PMID- 26737614 TI - Sudden cardiac arrest risk stratification based on 24-hour Holter ECG statistics. AB - This study examined the feasibility of using indices obtained from a long term Holter ECG record for sudden cardiac arrest (SCA) risk stratification. The ndices tested were the QT-RR interval co-variability and the alternans ratio percentile (ARP(theta)) which is defined as the theta(th) percentile of alternans ratios over a 24 hour period. The QT-RR interval co-variabilities are evaluated by the serial correlation coefficient between QT and RR trend sequences (QTRC). Previously reported Kalman filter technique and a simple smoothing spline method for the trend estimation are compared. Parameter theta in the alternans ratio percentile index was optimized to achieve the best classification accuracy. These indices were estimated from 26 cardiovascular outpatients for Holter ECG record. Patients were classified into high and low risk groups according to their clinical diagnosis, and the obtained indices were compared with those of 25 control subjects. A risk stratification using the two indices QTRC and ARP(theta) yielded an average sensitivity of 0.812 and a specificity of 0.925. The sensitivities and specificities of all three categories exceeded 0.8 except for the sensitivity to detect the high-risk patient group. Other short-term ECG parameters may need to be incorporated in order to improve the sensitivity. PMID- 26737615 TI - Ventricular ectopic beats classification using Sparse Representation and Gini Index. AB - In this study, we consider using sparse representation and the Gini Index (GI) for Arrhythmia classification. Our approach involves, first, designing a separate dictionary for each Arrhythmia class using a set of labeled training QRS complexes. Sparse representations, based on the designed dictionaries, of each new test QRS complex are then calculated. Its class is finally predicted using the winner-takes-all principle; that is, the class associated with the highest GI is chosen. Our experiments showed promising results for the classification of premature ventricular contractions using a patient-specific approach. For many of the subjects considered, our classifier attained accuracies close to 100 % on the test set. PMID- 26737616 TI - A supervised learning approach for the robust detection of heart beat in plethysmographic data. AB - Wearable devices equipped with photoplethysmography (PPG) sensors are gaining an increased interest in the context of biometric signal monitoring within clinical, e-health and fitness settings. When used in everyday life and during exercise, PPG traces are heavily affected by artifacts originating from motion and from a non constant positioning and contact of the PPG sensor with the skin. Many algorithms have been developed for the estimation of heart-rate from photoplethysmography signals. We remark that they were mainly conceived and tested in controlled settings and, in turn, do not provide robust performance, even during moderate exercise. Only a few of them have been designed for signals acquired at rest and during fitness. However, they provide the required resilience to motion artifacts at the cost of using computationally demanding signal processing tools. At variance with other methods from the literature, we propose a supervised learning approach, where a classifier is trained on a set of labelled data to detect the presence of heart beats at each position of a PPG signal, with only little preprocessing and postprocessing. We show that the results obtained on the TROIKA dataset using our approach are comparable with those shown in the original paper, providing a classification error of 14% in the detection of heart beat positions, that reduces to 2.86% on the heart-rate estimates after the postprocessing step. PMID- 26737617 TI - Large-scale physiological waveform retrieval via locality-sensitive hashing. AB - We propose a fast, scalable locality-sensitive hashing method for the problem of retrieving similar physiological waveform time series. When compared to the naive k-nearest neighbor search, the method vastly speeds up the retrieval time of similar physiological waveforms without sacrificing significant accuracy. Our result shows that we can achieve 95% retrieval accuracy or better with up to an order of magnitude of speed-up. The extra time required in advance to create the optimal data structure is recovered when query quantity equals 15% of the repository, while the method incurs a trivial additional memory cost. We demonstrate the effectiveness of this method on an arterial blood pressure time series dataset extracted from the ICU physiological waveform repository of the MIMIC-II database. PMID- 26737618 TI - A multi-feature based morphological algorithm for ST shape classification. AB - Abnormal ST segment is an important parameter for the diagnosis of myocardial ischemia and other heart diseases. As most abnormal ST segments sustain for only a few seconds, it is impractical for the doctors to detect and classify abnormal ones manually on time. Even though many ST segment classification algorithms are proposed to meet the rising demand of automatic myocardial ischemia diagnosis, they are often with lower recognition rate. The aim of this study is to detect abnormal ST segments precisely and classify them into more categories, and thus provide more detailed category information to help the clinicians make decisions. This study sums up ten common abnormal ST segments according to the clinical ECG records and proposes a morphological classification algorithm of ST segment based on multi-features. This algorithm consists of two parts: Feature points extraction and ST segment classification. In the first part, R wave is detected by using the 2B-spline wavelet transform, and mode-filtering method and morphological characteristics are used for other feature points extraction. In the ST segment classification process, ST segment level, variance, slope value, number of convex/concave points and other feature parameters are employed to classify the ST segment. This algorithm can classify abnormal ST segments into ten categories above. We evaluated the performance of the proposed algorithm based on ECG data in the European ST-T database. The global recognition rate of 92.7% and the best accuracy of 97% demonstrated the effectiveness of the proposed solution. PMID- 26737619 TI - ECG biometric identification: A compression based approach. AB - Using the electrocardiogram signal (ECG) to identify and/or authenticate persons are problems still lacking satisfactory solutions. Yet, ECG possesses characteristics that are unique or difficult to get from other signals used in biometrics: (1) it requires contact and liveliness for acquisition (2) it changes under stress, rendering it potentially useless if acquired under threatening. Our main objective is to present an innovative and robust solution to the above mentioned problem. To successfully conduct this goal, we rely on information theoretic data models for data compression and on similarity metrics related to the approximation of the Kolmogorov complexity. The proposed measure allows the comparison of two (or more) ECG segments, without having to follow traditional approaches that require heartbeat segmentation (described as highly influenced by external or internal interferences). As a first approach, the method was able to cluster the data in three groups: identical record, same participant, different participant, by the stratification of the proposed measure with values near 0 for the same participant and closer to 1 for different participants. A leave-one-out strategy was implemented in order to identify the participant in the database based on his/her ECG. A 1NN classifier was implemented, using as distance measure the method proposed in this work. The classifier was able to identify correctly almost all participants, with an accuracy of 99% in the database used. PMID- 26737620 TI - Fetal heart rate feature extraction from cardiotocographic recordings through autoregressive model's power spectral- and pole-based analysis. AB - The main objective of this work is to perform an autoregressive model (AR)-based power spectral analysis of the fetal heart rate (FHR) signal for the extraction of significant features for fetal welfare assessment. A group of features is directly computed from the AR-based spectrum while another group is computed from the poles representation. The presented method is applied to real cardiotocographic (CTG) signals and for different frequency bands, and the obtained results are very promising as they exhibit direct correlations between the extracted features and the fetal welfare in terms of umbilical pH. PMID- 26737621 TI - Monitoring the fetal heart rate variability during labor. AB - In respect to the main goal of our ongoing work for estimating the heart rate variability (HRV) from fetal electrocardiogram (FECG) signals for monitoring the health of the fetus, we investigate in this paper the possibility of extracting the fetal heart rate variability (HRV) directly from the abdominal composite recordings. Our proposed approach is based on a combination of two techniques: Periodic Component Analysis (PiCA) and recursive least square (RLS) adaptive filtering. The Fetal HRV of the estimated FECG signal is compared to a reference value extracted from an FECG signal recorded by using a spiral electrode attached directly to the fetal scalp. The results obtained show that the fetal HRV can be directly evaluated from the abdominal composite recordings without the need of recording an external reference signal. PMID- 26737622 TI - Electrohysterographic detection of uterine contractions in term pregnancy. AB - Uterine-contraction detection is a fundamental component of pregnancy monitoring. Electrohysterography (EHG) provides a non-invasive and accurate alternative to intrauterine pressure (IUP) measurements, and several techniques provide an estimated IUP (eIUP) based on the EHG alone. Commonly, EHG contraction detection is based on amplitude thresholding of the eIUP. We aim at improving the reliability of contraction detection, such that automatic contraction detection can be realized. An algorithm for template-matching of the eIUP signal is proposed. This method is based on Bayesian evidence using a Gaussian likelihood function to classify uterine activity. Gaussian templates are matched to the input signal, with weights obtained empirically from manually-annotated contraction events in a training data-set. The results show an improvement in contraction detection accuracy compared to threshold-based methods. The template matching method is adaptable to relevant features in the input training data, and is thus less sensitive to differences in eIUP derivation or measurement variability. The method allows for improved automatic uterine contraction detection in labor EHG data, while being extensible to e.g. preterm contraction detection. PMID- 26737623 TI - Uncovering statistical features of bradycardia severity in premature infants using a point process model. AB - Premature infants are susceptible to a variety of life-threatening events. Underdeveloped cardiovascular control due to an immature autonomic nervous system can lead to recurrent bradycardias that reduce blood flow and oxygen to critical organs, and result in long-term developmental disabilities or sudden death. In this study, we investigate the use of a novel point process framework to model heart rate dynamics in premature infants, including the full range of bradycardia severity. We find that the lognormal distribution accurately models the R-R interval time series, due to the long-tail nature of the distribution. We also find that the degree of bradycardia severity is correlated with distinct clustering features of the point-process indices in regions encompassing and adjacent to bradycardias. This underlying property in heart rate dynamics may provide valuable statistical information for quantifying the vulnerability of premature infants to develop bradycardia. PMID- 26737624 TI - Improvement of an automated neonatal seizure detector using a post-processing technique. AB - Visual recognition of neonatal seizures during continuous EEG monitoring in neonatal intensive care units (NICUs) is labor-intensive, has low inter-rater agreement and requires special expertise that is not available around the clock. Development of an accurate automated seizure detection system with a low false alarm rate will support clinical decision making and alleviate significantly the workload. However, this is an ongoing difficult challenge for engineers as the neonatal EEG signal is non-stationary and often includes complex patterns of seizures and artifacts. In this study, we show an improvement of our previously developed neonatal seizure detector (developed using heuristic if-then rules). In order to improve the detection accuracy, mean phase coherence as a new feature is used to characterize artifacts and also support vector machine is applied to perform the post-processing step to remove false detections. As a result, the false alarm rate drops 42% (from 2.6 h(-1) to 1.5 h(-1)), whereas the good detection rate reduces only by 4%. PMID- 26737625 TI - Assessment of quality of ECG for accurate estimation of Heart Rate Variability in newborns. AB - Heart Rate Variability has been recently used to determine the severity of Hypoxic Ischemic Encephalopathy in neonates. However, it was shown that ECG and subsequently Instantaneous Heart Rate can be heavily corrupted by artefacts which have to be manually removed. This work analyses a set of features to assess their sensitivity to normal and corrupted ECG in newborns. Specifically, the IHR signal is obtained by detecting R-Peaks using the Pan-Tompkins algorithm. Four features are extracted from both ECG and IHR signal using various temporal resolutions to discriminate normal and corrupted signal. The performance of these features in discrimination is then assessed using statistical tests. PMID- 26737626 TI - Rapid three dimensional two photon neural population scanning. AB - Recording the activity of neural populations at high sampling rates is a fundamental requirement for understanding computation in neural circuits. Two photon microscopy provides one promising approach towards this. However, neural circuits are three dimensional, and functional imaging in two dimensions fails to capture the 3D nature of neural dynamics. Electrically tunable lenses (ETLs) provide a simple and cheap method to extend laser scanning microscopy into the relatively unexploited third dimension. We have therefore incorporated them into our Adaptive Spiral Scanning (SSA) algorithm, which calculates kinematically efficient scanning strategies using radially modulated spiral paths. We characterised the response of the ETL, incorporated its dynamics using MATLAB models of the SSA algorithm and tested the models on populations of Izhikevich neurons of varying size and density. From this, we show that our algorithms can theoretically at least achieve sampling rates of 36.2Hz compared to 21.6Hz previously reported for 3D scanning techniques. PMID- 26737627 TI - Low-cost surface reconstruction for aesthetic results assessment and prediction in breast cancer surgery. AB - The high incidence and low mortality of breast cancer surgery has led to an increasing emphasis on the cosmetic outcome of surgical treatment. Advances in aesthetic evaluation, as well as surgical planning and outcome prediction, have been investigated by using geometrically precise 3D modelling of the breast surface prior to surgery and after the procedure. However, existing solutions are based on expensive site specific setups and remain weakly validated. In this paper, we explore the possibility of using low-cost RGBD cameras as an affordable and mobile system for breast surface reconstruction. The methodology relies on sensor calibration, uncertainty-driven point filtering, dense reconstruction and subsequent multi-view joint optimization to diffuse residual pose errors. Results from a phantom study, with ground truth obtained through commercially available scanners, indicate that the approach is promising with RMS errors in order of 2 mm. A clinical study shows the practical applicability of our method and compares favourably to high-end scanning solutions. PMID- 26737628 TI - Compact laser illumination system for endoscopic interventions. AB - External cold light sources as well as LEDs are commonly used for abdominal illumination in minimally invasive surgery. Still, both feature certain disadvantages. A new illumination system for endoscopes based on laser diodes is placed in the handle. No external light cables are needed. High conversion and coupling efficiencies and small package size allow for several diodes to be integrated, enabling color mixing and the adjustment of color temperatures. An optical module to collimate and combine the light is described. The heat to be dissipated is stored in a passive latent heat storage based on phase change materials surrounding the optical module. Thereby, operation time is considerably extended, as the handle's temperature is stabilized. To reduce the negative effect of coherent light on optical rough surfaces leading to patterns of spots, several devices for speckle reduction are developed and tested. By combining these components, an assembly of a powerful RGB laser light module for the integration in standard sized endoscopes is formed. PMID- 26737629 TI - Spectral study of metabolism-based autofluorescence and white-light reflectance for endoscopic tumor imaging. AB - Metabolism-based autofluorescence redox imaging is one of the promising options for non-invasive screening of digestive tumors. In this paper, autofluorescence from fluorescent coenzymes such as NADH and FAD related to cellular metabolism as well as total hemoglobin and oxygen saturation are analyzed based on a point spectrum. As a redox index based on the metabolism, the ratio of the 450nm-490nm fluorescence intensities for 365nm and 405nm excitation wavelengths (F365/F405) is used. Although F365/F405 is a good index in many samples, inversion and weakened contrast are observed. A Simplified models with and without collagen based on Lambert-Beer law are built to explain how F365/F405 depicts the tumor region. PMID- 26737630 TI - Self-contained diffuse optical imaging system for real-time detection and localization of vascular occlusions. AB - Free flap surgery is a procedure where healthy tissue is transferred from a donor site to a recipient site of the body to fill a defect without maintaining the original blood supply to the flap. The anastomosis of the vascular network of the flap to the blood vessels adjacent to the recipient site has associated risks of arterial and/or venous occlusions that must be promptly detected to avoid temporary or permanent tissue damage. In this work, we present a skin-contact diffusion optical imaging (DOI) system able to continuously provide a three dimensional representation of the flap oxygenation to promptly detect vascular occlusions potentially occurring in the flap. Multiple near-infrared LEDs and photodetectors were embedded into a self-contained optical sensor for prolonged monitoring of concentration changes of oxygenated (HbO) and deoxygenated hemoglobin (HbR) at multiple locations and depths. A time-efficient algorithm mapped measured oxygenation changes in a three-dimensional volume to allow surgeons and clinical personnel to detect and localize abnormal blood perfusion changes during or after surgery, in time for corrective intervention. The image reconstruction algorithm was validated using computerized flap models in which oxygenation was synthetically altered, whereas the optical system was preliminarily tested on a healthy forearm simulating a flap undergoing arterial and venous occlusions, proving the feasibility of implementing DOI in the form of a wearable patch for prolonged perfusion monitoring. PMID- 26737631 TI - The cerebral blood flow response dependency on stimulus pulse width is affected by stimulus current amplitude - a study of activation flow coupling. AB - The coupling of cerebral blood flow (CBF) to neuronal activation, referred to as activation flow coupling (AFC), has been a fundamental brain physiology property. The stimulus-evoked CBF response was usually considered as a surrogate marker for neuronal activity in AFC studies. The selection of appropriate stimulation parameters, e.g., current amplitude and pulse width, is of great importance yet the effect of pulse width changes remained contradictory in previous studies. In this work, we use laser speckle contrast imaging (LSCI) to study the spatiotemporal CBF response to hindpaw somatosensory stimulation of different pulse widths (0.3 ms vs 1 ms) and current amplitudes (3 mA vs 6 mA) in a rodent experiment. The results showed that the change of pulse width significantly affected the CBF peak value at a lower current level (p<;0.05). In addition, the duration for observing significantly different average CBF response, denoted as td, at various pulse widths, was dependent on stimulus current amplitude. At a lower amplitude (3 mA), td was 6.5 s; While at a higher amplitude (6 mA), td was 2.5 s. It was indicated that the changes of pulse width had longer influence on the average CBF response at a lower current amplitude. Our findings may help to understand and explain the inconsistent AFC with different stimulation parameters in fundamental brain physiology. PMID- 26737632 TI - Microfluidic paper-based analytical devices for colorimetric detection of urinary tract infection biomarkers on adult diapers. AB - Urinary tract infections (UTI) are common infection diseases in elderly patients. The conventional method of detecting UTI involves the collection of significant urine samples from the elderly patients. However, this is a very difficult and time-consuming procedure. This paper addresses the development of a microfluidic paper-based analytical device (MUPAD) to detect UTI from urine collected from adult diapers. The design and fabrication for the MUPAD is shown. The fabrication process involves melting solid wax on top of filter paper using a hot plate, followed by pattern transfer using a mold with rubbed wax. To demonstrate the feasibility of the proposed method, the MUPAD with deposited nitrite reagent had detected different concentrations of nitrite solutions from 0.5 ppm to 100 ppm spiked in urine samples. A calibration curve was obtained by plotting the gray scale intensity values against the various nitrite concentrations. The results showed that the proposed paper-based device holds great potential as low-cost, disposable solution to sensitively detect UTI markers in urine sampled from diapers. PMID- 26737633 TI - Development of hydrogel microtubes for microbe culture in open environment. AB - This paper describes a microbe culture system in an open environment using hydrogel microtubes. In recent years, oil production microbes, such as Aurantiochytrium, have been found and are studied to produce fuels of new age instead of fossil fuels. Biomass production by microbes is promising, where scale up, collection of the products and competition against other microbes are the most important challenges. Here, we propose to use hydrogel microtubes to encapsulate, culture, and protect microbes. The tubes can be micro- and mass fabricated. They allow oxygen and nutrition to go through while they prevent competitive microbes from intruding inside. The microbes and byproducts can be collected together with the tubes. In this paper, we demonstrate the proof-of concepts experiments: we fabricated hydrogel micro tubes and cultured Coryne glutamicum which produce lactic acid inside the tubes. The microbes were increased inside the tubes and protected even when competitive microbes existed in the culture media. Furthermore, we demonstrated how to collect microbes inside the tubes. PMID- 26737634 TI - Toad's egg-like cultivation process for forming microcarriers from nanofibrous hydrogel. AB - This paper proposes a new method for generating microcarries from bacterial cellulose (BC). BC, which is produced by specific bacteria, is a hydrogel composed of a three dimensional network structure formed by cellulose nanofibers. BC as an ECM-like nanofibrous material exhibits an excellent environment for cellular adhesion. Moreover, BC has a high biocompatibility and mechanical strength. From these properties, BC is expected to be applied for microcarriers, which is used for cultivating anchorage-dependent cells. Then, we developed a microfabrication process to create BC microcarriers by using gelatin microspheres as sacrificial architectures. In addition, the monodispersity of the formed BC microcarreirs was investigated. PMID- 26737635 TI - Monitoring time course of human whole blood coagulation using a microfluidic dielectric sensor with a 3D capacitive structure. AB - This paper reports on the design, fabrication, and testing of a microfluidic sensor for dielectric spectroscopy (DS) of human whole blood during coagulation. The sensor employs a three-dimensional (3D), parallel-plate, capacitive sensing structure with a floating electrode integrated into a microfluidic channel. Using an impedance analyzer and after a 5-point calibration, the sensor is shown to measure the real part of complex relative dielectric permittivity of human whole blood in a frequency range of 10kHz to 100MHz. The temporal variation of dielectric permittivity at 1MHz for human whole blood from three different healthy donors shows a peak in permittivity at ~ 4 to 5 minutes, which also corresponds to the onset of CaCl2-initiated coagulation of the blood sample verified visually. PMID- 26737636 TI - Manufacturing of microcirculation phantoms using rapid prototyping technologies. AB - In this paper, we describe a method for the manufacturing of a microcirculation phantom that may be used to investigate hemodynamics using optics based methods. We made an Acrylonitrile Butadiene Styrene (ABS) negative mold, manufactured in a Fused Deposition Modelling (FDM) printer, embedded it in Polydimethysilioxane (PDMS) and dissolved it from within using acetone. We successfully made an enlarged three-dimensional (3D) network of microcirculation, and tested it using red blood cell (RBC) analogues. This phantom may be used for testing medical imaging technology. PMID- 26737637 TI - Controlled thermal-sensitive liposomes release on a disposable microfluidic device. AB - High intensity focused ultrasound (HIFU) triggered drug release as one of promising approaches for local drug delivery is gaining more attention as ultrasound allows the deposition of the thermal and mechanical energies to a specific localized region in a noninvasive manner. Release of encapsulated drugs from a nano-carrier such as liposome could further achieve a higher local drug concentration and reduce the toxicity effects under the stimulus of temperature elevation. This paper presents a micro HIFU (MHIFU) microfluidic device to enable mimic the bulky HIFU transmission system without the need of high power consumption and control the release of low temperature-sensitive liposomes (LTSL). Moreover, by adjusting the input signal, the temperature can be elevated and maintained at 37 degrees C, 42 degrees C and 50 degrees C precisely with the error of +/-0.3 degrees C. The flow cytometry results show that HIFU-mediated drug delivery lead to an increase in uptake compared to water incubation-induced drug release at 42 degrees C. Microfluidic technology may offer a promising alternative method for investigation of the complex dynamics between ultrasound and organisms in an ultramicroscopic manner. PMID- 26737638 TI - Analysis of uterine activity in nonpregnant women by electrohysterography: A feasibility study. AB - With an overall effectiveness below 30%, in vitro fertilization (IVF) is in urgent need for improvements, especially in view of the increasing trend in postponing childbirth in developed societies. Abnormal contraction of the uterus may underlie impaired fertility and unsuccessful IVF. However, currently, there is no method for quantitative assessment of uterine activity and guidance of dedicated intervention. Analysis of the electrohysterogram (EHG) has been extensively used in pregnancy for quantifying uterine contractions. In this paper, we evaluate, for the first time, the use of EHG analysis for characterizing contractions in women in two different phases of the menstrual cycle, when the uterus is expected to be active and quiescent. In this preliminary study, by estimating the time evolution of the EHG signal energy, we derive the contraction frequency, fC, as a possible marker for quantifying the activity of the uterus and discriminate between active and quiescent status. Ultrasound (US) image sequences are simultaneously recorded and visually analyzed for a qualitative validation of the results. The high correlation (0.91) between fC obtained by EHG and US analysis and the measured different values of fC in the two phases motivate further research to confirm the value of EHG analysis for contraction quantification in nonpregnant women. PMID- 26737639 TI - Real-time feedback based control of cardiac restitution using optical mapping. AB - Cardiac restitution is the shortening of the action potential duration with an increase in the heart rate. A shorter action potential duration enables a longer diastolic interval which ensures that the heart gets adequate time to refill with blood. At higher rates however, restitution becomes steep and thus, can lead to unstable electrical activity (alternans) in the heart, leading to fatal cardiac rhythms. It has been proposed that maintaining a shallow slope of cardiac restitution could have potentially anti-arrhythmic effects. Previous studies involved the control of action potential duration (APD) or diastolic interval (DI) in isolated tissue samples based on the feedback from single microelectrode recordings. This limited the spatial resolution of the feedback system. Here, we aimed to develop a real time feedback control system that enabled the detection of APDs from various single pixels based on optical mapping recordings. Stimuli were applied after a predefined fixed DI after detection of an APD. We validated our algorithm using optical mapping movies from an ex-vivo rabbit heart. Thus, we provide an optical mapping based approach for the control of cardiac restitution and a potential means to validate its anti-arrhythmic effects. PMID- 26737640 TI - Heart rate calculation from ensemble brain wave using wavelet and Teager-Kaiser energy operator. AB - Electroencephalogram (EEG) signal artifacts are caused by various factors, such as, Electro-oculogram (EOG), Electromyogram (EMG), Electrocardiogram (ECG), movement artifact and line interference. The relatively high electrical energy cardiac activity causes EEG artifacts. In EEG signal processing the general approach is to remove the ECG signal. In this paper, we introduce an automated method to extract the ECG signal from EEG using wavelet and Teager-Kaiser energy operator for R-peak enhancement and detection. From the detected R-peaks the heart rate (HR) is calculated for clinical diagnosis. To check the efficiency of our method, we compare the HR calculated from ECG signal recorded in synchronous with EEG. The proposed method yields a mean error of 1.4% for the heart rate and 1.7% for mean R-R interval. The result illustrates that, proposed method can be used for ECG extraction from single channel EEG and used in clinical diagnosis like estimation for stress analysis, fatigue, and sleep stages classification studies as a multi-model system. In addition, this method eliminates the dependence of additional synchronous ECG in extraction of ECG from EEG signal process. PMID- 26737641 TI - Stream computing for biomedical signal processing: A QRS complex detection case study. AB - Recent developments in "Big Data" have brought significant gains in the ability to process large amounts of data on commodity server hardware. Stream computing is a relatively new paradigm in this area, addressing the need to process data in real time with very low latency. While this approach has been developed for dealing with large scale data from the world of business, security and finance, there is a natural overlap with clinical needs for physiological signal processing. In this work we present a case study of streams processing applied to a typical physiological signal processing problem: QRS detection from ECG data. PMID- 26737642 TI - Multi-channel audio-based estimation of the Pre-Ejection Period. AB - Systolic time intervals (STI) have significant diagnostic and prognostic value to assess the global cardiac function. Presently, STIs are regarded as a promising tool for long-term follow-up of patients with chronic cardiovascular diseases. Heart sound has proven to be a valuable approach for STI estimation, in particular for the Pre-Ejection Period (PEP). However, since the optimal auscultation site varies from individual to individual, as well as with the position of the body, its application in single-channel and fixed auscultation site setups poses practical difficulties. Hence, we extend our previous work on PEP estimation to a multi-channel sound acquisition setup, where signal redundancy is exploited. A channel selection method is proposed and the best channel is selected for PEP estimation. As a preliminary study, the devised algorithms were evaluated with respect to echocardiography reference on a set of 236 heartbeats collected from 8 healthy subjects in two sound auscultation sites. The channel selection approach led to 8.4% estimation error decrease, in comparison to a single-channel approach. Current results support our assumption that a multi-channel audio-based strategy can be applied to assess STI in personal health application scenarios. PMID- 26737643 TI - A low-complex multi-channel methodology for noise detection in phonocardiogram signals. AB - The phonocardiography (PCG) is an important technique for the diagnosis of several heart conditions. However, the PCG signal is highly prone to noise, which can be an obstacle for the detection and interpretation of physiological heart sounds. Thus, the detection and elimination of noise present in PCG signals is crucial for the accurate analysis of heart sounds, especially in p-health environments. Noise can be introduced by various internal factors (e.g., respiration and laughing) and by external conditions (e.g., phone ringing or door closing). To mention also that the noise frequency components are typically overlapped with the PCG spectrum, increasing the complexity of the analysis. The purpose of the present work consists in the detection of noisy periods willfully introduced during the performance of three different sets of tasks. The developed method returns the classification of the signal content, in a window-by-window analysis and can be divided in two distinct phases. The first step consists in the search for a noise free window using a feature obtained from the PCG time domain. In the second step, the noise free window is compared with the remaining signal. The classification between clean and contaminated PCG is performed using two features from the frequency domain. The algorithm was able to discriminate clean from contamined PCG sections with an average sensitivity and specificity of 95.59% and 92.68%, respectively. PMID- 26737644 TI - QRS complex detection in ECG signal for wearable devices. AB - This paper presents QRS complex detection algorithm based on dual slope technique, which is suitable for wearable electrocardiogram (ECG) applications. For cardiac patients of different arrhythmias, ECG signals are needed to be monitored over an extensive period of time. Thus, the wearable heart monitoring system needs computationally efficient QRS detection technique with good accuracy. In this paper, a method of QRS detection based on two slopes on both sides of an R peak is presented which is computationally efficient. Based on the slopes, first, a variable measuring steepness is developed, then by introducing an adjustable R-R interval based window and adaptive thresholding techniques, depending on the number of peaks detected in such window, R peaks are detected. The algorithm was evaluated against MIT/BIH arrhythmia database and achieved 99.16% detection rate with sensitivity of 0.9935 and positive predictivity of 0.9981. The method was compared with two widely used R peaks detection algorithms. PMID- 26737645 TI - Heart rate variability in cyclic alternating pattern during sleep in healthy and Nocturnal Front Lobe Epilepsy patients. AB - The aim of this paper is to assess heart rate variability (HRV) during the cyclic alternating pattern, which is a sleep phenomenon, composed by cortical events that interrupt the basal oscillation of the NREM sleep stage. These cortical events are called A-phases and classified into three subtypes: A1, A2, A3. In addition, a comparison between healthy and Nocturnal Front Lobe Epilepsy (NFLE) patients was carried out. HRV was assessed by means of a time-varying autoregressive (TVAR) model with an adaptive filtering prediction scheme and by the time-varying square root of the mean of the sum of the squares of differences (RMSSD) of the RR intervals. For each A-phase, two signal segments were evaluated, the first one before the onset of the A-phase and the second one after the onset of the A-phase. An increase in the sympathetic outflow was suggested by higher values of low-frequency (LF) power in the three A-phases after the onset of A-phases, where A3-phases showed the largest changes. Increases in LF power were related with increases in heart rate in the same signal segments. These differences were found in both healthy and NFLE patients. LF/HF ratio and normalized LF power in A1-phases resulted significantly higher in NFLE patients in comparison with healthy subjects, which could suggest that there is a shift in the sympatho-vagal balance towards a more sympathetically mediated control of heart rate involving A1-phases in NFLE patients. PMID- 26737646 TI - Is 50 Hz high enough ECG sampling frequency for accurate HRV analysis? AB - With the worldwide growth of mobile wireless technologies, healthcare services can be provided at anytime and anywhere. Usage of wearable wireless physiological monitoring system has been extensively increasing during the last decade. These mobile devices can continuously measure e.g. the heart activity and wirelessly transfer the data to the mobile phone of the patient. One of the significant restrictions for these devices is usage of energy, which leads to requiring low sampling rate. This article is presented in order to investigate the lowest adequate sampling frequency of ECG signal, for achieving accurate enough time domain heart rate variability (HRV) parameters. For this purpose the ECG signals originally measured with high 5 kHz sampling rate were down-sampled to simulate the measurement with lower sampling rate. Down-sampling loses information, decreases temporal accuracy, which was then restored by interpolating the signals to their original sampling rates. The HRV parameters obtained from the ECG signals with lower sampling rates were compared. The results represent that even when the sampling rate of ECG signal is equal to 50 Hz, the HRV parameters are almost accurate with a reasonable error. PMID- 26737647 TI - Comparison of HRV parameters derived from photoplethysmography and electrocardiography signals. AB - Heart rate variability (HRV) has become a useful tool in analysis of cardiovascular system in both research and clinical fields. HRV has been also used in other applications such as stress level estimation in wearable devices. HRV is normally obtained from ECG as the time interval of two successive R waves. Recently PPG has been proposed as an alternative for ECG in HRV analysis to overcome some difficulties in measurement of ECG. In addition, PPG-HRV is also used in some commercial devices such as modern optical wrist-worn heart rate monitors. However, some researches have shown that PPG is not a surrogate for heart rate variability analysis. In this work, HRV analysis was applied on beat to-beat intervals obtained from ECG and PPG in 19 healthy male subjects. Some important HRV parameters were calculated from PPG-HRV and ECG-HRV. Maximum of PPG and its second derivative were considered as two methods for obtaining the beat to-beat signals from PPG and the results were compared with those achieved from ECG-HRV. Our results show that the smallest error happens in SDNN and SD2 with relative error of 2.46% and 2%, respectively. The most affected parameter is pNN50 with relative error of 29.89%. In addition, in our trial, using the maximum of PPG gave better results than its second derivative. PMID- 26737648 TI - Breathing sounds characteristics correlate with structural changes of upper airway due to obstructive sleep apnea. AB - This paper reports on a pilot study of acoustic properties of respiratory sounds in relation to obstructive sleep apnea (OSA). Data were breathing sounds of 60 individuals in three groups of non-, Moderate and Severe OSA using the apnea/hypopnea index (AHI) (20 in each group). The sounds power spectral energy and phase responses were calculated for each respiratory phase, and investigated among the groups. The results of power spectral analysis, congruent with imaging studies' findings, suggest a regional narrowing in upper airway that shows its effect in low and high frequencies as an opposite pattern between the OSA and non OSA groups. The results of phase analysis also support an increased nonlinearity in high frequencies that is speculated to be related to the regional narrowing and thus regional elasticity of the airway during wakefulness. PMID- 26737649 TI - Identifying stable phase coupling associated with cerebral autoregulation using the synchrosqueezed cross-wavelet transform and low oscillation morlet wavelets. AB - A novel method of identifying stable phase coupling behavior of two signals within the wavelet transform time-frequency plane is presented. The technique employs the cross-wavelet transform to provide a map of phase coupling followed by synchrosqueezing to collect the stable phase regime information. The resulting synchrosqueezed cross-wavelet transform method (Synchro-CrWT) is illustrated using a synthetic signal and then applied to the analysis of the relationship between biosignals used in the analysis of cerebral autoregulation function. PMID- 26737650 TI - Non-Invasive measurement of blood pressure - Why we should look at BP traces rather than listen to Korotkoff sounds. AB - Accurate non-invasive measurement of blood pressure in unsupervised environments continues to be a challenge, particularly in the presence of movement artefact, electrical noise and most importantly cardiac arrhythmia which are common in those aged over 65 suffering from a range of chronic conditions. Large intra personal variability in signal morphometry and amplitudes further complicates the development of reliable signal processing algorithms for NIBP measurement. In this paper we demonstrate the effect of this variability and propose that the traditional methods of human blood pressure determination by sphygmomanometry should no longer be considered a gold standard for the calibration of NIBP devices. PMID- 26737651 TI - An improved artifact removal algorithm for continuous cardiac output and blood pressure recordings. AB - Measurement artifacts are common in hemodynamic recordings such as cardiac output and blood pressure. Manual artifact removal is cumbersome for large datasets, and automatic processing using algorithms may reduce workload and provide more reproducible outcomes. This paper presents an artifact removal algorithm which is more aggressive compared to a previously described method. The algorithm was evaluated on cardiac output (CO) and mean arterial pressure (MAP) recordings from 23 subjects measured by two different devices (LiDCO and Nexfin), and compared to the previously described method as a reference. Precision, recall and F-score was determined by agreement with manual inspection by an expert. Based on the total of all measurements from CO and MAP by LiDCO and CO and MAP by Nexfin, precision was 86%, 79%, 79% and 68% respectively (87%, 62%, 76% and 58% for the reference method), recall was 97%, 94%, 89% and 97% (31%, 6%, 28% and 6% for reference), F score was 91%, 85%, 84% and 80% (46%, 10%, 41% and 10% for reference). The proposed algorithm offers an improved performance in removing true artifacts, in some cases a reduced ability to preserve true measurements, but an improved overall accuracy. PMID- 26737652 TI - Effects of cuff inflation and deflation on pulse transit time measured from ECG and multi-wavelength PPG. AB - Pulse transit time (PTT), which refers to the time it takes a pulse wave to travel between two arterial sites is a promising index for cuff-less blood pressure (BP) estimation, as well as non-invasive assessment of arterial functions. However, it has not been investigated whether PTTs measured from ECG and different wavelength PPG are equally affected by the arterial status. Furthermore, comparison between the changes of different PTTs can provide enlightenment on the hardware implementation of the PTT-based BP estimation method. This work mainly studied the changes of PTTs calculated from electrocardiogram (ECG) and multi-wavelength photoplethysmogram (PPG) after exerting cuff pressure on the upper arm. A four-channel PPG acquisition system was developed to collect the multi-wavelength PPG signals of red, yellow, green and blue light at the fingertip simultaneously. Ten subjects participated in the experiment and their PTTs measured from different PPG and ECG signals before and after exerting cuff pressure were compared. This study found that within one minute after the four-minute cuff inflation and deflation process, the PTT measured from ECG and yellow PPG experienced a significant increase (p<;0.05) while the PTT from ECG and blue PPG had no statistical difference (p>0.9) compared with that before exerting cuff pressure. This indicates that PTTs calculated from different wavelength PPG have different recoverability from smooth muscle relaxation. Another interesting finding is that the PTT calculated from ECG and yellow PPG had a strong correlation (|r|>0.7) with the time difference between yellow PPG and other PPG signals, which implies the potential of the time difference between yellow PPG and other PPGs as a complementary to PTT-based model for blood pressure estimation. PMID- 26737653 TI - Recording system and data fusion algorithm for enhancing the estimation of the respiratory rate from photoplethysmogram. AB - The respiratory rate is a vital parameter that can provide valuable information about the health condition of a patient. The extraction of respiratory information from photoplethysmographic signal (PPG) was actually encouraged by the reported results, our main goal being to obtain accurate respiratory rate estimation from the PPG signal. We developed a fusion algorithm that identifies the best derived respiratory signals, from which is possible to extract the respiratory rate; based on these, a global respiratory rate is computed using the proposed fusion algorithm. The algorithm is qualitatively tested on real PPG signals recorded by an acquisition system we implemented, using a reflection pulse oximeter sensor. Its performance is also statistically evaluated using benchmark dataset publically available from CapnoBase.Org. PMID- 26737654 TI - Breathing rate estimation during sleep using audio signal analysis. AB - Sleep is associated with important changes in respiratory rate and ventilation. Currently, breathing rate (BR) is measured during sleep using an array of contact and wearable sensors, including airflow sensors and respiratory belts; there is need for a simplified and more comfortable approach to monitor respiration. Here, we present a new method for BR evaluation during sleep using a non-contact microphone. The basic idea behind this approach is that during sleep the upper airway becomes narrower due to muscle relaxation, which leads to louder breathing sounds that can be captured via ambient microphone. In this study we developed a signal processing algorithm that emphasizes breathing sounds, extracts breathing related features, and estimates BR during sleep. A comparison between audio-based BR estimation and BR calculated using the traditional (gold-standard) respiratory belts during in-laboratory polysomnography (PSG) study was performed on 204 subjects. Pearson's correlation between subjects' averaged BR of the two approaches was R=0.97. Epoch-by-epoch (30 s) BR comparison revealed a mean relative error of 2.44% and Pearson's correlation of 0.68. This study shows reliable and promising results for non-contact BR estimation. PMID- 26737655 TI - Rapid and stable measurement of respiratory rate from Doppler radar signals using time domain autocorrelation model. AB - Noncontact measurement of respiratory rate using Doppler radar will play a vital role in future clinical practice. Doppler radar remotely monitors the tiny chest wall movements induced by respiration activity. The most competitive advantage of this technique is to allow users fully unconstrained with no biological electrode attachments. However, the Doppler radar, unlike other contact-type sensors, is easily affected by the random body movements. In this paper, we proposed a time domain autocorrelation model to process the radar signals for rapid and stable estimation of the respiratory rate. We tested the autocorrelation model on 8 subjects in laboratory, and compared the respiratory rates detected by noncontact radar with reference contact-type respiratory effort belt. Autocorrelation model showed the effects of reducing the random body movement noise added to Doppler radar's respiration signals. Moreover, the respiratory rate can be rapidly calculated from the first main peak in the autocorrelation waveform within 10 s. PMID- 26737656 TI - Real-time obstructive sleep apnea detection from frequency analysis of EDR and HRV using Lomb Periodogram. AB - In this study, an effective real-time obstructive sleep apnea (OSA) detection method from frequency analysis of ECG-derived respiratory (EDR) and heart rate variability (HRV) is proposed. Compared to traditional Polysomnography (PSG) which needs several physiological signals measured from patients, the proposed OSA detection method just only use ECG signals to determine the time interval of OSA. In order to be feasible to be implemented in hardware to achieve the real time detection and portable application, the simplified Lomb Periodogram is utilized to perform the frequency analysis of EDR and HRV in this study. The experimental results of this work indicate that the overall accuracy can be effectively increased with values of Specificity (Sp) of 91%, Sensitivity (Se) of 95.7%, and Accuracy of 93.2% by integrating the EDR and HRV indexes. PMID- 26737657 TI - Automatic characterization of sleep need dissipation dynamics using a single EEG signal. AB - In the two-process model of sleep regulation, slow-wave activity (SWA, i.e. the EEG power in the 0.5-4 Hz frequency band) is considered a direct indicator of sleep need. SWA builds up during non-rapid eye movement (NREM) sleep, declines before the onset of rapid-eye-movement (REM) sleep, remains low during REM and the level of increase in successive NREM episodes gets progressively lower. Sleep need dissipates with a speed that is proportional to SWA and can be characterized in terms of the initial sleep need, and the decay rate. The goal in this paper is to automatically characterize sleep need from a single EEG signal acquired at a frontal location. To achieve this, a highly specific and reasonably sensitive NREM detection algorithm is proposed that leverages the concept of a single-class Kernel-based classifier. Using automatic NREM detection, we propose a method to estimate the decay rate and the initial sleep need. This method was tested on experimental data from 8 subjects who recorded EEG during three nights at home. We found that on average the estimates of the decay rate and the initial sleep need have higher values when automatic NREM detection was used as compared to manual NREM annotation. However, the average variability of these estimates across multiple nights of the same subject was lower when the automatic NREM detection classifier was used. While this method slightly over estimates the sleep need parameters, the reduced variability across subjects makes it more effective for within subject statistical comparisons of a given sleep intervention. PMID- 26737658 TI - Modeling sleep apnea severity using bioimpedance measurements. AB - Obstructive sleep apnea (OSA) is a common disorder in adults characterized by repetitive collapse of the pharynx. OSA prevalence increases in fluid retaining patients such as those with heart or renal failure, and worsens with overnight fluid accumulation in the neck. The objective of this study was to develop a new method of measuring changes in intracellular water (ICW) in the neck, and investigate metrics that represent total neck impedance and their relationship to sleep apnea severity. In 18 non-obese men, neck fluid volume (NFV) was measured before and after sleep using bioelectrical impedance at 50 kHz. For each participant, resistance and reactance was extracted from the impedance measurements. A model was developed to estimate the cell membrane capacitance which could represent changes in intracellular fluid in the neck. OSA severity was assessed using polysomnography to estimate the apnea-hypopnea index (AHI) as well as the obstructive AHI (OAHI). Our results showed a strong correlation between the changes in NFV from before to after sleep with the changes in cell membrane capacitance from before to after sleep, indicating an increase in ICW in the neck during sleep. Using linear stepwise regression we were also able to develop models to accurately predict AHI and OAHI using baseline anthropometric and bioimpedance measurements. These promising results demonstrate that non invasive measurements of bioimpedance can be used to develop a novel biomarker to model sleep apnea severity, and assess patients at high risk of OSA. PMID- 26737659 TI - Quantification of muscle activity during sleep for patients with neurodegenerative diseases. AB - Idiopathic REM sleep behavior disorder (iRBD) is a very strong predictor for later development of Parkinson's disease (PD), and is characterized by REM sleep without atonia (RSWA), resulting in increased muscle activity during REM sleep. Abundant studies have shown the loss of atonia during REM sleep, but our aim was to investigate whether iRBD and PD patients have increased muscle activity in both REM and NREM sleep compared to healthy controls. This was achieved by developing a semi-automatic algorithm for quantification of mean muscle activity per second during all sleep stages for the enrolled patients. The three groups examined included patients suffering from iRBD, PD and healthy control subjects (CO). To determine muscle activity, a baseline and threshold were established after pre-processing of the raw surface electromyography (sEMG) signal. The signal was then segmented according to the different sleep stages and muscle activity beyond the threshold was counted. The results were evaluated statistically using the two-sided Mann-Whitney U-test. The results suggested that iRBD patients also exhibit distinctive muscle activity characteristics in NREM sleep, however not as evident as in REM sleep, leading to the conclusion that RSWA still is the most distinct characteristic of RBD. Furthermore, the muscle activity of PD patients was comparable to that of controls with only slightly elevated amplitudes. PMID- 26737660 TI - A new method for attenuation of respiration artifacts in electrogastrographic (EGG) signals. AB - Electrogastrography (EGG) is a test method designed for noninvasive assessment of gastric slow waves propagation. The EGG signal is obtained from the electrodes respectively arranged on the surface of the patient's abdomen. A significant problem during recording of the EGG signal is the elimination of disturbances occurring during registration and unwanted components of other signals such as: components of electrocardiographic (ECG), baseline drift or respiratory disturbances. These components are generally present in the signals registered from the surface of the abdomen of the patient. Since EGG frequency components partly overlap with the frequency components of respiratory artifacts, conventional band-pass digital or analog filtering may cause distortion in electrogastrographic signal. In the paper a method for removing respiratory interference occurring during registration of EGG signal and the effect of filtration on selected parameters of EGG signal analysis is presented. Respiratory artifacts are removed through the use of adaptive filter working in the DCT domain. The applied adaptive filtering method involves the use of the signal including respiratory disturbances. This signal is recorded synchronously with the EGG signal using a thermistor placed near the nose of the patient. PMID- 26737661 TI - Multi-sources data analysis with sympatho-vagal balance estimation toward early bruxism episodes detection. AB - Sleep bruxism events detection system is presented, based on integrated, synchronized on-line analysis of EMG signal, heart rave variability (HRV) obtained from ECG recordings as well as sympatho-vagal balance estimated in real time as an possible early indicator of upcoming bruxism episodes. As an relative reliable alternative for very complex systems, only for clinical environment usage with audio and video recordings a pilot study toward elaboration of compact, comfortable for home usage device with early bruxism detection algorithms was carried out, preliminary tested on 10h sleeping registrations from group of 12 patients, clinically characterized by experts as Bruxers. As a result a set of decision rules regarding simultaneous monotonic increase of heart rate with significant increase of EMG signal amplitude during bruxism episode was elaborated. But a most promising observation, which can be useful for earlier prediction of upcoming bruxism episode seems to be a monotonic increase of LF/HF ratio in HRV power spectrum components, expressing sympatho-vagal balance of autonomous nervous system, which according to our assumptions take basic low level role in bruxism phenomena trigger and control. PMID- 26737662 TI - An open-source toolbox for standardized use of PhysioNet Sleep EDF Expanded Database. AB - PhysioNet Sleep EDF database has been the most popular source of data used for developing and testing many automatic sleep staging algorithms. However, the recordings from this database has been used in an inconsistent fashion. For example, arbitrary selection of start and end times from long term recordings, data-hypnogram mismatches, different performance metrics and hypnogram conversion from R&K to AASM. All these differences result in different data sections and performance metrics being used by researchers thereby making any direct comparison between algorithms very difficult. Recently, a superset of this database has been made available on PhysioNet, known as the Sleep EDF Expanded Database which includes 61 recordings. This provides an opportunity to standardize the way in which signals from this database should be used. With this goal in mind, we present in this paper a toolbox for automatically downloading and extracting recordings from the Sleep EDF Expanded database and converting them to a suitable format for use in MATLAB. This toolbox contains functions for selecting appropriate data for sleep analysis (based on our previous recommendations for sleep staging), hypnogram conversion and computation of performance metrics. Its use makes it simpler to start using the new sleep database and also provides a foundation for much-needed standardization in this research field. PMID- 26737663 TI - SoC-based architecture for biomedical signal processing. AB - Over the last decades, many algorithms have been proposed for processing biomedical signals. Most of these algorithms have been focused on the elimination of noise and artifacts existing in these signals, so they can be used for automatic monitoring and/or diagnosis applications. With regard to remote monitoring, the use of portable devices often requires a reduced number of resources and power consumption, being necessary to reach a trade-off between the accuracy of algorithms and their computational complexity. This paper presents a SoC (System-on-Chip) architecture, based on a FPGA (Field-Programmable Gate Array) device, suitable for the implementation of biomedical signal processing. The proposal has been successfully validated by implementing an efficient QRS complex detector. The results show that, using a reduced amount of resources, values of sensitivity and positive predictive value above 99.49% are achieved, which make the proposed approach suitable for telemedicine applications. PMID- 26737664 TI - Non-parametric frequency response function tissue modeling in bipolar electrosurgery. AB - High-frequency radio energy is applied to tissue therapeutically in a number of different medical applications. The ability to model the effects of RF energy on the collagen, elastin, and liquid content of the target tissue would allow for the refinement of the control of the energy in order to improve outcomes and reduce negative side-effects. In this paper, we study the time-varying impedance spectra of the circuit. It is expected that the collagen/elastin ratio does not change over time such that the time-varying impedance is a function of the liquid content. We apply a non-parametric model in which we characterize the measured impedance spectra by its frequency response function. The measurements indicate that the changing impedance as a function of time exhibit a polynomial shift which we characterize by a polynomial regression. Finally, we quantify the uncertainty to obtain prediction intervals for the estimated polynomial describing the time variation of the impedance spectra. PMID- 26737665 TI - Field programmable gate arrays implementation of Dual Tree Complex Wavelet Transform. AB - Due to the inherent time-varying characteristics of physiological systems, most biomedical signals (BSs) are expected to have non-stationary character. Therefore, any appropriate analysis method for dealing with BSs should exhibit adjustable time-frequency (TF) resolution. The wavelet transform (WT) provides a TF representation of signals, which has good frequency resolution at low frequencies and good time resolution at high frequencies, resulting in an optimized TF resolution. Discrete wavelet transform (DWT), which is used in various medical signal processing applications such as denoising and feature extraction, is a fast and discretized algorithm for classical WT. However, the DWT has some very important drawbacks such as aliasing, lack of directionality, and shift-variance. To overcome these drawbacks, a new improved discrete transform named as Dual Tree Complex Wavelet Transform (DTCWT) can be used. Nowadays, with the improvements in embedded system technology, portable real-time medical devices are frequently used for rapid diagnosis in patients. In this study, in order to implement DTCWT algorithm in FPGAs, which can be used as real time feature extraction or denoising operator for biomedical signals, a novel hardware architecture is proposed. In proposed architecture, DTCWT is implemented with only one adder and one multiplier. Additionally, considering the multi channel outputs of biomedical data acquisition systems, this architecture is capable of running N channels in parallel. PMID- 26737666 TI - Recognizing emotions from EEG subbands using wavelet analysis. AB - Objectively recognizing emotions is a particularly important task to ensure that patients with emotional symptoms are given the appropriate treatments. The aim of this study was to develop an emotion recognition system using Electroencephalogram (EEG) signals to identify four emotions including happy, sad, angry, and relaxed. We approached this objective by firstly investigating the relevant EEG frequency band followed by deciding the appropriate feature extraction method. Two features were considered namely: 1. Wavelet Energy, and 2. Wavelet Entropy. EEG Channels reduction was then implemented to reduce the complexity of the features. The ground truth emotional states of each subject were inferred using Russel's circumplex model of emotion, that is, by mapping the subjectively reported degrees of valence (pleasure) and arousal to the appropriate emotions - for example, an emotion with high valence and high arousal is equivalent to a 'happy' emotional state, while low valence and low arousal is equivalent to a 'sad' emotional state. The Support Vector Machine (SVM) classifier was then used for mapping each feature vector into corresponding discrete emotions. The results presented in this study indicated thatWavelet features extracted from alpha, beta and gamma bands seem to provide the necessary information for describing the aforementioned emotions. Using the DEAP (Dataset for Emotion Analysis using electroencephalogram, Physiological and Video Signals), our proposed method achieved an average sensitivity and specificity of 77.4% +/- 14.1% and 69.1% +/- 12.8%, respectively. PMID- 26737667 TI - Detection of stress/anxiety state from EEG features during video watching. AB - This paper studies the effect of stress/anxiety states on EEG signals during video sessions. The levels of arousal and valence that are induced to each subject while watching each video are self rated. These levels are mapped in stress and relaxed states and subjects that fufill criteria of adequate anxiety/stress scale were chosen leading to a subset of 18 subjects. Then, temporal, spectral and non linear EEG features are evaluated for being able to represent accurately states under investigation. Feature selection schemes choose the most significant of them in order to provide increased discrimination ability between relaxed and anxiety/stress states. PMID- 26737668 TI - Experimental evidence for the effects of the Demand-Control model on the cognitive arousal: An EEG based study. AB - The Demand-Control (DC) model has been extensively researched to find the imbalance of demand and control that cause work-related stress. Past research has been exclusively dedicated to evaluate the impact of this model on employees' well-being and job environment. However, the impact of high demands (strain hypothesis) and the influence of control (buffer hypothesis) on cognitive arousal have yet to be identified. We aimed to fill this void by measuring the influence of the DC model on the cognitive arousal. Electroencephalogram (EEG) was recorded to extract the cognitive arousal in an experiment that implemented the DC model. The experiment comprised four conditions having combination of varying demand and control. The strain and the buffer hypothesis were separately validated by the cognitive arousal in association with the task performance and subjective feedbacks. Results showed the maximum arousal and the worst performance occurred in high demand and low control condition. Also high control proved to significantly lower arousal and improved performance than in low control condition with high demand. PMID- 26737669 TI - Recognition and regionalization of emotions in the arousal-valence plane. AB - The emotion recognition systems have become important for the diversity of its applications. Several methodologies have been proposed based on how emotions are reflected in biological systems, such as facial expressions, the activity of the nervous system or the prosody of voice. The detection of emotions by voice processing is an approach that involves a noninvasive procedure that produces results with an acceptable rate of detection. In this work an algorithm for features extraction was developed, that efficiently classify different emotional states. Thus, emotions that have not been trained can be associated with a trained emotion both belonging to the same region of the valence-arousal plane. PMID- 26737670 TI - Brain activities during synchronized tapping task. AB - This study aims to investigate how people process information about other people to determine a response during human-to-human cooperative work. As a preliminary study, the mechanism of cooperative work was examined using interaction between a machine and a human. This machine was designed to have an "other person" model that simulates an emotional model of another person. The task performed in the experiment was a synchronized tapping task. Two models were prepared for this experiment, a simple model that does not employ the other person model and a synchronized model that employs the other person model. Subjects performed cooperative work with these machines. During the experiment, brain activities were measured using functional near-infrared spectroscopy. It was observed that the left inferior frontal gyrus was activated more with the synchronized model than the simple model. PMID- 26737671 TI - Retrieving the Hemodynamic Response Function in resting state fMRI: Methodology and application. AB - In this paper we present a procedure to retrieve the hemodynamic response function (HRF) from resting state functional magnetic resonance imaging (fMRI) data. The fundamentals of the procedures are further validated by considering simultaneous electroencephalographic (EEG) recordings. The typical HRF shape at rest for a group of healthy subject is presented. Then we present the modifications to the shape of the HRF at rest following two physiological modulations: eyes open versus eyes closed and propofol-induced modulations of consciousness. PMID- 26737672 TI - Temporal fluctuation analysis of tremor signal in Parkinson's disease and Essential tremor subjects. AB - Tremor is a common symptom shared in both Parkinson's disease (PD) and Essential tremor (ET) subjects. The differential diagnosis of PD and ET tremor is important since the treatment depends on specific medication. A novel feature was developed based on a hypothesis stating that the tremor of PD subject has a larger fluctuation while performing resting task than action task. Tremor signal was collected using a gyroscope sensor attached to subject's finger. The angular velocity signal was analyzed by transforming a one-dimensional to two-dimensional signal based on relation of different units of time-delay. The tremor fluctuation was defined as the area of 95% confidence ellipse covering the two-dimensional signal. Experimenting with 32 PD and 20 ET subjects, a ratio of fluctuation of resting to kinetic task can be a sensitive feature to discriminate PD from ET with 100% accuracy. PMID- 26737673 TI - Spatial analysis of muscular activations in stroke survivors. AB - We investigated the spatial patterns of electrical activity in stroke-affected muscles using the high density surface electromyogram (sEMG) grids. We acquired 128-channel sEMG signals from the impaired as well as contralateral Biceps Brachii (BB) muscles of stroke survivors and from healthy participants at various force levels from 20 to 60% of maximum voluntary contraction in an isometric non fatiguing recording protocol. We found the spatial sEMG pattern to be consistent across force levels in healthy and stroke subjects. However, once compared across sides (left vs right in healthy and impaired vs. contralateral in stroke) we found stroke-affected sides to be significantly different in distribution pattern of sEMG from the contralateral side. The sEMG activity areas were significantly shrunk on the affected sides indicating muscle atrophy due to stroke. PMID- 26737674 TI - Assessment of the activation patterns of the muscles involved in the FR test in diabetic neuropathic patients. AB - This study was designed to assess, in elderly neuropathic diabetic (DN) patients, the activation patterns of the main muscles involved in the Functional Reach (FR) Test, a well-recognized method to identify elderly subjects at risk of recurrent falls. Surface electromyographic (sEMG) analysis of Sternocleidomastoideus (Scm), Rectus Abdominis (RAbd), Erectores Spinae at L4 level (L4), Rectus Femoris (RF), Hamstrings (Ham), Tibialis Anterior (TA) and Soleus (Sol) was performed to this aim. Results in DN patients are compared with a control group (CH) of healthy age matched subjects. In DN patients, TA is identified as the first muscle to be recruited (ON at -34% of the FR-period) before the movement start, in order to initiate the body forward displacement. RF is the first muscle to be recruited after TA and, togheter with RAbd, showed a progressive earlier onset from CH group. Sol and Ham (ON after the FR-start), followed by L4, act mainly as tonic muscles, opposing the movement and preventing falls. Compared to the CH group, the DN subjects show an anticipatory recruitment (-34%+/-6%) of TA, showing a statistically significant difference (p<;0.05) in comparison to CH group, together with the Scm activation. Results suggest a trend of DN patients in anticipating the activation of the anterior muscles of the body. This is likely due to an attempt to compensate the neuropathy-related proprioception dysfunction and to adjust the movement timing. In conclusion, the present study shows that sEMG is a suitable tool to deepen the interpretation of the FR-test execution and proposes the earlier start of TA as a possible element to identify the presence of neuropathy in diabetic subjects. PMID- 26737675 TI - Evaluation of gender-related differences in co-contraction activity of shank muscles during gait. AB - This study aims to investigate the possible differences between genders in co contractions of tibialis anterior (TA) and gastrocnemius lateralis (GL), during walking at self-selected speed. To this purpose, the statistical gait analysis (SGA) was performed on seven female (F-group) and seven male (M-group) adults. SGA is a recently developed methodology for the characterization of gait, by averaging spatiotemporal and electromyographic parameters over hundreds of strides per subject. Co-contractions were assessed as the overlapping periods between TA and GL activity. Results showed that four co-contraction intervals are present during gait cycle in both groups. No relevant differences between genders were detected in onset-offset time instants of co-activations or in their temporal length. On the contrary, significant differences were observed in the number of strides where each co-contraction happens (i.e. the occurrence frequency). All the four co-contraction intervals result significantly (p<;0.05) more recurrent in females compared to males. This outcome suggests a larger presence of co-contraction activity in females walking, related to a female tendency for a more complex muscular strategy during gait. These findings could be useful to better understand gender differences in walking mechanisms and to develop separated normal walking reference frames for males and females. PMID- 26737676 TI - The occurrence frequency: A suitable parameter for the evaluation of the myoelectric activity during walking. AB - Many studies have recently addressed the quantification of the natural variability of myoelectric activity during walking, considering hundreds of strides. The availability of so many strides allows assessing a parameter seldom considered in classic surface EMG (sEMG) studies: the occurrence frequency, defined as the frequency each muscle activation occurs with, quantified by the number of strides in which a muscle is recruited with that specific activation modality. Aim of this study is to point out the occurrence frequency as a suitable parameter for the evaluation of the variability of the myoelectric activity during walking. This goal was pursued by means of the statistical gait analysis of sEMG signal acquired from Gastrocnemius Lateralis (GL) in six healthy subjects, with different characteristics. Results show that among these six subjects relevant differences were not detected in the temporal parameters, i.e., activation onset/offset instant and activation duration. In the same subjects, the values of the occurrence frequency ranged from 3% to 74% in the different activation modalities, indicating a large variability of this parameter. These findings show that occurrence frequency is able to provide further and different information with respect to classical temporal parameters. Thus, the occurrence frequency is proposed as a suitable parameter to support the classic temporal parameters in the evaluation of variability of myoelectric activity during walking. PMID- 26737677 TI - Wearable real-time ecg monitoring with emergency alert system for scuba diving. AB - Medical diagnosis is the first level for recognition and treatment of diseases. To realize fast diagnosis, we propose a concept of a basic framework for the underwater monitoring of a diver's ECG signal, including an alert system that warns the diver of predefined medical emergency situations. The framework contains QRS detection, heart rate calculation and an alert system. After performing a predefined study protocol, the algorithm's accuracy was evaluated with 10 subjects in a dry environment and with 5 subjects in an underwater environment. The results showed that, in 3 out of 5 dives as well as in dry environment, data transmission remained stable. In these cases, the subjects were able to trigger the alert system. The evaluated data showed a clear ECG signal with a QRS detection accuracy of 90 %. Thus, the proposed framework has the potential to detect and to warn of health risks. Further developments of this sample concept can imply an extension for monitoring different biomedical parameters. PMID- 26737678 TI - Muscle fatigue detection during dynamic contraction under blood flow restriction: Improvement of detection sensitivity using multivariable fatigue indices. AB - At present, in order to detect peripheral muscle fatigue, it is customary to perform a frequency domain analysis using surface electromyography data measured with bipolar leads, and extract characteristic quantities like mean power frequency and median frequency. However, there are times when muscle fatigue variables, typically represented by decreasing wave frequencies, do not occur under certain conditions such as dynamic contraction causing a blood flow restriction. This study has tried to improve muscle fatigue detection sensitivity by utilizing two approaches: alteration of electrode arrangements to monopolar leads and use of nonlinear analysis in addition to frequency domain analysis and time domain analysis. The multivariable fatigue indices calculated by using each analysis method are combined into one synthetic variable using the method named "end to end projection" proposed by Rogers and Macisaac. After the effective indices and combination patterns have been investigated, it was showed that the optimum number of combinations is around four. The results also indicate that the combination method has a potential to improve the detection accuracy and monopolar leads can detect muscle fatigue change more clearly than bipolar ones. PMID- 26737679 TI - Effect of muscular fatigue on fractal upper limb coordination dynamics and muscle synergies. AB - Rehabilitation exercises cause fatigue because tasks are repetitive. Therefore, inevitable human motion performance changes occur during the therapy. Although traditionally fatigue is considered an event that occurs in the musculoskeletal level, this paper studies whether fatigue can be regarded as context that influences lower-dimensional motor control organization and coordination at neural level. Non Negative Factorization Matrix (NNFM) and Detrended Fluctuations Analysis (DFA) are the tools used to analyze the changes in the coordination of motor function when someone is affected by fatigue. The study establishes that synergies remain fairly stable with the onset of fatigue, but the fatigue affects the dynamical coordination understood as a cognitive process. These results have been validated with 9 healthy subjects for three representative exercises for upper limb: biceps, triceps and deltoid. PMID- 26737680 TI - On optimal electrode configuration to estimate hand movements from forearm surface electromyography. AB - Understanding the movement of the hand from sEMG signals acquired on the forearm is key in the development of future prosthetics of the upper limb. Despite the technical advancement on this technique, state of the art of sEMG still relies strongly on optimal electrode placement which is typically performed by a specialist by mean of a heuristic search. Involving a specialist has few major disadvantages including high costs and relatively long schedules. This work searches an optimal electrode configuration which could reduce or avoid the intervention of a specialist. More than 200 different possible electrode configurations were assessed by means of the average recognition rate over 11 different movements of the hand, wrist, and fingers. It is shown that using two rows of 8 equally spaced electrodes around the circumference of the forearm could be an optimal trade-off solution to accomplish the task of recognizing hand movement (ARR = 92%) without the need for a specialist or very complex hardware. PMID- 26737681 TI - Age-related motor unit remodeling in the Tibialis Anterior. AB - Limited studies exist on the use of surface electromyogram (EMG) signal features to detect age-related motor unit remodeling in the Tibialis Anterior. Motor unit remodeling leads to declined muscle strength and force steadiness during submaximal contractions which are factors for risk of falls in the elderly. This study investigated the remodeling phenomena in the Tibialis Anterior using sample entropy and higher order statistics. Eighteen young (26.1 +/- 2.9 years) and twelve elderly (68.7 +/- 9.0 years) participants performed isometric dorsiflexion of the ankle at 20% maximal voluntary contraction (MVC) and their Tibialis Anterior (TA) EMG was recorded. Sample entropy, Gaussianity and Linearity Test statistics were calculated from the recorded EMG for each MVC. Shapiro-Wilk test was used to determine normality, and either a two-tail student t-test or Wilcoxon rank sum test was performed to determine significant difference in the EMG features between the young and old cohorts. Results show age-related motor unit remodeling to be depicted by decreased sample entropy (p <; 0.1), increased non Gaussianity (p <; 0.05) and lesser degree of linearity in the elderly. This is due to the increased sparsity of the MUAPs as a result of the denervation reinnervation process, and the decrease in total number of motor units. PMID- 26737682 TI - Detection of the Recovery Phase of in vivo gastric slow wave recordings. AB - Gastric motility is coordinated by bio-electrical events known as slow waves. Abnormalities in slow waves are linked to major functional and motility disorders. In recent years, the use of high-resolution (HR) recordings have provided a unique view of spatiotemporal activation profiles of normal and dysrhythmic slow wave activity. To date, in vivo studies of gastric slow wave activity have primarily focused on the activation phase of the slow wave event. In this study, the recovery phase of slow waves was investigated through the use of HR recording techniques. The recovery phase of the slow wave event was detected through the use of the signal derivative, computed via a wavelet transform. The activation to recovery interval (ARi) metric was computed as a difference between the recovery time and activation time. The detection method was validated with synthetic slow wave signals of varying morphologies with the addition of synthetic ventilator and high frequency noise. The methods was then applied to HR experimental porcine gastric slow wave recordings. Ventilator noise more than 10% of the slow wave amplitude affected the estimation of the ARi metric. Signal to noise ratio below 3 dB affected the ARi metric, but with minor deviation in accuracy. Experimental ARi values ranged from 3.7-4.7 s from three data sets, with significant differences across them. PMID- 26737683 TI - A system for automated quantification of cutaneous electrogastrograms. AB - Clinical evaluation of cutaneous electrogastrograms (EGG) is important for understanding the role of slow waves in functional motility disorders and may be a useful diagnostic aid. An automated software package has been developed which computes metrics of interest from EGG and from slow wave recordings from the gastric mucosa and serosa in a reliable and efficient manner. In particular, the frequency and amplitude of the gastric slow waves were computed, after which signal integrity checks were performed to assess if the signals are valid. For validation, manual estimates of the frequency and amplitude were compared to automated estimates. The methods were packaged into a software executable which processes the data and presents the results in an intuitive graphical and a spreadsheet formats. Automated EGG analysis allows for clinical translation of bio-electrical analysis for potential diagnostics, as commonly used in the cardiac field. PMID- 26737684 TI - Correlational analysis of electroencephalographic and end-tidal carbon dioxide signals during breath-hold exercise. AB - The central mechanism of breathing control is not totally understood. Several studies evaluated the correlation between electroencephalographic (EEG) power spectra and respiratory signals by performing resting state tasks or adopting hypercapnic/hypoxic stimuli. The observation of brain activity during voluntary breath hold tasks, might be an useful approach to highlight the areas involved in mechanism of breath regulation. Nevertheless, studies of brain activity with EEG could present some limitations due to presence of severe artifacts. When artifact rejection methods, as independent component analysis, cannot reliably clean EEG data, it is necessary to exclude noisy segments. In this study, global field power in the delta band and end-tidal CO2 were derived from EEG and CO2 signals respectively in 4 healthy subjects during a breath-hold task. The cross correlation function between the two signals was estimated taking into account the presence of missing samples. The statistical significance of the correlation coefficients at different time lags was assessed using surrogate data. Some simulations are introduced to evaluate the effect of missing data on the correlational analysis and their results are discussed. Results obtained on subjects show a significant correlation between changes in EEG power in the delta band and end-tidal CO2. Moreover, the changes in end-tidal CO2 were found to precede those of global field power. These results might help to better understand the cortical mechanisms involved in the control of breathing. PMID- 26737685 TI - Voice quality in patients suffering from bipolar disease. AB - People suffering from bipolar disease are more and more common. Such pathology can severely affect patients' lifestyle by wide, and sometimes extreme, mood swings. Biosignals can be very useful to understand this disease. Specifically, speech-related features have been seen to vary in depressed people with respect to healthy subjects. Usually prosodic, spectral and energy-related features are studied. Some further information, instead, can be provided studying voice quality. According to Laver's model, voice quality is sensitive and depends on both anatomic/physiologic issues and long-term muscular adjustments of the larynx or the supraglottal vocal tract. A pilot study on both bipolar patients and healthy control subjects, performed by means of the Long-Term Average Spectrum (LTAS) is presented. The effects on LTAS estimation of a F0-correction procedure are discussed. Pairwise statistical comparisons between subjects in euthymic and depressed states and euthymic and hypomanic states were performed. Significant differences were found in some frequency intervals in both cases. The F0 correction procedure modified the values of the significant frequency intervals in the euthymic/depressed comparison, that also was characterized by a change of F0. Noticeably, no statistically significant differences were found in control subjects acquired in the same mood state. Though the number of subjects is small, the results are encouraging given their coherence across patients and the lack of differences in the control group. Finally, this work suggests that particular vocal settings might be involved in different mood states. PMID- 26737686 TI - Arousal recognition system based on heartbeat dynamics during auditory elicitation. AB - This study reports on the recognition of different arousal levels, elicited by affective sounds, performed using estimates of autonomic nervous system dynamics. Specifically, as a part of the circumplex model of affect, arousal levels were recognized by properly combining information gathered from standard and nonlinear analysis of heartbeat dynamics, which was derived from the electrocardiogram (ECG). Affective sounds were gathered from the International Affective Digitized Sound System and grouped into four different levels of arousal. A group of 27 healthy volunteers underwent such elicitation while ECG signals were continuously recorded. Results showed that a quadratic discriminant classifier, as applied implementing a leave-one-subject-out procedure, achieved a recognition accuracy of 84.26%. Moreover, this study confirms the crucial role of heartbeat nonlinear dynamics for emotion recognition, hereby estimated through lagged Poincare plots. PMID- 26737687 TI - Unobtrusive heart rate estimation during physical exercise using photoplethysmographic and acceleration data. AB - Photoplethysmography (PPG) is a non-invasive, inexpensive and unobtrusive method to achieve heart rate monitoring during physical exercises. Motion artifacts during exercise challenge the heart rate estimation from wrist-type PPG signals. This paper presents a methodology to overcome these limitation by incorporating acceleration information. The proposed algorithm consisted of four stages: (1) A wavelet based denoising, (2) an acceleration based denoising, (3) a frequency based approach to estimate the heart rate followed by (4) a postprocessing step. Experiments with different movement types such as running and rehabilitation exercises were used for algorithm design and development. Evaluation of our heart rate estimation showed that a mean absolute error 1.96 bpm (beats per minute) with standard deviation of 2.86 bpm and a correlation of 0.98 was achieved with our method. These findings suggest that the proposed methodology is robust to motion artifacts and is therefore applicable for heart rate monitoring during sports and rehabilitation. PMID- 26737688 TI - Non-contact and noise tolerant heart rate monitoring using microwave doppler sensor and range imagery. AB - This paper describes a non-contact and noise-tolerant heart beat monitoring system. The proposed system comprises a microwave Doppler sensor and range imagery using Microsoft KinectTM. The possible application of the proposed system is a driver health monitoring. We introduce the sensor fusion approach to minimize the heart beat detection error. The proposed algorithm can subtract a body motion artifact from Doppler sensor output using time-frequency analysis. The body motion artifact is a crucially important problem for biosignal monitoring using microwave Doppler sensor. The body motion speed is obtainable from range imagery, which has 5-mm resolution at 30-cm distance. Measurement results show that the success rate of the heart beat detection is improved about 75% on average when the Doppler wave is degraded by the body motion artifact. PMID- 26737689 TI - Temporal and spectral analysis of internal carotid artery Doppler signal for normal and abnormal flow detection. AB - Detection of carotid artery stenosis is presently highly dependent on ultrasound imaging systems. This work presents a method that can detect the normal and abnormal blood flow in the carotid structure independent of Doppler angle by analysing the time and spectral domain representation of Doppler signal. In the proposed approach, time and spectral domain based features are extracted from the Doppler signals of internal carotid arteries. Further, these features are used in supervised machine learning approach to identify the presence of abnormal blood flow. The proposed method is evaluated on 100 subjects (200 signals) with equal number of normal and abnormal flow profiles. Experimental results show that the maximum classification accuracies of 79.3% and 82.9% are observed with k-nearest neighbours and support vector machine classifiers, respectively. PMID- 26737690 TI - Smartwatch-based driver alertness monitoring with wearable motion and physiological sensor. AB - Studies have shown that a high precision driver alertness monitoring system is an essential and a monetary countermeasure to reduce the road accidents. This paper presents a novel approach to measure the driver alertness, evaluated by a smartwatch device based on fusion of direct and indirect method. The driver chronic physiological state is monitor by adopting a photoplethysmography sensor on the driver finger that is connected to a wrist-type wearable device. A Bluetooth Low Energy module connected to the wearable device transmits the PPG data to the smartwatch in real-time. Meanwhile, the indirect method, driver steering wheel movement can be derived by utilizing the motion sensors integrated in the smartwatch which include a tri-axis accelerometer and a gyroscope sensors. The respiration signals can be derived from the PPG time- and frequency-domains attributes. The data obtained from both methods aforementioned are subsequently decomposed into relevant features in time, spectral context and phase space domain, and thus computes the alertness index. Here, the correlations between the extracted features and the subjective Koralinska Sleepiness Scale are studied as well along with the recorded experimental videos. This study reveals that the alertness index prediction accuracy can be reached up to 96.3% based on the descriptive extracted features. PMID- 26737691 TI - A constrained two-layer compression technique for ECG waves. AB - This paper proposes a constrained two-layer compression technique for electrocardiogram (ECG) waves, of which encoded parameters can be directly used for the diagnosis of arrhythmia. In the first layer, a single ECG beat is represented by one of the registered templates in the codebook. Since the required coding parameter in this layer is only the codebook index of the selected template, its compression ratio (CR) is very high. Note that the distribution of registered templates is also related to the characteristics of ECG waves, thus it can be used as a metric to detect various types of arrhythmias. The residual error between the input and the selected template is encoded by a wavelet-based transform coding in the second layer. The number of wavelet coefficients is constrained by pre-defined maximum distortion to be allowed. The MIT-BIH arrhythmia database is used to evaluate the performance of the proposed algorithm. The proposed algorithm shows around 7.18 CR when the reference value of percentage root mean square difference (PRD) is set to ten. PMID- 26737692 TI - Human emotion recognition using heart rate variability analysis with spectral bands based on respiration. AB - The work presented in this paper aims at assessing human emotion recognition by means of the analysis of the heart rate variability (HRV) with varying spectral bands based on respiratory frequency (RF). Three specific emotional states are compared corresponding to calm-neutral state (Relax), positive elicitation (Joy) and negative elicitation (Fear). Standard HRV analysis in time and frequency domain is performed. In order to better characterize the HRV component related to respiratory sinus arrhythmia, the high frequency (HF) band is centered on RF. Results reveal that the power content in low band (PLF), the normalized power content in HF band (PHFn) and the sympathovagal ratio (LF/HF) can be suitable indices to distinguish Relax and Joy. Mean heart rate and RF are significantly different between Relax and Fear. Different HRV indices show significant differences between Joy and Fear, such as pNN50, PLF, PHFn and LF/HF. Statistical analysis of HRV indices with HF centered in the RF results in a lower p-value than the ones with a HF standard band. PMID- 26737693 TI - Bayesian fusion of algorithms for the robust estimation of respiratory rate from the photoplethysmogram. AB - Respiratory rate (RR) is a key vital sign that is monitored to assess the health of patients. With the increase of the availability of wearable devices, it is important that RR is extracted in a robust and noninvasive manner from the photoplethysmogram (PPG) acquired from pulse oximeters and similar devices. However, existing methods of noninvasive RR estimation suffer from a lack of robustness, resulting in the fact that they are not used in clinical practice. We propose a Bayesian approach to fusing the outputs of many RR estimation algorithms to improve the overall robustness of the resulting estimates. Our method estimates the accuracy of each algorithm and jointly infers the fused RR estimate in an unsupervised manner, with aim of producing a fused estimate that is more accurate than any of the algorithms taken individually. This approach is novel in the literature, where the latter has so far concentrated on attempting to produce single algorithms for RR estimation, without resulting in systems that have penetrated into clinical practice. A publicly-available dataset, Capnobase, was used to validate the performance of our proposed model. Our proposed methodology was compared to the best-performing individual algorithm from the literature, as well as to the results of using common fusing methodologies such as averaging, median, and maximum likelihood (ML). Our proposed methodology resulted in a mean-absolute-error (MAE) of 1.98 breaths per minute (bpm), outperformed other fusing strategies (mean fusion: 2.95 bpm; median fusion: 2.33 bpm; ML: 2.30 bpm). It also outperformed the best single algorithm (2.39 bpm) and the benchmark algorithm proposed for use with Capnobase (2.22 bpm). We conclude that the proposed fusion methodology can be used to combine RR estimates from multiple sources derived from the PPG, to infer a reliable and robust estimation of the respiratory rate in an unsupervised manner. PMID- 26737694 TI - Heart rate variability during plateau waves of intracranial pressure: A pilot descriptive study. AB - This study aims to describe heart rate variability during the first episode of plateau waves of intracranial pressure (ICP) in Traumatic Brain Injury (TBI) in order to characterize and identify at bedside this cerebrovascular phenomenon. The general behavior of the heart rate variability (HRV) spectral measures expressed in the medians across patients is concordant with an increased HRV in the latter part of the baseline and plateau wave, followed by a decrease after the event and a new increase during the recovery. In low and high frequency bands the same increase is more marked in the parametric analysis. Interpretation of HRV may help clinicians to better identify the plateau waves and allow earlier management. PMID- 26737695 TI - Characterization and reduction of motion artifacts in photoplethysmographic signals from a wrist-worn device. AB - Methods for analyzing various motion artifacts in photoplethysmography (PPG) signals, recorded by a wristworn device are reported. The analysis looks both at intrinsic PPG signal properties, through standard deviation, skew and kurtosis, but also at its relationship to five possible motion reference signals, through the correlation coefficient and mutual information. The investigated references include the X, Y, Z accelerometer axes, acceleration magnitude and a different wavelength PPG channel. The latter showed higher correlation to the input PPG signal during movement. A wavelet based motion artifact reduction algorithm is described. The algorithm improves the visibility of the heart rate (HR) components in the frequency domain representation of the signals. PMID- 26737696 TI - Estimating instantaneous respiratory rate from the photoplethysmogram. AB - The photoplethysmogram (PPG) obtained from pulse oximetry shows the local changes of blood volume in tissues. Respiration induces variation in the PPG baseline due to the variation in venous blood return during each breathing cycle. We have proposed an algorithm based on the synchrosqueezing transform (SST) to estimate instantaneous respiratory rate (IRR) from the PPG. The SST is a combination of wavelet analysis and a reallocation method which aims to sharpen the time frequency representation of the signal and can provide an accurate estimation of instantaneous frequency. In this application, the SST was applied to the PPG and IRR was detected as the predominant ridge in the respiratory band (0.1 Hz - 1 Hz) in the SST plane. The algorithm was tested against the Capnobase benchmark dataset that contains PPG, capnography, and expert labelled reference respiratory rate from 42 subjects. The IRR estimation accuracy was assessed using the root mean square (RMS) error and Bland-Altman plot. The median RMS error was 0.39 breaths/min for all subjects which ranged from the lowest error of 0.18 breaths/min to the highest error of 13.86 breaths/min. A Bland-Altman plot showed an agreement between the IRR obtained from PPG and reference respiratory rate with a bias of -0.32 and limits agreement of -7.72 to 7.07. Extracting IRR from PPG expands the functionality of pulse oximeters and provides additional diagnostic power to this non-invasive monitoring tool. PMID- 26737697 TI - Spectral decomposition of pupillary unrest using wavelet entropy. AB - Respiratory and cardiovascular rhythms were discovered in the temporal fluctuations of pupil sizes. The mechanism is physiologically explainable but the potential clinical importance of pupillary unrest has not been studied extensively in the past. Here we analyzed the pupillograms of 29 healthy controls on different time scales and correlated the results to established indices of cardiovascular and cardiorespiratory autonomic function. We discovered a clear lateralization of pupil unrest dependencies. Correlation to vagal heart rate regulation and baroreflex sensitivity indicates the significance of the left pupil's fluctuations evaluating the status of the autonomic nervous system. PMID- 26737698 TI - Analysis of sympathovagal balance in patients with major depressive disorder using wavelet packet transform. AB - Elevated rates of cardiac morbidity have been frequently reported in major depressive disorder (MDD) patients as a result of the relationship between autonomic dysfunctions and varied cardiovascular activity. Heart rate variability (HRV) analysis is an important and non-invasive way for assessing the variances in autonomic nervous system activity of MDD patients. In spectral domain, HRV analysis is usually done by either Fourier transformation (FT) or discrete wavelet transformation (DWT) to divide the data into lowfrequency (LF) and high frequency (HF) bands. However, while FT is not a proper method for non-stationary HRV data, DWT does not exactly produce required frequency ranges of each LF and HF bands. The purpose of the present study is to investigate the spectral HRV measures obtained by wavelet packet transform (WPT) with absolutely excellent approximation to predefined frequency ranges of bands. Eighteen healthy controls and age- and gender-match eighteen patients with MDD were participated in this study. Sympathovagal balance (LF/HF ratio) that reflects the variation of sympathetic and parasympathetic activities was compared between two groups. Individuals with depression had a significantly higher LF/HF ratio. Our findings suggest that dysfunctions in coordination between sympathetic and parasympathetic nervous system activity in MDD patients can be evaluated by WPT based HRV analysis with high resolution decomposition for required LF and HF bands. PMID- 26737699 TI - Autonomic nervous system response to L-dopa in patients with advanced Parkinson's disease. AB - Levodopa is the main treatment method for reducing the symptoms of Parkinson's disease. Whereas it reduces the motor symptoms efficiently, its effect on autonomous nervous system is not clear. The information about effect of levodopa on heart rate variability is not coherent between the studies. In this study, ECG of 11 patients with Parkinson's disease was measured during levodopa challenge with pronounced dose of fast release levodopa to ensure the positive drug effect for deep brain stimulation treatment. Heart rate variability analysis was done at three time points, before administration of levodopa, 30 and 60 minutes after administration. After 30 minutes of administration, the HRV parameters show that parasympathetic nervous system activity is decreased and the sympatho-vagal balance is shifted towards sympathetic control. At 60 minutes after administration the parasympathetic nervous system activates slightly and causes a decrease in heart rate. PMID- 26737700 TI - Heart Rate monitoring during physical exercise using wrist-type photoplethysmographic (PPG) signals. AB - Heart rate monitoring using wrist-type using photoplethysmographic (PPG) signals during subjects' intensive exercises is a challenging problem, since signals are strongly affected by motion artifacts caused by unexpected movements. This paper presents a method that uses both time and frequency characteristics of signals; using sparse signal reconstruction for high-resolution spectrum estimation. Experimental results on type data sets recorded from 12 subjects during fast running at peak speed of 15 km/hour. The results have a performance with the average absolute error being 1.80 beat per minute. PMID- 26737701 TI - SSVEP-based BCI: A "Plug & play" approach. AB - Brain-Computer Interface (BCI) can provide users with an alternative/augmentative interaction path, based on the interpretation of their brain activity. Steady State Visual Evoked Potentials (SSVEP) paradigm has many appealing features, aiming at implementing BCI-enabled communication-control applications. In this paper, we present a complete signal processing chain for a self-paced, SSVEP based BCI. The proposed approach mostly focuses at reducing the user effort in dealing with BCI, featuring no need of user-specific calibration or training. In this paper, the classification algorithm is introduced and first validated on offline waveforms, aiming at improving classification accuracy and minimizing the false positive rate. Then, implementation of an online, self-paced SSVEP BCI is illustrated. The scheme refers to a four-way choice and exploits discrimination between intentional control states and nocontrol ones. Good performance is achieved, both in terms of true positive rate (>94%), as well as low false positive rate (0.26 min(-1)), even in experiments carried out outside lab controlled conditions. PMID- 26737702 TI - A new approach for SSVEP detection using PARAFAC and canonical correlation analysis. AB - This paper presents a new way for automatic detection of SSVEPs through correlation analysis between tensor models. 3-way EEG tensor of channel * frequency * time is decomposed into constituting factor matrices using PARAFAC model. PARAFAC analysis of EEG tensor enables us to decompose multichannel EEG into constituting temporal, spectral and spatial signatures. SSVEPs characterized with localized spectral and spatial signatures are then detected exploiting a correlation analysis between extracted signatures of the EEG tensor and the corresponding simulated signatures of all target SSVEP signals. The SSVEP that has the highest correlation is selected as the intended target. Two flickers blinking at 8 and 13 Hz were used as visual stimuli and the detection was performed based on data packets of 1 second without overlapping. Five subjects participated in the experiments and the highest classification rate of 83.34% was achieved, leading to the Information Transfer Rate (ITR) of 21.01 bits/min. PMID- 26737703 TI - P300 latency Jitter occurrence in patients with disorders of consciousness: Toward a better design for Brain Computer Interface applications. AB - In this study the P300 latency jitter has been explored in an EEG data set collected from a group of patients with disorders of consciousness (DOC; n=13) that was administered with an auditory Oddball paradigm under passive and active conditions. A method based on wavelet transform was applied to estimate single trial P300 waveforms. Preliminary results showed that 5 Vegetative State (VS) and 8 Minimally Conscious Staten (MCS) patients exhibited significantly higher values of P300 latency jitter as compared to those obtained from a control group of 12 healthy subjects. In addition, the magnitude of the P300 latency jitter negatively correlated with patients' clinical status. The existence of such phenomenon might substantially limit an effective use of Brain Computer Interface systems for communication. PMID- 26737704 TI - Avionic technology testing by using a cognitive neurometric index: A study with professional helicopter pilots. AB - In this study, we investigated the possibility to evaluate the impact of different avionic technologies on the mental workload of helicopter's pilots by measuring their brain activity with the EEG during a series of simulated missions carried out at AgustaWestland facilities in Yeovil (UK). The tested avionic technologies were: i) Head-Up Display (HUD); ii) Head-Mounted Display (HMD); iii) Full Conformal symbology (FC); iv) Flight Guidance (FG) symbology; v) Synthetic Vision System (SVS); and vi) Radar Obstacles (RO) detection system. It has been already demonstrated that in cognitive tasks, when the cerebral workload increases the EEG power spectral density (PSD) in theta band over frontal areas increases, and the EEG PSD in alpha band decreases over parietal areas. A mental workload index (MWL) has been here defined as the ratio between the frontal theta and parietal alpha EEG PSD values. Such index has been used for testing and comparing the different avionic technologies. Results suggested that the HUD provided a significant (p<;.05) workload reduction across all the flight scenarios with respect to the other technologies. In addition, the simultaneous use of FC and FG technologies (FC+FG) produced a significant decrement of the workload (p<;.01) with respect to the use of only the FC. Moreover, the use of the SVS technology provided on Head Down Display (HDD) with the simultaneous use of FC+FG and the RO seemed to produce a lower cerebral workload when compared with the use of only the FC. Interestingly, the workload estimation by means of subjective measures, provided by pilots through a NASA-TLX questionnaire, did not provide any significant differences among the different flight scenarios. These results suggested that the proposed MWL cognitive neurometrics could be used as a reliable measure of the user's mental workload, being a valid indicator for the comparison and the test of different avionic technologies. PMID- 26737705 TI - A lossless data reduction technique for wireless EEG recorders and its use in selective data filtering for seizure monitoring. AB - This paper presents a time-domain based lossless data reduction technique called Log2 Sub-band encoding, which is designed for reducing the size of data recorded on a wireless electroencephalogram (EEG) recorder. A data reduction unit can help to save power from the wireless transceiver and from the storage medium since it allows lower data transmission and read/write rates, and then extends the life time of the battery on the device. Our compression ratio(CR) results show that Log2 Sub-band encoding is comparable and even superior to Huffman coding, a well known entropy encoding method, whilst requiring minimal hardware resource, and it can also be used to extract features from EEG to achieve seizure detection during the compression process. The power consumption when compressing the EEG data is presented to evaluate the system0s overall improvement on its power performance, and our results indicate that a noticeable power saving can be achieved with our technique. The possibility of applying this method to other biomedical signals will also be noted. PMID- 26737706 TI - Local spatial correlation analysis of hand flexion/extension using intraoperative high-density ECoG. AB - We recorded motor cortical activity using highdensity electrocorticogram (ECoG) from three patients during awake craniotomy. Subjects repeatedly executed hand flexion/extension tasks according to auditory instructions. Clear event-related desynchronization (ERD) in beta band (8-32) Hz and event-related synchronization (ERS) in gamma band (60-200) Hz were observed. High frequency band (HFB: 60-200 Hz) activation was found to be more localized compared to low frequency band (LFB: 8-32 Hz) activation in all subjects. Local spatial correlation maps in LFB and HFB were constructed by computing the correlation between channels. Local spatial correlation dropped more in the ERD/ERS areas consistently in two subjects. The results indicate that ERD/ERS patterns are more spatially uncorrelated and denser ECoG electrode is necessary within these areas to map uncorrelated 'sources'. High resolution electrodes might improve both clinical functional mapping and brain machine interface outcomes in the near future. PMID- 26737707 TI - Automatic localization of epileptic spikes in eegs of children with infantile spasms. AB - A novel methodology is proposed for identifying epileptiform discharges associated with individuals exhibiting Infantile Spasms (ISS) also known as West Syndrome, which is characterized by electroencephalogram (EEG) recordings exhibiting hypsarrythmia (HYPS). The approach to identify these discharges consists of three stages: first - construct the time-frequency domain (TFD) of the EEG recording using matching pursuit TFD (MP-TFD), second - decompose the TFD matrix into two submatrices (W, H) using non-negative matrix factorization (NMF), and third - use the decomposed spectral and temporal vectors to locate the epileptiform discharges, referred to as spikes, during intervals of HYPS. The method was applied to an EEG dataset of five individuals and the identification of spike locations was compared with those which were visually identified by the epileptologists and those obtained using commercially available clinical analysis software. The MP-TFD method resulted in average true positive and false negative percentages of 86% and 14%, respectively, which represents a significant improvement over the clinical software, which achieved average true positive and false negative percentages of 4% and 96%, respectively. PMID- 26737708 TI - Using bio-signals to evaluate multi discomfort in image viewing - balancing visually induced motion sickness and field of view. AB - Visually induced motion sickness (VIMS) is a key factor triggering discomfort with image viewing systems. Reducing VIMS by shrinking the field of view (FOV) is effective though this increases discomfort through situational awareness loss. This paper derives an objective score from bio-signals to evaluate multifactor discomforts caused by VIMS and FOV. We also investigate the image characteristics that induce discomfort. The subjective score and LF/HFscore ratio index increase with FOV as expected. Another result is that for some image sequences the bio signal index increases significantly more at smallest FOV than with large FOV mode. This result suggests that the bio-signal index could be key indicator of multifactor discomfort, including balance of VIMS and FOV. PMID- 26737709 TI - An ERP study about the effects of different spatial frequencies and orientations on human brain activity. AB - Spatial, temporal frequencies as well as orientations are important visual stimulus properties, which will affect human perception. In this paper, we investigated the effects of gratings with different spatial, temporal frequencies and orientations on visual evoked potentials. Two positive components (P1 and P2) were observed after stimulation. Our results showed that the amplitude of P1 component was higher for gratings with 0.3 cycles per degree (cpd) spatial frequency compared to 0.05 and 0.1 cpd. While the amplitude differences of P2 component occurred between 0.05 and 0.1 cpd. The amplitude of both components were higher when subjects were viewing gratings at vertical orientation than horizontal orientation. PMID- 26737710 TI - EEG time and frequency domain analyses of primary insomnia. AB - In this work, we present a range of electroencephalographic (EEG) time and frequency domain features that can be used to characterize patients suffering with primary insomnia. When evaluated using 10 insomniacs and 10 healthy subjects, we found significant differences in the feature values between the two groups. Participants with primary insomnia were observed to have significantly elevated Hjorth's parameters particularly complexity, high zero crossing rates specifically during wake and sleep stage 1 and high gamma power in all sleep stages. Given the significant differences between the two groups, these features can be used to better understand the sleep dynamics of insomniacs and accurately discriminate insomniac EEG data from that of healthy subjects. PMID- 26737711 TI - Multiscale AM-FM methods on EEG signals for motor task classification. AB - In this manuscript, we present the use of customized, multiscale amplitude modulation frequency-modulation (AMFM) methods on electroencephalography (EEG) brain signals during the subject development a motor task: right hand and left hand. This approach is compared to various non-linear patterns and methods that have been applied in order to characterize and understand the dynamic behavior of the EEG signals. The AM-FM methods have been optimized in terms of multiscale filters for the mu band (8-12 Hz). The instantaneous AM-FM values are processed using their probability density function and classified using multiple layer perceptron (MLP) and the partial least squares regression (PLS). The system is tested using the standard BCI dataset with results with a precision to 89% and an area under the ROC to 91%. PMID- 26737712 TI - A quantitative evaluation of alcohol withdrawal tremors. AB - This paper evaluates the relation between Alcohol Withdrawal Syndrome tremors in the left and right hands of patients. By analyzing 122 recordings from 61 patients in emergency departments, we found a weak relationship between the left and right hand tremor frequencies (correlation coefficient of 0.63). We found a much stronger relationship between the expert physician tremor ratings (on CIWA Ar 0-7 scale) of the two hands, with a correlation coefficient of 0.923. Next, using a smartphone to collect the tremor data and using a previously developed model for obtaining estimated tremor ratings, we also found a strong correlation (correlation coefficient of 0.852) between the estimates of each hand. Finally, we evaluated different methods of combining the data from the two hands for obtaining a single tremor rating estimate, and found that simply averaging the tremor ratings of the two hands results in the lowest tremor estimate error (an RMSE of 0.977). Looking at the frequency dependence of this error, we found that higher frequency tremors had a much lower estimation error (an RMSE of 1.102 for tremors with frequencies in the 3-6Hz range as compared to 0.625 for tremors with frequencies in the 7-10Hz range). PMID- 26737713 TI - Amplitude and frequency changes in surface EMG of biceps femoris during five days Bruce Protocol treadmill test. AB - Electromyography (EMG) is one of the indirect tools in indexing fatigue. Fatigue can be detected when there are changes on amplitude and frequency. However, various outcomes from literature make researchers conclude that EMG is not a reliable tool to measure fatigue. This paper investigates EMG behavior of biceps femoris in median frequency and mean absolute value during five days of Bruce Protocol treadmill test. Before that, surface EMG signals are filtered using band pass filter cut-off at 20-500Hz and are de-noised using db45 1-decimated wavelet transform. Five participants achieved more than 85% of their maximal heart rate during the running activity. The authors also consider other markers of fatigue such as performance, muscle soreness and lethargy as indicators to adaptation and maladaptation conditions. Result shows that turning points of median frequency and mean absolute value are very significant in indexing fatigue and indicators to adaptation of resistive training. PMID- 26737714 TI - Wavelet-based motion artifact removal for electrodermal activity. AB - Electrodermal activity (EDA) recording is a powerful, widely used tool for monitoring psychological or physiological arousal. However, analysis of EDA is hampered by its sensitivity to motion artifacts. We propose a method for removing motion artifacts from EDA, measured as skin conductance (SC), using a stationary wavelet transform (SWT). We modeled the wavelet coefficients as a Gaussian mixture distribution corresponding to the underlying skin conductance level (SCL) and skin conductance responses (SCRs). The goodness-of-fit of the model was validated on ambulatory SC data. We evaluated the proposed method in comparison with three previous approaches. Our method achieved a greater reduction of artifacts while retaining motion-artifact-free data. PMID- 26737715 TI - Differentiating tremor patients using spiral analyses. AB - Essential tremor follows an autosomal dominant type of inheritance in the majority of patients, yet its genetic basis has not been identified. The age of onset in this tremor is bimodal, one in young age and another when they are old. The old onset is referred to as senile tremor in this study. The precise pathology is still not completely understood for both these tremors. We wanted to develop an easy diagnostic tool to differentiate these two tremors clinically. In this study, the spirals were asked to be drawn by 30 patients, 15 from each group. The spirals were recorded digitally from each hand, with and without the spiral template, using a Wacom intuos version 4 tablets. The aim of the study was to look at the easy diagnostic measures from these spirals to distinguish the two cohorts of patients. The first measure was to use the well-known clinical scores like the number of complete circles without the template, width, height, axis, and degree of severity. The second measure was to estimate the peak frequency and the peak amplitude for the position, velocity, and acceleration data, in the frequency domain. The well-known clinical scores, most of them, did not show any significant difference between the two patient cohorts except the degree of severity which showed significant difference. The peak frequency and the peak amplitude in most of the data were not significantly different between the two cohorts of patients, only the peak amplitude from the acceleration data showed significant difference. Thus, we could use these two parameters to differentiate between the two tremors patient groups, which would be an easy clinical diagnostic tool without the need for any complicated analyses. PMID- 26737716 TI - Effect of downsampling and compressive sensing on audio-based continuous cough monitoring. AB - This paper presents an efficient cough detection system based on simple decision tree classification of spectral features from a smartphone audio signal. Preliminary evaluation on voluntary coughs shows that the system can achieve 98% sensitivity and 97.13% specificity when the audio signal is sampled at full rate. With this baseline system, we study possible efficiency optimisations by evaluating the effect of downsampling below the Nyquist rate and how the system performance at low sampling frequencies can be improved by incorporating compressive sensing reconstruction schemes. Our results show that undersampling down to 400 Hz can still keep sensitivity and specificity values above 90% despite of aliasing. Furthermore, the sparsity of cough signals in the time domain allows keeping performance figures close to 90% when sampling at 100 Hz using compressive sensing schemes. PMID- 26737717 TI - Automatic assessment of voice quality in the context of multiple annotations. AB - Approaches to evaluate voice quality include perceptual analysis, and acoustical analysis. Perceptual analysis is subjective and depends mostly on the ability of a specialist to assess a pathology, whereas acoustical analysis is objective, but highly relies on the quality of the so called annotations that the specialist assigns to the voice signal. The quality of the annotations for acoustical analysis depends heavily on the expertise and knowledge of the specialist. We face a scenario where we have annotations performed by several specialists with different levels of expertise and knowledge. Traditional pattern recognition methods employed in acoustical analysis are no longer applicable, since these methods are designed for scenarios where a "ground-truth" label is assigned by the specialist. In this paper, we apply recent developments in machine learning for taking into account multiple annotators for acoustical analysis of voice signals. For the classification step we compare two techniques, one of them based on Gaussian Processes for regression with multiple annotators, and the other is a multi-class Logistic Regression model that measures the annotator performance in terms of sensitivity and specificity. The performance of classifiers is assessed in terms of Cohen's Kappa index. Results show that the multi-annotator classification schemes have better performance when compared to techniques based on a traditional classifier where the true label is estimated from the multiple annotations available using majority voting. PMID- 26737718 TI - Single pixel camera: An acquisition strategy based on the non-linear wavelet approximation. AB - Single pixel imaging opened the door to a cheaper camera architecture able to operate in a wide spectral range. Compressive sensing has been used with such an optical setup to reconstruct an image using l1-minimization. To avoid this type of reconstruction, we consider an adaptive approach leading to a direct restoration of an image and for which we propose a new acquisition strategy. Our technique allows one to acquire an image in the wavelet domain with a progressive non-linear acquisition strategy. This scheme is based on the non-linear approximation of the wavelet transform which takes advantage of the transformation's sparsity. This approximation is applied in a multiresolution way and is shown to offer high compression performance on simulated data. One application of the single pixel camera concerns time-resolved acquisition to observe fluorescence lifetime images of biological structures. PMID- 26737719 TI - Probabilistic graphical modeling of speckle statistics in laser speckle contrast imaging for noninvasive and label-free retinal angiography. AB - This paper introduces a noninvasive and label-free approach for retinal angiography using Laser speckle contrast imaging (LSCI). Retinal vessel structure is segmented using a Hidden Markov Random Field (HMRF) based model. Prior to that, k-means clustering is used to obtain initial parameter set and labels for HMRF. Final parameter set for HMRF is estimated using expectation-maximization (EM) algorithm and final labeling is achieved using maximum aposteriori (MAP) algorithm. Clique energy for HMRF is computed from eigenvalue analysis of structure tensor for each pixel. This helps to get connectivity in the direction of strongest tangents in its neighborhood, facilitating the tracking of fine vessels in retinal vascular network. Quantitative evaluation shows an average vessel segmentation accuracy of 96.41% in normal condition with substantial improvement in tracking capability of fine vessels. Changes in blood flow can be tracked and observed at segmented output; particularly applicable for the study of different pathological conditions. PMID- 26737720 TI - Detection and density estimation of goblet cells in confocal endoscopy for the evaluation of celiac disease. AB - Celiac Disease (CD) is an immune-mediated enteropathy, diagnosed in the clinical practice by intestinal biopsy and the concomitant presence of a positive celiac serology. Confocal Laser Endomicroscopy (CLE) allows skilled and trained experts to potentially perform in vivo virtual histology of small-bowel mucosa. In particular, it allows the qualitative evaluation of mucosa alteration such as a decrease in goblet cells density, presence of villous atrophy or crypt hypertrophy. We present a semi-automatic computer-based method for the detection of goblet cells from confocal endoscopy images, whose density changes in case of pathological tissue. After a manual selection of a suitable region of interest, the candidate columnar and goblet cells' centers are first detected and the cellular architecture is estimated from their position using a Voronoi diagram. The region within each Voronoi cell is then analyzed and classified as goblet cell or other. The results suggest that our method is able to detect and label goblet cells immersed in a columnar epithelium in a fast, reliable and automatic way. Accepting 0.44 false positives per image, we obtain a sensitivity value of 90.3%. Furthermore, estimated and real goblet cell densities are comparable (error: 9.7 +/- 16.9%, correlation: 87.2%, R(2) = 76%). PMID- 26737721 TI - Hot-spot selection and evaluation methods for whole slice images of meningiomas and oligodendrogliomas. AB - The paper presents a combined method for an automatic hot-spot areas selection based on penalty factor in the whole slide images to support the pathomorphological diagnostic procedure. The studied slides represent the meningiomas and oligodendrogliomas tumor on the basis of the Ki-67/MIB-1 immunohistochemical reaction. It allows determining the tumor proliferation index as well as gives an indication to the medical treatment and prognosis. The combined method based on mathematical morphology, thresholding, texture analysis and classification is proposed and verified. The presented algorithm includes building a specimen map, elimination of hemorrhages from them, two methods for detection of hot-spot fields with respect to an introduced penalty factor. Furthermore, we propose localization concordance measure to evaluation localization of hot spot selection by the algorithms in respect to the expert's results. Thus, the results of the influence of the penalty factor are presented and discussed. It was found that the best results are obtained for 0.2 value of them. They confirm effectiveness of applied approach. PMID- 26737722 TI - A spectral approach for the quantitative description of cardiac collagen network from nonlinear optical imaging. AB - The assessment of collagen structure in cardiac pathology, such as atrial fibrillation (AF), is essential for a complete understanding of the disease. This paper introduces a novel methodology for the quantitative description of collagen network properties, based on the combination of nonlinear optical microscopy with a spectral approach of image processing and analysis. Second-harmonic generation (SHG) microscopy was applied to atrial tissue samples from cardiac surgery patients, providing label-free, selective visualization of the collagen structure. The spectral analysis framework, based on 2D-FFT, was applied to the SHG images, yielding a multiparametric description of collagen fiber orientation (angle and anisotropy indexes) and texture scale (dominant wavelength and peak dispersion indexes). The proof-of-concept application of the methodology showed the capability of our approach to detect and quantify differences in the structural properties of the collagen network in AF versus sinus rhythm patients. These results suggest the potential of our approach in the assessment of collagen properties in cardiac pathologies related to a fibrotic structural component. PMID- 26737723 TI - Corneal deformation dynamics in normal and glaucoma patients utilizing scheimpflug imaging. AB - The purpose of this study was to explore the corneal deformation dynamics recorded in raw Scheimpflug images of CorVis ST tonometer to evaluate age- and glaucoma-related changes in corneal biomechanics. This was a prospective study in which 18 subjects were recruited and divided into three equal groups (healthy young, healthy older and older glaucoma group). Up to three measurements by CorVis ST tonometer were acquired on the left eye of each subject. Raw Scheimpflug images of CorVis ST were used to extract changes in anterior and posterior corneal profiles, which were further modeled by a Chebyshev polynomial expansion of optimally determined order. Corneal deformation dynamics were studied via time-varying series of Chebyshev polynomial coefficients, in which three phases of corneal deformation were determined. The first and the last phase of corneal dynamics were fitted with bilinear functions. Further, the slope of each linear trend in the model was tested between the groups. Statistically significant differences were observed in the final return phase of corneal dynamics between the older group of subjects and those of glaucoma subjects indicating possible biomechanical differences in their tissues that could only be observed with minimum applied pressure. PMID- 26737724 TI - Neurotransmitter vesicle movement dynamics in living neurons. AB - The communication between two neurons is established by endogenous chemical particles aggregated in vesicles that move along the axons. It is known that an abnormal transport of these vesicles is correlated with neurodegenerative diseases. The quantification of the dynamics of vesicles movement can therefore be a window to study early detection of such diseases. Nevertheless, most of the studies in the literature rely on manual tracking techniques. In this paper we present a novel methodology for quantifying neurotransmitter vesicle dynamics by using a combination of image tracking and classification algorithms. We use confocal microscopy videos of living neurons to detect and classify vesicles using support vector machine (SVM), while motion is extracted via global nearest neighbor (GNN) tracking approach. Results of the classification algorithm are presented and compared to a ground truth dataset defined by experts. Sensitivity of 90% and specificity of 97% were obtained at a much lower computational cost than an established method from the literature (0.24s/frame vs. 125s/frame). These preliminary results suggest the great potential of the method and tool we have been developing for single particle movement dynamics measure in living cells. PMID- 26737725 TI - Proof of concept of an automatic tool for bioluminescence imaging data analysis. AB - Bioluminescence Imaging (BLI) is an important molecular imaging tool to assess complex biological processes in vivo. BLI is a sensitive technique, which is frequently used in small-animal preclinical research, mainly in oncology and neurology. Tracking of labeled cells is one of the major applications. However, BLI data analysis for the segmentation of up-taking regions and their quantification is not trivial and it is usually an operator-dependent activity. In this work, a proof of concept of an automatic method to analyze BL images is presented which is based on a multi-step approach. Different segmentation algorithms (K-means, Gaussian Mixture Model (GMM), and GMM initialized by K means) were evaluated and an adequate image normalization step was suggested to include the background bioluminescence in the data analysis process. K-means segmentation is the most stable and accurate approach for different levels of signal intensity. PMID- 26737726 TI - Motion reduction and multidimensional denoising in Voltage-sensitive Dye imaging. AB - Optical Imaging using Voltage-sensitive Dyes is characterized by low fractional changes in fluorescent light intensity upon the application of a stimulus, which leads to slight value differences between pixels on an in-general noisy image sequence. The application of an anisotropic diffusion filtering scheme, in order to contribute to the denoising of the optical images, is proposed as one option to improve its quality and for a better understanding of the physiological processes they represent. We apply an image registration approach to compensate for motion artifacts, such that we do not need to mount a fixed cranial chamber onto the skull. In this work, electrical stimulation to the tibial nerve in a rat model was used to register evoke potentials, imaging the somatosensory cortex of the animal, which was previously stained with the RH1691 dye. PMID- 26737727 TI - Reduction of light source noise from optical intrinsic signals of mouse neocortex by using independent component analysis. AB - Because the optical intrinsic signal (OIS) of the brain is very weak, noise reduction is essential. Independent component analysis (ICA) is widely used for noise reduction. However, the applicability of ICA to the reduction of light source (LS) noise has not been discussed in detail. In addition, determining the proper number of independent components (ICs) for decomposition is very important to a reasonable classification of the ICs. In this study, we considered the applicability of ICA to LS noise reduction by modeling the impact of LS noise on OIS data. We propose a method for determining the number of ICs that uses the power spectral density of LS noise. To evaluate its usefulness, the method was applied to real OIS data of a mouse's cerebral cortex. PMID- 26737728 TI - A comparison of signal processing techniques for Intrinsic Optical Signal imaging in mice. AB - Intrinsic Optical Signal imaging is a technique which allows the visualisation and mapping of activity related changes within the brain with excellent spatial and temporal resolution. We analysed a variety of signal and image processing techniques applied to real mouse imaging data. The results were compared in an attempt to overcome the unique issues faced when performing the technique on mice and improve the understanding of post processing options available. PMID- 26737729 TI - Estimation of neuronal activity based on voltage-sensitive dye imaging in a moving preparation. AB - Voltage-sensitive dye imaging allows simultaneous recording of graded voltage changes of multiple neurons. While this experimental technique is a great tool to study neuronal network activity in neuroscience, the optical recording suffers from artifacts. In particular, bleaching of the dye and cell movement impede the analysis and interpretation of imaging results. In this paper, we present methods to tackle these two main artifacts. Cell movement during the experiment is corrected by an optical flow method. Bleaching decay is estimated based on a line fit of recordings without stimulus, which is subtracted from the rest of the recordings in the same experiment. Here, we use a leech ganglion as an example tissue to evaluate these processing procedures. This preparation allows simultaneous voltage-sensitive dye imaging of the entire neuronal network and intracellular recording of one cell's membrane voltage. Using the intracellularly recorded voltage as the ground truth reference, we show that our processing methods for the VSD imaging signal clearly improve the correlation between the real and the estimated voltage. Since other imaging techniques (e.g., calcium imaging) suffer from the same type of artifacts as voltage-sensitive dye imaging, our processing method might be useful for a wide range of biomedical imaging studies. PMID- 26737730 TI - Measuring blood flow velocity from intravital video recordings. AB - There is an obvious scientific interest in computing blood flow velocity from intravital microscopy using digital video cameras attached to microscopes. Therefore, software capable of measuring blood flow velocity from videos is of major importance. In this work, a novel software tool is presented. The software tackles three main issues in velocity measurement from videos, the registration, segmentation, and finally the measuring itself. The software was tested in chick chorioallantoic membrane (CAM) videos captured with different resolutions, frame rates, and even cameras. The obtained results show the robustness achieved. PMID- 26737731 TI - Measurement of vital sign in chick embryo using multi-channel diffuse speckle contrast analysis. AB - In poultry industry which is avian breeding program, the determination whether chick embryos survive in the artificial incubation periods or not is essential to reduce the financial resources. We developed the multi-channel diffuse speckle contrast analysis (DSCA) system composed of four optical fiber detectors enabling to achieve in-vivo measurements of deep tissue flow noninvasively. The system could confirm vital sign of the chick embryo in early incubation stage. Moreover, it demonstrates the change of relative blood flow index and depth information with simplicity, low cost, and flexibility. PMID- 26737732 TI - Spatial localization of ryanodine receptors in human cardiac cells. AB - We present a novel image processing method to determine the location of ryanodine receptors in cardiac cells. A semi-automatic manual validation by an expert has been used in order to establish the performance of the segmentation method. The approach provides high accuracy under different experimental conditions and it is robust to common sources of noise including experimental, molecular and biological fluctuations. PMID- 26737733 TI - A new modality of bidimensional Compton camera. AB - The concept of Compton camera originates from the need to improve sensitivity in Single Photon Emission Imaging, which uses hole collimators. It advocates electronic collimation which registers radiation emitted by the radiating object and scattered by a scattering detector placed before an absorption detector. The data consists of three dimensional conical projections of the activity density of a radio-tracer. An analytic reconstruction method of this density is presently not available. To evaluate its imaging power, we consider a particular two dimensional Compton camera in which the collected data consists of the set of integrals of the density on rotating V-lines. In this communication, we present simulation results obtained from an algebraic reconstruction technique, which illustrate and validate the imaging capability of this Compton camera modality. PMID- 26737734 TI - Tuning of a deformable image registration procedure for skin component mechanical properties assessment. AB - Several studies report the mechanical properties of skin tissues but their values largely depend on the measurement method. Therefore, we investigated the feasibility of recognizing the cellular constituents mechanical properties of pigmented skin by Confocal Laser Scanner Microscopy (CLSM). With this purpose, an healthy volunteer was examined in three areas nearby a pigmented skin lesion in two configurations: deforming and non deforming the nevus. The tissue displacement of the nevus was then assessed by means of deformable registration of the images in these two configurations. There are several registration strategy able to overcome this task, among them, we proposed two methods with different deformation models: a Free Form Deformation (FFD) model based on b spline and a second one based on Demons Registration Algorithm (DRA). These two strategies need the definition of several parameters in order to obtain optimal registration performances. Thus, we tuned these parameters by means of simulated data and evaluated their registration abilities on the real in vivo CLSM acquisitions in the two configurations. The results showed that the registration using DRA had a better performance in comparison to the FFD one, in particular in two out of the three areas the DRA performance was significantly better than the FFD one. The registration procedure highlighted deformation differences among the chosen areas. PMID- 26737735 TI - Intrinsic elastography and its dependence on arterial flow volume. AB - We propose a new estimation method of tissues stiffness from deformation induced by arterial pulsation. The new method was named Intrinsic Elastography (IE). Under two assumptions that the deformation induced by pulsation propagates throughout the body, and the propagation velocity (PV) is closely related to the mechanical properties of tissues, the IE can evaluate the tissue stiffness based on the PV. However, this method has an issue that the observed PVs change with the changes of amounts of the flow. In this paper, we propose the new estimation method in order to estimate true shear elasticity in spite of the changes. The results was compared to the results of SWI. The results was almost identical to the result of SWI, or showed the similar results. PMID- 26737736 TI - Using ultrasound image analysis to evaluate the role of elastography imaging in the diagnosis of carotid atherosclerosis. AB - Valid characterization of carotid atherosclerosis (CA) is a crucial public health issue, which would limit the major risk held by CA for both patient safety and state economies. CA is typically diagnosed and assessed using duplex ultrasonography (US). Elastrography Imaging (EI) is a promising US technique for quantifying tissue elasticity (ES). In this work, we investigated the association between ES of carotid atherosclerotic lesions, derived from EI, and texture indices, calculated from US image analysis. US and EI images of 23 atherosclerotic plaques (16 patients) were analyzed. Texture features derived from US image analysis (Gray-Scale Median (GSM), plaque area (A) and co occurrence-matrixderived features) were calculated. Statistical analysis revealed associations between US texture features and EI measured indices. This result indicates accordance in US and EI techniques and states the promising role of EI in diagnosis of CA. PMID- 26737737 TI - A texture analysis approach for objective uniformity evaluation in diagnostic ultrasound imaging: A preliminary study. AB - Ultrasound image uniformity is an important parameter for quality assurance in diagnostic ultrasounds, but it is usually assessed by a qualitative judgement of technicians so its estimation is rough and subjective. In this work a novel method is developed to give an objective measurement of the Bmode image uniformity over the whole field of view or some of its part: the Texture Distribution Analysis Method (TDAM) is based on a segmentation of the Region of Interest, depending on some texture features calculated from co-occurrence matrices. Results on a set of 10 test images with different non-uniformities (Uniformity Image Test Set or UITS) show a good sensitivity and agreement of TDAM with the mean judgment by 5 human observers (TUV): TDAM and TUV uniformity values are coherent for the whole UITS, nevertheless a high uncertainty in uniformity values has been observed (up to 28 percent). Preliminary results look encouraging and more efforts are worth to refine the method. PMID- 26737738 TI - Breast tumor classification in ultrasound images using neural networks with improved generalization methods. AB - Mammography, scintimammography and ultrasound images have been used to increase the specificity of breast cancer image diagnosis. Concerning breast cancer image diagnosis with ultrasound, some results found in the literature show better performance of morphological features in breast cancer lesion differentiation and that a reduced set of features shows a better performance than a large set of features. In this study we evaluated the performance of neural network classifiers, with different training stop criteria: mean square error, early stop and regularization. The last two criteria were developed to improve neural network generalization. Different sets of morphological features were used as neural network inputs. Training sets comprised of 22, 8, 7, 6, 5 and 4 features were employed. To select reduced sets of features, a scalar selection technique with correlation was used. The best results obtained for accuracy and area under the ROC curve were 96.98% and 0.98, respectively. The performance obtained with all 22 features is slightly better than the one obtained with a reduced set of features. PMID- 26737739 TI - HoG feature based detection of tissue deformations in ultrasound data. AB - The fast development of imaging techniques during last decades makes it possible to introduce intra-operative visualization as the integral part of surgical procedures. Therefore, the automated analysis of intra-operative ultrasound images is appreciated. The image processing, registration and visualization techniques help in better understanding and locate the operated region. To meet these needs, the paper presents an advanced algorithm for automated detection of tissue deformations caused by a biopsy needle. For this, feature set of Histogram of Gradients (HoG) is introduced. The extracted feature vectors are then used in image cell clustering step resulting in tissue deformation as well as biopsy needle detection. The applied there Kernelized Weighted C-Means clustering technique enables robust and accurate needle detection proven by sensitivity and specificity values at levels of 0.846 and 0.99, respectively. PMID- 26737740 TI - A semi-automatic process for estimating fetus velocity using ultrasound imaging and videos. AB - Contemporary technologies have positively affected everyday medical practice for the benefit of faster and more objective diagnoses. Image and video processing techniques have added potential to this effort, but still there is a long road ahead. In this paper a specially developed video processing methodology is described which determines the fetus velocity using B-mode ultrasonic video imaging. For that purpose, a semi-automated process using advanced computer vision and image processing tools is presented and evaluated. The results are presented with a detailed statistical analysis to verify the repeatability ad reliability of the method. PMID- 26737741 TI - High-contrast and low-computational complexity medical ultrasound imaging using beamspace capon method. AB - Several adaptive beamforming techniques have been proposed to improve the quality of medical ultrasound images. The beamspace (BS) Capon method is one common method used to depict high-resolution images with low computational complexity. However, the complexity is not low enough for real-time imaging in clinical situations because the conventional BS Capon method employs a time-delay process and a transition process from elementspace signal processing to BS signal processing at all points of interest. Thus, we propose a technique that replaces the time-delay process using a steering vector. In addition, the Capon method employs a spatial averaging (SA) technique to stabilize the estimation in intensity. However, when the averaging size is not adequate, the estimated intensity might be smaller than that given by the delay-and-sum (DAS) method. Because most medical diagnoses are presented based on the estimation of intensity acquired by the DAS beamformer, accurate estimation of intensity is also required. Therefore, we propose a compensation technique that uses both small and large sizes for SA. In an experiment, the -6 dB beam width, sidelobe level, and estimation error in the intensity of the proposed method were 0.17 mm, -27 dB, and 0.92 dB, respectively, where those of the conventional BS Capon method were 0.29 mm, -22 dB, and 8.1 dB. The complexity of the proposed method is one fourteenth that of the conventional method. Compared with conventional methods, the proposed method succeeded in depicting a higher-contrast image with accurate intensity estimation and lower computational complexity. PMID- 26737742 TI - Carotid ultrasound segmentation using radio-frequency derived phase information and gabor filters. AB - Ultrasound image segmentation is a field which has garnered much interest over the years. This is partially due to the complexity of the problem, arising from the lack of contrast between different tissue types which is quite typical of ultrasound images. Recently, segmentation techniques which treat RF signal data have also become popular, particularly with the increasing availability of such data from open-architecture machines. It is believed that RF data provides a rich source of information whose integrity remains intact, as opposed to the loss which occurs through the signal processing chain leading to Brightness Mode Images. Furthermore, phase information contained within RF data has not been studied in much detail, as the nature of the information here appears to be mostly random. In this work however, we show that phase information derived from RF data does elicit structure, characterized by texture patterns. Texture segmentation of this data permits the extraction of rough, but well localized, carotid boundaries. We provide some initial quantitative results, which report the performance of the proposed technique. PMID- 26737743 TI - Clutter Rejection methods in Doppler color flow imaging: Single-ensemble vs. multi-ensemble. AB - Clutter filter which efficiently increases the estimation accuracy of blood flow velocity attracts much attentions in Doppler color flow imaging. In this paper, we briefly introduce several state-of-the-art clutter suppression methods based on our recently works and categorize them to the singleensemble method and multi ensemble one. Then the computing complexity of all competing methods were analyzed in-depth to provide a valuable suggestion at the real clinical situations. Furthermore, two group of clinical experiments on volunteer's carotid artery and kidney data were used to evaluate performance between single-ensemble methods and multi-ensemble ones. The results verify that the single-ensemble method shows best clutter rejection when imaging single carotid vessel, while the multi-ensemble method achieves a higher performance for kidney imaging which includes multi-stage vessels. PMID- 26737744 TI - A simulation study on the choice of regularization parameter in l2-norm ultrasound image restoration. AB - Ultrasound image deconvolution has been widely investigated in the literature. Among the existing approaches, the most common are based on l2-norm regularization (or Tikhonov optimization) or the well-known Wiener filtering. However, the success of the Wiener filter in practical situations largely depends on the choice of the regularization hyperparameter. An appropriate choice is necessary to guarantee the balance between data fidelity and smoothness of the deconvolution result. In this paper, we revisit different approaches for automatically choosing this regularization parameter and compare them in the context of ultrasound image deconvolution via Wiener filtering. Two synthetic ultrasound images are used in order to compare the performances of the addressed methods. PMID- 26737745 TI - Scatterer reconstruction and parametrization of homogeneous tissue for ultrasound image simulation. AB - Numerical simulation of ultrasound images can facilitate the training of sonographers. A realistic appearance of simulated ultrasonic speckle is essential for a plausible ultrasound simulation. An efficient and realistic model for ultrasonic speckle is the convolution of the ultrasound point-spread function with a parametrized distribution of point scatterers. Nevertheless, for a given arbitrary tissue, such scatterer distributions that would generate a realistic image are not known a priori, and currently there is no principled method to extract such scatterer patterns for given target tissues to be simulated. In this paper we propose to solve the inverse problem, in which an underlying scatterer map for a given sample ultrasound image is estimated. From such scatterer maps, it is also shown that a parametrization distribution model can be built, using which other instances of the same tissue can be simulated by feeding into a standard speckle generation method. This enables us to synthesize images of different tissue types from actual ultrasound images to be used in simulations with arbitrary view angles and transducer settings. We show in numerical and physical tissue-mimicking phantoms and actual physical tissue that the appearance of the synthesized images closely match the real images. PMID- 26737746 TI - Dynamic estimation of myocardial deformation using ultrasound RF-data: A preliminary study. AB - Analytic minimization (AM) is one of elastography algorithms. In this study, a healthy male volunteer lying in lateral position was examined by an ultrasound system. The left ventricular long-axis view of the heart was acquired and the ultrasound radio frequency (RF) data were stored for estimation of myocardial deformation. The methods of AM and Linear polynomial curve fitting were used to calculate the displacement and strain, respectively. The myocardial deformation was dynamically estimated. The strain maps at approximately 50ms, 140ms, and 240ms after the beginning of the ventricle systole indicate the contraction of different myocardial segments. This study provides a potential method to assess the survival myocardium in patients with myocardial infarction in future study. PMID- 26737747 TI - Measurement of ultrasonic diaphragmatic motion. AB - The motion characteristics of the diaphragmatic muscle may provide useful information about normal and abnormal diaphragmatic function and indicate diaphragmatic weakness. The objective of this paper was to introduce a simple system for the quantitative analysis of ultrasonic diaphragmatic motion. The measurements routinely carried out by the experts were computed and these include: (i) excursion, (ii) inspiration time (Tinsp) and (iii) cycle duration (Ttot). The system was evaluated on four simulated videos and one real video. Manual and automated measurements were very close. Further work in a larger number of videos is needed for validating the proposed method. PMID- 26737748 TI - Weighted locality-constrained linear coding for lesion classification in CT images. AB - Computed tomography is a popular imaging modality for detecting abnormalities associated with abdominal organs such as the liver, kidney and uterus. In this paper, we propose a novel weighted locality-constrained linear coding (LLC) method followed by a weighted max-pooling method to classify liver lesions into three classes: cysts, metastases, hemangiomas. We first divide the lesions into same-size patches. Then, we extract the raw features in all patches followed by Principal Components Analysis (PCA) and apply K means to obtain a single LLC dictionary. Since the interior lesion patches and the boundary patches contribute different information in the image, we assign different weights on these two types of patches to obtain the LLC codes. Moreover, a weighted max pooling approach is also proposed to further evaluate the importance of these two types of patches in feature pooling. Experiments on 109 images of liver lesions were carried out to validate the proposed method. The proposed method achieves a best lesion classification accuracy of 96.33%, which appears to be superior compared with traditional image coding methods: LLC method and Bag-of-words method (BoW) and traditional features: Local Binary Pattern (LBP) features, uniform LBP and complete LBP, demonstrating that the proposed method provides better classification. PMID- 26737750 TI - Development and analysis of a finite element model to simulate pulmonary emphysema in CT imaging. AB - In CT imaging, pulmonary emphysema appears as lung regions with Low-Attenuation Areas (LAA). In this study we propose a finite element (FE) model of lung parenchyma, based on a 2-D grid of beam elements, which simulates pulmonary emphysema related to smoking in CT imaging. Simulated LAA images were generated through space sampling of the model output. We employed two measurements of emphysema extent: Relative Area (RA) and the exponent D of the cumulative distribution function of LAA clusters size. The model has been used to compare RA and D computed on the simulated LAA images with those computed on the models output. Different mesh element sizes and various model parameters, simulating different physiological/pathological conditions, have been considered and analyzed. A proper mesh element size has been determined as the best trade-off between reliable results and reasonable computational cost. Both RA and D computed on simulated LAA images were underestimated with respect to those calculated on the models output. Such underestimations were larger for RA (~ -44 / -26%) as compared to those for D (~ -16 / -2%). Our FE model could be useful to generate standard test images and to design realistic physical phantoms of LAA images for the assessment of the accuracy of descriptors for quantifying emphysema in CT imaging. PMID- 26737749 TI - Correlations between X-ray attenuation and GAG content of different cartilage layers based on contrast agent enhanced Micro-CT. AB - OBJECTIVES: To build the quantitative relationships between X-ray attenuation and glycosaminoglycan (GAG) content of different layers of progressive trypsin digested articular cartilage (AC) models based on the contrast agent enhanced Micro-CT. METHODS: Bovine AC samples were treated with 0.5% concentration of trypsin for different degeneration time, immersed in contrast agent and then scanned by Micro-CT to obtain the X-ray attenuation. Combining with histological analysis, the relationships between the X-ray attenuation and GAG optical density of the superficial and middle layer were analyzed. RESULTS: The X-ray mean attenuation increased about 16.48% (p<;0.01) in the superficial layer within the first 10-minute degeneration, 26.99% (p<;0.05) in the middle layer within the first 40-minute degeneration, but merely changed in the deep layer in the entire experiment. Contrary to the change of X-ray mean attenuation, the GAG optical density decreased from 31.98+/-13.00 to 11.69+/-4.23 (p<;0.01) in the superficial layer within the first 10-minute degeneration, from 82.94+/-7.35 to 3.85+/-3.31 (p<;0.01) in the middle layer within the entire degeneration and didn't slightly decrease from 96.10+/-2.50 to 91.45+/-1.90 (p<;0.05) until the last 10-minute degeneration in deep layer. In addition, the changes of the X-ray mean attenuation showed negative linear correlations with the GAG content in the superficial (r = -0.984, p<;0.01) and the middle layer (r = -0.960, p<;0.01), respectively. CONCLUSION: The contrast agent enhanced Micro-CT can elucidate the variation of GAG content in trypsin-induced progressive AC models by X-ray mean attenuation of different cartilage layers. PMID- 26737751 TI - Combined bone lesion analysis in 3D CT data of vertebrae. AB - Two novel statistically based methods for bone lesion detection and classification are presented. Together with the previously published MRF method [15], they form a triad of mutually complementary methods that promise, when fused, to enable higher reliability of bone lesion assessment. PMID- 26737752 TI - Quantitative study of osteoporosis model based on synchrotron radiation. AB - To investigate the changes of different periods of primary osteoporosis, we made quantitative analysis of osteoporosis using synchrotron radiation computed tomography (SRCT), together with histomorphometry analysis and finite element analysis (FEA). Tibias, femurs and lumbar vertebras were dissected from sham ovariectomy rats and ovariectomized rats suffering from osteoporosis at certain time points. The samples were scanned by SRCT and then FEA was applied based on reconstructed slices. Histomorphometry analysis showed that the structure of some trabecular in osteoporosis degraded as the bone volume decreased, for femurs, the bone volume fraction (BV/TV) decreased from 69% to 43%. That led to the increase of the thickness of trabecular separation (from 45.05MUm to 97.09MUm) and the reduction of the number of trabecular (from 7.99 mm(-1) to 5.97mm(-1)). Simulation of various mechanical tests indicated that, with the exacerbation of osteoporosis, the bones' ability of resistance to compression, bending and torsion gradually became weaker. The compression stiffness decreased from 1770.96 FMUm(-1) to 697.41 FMUm(-1), and it matched the histomorphometry analysis. This study suggested that the combination of both analysis could quantitatively analyze the bone strength in good accuracy. PMID- 26737753 TI - Detection of microcalcification with top-hat transform and the Gibbs random fields. AB - Breast cancer is one of the most common causes of death in women aged 40 and above. Early detection of breast cancer has been one of the prime topics of research in biomedical engineering area. Micro-calcifications (MCs) are the indicators of early stages of breast cancer, and the detection of these MCs will, in turn, lead to diagnosis and treatment of breast cancer at its earliest stages. This paper proposes a new method to detect MCs in a digital mammogram. The approach starts with the segmentation of the digital mammogram to isolate the breast region, using fuzzy C means clustering algorithm. The segmented image is then further segmented using top-hat transform to localize the region of interest. A watershed transform is used to isolate the region of interest from rest of the image. The Gibbs random fields are employed to analyze the pixels in conjunction with the devised clique patterns and detect MCs in the image. A thresholding is performed on the processed image where the MCs are detected. The proposed algorithm is highly effective in reducing the region of interest to the region which has a high probability of finding a calcification or MC. It has an overall detection rate of 94.4% and accuracy of 88.2% with a false negative detection rate of 5.6%, respectively. PMID- 26737754 TI - Algorithm for automatic angles measurement and screening for Developmental Dysplasia of the Hip (DDH). AB - Developmental Dysplasia of the Hip (DDH) is a medical term represent the hip joint instability that appear mainly in infants. The examination for this condition can be done by ultrasound for children under 6 months old and by X-ray for children over 6 months old. Physician's assessment is based on certain angles derived from those images, namely the Acetabular Angle, and the Center Edge Angle. In this paper, we are presenting a novel, fully automatic algorithm for measuring the diagnostic angles of DDH from the X-ray images. Our algorithm consists of Automatic segmentation and extraction of anatomical landmarks from X ray images. Both of Acetabular angle and Center edge angle are automatically calculated. The analysis included X-ray images for 16 children recruited for the purposed of this study. The automatically acquired angles accuracy for Acetabular Angle was around 85%, and an absolute deviation of 3.4 degrees +/-3.3 degrees compared to the physician's manually calculated angle. The results of this method are very promising for the future development of an automatic method for screening X-ray images DDH that complement and aid the physicians' manual methods. PMID- 26737755 TI - Alterations of diaphragm and rib cage morphometry in severe COPD patients by CT analysis. AB - Although it is known that in patients with COPD acute hyperinflation determines shortening of the inspiratory muscles, its effects on both diaphragm and rib cage morphology are still to be investigated. In this preliminary study the relationships between hyperinflation, emphysema, diaphragm and rib cage geometry were studied in 5 severe COPD patients and 5 healthy subjects. An automatic software was developed to obtain the 3-D reconstruction of diaphragm and rib cage from CT scans taken at total lung capacity (TLC) and residual volume (RV). Dome surface area (Ado), radius of curvature, length (Ld) and position (referred to xiphoid level) of the diaphragm and antero-posterior (A-P) and transverse (T) diameters of rib cage were calculated at both volumes. Ado and Ld were similar in COPD and controls when compared at similar absolute lung volumes. Radius of curvature was significantly higher in COPD than in controls only at TLC. In COPD, the range of diaphragm position was invariantly below the xiphoid level, while in controls the top of diaphragm dome was always above it. Rib cage diameters were not different at TLC. A-P diameter was greater in COPD than in controls at RV, while T diameters were similar. In conclusion, in severe COPD diaphragm and rib cage geometry is altered at RV. The lower position of diaphragm is associated to smaller A-P but not transversal rib cage diameters, such that rib cage adopts a more circular shape. PMID- 26737756 TI - A new computer-aided detection scheme based on assessment of local bilateral mammographic feature asymmetry - a preliminary evaluation. AB - Accurate segmentation of breast lesions depicting on two-dimensional projection mammograms has been proven very difficult and unreliable. In this study we investigated a new approach of a computer-aided detection (CAD) scheme of mammograms without lesion segmentation. Our scheme was developed based on the detection and analysis of region-of-interest (ROI)-based bilateral mammographic tissue or feature asymmetry. A bilateral image registration, image feature selection process, and naive Bayes linear classifier were implemented in CAD scheme. CAD performance predicting the likelihood of either an ROI or a subject (case) being abnormal was evaluated using 161 subjects from the mini-MIAS database and a leave-one-out testing method. The results showed that areas under receiver operating characteristic (ROC) curves were 0.87 and 0.72 on the ROI based and case-based evaluation, respectively. The study demonstrated that using ROI-based bilateral mammographic tissue asymmetry can provide supplementary information with high discriminatory power in order to improve CAD performance. PMID- 26737757 TI - A survey of remote optical photoplethysmographic imaging methods. AB - In recent years researchers have presented a number of new methods for recovering physiological parameters using just low-cost digital cameras and image processing. The ubiquity of digital cameras presents the possibility for many new, low-cost applications of vital sign monitoring. In this paper we present a review of the work on remote photoplethysmographic (PPG) imaging using digital cameras. This review specifically focuses on the state-of-the-art in PPG imaging where: 1) measures beyond pulse rate are evaluated, 2) non-ideal conditions (e.g., the presence of motion artifacts) are explored, and 3) use cases in relevant environments are demonstrated. We discuss gaps within the literature and future challenges for the research community. To aid in the continuing advancement of PPG imaging research, we are making available a website with the references collected for this review as well as information on available code and datasets of interest. It is our hope that this website will become a valuable resource for the PPG imaging community. The site can be found at: http://web.mit.edu/~djmcduff/www/ remote-physiology.html. PMID- 26737758 TI - Peripheral venous blood oxygen saturation can be non-invasively estimated using photoplethysmography. AB - Measurement of peripheral venous oxygen saturation (SvO2) is currently performed using invasive catheters or direct blood draw. The purpose of this study was to non-invasively determine SvO2 using a variation of pulse oximetry techniques. Artificial respiration-like modulations applied to the peripheral vascular system were used to infer regional SvO2 using photoplethysmography (PPG) sensors. To achieve this modulation, an artificial pulse generating system (APG) was developed to generate controlled, superficial perturbations on the finger using a pneumatic digit cuff. These low pressure and low frequency modulations affect blood volumes in veins to a much greater extent than arteries due to significant arterial-venous compliance differences. Ten healthy human volunteers were recruited for proof-ofconcept testing. The APG was set at a modulation frequency of 0.2 Hz (12 bpm) and 45-50 mmHg compression pressure. Initial analysis showed that induced blood volume changes in the venous compartment could be detected by PPG. Estimated arterial oxygen saturation (97% [IQR=96.1%-97.4%]) matches published values (95%-99%). Estimated venous oxygen saturation (93.2% [IQR=91. 93.9%]) agrees with reported ranges (92%-95%) measured in peripheral regions. The median difference between the two saturations was 3.6%, while the difference between paired measurements in each subject was statistically significant (p=0.002). These results demonstrate the feasibility of this method for real time, low cost, non-invasive estimation of SvO2. Further validation of this method is warranted. PMID- 26737759 TI - Development of a photon-cell interactive monte carlo simulation for non-invasive measurement of blood glucose level by Raman spectroscopy. AB - Turbidity variation is one of the major limitations in Raman spectroscopy for quantifying blood components, such as glucose, non-invasively. To overcome this limitation, we have developed a Raman scattering simulation using a photon-cell interactive Monte Carlo (pciMC) model that tracks photon migration in both the extra- and intracellular spaces without relying on the macroscopic scattering phase function and anisotropy factor. The interaction of photons at the plasma cell boundary of randomly oriented three-dimensionally biconcave red blood cells (RBCs) is modeled using geometric optics. The validity of the developed pciMCRaman was investigated by comparing simulation and experimental results of Raman spectroscopy of glucose level in a bovine blood sample. The scattering of the excitation laser at a wavelength of 785 nm was simulated considering the changes in the refractive index of the extracellular solution. Based on the excitation laser photon distribution within the blood, the Raman photon derived from the hemoglobin and glucose molecule at the Raman shift of 1140 cm(-1) = 862 nm was generated, and the photons reaching the detection area were counted. The simulation and experimental results showed good correlation. It is speculated that pciMCRaman can provide information about the ability and limitations of the measurement of blood glucose level. PMID- 26737760 TI - Surface plasmon resonance biosensor as a tool for the measurement of complex refractive indices. AB - Optical characterisation of liquids through the measurement of their complex refractive index is critical in environmental monitoring, food industry and medicine. While surface plasmon resonance is widely used for measurement of the real part of the refractive index there have been few studies to date on measurement of complex refractive index with this method. We present a systematic study which highlights the challenges associated with this approach. Instrument design and data analysis techniques are presented together with preliminary experimental results. PMID- 26737761 TI - Investigation of photoplethysmography, laser doppler flowmetry and near infrared spectroscopy during induced thermal stress. AB - Continuous assessment of blood flow, blood volume, and blood and tissue oxygenation are of vital importance in critically ill patients. Photoplethysmography (PPG), Pulse Oximetry (PO), Laser Doppler Flowmetry (LDF) and Near Infrared Spectroscopy (NIRS) are amongst the most widely used techniques to monitor such perfusion parameters. In this study, we investigated the feasibility of using dual-wavelength PPG signals on providing comparable information as LDF and NIRS, besides arterial oxygen saturation (SpO2) as measured by pulse oximetry. All three techniques were investigated on six healthy volunteers during whole-body cold exposure. PPG and LDF sensors were attached on the finger and hand respectively, while NIRS was positioned above the left forearm. Measurements at room temperature (24 degrees C) were followed and preceded by a cold exposure (10 degrees C). The results showed that changes in pulsatile PPG amplitudes and hemoglobin concentration estimated from finger PPG signals indicate strong similarities with gold-standard LDF and NIRS measurements. PMID- 26737762 TI - Discrete wavelength selection for the optical readout of a metamaterial biosensing system for glucose concentration estimation via a support vector regression model. AB - In this contribution, a method to select discrete wavelengths that allow an accurate estimation of the glucose concentration in a biosensing system based on metamaterials is presented. The sensing concept is adapted to the particular application of ophthalmic glucose sensing by covering the metamaterial with a glucose-sensitive hydrogel and the sensor readout is performed optically. Due to the fact that in a mobile context a spectrometer is not suitable, few discrete wavelengths must be selected to estimate the glucose concentration. The developed selection methods are based on nonlinear support vector regression (SVR) models. Two selection methods are compared and it is shown that wavelengths selected by a sequential forward feature selection algorithm achieves an estimation improvement. The presented method can be easily applied to different metamaterial layouts and hydrogel configurations. PMID- 26737763 TI - Pulse wave registration from radial artery using photoplethysmographic method. AB - This pilot study was aimed to investigate the possibilities to use the photoplethysmographic (PPG) method for the pulse wave registration from radial artery. The PPG sensor with different separation distances between light emitting diodes (LED) and photodiode was built. The PPG signal registration was carried out at the locations with two different depths of artery and at the locations without large blood vessels under the sensor. In addition, two different forces were applied on the sensor in order to decrease the blood volume in underlying tissue and lower the pulsations that originates from smaller vessels. As a result, it was found that the artery was possible to locate under the sensor, where the value of DC component is minimal. Furthermore, the pressure has to be applied on sensor and optimal separation distance has to be selected between LED and photodiode for the pulse wave registration from radial artery. Further studies and improvements of the sensor are needed. PMID- 26737764 TI - Noninvasive pulse transit time measurement for arterial stiffness monitoring in microgravity. AB - The use of a noninvasive hemodynamic monitor to estimate arterial stiffness, by measurement of pulse transit time (PTT), was demonstrated in microgravity. The monitor's utility for space applications was shown by establishing the correlation between ground-based and microgravity-based measurements. The system consists of a scale-based ballistocardiogram (BCG) and a toe-mounted photoplethysmogram (PPG). PTT was measured from the BCG I-wave to the intersecting tangents of the first trough and maximum first derivative of the PPG waveforms of each subject. The system was tested on a recent series of parabolic flights in which the PTT of nine subjects was measured on the ground and in microgravity. An average of 60.2 ms PTT increase from ground to microgravity environments was shown, and was consistent across all test subjects (standard deviation = 32.9 ms). This increase in PTT could be explained by a number of factors associated with microgravity and reported in previous research, including elimination of hydrostatic pressure, reduction of intrathoracic pressure, and reduction of mean arterial pressure induced by vasodilation. PMID- 26737765 TI - Feasibility of an electrodermal activity ring prototype as a research tool. AB - Electrodermal activity is an indicator of sympathetic activation and a useful tool for investigating psychological and physiological arousal. Novel wearable skin conductivity sensors offer portable low-cost solutions for long-term monitoring. In this article we compare the similarity of signals between a prototype of the wearable Moodmetric EDA Ring and a laboratory-grade skin conductance sensor in a psychophysiological experiment. The similarity of the signals was estimated by calculating the cosine distance between phasic features extracted from decomposed signals. The similarity was on average 83.3% +/- 16.4%. The compound error of the decomposition process was also investigated and no systematic bias was observed towards either device. We conclude that the prototype ring is a promising device for ecologically valid field studies. PMID- 26737766 TI - Stress of Kindergarten teachers: How we tried to detect and to reduce it by using a small and wearable ECG and acceleration measuring device? AB - In 2014 school year, four female teachers of Nazareth Kindergarten decided to resign (DRT) due to workplace stress caused by human relationships between themselves. Our preliminary interview investigation revealed there was a stressor (STR), a certain elder female teacher and her less polite words and attitude. Using small and wearable ECG and acceleration measuring device, we measured 24 hour's autonomic nervous system's activity (ASNA) and sleep behavior of the STR and surrounding teachers, and tried to evaluate their stress objectively and to understand the reason of STR's less polite behaviors. For comparison, we also measured female Mind-Body Medicine (MBM) patients suffering adjustment disorder and clinical depression. PMID- 26737767 TI - Ambient light cancellation in photoplethysmogram application using alternating sampling and charge redistribution technique. AB - To overcome a large DC offset, ambient light interference, and optical path variation, a robust PPG readout chip is fabricated using 0.13-MUm CMOS process. Against the large DC offset, a saturation detection and current feedback method can compensate a current of up to 30 MUA. To be robust against optical path variation, an automatic emitting light compensation method is adopted. To remove the ambient light interference, we propose an alternating sampling and charge redistribution technique, in which no additional power is consumed, and only three differential switches and one capacitor are required. The PPG readout channel consumes 26 MUW and has a input referred current noise of 260 pArms. PMID- 26737768 TI - pH measurements of FET-based (bio)chemical sensors using portable measurement system. AB - In this study we demonstrate the sensing capabilities of a portable multiplex measurement system for FET-based (bio)chemical sensors with an integrated microfluidic interface. We therefore conducted pH measurements with Silicon Nanoribbon FET-based Sensors using different measurement procedures that are suitable for various applications. We have shown multiplexed measurements in aqueous medium for three different modes that are mutually specialized in fast data acquisition (constant drain current), calibration-less sensing (constant gate voltage) and in providing full information content (sweeping mode). Our system therefore allows surface charge sensing for a wide range of applications and is easily adaptable for multiplexed sensing with novel FET-based (bio)chemical sensors. PMID- 26737769 TI - Visualization method based stiffness sensing system for endoscopes. AB - This research developed novel stiffness sensing system attachable to endoscope. The system is an extension of our previous force sensing systems utilizing force visualization mechanism. The sensing part is attached to endoscopes. The force is visualized at the sensing part, and can be measured as visual information via endoscopes. The sensing part also has a structure of limiting the pressing amount. By measuring force at the limitation, the stiffness can be measured. The developed sensing part has the features of no electrical components, disposable, simple, easy sterilization, MRI-compatibility, and low-cost. The validation of the system was experimentally shown. PMID- 26737770 TI - Performance comparison of Next Generation sequencing platforms. AB - Next Generation DNA Sequencing technologies offer ultra high sequencing throughput for very low prices. The increase in throughput and diminished costs open up new research areas. Moreover, number of clinicians utilizing DNA sequencing keeps growing. One of the main concern for researchers and clinicians who are adopting these platforms is their sequencing accuracy. We compared three of the most commonly used Next Generation Sequencing platforms; Ion Torrent from Life Technologies, GS FLX+ from Roche and HiSeq 2000 from Illumina. PMID- 26737771 TI - Genome-based microorganism classification using coalition formulation game. AB - Genome-based microorganism classification is the one of interesting issues in microorganism taxonomy. However, the advance in sequencing technology requires a low-complex algorithm to process a great amount of bio sequence data. In this paper, we suggest a coalition formation game for microorganism classification, which can be implemented in distributed manner. We extract word frequency feature from microorganism sequences and formulate the coalition game model that considers the distance among word frequency features. Then, we propose a coalition formation algorithm for clustering microorganisms with feature similarity. The performance of proposed algorithm is compared with that of conventional schemes by means of an experiment. According to the result, we showed that the correctness of proposed distributed algorithm is similar to that of conventional centralized schemes. PMID- 26737772 TI - Effect of low-expression gene filtering on detection of differentially expressed genes in RNA-seq data. AB - We compare methods for filtering RNA-seq lowexpression genes and investigate the effect of filtering on detection of differentially expressed genes (DEGs). Although RNA-seq technology has improved the dynamic range of gene expression quantification, low-expression genes may be indistinguishable from sampling noise. The presence of noisy, low-expression genes can decrease the sensitivity of detecting DEGs. Thus, identification and filtering of these low-expression genes may improve DEG detection sensitivity. Using the SEQC benchmark dataset, we investigate the effect of different filtering methods on DEG detection sensitivity. Moreover, we investigate the effect of RNA-seq pipelines on optimal filtering thresholds. Results indicate that the filtering threshold that maximizes the total number of DEGs closely corresponds to the threshold that maximizes DEG detection sensitivity. Transcriptome reference annotation, expression quantification method, and DEG detection method are statistically significant RNA-seq pipeline factors that affect the optimal filtering threshold. PMID- 26737773 TI - An optimal method to segment piecewise poisson distributed signals with application to sequencing data. AB - To analyze the next generation sequencing data, the so-called read depth signal is often segmented with standard segmentation tools. However, these tools usually assume the signal to be a piecewise constant signal and contaminated with zero mean Gaussian noise, and therefore modeling error occurs. This paper models the read depth signal with piecewise Poisson distribution, which is more appropriate to the next generation sequencing mechanism. Based on the proposed model, an opti mal dynamic programming algorithm with parallel computing is proposed to segment the piecewise signal, and furthermore detect the copy number variation. PMID- 26737774 TI - A multi-fold string kernel for sequence classification. AB - A novel framework is proposed to classify biological sequences using a kernel. It considers the topological information along with the primary structural information. The widely used string kernel for sequence classification does not take into account the structural information which might be available for biological sequences. The proposed kernels incorporate the additional structural information and thus make the features more informative. PMID- 26737775 TI - Tracking single-cells in overcrowded bacterial colonies. AB - Cell tracking enables data extraction from timelapse "cell movies" and promotes modeling biological processes at the single-cell level. We introduce a new fully automated computational strategy to track accurately cells across frames in time lapse movies. Our method is based on a dynamic neighborhoods formation and matching approach, inspired by motion estimation algorithms for video compression. Moreover, it exploits "divide and conquer" opportunities to solve effectively the challenging cells tracking problem in overcrowded bacterial colonies. Using cell movies generated by different labs we demonstrate that the accuracy of the proposed method remains very high (exceeds 97%) even when analyzing large overcrowded microbial colonies. PMID- 26737776 TI - Metabolite analysis in sepsis through conditional independence maps. AB - Sepsis is the response of the host to an infection that produces lesions in its own organs and tissues. Despite the great advances in modern medicine, including vaccines, antibiotics and intensive care, it is still the primary cause of death due to infection. Sepsis may result in shock, multi-organic failure and death unless there is a rapid identification of the infection and timely administration of treatment. Its mortality rates can reach up to 45.7% for septic shock, its most acute manifestation. In this paper we also present these conditional independence maps in the context of algebraic statistics. The results of this analysis over a small cohort of nine patients at three different times (ICU admission, 48h and ICU discharge) showed that there is a significant interaction between C3- DC / C4-OH (Hydroxybutyrylcarnitine) and C5 (Valerylcarnitin) for the three time snapshots. We also found a significant interaction between C3-DC / C4 OH (Hydroxybutyrylcarnitine) and C5 (Valerylcarnitine) and Isoleucine (Ile) at 48h and ICU discharge. PMID- 26737777 TI - SRIdent: A novel pipeline for real-time identification of species from high throughput sequencing reads in Metagenomics and clinical diagnostic assays. AB - New advances in rapid sequencing of large amounts of DNA have brought a great potential for the study of complex communities of microorganisms. One of the challenging problems is rapid identification of species from sequenced reads. Delays in the identification of pathogens are a barrier to the early diagnosis and proper treatment of infectious diseases. In this paper we proposed SRIdent (Short Read Identifier), an effective pipeline for real-time identification of species from high-throughput sequencing reads in Metagenomics and clinical diagnostic assays. This pipeline is based on generating k-mers from the short reads and searching the existence of DNA signatures in the Reads k-mers, by using Apache Hive data-warehousing. RkmerG (Read k-mers Generator) is a software program presented in this paper, for producing k-mers of the short reads, in order to use in the pipeline. The purpose of this study is to identify the species in a sample, directly from the reads without assembling and alignment. PMID- 26737778 TI - C. elegans locomotion analysis using algorithmic information theory. AB - This article investigates the use of algorithmic information theory to analyse C. elegans datasets. The ability of complexity measures to detect similarity in animals' behaviours is demonstrated and their strengths are compared to methods such as histograms. Introduced quantities are illustrated on a couple of real two dimensional C. elegans datasets to investigate the thermotaxis and chemotaxis behaviours. PMID- 26737779 TI - DNA assembly with de bruijn graphs on FPGA. AB - This project aims to see if accelerators based on FPGAs are worthwhile for DNA assembly. It involves reprogramming an already existing algorithm - called Ray - to be run either on such an accelerator or on a CPU to be able to compare both. It has been achieved using the OpenCL language. The focus is put on modifying and optimizing the original algorithm to better suit the new parallelization tool. Upon running the new program on some datasets, it becomes clear that FPGAs are a very capable platform that can fare better than the traditional approach, both on raw performance and energy consumption. PMID- 26737780 TI - Modeling HPV early promoter regulation. AB - In high risk forms, human papillomaviruses (HPV) can either induce or promote cancerous lesions, especially cervical cancer which is considered the second most common cancer in the women worldwide. HPV life cycle is tightly linked to the infected cell differentiation program and its evolution is strictly joined to the switch between the early and the late viral polycistronic promoters.The aim of this study is to develop a novel mathematical model which collects and structures the available biologic knowledge on the early promoter regulation for HPV in episomal form. The model includes the main regulation by E2 viral protein as well as a novel discovered co-regulation function mediated by the viral E1 protein. Only by including both E2 and E1 regulatory effect the model is able to correctly predict the temporal behaviour of the early promoter switching off. A possible use of the model as in silico tool to evaluate new antiviral therapies is discussed. PMID- 26737781 TI - A network-based approach to enrich gene signatures for the prediction of breast cancer metastases. AB - Despite the multiplicity of the gene expression analysis studies for the identification of genomics based origins of cancerous diseases, the presented gene signatures have generally little overlap. The genes do not function in isolation and therefore a more holistic approach that takes into account the interactions among them is needed. In this study we present a stepwise refinement methodology where starting from some initial set of biomarkers we expand and enrich this set taking into account existing biological information. In particular, we start with a 27 gene signature previously identified as indicative of the presence of circulating tumor cells (CTCs) in peripheral blood of breast cancer patients. We use the manually curated HINT database of protein-protein interactions as the background biological network to locate the network-based similarity of the input genes and how they connect to each other. The result is an enriched connected set of genes that is subsequently expanded to form an even bigger network based on the ability of the surrounding genes to strongly correlate with the phenotypes of a training set of breast cancer patient cases. The induced network is then used as a new gene signature for the classification of breast brain metastases in an independent dataset. The results are encouraging for the validity of this method. PMID- 26737782 TI - An approach for optimally extending mathematical models of signaling networks using omics data. AB - Mathematical modeling is a key process in Systems Biology and the use of computational tools such as Cytoscape for omics data processing, need to be integrated in the modeling activity. In this paper we propose a new methodology for modeling signaling networks by combining ordinary differential equation models and a gene recommender system, GeneMANIA. We started from existing models, that are stored in the BioModels database, and we generated a query to use as input for the GeneMANIA algorithm. The output of the recommender system was then led back to the kinetic reactions that were finally added to the starting model. We applied the proposed methodology to EGFR-IGF1R signal transduction network, which plays an important role in translational oncology and cancer therapy of non small cell lung cancer. PMID- 26737783 TI - A computational model of Dopamine and Acetylcholine aberrant learning in Basal Ganglia. AB - Basal Ganglia (BG) are implied in many motor and cognitive tasks, such as action selection, and have a central role in many pathologies, primarily Parkinson Disease. In the present work, we use a recently developed biologically inspired BG model to analyze how the dopamine (DA) level can affect the temporal response during action selection, and the capacity to learn new actions following rewards and punishments. The model incorporates the 3 main pathways (direct, indirect and hyperdirect) working in BG functioning. The behavior of 2 alternative networks (the first with normal DA levels, the second with reduced DA) is analyzed both in untrained conditions, and during training performed in different epochs. The results show that reduced DA causes delayed temporal responses in the untrained network, and difficult of learning during training, characterized by the necessity of much more epochs. The results provide interesting hints to understand the behavior of healthy and dopamine depleted subjects, such as parkinsonian patients. PMID- 26737784 TI - Identifying gene subnetworks associated with clinical outcome in ovarian cancer using Network Based Coalition Game. AB - The problem of identifying interacting genes that jointly are associated with a phenotype is considered. When the number of features are extremely large compared to the number of samples, there may be several subsets of features that provide acceptable levels of predictability. This is particularly true in cancer genomics, where we are interested in finding functionally related gene sets likely to jointly drive cancer phenotypes. In this paper, a novel game theoretic solution is proposed by modeling genes as players of a Coalition Game. This method discovers and develops informative gene subnetworks by integrating gene expression profiling of cancer tissues with protein-protein interaction (PPI) networks. These subnetworks are gradually developed by selective addition of candidate genes that present maximal Shapely values in coalition with subnetworks of genes. We applied the proposed algorithm to an ovarian cancer dataset (N = 201), in order to identify optimal subnetworks that can predict cancer progression risk in response to platinum-based therapy. We show improved predictive power of the proposed method when compared to state-of-the-art feature selection methods, with the added advantage of identifying potentially functional gene subnetworks that may provide insights into the mechanisms underlying cancer progression. PMID- 26737785 TI - Non-linear Bayesian framework to determine the transcriptional effects of cancer associated genomic aberrations. AB - While the tumorigenic effects of specific recurrent mutations in known cancer driver-genes is well-characterized, not much is known about the functional relevance of the vast majority of recurrent mutations observed across cancers. Prior studies have attempted to identify functional genomic aberrations by integrating multi-omics measurements in cancer samples with community-curated biological pathway networks. However, the majority of these approaches overlook the following biological considerations: i) signaling pathway networks are highly tissue-specific and their regulatory interactions differ across tissue types; ii) regulatory factors exhibit heterogeneous influence on downstream gene transcription; iii) epigenetic and genomic alterations exhibit nonlinear impact on gene transcription. In order to accommodate these biological effects, we propose a hybrid Bayesian method to learn tissue-specific pairwise influence models amongst genes and to predict a gene's expression level as a nonlinear function of its epigenetic and regulatory influences. We employ a novel tree based depth-penalization mechanism in order to capture the higher regulatory impact of closer neighbors in the regulatory network. Using a breast cancer multi omics dataset (N=1190), we show that our proposed method has superior prediction power over optimization-based regression models, with the additional advantage of revealing gene deregulations potentially driven by somatic mutations. PMID- 26737786 TI - Differentiating disease subtypes by using pathway patterns constructed from gene expressions and protein networks. AB - Gene expression profiles differ in different diseases. Even if diseases are at the same stage, such diseases exhibit different gene expressions, not to mention the different subtypes at a single lesion site. Distinguishing different disease subtypes at a single lesion site is difficult. In early cases, subtypes were initially distinguished by doctors. Subsequently, further differences were found through pathological experiments. For example, a brain tumor can be classified according to its origin, its cell-type origin, or the tumor site. Because of the advancements in bioinformatics and the techniques for accumulating gene expressions, researchers can use gene expression data to classify disease subtypes. Because the operation of a biopathway is closely related to the disease mechanism, the application of gene expression profiles for clustering disease subtypes is insufficient. In this study, we collected gene expression data of healthy and four myelodysplastic syndrome subtypes and applied a method that integrated protein-protein interaction and gene expression data to identify different patterns of disease subtypes. We hope it is efficient for the classification of disease subtypes in adventure. PMID- 26737787 TI - Effect of fibre orientation on diastolic mechanics of human ventricle. AB - Fibre orientation of myocardial wall plays a significant role in ventricular wall stress, which is assumed to be responsible for many cardiac mechanics, including ventricular remodelling, associated with heart failure. Previous studies, conducted to identify the effects of fibre orientation on left -ventricle (LV) diastolic mechanics, used only animal's myocardium properties (no human data) and therefore, may not apply for predicting human cardiac mechanics. In the present study, computational modelling of LV diastole was carried out to investigate the effects of fibre orientation on LV end diastolic pressure volume relation (EDPVR) and wall stress distribution using subject-specific in vivo passive properties of human myocardium for two human hearts. Results indicated that LV inflation increased when fibres were aligned more towards LV longitudinal axis and the effect was more notable when the fibre angle was higher in endocardium than epicardium wall. Changes in fibre angle distribution considerably altered fibre stress distribution of LV wall and the changes were significant in anterior and lateral regions of equatorial and apical locations. Furthermore, the regions of high fibre stress from midwall to endocardium were gradually confined towards endocardium with the decrease in fibre angle. Such information will be useful for future studies/diagnoses of LV mechanics in normal and pathological conditions. PMID- 26737788 TI - Can we hear ventricle dyssynchrony? Yes, we can. AB - This study introduces a method for detection of ventricular depolarization activity and the transfer of this activity into an audible stereo audio signal. Heart potentials are measured by an ultra-high-frequency high-dynamic-range electrocardiograph (UHF-ECG) with a 25-kHz sampling rate. Averaged and prolonged UHF amplitude envelopes of V1-3 and V4-6 leads at a frequency range of 500-1000 Hz are used as a modulating function for two carrier audio frequencies. The right speaker makes it possible to listen to the depolarization of the septum and right ventricle (V1-3) and the left speaker the left ventricle lateral wall (V4-6). In the healthy heart, both speakers can be heard simultaneously. A delayed L or R speaker represents the dyssynchronous electrical activation of the ventricles. Examples of the normal heart, right bundle branch block and left bundle branch block can be heard at www.medisig.com/uhfecg. PMID- 26737789 TI - Automatic segmentation of the left ventricle into 17 anatomical regions in cardiac MR imaging. AB - Analysis and characterization of anatomical segments in the left ventricle (LV) of the heart in cardiac MRI convey clinical significance. Based on the standard defined by the American Heart Association (AHA), the LV is divided into 17 anatomical segments. In this paper, we propose a novel method to automatically partition the LV into 17 segments, which allows automated analysis of these segments. Our method starts with assigning each slice with a section tag by using the papillary muscles and the LV cavity as references: basal, mid-cavity, apical and apex. It then partitions each slice into 4 or 6 segments by extracting the relevant points on the outer circle of a fitted cylinder and identifying the image orientation by using the lung as a reference. We evaluate our method on 45 patients with different cardiac conditions. The partition of mid-cavity has the best agreement with the ground truth, followed by basal and then apical sections for all groups of patients. PMID- 26737790 TI - Computer-based assessment of ventricular mechanical synchrony from magnetic resonance imaging. AB - Cardiac resynchronization therapy (CRT) has revolutionized the care of a substantial portion of patients with advanced heart failure (HF). From current guideline (NYHA III or IV heart failure, left ventricular ejection fraction <=35% and ECG QRS duration >= 120 ms), CRT improves clinical status in about 70% of those treated. Ideally, the ability to accurately predict likelihood of response will enhance the quality of treatment. This study aims to develop an automated method to assess left ventricular mechanical synchrony from magnetic resonance imaging (MRI), which has been considered as gold standard cardiac imaging for ventricular structure and function assessment. 26 healthy volunteers (age ranges from 24 years to 73 years) were prospectively recruited and underwent standard MRI scans. MRI images (e.g. 2-chamber, 3-chamber and 4-chamber views) were processed and atrioventricular junction (AVJ) motions were auto-tracked during cardiac cycle. The myocardial velocities Sm1 and Sm2 at systolic phase; Em and Am at early and late mitral filing phase, were derived respectively. The time to these measures (e.g., TSm1, TSm2, TEm and TAm) were determined and ventricular synchrony indices TSm1-SD-6, TSm2-SD-6, TEm-SD-6 and TAm-SD-6 (standard deviations of TSm1, TSm2, TEm and TAm for 6 AVJ points) were assessed and correlated with age. The computational time per dataset is approximately 5 minutes. One-way ANOVA analysis found that there were no significant differences in time to peak velocities in 6 segments. Second, linear regression analysis found that there were no significant correlation between TSm2-SD-6 and TAm-SD-6 with age, and fair positive correlation between TSm1-SD-6 and TEm-SD-6 with age. In this prospective study, noninvasive ventricular synchrony derived from typically acquired MRI images offers a novel method that may enable ventricular mechanical dyssynchrony assessment in heart failure. PMID- 26737791 TI - Automatic localization of mitral valve orifice in three-dimensional left cardiac model. AB - This study proposes a novel method to localize the mitral valve orifice in the three-dimensional left cardiac model reconstructed from Cardiac Magnetic Resonance (CMR) images. After acquiring both short axis and long axis CMR images, endocardium contours were delineated on all images while additional six points were marked to identify the mitral valve orifice on three long axis images. Contours from long axis images were registered to the short axis contours. The resulting registration parameters were stored. A three-dimensional surface model of the left cardiac structure was then reconstructed from the short axis contours. The six points representing mitral valve orifice in long axis images were projected onto the surface model using the registration parameters. A variational method was then applied to localize the mitral valve orifice on the surface model via minimizing the geodesic distance. Numerical examples show the robustness and effectiveness of the proposed method. Automatic location of mitral annulus orifice with the computational time per data set (22 frames) of five minutes would hold clinical potential as a real-time mitral valve assessment tool. PMID- 26737792 TI - Modelling of the nonlinear end-systolic pressure-volume relation and volume-at zero-pressure in porcine experiments. AB - The End-Systolic Pressure-Volume Relation (ESPVR) is generally modelled as a linear relationship between P and V as cardiac reflexes, such as the baroreflex, are typically suppressed in experiments. However, ESPVR has been observed to behave in a curvilinear fashion when cardiac reflexes are not suppressed, suggesting the curvilinear function may be more clinically appropriate. Data was gathered from 41 vena cava occlusion manoeuvres performed experimentally at a variety of PEEPs across 6 porcine specimens, and ESPVR determined for each pig. An exponential model of ESPVR was found to provide a higher correlation coefficient than a linear model in 6 out of 7 cases, and a lower Akaike Information Criterion (AIC) value in all cases. Further, the exponential ESPVR provided positive V0 values in a physiological range in 6 out of 7 cases analysed, while the linear ESPVR produced positive V0 values in only 3 out of 7 cases, suggesting linear extrapolation of ESPVR to determine V0 may be flawed. PMID- 26737793 TI - Myocardial contractility assessed by dynamic electrical impedance measurements during dobutamine stress. AB - In this study, the electrical impedance of myocardial tissue is measured dynamically during the cardial cycle. The multisine-based approach used to perform electrical impedance spectroscopy (EIS) measurements allows acquiring complete spectral impedance information of the tissue dynamics during contraction. Measurements are performed in situ in the left ventricule of swines during contractility stress tests induced by dobutamine infusion. Additionally, the ECG and the left ventricular (LV) pressure are also acquired synchronously to the impedance signals. The calculated impedance magnitude exhibits a periodic behavior during tissue contraction. The amplitude (peak-to-peak) of this signal is quantified and the compared to the maximum first derivative of the LV pressure (dP/dtmax) that is used as an indicator of contractility variations. The results show a linear correlation between impedance amplitude and dP/dtmax during dobutamine-increased contractility. The present work demonstrates how fast EIS measurements during heart contraction can represent a feasible method to assess changes in myocardial contractility. PMID- 26737794 TI - A proof-of-concept study for predicting the region of atherosclerotic plaque development based on plaque growth modeling in carotid arteries. AB - In this work, we present a computational model for plaque growth utilizing magnetic resonance data of a patient's carotid artery. More specifically, we model blood flow utilizing the Navier-Stokes equations, as well as LDL and HDL transport using the convection-diffusion equation in the arterial lumen. The accumulated LDL in the arterial wall is oxidized considering the protective effect of HDL. Macrophages recruitment and foam cells formation are the final step of the proposed multi-level modeling approach of the plaque growth. The simulated results of our model are compared with the follow-up MRI findings in 12 months regarding the change to the arterial wall thickness. WSS and LDL may indicate potential regions of plaque growth (R(2)=0.35), but the contribution of foam cells formation, macrophages and oxidized LDL increased the prediction significantly (R(2)=0.75). PMID- 26737795 TI - Prediction of atheromatic plaque evolution in carotids using features extracted from the arterial geometry. AB - Knowing the arterial geometry might be helpful in the assessment of a plaque rupture event. We present a proof of concept study implementing a novel method which can predict the evolution in time of the atheromatic plaque in carotids using only statistical features which are extracted from the arterial geometry. Four feature selection methods were compared: Quadratic Programming Feature Selection (QPFS), Minimal Redundancy Maximal Relevance (mRMR), Mutual Information Quotient (MIQ) and Spectral Conditional Mutual Information (SPECCMI). The classifier used is the Support Vector Machines (SVM) with linear and Gaussian kernels. The maximum accuracy that was achieved in predicting the variation in the mean value of the Lumen distance from the centerline and the thickness was 71.2% and 70.7% respectively. PMID- 26737796 TI - A particle filter framework for the estimation of heart rate from ECG signals corrupted by motion artifacts. AB - In this work, we describe a methodology to probabilistically estimate the R-peak locations of an electrocardiogram (ECG) signal using a particle filter. This is useful for heart rate estimation, which is an important metric for medical diagnostics. Some scenarios require constant in-home monitoring using a wearable device. This poses a particularly challenging environment for heart rate detection, due to the susceptibility of ECG signals to motion artifacts. In this work, we show how the particle filter can effectively track the true R-peak locations amidst the motion artifacts, given appropriate heart rate and R-peak observation models. A particle filter based framework has several advantages due to its freedom from strict assumptions on signal and noise models, as well as its ability to simultaneously track multiple possible heart rate hypotheses. Moreover, the proposed framework is not exclusive to ECG signals and could easily be leveraged for tracking other physiological parameters. We describe the implementation of the particle filter and validate our approach on real ECG data affected by motion artifacts from the MIT-BIH noise stress test database. The average heart rate estimation error is about 5 beats per minute for signal streams contaminated with noisy segments with SNR as low as -6 dB. PMID- 26737797 TI - Constructing energy expenditure regression model using heart rate with reduced training time. AB - Accurate estimation of energy expenditure (EE) is a key enabler for many applications of healthcare and wellness. Heart rate (HR) based EE estimation methods typically require extensive training time to establish a relationship between HR and EE. In this work, we propose a method where just the few most representative EE-HR data pairs are used to train the estimation model. Furthermore, we present a systematical methodology based on the ranking of the correlation coefficients between EE and HR to find the least amount of EE-HR data pairs required for training while satisfying the constraint of estimation accuracy. During the experimental evaluation, while the study participants walk and run on a treadmill, our method is compared to three different training paradigms: training the EE-HR model 1) using all available data collected during the experiment, 2) using the EE-HR data only during speed changes (or during monotonic HR changes) and 3) using the EE-HR data pairs collected during constant speed. The results show that our method could maintain a comparable EE estimation performance as shown by only 2~4% changes on the coefficient of variation of root mean-squared error (CV(RMSE)) for the testing dataset while saving nearly 91-97% training time for each individual. PMID- 26737798 TI - Estimation of respiratory rates based on photoplethysmographic measurements at the sternum. AB - The respiratory rate (RR) is a clinically important vital sign and is a frequently used parameter in the general hospital wards. In current clinical practice, the monitoring of the RR is by manual count of the chest movement for one minute. This paper addresses a new approach where the respiratory rate is extracted using photoplethysmography (PPG) on the chest bone (sternum). Sternal PPG signals were acquired from 10 healthy subjects resting in a supine position. As reference signals, finger PPG, electrocardiogram (ECG), and capnography were simultaneously recorded during spontaneous and paced breathing. The sternal PPG signals were then compared with the reference signals in terms of Bland-Altman analysis, the power spectrum analysis and the magnitude squared coherence. The Bland-Altman analysis showed an average bias of 0.21 breaths/min between RR extracted from sternal PPG and capnography. The respiratory power content at the sternum was 78.8 (38) % in terms of the median and (the interquartile range). The cardiac content was 19 (18.4) % within the cardiac region. The results from the magnitude squared coherence analysis was 0.97 (0.09) in the respiratory region (6 to 27 breaths/min) and 0.98 (0.01) in the cardiac pulse region (30-120 beats/min). This preliminary study demonstrates the possibility of monitoring the RR from sternal PPG on a healthy group of subjects during rest. PMID- 26737799 TI - Method for classifying cardiac arrhythmias using photoplethysmography. AB - Advances in mobile computing and miniature devices have contributed to the accelerated development of wearable technologies for clinical applications. The new trend of wearable technologies has fostered a growth of interest for sensors that can be easily integrated into wearable devices. In particular, photoplethysmography (PPG) is especially suitable for wearable sensing, as it is low-cost, noninvasive, and does not require wet electrodes like the electrocardiogram. Photoplethysmograph signals contain rich information about the blood pulsating variation which is strongly related to the electrical activities of the heart. Therefore, in this paper we hypothesize that the ambulatory PPG monitoring could be employed for arrhythmia detection and classification. This paper presents a method for classifying ventricular premature contraction (VPC) and ventricular tachycardia (VT) from normal sinus rhythm (NSR) and supraventricular premature contraction (SVPC) recorded in patients going through ablation therapy for arrhythmia. Although occasional VPCs are benign, the increase in the frequency of VPC events may lead to VT, which in turn,could evolve into ventricular fibrillation and sudden cardiac death. Therefore the accurate measurement of VPC frequency and early detection of VT events becomes essential for patients with cardiac disease. PMID- 26737800 TI - Seizure detection using regression tree based feature selection and polynomial SVM classification. AB - This paper presents a novel patient-specific algorithm for detection of seizures in epileptic patients with low hardware complexity and low power consumption. In the proposed approach, we first compute the spectrogram of the input fragmented EEG signals from three or four electrodes. Each fragmented data clip is one second in duration. Spectral powers and spectral ratios are then extracted as features. The features are then subjected to feature selection using regression tree. The selected features are then subjected to a polynomial support vector machine (SVM) classifier with degree of 2. The algorithm is tested using the intra-cranial EEG (iEEG) from the UPenn and Mayo Clinic's Seizure Detection Challenge database. It is shown that the proposed algorithm can achieve a sensitivity of 100.0%, an average area under curve (AUC) of 0.9818, a mean detection horizon of 5.8 seconds, and a specificity of 99.9% on using half of the training data for classification. The proposed approach also achieved a mean AUC of seizure detection and early seizure detection of 0.9136 on the testing data. PMID- 26737801 TI - Detection of seizures in intracranial EEG: UPenn and Mayo Clinic's Seizure Detection Challenge. AB - A system for detection of seizures in intracranial EEG is presented that is based on a combination of generative, discriminative and hybrid approaches. We present a methodology to effectively benefit from the advantages each classifier offers. In particular, Gaussian mixture models, Support Vector Machines, hybrid likelihood ratio and Gaussian supervector approaches are developed and combined for the task. This system participated in the UPenn and Mayo Clinic's Seizure Detection Challenge, ranking in the top 5 of over 200 participants. The drawbacks of the proposed method with respect to the winning solutions are critically assessed. PMID- 26737802 TI - Transcranial focal electrical stimulation reduces seizure activity and hippocampal glutamate release during status epilepticus. AB - Previously we demonstrated that noninvasive transcranial focal electrical stimulation (TFS) with sub-effective doses of diazepam reduces status epilepticus (SE)-induced neuronal damage. However, it was unclear if this neuroprotective effect is a consequence of the decrease in the glutamate release. The aim of the present study was to evaluate the effects of TFS on gamma-Aminobutyric acid (GABA) and glutamate release in the hippocampus during pilocarpine-induced SE. After pilocarpine administration, the rats showed progressive behavioral changes that culminated in SE with a significant increase of GABA and glutamate (95 and 128% respectively), even more evident at the end of the experiment (120 and 182% respectively), 5 hours after pilocarpine injection and was associated with the prevalence of high-voltage rhythmic spikes and increased spectral power in the 4 90 Hz bands. The TFS application during the SE decreased the convulsive expression, the prevalence of high-voltage rhythmic spikes and spectral power in 4-8 Hz and 30-90 Hz bands. These effects were associated with lower release of GABA and glutamate in the hippocampus. These results support the anticonvulsive and neuroprotective effects induced by TFS. PMID- 26737803 TI - Identification of brain regions of interest for epilepsy surgery planning using support vector machines. AB - In patients with intractable epilepsy, surgical resection is a promising treatment; however, post surgical seizure freedom is contingent upon accurate identification of the seizure onset zone (SOZ). Identification of the SOZ in extratemporal epilepsy requires invasive intracranial EEG (iEEG) recordings as well as resource intensive and subjective analysis by epileptologists. Expert inspection yields inconsistent localization of the SOZ which leads to comparatively poor post surgical outcomes for patients. This study employs recordings from 6 patients undergoing resection surgery in order to develop an automated and scalable system for identifying regions of interest (ROIs). Leveraging machine learning techniques and features used for seizure detection, a classification system was trained and tested on patients with Engel class I to class IV outcomes, demonstrating superior performance in the class I patients. Further, classification using features based upon both high frequency and low frequency oscillations was best able to identify channels suited for resection. This study demonstrates a novel approach to ROI identification and provides a path for developing tools to improve outcomes in epilepsy surgery. PMID- 26737804 TI - Locomotion and eye behaviour under controlled environment in individuals with Alzheimer's disease. AB - This study aimed to examine simple locomotion and eye behaviour of individuals with Posterior Cortical Atrophy (PCA) and typical Alzheimer's disease (tAD) within a simulated real-world environment. Posterior cortical atrophy (PCA) is a neurodegenerative condition characterised by parietal, occipital and occipito temporal tissue loss and progressive impairment of higher-order visual function in contrast to relatively spared memory and language. Targeted types of locomotion were walking in a series of corridors, up or down stairs, and across an open room with or without the presence of an obstacle. Eye tracking measures and inertial moment units (IMU) were used in this experiment, and resultant acceleration of left foot and fixation duration were extracted. Findings from three participants are presented as a case series: one control, one PCA and one tAD patient. The averaged resultant acceleration of PCA patient was the slowest in all types of locomotion, especially in stairs. The averaged resultant accelerations of PCA and tAD participants were slower than the control participant. The PCA participant had longer mean fixation durations than the tAD and control participants, however, mean fixation duration was similar between tAD and control participants. Results may help characterise locomotion and eye behaviour in PCA and tAD and may suggest ways to support effective diagnosis and assessment of disease progression. PMID- 26737806 TI - Investigation of automatically detected high frequency oscillations (HFOs) as an early predictor of seizure onset zone. AB - High frequency oscillations (HFOs) during inter-ictal state have been considered as a potential biomarker of epileptogenic regions in brain. The purpose of the current study is to improve and automatize the detection of HFOs basing on HFO distinguishing features followed by unsupervised clustering method, and to predict seizure onset zone (SOZ) using the clustered HFOs. The algorithm successfully separated HFOs of different sub-categories from noise, artifacts, and inter-ictal spikes. We tested this technique on two subjects, and assessed the performance of SOZ prediction by computing the overlapping rate of HFO generative channels and seizure onset channels. In both subjects, we were able to localize the seizure onset area 3 to 4 days before the actual onset of the seizure, with high specificity over 95%. The algorithm showed significant improvement comparing to another existing technique. PMID- 26737805 TI - Quantitative EEG markers in severe post-resuscitation brain injury with therapeutic hypothermia. AB - Therapeutic hypothermia has been regarded as one of the most effective post cardiac arrest (CA) treatments to improve survival and functional recovery. However, many clinical prognostic markers after resuscitation have become less reliable under hypothermia. In this study, we applied and compared two developed quantitative measures - information quantity (IQ) and sub-band IQ (SIQ) - to evaluate the accuracy of EEG markers on predicting cortical recovery under therapeutic hypothermia. A total of 14 rats under 9-min asphyxial-CA, leading to severe brain injury, were randomly divided into two groups: hypothermia (32 degrees C-34 degrees C) and normothermia (36.5-37.5 degrees C) (n=7 per group). For each rat, EEG and temperature were continuously recorded for the first 15 hrs. EEG was then recorded for serial 30 mins at 24, 48 and 72 hrs. The neurologic deficit score was evaluated daily to assess the neurologic recovery. Early SIQ and IQ were both significantly correlated with the 72-hr NDS, when the rats remained comatose. Both IQ and SIQ were able to discriminate the animals with good and bad functional outcomes starting from 1 hr after resuscitation. There was no significant difference in 72-hr NDS results (hypothermia (median (25th, 75th), 65 (52, 67)) versus normothermia (53.5 (52.25, 66.75))) (p>0.05) due to the high mortality rate (5/14) with severe brain injury. Contrary to IQ recovery but similarly to NDS scores, the SIQ recovery was not significantly different between the hypothermia (0.66+/-0.04) and normothermia (0.64+/-0.04) groups (p>0.05). IQ could identify the presence of high-frequency oscillations during the recovery from severe brain injury. We demonstrated that while SIQ was able to provide additional sub-band EEG information related to the recovery of different brain functions, both early IQ and SIQ markers are able to accurately predict neurologic outcome after CA. PMID- 26737807 TI - Optogenetic control of thalamus as a tool for interrupting penicillin induced seizures. AB - Penicillin epilepsy model, whose discharge resembles that of human absence epilepsy, is one of the most useful acute experimental epilepsy models. Though closed-loop optogenetic strategy of interrupting seizures was proved sufficient to switch off epilepsy by controlling thalamus in the post-lesion partial chronic epilepsy model, doubts still exist in absence epilepsy attenuation through silencing thalamus. Here we directly arrested the thalamus to modulate penicillin induced absence seizures through pseudorandom responsive stimulation on eNpHR transfected rats. Our data suggested that the duration of epileptiform bursts under light conditions, compared with no light conditions, did not increase or decrease when modulated specific eNpHR-expressing neurons in thalamus. PMID- 26737808 TI - Monitoring of cognitive state on mental retardation child using EEG, ECG and NIRS in four years study. AB - In this study, a monitoring system of cognitive state in usual behavior without restraint using wireless EEG, ECG and NIRS on developmental disorder children such as mental retardation was developed. By using this system we would like to investigate the education training effect on cognitive state in a mental retardation child in four years. The aim of special education is to make adaptations, accommodations and modification that allow a child with a mental retardation to succeed in classroom. This education training separated into two systems, resting state and studying state. After the measurement, we calculated the EEG power spectrum of alpha, theta bands and the low frequency power (LF), high frequency power (HF), and LH/HF value from the RR interval in ECG. At the same time we calculated the changes in concentration of oxyhemoglobin ([oxy-Hb]). The result in studying state showed theta power is lower than beta power in study state in the other hand beta power is lower than theta power in resting state From LF/HF activity we could know that sympathetic activity is increasing and from the result that has obtained from ECG, the parasympathetic activity is decreasing the time. NIRS showed the increasing in study states and decreasing in resting states at Fp2 area from oxyhemoglobin analysis. PMID- 26737809 TI - Pilot study of the cortical correlates and clinical effects of passive ankle mobilisation in children with upper motorneuron lesions. AB - Upper motoreuron lesions (UML) affects people of all ages and conditions and is a major cause of disability in the young. Whereas active exercise is recognised as paramount to restore the lost motor functions, passive mobilisation of the affected limbs is regarded as a means to safeguard muscular tissue properties during a period of disuse and lack of voluntary control, which often characterises the acute and sub-acute phases. The purpose of the present work is to study the cortical reactivity in UML patients who are treated for two weeks with a robotic passive ankle mobiliser, and the clinical effects of this treatment. The rationale is that, if passive mobilisation can affect positively the functional reorganisation at a cortical level, it could be proposed as a suitable tool to maintain afferentation and guide central nervous remapping, thus bridging the period of time when active exercise is impossible due to acute paresis. Preliminary results on 7 patients (aged 15.35+/-4.36) showed that this therapy is very well tolerated and suggest that its application could specifically improve ankle PROM and plantarflexor muscle length. EEG data showed improved desynchronisation in at least one frequency band in 3 patients of the study, thus confirming the effects of passive mobilisation on the cortical re organisation of some patients having UML. PMID- 26737810 TI - An EEG study of turning freeze in Parkinson's disease patients: The alteration of brain dynamic on the motor and visual cortex. AB - Freezing of gait is a very debilitating symptom affecting many patients with Parkinson's disease, leading to a reduced mobility and increased risk for falls. Turning is known to be the most provocative trigger for freezing of gait. However, the underlying brain dynamic changes associated with a turning freeze remain unknown. This study therefore used ambulatory EEG to investigate the brain dynamic changes associated with freezing of gait during turning. In addition, this study aimed to determine the most suitable EEG sensor location to detect freezing of gait during turning using our classification system. Data from four Parkinson's disease patients with freezing of gait was analysed using power spectral density and brain effective connectivity, comparing periods of successful turning with freezing of gait during turning. Results showed that freezing of gait during turning is associated with significant alterations in the high beta and theta power spectral densities across the occipital and parietal areas. Furthermore, brain effective connectivity showed that freezing during turning was associated with increased connectivity towards the visual area, which also had the highest accuracy to detect freezing episodes in the O1 regions by using power spectral density in our classification analyses. This is the first study to show cortical dynamic changes associated with freezing of gait during turning, providing valuable information to enhance the performance of future freezing of gait detection systems. PMID- 26737811 TI - A look at the strength of micro and macro EEG analysis for distinguishing insomnia within an HIV cohort. AB - HIV patients are often plagued by sleep disorders and suffer from sleep deprivation. However, there remains a wide gap in our understanding of the relationship between HIV status, poor sleep, overall function and future outcomes; particularly in the case of HIV patients otherwise well controlled on cART (combined anti-retroviral therapy). In this study, we compared two groups: 16 non-HIV subjects (seronegative controls) and 12 seropositive HIV patients with undetectable viral loads. We looked at sleep behavioral (macro-sleep) features and sleep spectral (micro-sleep) features obtained from human-scored overnight EEG recordings to study whether the scored EEG data can be used to distinguish between controls and HIV subjects. Specifically, the macro-sleep features were defined by sleep stages and included sleep transitions, percentage of time spent in each sleep stage, and duration of time spent in each sleep stage. The micro sleep features were obtained from the power spectrum of the EEG signals by computing the total power across all channels and frequencies, as well as the average power in each sleep stage and across different frequency bands. While the macro features do not distinguish between the two groups, there is a significant difference and a high classification accuracy for the scoring-independent micro features. This spectral separation is interesting because evidence suggests a relationship between sleep complaints and cognitive dysfunction in HIV patients stable on cART. Furthermore, there are currently no biomarkers that predict the early development of cognitive decline in HIV patients. Thus, a micro-sleep architectural approach could serve as a biomarker to identify HIV patients vulnerable to cognitive decline, providing an avenue to explore the utility of early intervention. PMID- 26737813 TI - Modulation of ERD/S by having a conscious target during lower-extremity motor imagery. AB - In the field of neurorehabilitation with brain-computer interfaces (BCIs) technology, an EEG feature, event-related desynchronization/synchronization (ERD/S) caused by motor imagery (MI) is widely used for estimating human motor intention. However, sufficient neurofeedback training is required for the use of the MI-based BCI system, because the ability to generate ERD/S is highly dependent on individuals. To find an effective MI condition for the BCI system, we hypothesize that having a conscious target during MI would enhance the extent of ERD/S. In the experiments, we investigated the individual effect of two types of MIs: leg extension (L) and leg extension with a conscious target (i.e., kicking a ball (KB)) on the resultant ERD/S. We evaluated time-frequency maps of ERD/S and statistically compared these two conditions (i.e., L and KB). As a result, a significant difference was found in beta-ERD (paired t-test, p <; 0.01), while there were no significant differences in mu-ERD and beta-ERS. These results suggest that having a conscious target during lower extremity MI would strengthen the ERD in beta frequency band compared to the case without target. PMID- 26737812 TI - To Score or Not to Score? A look at the distinguishing power of micro EEG analysis on an annotated sample of PSG studies conducted in an HIV cohort. AB - In this study, we used the Pittsburgh Sleep Quality Index to divide the subjects into two groups, good sleepers and bad sleepers. We computed sleep behavioral (macro-sleep architectural) features and sleep spectral (micro-sleep architectural) features in order to observe if the annotated EEG data can be used to distinguish between good and bad sleepers in a more quantitative manner. Specifically, the macro-sleep features were defined by sleep stages and included sleep transitions, percentage of time spent in each sleep stage, and duration of time spent in each sleep stage. The micro-sleep features were obtained from the power spectrum of the EEG signals by computing the total power across all channels and all frequencies, as well as the average power in each sleep stage and across different frequency bands. We found that while the scoring-independent micro features are significantly different between the two groups, the macro features are not able to significantly distinguish the two groups. The fact that the macro features computed from the scoring files cannot pick up the expected difference in the EEG signals raises the question as to whether human scoring of EEG signals is practical in assessing sleep quality. PMID- 26737814 TI - A novel approach for multiscale source analysis and modeling of epileptic spikes. AB - Multiscale recordings of brain electrical activity are often performed for presurgical evaluation in patients with focal epilepsy to facilitate the identification and precise delineation of the epileptogenic zone. However, data regarding the concordance of source models derived from recordings on different scales and their reciprocal validation against clinical outcomes remains scarce. This study aims to define a common source model that accurately depicts both scalp EEG and subdural EEG (ECoG) interictal spikes. To this purpose, the sLORETA method was applied to averaged spikes and source reconstruction results were implemented to outline the location and extent of an epileptic cortical patch. This estimated patch served as the basis for the spatiotemporal source model in a generative model of EEG. Spike activity was simulated on both scalp EEG and ECoG signal scales, with simulated traces resembling measured traces regarding their spatial distribution and amplitude compared to background. Simulated spikes served for the evaluation of source reconstruction with a known generator topography. The described setup allows for the validation and, ultimately, for the refinement of source reconstruction methods. It provides novel insights towards a thorough understanding of physiological and pathological brain processes and their representation in neuroelectric measurements. PMID- 26737815 TI - Toward non-hair-bearing brain-computer interfaces for neurocognitive lapse detection. AB - Recent advances in mobile electroencephalogram (EEG) acquisition based on dry electrodes have started moving Brain-Computer Interface (BCI) applications from well-controlled laboratory settings to real-world environments. However, the application mechanisms and high impedance of dry electrodes over the hair-covered areas remain challenging for everyday use of BCI. In addition, whole-scalp recordings are not always necessary or applicable due to various practical constrains. Therefore, alternative montages for EEG recordings to meet the everyday needs are in-demand. Inspired by our previous work on measuring non-hair bearing steady state visual evoked potentials for BCI applications, this study explores the feasibility and efficacy of detecting cognitive lapses of participants based on EEG signals collected from the non-hair-bearing areas. Study results suggest that informative EEG features associated with lapses could be assessed from non-hair-bearing areas with comparable accuracy obtained from the whole-scalp EEG. The design principles, validation processes and promising findings reported in this study may enable and/or facilitate numerous BCI applications in real-world environments. PMID- 26737816 TI - Extracting patterns of single-trial EEG using an adaptive learning algorithm. AB - The improvement of brain imaging technique brings about an opportunity for developing and investigating brain-computer interface (BCI) which is a way to interact with computer and environment. The measured brain activities usually constitute the signals of interest and noises. Applying the portable device and removing noise are the benefits to real-world BCI. In this study, one portable electroencephalogram (EEG) system non-invasively acquired brain dynamics through wireless transmission while six subjects participated in the rapid serial visual presentation (RSVP) paradigm. The event-related potential (ERP) was traditionally estimated by ensemble averaging (EA) to increase the signal-to-noise ratio. One adaptive filter of data-reusing radial basis function network (DR-RBFN) was also utilized as the estimator. The results showed that this portable EEG system stably acquired brain activities. Furthermore, the task-related potentials could be clearly explored from the limited samples of EEG data through DR-RBFN. According to the artifact-free data from the portable device, this study demonstrated the potential to move the BCI from laboratory research to real-life application in the near future. PMID- 26737817 TI - Activity in the left auditory cortex is associated with individual impulsivity in time discounting. AB - Impulsivity dictates individual decision-making behavior. Therefore, it can reflect consumption behavior and risk of addiction and thus underlies social activities as well. Neuroscience has been applied to explain social activities; however, the brain function controlling impulsivity has remained unclear. It is known that impulsivity is related to individual time perception, i.e., a person who perceives a certain physical time as being longer is impulsive. Here we show that activity of the left auditory cortex is related to individual impulsivity. Individual impulsivity was evaluated by a self-answered questionnaire in twelve healthy right-handed adults, and activities of the auditory cortices of bilateral hemispheres when listening to continuous tones were recorded by magnetoencephalography. Sustained activity of the left auditory cortex was significantly correlated to impulsivity, that is, larger sustained activity indicated stronger impulsivity. The results suggest that the left auditory cortex represent time perception, probably because the area is involved in speech perception, and that it represents impulsivity indirectly. PMID- 26737818 TI - Acoustic pressure reduction at rhythm deviants causes magnetoencephalographic response. AB - Rhythm is an element of music and is important for determining the impression of the music. To investigate the mechanism by which musical rhythmic changes are perceived, magnetoencephalographic responses to rhythm deviants were recorded from 11 healthy volunteers. Auditory stimuli consisting of physically controlled tones were adapted from a song. The auditory stimuli had a steady rhythm, but "early" and "late" deviants were inserted. Only the "early" deviant, which was a tone with a short duration, caused N100m-like prominent transient responses at around the offset of the deviant tone. The latency of the prominent response depended on the descending sound pressure of the deviant tone and was 65 ms after 50% descent. The results suggest that unexpected shortening of tone in a continuous rhythm evokes a transient response and that the response is caused by descending sound pressure of the shortened tone itself, not by the following tones. PMID- 26737819 TI - Responses in posterior parietal cortex to movement intention task with visual and tactile cues. AB - Posterior parietal cortex (PPC) is considered to be related to forming of motor intention. The detection of the direction intended movements and the type of intended movement is a challenging goal in neuroscience and engineering applications such as brain-computer interfacing (BCI). In previous studies, it has been reported that EEG signals extracted from PPC can be used to decode intended movement direction. However, it is not clear whether extracted EEG signals are related to motor intention, because visually evoked potential (VEP) which evoked by visual cue in their experiment may be included in their extracted EEG signals. The purpose of this study is to investigate the possibility of VEP mixed into extracted EEG signals. Therefore experiments with not only visual but also tactile cues were conducted. EEG components that could be related to PPC were extracted by using independent component analysis (ICA). We compared event related potential (ERP) waveforms between two experiments. In the result, ERP waveforms of the experiment with tactile cue were significantly different from that of the experiment with visual cue. This result suggests that VEP was included in the EEG signals extracted from PPC in the experiment with visual cue. PMID- 26737820 TI - A saliency based motion detection model of visual system considering visual adaptation properties. AB - The purpose of this study is to construct a mathematical model which predicts saliency regions in high-speed egocentric-motion movies, filmed by an embedded camera in a driving vehicle, by reproducing the characteristics of the area MT and MST neurons' receptive fields with consideration of visual adaptation properties. The area MT neurons integrate from the area V1 activation and respond well to regions where higher motion contrasts exist. While the area MST neurons detect global motions such as expansion, contraction, rotation, and so on. We modeled the area MT neurons' receptive fields as a center-surround spatial summation of counter sided motion vectors of visual scenery. The area MST neurons in our model integrate the responses of the MT neurons by convolving with spacial weight functions of which central portions are biased to preferred direction. Visual adaptations were taken as the primary delay filters for each visual feature channel to deplete the saliency of stationary objects and regions during particular frames. The simulation results for the movies which were taken in a running vehicle indicate that the proposed model detects more salient objects around the vanishing point than the conventional saliency based model. To evaluate the performance of proposed model, we defined the moving-NSS (normalized scan-path salience) scores as the averaged NSS scores in each moving time window. The moving-NSS scores for motion images of our model were higher than those of the conventional model. PMID- 26737821 TI - Estimation of the reaction times in tasks of varying difficulty from the phase coherence of the auditory steady-state response using the least absolute shrinkage and selection operator analysis. AB - Quantitative estimation of the workload in the brain is an important factor for helping to predict the behavior of humans. The reaction time when performing a difficult task is longer than that when performing an easy task. Thus, the reaction time reflects the workload in the brain. In this study, we employed an N back task in order to regulate the degree of difficulty of the tasks, and then estimated the reaction times from the brain activity. The brain activity that we used to estimate the reaction time was the auditory steady-state response (ASSR) evoked by a 40-Hz click sound. Fifteen healthy participants participated in the present study and magnetoencephalogram (MEG) responses were recorded using a 148 channel magnetometer system. The least absolute shrinkage and selection operator (LASSO), which is a type of sparse modeling, was employed to estimate the reaction times from the ASSR recorded by MEG. The LASSO showed higher estimation accuracy than the least squares method. This result indicates that LASSO overcame the over-fitting to the learning data. Furthermore, the LASSO selected channels in not only the parietal region, but also in the frontal and occipital regions. Since the ASSR is evoked by auditory stimuli, it is usually large in the parietal region. However, since LASSO also selected channels in regions outside the parietal region, this suggests that workload-related neural activity occurs in many brain regions. In the real world, it is more practical to use a wearable electroencephalography device with a limited number of channels than to use MEG. Therefore, determining which brain areas should be measured is essential. The channels selected by the sparse modeling method are informative for determining which brain areas to measure. PMID- 26737822 TI - The observation of theta wave modulation on brain training by 5 Hz-binaural beat stimulation in seven days. AB - Traditional buddhist meditation method maybe easy for someone with high experience. However, for the beginner, it is very difficult to keep mental concentration with the tradition way for more than 5 minutes. This research aims to observe effect of the new method for meditation in various analysis methods. A piano music mixed with a 5 Hz (theta band enhancement) binaural beat frequency was used to modulate the brain signals continuously for 7 days. Male of the average age of 33.5+/-3.84 and female of the average age of 28.6+/-2.49 were participated. All participants were acquired EEGs twice, before the experiment and seven days after the experiment. We also proposed the observations on the changes of absolute powers, relative powers and brain connectivity (coherence) of the participants. After seven days of training, the absolute power, relative power, and coherence were clearly closer to the normative database. We can initially say that the recommended meditation method can efficiently mimic the effect of having the traditional buddhist meditation on enhancing the delta and theta powers in the brain. PMID- 26737823 TI - The effect of lymph drainage on the myoelectric manifestation of vastus lateralis fatigue: Preliminary results. AB - Variations in surface electromyograms (EMGs) collected from the vastus lateralis muscle during isometric fatiguing contractions were investigated pre-post lymphatic drainage (intervention group, N=3) and pre-post rest (control group, N=3). The slope of conduction velocity and of EMG amplitude and spectral descriptors was computed from the start to the failure time; the instant after which subjects could not endure contractions. When compared to subjects in the control group, those in the intervention group endured longer. Similarly, muscle fatigue affected to a lesser extent EMGs following lymphatic drainage than following rest. These preliminary results suggest the lymphatic drainage may potentially delay muscle fatigue. PMID- 26737825 TI - Gait assessment using the Kinect RGB-D sensor. AB - Patients with concussions, strokes and neuromuscular disease such as Parkinson's disease, often have difficulties in keeping balance and suffer from abnormal gaits. Gait assessment conducted by a physician or therapist in clinics is standard clinical practice for assessing such injuries. However, this approach is subjective, leading to potential problems of unrepeatability, poor sensitivity and unreliability. To conduct the assessment in an objective way, a computer based gait assessment system is designed and presented in this paper. The system performs assessments on dynamic balance and gaits by analyzing the skeleton frames of a subject captured by the Microsoft Kinect RGB-D sensor. Results show that the proposed system effectively scores subjects. PMID- 26737824 TI - Difficulty-dependent trajectory planning during target-reaching movements. AB - This study explored how the difficulty of a task influenced motor control during target-reaching movements. During the experiment, twelve healthy subjects were recruited to perform target-reaching tasks with three different target sizes over three distances as quickly and accurately as possible using their index fingers. There were nine levels of difficulty of the tasks, with a combination of three target sizes and three distances, and the difficulty of the tasks could be measured by Fitts' law in terms of the index of difficulty (ID). The kinematic variables to represent movement performance were peak velocity (Vpeak), percentage time to peak velocity (PTPV), normalized jerk score (NJS) and fApEn (fuzzy approximate entropy). The results showed both distance and target size significantly influenced these parameters with the exception of the effect of the target size on Vpeak. Vpeak and fApEn were only linearly related to the ID when the individual target size across movement distances was considered. And a linear relationship between PTPV or NJS and ID was found. The increase in the difficulty of the task could lead to a shift from feedforward to feedback control by the central nerve system. The findings in this study contribute to an understanding of the underlying motor control during target reaching movements and can be applied as a quantitative method of evaluation in the clinic in the future. PMID- 26737826 TI - A basic study on quantitative evaluation of 3-dimensional foot contact with an inertial sensor for FES foot drop correction. AB - In these days, FES is used to control ankle dorsiflexion of hemiplegic gait. Since not only dorsiflexion but also 3-dimensional foot contact isimportant for gait stability in hemiplegic gait, evaluation and control system of 3-dimensional foot contact with FES is needed to correct foot movement. In this study, the timing of initial contact and the timing when foot movement became stationary in the sagittal plane were detected, and the inclination angles in the sagittal and the frontal planes at these timings were used for evaluation. Using the inclination angles, 10 m walking of a hemiplegic subject under the 4 different gait conditions were quantitatively evaluated. The gait conditions were without FES, stimulation to the tibialis anterior, stimulation to the common peroneal nerve, and stimulation to both the tibialis anterior and the common peroneal nerve. Result of evaluation with the inclination angles showed that stimulation to the tibialis anterior could control foot contact appropriately in the sagittal plane, and stimulation to the common peroneal nerve was better to control foot inclination angle in the frontal plane. Inclination angle at the beginning of the stance phase indicated that FES system which used in clinical site commonly is not appropriate to control 3-dimensional foot contact. It was shown that inclination angle at the beginning of the stance phase was useful to evaluate 3 dimensional foot movements for FES foot drop correction. PMID- 26737827 TI - Designing adaptive integral sliding mode control for heart rate regulation during cycle-ergometer exercise using bio-feedback. AB - This paper considers our developed control system which aims to regulate the exercising subjects' heart rate (HR) to a predefined profile. The controller would be an adaptive integral sliding mode controller. Here it is assumed that the controller commands are interpreted as biofeedback auditory commands. These commands can be heard and implemented by the exercising subject as a part of the control-loop. However, transmitting a feedback signal while the pedals are not in the appropriate position to efficiently exert force may lead to a cognitive disengagement of the user from the feedback controller. To address this problem this paper will employ a different form of control system regarding as "actuator based event-driven control system". This paper will claim that the developed event-driven controller makes it possible to effectively regulate HR to a predetermined HR profile. PMID- 26737828 TI - Ambiguity involving two illusory melodies induced by a simple configuration of tones. AB - Auditory scene analysis is essential in daily life to extract necessary information from complex acoustic environment and also from intricate development of music compositions. Auditory illusions and ambiguity are important factors in auditory scene analysis and have been studied extensively. We here report a novel form of ambiguity involving two illusory melodies implied by a very simple stimulus consisting of two sustained tones of different frequencies and an intermittently repeated tone of a frequency between the sustained tones. The measured time elapsed before a first perception change showed that illusion, ambiguity and disambiguation actually took place. We anticipate that the proposed illusion and ambiguity will provide a well-controlled approach for behavioral and neurophysiological studies of music recognition because of the simplicity of stimulus. PMID- 26737829 TI - Development of the obstacle detection system combining orientation sensor of smartphone and distance sensor. AB - In the existing walking support system, the range of detection is limited, and it is very difficult to detect obstacles such as a step or a hollow. Therefore, we aim at the development of a new walking support system for a visually-impaired person detecting neighboring obstacles by making use of a smartphone which is a high-performance portable information terminal. In this study, we have developed a walking support system combining the orientation sensor of the smartphone and a small distance sensor at the first stage. When we investigated its precision in detecting an obstacle, it was found that the system could detect obstacles which disturbed the walking of a visually-impaired person such as a step and a wall. We will find an appropriate key to detection to improve the detection precision of the system and make further improvements in the system by trial experiments in the future. PMID- 26737830 TI - EEG feature variations under stress situations. AB - The goal of this study is to identify EEG parameters and electrode positions with the highest significant values to differentiate between tasks and relax periods. Different signals were recorded as 12 subjects are doing arithmetic and memory tasks under stress condition. The test consisted of an initial and final 5-minute relax periods and three 4-minute performance phases with increased stress level. theta and alpha bands concentrated mainly features whose variation were significant, and F3 and P4 were the best positions to distinguish between performed tasks and arousal level. PMID- 26737831 TI - Effect of homogenous object stiffness on tri-digit grasp properties. AB - This paper presents experimental findings on how humans modulate their muscle activity while grasping objects of varying levels of compliance. We hypothesize that one of the key abilities that allows humans to successfully cope with uncertainties while grasping compliant objects is the ability to modulate muscle activity to control both grasp force and stiffness in a way that is coherent with the task. To that end, subjects were recruited to perform a grasp and lift task with a tripod-grasp device with contact surfaces of variable compliance. Subjects performed the task under four different compliance conditions while surface EMG from the main finger flexor and extensor muscles was recorded along with force and torque data at the contact points. Significant increases in the extensor muscle (the antagonist in the task) and co-contraction levels were found with increasing compliance at the contact points. These results suggest that the motor system may employ a strategy of increasing co-contraction, and thereby stiffness, to counteract the decreased stability in grasping compliant objects. Future experiments will examine the extent to which this phenomenon is also related to specific task features, such as precision versus power grasp and object weight. PMID- 26737832 TI - Machine learning methods for credibility assessment of interviewees based on posturographic data. AB - This paper discusses the advantages of using posturographic signals from force plates for non-invasive credibility assessment. The contributions of our work are two fold: first, the proposed method is highly efficient and non invasive. Second, feasibility for creating an autonomous credibility assessment system using machine-learning algorithms is studied. This study employs an interview paradigm that includes subjects responding with truthful and deceptive intent while their center of pressure (COP) signal is being recorded. Classification models utilizing sets of COP features for deceptive responses are derived and best accuracy of 93.5% for test interval is reported. PMID- 26737833 TI - 3D position estimation using a single coil and two magnetic field sensors. AB - This paper presents an algorithm which enables the estimation of relative 3D position of a sensor module with two magnetic sensors with respect to a magnetic field source using a single transmitting coil. Starting with the description of the ambiguity problem caused by using a single coil, a system concept comprising two sensors having a fixed spatial relation to each other is introduced which enables the unique determination of the sensors' position in 3D space. For this purpose, an iterative two-step algorithm is presented: In a first step, the data of one sensor is used to limit the number of possible position solutions. In a second step, the spatial relation between the sensors is used to determine the correct sensor position. PMID- 26737834 TI - Lumbar joint torque estimation based on simplified motion measurement using multiple inertial sensors. AB - We estimate lumbar torque based on motion measurement using only three inertial sensors. First, human motion is measured by a 6-axis motion tracking device that combines a 3-axis accelerometer and a 3-axis gyroscope placed on the shank, thigh, and back. Next, the lumbar joint torque during the motion is estimated by kinematic musculoskeletal simulation. The conventional method for estimating joint torque uses full body motion data measured by an optical motion capture system. However, in this research, joint torque is estimated by using only three link angles of the body, thigh, and shank. The utility of our method was verified by experiments. We measured motion of bendung knee and waist simultaneously. As the result, we were able to estimate the lumbar joint torque from measured motion. PMID- 26737835 TI - Development and preliminary testing of an instrumented object for force analysis during grasping. AB - This paper presents the design and realization of an instrumented object for force analysis during grasping. The object, with spherical shape, has been constructed with three contact areas in order to allow performing a tripod grasp. Force Sensing Resistor (FSR) sensors have been employed for normal force measurements, while an accelerometer has been used for slip detection. An electronic board for data acquisition has been embedded into the object, so that only the cables for power supply exit from it. Validation tests have been carried out for: (i) comparing the force measurements with a ground truth; (ii) assessing the capability of the accelerometer to detect slippage for different roughness values; (iii) evaluating object performance in grasp trials performed by a human subject. PMID- 26737836 TI - A kicking simulator to investigate the foot-ball interaction during a rugby place kick. AB - Foot-ball interaction is an important aspect in rugby place kicking but has received very little attention in literature. This preliminary study presents an adjustable mechanical kicking simulator used to investigate different foot positions and orientations during the foot-ball interaction on resultant ball motion. It was found that changes in foot position and orientation during ball contact can have a large influence on ball motion. It is believed that with further research an optimal place-kicking technique can be found to maximize energy transfer to the ball while still maintaining accuracy. PMID- 26737837 TI - Statically vs dynamically balanced gait: Analysis of a robotic exoskeleton compared with a human. AB - In recent years exoskeletons able to replicate human gait have begun to attract growing popularity for both assistive and rehabilitative purposes. Although wearable robots often need the use of external support in order to maintain stability, the REX exoskeleton by REX Bionics is able to self-balance through the whole cycle. However this statically balanced gait presents important differences with the dynamically balanced gait of human subjects. This paper will examine kinematic and kinetic differences between the gait analysis performed on a subject wearing the REX exoskeleton and human gait analysis data as presented in literature. We will also provide an insight on the impact that these differences can have for both rehabilitative and assistive applications. PMID- 26737838 TI - EMG-based learning approach for estimating wrist motion. AB - This paper proposes an EMG based learning approach for estimating the displacement along the 2-axes (abduction/adduction and flexion/extension) of the human wrist in real-time. The algorithm extracts features from the EMG electrodes on the upper and forearm and uses Support Vector Regression to estimate the intended displacement of the wrist. Using data recorded with the arm outstretched in various locations in space, we train the algorithm so as to allow robust prediction even when the subject moves his/her arm across several positions in space. The proposed approach was tested on five healthy subjects and showed that a R(2) index of 63.6% is obtained for generalization across different arm positions and wrist joint angles. PMID- 26737839 TI - Development of a phantom mimicking the functional and structural behaviors of the thigh muscles characterized with magnetic resonance elastography technique. AB - Magnetic Resonance Elastography (MRE) is a non invasive technique based on the propagation of shear waves in soft tissues providing the quantification of the mechanical properties [1]. MRE was successfully applied to healthy and pathological muscles. However, the MRE muscle methods must be further improved to characterize the deep muscles. A way will be to develop phantom mimicking the muscle behavior in order to set up new MRE protocol. Thus, the purpose of this study is to create a phantom composed of a similar skeletal muscle architecture (fiber, aponorosis) and equivalent elastic properties as a function of the muscle state (passive or active). Two homogeneous phantoms were manufactured with different concentrations of plastisol to simulate the elastic properties in relaxed (50% of plastisol) and contracted (70% of plastisol) muscle conditions. Moreover, teflon tubing pipes (D = 0.9 mm) were thread in the upper part of the phantom (50%) to represent the muscle fibers and a plastic sheet (8 * 15 cm) was also included in the middle of the phantom to mimic the aponeurosis structure. Subsequently, MRE tests were performed with two different pneumatic drivers, tube and round, (f = 90Hz) to analyze the effect of the type of driver on the wave propagation. Then, the wavelength was measured from the phase images to obtain the elastic properties (shear modulus). Both phantoms revealed elastic properties which were in the same range as in vivo muscle in passive (MU(50%) = 2.40 +/- 0.18 kPa ) and active (6.24 +/- 0.21 kPa) states. The impact of the type of driver showed higher values (about 1.2kPa) with the tube. The analysis of the wave behavior revealed a sliding along the plastic sheet as it was observed for in vivo muscle study. The wave was also sensitive to the presence of the fibers where gaps were identified. The present study demonstrates the ability of the phantom to mimic the structural and functional properties of the muscle. PMID- 26737840 TI - Time-varying identification of ankle dynamic joint stiffness during movement with constant muscle activation. AB - Dynamic joint stiffness defines the torque generated at the joint in response to position perturbations. Dynamic stiffness is modulated by the angular position and the muscle activation level, making it difficult to estimate during large movements and/or time-varying muscle contractions. This paper presents a new methodology for estimating dynamic joint stiffness during movement and muscle activation. For this, we formulate a novel, nonlinear, dynamic joint stiffness model and present a new algorithm to estimate its parameters. The algorithm assumes that the variability in the model parameters is a function of the mean joint position. Using this methodology we estimated the dynamic joint stiffness at the ankle throughout ramp and hold displacements during a constant muscle contraction. The estimated model accurately predicted the intrinsic and reflex torques produced at the ankle as a response to small position perturbations during large displacement with muscle activation. Preliminary results show that during muscle contraction, ankle intrinsic stiffness estimated during movement is significantly lower than that estimated during quasi-stationary experiments. PMID- 26737841 TI - Identification of time-varying dynamics of reflex EMG in the ankle plantarflexors during time-varying, isometric contractions. AB - The dynamic relationship between the joint position and reflex EMG in ankle muscles of healthy human subjects was studied for time-varying (TV) contractions. A linear parameter varying (LPV) identification algorithm was used to estimate the Hammerstein system relating ankle position to the reflex EMG response. The estimated Hammerstein system comprised a time-invariant (TI) linear element and a TV static nonlinearity that resembled a half-wave rectifier with a threshold and linear gain. The results demonstrated a systematic change in the reflex nonlinearity with the activation level. The gain of TV nonlinearity increased with activation level reaching its peak at 20-30% maximum voluntary contraction and then decreased. The threshold of the nonlinearity decreased with increasing activation level reaching it minimum at the same point where the gain was maximal. Using the LPV-Hammerstein method in this work, the underlying TV dynamics were extracted from small number of trials. Thus, this method can be used to study stretch reflexes in subjects with neuromuscular disorders. PMID- 26737842 TI - Recovery response latencies to tripping perturbations during gait decrease with practice. AB - There are several control mechanisms that contribute to keep gait stability under the presence of perturbations. For larger perturbations, responses with longer latencies produce adequate reactions to the perturbation. Latencies might be shorter, and the risk for falling might decrease provided that the reaction is adequate. It is possible that training the recovery responses through a sequence of perturbations induce some changes in the reactions. The goal of this paper is to test if the recovery response mechanisms might change during a training session with multiple perturbations. Differences in the recovery reactions executed at the beginning and at the end of a sequence of perturbations were analyzed. The latency of the burst in the Rectus Femoris (RF), measured with surface EMG (sEMG), showed a significant reduction during the course of the experimental session. When trials are repeated, subjects are able to generate a more appropriate response to the perturbations. PMID- 26737843 TI - Predicting daily gait behaviors after anterior cruciate ligament surgery: A case study. AB - After surgical interventions such as anterior cruciate ligament reconstruction (ACLr), people exhibit altered gait mechanics due to joint impairments. Persistence of altered mechanics after resolution of impairments may be related to daily reinforcement of maladaptive behavior. Quantifying the contribution of such maladaptive motor strategies requires continuous monitoring of locomotor behaviors in the home setting. In this paper, we investigate an inertial sensor based approach to monitoring ambient activities. We evaluate the relative performance of our predictive algorithm on one control and one individual post ACL reconstruction. PMID- 26737844 TI - Investigation of adaptive split-belt treadmill walking by the hindlimbs of rats. AB - In this study, we investigated the adaptive behavior during hindlimb locomotion of rats on a split-belt treadmill. We measured and analyzed the movement of intact rats walking by the hindlimbs on the splitbelt treadmill with two conditions: symmetric and asymmetric belt speed. In addition, we conducted the dynamic simulation of a neuromusculoskeletal model of rat's hindlimb walking on a split-belt treadmill. We investigated the immediate modulations of the duty factors and relative phase between the right and left limbs depending on the conditions of the treadmill. The results of the simulation were qualitatively similar to those of the measurement experiment. Furthermore, these results were qualitatively similar to the measurement data of the humans and cats in the previous studies. This suggests that our model have the essential aspects to produce the adaptive split-belt treadmill walking in dynamics viewpoints. PMID- 26737845 TI - Classification of older adults with/without a fall history using machine learning methods. AB - Falling is a serious problem in an aged society such that assessment of the risk of falls for individuals is imperative for the research and practice of falls prevention. This paper introduces an application of several machine learning methods for training a classifier which is capable of classifying individual older adults into a high risk group and a low risk group (distinguished by whether or not the members of the group have a recent history of falls). Using a 3D motion capture system, significant gait features related to falls risk are extracted. By training these features, classification hypotheses are obtained based on machine learning techniques (K Nearest-neighbour, Naive Bayes, Logistic Regression, Neural Network, and Support Vector Machine). Training and test accuracies with sensitivity and specificity of each of these techniques are assessed. The feature adjustment and tuning of the machine learning algorithms are discussed. The outcome of the study will benefit the prediction and prevention of falls. PMID- 26737846 TI - Design of a breathing mattress based on the respiratory movement of kangaroo mother care for the development of neonates. AB - Kangaroo mother care (KMC) benefits the development of neonates. This paper focuses on the design and implementing the extension of KMC for infants at Neonatal Intensive Care Units (NICU). A breathing mattress is proposed to comfort infants and stimulate them to breathe regularly by mimicking the movement of the parent's chest during KMC. The incubator mattress simulates the breathing of the parent's chest with embedded electronics and pneumatic technology for mattress motion actuating systems. The stakeholders, including the child, parents and NICU staff, were directly involved during the concept development, prototyping and evaluation. PMID- 26737847 TI - Respiratory signal derived from the smartphone built-in accelerometer during a Respiratory Load Protocol. AB - The scope of our work focuses on investigating the potential use of the built-in accelerometer of the smartphones for the recording of the respiratory activity and deriving the respiratory rate. Five healthy subjects performed an inspiratory load protocol. The excursion of the right chest was recorded using the built-in triaxial accelerometer of a smartphone along the x, y and z axes and with an external uniaxial accelerometer. Simultaneously, the respiratory airflow and the inspiratory mouth pressure were recorded, as reference respiratory signals. The chest acceleration signal recorded in the z axis with the smartphone was denoised using a scheme based on the ensemble empirical mode decomposition, a noise data assisted method which decomposes nonstationary and nonlinear signals into intrinsic mode functions. To distinguish noisy oscillatory modes from the relevant modes we use the detrended fluctuation analysis. We reported a very strong correlation between the acceleration of the z axis of the smartphone and the reference accelerometer across the inspiratory load protocol (from 0.80 to 0.97). Furthermore, the evaluation of the respiratory rate showed a very strong correlation (0.98). A good agreement was observed between the respiratory rate estimated with the chest acceleration signal from the z axis of the smartphone and with the respiratory airflow signal: Bland-Altman limits of agreement between -1.44 and 1.46 breaths per minute with a mean bias of -0.01 breaths per minute. This preliminary study provides a valuable insight into the use of the smartphone and its built-in accelerometer for respiratory monitoring. PMID- 26737848 TI - Implementation of a smartphone wireless accelerometer platform for establishing deep brain stimulation treatment efficacy of essential tremor with machine learning. AB - Essential tremor (ET) is a highly prevalent movement disorder. Patients with ET exhibit a complex progressive and disabling tremor, and medical management often fails. Deep brain stimulation (DBS) has been successfully applied to this disorder, however there has been no quantifiable way to measure tremor severity or treatment efficacy in this patient population. The quantified amelioration of kinetic tremor via DBS is herein demonstrated through the application of a smartphone (iPhone) as a wireless accelerometer platform. The recorded acceleration signal can be obtained at a setting of the subject's convenience and conveyed by wireless transmission through the Internet for post-processing anywhere in the world. Further post-processing of the acceleration signal can be classified through a machine learning application, such as the support vector machine. Preliminary application of deep brain stimulation with a smartphone for acquisition of a feature set and machine learning for classification has been successfully applied. The support vector machine achieved 100% classification between deep brain stimulation in 'on' and 'off' mode based on the recording of an accelerometer signal through a smartphone as a wireless accelerometer platform. PMID- 26737849 TI - Visual methods to assess cold fingers and experimental verification. AB - Cold fingers is complaint of many people. To independently assess actual finger temperature, this paper uses prototype sensors to capture blood vessel width and blood flow rates. We verify their feasibility for future home healthcare use along with far infrared camera outputs. We elucidate the impact of three remedies, massage, hot cocoa, and shoulder exercises, on 7 subjects. PMID- 26737850 TI - Portable electrocardiograph through android application. AB - An electrocardiograph was designed and implemented, being capable of obtaining electrical signals from the heart, and sending this data via Bluetooth to a tablet, in which the signals are graphically shown. The user interface is developed as an Android application. Because of the technological progress and the increasing use of full portable systems, such as tablets and cell phones, it is important to understand the functioning and development of an application, which provides a basis for conducting studies using this technology as an interface. The project development includes concepts of electronics and its application to achieve a portable and functional final project, besides using a specific programmable integrated circuit for electrocardiogram, electroencephalogram and electromyogram, the ADS1294. Using a simulator of cardiac signals, 36 different waveforms were recorded, including normal sinus rhythm, arrhythmias and artifacts. Simulations include variations of heart rate from 30 to 190 beats per minute (BPM), with variations in peak amplitude of 1 mV to 2 mV. Tests were performed with a subject at rest and in motion, observing the signals obtained and the damage to their interpretation due to the introduction of muscle movement artifacts in motion situations. PMID- 26737851 TI - Online and automated reliable system design to remove blink and muscle artefact in EEG. AB - Electroencephalograms (EEGs) are progressively emerging as a significant measure of brain activity and are very effective tool for the diagnosis and treatment of mental and brain diseases and disorders including sleep apnea, Alzheimer's disease and Neurodevelopmental disorders. However, EEG signal is mixed with other biological signals including Ocular and Muscular artefacts making it difficult to extract the diagnostic features. Therefore, the contaminated EEG channels are often discarded by the medical practitioners resulting less accurate diagnosis. In this paper we propose a real-time low-complexity and reliable system design methodology to remove these artefacts and noise in an automated fashion to aid online diagnosis under the pervasive personalized healthcare set-up without the need of any reference electrode. The simulation and hardware performance of the proposed methodology are measured and compared in terms of correlation and regression statistics lying above 80% and 67% which are much improved over the state-of-the art methodologies. PMID- 26737852 TI - Designing a patient monitoring system for bipolar disorder using Semantic Web technologies. AB - The new movement to personalize treatment plans and improve prediction capabilities is greatly facilitated by intelligent remote patient monitoring and risk prevention. This paper focuses on patients suffering from bipolar disorder, a mental illness characterized by severe mood swings. We exploit the advantages of Semantic Web and Electronic Health Record Technologies to develop a patient monitoring platform to support clinicians. Relying on intelligently filtering of clinical evidence-based information and individual-specific knowledge, we aim to provide recommendations for treatment and monitoring at appropriate time or concluding into alerts for serious shifts in mood and patients' non response to treatment. PMID- 26737853 TI - Improvement of emotional healthcare system with stress detection from ECG signal. AB - Our emotional healthcare system is designed to cope with users' negative emotions in daily life. To make the system more intelligent, we integrated emotion recognition by facial expression to provide appropriate services based on user's current emotional state. Our emotion recognition by facial expression has confusion issue to recognize some positive, neutral and negative emotions that make the emotional healthcare system provide a relaxation service even though users don't have negative emotions. Therefore, to increase the effectiveness of the system to provide the relaxation service, we integrate stress detection from ECG signal. The stress detection might be able to address the confusion issue of emotion recognition by facial expression to provide the service. Indeed, our results show that integration of stress detection increases the effectiveness and efficiency of the emotional healthcare system to provide services. PMID- 26737854 TI - Prediction of Happy-Sad mood from daily behaviors and previous sleep history. AB - We collected and analyzed subjective and objective data using surveys and wearable sensors worn day and night from 68 participants for ~30 days each, to address questions related to the relationships among sleep duration, sleep irregularity, self-reported Happy-Sad mood and other daily behavioral factors in college students. We analyzed this behavioral and physiological data to (i) identify factors that classified the participants into Happy-Sad mood using support vector machines (SVMs); and (ii) analyze how accurately sleep duration and sleep regularity for the past 1-5 days classified morning Happy-Sad mood. We found statistically significant associations amongst Sad mood and poor health related factors. Behavioral factors including the frequency of negative social interactions, and negative emails, and total academic activity hours showed the best performance in separating the Happy-Sad mood groups. Sleep regularity and sleep duration predicted daily Happy-Sad mood with 65-80% accuracy. The number of nights giving the best prediction of Happy-Sad mood varied for different individuals. PMID- 26737855 TI - Assessment of cardiovascular risk based on a data-driven knowledge discovery approach. AB - The cardioRisk project addresses the development of personalized risk assessment tools for patients who have been admitted to the hospital with acute myocardial infarction. Although there are models available that assess the short-term risk of death/new events for such patients, these models were established in circumstances that do not take into account the present clinical interventions and, in some cases, the risk factors used by such models are not easily available in clinical practice. The integration of the existing risk tools (applied in the clinician's daily practice) with data-driven knowledge discovery mechanisms based on data routinely collected during hospitalizations, will be a breakthrough in overcoming some of these difficulties. In this context, the development of simple and interpretable models (based on recent datasets), unquestionably will facilitate and will introduce confidence in this integration process. In this work, a simple and interpretable model based on a real dataset is proposed. It consists of a decision tree model structure that uses a reduced set of six binary risk factors. The validation is performed using a recent dataset provided by the Portuguese Society of Cardiology (11113 patients), which originally comprised 77 risk factors. A sensitivity, specificity and accuracy of, respectively, 80.42%, 77.25% and 78.80% were achieved showing the effectiveness of the approach. PMID- 26737856 TI - Automated information extraction from free-text EEG reports. AB - In this study we have developed a supervised learning to automatically detect with high accuracy EEG reports that describe seizures and epileptiform discharges. We manually labeled 3,277 documents as describing one or more seizures vs no seizures, and as describing epileptiform discharges vs no epileptiform discharges. We then used Naive Bayes to develop a system able to automatically classify EEG reports into these categories. Our system consisted of normalization techniques, extraction of key sentences, and automated feature selection using cross validation. As candidate features we used key words and special word patterns called elastic word sequences (EWS). Final feature selection was accomplished via sequential backward selection. We used cross validation to predict out of sample performance. Our automated feature selection procedure resulted in a classifier with 38 features for seizure detection, and 23 features for epileptiform discharge detection. The average [95% CI] area under the receiver operating curve was 99.05 [98.79, 99.32]% for detecting reports with seizures, and 96.15 [92.31, 100.00]% for detecting reports with epileptiform discharges. The methodology described herein greatly reduces the manual labor involved in identifying large cohorts of patients for retrospective neurophysiological studies of patients with epilepsy. PMID- 26737857 TI - Post-surgical complication prediction in the presence of low-rank missing data. AB - The problem of missing data has made it difficult to analyze Electronic Health Records (EHR). In EHR data, the "missingness" often results from the low-rank property: each patient is considered a mixture of prototypical patients, and certain types of patients will have similar missing entries in their records. However, most existing methods to deal with missing data fail to capture this low rank property of missing data. Hence we propose to use matrix factorization and matrix completion methods to perform prediction in the presence of missing data. We validated our methods in the task of post-surgical complication prediction and experimental results show that our method can improve the prediction accuracy significantly. PMID- 26737858 TI - How to extract clinically useful information from large amount of dialysis related stored data. AB - The basic storage infrastructure used to gather data from the technological evolution also in the healthcare field was leading to the storing into public or private repository of even higher quantities of data related to patients and their pathological evolution. Big data techniques are spreading also in medical research. By these techniques is possible extract information from complex heterogeneous sources, realizing longitudinal studies focused to correlate the patient status with biometric parameters. In our work we develop a common data infrastructure involving 4 clinical dialysis centers between Lombardy and Switzerland. The common platform has been build to store large amount of clinical data related to 716 dialysis session of 70 patient. The platform is made up by a combination of a MySQL((r)) database (Dialysis Database) and a MATLAB-based mining library (Dialysis MATlib). A statistical analysis of these data has been performed on the data gathered. These analyses led to the development of two clinical indexes, representing an example of transformation of big data into clinical information. PMID- 26737859 TI - A proposal for improvement of genotyping performance for ethnically homogeneous population using DNA microarray. AB - DNA microarray is used to determine the genotypes of several hundred thousand to several million SNPs (Single Nucleotide Polymorphisms) on multiple samples at a time. In the conventional method of genotyping using DNA microarray, it is assumed that each SNP has three types of genotypes: two homozygous and one heterozygous genotypes. However, in an ethnically homogeneous population, there are cases when all the samples of a SNP belong to one homozygous genotype, and there are some other cases, especially in the SNPs of low MAFs (Minor Allele Frequencies), each sample belongs to either of the two genotypes: one homozygous and one heterozygous genotypes. In those cases, the conventional method of genotyping may fail to properly determine the genotypes of the samples. In this paper, we propose a new genotyping method, which can be used as a post-processing technique of the conventional genotyping method, for re-judgment of the SNPs having one or two types of genotypes. The proposed method takes fluctuations of the fluorescence intensities of the signals of DNA microarray into account, assigns genotypes to samples from those genotype patterns that may occur under natural mating conditions and applies different genotype judgment methods depending on the number of genotype clusters of a SNP. We evaluate our proposed method using the data of 1000 Genome Project and have found that our proposed method is able to improve the genotyping performance of the conventional method. PMID- 26737860 TI - Comparison between Decision Tree and Genetic Programming to distinguish healthy from stroke postural sway patterns. AB - Maintaining balance is a motor task of crucial importance for humans to perform their daily activities safely and independently. Studies in the field of Artificial Intelligence have considered different classification methods in order to distinguish healthy subjects from patients with certain motor disorders based on their postural strategies during the balance control. The main purpose of this paper is to compare the performance between Decision Tree (DT) and Genetic Programming (GP) - both classification methods of easy interpretation by health professionals - to distinguish postural sway patterns produced by healthy and stroke individuals based on 16 widely used posturographic variables. For this purpose, we used a posturographic dataset of time-series of center-of-pressure displacements derived from 19 stroke patients and 19 healthy matched subjects in three quiet standing tasks of balance control. Then, DT and GP models were trained and tested under two different experiments where accuracy, sensitivity and specificity were adopted as performance metrics. The DT method has performed statistically significant (P < 0.05) better in both cases, showing for example an accuracy of 72.8% against 69.2% from GP in the second experiment of this paper. PMID- 26737861 TI - Clustering Emergency Department patients - an assessment of group normality. AB - This paper presents an investigation into clustering of vital signs from Emergency Department patients with an intention of uncovering distinct thresholds for groups of patients. Emergency Department clinicians have to deal with an enormous spectrum of symptoms and diseases. The variety in patients is a cause for false alarms which greatly burden clinicians. Better targeted alarm thresholds may mitigate the risk of alarm fatigue. The study is based on vital signs from a prospective cohort study at a Danish Hospital coupled with health registry data, and utilizes k-means clustering and novel evaluation metrics for cluster assessment. All combinations of 5 key vital signs are clustered in a range from 2..20. We evaluate the clustering of respiration and arterial peripheral oxygen saturation for k=7. The study fails to identify distinct groups, but does uncover relevant traits and contribute with an evaluation strategy for further studies. PMID- 26737862 TI - explICU: A web-based visualization and predictive modeling toolkit for mortality in intensive care patients. AB - Preventing mortality in intensive care units (ICUs) has been a top priority in American hospitals. Predictive modeling has been shown to be effective in prediction of mortality based upon data from patients' past medical histories from electronic health records (EHRs). Furthermore, visualization of timeline events is imperative in the ICU setting in order to quickly identify trends in patient histories that may lead to mortality. With the increasing adoption of EHRs, a wealth of medical data is becoming increasingly available for secondary uses such as data exploration and predictive modeling. While data exploration and predictive modeling are useful for finding risk factors in ICU patients, the process is time consuming and requires a high level of computer programming ability. We propose explICU, a web service that hosts EHR data, displays timelines of patient events based upon user-specified preferences, performs predictive modeling in the back end, and displays results to the user via intuitive, interactive visualizations. PMID- 26737863 TI - Using a generalised identity reference model with archetypes to support interoperability of demographics information in electronic health record systems. AB - Computerised identity management is in general encountered as a low-level mechanism that enables users in a particular system or region to securely access resources. In the Electronic Health Record (EHR), the identifying information of both the healthcare professionals who access the EHR and the patients whose EHR is accessed, are subject to change. Demographics services have been developed to manage federated patient and healthcare professional identities and to support challenging healthcare-specific use cases in the presence of diverse and sometimes conflicting demographic identities. Demographics services are not the only use for identities in healthcare. Nevertheless, contemporary EHR specifications limit the types of entities that can be the actor or subject of a record to health professionals and patients, thus limiting the use of two level models in other healthcare information systems. Demographics are ubiquitous in healthcare, so for a general identity model to be usable, it should be capable of managing demographic information. In this paper, we introduce a generalised identity reference model (GIRM) based on key characteristics of five surveyed demographic models. We evaluate the GIRM by using it to express the EN13606 demographics model in an extensible way at the metadata level and show how two level modelling can support the exchange of instances of demographic identities. This use of the GIRM to express demographics information shows its application for standards-compliant two-level modelling alongside heterogeneous demographics models. We advocate this approach to facilitate the interoperability of identities between two-level model-based EHR systems and show the validity and the extensibility of using GIRM for the expression of other health-related identities. PMID- 26737864 TI - Analysis of daily oxygen saturation for detecting deterioration in the condition of COPD patients. AB - This study presents a novel threshold algorithm that is applied to daily self measured SpO(2) data for management of COPD patients in remote patient monitoring to improve accuracy of detection of exacerbation. Conventional approaches based on a fixed threshold applied to a single SpO(2) reading result in high false alarm rates. We model the SpO(2) time series data as a combination of a trend and a stochastic component (residual) and use the standard deviation of residuals to identify exacerbations. Deterioration in the condition of a patient results in an increase in the standard deviation of the residual (sigma(res)), from 2% or less when the patient is in a healthy condition to 4% or more when the condition deteriorates. We present results from retrospective analysis of SpO(2) data measured in patients with COPD as part of a long term project to monitor frail elderly, and compare results from the new approach with those from the conventional approach. PMID- 26737865 TI - Future trends in Picture Archiving and Communication System (PACS). AB - This research investigates the opinions of radiologists regards requirements for improving current Picture Archiving and Communication System (PACS). Responses to a questionnaire were collected from 120 of the 200 radiologists in five governmental hospitals of Kuwait. The study the determines the importance of the solutions for future PACS from the radiologists point of view as: PACS must be integrated with other hospital information systems (100%); there must be multi hospital PACS access across different organizations (99%); web based PACS solutions (97%) and PACS applications in mobile phones (97%) are seen as an improved solution for future PACS. Whereas, the radiologists expressed strong concerns over the barriers for implementing web PACS solutions including: technical issues (91%); lack of training (85%); and cost (76%). PMID- 26737866 TI - An mHealth system for toxicity monitoring of paediatric oncological patients using Near Field Communication technology. AB - Home-based monitoring might be useful to reduce the burden of long-lasting oncological treatment for children. Current telemonitoring applications focus on chronic diseases or elderly people. Based on the workflow for different stakeholders and the identification of parameters important in paediatric oncology, we developed a prototype of a smartphone-based telehealth system using Near Field Communication technology for monitoring paediatric neuroblastoma patients at home. The parameters blood pressure, heart rate, temperature, body weight, C-reactive protein, white blood cell count, wellbeing, pain level, nausea level and skin alterations could be monitored using a smartphone, a designated app, point-of-care measurement devices and a smart-poster containing RFID tags. The system has been designed to increase the quality of life for paediatric cancer patients. As a future step, a clinical trial is currently being planned to evaluate the system in clinical setting. PMID- 26737867 TI - Impact of hierarchies of clinical codes on predicting future days in hospital. AB - Health insurance claims contain valuable information for predicting the future health of a population. Nowadays, with many mature machine learning algorithms, models can be implemented to predict future medical costs and hospitalizations. However, it is well-known that the way in which the data are represented significantly affects the performance of machine learning algorithms. In health insurance claims, key clinical information mainly comes from the associated clinical codes, such as diagnosis codes and procedure codes, which are hierarchically structured. In this study, it is investigated whether the hierarchies of such clinical codes can be utilized to improve predictive performance in the context of predicting future days in hospital. Empirical investigations were done on data sets of different sizes, considering that the frequency of the appearance of lower-level (more specific) clinical codes could vary significantly in populations of different sizes. The use of bagged trees with feature sets that include only basic demographic features, low-level, medium level, high-level clinical codes, and a full feature set were compared. The main finding from this study is that different hierarchies of clinical codes do not have a significant impact on the predictive power. Some other findings include: 1) Sample size greatly affects the predictive outcome (more observations result in more stable and more accurate outcomes); 2) Combined use of enriched demographic features and clinical features give better performance as compared to using them separately. PMID- 26737868 TI - Human-centered design of a cyber-physical system for advanced response to Ebola (CARE). AB - We describe the process towards the design of a safe, reliable, and intuitive emergency treatment unit to facilitate a higher degree of safety and situational awareness for medical staff, leading to an increased level of patient care during an epidemic outbreak in an unprepared, underdeveloped, or disaster stricken area. We start with a human-centered design process to understand the design challenge of working with Ebola treatment units in Western Africa in the latest Ebola outbreak, and show preliminary work towards cyber-physical technologies applicable to potentially helping during the next outbreak. PMID- 26737869 TI - A reliability assessment software using Kinect to complement the clinical evaluation of Parkinson's disease. AB - Parkinson's disease is characterized by alterations in the gait pattern that may increase the risk of falls. Variations in the gait pattern cannot be objectively measured in clinical examination, so it is necessary to adapt devices to measure objectively, valid and replicable changes in gait patterns that are part of the evolution of the disease and / or pharmacotherapy. In an interdisciplinary effort, we developed the "e-Motion Capture System" software, which is able to calculate motor (cadence, stride and step length) and spatiotemporal (velocity and acceleration) parameters that affect quality of life in patients with Parkinson's disease. In this paper, we show results of the comparison between our e-Motion software and a benchmark reference, multiple-camera 3D motion capture system to track a gait pattern. This analysis was performed to compare the spatial locations of the ankles of a volunteer under indoor controlled conditions. Our results for the comparison between e-Motion and the 3D motion capture system show excellent agreement. PMID- 26737870 TI - Implementation of new dry electrodes and comparison with conventional Ag/AgCl electrodes for whole body electrical bioimpedance application. AB - Reusable electrodes, when embedded into devices, can provide new ways of physiological measurements, and improve the usability and comfort of monitoring systems using whole body electrical bioimpedance in the areas of medical, nutrition and sports. However, good electrical and mechanical contacts between electrode and skin are very important, as it defines the quality of the signal, requiring generally the use of consumable. This paper introduces innovative dry electrodes and compares their electrical behavior with those of a traditional Ag/AgCl electrolytic one. Thanks to the campaigns of measurements involving Caucasian healthy volunteers, three designs of experiments are conducted to lead to choose the optimized set: material, supply, using conditions. PMID- 26737871 TI - Development of an excretion care support robot with human cooperative characteristics. AB - To support care giving in an aging society with a shrinking population, various life support robots are being developed. In the authors' laboratory, an excretion care support robot (ECSR) with human cooperative characteristic has been developed to relieve the burden of caregivers and improve the quality of life for bedridden persons. This robot consists of a portable toilet with storage tank and a mobile robot which can run autonomously to conduct the cooperative work with others. Our research is focused on how to improve the motion accuracy and how the robot can cooperate with users. In this paper, to enable the ECSR could precisely move in the indoor environment, a proper controller is proposed considering the center of gravity shift and load changes. Then, to perform the cooperative task, two acceleration sensors are used to recognize the users' intended posture and position when moving from bed to toilet. The robot's target angle and position are determined by the user's posture. The effectiveness of the proposed method is verified by a pseudo excretion support experiment. PMID- 26737872 TI - Surgical energy device using steam jet for robotic assisted surgery. AB - In robotic assisted surgery, the carbonization and the adherence of coagulated tissues caused by surgical energy devices are problems. We propose a surgical energy device using a steam jet to solve the problems. The device applies a steam jet and performs coagulation and hemostasis. The exposed tissue is heated quickly with latent heat of the steam. The carbonization and the adherence of the tissue can be avoided. We prototyped a steam jet coagulator to prove the concept. The coagulator was mounted on the laparoscopic surgical robot. The effectiveness of the coagulation and hemostasis using steam was confirmed by the in vitro experiment on the chicken's liver and the in vivo experiments on the pig's spleen under the robotic assisted laparoscopic environment. PMID- 26737873 TI - A Multi-techniques Approach to assess reprocessing of Single-use electrosurgical pencils. AB - Reprocessing and reuse of single-use electrosurgical pencils (EPs) is a diffused practice in countries with limited access to healthcare subvention system and in developing countries. However, safety and efficacy issues are associated to this practice, requiring specific methods for checking the reprocessed device before clinical re-use. This study aimed at defining a set of testing methods for assessing thermal and surface characteristics of reprocessed single-use EPs and evaluating the suitability of these techniques for revealing modifications between brand new and reprocessed single-use EPs. We reported a multi-technique approach based on optical and electron microscopy, X-rays spectroscopy and thermal analysis. The assessment of a total of 30 variables of interest on both brand new and reprocessed devices, allowed to identify the most informative ones. Seven of the evaluated variables were found to differentiate the reprocessed device from the new ones in a significant way. The presented methods deserve potential for tracking modifications during the device lifecycle. PMID- 26737874 TI - Design, development and characterization of a modular end effector for MIS procedures. AB - The Minimally Invasive Surgery (MIS) paradigm is well established in modern surgical procedures. Although MIS is successful from the patient's viewpoint, the use of rigid instruments inserted through small skin incisions leads to dexterity constraints and loss of degree of motion. Robotics has been introduced as support for augmenting dexterity during interventions, restoring hand-eye coordination and providing tools with enhanced degrees of motion. However, surgical robots have high costs and large footprint, pushing the research towards the development of modular robots to be used in Naturally Orifice Trans-luminal Endoscopic Surgery (NOTES) procedures. The main need of having simple and cheap tools able to be interchanged during the surgical procedure became crucial. In this paper an innovative modular end-effector based on a compliant soft actuation system able to provide up to 5.78 N gripping forces is presented. PMID- 26737875 TI - 3D vs 2D laparoscopic systems: Development of a performance quantitative validation model. AB - BACKGROUND: The new technology ensures 3D laparoscopic vision by adding depth to the traditional two dimensions. This realistic vision gives the surgeon the feeling of operating in real space. Hospital of Treviglio-Caravaggio isn't an university or scientific institution; in 2014 a new 3D laparoscopic technology was acquired therefore it led to evaluation of the of the appropriateness in term of patient outcome and safety. The project aims at achieving the development of a quantitative validation model that would ensure low cost and a reliable measure of the performance of 3D technology versus 2D mode. In addition, it aims at demonstrating how new technologies, such as open source hardware and software and 3D printing, could help research with no significant cost increase. For these reasons, in order to define criteria of appropriateness in the use of 3D technologies, it was decided to perform a study to technically validate the use of the best technology in terms of effectiveness, efficiency and safety in the use of a system between laparoscopic vision in 3D and the traditional 2D. METHODS: 30 surgeons were enrolled in order to perform an exercise through the use of laparoscopic forceps inside a trainer. The exercise consisted of having surgeons with different level of seniority, grouped by type of specialization (eg. surgery, urology, gynecology), exercising videolaparoscopy with two technologies (2D and 3D) through the use of a anthropometric phantom. The target assigned to the surgeon was that to pass "needle and thread" without touching the metal part in the shortest time possible. The rings selected for the exercise had each a coefficient of difficulty determined by depth, diameter, angle from the positioning and from the point of view. RESULTS: The analysis of the data collected from the above exercise has mathematically confirmed that the 3D technique ensures a learning curve lower in novice and greater accuracy in the performance of the task with respect to 2D. PMID- 26737876 TI - Modelling Tumor Treating Fields for the treatment of lung-based tumors. AB - Tumor Treating Fields (TTFields), low-intensity electric fields in the frequency range of 100-500 kHz, exhibit antimitotic activity in cancer cells. TTFields were approved by the U. S. Food and Drug Administration for the treatment of recurrent glioblastoma in 2011. Preclinical evidence and pilot studies suggest that TTFields could be effective for treating certain types of lung cancer, and that treatment efficacy depends on the electric field intensity. To optimize TTFields delivery to the lungs, it is important to understand how TTFields distribute within the chest. Here we present simulations showing how TTFields are distributed in the thorax and torso, and demonstrate how the electric field distribution within the body can be controlled by personalizing the layout of the arrays used to deliver the field. PMID- 26737877 TI - Modeling Tumor Treating Fields (TTFields) application in single cells during metaphase and telophase. AB - Effects of electric fields on biological cells have been extensively studied but primarily in the low and high frequency regimes. Low frequency AC fields have been investigated for applications to nerve and muscle stimulation or to examine possible environmental effects of 60 Hz excitation. High frequency fields have been studied to understand tissue heating and tumor ablation. Biological effects at intermediate frequencies (in the 100-500 kHz regime) have only recently been discovered and are now being used clinically to disrupt cell division, primarily for the treatment of recurrent glioblastoma multiforme. In this study, we develop a computational framework to investigate the mechanisms of action of these Tumor Treating Fields (TTFields) and to understand in vitro findings observed in cell culture. Using Finite Element Method models of isolated cells we show that the intermediate frequency range is unique because it constitutes a transition region in which the intracellular electric field, shielded at low frequencies, increases significantly. We also show that the threshold at which this increase occurs depends on the dielectric properties of the cell membrane. Furthermore, our models of different stages of the cell cycle and of the morphological changes associated with cytokinesis show that peak dielectrophoretic forces develop within dividing cells exposed to TTFields. These findings are in agreement with in vitro observations, and enhance our understanding of how TTFields disrupt cellular function. PMID- 26737878 TI - Neutron distribution and induced activity inside a Linac treatment room. AB - Induced radioactivity and photoneutron contamination inside a radiation therapy bunker of a medical linear accelerator (Linac) is investigated in this work. The Linac studied is an Elekta Precise electron accelerator which maximum treatment photon energy is 15 MeV. This energy exceeds the photonuclear reaction threshold (around 7 MeV for high atomic number metals). The Monte Carlo code MCNP6 has been used for quantifying the neutron contamination inside the treatment room for different gantry rotation configuration. Walls activation processes have also been simulated. The approach described in this paper is useful to prevent the overexposure of patients and medical staff. PMID- 26737879 TI - Analysis of Low Intensity Laser Therapy as adjuvant to Photodynamic Therapy in Nonmelanoma Skin Cancer. AB - The combination of Low Intensity Laser Therapy and Photodynamic Therapy constitutes a minimal invasive and highly selective alternative for the treatment of skin tumors. Photodynamic effectiveness, specially the absence of recurrence, highly depends on the type of tumor, as well as on several parameters such as those related with the optical source. Therefore it is important to have predictive tools to provide an appropriate treatment planning. This work proposes the use of a complex predictive model that includes a three-dimensional meshing of the considered tumor geometry and the optical propagation therein by a three dimensional Monte Carlo method. The proposed tool is applied to three different types of skin tumors, squamous cell carcinoma, nodular and infiltrative basal cell carcinomas. The estimated volume of treatment, depending on the tumor type and source parameters, allows an appropriate treatment planning in order to avoid undesirable tumor recurrence. PMID- 26737880 TI - A dual-use imaging system for pre-clinical small animal radiation research. AB - The current cone beam computed tomography (CBCT) system on the small animal radiation research platform (SARRP) is less effective in localizing soft-tissue targets. On the contrary, molecular optical imaging techniques, such as bioluminescence tomography (BLT) and fluorescence tomography (FT), can provide high contrast soft tissue images to complement CBCT and offer functional information. In this study, we present a dual-use optical imaging system that enables BLT/FT for both on-board and stand-alone applications. The system consists of a mobile cart and an imaging unit. Multi-projection optical images can be acquired in a range of -90 degrees ~90 degrees angles. An optical fiber driven by an X-Y-Z Cartesian stage serves as an excitation light source specifically for FT. Our results show that the accuracy and reproducibility of the system meets the requirements set by the pre-clinical workflow (<;0.1 mm and 0.5 degree error). Preliminary experiments demonstrate the feasibility of bioluminescent imaging in a tissue-simulating phantom with a luminescent source embedded. In a considerable light-tight environment, we can achieve average background optical intensity significantly lower than the luminescent signal (<; 5%). PMID- 26737881 TI - Preclinical evaluation of a miniaturized Deep Brain Stimulation electrode lead. AB - The effect of miniaturizing the electrode lead for Deep Brain Stimulation (DBS) therapy was investigated in this work. A direct comparison was made between a miniature lead (0.65 mm diameter) and a lead of standard size (1.3 mm). Acute in vivo implantation in two cat brains was performed to evaluate surgical trauma and confirm capacity to target thalamic nuclei. Insertion into a homogeneous gel model of neural tissue was used to compare insertion forces while visualizing the process. The standard size cannula, used first to guide lead insertion, required substantially higher insertion force compared with the miniature version and produced a significantly larger region of tissue disruption. The characteristic hemorrhage and edema extended 119-352 MUm from the implanted track surface of the miniature lead and cannula, while these extended 311-571 MUm for the standard size lead and cannula. A miniature DBS implant can reduce the extent of trauma and could potentially help improve neural function preservation after functional neurosurgery. PMID- 26737882 TI - A microfabricated coil for implantable applications of magnetic spinal cord stimulation. AB - In this paper, a microfabricated inductive coil comprising of 125-turn coil windings and a MnZn-based magnetic core in a volume of 200 mm(3) is presented for the magnetic neural stimulation in a spinal cord. The coil winding with the parallel-linkage design instead of the typical serial-linkage one is proposed not only to provide better design flexibility to the current mode driving circuit but also to simplify the fabrication process of the 3-D inductive coil, which can further advance the coil miniaturization. Experimental results show the microcoil with a 1.5 A, 1 kHz square-wave current input can induce a voltages of ~220 MUV on the conducting wire with an impedance of ~0.2 Omega @ 1 kHz, 1 mm separation. PMID- 26737883 TI - Low-latency system for evaluation of image-enhancement-algorithms on patients using subretinal implants. AB - In this paper, a real-time system consisting of a camera device, computational unit and head mounted display, adjusted to the needs of patients using subretinal implants, is presented. Retinal implants demonstrated to partially restore useful vision to patients suffering from hereditary retinal degeneration diseases. Even though various implant-mediated visual perceptions in daily-life were reported, perceived vision could be enhanced using algorithms well known from image processing. Due to strict area limitations subretinal implants can only cover well-chosen and carefully examined functionality within the silicon device. To gain flexibility in testing different kinds of image enhancement algorithms, a software solution allowing quick changes is desired. The system presented here, allows recording and displaying reality on a head mounted display with low latency, while maintaining true to scale representation. Additionally different types of pixel-based image-enhancement-algorithms can be applied on the captured content to modify the perceived image. PMID- 26737884 TI - Study of intracranial pressure in human brain during transcranial magnetic stimulation. AB - This paper presents the results of cranial force in human brain due to electromagnetic pulse during transcranial magnetic stimulation. To model the force in a realistic brain, we used three dimensional magnetic resonance image of the 26 years old female subject. Simulation results show that during TMS procedure, there is a small force generated within the cranial tissue layers along with a torque value in different layers of brain tissues. The force depends on the magnitude of the magnetic field generated by the TMS coil. PMID- 26737885 TI - How electrode montage affects transcranial direct current stimulation of the human motor cortex. AB - Several different electrode configurations were originally proposed to induce excitability changes in the hand area of the motor cortex in transcranial direct current stimulation (tDCS). However only one was found to efficiently affect cortical excitability: anode/cathode over the primary motor cortex and return electrode placed over the contralateral orbit (M-CF configuration). In this work we used the finite element method to calculate the electric field (E-field) induced in a realistic human head model in all the proposed electrode configurations. In order to analyze the results, average values of the E-field's magnitude and polar/azimuthal angles were calculated in several cortical motor and premotor areas which may have an effect on the output of the primary motor cortex. The average E-field's magnitude at the hand-knob (HK) was similar between the M-CF configuration (0.16 V/m) and a few other tested configurations, the same happening for the average polar angle (129 degrees ). However this configuration achieved the highest mean E-field values over premotor (PM) areas (0.21 V/m). These results show that the polar angle and the average magnitude of the E-field evaluated at the HK and at the PM cortex might be important parameters in predicting the success of a specific electrode montage in tDCS. PMID- 26737886 TI - Optimization of coil geometries for bone fracture healing via dielectrophoretic force stimulation - a simulation study. AB - In this paper we propose a novel technique for shortening fracture healing times based on the use of dielectrophoretic forces (DEPFs). If a non-uniform electromagnetic field is applied around a fracture site, red blood cells within the blood will be polarized; creating electrical dipoles. The dielectrophoretic forces resulting from the interaction of these dipoles and the electromagnetic field, can be used to manipulate blood flow at a fracture site, promote vascularization, increase transmembrane signaling, increase supply of nutrients, necessary hormones and growth factors at the fracture site and thus may help bone healing. For the generation of non-uniform fields we considered three different coil designs (linear, parabolic and square root) and using Mathcad numerically studied the dielectrophoretic forces for a long bone fracture where the main arteries are vertically-oriented and the blood flow is downward. The gravitational force and the drag force on the red blood cells determine the steady state blood flow. The dielectrophoretic force added to the force balance is functional in increasing the blood flow. The ratio of the velocity in the presence of dielectrophoresis to the velocity without dielectrophoresis (called here as the Dielectrophoretic Force Factor, K(DEpF)) is a good measure of the performance of the dielectrophoresis, since it indicates the increase in blood flow. It was found that the dielectorophoretic force reaches peak levels at a frequency range between 5-15 Hz. At 5 Hz, the average value of dielectrophoretic force factor is 1.90, 2.51 and 1.61 for the linear, parabolic and the square root coils, respectively. The parabolic coil results in the best DEPF and therefore would be the configuration to use in an experimental study to determine if DEPF is useful for bone healing. PMID- 26737887 TI - Automatic vs. clinical assessment of fall risk in older individuals: A proof of concept. AB - Falling in elderly is a worldwide major problem because it can lead to severe injuries, and even sudden death. Fall risk prediction would provide rapid intervention, as well as reducing the over burden of healthcare systems. Such prediction is currently performed by means of clinical scales. Among them, the Tinetti Scale is one of the better established and mostly used in clinical practice. In this work, we proposed an automatic method to assess the Tinetti scores using a wearable accelerometer. The balance and gait characteristics of 13 elderly subjects have been scored by an expert clinician while performing 8 different motor tasks according to the Tinetti Scale protocol. Two statistical analysis were selected. First, a linear regression study was performed between the Tinetti scores and 8 features (one feature for each task). Second, the generalization quality of the regression model was assessed using a Leave-One SubjectOut approach. The multiple linear regression provided a high correlation between the Tinetti scores and the features proposed (adj. R(2) = 0.948; p = 0.003). Moreover, six of the eight features added statistically significantly to the prediction of the scores (p <; 0.05). When testing the generalization capability of the model, a moderate linear correlation was obtained (R(2) = 0.67; p <; 0.05). The results suggested that the automatic method might be a promising tool to assess the falling risk of older individuals. PMID- 26737888 TI - Gait analysis and estimation of changes in fall risk factors. AB - Falls are a major problem for older adults. A continuous gait monitoring that provides fall risk assessment would allow timely interventions aiming for preventing falls. The objective of this work was to find out whether gait variables calculated from the acceleration signal measured during walk task in the baseline assessment can predict changes in commonly used fall risk assessment scales after 12 months follow-up. Forty two subjects were measured during walk test with a triaxial acceleration sensor worn on a waist belt at the lower back near the centre of mass. The fall risk was assessed using a test protocol, which included several assessment methods. Gait analysis was able to predict a decline in ABC, BBS and GDS total scores and slower time in STS-5 after twelve-months follow-up. A subsequent study is needed to confirm the model's suitability for data recorded in everyday lives. PMID- 26737889 TI - Context focused older adult mobility and gait assessment. AB - This paper presents an initial overview of insights gained into how older adults mobilize in the home and community, based on data from inertial sensors which were worn by study participants over a 7-day period. The addition of a wearable camera provided additional contextual information which can be used to assess mobility and understand the factors that influence it in the free living environment. Seven days of data collected from a group of older adults who had experienced one or more falls in the previous six months was compared to that of a control group with no history of falling. Results showed that both groups spent relatively little time walking in challenging environmental conditions, and that the fallers spent significantly less time walking under regular conditions (no effect on gait) and outdoors. Analysis of gait metrics showed that the fallers were slightly slower in general, and more noticeable differences were observed when the participants were regrouped according to mobility levels determined from baseline assessments using traditional methods. PMID- 26737890 TI - Camera-based fall detection using a particle filter. AB - More than thirty percent of persons over 65 years fall at least once a year and are often not able to get up again. The lack of timely aid after such a fall incident can lead to severe complications. This timely aid can however be assured by a camera-based fall detection system triggering an alarm when a fall occurs. Most algorithms described in literature use the biggest object detected using background subtraction to extract the fall features. In this paper we compare the performance of our state-of-the-art fall detection algorithm when using only background subtraction, when using a particle filter to track the person and a hybrid method in which the particle filter is only used to enhance the background subtraction and not for the feature extraction. We tested this using our simulation data set containing reenactments of real-life falls. This comparison shows that this hybrid method significantly increases the sensitivity and robustness of the fall detection algorithm resulting in a sensitivity of 76.1% and a PPV of 41.2%. PMID- 26737891 TI - Can a Visual Biofeedback system based on predictive information improve postural performance? AB - The aim of this study is to assess if predictive information can be used to implement visual biofeedback (VBF) systems to improve postural performance. The Centre of Pressure (CoP) coordinates, extracted directly from a force plate, are used to implement two different realtime VBF, which respectively use current CoP coordinates (VBF(real_time)) and predictive stability information (VBF(predictive)). Predictive coordinates are calculated in agreement with time to collision theory, using the real-time CoP components. In both VBF, subjects know if they are or are not in the stability area by an emoticon image displayed on the computer monitor. The expression of emoticon was smiling if the CoP coordinates were inside the area of stability, it was sad if the CoP coordinates exceed the stability area. Two groups of eighteen healthy young subjects performed the protocol in two different sequences: noVBF-VBF(real_time) and noVBF VBF(predictive). Each condition was repeated three times, and its effect was studied by four parameters extracted directly from CoP coordinates (sway path, sway area, mean amplitude and mean frequency). Both VBFs determine a modification of postural parameters compared to the baseline condition (noVBF) with decrease of sway area and mean amplitude and increase of mean frequency. The comparison between the two VBFs shows significant difference for all parameters except for mean frequency. In particular, sway path, sway area and mean amplitude values for the VBF(predictive) decreased more than the same values for the VBF(real_time). The preliminary results may prove useful for the possibility of using this kind of VBF as a tool to improve postural performance. PMID- 26737892 TI - Angular sway propagation in One Leg Stance and quiet stance with Inertial Measurement Units for older adults. AB - Postural stability degrades with age, threating the health and life quality of the older adults. One Leg Stance (OLS) is one of the standard and commonly adopted assessments for postural stability, and the postural sway in OLS has been demonstrated to be related with age. The propagation of postural sway between body segments could be a hint to the underlying mechanism of balance control. However, it is not yet fully understood. Therefore, the aim of this paper was to study the angular sways and their propagation of the head, trunk, and lower limb in healthy older adults. A cross-correlation of the normalized angular speeds was performed and the experiment with 68 older adults was conducted. The results showed that the head, hip and ankle joints affected the transfer of angular sway with a relatively lower correlation and longer latency. PMID- 26737893 TI - Low frequency overactivation in dyslexia: Evidence from resting state Magnetoencephalography. AB - In this study, we compared the brain activation profiles obtained from resting state Magnetoencephalographic (MEG) activity in 15 dyslexic patients with the profiles of 15 normal controls, using power spectral density (PSD) analysis. We first estimated intracranial dipolar MEG sources on a dense grid on the cortical surface and then projected these sources on a standardized atlas with 68 regions of interest (ROIs). Averaging the PSD values of all sources in each ROI across all control subjects resulted in a normative database that was used to convert the PSD values of dyslexic patients into z-scores in eight distinct frequency bands. We found that dyslexic patients exhibited statistically significant overactivation in the delta band (0.1-4 Hz) in the right temporal (entorhinal and insula), left inferior frontal (Broca's area), and right inferior frontal regions. Overactivation may be interpreted as a compensatory mechanism for reading characterizing dyslexic patients. These findings suggest that resting state MEG activation maps may be used as specific biomarkers that can help with the diagnosis of and assess the efficacy of intervention in dyslexia. PMID- 26737894 TI - Brain activation profiles in mTBI: Evidence from combined resting-state EEG and MEG activity. AB - In this study, we compared the brain activation profiles obtained from resting state Electroencephalographic (EEG) and Magnetoencephalographic (MEG) activity in six mild traumatic brain injury (mTBI) patients and five orthopedic controls, using power spectral density (PSD) analysis. We first estimated intracranial dipolar EEG/MEG sources on a dense grid on the cortical surface and then projected these sources on a standardized atlas with 68 regions of interest (ROIs). Averaging the PSD values of all sources in each ROI across all control subjects resulted in a normative database that was used to convert the PSD values of mTBI patients into z-scores in eight distinct frequency bands. We found that mTBI patients exhibited statistically significant overactivation in the delta, theta, and low alpha bands. Additionally, the MEG modality seemed to better characterize the group of individual subjects. These findings suggest that resting-state EEG/MEG activation maps may be used as specific biomarkers that can help with the diagnosis of and assess the efficacy of intervention in mTBI patients. PMID- 26737895 TI - Analysis of upper limb movement in Multiple Sclerosis subjects during common daily actions. AB - The goal of this study was to investigate the movement and muscle activity of the upper limb during common activities of daily life in people with Multiple Sclerosis (PwMS) with low and mild-moderate level of upper limb impairments. We found significant changes in muscles activity in PwMS compared to healthy subjects when holding and lifting objects used in everyday life. These differences were particularly remarkable in subjects with moderate level of impairment, in which the disease affected also movement smoothness. Remarkably, the smoothness of the movement during the interaction with common objects of daily activities highly correlated with the subjects' ability measured with the Abilhand scale. PMID- 26737897 TI - Development of a robotic evaluation system for the ability of proprioceptive sensation in slow hand motion. AB - This paper proposes a simple diagnostic methodology for checking the ability of proprioceptive/kinesthetic sensation by using a robotic device. The perception ability of virtual frictional forces is examined in operations of the robotic device by the hand at a uniform slow velocity along the virtual straight/circular path. Experimental results by healthy subjects demonstrate that percentage of correct answers for the designed perceptual tests changes in the motion direction as well as the arm configuration and the HFM (human force manipulability) measure. It can be supposed that the proposed methodology can be applied into the early detection of neuromuscular/neurological disorders. PMID- 26737898 TI - Brain-computer interfacing in amyotrophic lateral sclerosis: Implications of a resting-state EEG analysis. AB - Despite decades of research on EEG-based brain-computer interfaces (BCIs) in patients with amyotrophic lateral sclerosis (ALS), there is still little known about how the disease affects the electromagnetic field of the brain. This may be one reason for the present failure of EEG-based BCI paradigms for completely locked-in ALS patients. In order to help understand this failure, we have recorded resting state data from six ALS patients and thirty-two healthy controls to investigate for group differences. While similar studies have been attempted in the past, none have used high-density EEG or tried to distinguish between physiological and non-physiological sources of the EEG. We find an ALS-specific global increase in gamma power (30-90 Hz) that is not specific to the motor cortex, suggesting that the mechanism behind ALS affects non-motor cortical regions even in the absence of comorbid cognitive deficits. PMID- 26737896 TI - Real-time monitoring of cerebral blood flow by laser speckle contrast imaging after cardiac arrest in rat. AB - Cardiac arrest (CA) results in global brain ischemia. To explore the role of cerebral blood flow (CBF) during ischemia, laser speckle contrast imaging (LSCI), a full-field high-resolution optical imaging technique, was used for real-time monitoring of the fluctuations of CBF in a rat model of asphyxial-CA. The temporal changes of CBF were characterized and the relationship between CBF and mean arterial pressure (MAP) was evaluated. Asphyxial-CA led to transient CBF dysregulation, manifested by changes in CBF velocity were significantly impacted by MAP. Hyperemia is aligned with a bolus injection of vecuronium, the first two minutes of asphyxia, the time of epinephrine injection and cardiopulmonary resuscitation, and then lasted for 13 min after the return of spontaneous respiratory (ROSC), followed by hypoperfusion about 55-70% of baseline level no later than 40 min after ROSC. Interestingly, we found that the velocity of venule blood flow increased more than that of the arteriole blood flow during the hyperemia (176% vs 120%). Our study, for the first time, shows real-time CBF changes during and immediately after asphyxial-CA, with high spatial and temporal resolution images. The quantified cerebro-vascular response during the different phases of recovery after CA may underlie the mechanism of injury and recovery after brain ischemia. The study provides a new technique to study the neurovascular coupling and metabolic regulation of CBF after CA. PMID- 26737899 TI - Multimodal approach to estimate the ocular movements during EEG recordings: A coupled tensor factorization method. AB - This paper deals with coupled tensor factorization. A relaxed criterion derived from the advanced coupled matrix-tensor factorization (ACMTF) proposed by Acar et al. is described. The proposed relaxed ACMTF (RACMTF) criterion is based on weaker assumptions that are thus more often satisfied when dealing with actual data. Numerical simulations show the benefit of using jointly two data sets when the underlying factors are highly correlated, especially if one of the modality is less noisy than the other one. The proposed method is finally applied on actual Gaze&EEG data to estimate the ocular artifacts into the EEG recordings. PMID- 26737900 TI - Atrial signal extraction in atrial fibrillation electrocardiograms using a tensor decomposition approach. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice and remains a major challenge in cardiology. The noninvasive analysis of AF usually requires the estimation of the atrial activity (AA) signal in surface electrocardiogram (ECG) recordings. The present contribution puts forward a tensor decomposition approach for noninvasive AA extraction in AF ECG recordings. As opposed to the matrix approach, tensor decompositions are generally unique under mild conditions and have the potential to perform source separation in scenarios with a limited number of electrodes. An experimental study on a synthethic signal model and a real AF ECG recording evaluates the performance of the so-called block term tensor decomposition approach as compared to matrix techniques such as principal component analysis and independent component analysis. PMID- 26737901 TI - Tensor-based detection of T wave alternans using ECG. AB - T wave alternans is defined as changes in the T wave amplitude in an ABABAB pattern. It can be found in ECG signals of patients with heart diseases and is a possible indicator to predict the risk on sudden cardiac death. Due to its low amplitude, robust automatic T wave alternans detection is a difficult task. We present a new method to detect T wave alternans in multichannel ECG signals. The use of tensors (multidimensional matrices) permits the combination of the information present in different channels, making detection more reliable. The possibility of decomposition of incomplete tensors is exploited to deal with noisy ECG segments. Using a sliding window of 128 heartbeats, a tensor is constructed of the T waves of all channels. Canonical Polyadic Decomposition is applied to this tensor and the resulting loading vectors are examined for information about the T wave behavior in three dimensions. T wave alternans is detected using a sign change counting method that is able to extract both the T wave alternans length and magnitude. When applying this novel method to a database of patients with multiple positive T wave alternans tests using the clinically available spectral method tests, both the length and the magnitude of the detected T wave alternans is larger for these subjects than for subjects in a control group. PMID- 26737902 TI - Localization of spatially distributed brain sources after a tensor-based preprocessing of interictal epileptic EEG data. AB - This paper addresses the localization of spatially distributed sources from interictal epileptic electroencephalographic data after a tensor-based preprocessing. Justifying the Canonical Polyadic (CP) model of the space-time frequency and space-time-wave-vector tensors is not an easy task when two or more extended sources have to be localized. On the other hand, the occurrence of several amplitude modulated spikes originating from the same epileptic region can be used to build a space-time-spike tensor from the EEG data. While the CP model of this tensor appears more justified, the exact computation of its loading matrices can be limited by the presence of highly correlated sources or/and a strong background noise. An efficient extended source localization scheme after the tensor-based preprocessing has then to be set up. Different strategies are thus investigated and compared on realistic simulated data: the "disk algorithm" using a precomputed dictionary of circular patches, a standardized Tikhonov regularization and a fused LASSO scheme. PMID- 26737903 TI - Complex tensor based blind source separation of EEG for tracking P300 subcomponents. AB - Complex tensor factorisation of correlated brain sources is addressed in this paper. The electrical brain responses due to motory, sensory, or cognitive stimuli, i.e. event related potentials (ERPs), particularly P300, have been used for cognitive information processing. P300 has two subcomponents, P3a and P3b which are correlated and therefore, the traditional blind source separation approaches cannot solve the problem. In this work, a complex-valued tensor factorisation of electroencephalography (EEG) signals is introduced with the aim of separating P300 subcomponents. The proposed method uses complex-valued statistics to exploit the data correlation. In this way, the variations of P3a and p3b can be tracked for the assessment of the brain state. The results of this work will be compared with those of spatial principal component analysis (SPCA) method. PMID- 26737904 TI - Tensor based tumor tissue type differentiation using magnetic resonance spectroscopic imaging. AB - Magnetic resonance spectroscopic imaging (MRSI) has the potential to characterise different tissue types in brain tumors. Blind source separation techniques are used to extract the specific tissue profiles and their corresponding distribution from the MRSI data. A 3-dimensional MRSI tensor is constructed from in vivo 2D MRSI data of individual tumor patients. Non-negative canonical polyadic decomposition (NCPD) with common factor in mode-1 and mode-2 and l(1) regularization on mode-3 is applied on the MRSI tensor to differentiate various tissue types. Initial in vivo study shows that NCPD has better performance in identifying tumor and necrotic tissue type in high grade glioma patients compared to previous matrix-based decompositions, such as non-negative matrix factorization and hierarchical non-negative matrix factorization. PMID- 26737905 TI - Detection of G-Induced Loss of Consciousness (G-LOC) prognosis through EMG monitoring on gastrocnemius muscle in flight. AB - G-Induced Loss of Consciousness (G-LOC) is mainly caused by the sudden acceleration in the direction of +Gz axis from the fighter pilots, and is considered as an emergent situation of which fighter pilots are constantly aware. In order to resist against G-LOC, fighter pilots are subject to run Anti-G straining maneuver (AGSM), which includes L-1 respiration maneuvering and muscular contraction of the whole body. The purpose of this study is to create a G-LOC warning alarm prior to G-LOC by monitoring the Electromyogram (EMG) of the gastrocnemius muscle on the calf, which goes under constant muscular contraction during the AGSM process. EMG data was retrieved from pilots and pilot trainees of the Korean Air Force, during when subjects were under high G-trainings on a human centrifugal simulator. Out of the EMG features, integrated absolute value (IAV), reflecting muscle contraction, and waveform length (WL), reflecting muscle contraction and fatigue, have shown a rapid decay during the alarm phase, 3 seconds before G-LOC, compared to that of a normal phase withstanding G-force. Such results showed consistency amongst pilots and pilot trainees who were under G-LOC. Based on these findings, this study developed an algorithm which can detect G-LOC prognosis during flight, and at the same time, generate warning signals. The probability of G-LOC occurrence is detected through monitoring the decay trend and degree of the IVA and WL value of when the pilot initiates AGSM during sudden acceleration above 6G. Conclusively, this G-LOC prognosis detecting and warning system is a customized, real-time countermeasure which enhanced the accuracy of detecting G-LOC. PMID- 26737906 TI - On sweat analysis for quantitative estimation of dehydration during physical exercise. AB - Quantitative estimation of water loss during physical exercise is of importance because dehydration can impair both muscular strength and aerobic endurance. A physiological indicator for deficit of total body water (TBW) might be the concentration of electrolytes in sweat. It has been shown that concentrations differ after physical exercise depending on whether water loss was replaced by fluid intake or not. However, to the best of our knowledge, this fact has not been examined for its potential to quantitatively estimate TBW loss. Therefore, we conducted a study in which sweat samples were collected continuously during two hours of physical exercise without fluid intake. A statistical analysis of these sweat samples revealed significant correlations between chloride concentration in sweat and TBW loss (r = 0.41, p <; 0.01), and between sweat osmolality and TBW loss (r = 0.43, p <; 0.01). A quantitative estimation of TBW loss resulted in a mean absolute error of 0.49 l per estimation. Although the precision has to be improved for practical applications, the present results suggest that TBW loss estimation could be realizable using sweat samples. PMID- 26737907 TI - Efficient estimation of tissue thicknesses using sparse approximation for Gaussian processes. AB - Highly accurate localization of the human skull is vital in cranial radiotherapy. Marker-less optical head tracking provides a fast and accurate way to monitor this motion. Recent research has given evidence that marker-less tracking of the forehead benefits from tissue thickness information in addition to the 3D surface geometry. Using Gaussian Processes (GPs) tissue thickness is determined from optical backscatter of a sweeping laser. However, the computational complexity of the GPs scales cubically with the number of training samples. A full head scan contains 1024 points, whereas scans from several perspectives may be required for a comprehensive model for each subject. In five subjects, we thus evaluate sparse approximation methods to reduce the computational effort. We found a better - computation time versus root mean square error (RMSE) - tradeoff for a simple subset of data (SoD) technique. The increase of RMSE when dropping data was not found steep enough to justify the computational overhead of a better approximation by inducing point methods (namely FITC). Promising results were, however, obtained when clustering the training data before selecting the subset. PMID- 26737908 TI - Classification strategies for a single-trial binary Brain Computer Interface based on remembering unpleasant odors. AB - A Brain Computer Interface (BCI) is a useful instrument to support human communication. In recent years, BCI systems have been frequently implemented by using EEG. Regarding the communication paradigm used, there exists a very large number of strategies and, recently, the remembering of unpleasant odors has been also defined. However, the quality of the signals collected by this last paradigm is very poor, due to the absence of a real stimulus (the stimulus consists in remembering a disgusting situation). For this reason, a crucial node is the choice of a very efficient classification algorithm to improve the accuracy of the BCI. The present paper describes a and compares classification strategies for such type of BCI systems. The proposed methods and the experimental setup are described and experimental measurements are presented and discussed. PMID- 26737909 TI - Phenotypic characterisation of Crohn's disease severity. AB - Crohn's disease (CD) is a highly heterogeneous disease, with great variation in patient severity. Using supervised machine learning techniques to predict severity from common laboratory and clinical measurements, we found that high levels of C-reactive protein and low levels of lymphocytes and albumin are important predictive factors. Building upon this knowledge, we used extreme value theory to create a probabilistic model that combines information about behaviour in the extremes of these lab measurements to produce a single risk score over time. We then clustered these patient risk scores to identify several common clinical trajectories for CD patients. PMID- 26737910 TI - Effective compression and reconstruction of human skin hyperspectral reflectance databases. AB - In this paper, we investigate techniques for reducing the dimensionality of skin hyperspectral reflectance databases and maintaining a high degree of fidelity during data reconstruction. We compare results obtained using principal components analysis (PCA) with results provided by a piecewise PCA approach that explores the different roles performed by the main light attenuation agents acting within the cutaneous tissues in the ultraviolet (UV), visible and near infrared (NIR) domains. Our investigation encapsulates not only skin spectral responses obtained by varying the contents of these agents, but also responses resulting from the absence of melanin pigmentation associated with the vitiligo condition. PMID- 26737911 TI - Frame-based compressive sensing MR image reconstruction with balanced regularization. AB - This paper addresses the frame-based MR image reconstruction from undersampled k space measurements by using a balanced l(1)-regularized approach. Analysis-based and synthesis-based approaches are two common methods in l(1)-regularized image restoration. They are equivalent under the orthogonal transform, but there exists a gap between them under redundant transform such as frame. Thus the third approach was developed to reduce the gap by penalizing the distance between the representation vector and the canonical frame coefficient of the estimated image, this balanced approach bridges the synthesis-based and analysis-based approaches and balances the fidelity, sparsity and smoothness of the solution. These frame based approaches have been studied and compared for optical image restoration over the last few years. In this paper, we further study and compare these three approaches for the compressed sensing MR image reconstruction under redundant frame domain. These l(1)-regularized optimization problems are solved by using a variable splitting strategy and the classical alternating direction method of multiplier (ADMM). Numerical simulation results show that the balanced approach can reduce the gap between the analysis-based and synthesis-based approaches and are even better than these two approaches under our experimental conditions. PMID- 26737912 TI - Analysis of the electrical patterns and structural remodeling in atrial fibrillation. AB - Catheter ablation of atrial fibrillation (AF) is a promising therapy, whose success is limited by uncertainty in the knowledge of the mechanisms sustaining the arrhythmia. Many theories based on atrial electrical activation or on atrial structural remodeling have been proposed to target AF mechanisms. We hypothesized two prospective approaches could be linked and both computational analysis of atrial electrical patterns and fibrotic tissue location and extent could give further insights on the role of rotors and spatial relationship between them and atrial fibrosis. This paper presents some preliminary results aimed at the integration of information derived from electrical patterns and structural remodeling in AF patients. Electrical patterns were analyzed by applying the standard procedure based on the Hilbert transform (HT) and with sinusoidal wavelet recomposition (SR). In addition, a new technique based on the detection of maximum negative derivative of the unipolar electrograms and a modified version of signal recomposition (NDSR) was tested.A patient-specific anatomical model was derived by segmenting magnetic resonance angiographic (MRA) data applying an edge based level set approach guided by a phase-based edge detector. A multimodality affine registration was applied to register MRA and delayed enhanced MR imaging (DE-MRI). Following this registration step, gray intensity levels from DE-MRI were used asa texture of the 3D model to visualize fibrosis location and quantify its extent.In view of a future integration of electrical activation patterns onthe patient-specific anatomical model, detected atrial activation timings (AAT) and derived parameters were validated with manual annotation performed by an expert cardiologist and the atrial model was compared with the anatomical map used to guide the ablation procedure. PMID- 26737913 TI - Backprojection regularization with weighted ramp filter for tomographic reconstruction. AB - Although filtered backprojection (FBP) is popular, backprojection then filtering (BPF) still receives a few attentions. Usually, BPF is inferior to FBP in terms of reconstruction quality. There are two main causes. First, BPF has to use a 2 dimensional discrete ramp filter formed by sampling the continuous ramp filter, resulting in DC shift and aliasing artefacts. Second, the common ramp filter amplifies high frequency noise much. To address such two issues, a weighted ramp filter is investigated to reduce the amplification of high frequency noise, and then a total-variation based backprojection regularization (BPR) method is developed to mitigate the DC shift and improve the robustness to noise. The experimental results show that BPR outperforms FBP for low-dose CT imaging reconstruction. PMID- 26737914 TI - Algorithm for simulation of craniotomies assisted by peripheral for 3D virtual navigation. AB - Neurosurgical procedures require high precision and an accurate localization of the structures. For that reason and due to the advances in 3D visualization, the software for planning and training neurosurgeries has become an important tool for neurosurgeons and students, but the manipulation of the 3D structures is not always easy for the staff that usually works with 2D images. This paper describes a system developed in open source software that allows performing a virtual craniotomy (a common procedure in neurosurgery that enables the access to intracranial lesions) in 3D slicer; the system includes a peripheral input in order to permit the manipulation of the 3D structures according to camera movements and to guide the movement of the craniotomy tool. PMID- 26737915 TI - A partial reconstruction scheme for continuous wave diffuse optical tomography with reflection geometry. AB - Image quality and photon measurement with good SNR (signal to noise ratio) in continuous wave diffuse optical tomography depend on the source detector density and sensitivity of photo detector. For large volume objects, it is difficult to obtain detectable light intensity with good SNR over the whole boundary. As an alternative, instead of the full boundary, the measurements are taken over a semi circle as in reflection geometry and a partial reconstruction scheme for the same is proposed in this paper. The cross-sectional optical parameters are reconstructed for different half of the sample with modified boundary conditions and finally the average of all the reconstructions are considered as the final reconstructed image. Simulation and experimental results have been illustrated to validate the proposed method. The main advantage of this scheme is to improve signal to noise ratio which controls the quality of reconstruction in actual phantoms. The use of continuous wave measurement makes the system cost effective as well. PMID- 26737916 TI - Dual-dictionary learning based MR image reconstruction with self-adaptive dictionaries. AB - Dual-dictionary learning method utilizes two dictionaries at two different resolution levels, a high resolution dictionary trained with full-data training set, and a low resolution dictionary co-trained with corresponding undersampled dataset. This method effectively incorporates a priori knowledge of typical structures, specific features and local details, leading to its success in magnetic resonance (MR) image reconstruction from highly undersampled k-space data. In this paper, we improve this dual-dictionary learning method by using self-adaptive dictionaries. The two level dictionaries are updated correspondingly in the inner iteration after updating the reconstruction result to maintain their matching accuracy. Experimental results show that the proposed method can improve the reconstruction quality efficiently and enhance the robustness significantly. PMID- 26737917 TI - Multiple-instance learning for breast cancer detection in mammograms. AB - This paper describes an experimental computer-aided detection and diagnosis system for breast cancer, the most common form of cancer among women, using mammography. The system relies on the Multiple-Instance Learning (MIL) paradigm, which has proven useful for medical decision support in previous works from our team. In the proposed framework, the breasts are first partitioned adaptively into regions. Then, either textural features, or features derived from the detection of masses and microcalcifications, are extracted from each region. Finally, feature vectors extracted from each region are combined using an MIL algorithm (Citation k-NN or mi-Graph), in order to recognize "normal" mammography examinations or to categorize examinations as "normal", "benign" or "cancer". An accuracy of 91.1% (respectively 62.1%) was achieved for normality recognition (respectively three-class categorization) in a subset of 720 mammograms from the DDSM dataset. The paper also discusses future improvements, that will make the most of the MIL paradigm, in order to improve "benign" versus "cancer" discrimination in particular. PMID- 26737918 TI - Examining the feasibility of a Microsoft Kinect TM based game intervention for individuals with anterior cruciate ligament injury risk. AB - We describe a feasibility study in which the Microsoft Kinect is used for a game based exercise to strengthen posterior chain muscles which are often weak in those at high risk of anterior cruciate ligament (ACL) injury. In the game, subjects perform a single posterior chain strengthening exercise. The game uses a side-scrolling video display driven by a hip abduction exercise while a player lies down on the floor. Leg lifts beyond a predetermined angle trigger the jumping action of an animated tiger. We describe the scene and game control, which uses depth images from the Kinect. Although Kinect-based skeletal data are used for many games, the skeletal model does not yield good estimates for positions on the floor. Our proposed system uses multiple leg angle estimators for different angle regions to recognize the player lying down and capture the angle between two legs. We conducted an experiment that validates our system with marker-based Vicon ground truth data. We also present results of an end-to-end test using the game, showing feasibility. PMID- 26737919 TI - Breast tumor detection using UWB circular-SAR tomographic microwave imaging. AB - This paper describes the possibility of detecting tumors in human breast using ultra-wideband (UWB) circular synthetic aperture radar (CSAR). CSAR is a subset of SAR which is a radar imaging technique using a circular data acquisition pattern. Tomographic image reconstruction is done using a time domain global back projection technique adapted to CSAR. Experiments are conducted on a breast phantoms made of pork fat emulating normal and cancerous conditions. Preliminary experimental results show that microwave imaging of a breast phantom using UWB CSAR is a simple and low-cost method, efficiently capable of detecting the presence of tumors. PMID- 26737920 TI - High resolution depth-resolved imaging from multi-focal images for medical ultrasound. AB - An ultrasound imaging technique providing sub-diffraction limit axial resolution for point sources is proposed. It is based on simultaneously acquired multi-focal images of the same object, and on the image metric of sharpness. The sharpness is extracted by image data and presents higher values for in-focus images. The technique is derived from biological microscopy and is validated here with simulated ultrasound data. A linear array probe is used to scan a point scatterer phantom that moves in depth with a controlled step. From the beamformed responses of each scatterer position the image sharpness is assessed. Values from all positions plotted together form a curve that peaks at the receive focus, which is set during the beamforming. Selection of three different receive foci for each acquired dataset will result in the generation of three overlapping sharpness curves. A set of three calibration curves combined with the use of a maximum likelihood algorithm is then able to estimate, with high precision, the depth location of any emitter fron each single image. Estimated values are compared with the ground truth demonstrating that an accuracy of 28.6 MUm (0.13lambda) is achieved for a 4 mm depth range. PMID- 26737921 TI - Biomagnetic measurement system for supine subjects with expanded sensor array and real-time noise reduction. AB - A biomagnetic measurement system was developed, suitable for the detection of magnetospinogram (MSG) and magnetocardiogram (MCG) signals from the dorsal surface of supine subjects. It is effective for noninvasively observing the electric activity of the spinal cord and/or heart. These biomagnetic signals are extremely weak, and magnetic flux sensors based on superconducting quantum interference devices (SQUIDs) are necessary to detect them. However, highly sensitive magnetic field measurement often suffers from ultra low-band circumstance noise mainly caused by transportation in urban areas. We applied reference sensors for monitoring the circumstance noise, and their outputs multiplied by appropriate weight coefficients were directly input to the feedback coil of a SQUID gradiometer. Synthesized in-phase components reduced the ultra low-band noise by approximately 90%. Both the MSG and MCG signals were successfully detected in a moderately magnetically shielded room. Even though the MCG signal band overlapped the ultra low-band noise, the signal-to-noise ratio was improved. PMID- 26737922 TI - Toward development of mobile application for hand arthritis screening. AB - Arthritis is one of the most common health problems affecting people throughout the world. The goal of the work presented in this paper is to provide individuals, who may be developing or have developed arthritis, with a mobile application to assess and monitor the progress of their disease using their smartphone. The image processing algorithm includes finger border detection algorithm to monitor joint thickness and angular deviation abnormalities, which are common symptoms of arthritis. In this work, we have analyzed and compared gradient, thresholding and Canny algorithms for border detection. The effect of image spatial resolution (down-sampling) is also investigated. The results calculated based on 36 joint measurements show that the mean errors for gradient, thresholding, and Canny methods are 0.20, 2.13, and 2.03 mm, respectively. In addition, the average error for different image resolutions is analyzed and the minimum required resolution is determined for each method. The results confirm that recent smartphone imaging capabilities can provide enough accuracy for hand border detection and finger joint analysis based on gradient method. PMID- 26737923 TI - Impedance analysis of different cell monolayers grown on gold-film electrodes. AB - Impedance analysis of mammalian cells grown on planar film electrodes provides a label-free, non-invasive and unbiased observation of cell-based assays addressing the biological response to drugs, toxins or stressors in general. Whereas the time course of the measured impedance at one particular frequency has been used a lot for quantitative monitoring, in-depth analysis of the frequency-dependent impedance spectra is rarely performed. This study summarizes and validates the existing model for spectral analysis by applying it to eight different cell types from different mammalian tissues. Model parameters correctly predict the functional and/or structural properties of the individual cells under study. PMID- 26737924 TI - Sensor-based microphysiometry. AB - The capability of continuously monitoring cells and tissues in real-time for hours or days supports the value of a sensor-based microphysiometric approach. While there are widespread applications now for in-vitro settings, the use for smart, implanted devices is just beginning. The spectrum of analysed functional parameters comprises cellular morphological dynamics, metabolic activity and patterns of electric activity. An outline of a study on human tumor tissue samples gives an example of the potential benefits and challenges of in-vitro microphysiometry. PMID- 26737925 TI - In-vivo cell and tissue monitoring with active implants. AB - Active implant systems are becoming increasingly important in modern medicine. We describe the development of an implantable system for the monitoring of dissolved oxygen. Tissue oxygen saturation plays a leading role in many pathophysiological processes in the human body such as the growth of malignant tumors or the viability of transplanted organs. The implant allows monitoring the tissue oxygenation in vivo with a wireless interface to an external device. An improved self-calibration technique is described to minimize sensor drift with electrochemical sensors in vivo for a better long term stability of the implant system. The sensor was coated with a hydrogel membrane to avoid convection artifacts during calibration procedure. PMID- 26737926 TI - Online, label-free monitoring of organ-on-a-chip models: The case for microphysiometry. AB - Primarily composed of cells on a porous membrane embedded in microfluidic channels, organ-on-a-Chip (OOC) models are coming into the spotlight as an innovative, new approach to in vitro modeling. However, more work is required to understand the impact OOCs have on cellular function including basal metabolism, barrier resistance and oxygen consumption. Electrochemical sensor-based cellular microphysiometry provides a noninvasive, real-time methodology for monitoring these attribute and can be applied to develop robust, automated assays for organ toxicology, but only few to date have been used with OOCs. In this presentation, we define organ-on-a-chip systems, outline which have been studied with integrated sensors, and present a novel method to study cells cultured directly on a porous membrane. PMID- 26737927 TI - Dynamic monitoring of cellular metabolic activity in combination with live cell imaging. AB - We present an automated analysis of the cellular dynamic metabolic activity in combination with live cell imaging, an essential factor for understanding the fundamental cellular physiological responses. For that purpose, we utilized the Intelligent Microplate Reader, a new analysis platform for marker-free cell-based assays in real-time. To demonstrate the benefit of the platform, we analyzed the relationship between various dynamic cell parameters (extracellular acidification, oxygen uptake, cell morphology, cell density and cell migration) of L929, a mouse fibroblast cell line, under the influence of sodium dodecyl sulfate. The dynamic kinetics of the monitored parameters are consistent and revealing much information about the activity occurring in the cells. PMID- 26737928 TI - Application of algae-biosensor for environmental monitoring. AB - Environmental problems including water and air pollution, over fertilization, insufficient wastewater treatment and even ecological disaster are receiving greater attention in the technical and scientific area. In this paper, a method for water quality monitoring using living green algae (Chlorella Kessleri) with the help of the intelligent mobile lab (IMOLA) is presented. This measurement used two IMOLA systems for measurement and reference simultaneously to verify changes due to pollution inside the measurement system. The IMOLA includes light emitting diodes to stimulate photosynthesis of the living algae immobilized on a biochip containing a dissolved oxygen microsensor. A fluid system is used to transport algae culture medium in a stop and go mode; 600s ON, 300s OFF, while the oxygen concentration of the water probe is measured. When the pump stops, the increase in dissolved oxygen concentration due to photosynthesis is detected. In case of a pollutant being transported toward the algae, this can be detected by monitoring the photosynthetic activity. Monitoring pollution is shown by adding emulsion of 0,5mL of Indonesian crude palm oil and 10mL algae medium to the water probe in the biosensor. PMID- 26737929 TI - Impulse radio ultra wideband wireless transmission of dopamine concentration levels recorded by fast-scan cyclic voltammetry. AB - This paper demonstrates the feasibility of utilizing impulse radio ultra wideband (IR-UWB) signaling technique for reliable, wireless transmission of dopamine concentration levels recorded by fast-scan cyclic voltammetry (FSCV) at a carbon fiber microelectrode (CFM) to address the problem of elevated data rates in high channel-count neurochemical monitoring. Utilizing an FSCV-sensing chip fabricated in AMS 0.35MUm 2P/4M CMOS, a 3-5-GHz, IR-UWB transceiver (TRX) chip fabricated in TSMC 90nm 1P/9M RF CMOS, and two off-chip, miniature, UWB antennae, wireless transfer of pseudo-random binary sequence (PRBS) data at 50Mbps over a distance of <;1m is first shown with bit-error rates (BER) <; 10(-3). Further, IR-UWB wireless transmission of dopamine concentration levels prerecorded with FSCV at a CFM during flow injection analysis (FIA) is also demonstrated with transmitter (TX) power dissipation of only ~4.4MUW from 1.2V, representing two orders of magnitude reduction in TX power consumption compared to that of a conventional frequency-shift-keyed (FSK) link operating at ~433MHz. PMID- 26737930 TI - Dual-path NMR receiver using double transceiver microcoils. AB - We present a fully integrated CMOS dual path front-end receiver for NMR applications. Instead of conventional NMR systems which are using one transceiver coil, we propose a dual-path receiver in which it has two transceiver microcoils. This structure cancels the background signal and consequently improving the sensitivity. Spectral simulations of the dual-path receiver are used to verify cancellation of the background signal in this structure. The front-end receiver contains two differential low-noise amplifiers (LNA), two voltage buffers (for conventional mode), two phase shifters, two variable gain amplifiers (VGA), one differential LNA and voltage buffer at the end. This chain of dual-path receiver is designed for 21 MHz NMR settings. The front-end receiver achieves an input referred noise of 2.7 nV/?Hz and voltage gain of 80 dB. The chip is designed in a 0.13-MUm CMOS technology and occupies an area of 1 mm * 2 mm. PMID- 26737931 TI - An ultra low power feature extraction and classification system for wearable seizure detection. AB - In this paper we explore the use of a variety of machine learning algorithms for designing a reliable and low-power, multi-channel EEG feature extractor and classifier for predicting seizures from electroencephalographic data (scalp EEG). Different machine learning classifiers including k-nearest neighbor, support vector machines, naive Bayes, logistic regression, and neural networks are explored with the goal of maximizing detection accuracy while minimizing power, area, and latency. The input to each machine learning classifier is a 198 feature vector containing 9 features for each of the 22 EEG channels obtained over 1 second windows. All classifiers were able to obtain F1 scores over 80% and onset sensitivity of 100% when tested on 10 patients. Among five different classifiers that were explored, logistic regression (LR) proved to have minimum hardware complexity while providing average F-1 score of 91%. Both ASIC and FPGA implementations of logistic regression are presented and show the smallest area, power consumption, and the lowest latency when compared to the previous work. PMID- 26737932 TI - Ultra low-power transceiver with novel FSK modulation technique and efficient FSK to-ASK demodulation. AB - Energy-efficient and high-data rate are desired in biomedical devices transceivers. A high-performance transmitter (Tx) and an ultra-low-power receiver (Rx) dedicated to medical implants communications operating at Industrial, Scientific and Medical (ISM) frequency band are presented. Tx benefits from a new efficient Frequency-Shift Keying (FSK) modulation technique which provides up to 20 Mb/s of data-rate and consumes only 0.084 nJ/b validated through fabrication. The receiver consists of an FSK-to-ASK conversion based receiver with OOK fully passive wake-up device (WuRx). This WuRx is battery less with energy harvesting technique which plays an important role in making the RF transceiver energy efficient. The Rx is achieved with a reduced hardware architecture which does not use an accurate local oscillator, high-Q external inductor and I/Q signal path. The Rx shows -78 dBm sensitivity for 8 Mbps data rate while consuming 639 MUW. The proposed circuits are implemented in IBM 0.13 MUm CMOS technology with 1.2 V supply voltage. PMID- 26737933 TI - Integrated electronic system for implantable sensory NFC tag. AB - We have designed the complete electronic system for an implanted sensory NFC-A tag (type 1) that monitors a physiological parameter, e.g. blood glucose, dehydration, bladder pressure, to name some of the target applications that we pursue. The tag is meant to be implanted under the skin and is powered by an NFC reader held close to it, such as a smart phone or a smart watch. The electronic system consists of a sensor front-end, ADC, NFC-A transceiver and NFC power harvester. In its present status, the physical layer of the communication and the power harvester have been implemented on one ASIC, and the sensor front-end and ADC on another, while the digital circuits realizing the higher level NFC protocol have been implemented on an FPGA. Simulations and a few preliminary test results are presented in this paper. The ultimate goal after thorough testing of this first prototype is to integrate all of these modules on a single ASIC. PMID- 26737934 TI - Multichannel spike detector with an adaptive threshold based on a Sigma-delta control loop. AB - In this paper, we present a digital spike detector using an adaptive threshold which is suitable for real time processing of 32 electrophysiological channels in parallel. Such a new scheme is based on a Sigma-delta control loop that precisely estimates the standard deviation of the amplitude of the noise of the input signal to optimize the detection rate. Additionally, it is not dependent on the amplitude of the input signal thanks to a robust algorithm. The spike detector is implemented inside a Spartan-6 FPGA using low resources, only FPGA basic logic blocks, and is using a low clock frequency under 6 MHz for minimal power consumption. We present a comparison showing that the proposed system can compete with a dedicated off-line spike detection software. The whole system achieves up to 100% of true positive detection rate for SNRs down to 5 dB while achieving 62.3% of true positive detection rate for an SNR as low as -2 dB at a 150 AP/s firing rate. PMID- 26737935 TI - Microfabricated multi-electrode device for detecting oligodendrocyte-regulated changes in axonal conduction velocity. AB - Myelin disorders cause cognitive dysfunction, but little is known about how abnormal myelin sheath affects neural activities at the network level. One reason for the lack is a technical difficulty in simultaneous monitoring of changes in both the axonal conduction and network activity. Then, we aimed to develop a culture device to detect myelination dependent changes in axonal conduction velocity in a neuronal network. The photolithographically fabricated device has microtunnels for guiding axons. Two microelectrodes and an oligodendrocyte (OL) culture compartment are set at each microtunnel. This configuration allows us to monitor changes in conduction velocity of axons wrapped by OLs. Neurons and OLs dissected from rat cortical tissues were cultured in the culture device. An immunocytochemical study indicated axonal growth and maturation of OL at 42 days in vitro (DIV), suggesting that neuron-OL co-culture was maintained in microtunnels. Propagating action potentials of individual axons were detected from spontaneous neural activities with a spike sorting method and their conduction velocities were examined. Conduction velocity without seeding OLs was 0.31 m/s, which was consistent with that of previous reports with unmyelinated axons. Although no apparent myelin sheath was observed in OL culture compartments, conduction delay with seeding OLs was approximately half as long as that without seeding OLs at 45 DIV. These results suggest that the culture device enables us to detect the OL-regulated changes in axonal conduction in the neuronal network. PMID- 26737936 TI - Comparison of foam-based and spring-loaded dry EEG electrodes with wet electrodes in resting and moving conditions. AB - The introduction of dry electrodes for EEG measurements has opened up possibilities of recording EEG outside of standard clinical environments by reducing required preparation and maintenance. However, the signal quality of dry electrodes in comparison with wet electrodes has not yet been evaluated under activities of daily life (ADL) or high motion tasks. In this study, we compared the performances of foam-based and spring-loaded dry electrodes with wet electrodes under three different task conditions: resting state, walking, and cycling. Our analysis showed that signals obtained by the 2 types of dry electrodes and obtained by wet electrodes displayed high correlation for all conditions, while being prone to similar environmental and electrode-based artifacts. Overall, our results suggest that dry electrodes have a similar signal quality in comparison to wet electrodes during motion and may be more practical for use in mobile and real-time motion applications due to their convenience. In addition, we conclude that as with wet electrodes, post-processing can mitigate motion artifacts in ambulatory EEG acquisition. PMID- 26737937 TI - A new generation of double-sided intramuscular electrodes for multi-channel recording and stimulation. AB - In this work, a new generation of intramuscular multi-channel electrode for EMG recording and muscle stimulation is presented. The electrode is based on double sided polyimide microtechnology, and features electrode contacts on both sides of a thin polyimide filament. The structure is attached to a cannula, allowing insertion and application of the electrode system similar to conventional intramuscular wire electrodes. In the presented design, the electrode has 12 small recording sites on one side of the structure, and 3 large stimulation sites on the other side. Applications of the system include diagnosis and treatment of tremor. To this end, the electrode has been successfully tested in tremor patients. In the future, the concept will be extended to other fields of application including intraneural electrodes. PMID- 26737938 TI - Design of a flexible parylene-based multi-electrode array for multi-region recording from the rat hippocampus. AB - The hippocampus is a critical deep brain structure in several aspects. It is directly related to the formation of new long-term declarative memory. The malfunction of the hippocampus closely relates to various disease and pathological conditions. It is also a model structure for the study of cortical function and synaptic plasticity in general because of its special neuro anatomical structure and intrinsic connections within the hippocampus formation. Both the understanding of roles that the hippocampus plays in recognition memory and the study of neural plasticity require simultaneously recording of neural activities from multiple sub-regions of the hippocampus from behavioral animals. However the distribution of cells in the hippocampus make the recording from multiple sub-regions a big challenge with the traditional uni-length micro-wire arrays. Well-designed electrode arrays are required to reach multiple regions simultaneously because of the distinctive double C shape of the hippocampus cell body layers. In this work, we designed a multi-shanks electrode which uses Parylene C, a highly biocompatible and flexible polymer, as a base and has multiple recording sites specially positioned along the longitudinal axis to fit the curvy shape of the rat hippocampus. PMID- 26737939 TI - Fused silica microlenses for hermetic packages as part of implantable optrodes. AB - The request for stable and reliable devices is tremendous in the field of optogenetics. So far, no device which is called optrode, encapsulating the needed light source hermetically, can be found. We therefore introduce a novel optrode concept consisting of polyimide, silicone as well as a silicon- and fused silica based hermetic package. One of the main features of the hermetic package is the integration of custom-made microlenses. These microlenses are fabricated using thermal reflow of photoresist. Chosen parameters for remelting the photoresist AZ9260 are 2 min @ 160 degrees C. An additional dry etching step is introduced to transfer the resist pattern into a fused silica substrate. We were able to fabricate lenses in diameters ranging from 25 MUm to 1300 MUm. The focal lengths of the etched lenses vary from 630 MUm to 5500 MUm for lens diameter ranging from 200 MUm to 900 MUm. Deviations of the transferred pattern to an ideal sphere range from 0.055 % and -0.151 % to 0.040 % and -0.003 % (300 MUm and 700 MUm lens diameter) and can be neglected. PMID- 26737940 TI - Topographical strategies to control neural outgrowth. AB - In this work a synergistic approach is used to investigate how directional anisotropic surfaces (i.e., nanogratings) control the alignment of PC12 neurites. Finite Element models were used to assess the distribution of stresses in non spread growth cones and filopodia. The stress field was assumed to be the main triggering cause fostering the increase and stabilization of filopodia, so the local stress maxima were directly related to the neuritic orientation. Moreover, a computational framework was implemented within an open source Java environment (CX3D), and in silico simulations were carried out to reproduce and predict biological experiments. No significant differences were found between biological experiments and in silico simulations (alignment angle, p = 0.4685; tortuosity, p = 0.9075) with a standard level of confidence (95%). PMID- 26737941 TI - The Ninapro database: A resource for sEMG naturally controlled robotic hand prosthetics. AB - The dexterous natural control of robotic prosthetic hands with non-invasive techniques is still a challenge: surface electromyography gives some control capabilities but these are limited, often not natural and require long training times; the application of pattern recognition techniques recently started to be applied in practice. While results in the scientific literature are promising they have to be improved to reach the real needs. The Ninapro database aims to improve the field of naturally controlled robotic hand prosthetics by permitting to worldwide research groups to develop and test movement recognition and force control algorithms on a benchmark database. Currently, the Ninapro database includes data from 67 intact subjects and 11 amputated subject performing approximately 50 different movements. The data are aimed at permitting the study of the relationships between surface electromyography, kinematics and dynamics. The Ninapro acquisition protocol was created in order to be easy to be reproduced. Currently, the number of datasets included in the database is increasing thanks to the collaboration of several research groups. PMID- 26737942 TI - Towards low-dimensionsal proportional myoelectric control. AB - One way of enhancing the dexterity of powered myoelectric prostheses is via proportional and simultaneous control of multiple degrees-of-freedom (DOFs). Recently, it has been demonstrated that the reconstruction of finger movement is feasible by using features of the surface electromyogram (sEMG) signal. In such paradigms, the number of predictors and target variables is usually large, and strong correlations are present in both the input and output domains. Synergistic patterns in the sEMG space have been previously exploited to facilitate kinematics decoding. In this work, we propose a framework for simultaneous input output dimensionality reduction based on the generalized eigenvalue problem formulation of multiple linear regression (MLR). We demonstrate that the proposed methodology outperforms simultaneous input-output dimensionality reduction based on principal component analysis (PCA), while the prediction accuracy of the full rank regression (FRR) method can be achieved by using only a few relevant dimensions. PMID- 26737943 TI - A multi-channel biomimetic neuroprosthesis to support treadmill gait training in stroke patients. AB - This study presents an innovative multi-channel neuroprosthesis that induces a biomimetic activation of the main lower-limb muscles during treadmill gait training to be used in the rehabilitation of stroke patients. The electrostimulation strategy replicates the physiological muscle synergies used by healthy subjects to walk on a treadmill at their self-selected speed. This strategy is mapped to the current gait sub-phases, which are identified in real time by a custom algorithm. This algorithm divides the gait cycle into six sub phases, based on two inertial sensors placed laterally on the shanks. Therefore, the pre-defined stimulation profiles are expanded or stretched based on the actual gait pattern of each single subject. A preliminary experimental protocol, involving 10 healthy volunteers, was carried out to extract the muscle synergies and validate the gait-detection algorithm, which were afterwards used in the development of the neuroprosthesis. The feasibility of the neuroprosthesis was tested on one healthy subject who simulated different gait patterns, and a chronic stroke patient. The results showed the correct functioning of the system. A pilot study of the neurorehabilitation treatment for stroke patients is currently being carried out. PMID- 26737944 TI - Moving toward automatic and standalone delineation of seismocardiogram signal. AB - The purpose of this research is to propose an algorithm that could accomplish automatic delineation of the seismocardiogram (SCG) signal without using a reference electrocardiogram R-wave. As a result, the SCG signal could be used, as a stand-alone solution for many cardiovascular medical applications such as hemorrhage detection, cardiac computed tomographic gating, cardiac resynchronization therapy, hemodynamics estimations and diastolic timed vibration. Multiple envelopes were derived from the seismocardiogram signal by using filtering and triple integration. The first envelope is referred as the heart rate envelope, which has the characteristics of having a period of exactly one cardiac cycle and its purpose is to replace the ECG R-wave as a reference point. Our dataset is based on the lower body negative pressure (LBNP) test that was conducted on 18 individuals, containing 21610 cardiac cycles. For 94% of the LBNP dataset, the aforementioned envelope estimated heart rate within 3 beats per minute. Three different peaks of the SCG signal are of our interest: isovolumic contraction (IM), aortic valve opening (AO) and aortic valve closure (AC). For each of these desired peaks of the SCG signal, a different envelope was designed in a manner that its peak is very close to IM, AO and AC, respectively. For the same lower body negative pressure data set, a mean difference of (9, 9, 6) and standard deviation of (8, 9, 9) millisecond between the peak of envelopes and IM, AO and AC is accomplished. This could be used as a good initial estimation of the annotation points. PMID- 26737945 TI - Ballistocardiogram of baby during sleep. AB - Ballistocardiogram (BCG), which displays the mechanical activity of heart, has been a subject of interest for several years due to its advantages in taking unobtrusive physiological measurements. In the field of sleep science, researchers actively study sleep architecture and clinically apply various sleep related conditions through BCG-derived biological information such as the heartbeat, respiration and body movements of subjects. However, most of these studies have involved only adults. This area of research may be even more important with babies to monitor their biological signals without confinement. For this reason, we developed a physiological signal monitoring bed for baby by using a load cell. Heartbeat and respiration information was assessed with average respective performance errors of 1.53% and 2.53% compared to commercial equipment. The results showed the possibility of applying BCG technology to baby. Therefore, we expect that BCG-derived signals can be extensively applied to analyze sleep architecture and clinical applications in baby as they are with adults. PMID- 26737946 TI - MRI-based aortic blood flow model in 3D ballistocardiography. AB - Ballistocardiography (BCG) is a non-invasive technique which measures the acceleration of a body induced by cardiovascular activity, namely the force exerted by the beating heart. A one dimensional aortic flow model based on the transmission lines theory is developped and applied to the simulation of three dimensional BCG. A four-element Windkessel model is used to generate the pressure wave. Using transverse MRI slices of a human subject, a reconstruction of the aorta allows the extraction of parameters used to relate the local change in mass of the 1D flow model to 3D acceleration BCG. Simulated BCG curves are then compared qualitatively with the ensemble average curves of the same subject recorded in sustained microgravity. Confirming previous studies, the main features of the y-axis are well simulated. The simulated z-axis, never attempted before, shows important similarities. The simulated x-axis is less faithful and suggests the presence of reflections. PMID- 26737947 TI - Robust heartbeat detection from in-home ballistocardiogram signals of older adults using a bed sensor. AB - We propose a simple and robust method to detect heartbeats using the ballistocardiogram (BCG) signal that is produced by a hydraulic bed sensor placed under the mattress. The proposed method is found beneficial especially when the BCG signal does not display consistent J-peaks, which can often be the case for overnight, in-home monitoring, especially with frail seniors. Heartbeat detection is based on the short-time energy of the BCG signal. Compared with previous methods that rely on the J-peaks observed from the BCG amplitude, we are able to achieve considerable improvement even when significant distortions are present. Test results are included for different BCG waveform patterns from older adults. PMID- 26737948 TI - Biophone: Physiology monitoring from peripheral smartphone motions. AB - The large-scale adoption of smartphones during recent years has created many opportunities to improve health monitoring and care delivery. In this work, we demonstrate that motion sensors available in off-the-shelf smartphones can capture physiological parameters of a person during stationary postures, even while being carried in a bag or a pocket. In particular, we develop methods to extract heart and breathing rates from accelerometer data and compare them with measurements obtained with FDA-cleared sensors. We evaluated their accuracy on 12 people across different still body postures (pre- and post- exercise) and were able to reach mean absolute errors of 1.16 beats per minute (STD: 3) and 0.26 breaths per minute (STD: 0.5) when considering different conditions. Furthermore, we evaluated the same methods during regular phone activities, such as when watching a video or listening to a conversation, yielding increased but still comparable error rates for some conditions. PMID- 26737949 TI - Use of seismocardiogram for the beat-to-beat assessment of the Pulse Transit Time: A pilot study. AB - We propose a new methodology for the estimation of Pulse Transit Time, PTT, based on the use of the seismocardiogram for the identification of the aortic valve opening, AO. This method has been implemented to obtain a first description of the AO-derived PTT beat-to-beat variability at rest and during the recovery after a cycloergometer exercise at 25W and 100W, its relation with systolic blood pressure, S(BP), and its difference with respect to variability of the Pulse Arrival Time, PAT (i.e. the BP transit time estimated by considering the ECG R peak instead of AO as proximal site). Our preliminary data indicate that 1) the fast components of the PTT variability are only marginally influenced by respiration; 2) only the slower components of the PTT variability are correlated with systolic BP; 3) major differences exist in the dynamics of PTT and PAT, being PAT variability significantly larger and importantly influenced by the beat to-beat changes occurring in the Pre Ejection Period. PMID- 26737950 TI - Hardware-in-the-loop simulation and energy optimization of cardiac pacemakers. AB - Implantable cardiac pacemakers are medical devices that can monitor and correct abnormal heart rhythms. To provide the necessary safety assurance for pacemaker software, both testing and verification of the code, as well as testing the entire pacemaker hardware in the loop, is necessary. In this paper, we present a hardware testbed that enables detailed hardware-in-the-loop simulation and energy optimisation of pacemaker algorithms with respect to a heart model. Both the heart and the pacemaker models are encoded in Simulink/StateflowTM and translated into executable code, with the pacemaker executed directly on the microcontroller. We evaluate the usefulness of the testbed by developing a parameter synthesis algorithm which optimises the timing parameters based on power measurements acquired in real-time. The experiments performed on real measurements successfully demonstrate that the testbed is capable of energy minimisation in real-time and obtains safe pacemaker timing parameters. PMID- 26737951 TI - Vestibular implants: Hope for improving the quality of life of patients with bilateral vestibular loss. AB - The vestibular system plays an essential role in crucial tasks such as postural control, gaze stabilization, and spatial orientation. Currently, there is no effective treatment for a bilateral loss of the vestibular function (BVL). The quality of life of affected patients is significantly impaired. During the last decade, our group has explored the potential of using electrical stimulation to artificially restore the vestibular function. Our vestibular implant prototype consists of a custom modified cochlear implant featuring one to three vestibular electrodes implanted in the proximity of the ampullary branches of the vestibular nerve; in addition to the main cochlear array. Special surgical techniques for safe implantation of these devices have been developed. In addition, we have developed stimulation strategies to generate bidirectional eye movements as well as the necessary interfaces to capture the signal from a motion sensor (e.g., gyroscope) and use it to modulate the stimulation signals delivered to the vestibular nerves. To date, 24 vestibular electrodes have been implanted in 11 BVL patients. Using a virtual motion profile to modulate the "baseline" electrical stimulation, vestibular responses could be evoked with 21 electrodes. Eye movements with mean peak eye velocities of 32 degrees /s and predominantly in the plane of the stimulated canal were successfully generated. These are within the range of normal compensatory eye movements during walking and were large enough to have a significant effect on the patients' visual acuity. These results indicate that electrical stimulation of the vestibular nerve has a significant functional impact; eye movements generated this way could be sufficient to restore gaze stabilization during essential everyday tasks such as walking. The innovative concept of the vestibular implant has the potential to restore the vestibular function and have a central role in improving the quality of life of BVL patients in the near future. PMID- 26737952 TI - Intersubject assessment of implantable antenna performance for intracranial pressure monitoring. AB - This work focuses on the assessment of an implantable antenna performance designed for Intracranial Pressure (ICP) monitoring applications. A simplified three-layer canonical model, exclusively designed for antenna tuning inside anatomical human head, is evaluated. Inter-subject variability is studied using four different human head anatomical models which are part of the Virtual Family by Foundation for Research on Information Technologies in Society (IT'IS) and have been extensively used in the literature. Simulations are performed within MedRadio band, which is worldwide available, and has been allocated exclusively for medical applications. The results highlight the suitability of the proposed simplified model for antenna fine-tuning. Moreover, no significant detuning effects are observed among the anatomical models, as the antenna maintain sits resonance, radiation and safety performance. PMID- 26737953 TI - Wrong detection of ventricular fibrillation in an implantable cardioverter defibrillator caused by the movement near the MRI scanner bore. AB - The static magnetic field generated by MRI systems is highly non-homogenous and rapidly decreases when moving away from the bore of the scanner. Consequently, the movement around the MRI scanner is equivalent to an exposure to a time varying magnetic field at very low frequency (few Hz). For patients with an implanted cardiac stimulators, such as an implantable cardioverter/defibrillator (ICD), the movements inside the MRI environment may thus induce voltages on the loop formed by the leads of the device, with the potential to affect the behavior of the stimulator. In particular, the ICD's detection algorithms may be affected by the induced voltage and may cause inappropriate sensing, arrhythmia detections, and eventually inappropriate ICD therapy.We performed in-vitro measurements on a saline-filled humanshaped phantom (male, 170 cm height), equipped with an MRconditional ICD able to transmit in real-time the detected cardiac activity (electrograms). A biventricular implant was reproduced and the ICD was programmed in standard operating conditions, but with the shock delivery disabled. The electrograms recorded in the atrial, left and right ventricle channels were monitored during rotational movements along the vertical axis, in close proximity of the bore. The phantom was also equipped with an accelerometer and a magnetic field probe to measure the angular velocity and the magnetic field variation during the experiment. Pacing inhibition, inappropriate detection of tachyarrhythmias and of ventricular fibrillation were observed. Pacing inhibition began at an angular velocity of about 7 rad/s, (dB/dt of about 2 T/s). Inappropriate detection of ventricular fibrillation occurred at about 8 rad/s (dB/dt of about 3 T/s). These findings highlight the need for a specific risk assessment of workers with MR-conditional ICDs, which takes into account also effects that are generally not considered relevant for patients, such as the movement around the scanner bore. PMID- 26737954 TI - Motion compensation in a tomographic ultrasound imaging system: Toward volumetric scans of a limb for prosthetic socket design. AB - Current methods of prosthetic socket fabrication remain subjective and ineffective at creating an interface to the human body that is both comfortable and functional. Though there has been recent success using methods like magnetic resonance imaging and biomechanical modeling, a low-cost, streamlined, and repeatable process has not been fully demonstrated. Medical ultrasonography, which has significant potential to expand its clinical applications, is being pursued to acquire data that may quantify and improve the design process and fabrication of prosthetic sockets. This paper presents a new multi-modal imaging approach for acquiring volumetric images of a human limb, specifically focusing on how motion of the limb is compensated for using optical imagery. PMID- 26737955 TI - Transthoracic ventricular fibrillation charge thresholds. AB - Standards, including IEC 60479-1 and -2, provide current-based ventricular fibrillation thresholds (VFT) for stimuli durations between 0.1 ms and 10 s. It has been established that the amount of electrical charge, not the current calculated by root-mean-square, is most representative of the effects of cardiac stimulation. There are no unified models that present transthoracic charge VFTs for a wide range of stimuli durations. This work proposes a new unified charge model applicable to transthoracic stimuli durations ranging over 1 MUs - 300 s. VFTs were compiled from our previous animal work and from other published reports, including from the studies that provided the raw data for IEC 60479-1 and -2. Our study goal was to cover a wide range of stimuli durations, for which reliable data exists. Consistent data were found for stimuli durations covering the range of 1 MUs - 300 s where VFTs were expressed as charge. The model predicted a transthoracic charge VFT of 1 mC at 1 MUs duration. The charge VFT increased with stimulus duration and reached 10 C at 300 s. Presenting the first charge-based transthoracic VFT model covering stimuli durations over 1 MUs - 300 s, we found 3 behavioral regions of charge VFT vs. DURATION: For short stimuli durations, 1 MUs - 10 ms, VFTs followed a classic Weiss charge strength-duration curve. For long stimuli, longer than 5 s, charge VFTs can be approximated using a 38 mArms constant current model. From 10 ms to 5 s, charge VFTs tracked through a transition zone that could be approximated as a constant charge model Q~100 mC. PMID- 26737956 TI - Pigment network-based skin cancer detection. AB - Diagnosing skin cancer in its early stages is a challenging task for dermatologists given the fact that the chance for a patient's survival is higher and hence the process of analyzing skin images and making decisions should be time efficient. Therefore, diagnosing the disease using automated and computerized systems has nowadays become essential. This paper proposes an efficient system for skin cancer detection on dermoscopic images. It has been shown that the statistical characteristics of the pigment network, extracted from the dermoscopic image, could be used as efficient discriminating features for cancer detection. The proposed system has been assessed on a dataset of 200 dermoscopic images of the 'Hospital Pedro Hispano' [1] and the results of cross validation have shown high detection accuracy. PMID- 26737957 TI - Texture analysis for colorectal tumour biopsies using multispectral imagery. AB - Colorectal cancer is one of the most common cancers in the world. As part of its diagnosis, a histological analysis is often run on biopsy samples. Multispecral imagery taken from cancer tissues can be useful to capture more meaningful features. However, the resulting data is usually very large having a large number of varying feature types. This papers aims to investigate and compare the performances of multispectral imagery taken from colorectal biopsies using different techniques for texture feature extraction inclduing local binary patterns, Haraclick features and local intensity order patterns. Various classifiers such as Support Vector Machine and Random Forest are also investigated. The results show the superiority of multispectral imaging over the classical panchromatic approach. In the multispectral imagery's analysis, the local binary patterns combined with Support Vector Machine classifier gives very good results achieving an accuracy of 91.3%. PMID- 26737958 TI - Ensemble learning approaches to predicting complications of blood transfusion. AB - Of the 21 million blood components transfused in the United States during 2011, approximately 1 in 414 resulted in complication [1]. Two complications in particular, transfusion-related acute lung injury (TRALI) and transfusion associated circulatory overload (TACO), are especially concerning. These two alone accounted for 62% of reported transfusion-related fatalities in 2013 [2]. We have previously developed a set of machine learning base models for predicting the likelihood of these adverse reactions, with a goal towards better informing the clinician prior to a transfusion decision. Here we describe recent work incorporating ensemble learning approaches to predicting TACO/TRALI. In particular we describe combining base models via majority voting, stacking of model sets with varying diversity, as well as a resampling/boosting combination algorithm called RUSBoost. We find that while the performance of many models is very good, the ensemble models do not yield significantly better performance in terms of AUC. PMID- 26737960 TI - Improving medical diagnosis reliability using Boosted C5.0 decision tree empowered by Particle Swarm Optimization. AB - Improving accuracy of supervised classification algorithms in biomedical applications is one of active area of research. In this study, we improve the performance of Particle Swarm Optimization (PSO) combined with C4.5 decision tree (PSO+C4.5) classifier by applying Boosted C5.0 decision tree as the fitness function. To evaluate the effectiveness of our proposed method, it is implemented on 1 microarray dataset and 5 different medical data sets obtained from UCI machine learning databases. Moreover, the results of PSO + Boosted C5.0 implementation are compared to eight well-known benchmark classification methods (PSO+C4.5, support vector machine under the kernel of Radial Basis Function, Classification And Regression Tree (CART), C4.5 decision tree, C5.0 decision tree, Boosted C5.0 decision tree, Naive Bayes and Weighted K-Nearest neighbor). Repeated five-fold cross-validation method was used to justify the performance of classifiers. Experimental results show that our proposed method not only improve the performance of PSO+C4.5 but also obtains higher classification accuracy compared to the other classification methods. PMID- 26737959 TI - Robust automatic breast cancer staging using a combination of functional genomics and image-omics. AB - Breast cancer is one of the leading cancers worldwide. Precision medicine is a new trend that systematically examines molecular and functional genomic information within each patient's cancer to identify the patterns that may affect treatment decisions and potential outcomes. As a part of precision medicine, computer-aided diagnosis enables joint analysis of functional genomic information and image from pathological images. In this paper we propose an integrated framework for breast cancer staging using image-omics and functional genomic information. The entire biomedical imaging informatics framework consists of image-omics extraction, feature combination, and classification. First, a robust automatic nuclei detection and segmentation is presented to identify tumor regions, delineate nuclei boundaries and calculate a set of image-based morphological features; next, the low dimensional image-omics is obtained through principal component analysis and is concatenated with the functional genomic features identified by a linear model. A support vector machine for differentiating stage I breast cancer from other stages are learned. We experimentally demonstrate that compared with a single type of representation (image-omics), the combination of image-omics and functional genomic feature can improve the classification accuracy by 3%. PMID- 26737961 TI - Towards a predictive model for Guillain-Barre syndrome. AB - The severity of Guillain-Barre Syndrome (GBS) varies among subtypes, which can be mainly Acute Inflammatory Demyelinating Polyneuropathy (AIDP), Acute Motor Axonal Neuropathy (AMAN), Acute Motor Sensory Axonal Neuropathy (AMSAN) and Miller Fisher Syndrome (MF). In this study, we use a real dataset that contains clinical, serological, and nerve conduction tests data obtained from 129 GBS patients. We apply C4.5 decision tree, SVM (Support Vector Machines) using a Gaussian kernel, and kNN (k Nearest Neighbour) to predict four GBS subtypes. Accuracies were calculated and averaged across 30 10-fold cross-validation (10 FCV) runs. C4.5 obtained 0.9211 (+/-0.0109), kNN 0.9179 (+/-0.0041), and SVM 0.9154 (+/-0.0069). This is an ongoing research project and further experiments are being conducted. PMID- 26737962 TI - Low-complexity EEG-based eye movement classification using extended moving difference filter and pulse width demodulation. AB - This paper presents an eye movement classification algorithm for EEG-based brain computer interface. The proposed system first used a low-complexity extended moving difference filter to acquire clean pulse waveform of eye-movement events. Then, a pulse width demodulation algorithm was designed to identify eye-movement events of left/right/up/down directions. The eye blinking events can be easily eliminated by excluding the pulses with small pulse-width, and thus the detection rate can be improved. Besides, the pulse width demodulation requires only addition operations to achieve a near 90% averaged detection. The computation complexity is much lower than those of other works in the literature. PMID- 26737963 TI - Reliability over time of EEG-based mental workload evaluation during Air Traffic Management (ATM) tasks. AB - Machine-learning approaches for mental workload (MW) estimation by using the user brain activity went through a rapid expansion in the last decades. In fact, these techniques allow now to measure the MW with a high time resolution (e.g. few seconds). Despite such advancements, one of the outstanding problems of these techniques regards their ability to maintain a high reliability over time (e.g. high accuracy of classification even across consecutive days) without performing any recalibration procedure. Such characteristic will be highly desirable in real world applications, in which human operators could use such approach without undergo a daily training of the device. In this work, we reported that if a simple classifier is calibrated by using a low number of brain spectral features, between those ones strictly related to the MW (i.e. Frontal and Occipital Theta and Parietal Alpha rhythms), those features will make the classifier performance stable over time. In other words, the discrimination accuracy achieved by the classifier will not degrade significantly across different days (i.e. until one week). The methodology has been tested on twelve Air Traffic Controls (ATCOs) trainees while performing different Air Traffic Management (ATM) scenarios under three different difficulty levels. PMID- 26737964 TI - Single trial EEG classification applied to a face recognition experiment using different feature extraction methods. AB - Research on brain machine interface (BMI) has been developed very fast in recent years. Numerous feature extraction methods have successfully been applied to electroencephalogram (EEG) classification in various experiments. However, little effort has been spent on EEG based BMI systems regarding familiarity of human faces cognition. In this work, we have implemented and compared the classification performances of four common feature extraction methods, namely, common spatial pattern, principal component analysis, wavelet transform and interval features. High resolution EEG signals were collected from fifteen healthy subjects stimulated by equal number of familiar and novel faces. Principal component analysis outperforms other methods with average classification accuracy reaching 94.2% leading to possible real life applications. Our findings thereby may contribute to the BMI systems for face recognition. PMID- 26737965 TI - Investigation of window size in classification of EEG-emotion signal with wavelet entropy and support vector machine. AB - When dealing with patients with psychological or emotional symptoms, medical practitioners are often faced with the problem of objectively recognizing their patients' emotional state. In this paper, we approach this problem using a computer program that automatically extracts emotions from EEG signals. We extend the finding of Koelstra et. al [IEEE trans. affective comput., vol. 3, no. 1, pp. 18-31, 2012] using the same dataset (i.e. the DEAP: dataset for emotion analysis using electroencephalogram, physiological and video signals), where we observed that the accuracy can be further improved using wavelet features extracted from shorter time segments. More precisely, we achieved accuracy of 65% for both valence and arousal using the wavelet entropy of 3 to 12 seconds signal segments. This improvement in accuracy entails an important discovery that information on emotions contained in the EEG signal may be better described in term of wavelets and in shorter time segments. PMID- 26737966 TI - A comparison of ERP spatial filtering methods for optimal mental workload estimation. AB - Mental workload estimation is of crucial interest for user adaptive interfaces and neuroergonomics. Its estimation can be performed using event-related potentials (ERPs) extracted from electroencephalographic recordings (EEG). Several ERP spatial filtering methods have been designed to enhance relevant EEG activity for active brain-computer interfaces. However, to our knowledge, they have not yet been used and compared for mental state monitoring purposes. This paper presents a thorough comparison of three ERP spatial filtering methods: principal component analysis (PCA), canonical correlation analysis (CCA) and the xDAWN algorithm. Those methods are compared in their performance to allow for an accurate classification of mental workload when applied in an otherwise similar processing chain. The data of 20 healthy participants that performed a memory task for 10 minutes each was used for classification. Two levels of mental workload were considered depending on the number of digits participants had to memorize (2/6). The highest performances were obtained using the CCA filtering and the xDAWN algorithm respectively with 98% and 97% of correct classification. Their performances were significantly higher than that obtained using the PCA filtering (88%). PMID- 26737967 TI - Clustering analysis to identify distinct spectral components of encephalogram burst suppression in critically ill patients. AB - Millions of patients are admitted each year to intensive care units (ICUs) in the United States. A significant fraction of ICU survivors develop life-long cognitive impairment, incurring tremendous financial and societal costs. Delirium, a state of impaired awareness, attention and cognition that frequently develops during ICU care, is a major risk factor for post-ICU cognitive impairment. Recent studies suggest that patients experiencing electroencephalogram (EEG) burst suppression have higher rates of mortality and are more likely to develop delirium than patients who do not experience burst suppression. Burst suppression is typically associated with coma and deep levels of anesthesia or hypothermia, and is defined clinically as an alternating pattern of high-amplitude "burst" periods interrupted by sustained low-amplitude "suppression" periods. Here we describe a clustering method to analyze EEG spectra during burst and suppression periods. We used this method to identify a set of distinct spectral patterns in the EEG during burst and suppression periods in critically ill patients. These patterns correlate with level of patient sedation, quantified in terms of sedative infusion rates and clinical sedation scores. This analysis suggests that EEG burst suppression in critically ill patients may not be a single state, but instead may reflect a plurality of states whose specific dynamics relate to a patient's underlying brain function. PMID- 26737968 TI - Enhanced robustness of myoelectric pattern recognition to across-day variation through invariant feature extraction. AB - Robust pattern recognition is critical for myoelectric prosthesis (MP) developed in the laboratory to be used in real life. This study focuses on the robustness of MP control during the usage across many days. Due to the variability inhered in extended electromyography (EMG) signals, the distribution of EMG features extracted from several days' data may have large intra-class scatter. However, as the subjects perform the same motion type in different days, we hypothesize there exist some invariant characteristics in the EMG features. Therefore, give a set of training data from several days, it is possible to find an invariant component in them. To this end, an invariant feature extraction (IFE) framework based on kernel fisher discriminant analysis is proposed. A desired transformation, which minimizes the intra-class (within a motion type) scatter meanwhile maximizes the inter-class (between different motion types) scatter, is found. Five intact limbed subjects and three transradial-amputee subjects participated in an experiment lasting ten days. The results show that the generalization ability of the classifier trained on previous days to the unseen testing days can be improved by IFE. IFE significantly outperforms Baseline (original input feature) in classification accuracy, both for intact-limbed subjects and amputee subjects (average 88.97% vs. 91.20% and 85.09% vs. 88.22%, p <; 0.05). PMID- 26737969 TI - A robust myoelectric pattern recognition using online sequential extreme learning machine for finger movement classification. AB - A robust myoelectric pattern-recognition-system requires a system that should work in the real application as good as in the laboratory. However, this demand should be handled properly and rigorously to achieve a robust myoelectric system. Electrode shift is an issue that usually emerges when dealing with robustness issue. In daily life, the placement of electrodes becomes a significant issue that can downgrade the performance of the system. This paper proposed a new way to overcome the robustness issue by conducting an update to the system to anticipate changes in the future such as electrode shift, improvement in muscle strength or any other issue. Such update will be used to generate an adaptation. The adaptation is done according to the user's need by employing an online sequential extreme learning (OS-ELM) to learn the training data chunk by chunk. OS-ELM enables the myoelectric system to learn from a small number of data to avoid cumbersome training process. The day-to-day experiment shows that the proposed system can maintain its performance on average accuracy around 85% whereas the non-adaptive system could not. PMID- 26737970 TI - Residuals of autoregressive model providing additional information for feature extraction of pattern recognition-based myoelectric control. AB - Myoelectric control based on pattern recognition has been studied for several decades. Autoregressive (AR) features are one of the mostly used feature extraction methods among myoelectric control studies. Almost all previous studies only used the AR coefficients without the residuals of AR model for classification. However, the residuals of AR model contain important amplitude information of the electromyography (EMG) signals. In this study, we added the residuals to the AR features (AR+re) and compared its performance with the classical sixth-order AR coefficients. We tested six unilateral transradial amputees and eight able-bodied subjects for eleven hand and wrist motions. The classification accuracy (CA) of the intact side for amputee subjects and the right hand for able-bodied subjects showed that the CA of AR+re features was slightly but significantly higher than that of classical AR features (p = 0.009), which meant that residuals could provide additional information to classical AR features for classification. Interestingly, the CA of the affected side for amputee subjects showed that there was no significant difference between the CA of AR+re features and classical AR features (p > 0.05). We attributed this to the fact that the amputee subjects could not use their affected side to produce consistent EMG patterns as their intact side or the dominant hand of the able bodied subjects. Since the residuals were already available when the AR coefficients were computed, the results of this study suggested adding the residuals to classical AR features to potentially improve the performance of pattern recognition-based myoelectric control. PMID- 26737971 TI - Unsupervised learning technique for surface electromyogram denoising from power line interference and baseline wander. AB - We present a novel approach to single-channel power line interference (PLI) and baseline wander (BW) removal from surface electromyograms (EMG). It is based on non-negative matrix factorization (NMF) using a priori knowledge about the interferences. It performs a linear decomposition of the input signal spectrogram into non-negative components, which represent the PLI, BW and EMG spectrogram estimates. They all exhibit very different time-frequency patterns: PLI and BW are both sparse whereas EMG is noise-like. Initialization of the classical NMF algorithm with accurately designed PLI, BW and EMG structures and a carefully adjusted matrix decomposition rank increases the separation performance. The comparative study suggests that the proposed method outperforms two state-of-the art reference methods. PMID- 26737972 TI - A comparison of classification based confidence metrics for use in the design of myoelectric control systems. AB - In many pattern recognition applications, confidence scores are used to extract more information than discrete class membership alone, yet they have not traditionally been leveraged in myoelectric control. In this work, the confidence scores of eight common classification schemes were examined. Their role in rejecting inadvertent motions is investigated, and the tradeoffs observed in the design of rejection capable control schemes are demonstrated. It is shown that the distribution of confidences can varying greatly between classifiers, even when classification performance is similar. As a specific example, an ensemble of support vector machines in a one against one configuration (SVM1vs1) outperforms the previously reported LDAR myoelectric pattern recognition rejection scheme in terms of accuracy-rejection curves (ARC) and false acceptance/rejection (FAR) curves. PMID- 26737973 TI - Individual finger classification from surface EMG: Influence of electrode set. AB - The aim of this work was to minimize the number of channels, determining acceptable electrode locations and optimizing electrode-recording configurations to decode isometric flexion and extension of individual fingers. Nine healthy subjects performed cyclical isometric contractions activating individual fingers. During the experiment they tracked a moving visual marker indicating the contraction type (flexion/extension), desired activation level and the finger that should be employed. Surface electromyography (sEMG) signals were detected from the forearm muscles using a matrix of 192 channels (24 longitudinal columns and 8 transversal rows, 10 mm inter-electrode distance). The classification was evaluated in the context of a linear discriminant analysis (LDA) with different sets of EMG electrodes: A) one linear array of 8 electrodes, B) two arrays of 8 electrodes each, C) a set with one electrode on the barycenter of each sEMG activity area, D) all the recorded channels. The results showed that the classification accuracy depended on the electrode set (F=14.67, p<;0.001). The best reduction approaches were the barycenter calculation and the use of two linear arrays of electrodes, which performed similarly to each other (both > 82% of average success rate). Considering the computation time and electrode positioning, it is concluded that two arrays of 8 electrodes provide an optimal configuration to classify the isometric flexion and extension of individual fingers. PMID- 26737974 TI - Automated cardiac time interval measurement for Modified Myocardial Performance Index calculation of right ventricle. AB - The Modified Myocardial Performance Index (Mod-MPI) has sparked great interest as a parameter for fetal cardiac function assessment. However, measurement of this index requires expertise and its clinical application might be limited, owing to its poor repeatability. Research groups have been investigating left Mod-MPI (that is, Mod-MPI from left ventricle valve events), and an automated algorithm has been developed for left Mod-MPI calculation in our previous study. Right MPI is also important as it becomes abnormal earlier than left MPI in some pathologies; however, for use across the gestational age spectrum, it requires two-image acquisition. This paper presents an automated method to detect valve movements during atrioventricular outflow and ventricular inflow and to further calculate the time intervals required for right MPI calculation. Ninety pulsed wave Doppler ultrasound images of the right ventricle in fetuses, forty-five showing outflow and forty-five inflow, were analyzed to automatically detect the valve clicks generated by tricuspid valve movement in inflow waves, and pulmonary valve movement in outflow waves. The morphological characteristics of waves were combined with intensity information to locate clicks. This automated method can detect valve movement events with a high positive predictive value (96.20-98.96%) and sensitivity (97.95-100.00%), using manual annotation from an expert ultrasonographer as the gold standard for evaluation. PMID- 26737975 TI - Classification of LV wall motion in cardiac MRI using kernel Dictionary Learning with a parametric approach. AB - In this paper, we propose a parametric approach for the assessment of wall motion in Left Ventricle (LV) function in cardiac cine-Magnetic Resonance Imaging (MRI). Time-signal intensity curves (TSICs) are identified in Spatio-temporal image profiles extracted from different anatomical segments in a cardiac MRI sequence. Different parameters are constructed from specific TSICs that present a decreasing then increasing shape reflecting dynamic information of the LV contraction. The parameters extracted from these curves are related to: 1) an average curve based on a clustering process, 2) curve skewness and 3) cross correlation values between each average clustered curve and a patient-specific reference. Several tests are performed in order to construct different vectors to train a sparse classifier based on kernel Dictionary Learning (DL). Results are compared with other classifiers like Support Vector Machine (SVM) and Discriminative Dictionary Learning. The best classification performance is obtained with information of skewness and the average curve with an accuracy about 94% using the mentioned sparse based kernel DL with a radial basis function kernel. PMID- 26737976 TI - A technique for visualising three-dimensional left atrial cardiac activation data in two dimensions with minimal distance distortion. AB - Electro-anatomic mapping and medical imaging systems, used during clinical procedures for treatment of atrial arrhythmias, frequently record and display measurements on an anatomical surface of the left atrium. As such, obtaining a complete picture of activation necessitates simultaneous views from multiple angles. In addition, post-processing of three-dimensional surface data is challenging, since algorithms are typically applicable to planar or volumetric data. We applied a surface flattening methodology to medical imaging data and electro-anatomic mapping data to generate a two-dimensional representation that best preserves distances, since the calculation of many clinically relevant metrics, including conduction velocity and rotor trajectory identification require an accurate representation of distance. Distance distortions were small and improved upon exclusion of the pulmonary veins. The technique is demonstrated using maps of local activation time, based on clinical data, and plotting rotor core trajectories, using simulated data. PMID- 26737977 TI - Quantification of velocity reduction after flow diverter placement in intracranial aneurysm: An ex vivo study with 3D printed replicas. AB - Phase contrast MRI (pcMRI) was used to measure flow before and after placement of a flow diverter (n = 3). Decreases from 18% to 31% in flow velocity were seen in the inflow jet of the aneurysms. Flow patterns were also compared. It was observed that the gross aneurysmal flow patterns were maintained after flow diverter placement despite decreased fluid velocities. All measurements were carried out in 3D printed aneurysm replicas. PMID- 26737978 TI - Segmentation of the left ventricle in cardiac MRI using a probabilistic data association active shape model. AB - The 3D segmentation of endocardium of the left ventricle (LV) in cardiac MRI volumes is a challenging problem due to the intrinsic properties of this image modality. Typically, the object shape and position are estimated to fit the observed features collected from the images. The difficulty inherent to the LV segmentation in MRI is that the images contain outliers (i.e., observations not belonging to the LV border) due to the presence of other structures. This paper proposes a robust approach based on the Active Shape Model (ASM) that is able to circumvent the above problem. More specifically, the ASM will be guided by probabilistic data association filtering (PDAF) of strokes (i.e. line segments) computed in the neighborhood of the shape model. Thus, the proposed approach, termed herein as ASM-PDAF, will perform the following main steps: 1) edge detection (low-level features) in the vicinity of the shape model; 2) edge grouping (mid-level features) to obtain potential LV strokes; and 3) filtering using a PDAF framework (high-level features) to update the ASM. Experimental results on a public cardiac MRI database show that the proposed approach outperforms previous literature research. PMID- 26737979 TI - Automated quantification of epicardial adipose tissue in cardiac magnetic resonance imaging. AB - Cardiovascular disease is one of the leading causes of death worldwide. Epicardial adipose tissue (EAT) has emerged as an independent predictor of high cardiometabolic risk. Cardiovascular MRI has proven to be a feasible and reproducible method to assess EAT quantitatively. We present a novel approach for the automated quantification of EAT using "a priori" anatomical information. We extracted a region of interest (ROI) in the end-diastolic heart phase followed by a GVF-snake algorithm to smooth it. For the EAT and endocardial boundary detection, a Law's texture filter is applied. Left and right ventricle are localized using spatial prior information. Then, thresholding is applied to quantify the cardiac muscle. For the EAT, it is differentiated from the paracardial fat by K-cosine curvature analysis. Results for 10 morbidly obese patients show no significant differences between manual and automatic quantification with a remarkable time and effort saving between them. PMID- 26737980 TI - Towards a workflow driven design for mHealth devices within temporary eye clinics in low-income settings. AB - Only a small minority of mobile healthcare technologies that have been successful in pilot studies have subsequently been integrated into healthcare systems. Understanding the reasons behind this discrepancy is crucial if such technologies are to be adopted. We believe that the mismatch is due to a breakdown in the relation between technical soundness of the original mobile health (mHealth) device design, and integration into healthcare provision workflows. Quantitative workflow modelling provides an opportunity to test this hypothesis. In this paper we present our current progress in developing a clinical workflow model for mobile eye assessment in low-income settings. We test the model for determining the appropriateness of design parameters of a mHealth device within this workflow, by assessing their impact on the entire clinical workflow performance. PMID- 26737981 TI - The use of technology in Suicide Prevention. AB - Suicide is one of the leading causes of death globally, and is notably a significant cause of death amongst young people. A suicide outcome is a complex combination of personal, social, and health factors, and therefore suicide prevention is a challenge, requiring a systems approach incorporating public health strategies, screening at-risk individuals, targeted interventions, and follow-up for suicide survivors and those bereaved by suicide. Engineering practice has been implicated in the hindrance of the adoption of suicide prevention strategies, such as installing safety barriers at the Golden Gate Bridge, however technological developments offer new opportunities in suicide prevention, and the potential to reduce the number of deaths by suicide. We present an overview of current technological developments which are facilitating research in the field of suicide prevention, including multiple modes of screening such as network analysis of mobile-phone collected connectivity data, automatic detection of suicidality from social media content, and crisis detection from acoustic variability in speech patterns. The current field of mhealth apps for suicide prevention is assessed, and an innovative app for an Indigenous population is presented. From this overview, future challenges - technical and ethical - are discussed. PMID- 26737982 TI - Monitoring of compliance on an individual treatment through mobile innovations. AB - The present work examines the potential of smartphone usage for offering health services to elderly patients. The purpose of this work is the design, development, and implementation of a telemedicine application. This application aims to improve the monitoring mode and increase patient adherence to the instructions assigned by the medical staff. It consists of three parts: the doctor's application (Web Application), the patient's application (Android Application) and the Web Server of the platform, where the database is stored necessary for the smooth operation of the platform. Also the Web Server hosts the doctor's Web Application. The Web Application is based on web front-end technologies, providing the medical personnel with a variety of features and useful actions. These actions and capabilities are mainly relevant to the assignment of instructions to patients and the monitoring of their health progress. The Android Application has been implemented and validated for the Android-based mobile devices operating system and consists of a handy and user friendly environment, equipped with the right tools so that the patient has the ability to update the system on the progress of his/her health by storing the appropriate measurements. Both applications also provide customization capabilities in regards to the patients' and doctors' profile. PMID- 26737983 TI - Real-time multimedia communications in medical emergency - the CONCERTO project solution. AB - The management of medical emergency, in particular cardiac emergency, requests prompt intervention and the possibility to communicate in real time from the emergency area / ambulance to the hospital as much diagnostic information as possible about the patient. This would enable a prompt emergency diagnosis and operation and the possibility to prepare the appropriate actions in the suitable hospital department. To address this scenario, the CONCERTO European project proposed a wireless communication system based on a novel cross-layer architecture, including the integration of building blocks for medical media content fusion, delivery and access. This paper describes the proposed system architecture, outlining the developed components and mechanisms, and the evaluation of the proposed system, carried out in a hospital with the support of medical staff. The technical results and the feedback received highlight the impact of the CONCERTO approach in the healthcare domain, in particular in enabling a prompt and reliable diagnosis in challenging medical emergency scenarios. PMID- 26737984 TI - An environment for representing and using medical checklists on mobile devices. AB - Checklists have been recently introduced in the medical practice playing the role of summarized guidelines, streamlined for rapid consultations. However, there are still some barriers preventing their widespread diffusion. Those concern the representation, dissemination and update of their underlying knowledge, as well as the means currently adopted for their actual use, that is still mostly paper based. In this paper we propose a new platform for the implementation and use of checklists. First, an editor supports domain experts in porting the checklist from the traditional paper-based format into an electronic one. Then, an application allows the distribution and usage of checklists on portable devices such as smartphones and tablets, exploiting their additional features in comparison with those made available by Personal Computers. The platform will be illustrated through some examples designed to support volunteers and paramedic staff in dealing with emergency situations. PMID- 26737985 TI - Real time heart rate variability assessment from Android smartphone camera photoplethysmography: Postural and device influences. AB - The aim of this paper is to present a smartphone based system for real-time pulse to-pulse (PP) interval time series acquisition by frame-to-frame camera image processing. The developed smartphone application acquires image frames from built in rear-camera at the maximum available rate (30 Hz) and the smartphone GPU has been used by Renderscript API for high performance frame-by-frame image acquisition and computing in order to obtain PPG signal and PP interval time series. The relative error of mean heart rate is negligible. In addition, measurement posture and the employed smartphone model influences on the beat-to beat error measurement of heart rate and HRV indices have been analyzed. Then, the standard deviation of the beat-to-beat error (SDE) was 7.81 +/- 3.81 ms in the worst case. Furthermore, in supine measurement posture, significant device influence on the SDE has been found and the SDE is lower with Samsung S5 than Motorola X. This study can be applied to analyze the reliability of different smartphone models for HRV assessment from real-time Android camera frames processing. PMID- 26737986 TI - Jet injection of a monoclonal antibody: A preliminary study. AB - Monoclonal antibodies (mAbs) represent a major group of biotherapeutics. The high concentration and volume of drug administered together with a shift to administration via the subcutaneous route have generated interest in alternative delivery technologies. The feasibility of using a novel, highly controllable jet injection technology to deliver a mAb is presented. The effect of delivery parameters on protein structure were evaluated and compared with delivery using a conventional needle and syringe. Injection of mAb into a rat model showed that jet injection using the device resulted in more rapid absorption and longer duration of exposure. PMID- 26737987 TI - A compound ampoule for large-volume controllable jet injection. AB - We present a new design for a needle-free injector ampoule, using two concentric pistons to pressurize the fluid during the injection. The smaller, inner piston is used to provide an initial high-velocity piercing jet; it then engages the outer piston to deliver the remaining drug via a low-velocity jet. The goal of this design is to enable needle-free delivery of relatively large volumes to controlled depths in tissue, a task impractical with conventional ampoules and actuators. We demonstrate this concept by constructing a 1.2mL ampoule, measuring the jet velocity it produces in free air, and performing a set of injections into post-mortem porcine tissue. The ampoule smoothly produces the two desired phases of an injection, with a smooth transition of jet velocity as the two pistons engage. The injection is able to penetrate porcine skin to a controlled depth and deliver fluid to the subcutaneous and/or intramuscular layers, though further investigation is required to ensure that all of the fluid delivered can be retained at the desired depth. PMID- 26737988 TI - Adaptive controller for a needle free jet-injector system. AB - A nonlinear, sliding mode adaptive controller was created for a needle-free jet injection system. The controller was based on a simplified lumped-sum parameter model of the jet-injection mechanics. The adaptive control scheme was compared to a currently-used Feed-forward+PID controller in both ejection of water into air, and injection of dye into ex-vivo porcine tissue. The adaptive controller was more successful in trajectory tracking and was more robust to the biological variations caused by a tissue load. PMID- 26737989 TI - The effect of jet shape on jet injection. AB - The effects of the dispersion pattern of a needle-free jet injector are explored. The shape of the jets were compared using a high-speed video camera and jet injections of collimated and dispersed fluid jets with a Lorentz-force actuated jet injector were made into acrylamide gel and post-mortem porcine tissue. A custom-built high-speed X-ray imaging system was used in order to observe the dynamics of the dispersion mechanism for each injection in real time. We show that a collimated jet stream results in greater tissue penetration than a dispersed jet stream. PMID- 26737990 TI - Optimization of drug viscosity used in gas-powered liquid jet injectors. AB - This paper describes the effect of drug viscosity on the performance of gas powered liquid jet injectors. The analysis is accomplished utilizing a Computational Fluid Dynamics (CFD) model that obtains the stagnation pressure at the nozzle outlet. The technique is based on previous work used to predict gas power driven injector piston velocity with time. The results depict the variation in average and peak injector stagnation pressure for three different driven pressures; driving injections which vary from 0.2 cP to 87 cP in viscosity. Furthermore, a numerical representation of jet shape is also obtained to verify the effect of viscosity on jet geometry. These results demonstrate that increasing viscosity by 10 times that of water produces only a slight decrease in injector stagnation pressure and produces jets with greater confinement, which will display better characteristics for puncturing the skin. PMID- 26737991 TI - Human feasibility study of fluorescence spectroscopy guided optical biopsy needle for prostate cancer diagnosis. AB - Current prostate biopsy cores have a very low diagnostic yield. These biopsies often fail to diagnose prostate cancer since 90% of cores are histopathologically classified as benign. The concentrations of endogenous fluorophores in prostate tissue vary with disease states. Thus, fluorescence spectroscopy could be utilized to quantify these variations for identification of malignant lesions. We investigated clinical feasibility of a 14 gauge (1.98 mm) optical biopsy needle guided by fluorescence spectroscopy for real-time in vivo prostate cancer diagnosis. Built-in optical sensor has 8*100MUm fibers for tissue excitation and a single 200MUm fiber to collect spectral data. Custom-made fluorometer has 2 light-emitting diodes at 290 and 340 nm and a spectrometer. User interface for fluorometer operation and data collection was developed using LabView software. Each spectral data acquisition required ~2 seconds. The in vivo biopsies were performed during radical retropubic prostatectomy surgery on the exposed prostate with blood flow to the gland intact. A tissue biopsy core was obtained from each biopsy site after acquisition of spectral data. Above procedure was repeated ex vivo after surgical excision of the prostate. Biopsy cores were histopathologically classified as either benign or malignant and correlated with corresponding spectral data. Partial Least Square analysis was performed to determine diagnostically significant principal components as potential classifiers. A linear support vector machine and leave-one-out cross validation method was employed for tissue classification. Thirteen patients were consented to the study. Histopathological analysis found cancer in 29/208 in vivo and 51/224 ex vivo viable biopsy cores. Study results show 72% sensitivity, 66% specificity, and 93% negative predictive value for in vivo and 75%, 80%, and 93%, respectively, for ex vivo malignant versus benign prostatic tissue classification. Optical biopsy needle has a very high negative predictive value to indicate benign tissue while sufficient sensitivity for targeting areas suspicious for cancer within the prostate gland. Hence, the optical biopsy needle can increase the diagnostic yield of prostate biopsies with consequent improvement in patient care. PMID- 26737992 TI - Analysis of the microcirculatory pulse wave: age-related alterations. AB - Morphological analysis of the pulse wave of central blood pressure signal is commonly used for the study of cardiac and vascular properties, but very few attempts were performed for analyzing the peripheral pulse wave of blood flow. In this work, we analyzed this waveform using classical methods, based on the application of FFT, followed by principal components analysis, for assessing the properties of the blood flow. As a sample problem, we evaluated the capability of the proposed method of assessing the alterations correlated with the aging of the vascular system. Results show a good discrimination between the different age groups, confirming the validity of the approach. PMID- 26737993 TI - Ageing of the couplings between cardiac, respiratory and myogenic activity in humans. AB - The balance and functionality of the cardiovascular system are maintained by a network of couplings between the different oscillations involved. We study the effect of ageing on these interactions through the application of wavelet analysis, and by the use of dynamical Bayesian inference to compute coupling functions. The method, applied to phases extracted from microvascular flow recorded by laser Doppler flowmetry (LDF), reveals the coupling functions between oscillations propagated to the smallest vessels. Consistent with earlier work based on analysis of cardiac and respiratory phases obtained from direct measurements, our analysis demonstrates an impairment of the propagated cardio respiratory coupling with ageing. The coupling weakens despite the increased cardiac component in the LDF with ageing. Our results bring new insight to the effect of ageing on cardiovascular regulation that might help improve the diagnostic potential of LDF monitors. PMID- 26737994 TI - Analysis of microvascular perfusion with multi-dimensional complete ensemble empirical mode decomposition with adaptive noise algorithm: Processing of laser speckle contrast images recorded in healthy subjects, at rest and during acetylcholine stimulation. AB - Laser speckle contrast imaging (LSCI) is a full-field imaging modality to monitor microvascular blood flow. It is able to give images with high temporal and spatial resolutions. However, when the skin is studied, the interpretation of the bidimensional data may be difficult. This is why an averaging of the perfusion values in regions of interest is often performed and the result is followed in time, reducing the data to monodimensional time series. In order to avoid such a procedure (that leads to a loss of the spatial resolution), we propose to extract patterns from LSCI data and to compare these patterns for two physiological states in healthy subjects: at rest and at the peak of acetylcholine-induced perfusion peak. For this purpose, the recent multi-dimensional complete ensemble empirical mode decomposition with adaptive noise (MCEEMDAN) algorithm is applied to LSCI data. The results show that the intrinsic mode functions and residue given by MCEEMDAN show different patterns for the two physiological states. The images, as bidimensional data, can therefore be processed to reveal microvascular perfusion patterns, hidden in the images themselves. This work is therefore a feasibility study before analyzing data in patients with microvascular dysfunctions. PMID- 26737995 TI - Wavelet analysis of the Laser Doppler signal to assess skin perfusion. AB - The hemodynamics of skin microcirculation can be clinically assessed by means of Laser Doppler Fluxmetry. Laser Doppler signals show periodic oscillations because of fluctuations of microvascular perfusion (flowmotion), which are sustained by contractions and relaxations of arteriolar walls rhythmically changing vessels diameter (vasomotion). The wavelet analysis applied to Laser Doppler signals displays six characteristic frequency intervals, from 0.005 to 2 Hz. Each interval is assigned to a specific structure of the cardiovascular system: heart, respiration, vascular myocites, sympathetic terminations, and endothelial cells (dependent and independent on nitric oxide). Therefore, mechanisms of skin perfusion can be investigated through wavelet analysis. In the present work, examples of methods and results of wavelet analysis applied to Laser Doppler signals are reported. Laser Doppler signals were acquired in two groups of patients to check possible changes in vascular activities, before and after occlusive reactive hyperaemia, and before and after revascularization. PMID- 26737996 TI - Monitoring the microcirculation at the bedside using hand-held imaging microscopes: Automatic tracking of erythrocytes. AB - In recent years, the development of portable microscopy devices that enable the noninvasive bedside evaluation of the mucosal microcirculation in critically ill patients has expanded the research on this level of the cardiovascular system. Several semi-quantitative scores have been defined to assess the peripheral perfusion, based on videos of the microcirculation. However, they are cumbersome and time-consuming processes, highlighting the need for the development of automated software techniques, to reduce physicians workload and ensure prompt and objective patient evaluation. We developed a rapid, automatic method for the quantitative assessment of erythrocyte velocities in Incident Dark Field (IDF) illumination videos of capillary flow. The technique, based on Kalman filter object tracking, was tested in 35 IDF videos against space-time diagrams, showing high correlation (r = 0.96) and agreement (bias = 3.3 MUm/s) with space-time diagrams (STD), below 200 MUm/s. PMID- 26737997 TI - Skin blood flow and temperature oscillations during cold pressor test. AB - We study the relationship between the blood flow and skin temperature variations under a cold pressor test (CPT). The simultaneous laser Doppler flowmetry (LDF) and skin temperature (ST) measurements were carried out for 8 healthy subjects on the skin surface of the distal phalanx of the second (LDF) and third (ST) fingers. The skin blood perfusion decreases stepwise about twice during contralateral CPT for all 8 subjects. The temperature of the finger pad decays monotonically during the test and dropped about 1 degrees C in mean. The power spectral densities of LDF flow and ST variations are also affected by the CPT, but subjects under study demonstrate two different types of reaction. LDF pulsations at the frequency about 0.1 Hz, which corresponds to the myogenic mechanism of vascular tone regulation, decreases in 5 subjects and increases in other 3 subjects. However in all subjects the ST pulsations behave contradictory, namely, the changes in amplitude of blood perfusion and ST pulsations due to cold pressor test are strongly anticorrelated. We discuss possible mechanisms of vascular reaction that can cause the behavior observed. PMID- 26737998 TI - An automated system for quantitative analysis of newborns' oral-motor behavior and coordination during bottle feeding. AB - In this work a novel unobtrusive technology-aided system is presented and tested for the assessment of newborns' oral-motor behavior and coordination during bottle feeding. A low-cost monitoring device was designed and developed in order to record Suction (S) and Expression (E) pressures from a typical feeding bottle. A software system was developed to automatically treat the data and analyze them. A set of measures of motor control and coordination has been implemented for the specific application to the analysis of sucking behavior. Experimental data were collected with the developed system on two groups of newborns (Healthy vs. Low Birth Weight) in a clinical setting. We identified the most sensitive S features to group differences, and analyzed their correlation with S/E coordination measures. Then, Principal Component Analysis (PCA) was used to explore the system suitability to automatically identify peculiar oral behaviors. Results suggest the suitability of the proposed system to perform an objective technology-aided assessment of the newborn's oral-motor behavior and coordination during the first days of life. PMID- 26737999 TI - Sensorized toys for measuring manipulation capabilities of infants at home. AB - Preterm infants, i.e. babies born after a gestation period shorter than 37 weeks, spend less time exploring objects. The quantitative measurement of grasping actions and forces in infants can give insights on their typical or atypical motor development. The aim of this work was to test a new tool, a kit of sensorized toys, to longitudinally measure, monitor and promote preterm infants manipulation capabilities with a purposive training in an ecological environment. This study presents preliminary analysis of grasping activity. Three preterm infants performed 4 weeks of daily training at home. Sensorized toys with embedded pressure sensors were used as part of the training to allow quantitative analysis of grasping (pressure and acceleration applied to toys while playing). Each toy was placed on the midline, while the infant was in supine position. Preliminary data show differences in the grasping parameters in relation to infants age and the performed daily training. Ongoing clinical trial will allow a full validation of this new tool for promoting object exploration in preterm infants. PMID- 26738000 TI - Sensorized graspable devices for the study of motor imitation in infants. AB - Researches regarding neonatal imitation are of great clinical interest since they can provide evidences of an innate mechanism underlying action understanding; the study can be led through the analysis of infants' spontaneous movements, like grasping, that are recognized as markers of neural activity. To this aim, a portable and non-intrusive device has been designed and developed to measure infants' grasping during the presentation of specific visual stimuli. The device is composed of two soft handles with embedded pressure sensors. During trials action observation should produce an increase of the measured pressure exerted by the infant's hand, according to the imitation-based paradigm of the defined clinical protocol. The final prototype has been tested within a pilot study and it has been proved to be suitable for monitoring infants' imitation abilities, meeting all the clinical specifications in terms of size, weight, safety and sensitivity. Preliminary acquired results are a starting point to clarify mechanisms related to imitation and sensorimotor system growth. The present methodology could be employed to boosts investigation on the development of mirror neurons in infants. PMID- 26738001 TI - Sensorized pacifier to quantify the rhythmicity of non-nutritive sucking: A preliminary study on newborns. AB - Non-nutritive sucking (NNS) is one of the most significant spontaneous actions of infants. The suction/expression rhythmicity of NNS remains unknown. We developed a sensorized pacifier for an objective measurement of NNS. Two miniaturized digital pressure sensors are embedded into a commercial pacifier and they acquired suction and expression pressures simultaneously. Experimental tests with nine newborns confirmed that our device is suitable for the measurement of the natural NNS behavior and for the extrapolation of parameters related to the suction/expression rhythmicity. Preliminary results encourage future studies to evaluate the possibility to use these parameters as indicators of oral feeding readiness of premature infants. PMID- 26738002 TI - Artificial nociception and motor responses to pain, for humans and robots. AB - This concept paper describes nociception and the role of pain in humans. Understanding the mechanisms of pain can give insight into the implementation of artificial pain for robots. Identification of noxious contacts could help robots to elicit reactions in order to avoid or minimize damage to the robot and the environment. The information processing of artificial pain can also be used to optimally regulate incoming sensory information and prevent accidents or real pain to the users of robotic systems and prostheses, improving the performance of robots and their interaction with human users. Besides the applications of artificial nociception for robotic manipulation and intelligent prostheses, the development of computational models of pain mechanisms for the discrimination of noxious stimuli from innocuous touch can find crucial clinical applications, addressing the vulnerable non-verbal population who are unable to report pain. PMID- 26738003 TI - Gait rehabilitation with a high tech platform based on virtual reality conveys improvements in walking ability of children suffering from acquired brain injury. AB - The Gait Real-time Analysis Interactive Lab (GRAIL) is an instrumented multi sensor platform based on immersive virtual reality for gait training and rehabilitation. Few studies have been included GRAIL to evaluate gait patterns in normal and disabled people and to improve gait in adults, while at our knowledge no evidence on its use for the rehabilitation of children is available. In this study, 4 children suffering from acquired brain injury (ABI) underwent a 5 session treatment with GRAIL, to improve walking and balance ability in engaging VR environments. The first and the last sessions were partially dedicated to gait evaluation. Results are promising: improvements were recorded at the ankle level, selectively at the affected side, and at the pelvic level, while small changes were measured at the hip and knee joints, which were already comparable to healthy subjects. All these changes also conveyed advances in the symmetry of the walking pattern. In the next future, a longer intervention will be proposed and more children will be enrolled to strongly prove the effectiveness of GRAIL in the rehabilitation of children with ABI. PMID- 26738004 TI - Nonlinear analysis of EEG in major depression with fractal dimensions. AB - Major depressive disorder (MDD) is a psychiatric mood disorder characterized by cognitive and functional impairments in attention, concentration, learning and memory. In order to investigate and understand its underlying neural activities and pathophysiology, EEG methodologies can be used. In this study, we estimated the nonlinearity features of EEG in MDD patients to assess the dynamical properties underlying the frontal and parietal brain activity. EEG data were obtained from 16 patients and 15 matched healthy controls. A wavelet-chaos methodology was used for data analysis. First, EEGs of subjects were decomposed into 5 EEG sub-bands by discrete wavelet transform. Then, both the Katz's and Higuchi's fractal dimensions (KFD and HFD) were calculated as complexity measures for full-band and sub-bands EEGs. Last, two-way analyses of variances were used to test EEG complexity differences on each fractality measures. As a result, a significantly increased complexity was found in both parietal and frontal regions of MDD patients. This significantly increased complexity was observed not only in full-band activity but also in beta and gamma sub-bands of EEG. The findings of the present study indicate the possibility of using the wavelet-chaos methodology to discriminate the EEGs of MDD patients from healthy controls. PMID- 26738005 TI - Volume conduction effects on bivariate Lempel-Ziv Complexity of Alzheimer's disease electroencephalograms. AB - The spurious increase in coherence of electroencephalogram (EEG) signals between distant electrode points has long been understood to be due to volume conduction of the EEG signal. Reducing the volume conduction components of EEG recordings in pre-processing attenuates this. However, the effect of volume conduction on non linear signal processing of EEG signals is yet to be fully described. This pilot study aimed to investigate the impact of volume conduction on results calculated with a distance based, bivariate form of Lempel-Ziv Complexity (dLZC) by analyzing EEG signals from Alzheimer's disease (AD) patients and healthy age matched controls with and without pre-processing with Current Source Density (CSD) transformation. Spurious statistically significant differences between AD patients and control's EEG signals seen without CSD pre-processing were not seen with CSD volume conduction mitigation. There was, however, overlap in the region of electrodes which were seen to hold this statistically significant information. These results show that, while previously published findings are still valid, volume conduction mitigation is required to ensure non-linear signal processing methods identify changes in signals only due to the purely local signal alone. PMID- 26738006 TI - Convergent Cross Mapping: Basic concept, influence of estimation parameters and practical application. AB - In neuroscience, data are typically generated from neural network activity. Complex interactions between measured time series are involved, and nothing or only little is known about the underlying dynamic system. Convergent Cross Mapping (CCM) provides the possibility to investigate nonlinear causal interactions between time series by using nonlinear state space reconstruction. Aim of this study is to investigate the general applicability, and to show potentials and limitation of CCM. Influence of estimation parameters could be demonstrated by means of simulated data, whereas interval-based application of CCM on real data could be adapted for the investigation of interactions between heart rate and specific EEG components of children with temporal lobe epilepsy. PMID- 26738007 TI - Evaluation of resting-state magnetoencephalogram complexity in Alzheimer's disease with multivariate multiscale permutation and sample entropies. AB - Alzheimer's disease (AD) is one of the fastest growing neurological diseases in the world. We evaluate multivariate multiscale sample entropy (mvMSE) and multivariate multiscale permutation entropy (mvMPE) approaches to distinguish resting-state magnetoencephalogram (MEG) signals of 36 AD patients from those of 26 normal controls. We also discuss about choosing the appropriate embedding dimension value as an effective parameter for mvMPE and MPE for the first time. The results illustrate that both the mvMPE and mvMSE can be useful in the diagnosis of AD, although with different running times and abilities. In addition, our findings show that the MEG complexity analysis performed on deeper time scales by mvMPE and mvMSE may be a useful tool to characterize AD. In most scale factors, the average of the mvMPE and mvMSE values of AD patients are lower than those of controls. PMID- 26738008 TI - Comparison of brain network models using cross-frequency coupling and attack strategies. AB - Several neuroimaging studies have suggested that functional brain connectivity networks exhibit "small-world" characteristics, whereas recent studies based on structural data have proposed a "rich-club" organization of brain networks, whereby hubs of high connection density tend to connect among themselves compared to nodes of lower density. In this study, we adopted an "attack strategy" to compare the rich-club and small-world organizations and identify the model that describes best the topology of brain connectivity. We hypothesized that the highest reduction in global efficiency caused by a targeted attack on each model's hubs would reveal the organization that better describes the topology of the underlying brain networks. We applied this approach to magnetoencephalographic data obtained at rest from neurologically intact controls and mild traumatic brain injury patients. Functional connectivity networks were computed using phase-to-amplitude cross-frequency coupling between the delta and beta frequency bands. Our results suggest that resting state MEG connectivity networks follow a rich-club organization. PMID- 26738010 TI - Benefits of ICA in the Case of a Few Channel EEG. AB - Independent Component Analysis (ICA) is often used at the signal preprocessing stage in EEG analysis for its ability to filter out artifacts from the signal. The benefits of using ICA are the most apparent when multi-channel signal is recorded. The question is, however, what kind of benefits (if any) can be obtained when ICA is applied for a few channel recording. We addressed this question in this paper by setting up the hypothesis that even in the case of only three channels, ICA can rearrange the sources to new mixtures in such a way that the true brain sources will be enhanced in some components, and the artifacts will be enhanced in others. To verify our hypothesis we applied three popular ICA algorithms to preprocess data from a benchmark file (motor imagery file from the II BCI Competition). Our results, presented in terms of classification precision, show that all ICA algorithms enhanced the signal to noise ratio for components correlating with signals recorded over C3 and C4 channels (the classification precision was higher in their case) and lessened the signal to noise ratio for components correlating with signals recorded over Cz channels. PMID- 26738009 TI - Spatial variation in automated burst suppression detection in pharmacologically induced coma. AB - Burst suppression is actively studied as a control signal to guide anesthetic dosing in patients undergoing medically induced coma. The ability to automatically identify periods of EEG suppression and compactly summarize the depth of coma using the burst suppression probability (BSP) is crucial to effective and safe monitoring and control of medical coma. Current literature however does not explicitly account for the potential variation in burst suppression parameters across different scalp locations. In this study we analyzed standard 19-channel EEG recordings from 8 patients with refractory status epilepticus who underwent pharmacologically induced burst suppression as medical treatment for refractory seizures. We found that although burst suppression is generally considered a global phenomenon, BSP obtained using a previously validated algorithm varies systematically across different channels. A global representation of information from individual channels is proposed that takes into account the burst suppression characteristics recorded at multiple electrodes. BSP computed from this representative burst suppression pattern may be more resilient to noise and a better representation of the brain state of patients. Multichannel data integration may enhance the reliability of estimates of the depth of medical coma. PMID- 26738011 TI - Clusters of mu rhythm from EEG data: A comparative study between 61 and 19 channel datasets. AB - The EEG mu rhythm is a sensorimotor oscillation which is desynchronized by voluntary movement execution. Independent Component Analysis (ICA) allows the decomposition of recorded scalp EEG data into temporally, functionally, and spatially independent source signals. Clustering techniques applied to independent sources resolved with ICA have been proven to be successful in the identification of clusters of sensorimotor mu rhythm across different subjects. The present work deals with the issue regarding the minimum number of data channels that is recommended to find reliable clusters of mu rhythm. Left and right mu clusters were identified from high-density EEG recordings (61 channels) belonging to a publicly available EEG database. A second dataset was created by selecting a small subset of the same high-density EEG recordings. Specifically, only the 19 channels belonging to the standard 10-20 International System were used for the identification of left and right mu clusters. Quantitative parameters computed from mu clusters obtained from both the 61-channel and the 19 channel datasets were statistically compared. The obtained results suggest that clusters of mu rhythm in sensorimotor areas can be reliably found from a lower number of EEG channels compared to high-density electrodes configuration. PMID- 26738012 TI - Neurophysiological correlates in Mild Cognitive Impairment detected using group Independent Component Analysis. AB - Alzheimer's disease is the most prevalent cause of dementia. Mild Cognitive Impairment (MCI) is defined as a grey area between intact cognitive functioning and clinical dementia. Electroencephalography (EEG) has been used to identify biomarkers in dementia. Currently, there is a great interest in translating the study from raw signals to signal generators, trying to keep the relationship with neurophysiology. In the current study, EEG recordings during an encoding task were acquired in MCI subjects and healthy controls. Data was decomposed using group Independent Component Analysis (gICA) and the most neuronal components were analyzed using Phase Intertrial Coherence (PIC) and Phase shift Intertrial Coherence (PsIC). MCI subjects exhibited an increase of PIC in the theta band, while controls showed increase in PsIC in the alpha band. Correlation between PIC and PsIC and clinical scales were also found. Those findings indicate that the methodology proposed based in gICA can help to extract information from EEG recordings with neurophysiological meaning. PMID- 26738013 TI - Comparison between different similarity measure functions for optimal clustering AEPs Independent Components. AB - A critical part of applying Independent Component Analysis (ICA) to any neurophysiological data is the selection of relevant independent Components (ICs); i. e., to decide which ICs have neurological meaning. Standard ICA implementation supposes a square mixing matrix; this results in as many ICs as EEG channels. In this work, responses to repetitive auditory stimuli are the most important signals (Auditory Evoked Potentials, AEPs); so the ICs of interest should be repetitive and time-locked with the stimuli. In this paper an update of a previously proposed procedure for the objective selection of ICs using Mutual Information (MI) and cluster analysis is presented. This time, four different similarity functions are evaluated and three inter/intra-cluster quality criteria are explored to determine optimal cluster numbers to both synthetic AEPs and data from normal hearing children, so that to identify ICs related with the auditory response. The numbers of clusters and the similarity function that yield best results in both datasets, in other words optimal clustering AEPs ICs, were 8 and Euclidean link-clustering average respectively. PMID- 26738014 TI - Non-parametric group-level statistics for source-resolved ERP analysis. AB - We have developed a new statistical framework for group-level event-related potential (ERP) analysis in EEGLAB. The framework calculates the variance of scalp channel signals accounted for by the activity of homogeneous clusters of sources found by independent component analysis (ICA). When ICA data decomposition is performed on each subject's data separately, functionally equivalent ICs can be grouped into EEGLAB clusters. Here, we report a new addition (statPvaf) to the EEGLAB plug-in std_envtopo to enable inferential statistics on main effects and interactions in event related potentials (ERPs) of independent component (IC) processes at the group level. We demonstrate the use of the updated plug-in on simulated and actual EEG data. PMID- 26738015 TI - Accurate heart rate estimation from camera recording via MUSIC algorithm. AB - In this paper, we propose an algorithm to extract heart rate frequency from video camera using the Multiple SIgnal Classification (MUSIC) algorithm. This leads to improved accuracy of the estimated heart rate frequency in cases the performance is limited by the number of samples and frame rate. Monitoring vital signs remotely can be exploited for both non-contact physiological and psychological diagnosis. The color variation recorded by ordinary cameras is used for heart rate monitoring. The orthogonality between signal space and noise space is used to find more accurate heart rate frequency in comparison with traditional methods. It is shown via experimental results that the limitation of previous methods can be overcome by using subspace methods. PMID- 26738016 TI - Bacterial colony counting by Convolutional Neural Networks. AB - Counting bacterial colonies on microbiological culture plates is a time consuming, error-prone, nevertheless fundamental task in microbiology. Computer vision based approaches can increase the efficiency and the reliability of the process, but accurate counting is challenging, due to the high degree of variability of agglomerated colonies. In this paper, we propose a solution which adopts Convolutional Neural Networks (CNN) for counting the number of colonies contained in confluent agglomerates, that scored an overall accuracy of the 92.8% on a large challenging dataset. The proposed CNN-based technique for estimating the cardinality of colony aggregates outperforms traditional image processing approaches, becoming a promising approach to many related applications. PMID- 26738017 TI - A clinically oriented system for melanoma diagnosis using a color representation. AB - Computer Aided-Diagnosis (CAD) systems have been proposed to help dermatologists diagnose melanomas. However, these systems fail to provide a medical explanation for the diagnosis. This makes the dermatologists unsure about their use, since they are not easy to understand. In this paper we propose a CAD system that extracts a clinically inspired color description of the lesion and then, uses this information to discriminate melanomas from benign lesions. The proposed system is also capable of showing the extracted color features, making the system and its decisions more comprehensible for practitioners. The development of this system is hampered by the lack of a database of detailed annotate dermoscopy images. Nonetheless, we are able to tackle this issue using an image annotation framework based on the Correspondence-LDA algorithm. This method is applied with success to the identification of relevant colors in dermoscopy images, obtaining an average Precision of 84.9% and a Recall of 85.5%. The proposed color representation is then used to classify skin lesions, resulting in a Sensitivity of 78.9% and Specificity of 76.7%, these values are promising and comparable with the state-of-the art. PMID- 26738018 TI - Morphological analysis and feature extraction of neurons from mouse cortices multiscale 3D microscopic images. AB - In this paper, we propose a framework to analyze the morphology of mouse neurons in the layer V of the cortex from 3D microscopic images. We are given 8 sets of images, each of which is composed of a 10x image showing the whole neurons, and a few (2 to 5) 40x images focusing on the somas. The framework consists in segmenting the neurons on both types of images to compute a set of specific morphological features, and in matching the neurons in the 40x images to their counterparts in the 10x images to combine the features we obtained, in a fully automatic fashion. PMID- 26738019 TI - Analysis of white blood cell dynamics in nailfold capillaries. AB - Based on video data acquired with low-cost, portable microscopy equipment, we introduce a semi-automatic method to count visual gaps in the blood flow as a proxy for white blood cells (WBC) passing through nailfold capillaries. Following minimal user interaction and a pre-processing stage, our method consists in the spatio-temporal segmentation and analysis of capillary profiles. Besides the mere count information, it also estimates the speed associated with every WBC event. The accuracy of our algorithm is validated through the analysis of two capillaries acquired from one healthy subject. Results are compared with manual counts from four human raters and confronted with related physiological data reported in literature. PMID- 26738020 TI - The detection of breathing behavior using Eulerian-enhanced thermal video. AB - The current gold standard for detecting and distinguishing between types of sleep apnea is expensive and invasive. This paper aims to examine the potential of inexpensive and unobtrusive thermal cameras in the identification and distinction between types of sleep apnea. A thermal camera was used to gather video of a subject performing regular nasal breathing, nasal hyperventilation and an additional trial simulating one type of sleep apnea. Simultaneously, a respiratory inductance plethysmography (RIP) band gathered respiratory data. Thermal video of all three trials were subjected to Eulerian Video Magnification; a procedure developed at MIT for enhancing subtle color variations in video data. Post magnification, nasal regions of interest were defined and mean region intensities were found for each frame of each trial. These signals were compared to determine the best performing region and compared to RIP data to validate breathing behavior. While some regions performed better, all region intensity signals depicted correct breathing behavior. The mean intensity signals for normal breathing and hyperventilation were correct and correlated well with RIP data. Furthermore, the RIP data resulting from the sleep apnea simulation clearly depicted chest movement while the corresponding mean intensity signal depicted lack of cyclical air flow. These results indicate that a subject's breathing behavior can be captured using thermal video and suggest that, with further development and additional equipment, thermal video can be used to detect and distinguish between types of sleep apnea. PMID- 26738021 TI - Analyzing dynamic cellular morphology in time-lapsed images enabled by cellular deformation pattern recognition. AB - Computational analysis of cellular morphology aims to provide quantitative information of the global organizational and physiological state of cells, and has long been a major topic of biomedical research. Instead of analyzing morphology of static cells, we concentrate on live-cell deformation in a period of time. According to our observation of dynamic cell behavior, we have assumed that the pattern of cellular deformation is relevant to the cellular state. Moreover, based on our assumption an innovative approach for characterizing the deformation pattern is described and applied into cell classification. After normalizing and aligning cell image sequences, we extract the continuity of deformation at each angle through time-lapse. Then the deformation pattern is given by the histogram of the continuity of deformation. Experimental results demonstrate that the cellular deformation pattern provided by our approach can be applied to discriminate cellular activation. In addition, the deformation pattern recognition makes remarkable progress in the classification of cells. PMID- 26738022 TI - High temporal resolution functional MRI with partial separability model. AB - Even though the hemodynamic response is a slow phenomenon, high temporal resolution in functional fMRI can enable better differentiation between the signal of interest and physiological noise or increase the statistical power of functional studies. To increase the temporal resolution, several methods have been developed to decrease the repetition time, TR, such as simultaneous multi slice imaging and MR encephalography approaches. In this work, a method using a fast acquisition and a partial separability model is presented to achieve a multi slice fMRI protocol at a temporal resolution of 75 ms. The method is demonstrated on a visual block task. PMID- 26738023 TI - Fast reference based MRI. AB - In many clinical MRI scenarios, existing imaging information can be used to significantly shorten acquisition time or improve Signal to Noise Ratio (SNR). In those cases, a previously acquired image can serve as a reference image, that may exhibit similarity in some sense to the image being acquired. Examples include similarity between adjacent slices in high resolution MRI, similarity between various contrasts in the same scans and similarity between different scans of the same patients. In this paper we present a general framework for utilizing reference images for fast MRI. We take into account that the reference image may exhibit low similarity with the acquired image and develop a hybrid adaptive weighted approach for sampling and reconstruction. Experiments demonstrate the performance of the method in three different clinical MRI scenarios: SNR improvement in high resolution brain MRI, utilizing similarity between T2 weighted and fluid-attenuated inversion recovery (FLAIR) for fast FLAIR scanning and utilizing similarity between baseline and follow-up scans for fast follow-up scanning. PMID- 26738024 TI - An easily-achieved time-domain beamformer for ultrafast ultrasound imaging based on compressive sensing. AB - In ultrafast ultrasound imaging technique, how to maintain the high frame rate, and at the same time to improve the image quality as far as possible, has become a significant issue. Several novel beamforming methods based on compressive sensing (CS) theory have been proposed in previous literatures, but all have their own limitations, such as the excessively large memory consumption and the errors caused by the short-time discrete Fourier transform (STDFT). In this study, a novel CS-based time-domain beamformer for plane-wave ultrasound imaging is proposed and its image quality has been verified to be better than the traditional DAS method and even the popular coherent compounding method on several simulated phantoms. Comparing to the existing CS method, the memory consumption of our method is significantly reduced since the encoding matrix can be sparse-expressed. In addition, the time-delay calculations of the echo signals are directly accomplished in time-domain with a dictionary concept, avoiding the errors induced by the short-time Fourier translation calculation in those frequency-domain methods. The proposed method can be easily implemented on some low-cost hardware platforms, and can obtain ultrasound images with both high frame rate and good image quality, which make it has a great potential for clinical application. PMID- 26738025 TI - A compressed sensing based approach on Discrete Algebraic Reconstruction Technique. AB - Discrete tomography (DT) techniques are capable of computing better results, even using less number of projections than the continuous tomography techniques. Discrete Algebraic Reconstruction Technique (DART) is an iterative reconstruction method proposed to achieve this goal by exploiting a prior knowledge on the gray levels and assuming that the scanned object is composed from a few different densities. In this paper, DART method is combined with an initial total variation minimization (TvMin) phase to ensure a better initial guess and extended with a segmentation procedure in which the threshold values are estimated from a finite set of candidates to minimize both the projection error and the total variation (TV) simultaneously. The accuracy and the robustness of the algorithm is compared with the original DART by the simulation experiments which are done under (1) limited number of projections, (2) limited view problem and (3) noisy projections conditions. PMID- 26738026 TI - Reference guided CS-MRI with gradient orientation priors. AB - The theory of Compressed sensing (CS) provides a systematic framework for MR image reconstruction from under-sampled k-space data. However, severe aliasing artifacts still occurs in the case of high acceleration. Thereupon, an extensive body of works investigates exploiting additional prior information extracted from a reference image which can be acquired with relative ease in many MR applications. In this work, we propose a novel reference guided CS-MRI reconstruction method using gradient orientation priors (GOP). Specifically, we regularize the tangent vector in the target image to be perpendicular to the corresponding normal vector in the reference image over all spatial locations. The proposed method was validated using multi-scan experiment data and is shown to provide high speed and high quality imaging. PMID- 26738027 TI - A novel 3D Cartesian random sampling strategy for Compressive Sensing Magnetic Resonance Imaging. AB - In this work we propose a novel acquisition strategy for accelerated 3D Compressive Sensing Magnetic Resonance Imaging (CS-MRI). This strategy is based on a 3D cartesian sampling with random switching of the frequency encoding direction with other K-space directions. Two 3D sampling strategies are presented. In the first strategy, the frequency encoding direction is randomly switched with one of the two phase encoding directions. In the second strategy, the frequency encoding direction is randomly chosen between all the directions of the K-Space. These strategies can lower the coherence of the acquisition, in order to produce reduced aliasing artifacts and to achieve a better image quality after Compressive Sensing (CS) reconstruction. Furthermore, the proposed strategies can reduce the typical smoothing of CS due to the limited sampling of high frequency locations. We demonstrated by means of simulations that the proposed acquisition strategies outperformed the standard Compressive Sensing acquisition. This results in a better quality of the reconstructed images and in a greater achievable acceleration. PMID- 26738028 TI - The effects of temperature changes on retinal ganglion cell responses to electrical stimulation. AB - Little is known about how the retina's response to electrical stimulation is modified by temperatures. In vitro experiments are often used to inform in vivo studies, hence it is important to understand what changes occur at physiological temperature. To investigate this, we recorded from eight RGCs in vitro at three temperatures; room temperature (24 degrees C), 30 degrees C and 34 degrees C. Results show that response latencies and thresholds are reduced, bursting spike rates in response to stimulation increases, and the spiking becomes more consistently locked to the stimulus at higher temperatures. PMID- 26738029 TI - High-channel-count, high-density microelectrode array for closed-loop investigation of neuronal networks. AB - We present a system for large-scale electrophysiological recording and stimulation of neural tissue with a planar topology. The recording system has 65,536 electrodes arranged in a 256 * 256 grid, with 25.5 MUm pitch, and covering an area approximately 42.6 mm(2). The recording chain has 8.66 MUV rms input referred noise over a 100 ~ 10k Hz bandwidth while providing up to 66 dB of voltage gain. When recording from all electrodes in the array, it is capable of 10-kHz sampling per electrode. All electrodes can also perform patterned electrical microstimulation. The system produces ~ 1 GB/s of data when recording from the full array. To handle, store, and perform nearly real-time analyses of this large data stream, we developed a framework based around Xilinx FPGAs, Intel x86 CPUs and the NVIDIA Streaming Multiprocessors to interface with the electrode array. PMID- 26738030 TI - A method for voltage measurements of cancerous vs non-cancerous omentum. AB - This paper presents and elaborates upon the practicalities of a method which enables the recording of voltage measurements from omental tissue in patients with advanced ovarian cancer. The key components of the proposed low-cost experimental setup are a tungsten electrode, a Ag/AgCl reference electrode and an instrumentation amplifier. Intriguingly, potential difference recordings between cancerous omentum and tissue culture media and between non-cancerous omentum and media, differ for tissue samples coming from the same patient. Further studies are warranted to assess the potential prognostic value of voltage measurements in cancerous tissue. PMID- 26738031 TI - A miniaturized monitoring system for electrochemical biosensing using Shewanella oneidensis in environmental applications. AB - We present a miniaturized, free-floating monitoring system which makes use of electron transfer in Shewanella oneidensis sequestered behind a permeable membrane while maintaining diffusive contact with the environment, allowing for sensing environmental conditions. The system makes use of a commercial off-the shelf (COTS) integrated circuit (IC) which sets a potential between a working electrode and a Ag/AgCl reference electrode while recording the resulting current from the electroactive cells. We successfully sensed both pyruvate and the environmental presence of E. coli via changes in the currents sensed. This work will enable the development of mobile aquatic sensing systems which make use of bacterial electron transfer as a transduction method. Further miniaturization of the recording mote, electrodes, packaging, and system is discussed. PMID- 26738032 TI - Electrochemistry provides a simple way to monitor Pseudomonas aeruginosa metabolites. AB - Pseudomonas aeruginosa is one of the most common bacteria responsible for nosocomial infections. To imagine new therapies, understanding virulence mechanisms and the associated communication system of the bacterium (its quorum sensing) is a target of the first importance. Electrochemistry is a promising tool for real-time in situ monitoring of electroactive species issued from P. aeruginosa communication system. This contribution deals with the electrochemical characterization of the main bacteria electroactive metabolites: Pseudomonas Quinolone Signal, pyocyanin and 2'-aminoacetophenone. These metabolites were electrochemically characterized and further detected in supernatant of P. aeruginosa PA01 strain grown in LB medium. PMID- 26738033 TI - An RFID-based on-lens sensor system for long-term IOP monitoring. AB - In this paper, an RFID-based on-lens sensor system is proposed for noninvasive long-term intraocular pressure monitoring. The proposed sensor IC, fabricated in a 0.18um CMOS process, consists of capacitive sensor readout circuitry, RFID communication circuits, and digital processing units. The sensor IC is integrated with electroplating capacitive sensors and a receiving antenna on the contact lens. The sensor IC can be wirelessly powered, communicate with RFID compatible equipment, and perform IOP measurement using on-lens capacitive sensor continuously from a 2cm distance while the incident power from an RFID reader is 20 dBm. The proposed system is compatible to Gen2 RFID protocol, extending the flexibility and reducing the self-developed firmware efforts. PMID- 26738034 TI - CMOS dielectrophoretic Lab-on-Chip platform for manipulation and monitoring of cells. AB - We propose a novel Complementary Metal Oxide Semiconductor (CMOS) based Lab-on Chip (LoC) platform for trapping, rotation and detection of cells and microorganism utilizing dielectrophoresis (DEP). DEP is a highly selective function of the permittivity, size and shape of the entity, and also depends on the permittivity of its environment; these dependencies can be used to identify and trap particles of interest with high precision. Real-time monitoring of such cellular manipulation is also desirable. Towards this goal, we have implemented a three-dimensional (3D) octa-pole electrode structure directly using the built-in metal layers of standard complementary metal-oxide-semiconductor (CMOS) process and demonstrate trapping and rotating of yeast cells. Moreover, we implement an impedance readout circuitry to monitor this process in situ. Paper presented both simulation and experimental results validating the platform. PMID- 26738035 TI - A CMOS sensor for rapid testing of pathogen susceptibility to pore-forming antibiotics. AB - An integrated CMOS chip is implemented in 0.13MUm technology that detects the efficacy of pore-forming antibiotics on bacterial samples in 10 minutes. The chip has been tested using two strains of E. coli and polymyxin B as the model antibiotic. An array of potassium-sensitive ISFETs and their readout circuits are integrated on the CMOS chip and a potassium-sensitive membrane is directly attached to the top metal electrodes, to measure potassium efflux from the affected bacterial cells. PMID- 26738036 TI - Comparative testing of piezoelectric and printed strain sensors in characterization of chewing. AB - Results of recent research suggest that there may be a relationship between the eating rate and the total energy intake in a meal. The chewing rate is an indicator of the eating rate that may be measured by a sensor. A number of wearable solutions have been presented for the automatic detection of chewing, but little work has been done on counting chews automatically. With recent developments in printing technologies, it is possible to draw or print application specific sensors. This paper provides a comparison between an off the shelf piezoelectric strain sensor and a plotter drawn strain sensor for quantifying the number of chews for several food items. Piezoelectric strain sensor and plotter drawn strain sensors were able to achieve absolute mean error rates of 8.09 +/- 7.16% and 8.26 +/- 7.51% respectively for estimating the number of chew counts. This shows that a plotter drawn sensor can achieve similar performance while potentially providing an easily reconfigurable solution. PMID- 26738037 TI - Effects of stray capacitance to ground in three electrode monopolar needle bioimpedance measurements. AB - Positive phase angle is documented and analyzed in a three electrode monopolar needle measurement. Inductance equivalent behavior of the stray capacitance to ground is described as error source in a non-inductive sample measurement. PMID- 26738038 TI - Thin-film microelectronic wearable body sensors. AB - This review of various applications of well-established thin-film processing techniques to wearable body sensors gives examples of work done in the author's laboratory over many years. Sensors for the vital signs of body temperature, electrocardiogram, heart rate, breathing pattern and breathing rate are presented along with other applications. Thin-film based sensors have the advantage of small size, high surface area to mass ratio, flexibility, capability for batch production, and compatibility with other microelectronic technologies. PMID- 26738039 TI - Detection and classification of tastants in vivo using a novel bioelectronic tongue in combination with brain-machine interface. AB - The mammalian gustatory system is acknowledged as one of the most valid chemosensing systems. The sense of taste particularly provides critical information about ingestion of toxic and noxious chemicals. Thus the potential of utilizing rats' gustatory system is investigated in detecting sapid substances. By recording electrical activities of neurons in gustatory cortex, a novel bioelectronic tongue system is developed in combination with brain-machine interface technology. Features are extracted in both spikes and local field potentials. By visualizing these features, classification is performed and the responses to different tastants can be prominently separated from each other. The results suggest that this in vivo bioelectronic tongue is capable of detecting tastants and will provide a promising platform for potential applications in evaluating palatability of food and beverages. PMID- 26738040 TI - Design of an implantable artificial dural window for chronic two-photon optical imaging in non-human primates. AB - Optical functional imaging methods such as calcium imaging have become a powerful tool for investigating neural activity in-vivo. Here, we present a design for a titanium implantable chamber with transparent silicone artificial dura which enables two-photon calcium imaging in non-human primates. This chamber accommodates imaging with high numerical aperture multiphoton objective lenses, and remains sealed, protecting the brain from the surrounding environment. In addition, we describe a tunable tissue stabilization system to apply gentle mechanical pressure to stabilize tissue during imaging. Our results suggest that two-photon calcium imaging may soon facilitate a new class of circuit and systems neuroscience experiments in non-human primates. PMID- 26738041 TI - Beamformer-based imaging of phase-amplitude coupling using electromagnetic brain activity. AB - Phase-amplitude coupling (PAC) between neural oscillations of different frequencies plays a crucial role in cognitive processing. Assessing the PAC at both sensor and source levels may encounter the problem of spurious coupling because of the volume conduction, field spread, and source leakage. This paper presents a novel method, beamformer-based imaging of PAC (BIPAC), to estimate PAC between sources from electromagnetic signals. For each targeted brain region, this method can extract the source component with the maximum PAC to the reference signal. The results from two simulated MEG data sets demonstrated that the proposed method can achieve high localization accuracy and low spurious coupling. PMID- 26738042 TI - An extendable simulation framework for benchmarking EEG-based brain connectivity estimation methodologies. AB - Due to its high temporal resolution, electroencephalography (EEG) is a promising research tool for studying functional and effective brain interaction. Yet, it is rather uncommon for researchers to validate their connectivity estimation methodologies prior to applying them to real data, even though problems have been pointed out regarding the validity of some of the predominant approaches. We here provide an extendable simulation framework that enables researchers to test their analysis pipelines on customizable realistically simulated EEG data. We define three simple criteria to measure source localization, connectivity detection and directionality estimation performance. All data and code needed to generate pseudo-EEG data and to benchmark a method's estimation performance are provided. PMID- 26738043 TI - Identification of the Default Mode Network with electroencephalography. AB - The Default Mode Network (DMN) is a brain resting-state network that is closely linked to consciousness and neuropsychiatric disorders. The DMN is routinely identified with functional magnetic resonance imaging (fMRI) or positron emission tomography (PET). However, both of these methods impose restrictions on the groups of patients that can be examined. We show that the DMN can also be identified by electroencephalography (EEG). Instructing subjects to alternate between self-referential memory recall and focusing on their breathing induces a spatial pattern of spectral band power modulation in the theta- and alpha-band (4 16 Hz) that is consistent with the DMN pattern observed with PET and fMRI. Since EEG is a portable, cheap, and safe technology, our work enables the characterization of DMN alterations in patient groups that are difficult to study with fMRI or PET. PMID- 26738044 TI - Predicting hand forces from scalp electroencephalography during isometric force production and object grasping. AB - In this study, we demonstrate the feasibility of predicting hand forces from brain activity recorded with scalp electroencephalography (EEG). Ten able-bodied subjects participated in two tasks: an isometric force production task and a grasp-and-lift task using unconstrained and constrained grasps. We found that EEG electrodes spanning central areas of the scalp were highly correlated to force rate trajectories. Moreover, EEG grand averages in central sites resembled force rate trajectories as opposed to force trajectories. The grasp-and-lift task resulted in higher decoding accuracies than the isometric force production task: across nine subjects, median accuracies for the isometric force production task were r=0.35 whereas median accuracies for unconstrained grasping were r=0.51 and for constrained grasping were r=0.50. Such results could lead to an understanding of the neural representation behind the control of hand forces and could be implemented in the neural control of closed-loop hand-based neuroprostheses. PMID- 26738045 TI - Gender effect in human brain responses to bottom-up and top-down attention using the EEG 3D-Vector Field Tomography. AB - The effect of gender in rapidly allocating attention to objects, features or locations, as reflected in brain activity, is examined in this study. A visual attention task, consisting of bottom-up (visual pop-out) and top-down (visual search) conditions during stimuli of four triangles, i.e., a target and three distractors, was engaged. In pop-out condition, both color and orientation of the distractors differed from target, while in search condition they differed only in orientation. During the task, high-density EEG (256 channels) data were recorded and analyzed by means of behavioral, event-related potentials, i.e., the P300 component and brain source localization analysis using 3D-Vector Field Tomography (3D-VFT). Twenty subjects (half female; 32+/-4.7 years old) participated in the experiments, performing 60 trials for each condition. Behavioral analysis revealed that both female and male outperformed in the pop-out condition compared to the search one, with respect to accuracy and reaction time, whereas no gender related statistical significant differences were found. Nevertheless, in the search condition, higher P300 amplitudes were detected for females compared to males (p <; 7 . 10(-3)). Moreover, the findings suggested that the maximum activation in females was located mainly in the left inferior frontal and superior temporal gyri, whereas in males it was found in the right inferior frontal and superior temporal gyri. Overall, the experimental results show that visual attention depends on contributions from different brain lateralization linked to gender, posing important implications in studying developmental disorders, characterized by gender differences. PMID- 26738046 TI - Deducing the reachable space from fingertip positions. AB - The reachable space of the hand has received significant interests in the past from relevant medical researchers and health professionals. The reachable space was often computed from the joint angles acquired from a motion capture system such as gloves or markers attached to each bone of the finger. However, the contact between the hand and device can cause difficulties particularly for hand with injuries, burns or experiencing certain dermatological conditions. This paper introduces an approach to find the reachable space of the hand in a non contact measurement form utilizing the Leap Motion Controller. The approach is based on the analysis of each position in the motion path of the fingertip acquired by the Leap Motion Controller. For each position of the fingertip, the inverse kinematic problem was solved under the physiological multiple constraints of the human hand to find a set of all possible configurations of three finger joints. Subsequently, all the sets are unified to form a set of all possible configurations specific for that motion. Finally, a reachable space is computed from the configuration corresponding to the complete extension and the complete flexion of the finger joint angles in this set. PMID- 26738047 TI - Shifting the balance of human standing: Inter-limb coordination for the control of a robotic balance simulation. AB - Learning to maintain standing balance in the presence of a paretic limb is an important recovery process for many stroke survivors. In this study, we used a robotic balance simulator to investigate whether manipulating medial-lateral or anterior-posterior torque contributions (i.e. input gains) could shift the control of balance toward a targeted lower limb in healthy controls. Manipulation of medial-lateral (ML) torque gains shifted the vertical load distribution toward the virtually weakened limb, but did not result in a significant shift in anterior-posterior (AP) torque control. Instead individual participants were observed to shift AP torque control in either direction, although participants more often shifted control toward the virtually weakened limb at larger ML asymmetries. In contrast, manipulation of AP torque gains did not produce any observable changes in measured torque signals. The shift in torque contributions during ML manipulations shows promise as an implicit training method for reducing weight-bearing asymmetry. However, further work is required to ensure both vertical load and AP torque control shift in the desired direction as well as to determine the applicability of the protocol in a patient population. PMID- 26738048 TI - The effect of behavioral preferences on skill acquisition in determining unspecified, suitable action patterns to control humanoid robots. AB - This research investigated the effect of behavioral preferences on learning efficiency when attempting to determine unspecified, but suitable action sequences for unfamiliar tasks. The goal of this research was to develop a skill acquisition support system for the elderly to aid them in using unfamiliar IT products, particularly those of welfare systems. Here, behavioral preference is defined as the type of action sequences that people would prefer to adopt for completing unfamiliar tasks. To achieve this goal, this research investigated the action sequences of participants when they attempt to control the posture of an unfamiliar humanoid robot with an unfamiliar controller. The participants were assigned the task of making the humanoid stand on one foot. Machine-learning based methods were presented for analyzing the behavioral preferences. The analysis results indicate that participants having behavioral preferences of adopting random action sequences can complete the task in a much shorter time, compared to participants having a behavioral preference of adopting action sequences similar to those of previous actions. PMID- 26738049 TI - Evaluation of passive polarized stereoscopic 3D display for visual & mental fatigues. AB - Visual and mental fatigues induced by active shutter stereoscopic 3D (S3D) display have been reported using event-related brain potentials (ERP). An important question, that is whether such effects (visual & mental fatigues) can be found in passive polarized S3D display, is answered here. Sixty-eight healthy participants are divided into 2D and S3D groups and subjected to an oddball paradigm after being exposed to S3D videos with passive polarized display or 2D display. The age and fluid intelligence ability of the participants are controlled between the groups. ERP results do not show any significant differences between S3D and 2D groups to find the aftereffects of S3D in terms of visual and mental fatigues. Hence, we conclude that passive polarized S3D display technology may not induce visual and/or mental fatigue which may increase the cognitive load and suppress the ERP components. PMID- 26738050 TI - Comparing features extractors in EEG-based cognitive fatigue detection of demanding computer tasks. AB - An electroencephalography (EEG)-based classification system could be used as a tool for detecting cognitive fatigue from demanding computer tasks. The most widely used feature extractor in EEG-based fatigue classification is power spectral density (PSD). This paper investigates PSD and three alternative feature extraction methods, in order to find the best feature extractor for the classification of cognitive fatigue during cognitively demanding tasks. These compared methods are power spectral entropy (PSE), wavelet, and autoregressive (AR). Bayesian neural network was selected as the classifier in this study. The results showed that the use of PSD and PSE methods provide an average accuracy of 60% for each computer task. This finding is slightly improved using the wavelet method which has an average accuracy of 61%. The AR method is the best feature extractor compared with the PSD, PSE and wavelet in this study with accuracy of 75.95% in AX-continuous performance test (AX-CPT), 75.23% in psychomotor vigilance test (PVT) and 76.02% in Stroop task (p-value <; 0.05). PMID- 26738051 TI - Dependence of gait parameters on height in typically developing children. AB - In clinical gait analysis is fundamental to have access to normative data, to be used as a reference in the interpretation of pathological walking. In a paediatric population this may be complicated by the dependence of gait parameters on child growth. The aim of this work is to provide the correlations of spatial-temporal gait parameters with children's height. We obtained the regression lines of cadence, double support, and gait phases, with respect to height, from a sample of 85 normally typically developing children aged 6 to 11. Our analysis of gait phases was not limited to the traditional analysis of stance and swing, but rather focused on the sub-phases of stance - heel contact, flat foot contact, push off - which proved to be an innovative approach to gait analysis. Heel contact decreased, flat foot contact increased and push off remained essentially unchanged with respect to children's height. These results may be useful in the interpretation of gait data in developing children, and the regression lines obtained may be used to normalize their gait parameters. PMID- 26738052 TI - Estimation of physiological sub-millimeter displacement with CW Doppler radar. AB - Doppler radar physiological sensing has been studied for non-contact detection of vital signs including respiratory and heartbeat rates. This paper presents the first micrometer resolution Wi-Fi band Doppler radar for sub-millimeter physiological displacement measurement. A continuous-wave Doppler radar working at 2.4GHz is used for the measurement. It is intended for estimating small displacements on the body surface resulting from physiological activity. A mechanical mover was used as target, and programmed to conduct sinusoidal motions to simulate pulse motions. Measured displacements were compared with a reference system, which indicates a superior performance in accuracy for having absolute errors less than 10MUm, and relative errors below 4%. It indicates the feasibility of highly accurate non-contact monitoring of physiological movements using Doppler radar. PMID- 26738053 TI - Sleep stage classification by body movement index and respiratory interval indices using multiple radar sensors. AB - Disturbed sleep has become more common in recent years. To increase the quality of sleep, undergoing sleep observation has gained interest as an attempt to resolve possible problems. In this paper, we evaluate a non-restrictive and non contact method for classifying real-time sleep stages and report on its potential applications. The proposed system measures body movements and respiratory signals of a sleeping person using a multiple 24-GHz microwave radar placed beneath the mattress. We determined a body-movement index to identify wake and sleep periods, and fluctuation indices of respiratory intervals to identify sleep stages. For identifying wake and sleep periods, the rate agreement between the body-movement index and the reference result using the R&K method was 83.5 +/- 6.3%. One-minute standard deviations, one of the fluctuation indices of respiratory intervals, had a high degree of contribution and showed a significant difference across the three sleep stages (REM, LIGHT, and DEEP; p <; 0.001). Although the degree that the 5-min fractal dimension contributed-another fluctuation index-was not as high as expected, its difference between REM and DEEP sleep was significant (p <; 0.05). We applied a linear discriminant function to classify wake or sleep periods and to estimate the three sleep stages. The accuracy was 79.3% for classification and 71.9% for estimation. This is a novel system for measuring body movements and body-surface movements that are induced by respiration and for measuring high sensitivity pulse waves using multiple radar signals. This method simplifies measurement of sleep stages and may be employed at nursing care facilities or by the general public to increase sleep quality. PMID- 26738054 TI - Distributed pressure sensors for a urethral catheter. AB - A flexible strip that incorporates multiple pressure sensors and is capable of being fixed to a urethral catheter is developed. The urethral catheter thus instrumented will be useful for measurement of pressure in a human urethra during urodynamic testing in a clinic. This would help diagnose the causes of urinary incontinence in patients. Capacitive pressure sensors are fabricated on a flexible polyimide-copper substrate using surface micromachining processes and alignment/assembly of the top and bottom portions of the sensor strip. The developed sensor strip is experimentally evaluated in an in vitro test rig using a pressure chamber. The sensor strip is shown to have adequate sensitivity and repeatability. While the calibration factors for the sensors on the strip vary from one sensor to another, even the least sensitive sensor has a resolution better than 0.1 psi. PMID- 26738055 TI - Capacitive ECG recording and beat-to-beat interval estimation after major cardiac event. AB - Today, heart diseases are the most common cause of death in the U.S.. Due to improved healthcare, more and more patients survive a major cardiac event, e.g. a heart attack. However, participation in everyday activity (e.g. driving a car) can be impaired afterwards. Patients might benefit from heart activity monitoring while driving using a capacitive ECG (cECG). However, it is unknown whether cECG is an appropriate monitoring tool for such patients. In this work, first results from a study including 10 patients having survived at least one major cardiac event are presented. It is shown that cECG can be used to diagnose heart rhythm deviations and estimate beat-to-beat intervals similar to conventional ECG. PMID- 26738056 TI - A breath sampling system assessing the influence of respiratory rate on exhaled breath composition. AB - This work presents a computerized system to monitor mouth pressure, tidal volume, exhaled airflow, respiration rate and end-tidal partial pressure of CO2 during breath collection. The system was used to investigate the effect of different respiratory rates on the volatile organic compounds (VOCs) concentrations in exhaled breath. For this purpose, VOCs with well-defined biochemical pathways and different chemical and physical properties were selected as biomarkers related to metabolism (acetone and isopropyl alcohol), cholesterol synthesis (isoprene) and intestinal microflora activity (ethanol). Mixed breath was collected from a nominally healthy volunteer in resting conditions by filling a Nalophan bag. The subject followed a regimented breathing pattern at different respiratory rates (10, 30 and 50 breaths per minute). Results highlight that ventilation pattern strongly influences the concentration of the selected compounds. The proposed system allows exhaled breath to be collected also in patients showing dyspnea such as in case of chronic heart failure, asthma and pulmonary diseases. PMID- 26738057 TI - Noninvasive ambulatory measurement system of cardiac activity. AB - This work implements a noninvasive system that measures the movements caused by cardiac activity. It uses unobtrusive Electro-Mechanical Films (EMFi) on the seat and on the backrest of a regular chair. The system detects ballistocardiogram (BCG) and respiration movements. Real data was obtained from 54 volunteers. 19 of them were measured in the laboratory and 35 in a hospital waiting room. Using a BIOPAC acquisition system, the ECG was measured simultaneously to the BCG for comparison. Wavelet Transform (WT) is a better option than Empirical Mode Decomposition (EMD) for signal extraction and produces higher effective measurement time. In the laboratory, the best results are obtained on the seat. The correlation index was 0.9800 and the Bland-Altman limits of agreement were 0.7136 +/- 4.3673 [BPM]. In the hospital waiting room, the best results are also from the seat sensor. The correlation index was 0.9840, and the limits of agreement were 0.4386 +/- 3.5884 [BPM]. The system is able to measure BCG in an unobtrusive way and determine the cardiac frequency with high precision. It is simple to use, which means the system can easily be used in non-standard settings: resting in a chair or couch, at the gym, schools or in a hospital waiting room, as shown. PMID- 26738058 TI - Collecting a citizen's digital footprint for health data mining. AB - This paper describes a case study for collecting digital footprint data for the purpose of health data mining. The case study involved 20 subjects residing in Finland who were instructed to collect data from registries which they evaluated to be useful for understanding their health or health behaviour, current or past. 11 subjects were active, sending 100 data requests to 49 distinct organizations in total. Our results indicate that there are still practical challenges in collecting actionable digital footprint data. Our subjects received a total of 75 replies (reply rate of 75.0%) and 61 datasets (reception rate of 61%). Out of the received data, 44 datasets (72.1%) were delivered in paper format, 4 (6.6%) in portable document format and 13 (21.3%) in structured digital form. The time duration between the sending of the information requests and reception of a reply was 26.4 days on the average. PMID- 26738059 TI - Pattern of active and inactive sequences of diabetes self-monitoring in mobile phone and paper diary users. AB - In a pilot randomized controlled trial involving overweight or obese participants with type 2 diabetes, we find that smartphone users have sharply higher adherence to self-monitoring of diet, physical activity, blood glucose, and body weight, as compared to paper diary users. By characterizing the pattern of adherence with the probability of continuation of active and inactive sequences of self monitoring, we find that smartphone users have longer active sequences of self monitoring of all four behaviors that were being monitored. Smartphone users are also quicker to resume self-monitoring of diet and physical activity after a lapse in self-monitoring, whereas paper diary users have shorter inactive sequences for monitoring blood glucose and body weight. The findings are informative for data collection methodology in this burgeoning area of research. PMID- 26738060 TI - Textual summarization of events leading to health alerts. AB - Extracting information from the sensors installed in the homes of elderly pose a unique set of challenges. Add to it the short amount of time the clinicians and nurses have to analyze this data, and the problem becomes more complicated. A system already in place at an "Aging in Place" facility monitors the activities of residents through multiple non-intrusive sensors and sends alerts on detecting an unusual event. We present an approach to generate textual summaries of events leading to the alerts. We analyze our system using four case studies and also list the comments provided by collaborators in healthcare domain. The system was then iterated to take some of those suggestions into account to give a glimpse of what an ideal system should look like. PMID- 26738061 TI - The shape of health: A comparison of five alternative ways of visualizing personal health and wellbeing. AB - The combination of clinical and personal health and wellbeing data can tell us much about our behaviors, risks and overall status. The way this data is visualized may affect our understanding of our own health. To study this effect, we conducted a small experiment with 30 participants in which we presented a holistic overview of the health and wellbeing of two modeled individuals, one of them with metabolic syndrome. We used an insight-based methodology to assess the effectiveness of the visualizations. The results show that adequate visualization of holistic health data helps users without medical background to better understand the overall health situation and possible health risks related to lifestyles. Furthermore, we found that the application of insight-based methodology in the health and wellbeing domain remains unexplored and additional research and methodology development are needed. PMID- 26738062 TI - Predicting energy expenditure from photo-plethysmographic measurements of heart rate under beta blocker therapy: Data driven personalization strategies based on mixed models. AB - Energy expenditure have been often estimated using computational models based on heart rate (HR) and appropriate personalization strategies to account for users cardio-respiratory characteristics. However, medications like beta blockers which are prescribed to treat several cardiac conditions have a direct influence on the cardiovascular system and may impact the relationship between HR and energy expenditure during physical activity (AEE). This study proposes to estimate AEE from HR using mixed models (MIX-REG) by introducing a novel method to personalize the prediction equation. We selected as features to represent the individual random effect in the MIX-REG model those subject characteristics which minimized both estimation error (RMSE) and between-subjects error bias variability. Data from 17 patients post-myocardial infarction were collected during a laboratory protocol. AEE was measured using indirect calorimetry and HR using an innovative wrist worn activity monitor equipped with the Philips Cardio and Motion Monitoring Module (CM3-Generation-1), which is an integrated module including a photo-plethysmographic and accelerometer sensor. The presented method showed large AEE estimation accuracy (RMSE = 1.35 kcal/min) which was comparable to that of models personalized using data from laboratory calibration protocols (HR-FLEX) and was superior to multi-linear regression and MIX-REG models trained using a stepwise features selection procedure. PMID- 26738063 TI - Experimental evaluation of a smartphone based Step Length estimation. AB - Step Length (SL) is an essential parameter in the healthcare field to monitor the gait of patients affected by motor disorders such as Freezing of Gait (FoG), a motor block that provokes an interruption of the normal gait cycle. As a consequence spatio-temporal parameters of gait, in particular SL, are strongly altered before and during a FoG event. In this work we present a non-intrusive and non-invasive architecture applicable in this clinical scenario and we evaluate its reliability of SL estimation on 8 healthy subjects. We obtained mean errors of 7.77%, 6.99% and 6.44% for low, normal and high velocity respectively, which is a sufficient accuracy for FoG detection. PMID- 26738064 TI - The quantitative prediction of HLA-B*2705 peptide binding affinities using Support Vector Regression to gain insights into its role for the Spondyloarthropathies. AB - Computational methods are increasingly utilised in many immunoinformatics problems such as the prediction of binding affinity of peptides. The peptides could provide valuable insight into the drug design and development such as vaccines. Moreover, they can be used to diagnose diseases. The presence of human class I MHC allele HLA-B*2705 is one of the strong hypothesis that would lead spondyloarthropathies. In this paper, Support Vector Regression is used in order to predict binding affinity of peptides with the aid of experimentally determined peptide-MHC binding affinities of 222 peptides to HLA-B*2705 to get more insight into this problematic disease. The results yield a high correlation coefficient as much as 0.65 and the SVR-based predictive models can be considered as a useful tool in order to predict the binding affinities for newly discovered peptides. PMID- 26738065 TI - Extension to distributed annotation system: Summary and summaryplot commands. AB - In recent years, the development of high-throughput sequencing technologies provided an effective way to generate data from entire genomes and test variants from thousands of individuals. The information acquired from analysing the data generated from high-throughput sequencing technologies provided useful insights into applications like whole-exome sequencing and targeted sequencing to discover the genetic cause of complex diseases and drug responses. The Distributed Annotation System (DAS) is one of the proposed solution developed to share and unify biological data from multiple local and remote DAS annotation servers. The researchers can use DAS to request data from federated or centralised databases and integrate them into a unified view. Furthermore, with the use of Reference DAS servers, structural and sequence data can be used to accompany annotation data, for the pursue of new knowledge for a particular feature or region. In this paper, two additional commands, summary and summary-plot commands, to the existing DAS protocol are proposed and implemented. The proposed commands were created in order to give the users the capabilities to request a summary of features for a particular region of interest. The summary command was created in order to extend the capabilities of the current DAS protocol, while the summaryplot command was created to provide a more user-friendly alternative to standard XML DAS responses. Finally, three examples are presented based on the GENCODE annotation data. PMID- 26738066 TI - Metabolomic pathway visualization tool outsourcing editing function. AB - Recent rapid improvements of measuring instrument enables us to perform various omics studies to simultaneous profile multiple molecules, which provides a holistic view of various molecular interactions, such as signal transaction, protein interactions, and metabolic pathways. Metabolomics is recently emerged omics that can identify and quantify low weight metabolites usually defined as organic molecules whose size is <; 1500 Da. In comparison to the other omics, the development of software tools to deal with metabolomic data is not matured. Conventional pathway drawing and visualization tool provide tool-specific unique functions, however, such user interface requires users to learn the usage and prevention for the use of these tools. Here, we developed a more generic pathway visualization tool. This tool incorporate pathway data yielded by common drawing tools, e.g. MS PowerPoint, and visualize the quantified values on the pathways. The statistical results also can be overlaid on each metabolite. The developed tools facilitate the interpreting metabolomic data in pathway forms. PMID- 26738067 TI - A Bayesian Network-based approach for discovering oral cancer candidate biomarkers. AB - Oral cancer can arise in the head and neck region. Due to the aggressive nature of the disease, which often leads to poor prognosis, Oral Squamous Cell Carcinoma (OSCC) constitutes the 8(th) most common neoplasms in humans. In the present work we formulate gene interaction network from oral cancer genomic data using Dynamic Bayesian Networks (DBNs). Four modules were extracted after applying a clustering technique to the network. We consequently explore them by applying topological and functional analysis methods in order to identify significant network nodes. Our analysis revealed that these important nodes may correspond to candidate biomarkers of the disease. PMID- 26738068 TI - Dynamic partial reconfiguration implementation of the SVM/KNN multi-classifier on FPGA for bioinformatics application. AB - Bioinformatics data tend to be highly dimensional in nature thus impose significant computational demands. To resolve limitations of conventional computing methods, several alternative high performance computing solutions have been proposed by scientists such as Graphical Processing Units (GPUs) and Field Programmable Gate Arrays (FPGAs). The latter have shown to be efficient and high in performance. In recent years, FPGAs have been benefiting from dynamic partial reconfiguration (DPR) feature for adding flexibility to alter specific regions within the chip. This work proposes combing the use of FPGAs and DPR to build a dynamic multi-classifier architecture that can be used in processing bioinformatics data. In bioinformatics, applying different classification algorithms to the same dataset is desirable in order to obtain comparable, more reliable and consensus decision, but it can consume long time when performed on conventional PC. The DPR implementation of two common classifiers, namely support vector machines (SVMs) and K-nearest neighbor (KNN) are combined together to form a multi-classifier FPGA architecture which can utilize specific region of the FPGA to work as either SVM or KNN classifier. This multi-classifier DPR implementation achieved at least ~8x reduction in reconfiguration time over the single non-DPR classifier implementation, and occupied less space and hardware resources than having both classifiers. The proposed architecture can be extended to work as an ensemble classifier. PMID- 26738069 TI - An ECG oximetry system for identifying obstructive and central apnoea events. AB - An automatic algorithm for processing simultaneously acquired electrocardiogram (ECG) and oximetry signals that identifies epochs of pure central apnoea, epochs containing obstructive apnoea and epochs of normal breathing is presented. The algorithm uses time and spectral features from the ECG derived heart-rate and respiration information, as well as features capturing desaturations from the oximeter sensor. Evaluation of performance of the system was achieved by using leave-one-record-out cross validation on the St. Vincent's University Hospital / University College Dublin Sleep Apnea Database from the Physionet collections of recorded physiologic signals. When classifying the three epoch types, our system achieved a specificity of 80%, a sensitivity to central apnoea of 44% and sensitivity to obstructive apnoea of 35%. A sensitivity of 81% was achieved when the central and obstructive epochs were combined into one class. PMID- 26738070 TI - Sleep apnoea episodes recognition by a committee of ELM classifiers from ECG signal. AB - This paper describes a system for the recognition of sleep apnoea episodes from ECG signals using a committee of extreme learning machine (ELM) classifiers. RR interval parameters (heart rate variability) have been used as the identifying features as they are directly affected by sleep apnoea. The MIT PhysioNet Apnea ECG database was used. A committee of five ELM classifiers has been employed to classify one-minute epochs of ECG into normal or apnoeic epochs. Our results show that the classification performance from the committee of networks was superior to the results of a single ELM classifier for fan-outs from 1 to 100. Classification performance reached a plateau at a fan-out of 10. The maximum accuracy was 82.5% with a sensitivity of 81.9% and a specificity of 82.8%. The results were comparable to other published research with the same input data. PMID- 26738071 TI - Sleep apnea detection using time-delayed heart rate variability. AB - Sleep apnea is a sleep disorder distinguished by repetitive absence of breathing. Compared with the traditional expensive and cumbersome methods, sleep apnea diagnosis or screening with physiological information that can be easily acquired is needed. This paper describes algorithms using heart rate variability (HRV) to automatically detect sleep apneas as long as it can be easily acquired with unobtrusive sensors. Because the changes in cardiac activity are usually hysteretic than the presence of apneas with a few minutes, we propose to use the delayed HRV features to identify the episodes with sleep apneic events. This is expected to help improve the apnea detection performance. Experiments were conducted with a data set of 23 sleep apnea patients using support vector machine (SVM) classifiers and cross validations. Results show that using eleven HRV features with a time delay of 1.5 minutes rather than the features without time delay for SA detection, the overall accuracy increased from 74.9% to 76.2% and the Cohen's Kappa coefficient increased from 0.49 to 0.52. Further, an accuracy of 94.5% and a Kappa of 0.89 were achieved when applying subject-specific classifiers. PMID- 26738072 TI - A gender-aware framework for the daytime detection of obstructive sleep apnea. AB - Sleep is an activity that is necessary for our survival. While the body may be still during sleep, the brain is actively progressing through repeating cycles of light and deep sleep whose purpose is physical and mental recovery and regeneration. Obstructive sleep apnea (OSA) is a sleep disorder in which breathing is frequently and repeatedly stopped during sleep. OSA severely interrupts the normal sleep cycle and the regeneration work associated with it and can thus result in detrimental health consequences. OSA, with all the adverse health effects associated with it, places a significant burden on the US healthcare system. Polysomnography (PSG) - the gold standard OSA diagnostic test is an overnight sleep test that monitors the biophysiological changes that occur during sleep. The test is notorious for its intrusiveness, discomfort, prohibitive cost, and scarcity - all reasons contributing to OSA being a severely underdiagnosed sleep disorder. In this paper, we propose a system that can serve as an early-stage OSA diagnostic tool that can non-intrusively, affordably and accurately screen patients for the disorder before proceeding with a full-night PSG. Unlike existing tools, our solution is gender-aware and does not rely on detecting apneic events in the data to make a diagnosis; rather, it is designed to trigger brain responses that are indicative of the disorder. Our tool can therefore make diagnoses even while patients are awake and breathing normally. The system was tested in a pilot study of 21 patients and our preliminary results show an average accuracy of 96.25%. PMID- 26738073 TI - Breath-by-breath detection of apneic events for OSA severity estimation using non contact audio recordings. AB - Obstructive sleep apnea (OSA) is a prevalent sleep disorder, characterized by recurrent episodes of upper airway obstructions during sleep. We hypothesize that breath-by-breath audio analysis of the respiratory cycle (i.e., inspiration and expiration phases) during sleep can reliably estimate the apnea hypopnea index (AHI), a measure of OSA severity. The AHI is calculated as the average number of apnea (A)/hypopnea (H) events per hour of sleep. Audio signals recordings of 186 adults referred to OSA diagnosis were acquired in-laboratory and at-home conditions during polysomnography and WatchPat study, respectively. A/H events were automatically segmented and classified using a binary random forest classifier. Total accuracy rate of 86.3% and an agreement of kappa=42.98% were achieved in A/H event detection. Correlation of r=0.87 (r=0.74), diagnostic agreement of 76% (81.7%), and average absolute difference AHI error of 7.4 (7.8) (events/hour) were achieved in in-laboratory (at-home) conditions, respectively. Here we provide evidence that A/H events can be reliably detected at their exact time locations during sleep using non-contact audio approach. This study highlights the potential of this approach to reliably evaluate AHI in at home conditions. PMID- 26738074 TI - Pulse oximetry recorded from the Phone Oximeter for detection of obstructive sleep apnea events with and without oxygen desaturation in children. AB - Obstructive sleep apnea (OSA) disrupts normal ventilation during sleep and can lead to serious health problems in children if left untreated. Polysomnography, the gold standard for OSA diagnosis, is resource intensive and requires a specialized laboratory. Thus, we proposed to use the Phone OximeterTM, a portable device integrating pulse oximetry with a smartphone, to detect OSA events. As a proportion of OSA events occur without oxygen desaturation (defined as SpO2 decreases >= 3%), we suggest combining SpO2 and pulse rate variability (PRV) analysis to identify all OSA events and provide a more detailed sleep analysis. We recruited 160 children and recorded pulse oximetry consisting of SpO2 and plethysmography (PPG) using the Phone OximeterTM, alongside standard polysomnography. A sleep technician visually scored all OSA events with and without oxygen desaturation from polysomnography. We divided pulse oximetry signals into 1-min signal segments and extracted several features from SpO2 and PPG analysis in the time and frequency domain. Segments with OSA, especially the ones with oxygen desaturation, presented greater SpO2 variability and modulation reflected in the spectral domain than segments without OSA. Segments with OSA also showed higher heart rate and sympathetic activity through the PRV analysis relative to segments without OSA. PRV analysis was more sensitive than SpO2 analysis for identification of OSA events without oxygen desaturation. Combining SpO2 and PRV analysis enhanced OSA event detection through a multiple logistic regression model. The area under the ROC curve increased from 81% to 87%. Thus, the Phone OximeterTM might be useful to monitor sleep and identify OSA events with and without oxygen desaturation at home. PMID- 26738075 TI - Blood pressure and pulse interval coupling: A copula approach. AB - In this paper a copula approach is applied as a tool for assessing the measure of statistical dependence of parallel cardiovascular time series. Families of Archimedean copulas (Clayton, Frank and Gumbel) are applied to pulse interval, systolic and diastolic blood pressure recorded from male Wistar rats at baseline conditions, and to their isodistributional surrogates with the same marginal, but randomized joint distribution functions. The influence of time offset of the parallel time series is explored. The amount of data required for a stable working point is discussed. PMID- 26738076 TI - Complexity of cerebral blood flow velocity and arterial blood pressure in subarachnoid hemorrhage using time-frequency analysis. AB - We investigated changes of time-frequency (TF) complexity, in terms of Renyi entropy and a measure of concentration, of middle cerebral blood flow velocity (CBFV) and arterial blood pressure in relation to the development of cerebral vasospasm in 15 patients after aneurysmal subarachnoid hemorrhage. Interhemispheric differences in the period of no vasospasm and vasospasm were also compared. Results show reduced complexity of TF representations of CBFV on the side of aneurysm before vasospasm was identified. This potentially can serve as an early-warning indicator of future derangement of cerebral circulation. PMID- 26738077 TI - Recurrence quantification analysis applied to spatiotemporal pattern analysis in high-density mapping of human atrial fibrillation. AB - Spatiotemporal complexity of atrial fibrillation (AF) patterns is often quantified by annotated intracardiac contact mapping. We introduce a new approach that applies recurrence plot (RP) construction followed by recurrence quantification analysis (RQA) to epicardial atrial electrograms, recorded with a high-density grid of electrodes. In 32 patients with no history of AF (aAF, n=11), paroxysmal AF (PAF, n=12) and persistent AF (persAF, n=9), RPs were constructed using a phase space electrogram embedding dimension equal to the estimated AF cycle length. Spatial information was incorporated by 1) averaging the recurrence over all electrodes, and 2) by applying principal component analysis (PCA) to the matrix of embedded electrograms and selecting the first principal component as a representation of spatial diversity. Standard RQA parameters were computed on the constructed RPs and correlated to the number of fibrillation waves per AF cycle (NW). Averaged RP RQA parameters showed no correlation with NW. Correlations improved when applying PCA, with maximum correlation achieved between RP threshold and NW (RR1%, r=0.68, p <; 0.001) and RP determinism (DET, r=-0.64, p <; 0.001). All studied RQA parameters based on the PCA RP were able to discriminate between persAF and aAF/PAF (DET persAF 0.40 +/- 0.11 vs. 0.59 +/- 0.14/0.62 +/- 0.16, p <; 0.01). RP construction and RQA combined with PCA provide a quick and reliable tool to visualize dynamical behaviour and to assess the complexity of contact mapping patterns in AF. PMID- 26738078 TI - Cardiorespiratory Phase Synchronization in OSA subjects during wake and sleep states. AB - Cardiorespiratory Phase Synchronization (CRPS) is a manifestation of coupling between cardiac and respiratory systems complementary to Respiratory Sinus Arrhythmia. In this work, we investigated CRPS during wake and sleep stages in Polysomnographic (PSG) recordings of 30 subjects suspected from Obstructive Sleep Apnea (OSA). The population was classified into three severity groups according to the Apnea Hypopnea Index (AHI): G1 (AHI<;15), G2 (15<;=AHI<;30) and G3 (AHI>30). The synchrogram between single lead ECG and respiratory abdominal band signals from PSG was computed with the Hilbert transform technique. The different phase locking ratios (PLR) m:n were monitored throughout the night. Ratio 4:1 was the most frequent and it became more dominant as OSA severity increased. CRPS was characterized by the percentage of synchronized time (%Sync) and the average duration of synchronized epochs (AvDurSync) using three different thresholds. Globally, we observed that %Sync significantly decreased and AvDurSync slightly increased with OSA severity. A high synchronization threshold enhanced these population differences. %Sync was significantly higher in NREM than in REM sleep in G2 and G3 groups. Population differences observed during sleep did not translate to the initial wake state. Reduced CRPS could be an early marker of OSA severity during sleep, but further studies are needed to determine whether CRPS is also present during wakefulness. PMID- 26738079 TI - Dynamic response of cardiac autonomic nervous system activity to habitual exercise during gradual variation of breathing frequency. AB - The purpose of this study is to measure cardiac autonomic nervous system activity during breathing control with gradual alteration of the frequency between habitual exercise and sedentary young male subjects. In this study, to evaluate CANS activity, Tone-Entropy analysis, which is based on statistical property of acceleration between consecutive R-R intervals, was used. Sixteen healthy young male subjects (21.6+/-1.4yrs) were participated in these experiments and their R R interval sequences were recorded. The controlled breathing trials let the subjects synchronize their breathing frequency ranging 3 to 30 breathing per minute. After that, breathing frequency was gradually and reversely decreased from 30 to 3 breathing per minute. Before and after the breathing controlled trials, 5 minute voluntary breathing trials were performed. Our results showed that total CANS activities of HE group were activated more than those of SE group in the entire sections and also that, as compared with HE group, maximum of average HR in SE group was appeared at 30 breathing per minute and it is recognized that the statistically significant difference between HE and SE group was shown. In conclusion, our results suggest that efficiency of cardiac function on habitual exercise in breathing control may be quantitatively and graphically evaluated with HR and Tone-Entropy analysis without any physical stimulation. PMID- 26738080 TI - Large scale fusion of brain imaging modalities and features using Markov-style dynamics in a feature meta-space. AB - Brain imaging technology provides a way to sample various aspects of the brain albeit incompletely, providing a rich set of features crossing rest and task conditions, and an ever-growing number of imaging modalities. The conditions being studied with brain imaging data are often extremely complex and it is becoming more common for researchers to employ more than one imaging or biological data modality (e.g., genetics) in their investigations. While the field has advanced significantly in its approach to multimodal data, the vast majority of studies still ignore joint information among two or more features, modalities or tasks. We propose an intuitive framework based on Markov-style flows for understanding information exchange between features in what we are calling a feature meta-space: that is, a space consisting of an arbitrary number of individual feature spaces, where the features can have any dimension and can be drawn from any data source or modality. We present preliminary work demonstrating the ability of this new framework to identify relationships between disparate features of varying dimensionality. PMID- 26738081 TI - High-sensitive and high-efficient biochemical analysis method using a bionic electronic eye in combination with a smartphone-based colorimetric reader system. AB - Bionic electronic eye (Bionic e-Eye), a developed smartphone-based colorimetric reader system, consists of smartphone or pad (iPhone 4s or iPad 3) as detection instrument and portable accessory as illumination provider, integrating with a wide-angle lens, a piece of lowest-power electro luminescent and a custom-made dark hood. A 96-well microtiter plate (MTP) was positioned on the electro luminescent and Bionic e-Eye captures the detection images by the back camera of smartphone. Being similar to human visual system, the hue, saturation and value (HSV, also called hex cone model) color model was employed in image processing algorithm of Bionic e-Eye. Optimized system dimension was determined by the system steadiness experiment of different photograph distances. Moreover, the commercially available BCA protein assay and CCK8 cell number assay were carried out to evaluate this Bionic e-Eye. Analytical performance of Bionic e-Eye had the better precision, higher sensitivity than microtiter plate reader (MTPR) and previous smartphone-based colorimetric reader for both two assays. Also, Bionic e Eye using optical image detection had simultaneous and synchronous working mode, while MPTR using machine moving detection had asynchronous working mode in high throughput detection. Therefore, Bionic e-Eye will be an ideal point-of-care (POC) colorimetric detection device in the field of clinical application, industrial quality control, environment monitoring, and food assessment. PMID- 26738082 TI - Computer-based automatic identification of neurons in gigavoxel-sized 3D human brain images. AB - Achieving a comprehensive knowledge of the human brain cytoarchitecture is a fundamental step to understand how the nervous system works, i.e., one of the greatest challenge of 21(st) century science. The recent development of biological tissue labeling and automated microscopic imaging systems has permitted to acquire images at the micro-resolution, which produce a huge quantity of data that cannot be manually analyzed. In case of mammals brain, automatic methods to extract objective information at the microscale have been applied until now to mice, macaque and cat 3D volume images. Here we report a method to automatically localize neurons in a sample of human brain removed during a surgical procedure for the treatments of drug resistant epilepsy in a child with hemimegalencephaly, whose neurons and neurites were fluorescence labelled and finally imaged using the two-photon fluorescence microscope. The method provides the map of both parvalbuminergic neurons and all other cells nuclei with a satisfactory f-score measured using more than two thousand human labelled soma. PMID- 26738083 TI - An automated and high-throughput Photomotor Response platform for chemical screens. AB - The zebrafish (Danio rerio) is a well-established vertebrate model organism. Its embryos are used extensively in biology and medicine to perform chemical screens to identify drug candidates or to evaluate teratogenicity and embryotoxicity of substances. Behavioral readouts are increasingly used to assess the effects of compounds on the nervous system. Early stage zebrafish show characteristic behavioral features at stages between 30 and 42 hours post fertilization (hpf) when exposed to a short and bright light flash. This so-called Photomotor Response (PMR) is a reaction of the nervous system of the fish and can be used as a marker in screenings for neuroactive chemicals. To probe a broad and diverse chemical space, many different substances have to be tested and repeated observations are necessary to warrant statistical significance of the results. Although PMR-based chemical screens must use a large number of specimens, there is no sophisticated, automated high-throughput platform available which ensures minimal human intervention. Here we report a PMR platform that was developed by combining an improved automatic sample handling with a remotely controllable microscope setup and an image analysis pipeline. Using infrared illumination during automatic sample preparation, we were able to eliminate excess amounts of visible light that could potentially alter the response results. A remotely controlled microscope setup allows us to screen entire 96-well microtiter plates without human presence that could disturb the embryos. The development of custom video analysis software, including single egg detection, enables us to detect variance among treated specimens and extract easy to interpret numerical values representing the PMR motion. By testing several neuroactive compounds we validated the workflow that can be used to analyze more than one thousand zebrafish eggs on a single 96-well plate. PMID- 26738084 TI - High-throughput analysis of tissue-based biomarkers in digital pathology. AB - By simultaneously processing a large number of tissue samples, the tissue microarray (TMA) technology allows standardized screening of protein expression using immunohistochemistry thereby providing a very efficient way for tissue based biomarker analysis. Nowadays, whole slide imaging is becoming standard in digital pathology and enables image sharing, archiving and also processing. In this paper, we present methods for processing TMA images in order to correctly identify the numerous tissue samples and to register images from consecutive TMA sections. PMID- 26738085 TI - Leveraging the crowd for annotation of retinal images. AB - Medical data presents a number of challenges. It tends to be unstructured, noisy and protected. To train algorithms to understand medical images, doctors can label the condition associated with a particular image, but obtaining enough labels can be difficult. We propose an annotation approach which starts with a small pool of expertly annotated images and uses their expertise to rate the performance of crowd-sourced annotations. In this paper we demonstrate how to apply our approach for annotation of large-scale datasets of retinal images. We introduce a novel data validation procedure which is designed to cope with noisy ground-truth data and with non-consistent input from both experts and crowd workers. PMID- 26738086 TI - Wearable technology and ECG processing for fall risk assessment, prevention and detection. AB - Falls represent one of the most common causes of injury-related morbidity and mortality in later life. Subjects with cardiovascular disorders (e.g., related to autonomic dysfunctions and postural hypotension) are at higher risk of falling. Autonomic dysfunctions increasing the risk of falling in the short and mid-term could be assessed by Heart Rate Variability (HRV) extracted by electrocardiograph (ECG). We developed three trials for assessing the usefulness of ECG monitoring using wearable devices for: risk assessment of falling in the next few weeks; prevention of imminent falls due to standing hypotension; and fall detection. Statistical and data-mining methods are adopted to develop classification and regression models, validated with the cross-validation approach. The first classifier based on HRV features enabled to identify future fallers among hypertensive patients with an accuracy of 72% (sensitivity: 51.1%, specificity: 80.2%). The regression model to predict falls due to orthostatic dropdown from HRV recorded before standing achieved an overall accuracy of 80% (sensitivity: 92%, specificity: 90%). Finally, the classifier to detect simulated falls using ECG achieved an accuracy of 77.3% (sensitivity: 81.8%, specificity: 72.7%). The evidence from these three studies showed that ECG monitoring and processing could achieve satisfactory performances compared to other system for risk assessment, fall prevention and detection. This is interesting as differently from other technologies actually employed to prevent falls, ECG is recommended for many other pathologies of later life and is more accepted by senior citizens. PMID- 26738087 TI - Maintaining patients' social contacts through displaying nonverbal awareness information on mobile devices. AB - Awareness systems had been invented for supporting groups collaborating simultaneously over a network. They provide each group member with real-time information about the state of affairs on the remote locations of the other members. Awareness systems have also been observed to help remote collaborators develop the same shared sense of community that often emerges within co-located work groups, and this effect of creating or maintaining group cohesion is an important goal in itself. Purely social awareness systems can be employed by any kind of group, e.g. families, without shared work tasks. As a means of preventing loneliness they can be regarded as examples of biomedical technology. In this paper a demonstrator of an awareness-enhanced instant messaging system for elderly living alone is described along with assumptions about group processes that led to its specification. PMID- 26738088 TI - Wearable devices- from healthy lifestyle to active ageing. AB - As wearable and mobile technologies are becoming more available and can provide more information and knowledge to users, new challenges and opportunities opens for industry and healthcare organizations. The future use of wearable by health and wellbeing users, from fitness tracking, to chronic disease management and independent living will create ecosystem for the population that will be adapted to their changing needs along lifespan in health and disease. This will also drive a change in healthcare delivery models and the relationship between patient and healthcare providers. It raises challenges for the healthcare systems as well as for the industry in implementing these new technologies, data privacy and security, regulation, adaptation of the systems to the individual and the growing amount of information in clinical practice and workflows. In this paper the vision, barriers, the gaps and opportunities will be discussed. PMID- 26738089 TI - Setting the scene: Mobile and wearable technology for managing healthcare and wellbeing. AB - The growing proliferation of mobile and wearable technology (MWT) offers interesting use cases when applied to health and wellness management. Current trends towards more longer term health and wellness management coupled with global challenges around the provision of healthcare to aging populations with tighter budget constraints, create rich opportunities to exploit this new technology to maintain health and wellness. This paper provides an overview of commonly available MWT and examines how it can be used in health and wellness systems. Case studies are given from two recent research projects and the issues and challenges that arise in the use of MWT are discussed. We conclude that MWT offers some key advantages in some healthcare situations, but that care must be taken to select appropriate technology for each use. PMID- 26738090 TI - Building neuroscientific evidence and creating best practices for Active and Healthy Aging through ubiquitous exergaming and Living Labs. AB - Ageing is a major global demographic trend, which seems to be intensified. The earlier detection of risks associated with ageing, can enable earlier intervention to ameliorate their negative consequences. Many of these recent efforts are associated with the use of Information and Communication Technologies (ICTs) and the stemming from them innovations in the fight against this age related decline and frailty. Ubiquitous unobtrusive monitoring and training (recently much blended by means of exergames) has become reality due to the availability of new mobile sensors and devices and the emergence of new technologies and services. The current piece of work presents the different milestones we have achieved as best practices during the past seven years of piloting training and exergaming ICT components in an effort to support Active and Healthy Aging. Our impact verification and results validation methodologies are revisited here in an effort to outline best practices and build up neuroscientific evidence. Finally, this paper demonstrates how the construction of an Active and Healthy Aging Living Lab was materialised in an attempt to gauge evidence based research in the field of active and health aging. PMID- 26738091 TI - Smartphone-based system to improve transportation access for the cognitively impaired. AB - This project developed and evaluated a smartphone-based system to improve mobility and transportation access for the cognitively impaired. The proposed system is intended to allow the cognitively impaired to use public transportation systems, community transportation and dedicated transportation services for the disabled with greater ease and safety. Individuals with cognitive disabilities are often unable to operate an automobile, or may require a prolonged recovery period before resuming driving. Public transportation systems represent a significant means to allow these individuals to maintain independence. Yet public transportation systems can pose significant challenges to individuals with cognitive impairment. The goal of this project is to develop a system to reduce these barriers via a technological solution consisting of components developed both for the cognitively impaired user and their caregiver or family member. The first component consists of a cognitive prosthetic device featuring traditional memory cueing and reminders as well as custom location-based transportation specific functions. This cognitive mobility assistant will leverage the computing power and GPS location determination capabilities of inexpensive, powerful smart phones. The second component consists of a management application which offers caregivers the ability to configure and program the reminder and transit functions remotely via the Internet. Following completion of the prototype system a pilot human test was performed with cognitively disabled individuals and family members or caregivers to assess the usability and acceptability of both system components. PMID- 26738092 TI - Novel method to form adaptive internal impedance profiles in walkers. AB - This paper proposes a novel approach to improve walking in prosthetics, orthotics and robotics without closed loop controllers. The approach requires impedance profiles to be formed in a walker and uses state feedback to update the profiles in real-time via a simple policy. This approach is open loop and inherently copes with the challenge of uncertain environment. In application it could be used either online for a walker to adjust its impedance profiles in real-time to compensate for environmental changes, or offline to learn suitable profiles for specific environments. So far we have conducted simulations and experiments to investigate the transient and steady state gaits obtained using two simple update policies to form damping profiles in a passive dynamic walker known as the rimless wheel (RW). The damping profiles are formed in the motor that moves the RW vertically along a rail, analogous to a knee joint, and the two update equations were designed to a) control the angular velocity profile and b) minimise peak collision forces. Simulation results show that the velocity update equation works within limits and can cope with varying ground conditions. Experiment results show the angular velocity average reaching the target as well as the peak force update equation reducing peak collision forces in real-time. PMID- 26738093 TI - A novel approach to low cost, wide range motion capture system: Validation and application to human behavior analysis. AB - From new hardware arise possibilities to develop novel methods of monitoring human behavior. In this paper we present a low cost system using two RGB-D cameras in a 3m * 8m space. Using developed software, we are able to easily collect, combine, visualize, modify, and analyze data. To validate the system, we measured human behavior in a walking experiment (N = 11). The data obtained from the system showed an accurate measurement and validated our approach for Human Interaction analysis. PMID- 26738094 TI - Active catheter driven by a thermo-hydraulic actuation. AB - Catheters and flexible endoscopes are usually steered by mechanical wires that are driven from their base. Due to friction and buckling there is a need to place the driving actuator of the catheter at the catheter's tip. Such active catheter's manoeuvrability is much higher than wire-driven ones. A problem with active catheters is the difficulty to create high enough bending using micro actuators placed at the catheter's tip. Our actuation method is an attempt to overcome this difficulty by using a novel thermo-hydraulic actuation method. The magnitude of the bending torque of our actuator is created by internal hydraulic pressure in the tube and the steering direction is controlled by the thermal micro-actuator embedded in the wall of the tube. In this paper we present the modelling, optimization, design and testing of an initial prototype of such an actuator. We found that a 4 mm OD actuator made of TPU can bend to +/-12 degrees . PMID- 26738095 TI - Toward hybrid force/position control for the Cerberus epicardial robot. AB - Gene therapies have emerged as a promising treatment for congestive heart failure, yet they lack a method for minimally invasive, uniform delivery. To address this need we developed Cerberus, a minimally invasive parallel wire robot for cardiac interventions. Prior work on Cerberus was limited to controlling the device using only position feedback. In order to ensure safety for both the patient and the device, as well as to improve the performance of the device, this paper presents work on enhancing the existing system with force feedback capabilities. By modeling the statics of the system and developing a tension distribution optimization technique, existing position control schemes were modified to a hybrid force/position controller. Experimental results show that using a hybrid force-position control scheme as opposed to position decreases positioning error by 38%. PMID- 26738096 TI - A novel gastroscope intervention mechanism with circumferentially pneumatic driven clamping function. AB - Robotic assisted gastroscope delivery could solve various problems like understaffing, radiation and infection risk. The friction rollers commonly used in the few existed systems for traditional flexible endoscope, however, has potential risk of destroying scopes for non-uniform clamping. This research develops a novel gastroscope intervention mechanism (GIM) with a specially designed airbag. It evenly clamps the gastroscope with circumferential uniform pneumatic pressure. The GIM realizes axial and radial motion by means of the relay delivery mode similar to clinician's operation. The critical slipping force at different air pressure was analyzed to provide guidelines for safe intervention. Experiments were performed to evaluate the delivery accuracy and velocity and measure the critical slipping force. The results showed the axial and radial accuracy for delivery are 0.025+/-0.2mm and -0.03+/-0.25deg, respectively. The average velocity of 6.00mm.s(-1) and 75 deg.s(-1) were achieved to push/pull and twist the gastroscope. The relationship between the critical slipping force and air pressure could be fitted with a quadratic polynomial. PMID- 26738097 TI - Characterization of Corneal Indentation Hysteresis. AB - Corneal indentation is adapted for the design and development of a characterization method for corneal hysteresis behavior - Corneal Indentation Hysteresis (CIH). Fourteen porcine eyes were tested using the corneal indentation method. The CIH measured in enucleated porcine eyes showed indentation rate and intraocular pressure (IOP) dependences. The CIH increased with indentation rate at lower IOP (<; 25 mmHg) and decreased with indentation rate at higher IOP (> 25 mmHg). The CIH was linear proportional to the IOP within an individual eye. The CIH was positively correlated with the IOP, corneal in-plane tensile stress and corneal tangent modulus (E). A new method based on corneal indentation for the measurement of Corneal Indentation Hysteresis in vivo is developed. To our knowledge, this is the first study to introduce the corneal indentation hysteresis and correlate the corneal indentation hysteresis and corneal tangent modulus. PMID- 26738098 TI - Cardiorespiratory adaptation to breath-holding in air: Analysis via a cardiopulmonary simulation model. AB - Apnea via breath-holding (BH) in air induces cardiorespiratory adaptation that involves the activation of several reflex mechanisms and their complex interactions. Hence, the effects of BH in air on cardiorespiratory function can become hardly predictable and difficult to be interpreted. Particularly, the effect on heart rate is not yet completely understood because of the contradicting results of different physiological studies. In this paper we apply our previously developed cardiopulmonary model (CP Model) to a scenario of BH with a twofold intent: (1) further validating the CP Model via comparison against experimental data; (2) gaining insights into the physiological reasoning for such contradicting experimental results. Model predictions agreed with published experimental animal and human data and indicated that heart rate increases during BH in air. Changes in the balance between sympathetic and vagal effects on heart rate within the model proved to be effective in inverting directions of the heart rate changes during BH. Hence, the model suggests that intra-subject differences in such sympatho-vagal balance may be one of the reasons for the contradicting experimental results. PMID- 26738100 TI - On the roles of vascular smooth muscle contraction in cerebral blood flow autoregulation - a modeling perspective. AB - We here review existing models of vascular smooth muscle cell, endothelial cell and cell-cell communication, which have been developed to better understand vascular tone and blood flow autoregulation. In particular, we discuss models that intended to explain modulation of myogenic tone by intraluminal pressure in resistance arterioles. Modeling efforts in the recent past have witnessed a shift from empirical models to models with mechanistic details that underscore different physical aspects of vascular regulation. Future models should synthesize mechanistic interactions in a hierarchy, from molecular regulation of ion channels to whole organ blood flow control. PMID- 26738099 TI - Modeling of deep breath vasoconstriction reflex. AB - Deep breaths akin to sighs have been reported to cause peripheral vasoconstriction. Our previous simulation studies have shown that this phenomenon cannot be reproduced in existing circulatory control models without inclusion of a respiratory-vascular coupling mechanism. To better understand this "sigh vasoconstriction reflex", we investigated the effect of spontaneous and passively induced sighs as well as spontaneous breathing on peripheral vasoconstriction during wakefulness and non-rapid eye movement sleep in human subjects. We found that both spontaneous and induced sighs caused vasoconstriction during wakefulness and sleep. The coupling between respiration and vasoconstriction is also present even in an absence of deep breaths. The coupling mechanism is largely linear with increased nonlinearity during induced sighs. Since peripheral vascular resistance modulation is known to be sympathetically mediated, investigation of this coupling could potentially allow us to assess sympathetic function through non-invasive measurements and simple interventions. PMID- 26738101 TI - A simulation model to study the role of the extracranial venous drainage pathways in intracranial hemodynamics. AB - Alterations in the extracranial venous circulation due to posture changes, and/or extracranial venous obstructions in patients with vascular diseases, can have important implications on cerebral hemodynamics. A hemodynamic model for the study of cerebral venous outflow was developed to investigate the correlations between extracranial blood redistributions and changes in the intracranial environment. Flow data obtained with both magnetic resonance (MR) and Echo-Color Doppler (ECD) technique are used to validate the model. The very good agreement between simulated supine and upright flows and experimental results means that the model can correctly reproduce the main factors affecting the extracranial venous circulation. PMID- 26738102 TI - Verification and validation of physiology simulators. AB - In this paper we describe a general method to provide verification and validation of physiological simulators. We also present an application of this method and key results. PMID- 26738103 TI - Estimating a dynamic state to relate neural spiking activity to behavioral signals during cognitive tasks. AB - An important question in neuroscience is understanding the relationship between high-dimensional electrophysiological data and complex, dynamic behavioral data. One general strategy to address this problem is to define a low-dimensional representation of essential cognitive features describing this relationship. Here we describe a general state-space method to model and fit a low-dimensional cognitive state process that allows us to relate behavioral outcomes of various tasks to simultaneously recorded neural activity across multiple brain areas. In particular, we apply this model to data recorded in the lateral prefrontal cortex (PFC) and caudate nucleus of non-human primates as they perform learning and adaptation in a rule-switching task. First, we define a model for a cognitive state process related to learning, and estimate the progression of this learning state through the experiments. Next, we formulate a point process generalized linear model to relate the spiking activity of each PFC and caudate neuron to the stimated learning state. Then, we compute the posterior densities of the cognitive state using a recursive Bayesian decoding algorithm. We demonstrate that accurate decoding of a learning state is possible with a simple point process model of population spiking. Our analyses also allow us to compare decoding accuracy across neural populations in the PFC and caudate nucleus. PMID- 26738104 TI - Characterization of fear conditioning and fear extinction by analysis of electrodermal activity. AB - Electrodermal activity (EDA) is a measure of physical arousal, which is frequently measured during psychophysical tasks relevant for anxiety disorders. Recently, specific protocols and procedures have been devised in order to examine the neural mechanisms of fear conditioning and extinction. EDA reflects important responses associated with stimuli specifically administrated during these procedures. Although several previous studies have demonstrated the reproducibility of measures estimated from EDA, a mathematical framework associated with the stimulus-response experiments in question and, at the same time, including the underlying emotional state of the subject during fear conditioning and/or extinction experiments is not well studied. We here propose an ordinary differential equation model based on sudomotor nerve activity, and estimate the fear eliciting stimulus using a compressed sensing algorithm. Our results show that we are able to recover the underlying stimulus (visual cue or mild electrical shock). Moreover, relating the time-delay in the estimated stimulation to the visual cue during extinction period shows that fear level decreases as visual cues are presented without shock, suggesting that this feature might be used to estimate the fear state. These findings indicate that a mathematical model based on electrodermal responses might be critical in defining a low-dimensional representation of essential cognitive features in order to describe dynamic behavioral states. PMID- 26738105 TI - Cognitive state prediction using an EM algorithm applied to Gamma distributed data. AB - Behavioral tests are widely used to quantify features of cognitive processing. For a large class of behavioral signals, the observed variables are non-Gaussian and dynamic; classical estimation algorithms are ill-suited to modeling such data. In this research, we propose a mathematical framework to predict a cognitive state variable related to behavioral signals, which are best modeled using a Gamma distribution. The proposed algorithm combines a Gamma Smoother and EM algorithm in the prediction process. The algorithm is applied to reaction time recorded from subjects performing a Multi-Source Interference Task (MSIT) to dynamically quantify their cognitive flexibility through the course of the experiment. PMID- 26738106 TI - Package architecture and component design for an implanted neural stimulator with closed loop control. AB - An implanted neural stimulator with closed loop control requires electrodes for stimulation pulses and recording neuron activity. Our system features arrays of 64 electrodes. Each electrode can be addressed through a cross bar switch, to enable it to be used for stimulation or recording. This electrode switch, a bank of low noise amplifiers with an integrated analog to digital converter, power conditioning electronics, and a communications and control gate array are co located with the electrode array in a 14 millimeter diameter satellite package that is designed to be flush mounted in a skull burr hole. Our system features five satellite packages connected to a central hub processor-controller via ten conductor cables that terminate in a custom designed, miniaturized connector. The connector incorporates features of high reliability, military grade devices and utilizes three distinct seals to isolate the contacts from fluid permeation. The hub system is comprised of a connector header, hermetic electronics package, and rechargeable battery pack, which are mounted on and electrically interconnected by a flexible circuit board. The assembly is over molded with a compliant silicone rubber. The electronics package contains two antennas, a large coil, used for recharging the battery and a high bandwidth antenna that is used to download data and update software. The package is assembled from two machined alumina pieces, a flat base with brazed in, electrical feed through pins and a rectangular cover with rounded corners. Titanium seal rings are brazed onto these two pieces so that they can be sealed by laser welding. A third system antenna is incorporated in the flexible circuit board. It is used to communicate with an externally worn control package, which monitors the health of the system and allows both the user and clinician to control or modify various system function parameters. PMID- 26738107 TI - Neural signal processing and closed-loop control algorithm design for an implanted neural recording and stimulation system. AB - A fully autonomous intracranial device is built to continually record neural activities in different parts of the brain, process these sampled signals, decode features that correlate to behaviors and neuropsychiatric states, and use these features to deliver brain stimulation in a closed-loop fashion. In this paper, we describe the sampling and stimulation aspects of such a device. We first describe the signal processing algorithms of two unsupervised spike sorting methods. Next, we describe the LFP time-frequency analysis and feature derivation from the two spike sorting methods. Spike sorting includes a novel approach to constructing a dictionary learning algorithm in a Compressed Sensing (CS) framework. We present a joint prediction scheme to determine the class of neural spikes in the dictionary learning framework; and, the second approach is a modified OSort algorithm which is implemented in a distributed system optimized for power efficiency. Furthermore, sorted spikes and time-frequency analysis of LFP signals can be used to generate derived features (including cross-frequency coupling, spike-field coupling). We then show how these derived features can be used in the design and development of novel decode and closed-loop control algorithms that are optimized to apply deep brain stimulation based on a patient's neuropsychiatric state. For the control algorithm, we define the state vector as representative of a patient's impulsivity, avoidance, inhibition, etc. Controller parameters are optimized to apply stimulation based on the state vector's current state as well as its historical values. The overall algorithm and software design for our implantable neural recording and stimulation system uses an innovative, adaptable, and reprogrammable architecture that enables advancement of the state of-the-art in closed-loop neural control while also meeting the challenges of system power constraints and concurrent development with ongoing scientific research designed to define brain network connectivity and neural network dynamics that vary at the individual patient level and vary over time. PMID- 26738108 TI - An implantable 64-channel neural interface with reconfigurable recording and stimulation. AB - Next generation implantable medical devices will have the potential to provide more precise and effective therapies through adaptive closed-loop controllers that combine sensing and stimulation across larger numbers of electrode channels. A major challenge in the design of such devices is balancing increased functionality and channel counts with the miniaturization required for implantation within small anatomical spaces. Customized therapies will require adaptive systems capable of tuning which channels are sensed and stimulated to overcome variability in patient-specific needs, surgical placement of electrodes, and chronic physiological responses. In order to address these challenges, we have designed a miniaturized implantable fully-reconfigurable front-end system that is integrated into the distal end of an 8-wire lead, enabling up to 64 electrodes to be dynamically configured for sensing and stimulation. Full reconfigurability is enabled by two custom 32*2 cross-point switch (CPS) matrix ASICs which can route any electrode to either an amplifier with reprogrammable bandwidth and integrated ADC or to one of two independent stimulation channels that can be driven through the lead. The 8-wire circuit includes a digital interface for robust communication as well as a charge-balanced powering scheme for enhanced safety. The system is encased in a hermetic package designed to fit within a 14 mm bur-hole in the skull for neuromodulation of the brain, but could easily be adapted to enhance therapies across a broad spectrum of applications. PMID- 26738109 TI - Fast and effective estimation of narrowband components for bioelectrical signals. AB - In this paper we propose a novel approach for estimating narrowband components from bioelectrical signals. The approach is based on the notion of modulated quadratic variation, introduced as a measure of variability for narrowband signals. The algorithm is the closed-form solution to a constrained convex optimization problem, where narrowband components are estimated tracking the slow variations around a central frequency in the measured signal. The approach is general and can be applied to any bioelectrical signal, either for diagnostic or denoising purposes. In this paper we assess its performance on ECG and EMG signals. Numerical results show its effectiveness in removing narrowband artifacts, such as power-line interference, while preserving signal morphology. It greatly outperforms conventional notch filtering. Moreover, it is also very fast, as its computational complexity is linear in the size of the vector to process. PMID- 26738110 TI - Semi-supervised segmentation of EEG data in BCI systems. AB - This work investigates the use of a semi-supervised, autoregressive switching multiple model (AR-SMM) framework for the segmentation of EEG data applied to brain computer interface (BCI) systems. This gives the possibility of identifying and learning novel modes within the data, giving insight on the changing dynamics of the EEG data and possibly also offering a solution for shorter training periods in BCIs. Furthermore it is shown that the semi-supervised model allocation process is robust to different starting positions and gives consistent results. PMID- 26738111 TI - From molecular model to sparse representation of chromatographic signals with an unknown number of peaks. AB - Analysis of a fluid mixture using a chromatographic system is a standard technique for many biomedical applications such as in-vitro diagnostic of body fluids or air and water quality assessment. The analysis is often dedicated towards a set of molecules or biomarkers. However, due to the fluid complexity, the number of mixture components is often larger than the list of targeted molecules. In order to get an analysis as exhaustive as possible and also to take into account possible interferences, it is important to identify and to quantify all the components that are included in the chromatographic signal. Thus the signal processing aims to reconstruct a list of an unknown number of components and their relative concentrations. We address this question as a problem of sparse representation of a chromatographic signal. The innovative representation is based on a stochastic forward model describing the transport of elementary molecules in the chromatography column as a molecular random walk. We investigate three methods: two probabilistic Bayesian approaches, one parametric and one non parametric, and a determinist approach based on a parsimonious decomposition on a dictionary basis. We examine the performances of these 3 approaches on an experimental case dedicated to the analysis of mixtures of the micro-pollutants Polycyclic Aromatic Hydrocarbons (PAH) in a methanol solution in two cases of high and low signal to noise ratio (SNR). PMID- 26738112 TI - A parametric Probabilistic Context-Free Grammar for food intake analysis based on continuous meal weight measurements. AB - Monitoring and modification of eating behaviour through continuous meal weight measurements has been successfully applied in clinical practice to treat obesity and eating disorders. For this purpose, the Mandometer, a plate scale, along with video recordings of subjects during the course of single meals, has been used to assist clinicians in measuring relevant food intake parameters. In this work, we present a novel algorithm for automatically constructing a subject's food intake curve using only the Mandometer weight measurements. This eliminates the need for direct clinical observation or video recordings, thus significantly reducing the manual effort required for analysis. The proposed algorithm aims at identifying specific meal related events (e.g. bites, food additions, artifacts), by applying an adaptive pre-processing stage using Delta coefficients, followed by event detection based on a parametric Probabilistic Context-Free Grammar on the derivative of the recorded sequence. Experimental results on a dataset of 114 meals from individuals suffering from obesity or eating disorders, as well as from individuals with normal BMI, demonstrate the effectiveness of the proposed approach. PMID- 26738113 TI - Accurate measurement of respiratory airflow waveforms using depth data. AB - Respiratory disorders are a very common and growing health problem. Signal waveforms of respiratory airflow and volume may indicate pathological signs of several diseases and, thus, it would be important to measure them accurately. Currently, devices used in respiration measurements are mostly obtrusive in nature interfering with the natural respiration patterns. We used a depth camera for the continuous measurement of respiratory function without contact on a subject. We propose a novel calibration method which enables accurate estimates of the respiratory airflow waveforms from the depth camera data. Eight subjects were measured with the depth camera and spirometer at the same time using different breathing styles. Results show that not only the respiratory volume and respiratory rate (RR) can be computed precisely from the estimated respiratory airflow, but also the respiratory airflow waveforms are very accurate. This offers interesting opportunities, e.g. in pulmonary and critical care medicine, when objective measurements are required. PMID- 26738114 TI - A robust heartbeat detector not depending on ECG sampling rate. AB - All ECG processing algorithms start with heart beat detection, making the reliability of this step crucial for the quality of the whole interpretation. This paper presents a regression-based QRS detector that is robust to singular outliers and high frequency noise present in real signals. Our algorithm consists of three steps: best fitted segments are determined in sliding windows of two different lengths, then a function of running angle between segments is calculated, and finally based on all such functions a probability of heart beat occurrence is derived and evaluated. The algorithm does not use signal filtering, and the moving window length and step do not rely on the sampling interval. Consequently, it allows for missing data and works equally well for a wide range of sampling frequencies. PMID- 26738115 TI - Transfer entropy analysis of maternal and fetal heart rate coupling. AB - Although evidence of the short term relationship between maternal and fetal heart rates has been found in previous model-based studies, knowledge about the mechanism and patterns of the coupling during gestation is still limited. In this study, a model-free method based on Transfer Entropy (TE) was applied to quantify the maternal-fetal heart rate couplings in both directions. Furthermore, analysis of the lag at which TE was maximum and its changes throughout gestation, provided more information about the mechanism of coupling and its latency. Experimental results based on fetal electrocardiograms (fECGs) and maternal ECG showed the evidence of coupling for 62 out of 65 healthy mothers and fetuses in each direction, by statistically validating against the surrogate pairs. The fetuses were divided into three gestational age groups: early (16-25 weeks), mid (26-31 weeks) and late (32-41 weeks) gestation. The maximum TE from maternal to fetal heart rate significantly increased from early to mid gestation, while the coupling delay on both directions decreased significantly from mid to late gestation. These changes occur concomitant with the maturation of the fetal sensory and autonomic nervous systems with advancing gestational age. In conclusion, the application of TE with delays revealed detailed information about the changes in fetal-maternal heart rate coupling strength and latency throughout gestation, which could provide novel clinical markers of fetal development and well-being. PMID- 26738116 TI - Use of multiscale entropy to facilitate artifact detection in electroencephalographic signals. AB - Electroencephalographic (EEG) signals present a myriad of challenges to analysis, beginning with the detection of artifacts. Prior approaches to noise detection have utilized multiple techniques, including visual methods, independent component analysis and wavelets. However, no single method is broadly accepted, inviting alternative ways to address this problem. Here, we introduce a novel approach based on a statistical physics method, multiscale entropy (MSE) analysis, which quantifies the complexity of a signal. We postulate that noise corrupted EEG signals have lower information content, and, therefore, reduced complexity compared with their noise free counterparts. We test the new method on an open-access database of EEG signals with and without added artifacts due to electrode motion. PMID- 26738117 TI - Effect of the average delay and mean connectivity of the Kuramoto model on the complexity of the output electroencephalograms. AB - Cognitive functions result from the interplay of distributed brain areas operating in large-scale networks. These networks can be modelled with a number of parameters that represent their underlying dynamics. One particularly fruitful model to simulate key aspects of the large-scale brain networks is the Kuramoto model, which simulates the phase evolution of several weakly coupled oscillators that represent the mean oscillatory behavior of different cortical regions. Here, we inspected the dependency of two widespread nonlinear complexity markers, Sample Entropy (SampEn) and Lempel-Ziv Complexity (LZC), on EEG activity generated with a Kuramoto phase model where the time delay and connectivity strength among oscillators varied. We also added different levels of noise to the electroencephalogram (EEG) signals. Our results indicated that both complexity metrics reflected the changes in the delays and global synchrony levels, but we found that SampEn was slightly more sensitive to the state transition and its results were less affected by the presence of noise. These results help in the effort to understand the dynamics of EEG recordings and their relationship to large-scale networks. PMID- 26738118 TI - Effect of data length and bin numbers on distribution entropy (DistEn) measurement in analyzing healthy aging. AB - Complexity analysis of a given time series is executed using various measures of irregularity, the most commonly used being Approximate entropy (ApEn), Sample entropy (SampEn) and Fuzzy entropy (FuzzyEn). However, the dependence of these measures on the critical parameter of tolerance 'r' leads to precarious results, owing to random selections of r. Attempts to eliminate the use of r in entropy calculations introduced a new measure of entropy namely distribution entropy (DistEn) based on the empirical probability distribution function (ePDF). DistEn completely avoids the use of a variance dependent parameter like r and replaces it by a parameter M, which corresponds to the number of bins used in the histogram to calculate it. When tested for synthetic data, M has been observed to produce a minimal effect on DistEn as compared to the effect of r on other entropy measures. Also, DistEn is said to be relatively stable with data length (N) variations, as far as synthetic data is concerned. However, these claims have not been analyzed for physiological data. Our study evaluates the effect of data length N and bin number M on the performance of DistEn using both synthetic and physiologic time series data. Synthetic logistic data of 'Periodic' and 'Chaotic' levels of complexity and 40 RR interval time series belonging to two groups of healthy aging population (young and elderly) have been used for the analysis. The stability and consistency of DistEn as a complexity measure as well as a classifier have been studied. Experiments prove that the parameters N and M are more influential in deciding the efficacy of DistEn performance in the case of physiologic data than synthetic data. Therefore, a generalized random selection of M for a given data length N may not always be an appropriate combination to yield good performance of DistEn for physiologic data. PMID- 26738119 TI - Analysis of biceps brachii sEMG signal using Multiscale Fuzzy Approximate Entropy. AB - In this work, an attempt has been made to differentiate sEMG signals under muscle fatigue and non-fatigue conditions using multiscale features. Signals are recorded from biceps brachii muscle of 50 normal adults during repetitive dynamic contractions. After preprocessing, the signal is divided into six segments, out of which first and last segments are considered for this analysis. Fuzzy Approximate Entropy (fApEn) is computed for each subject in the time scales ranging from 1 to 10. Features such as median, low scale median and high scale median are extracted from Multiscale Fuzzy Approximate Entropy (MSfApEn) and used for further analysis. The results show an increase in amplitude of the sEMG signals under fatigue condition. The MSfApEn values are higher in the case of nonfatigue indicating more complexity. The features extracted for the series are effective in differentiating the two conditions. The statistical t test performed indicated high statistical significance (p-value <;<;0.001) It appears that this method of analysis can be used for clinical evaluation of muscles. PMID- 26738120 TI - Instantaneous transfer entropy for the study of cardio-respiratory dynamics. AB - Measures of transfer entropy have been proposed to quantify the directional coupling and strength between two complex physiological variables. Particular attention has been given to nonlinear interactions within cardiovascular and respiratory dynamics as influenced by the autonomic nervous system. However, standard transfer entropy estimates have shown major limitations in dealing with issues concerning stochastic system modeling, limited observations in time, and the assumption of stationarity of the considered physiological variables. Moreover, standard estimates are unable to track time-varying changes in nonlinear coupling with high resolution in time. Here, we propose a novel definition of transfer entropy linked to inhomogeneous point-process theory. Heartbeat and respiratory dynamics are characterized through discrete time series, and modeled through probability density functions (PDFs) which characterize and predict the time until the occurrence of the next physiological event as a function of the past history. As the derived measures of entropy are instantaneously defined through continuos PDFs, a novel index (the Instantaneous point-process Transfer Entropy, ipT ransfEn) is able to provide instantaneous tracking of the information transfer. The new measure is tested on experimental data gathered from 16 healthy subjects undergoing postural changes, showing fast tracking of the tilting events and low variability during the standing phase. PMID- 26738121 TI - Circular particle detection using sectored ring mask for synchrotron PCXI images. AB - Cystic Fibrosis (CF) is a genetic disorder that compromises the respiratory function and the ability of the mucociliary transit (MCT) system. One of the most recent researches introduced a noble method to investigate the progress of the treatment, in which small particles with mostly circular shape injected to the respiratory system and the images were taken using Synchrotron X-ray beam. Since the small particles flow through the respiratory system of the body, the direct observation of MCT measurement will help to understand the progress of the treatment. Identifying the particle is the critical step towards the automatic analysis of the image. However, the objects of interests are usually very small, not perfect circular shape and slightly overlapped from each other with lots of noise due to radiation. This paper proposes a robust and effective detection method of such particles using sectored ring mask (SRM) with gradient descent method. The proposed method extracts strong edges of the particles and the edge line gradients and circle fitting algorithm will filter out invalid edges, resulting in clear particle edge detection. The proposed method has validated through experimental study and presented robust detection rates of 91.9% precision and 89.0% recall. PMID- 26738122 TI - Feasibility assessment of CT-based thermometry for temperature monitoring during thermal procedure: Influence of ROI size and scan setting on metrological properties. AB - Computed tomography (CT) thermometry belongs to the wide class of non-invasive temperature monitoring techniques, which includes ultrasound and Magnetic Resonance thermometry. Non-invasive techniques are particularly attractive to be used in hyperthermal procedures for their ability to produce a three-dimensional temperature map and because they overcome the risks related to the insertion of sensing elements. PMID- 26738123 TI - Mooney-Rivlin biomechanical modeling of lung with Inhomogeneous material. AB - In this study, the Mooney-Rivlin material with hyperelastic strain energy was proposed for biomechanical modeling of the lung. We modeled the lung as an inhomogeneous Mooney-Rivlin material with uncoupled deviatoric and volumetric behavior. The proposed method was evaluated on the lungs of eight lung cancer patients. For each patient, the lung was segmented from the 4D-CT images and tetrahedral volume mesh of the lung in phase 50% was created by using the adaptive mesh generation toolkit. The demons deformable registration algorithm was used to extract the displacement vector fields (DVFs). The Jacobian of the deformation gradient was calculated from DVFs, and the lung strain energy function was optimized to improve the tumor center of mass (TCM) motion simulation accuracy between respiratory phase 50% and 0%. The average TCM motion simulation error for the proposed strategy is 1.95 mm for eight patients. We observed 13% improvement in the TCM position prediction compared with the homogeneous Mooney-Rivlin modeling. PMID- 26738124 TI - Robust catheter identification and tracking in X-ray angiographic sequences. AB - Coronary artery disease (CAD) is one of the major causes of death worldwide. Today X-ray angiography is a standard method for CAD diagnosis. Usually, the quality of these images is not good enough. Noise, camera and heart motions, non uniform illumination and even the presence of catheter are sources of quality degradation. The existence of catheter can produce difficulties in vessel extraction methods because catheter is structurally similar to arteries. In this paper we propose a fully automatic method for catheter detection and tracking during the whole angiography sequence. In this method with a vesselness map, we smooth each frame using guided filter. The catheter is detected in the first frame using Hough transform. We then fit a second order polynomial on the catheter and accurately track it throughout the sequence. Our method is tested on 25 X-ray angiography sequences where a precision of 0.9597 is achieved. PMID- 26738125 TI - Cone-Beam Computed Tomography contrast validation of an artificial periodontal phantom for use in endodontics. AB - Validation of image processing techniques such as endodontic segmentations in cone-beam computed tomography (CBCT) is a challenging issue because of the lack of ground truth in in vivo experiments. The purpose of our study was to design an artificial surrounding tissues phantom able to provide CBCT image quality of real extracted teeth, similar to in vivo conditions. Note that these extracted teeth could be previously scanned using micro computed tomography (MUCT) to access true quantitative measurements of the root canal anatomy. Different design settings are assessed in our study by comparison to in vivo images, in terms of the contrast-to-noise ratio (CNR) obtained between different anatomical structures. Concerning the root canal and the dentine, the best design setup allowed our phantom to provide a CNR difference of only 3% compared to clinical cases. PMID- 26738126 TI - 3D Riesz-wavelet based Covariance descriptors for texture classification of lung nodule tissue in CT. AB - In this paper we present a novel technique for characterizing and classifying 3D textured volumes belonging to different lung tissue types in 3D CT images. We build a volume-based 3D descriptor, robust to changes of size, rigid spatial transformations and texture variability, thanks to the integration of Riesz wavelet features within a Covariance-based descriptor formulation. 3D Riesz features characterize the morphology of tissue density due to their response to changes in intensity in CT images. These features are encoded in a Covariance based descriptor formulation: this provides a compact and flexible representation thanks to the use of feature variations rather than dense features themselves and adds robustness to spatial changes. Furthermore, the particular symmetric definite positive matrix form of these descriptors causes them to lay in a Riemannian manifold. Thus, descriptors can be compared with analytical measures, and accurate techniques from machine learning and clustering can be adapted to their spatial domain. Additionally we present a classification model following a "Bag of Covariance Descriptors" paradigm in order to distinguish three different nodule tissue types in CT: solid, ground-glass opacity, and healthy lung. The method is evaluated on top of an acquired dataset of 95 patients with manually delineated ground truth by radiation oncology specialists in 3D, and quantitative sensitivity and specificity values are presented. PMID- 26738127 TI - Comparative analysis of different hip implants within a realistic human model located inside a 1.5T MRI whole body RF coil. AB - Temperature rise in surrounding tissues of a large orthopedic metallic implant subject to MRI is a significant point of concern today. Numerical electromagnetic and thermal modeling offers a way to model this complex problem with a sufficient degree of accuracy. We developed a workflow for realistic implant modeling, which includes an MRI coil, a multi-tissue human model, and accurately registered hip implants. We also obtained differences in the power loss density rises generated due to the presence of three hip implants placed in a phantom or a realistic human model, located inside a 1.5 T coil. PMID- 26738128 TI - Quantification of errors in cerebral blood flow measurements due to dispersion in arterial spin labelling. AB - The accuracy of cerebral blood flow (CBF) measurements using arterial spin labelling (ASL) is particularly affected by dispersion. In spite of this, however, the current recommended implementation of ASL - the white paper (WP) - does not account for dispersion, which leads to the introduction of errors in CBF. In fact, these errors are also likely to vary with the arterial transit time (ATT), which is the transport time from the labelling region to the tissue. Using pseudo-continuous ASL, this study assesses a variety of dispersion models in comparison with the WP quantification formula, enabling the errors introduced by the WP to be quantified. In particular, this study shows that the WP quantification only holds for ATTs below 1.25s - and that this ATT value reduces further as dispersion occurs. The levels of dispersion beyond which the WP introduces significant error are also quantified, such that provided the dispersion levels fall below the thresholds determined in this study, the WP can still measure CBF with reasonable accuracy. PMID- 26738129 TI - Tag removal in cardiac tagged MRI images using coupled dictionary learning. AB - Tagged Magnetic Resonance Imaging (tMRI) is considered to be the gold standard for quantitative assessment of the cardiac local functions. However, the tagging patterns and low myocardium-to-blood-pool contrast of tagged images bring great challenges to cardiac image processing and analysis tasks such as myocardium segmentation and tracking. Hence, there has been growing interest in techniques for removing tagging lines. In this work, a method for removing tagging patterns in tagged MR images using a coupled dictionary learning (CDL) model is proposed. In this model, identical sparse representations are assumed for image patches in the tagged MRI and corresponding cine MRI image spaces. First, we learn a dictionary for the tagged MRI image space. Then, we compute a dictionary for the cine MRI image space so that corresponding tagged and cine patches have the same sparse codes in terms of their respective dictionaries. Finally, in order to produce the de-tagged (cine version) of a test tagged image, the sparse codes of the tagged patches and the trained cine dictionary are used together to construct the de-tagged patches. We have tested this tag removal method on a dataset of tagged cardiac MR images. Our experimental results compared favorably with a recently proposed tag removal method that removes tags in the frequency domain using an optimal band-stop filter of harmonic peaks. PMID- 26738130 TI - Mapping of arterial location for the design of automated identification and analysis algorithms in whole body MRA. AB - Technological and medical advances have led to the realisation of full body imaging, with systemic diagnostic approaches becoming increasingly more prevalent. In the imaging of atherosclerotic disease, contrast -enhanced whole body MRA has been demonstrated to enable detection of stenosis with a high sensitivity and specificity. Characterization of the systemic cardiovascular disease burden has significant prognostic value. A whole-body acquisition does however generate a large volume of three-dimensional data and as such there are expected to be significant advantages in developing automated techniques for the analysis of these images. Improved radiological workflow, reduced analysis time and increased analytical standardization are expected to be among the benefits offered by this approach. As part of a process of automated software development this study aimed to collect and validate arterial location ground truth. The data will be used to inform the development of semi-automated vascular identity tools, and allow the potential for the further development of semi-automated anatomically informed cardiovascular disease analysis and reporting. PMID- 26738131 TI - Investigation of the performance of variable-density Z-spectrum acquisition scheme in MR chemical exchange saturation transfer effect quantification. AB - Chemical exchange saturation transfer (CEST) MRI emerges as a powerful imaging method to probe chemical exchange between bulk water and labile protons. Conventional CEST imaging needs detailed Z-spectrum acquisition, even at frequencies with limited information for CEST parameter quantification, which harms imaging efficiency and is not favorable in practical applications. In this study, a variable-density Z-spectrum acquisition scheme was proposed. Data with saturation frequencies close to water, labile protons and their negative frequency offset was densely sampled, while the remaining part was sparsely acquired. The accuracy of the proposed method in CEST ratio measurement was investigated with numerical simulation. Compared to the conventionally evenly distributed Z-spectrum acquisition method, the proposed scheme showed significant improvement of CEST ratio characterization with existence of noise and static magnetic field inhomogeneity. With the additional advantage of easy implementation, the developed Z-spectrum acquisition scheme provides a useful framework for accurate CEST parameter quantification without compromising the imaging time. PMID- 26738132 TI - Automatic cerebral microbleeds detection from MR images via Independent Subspace Analysis based hierarchical features. AB - With the development of susceptibility weighted imaging (SWI) technology, cerebral microbleed (CMB) detection is increasingly essential in cerebrovascular diseases diagnosis and cognitive impairment assessment. Clinical CMB detection is based on manual rating which is subjective and time-consuming with limited reproducibility. In this paper, we propose a computer-aided system for automatic detection of CMBs from brain SWI images. Our approach detects the CMBs within three stages: (i) candidates screening based on intensity values (ii) compact 3D hierarchical features extraction via a stacked convolutional Independent Subspace Analysis (ISA) network (iii) false positive candidates removal with a support vector machine (SVM) classifier based on the learned representation features from ISA. Experimental results on 19 subjects (161 CMBs) achieve a high sensitivity of 89.44% with an average of 7.7 and 0.9 false positives per subject and per CMB, respectively, which validate the efficacy of our approach. PMID- 26738133 TI - 2-DOF auto-calibration for a 3D endoscope system based on active stereo. AB - For endoscopic medical treatment, measuring the size and shape of lesions, such as tumors, is important. We are developing a 3D endoscope system to measure the shape and size of living tissues based on active stereo. In previous works, our group attached a pattern projector outside the endoscope head. Since this increased the diameter of the endoscope, the burden and the risks of the patients would increase. In this paper, we set the pattern projector inside the instrument channel of the endoscope instead of mounting it outside, so that it can be deployed whenever required. This does not increase the size of the endoscope and facilitates the measuring process. However, since the projector is not physically fixed to the endoscope anymore prior to the operation, we propose an "auto calibration" technique where extrinsic parameters are calibrated intra operatively from a point marker on the projector observed simultaneously on the target surface. In the experiment, we show that the external parameters were successfully calibrated to obtain 3D reconstructions properly with the overall systems. The accuracy of the auto-calibration was validated by confirming that the epipolar constraints were kept, and a 3D reconstruction of a human tissue was demonstrated. PMID- 26738134 TI - A fiberoptic sensor for tissue carbon dioxide monitoring. AB - We present a new fiberoptic carbon dioxide sensor for transcutaneous and mucosa (indwelling) blood gas monitoring. The sensor is based on optical fluorescence of molecules sensitive to pH changes associated with dissolved CO2. A three layer chemical coating was dip-coated onto the distal tip of an optical fiber (600MUm core radius). It contained the 50mg/ml 'polym H7', a coating polymer bonded to a fluorescence indicator dye, along with 125mg/ml of the transfer agent tetraoctylammonium hydroxide (TONOH). Light from a blue (460 nm) LED was launched into the fiber to excite the sensing film. The sensing film fluoresced green (530 nm), the intensity of which decreased in the presence of CO2. The sensor was tested in vitro, finding a correlation between change in fluorescence (in AU) and aqueous CO2 concentration with a minimum detection threshold of 40%. The sensor is being developed for medical applications where its small size and ability to continuously monitor the partial pressure of CO2 (PCO2) will make it an extremely useful diagnostic tool. PMID- 26738135 TI - Development of NIRS probe based on LED sensing that enables multimodal integration. AB - We propose LED sensing which provides the miniaturization and symmetrization for NIRS sensor system. In order to make it into practical application, the spectral responses of LEDs were investigated and then formula for calculating changes in hemoglobin concentrations were established. In blood phantom experiment, temporal changes in hemoglobin concentration were observed by CW-NIRS using LED sensing. PMID- 26738136 TI - Real-time biochemical sensor based on Raman scattering with CMOS contact imaging. AB - This work presents a biochemical sensor based on Raman scattering with Complementary metal-oxide-semiconductor (CMOS) contact imaging. This biochemical optical sensor is designed for detecting the concentration of solutions. The system is built with a laser diode, an optical filter, a sample holder and a commercial CMOS sensor. The output of the system is analyzed by an image processing program. The system provides instant measurements with a resolution of 0.2 to 0.4 Mol. This low cost and easy-operated small scale system is useful in chemical, biomedical and environmental labs for quantitative bio-chemical concentration detection with results reported comparable to a highly cost commercial spectrometer. PMID- 26738137 TI - Investigation of photoplethysmography and arterial blood oxygen saturation from the ear-canal and the finger under conditions of artificially induced hypothermia. AB - Pulse oximeters relay on the technique of photoplethysmography (PPG) to estimate arterial oxygen saturation (SpO2). In conditions of poor peripheral perfusion such as hypotension, hypothermia, and vasoconstriction, pulse oximeters become inaccurate or provide no reading. This is due to the poor quality of the PPG signals detected at that instance. In order to overcome this problem, the ear canal has been proposed as a alternative measurement site for measuring reliable SpO2. Hence, an ear canal PPG sensor was developed along with a PPG processing system. The performance of the sensor was evaluated by measuring the red and infrared PPGs and SpO2 from 10 healthy volunteers undergoing artificially induced hypothermia. The results from the ear canal sensor were compared with simultaneously acquired results from the finger. Hypothermia was induced by exposing the volunteers to cold temperatures of 10 +/- 1 degrees C. The results acquired suggest that the ear canal pulse oximeter endures more in estimating SpO2 values accurately when compared with the more common finger pulse oximeter. PMID- 26738138 TI - Organic FET-based DNA hybridization sensor with sub-picomolar sensitivity. AB - In this paper, a novel approach for DNA hybridization detection by means of organic field-effect transistors-based biosensors (bioFETs) is proposed. The reported device, namely Organic Charge-Modulated FET (OCMFET), is conceived for overcoming the main limitations of bioFETs, related to design, materials and measurement conditions. In particular, record performances in terms of sensitivity and selectivity will be reported. Moreover, as innovative features among bioFETs, the detection ability of the OCMFET at relatively high ionic strengths will be carefully discussed, unravelling the interactions between the bioreceptors characteristics at the nano-scale and the device polarization. PMID- 26738139 TI - An electrochemical biosensor based on gold microspheres and nanoporous gold for real-time detection of superoxide anion in skeletal muscle tissue. AB - Superoxide anion (SOA) as a member of reactive oxygen species (ROS) group is involved in various physiological and pathological states. For instance, generation of SOA is known to increase with skeletal muscle contractile activity and fatigue. It is therefore important to selectively detect and accurately quantify the release of SOA within both physiological and pathological levels. We report fabrication and characterization of a cytochrome-c functionalized SOA biosensor built on commercially available miniaturized screen-printed electrodes made of gold microspheres. The device was first tested and calibrated in a xanthine/xanthine oxidase (XOD) system and then employed to detect SOA release from C2C12 myoblasts and myotubes upon stimulation with PMA. PMID- 26738140 TI - Measuring the mechanical efficiency of a working cardiac muscle sample at body temperature using a flow-through calorimeter. AB - We have developed a new 'work-loop calorimeter' that is capable of measuring, simultaneously, the work-done and heat production of isolated cardiac muscle samples at body temperature. Through the innovative use of thermoelectric modules as temperature sensors, the development of a low-noise fluid-flow system, and implementation of precise temperature control, the heat resolution of this device is 10 nW, an improvement by a factor of ten over previous designs. These advances have allowed us to conduct the first flow-through measurements of work output and heat dissipation from cardiac tissue at body temperature. The mechanical efficiency is found to vary with peak stress, and reaches a peak value of approximately 15 %, a figure similar to that observed in cardiac muscle at lower temperatures. PMID- 26738141 TI - A magnetic force sensor on a catheter tip for minimally invasive surgery. AB - This paper presents a magnetically guided catheter for minimally invasive surgery (MIS) with a magnetic force sensing tip. The force sensing element utilizes a magnetic Hall sensor and a miniature permanent magnet mounted on a flexible encapsulation acting as the sensing membrane. It is capable of high sensitivity and robust force measurements suitable for in-vivo applications. A second larger magnet placed on the catheter allows the catheter to be guided by applying magnetic fields. Precise orientation control can be achieved with an external magnetic manipulation system. The proposed device can be used in many applications of minimally invasive surgery (MIS) to detect forces applied on tissue during procedures or to characterize different types of tissue for diagnosis. PMID- 26738142 TI - Validation of non-invasive monitoring device to evaluate sleep quality. AB - This paper presents the validation of a noninvasive sleep monitoring device and sleep quality evaluation. The system is based on an array of pressure sensors positioned on the bed that can measure relevant parameters to estimate sleep quality. This device can measure time in bed (TB), body movements (BM), the thorax expansion, periods out of bed (POB) and apnea events. We compare the results of the unobtrusive pressure sensor array with traditional polysomnography (PSG). The algorithms developed for the device provide a very good detection of all the parameters required to estimate sleep quality as compared to the gold standard data for a study of 30 patients. For the periods out of bed it presents a sensibility (Se) and specificity (Sp) of 100%. To grade the severity of sleep apnea we compare the number of events per hour or apnea-hypopnea index (AHI) obtained by the device and the PSG; obtaining a Se of 94% and a Sp of 61%. These results validate the use of the device for screening of sleep apnea disease. PMID- 26738143 TI - NIR photoacoustic spectroscopy for non-invasive glucose measurement. AB - The use of near infra red (NIR) photoacoustic spectroscopy (PAS) for continuous non-invasive glucose measurement is outlined in the paper. A photoacoustic (PA) measurement apparatus was constructed and PA measurements were made on glucose solutions at multiple NIR excitation wavelengths. A variety of time and frequency domain features, including amplitude and area based features, were extracted from the PA measurements. These features were observed to be proportional to the glucose concentration of the sample. PA measurements from samples of whole blood at different glucose concentrations showed similar results. Subsequently, in vivo PA measurements made on a cohort of 30 volunteers were calibrated using a quadratic fit, and the results were compared to reference glucose concentrations made using a regular blood glucose meter. A comparison of 196 measurement pairs of predicted and reference glucose concentrations using a Clarke Error Grid gave a point distribution of 87.24% and 12.76% over zones A and B of the grid, with no measurement pairs falling in unacceptable zones C-E of the error grid. The predicted measurements had a mean absolute difference (MAD) of 12.57 +/- 13.90 mg/dl and a mean absolute relative difference (MARD) of 9.61% +/- 10.55%. This is an improvement over previous results obtained using PAS and other non-invasive techniques, validating the potential of PAS for continuous noninvasive glucose monitoring. PMID- 26738144 TI - An analysis on driver drowsiness based on reaction time and EEG band power. AB - Falling asleep during driving is a serious problem that has resulted in fatal accidents worldwide. Thus, there is a need to detect driver drowsiness to counter it. This study analyzes the changes in the electroencephalography (EEG) collected from 4 subjects driving under monotonous road conditions using a driving simulator. The drowsiness level of the subjects is inferred from the time taken to react to events. The results from the analysis of the reaction time shows that drowsiness occurs in cycles, which correspond to short sleep cycles known as 'microsleeps'. The results from a time-frequency analysis of the four frequency bands' power reveals differences between trials with fast and slow reaction times; greater beta band power is present in all subjects, greater alpha power in 2 subjects, greater theta power in 2 subjects, and greater delta power in 3 subjects, for fast reaction trials. Overall, this study shows that reaction time can be used to infer the drowsiness, and subject-specific changes in the EEG band power may be used to infer drowsiness. Thus the study shows a promising prospect of developing Brain-Computer Interface to detect driver drowsiness. PMID- 26738145 TI - Fundamental study of functional changes to female brain induced by pregnancy and childbirth. AB - In this study, we investigated variations in a women's cognitive function during a time of pregnancy and childbearing. Volunteers were composed of 114 healthy women ranging in age from 23-43 years with an average age of 31.8 years (SD=4.3). Further, 79 were pregnant and 35 were not pregnant. All the pregnant women were expecting their first child and continued with the cognitive function analysis after their childbearing was concluded. We instructed the pregnant women to carry out five kinds of tests: simple reaction, SR; choice reaction, CR; working memory, WM; one card learning, OC; and divided attention, DA using card games through a cognitive function test called "CogHealth", and compared them to a nonpregnant group. In the results of the four measurement tasks (SR, CR, WM, and DA), there were no significant differences across the three groups in the responses with the tasks. However, the response times relating to the OC learning in the postnatal women were significantly smaller, as contrasted with the times for the pregnant and the nonpregnant women (F(2,144)=4.248, P <; 0.05). Furthermore, we compared their cognitive functions between pregnant and postnatal states in corresponding volunteers in the responses with the same tasks. We also demonstrated the fact that postnatal women responded more quickly to tasks in the OC (t(32)=2.95, P <; 0.01) and the WM (t(32)=3.03, P <; 0.01) categories than responses to performing the tasks during their pregnancy. Our findings support the idea that the functions of pregnant/postnatal women are not failing, or rather postnatal women are more responsive in their reaction times with their memories by 2.7-6.2%, than the responses in both pregnant and nonpregnant women. PMID- 26738146 TI - The first impression is what matters: a neuroaesthetic study of the cerebral perception and appreciation of paintings by Titian. AB - In this paper we measured the neuroelectrical and the eye-movements activities in a group of 27 healthy subjects during their visit of a fine arts gallery in which a series of masterpieces of the Italian painter Tiziano Vecellio (also known as Titian, 1488-1576) were shown. The pictures chosen for the visit were 10 portraits and 10 of religious subjects. Each picture was observed for a minute. A mobile EEG device with an eye-tracker was used for this experiment. Evaluation of the appreciation of the pictures was performed by using the neuroelectrical approach-withdrawal index (AW). High value of AW means high appreciation of the picture. The number of eye fixations performed by the subjects during the observation of the pictures was also analyzed. Results showed that in the examined group the AW index was significant higher during the observation of portraits than during the observation of the religious subjects (as resulted from an ANOVA performed on AW index, with a p<;0,007). Interestingly, the average AW index estimated in the first 20 seconds of the observation of the pictures remains highly correlated with the AW index evaluated for the second part of the data (from 20 s to one minute) for all the 20 pictures examined (r = 0,82, p<;0,0001). In addition, the number of eye fixations performed by the subjects in the first 5 or 10 seconds of observation of the pictures that were most appreciated are significantly higher than the number of eye fixations performed on pictures that subjects did not like (p<;0,048 and p<;0,0018, respectively). Such difference vanishes if the entire period of observation of the pictures of one minute is used (p = 0,54). Taken together, such results seem to suggest that the neuroelectrical correlates of the perception of "good" or "bad" pictures are rapidly formed in our brain, within the first 10-20 seconds from the exposition to the picture. PMID- 26738147 TI - Eye tracking and EEG synchronization to analyze microsaccades during a workload task. AB - Electroencephalography (EEG) and eye tracking are two fields that have evolved independently to study topics such as mental workload, attention and fatigue in cognitive neuroscience. However, little research has been devoted to integrating data from these two fields. In this paper, we investigate the utility of a specific type of eye movement, microsaccades, to analyze cognitive activity. We assess mental workload using event related potentials (ERPs) correlated with microsaccades during experiments where task complexity is designed to be greater with an increase in visual degradation. We also develop a modified eye movement algorithm to identify microsaccades during tasks that permit regular saccades and blinks. We compare ERPs at microsaccade onset locked epochs to those of stimulus onset locked epochs. Our results show a clear correlation of ERP activations to both latency and activation areas. These findings provide important insights for analyzing sophisticated tasks in a non-invasive fashion. PMID- 26738148 TI - Evaluation of the Audio Bracelet for Blind Interaction for improving mobility and spatial cognition in early blind children - A pilot study. AB - This study was designed to assess the effectiveness of the Audio Bracelet for Blind Interaction (ABBI) system for improving mobility and spatial cognition in visually impaired children. The bracelet is worn on the wrist and the key feature is to provide an audio feedback about body movements to help visually impaired children to build a sense of space. Nine early blind children took part at this study. The study lasted 12 weeks. Once per week each child participated in a 45 minutes ABBI rehabilitation with trained professionals. He also had to use it one hour per day at home alone or with one relative. The mobility and spatial cognition abilities were measured before and after a 12-weeks rehabilitation program with three different tests. Results showed that the use of the Audio Bracelet for Blind Interaction allowed the early blind children to significantly improve their mobility and spatial abilities. Although an extended study including a larger number of participants is needed to confirm these data, the present results are encouraging. They do suggest that ABBI could be used for rehabilitate the sense of space in visually impaired children. PMID- 26738149 TI - Handedness change after dominant side amputation: Evaluation from a hand laterality judgment task. AB - Amputation of the dominant hand forces patients to use their non-dominant hand exclusively. Whether this chronic forced use of the non-dominant hand would affect the handedness preference remains an open question. In this study, the handedness preference in amputees was evaluated using a hand laterality judgment task by comparing recognition speeds of their lost hand and remaining hand. A handedness index was defined as lateralization between response times to the left hand and the right hand. Healthy controls responded faster to the pictures of dominant hand than that of non-dominant hand, while amputees did not show this handedness advantage. The handedness index was significantly correlated to the response time, accuracy, amputation age and the time post amputation. Amputees with poorer performance experienced severer handedness change and new amputees were more likely to suffer handedness change. Our results suggest that handedness is changed after dominant side amputation and the handedness change might not be induced by chronic use of the intact hand. PMID- 26738150 TI - Wireless data and power transfer of an optogenetic implantable visual cortex stimulator. AB - In this paper, the wireless data and power transfer for a novel optogenetic visual cortex implant system was demonstrated by using pork tissue mimic in-vitro at the ISM 2.4 GHz and 13.5 MHz frequency band respectively. The observed data rate was 120 kbps with no loss in data for up to a thickness of 35 mm in both water & pork. To increase the power level of the implant a Class E power amplifier is separately designed and simulated for the transmitter end and has an output power of around 223 mW with an efficiency of 81.83%. The transferred power at the receiver was measured to be 66.80 mW for the pork tissue medium considering a distance of 5 mm between the transmitter and the receiver coils, with a coupling coefficient of ~0.8. This serves the power requirement of the visual cortex implant. PMID- 26738151 TI - A disposable emulsion droplet generation lab chips driven by vacuum module for manipulation of blood cells. AB - This paper presents a novel disposable emulsion droplet generation lab chip driven by vacuum module for monodisperse emulsions generation and blood cell encapsulation. Emulsion droplet is a powerful tool in miniaturized analysis systems for high throughput processing. It shows great potential in chemical and biological reactions like speeding up the reaction and reducing the cost of reagents. Most research groups use syringe pumps providing positive pressure to drive the fluids. However, the long tubing connection and high cost make the microfluidic systems complicate and unsuitable for lab-on-a-chip (LOC) device. In this paper, our emulsion droplet generation lab chip with disposable vacuum module, made of shape memory polymer, provides a negative pressure to drive the fluids. This lab chip could achieve creating monodisperse emulsion droplets by manipulating two-phase microfluidic within 1 set of vacuum module and mini heater. In the meantime, the waste is gathered into the cavity of vacuum module. This makes this lab chip safe while using biological samples. The vacuum module shows the advantages of compact, simple structure, and east-to-attach with the microfluidic device and great performance in the experiments. PMID- 26738152 TI - Stretchable metal oxide thin film transistors on engineered substrate for electronic skin applications. AB - Electronic skins aim at providing distributed sensing and computation in a large area and elastic membrane. Control and addressing of high-density soft sensors will be achieved when thin film transistor matrices are also integrated in the soft carrier substrate. Here, we report on the design, manufacturing and characterization of metal oxide thin film transistors on these stretchable substrates. The TFTs are integrated onto an engineered silicone substrate with embedded strain relief to protect the devices from catastrophic cracking. The TFT stack is composed of an amorphous In-Ga-Zn-O active layer, a hybrid AlxOy/Parylene dielectric film, gold electrodes and interconnects. All layers are prepared and patterned with planar, low temperature and dry processing. We demonstrate the interconnected IGZO TFTs sustain applied tensile strain up to 20% without electrical degradation and mechanical fracture. Active devices are critical for distributed sensing. The compatibility of IGZO TFTs with soft and biocompatible substrates is an encouraging step towards wearable electronic skins. PMID- 26738153 TI - Surface texture detection with artificial fingers. AB - This paper highlights the potential of using prosthetic devices to sense surface textures; an important characteristic of a lower arm that is often neglected. An artificial finger equipped with a piezoelectric sensor, mounted on a fingertip, has been designed to detect surface textures of different dimensions. Signal frequencies generated during the exploratory movement of the artificial finger reliably correlate to all the widths of grooves and ridges of the surface textures under investigation. This capability provides a positive outlook in recreating a touch sensation that has been previously lost from natural fingers and palms. PMID- 26738154 TI - A novel multiple electrode direct current technique for characterisation of tissue resistance during surgery. AB - Electrochemical and electrical characteristics have the potential to help differentiate between, and assess the health state of, different biological tissues. However, measurement and interpretation of these characteristics is non trivial. We propose a new DC galvanostatic sensing method for application to laparoscopic cancer surgery. This presents a simple and cost-effective measurement coupled with straightforward data interpretation. This paper describes the electrochemical and electrical theory underpinning the technique. Additionally, we describe a measurement system employing this technique and present an investigation into the feasibility of using it for measuring the resistance of different tissue types. Measurements were performed on ex vivo porcine liver, colon and rectum tissues. Outputs were consistent with theory and showed a significant difference between the resistance of the different tissue types, (one-way ANOVA, F(2, 28) = 1369, p <; 0.01). These findings indicate that this novel technique may be viable as a low cost method for the discrimination and health assessment of tissues in clinical scenarios. PMID- 26738155 TI - Embedded electro-conductive yarn for shape sensing of soft robotic manipulators. AB - Flexible soft and stiffness-controllable surgical manipulators enhance the manoeuvrability of surgical tools during Minimally Invasive Surgery (MIS), as opposed to conventional rigid laparoscopic instruments. These flexible and soft robotic systems allow bending around organs, navigating through complex anatomical pathways inside the human body and interacting inherently safe with its soft environment. Shape sensing in such systems is a challenge and one essential requirement for precise position feedback control of soft robots. This paper builds on our previous work integrating multiple optical fibres into a soft manipulator to estimate the robot's pose using light intensity modulation. Here, we present an enhanced version of our embedded bending/shape sensor based on electro-conductive yarn. The new system is miniaturised and able to measure bending behaviour as well as elongation. The integrated yarn material is helically wrapped around an elastic strap and protected inside a 1.5mm outer diameter stretchable pipe. Three of these resulting stretch sensors are integrated in the periphery of a pneumatically actuated soft manipulator for direct measurement of the actuation chamber lengths. The capability of the sensing system in measuring the bending curvature and elongation of the arm is evaluated. PMID- 26738156 TI - Developing technologies for the elderly: To whom are we really developing? AB - The increasing number of older adults worldwide boosted the proposal of applications specifically targeting their needs. While the elderly serve as the target audience, this article argues that in many cases they are being treated as any other age group, disregarding their unique characteristics and expectations, which might eventually result in applications that, despite being used by the elderly, are adapted applications to cope with their disabilities, instead of approaches that leverage their abilities and views. As a first step of this discussion, this article aims to show how, in different stages of design and development, we are jump-starting the whole process putting our own assumptions and views where those of the elderly should be. PMID- 26738157 TI - A tool for home-based rehabilitation allowing for clinical evaluation in a visual markerless scenario. AB - This work deals with the design of an interactive monitoring tool for home-based physical rehabilitation. The software platform includes a video processing stage and the exercise performance evaluation. Image features are extracted by a Kinect v2 sensor and elaborated to return the exercises score. Furthermore the tool provides to physiotherapists a quantitative exercise evaluation of subject's performances. The proposed tool for home rehabilitation has been tested on 5 subjects and 5 different exercises and results are presented. In particular both exercises and relative evaluation indexes were selected by specialists in neurorehabilitation. PMID- 26738159 TI - Passive wireless sensor systems can recognize activites of daily living. AB - The ability to determine what activity of daily living a person performs is of interest in many application domains. It is possible to determine the physical and cognitive capabilities of the elderly by inferring what activities they perform in their houses. Our primary aim was to establish a proof of concept that a wireless sensor system can monitor and record physical activity and these data can be modeled to predict activities of daily living. The secondary aim was to determine the optimal placement of the sensor boxes for detecting activities in a room. A wireless sensor system was set up in a laboratory kitchen. The ten healthy participants were requested to make tea following a defined sequence of tasks. Data were collected from the eight wireless sensor boxes placed in specific places in the test kitchen and analyzed to detect the sequences of tasks performed by the participants. These sequence of tasks were trained and tested using the Markov Model. Data analysis focused on the reliability of the system and the integrity of the collected data. The sequence of tasks were successfully recognized for all subjects and the averaged data pattern of tasks sequences between the subjects had a high correlation. Analysis of the data collected indicates that sensors placed in different locations are capable of recognizing activities, with the movement detection sensor contributing the most to detection of tasks. The central top of the room with no obstruction of view was considered to be the best location to record data for activity detection. Wireless sensor systems show much promise as easily deployable to monitor and recognize activities of daily living. PMID- 26738158 TI - Preliminary exploration of the measurement of walking speed for the apoplectic people based on UHF RFID. AB - The number of the apoplectic people is increasing while population aging is quickening its own pace. The precise measurement of walking speed is very important to the rehabilitation guidance of the apoplectic people. The precision of traditional measuring methods on speed such as stopwatch is relatively low, and high precision measurement instruments because of the high cost cannot be used widely. What's more, these methods have difficulty in measuring the walking speed of the apoplectic people accurately. UHF RFID tag has the advantages of small volume, low price, long reading distance etc, and as a wearable sensor, it is suitable to measure walking speed accurately for the apoplectic people. In order to measure the human walking speed, this paper uses four reader antennas with a certain distance to reads the signal strength of RFID tag. Because RFID tag has different RSSI (Received Signal Strength Indicator) in different distances away from the reader, researches on the changes of RSSI with time have been done by this paper to calculate walking speed. The verification results show that the precise measurement of walking speed can be realized by signal processing method with Gaussian Fitting-Kalman Filter. Depending on the variance of walking speed, doctors can predict the rehabilitation training result of the apoplectic people and give the appropriate rehabilitation guidance. PMID- 26738160 TI - Augmenting white cane reliability using smart glove for visually impaired people. AB - The independent mobility problem of visually impaired people has been an active research topic in biomedical engineering: although many smart tools have been proposed, traditional tools (e.g., the white cane) continue to play a prominent role. In this paper a low cost smart glove is presented: the key idea is to minimize the impact in using it by combining the traditional tools with a technological device able to improve the movement performance of the visually impaired people. PMID- 26738161 TI - Reduction in time-to-sleep through EEG based brain state detection and audio stimulation. AB - We developed an EEG- and audio-based sleep sensing and enhancing system, called iSleep (interactive Sleep enhancement apparatus). The system adopts a closed-loop approach which optimizes the audio recording selection based on user's sleep status detected through our online EEG computing algorithm. The iSleep prototype comprises two major parts: 1) a sleeping mask integrated with a single channel EEG electrode and amplifier, a pair of stereo earphones and a microcontroller with wireless circuit for control and data streaming; 2) a mobile app to receive EEG signals for online sleep monitoring and audio playback control. In this study we attempt to validate our hypothesis that appropriate audio stimulation in relation to brain state can induce faster onset of sleep and improve the quality of a nap. We conduct experiments on 28 healthy subjects, each undergoing two nap sessions - one with a quiet background and one with our audio-stimulation. We compare the time-to-sleep in both sessions between two groups of subjects, e.g., fast and slow sleep onset groups. The p-value obtained from Wilcoxon Signed Rank Test is 1.22e-04 for slow onset group, which demonstrates that iSleep can significantly reduce the time-to-sleep for people with difficulty in falling sleep. PMID- 26738162 TI - Computational modelling of fatty acid transport in the human placenta. AB - Fatty acids are critical for normal fetal growth and development. The placenta mediates the transfer of fatty acids from the maternal to the fetal circulation. Yet, the mechanisms of fatty acid transport are not fully understood. The development of a computational model alongside experiments will test our understanding of the transfer mechanisms. Modelling experimental data suggest the presence of a metabolic pool within placental tissue that could represent the rate-limiting factor for fatty acid transfer. In addition the model suggests a slower flux capacity of the fetal-side of the placenta compared with the maternal side. The model provides key insights into placental fatty acid transfer which will form the basis for future experimentation. PMID- 26738163 TI - Mixed model of dietary fat effect on postprandial glucose-insulin metabolism from carbohydrates in type 1 diabetes. AB - In this study we introduce an extension of a previously developed model of glucose-insulin metabolism in type 1 diabetes (T1D) from carbohydrates that includes the effect of dietary fat on postprandial glycemia. We include two compartments that represent plasma triglyceride and nonesterified fatty acid (NEFA) concentration, in addition to a mathematical representation of delayed gastric emptying and insulin resistance, which are the most well-known effects of dietary fat metabolism. Simulation results show that postprandial glucose as well as lipid levels in our model approximates clinical data from T1D patients. PMID- 26738164 TI - Tissue specific simulations of interstitial cells of cajal networks using unstructured meshes. AB - Gastrointestinal motility is facilitated by specialized pacemaker cells called Interstitial Cells of Cajal (ICC). ICC play a critical role in coordinating normal motility and its degradation in the gastrointestinal tract is associated with many functional motility disorders. Nonetheless, the degree of degradation and associated clinical impact remains unclear. Continuum modeling frameworks offers a virtual mean to simulate the electrical activity, and analyze the ICC activity in both normal and diseased states. Confocal images of the ICC networks were obtained from the intestine of normal mice. In this study, a new approach is presented where meshes of ICC networks were generated using a Delaunay triangulation and used to solve finite-element based reaction-diffusion equations describing gastrointestinal electrophysiology. The electrical activity was simulated on the ICC network and solutions were compared to those of a regular mesh based on individual pixel locations. The simulation results showed the proposed approach to be approximately 80% more efficient than a pixel-based mesh. The difference in activation time for the entire network between the different methods was observed to be around 4% (about 20 ms). The proposed approach will enable efficient examination of the ICC slow wave activity in larger networks and for longer temporal duration that has been previously impossible. This will provide valuable insights relating ICC degradation to gastrointestinal motility disorders. PMID- 26738165 TI - Mathematical analysis of dermal absorption rate of heavy metals. AB - Presently 90 - 95% of children in the US wear disposable diapers before completing their toilet training at average age of 30 months. The diaper absorbs urine and liquid component from feces contaminated with excreted toxicants. In this initial study, we posit that the long contact between the diaper and the skin leads to increased dermal reabsorption of excreted body toxicants, mainly heavy metals, which are statistically associated with autism and neurodevelopmental disorder. We developed a mathematical model to analyse the increase of the level of toxicants due to dermal reabsorption after excretion. This simple kinetic model gives us the average reabsorbtion factor in the range of 1.6 to 5. The limitation of this work is that only mathematical model has been considered and it has not been verified experimentally. PMID- 26738166 TI - Characterization of parafoveal hemodynamics associated with diabetic retinopathy with adaptive optics scanning laser ophthalmoscopy and computational fluid dynamics. AB - Diabetic retinopathy (DR) remains the leading cause of visual loss in working age adults in the United States and other developed countries worldwide. Previous studies have reported hemodynamic changes in the diabetic eye that precede clinically evident pathological alterations of the retinal microvasculature. There exists a pressing need for new methods to allow greater understanding of these early hemodynamic changes that occur in DR. In the current study, we propose a noninvasive method for the assessment of hemodynamics around the fovea (a region of the eye of paramount importance for vision). The proposed methodology combines adaptive optics scanning laser ophthalmoscopy and computational fluid dynamics modeling and simulation. Our preliminary results indicate that the technique presented here is feasible for the assessment of hemodynamics in the foveal region of the eye and, moreover, that it is capable of detecting differences in hemodynamics between eyes that may be associated with DR status. We believe that the proposed methodology has the potential to become a useful tool for the evaluation of human retinal hemodynamics in a clinical context. PMID- 26738167 TI - Spatiotemporal dynamics of synaptic drive in urinary bladder syncytium: A computational investigation. AB - The urinary bladder wall is composed of the detrusor smooth muscle (DSM) in which adjacent cells are electrically coupled to form a three dimensional syncytium. The structural complexity of the tissue is further enhanced by a distributed innervation pattern. Experimental techniques employed in order to analyze detrusor excitability have been unable as yet to provide a satisfactory understanding of either the normal electrical functioning of the tissue, or of the changes that come about in pathological conditions. Our work aims at exploring the interplay between factors that determines the spread of junction potentials in the tissue which is critical for generation of action potential and subsequent contraction of the bladder wall. Results from our model suggest that in the detrusor syncytium, the mean interval between subsequent spontaneous neurotransmitter releases at a single varicosity is about 91.5 seconds such that in the normally functioning tissue, spontaneous transient depolarizations (STDs) occur with a mean interval of 2-7 seconds. Increase in neurotransmitter release frequency might result in higher excitability of the tissue, leading to bladder instability. Results also indicate that increase in intercellular coupling is another probable cause for such a pathophysiological scenario. PMID- 26738168 TI - Robust heart rate estimation using wrist-based PPG signals in the presence of intense physical activities. AB - Heart rate tracking from a wrist-type photoplethysmogram (PPG) signal during intensive physical activities is a challenge that is attracting more attention thanks to the introduction of wrist-worn wearable computers. Commonly-used motion artifact rejection methods coupled with simple periodicity-based heart rate estimation techniques are incapable of achieving satisfactory heart rate tracking performance during intense activities. In this paper, we propose a two-stage solution. Firstly, we introduce an improved spectral subtraction method to reject the spectral components of motion artifacts. Secondly, instead of using heuristic mechanisms, we formalize the spectral peaks selection process as the shortest path search problem and validate its effectiveness. Analysis on the experimental results based on a published database shows that: (1) Our proposed method outperforms three other comparable methods with regards to heart rate estimation error. (2) The proposed method is a promising candidate for both offline cardiac health analysis and online heart rate tracking in daily life, even during intensive physical motions. PMID- 26738169 TI - Accurate walking and running speed estimation using wrist inertial data. AB - In this work, we present an accelerometry-based device for robust running speed estimation integrated into a watch-like device. The estimation is based on inertial data processing, which consists in applying a leg-and-arm dynamic motion model to 3D accelerometer signals. This motion model requires a calibration procedure that can be done either on a known distance or on a constant speed period. The protocol includes walking and running speeds between 1.8km/h and 19.8km/h. Preliminary results based on eleven subjects are characterized by unbiased estimations with 2(nd) and 3(rd) quartiles of the relative error dispersion in the interval +/-5%. These results are comparable to accuracies obtained with classical foot pod devices. PMID- 26738170 TI - A novel method for assessing the severity of levodopa-induced dyskinesia using wearable sensors. AB - Patients with Parkinson's disease often experience significant changes in the severity of dyskinesia when they undergo titration of their medications. Dyskinesia is marked by involuntary jerking movements that occur randomly in a burst-like fashion. The burst-like nature of such movements makes it difficult to estimate the clinical scores of severity of dyskinesia using wearable sensors. Clinical observations are generally made over intervals of 15-30 s. On the other hand, techniques designed to estimate the severity of dyskinesia based on the analysis of wearable sensor data typically use data segments of approximately 5 s. Consequently, some data segments might include dyskinetic movements, whereas others might not. Herein, we propose a novel method suitable to automatically select data segments from the training dataset that are marked by dyskinetic movements. The proposed method also aggregates results derived from the testing dataset using a machine learning algorithm to estimate the severity of dyskinesia from wearable sensor data. Results obtained from the analysis of sensor data collected from seven subjects with Parkinson's disease showed a marked improvement in the accuracy of the estimation of clinical scores of dyskinesia. PMID- 26738171 TI - Physical activity profiling: Activity-specific step counting and energy expenditure models using 3D wrist acceleration. AB - In this paper, we present the evaluation of a new physical activity profiling system embedded in a wrist-located device. We propose a step counting and an energy expenditure (EE) method, and evaluate their accuracy against gold standard references. To this end, we used an actimetry sensor on the waist and an indirect calorimetry monitoring device on a population of 13 subjects to obtain step count and metabolic equivalent task (kcal/kg/h) referenced values. The subjects followed a protocol that spanned a given set of activities (lying, standing, walking, running) at a wide range of intensities. The performance of the EE model was characterized by a root-mean-square error (RMSE) of 1.22+/-0.34kcal/min, and step-count model at regular walking/running speeds by 0.71+/-0.06step/10sec. PMID- 26738172 TI - Detection of essential hypertension with physiological signals from wearable devices. AB - Early detection of essential hypertension can support the prevention of cardiovascular disease, a leading cause of death. The traditional method of identification of hypertension involves periodic blood pressure measurement using brachial cuff-based measurement devices. While these devices are non-invasive, they require manual setup for each measurement and they are not suitable for continuous monitoring. Research has shown that physiological signals such as Heart Rate Variability, which is a measure of the cardiac autonomic activity, is correlated with blood pressure. Wearable devices capable of measuring physiological signals such as Heart Rate, Galvanic Skin Response, Skin Temperature have recently become ubiquitous. However, these signals are not accurate and are prone to noise due to different artifacts. In this paper a) we present a data collection protocol for continuous non-invasive monitoring of physiological signals from wearable devices; b) we implement signal processing techniques for signal estimation; c) we explore how the continuous monitoring of these physiological signals can be used to identify hypertensive patients; d) We conduct a pilot study with a group of normotensive and hypertensive patients to test our techniques. We show that physiological signals extracted from wearable devices can distinguish between these two groups with high accuracy. PMID- 26738173 TI - Evaluation of the beat-to-beat detection accuracy of PulseOn wearable optical heart rate monitor. AB - Heart rate variability (HRV) provides significant information about the health status of an individual. Optical heart rate monitoring is a comfortable alternative to ECG based heart rate monitoring. However, most available optical heart rate monitoring devices do not supply beat-to-beat detection accuracy required by proper HRV analysis. We evaluate the beat-to-beat detection accuracy of a recent wrist-worn optical heart rate monitoring device, PulseOn (PO). Ten subjects (8 male and 2 female; 35.9+/-10.3 years old) participated in the study. HRV was recorded with PO and Firstbeat Bodyguard 2 (BG2) device, which was used as an ECG based reference. HRV was recorded during sleep. As compared to BG2, PO detected on average 99.57% of the heartbeats (0.43% of beats missed) and had 0.72% extra beat detection rate, with 5.94 ms mean absolute error (MAE) in beat to-beat intervals (RRI) as compared to the ECG based RRI BG2. Mean RMSSD difference between PO and BG2 derived HRV was 3.1 ms. Therefore, PO provides an accurate method for long term HRV monitoring during sleep. PMID- 26738174 TI - E3D hand movement velocity reconstruction using power spectral density of EEG signals and neural network. AB - Three dimensional (3D) limb motion trajectory is predictable with a non-invasive brain-computer interface (BCI). To date, most non-invasive motion trajectory prediction BCIs use potential values of electroencephalographic (EEG) signals as the input to a multiple linear regression (mLR) based kinetic data estimator. We investigated the possible improvement in accuracy of 3D hand movement prediction (i.e., the correlation of registered and reconstructed hand velocities) by replacing raw EEG potentials with spectrum power values of specific EEG bands. We also investigated if a non-linear neural network based estimator outperformed the mLR approach. The spectrum power model provided significantly higher accuracy (R~0.60) compared to the similar EEG potentials based approach (R~0.45). Additionally, when replacing the mLR based kinetic data estimation module with a feed-forward neural network (NN) we found the NN based spectrum power model provided higher accuracy (R~0.70) compared to the similar mLR based approach (R~0.60). PMID- 26738175 TI - Effect of negative and positive emotions on EEG spectral asymmetry. AB - The aim of the study was to evaluate the applicability of electroencephalogram (EEG) spectral asymmetry index (SASI) for discrimination of the effect of negative and positive emotions on human brain bioelectrical activity. SASI has been previously proposed as a method to detect depression based on the balance of EEG theta and beta frequency band powers. Emotions were evoked on 22 healthy subjects using emotional pictures portraying humans from International Affective Picture System (IAPS) and late response to stimuli was examined (1700-2200 ms). Electroencephalogram (EEG) was recorded in 30 channels divided into 10 brain regions: left frontal, right frontal, left temporal, right temporal, frontal, frontocentral, central, centroparietal, parietal and occipital. Negative stimuli, compared to neutral stimuli, significantly increased SASI in frontocentral, central, centroparietal, parietal and occipital areas. Positive stimuli, compared to neutral stimuli, significantly decreased SASI in left temporal, centroparietal, parietal and occipital areas. The results indicate that SASI provides a good discrimination between the effects of negative, neutral and positive emotions on human EEG. PMID- 26738176 TI - A time-frequency respiration tracking system using non-contact bed sensors with harmonic artifact rejection. AB - Sleep apnea is a breathing disorder that affects many individuals and has been associated with serious health conditions such as cardiovascular disease. Clinical diagnosis of sleep apnea requires that a patient spend the night in a sleep clinic while being wired up to numerous obtrusive sensors. We are developing a system that utilizes respiration rate and breathing amplitude inferred from non-contact bed sensors (i.e. load cells placed under bed supports) to detect sleep apnea. Multi-harmonic artifacts generated either biologically or as a result of the impulse response of the bed have made it challenging to track respiration rate and amplitude with high resolution in time. In this paper, we present an algorithm that can accurately track respiration on a second-by-second basis while removing noise harmonics. The algorithm is tested using data collected from 5 patients during overnight sleep studies. Respiration rate is compared with polysomnography estimations of respiration rate estimated by a technician following clinical standards. Results indicate that certain subjects exhibit a large harmonic component of their breathing signal that can be removed by our algorithm. When compared with technician transcribed respiration rates using polysomnography signals, we demonstrate improved accuracy of respiration rate tracking using harmonic artifact rejection (mean error: 0.18 breaths/minute) over tracking not using harmonic artifact rejection (mean error: -2.74 breaths/minute). PMID- 26738177 TI - Relating tribological stimuli to somatosensory electroencephalographic responses. AB - The present study deals with the extraction of neural correlates evoked by tactile stimulation of the human fingertip. A reciprocal sliding procedure was performed using a home-built tribometer while simultaneously electroencephalographic (EEG) data from the somatosensory cortex was recorded. The tactile stimuli were delivered by a sliding block with equidistant, perpendicular ridges. The experiments were designed and performed in a fully passive way to prevent attentional locked influences from the subjects. In order to improve the signal-to-noise ratio (SNR) of event related single-trials (ERPs), nonlocal means in addition to 2D-anisotropic denoising schemes based on tight Gabor frames were applied. This novel approach allowed for an easier extraction of ERP alternations. A negative correlation between the latency of the P100 component of the resulting brain responses and the intensity of the underlying lateral forces was found. These findings lead to the conclusion that an increasing stimulus intensity results in a decreasing latency of the brain responses. PMID- 26738178 TI - Comparison of EEG and MEG in source localization of induced human gamma-band oscillations during visual stimulus. AB - High frequency gamma oscillations are indications of information processing in cortical neuronal networks. Recently, non-invasive detection of these oscillations have become one of the main research areas in magnetoencephalography (MEG) and electroencephalography (EEG) studies. The aim of this study, which is a continuation of our previous MEG study, is to compare the capability of the two modalities (EEG and MEG) in localizing the source of the induced gamma activity due to a visual stimulus, using a spatial filtering technique known as dynamic imaging of coherent sources (DICS). To do this, the brain activity was recorded using simultaneous MEG and EEG measurement and the data were analyzed with respect to time, frequency, and location of the strongest response. The spherical head modeling technique, such as, the three-shell concentric spheres and an overlapping sphere (local sphere) have been used as a forward model to calculate the external electromagnetic potentials and fields recorded by the EEG and MEG, respectively. Our results from the time-frequency analysis, at the sensor level, revealed that the parieto-occipital electrodes and sensors from both modalities showed a clear and sustained gamma-band activity throughout the post-stimulus duration and that both modalities showed similar strongest gamma-band peaks. It was difficult to interpret the spatial pattern of the gamma-band oscillatory response on the scalp, at the sensor level, for both modalities. However, the source analysis result revealed that MEG3 sensor type, which measure the derivative along the longitude, showed the source more focally and close to the visual cortex (cuneus) as compared to that of the EEG. PMID- 26738179 TI - Towards the assessment of listening effort in real life situations: Mobile EEG recordings in a multimodal driving situation. AB - The EEG estimation of listening effort has been proven to efficiently map subjectively perceived effort on an objective scale. However, it has mostly been performed in controlled audiometric laboratory environments. In this study, we investigated the feasibility of the EEG listening effort assessment in a multisensory demanding environment. For this purpose, two mobile EEG acquisition systems were used to extract the objective listening effort of the ongoing oscillatory activity (OLEosc) while driving. As an auditory paradigm was presented to trigger listening effort, the simulated driving scenario served as a competing task responding to different modalities. The OLEosc was compared with a subjective rating of the expended listening effort and the task performance. Furthermore, we considered time resolved listening effort profiles over the duration of the paradigm. The results showed that the practical assessment of listening effort in a multimodal real life setting is viable. The OLEosc could be extracted and followed the subjective listening effort. Moreover, the analysis of the dynamic listening effort profiles unveiled further information such as "surrender effects", when the subjects ceased to solve the auditory task due to the intense multimodal load. PMID- 26738180 TI - Analyzing OCT images of age-related macular degeneration patients to identify spatial health correlations. AB - An approach to automatically group age-related macular degeneration (AMD) patients having similar retinal health profiles by clustering Optical Coherence Tomography (OCT) images is described. Spatial health patterns within and across profiles are discovered by identifying segments of images that have similar levels of health in a given retina region. Segmentations of various sizes are considered and the segmentation where the segment similarity most closely matches the discovered health profiles is used to identify health patterns. Our experiments with OCT images of 10 AMD patients show that - i) health profiles generated by clustering closely correspond to those identified by a physician expert, ii) a rich set of spatial patterns can be discovered within and across profiles using regular image segmentation, and iii) new images can be successfully classified into existing profiles so that physicians can provide effective profile-based treatments. PMID- 26738181 TI - Morphological analysis of neurons: Automatic identification of elongations. AB - Our study is focused on the development of a new method for the automatic analysis of cell images. We focused on neurons (cells line SH-SY5Y) treated/untreated with ultrasound and stained with Haematoxylin-Eosin. The aim of the algorithm is the automatic detection of the cell body as well as the determination of the number and the length of neuron elongations. Starting point of the algorithm was the convolution of an image with a bank of rotating Gaussian kernels and the construction of a module map. Then several strategies were implemented to detect cell bodies and to detect and extract data about cell elongations. We have also realized a graphical user interface allowing the loading, saving and processing of images. Results show that this method is able to properly and efficiently detect cell contours and elongations. The automated evaluation is in strong agreement with manual evaluation performed by an expert operator, with an average error of 11% with most parameter combinations. This tool constitutes an important support in biological research activities, where operators need to analyze a large number of images to investigate about cell morphology before and after a treatment. PMID- 26738182 TI - Unsupervised HEp-2 mitosis recognition in indirect immunofluorescence imaging. AB - Automated HEp-2 mitotic cell recognition in IIF images is an important and yet scarcely explored step in the computer-aided diagnosis of autoimmune disorders. Such step is necessary to assess the goodness of the HEp-2 samples and helps the early diagnosis of the most difficult or ambiguous cases. In this work, we propose a completely unsupervised approach for HEp-2 mitotic cell recognition that overcomes the problem of mitotic/non-mitotic class imbalance due to the limited number of mitotic cells. Our technique automatically selects a limited set of candidate cells from the HEp-2 slide and then applies a clustering algorithm to identify the mitotic ones based on their texture. Finally, a second stage of clustering discriminates between positive and negative mitoses. Experiments on public IIF images demonstrate the performance of our technique compared to previous approaches. PMID- 26738183 TI - Characterization of the role of collagen network structure and composition in cancer cell migration. AB - The geometry of 3D collagen networks is a key factor that influences the behavior of live cells within extra-cellular matrices. This paper presents a method for automatic quantification of the 3D collagen network geometry with fiber resolution in confocal reflection microscopy images. The proposed method is based on a smoothing filter and binarization of the collagen network followed by a fiber reconstruction algorithm. The method is validated on 3D collagen gels with various collagen and Matrigel concentrations. The results reveal that Matrigel affects the collagen network geometry by decreasing the network pore size while preserving the fiber length and fiber persistence length. The influence of network composition and geometry, especially pore size, is preliminarily analyzed by quantifying the migration patterns of lung cancer cells within microfluidic devices filled with three different hydrogel types. The experiments reveal that Matrigel, while decreasing pore size, stimulates cell migration. Further studies on this relationship could be instrumental for the study of cancer metastasis and other biological processes involving cell migration. PMID- 26738184 TI - Semiautomatic detection of villi in confocal endoscopy for the evaluation of celiac disease. AB - Celiac Disease (CD) is an immune-mediated enteropathy, diagnosed in the clinical practice by intestinal biopsy and the concomitant presence of a positive celiac serology. Confocal Laser Endomicroscopy (CLE) allows skilled and trained experts to potentially perform in vivo virtual histology of small-bowel mucosa. In particular, it allows the qualitative evaluation of mucosa alteration such as a decrease in goblet cells density, presence of villous atrophy or crypt hypertrophy. We present a semi-automatic method for villi detection from confocal endoscopy images, whose appearance change in case of villous atrophy. Starting from a set of manual seeds, a first rough segmentation of the villi is obtained by means of mathematical morphology operations. A merge and split procedure is then performed, to ensure that each seed originates a different region in the final segmentation. A border refinement process is finally performed, evolving the shape of each region according to local gradient intensities. Mean and median Dice coefficients for 290 villi originating from 66 images when compared to manually obtained ground truth are 80.71% and 87.96% respectively. PMID- 26738185 TI - Simulation of cellular changes on Optical Coherence Tomography of human retina. AB - We present a methodology to assess cell level alterations on the human retina responsible for functional changes observable in the Optical Coherence Tomography data in healthy ageing and in disease conditions, in the absence of structural alterations. The methodology is based in a 3D multilayer Monte Carlo computational model of the human retina. The optical properties of each layer are obtained by solving the Maxwell's equations for 3D domains representative of small regions of those layers, using a Discontinuous Galerkin Finite Element Method (DG-FEM). Here we present the DG-FEM Maxwell 3D model and its validation against Mie's theory for spherical scatterers. We also present an application of our methodology to the assessment of cell level alterations responsible for the OCT data in Diabetic Macular Edema. It was possible to identify which alterations are responsible for the changes observed in the OCT scans of the diseased groups. PMID- 26738186 TI - A decision support system based on an ensemble of random forests for improving the management of women with abnormal findings at cervical cancer screening. AB - In most cases, cervical cancer (CxCa) develops due to underestimated abnormalities in the Pap test. Today, there are ancillary molecular biology techniques available that provide important information related to CxCa and the Human Papillomavirus (HPV) natural history, including HPV DNA tests, HPV mRNA tests and immunocytochemistry techniques such as overexpression of p16. These techniques are either highly sensitive or highly specific, however not both at the same time, thus no perfect method is available today. In this paper we present a decision support system (DSS) based on an ensemble of Random Forests (RFs) for the intelligent combination of the results of classic and ancillary techniques that are available for CxCa detection, in order to exploit the benefits of each technique and produce more accurate results. The proposed system achieved both, high sensitivity (86.1%) and high specificity (93.3%), as well as high overall accuracy (91.8%), in detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+). The system's performance was better than any other single test involved in this study. Moreover, the proposed architecture of employing an ensemble of RFs proved to be better than the single classifier approach. The presented system can handle cases with missing tests and more importantly cases with inadequate cytological outcome, thus it can also produce accurate results in the case of stand-alone HPV-based screening, where Pap test is not applied. The proposed system may identify women at true risk of developing CxCa and guide personalised management and therapeutic interventions. PMID- 26738187 TI - Using sequential patterns as features for classification models to make accurate predictions on ICU events. AB - Pattern mining algorithms have previously been utilized to extract informative rules in various clinical contexts. However, the number of generated patterns are numerous. In most cases, the extracted rules are directly investigated by clinicians for understanding disease diagnoses. The elicitation of important patterns for clinical investigation places a significant demand for precision and interpretability. Hence, it is essential to obtain a set of informative interpretable patterns for building advanced learning models about a patient's physiological condition, specially in critical care units. In this study, a two stage sequential contrast patterns based classification framework is presented, which is used to detect critical patient events like hypotension. In the first stage, we obtain a set of sequential patterns by using a contrast mining algorithm. These sequential patterns undergo post-processing, for conversion to binary valued and frequency based features for developing a classification model, in the second stage. Our results on eight critical care datasets demonstrate better predictive capabilities, when sequential patterns are used as features. PMID- 26738188 TI - From data to the decision: A software architecture to integrate predictive modelling in clinical settings. AB - The application of statistics and mathematics over large amounts of data is providing healthcare systems with new tools for screening and managing multiple diseases. Nonetheless, these tools have many technical and clinical limitations as they are based on datasets with concrete characteristics. This proposition paper describes a novel architecture focused on providing a validation framework for discrimination and prediction models in the screening of Type 2 diabetes. For that, the architecture has been designed to gather different data sources under a common data structure and, furthermore, to be controlled by a centralized component (Orchestrator) in charge of directing the interaction flows among data sources, models and graphical user interfaces. This innovative approach aims to overcome the data-dependency of the models by providing a validation framework for the models as they are used within clinical settings. PMID- 26738189 TI - Development of sleep apnea syndrome screening algorithm by using heart rate variability analysis and support vector machine. AB - Although sleep apnea syndrome (SAS) is a common sleep disorder, most patients with sleep apnea are undiagnosed and untreated because it is difficult for patients themselves to notice SAS in daily living. Polysomnography (PSG) is a gold standard test for sleep disorder diagnosis, however PSG cannot be performed in many hospitals. This fact motivates us to develop an SAS screening system that can be used easily at home. The autonomic nervous function of a patient changes during apnea. Since changes in the autonomic nervous function affect fluctuation of the R-R interval (RRI) of an electrocardiogram (ECG), called heart rate variability (HRV), SAS can be detected through monitoring HRV. The present work proposes a new HRV-based SAS screening algorithm by utilizing support vector machine (SVM), which is a well-known pattern recognition method. In the proposed algorithm, various HRV features are derived from RRI data in both apnea and normal respiration periods of patients and healthy people, and an apnea/normal respiration (A/N) discriminant model is built from the derived HRV features by SVM. The result of applying the proposed SAS screening algorithm to clinical data demonstrates that it can discriminate patients with sleep apnea and healthy people appropriately. The sensitivity and the specificity of the proposed algorithm were 100% and 86%, respectively. PMID- 26738190 TI - Emergency response nurse scheduling with medical support robot by multi-agent and fuzzy technique. AB - In this paper, a new co-operative re-scheduling method corresponding the medical support tasks that the time of occurrence can not be predicted is described, assuming robot can co-operate medical activities with the nurse. Here, Multi Agent-System (MAS) is used for the co-operative re-scheduling, in which Fuzzy Contract-Net (FCN) is applied to the robots task assignment for the emergency tasks. As the simulation results, it is confirmed that the re-scheduling results by the proposed method can keep the patients satisfaction and decrease the work load of the nurse. PMID- 26738191 TI - Comparison of unsupervised feature selection methods for high-dimensional regression problems in prediction of peptide binding affinity. AB - Identification of robust set of predictive features is one of the most important steps in the construction of clustering, classification and regression models from many thousands of features. Although there have been various attempts to select predictive feature sets from high-dimensional data sets in classification and clustering, there is a limited attempt to study it in regression problems. As semi-supervised and supervised feature selection methods tend to identify noisy features in addition to discriminative variables, unsupervised feature selection methods (USFSMs) are generally regarded as more unbiased approach. Therefore, in this study, along with the entire feature set, four different USFSMs are considered for the quantitative prediction of peptide binding affinities being one of the most challenging post-genome regression problems of very high dimension comparted to extremely small size of samples. As USFSMs are independent of any predictive method, support vector regression was then utilised to assess the quality of prediction. Given three different peptide binding affinity data sets, the results suggest that the regression performance of USFMs depends generally on the datasets. There is no particular method that yields the best performance compared to their performances in the classification problems. However, a closer investigation of the results appears to suggest that the spectral regression-based approach yields slightly better performance. To the best of our knowledge, this is the first study that presents comprehensive comparison of USFSMs in such high-dimensional regression problems, particularly in biological domain with an application in the prediction of peptide binding affinity, and provides a number of practical suggestions for future practitioners. PMID- 26738192 TI - Inference of nonlinear gene regulatory networks through optimized ensemble of support vector regression and dynamic Bayesian networks. AB - Comprehensive understanding of gene regulatory networks (GRNs) is a major challenge in systems biology. Most methods for modeling and inferring the dynamics of GRNs, such as those based on state space models, vector autoregressive models and G1DBN algorithm, assume linear dependencies among genes. However, this strong assumption does not make for true representation of time-course relationships across the genes, which are inherently nonlinear. Nonlinear modeling methods such as the S-systems and causal structure identification (CSI) have been proposed, but are known to be statistically inefficient and analytically intractable in high dimensions. To overcome these limitations, we propose an optimized ensemble approach based on support vector regression (SVR) and dynamic Bayesian networks (DBNs). The method called SVR-DBN, uses nonlinear kernels of the SVR to infer the temporal relationships among genes within the DBN framework. The two-stage ensemble is further improved by SVR parameter optimization using Particle Swarm Optimization. Results on eight insilico-generated datasets, and two real world datasets of Drosophila Melanogaster and Escherichia Coli, show that our method outperformed the G1DBN algorithm by a total average accuracy of 12%. We further applied our method to model the time-course relationships of ovarian carcinoma. From our results, four hub genes were discovered. Stratified analysis further showed that the expression levels Prostrate differentiation factor and BTG family member 2 genes, were significantly increased by the cisplatin and oxaliplatin platinum drugs; while expression levels of Polo-like kinase and Cyclin B1 genes, were both decreased by the platinum drugs. These hub genes might be potential biomarkers for ovarian carcinoma. PMID- 26738193 TI - Novel protein weight matrix generated from amino acid indices. AB - In recent years, numerous protein weight matrices have been developed that include physical characteristics of proteins, such as local sequence-structure information, alpha-helix information, secondary structure information and solvent accessibility states. These protein weight matrices are shown to have generally improved protein sequence alignments over classical protein weight matrices, like Point Accepted Mutation (PAM), Blocks of Amino Acid Substitution (BLOSUM), and GONNET matrices, where important limitations have been observe in recent works. In this paper, a novel protein weight matrix is constructed and presented. This protein weight matrix is not considered based on the mutation rate, like PAM or BLOSUM matrices, but on the physicochemical properties of each amino acid. In the literature, over 500 amino acid indices exist, each one representing a unique biological protein feature. For this study, 25 amino acid indices were selected. These amino acid indices represent general and widely accepted features of the amino acids. By using the proposed protein weight matrix the following advantages can be obtained compared to the classical protein weight matrices. The proposed protein weight matrix is not biased to specific groups of protein sequences as the values are calculated from the amino acid indices, and not from the protein sequences. Additionally, for the proposed protein weight matrix, the same matrix can be considered regardless of the protein sequence's homology to be aligned or the mutation rate presented. A correlation to the physical characterisations of the amino acids that the protein weight matrix derived from can be achieved. Different similarity matrices can be generated when different physical characterisations of amino acids are considered. PMID- 26738194 TI - Integrative analysis of LC-MS based glycomic and proteomic data. AB - Studies associating changes in the levels of glycans and proteins with the onset of cancer have been widely investigated to identify clinically relevant diagnostic biomarkers. Advances in liquid chromatography mass spectrometry (LC MS) have enabled high-throughput identification and quantitative analysis of these biomolecules. While results from separate analyses of glycans and proteins have been reported widely, the mutual information obtained by combining the two has been relatively unexplored. In this study, we investigate integrative analysis of glycans and proteins to take advantage complementary information to improve the ability to distinguish cancer cases from controls. Specifically, SVM RFE algorithm is utilized to select a panel of N-glycans and proteins from LC-MS data previously acquired by analysis of sera from two cohorts in a liver cancer study. Improved performances are observed by integrative analysis compared to separate glycomic and proteomic studies in distinguishing liver cancer cases from patients with liver cirrhosis. PMID- 26738195 TI - Pan-cancer analysis for studying cancer stage using protein expression data. AB - Pan-cancer analyses attempt to discover similar features among multiple cancers in order to identify fundamental patterns common to cancer development and progression. Pan-cancer analysis at the level of protein expression is particularly important because protein expression is more immediately related to patient phenotype than genomic or transcriptomic data. This study aims to analyze differentially expressed (DE) proteins between early and advanced cases of multiple cancer types through the usage of reverse-phase protein array data. The relevance of these proteins is further investigated by developing predictive models using K-nearest neighbor and linear discriminant analysis classifiers. The results of this study suggest that a pan-cancer analysis may be highly complementary to standard analysis of an individual cancer for identifying biologically relevant DE proteins, and can assist in developing effective predictive models for cancer progression. PMID- 26738196 TI - A visual tool for DNA repeats screening. AB - DNA sequence analysis has been developing to reveal some hidden structure, to distinguish coding from noncoding regions in DNA sequence, and to explore structural similarity among DNA sequences. DNA repeats are associated with human disease, seems to play a role in genome organization and evolution and are important in regulatory processes. A lot of the methods for finding repeated sequences use signal processing techniques which implies distances, similarities and consensus sequences to generate candidate sequences. This paper presents results obtained using a mapping algorithm and a custom dot-plot analysis combined with image processing techniques, to isolate the position of DNA patterns with different lengths. PMID- 26738197 TI - Optical detection of carotenoids in living tissue as a measure of fruit and vegetable intake. AB - Circulating blood carotenoids have long been accepted as the most accurate biomarker of total fruit and vegetable intake. Recent technological developments have led to a novel optical detection method of carotenoids in living human tissue, allowing for a non-invasive and rapid method to assess fruit and vegetable intake. Future technological advances to increase sensitivity and molecular specificity, reduce cost, and detect other biomedically important compounds would expand use of this methodology. PMID- 26738198 TI - Mobile evaluation of human energy balance and weight control: Potential for future developments. AB - Quantification of energy storage is essential in understanding energy balance and can be determined by bioelectrical impedance analysis (BIA). Here, we have developed a smartphone form factor multi-frequency BIA device that incorporates an analog front end for body composition measurements. The device was compared against a reference gel-electrode based BIA system in a clinical trial of 311 subjects for predicting BIA equations by calibrating the impedance index to body composition data from dual energy X-ray absorptiometry (DXA). Strong correlations were observed between DXA-based lean soft tissue and the impedance index generated at 50 KHz (R(2)=0.87; p<;0.001). A similar trend was also evident at higher frequencies which matched results from the reference gel-electrode BIA device. The findings support the role of our consumer-oriented mobile Health initiative for multi-frequency BIA assessments to aid weight management. PMID- 26738199 TI - Immediate biofeedback for energy balance via expired breath delta(13)CO2. AB - Expired breath delta(13)CO2 measured in real time serves as a useful biomarker of altered macronutrient metabolism in response to changes in energy balance. Altered breath delta(13)CO2 is believed to be a result of changes in macronutrient oxidation and the kinetic isotope effect where enzymatic processes discriminate against metabolites naturally enriched with (13)C. Use of breath delta(13)CO2 as a rapid biofeedback of energy balance status will enhance an individual's ability to modify behavior during weight loss efforts. Herein we describe a novel approach for immediate biofeedback for energy deficit using a moderate exercise challenge. Our new mid-infrared isotope ratio-meter for delta(13)CO2 is a step toward miniaturization of a personal device for instant biofeedback for people attempting to lose weight. PMID- 26738200 TI - Development of technique for laser welding of biological tissues using laser welding device and nanocomposite solder. AB - The laser device for welding of biological tissues has been developed involving quality control and temperature stabilization of weld seam. Laser nanocomposite solder applied onto a wound to be weld has been used. Physicochemical properties of the nanocomposite solder have been elucidated. The nature of the tissue organizing nanoscaffold has been analyzed at the site of biotissue welding. PMID- 26738201 TI - [Erratum: More about miltefosine in the treatment of mucosal leishmaniasis]. PMID- 26738202 TI - [Clinical practice guideline for ANCA-associated vasculitis with renal involvement]. AB - The ANCA-associated vasculitis (AAV) is a group of systemic conditions characterized by inflammation and necrosis in small and medium vessels. AAV with different levels of disease severity could respond to different therapeutics protocols. Early diagnosis and treatment could significantly improve the outcome of the disease. The objective was to investigate the quality evidence in different therapeutical protocols proposed to AAV with renal involvement in pediatrics and adults patients and evaluate the ANCA applicability in AAV diagnosis and outcome. Using methodological search filters, we identified literature in Medline, Embase, Lilacs and Cochrane Trials Register published between 1997 and July 2015. From 4236 articles, 59 were included. The quality of evidence was assessed using the check list designed by the Cochrane Renal Group. The strength of recommendation was determinated by Levels of Evidence (Oxford Centre for Evidence-based Medicine). On the basis of current evidence, 20 recommendations were elaborated for the treatment and monitoring of patients with AAV with renal involvement in several clinical scenarios, in order to provide physicians a rational approach in daily clinical practice. PMID- 26738203 TI - Response to Letter Regarding Article, "Myosin Activator Omecamtiv Mecarbil Increases Myocardial Oxygen Consumption and Impairs Cardiac Efficiency Mediated by Resting Myosin ATPase Activity". PMID- 26738204 TI - Impact of the Nationwide Intravenous Selenium Product Shortage on the Development of Selenium Deficiency in Infants Dependent on Long-Term Parenteral Nutrition. AB - BACKGROUND: For patients dependent on parenteral nutrition (PN), selenium must be supplemented intravenously. A nationwide intravenous selenium shortage began in April 2011. The impact of this shortage on PN-dependent infants was evaluated by examining the provision of selenium, development of biochemical deficiency, and costs associated with the shortage. MATERIALS AND METHODS: This single-center, retrospective study included PN-dependent infants aged <=1 year who weighed <=30 kg, received PN for >=1 month, and had >=1 serum selenium measurement. The primary outcome was the incidence of biochemical selenium deficiency. Secondary outcomes included severity of biochemical deficiency, clinical manifestations, costs, and relationship between serum selenium levels and selenium dose. RESULTS: The average selenium dose decreased 2-fold during the shortage (2.1 +/- 1.2 ug/kg/d; range, 0.2-4.6 ug/kg/d) versus the nonshortage period (3.8 +/- 1 ug/kg/d; range, 2.4-6 ug/kg/d; P < .001). A linear relationship between serum selenium concentration and selenium dose was observed (r(2) = 0.42), with a dose of 6 ug/kg/d expected to result in normal serum levels in most cases. Similar proportions of patients developed biochemical deficiency in both groups: shortage period, 59.1%; nonshortage, 66.7%; P = .13. The severity of biochemical deficiency was similar between groups. A significant increase in incremental cost during the shortage was observed. CONCLUSION: This is the first study examining the impact of the intravenous selenium shortage on PN-dependent infants. Both groups exhibited similarly high incidences of biochemical selenium deficiency, suggesting higher empiric doses may benefit this population. However, ongoing shortages limit the ability to provide supplementation. PMID- 26738205 TI - Ethanol Lock Efficacy and Associated Complications in Children With Intestinal Failure. AB - BACKGROUND: Prophylactic ethanol lock therapy (ELT) reduces central line associated bloodstream infections (CLA-BSIs) in children with intestinal failure (IF). However, the risk of associated complications is unclear. We aim to describe our experience with prophylactic ethanol locks in a cohort of patients with IF. MATERIALS AND METHODS: Thirty patients on ELT from 2010-2013 were identified by review of our intestinal rehabilitation registry. Patient demographics, CLA-BSI events, and line complications were extracted. Comparisons in infection and complication rates when on and off ELT were made using a Poisson mixed-effect regression model. RESULTS: CLA-BSIs when on and off ELT were 3.1 and 5.5 per 1000 catheter days, respectively (P <015). Overall complication rates were similar in both groups. In those patients who experienced a complication, the complication rates on ELT compared with time off ELT were significantly lower (P <003). Line perforation or breakage rates declined significantly when on ELT, from 1.8 to 1.53 per 1000 catheter days (P <006). Line occlusion rates also decreased on ELT, from 0.6 to 0.3 per 1000 catheter days (P =056). Infecting organisms were not different on and off ELT, and patients experienced a similar number of polymicrobial infections on or off therapy. Klebsiella pneumoniae was the most common infecting organism in both groups. CONCLUSIONS: Ethanol lock therapy use reduces both CLA-BSI and central line complication rates in children with IF. These results underscore the safety and efficacy of ELT use in this population. PMID- 26738207 TI - Author Reply. PMID- 26738206 TI - Novel Attributions of TREMs in Immunity. AB - The emerging role of the TREMs (Triggering Receptors Expressed by Myeloid cells) family in inflammation makes it important to explore their molecular mechanisms governing key pathways in inflammatory diseases. The TREMs family interaction with microbial products make it a strong candidate to target inflammatory diseases and raises an important question of its potential as a useful target in inflammatory diseases caused by products other than microbes, for example psoriasis. The interaction of TREMs with various immune responses can be of key importance in handling inflammatory diseases. The well established interaction of TREM-1 with microbial products like LPS and the emerging interactions with products from different important diseases of brain, heart, lungs and skin demands its full investigation as a therapeutic target. The post translational modifications (PTMs) that might regulate the functions of genes are also discussed and its future potential is reviewed. Furthermore, Its close cross talk with TLRs, NLRs and NODs is also reviewed in context of developing novel therapeutics. PMID- 26738208 TI - Save Money on Your Meds: Prices can vary widely from store to store, even in the same town. The trick is to shop around. PMID- 26738209 TI - Making the World Safe From Superbugs. AB - In this final installment of our 3-part series, we review the progress-- and work yet to be done--to stop the antibiotic overuse in meat and poultry production that gives rise to dangerous bacteria. Plus, learn what protections consumers deserve and should demand. PMID- 26738211 TI - Tom Reilly--In Memoriam. PMID- 26738212 TI - Sport Science in the 2010 Vancouver Winter Olympics. PMID- 26738213 TI - Local Dental Networks: Trendy or Transformational?. PMID- 26738214 TI - The feasibility of using an alcohol screening tool in a UK dental setting to identify patients' alcohol consumption. PMID- 26738215 TI - Long-term evaluation of the clinical effectiveness of community milk fluoridation in Bulgaria. AB - OBJECTIVE: To determine the clinical effectiveness of a community milk fluoridation programme. BASIC RESEARCH DESIGN: Parallel arm 5-year cohort study, with final cross-sectional comparisons between groups. PARTICIPANTS: 3-year-olds in 8 Bulgarian cities/towns entered the cohort study with random samples (n = 1,782) recruited at baseline in 2004. After 5 years in 2009 sub-samples (about 30%) of these now aged 8 were randomly selected in intervention sites for follow up examination (n = 454); 276 controls were examined at the age 8 years. For cross-sectional comparisons, in 2004, 284 3-year-olds from control cities were baseline examined for caries, then 276 children at the age 8 years in 2009. INTERVENTIONS: In six intervention communities: 1,498 examined children received 0.5 mg F in 100 or 200 ml school milk or yogurt provided each school day; a further 180 received non-fluoridated milk. In two control communities, fluoride was not added to 284 children's school milk. MAIN OUTCOME MEASURES: Dental caries experience of primary, and permanent teeth. RESULTS: For primary teeth, caries increments were 46% (p < 0.001) and 30% (p < 0.01) lower in the fluoridated milk groups compared with non-fluoridated milk groups in the intervention and control communities, respectively. For permanent teeth those reductions were 61% and 53% (p < 0.001). The cross-sectional comparisons of 8-year-olds showed significant changes in dental caries experience over time; in children consuming fluoridated milk the level of dmfs fell by 43% (2004 and 2009) against 11% in the control group. Among children consuming fluoridated milk the DMFS fell 68% against rising 3% in the controls. CONCLUSIONS: Fluoridated milk delivered daily in schools in Bulgaria resulted in substantially lower caries development compared with children in schools receiving milk without added fluoride. The nation-wide experiences from milk fluoridation indicate that such a public health scheme can be effective to the global fight against dental caries of children. PMID- 26738216 TI - Is the value of oral health related to culture and environment, or function and aesthetics? AB - OBJECTIVE: To examine the disutility of tooth loss. It compared how people value their teeth in two countries which are culturally similar in order to explore the effect of culture on self-perceptions of oral health. BASIC RESEARCH DESIGN: Cross sectional study. PARTICIPANTS: Participants were recruited from subjects attending two hospitals in Turkey and in Iran. INTERVENTIONS: Nineteen descriptions of mouths with varying degrees and types of tooth loss were presented to the participants. They were shown mouth models of partially edentate dentitions and the teeth missing were explained in relation to the participants own mouth. The participants were specifically asked to consider the role their teeth played in function (chewing), communication (speech) and aesthetics (looks) along with "all the other things that make your mouth important". MAIN OUTCOME MEASURES: The participants were asked to indicate on a visual analogue scale how they would value the health of their mouth if they lost the tooth/teeth described and the resultant space was left unrestored. RESULTS: Overall 152 subjects participated, 78 in Turkey and 74 in Iran with 83 being female and 69 male. Their mean age was 29.5 years (SD 9.3), 62.5% had experienced tooth loss and 37.5% had complete (or completely restored) dentitions. Although there were no differences between the two countries in the degree of utility people attached to anterior teeth, Turkish participants attached significantly more disutility than Iranians to the loss of premolar and molar teeth (p < 0.003). CONCLUSION: Country of origin had an influence on the value placed on certain parts of the dentition and this effect is independent of the number of missing teeth, gender and age. This implies that attitudes to oral health are influenced by prevalent cultural attitudes more than by function. PMID- 26738217 TI - Time trends and determinants of acute odontogenic maxillofacial infections in Lithuania: a retrospective national 2009-2013 treatment data audit. AB - OBJECTIVES: To examine the distribution of treatment facilities accepting patients with acute odontogenic maxillofacial infections (AOMIs), time trends in incidence and relate these infections with a number of determinants. METHODS: A national Lithuanian retrospective study gathered data on all patients treated in outpatient/inpatient treatment facilities. Adjusted Incidence Ratios (AIRs) of AOMIs were calculated separately for each type of infection and for each year. Administrative districts (ADs) were grouped into low, medium, and high thirds based on the regional determinants: socio-economic index (R-SEI), access to basic (R-BDCI) or specialized dental care (R-SDCI) and index of systemic diseases (R ISD). RESULTS: There were no statistically significant geographical differences in the distribution of TFs providing care for patients with AOMIs. Numbers of treatment facilities consistently increased from 2009 to 2013, but there was no consistent increase/decrease in the incidence of AOMIs (-1%). Regions with the highest R-SEI tended to have a higher incidence of AOMIs as compared to regions with medium or low R-SEI. When controlled for other determinants, lower R-BDCI/R SDCI scores were associated with a higher incidence of AOMIs. CONCLUSIONS: High annual incidences (-1% of a total population) were diagnosed and treated for AOMIs, but there was no consistent time trend for these infections. PMID- 26738218 TI - Patient safety in domiciliary dental care for elderly nursing home residents in Sweden. AB - OBJECTIVE: To analyse patient safety in domiciliary dental care, with data from a quality registry. DESIGN: Retrospective analysis. CLINICAL SETTING: Domiciliary dental care, private caregiver, Sweden, 2012-2014. METHODS: All reported events in the quality registry at a provider of domiciliary dental care, (2012-05-01 to 2014-06-30) were categorized into 14 domains, and for severity as 'minor', 'moderate', or 'serious' events. The reported events were also independently assessed by an experienced reviewer for national requirements of reporting patient safety related events. RESULTS: The quality registry covered 724 (0.03%) reported events during 218,586 consecutive treatment sessions in domiciliary dental care, including 628,070 registered dental procedures. Fifty (6.9%) of the reported events were patient safety related, of which 11 (1.5%) events were reportedly of minor severity, 20 (2.8%) as moderate, and 19 (2.6%) as serious. For all degrees of severity, the most frequently reported events were related to problems with patient identity control (3.3%). None of the events required reporting to national authorities. CONCLUSIONS: Domiciliary dental care has a low frequency of patient safety related events (0.03% of all treatments). Identity controls need to be emphasised in nursing homes or where individuals are dependent on the care of others. PMID- 26738219 TI - Dental anxiety and oral health in 15-year-olds: a repeated cross-sectional study over 30 years. AB - OBJECTIVES: To report the prevalence of dental anxiety in Swedish 15-year-olds over a 30-year period (1973-2003) and how dental anxiety relates to oral health. BASIC RESEARCH DESIGN: The study used a repeated cross-sectional design. PARTICIPANTS: In 1973, 1983, 1993, and 2003, random samples of 96 to 107 15-year olds were selected from the city of Jonkoping, Sweden, 405 overall. MAIN OUTCOME MEASURES: Dental anxiety (DA) and its association with oral health (caries, gingivitis, plaque, fillings) were analysed (alpha = 0.05). RESULTS: The proportions of dentally anxious during the period were 38% (n = 37) in 1973, 26% (n = 28) in 1983, 18% (n = 15) in 1993 and 13% (n = 12) in 2003 a clearly decreasing trend with time. The strongest predictor of DA was gender, with girls reporting higher levels of DA. In three of the four examination years, adolescents with DA had more filled permanent surfaces than those without DA. Those with DA had a greater caries experience only in 1973. No associations were found between DA and plaque or gingivitis. Multivariate logistic modelling confirmed that DA decreased over time and that girls had higher levels of DA. CONCLUSIONS: This study showed a clear decrease in DA in 15-year-olds over a 30 year period, with a greater proportion of girls being more dentally anxious. The results also indicate a relationship between DA and oral health; the dentally anxious having more filled surfaces and, only in 1973, more decayed tooth surfaces. PMID- 26738220 TI - Development and evaluation of a Dental Patient Feedback on Consultation skills (DPFC) measure to enhance communication. AB - OBJECTIVES: To adapt an existing medical questionnaire on patient-provider communication for use in the dental setting, and to evaluate the performance of the measure in a first dental encounter (validity and reliability). METHODS: A patient feedback questionnaire on consultation skills was adapted for use in dental settings through content and convergent validity. A survey of dentist consultation skills was conducted among adults attending a teaching hospital. Patients self-completed a 16-item Dental Patient Feedback on Consultation skills (DPFC) questionnaire during their first dental consultations. Repeat assessments were conducted on -10% of the sample. Variations in DPFC responses (scale and item level) were examined in relation to socio-demographics and dental attendance pattern in bivariate and regression analyses. Internal reliability (Cronbach's alpha) and test-retest reliability (Intraclass Correlation Coefficient - ICC) were examined. RESULTS: A DPFC questionnaire was derived following minor modifications. The clarity of items ranged from 81.1-100% and content validity index ranged from 0.73-1.00. Exploratory item factor analysis showed a one dimensional construct. The response rate to the survey was 90.5% (389/430). Variations in DPFC scores with respect to global rating of satisfaction were apparent (P < 0.001). Cronbach's alpha value was 0.94 and ICC value was 0.89. Bivariate and regression analyses identified dental attendance pattern as a key factor associated with DPFC (P < 0.05); but no significant differences were observed with respect to socio-demographic factors. CONCLUSIONS: A DPFC questionnaire was adapted with acceptable validity and reliability. Dental service utilization pattern was associated with dentist-patient clinical communication rather than socio-demographics. PMID- 26738221 TI - Listening to older adults: community consultation on a new dental service. AB - BACKGROUND: Increased life expectancy, retention of a natural dentition often heavily restored, and increasing risks of oral disease mean that older people have particular dental needs and yet uptake of care is low. A new health and wellbeing centre in south London offering student-delivered care has been built to serve the local community. Community views could informed the planning of acceptable care for older people. OBJECTIVE: To explore the views and expectations of older adults towards dental services and ascertain how a new dental centre may best provide dental care. RESEARCH DESIGN: This qualitative study used in-depth and triad interviews to explore the views of older people. Purposive sampling of local centres/groups for older adults was undertaken and all willing clients interviewed. Interviews were audio recorded, transcribed and analysed using Framework Methodology with emerging themes categorised according to Maxwell's six descriptors of quality. RESULTS: Nine sessions (five triad and four in-depth interviews) involving 17 older adults were conducted in local day centres. Barriers to dental care were largely related to fear, cost, transport, lack of perceived need and the attitude of clinicians. Outcomes related to acceptability featured highly in a dental service for older adults; the overarching principles of 'delivering mutual benefit' for students and older people, 'experiencing warm humanity' and 'restoring dignity and worth' were central to their views of quality care. The importance of clinicians, whether student or staff, delivering person centred care with warm humanity was dominant: comprising 'welcoming', 'valuing', 'listening' 'communicating' and 'caring' for older adults to enhance relationships and contributing to 'restoring dignity and worth'. CONCLUSION: Community engagement identified a willingness amongst older adults to utilise dental services where mutual benefit was perceived and, importantly, there were low barriers to care and a warm humanity was exhibited. PMID- 26738223 TI - Perceived mental stress in relation to oral health over time in middle-aged Swedish women. AB - OBJECTIVES: To study perceived mental stress in relation to oral health among Swedish middle-aged women over a 36-year period, including considerations concerning smoking and socioeconomic status (SES). METHODS: This combined medical and dental study includes three cross-sectional (1968/9 N = 746, 1980/1 N = 432, 2004/5 N = 500) surveys of 38- and 50-year-old women included in the Prospective Population Study of Women in Gothenburg, Sweden. Panoramic radiography was used to register the number of teeth, filled teeth and decayed teeth and the level of periodontal bone loss. The information concerning perceived mental stress, smoking and education (chosen to represent SES) was questionnaire-based. RESULTS: Perceived mental stress increased over the 36-year period, but was not related to oral health. The time of examination year had a protective effect on oral health, with a larger number of remaining teeth, fewer decayed teeth and less periodontal bone loss in the later examination year, 2004/5, compared with 1968/9. Risk factors for poor oral health were smoking, greater age (50 vs. 38 years) and low educational level. Smokers had fewer filled teeth than non-smokers except in 2004/5, and there was a shift over time towards fewer filled teeth among highly educated women. CONCLUSIONS: A remarkable increase in perceived mental stress was seen among the women over time, but was not associated with oral health. Smoking, greater age and low educational were risk factors for poor oral health, whereas a later examination year was a protective factor. PMID- 26738222 TI - A retrospective audit of population service access trends for cleft lip and cleft palate patients. AB - Population prevalence of orofacial clefts (OFCs) is well documented but the service utilisation patterns of these patients have received limited consideration. OBJECTIVE: To analyse 10-year trends in the utilisation of subsidised OFC related services in Australia. DESIGN: Retrospective audit of service utilisation and claims datasets. METHODS: Using state-wide hospital admission data, all persons treated for Cleft Palate Only (CPO) and Cleft Lip Only (CLO) as their primary diagnosis from 1999 to 2009 in Western Australia were included in the data frameset. Additionally, National Medicare out-of-hospital claims from 2003 to 2013 were added to the data frameset. The socioeconomic status and accessibility to services were analysed as effectors of service-mix such as age group, gender and geographic location. RESULTS: Of 721 in-hospital care episodes in Western Australia, 69% had CPO and 31% CLO as their principal diagnosis. Hospitalisations occurred from 0-69 years of age, but three quarters of all episodes occurred from 0-4 years of age (averaging one to two episodes per child). Whilst total hospitalisations were about four times higher for patients resident in high access areas, adjustment for population found the poorest 20% of the population having substantially lower hospital admission rates than the rest of the population. In Australia, claims for out-of-hospital cleft-related services varied between States. The overall pattern of out-of-hospital Medicare claims nationwide showed orthodontic services having the highest number of claims, followed by prosthodontic then oral surgical services. CONCLUSION: These data provide a picture of diverse service utilisation and leads to some interesting conclusions about geographic and economic access as well as cost shifts between State and Commonwealth. PMID- 26738225 TI - Caregiver financial distress, depressive symptoms and limited social capital as barriers to children's dental care in a mid-western county in the United States. AB - OBJECTIVE: To identify barriers to children's access to dental care. BASIC RESEARCH DESIGN: A cross-sectional health survey. SETTING: All residential census tracts in Genesee County, Michigan, USA. PARTICIPANTS: 498 adults who reported having children in their households, extracted from 2,932 randomly selected adult participants in the 2009 and 2011 surveys. MAIN MEASURES: Stepwise logistic regression was used to predict two dependent variables: children's lack of any visits to dentists' offices and unmet dental care needs (defined as needing dental care but not receiving it due to cost) in the previous year as reported by the adults. Independent variables included gender, age, education, race/ethnicity, financial planning, financial distress, fear of crime, stress, depressive symptoms, experiences of discrimination, and neighbourhood social capital. RESULTS: Of the 498 adults, 29.9% reported that they had children who had not visited a dentist in the past 12 months and 13% reported that they had household children with unmet dental care needs in the past year. Adults who reported higher depressive symptoms, lower neighbourhood social capital, greater financial distress, and who were younger were more likely to have household children who did not visit a dentist in the past year. Financial distress was the only significant predictor when controlling for other variables to predict unmet dental care needs. CONCLUSIONS: Factors beyond financial distress affect children's dental care; these include parental depressive symptoms and lower neighbourhood social capital. Interventions promoting parental mental health and social integration may increase dental care among children. PMID- 26738224 TI - Dental utilization disparities in a Jewish context: reasons and potential solutions. AB - Demographic discrepancies in dental healthcare utilization and access to care have historically been studied and attributed to such factors as socioeconomic status, race, and ethnicity. Such potential discrepancies and contributing factors amongst the Jewish population have been little explore. OBJECTIVE: To examine the frequency of dental visits among Jewish subgroups and explored possible explanatory factors for differences in dental healthcare utilization, such as financial constraints, dental anxiety, religious perspectives on health, lack of perceived need, poor accessibility, and scheduling conflicts. BASIC RESEARCH DESIGN: Cross-sectional study. PARTICIPANTS: A religiously diverse non clinical sample of 169 Jews completed measures on demographics, dental visit frequency, dental anxiety, and general religiousness. RESULTS: On average, Orthodox Jews visit the dentist less often than non-Orthodox Jews (OR = 0.43) and Ultra-Orthodox Jews markedly less (OR = 0.23). Moreover, differences between these groups in dental visits were largely mediated by differences in dental anxiety, poor accessibility, lack of perceived need and scheduling conflicts. CONCLUSION: These results identify a population that is at risk for poor oral health and suggests possible preventive and corrective interventions. PMID- 26738226 TI - [Vaccines, a fundamental tool to maintain and improve population health]. PMID- 26738227 TI - [THE SCHOOL NURSE AND PRIMARY HEALTH NURSE, APROPOS THE DIABETES CARE AT SCHOOL IN EXTREMADURA]. AB - The amount of chronic health problems in students is increasing with the time (food allergies, diabetes mellitus...). The presence of a school nurse in the educational sites could be the key to control this kind of health issues. OBJECTIVE: Overhaul the function of a possible nurse in the schools of our region, with the target of trying to control and prevent diabetes mellitus and other illnesses. METHODOLOGY: We have reviewed the figure of a school nurse and the diabetes care in non-university schools, using scientific sources of information and the own experience. RESULTS: Many countries of the European environment are performing really important activities which have their benefits on the students'health; using the figure of a school nurse. However, the presence of this person is generally not constant in the educational sites, and requires some improvements. CONCLUSIONS: We must promote the establishment of school nurses in Spain so that we can take care and prevent many health problems which mostly affect youth and childhood. PMID- 26738228 TI - [IMPACT OF LATERALITY-LOCATION IN THE CONSUMPTION OF HEALTH PRODUCTS IN A HEMODIALYSIS UNIT]. AB - INTRODUCTION. The objective is to determine whether laterality-location inside shopping cures three health resources (gauze, bandages and physiological sera [PS] from 10 cc) influences the amount of material consumed in the Cabinet of Hemodialysis of the Fundaci6 Puigvert. METHODOLOGY: Quasi-experimental study with no control group post test type. The sample consisted of thirty expert nurses (non-probability convenience sampling). The study was conducted between March and August 2014. For two months, the three medical devices remained on the right side of the carriage cures for two months in the middle and finally two months on the left side. The analysis was performed using SPSS statistical software, for all tests a significance level < .005 was used. RESULTS: Average age of 40.4 years and a mean old in the Cabinet of 14 years. Increased consumption and gauze PS is observed when the products are placed on the right side of center but is not significant (p > .005). Dressings consumption is higher on the right than in the center (p < .001). The consumption of the three health products is lower on the left side of the truck when placed in the center (p <.001) or right side (p < .001). CONCLUSIONS: The laterality-location has a direct influence on the consumption of medical supplies. Consumption on the left side is less than in the center and on the right side. The laterality-location is a good management strategy. PMID- 26738229 TI - [ADMINISTRATION OF ENTERAL NUTRITION. USE OF INFUSION PUMPS]. AB - Enteral nutrition (NE) is a technique of artificial nutrition that enables management by digestive tract of a defined mixture of nutrients and water, by means of probes implanted nasally or by enterostomies (eg: gastrostomy). Whenever the patient present limitations for voluntary oral ingestion or swallowing of the nutrients, and digestive capacity permitted to absorb nutrients, will draw the administration through a tube. Concern for the nutritional status of the patients is a more present reality among health professionals have demonstrated the direct relationship between malnutrition and morbidity and mortality of hospitalized patients. Enteral nutrition has become a useful procedure for the treatment of these patients, reducing their morbidity and mortality. The NE can be administered by infusion by gravity drip (less clinical use) pump and syringe (bolus), taking into account the speed of it, thus avoiding a large number of complications (usually due to too rapid administrations), so the method employed will be adjusted to the needs of each patient, whereas, the tolerance and its risk of aspiration. In this paper we will focus on the NE by infusion pump administration emphasizing the reduction of complications with this methodology against the administration by bolus (syringe). PMID- 26738230 TI - [HUMAN IMMUNODEFICIENCY VIRUS: WHAT HAS BEEN PUBLISHED BETWEEN 2008-2012 IN IBEROAMERICA? ASSESSING NURSING PRODUCTION]. AB - AIM: By 2013, 35.3 million people are living with HIV in the world. The objective of our study is to evaluate the scientific activity and the production of VIH in Spanish between the years 2008 and 2012. MATERIAL AND METHODS: Bibliometric, descriptive of cross section study of articles published between 2008 and 2012 into Spanish and Portuguese with about 14 variables. RESULTS: 830 articles have been reviewed (46.9% original articles) 141 journals other than 18 countries. In 61% of cases the main author was a graduate in medicine and 27.7% was a nurse. 38.9% of the articles are based on issues of treatment and tertiary prevention of HIV infection. DISCUSSION: Despite being a problem with high incidence, the Spanish nursing published little about HIV/AIDS infection, unlike the Brazilian companions, who either by rebound or topicality of the theme, see increased their publications and interventions in recent years. PMID- 26738231 TI - [FERTILITY PRESERVATION OF WOMEN: OOCYTE VITRIFICATION]. AB - Cryopreservation ofhuman oocytes to delay fertility also be an option for women who are going to be subjected to a cancer/autoimmune treatment. It allows for creating a bank of oocytes for donation in assisted reproduction centers. The legislation allows the use of cryopreserved oocytes throughout the reproductive life of women with what conservation could last up to 48-50 years. Oocyte vitrification is a ultrafast freezing method in which cryoprotectants are used to prevent the formation of ice crystals within the cell. Treatment for oocyte vitrification process is similar to IVF treatment, ending at the time of obtaining the ova. The eggs obtained in the laboratory are classified according to maturity and quality. The apartments will be cryopreserved by vitrification technique tanks and maintained in liquid nitrogen until used for reproductive purposes. PMID- 26738232 TI - [TUTORS AND NURSING STUDENTS WITH FOCUS ON PRIMARY CARE]. AB - Primary Health Care sets up an area influenced by the relationship between professionals and users, in which different disciplines, such as nursing, develop their learning procedures both in graduate and postgraduate training. In this context, students are tutored by professionals who have developed teaching skills. Along these lines, this manuscript aims to identifying the different types of nursing students and tutors who develop their teaching skills in Primary Health Centers. To this purpose, we invite the reader to know the historical and current milestones that characterize teaching systems and influence learning profiles of students and teachers. PMID- 26738233 TI - [THE REVISTA ROL CONTRIBUTION TO THE DEVELOPMENT OF SPANISH NURSING]. AB - In 1978, a year after the integration of nursing studies at the university, was born the first Spanish journal of nursing: ROL de Enfermeria. From then until now, this scientific publication has made history with the nursing profession. Through this work we have analyzed, by a bibliographical review, the scientific production of this tour between 1978 and December 2014. The number of published articles has been 4651, of which more than half have tried topics about nursing as a profession and problems of collaboration. PMID- 26738234 TI - [Comprehensive geriatric assessment]. PMID- 26738235 TI - [Interview with Isidro Garcia]. PMID- 26738236 TI - [Non-vaccination of children hinders collective immunity and increases the risk of recurrence of diseases that are almost under control]. PMID- 26738237 TI - [Interview with Jose Maria Arevalo La Calle]. PMID- 26738238 TI - [Building from unity and diversity]. PMID- 26738239 TI - [The European University of Madrid and the University Hospital Infanta Sofia innovate for excellence in clinical practice in nursing degree]. PMID- 26738240 TI - [Editorial]. PMID- 26738241 TI - [Role of NO signaling pathway in regulation of vascular tone--new aspects]. AB - Nitric oxide (NO) participates in the control of the cardiovascular system where two constitutive isoforms of NO-synthase were discovered: endothelial and neuronal. Both isoforms were observed in various cells, however, endothelial NO synthase is predominantly present in the endothelium. Injury of the endothelium disturbs the balance between vasodilation and vasoconstriction and triggers different pathological alterations. In addition, whereas the intact endothelium protects vascular smooth muscle from oxidative attack, intervention in the vascular wall integrity increases the concentration of vascular superoxides, thus disturbing the effects of NO. Morphological evidence demonstrated that both isoforms of NO-synthase were expressed also in smooth muscle cells and functional studies revealed that different pathological interventions in endothelial function (such as oxidative stress or hypertension) were associated with NO generation in the vascular media. In this case, the generation of NO by vascular smooth muscle may represent a physiologically relevant compensation of endothelial NO deficiency. Whereas long-term inhibition of endothelial NO synthase resulted in an unequivocal pattern of cardiovascular changes, inhibition of neuronal NO-synthase led to opposite effects, suggesting a specific position of neuronal NO-synthase in the regulation of cardiovascular tone. The specificity of endothelial or neuronal NO function seems to be related to a particular circulatory area and it is presumably determined by mutual interactions with other regulatory systems (sympathoadrenergic, renin-angiotensin, etc.). PMID- 26738242 TI - [The importance of selected intestinal hormones in the regulation of food intake and perspectives of their use in the treatment of obesity]. AB - Obesity currently represents one of the most important global health problems. According to the World health organization's prediction the number of obese patients in the adult population will increase to 700 million by 2015. The reasons of constantly increasing prevalence of obesity include a combination of genetic predisposition, the predominance of energy intake over energy expenditure due to easy availability of calorie-rich meals and permanently decreasing energy expenditure from physical activity. Understanding the precise mechanisms of food intake regulation is essential for development of body weight-reducing drugs with long-term effects. The central nervous system plays the main role in the regulation of food intake. This system is influenced by a number of long-acting and short-acting peripheral signals informing about the degree of saturation, the amount of energy reserves and the overall state of energy homeostasis. Hormones produced in the gastrointestinal tract play an important role in the regulation of food intake. The aim of this article is to summarize the significance of selected gut hormones in the regulation of food intake and to discuss their possible use in the treatment of obesity and its associated comorbidities. PMID- 26738243 TI - [Calcium sensitivity in vascular smooth muscle cell during hypoxic pulmonary vasoconstriction]. AB - Hypoxic pulmonary vasoconstriction is a means of optimising the oxygenation of blood in the lungs by redistributing the flow from poorly ventilated areas into well ventilated ones. It is caused by a direct effect of hypoxia on pulmonary vascular smooth muscle cells. For a vascular smooth muscle cell to contract, an increased intracellular concentration of calcium is needed. However, the contraction force can also be regulated independently of calcium concentration by calcium sensitivity. The sensitivity is regulated mainly by activation/deactivation of myosin light chain phosphatase. Several metabolic pathways converge on this enzyme. The increase in calcium sensitivity is an important process during hypoxic pulmonary vasoconstriction. PMID- 26738244 TI - [Intestinal microbiota and the brain: multilevel interactions in health and disease]. AB - Commensal bacteria of the digestive tract are separated from the brain by multiple barriers. Despite that bacteria residing in the intestine and the neurons of the brain interact by neural and humoral pathways. Mental processes, such as the stress response, may affect the composition and function of intestinal bacteria via the brain-gut axis. On the other hand, intestinal bacteria can influence the processes in the brain through the gut-brain axis. Disruption of these interactions may be involved in various alterations both in the function of the gastrointestinal tract and the brain function. PMID- 26738245 TI - [Adenosine and its role in physiology]. AB - Adenosine is not just a major component of adenine nucleotides and ribonucleic acids, but also has its own signaling functions. ExtraceIlular level of adenosine in an organism is strictly maintained through the balance between its formation, degradation and transport. Adenosine is formed by enzymatic degradation of adenosine triphosphate and eliminated by phosphorylation to adenosine monophosphate or by deamination to inosine. Transport of adenosine across the cell membrane is ensured by equilibrative and concentrative nucleoside transporters. All these processes participate in maintenance of adenosine level under normal conditions, but a balanced equilibrium can be disrupted in some pathophysiological situations. Extracellular adenosine as a signaling molecule binds to adenosine receptors, which may trigger via their cognate trimeric G proteins different signaling pathways. In this way, adenosine regulates energy homeostasis and affects the function of various organs. Targeted pharmacological manipulations of specific adenosine receptor subtypes or enzymes involved in its metabolism can potentially be used for therapeutic purposes. PMID- 26738246 TI - Be vigilant for neonatal abstinence syndrome. PMID- 26738247 TI - Playing it safe: exercise and cardiovascular health. AB - Regular physical activity controls acquired cardiovascular risk factors such as obesity, diabetes mellitus, hypertension and hyperlipidaemia. Exercise is generally associated with a 50% reduction in adverse events from coronary artery disease (CAD). The benefits of exercise extend well beyond the cardiovascular system. Recent evidence suggests that exercise prevents cell senescence, and active individuals are at lower risk of developing certain malignancies including cancer of the prostate and the colon, osteoporosis, depression and dementia. Individuals who exercise regularly extend their life expectancy by three to seven years. Healthy individuals should engage in 150 minutes of moderate-intensity, aerobic exercise per week. Recent studies have demonstrated that even lower volumes of exercise below these recommendations confer health benefits, which is highly relevant to individuals with established cardiac disease including heart failure. Sudden cardiac death in athletes under 35 is rare with.estimates ranging from 1 in 50,000 to 1 in 200,000. Hereditary and congenital abnormalities of the heart are the most common cause of nontraumatic death during sport in young athletes. In middle-aged recreational athletes more than 90% of sudden cardiac deaths occur in males and more than 90% are caused by atherosclerotic CAD. The AHA and the ESC advocate pre-participation screening of young athletes. The ECG has the ability to detect congenital accessory pathways and ion channelopathies, and is frequently abnormal in individuals with cardiomyopathy. Screening with a 12-lead ECG in older athletes is of limited value given the overwhelming contribution of atherosclerotic CAD to sudden cardiac death. PMID- 26738248 TI - Management of heart failure with preserved ejection fraction. AB - Heart failure affects nearly one million people in the UK. Half of these patients have normal, or near normal, left ventricular ejection fraction and are classified as heart failure with preserved ejection fraction (HFpEF). Newer imaging techniques have confirmed that systolic function in HFpEF patients is not completely normal, with reduced long axis function and extensive but subtle changes on exercise. Patients are likely to be older women with a history of hypertension. Other cardiovascular risk factors, such as diabetes mellitus, atrial fibrillation and coronary artery disease are prevalent in the HFpEF population. Clinical symptoms and signs in HFpEF are often nonspecific although the primary symptoms are breathlessness, fatigue and fluid retention. There is still no single diagnostic test for HFpEF and the cornerstone in the assessment remains a thorough medical history and physical examination. The duration and extent of the symptoms are relevant and it is useful to classify patients according to the NYHA functional assessment. Physical examination should include the patient's BMI and weight, heart rate and rhythm, lying and standing blood pressure and auscultation to rule out valvular disease and pulmonary congestion. Estimating the jugular venous pressure and the presence of peripheral oedema allows assessment of the patient's volume status. Patients with heart failure should be referred to heart failure nurses and have follow-up with local cardiology services as these have both been shown to reduce mortality. PMID- 26738249 TI - Diagnosis directs treatment in fungal infections of the skin. AB - Dermatophyte fungi are confined to the keratin layer of the epidermis and include three genera: Microsporum, Epidermophyton and Trichophyton. These infections can be transmitted by human contact (anthropophilic), from the soil (geophilic) and by animal (zoophilic) spread. Dermatophyte infections usually present as an erythematous, scaly eruption, which may or may not be itchy. Asymmetry is an important clinical clue to fungal infection, as is annular morphology. Examination under ultraviolet (Wood's light) can be helpful. The gold standard for diagnosing cutaneous fungal infections is microscopy and culture of scale, hair or nail, and a definite diagnosis is desirable before commencing treatment, especially with oral therapy. Any dermatophyte species affecting the body can affect the hands. The most common organism is T. rubrum. Tinea corporis infection affects the trunk mainly in children and adolescents, and all genera of dermatophyte can cause it. Tinea cruris infection involves the groin region and is more common in men than women. T. rubrum is the most common causative dermatophyte. The clinical features of tinea capitis include patchy hair loss with varying degrees of scale, erythema and pustules. Infected hairs tend to break at the base, leaving stubble. Occasionally, there is invasion of the visible epidermis, resulting in a boggy, painful swelling with associated alopecia and regional lymphadenopathy known as a kerion. PMID- 26738250 TI - Pigmentation disorders. PMID- 26738251 TI - Helping our patients to understand risk. PMID- 26738252 TI - Independently from mitral regurgitation, Barlow disease may cause left ventricular enlargement and thereby anticipation of surgery. PMID- 26738253 TI - Timing of surgery in Barlow disease. PMID- 26738254 TI - Metopic suture and RUNX2, a key transcription factor in osseous morphogenesis with possible important implications for human brain evolution. AB - BACKGROUND: Overall, the comparative data available on the timing of metopic suture closure in present-day and fossil members of human lineage, as well as great apes, seem to indicate that human brain evolution occurred within a complex network of fetopelvic constraints, which required modification of frontal neurocranial ossification patterns, involving delayed fusion of the metopic suture. It is very interesting that the recent sequencing of the Neanderthal genome has revealed signs of positive selection in the modern human variant of the RUNX2 gene, which is known to affect metopic suture fusion in addition to being essential for osteoblast development and proper bone formation. It is possible that an evolutionary change in RUNX2, affecting aspects of the morphology of the upper body and cranium, was of importance in the origin of modern humans. Thus, to contribute to a better understanding of the molecular evolution of this gene probably implicated in human evolution, we performed a comparative bioinformatic analysis of the coding sequences of RUNX2 in Homo sapiens and other non-human Primates. RESULTS: We found amino-acid sequence differences between RUNX2 protein isoforms of Homo sapiens and the other Primates examined, that might have important implications for the timing of metopic suture closure. CONCLUSIONS: Further studies are needed to clear the potential distinct developmental roles of different species-specific RUNX2 N-terminal isoforms. Meantime, our bioinformatic analysis, regarding expression of the RUNX2 gene in Homo sapiens and other non-human Primates, has provided a contribution to this important issue of human evolution. PMID- 26738255 TI - Diabetic foot prevention: the role of exercise therapy in the treatment of limited joint mobility, muscle weakness and reduced gait speed. AB - OBJECTIVE: It is well known that limited joint mobility of the ankle and foot level, impaired muscular performance and reduced gait speed are risk factors for ulceration in diabetic foot. The aim of this study was to evaluate the effect of an experimental protocol of exercise therapy on joint mobility, muscular strength and gait speed in a group of long-term diabetic subjects. METHODS: The protocol consisted of a 12-week supervised training program; both joint mobility and muscular strength at the ankle were measured before and after exercise therapy respectively by an inclinometer and isometric dynamometers in 26 diabetic subjects and compared to 17 healthy controls. RESULTS: Ankle joint mobility of plantar flexion was reduced about 36% and dorsal flexion by about 23% in diabetic subjects compared to controls (p < 0.001), but significantly increased after exercise therapy (p < 0.001 for both). Ankle muscular strength in plantar flexion was reduced by about 51% and in dorsal flexion by 30% in diabetic patients compared to controls, but these also significantly increased after exercise therapy (p < 0.001). Consequently, patients' walking speed increased after exercise therapy by 0.28 m/s (p < 0.001). CONCLUSION: A 12-week supervised program of exercise therapy significantly improves joint mobility, muscular performance and walking speed in diabetic patients--thus limiting one of the pathogenic factors of diabetic foot and potentially preventing disability. PMID- 26738256 TI - A case of congenital left brachium agenesis (amelia, brachiomelia monobrachium) in Sahel goat ecotype. AB - This rare case of amelia in a doe-goat was observed in Tarka local government area, Benue State, middle belt region of Nigeria. The congenital deformity consisted of complete agenesis of the affected fore limb; the defect is commonly unilaterally manifested. The present congenitally impaired goat was approximately one and a half years old, and was a second kiddling of a normal multiparous dam. The left fore limb was grossly vestigial in development, while the homologous right hoof was splayed; the hind limbs were anatomically normal. Radiographs revealed morphological aberrations in intergumentary, skeletal, vascular, nervous systems and musculature of the affected limb. Sahel goat is alien to this developmental syndrome and this is to the best of our knowledge--the first case report of left sided brachial agenesia, (amelia) in a doe-goat of this breed. By season of occurrence, the hypothesis of interplay between genetics, climate and environment at large in the pathogenesis of this hereditary anomaly is raised and supported by the abundance of phytoteratogens in alternative diets in the dry seasons. The condition is compatible with life but may contribute to reproductive and economic loss in farms. PMID- 26738257 TI - The anatomy of vena cava in the work of Aretaeus of Cappadocia. AB - Aretaeus of Cappadocia did not deal systematically with the study of anatomy, as it can be assumed from the thorough study of his remaining work, as well as the references to the topics and the fragments of his lost treatises. We could also extract useful information on anatomy through his analytical descriptions about the various diseases in his remaining work. A perfect example is the anatomy of the upper and inferior vena cava exposed in his work on acute diseases. PMID- 26738258 TI - The anatomical knowledge of Joaquin Albarran (1860-1912). AB - Joaquin Maria Albarran (1860-1912) is broadly known as a brilliant mind and a pioneer of modern urology, in spite of his short life. Born in Cuba and being early an orphan, he was sent to Barcelona to study Medicine. Graduate at the age of seventeen, he continued his studies in Paris, where he was trained in surgery and urology, and spent the rest of his life having an extraordinary career as urology surgeon, chief of the Urology Department in Necker Hospital and professor at Paris Faculty of Medicine. Since his first studies, he had been passionate with anatomy, histology, pathology and microbiology and embodied in his books, today considered as classics, a great amount of the special knowledge he had for these fields and the most accurate descriptions of the operative techniques for the urinary tract system. PMID- 26738259 TI - Comparative morphometric analysis of the gastrointestinal tract of the captive greater cane rat (Thryonomys swinderianus) and African giant pouched rat (Cricetomys gambianus). AB - The greater cane rats (Thryonomys swinderianus) and African giant pouched rats (Cricetomys gambianus) are among the largest rodents in Africa, undergoing domestications for meat and research purposes. The aim of this study was to explore whether there are any quantitative anatomical gastrointestinal adaptations associated with their omnivorous or herbivorous diets. In the African giant rat, the mean gastrointestinal tract length and colon width of the males were significantly higher than their females counterpart (P < 0.05 and P < 0.01, respectively). In a similar way, the mean gastrointestinal tract weight, stomach length and jejunal width in males greater cane rat were significantly higher than in the females (P < 0.05, P < 0.01 and P < 0.01 respectively). The monogastric, omnivores African giant pouched rats had mean significant stomach length and width than greater cane rat (P < 0.01 and P < 0.01 respectively). Also, the duodenal length, jejunal and ileal widths were higher in the former than in the latter (P < 0.05, P < 0.05 and P < 0.01 respectively). The monogastric, herbivore greater cane rats had higher mean cecal width and colon length than the African giant pouched rat (P < 0.01 and P < 0.01 respectively). In conclusion, the African giant pouched rat had larger stomach and longer and wider small intestine, compared to the greater cane rat, which instead had more prominent cecum and wider and longer colon. This suggests that greater cane rats are hindgut fermenting herbivores (cecal fermenter), as is the case in most rodent species. PMID- 26738260 TI - The fourth slip of the flexor digitorum brevis muscle of the human foot. A systematic review and meta-analysis. AB - The flexor digitorum brevis muscle, and in particular its fourth slip, has a significant clinical and surgical importance in medical practice. However, as for the majority of tendons destined to the little toe, the fourth slip is undergoing a phylogenetic degeneration. The aim of this meta-analysis is to conduct an evidence synthesis on the prevalence of FDB-5 and its variants in humans. Twenty two studies met pre-defined inclusion criteria with a total of 2789 feet and 416 cadavers. Meta-analytical results of fourth slip agenesis were as follows; a) a true prevalence rate of 31.3%, b) a crude prevalence rate of 47%, c) a bilateral prevalence rate of 38.2%, d) a true prevalence rate of 77.3% in Indian populations, e) a true prevalence rate of ~ 20% in Japanese, Chinese, American, European and Turkish populations, f) an Odds Ratio of 1.5 significantly in favor for female gender, g) non-significance for hand side, h) a true prevalence rate of a thin fourth slip of 47.7%, and i) a true prevalence rate of the variations of its origin in 12.3%. The knowledge of the frequency of flexor digitorum brevis fourth slip agenesis and variations in relation to the demographic characteristics of patients would be of importance for tendon repair, tendon transfer or soft tissue reconstruction in foot surgery. PMID- 26738261 TI - Morpho-structural alterations of sub-chondral bone tissue in patients with osteoarthritis: a scanning electron microscopy study. AB - Osteoarthritis focuses principally on the degeneration of articular cartilage as a primary cause of the disease. The pathophysiological process of osteoarthritis is characterized by alteration of chondrocytes and the increased bone formation by sub-chondral osteoblasts. Infiltration of macrophages and perivascular T and B lymphocytes is observed, and these infiltrates have been demonstrated in both early and advanced disease. The morphological and phenotypic characteristics of osteocytic cells attached to the normal and the osteoarthritic matrix differ from each other, suggesting that specific signalling pathways arise or are altered between matrix and cells. On this basis, we have examined biopsies of bone obtained by normal femur and by femur of subjects affected by osteoarthritis using techniques of scanning electron microscopy in order to identify the morphostructural alterations that occur in the sub-chondral bone. Our results have shown that the bone tissue of subjects not affected by any disease of bone presents a well-organized structure, while the bone tissue obtained by patients affected by osteoarthritis shows a derangement of tissue itself possibly correlated with altered function of the osteoblasts, that during the pathological process produce a less mineralized extracellular matrix with consequent loss of the normal bone structure. In our opinion, during the osteoarthritic process there would be a defective signalling between bone cells leading to the production of an irregular, amorphous extracellular matrix by osteoblasts, characteristic of the pathological condition. PMID- 26738262 TI - Educational improvement in Medical English Practice: Questionnaire survey to sophomore medical students of Hokkaido University. AB - In the past, we made several efforts making curriculum changes to Medical English Practice, however, these changes did not improve motivation effectively. We have completely modified the curriculum in 2012, and performed a questionnaire survey to 112 sophomore medical students. In the final exam, students answered a questionnaire assessing all classes of the course by scoring 3 points (no change required), 2 points (minor change required), and 1 point (major change required or discontinue). In addition, students could write free comments about potential contents they would like to add to the curriculum. Each class was assessed as more than or equal to 2.5 points on average (range: 2.50-2.96). Potential contents students want to add are: 1. Speaking (45 students [55%]), 2. Listening (30 students [37%]), 3. Reading (6 students [7%]), 4. Writing (1 student [1%]). The most frequent suggestion was to include group discussions in speaking (27 students [33%]), followed by listening on topics of healthcare systems (11 students [13%]). Many students suggested to include conversation classes in small groups, or classes in which international students introduce the structure of healthcare systems of their home countries to the curriculum. Increasing the participation of international faculty, staff and students in the Medical English Practice might contribute to the improvement of medical students' motivation. PMID- 26738263 TI - [Image of the month. Thrombus formation (intravital microscopy)]. PMID- 26738264 TI - [CRITICAL VIEWPOINT ON THE CURRENT APPROACH OF LOCALIZED PANCREATIC DUCTAL ADENOCARCINOMA]. AB - Surgical resection followed by chemotherapy is the actual standard of care for localized, deemed resectable, pancreatic ductal adenocarcinoma. Despite a better selection of surgical candidates and the actual performance of expert teams, the proportion of patients with a prolonged survival has not been ameliorated during the last three decades. The morphological determinants of resectability are the subject of limitations. In the future, only a better understanding of the biological process, an earlier diagnosis of purely localized disease and more efficient systemic therapies may lead to a better prognosis. Meanwhile, taking into account the prognostic factors associated with a lower chance of cure is currently a matter of debate. The optimal therapeutic sequence, being a surgery first or a neoadjuvant approach is controversial. The theoretical advantages of preoperative chemotherapy eventually associated with chemo-radiation are demonstrated in other tumours and applicable to pancreatic cancer without any excess of operative mortality, early progression rates and, on the contrary with positive survival data. The completion rates of multi-modal therapy are in favour of the preoperative approach, which also gives the opportunity to select the best candidates for surgical resection. PMID- 26738265 TI - [A case of Sneddon's syndrome associated with Moskowitz's syndrome]. AB - Sneddon's syndrome is a rare vascular disease affecting mainly skin and brain arterioles leading to their occlusion. The two main features of this syndrome are livedo racemosa and ischemic stroke. Here, we describe the case of a 37-year-old woman with a past medical history of Moskowitz's syndrome and migraine, and a 2 year history of livedo racemosa and Raynaud's phenomenon. She presented with acute aphasia related to cortical ischemic stroke. Extensive diagnostic workup allowed to diagnose a Sneddon's syndrome. Her symptoms improved on a platelet aggregation inhibitor (aspirin), and speech therapy. This condition can be associated with other disorders affecting small vessels such as illustrated in this case with Moskowitz's syndrome. PMID- 26738266 TI - [Belgian register and reference centers for gestational trophoblastic diseases]. AB - Gestational trophoblastic diseases include placental pathologies comprising fertilization abnormalities (hydatidiform moles) and malignant lesions (choriocarcinoma, placental site trophoblastic tumor and epithelioid trophoblastic tumor). Due to their low incidence and heterogeneity, their diagnosis, management and treatment are not always optimal. Following the example of other European countries, a national registration system with two reference centers has been set up to guide physicians and patients and to propose individualized management. The centers offer their expertise through a systematic centralised pathology review by a panel of experts. HCG values are plotted in regression curves. In case of gestational trophoblastic neoplasia, an imaging work-up is proposed, from which the FIGO score and stage are derived and will guide the choice of treatment. Belgian centers offer a multidisciplinary approach, in partnership with the referent physician. More information for practitioners and patients is available on a web site: www.mole-chorio-bgog.eu, which also harbours a forum of discussion. PMID- 26738267 TI - [Light pollution. A connection between ecology and health]. AB - Light pollution is defined as the abnormal and disturbing nocturnal presence of light, its adverse consequences on flora, fauna, and, ecosystems, and its suspected or proven effects on human health. Light pollution is a quite recent and increasing phenomenon within our society; it leads to a major environmental damage not only on wildlife, but also on human health (cancers, obesity, fatigue, depression...). The solutions to this problem are however simple, efficient and, de facto, inexpensive because they involve a substantial energy saving. PMID- 26738268 TI - [Biopsy of suspicious lesions in patients with breast cancer]. AB - Discordances between hormone receptors and HER2 status in primary and metastatic breast cancer have been reported by several studies. In this context, systematic biopsies could be clinically relevant in breast cancer to confirm the biological characteristics of a suspicious lesion. In this article, illustrated by 2 case reports and based on a recent review on this topic, we discuss the clinical significance of receptor discordances and possible diagnosis of a secondary primary tumor. The role of these biopsies for the identification of new therapeutic targets is also envisaged as well as underlying mechanisms for receptors' modification like tumoral heterogeneity, clonal selection and technical artifacts. PMID- 26738269 TI - [Old phenotype and new genotypes. Pituitary adenomas]. AB - Gigantism and acromegaly, usually caused by a pituitary adenoma linked inappropriate secretion of growth hormone (GH), are generally considered as very rare diseases, even if, according to some authors, their cumulative prevalence is about 1/5000. Starting from the historical case of a giant from Liege we shall describe the different types of GH pituitary adenomas and their pathophysiology. We shall particularly discuss rare forms of inherited GH secreting pituitary adenomas like the FIPA (familial inherited isolated pituitary adenomas) and the X LAG (X linked acrogigantism), both described for the first time in Liege, in 2000 and 2014, respectively. PMID- 26738270 TI - [Vedolizumab (Entyvio(r)) for the treatment of inflammatory bowel diseases]. AB - Anti-TNF agents are highly effective in treating inflammatory bowel diseases, but loss of response and side-effects leading to drug interruption are often reported. New molecules are needed to treat these patients. Vedolizumab is a fully humanized anti-body inhibiting the migration of circulating lymphocytes to the gut by binding the integrin alpha4beta7. In ulcerative colitis, clinical response, remission and mucosal healing were observed at 6 weeks in 47%, 17% and 40% of the patients, respectively. The maintenance study demonstrated 42% and 52% of clinical remission and response at week 52. In Crohn's disease, clinical response and remission were respectively observed in 15% and 31% of the patients at 6 weeks. Clinical remission at week 52 was 39%. The time to clinical response was longer in patients who had failed anti-TNF. The safety profile is excellent with the same proportion of side-effects in the placebo and in the treated groups. The most frequently reported adverse events were pharyngitis and headaches. PMID- 26738271 TI - [EMPA-REG OUTCOME: Empagliflozin reduces mortality in patients with type 2 diabetes at high cardiovascular risk]. AB - EMPA-REG OUTCOME is an international, prospective, placebo-controlled clinical trial investigating the cardiovascular outcomes of empagliflozin, an inhibitor of sodium-glucose cotransporters type 2 (SGLT2), in patients with type 2 diabetes mellitus and known cardiovascular disease. The trial succeeded in reaching the primary objective of non-inferiority and, in addition, showed, after a median follow up of 3.1 years, a superiority of empagliflozin (10 or 25 mg/day) versus placebo as regards the primary composite cardiovascular endpoint (hasard ratio or HR = 0.86; 95% CI 0.74-0.99; P = 0.04), hospitalisations for heart failure ( 35%), cardiovascular mortality (-38%) and all-cause mortality (-32%, each p < 0.001). The reductionin mortality appeared early (< 6 months) and concerned all subgroups, without any obvious heterogeneity. This reduction in mortality does not seem to be fully explained by the concomitant slight reductions in HbA1c, body weight, waist circumference, blood pressure and serum uric acid levels in the empagliflozin groups versus the placebo group. Finally, the tolerance and safety profile of empagliflozin was good, with only a moderate increase in benign mycotic genital infections, a well-known adverse event with SGLT2 inhibitors. The remarkable effects of empagliflozin in the EMPA-REG OUTCOME trial, especially on mortality, should modify the management of patients with type 2 diabetes and a high cardiovascular risk in a near future. PMID- 26738272 TI - Leading Quality and Safety. Getting to zero harm must start at the top. PMID- 26738273 TI - AN INTERVIEW WITH ACHE'S 2015-2016 CHAIRMAN. PMID- 26738274 TI - Accelerating the Adoption of a Safety Culture. PMID- 26738275 TI - Targeting Zero Harm. Sharing Best Practices and Engaging the Care Team. PMID- 26738276 TI - Balancing Issues of Medical Futility. Leaders must ensure policies exist and are followed. PMID- 26738277 TI - The 3 Whys of Compelling Communication. To make your message "stick," include three key points. PMID- 26738278 TI - Replacing a Revolving Door. Care transition programs that address homelessness are one way to reduce emergency visits. PMID- 26738279 TI - The Evolving Safety-Net Hospitals. They are meeting the opportunities and challenges of the Affordable Care Act. PMID- 26738280 TI - CEO Considerations During Transition. The way in which CEO roles will transform after a partnership requires careful attention. PMID- 26738281 TI - Making the Case for Virtual Healthcare. What CEOs and trustees need to know about this emerging field. PMID- 26738282 TI - Measuring for Quality Improvement. Standardized quality-of-care measures have led to better outcomes--but more work remains. PMID- 26738283 TI - Achieving Medicare Breakeven. Ten factors are key to developing a culture of cost reduction and productivity improvement. PMID- 26738284 TI - [The Infectious and Pathogenic Characteristics of Rabies Virus Strain CTNCEC25]. AB - To investigate the phenotypic characteristics of the strain of the rabies virus CTNCEC25, the strain of the China rabies virus CTN-1 adapted to primary chicken embryo cells (CECs), Vero cells, and mouse neuroblastoma N2a cells was inoculated with CTNCEC25 and parental CTN-1 strains to explore the cytopathic effect (CPE) and growth kinetics of CTNCEC25 on cultured cells. To determine the pathogenicity of CTNCEC25, suckling mice, adult mice, guinea pigs and rabbits were inoculated with CTNCEC25 via the intracerebral route and their survival monitored every day. Furthermore, the CTNCEC25 strain was passed serially in CECs for 20 passages and then 3 passages in the brains of suckling mice to determine phenotypic stability. CTNCEC25 achieved similar growth kinetics in Vero cells and N2a cells compared with parental CTN-1, but CTNCEC25 replicated more efficiently in CECs than the CTN-1 strain with a titer 72 h after infection reaching 10(7.5-7.6) FFU/mL, which was significantly higher than the 10(5.8) FFU/mL achieved by its parental strain, CTN-1. Moreover, CTNCEC25 induced apparent CPE in Vero cells, CECs and N2a cells. Analyses of intracerebral inoculation demonstrated that CTNCEC25 was attenuated profoundly in adult mice and was completely apathogenic to guinea pigs and rabbits, though it caused death in suckling mice. The CTNCEC25 strain proliferated steadily after serial passage in CECs and the brains of suckling mice, and remained avirulent in adult mice. These results suggest that CTNCEC25 is a highly attenuated and genetically stable strain of the rabies virus. CTNCEC25 replicated stably and efficiently in cultured cells and achieved high titers, so it could be a promising and safe vaccine strain for rabies prevention in China. PMID- 26738285 TI - [Establishment and Preliminary Application of the SYBR Green I Real-time PCR Assay for Detection of the Bovine Enterovirus]. AB - The bovine enterovirus (BEV) is a pathogen found the digestive tracts of cattle. Recently, the BEV was discovered in cattle in a province in China. A rapid and effective detection method for the BEV is essential. An assay was carried out using two specific primers designed to amplify a highly conserved sequence of the 3D gene. A recombinant plasmid containing the target gene 3D was constructed as a standard control. The limit of detection of the reaction was 7.13 x 10(1) plasmid copies/MUL of initial templates, which was tenfold more sensitive than the conventional reverse-transcription-polymerase chain reaction (RT-PCR). Moreover, the assay was highly specific because all negative controls and other viruses of clinical relevance did not develop positive results. Assay performance on field samples was evaluated on 44 (41 diarrhea and 3 aerosol) samples and compared with the conventional RT-PCR assay. Sixteen diarrhea samples were positive (16/41, 39. 02%) and 3 aerosol samples were positive (3/3, 100%). Preliminary results for clinical detection showed that the SYBR Green I real-time PCR assay was highly sensitive, specific and reproducible. The robustness and high-throughput performance of the developed assay make it a powerful tool in diagnostic applications for epidemics and in BEV research. PMID- 26738286 TI - [Structure and Function of an Alternative Splicing Isoform of Stimulator of Interferon Genes STING(sv)]. AB - Stimulator of interferon genes (STING) is an important protein of the innate immune response, and protects against viral infections. To search for an alternative splicing isoform of STING, we undertook rapid amplification of cDNA ends (RACE) and RT-PCR with RNA extracted from human embryonic kidney (HEK) 293 cells and primers designed according to the mRNA sequence of full-length STING(NM 198282. 82). The new sequence was compared using a bioinformatics method. Then, a newly discovered, alternative splicing isoform of STING, named "STING(sv)", and STING(wt) were subcloned into the eukaryotic expression vector pEGFP-C1 and pcDNA 3. 1. Whole-cell extracts were analyzed by western blotting and then probed with monoclonal antibody against enhanced green fluorescent protein (EGFP) after transfection of EGFP-STING(wt) and EGFP-STING(wt) plasmids in HEK293 cells. pcDNA STING(wt) and pcDNA-STING(wt) were transfected in HEK293 cells, and the luciferase assay carried out. Compared with STING(wt), STING(sv) lacks exon 7 so that shift in the reading frame may produce a protein with a different C-terminal in amino acids 1-30. Western blotting confirmed an expected strong band at 58 x 10(3) kD. The functional luciferase assay showed that STING(sv) inhibited the activity of the interferon (IFN)-beta promoter. STING(sv) can be expressed in multiple tissues and distinct cell lines. Our discovery of a new, alternative splicing isoform of STING provides new insights into the functional regulation of STING. STING(sv) could be a dominant negative inhibitor for the activity of the IFN-beta promoter in the virus-infection pathway. Hence, STING(sv) could participate in the "fine tuning" of the virus-induced activation of IFN. Therefore, exploring the role of STING(sv) in the pathogenesis of human diseases could be very worthwhile. PMID- 26738287 TI - [Inactivation of EV71 by Exposure to Heat and Ultraviolet Light]. AB - Enterovirus 71 (EV71) is a major agent of hand, foot and mouth disease that can cause a severe burden of disease to children. To identify an effective method for the control and prevention of EV71, we studied the effect of exposure to heat and ultraviolet (UV) light upon EV71 inactivation. We found that exposure to 50 degrees C could not inactivate the infectivity of EV71. However, exposure to 60 degrees C and 70 degrees C could inactivate EV71 effectively. EV71 could be inactivated after exposure to UV light at a distance between the sample and a lamp of 30 cm for 30 min or 60 min because viral genomic RNA was destroyed. However, fetal bovine serum (FBS) could attenuate the inactivation proffered by heat and UV light. Attenuation effects of FBS were correlated positively with FBS concentration. Hence, EV71 can be inactivated by exposure to heat and UV light, and our results could provide guidance on prevention of the spread of EV71. PMID- 26738288 TI - [Construction and Function Verification of a Novel Shuttle Vector Containing a Marker Gene Self-deletion System]. AB - For rapid and accurate screening of recombinant modified vaccinia virus Ankara (rMVA) that satisfied the quality standards of clinical trials, a novel shuttle vector that can delete the marker gene automatically during virus propagation was construted: pZL-EGFP. To construct the pZL-EGFP, the original shuttle vector pSC11 was modified by replacing the LacZ marker gene with enhanced green fluorescent protein (EGFP) and then inserting homologous sequences of TKL into the flank regions of EGFP. Baby hamster kidney (BHK)-21 cells were cotransfected with pZL-EGFP and MVA, and underwent ten passages and one plaque screening to obtain the EGFP-free rMVA carrying the exogenous gene. Resulting rMVA was tested by polymerase chain reaction and western blotting to verify pZL-EGFP function. A novel shuttle vector pZL-EGFP containing an EGFP marker gene which could be deleted automatically was constructed. This gene deletion had no effect on the activities of rMVA, and the exogenous gene could be expressed stably. These results suggest that rMVA can be packaged efficiently by homologous recombination between pZL-EGFP and MVA in BHK-21 cells, and that the carried EGFP gene can be removed automatically by intramolecular homologous recombination during virus passage. Meanwhile, the gene deletion had no influence on the activities of rMVA and the expression of exogenous target gene. This study lays a solid foundation for the future research. PMID- 26738289 TI - [Rescue and Amplification of Recombinant Human Adenovirus Type 41 in 293 Cells]. AB - Human adenovirus type 41 (HAdV-41) is considered to be a "fastidious adenovirus". E1-deleted HAdV-41 cannot be rescued or amplified in 293 cells. To propagate recombinant HAdV-41 in 293 cells, the backbone plasmid pAdbone41 was reconstructed. That is, the E3 coding sequence of HAdV-41 was deleted and replaced with the HAdV-5 E4orf6 gene; and the E1A enhancer of HAdV-5 was inserted upstream of the E4 promoter of HAdV-41. Novel adenoviral plasmid pAd41E4EE-GFP was generated by homologous recombination of the shuttle plasmid pSh41-GFP with the modified backbone plasmid in the Escherichia coli BJ5183 strain. Adenovirus HAdV-41-E4EE-GFP was rescued by transfecting 293 cells with linearized pAd41E4EE GFP. After seven rounds of propagation, viruses were purified by the CsCl ultracentrifugation method. HAdV-41-E4EE-GFP in 1.0 ml with a particle titer of 8 x 10(10) vp/mL was obtained which had a particle-to-infectious ratio of 50 : 1. The genome of HAdV-41-E4EE-GFP was confirmed by restriction analyses and polymerase chain reaction. These results showed that a novel HAdV-41 vector system was established in which recombinant HAdV-41 could be constructed and packaged in 293 cells. PMID- 26738290 TI - [Expression of Chimeric Influenza Hemagglutinin Antigen (cH7/3) using the Baculovirus Expression System and Identification of its Biological Activities]. AB - Hemagglutinin (HA) contains a head domain with a high degree of variability and a relatively conserved stem region. HA is the major viral antigen on the surface of the influenza virus. To define the biologic activities of chimeric HA bearing different head domains and stem regions or their potential use, a HA chimeric gene containing the head domain of the H7 subtype virus and stem region of the H3 subtype virus was modified and expressed using a baculovirus expression vector. Then, the secreted protein was purified and its biologic activities characterized. Approximately 1.4 mg/mL cH7/3 HA could be obtained, and its molecular weight was ~ 70 kD. The trimer form of cH7/3 protein had hemagglutination activity and could be recognized by specific antibodies. The method described here can be used for further studies on the screening of HA stem reactive antibodies or the development of vaccines with conserved epitopes. PMID- 26738291 TI - [Screening of the Stable Expressing HPV18 E5 Protein Cell Line and its Influence on Cell Proliferation and the Cell Cycle]. AB - We wished to screen the cell line that stably expresses the HPV18E5 protein, and to ascertain the influence of HPV18E5 protein on cell proliferation and the cell cycle. The HPV18E5 gene was amplified by the polymerase chain reaction. Then, the His-tag pSecTag-HPV18E5 eukaryotic expression vector was constructed by digestion ligation and connection. The recombinant plasmid was transfected into Balb/c3T3 cells with lipofectamine, and positive cell lines were screened by a culture medium containing bleomycin. HPV18E5 expression in cells was confirmed by western blotting and immuno-enzymatic methods. The influence of HPV18E5 on cell proliferation and the cell cycle were detected by Cell Counting Kit-8 and flow cytometry, respectively. The pSecTag-HPV18E5 eukaryotic expression vector was constructed. After 21-day selection in a culture medium containing 400 MUg/mL bleomycin, stably expressing HPV18E5 protein cells were harvested. Compared with control groups, cell proliferation in HPV18E5 stably expressed cells was obviously increased, as was the S phase in the cell cycle. Our results suggested that HPV18E5 influences cell proliferation and the cell cycle. Our study has laid the foundation of the biologic properties of HPV18E5 protein, which will aid further studies on the mechanism of action of carcinogenesis. PMID- 26738292 TI - [Identification of MicroRNA-like Viral Small RNAs from AaeDV]. AB - Several virus families have been shown to encode microRNAs (miRNAs), which have roles in the infection and replication of viruses in host cells. These virus encoded miRNAs are identified in double-stranded DNA virus (dsDNA virus) and in several RNA virus families, but not in single-stranded DNA virus (ssDNA virus). We used a bioinformatics approach based on VMir, miRNAFold and MaturePred software to predict virus-encoded miRNA-like small RNAs from the genome of a ssDNA virus: Aedes aegypti densovirus (AaeDV). Northern blotting and stem-loop reverse transcription-polymerase chain reaction (RT-PCR) were used to detect predicted small RNAs. A miRNA-like small RNA termed "AaeDVMD" was identified by stem-loop RT-PCR from predicted candidates. This is the first report demonstrating that a ssDNA virus can encode miRNA-like small RNAs. These data will aid further exploration of the interaction between the AaeDV and its mosquito host. PMID- 26738294 TI - [Selection and Identification of the Biological Characteristics of a Cold-adapted Genotype G1P[8] ZTR-68 Rotavirus by Serial Cold-adapted Passaging]. AB - We wished to select a cold-adapted genotype G1P[8] ZTR-68 rotavirus (China southwest strain) in MA104 cells for possible use as a live vaccine. ZTR-68 was recovered originally from children with diarrhea. The virus was cultivated at 37 degrees C at the first passage. Then, the cultivation temperature was decreased stepwise by 3 degrees C per eight passages. In total, the virus was passaged 32 times, and cultivation was terminated at 28 degrees C. Biological characteristics of the virus were analyzed during serial passages. There was no difference between the migration patterns of genomic dsRNA segments according to polyacrylamide gel electrophoresis of original and cold-adapted viruses. Infectious and red cell-agglutination titers of cold-adapted virus were lower than those of the parent virus. Also, the virus formed small-size plaques with irregular shapes at 31 degrees C and 28 degrees C. These results suggested that a genetically stable attenuated virus can be obtained through serial cold-adapted passages. Thus, an alternative strategy is provided by cold-adaption for development of attenuated live rotavirus vaccines. PMID- 26738293 TI - [Investigation of a Patient with Pre-vaccine-derived Poliovirus in Shandong Province, China]. AB - To analyze the genetic characteristics of a polio-I highly variant vaccine recombinant virus in Shandong Province (China) in 2011 and to identify isolates from healthy contacts, two stool specimens from one patient with acute flaccid paralysis (AFP) and 40 stool specimens from his contacts were collected for virus isolation. The complete genome of poliovirus and VP1 coding region of the non polio enterovirus were sequenced. Homologous comparison and phylogenetic analyses based on VP1 sequences were undertaken among coxsackievirus (CV) B1, CV-B3 isolates, and those in GenBank. One poliovirus (P1/11186), CV-A4 and CV-A8 were isolated from the AFP patient; one CV-A2, Echovirus 3 (E-3), E-12 and E-14, ten CV-B1, and five CV-B3 strains were isolated from his contacts. These results led us to believe that there may be a human enterovirus epidemic in this area, and that surveillance must be enhanced. P1/11186 was a type-1 vaccine-related poliovirus; it combined with type-2 and type-3 polioviruses in 2A and 3A regions, respectively. There were 25 nucleotide mutations with 9 amino-acid alterations in the entire genome. There were 8 nucleotide mutations with 5 amino-acid alterations in the VP1 region compared with the corresponding Sabin strains. Homology analyses suggested that the ten CV-B1 isolates had 97.0%-100% nucleotide and 98.9%-100% amino-acid identities with each other, as well as 92.6%-100% nucleotide and 99.2%-100% amino-acid identities among the five CV-B3 isolates. Phylogenetic analyses on the complete sequences of VP1 among CV-B1 and CV-B3 isolates showed that Shandong strains, together with strains from other provinces in China, had a close relationship and belonged to the same group. PMID- 26738295 TI - [Prevalence and Analyses of the Changing Etiology of Hand, Foot and Mouth Disease in China]. AB - Hand, foot, and mouth disease (HFMD) is a viral infectious disease regarded to be a public-health problem worldwide. Since the 1990s, HFMD began to spread in the Asia-Pacific region (especially in South-East Asia). HFMD outbreaks have occurred in mainland China frequently since 2008, and the morbidity and mortality of HFMD has continued to increase in recent years. In mainland China, enterovirus A serotype enterovirus A71 (EV-A71) and coxsackievirus A16 (CVA16) have been the major pathogens of HFMD during these years. However, the etiological spectrum of HFMD changes with time. This review focuses mainly on the etiological spectrum of HFMD and changes in epidemic patterns in mainland China. PMID- 26738296 TI - [Research Progress in the Function of SUMOylation during Infection by the Influenza Virus]. AB - The influenza virus has evolved numerous mechanisms to overcome host defenses for its benefit. It can also manipulate the immune system to stop it monitoring and clearing the virus. Small ubiquitin-like modifier (SUMO)ylation is emerging as a key post-translational modification that plays an important part in virus replication. This brief review focuses on recent findings on the roles of SUMOylation during infection by the influenza virus. As such, it will aid understanding of the mechanism of action of infection by the influenza virus, and help to provide new strategies for anti-viral treatment. PMID- 26738297 TI - [Research Progress in Membrane Fusion of the Respiratory Syncytial Virus]. AB - The respiratory syncytial virus (RSV) is one of the most common causes of acute infection of the lower respiratory tract among children. For viruses in the Paramyxoviridae subfamily, membrane fusion requires a specific interaction between two glycoproteins: the fusion protein and attachment protein. Membrane fusion of the RSV appears to be unique among paramyxoviruses in that fusion is accomplished by the fusion protein alone without help from the attachment protein. Here, we review recent achievements and advances in the study of membrane fusion triggered by the RSV published in high-impact-factor journals. We also review and make a comparative analysis of the popular hypotheses regarding membrane fusion of the RSV. Finally, we discuss the "hot topics" in current research and controversial data published in recent years in the hope of providing references for Chinese researchers. PMID- 26738298 TI - [Application of Next-generation Sequencing Techniques in the Dynamics of HIV-1 Quasispecies]. AB - In the last decade, next-generation sequencing (NGS) technology, which is characterized by being high-throughput, rapid, sensitive, and accurate, has developed rapidly. Main components of NGS are platforms: 454 sequencing; illumina sequencing; ion torrent sequencing; SOLID sequencing. NGS is used widely for the human immunodeficiency virus (HIV)-1. In this review, we focus on applications of the dynamics of HIV-1 quasispecies. PMID- 26738299 TI - [Research Progress in the Core Proteins of the Classical Swine Fever Virus]. AB - The core protein (CP) of the classical swine fever virus (CSFV) is one of its structural proteins. Apart from forming the nucleocapsid to protect internal viral genomic RNA, this protein is involved in transcriptional regulation. Also, during viral infection, the CP is involved in interactions with many host proteins. In this review, we combine study of this protein with its disorders, structural/functional characteristics, as well as its interactions with the non structural proteins NS3, NS5B and host proteins such as SUMO-1, UBC9, OS9 and IQGAP1. We also summarize the important part played by the CP in CSFV pathogenicity, virulence and replication of genomic RNA. We also provide guidelines for further studies in the CP of the CSFV. PMID- 26738300 TI - [Advances in Understanding of the Infection/Replication Mechanisms and Virulence Determinants of the Porcine Reproductive and Respiratory Syndrome Virus]. AB - The porcine reproductive and respiratory syndrome virus (PRRSV) can cause reproductive barriers in breeding pigs and respiratory symptoms in piglets. In this review, we summarize research progress of the infection and replication mechanisms of the PRRSV. We also review the virulence determinants of the PRRSV. All these fundamental studies are important for the control and elimination of the PRRSV. PMID- 26738301 TI - [CHANGE IN THE CONDITION OF LOWER LIMB VEINS IN COSMONAUTS ON LONG-DURATION MISSIONS]. AB - The paper reports changes in the main parameters of the lower limb veins in 36 cosmonauts in the course of 6-month space missions. Major reduction in the leg volume was shown in all cosmonauts, as well as a significant increase of venous capacity and compliance. Rate of vein filling exhibited different trends, i.e. decreased in the majority of cosmonauts (n = 26, 74%) and increased in the rest (n = 9, 26%). Increases in venous capacity, compliance and filling rate may impact orthostatic stability (OS). These changes are among the pathophysiological mechanisms of the OS loss in space flight. PMID- 26738302 TI - [INVESTIGATION OF BLOOD BIOCHEMICAL INDICES DURING BICYCLE ERGOMETRY]. AB - Our investigations showed that physical work (bicycle ergometry) alters the biochemical status of male volunteers. On the 5th minute of bicycle endometry capillary blood looses significantly glucose and increases magnesium, phosphorus and particularly lactic acid. Creatine phosphokinase activity and trygliceride levels did not deviate much from baseline values. All the changes had a similar trend equally in the supine and sitting position. Therefore, biochemical investigations may complement essentially the physiological and neurophysiological tests of human adaptability to physical loads. The investigation utilized the dry chemistry technology of rapid biochemical diagnostics. PMID- 26738303 TI - [INTERHEMISPHERIC DIFFERENCES BETWEEN ENCEPHALOGRAPHY ALPHA SPECTRAL POWER INDICES DURING BICYCLE ERGOMETRY]. AB - The EEG recording from 30 supine volunterrs during bicycle ergometry with the load growing incrementally to a submaximal heart rate was made in order to study alpha spectra and their interhemispheric differences. Comparative analysis of EEG records demonstrated a statistical gain of the alpha-power in both hemispheres at the final step of aerobic work and throughout the period of recovery with power reaching the highest values in the left hemisphere. Analysis of interhemispheric differences points to activation of the right hemisphere over the whole period of the investigation. PMID- 26738304 TI - [OPTIMAL HYPERCAPNIC HYPOXIA CONDITIONS FOR INCREASING RESISTANCE TO ACUTE HYPOXIA]. AB - The study was focused on finding an optimal length of hypercapnia-hypoxia sessions of training resistance to acute hypoxia and looking for benefits from reoxygenation intervals and intermittent training over daytime. It turned out that 3 days of a 5-minute hypercapnia-hypoxia session per day improved resistance to acute hypoxia explicitly and that a 30-minute session increased resistance to the highest rate. Two training sessions per day are no better than one session. Hypercapnia-hypoxia training with reoxygenation intervals are the least effective in comparison to the other modes of training. PMID- 26738305 TI - [EFFECTS OF HYPOXIA AND GROWTH FACTORS ON THE ANGIOGENIC ACTIVITY OF MULTIPOTENT MESENCHYMAL STROMAL CELLS]. AB - The effects of fetal calf serum (FCS) growth factor concentration and cell growth phase on production of angiogenic mediators by mesenchymal stromal cells (MSCs) at different O2 levels (20 and 5%) was studied. For this purpose vascular endothelial growth factor (VEGF-A) production was measured in MSC-conditioned medium (CM); besides, branching vessels as well as vessel end points (ramification) in the chorioallantoic membrane of Japanese quail eggs (Coturnix coturnix japonica) were counted following MSC-CM application. During the standard cultivation (20% O2; 10% FCS) the total number of vessels was 1.6 times higher comparing with hypoxic condition (5% O2; 10% FCS) due to increase in ramification, the number of branching vessels did not change. Maximal (double) increase in the total vessel number was observed when CM from MSCs after hypoxia plus serum deprivation was added. VEGF-A synthesis linearly increased with FCS concentration both at 20% and 5% O2. In all cases VEGF-A level was higher at hypoxia. No direct correlation between the VEGF-A concentration and total number of vessels was noted indicating that hypoxia possibly stimulates synthesis of additional angiogenic factors to enhance vascular growth despite the drastic serum deprivation. At 20% oxygen, exponentially growing MSCs showed the highest angiogenic activity and the ramification increased in 1.6 times. Depending on O2, MSCs produced angiogenic factors required at different stages of vascularization. Specifically, mediators of ramification were accumulated in the standard conditions (20% O2) and factors stimulating growth of branching vessels--in hypoxia. PMID- 26738306 TI - [MODIFICATION OF THE PROTON BEAM PHYSICAL PARAMETERS AND RADIOBIOLOGICAL CHARACTERISTICS BY ELEMENTS OF SPACECRAFT RADIATION PROTECTION]. AB - The experiment was performed with outbred ICR (CD-1). female mice (SPF). The animals were irradiated by 171 MeV protons at a dose of 20 cGy. The spacecraft radiation protection elements used in the experiment were a construction of wet hygiene wipes called a "protective blind", and a glass plate imitating an ISS window. Physical obstacles on the path of 171 MeV protons increase their linear energy transfer leading to the absorbed dose elevation and strengthening of the radiobiological effect. In the experiment, two types of obstacles together raised the absorbed dose from 20 to 23.2 cGy. Chemically different materials (glass and water in the wipes) were found to exert unequal modifying effects on physical and biological parameters of the proton-irradiated mice. There was a distinct dose dependent reduction of bone marrow cellularity within the dose range from 20 cGy to 23.2 cGy in 24 hours after exposure. No modifying effect of the radiation protection elements on spontaneous motor activity was discovered when compared with entrance protons. The group of animals protected by the glass plate exhibited normal orientative-trying reactions and weakened grip with the forelimbs. Rationalization of physical methods of spacecrew protection should be based as on knowledge in physical dosimetry (ionizing chambers, thermoluminescent, track detectors etc.), so the radiobiological criteria established in experiments with animals. PMID- 26738307 TI - [STUDIES OF THE ANTIHYPOXIC AND ANTIAMNESTIC EFFECTS OF MELATONIN IN ANIMALS]. AB - Experiments with mice showed that in a multitude of acute hypoxia models (normobaric hypoxic hypoxia with hypercapnia, hypobaric, hemic and histotaxic) the antihypoxic action of a single intra-abdominal dose of melatonin surpasses greatly amtisol, the standard antihypoxic agent. Single melatonin injection produced a strong antiamnestic action on various amnestic models (scopolamine induced, acute normobaric hypoxia with hypercapnia, and a combination of extreme factors) which was much better than of pyracetame, a well-known nootropic (mind stimulating) drug. Increase of the melatonin dose from 1 mg/kg to 20 mg/kg amplified both the antihypoxic and antiamnestic effects. Melatonin inhibited orthodromal population responses in surviving sections of rat's hippocampus (by 24 +/- 3% at 2 mM; by 72 +/- 6% at 5 mM). Besides, the inhibiting action of lusindol, a blocker of melatonin receptors MT1 and MT2--was virtually fully neutralized. Therefore, melatonin inhibits transmission within the Schaffer collateral--CA1 pyramidal neurons synapse by stimulation of melatonin receptors MT1 and MT2; higher melatonin concentrations (0.5 to 5 mM) enhance its effectiveness. PMID- 26738308 TI - [ROLE OF THE SYMPATHOADRENOMEDULLARY SYSTEM IN FORMATION OF PILOT'S ADAPTATION TO FLIGHT LOADS]. AB - Purpose of the work was to evaluate the sympathoadrenomedullary functions and associated psychophysiological reactions of pilots as a function of flight hours on highly maneuverable aircraft. Volunteers to the investigation were 78 pilots (41 pilots of maneuverable aircraft and 37 pilots of bombers and transporters). Selected methods were to enable comprehensive evaluation of the body functioning against flight loads. Our results evidence that piloting of high maneuverable aircraft but not of bombing and transporting aircrafts activates the sympathoadrenomedullary system significantly. This is particularly common to young pilots with the total flying time less than 1000 hours. Adaptive changes to flight factors were noted to develop with age and experience. PMID- 26738309 TI - [SCREENING-EVALUATION OF THE CARDIAC ARTERY DISEASE IN CIVIL PILOTS OF THE SENIOR AGE GROUP]. AB - Early diagnostics of cardiac artery disease (CAD) is essential for annual medical flight certification. The investigation was aimed at screening-evaluation of senior civil pilots for CAD using the criteria of ECG findings during the submaximal bicycle ergometry test (BT). The investigation embraced 1189 civil pilots, on reaching the age of 55 years and older in 2009-2010. BT with ECG recording was completed by 976 pilots (82.1%). The test was considered CAD negative in 909 pilots (93.1 %) and CAD positive in 9 pilots (0.9%); of 53 doubtful tests (5.5%), CAD was stated by the ST-criterion in 40 pilots (4.1%) and because of arrhythmias in 13 pilots (1.4%). In 5 cases (0.5%) test results were uninterpretable. Further analysis of the screening results led to diagnosing of clinically significant atherosclerosis of coronary arteries in 17 pilots (1.75%). PMID- 26738310 TI - [THRESHOLD VALUES OF MAIN PARAMETERS OF THE BLOOD PRESSURE DIURNAL PROFILE IN MEN WITH ISOLATED CLINICAL ARTERIAL HYPERTENSION LIVING BEYOND THE ARCTIC CIRCLE]. AB - The purpose was to calculate thresholds of diurnal blood pressure parameters (BP) in men with isolated clinical hypertension (ICH) living beyond the Arctic circle, and selection of those parameters that will be particularly informative for differential diagnostics of ICH and essential hypertension (EH) in this contingent. Fifty male subjects were distributed in the ICH group (n = 25) and normotensive group with one and more cardiovascular risk factors (n = 25). No drug therapy was provided during diurnal BP monitoring (DBPM). ICH was diagnosed in the event of increased office BP, normal DBPM values and self-monitoring of BP (BPSM). ROC-analysis was applied to calculate thresholds of the BP diurnal profile for men with ICH and identify the most useful ones. Specifically, these include the following thresholds: average daily systolic BP (SBP) (> 122 mm Hg), average daytime SBP (> 127 mm Hg) and average nighttime SBP (> 108 mmHg), and SBP time indices over 24 hrs. (> 16.7%) and daytime (> 14.4 %). The range of scatter of these values allows differential diagnostics of both ICH and EH which is important for health expertise of male dwellers in the region. Early ICH detection in men with high cardiovascular risks and prescription of anti hypertension therapy will reduce the probability of ICH progression to stable hypertension, prevent damage to target-organs and mitigate the total cardiovascular risk. PMID- 26738311 TI - [HARDWARE-SOFTWARE COMPLEX FOR TESTING AND TRAINING OF THE MUSCLES OF THE SHOULDER GIRDLE IN MASS SPORT AND REGENERATIVE MEDICINE]. PMID- 26738312 TI - Environmental Health Without Borders. PMID- 26738313 TI - Legionnaires' Disease Outbreak at a Long-Term Care Facility Caused by a Cooling Tower Using an Automated Disinfection System--Ohio, 2013. AB - On July 9, 2013, an outbreak of Legionnaires' disease (LD) was identified at Long Term Care Facility A in central Ohio. This article describes the investigation of the outbreak and identification of the outbreak source, a cooling tower using an automated biocide delivery system. In total, 39 outbreak LD cases were identified; among these, six patients died. Water samples from a cooling tower were positive for Legionella pneumophila serogroup 1, reactive to monoclonal antibody 2, with matching sequence type to a patient isolate. An electronic control system turned off cooling tower pumps during low-demand periods, preventing delivery of disinfectant by a timed-release system, and leading to amplification of Legionella in the cooling tower. Guidelines for tower maintenance should address optimal disinfection when using automated systems. PMID- 26738314 TI - Geothermal Gases--Community Experiences, Perceptions, and Exposures in Northern California. AB - Lake County, California, is in a high geothermal-activity area. Over the past 30 years, the city of Clearlake has reported health effects and building evacuations related to geothermal venting. Previous investigations in Clearlake revealed hydrogen sulfide at levels known to cause health effects and methane at levels that can cause explosion risks. The authors conducted an investigation in multiple cities and towns in Lake County to understand better the risk of geothermal venting to the community. They conducted household surveys and outdoor air sampling of hydrogen sulfide and methane and found community members were aware of geothermal venting and some expressed concerns. The authors did not, however, find hydrogen sulfide above the California Environmental Protection Agency air quality standard of 30 parts per billion over one hour or methane above explosive thresholds. The authors recommend improving risk communication, continuing to monitor geothermal gas effects on the community, and using community reports and complaints to monitor and document geothermal venting incidents. PMID- 26738315 TI - Prevalence of Lead Hazards and Soil Arsenic in U.S. Housing. AB - The American Healthy Homes Survey, June 2005-March 2006, measured levels of lead and arsenic in homes nationwide. Based on a three-stage cluster sample of 1,131 housing units, key statistically weighted estimates of the prevalence of lead based paint (LBP) and LBP hazards associated with paint, dust, and soil, and arsenic in dust and soil, were as follows: 37.1 million homes (35%) had some LBP; 23.2 million (22%) had one or more LBP hazards; 93% of the homes with LBP were built before 1978. The highest prevalence of LBP and LBP hazards was in the Northeast and Midwest. Over three million homes with children under six years of age had LBP hazards, including 1.1 million low-income households (< $30,000/yr.). Less than 5% of homes had detectable levels of arsenic in dust (>= 5 MUg/ft2). Arsenic in soil (for homes with yard soil) averaged 6.6 parts per million (ppm). Many homes had soil arsenic levels of 20 ppm or greater, including 16% of homes with wooden structures in the yard and 8% of homes without such structures. PMID- 26738317 TI - Improving State and Local Capacity to Assess and Manage Risks Associated With Private Wells and Other Drinking Water Systems Not Covered by the Safe Drinking Water Act. PMID- 26738318 TI - Striving to Achieve the Mission of CDC's National Environmental Public Health Tracking Program. PMID- 26738316 TI - A Community-Driven Intervention in Tuftonboro, New Hampshire, Succeeds in Altering Water Testing Behavior. AB - Maximum contaminant levels created by the U.S. Environmental Protection Agency under the Safe Drinking Water Act do not apply to private wells. Rather, the onus is on individual households to undertake regular water testing. Several barriers exist to testing and treating water from private wells, including a lack of awareness about both well water as a potential source of contaminants and government-recommended water testing schedules; a health literacy level that may not be sufficient to interpret complex environmental health messages; the inconvenience of water testing; the financial costs of testing and treatment; and a myriad of available treatment options. The existence of these barriers is problematic because well water can be a source of hazardous contaminants. This article describes an initiative--undertaken by the Tuftonboro (New Hampshire) Conservation Commission, with support from state agencies and a research program at Dartmouth College--to increase water testing rates in a rural region with a relatively high number of wells. The project prompted more water tests at the state laboratory in one day than in the prior six years. This suggests that community-driven, collaborative efforts to overcome practical barriers could be successful at raising testing rates and ultimately improving public health. PMID- 26738319 TI - [Updated Relationship of microRNA with male reproduction]. AB - Spermatogenesis is a unique process of cell differentiation, which involves the regulation of a series of complicated post-transcriptional expressions. MicroRNAs (miRNAs) are a class of none-coding RNAs that play important roles in regulating post-transcriptional gene silencing. MiRNAs are expressed in a cell-specific manner in spermatogenesis and participate in the maturation and differentiation of male germ cells. The specifically altered seminal plasma miRNA is closely related with spermatogenic dysfunction and therefore can be used as a novel biomarker for the diagnosis of male infertility. A deeper insight into these specific miRNAs may point a new direction in the studies of the molecular mechanisms of spermatogenesis and spermatogenic dysfunction. PMID- 26738320 TI - [Androgen may improve erectile function in castrated rats by regulating the ERK1/2 pathway]. AB - OBJECTIVE: To investigate the role of the extracellular signal-regulated protein kinase 1/2 (ERK1/2) pathway in erectile dysfunction (ED) caused by the absence of testosterone (T). METHODS: We randomly divided 30 eight-week-old healthy male SD rats into groups A (control) , B (castration), and C (castration + androgen replacement). The rats in groups B and C were castrated surgically, and those in C injected with T undecanoate (100 mg/kg) at 1 week after castration, while the others with 0.9% normal saline instead. At 1 month after treatment, we determined the serum T level, intracavernous pressure (ICP), and mean carotid arterial pressure (MAP) of the rats, and detected the expressions of ERK1/2 and endothelial nitric oxide synthase (eNOS) by Western blot. RESULTS: The serum T level was significantly lower in group B ([1.27 +/- 0.48] nmol/L) than in A ([17.14 +/- 1.07] nmol/L) and C ([16.24 +/- 1.90] nmol/L) (P < 0.05), and so were ICP and MAP (P < 0.05). The expression of ERK1/2 showed no statistically significant differences among the three groups (P > 0.05), that of phosphatase ERK1/2 was markedly higher while that of eNOS remarkably lower in group B than in A and C (both P < 0.05). CONCLUSION: Androgen replacement may improve the erectile function of castrated rats by regulating the ERK1/2 pathway. PMID- 26738321 TI - [Inhibitory effect of Genipin on uncoupling protein-2 and energy metabolism of androgen-independent prostate cancer cells]. AB - OBJECTIVE: To explore whether the inhibitory effect of Genipin on uncoupling protein-2 (UCP-2) in mitochondria is involved in energy metabolism of androgen independent PC3 prostate cancer cells. METHODS: PC3 prostate cancer cells were cultured and treated with Genipin at the concentrations of 40, 80, and 160 MUmol/L for 48 hours. Then the proliferation of the cells was detected by MTT assay, the expression of UCP-2 mRNA determined by RT-PCR, and the content of intracellular pyruvic acid (PA) and the activity of succinate dehydrogenase (SDH) in the mitochondria measured by visible spectrophotometry. RESULTS: With the increased concentration of Genipin, the proliferative activity of the PC-3 cells, the expression level of UCP-2 mRNA, the content of intracellular PA and the activity of SDH in the cells were all decreased, namely, with the enhanced inhibitory effect of Genipin on UCP-2, a trend of reduction was observed in the proliferation of the cells, intracellular PA content, and SDH activity in the mitochondria. CONCLUSION: Genipin is involved in the energy metabolism of androgen-independent PC3 prostate cancer cells by reducing the content of intracellular PA and the activity of SDH in the mitochondria, which may be associated with its inhibitory effect on UCP-2. PMID- 26738322 TI - [Correlation of the second to fourth digit ratio with the body mass index of infertile men]. AB - OBJECTIVE: To investigate the relationship between the second to the fourth digit ratio (2D:4D) and body mass index (BMI) in infertile men of the Han ethnic group in Ningxia. METHODS: Using anthropometry, we calculated the mean ratio of 2D:4D and BMI of 197 infertile men and 148 normal healthy male controls, followed by analysis of their relationship. RESULTS: The BMI was correlated positively with the 2D:4D ratio of the left hand in the infertile men (P < 0.05) and in the patients with a higher 2D:4D ratio of the left hand (P < 0.05), but negatively with the 2D:4D ratio of the righ/left (Dr-1) (left: P < 0.01; Dr-l: P < 0.05). The mean 2D: 4D ratio and BMI were both lower in the normal control than in the infertile men, with statistically significant differences in BMI (P < 0.05) and the 2D:4D ratio of the left hand (P < 0.05). CONCLUSION: There is a correlation between the 2D:4D ratio and BMI in infertile men. PMID- 26738323 TI - [Expression ratio of the nerve growth factor receptor TrkA to p75NTR correlates with the clinical stage and pathological grade of prostate cancer]. AB - OBJECTIVE: To investigate the expressions and action mechanisms of nerve growth factor (NGF) receptors TrkA and p75NTR in the oncogenesis and progression of prostate cancer (PCa). METHODS: Using immunohistochemistry, we detected the expressions of TrkA and p75NTR in 62 PCa and 35 benign prostatic hyperplasia (BPH) samples, and conducted statistical analysis on the basis of clinical data. RESULTS: Independent-samples t-test showed that, along with poorer tissue differentiation or higher clinical stage of PCa, the expression of TrkA was significantly up-regulated, that of p75NTR remarkably down-regulated, and the expression ratio of TrkA to p75NTR markedly increased. The TrkA/p75NTR ratio was 0.32 in the BPH, 0.52 in the PCa tissue with Gleason score of 6, 1.65 in the PCa tissue with Gleason score of 7, 5.75 in the PCa tissue with Gleason score >= 8, 0.89 in the clinical stage of pT2, 1.5 in pT3 a, 3.75 in pT3b, and 7.00 in pTxN1. CONCLUSION: The abnormally increased expression ratio of TrkA to p75NTR might be one of the essential features of malignant transformation of prostate cells. A higher TrkA/p75NTR expression ratio may be associated with a lower tissue differentiation, a higher clinical stage or Gleason score, and therefore a poorer prognosis. PMID- 26738324 TI - [Successful pregnancy following laser-assisted selection of viable but immotile spermatozoa for intracytoplasmic sperm injection: A report of 2 cases]. AB - OBJECTIVE: To investigate the feasibility and clinical application value of selecting viable spermatozoa by noncontact diode laser. METHODS: We obtained immotile spermatozoa from 2 infertile men with obstructive azoospermia or severe asthenospermia and selected viable spermatozoa using a single laser shot at the sperm tail. Those that responded to the laser shot by a curling reaction of the tail were regarded as presumably viable and used for intracytoplasmic sperm injection (ICSI). RESULTS: The mean fertilization rate was 88.89% after ICSI with the laser-selected viable spermatozoa. Both of the embryo transfers resulted in a single pregnancy. CONCLUSION: Noncontact diode laser is a useful alternative for the assessment of sperm viability, which may help to achieve successful pregnancy. PMID- 26738325 TI - [Factors influencing the clinical pregnancy rate following intrauterine insemination]. AB - OBJECTIVE: To investigate the factors that affect the clinical pregnancy rate after intrauterine insemination (IUI). METHODS: We retrospectively analyzed the clinical data of 611 IUI cycles and analyzed the relationship of the clinical pregnancy rate after IUI with the female age, infertility duration, type of infertility, cycle number, cycle protocol, thickness and type of endometrium, and semen parameters before processing. RESULTS: The clinical pregnancy rate was significantly higher in the ovulation induction than in the natural ovulation cycles (23.03% vs 11.03%, P < 0.01), but lower in the 4th cycle and above than in the 1st, 2nd, and 3rd cycles (2.04% vs 21.30%, 18.13%, and 12.67%, P < 0.01). Marked decreases were found in the clinical pregnancy rate in the females aged >= 40 years and the cases with pre-processing total progressively motile sperm count (TPMSC) < 10 x 10(6), progressive motile sperm < 20%, or morphologically normal sperm < 2% (all P < 0.05). Logistic regression analysis revealed the cycle protocol, cycle number, and percentage of progressively motile sperm as three predictive variables affecting the clinical pregnancy rate after IUI (P < 0.05). CONCLUSION: The cycle protocol, cycle number, percentage of progressively motile sperm, female age, TPMSC, and sperm morphology are the main factors affecting the clinical pregnancy rate following IUI, while infertility duration, type of infertility, and thickness and type of endometrium exert little influence. PMID- 26738326 TI - [Nasal endoscopy-assisted bulboprostatic anastomosis for posterior urethral stricture]. AB - OBJECTIVE: To study the clinical value and operation skills of nasal endoscopy assisted bulboprostatic anastomosis in the treatment of posterior urethral stricture. METHODS: Between January 2012 and November 2014, we performed nasal endoscopy-assisted bulboprostatic anastomosis for 12 male patients with posterior urethral stricture. We recorded the operation time, blood loss, exposure of operation visual field, and success rate of anastomosis and summarized the operation skills. RESULTS: Eight of the patients experienced first-stage recovery. Two underwent a urethral dilation at 3 months postoperatively, 1 received 10 urethral dilations within 5 months after surgery, and 1 underwent internal urethrotomy after failure in urethral dilation, but all the 4 cases were cured. CONCLUSION: Nasal endoscopy can significantly improve the operation field exposure, elevate the precision, reduce the difficulty, and enhance the efficiency of bulboprostatic anastomosis in the treatment of posterior urethral stricture. PMID- 26738327 TI - [Genotypes of human papilloma virus in male condyloma acuminata patients in Lishui area]. AB - OBJECTIVE: To explore the genotypes of human papilloma virus (HPV) in male patients with condyloma acuminate in Lishui area of Zhejiang Province, China. METHODS: Using HybriMax, we identified the genotypes of HPV of the verruca samples from 110 male condyloma acuminate patients aged 16 - 65 years in Lishui area. RESULTS: HPV infection was detected in 107 (97.27%) of the condyloma acuminate patients, including 76 cases (71.02%) of simple infection and 31 cases (28.97%) of multiple infection. The peak age of infection was 21 - 40 years old. Totally, 14 genotypes of HPV were identified, including the high-risk genotypes as HPV16, 53, 52, 33, CP8304, 58, 51, 45, 66, 68, and 59, which accounted for 44.85% of the cases, and the low-risk ones as HPV6, 11, and 19 (43), with an infection rate of 93.45%. CONCLUSION: The low-risk genotype is a dominant type of HPV infection and the rates of high-risk genotype and multiple infection are high among the male condyloma acuminate patients in Lishui area. PMID- 26738328 TI - [Combination therapy of Xipayimaizipizi Capsules and Tamsulosin for benign prostatic hyperplasia]. AB - OBJECTIVE: To evaluate the efficacy and safety of the combination therapy of Xipayimaizipizi Capsules and Tamsulo- sin in the treatment of benign prostatic hyperplasia (BPH). METHODS: We randomly assigned 60 BPH patients to a control and a combination group of equal number, the former aged 62.03 +/- 10.19 years with a disease course of 3.24 +/- 2.18 years and the latter aged 64.77 +/- 10.33 years with a disease course of 4.09 +/- 2.63 years. We treated the patients in the control group with Tamsulosin at 0.2 mg qd and those in the combination group with Tamsulosin at 0.2 mg qd plus Xipayimaizipizi at 0.5 g tid, respectively, both for 4 weeks. Then, we obtained the mean frequency of nocturnal urination, maximal urinary flow rate (Qmax), residual urine volume, International Prostate Symptom Score (IPSS) , and quality of life scores (QOL) of the patients, and recorded their adverse reactions. RESULTS: Before treatment, the nocturnal urination frequency, Qmax, IPSS, and QOL were 3.60 +/- 1.81, (10.40 +/- 3.53) ml/min, 22.47 +/- 8.58, and 4.43 +/- 1.50 in the control group, as compared with 3.43 +/- 1.61, (10.14 +/- 3.43) ml/min, 21.93 +/- 8.79, and 4.73 +/- 1.31 in the combination group. After 4 weeks of medication, the combination group showed more significant improvement than the control in the nocturnal urination frequency (1.30 +/- 1.18 vs 2.27 +/- 1.60), Qmax ([13.85 +/- 3.15] vs [14.36 +/- 3.03] ml/min), IPSS (13.00 +/- 1.53 vs 17.20 +/- 8.43), and QOL (2.57 +/- 1.61 vs 2.93 +/- 1.68), all significantly better than the baseline (P < 0.05). The combination therapy achieved remarkable improvement as compared with the control in the nocturnal urination frequency (- [2.13 +/- 1.11] vs -[1.73 +/- 1.07]), IPSS (- [8.93 ?6.01] vs -[4.80 +/- 3.87]), and QOL (- [2.17 +/- 1.12] vs -[1.50 +/- 1.01]) (P < 0.05), but exhibited no significant differences from the latter in Qmax ([3.72 +/- 2.281 vs [3.95 +/- 2.53] ml/min) and residual urine volume (- [34.30 +/- 37.43] vs - [26.43 +/- 30.49] ml) (P > 0.05). Adverse reactions were found in 5 cases in the combination group (16.67%) and 3 cases in the control (10%) , with no remarkable differences between the two groups (P > 0.05). CONCLUSION: The combination therapy of Xipayimaizipizi Capsules and Tamsulosin can improve the symptoms of BPH and the patients quality of life of. PMID- 26738329 TI - [Efficacy of Shugan Yiyang Capsules combined with sertraline on premature ejaculation]. AB - OBJECTIVE: To observe the clinical effect of Shugan Yiyang Capsules combined with sertraline in the treatment of premature ejaculation (PE). METHODS: We randomly assigned 192 PE patients to receive sertraline hydrochloride 50 mg qd (control group, n = 96) or sertraline hydrochloride 50 mg qd plus Shugan Yiyang Capsules at the dose of 4 capsules tid ( combination therapy group, n = 96) , both for 6 weeks. We compared the intravaginal ejaculatory latency time (IELT) and Chinese Index of Premature Ejaculation ( CIPE) scores between the two groups of patients before and after medication and at 6 weeks after drug withdrawal. RESULTS: Compared with the baseline, the IELT was significantly increased after 6 weeks of medication in the combination therapy group ([1.41 +/- 0.53] vs [6.69 +/- 3.56] min, P < 0.05) and the control group ([1.43 +/- 0.48] vs [5.37 +/- 2.91] min, P < 0.05), and so was the CIPE score in the former (9. 80 +/- 2.06 vs 21.62 +/- 4.76, P < 0.05) and the latter group ([9.41 +/- 1.97] vs [20.85 +/- 4.83] , P < 0.05). In comparison with the pre-medication indexes, the IELT ([3.77 +/- 1.63] min) and CIPE score (16.92 +/- 3.37) of the combined therapy group were remarkably improved at 6 weeks after drug withdrawal (P < 0.05), but not those of the control ([1.19 +/- 1.34] min and 10.59 +/- 2.38, P > 0.05). CONCLUSION: Shugan Yiyang Capsules combined with sertraline have a definite and lasting effect on premature ejaculation. PMID- 26738330 TI - [Non-coding RNAs in castration-resistant prostate cancer]. AB - Non-coding RNAs (ncRNAs) are a large class of RNA molecules that do not encode proteins, regulate gene expressions multifacetedly, and influence the metabolism, proliferation, differentiation and apoptosis of cells as well as the occurrence and progression of tumors. Some of the ncRNAs act as cancer genes, such as miR 19a, miR-125b, miR-616, miR-7, miR-221, MALAT-1, and PRNCR1, which are upregulated in castration-resistant prostate cancer (CRPC) tissues or cell lines, and promote the development and progression of CRPC, some act as tumor suppressor genes, including miR-185, miR-342, miR-15, miR-16, and miR-146, which are downregulated in CRPC tissues or cell lines and inhibit or delay the occurrence of CRPC, and still others, such as miR-7, miR-19a, miR-125b, miR-221, and MALAT 1, are differentially expressed in the serum or tissue and can be used as potential biomarkers for the early diagnosis and prognosis of CRPC. This article presents an overview on the roles of ncRNAs in the occurrence, progression, diagnosis, and prognosis of CRPC and advances in their studies. PMID- 26738331 TI - [Related reproductive issues on male autosomal dominant polycystic kidney disease]. AB - Autosomal dominant polycystic kidney disease (ADPKD) is a most common inherited renal disease, about 50% with a family history, although the exact etiology not yet clear. To date, ADPKD, a multisystem disorder without effective preventive and therapeutic means, has been shown to be detrimental to human health. Recent studies show that severe oligoasthenozoospermia, necrospermia, immotile sperm, azoospermia, epididymal cyst, seminal vesicle cyst, and ejaculatory duct cyst found in male ADPKD patients may lead to male infertility, though the specific mechanisms remain unknown. Structural anomaly of spermatozoa, defect of polycystin, mutation of PKD genes, and micro-deletion of the AZF gene could be the reasons for the higher incidence of abnormal semen quality in male ADPKD patients. Assisted reproductive techniques can increase the chances of pregnancy, whereas the health of the offspring should be taken into consideration. This article presents an overview of reproductive issues concerning infertile male ADPKD patients from the perspective of the morbidity, pathophysiological mechanism, diagnosis, and management of the disease. PMID- 26738332 TI - [Male reproductive toxicity of bisphenol A]. AB - The reproductive toxicity of environmental endocrine disruptors has attracted substantial attention from researchers in recent years. Bisphenol A (BPA) is among the most prominent environmental estrogens worldwide, demonstrated to be related with the impairment of male reproductive function as well as other health problems, such as diabetes, obesity, cardiovascular diseases, and cancer. BPA acts primarily by mimicking antiandrogenic and estrogenic effects, disturbing the hypothalamic-pituitary-testicular axis and modulating gene expressions and enzyme activities in the hormone biosynthesis affecting steroids or its receptors. BPA is also involved in DNA methylation and the effects of epigenetics, resulting in dyszoospermia, oligoasthenoteratospermia/azoospermia and/or infertility in males. This review addresses the effects of BPA on male reproductive function, focusing on the mechanisms of its toxicity on spermatogenesis, semen quality, and the reproductive system. PMID- 26738333 TI - [FSH and FSHR gene polymorphisms and male infertility: An update]. AB - Follicle-stimulating hormone (FSH) is synthesized and secreted by the anterior pituitary, which binds to its receptors expressed on the membrane of Sertoli cells in the testis to bring about spermatogenesis. With the development of DNA sequencing technology, FSH SNPs rs10835638 and FSHR SNPs rs6165, rs6166, and rs1394205 were detected, which might directly affect the expression of FSH and activity of FSHR, resulting in male spermatogenic dysfunction. This review focuses on the relationship of FSH and FSHR gene polymorphisms with male infertility. PMID- 26738334 TI - [Arabian gum CVI Gummi arabicum Acadia Senegal Willd]. PMID- 26738335 TI - [ANDREAS VESALIUS. DE SIERINITIALEN IN 'DE HUMANI CORPORIS FABRICA LIBRI SEPTEM']. PMID- 26738336 TI - Preface. PMID- 26738337 TI - Cognitive problems related to vertebrobasilar circulation. AB - Neurodegenerative disorders are characterized by decreased regional cerebral blood flow. Supporting this concept, both cognitive training exercises and physical activity promote blood flow increase and correlate with healthy cognitive aging. The terminal branches of the posterior circulation supply blood to areas of the brain, such as the thalamus, hippocampus, occipital lobe, and cerebellum, involved with important intellectual functions, particularly recent memory, visual-spatial functioning, and visuomotor adaptations. Amnesia and visual agnosia may be a complication of not only posterior circulation infarctions but also vertebrobasilar insufficiency (VBI) without accompanying structural infarcts. The cognitive impairment maybe a manifestation of transient attacks and may persist beyond resolution of symptoms related to ischemia. Early recognition of cognitive deficits in the VBI patient is important because several recent reports show stent placements or medical treatment may improve cognition. PMID- 26738338 TI - Role of autophagy in the pathogenesis of Alzheimer disease. AB - Alzheimer disease (AD) is the most common progressive neurodegenerative disorder causing increased morbidity and mortality. It is characterized by accumulation of amyloid-beta in neurons. As there is no known definitive treatment of this disorder, studies trying to determine its exact pathogenetic pathways and target therapies for these specific pathways are being rapidly conducted. Autophagy is one of the areas of interest in studies on the pathogenesis of AD. It is a process of self-digestion that is thought to be a response to stressors and allows cells to adapt to environmental changes. There is accumulating evidence showing an association between autophagy and some disorders like cancer, infectious disease, and, in particular, neurodegenerative disorders. Growing attention has been focused on impaired autophagy in neurodegenerative disorders including AD, resulting in buildup of toxic molecules because of inappropriate activation of proteases or defective proteolysis. The question of whether autophagic response may be precisely modulated to prevent or treat neurodegenerative disorders like AD is still unanswered. In the future, it is thought that the autophagic process may be the one of the cornerstones of the treatment of AD. In this review, we summarize the knowledge of autophagy in the pathogenesis of AD in light of the current literature. PMID- 26738339 TI - Age-related macular degeneration and Alzheimer disease. AB - This review highlight the similarities in the pathogenesis between Alzheimer disease and age-related macular degeneration. All studies published between 1990 and 2014 were reviewed to identify the common pathological pathways. Alzheimer disease and age-related macular degeneration share common features such as vitronectin and amyloid-beta accumulation, increased oxidative stress, and apolipoprotein and complement activation pathways, which are reviewed as histologic and immunologic common features. PMID- 26738340 TI - Why is Alzheimer disease confused with other dementias? AB - Alzheimer disease (AD) is the most common cause of dementia. The cardinal manifestation of AD is progressive loss of memory. However, there are some nonamnestic presentations of AD, also called atypical AD. Symptoms of AD can sometimes start suddenly. In the presence of atypical symptoms or sudden onset, it may be difficult to distinguish AD from other dementias. We would like to discuss the confusing features of atypical AD that mimic other dementias. In this review, the literature associated with confusing features of AD, suggesting other dementia syndromes, is reviewed. In addition, a case of semantic dementia (SD) with the complaint of forgetfulness previously diagnosed as AD is presented together with clinical and radiological clues of the differential diagnosis of dementia syndromes. As in our representative SD case, a careful clinical history, a detailed mental evaluation, and neuroimaging will overcome this difficulty in diagnosis. PMID- 26738341 TI - Postoperative cognitive dysfunction and Alzheimer disease. AB - Alzheimer disease (AD) is the most prevalent neurodegenerative disorder in elderly people. Patients with AD appear to be particularly at risk for cognitive deterioration following anesthesia. Some in vitro studies suggest that exposure to general anesthesia (GA) promotes the AD process. On the other hand, there are no clinical studies that clearly demonstrate that GA is a cause of cognitive dysfunction in patients with probable AD. The aim of this research was to discuss the relation between postoperative cognitive dysfunction (POCD) and AD according to the literature. In vivo studies examining AD biomarkers postoperatively and in vitro studies exploring amyloid-beta (Abeta) converge to indicate that anesthetics could affect AD pathogenesis, either directly or indirectly. Careful evaluation of the mental state should be mandatory for all elderly patients undergoing GA. Long-term prospective, randomized clinical studies are required to examine the relationship between POCD and AD. PMID- 26738342 TI - Nutritional issues in dementia patients. AB - Dementia is an inevitable disease of aging, leading not only to diminished cognitive ability but also behavioral changes, malnutrition, pressure sores, and infections. Acknowledging common problems and their solutions is essential for any health service worker who deals with demented geriatric patients. PMID- 26738343 TI - Alzheimer disease and anesthesia. AB - Alzheimer disease (AD) is one of the most common neurodegenerative diseases and the most prevalent form of dementia. Some factors in the development of AD, age being the best-known one, have been suggested; however, no causes have been found yet. The pathophysiology of the disease is highly complex, current therapies are palliative, and a cure is still lacking. Adverse effects of anesthetics in the elderly have been reported since the 1950s; however, awareness of this old problem has recently gained inportance again. Whether exposure to surgery and general anesthesia (GA) is associated with the development of AD has been questioned. As the population is aging, many elderly patients will need to be anesthetized, and maybe some were already anesthetized before they were diagnosed. Exposure to anesthetics has been demonstrated to promote pathogenesis of AD in both in vitro and in vivo studies. However, to date, there have not been any clinical trials to address a link between exposure to GA and the development of AD in humans. Therefore, before making any conclusions we need further studies, but we should be aware of the potential risks and take cautions with vulnerable elderly patients. PMID- 26738344 TI - A comparison of hair and serum trace elements in patients with Alzheimer disease and healthy participants. AB - BACKGROUND/AIM: To determine whether there was a difference between serum and hair trace elements' concentrations in patients with Alzheimer disease (AD) and healthy participants. MATERIALS AND METHODS: Hair and serum copper, selenium, zinc, magnesium, manganese, and iron levels were measured by inductively coupled plasma-mass spectrometry in patients with AD and healthy participants, and the obtained results were statistically compared. RESULTS: The mean hair selenium and zinc levels of patients with AD were significantly lower than the levels found for control participants (P < 0.05). Patients with AD had significantly higher mean hair copper and manganese levels than the controls. There were no significant differences between AD patients and controls with respect to the hair iron and magnesium levels (P > 0.05). Hair and serum trace element (copper, selenium, zinc, magnesium, manganese, and iron) levels in patients with AD showed no significant difference according to mini mental test scores or sex (P > 0.05). CONCLUSION: Some trace element levels may change in patients with AD. Due to the more permanent status, the analysis of these element levels in hair might be superior to blood analysis. PMID- 26738345 TI - Alzheimer disease, inflammation, and novel inflammatory marker: resistin. AB - BACKGROUND/AIM: Inflammation may play an important role in Alzheimer disease (AD) pathogenesis. A growing amount of evidence indicates that resistin has hallmark regulatory functions such as inflammatory states. The aim of this study was to determine whether plasma resistin levels would be useful in the diagnosis of patients with AD and to investigate the relationships between resistin and other inflammatory markers such as hs-CRP and TNF-alpha. Materials and methods: In this cross-sectional study, 38 AD patients and 32 control subjects with normal cognitive function aged 65 years and over were included. The diagnosis of AD was made according to DSM-IV and NINCDS-ADRDA criteria. Serum levels of resistin were measured with an enzyme-linked immunosorbent assay method using the human resistin E50 kit. Results: The median resistin level of AD patients was significantly higher than in the control group (86.3 vs. 70.8 pg/mL, P = 0.002). Overall accuracy of resistin in determining AD was 70.66%, with sensitivity, specificity, PPV, and NPV of 75.0%, 65.5%, 73.0%, and 67.9%, respectively. There was no statistically significant difference between AD patients and control subjects with respect to hs-CRP and TNF-alpha levels. Conclusion: Resistin levels may be considered as a predictor of AD and it may predict activation of the immune system in AD pathophysiology. PMID- 26738346 TI - Forensic medicine evaluation of Alzheimer patients: a series from Ankara, Turkey. AB - BACKGROUND/AIM: Pathophysiological changes due to Alzheimer disease and increasing age might result in situations requiring forensic evaluation in the elderly. Judicial bodies might need forensic evaluation of trauma and the decision-making capacity of Alzheimer patients. This study aimed to determine the demographic and clinical characteristics of Alzheimer patients seen for forensic evaluation. MATERIALS AND METHODS: Forensic records issued by the Department of Forensic Medicine of Hacettepe University in 2012 and 2013 were investigated. Patients with Alzheimer disease were included in the study and were analyzed in terms of age, sex, reason for application, comorbid medical conditions, occupation, and place and status of living. RESULTS: There were 30 Alzheimer patients examined in the study period. Of these, 17 (56.6%) were male and 13 (43.3%) were female. The patients' ages ranged between 51 and 90 years, and the mean age was 78.7 years. The majority of cases (25, 83.3%) were transferred for evaluation of decision-making capacity, while only 5 (17.7%) were referred to our department for forensic reporting of bodily damage. CONCLUSION: Forensic reporting of bodily damage in Alzheimer patients is similar to common injury cases. However, in conditions requiring evaluation of decision-making capacity in Alzheimer patients, all records should be carefully examined and a complete neuropsychiatric evaluation should be performed. PMID- 26738347 TI - Vitamin D status and its association with gradual decline in cognitive function. AB - BACKGROUND/AIM: To compare plasma vitamin D concentrations among patients with normal cognitive function (control group), mild cognitive impairment (MCI), and Alzheimer disease (AD). MATERIALS AND METHODS: In total, 158 patients with AD, 228 patients with MCI, and 603 control subjects were included. Plasma levels of 25-hydroxyvitamin D were measured after comprehensive geriatric assessment and compared among groups. SPSS 15.0 was used for statistical analysis. RESULTS: Mean levels of 25-hydroxyvitamin D were significantly different among the 3 groups of AD patients, MCI patients, and controls (P < 0.001). Post hoc analysis revealed that the levels were significantly lower in the MCI group than the control group (P = 0.002) and significantly lower in the AD group than the control group (P = 0.003). Multivariate analysis showed that age (OR: 1.070, 95% CI: 1.025-1.116, P = 0.002), instrumental activities of daily living score (OR: 0.920, 95% CI: 0.850 0.995, P = 0.037), 25-hydroxyvitamin D level (OR: 0.959, 95% CI: 0.932-0.987, P = 0.004), and diabetes mellitus (OR: 2.476, 95% CI: 1.153-5.319, P = 0.020) were factors independently associated with AD. CONCLUSION: This study demonstrated that there is a correction between plasma 25-hydroxyvitamin D levels and cognitive functions. PMID- 26738348 TI - Potential genetic biomarkers in the early diagnosis of Alzheimer disease: APOE and BIN1. AB - BACKGROUND/AIM: Alzheimer disease (AD) is triggered by interactions of multiple genetic and environmental factors. The APOE gene E4 allele is the best-known risk factor for AD, yet it represents a small ratio of genetic factors. According to genome-wide association studies, the BIN1 gene is the second important risk factor for AD, following the APOE gene. We aimed to identify a novel biomarker indicating susceptibility to AD by investigating APOE alleles and BIN1 gene polymorphisms in a Turkish population. MATERIALS AND METHODS: Fifty-three AD patients and 56 controls were included to examine polymorphism and allele frequency of the APOE and BIN1 genes. Genomic DNAs were isolated from whole blood by SDS/proteinase K treatment, phenol-chloroform extraction, and ethanol precipitation. RFLP was done for identification of polymorphisms in the APOE gene and allele-specific PCR was used for the BIN1 gene. RESULTS: Frequency of the APOE E4 allele was higher in the AD patient group, while the frequency of the E2 allele was higher in controls. The E4/E4 genotype was detected in the AD patient group, while this genotype was not observed in the controls. The frequencies of BIN1 alleles were similar in both groups. CONCLUSION: There was a strong association between AD and the APOE E4 allele, while no such relation was observed with BIN1 gene polymorphism. PMID- 26738349 TI - Plasma 8-isoPGF2alpha and serum melatonin levels in patients with minimal cognitive impairment and Alzheimer disease. AB - BACKGROUND/AIM: F2alpha-isoprostane is accepted as an oxidative stress indicator and melatonin shows neuroprotective effects by antioxidative and antiamyloidogenic influences. By measuring these in patients diagnosed with minimal cognitive impairment (MCI) and Alzheimer-type dementia, we intended to demonstrate whether the measurement of these markers contributes to early diagnosis of Alzheimer disease (AD) in the MCI stage or not. MATERIALS AND METHODS: Three groups (n = 63) were created: the AD group, MCI group, and control group. Serum melatonin levels were measured by radioimmunoassay method, and plasma total 8-isoPGF2alpha levels were measured by enzyme immunoassay method. RESULTS: Significant differences were observed in the melatonin levels between the MCI group and AD group (P = 0.009), and in 8-isoPGF2alpha levels between the AD group and control group (P = 0.022). A negative correlation between mini mental state examination (MMSE) scores and 8-isoPGF2a levels (r = -0.459, P < 0.001) and positive correlation between MMSE scores and melatonin levels (r = 0.317, P = 0.011) were found. CONCLUSION: Although the plasma 8-isoPGF2alpha and serum melatonin levels in MCI were not found to be good early diagnostic markers to indicate risk of AD, results were found to support the role of oxidative stress in AD. PMID- 26738350 TI - Malnutrition is associated with dementia severity and geriatric syndromes in patients with Alzheimer disease. AB - BACKGROUND/AIM: Malnutrition is associated with increased morbidity and mortality in patients with Alzheimer disease (AD). In this study, we aimed to screen for malnutrition and geriatric syndromes and seek their associations in patients with AD. MATERIALS AND METHODS: The Mini Mental State Examination (MMSE), Mini Nutritional Assessment (MNA), Katz Activities of Daily Living (ADL), and Lawton Instrumental Activities of Daily Living (IADL) tests were applied. Mean daily oral fluid intake was assessed according to patients' and relatives' declarations. RESULTS: Seventy-six patients with a mean age of 79 +/- 7.4 years were included. Most of the patients had mild or moderate dementia. Malnutrition was associated with increased rates of hospitalization and falls, dysphagia, insomnia, agitation, delusions, hallucinations, immobility, and incontinence. A daily fluid intake of < 1100 mL was associated with malnutrition risk. Multivariate linear regression analysis revealed independent correlations of lower MNA score with lower ADL score, lower daily oral fluid intake, lower MMSE score, and female sex. CONCLUSION: Dependency, inadequate fluid intake, advanced dementia stage, and female sex were independently associated with malnutrition. Malnutrition also seemed to be associated with sleep disturbances, psychological problems, immobility, falls, and increased hospitalization risk in these patients. Daily oral fluid intake may be a practical tool in the screening of malnutrition. PMID- 26738351 TI - Association of CLU and TLR2 gene polymorphisms with late-onset Alzheimer disease in a northwestern Iranian population. AB - BACKGROUND/AIM: A number of genetic variants from different genes have been reported to be related to late-onset Alzheimer disease (LOAD) susceptibility. From these genes, polymorphisms in CLU and TLR2 have been replicated in several studies. In this study we examined the association of rs11136000 in CLU and the TLR2 -196 to -174 del polymorphism with the risk of LOAD in a northwestern Iranian population. MATERIALS AND METHODS: We conducted a case-control study with a dataset of 160 LOAD patients and 163 healthy controls. To examine polymorphisms of CLU and TLR2 in LOAD we used the PCR/RFLP method and genotype frequencies were statistically determined. RESULTS: There was no association between CLU polymorphism and the risk of LOAD, but for deletion in TLR2 we found significant differences between LOAD and the control group (P > 0.001, OR = 0.55). CONCLUSION: This result suggests that the TLR2 -196 to -174 del polymorphism is an additional risk factor for LOAD. Allelic frequencies of CLU may have no effect on risk of LOAD. PMID- 26738352 TI - The reliability and validity of the Turkish version of the Neuropsychiatric Inventory-Clinician. AB - BACKGROUND/AIM: The Neuropsychiatric Inventory-Clinician (NPI-C) scale is one of the best-known scales for evaluating the behavioral and psychological symptoms of dementia. This study aimed to assess the reliability and validity of the Turkish version of the NPI-C scale in patients with Alzheimer disease (AD). MATERIALS AND METHODS: The NPI-C scale was administered to 125 patients with AD. For reliability, both Cronbach's alpha and interrater reliability were analyzed. The Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD) scale was applied for validity and, in addition, the Mini Mental State Examination (MMSE), Instrumental Activities of Daily Living (IADL) scale, and Disability Assessment of Dementia (DAD) scale were completed. RESULTS: The Turkish version of the NPI-C scale showed high internal consistency (Cronbach's alpha = 0.75) and mostly good interrater reliability. Assessments of validity showed that the NPI-C and corresponding BEHAVE-AD domains were found to be significantly correlated, between 0.925 and 0.195. Moreover, the correlations between NPI-C and MMSE were significant for all domains except the dysphoria, anxiety, and elation/euphoria domains. When we conducted a correlation analysis of NPI-C with IADL, all domains were statistically significantly correlated except aggression, anxiety, elation/euphoria, and dysphoria. CONCLUSION: The Turkish version of the NPI-C scale was found to be a reliable and valid instrument to assess neuropsychiatric symptoms in Turkish elderly subjects with AD. PMID- 26738353 TI - Evaluation of retinal nerve fiber layer thickness in Alzheimer disease using spectral-domain optical coherence tomography. AB - BACKGROUND/AIM: To evaluate the retinal nerve fiber layer (RNFL) thickness in patients with Alzheimer disease (AD) and to compare the results with those of healthy controls. MATERIALS AND METHODS: Forty patients (mean age: 75.02 +/- 6.34 years; 23 women) with untreated AD and 40 age-, sex-, and education-matched healthy patients were examined in this case-control prospective study. All patients underwent detailed ophthalmic and neurological examination. The Mini Mental State Examination (MMSE) was performed and RNFL thickness was measured using spectral-domain optical coherence tomography. The association between RNFL and MMSE score was also assessed. RESULTS: The average RNFL thickness was 84 +/- 7.0 um in AD patients and 107 +/- 6.3 um in healthy subjects (P < 0.001). The mean MMSE score was 21.9 +/- 2.13 in AD patients. There was no significant correlation between the RNFL thickness and MMSE score. CONCLUSION: Patients with AD had reduced RNFL thickness in all quadrants compared with the control group. This finding suggests that RNFL thickness analysis may be useful in the early diagnosis of AD. PMID- 26738354 TI - The effects and interactions of APOE and APH-1A polymorphisms in Alzheimer disease. AB - BACKGROUND/AIM: Alzheimer disease (AD) is characterized by the accumulation of senile plaques composed of amyloid beta-peptide, which is derived from beta amyloid precursor protein through degradation by beta-secretase and y-secretase complexes. One of the major components of y-secretase complex, anterior pharynx defective-1 (APH-1), is responsible for the activity of the gamma-secretase complex. In this study, we searched for not only the most known common genetic risk factor, APOE, but also the APH-1a gene polymorphism in AD patients in a Turkish population. MATERIALS AND METHODS: In this study, 49 AD patients and 45 healthy controls were included. The genetic polymorphisms and allele frequencies of APOE and APH-1a were investigated. Patients were evaluated for behavioral, cognitive, and functional domains by detailed neurocognitive tests, and comparison between the above-mentioned polymorphisms and disease severity was made. RESULTS: Although there was an increased tendency of the APO epsilon4 allele in the AD group, no statistically significant difference was detected either in APOE or APH-1a polymorphisms, not suggesting a strong susceptibility to the development of AD. CONCLUSION: While searching for the pathogenesis of AD in order to develop novel diagnostic as well as therapeutic approaches, analysis of other genes with a possible role in AD is warranted. PMID- 26738355 TI - Neurodegeneration in ocular and central nervous systems: optical coherence tomography study in normal-tension glaucoma and Alzheimer disease. AB - BACKGROUND/AIM: To evaluate, in vivo, the optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) in patients with normal-tension glaucoma (NTG) and those with Alzheimer disease (AD) in comparison with healthy subjects. MATERIALS AND METHODS: This cross-sectional study included 18 patients with NTG, 20 with AD, and 20 control subjects. An ophthalmologic examination and OCT scans of both eyes were performed in all patients. RESULTS: There was a significant reduction in peripapillary RNFL thickness and macular GCC thickness and a significant increase in the global loss volume (GLV) rate in both the NTG and AD patients when compared to the control subjects (P = 0.004, P = 0.006, P < 0.001, respectively). The statistical evaluation showed no difference in any RNFL or GCC parameters between the AD and NTG groups (P > 0.05). There was a negative correlation between disease duration and average RNFL and GCC thicknesses (r = -0.350, P = 0.027 and r = -0.471, P = 0.002, respectively) and a positive correlation between duration and GLV (r = 0.427, P = 0.006) in the AD group. CONCLUSION: The average RNFL thickness, GCC thickness, and GLV rates may help in the diagnosis of AD as an additional examination and may provide some important clues about the duration of the disease. PMID- 26738356 TI - Is Alzheimer disease related to age-related macular degeneration? AB - BACKGROUND/AIM: To compare the cognitive functions and define the frequency of Alzheimer disease (AD) between participants with and without age-related macular degeneration (AMD). MATERIALS AND METHODS: Fifty-nine patients with late-stage AMD (74.3 +/- 7.3 years) and 49 age-, sex-, and education-matched control subjects were compared for the presence of AD according to the guidelines of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA). Detailed neuropsychological tests were performed for all subjects. RESULTS: Neuropsychiatric tests scores were lower in the AMD group than the control group. The frequency of AD was higher in patients with AMD (40.7% in AMD and 20.4% in control group, P = 0.03), and particularly higher in late dry (nonvascular) AMD (d-AMD) patients (71.4% in d-AMD and 31.1% in late wet (vascular) AMD, P = 0.007). d-AMD patients performed worse than controls on all tests. There was also an association between age, sex, and low education and neuropsychiatric tests scores (P < 0.01). However, there was no association between visual acuity and neuropsychiatric tests scores. CONCLUSION: The increased frequency of AD in patients with AMD is significant. This study demonstrated the importance of cognitive assessment in patients with AMD, particularly in the d-AMD type. PMID- 26738357 TI - Nerve growth factor receptors in dementia. AB - BACKGROUND/AIM: Nerve growth factor (NGF) promotes the survival and differentiation of sensory and sympathetic neurons. Several studies have found that certain neuropathological factors stimulate NGF receptor expression and release the truncated nerve growth factor receptor (TNGFR) to biological fluids. The aim of this pilot study was to determine urine TNGFR levels in patients with dementia and to verify whether TNGFR can be used as a biomarker of dementia. MATERIALS AND METHODS: Twelve patients with dementia and 12 healthy individuals were asked to voluntarily participate in this study. Ages, sexes, and weights were matched. The first morning urine samples were collected and the concentrations of TNGFR in the urine samples were measured by fluoroimmunoassay. RESULTS: The mean levels of TNGFR in the urine samples of the healthy control subjects and the patients with dementia were 164 +/- 23 and 341 +/- 66 ng / mg creatinine respectively. A positive relationship was found between the levels of TNGFR in different ages of both control and patient subgroups. This is consistent with the previous observations that pathological condition may stimulate the NGF receptor expression. CONCLUSION: These findings might be of assistance to evaluate the development of the memory loss associated with Alzheimer disease and other age-associated diseases. PMID- 26738358 TI - Effect of Capparis spinosa L. on cognitive impairment induced by D-galactose in mice via inhibition of oxidative stress. AB - BACKGROUND/AIM: To determine the phenolic acid levels and DNA damage protection potential of Capparis spinosa L. seed extract and to investigate the effect of the extract on cognitive impairment and oxidative stress in an Alzheimer disease mice model. MATERIALS AND METHODS: Thirty BALB/c mice divided into 5 groups (control, D-galactose, D-galactose + C. spinosa 50, D-galactose + C. spinosa 100, D-galactose + C. spinosa 200) were used. Mice were administered an injection of D galactose (100 mg/kg, subcutaneous) and orally administered C. spinosa (50, 100, or 200 mg/kg) daily for 8 weeks. RESULTS: Syringic acid was detected and the total amount was 204.629 ug/g. Addition of 0.05 mg/mL C. spinosa extract provided significant protection against the damage of DNA bands. C. spinosa attenuated D galactose-induced learning dysfunctions in mice and significantly increased memory retention. Malondialdehyde (MDA) levels increased and superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) activities decreased in the D-galactose group. C. spinosa (200 mg/kg body weight) significantly decreased MDA level and increased SOD, GPx, and CAT activities. CONCLUSION: These results show that C. spinosa has the potential in ameliorating cognitive deficits induced by D-galactose in mice and the antioxidant activity may partially account for the improvement of learning and memory function. PMID- 26738359 TI - The connection between MCI and Alzheimer disease: neurocognitive clues. AB - BACKGROUND/AIM: Mild cognitive impairment (MCI) is defined as a pathological stage between 'healthy aging' and 'dementia' In this study, cases of MCI were compared with early-stage Alzheimer disease (AD) and age-related cognitive decline (ARCD) in terms of cognitive profiles in order to find a connection between MCI and AD. MATERIALS AND METHODS: Patients who were comparable in terms of age and sex and who met the criteria of MCI, ARCD, or early-stage AD were included in the study retrospectively. Wechsler memory scale, executive function, visuospatial, language, and memory tests were applied to all subjects. Additionally, all patients completed a mini-mental state examination test, geriatric depression scale, and activities of daily living scale. RESULTS: Complex attention tests and long-term memory tests were more impaired in MCI patients when compared with ARCD. However, there were no significant differences between the MCI and ARCD cases in activities of daily living. Memory and executive functions were more deteriorated in patients with AD in comparison to MCI. CONCLUSION: During the follow-up period of ARCD, impairment in orientation, complex attention, and long-term memory should suggest the diagnosis of MCI. When personal information and executive functions are affected in MCI, AD should be carefully considered. PMID- 26738360 TI - Molecular docking and ex vivo and in vitro anticholinesterase activity studies of Salvia sp. and highlighted rosmarinic acid. AB - BACKGROUND/AIM: To evaluate acetylcholinesterase (AChE) inhibitory activity and antioxidant capacity of the major molecule from Salvia sp., rosmarinic acid, as a drug candidate molecule for treatment of Alzheimer disease (AD). MATERIALS AND METHODS: The AChE inhibitory activity of different extracts from Salvia trichoclada, Salvia verticillata, and Salvia fruticosa was determined by the Ellman and isolated guinea pig ileum methods, and the antioxidant capacity was determined with DPPH. The AChE inhibitory activity of the major molecule rosmarinic acid was determined by in silico docking and isolated guinea pig ileum methods. RESULTS: The methanol extract of Salvia trichoclada showed the highest inhibition on AChE. The same extract and rosmarinic acid showed significant contraction responses on isolated guinea pig ileum. All the extracts and rosmarinic acid showed high radical scavenging capacities. Docking results of rosmarinic acid showed high affinity to the selected target, AChE. CONCLUSION: In this study in vitro and ex vivo studies and in silico docking research of rosmarinic acid were used simultaneously for the first time. Rosmarinic acid showed promising results in all the methods tested. PMID- 26738361 TI - The value of FDG-PET/CT by using 3-dimensional stereotactic surface projection software analysis in the differential diagnosis of dementia. AB - BACKGROUND/AIM: To retrospectively reevaluate brain fluor-18-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging studies with 3-dimensional stereotactic surface projection (NEUROSTAT) software in order to detect changes in regional brain metabolism and to find out its contribution to the final diagnosis. MATERIALS AND METHODS: A total of 48 cases were included in this study. According to clinical evaluation and neuropsychometric test results, there were 17 (35%) patients with probable Alzheimer disease (AD), 17 (35%) patients with probable frontotemporal dementia (FTD), and 14 (30%) patients with undefined advanced dementia. Brain FDG-PET imaging studies were interpreted visually and also using 3-dimensional stereotactic surface projection. RESULTS: Clinic and PET findings were consistent in 20 patients and inconsistent in 14 patients. When consensus diagnosis was taken as the reference, the sensitivity, specificity, accuracy, and positive and negative predictive values of FDG-PET imaging were 93%, 85%, 90%, 90%, and 89% respectively, for AD diagnosis. The same values were 85%, 93%, 90%, 89%, and 90%, respectively, for FTD definition. CONCLUSION: Using automatized programs that enable quantitative evaluation of regional brain glucose metabolism, in addition to visual evaluation, may increase diagnostic efficiency, as well as minimize interobserver and/or intercenter variability. PMID- 26738362 TI - A Turkish 3-center study evaluation of serum folic acid and vitamin B12 levels in Alzheimer disease. AB - BACKGROUND/AIM: Alzheimer disease, a common proteopathy of advanced age, is characterized by cortical atrophy, neuron degeneration, neuronal loss, and accumulation of extracellular amyloid beta plaques. We aimed to investigate serum vitamin B12 and folic acid levels in Alzheimer disease and other dementia patients, as a potential screening test to detect presymptomatic Alzheimer disease in Turkish patients. MATERIALS AND METHODS: We evaluated folic acid and vitamin B12 levels in Alzheimer disease patients as well as in other dementia and geriatric patients from Ankara, Dokuz Eylul, and Cukurova university hospitals; 290 female and male geriatric subjects were enrolled. Vitamin B12 and folic acid levels were measured using Roche E170 and Beckman Coulter DXI 800 immunoassays (chemiluminescence) according to the manufacturers' guideline in all centers. RESULTS: We evaluated the results of folic acid and vitamin B12 in Alzheimer disease, other dementias and geriatric patients. No significant difference between the groups regarding the routine control of biochemical parameters was observed. CONCLUSION: Currently, serum folic and vitamin B12 levels are not diagnostically reliable tests for screening presymptomatic Alzheimer disease. However, the results may statistically be significant if we increase the sample size. PMID- 26738363 TI - Prevalence of cognitive impairment and related risk factors in community-dwelling elderly in Kayseri, Turkey. AB - BACKGROUND/AIM: The increased rate of elderly individuals in the general population leads to functional decline because of cognitive impairment (CImp). We aimed to detect the prevalence of CImp and related risk factors in community dwelling elders living in an urban area (Kayseri, Turkey). MATERIALS AND METHODS: This is a cross-sectional, population-based study conducted in a sample of 900 community-dwelling elders aged 60 years and older. Cognitive status and depressive symptoms were assessed by standardized Mini Mental State Examination (MMSE) and the Geriatric Depression Scale (GDS), respectively. RESULTS: The mean age of the participants was 71.6 +/- 0.18 years, of whom 47.9% were female. Prevalences of CImp and depressive symptoms were 26.1% and 24.9%, respectively. Female sex, illiteracy, low income, increased age, being a housewife, being a nonsmoker, being depressive, being single, and having more than four children were significantly related with CImp based on univariate logistic regression analysis. However, in multivariate logistic regression analysis, it was found that being illiterate, being depressive, and having an increased number of children were determinants of CImp in the elderly. Self-reported chronic diseases were not detected as risk factors for CImp. CONCLUSION: Increasing socioeconomic status and education levels and preventing depression should be accepted as primary protective measures for CImp. PMID- 26738364 TI - Impaired cognitive performance and hippocampal atrophy in Parkinson disease. AB - BACKGROUND/AIM: Dementia is common in Parkinson disease (PD). Since magnetic resonance imaging has been used, hippocampal atrophy has been shown in PD patients with or without dementia. In this study we sought the correlation of cognitive decline with bilateral hippocampal volume in PD patients. MATERIALS AND METHODS: Thirty-three patients with diagnosis of idiopathic PD and 16 healthy subjects were included in this study. PD patients were divided into two groups as normal cognitive function and mild cognitive impairment (MCI). The Mini-Mental State Examination and detailed cognitive assessment tests were performed for all patients for cognitive analyses. Depression was excluded by the Geriatric Depression Scale. RESULTS: The mean onset age of disease was 55 years for PD patients without dementia and 59 for PD patients with MCI. According to the Hoehn Yahr scales, 24% of patients had grade 1, 58% had grade 2, and 18% had grade 3 disease. Right and left hippocampal volumes decreased along with cognitive test scores in PD patients. Increased right hippocampal volume was correlated with forward number test in the MCI-PD group. CONCLUSION: These findings suggest that memory deficit is associated with hippocampal atrophy in PD patients. PMID- 26738365 TI - Test your memory-Turkish version (TYM-TR): reliability and validity study of a cognitive screening test. AB - BACKGROUND/AIM: The test your memory (TYM) is reported to be a sensitive cognitive function assessment scale for people with dementia. The aim of the present study was to investigate the reliability and validity of an adapted Turkish version of the TYM (TYM-TR) among Turkish dementia patients. MATERIALS AND METHODS: The TYM-TR was given to 59 patients with dementia aged 60+ and 336 normal controls aged 23-75+. The diagnostic utility of the TYM-TR was compared with that of the mini-mental state examination (MMSE) to validate it. RESULTS: The internal consistency of the TYM-TR was a = 0.85. The test-retest reliability was 0.97 (P < 0.001). The TYM-TR showed a statistically significant correlation with MMSE; r (57) = 0.628 P < 0.001. The TYM-TR distinguished dementia patients from controls (AUC = 0.994). A cut-off point of 34 was optimal for detecting dementia with a sensitivity of 96.61% and a specificity of 96.13% [95% CI (0.981 0.999)]. CONCLUSION: The Turkish version of the TYM was found to have good reliability and validity to distinguish dementia in the Turkish population. PMID- 26738366 TI - Basic thoracic ultrasound for the respiratory physician. AB - Thoracic ultrasound (TUS) evolved in the last ten years as the method of choice for evaluating pleural abnormalities and for guiding lung procedures. TUS can "see" almost all structures in the chest, including thoracic wall, pleura, pleural space, the heart, the great vessels and the peripheral layers of the lungs. However, there is still a great need to develop TUS services in respiratory departments in Romania. To facilitate this development we reviewed the literature and selected what we considered to be essential practical information for the beginner in TUS, including technique, normal findings, and common abnormalities. Moreover, we describe here a step-by-step scanning technique for chest physicians. Our aim is to raise awareness of TUS. Because TUS is rapid, accurate, noninvasive and can be applied in any ward, we recommend facilitating the training of all junior respiratory doctors in this technique, as it is likely to improve patient experience, clinical effectiveness and to reduce costs with chest radiographs or CT scans in the future. PMID- 26738367 TI - Prevalence of anemia and its impact on mortality in patients with acute exacerbation of chronic obstructive pulmonary disease in a developing country setting. AB - Chronic Obstructive Pulmonary Disease (COPD) is going to be the third most common cause of death worldwide. The natural course of COPD is interrupted by acute exacerbations (AECOPD) with an overall mortality rate of 10%. Anemia is a well known independent predictor of mortality in several chronic diseases. Little is known about the impact of anemia on mortality in AECOPD. The aims of this study were to determine the prevalence of anemia in AECOPD patients and its impact on mortality in a developing country setting. We retrospectively studied 200 hospitalized patients with AECOPD (100 died in hospital and 100 survived) in Imam Khomeini teaching hospital, Urmia, Iran. Prevalence of anemia between deceased and surviving patients compared by using x-square test. Mean admission day Hb and Hct level were compared between the two groups by using Student t-test. Anemia was defined according to WHO criteria: Hb<13 g/dl in males; Hb<12 g/dl in females. The prevalence of anemia was significantly higher in patients who died in hospital compared to those who survived (72% vs. 49%, p=0.001 and OR=2.68). The mean +/-SD Hb level was 11.5+/-2.7 g/dl among deceased patients vs. 13.0+/ 2.0 g/dl among survivors (p value<0.001). The duration of hospitalization was significantly higher (p<0,001) in anemic patients (mean 13.28 days in anemic vs. 7.0 days in non-anemic patients). In bivariate correlation analysis, Hb was positively correlated with FEV1 (r=+0.210, p=0.011) and negatively with duration of hospitalization (r=-0.389, p=0.000). Anemia was common in AECOPD patients in this developing country setting and was significantly associated with in hospital mortality. PMID- 26738368 TI - Echocardiographic Evaluation of the Relationship Between inflammatory factors (IL6, TNFalpha, hs-CRP) and Secondary Pulmonary Hypertension in patients with COPD. A Cross sectional study. AB - BACKGROUND: Inflammatory mechanism appears to play a major role in the pathogenesis of various types of human pulmonary hypertension such as idiopathic PAH (IPAH) and PAH associated" with connective tissue disease. Although we know that inflammatory factors such as IL6 and TNFalpha have an important role in IPAH, there is limited information about the relationship between acute phase reactants and pulmonary hypertension occurring secondary to pulmonary diseases such as chronic obstructive pulmonary diseases (COPD). METHODS: This cross sectional study was carried out on 94 patients who had COPD. Patients with a recent history of systemic steroid and acetylsalicylic acid (ASA) use, infection, trauma or surgery, gastrointestinal bleeding, coronary artery disease (CAD) and Hypertension were excluded. Body plethysmography and transthoracic echocardiography were done. Blood samples for each patient included were drawn for complete blood count (CBC), IL6, TNFalpha and highly sensitive C reactive protein (hs-CRP). RESULTS: Twenty patients (28.6%) had pulmonary hypertension. The difference between the mean IL6 and hs-CRP in patients with and without pulmonary hypertension was significant (7 pg/ml vs. 4.4 pg/ml and 13.04 pg/ml vs. 3.31 pg/ml) (p=0.006 and p=0.000). There was a correlation between IL6 and mean pulmonary arterial pressure (r=0.35, p=0.003). After adjustment forage, sex, serum Hemoglobin, Hematocrit, O2Sat, FEV1, FVC the relationship between the IL6, hs-CRP and the presence of pulmonary hypertension remained significant (p=0.022, p=0.026). CONCLUSION: Inflammatory factors such as IL6 and hs-CRP are independent risk factors for pulmonary hypertension in COPD patients. PMID- 26738369 TI - Can a simple forced inspiratory maneuver help identify subjects at risk for sleep disordered breathing? AB - Application of a negative pressure has been utilized in experimental settings to demonstrate abnormal upper airways compliance. We hypothesized that a simple forced inspiratory maneuver could be used as a screening test for this abnormality in an epidemiological setting. 277 men and women, aged 30 years or more, who attended a Preventive Medicine Centre, volunteered for completing a sleep questionnaire, having standard anthropometric measurements, a non-invasive upper airways examination, and for performing an oronasal peak inspiratory maneuver. The peak inspiratory flow (PIF) of 127 females was significantly less compared to that of the 137 males (211+/-47 vs. 269+/-59 l.min-1). PIF was significantly inversely related to age in both sexes; a positive correlation with height was found in males only. Males with enlarged soft palates had a significantly lower PIF (256+/-54 vs. 277+/-62 l.min-1; p=0.04). No difference in PIF was found in subjects who stated that they experienced breathing pauses during sleep. Habitual snoring males had a significantly lower PIF as compared to the non-snorers (251+/-59 vs. 282+/-57 l.min-1; p=0.003); after adjustment for age, this difference was borderline significant (p=0.06). A forced inspiratory flow maneuver yielded a PIF which was different between genders, was age dependent in both sexes, and related to height in males. PIF did not identify male subjects with breathing pauses during sleep, but was associated with a larger soft palate and was borderline decreased in habitual snoring males. The present results suggest that, with further validation, the PIF test could represent a simple means to indirectly explore upper airways compliance. PMID- 26738370 TI - The role of FENO and spirometry in the evaluation of obstruction in pediatric asthma. AB - INTRODUCTION: The fractional exhaled nitric oxide concentration (FENO) is used as a noninvasive biomarker for asthmatic inflammation. The role in establishing an asthma diagnosis is still under research. Spirometry remains the main investigation for the diagnosis and monitoring of asthma. OBJECTIVES: The aim of the study was to assess the correlation between FENO level and the values of spirometric parameters defining airflow obstruction. MATERIALS AND METHODS: The longitudinal study included a group of 89 children admitted to the Pediatric Clinic of "Grigore Alexandrescu" Emergency Clinical Hospital for Children. The inclusion criteria were: (i) a previously known diagnosis of asthma, (ii) age range between 5 and 18 years old. All patients underwent pulmonary function testing and measurement of FENO. RESULTS: Significant correlations were identified between FENO and a part of spirometric parameters: MEF75 (p=0.007), MEF50 (p=0.0.28), MEF25 (p=0.011) and PEF (p=0.020), but not with FEV1 (p=0.090), nor FVC (p=0.308). However, multiple linear regression analysis revealed that spirometric parameters poorly predict FENO variation (R=0.062, p=0.82). In adition, binary logistic regression analysis (LR) showed that FENO can not be used as a reliable biomarker (p=0.169) for the estimation of the risk for obstructive dysfunction. CONCLUSION: The level of exhaled nitric oxide does not correlate with the values of spirometric values. More studies with a large number of patients are needed for establishing the role of FENO in the evaluation of airflow obstruction. PMID- 26738371 TI - Unexplained basal oxygen desaturation in a patient with haemoglobinopathy. AB - Haemoglobinathies are a heterogeneous group of congenital disorders that affect the structure, function or production of haemoglobin. Some of them due to its low affinity to oxygen may be accompanied by cyanosis and mild anemia. For this reason, in the differential diagnosis we should include heart and lung diseases and its presence be suspected in families or young patients with an unexplained basal oxygen desaturation. PMID- 26738372 TI - Sarcoidosis and Aspergillosis: case presentation. AB - Sarcoidosis is a multisystemic inflammatory disease of unknown etiology, characterized by noncaseous epithelioid cell granulomas. The evolution of the disease may be complicated by opportunistic infections such as aspergillosis, that usually appears in type IV sarcoidosis. We present the case of a 74 year-old women with a history of sarcoidosis for over 7 years, who presented for hemoptysis. She was diagnosed with pulmonary cavitary aspergillosis and treatment with ltraconazole was initiated. The patient was monitored every two months. At the one year follow up, the patient was asymptomatic, with a good treatment tolerance and no decline in lung function, despite the pulmonary fibrosis. The sputum exams continued to be positive for Aspergillus, the HRCT-scan described a chronic pulmonary aspergillosis. The antifungical treatment was continued, under careful monitoring. The patient remained asymptomatic with no further decline in lung volumes. The particularity of the case consists in the lack of symptoms, despite pulmonary fibrosis, and the therapeutic challenges of chronic pulmonary aspergillosis. PMID- 26738373 TI - Pulmonary hypertension and von Recklinghausen's disease: association and therapeutic difficulties. AB - The neurofibromatosis type 1 (NF1) or Von Recklinghausen's disease is a genetic disorder. The cafe-au-lait spots and neurofibromas are the most common manifestations. Respiratory symptoms are rare in this disease, described as neurofibromas, infiltrative lesions, cysts, bubbles or emphysema. Pulmonary hypertension is rarely reported. It is due to the plexiform lesions in pulmonary arterioles or to parenchymal lung lesions reducing the vascular bed. We report a case of idiopathic precapillary pulmonary hypertension in a young patient with Von Recklinghausen's disease. PMID- 26738374 TI - Types of Interventions for Smoking Prevention and Cessation in Children and Adolescents. AB - Smoking among children and adolescents is a pressing public health issue that demands the development, improvement and implementation of programmes aimed at the prevention and cessation of smoking on a global scale. The objective of our article is to review the main types of interventions for smoking prevention and cessation among children and adolescents. These interventions are based on a wide variety of approaches and include school-based programmes, primary and secondary care-based interventions, programmes targeting parents and family, community based programmes, social marketing programmes and media campaigns, legislative interventions and computer and other IT-based interventions. Generally, there is still a paucity of low level evidence regarding the efficacy of most smoking prevention and cessation programmes for children and adolescents except for a few particular types of interventions that are reasonably well documented. PMID- 26738375 TI - Cardioembolic events in young patients: beyond the heart. PMID- 26738376 TI - [Role of insulin resistance and beta cell function in the development of newly diagnosed type 2 diabetes]. AB - OBJECTIVE: To assess the possible role of insulin resistance (IR) and beta cell function in the pathophysiology of newly diagnosed type 2 diabetics (T2DM). METHODS: An oral glucose tolerance test was obtained at the health cohort baseline. Subjects with normal glucose tolerance (NGT, n = 269), impaired glucose regulation (IGR, n = 269) and newly diagnosed type 2 diabetics (T2DM, n = 269) were defined by ADA criteria. Subjects with NGT and IGR were selected from residents living in the same community of diabetic patients with the same gender and age (+/- 3 years old). The T2DM group was sub-classified as isolated fasting hyperglycemia (IFH), isolated post-challenge hyperglycemia (IPH) and combined hyperglycemia (CH). The IGR group was sub-classified as impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and combined glucose intolerance (CGI). Homeostasis model assessment of insulin resistance (HOMA-IR), beta cell function (HOMA-beta) and deposition index (DI) were to evaluate the insulin resistance or sensitivity, islet beta cell function and that when insulin compensated respectively. RESULTS: From NGT to T2DM, HOMA-IR increased while HOMA-beta and DI decreased significantly (P < 0.05). After the adjustment of age, gender, obesity and hypertension, IFG and CGI subgroup had statistically higher HOMA-IR and lower HOMA-beta and DI, and IGT subgroup only had lower HOMA-beta and DI than NGT subgroup (P < 0.05). Compared to IGT subgroup, IFG and CGI subgroup had significantly higher HOMA-IR and lower HOMA-beta and DI (P < 0.05). IFH and CH subgroup had statistically higher HOMA-IR and lower HOMA-beta and DI than IFH subgroup (P < 0.05), DI of CH subgroup significantly decreased than that of IPH subgroup (P < 0.05). IFH and CH subgroup had statistically higher HOMA-IR and lower HOMA-beta and DI than IFG and CGI subgroup respectively. HOMA-beta and DI decreased of IPH subgroup compared to IGT subgroup, and multiple linear regression analysis showed that HOMA-IR had significant influence on fasting plasma glucose (FPG) in NGT (P < 0.05), whereas two-hour plasma glucose and FPG were influenced by DI (P < 0.05) in the progression. CONCLUSIONS: Both basic beta cell dysfunction and IR exist in IFG and CGI, while only basic beta cell dysfunction exist in IGT. The basic beta cell dysfunction and IR are the primary features of fasting hyperglycemia, and basic beta cell dysfunction also contribute to post- challenge hyperglycemia. PMID- 26738377 TI - [Analysis of occupational burnout and its influencing factors of colliery migrant workers in Guizhou Province]. AB - OBJECTIVE: To understand the status of occupational burnout of colliery migrant workers and its influencing factors. METHODS: The occupational burnout of 1161 colliery migrant workers in Jinsha County, Guizhou Province was measured with MBI GS and the self-made questionnaire. RESULTS: All dimensions of MBI-GS Cronbach's alpha coefficient was in the range of 0.86-0.88, all 15 items of MBI-GS were subjected to factor analysis, and three latent factors were identified, which explained 68.86% of the total variance and consisted with the theory model. The score of occupational burnout of each dimension, differences in different individual characteristics (physical examination, sleep, et al) were statistically significant (P <0.05). The influence factors of occupational burnout of colliery migrant workers were physical examination, chronic disease, smoking, physical exercise, sleep, initial work in coal mine, production post and labor intensity. CONCLUSION: MBI-GS can be used to study the occupational burnout of colliery migrant workers. Different individual characteristics effect the occurrence of occupational burnout. PMID- 26738378 TI - [A twin study on genetic and environmental factors of adolescents violence behaviors]. AB - OBJECTIVE: To explore the influence of genetic and environmental factors on adolescents violence behaviors. METHODS: The violence behaviors of 111 twin pairs from Chongqing (aged from 11 to 18 years) were investigated with risk behavior questionnaire-adolescent (RBQ-A). The Parenting Styles and Dimensions Questionnaire (PSDQ) and Stressful Life Event (SLE) and the General Functioning Scale of the MacMaster Family Activity Device (FAD-GFS) were applied to assess their environment factors. Structural equation modeling was performed to evaluate the effects of the additive genetic factors (A), shared environment factors (C) and individual specific environmental factors (E) on the adolescents violence behaviors. RESULTS: The effects of A and E on adolescents violence behaviors were 0.41 (95% CI 0.19-0.58) and 0.59 (95% CI 0.42-0.81) respectively. There were significantly negative correlation between violence behaviors and authoritative parenting-style (r = -0.140, P < 0.05), the score of adolescents violence behaviors was positively correlated with repressive-parenting-style score (r = 0.133, P < 0.05), the score of adolescents violence behaviors were not significantly correlated with the family functions, stress life events and the parenting education level and occupation. CONCLUSION: Adolescents violence behaviors were influenced by additive genetic factors and individual specific environmental factors. Environmental plays an important role. It should not been ignored that parental rearing pattern play a role in adolescents violence behaviors. PMID- 26738379 TI - [Relationship between cyberbullying and the suicide related psychological behavior among middle and high school students in Anhui Province]. AB - OBJECTIVE: To examine the prevalence rate of cyberbullying in middle and high school students in Anhui Province and explore the relationship between cyberbullying and suicide related psychological behavior. METHODS: A total of 5726 middle and high school students from the 7th to the 12th grades in three regular middle schools and three regular high schools recruited from three cities in the Anhui Province (Tongling, Chuzhou, and Fuyang). Tongling, Chuzhou, and Fuyang are in the south, middle and north of Anhui, respectively. Each city was selected one regular middle school and one regular high school, and 8 classes were selected form each grade from each school. A stratified cluster random sampling method was used to randomly select 5726 participants among the six schools. Self-reports on cyberbullying and suicide related psychological behavior were collected. RESULTS: Among these 5726 adolescents, 46.8% of them involved in cyberbullying. Among them, 3.2% were bullies, 23.8% were victims, and 19.8% were both. Prevalence rates of suicide idea, suicide plan, suicide preparation, suicide implementation were 19.3%, 6.9%, 4.7% and 1.8%, respectively. Cyberbullying involvement, as victims, bullies or bully-victims, increased the risk of four kinds of suicide related psychological behavior (suicide idea, suicide plan, suicide preparation, suicide implementation) (P < 0.05). CONCLUSION: Cyberbullying has become a common occurrence in middle and high school students. Additionally, cyberbullying is closely related to suicide related psychological behavior among middle and high school students. PMID- 26738380 TI - [Relationships between serum Ghrelin and body composition and lipid metabolism related cytokines among 591 adult Chinese from 3 Provinces]. AB - OBJECTIVE: To describe the relationships between serum Ghrelin and body composition and lipid metabolism-related cytokines among Chinese adults. METHODS: A total of 591 adults younger than 60 years were selected from urban and rural areas of Liaoning, Henan and Hunan Provinces. Height, body weight, waist circumference, hip circumference, body mass index (BMI), waist-hip ratio (WHR), body fat percentage (% BF), blood lipid, serum leptin, Ghrelin and Ca were measured in all samples. RESULTS: The mean serum Ghrelin concentration in males was 24.12 MUg/L and in females 23.62 MUg/L. There were no significant differences between different genders. With the increasing concentration in serum Ghrelin, a significant decreasing trend (P < 0.05) was found in waist circumference, BMI, WHR, overweight/obesity rates, central obesity rates, BF%, TC, TG, LDL-C and serum leptin. A significant increasing trend (P < 0.05) was found in HDL-C and ApoA1/ApoB, and no significant change in hip circumference and serum Ca were found. Correlations showed that there was a significant correlation among serum Ghrelin, BMI, waist circumference, WHR, BF%, TC, LDL-C and leptin (P < 0.05). CONCLUSIONS: Serum Ghrelin level correlates strongly with body composition and lipid metabolism-related cytokines, and can have a more closely associations with BF% and leptin. PMID- 26738381 TI - [Study on iron store status for women in the poor rural areas in China from 2010 to 2012]. AB - OBJECTIVE: To quantitatively assess the concentration and the distribution of the body iron (BI) for women in the poor rural areas. METHODS: Resampling based on the blood sample of Nutrition and Health Survey in China from 2010 to 2012, serum ferritin (SF) and serum soluble transferrin receptor (sTfR) were measured for the selected blood samples by immunoturbidimetric assay. BI was calculated, and the concentrations and distribution in different aged subgroup were assessed. Distribution of BI subgrouped in different aged women was compared. The correlations of BI to hemoglobin (Hb), SF and sTfR were analyzed. RESULTS: The average levels of BI were (7.35 +/- 2.37) mg/kg for schoolgirls aged 6-11 years, (6.50 +/- 3.59) mg/kg for adolescent girls aged 12-17 years, (6.07 +/- 4.78) mg/kg for women of childbearing aged 18-44 years, (8.60 +/- 4.45) mg/kg for women aged 45-59 years, and (10.35 +/- 3.38) mg/kg for elderly female aged >= 60 years, respectively. The proportion of low BI in the 12-17 years and 18-44 years women was the highest. BI level was positively correlated to SF and negatively correlated to sTfR (P < 0.01). BI level was positively correlated to Hb in the BI < 0 mg/kg subgroup. CONCLUSION: The BI methodology allows the full range of iron status of populations to be evaluated. The iron status for adolesecent girls aged 12-17 years and women of childbearing aged 18-44 years should be improved. PMID- 26738382 TI - [Comparative study on electronic sphygmomanometer and mercury sphygmomanometer among adults in the field study]. AB - OBJECTIVE: To compare the electronic sphygmomanometer with mercury sphygmomanometer on measuring the average blood pressure, prevalence of hypertension in a same population. To set up a numerical relationship between two blood pressure value of the two devices. METHODS: 544 adults of >= 18 years old were from 6 neighborhood of Hunan Province. OMRON HEM-907 and mercury sphygmomanometer were used to test the difference. The blood pressure value of mercury sphygmomanometer was gold standard. The difference of systolic pressure and diastolic pressure of two devices was tested using paired t test and Bland Altman analysis. Chi-square test was used to analyze the two prevalence of hypertension among the same population. The equation of linear regression was established using the value of blood pressure of two devices. RESULTS: Paired t test showed the statistical difference on the systolic pressure and diastolic pressure of two devices (P < 0.0001). Chi-square test presented a higher prevalence of hypertension by using the electronic sphygmomanometer (P < 0.0001). Bland-Altman analysis showed mercury sphygmomanometer couldn't be simply replaced by electronic sphygmomanometer. The two independent equation of linear regression was calculated on systolic pressure and diastolic pressure. CONCLUSION: The difference still existed when using the electronic sphygmomanometer and mercury sphygmomanometer at a large scale population. It's important to conduct the comparative study on electronic sphygmomanometer and mercury sphygmomanometer. PMID- 26738383 TI - [Quantitative detection on contamination of Listeria monocytogenes isolated from retail ready-to-eat meats in Beijing]. AB - OBJECTIVE: To survey the contamination of L. monocytogenes isolated from retail ready-to-eat meats in Beijing. METHODS: Ready-to-eat meats were quantitatively detected for L. monocytogenes using MPN method. L. monocytogenes isolates were analyzed by PFGE. RESULTS: Fourteen out of 197 ready-to-eat meat samples were positive for L. monocytogenes with the contamination rate of 7.11% and the geometry mean contamination level of 14.31 MPN/g. The contamination of L. monocytogenes isolated from free trade market (13.89%) was more severe than those from specificity store (8.57%), supermarket (5.75%) and restaurant (2.56%), while supermarket had the highest mean contamination level of 22.78 MPN/g. A total of 13 PFGE types were characterized using DICE-UPGMA analysis through BioNumerics 7.1 software. There were two isolates from the same free trade market share the same PFGE type, which suggested the same contamination source of both samples. CONCLUSION: Contamination of L. monocytogenes exist in retail ready-to-eat meats. The contamination level of L. monocytogenes isolated from free trade market is more severe than those from specificity store, supermarket and restaurant. PMID- 26738384 TI - [Analysis of heavy metals monitoring results in food in Shaoxing in 2014]. AB - OBJECTIVE: To investigate heavy metals contamination level in food in Shaoxing, and to provide basis evidence for supervising heavy metals pollution in food and environmental pollution control in Shaoxing. METHODS: Food samples in 2014 were detected for lead, cadmium, mercury, arsenic, nickel, copper and chromium by national standard methods, and the results were evaluated by GB 2762-2012 Pollutants limits in food. RESULTS: 1384 samples from 10 food categories were collected and tested for lead, cadmium, mercury and arsenic, the over standard rates were 2.0%, 3.0%, 1.5% and 0.22%, respectively, the median were 0.019, 0.0085, 0.0024 and 0.015 mg/kg, respectively; 273 samples were collected and tested for nickel, the detection rate was 48.4%, the median was 0.010 mg/kg; 255 samples were collected and tested for chromium, the detection rate was 14.9%, the median was 0.0050 mg/kg; 486 samples were collected and tested for copper, the detection rate was 94.0%, the median was 1.34 mg/kg. The heavy metals over standard rate of aquatic products, animal internal organs and grain were relatively high, 16.9%, 7.9% and 7.3% cadmium in swimming crabs exceeded standard seriously, the over standard rate was 38.9%. CONCLUSION: The overall pollution of heavy metals in food are not high in Shaoxing in 2014, but some food (aquatic products, animal internal organs and grain) pollution are relatively outstanding, and have the over standard problems of lead, cadmium, mercury and arsenic. PMID- 26738385 TI - [Levels of polychlorinated dibenzo-p-dioxins and dibenzofurans in fish from Shenzhen over the past decade]. AB - OBJECTIVE: To analyze the contamination levels and profiles of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in fish samples in Shenzhen areas of China, and to reveal the status of PCDD/Fs pollution for fish samples in a decade. METHODS: The fish samples including freshwater and saltwater fishes, were collected and analyzed from 2004 to 2013, and PCDD/Fs were detected by isotope dilution HRGC/HRMS using multiple ion detection mode (MID), which was an advanced and authority technique referenced US EPA1613 method. RESULTS: The average concentration of PCDD/Fs in fish was 0.90 pg/(g wet weight), and the average total toxicity equivalency factor (TEQ) calculated on the basis of the toxic equivalency factor (TEF) published by the World Health Organization (WHO) in 2005 was 0.088 pg WHO-TEQ/(g, wet weight). PCDD/Fs levels in fishes varied widely depending on the species. The PCDD/Fs average contamination levels of fish in 10 years did not exceeded the limit standards of European Commission. The evaluation dietary intake of PCDD/Fs from fish for local residents was 4.80 pg WHO-TEQ/(kg . BW . m). CONCLUSION: The PCDD/Fs levels in fish in a decade was less than the maximum limit standards set by European Commission 2011. PMID- 26738386 TI - [Correlationship between congenital heart disease and polymorphism of MTHFR gene]. AB - OBJECTIVE: To investigate the association between genetic variations in methylenetetrahydrofolate reductase MTHFR and the risk of congenital heart disease. METHODS: Conducted a case-control study, calculated the sample size by formulas. The sample including 150 isolated CHD cases and 150 controls comparable with the patients in age and sex. They were genotyped for detecting MTHFR C677T, A1298C, G1793A polymorphisms by polymerase chain reaction and restriction fragment length polymorphism analysis (PCR-RFLP) methods. RESULTS: For the 677, compared with wild CC genotype, heterozygosity CT increased the risk of CHD (OR = 2.249, 95% CI 1.305-3.877, P = 0.003), the homozygous mutant genotype TT was associated with the risk of CHD significantly (OR = 3.121, 95% CI 1.612-6.043, P = 0.001). Compared with the wild allete, mutant allete increased the risk of CHD by 1.813 (95% CI 1.310-2.508, P = 0.000). For the 1298, Compared with wild AA genotype, heterozygosity AC increased the risk of CHD (OR = 2.177, 95% CI 1.183 4.077, P = 0.011). The mutant allete C increased the risk of CHD by 2.017 (95% CI 1.128-3.604, P = 0.016). For the 1793, The proportion of the heterozygote GA and homozygote AA had no statistical differences in the two groups (P = 0.145), also the mutant allete and wild allete (P = 0.158). There were joint effects of MTHFR C677T and MTHFR A1298C, MTHFR A1298C and MTHFR G1793A. CONCLUSION: Genetic polymorphisms in MTHFR C677T and MTHFR A1298C might contribute to the risk of developing CHD, joint effects were found of MTHFR C677T and MTHFR A1298C, MTHFR A1298C and MTHFR G1793A. PMID- 26738387 TI - [Comparison of two methods in calculating the cumulative cadmium intake (CCI) from rice in the cadmium polluted area]. AB - OBJECTIVE: To explore a more accurate method for calculating the cumulative cadmium intake from rice. METHODS: The cumulative cadmium intake from rice was calculated by using the age coefficient method and the curve equation of rice consumption, and the results were compared. RESULTS: There was little difference between the two results in male and female group. But the equation calculation values was more closer to the actual values and it was similar between different gender. But the result calculated by the age coefficient method between different gender was significantly different. CONCLUSION: In the area that rice is the main medium of dietary cadmium intake, there was little difference between the two methods. Using curve equation of rice consumption to calculate the cumulative cadmium intake from rice is more feasible. PMID- 26738388 TI - [Effects of lingonberry extraction on the mice cognitive function damaged by chronic stress]. AB - OBJECTIVE: To study the effects of lingonberry extraction on mice cognitive impairment caused by chronic stress. METHODS: Kunming mice were randomly divided into six groups, which were control group, stress model group, the fluoxetine group (dose of 4.4 mg . kg(-1) . d(-1)), lingonberry extraction low, medium and high dose group (respectively 50, 100 and 200 mg . kg(-1) . d(-1)). All groups were given chronic uncertainty stress but the control group, and were intragastric administration for 18 days. Then the cognition of the mice was tested by using water maze, the contents of the SOD, GSH-Px, MDA and the activity of the neurotransmitters such as noradreline (NE), serotonin (5-HT), glucocorticoids (GC), acetylcholinesterase (AchE) were measured by using kit. RESULTS: Lingonberry extraction improved the cognition and memory of the mice induced by chronic uncertainty stress, increased the content of the SOD and GSH Px in mice brain, and decreased the content of oxidative damage markers MDA. Lingonberry extraction could also inhibit the increase of GC, inhibit the activity of AchE in blood serum, elevated the content of 5-HT and NE in mice blood serum and brain. CONCLUSION: Lingonberry extraction improved the cognition and memory of the mice induced by chronic uncertainty stress. The possible mechanism was that lingonberry enhanced the antioxidative ability of tissue and improved the disorder of neurotransmitter levels caused by chronic stress. PMID- 26738389 TI - [Effects of atrazine on function of murine peritoneal macrophages in vitro]. AB - OBJECTIVE: To investigate the effects of atrazine (ATZ) on function of peritoneal macrophages in vitro, and to provide data for its immunotoxicity evaluation. METHODS: The murine peritoneal macrophages were isolated from mice. After treated with ATZ at different doses, cells viability was detected by MTT assay, and phagocytosis was evaluated by neutral red absorption. NO and TNF-alpha release were detected with nitrate reductase method and ELISA method, respectively. ROS was measured by DCFH-DA and flow cytometry. RESULTS: The IC50 values of the peritoneal macrophages for the MTT assay were (887.4 +/- 1.11), (360.2 +/- 1.13) and (270.6 +/- 1.20) MUmol/L after 24, 48 and 72 h. While for the NR absorption were (214.2 +/- 1.14), (120.0 +/- 1.10) and (42.60 +/- 1.12) MUmol/L. After dosed for 24 h and 72 h, the NO release of low dose groups were higher than those of the controls, while the NO release of high dose groups showed a downward trend when compared with the control's. After treatment for 72 h, the TNF-alpha secretion of low dose groups (0.01, 0.1 MUmol/L) were significantly higher than that of the control (P < 0.05), and TNF-alpha secretion in the other groups were lower when compared with that of the control (P < 0.05). After exposure for 24 h or 72 h, the ROS release was promoted in both 0.01 and 1 MUmol/L ATZ groups (P < 0.05), however, the ROS release were lowered in the 100 MUmol/L ATZ group. CONCLUSION: ATZ can affect the cells viability and phagocytosis of peritoneal macrophages. Meanwhile the TNF-alpha secretion, NO release as well as ROS release are disturbed in peritoneal macrophages exposed to ATZ. PMID- 26738390 TI - [Effects of resveratrol on Nrf2 signal pathway of chronic lead-exposed mouse brain tissue]. AB - OBJECTIVE: To evaluate the effect of resveratrol on NF-E2-related factor 2 (Nrf2) signal pathway in the process of oxidative stress of mice brain tissue induced by chronic lead exposure. METHODS: A total of 48 healthy weaned C57BL/6 male mice were randomly divided into four groups (12 mice each group), control group, lead poisoning model group, lead poisoning coupled with resveratrol intervention group and resveratrol group. The lead poisoning mice model had been made by exposed to 0.2% lead acetate solution in the drinking water for 12 weeks. At the same time, the mice in the intervention group and resveratrol group were fed with resveratrol (50 mg/(kg . d)) by oral gavage and the other two groups were treated with the same volume of solvent, sodium carboxymethylcellulose. The serum and brain tissues were removed and used for detecting the lead concentration and measuring the activity of GSH-Px and the content of GSH and MDA. The levels of protein Nrf2 and gamma-GCS were determined by western blot. RESULTS: Compared with the poisoning model group, GSH-Px activity and GSH content were significantly increased (P < 0.05), and MDA content was significantly decreased in the brain tissue intervened by resveratrol (P < 0.05). The protein expression of Nrf2 and gamma-GCS were induced in the brain tissue of the intervention group (P < 0.05). CONCLUSION: Resveratrol could reduce the oxidation damage caused by chronic lead exposure in drinking water which may due to the protein activation of Nrf2, further up-regulated expression of targeting gamma-GCS and adjusted dynamic balance of GSH system. PMID- 26738391 TI - [Joint actions of Myriophyllum verticillatum L and its rhizospheric microorganisms on Microcystis aeruginosa and the mathematical model analysis]. AB - OBJECTIVE: To study the inhibition effect on blue-green algae of higher aquatic plants with their rhizosphere microorganisms and its mathematical model. METHODS: The inhibitory effects of sterile and containing bacterium Myriophyllum verticillatum L root extracts on Microcystis aeruginosa were studied respectively, and the difference-differential equation of algal growth and partial functional differential equation were established according to the algal inhibiting effect. RESULTS: (1) The sterile and containing bacterium Myriophyllum verticillatum L root extracts showed at some degree inhibitory effects on M. aeruginosa, and containing bacteria root extract had more potent algal inhibiting effect, and very lower half maximal effective concentration (EC50). (2) The established inhibitory mathematical models can effectively predicted and calculated algal densities and EC50 at varying exposure time and different environment. CONCLUSION: The rhizospheric microorganisms can effectively enhanced the inhibiting effect of Myriophyllum verticillatum L on M. aeruginosa. PMID- 26738392 TI - [Investigation on contamination situation of malachite green in freshwater fish and its dietary exposure assessment of Shaanxi Province]. AB - OBJECTIVE: To investigate the residue levels of malachite green (MG) in freshwater fish and assess the dietary MG exposure of Shaanxi residents. The second aim was to assess the health risk of intaking MG from freshwater fish for Shaanxi residents. METHODS: The samples were determined by UPLC-MS/MS after purified by neutral alumina SPE cartridges and separated by waters-BEH C18 column (2.1 mm x 100 mm, 2.5 MUm). The MOE method was used to assess the risk of intaking MG from freshwater fish for Shaanxi residents. RESULTS: The average detection rate of MG in freshwater fish in Shaanxi province was 7.32% and the highest residue level was 428 MUg/kg. The detection rate was quite different in different fish species. The catfish devoted the highest detection rate which was 28.57%. In ten cities of Shaanxi, the highest detection rate was obtained from Yulin which was 33.33%. CONCLUSION: The health risk of intaking MG from freshwater fish is quite low for Shaanxi residents, however the contamination of illegal use of MG in freshwater fish was severe in Shaanxi Province. Supervision and inspection of MG should be strengthened in fish farming. PMID- 26738393 TI - [Meta analysis of the nutrition intervention effect of Yingyangbao on infants and young children in China]. AB - OBJECTIVE: To systematically review the nutritional effect of YYB on infants and young children in poor rural regions. METHODS: Medline, PubMed, Cochrane Library, CNKI and other sources of nutrition and health information were retrieved with the predetermined key words. The quality of the obtained literatures was evaluated with the criteria established in this study. RveMan 5.3 was used in the meta analysis. RESULTS: Thirteen groups of qualified data from nine YYB intervention studies were used. The results showed that YYB significantly increased the level of Hb (MD = 0.94, 95% CI 0.94-1.15, P < 0.01), reduced the prevalence of anemia (RR = 0.34, 95% CI 0.25-0.46, P < 0.01). YYB showed no significant effect on WAZ and HAZ, but significant increase of WHZ was demonstrated by the analytical data (MD = 0.42, 95% CI 0.19-0.65, P < 0.01). Additionally YYB intervention groups also showed the prevalence of underweight (RR = 0.53, 95% CI 0.32-0.88, P < 0.05). CONCLUSION: As an infant complementary food supplement, YYB improved the nutrition status of infants and young children including increased Hb level, declined anemia prevalence and wasting rate. PMID- 26738394 TI - Effects of serum indices interference on hormonal results from the Abbott Architect i2000 immunoassay analyser. AB - The routine chemical assays are affected by sample haemolysis, icterus and lipaemia, collectively known as serum indices; however, little attention has been given to the consequences of these conditions on hormonal assays (immunoassays). In this study, we assess the impact of interferences from exogenous serum indices on various endocrine assays performed on the Abbott Architect i2000 system. The pool of 20 serum samples was derived from a hospitalised population. The diluted serum samples were spiked with red cell haemolysate, Intralipid and bilirubin. The interferences were studied at baseline; 12.5%, 25%, 50%, 75% and 100% of 5.0 g/L haemoglobin; 1% of 20% Intralipid; and 0.342 mmol/L of bilirubin according to the EP7-A2 guideline (Interference Testing in Clinical Chemistry; CLSI, USA). Aliquots were analysed in duplicate and/or triplicate for various hormones on the Abbott Architect i2000 immunoassay analyser. Serum ferritin (r2=0.84; P=0.074) and TSH (r2=0.81; P=0.52) levels showed a direct relationship with haemolysis and therefore overestimated because of the effects of haemolysis. The vitamin B12 level progressively decreased as the amount of haemolysis increased (r2=-0.76; P=0.136). There was a significant decrease in progesterone concentration owing to lipaemia (r2=-0.983; P=0.003). For icteric interferences, a strong inverse correlation was observed for folic acid and was shown to be statistically significant (r2=-0.94; P=0.017). Assays for ferritin, TSH, vitamin B12, folic acid and progesterone showed various degrees of interference because of the variability in serum indices. PMID- 26738395 TI - Pentraxin-3 and nitric oxide as indicators of disease severity in alcoholic cirrhosis. AB - Recent studies have indicated that pentraxin-3 can be used as a marker to assess the severity of hepatic fibrosis in non-alcoholic steatohepatitis. The present study was designed to assess pentraxin-3, nitric oxide and tumour necrosis factor alpha (TNFalpha) in alcoholic cirrhosis and their association with disease severity. We enrolled 47 alcoholic cirrhosis cases and 32 controls. Serum pentraxin-3, nitric oxide (NO) and TNFalpha levels were estimated in both groups. Serum pentraxin-3, NO and TNFalpha were significantly increased in alcoholic cirrhosis patients compared to controls. Pentraxin-3 had a significant positive correlation with TNFalpha (r=0.303, P=0.039), Child-Pugh score (r=0.394, P=0.006) and MELD score (r=0.291, P=0.047) in alcoholic cirrhosis cases. Also we found positive association between NO with Child-Pugh score (r=0.391, P=0.007) and MELD score (r=0.311, P=0.033) in these cases. Linear regression analysis shows significant association of pentraxin-3 and NO (beta=0.375, r2=0.141, P=0.009). We conclude that elevated pentraxin-3 and NO levels are associated with severity of alcoholic cirrhosis. PMID- 26738396 TI - No role for tri-iodothyronine (T3) testing in the assessment of levothyroxine (T4) over-replacement in hypothyroid patients. AB - Tri-iodothyronine (T3) is a sensitive marker of endogenous hyperthyroidism. In levothyroxine (T4)-induced hyperthyroidism, there is no reason for T3 to be elevated, but this test is often requested in over-treated hypothyroid patients. This study investigated how informative T3 levels are in these patients. Our hypothesis is that T3 measurement would not add anything to the assessment of T4 over-replacement in primary hypothyroidism. Over a 15-week period, consecutive thyroid function test requests in patients on levothyroxine had T3 levels measured if thyroid-stimulating hormone (TSH) was below the reference range (RR; <0.27 miu/L) and free T4 was within or above the RR (12-22 pmol/L). Those with fully suppressed TSH (<0.02 mu/L) and high free T4 (>27 pmol/L) were defined as being over-replaced, while those with low, but measurable TSH and a normal free T4 were defined as unlikely to be over- replaced (control group). Receiver operating characteristic (ROC) curve analysis was used to assess the discriminant power of T3 to detect over-replacement. Of the 542 patients examined, 33 were included in the over-replaced group and 236 patients in the control group. A total of 273 patients were excluded for not fulfilling the criteria for either of these groups. In the over-replaced group, none had a raised T3. The most discriminant T3 level, using ROC curve analysis, was 1.6 nmol/L (RR=1.3-2.6 nmol/L), with a corresponding sensitivity and specificity of 58% and 71%, respectively (P=0.16). T3 levels bear little relation to thyroid status in patients on levothyroxine replacement, and normal levels can be seen in over replaced patients. Measurement of T3 in this situation is of doubtful clinical value. WHAT'S ALREADY KNOWN ABOUT THIS TOPIC?: Thyroid function tests are the way that adequacy of levothyroxine replacement is determined. Where the test is available, T3 is often requested together with T4 and TSH by clinicians. The question is whether T3 measurement adds any further information. WHAT DOES THIS ARTICLE ADD?: The presented data supports the position that T3 measurement does not add anything to the interpretation of thyroid hormone levels in subjects with hypothyroidism on levothyroxine replacement therapy. Unnecessary testing could be avoided if this were more widely appreciated. In addition, over-replacement, with its attendant risks, would be more readily recognised and not wrongly excluded on the basis of a falsely reassuring normal T3 result. PMID- 26738397 TI - Evaluation of antioxidant status of female diabetic patients in Nnamdi Azikiwe University Teaching Hospital, Anambra State, Nigeria. AB - Diabetes mellitus has become an onerous disease to developing countries such as Nigeria. Rapid acceptance of urbanisation and sedentary life styles pose an encumbrance to its prevention and management. Increased oxidative stress in diabetes mellitus has been implicated as a culprit in perpetuating antioxidant depletion and diabetic complications in diabetes mellitus individuals. This study aims to evaluate the level of antioxidant status in type 2 diabetes mellitus (DM) female participants visiting the out-patient diabetic clinic of Nnamdi Azikiwe University Teaching Hospital (NAUTH), Nnewi, Anambra State, Nigeria. A total of 86 participants aged 51+/-10 years were recruited for this study. The test group consists of 43 already confirmed type 2 diabetes mellitus females, while the control group consists of 43 apparently healthy females. The test subjects were further subgrouped into good and poor glycaemic control groups, using a cut-off of <7% for HbA1c. Whole blood was collected from participants and aliquoted into specified sample containers for analysis of the following parameters: random blood glucose (RBG; mg/dL), glycosylated haemoglobin (HbA1c; %), glutathione reductase (GR; U/L) and total antioxidant status (TAS; mmol/L). Results from this study showed that the mean differences in RBG (197.74+/-49.29 mg/dL) and HbA1c (9.86+/-1.44%) were significantly higher in the test group compared to the control group RBG (104.79+/-11.33 mg/dL) and HbA1c (5.21+/-1.23%) (P<0.05). The mean differences of GR (45.81+/-20.45 U/L) and TAS (1.81+/-1.04 mmol/L) were significantly lower in the test group compared to the control group GR (61.21+/ 14.34 U/L) and TAS (2.73+/-2.08 mmol/L) (P<0.05). The poor glycaemic test group was observed to have the highest RBG (200.34+/-50.4 mg/dL) and HbA1c (10.23+/ 1.33%) compared both to good glycaemic test group RBG (186.38+/-45.39 mg/dL), HbA1c (6.54+/-0.45%) and non-diabetic group RBG (104.79+/-11.33 mg/dL) and HbA1c (5.21+/-1.23%) (P<0.05). Glutathione reductase (40.66+/-15.48 U/L) and TAS (1.80+/-1.08 mmol/L) were significantly more depleted in the poor glycaemic test group compared to the non-diabetic group GR (61.21+/-14.34 U/L), TAS (2.73+/-2.08 mmol/L) and good glycaemic test group GR (68.38+/-25.09 U/L), TAS (1.86+/-0.92 mmol/L) (P<0.05). Out of the 43 participants in the test group, only 18.6% had good glycaemic control and 81.4% had poor glycaemic control. There were significant negative correlations between RBG and TAS (r=-0.260; P=0.015); RBG and GR (r=-0.403; P=0.000) and HbA1c and GR (r=-0.471; P=0.000) (P<0.05). However, HbA1c and TAS showed no significant correlation (r=-0.170; P=0.119) (P>0.05). This study concludes that there is antioxidant depletion in females with type 2 diabetes. PMID- 26738398 TI - TNFAIP3 and TNIP1 polymorphisms confer psoriasis risk in South Indian Tamils. AB - Psoriasis is a chronic inflammatory skin disease with genetic and environmental factors having an important role in its aetiology. Several genome-wide association studies have reported the association of the genes of the TNFalpha signalling, tumour necrosis factor alpha-induced protein 3 (TNFAIP3), TNFAIP3 interacting protein 1 (TNIP1) with psoriasis in Western and Chinese populations. The aim of this study is to demonstrate whether the TNFAIP3 and TNIP1 genes contribute to the risk of psoriasis in the ethnically distinct South Indian population. 360 psoriatic subjects and 360 healthy controls were recruited in this case control study. TNFAIP3 (rs610604) and TNIP1 (rs17728338) polymorphisms were typed by using TaqMan 5 allele discrimination assay. The results demonstrated that the SNPs rs610604 and rs17728338 of the TNFAIP3 and TNIP1 genes, respectively, were associated with psoriasis in our population at both allelic and genotypic levels. Thus, our results suggest that TNFAIP3 (rs610604) and TNIP1 (rs17728338) polymorphisms confer increased risk of psoriasis and may play a vital role in its pathogenesis in our ethnic South Indian Tamils. PMID- 26738399 TI - Antimicrobial properties of mucus from the brown garden snail Helix aspersa. AB - Research into naturally occurring antimicrobial substances has yielded effective treatments. One area of interest is peptides and proteins produced by invertebrates as part of their defence system, including the contents of mollusc mucus. Mucus produced by the African giant land snail, Achatina fulica has been reported to contain two proteins with broad-spectrum antibacterial activity. Mucus from the brown garden snail, Helix aspersa, appears to have skin regeneration properties. This study sought to investigate the antimicrobial properties of H. aspersa mucus. Mucus was collected from H. aspersa snails, diluted in phosphate-buffered saline (PBS), with the supernatant tested against a wide range of organisms in a disc-diffusion antimicrobial assay. This was followed with comparative experiments involving A. fulica, including bacteriophage assays. Mucus from both species of snail was passed through a series of protein size separation columns in order to determine the approximate size of the antimicrobial substance. Electrophoresis was also carried out on the H. aspersa mucus. Results indicated that H. aspersa mucus had a strong antibacterial effect against several strains of Pseudomonas aeruginosa and a weak effect against Staphylococcus aureus. Mucus from A. fulica also inhibited the growth of S. aureus, but the broad spectrum of activity reported by other workers was not observed. Antimicrobial activity was not caused by bacteriophage. Size separation experiments indicated that the antimicrobial substance(s) in H. aspersa were between 30 and 100 kDa. Electrophoresis revealed two proteins in this region (30-40 kDa and 50-60 kDa). These do not correspond with antimicrobial proteins previously reported in A. fulica. This study found one or more novel antimicrobial agents in H. aspersa mucus, with a strong effect against P. aeruginosa. PMID- 26738400 TI - Enterococcus faecalis as multidrug resistance strains in clinical isolates in Imam Reza Hospital in Kermanshah, Iran. AB - The current study aimed to investigate the prevalence of vancomycin-resistant Enterococcus in E. faecalis and E. faecium and antimicrobial susceptibility patterns, then dominant genes responsible for vancomycin resistance were determined. For this propose, 180 clinical isolates of Enterococcus were subjected for identification and antibiotic susceptibility assay. Then, the gene responsible vancomycin resistant strains were determined. The results demonstrated the E. faecalis as a dominant Enterococcus. Resistance to erythromycin was dominant and multidrug resistance strains observed in E. faecalis. vanA was responsible for vancomycin resistance. In conclusion, a high rate of resistance to antibiotics in Enterococcus is clearly problematic, and a novel strategy is needed to decrease resistance in Enterococcus. PMID- 26738401 TI - Audit and review for evidence-based red cell wastage reduction measures. AB - Stocks of red blood cells (RBC) are held to ideally match supply and demand; hold too great a stock and unnecessary wastage occurs; too low a stock results in delay or lack of blood for the patient. Blood is a precious resource and its supply needs to be managed effectively. The aim was to identify how RBC units are wasted and propose laboratory-based reduction measures that would not compromise the clinical requirements of the patient. Wastage of RBC was investigated using a 'dashboard' query of a laboratory information management system. By employing service improvement tools, proposals were made to reduce unnecessary RBC waste while ensuring an adequate supply to the patient. The efficacy of those proposals was examined using the same dashboard to compare similar periods before and after their introduction. The reduction in RBC wastage for all groups during an eight month period (December to July) was from 6.4% (5.3% non-AB or B RhD-positive) pre implementation to 4.4% (2.5% non-AB/B RhD-positive) post-implementation. Group O RhD-negative wastage reduced from 10.4% to 4.4% after introduction of waste saving proposals. However, there was an increase in staff time required to introduce the changes and in associated Group and Screen testing (3.4 to 3.8 per unit issued). RBC wastage was significantly reduced (P<0.0001) by 32.8% (52%, non AB/B RhD-positive), saving approximately 225 RBC units per annum. Financially, increased associated costs did not negate the savings made by the measures introduced. PMID- 26738402 TI - A post-antibiotic era looms: can plant natural product research fill the void? AB - Antimicrobial resistance is increasing among certain pathogenic bacteria to the extent that treatment efficacy is no longer always assured. According to the CDC, as few as six new antibiotics have been released for use over the past 30 years. Resistance has already been observed to each of these. Eleven plant natural products have been approved for therapeutic use during the same period--none of them being antimicrobial agents. We have learned through experience that some microorganisms will inevitably overcome antibiotic treatment in certain situations, and then spread. It is clear that the rate of new antimicrobial development is insufficient to meet our current and future needs, which should be addressed in order to guarantee the effective future of antimicrobial chemotherapy. However, in recent years there has been an increase in the number of peer-reviewed reports of antimicrobial efficacy among plant-derived secondary metabolites. A limitation with these reports is the wide range of modified in vitro methods used to determine antimicrobial efficacy of these products, showing an absence of the type of standardisation that is the norm when testing the efficacy of single- or combined-agent conventional antimicrobials in the laboratory, thereby making inter-study comparison difficult. Overall, despite the large diversity in preparation and testing strategies used currently for natural product plant-derived antimicrobials, our investigations suggest that the field shows promise in the provision of novel antimicrobial agents, even as exemplified by our selected example, Inula helenium (Elecampane). PMID- 26738403 TI - Low serum creatine kinase activity in hospital patients. PMID- 26738404 TI - Bacteraemia caused by Fusobacterium necrophorum: a clinical approach to Lemierre's syndrome. PMID- 26738405 TI - How reliable are cough swabs for the detection of Pseudomonas aeruginosa in adult patients with cystic fibrosis? PMID- 26738407 TI - Direct in situ observation of ZnO nucleation and growth via transmission X-ray microscopy. AB - The nucleation and growth of a nanostructure controls its size and morphology, and ultimately its functional properties. Hence it is crucial to investigate growth mechanisms under relevant growth conditions at the nanometer length scale. Here we image the nucleation and growth of electrodeposited ZnO nanostructures in situ, using a transmission X-ray microscope and specially designed electrochemical cell. We show that this imaging technique leads to new insights into the nucleation and growth mechanisms in electrodeposited ZnO including direct, in situ observations of instantaneous versus delayed nucleation. PMID- 26738409 TI - Water Dynamics in Shewanella oneidensis at Ambient and High Pressure using Quasi Elastic Neutron Scattering. AB - Quasielastic neutron scattering (QENS) is an ideal technique for studying water transport and relaxation dynamics at pico- to nanosecond timescales and at length scales relevant to cellular dimensions. Studies of high pressure dynamic effects in live organisms are needed to understand Earth's deep biosphere and biotechnology applications. Here we applied QENS to study water transport in Shewanella oneidensis at ambient (0.1 MPa) and high (200 MPa) pressure using H/D isotopic contrast experiments for normal and perdeuterated bacteria and buffer solutions to distinguish intracellular and transmembrane processes. The results indicate that intracellular water dynamics are comparable with bulk diffusion rates in aqueous fluids at ambient conditions but a significant reduction occurs in high pressure mobility. We interpret this as due to enhanced interactions with macromolecules in the nanoconfined environment. Overall diffusion rates across the cell envelope also occur at similar rates but unexpected narrowing of the QENS signal appears between momentum transfer values Q = 0.7-1.1 A(-1) corresponding to real space dimensions of 6-9 A. The relaxation time increase can be explained by correlated dynamics of molecules passing through Aquaporin water transport complexes located within the inner or outer membrane structures. PMID- 26738410 TI - Contemporary Attitudes and Practice Patterns of North American Urologists in Investigating Stone-Forming Patients-A Survey of Endourological Society Members. AB - INTRODUCTION: Recent evidence would suggest a low rate of metabolic assessment in stone formers, even in those deemed as high risk. We wished to assess the attitudes and practice patterns of metabolic work up in North American members of the Endourological Society as part of the management of stone-forming patients. METHODS: A 12-question online multiple-choice questionnaire (using Survey Monkey((r))) was distributed to all members of the Endourological Society through e-mail. Descriptive analyses were performed. RESULTS: A total of 124 North American members of the Endourological Society responded (90% endourologists, 65% fellowship trained). Ninety-seven percent perform metabolic assessments without referring to a consultant. Eighty-three percent use a commercial analysis company and 17% request serum or urine parameters individually. Ninety-seven percent believe that 24-48-hour urine collection is a better way of assessing patients for metabolic abnormalities than a "basic analysis." Many respondents (37%) would be more likely to metabolically assess if results were easier to interpret, and 35% would like assistance/advice in the interpretation of results. At initial investigation of a first-time stone former, 87% of respondents use serum chemistry, 48% use 24-hour urine, 26% use 48-hour urine (two consecutive 24-hour urine collections), 54% send stone for analysis, and 7% do not investigate. On recurrent stone formers, 69% use serum chemistry, 73% use 24/48-hour urine, and 23% send stone for analysis. On routine follow-up, 36% check serum chemistry, 55% use 24-hour urine, 2% use 48-hour urine, and 29% do not metabolically evaluate. The majority agree that pharmacologic therapy plays a strong role in preventing recurrence (90%). After initiating pharmacologic therapy, 59% reassess using serum chemistry and 84% and 7% use 24/48-hour urine collection, respectively. Physicians re-evaluate patients after 1 month (7%), 1-2 months (10%), 2-4 months (44%), 4-6 months (30%), or after 6-12 months (7%). CONCLUSION: This snapshot assessment of Endourological Society members' practices in the metabolic investigation of stone-forming patients demonstrates wide testing variations. Many physicians expressed interest in assistance/advice in the interpretation of the metabolic assessment results. PMID- 26738412 TI - Hypercoagulabilty, venous thromboembolism, and death in patients with cancer. A Multi-State Model. AB - Venous thromboembolism (VTE) is a frequent complication of malignancy. The aim of this study was to investigate whether multi-state modelling may be a useful quantitative approach to dissect the complex epidemiological relationship between hypercoagulability, VTE, and death in cancer patients. We implemented a three state/three-transition unidirectional illness-death model of cancer-associated VTE in data of 1,685 cancer patients included in a prospective cohort study, the Vienna Cancer and Thrombosis Study (CATS). During the two-year follow-up period, 145 (8.6 %) patients developed VTE, 79 (54.5 %) died after developing VTE, and 647 (38.4 %) died without developing VTE, respectively. VTE events during follow up were associated with a three-fold increase in the risk of death (Transition Hazard ratio (HR)=2.98, 95 % confidence interval [CI]: 2.36-3.77, p< 0.001). This observation was independent of cancer stage. VTE events that occurred later during follow-up exerted a stronger impact on the risk of death than VTE events that occurred at earlier time points (HR for VTE occurrence one year after baseline vs at baseline=2.30, 95 % CI: 1.28-4.15, p=0.005). Elevated baseline D dimer levels emerged as a VTE-independent risk factor for mortality (HR=1.07, 95 % CI: 1.05-1.08, p< 0.001), and also predicted mortality risk in patients who developed VTE. A higher Khorana Score predicted both the risk for VTE and death, but did not predict mortality after cancer-associated VTE. In conclusion, multi state modeling represents a very potent approach to time-to-VTE cohort data in the cancer population, and should be used for both observational and interventional studies on cancer-associated VTE. PMID- 26738414 TI - Resistive Switching Mechanisms on TaOx and SrRuO3 Thin-Film Surfaces Probed by Scanning Tunneling Microscopy. AB - The local electronic properties of tantalum oxide (TaOx, 2 <= x <= 2.5) and strontium ruthenate (SrRuO3) thin-film surfaces were studied under the influence of electric fields induced by a scanning tunneling microscope (STM) tip. The switching between different redox states in both oxides is achieved without the need for physical electrical contact by controlling the magnitude and polarity of the applied voltage between the STM tip and the sample surface. We demonstrate for TaOx films that two switching mechanisms operate. Reduced tantalum oxide shows resistive switching due to the formation of metallic Ta, but partial oxidation of the samples changes the switching mechanism to one mediated mainly by oxygen vacancies. For SrRuO3, we found that the switching mechanism depends on the polarity of the applied voltage and involves formation, annihilation, and migration of oxygen vacancies. Although TaOx and SrRuO3 differ significantly in their electronic and structural properties, the resistive switching mechanisms could be elaborated based on STM measurements, proving the general capability of this method for studying resistive switching phenomena in different classes of transition metal oxides. PMID- 26738417 TI - High serum uric acid and risk of nonalcoholic fatty liver disease: A systematic review and meta-analysis. AB - OBJECTIVES: Emerging evidence connects serum uric acid (SUA) levels to nonalcoholic fatty liver disease (NAFLD). The objective of this study was to systematically evaluate the association between SUA levels and risk of NAFLD by conducting a meta-analysis of available observational studies. DESIGN AND METHODS: We searched for relevant studies in PubMed, Embase, China National Knowledge Infrastructure, and Wanfang databases until October 2014. All observational studies that evaluated SUA levels and NAFLD risks were included. Pooled adjusted odds ratio (OR) and corresponding 95% confidence intervals (CI) were calculated comparing the highest to lowest SUA category. RESULTS: Four cross sectional studies, two prospective studies, and three retrospective studies involving 55,573 participants were identified. In overall risk estimates, the pooled OR of NAFLD occurrence was 1.92 (95% CI: 1.59-2.31) comparing the highest to lowest SUA levels in a random effect model. Subgroup analysis showed that high SUA levels increased the risk of NAFLD in cross-sectional studies (OR: 2.18; 95% CI: 1.58-3.03), retrospective studies (OR 1.82; 95% CI: 1.43-2.33), and prospective studies (OR 1.43; 95% CI: 1.20-1.71). The risk of NAFLD seemed more pronounced among women (OR 1.85; 95% CI: 1.43-2.38) than among men (OR 1.56; 95% CI: 1.30-1.86). CONCLUSION: This meta-analysis suggests that increased SUA level is associated with an exacerbated risk of NAFLD. This increased risk is probably independent of conventional NAFLD risk factors. PMID- 26738422 TI - Long-term treatment of neurofibromatosis 1 with ketotifen. A report of three cases. PMID- 26738424 TI - Chi and dLMO function antagonistically on Notch signaling through directly regulation of fng transcription. AB - Gene apterous (ap), chip (chi) and beadex (bx) play important roles in the dorsal ventral compartmentalization in Drosophila wing discs. Meanwhile, Notch signaling is essential to the same process. It has been reported that Ap and Chi function as a tetramer to regulate Notch signaling. At the same time, dLMO (the protein product of gene bx) regulates the activity of Ap by competing its binding with Chi. However, the detailed functions of Chi and dLMO on Notch signaling and the relevant mechanisms remain largely unknown. Here, we report the detailed functions of Chi and dLMO on Notch signaling. Different Chi protein levels in adjacent cells could activate Notch signaling mainly in the cells with higher level of Chi. dLMO could induce antagonistical phenotypes on Notch signaling compared to that induced by Chi. These processes depend on their direct regulation of fringe (fng) transcription. PMID- 26738425 TI - Quantifying Drug-Induced Nanomechanics and Mechanical Effects to Single Cardiomyocytes for Optimal Drug Administration To Minimize Cardiotoxicity. AB - Contrary to the well-studied dynamics and mechanics at organ and tissue levels, there is still a lack of good understanding for single cell dynamics and mechanics. Single cell dynamics and mechanics may act as an interface to provide unique information reflecting activities at the organ and tissue levels. This research was aimed at quantifying doxorubicin- and dexrazoxane-induced nanomechanics and mechanical effects to single cardiomyocytes, to reveal the therapeutic effectiveness of drugs at the single cell level and to optimize drug administration for reducing cardiotoxicity. This work employed a nanoinstrumentation platform, including a digital holographic microscope combined with an atomic force microscope, which can characterize cell stiffness and beating dynamics in response to drug exposures in real time and obtain time-dose dependent effects of cardiotoxicity and protection. Through this research, an acute increase and a delayed decrease of surface beating force induced by doxorubicin was characterized. Dexrazoxane treated cells maintained better beating force and mechanical functions than cells without any treatment, which demonstrated cardioprotective effects of dexrazoxane. In addition, combined drug effects were quantitatively evaluated following various drug administration protocols. Preadministration of dexrazoxane was demonstrated to have protective effects against doxorubicin, which could lead to better strategies for cardiotoxicity prevention and anticancer drug administration. This study concluded that quantification of nanomechanics and mechanical effects at the single cell level could offer unique insights of molecular mechanisms involved in cellular activities influencing organ and tissue level responses to drug exposure, providing a new opportunity for the development of effective and time dose-dependent strategies of drug administration. PMID- 26738427 TI - BDNF Val66Met genotype and neuroticism predict life stress: A longitudinal study from childhood to adulthood. AB - The brain-derived neurotrophic factor gene (BDNF) Val66Met polymorphism and life stress have been associated with negative emotionality (e.g., neuroticism), but relevant evidence is far from unequivocal. Possible confounding factors include the type and timing of stressful events measured, such as childhood adversity vs. recent stressful events, and variable gene * environment interactions. The aim of this study was to longitudinally assess the BDNF Val66Met polymorphism and environment interaction effect on neuroticism in a population representative sample, depending upon the type of stress, gender and family relations. In the original older cohort of the Estonian Children Personality Behavior and Health Study (ECPBHS, n=593), neuroticism was measured at age 15 (parental assessment), 18 and 25 (self-assessments). Childhood stress was reported at age 15, quality of family relations was measured at age 18, and recent stressful life events at age 25. The BDNF Val66Met polymorphism interacted with recent stressful life events, but not with childhood adversities, to impact neuroticism. Interestingly, in female participants, neuroticism at age 18 predicted future stressful life events dependent upon genotype: individuals with Val/Val genotype and high neuroticism experienced higher, but Met-allele carriers with high neuroticism lower stress exposure at age 25. Similar tendencies were observed using parental assessments at age 15. The protective effect of Met-allele in the high stress exposure group could result from better early family environment. In conclusion, we herewith provide further evidence for a role of BDNF gene variance contributing to plasticity in response to environmental demands. PMID- 26738428 TI - Abuse-related neurochemical and behavioral effects of cathinone and 4 methylcathinone stereoisomers in rats. AB - Cathinone and many of its analogs produce behavioral effects by promoting transporter-mediated release of the monoamine neurotransmitters dopamine, norepinephrine and/or serotonin. Stereoselectivity is one determinant of neurochemical and behavioral effects of cathinone analogs. This study compared effectiveness of the S(-) and R(+) enantiomers of cathinone and 4-methylcathinone to produce in vitro monoamine release and in vivo abuse-related behavioral effects in rats. For neurochemical studies, drug effects were evaluated on monoamine release through dopamine, norepinephrine, and serotonin transporters (DAT, NET and SERT, respectively) in rat brain synaptosomes. For behavioral studies, drug effects were evaluated on responding for electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. The cathinone enantiomers differed in potency [S(-)>R(+)], but both enantiomers were >50-fold selective at promoting monoamine release through DAT vs. SERT, and both enantiomers produced ICSS facilitation. The 4-methylcathinone enantiomers also differed in potency [S(-)>R(+)]; however, in neurochemical studies, the decrease in potency from S(-) to R(+)4-methylcathinone was less for DAT than for SERT, and as a result, DAT vs. SERT selectivity was greater for R(+) than for S(-)4 methylcathinone (4.1- vs. 1.2-fold). Moreover, in behavioral studies, S(-)4 methylcathinone produced only ICSS depression, whereas R(+)4-methylcathinone produced ICSS facilitation. This study provides further evidence for stereoselectivity in neurochemical and behavioral actions of cathinone analogs. More importantly, stereoselective 4-methylcathinone effects on ICSS illustrate the potential for diametrically opposite effects of enantiomers in a preclinical behavioral assay of abuse potential. PMID- 26738429 TI - New concepts on BARD1: Regulator of BRCA pathways and beyond. AB - For nearly two decades most research on BARD1 was closely linked to research on BRCA1, the breast cancer predisposition gene. The co-expression of BARD1 and BRCA1 genes in most tissues, the nearly identical phenotype of Bard1 and Brca1 knock-out mice, and the fact that BRCA1 and BARD1 proteins form a stable complex, led to the general assumption that BARD1 acts as an accessory to BRCA1. More recent research on both proteins showed that BRCA1 and BARD1 might have common as well as separate functions. This review is an overview of how BARD1 functions and controls BRCA1. It highlights also experimental evidence for dominant negative, tumor promoting, functions of aberrant isoforms of BARD1 that are associated with and drivers of various types of cancer. PMID- 26738430 TI - How to understand the results of the climate change summit: Conference of Parties21 (COP21) Paris 2015. PMID- 26738431 TI - Central Trochlear Nerve Palsy due to Stroke: Report and Clinical Correlation of Two Cases. PMID- 26738433 TI - Use of registration-based contour propagation in texture analysis for esophageal cancer pathologic response prediction. AB - Change in PET-based textural features has shown promise in predicting cancer response to treatment. However, contouring tumour volumes on longitudinal scans is time-consuming. This study investigated the usefulness of contour propagation in texture analysis for the purpose of pathologic response prediction in esophageal cancer. Forty-five esophageal cancer patients underwent PET/CT scans before and after chemo-radiotherapy. Patients were classified into responders and non-responders after the surgery. Physician-defined tumour ROIs on pre-treatment PET were propagated onto the post-treatment PET using rigid and ten deformable registration algorithms. PET images were converted into 256 discrete values. Co occurrence, run-length, and size zone matrix textures were computed within all ROIs. The relative difference of each texture at different treatment time-points was used to predict the pathologic responders. Their predictive value was assessed using the area under the receiver-operating-characteristic curve (AUC). Propagated ROIs from different algorithms were compared using Dice similarity index (DSI). Contours propagated by the fast-demons, fast-free-form and rigid algorithms did not fully capture the high FDG uptake regions of tumours. Fast demons propagated ROIs had the least agreement with other contours (DSI = 58%). Moderate to substantial overlap were found in the ROIs propagated by all other algorithms (DSI = 69%-79%). Rigidly propagated ROIs with co-occurrence texture failed to significantly differentiate between responders and non-responders (AUC = 0.58, q-value = 0.33), while the differentiation was significant with other textures (AUC = 0.71-0.73, p < 0.009). Among the deformable algorithms, fast demons (AUC = 0.68-0.70, q-value < 0.03) and fast-free-form (AUC = 0.69-0.74, q value < 0.04) were the least predictive. ROIs propagated by all other deformable algorithms with any texture significantly predicted pathologic responders (AUC = 0.72-0.78, q-value < 0.01). Propagated ROIs using deformable registration for all textures can lead to accurate prediction of pathologic response, potentially expediting the temporal texture analysis process. However, fast-demons, fast-free form, and rigid algorithms should be applied with care due to their inferior performance compared to other algorithms. PMID- 26738435 TI - Not all participatory styles are created equal. PMID- 26738434 TI - Irisin promotes osteoblast proliferation and differentiation via activating the MAP kinase signaling pathways. AB - Physical exercise is able to improve skeletal health. However, the mechanisms are poorly known. Irisin, a novel exercise-induced myokine, secreted by skeletal muscle in response to exercise, have been shown to mediate beneficial effects of exercise in many disorders. In the current study, we demonstrated that irisin promotes osteoblast proliferation, and increases the expression of osteoblastic transcription regulators, such as Runt-related transcription factor-2, osterix/sp7; and osteoblast differentiation markers, including alkaline phosphatase, collagen type 1 alpha-1, osteocalcin, and osteopontin in vitro. Irisin also increase ALP activity and calcium deposition in cultured osteoblast. These osteogenic effects were mediated by activating the p38 mitogen-activated protein kinase (p-p38 MAPK) and extracellular signal-regulated kinase (ERK). Inhibition of p38 MAPK by SB023580 or pERK by U0126 abolished the proliferation and up-regulatory effects of irisin on Runx2 expression and ALP activity. Together our observation suggest that irisin directly targets osteoblast, promoting osteoblast proliferation and differentiation via activating P38/ERK MAP kinase signaling cascades in vitro. Whether irisin can be utilized as the therapeutic agents for osteopenia and osteoporosis is worth to be further pursued. PMID- 26738438 TI - Sea cucumbers with an anti-inflammatory effect on endothelial cells and subcutaneous but not on epicardial adipose tissue. AB - OBJECTIVE: epicardial adipose tissue (EAT) from patients with coronary artery disease (CAD) contains higher levels of inflammatory proteins and lower adiponectin levels than subcutaneous adipose tissue (SAT), enhancing the progression of atherosclerosis. Since products from sea cucumber have anti inflammatory properties, we investigated its effect on EAT, SAT and endothelial cells. METHODS: stromal cells or explants from EAT and SAT were obtained from patients with cardiovascular disease. Extracts were obtained after hydrolysis by food-grade enzymes at different times. Proteins were identified by LC-MALDI mass spectrometry. Adipogenesis and adiponectin induction were determined on stromal cells in the presence/absence of extracts. The bioavailability of the extracts was tested on a Caco-2 cell culture model in vitro. The bioavailable fraction was probed on endothelial cells and EAT or SAT explants. Vascular cell adhesion protein (VCAM-1), intercellular adhesion molecule (ICAM-1), IL-6 and adiponectin were determined by real time polymerase chain reaction (RT-PCR). RESULTS: our results showed that H. forskali and P. tremulus extracts contained compounds with anti-oxidant and anti-inflammatory properties. The bioavailable fraction of P. tremulus reduced VCAM-1 (p < 0.01) and IL-6 (p < 0.05) expression levels in endothelial cells while bioavailable compounds from H. forskali decreased ICAM-1 expression in SAT (p < 0.05). No effect was observed on EAT. CONCLUSION: these results suggest that sea cucumber extracts might be used for the prevention of endothelial cells and SAT inflammation. PMID- 26738441 TI - Corrigendum: Rapid alteration of protein phosphorylation during postmortem: implication in the study of protein phosphorylation. PMID- 26738442 TI - The kinetics and mechanism of photooxygenation of 4'-diethylamino-3 hydroxyflavone. AB - The photolysis reactions of 4'-diethylamino-3-hydroxyflavone (D), a versatile fluorescent probe showing excited-state intramolecular proton transfer (ESIPT), and the magnesium chelate of D (MgD(2+)) have been studied in acetonitrile solution. Upon UV irradiation both species were oxidized into O-4 diethylaminobenzoyl salicylic acid, differently from the photoreaction of the parent compound 3-hydroxyflavone (3HF) which was described to undergo rearrangement to 3-hydroxy-3-phenyl-indan-1,2-dione. The photooxygenation of the Mg(2+) complex was found to be significantly faster than the reaction of the pure dye. As the kinetic analysis of the absorption spectra of samples under irradiation showed, the rate coefficients for the oxygenations of the excited state dye and complex have close values, kox(D*) = 2.4 * 10(7) min(-1), kox(MgD(2+)*) = 3.9 * 10(7) min(-1); the difference arises from the higher photooxygenation quantum yield of the complex, Phi(MgD(2+)) = 2.3 * 10(-3), than the respective value for the pure dye, Phi(D) = 1.5 * 10(-4). The potential energy surface of the photooxygenation of D was calculated assuming a reaction path in which the phototautomer formed from Dvia ESIPT, reacts in its triplet state with triplet molecular oxygen O2, a mechanism similar to that suggested for the photoreaction of the parent 3HF. The moderate values for the transition state energies confirmed the plausibility of the hypothetical mechanism. PMID- 26738439 TI - Creation of chimeric human/rabbit APOBEC1 with HIV-1 restriction and DNA mutation activities. AB - APOBEC1 (A1) proteins from lagomorphs and rodents have deaminase-dependent restriction activity against HIV-1, whereas human A1 exerts a negligible effect. To investigate these differences in the restriction of HIV-1 by A1 proteins, a series of chimeric proteins combining rabbit and human A1s was constructed. Homology models of the A1s indicated that their activities derive from functional domains that likely act in tandem through a dimeric interface. The C-terminal region containing the leucine-rich motif and the dimerization domains of rabbit A1 is important for its anti-HIV-1 activity. The A1 chimeras with strong anti-HIV 1 activity were incorporated into virions more efficiently than those without anti-HIV-1 activity, and exhibited potent DNA-mutator activity. Therefore, the C terminal region of rabbit A1 is involved in both its packaging into the HIV-1 virion and its deamination activity against both viral cDNA and genomic RNA. This study identifies the novel molecular mechanism underlying the target specificity of A1. PMID- 26738443 TI - Preparation and evaluation of novel microemulsion-based hydrogels for dermal delivery of benzocaine. AB - The purpose of the current research was to prepare and evaluate the potential use of microemulsion-based hydrogel (MBH) formulations for dermal delivery of benzocaine (BZN). The pseudoternary-phase diagrams were constructed for various microemulsions composed of isopropyl myristate (IPM) as oil phase, Span 20, Tween 20, Tween 80, cremophor EL and cremophor RH40 as surfactants, ethanol as cosurfactant and distilled water as aqueous phase. Finally, concentration of BZN in microemulsions was 2% (w/w). The physicochemical properties, such as conductivity, viscosity, pH, droplet size, polydispersity index and zeta potential of microemulsions, were measured. Carbopol 940 was used to convert BZN loaded microemulsions into gel form without affecting their structure. Furthermore, excised rat abdominal skin was used to compare permeation and penetration properties of BZN loaded M3 and M3BHs with BZN solution. According to ex vivo study results, BZN-loaded M3BH1 showed highest flux values and high release rate values, and furthermore, this gel formulation had low surfactant content. Finally, in order to learn the localization of formulations within the dermal penetration, formulations and BZN solution were labeled with red oil O and subjected to fluorescence observation. In conclusion, BZN-loaded MBHs could be offered as a promising strategy for dermal drug delivery. PMID- 26738445 TI - The emerging role of signal transducer and activator of transcription 3 in cerebral ischemic and hemorrhagic stroke. AB - Signal transducers and activators of transcription (STATs) comprise a family of cytoplasmic transcription factors that mediate intracellular signaling. This signaling is typically generated at cell surface receptors, the activation of which results in the translocation of STATs to the nucleus. STATs are involved in biological events as diverse as embryonic development, programmed cell death, organogenesis, innate immunity, adaptive immunity and cell growth regulation in organisms ranging from slime molds to insects to humans. Numerous studies have demonstrated the activation of STAT3 in neurological diseases, particularly in cerebral ischemic and hemorrhagic stroke. Additionally, STAT3 has also been reported to play a critical role in neuroprotective therapies. In light of the pleiotropic effects of STAT3 on the nervous system, we present the elaborate network of roles that STAT3 plays in cerebral ischemia and hemorrhage in this review. First, we introduce basic knowledge regarding STAT3 and briefly summarize the activation, inactivation, and regulation of the STAT3 pathway. Next, we describe the activation of STAT3 following cerebral ischemia and hemorrhage. Subsequently, we discuss the physiopathological roles of STAT3 in cerebral ischemia and hemorrhage. Moreover, we summarize several significant cerebral ischemic and hemorrhagic stroke treatments that target the STAT3 signaling pathway, including pharmacological and physical therapies. Finally, we highlight research progress on STAT3 in stroke. This review presents the important roles of STAT3 in the nervous system and may contribute to the promotion of STAT3 as a new therapeutic target. PMID- 26738446 TI - [Author's response to article "The complications of brain biopsies", by J. Ibanez et al]. PMID- 26738448 TI - Cyclosporine A promotes cell proliferation, collagen and alpha-smooth muscle actin expressions in rat gingival fibroblasts by Smad3 activation and miR-29b suppression. AB - OBJECTIVES: Transforming growth factor (TGF)-beta/Smad3 signaling promotes tissue fibrosis, and miR-29b is a downstream inhibitor of TGF-beta/Smad3-mediated fibrosis, both of which may be involved in the pathogenesis of cyclosporine A induced gingival overgrowth. The aim of this study is to investigate the effect of miR-29b and TGF-beta/Smad3 signaling in cyclosporine A-stimulated rat gingival fibroblasts. MATERIAL AND METHODS: We explored the effect of cyclosporine A on cell proliferation, type Iota collagen (COL1) and alpha-smooth muscle actin (alpha-SMA) expressions in rat gingival fibroblasts with the Cell Counting Kit-8 assay, real-time polymerase chain reaction, western blot and immunofluorescence. The expressions of TGF-beta1, Smad3 and miR-29b were also evaluated after cyclosporine A treatment. The effects of Smad3 and miR-29b on cyclosporine A induced alterations were further determined by Smad3 knockdown and miR-29b overexpression using transient transfection experiments. RESULTS: We found that cyclosporine A increased cell proliferation, COL1 and alpha-SMA expressions in rat gingival fibroblasts. TGF-beta1 mRNA and protein expressions were upregulated and phosphorylated Smad3 was activated by cyclosporine A treatment, while miR-29b expression was significantly suppressed. Moreover, Smad3 knockdown and miR-29b overexpression reversed cyclosporine A-enhanced cell proliferation, COL1 and alpha-SMA expressions in gingival fibroblasts. In addition, the suppression of miR-29b upon cyclosporine A exposure was significantly elevated by Smad3 knockdown, whereas cyclosporine A-induced Smad3 activation was not altered by miR 29b overexpression. CONCLUSIONS: These results suggest that cyclosporine A promotes cell proliferation, collagen and alpha-SMA expressions in rat gingival fibroblasts by Smad3 activation and miR-29b suppression. PMID- 26738451 TI - Worst clinical cases: techniques and outcomes. A series of case reports from AO Trauma Italy. PMID- 26738450 TI - The single-chain anti-TNF-alpha antibody DLX105 induces clinical and biomarker responses upon local administration in patients with chronic plaque-type psoriasis. AB - It is not clear whether TNF-alpha antagonists used in the treatment of psoriasis need to act systemically, or whether local inhibition of skin-produced TNF-alpha would be sufficient to silence skin inflammation. To answer this question, we conducted two multicentre, double-blinded, randomized, placebo-controlled clinical trials with the novel single-chain anti-TNF-alpha-PENTRA((r)) -antibody DLX105. Upon intra-dermal injection, DLX105 induced a mean local PASI decrease of 33% over baseline after 2 weeks of treatment, while the placebo response was only 12% (P = 0.001). The clinical response was accompanied by changes in biomarkers such as reductions in K16, Ki67 and epidermal thickness as well as decreased mRNA levels of IL-17, TNF-alpha, IL-23p19, IL-12p40 and IFN-gamma. Next, we applied the drug topically twice daily in a 0.5% hydrogel formulation. While the local PASI did not change, topical DLX105 mediated significant reductions of mRNA levels of key proinflammatory cytokines when compared to placebo, and this effect was further enhanced after weekly tape stripping of plaques to increase drug penetration. These results suggest that longer treatment periods and/or increased local drug concentrations might result in better therapeutic efficacy of topically applied DLX105. In sum, we can show for the first time that local inhibition of TNF-alpha is sufficient to mediate a biological response in psoriasis that translates into clinical efficacy. PMID- 26738452 TI - Management of a humeral shaft non-union after a Gustilo III C fracture. AB - A 25-year-old man was admitted to our Department with an open humeral shaft fracture (Gustilo III C); two large wounds were noticed with ulnar artery and median nerve completely dissected. Initial primary treatment included irrigation, debridement and fracture stabilization with a monolateral external fixator followed by vascular and nerve repair and wound closure. At 6 months follow up the patient was able to use his arm without any painful stimuli and a CT scan showed the presence of postero-medial callus formation. Consequently, the external fixator was removed and the patient was discharged to physiotherapy. After 7 months, the patient presented with severe pain and functional impairment with no history of trauma. X rays showed recent re-fracture on a background of oligotrophic nonunion. Revision surgery included debridement of the non-union bone edges, reaming of the medullary canal and insertion of a humeral nail. Six months later osseous healing was noted with complete restoration of shoulder and elbow movement and partial recovery of the median nerve. PMID- 26738453 TI - Simultaneous bilateral "floating arm" of the humeri: an uncommon presentation of a rare complex injury and review of the literature. AB - The timing of definitive fixation for simultaneous fractures of the humerus in polytrauma patient is controversial. We report on the management of a patient that sustained bilateral "floating arm" fractures of the humeri. When dealing with such injury patterns, it is important to always carry out stabilization of the humeral diaphysis first and afterwards to treat the sub-injury or over-injury fractures. Our patient healed after twelve weeks in both humeri. After seven years MEPS showed excellent and good results in the right and left arms, while UCLA scores proved excellent in both sides. We encountered no intraoperative and postoperative complications. PMID- 26738454 TI - Floating elbow in a polytrauma patient: timing and surgical strategy. AB - A 22-year-old man was admitted to our hospital because of polytrauma following a car accident. The instrumental investigations detected parenchymatous and bone lesions, including a floating elbow (articular distal humerus fracture associated with ipsilateral forearm fracture). After initial temporary stabilization with external fixator and restoration of hemodynamics, we proceeded to the fixation of the upper limb. To reduce local and general risks of complications, a two-stage reconstruction technique has been applied. PMID- 26738455 TI - Multiple ruptures of the extensor tendons after volar fixation for distal radius fracture: a case report. AB - A 62-year-old woman was admitted to our hospital after a bicycle accident with a displaced left (non-dominant) distal radius fracture. After closed reduction a long cast was applied. Due to loss of reduction, twenty-four days later open reduction internal fixation with locking compression plate (LCP) was performed. The patient returned to her normal activities but nineteen months after surgery showed functional impairment of the left thumb for Extensor Pollicis Longus (EPL) injury for which she necessitated transposition surgery. Twenty-six months after ORIF, functional deficit of the extension of the third and fourth left finger was noted secondary to injury of extensor tendons. Ultrasound and CT scan showed protrusion of the angular stability screws in LCP plate that caused a progressive wear resulting in rupture of the extensor tendons. Another tendon transposition surgery was performed with dorsal approach while the plate was removed utilising the original volar incision. Reconstruction of distal radius fractures with volar plating, requires accurate plate application with precise measurement of the length of the screws in order to prevent dorsal protrusion and thus avoiding tendon injuries. PMID- 26738447 TI - Recent progress on lipid lateral heterogeneity in plasma membranes: From rafts to submicrometric domains. AB - The concept of transient nanometric domains known as lipid rafts has brought interest to reassess the validity of the Singer-Nicolson model of a fluid bilayer for cell membranes. However, this new view is still insufficient to explain the cellular control of surface lipid diversity or membrane deformability. During the past decades, the hypothesis that some lipids form large (submicrometric/mesoscale vs nanometric rafts) and stable (>min vs s) membrane domains has emerged, largely based on indirect methods. Morphological evidence for stable submicrometric lipid domains, well-accepted for artificial and highly specialized biological membranes, was further reported for a variety of living cells from prokaryot es to yeast and mammalian cells. However, results remained questioned based on limitations of available fluorescent tools, use of poor lipid fixatives, and imaging artifacts due to non-resolved membrane projections. In this review, we will discuss recent evidence generated using powerful and innovative approaches such as lipid-specific toxin fragments that support the existence of submicrometric domains. We will integrate documented mechanisms involved in the formation and maintenance of these domains, and provide a perspective on their relevance on membrane deformability and regulation of membrane protein distribution. PMID- 26738456 TI - Bilateral femoral shaft fractures complicated by fat and pulmonary embolism: a case report. AB - A 25-year-old man was admitted to our hospital because of pulmonary embolism and suspected fat embolism after sustaining bilateral femoral shaft fracture. A left arm weakness, tachycardia and sudden hemoglobin drop delayed his definitive fixation with intramedullary nailing. His clinical course was further complicated by bleeding from the pin sites of the external fixators which had initially been used to temporarily stabilize his femoral fractures (clotting disturbances). A lower leg Doppler ultrasound and a new pelvic-chest CT angiography excluded any remaining thrombus, meanwhile the embolus had broken in smaller pieces, more distally. His unfractionated heparin was revised to a Low Molecular Weight Heparin at prophylactic dose. After a 10 day period and when his condition had been improved bilateral reamed nailing was performed. Although bilateral closed femoral shaft fractures should be stabilized early, fat embolism syndrome (FES) and thromboembolic events (TEV) should always be kept in mind in these patients. PMID- 26738457 TI - Late recurrent peripheral upper limb ischemia after non-union of a clavicle fracture. AB - A 74-year-old woman was referred to our hospital due to recurrent episodes of upper limb ischemia. Her past medical history included a clavicle non-union developed after a clavicle midshaft fracture that had occurred 30 years previously. After a long asymptomatic period, she started showing symptoms of chronic ischemia to the left arm that were misdiagnosed. Thoracic outlet syndrome (TOS) is a rare but possible complication of mal-union and non-union of clavicle fractures; symptoms related to arterial involvement (ATOS) amount to less than 1% of all existing forms of thoracic outlet syndrome. In case of clavicle non-union, local instability plays a key role in determining the initial injury to the vessels and the recurrence of symptoms. Restoration of local bone stability and anatomy, obtained by compression plating and autologous bone grafting, combined with an appropriate vascular surgery, is essential to achieve a clinical resolution of symptoms and to avoid the recurrence of symptomatology as seen in the herein case. PMID- 26738458 TI - The treatment of femoral bone loss by axial external fixation and susbequent locking plate application: a case report. AB - A 20-year-old man was admitted to our hospital having sustianed bilateral high energy femoral fractures. The right femoral fracture was an open grade 3B with OTA grade 3 bone loss. The patient had also a brain contusion with a subdural haematoma and a closed fracture of the left clavicle. Initial management included temporarily stabilisation of the femoral fractures wth external fixators and prompt transfer to the intensive care unit. Three weeks later the external fixator of the right femur was converted to an hybrid system, and the fixator of the left side was removed and a reamed intramedullary locking nail was applied. Two months after the accident the patient underwent bone transport (11 cm long) of the right femur with an monolateral external fixation. When the final length was achieved there were knee stiffness (ROM 0 degrees to 30 degrees ) and non union of the docking site. Therefore, the patient underwent a Judet's procedure to treat the knee stiffness and stabilisation of the non united femur with a locking plate (LISS). After the operation the patient started progressive weight bearing. A year after trauma and following union of the femur, the patient underwent soft tissue reconstruction of the anterior side of the thigh with a free vascularised flap. At final follow upo the patient had a good functional recovery with return to his previous occupation. PMID- 26738459 TI - Correction of multiple complex lower limb deformities by intramedullary nailing. AB - A female patient presented to our institution suffering from long bone post traumatic multiple deformities. Her walking was limited, painful and teetering. It had worsened over the past months. The right leg was shortened by 6 cm compared to the contralateral. The right femur was 18 degrees varus, the right tibia was 16 degrees valgus, the left tibia was 12 degrees varus. Both knee joints showed marked radiographic signs of osteosclerosis. After a thorough study with simulations using paper models, we carried out three osteotomies, two open wedge and one cuneiform, stabilizing them with intramedullary nails. We conducted the operation in two stages, in order to avoid an excessive surgical stress that could give rise to complications such as DVT, fat embolism, and respiratory insufficiency. This allowed a rapid recovery of her weight bearing and walking capacity, reducing significantly also the leg length discrepancy. She progressed uneventfully to healing of the osteotomy sites and she returned to her previous occupation. PMID- 26738460 TI - Unexpected tibial non-union after minimally invasive bridge plating: a case report. AB - A fit 42-year-old woman presented to our department with a closed isolated distal tibial and fibular shaft fracture (AO 42-B1.3), which was addressed with a minimally invasive plate osteosynthesis (MIPO) with a bridging technique for both the tibia and the fibula. No risk factors for healing issues were known at the time of surgery. At the 6-month follow-up, the leg was still painful during walking and the fracture site was still evident on the radiographs. Bone and CT scans confirmed the diagnosis of oligotrophic non-union. A revision surgery was then successfully performed with a reamed IM tibial nail and a fibular osteotomy taking into consideration both biological and mechanical factors. Surgeons must treat tibial shaft fractures avoiding unnecessary damage to soft tissue, restoring an appropriate reduction of the bony segment and providing an adequate fixation; however, other factors may play a role in the development of "unexpected non-union". PMID- 26738461 TI - Open pelvic fracture associated with lumbosacral dislocation and extensive perineal injury. AB - Open pelvic fractures are caused by high-energy trauma. Injuries to other organs are common and the mortality rate can be as high as 50%. Perineal injury is reported in 5% of open pelvic fractures. We report a case of a 31-year-old man that had an open pelvic injury with Denis zone III fracture of the sacrum, lumbosacral dislocation, symphysis dislocation, bilateral pubic rami fractures and an extensile perineal wound. He underwent an early diverting colostomy in order to prevent pelvic sepsis and subsequent stage reconstruction of the pelvic ring. At a 4-year follow-up a full recovery was present. The aim of this paper is to underline the importance of a safe, approach to manage open pelvic fractures. PMID- 26738462 TI - From plate to nail: a case-report of proximal humerus non-union. AB - The rate of non-union is estimated to be 1.1% to 10% following closed treatment of proximal humerus fracture. Treatment options include revision of fixation and biological enhancement using osteoprogenitor cells, growth factors and scaffolds. However, it is essential to plan the correct type of reconstructive strategy based on the evaluation of the non-union type. The use of the Non-Union Scoring System (NUSS) in this respect can aid the clinician to reach the right decision. We report a case of a 40 years old man who developed an aseptic proximal humerus non-union treated initially with ORIF (Philos((r)) plate), bone substitute (Orthoss((r))) and bone morphogenetic protein 7 (BMP-7). Due to implant failure, twelve weeks later the fixation was revised to Titanium Cannulated Humeral Nail. Osseous healing was noted 5 months later. PMID- 26738463 TI - Posterior sternoclavicular joint dislocation with brachiocephalic vein injury: a case report. AB - Posterior dislocation of the clavicle is an uncommon injury, usually related to road traffic or contact sports accidents. The close proximity of vital structures in the mediastinum should alert the surgeon avoiding a closed reduction in the emergency setting. A multidisciplinary team of expert surgeons should be involved and a combined procedure performed. Nevertheless, the risk of developing complications is high. We report this case in order to outline one of the potential complications, to discuss appropriate imaging studies and to describe the details of a safe surgical approach. PMID- 26738465 TI - Evaluation of emergency pediatric tracheal intubation by pediatric anesthesiologists on inpatient units and the emergency department. AB - BACKGROUND AND OBJECTIVES: There are limited data on pediatric emergency tracheal intubation on inpatient units and in the emergency department by anesthesiologists. This retrospective cohort study was designed to describe the frequency of difficult intubation and adverse events associated with emergency tracheal intubation performed by pediatric anesthesiologists in a large children's hospital. METHODS: All emergency tracheal intubation on inpatient units and the emergency department performed by pediatric anesthesiologists over a 7-year period in children <18 years were identified by querying our perioperative clinical information system. Medical records were comprehensively reviewed to describe the emergency intubation process and outcomes. RESULTS: One hundred and thirty-two intubations from 120 children (median age 3.3 years) were eligible. The majority of emergency tracheal intubations were successful with 1-2 laryngoscopy attempts, while 14 (10.6%) were difficult. Despite grade 3 view in 3/14 cases, the airway was secured after multiple direct laryngoscopy attempts. Eleven required use of an alternative airway device to secure the airway. A preexisting airway abnormality or craniofacial abnormality was present in 57% of cases with difficult intubation including half with micrognathia or retrognathia. Major intubation-related adverse events such as aspiration, occurred in 5 (3.8%) emergency tracheal intubations. Mild-to-moderate intubation-related adverse events occurred in 23 (17.4%) emergency tracheal intubations including mainstem bronchus intubation (13.6%). CONCLUSION: A significant rate of difficult intubation and mild-to-moderate intubation-related adverse events were found in emergency tracheal intubations on inpatient units and the emergency department in children performed by a pediatric anesthesiology emergency airway team. Difficult intubation was observed frequently in children with preexisting airway and craniofacial abnormalities and often required the use of an alternative airway device to successfully secure the airway. PMID- 26738466 TI - Product Exclusivity Granted by the U.S. Food and Drug Administration. PMID- 26738467 TI - The origin and significance of additional aneuploidy events in couples undergoing preimplantation genetic diagnosis for translocations by array comparative genomic hybridization. AB - Diagnostic application of array comparative genomic hybridization (aCGH) in preimplantation genetic diagnosis for reciprocal and Robertsonian translocations has revealed 55-65% embryos with additional aneuploidies with or without translocation-related imbalances. The occurrence of these extra abnormalities with the balanced form of the translocation reduces the number of embryos suitable for transfer. Eighty-three embryos were followed up on days 5-7 of development from 23 infertile or sub-fertile carriers for whole chromosome and segmental aneuploidies present in addition to the balanced or unbalanced translocations detected on aCGH diagnosis. Embryos were analysed by fluorescence in-situ hybridization (n = 63) and aCGH (n = 20). Meiotic aneuploidy affected 35% of embryos and 47% had mitotic events; 15% had both types. Meiotic and mitotic events were almost equal (60 versus 64), 97 affected whole chromosomes (58 meiotic, 39 mitotic) and 27 were segmental (two meiotic, 25 mitotic). In 85.5% of embryos with whole chromosome additional aneuploidies, the aneuploidy was present throughout or in more than 50% of cells. All embryos diagnosed as abnormal (translocation balanced or unbalanced) after aCGH diagnosis at cleavage stage would have remained unsuitable for transfer if tested at later stages of development. Additional aneuploidies merit full consideration when considering the choice of embryos to transfer. PMID- 26738469 TI - Development of new SNP derived cleaved amplified polymorphic sequence marker set and its successful utilization in the genetic analysis of seed color variation in barley. AB - The aim of the present study was to develop a new cost effective PCR based CAPS marker set using advantages of high-throughput SNP genotyping. Initially, SNP survey was made using 20 diverse barley genotypes via 9k iSelect array genotyping that resulted in 6334 polymorphic SNP markers. Principle component analysis using this marker data showed fine differentiation of barley diverse gene pool. Till this end, we developed 200 SNP derived CAPS markers distributed across the genome covering around 991cM with an average marker density of 5.09cM. Further, we genotyped 68 CAPS markers in an F2 population (Cheri*ICB181160) segregating for seed color variation in barley. Genetic mapping of seed color revealed putative linkage of single nuclear gene on chromosome 1H. These findings showed the proof of concept for the development and utility of a newer cost effective genomic tool kit to analyze broader genetic resources of barley worldwide. PMID- 26738468 TI - Safety and efficacy of prothrombin complex concentrate as first-line treatment in bleeding after cardiac surgery. AB - BACKGROUND: Bleeding after cardiac surgery requiring surgical reexploration and blood component transfusion is associated with increased morbidity and mortality. Although prothrombin complex concentrate (PCC) has been used satisfactorily in bleeding disorders, studies on its efficacy and safety after cardiopulmonary bypass are limited. METHODS: Between January 2005 and December 2013, 3454 consecutive cardiac surgery patients were included in an observational study aimed at investigating the efficacy and safety of PCC as first-line coagulopathy treatment as a replacement for fresh frozen plasma (FFP). Starting in January 2012, PCC was introduced as solely first-line treatment for bleeding following cardiac surgery. RESULTS: After one-to-one propensity score-matched analysis, 225 pairs of patients receiving PCC (median dose 1500 IU) and FFP (median dose 2 U) were included. The use of PCC was associated with significantly decreased 24-h post-operative blood loss (836 +/- 1226 vs. 935 +/- 583 ml, p < 0.0001). Propensity score-adjusted multivariate analysis showed that PCC was associated with significantly lower risk of red blood cell (RBC) transfusions (odds ratio [OR] 0.50; 95% confidence interval [CI] 0.31-0.80), decreased amount of RBC units (beta unstandardised coefficient -1.42, 95% CI -2.06 to -0.77) and decreased risk of transfusion of more than 2 RBC units (OR 0.53, 95% CI 0.38-0.73). Patients receiving PCC had an increased risk of post-operative acute kidney injury (AKI) (OR 1.44, 95% CI 1.02-2.05) and renal replacement therapy (OR 3.35, 95% CI 1.13 9.90). Hospital mortality was unaffected by PCC (OR 1.51, 95% CI 0.84-2.72). CONCLUSIONS: In the cardiac surgery setting, the use of PCC compared with FFP was associated with decreased post-operative blood loss and RBC transfusion requirements. However, PCC administration may be associated with a higher risk of post-operative AKI. PMID- 26738471 TI - Endohedral Ca@B38: stabilization of a B38(2-) borospherene dianion by metal encapsulation. AB - Based on extensive global-minimum searches and first-principles electronic structure calculations, we present the viability of an endohedral metalloborospherene Cs Ca@B38 () which contains a Cs B38(2-) () dianion composed of interwoven boron double chains with a sigma + pi double delocalization bonding pattern, extending the Bn(q) (q = n - 40) borospherene family from n = 39-42 to n = 38. Transition metal endohedral complexes Cs M@B38 (M = Sc, Y, Ti) (, , ) based on Cs B38(2-) () are also predicted. PMID- 26738470 TI - Effects of rehabilitation approaches for runners with patellofemoral pain: protocol of a randomised clinical trial addressing specific underlying mechanisms. AB - BACKGROUND: Patellofemoral pain (PFP) is highly prevalent in runners, and often leads to functional limitations and cessation of running. Training errors as well as decreased lower limb strength and control during running have all been associated with PFP. While strengthening and gait retraining are commonly used by clinicians, no randomised clinical trial has compared these modalities in runners with PFP. The primary objective of this randomised clinical trial will be to compare the effects of three rehabilitation programs targeting different key factors on symptoms and functional limitations of runners with PFP. The secondary objective will be to explore the factors leading to clinical improvement. METHODS/DESIGN: We will conduct a single-blind randomised clinical trial to compare three different 8 week rehabilitation programs: Group 1 will receive education on symptoms management based on training modifications; Group 2 will receive an exercise program targeting lower limb strengthening and control in addition to the education component of Group 1; Group 3 will receive running gait retraining advice as well as the education component of Group 1. Sixty-nine runners with PFP will be recruited and will be seen by independent physiotherapists on five visits through 8 weeks. The primary outcome measure will be symptoms and functional limitations measured by the Knee Outcome Survey - Activities of Daily Living Scale questionnaire at baseline, and at the four, eight and 20 weeks follow-up. Secondary outcomes will include pain level measured using visual analog scales, and running mileage. Lower limb kinematics and kinetics during running, and isometric strength will also be evaluated at baseline and 8 weeks follow-up. The effects of rehabilitation programs on measures of symptoms and functional limitations will be assessed using a 2-way ANOVA (Groups x Time). Regression analyses will be used to identify if changes in running mechanics or strength are determinants of clinical success. DISCUSSION: Studies with a high level of evidence are needed to determine the best rehabilitation interventions for runners with PFP. This randomised clinical trial will be the first to compare programs targeting different key factors linked with PFP. Results may guide clinicians and improve their clinical outcomes when treating runners with PFP. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02352909. Registered on December 3, 2014. PMID- 26738472 TI - Therapeutic Potential of T Cell Chimeric Antigen Receptors (CARs) in Cancer Treatment: Counteracting Off-Tumor Toxicities for Safe CAR T Cell Therapy. AB - A chimeric antigen receptor (CAR) is a recombinant fusion protein combining an antibody-derived targeting fragment with signaling domains capable of activating T cells. Recent early-phase clinical trials have demonstrated the remarkable ability of CAR-modified T cells to eliminate B cell malignancies. This review describes the choice of target antigens and CAR manipulations to maximize antitumor specificity. Benefits and current limitations of CAR-modified T cells are discussed, with a special focus on the distribution of tumor antigens on normal tissues and the risk of on-target, off-tumor toxicities in the clinical setting. We present current methodologies for pre-evaluating these risks and review the strategies for counteracting potential off-tumor effects. Successful implementation of these approaches will improve the safety and efficacy of CAR T cell therapy and extend the range of cancer patients who may be treated. PMID- 26738473 TI - RNA Interference (RNAi)-Based Therapeutics: Delivering on the Promise? AB - A resurgence in clinical trials using RNA interference (RNAi) occurred in 2012. Although there were initial difficulties in achieving efficacious results with RNAi without toxic side effects, advances in delivery and improved chemistry made this resurgence possible. More than 20 RNAi-based therapeutics are currently in clinical trials, and several of these are Phase III trials. Continued positive results from these trials have helped bolster further attempts to develop clinically relevant RNAi therapies. With a wide variety of disease targets to choose from, the first RNAi therapeutic to be clinically approved is not far off. This review covers recently established and completed clinical trials. PMID- 26738474 TI - Structure-Driven Developments of 26S Proteasome Inhibitors. AB - The 26S proteasome is a 2.5-MDa complex, and it operates at the executive end of the ubiquitin-proteasome pathway. It is a proven target for therapeutic agents for the treatment of some cancers and autoimmune diseases, and moreover, it has potential as a target of antibacterial agents. Most inhibitors, including all molecules approved for clinical use, target the 20S proteolytic core complex; its structure was determined two decades ago. Hitherto, efforts to develop inhibitors targeting the 19S regulatory particle subunits have been less successful. This is, in part, because the molecular architecture of this subcomplex has been, until recently, poorly understood, and high-resolution structures have been available only for a few subunits. In this review, we describe, from a structural perspective, the development of inhibitory molecules that target both the 20S and 19S subunits of the proteasome. We highlight the recent progress achieved in structure-based drug-discovery approaches, and we discuss the prospects for further improvement. PMID- 26738475 TI - Triclosan: A Widespread Environmental Toxicant with Many Biological Effects. AB - Triclosan (TCS) is a broad-spectrum antimicrobial agent that has been added to personal care products, including hand soaps and cosmetics, and impregnated in numerous different materials ranging from athletic clothing to food packaging. The constant disposal of TCS into the sewage system is creating a major environmental and public health hazard. Owing to its chemical properties of bioaccumulation and resistance to degradation, TCS is widely detected in various environmental compartments in concentrations ranging from nanograms to micrograms per liter. Epidemiology studies indicate that significant levels of TCS are detected in body fluids in all human age groups. We document here the emerging evidence--from in vitro and in vivo animal studies and environmental toxicology studies--demonstrating that TCS exerts adverse effects on different biological systems through various modes of action. Considering the fact that humans are simultaneously exposed to TCS and many TCS-like chemicals, we speculate that TCS induced adverse effects may be relevant to human health. PMID- 26738477 TI - Oxysterols: Old Tale, New Twists. AB - Oxysterols have long been known for their important role in cholesterol homeostasis, where they are involved in both transcriptional and posttranscriptional mechanisms for controlling cholesterol levels. However, they are increasingly associated with a wide variety of other, sometimes surprising cell functions. They are activators of the Hedgehog pathway (important in embryogenesis), and they act as ligands for a growing list of receptors, including some that are of importance to the immune system. Oxysterols have also been implicated in several diseases such as neurodegenerative diseases and atherosclerosis. Here, we explore the latest research into the roles oxy-sterols play in different areas, and we evaluate the current evidence for these roles. In addition, we outline critical concepts to consider when investigating the roles of oxysterols in various situations, which includes ensuring that the concentration and form of the oxysterol are relevant in that context--a caveat with which many studies have struggled. PMID- 26738479 TI - Design of Next-Generation G Protein-Coupled Receptor Drugs: Linking Novel Pharmacology and In Vivo Animal Models. AB - Despite the fact that G protein-coupled receptors (GPCRs) are the most successful drug targets in history, this supergene family of cell surface receptors has yet to be fully exploited as targets in the treatment of human disease. Here, we present optimism that this may change in the future by reviewing the substantial progress made in the understanding of GPCR molecular pharmacology that has generated an extensive toolbox of ligand types that include orthosteric, allosteric, and bitopic ligands, many of which show signaling bias. We discuss how combining these advances with recently described transgenic, chemical genetic, and optogenetic animal models will provide the framework to allow for the rational design of next-generation GPCR drugs that possess increased therapeutic efficacy and decreased adverse/toxic responses. PMID- 26738476 TI - Targeting Prefrontal Cortical Systems for Drug Development: Potential Therapies for Cognitive Disorders. AB - Medications to treat cognitive disorders are increasingly needed, yet researchers have had few successes in this challenging arena. Cognitive abilities in primates arise from highly evolved N-methyl-d-aspartate (NMDA) receptor circuits in layer III of the dorsolateral prefrontal cortex. These circuits have unique modulatory needs that can differ from the layer V neurons that predominate in rodents, but they offer multiple therapeutic targets. Cognitive improvement often requires low doses that enhance the pattern of information held in working memory, whereas higher doses can produce nonspecific changes that obscure information. Identifying appropriate doses for clinical trials may be helped by assessments in monkeys and by flexible, individualized dose designs. The use of guanfacine (Intuniv) for prefrontal cortical disorders was based on research in monkeys, supporting this approach. Coupling our knowledge of higher primate circuits with the powerful methods now available in drug design will help create effective treatments for cognitive disorders. PMID- 26738478 TI - The Emerging Role of Spinal Dynorphin in Chronic Pain: A Therapeutic Perspective. AB - Notable findings point to the significance of the dynorphin peptide neurotransmitter in chronic pain. Spinal dynorphin neuropeptide levels are elevated during development of chronic pain and sustained during persistent chronic pain. Importantly, knockout of the dynorphin gene prevents development of chronic pain in mice, but acute nociception is unaffected. Intrathecal (IT) administration of opioid and nonopioid dynorphin peptides initiates allodynia through a nonopioid receptor mechanism; furthermore, antidynorphin antibodies administered by the IT route attenuate chronic pain. Thus, this review presents the compelling evidence in the field that supports the role of dynorphin in facilitating the development of a persistent pain state. These observations illustrate the importance of elucidating the control mechanisms responsible for the upregulation of spinal dynorphin in chronic pain. Also, spinal dynorphin regulation of downstream signaling molecules may be implicated in hyperpathic states. Therapeutic strategies to block the upregulation of spinal dynorphin may provide a nonaddictive approach to improve the devastating condition of chronic pain that occurs in numerous human diseases. PMID- 26738480 TI - Nuclear Receptors as Therapeutic Targets in Liver Disease: Are We There Yet? AB - Nuclear receptors (NR) are ligand-modulated transcription factors that play diverse roles in cell differentiation, development, proliferation, and metabolism and are associated with numerous liver pathologies such as cancer, steatosis, inflammation, fibrosis, cholestasis, and xenobiotic/drug-induced liver injury. The network of target proteins associated with NRs is extremely complex, comprising coregulators, small noncoding microRNAs, and long noncoding RNAs. The importance of NRs as targets of liver disease is exemplified by the number of NR ligands that are currently used in the clinics or in clinical trials with promising results. Understanding the regulation by NR during pathophysiological conditions, and identifying ligands for orphan NR, points to a potential therapeutic approach for patients with liver diseases. An overview of complex NR metabolic networks and their pharmacological implications in liver disease is presented here. PMID- 26738481 TI - TRAPLINE: a standardized and automated pipeline for RNA sequencing data analysis, evaluation and annotation. AB - BACKGROUND: Technical advances in Next Generation Sequencing (NGS) provide a means to acquire deeper insights into cellular functions. The lack of standardized and automated methodologies poses a challenge for the analysis and interpretation of RNA sequencing data. We critically compare and evaluate state of-the-art bioinformatics approaches and present a workflow that integrates the best performing data analysis, data evaluation and annotation methods in a Transparent, Reproducible and Automated PipeLINE (TRAPLINE) for RNA sequencing data processing (suitable for Illumina, SOLiD and Solexa). RESULTS: Comparative transcriptomics analyses with TRAPLINE result in a set of differentially expressed genes, their corresponding protein-protein interactions, splice variants, promoter activity, predicted miRNA-target interactions and files for single nucleotide polymorphism (SNP) calling. The obtained results are combined into a single file for downstream analysis such as network construction. We demonstrate the value of the proposed pipeline by characterizing the transcriptome of our recently described stem cell derived antibiotic selected cardiac bodies ('aCaBs'). CONCLUSION: TRAPLINE supports NGS-based research by providing a workflow that requires no bioinformatics skills, decreases the processing time of the analysis and works in the cloud. The pipeline is implemented in the biomedical research platform Galaxy and is freely accessible via www.sbi.uni-rostock.de/RNAseqTRAPLINE or the specific Galaxy manual page (https://usegalaxy.org/u/mwolfien/p/trapline---manual). PMID- 26738483 TI - The role of gender on malaria preventive behaviour among rural households in Kenya. AB - BACKGROUND: Malaria remains a major health and development challenge in the sub Saharan African economies including Kenya, yet it can be prevented. Technologies to prevent malaria are available but are not universally adopted by male- and female-headed households. The study thus, examined the role of gender in malaria prevention, examining adoption behaviour between male- and female-headed households in Kenya. METHODS: The study uses a recent baseline cross-section survey data collected from 2718 households in parts of western and eastern Kenya. Two separate models were estimated for male- and female-headed households to determine if the drivers of adoption differ between the two categories of households. RESULTS: The findings from the study show that: access to public health information, residing in villages with higher experience in malaria prevention, knowledge on the cause and transmission of malaria significantly increase the number of practices adopted in both male- and female-headed households. On the other hand, formal education of the household head and livestock units owned exhibited a positive and significant effect on adoption among male-headed households, but no effect among female-headed households. CONCLUSIONS: The findings from thus study suggest that universal policy tools can be used to promote uptake of integrated malaria prevention practices, for female- and male-headed households. PMID- 26738482 TI - Relationship between cardiac diffusion tensor imaging parameters and anthropometrics in healthy volunteers. AB - BACKGROUND: In vivo cardiac diffusion tensor imaging (cDTI) is uniquely capable of interrogating laminar myocardial dynamics non-invasively. A comprehensive dataset of quantative parameters and comparison with subject anthropometrics is required. METHODS: cDTI was performed at 3T with a diffusion weighted STEAM sequence. Data was acquired from the mid left ventricle in 43 subjects during the systolic and diastolic pauses. Global and regional values were determined for fractional anisotropy (FA), mean diffusivity (MD), helix angle gradient (HAg, degrees/%depth) and the secondary eigenvector angulation (E2A). Regression analysis was performed between global values and subject anthropometrics. RESULTS: All cDTI parameters displayed regional heterogeneity. The RR interval had a significant, but clinically small effect on systolic values for FA, HAg and E2A. Male sex and increasing left ventricular end diastolic volume were associated with increased systolic HAg. Diastolic HAg and systolic E2A were both directly related to left ventricular mass and body surface area. There was an inverse relationship between E2A mobility and both age and ejection fraction. CONCLUSIONS: Future interpretations of quantitative cDTI data should take into account anthropometric variations observed with patient age, body surface area and left ventricular measurements. Further work determining the impact of technical factors such as strain and SNR is required. PMID- 26738484 TI - Molecular forensics in avian conservation: a DNA-based approach for identifying mammalian predators of ground-nesting birds and eggs. AB - BACKGROUND: The greater sage-grouse (Centrocercus urophasianus) is a ground nesting bird from the Northern Rocky Mountains and a species at risk of extinction in in multiple U.S. states and Canada. Herein we report results from a proof of concept that mitochondrial and nuclear DNAs from mammalian predator saliva could be non-invasively collected from depredated greater sage-grouse eggshells and carcasses and used for predator species identification. Molecular forensic approaches have been applied to identify predators from depredated remains as one strategy to better understand predator-prey dynamics and guide management strategies. This can aid conservation efforts by correctly identifying predators most likely to impact threatened and endangered species. DNA isolated from non-invasive samples around nesting sites (e.g. fecal or hair samples) is one method that can increase the success and accuracy of predator species identification when compared to relying on nest remains alone. RESULTS: Predator saliva DNA was collected from depredated eggshells and carcasses using swabs. We sequenced two partial fragments of two mitochondrial genes and obtained microsatellite genotypes using canid specific primers for species and individual identification, respectively. Using this multilocus approach we were able to identify predators, at least down to family, from 11 out of 14 nests (79%) and three out of seven carcasses (47%). Predators detected most frequently were canids (86%), while other taxa included rodents, a striped skunk, and cattle. We attempted to match the genotypes of individual coyotes obtained from eggshells and carcasses with those obtained from fecal samples and coyotes collected in the areas, but no genotype matches were found. CONCLUSION: Predation is a main cause of nest failure in ground-nesting birds and can impact reproduction and recruitment. To inform predator management for ground-nesting bird conservation, accurate identification of predator species is necessary. Considering predation can have a high impact on recruitment, predation events are very difficult to observe, and predator species are difficult to identify visually from nest remains, molecular approaches that reduce the need to observe or handle animals offer an additional tool to better understand predator-prey dynamics at nesting sites. PMID- 26738485 TI - Reclassification of Achromobacter spiritinus Vandamme et al. 2013 as a later heterotypic synonym of Achromobacter marplatensis Gomila et al. 2011. AB - A repeat multi-locus sequence analysis (MLSA) of concatenated nusA, eno, rpoB, gltB, lepA, nuoL and nrdA sequences of strains classified as Achromobacter marplatensis was performed. The results revealed that earlier reported sequence data of the proposed type strain were erroneous, and that the corrected concatenated sequence divergence between the A. marplatensis LMG 26219T (=CCUG 56371T) sequence type and that of strains of Achromobacter spiritinus was well below the 2.1% threshold value that delineates species of the genus Achromobacter. These results therefore demonstrated that strains which were classified as A. spiritinus should be reclassified as A. marplatensis and that the name Achromobacter spiritinus should no longer be used. An emendation of the description of Achromobacter marplatensis is warranted. PMID- 26738486 TI - Kinetics of arterial carbon dioxide during veno-venous extracorporeal membrane oxygenation support in an apnoeic porcine model. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a technique widely used worldwide to improve gas exchange. Changes in ECMO settings affect both oxygen and carbon dioxide. The impact on oxygenation can be followed closely by continuous pulse oximeter. Conversely, carbon dioxide equilibrates much slower and is not usually monitored directly. METHODS: We investigated the time to stabilization of arterial carbon dioxide partial pressure (PaCO2) following step changes in ECMO settings in 5 apnoeic porcine models under veno-venous ECMO support with polymethylpentene membranes. We collected sequential arterial blood gases at a pre-specified interval of 50 min using a sequence of standardized blood and sweep gas flow combinations. RESULTS: Following the changes in ECMO parameters, the kinetics of carbon dioxide was dependent on sweep gas and ECMO blood flow. With a blood flow of 1500 mL/min, PaCO2 takes longer than 50 min to equilibrate following the changes in sweep gas flow. Furthermore, the sweep gas flow from 3.0 to 10.0 L/min did not significantly affect PaCO2. However, with a blood flow of 3500 mL/min, 50 min was enough for PaCO2 to reach the equilibrium and every increment of sweep gas flow (up to 10.0 L/min) resulted in additional reductions of PaCO2. CONCLUSIONS: Fifty minutes was enough to reach the equilibrium of PaCO2 after ECMO initiation or after changes in blood and sweep gas flow with an ECMO blood flow of 3500 ml/min. Longer periods may be necessary with lower ECMO blood flows. PMID- 26738488 TI - Extracellular stress stimuli alter galectin expression profiles and adhesion characteristics of HL-60 cells. AB - Galectins, a family of soluble beta-galactoside-binding proteins, are involved in the regulation of various cellular functions, which are essential for adaptive cellular stress responses (CSRs). Although expression patterns of galectins and galectin-binding glycans change during tissue development and cancer, the requirement and role of galectin networks in the CSRs are not completely understood. In this study, we report that the treatment of human promyelocytic HL 60 cells with stimuli mimicking hypoxia (CoCl2), inducing the endoplasmic reticulum stress (tunicamycin), and stimulating cell differentiation, result in stress-specific differential expression of galectin transcripts. In addition, we show that CoCl2 increases the expression of cell surface glycans recognized by both beta-galactoside- and GlcNAc-binding lectins. Thus, microenvironmental stress changes the glycobiological status of cells representing expression profiles of endogenous lectins and corresponding glycans. These findings introduce a novel classification of galectins in HL-60 cells, which suggests diverse functions of galectin members in CSRs. PMID- 26738489 TI - N6-benzyladenine and kinetin influence antioxidative stress parameters in human skin fibroblasts. AB - N6-benzyladenine and kinetin are adenine-type cytokinins that play various roles in many aspects of plant development and stimulate anabolic processes in plant cells. The aim of this study was to examine the effect of N6-benzyladenine and kinetin on basic oxidative stress parameters, such as antioxidative enzyme activity, reduced glutathione and thiol group content, and lipid peroxidation. The results show a stimulatory effect of kinetin and N6-benzyladenine on antioxidative enzyme activity, as well as reduced glutathione and thiol group content. Cytokinins caused a decrease in membrane phospholipid peroxidation and exhibited protective properties against malondialdehyde production. The present findings reveal that both N6-benzyladenine and kinetin exhibit multiple and complex actions in fibroblast cells in vitro. Both show antioxidant properties and are potentially powerful agents with applications in the prevention and treatment of many diseases connected with oxidative stress in skin, for example, psoriasis. PMID- 26738487 TI - Recombinant human deoxyribonuclease attenuates oxidative stress in a model of eosinophilic pulmonary response in mice. AB - The inflammatory cells infiltrating the airways produce several mediators, such as reactive oxygen species (ROS). ROS and the oxidant-antioxidant imbalance might play an important role in the modulation of airways inflammation. In order to avoid the undesirable effects of ROS, various endogenous antioxidant strategies have evolved, incorporating both enzymatic and non-enzymatic mechanisms. Recombinant human deoxyribonuclease (rhDNase) in clinical studies demonstrated a reduction in sputum viscosity, cleaving extracellular DNA in the airways, and facilitating mucus clearance, but an antioxidant effect was not studied so far. Therefore, we evaluated whether the administration of rhDNase improves oxidative stress in a murine model of asthma. Mice were sensitized by two subcutaneous injections of ovalbumin (OVA), on days 0 and 7, followed by three lung challenges with OVA on days 14, 15, and 16. On days 15 and 16, after 2 h of the challenge with OVA, mice received 1 mg/mL of rhDNase in the lungs. Bronchoalveolar lavage fluid and lung tissue were obtained on day 17, for inflammatory and oxidative stress analysis. We showed that rhDNase did not alter the population of inflammatory cells, such as eosinophil cells, in OVA-treated rhDNase group but significantly improved oxidative stress in lung tissue, by decreasing oxygen reactive species and increasing superoxide dismutase/catalase ratio, glutathione peroxidase activity, and thiol content. Our data provide the first evidence that rhDNase decreases some measures of oxidative stress and antioxidant status in a murine model of asthma, with a potential antioxidant effect to be further studied in human asthma. PMID- 26738490 TI - Genome-wide analysis of tunicamycin-induced endoplasmic reticulum stress response and the protective effect of endoplasmic reticulum inhibitors in neonatal rat cardiomyocytes. AB - Tunicamycin (TM) is an inducer of endoplasmic reticulum (ER) stress. However, which genes related to ER stress was induced in cardiomyocytes on a genome-wide scale remains poorly understood. Salubrinal and its derivatives are ER stress inhibitors. However, the cellular protection mechanisms remain unresolved. Neonatal rat cardiomyocytes were cultured from ventricles of one-day-old Wistar rats. Cells were exposed to salubrinal, its derivatives (PP1-12, PP1-24) or vehicle followed by TM treatment at different times. Total RNA was isolated from cells for RNA-sequencing analysis. The expressions of 189, 182, 556, 860, and 1314 genes were changed in cells exposed to TM for 1, 3, 6, 12, and 24 h. Five well-known UPR genes (Hspa5, Hsp90b1, Calr, Ddit3, and Atf4) were significantly increased in a time-dependent manner. Six not well-known genes (Hyou1, Herpud1, Manf, Creld2, Sdf2l1, and Slc3a2) were highlighted to be involved in ER stress. Compared with TM-only treated cells, the expressions of 36 genes upregulated by TM and 74 genes downregulated by TM were reversed by salubrinal. In comparison, 121 genes upregulated by TM and 92 genes downregulated by TM were reversed by PP1 12. Most genes altered by salubrinal are in the category of transcription (1 h) and cell cycle (24 h). Most genes altered by PP1-12 are in the category of response to ER stress (3 h) and cell cycle (24 h). Our findings help elucidate the mechanism for TM treatment and may be useful for future drug screens involved in ER stress. PMID- 26738492 TI - The enzyme L-isoaspartyl (D-aspartyl) methyltransferase is required for VEGF dependent endothelial cell migration and tubulogenesis. AB - The protein L-isoaspartyl (D-aspartyl) methyltransferase (PIMT) methylates proteins carrying altered aspartyl residues in their structure. PIMT is postulated to limit the accumulation of these damaged proteins with abnormal aspartyl residues. However, little is known about the role of PIMT in tumor growth and almost nothing about its involvement in angiogenic processes. We previously reported that PIMT was up-regulated when endothelial cells were detached from extracellular matrix, leading us to postulate that PIMT could play a critical role during angiogenic steps, since the contacts between endothelial cells and the extracellular matrix are intensively regulated during this process. Here, we demonstrated that PIMT down-regulation by siRNA in human umbilical vein endothelial cells (HUVECs) inhibited both cell migration and tube formation in vitro when stimulated by vascular endothelial growth factor (VEGF). Conversely, overexpression of wild-type PIMT promoted HUVEC migration in the presence of VEGF, while this response was prevented in cells transfected with the inactive mutant PIMT(D83V). Similar results were obtained with the two forms of PIMT regarding their capacity to regulate the action of VEGF during the formation of capillary-like structures in vitro. Together, these data highlight the importance of the catalytic activity of PIMT to mediate VEGF effects during endothelial cell migration and tube formation in angiogenesis. Furthermore, these results identify a new function for PIMT as an enzyme involved in pro-angiogenic processes. PMID- 26738491 TI - Color reduction of melanin by lysosomal and peroxisomal enzymes isolated from mammalian cells. AB - Lysosomes and peroxisomes are organelles with many functions in all eukaryotic cells. Lysosomes contain hydrolytic enzymes (lysozyme) that degrade molecules, whereas peroxisomes contain enzymes such as catalase that convert hydrogen peroxide (H2O2) to water and oxygen and neutralize toxicity. In contrast, melanin is known as a helpful element to protect the skin against harmful ultraviolet rays. However, a high quantity of melanin leads to hyperpigmentation or skin cancer in human. New materials have already been discovered to inhibit tyrosinase in melanogenesis; however, melanin reduction does not suggest their preparation. In this study, we report that the color intensity because of melanin decreased by the cellular activation of lysosomes and peroxisomes. An increase in the superficial intensity of lysosome and peroxisome activities of HeLa cells was observed. In addition, a decrease in the amount of melanin has also been observed in mammalian cells without using any other chemical, showing that the process can work in vivo for treating melanin. Therefore, the results of this study indicate that the amount of melanin decreases by the lysosome and peroxisome activity after entering the cells, and functional organelles are effective in color reduction. This mechanism can be used in vivo for treating melanin. PMID- 26738493 TI - B cell translocation gene 2 (Btg2) is regulated by Stat3 signaling and inhibits adipocyte differentiation. AB - Btg2, a member of a family of antiproliferative proteins, is involved in downregulation of the JAK2-Stat3 signaling pathway. Here, we present evidence that the inhibitory effect of Btg2 on adipogenesis is suppressed by the proadipogenic activity of the Stat3 signaling pathway. Btg2 expression fluctuates during adipogenic differentiation of preadipocytes. Btg2 is also expressed at different levels in fat tissues from lean and obese mice. Furthermore, knockdown of Btg2 expression enhanced lipid accumulation and upregulated the expression of adipogenic marker genes. To gain insights into the molecular mechanisms of Btg2 action in adipocytes, adipocytes were treated with previously identified bioactive compounds and the expression of Btg2 was assessed. This effort identified the small molecule WP1066, a known Stat3 inhibitor, as an inducer of Btg2 expression. In line with this observation, siRNA-mediated silencing of Stat3 resulted in upregulated Btg2 expression and decreased lipid accumulation. Furthermore, siRNA-mediated silencing of Btg2 attenuated WP1066-mediated inhibition of adipocyte differentiation. We discuss a model for the role of Btg2 in adipogenesis and propose that Btg2 and Stat3 act in a functional hierarchy. PMID- 26738494 TI - A facile and dynamic assay for the detection of peptide aggregation. AB - We report on a facile method to detect the aggregation and co-aggregation of peptides by tryptophan fluorescence spectroscopy. Peptide aggregates (PAs) play a pivotal role in neurodegenerative diseases, such as Alzheimer's and Parkinson's. The detection of the formation of aggregates, especially in the early stage, will facilitate the diagnosis and treatment of the associated disease. In this study, by choosing a tryptophan-containing peptide of EP2, we investigated its fluorescence spectroscopic characteristics in the process of PAs. The results showed that the intensity of emission spectra was significantly enhanced with the formation of PAs within 48 h. In addition, by employing EP2 as a fluorescence probe, we found that EP2 was able to effectively monitor the aggregation of other peptides/proteins that are otherwise difficult to detect with conventional approach. Thus, these preliminary data provide a promising diagnostic tool to detect the formation of PAs. PMID- 26738495 TI - Development and application of a high-throughput sample cleanup process based on 96-well plate for simultaneous determination of 16 steroids in biological matrices using liquid chromatography-triple quadrupole mass spectrometry. AB - A novel high-throughput sample pretreatment system was developed by the integration of protein precipitation (PP), phospholipid removal (PPR), and hollow fiber liquid-phase microextraction (HF-LPME) into two simple 96-well plates and a matching 96-grid lid. With this system, 16 steroids were separated from biological matrices of plasma, milk, and urine and analyzed by liquid chromatography-triple quadrupole mass spectrometry. In the tandem sample cleanup process, the prepositive PP and PPR step preliminarily removed some of the interferences from the biological matrices. The following HF-LPME step kept the residual interference out of the hollow fiber and enriched the steroids in the hollow fiber to achieve high sensitivity. By a series of method optimizations, acetonitrile was chosen as the crash solvent for PP and PPR. A mixture of octanol and toluene (1:1 v/v) was used as the acceptor phase for HF-LPME. The extraction was conducted at 80 rpm for 50 min in a donor phase containing 1 mL 20% sodium chloride at 25 degrees C. Under these conditions, the limits of detection for the 16 steroids were 3.6-300.0 pg(.)mL(-1) in plasma, 3.0-270.0 pg.mL(-1) in milk, and 2.2-210.0 pg(.)mL(-1) in urine. The recoveries of the 16 steroids were 81.9-97.9% in plasma (relative standard deviation 1.0-8.0%), 80.6-97.7% in milk (relative standard deviation 0.8-5.4%), and 87.3-98.7% in urine (relative standard deviation 1.0-4.9%). Further, the integrated 96-well platform of PP, PPR, and HF-LPME enabled us to run this assay in an automatic and high-throughput fashion. The reliability of the method was further corroborated by evaluation of its applicability in plasma and urine samples from volunteers and fresh bovine milk from local dairy enterprises. PMID- 26738496 TI - Mental Health and Associated Sexual Health Behaviours in a Sample of Young People Attending a Music Festival in Melbourne, Victoria. AB - Poor mental health has previously been associated with risky sexual health behaviours among young people internationally and in clinical samples, but little is known about this relationship in non-clinical settings. We conducted a cross sectional survey with a convenience sample of 1345 Australians aged 15-29. Multivariable logistic regression was used to identify sexual health behaviours independently associated with recent poor mental health including contraception use, STI testing, sexting and age at first sexual intercourse. Recent poor mental health was reported by 29.7 % of participants and independently associated with female gender (OR 1.8; 95 % CI 1.4-2.4), not identifying as heterosexual (OR 3.0; 95 % CI 2.1-4.4) and young age at first sexual intercourse among female participants (OR 1.4; 95 % CI 1.0-2.0). Results suggest mental health is largely driven by variables other than sexual health behaviours, although youth mental health services should consider inclusion of sexual health promotion within the scope of their services. PMID- 26738498 TI - Retraction Note to: The prognostic relevance of node metastases in optimally cytoreduced advanced ovarian cancer. PMID- 26738497 TI - Family Aided Community Treatment for the Treatment of Early Psychosis: A Proof of Concept Study. AB - Major psychotic disorders are one of the leading causes of disability worldwide. If these conditions are identified early and treatment promptly implemented, the prognosis is improved. This study examined the impact of a yearlong family aided community treatment (FACT) intervention upon psychiatric symptoms. Psychiatric symptom scores improved with the FACT intervention. Improved training on early recognition for mental health clinicians, implementation of a specific treatment model in community settings and policy around treatment funding allocation are implications of this study. PMID- 26738499 TI - Anti-inflammatory effect of laser acupuncture in ST36 (Zusanli) acupoint in mouse paw edema. AB - Low-level laser therapy (LLLT) in acupuncture is a low-power laser applied to acupoints for providing luminous energy, capable to produce photobiological induction that results in biochemical, bioelectric, and bioenergetic effects. ST36 (Zusanli) is a point of acupuncture commonly used for treatment of several pathological alterations, such as inflammation, acute pain, and gastrointestinal disorders. In this study, we evaluated the anti-inflammatory effect of LLLT (830 nm, 4 J/cm(2)) in ST36 acupoint through the model of carrageenan-induced paw edema in mice and the possible mechanisms involved. Female Swiss mice were treated with LLLT in ST36 before the paw edema induction, which was measured by means of a digital micrometer and the temperature through a high-resolution digital thermograph. After this, the levels of reactive oxygen species (ROS), lipid hydroperoxides (LOOH), and reduced glutathione (GSH) were quantified. In another set of experiments, the paw edema was induced by bradykinin, histamine, and prostaglandin E2 (PGE2). LLLT in ST36 acupoint significantly inhibited the edema formation for 4 h after the carrageenan injection and reduced the paw temperature in 10 %. Furthermore, LLLT also reduced the levels of ROS (55 %) and LOOH (50 %) but, however, did not alter the GSH levels. LLLT in ST36 reduced the paw edema induced by bradykinin (30 min, 6 %, 60 min, 7 %), histamine (30 min, 11 %), and PGE2 (90 min, 10 %, 120 min, 16 %). In conclusion, these results prove that LLLT in ST36 acupoint produces a relevant anti-inflammatory effect, reducing edema, temperature, and free radicals levels in mice paw. PMID- 26738501 TI - Wide-range Vacuum Measurements from MWNT Field Emitters Grown Directly on Stainless Steel Substrates. AB - The field emission properties and the vacuum measurement application are investigated from the multi-walled carbon nanotubes (MWNTs) grown directly on catalytic stainless steel substrates. The MWNT emitters present excellent emission properties after the acid treatment of the substrate. The MWNT gauge is able to work down to the extreme-high vacuum (XHV) range with linear measurement performance in wide range from 10(-11) to 10(-6) Torr. A modulating grid is attempted with improved gauge sensitivity. The extension of the lower pressure limit is attributed largely to low outgassing effect due to direct growth of MWNTs and justified design of the electron source. PMID- 26738500 TI - Safety assessment of trans-tympanic photobiomodulation. AB - We evaluated functional and morphological changes after trans-tympanic laser application using several different powers of photobiomodulation (PBM). The left (L) ears of 17 rats were irradiated for 30 min daily over 14 days using a power density of 909.1 (group A, 5040 J), 1136.4 (group B, 6300 J), and 1363.6 (group C, 7560 J) mW/cm(2). The right (N) ears served as controls. The safety of PBM was determined by endoscopic findings, auditory brainstem response (ABR) thresholds, and histological images of hair cells using confocal microscopy, and light microscopic images of the external auditory canal (EAC) and tympanic membrane (TM). Endoscopic findings revealed severe inflammation in the TM of C group; no other group showed damage in the TM. No significant difference in ABR threshold was found in the PBM-treated groups (excluding the group with TM damage). Confocal microscopy showed no histological difference between the AL and AN, or BL and BN groups. However, light microscopy showed more prominent edema, inflammation, and vascular congestion in the TM of BL ears. This study found a dose-response relationship between laser power parameters and TM changes. These results will be useful for defining future allowance criteria for trans-tympanic laser therapies. PMID- 26738504 TI - Roles of low-density lipoprotein receptor-related protein 1 in tumors. AB - Low-density lipoprotein receptor-related protein 1 (LRP1, also known as CD91), a multifunctional endocytic and cell signaling receptor, is widely expressed on the surface of multiple cell types such as hepatocytes, fibroblasts, neurons, astrocytes, macrophages, smooth muscle cells, and malignant cells. Emerging in vitro and in vivo evidence demonstrates that LRP1 is critically involved in many processes that drive tumorigenesis and tumor progression. For example, LRP1 not only promotes tumor cell migration and invasion by regulating matrix metalloproteinase (MMP)-2 and MMP-9 expression and functions but also inhibits cell apoptosis by regulating the insulin receptor, the serine/threonine protein kinase signaling pathway, and the expression of Caspase-3. LRP1-mediated phosphorylation of the extracellular signal-regulated kinase pathway and c-jun N terminal kinase are also involved in tumor cell proliferation and invasion. In addition, LRP1 has been shown to be down-regulated by microRNA-205 and methylation of LRP1 CpG islands. Furthermore, a novel fusion gene, LRP1-SNRNP25, promotes osteosarcoma cell invasion and migration. Only by understanding the mechanisms of these effects can we develop novel diagnostic and therapeutic strategies for cancers mediated by LRP1. PMID- 26738503 TI - The Insertion and Management of External Ventricular Drains: An Evidence-Based Consensus Statement : A Statement for Healthcare Professionals from the Neurocritical Care Society. AB - External ventricular drains (EVDs) are commonly placed to monitor intracranial pressure and manage acute hydrocephalus in patients with a variety of intracranial pathologies. The indications for EVD insertion and their efficacy in the management of these various conditions have been previously addressed in guidelines published by the Brain Trauma Foundation, American Heart Association and combined committees of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons. While it is well recognized that placement of an EVD may be a lifesaving intervention, the benefits can be offset by procedural and catheter-related complications, such as hemorrhage along the catheter tract, catheter malposition, and CSF infection. Despite their widespread use, there are a lack of high-quality data regarding the best methods for placement and management of EVDs to minimize these risks. Existing recommendations are frequently based on observational data from a single center and may be biased to the authors' view. To address the need for a comprehensive set of evidence-based guidelines for EVD management, the Neurocritical Care Society organized a committee of experts in the fields of neurosurgery, neurology, neuroinfectious disease, critical care, pharmacotherapy, and nursing. The Committee generated clinical questions relevant to EVD placement and management. They developed recommendations based on a thorough literature review using the Grading of Recommendations Assessment, Development, and Evaluation system, with emphasis placed not only on the quality of the evidence, but also on the balance of benefits versus risks, patient values and preferences, and resource considerations. PMID- 26738505 TI - Can prostatic arterial embolisation (PAE) reduce the volume of the peripheral zone? MRI evaluation of zonal anatomy and infarction after PAE. AB - OBJECTIVES: To assess the impact of prostatic arterial embolisation (PAE) on various prostate gland anatomical zones. METHODS: We retrospectively reviewed paired MRI scans obtained before and after PAE for 25 patients and evaluated changes in volumes of the median lobe (ML), central gland (CG), peripheral zone (PZ) and whole prostate gland (WPV) following PAE. We used manual segmentation to calculate volume on axial view T2-weighted images for ML, CG and WPV. We calculated PZ volume by subtracting CG volume from WPV. Enhanced phase on dynamic contrasted-enhanced MRI was used to evaluate the infarction areas after PAE. Clinical results of International Prostate Symptom Score and International Index of Erectile Function questionnaires and the urodynamic study were evaluated before and after PAE. RESULTS: Significant reductions in volume were observed after PAE for ML (26.2 % decrease), CG (18.8 %), PZ (16.4 %) and WPV (19.1 %; p < 0.001 for all these volumes). Patients with clinical failure had smaller volume reductions for WPV, ML and CG (all p < 0.05). Patients with significant CG infarction after PAE displayed larger WPV, ML and CG volume reductions (all p < 0.01). CONCLUSIONS: PAE can significantly decrease WPV, ML, CG and PZ volumes, and poor clinical outcomes are associated with smaller volume reductions. KEY POINTS: * The MRI segmentation method provides detailed comparisons of prostate volume change. * Prostatic arterial embolisation (PAE) decreased central gland and peripheral zone volumes. * Prostates with infarction after PAE showed larger decreases in volume. * A larger decrease in prostate volume is associated with clinical success. PMID- 26738507 TI - Assessment of two-dimensional (2D) and three-dimensional (3D) lower limb measurements in adults: Comparison of micro-dose and low-dose biplanar radiographs. AB - OBJECTIVE: To evaluate reliability of 2D and 3D lower limb measurements in adults using micro-dose compared to low-dose biplanar radiographs(BPR). MATERIALS AND METHODS: One hundred patients (mean 54.9 years) were examined twice using micro dose and low-dose BPR. Length and mechanical axis of lower limbs were measured on the antero-posterior(ap) micro-dose and low-dose images by two independent readers. Femoral and tibial torsions of 50 patients were measured by two independent readers using reconstructed 3D-models based on the micro-dose and low dose BPR. Intermethod and interreader agreements were calculated using descriptive statistics, intraclass-correlation-coefficient(ICC), and Bland-Altman analysis. RESULTS: Mean interreader-differences on micro-dose were 0.3 cm(range 0 1.0)/ 0.7 degrees (0-2.9) for limb length/axis and 0.4 cm (0-1.0)/0.8 degrees (0 3.3) on low-dose BPR. Mean intermethod-difference was 0.04 cm +/- 0.2/0.04 degrees +/- 0.6 for limb length/axis. Interreader-ICC for limb length/axis was 0.999/0.991 on micro-dose and 0.999/0.987 on low-dose BPR. Interreader-ICC for micro-dose was 0.879/0.826 for femoral/ tibial torsion, for low-dose BPR was 0.924/0.909. Mean interreader-differences on micro-dose/low-dose BPR were 3 degrees (0-13 degrees )/2 degrees (0 degrees -12 degrees ) for femoral and 4 degrees (0-18 degrees )/3 degrees (0 degrees -10 degrees ) for tibial torsion. Mean intermethod-difference was -0.1 degrees +/- 5.0/-0.4 degrees +/- 2.9 for femoral/tibial torsion. Mean dose-area-product was significantly lower (9.9 times;p < 0.001) for micro-dose BPR. CONCLUSION: 2D-and 3D-measurements of lower limbs based on micro-dose BPR are reliable and provide a 10-times lower radiation dose. KEY POINTS: * Lower limb length and mechanical axis can be reliably measured with micro-dose. * Femoral and tibial torsion can be reliably assessed with micro-dose. * Micro-dose allows a huge reduction of radiation exposure. PMID- 26738506 TI - Diffusion-weighted MR imaging of the pancreas: optimizing b-value for visualization of pancreatic adenocarcinoma. AB - OBJECTIVES: To determine the optimal b-value of 3.0-T diffusion-weighted imaging (DWI) for visualizing pancreatic adenocarcinomas METHODS: Fifty-five patients with histologically confirmed pancreatic adenocarcinoma underwent DWI with different b-values (b = 500, 1000, 1500, and 2000 s/mm(2)) at 3.0 T. For each b value, we retrospectively evaluated DWI findings of pancreatic adenocarcinomas (clear hyperintensity relative to the surrounding pancreas, hyperintensity with an unclear distal border, and isointensity) and image quality, and measured tumour-to-pancreas signal intensity (SI) ratios. DWI findings, image quality, and tumour-to-pancreas SI ratios were compared between the four b-values. RESULTS: There was a significantly higher incidence of tumours showing clear hyperintensity on DWI with b-value of 1500 s/mm(2) than on that with b-value of 1000 s/mm(2) (P < 0.001), and on DWI with b-value of 1000 s/mm(2) than on that with b-value of 500 s/mm(2) (P < 0.001). The tumour-to-distal pancreas SI ratio was higher with b-value of 1500 s/mm(2) than with b-value of 1000 s/mm(2) (P < 0.001), and with b-value of 1000 s/mm(2) than with b-value of 500 s/mm(2) (P < 0.001). A lower image quality was obtained at increasing b-values (P < 0.001); the lowest scores were observed with b-value of 2000 s/mm(2). CONCLUSIONS: The use of b = 1500 s/mm(2) for 3.0-T DWI can improve the delineation of pancreatic adenocarcinomas. KEY POINTS: * Diffusion-weighted imaging (DWI) has been used for diagnosing pancreatic adenocarcinoma * The techniques for DWI, including the choice of b-values, vary considerably * DWI often fails to delineate pancreatic adenocarcinomas because of hyperintense pancreas * DWI with a higher b-value can improve the tumour delineation * The lowest image quality was obtained on DWI with b-value = 2000 s/mm (2). PMID- 26738508 TI - Endorsement of the CONSORT statement by Chinese journals of Traditional Chinese Medicine: a survey of journal editors and review of journals' instructions for authors. AB - BACKGROUND: We aimed to assess the endorsement of the Consolidation Standards of Reporting Trials (CONSORT) statement by Chinese journals of Traditional Chinese Medicine (TCM) and its incorporation into their editorial processes. METHODS: PubMed, Embase and major Chinese databases were searched to identify journals of TCM from China for inclusion. The latest 'instruction for authors' (IFA) of each included journal was obtained and any text mentioning CONSORT or CONSORT extension papers was extracted. Subsequently, the editor of each of the included journals was surveyed about their journal's endorsement of the CONSORT recommendations and their incorporation into editorial and peer review processes. RESULTS: Sixty-three journals of TCM from China were examined. Of these, only three (5%) and one (2%) of the 63 journals mentioned the CONSORT statement and extension papers, respectively, in their IFA. Fifty-four of 63 (86%) of surveyed journals responded, with the majority of respondents being editors. Only 20% (11/54) of the respondents reported that they had any knowledge of the CONSORT statement. Only 6% (3/54) of the editors reported that they required authors to comply with the CONSORT statement or that they incorporated it into their peer review and editorial processes. CONCLUSIONS: TCM journals in China endorsing the CONSORT statement constituted a small percentage of the total. The majority of editors surveyed were not familiar with the content of the CONSORT statement and extension papers. We strongly recommend that the China Periodicals Association issue a policy to promote the endorsement of the CONSORT statement and conduct relevant training for journal editors in China. PMID- 26738510 TI - Ectopic intrapleural thymoma: a rare location in the thoracic cavity. AB - We present a patient with a large thymoma on the right thoracic cavity developing from the visceral pleura. This is a rare location for this tumour, and only a few had been reported to date in the literature. PMID- 26738512 TI - Maternal use of oral contraceptives and risk of birth defects in Denmark: prospective, nationwide cohort study. AB - STUDY QUESTION: Is oral contraceptive use around the time of pregnancy onset associated with an increased risk of major birth defects? METHODS: In a prospective observational cohort study, data on oral contraceptive use and major birth defects were collected among 880,694 live births from Danish registries between 1997 and 2011. We conservatively assumed that oral contraceptive exposure lasted up to the most recently filled prescription. The main outcome measure was the number of major birth defects throughout one year follow-up (defined according to the European Surveillance of Congenital Anomalies classification). Logistic regression estimated prevalence odds ratios of any major birth defect as well as categories of birth defect subgroups. STUDY ANSWER AND LIMITATIONS: Prevalence of major birth defects (per 1000 births) was consistent across each oral contraceptive exposure group (25.1, never users; 25.0, use >3 months before pregnancy onset (reference group); 24.9, use 0-3 months before pregnancy onset (that is, recent use); 24.8, use after pregnancy onset). No increase in prevalence of major birth defects was seen with oral contraceptive exposure among women with recent use before pregnancy (prevalence odds ratio 0.98 (95% confidence interval 0.93 to 1.03)) or use after pregnancy onset (0.95 (0.84 to 1.08)), compared with the reference group. There was also no increase in prevalence of any birth defect subgroup (for example, limb defects). It is unknown whether women took oral contraceptives up to the date of their most recently filled prescription. Also, the rarity of birth defects made disaggregation of the results difficult. Residual confounding was possible, and the analysis lacked information on folate, one of the proposed mechanisms. WHAT THIS STUDY ADDS: Oral contraceptive exposure just before or during pregnancy does not appear to be associated with an increased risk of major birth defects. FUNDING, COMPETING INTERESTS, DATA SHARING: BMC was funded by the Harvard T H Chan School of Public Health's Maternal Health Task Force and Department of Epidemiology Rose Traveling Fellowship; training grant T32HD060454 in reproductive, perinatal, and paediatric epidemiology and award F32HD084000 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development; and grant T32CA09001 from the National Cancer Institute. The authors have no competing interests or additional data to share. PMID- 26738517 TI - An audit of hepatitis B vaccination for men who have sex with men before and after sexual health service integration. AB - Scottish Government guidelines identify hepatitis B vaccination as a key standard reflecting access to sexual health care for men who have sex with men (MSM). This audit was performed before and after service redesign to assess the impact of the integration of genitourinary medicine and sexual and reproductive health services on the provision of care to MSM. There was no significant difference between the proportion of males receiving at least one dose of vaccination (p = 0.64, chi(2 )= 0.222), but a significant drop in the proportion of males receiving three doses of vaccination pre- and post-integration (p = 0.0157, chi(2 )= 5.834). Advised standards are being met but follow up and recall require improvement if previously reported completion rates are required for protection. PMID- 26738514 TI - Effectiveness of prognosticating pulmonary embolism using the ESC algorithm and the Bova score. AB - The prognostic value of the European Society of Cardiology (ESC) 2014 algorithm and the Bova score has lacked adequate validation. According to the ESC 2014 guidelines and the Bova score, we retrospectively risk stratified normotensive patients with PE who were enrolled in the PROTECT study. This study used a complicated course (which consisted of death from any cause, haemodynamic collapse, or recurrent PE) as the primary endpoint, and follow-up occurred through 30 days after the PE diagnosis. Of 848 patients, 37 % had a sPESI of 0 and 5 (1.6 %; 95 % confidence interval [CI], 0.5-3.7 %) experienced a complicated course. Of 143 patients with a sPESI of 0 points and negative computed tomographic pulmonary angiography (CTPA) for right ventricle (RV) dysfunction, three (2.1 %; 95 % CI, 0.4-6.0 %) experienced a complicated course. Four hundred seventy-eight (56 %) patients with a sPESI >= 1 had echocardiographic evidence of RV dysfunction or elevated troponin level or none, and 48 (10 %, 95 % CI, 7.5 13.1 %) experienced a complicated course. Fifty-seven (6.7 %) patients with a sPESI >= 1 had echocardiographic RV dysfunction and elevated troponin level, and 10 (17.5 %; 95 % CI, 8.8-29.9 %) experienced a complicated course, compared to 21.6 % (8 of 37 patients, 21.6 %; 95 % CI, 9.8-38.2 %) in Bova risk class III. In conclusion, the ESC 2014 prognostic algorithm is effective in the risk stratification of normotensive patients with PE. Use of CTPA did not improve the ability for identification of low-risk PE. Bova risk scoring did not significantly improve identification of intermediate-high risk PE. PMID- 26738518 TI - A re-audit of the management of gonorrhoea. AB - A re-audit of the management of gonorrhoea was undertaken in 2014. Six out of nine auditable outcomes were met in the second audit (2014) compared with three out of eight in the first audit (2012). The new measures that were introduced following the original audit may have helped to improve outcomes. However, electronic patient records were introduced in December 2012. Documentation was much improved with the use of patient record templates and this has contributed considerably to the improved outcomes. PMID- 26738519 TI - At-Line Cellular Screening Methodology for Bioactives in Mixtures Targeting the alpha7-Nicotinic Acetylcholine Receptor. AB - The alpha7-nicotinic acetylcholine receptor (alpha7-nAChR) is a ligand-gated ion channel expressed in different regions of the central nervous system (CNS). The alpha7-nAChR has been associated with Alzheimer's disease, epilepsy, and schizophrenia, and therefore is extensively studied as a drug target for the treatment of these diseases. Important sources for new compounds in drug discovery are natural extracts. Since natural extracts are complex mixtures, identification of the bioactives demands the use of analytical techniques to separate a bioactive from inactive compounds. This study describes screening methodology for identifying bioactive compounds in mixtures acting on the alpha7 nAChR. The methodology developed combines liquid chromatography (LC) coupled via a split with both an at-line calcium (Ca(2+))-flux assay and high-resolution mass spectrometry (MS). This allows evaluation of alpha7-nAChR responses after LC separation, while parallel MS enables compound identification. The methodology was optimized for analysis of agonists and positive allosteric modulators, and was successfully applied to screening of the hallucinogen mushroom Psilocybe Mckennaii The crude mushroom extract was analyzed using both reversed-phase and hydrophilic interaction liquid chromatography. Matching retention times and peak shapes of bioactives found with data from the parallel MS measurements allowed rapid pinpointing of accurate masses corresponding to the bioactives. PMID- 26738520 TI - Characterization of Differentiated SH-SY5Y as Neuronal Screening Model Reveals Increased Oxidative Vulnerability. AB - The immortalized and proliferative cell line SH-SY5Y is one of the most commonly used cell lines in neuroscience and neuroblastoma research. However, undifferentiated SH-SY5Y cells share few properties with mature neurons. In this study, we present an optimized neuronal differentiation protocol for SH-SY5Y that requires only two work steps and 6 days. After differentiation, the cells present increased levels of ATP and plasma membrane activity but reduced expression of energetic stress response genes. Differentiation results in reduced mitochondrial membrane potential and decreased robustness toward perturbations with 6 hydroxydopamine. We are convinced that the presented differentiation method will leverage genetic and chemical high-throughput screening projects targeting pathways that are involved in the selective vulnerability of neurons with high energetic stress levels. PMID- 26738529 TI - Voxel-Based Morphometry for Separation of Schizophrenia From Other Types of Psychosis in First-Episode Psychosis: Diagnostic Test Review. AB - Subtle but widespread deficit in the cortical and subcortical grey matter is a consistent neuroimaging observation in schizophrenia. Several studies have used voxel based morphometry (VBM) to investigate the nature of this structural deficit. We conducted a diagnostic test review to explore the diagnostic potential of VBM in differentiating schizophrenia from other types of first episode psychoses. PMID- 26738528 TI - Working Memory in Unaffected Relatives of Patients With Schizophrenia: A Meta Analysis of Functional Magnetic Resonance Imaging Studies. AB - Working memory deficits, a core cognitive feature of schizophrenia may arise from dysfunction in the frontal and parietal cortices. Numerous studies have also found abnormal neural activation during working memory tasks in patients' unaffected relatives. The aim of this study was to systematically identify and anatomically localize the evidence for those activation differences across all eligible studies. Fifteen functional magnetic resonance imaging (fMRI) manuscripts, containing 16 samples of 289 unaffected relatives of patients with schizophrenia, and 358 healthy controls were identified that met our inclusion criteria: (1) used a working memory task; and (2) reported standard space coordinates. Activation likelihood estimation (ALE) identified convergence across studies. Compared to healthy controls, patients' unaffected relatives showed decreases in neural activation in the right middle frontal gyrus (BA9), as well as right inferior frontal gyrus (BA44). Increased activation was seen in relatives in the right frontopolar (BA10), left inferior parietal lobe (BA40), and thalamus bilaterally. These results suggest that the familial risk of schizophrenia is expressed in changes in neural activation in the unaffected relatives in the cortical-subcortical working memory network that includes, but is not restricted to the middle prefrontal cortex. PMID- 26738533 TI - MCNP6 model of the University of Washington clinical neutron therapy system (CNTS). AB - A MCNP6 dosimetry model is presented for the Clinical Neutron Therapy System (CNTS) at the University of Washington. In the CNTS, fast neutrons are generated by a 50.5 MeV proton beam incident on a 10.5 mm thick Be target. The production, scattering and absorption of neutrons, photons, and other particles are explicitly tracked throughout the key components of the CNTS, including the target, primary collimator, flattening filter, monitor unit ionization chamber, and multi-leaf collimator. Simulations of the open field tissue maximum ratio (TMR), percentage depth dose profiles, and lateral dose profiles in a 40 cm * 40 cm * 40 cm water phantom are in good agreement with ionization chamber measurements. For a nominal 10 * 10 field, the measured and calculated TMR values for depths of 1.5 cm, 5 cm, 10 cm, and 20 cm (compared to the dose at 1.7 cm) are within 0.22%, 2.23%, 4.30%, and 6.27%, respectively. For the three field sizes studied, 2.8 cm * 2.8 cm, 10.4 cm * 10.3 cm, and 28.8 cm * 28.8 cm, a gamma test comparing the measured and simulated percent depth dose curves have pass rates of 96.4%, 100.0%, and 78.6% (depth from 1.5 to 15 cm), respectively, using a 3% or 3 mm agreement criterion. At a representative depth of 10 cm, simulated lateral dose profiles have in-field (? 10% of central axis dose) pass rates of 89.7% (2.8 cm * 2.8 cm), 89.6% (10.4 cm * 10.3 cm), and 100.0% (28.8 cm * 28.8 cm) using a 3% and 3 mm criterion. The MCNP6 model of the CNTS meets the minimum requirements for use as a quality assurance tool for treatment planning and provides useful insights and information to aid in the advancement of fast neutron therapy. PMID- 26738530 TI - Schizophrenia Spectrum Disorders in a Danish 22q11.2 Deletion Syndrome Cohort Compared to the Total Danish Population--A Nationwide Register Study. AB - OBJECTIVE: Cross-sectional studies have shown associations between 22q11.2 deletion syndrome and schizophrenia. However, large-scale prospective studies have been lacking. We, therefore, conducted the first large-scale population based study on the risk of being diagnosed with schizophrenia in persons identified with 22q11.2 deletion syndrome. METHODS: Danish nationwide registers were linked to establish a cohort consisting of all Danish citizens born during 1955-2004 and the cohort was followed from January 1, 1994 until December 31, 2013. Data were analyzed using survival analyses and adjusted for calendar year, age, sex, and parental mental health history. RESULTS: A total of 156 individuals with 22q11.2 deletion syndrome were identified, out of which 6 individuals were diagnosed with schizophrenia spectrum disorders following identification with 22q11 deletion syndrome. Identified carriers of 22q11.2 deletion had an 8.13(95% CI: 3.65-18.09) fold increased risk of schizophrenia spectrum disorder. CONCLUSIONS: Carriers of a 22q11.2 deletion who had been clinically identified had a highly increased risk of schizophrenia spectrum disorders. PMID- 26738536 TI - Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma. AB - Cutaneous T-cell lymphoma (CTCL) is characterized by proliferation of malignant T cells in a chronic inflammatory environment. With disease progression, bacteria colonize the compromised skin barrier and half of CTCL patients die of infection rather than from direct organ involvement by the malignancy. Clinical data indicate that bacteria play a direct role in disease progression, but little is known about the mechanisms involved. Here, we demonstrate that bacterial isolates containing staphylococcal enterotoxin A (SEA) from the affected skin of CTCL patients, as well as recombinant SEA, stimulate activation of signal transducer and activator of transcription 3 (STAT3) and upregulation of interleukin (IL)-17 in immortalized and primary patient-derived malignant and nonmalignant T cells. Importantly, SEA induces STAT3 activation and IL-17 expression in malignant T cells when cocultured with nonmalignant T cells, indicating an indirect mode of action. In accordance, malignant T cells expressing an SEA-nonresponsive T-cell receptor variable region beta chain are nonresponsive to SEA in monoculture but display strong STAT3 activation and IL-17 expression in cocultures with SEA responsive nonmalignant T cells. The response is induced via IL-2 receptor common gamma chain cytokines and a Janus kinase 3 (JAK3)-dependent pathway in malignant T cells, and blocked by tofacitinib, a clinical-grade JAK3 inhibitor. In conclusion, we demonstrate that SEA induces cell cross talk-dependent activation of STAT3 and expression of IL-17 in malignant T cells, suggesting a mechanism whereby SEA-producing bacteria promote activation of an established oncogenic pathway previously implicated in carcinogenesis. PMID- 26738537 TI - A systems approach to hemostasis: 4. How hemostatic thrombi limit the loss of plasma-borne molecules from the microvasculature. AB - Previous studies have shown that hemostatic thrombi formed in response to penetrating injuries have a core of densely packed, fibrin-associated platelets overlaid by a shell of less-activated, loosely packed platelets. Here we asked, first, how the diverse elements of this structure combine to stem the loss of plasma-borne molecules and, second, whether antiplatelet agents and anticoagulants that perturb thrombus structure affect the re-establishment of a tight vascular seal. The studies combined high-resolution intravital microscopy with a photo-activatable fluorescent albumin marker to simultaneously track thrombus formation and protein transport following injuries to mouse cremaster muscle venules. The results show that protein loss persists after red cell loss has ceased. Blocking platelet deposition with an alphaIIbbeta3antagonist delays vessel sealing and increases extravascular protein accumulation, as does either inhibiting adenosine 5'-diphosphate (ADP) P2Y12receptors or reducing integrin dependent signaling and retraction. In contrast, sealing was unaffected by introducing hirudin to block fibrin accumulation or a Gi2alpha gain-of-function mutation to expand the thrombus shell. Collectively, these observations describe a novel approach for studying vessel sealing after injury in real time in vivo and show that (1) the core/shell architecture previously observed in arterioles also occurs in venules, (2) plasma leakage persists well beyond red cell escape and mature thrombus formation, (3) the most critical events for limiting plasma extravasation are the stable accumulation of platelets, ADP-dependent signaling, and the emergence of a densely packed core, not the accumulation of fibrin, and (4) drugs that affect platelet accumulation and packing can delay vessel sealing, permitting protein escape to continue. PMID- 26738538 TI - Mouse host unlicensed NK cells promote donor allogeneic bone marrow engraftment. AB - Natural killer (NK) cells exist as subsets based on expression of inhibitory receptors that recognize major histocompatibility complex I (MHCI) molecules. NK cell subsets bearing MHCI binding receptors for self-MHCI have been termed as "licensed" and exhibit a higher ability to respond to stimuli. In the context of bone marrow transplantation (BMT), host licensed-NK (L-NK) cells have also been demonstrated to be responsible for the acute rejection of allogeneic and MHCI deficient BM cells (BMCs) in mice after lethal irradiation. However, the role of recipient unlicensed-NK (U-NK) cells has not been well established with regard to allogeneic BMC resistance. After NK cell stimulation, the prior depletion of host L-NK cells resulted in a marked increase of donor engraftment compared with the untreated group. Surprisingly, this increased donor engraftment was reduced after total host NK cell depletion, indicating that U-NK cells can actually promote donor allogeneic BMC engraftment. Furthermore, direct coculture of U-NK cells with allogeneic but not syngeneic BMCs resulted in increased colony-forming unit cell growth in vitro, which was at least partially mediated by granulocyte macrophage colony-stimulating factor (GM-CSF) production. These data demonstrate that host NK cell subsets exert markedly different roles in allogeneic BMC engraftment where host L- and U-NK cells reject or promote donor allogeneic BMC engraftment, respectively. PMID- 26738539 TI - Arf6 controls platelet spreading and clot retraction via integrin alphaIIbbeta3 trafficking. AB - Platelet and megakaryocyte endocytosis is important for loading certain granule cargo (ie, fibrinogen [Fg] and vascular endothelial growth factor); however, the mechanisms of platelet endocytosis and its functional acute effects are understudied. Adenosine 5'-diphosphate-ribosylation factor 6 (Arf6) is a small guanosine triphosphate-binding protein that regulates endocytic trafficking, especially of integrins. To study platelet endocytosis, we generated platelet specific Arf6 knockout (KO) mice. Arf6 KO platelets had less associated Fg suggesting that Arf6 affects alphaIIbbeta3-mediated Fg uptake and/or storage. Other cargo was unaffected. To measure Fg uptake, mice were injected with biotinylated- or fluorescein isothiocyanate (FITC)-labeled Fg. Platelets from the injected Arf6 KO mice showed lower accumulation of tagged Fg, suggesting an uptake defect. Ex vivo, Arf6 KO platelets were also defective in FITC-Fg uptake and storage. Immunofluorescence analysis showed initial trafficking of FITC-Fg to a Rab4-positive compartment followed by colocalization with Rab11-positive structures, suggesting that platelets contain and use both early and recycling endosomes. Resting and activated alphaIIbbeta3 levels, as measured by flow cytometry, were unchanged; yet, Arf6 KO platelets exhibited enhanced spreading on Fg and faster clot retraction. This was not the result of alterations in alphaIIbbeta3 signaling, because myosin light-chain phosphorylation and Rac1/RhoA activation were unaffected. Consistent with the enhanced clot retraction and spreading, Arf6 KO mice showed no deficits in tail bleeding or FeCl3-induced carotid injury assays. Our studies present the first mouse model for defining the functions of platelet endocytosis and suggest that altered integrin trafficking may affect the efficacy of platelet function. PMID- 26738544 TI - Corrigendum. AB - Azab S, Hirshon JM, Hayes B, et al. Epidemiology of acute poisoning in children presenting to the Poisoning Treatment Center at Ain Shams University in Cairo, Egypt, 2009-2013. Clin Toxicol 2015;54:20-26. http://dx.doi.org/10.3109/15563650.2015.1112014. When the above article was published online and in print, the name of Jon Mark Hirshon was incorrectly spelt. In addition, the affiliation for Gordon Smith was incorrectly listed and should have been given as "Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA".The authors apologise for this error. PMID- 26738543 TI - An inverted dielectrophoretic device for analysis of attached single cell mechanics. AB - Dielectrophoresis (DEP), the force induced on a polarizable body by a non-uniform electric field, has been widely used to manipulate single cells in suspension and analyze their stiffness. However, most cell types do not naturally exist in suspension but instead require attachment to the tissue extracellular matrix in vivo. Cells alter their cytoskeletal structure when they attach to a substrate, which impacts cell stiffness. It is therefore critical to be able to measure mechanical properties of cells attached to a substrate. We present a novel inverted quadrupole dielectrophoretic device capable of measuring changes in the mechanics of single cells attached to a micropatterned polyacrylamide gel. The device is positioned over a cell of defined size, a directed DEP pushing force is applied, and cell centroid displacement is dynamically measured by optical microscopy. Using this device, single endothelial cells showed greater centroid displacement in response to applied DEP pushing force following actin cytoskeleton disruption by cytochalasin D. In addition, transformed mammary epithelial cell (MCF10A-NeuT) showed greater centroid displacement in response to applied DEP pushing force compared to untransformed cells (MCF10A). DEP device measurements were confirmed by showing that the cells with greater centroid displacement also had a lower elastic modulus by atomic force microscopy. The current study demonstrates that an inverted DEP device can determine changes in single attached cell mechanics on varied substrates. PMID- 26738545 TI - Effects of Parental Temperature and Nitrate on Seed Performance are Reflected by Partly Overlapping Genetic and Metabolic Pathways. AB - Seed performance is affected by the seed maturation environment, and previously we have shown that temperature, nitrate and light intensity were the most influential environmental factors affecting seed performance. Seeds developed in these environments were selected to assess the underlying metabolic pathways, using a combination of transcriptomics and metabolomics. These analyses revealed that the effects of the parental temperature and nitrate environments were reflected by partly overlapping genetic and metabolic networks, as indicated by similar changes in the expression levels of metabolites and transcripts. Nitrogen metabolism-related metabolites (asparagine, gamma-aminobutyric acid and allantoin) were significantly decreased in both low temperature (15 degrees C) and low nitrate (N0) maturation environments. Correspondingly, nitrogen metabolism genes (ALLANTOINASE, NITRATE REDUCTASE 1, NITRITE REDUCTASE 1 and NITRILASE 4) were differentially regulated in the low temperature and nitrate maturation environments, as compared with control conditions. High light intensity during seed maturation increased galactinol content, and displayed a high correlation with seed longevity. Low light had a genotype-specific effect on cell surface-encoding genes in the DELAY OF GERMINATION 6-near isogenic line (NILDOG6). Overall, the integration of phenotypes, metabolites and transcripts led to new insights into the regulation of seed performance. PMID- 26738546 TI - Diversity and Evolution of Ascorbate Peroxidase Functions in Chloroplasts: More Than Just a Classical Antioxidant Enzyme? AB - Reactive oxygen species (ROS) have dual functions in plant cells as cytotoxic molecules and emergency signals. The balance between the production and scavenging of these molecules in chloroplasts, major sites for the production of ROS, is one of the key determinants for plant acclimation to stress conditions. The water-water cycle is a crucial regulator of ROS levels in chloroplasts. In this cycle, the stromal and thylakoid membrane-attached isoforms of ascorbate peroxidase (sAPX and tAPX, respectively) are involved in the metabolism of H2O2 Current genome and phylogenetic analyses suggest that the first monofunctional APX was generated as sAPX in unicellular green algae, and that tAPX occurred in multicellular charophytes during plant evolution. Chloroplastic APXs, especially tAPX, have been considered to be the source of a bottleneck in the water-water cycle, at least in higher plants, because of their high susceptibility to H2O2 A number of studies have succeeded in improving plant stress resistance by reinforcing the fragile characteristics of the enzymes. However, researchers have unexpectedly failed to find a 'stress-sensitive phenotype' among loss-of-function mutants, at least in laboratory conditions. Interestingly, the susceptibility of enzymes to H2O2 may have been acquired during plant evolution, thereby allowing for the flexible use of H2O2 as a signaling molecule in plants, and this is supported by growing lines of evidence for the physiological significance of chloroplastic H2O2 as a retrograde signal in plant stress responses. By overviewing historical, biochemical, physiological and genetic studies, we herein discuss the diverse functions of chloroplastic APXs as antioxidant enzymes and signaling modulators. PMID- 26738547 TI - Arabidopsis FH1 Formin Affects Cotyledon Pavement Cell Shape by Modulating Cytoskeleton Dynamics. AB - Plant cell morphogenesis involves concerted rearrangements of microtubules and actin microfilaments. We previously reported that FH1, the main Arabidopsis thaliana housekeeping Class I membrane-anchored formin, contributes to actin dynamics and microtubule stability in rhizodermis cells. Here we examine the effects of mutations affecting FH1 (At3g25500) on cell morphogenesis and above ground organ development in seedlings, as well as on cytoskeletal organization and dynamics, using a combination of confocal and variable angle epifluorescence microscopy with a pharmacological approach. Homozygous fh1 mutants exhibited cotyledon epinasty and had larger cotyledon pavement cells with more pronounced lobes than the wild type. The pavement cell shape alterations were enhanced by expression of the fluorescent microtubule marker GFP-microtubule-associated protein 4 (MAP4). Mutant cotyledon pavement cells exhibited reduced density and increased stability of microfilament bundles, as well as enhanced dynamics of microtubules. Analogous results were also obtained upon treatments with the formin inhibitor SMIFH2 (small molecule inhibitor of formin homology 2 domains). Pavement cell shape in wild-type (wt) and fh1 plants in some situations exhibited a differential response towards anti-cytoskeletal drugs, especially the microtubule disruptor oryzalin. Our observations indicate that FH1 participates in the control of microtubule dynamics, possibly via its effects on actin, subsequently influencing cell morphogenesis and macroscopic organ development. PMID- 26738548 TI - A Low Glutathione Redox State Couples with a Decreased Ascorbate Redox Ratio to Accelerate Flowering in Oncidium Orchid. AB - Glutathione (GSH) plays multiple roles in plants, including stress defense and regulation of growth/development. Previous studies have demonstrated that the ascorbate (AsA) redox state is involved in flowering initiation in Oncidium orchid. In this study, we discovered that a significantly decreased GSH content and GSH redox ratio are correlated with a decline in the AsA redox state during flowering initiation and high ambient temperature-induced flowering. At the same time, the expression level and enzymatic activity of GSH redox-regulated genes, glutathione reductase (GR1), and the GSH biosynthesis genes gamma glutamylcysteine synthetase (GSH1) and glutathione synthase (GSH2), are down regulated. Elevating dehydroascorbate (DHA) content in Oncidium by artificial addition of DHA resulted in a decreased AsA and GSH redox ratio, and enhanced dehydroascorbate reductase (DHAR) activity. This demonstrated that the lower GSH redox state could be influenced by the lower AsA redox ratio. Moreover, exogenous application of buthionine sulfoximine (BSO), to inhibit GSH biosynthesis, and glutathione disulfide (GSSG), to decrease the GSH redox ratio, also caused early flowering. However, spraying plants with GSH increased the GSH redox ratio and delayed flowering. Furthermore, transgenic Arabidopsis overexpressing Oncidium GSH1, GSH2 and GR1 displayed a high GSH redox ratio as well as delayed flowering under high ambient temperature treatment, while pad2, cad2 and gr1 mutants exhibited early flowering and a low GSH redox ratio. In conclusion, our results provide evidence that the decreased GSH redox state is linked to the decline in the AsA redox ratio and mediated by down-regulated expression of GSH metabolism related genes to affect flowering time in Oncidium orchid. PMID- 26738549 TI - Identification of a Major Lipid Droplet Protein in a Marine Diatom Phaeodactylum tricornutum. AB - Various kinds of organisms, including microalgae, accumulate neutral lipids in distinct intracellular compartments called lipid droplets. Generally, lipid droplets are generated from the endoplasmic reticulum, and particular proteins localize on their surface. Some of these proteins function as structural proteins to prevent fusion between the lipid droplets, and the others could have an enzymatic role or might be involved in intracellular membrane trafficking. However, information about lipid droplet proteins in microalgae is scarce as compared with that in animals and land plants. We focused on the oil-producing, marine, pennate diatom Phaeodactylum tricornutum that forms lipid droplets during nitrogen deprivation and we investigated the proteins located on the lipid droplets. After 6 d of cultivation in a nitrate-deficient medium, the mature lipid droplets were isolated by sucrose density gradient centrifugation. Proteomic analyses revealed five proteins, with Stramenopile-type lipid droplet protein (StLDP) being the most abundant protein in the lipid droplet fraction. Although the primary sequence of StLDP did not have homology to any known lipid droplet proteins, StLDP had a central hydrophobic domain. This structural feature is also detected in oleosin of land plants and in lipid droplet surface protein (LDSP) of Nannochloropsis species. As a proline knot motif of oleosin, conservative proline residues existed in the hydrophobic domain. StLDP was up regulated during nitrate deprivation, and fluctuations of StLDP expression levels corresponded to the size of the lipid droplets. PMID- 26738551 TI - Re: Capsule to Calculus Optical Dissection for Tract Creation During Difficult Percutaneous Nephrolithotomy (From: Thummar HG, Khater U, Gupta K, Gupta M. 2015;29. doi: 10.1089/vid.2015.0009). PMID- 26738550 TI - Nutrition support practices in critically ill head-injured patients: a global perspective. AB - BACKGROUND: Critical illness following head injury is associated with a hypermetabolic state but there are insufficient epidemiological data describing acute nutrition delivery to this group of patients. Furthermore, there is little information describing relationships between nutrition and clinical outcomes in this population. METHODS: We undertook an analysis of observational data, collected prospectively as part of International Nutrition Surveys 2007-2013, and extracted data obtained from critically ill patients with head trauma. Our objective was to describe global nutrition support practices in the first 12 days of hospital admission after head trauma, and to explore relationships between energy and protein intake and clinical outcomes. Data are presented as mean (SD), median (IQR), or percentages. RESULTS: Data for 1045 patients from 341 ICUs were analyzed. The age of patients was 44.5 (19.7) years, 78% were male, and median ICU length of stay was 13.1 (IQR 7.9-21.6) days. Most patients (94%) were enterally fed but received only 58% of estimated energy and 53% of estimated protein requirements. Patients from an ICU with a feeding protocol had greater energy and protein intakes (p <0.001, 0.002 respectively) and were more likely to survive (OR 0.65; 95% CI 0.42-0.99; p = 0.043) than those without. Energy or protein intakes were not associated with mortality. However, a greater energy and protein deficit was associated with longer times until discharge alive from both ICU and hospital (all p <0.001). CONCLUSION: Nutritional deficits are commonplace in critically ill head-injured patients and these deficits are associated with a delay to discharge alive. PMID- 26738552 TI - Biodiversity patterns of plankton assemblages at the extremes of the Red Sea. AB - The diversity of microbial plankton has received limited attention in the main basin of the Red Sea. This study investigates changes in the community composition and structure of prokaryotes and eukaryotes at the extremes of the Red Sea along cross-shelf gradients and between the surface and deep chlorophyll maximum. Using molecular methods to target both the 16S and 18S rRNA genes, it was observed that the dominant prokaryotic classes were Acidimicrobiia, Alphaproteobacteria and Cyanobacteria, regardless of the region and depth. The eukaryotes Syndiniophyceae and Dinophyceae between them dominated in the north, with Bacillariophyceae and Mamiellophyceae more prominent in the southern region. Significant differences were observed for prokaryotes and eukaryotes for region, depth and distance from shore. Similarly, it was noticed that communities became less similar with increasing distance from the shore. Canonical correspondence analysis at the class level showed that Mamiellophyceae and Bacillariophyceae correlated with increased nutrients and chlorophyll a found in the southern region, which is influenced by the input of Gulf of Aden Intermediate Water. PMID- 26738553 TI - Virome-associated antibiotic-resistance genes in an experimental aquaculture facility. AB - We report the comprehensive characterization of viral and microbial communities within an aquaculture wastewater sample, by a shotgun sequencing and 16S rRNA gene profiling metagenomic approach. Caudovirales had the largest representation within the sample, with over 50% of the total taxonomic abundance, whereas approximately 30% of the total open reading frames (ORFs) identified were from eukaryotic viruses (Mimiviridae and Phycodnaviridae). Antibiotic resistance genes (ARGs) within the virome accounted for 0.85% of the total viral ORFs and showed a similar distribution both in virome and in microbiome. Among the ARGs, those encoding proteins involved in the modulation of antibiotic efflux pumps were the most abundant. Interestingly, the taxonomy of the bacterial ORFs identified in the viral metagenome did not reflect the microbial taxonomy as deduced by 16S rRNA gene profiling and shotgun metagenomic analysis. A limited number of ARGs appeared to be mobilized from bacteria to phages or vice versa, together with other bacterial genes encoding products involved in general metabolic functions, even in the absence of any antibiotic treatment within the aquaculture plant. Thus, these results confirm the presence of a complex phage-bacterial network in the aquaculture environment. PMID- 26738554 TI - Are freshwater bacterioplankton indifferent to variable types of amino acid substrates? AB - A wide range of carbon compounds sustain bacterial activity and growth in freshwater ecosystems and the amount and quality of these substrates influence bacterial diversity and metabolic function. Biologically labile low-molecular weight compounds, such as dissolved free amino acids, are particularly important substrates and can fuel as much as 20% of the total heterotrophic production. In this study, we show that extensive laboratory incubations with variable amino acids as substrates caused only minimal differences in bacterial growth rate, growth yield, quantitative amino acid usage, community composition and diversity. This was in marked contrast to incubations under dark or light regimes, where significant responses were observed in bacterial community composition and with higher diversity in the dark incubations. While a few individual taxa still responded to amendment with specific amino acids, our results suggest that compositional shifts in the specific supply of amino acids and possibly also other labile organic substrates have a minor impact on heterotrophic bacterioplankton communities, at least in nutrient rich lakes and compared to other prevailing environmental factors. PMID- 26738555 TI - The fate of antibiotic resistance genes and class 1 integrons following the application of swine and dairy manure to soils. AB - The goal of this study was to determine the fate of antibiotic resistance genes (ARGs) and class 1 integrons following the application of swine and dairy manure to soil. Soil microcosms were amended with either manure from swine fed subtherapeutic levels of antibiotics or manure from dairy cows that were given antibiotics only rarely and strictly for veterinary purposes. Microcosms were monitored for 6 months using quantitative PCR targeting 16S rRNA genes (a measure of bacterial biomass), intI1, erm(B), tet(A), tet(W) and tet(X). Swine manure had 10- to 100-fold higher levels of ARGs than the dairy manure, all of which decayed over time after being applied to soil. A modified Collins-Selleck model described the decay of ARGs in the soil microcosms well, particularly the characteristic in which the decay rate declined over time. By the completion of the soil microcosm experiments, ARGs in the dairy manure-amended soils returned to background levels, whereas the ARGs in swine manure remained elevated compared to control microcosms. Our research suggests that the use of subtherapeutic use of antibiotics in animal feed could lead to the accumulation of ARGs in soils to which manure is applied. PMID- 26738556 TI - Antibiotic resistance genes across a wide variety of metagenomes. AB - The distribution of potential clinically relevant antibiotic resistance (AR) genes across soil, water, animal, plant and human microbiomes is not well understood. We aimed to investigate if there were differences in the distribution and relative abundances of resistance genes across a variety of ecological niches. All sequence reads (human, animal, water, soil, plant and insect metagenomes) from the MG-RAST database were downloaded and assembled into a local sequence database. We show that there are many reservoirs of the basic form of resistance genes e.g. blaTEM, but the human and mammalian gut microbiomes contain the widest diversity of clinically relevant resistance genes using metagenomic analysis. The human microbiomes contained a high relative abundance of resistance genes, while the relative abundances varied greatly in the marine and soil metagenomes, when datasets with greater than one million genes were compared. While these results reflect a bias in the distribution of AR genes across the metagenomes, we note this interpretation with caution. Metagenomics analysis includes limits in terms of detection and identification of AR genes in complex and diverse microbiome population. Therefore, if we do not detect the AR gene is it in fact not there or just below the limits of our techniques? PMID- 26738557 TI - Taxonomic analysis of the microbial community in stored sugar beets using high throughput sequencing of different marker genes. AB - Post-harvest colonization of sugar beets accompanied by rot development is a serious problem due to sugar losses and negative impact on processing quality. Studies on the microbial community associated with rot development and factors shaping their structure are missing. Therefore, high-throughput sequencing was applied to describe the influence of environment, plant genotype and storage temperature (8 degrees C and 20 degrees C) on three different communities in stored sugar beets, namely fungi (internal transcribed spacers 1 and 2), Fusarium spp. (elongation factor-1alpha gene fragment) and oomycetes (internal transcribed spacers 1). The composition of the fungal community changed during storage mostly influenced by the storage temperature followed by a weak environmental effect. Botrytis cinerea was the prevalent species at 8 degrees C whereas members of the fungal genera Fusarium and Penicillium became dominant at 20 degrees C. This shift was independent of the plant genotype. Species richness within the genus Fusarium also increased during storage at both temperatures whereas the oomycetes community did not change. Moreover, oomycetes species were absent after storage at 20 degrees C. The results of the present study clearly show that rot development during sugar beet storage is associated with pathogens well known as causal agents of post-harvest diseases in many other crops. PMID- 26738558 TI - Carbon Dioxide Activation by Scandium Atoms and Scandium Monoxide Molecules: Formation and Spectroscopic Characterization of ScCO3 and OCScCO3 in Solid Neon. AB - The reactions of carbon dioxide with scandium monoxide molecules and scandium atoms are investigated using matrix isolation infrared spectroscopy in solid neon. The species formed are identified by the effects of isotopic substitution on their infrared spectra as well as density functional calculations. The results show that the ground state ScO molecule reacts with carbon dioxide to form the carbonate complex ScCO3 spontaneously on annealing. The ground state Sc atom reacts with two carbon dioxide molecules to give the carbonate carbonyl complex OCScCO3 via the previously reported OScCO insertion intermediate on annealing. The observation of these spontaneous reactions is consistent with theoretical predictions that both the Sc + 2CO2 -> OCScCO3 and ScO + CO2 -> ScCO3 reactions are thermodynamically exothermic and are kinetically facile, requiring little or no activation energy. PMID- 26738559 TI - Low immunoglobulin levels increase the risk of severe hypogammaglobulinemia in granulomatosis with polyangiitis patients receiving rituximab. AB - BACKGROUND: Randomized controlled trials and retrospective studies in ANCA associated vasculitis (AAV) concurred that rituximab (RTX) is effective to induce and maintain remission. Infections and hypogammaglobulinemia during RTX were usually infrequent and uncomplicated. But in the Tromso study cohort, 45% of patients with granulomatosis with polyangiitis (GPA) developed hypogammaglobulinemia during RTX maintenance leading to its discontinuation in 62%. METHODS: To explain these differences in outcome when using RTX in AAV to maintain remission, we used statistical structural methods to compare the Tromso study cohort with other published cohorts. RESULTS: GPA patients' characteristics of the Tromso study cohort were not so different compared with other cohorts. Rates of hypogammaglobulinemia and discontinuation of RTX seemed closely related to the cut-off used and to the levels of immunoglobulin (Ig) at baseline. Combination of low IgG serum levels at baseline (7.7 g/L) and low cut-off to define hypogammaglobulinemia in the Tromso study cohort explained the high rate of hypogammaglobulinemia and discontinuation of RTX. CONCLUSIONS: Patients' characteristics in the Tromso study cohort were not skewed, apart from IgG levels. Low IgG level at baseline seemed to contribute the most to hypogammaglobulinemia and its complications. PMID- 26738560 TI - Short-term cessation of statin therapy does not alter aerobic exercise performance in physically active middle-aged adults. AB - OBJECTIVES: Physically active adults may be especially vulnerable to the adverse muscular side effects of statins. We determined if short-term cessation of statin therapy would improve aerobic exercise performance in middle-aged adults engaged in regular aerobic exercise training. METHODS: Physically active middle-aged adults on statin therapy >=6 mo (n = 16; 58 +/- 10 y) or not taking lipid lowering medications (controls) (n = 19; 51 +/- 9 y) completed a peak oxygen consumption (VO2peak) and time to exhaustion test on a cycle ergometer 2-7 d apart. Tests were repeated following 1 mo of statin cessation or a 1 mo period for controls. Questionnaires were administered to assess exercise history and muscle complaints. RESULTS: Statin users reported little or no muscle complaints and participation in aerobic exercise was similar between groups (p>=0.13). The lower VO2peak (37.3 +/- 9.0 vs. 43.1 +/- 4.9 ml/kg/min; p = 0.02) and time to exhaustion (21.9 +/- 4.4 vs. 26.0 +/- 6.3 min; p = 0.04) in statin users versus controls did not persist after controlling for age (p>=0.08). Aerobic exercise performance did not change with 1 mo of statin cessation (p>=0.54). No changes were observed in controls when tests were repeated 1 mo later (p>=0.38). CONCLUSION: Short-term cessation of statin therapy does not alter maximal aerobic capacity or aerobic endurance in physically active middle-aged adults with few or no statin muscle complaints. PMID- 26738561 TI - Antigenic mapping of an H9N2 avian influenza virus reveals two discrete antigenic sites and a novel mechanism of immune escape. AB - H9N2 avian influenza virus is a major cause of poultry production loss across Asia leading to the wide use of vaccines. Efficacy of vaccines is often compromised due to the rapid emergence of antigenic variants. To improve the effectiveness of vaccines in the field, a better understanding of the antigenic epitopes of the major antigen, hemagglutinin, is required. To address this, a panel of nine monoclonal antibodies were generated against a contemporary Pakistani H9N2 isolate, which represents a major Asian H9N2 viral lineage. Antibodies were characterized in detail and used to select a total of 26 unique 'escape' mutants with substitutions across nine different amino acid residues in hemagglutinin including seven that have not been described as antigenic determinants for H9N2 viruses before. Competition assays and structural mapping revealed two novel, discrete antigenic sites "H9-A" and "H9-B". Additionally, a second subset of escape mutants contained amino acid deletions within the hemagglutinin receptor binding site. This constitutes a novel method of escape for group 1 hemagglutinins and could represent an alternative means for H9N2 viruses to overcome vaccine induced immunity. These results will guide surveillance efforts for arising antigenic variants as well as evidence based vaccine seed selection and vaccine design. PMID- 26738562 TI - Identification and classification of small molecule kinases: insights into substrate recognition and specificity. AB - BACKGROUND: Many prokaryotic kinases that phosphorylate small molecule substrates, such as antibiotics, lipids and sugars, are evolutionarily related to Eukaryotic Protein Kinases (EPKs). These Eukaryotic-Like Kinases (ELKs) share the same overall structural fold as EPKs, but differ in their modes of regulation, substrate recognition and specificity-the sequence and structural determinants of which are poorly understood. RESULTS: To better understand the basis for ELK specificity, we applied a Bayesian classification procedure designed to identify sequence determinants responsible for functional divergence. This reveals that a large and diverse family of aminoglycoside kinases, characterized members of which are involved in antibiotic resistance, fall into major sub-groups based on differences in putative substrate recognition motifs. Aminoglycoside kinase substrate specificity follows simple rules of alternating hydroxyl and amino groups that is strongly correlated with variations at the DFG + 1 position. CONCLUSIONS: Substrate specificity determining features in small molecule kinases are mostly confined to the catalytic core and can be identified based on quantitative sequence and crystal structure comparisons. PMID- 26738563 TI - Premature subclinical atherosclerosis in children and young adults with juvenile idiopathic arthritis. A review considering preventive measures. AB - Many studies show that Juvenile Idiopathic Arthritis (JIA) is associated with early subclinical signs of atherosclerosis. Chronic inflammation per se may be an important driver but other known risk factors, such as dyslipidemia, hypertension, insulin insensitivity, a physically inactive lifestyle, obesity, and tobacco smoking may also contribute substantially. We performed a systematic review of studies through the last 20 years on early signs of subclinical atherosclerosis in children and adolescents with JIA with the purpose of investigating whether possible risk factors, other than inflammation, were considered.We found 13 descriptive cross sectional studies with healthy controls, one intervention study and two studies on adults diagnosed with JIA. Only one study addressed obesity, and physical activity (PA) has only been assessed in one study on adults with JIA and only by self-reporting. This is important as studies on PA in children with JIA have shown that most patients are less physically active than their healthy peers, and as physical inactivity in several large studies of normal schoolchildren is found to be associated with increased clustering of risk factors for cardiovascular disease. It is thus possible that an inactive lifestyle in patients with JIA is an important contributor to development of the subclinical signs of atherosclerosis seen in children with JIA, and that promotion of an active lifestyle in childhood and adolescence may diminish the risk for premature atherosclerotic events in adulthood. PMID- 26738564 TI - Single-Readout High-Density Memristor Crossbar. AB - High-density memristor-crossbar architecture is a very promising technology for future computing systems. The simplicity of the gateless-crossbar structure is both its principal advantage and the source of undesired sneak-paths of current. This parasitic current could consume an enormous amount of energy and ruin the readout process. We introduce new adaptive-threshold readout techniques that utilize the locality and hierarchy properties of the computer-memory system to address the sneak-paths problem. The proposed methods require a single memory access per pixel for an array readout. Besides, the memristive crossbar consumes an order of magnitude less power than state-of-the-art readout techniques. PMID- 26738567 TI - Deterministic Control of Magnetization Dynamics in Reconfigurable Nanomagnetic Networks for Logic Applications. AB - Information processing based on nanomagnetic networks is an emerging area of spintronics, as the energy consumption and integration density of the current semiconductor technology are reaching their fundamental limits. Nanomagnet-based devices rely on manipulating the magnetic ground states for device operations. While the static behavior of nanomagnets has been explored, little information is available on their dynamic behavior. Here, we demonstrate an additional functionality based on their collective dynamic response and explore the concept utilizing networks of bistable rhomboid nanomagnets. The control of the magnetic ground states of the networks was achieved by the geometrical design of the nanomagnets instead of the conventional interelement dipolar coupling. Dynamic responses of both the ferromagnetic and antiferromagnetic ground states were monitored using broadband ferromagnetic resonance spectroscopy, the Brillouin light scattering technique, and direct magnetic force microscopy. Micromagnetic simulations and numerical calculations validate our experimental observations. This method would have potential implications for low-power magnonic devices based on reconfigurable microwave properties. PMID- 26738565 TI - Heterogeneous alleles comprising G6PD deficiency trait in West Africa exert contrasting effects on two major clinical presentations of severe malaria. AB - BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency exhibits considerable allelic heterogeneity which manifests with variable biochemical and clinical penetrance. It has long been thought that G6PD deficiency confers partial protection against severe malaria, however prior genetic association studies have disagreed with regard to the strength and specificity of a protective effect, which might reflect differences in the host genetic background, environmental influences, or in the specific clinical phenotypes considered. METHODS: A case-control association study of severe malaria was conducted in The Gambia, a region in West Africa where there is considerable allelic heterogeneity underlying expression of G6PD deficiency trait, evaluating the three major nonsynonymous polymorphisms known to be associated with enzyme deficiency (A968G, T542A, and C202T) in a cohort of 3836 controls and 2379 severe malaria cases. RESULTS: Each deficiency allele exhibited a similar trend toward protection against severe malaria overall (15-26% reduced risk); however, in stratifying severe malaria to two of its constituent clinical subphenotypes, severe malarial anaemia (SMA) and cerebral malaria (CM), the three deficiency alleles exhibited trends of opposing effect, with risk conferred to SMA and protection with respect to CM. To assess the overall effect of G6PD deficiency trait, deficiency alleles found across all three loci were pooled. G6PD deficiency trait was found to be significantly associated with protection from severe malaria overall (OR 0.83 [0.75-0.92], P = 0.0006), but this was limited to CM (OR 0.73 [0.61-0.87], P = 0.0005), with a trend toward increased risk for SMA, especially in fully-deficient individuals (OR 1.43 [0.99-2.08], P = 0.056). Sex stratified testing largely comported with these results, with evidence suggesting that protection by G6PD deficiency trait is conferred to both males and females, though susceptibility to SMA may be restricted to fully-deficient male hemizygotes. CONCLUSIONS: In a part of Africa where multiple alleles contribute to expression of G6PD deficiency trait, these findings clarify and extend previous work done in populations where a single variant predominates, and taken together suggest a causal role for G6PD deficiency trait itself with respect to severe malaria, with opposing effects seen on two major clinical subphenotypes. PMID- 26738566 TI - Modeling autosomal dominant optic atrophy using induced pluripotent stem cells and identifying potential therapeutic targets. AB - BACKGROUND: Many retinal degenerative diseases are caused by the loss of retinal ganglion cells (RGCs). Autosomal dominant optic atrophy is the most common hereditary optic atrophy disease and is characterized by central vision loss and degeneration of RGCs. Currently, there is no effective treatment for this group of diseases. However, stem cell therapy holds great potential for replacing lost RGCs of patients. Compared with embryonic stem cells, induced pluripotent stem cells (iPSCs) can be derived from adult somatic cells, and they are associated with fewer ethical concerns and are less prone to immune rejection. In addition, patient-derived iPSCs may provide us with a cellular model for studying the pathogenesis and potential therapeutic agents for optic atrophy. METHODS: In this study, iPSCs were obtained from patients carrying an OPA1 mutation (OPA1 (+/-) iPSC) that were diagnosed with optic atrophy. These iPSCs were differentiated into putative RGCs, which were subsequently characterized by using RGC-specific expression markers BRN3a and ISLET-1. RESULTS: Mutant OPA1 (+/-) -iPSCs exhibited significantly more apoptosis and were unable to efficiently differentiate into RGCs. However, with the addition of neural induction medium, Noggin, or estrogen, OPA1 (+/-) -iPSC differentiation into RGCs was promoted. CONCLUSIONS: Our results suggest that apoptosis mediated by OPA1 mutations plays an important role in the pathogenesis of optic atrophy, and both noggin and beta-estrogen may represent potential therapeutic agents for OPA1-related optic atrophy. PMID- 26738568 TI - Global optimization of clusters of rigid molecules using the artificial bee colony algorithm. AB - The global optimization of molecular clusters is an important topic encountered in many fields of chemistry. In our previous work (Phys. Chem. Chem. Phys., 2015, 17, 24173), we successfully applied the recently introduced artificial bee colony (ABC) algorithm to the global optimization of atomic clusters and introduced the corresponding software "ABCluster". In the present work, ABCluster was extended to the optimization of clusters of rigid molecules. Here "rigid" means that all internal degrees of freedom of the constituent molecules are frozen. The algorithm was benchmarked by TIP4P water clusters (H2O)N (N <= 20), for which all global minima were successfully located. It was further applied to various clusters of different chemical nature: 10 microhydration clusters, 4 methanol microsolvation clusters, 4 nonpolar clusters and 2 ion-aromatic clusters. In all the cases we obtained results consistent with previous experimental or theoretical studies. PMID- 26738570 TI - The science to look out for in 2016. PMID- 26738569 TI - TGF-beta1 Upregulates the Expression of Triggering Receptor Expressed on Myeloid Cells 1 in Murine Lungs. AB - Triggering receptor expressed on myeloid cells 1 (TREM-1) increases the expression of TGF-beta family genes, which are known as profibrogenic cytokines in the pathogenesis of pulmonary fibrosis. In this study, we determined whether TGF-beta1 regulated the expression of TREM-1 in a mouse model of pulmonary fibrosis. The expression of TGF-beta1 and TREM-1 was increased on day 7, 14, and 21 after single intratracheal injection of bleomycin (BLM). And there was positive correlation between the expression of TGF-beta1 and TREM-1. TGF-beta1 increased expression of TREM-1 mRNA and protein in a time- and dose-dependent manner in mouse macrophages. The expression of the activator protein 1 (AP-1) was increased in lung tissues from mouse after BLM injection and in mouse macrophages after TGF-beta1 treatment, respectively. TGF-beta1 significantly increased the relative activity of luciferase in the cells transfected with plasmid contenting wild type-promoter of TREM-1. But TGF-beta1 had no effect on the activity of luciferase in the cells transfected with a mutant-TREM1 plasmid carrying mutations in the AP-1 promoter binding site. In conclusion, we found the expression of TREM-1 was increased in lung tissues from mice with pulmonary fibrosis. TGF-beta1 increased the expression of TREM-1 in mouse macrophages partly via the transcription factor AP-1. PMID- 26738571 TI - Come together. PMID- 26738572 TI - Constructive engagement is the key to climate action. PMID- 26738574 TI - China embraces precision medicine on a massive scale. PMID- 26738576 TI - Antarctic clouds studied for first time in five decades. PMID- 26738575 TI - Dogs thwart effort to eradicate Guinea worm. PMID- 26738577 TI - Dutch lead European push to flip journals to open access. PMID- 26738578 TI - The physics of life. PMID- 26738579 TI - Renewables: Share data on wind energy. PMID- 26738581 TI - Climate mitigation: UK budget cuts erode Paris promises. PMID- 26738582 TI - Migrant workers: China boom leaves children behind. PMID- 26738583 TI - Antibodies: Half of samples fail protein-blot tests. PMID- 26738584 TI - Water treatment: Recover wastewater resources locally. PMID- 26738585 TI - Collaboration: Come together to study life's origins. PMID- 26738586 TI - Astrophysics: Why black holes pulse brightly. PMID- 26738587 TI - Virology: Host protein clips bird flu's wings in mammals. PMID- 26738589 TI - Autophagy maintains stemness by preventing senescence. AB - During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia. PMID- 26738591 TI - Evidence for a new phase of dense hydrogen above 325 gigapascals. AB - Almost 80 years ago it was predicted that, under sufficient compression, the H-H bond in molecular hydrogen (H2) would break, forming a new, atomic, metallic, solid state of hydrogen. Reaching this predicted state experimentally has been one of the principal goals in high-pressure research for the past 30 years. Here, using in situ high-pressure Raman spectroscopy, we present evidence that at pressures greater than 325 gigapascals at 300 kelvin, H2 and hydrogen deuteride (HD) transform to a new phase--phase V. This new phase of hydrogen is characterized by substantial weakening of the vibrational Raman activity, a change in pressure dependence of the fundamental vibrational frequency and partial loss of the low-frequency excitations. We map out the domain in pressure temperature space of the suggested phase V in H2 and HD up to 388 gigapascals at 300 kelvin, and up to 465 kelvin at 350 gigapascals; we do not observe phase V in deuterium (D2). However, we show that the transformation to phase IV' in D2 occurs above 310 gigapascals and 300 kelvin. These values represent the largest known isotropic shift in pressure, and hence the largest possible pressure difference between the H2 and D2 phases, which implies that the appearance of phase V of D2 must occur at a pressure of above 380 gigapascals. These experimental data provide a glimpse of the physical properties of dense hydrogen above 325 gigapascals and constrain the pressure and temperature conditions at which the new phase exists. We speculate that phase V may be the precursor to the non-molecular (atomic and metallic) state of hydrogen that was predicted 80 years ago. PMID- 26738590 TI - Repetitive patterns in rapid optical variations in the nearby black-hole binary V404 Cygni. AB - How black holes accrete surrounding matter is a fundamental yet unsolved question in astrophysics. It is generally believed that matter is absorbed into black holes via accretion disks, the state of which depends primarily on the mass accretion rate. When this rate approaches the critical rate (the Eddington limit), thermal instability is supposed to occur in the inner disk, causing repetitive patterns of large-amplitude X-ray variability (oscillations) on timescales of minutes to hours. In fact, such oscillations have been observed only in sources with a high mass-accretion rate, such as GRS 1915+105 (refs 2, 3). These large-amplitude, relatively slow timescale, phenomena are thought to have physical origins distinct from those of X-ray or optical variations with small amplitudes and fast timescales (less than about 10 seconds) often observed in other black-hole binaries-for example, XTE J1118+480 (ref. 4) and GX 339-4 (ref. 5). Here we report an extensive multi-colour optical photometric data set of V404 Cygni, an X-ray transient source containing a black hole of nine solar masses (and a companion star) at a distance of 2.4 kiloparsecs (ref. 8). Our data show that optical oscillations on timescales of 100 seconds to 2.5 hours can occur at mass-accretion rates more than ten times lower than previously thought. This suggests that the accretion rate is not the critical parameter for inducing inner-disk instabilities. Instead, we propose that a long orbital period is a key condition for these large-amplitude oscillations, because the outer part of the large disk in binaries with long orbital periods will have surface densities too low to maintain sustained mass accretion to the inner part of the disk. The lack of sustained accretion--not the actual rate--would then be the critical factor causing large-amplitude oscillations in long-period systems. PMID- 26738592 TI - Partially oxidized atomic cobalt layers for carbon dioxide electroreduction to liquid fuel. AB - Electroreduction of CO2 into useful fuels, especially if driven by renewable energy, represents a potentially 'clean' strategy for replacing fossil feedstocks and dealing with increasing CO2 emissions and their adverse effects on climate. The critical bottleneck lies in activating CO2 into the CO2(*-) radical anion or other intermediates that can be converted further, as the activation usually requires impractically high overpotentials. Recently, electrocatalysts based on oxide-derived metal nanostructures have been shown to enable CO2 reduction at low overpotentials. However, it remains unclear how the electrocatalytic activity of these metals is influenced by their native oxides, mainly because microstructural features such as interfaces and defects influence CO2 reduction activity yet are difficult to control. To evaluate the role of the two different catalytic sites, here we fabricate two kinds of four-atom-thick layers: pure cobalt metal, and co existing domains of cobalt metal and cobalt oxide. Cobalt mainly produces formate (HCOO(-)) during CO2 electroreduction; we find that surface cobalt atoms of the atomically thin layers have higher intrinsic activity and selectivity towards formate production, at lower overpotentials, than do surface cobalt atoms on bulk samples. Partial oxidation of the atomic layers further increases their intrinsic activity, allowing us to realize stable current densities of about 10 milliamperes per square centimetre over 40 hours, with approximately 90 per cent formate selectivity at an overpotential of only 0.24 volts, which outperforms previously reported metal or metal oxide electrodes evaluated under comparable conditions. The correct morphology and oxidation state can thus transform a material from one considered nearly non-catalytic for the CO2 electroreduction reaction into an active catalyst. These findings point to new opportunities for manipulating and improving the CO2 electroreduction properties of metal systems, especially once the influence of both the atomic-scale structure and the presence of oxide are mechanistically better understood. PMID- 26738593 TI - Slab melting as a barrier to deep carbon subduction. AB - Interactions between crustal and mantle reservoirs dominate the surface inventory of volatile elements over geological time, moderating atmospheric composition and maintaining a life-supporting planet. While volcanoes expel volatile components into surface reservoirs, subduction of oceanic crust is responsible for replenishment of mantle reservoirs. Many natural, 'superdeep' diamonds originating in the deep upper mantle and transition zone host mineral inclusions, indicating an affinity to subducted oceanic crust. Here we show that the majority of slab geotherms will intersect a deep depression along the melting curve of carbonated oceanic crust at depths of approximately 300 to 700 kilometres, creating a barrier to direct carbonate recycling into the deep mantle. Low-degree partial melts are alkaline carbonatites that are highly reactive with reduced ambient mantle, producing diamond. Many inclusions in superdeep diamonds are best explained by carbonate melt-peridotite reaction. A deep carbon barrier may dominate the recycling of carbon in the mantle and contribute to chemical and isotopic heterogeneity of the mantle reservoir. PMID- 26738594 TI - Influence of extreme weather disasters on global crop production. AB - In recent years, several extreme weather disasters have partially or completely damaged regional crop production. While detailed regional accounts of the effects of extreme weather disasters exist, the global scale effects of droughts, floods and extreme temperature on crop production are yet to be quantified. Here we estimate for the first time, to our knowledge, national cereal production losses across the globe resulting from reported extreme weather disasters during 1964 2007. We show that droughts and extreme heat significantly reduced national cereal production by 9-10%, whereas our analysis could not identify an effect from floods and extreme cold in the national data. Analysing the underlying processes, we find that production losses due to droughts were associated with a reduction in both harvested area and yields, whereas extreme heat mainly decreased cereal yields. Furthermore, the results highlight ~7% greater production damage from more recent droughts and 8-11% more damage in developed countries than in developing ones. Our findings may help to guide agricultural priorities in international disaster risk reduction and adaptation efforts. PMID- 26738595 TI - The calcium sensor synaptotagmin 7 is required for synaptic facilitation. AB - It has been known for more than 70 years that synaptic strength is dynamically regulated in a use-dependent manner. At synapses with a low initial release probability, closely spaced presynaptic action potentials can result in facilitation, a short-term form of enhancement in which each subsequent action potential evokes greater neurotransmitter release. Facilitation can enhance neurotransmitter release considerably and can profoundly influence information transfer across synapses, but the underlying mechanism remains a mystery. One proposed mechanism is that a specialized calcium sensor for facilitation transiently increases the probability of release, and this sensor is distinct from the fast sensors that mediate rapid neurotransmitter release. Yet such a sensor has never been identified, and its very existence has been disputed. Here we show that synaptotagmin 7 (Syt7) is a calcium sensor that is required for facilitation at several central synapses. In Syt7-knockout mice, facilitation is eliminated even though the initial probability of release and the presynaptic residual calcium signals are unaltered. Expression of wild-type Syt7 in presynaptic neurons restored facilitation, whereas expression of a mutated Syt7 with a calcium-insensitive C2A domain did not. By revealing the role of Syt7 in synaptic facilitation, these results resolve a longstanding debate about a widespread form of short-term plasticity, and will enable future studies that may lead to a deeper understanding of the functional importance of facilitation. PMID- 26738597 TI - The unsung heroes of scientific software. PMID- 26738596 TI - Species difference in ANP32A underlies influenza A virus polymerase host restriction. AB - Influenza pandemics occur unpredictably when zoonotic influenza viruses with novel antigenicity acquire the ability to transmit amongst humans. Host range breaches are limited by incompatibilities between avian virus components and the human host. Barriers include receptor preference, virion stability and poor activity of the avian virus RNA-dependent RNA polymerase in human cells. Mutants of the heterotrimeric viral polymerase components, particularly PB2 protein, are selected during mammalian adaptation, but their mode of action is unknown. We show that a species-specific difference in host protein ANP32A accounts for the suboptimal function of avian virus polymerase in mammalian cells. Avian ANP32A possesses an additional 33 amino acids between the leucine-rich repeats and carboxy-terminal low-complexity acidic region domains. In mammalian cells, avian ANP32A rescued the suboptimal function of avian virus polymerase to levels similar to mammalian-adapted polymerase. Deletion of the avian-specific sequence from chicken ANP32A abrogated this activity, whereas its insertion into human ANP32A, or closely related ANP32B, supported avian virus polymerase function. Substitutions, such as PB2(E627K), were rapidly selected upon infection of humans with avian H5N1 or H7N9 influenza viruses, adapting the viral polymerase for the shorter mammalian ANP32A. Thus ANP32A represents an essential host partner co opted to support influenza virus replication and is a candidate host target for novel antivirals. PMID- 26738599 TI - Essential Tremor with Head Tremor: Trait or State? PMID- 26738601 TI - Effect of calcium cyanamide, ammonium bicarbonate and lime mixture, and ammonia water on survival of Ralstonia solanacearum and microbial community. AB - The inorganic nitrogenous amendments calcium cyanamide (CC), ammonia water (AW), and a mixture of ammonium bicarbonate with lime (A+L) are popularly used as fumigants to control soil-borne disease in China. However, it is unclear which of these fumigants is more effective in controlling R. solanacearum. This present study compared the efficiencies of the three nitrogenous amendments listed above at four nitrogen levels in suppressing the survival of R. solanacearum in soil. The CC showed the best ability to suppress R. solanacearum due to its highest capacity to increase soil and NO2(-) contents and pH. However, AW was more suitable to controlling bacterial wilt caused by R. solanacearum because it had a lower cost and its application rate of 0.25 g N kg(-1) soil could effectively suppress the survival of R. solanacearum. Additionally, soil microbial activity and community populations were restored to their initial state four weeks after the application of each fumigant, indicating that the three fumigants had few detrimental impacts on soil microbial activity and community structure with an exception of the suppression of R. solanacearum. The present study provides guidance for the selection of a suitable alkaline nitrogenous amendment and its application rate in controlling bacterial wilt. PMID- 26738603 TI - Large-Area Nanoparticle Films by Continuous Automated Langmuir-Blodgett Assembly and Deposition. AB - The operating parameters and resulting surface morphology of automated Langmuir Blodgett deposition of monosized micrometer-scale silica colloids from an aqueous suspension are investigated. This apparatus allows continuous roll-to-roll deposition of particles into well-ordered arrays. The reproducible deposition of particle monolayers at low to moderate deposition rates at web speeds of less than 10 mm/s is possible and accurately characterized by a simple mass balance of particles deposited from solution. At faster deposition rates, Landau-Levich flow increases the film thickness such that flow instabilities hinder uniform particle deposition. A simple phase diagram outlines transitions from dispersed to multilayer coatings and from uniform to erratic deposition patterns. While the threshold of maximum deposition rate is well-defined for these conditions, changing operating parameters, particle size, and fluid viscosity and evaporation rate, the maximum speed can be increased significantly. PMID- 26738600 TI - Molecular pathogenesis of sporadic colorectal cancers. AB - Colorectal cancer (CRC) results from the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic mucosa to adenocarcinoma. Approximately 75% of CRCs are sporadic and occur in people without genetic predisposition or family history of CRC. During the past two decades, sporadic CRCs were classified into three major groups according to frequently altered/mutated genes. These genes have been identified by linkage analyses of cancer-prone families and by individual mutation analyses of candidate genes selected on the basis of functional data. In the first half of this review, we describe the genetic pathways of sporadic CRCs and their clinicopathologic features. Recently, large-scale genome analyses have detected many infrequently mutated genes as well as a small number of frequently mutated genes. These infrequently mutated genes are likely described in a limited number of pathways. Gene-oriented models of CRC progression are being replaced by pathway-oriented models. In the second half of this review, we summarize the present knowledge of this research field and discuss its prospects. PMID- 26738604 TI - Corrigendum: 3D hierarchical porous graphene aerogel with tunable meso-pores on graphene nanosheets for high-performance energy storage. PMID- 26738608 TI - Central nervous system EBV lymphoproliferative disorder in a patient with rhabdomyosarcoma. AB - Epstein-Barr virus associated lymphoproliferative disorder (EBV-LPD) occurs in patients with immunodeficiency, but it has not been well described in patients who have received chemotherapy for solid tumors. We describe a child with rhabdomyosarcoma who developed isolated central nervous system (CNS) EBV-LPD during combination chemotherapy with vincristine, actinomycin D and cyclophosphamide. The patient was treated with high-dose methotrexate (HD-MTX) for CNS EBV-LPD and then treated with rituximab in addition to HD-MTX because of the emergence of LPD in the liver. I.v. rituximab combined with HD-MTX might be effective therapy for CNS EBV-LPD. PMID- 26738610 TI - Benzo[a]pyrene/aryl hydrocarbon receptor signaling inhibits osteoblastic differentiation and collagen synthesis of human periodontal ligament cells. AB - BACKGROUND AND OBJECTIVE: Cigarette smoking has detrimental effects on periodontal tissue, and is known to be a risk factor for periodontal disease, including the loss of alveolar bone and ligament tissue. However, the direct effects of cigarette smoking on periodontal tissue remain unclear. Recently, we demonstrated that benzo[a]pyrene (BaP), which is a prototypic member of polycyclic aryl hydrocarbons and forms part of the content of cigarettes, attenuated the expression of extracellular matrix remodeling-related genes in human periodontal ligament (PDL) cells (HPDLCs). Thus, we aimed to examine the effects of BaP on the osteoblastic differentiation and collagen synthesis of HPDLCs. MATERIAL AND METHODS: HPDLCs were obtained from healthy molars of three patients, and quantitative reverse transcription-polymerase chain reaction were performed for gene expression analyses of cytochrome P450 1A1 and 1B1, alkaline phosphatase, bone sialoprotein and aryl hydrocarbon receptor (AhR), a receptor for polycyclic aryl hydrocarbons. We have also analyzed the role of the AhR, using 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191), which is an AhR antagonist. RESULTS: The treatment of HPDLCs with BaP reduced mRNA expression of osteogenic genes, alkaline phosphatase activity, mineralization and collagen synthesis. The treatment with CH-223191 subsequently restored the observed suppressive effects of BaP on HPDLCs. CONCLUSIONS: The present results suggest that BaP exerts inhibitory effects on the maintenance of homeostasis in HPDL tissue, such as osteoblastic differentiation and collagen synthesis of HPDLCs, and that this signaling pathway could be suppressed by preventing the transactivity of AhR. Future studies may unveil a role for the inhibition of AhR as a promising therapeutic agent for periodontal disease caused by cigarette smoking. PMID- 26738606 TI - Insulin-like growth factor 1 receptor expression and IGF1R 3129G > T polymorphism are associated with response to neoadjuvant chemotherapy in breast cancer patients: results from the NEOZOTAC trial (BOOG 2010-01). AB - BACKGROUND: The insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis and therapy resistance. This study aims to elucidate whether variation in the IGF-1 pathway is predictive for pathologic response in early HER2 negative breast cancer (BC) patients, taking part in the phase III NEOZOTAC trial, randomizing between 6 cycles of neoadjuvant TAC chemotherapy with or without zoledronic acid. METHODS: Formalin-fixed paraffin-embedded tissue samples of pre-chemotherapy biopsies and operation specimens were collected for analysis of IGF-1 receptor (IGF-1R) expression (n = 216) and for analysis of 8 candidate single nucleotide polymorphisms (SNPs) in genes of the IGF-1 pathway (n = 184) using OpenArray(r) RealTime PCR. Associations with patient and tumor characteristics and chemotherapy response according to Miller and Payne pathologic response were performed using chi-square and regression analysis. RESULTS: During chemotherapy, a significant number of tumors (47.2 %) showed a decrease in IGF-1R expression, while in a small number of tumors an upregulation was seen (15.1 %). IGF-1R expression before treatment was not associated with pathological response, however, absence of IGF-1R expression after treatment was associated with a better response in multivariate analysis (P = 0.006) and patients with a decrease in expression during treatment showed a better response to chemotherapy as well (P = 0.020). Moreover, the variant T allele of 3129G > T in IGF1R (rs2016347) was associated with a better pathological response in multivariate analysis (P = 0.032). CONCLUSIONS: Absent or diminished expression of IGF-1R after neoadjuvant chemotherapy was associated with a better pathological response. Additionally, we found a SNP (rs2016347) in IGF1R as a potential predictive marker for chemotherapy efficacy in BC patients treated with TAC. TRIAL REGISTRATION: ClinicalTrials.gov NCT01099436 . Registered April 6, 2010. PMID- 26738611 TI - Sotos syndrome: An unusual presentation with intrauterine growth restriction, generalized lymphedema, and intention tremor. AB - Sotos syndrome is a childhood overgrowth syndrome characterized clinically by a distinctive facial gestalt, advanced bone age, childhood overgrowth, and non progressive developmental delay; and genetically by haploinsufficiency of the Nuclear receptor binding SET Domain 1 (NSD1) gene. Generalized lymphedema has not previously been associated with Sotos syndrome. Generalized lymphedema has been associated with mutations in several genes including FLT4. This gene is involved in the regulation of VEGFR3, a key governor of lymphatic-endothelial cell development and function. We report on a 28-year-old Caucasian female with a de novo NSD1 intragenic mutation, c.5841_5848dup: p.Leu1950Serfs*22, who presented with characteristic clinical features of Sotos syndrome. Unusually this case includes atypical features of intrauterine growth retardation and post-pubertal onset of primary lymphedema. To our knowledge, no link between Sotos syndrome and generalized lymphedema has previously been described in the literature. We propose a mechanism by which disruptions in NSD1 gene may lead to generalized lymphedema. Aberrations of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)-signaling pathway has been identified in both Sotos syndrome and lymphedema. This finding extends the known phenotype of Sotos syndrome through the inclusion of lymphedema. This case also indicates that presence of low birth weight does not exclude the possibility of Sotos syndrome. PMID- 26738614 TI - Role of STIM1-Orai1 system in intra-cellular calcium elevation induced by ATP in cultured human keratinocytes. PMID- 26738619 TI - Racial and ethnic differences in women's preferences for features of contraceptive methods. AB - OBJECTIVES: To understand women's preferences for specific features of contraceptive methods, the extent to which features of existing methods match women's preferences and whether this match differs by racial and ethnic subgroups. STUDY DESIGN: Using data from 1783 women in family planning and abortion clinics across the United States, we performed analyses of racial and ethnic differences in contraceptive features reported to be "extremely important" by participants. We explored how preferences vary for more and less effective contraceptive methods. RESULTS: In multivariate analysis, non-Hispanic Black, Latinas and Asian Pacific Islander women were more likely to report the following features as extremely important compared to non-Hispanic Whites (p<0.05): being able to stop using the method at any time, using a method only with intercourse and the method not changing her menstrual periods. Non-Hispanic Black and Latina women were statistically more likely to report that protection against sexually transmitted diseases, having control over when and whether to use the method and being able to become pregnant after stopping use were extremely important. The contraceptive feature preferences of racial and ethnic minority women in our study had a relatively lower match with high efficacy methods and higher match for low efficacy methods compared to White women (p<0.05). CONCLUSIONS: High rates of unintended pregnancy among minority women may be due in part to differences in contraceptive features preferences and discrepancy between their preferences and the features of currently available highly effective methods. IMPLICATIONS: In the context of disparities in rates of unintended pregnancy by racial and ethnic group, this variation in preferences for contraceptive features by race/ethnicity may explain differences in contraceptive use and can inform the development of more acceptable methods of contraception. PMID- 26738620 TI - Comparison of outcomes at 6 weeks following postpartum intrauterine contraceptive device insertions by doctors and nurses in India: a case-control study. AB - OBJECTIVE: As part of a strategy to revitalize postpartum family planning services, Government of India revised its policy in 2013 to permit trained nurses and midwives to insert postpartum intrauterine contraceptive devices (PPIUCDs). This study compares two key outcomes of PPIUCD insertions--expulsion and infection--for physicians and nurses/midwives to generate evidence for task sharing. STUDY DESIGN: We analyzed secondary data from the PPIUCD program in seven states using a case-control study design. We included facilities where both doctors and nurses/midwives performed PPIUCD insertions and where five or more cases of expulsion and/or infection were reported during the study period (January-December 2013). For each case of expulsion and infection, we identified a time-matched control who received a PPIUCD at the same facility and had no complaints. We performed a multiple logistic regression analysis focusing on provider cadre while controlling for potential confounding factors. RESULTS: In 137 facilities, 792 expulsion and 382 infection cases were matched with 1041 controls. Provider type was not significantly associated with either expulsion [odds ratio (OR) 1.84; 95% confidence interval (CI): 0.82-4.12] or infection (OR 0.73; 95% CI: 0.39-1.37). Compared with centralized training, odds of expulsion were higher for onsite (OR 2.32, 95% CI: 1.86-2.89) and on-the-job training (OR 1.23, 95% CI: 1.11-1.36), but odds of infection were lower for onsite (OR 0.45, 95% CI: 0.27-0.75) and on-the-job training (OR 0.31, 95% CI: 0.25-0.37). CONCLUSION: Trained nurses and midwives who conduct deliveries at public health facilities can perform PPIUCD insertions as safely as physicians. IMPLICATIONS: Institutional deliveries are increasing in India, but most normal vaginal deliveries at public health facilities are attended by nurses and midwives due to a shortage of physicians. Task sharing with nurses and midwives can increase women's access to and the acceptability of quality PPIUCD services. PMID- 26738621 TI - Polymer networks with bicontinuous gradient morphologies resulting from the competition between phase separation and photopolymerization. AB - Poly(ethyl acrylate)/poly(methyl methacrylate) (PEA/PMMA) polymer networks (IPNs) with spatially graded bicontinuous morphology were designed and controlled by taking advantage of the spinodal decomposition process induced by photopolymerization of the MMA monomer. Spatial gradients of the quench depth, induced by the gradients of light intensity, were generated along the path of the excitation light travelling through the mixture. Bicontinuous structures with uniaxial gradient of characteristic length scales were obtained by two different methods: simply irradiating the mixture with strong light intensity along the Z direction and using the so-called computer-assisted irradiation (CAI) method with moderate intensity to generate the light intensity gradient exclusively in the XY plane. These experimental results suggest that the combination of these two irradiation methods could provide polymer materials with biaxially co-continuous gradient morphology. An analysis method using the concept of spatial correlation function was developed to analyze the time-evolution of these graded structures. The experimental results obtained in this study suggest a promising method to design gradient polymers in the bulk state (3D) as well as on the surface (2D) by taking advantage of photopolymerization. PMID- 26738625 TI - Joint assembly of suction catheter and endotracheal tube: Aid for tracheostomy tube exchange. PMID- 26738624 TI - Effects of decompressive cervical surgery on blood pressure in cervical spondylosis patients with hypertension: a time series cohort study. AB - BACKGROUND: Patients with cervical spondylosis myelopathy (CSM) and complicated with hypertension are often experiencing a blood pressure decrease after taking cervical decompressive surgery in clinical observations, but how this blood pressure reduction is associated with the surgery, which cut cervical sympathetic nervous, has never been rigorously assessed. Thus, the purpose of this study is to investigate the effect of cervical decompressive surgery on blood pressure among CSM patients with hypertension. METHODS/DESIGN: The study will be a time series cohort study. Fifty eligible patients will be selected consecutively from the Peking University First Hospital. Two 24-h ambulatory blood pressure measurement (ABPM) will be taken before the surgery, apart by at least 3 days. The patients will be followed up for another two ABPMs at 1 and 3 months after the surgery. We will recruit subjects with cervical spondylosis myelopathy meeting operation indications and scheduled for receiving cervical decompressive surgery, aged 18-84 years, have a history of hypertension or office systolic blood pressure >=140 mmHg on initial screening, and willing to participate in the study and provide informed consent. Exclusion criteria includes a history of known secondary hypertension, visual analogue scale (VAS) score >=4, and unable to comply with study due to severe psychosis. The change in systolic ABPs over the four times will be analyzed to observe the overall pattern of the blood pressure change in relation to the surgery, but the primary analysis will be the comparison of systolic ABP between the 2(nd) and 3(rd), 4(th) measurements (before and after the surgery). We will also calculate the regression-to-the-mean adjusted changes in systolic ABP as sensitivity analysis. Secondary endpoints are the changes in 24 h ABPM diastolic blood pressure, blood pressure control status, the use and dose adjustment of antihypertensive medication, and the incidence of operative complications. Primary outcome analyses will be carried out using analysis of covariance, as well as the first secondary endpoint. DISCUSSION: This study will inform us the important knowledge about cervical sympathetic nervous system (SNS) and blood pressure. Once confirmed, it may help to produce new method for control of hypertension, which is the leading cause of death in the world. TRIAL REGISTRATION: The study is registered to Clinical Trials.gov (NCT02016768). PMID- 26738626 TI - Dosimetric impact of the low-dose envelope of scanned proton beams at a ProBeam facility: comparison of measurements with TPS and MC calculations. AB - Due to the low-dose envelope of scanned proton beams, the dose output depends on the size of the irradiated field or volume. While this field size dependence has already been extensively investigated by measurements and Monte Carlo (MC) simulations for single pencil beams or monoenergetic fields, reports on the relevance of this effect for analytical dose calculation models are limited. Previous studies on this topic only exist for specific beamline designs. However, the amount of large-angle scattered primary and long-range secondary particles and thus the relevance of the low-dose envelope can considerably be influenced by the particular design of the treatment nozzle. In this work, we therefore addressed the field size dependence of the dose output at the commercially available ProBeam((r)) beamline, which is being built in several facilities worldwide. We compared treatment planning dose calculations with ionization chamber (IC) measurements and MC simulations, using an experimentally validated FLUKA MC model of the scanning beamline. To this aim, monoenergetic square fields of three energies, as well as spherical target volumes were studied, including the investigation on the influence of the lateral spot spacing on the field size dependence. For the spherical target volumes, MC as well as analytical dose calculation were found in excellent agreement with the measurements in the center of the spread-out Bragg peak. In the plateau region, the treatment planning system (TPS) tended to overestimate the dose compared to MC calculations and IC measurements by up to almost 5% for the smallest investigated sphere and for small monoenergetic square fields. Narrower spot spacing slightly enhanced the field size dependence of the dose output. The deviations in the plateau dose were found to go in the clinically safe direction, i.e. the actual deposited dose outside the target was found to be lower than predicted by the TPS. Thus, the moderate overestimation of dose to normal tissue by the TPS is likely to result in no severe consequences in clinical cases, even for the most critical cases of small target volumes. PMID- 26738627 TI - Ultrasonographic Evaluation of Optic Nerve Sheath Diameter among Healthy Chinese Adults. AB - The aim of the work described here was to establish the range for optic nerve sheath diameter (ONSD) and potential factors influencing ONSD in healthy Chinese adults. Both ONSDs were measured twice in the sagittal and transversal planes by two observers. The final ONSD value for each participant was the average of 16 measurements of both eyes. The ONSD range (N = 3680) among 230 participants was 2.65-4.30 mm. The upper ONSD limit was lower than those in previous studies in Caucasian and African samples. Simple linear regression analyses revealed that the ONSD was correlated with sex, body mass index and waistline and head circumference. After adjustment for potential confounds between these factors, sex (coefficient = 0.225, p < 0.001) and body mass index (coefficient = 0.042, p < 0.001) were independently associated with ONSD. Underweight women had the smallest ONSD. These results suggest that racial, sex, and body mass index differences should be noted when assessing ultrasonographic criteria. PMID- 26738628 TI - The Imaging Modulography Technique Revisited for High-Definition Intravascular Ultrasound: Theoretical Framework. AB - Mechanical characterization of atherosclerotic lesions remains an essential step for the detection of vulnerable plaques (VPs). Recently, an intravascular ultrasound (IVUS) elasticity reconstruction method (iMOD) has been tested in vivo by our group. The major limitation of iMOD is the need to estimate the strain field in the entire VP despite attenuated depth penetration signals when using high-definition (HD) IVUS systems. Therefore, an extended iMOD approach (E-iMOD) was designed and applied to coronary lesions of patients imaged in vivo with IVUS. The E-iMOD method (i) quantified necrotic core areas with a mean absolute relative error of 3.5 +/- 3.5% and (ii) identified Young's moduli of the necrotic cores and fibrous regions with mean values of 5.7 +/- 0.8 kPa and 794.5 +/- 22.0 kPa instead of 5 kPa and 800 kPa, respectively. This study demonstrates the potential of the improved HD-IVUS modulography technique E-iMOD to characterize coronary VPs. PMID- 26738629 TI - The Skin Acts to Maintain Muscle Shear Modulus. AB - It is not clear how the tissues covering the skeletal muscles affect the muscles' mechanical properties. The main purpose of this study was to examine changes in muscle shear modulus as a representative mechanical property of muscle with and without the covering tissues of skin and epimysium (fascia). Shear modulus of the medial gastrocnemius (MG) muscle was determined using ultrasound shear-wave elastography in the Thiel's embalmed cadavers under three different conditions: original (intact cadavers), removal of the skin on the MG and subsequent removal of the epimysium. Muscle shear modulus significantly decreased by 50% after removal of the skin, whereas no additional changes in shear modulus were observed after subsequent removal of the epimysium. This study suggests that the skin is a main contributor for maintaining the muscle mechanical properties among tissues covering the skeletal muscle. PMID- 26738630 TI - Polymorphisms of two loci at the oxytocin receptor gene in populations of Africa, Asia and South Europe. AB - BACKGROUND: The oxytocin (OT) system is known to be implicated in the regulation of complex social behavior, particularly empathy and parenting. The goal of this study was to estimate the gender and population differences in polymorphisms of two oxytocin receptor gene SNPs, rs53576 and rs2254298, in four populations. RESULTS: These data were compared with each other and with 14 samples from the corresponding regions retrieved from the 1000 Genomes database. Low level of heterozygosity was observed for both SNPs in all populations in this study (rs53576: Catalonian, Hobs = 0.413; Hadza, Hobs = 0.556; sr2254698: Khanty-Mansi, Hobs = 0.250; Datoga, Hobs = 0.550). The amount of variance due to regional variability was almost equal for both SNPs (rs53576: FRT = 0.086, rs2554298: FRT = 0.072), whereas variance for the population level of variability was twice bigger for rs2554298 (rs53576: FST = 0.127, rs2554298: FST = 0.162). Pairwise coefficients of fixation demonstrate that the Hadza were well differentiated from other African populations except of Datoga, the Datoga were weakly differentiated from other African origin populations, the Ob Ugric people were extremely differentiated from all other populations. Catalans were extremely differentiated of Asian populations. CONCLUSIONS: It is hypothesized on the base of spatial distribution of the evolutionary novel A alleles of the both OXTR gene loci, that the spread of alleles of rs22542298 and rs53376 SNPs may be associated to some extant with manipulation of parental investment in humans. PMID- 26738634 TI - Joint effects of sensory feedback and interoceptive awareness on conscious error detection: Evidence from event related brain potentials. AB - Error awareness has been argued to depend on sensory feedback and interoceptive awareness (IA) (Ullsperger, Harsay, Wessel, & Ridderinkhof, 2010). We recorded EEG while participants performed a speeded Go/No-Go task in which they signaled error commission. Visibility of the effector was manipulated, while IA was measured with a heartbeat perception task. The late Pe was larger for aware than unaware errors. The ERN was also found to be modulated by error awareness, but only when the hand was visible, suggesting that its sensitivity to error awareness depends on the availability of visual sensory feedback. Only when the response hand was visible, the late Pe amplitude to aware errors correlated with IA, suggesting that sensory feedback and IA synergistically contribute to the emergence of error awareness. These findings underscore the idea that several sources of information accumulate in time following action execution in order to enable errors to break through and reach awareness. PMID- 26738633 TI - Attachment status and mother-preschooler parasympathetic response to the strange situation procedure. AB - BACKGROUND: Early attachment relationships are important for children's development of behavioral and physiological regulation strategies. Parasympathetic nervous system activity, indexed by respiratory sinus arrhythmia (RSA), is a key indicator of self-regulation, with links to numerous developmental outcomes. Attachment-related changes in and associations between mother and child RSA during the Strange Situation procedure (SSP) can elucidate individual differences in physiological response to stress that are important for understanding the development of and intervention for psychopathology. METHODS: A sample of 142 at-risk mothers and preschool-age children participated in the SSP and provided time-synchronized RSA data during the 7 episodes, which included 2 separations and 2 reunions. Attachment classifications were obtained using the Cassidy et al. (1992) coding system. Linear mixed-effects models were constructed to examine attachment-related change in RSA during the SSP and the concordance between mother and child RSA over time. RESULTS: Findings demonstrated attachment related differences in children's RSA. Secure children's RSA was relatively stable over time, whereas insecure-avoidant children showed RSA increases during the first separation and insecure-resistant children's RSA declined across the SSP. Mothers showed RSA withdrawal during separation regardless of child's attachment classification. Mother-child RSA showed a positive concordance that was strongest in the insecure-resistant group, compared with the other groups. CONCLUSIONS: Results support attachment theories concerning parasympathetic response to stress and the role of the mother-child relationship in physiological regulation. Our findings advance previous research by focusing on at-risk mother preschooler dyads within diverse attachment classifications. PMID- 26738635 TI - CXCL5 signaling is a shared pathway of neuroinflammation and blood-brain barrier injury contributing to white matter injury in the immature brain. AB - BACKGROUND: In very preterm infants, white matter injury is a prominent brain injury, and hypoxic ischemia (HI) and infection are the two primary pathogenic factors of this injury. Microglia and microvascular endothelial cells closely interact; therefore, a common signaling pathway may cause neuroinflammation and blood-brain barrier (BBB) damage after injury to the immature brain. CXC chemokine ligand 5 (CXCL5) is produced in inflammatory and endothelial cells by various organs in response to insults. CXCL5 levels markedly increased in the amniotic cavity in response to intrauterine infection and preterm birth in clinical studies. The objective of this study is to determine whether CXCL5 signaling is a shared pathway of neuroinflammation and BBB injury that contributes to white matter injury in the immature brain. METHODS: Postpartum day 2 (P2) rat pups received lipopolysaccharide (LPS) followed by 90-min HI. Immunohistochemical analyses were performed to determine microglial activation, neutrophil infiltration, BBB damage, and myelin basic protein and glial fibrillary acidic protein expression. Immunofluorescence experiments were performed to determine the cellular distribution of CXCL5. Pharmacological tests were performed to inhibit or enhance CXCL5 activity. RESULTS: On P2, predominant increases in microglial activation and BBB damage were observed 24 h after LPS sensitized HI induction, and white matter injury (decreased myelination and increased astrogliosis) was observed on P12 compared with controls. Immunohistochemical analyses revealed increased CXCL5 expression in the white matter 6 and 24 h after insult. Immunofluorescence experiments revealed upregulated CXCL5 expression in the activated microglia and endothelial cells 24 h after insult. CXCL5 inhibition by SB225002, a selective nonpeptide inhibitor of CXCR2, significantly attenuated microglial activation and BBB damage, increased myelination, and reduced astrogliosis in the white matter after LPS-sensitized HI. In addition, CXCL5-sensitized HI or CXCL5 alone significantly induced BBB damage and white matter injury in association with different neuroinflammation mechanisms. CXCL5-sensitized HI-induced microglial activation and neutrophil infiltration, whereas CXCL5 alone predominately caused neutrophil infiltration. CONCLUSIONS: CXCL5 is a potential biomarker for white matter injury in preterm infants. Pharmacological blockade of CXCL5 signaling that attenuates dysregulated neuroinflammation can be used a therapeutic strategy against white matter injury in the immature brain. PMID- 26738636 TI - Eccentric circummeatal based flap with limited urethral mobilization: An easy technique for distal hypospadias repair. AB - BACKGROUND: Hypospadias is a common congenital anomaly. Over 300 techniques have been described for repairing hypospadias. OBJECTIVE: Eccentric circummeatal based flap with combined limited urethral mobilization technique (ECMB-LUM) is a simple procedure to repair distal hypospadias with minimal complication rate. This study presents results of this technique, highlighting surgical pitfalls to achieve the best result. STUDY DESIGN: Medical records of patients with distal hypospadias operated on using the same technique between 1998 and 2011 were reviewed retrospectively. Age at surgery, position of meatus preoperatively and postoperatively, duration of urethral catheterization and hospitalization, early and late complications, previous hypospadias repairs, and secondary surgical interventions were evaluated. In the surgical technique an eccentric circummeatal based flap is outlined. The proximal part of the flap is dissected from the underlying urethra and Buck's fascia. If the flap is not long enough, the distal urethra is mobilized a few millimeters (Figure). The eccentric flap is sutured to the tip of the glans. The glans wings are approximated in the midline. A urethral catheter of 6 Fr or 8 Fr is passed and left in the bulbous urethra or the urinary bladder. Diverged limbs of corpus spongiosum are approximated on the urethra, then, the glans and skin of the penile shaft are sutured. RESULTS: Of the 171 consecutive patients operated on using the ECMB-LUM technique; 115 had coronal, 47 had subcoronal, and nine had glanular meatus. The mean age at surgery was 4.5 (1-17) years. Patients were hospitalized for 2.2 +/- 0.7 days. Mean duration of urethral catheterization was 2.3 +/- 0.5 days. All but eight patients had ECBF LUM as primary repair. There were no early complications such as bleeding, hematoma, and wound infection. All patients voided spontaneously after catheter removal. Late complications were meatal stenosis, urethrocutaneous fistula, meatal regression, and glandular dehiscence (Table). These patients were treated using dilatation, fistula repair, meatoplasty, and secondary repair with the same technique, respectively. Eventually all patients had a vertical slit-like meatus on the tip of a natural looking glans. DISCUSSION: The most commonly used distal hypospadias repair techniques are glanular approximation, meatal advancement and glanuloplasty, Koff, Mathieu, Thiersch-Duplay procedure, tubularized incised plate repairs, and modifications of these techniques. Cosmetic and functional results and complication rates of ECMB-LUM technique are comparable with those of the commonly used techniques. PMID- 26738639 TI - Occupation-Based Intervention for Addictive Disorders: A Systematic Review. AB - Addictive disorders disrupt individuals' occupational lives, suggesting that occupational therapists can play a crucial role in addiction rehabilitation. Occupation-based interventions are those in which an occupation is performed, and occupations are defined as those activities a person engages in to structure time and create meaning in one's life. This review asked: In persons with addictive disorders, are occupation-based interventions more effective than treatment as usual in improving short and long-term recovery outcomes? A systematic literature search was performed by a medical librarian in Ovid MEDLINE, PsychINFO, Social Work Abstracts, OTSeeker, HealthSTAR, CINAHL, and ACPJournalClub. Authors screened 1095 articles for inclusion criteria (prospective outcome studies examining the effectiveness of an occupation-based intervention with a sample primarily consisting of a diagnosis of a substance-related or addictive disorder and with at least five participants), and two authors appraised the resulting 66 articles using a standard appraisal tool, yielding 26 articles for qualitative synthesis and 8 with shared outcome measures for quantitative analysis. Occupation-based interventions in the areas of work, leisure, and social participation were found to have been used to treat addictive disorders. Occupation-based interventions in the area of social participation all elicited better outcomes than their respective control/comparison groups. Not all occupation-based interventions in the area of leisure elicited better outcomes than their comparison group, but in the eight articles with shared outcome measures, quantitative analysis demonstrated leisure interventions produced larger effect sizes than social participation interventions. PMID- 26738640 TI - Studying Psychosocial Barriers to Drug Treatment Among Chinese Methamphetamine Users Using A 3-Step Latent Class Analysis. AB - Given the growth in methamphetamine use in China during the 21st century, we assessed perceived psychosocial barriers to drug treatment among this population. Using a sample of 303 methamphetamine users recruited via Respondent Driven Sampling, we use Latent Class Analysis (LCA) to identify possible distinct latent groups among Chinese methamphetamine users on the basis of their perceptions of psychosocial barriers to drug treatment. After covariates were included to predict latent class membership, the 3-step modeling approach was applied. Our findings indicate that the Chinese methamphetamine using population was heterogeneous on perceptions of drug treatment barriers; four distinct latent classes (subpopulations) were identified--Unsupported Deniers, Deniers, Privacy Anxious, and Low Barriers--and individual characteristics shaped the probability of class membership. Efforts to link Chinese methamphetamine users to treatment may require a multi-faceted approach that attends to differing perceptions about impediments to drug treatment. PMID- 26738642 TI - [Intestinal occlusion secondary to a retained surgical item]. AB - BACKGROUND: Retained surgical items after a surgical procedure is a real, existing, and preventable problem that affects the safety of the surgical patient. Its incidence is not exactly known due to under-reporting of occurrence, due to the potential risk of lawsuits. CLINICAL CASE: A 31 year-old women that had an elective caesarean, apparently without complications. In the immediate post-operative period, clinical features appeared that were compatible with intestinal obstruction, such as inability to channel gas, bloating, abdominal pain and vigorous peristalsis. The diagnosis is made by the recent history of abdominal-pelvic surgery and the finding of a foreign body on a simple x-ray of the abdomen. The patient was operated upon, with a satisfactory outcome, and was discharged 5 days later. CONCLUSION: A retained surgical instrument is an under reported event that represents a medical-legal problem, leading to various complications, including death if it is not diagnosed and treated early. It is important to know the risk factors and adopt a culture of prevention through perioperative monitoring of equipment and instruments used during the surgical act. PMID- 26738641 TI - Development and Preliminary Testing of a Promotora-Delivered, Spanish Language, Counseling Intervention for Heavy Drinking among Male, Latino Day Laborers. AB - This study developed and then tested the feasibility, acceptability and initial efficacy of a 3-session, culturally adapted, intervention combining motivational enhancement therapy (MET) and strengths-based case management (SBCM) delivered by promotoras in Spanish to reduce heavy drinking among male, Latino day laborers. A pilot two-group randomized trial (N=29) was conducted to evaluate the initial efficacy of MET/SBCM compared to brief feedback (BF). Alcohol-related measures were assessed at 6, 12 and 18weeks after baseline. Most intervention group participants (12/14) attended all counseling sessions and most participants (25/29) remained in the study at 18weeks. Alcohol related measures improved in both groups over time with no statistically significant differences observed at any of the time points. However the comparative effect size of MET/SBCM on weekly drinking was in the large range at 6-weeks and in the moderate range at 12-weeks. Post hoc analyses identified a statistically significant reduction in number of drinks over time for participants in the intervention group but not for control group participants. Despite the extreme vulnerability of the population, most participants completed all sessions of MET/SBCM and reported high satisfaction with the intervention. We feel our community partnership facilitated these successes. Additional studies of community-partnered and culturally adapted interventions are needed to reduce heavy drinking among the growing population of Latinos in the U.S. PMID- 26738643 TI - [Treatment of thoracic disc herniation. Case report]. AB - BACKGROUND: Herniated thoracic intervertebral disc is a rare cause of spinal cord compression. Its frequency varies from 0.15% to 1.7% of all disc herniations, and produces symptoms in 0.5% to 0.8%. CLINICAL CASES: Case 1. A 50-year-old woman, with pain and burning sensation in left hemithorax of four months of onset. It was treated as a herpetic syndrome, with no improvement. She was seen after thirteen days of exacerbation of clinical symptoms. The physical examination showed asymmetric paraparesis, lower left pelvic limb 1/5, and right pelvic limb 3/5 sensory level T8, with left Babinski positive. A thoracic disc herniation in space T8-T9 was diagnosed. CASE 2: A 55-year-old patient with a history of presenting pain in lumbar area of 5 years onset. She also had radicular pain that radiated to the right pelvic limb, with intensity 10/10 on a Visual Analogue Scale. Her physical examination showed muscle strength 5/5, with normal sensitivity in all dermatomes and tendon reflexes, and a positive right Babinski. Thoracic disc herniation T7-T8 level was diagnosed. DISCUSSION: Due to anatomical conditions that define this type of hernia, the extracavitary posterolateral approach should be the recommended surgical procedure when the simultaneously performed anterior decompression and fixation with posterior instrumentation are the treatments proposed. CONCLUSION: Despite the different anatomical structures of this special area, it was possible to obtain satisfactory results for both clinical cases. PMID- 26738644 TI - [Difficulties in the percutaneous approach of the acute coronary syndrome with associated axillobifemoral bypass]. AB - BACKGROUND: Peripheral arterial disease and coronary artery disease are frequently associated. The percutaneous approach may sometimes involve additional difficulties to the coronary artery disease. CLINICAL CASE: The case is presented on an 82 year-old male patient with multiple cardiovascular risk factors, a Leriche syndrome and axillobifemoral bypass, who was admitted to hospital due to an inferior myocardial infarction. The procedure approach (radial, brachial, or femoral access routes for percutaneous coronary treatment) and associated complications from the procedure are discussed. CONCLUSION: Although technical improvements and/or treatment of peripheral vascular lesions may allow percutaneous coronary intervention, individual risk and benefit in each patient must be assessed. PMID- 26738645 TI - [Acute urinary retention secondary to giant prolapsed ureterocele in a young adult woman. Case report]. AB - BACKGROUND: Ureterocele is a cystic dilation of the distal ureteral segment. The incidence in women ranges from 1/5,000 to 1/12,000. In adults, they are poorly diagnosed and are asymptomatic. Prolapse through the urethra is uncommon, and involves acute urine retention and a reducible vulvar tumour. CLINICAL CASE: Woman of 24 years old, two previous caesarean and two abortions. She had incomplete bladder emptying, intermittent voiding, bladder straining and tenesmus, three months before admission. After the voiding effort she presented with acute urine retention with sudden onset of tumour in the vulva. The tumour was manually reduced under regional anaesthesia. A cystoscopy was performed, finding an ischaemic de-roofing of the anterior wall of the ureterocele, causing vesicoureteral reflux grade IV. Surgical correction was performed with Cohen re implantation and insertion of a double-J catheter. The catheter was removed 30 days later, with a successful post-operative course. DISCUSSION: Its aetiology is unclear, and most are diagnosed by ultrasound in the prenatal period. The clinical presentation is variable, from urinary tract infection to prolapse. Despite its size, it may cause complications such as ischaemic de-roofing, which if diagnosed soon may be resolved successfully, as with this patient. CONCLUSION: The results and treatment may be favourable when no renal impact or concomitant anatomical changes are present, as is the case of this patient. PMID- 26738646 TI - [Safety of reducing the recovery time after percutaneous and laparoscopic liver biopsy]. AB - BACKGROUND: Liver biopsy is the main diagnostic tool for the study of the liver, and as such, its inherent complications have been minimised as much as possible over the years, through the modification of several factors regarding its procedure, including post-biopsy recovery time. The aim of this study was to evaluate the safety in the reduction of post-liver biopsy recovery time. MATERIAL AND METHODS: A non-blinded, randomised clinical trial was conducted in the "Hermanos Ameijeiras" Hospital from November 2011 to October 2012, on 128 patients in order to assess safety when reducing post-biopsy recovery times. The patients were randomised into 2 groups. Group A was allowed a 6-hour recovery time, while Group B was allowed a 2-hour recovery time after liver biopsy. Complications were fully recorded. The Chi squared test of homogeneity and Student t test was used as appropriate, in the statistical analysis, a significance level of 0.05 was set. RESULTS: The main biopsy indication was elevated plasma transaminases. Pain in the puncture site was the most recurrent complication (67.2%), and the most serious complication was subcapsular liver haematoma in two cases (1.6%). There were no differences regarding the liver biopsy technique that could have caused complications in any group. CONCLUSIONS: There were no significant differences between 2 hours and 6 hours post-liver biopsy recovery time in terms of complications, so it is considered that after two hours the patient is incorporated more quickly into their activities, and the institution spends less material and human resources. PMID- 26738647 TI - [Laparoscopic radical trachelectomy for preservation of fertility in early cervical cancer. A case report]. AB - BACKGROUND: Radical hysterectomy is the standard treatment for patients with early-stage cervical cancer. However, for women who wish to preserve fertility, radical trachelectomy is a safe and viable option. OBJECTIVE: To present the first case of laparoscopic radical trachelectomy performed in the National Cancer Institute, and published in Mexico. CLINICAL CASE: Patient, 34 years old, gravid 1, caesarean 1, stage IB1 cervical cancer, squamous, wishing to preserve fertility. She underwent a laparoscopic radical trachelectomy and bilateral dissection of the pelvic lymph nodes. Operation time was 330minutes, and the estimated blood loss was 100ml. There were no intraoperative or postoperative complications. The final pathology reported a tumour of 15mm with infiltration of 7mm, surgical margins without injury, and pelvic nodes without tumour. After a 12 month follow-up, the patient is having regular periods, but has not yet tried to get pregnant. No evidence of recurrence. CONCLUSIONS: Laparoscopic radical trachelectomy and bilateral pelvic lymphadenectomy is a safe alternative in young patients who wish to preserve fertility with early stage cervical cancer. PMID- 26738648 TI - [Effectiveness of physiotherapy on painful shoulder impingement syndrome]. AB - BACKGROUND: Painful shoulder impingement syndrome is one of the first reasons for care in rehabilitation centres. As the evidence regarding the effectiveness of physical measures as adjuvant treatment is limited, the aim of this study was to determine the effectiveness of physiotherapy on shoulder pain. MATERIAL AND METHODS: A retrospective and analytical study was conducted using the medical records of patients with shoulder pain who attended in a rehabilitation centre from October 2010 to September 2011. The demographic and clinical data were collected, and the clinical improvement was determined as: complete, incomplete, or no improvement. STATISTICAL ANALYSIS: Chi squared was used to determine whether there were differences between the different modalities of physiotherapy, as well as the level of improvement. RESULTS: The study included a total of 181 patients, with a mean age of 54.3 years, and a mean of 4.6 months of onset of pain. The physiotherapy treatments included: warm compresses plus interferential current (60.2%), and warm compresses plus ultrasound (17.1%). Just over half (53.6%) obtained a moderate recovery, 36.4% slight improvement, and 9.9% no improvement. No significant differences were found between the different forms of therapy. CONCLUSIONS: The supervised rehabilitation program consists of 9 sessions of physiotherapy. A functional improvement of 90% was obtained, without finding any statistical differences between the therapies used. PMID- 26738649 TI - [Bacterial resistance in acne? A meta-analysis of the controversy]. AB - BACKGROUND: Acne is one of the dermatological pathologies with the highest incidence around the world. It is a multifactorial disease and its treatment can be complex. Propionibacterium acnes play a key role in the inflammation of this dermatosis. Topical antibiotics, including mainly erythromycin and clindamycin, have been used, but there is controversy over their use due to the widely documented bacterial resistance. For this reason a meta-analysis of the publications over the past 10 years is presented in order to confirm this hypothesis. MATERIAL AND METHODS: A search was made of the publications over the past 10 years that included the results of antibiogams of patients with acne. MeSH type searches were performed with the terms "acne vulgaris", "Propionibacterium acnes", "topical administration", "treatment", "erythromycin", "clindamycin", "nadifloxacin", "antibacterial agent", "bacterial drug resistance" in PubMed, Ovid, EBSCO, Cochrane, ScienceDirect and ClinicalKey meta-searches. RESULTS: A total of 13 articles were found that met the inclusion criteria. The mean odds ratio (OR 1.24, 95% CI) of the articles showed a slight tendency toward resistance of Propionibacterium acnes. CONCLUSIONS: An increase in bacterial resistance to topical erythromycin and clindamycin can be confirmed, thus the use of these antibiotics is recommended in selective cases for short periods, and in combination with benzoyl peroxide for the best clinical outcome in patients with acne vulgaris. PMID- 26738650 TI - [Diagnosis and treatment of the complications of otitis media in adults. Case series and literature review]. AB - BACKGROUND: The complications of otitis media (intra-cranial and extra-cranial) used to have a high morbidity and mortality in the pre-antibiotic era, but these are now relatively rare, mainly due to the use of antibiotics and the use of ventilation tubes, reducing the incidence of such complications significantly. Currently, an early suspicion of these complications is a major challenge for diagnosis and management. CLINICAL CASES: The cases of 5 patients (all male) are presented, who were diagnosed with complicated otitis media, 80% (4) with a mean age of 34.6 years (17-52). There was major comorbidity in 60% (3), with one patient with diabetes mellitus type 2, and two with chronic renal failure. There were 3 (60%) intra-cranial complications: one patient with thrombosis of the sigmoid sinus and a cerebellar abscess; another with a retroauricular and brain abscess, and a third with meningitis. Of the 2 (40%) extra-cranial complications: one patient had a Bezold abscess, and the other with a soft tissue abscess and petrositis. All patients were managed with surgery and antibiotic therapy, with 100% survival (5), and with no neurological sequelae. The clinical course of otitis media is usually short, limiting the infection process in the majority of patients due to the immune response and sensitivity of the microbe to the antibiotic used. However, a small number of patients (1-5%) may develop complications. CONCLUSION: Otitis media is a common disease in our country, complications are rare, but should be suspected when the picture is of torpid evolution with clinical worsening and manifestation of neurological signs. PMID- 26738651 TI - [Hydatidosis simulating a cardiac tumour with pulmonary metastases]. AB - BACKGROUND: The presence of multiple symptomatic pulmonary nodules and one cardiac tumour in a child requires urgent diagnosis and treatment. Until a few decades ago, the diagnosis of a cardiac tumour was difficult and was based on a high index of suspicion from indirect signs, and required angiocardiography for confirmation. Echocardiography and other imaging techniques have also helped in the detection of cardiac neoplasms. However, it is not always easy to make the correct diagnosis. CLINICAL CASE: The case is presented of a 12 year-old boy with pulmonary symptoms, and diagnosed with a cardiac tumour with lung metastases. The presence of numerous pulmonary nodules was confirmed in our hospital. The echocardiogram detected a solid cardiac nodule in the right ventricle. Magnetic resonance imaging confirmed the findings and the diagnosis. Puncture-aspiration of a lung nodule gave the diagnosis of hydatidosis. He underwent open-heart surgery with cardiac cyst resection and treated with anthelmintics. The lung cysts were then excised, and he recovered uneventfully. DISCUSSION: This child had multiple pulmonary nodules and a solid cardiac nodule, and was suspected of having a cardiac tumour with pulmonary metastases. However, given the clinical history, background and morphology of pulmonary nodules, another possible aetiology for consideration is echinococcosis. The clinical picture of cardiac hydatidosis and its complications is highly variable. The clinical history is essential in these cases, as well as having a high index of suspicion. CONCLUSION: Hydatidosis should be included in the differential diagnosis of a solid, echogenic, cardiac nodule. The treatment for cardiopulmonary hydatid cysts is surgical, followed by anthelmintics. PMID- 26738652 TI - [Effectiveness of Trauma Evaluation and Management course for Mexican senior medical students: When to implement it?]. AB - BACKGROUND: Trauma Evaluation and Management course was designed to develop trauma cognitive skills in senior medical students. Its effectiveness has been demonstrated in many regions, except in Latin America, where it has been poorly studied. The objective was to determine the Trauma Evaluation and Management course effectiveness, and whether greater effectiveness is achieved in basic- or clinic-cycle students, as well as student perception. MATERIAL Y METHODS: Descriptive, observational, longitudinal and prospective study. Two tests were performed, pre- and post-course; the manual was read by the students prior to both tests. Students were divided into 2 groups: group A (consisting of 71 basic cycle medical students) and group B (consisting of 44 clinical-cycle medical students). RESULTS: Group A achieved a 2.45 increase (p<0.01) in the post-course evaluation compared with pre-course test. Group B increased the mean score by 2.25 (p>0.05) from pre- to post-course tests. There was a significant difference between groups in both evaluations (pre-course test p<0.01 and post-course test p>0.05), with no difference in improvement (p>0.05). Using a questionnaire, 92.17% of the students totally agreed that the course improved their trauma knowledge, 76.52% that it increased their trauma clinical skills, with 94.78% being totally satisfied with the course, and 86.09% totally agreed that Trauma Evaluation and Management course should be in Medicine curriculum. CONCLUSIONS: Trauma Evaluation and Management course improves trauma cognitive skills, and undergraduate medical students in Mexico broadly accept it. PMID- 26738653 TI - [Versatility of the microvascular fibular flap in limb reconstruction]. AB - BACKGROUND: The structural characteristics of the fibula, strength, shape, length and limited donor site morbidity make it more suitable for reconstructing long bone defects larger than 6cm in the limbs. MATERIAL AND METHODS: A descriptive study was conducted using a non-probabilistic sample of consecutive cases undergoing on limb reconstruction with free fibular flap in the period from January 2010 to January 2015 in the Mexican Institute of Social Security No. 21, Monterrey Nuevo Leon. RESULTS: The mean age of the ten cases included was 25 years, with the most common diagnosis being trauma in 4 patients, osteosarcoma in 2, followed by one congenital pseudoarthrosis of the tibia, one non-union fracture, and one gunshot wounds, respectively. The most common location was tibia, followed by humerus, radius, ulna and femur. CONCLUSIONS: This study has shown that the fibular free flap can be an excellent option for management of long bone defects, regardless of cause of the injury. One or more skin islands can be added for coverage in exposure of deep tissue and osteosynthesis material, thus preserving the septocutaneous perforators. PMID- 26738654 TI - [Anaesthetic management of patients in the third trimester of pregnancy undergoing urgent laparoscopic surgery. Experience in a general hospital]. AB - BACKGROUND: Laparoscopic surgery is well accepted as a safe technique when performed on a third trimester pregnant woman. OBJECTIVE: The aim is to describe the anaesthetic management of a group of patients undergoing this type of surgery. MATERIAL AND METHODS: An analysis was made of records of 6 patients in their third trimester of pregnancy and who underwent urgent laparoscopic surgery from 2011 to 2013. CLINICAL CASES: The study included 6 patients, with a diagnosis of acute cholecystitis in 4 of them. The other 2 patients had acute appendicitis, both of who presented threatened preterm labour. CONCLUSION: The most frequent indications for laparoscopic surgery during the last trimester of birth were found to be acute cholecystitis and acute appendicitis. Acute appendicitis is related to an elevated risk of presenting threatened preterm labour. PMID- 26738655 TI - Small but smart: MicroRNAs orchestrate atherosclerosis development and progression. AB - MicroRNAs (miRNAs) are short non-coding RNA able to bind specific sequences on target messenger RNAs (mRNAs) and thereby to post-transcriptionally modulate gene expression. Being expressed in all vertebrate cell types, miRNAs have emerged as key players in a wide array of biological processes, including cell proliferation, differentiation and apoptosis. Over the past decade, knowledge concerning the contribution of miRNAs to human pathology has grown with an astonishing pace. In particular, a major involvement of miRNAs in atherosclerosis as a leading cause of global mortality has been supported by ample evidence from in vitro, in vivo and clinical studies. This review aims to summarize and highlight current concepts of miRNA function in the continuum of atherogenesis ranging from risk factors (i.e. dyslipidemia, diabetes, hypertension), to endothelial dysfunction up to the events leading to plaque rupture. Areas in need for further research and potential perspectives for translational applications will be scrutinized. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernandez Hernando and Yajaira Suarez. PMID- 26738656 TI - An extension of olfactometry methods: An expandable, fully automated, mobile, MRI compatible olfactometer. AB - BACKGROUND: fMRI experiments on olfaction offer new insights into the complex, but in contrast to other sensory systems, less studied cognition of odors. To perform these experiments is still a challenge. NEW METHOD: To address the challenge posed by MR settings, an olfactometer design is presented including specific improvements to the limited number of already existing olfactometers. Innovative features such as pneumatically controlled pinch valves, useable in the scanner and providing exact stimulus timing as well as a 3D-printed nasal mask inlet for common sleep laboratory masks that can be used for lateral divided stimulus presentation are introduced. To ensure a fully automated and mobile system, the use of a flexible and easily-adapted Matlab-Code and a portable adaptable container system are presented. RESULTS: The functional efficiency of these features are proven by results of an fMRI study as well as testing temporal resolution and concentration stability with a mass spectrometer. COMPARISON WITH EXISTING METHODS: The 24-channel olfactometer design presented here provides an inexpensive alternative to the currently available olfactometers including the achievement of fast onset times, lateral divided stimulus presentation and high flexibility and adaptability to different scientific questions. CONCLUSION: The olfactometer design presented in this paper can be seen as a realistic and feasible solution to overcome the challenges of presenting olfactory stimuli within the MR setting. PMID- 26738657 TI - The development of a non-invasive behavioral model of thermal heat stress in laboratory mice (Mus musculus). AB - BACKGROUND: Many behavioral and physiological studies of laboratory mice employ invasive methods such as radio telemetry to measure key aspects of behavior and physiology. Radio telemetry requires surgical implants, which may impact mouse health and behavior, and thus reduce the reliability of the data collected. NEW METHOD: We developed a method to measure key aspects of thermoregulatory behavior without compromising animal welfare. We examined the thermoregulatory response to heat stress in a custom-built arena that permitted the use of simultaneous and continuous infrared thermography (IRT) and video capture. This allowed us to measure changes in surface body temperature and determine total distance traveled using EthoVision XT animal tracking software. RESULTS: Locomotor activity and surface body temperature differed between heat-stressed mice and mice kept within their thermal comfort zone. The former had an increase in surface body temperature and a decline in locomotor activity, whereas the latter had a stable surface body temperature and showed greater activity levels. METHODS: Surface body temperature and locomotor activity are conventionally quantified by measurements taken at regular intervals, which limit the use and accuracy of the data. We obtained data of high resolution (i.e., recorded continuously) and accuracy that allowed for the examination of key physiological measurements such as energy expenditure and peripheral vasomotor tone. CONCLUSIONS: This novel experimental method for studying thermoregulatory behavior in mice using non invasive tools has advantages over radio-telemetry and represents an improvement in laboratory animal welfare. PMID- 26738658 TI - Controlled microfluidics to examine growth-factor induced migration of neural progenitors in the Drosophila visual system. AB - BACKGROUND: The developing visual system in Drosophila melanogaster provides an excellent model with which to examine the effects of changing microenvironments on neural cell migration via microfluidics, because the combined experimental system enables direct genetic manipulation, in vivo observation, and in vitro imaging of cells, post-embryo. Exogenous signaling from ligands such as fibroblast growth factor (FGF) is well-known to control glia differentiation, cell migration, and axonal wrapping central to vision. NEW METHOD: The current study employs a microfluidic device to examine how controlled concentration gradient fields of FGF are able to regulate the migration of vision-critical glia cells with and without cellular contact with neuronal progenitors. RESULTS: Our findings quantitatively illustrate a concentration-gradient dependent chemotaxis toward FGF, and further demonstrate that glia require collective and coordinated neuronal locomotion to achieve directionality, sustain motility, and propagate long cell distances in the visual system. COMPARISON WITH EXISTING METHOD(S): Conventional assays are unable to examine concentration- and gradient-dependent migration. Our data illustrate quantitative correlations between ligand concentration/gradient and glial cell distance traveled, independent or in contact with neurons. CONCLUSIONS: Microfluidic systems in combination with a genetically-amenable experimental system empowers researchers to dissect the signaling pathways that underlie cellular migration during nervous system development. Our findings illustrate the need for coordinated neuron-glia migration in the Drosophila visual system, as only glia within heterogeneous populations exhibited increasing motility along distances that increased with increasing FGF concentration. Such coordinated migration and chemotactic dependence can be manipulated for potential therapeutic avenues for NS repair and/or disease treatment. PMID- 26738659 TI - Percutaneous Left Atrial Appendage Closure With the Watchman Device: Long-Term Results Up to 5 Years. AB - OBJECTIVES: The aim of this study was to evaluate long-term outcomes in patients with atrial fibrillation undergoing percutaneous left atrial appendage (LAA) closure with the Watchman device. BACKGROUND: Atrial fibrillation is one of the most common arrhythmias and is associated with a high risk for cardioembolic ischemic events, most notably stroke. Percutaneous LAA closure is an alternative to oral anticoagulation, because most thrombi originate from the LAA. METHODS: All consecutive patients with minimum CHADS2 or CHA2DS2-VASc scores of 1 who underwent LAA closure with the Watchman device between June 2006 and August 2010 were eligible. Follow-up examinations were performed after 45 days to 3 months, 6 months, and 1 year and thereafter annually. Afterward, alternating office visits and telephone follow-up were performed every 6 months. RESULTS: A total of 102 patients were included. The mean age was 71.6 +/- 8.8 years, and 37.3% were women. The mean CHADS2 and CHA2DS2-VASc scores were 2.7 +/- 1.3 and 4.3 +/- 1.7, respectively. Procedural success was achieved in 96.1% of patients. During a mean follow-up period of 3.0 +/- 1.6 years, the annual rates of transient ischemic attack, stroke, intracranial hemorrhage, and death were 0.7%, 0.7%, 1.1%, and 3.5%, respectively. CONCLUSIONS: LAA closure with the Watchman device is safe and feasible for stroke protection in patients with atrial fibrillation. Low ischemic events rates demonstrate its effectiveness during long-term follow-up. PMID- 26738660 TI - Closing the Oval Door. PMID- 26738662 TI - Measure Twice, Close Once: Effect of Volume Loading on Left Atrial Appendage Closure. PMID- 26738661 TI - Changes in Left Atrial Appendage Dimensions Following Volume Loading During Percutaneous Left Atrial Appendage Closure. AB - OBJECTIVES: This study sought to determine whether volume loading alters the left atrial appendage (LAA) dimensions in patients undergoing percutaneous LAA closure. BACKGROUND: Percutaneous LAA closure is increasingly performed in patients with atrial fibrillation and contraindications to anticoagulation, to lower their stroke and systemic embolism risk. The safety and efficacy of LAA closure relies on accurate device sizing, which necessitates accurate measurement of LAA dimensions. LAA size may change with volume status, and because patients are fasting for these procedures, intraprocedural measurements may not be representative of true LAA size. METHODS: Thirty-one consecutive patients undergoing percutaneous LAA closure who received volume loading during the procedure were included in this study. After an overnight fast and induction of general anesthesia, patients had their LAA dimensions (orifice and depth) measured by transesophageal echocardiography before and after 500 to 1,000 ml of intravenous normal saline, aiming for a left atrial pressure >12 mm Hg. RESULTS: Successful implantation of LAA closure device was achieved in all patients. The average orifice size of the LAA at baseline was 20.5 mm at 90 degrees , and 22.5 mm at 135 degrees . Following volume loading, the average orifice size of the LAA increased to 22.5 mm at 90 degrees , and 23.5 mm at 135 degrees . The average increase in orifice was 1.9 mm (p < 0.0001). The depth of the LAA also increased by an average of 2.5 mm after volume loading (p < 0.0001). CONCLUSIONS: Intraprocedural volume loading with saline increased the LAA orifice and depth dimensions during LAA closure. Operators should consider optimizing the left atrial pressure with volume loading before final device sizing. PMID- 26738664 TI - Balancing Optimal Outcomes With Access to Care: It Can Be Done! PMID- 26738663 TI - Regional Systems of Care to Optimize Outcomes in Patients Undergoing Transcatheter Aortic Valve Replacement. AB - OBJECTIVES: This study sought to describe the development of a multicenter, transcatheter aortic valve replacement program and regional systems of care intended to optimize coordinated, efficient, and appropriate delivery of this new therapy. BACKGROUND: Transcatheter aortic valve replacement (TAVR) has become an accepted treatment option for patients with severe aortic stenosis who are at high surgical risk. Regional systems of care have led to improvements in outcomes for patients undergoing intervention for myocardial infarction, cardiac arrest, and stroke. We implemented a regional system of care for patients undergoing TAVR in British Columbia, Canada. METHODS: We describe a prospective observational cohort of 583 patients who underwent TAVR in British Columbia between 2012 and 2014. Regionalization of TAVR care in British Columbia refers to a centrally coordinated, funded, and evaluated program led by a medical director and a multidisciplinary advisory group that oversees planning, access to care, and quality of outcomes at the 4 provincial sites. Risk-stratified case selection for transfemoral TAVR is performed by heart teams at each site on the basis of consensus provincial indications. Referrals for lower volume and more complicated TAVR, including nontransfemoral access and valve-in-valve procedures, are concentrated at a single site. In-hospital and 30-day outcomes are reported. RESULTS: The median age was 83 years (interquartile range [IQR]: 78 to 87 years) and median STS score was 6% (IQR: 4% to 8%). Transfemoral access was performed in 499 (85.6%) cases and nontransfemoral in 84 (14.4%). Transcatheter valve-in-valve procedures in for failed bioprosthetic valves were performed in 43 patients (7.4%). A balloon-expandable valve was inserted in 386 (66.2%) and a self expanding valve in 189 (32.4%). All-cause 30-day mortality was 3.5%. All-cause in hospital mortality and disabling stroke occurred in 3.1% and 1.9%, respectively. Median length of stay was 3 days (IQR: 3 to 6 days), with 92.8% of patients discharged directly home. CONCLUSIONS: This experience demonstrates the potential benefits of a regional system of care for TAVR. Excellent outcomes were demonstrated: most patients had short in-hospital stays and were discharged directly home. PMID- 26738665 TI - The Association of Previous Revascularization With In-Hospital Outcomes in Acute Myocardial Infarction Patients: Results From the National Cardiovascular Data Registry. AB - OBJECTIVES: The aim of this study was to compare outcomes of ST-segment elevation myocardial infarction (STEMI) patients with a history of coronary artery bypass graft surgery (CABG), previous percutaneous coronary intervention (PCI), or no previous revascularization undergoing primary PCI. BACKGROUND: Limited data exist regarding door-to-balloon times and clinical outcomes of STEMI patients with a history of CABG or PCI undergoing primary PCI. METHODS: We examined 15,628 STEMI patients who underwent primary PCI at 297 sites in the United States. We used multivariable logistic regression analyses to compare door-to-balloon time delays >90 min and in-hospital major adverse cardiovascular or cerebrovascular events (MACCE). RESULTS: Patients with previous CABG were significantly older and more likely to have multiple comorbidities (p < 0.0001). Previous CABG was associated with a lower likelihood of a door-to-balloon time <=90 min compared with patients with no previous revascularization. However, no significant differences in door to-balloon times were noted between patients with previous PCI and those without previous revascularization. The unadjusted MACCE risk was significantly higher in patients with a history of CABG compared with patients without previous revascularization (odds ratio: 1.68, 95% confidence interval: 1.23 to 2.31). However, after multivariable risk adjustment, there were no significant differences in MACCE risk between the 2 groups. No significant differences in in hospital outcomes were seen in patients with a previous PCI and those without previous revascularization. CONCLUSIONS: In a large cohort of STEMI patients undergoing primary PCI, patients with previous CABG were more likely to have reperfusion delays, yet risk-adjusted, in-hospital outcomes were similar to those without previous revascularization. No significant differences in reperfusion timeliness and in-hospital outcomes were seen in patients with a history of PCI compared with patients without previous revascularization. PMID- 26738666 TI - Timely Primary Percutaneous Coronary Intervention: A Call to Action in the Post Coronary Artery Bypass Graft Patient. PMID- 26738667 TI - Effect of Ischemia Duration and Door-to-Balloon Time on Myocardial Perfusion in ST-Segment Elevation Myocardial Infarction: An Analysis From HORIZONS-AMI Trial (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction). AB - OBJECTIVES: This study sought to investigate the effect of treatment delay on microvascular reperfusion in ST-segment elevation myocardial infarction (STEMI) patients from the large, multicenter, prospective HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial. BACKGROUND: Despite restoration of epicardial blood flow during primary percutaneous coronary intervention (PCI), one-third of patients do not obtain myocardial perfusion due to impairment in the microvascular circulation. METHODS: We examined the effect of symptom onset-to-balloon time (SBT) and door-to-balloon time (DBT) on myocardial reperfusion during primary PCI in STEMI, utilizing resolution of ST-segment elevation (STR) and the myocardial blush grade (MBG). The primary analysis was the relationships between SBT <=2, >2 to 4, and >4 h and DBT <=1, >1 to 1.5, >1.5 to 2, and >2 h with MBG and STR. Clinical risk was assessed using a modified version of the Thrombolysis In Myocardial Infarction risk score for STEMI. RESULTS: In 2,056 patients, absent microvascular perfusion (MBG 0/1) and STR (STR <30%) after primary PCI was significantly more common in patients with longer SBT, in patients with both low and high clinical risk profiles. By multivariable analysis, SBT (p < 0.0001), anterior infarction (p < 0.0001), reference vessel diameter (p = 0.005), lesion minimum lumen diameter (p < 0.0001), hyperlipidemia (p = 0.03), and current smoking (p = 0.001) were independent predictors of MBG 0/1, whereas SBT (p = 0.007), anterior infarction (p < 0.0001), and history of renal insufficiency (p = 0.0002) were independent predictors of absent STR. DBT (p < 0.0001) was an independent predictor of MBG 0/1. MBG 0/1 and STR<30% identified patients with increased 3-year mortality. CONCLUSIONS: The present study suggests that delay in mechanical reperfusion therapy during STEMI is associated with greater injury to the microcirculation. PMID- 26738668 TI - Door-to-Balloon Time as a Process Metric for Treatment of ST-Segment Elevation Myocardial Infarction: Time to "Tap Out"? PMID- 26738670 TI - A Bigger Look Into the "Therapeutic Window" of Platelet Reactivity to Adenosine Diphosphate. PMID- 26738669 TI - Is There an Ideal Level of Platelet P2Y12-Receptor Inhibition in Patients Undergoing Percutaneous Coronary Intervention?: "Window" Analysis From the ADAPT DES Study (Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents). AB - OBJECTIVES: This study sought to determine whether there is an ideal level of platelet reactivity (PR) to optimize safety and efficacy within the large multicenter ADAPT-DES (Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents) study of 8,582 patients receiving successful drug-eluting stent implantation. BACKGROUND: Patients with high PR on clopidogrel have a greater incidence of adverse ischemic events after stent implantation, whereas low PR may increase bleeding. Due to limited sample size, previous studies have not been able to adjust for differences in baseline characteristics that may confound the relationship of PR and outcomes. METHODS: In the ADAPT-DES study, routine platelet function testing (VerifyNow) was performed following clopidogrel loading. To characterize the independent association between PR and clinical events, patients were stratified into quintiles of P2Y12 reaction units (PRU). RESULTS: The PRU medians of the 5 quintiles were 57, 130, 187, 244, and 317 (most to least inhibited). There was a monotonic association between successively higher PRU quintiles and stent thrombosis, whereas for clinically relevant bleeding, the greatest risk occurred in the lowest PRU quintile, with similar risks across the 4 higher quintiles. These relationships remained significant in fully adjusted multivariable analyses (adjusted hazard ratio [HR] for stent thrombosis in Q5 versus Q1: 2.32; 95% confidence interval [CI]: 1.17 to 4.59; p = 0.02; adjusted HR for clinically relevant bleeding in Q5 versus Q1: 0.61; 95% CI: 0.47 to 0.77; p < 0.001). However, there were no significant independent associations between the level of PRU and mortality. CONCLUSIONS: In this large observational study, increasing PRU was associated with a monotonic increase in stent thrombosis, whereas bleeding risk was confined to the lowest PRU quintile, suggesting an optimal therapeutic window of platelet inhibition at moderately inhibited PRU. However, there was no demonstrable threshold effect for PRU and mortality in adjusted analyses, perhaps due to the offsetting impact of bleeding and ischemia across the spectrum of platelet inhibition. (Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents [ADAPT-DES]; NCT00638794). PMID- 26738671 TI - Limitation of Infarct Size and No-Reflow by Intracoronary Adenosine Depends Critically on Dose and Duration. AB - OBJECTIVES: In the absence of effective clinical pharmacotherapy for prevention of reperfusion-mediated injury, this study re-evaluated the effects of intracoronary adenosine on infarct size and no-reflow in a porcine model of acute myocardial infarction using clinical bolus and experimental high-dose infusion regimens. BACKGROUND: Despite the clear cardioprotective effects of adenosine, when administered prior to ischemia, studies on cardioprotection by adenosine when administered at reperfusion have yielded contradictory results in both pre clinical and clinical settings. METHODS: Swine (54 +/- 1 kg) were subjected to a 45-min mid-left anterior descending artery occlusion followed by 2 h of reperfusion. In protocol A, an intracoronary bolus of 3 mg adenosine injected over 1 min (n = 5) or saline (n = 10) was administered at reperfusion. In protocol B, an intracoronary infusion of 50 MUg/kg/min adenosine (n = 15) or saline (n = 21) was administered starting 5 min prior to reperfusion and continued throughout the 2-h reperfusion period. RESULTS: In protocol A, area-at risk, infarct size, and no-reflow were similar between groups. In protocol B, risk zones were similar, but administration of adenosine resulted in significant reductions in infarct size from 59 +/- 3% of the area-at-risk in control swine to 46 +/- 4% (p = 0.02), and no-reflow from 49 +/- 6% of the infarct area to 26 +/- 6% (p = 0.03). CONCLUSIONS: During reperfusion, intracoronary adenosine can limit infarct size and no-reflow in a porcine model of acute myocardial infarction. However, protection was only observed when adenosine was administered via prolonged high-dose infusion, and not via short-acting bolus injection. These findings warrant reconsideration of adenosine as an adjuvant therapy during early reperfusion. PMID- 26738672 TI - Adenosine as Adjunctive Therapy for Acute Myocardial Infarction: Is It Time for Another Clinical Trial? PMID- 26738674 TI - Pulmonary Artery Denervation for Pulmonary Artery Hypertension. PMID- 26738673 TI - Pulmonary Artery Denervation Attenuates Pulmonary Arterial Remodeling in Dogs With Pulmonary Arterial Hypertension Induced by Dehydrogenized Monocrotaline. AB - OBJECTIVES: This study aimed to investigate sympathetic nerve (SN) ultrastructural changes and hemodynamic and pulmonary artery (PA) pathological improvements by pulmonary arterial denervation (PADN) in animals with pulmonary arterial hypertension (PAH), as well as the underlying mechanisms. BACKGROUND: SN overactivity plays a role in PAH. Previous studies have reported short-term improvements in pulmonary arterial pressure (PAP) and cardiac function by PADN, but PA remodeling and the associated mechanisms remain unclear. METHODS: Forty dogs were randomly (ratio of 1:3) assigned to the control (intra-atrial injection of N-dimethylacetamide, 3 mg/kg) and test (intra-atrial injection of dehydrogenized-monocrotaline, 3 mg/kg) groups. After 8 weeks, the animals in the test group with a mean PAP >25 mm Hg (n = 20) were randomized (ratio of 1:1) into the sham and PADN groups. At 14 weeks, the hemodynamics, medial wall thickness and PA muscularization, and messenger ribonucleic acid expression of genes in lung tissues were measured. Another 35 PAH dogs were used to measure the SN conduction velocity, electron microscopic assessment, and nerve distribution. RESULTS: PADN induced significant SN demyelination and axon loss and slowed SN conduction velocity over time, with resulting profound reductions in the mean PAP (23.5 +/- 2.3 mm Hg vs. 33.7 +/- 5.8 mm Hg), pulmonary vessel resistance (3.5 +/- 2.3 Wood units vs. 7.7 +/- 1.7 Wood units), medial wall thickness (22.3 +/- 3.3% vs. 30.4 +/- 4.1%), and full muscularization (40.3 +/- 9.3% vs. 57.1 +/- 5.7%) and increased nonmuscularization (29.8 +/- 6.1% vs. 12.9 +/- 4.9%) compared with the Sham group (all p < 0.001). PADN inhibited the messenger ribonucleic acid expression of genes correlated with inflammation, proliferation, and vasoconstriction. CONCLUSIONS: PADN induces permanent SN injury and subsequent improvements in hemodynamics and PA remodeling in animals with PAH through mechanisms that may be experimentally and clinically beneficial. PMID- 26738675 TI - Calcified Neoatherosclerosis Causing "Undilatable" In-Stent Restenosis: Insights of Optical Coherence Tomography and Role of Rotational Atherectomy. PMID- 26738676 TI - Overexpansion of the SAPIEN 3 Transcatheter Heart Valve: A Feasibility Study. PMID- 26738677 TI - ECG-Independent Calculation of Instantaneous Wave-Free Ratio. PMID- 26738678 TI - The Journal Is Now Biweekly. PMID- 26738679 TI - 2-Year Follow-Up of the First in Human Transapical Implantation of Transcatheter Inverted Aortic Valve to Treat Native Mitral Valve Stenosis. PMID- 26738680 TI - Intimomedial Abrasion Complicating Coronary Thrombus Aspiration. PMID- 26738681 TI - An Unusual Case of Stent-in-Stent Thrombosis. PMID- 26738682 TI - Catheter-Based Edge-to-Edge Mitral Valve Repair After Partial Rupture of Surgical Annuloplasty Ring. PMID- 26738683 TI - Emergent Extracorporeal Circulation for Refractory Ventricular Fibrillation via Transapical Cannulation as an Arterial Line During Transapical Transcatheter Aortic Valve Replacement. PMID- 26738686 TI - Greenhouse gas emissions of an agro-biogas energy system: Estimation under the Renewable Energy Directive. AB - Agro-biogas from energy crops and by-products is a renewable energy carrier that can potentially contribute to climate change mitigation. In this context, application of the methodology defined by the Renewable Energy Directive 2009/28/EC (RED) was performed in order to estimate the 100-year Global Warming Potential (GWP100) associated with an agro-biogas supply chain (SC) in Southern Italy. Doing so enabled calculation of Greenhouse Gas (GHG) emission saving in order to verify if it is at least equal to 35% compared to the fossil fuel reference system, as specified by the RED. For the assessment, an attributional Life Cycle Assessment (LCA) approach (International Organization for Standardization (ISO), 2006a,b) was integrated with the RED methodology applied following the guidelines reported in COM(2010)11 and updated by SWD(2014)259 and Report EUR 27215 EN (2015). Moreover, primary data were collected with secondary data extrapolated from the Ecoinvent database system. Results showed that the GWP100 associated with electricity production through the biogas plant investigated was equal to 111.58gCO2eqMJe(-1) and so a 40.01% GHG-emission saving was recorded compared to the RED reference. The highest contribution comes from biomass production and, in particular, from crop cultivation due to production of ammonium nitrate in the overall amount used for crop cultivation. Based upon the findings of the study, the GHG saving calculated slightly exceeds the related minimum proposed by the RED: therefore, improvements are needed anyway. In particular, the authors documented that through replacement of ammonium nitrate with urea the GHG-emission saving would increase to almost 68%, thus largely satisfying the RED limit. In addition, the study highlighted that conservation practices, such as NT, can significantly enable reduction of the GHG-emissions coming from agricultural activities. Therefore, those practices should be increasingly adopted for cultivation of energy crops, because the latter significantly contribute to biogas production yield enhancement. PMID- 26738688 TI - Multiplex RT-PCR detection of H3N2 influenza A virus in dogs. AB - A multiplex RT-PCR (mRT-PCR) assay to detect H3N2 CIV genomic segments was developed as a rapid and cost-effective method. Its performance was evaluated with forty-six influenza A viruses from different hosts using three primer sets which amplify four segments of H3N2 CIV simultaneously. The mRT-PCR has been successful in detecting the viral segments, indicating that it can improve the speed of diagnosis for H3N2 CIV and its reassortants. PMID- 26738689 TI - Prevalence of Hyperoxaluria in Urinary Stone Formers: Chronological and Geographical Trends and a Literature Review. AB - PURPOSE: To report chronological trends and geographical distributions related to the prevalence of hyperoxaluria in stone-forming patients. MATERIALS AND METHODS: We systematically reviewed the existing literature between 1982 and 2013 seeking studies that assessed for hyperoxaluria (>45 mg/day [499.5 MUmol/24 hour]) in recurrent stone formers. Studies that performed 24-hour urine analysis for urine oxalate in patients with recurrent urinary stones were included. Studies were divided chronologically and by geographical region, and prevalence rates of hyperoxaluria were compared between groups. RESULTS: Our literature search provided 22 peer-reviewed articles involving 3636 patients in total. Ten studies were performed between 1982 and 2000, and 12 studies were performed between 2001 and 2013. The prevalence of hyperoxaluria in stone-forming patient cohorts was 24.8% and 45.1% (p = 0.019) in studies performed between 1982 and 2000 and 2001 and 2013, respectively. Hyperoxaluria rates were significantly higher in non American cohorts compared with American cohorts (40.7% vs 23.0%; p = 0.018). Reported hyperoxaluria rates were higher in Asian countries compared with Western countries (56.8% and 23.8%; p < 0.001). CONCLUSIONS: The prevalence of hyperoxaluria in stone-forming patients has increased over the past two decades and may be a contributing factor to the rising global prevalence of urolithiasis. A geographical disparity in hyperoxaluria may exist between Asian and Western countries. Future studies are needed to explain these trends and their consequences. PMID- 26738690 TI - Reply: Externalities and citation practices. PMID- 26738691 TI - Zero-Point Energy Constraint for Unimolecular Dissociation Reactions. Giving Trajectories Multiple Chances To Dissociate Correctly. AB - A zero-point energy (ZPE) constraint model is proposed for classical trajectory simulations of unimolecular decomposition and applied to CH4* -> H + CH3 decomposition. With this model trajectories are not allowed to dissociate unless they have ZPE in the CH3 product. If not, they are returned to the CH4* region of phase space and, if necessary, given additional opportunities to dissociate with ZPE. The lifetime for dissociation of an individual trajectory is the time it takes to dissociate with ZPE in CH3, including multiple possible returns to CH4*. With this ZPE constraint the dissociation of CH4* is exponential in time as expected for intrinsic RRKM dynamics and the resulting rate constant is in good agreement with the harmonic quantum value of RRKM theory. In contrast, a model that discards trajectories without ZPE in the reaction products gives a CH4* -> H + CH3 rate constant that agrees with the classical and not quantum RRKM value. The rate constant for the purely classical simulation indicates that anharmonicity may be important and the rate constant from the ZPE constrained classical trajectory simulation may not represent the complete anharmonicity of the RRKM quantum dynamics. The ZPE constraint model proposed here is compared with previous models for restricting ZPE flow in intramolecular dynamics, and connecting product and reactant/product quantum energy levels in chemical dynamics simulations. PMID- 26738692 TI - Compact Nonlinear Yagi-Uda Nanoantennas. AB - Nanoantennas have demonstrated unprecedented capabilities for manipulating the intensity and direction of light emission over a broad frequency range. The directional beam steering offered by nanoantennas has important applications in areas including microscopy, spectroscopy, quantum computing, and on-chip optical communication. Although both the physical principles and experimental realizations of directional linear nanoantennas has become increasingly mature, angular control of nonlinear radiation using nanoantennas has not been explored yet. Here we propose a novel concept of nonlinear Yagi-Uda nanoantenna to direct second harmonic radiation from a metallic nanosphere. By carefully tuning the spacing and dimensions of two lossless dielectric elements, which function respectively as a compact director and reflector, the second harmonic radiation is deflected 90 degrees with reference to the incident light (pump) direction. This abnormal light-bending phenomenon is due to the constructive and destructive interference between the second harmonic radiation governed by a special selection rule and the induced electric dipolar and magnetic quadrupolar radiation from the two dielectric antenna elements. Simultaneous spectral and spatial isolation of scattered second harmonic waves from incident fundamental waves pave a new way towards nonlinear signal detection and sensing. PMID- 26738693 TI - [Relationship between metabolic syndrome and lower urinary tract symptoms in men]. PMID- 26738694 TI - Effect of p53 Arg72Pro polymorphism on the induction of micronucleus by aflatoxin B1 in in vitro in human blood lymphocytes. AB - Aflatoxin B1 (AFB1) is a class 1 carcinogen produced by Aspergillus flavus and Aspergillus parasiticus that can contaminate a variety of food substances, the liver being its target organ. A common p53 Arg72Pro polymorphism resulting in the substitution of an arginine amino acid by proline amino acid in the transactivating domain has been demonstrated to affect p53 function. The aim of this study is to investigate association between p53 Arg72Pro polymorphism and the frequencies of spontaneous and AFB1-induced DNA damage in peripheral blood lymphocytes from 100 healthy individuals in Turkish population. In vitro cytokinesis-blocked micronucleus (CBMN) assay was used to detect the spontaneous and AFB1-induced DNA damage whereas, genotyping of p53 Arg72Pro polymorphism was carried out by using a polymerase chain reaction restriction fragment length polymorphism assay. During 68 h incubation time, lymphocytes treated with AFB1 (1.56 MUg/mL) and S9 mix for a total of 3 h (48-51 h). Treatment of the lymphocytes with AFB1 significantly increased the overall frequencies of micronucleus (MN) when compared to untreated cultures (1.23 +/- 0.05 versus 0.55 +/- 0.02; p <0.001). Moreover, genotype analysis revealed a statistically significant association between Pro/Pro genotype of p53 Arg72Pro polymorphism and increased frequencies of MN both spontaneous and AFB1-induced cultures when compared Arg/Arg genotype (0.69 +/- 0.19 versus 0.46 +/- 0.13, p < 0.001; 1.59 +/ 0.65 versus 1.01 +/- 0.41 p < 0.001; respectively). Our data indicate that p53 Arg72Pro polymorphism plays a significant role in human sensitivity to the genotoxic effects of AFB1. Further investigations in larger sample size and with different ethnic origins as well as including more functional single nucleotide polymorphisms might lead to the identification of novel genetic factors responsible for susceptibility to human carcinogens such as AFB1. PMID- 26738695 TI - Freestanding Flag-Type Triboelectric Nanogenerator for Harvesting High-Altitude Wind Energy from Arbitrary Directions. AB - Wind energy at a high altitude is far more stable and stronger than that near the ground, but it is out of reach of the wind turbine. Herein, we develop an innovative freestanding woven triboelectric nanogenerator flag (WTENG-flag) that can harvest high-altitude wind energy from arbitrary directions. The wind-driven fluttering of the woven unit leads to the current generation by a coupled effect of contact electrification and electrostatic induction. Systematic study is conducted to optimize the structure/material parameters of the WTENG-flag to improve the power output. This 2D WTENG-flag can also be stacked in parallel connections in many layers for a linearly increased output. Finally, a self powered high-altitude platform with temperature/humidity sensing/telecommunicating capability is demonstrated with the WTENG-flag as a power source. Due to the light weight, low cost, and easy scale-up, this WTENG flag has great potential for applications in weather/environmental sensing/monitoring systems. PMID- 26738696 TI - High prevalence of hypertension among an ethnic group in Sudan: implications for prevention. AB - OBJECTIVE: Hypertension is an emerging non-communicable disease in developing countries. Due to its silent nature and serious complications, active screening is essential in order to prevent complications. For instance, premature mortality from cardiovascular diseases could be prevented by the effective control of hypertension. The aim of this study was to determine the prevalence of undiagnosed hypertension among Nuba ethnic group living in Atbara city, north Sudan and to identify the associated risk factors. SUBJECT AND METHODS: All consenting 500 adults from Nuba tribe who live in El Wihda District, Atbara were included. Blood pressure (BP) and body mass index were measured. Standard interviewing procedures were used to record medical history, socio-demographic data, and lifestyle characteristics. RESULTS: Among the 500 participants, females were 364 (72.8%) and males were 136 (27.2%). The overall prevalence of undiagnosed hypertension was 49.4% (30.8% stage 1 hypertension and 18.6% stage 2 hypertension). In addition, 41% of the population was having prehypertension. The significant risk factors for high BP were: male sex, age above 45 years, overweight, illiteracy, and alcohol consumption. CONCLUSION: Undiagnosed high BP is very common among Nuba ethnic group; therefore, active screening and early management are recommended to prevent complications. PMID- 26738697 TI - Use of Raman optical tweezers for cell cycle analysis. AB - We report the results of our investigations on the use of Raman optical tweezers for label free analysis of cells in different phases of their cell cycle. The studies performed on human colon adenocarcinoma (Colo-205) cells synchronized in G0/G1 and G2/M phases showed that the DNA Raman band at 783 cm(-1) in the Raman spectra of optically trapped cells can provide information about the DNA content in the nucleus of the cell without the need for the isolation of the nucleus. The histograms of intensity of this band among the cell populations were found to corroborate the results obtained from fluorescence image cytometry performed on DAPI stained cells. PMID- 26738698 TI - Metal-free organic dyes for TiO2 and ZnO dye-sensitized solar cells. AB - We report the synthesis and characterization of new metal-free organic dyes (namely B18, BTD-R, and CPTD-R) which designed with D-pi-A concept to extending the light absorption region by strong conjugation group of pi-linker part and applied as light harvester in dye sensitized solar cells (DSSCs). We compared the photovoltaic performance of these dyes in two different photoanodes: a standard TiO2 mesoporous photoanode and a ZnO photoanode composed of hierarchically assembled nanostructures. The results demonstrated that B18 dye has better photovoltaic properties compared to other two dyes (BTD-R and CPTD-R) and each dye has higher current density (Jsc) when applied to hierarchical ZnO nanocrystallites than the standard TiO2 mesoporous film. Transient photocurrent and photovoltage decay measurements (TCD/TVD) were applied to systematically study the charge transport and recombination kinetics in these devices, showing the electron life time (tauR) of B18 dye in ZnO and TiO2 based DSSCs is higher than CPTD-R and BTD-R based DSSCs, which is consistent with the photovoltaic performances. The conversion efficiency in ZnO based DSSCs can be further boosted by 35%, when a compact ZnO blocking layer (BL) is applied to inhibit electron back reaction. PMID- 26738700 TI - Health security: the defining challenge of 2016. PMID- 26738699 TI - Earliest tea as evidence for one branch of the Silk Road across the Tibetan Plateau. AB - Phytoliths and biomolecular components extracted from ancient plant remains from Chang'an (Xi'an, the city where the Silk Road begins) and Ngari (Ali) in western Tibet, China, show that the tea was grown 2100 years ago to cater for the drinking habits of the Western Han Dynasty (207BCE-9CE), and then carried toward central Asia by ca.200CE, several hundred years earlier than previously recorded. The earliest physical evidence of tea from both the Chang'an and Ngari regions suggests that a branch of the Silk Road across the Tibetan Plateau, was established by the second to third century CE. PMID- 26738701 TI - Time to eliminate rabies. PMID- 26738702 TI - Editing the genome--will society catch up with science? PMID- 26738703 TI - Time for a prepublication culture in clinical research? PMID- 26738705 TI - Wakley Prize 2015: a lesson in medical humanism. PMID- 26738707 TI - 2015: review of the year. PMID- 26738708 TI - Scientists welcome new global climate change pact. PMID- 26738710 TI - Tuberculosis in young refugees. PMID- 26738711 TI - Health assistance of displaced people along the Balkan route. PMID- 26738712 TI - Refugees in the eastern Mediterranean region. PMID- 26738713 TI - Refugee and migrant health: a priority in the WHO European Region. PMID- 26738714 TI - Ebola vaccination. PMID- 26738715 TI - Ebola vaccination. PMID- 26738716 TI - Ebola vaccination - Authors' reply. PMID- 26738717 TI - Department of Error. PMID- 26738718 TI - Extreme, expedition, and wilderness medicine. AB - Extreme, expedition, and wilderness medicine are modern and rapidly evolving specialties that address the spirit of adventure and exploration. The relevance of and interest in these specialties are changing rapidly to match the underlying activities, which include global exploration, adventure travel, and military deployments. Extreme, expedition, and wilderness medicine share themes of providing best available medical care in the outdoors, especially in austere or remote settings. Early clinical and logistics decision making can often have important effects on subsequent outcomes. There are lessons to be learned from out-of-hospital care, military medicine, humanitarian medicine, and disaster medicine that can inform in-hospital medicine, and vice-versa. The future of extreme, expedition, and wilderness medicine will be defined by both recipients and practitioners, and empirical observations will be transformed by evidence based practice. PMID- 26738719 TI - Pre-hospital emergency medicine. AB - Pre-hospital care is emergency medical care given to patients before arrival in hospital after activation of emergency medical services. It traditionally incorporated a breadth of care from bystander resuscitation to statutory emergency medical services treatment and transfer. New concepts of care including community paramedicine, novel roles such as emergency care practitioners, and physician delivered pre-hospital emergency medicine are re-defining the scope of pre-hospital care. For severely ill or injured patients, acting quickly in the pre-hospital period is crucial with decisions and interventions greatly affecting outcomes. The transfer of skills and procedures from hospital care to pre hospital medicine enables early advanced care across a range of disciplines. The variety of possible pathologies, challenges of environmental factors, and hazardous situations requires management that is tailored to the patient's clinical need and setting. Pre-hospital clinicians should be generalists with a broad understanding of medical, surgical, and trauma pathologies, who will often work from locally developed standard operating procedures, but who are able to revert to core principles. Pre-hospital emergency medicine consists of not only clinical care, but also logistics, rescue competencies, and scene management skills (especially in major incidents, which have their own set of management principles). Traditionally, research into the hyper-acute phase (the first hour) of disease has been difficult, largely because physicians are rarely present and issues of consent, transport expediency, and resourcing of research. However, the pre-hospital phase is acknowledged as a crucial period, when irreversible pathology and secondary injury to neuronal and cardiac tissue can be prevented. The development of pre-hospital emergency medicine into a sub-specialty in its own right should bring focus to this period of care. PMID- 26738720 TI - Lifelines. PMID- 26738721 TI - Tandem photoaffinity labeling of a target protein using a linker with biotin, alkyne and benzophenone groups and a bioactive small molecule with an azide group. AB - A novel linker containing biotin, alkyne and benzophenone groups (1) was synthesized to identify target proteins using a small molecule probe. This small molecule probe contains an azide group (azide probe) that reacts with an alkyne in 1 via an azide-alkyne Huisgen cycloaddition. Cross-linking of benzophenone to the target protein formed a covalently bound complex consisting of the azide probe and the target protein via 1. The biotin was utilized via biotin-avidin binding to identify the cross-linked complex. To evaluate the effectiveness of 1, it was applied in a model system using an allene oxide synthase (AOS) from the model moss Physcomitrella patens (PpAOS1) and an AOS inhibitor that contained azide group (3). The cross-linked complex consisting of PpAOS1, 1 and 3 was resolved via SDS-PAGE and visualized using a chemiluminescent system. The method that was developed in this study enables the effective identification of target proteins. PMID- 26738722 TI - The van der Waals interactions in rare-gas dimers: the role of interparticle interactions. AB - We investigate the potential energy curves of rare-gas dimers with various ranges and strengths of interparticle interactions (nuclear-electron, electron-electron, and nuclear-nuclear interactions). Our investigation is based on the highly accurate coupled-cluster theory associated with those interparticle interactions. For comparison, the performances of the corresponding Hartree-Fock theory, second order Moller-Plesset perturbation theory, and density functional theory are also investigated. Our results reveal that when the interparticle interactions retain the long-range Coulomb tails, the nature of van der Waals interactions in the rare-gas dimers remains similar. By contrast, when the interparticle interactions are sufficiently short-range, the conventional van der Waals interactions in the rare-gas dimers completely disappear, yielding purely repulsive potential energy curves. PMID- 26738723 TI - Transcriptional analysis of porcine intestinal mucosa infected with Salmonella Typhimurium revealed a massive inflammatory response and disruption of bile acid absorption in ileum. AB - Infected pork meat is an important source of non-typhoidal human salmonellosis. Understanding of molecular mechanisms involved in disease pathogenesis is important for the development of therapeutic and preventive strategies. Thus, hereby we study the transcriptional profiles along the porcine intestine during infection with Salmonella Typhimurium, as well as post-transcriptional gene modulation by microRNAs (miRNA). Sixteen piglets were orally challenged with S. Typhimurium. Samples from jejunum, ileum and colon, collected 1, 2 and 6 days post infection (dpi) were hybridized to mRNA and miRNA expression microarrays and analyzed. Jejunum showed a reduced transcriptional response indicating mild inflammation only at 2 dpi. In ileum inflammatory genes were overexpressed (e.g., IL-1B, IL-6, IL-8, IL1RAP, TNFalpha), indicating a strong immune response at all times of infection. Infection also down-regulated genes of the FXR pathway (e.g., NR1H4, FABP6, APOA1, SLC10A2), indicating disruption of the bile acid absorption in ileum. This result was confirmed by decreased high-density lipoprotein cholesterol in serum of infected pigs. Ileal inflammatory gene expression changes peaked at 2 dpi and tended to resolve at 6 dpi. Furthermore, miRNA analysis of ileum at 2 dpi revealed 62 miRNAs potentially regulating target genes involved in this inflammatory process (e.g., miR-374 and miR-451). In colon, genes involved in epithelial adherence, proliferation and cellular reorganization were down regulated at 2 and 6 dpi. In summary, here we show the transcriptional changes occurring at the intestine at different time points of the infection, which are mainly related to inflammation and disruption of the bile acid metabolism. PMID- 26738724 TI - Diagnosis of an imported Plasmodium ovale wallikeri infection in Malaysia. AB - Plasmodium ovale is rare and not exactly known to be autochthonous in Malaysia. There are two distinct forms of the parasite, namely P. ovale curtisi (classic form) and P. ovale wallikeri (variant form). Here, the first sequence confirmed case of an imported P. ovale wallikeri infection in Malaysia is presented. Microscopy found Plasmodium parasites with morphology similar to P. ovale or Plasmodium vivax in the blood films. Further confirmation using polymerase chain reaction (PCR) targeting the small-subunit rRNA gene of the parasite was unsuccessful. Genus-specific PCR was then performed and the product was sequenced and analysed. Sequence analyses confirmed the aetiological agent as P. ovale wallikeri. New species-specific primers (rOVA1v and rOVA2v) were employed and P. ovale wallikeri was finally confirmed. The findings highlight the need to look out for imported malaria infections in Malaysia and the importance of a constantly updated and validated diagnostic technique. PMID- 26738726 TI - The levels of blood mercury and inflammatory-related neuropeptides in the serum are correlated in children with autism spectrum disorder. AB - Tachykinins (substance P, neurokinin A, and neurokinin B) are pro-inflammatory neuropeptides that may play an important role in some autoimmune neuroinflammatory diseases, including autism spectrum disorder (ASD). Mercury (Hg) is a neurotoxicant, and potentially one of the main environmental triggers for ASD as it induces neuroinflammation with a subsequent release of neuropeptides. This is the first study to explore the potentially causal relationship between levels of serum neurokinin A and blood mercury (BHg) in children with ASD. Levels of serum neurokinin A and BHg were measured in 84 children with ASD, aged between 3 and 10 years, and 84 healthy-matched children. There was a positive linear relationship between the Childhood Autism Rating Scale (CARS) and both serum neurokinin A and BHg. ASD children had significantly higher levels of serum neurokinin A than healthy controls (P < 0.001). Increased levels of serum neurokinin A and BHg were respectively found in 54.8 % and 42.9 % of the two groups. There was significant and positive linear relationship between levels of serum neurokinin A and BHg in children with moderate and severe ASD, but not in healthy control children. It was found that 78.3 % of the ASD patients with increased serum levels of neurokinin A had elevated BHg levels (P < 0.001). Neuroinflammation, with increased levels of neurokinin A, is seen in some children with ASD, and may be caused by elevated BHg levels. Further research is recommended to determine the pathogenic role of increased levels of serum neurokinin A and BHg in ASD. The therapeutic role of tachykinin receptor antagonists, a potential new class of anti-inflammatory medications, and Hg chelators, should also be studied in ASD. PMID- 26738725 TI - Local admixture of amplified and diversified secreted pathogenesis determinants shapes mosaic Toxoplasma gondii genomes. AB - Toxoplasma gondii is among the most prevalent parasites worldwide, infecting many wild and domestic animals and causing zoonotic infections in humans. T. gondii differs substantially in its broad distribution from closely related parasites that typically have narrow, specialized host ranges. To elucidate the genetic basis for these differences, we compared the genomes of 62 globally distributed T. gondii isolates to several closely related coccidian parasites. Our findings reveal that tandem amplification and diversification of secretory pathogenesis determinants is the primary feature that distinguishes the closely related genomes of these biologically diverse parasites. We further show that the unusual population structure of T. gondii is characterized by clade-specific inheritance of large conserved haploblocks that are significantly enriched in tandemly clustered secretory pathogenesis determinants. The shared inheritance of these conserved haploblocks, which show a different ancestry than the genome as a whole, may thus influence transmission, host range and pathogenicity. PMID- 26738727 TI - Quinolinic acid induces cell apoptosis in PC12 cells through HIF-1-dependent RTP801 activation. AB - Neurological disease comprises a series of disorders featuring brain dysfunction and neuronal cell death. Among the factors contributing to neuronal death, excitotoxicity induced by excitatory amino acids, such as glutamate, plays a critical role. However, the mechanisms about how the excitatory amino acids induce neuronal death remain elucidated. In this study, we investigated the role of HIF-1alpha (hypoxia inducible factor-1alpha) and RTP801 in cell apoptosis induced by quinolinic acid (QUIN), a glutamatergic agonist, in PC12 cells. We found that QUIN at 5 MUM increased the expression of HIF-1alpha significantly with a peak at 24 h. After the treatment with QUIN (5-20 MUM) for 24 h, the cells exhibited decreased viability and cell apoptosis with a concomitant increased expression of apoptosis related proteins. QUIN treatment also induced the generation of intracellular reactive oxygen species and RTP801 up-regulation in a HIF-1alpha-dependent manner that were inhibited by 2-methoxyestradiol, a HIF 1alpha inhibitor. Importantly, HIF-1 or RTP801 invalidation by siRNA rescued the cell apoptosis induced by QUIN or cobalt chloride, a chemical inducer of HIF-1. Taken together, these findings support the concept that neurotoxicity induced by QUIN is associated with HIF-1-dependent RTP801 activation and provide insight into the potential of RTP801 inhibitor in treatment of neurological disorders. PMID- 26738729 TI - EPSM2015, Engineering and Physical Sciences in Medicine : Museum of New Zealand Te Papa Tongarewa, Wellington, 8-12 November 2015, Conference abstracts. PMID- 26738728 TI - Potential roles of fibroblast growth factor 21 in the brain. AB - Fibroblast growth factor 21 (FGF21) is an endocrine hormone, playing an important role in the regulation of metabolism. FGF21 is primarily expressed by several tissues, including liver, pancreas, thymus, heart, muscle, adipose tissue, and brain. In addition to the effects of FGF21 in lowering glucose and lipid levels, increasing insulin sensitivity and regulating energy homeostasis in rodents and non-human primate models of diabetes and obesity, previous reports have demonstrated that FGF21 also plays an important role in the brain involving it in potential effects in metabolic regulation, neuroprotection and cognition. In this review, the current available evidence from both in vitro and in vivo investigations regarding the roles of FGF21 and its function in the brain are comprehensively summarized. In addition, the mechanistic insights regarding the roles of FGF21 in the brain and its potential neuroprotective benefits are also presented and discussed. PMID- 26738730 TI - Bilateral Superior Semicircular Canal Dehiscence and Tullio Phenomenon. PMID- 26738731 TI - Cannabidiol Post-Treatment Alleviates Rat Epileptic-Related Behaviors and Activates Hippocampal Cell Autophagy Pathway Along with Antioxidant Defense in Chronic Phase of Pilocarpine-Induced Seizure. AB - Abnormal and sometimes severe behavioral and molecular symptoms are usually observed in epileptic humans and animals. To address this issue, we examined the behavioral and molecular aspects of seizure evoked by pilocarpine. Autophagy can promote both cell survival and death, but there are controversial reports about the neuroprotective or neurodegenerative effects of autophagy in seizure. Cannabidiol has anticonvulsant properties in some animal models when used as a pretreatment. In this study, we investigated alteration of seizure scores, autophagy pathway proteins, and antioxidant status in hippocampal cells during the chronic phase of pilocarpine-induced epilepsy after treatment with cannabidiol. Cannabidiol (100 ng, intracerebroventricular injection) delayed the chronic phase of epilepsy. Single administration of cannabidiol during the chronic phase of seizure significantly diminished seizure scores such as mouth clonus, head nodding, monolateral and bilateral forelimb clonus and increased the activity of catalase enzyme and reduced glutathione content. Such a protective effect in the behavioral scores of epileptic rats was also observed after repeated administrations of cannabidiol at the onset of the silent phase. Moreover, the amount of Atg7, conjugation of Atg5/12, Atg12, and LC3II/LC3I ratio increased significantly in epileptic rats treated with repeated injections of cannabidiol. In short, our results suggest that post-treatment of Cannabidiol could enhance the induction of autophagy pathway and antioxidant defense in the chronic phase of epilepsy, which could be considered as the protective mechanisms of cannabidiol in a temporal lobe epilepsy model. PMID- 26738732 TI - Autophagy Promotes Peripheral Nerve Regeneration and Motor Recovery Following Sciatic Nerve Crush Injury in Rats. AB - Autophagy maintains cellular homeostasis by stimulating the lysosomal degradation of cytoplasmic structures, including damaged organelles and dysfunctional proteins. The role of autophagy in the renewal and regeneration of injured peripheral nerves remains poorly understood. The current study investigated the role of autophagy in peripheral nerve regeneration and motor function recovery following sciatic nerve crush injury in rats by stimulating or suppressing autophagy and detecting the presence of autophagosomes and LC3-II expression by electron microscopy and Western blotting, respectively. Neurobehavioral function was tested by CatWalk gait analysis 1, 2, 3, and 6 weeks after injury, and the expression of neurofilament (NF)-200 and myelin basic protein (MBP) at the injury site was examined by immunocytochemistry. Apoptosis at the lesion site was determined by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Treatment of injured rats with the autophagy inducer rapamycin increased the number of autophagosomes and LC3-II expression while reducing the number of apoptotic cells at the lesion; this was associated with an upregulation of MBP and NF-200 expression and increased motor function recovery as compared to sham operated rats and those that were subjected to crush injury but untreated. The opposite effects were observed in rats treated with the autophagy inhibitor 3 methyladenine. These data indicate that the modulation of autophagy in peripheral nerve injury could be an effective pharmacological approach to promote nerve regeneration and reestablish motor function. PMID- 26738733 TI - Significant but reasonable radiation exposure from computed tomography-related medical imaging in the ICU. AB - Admission to an intensive care unit (ICU) is associated with increased medical imaging and radiation exposure, yet few studies have estimated the risk of cancer associated with these examinations. The purpose of this study was to review computed tomography (CT) scans performed on patients admitted to two urban academic ICUs, predict their radiation exposure, and calculate their estimated lifetime attributable risk of cancer (LAR). An electronic chart review was performed on all CT scans performed between January 2007 and December 2011. The estimated effective dose of radiation was calculated for each CT, and the LAR for each patient was predicted. Mean radiation exposure was 22.2 +/- 25.0 mSv with a mean LAR of 0.1 +/- 0.2 % and a median of 0.6 % with a range of <0.001 to 3.4 %. Our cohort received radiation doses higher than recommended by guidelines; however, the critical nature of their admission may have warranted these imaging studies. Estimated risk of cancer in this population was overall low. PMID- 26738734 TI - Bioactivity and laundering resistance of five commercially available, factory treated permethrin-impregnated fabrics for the prevention of mosquito-borne diseases: the need for a standardized testing and licensing procedure. AB - Personal protective measures against hematophagous vectors constitute the first line of defense against arthropod-borne diseases. In this regard, a major advance has been the development of residual insecticides that can be impregnated into clothing. Currently, however, information on specific treatment procedures, initial insecticide concentrations, arthropod toxicity, residual activity, and laundering resistance is either fragmentary or non-existent, and no World Health Organization Pesticides Evaluation Scheme or other guidelines exist for the standardized testing and licensing of insecticide-treated clothing. The aim of this study was to analyze the insecticide content, contact toxicity, laundering resistance, and residual activity of five commercially available and commonly used permethrin-treated fabrics-Insect Shield, ExOfficio, Sol's Monarch T-shirts, battle dress uniforms (BDUs), and Labonal socks-against vector-competent Aedes aegypti, Anopheles stephensi, and Culex pipiens mosquitoes under laboratory conditions. Prior to laundering, permethrin concentrations ranged from 4300 to 870 mg/m(2) whereas, after 100 defined machine launderings, the remaining permethrin content fell to between 1800 and 20 mg/m(2), a percentage permethrin loss of 58.1 to 98.5 %. The highest 99 % knockdown (KD99) efficacy of permethrin was detected in Ae. aegypti, followed by An. stephensi and Cx. pipiens demonstrating that Ae. aegypti is the most sensitive species and Cx. pipiens the least sensitive. After 100 launderings, the remaining biocidal efficacy differed markedly among the five brands, with KD99 times varying from 38.8 +/- 2.9 to >360 min for Ae. aegypti, from 44 +/- 3.5 to >360 min for An. stephensi, and from 98 +/- 10.6 to >360 min for Cx. pipiens. Overall, the ranking of the residual biocidal efficacies within the five brands tested was as follows: BDU ~ Labonal > Sol's Monarch > ExOfficio > Insect Shield. When applying German Armed Forces licensing conditions, none of the four products available in the civilian market would completely meet all the necessary efficacy and safety requirements fulfilled by BDUs. Therefore, we strongly recommend standardized testing and licensing procedures for insecticide-treated clothing, with defined cutoff values for initial maximum and post-laundering minimum concentrations of permethrin as well as figures for permethrin migration rates, arthropod toxicity, homogeneity on fabrics, residual activity, and laundering resistance. PMID- 26738735 TI - Reptile Toll-like receptor 5 unveils adaptive evolution of bacterial flagellin recognition. AB - Toll-like receptors (TLR) are ancient innate immune receptors crucial for immune homeostasis and protection against infection. TLRs are present in mammals, birds, amphibians and fish but have not been functionally characterized in reptiles despite the central position of this animal class in vertebrate evolution. Here we report the cloning, characterization, and function of TLR5 of the reptile Anolis carolinensis (Green Anole lizard). The receptor (acTLR5) displays the typical TLR protein architecture with 22 extracellular leucine rich repeats flanked by a N- and C-terminal leucine rich repeat domain, a membrane-spanning region, and an intracellular TIR domain. The receptor is phylogenetically most similar to TLR5 of birds and most distant to fish TLR5. Transcript analysis revealed acTLR5 expression in multiple lizard tissues. Stimulation of acTLR5 with TLR ligands demonstrated unique responsiveness towards bacterial flagellin in both reptile and human cells. Comparison of acTLR5 and human TLR5 using purified flagellins revealed differential sensitivity to Pseudomonas but not Salmonella flagellin, indicating development of species-specific flagellin recognition during the divergent evolution of mammals and reptiles. Our discovery of reptile TLR5 fills the evolutionary gap regarding TLR conservation across vertebrates and provides novel insights in functional evolution of host-microbe interactions. PMID- 26738737 TI - Socioeconomic Inequalities in the Utilization of Colorectal Stents for the Treatment of Malignant Bowel Obstruction. AB - BACKGROUND: Colorectal stents are increasingly employed as a bridge to surgery or for palliative relief of malignant large bowel obstruction. AIM: To explore determinants of inpatient colorectal stent utilization (CRSU). METHODS: An analysis of the 2012 National Inpatient Sample was performed. International Classification of Diseases, 9th revision, codes were used to identify discharges associated with CRSU and patient/hospital factors for inclusion in a logistic regression model. RESULTS: We identified 217,055 inpatient colonoscopies, approximating 1.1 million inpatient colonoscopies nationwide. Colorectal stents were placed in 1.4 % of all procedures. Across all racial groups, Medicare was the most common payer. Patients with commercial insurance had lower CRSU compared with Medicare patients [adjusted odds ratio (OR) 0.83, 95 % confidence interval (CI) 0.75-0.92]. No gender disparities were identified (OR 0.96, 95 % CI 0.89 1.03). In addition, no racial differences in CRSU existed between Caucasians versus African-Americans (OR 0.94, 95 % CI 0.83-1.06) and Caucasians versus Hispanics (OR 0.96, 95 % CI 0.83-1.1). Compared with patients living in less affluent neighborhoods, those residing in more affluent areas had higher CRSU (OR 1.65, 95 % CI 1.46-1.86). This displayed a linear relationship with the odds of CRSU increasing as household income increased. Less affluent patients also had the highest total charges and longest wait time to CRSU. CRSU was highest among patients treated in larger medical centers (OR 1.7, 95 % CI 1.51-1.93) and teaching hospitals (OR 3.9, 95 % CI 3.2-4.8). CONCLUSION: Individuals from less affluent neighborhoods have lower colorectal stent utilization. This disparity is independent of race and likely related to poorer access to healthcare resources. PMID- 26738736 TI - IL-6/STAT3 Plays a Regulatory Role in the Interaction Between Pancreatic Stellate Cells and Cancer Cells. AB - BACKGROUND: Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis, a characteristic feature of pancreatic cancer. Although it is still controversial, previous studies have suggested that PSCs promote the progression of pancreatic cancer by regulating the cell functions of cancer cells. PSCs produce large amounts of IL-6, which promotes the accumulation of myeloid-derived suppressor cells via a signal transducers and activator of transcription 3 (STAT3)-dependent mechanism. But the role of IL-6/STAT3 pathway in the interaction between PSCs and pancreatic cancer cells remains largely unknown. AIMS: To clarify the role of IL-6/STAT3 in the interaction between PSCs and cancer cells. METHODS: Human pancreatic cancer cells (Panc-1 and SUIT-2 cells) were treated with conditioned medium of immortalized human PSCs (PSC-CM). The effects of PSC-CM and IL-6 neutralization on the mRNA expression profiles were examined using Agilent's microarray. Activation of STAT3 was assessed by Western blotting using an anti-phospho-specific antibody. Cellular migration was examined by a two-chamber assay. The expression of markers related to epithelial mesenchymal transition (EMT) was assessed by real-time reverse transcription PCR. RESULTS: PSC-CM induced the activation of STAT3 in pancreatic cancer cells. Neutralization of IL-6 suppressed the PSC-CM-induced upregulation of genes including complement factor B, lipocalin, and chemokine (C-C motif) ligand 20. Inhibition of IL-6/STAT3 pathway by anti-IL-6 antibody or a STAT3 inhibitor (NSC74859) inhibited the PSC-CM-induced migration and the expression of EMT related markers (Snail and cadherin-2) in pancreatic cancer cells. CONCLUSION: IL 6/STAT3 pathway regulates the PSC-induced EMT and alterations in gene expression in pancreatic cancer cells. PMID- 26738738 TI - Choledocholithiasis Without Cholelithiasis: Should the Gallbladder Stay or Should It Go? PMID- 26738739 TI - Capillary Penetration into Inclined Circular Glass Tubes. AB - The spontaneous penetration of a wetting liquid into a vertical tube against the force of gravity and the imbibition of the same liquid into a horizontal tube (or channel) are both driven by capillary forces and described by the same fundamental equations. However, there have been few experimental studies of the transition from one orientation to the other. We report systematic measurements of capillary penetration of polydimethylsiloxane oils of viscosities 9.6, 19.2, and 48.0 mPa.s into glass capillary tubes. We first report the effect of tube radii R between 140 and 675 MUm on the dynamics of spontaneous imbibition. We show that the data can be fitted using the exact numerical solution to the governing equations and that these are similar to fits using the analytical viscogravitational approximation. However, larger diameter tubes show a rate of penetration slower than expected using an equilibrium contact angle and the known value of liquid viscosity. To account for the slowness, an increase in viscosity by a factor (eta/rho)(scaling) is needed. We show full agreement with theory requires the ratio R/kappa(-1) ~ 0.1 or less, where kappa(-1) is the capillary length. In addition, we propose an experimental method that enables the determination of the dynamic contact angle during imbibition, which gives values that agree with the literature values. We then report measurements of dynamic penetration into the tubes of R = 190 and 650 MUm for a range of inclination angles to the horizontal, phi, from 5 to 90 degrees . We show that capillary penetration can still be fitted using the viscogravitational solution, rather than the Bosanquet solution which describes imbibition without gravity, even for inclination angles as low as 10 degrees . Moreover, at these low angles, the effect of the tube radius is found to diminish and this appears to relate to an effective capillary length, kappa(-1)(phi) = (gamma(LV)/rhog sin phi)(1/2). PMID- 26738741 TI - Corrigendum: Zebrafish Models for Human Acute Organophosphorus Poisoning. PMID- 26738740 TI - ELF5 isoform expression is tissue-specific and significantly altered in cancer. AB - BACKGROUND: E74-like factor 5 (ELF5) is an epithelial-specific member of the E26 transforming sequence (ETS) transcription factor family and a critical regulator of cell fate in the placenta, pulmonary bronchi, and milk-producing alveoli of the mammary gland. ELF5 also plays key roles in malignancy, particularly in basal like and endocrine-resistant forms of breast cancer. Almost all genes undergo alternative transcription or splicing, which increases the diversity of protein structure and function. Although ELF5 has multiple isoforms, this has not been considered in previous studies of ELF5 function. METHODS: RNA-sequencing data for 6757 samples from The Cancer Genome Atlas were analyzed to characterize ELF5 isoform expression in multiple normal tissues and cancers. Extensive in vitro analysis of ELF5 isoforms, including a 116-gene quantitative polymerase chain reaction panel, was performed in breast cancer cell lines. RESULTS: ELF5 isoform expression was found to be tissue-specific due to alternative promoter use but altered in multiple cancer types. The normal breast expressed one main isoform, while in breast cancer there were subtype-specific alterations in expression. Expression of other ETS factors was also significantly altered in breast cancer, with the basal-like subtype demonstrating a distinct ETS expression profile. In vitro inducible expression of the full-length isoforms 1 and 2, as well as isoform 3 (lacking the Pointed domain) had similar phenotypic and transcriptional effects. CONCLUSIONS: Alternative promoter use, conferring differential regulatory responses, is the main mechanism governing ELF5 action rather than differential transcriptional activity of the isoforms. This understanding of expression and function at the isoform level is a vital first step in realizing the potential of transcription factors such as ELF5 as prognostic markers or therapeutic targets in cancer. PMID- 26738742 TI - Negotiating "The Social" and Managing Tuberculosis in Georgia. AB - In this paper I utilize anthropological insights to illuminate how health professionals and patients navigate and negotiate what for them is social about tuberculosis in order to improve treatment outcomes and support patients as human beings. I draw on ethnographic research about the implementation of the DOTS (Directly Observed Therapy, Short Course) approach in Georgia's National Tuberculosis Program in the wake of the Soviet healthcare system. Georgia is a particularly unique context for exploring these issues given the country's rich history of medical professionalism and the insistence that the practice of medicine is a moral commitment to society. I argue for critical attention to the ways in which treatment recipients and providers navigate what, for them, is "social" about therapeutic practices and their significance for avoiding biological and social reductionism. PMID- 26738743 TI - Carcinogenesis of nasopharyngeal carcinoma: an alternate hypothetical mechanism. AB - Current proposed mechanisms implicate both early and latent Epstein-Barr virus (EBV) infection in the carcinogenic cascade, whereas epidemiological studies have always associated nasopharyngeal carcinoma (NPC) with early childhood EBV infection and with chronic ear, nose, and sinus conditions. Moreover, most patients with NPC present with IgA antibody titers to EBV capsid antigen (VCA IgA), which can precede actual tumor presentation by several years. If early childhood EBV infection indeed constitutes a key event in NPC carcinogenesis, one would have to explain the inability to detect the virus in normal nasopharyngeal epithelium of patients at a high risk for EBV infection. It is perhaps possible that EBV resides within the salivary glands, instead of the epithelium, during latency. This claim is indirectly supported by observations that the East Asian phenotype shares the characteristics of an increased susceptibility to NPC and immature salivary gland morphogenesis, the latter of which is influenced by the association of salivary gland morphogenesis with an evolutionary variant of the human ectodysplasin receptor gene (EDAR), EDARV370A. Whether the immature salivary gland represents a more favorable nidus for EBV is uncertain, but in patients with infectious mononucleosis, EBV has been isolated in this anatomical organ. The presence of EBV-induced lymphoepitheliomas in the salivary glands and lungs further addresses the possibility of submucosal spread of the virus. Adding to the fact that the fossa of Rosen Muller contains a transformative zone active only in the first decade of life, one might be tempted to speculate the possibility of an alternative carcinogenic cascade for NPC that is perhaps not dissimilar to the model of human papillomavirus and cervical cancer. PMID- 26738744 TI - Telling patients of incidental genetic findings is questionable, researchers warn. PMID- 26738745 TI - Beverage purchases from stores in Mexico under the excise tax on sugar sweetened beverages: observational study. AB - STUDY QUESTION: What has been the effect on purchases of beverages from stores in Mexico one year after implementation of the excise tax on sugar sweetened beverages? METHODS: In this observational study the authors used data on the purchase of beverages in Mexico from January 2012 to December 2014 from an unbalanced panel of 6253 households providing 205 112 observations in 53 cities with more than 50 000 inhabitants. To test whether the post-tax trend in purchases was significantly different from the pretax trend, the authors used a difference in difference fixed effects model, which adjusts for both macroeconomic variables that can affect the purchase of beverages over time, and pre-existing trends. The variables used in the analysis included demographic information on household composition (age and sex of household members) and socioeconomic status (low, middle, and high). The authors compared the predicted volumes (mL/capita/day) of taxed and untaxed beverages purchased in 2014-the observed post-tax period-with the estimated volumes that would have been purchased if the tax had not been implemented (counterfactual) based on pretax trends. STUDY ANSWER AND LIMITATIONS: Relative to the counterfactual in 2014, purchases of taxed beverages decreased by an average of 6% (-12 mL/capita/day), and decreased at an increasing rate up to a 12% decline by December 2014. All three socioeconomic groups reduced purchases of taxed beverages, but reductions were higher among the households of low socioeconomic status, averaging a 9% decline during 2014, and up to a 17% decrease by December 2014 compared with pretax trends. Purchases of untaxed beverages were 4% (36 mL/capita/day) higher than the counterfactual, mainly driven by an increase in purchases of bottled plain water. WHAT THIS STUDY ADDS: The tax on sugar sweetened beverages was associated with reductions in purchases of taxed beverages and increases in purchases of untaxed beverages. Continued monitoring is needed to understand purchases longer term, potential substitutions, and health implications. FUNDING, COMPETING INTERESTS, DATA SHARING: This work was supported by grants from Bloomberg Philanthropies and the Robert Wood Johnson Foundation and by the Instituto Nacional de Salud Publica and the Carolina Population Center. The authors have no competing interests. No additional data are available. PMID- 26738748 TI - Effect of semen quality on human sex ratio in in vitro fertilization and intracytoplasmic sperm injection: an analysis of 27,158 singleton infants born after fresh single-embryo transfer. AB - OBJECTIVE: To evaluate the effect of semen quality on human sex ratio in in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 27,158 singleton infants born between 2007 and 2012 after fresh single-embryo transfer. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Proportion of male infants among liveborn infants. RESULT(S): There were 14,996 infants born after IVF, 12,164 infants born after ICSI with ejaculated sperm, and 646 infants born after ICSI with nonejaculated sperm. The sex ratio of IVF was 53.1% (95% confidence interval [CI], 52.3-53.9); the sex ratio of ICSI with ejaculated and nonejaculated sperm demonstrated as statistically significant reduction (48.2%; 95% CI, 47.3-49.1 and 47.7%; 95% CI, 43.8-51.6, respectively). In IVF, lower sperm motility, including asthenozoospermia (sperm motility <40%), was associated with a statistically significantly lower sex ratio compared with normal sperm (51.0%; 95% CI, 48.6-53.3 vs. 53.4%; 95% CI, 52.5-54.3). In ICSI with ejaculated sperm, there was no association between sperm motility and sex ratio. Sperm concentration was not associated with sex ratio in both IVF and ICSI. CONCLUSION(S): In IVF, lower sperm motility was associated with a statistically significant reduction in sex ratio; ICSI with either ejaculated or nonejaculated sperm was associated with a statistically significant reduction in sex ratio regardless of semen quality. PMID- 26738749 TI - Taibaiella coffeisoli sp. nov., isolated from the soil of a coffee plantation. AB - A Gram-stain-negative, obligately aerobic, non-motile, non-sporulating, rod shaped bacterium, designated TZCO2T, was isolated from the soil of an irrigated coffee plantation in Arusha, Tanzania, East Africa. Phylogenetic analysis, based on 16S rRNA gene sequences, indicated that the isolate is affiliated with the genus Taibaiella in the family Chitinophagaceae. Its closest relative is Taibaiella koreensis THG-DT86T (96.7%). The pH and temperature ranges for growth were pH 6.0-8.5 (optimum 7.0-7.5) and 10-35 degrees C (optimum 30 degrees C, respectively. The predominant fatty acids were iso-C15:0 (32.4%), iso-C15:1 G (22.6%), iso-C17:0 (15.1%) and iso-C17:0 3-OH (10.0%) The only isoprenoid quinone detected in strain TZCO2T was menaquinone-7 (MK-7); the major polar lipids were phosphoaminolipid, phosphatidylethanolamine, unidentified aminolipids and lipids. The DNA G+C content was 51.9 mol%. Physiological and chemotaxonomic data further confirmed that strain TZCO2T is distinct from other members of the genus Taibaiella. Thus, strain TZCO2T is considered to represent a novel species of the genus, for which the name Taibaiella coffeisoli sp. nov. is proposed. The type strain is TZCO2T (=NCAIM B 02601T=CCM 8601T). PMID- 26738750 TI - Maternal high-fat diet influences outcomes after neonatal hypoxic-ischemic brain injury in rodents. AB - The typical US diet has >30% calories from fat; yet, typical laboratory diets contain 17% calories from fat. This disparity could confound the clinical relevance of findings in cerebral ischemia models. We compared outcomes after neonatal brain injury in offspring of rat dams fed standard low-fat chow (17% fat calories) or a higher fat diet (34% fat calories) from day 7 of pregnancy. On postnatal day 7, hypoxic-ischemic injury was induced by right carotid ligation, followed by 60, 75 or 90 min 8% oxygen exposure. Sensorimotor function, brain damage, and serum and brain fatty acid content were compared 1 to 4 weeks later. All lesioned animals developed left forepaw placing deficits; scores were worse in the high-fat groups (p < 0.0001, ANOVA). Similarly, reductions in left forepaw grip strength were more pronounced in the high-fat groups. Severity of right hemisphere damage increased with hypoxia-ischemia duration but did not differ between diet groups. Serum and brain docosahexaenoic acid fatty acid fractions were lower in high-fat progeny (p < 0.05, ANOVA). We speculate that the high-fat diet disrupted docosahexaenoic acid-dependent recovery mechanisms. These findings have significant implications both for refinement of neonatal brain injury models and for understanding the impact of maternal diet on neonatal neuroplasticity. PMID- 26738752 TI - Convergent recruitment of new pollinators is triggered by independent hybridization events in Narcissus. AB - Hybridization can generate new species if some degree of isolation prevents gene flow between the hybrids and their progenitors. The recruitment of novel pollinators by hybrids has been hypothesized to be one way in which such reproductive isolation can be achieved. We tested whether pollinators contributed to isolation between two natural Narcissus hybrids and their progenitors using pollination experiments, observations, plus morphological and floral-volatile measurements. These hybrids share the same maternal but different paternal progenitors. We found that only the hybrids were visited by and pollinated by ants. The two hybrids exceeded their progenitors in floral-tube aperture size and nectar production. The emission of floral volatiles by hybrid plants was not only equal to or higher than the progenitor species, but also contained some new compounds not produced by the progenitors. The recruitment of ants as novel pollinators in the hybrids involved the combination of increased nectar secretion and the production of novel floral scent compounds. A breakdown of chemical defence against ants may also be involved. This study provides support for the hypothesis that the recruitment of novel pollinators can contribute to reproductive isolation between hybrids and their progenitors. PMID- 26738753 TI - Correspondence between the habitat of the threatened pudu (Cervidae) and the national protected-area system of Chile. AB - BACKGROUND: Currently, many species are facing serious conservation problems due to habitat loss. The impact of the potential loss of biodiversity associated with habitat loss is difficult to measure. This is particularly the case with inconspicuous species such as the threatened pudu (Pudu puda), an endemic Cervidae of temperate forests of Chile and Argentina. To evaluate the effectiveness of the Chilean protected-area system in protecting the habitat of the pudu, we measured the congruence between this specie's potential distribution and the geographical area occupied by the protected areas in central and southern Chile. The measurements of congruency were made using the Maxent modeling method. RESULTS: The potential habitat of the pudu was found to be poorly represented in the system (3-8%) and even the most suitable areas for the species are not currenly protected. According to these results, the protected area network cannot be considered as a key component of the conservation strategy for this species. CONCLUSIONS: The results presented here also serve as a guide for the reevaluation of current pudu conservation strategies, for the design of new field studies to detect the presence of this species in human-disturbed areas or remaining patches of native forest, and for the implementation of corridors to maximize the success of conservation efforts. PMID- 26738751 TI - Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals. AB - Risk factors and cognitive sequelae of brain arteriolosclerosis pathology are not fully understood. To address this, we used multimodal data from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative data sets. Previous studies showed evidence of distinct neurodegenerative disease outcomes and clinical-pathological correlations in the "oldest-old" compared to younger cohorts. Therefore, using the National Alzheimer's Coordinating Center data set, we analyzed clinical and neuropathological data from two groups according to ages at death: < 80 years (n = 1008) and >=80 years (n = 1382). In both age groups, severe brain arteriolosclerosis was associated with worse performances on global cognition tests. Hypertension (but not diabetes) was a brain arteriolosclerosis risk factor in the younger group. In the >= 80 years age at death group, an ABCC9 gene variant (rs704180), previously associated with aging-related hippocampal sclerosis, was also associated with brain arteriolosclerosis. A post-hoc arterial spin labeling neuroimaging experiment indicated that ABCC9 genotype is associated with cerebral blood flow impairment; in a convenience sample from Alzheimer's Disease Neuroimaging Initiative (n = 15, homozygous individuals), non-risk genotype carriers showed higher global cerebral blood flow compared to risk genotype carriers. We conclude that brain arteriolosclerosis is associated with altered cognitive status and a novel vascular genetic risk factor. PMID- 26738754 TI - One hundred years of clostridial butanol fermentation. AB - Butanol has been widely used as an important industrial solvent and feedstock for chemical production. Also, its superior fuel properties compared with ethanol make butanol a good substitute for gasoline. Butanol can be efficiently produced by the genus Clostridium through the acetone-butanol-ethanol (ABE) fermentation, one of the oldest industrial fermentation processes. Butanol production via industrial fermentation has recently gained renewed interests as a potential solution to increasing pressure of climate change and environmental problems by moving away from fossil fuel consumption and moving toward renewable raw materials. Great advances over the last 100 years are now reviving interest in bio-based butanol production. However, several challenges to industrial production of butanol still need to be overcome, such as overall cost competitiveness and development of higher performance strains with greater butanol tolerance. This minireview revisits the past 100 years of remarkable achievements made in fermentation technologies, product recovery processes, and strain development in clostridial butanol fermentation through overcoming major technical hurdles. PMID- 26738755 TI - Bacteriophage exploitation of bacterial biofilms: phage preference for less mature targets? AB - Robust evidence is somewhat lacking for biofilm susceptibility to bacteriophages in nature, contrasting often substantial laboratory biofilm vulnerability to phages. To help bridge this divide, I review a two-part scenario for 'heterogeneous' phage interaction even with phage-permissive single-species biofilms. First, through various mechanisms, those bacteria which are both more newly formed and located at biofilm surfaces may be particularly vulnerable to phage adsorption, rather than biofilm matrix being homogeneously resistant to phage penetration. Second, though phage infection of older, less metabolically active bacteria may still be virion productive, nevertheless the majority of phage population growth in association with biofilm bacteria could involve infection particularly of those bacteria which are more metabolically active and thereby better able to support larger phage bursts, versus clonally related biofilm bacteria equivalently supporting phage production. To the extent that biofilms are physiologically or structurally heterogeneous, with phages exploiting particularly relatively newly divided biofilm-surface bacteria, then even effective phage predation of natural biofilms could result in less than complete overall biofilm clearance. Phage tendencies toward only partial exploitation of even single-species biofilms could be consistent with observations that chronic bacterial infections in the clinic can require more aggressive or extensive phage therapy to eradicate. PMID- 26738756 TI - Variability in Golimumab Exposure: A 'Real-Life' Observational Study in Active Ulcerative Colitis. AB - BACKGROUND AND AIMS: Golimumab has been approved recently to treat refractory moderate-to-severe ulcerative colitis [UC]. To date it is not clear why a considerable fraction of patients do not respond, or lose initial response, to golimumab therapy. Our aim was to investigate whether a low golimumab serum concentration and/or a positive anti-golimumab antibody status reduces the efficacy of this drug in patients with UC. METHODS: Serum samples of 21 patients with moderate-to-severe UC were collected during the first 14 weeks of golimumab therapy. For measurement of golimumab serum concentrations, both a tumour necrosis factor [TNF]-coated enzyme-linked immunosorbent assay [ELISA] and a sandwich-type ELISA were developed. Anti-golimumab antibodies were measured using a bridging ELISA and a newly-developed drug-tolerant immunoassay. Clinical response and mucosal healing were assessed 14 weeks after start of treatment. RESULTS: Out of 21 patients, 10 [48%] reached partial clinical response at Week 14. Median [interquartile range] serum golimumab concentration was significantly higher in partial clinical responders than in non-responders: 10.0 [7.8-10.5] ug/ml versus 7.4 [4.8-8.3] ug/ml at Week 2 [p = 0.035] and 5.1 [4.0-7.9] ug/ml versus 2.1 [1.8-4.2] ug/ml at week 6 [p = 0.037]. Four out of 21 UC patients developed anti-golimumab antibodies, detectable only using a drug-tolerant immunoassay, and three had a partial clinical response at that time. Clinical non responders had a significantly more severe colitis, indicated by a higher endoscopic Mayo score at baseline compared with partial clinical responders [p = 0.048]. CONCLUSION: Adequate exposure to golimumab drives clinical response. A worse disease at baseline influences clinical response rate negatively. PMID- 26738757 TI - Non-adherence to Anti-TNF Therapy is Associated with Illness Perceptions and Clinical Outcomes in Outpatients with Inflammatory Bowel Disease: Results from a Prospective Multicentre Study. AB - BACKGROUND AND AIMS: Non-adherence to anti-tumour necrosis factor [TNF] agents in patients with inflammatory bowel disease [IBD] is a serious problem. In this study, we assessed risk factors for non-adherence and examined the association between adherence to anti-TNF agents and loss of response [LOR]. METHODS: In this multicentre, 12-month observational study, outpatients with IBD were included. Demographic and clinical characteristics were recorded. Adherence was measured with the Modified Morisky Adherence Scale-8 [MMAS-8] and 12-month pharmacy refills [medication possession ratio, MPR]. Risk factors included demographic and clinical characteristics, medication beliefs, and illness perceptions. Cox regression analysis was performed to determine the association between MPR and LOR to anti-TNF, IBD-related surgery or hospitalisation, dose intensification, or discontinuation of anti-TNF. RESULTS: In total, 128 patients were included [67 infliximab, 61 adalimumab], mean age 37 ( +/- standard deviation [SD] 14) years, 71 [56%] female. Median disease duration was 8 (interquartile range [IQR] 4-14) years. Clinical disease activity was present in 41/128 [32%] patients, 36/127 [28%] patients had an MMAS-8 < 6 ['low adherence'], and 25/99 [25%] patients had an MPR < 80% [non-adherence]. Risk factors for non-adherence included adalimumab use (odds ratio [OR] 10.1, 95% confidence interval [CI] 2.62-40.00), stronger emotional response [OR 1.16, 95% CI 1.02-1.31], and shorter timeline perception, i.e. short perceived illness duration [OR 0.60, 95% CI 0.38-0.96]. Adherence is linearly and negatively [OR 0.14, 95% CI 0.03-0.63] associated with LOR. CONCLUSION: Non-adherence to anti-TNF agents is strongly associated with LOR to anti-TNF agents, adalimumab use, and illness perceptions. The latter may provide an important target for interventions aimed at improving adherence and health outcomes. PMID- 26738761 TI - Novel features of 3q29 deletion syndrome: Results from the 3q29 registry. AB - 3q29 deletion syndrome is caused by a recurrent, typically de novo heterozygous 1.6 Mb deletion, but because incidence of the deletion is rare (1 in 30,000 births) the phenotype is not well described. To characterize the range of phenotypic manifestations associated with 3q29 deletion syndrome, we have developed an online registry (3q29deletion.org) for ascertainment of study subjects and phenotypic data collection via Internet-based survey instruments. We report here on data collected during the first 18 months of registry operation, from 44 patients. This is the largest cohort of 3q29 deletion carriers ever assembled and surveyed in a systematic way. Our data reveal that 28% of registry participants report neuropsychiatric phenotypes, including anxiety disorder, panic attacks, depression, bipolar disorder, and schizophrenia. Other novel findings include a high prevalence (64%) of feeding problems in infancy and reduced weight at birth for 3q29 deletion carriers (average reduction 13.9 oz (394 g), adjusted for gestational age and sex, P = 6.5e-07). We further report on the frequency of heart defects, autism, recurrent ear infections, gastrointestinal phenotypes, and dental phenotypes, among others. We also report on the expected timing of delayed developmental milestones. This is the most comprehensive description of the 3q29 deletion phenotype to date. These results are clinically actionable toward improving patient care for 3q29 deletion carriers, and can guide the expectations of physicians and parents. These data also demonstrate the value of patient-reported outcomes to reveal the full phenotypic spectrum of rare genomic disorders. PMID- 26738763 TI - Epidemiologic and Microbiologic Characteristics of Occult Bacteremia Among Febrile Children in Southern Israel, Before and After Initiation of the Routine Antipneumococcal Immunization (2005-2012). AB - BACKGROUND: Little is known about the incidence and dynamics of occult bacteremia (OB) among infants/young children following the introduction of pneumococcal conjugate vaccines (PCVs) into the national immunization program in Israel in 2009-2010. The aim of this study was to characterize the epidemiologic and microbiologic picture of OB among febrile infants/children aged 3-36 months in southern Israel, before and after PCVs introduction. METHODS: Retrospective study enrolling all infants/young children attending the emergency room of a tertiary medical center in southern Israel with fever without source, discharged, and reported with a positive blood culture. RESULTS: Of 453 true bacteremias, 89 (19.6%) were defined as OB. OB rate was 0.22%; a significant decrease was recorded in OB rates, with the highest rate during 2005 (0.34%) and the lowest during 2011 (0.15%). OB cases decreased in post-PCV (2010-2012) versus prevaccination period (2005-2009) from 66/22,256 cases (0.3%) to 23/13,213 cases (0.17%; p = 0.03). Most frequent single OB pathogens were Streptococcus pneumoniae, Streptococcus viridans spp., and Kingella kingae (39.3%, 10.1%, and 9.0%, respectively); Enterobacteriaceae spp. were isolated in 10 cases (11.2%). No changes were recorded in S. pneumoniae-OB cases; K. kingae-OB decreased significantly (p = 0.047). None of the S. pneumoniae serotypes isolated during 2011-2012 belonged to 13-valent PCV (PCV13). An increase in non PCV13 serotypes was recorded during 2011-2012 (3/3, 100% vs. 7/32, 21.9%, p = 0.01). CONCLUSION: OB rates decreased significantly following the introduction of PCVs. S. pneumoniae was the most frequent isolated pathogen in OB, but in lower percentages compared with the medical literature. No PCV13 serotypes were detected as a cause of OB during 2011-2012. PMID- 26738764 TI - Correction: Developing a new endograft for the treatment of juxtarenal aortic aneurysms: definition and experimentation, Correction: Glutamine treatment attenuates hyperglycemia-induced mitochondrial stress and apoptosis in umbilical vein endothelial cells. PMID- 26738767 TI - Overdiagnosis and overtreatment of malaria in children in a secondary healthcare centre in Sekondi-Takoradi, Ghana. AB - Overdiagnosis and overtreatment of malaria is a major problem in children in malaria-endemic countries. This retrospective study identified children who were admitted with fever and were treated with or without anti-malarial medications and discharged at the Paediatric Unit of the Effia-Nkwanta Regional Hospital. The medical records of all children were searched, retrieved and assessed. A total of 1160 records from children (age range, 0-12 years) were reviewed and evaluated. Of the total number, 21.3% had laboratory confirmed malaria, 38.4% were malaria negative, while 40.3% had no malaria tests performed. In addition, the results showed that 4.5% of the laboratory confirmed malaria positive cases were not given anti-malarial medication while 84.1% of the malaria negative cases were given these incorrectly. Furthermore, 78.2% of the children with no malaria tests were prescribed anti-malarial medication. The presumptive diagnosis of malaria should be abandoned and the installation of a functional laboratory services promoted. PMID- 26738766 TI - Genomic structure and expression of the human serotonin 2A receptor gene (HTR2A) locus: identification of novel HTR2A and antisense (HTR2A-AS1) exons. AB - BACKGROUND: The serotonin 2A receptor is widely implicated in genetic association studies and remains an important drug target for psychiatric, neurological, and cardiovascular conditions. RNA sequencing redefined the architecture of the serotonin 2A receptor gene (HTR2A), revealing novel mRNA transcript isoforms utilizing unannotated untranslated regions of the gene. Expression of these untranslated regions is modulated by common single nucleotide polymorphisms (SNPs), namely rs6311. Previous studies did not fully capture the complexity of the sense- and antisense-encoded transcripts with respect to novel exons in the HTR2A gene locus. Here, we comprehensively catalogued exons and RNA isoforms for both HTR2A and HTR2A-AS1 using RNA-Seq from human prefrontal cortex and multiple mouse tissues. We subsequently tested associations between expression of newfound gene features and common SNPs in humans. RESULTS: We find that the human HTR2A gene spans ~66 kilobases and consists of 7, rather than 4 exons. Furthermore, the revised human HTR2A-AS1 gene spans ~474 kilobases and consists of 18, rather than 3 exons. Three HTR2A exons directly overlap with HTR2A-AS1 exons, suggesting potential for complementary nucleotide interactions. The repertoire of possible mouse Htr2a splice isoforms is remarkably similar to humans and we also find evidence for overlapping sense-antisense transcripts in the same relative positions as the human transcripts. rs6311 and SNPs in high linkage disequilibrium are associated with HTR2A-AS1 expression, in addition to previously described associations with expression of the extended 5' untranslated region of HTR2A. CONCLUSIONS: Our proposed HTR2A and HTR2A-AS1 gene structures dramatically differ from current annotations, now including overlapping exons on the sense and anti-sense strands. We also find orthologous transcript isoforms expressed in mice, providing opportunities to elucidate the biological roles of the human isoforms using a model system. Associations between rs6311 and expression of HTR2A and HTR2A-AS1 suggest this polymorphism is capable of modulating the expression of the sense or antisense transcripts. Still unclear is whether these SNPs act directly on the expression of the sense or antisense transcripts and whether overlapping exons are capable of interacting through complimentary base-pairing. Additional studies are necessary to determine the extent and nature of interactions between the SNPs and the transcripts prior to interpreting these findings in the context of phenotypes associated with HTR2A. PMID- 26738768 TI - Psychological correlates of suicidality in HIV/AIDS in semi-urban south-western Uganda. AB - There is a paucity of data on the prevalence of suicidality in HIV/AIDS, and associated psychological factors in sub-Saharan Africa, shown to be high in Uganda. Yet, the region accounts for over 70% of the world HIV burden. Our study used a cross-sectional survey of 226 HIV-positive (HIV+) adults and adolescents (aged 15-17 years) in Mbarara, Uganda. The relationship between suicidality and depressed mood, anxiety symptoms, state anger, self-esteem, trait anger and hopelessness was examined; anger was the predominant factor in suicidality, suggesting that anger management could potentially lower the prevalence of suicidality. PMID- 26738771 TI - Nematic field transfer in a two-dimensional protein fibril assembly. AB - We perform Atomic Force Microscopy and numerical simulations of a bimodal solution containing long, semiflexible beta-lactoglobulin fibrils and short, flexible beta-lactoglobulin linear aggregates at an air-water interface. Short aggregates orient perpendicular to fibrils at very short distances and preferentially parallel at intermediate distances. At even larger distances an isotropic distribution is observed. Parallel ordering coincides with aggregate stretching: by straightening, small aggregates are able to approach the fibrils within a distance smaller than their radius of gyration. These findings contribute to the understanding of how anisotropic interactions are transferred in two-dimensional bimodal nematic fields of biopolymers at liquid interfaces. PMID- 26738773 TI - Pluripotent Human embryonic stem cell derived neural lineages for in vitro modelling of enterovirus 71 infection and therapy. AB - BACKGROUND: The incidence of neurological complications and fatalities associated with Hand, Foot & Mouth disease has increased over recent years, due to emergence of newly-evolved strains of Enterovirus 71 (EV71). In the search for new antiviral therapeutics against EV71, accurate and sensitive in vitro cellular models for preliminary studies of EV71 pathogenesis is an essential prerequisite, before progressing to expensive and time-consuming live animal studies and clinical trials. METHODS: This study thus investigated whether neural lineages derived from pluripotent human embryonic stem cells (hESC) can fulfil this purpose. EV71 infection of hESC-derived neural stem cells (NSC) and mature neurons (MN) was carried out in vitro, in comparison with RD and SH-SY5Y cell lines. RESULTS: Upon assessment of post-infection survivability and EV71 production by the various types, it was observed that NSC were significantly more susceptible to EV71 infection compared to MN, RD (rhabdomyosarcoma) and SH-SY5Y cells, which was consistent with previous studies on mice. The SP81 peptide had significantly greater inhibitory effect on EV71 production by NSC and MN compared to the cancer-derived RD and SH-SY5Y cell lines. CONCLUSIONS: Hence, this study demonstrates that hESC-derived neural lineages can be utilized as in vitro models for studying EV71 pathogenesis and for screening of antiviral therapeutics. PMID- 26738774 TI - The stem cell zinc finger 1 (SZF1)/ZNF589 protein has a human-specific evolutionary nucleotide DNA change and acts as a regulator of cell viability in the hematopoietic system. AB - The stem cell zinc finger 1 (SZF1)/ZNF589 protein belongs to the large family of Kruppel-associated box domain-zinc finger (KRAB-ZNF) transcription factors, which are present only in higher vertebrates and epigenetically repress transcription by recruiting chromatin-modifying complexes to the promoter regions of their respective target genes. Although the distinct biological functions of most KRAB ZNF proteins remain unknown, recent publications indicate their implication in fundamental processes, such as cell proliferation, apoptosis, differentiation, development, and tumorigenesis. SZF1/ZNF589 was first identified as a gene with SZF1-1 isoform specifically expressed in CD34(+) hematopoietic cells, strongly suggesting a role in epigenetic control of gene expression in hematopoietic stem/progenitor cells (HSPCs). However, the function of SZF1/ZNF589 in hematopoiesis has not yet been elucidated. Our study reveals SZF1/ZNF589 as a gene with a human-specific nucleotide DNA-change, conferring potential species specific functional properties. Through shRNA-mediated loss-of-function experiments, we found that changes in expression of fundamental apoptosis controlling genes are induced on SZF1/ZNF589 knockdown, resulting in inhibited growth of hematopoietic cell lines and decreased progenitor potential of primary human bone marrow CD34(+) cells. Moreover, we found that the SZF1/ZNF589 gene is differentially regulated during hypoxia in CD34(+) HSPCs in a cytokine-dependent manner, implicating its possible involvement in the maintenance of the hypoxic physiologic status of hematopoietic stem cells. Our results establish the role of SZF1/ZNF589 as a new functional regulator of the hematopoietic system. PMID- 26738772 TI - Antimicrobial peptides and wound healing: biological and therapeutic considerations. AB - Repair of tissue wounds is a fundamental process to re-establish tissue integrity and regular function. Importantly, infection is a major factor that hinders wound healing. Multicellular organisms have evolved an arsenal of host-defense molecules, including antimicrobial peptides (AMPs), aimed at controlling microbial proliferation and at modulating the host's immune response to a variety of biological or physical insults. In this brief review, we provide the evidence for a role of AMPs as endogenous mediators of wound healing and their promising therapeutic potential for the treatment of non-life-threatening skin and other epithelial injuries. PMID- 26738776 TI - Creating an anthropomorphic digital MR phantom--an extensible tool for comparing and evaluating quantitative imaging algorithms. AB - Assessing and mitigating the various sources of bias and variance associated with image quantification algorithms is essential to the use of such algorithms in clinical research and practice. Assessment is usually accomplished with grid based digital reference objects (DRO) or, more recently, digital anthropomorphic phantoms based on normal human anatomy. Publicly available digital anthropomorphic phantoms can provide a basis for generating realistic model-based DROs that incorporate the heterogeneity commonly found in pathology. Using a publicly available vascular input function (VIF) and digital anthropomorphic phantom of a normal human brain, a methodology was developed to generate a DRO based on the general kinetic model (GKM) that represented realistic and heterogeneously enhancing pathology. GKM parameters were estimated from a deidentified clinical dynamic contrast-enhanced (DCE) MRI exam. This clinical imaging volume was co-registered with a discrete tissue model, and model parameters estimated from clinical images were used to synthesize a DCE-MRI exam that consisted of normal brain tissues and a heterogeneously enhancing brain tumor. An example application of spatial smoothing was used to illustrate potential applications in assessing quantitative imaging algorithms. A voxel-wise Bland-Altman analysis demonstrated negligible differences between the parameters estimated with and without spatial smoothing (using a small radius Gaussian kernel). In this work, we reported an extensible methodology for generating model based anthropomorphic DROs containing normal and pathological tissue that can be used to assess quantitative imaging algorithms. PMID- 26738778 TI - Detecting reliable non interacting proteins (NIPs) significantly enhancing the computational prediction of protein-protein interactions using machine learning methods. AB - Protein-protein interactions (PPIs) play a vital role in most biological processes. Hence their comprehension can promote a better understanding of the mechanisms underlying living systems. However, besides the cost and the time limitation involved in the detection of experimentally validated PPIs, the noise in the data is still an important issue to overcome. In the last decade several in silico PPI prediction methods using both structural and genomic information were developed for this purpose. Here we introduce a unique validation approach aimed to collect reliable non interacting proteins (NIPs). Thereafter the most relevant protein/protein-pair related features were selected. Finally, the prepared dataset was used for PPI classification, leveraging the prediction capabilities of well-established machine learning methods. Our best classification procedure displayed specificity and sensitivity values of 96.33% and 98.02%, respectively, surpassing the prediction capabilities of other methods, including those trained on gold standard datasets. We showed that the PPI/NIP predictive performances can be considerably improved by focusing on data preparation. PMID- 26738780 TI - Paeoniflorin inhibits imiquimod-induced psoriasis in mice by regulating Th17 cell response and cytokine secretion. AB - Paeoniflorin (PF) is the main active ingredients of radix paeoniae rubra and radix paeoniae alba, which are used widely in Traditional Chinese Medicine. This study aimed to assess the capacity of PF to inhibit imiquimod (IMQ)-induced psoriasis. Mice treated with IMQ were divided into four groups and administered 240mg/kg/day or 120mg/kg/day of PF, 1mg/kg/day of methotrexate (MTX), or normal saline intragastrically. Weight-matched mice treated with vaseline were used as controls. Morphology, structural features, keratinocyte proliferation and differentiation, inflammatory cell infiltration, levels of Th1/Th2/Th17/Treg cytokine mRNA, and phosphorylation of Th17 differentiation-related proteins were assessed. Mouse spleen cells were incubated under Th17 polarizing conditions, then with PF (2, 20, and 200MUg/ml) and cell viability, Th17 differentiation, and Th17 cytokines and the orphan nuclear receptor (RORgammat) mRNA levels were assessed. PF alleviated IMQ-induced keratinocyte proliferation and inflammatory cell infiltration, and reduced mRNA levels of Th17 cytokines at day 4 and phosphorylation of Th17 differentiation-related proteins. However, 2, 20, or 200MUg/ml PF did not affect spleen cell viability, and 2 and 20MUg/ml PF reduced IL-17 secretion under Th17 polarizing conditions. Finally, 2 and 20MUg/ml PF inhibited mRNA expression of Th17 cytokines and phosphorylation of Stat3 in spleen cells under Th17 polarizing conditions. These results suggest that PF inhibits IMQ-induced psoriasis by regulating Th17 cell response and cytokine secretion via phosphorylation of Stat3. PMID- 26738783 TI - Immuno-modulating properties of saliphenylhalamide, SNS-032, obatoclax, and gemcitabine. AB - Influenza A viruses (IAVs) impact the public health and global economy by causing yearly epidemics and occasional pandemics. Several anti-IAV drugs are available and many are in development. However, the question remains which of these antiviral agents may allow activation of immune responses and protect patients against co- and re-infections. To answer to this question, we analysed immuno modulating properties of the antivirals saliphenylhalamide (SaliPhe), SNS-032, obatoclax, and gemcitabine, and found that only gemcitabine did not impair immune responses in infected cells. It also allowed activation of innate immune responses in lipopolysaccharide (LPS)- and interferon alpha (IFNalpha)-stimulated macrophages. Moreover, immuno-mediators produced by gemcitabine-treated IAV infected macrophages were able to prime immune responses in non-infected cells. Thus, we identified an antiviral agent which might be beneficial for treatment of patients with severe viral infections. PMID- 26738784 TI - A novel method for nucleos(t)ide analogues susceptibility assay of hepatitis B virus by viral polymerase transcomplementation. AB - Nucleos(t)ide analogues (NUCs) susceptibility assay is important for the study of hepatitis B virus (HBV) drug resistance. The purpose of susceptibility assay is to test the sensitivity of a specific HBV variant to NUCs in vitro, by which assesses if and to what extent the mutant virus is resistant to a specific NUC. Among the existing susceptibility assay methods, stable cell line expressing the specific variant is one of the commonly used assessment systems based on its high repeatability. However, establishment of stable cell lines expressing individual variant is laborious and time-consuming. In the present study, we developed a novel strategy for rapidly establishing HBV replicating stable cell lines. We first established an acceptor cell line stably transfected with a polymerase-null HBV 1.1mer genome DNA, then lentiviruses expressing different mutant HBV polymerases were transduced into the acceptor cell line respectively. Stable cell lines replicating HBV DNA with the trans-complemented HBV polymerases were established by antibiotics selection. Lamivudine and entecavir susceptibility data from these polymerase-complementing cell lines were validated by comparing with other assays. Taken together, this transcomplementation strategy for establishment of stable cell lines replicating HBV DNA with clinically isolated HBV polymerase provides a new tool for NUC susceptibility assay of HBV. PMID- 26738787 TI - Should we consider pancreaticogastrostomy the best method of reconstruction after pancreaticoduodenectomy? PMID- 26738789 TI - Changes in Body Weight From Young Adulthood to Middle Age and Its Association With Blood Pressure and Hypertension: A Cross-Sectional Study in Hong Kong Chinese Women. AB - BACKGROUND: Few studies have examined the associations of weight changes from young adulthood to middle age with blood pressure (BP) and hypertension among Hong Kong Chinese women. METHODS AND RESULTS: Weight at age 18 (W18), current weight (Wcurrent), height, BP, demographics, and lifestyle factors were obtained from 1253 female nurses (35-65 years) by a self-administered questionnaire through mail survey in Hong Kong. The conditional relative weight (CRW; a residual of Wcurrent regressed on W18) was used to express the relative weight change from age 18 to current age. The study results show that from young adulthood to middle age, 76.9%, 15.1%, and 8.0% of women had weight gain, weight loss, and stable weight, respectively. Women in the weight loss group had heavier W18 than those in the weight gain group (P<0.05). Higher weight gain was associated with higher BP (P for trend <0.01). Women who belonged to the heaviest 10% both at age 18 and at present had highest BP than women in other weight categories. By giving W18, a 1-kg increase in weight change predicted 0.63 and 0.42 mm Hg increases in systolic and diastolic BP, respectively (both P<0.001) and 12% greater odds of being hypertension (95% confidence interval, 1.08, 1.17). The CRW was positively associated with BP and hypertension; no interaction was found between CRW and Wcurrent on BP/hypertension. CONCLUSIONS: A majority of Chinese women tended to become heavier throughout adult life. More weight gain led to the higher BP. Weight change is an independent predictor for later-life BP and hypertension. PMID- 26738788 TI - Overexpression of Nitric Oxide Synthase Restores Circulating Angiogenic Cell Function in Patients With Coronary Artery Disease: Implications for Autologous Cell Therapy for Myocardial Infarction. AB - BACKGROUND: Circulating angiogenic cells (CACs) are peripheral blood cells whose functional capacity inversely correlates with cardiovascular risk and that have therapeutic benefits in animal models of cardiovascular disease. However, donor age and disease state influence the efficacy of autologous cell therapy. We sought to determine whether age or coronary artery disease (CAD) impairs the therapeutic potential of CACs for myocardial infarction (MI) and whether the use of ex vivo gene therapy to overexpress endothelial nitric oxide (NO) synthase (eNOS) overcomes these defects. METHODS AND RESULTS: We recruited 40 volunteers varying by sex, age (< or >=45 years), and CAD and subjected their CACs to well established functional tests. Age and CAD were associated with reduced CAC intrinsic migration (but not specific response to vascular endothelial growth factor, adherence of CACs to endothelial tubes, eNOS mRNA and protein levels, and NO production. To determine how CAC function influences therapeutic potential, we injected the 2 most functional and the 2 least functional CAC isolates into mouse hearts post MI. The high-function isolates substantially improved cardiac function, whereas the low-function isolates led to cardiac function only slightly better than vehicle control. Transduction of the worst isolate with eNOS cDNA adenovirus increased NO production, migration, and cardiac function of post-MI mice implanted with the CACs. Transduction of the best isolate with eNOS small interfering RNA adenovirus reduced all of these capabilities. CONCLUSIONS: Age and CAD impair multiple functions of CACs and limit therapeutic potential for the treatment of MI. eNOS gene therapy in CACs from older donors or those with CAD has the potential to improve autologous cell therapy outcomes. PMID- 26738793 TI - Data gaps limit the translational potential of preclinical research. AB - The absence of mouse pharmacokinetic reference data hinders translation. An analysis of recent literature highlights a systematic lack of discussion regarding rationale for the selection of dosing paradigms in preclinical studies, and in particular for neuroscience studies in which the lack of brain penetration can limit target-organ exposure. We propose solutions to improve study design. PMID- 26738790 TI - Prognostic Benefits of Carvedilol, Bisoprolol, and Metoprolol Controlled Release/Extended Release in Hemodialysis Patients with Heart Failure: A 10-Year Cohort. AB - BACKGROUND: Heart failure is a highly prevalent cardiovascular complication among patients receiving long-term hemodialysis, but the benefits of carvedilol, bisoprolol, and metoprolol controlled release/extended release on the outcomes of these patients remain unclear. In this study, we address the use of these 3 beta blockers and their associations with mortality. METHODS AND RESULTS: Long-term hemodialysis patients, aged >=35 years, with new-onset heart failure and receiving various medications were identified through the use of 1999-2010 data from the Taiwan National Health Insurance Research Database. From the total of 4435 heart failure patients, we selected 1700 new users of the 3 beta-blockers (study group) and 1700 nonusers (control group), by using matched cohorts according to their propensity scores, and then compared the 5-year all-cause mortality rates by using Cox proportional hazard regressions and time-dependent covariate adjustment. During 3944 person-years of follow-up, 666 (39.2%) deaths occurred within the study group, compared with 918 (54%) deaths during 2893 person-years of follow-up in the control group. The 5-year mortality rate for the study (control) group was 54.5% (70.3%); P<0.001. Adjusted hazard regression analyses revealed that the therapeutic effects of beta-blockers remained significant for all-cause mortality (hazard ratio 0.80, 95% CI 0.72 to 0.90). Subgroup analyses revealed that patients in the study group receiving beta blockers plus renin-angiotensin system antagonists exhibited the lowest mortality rate, while the highest mortality rate was found among patients in the control group receiving neither beta-blockers nor renin-angiotensin system antagonists. CONCLUSIONS: This study demonstrates that the 3 beta-blockers were associated with improved survival in long-term hemodialysis patients with heart failure. PMID- 26738794 TI - Increased internalization of complement inhibitor CD59 may contribute to endothelial inflammation in obstructive sleep apnea. AB - Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH) during transient cessation of breathing, triples the risk for cardiovascular diseases. We used a phage display peptide library as an unbiased approach to investigate whether IH, which is specific to OSA, activates endothelial cells (ECs) in a distinctive manner. The target of a differentially bound peptide on ECs collected from OSA patients was identified as CD59, a major complement inhibitor that protects ECs from the membrane attack complex (MAC). A decreased proportion of CD59 is located on the EC surface in OSA patients compared with controls, suggesting reduced protection against complement attack. In vitro, IH promoted endothelial inflammation predominantly via augmented internalization of CD59 and consequent MAC deposition. Increased internalization of endothelial CD59 in IH appeared to be cholesterol-dependent and was reversed by statins in a CD59 dependent manner. These studies suggest that reduced complement inhibition may mediate endothelial inflammation and increase vascular risk in OSA patients. PMID- 26738796 TI - Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies. AB - Engineered T cell therapies have begun to demonstrate impressive clinical responses in patients with B cell malignancies. Despite this efficacy, many patients are unable to receive T cell therapy because of failure of in vitro expansion, a necessary component of cell manufacture and a predictor of in vivo activity. To evaluate the biology underlying these functional differences, we investigated T cell expansion potential and memory phenotype during chemotherapy in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). We found that patients with T cell populations enriched for early lineage cells expanded better in vitro and that patients with ALL had higher numbers of these cells with a corresponding enhancement in expansion as compared to cells from patients with NHL. We further demonstrated that early lineage cells were selectively depleted by cyclophosphamide and cytarabine chemotherapy and that culture with interleukin-7 (IL-7) and IL-15 enriched select early lineage cells and rescued T cell expansion capability. Thus, early lineage cells are essential to T cell fitness for expansion, and enrichment of this population either by timing of T cell collection or culture method can increase the number of patients eligible to receive highly active engineered cellular therapies. PMID- 26738795 TI - Sources of HIV infection among men having sex with men and implications for prevention. AB - New HIV diagnoses among men having sex with men (MSM) have not decreased appreciably in most countries, even though care and prevention services have been scaled up substantially in the past 20 years. To maximize the impact of prevention strategies, it is crucial to quantify the sources of transmission at the population level. We used viral sequence and clinical patient data from one of Europe's nationwide cohort studies to estimate probable sources of transmission for 617 recently infected MSM. Seventy-one percent of transmissions were from undiagnosed men, 6% from men who had initiated antiretroviral therapy (ART), 1% from men with no contact to care for at least 18 months, and 43% from those in their first year of infection. The lack of substantial reductions in incidence among Dutch MSM is not a result of ineffective ART provision or inadequate retention in care. In counterfactual modeling scenarios, 19% of these past cases could have been averted with current annual testing coverage and immediate ART to those testing positive. Sixty-six percent of these cases could have been averted with available antiretrovirals (immediate ART provided to all MSM testing positive, and preexposure antiretroviral prophylaxis taken by half of all who test negative for HIV), but only if half of all men at risk of transmission had tested annually. With increasing sequence coverage, molecular epidemiological analyses can be a key tool to direct HIV prevention strategies to the predominant sources of infection, and help send HIV epidemics among MSM into a decisive decline. PMID- 26738798 TI - Congenital Aniridia and the Ocular Surface. AB - Aniridia is a congenital pan-ocular disorder caused by haplo-insufficiency of Pax6, a crucial gene for proper development of the eye. Aniridia affects a range of eye structures, including the cornea, iris, anterior chamber angle, lens, and fovea. The ocular surface, in particular, can be severely affected by a progressive pathology termed aniridia-associated keratopathy (AAK), markedly contributing to impaired vision. The purpose of this review is to provide an update of the current knowledge of the genetic, clinical, micro-morphological, and molecular aspects of AAK. We draw upon material presented in the literature and from our own observations in large aniridia cohorts. We summarize signs and symptoms of AAK, describe current options for management, and discuss the latest research findings that may lead to better diagnosis and new treatment or prevention strategies for this debilitating ocular surface condition. PMID- 26738797 TI - A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer. AB - Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes. PMID- 26738799 TI - Challenges and Strategies for Regenerating the Lacrimal Gland. AB - The lacrimal gland produces the aqueous component of tears, including electrolytes, peptides, and glycoproteins necessary to maintain homeostasis and optical properties of the ocular surface. Stem cells that contribute to the homeostasis of the lacrimal gland are under extensive study. It is still unclear whether such stem cells are of mesenchymal or epithelial origin. It is also possible that a unique epithelial stem cell undergoes epithelial-mesenchymal transition and contributes to the mesenchyme. Developmental studies in mice have shown that a network of growth factors contributes to epithelial-mesenchymal interaction during morphogenesis of the lacrimal gland. Recently, the developmental process was successfully recapitulated in vitro, providing a valuable tool for study of lacrimal gland development and possibly opening doors to regenerative therapy. While further studies are required to identify and appreciate the potential of lacrimal gland stem cells, advances in stem cell biology in general should become a catalyst towards developing regenerative therapy of the lacrimal gland. PMID- 26738801 TI - Crystal structures of Mycobacterium tuberculosis HspAT and ArAT reveal structural basis of their distinct substrate specificities. AB - Aminotransferases of subfamily Ibeta, which include histidinol phosphate aminotransferases (HspATs) and aromatic amino acid aminotransferases (ArATs), are structurally similar but possess distinct substrate specificities. This study, encompassing structural and biochemical characterisation of HspAT and ArAT from Mycobacterium tuberculosis demonstrates that the residues lining the substrate binding pocket and N-terminal lid are the primary determinants of their substrate specificities. In mHspAT, hydrophilic residues in the substrate binding pocket and N-terminal lid allow the entry and binding of its preferential substrate, Hsp. On the other hand, the hydrophobic nature of both the substrate binding pocket and the N-terminal lid of mArAT is responsible for the discrimination of a polar substrate such as Hsp, while facilitating the binding of Phe and other aromatic residues such as Tyr and Trp. In addition, the present study delineates the ligand induced conformational rearrangements, providing insights into the plasticity of aminotransferases. Furthermore, the study also demonstrates that the adventitiously bound ligand 2-(N-morpholino)ethanesulfonic acid (MES) is indeed a specific inhibitor of HspAT. These results suggest that previously untapped morpholine-ring scaffold compounds could be explored for the design of new anti-TB agents. PMID- 26738802 TI - A single oral dose of flavan-3-ols enhances energy expenditure by sympathetic nerve stimulation in mice. AB - Numerous clinical studies have found that ingestion of chocolate reduces the risk of metabolic syndrome, however, the mechanisms were remain unclear. We have reported that a single dose of a flavan-3-ol fraction derived from cocoa (FL) enhanced energy expenditure (EE) and increased the mRNA expression levels of uncoupling proteins (UCPs) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha), and the protein level of phosphorylated AMP activated protein kinase (AMPK)alpha in tissues, along with plasma adrenaline level. In the present study, we examined whether the EE enhancing activity of FL is mediated by adrenergic effect using several adrenalin receptor (AR) blockers. In the first study, mice were butoxamine, as beta2AR blocker, with vehicle or 10mg/kg FL orally. We found that pretreatment with butoxamine prevented the increases of EE, the mRNA expression of UCP-3, and phosphorylated AMPKalpha that were induced in the gastrocnemius muscle of mice by 10mg/kg FL. Secondly, mice were given SR52930, as beta3AR blocker. Pretreatment with SR52930 prevented the increases of EE, the mRNA expression of UCP-3, and phosphorylated AMPKalpha that were induced in the gastrocnemius muscle of mice by 10mg/kg FL. Pretreatment with a combination of both blockers also reduced the increments in mRNA expression levels of UCPs and PGC-1alpha, however, phosphorylated AMPKalpha in skeletal muscle was rather increased. These results suggest that the ability of a single oral dose of FL to enhance metabolic activity is mediated by sympathetic nerve system (SNS). PMID- 26738803 TI - The role of E3 ubiquitin-ligases MuRF-1 and MAFbx in loss of skeletal muscle mass. AB - The ubiquitin-proteasome system (UPS) is the main regulatory mechanism of protein degradation in skeletal muscle. The ubiquitin-ligase enzymes (E3s) have a central role in determining the selectivity and specificity of the UPS. Since their identification in 2001, the muscle specific E3s, muscle RING finger-1 (MuRF-1) and muscle atrophy F-box (MAFbx), have been shown to be implicated in the regulation of skeletal muscle atrophy in various pathological and physiological conditions. This review aims to explore the involvement of MuRF-1 and MAFbx in catabolism of skeletal muscle during various pathologies, such as cancer cachexia, sarcopenia of aging, chronic kidney disease (CKD), diabetes, and chronic obstructive pulmonary disease (COPD). In addition, the effects of various lifestyle and modifiable factors (e.g. nutrition, exercise, cigarette smoking, and alcohol) on MuRF-1 and MAFbx regulation will be discussed. Finally, evidence of potential strategies to protect against skeletal muscle wasting through inhibition of MuRF-1 and MAFbx expression will be explored. PMID- 26738804 TI - Streptococcus uberis strains isolated from the bovine mammary gland evade immune recognition by mammary epithelial cells, but not of macrophages. AB - Streptococcus uberis is frequently isolated from the mammary gland of dairy cattle. Infection with some strains can induce mild subclinical inflammation whilst others induce severe inflammation and clinical mastitis. We compared here the inflammatory response of primary cultures of bovine mammary epithelial cells (pbMEC) towards S. uberis strains collected from clinical or subclinical cases (seven strains each) of mastitis with the strong response elicited by Escherichia coli. Neither heat inactivated nor live S. uberis induced the expression of 10 key immune genes (including TNF, IL1B, IL6). The widely used virulent strain 0140J and the avirulent strain, EF20 elicited similar responses; as did mutants defective in capsule (hasA) or biofilm formation (sub0538 and sub0539). Streptococcus uberis failed to activate NF-kappaB in pbMEC or TLR2 in HEK293 cells, indicating that S. uberis particles did not induce any TLR-signaling in MEC. However, preparations of lipoteichoic acid (LTA) from two strains strongly induced immune gene expression and activated NF-kappaB in pbMEC, without the involvement of TLR2. The immune-stimulatory LTA must be arranged in the intact S. uberis such that it is unrecognizable by the relevant pathogen receptors of the MEC. The absence of immune recognition is specific for MEC, since the same S. uberis preparations strongly induced immune gene expression and NF-kappaB activity in the murine macrophage model cell RAW264.7. Hence, the sluggish immune response of MEC and not of professional immune cells to this pathogen may aid establishment of the often encountered belated and subclinical phenotype of S. uberis mastitis. PMID- 26738806 TI - 1-Phenylethynylpyrene (PEPy) as a novel blue-emitting dye for qPCR assay. AB - An alkyl azide derivative of 1-phenylethynylpyrene (PEPy) dye was prepared and used in the functionalization of oligonucleotides via click chemistry. Spectral and photo-physical properties of the PEPy-modified oligonucleotides as a single strand, and in perfect or mismatched duplexes, have been studied. A series of PEPy-Dabcyl fluorogenic TaqMan probes were synthesized and tested in qPCR. PEPy proved to be a superior substitute for AMCA as a short wavelength fluorescent dye for qPCR probes. PEPy probes were shown to significantly reduce Cq (a fractional PCR cycle used for quantification) vs. AMCA labeled probes, thus improving on the reliability of detection. Moreover, a larger increase of fluorescence during amplification was observed in the case of PEPy probes that makes this dye very suitable for an end-point PCR technique. This study broadens the panel of fluorescent dyes suitable for the use in probes for quantitative real-time PCR. PMID- 26738805 TI - A common TLR1 polymorphism is associated with higher parasitaemia in a Southeast Asian population with Plasmodium falciparum malaria. AB - BACKGROUND: The factors leading to poor outcomes in malaria infection are incompletely understood. Common genetic variation exists in the human genes for Toll like receptors (TLRs) that alter host responses to pathogen-associated molecular patterns. Genetic variation in TLR1 and TLR6 could alter the risk of development of complicated malaria and ability of the host to control the parasite burden during acute Plasmodium falciparum infection. METHODS: Five single nucleotide polymorphisms in TLR1 and TLR6 in 432 patients with clinical P. falciparum monoinfection acquired on the Thai-Myanmar border were genotyped. Using logistic regression, associations with the development of complicated malaria and the percentage of infected erythrocytes (parasitaemia) on the day of presentation to clinical care (day zero) were tested. RESULTS: Genotypes carrying the T (major) allele of TLR1 rs5743551--an allele associated with improved outcomes in sepsis--were associated with higher parasitaemia measured on day zero (p = 0.03). DISCUSSION: Since malaria exerts strong genetic pressure on the human genome, protection from parasitaemia associated with TLR1 rs5743551 may account for the maintenance of an allele associated with poor outcomes in Caucasians with sepsis. CONCLUSION: These data suggest that genetic variation in TLR1 has effects on the host response to Plasmodium falciparum malaria in Asian populations. Genotypes from TLR6 showed no evidence of association with either complicated malaria or parasite burden. PMID- 26738807 TI - A reduced-order modeling for efficient design study of artificial valve in enlarged ventricular outflow tracts. AB - A computational approach is proposed for efficient design study of a reducer stent to be percutaneously implanted in enlarged right ventricular outflow tracts (RVOT). The need for such a device is driven by the absence of bovine or artificial valves which could be implanted in these RVOT to replace the absent or incompetent native valve, as is often the case over time after Tetralogy of Fallot repair. Hemodynamics are simulated in the stented RVOT via a reduce order model based on proper orthogonal decomposition, while the artificial valve is modeled as a thin resistive surface. The reduced order model is obtained from the numerical solution on a reference device configuration, then varying the geometrical parameters (diameter) for design purposes. To validate the approach, forces exerted on the valve and on the reducer are monitored, varying with geometrical parameters, and compared with the results of full CFD simulations. Such an approach could also be useful for uncertainty quantification. PMID- 26738808 TI - On determining the height of the potential barrier at grain boundaries in ion conducting oxides. AB - The validity and limitations of two quantitative approaches for estimating the height of the potential barrier at grain boundaries, Psigb, in polycrystalline ionic conductors are examined both theoretically and experimentally. The linear diffusion model recently proposed by Kim and Lubomirsky determines Psigb from the value of the power exponent of the current (Igb)-voltage (Ugb) relationship at the grain boundary, dln(Igb)/dln(Ugb), while the conventional approach calculates Psigb from the ratio of the grain boundary resistivity to the grain core resistivity. The results of our theoretical analysis demonstrate that both approaches should yield consistent values for Psigb if the ionic current through the grain boundary is limited exclusively by space charge. While the value of Psigb obtained by the power law procedure is relatively insensitive to other causes of current obstruction, e.g. current constriction and/or local structural disorder, the resistivity ratio method, if not explicitly corrected for these additional limitations, results in a considerable overestimate of the grain boundary potential barrier. Hence, it is possible to distinguish between grain boundary resistance due to the presence of space charge and that due to additional sources by comparing the values of Psigb determined using each of the two methods. Our theoretical analysis is confirmed experimentally with 3 mol% Gd doped ceria with and without an additional source of current constriction across the grain boundary. PMID- 26738809 TI - Assessment of in vitro genotoxic and cytotoxic effects of flurbiprofen on human cultured lymphocytes. AB - Flurbiprofen is non-steroidal anti-inflammatory drug which is commonly used for its analgesic, antipyretic, and anti-inflammatory effects. The purpose of the study was to explore the genotoxic and cytotoxic effects of flurbiprofen in human cultured lymphocytes by sister chromatid exchange, chromosome aberration, and cytokinesis-blocked micronucleus tests. 10, 20, 30, and 40 MUg/mL concentrations of flurbiprofen (solvent is DMSO) were used to treatment of human cultured lymphocytes at two different treatment periods (24 and 48 h). Flurbiprofen had no significant genotoxic effect in any of these tests. But exposing to flurbiprofen for 24 and 48 h led to significant decrease on proliferation index, mitotic index, and nuclear division index (NDI). Also, all decreases were concentration dependent (except NDI at 24 h treatment period). Consequently, the findings of this research showed that flurbiprofen had cytotoxic effects in human blood lymphocytes. PMID- 26738810 TI - Multiscale Model for the Assembly Kinetics of Protein Complexes. AB - The assembly of proteins into high-order complexes is a general mechanism for these biomolecules to implement their versatile functions in cells. Natural evolution has developed various assembling pathways for specific protein complexes to maintain their stability and proper activities. Previous studies have provided numerous examples of the misassembly of protein complexes leading to severe biological consequences. Although the research focusing on protein complexes has started to move beyond the static representation of quaternary structures to the dynamic aspect of their assembly, the current understanding of the assembly mechanism of protein complexes is still largely limited. To tackle this problem, we developed a new multiscale modeling framework. This framework combines a lower-resolution rigid-body-based simulation with a higher-resolution Calpha-based simulation method so that protein complexes can be assembled with both structural details and computational efficiency. We applied this model to a homotrimer and a heterotetramer as simple test systems. Consistent with experimental observations, our simulations indicated very different kinetics between protein oligomerization and dimerization. The formation of protein oligomers is a multistep process that is much slower than dimerization but thermodynamically more stable. Moreover, we showed that even the same protein quaternary structure can have very diverse assembly pathways under different binding constants between subunits, which is important for regulating the functions of protein complexes. Finally, we revealed that the binding between subunits in a complex can be synergistically strengthened during assembly without considering allosteric regulation or conformational changes. Therefore, our model provides a useful tool to understand the general principles of protein complex assembly. PMID- 26738811 TI - Identification of Plasma Biomarkers of Human Intracerebral Hemorrhage Subtypes through Microarray Technology. AB - BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating form of stroke and depending on the underlying cause, primary ICH is mainly caused by hypertension (HTN-ICH) or cerebral amyloid angiopathy (CAA-ICH). Currently, neuroimaging markers are required to identify the pattern for each etiology. The discovery of new biomarkers to improve the management of this pathology is therefore needed. METHODS: A microarray analysis was carried out to analyze gene expression differences in blood samples from patients (>1.5 months since the last ICH event) who suffered a CAA-ICH and HTN-ICH, and controls. The results were replicated by quantitative polymerase chain reaction and the plasma protein level of the best candidate was measured with enzyme-linked immunosorbent assay. RESULTS: The microarray analysis and the validation study revealed an increase in Golgin A8 Family, Member A (GOLGA8A) mRNA and protein levels in ICH cases compared to controls (P < .01), although no differences were found between specific ICH etiologies. GOLGA8A plasma levels were also associated with the presence of multiple hemorrhages (P < .05). CONCLUSIONS: The GOLGA8A level was increased in the blood of patients who suffered a primary ICH. We did not, however, find any candidate biomarker that distinguished CAA-ICH from HTN-ICH. The role of GOLGA8A in this fatal disorder has yet to be determined. PMID- 26738813 TI - Endovascular Therapy for Infectious Intracranial Aneurysm: A Report of Four Cases. AB - BACKGROUND: Infectious intracranial aneurysms (IIAs) are rare but can cause substantial morbidity and mortality. We aimed to re-evaluate the role of endovascular therapy for the treatment of IIAs. METHODS: This study is a retrospective review of patients diagnosed with IIAs and treated by endovascular therapy in our institutions over the past 13 years. RESULTS: Four patients were diagnosed with infectious endocarditis with a total of 5 IIAs. Three of the 4 patients had ruptured IIAs. Two presented with intracerebral hemorrhage, one with subarachnoid hemorrhage, and one with cerebral infarction. The distal middle cerebral artery (MCA) was the most common site, followed by the distal segment of the posterior cerebral artery. Three patients were treated by parent artery occlusion and one by direct aneurysm obliteration. There were no periprocedural complications. One IIA treated by direct aneurysm occlusion was recanalized within 1 year and required a second embolization. Outcomes were measured by the modified Rankin Scale on discharge: 2 patients scored 0, 1 patient scored 1, and 1 patient scored 3. CONCLUSION: IIAs located deep in the brain or on the peripheral MCA can be safely treated with endovascular therapy even when they are lying in the eloquent cortex. PMID- 26738812 TI - Phosphodiesterase-5 Inhibitor PF-03049423 Effect on Stroke Recovery: A Double Blind, Placebo-Controlled Randomized Clinical Trial. AB - BACKGROUND: The therapeutic potential of phosphodiesterase-5 inhibitor PF 03049423 was evaluated in a phase 2, multicenter, randomized, double-blind, placebo-controlled study of subjects with acute ischemic stroke ( CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov, unique identifier: NCT01208233; http://www.clinicaltrialsregister.eu, EudraCT number: 2010-021414 32). MATERIALS AND METHODS: Subjects (N = 70) received PF-03049423 6 mg (or placebo, N = 67) once daily, orally, commencing between 24 and 78 hours of stroke onset, and continuing for 90 days. Postbaseline efficacy assessments were performed on Days 7, 14, 30, 60, and 90. Modified Rankin Scale (mRS), Barthel Index, National Institutes of Health Stroke Scale, Box and Blocks Test, Hand-Grip Strength Test, 10-Meter Walk Test, Repeatable Battery Assessment of Neuropsychological Status Naming and Coding Subtests, Line Cancellation Test, and Recognition Memory Test were administered to evaluate poststroke recovery. The primary endpoint was the mRS responder rate (score 0-2 at Day 90). The study included a planned interim analysis of efficacy data. RESULTS: The primary efficacy analysis using logistic regression showed no statistically significant difference between PF-03049423 6 mg and placebo (responder rate of 42.6% and 46.2%, respectively). Although PF-03049423 showed a satisfactory safety and tolerability profile, no signal of efficacy emerged from any of the outcome measures. CONCLUSIONS: PF-03049423 showed no therapeutic potential for acute ischemic stroke. PMID- 26738814 TI - Association of Sleep Duration with Stroke in Diabetic Patients: Analysis of the National Health Interview Survey. AB - BACKGROUND: Habitual sleep duration is increasingly being recognized as an important risk factor for stroke. We sought to describe the association between sleep duration and stroke in a cohort of individuals with diabetes. METHODS: Data from the National Health Interview Survey for the years 2004-2013 were used. Only those answering "yes" to the question "Have you EVER been told by a doctor or other health professional that you have diabetes or sugar diabetes?" were included in the analysis. Sleep duration was categorized as short (<=6 hours), normal (7-8 hours), or long (>=9 hours). Self-reported diagnosis of stroke was the main outcome of interest. FINDINGS: A total number of 26,364 self-reported diabetic individuals provided data for analysis. Stroke was reported in 9.1% of short sleepers, 16.1% of long sleepers, and 8.3% of normative sleepers (P < .05). In the unadjusted model, short and long sleepers had an increased odds of stroke compared to normal sleepers (odds ratio [OR] = 1.12, 95% confidence interval [CI]: 1.02-1.23, P = .01; and OR = 2.18, 95% CI: 1.96-2.42, P = .01; respectively), but the association between short sleep and stroke became nonsignificant after multivariate adjustment (OR = 1.15, 95% CI: .95-1.40, P = .16) except in white participants. The association between long sleep duration and stroke persisted (OR = 1.46, 95% CI: 1.16-1.84, P = .01), especially in males (OR = 1.62, 95% CI: 1.14-2.28) and in white participants (OR = 1.97, 95% CI: 1.47 2.65). CONCLUSION: In diabetic patients, abnormal sleep duration was associated with increased risk of stroke, and this association varied among different sex and ethnic groups. PMID- 26738815 TI - Long-Term Mortality and Its Risk Factors in Stroke Survivors. AB - BACKGROUND: Stroke is one of the leading causes of mortality worldwide. Understanding the risk factors associated with stroke mortality is important to improve patient management. Few studies have examined long-term mortality and its associated predictive risk factors. METHODS: We examined long-term mortality in 1137 patients with acute stroke and compared it to a geographically age- and sex matched, stroke-free control group. We followed the stroke patients for as long as 16.4 years. In 1018 of these patients we assessed the effect of demographic, clinical, and hematological factors on mortality. RESULTS: At the end of the study period, 51.7% of the patients and 32.7% of the stroke-free control individuals had died (hazard ratio 2.2, confidence interval 1.9-2.5, P < .001). A total of 72.5% of the patients and 53% of the controls with 12 years' follow-up (n = 570) had died (P < .001). Regression analyses indicate that, in addition to known risk factors such as age, diabetes, and stroke severity, both low cholesterol (P < .001) and hemoglobin (P < .002), hyperhomocysteinemia (P = .005), and elevated serum creatinine (P < .001) at index stroke are associated with increased long-term mortality. CONCLUSIONS: Stroke patients surviving the first year after stroke have a markedly increased mortality rate as seen in long term follow-up. Furthermore, the results from this study indicate that changes in creatinine, homocysteine, and hemoglobin should be followed more carefully as standard practice after acute stroke. PMID- 26738817 TI - Sarcopenia in patients undergoing maintenance hemodialysis: incidence rate, risk factors and its effect on survival risk. AB - BACKGROUND: Sarcopenia is a degenerative syndrome mainly characterized by the atrophy of skeletal muscle, along with the decrease of muscle strength and function. However, there are currently few studies concerning sarcopenia in patients undergoing maintenance hemodialysis dialysis (MHD). This study was aimed to investigate the incidence of sarcopenia in MHD patients and its influencing factors, as well as its impact on survival risk. METHOD: All 131 MHD patients enrolled in our study were tested with bioelectrical impedance analysis (BIA) and grip strength. Demographic data was collected and anthropometric measurement and laboratory examination were conducted. RESULTS: The total incidence of sarcopenia within the 131 MHD patients was 13.7% and the incidence of sarcopenia in patients over 60 years was 33.3%. The dialysis duration, with or without diabetes, serum phosphorus and pre-albumin levels of sarcopenic patients were significantly different from those of non-sarcopenicones; the modified quantitative subjective global assessment (MQSGA) scores of sarcopenic patients were higher than those without sarcopenia. Multivariate analysis showed that dialysis duration, diabetes and serum phosphorus level were independent risk factors for sarcopenia in MHD patients. Kaplan-Meier survival analysis showed a one-year survival of 88.9% in sarcopenic patients, which was significantly lower than non-sarcopenic patients. CONCLUSION: The incidence of sarcopenia in MHD patients was high and increased gradually with age. Dialysis duration, diabetes, serum phosphorus level and malnutrition predisposed the patients to sarcopenia. One-year follow-up found that the mortality risk of sarcopenic patients was higher than that of non sarcopenic patients. PMID- 26738816 TI - Multi-reporter selection for the design of active and more specific zinc-finger nucleases for genome editing. AB - Engineered nucleases have transformed biological research and offer great therapeutic potential by enabling the straightforward modification of desired genomic sequences. While many nuclease platforms have proven functional, all can produce unanticipated off-target lesions and have difficulty discriminating between homologous sequences, limiting their therapeutic application. Here we describe a multi-reporter selection system that allows the screening of large protein libraries to uncover variants able to discriminate between sequences with substantial homology. We have used this system to identify zinc-finger nucleases that exhibit high cleavage activity (up to 60% indels) at their targets within the CCR5 and HBB genes and strong discrimination against homologous sequences within CCR2 and HBD. An unbiased screen for off-target lesions using a novel set of CCR5-targeting nucleases confirms negligible CCR2 activity and demonstrates minimal off-target activity genome wide. This system offers a straightforward approach to generate nucleases that discriminate between similar targets and provide exceptional genome-wide specificity. PMID- 26738818 TI - Measles immunisation: time to close the gap. PMID- 26738819 TI - From START to finish: implications of the START study. PMID- 26738821 TI - Corrections. PMID- 26738820 TI - Camels, MERS-CoV, and other emerging infections in east Africa. PMID- 26738823 TI - Corrections. PMID- 26738822 TI - Corrections. PMID- 26738825 TI - Whole-genome sequencing for the diagnosis of drug-resistant tuberculosis. PMID- 26738826 TI - How to minimise antibiotic resistance. PMID- 26738827 TI - Symptoms closely associated with Ebola virus disease. PMID- 26738828 TI - Mother-to-child transmission of hepatitis B in sub-Saharan Africa. PMID- 26738829 TI - Elimination of mother-to-child transmission of hepatitis B. PMID- 26738830 TI - Respiratory co-morbidities in people with HIV. PMID- 26738831 TI - Assessing the quality of tuberculosis care in India. PMID- 26738832 TI - Assessing the quality of tuberculosis care in India - Authors' response. PMID- 26738833 TI - Use of standardised patients to assess quality of tuberculosis care. PMID- 26738834 TI - Cholera in Iraq strains the fragile state. PMID- 26738835 TI - Sex education in China leaves young vulnerable to infection. PMID- 26738836 TI - Europe's migrants face unacceptable humanitarian situation. PMID- 26738840 TI - Mycetoma: a unique neglected tropical disease. AB - Mycetoma can be caused by bacteria (actinomycetoma) or fungi (eumycetoma) and typically affects poor communities in remote areas. It is an infection of subcutaneous tissues resulting in mass and sinus formation and a discharge that contains grains. The lesion is usually on the foot but all parts of the body can be affected. The causative microorganisms probably enter the body by a thorn prick or other lesions of the skin. Mycetoma has a worldwide distribution but is restricted to specific climate zones. Microbiological diagnosis and characterisation of the exact organism causing mycetoma is difficult; no reliable serological test exists but molecular techniques to identify relevant antigens have shown promise. Actinomycetoma is treated with courses of antibiotics, which usually include co-trimoxazole and amikacin. Eumycetoma has no acceptable treatment at present; antifungals such as ketoconazole and itraconazole have been used but are unable to eradicate the fungus, need to be given for long periods, and are expensive. Amputations and recurrences in patients with eumycetoma are common. PMID- 26738841 TI - Tularaemia: clinical aspects in Europe. AB - Tularaemia is a zoonotic disease caused by Francisella tularensis, a Gram negative, facultative intracellular bacterium. Typically, human and animal infections are caused by F tularensis subspecies tularensis (type A) strains mainly in Canada and USA, and F tularensis subspecies holarctica (type B) strains throughout the northern hemisphere, including Europe. In the past, the epidemiological, clinical, therapeutic, and prognostic aspects of tularaemia reported in the English medical literature were mainly those that had been reported in the USA, where the disease was first described. Tularaemia has markedly changed in the past decade, and a large number of studies have provided novel data for the disease characteristics in Europe. In this Review we aim to emphasise the specific and variable aspects of tularaemia in different European countries. In particular, two natural lifecycles of F tularensis have been described in this continent, although not fully characterised, which are associated with different modes of transmission, clinical features, and public health burdens of tularaemia. PMID- 26738842 TI - Classic Whipple's disease diagnosed by (18)F-fluorodeoxyglucose PET. PMID- 26738843 TI - Superamphiphobic Silicon-Nanowire-Embedded Microsystem and In-Contact Flow Performance of Gas and Liquid Streams. AB - Gas and liquid streams are invariably separated either by a solid wall or by a membrane for heat or mass transfer between the gas and liquid streams. Without the separating wall, the gas phase is present as bubbles in liquid or, in a microsystem, as gas plugs between slugs of liquid. Continuous and direct contact between the two moving streams of gas and liquid is quite an efficient way of achieving heat or mass transfer between the two phases. Here, we report a silicon nanowire built-in microsystem in which a liquid stream flows in contact with an underlying gas stream. The upper liquid stream does not penetrate into the lower gas stream due to the superamphiphobic nature of the silicon nanowires built into the bottom wall, thereby preserving the integrity of continuous gas and liquid streams, although they are flowing in contact. Due to the superamphiphobic nature of silicon nanowires, the microsystem provides the best possible interfacial mass transfer known to date between flowing gas and liquid phases, which can achieve excellent chemical performance in two-phase organic syntheses. PMID- 26738844 TI - Cognitive effects of donepezil therapy in patients with brain tumors: a pilot study. AB - Cognitive dysfunction is prevalent among brain tumor patients treated with radiotherapy (RT) and chemotherapy. However, there are no approved pharmacological interventions for cognitive dysfunction in cancer patients. The goal of this pilot study was to examine the efficacy of donepezil, an acetylcholinesterase inhibitor used to treat Alzheimer's disease, in improving cognitive functions in brain tumor patients previously treated with RT + chemotherapy or chemotherapy alone. Fifteen patients with a brain tumor received a single daily dose of donepezil for 24 weeks (5 mg for 4 weeks, then 10 mg for 20 weeks). Patients completed cognitive evaluations prior to initiating therapy (baseline), and about 12 weeks (mid-study) and 24 weeks (end-of-study) subsequent to initiation of donepezil therapy. The results of linear mixed models analysis, controlling for each patient's baseline cognitive test score, showed a significant post-baseline improvement in attention (WAIS-III digit span forward; p = 0.037), graphomotor speed (WAIS-III digit symbol; p = 0.035) and visual memory (BVMT-R-delay; p = 0.025). There was also an improvement in self-reported quality of life (FACT-Br, social well-being subscale; p = 0.01). The findings of this pilot study suggest that treatment with donepezil may improve some aspects of cognitive functions and quality of life in brain tumor patients. Similar findings were reported in two prior trials of donepezil in brain tumor survivors. PMID- 26738845 TI - Expression and prognostic value of the WEE1 kinase in gliomas. AB - High-grade gliomas have an aggressive clinical course and new clinical biomarkers and therapeutic targets are highly needed. WEE1 is a regulator of the G2 checkpoint in glioblastoma (GBM) cells. Inhibition of this kinase has, in experimental glioma studies, been suggested to enhance sensitivity to irradiation and temozolomide. However, expression level and prognostic potential of WEE1 protein in gliomas remain uninvestigated. In this study, glioma samples from 235 patients across all four WHO grades were analyzed by immunohistochemistry. Using image analysis, we calculated the area fraction of WEE1 positive nuclei. We found that WEE1 protein was localized in tumor cell nuclei and expressed in all glioma types and grades. Although WEE1 protein levels are higher in GBMs (mean 24.5%) relative to grade III (mean 14,0%, p < 0.05) and grade II (mean 6.8%, p < 0.001) gliomas, high WEE1 protein was associated with better survival in GBMs (p = 0.002). This was confirmed in multivariate analysis (HR 0.60, p = 0.003) even when adjusted for MGMT status (HR 0.60, p = 0.005). In conclusion, we report a nuclear expression of WEE1 protein in all glioma grades and types. The WEE1 positive nuclear area was correlated with malignancy grade but it was inversely associated with prognosis in GBM. Although WEE1 is a frequently occurring protein and has been proposed as a novel target in GBM, the role of WEE1 in glioma patient survival appears to be connected to the MGMT status and is more complex than previously anticipated. PMID- 26738846 TI - Comparative transcriptome analysis reveals insights into the streamlined genomes of haplosclerid demosponges. AB - Sponges (Porifera) are one of the most ancestral metazoan groups. They are characterized by a simple body plan lacking the true tissues and organ systems found in other animals. Members of this phylum display a remarkable diversity of form and function and yet little is known about the composition and complexity of their genomes. In this study, we sequenced the transcriptomes of two marine haplosclerid sponges belonging to Demospongiae, the largest and most diverse class within phylum Porifera, and compared their gene content with members of other sponge classes. We recovered 44,693 and 50,067 transcripts expressed in adult tissues of Haliclona amboinensis and Haliclona tubifera, respectively. These transcripts translate into 20,280 peptides in H. amboinensis and 18,000 peptides in H. tubifera. Genes associated with important signaling and metabolic pathways, regulatory networks, as well as genes that may be important in the organismal stress response, were identified in the transcriptomes. Futhermore, lineage-specific innovations were identified that may be correlated with observed sponge characters and ecological adaptations. The core gene complement expressed within the tissues of adult haplosclerid demosponges may represent a streamlined and flexible genetic toolkit that underlies the ecological success and resilience of sponges to environmental stress. PMID- 26738847 TI - Molecular mapping and characterization of the silkworm apodal mutant. AB - The morphological diversity of insects is important for their survival; in essence, it results from the differential expression of genes during development of the insect body. The silkworm apodal (ap) mutant has degraded thoracic legs making crawling and eating difficult and the female is sterile, which is an ideal subject for studying the molecular mechanisms of morphogenesis. Here, we confirmed that the infertility of ap female moths is a result of the degradation of the bursa copulatrix. Positional cloning of ap locus and expression analyses reveal that the Bombyx mori sister of odd and bowl (Bmsob) gene is a strong candidate for the ap mutant. The expression of Bmsob is down-regulated, while the corresponding Hox genes are up-regulated in the ap mutant compared to the wild type. Analyses with the dual luciferase assay present a declined activity of the Bmsob promoter in the ap mutant. Furthermore, we demonstrate that Bmsob can inhibit Hox gene expression directly and by suppressing the expression of other genes, including the BmDsp gene. The results of this study are an important contribution to our understanding of the diversification of insect body plan. PMID- 26738848 TI - Functional gastrointestinal disorders and incidence of type 2 diabetes: Evidence from the E3N-EPIC cohort study. AB - OBJECTIVE: Functional gastrointestinal disorders (FGID) such as diarrhoea and constipation can reflect intestinal dysfunction, especially with regard to intestinal microbiota, which, in turn, have been associated with chronic conditions, including obesity and insulin resistance. However, little is known of the association between FGID and type 2 diabetes (T2D) risk. DESIGN AND METHODS: This analysis aimed to determine the influence of diarrhoea, constipation and alternating bouts of diarrhoea/constipation on T2D risk in 62,683 women from the prospective E3N-EPIC cohort. RESULTS: A total of 1795 T2D cases were recorded during follow-up. Compared with women who had normal gastrointestinal transits, women with chronic diarrhoea or alternating diarrhoea/constipation were at increased risk of T2D (HR: 1.29, 95% CI: 1.00-1.65 vs. HR: 1.32, 95% CI: 1.15 1.52, respectively), whereas women with constipation had a decreased risk (HR: 0.67, 95% CI: 0.57-0.78). There was no interaction between FGID and body mass index for risk of T2D. Also, these associations were independent of dietary habits such as coffee, fruit and vegetable consumption, and even of the use of laxatives and psychotropic drugs. CONCLUSION: The present analysis showed, for the first time, a limited association between FGID and T2D risk in a large prospective cohort, and supports the hypothesis of a relationship between gastrointestinal function and diabetes. The presence of gastrointestinal transit disorders may assist in screening for subjects at higher risk of diabetes beyond the conventional risk factors. PMID- 26738849 TI - Emergence of Infections due to a Polymyxin B-Resistant KPC-2-Producing Klebsiella pneumoniae in Critically Ill Patients: What Is the Role of a Previous Colonization? PMID- 26738850 TI - HNK-1 Carrier Glycoproteins Are Decreased in the Alzheimer's Disease Brain. AB - The human natural killer-1 (HNK-1), 3-sulfonated glucuronic acid, is a glycoepitope marker of cell adhesion that participates in cell-cell and cell extracellular matrix interactions and in neurite growth. Very little is known about the regulation of the HNK-1 glycan in neurodegenerative disease, particularly in Alzheimer's disease (AD). In this study, we investigate changes in the levels of HNK-1 carrier glycoproteins in AD. We demonstrate an overall decrease in HNK-1 immunoreactivity in glycoproteins extracted from the frontal cortex of AD subjects, compared with levels from non-demented controls (NDC). Immunoblotting of ventricular post-mortem and lumbar ante-mortem cerebrospinal fluid with HNK-1 antibodies indicate similar levels of carrier glycoproteins in AD and NDC samples. Decrease in HNK-1 carrier glycoproteins were not paralleled by changes in messenger RNA (mRNA) levels of the enzymes involved in the synthesis of the glycoepitope, beta-1,4-galactosyltransferase (beta4GalT), glucuronyltransferases GlcAT-P and GlcAT-S, or sulfotransferase HNK-1ST. Over expression of amyloid precursor protein in Tg2576 transgenic mice and in vitro treatment of SH-SY5Y neuroblastoma cells with the amyloidogenic Abeta42 peptide resulted in a decrease in HNK-1 immunoreactivity levels in brain and cellular extracts, whereas the levels of soluble HNK-1 glycoproteins detected in culture media were not affected by Abeta treatment. HNK-1 levels remain unaffected in the brain extracts of Tg-VLW mice, a model of mutant hyperphosphorylated tau, and in SH-SY5Y cells over-expressing hyperphosphorylated wild-type tau. These results provide evidence that cellular levels of HNK-1 carrier glycoforms are decreased in the brain of AD subjects, probably influenced by the beta-amyloid protein. PMID- 26738851 TI - GSK-3beta and MMP-9 Cooperate in the Control of Dendritic Spine Morphology. AB - Changes in the morphology of dendritic spines are prominent during learning and in different neurological and neuropsychiatric diseases, including those in which glycogen synthase kinase-3beta (GSK-3beta) has been implicated. Despite much evidence of the involvement of GSK-3beta in functional synaptic plasticity, it is unclear how GSK-3beta controls structural synaptic plasticity (i.e., the number and shape of dendritic spines). In the present study, we used two mouse models overexpressing and lacking GSK-3beta in neurons to investigate how GSK-3beta affects the structural plasticity of dendritic spines. Following visualization of dendritic spines with DiI dye, we found that increasing GSK-3beta activity increased the number of thin spines, whereas lacking GSK-3beta increased the number of stubby spines in the dentate gyrus. Under conditions of neuronal excitation, increasing GSK-3beta activity caused higher activity of extracellularly acting matrix metalloproteinase-9 (MMP-9), and MMP inhibition normalized thin spines in GSK-3beta overexpressing mice. Administration of the nonspecific GSK-3beta inhibitor lithium in animals with active MMP-9 and animals lacking MMP-9 revealed that GSK-3beta and MMP-9 act in concert to control dendritic spine morphology. Altogether, our data demonstrate that the dysregulation of GSK-3beta activity has dramatic consequences on dendritic spine morphology, implicating MMP-9 as a mediator of GSK-3beta-induced synaptic alterations. PMID- 26738852 TI - Resveratrol Pretreatment Decreases Ischemic Injury and Improves Neurological Function Via Sonic Hedgehog Signaling After Stroke in Rats. AB - Resveratrol has neuroprotective effects for ischemic cerebral stroke. However, its neuroprotective mechanism for stroke is less well understood. Beneficial actions of the activated Sonic hedgehog (Shh) signaling pathway in stroke, such as improving neurological function, promoting neurogenesis, anti-oxidative, anti apoptotic, and pro-angiogenic effects, have been noted, but relatively little is known about the role of Shh signaling in resveratrol-reduced cerebral ischemic injury after stroke. The present study tests whether the Shh pathway mediates resveratrol to decrease cerebral ischemic injury and improve neurological function after stroke. We observed that resveratrol pretreatment significantly improved neurological function, decreased infarct volume, enhanced vitality, and reduced apoptosis of neurons in vivo and vitro after stroke. Meanwhile, expression levels of Shh, Ptc-1, Smo, and Gli-1 mRNAs were significantly upregulated and Gli-1 was relocated to the nucleus. Intriguingly, in vivo and in vitro inhibition of the Shh signaling pathway with cyclopamine, a Smo inhibitor, completely reversed the above effects of resveratrol. These results suggest that decreased cerebral ischemic injury and improved neurological function by resveratrol may be mediated by the Shh signaling pathway. PMID- 26738853 TI - MicroRNA-146a Promotes Oligodendrogenesis in Stroke. AB - Stroke induces new myelinating oligodendrocytes that are involved in ischemic brain repair. Molecular mechanisms that regulate oligodendrogenesis have not been fully investigated. MicroRNAs (miRNAs) are small non-coding RNA molecules that post-transcriptionally regulate gene expression. MiR-146a has been reported to regulate immune response, but the role of miR-146a in oligodendrocyte progenitor cells (OPCs) remains unknown. Adult Wistar rats were subjected to the right middle cerebral artery occlusion (MCAo). In situ hybridization analysis with LNA probes against miR-146a revealed that stroke considerably increased miR-146a density in the corpus callosum and subventricular zone (SVZ) of the lateral ventricle of the ischemic hemisphere. In vitro, overexpression of miR-146a in neural progenitor cells (NPCs) significantly increased their differentiation into O4+ OPCs. Overexpression of miR-146a in primary OPCs increased their expression of myelin proteins, whereas attenuation of endogenous miR-146a suppressed generation of myelin proteins. MiR-146a also inversely regulated its target gene IRAK1 expression in OPCs. Attenuation of IRAK1 in OPCs substantially increased myelin proteins and decreased OPC apoptosis. Collectively, our data suggest that miR-146a may mediate stroke-induced oligodendrogenesis. PMID- 26738854 TI - Hyperglycemia-Induced Oxidative-Nitrosative Stress Induces Inflammation and Neurodegeneration via Augmented Tuberous Sclerosis Complex-2 (TSC-2) Activation in Neuronal Cells. AB - Diabetes is a systemic disease mainly characterized by chronic hyperglycemia and with extensive and long-lasting spiteful complications in central nervous systems (CNS). Astrocytes play an important role in the defense mechanism of CNS, with great ability of withstanding accumulation of toxic substances. Apart from functional disorders, hyperglycemia leads to slow progressive structural abnormalities in the CNS through oxidative stress pathways. However, the molecular mechanism by which neurons die under oxidative stress induced by high glucose (HG) remains largely unclear. Here, we report that HG-induced inflammation and neurodegeneration in brain tissues, brain astrocytes (C6), and pheochromocytoma (PC-12) cells are cultured in HG conditions. Our results show that the increases in phosphorylation of Akt and ERK1/2MAPK are associated with increased accumulations of reactive oxygen species (ROS) in neuronal cells, which simultaneously enhanced phosphorylations of tuberous sclerosis complex-2 (TSC-2) and mammalian target of rapamycin (mTOR) in the diabetic brain and in HG-exposed neuronal cells. Pharmacologic inhibition of Akt or ERK1/2 or siRNA-mediated gene silencing of TSC-2 suppressed the strong downregulation of TSC-2-mTOR activation. Findings of this study also demonstrate that HG resulted in phosphorylation of NF kappaB, coinciding with the increased production of inflammatory mediators and activation of neurodegenerative markers. Pretreatment of cells with antioxidants, phosphoinositide3-kinase (PI3-K)/Akt, and ERK1/2 inhibitors significantly reduced HG-induced TSC-2 phosphorylation and restored NF-kappaB protein expression leading to decreased production of inflammatory mediators and neurodegenerative markers. These results illustrate that ROS functions as a key signaling component in the regulatory pathway induced by elevated glucose in neuronal cell activation leading to inflammation and neurodegeneration. PMID- 26738855 TI - Anthocyanins Reversed D-Galactose-Induced Oxidative Stress and Neuroinflammation Mediated Cognitive Impairment in Adult Rats. AB - Aging is a major factor involved in neurological impairments, decreased anti oxidant activities, and enhanced neuroinflammation. D-galactose (D-gal) has been considered an artificial aging model which induces oxidative stress and inflammatory response resulting in memory and synaptic dysfunction. Dietary supplementation exerts valuable effects against oxidative stress and neuroinflammation. Polyphenolic flavonoids, such as anthocyanins, have been reported as an anti-inflammatory and anti-oxidant agents against various neurodegenerative diseases. Recently, our group reported anthocyanin neuroprotection of the developing rat brain against ethanol-induced oxidative stress and neurodegenaration and ethanol-induced neuronal apoptosis via GABAB1 receptor intracellular signaling in prenatal rat hippocampus. Here, we examined the protective effect of anthocyanin neuroprotection against D-gal-induced oxidative and inflammatory response in the hippocampus and cortex regions and explore the potential mechanism of its action. Our results indicated that anthocyanins treatment significantly improved behavioral performance of D-gal treated rats in Morris water maze and Y-maze tests. One of the potential mechanisms of this action was decreased expression of the receptor for advance glycation end product, reduced level of reactive oxygen species (ROS) and lipid peroxidation as well as markers of the Alzheimer's disease. Furthermore, the results also indicated that anthocyanins inhibited activated astrocytes and neuroinflammation via suppression of various inflammatory markers including p-NF- K B, inducible nitric oxide synthase (iNOS), and tumor necrosis factor-alpha (TNF alpha) in the hippocampus and cortex regions of D-gal-treated rats brain. Moreover, anthocyanins abrogated neuroapoptosis via C-jun N-terminal kinase (p JNK) suppression and improved deregulated synaptic proteins including synaptophysin, synaptosomal-associated protein (SNAP)-23, SNAP-25, and phosphorylated CREB. This data suggests that anthocyanins could be a safe and promising anti-oxidant and anti-neuroinflammatory agent for age-related neurodegenerative diseases such as Alzheimer's disease. PMID- 26738857 TI - Slit2/Robo1 Mediation of Synaptic Plasticity Contributes to Bone Cancer Pain. AB - Synaptic plasticity is fundamental to spinal sensitivity of bone cancer pain. Here, we have shown that excitatory synaptogenesis contributes to bone cancer pain. New synapse formation requires neurite outgrowth and an interaction between axons and dendrites, accompanied by the appositional organization of presynaptic and postsynaptic specializations. We have shown that Slit2, Robo1, and RhoA act as such cues that promote neurite outgrowth and guide the axon for synapse formation. Sarcoma inoculation induces excitatory synaptogenesis and bone cancer pain which are reversed by Slit2 knockdown but aggravated by Robo1 knockdown. Synaptogenesis of cultured neurons are inhibited by Slit2 knockdown but enhanced by Robo1 knockdown. Sarcoma implantation induces an increase in Slit2 and decreases Robo1 and RhoA, while Slit2 knockdown results in an increase of Robo1 and RhoA. These results have demonstrated a molecular mechanism of synaptogenesis in bone cancer pain. PMID- 26738856 TI - TLX-Its Emerging Role for Neurogenesis in Health and Disease. AB - The orphan nuclear receptor TLX, also called NR2E1, is a factor important in the regulation of neural stem cell (NSC) self-renewal, neurogenesis, and maintenance. As a transcription factor, TLX is vital for the expression of genes implicated in neurogenesis, such as DNA replication, cell cycle, adhesion and migration. It acts by way of repressing or activating target genes, as well as controlling protein-protein interactions. Growing evidence suggests that dysregulated TLX acts in the initiation and progression of human disorders of the nervous system. This review describes recent knowledge about TLX expression, structure, targets, and biological functions, relevant to maintaining adult neural stem cells related to both neuropsychiatric conditions and certain nervous system tumours. PMID- 26738858 TI - Abnormal O-GlcNAcylation of Pax3 Occurring from Hyperglycemia-Induced Neural Tube Defects Is Ameliorated by Carnosine But Not Folic Acid in Chicken Embryos. AB - Neural tube defects (NTDs) are among the most common of the embryonic abnormalities associated with hyperglycemic gestation. In this study, the molecular mechanisms of embryonic neurogenesis influenced by hyperglycemia was investigated using chicken embryo models. High-concentration glucose was administered into chicken eggs and resulted in increased plasma and brain tissue glucose, and suppressed expression of glucose transporters (GLUTs). The rate of NTD positively correlated with hyperglycemia. Furthermore, abnormally increased O GlcNAcylation, a nutritionally responsive modification, of the key neural tube marker Pax3 protein led to the loss of this protein. This loss was not observed in a folate-deficiency NTD induced by methotrexate. Carnosine, an endogenous dipeptide, showed significant recovery effects on neural tube development. In contrast, folic acid, a well-known periconceptional agent, surprisingly showed relatively minimal effect. Higher expression levels of the Pax3 protein were found in the carnosine-treated groups, while lower expression levels were found in folic acid groups. Furthermore, the abnormal O-GlcNAcylation of the Pax3 protein was restored by carnosine. These results suggest new insights into using endogenous nutrients for the protection of embryonic neurodevelopment affected by diabetes gestation. The abnormal excessive O-GlcNAcylation of Pax3 may be responsible for the neural tube defects associated with hyperglycemia. PMID- 26738859 TI - Association of Parkinson's Disease GWAS-Linked Loci with Alzheimer's Disease in Han Chinese. AB - Alzheimer's disease (AD) and Parkinson's disease (PD) have overlapping pathological mechanisms and genetic background, suggesting it would be meaningful to replicate PD-related genetic variants in AD population to identify new loci of AD. Here, in order to discover potential AD-related loci, we investigated the association between late-onset AD (LOAD) susceptibility and nine single nucleotide polymorphisms (SNPs) (rs11724635 of BST1, rs12637471 of MCCC1, rs15553999 of TMEM229, rs17649553 of MAPT, rs34311866 of TMEM175-GAK-DGKQ, rs356182 of SNCA, rs6430538 of ACMSD-TMEM163, rs76904798 of LRRK2 and rs823118 of RAB7L1-NUCKS1) which were reported to have genome-wide significant associations with PD risk in a recent Genome Wide Association Study performed among white population. We included 2350 samples comprising with 992 sporadic LOAD patients and 1358 gender- and age-matched control subjects who were unrelated northern Han Chinese residents. Finally, among these included genetic variants, only rs76904798 of LRRK2 was proved to significantly reduce LOAD risk in a multivariate analysis in a dominant model after adjusting for age, sex, and apolipoprotein E (APOE) epsilon4 status (OR = 0.616; 95 % CI 0.446-0.849; Bonferroni corrected P = 0.027). In addition, when these data were stratified by APOE epsilon4 status, rs76904798 was still evident among subjects without APOE epsilon4 allele. Our results first time indicated rs76904798 of LRRK2 is also a common risk genetic variant for LOAD susceptibility in a northern Han Chinese people. PMID- 26738860 TI - The M2 phenotype of tumor-associated macrophages in the stroma confers a poor prognosis in pancreatic cancer. AB - Macrophages play a critical role in the initiation and progression of various solid tumors. However, their prognostic significance in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. This study investigated the distribution patterns of macrophages in PDAC and possible association with the overall survival (OS). We found significant differences in macrophage density (identified by CD68 and CD163 immunopositivity; p < 0.001 for both) between primary cancer and paired adjacent normal tissues. Most macrophages in cancerous pancreatic tissues were located in the stroma rather than the islets (p = 0.032 and p < 0.001). We also demonstrated that a high total macrophage density (characterized by CD68 immunopositivity) correlated with an absence of jaundice before surgery (p = 0.03) and that a high density of M2 macrophages (characterized by CD163 immunopositivity) in the stroma strongly correlated with the tumors located in the tail and body of the pancreas (p = 0.04). In addition, OS was shorter in patients with high-density M2 macrophage infiltration than in those with low-density M2 macrophage infiltration (p = 0.012). Moreover, multivariate analysis revealed that dense M2 macrophage infiltration into the stroma was an independent prognostic factor for PDAC patients (p = 0.02). PMID- 26738861 TI - Clinical role of HER2 gene amplification and chromosome 17: a study on 154 IHC equivocal cases of invasive breast carcinoma patients. AB - Accurate evaluation of human epidermal growth factor receptor 2 (HER2) status is quite crucial for invasive breast tumor patients in order to select anti-HER2 therapy for effective clinical outcomes. Immunohistochemistry (IHC) assay is routinely used to evaluate the HER2 oncoprotein overexpression but is unable to explain the chromosomal and genetic alterations and has been considered as a hot issue in IHC-equivocal cases. We investigated these molecular aberrations in correlation with prognostic factors. A cohort of 154 IHC-equivocal (+2) cases was selected and retrospectively analyzed by dual-probe fluorescence in situ hybridization (FISH) assay by using locus-specific HER2 and centromere enumeration probes (CEP17) for the identification of HER2 proto-oncogene amplification and chromosomal copy number per cell, respectively. The data were analyzed by SPSS 16.0 version using chi-square test (p < 0.05). We identified 36 out of 154 cases (23.4 %) showing HER2 gene amplification (average HER2 gene copies per cell >4 or <4 with HER2/CEP17 ratio >2) in concordance with HER2 oncoprotein overexpression, and significant correlation was observed with prognostic parameters including histological type, tumor grade II to III, histology and pathological type, lymphatic invasion, ductal carcinoma in situ (DCIS), and estrogen-positive and progesterone-negative receptors. Of the 154 cases, 18 cases (11.7 %) showed polysomy 17 with CEP17 probe signals per cell >=3 and 22 cases (14.3 %) presented monosomy 17 (CEP17 probe signals per cell <=1). Our data indicate that the use of anti-HER2 therapy should not be suggested unless true evaluation of HER2 protein expression is made regarding gene amplification essentially in IHC-ambiguous invasive breast tumors. PMID- 26738862 TI - Doxorubicin nanobubble for combining ultrasonography and targeted chemotherapy of rabbit with VX2 liver tumor. AB - A new class of multifunctional nanobubble using poly(lactic-co-glycolic acid) (PLGA) has been developed as ultrasound imaging contrast agents, doxorubicin carriers, and enhancers of ultrasound-mediated drug delivery. The doxorubicin nanobubble (DOX-NB) wrapping carbon tetrafluoride gas was prepared with double emulsion method. We evaluated the enhanced ultrasonic function of the DOX-NB in vivo; its antitumor function was confirmed. The diameter of the prepared bubble was 500 nm, and the potential was -23 mV. The drug loading and encapsulation efficiency of the bubble were 78.6 and 7.4 %, respectively. Therefore, the DOX-NB greatly enhanced ultrasound imaging in vivo. Ultrasound combined with DOX-NB had significant antitumor effect. Compared with other groups, the tumor growth rate and the proliferation index were the lowest while the survival rate and apoptosis index were the highest. PMID- 26738863 TI - Overexpression of ADAMTS5 can regulate the migration and invasion of non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is the major cause of cancer-related lethality among human cancer patients globally, and the poor prognosis of this cancer is mainly explained by metastasis, so it is essential to find out the molecule mechanisms and a novel therapeutic for NSCLC. A disintegrin and metalloprotease with thrombospondin motif 5 (ADAMTS5) belongs to the protease family. It has been reported to participate in tumor migration and invasion. In this study, we showed that the expression of ADAMTS5 was higher in lung cancer tissues by Western blot. The immunohistochemistry analysis was performed in 140 NSCLC cases, and the result indicated that ADAMTS5 was significantly associated with clinical pathologic variables. The Kaplan-Meier curve showed that the high expression of ADAMTS5 was related to poor prognosis of lung cancer patients. Wound healing assays and transwell migration assays revealed that the high expression of ADAMTS5 promoted the migration and invasion of NSCLC. In a word, our findings suggest that ADAMTS5 can regulate the migration and invasion of NSCLC and it may be a useful target of therapy in NSCLC. PMID- 26738864 TI - miR-488 acts as a tumor suppressor gene in gastric cancer. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that modulate development, cell proliferation, and apoptosis. The deregulated expression of microRNAs is found in carcinogenesis including gastric cancer (GC). In this study, we showed that the expression levels of miR-488 were downregulated in GC tissues compared to in non tumor tissues. In addition, the expression of miR-488 was also lower in GC cell lines in contrast with the gastric epithelial cell line (GES). In addition, the expression level of miR-488 was negatively correlated with the TNM stage in GC patients, and lower miR-488 expression was found in tumors with advanced TNM stage. The ectopic expression of miR-488 suppressed the GC cell proliferation, cell cycle, colony information, and migration. PAX6 was identified as a direct target gene of miR-488 in HGC-27. Moreover, we found that the expression level of PAX6 was upregulated in the GC tissues compared with the non-tumor tissues. The PAX6 expression level was correlated with the cancer TNM stage, and higher PAX6 expression was found in tumors with advanced TNM stage. Furthermore, there was an inverse correlation between PAX6 and miR-488 expression levels in GC tissues. Therefore, these studies demonstrated that miR-488 might act as a tumor suppressor miRNA in the development of GC. PMID- 26738865 TI - Expression of SRPK1 in gliomas and its role in glioma cell lines viability. AB - Among factors regulating the splicing of major importance is serine/arginine protein kinase 1 (SRPK1) that phosphorylates SR splicing factors. SRPK1 is expressed in the mammalian central nervous system in a region- and neuron specific manner. Based on previous observations that glial cells are practically devoid of SRPK1 and reports showing aberrant expression of SRPK1 in numerous tumors, but with conflicting roles, this study aims to investigate the expression of SRPK1 in glioma and its influence on tumor cell biological features. As shown by immunohistochemical analysis, malignant glioma cells express SRPK1 in glioblastomas with significant association between SRPK1 expression and patients' survival. SRPK1 expression was also significantly upregulated at the messenger RNA (mRNA) and protein level in glioma cell lines. Small interfering RNA-mediated downregulation of SRPK1 had little effect on cell viability, while it slightly enhanced the sensitivity of cells to killing by cisplatin. These results support the idea that at least in vitro, the effect of SRPK1 knockdown on the viability of glioma cell lines is rather limited, while the in vivo effects could be attributed to the modulation of angiogenesis by SRPK1. PMID- 26738866 TI - A panel of autoantibodies as potential early diagnostic serum biomarkers in patients with cervical cancer. AB - The study was designed to test whether circulating autoantibodies against associated antigens (TAAs) were altered in early cervical cancer and benign cervical tumors. A total of 111 cervical cancer patients, 137 cervical benign tumor patients, and 160 healthy volunteers matched in age were recruited in this study. The expression of autoantibodies was tested using in-house developed enzyme-linked immunosorbent assay (ELISA) with linear peptide envelope antigens derived from TAAs. One-way ANOVA test showed that there was no difference in the CD25 autoantibody expression among the cervical cancer group, benign tumor group, and healthy control group (P = 0.063; P = 0.191). The expression of autoantibodies against survivin and TP53 in the cervical cancer group was significantly higher than that in the benign tumor group (P < 0.001; P < 0.001). The levels of autoantibodies against cyclinB-1 and ANXA-1 were higher in the cervical cancer group than in the healthy control group (P = 0.010; P = 0.001), while autoantibodies in the cervical cancer group showed no difference in expression compared with that in the benign tumor group. The panel of five TAAs showed a sensitivity of 37.8 % and a specificity of 90 %, which was much higher than the sensitivity of the single-TAA testing group. The data from this study further support our previous hypothesis that the detection of autoantibodies for the diagnosis of a specific cancer type can be enhanced using a panel of several selected TAAs as target antigens. PMID- 26738867 TI - Diagnostic significance of elevated expression of HBME-1 in papillary thyroid carcinoma. AB - This study examined the association between hector battifora mesothelial antigen 1 (HBME-1) expression and papillary thyroid carcinoma (PTC). A total of 206 patients were enrolled in the current study including 96 PTC patients and 110 patients with benign thyroid nodules (BTN). Immunohistochemistry (Envision) were performed to assess the expression of HBME-1. Receiver operating characteristic curve (ROC) curves were applied to evaluate the diagnostic tumor node metastasis (TNM) value of HBME-1. Specimens from 96 patients with PTC and 110 patients with BTC were reviewed. HBME-1 was positively immunostained in PTC tissue, which was significantly higher than that in BTN tissues (77.1 vs. 5.77 %, P < 0.05). Immunohistochemistry also identified that HBME-1 expression did not show any statistically significant differences based on gender, age, tumor size, TNM stage, and lymph node metastasis (P > 0.05). Importantly, HBME-1 expression was correlated with infiltration levels and differential levels in PTC (both P < 0.05). HBME-1 was found to have high sensitivity (94.5 %) and specificity (77.08 %) for PTC diagnosis. Moreover, HBME-1 had a high specificity (83.33 %) at identifying the differential levels of PTC, but a low sensitivity (22.92 %). The sensitivity and specificity of HBME-1 identifying the infiltration levels of PTC were, respectively, 72.70 and 72.00 %. HBME-1 was highly expressed in PTC tissues, and HBME-1 can serve as a potential biomarker in the diagnosis of PTC. PMID- 26738868 TI - Neferine induces autophagy of human ovarian cancer cells via p38 MAPK/ JNK activation. AB - Ovarian cancer is the most lethal gynecological malignancy. Patients usually have poor prognosis because of late diagnosis, relapse, and chemoresistance. It is pressing to seek novel agent for the treatment of ovarian cancer. Neferine is a bisbenzylisoquinoline alkaloid isolated from the embryos of lotus (Nelumbo nucifera). In this study, we investigated the antitumor effect of neferine on ovarian cancer cells. We found that neferine exhibited growth-inhibitory effect on human ovarian cancer cells, whereas showing less cytotoxic to non-malignant fallopian tube epithelial cells. Furthermore, we demonstrated that neferine induced autophagy and inactivated the mTOR pathway. Finally, we found that both p38 MAPK and JNK signaling pathways were activated by neferine treatment and contributed to the induction of autophagy in ovarian cancer cells. In conclusion, our findings showed that neferine induced autophagy of human ovarian cancer cells via p38 MAPK/JNK activation. Neferine may be explored as a promising antitumoral agent in ovarian cancer. PMID- 26738869 TI - Decreased CK1delta expression predicts prolonged survival in colorectal cancer patients. AB - Cancers arising from the large intestine or rectum are called colorectal cancer (CRC) and represent the fourth leading cause of cancer-related death worldwide. Since casein kinase 1 (CK1) isoforms are involved in many cellular processes and have been reported to be deregulated in various tumor entities, CK1 has become an interesting drug target. In this study, we examined the potential of CK1delta expression levels in tumor tissue of CRC patients as a prognostic biomarker. We show by quantitative RNA expression analyses that decreased CK1delta expression levels in tumor tissue predict prolonged survival rates. Random sampling of CK1delta stained tumor tissue indicates that CK1delta gene expression corresponds with CK1delta protein expression. Especially in low grade (grade 1, grade 2) and in UICC II/III classified tumors decreased CK1delta RNA levels correlate with significantly improved survival rates when the tumor was located in the right colon. We furthermore found gender-specific differences within these subgroups, revealing most significant increase in overall survival rates in male patients with tumors in right colon expressing low levels of CK1delta RNA. Results become even clearer, when only male patients over 50 years were considered. Together, these findings support the assumption that CK1delta might be a prognostic biomarker for CRC thereby providing an interesting drug target for the development of new therapy concepts. PMID- 26738870 TI - Identification of novel NRAGE involved in the radioresistance of esophageal cancer cells. AB - Radiotherapy (RT) is one main method for the treatment of esophageal squamous cell carcinoma (ESCC), and the radioresistance is the predominant cause of patients with local recurrence. The previous results of gene microarray and subsequent verification showed that NRAGE might be involved in radiation resistance of ESCC cells. In this study, we reestablished human esophageal carcinoma radioresistant cell lines TE13R120 and ECA109R60 with gradient dose irradiation as previously reported, respectively. NRAGE expression was high in TE13R120 and ECA109R60 cells and was correlative with ionizing radiation (IR) resistance in clinic. However, the radiosensitivity of TE13R120 cells had a remarkable increase detected by colony formation assays after siRNA against NRAGE (siNRG) transfection into TE13R120 cells. Compared with TE13 cells, an increasing number of TE13R120 cells with NRAGE overexpression in S phase and a lower ratio in G2/M were observed by flow cytometry method (FCM). Intriguingly, the above changes were partially reversed in TE13R120 cells treated with siNRG. More importantly, the ectopic subcellular localization of NRAGE mediated nuclear translocation of beta-catenin which may be one reason of IR resistance of esophageal carcinoma cell. These data indicate that NRAGE extremely may be a pivotal factor involved in Wnt/beta-catenin signal pathway, mediating nuclear translocation of beta-catenin and then facilitating the formation of radioresistance of ESCC. PMID- 26738871 TI - A Combination of Shape and Texture Features for Classification of Pulmonary Nodules in Lung CT Images. AB - Classification of malignant and benign pulmonary nodules is important for further treatment plan. The present work focuses on the classification of benign and malignant pulmonary nodules using support vector machine. The pulmonary nodules are segmented using a semi-automated technique, which requires only a seed point from the end user. Several shape-based, margin-based, and texture-based features are computed to represent the pulmonary nodules. A set of relevant features is determined for the efficient representation of nodules in the feature space. The proposed classification scheme is validated on a data set of 891 nodules of Lung Image Database Consortium and Image Database Resource Initiative public database. The proposed classification scheme is evaluated for three configurations such as configuration 1 (composite rank of malignancy "1" and "2" as benign and "4" and "5" as malignant), configuration 2 (composite rank of malignancy "1","2", and "3" as benign and "4" and "5" as malignant), and configuration 3 (composite rank of malignancy "1" and "2" as benign and "3","4" and "5" as malignant). The performance of the classification is evaluated in terms of area (A z) under the receiver operating characteristic curve. The A z achieved by the proposed method for configuration-1, configuration-2, and configuration-3 are 0.9505, 0.8822, and 0.8488, respectively. The proposed method outperforms the most recent technique, which depends on the manual segmentation of pulmonary nodules by a trained radiologist. PMID- 26738872 TI - Massive life-threatening bifrontal epidural hematoma following placement of an external ventricular drain. PMID- 26738873 TI - Intraventricular schwannoma in a child. Literature review and case illustration. AB - BACKGROUND: Intraventricular schwannoma remains a rare entity in the literature. Controversy exists on the possible pathogenesis of such a tumor within cerebral ventricles. Literature is sparse on tumor characteristics and differences between pediatric and adult patients. CASE REPORT: We present a case of intraventricular schwannoma in a 9-year-old patient presenting with headache, hemiparesis, and focal seizure. Brain CT scan and MRI revealed an intraventricular tumor within left atrium of lateral ventricle. The patient underwent total resection of the tumor via posterior parietal approach. Histopathological exam was in favor of schwannoma. Postoperative brain MRI and MRS showed no recurrence after 18 months. CONCLUSION: Our review of the literature indicates there are some significant differences between pediatric and adult cases in different aspects including gender predominance, intraventricular location, malignant transformation, tendency for recurrence, and surgical outcome. This needs to be taken into account in the literature. PMID- 26738874 TI - A medulloblastoma showing an unusually long doubling time: reflection of its singular nature. AB - CASE DESCRIPTION: In this paper, we present a case of a 4-year-old male diagnosed with a desmoplastic, SHH-type medulloblastoma. Retrospectively, we discovered that the patient underwent an MRI scan at 21 months for reasons unrelated, revealing a T1-enhanced lesion at the vermis, later recognized as the source of the tumor. This unique case provides us with a glimpse into the natural history of this tumor. Our ability to measure tumor volume at two defined time points, 31 months apart, enabled us to deduce the tumor's doubling time. This is defined as the time of one cell cycle divided by the amount of cycling cells, multiplied by cell loss factor. Potential doubling time (Tpot) and actual doubling time (Td), calculated using the Gompertzian model, are the most clinically relevant with regard to a tumor's response to radiotherapy. Here, we show an actual doubling time (Td) of 78 days, and an extrapolated tumor diameter at the time of birth of 0.25 mm. CLINICAL RELEVANCE: These results both support the medulloblastoma's embryonic origin, and indicating a threefold longer actual doubling time when compared to previous studies. Taking into account the reported range of medulloblastoma potential doubling time, we deduced a cell loss factor of between 48.9 and 95.5 %. These percentages fall in line with other malignant tumors. Although limited due to the obvious reliance on only two points in time and using the Gompertzian model to complete the remainder, to the best of our knowledge, this is the longest follow-up period reported for medulloblastoma. We have described how a unique turn of events enabled us to get a glimpse into the in situ development of a medulloblastoma over a 31-month period. Regarded sometimes as an idiosyncratic tumor comprised of an array of molecular changes, the complexity of medulloblastoma is displayed here, by revealing for the first time an actual doubling time three- to fourfold the previously known length. PMID- 26738875 TI - Experimental realization of non-adiabatic universal quantum gates using geometric Landau-Zener-Stuckelberg interferometry. AB - High fidelity universal gates for quantum bits form an essential ingredient of quantum information processing. In particular, geometric gates have attracted attention because they have a higher intrinsic resistance to certain errors. However, their realization remains a challenge because of the need for complicated quantum control on a multi-level structure as well as meeting the adiabatic condition within a short decoherence time. Here, we demonstrate non adiabatic quantum operations for a two-level system by applying a well-controlled geometric Landau-Zener-Stuckelberg interferometry. By characterizing the gate quality, we also investigate the operation in the presence of realistic dephasing. Furthermore, the result provides an essential model suitable for understanding an interplay of geometric phase and Landau-Zener-Stuckelberg process which are well explored separately. PMID- 26738877 TI - Corrigendum: Gene expression profiling of pre-eclamptic placentae by RNA sequencing. PMID- 26738876 TI - MicroRNA profiling of antler stem cells in potentiated and dormant states and their potential roles in antler regeneration. AB - MicroRNAs (miRNAs) can effectively regulate gene expression at the post transcriptional level and play a critical role in tissue growth, development and regeneration. Our previous studies showed that antler regeneration is a stem cell based process and antler stem cells reside in the periosteum of a pedicle, the permanent bony protuberance, from which antler regeneration takes place. Antlers are the only mammalian organ that can fully regenerate and hence provide a unique opportunity to identify miRNAs that are involved in organ regeneration. In the present study, we used next generation sequencing technology sequenced miRNAs of the stem cells derived from either the potentiated or the dormant pedicle periosteum. A population of both conserved and 20 deer-specific miRNAs was identified. These conserved miRNAs were derived from 453 homologous hairpin precursors across 88 animal species, and were further grouped into 167 miRNA families. Among them, the miR-296 is embryonic stem cell-specific. The potentiation process resulted in the significant regulation (>+/-2 Fold, q value <0.05) of conserved miRNAs; 8 miRNA transcripts were down- and 6 up-regulated. Several GO biology processes and the Wnt, MAPK and TGF-beta signaling pathways were found to be up-regulated as part of antlerogenic stem cell potentiation process. This research has identified miRNAs that are associated either with the dormant or the potentiated antler stem cells and identified some target miRNAs for further research into their role played in mammalian organ regeneration. PMID- 26738878 TI - A comprehensive analysis of metabolic changes in the salvaged penumbra. AB - INTRODUCTION: We aimed to assess metabolite profiles in peri-infarct tissue with magnetic resonance spectroscopy (MRS) and correlate these with early and late clinical recovery. METHODS: One hundred ten anterior circulation ischemic stroke patients presenting to hospital within 4.5 h of symptom onset and treated with intravenous thrombolysis were studied. Patients underwent computer tomography perfusion (CTP) scanning and subsequently 3-T magnetic resonance imaging (MRI) 24 h after stroke onset, including single-voxel, short-echo-time (30 ms) MRS, and diffusion- and perfusion-weighted imaging (DWI and PWI). MRS voxels were placed in the peri-infarct region in reperfused penumbral tissue. A control voxel was placed in the contralateral homologous area. RESULTS: The concentrations of total creatine (5.39 vs 5.85 mM, p = 0.044) and N-acetylaspartic acid (NAA, 6.34 vs 7.13 mM +/- 1.57, p < 0.001) were reduced in peri-infarct tissue compared to the matching contralateral region. Baseline National Institutes of Health Stroke Score was correlated with glutamate concentration in the reperfused penumbra at 24 h (r (2) = 0.167, p = 0.017). Higher total creatine was associated with better neurological outcome at 24 h (r (2) = 0.242, p = 0.004). Lower peri-infarct glutamate was a stronger predictor of worse 3-month clinical outcome (area under the curve (AUC) 0.89, p < 0.001) than DWI volume (AUC = 0.79, p < 0.001). CONCLUSION: Decreased glutamate, creatine, and NAA concentrations are associated with poor neurological outcome at 24 h and greater disability at 3 months. The significant metabolic variation in salvaged tissue may potentially explain some of the variability seen in stroke recovery despite apparently successful reperfusion. PMID- 26738879 TI - Predicting copper phytotoxicity based on pore-water pCu. AB - The free ion activity and "biotic ligand" models predict that the free metal ion and other pore-water parameters describe terrestrial phytotoxicity. In this study, pore-water chemistry and measured Cu(2+) was used to describe phytotoxicity of cucumber (Cucumis sativa L) in 10 contrasting soils at different soil Cu loadings. Both soil solution Cu (Cu(pw)) and Cu(2+) successfully described the response variable for all ten soils with R(2) values of 0.73 and 0.66, respectively. Separation of soils as acid and alkaline and fitting separately showed that there was a strongly significant fit for both log Cu(2+) and log Cu(pw) in acidic soils (R(2) = 0.92 and 0.86, respectively) but weakly significant fit for alkaline soils. The pCu EC50 and EC10 values in all acidic soils for cucumber were 5.83 (6.03-5.63) and 7.53 (8.27-7.00), respectively. In our dataset alkaline soils need to be treated individually. In addition, pCu could be predicted based on pH and total concentration alone. Despite only 12 weeks 'ageing' there was quantitative agreement between pCu model from this study and predicted pCu from Sauve et al. This agreement from studies performed independently indicates that, at least in the case of Cu(2+), the difference in an ageing period of >=10 years appears minimal. PMID- 26738880 TI - Aeshnid dragonfly larvae as bioindicators of methylmercury contamination in aquatic systems impacted by elevated sulfate loading. AB - Methylmercury (MeHg) levels in dragonfly larvae and water were measured over two years in aquatic systems impacted to varying degrees by sulfate releases related to iron mining activity. This study examined the impact of elevated sulfate loads on MeHg concentrations and tested the use of MeHg in dragonfly larvae as an indicator of MeHg levels in a range of aquatic systems including 16 river/stream sites and two lakes. MeHg concentrations in aeshnid dragonfly larvae were positively correlated (R(2) = 0.46, p < 0.01) to peak MeHg concentrations in the dissolved phase for the combined years of 2012 and 2013. This relation was strong in 2012 (R(2) = 0.85, p < 0.01), but showed no correlation in 2013 (R(2) = 0.02, p > 0.05). MeHg in dragonfly larvae were not elevated at the highest sulfate sites, but rather the reverse was generally observed. Record rainfall events in 2012 and above average rainfall in 2013 likely delivered the majority of Hg and MeHg to these systems via interflow and activated groundwater flow through reduced sediments. As a result, the impacts of elevated sulfate releases due to mining activities were not apparent in these systems where little of the sulfate is reduced. Lower bioaccumulation factors for MeHg in aeshnid dragonfly larvae were observed with increasing dissolved organic carbon (DOC) concentrations. This finding is consistent with previous studies showing that MeHg in high DOC systems is less bioavailable; an equilibrium model shows that more MeHg being associated with DOC rather than algae at the base of the food chain readily explains the lower bioaccumulation factors. PMID- 26738882 TI - Tough Decisions for Premature Triplets. AB - When infants are born at the borderline of viability, doctors and parents have to make tough decisions about whether to institute intensive care or provide only palliative care. Often, these decisions are made in moments of profound emotional turmoil, and parents receive different information from different health professionals. Communication can become garbled. It may be difficult to tell when and whether the patient's clinical condition has changed enough so that certain choices that had once been permissible become impermissible. In this "Ethics Rounds," we present a case of triplets born at the borderline of viability. We sought comments from the triplets' parents, the doctors and ethicist who were caring for the infants, and a bioethicist/neonatologist from another hospital. PMID- 26738883 TI - Parental Depression and Pancreatic Enzymes Adherence in Children With Cystic Fibrosis. AB - BACKGROUND: Treatment adherence in cystic fibrosis (CF) is often poor, however, less is known about adherence to pancreatic enzymes, a critical component of the CF treatment regimen. Parent caregivers often report elevations in depression, and parental depression may adversely affect children's adherence. METHODS: This prospective study evaluated adherence to pancreatic enzymes in 83 patients (1-13 years) . Adherence was measured across 3 months with electronic pill-caps . Weight was measured at baseline and a 3-month follow-up. Parental depressive symptoms were evaluated by using the Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: Adherence to pancreatic enzymes was 49.4% +/- 3.4%. Adherence was higher at school (94.4% +/- 6.1%) than at home (42.3% +/- 3.1%), and higher for toddlers (50.6% +/- 5.2%) than for school-aged children (37.5% +/- 3.7%). Parents reported high rates of depressive symptoms (30% in the clinical range, 18% with moderate symptoms). Children of parents with symptoms of depression versus those without were less adherent (34.8% +/- 4.5% vs 48.5% +/- 4.1%), and adherence to enzymes was significantly related to 3-month weight outcomes. Average gain in weight z scores across 3 months was 0.5 +/- 0.2for children who were >50% adherent and -0.1 +/- 6.1for children who were <33% adherent. Parental depression had a signifcant, indirect effect on weight via adherence (-0.005 +/- 0.003 gain in weight z score per CES-D unit ). CONCLUSIONS: High rates of parental depressive symptoms, coupled with its negative effects on adherence, suggest that measuring and treating parental depression may improve children's adherence to therapy. PMID- 26738885 TI - In utero Exposure to beta-2-Adrenergic Receptor Agonist Drugs and Risk for Autism Spectrum Disorders. AB - OBJECTIVES: The purpose of this study was to investigate associations between use of beta-2-adrenergic receptor (B2AR) agonist drugs during pregnancy and risk for autism spectrum disorders (ASD). METHODS: A case-control study was conducted by using Denmark's health and population registers. Among children born between 1997 and 2006, 5200 cases with ASD admission diagnoses and 52 000 controls without ASD were identified and individually matched on month and year of birth. Conditional logistic regression models were used to estimate odds ratios (OR) and confidence intervals (CI) for any B2AR agonist exposure during pregnancy, preconception, and by trimester. RESULTS: In total, 3.7% of cases and 2.9% of controls were exposed to B2ARs during pregnancy. Use of B2ARs during pregnancy was associated with increased risk of ASD, even after adjustment for maternal asthma and other covariates (OR: 1.3, 95% CI: 1.1-1.5). The elevated risk was observed with use of B2AR during preconception (OR: 1.3, 95% CI: 1.0-1.6), first trimester (OR: 1.3, 95% CI: 1.1-1.5), second trimester (OR: 1.5, 95% CI: 1.1-1.7), and the third trimester (OR: 1.4, 95% CI: 1.1-1.7). There was some evidence that longer B2AR within-pregnancy use was associated with the increased risk. CONCLUSIONS: B2AR agonist exposure during pregnancy may be associated with an increased risk for ASD. If the effect is real, any intervention must be balanced against benefits of indicated medication use by pregnant women. PMID- 26738884 TI - Seasonal Effectiveness of Live Attenuated and Inactivated Influenza Vaccine. AB - BACKGROUND: Few observational studies have evaluated the relative effectiveness of live attenuated (LAIV) and inactivated (IIV) influenza vaccines against medically attended laboratory-confirmed influenza. METHODS: We analyzed US Influenza Vaccine Effectiveness Network data from participants aged 2 to 17 years during 4 seasons (2010-2011 through 2013-2014) to compare relative effectiveness of LAIV and IIV against influenza-associated illness. Vaccine receipt was confirmed via provider/electronic medical records or immunization registry. We calculated the ratio (odds) of influenza-positive to influenza-negative participants among those age-appropriately vaccinated with either LAIV or IIV for the corresponding season. We examined relative effectiveness of LAIV and IIV by using adjusted odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression. RESULTS: Of 6819 participants aged 2 to 17 years, 2703 were age appropriately vaccinated with LAIV (n = 637) or IIV (n = 2066). Odds of influenza were similar for LAIV and IIV recipients during 3 seasons (2010-2011 through 2012 2013). In 2013-2014, odds of influenza were significantly higher among LAIV recipients compared with IIV recipients 2 to 8 years old (OR 5.36; 95% CI, 2.37 to 12.13). Participants vaccinated with LAIV or IIV had similar odds of illness associated with influenza A/H3N2 or B. LAIV recipients had greater odds of illness due to influenza A/H1N1pdm09 in 2010-2011 and 2013-2014. CONCLUSIONS: We observed lower effectiveness of LAIV compared with IIV against influenza A/H1N1pdm09 but not A(H3N2) or B among children and adolescents, suggesting poor performance related to the LAIV A/H1N1pdm09 viral construct. PMID- 26738887 TI - The Complex Etiology of Autism Presents Challenges in Risk Communication. PMID- 26738886 TI - Internet Alcohol Marketing and Underage Alcohol Use. AB - BACKGROUND AND OBJECTIVE: Internet alcohol marketing is not well studied despite its prevalence and potential accessibility and attractiveness to youth. The objective was to examine longitudinal associations between self-reported engagement with Internet alcohol marketing and alcohol use transitions in youth. METHODS: A US sample of 2012 youths aged 15 to 20 was surveyed in 2011. An Internet alcohol marketing receptivity score was developed, based on number of positive responses to seeing alcohol advertising on the Internet, visiting alcohol brand Web sites, being an online alcohol brand fan, and cued recall of alcohol brand home page images. We assessed the association between baseline marketing receptivity and both ever drinking and binge drinking (>=6 drinks per occasion) at 1-year follow-up with multiple logistic regression, controlling for baseline drinking status, Internet use, sociodemographics, personality characteristics, and peer or parent drinking. RESULTS: At baseline, ever-drinking and binge-drinking prevalence was 55% and 27%, respectively. Many (59%) reported seeing Internet alcohol advertising, but few reported going to an alcohol Web site (6%) or being an online fan (3%). Higher Internet use, sensation seeking, having family or peers who drank, and past alcohol use were associated with Internet alcohol marketing receptivity, and a score of 1 or 2 was independently associated with greater adjusted odds of initiating binge drinking (odds ratio 1.77; 95% confidence interval, 1.13-2.78 and odds ratio 2.15; 95% confidence interval, 1.06-4.37 respectively) but not with initiation of ever drinking. CONCLUSIONS: Although high levels of engagement with Internet alcohol marketing were uncommon, most underage youths reported seeing it, and we found a prospective association between receptivity to this type of alcohol marketing and future problem drinking, making additional research and ongoing surveillance important. PMID- 26738888 TI - Long inverted repeat transiently stalls DNA replication by forming hairpin structures on both leading and lagging strands. AB - Long inverted repeats (LIRs), often found in eukaryotic genomes, are unstable in Escherichia coli where they are recognized by the SbcCD (the bacterial Mre11/Rad50 homologue), an endonuclease/exonuclease capable of cleaving hairpin DNA. It has long been postulated that LIRs form hairpin structures exclusively on the lagging-strand template during DNA replication, and SbcCD cleaves these hairpin-containing lagging strands to generate DNA double-strand breaks. Using a reconstituted oriC plasmid DNA replication system, we have examined how a replication fork behaves when it meets a LIR on DNA. We have shown that leading strand synthesis stalls transiently within the upstream half of the LIR. Pausing of lagging-strand synthesis at the LIR was not clearly observed, but the pattern of priming sites for Okazaki fragment synthesis was altered within the downstream half of the LIR. We have found that the LIR on a replicating plasmid was cleaved by SbcCD with almost equal frequency on both the leading- and lagging-strand templates. These data strongly suggest that the LIR is readily converted to a cruciform DNA, before the arrival of the fork, creating SbcCD-sensitive hairpin structures on both leading and lagging strands. We propose a model for the replication-dependent extrusion of LIRs to form cruciform structures that transiently impede replication fork movement. PMID- 26738889 TI - A mathematical approach to virus therapy of glioblastomas. AB - BACKGROUND: It is widely believed that the treatment of glioblastomas (GBM) could benefit from oncolytic virus therapy. Clinical research has shown that Vesicular Stomatitis Virus (VSV) has strong oncolytic properties. In addition, mathematical models of virus treatment of tumors have been developed in recent years. Some experiments in vitro and in vivo have been done and shown promising results, but have been never compared quantitatively with mathematical models. We use in vitro data of this virus applied to glioblastoma. RESULTS: We describe three increasingly realistic mathematical models for the VSV-GBM in vitro experiment with progressive incorporation of time-delay effects. For the virus dynamics, we obtain results consistent with the in vitro experimental speed data only when applying the more complex and comprehensive model, with time-delay effects both in the reactive and diffusive terms. The tumor speed is given by the minimum of a very simple function that nonetheless yields results within the experimental measured range. CONCLUSIONS: We have improved a previous model with new ideas and carefully incorporated concepts from experimental results. We have shown that the delay time tau is the crucial parameter in this kind of models. We have demonstrated that our new model can satisfactorily predict the front speed for the lytic action of oncolytic VSV on glioblastoma observed in vitro. We provide a basis that can be applied in the near future to realistically simulate in vivo virus treatments of several cancers. PMID- 26738890 TI - Calcium intake by adolescents: a population-based health survey. AB - OBJECTIVE: To analyze calcium intake in adolescents according to sociodemographic variables, health-related behaviors, morbidities, and body mass index. METHODS: This was a cross-sectional population-based study, with a two-stage cluster sampling that used data from a survey conducted in Campinas, Sao Paulo, Brazil, between 2008 and 2009. Food intake was assessed using a 24-hour dietary recall. The study included 913 adolescents aged 10-19 years. RESULTS: Average nutrient intake was significantly lower in the segment with lower education of the head of the family and lower per capita family income, in individuals from other cities or states, those who consumed fruit less than four times a week, those who did not drink milk daily, those who were smokers, and those who reported the occurrence of headaches and dizziness. Higher mean calcium intake was found in individuals that slept less than seven hours a day. The prevalence of calcium intake below the recommendation was 88.6% (95% CI: 85.4-91.2). CONCLUSION: The results alert to an insufficient calcium intake and suggest that certain subgroups of adolescents need specific strategies to increase the intake of this nutrient. PMID- 26738891 TI - Prevalence of musculoskeletal pain in adolescents and association with computer and videogame use. AB - OBJECTIVE: This study investigated the presence of musculoskeletal symptoms in high school adolescents from public schools and its association with electronic device use. METHODS: The sample consisted of 961 boys and girls aged 14-19 years who answered a questionnaire regarding the use of computers and electronic games, and questions about pain symptoms and physical activity. Furthermore, anthropometric assessments of all volunteers were performed. The chi-squared test and a multiple logistic regression model were used for the inferential analysis. RESULTS: The presence of musculoskeletal pain symptoms was reported by 65.1% of the adolescents, being more prevalent in the thoracolumbar spine (46.9%), followed by pain in the upper limbs, representing 20% of complaints. The mean time of use for computers and electronic games was 1.720 and 583 minutes per week, respectively. The excessive use of electronic devices was demonstrated to be a risk factor for cervical and lumbar pain. Female gender was associated with the presence of pain in different body parts. Presence of a paid job was associated with cervical pain. CONCLUSION: A high prevalence of musculoskeletal pain in adolescents, as well as an increased amount of time using digital devices was observed. However, it was only possible to observe an association between the increased use of these devices and the presence of cervical and low back pain. PMID- 26738893 TI - A common soil handling technique can generate incorrect estimates of soil biota effects on plants. PMID- 26738894 TI - Gastric Bypass in Older Patients: Complications, Weight Loss, and Resolution of Comorbidities at 2 Years in a Matched Controlled Study. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) has recently been authorized for use in older patients. The objective of this single-center study was to evaluate 2 year weight loss in patients >=60 years compared with younger matched patients undergoing RYGB. Secondary aims were to record complications and the resolution of comorbidities in a 2-year follow-up. METHODS: Of 722 patients with at least 2 years follow-up data, 48 elderly patients were matched with 92 young (<40 years) and 96 middle-aged (40-59 year) patients, according to sex, baseline body mass index, and date of surgery. Weight loss, remission of comorbidities, death, and early (30-day) and 2-year complication rates were compared. RESULTS: There were three deaths in the elderly group and none in the other groups. The early complication rate was not significantly different in the elderly group (17.8 %) compared with the young (11.5 %, p = 0.637) and middle-aged (13.7 %, p = 1.000) groups. The 2-year complication rates were not significantly different in the elderly group (9.3 %) compared with the young (23.5 %, p = 0.107) and middle-aged (13.2 %, p = 1.000) groups. The 2-year weight loss was lower in the elderly group (31.8 +/- 7.2 %; p < 0.001) than in the young group (38.3 +/- 6.9 %) but was not significantly different from that in the middle-aged group (34.4 +/- 8.0 %; p = 0.145). Remission rates for diabetes and obstructive sleep apnea were lower in the elderly than in the two younger groups. CONCLUSION: After bariatric surgery, major weight loss was observed in patients older than 60, but remission of metabolic comorbidities was less marked than in younger subjects. PMID- 26738895 TI - NICE-Accredited Commissioning Guidance for Weight Assessment and Management Clinics: a Model for a Specialist Multidisciplinary Team Approach for People with Severe Obesity. AB - Despite increasing prevalence of obesity, no country has successfully implemented comprehensive pathways to provide advice to all the severely obese patients that seek treatment. We aimed to formulate pathways for referral into and out of weight assessment and management clinics (WAMCs) that include internal medicine/primary care physicians as part of a multidisciplinary team that could provide specialist advice and interventions, including referral for bariatric surgery. Using a National Institute of Health and Care Excellence (NICE) accredited process, a Guidance Development Group conducted a literature search identifying existing WAMCs. As very few examples of effective structures and clinical pathways existed, the current evidence base for optimal assessment and management of bariatric surgery patients was used to reach a consensus. The model we describe could be adopted internationally by health services to manage severely obese patients. PMID- 26738896 TI - Resectable left lower lobe non-small cell lung cancer with lymph node metastasis is related to unfavorable outcomes. AB - BACKGROUND: Despite numerous previous studies, the consideration of tumor location as a prognostic factor in resectable non-small cell lung cancer (NSCLC) remains controversial. The present study analyzed the association between tumor location and clinical outcome in patients with resectable NSCLC who had undergone lobectomy with systematic lymphadenectomy and who had presented with varying nodal statuses. METHODS: The data from a cohort of 627 eligible patients treated in Sun Yat-sen University Cancer Center between January 2000 and December 2008 were retrospectively collected, and the nodal statuses of patients with different tumor locations were compared. Cox proportional hazards regression model was used to determine the independent factors related to cancer-specific survival (CSS). RESULTS: Multivariate analysis demonstrated that left lower lobe (LLL) tumors [hazard ratio (HR): 1.465, 95% confidence interval (CI) 1.090-1.969, P = 0.011], lymph node metastasis (HR: 2.742, 95% CI 2.145-3.507, P < 0.001), and a tumor size of >4 cm (HR: 1.474, 95% CI 1.151-1.888, P = 0.002) were three independent prognosticators in patients with resectable NSCLC. However, LLL tumors were associated only with CSS in node-positive patients (HR: 1.528, 95% CI 1.015 2.301, P = 0.042), and a tumor size of >4 cm was the only independent risk predictor in the node-negative subgroup (HR: 1.889, 95% CI 1.324-2.696, P < 0.001). CONCLUSIONS: Tumor location is related to the long-term CSS of NSCLC patients with lymph node metastasis. LLL tumors may be upstaged in node-positive patients to facilitate an optimal treatment strategy. PMID- 26738897 TI - Effect of Surgical Caseload on Revision Rate Following Total and Unicompartmental Knee Replacement. AB - BACKGROUND: High-volume surgeons attain the best results following unicompartmental knee replacement (UKR), but the exact relationship between caseload and outcome is not clear. It is not known whether this effect is due to patient selection or surgical skill nor whether a similar effect is seen in total knee replacement (TKR). The aim of this study was to quantify the effect of surgical caseload on survival of both TKR and UKR. METHODS: This study was based on 459,280 patient records (422,149 TKRs and 37,131 UKRs) from the National Joint Registry for England and Wales. The caseload-outcome relationship was characterized graphically and quantified using regression techniques. Patient selection was compared among high, medium, and low-volume surgeons. Prosthetic survival was compared between UKRs (performed by high, medium, and low-volume surgeons) and matched TKRs. RESULTS: Caseload affected survival of TKR and, more strongly, of UKR. The revision rate following UKR dropped steeply until the volume reached ten cases per year, plateauing at thirty cases. For surgeons performing fewer than ten UKRs per year, the mean eight-year rate of survival of the UKRs was 87.9% (95% confidence interval [CI] = 86.9% to 88.8%) compared with 92.4% (95% CI = 90.9% to 93.6%) for those who performed thirty UKRs or more per year. Analysis of the TKRs showed a linear decrease in revision rate as caseload increased (hazard ratio [HR] for revision = 0.99 [95% CI = 0.98 to 0.99] for every five-case increase in caseload). Surgeons who performed a lower volume of UKRs tended to operate on younger and healthier patients and were more likely to perform revisions to treat loosening and pain. After matching of patients who had undergone UKR with those who had undergone TKR, the surgeons who performed a high volume of UKRs were found to have an eight-year revision/revision rate similar to that seen after TKR (HR for revision or reoperation = 1.10 [95% CI = 0.99 to 1.22] favoring TKR). CONCLUSIONS: This study confirmed the importance of surgical caseload in determining the survival of UKR and, to a lesser extent, TKR. The reasons for this effect are complex and not fully explained by variables recorded in the National Joint Registry; however, the patient selection and revision threshold of lower-volume surgeons may be a factor. Examination of matched patients in this study demonstrated that high-volume surgeons can achieve revision/reoperation rates similar to those observed following TKR. PMID- 26738898 TI - Effect of Compliance Counseling on Brace Use and Success in Patients with Adolescent Idiopathic Scoliosis. AB - BACKGROUND: Outcomes of orthotic management of idiopathic scoliosis depend on patient compliance with brace wear. The purpose of this study was to determine if counseling based on objective compliance data increases brace wear and therefore reduces the likelihood of surgery. METHODS: Two hundred and twenty-two patients with adolescent idiopathic scoliosis were prospectively enrolled in a study to determine if physician counseling based on data obtained from compliance monitors (sensors embedded in the brace) improves brace use and decreases curve progression. Patients were placed into two groups. In the counseled group, patients were aware of the compliance monitor in the brace and were counseled at each visit regarding downloaded brace-usage data. The patients in the noncounseled group were not told the purpose of the monitor in their brace, and the compliance data were not made available to the physician, orthotist, or patient. RESULTS: Ninety-three patients who were counseled with use of the compliance data and seventy-eight patients who were not so counseled completed bracing or underwent surgery; twenty-five patients were lost to follow-up before completing brace treatment, and twelve were still undergoing brace treatment at the time of the study review. The average curve magnitude at the initiation of bracing was 33.2 degrees in the counseled group and 33.9 degrees in the noncounseled group (p = 0.21 [not significant]). Patients in the counseled group wore their orthosis an average of 13.8 hours per day throughout their management, while noncounseled patients wore their brace an average of 10.8 hours per day (p = 0.002). Of the counseled patients who finished brace treatment, 59% did not have curve progression of >=6 degrees , whereas 25% had progression to >=50 degrees or to surgery. In the noncounseled group, 46% did not have curve progression of >=6 degrees , whereas 36% had progression to >=50 degrees or to surgery. Noncounseled patients who had curve progression to a magnitude requiring surgery wore their brace an average of 9.6 hours per day compared with 12.6 hours per day for the counseled patients who required surgery. The amount of daily brace wear by children who did not have curve progression to a magnitude requiring surgery was significantly greater than that by children who did require surgery (p = 0.029). CONCLUSIONS: Providing patients undergoing bracing for adolescent idiopathic scoliosis with feedback about their compliance with brace wear improves that compliance. Patients who wore their brace more hours per day had less curve progression. Patients in both groups who had curve progression to a magnitude requiring surgery wore their brace less than their counterparts for whom bracing was successful. Compliance monitoring and counseling based on that monitoring should become part of the clinical orthotic management of patients with adolescent idiopathic scoliosis. PMID- 26738899 TI - Diabetes Is Related to Worse Patient-Reported Outcomes at Two Years Following Spine Surgery. AB - BACKGROUND: Diabetes has been associated with poor outcomes following elective spine surgery. The purpose of our study was to determine if diabetes predicts worse patient-reported outcomes at two years postoperatively and to evaluate the effect of perioperative blood glucose levels and control on patient-reported outcomes in patients with diabetes. METHODS: One thousand and five patients undergoing elective spine surgery were included in this prospective cohort study. The presence of diabetes and baseline and one and two-year patient-reported outcomes (Short Form-12 [SF-12], EuroQol-5D [EQ-5D], Oswestry Disability Index [ODI] or Neck Disability Index [NDI], and Numeric Rating Scale [NRS] pain scores) were recorded. The mean blood glucose measurements in patients with diabetes were collected during the postoperative period. Multivariable linear regression analyses were performed to determine predictors of one and two-year outcomes as well as the relationship between perioperative blood glucose and patient-reported outcomes in patients with diabetes. RESULTS: Four hundred and thirty-four patients (43%) had diabetes. When compared with patients without diabetes at two years, patients with diabetes had lower SF-12 Physical Component Summary scores (34.4 points for the diabetic group compared with 38.6 points for the non diabetic group), lower EQ-5D scores (0.67 for the diabetic group compared with 0.74 for the non-diabetic group), higher ODI or NDI scores (32.1 points for the diabetic group compared with 26.8 points for the non-diabetic group), and higher NRS scores (5.1 points for the diabetic group compared with 4.3 points for the non-diabetic group) (p < 0.05 for all). Although patients with diabetes improved significantly over time, they did not improve to the extent that patients without diabetes did in the ODI or NDI and EQ-5D scores (p < 0.05). Diabetes and preoperative opioid use were independent predictors of decreased SF-12 scores, decreased EQ-5D scores, increased ODI or NDI scores, and increased NRS scores (p < 0.05). Diabetes was associated with increased ODI or NDI (by 6.6 points) and decreased EQ-5D (by 0.1) at two years. Perioperative blood glucose control did not predict outcomes at either one or two years in patients with diabetes. CONCLUSIONS: Diabetes was associated with worse patient-reported outcomes when patients with diabetes were compared with patients without diabetes at two years following elective spine surgery. Although patients with diabetes improved when compared from baseline to the time following elective spine surgery, they did not improve to the same extent as patients without diabetes in the ODI or NDI and EQ 5D scores. Providers may use this information to counsel patients with diabetes on expectations following spine surgery. PMID- 26738901 TI - Repair of Intraoperative Injury to the Medial Collateral Ligament During Primary Total Knee Arthroplasty. AB - BACKGROUND: Optimal treatment for intraoperative injury to the medial collateral ligament (MCL) during primary total knee arthroplasty remains controversial. While some advocate primary ligament repair and a period of bracing, others suggest conversion to a knee prosthesis with increased intrinsic constraint. The purpose of this study was to characterize the outcomes of primary repair followed by bracing. METHODS: We performed a retrospective review of consecutive primary total knee arthroplasties to identify patients with intraoperative MCL laceration or avulsion treated with primary repair. Midsubstance lacerations were treated with end-to-end suture repair, whereas a screw-and-washer construct, suture, and/or suture anchors were used for reattachment of avulsions. All patients were instructed to wear an unlocked hinged knee brace for six weeks postoperatively. Patients were evaluated at a minimum of two years postoperatively for evidence of instability or other modes of failure and complications. RESULTS: An intraoperative MCL injury occurred during forty-eight (1.2%) of the 3922 total knee arthroplasties that had been performed. One patient died less than two years postoperatively, one was lost to follow-up, and one underwent an intraoperative conversion to a constrained total knee arthroplasty, leaving forty-five total knee arthroplasties available for study. There were twenty-four midsubstance lacerations and twenty-one avulsions; thirty-five of these injuries occurred during a cruciate-retaining total knee arthroplasty and ten, during a posterior stabilized total knee arthroplasty. At a mean of ninety-nine months (range, twenty-four to 214 months), there were no symptoms or physical examination findings of instability. The mean Hospital for Special Surgery knee score increased from 47 preoperatively to 85 at the time of follow-up (p < 0.001). Five knees required intervention for stiffness (four manipulations and one revision), and two required revision for aseptic loosening. CONCLUSIONS: Our results suggest that intraoperative MCL injury can be treated with primary repair followed by hinged knee bracing without the need for increased prosthetic constraint. Stiffness, however, was a common complication. PMID- 26738900 TI - Addition of Mesenchymal Stem Cells to Autologous Platelet-Enhanced Fibrin Scaffolds in Chondral Defects: Does It Enhance Repair? AB - BACKGROUND: The chondrogenic potential of culture-expanded bone-marrow-derived mesenchymal stem cells (BMDMSCs) is well described. Numerous studies have also shown enhanced repair when BMDMSCs, scaffolds, and growth factors are placed into chondral defects. Platelets provide a rich milieu of growth factors and, along with fibrin, are readily available for clinical use. The objective of this study was to determine if the addition of BMDMSCs to an autologous platelet-enriched fibrin (APEF) scaffold enhances chondral repair compared with APEF alone. METHODS: A 15-mm-diameter full-thickness chondral defect was created on the lateral trochlear ridge of both stifle joints of twelve adult horses. In each animal, one defect was randomly assigned to receive APEF+BMDMSCs and the contralateral defect received APEF alone. Repair tissues were evaluated one year later with arthroscopy, histological examination, magnetic resonance imaging (MRI), micro-computed tomography (micro-CT), and biomechanical testing. RESULTS: The arthroscopic findings, MRI T2 map, histological scores, structural stiffness, and material stiffness were similar (p > 0.05) between the APEF and APEF+BMDMSC treated repairs at one year. Ectopic bone was observed within the repair tissue in four of twelve APEF+BMDMSC-treated defects. Defects repaired with APEF alone had less trabecular bone edema (as seen on MRI) compared with defects repaired with APEF+BMDMSCs. Micro-CT analysis showed thinner repair tissue in defects repaired with APEF+BMDMSCs than in those treated with APEF alone (p < 0.05). CONCLUSIONS: APEF alone resulted in thicker repair tissue than was seen with APEF+BMDMSCs. The addition of BMDMSCs to APEF did not enhance cartilage repair and stimulated bone formation in some cartilage defects. CLINICAL RELEVANCE: APEF supported repair of critical-size full-thickness chondral defects in horses, which was not improved by the addition of BMDMSCs. This work supports further investigation to determine whether APEF enhances cartilage repair in humans. PMID- 26738902 TI - Comprehensive Analysis of a Recalled Modular Total Hip System and Recommendations for Management. AB - BACKGROUND: Recent total hip arthroplasty designs have introduced modularity at the neck-stem junction. There are reports of failure of this class of designs due to corrosion at the modular junction. The purpose of this study was to evaluate patients implanted with a recently recalled modular total hip arthroplasty system. METHODS: This was a prospective study of 216 total hip arthroplasties in 195 patients performed by a single surgeon. All hips had a titanium-alloy stem, but 199 had a modular cobalt-chromium neck and seventeen were monolithic. The mean patient age was 65.4 years (range, twenty to eighty-eight years); seventy nine were men and 116 were women. Patients were evaluated for infection and with metal ion assays and MRI (magnetic resonance imaging). Intraoperative tissue samples were graded, and retrieved implants were examined. RESULTS: At a mean follow-up of 19.3 months, eighty (37%) of 216 hips had been revised. An adverse local tissue reaction (ALTR) was the cause for revision in seventy-three of these eighty hips; all had the modular neck design. Assay results for the patients requiring revision showed higher levels of cobalt (mean, 8.6 ng/mL) than chromium (mean, 1.8 ng/mL). MRI showed moderate to severe levels of synovial response in sixty-three of 166 hips. The mean ALVAL (aseptic lymphocyte-dominated vasculitis associated lesion) score for the revised hips was 8.1. Corrosion was visible on all tapers at the neck-stem junction but not the head-neck junction. CONCLUSIONS: Early failures of modular total hip arthroplasty occur due to fretting and corrosion at the neck-stem junction, resulting in ALTR. Surveillance utilizing metal ion levels and MRI may be indicated for all patients regardless of symptoms, as the early survivorship is poor and the ultimate failure rate may be catastrophically high. PMID- 26738903 TI - Angiotensin-(1-7) Attenuates Skeletal Muscle Fibrosis and Stiffening in a Mouse Model of Extremity Sarcoma Radiation Therapy. AB - BACKGROUND: Radiation-induced fibrosis (RIF) of musculoskeletal tissue is a common complication of radiation therapy for extremity soft-tissue sarcoma, with no standardized strategy for prevention and treatment. Angiotensin-(1-7) (Ang-[1 7]), a well-tolerated endogenous heptapeptide hormone with antitumor and antifibrotic properties, was tested as a radioprotectant for RIF and stiffening of irradiated muscles. METHODS: Male CD-1 mice were randomized to one of three treatment groups: control, simulated sarcoma radiation therapy to the gastrocnemius and soleus muscles, or radiation therapy along with continuous Ang (1-7) delivery initiated three days before radiation therapy. The biologically equivalent dose of radiation (~100.3 Gy) absorbed by normal musculature during the course of radiation therapy for extremity sarcoma was delivered by means of four dose fractions of 7.3 Gy over two weeks. Fibrosis (n = 5 per group) and mechanical properties (n = 4 to 6 per group) of the muscles were measured at six weeks and four months after radiation therapy, and the intramuscular concentration of the profibrotic cytokines transforming growth factor-beta (TGF beta) and connective tissue growth factor (CTGF) (n = 8 to 10 per group) were measured at six weeks. RESULTS: Interstitial (p < 0.01) and perivascular (p < 0.05) fibrosis increased significantly in the muscles treated with radiation therapy alone versus the nonirradiated controls at both six weeks (interstitial, +89%; perivascular, +112%) and four months (interstitial, +154%; perivascular, +88%). The muscles treated with radiation alone also exhibited increased tension (p < 0.01) versus nonirradiated controls at both six weeks (+779%) and four months (+1761%) when placed under 5% strain, and at four months (+1390%; p < 0.001) under 10% strain. At four months, muscle stiffness had increased in the mice treated with radiation therapy alone (+90%; p = 0.002) compared with nonirradiated controls. TGF-beta production was also greater in this group at six weeks (+37%; p = 0.06) versus control. Ang-(1-7) administration prevented RIF and stiffening, with no differences observed for any other outcome between those receiving radiation therapy with Ang-(1-7) and the nonirradiated controls. Likewise, Ang-(1-7) mitigated the increase in TGF-beta and CTGF concentration from radiation therapy. CONCLUSIONS: Ang-(1-7) attenuated RIF, stiffening, and production of profibrotic cytokines that were elevated in mouse skeletal muscles after simulated radiation therapy for extremity sarcoma. CLINICAL RELEVANCE: Ang (1-7) may serve as a potential therapy for the prevention of RIF in patients who require radiation therapy as adjuvant treatment for soft-tissue sarcoma. PMID- 26738904 TI - Changes in Muscle Oxygen Saturation Have Low Sensitivity in Diagnosing Chronic Anterior Compartment Syndrome of the Leg. AB - BACKGROUND: Near-infrared spectroscopy measures muscle oxygen saturation (StO2) in the skeletal muscle and has been proposed as a noninvasive tool for diagnosing chronic anterior compartment syndrome (CACS). The purpose of this study was to investigate the diagnostic value of changes in StO2 during and after exercise in patients with CACS. METHODS: The study comprised 159 consecutive patients with exercise-induced leg pain. Near-infrared spectroscopy was used to measure StO2 continuously before, during, and after an exercise test. One minute post exercise, intramuscular pressure was recorded in the same muscle. The cohort was divided into patients with CACS (n = 87) and patients without CACS (n = 72) according to the CACS diagnostic criteria. Reoxygenation at rest after exercise was calculated as the time period required for the level of muscular StO2 to reach 50% (T50), 90% (T90), and 100% (T100) of the baseline value. RESULTS: The lowest level of StO2 during exercise was 1% (range, 1% to 36%) in the patients with CACS and 3% (range, 1% to 54%) in the patients without CACS. The sensitivity was 34% and the specificity was 43% when an StO2 level of <=8% at peak exercise was used to indicate CACS. The sensitivity and the specificity were only 1% when an StO2 level of <=50% at peak exercise was used to indicate CACS. The time period for reoxygenation was seven seconds (range, one to forty-three seconds) at T50, twenty-eight seconds (range, seven to seventy-seven seconds) at T90, and forty-two seconds (range, seven to 200 seconds) at T100 in the patients with CACS and ten seconds (range, one to forty-nine seconds) at T50, thirty-two seconds (range, four to 138 seconds) at T90, and forty-eight seconds (range, four to 180 seconds) at T100 in the patients without CACS. When thirty seconds or more at T90 was set as the cutoff value for a prolonged time for reoxygenation, indicating a diagnosis of CACS, the sensitivity was 38% and the specificity was 50%. CONCLUSIONS: Changes in muscle oxygen saturation during and after an exercise test that elicits leg pain cannot be used to distinguish between patients with CACS and patients with other causes of exercise-induced leg pain. PMID- 26738905 TI - Hip Dysplasia in the Young Adult. AB - Hip dysplasia is a leading precursor of osteoarthritis and is seen in 20% to 40% of patients with osteoarthritis of the hip. An increase in mechanical stress on the cartilage matrix with failure of the acetabular labrum represents the major pathomechanism of degeneration. Because the prevalence of associated femoral deformities is high (>50%), the structural anatomy of the dysplastic hip must be assessed in multiple planes using radiographs and, if needed, advanced imaging modalities. Acetabular osteotomy (periacetabular and/or rotational) is the most commonly used procedure for the treatment of the majority of dysplastic hips in adults. Modern total hip replacement remains an excellent option for the more arthritic joints. Difficulties can arise from anatomical abnormalities and previous operations. PMID- 26738906 TI - Which Global Rating Scale? A Comparison of the ASSET, BAKSSS, and IGARS for the Assessment of Simulated Arthroscopic Skills. AB - BACKGROUND: With the move to competency-based models of surgical training, a number of assessment methods have been developed. Of these, global rating scales have emerged as popular tools, and several are specific to the assessment of arthroscopic skills. Our aim was to determine which one of a group of commonly used global rating scales demonstrated superiority in the assessment of simulated arthroscopic skills. METHODS: Sixty-three individuals of varying surgical experience performed a number of arthroscopic tasks on a virtual reality simulator (VirtaMed ArthroS). Performance was blindly assessed by two observers using three commonly used global rating scales used to assess simulated skills. Performance was also assessed by validated objective motion analysis. RESULTS: All of the global rating scales demonstrated construct validity, with significant differences between each skill level and each arthroscopic task (p < 0.002, Mann Whitney U test). Interrater reliability was excellent for each global rating scale. Correlations of global rating scale ratings with motion analysis were high and strong for each global rating scale when correlated with time taken (Spearman rho, -0.95 to -0.76; p < 0.001), and correlation with total path length was significant and moderately strong (Spearman rho, -0.94 to -0.64; p < 0.001). CONCLUSIONS: No single global rating scale demonstrated superiority as an assessment tool. CLINICAL RELEVANCE: For these commonly used arthroscopic global rating scales, none was particularly superior and any one score could therefore be used. Agreement on using a single score seems sensible, and it would seem unnecessary to develop further scales with the same domains for these purposes. PMID- 26738908 TI - Erratum. AB - In the article entitled "Treatment of Nontraumatic Rotator Cuff Tears: A Randomized Controlled Trial with Two Years of Clinical and Imaging Follow-up" (2015 Nov 4; 97[21]: 1729-37), two footnotes in Table VI were incorrectly transposed. Specifically, "The values are given as the number of shoulders, with the percentage in parentheses. The values are given as the mean and the standard deviation." should have read "The values are given as the mean and the standard deviation. The values are given as the number of shoulders, with the percentage in parentheses." PMID- 26738909 TI - Development and Validation of Perioperative Risk-Adjustment Models for Hip Fracture Repair, Total Hip Arthroplasty, and Total Knee Arthroplasty. AB - BACKGROUND: Comparing outcomes across providers requires risk-adjustment models that account for differences in case mix. The burden of data collection from the clinical record can make risk-adjusted outcomes difficult to measure. The purpose of this study was to develop risk-adjustment models for hip fracture repair (HFR), total hip arthroplasty (THA), and total knee arthroplasty (TKA) that weigh adequacy of risk adjustment against data-collection burden. METHODS: We used data from the American College of Surgeons National Surgical Quality Improvement Program to create derivation cohorts for HFR (n = 7000), THA (n = 17,336), and TKA (n = 28,661). We developed logistic regression models for each procedure using age, sex, American Society of Anesthesiologists (ASA) physical status classification, comorbidities, laboratory values, and vital signs-based comorbidities as covariates, and validated the models with use of data from 2012. RESULTS: The derivation models' C-statistics for mortality were 80%, 81%, 75%, and 92% and for adverse events were 68%, 68%, 60%, and 70% for HFR, THA, TKA, and combined procedure cohorts. Age, sex, and ASA classification accounted for a large share of the explained variation in mortality (50%, 58%, 70%, and 67%) and adverse events (43%, 45%, 46%, and 68%). For THA and TKA, these three variables were nearly as predictive as models utilizing all covariates. HFR model discrimination improved with the addition of comorbidities and laboratory values; among the important covariates were functional status, low albumin, high creatinine, disseminated cancer, dyspnea, and body mass index. Model performance was similar in validation cohorts. CONCLUSIONS: Risk-adjustment models using data from health records demonstrated good discrimination and calibration for HFR, THA, and TKA. It is possible to provide adequate risk adjustment using only the most predictive variables commonly available within the clinical record. This finding helps to inform the trade-off between model performance and data collection burden as well as the need to define priorities for data capture from electronic health records. These models can be used to make fair comparisons of outcome measures intended to characterize provider quality of care for value based-purchasing and registry initiatives. PMID- 26738910 TI - Understanding Orthopaedic Registry Studies: A Comparison with Clinical Studies. AB - Orthopaedic registries are valuable for monitoring patient outcomes in real-world settings. Registries are useful for identifying procedure incidence and device utilization, evaluating outcomes, determining patients at risk for complications and reoperations, identifying devices in recall situations, assessing comparative effectiveness of procedures and devices, and providing data for research studies. In the present report, we describe how orthopaedic registries can be used to conduct research and how they compare with randomized controlled trials (RCTs) in regard to methodology. Using an example, a comparison of the performance of mobile and fixed bearings in total knee arthroplasty, we evaluate the differences between, and the similarities of, RCTs and registry cohort studies with regard to how they are conducted and how their findings are reported. Orthopaedic registry studies differ from RCTs in many ways and offer certain advantages. The strengths and limitations of registry cohort studies and RCTs must be understood to properly evaluate the literature. PMID- 26738911 TI - Compliance Counseling Improves Outcomes of Bracing for Patients with Idiopathic Scoliosis. Commentary on an article by Lori A. Karol, MD, et al.: "Effect of Compliance Counseling on Brace Use and Success in Patients with Adolescent Idiopathic Scoliosis". PMID- 26738912 TI - Cartilage Resurfacing: Unresolved Enigma. Commentary on an article by L.R. Goodrich, DVM, PhD, et al.: "Addition of Mesenchymal Stem Cells to Autologous Platelet-Enhanced Fibrin Scaffolds in Chondral Defects. Does It Enhance Repair?". PMID- 26738913 TI - Co-trimoxazole in addition to antiretroviral therapy may reduce malaria risk in HIV positive adults. PMID- 26738915 TI - Paraclostridium benzoelyticum gen. nov., sp. nov., isolated from marine sediment and reclassification of Clostridium bifermentans as Paraclostridium bifermentans comb. nov. Proposal of a new genus Paeniclostridium gen. nov. to accommodate Clostridium sordellii and Clostridium ghonii. AB - Twenty-three rod-shaped, endospore-forming, Gram-stain-positive, obligately anaerobic bacteria were isolated from different marine sediment samples of Gujarat. All 23 strains shared 16S rRNA gene sequence similarity of ~100 %. Strain JC272T was designated the type strain and shared highest sequence similarity with Clostridium bifermentans ATCC 638T (99.8 %), Clostridium ghonii JCM 1400T (98.0 %), Clostridium sordellii ATCC 9714T (97.9 %) and other members of the genus Clostridium ( < 96.4 %). C16 : 0, C18 : 0, C17 : 0, C16 : 1omega9c and iso-C16 : 0 were the major (>5 %) fatty acids. Strain JC272T contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine and two unidentified amino lipids. Genome-based analysis of average nucleotide identity (ANI) and in silico DNA-DNA hybridization (DDH) of strain JC272T with C. bifermentans ATCC 638T yielded values of 94.35 and 58.5 +/- 2.8 %, respectively. The DNA G+C content of strain JC272T was 28.3 mol%. Strain JC272T together with C. bifermentans were found to fall outside Clostridium rRNA cluster I considered as Clostridium senso stricto. Based on ANI value, in-silico DDH, and distinct morphological and physiological differences from the previously described taxa, we suggest that strain JC272T represents a novel species of a new genus in the family Clostridiaceae, for which the name Paraclostridium benzoelyticum gen. nov., sp. nov. is proposed. The type strain is JC272T ( = KCTC 15476T = LMG 28745T). It is also proposed to transfer C. bifermentans to this new genus, as Paraclostridium bifermentans comb. nov. (type strain ATCC 638T = DSM 14991T = JCM 1386T). The genus Paeniclostridium gen. nov. is proposed to accommodate C. sordellii and C. ghonii as Paeniclostridium sordellii comb. nov. (type strain ATCC 9714T = LMG 15708T = JCM 3814T) and Paeniclostridium ghonii comb. nov. (type strain ATCC 25757T = DSM 15049T = JCM 1400T). PMID- 26738917 TI - Concussion: doctor who took on the might of American football hits the big screen. PMID- 26738919 TI - Development and Psychometric Properties of the Yoga Self-Efficacy Scale (YSES). AB - BACKGROUND: Yoga is a behavioral practice that uses physical movement, breathing, and meditation to improve health and promote personal transformation. Ancient yoga philosophy proposed that an individual's confidence about yoga, a concept similar to self-efficacy, will affect the likelihood of improved health from yoga practice. The purpose of this study was to develop and examine the psychometric properties of a self-efficacy measure for yoga practice (the Yoga Self-Efficacy Scale; YSES). METHODS: Yoga practitioners were recruited to evaluate the psychometric properties of YSES via a secure online survey. We collected data on additional measures to further examine construct validity. After two weeks, participants were invited to complete YSES items again to assess test-retest reliability. RESULTS: A majority of participants (N = 309) were White (85%), female (82%), and yoga instructors (56%). The 12-item YSES is unidimensional with a Cronbach's alpha of 0.93. Test-retest reliability is r = 0.79 (n = 170). YSES scores are positively correlated with health competence, health-related quality of life, and years practicing yoga, supporting construct validity. Also, yoga teachers scored significantly higher on the YSES than non-teachers (p < 0.001). Non-significant relationships with education, income and sex supported discriminant validity. YSES maintained internal consistency and construct validity for all yoga styles surveyed. CONCLUSION: YSES is a reliable and valid measure of self-efficacy for yoga practice that may provide insight into barriers to adopting and maintaining yoga as a health behavior. PMID- 26738920 TI - Decline of CSF orexin (hypocretin) levels in Prader-Willi syndrome. AB - Prader-Willi syndrome is a congenital neurodevelopmental disorder resulting from deletion of the paternal copies of genes within the chromosome region 15q11-q13. Patients with Prader-Willi syndrome often exhibit excessive daytime sleepiness, excessive appetite, and obesity. As is the case in narcolepsy, orexin (hypocretin) may be responsible for these symptoms. However, reports showing cerebrospinal fluid orexin levels in Prader-Willi syndrome patients have been limited. The aim of this study was to examine the relationship between the characteristic symptoms of Prader-Willi syndrome and cerebrospinal fluid orexin levels. We clinically identified 14 Prader-Willi syndrome patients and examined their cerebrospinal fluid orexin levels. A total of 12 patients with a 15q11-q13 deletion and two patients with maternal uniparental disomy of chromosome 15 were identified. A total of 37 narcoleptic patients and 14 idiopathic hypersomnia patients were recruited for comparison. Cerebrospinal fluid orexin levels (median [25-75 percentiles]) in the 14 Prader-Willi syndrome patients were intermediate (192 [161-234.5] pg/ml), higher than in the narcoleptic patients, but lower than in the idiopathic hypersomnia patients. Body mass index of the Prader-Willi syndrome patients was higher than in the narcoleptic and idiopathic hypersomnia patients. There was also a negative correlation between Epworth sleepiness scale scores and orexin levels in Prader-Willi syndrome patients. Decreased cerebrospinal fluid orexin levels in Prader-Willi syndrome may play an important role in severity of obesity and excessive daytime sleepiness. PMID- 26738921 TI - Evaluation of Executive Functions in Patients With Childhood Absence Epilepsy. AB - OBJECTIVE: The aim of this study was to evaluate the executive function of patients with typical absence epilepsy. METHODS: Thirty-eight (19 healthy children and 19 patients) individuals were enrolled in this study. Neurocognitive function tests, such as the Serial Digit Learning Test, Wisconsin Card Sorting Test, Visual Aural Digit Span Test-Form B, KAS-Animal Test, Trail Making Test-A Time Test, and STROOP Test, were given to all of the participants. RESULTS: There was a significant difference between the groups on the Serial Digit Learning Test (P = .037) and on a subtest of the Wisconsin Card Sorting Test. As for the Wisconsin Card Sorting Test performance, there were significant differences in perseverative errors and perseverative responses between the patient and control groups (P = .011 and P = .010, respectively). CONCLUSION: Long-term risk for learning impairments, failure in executive abilities, and short-term memory and attention disorders can occur in children with absence epilepsy. PMID- 26738923 TI - Reliability of rapid diagnostic tests in diagnosing pregnancy and infant associated malaria in Nigeria. AB - BACKGROUND: The effective management of maternal and infant malaria requires rational and prompt diagnosis. This study aims to determine the diagnostic efficiency of malaria RDT in infants and pregnant women. METHODS: The study was conducted on infants (n=200), pregnant women (n=80) and non-pregnant women (n=100) who were recruited from two hospitals in Lagos, Nigeria. Plasmodium falciparum infections were assessed in the febrile subjects by microscopic examinations of blood smears and by RDT. RESULTS: The lowest (44.3%) and the highest (83.3%) sensitivity (SS) values were recorded in the infants and pregnant women, respectively. Other diagnostic parameters, including the specificity (SP, 97.5%), positive predictive value (PPV, 92.1%) and negative predictive value (NPV, 72.8%), in the infants were greater than the values recorded in non pregnant (SP=77.5%, PPV=83.9%, NPV=70.5%) and pregnant women populations (SP=65.6%, PPV=78.4%, NPV=72.4%). The diagnostic efficiency of malaria RDT exhibited higher sensitivity in women in early gestational stages (1st trimester=78.6% and 2nd trimester=88.0%) compared with those in the 3rd trimester (71.4%). The sensitivity of malaria RDT (100.0%) was significantly higher in the multigravid women than in the primigravida (78.6%) and secundigravida women (77.8%, P<0.05). The sensitivity of the RDT significantly increased with the intensity of the malarial parasites (P<0.05). CONCLUSION: Malaria is endemic in the study populations. Malaria RDT can serve as a first-line of diagnosis for pregnant women in early gestational stages and multigravid women and can aid the differential diagnoses of other diseases due to its high specificity in infants. PMID- 26738927 TI - Detecting the Anomaly Zone in Species Trees and Evidence for a Misleading Signal in Higher-Level Skink Phylogeny (Squamata: Scincidae). AB - The anomaly zone, defined by the presence of gene tree topologies that are more probable than the true species tree, presents a major challenge to the accurate resolution of many parts of the Tree of Life. This discrepancy can result from consecutive rapid speciation events in the species tree. Similar to the problem of long-branch attraction, including more data via loci concatenation will only reinforce the support for the incorrect species tree. Empirical phylogenetic studies often employ coalescent-based species tree methods to avoid the anomaly zone, but to this point these studies have not had a method for providing any direct evidence that the species tree is actually in the anomaly zone. In this study, we use 16 species of lizards in the family Scincidae to investigate whether nodes that are difficult to resolve place the species tree within the anomaly zone. We analyze new phylogenomic data (429 loci), using both concatenation and coalescent-based species tree estimation, to locate conflicting topological signal. We then use the unifying principle of the anomaly zone, together with estimates of ancestral population sizes and species persistence times, to determine whether the observed phylogenetic conflict is a result of the anomaly zone. We identify at least three regions of the Scincidae phylogeny that provide demographic signatures consistent with the anomaly zone, and this new information helps reconcile the phylogenetic conflict in previously published studies on these lizards. The anomaly zone presents a real problem in phylogenetics, and our new framework for identifying anomalous relationships will help empiricists leverage their resources appropriately for investigating and overcoming this challenge. PMID- 26738925 TI - The neurotranscriptome of the Aedes aegypti mosquito. AB - BACKGROUND: A complete genome sequence and the advent of genome editing open up non-traditional model organisms to mechanistic genetic studies. The mosquito Aedes aegypti is an important vector of infectious diseases such as dengue, chikungunya, and yellow fever and has a large and complex genome, which has slowed annotation efforts. We used comprehensive transcriptomic analysis of adult gene expression to improve the genome annotation and to provide a detailed tissue specific catalogue of neural gene expression at different adult behavioral states. RESULTS: We carried out deep RNA sequencing across all major peripheral male and female sensory tissues, the brain and (female) ovary. Furthermore, we examined gene expression across three important phases of the female reproductive cycle, a remarkable example of behavioral switching in which a female mosquito alternates between obtaining blood-meals from humans and laying eggs. Using genome-guided alignments and de novo transcriptome assembly, our re-annotation includes 572 new putative protein-coding genes and updates to 13.5 and 50.3 % of existing transcripts within coding sequences and untranslated regions, respectively. Using this updated annotation, we detail gene expression in each tissue, identifying large numbers of transcripts regulated by blood-feeding and sexually dimorphic transcripts that may provide clues to the biology of male- and female-specific behaviors, such as mating and blood-feeding, which are areas of intensive study for those interested in vector control. CONCLUSIONS: This neurotranscriptome forms a strong foundation for the study of genes in the mosquito nervous system and investigation of sensory-driven behaviors and their regulation. Furthermore, understanding the molecular genetic basis of mosquito chemosensory behavior has important implications for vector control. PMID- 26738929 TI - Impact of positional relationship of commissures on cusp function after valve sparing root replacement for regurgitant bicuspid aortic valve. AB - OBJECTIVES: The aim of this study is to investigate the longitudinal valve function after valve-sparing root replacement in patients with bicuspid aortic valves (BAVs), in terms of both transvalvular pressure gradient (TVPG) and freedom from aortic regurgitation. METHODS: In this non-randomized retrospective study, two different approaches were chosen for correcting the circumferential orientation of commissures during aortic root reimplantation for Sievers type I BAV: (i) 180 degrees orientation, in which both cusps occupy equal surface areas and (ii) preserving native commissural orientation. From 2005 to 2015, 41 consecutive patients with Sievers type I BAV undergoing valve-sparing root replacement were divided into two groups according to the techniques: native orientation group and 180 degrees group. RESULTS: The native orientation group included 22 patients (age, 45.1 +/- 13.6 years) and the 180 degrees group included 19 patients (age, 36.6 +/- 13.7 years; P = 0.053). There was no significant difference in preoperative variables between the two groups. Postoperative and follow-up echocardiography revealed the following: the average TVPG at the time of discharge in the native orientation and the 180 degrees groups was 17.3 +/- 6.6 and 21.7 +/- 11.1 mmHg (P = 0.16), respectively, at peak and 10.0 +/- 3.7 and 11.7 +/- 6.0 mmHg (P = 0.33), respectively, at mean; at follow-up, the corresponding values were 19.1 +/- 6.6 and 22.9 +/- 10.6 mmHg (P = 0.24) at peak and 9.9 +/- 3.8 and 13.2 +/- 7.2 mmHg (P = 0.12) at mean. Thus, there was a trend towards higher TVPG in the 180 degrees group. The difference between the preoperative and postoperative commissural angles was correlated with higher postoperative peak and mean TVPG (r = 0.53, P = 0.041, 95% confidence interval, 0.029-0.82 at peak and r = 0.58, P = 0.024, 95% confidence interval, 0.092-0.84 at mean). CONCLUSIONS: In terms of freedom from aortic regurgitation and valve function, similar outcomes were achieved in both despite different repair techniques used for fixation of commissures during valve-sparing aortic root replacement in BAV. However, attention should be paid to patients with 180 degrees commissural reposition because of a trend towards higher TVPG. PMID- 26738930 TI - Down-sizing of cryopreserved homografts is a valuable technique, but do not make them too small. PMID- 26738932 TI - Deformation of a soft helical filament in an axial flow at low Reynolds number. AB - We perform a numerical investigation of the deformation of a rotating helical filament subjected to an axial flow, under low Reynolds number conditions, motivated by the propulsion of bacteria using helical flagella. Given its slenderness, the helical rod is intrinsically soft and deforms due to the interplay between elastic forces and hydrodynamic loading. We make use of a previously developed and experimentally validated computational tool framework that models the elasticity of the filament using the discrete elastic rod method and the fluid forces are treated using Lighthill's slender body theory. Under axial flow, and in the absence of rotation, the initially helical rod is extended. Above a critical flow speed its configuration comprises a straight portion connected to a localized helix near the free end. When the rod is also rotated about its helical axis, propulsion is only possible in a finite range of angular velocity, with an upper bound that is limited by buckling of the soft helix arising due to viscous stresses. A systematic exploration of the parameter space allows us to quantify regimes for successful propulsion for a number of specific bacteria. PMID- 26738931 TI - Molecular identification of tobacco leaf curl disease in Sichuan province of China. AB - BACKGROUND: Tobacco leaf curl disease (TLCD) is caused by begomoviruses in Geminiviridae, and infected plants exhibit leaf thickening, downward leaf curling, vein swelling as well as stunting symptoms. It is one of the economically important diseases in tropical and subtropical tobacco-growing areas. Seven monopartite begomoviruses have been identified causing TLCD in China. FINDINGS: In this study, two begomoviruses were identified, characterized and polygenetically analyzed to be responsible for TLCD in Sichuan province, China. The complete genomes of two isolates SC230 and SC379 from diseased tobacco samples were cloned and sequenced to be 2738 nucleotides (nts) and 2748 nts in size, respectively. Sequence alignment indicated that SC230 and SC379 were most closely related to Tomato yellow leaf curl China virus (TYLCCNV CN[CN:Sc226:Mal:12]) and Papaya leaf curl China virus (PaLCuCNV CN[CN:Gx30:Lyc:03]), with a sequence identity of 99.2 and 99.2 %, respectively. The infection rate of TYLCCNV and PaLCuCNV was 100 and 34.78 %, respectively and the co-infection rate was 34.78 % in fields. Betasatellites of SC230 and SC379 share the highest sequence identity with Tomato yellow leaf curl China betasatellite (TYLCCNB-CN[CN:Sc176:Malva:12]) and TYLCCNB-CN[CN:Yn149:Tom:09], with a sequence identity of 95.2 and 97.2 % respectively. Sequence identity between betasatellites of SC230 and SC379 was 89.6 %. And TYLCCNB was detected in all the samples. CONCLUSION: Co-infection of TYLCCNV and PaLCuCNV was identified in tobacco plants with typical symptoms of TLCD from Sichuan province in China, and this is the first report of PaLCuCNV infecting tobacco in China. TYLCCNV/TYLCCNB disease complex is widespread in tobacco-growing areas in Panzhihua city of Sichuan. PMID- 26738934 TI - Modelling the effects of contaminated environments on HFMD infections in mainland China. AB - Hand-foot-mouth disease (HFMD) has spread widely in mainland China increasing in prevalence in most years with serious consequences for child health. The HFMD virus can survive for a long period outside the host in suitable conditions, and hence contaminated environments may play important roles in HFMD infection. A new mathematical model was proposed and used to investigate the roles that asymptomatic individuals and contaminated environments played in HFMD dynamics. The model includes both direct transmission between susceptible and infected individuals and indirect transmission via free-living infectious unites in the environment. Theoretical analysis shows that the disease goes to extinction if the basic reproduction number is less than unity, whilst otherwise the disease persists. By fitting the proposed model to surveillance data we estimated the basic reproduction number as 1.509. Numerical simulations show that increasing the rate of virus clearance and decreasing transmission rates can delay epidemic outbreaks and weaken the severity of HFMD. Sensitivity analysis indicated that the basic reproduction number is sensitive to the transmission rate induced by asymptomatic infectious individuals and parameters associated with contaminated environments such as the indirect transmission rate, the rate of clearance and the virus shedding rates. This implies that asymptomatic infectious individuals and contaminated environments contribute substantially to new HFMD infections, and so would be targets for effective control measures. PMID- 26738935 TI - Inhibition of fatty acid amide hydrolase exerts cutaneous anti-inflammatory effects both in vitro and in vivo. PMID- 26738938 TI - Stereotactic breast irradiation with kilovoltage x-ray beams. AB - The purpose of this work is to determine, using Monte Carlo simulation and a realistic patient model, the characteristics of the resultant absorbed dose distributions when breast tumors are irradiated using small-field stereotactic body radiation therapy (SBRT) with kilovoltage x-ray beams instead of the standard megavoltage energies currently in use. The Rensselaer Polytechnic Institute (RPI) female phantom was used to model a pair of small-field SBRT breast treatments: in one treatment the tumor at depth and another one with the tumor located close to the breast surface. Each treatment consisted of 300 circular beams aimed at the tumor from a plurality of positions. The PENELOPE Monte Carlo code was used to determine the absorbed dose distribution for each beam and subsequently an optimization algorithm determined each beam weight according to a set of prescription goals. Both kilo- and megavoltage beam treatments were modeled, the latter to be used as a reference. Cumulative dose volume histograms for eleven structures were used to compare the kilovoltage and reference treatments. Integral dose values are also reported. Absorbed dose distributions for the target volumes as well as the organs at risk were within the parameters reported in a clinical trial for both treatments. While for the ipsilateral healthy breast tissue the megavoltage treatment does offer an advantage in terms of less volume irradiated to intermediate doses, for the contralateral structures, breast and lung, the low penetration ability of the kilovoltage treatment results in a lower maximum dose. Skin dose is higher for the kilovoltage treatment but still well within the tolerance limits reported in the clinical trial. PMID- 26738936 TI - Targeting indoor residual spraying for malaria using epidemiological data: a case study of the Zambia experience. AB - BACKGROUND: In Zambia and other sub-Saharan African countries affected by ongoing malaria transmission, indoor residual spraying (IRS) for malaria prevention has typically been implemented over large areas, e.g., district-wide, and targeted to peri-urban areas. However, there is a recent shift in some countries, including Zambia, towards the adoption of a more strategic and targeted IRS approach, in coordination with increased emphasis on universal coverage of long-lasting insecticidal nets (LLINs) and effective insecticide resistance management. A true targeted approach would deliver IRS to sub-district areas identified as high risk, with the goal of maximizing the prevention of malaria cases and deaths. RESULTS: Together with the Government of the Republic of Zambia, a new methodology was developed applying geographic information systems and satellite imagery to support a targeted IRS campaign during the 2014 spray season using health management information system data. DISCUSSION/CONCLUSION: This case study focuses on the developed methodology while also highlighting the significant research gaps which must be filled to guide countries on the most effective strategy for IRS targeting in the context of universal LLIN coverage and evolving insecticide resistance. PMID- 26738940 TI - Ferrate(VI) as a greener oxidant: Electrochemical generation and treatment of phenol. AB - Ferrate(VI) (Fe(VI)O4(2-), Fe(VI)) is a greener oxidant in the treatment of drinking water and wastewater. The electrochemical synthesis of Fe(VI) may be considered environmentally friendly because it involves one-step process to convert Fe(0) to Fe(VI) without using harmful chemicals. Electrolysis was performed by using a sponge iron as an anode in NaOH solution at different ionic strengths. The cyclic voltammetric (CV) curves showed that the sponge iron had higher electrical activity than the grey cast iron. The optimum current density was 0.054mAcm(-2) in 10M NaOH solution, which is much lower than the electrolyte concentrations used in other electrode materials. A comparison of current efficiency and energy consumption was conducted and is briefly discussed. The generated ferrate solution was applied to degrade phenol in water at two levels (2mgL(-1) and 5mgL(-1)). The maximum removal efficiency was ~70% and the optimum pH for phenol treatment was 9.0. Experiments on phenol removal using conventional coagulants (ferric chloride (FeCl3) and polyaluminium chloride (PAC)) were performed independently to demonstrate that removal of phenol by Fe(VI) occurred mainly by oxidative transformation. A combination of Fe(VI) and coagulant may be advantageous in enhancing removal efficiency, adjusting pH, and facilitating flocculation. PMID- 26738941 TI - Antibodies as stratagems against cancer. AB - Antibodies have been in the frontline of anticancer research during the last few decades, since a number of different ways have been discovered to utilize them as parts or main components of anticancer drugs. Antibodies are used as the only component of some anticancer drugs, but they can also be conjugated with a variety of substances. Antibody engineering methods such as humanization, chimerization and Fc engineering are applied in order to modify their properties according to the requirements of anticancer drug application. Given the continuous advances in biology and informatics, the role of antibodies in anticancer treatment is expected to be prominent. PMID- 26738942 TI - Post-entry blockade of small ruminant lentiviruses by wild ruminants. AB - Small ruminant lentivirus (SRLV) infection causes losses in the small ruminant industry due to reduced animal production and increased replacement rates. Infection of wild ruminants in close contact with infected domestic animals has been proposed to play a role in SRLV epidemiology, but studies are limited and mostly involve hybrids between wild and domestic animals. In this study, SRLV seropositive red deer, roe deer and mouflon were detected through modified ELISA tests, but virus was not successfully amplified using a set of different PCRs. Apparent restriction of SRLV infection in cervids was not related to the presence of neutralizing antibodies. In vitro cultured skin fibroblastic cells from red deer and fallow deer were permissive to the SRLV entry and integration, but produced low quantities of virus. SRLV got rapidly adapted in vitro to blood derived macrophages and skin fibroblastic cells from red deer but not from fallow deer. Thus, although direct detection of virus was not successfully achieved in vivo, these findings show the potential susceptibility of wild ruminants to SRLV infection in the case of red deer and, on the other hand, an in vivo SRLV restriction in fallow deer. Altogether these results may highlight the importance of surveilling and controlling SRLV infection in domestic as well as in wild ruminants sharing pasture areas, and may provide new natural tools to control SRLV spread in sheep and goats. PMID- 26738943 TI - Association of reduced Connexin 43 expression with retinal vascular lesions in human diabetic retinopathy. AB - Connexin 43 (Cx43) downregulation promotes apoptosis in retinal vascular cells of diabetic animal models; however, its relevance to human diabetic retinopathy has not been established. In this study, we investigated whether diabetes alters Cx43 expression and promotes retinal vascular lesions in human retinas. Diabetic human eyes (aged 64-94 years) and non-diabetic human eyes (aged 61-90 years) were analyzed in this study. Retinal protein samples and retinal capillary networks were assessed for Cx43 level by Western blot (WB) analysis and immunostaining. In parallel, retinal capillary networks were stained with hematoxylin and periodic acid Schiff to determine the extent of pericyte loss (PL) and acellular capillaries (AC) in these retinas. Cx43 protein expression was significantly reduced in the diabetic retinas compared to non-diabetic retinas as indicated by WB analysis (81 +/- 11% of control). Additionally, a significant decrease in the number of Cx43 plaques per unit length of vessel was observed in the diabetic retinas compared to those of non-diabetic retinas (62 +/- 10% of control; p < 0.005). Importantly, a strong inverse relationship was noted between Cx43 expression and the relative number of AC (r = -0.89; p < 0.0005), and between Cx43 expression and number of pericyte loss (r = -0.88; p < 0.0005). Overall, these results show that Cx43 expression is reduced in the human diabetic retinas and Cx43 reduction is associated with increased vascular cell death. These findings suggest that diabetes decreases retinal Cx43 expression and that the development of PL and AC is associated with reduced Cx43 expression in human diabetic retinopathy. PMID- 26738945 TI - Row, row, row your way to treating postural tachycardia syndrome. PMID- 26738946 TI - Failure rate and conductor externalization in the Biotronik Linox/Sorin Vigila implantable cardioverter-defibrillator lead. AB - BACKGROUND: We observed a case of conductor externalization in a Biotronik Linox lead. OBJECTIVE: The purpose of this study was to investigate lead performance of the Linox lead and the identical Sorin Vigila lead and prevalence of conductor externalization. METHODS: We compared lead performance of all Linox and Vigila leads implanted at our center (BL group; n = 93) with that of all Boston Scientific Endotak Reliance leads (ER group; n = 190) and Medtronic Sprint Quattro leads (SQ group; n = 202) implanted during the same period. We screened all patients in the BL group for conductor externalization. RESULTS: We identified 8 cases of lead failures in the BL group (index case of conductor externalization, 6 cases of nonphysiological high-rate sensing, and 1 case of high-voltage conductor fracture). Prospective fluoroscopic screening of 98% of all active BL group cases revealed 1 additional case of conductor externalization. The median follow-up was 41, 27, and 29 months for the BL group, ER group, and SQ group, respectively; lead survival was 94.9%, 99.2%, and 100% at 3 years and 88%, 97.5%, and 100% at 5 years (P = .038 for BL group vs ER group and P = .007 for BL group vs SQ group using the log-rank test). Younger age at implant was an independent predictor of lead failure in the BL group (adjusted hazard ratio 0.85; 95% confidence interval 0.77-0.94; P = .001). CONCLUSION: At our center, survival of the Linox lead is 88% at 5 years and significantly worse than that of other leads. Conductor externalization is present in a minority of failed Linox leads. Younger age at implant is an independent predictor of Linox lead failure. PMID- 26738948 TI - Initial Experience of Applying TWIST-Dixon With Flexible View Sharing in Breast DCE-MRI. AB - INTRODUCTION: We developed a new fast imaging technique with flexible time resolved angiography with stochastic trajectories (TWIST) view sharing to achieve variable temporal resolution and with flexible echo time Dixon to achieve robust fat suppression and to evaluate its application in breast dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: The TWIST Dixon technique was improved with more flexible view sharing and echo times (TWIST-Dixon-Flex). In a dynamic series, each measurement can be separately prescribed as "full," "partial," or "center-only." The spatial and temporal resolution can then be adjusted throughout the measurements to match the dynamic characteristics of contrast enhancement at different phases. The potential advantages of TWIST-Dixon-Flex were evaluated with 18 clinical breast DCE MRI cases. A mixed-effects analysis of variance (ANOVA) was performed to compare the image quality with that of the conventional images. RESULTS: The ANOVA showed that the quality of postcontrast TWIST-Dixon-Flex images was significantly higher than that of the conventional images. The TWIST-Dixon-Flex technique also provided the capability to detect differences in rapid contrast uptake from different regions of the breast tumor, which is not possible with conventional breast DCE-MRI. CONCLUSION: The new TWIST-Dixon-Flex technique provides potentially valuable information about early tumor enhancement, and maintains excellent image quality at peak and postcontrast enhancement. This technique could help overcome the compromise on spatial over temporal resolution in clinical breast imaging. PMID- 26738950 TI - Dietary Sodium Restriction in Heart Failure: A Recommendation Worth its Salt? PMID- 26738949 TI - Impact of Dietary Sodium Restriction on Heart Failure Outcomes. AB - OBJECTIVES: This study sought to evaluate the impact of sodium restriction on heart failure (HF) outcomes. BACKGROUND: Although sodium restriction is advised for patients with HF, data on sodium restriction and HF outcomes are inconsistent. METHODS: We analyzed data from the multihospital HF Adherence and Retention Trial, which enrolled 902 New York Heart Association functional class II/III HF patients and followed them up for a median of 36 months. Sodium intake was serially assessed by a food frequency questionnaire. Based on the mean daily sodium intake prior to the first event of death or HF hospitalization, patients were classified into sodium restricted (<2,500 mg/d) and unrestricted (>=2,500 mg/d) groups. Study groups were propensity score matched according to plausible baseline confounders. The primary outcome was a composite of death or HF hospitalization. The secondary outcomes were cardiac death and HF hospitalization. RESULTS: Sodium intake data were available for 833 subjects (145 sodium restricted, 688 sodium unrestricted), of whom 260 were propensity matched into sodium restricted (n = 130) and sodium unrestricted (n = 130) groups. Sodium restriction was associated with significantly higher risk of death or HF hospitalization (42.3% vs. 26.2%; hazard ratio [HR]: 1.85; 95% confidence interval [CI]: 1.21 to 2.84; p = 0.004), derived from an increase in the rate of HF hospitalization (32.3% vs. 20.0%; HR: 1.82; 95% CI: 1.11 to 2.96; p = 0.015) and a nonsignificant increase in the rate of cardiac death (HR: 1.62; 95% CI: 0.70 to 3.73; p = 0.257) and all-cause mortality (p = 0.074). Exploratory subgroup analyses suggested that sodium restriction was associated with increased risk of death or HF hospitalization in patients not receiving angiotensin converting enzyme inhibitor or angiotensin receptor blocker (HR: 5.78; 95% CI: 1.93 to 17.27; p = 0.002). CONCLUSIONS: In symptomatic patients with chronic HF, sodium restriction may have a detrimental impact on outcome. A randomized clinical trial is needed to definitively address the role of sodium restriction in HF management. (A Self-management Intervention for Mild to Moderate Heart Failure [HART]; NCT00018005). PMID- 26738951 TI - The Uncertainty of Sodium Restriction in Heart Failure: We Can Do Better Than This. PMID- 26738953 TI - Air Pollution in Patients With Heart Failure: Lessons From a Mechanistic Pilot Study of a Filter Intervention. PMID- 26738952 TI - Respiratory Filter Reduces the Cardiovascular Effects Associated With Diesel Exhaust Exposure: A Randomized, Prospective, Double-Blind, Controlled Study of Heart Failure: The FILTER-HF Trial. AB - OBJECTIVES: The goal of this study was to test the effects of a respiratory filter intervention (filter) during controlled pollution exposure. BACKGROUND: Air pollution is considered a risk factor for heart failure (HF) decompensation and mortality. METHODS: This study was a double-blind, randomized to order, controlled, 3-way crossover, single-center clinical trial. It enrolled 26 patients with HF and 15 control volunteers. Participants were exposed in 3 separate sessions to clean air, unfiltered diesel exhaust exposure (DE), or filtered DE. Endpoints were endothelial function assessed by using the reactive hyperemia index (RHi), arterial stiffness, serum biomarkers, 6-min walking distance, and heart rate variability. RESULTS: In patients with HF, DE was associated with a worsening in RHi from 2.17 (interquartile range [IQR]: 1.8 to 2.5) to 1.72 (IQR: 1.5 to 2.2; p = 0.002) and an increase in B-type natriuretic peptide (BNP) from 47.0 pg/ml (IQR: 17.3 to 118.0 pg/ml) to 66.5 pg/ml (IQR: 26.5 to 155.5 pg/ml; p = 0.004). Filtration reduced the particulate concentration (325 +/- 31 MUg/m(3) vs. 25 +/- 6 MUg/m(3); p < 0.001); in the group with HF, filter was associated with an improvement in RHi from 1.72 (IQR: 1.5 to 2.2) to 2.06 (IQR: 1.5 to 2.6; p = 0.019) and a decrease in BNP from 66.5 pg/ml (IQR: 26.5 to 155.5 pg/ml) to 44.0 pg/ml (IQR: 20.0 to 110.0 pg/ml; p = 0.015) compared with DE. In both groups, DE decreased the 6-min walking distance and arterial stiffness, although filter did not change these responses. DE had no effect on heart rate variability or exercise testing. CONCLUSIONS: To our knowledge, this trial is the first to show that a filter can reduce both endothelial dysfunction and BNP increases in patients with HF during DE. Given these potential benefits, the widespread use of filters in patients with HF exposed to traffic-derived air pollution may have beneficial public health effects and reduce the burden of HF. (Effects of Air Pollution Exposure Reduction by Filter Mask on Heart Failure; NCT01960920). PMID- 26738954 TI - Lipoprotein(a) and Heart Failure: Another Reason to Study Interventions in Patients With Very High Levels of Lipoprotein(a)? PMID- 26738955 TI - Why Dr. Robert Califf's Nomination for Commissioner of the Food and Drug Administration Is Good for Heart Failure Patients. PMID- 26738956 TI - Is Pump the Answer to Heart Failure With Preserved Ejection Fraction? PMID- 26738957 TI - Reply: Is Pump the Answer to Heart Failure With Preserved Ejection Fraction? PMID- 26738960 TI - New approaches for improving cardiovascular risk assessment. AB - INTRODUCTION AND OBJECTIVES: Clinical guidelines recommend the use of cardiovascular risk assessment tools (risk scores) to predict the risk of events such as cardiovascular death, since these scores can aid clinical decision-making and thereby reduce the social and economic costs of cardiovascular disease (CVD). However, despite their importance, risk scores present important weaknesses that can diminish their reliability in clinical contexts. This study presents a new framework, based on current risk assessment tools, that aims to minimize these limitations. METHODS: Appropriate application and combination of existing knowledge is the main focus of this work. Two different methodologies are applied: (i) a combination scheme that enables data to be extracted and processed from various sources of information, including current risk assessment tools and the contributions of the physician; and (ii) a personalization scheme based on the creation of patient groups with the purpose of identifying the most suitable risk assessment tool to assess the risk of a specific patient. RESULTS: Validation was performed based on a real patient dataset of 460 patients at Santa Cruz Hospital, Lisbon, Portugal, diagnosed with non-ST-segment elevation acute coronary syndrome. Promising results were obtained with both approaches, which achieved sensitivity, specificity and geometric mean of 78.79%, 73.07% and 75.87%, and 75.69%, 69.79% and 72.71%, respectively. CONCLUSIONS: The proposed approaches present better performances than current CVD risk scores; however, additional datasets are required to back up these findings. PMID- 26738961 TI - Bioresorbable scaffolds for primary angioplasty: Optical coherence tomography follow-up. PMID- 26738962 TI - Drug response in organoids generated from frozen primary tumor tissues. AB - Primary tumor organoids grown in three-dimensional culture provide an excellent platform for studying tumor progression, invasion, and drug response. However, organoid generation protocols require fresh tumor tissue, which limits organoid research and clinical use. This study investigates cellular morphology, viability, and drug response of organoids derived from frozen tissues. The results demonstrate that viable organoids can be grown from flash-frozen and thawed tissue and from bulk tissues slowly frozen in DMSO supplemented media. While the freezing process affects the basal metabolic rate of the cells, the optical metabolic imaging index correlates between organoids derived from fresh and frozen tissue and can be used to detect drug response of organoids grown from frozen tissues. The slow, DMSO frozen tissue yielded organoids with more accurate drug response than the flash frozen tissues, and thus bulk tissue should be preserved for subsequent organoid generation by slow freezing in DMSO supplemented media. PMID- 26738964 TI - Contrast-enhanced transrectal ultrasonography for the detection of diffuse prostate cancer. AB - AIM: To evaluate the diagnostic accuracy of contrast-enhanced transrectal ultrasonography (CE-TRUS) versus baseline TRUS (combination of grey-scale and colour Doppler imaging) for diffuse prostate cancer. MATERIALS AND METHODS: Forty six patients without an obvious focal mass on baseline TRUS (grey-scale and colour Doppler), underwent additional CE-TRUS and TRUS-guided biopsy due to elevated levels of prostate-specific antigen (PSA >=4 ng/ml) and/or abnormal digital rectal examination (DRE). In all patients, CE-TRUS was performed with intravenous injection of a contrast agent (sulphur hexafluoride microbubble; SonoVue, 2.4 ml) before biopsy. TRUS-guided biopsy targeted suspicious areas detected on CE-TRUS imaging or sampled the outer gland of the normal prostate. The final diagnosis was based on results of the TRUS-guided biopsy. The diagnostic accuracy of baseline TRUS and CE-TRUS for diffuse prostatic lesions was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Diffuse prostate cancer was present in 32 (69.5%) patients and absent in 14 (30.5%) patients. Nineteen patients had diffuse prostate cancer that was not detected by baseline TRUS, whereas 15 cases were identified using CE-TRUS. Conversely, five patients had benign prostatic hypertrophy (BPH) that was diagnosed as cancer by CE-TRUS, and two of these patients were diagnosed with BPH by baseline TRUS. The combined sensitivity, specificity, and accuracy were 87.5%, 64.2%, and 80.4%, respectively, for CE-TRUS, and 40.6%, 78.5%, and 52.1%, respectively, for baseline TRUS. The area under the ROC curve (AUC) values for the diagnostic accuracy of baseline CE-TRUS versus TRUS for diffuse prostate cancer differed significantly at 0.904 and 0.667, respectively (Z=4.098, p<0.0001). CONCLUSION: CE-TRUS exhibited greater diagnostic accuracy for diffuse prostate cancer than baseline TRUS. CE-TRUS may improve cancer detection over baseline TRUS imaging for the diagnosis of diffuse prostate cancer in patients with an elevated PSA level. CE-TRUS detects diffuse prostate cancer without an obvious focal mass on routine TRUS or clinical examination, and therefore, may help identify patients who do not need a repeat biopsy or who do not need to undergo systematic 12-core invasive sampling biopsies. PMID- 26738965 TI - Audit of radiology communication systems for critical, urgent, and unexpected significant findings. AB - AIM: To determine the compliance of UK radiology departments and trusts/healthcare organisations with National Patient Safety Agency and Royal College of Radiologist's published guidance on the communication of critical, urgent, and unexpected significant radiological findings. MATERIALS AND METHODS: A questionnaire was sent to all UK radiology department audit leads asking for details of their current departmental policy regarding the issuing of alerts; use of automated electronic alert systems; methods of notification of clinicians of critical, urgent, and unexpected significant radiological findings; monitoring of results receipt; and examples of the more common types of serious pathologies for which alerts were issued. RESULTS: One hundred and fifty-four of 229 departments (67%) responded. Eighty-eight percent indicated that they had a policy in place for the communication of critical, urgent, and unexpected significant radiological findings. Only 34% had an automated electronic alert system in place and only 17% had a facility for service-wide electronic tracking of radiology reports. In only 11 departments with an electronic acknowledgement system was someone regularly monitoring the read rate. CONCLUSION: There is wide variation in practice across the UK with regard to the communication and monitoring of reports with many departments/trusts not fully compliant with published UK guidance. Despite the widespread use of electronic systems, only a minority of departments/trusts have and use electronic tracking to ensure reports have been read and acted upon. PMID- 26738966 TI - Diphenyl diselenide elicits antidepressant-like activity in rats exposed to monosodium glutamate: A contribution of serotonin uptake and Na(+), K(+)-ATPase activity. AB - Depression is a disorder with symptoms manifested at the psychological, behavioral and physiological levels. Monosodium glutamate (MSG) is the most widely used additive in the food industry; however, some adverse effects induced by this additive have been demonstrated in experimental animals and humans, including functional and behavioral alterations. The aim of this study was to investigate the possible antidepressant-like effect of diphenyl diselenide (PhSe)2, an organoselenium compound with pharmacological properties already documented, in the depressive-like behavior induced by MSG in rats. Male and female newborn Wistar rats were divided in control and MSG groups, which received, respectively, a daily subcutaneous injection of saline (0.9%) or MSG (4g/kg/day) from the 1st to 5th postnatal day. At 60th day of life, animals received (PhSe)2 (10mg/kg, intragastrically) 25min before spontaneous locomotor and forced swimming tests (FST). The cerebral cortices of rats were removed to determine [(3)H] serotonin (5-HT) uptake and Na(+), K(+)-ATPase activity. A single administration of (PhSe)2 was effective against locomotor hyperactivity caused by MSG in rats. (PhSe)2 treatment protected against the increase in the immobility time and a decrease in the latency for the first episode of immobility in the FST induced by MSG. Furthermore, (PhSe)2 reduced the [(3)H] 5-HT uptake and restored Na(+), K(+)-ATPase activity altered by MSG. In the present study a single administration of (PhSe)2 elicited an antidepressant-like effect and decrease the synaptosomal [(3)H] 5-HT uptake and an increase in the Na(+), K(+) ATPase activity in MSG-treated rats. PMID- 26738967 TI - Neuronal and brain morphological changes in animal models of schizophrenia. AB - Schizophrenia, a severe and debilitating disorder with a high social burden, affects 1% of the adult world population. Available therapies are unable to treat all the symptoms, and result in strong side effects. For this reason, numerous animal models have been generated to elucidate the pathophysiology of this disorder. All these models present neuronal remodeling and abnormalities in spine stability. It is well known that the complexity in dendritic arborization determines the number of receptive synaptic contacts. Also the loss of dendritic spines and arbor stability are strongly associated with schizophrenia. This review evaluates changes in spine density and dendritic arborization in animal models of schizophrenia. By understanding these changes, pharmacological treatments can be designed to target specific neural systems to attenuate neuronal remodeling and associated behavioral deficits. PMID- 26738968 TI - Neuronal calcium sensor-1 deletion in the mouse decreases motivation and dopamine release in the nucleus accumbens. AB - Calcium sensors detect intracellular calcium changes and interact with downstream targets to regulate many functions. Neuronal Calcium Sensor-1 (NCS-1) or Frequenin is widely expressed in the nervous system, and involved in neurotransmission, synaptic plasticity and learning. NCS-1 interacts with and regulates dopamine D2 receptor (D2R) internalization and is implicated in disorders like schizophrenia and substance abuse. However, the role of NCS-1 in behaviors dependent on dopamine signaling in the striatum, where D2R is most highly expressed, is unknown. We show that Ncs-1 deletion in the mouse decreases willingness to work for food. Moreover, Ncs-1 knockout mice have significantly lower activity-dependent dopamine release in the nucleus accumbens core in acute slice recordings. In contrast, food preference, responding for conditioned reinforcement, ability to represent changes in reward value, and locomotor response to amphetamine are not impaired. These studies identify novel roles for NCS-1 in regulating activity-dependent striatal dopamine release and aspects of motivated behavior. PMID- 26738969 TI - Tipepidine, a non-narcotic antitussive, exerts an antidepressant-like effect in the forced swimming test in adrenocorticotropic hormone-treated rats. AB - We investigated whether tipepidine exerts an antidepressant-like effect in the forced swimming test in adrenocorticotropic hormone (ACTH)-treated rats, which is known as a treatment-resistant depression model, and we studied the pharmacological mechanisms of the effects of tipepidine. Male Wistar rats (5-7 weeks old) were used in this study. Tipepidine (20 and 40 mg/kg, i.p.) decreased the immobility time in the forced swimming test in ACTH-treated rats. The anti immobility effect of tipepidine was blocked by a catecholamine-depleting agent, alpha-methyl-p-tyrosine (300 mg/kg, s.c.), but not by a serotonin-depleting agent, p-chlorophenylalanine. The anti-immobility effect of tipepidine was also blocked by a dopamine D1 receptor antagonist, SCH23390 (0.02 mg/kg, s.c.) and an adrenaline alpha2 receptor antagonist, yohimbine (2 mg/kg, i.p.). In microdialysis technique, tipepidine (40 mg/kg, i.p.) increased the extracellular dopamine level of the nucleus accumbens (NAc) in ACTH-treated rats. These results suggest that tipepidine exerts an antidepressant-like effect in the forced swimming test in ACTH-treated rats, and that the effect of tipepidine is mediated by the stimulation of dopamine D1 receptors and adrenaline alpha2 receptors. The results also suggest that an increase in the extracellular dopamine level in the NAc may be involved in the antidepressant-like effect of tipepidine in ACTH treated rats. PMID- 26738971 TI - Enclosing a pen reduced time to response to questionnaire mailings. AB - OBJECTIVES: To assess the effectiveness of including a pen in postal questionnaires on response rate, necessity of reminders, time to response, and completeness of response to the primary outcome question (POQ). STUDY DESIGN AND SETTING: A two-arm randomized controlled trial (RCT) embedded within the screening of older women for prevention of fracture trial (SCOOP). Women, aged 70 75 years, were randomized to receive a pen with their questionnaire (n = 3,826) or to receive the questionnaire alone (n = 3,829). The results were combined with another embedded RCT in a meta-analysis. RESULTS: A response rate of 92.4% was observed in the pen group compared with 91.3% in the control group (odds ratio [OR] = 1.16; 95% confidence interval [CI]: 0.98, 1.37; P = 0.08). There was a difference in reminders required (OR = 0.88; 95% CI: 0.79, 0.98; P = 0.02), time to response (hazard ratio = 1.06; 95% CI: 1.01, 1.11; P = 0.01) and some difference in the completeness of response to the POQ (OR = 1.18; 95% CI: 1.00, 1.39; P = 0.05). The pooled OR from the meta-analysis for response rate was 1.21 (95% CI: 1.05, 1.39; P = 0.01). CONCLUSION: Inclusion of a pen with postal questionnaires potentially has a positive impact on response rates and the number of reminders required. There may be some reduction in time to response. Studies of different participant groups are needed to test the effectiveness over more diverse populations. PMID- 26738972 TI - Effects of sodium nitroprusside on mouse erythrocyte catalase activity and malondialdehyde status. AB - There is controversy about the anti- or pro-oxidative effects of the nitric oxide (NO)-donor sodium nitroprusside (SNP). Hence, the activity of the antioxidant enzyme catalase (CAT) and the status of malondialdehyde (MDA) were investigated after a 2.5 mg/kg dose of SNP had been i.p. administered to different and comparable groups of mice (n = 48). The drug was administered at two different circadian times (1 and 13 h after light onset [HALO]). There were, irrespectively of sampling time, no significant differences in the means of CAT activity and MDA status between control and SNP-treated groups, no matter the treatment time. However, CAT activity was significantly (Student's t-test, p < 0.001) increased 1 h following SNP administration at 1 HALO, whereas the significant (p < 0.001) increase in the enzyme activity was found only 3 h after injection at 13 HALO. The drug dosing either at 1 or 13 HALO resulted in no significant differences of MDA status between control and treated groups regardless to the sampling time. Two-way analysis of variance (ANOVA) detected a significant (F0.05(7,88)= 5.3; p < 0.0006) interaction between sampling time and treatment in mice injected at 1 HALO, suggesting the influence of treatment on sampling-time-related changes in CAT activity. However, ANOVA validated no interaction between the two factors in mice treated at 13 HALO, illustrating that the sampling-time differences in enzyme activity were greater. Furthermore, two-way ANOVA revealed no interaction in the variation of MDA status in animals treated either at 1 or 13 HALO. This study indicates that SNP significantly affected the anti-oxidant system. PMID- 26738973 TI - High sensitive and direct fluorescence detection of single viral DNA sequences by integration of double strand probes onto microgels particles. AB - A novel class of probes for fluorescence detection was developed and combined to microgel particles for a high sensitive fluorescence detection of nucleic acids. A double strand probe with an optimized fluorescent-quencher couple was designed for the detection of different lengths of nucleic acids (39 nt and 100 nt). Such probe proved efficient in target detection in different contests and specific even in presence of serum proteins. The conjugation of double strand probes onto polymeric microgels allows for a sensitive detection of DNA sequences from HIV, HCV and SARS corona viruses with a LOD of 1.4 fM, 3.7 fM and 1.4 fM, respectively, and with a dynamic range of 10(-9)-10(-15) M. Such combination enhances the sensitivity of the detection of almost five orders of magnitude when compared to the only probe. The proposed platform based on the integration of innovative double strand probe into microgels particles represents an attractive alternative to conventional sensitive DNA detection technologies that rely on amplifications methods. PMID- 26738974 TI - New routes for improving adhesion at the metal/alpha-Al2O3(0001) interface. AB - With the advent of new steel grades, galvanic protection by zinc coating faces a new paradigm. Indeed, enrichment in strengthening elements prone to oxidation, such as Al, Mn, and Si, leads to the formation of oxide films that are poorly wet by zinc. We study herein routes for the improvement of adhesion at the model Zn/alpha-Al2O3 interface by the addition of metals. As a first step, with the help of ab initio results on the adsorption characteristics of transition metal adatoms at alpha-alumina surfaces, we establish and rationalize clear trends in both the behavior of metal-alumina interaction strength and the relative thermodynamic stability of configurations with weakly and strongly bound metal adatoms. The reasons for the enhanced binding strength of transition metals, such as Cr, maintained regardless of the precise alumina termination and the surface charge state are pointed out. On these grounds, possible improvements of adhesion under realistic conditions are discussed. It is predicted that enrichment in transition metals, such as Cr, may produce strongly adhesive interfaces that lead to cohesive cleavage. PMID- 26738975 TI - The adherens junction is lost during normal pregnancy but not during ovarian hyperstimulated pregnancy. AB - During early pregnancy in the rat, the luminal uterine epithelial cells (UECs) must transform to a receptive state to permit blastocyst attachment and implantation. The implantation process involves penetration of the epithelial barrier, so it is expected that the transformation of UECs includes alterations in the lateral junctional complex. Previous studies have demonstrated a deepening of the tight junction (zonula occludens) and a reduction in the number of desmosomes (macula adherens) in UECs at the time of implantation. However, the adherens junction (zonula adherens), which is primarily responsible for cell-cell adhesion, has been little studied during early pregnancy. This study investigated the adherens junction in rat UECs during the early stages of normal pregnancy and ovarian hyperstimulated (OH) pregnancy using transmission electron microscopy. The adherens junction is present in UECs at the time of fertilisation, but is lost at the time of blastocyst implantation during normal pregnancy. Interestingly, at the time of implantation after OH, adherens junctions are retained and may impede blastocyst penetration of the epithelium. The adherens junction anchors the actin-based terminal web, which is known to be disrupted in UECs during early pregnancy. However, artificial disruption of the terminal web, using cytochalasin D, did not cause removal of the adherens junction in UECs. This study revealed that adherens junction disassembly occurs during early pregnancy, but that this process does not occur during OH pregnancy. Such disassembly does not appear to depend on the disruption of the terminal web. PMID- 26738977 TI - Transesophageal Echocardiography and Mitral Valve Repair: Chasing a "Not-So Moving" Target. PMID- 26738978 TI - CASE 6-2016Cardiopulmonary Bypass as a Bridge to Clinical Recovery From Cardiovascular Collapse During Graft Reperfusion in Liver Transplantation. PMID- 26738979 TI - TIA1 oxidation inhibits stress granule assembly and sensitizes cells to stress induced apoptosis. AB - Cytoplasmic stress granules (SGs) are multimolecular aggregates of stalled translation pre-initiation complexes that prevent the accumulation of misfolded proteins, and that are formed in response to certain types of stress including ER stress. SG formation contributes to cell survival not only by suppressing translation but also by sequestering some apoptosis regulatory factors. Because cells can be exposed to various stresses simultaneously in vivo, the regulation of SG assembly under multiple stress conditions is important but unknown. Here we report that reactive oxygen species (ROS) such as H2O2 oxidize the SG-nucleating protein TIA1, thereby inhibiting SG assembly. Thus, when cells are confronted with a SG-inducing stress such as ER stress caused by protein misfolding, together with ROS-induced oxidative stress, they cannot form SGs, resulting in the promotion of apoptosis. We demonstrate that the suppression of SG formation by oxidative stress may underlie the neuronal cell death seen in neurodegenerative diseases. PMID- 26738980 TI - Confirmatory factor analysis of psychotic-like experiences in a general population sample. AB - Psychotic-like experiences (PLEs) are sub-psychotic expressions of the psychosis continuum. Several studies have suggested multifactorial models, including a bifactor model, of the putative PLEs assessed with the popular Community Assessment of Psychic Experiences (CAPE) questionnaire. Our confirmatory results in a gender-balanced population of adolescents and young adults support a three factor Paranoia-Delusions-Hallucinations structure of PLEs, which excludes Grandiosity and Common Paranormal Beliefs. The best latent models achieved excellent fit when taking the categorical nature of the responses into consideration. PMID- 26738981 TI - Extreme sensory processing patterns and their relation with clinical conditions among individuals with major affective disorders. AB - Previous studies highlighted the involvement of sensory perception in emotional processes. However, the role of extreme sensory processing patterns expressed in hyper- or hyposensitivity was not thoroughly considered. The present study, in real life conditions, examined the unique sensory processing patterns of individuals with major affective disorders and their relationship with psychiatric symptomatology. The sample consisted of 105 participants with major affective conditions ranging in age from 20 to 84 years (mean=56.7+/-14.6). All participants completed the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A), the second version of the Beck Depression Inventory (BDI-II), and Adolescent/Adult Sensory Profile (AASP). Sensory sensitivity/avoiding hypersensitivity patterns and low registration (a hyposensitivity pattern) were prevalent among our sample as compared to normative data. About seventy percent of the sample showed lower seeking tendency. Stepwise regression analyses revealed that depression and anxious/cyclothymic affective temperaments were predicted by sensory sensory/avoiding. Anxious and irritable affective temperaments were predicted by low registration. Hyperthymic affective temperament and lower severity of depression were predicted by sensation seeking. Hyposensitivity or hypersensitivity may be "trait" markers of individuals with major affective disorders. Interventions should refer to the individual unique sensory profiles and their behavioral and functional impact in the context of real life. PMID- 26738982 TI - Ontogenetic explanation for tegmen tympani dehiscence and superior semicircular canal dehiscence association. AB - OBJECTIVES: To analyze the ontogeny of the superior semicircular canal and tegmen tympani and determine if there are common embryological factors explaining both associated dehiscence. METHODS: We analyzed 77 human embryological series aged between 6 weeks and newborn. Preparations were serially cut and stained with Masson's trichrome technique. RESULTS: The tegmental prolongation of tegmen tympani and superior semicircular canal originate from the same structure, the otic capsule, and have the same type of endochondral ossification; while the extension of the squamous prolongation of tegmen tympani runs from the temporal squama and ossification is directly of intramembranous type. The nuclei of ossification of the superior and external semicircular canals and accessory of tegmen collaborate in the ossification of the tegmental extension and by growth extend to the tegmental prolongation. This fact plus the fact that both structures share a common layer of external periosteum could explain the coexistence of lack of bone coverage in tegmen and superior semicircular canal. CONCLUSION: The development of the semicircular canal and tegmen tympani could explain the causes of the association of both dehiscences. PMID- 26738983 TI - Immunochemical Determination of Pyocyanin and 1-Hydroxyphenazine as Potential Biomarkers of Pseudomonas aeruginosa Infections. AB - A novel immunochemical approach to diagnose Pseudomonas aeruginosa infections is reported, which is based on the quantification of relevant and specific virulence factors secreted by this microorganism. Specific antibodies have been raised using hapten PC1 (a 1:1 mixture of 9-hydroxy- and 6-hydroxy-phenazine-2 carobxylic acids), designed to recognize 1-hydroxyphenazine (1-OHphz), which is the main metabolite of pyocyanin (PYO). PYO is one of the most important virulence factors produced by nearly all P. aeruginosa strains, and other species do not produce this factor. With these antibodies, an immunochemical analytical procedure able to quantify both 1-OHphz and PYO in complex clinical samples has been developed. 1-OHphz can be directly measured in solubilized sputum samples diluted 20 times with the assay buffer. Quantification of PYO is accomplished after conversion to 1-OHphz in just 20 min under basic conditions. A LOD of 0.60 +/- 0.01 nM (4.80 +/- 0.08 nmol kg(-1) sputum) is reached for both biomarker targets under the conditions established, a value that is much below the reported concentrations on sputum samples obtained from infected patients (up to 100 MUM). The assay is robust, reproducible, accurate, can be run in about 2 h, and many samples can be measured simultaneously. The present reported assay could represent a significant improvement in the diagnosis of infectious diseases caused by this pathogen. PMID- 26738984 TI - Visualisation of newly synthesised collagen in vitro and in vivo. AB - Identifying collagen produced de novo by cells in a background of purified collagenous biomaterials poses a major problem in for example the evaluation of tissue-engineered constructs and cell biological studies to tumor dissemination. We have developed a universal strategy to detect and localize newly deposited collagen based on its inherent association with dermatan sulfate. The method is applicable irrespective of host species and collagen source. PMID- 26738985 TI - Apoptosis-related microRNA changes in the right atrium induced by remote ischemic perconditioning during valve replacement surgery. AB - We previously found that remote ischemic perconditioning (RIPerc) was effective in attenuating myocardial injury during cardiac surgery. Given that microRNAs (miRs) act as an important player in ischemic/reperfusion (I/R) injury and apoptosis, this study aimed to investigate whether RIPerc reduces apoptosis in atrial myocardium and which apoptosis-related miRs are involved during valve replacement surgery. Here, we demonstrated that RIPerc inhibited apoptosis in atrial myocardium during cardiac ischemia and that 17 miRs showed at least a 1.5 fold change in expression after ischemia. Of the 17 miRs, 9 miRs, including miR 1, miR-21, miR-24, and miR-195, which are related to apoptosis, exhibited different expression patterns in the RIPerc group compared with the control. Using qRT-PCR and Western blotting, we demonstrated that miR-1 and miR-195 were downregulated and that their common putative target gene Bcl-2 was upregulated in the RIPerc group. However, the differences in miR-21 and miR-24 expression, together with programmed cell death 4 (PDCD4), which is the target gene of miR 21, were not significant. These findings provide some insight into the role of miRs in the cardioprotective effects induced by RIPerc. PMID- 26738986 TI - Tris-hydroxymethyl-aminomethane enhances capsaicin-induced intracellular Ca(2+) influx through transient receptor potential V1 (TRPV1) channels. AB - Non-selective transient receptor potential vanilloid (TRPV) cation channels are activated by various insults, including exposure to heat, acidity, and the compound capsaicin, resulting in sensations of pain in the skin, visceral organs, and oral cavity. Recently, TRPV1 activation was also demonstrated in response to basic pH elicited by ammonia and intracellular alkalization. Tris-hydroxymethyl aminomethane (THAM) is widely used as an alkalizing agent; however, the effects of THAM on TRPV1 channels have not been defined. In this study, we characterized the effects of THAM-induced TRPV1 channel activation in baby hamster kidney cells expressing human TRPV1 (hTRPV1) and the Ca(2+)-sensitive fluorescent sensor GCaMP2 by real-time confocal microscopy. Notably, both capsaicin (1 MUM) and pH 6.5 buffer elicited steep increases in the intracellular Ca(2+) concentration ([Ca(2+)]i), while treatment with THAM (pH 8.5) alone had no effect. However, treatment with THAM (pH 8.5) following capsaicin application elicited a profound, long-lasting increase in [Ca(2+)]i that was completely inhibited by the TRPV1 antagonist capsazepine. Taken together, these results suggest that hTRPV1 pre activation is required to provoke enhanced, THAM-induced [Ca(2+)]i increases, which could be a mechanism underlying pain induced by basic pH. PMID- 26738987 TI - Anti-Inflammatory Effects of Ginsenoside-Rh2 Inhibits LPS-Induced Activation of Microglia and Overproduction of Inflammatory Mediators Via Modulation of TGF beta1/Smad Pathway. AB - Microglia activation plays an important role in neuroinflammation and contributes to several neurological disorders. Hence, inhibition of both microglia activation and pro-inflammatory cytokines may lead to the effective treatment of neurodegenerative diseases. In this study, we found that GRh2 inhibited the inflammatory response to lipopolysaccharide (LPS) and prevented the LPS-induced neurotoxicity in microglia cells. GRh2 significantly decreased the generation of nitric oxide production, and tumor necrosis factor-alpha, interleukin (IL)-6, IL 1beta, cyclooxygenase-2 and inducible nitric oxide synthase in LPS-induced activated microglia cells. Furthermore, GRh2 (20 and 50 MUM) significantly increased TGF-beta1 expression and reduced the expression of Smad. These results suggest that GRh2 effectively inhibits microglia activation and production of pro inflammatory cytokines via modulating the TGF-beta1/Smad pathway. PMID- 26738988 TI - Effects of RAGE-Specific Inhibitor FPS-ZM1 on Amyloid-beta Metabolism and AGEs Induced Inflammation and Oxidative Stress in Rat Hippocampus. AB - An increased level of advanced glycation end products (AGEs) is observed in brains of patients with Alzheimer's disease (AD). AGEs and receptor for AGEs (RAGE) play important roles in the pathogenesis of AD. FPS-ZM1 is a high-affinity RAGE-specific blocker that inhibits amyloid-beta binding to RAGE, neurological damage and inflammation in the APP(sw/0) transgenic mouse model of AD. FPS-ZM1 is not toxic to mice and can easily cross the blood-brain barrier. In this study, an AGEs-RAGE-activated rat model were established by intrahippocampal injection of AGEs, then these rats were treated with intraperitoneal administration of FPS-ZM1 and the possible neuroprotective effects were investigated. We found that AGEs administration induced an-regulation of Abeta production, inflammation, and oxidative stress, and an increased escape latency of rats in the Morris water maze test, all of these are significantly reduced by FPS-ZM1 treatment. Our results suggest that the AGEs-RAGE pathway is responsible for cognitive deficits, and therefore may be a potential treatment target. FPS-ZM1 might be a novel therapeutic agent to treat AD patients. PMID- 26738989 TI - A Time-Limited and Partially Reversible Model of Hypoganglionosis Induced by Benzalkonium Chloride Treatment. AB - Serosal application of benzalkonium chloride (BAC) has been previously applied to produce a model of aganglionosis; however, confusion remains regarding the extent of chemical ablation of enteric myenteric plexus after BAC treatment. The time sequence of BAC-induced effects on the myenteric plexus of the rat colon was determined and followed the morphologic changes. After sacrifice of animals 7, 14, 28, 56, 84 or 168 days postintervention, colonic tissue samples were removed, fixed in formalin, and cut into 5-MUm longitudinal sections for histological analysis. The neural analysis was used to re-evaluate BAC treatments for the appropriate model. Compared with rats in sham groups, rats in 0.1 %-30-min BAC group maintained only 15.27 +/- 4.80 % of ganglia per section in a 1-cm/5-MUm slice and 11.76 +/- 2.30 % of ganglionic cells after 28 days, the lower and stable number of ganglionic cells between Day 7 and 84 (from 11.67 +/- 2.10 to 19.05 +/- 5.10 %). Although an increase, ganglionic cell numbers did not recover at Day168 when compared with the numbers in sham groups. The results showed that characteristics of rats in the 0.1 %-30-min BAC group between Day 7 and 84 most closely kept in stable state, suggesting that these treatment parameters are ideal for producing a hypoganglia model of hypoganglionosis. PMID- 26738990 TI - Mexiletine and its Interactions with Classical Antiepileptic Drugs: An Isobolographic Analysis. AB - Using the mouse maximal electroshock test, the reference model of tonic-clonic seizures, the aim of the present study was to determine the type of interaction between mexiletine (a class IB antiarrhythmic drug) and classical antiepileptics: valproate, carbamazepine, phenytoin, and phenobarbital. Isobolographic analysis of obtained data indicated antagonistic interactions between mexiletine and valproate (for fixed ratio combinations of 1:1 and 3:1). Additivity was observed between mexiletine and valproate applied in proportion of 1:3 as well as between mexiletine and remaining antiepileptics for the fixed ratios of 1:3, 1:1, and 3:1. Neither motor performance nor long-term memory were impaired by mexiletine or antiepileptic drugs regardless of whether they were administered singly or in combination. Mexiletine did not significantly affected brain concentrations of carbamazepine, phenobarbital or phenytoin. In contrast, the antiarrhythmic drug decreased by 23 % the brain level of valproate. This could be, at least partially, the reason of antagonistic interaction between the two drugs. In conclusion, the observed additivity suggests that mexiletine can be safely applied in epileptic patients treated with carbamazepine, phenytoin or phenobarbital. Because of undesirable pharmacodynamics and pharmacokinetic interactions with valproate, mexiletine should not be used in such combinations. PMID- 26738991 TI - Upregulated P2X3 Receptor Expression in Patients with Intractable Temporal Lobe Epilepsy and in a Rat Model of Epilepsy. AB - Purinergic P2X3 receptors (P2X3Rs) play extensive roles in nerve cells in the central nervous system, particularly in hyperexcitability and calcium (Ca(2+)) influx. However, the role of P2X3Rs in epilepsy has not been previously investigated. To determine the relationship between P2X3Rs and epilepsy, the expression and cellular location of P2X3Rs in patients with intractable temporal lobe epilepsy (TLE) and in a lithium chloride-pilocarpine-induced chronic rat model of epilepsy were assessed. Furthermore, the function of P2X3Rs was assessed in vitro. Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were used to evaluate the expression levels of P2X3Rs in brain tissues from TLE patients and an epileptic rat model, whereas immunofluorescence labeling was applied to determine the distribution of target proteins. Whole-cell recording was subsequently performed to identify the influence of P2X3Rs on seizure-like discharges. P2X3Rs were located at the cell bodies and dendrites of neurons with significantly increased expression in the TLE patients and epileptic rat model. In vitro, P2X3R activation accelerated sustained repetitive firing, whereas P2X3R inhibition led to relatively low-frequency discharges. To the best of our knowledge, this is the first study provide evidence that upregulated P2X3R expression exists in both epileptic humans and rats and may aggravate the epileptic state in vitro. Thus, P2X3Rs may represent a novel therapeutic target for antiepileptic drugs. PMID- 26738992 TI - The Administration of Levocabastine, a NTS2 Receptor Antagonist, Modifies Na(+), K(+)-ATPase Properties. AB - Neurotensin behaves as a neuromodulator or as a neurotransmitter interacting with NTS1 and NTS2 receptors. Neurotensin in vitro inhibits synaptosomal membrane Na(+), K(+)-ATPase activity. This effect is prevented by administration of SR 48692 (antagonist for NTS1 receptor). The administration of levocabastine (antagonist for NTS2 receptor) does not prevent Na(+), K(+)-ATPase inhibition by neurotensin when the enzyme is assayed with ATP as substrate. Herein levocabastine effect on Na(+), K(+)-ATPase K(+) site was explored. For this purpose, levocabastine was administered to rats and K(+)-p-nitrophenylphosphatase (K(+)-p-NPPase) activity in synaptosomal membranes and [(3)H]-ouabain binding to cerebral cortex membranes were assayed in the absence (basal) and in the presence of neurotensin. Male Wistar rats were administered with levocabastine (50 MUg/kg, i.p., 30 min) or the vehicle (saline solution). Synaptosomal membranes were obtained from cerebral cortex by differential and gradient centrifugation. The activity of K(+)-p-NPPase was determined in media laking or containing ATP plus NaCl. In such phosphorylating condition enzyme behaviour resembles that observed when ATP hydrolyses is recorded. In the absence of ATP plus NaCl, K(+)-p-NPPase activity was similar for levocabastine or vehicle injected (roughly 11 MUmole hydrolyzed substrate per mg protein per hour). Such value remained unaltered by the presence of 3.5 * 10(-6) M neurotensin. In the phosphorylating medium, neurotensin decreased (32 %) the enzyme activity in membranes obtained from rats injected with the vehicle but failed to alter those obtained from rats injected with levocabastine. Levocabastine administration enhanced (50 %) basal [(3)H] ouabain binding to cerebral cortex membranes but failed to modify neurotensin inhibitory effect on this ligand binding. It is concluded that NTS2 receptor blockade modifies the properties of neuronal Na(+), K(+)-ATPase and that neurotensin effect on Na(+), K(+)-ATPase involves NTS1 receptor and -at least partially- NTS2 receptor. PMID- 26738993 TI - Integrating Rapid Diagnostics and Antimicrobial Stewardship in Two Community Hospitals Improved Process Measures and Antibiotic Adjustment Time. AB - OBJECTIVE To assess the impact of Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) mass spectrometry for rapid pathogen identification directly from early-positive blood cultures coupled with an antimicrobial stewardship program (ASP) in two community hospitals. Process measures and outcomes prior and after implementation of MALDI-TOF/ASP were evaluated. DESIGN Multicenter retrospective study. SETTING Two community hospitals in a system setting, Houston Methodist (HM) Sugar Land Hospital (235 beds) or HM Willowbrook Hospital (241 beds). PATIENTS Patients >= 18 years of age with culture-proven Gram-negative bacteremia. INTERVENTION Blood cultures from both hospitals were sent to and processed at our central microbiology laboratory. Clinical pharmacists at respective hospitals were notified of pathogen ID and susceptibility results. RESULTS We evaluated 572 patients for possible inclusion. After pre-defined exclusion criteria, 151 patients were included in the pre intervention group and 242 were included in the intervention group. After MALDI TOF/ASP implementation, the mean identification time after culture positivity was significantly reduced from 32 hours (+/-16 hours) to 6.5 hours (+/-5.4 hours) (P<.001); mean time to susceptibility results was significantly reduced from 48 (+/-22) hours to 23 (+/-14) hours (P<.001); and time to therapy adjustment was significantly reduced from 75 (+/-59) hours to 30 (+/-30) hours (P<.001). Mean hospital costs per patient were $3,411 less in the intervention group compared with the pre-intervention group ($18,645 vs $15,234; P=.04). CONCLUSION This study is the first to analyze the impact of MALDI-TOF coupled with an ASP in a community hospital setting. Time to results significantly differed with the use of MALDI-TOF, and time to appropriate therapy was significantly improved with the addition of ASP. PMID- 26738995 TI - Corrigendum: Plasmodium berghei ANKA causes intestinal malaria associated with dysbiosis. PMID- 26738996 TI - Turnover Intentions of Employees With Informal Eldercare Responsibilities: The Role of Core Self-Evaluations and Supervisor Support. AB - As longevity increases, so does the need for care of older relatives by working family members. This research examined the interactive effect of core self evaluations and supervisor support on turnover intentions in two samples of employees with informal caregiving responsibilities. Data were obtained from 57 employees from Australia (Study 1) and 66 employees from the United States and India (Study 2). Results of Study 1 revealed a resource compensation effect, that is, an inverse relationship between core self-evaluations and turnover intentions when supervisor care support was low. Results of Study 2 extended these findings by demonstrating resource boosting effects. Specifically, there was an inverse relationship between core self-evaluations and subsequent turnover intentions for those with high supervisor work and care support. In addition, employees' satisfaction and emotional exhaustion from their work mediated the inverse relationship between core self-evaluations and subsequent turnover intentions when supervisor work support and care support were high. Overall, these findings highlight the importance of employee- and supervisor-focused intervention strategies in organizations to support informal caregivers. PMID- 26738994 TI - Clinical features, Outcomes and Molecular Profiles of Drug Resistance in Tuberculous Meningitis in non-HIV Patients. AB - Tuberculous meningitis continues to be a serious problem for physicians because it is difficult to make an early diagnosis and the consequences of delaying treatment are severe. The objective of this study is to provide data for the optimization of diagnostic and timely treatment of tuberculous meningitis. Of the 401 human immunodeficiency virus (HIV)-negative tuberculous meningitis patients in our study, 332 were found to have an impaired blood brain barrier (82.8%). Nearly 17.0% of patients failed to be timely diagnosed. Headache (53.6%) and fever (48.6%) were the most common features, and Computed Tomography/Magnetic Resonance Imaging (CT/MRI) detected 96 patients (23.9%) with abnormal meningeal imaging. Cerebrospinal fluid real-time polymerase chain reaction was positive in 73.8% of the tuberculous meningitis patients, whereas, smears and cultures detected only 6.7% and 5.2%, respectively. Further analysis identified striking differences between drug-resistant and drug-susceptible tuberculous meningitis. Patients with drug resistance correlated with grave prognosis. Tuberculous meningitis diagnosis should overall embody clinical symptoms, laboratory and cerebral imaging findings, and more sensitive diagnostic approaches are still warranted. Our data suggest cerebrospinal fluid polymerase chain reaction for mycobacterial DNA and molecular drug susceptibility testing as routine assays for suspected tuberculous meningitis patients, and observation of the blood brain barrier function could be performed for individual management. PMID- 26738997 TI - Evaluating an Online Resourcefulness Training Intervention Pilot Test Using Six Critical Parameters. AB - Few resources are available to help grandmother caregivers to grandchildren manage their complex family situations that may have immediate and long-term consequences for themselves and their families. Resourcefulness training is an intervention designed to help grandmothers improve their ability to deal with these problems. The purpose of this pilot study was to evaluate the necessity, feasibility, acceptability, fidelity, safety, and effectiveness (i.e., effect sizes) of an online, computer-based resourcefulness training intervention that was adapted from a face-to-face intervention. Twelve grandmothers raising or living with grandchildren participated in the pilot intervention that included (a) watching an instructional video on resourcefulness, (b) completing two online questionnaires over a 6-week time period, and (c) writing in an online journal every day for 4 weeks. Data are evaluated within the context of the six parameters important to intervention development. Qualitative and quantitative results provide initial support for all six parameters. Recommendations to improve aspects of the intervention are discussed. PMID- 26738998 TI - "Death Is Better Than Misery": Elders' Accounts of Abuse and Neglect in Ethiopia. AB - As the proportion of elders in developing nations increases and the ability of families to meet their needs is stretched thin, the risk of elder abuse will grow. This study examined the types and nature of abuse and neglect from the perspective of elders in Ethiopia who experienced abuse in noninstitutional settings. A qualitative design guided by hermeneutic phenomenology was used to explore the lived experiences of abuse and neglect of 15 Ethiopian elders. Nine women and six men ranging in age from 64 to 93 years were interviewed. Most were victims of multiple forms of abuse, especially financial exploitation, emotional abuse, and neglect. Economic vulnerability was a clear underlying factor contributing to elders' risk for encountering abuse. Effective prevention efforts must address the societal level factors that ultimately contribute to elder abuse while also holding individuals responsible for their harmful behaviors against elders. PMID- 26739001 TI - Response to Dr. Palma's letter to the editor. PMID- 26738999 TI - eQTL analysis links inflammatory bowel disease associated 1q21 locus to ECM1 gene. AB - Genome-wide association studies (GWAS) have been highly successful in inflammatory bowel disease (IBD) with 163 confirmed associations so far. We used expression quantitative trait loci (eQTL) mapping to analyze IBD associated regions for which causative gene from the region is still unknown. First, we performed an extensive literature search and in silico analysis of published GWAS in IBD and eQTL studies and extracted 402 IBD associated SNPs assigned to 208 candidate loci, and 9562 eQTL correlations. When crossing GWA and eQTL data we found that for 50 % of loci there is no eQTL gene, while for 31.2 % we can determine one gene, for 11.1 % two genes and for the remaining 7.7 % three or more genes. Based on that we selected loci with one, two, and three or more eQTL genes and analyzed them in peripheral blood lymphocytes and intestine tissue samples of 606 Slovene patients with IBD and in 449 controls. Association analysis of selected SNPs showed statistical significance for three (rs2631372 and rs1050152 on 5q locus and rs13294 on 1q locus) out of six selected SNPs with at least one phenotype. Furthermore, with eQTL analysis of selected chromosomal regions, we confirmed a link between SNP and gene for four (SLC22A5 on 5q, ECM1 on 1q, ORMDL3 on 17q, and PUS10 on 2p locus) out of five selected regions. For 1q21 loci, we confirmed gene ECM1 as the most plausible gene from this region to be involved in pathogenesis of IBD and thereby contributed new eQTL correlation from this genomic region. PMID- 26739002 TI - Heterotypic seeding of Tau fibrillization by pre-aggregated Abeta provides potent seeds for prion-like seeding and propagation of Tau-pathology in vivo. AB - Genetic, clinical, histopathological and biomarker data strongly support Beta amyloid (Abeta) induced spreading of Tau-pathology beyond entorhinal cortex (EC), as a crucial process in conversion from preclinical cognitively normal to Alzheimer's Disease (AD), while the underlying mechanism remains unclear. In vivo preclinical models have reproducibly recapitulated Abeta-induced Tau-pathology. Tau pathology was thereby also induced by aggregated Abeta, in functionally connected brain areas, reminiscent of a prion-like seeding process. In this work we demonstrate, that pre-aggregated Abeta can directly induce Tau fibrillization by cross-seeding, in a cell-free assay, comparable to that demonstrated before for alpha-synuclein and Tau. We furthermore demonstrate, in a well-characterized cellular Tau-aggregation assay that Abeta-seeds cross-seeded Tau-pathology and strongly catalyzed pre-existing Tau-aggregation, reminiscent of the pathogenetic process in AD. Finally, we demonstrate that heterotypic seeded Tau by pre aggregated Abeta provides efficient seeds for induction and propagation of Tau pathology in vivo. Prion-like, heterotypic seeding of Tau fibrillization by Abeta, providing potent seeds for propagating Tau pathology in vivo, as demonstrated here, provides a compelling molecular mechanism for Abeta-induced propagation of Tau-pathology, beyond regions with pre-existing Tau-pathology (entorhinal cortex/locus coeruleus). Cross-seeding along functional connections could thereby resolve the initial spatial dissociation between amyloid- and Tau pathology, and preferential propagation of Tau-pathology in regions with pre existing 'silent' Tau-pathology, by conversion of a 'silent' Tau pathology to a 'spreading' Tau-pathology, observed in AD. PMID- 26739003 TI - Life in the clouds: are tropical montane cloud forests responding to changes in climate? AB - The humid tropics represent only one example of the many places worldwide where anthropogenic disturbance and climate change are quickly affecting the feedbacks between water and trees. In this article, we address the need for a more long term perspective on the effects of climate change on tropical montane cloud forests (TMCF) in order to fully assess the combined vulnerability and long-term response of tropical trees to changes in precipitation regimes, including cloud immersion. We first review the ecophysiological benefits that cloud water interception offers to trees in TMCF and then examine current climatological evidence that suggests changes in cloud base height and impending changes in cloud immersion for TMCF. Finally, we propose an experimental approach to examine the long-term dynamics of tropical trees in TMCF in response to environmental conditions on decade-to-century time scales. This information is important to assess the vulnerability and long-term response of TMCF to changes in cloud cover and fog frequency and duration. PMID- 26739004 TI - Clinical Relevance of Detection of HHV-6 by PCR DNA Test in the Blood for Diagnosing Myocarditis. PMID- 26739005 TI - Modified Technique to Create Diabolo Stent Configuration. AB - Diabolo stent configuration aids in stent positioning, stability, and creating a controlled defect with a predetermined size. A number of techniques to create the diabolo configuration have been previously described. The indications for creating a controlled "defect" are rapidly growing and include the Fontan circulation, patients with severe end-stage pulmonary hypertension, restrictive atrial communication in the setting of hypoplastic right or left heart syndrome, and diastolic left heart failure. We describe an alternative technique using a prefabricated readily available tool (gooseneck snare) to create a diabolo stent configuration. The chosen balloon expandable stent is mounted on a 5-mm gooseneck snare centered on an angioplasty catheter larger than 5 mm diameter. When deployed, the snare restricts the central waist to 5 mm and both ends expand to a larger diameter creating a dumbbell/diabolo configuration. A total of six diablo stent configurations were successfully implanted in four patients with failing Fontan physiology; five to create a transcatheter fenestration and one to relieve atrial septal restriction. Data expressed as median and IQR. Their weight was 24.8 kg (19.6-46.95), and age years was 9.2 (6.28-13.23). There were no complications and a consistent diabolo configuration with a 5-mm central waist was created in all patients. The snare serves as a sterile, preconfigured, radiopaque, readily available tool of adequate length and strength, to create consistent diabolo stent configuration without any modifications. This technique is a simple, reproducible, and easy to learn. PMID- 26739006 TI - Surgical Quality Predicts Length of Stay in Patients with Congenital Heart Disease. AB - Historically, the primary marker of quality for congenital cardiac surgery has been postoperative mortality. The purpose of this study was to determine whether additional markers (10 surgical metrics) independently predict length of stay (LOS), thereby providing specific targets for quality improvement. Ten metrics (unplanned ECMO, unplanned cardiac catheterization, revision of primary repair, delayed closure, mediastinitis, reexploration for bleeding, complete heart block, vocal cord paralysis, diaphragm paralysis, and change in preoperative diagnosis) were defined in 2008 and subsequently collected from 1024 consecutive index congenital cardiac cases, yielding 990 cases. Four patient characteristics and 22 case characteristics were used for risk adjustment. Univariate and multivariable analyses were used to determine independent associations between each metric and postoperative LOS. Increased LOS was independently associated with revision of the primary repair (p = 0.014), postoperative complete heart block requiring a permanent pacemaker (p = 0.001), diaphragm paralysis requiring plication (p < 0.001), and unplanned postoperative cardiac catheterization (p < 0.001). Compared with patients without each metric, LOS was 1.6 (95 % CI 1.1-2.2, p = 0.014), 1.7 (95 % CI 1.2-2.3, p = 0.001), 1.8 (95 % CI 1.4-2.3, p < 0.001), and 2.0 (95 % CI 1.7-2.4, p < 0.001) times as long, respectively. These effects equated to an additional 4.5-7.8 days in hospital, depending on the metric. The other 6 metrics were not independently associated with increased LOS. The quality of surgery during repair of congenital heart disease affects outcomes. Reducing the incidence of these 4 specific surgical metrics may significantly decrease LOS in this population. PMID- 26739007 TI - Analysis of cell-cell junctions in human amnion and chorionic plate affected by chorioamnionitis. AB - Chorioamnionitis is an acute inflammatory reaction associated with the premature rupture of the fetal membranes. It is caused mainly by invasion of bacteria from the vaginal tract that can penetrate the intact membranes and invade the amnion cavity and the decidua. Tight junctions (TJs) and adherent junctions (AJs) are intercellular junctions crucial for epithelia adhesion and permeability regulation in a wide variety of tissues and organs. Our aim is to investigate if TJ and AJ molecules are involved in human chorioamnionitis. We studied the protein expression (by immunohistochemistry and western blotting) and the mRNA levels (by RT-PCR) of some junction proteins such as Zonula Occludens-1 (ZO-1), occludin, VE-cadherin and beta-catenin in fetal membranes from women with chorioamnionitis compared to those membranes derived from idiopathic pregnancies. Western blotting and immunohistochemical data established that occludin expression was decreased in amnion with chorioamnionitis compared to amnion from idiopathic pregnancies. Samples tested for ZO-1, VE-cadherin and beta-catenin (proteins and mRNAs) showed no differences between idiopathic and pathological membranes. One of the most relevant results is the decrease of occludin in membranes with chorioamnionitis. Since we have previously demonstrated that some cytokines, particularly elevated in the chorioamnionitis, cause the disruption of TJs in placental villi, we suggest that the decrease of occludin in amnion may be the first change that leads to the rupture of the amniotic membrane in this pathology. PMID- 26739008 TI - Assessment of groundwater quality in the coastal area of Sindh province, Pakistan. AB - Groundwater is a highly important resource, especially for human consumption and agricultural production. This study offers an assessment of groundwater quality in the coastal areas of Sindh province in Pakistan. Fifty-six samples of groundwater were taken at depths ranging from 30 to 50 m. Bacteriological and physico-chemical analyses were performed using the Standard Methods for the Examination of Water and Wastewater. These were supplemented with expert interviews and observations to identify the usage of water and potential sources of pollution. The quality of the groundwater was found to be unsuitable for human consumption, despite being used for this purpose. The concentrations of sulfate and phosphate were well within the tolerance limits. Most critical were the high levels of organic and fecal pollution followed by turbidity and salinity. Metal concentrations (As, Ca, Cr, Cu, Fe, Mg, Mn, Ni, Pb, and Zn) were also determined, and Ni and Pb strongly exceeded health standards. The study stresses the need for significant improvements of the irrigation, sanitation, and sewage infrastructure. PMID- 26739009 TI - Economics, energy, and environmental assessment of diversified crop rotations in sub-Himalayas of India. AB - Reducing the carbon footprint and increasing energy use efficiency of crop rotations are the two most important sustainability issues of the modern agriculture. Present study was undertaken to assess economics, energy, and environmental parameters of common diversified crop rotations (maize-tomato, and maize-toria-wheat) vis-a-vis traditional crop rotations like maize-wheat, maize + ginger and rice-wheat of the north-western Himalayan region of India. Results revealed that maize-tomato and maize + ginger crop rotations being on par with each other produced significantly higher system productivity in terms of maize equivalent yield (30.2-36.2 t/ha) than other crop rotations (5.04-7.68 t/ha). But interestingly in terms of energy efficiencies, traditional maize-wheat system (energy efficiency 7.9, human energy profitability of 177.8 and energy profitability of 6.9 MJ/ha) was significantly superior over other systems. Maize + ginger rotation showed greater competitive advantage over other rotations because of less consumption of non-renewable energy resources. Similarly, maize tomato rotation had ability of the production process to exploit natural resources due to 14-38% less use of commercial or purchased energy sources over other crop rotations. Vegetable-based crop rotations (maize + ginger and maize tomato) maintained significantly the least carbon footprint (0.008 and 0.019 kg CO2 eq./kg grain, respectively) and the highest profitability (154,322 and 274,161 Rs./ha net return, respectively) over other crop rotations. As the greatest inputs of energy and carbon across the five crop rotations were nitrogen fertilizer (15-29% and 17-28%, respectively), diesel (14-24% and 8-19%, respectively) and irrigation (10-27% and 11-44%, respectively), therefore, alternative sources like organic farming, conservation agriculture practices, soil and water conservation measures, rain water harvesting etc. should be encouraged to reduce dependency of direct energy and external carbon inputs particularly in sub-Himalayas of India. PMID- 26739010 TI - Ecological stoichiometric characteristics and element reserves of three stands in a closed forest on the Chinese loess plateau. AB - Populus davidiana, Leuchtenbergia principis, and Pinus tabulaeformis are important greening tree species with a cosmopolitan distribution. However, the stoichiometric characteristics and element reserves of stands of these three species are not particularly clear. In this study, we conducted a plot-level investigation of forest stands of these species in the loess area; these have been closed forest stands more than 28 years. Trees were sampled from an area of 50 m * 20 m (in 6, 8, and 9 plots, respectively), which was sufficient for shrub (2 m * 2 m), herbal species, and litter (1 m * 1 m) investigations. The C, N, and P concentrations and the C:N:P stoichiometry in five different soil layers (0-10 cm, 10-20 cm, 20-30 cm, 30-50 cm, and 50-100 cm) and in the leaves, stems, branches, and roots of the plants were examined. The soil element concentrations and density were affected by soil depth. The element content had a significantly negative correlation with soil depth, and element density differed significantly among the soil layers. A particular element in a particular organ differed significantly between the forest stands, and the same element in different organs of the same stand was also significantly different. The C, N, and P element reserves in the soil were considerably higher than in the plants. Our results indicate that there are different stoichiometric characteristics and element reserves of the three stands in a closed forest on the Chinese loess plateau, which may provide a reference when we develop and optimize the structure of forest stands. PMID- 26739011 TI - Monitoring changes in landscape pattern: use of Ikonos and Quickbird images. AB - This paper aimed to analyze short-term changes in landscape pattern that primarily results from building development in the east coast of Mersin Province (Turkey). Three sites were selected. Ikonos (2003) and Quickbird (2009) images for these sites were classified, and land cover transformations were quantitatively analyzed using cross-tabulation of classification results. Changes in landscape structure were assessed by comparing the calculated values of area/edge and shape metrics for the earlier and later dates. Area/edge metrics included percentage of land and edge density, while shape metrics included perimeter-area ratio, fractal dimension, and related circumscribing circle (RCC) metrics. Orchards and buildings were dominating land cover classes. Variations in patch edge, size, and shapes were also analyzed and discussed. Degradation of prime agricultural areas due to building development and implications of such development on habitat fragmentation were highlighted. PMID- 26739012 TI - Effects of grafting on the cadmium accumulation characteristics of the potential Cd-hyperaccumulator Solanum photeinocarpum. AB - The effects of grafting on the cadmium (Cd) accumulation characteristics of the potential Cd-hyperaccumulator Solanum photeinocarpum were studied under Cd stress in our experiment. Four treatments were used in the experiment: ungrafted (UG), self-rooted grafting by the same S. photeinocarpum seedling (SG), self-rooted grafting by two different development stages of S. photeinocarpum seedlings (DG), and grafting on the rootstock of wild potato (PG). SG and DG decreased the root, scion stem, leaf, whole shoot, and whole plant biomasses compared with UG, but increased the rootstock stem biomass, while only PG increased the root and whole plant biomasses. SG and DG increased the Cd contents in the different organs of S. photeinocarpum compared with UG, while PG decreased the Cd content compared with UG. The Cd extraction by the whole plant of S. photeinocarpum was ranked as DG > SG > UG > PG. Additionally, the antioxidant enzyme activities in SG and DG were enhanced compared with UG, while that of PG was reduced compared with UG. The grafting increased the DNA methylation levels and changed the methylation patterns of S. photeinocarpum compared with UG. Therefore, SG and DG can increase the Cd accumulation in S. photeinocarpum, which can be used for the phytoremediation of Cd-contaminated soil. PMID- 26739013 TI - Efficacy study of olmesartan medoxomil on coronary atherosclerosis progression and epicardial adipose tissue volume reduction in patients with coronary atherosclerosis detected by coronary computed tomography angiography: study protocol for a randomized controlled trial. AB - BACKGROUND: Epicardial adipose tissue (EAT) is a newly discovered independent risk factor for coronary atherosclerosis. There is a scarcity of information on the reduction of EAT volume to reduce atherosclerosis risk. Coronary computed tomography angiography (CCTA) has emerged as a noninvasive imaging method for the analysis of coronary atherosclerosis and EAT volume. The purpose of this trial is to determine whether olmesartan medoxomil is effective at both treatment of coronary atherosclerosis progression and EAT volume reduction in patients with coronary atherosclerosis detected by CCTA. METHODS/DESIGN: This study is a prospective, single-center, open-label, randomized controlled clinical trial aimed at exploring the efficacy of olmesartan medoxomil on coronary atherosclerosis and EAT. A total of 194 patients with coronary stenosis greater than 30 % and less than 70 % detected by CCTA will be randomly divided into olmesartan medoxomil or conventional antihypertensive medication groups (1:1 ratio). The primary outcome measures include coronary atherosclerosis progression and EAT volume reduction, as detected by CCTA at 12 months. The secondary outcome measures include the levels of blood lipids, glucose, high-sensitivity C-reactive protein, IL-6, monocyte chemotactic protein 1, TNF-alpha, matrix metalloproteinase 9, NO, endothelin 1, adiponectin, and leptin at baseline and after 6 and 12 months. DISCUSSION: Treatments aimed at reducing EAT volume can eventually achieve an antiatherosclerotic effect. This is the first trial designed to explore the effect of olmesartan medoxomil on both coronary atherosclerosis progression and EAT volume reduction in patients with coronary atherosclerosis detected by CCTA. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02360956 . PMID- 26739016 TI - Severe hemolytic anemia caused by the NIPRO extracorporeal left ventricular assist device. AB - A 56-year-old woman with dilated cardiomyopathy underwent mitral and tricuspid annuloplasty, and simultaneous deployment of an extracorporeal left ventricular assist device (LVAD). Subsequently, she developed hemolytic anemia. Although the LVAD system was repeatedly exchanged and the mitral annular ring was removed, her hemolytic anemia did not improve. Finally, the NIPRO LVAD was replaced with Gyro Pump(r), and her anemia was ameliorated. It appears important to consider the possibility of hemolytic anemia as a LVAD-related complication, although it would be rare. PMID- 26739014 TI - Aspartyl Protease-Mediated Cleavage of BAG6 Is Necessary for Autophagy and Fungal Resistance in Plants. AB - The Bcl-2-associated athanogene (BAG) family is an evolutionarily conserved group of cochaperones that modulate numerous cellular processes. Previously we found that Arabidopsis thaliana BAG6 is required for basal immunity against the fungal phytopathogen Botrytis cinerea. However, the mechanisms by which BAG6 controls immunity are obscure. Here, we address this important question by determining the molecular mechanisms responsible for BAG6-mediated basal resistance. We show that Arabidopsis BAG6 is cleaved in vivo in a caspase-1-like-dependent manner and via a combination of pull-downs, mass spectrometry, yeast two-hybrid assays, and chemical genomics, we demonstrate that BAG6 interacts with a C2 GRAM domain protein (BAGP1) and an aspartyl protease (APCB1), both of which are required for BAG6 processing. Furthermore, fluorescence and transmission electron microscopy established that BAG6 cleavage triggers autophagy in the host that coincides with disease resistance. Targeted inactivation of BAGP1 or APCB1 results in the blocking of BAG6 processing and loss of resistance. Mutation of the cleavage site blocks cleavage and inhibits autophagy in plants; disease resistance is also compromised. Taken together, these results identify a mechanism that couples an aspartyl protease with a molecular cochaperone to trigger autophagy and plant defense, providing a key link between fungal recognition and the induction of cell death and resistance. PMID- 26739017 TI - Response to comments on to our published article entitled: 'Comparison of ProTaper, RaCe and Safesider instruments in the induction of dentinal microcracks: a micro-CT study'. PMID- 26739019 TI - Corrigendum. PMID- 26739018 TI - Critical appraisal of some methodological aspects of using micro-CT technology in the study of dentinal microcracks in endodontics. PMID- 26739022 TI - Rhizobium ipomoeae sp. nov., isolated from a water convolvulus field. AB - A bacterial strain, designated shin9-1T, was isolated from a water sample taken from a water convolvulus field in Taiwan and characterized using a polyphasic taxonomical approach. Cells of strain shin9-1T were aerobic, Gram-stain-negative, rod-shaped and surrounded by a thick capsule and formed cream-coloured colonies. Growth occurred at 10-45 degrees C (optimum, 30 degrees C), with 0-3.0% NaCl (optimum, 0.5%) and at pH 7.0-9.0 (optimum, pH 7.0). Strain shin9-1T did not form nodules on a legume plant, Macroptilium atropurpureum, and the nodulation genes nodA, nodC and the nitrogenase reductase gene nifH were not detected by PCR. Phylogenetic analyses based on 16S rRNA and three housekeeping gene sequences (recA, atpD and rpoB) showed that strain shin9-1T belonged to the genus Rhizobium. Strain shin9-1T had the highest level of 16S rRNA gene sequence similarity with respect to Rhizobium daejeonense L61T (97.6 %). The major fatty acid of strain shin9-1T was C18:1omega7c. The polar lipid profile consisted of phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, diphosphatidylglycerol, phosphatidylmonomethylethanolamine and several uncharacterized lipids. The DNA G+C content was 58.3 mol%. The DNA-DNA relatedness of strain shin9-1T with respect to recognized species of the genus Rhizobium was less than 70%. Phenotypic characteristics of the novel strain also differed from those of the most closely related species of the genus Rhizobium. On the basis of the phylogenetic inference and phenotypic data, strain shin9-1T should be classified as a representative of a novel species, for which the name Rhizobium ipomoeae sp. nov. is proposed. The type strain is shin9-1T (=LMG 27163T=KCTC 32148T). PMID- 26739023 TI - Anne Mackie: Optimistic, direct, and pragmatic. PMID- 26739025 TI - A novel TUBB3 mutation in a sporadic patient with asymmetric cortical dysplasia. AB - Recent advances in molecular technology have led to the discovery of several genes related to human malformations of cortical development (MCDs). The beta tubulin class III gene (TUBB3) was identified as a gene responsible for MCDs. Although mouse-model experiments have not revealed any findings of neuronal migration disorders, human TUBB3 mutations have been identified in patients with congenital fibrosis of the extraocular muscles. Since the discovery of a TUBB3 mutation, only 15 mutations have been identified. In this study, comprehensive mutation screening through next-generation sequencing identified a novel TUBB3 mutation (p.Ser230Leu) in a sporadic patient with moderate developmental delay associated with mild MCD. Compared to patients with the alpha-tubulin class 1a gene (TUBA1A) mutations, patients with TUBB3 mutations show milder phenotypic manifestations and milder MCD. Therefore, patients with milder MCD manifestations may be under-diagnosed, and TUBB3 mutations may be rarely identified. Additional genotype-phenotype information should be accumulated for further understanding of the TUBB3 functional relevance. PMID- 26739026 TI - Voluntary euthanasia is now legal in Quebec, says appeal court. PMID- 26739029 TI - Studies abound on how far north Ixodes scapularis ticks are transported by birds. AB - Several studies report migratory songbirds transporting ticks northward during spring migration in Canada. The blacklegged tick, Ixodes scapularis, has been documented on Neotropical songbirds as far as Slave Lake, Alberta during northbound spring migration. In addition, Ixodes ticks have been collected from passerine migrants as far north as Watson Lake, Yukon (north of 60th latitude). The presence of Amblyomma ticks parasitizing long-distance migrants, which are moving from wintering grounds in the Neotropics to breeding grounds in Canada, confirms Neotropical songbirds transport ixodid ticks into Canada. Our avian, tick-host studies document 22 species of ticks on wild birds in Canada, and the majority of these species are not indigenous in Canada. Some of these songbird transported ticks originate from as far south as Brazil. Clearly, passerine migrants transport ticks long distances into Canada during northward spring migration. The importation of ticks into Canada by migratory songbirds is no longer a "hypothesis," it is a fact. PMID- 26739028 TI - Uptake of services for prevention of mother-to-child transmission of HIV in a community cohort in rural Tanzania from 2005 to 2012. AB - BACKGROUND: Estimates of population-level coverage with prevention of mother-to child transmission (PMTCT) services are vital for monitoring programmes but are rarely undertaken. This study describes uptake of PMTCT services among HIV positive pregnant women in a community cohort in rural Tanzania. METHODS: Kisesa cohort incorporates demographic and HIV sero-surveillance rounds since 1994. Cohort data were linked retrospectively to records from four Kisesa clinics with PMTCT services from 2009 (HIV care and treatment clinic (CTC) available in one facility from 2008; referrals to city hospitals for PMTCT and antiretroviral treatment (ART) from 2005). The proportion of HIV-positive pregnant women residing in Kisesa in 2005-2012 who accessed PMTCT service components (based on linkage to facility records) was calculated per HIV-positive pregnancy and by year, with adjustments made to account for the sensitivity of the linkage algorithm. RESULTS: Out of 1497 HIV-positive pregnancies overall (to 849 women), 26% (n = 387/1497) were not linked to any facility records, 35% (n = 519/1497) registered for ANC but not HIV services (29% (n = 434/1497) were not tested at ANC or diagnosed previously), 8% (n = 119/1497) enrolled in PMTCT but not CTC services (6 % (n = 95/1497) received antiretroviral prophylaxis), and 32% (n = 472/1497) registered for CTC (14% (n = 204/1497) received ART or prophylaxis) (raw estimates). Adjusted estimates for coverage with ANC were 92%, 57% with HIV care, and 29 % with antiretroviral drugs in 2005-2012, trending upwards over time. CONCLUSIONS: Population-level coverage with PMTCT services was low overall, with weaknesses throughout the service continuum, but increased over time. Option B+ should improve coverage with antiretrovirals for PMTCT through simplified decisions for initiating ART, but will rely on strengthening access to CTC services. PMID- 26739030 TI - Serological and molecular evidence for spotted fever group Rickettsia and Borrelia burgdorferi sensu lato co-infections in The Netherlands. AB - Only a few reported cases indicate that Rickettsia helvetica and Rickettsia monacensis can cause disease in humans. Exposure to these two spotted fever group (SFG) rickettsiae occurs through bites of Ixodes ricinus, also the primary vector of Lyme borreliosis in Europe. To date, it is unclear how often exposure to these two microorganisms results in infection or disease. We show that of all the Borrelia burgdorferi s.l.-positive ticks, 25% were co-infected with rickettsiae. Predominantly R. helvetica was detected while R. monacensis was only found in approximately 2% of the ticks. In addition, exposure to tick-borne pathogens was compared by serology in healthy blood donors, erythema migrans (EM)-patients, and patients suspected of Lyme neuroborreliosis (LNB). As could be expected, seroreactivity against B. burgdorferi sensu lato was lower in blood donors (6%) compared to EM patients (34%) and suspected LNB cases (64%). Interestingly, seroreactivity against SFG Rickettsia antigens was not detected in serum samples from blood donors (0%), but 6% of the EM patients and 21% of the LNB suspects showed anti-rickettsial antibodies. Finally, the presence of B. burgdorferi s.l. and Rickettsia spp. in cerebrospinal fluid samples of a large cohort of patients suspected of LNB (n=208) was investigated by PCR. DNA of B. burgdorferi s.l., R. helvetica and R. monacensis was detected in seventeen, four and one patient, respectively. In conclusion, our data show that B. burgdorferi s.l. and SFG rickettsiae co-infection occurs in Dutch I. ricinus and that Lyme borreliosis patients, or patients suspected of Lyme borreliosis, are indeed exposed to both tick-borne pathogens. Whether SFG rickettsiae actually cause disease, and whether co-infections alter the clinical course of Lyme borreliosis, is not clear from our data, and warrants further investigation. PMID- 26739031 TI - Detection of Babesia venatorum, Anaplasma phagocytophilum and Candidatus Neoehrlichia mikurensis in Ixodes persulcatus ticks from Mongolia. AB - Information about the prevalence and geographical distribution of tick-borne pathogens Anaplasma phagocytophilum, Candidatus Neoehrlichia mikurensis, and Babesia spp. is still rare in Mongolia. We tested 275 Ixodes persulcatus ticks for A. phagocytophilum, Cand. N. mikurensis and Babesia spp. and 125 Dermacentor nuttalli ticks especially for Babesia spp. using different PCR methods. Ticks were collected from three provinces (Selenge, Arkhangai, Khentii) in Mongolia. DNA of A. phagocytophilum, Cand. N. mikurensis and Babesia spp. were found with a prevalence of 6.2%, 1.5% and 3.3% in each case in I. persulcatus ticks. This is the first time Cand. N. mikurensis was found in ticks from Mongolia. Sequence analysis of Babesia spp.-positive amplicons showed exclusively B. venatorum, which had also not been mentioned in Mongolia before. On the contrary, all D. nuttalli ticks tested negatively for Babesia spp. This study demonstrates that all three zoonotic pathogens are present in I. persulcatus ticks in Mongolia, and justify the need for further investigations of a more detailed genetic characterization of these pathogens. PMID- 26739033 TI - Brain regulation of appetite in twins. AB - BACKGROUND: Neural responses to highly energetic food cues are robust and are suppressed by eating. It is not known if neural responsiveness to food cues is an inherited trait and possibly even one that mediates the genetic influences on body weight that have been previously observed. OBJECTIVE: We investigated the inherited influence on brain responses to high-calorie visual food cues before and after a meal. DESIGN: With the use of a monozygotic twin study design, 21 healthy monozygotic twin pairs consumed a standardized breakfast and, 3.5 h later, underwent the first of 2 functional MRI (fMRI) scans with the use of visual food cues. After the first fMRI session, twins consumed a standardized meal, which was followed by the second fMRI. Serial ratings of appetite and food appeal were obtained. An ad libitum buffet was used to measure total caloric and macronutrient intakes. Intraclass correlations (ICCs) were used to test for inherited influences by comparing whether intrapair similarity was greater than interpair similarity. RESULTS: Body mass index was highly correlated within twin pairs (ICC: 0.96; P < 0.0001). ICCs also showed a strong intrapair similarity for the meal-induced change in hunger (ICC: 0.41; P = 0.03), fullness (ICC: 0.39; P = 0.04), and the appeal of fattening food (ICC: 0.57; P < 0.001). Twins ate a similar number of kilocalories at the buffet (ICC: 0.43; P = 0.02). Before the meal, the global brain activation across regions involved in satiety processing was not more similar in twins than in unrelated individuals. However, significant ICCs were present after the meal (ICC: 0.39; P = 0.04) and for the meal-induced change in activation by high-calorie visual food cues (ICC: 0.52; P < 0.01). CONCLUSION: Inherited factors influence both satiety perception and the effect of a meal to alter regional brain responses to images of highly energetic food. This trial was registered at clinicaltrials.gov as NCT02483663. PMID- 26739034 TI - Changes in plasma phosphate during in-patient treatment of children with severe acute malnutrition: an observational study in Uganda. AB - BACKGROUND: Children treated for severe acute malnutrition (SAM) are at risk of refeeding hypophosphatemia. Therapeutic diets have only recently become fortified with phosphorus to meet United Nations (UN) specifications, but to our knowledge no studies have investigated the effect. OBJECTIVE: The aim was to assess concentrations and correlates of plasma phosphate (P-phosphate) at admission and during treatment and to identify correlates of changes in P-phosphate. DESIGN: This was a prospective observational study in 6- to 59-mo-old children admitted for treatment of SAM to Mulago Hospital, Uganda. P-phosphate was measured at admission, on the second day of treatment with a therapeutic formula containing 75 kcal/100 mL and 560 mg phosphorus/L (F-75, Nutriset), at the start of the transition to a therapeutic formula containing 100 kcal/100 mL and 579 mg phosphorus/L (F-100; Nutriset), at day 2 of transition, and at discharge. RESULTS: Among 120 children, mean +/- SD P-phosphate at admission was 1.04 +/- 0.31 mmol/L and increased by 0.43 (95% CI: 0.35, 0.52) mmol/L during the first 2 d and more slowly toward discharge. Most (79%) children experienced their lowest P-phosphate concentration at admission, and none developed severe hypophosphatemia. P-phosphate was lowest in children with edema and with elevated C-reactive protein, and a lower increase was seen with increasing caretaker reported severity of illness. Partially or fully replacing F-75 with rice porridge (i.e., a local practice to reduce diarrhea) during the first 2 d of stabilization was associated with a 0.34-mmol/L (95% CI: 0.18, 0.50 mmol/L) lower increase in P-phosphate during the same first 2 d. CONCLUSIONS: F-75, which complies with UN specifications and provides 73 mg phosphorus . kg(-1) . d(-1) (130 mL . kg(-1) . d(-1)), seems to prevent refeeding hypophosphatemia in children with SAM. Replacing this formula with rice porridge during the first days of treatment to manage diarrhea may have an adverse effect on P-phosphate concentrations. This study was registered at http://www.isrctn.com as ISRCTN55092738. PMID- 26739035 TI - Egg consumption and risk of type 2 diabetes: a meta-analysis of prospective studies. AB - BACKGROUND: Observational data on the association between egg consumption and risk of type 2 diabetes mellitus (DM) have been inconsistent. Because eggs are a good source of protein and micronutrients and are inexpensive, it is important to clarify their role in the risk of developing DM. OBJECTIVE: We conducted a meta analysis of published prospective cohort studies to evaluate the relation of egg consumption with the risk of DM. DESIGN: We searched PubMed, Ovid, Cochrane, and Google Scholar (up to October 2015) to retrieve published studies. We used RRs from extreme categories of egg consumption for the main analysis but also evaluated dose response by using cubic splines and generalized least squares regression. RESULTS: We identified 12 cohorts for a total of 219,979 subjects and 8911 cases of DM. When comparing the highest with the lowest category of egg intake, pooled multivariate RRs of DM were 1.09 (95% CI: 0.99, 1.20) using the fixed-effect model and 1.06 (95% CI: 0.86, 1.30) using the random-effect model. There was evidence for heterogeneity (I(2) = 73.6%, P < 0.001). When stratified by geographic area, there was a 39% higher risk of DM (95% CI: 21%, 60%) comparing highest with lowest egg consumption in US studies (I(2) = 45.4%, P = 0.089) and no elevated risk of DM with egg intake in non-US studies (RR = 0.89; 95% CI: 0.79, 1.02 using the fixed-effect model, P < 0.001 comparing US with non US studies). In a dose-response assessment using cubic splines, elevated risk of DM was observed in US studies among people consuming >=3 eggs/wk but not in non US studies. CONCLUSIONS: Our meta-analysis shows no relation between infrequent egg consumption and DM risk but suggests a modest elevated risk of DM with >=3 eggs/wk that is restricted to US studies. PMID- 26739036 TI - Maternal anemia and risk of adverse birth and health outcomes in low- and middle income countries: systematic review and meta-analysis. AB - BACKGROUND: Anemia is a leading cause of maternal deaths and adverse pregnancy outcomes in developing countries. OBJECTIVES: We conducted a systematic review and meta-analysis to estimate the pooled prevalence of anemia, the association between maternal anemia and pregnancy outcomes, and the population-attributable fraction (PAF) of these outcomes that are due to anemia in low- and middle-income countries. DESIGN: PubMed, EMBASE, CINAHL, and the British Nursing Index were searched from inception to May 2015 to identify cohort studies of the association between maternal anemia and pregnancy outcomes. The anemic group was defined as having hemoglobin concentrations <10 or <11 g/dL or hematocrit values <33% or <34% depending on the study. A metaregression and stratified analysis were performed to assess the effects of study and participant characteristics on adverse pregnancy risk. The pooled prevalence of anemia in pregnant women by region and country-income category was calculated with the use of a random effects meta-analysis. RESULTS: Of 8182 articles reviewed, 29 studies were included in the systematic review, and 26 studies were included in the meta analysis. Overall, 42.7% (95% CI: 37.0%, 48.4%) of women experienced anemia during pregnancy in low- and middle-income countries. There were significantly higher risks of low birth weight (RR: 1.31; 95% CI: 1.13, 1.51), preterm birth (RR: 1.63; 95% CI: 1.33, 2.01), perinatal mortality (RR: 1.51; 95% CI: 1.30, 1.76), and neonatal mortality (RR: 2.72; 95% CI: 1.19, 6.25) in pregnant women with anemia. South Asian, African, and low-income countries had a higher pooled anemia prevalence than did other Asian and upper-middle-income countries. Overall, in low- and middle-income countries, 12% of low birth weight, 19% of preterm births, and 18% of perinatal mortality were attributable to maternal anemia. The proportion of adverse pregnancy outcomes attributable to anemia was higher in low-income countries and in the South Asian region. CONCLUSION: Maternal anemia remains a significant health problem in low- and middle-income countries. PMID- 26739037 TI - Prenatal supplementation with Corn Soya Blend Plus reduces the risk of maternal anemia in late gestation and lowers the rate of preterm birth but does not significantly improve maternal weight gain and birth anthropometric measurements in rural Cambodian women: a randomized trial. AB - BACKGROUND: Corn Soya Blend (CSB) Plus is a fortified dietary supplement used to help Cambodian women meet their nutritional requirements in pregnancy, although little is known about its ability to improve pregnancy outcomes. OBJECTIVE: This study assessed the effect of prenatal CSB Plus supplementation on birth weight and secondary outcomes of low birth weight (<2500 g), small for gestational age, birth length and head circumference, preterm birth (<37 wk), maternal weight gain, and anemia at 24-28 wk, 30-32 wk, and 36-38 wk of gestation among rural Cambodian women. DESIGN: A cluster-randomized trial was conducted in 75 villages in Kampong Chhnang Province, in which 547 women received CSB Plus (treatment) during the first trimester until delivery or continued their normal diet (control) based on their village residence. All women received routine daily iron folic acid tablets and were treated with additional iron folic acid if they were anemic (hemoglobin <11 g/dL). Cluster-adjusted linear mixed-effect and logistic regression models were used to examine group differences. RESULTS: There was no significant difference in birth weight between the CSB Plus and control group (46 g; 95% CI: -31, 123 g; P = 0.24). Significant reductions were observed in preterm birth (OR = 0.33; 95% CI: 0.12, 0.89) and anemia at 36-38 wk (OR = 0.51; 95% CI: 0.34, 0.77). There were no significant differences in low birth weight, small for gestational age, birth length, head circumference, or maternal weight gain. A higher rate of fetal loss was observed in the treatment group (10.2% compared with 3.7%; P < 0.01). CONCLUSIONS: In Cambodian women, CSB Plus consumed during pregnancy did not significantly increase maternal weight gain or improve birth size but did reduce maternal anemia in late gestation and preterm birth in comparison with women consuming a normal diet. The unexpectedly higher rate of fetal loss in the treatment group is concerning and warrants further investigation. This trial was registered at clinicaltrials.gov as NCT01413776. PMID- 26739038 TI - Short children with a low midupper arm circumference respond to food supplementation: an observational study from Burkina Faso. AB - BACKGROUND: The management of children with moderate acute malnutrition (MAM) is based on food supplementation in outpatient programs. When midupper arm circumference (MUAC) is used as the sole admission criterion, it is common practice to exclude children with lengths <67 cm from treatment. The WHO calls for research to determine the treatment effect among children with MAM included by MUAC and aged >=6 mo with lengths <67 cm. OBJECTIVE: We hypothesized that among children given supplementary feeding based on an MUAC of 115-124 mm as the sole criterion, there would be no difference in growth rate between children <67 cm and those >=67 cm in length at program admission. DESIGN: This was an observational study nested in a randomized trial that investigated the effectiveness of new formulations of corn-soy blend and lipid-based nutrient supplements. Children aged 6-23 mo were included if their MUAC was between 115 and 124 mm but with a weight-for-height z score (WHZ) >=-2. This cohort was divided into 2 groups by length at admission: <67 cm ("short") and >=67 cm ("long"). Linear mixed-effects models and regression models were used to compare gains in weight and MUAC while adjusting for intervention, season, sex, age, and site. RESULTS: Weight-gain velocity (expressed as g . kg(-1) . d(-1)) and MUAC gain velocity (expressed as 0.01 mm . cm(-1) . d(-1)) were not different between short and long children. Weight-gain velocity was slightly higher in the shortest quartile of length (P = 0.03), whereas there was no effect modification by stunting across length quartiles (P = 0.32). CONCLUSIONS: We found no evidence of a difference in percentage of weight gain or weight-gain velocity during supplementary feeding in short or long children aged 6-23 mo. We recommend a policy change to include children <67 cm in supplementary feeding programs if their MUAC is between 115 and 124 mm and their WHZ is >=-2. This could benefit millions of children currently excluded from supplementary feeding. This trial was registered at www.controlled-trials.com as ISRCTN42569496. PMID- 26739043 TI - Microfluidic processing of concentrated surfactant mixtures: online SAXS, microscopy and rheology. AB - We investigate the effect of microfluidic flow on the microstructure and dynamics of a model surfactant mixture, combining synchrotron Small Angle X-ray Scattering (SAXS), microscopy and rheology. A system comprising a single-chain cationic surfactant, hexadecyl trimethyl ammonium chloride (C16TAC), a short-chain alcohol (1-pentanol) and water was selected for the study due to its flow responsiveness and industrial relevance. Model flow fields, including sequential contraction expansion (extensional) and rotational flows, were investigated and the fluid response in terms of the lamellar d-spacing, orientation and birefringence was monitored in situ, as well as the recovery processes after cessation of flow. Extensional flows are found to result in considerable d-spacing increase (from approx 59 A to 65 A). However, under continuous flow, swelling decreases with increasing flow velocity, eventually approaching the equilibrium values at velocities ?2 cm s(-1). Through individual constrictions we observe the alignment of lamellae along the flow velocity, accompanied by increasing birefringence, followed by an orientation flip whereby lamellae exit perpendicularly to the flow direction. The resulting microstructures are mapped quantitatively onto the flow field in 2D with 200 MUm spatial resolution. Rotational flows alone do not result in appreciable changes in lamellar spacing and flow type and magnitude evidently impact the fluid microstructure under flow, as well as upon relaxation. The findings are correlated with rheological properties measured ex situ to provide a mechanistic understanding of the effect of flow imposed by tubular processing units in the phase behavior and performance of a model surfactant system with ubiquitous applications in personal care and coating industries. PMID- 26739042 TI - Construction of high resolution genetic linkage maps to improve the soybean genome sequence assembly Glyma1.01. AB - BACKGROUND: A landmark in soybean research, Glyma1.01, the first whole genome sequence of variety Williams 82 (Glycine max L. Merr.) was completed in 2010 and is widely used. However, because the assembly was primarily built based on the linkage maps constructed with a limited number of markers and recombinant inbred lines (RILs), the assembled sequence, especially in some genomic regions with sparse numbers of anchoring markers, needs to be improved. Molecular markers are being used by researchers in the soybean community, however, with the updating of the Glyma1.01 build based on the high-resolution linkage maps resulting from this research, the genome positions of these markers need to be mapped. RESULTS: Two high density genetic linkage maps were constructed based on 21,478 single nucleotide polymorphism loci mapped in the Williams 82 x G. soja (Sieb. & Zucc.) PI479752 population with 1083 RILs and 11,922 loci mapped in the Essex x Williams 82 population with 922 RILs. There were 37 regions or single markers where marker order in the two populations was in agreement but was not consistent with the physical position in the Glyma1.01 build. In addition, 28 previously unanchored scaffolds were positioned. Map data were used to identify false joins in the Glyma1.01 assembly and the corresponding scaffolds were broken and reassembled to the new assembly, Wm82.a2.v1. Based upon the plots of the genetic on physical distance of the loci, the euchromatic and heterochromatic regions along each chromosome in the new assembly were delimited. Genomic positions of the commonly used markers contained in BARCSOYSSR_1.0 database and the SoySNP50K BeadChip were updated based upon the Wm82.a2.v1 assembly. CONCLUSIONS: The information will facilitate the study of recombination hot spots in the soybean genome, identification of genes or quantitative trait loci controlling yield, seed quality and resistance to biotic or abiotic stresses as well as other genetic or genomic research. PMID- 26739040 TI - Stem Cell-Associated Marker Expression in Canine Hair Follicles. AB - Functional hair follicle (HF) stem cells (SCs) are crucial to maintain the constant recurring growth of hair. In mice and humans, SC subpopulations with different biomarker expression profiles have been identified in discrete anatomic compartments of the HF. The rare studies investigating canine HF SCs have shown similarities in biomarker expression profiles to that of mouse and human SCs. The aim of our study was to broaden the current repertoire of SC-associated markers and their expression patterns in the dog. We combined analyses on the expression levels of CD34, K15, Sox9, CD200, Nestin, LGR5 and LGR6 in canine skin using RT qPCR, the corresponding proteins in dog skin lysates, and their expression patterns in canine HFs using immunohistochemistry. Using validated antibodies, we were able to define the location of CD34, Sox9, Keratin15, LGR5 and Nestin in canine HFs and confirm that all tested biomarkers are expressed in canine skin. Our results show similarities between the expression profile of canine, human and mouse HF SC markers. This repertoire of biomarkers will allow us to conduct functional studies and investigate alterations in the canine SC compartment of different diseases, like alopecia or skin cancer with the possibility to extend relevant findings to human patients. PMID- 26739044 TI - Antibody Response to Hypervariable Region 1 Interferes with Broadly Neutralizing Antibodies to Hepatitis C Virus. AB - Hypervariable region 1 (HVR1) (amino acids [aa] 384 to 410) on the E2 glycoprotein of hepatitis C virus contributes to persistent infection by evolving escape mutations that attenuate binding of inhibitory antibodies and by blocking access of broadly neutralizing antibodies to their epitopes. A third proposed mechanism of immune antagonism is that poorly neutralizing antibodies binding to HVR1 interfere with binding of other superior neutralizing antibodies. Epitope mapping of human monoclonal antibodies (HMAbs) that bind to an adjacent, conserved domain on E2 encompassing aa 412 to 423 revealed two subsets, designated HC33 HMAbs. While both subsets have contact residues within aa 412 to 423, alanine-scanning mutagenesis suggested that one subset, which includes HC33.8, has an additional contact residue within HVR1. To test for interference of anti-HVR1 antibodies with binding of antibodies to aa 412 to 423 and other E2 determinants recognized by broadly neutralizing HMAbs, two murine MAbs against HVR1 (H77.16) and aa 412 to 423 (H77.39) were studied. As expected, H77.39 inhibited the binding of all HC33 HMAbs. Unexpectedly, H77.16 also inhibited the binding of both subsets of HC33 HMAbs. This inhibition also was observed against other broadly neutralizing HMAbs to epitopes outside aa 412 to 423. Combination antibody neutralization studies by the median-effect analysis method with H77.16 and broadly reactive HMAbs revealed antagonism between these antibodies. Structural studies demonstrated conformational flexibility in this antigenic region, which supports the possibility of anti-HVR1 antibodies hindering the binding of broadly neutralizing MAbs. These findings support the hypothesis that anti-HVR1 antibodies can interfere with a protective humoral response against HCV infection. IMPORTANCE: HVR1 contributes to persistent infection by evolving mutations that escape from neutralizing antibodies to HVR1 and by shielding broadly neutralizing antibodies from their epitopes. This study provides insight into a new immune antagonism mechanism by which the binding of antibodies to HVR1 blocks the binding and activity of broadly neutralizing antibodies to HCV. Immunization strategies that avoid the induction of HVR1 antibodies should increase the inhibitory activity of broadly neutralizing anti-HCV antibodies elicited by candidate vaccines. PMID- 26739045 TI - The Synthetic Antiviral Drug Arbidol Inhibits Globally Prevalent Pathogenic Viruses. AB - Arbidol (ARB) is a synthetic antiviral originally developed to combat influenza viruses. ARB is currently used clinically in several countries but not in North America. We have previously shown that ARB inhibits in vitro hepatitis C virus (HCV) by blocking HCV entry and replication. In this report, we expand the list of viruses that are inhibited by ARB and demonstrate that ARB suppresses in vitro infection of mammalian cells with Ebola virus (EBOV), Tacaribe arenavirus, and human herpesvirus 8 (HHV-8). We also confirm suppression of hepatitis B virus and poliovirus by ARB. ARB inhibited EBOV Zaire Kikwit infection when added before or at the same time as virus infection and was less effective when added 24 h after EBOV infection. Experiments with recombinant vesicular stomatitis virus (VSV) expressing the EBOV Zaire glycoprotein showed that infection was inhibited by ARB at early stages, most likely at the level of viral entry into host cells. ARB inhibited HHV-8 replication to a similar degree as cidofovir. Our data broaden the spectrum of antiviral efficacy of ARB to include globally prevalent viruses that cause significant morbidity and mortality. IMPORTANCE: There are many globally prevalent viruses for which there are no licensed vaccines or antiviral medicines. Some of these viruses, such as Ebola virus or members of the arenavirus family, rapidly cause severe hemorrhagic diseases that can be fatal. Other viruses, such as hepatitis B virus or human herpesvirus 8 (HHV-8), establish persistent infections that cause chronic illnesses, including cancer. Thus, finding an affordable, effective, and safe drug that blocks many viruses remains an unmet medical need. The antiviral drug arbidol (ARB), already in clinical use in several countries as an anti-influenza treatment, has been previously shown to suppress the growth of many viruses. In this report, we expand the list of viruses that are blocked by ARB in a laboratory setting to include Ebola virus, Tacaribe arenavirus, and HHV-8, and we propose ARB as a broad-spectrum antiviral drug that may be useful against hemorrhagic viruses. PMID- 26739046 TI - beta-Catenin, a Transcription Factor Activated by Canonical Wnt Signaling, Is Expressed in Sensory Neurons of Calves Latently Infected with Bovine Herpesvirus 1. AB - Like many Alphaherpesvirinae subfamily members, bovine herpesvirus 1 (BoHV-1) expresses an abundant transcript in latently infected sensory neurons, the latency-related (LR)-RNA. LR-RNA encodes a protein (ORF2) that inhibits apoptosis, interacts with Notch family members, interferes with Notch-mediated transcription, and stimulates neurite formation in cells expressing Notch. An LR mutant virus containing stop codons at the amino terminus of ORF2 does not reactivate from latency or replicate efficiently in certain tissues, indicating that LR gene products are important. In this study, beta-catenin, a transcription factor activated by the canonical Wnt signaling pathway, was frequently detected in ORF2-positive trigeminal ganglionic neurons of latently infected, but not mock infected, calves. Conversely, the lytic cycle regulatory protein (BoHV-1 infected cell protein 0, or bICP0) was not frequently detected in beta-catenin-positive neurons in latently infected calves. During dexamethasone-induced reactivation from latency, mRNA expression levels of two Wnt antagonists, Dickkopf-1 (DKK-1) and secreted Frizzled-related protein 2 (SFRP2), were induced in bovine trigeminal ganglia (TG), which correlated with reduced beta-catenin protein expression in TG neurons 6 h after dexamethasone treatment. ORF2 and a coactivator of beta-catenin, mastermind-like protein 1 (MAML1), stabilized beta catenin protein levels and stimulated beta-catenin-dependent transcription in mouse neuroblastoma cells more effectively than MAML1 or ORF2 alone. Neuroblastoma cells expressing ORF2, MAML1, and beta-catenin were highly resistant to cell death following serum withdrawal, whereas most cells transfected with only one of these genes died. The Wnt signaling pathway interferes with neurodegeneration but promotes neuronal differentiation, suggesting that stabilization of beta-catenin expression by ORF2 promotes neuronal survival and differentiation. IMPORTANCE: Bovine herpesvirus 1 (BoHV-1) is an important pathogen of cattle, and like many Alphaherpesvirinae subfamily members establishes latency in sensory neurons. Lifelong latency and the ability to reactivate from latency are crucial for virus transmission. Maintaining the survival and normal functions of terminally differentiated neurons is also crucial for lifelong latency. Our studies revealed that BoHV-1 gene products expressed during latency stabilize expression of the transcription factor beta catenin and perhaps its cofactor, mastermind-like protein 1 (MAML1). In contrast to expression during latency, beta-catenin expression in sensory neurons is not detectable following treatment of latently infected calves with the synthetic corticosteroid dexamethasone to initiate reactivation from latency. A viral protein (ORF2) expressed in a subset of latently infected neurons stabilized beta catenin and MAML1 in transfected cells. ORF2, beta-catenin, and MAML1 also enhanced cell survival when growth factors were withdrawn, suggesting that these genes enhance survival of latently infected neurons. PMID- 26739047 TI - Human Cytomegalovirus Stimulates the Synthesis of Select Akt-Dependent Antiapoptotic Proteins during Viral Entry To Promote Survival of Infected Monocytes. AB - Primary peripheral blood monocytes are responsible for the hematogenous dissemination of human cytomegalovirus (HCMV) following a primary infection. To facilitate viral spread, we have previously shown HCMV to extend the short 48-h life span of monocytes. Mechanistically, HCMV upregulated two specific cellular antiapoptotic proteins, myeloid leukemia sequence 1 (Mcl-1) and heat shock protein 27 (HSP27), to block the two proteolytic cleavages necessary for the formation of fully active caspase 3 and the subsequent initiation of apoptosis. We now show that HCMV more robustly upregulated Mcl-1 than normal myeloid growth factors and that Mcl-1 was the only myeloid survival factor to rapidly induce HSP27 prior to the 48-h cell fate checkpoint. We determined that HCMV glycoproteins gB and gH signal through the cellular epidermal growth factor receptor (EGFR) and alphavbeta3 integrin, respectively, during viral entry in order to drive the increase of Mcl-1 and HSP27 in an Akt-dependent manner. Although Akt is known to regulate protein stability and transcription, we found that gB- and gH-initiated signaling preferentially and cooperatively stimulated the synthesis of Mcl-1 and HSP27 through mTOR-mediated translation. Overall, these data suggest that the unique signaling network generated during the viral entry process stimulates the upregulation of select antiapoptotic proteins allowing for the differentiation of short-lived monocytes into long-lived macrophages, a key step in the viral dissemination strategy. IMPORTANCE: Human cytomegalovirus (HCMV) infection is endemic within the human population. Although primary infection is generally asymptomatic in immunocompetent individuals, HCMV is a significant cause of morbidity and mortality in the immunocompromised. The multiorgan inflammatory diseases associated with symptomatic HCMV infection are a direct consequence of the monocyte-mediated systemic spread of the virus. In order for peripheral blood monocytes to facilitate viral dissemination, HCMV subverts the short 48-h life span of monocytes by inducing the expression of cellular antiapoptotic proteins Mcl-1 and HSP27. Here, we demonstrate that the rapid and simultaneous upregulation of Mcl-1 and HSP27 is a distinctive feature of HCMV-induced monocyte survival. Moreover, we decipher the signaling pathways activated during viral entry needed for the robust synthesis of Mcl-1 and HSP27. Identifying the virus-specific mechanisms used to upregulate select cellular factors required for the survival of HCMV-infected monocytes is important to the development of new classes of anti-HCMV drugs. PMID- 26739048 TI - Leukocyte Immunoglobulin-Like Receptor 1-Expressing Human Natural Killer Cell Subsets Differentially Recognize Isolates of Human Cytomegalovirus through the Viral Major Histocompatibility Complex Class I Homolog UL18. AB - Immune responses of natural killer (NK) cell are controlled by the balance between activating and inhibitory receptors, but the expression of these receptors varies between cells within an individual. Although NK cells are a component of the innate immune system, particular NK cell subsets expressing Ly49H are positively selected and increase in frequency in response to cytomegalovirus infection in mice. Recent evidence suggests that in humans certain NK subsets also have an increased frequency in the blood of human cytomegalovirus (HCMV)-infected individuals. However, whether these subsets differ in their capacity of direct control of HCMV-infected cells remains unclear. In this study, we developed a novel in vitro assay to assess whether human NK cell subsets have differential abilities to inhibit HCMV growth and dissemination. NK cells expressing or lacking NKG2C did not display any differences in controlling viral dissemination. However, when in vitro-expanded NK cells were used, cells expressing or lacking the inhibitory receptor leukocyte immunoglobulin-like receptor 1 (LIR1) were differentially able to control dissemination. Surprisingly, the ability of LIR1(+) NK cells to control virus spread differed between HCMV viral strains, and this phenomenon was dependent on amino acid sequences within the viral ligand UL18. Together, the results here outline an in vitro technique to compare the long-term immune responses of different human NK cell subsets and suggest, for the first time, that phenotypically defined human NK cell subsets may differentially recognize HCMV infections. IMPORTANCE: HCMV infection is ubiquitous in most populations; it is not cleared by the host after primary infection but persists for life. The innate and adaptive immune systems control the spread of virus, for which natural killer (NK) cells play a pivotal role. NK cells can respond to HCMV infection by rapid, short-term, nonspecific innate responses, but evidence from murine studies suggested that NK cells may display long-term, memory-like responses to murine cytomegalovirus infection. In this study, we developed a new assay that examines human NK cell subsets that have been suggested to play a long-term memory-like response to HCMV infection. We show that changes in an HCMV viral protein that interacts with an NK cell receptor can change the ability of NK cell subsets to control HCMV while the acquisition of another receptor has no effect on virus control. PMID- 26739049 TI - The High Degree of Sequence Plasticity of the Arenavirus Noncoding Intergenic Region (IGR) Enables the Use of a Nonviral Universal Synthetic IGR To Attenuate Arenaviruses. AB - Hemorrhagic fever arenaviruses (HFAs) pose important public health problems in regions where they are endemic. Concerns about human-pathogenic arenaviruses are exacerbated because of the lack of FDA-licensed arenavirus vaccines and because current antiarenaviral therapy is limited to an off-label use of ribavirin that is only partially effective. We have recently shown that the noncoding intergenic region (IGR) present in each arenavirus genome segment, the S and L segments (S IGR and L-IGR, respectively), plays important roles in the control of virus protein expression and that this knowledge could be harnessed for the development of live-attenuated vaccine strains to combat HFAs. In this study, we further investigated the sequence plasticity of the arenavirus IGR. We demonstrate that recombinants of the prototypic arenavirus lymphocytic choriomeningitis virus (rLCMVs), whose S-IGRs were replaced by the S-IGR of Lassa virus (LASV) or an entirely nonviral S-IGR-like sequence (Ssyn), are viable, indicating that the function of S-IGR tolerates a high degree of sequence plasticity. In addition, rLCMVs whose L-IGRs were replaced by Ssyn or S-IGRs of the very distantly related reptarenavirus Golden Gate virus (GGV) were viable and severely attenuated in vivo but able to elicit protective immunity against a lethal challenge with wild type LCMV. Our findings indicate that replacement of L-IGR by a nonviral Ssyn could serve as a universal molecular determinant of arenavirus attenuation. IMPORTANCE: Hemorrhagic fever arenaviruses (HFAs) cause high rates of morbidity and mortality and pose important public health problems in regions where they are endemic. Implementation of live-attenuated vaccines (LAVs) will represent a major step to combat HFAs. Here we document that the arenavirus noncoding intergenic region (IGR) has a high degree of plasticity compatible with virus viability. This observation led us to generate recombinant LCMVs containing nonviral synthetic IGRs. These rLCMVs were severely attenuated in vivo but able to elicit protective immunity against a lethal challenge with wild-type LCMV. These nonviral synthetic IGRs can be used as universal molecular determinants of arenavirus attenuation for the rapid development of safe and effective, as well as stable, LAVs to combat HFA. PMID- 26739050 TI - Cellular Transcriptional Coactivator RanBP10 and Herpes Simplex Virus 1 ICP0 Interact and Synergistically Promote Viral Gene Expression and Replication. AB - To investigate the molecular mechanism(s) by which herpes simplex virus 1 (HSV-1) regulatory protein ICP0 promotes viral gene expression and replication, we screened cells overexpressing ICP0 for ICP0-binding host cell proteins. Tandem affinity purification of transiently expressed ICP0 coupled with mass spectrometry-based proteomics technology and subsequent analyses showed that ICP0 interacted with cell protein RanBP10, a known transcriptional coactivator, in HSV 1-infected cells. Knockdown of RanBP10 in infected HEp-2 cells resulted in a phenotype similar to that observed with the ICP0-null mutation, including reduction in viral replication and in the accumulation of viral immediate early (ICP27), early (ICP8), and late (VP16) mRNAs and proteins. In addition, RanBP10 knockdown or the ICP0-null mutation increased the level of histone H3 association with the promoters of these viral genes, which is known to repress transcription. These effects observed in wild-type HSV-1-infected HEp-2 RanBP10 knockdown cells or those observed in ICP0-null mutant virus-infected control HEp-2 cells were remarkably increased in ICP0-null mutant virus-infected HEp-2 RanBP10 knockdown cells. Our results suggested that ICP0 and RanBP10 redundantly and synergistically promoted viral gene expression by regulating chromatin remodeling of the HSV-1 genome for efficient viral replication. IMPORTANCE: Upon entry of herpesviruses into a cell, viral gene expression is restricted by heterochromatinization of the viral genome. Therefore, HSV-1 has evolved multiple mechanisms to counteract this epigenetic silencing for efficient viral gene expression and replication. HSV-1 ICP0 is one of the viral proteins involved in counteracting epigenetic silencing. Here, we identified RanBP10 as a novel cellular ICP0-binding protein and showed that RanBP10 and ICP0 appeared to act synergistically to promote viral gene expression and replication by modulating viral chromatin remodeling. Our results provide insight into the mechanisms by which HSV-1 regulates viral chromatin remodeling for efficient viral gene expression and replication. PMID- 26739052 TI - Requirement for the E1 Helicase C-Terminal Domain in Papillomavirus DNA Replication In Vivo. AB - The papillomavirus (PV) E1 helicase contains a conserved C-terminal domain (CTD), located next to its ATP-binding site, whose function in vivo is still poorly understood. The CTD is comprised of an alpha helix followed by an acidic region (AR) and a C-terminal extension termed the C-tail. Recent biochemical studies on bovine papillomavirus 1 (BPV1) E1 showed that the AR and C-tail regulate the oligomerization of the protein into a double hexamer at the origin. In this study, we assessed the importance of the CTD of human papillomavirus 11 (HPV11) E1 in vivo, using a cell-based DNA replication assay. Our results indicate that combined deletion of the AR and C-tail drastically reduces DNA replication, by 85%, and that further truncation into the alpha-helical region compromises the structural integrity of the E1 helicase domain and its interaction with E2. Surprisingly, removal of the C-tail alone or mutation of highly conserved residues within the domain still allows significant levels of DNA replication (55%). This is in contrast to the absolute requirement for the C-tail reported for BPV1 E1 in vitro and confirmed here in vivo. Characterization of chimeric proteins in which the AR and C-tail from HPV11 E1 were replaced by those of BPV1 indicated that while the function of the AR is transferable, that of the C-tail is not. Collectively, these findings define the contribution of the three CTD subdomains to the DNA replication activity of E1 in vivo and suggest that the function of the C-tail has evolved in a PV type-specific manner. IMPORTANCE: While much is known about hexameric DNA helicases from superfamily 3, the papillomavirus E1 helicase contains a unique C-terminal domain (CTD) adjacent to its ATP-binding site. We show here that this CTD is important for the DNA replication activity of HPV11 E1 in vivo and that it can be divided into three functional subdomains that roughly correspond to the three conserved regions of the CTD: an alpha helix, needed for the structural integrity of the helicase domain, followed by an acidic region (AR) and a C-terminal tail (C-tail) that have been shown to regulate the oligomerization of BPV1 E1 in vitro. Characterization of E1 chimeras revealed that, while the function of the AR could be transferred from BPV1 E1 to HPV11 E1, that of the C-tail could not. These results suggest that the E1 CTD performs multiple functions in DNA replication, some of them in a virus type-specific manner. PMID- 26739051 TI - Activation of RNase L by Murine Coronavirus in Myeloid Cells Is Dependent on Basal Oas Gene Expression and Independent of Virus-Induced Interferon. AB - The oligoadenylate synthetase (OAS)-RNase L pathway is a potent interferon (IFN) induced antiviral activity. Upon sensing double-stranded RNA, OAS produces 2',5' oligoadenylates (2-5A), which activate RNase L. Murine coronavirus (mouse hepatitis virus [MHV]) nonstructural protein 2 (ns2) is a 2',5'-phosphodiesterase (PDE) that cleaves 2-5A, thereby antagonizing RNase L activation. PDE activity is required for robust replication in myeloid cells, as a mutant of MHV (ns2(H126R)) encoding an inactive PDE fails to antagonize RNase L activation and replicates poorly in bone marrow-derived macrophages (BMM), while ns2(H126R) replicates to high titer in several types of nonmyeloid cells, as well as in IFN receptor deficient (Ifnar1(-/-)) BMM. We reported previously that myeloid cells express significantly higher basal levels of OAS transcripts than nonmyeloid cells. Here, we investigated the contributions of Oas gene expression, basal IFN signaling, and virus-induced IFN to RNase L activation. Infection with ns2(H126R) activated RNase L in Ifih1(-/-) BMM to a similar extent as in wild-type (WT) BMM, despite the lack of IFN induction in the absence of MDA5 expression. However, ns2(H126R) failed to induce RNase L activation in BMM treated with IFNAR1-blocking antibody, as well as in Ifnar1(-/-) BMM, both expressing low basal levels of Oas genes. Thus, activation of RNase L does not require virus-induced IFN but rather correlates with adequate levels of basal Oas gene expression, maintained by basal IFN signaling. Finally, overexpression of RNase L is not sufficient to compensate for inadequate basal OAS levels. IMPORTANCE: The oligoadenylate synthetase (OAS) RNase L pathway is a potent antiviral activity. Activation of RNase L during murine coronavirus (mouse hepatitis virus [MHV]) infection of myeloid cells correlates with high basal Oas gene expression and is independent of virus induced interferon secretion. Thus, our data suggest that cells with high basal Oas gene expression levels can activate RNase L and thereby inhibit virus replication early in infection upon exposure to viral double-stranded RNA (dsRNA) before the induction of interferon and prior to transcription of interferon stimulated antiviral genes. These findings challenge the notion that activation of the OAS-RNase L pathway requires virus to induce type I IFN, which in turn upregulates OAS gene expression, as well as to provide dsRNA to activate OAS. Our data further suggest that myeloid cells may serve as sentinels to restrict viral replication, thus protecting other cell types from infection. PMID- 26739053 TI - Characterization of Antibody Bipolar Bridging Mediated by the Human Cytomegalovirus Fc Receptor gp68. AB - The human cytomegalovirus glycoprotein gp68 functions as an Fc receptor for host IgGs and can form antibody bipolar bridging (ABB) complexes in which gp68 binds the Fc region of an antigen-bound IgG. Here we show that gp68-mediated endocytosis transports ABB complexes into endosomes, after which the complex is routed to lysosomes, presumably for degradation. These results suggest gp68 contributes to evasion of IgG-mediated immune responses by mediating destruction of host IgG and viral antigens. PMID- 26739054 TI - Deep Sequencing Reveals Potential Antigenic Variants at Low Frequencies in Influenza A Virus-Infected Humans. AB - Influenza vaccines must be frequently reformulated to account for antigenic changes in the viral envelope protein, hemagglutinin (HA). The rapid evolution of influenza virus under immune pressure is likely enhanced by the virus's genetic diversity within a host, although antigenic change has rarely been investigated on the level of individual infected humans. We used deep sequencing to characterize the between- and within-host genetic diversity of influenza viruses in a cohort of patients that included individuals who were vaccinated and then infected in the same season. We characterized influenza HA segments from the predominant circulating influenza A subtypes during the 2012-2013 (H3N2) and 2013 2014 (pandemic H1N1; H1N1pdm) flu seasons. We found that HA consensus sequences were similar in nonvaccinated and vaccinated subjects. In both groups, purifying selection was the dominant force shaping HA genetic diversity. Interestingly, viruses from multiple individuals harbored low-frequency mutations encoding amino acid substitutions in HA antigenic sites at or near the receptor-binding domain. These mutations included two substitutions in H1N1pdm viruses, G158K and N159K, which were recently found to confer escape from virus-specific antibodies. These findings raise the possibility that influenza antigenic diversity can be generated within individual human hosts but may not become fixed in the viral population even when they would be expected to have a strong fitness advantage. Understanding constraints on influenza antigenic evolution within individual hosts may elucidate potential future pathways of antigenic evolution at the population level. IMPORTANCE: Influenza vaccines must be frequently reformulated due to the virus's rapid evolution rate. We know that influenza viruses exist within each infected host as a "swarm" of genetically distinct viruses, but the role of this within-host diversity in the antigenic evolution of influenza has been unclear. We characterized here the genetic and potential antigenic diversity of influenza viruses infecting humans, some of whom became infected despite recent vaccination. Influenza virus between- and within-host genetic diversity was not significantly different in nonvaccinated and vaccinated humans, suggesting that vaccine-induced immunity does not exert strong selective pressure on viruses replicating in individual people. We found low-frequency mutations, below the detection threshold of traditional surveillance methods, in nonvaccinated and vaccinated humans that were recently associated with antibody escape. Interestingly, these potential antigenic variants did not reach fixation in infected people, suggesting that other evolutionary factors may be hindering their emergence in individual humans. PMID- 26739055 TI - Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection. AB - The cholesterol synthesis pathway is a ubiquitous cellular biosynthetic pathway that is attenuated therapeutically by statins. Importantly, type I interferon (IFN), a major antiviral mediator, also depresses the cholesterol synthesis pathway. Here we demonstrate that attenuation of cholesterol synthesis decreases gammaherpesvirus replication in primary macrophages in vitro and reactivation from peritoneal exudate cells in vivo. Specifically, the reduced availability of the intermediates required for protein prenylation was responsible for decreased gammaherpesvirus replication in statin-treated primary macrophages. We also demonstrate that statin treatment of a chronically infected host attenuates gammaherpesvirus latency in a route-of-infection-specific manner. Unexpectedly, we found that the antiviral effects of statins are counteracted by type I IFN. Our studies suggest that type I IFN signaling counteracts the antiviral nature of the subdued cholesterol synthesis pathway and offer a novel insight into the utility of statins as antiviral agents. IMPORTANCE: Statins are cholesterol synthesis inhibitors that are therapeutically administered to 12.5% of the U.S. POPULATION: Statins attenuate the replication of diverse viruses in culture; however, this attenuation is not always obvious in an intact animal model. Further, it is not clear whether statins alter parameters of highly prevalent chronic herpesvirus infections. We show that statin treatment attenuated gammaherpesvirus replication in primary immune cells and during chronic infection of an intact host. Further, we demonstrate that type I interferon signaling counteracts the antiviral effects of statins. Considering the fact that type I interferon decreases the activity of the cholesterol synthesis pathway, it is intriguing to speculate that gammaherpesviruses have evolved to usurp the type I interferon pathway to compensate for the decreased cholesterol synthesis activity. PMID- 26739056 TI - Prolactin Regulatory Element Binding Protein Is Involved in Hepatitis C Virus Replication by Interaction with NS4B. AB - It has been proposed that the hepatitis C virus (HCV) NS4B protein triggers the membranous HCV replication compartment, but the underlying molecular mechanism is not fully understood. Here, we screened for NS4B-associated membrane proteins by tandem affinity purification and proteome analysis and identified 202 host proteins. Subsequent screening of replicon cells with small interfering RNA identified prolactin regulatory element binding (PREB) to be a novel HCV host cofactor. The interaction between PREB and NS4B was confirmed by immunoprecipitation, immunofluorescence, and proximity ligation assays. PREB colocalized with double-stranded RNA and the newly synthesized HCV RNA labeled with bromouridine triphosphate in HCV replicon cells. Furthermore, PREB shifted to detergent-resistant membranes (DRMs), where HCV replication complexes reside, in the presence of NS4B expression in Huh7 cells. However, a PREB mutant lacking the NS4B-binding region (PREBd3) could not colocalize with double-stranded RNA and did not shift to the DRM in the presence of NS4B. These results indicate that PREB locates at the HCV replication complex by interacting with NS4B. PREB silencing inhibited the formation of the membranous HCV replication compartment and increased the protease and nuclease sensitivity of HCV replicase proteins and RNA in DRMs, respectively. Collectively, these data indicate that PREB promotes HCV RNA replication by participating in the formation of the membranous replication compartment and by maintaining its proper structure by interacting with NS4B. Furthermore, PREB was induced by HCV infection in vitro and in vivo. Our findings provide new insights into HCV host cofactors. IMPORTANCE: The hepatitis C virus (HCV) protein NS4B can induce alteration of the endoplasmic reticulum and the formation of a membranous web structure, which provides a platform for the HCV replication complex. The molecular mechanism by which NS4B induces the membranous HCV replication compartment is not understood. We screened for NS4B-associated membrane proteins by tandem affinity purification and proteome analysis, followed by screening with small interfering RNA. We identified prolactin regulatory element binding (PREB) to be a novel HCV host cofactor. PREB is induced by HCV infection and recruited into the replication complex by interaction with NS4B. Recruited PREB promotes HCV RNA replication by participating in the formation of the membranous HCV replication compartment. To our knowledge, the effect of NS4B-binding protein on the formation of the membranous HCV replication compartment is newly described in this report. Our findings are expected to provide new insights into HCV host cofactors. PMID- 26739058 TI - A Recombinant Adenovirus Expressing Ovine Interferon Tau Prevents Influenza Virus Induced Lethality in Mice. AB - Ovine interferon tau (IFN-tau) is a unique type I interferon with low toxicity and a broad host range in vivo. We report the generation of a nonreplicative recombinant adenovirus expressing biologically active IFN-tau. Using the B6.A2G Mx1 mouse model, we showed that single-dose intranasal administration of recombinant Ad5-IFN-tau can effectively prevent lethality and disease induced by highly virulent hv-PR8 influenza virus by activating the interferon response and preventing viral replication. PMID- 26739057 TI - Chaperone-Assisted Protein Folding Is Critical for Yellow Fever Virus NS3/4A Cleavage and Replication. AB - DNAJC14, a heat shock protein 40 (Hsp40) cochaperone, assists with Hsp70-mediated protein folding. Overexpressed DNAJC14 is targeted to sites of yellow fever virus (YFV) replication complex (RC) formation, where it interacts with viral nonstructural (NS) proteins and inhibits viral RNA replication. How RCs are assembled and the roles of chaperones in this coordinated process are largely unknown. We hypothesized that chaperones are diverted from their normal cellular protein quality control function to play similar roles during viral infection. Here, we show that DNAJC14 overexpression affects YFV polyprotein processing and alters RC assembly. We monitored YFV NS2A-5 polyprotein processing by the viral NS2B-3 protease in DNAJC14-overexpressing cells. Notably, DNAJC14 mutants that did not inhibit YFV replication had minimal effects on polyprotein processing, while overexpressed wild-type DNAJC14 affected the NS3/4A and NS4A/2K cleavage sites, resulting in altered NS3-to-NS3-4A ratios. This suggests that DNAJC14's folding activity normally modulates NS3/4A/2K cleavage events to liberate appropriate levels of NS3 and NS4A and promote RC formation. We introduced amino acid substitutions at the NS3/4A site to alter the levels of the NS3 and NS4A products and examined their effects on YFV replication. Residues with reduced cleavage efficiency did not support viral RNA replication, and only revertant viruses with a restored wild-type arginine or lysine residue at the NS3/4A site were obtained. We conclude that DNAJC14 inhibition of RC formation upon DNAJC14 overexpression is likely due to chaperone dysregulation and that YFV probably utilizes DNAJC14's cochaperone function to modulate processing at the NS3/4A site as a mechanism ensuring virus replication. IMPORTANCE: Flaviviruses are single stranded RNA viruses that cause a wide range of illnesses. Upon host cell entry, the viral genome is translated on endoplasmic reticulum (ER) membranes to produce a single polyprotein, which is cleaved by host and viral proteases to generate viral proteins required for genome replication and virion production. Several studies suggest a role for molecular chaperones during these processes. While the details of chaperone roles have been elusive, in this report we show that overexpression of the ER-resident cochaperone DNAJC14 affects YFV polyprotein processing at the NS3/4A site. This work reveals that DNAJC14 modulation of NS3/4A site processing is an important mechanism to ensure virus replication. Our work highlights the importance of finely regulating flavivirus polyprotein processing. In addition, it suggests future studies to address similarities and/or differences among flaviviruses and to interrogate the precise mechanisms employed for polyprotein processing, a critical step that can ultimately be targeted for novel drug development. PMID- 26739059 TI - Molecular chaperone CCT3 supports proper mitotic progression and cell proliferation in hepatocellular carcinoma cells. AB - CCT3 was one of the subunits of molecular chaperone CCT/TRiC complex, which plays a central role in maintaining cellular proteostasis. We demonstrated that expressions of CCT3 mRNA and protein are highly up-regulated in hepatocellular carcinoma (HCC) tissues, and high level of CCT3 is correlated with poor survival in cancer patients. In HCC cell lines, CCT3 depletion suppresses cell proliferation by inducing mitotic arrest at prometaphase and apoptosis eventually. We also identified CCT3 as a novel regulator of spindle integrity and as a requirement for proper kinetochore-microtubule attachment during mitosis. Moreover, we found that CCT3 depletion sensitizes HCC cells to microtubule destabilizing drug Vincristine. Collectively, our study suggests that CCT3 is indispensible for HCC cell proliferation, and provides a potential drug target for treatment of HCC. PMID- 26739060 TI - MMGZ01, an anti-DLL4 monoclonal antibody, promotes nonfunctional vessels and inhibits breast tumor growth. AB - Increasing evidence suggests that DLL4 (Delta-like 4)-Notch signaling plays a critical role in cell fate determination and differentiation in tissues. Blocking DLL4-Notch signaling results in inhibition of tumor growth, which is associated with increased nonfunctional vessels and poor perfusion in the tumor. We successfully generated a human DLL4 monoclonal antibody MMGZ01 that binds specifically to DLL4 to disrupt the interaction between DLL4 and Notch1. MMGZ01 showed high affinity to DLL4 to inhibit the DLL4-mediated human umbilical vein endothelial cell (HUVEC) phenotype. Furthermore, MMGZ01 stimulated HUVEC vessel sprouting and tubule formation in vitro. In addition, MMGZ01 had a pronounced effect in promoting immature vessels and reduced breast cancer cell growth in vivo. Finally, MMGZ01 treatment inhibited the proliferation of breast cancer cells, induced tumor cell apoptosis, suppressed mammosphere formation, decreased CD44(+)/CD24(-) cell population, and reduced epithelial mesenchymal transition (EMT). These findings suggest that antagonism of the DLL4-Notch signaling pathway might provide a potential therapeutic approach for breast cancer treatment. PMID- 26739061 TI - Astemizole-Histamine induces Beclin-1-independent autophagy by targeting p53 dependent crosstalk between autophagy and apoptosis. AB - Apoptosis and autophagy are genetically regulated, evolutionarily conserved processes that can jointly seal cancer cell fates, and numerous death stimuli are capable of activating either pathway. Although crosstalk between apoptosis and autophagy is quite complex and sometimes contradictory, it remains a key factor determining the outcomes of death-related pathologies such as cancer. In the present study, exposure of MCF-7 breast cancer cells to HIS and the H1 receptor antagonist AST both alone and together with HIS (AST-HIS) led to generation of intracellular ROS, which induced massive cellular vacuolization through dilation of the ER and mitochondria. Consequently, apoptosis by Bax translocation, cytochrome c release, and caspase activation were triggered. In addition, AST-HIS caused ER stress-induced autophagy in MCF-7 cells, as evidenced by an increased LC3-II/LC3-I ratio, with surprisingly no changes in Beclin-1 expression. Non canonical autophagy was induced via p53 phosphorylation, which increased p53-p62 interactions to enhance Beclin-1-independent autophagy as evidenced by immunocytochemistry and immunoprecipitation. In the absence of Beclin-1, enhanced autophagy further activated apoptosis through caspase induction. In conclusion, these findings indicate that AST-HIS-induced apoptosis and autophagy can be regulated by ROS-mediated signaling pathways. PMID- 26739062 TI - Commensal bacteria modulate the tumor microenvironment. AB - It has been recently shown that gut microbes modulate whole host immune and hormonal factors impacting the fate of distant preneoplastic lesions toward malignancy or regression. This raises the possibility that the tumor microenvironment interacts with broader systemic microbial-immune networks. These accumulated findings suggest novel therapeutic opportunities for holobiont engineering in emerging tumor microenvironments. PMID- 26739065 TI - Glycyrrhetinic acid inhibits contact hypersensitivity induced by trichophytin via dectin-1. AB - Trichophyton infection is highly prevalent and tends to be recurrent. Therefore, it is important to develop new therapeutic agents. Previously, we established a mouse model of Trichophyton-induced contact hypersensitivity (CHS) and demonstrated that dectin-1 was involved in inflammation induced by trichophytin, the Trichophyton antigen. Here, we used that model to investigate glycyrrhetinic acid (GA) from plants of the genus Glycyrrhiza as a potential anti-inflammatory agent against superficial mycoses. GA suppressed swelling and the expression of inflammatory cytokines, including macrophage inflammatory protein (MIP)-2, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma mRNA. Anti-MIP-2 antibody suppressed trichophytin-induced inflammation, and antidectin-1 antibody suppressed zymosan-induced MIP-2 production in keratinocyte cells. These results suggest that MIP-2 is produced by dectin-1 activation and is involved in inflammation associated with CHS to trichophytin. GA also suppressed zymosan-induced MIP-2 and interleukin (IL)-8, production in mouse and human macrophages and keratinocytes. Furthermore, GA suppressed the phosphorylation of spleen tyrosine kinase (Syk) and inhibitor of nuclear factor-kappa B (IkappaBalpha) and the degradation of IkappaBalpha in zymosan-simulated RAW264.7 cells. The results of this study suggest that GA suppresses inflammation induced by trichophytin, partly by the downregulation of Syk phosphorylation. PMID- 26739063 TI - LMTK3 escapes tumour suppressor miRNAs via sequestration of DDX5. AB - Lemur tyrosine kinase-3 (LMTK3) plays an important role in cancer progression and is associated with breast, lung, gastric and colorectal cancer. MicroRNAs (miRNAs) are small endogenous non-coding RNAs that typically repress target genes at post-transcriptional level and have an important role in tumorigenesis. By performing a miRNA expression profile, we identified a subset of miRNAs modulated by LMTK3. We show that LMTK3 induces miR-34a, miR-196-a2 and miR-182 levels by interacting with DEAD-box RNA helicase p68 (DDX5). LMTK3 binds via DDX5 to the pri-miRNA of these three mature miRNAs, thereby sequestrating them from further processing. Ectopic expression of miR-34a and miR-182 in LMTK3-overexpressing cell lines (MCF7-LMTK3 and MDA-MB-231-LMTK3) inhibits breast cancer proliferation, invasion and migration. Interestingly, miR-34a and miR-182 directly bind to the 3'UTR of LMTK3 mRNA and consequently inhibit both its stability and translation, acting as tumour suppressor-like miRNAs. In aggregate, we show that LMTK3 is involved in miRNA biogenesis through modulation of the Microprocessor complex, inducing miRNAs that target LMTK3 itself. PMID- 26739067 TI - Molecular detection of Porcine astrovirus in Sichuan Province, China. AB - BACKGROUND: Porcine astrovirus (PoAstV) is widely distributed worldwide, and is highly prevalent among piglets with or without diarrhea, existing as at least five distinct lineages (PoAstV1-PoAstV5) within the genus Mamastrovirus. However, our knowledge of the diversity and epidemiology of PoAstV in China is limited. RESULTS: In this study, fecal samples from 21/120 (17.5 %) domestic pigs, including 18/100 (18 %) diarrheic and 3/20 (15 %) healthy pigs, and from 1/9 (11.1 %) healthy wild boars tested in Sichuan Province were positive for PoAstV on reverse transcription-PCR. Of the 22 positive samples, 13.6 % were positive for PoAstV only, whereas 40.9 % also contained Porcine epidemic diarrhea virus (PEDV), 22.7 % also contained porcine group A rotavirus (PRoVA), and 22.7 % also contained PEDV and PRoVA. A phylogenetic analysis of the RdRp gene revealed genetic heterogeneity among the PoAstV sequences and two lineages were detected in this study, with PoAstV-2 predominant. PoAstV-5 was detected in wild boars for the first time. CONCLUSIONS: PoAstV infections exist in Sichuan Province regardless of the disease status in the pig population, either alone or in combination with other enteric viruses, and may be associated with diarrhea. PMID- 26739068 TI - L10P mutation in DJ-1 gene induced oxidative stress and mitochondrial disfunction. AB - OBJECTIVE: To investigate the effect of the L10P mutation on the cellular mitochondrial disfunction. METHODS: Spectrophotometer, flow cytometry and electron microscope was utilized to examine cell viability, reactive oxygen species (ROS), mitochondrial transmembrane potential, complex I activity and mitochondrial morphous of the HEK293 monoclone cell lines, in which wild-type and L10P mutant DJ-1 protein are stably expressed. RESULTS: Compared with the cell lines expressing empty vector, we found the ROS levels were elevated, the cell viability, mitochondrial transmembrane potential, complex I activity were reduced in the cells expressing L10P mutant DJ-1 protein (P<0.05). We also found mitochondria in these cells were swelling and some mitochondria were vacuolar degeneration. These phenomena were more obvious when rotenone was used. But in the cells expressing wild-type DJ-1, ROS levels were lower, the cell viability, mitochondrial transmembrane potential, and complex I activity were higher than other cell lines (P<0.05), especially under the induction of rotenone. These results suggested that L10P mutant DJ-1 protein probably lost the ability of anti oxidative stress and affect the normal function of mitochondria. CONCLUSION: The L10P DJ-1 mutation results in a toxic protein, which lacks the protective function of wild-type protein on mitochondria due to the decrease in the ability of anti-oxidative stress. PMID- 26739069 TI - [Ceramide participates in cell programmed death induced by Type II anti-CD20 mAb]. AB - OBJECTIVE: To explore the exact mechanisms of programmed cell death (PCD) induced by Type II anti-CD20 mAb in CD20+ non-Hodgkin lymphoma (NHL) cells, and to provide theoretical basis for anti-tumor ability of new CD20 mAb.? METHODS: After incubation with Rituximab (a Type I anti-CD20 mAb) and Tositumomab (a Type II anti-CD20 mAb), Raji cells were stained by annexin V & propidium iodide (PI). The ratio of programmed death cells were measured by two channel flow cytometry (FCM). Before the treatment of anti-CD20 mAbs, Raji cells was incubated with a caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone (Z-VAD-FMK) and a dihydroceramide synthase inhibitor fumonisin B1 (FB1) for 30 minutes to assess their inhibitory effect on PCD. High performance liquid chromatography (HPLC) was utilized to compare the ratio of programmed death cells between the pretreatment group (treated by Rituximab and Tositumomab) and the non-pretreatment group. The anti-CD20 mAbs-treated Raji cells were collected, and the ceramide levels in the Raji cells in the different pretreatment groups were also examined by HPLC, and the inhibitory effect of FB1 on the changes of ceramide levels in the Raji cells was measured. The Raji cells were incubated with different concentration C2-ceramide, C2-Ceramide-induced PCD was also evaluated by annexin V & PI staining after 16 hours. ? RESULTS: Tositumomab (10 ug/mL) but not Rituximab (10 ug/mL) can induce significant PCD (28.6+/-4.2)% in Raji cells, with significant difference (t=26.48, P<0.01), which cannot be blocked by Z-VAD-FMK with a concentration range from 10 to 30 umol/L (F=3.01, P>0.05). The cellular ceramide levels in Raji cells were significantly elevated after the treatment of Tositumomab (t=28.48, P<0.01). C2-ceramide can significantly induce PCD in Raji cells in a dose-dependent manner with a concentration range from 5 to 40 umol/L (F=2.71, P>0.05). The dihydroceramide synthase inhibitor FB1 can significantly inhibit the elevated cellular ceramide levels (F=20.18, P<0.01) and cell programmed death induced by Tositumomab (F=17.02, P<0.01).? CONCLUSION: Type II but not Type I anti-CD20 mAbs can induce caspase independent PCD in CD20+ NHL cells through the elevation of cellular ceramide levels. The PCD is not associated with classic caspase pathway. PMID- 26739070 TI - [Potentiation of cisplatin induced apoptosis by low molecular weight heparin in human hepatocellular carcinoma cell]. AB - OBJECTIVE: To explore the effects of low molecular weight heparin (LMWH) on cisplatin (DDP)- induced apoptosis in human hepatocellular carcinoma cell and the underlying mechanisms.? METHODS: Hepatocellular carcinoma SMMC-7721 cells were divided into a control group, a LMWH group, a DDP group and a LMWH plus DDP group. The effect of the drugs on proliferation of hepatocellular carcinoma SMMC 7721 cells were evaluated by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) assay, and the apoptosis were detected by acridine orange/ethidium bromide (AO/EB) double fluorescence method and flow cytometry method. The expression levels of apoptosis-related protein Fas, Bcl-2 and Bax were detected by quantitative real-time PCR and Western blot.? RESULTS: Compared with the control group, the proliferation of SMMC-7721 cells was inhibited in the DDP group and the LMWH plus DDP group (both P<0.05). The mRNA and protein levels of Fas, Bcl-2, Bax in the SMMC-7721 cells were not obviously changed in the LMWH group (all P>0.05). The Fas level was increased obviously (P<0.05), while the Bcl 2 level moderately reduced (P<0.05), Bax were not obviously changed in the DDP group (P>0.05). Compared with the control group and the DDP group, the Bcl-2 level was reduced significantly in the LMWH plus DDP group (both P<0.05), while the level of Bax was increased obviously (both P<0.05). Compared with control group, the Fas level was increased significantly in the LMWH plus DDP group (P<0.05), but the increase was not significant compared with the DDP group (P>0.05).? CONCLUSION: LMWH can enhance the cisplatin-induced apoptosis in SMMC 7721 cells, which might be related to activation of mitochondrial pathway. PMID- 26739071 TI - [Expression of Maspin in bladder carcinoma and the relationship between Maspin and lymph node metastasis]. AB - OBJECTIVE: To examine the expression of Maspin in the bladder carcinoma, and to explore the relationship among Maspin expression, clinical pathology and lymph node metastasis.? METHODS: The expression of Maspin in 72 bladder cancer tissues and 12 normal bladder tissues were detected by immunohistochemistry. Preoperative pelvic CT images and postoperative pathological results of lymph node metastasis in 72 bladder cancer patients were analyzed retrospectively. The sensibility, specificity, positive predictive value and negative predictive value were calculated, and the advantage for diagnosis of lymph node metastasis was compared between Maspin examination and CT scan.? RESULTS: 1) The expression of Maspin in 72 bladder cancer tissues was significantly lower than that in the normal bladder tissues (P<0.05); 2) The expression of Maspin was obviously decreased with the progress in clinical stage, pathlogical grade and lymph node metastasis, with significant difference (all P<0.05); 3) There were 27 patients diagnosed as pelvic lymph node metastasis by CT scan, and the positive rate was 37.5% (27/72); there were 22 patients diagnosed as pelvic lymph node metastasis by pathological results, and the positive rate was 30.5% (22/72). The pathological diagnose for pelvic lymph node metastasis was the gold standard. The sensitivity, specificity, positive predictive value and negative predictive value for CT was 45.5%, 73.3%, 37.0%, and 66.7%, respectively; the sensibility, specificity, positive predictive value and negative predictive value was 81.8%, 50%, 41.8% and 86.2% in the diagnosis of lymph node metastasis for the 72 bladder cancer cases by Maspin examination; the sensitivity, specificity, positive predictive value and negative predictive was 90.9%, 78.0%, 64.5% and 95.0% in the diagnose of lymph node metastasis by Maspin examination combined with CT scan.? CONCLUSION: The expression of Maspin in bladder cancer is significantly lower than that in normal bladder cancer, and a statistically significant correlation is also observed between Maspin expression and lymph node metastasis. Maspin maybe a valuable biomarker in diagnose of bladder cancer with lymph node metastasis. Maspin examination combined with CT scan has more advantage in the evaluation of bladder cancer with lymph node metastasis than Maspin or CT alone. PMID- 26739072 TI - [Role of NF-kappaB p65 and p38 MAPK in lung injury in rats suffered chronic intermittent hypoxia]. AB - OBJECTIVE: To explore the role of NF-kappaB p65 and p38 MAPK in lung injury in rats suffered chronic intermittent hypoxia.? METHODS: Experiment were divided into a control group and a hypoxia group (n=20). After 5 weeks of hypoxia treatment, the expression of NF-kappaB p65 and p38 MAPK in lung tissues of rats were detected by optical microscope and immunohistochemical techniques and Western blot.? RESULTS: Pathological examination showed pulmonary interval thickness was (0.45 +/- 0.12) MUm and (2.15 +/- 0.49) MUm in the control and hypoxia group, respectively (P<0. 05). Compared with the control group, the levels of both NF-kappaB p65 and p38 MAPK were increased in the hypoxia group (P<0. 01), which were confirmed by Western blot.? CONCLUSION: NF-kappaB p65 and p38 MAPK may play important roles in lung injury reconstruction in of the rats treated by chronic intermittent hypoxia. PMID- 26739073 TI - [Effects of Faecalibacterium prausnitzii supernatant on Th17 cell and IL-17A in dextran sulfate sodium-induced ulcerative colitis mice]. AB - OBJECTIVE: To explore the protective and therapeutic effects of Faecalibacterium prausnitzii (Fp) supernatant on ulcerative colitis (UC) in mice induced by dextran sulfate sodium (DSS) and the underlying mechanisms.? METHODS: Forty male mice were randomly divided into a control group, a model group, a treatment group and a prevention group (n=10 in each group). The colorectal histopathologic damage score (HDS) were calculated; the proportion of helper T cell (Th17) in mononuclear cells (MNC) in spleen, the levels of IL-17A and IL-6 in plasma were detected; the mRNA levels of transcription factor retinoic acid-related orphan receptor-gammat (ROR-gammat), interleukin (IL)-17A and IL-6 in colon mucosa tissues were also determined.? RESULTS: Compared with the model group, the colon HDS in the treatment group and the prevention group were significantly decreased (both P<0.05), but there was no significant difference in the treatment group and the prevention group (P>0.05). The proportion of Th17 cells in spleen in the treatment group and the prevention group was also remarkably lower than that in the model group (both P<0.01). The levels of IL-17A and IL-6 in plasma in the treatment group were significantly lower than those in the model group (both P<0.05). The mRNA expression of ROR-gammat, IL-17A and IL-6 in the colon mucosa tissues in the treatment group were remarkably lower than those in the model group (all P<0.05). But there was no statistic difference in the level of IL-6 in the plasma and the colon mucosa tissues between the prevention group and the model group (P>0.05).? CONCLUSION: Fp supernatant has protective and therapeutic effects on ulcerative colitis in mice induced by DSS, which might be mediated by decrease of Th17 and IL-17A levels in the plasma and the colon mucosa tissues. Fp supernatant also can decrease mice colitis by reducing IL-6 levels. PMID- 26739074 TI - [Multidrug-resistant Acinetobacter Baumannii infection in Intensive Care Unit: A retrospective analysis]. AB - OBJECTIVE: To analyze the clinical characteristics of patients with bloodstream Acinetobacter baumannii infection in Intensive Care Unit (ICU).? METHODS: Eighty three ICU patients with bloodstream Acinetobacter baumannii infection from January 2012 to March 2015 were retrospectively analyzed, including infection related risk factors, drug-resistant bacteria, treatments and prognosis.? RESULTS: Among 83 patients, 60 patients (72.29%) were male, 23 (27.71%) were female. The youngest patient was 40 days old, the oldest was 92 years old, the age was (46.23+/-19.22) years old. In total, there were 20 patients (24.10%) with plural bacterial infection in blood, 60 (72.29%) with more than 3 kinds of disorders, 52 patients suffered homologous bacterial infection in blood and other organs. Among these cases, lower respiratory tract had the highest percentage of homologous bacteria (29 cases), followed by catheter (11 cases), wound secretion (8 cases), cerebrospinal fluid (3 cases) and ascites (1 case). The risk factors of bloodstream infection by Acinetobacter baumannii included catheterization, serious primary disease and basic disease, usage of corticosteroids, surgery and invasive operation and so on. Acinetobacter baumannii were highly resistant. Most of them were multi-drug resistance, and some were pan-drug resistance. It showed more than 80% drug resistant rate to antibiotics except sulbactam, cefopcrazone and amikacin. Among 83 patients, 55 cases (66.26%) were dead, 25 cases (30.12%) were improved and 3 cases (3.62%) were cured.? CONCLUSION: Acinetobacter baumannii are highly and multidrug-resistant to commonly used antibiotics. Patients in ICU suffering serious basic diseases should be shorten hospitalization time, restricted the use of breathing machine and immunosuppressant. It must carry out disinfection for invasive operation to reduce the risk of bloodstream infections, and the abuse of antibiotics must be avoided to slow bacteria resistance. PMID- 26739075 TI - [Clinical features of patients with primary biliary cirrhosis]. AB - OBJECTIVE: To determine features of the clinical manifestation in patients with primary biliary cirrhosis (PBC), and to provide a scientific basis for diagnosis of PBC.? METHODS: A total of 102 patients with PBC treated in the Second Xiangya Hospital, Central South University, from January 2013 to January 2015 were retrospectively analyzed. The patients' general condition, clinical manifestations, serum biochemical and immunological parameters were detected.? RESULTS: Of the 102 PBC patients, 91 (89.21%) patients were female. The main symptoms in these patients were fatigue, poor appetite, dry mouth, nausea, vomiting, pruritus, stomachache, and abdominal distension. The major signs were jaundice, splenomegaly, hepatomegaly, edema, and ascites. The main features of serum biochemical parameters in these patients included the increase of alkaline phosphatase and gamma glutamyltranspeptidase (GGT), especially the GGT. The anti mitochondrial antibodies-M2 (AMA-M2) in 81 and 21 patients was positive and negative, respectively. The differences between the AMA-MA positive and negative groups were not statistically significant (P>0.05). According to clinical manifestation, 102 patients were classified into 2 groups: A non-cirrhosis group (n=56) and a cirrhosis group (n=46). The positive rates in these 2 groups, such as ANA, AMA-M2, anti-gp210, anti-Sp100, anti-Ro52, anti-PML, were 54.35%, 89.13%, 41.30%, 13.04%, 43.38% and 10.87% vs 57.14%, 71.43%, 42.86%, 12.5%, 51.79% and 3.71%, respectively, with no significant difference between them (P>0.05). However, there was significant difference in the positive rate of anti-3E-EPO between the above 2 groups (86.78% vs 58.93%, P<0.05). The positive rates of AMA M2 and anti-3E-EPO in 30 patients diagnosed by hepatic histopathological examination were higher than those of other antibodies.? CONCLUSION: PBC mainly affects middle-aged women, and its clinical manifestation is various. The autoantibody tests play an important role in diagnosis of PBC. Checking for AMA A2 and anti-3E-BPO can improve the positive rate of PBC. Liver histopathological examination may provide useful information on disease severity, which can determine the histological stage when the patient's serum autoantibodies are negative. PMID- 26739076 TI - [Therapeutic methods and their effects on patients with cornual pregnancy]. AB - OBJECTIVE: To evaluate the therapeutic methods and their effects on patients with cornual pregnancies.? METHODS: A retrospective study was performed on 83 patients, who were diagnosed as cornual pregnancy at Drum Tower Hospital from June 2010 to April 2015. The patients were divided into 5 groups: a laparoscope group, angle resection and uterine repair guided by laparoscope (n=16); a surgery group, operated with angle resection and uterine repair (n=49); an abortion group, guided by ultrasound or laparoscope (n=6); a drug group, treated by methotrexate and mifepristone (n=8) and a pregnancy bursal puncture group (n=4). We compared the general conditions, surgery circumstances and average days in hospital among the laparoscope group, the surgery group, and the abortion group. Moreover, we also investigated the outcomes of the drug group and pregnancy bursal puncture group.? RESULTS: Compared with the surgery group, the intraoperative blood loss in the laparoscope group and abortion group was less (P<0.05). The length of procedure and average days in hospital between the surgery group and the laparoscope group were not statistically significant (P>0.05). The length of procedure in the abortion group was less than that in the laparoscope group or the surgery group (P<0.05). The cure rate was 100%.? CONCLUSION: The therapeutic methods based on patient's condition can improve the curative effect and prognosis in cornual pregnancy, which can keep the integrity of generative organs with less injury. The laparoscope might be a main therapeutic method for cornual pregnancy due to its safety, effectiveness, and minimal invasion. PMID- 26739077 TI - [Surgical treatment for thoracic spinal tuberculosis with intraspinal abscesses by unilateral vertebral lamina limited decompression via posterior-only approach]. AB - OBJECTIVE: To investigate the clinical efficacy and feasibility of surgical treatment for thoracic spinal tuberculosis with intraspinal abscesses by internal fixation, unilateral vertebral lamina limited decompression, debridement, together with interbody and posterior fusion via a posterior only approach.? METHODS: A total of 37 pantients (24 males and 13 females) with thoracic spinal tuberculosis complicated with intraspinal abscess lesions were admitted to our hospital, with age 13-68(39.7 +/- 9.1) years old. Spinal lesions of segmental kyphosis Cobb angle was 8 degrees -62 degrees (29.6 degrees +/- 3.6 degrees ). Frankel grade system was used to assess neurological function. According to the system, there were 3, 7, 19 and 8 cases for grade B, C, D and E, respectively. All 37 cases were treated with internal fixation, unilateral vertebral lamina limited decompression, debridement, together with interbody and posterior fusion via a posterior only approach.? RESULTS: The mean duration for follow-up was 24 90 (53.0 +/- 15.7) months. Intraoperative dural tear occurred in 1 cases with cerebrospinal fluid leakage after operation; 2 cases showed postoperative neurological complications; delayed wound healing occurred in 2 cases. The postoperative kyphotic angle was 5 degrees -21 degrees (8.3 degrees +/- 1.3 degrees ). The kyphotic angle was 8 degrees -26 degrees (10.1 degrees +/- 1.9 degrees ) at the last follow-up. By the time of the last follow-up, all patients with preoperative neurological symptoms improved at different degree. According to Frankel classification, 2 cases recovered from grade B to D, 1 case from grade B to E, 3 cases from grade C to D, 4 cases from grade C to E, 13 cases from grade D to E. No failure in fixation and pseudarthrosis. All patients obtained satisfactory bone graft fusion.? CONCLUSION: Posterior internal fixation, unilateral vertebral lamina limited decompression, debridement, together with interbody and posterior fusion might be a effective and feasible method for treatment of thoracic spinal tuberculosis with intraspinal abscess lesions. PMID- 26739078 TI - [Application of individual light-curing resin tray as edge plastic material in complete denture modulo]. AB - OBJECTIVE: To investigate clinical effect of individual light-curing resin tray as edge plastic material in complete denture modulo.? METHODS: A total of 30 patients with poor condition for alveolar ridge of mandible were chosen individual tray with individual light-curing resin tray for material edge shaping or traditional individual impression tray for edge shaping cream to produce complete denture. The operability, questionnaire about denture retention, comfort, mucosal cases and chewing function in the process of shaping the edge were investigated three months later after wearing dentures.? RESULTS: There was no significant difference in retention, comfort, mucosa and the chewing function between the two mandibular denture impression methods. However, the patients with individual light-curing resin tray as edge shaping material felt better in the process than that in the patients with die-cream as the edge shaping material (P<0.05). Furthermore, the manipulation with individual light-curing resin tray as edge shaping material is easy for doctor.? CONCLUSION: Although the clinical effect of Individual light-curing resin tray material as the edge shaping material is equal to that of impression cream, it saves time and human resource. Moreover, it is more acceptable for the patients and thus it can be spread in clinics. PMID- 26739079 TI - [Signal intensity-time curve and quantitative dynamic contrast-enhanced magnetic resonance imaging in differentiating neoplasms of uterus]. AB - OBJECTIVE: To evaluate signal intensity-time (SI-Time) curve and quantitative dynamic contrast-enhanced 3.0T magnetic resonance imaging in diagnosis and differentiating neoplasm of uterus.? METHODS: A total of 42 cases of uterine neoplasm (20 were malignant and 22 were benign) were evaluated in our study. All cases received dynamic contrast-enhanced scanning on 3.0T MRI. The raw data was processed by Siemens Tissue 4D software and the SI-Time curve was obtained and analyzed. Pharmacokinetic modeling of Tofts with a modeled vascular input function was used for calculating volume parameters: volume transfer constant (Ktrans), reverse volume transfer constant (Kep), the extravascular extracellular space volume per unit volume of tissue (Ve). The correlation of these parameters at each groups were investigated. The SI-Time curve and the data of perfusion parameters between the 2 groups were compared by T test.? RESULTS: Among 20 malignant tumors, 12 were cervical carcinoma and 8 were endometrial cancer. Among the benign tumors, 13 were leiomyomas, 3 were endometrial polyp, 3 were endometrial hyperplasia, and 3 were adenomyosis. 59.1% cases of benign tumors belong to Type I curve and 65% cases of malignant tumors belong to Type II curve. There was significant difference in SI-Time curve between benign and malignant tumors (P=0.011). If Type I curve was used as diagnostic criteria for benign tumors, and Type II and III curve were for malignant tumors, the diagnostic sensitivity, specificity, positive predictive value, negative predictive value were 90.0%, 59.1%, 66.7%, and 86.7%, respectively. Ve was 0.477 +/- 0.143 in malignant and 0.614 +/- 0.146 in control group with significant difference (P=0.004). Ve was 0.477 +/- 0.143 in malignant and 0.589 0.176 in benign group with significant difference (P=0.004). Ktrans was (0.178 +/- 0.067) min-1 in malignant and (0.263 +/- 0.111) min-1 in control group with significant difference (P=0.003). Ktrans was (0.182 +/- 0.096) min-1 in benign and (0.263 +/- 0.111) min-1 in control group with significant difference (P=0.011). ? CONCLUSION: The type of SI-Time curve and perfusion parameters were important for differentiating benign and malignant uterine tumors in dynamic enhanced MRI. These parameters provide a supplement for conventional morphological MR diagnosis. PMID- 26739080 TI - [Combination of cerebral angiography and abdominal angiography in patients with ischemic stroke]. AB - OBJECTIVE: To explore the imaging characteristics of cerebral stenosis and peripheral vascular stenosis in patients with ischemic stroke.? METHODS: The data collected from 1 060 patients with ischemic stroke, who were examined by cerebral angiography and abdominal angiography, were retrospectively analyzed. All relevant parameters for atherosclerosis were recorded. Then the correlation of cerebrovascular stenosis with peripheral vascular stenosis was analyzed, and the risk factors of multi-artery stenosis and ulcerative plaque were examined.? RESULTS: Peripheral vascular stenosis was closely correlated to cerebrovascular stenosis (r=0.236, P<0.01). The stenosis degree and quantity of cerebrovascular were positively correlated with peripheral vascular stenosis (r=0.228, P<0.01; r=0.231, P<0.01). The age (OR=1.059, 95% CI: 1.015-1.117; P<0.05), smoking (OR=3.423, 95% CI: 1.524-7.780; P<0.01) and diabetes (OR=3.651, 95% CI: 1.536 8.425; P<0.01) were risk factors for the occurrence of multi-artery stenosis. But the risk factor of ulcerative plaque was not found by single factor analysis.? CONCLUSION: The cerebral angiography combined abdominal angiography is an effective method to identify cerebrovascular and peripheral vascular stenosis in the patients with stroke. Age, smoking and diabetes are independent risk factors for multi-artery stenosis in patients with ischemic stroke. PMID- 26739081 TI - [Effect of early scream sound stress on learning and memory in female rats]. AB - OBJECTIVE: To investigate the effect of early scream sound stress on the ability of spatial learning and memory, the levels of norepinephrine (NE) and corticosterone (CORT) in serum, and the morphology of adrenal gland.? METHODS: Female Sprague-Dawley (SD) rats were treated daily with scream sound from postnatal day 1(P1) for 21 d. Morris water maze was used to measure the spatial learning and memory ability. The levels of serum NE and CORT were determined by radioimmunoassay. Adrenal gland of SD rats was collected and fixed in formalin, and then embedded with paraffin. The morphology of adrenal gland was observed by HE staining.? RESULTS: Exposure to early scream sound decreased latency of escape and increased times to cross the platform in Morris water maze test (P<0.05). The levels of serum NE was significantly elevated, with an obvious tendency in the increase of CORT level (P<0.05). The morphology of adrenal gland was also influenced. ? CONCLUSION: Newborn female rats subjected to scream sound stress can enhance spatial learning and memory ability in adulthood, which is related to activation of the hypothalamo-pituitary-adrenal axis and sympathetic nervous system. PMID- 26739082 TI - [Satisfaction degree in outpatients and the influential factors at national essential medicine system in primary health care institutions of Yiyang]. AB - OBJECTIVE: To analyze the satisfaction degree in outpatients and influential factors at national essential medicine system in primary health care institution of Yiyang and to provide useful information for the sustainable development of the national essential medicine system in China.? METHODS: A multi-stage random sampling method was conducted. A total of 525 outpatients were randomly selected in 21 primary health care institution. Their satisfaction degree on national essential medicine system were investigated through anonymous survey.? RESULTS: Categories of medical institutions, age, education, medicare categories and occupation were influential factors, with statistical significance (P<0.05). ? CONCLUSION: There's no difference among different class of outpatients' attitude on national essential medicine system. Categories of medical institutions, age, education, medicare categories and occupation are influential factors for outpatients' attitude. PMID- 26739083 TI - [Risk factors for type 2 diabetes complicated with hypertension in adult residents in Liuyang]. AB - OBJECTIVE: To investigate the risk factors for type 2 diabetes complicated with hypertension in adult residents in Liuyang, Hunan Province, P. R. China.? METHODS: The residents aged at or over 18 were selected through a method of multi stage cluster random sampling from 10 towns in Liuyang. Questionnaires, physical measurements and laboratory tests were conducted. Type 2 diabetes complicated with hypertension were served as an experimental group, while simple diabetes, non-diabetes and non-hypertension (healthy control), or non-complication and healthy group (simple hypertension, simple diabetes, and healthy group) were served as control group, respectively. Three kinds of logistic regression model were used to analyze the risk factors for type 2 diabetes complicated with hypertension.? RESULTS: A total of 5 669 residents were included in the analysis, and the response rate was 97.74%. The results showed that the prevalence of type 2 diabetes complicated with hypertension of residents at or over 18 years old in Liuyang was 2.6% (95%CI: 2.2%, 3.1%). Logistic regression analyses demonstrated that for people at or over 60 years old, obesity and abnormal triglyceride were the independent risk factors for type 2 diabetes complicated with hypertension.? CONCLUSION: Aging, obesity and abnormal triglyceride can increase the risk of type 2 diabetes complicated with hypertension in adult residents in Liuyang. PMID- 26739084 TI - [Reliability and validity of the Chinese Eating Assessment Tool (EAT-10) in evaluation of acute stroke patients with dysphagia]. AB - OBJECTIVE: To study the reliability and validity of the Chinese Eating Assessment Tool (EAT-10) in evaluation of acute stroke patients with dysphagia.? METHODS: The inpatients of stroke were assessed with Chinese EAT-10. As a golden standard for evaluation of dysphagia, videofluoroscopic swallow study (VFSS) test was used to judge the reliability and validity of EAT-10.? RESULTS: A total of 130 qualified questionnaires were collected. The Cronbach's alpha coefficient for Chinese EAT-10 scale was 0.845. The total score of each item was related. The lowest or highest correlation coefficient for the item 2 or 3 was 0.271 or 0.772. The retest reliability was greater than 0.7, which met the requirements. According to the investigator consistency reliability test, the value collected from the investigator in the item 2 kept constant. The consistent correlation coefficient of the remaining nine items was more than 0.7. The consistency between each item and the mean score was high. The EAT-10 with the cut-off point at 1 was an optimal cut-off point. With the cut-off value of 1 (EAT-10 score >= 1), the sensitivity and specificity for EAT-10 was 77.9% and 66.1%, respectively. The positive predictive value (PPV) and negative value (NPV) was 71.6% and 73.2%, respectively, with 2.30 LHR+ and 0.33 LHR- for dysphagia. ? CONCLUSION: The Chinese EAT-10 has a good reliability and validity in evaluation of the acute stroke patients with dysphagia. The sensitivity and negative value are the best with the cut-off value of 1 (EAT-10 score >= 1). It offers a good way to discriminate dysphagia, impaired efficacy, penetrations, and aspirations in acute stroke patients. PMID- 26739085 TI - [Current status and clinical progress of capsule retention]. AB - Small bowel capsule endoscopy has been now widely applied for patients who are highly suspected of small bowel disease with occult bleeding and unexplained abdominal pain. Capsule retention is a major complication, with an overall incidence of 1%-2%, commonly seen in the detection of Crohn's disease and small bowel tumors. Most cases run asymptomatically after retention, while intestinal obstruction or perforation can occur ralely. Conservative methods, endoscopic or surgical interventions are performed to deal with the retention. Patency capsule is currently used as a novel tool to reduce the risk of capsule retention. PMID- 26739086 TI - [A case of repeated unconsciousness caused by excrescence locking bicuspid aortic valve]. AB - We received a patient who repeated unconsciousness due to excrescence locking bicuspid aortic valve. He experienced unconsciousness and treatments with anti infection, surgical operation, valve replacement and recovery. It was a rare case, which made us realize that the heart color Doppler ultrasound should be regularly performed in patients with aortic valve abnormalities. Once patients were found to have infective endocarditis combined with the valve vegetations, they should be formally treated as soon as possible. PMID- 26739087 TI - Early experience with fat grafting as an adjunct for secondary burn reconstruction in the hand: Technique, hand function assessment and aesthetic outcomes. AB - INTRODUCTION: Fat transfer is increasingly used as part of our reconstructive armamentarium to address the challenges encountered in secondary burn reconstruction. The aim of this study was to review our experience with autologous fat transfer in relation to hand function, scarring and cosmesis, in patients undergoing secondary reconstruction after burns. METHOD: Retrospective analysis of burn patients (2010-2013) who underwent autologous fat transfer to improve scarring, contour deformity and/or scar contracture was performed. Hand function was assessed using grip strength measurement, Total Active Movement (TAM), the Disabilities of the Arm, Shoulder and Hand (DASH) Questionnaire and Michigan Hand Outcome Questionnaire (MHQ). Patients' satisfaction was assessed using the Patient Observer Scar Assessment Scale (POSAS). RESULTS: Thirteen patients were included in this analysis. The average time from burns and from fat transfer were 2.3 years (10 months-3.9 years) and 9.1 months (3 months-1.3 years), respectively. There was a statistically significant improvement in TAM measurement. The total score, activity of daily living score and satisfaction score of the MHQ also statistically increased following fat transfer. The changes in function score, work score and pain score of the MHQ were not significant. Grip strength measurement and DASH score did not show improvement. For scar assessment, total score and overall score of POSAS improved significantly. Similarly, scores for scar colour, scar thickness, scar stiffness and scar regularity increased significantly. DISCUSSION: Autologous fat transfer directly replaces volume loss in the subcutaneous layer, physically releases tethered skin from underlying tissues and exerts downstream regenerative effects. Skin quality improvements combined with replacement of the subcutaneous adipose volume in the hand reduces overall scar tightness and tissue tethering and has the potential to enhance hand therapy. In our series, modest improvement in range of movement, scar quality and hand outcome scores were demonstrated following a single session of fat transfer. PMID- 26739088 TI - Construction of an immunorelated protein-protein interaction network for clarifying the mechanism of burn. AB - BACKGROUND AND AIM: Severe burn is known to induce a series of pathological responses resulting in increased susceptibility to systemic inflammatory response and multiple organ failure, but the underlying molecular mechanism remains unclear at present. The main aim of this study was to expand our understanding of the events leading to circulating leukocyte response after burn by subjecting the gene expression profiles to a bioinformatic analysis. MATERIALS AND METHODS: Comprehensive gene expression analysis was performed to identify differentially expressed genes (DEGs) using the expression profile GSE7404 (Mus musculus, circulating leukocyte, 25% of total body surface area (TBSA), full thickness) downloaded from the Gene Expression Omnibus, followed by the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. In addition, a postburn protein-protein interaction (PPI) network was constructed to identify potential biomarkers. RESULTS: Maximum changes in the gene expression profile were detected 1 day post burn. Separate Gene Ontology (GO) functional enrichment analysis for upregulated and downregulated DEGs revealed significant alterations of genes related to biological process such as "response to stimuli," "metabolic," "cellular and immune system processes," "biological regulation," and "death" in the leukocyte transcriptome after the burn. The KEGG pathway enrichment analysis showed that the upregulated DEGs were significantly enriched in the nodes of immunorelated and signal transduction-related pathways, and the downregulated genes were significantly enriched for the immunorelated pathways. The PPI network and module analysis revealed that, 1 day after the burn, lymphocyte-specific protein tyrosine kinase (Lck) (downregulated), Jun (upregulated), Cd19 (downregulated), Stat1 (downregulated), and Cdk1 (upregulated) were located centrally in both the PPI network and modules. CONCLUSIONS: Based on an integrated bioinformatic analysis, we concluded that Lck, Jun, Cd19, Stat1, and Cdk1 may be critical 1 day after the burn. These findings expand our understanding of the molecular mechanisms of this important pathological process. Further studies are needed to support our work, focused on identifying candidate biomarkers with sufficient predictive power to act as prognostic and therapeutic biomarkers for burn injury. PMID- 26739090 TI - Cyclic dinucleotide detection with riboswitch-G-quadruplex hybrid. AB - A cyclic dinucleotide riboswitch has been fused with a G-quadruplex motif to produce a conditional riboswitch-peroxidase-mimicking sensor that oxidizes both colorimetric and fluorogenic substrates in the presence of c-di-GMP. We find that signal-to-noise ratio could be improved by using a two-, not three-, floor split G-quadruplex for this conditional peroxidase-mimicking riboswitch. PMID- 26739091 TI - ENDOCRINE TUMOURS: The genomics of adrenocortical tumors. AB - The last decade witnessed the emergence of genomics, a set of high-throughput molecular measurements in biological samples. These pan-genomic and agnostic approaches have revolutionized the molecular biology and genetics of malignant and benign tumors. These techniques have been applied successfully to adrenocortical tumors. Exome sequencing identified new major drivers in all tumor types, including KCNJ5, ATP1A1, ATP2B3 and CACNA1D mutations in aldosterone producing adenomas (APA), PRKACA mutations in cortisol-producing adenomas (CPA), ARMC5 mutations in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) and ZNRF3 mutations in adrenocortical carcinomas (ACC). Moreover, the various genomic approaches - including exome sequencing, transcriptome, miRNome, genome and methylome - converge into a single molecular classification of adrenocortical tumors. Especially for ACC, two main molecular groups have emerged, showing major differences in outcomes. These ACC groups differ by their gene expression profiles, but also by recurrent mutations and specific DNA hypermethylation patterns in the subgroup of poor outcome. The clinical impact of these findings is just starting. The main altered signaling pathways now become therapeutic targets. The molecular groups of diseases individualize robust subtypes within diseases such as APA, CPA, PBMAH and ACC. A revised nosology of adrenocortical tumors should impact the clinical research. Obvious consequences also include genetic counseling for the new genetic diseases such as ARMC5 mutations in PBMAH, and a better prognostication of ACC based on targeted measurements of a few discriminant molecular alterations. Identifying the main molecular groups of adrenocortical tumors by extensively gathering the molecular variations is a significant step forward towards precision medicine. PMID- 26739092 TI - Assessing the potential impact of artemisinin and partner drug resistance in sub Saharan Africa. AB - BACKGROUND: Artemisinin and partner drug resistant malaria parasites have emerged in Southeast Asia. If resistance were to emerge in Africa it could have a devastating impact on malaria-related morbidity and mortality. This study estimates the potential impact of artemisinin and partner drug resistance on disease burden in Africa if it were to emerge. METHODS: Using data from Asia and Africa, five possible artemisinin and partner drug resistance scenarios are characterized. An individual-based malaria transmission model is used to estimate the impact of each resistance scenario on clinical incidence and parasite prevalence across Africa. Artemisinin resistance is characterized by slow parasite clearance and partner drug resistance is associated with late clinical failure or late parasitological failure. RESULTS: Scenarios with high levels of recrudescent infections resulted in far greater increases in clinical incidence compared to scenarios with high levels of slow parasite clearance. Across Africa, it is estimated that artemisinin and partner drug resistance at levels similar to those observed in Oddar Meanchey province in Cambodia could result in an additional 78 million cases over a 5 year period, a 7% increase in cases compared to a scenario with no resistance. A scenario with high levels of slow clearance but no recrudescence resulted in an additional 10 million additional cases over the same period. CONCLUSION: Artemisinin resistance is potentially a more pressing concern than partner drug resistance due to the lack of viable alternatives. However, it is predicted that a failing partner drug will result in greater increases in malaria cases and morbidity than would be observed from artemisinin resistance only. PMID- 26739093 TI - Staphylococcal LTA-Induced miR-143 Inhibits Propionibacterium acnes-Mediated Inflammatory Response in Skin. AB - Staphylococcus epidermidis (S. epidermidis) plays a critical role in modulating cutaneous inflammatory responses in skin. Although S. epidermidis has been shown to co-colonize with Propionibacterium acnes (P. acnes) in acne lesions, it is unclear whether S. epidermidis is involved in the regulation of P. acnes-induced inflammatory responses. In this study, we demonstrated that S. epidermidis inhibited P. acnes-induced inflammation in skin. P. acnes induced the expression of interleukin-6 and tumor necrosis factor-alpha via the activation of toll-like receptor (TLR) 2 in both keratinocytes and mouse ears. Staphylococcal lipoteichoic acid activated TLR2 to induce miR-143 in keratinocytes, and miR-143, in turn, directly targeted 3' UTR of TLR2 to decrease the stability of TLR2 mRNA and then decreased TLR2 protein, thus inhibiting P. acnes-induced proinflammatory cytokines. The inhibitory effect of miR-143 was further confirmed in vivo as the administration of miR-143 antagomir into mouse ears abrogated the inhibitory effect of lipoteichoic acid on P. acnes-induced inflammation in skin. Taken together, these observations demonstrate that staphylococcal lipoteichoic acid inhibits P. acnes-induced inflammation via the induction of miR-143, and suggest that local modulation of inflammatory responses by S. epidermidis at the site of acne vulgaris might be a beneficial therapeutic strategy for management of P. acnes-induced inflammation. PMID- 26739094 TI - IFN-gamma Primes Keratinocytes for HSV-1-Induced Inflammasome Activation. AB - Inflammasomes are immune complexes that induce an inflammatory response upon sensing of different stress signals. This effect is mainly mediated by activation and secretion of the proinflammatory cytokines proIL-1beta and -18. Here we report that infection of human primary keratinocytes with the double-stranded DNA viruses modified vaccinia virus Ankara (MVA) or herpes simplex virus type 1 (HSV 1)-induced secretion of mature IL-1beta and -18. This secretion was dependent on several inflammasome complexes; however, the absent in melanoma 2 (AIM2) inflammasome, which is activated by binding of double-stranded DNA, played the most important role. Whereas prestimulation of keratinocytes with IFN-gamma moderately increased MVA-induced IL-1beta and IL-18 secretion, it was essential for substantial secretion of these cytokines in response to herpes simplex virus type 1 infection. IFN-gamma partially restored HSV-1 suppressed proIL-1beta expression and was also required for inflammasome activation. Most importantly, IFN-gamma strongly suppressed virus replication in keratinocytes in vitro and ex vivo, which was independent of inflammasome activation. Our results suggest that, similar to Herpesviridae infection in mice, HSV-1 replication in human skin is controlled by a positive feedback loop of keratinocyte-derived IL-1/IL-18 and IFN gamma expressed by immune cells. PMID- 26739095 TI - Sustained Akt Activity Is Required to Maintain Cell Viability in Seborrheic Keratosis, a Benign Epithelial Tumor. AB - Seborrheic keratoses (SKs) are common benign skin tumors that share many morphological features with their malignant counterpart, squamous cell carcinoma. SKs frequently have acquired oncogenic mutations in the receptor tyrosine kinase/phosphatidylinositol 3-kinase/Akt signaling cascade. We developed a reliable culture system to study SKs in vitro and screened these cells using a library of selective kinase inhibitors to evaluate effects on cell survival. These benign tumors are sensitive to inhibition by ATP-competitive Akt inhibitors, including A-443654 and GSK690693. RNA interference-mediated Akt suppression mimicked the effects of enzyme inhibition in cultured cells. Akt inhibition suppressed phosphorylation of downstream targets of Akt kinase that are critical for cell survival, including MDM2 and FOXO3a, and induced apoptosis. Cell death was also dependent on p53, mutations in which, although common in cutaneous squamous cell carcinoma, have not been identified in SKs. Intact explants of SKs were also sensitive to Akt inhibition. In addition to the obvious therapeutic implications of these findings, identifying the signaling characteristics that differentiate benign and malignant tumors may inform our understanding of the malignant state. PMID- 26739097 TI - Development of a complementary PET/MR dual-modal imaging probe for targeting prostate-specific membrane antigen (PSMA). AB - We tried to develop a dual-modal PET/MR imaging probe using a straightforward one pot method by encapsulation with specific amphiphiles. In this study, iron oxide (IO) nanoparticles were encapsulated with three amphiphiles containing PEG, DOTA and the prostate-specific membrane antigen (PSMA)-targeting ligand in aqueous medium. The diameter of the prepared nanoparticle DOTA-IO-GUL was 11.01+/-1.54nm. DOTA-IO-GUL was labeled with (68)Ga in high efficiency. The DOTA-IO-GUL showed a dose-dependent binding to LNCaP (PSMA positive) cells via a competitive binding study against (125)I-labeled MIP-1072 (PSMA-targeting agent). Additionally, PET and MR imaging results showed PSMA selective uptake by only 22Rv1 (PSMA positive) but not PC-3 (PSMA negative) in dual-tumor xenograft mouse model study. MR imaging showed high resolution, and PET imaging enabled quantification and confirmation of the specificity. In conclusion, we have successfully developed the specific PSMA-targeting IO nanoparticle, DOTA-IO-GUL, as a dual-modality probe for complementary PET/MR imaging. FROM THE CLINICAL EDITOR: The combination of using Positron Emission Tomography (PET) and computed tomography (CT) in clinical practice is now the norm. With advances in technology, the next step would be to develop combined PET and Magnetic Resonance (MR) dual-imaging. In this article, the authors described their positive study on the development of a dual-modal PET/MR imaging probe using a prostate cancer model. PMID- 26739101 TI - Whole Exome Sequencing and Heterologous Cellular Electrophysiology Studies Elucidate a Novel Loss-of-Function Mutation in the CACNA1A-Encoded Neuronal P/Q Type Calcium Channel in a Child With Congenital Hypotonia and Developmental Delay. AB - BACKGROUND: A 4-year-old boy born at 37 weeks' gestation with intrauterine growth retardation presented with developmental delay with pronounced language and gross motor delay, axial hypotonia, and dynamic hypertonia of the extremities. Investigations including the Minnesota Newborn Screen, thyroid stimulating hormone/thyroxin, and inborn errors of metabolism screening were negative. Cerebral magnetic resonance imaging and spectroscopy were normal. Genetic testing was negative for coagulopathy, Smith-Lemli-Opitz, fragile X, and Prader Willi/Angelman syndromes. Whole genome array analysis was unremarkable. METHODS: Whole exome sequencing was performed through a commercial testing laboratory to elucidate the underlying etiology for the child's presentation. A de novo mutation was hypothesized. In attempt to establish pathogenicity of our candidate variant, cellular electrophysiologic functional analysis of the putative de novo mutation was performed using patch-clamp technology. RESULTS: Whole exome sequencing revealed a p.P1353L variant in the CACNA1A gene, which encodes for the alpha1-subunit of the brain-specific P/Q-type calcium channel (CaV2.1). This presynaptic high-voltage-gated channel couples neuronal excitation to the vesicular release of neurotransmitter and is implicated in several neurologic disorders. DNA Sanger sequencing confirmed that the de novo mutation was absent in both parents and present in the child only. Electrophysiologic analysis of P1353L-CACNA1A demonstrated near complete loss of function, with a 95% reduction in peak current density. CONCLUSIONS: Whole exome sequencing coupled with cellular electrophysiologic functional analysis of a de novoCACNA1A missense mutation has elucidated the probable underlying pathophysiologic mechanism responsible for the child's phenotype. Genetic testing of CACNA1A in patients with congenital hypotonia and developmental delay may be warranted. PMID- 26739104 TI - Dynamic time warping in phoneme modeling for fast pronunciation error detection. AB - The presented paper describes a novel approach to the detection of pronunciation errors. It makes use of the modeling of well-pronounced and mispronounced phonemes by means of the Dynamic Time Warping (DTW) algorithm. Four approaches that make use of the DTW phoneme modeling were developed to detect pronunciation errors: Variations of the Word Structure (VoWS), Normalized Phoneme Distances Thresholding (NPDT), Furthest Segment Search (FSS) and Normalized Furthest Segment Search (NFSS). The performance evaluation of each module was carried out using a speech database of correctly and incorrectly pronounced words in the Polish language, with up to 10 patterns of every trained word from a set of 12 words having different phonetic structures. The performance of DTW modeling was compared to Hidden Markov Models (HMM) that were used for the same four approaches (VoWS, NPDT, FSS, NFSS). The average error rate (AER) was the lowest for DTW with NPDT (AER=0.287) and scored better than HMM with FSS (AER=0.473), which was the best result for HMM. The DTW modeling was faster than HMM for all four approaches. This technique can be used for computer-assisted pronunciation training systems that can work with a relatively small training speech corpus (less than 20 patterns per word) to support speech therapy at home. PMID- 26739102 TI - Metachronous Prostate Metastasis of Renal Cell Carcinoma: Case Report and Review of the Literature. PMID- 26739099 TI - Systemic and local immune responses in sheep after Neospora caninum experimental infection at early, mid and late gestation. AB - Besides its importance in cattle, Neospora caninum may also pose a high risk as abortifacient for small ruminants. We have recently demonstrated that the outcome of experimental infection of pregnant sheep with 10(6) Nc-Spain7 tachyzoites is strongly dependent on the time of gestation. In the current study, we assessed peripheral and local immune response in those animals. Serological analysis revealed earlier and higher IFN-gamma and IgG responses in ewes infected at early (G1) and mid (G2) gestation, when abortion occurred. IL-4 was not detected in sera from any sheep. Inflammatory infiltrates in the placenta mainly consisted of CD8+ and, to a lesser extent, CD4+ T cells and macrophages (CD163+). The infiltrate was more intense in sheep infected at mid-gestation. In the foetal mesenchyme, mostly free tachyzoites were found in animals infected at G1, while those infected in G2 displayed predominantly particulate antigen, and parasitophorous vacuoles were detected in sheep infected at G3. A similar pattern of placental cytokine mRNA expression was found in all groups, displaying a strengthened upregulation of IFN-gamma and IL-4 and milder increases of TNF-alpha and IL-10, reminiscent of a mixed Th1 and Th2 response. IL-12 and IL-6 were only slightly upregulated in G2, and TGF-beta was downregulated in G1 and G2, suggestive of limited T regulatory (Treg) cell activity. No significant expression of TLR2 or TLR4 could be detected. In summary, this study confirms the pivotal role of systemic and local immune responses at different times of gestation during N. caninum infection in sheep. PMID- 26739105 TI - Change Point Detection in Correlation Networks. AB - Many systems of interacting elements can be conceptualized as networks, where network nodes represent the elements and network ties represent interactions between the elements. In systems where the underlying network evolves, it is useful to determine the points in time where the network structure changes significantly as these may correspond to functional change points. We propose a method for detecting change points in correlation networks that, unlike previous change point detection methods designed for time series data, requires minimal distributional assumptions. We investigate the difficulty of change point detection near the boundaries of the time series in correlation networks and study the power of our method and competing methods through simulation. We also show the generalizable nature of the method by applying it to stock price data as well as fMRI data. PMID- 26739109 TI - Ion mobility mass spectrometry of peptide, protein, and protein complex ions using a radio-frequency confining drift cell. AB - Ion mobility mass spectrometry experiments enable the characterization of mass, assembly, and shape of biological molecules and assemblies. Here, a new radio frequency confining drift cell is characterized and used to measure the mobilities of peptide, protein, and protein complex ions. The new drift cell replaced the traveling-wave ion mobility cell in a Waters Synapt G2 HDMS. Methods for operating the drift cell and determining collision cross section values using this experimental set up are presented within the context of the original instrument control software. Collision cross sections for 349 cations and anions are reported, 155 of which are for ions that have not been characterized previously using ion mobility. The values for the remaining ions are similar to those determined using a previous radio-frequency confining drift cell and drift tubes without radial confinement. Using this device under 2 Torr of helium gas and an optimized drift voltage, denatured and native-like ions exhibited average apparent resolving powers of 14.2 and 16.5, respectively. For ions with high mobility, which are also low in mass, the apparent resolving power is limited by contributions from ion gating. In contrast, the arrival-time distributions of low mobility, native-like ions are not well explained using only contributions from ion gating and diffusion. For those species, the widths of arrival-time distributions are most consistent with the presence of multiple structures in the gas phase. PMID- 26739108 TI - ERK5 induces ankrd1 for catecholamine biosynthesis and homeostasis in adrenal medullary cells. AB - Extracellular signal-regulated kinases (ERKs) play important roles in proliferation, differentiation and gene expression. In our previous study, we demonstrated that both ERK5 and ERK1/2 were responsible for neurite outgrowth and tyrosine hydroxylase (TH) expression in rat pheochromocytoma cells (PC12) (J Biol Chem 284, 23,564-23,573, 2009). However, the functional differences between ERK5 and ERK1/2 signaling in neural differentiation remain unclear. In the present study, we show that ERK5, but not ERK1/2 regulates TH levels in rat sympathetic neurons. Furthermore, microarray analysis performed in PC12 cells using ERK5 and ERK1/2-specific inhibitors, identified ankyrin repeat domain 1 (ankrd1) as an ERK5-dependent and ERK1/2-independent gene. Here, we report a novel role of the ERK5/ankrd1 signaling in regulating TH levels and catecholamine biosynthesis. Ankrd1 mRNA was induced by nerve growth factor in time- and concentration dependent manners. TH levels were reduced by ankrd1 knockdown with no changes in the mRNA levels, suggesting that ankrd1 was involved in stabilization of TH protein. Interestingly, ubiquitination of TH was enhanced and catecholamine biosynthesis was reduced by ankrd1 knockdown. Finally, we examined the relationship of ERK5 to TH levels in human adrenal pheochromocytomas. Whereas TH levels were correlated with ERK5 levels in normal adrenal medullas, ERK5 was down regulated and TH was up-regulated in pheochromocytomas, indicating that TH levels are regulated by alternative mechanisms in tumors. Taken together, ERK5 signaling is required for catecholamine biosynthesis during neural differentiation, in part to induce ankrd1, and to maintain appropriate TH levels. This pathway is disrupted in pathological conditions. PMID- 26739110 TI - Assessment of antimutagenic action of Celtis glabrata Steven ex Planch. (Cannabaceae) extracts against base pair exchange and frame shift mutations on Salmonella typhimurium TA98 and TA100 strains by Ames test. AB - CONTEXT: Celtis glabrata is used in Turkey for the treatment of various health disorders. OBJECTIVE: The acetone, chloroform, ethanol, and methanol extracts of C. glabrata leaf, fruit, and seed were investigated to evaluate their antimutagenic activities. MATERIAL AND METHODS: The antimutagenicity of these extracts was determined by Ames test against mutagens (4-nitro-O phenylenediamine, 2-aminofluorene (2-AF), and sodium azide (SA)). The extracts were used at concentrations between 5 and 0.005 mg/plate. RESULTS: The ethanol extracts of leaves exhibited strong antimutagenicity (70%) against 2-AF with S9 at 5 mg/plate on TA98. But methanol (61%, 53%) and acetone (53%, 52%) also revealed strong inhibition rates at concentrations of >= 0.5 mg/plate. Among the extracts, the highest activity (96%) was obtained from acetone extract against SA without S9, followed by chloroform extract (91%) at a dose of 5 mg/plate on TA100 with S9. Ethanol (without S9) and chloroform (with S9) extracts showed strong antimutagenicity at all doses. Exception of chloroform and acetone (without S9), all fruit extracts (with/without S9) manifested strong antimutagenicity at doses of >= 0.5 mg/plate on TA98 strain. Ethanol extracts revealed 68% inhibition against 2-AF on TA98. Acetone and ethanol extracts manifested 84% and 82% inhibition against SA on TA100, respectively. All the extracts of seeds revealed strong inhibition against 2-AF at >= 0.5 mg/plate doses on TA98, but acetone extract showed excellent antimutagenicity (94%). Moreover, the chloroform (74, 73, 63, 54%), acetone (74, 72, 70, 65%) and methanol (74, 67, 63, 61%) extracts of seeds revealed strong antimutagenic activity on TA100 against SA with S9. DISCUSSION AND CONCLUSION: This plant may be natural source of antimutagenic agents. PMID- 26739111 TI - The effect of recombination under short-circuit conditions on the determination of charge transport properties in nanostructured photoelectrodes. AB - We report on the commonly unaccounted for process of recombination under short circuit conditions in nanostructured photoelectrodes with special attention to the charge collection efficiency. It is observed that when recombination under short circuit conditions is significant, small perturbation methods overestimate the charge-collection efficiency, which is related to the inaccurate determination of the electron diffusion coefficient and diffusion length. PMID- 26739113 TI - Preparing Nurse Practitioners for Competence in Providing Sexual Health Care. PMID- 26739114 TI - Antibiotic resistance evaluation and clinical analysis of acute appendicitis; report of 1431 consecutive worldwide patients: A cohort study. AB - BACKGROUND: Acute appendicitis (AA) is one of the most common diseases affecting especially young but also older people. A systematic evaluation of bacteriology of AA has been frequently conducted in children but is not well known and discussed in adult population. STUDY DESIGN: The study has been obtained from two multicenter prospective observational studies (CIAO and CIAOW studies). The aim of the study is to analyze the intra-abdominal bacteriology in AA and its relation with clinical outcomes. RESULTS: Patients included were 1431, 806 male (56.3%). The mean/median age was 38.9 (SD +/- 18.4) and 35 (range 18-94). Clinical condition at the admission was sepsis in 623 patients (43.5%), severe sepsis and septic shock in 29 (2%) and 10 (0.7%). Peritonitis was localized in 1107 patients (77.4%) and generalized in 324 (22.6%). Adequate source-control and empirical antimicrobial therapy were reported in 95.2% and 88.7% of the patients. 47 isolated bacteria (6.8%) were resistant. Two (4.2%) were health-care associated infections and 45 (95.7%) were community-acquired infections. Univariate analysis showed factor associated to resistant bacteria was the inadequacy of the empiric antimicrobial therapy (p = 0.013); at multivariated analysis factors associated with mortality were age>70 years (p = 0.003) and severe sepsis at the admission (p = 0.02); factors associated to ICU admission were: severe sepsis (p < 0.0001), generalized peritonitis (p < 0.0001), malignancy (p < 0.0001) and cardiovascular disease (p < 0.0001). CONCLUSION: The evolution of antimicrobial resistance, in common community-acquired infections, combined with lack of new antibiotics development are strictly linked to clinical outcomes. Adequate empirical antimicrobial therapy is fundamental to counteract bacterial resistance. PMID- 26739115 TI - Label-free cell cycle analysis for high-throughput imaging flow cytometry. AB - Imaging flow cytometry combines the high-throughput capabilities of conventional flow cytometry with single-cell imaging. Here we demonstrate label-free prediction of DNA content and quantification of the mitotic cell cycle phases by applying supervised machine learning to morphological features extracted from brightfield and the typically ignored darkfield images of cells from an imaging flow cytometer. This method facilitates non-destructive monitoring of cells avoiding potentially confounding effects of fluorescent stains while maximizing available fluorescence channels. The method is effective in cell cycle analysis for mammalian cells, both fixed and live, and accurately assesses the impact of a cell cycle mitotic phase blocking agent. As the same method is effective in predicting the DNA content of fission yeast, it is likely to have a broad application to other cell types. PMID- 26739116 TI - Accuracy of continuous glucose monitoring during differing exercise conditions. AB - AIM: Depending on intensity, exercise may induce a strong hormonal and metabolic response, including acid-base imbalances and changes in microcirculation, potentially interfering with the accuracy of continuous glucose monitoring (CGM). The present study aimed at comparing the accuracy of the Dexcom G4 Platinum (DG4P) CGM during continuous moderate and intermittent high-intensity exercise (IHE) in adults with type 1 diabetes (T1DM). METHODS: Ten male individuals with well-controlled T1DM (HbA1c 7.0 +/- 0.6% [54 +/- 6 mmol/mol]) inserted the DG4P sensor 2 days prior to a 90 min cycling session (50% VO2peak) either with (IHE) or without (CONT) a 10s all-out sprint every 10 min. Venous blood samples for reference glucose measurement were drawn every 10 min and euglycemia (target 7 mmol/l) was maintained using an oral glucose solution. Additionally, lactate and venous blood gas variables were determined. RESULTS: Mean reference blood glucose was 7.6 +/- 0.2 mmol/l during IHE and 6.7 +/- 0.2 mmol/l during CONT (p<0.001). IHE resulted in significantly higher levels of lactate (7.3 +/- 0.5 mmol/l vs. 2.6 +/- 0.3 mmol/l, p<0.001), while pH values were significantly lower in the IHE group (7.27 vs. 7.38, p=0.001). Mean absolute relative difference (MARD) was 13.3 +/- 2.2% for IHE and 13.6 +/- 2.8% for CONT suggesting comparable accuracy (p=0.90). Using Clarke Error Grid Analysis, 100% of CGM values during both IHE and CONT were in zones A and B (IHE: 77% and 23%; CONT: 78% and 22%). CONCLUSIONS: The present study revealed good and comparable accuracy of the DG4P CGM system during intermittent high intensity and continuous moderate intensity exercise, despite marked differences in metabolic conditions. This corroborates the clinical robustness of CGM under differing exercise conditions. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02068638. PMID- 26739118 TI - Pruritic Lesions During Pregnancy: An Unusual Presentation of a Rare Variant of Multibacillary Leprosy. PMID- 26739119 TI - Intralesional Sodium Thiosulfate to Treat Calciphylaxis. PMID- 26739117 TI - Connexin32: a mediator of acetaminophen-induced liver injury? AB - Connexin32 is the building block of hepatocellular gap junctions, which control direct intercellular communication and thereby act as goalkeepers of liver homeostasis. This study was set up to investigate whether connexin32 is involved in hepatotoxicity induced by the analgesic and antipyretic drug acetaminophen. To this end, whole body connexin32 knock-out mice were overdosed with acetaminophen followed by sampling at different time points within a 24-h time frame. Evaluation was done based upon a series of clinically and mechanistically relevant read-outs, including protein adduct formation, histopathological examination, measurement of alanine aminotransferase activity, cytokine production, levels of reduced and oxidized glutathione and hepatic protein amounts of proliferating cell nuclear antigen. In essence, it was found that genetic ablation of connexin32 has no influence on several key events in acetaminophen-induced hepatotoxicity, including cell death, inflammation or oxidative stress, yet it does affect production of protein adducts as well as proliferating cell nuclear antigen steady-state protein levels. This outcome is not in line with previous studies, which are contradicting on their own, as both amplification and alleviation of this toxicological process by connexin32 have been described. This could question the suitability of the currently available models and tools to investigate the role of connexin32 in acetaminophen-triggered hepatotoxicity. PMID- 26739121 TI - A Regional Climate Mode Discovered in the North Atlantic: Dakar Nino/Nina. AB - The interrannual variability of coastal sea surface temperature (SST) anomalies confined off Senegal is explored from a new viewpoint of the ocean-land atmosphere interaction. The phenomenon may be classified into "coastal Nino/Nina" in the North Atlantic as discussed recently in the Northeastern Pacific and Southeastern Indian Oceans. The interannual variability of the regional mixed layer temperature anomaly that evolves in boreal late fall and peaks in spring is associated with the alongshore wind anomaly, mixed-layer depth anomaly and cross shore atmospheric pressure gradient anomaly, suggesting the existence of ocean land-atmosphere coupled processes. The coupled warm (cold) event is named Dakar Nino (Nina). The oceanic aspect of the Dakar Nino (Nina) may be basically explained by anomalous warming (cooling) of the anomalously thin (thick) mixed layer, which absorbs shortwave surface heat flux. In the case of Dakar Nina, however, enhancement of the entrainment at the bottom of the mixed-layer is not negligible. PMID- 26739122 TI - Self-assembled nanostructured resistive switching memory devices fabricated by templated bottom-up growth. AB - Metal-oxide-based resistive switching memory device has been studied intensively due to its potential to satisfy the requirements of next-generation memory devices. Active research has been done on the materials and device structures of resistive switching memory devices that meet the requirements of high density, fast switching speed, and reliable data storage. In this study, resistive switching memory devices were fabricated with nano-template-assisted bottom up growth. The electrochemical deposition was adopted to achieve the bottom-up growth of nickel nanodot electrodes. Nickel oxide layer was formed by oxygen plasma treatment of nickel nanodots at low temperature. The structures of fabricated nanoscale memory devices were analyzed with scanning electron microscope and atomic force microscope (AFM). The electrical characteristics of the devices were directly measured using conductive AFM. This work demonstrates the fabrication of resistive switching memory devices using self-assembled nanoscale masks and nanomateirals growth from bottom-up electrochemical deposition. PMID- 26739120 TI - Osteoinductive PolyHIPE Foams as Injectable Bone Grafts. AB - We have recently fabricated biodegradable polyHIPEs as injectable bone grafts and characterized the mechanical properties, pore architecture, and cure rates. In this study, calcium phosphate nanoparticles and demineralized bone matrix (DBM) particles were incorporated into injectable polyHIPE foams to promote osteoblastic differentiation of mesenchymal stem cells (MSCs). Upon incorporation of each type of particle, stable monoliths were formed with compressive properties comparable to control polyHIPEs. Pore size quantification indicated a negligible effect of all particles on emulsion stability and resulting pore architecture. Alizarin red calcium staining illustrated the incorporation of calcium phosphate particles at the pore surface, while picrosirius red collagen staining illustrated collagen-rich DBM particles within the monoliths. Osteoinductive particles had a negligible effect on the compressive modulus (~30 MPa), which remained comparable to human cancellous bone values. All polyHIPE compositions promoted human MSC viability (~90%) through 2 weeks. Furthermore, gene expression analysis indicated the ability of all polyHIPE compositions to promote osteogenic differentiation through the upregulation of bone-specific markers compared to a time zero control. These findings illustrate the potential for these osteoinductive polyHIPEs to promote osteogenesis and validate future in vivo evaluation. Overall, this work demonstrates the ability to incorporate a range of bioactive components into propylene fumarate dimethacrylate-based injectable polyHIPEs to increase cellular interactions and direct specific behavior without compromising scaffold architecture and resulting properties for various tissue engineering applications. PMID- 26739123 TI - A possible role for the immune system in adult neurogenesis: new insights from an invertebrate model. AB - Persistent neurogenesis in the adult brain of both vertebrates and invertebrates was previously considered to be driven by self-renewing neuronal stem cells of ectodermal origin. Recent findings in an invertebrate model challenge this view and instead provide evidence for a recruitment of neuronal precursors from a non neuronal source. In the brain of adult crayfish, a neurogenic niche was identified that contributes progeny to the adult central olfactory pathway. The niche may function in attracting cells from the hemolymph and transforming them into cells with a neuronal fate. This finding implies that the first-generation neuronal precursors located in the crayfish neurogenic niche are not self renewing. Evidence is summarized in support of a critical re-evaluation of long term self-renewal of mammalian neuronal stem cells. Latest findings suggest that a tight link between the immune system and the system driving adult neurogenesis may not only exist in the crayfish but also in mammals. PMID- 26739124 TI - Can we safely deform a plate to fit every bone? Population-based fit assessment and finite element deformation of a distal tibial plate. AB - Anatomically precontoured plates are commonly used to treat periarticular fractures. A well-fitting plate can be used as a tool for anatomical reduction of the fractured bone. Recent studies highlighted that some plates fit poorly for many patients due to considerable shape variations between bones of the same anatomical site. While it is impossible to design one shape that fits all, it is also burdensome for the manufacturers and hospitals to produce, store and manage multiple plate shapes without the certainty of utilization by a patient population. In this study, we investigated the number of shapes required for maximum fit within a given dataset, and if they could be obtained by manually deforming the original plate. A distal medial tibial plate was automatically positioned on 45 individual tibiae, and the optimal deformation was determined iteratively using finite element analysis simulation. Within the studied dataset, we found that: (i) 89% fit could be achieved with four shapes, (ii) 100% fit was impossible through mechanical deformation, and (iii) the deformations required to obtain the four plate shapes were safe for the stainless steel plate for further clinical use. The proposed framework is easily transferable to other orthopaedic plates. PMID- 26739125 TI - Needle-Stick Injury Caused by a Patient With Severe Fever With Thrombocytopenia Syndrome in Korea. PMID- 26739126 TI - Targeted pruning of a neuron's dendritic tree via femtosecond laser dendrotomy. AB - Neurons are classified according to action potential firing in response to current injection. While such firing patterns are shaped by the composition and distribution of ion channels, modelling studies suggest that the geometry of dendritic branches also influences temporal firing patterns. Verifying this link is crucial to understanding how neurons transform their inputs to output but has so far been technically challenging. Here, we investigate branching-dependent firing by pruning the dendritic tree of pyramidal neurons. We use a focused ultrafast laser to achieve highly localized and minimally invasive cutting of dendrites, thus keeping the rest of the dendritic tree intact and the neuron functional. We verify successful dendrotomy via two-photon uncaging of neurotransmitters before and after dendrotomy at sites around the cut region and via biocytin staining. Our results show that significantly altering the dendritic arborisation, such as by severing the apical trunk, enhances excitability in layer V cortical pyramidal neurons as predicted by simulations. This method may be applied to the analysis of specific relationships between dendritic structure and neuronal function. The capacity to dynamically manipulate dendritic topology or isolate inputs from various dendritic domains can provide a fresh perspective on the roles they play in shaping neuronal output. PMID- 26739127 TI - A cross-sectional survey of the Maltese general public on medication wastage. AB - BACKGROUND: Medication wastage is a global issue, with key public health implications in terms of safety, the environment and the economy. A recently conducted systematic review of the published literature identified a lack of focus on the views of healthcare professionals and the general public. OBJECTIVE: To explore awareness, attitudes and behaviours relating to medication wastage amongst the general public in Malta. SETTING: Malta. METHOD: Survey methodology employing a pre-piloted questionnaire was developed from theoretical frameworks of behaviour. Questionnaire items comprised open, closed and 5-point Likert scales. Medication adherence as a possible factor associated with wastage was measured using the 8-item Morisky Medication Adherence Scale. Random sample of 1920 was obtained from the Maltese electoral register 2013. Ethical approval was obtained. MAIN OUTCOME MEASURES: Awareness, attitudes and behaviours relating to medication wastage amongst the general public in Malta. RESULTS: Response rate was 20.4 %. The majority (70.6 %) agreed that they were fully aware of the issue of wastage and 71.9 % disagreed that they had no interest in wastage. The following were significantly related to increased awareness of wastage: older age (p = 0.003), pensioners (p = 0.011), on regular medication (p = 0.021) and obtaining free medication (p = 0.026). Lack of interest in wastage was significantly related to obtaining free medication by government (p = 0.022), with those purchasing medication being significantly more interested (p = 0.028). While 75.1 % of respondents on regular medication self-reported not being fully adherent, there were no associations with awareness (p = 0.100) and interest in wastage (p = 0.385). Unemployed were more likely to report contribution towards wastage (p = 0.010) and the presence of a healthcare professional as family member was significantly related to confidence in ability to reduce wastage (p = 0.009). 46.2 % claimed to have unused medication at home and improvement in patient's medical condition was the main reason for this. CONCLUSION: More effort is warranted to raise awareness of the public as an initial step in promoting behavioural change in relation to medication wastage. PMID- 26739128 TI - Medicines reconciliation in comparison with NICE guidelines across secondary care mental health organisations. AB - BACKGROUND: Medicines reconciliation-identifying and maintaining an accurate list of a patient's current medications-should be undertaken at all transitions of care and available to all patients. OBJECTIVE: A self-completion web survey was conducted for chief pharmacists (or equivalent) to evaluate medicines reconciliation levels in secondary care mental health organisations. SETTING: The survey was sent to secondary care mental health organisations in England, Scotland, Northern Ireland and Wales. METHOD: The survey was launched via Bristol Online Surveys. Quantitative data was analysed using descriptive statistics and qualitative data was collected through respondents free-text answers to specific questions. MAIN OUTCOMES MEASURE: Investigate how medicines reconciliation is delivered, incorporate a clear description of the role of pharmacy staff and identify areas of concern. RESULTS: Forty-two (52 % response rate) surveys were completed. Thirty-seven (88.1 %) organisations have a formal policy for medicines reconciliation with defined steps. Results show that the pharmacy team (pharmacists and pharmacy technicians) are the main professionals involved in medicines reconciliation with a high rate of doctors also involved. Training procedures frequently include an induction by pharmacy for doctors whilst the pharmacy team are generally trained by another member of pharmacy. Mental health organisations estimate that nearly 80 % of medicines reconciliation is carried out within 24 h of admission. A full medicines reconciliation is not carried out on patient transfer between mental health wards; instead quicker and less exhaustive variations are implemented. 71.4 % of organisations estimate that pharmacy staff conduct daily medicine reconciliations for acute admission wards (Monday to Friday). However, only 38 % of organisations self-report to pharmacy reconciling patients' medication for other teams that admit from primary care. CONCLUSION: Most mental health organisations appear to be complying with NICE guidance on medicines reconciliation for their acute admission wards. However, medicines reconciliation is conducted less frequently on other units that admit from primary care and rarely completed on transfer when it significantly differs to that on admission. Formal training and competency assessments on medicines reconciliation should be considered as current training varies and adherence to best practice is questionable. PMID- 26739129 TI - 44th ESCP International Symposium on Clinical Pharmacy Medicines Information: Making Better Decisions : Lisbon, Portugal, 28-30 October 2015. PMID- 26739130 TI - Clinical and conventional pharmacy services in Polish hospitals: a national survey. AB - BACKGROUND: Pharmacist-led care services within the hospital pharmacy setting have a significant impact on efficient drug management processes. The work of pharmacists is directly associated with the provision of drugs and medical supplies along with additional clinical, administrative, organizational and educational duties. Depending on the country, these practice roles may differ to a significant extent. OBJECTIVE: The aim of this research was to explore the role of the hospital pharmacist and the provision of both clinical and traditional pharmaceutical services for patients and medical staff in Polish general hospitals. SETTING: Hospital pharmacies from all general hospitals in Poland. METHOD: A cross-sectional study was conducted, utilizing an anonymous questionnaire as the research instrument. Heads of hospital pharmacies were requested to participate in this study and complete the questionnaire. The survey was initially piloted to improve the research method. MAIN OUTCOME MEASURE: The types of pharmaceutical services performed in Polish general hospitals. RESULTS: 166 hospital pharmacies took part in this survey. The overall response rate was 60.8 %. The total number of full-time equivalent (FTE) professionals employed within the surveyed hospital pharmacies was approximately 833. The procurement and distribution of drugs were identified as pharmaceutical services performed by most of the participants. The significant majority of pharmacists were also involved in compounding, adverse drug reaction monitoring and rational drug management services. Eleven (7 %) of the responding pharmacists had direct contact with patients and 7 (4 %) pharmacists took part in ward rounds. More precise legal regulations regarding hospital pharmacy practice were measures indicated by most pharmacists as necessary changes required in the hospital pharmacy system. CONCLUSION: Polish hospital pharmacists provide various pharmaceutical services. Their work is closely related with direct provision of drugs. There is an observed inadequate level of clinical services provided in comparison to clinical settings in other countries. PMID- 26739131 TI - Corrigendum: Efficient amplification of self-gelling polypod-like structured DNA by rolling circle amplification and enzymatic digestion. PMID- 26739134 TI - Need to improve awareness and management of hepatitis B reactivation in patients receiving immunosuppressive therapy. AB - Hepatitis B reactivation in patients receiving immunosuppressive therapy is not an uncommon event because of upsurge in the development of more potent and new immunosuppressive therapy (IST) including monoclonal antibodies leading to profound B cell depletion. However, this condition is still not being commonly made known to practising clinicians. More importantly, serious adverse outcomes including liver decompensation and death have been reported from time to time. This is likely related to the insufficient efforts to disseminate the knowledge or inattentive attitude from clinicians towards the need for hepatitis B virus screening before starting IST. It is of crucial importance, as these adverse outcomes are largely preventable by prophylactic or early treatment by antiviral agents. The risk of hepatitis B reactivation depends on the type and duration of the IST, patient characteristics and disease conditions. While we are eagerly waiting for a more cohesive consensual management recommendations from the different specialties who are involved in managing these patients, consolidated data are readily available for clinicians to define whether their patients would have a low or a high risk of hepatitis B reactivation. A management strategy without ambiguity should be formulated. PMID- 26739135 TI - Prevention and management of hepatitis B virus reactivation in cancer patients. AB - Hepatitis B virus (HBV) reactivation during immunosuppressive therapy is common in patients with solid tumor or hematological malignancies. It is associated with significant morbidity and mortality due to hepatitis flare and/or hepatic decompensation. These consequences arising from HBV reactivation are, however, largely preventable. Routine screening for HBV serologic status is recommended for all cancer patients undergoing chemotherapy or biologics. By recognizing different serological patterns (which represent either overt or occult HBV infection) and the types of immunosuppressive therapies prescribed, a risk adapted approach can be established. Prophylactic therapy with nucleos(t)ide analogues (prior to or concomitantly with the commencement of immunosuppressive therapies) is more effective than pre-emptive therapy (starting antiviral when HBV DNA level is rising) in high-risk individuals. Entecavir has been proven to be more effective than lamivudine according to recent studies. Close monitoring of serum HBV level is the preferred strategy in low-risk patients. However, the optimal interval of DNA monitoring and the duration of therapy remain unknown. PMID- 26739133 TI - Mathematical Frameworks for Oscillatory Network Dynamics in Neuroscience. AB - The tools of weakly coupled phase oscillator theory have had a profound impact on the neuroscience community, providing insight into a variety of network behaviours ranging from central pattern generation to synchronisation, as well as predicting novel network states such as chimeras. However, there are many instances where this theory is expected to break down, say in the presence of strong coupling, or must be carefully interpreted, as in the presence of stochastic forcing. There are also surprises in the dynamical complexity of the attractors that can robustly appear-for example, heteroclinic network attractors. In this review we present a set of mathematical tools that are suitable for addressing the dynamics of oscillatory neural networks, broadening from a standard phase oscillator perspective to provide a practical framework for further successful applications of mathematics to understanding network dynamics in neuroscience. PMID- 26739137 TI - Prospective clinical and radiostereometric analysis of the Fitmore short-stem total hip arthroplasty. AB - INTRODUCTION: Uncemented short, curved femoral stems may help save proximal bone stock during total hip arthroplasty (THA) and facilitate insertion in minimal invasive surgery. The aim of this 2 year, prospective, single-center study was to examine the stability and migration of the Fitmore ((r)) stem in THA using model based radiostereometric analysis (RSA), and thus predict the implant's long-term survival. In addition, we evaluated the stem's clinical performance using standard clinical measures. PATIENTS AND METHODS: We conducted a prospective cohort study of 34 THA patients who received the short Fitmore Hip Stem (Zimmer, Winterthur, Switzerland). At 3, 6, 12 and 24 months postoperatively, the patients underwent clinical evaluation and radiostereometric analysis (RSA) to measure stem migration. RESULTS: RSA analysis revealed a mean subsidence of -0.39 mm (95 % CI -0.60 to -0.18) at 3 months with no further migration after 2 years. Mean internal rotation along the longitudinal axis was 1.09 degrees (95 % CI 0.52 1.66) at 2 years, versus 0.85 degrees (95 % CI 0.44-1.26) at 3 months. The Harris hip score improved from 60 (range 30-80) preoperatively to 99 (range 83 100) after 2 years. Three patients underwent revision due to deep infection, non specific thigh pain and aseptic loosening in one case. CONCLUSION: We conclude that the Fitmore Hip Stem stabilizes after 3 months and achieves good short-term clinical results in most cases. PMID- 26739138 TI - Measurement of rotational and coronal alignment in total knee arthroplasty using a navigation system is reproducible. AB - INTRODUCTION: Intraoperative kinematic analysis using a navigation system in total knee arthroplasty (TKA) has been increasing. The purpose of the present study was to assess the reproducibility of the intraoperative kinematics analysis in TKA using the image-free knee navigation system. MATERIALS AND METHODS: Fifty one knees in 45 patients who received TKA, performed by a single surgeon (the senior consultant) with the resident, were included in this retrospective study. There were 7 men and 38 women and the mean age was 74.3 years. Cruciate retaining (CR) type and posterior stabilized (PS) type implants were inserted into 38 and 13 knees. The senior consultant and the resident analyzed initial kinematics, the axial rotation of the tibia and the coronal alignment of the lower limb, three times in each knee on manual passive knee flexion intraoperatively using the navigation system. Intra-class correlation coefficients (ICC) with 95 % confidence intervals were calculated to determine the reproducibility of this analysis. RESULTS: In regard to intra-rater reproducibility with axial rotation of the tibia, the ICC of the senior consultant was 0.965 for CR knees and 0.972 for PS knees while the ICC of the resident were 0.966 and 0.956. Inter-rater reproducibility was excellent for both knee types (ICC, 0.885 for CR knees and 0.864 for PS knees). In regard to intra-rater reproducibility with coronal alignment of the lower limb, ICC of the senior consultant was 0.990 for CR knees and 0.996 for PS knees while those of the resident were 0.990 and 0.995. Inter rater reproducibility was also excellent for both knee types (ICC, 0.978 for CR knees and 0.994 for PS knees). CONCLUSIONS: Manual intraoperative kinematic analysis using a navigation system in TKA showed excellent reproducibility. This result may encourage further studies about intraoperative kinematic analysis using a navigation system in TKA. PMID- 26739136 TI - Natural product discovery: past, present, and future. AB - Microorganisms have provided abundant sources of natural products which have been developed as commercial products for human medicine, animal health, and plant crop protection. In the early years of natural product discovery from microorganisms (The Golden Age), new antibiotics were found with relative ease from low-throughput fermentation and whole cell screening methods. Later, molecular genetic and medicinal chemistry approaches were applied to modify and improve the activities of important chemical scaffolds, and more sophisticated screening methods were directed at target disease states. In the 1990s, the pharmaceutical industry moved to high-throughput screening of synthetic chemical libraries against many potential therapeutic targets, including new targets identified from the human genome sequencing project, largely to the exclusion of natural products, and discovery rates dropped dramatically. Nonetheless, natural products continued to provide key scaffolds for drug development. In the current millennium, it was discovered from genome sequencing that microbes with large genomes have the capacity to produce about ten times as many secondary metabolites as was previously recognized. Indeed, the most gifted actinomycetes have the capacity to produce around 30-50 secondary metabolites. With the precipitous drop in cost for genome sequencing, it is now feasible to sequence thousands of actinomycete genomes to identify the "biosynthetic dark matter" as sources for the discovery of new and novel secondary metabolites. Advances in bioinformatics, mass spectrometry, proteomics, transcriptomics, metabolomics and gene expression are driving the new field of microbial genome mining for applications in natural product discovery and development. PMID- 26739139 TI - Biomechanical effect of unloader braces for medial osteoarthritis of the knee: a systematic review (CRD 42015026136). AB - PURPOSE: There is a lack of consensus regarding biomechanical effects of unloader braces for the treatment of medial osteoarthritis (OA) of the knee. The purpose of this study was to perform a systematic review of studies examining the biomechanical effect of unloader braces. METHODS: A systematic search for articles about the biomechanical effect of unloader braces was performed. Primary outcome measure was the influence of the brace on the knee adduction moment. Data sources were Pubmed central and google scholar. RESULTS: Twenty-four articles were included. Twenty articles showed that valgus unloader braces significantly decrease the knee adduction moment. Seven of those studies reported a decrease of pain in braced patients (secondary outcome measure). Positive effects on the knee adduction moment could be found for custom made braces for conventional knee braces and for a foot ankle orthosis. Four studies could not show any effect of knee unloader braces on the knee adduction moment although one of these studies found decreased pain in braced patients. One of these studies examined healthy patients with a neutral axis. CONCLUSION: This systematic review could demonstrate evidence that unloader braces reduce the adduction moment of the knee. Foresighted, a systematic review about the clinical effect of unloader braces is required. PMID- 26739140 TI - The neuroimaging of Leigh syndrome: case series and review of the literature. AB - Leigh syndrome by definition is (1) a neurodegenerative disease with variable symptoms, (2) caused by mitochondrial dysfunction from a hereditary genetic defect and (3) accompanied by bilateral central nervous system lesions. A genetic etiology is confirmed in approximately 50% of patients, with more than 60 identified mutations in the nuclear and mitochondrial genomes. Here we review the clinical features and imaging studies of Leigh syndrome and describe the neuroimaging findings in a cohort of 17 children with genetically confirmed Leigh syndrome. MR findings include lesions in the brainstem in 9 children (53%), basal ganglia in 13 (76%), thalami in 4 (24%) and dentate nuclei in 2 (12%), and global atrophy in 2 (12%). The brainstem lesions were most frequent in the midbrain and medulla oblongata. With follow-up an increased number of lesions from baseline was observed in 7 of 13 children, evolution of the initial lesion was seen in 6, and complete regression of the lesions was seen in 3. No cerebral white matter lesions were found in any of the 17 children. In concordance with the literature, we found that Leigh syndrome follows a similar pattern of bilateral, symmetrical basal ganglia or brainstem changes. Lesions in Leigh syndrome evolve over time and a lack of visible lesions does not exclude the diagnosis. Reversibility of lesions is seen in some patients, making the continued search for treatment and prevention a priority for clinicians and researchers. PMID- 26739142 TI - Patient-Reported Defecation and Micturition Problems Among Adults Treated for Sacrococcygeal Teratoma During Childhood--The Need for New Surveillance Strategies. AB - BACKGROUND: To evaluate defecation and micturition complaints in adults treated for sacrococcygeal teratoma (SCT) during childhood and to identify risk factors for soiling, urinary incontinence, and constipation beyond childhood. PROCEDURE: Records of patients aged >=18 treated for SCT during infancy in the Netherlands were retrospectively reviewed. Frequency and severity of soiling, constipation, and urinary incontinence were evaluated using questionnaires designed in line with the Krickenbeck classification. Problems during childhood were compared to outcomes at adult age in part of the cohort. Associations between patient- and disease-related factors with complaints beyond childhood were analyzed with the chi-square test or Fisher's exact test, when appropriate. RESULTS: Of 47 included patients (mean age 26.2 years, SD +/-6.5), 49% reported at least one defecation or micturition complaint. Urinary incontinence was present in 30% and had a greater negative impact than soiling (24%). Ten patients (21%) reported constipation; five found this severely bothering. Three patients reported social restrictions due to defecation or micturition complaints (6.4%). While sex and tumor histology were not identified as risk factors, a tumor diameter of >10 cm and Altman type I or type II SCT were associated with constipation during adulthood. CONCLUSIONS: One-third of the patients treated for SCT during childhood reported urinary and defecation problems beyond childhood. In only a minority of cases, these led to social restrictions. A greater tumor diameter was associated with a higher risk of constipation during adulthood. Prolonged surveillance strategies are advised for all patients with SCT. PMID- 26739141 TI - Third-generation dual-source 70-kVp chest CT angiography with advanced iterative reconstruction in young children: image quality and radiation dose reduction. AB - BACKGROUND: Many technical updates have been made in multi-detector CT. OBJECTIVE: To evaluate image quality and radiation dose of high-pitch second- and third-generation dual-source chest CT angiography and to assess the effects of different levels of advanced modeled iterative reconstruction (ADMIRE) in newborns and children. MATERIALS AND METHODS: Chest CT angiography (70 kVp) was performed in 42 children (age 158 +/- 267 days, range 1-1,194 days). We evaluated subjective and objective image quality, and radiation dose with filtered back projection (FBP) and different strength levels of ADMIRE. For comparison were 42 matched controls examined with a second-generation 128-slice dual-source CT scanner (80 kVp). RESULTS: ADMIRE demonstrated improved objective and subjective image quality (P < .01). Mean signal/noise, contrast/noise and subjective image quality were 11.9, 10.0 and 1.9, respectively, for the 80 kVp mode and 11.2, 10.0 and 1.9 for the 70 kVp mode. With ADMIRE, the corresponding values for the 70 kVp mode were 13.7, 12.1 and 1.4 at strength level 2 and 17.6, 15.6 and 1.2 at strength level 4. Mean CTDIvol, DLP and effective dose were significantly lower with the 70-kVp mode (0.31 mGy, 5.33 mGy*cm, 0.36 mSv) compared to the 80-kVp mode (0.46 mGy, 9.17 mGy*cm, 0.62 mSv; P < .01). CONCLUSION: The third-generation dual-source CT at 70 kVp provided good objective and subjective image quality at lower radiation exposure. ADMIRE improved objective and subjective image quality. PMID- 26739143 TI - Mixing characteristics of sludge simulant in a model anaerobic digester. AB - This study aims to investigate the mixing characteristics of a transparent sludge simulant in a mechanically agitated model digester using flow visualisation technique. Video images of the flow patterns were obtained by recording the progress of an acid-base reaction and analysed to determine the active and inactive volumes as a function of time. The doughnut-shaped inactive region formed above and below the impeller in low concentration simulant decreases in size with time and disappears finally. The 'cavern' shaped active mixing region formed around the impeller in simulant solutions with higher concentrations increases with increasing agitation time and reaches a steady state equilibrium size, which is a function of specific power input. These results indicate that the active volume is jointly determined by simulant rheology and specific power input. A mathematical correlation is proposed to estimate the active volume as a function of simulant concentration in terms of yield Reynolds number. PMID- 26739144 TI - The optimization of operating parameters on microalgae upscaling process planning. AB - The upscaling process planning developed in this study primarily involved optimizing operating parameters, i.e., dilution ratios, during process designs. Minimal variable cost was used as an indicator for selecting the optimal combination of dilution ratios. The upper and lower mean confidence intervals obtained from the actual cultured cell density data were used as the final cell density stability indicator after the operating parameters or dilution ratios were selected. The process planning method and results were demonstrated through three case studies of batch culture simulation. They are (1) final objective cell densities were adjusted, (2) high and low light intensities were used for intermediate-scale cultures, and (3) the number of culture days was expressed as integers for the intermediate-scale culture. PMID- 26739146 TI - Bypass versus angio plasty in severe ischaemia of the leg - 2 (BASIL-2) trial: study protocol for a randomised controlled trial. AB - BACKGROUND: Severe limb ischaemia is defined by ischaemic rest/night pain, tissue loss, or both, secondary to arterial insufficiency and is increasingly caused by infra-popliteal (below the knee) disease, mainly as a result of the increasing worldwide prevalence of diabetes. Currently, it is unknown whether vein bypass surgery or the best endovascular treatment (angioplasty or stenting) represents the optimal revascularisation strategy in terms of amputation-free survival, overall survival, relief of symptoms, quality of life and cost-effective use of health care resources. METHODS/DESIGN: The Bypass vs. Angioplasty in Severe Ischaemia of the Leg - 2 Trial is a UK National Institute of Health Research, Health Technology Assessment funded, multi-centre randomised controlled trial that compares, at the point of clinical equipoise, the clinical and cost effectiveness of a 'vein bypass first' and a 'best endovascular treatment first' revascularisation strategy for severe limb ischaemia due to infra-popliteal disease. The primary clinical outcome is amputation-free survival defined as the time to major (above the ankle) amputation of the trial limb or death from any cause. The primary outcome for the cost-effectiveness analysis is cost per quality-adjusted life year. Secondary outcomes include overall survival, quality of life, in-hospital mortality and morbidity, repeat and crossover interventions, healing of tissue loss and haemodynamic changes following revascularisation. Sample size is estimated at 600 patients. An economic evaluation will be conducted from the perspective of the National Health Service and comprise a 'within-study' analysis, based on prospectively collected trial data and a 'model based' analysis, which will extrapolate and compare costs and effects beyond the study follow-up period. DISCUSSION: The BASIL-2 trial is designed to be pragmatic and represent current practice within the United Kingdom. Patients with severe limb ischaemia can only be randomised into the trial where clinical equipose exists. The advent of hybrid operating procedures should not be a barrier to randomisation, should a patient require inflow correction prior to tibial revascularisation. TRIAL REGISTRATION: ISRCTN: 27728689 Date of registration: 12 May 2014. PMID- 26739145 TI - Clinical diagnostics and therapy monitoring in the congenital disorders of glycosylation. AB - Abnormal protein glycosylation is observed in many common disorders like cancer, inflammation, Alzheimer's disease and diabetes. However, the actual use of this information in clinical diagnostics is still very limited. Information is usually derived from analysis of total serum N-glycan profiling methods, whereas the current use of glycoprotein biomarkers in the clinical setting is commonly based on protein levels. It can be envisioned that combining protein levels and their glycan isoforms would increase specificity for early diagnosis and therapy monitoring. To establish diagnostic assays, based on the mass spectrometric analysis of protein-specific glycosylation abnormalities, still many technical improvements have to be made. In addition, clinical validation is equally important as well as an understanding of the genetic and environmental factors that determine the protein-specific glycosylation abnormalities. Important lessons can be learned from the group of monogenic disorders in the glycosylation pathway, the Congenital Disorders of Glycosylation (CDG). Now that more and more genetic defects are being unraveled, we start to learn how genetic factors influence glycomics profiles of individual and total serum proteins. Although only in its initial stages, such studies suggest the importance to establish diagnostic assays for protein-specific glycosylation profiling, and the need to look beyond the single glycoprotein diagnostic test. Here, we review progress in and lessons from genetic disease, and review the increasing opportunities of mass spectrometry to analyze protein glycosylation in the clinical diagnostic setting. Furthermore, we will discuss the possibilities to expand current CDG diagnostics and how this can be used to approach glycoprotein biomarkers for more common diseases. PMID- 26739148 TI - Neoadjuvant chemotherapy plus intensity-modulated radiotherapy versus concurrent chemoradiotherapy plus adjuvant chemotherapy for the treatment of locoregionally advanced nasopharyngeal carcinoma: a retrospective controlled study. AB - BACKGROUND: In the era of intensity-modulated radiotherapy (IMRT), the role of neoadjuvant chemotherapy (NAC) for locoregionally advanced nasopharyngeal carcinoma (NPC) is under-evaluated. The aim of this study was to compare the efficacy of NAC plus IMRT and concurrent chemoradiotherapy (CCRT) plus adjuvant chemotherapy (AC) on locoregionally advanced NPC. METHODS: Between January 2004 and December 2008, 240 cases of locoregionally advanced NPC confirmed by pathologic assessment in Sun Yat-sen University Cancer Center were reviewed. Of the 240 patients, 117 received NAC followed by IMRT, and 123 were treated with CCRT plus AC. The NAC + IMRT group received a regimen that included cisplatin and 5-fluorouracil (5-FU). The CCRT + AC group received cisplatin concurrently with radiotherapy, and subsequently received adjuvant cisplatin and 5-FU. The survival rates were assessed by Kaplan-Meier analysis, and the survival curves were compared using a log-rank test. Multivariate analysis was conducted using the Cox proportional hazard regression model. RESULTS: The 5-year overall survival (OS), locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) were 78.0, 87.9, 79.0, and 69.8%, respectively, for the NAC + IMRT group and 78.7, 84.8, 76.2, and 65.6%, respectively, for the CCRT + AC group. There were no significant differences in survival between the two groups. In multivariate analysis, age (<50 years vs. >=50 years) and overall stage (III vs. IV) were found to be independent predictors for OS and DFS; furthermore, the overall stage was a significant prognostic factor for DMFS. Compared with the CCRT + AC protocol, the NAC + IMRT protocol significantly reduced the occurrence rates of grade 3-4 nausea-vomiting (6.5 vs. 1.5%, P = 0.023) and leukopenia (9.7 vs. 0.8%, P = 0.006). CONCLUSIONS: The treatment outcomes of the NAC + IMRT and CCRT + AC groups were similar. Distant metastasis remained the predominant mode of treatment failure. PMID- 26739150 TI - Current Recommendations for Minimally Invasive Surgical Staging in Ovarian Cancer. AB - OPINION STATEMENT: Minimally invasive surgery (MIS) currently is performed to stage and treat ovarian cancer at different stages of disease; however, the higher level of evidence from existing studies is IIB. Despite the absence of randomized controlled trials, MIS represents a safe and adequate procedure for treating and staging early ovarian cancer, and its use has increased significantly in clinical practice. Major concerns are related to minimizing tumor disruption or dissemination, removing the adnexal mass intact, adequate retroperitoneal staging, and fertility-sparing surgery for young patients. The main goal for patients with advanced ovarian cancer is to determine the best therapeutic strategy by evaluating the risks and benefits of primary debulking surgery versus neoadjuvant chemotherapy followed by interval debulking surgery. The use of staging laparoscopy in patients with advanced epithelial ovarian cancer appears to be the most researched and accepted approach. Regarding other types and stages of ovarian cancer, although the evidence is very promising, clinical trials performed by expert gynecologic oncology surgeons in referral centers are still needed to prove the efficacy of such an approach in these patients. In particular, MIS has provided an opportunity to remove localized recurrences, with both retroperitoneal and intraperitoneal diffusion. PMID- 26739151 TI - Does Radiation Have a Role in Advanced Stage Hodgkin's or Non-Hodgkin Lymphoma? AB - OPINION STATEMENT: Radiation therapy (RT) is one of the most effective agents available in the treatment of lymphomas. However, it is a local treatment, and today, with systemic treatments assuming a primary role for induction of response, RT is primarily used for consolidation. For advanced stage lymphomas, the indications for the use of RT have been questioned and debated, and proper randomized evidence is sparse. RT has significant long-term side effects, and the very extended RT fields of the past yielded unacceptable toxicity in many patients. Modern advanced imaging and conformal RT techniques now enable treatment of larger and anatomically more challenging target volumes with much less radiation to normal tissues and consequently much lower risks of long-term complications. The modern concept of involved site radiation therapy (ISRT) has now been accepted as standard in lymphomas. In advanced Hodgkin lymphoma (HL), RT to residual disease and/or initial bulk benefits some patients, depending on the chemotherapy regimen used. The more intensive the chemotherapy regimen, the fewer patients benefit from RT. In advanced aggressive non-Hodgkin lymphoma (NHL), most of the evidence comes from the most common type, the diffuse large B cell lymphoma (DLBCL). In patients treated with modern immunochemotherapy, RT to initial bulky disease or extralymphatic involvement is beneficial. For both HL and aggressive NHL, RT to residual masses after systemic treatment is of benefit. The role of PET in the evaluation and indication for RT to residual masses has not been tested in randomized trials. In advanced indolent NHL, very low dose RT offers excellent palliation with very few side effects. Modern RT in advanced lymphomas warrants further evaluation in randomized trials. PMID- 26739152 TI - The Problem of Carbapenemase-Producing-Carbapenem-Resistant-Enterobacteriaceae Detection. AB - The emergence and spread of carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CP-CRE) are a significant clinical and public health concern. Reliable detection of CP-CRE is the first step in combating this problem. There are both phenotypic and molecular methods available for CP-CRE detection. There is no single detection method that is ideal for all situations. PMID- 26739153 TI - Species-Level Identification of Actinomyces Isolates Causing Invasive Infections: Multiyear Comparison of Vitek MS (Matrix-Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry) to Partial Sequencing of the 16S rRNA Gene. AB - Actinomyces species are uncommon but important causes of invasive infections. The ability of our regional clinical microbiology laboratory to report species-level identification of Actinomyces relied on molecular identification by partial sequencing of the 16S ribosomal gene prior to the implementation of the Vitek MS (matrix-assisted laser desorption ionization-time of flight mass spectrometry [MALDI-TOF MS]) system. We compared the use of the Vitek MS to that of 16S rRNA gene sequencing for reliable species-level identification of invasive infections caused by Actinomyces spp. because limited data had been published for this important genera. A total of 115 cases of Actinomyces spp., either alone or as part of a polymicrobial infection, were diagnosed between 2011 and 2014. Actinomyces spp. were considered the principal pathogen in bloodstream infections (n = 17, 15%), in skin and soft tissue abscesses (n = 25, 22%), and in pulmonary (n = 26, 23%), bone (n = 27, 23%), intraabdominal (n = 16, 14%), and central nervous system (n = 4, 3%) infections. Compared to sequencing and identification from the SmartGene Integrated Database Network System (IDNS), Vitek MS identified 47/115 (41%) isolates to the correct species and 10 (9%) isolates to the correct genus. However, the Vitek MS was unable to provide identification for 43 (37%) isolates while 15 (13%) had discordant results. Phylogenetic analyses of the 16S rRNA sequences demonstrate high diversity in recovered Actinomyces spp. and provide additional information to compare/confirm discordant identifications between MALDI-TOF and 16S rRNA gene sequences. This study highlights the diversity of clinically relevant Actinomyces spp. and provides an important typing comparison. Based on our analysis, 16S rRNA gene sequencing should be used to rapidly identify Actinomyces spp. until MALDI-TOF databases are optimized. PMID- 26739154 TI - PCR-Based Rapid Identification System Using Bridged Nucleic Acids for Detection of Clarithromycin-Resistant Mycobacterium avium-M. intracellulare Complex Isolates. AB - The nontuberculous mycobacteria (NTM) cause miscellaneous disorders in humans, especially in the lungs, which present with a variety of radiological features. To date, knowledge of the pathogenic role of the Mycobacterium avium intracellulare complex (MAC) in the human lung and the definitive criteria for initiating multidrug therapy are still lacking. However, there is little doubt that clarithromycin is the most efficacious drug among the various treatment regimens for lung NTM. In this study, with the use of a bridged nucleic acid (BNA) probe a detection system based on a real-time PCR (BNA-PCR) for the identification of the point mutations at position 2058 or 2059 in domain V of the 23S rRNA gene responsible for clarithromycin resistance was developed and has been assessed using MAC isolates from clinical samples. Out of 199 respiratory specimens, the drug susceptibility test demonstrated 12 strains resistant to clarithromycin, while the BNA-PCR showed 8 strains carrying the point mutation at position 2058 or 2059 of the 23S rRNA gene. This system revealed that there were mycobacterial strains resistant to clarithromycin which do not carry previously identified resistance genes. This paper documents a novel system for detecting clarithromycin-resistant strains and demonstrates that although these mutations are tacitly assumed to account for >90% of the reported resistant mutants, there is a significant fraction of resistant mutants that do not harbor these mutations. Therefore, unknown mechanisms affecting clarithromycin resistance remain to be elucidated. PMID- 26739155 TI - Variable-Number Tandem-Repeat Analysis of Respiratory and Household Water Biofilm Isolates of "Mycobacterium avium subsp. hominissuis" with Establishment of a PCR Database. AB - "Mycobacterium aviumsubsp.hominissuis" is an important cause of pulmonary disease. It is acquired from environmental sources, but there is no methodology for large population studies. We evaluated the potential of variable-number tandem-repeat (VNTR) analysis. Clinical and household biofilmM. aviumisolates underwent molecular identification. Testing for IS901was done to separateM. aviumsubsp.aviumfromM. aviumsubsp.hominissuis VNTR types were defined using VNTR loci, and subtyping was performed using 3'hsp65and internal transcribed spacer (ITS) sequencing. Forty-nine VNTR types and eight subtypes ofM. aviumsubsp.hominissuis(IS901negative) were identified among 416 isolates ofM. aviumfrom 121 patients and 80 biofilm sites. Of those types, 67% were found only among patient isolates, 11% only among household water isolates, and 23% among both. Of 13 VNTR types that included >=4 patients, the majority (61.5%) represented geographic clustering (same city). Most VNTR types with multiple patients belonged to the same 3'hsp65sequence code (sequevar). A total of 44 isolates belonging to fourM. aviumsubsp.hominissuisVNTR types (8%), including three with the rare Mav-F ITS sequence and 0/8 subspecies, produced amplicons with IS901PCR primers. By sequencing, all 44 amplicons were not IS901but ISMav6, which was recently observed in Japan but had not been previously described among U.S. isolates. VNTR analysis ofM. aviumsubsp.hominissuisisolates is easier and faster than pulsed-field gel electrophoresis. Seven VNTR loci separated 417 isolates into 49 types. No isolates ofM. aviumsubsp.aviumwere identified. The distributions of the VNTR copy numbers, the allelic diversity, and the low prevalence of ISMav6 differed from the findings for respiratory isolates reported from Japan. PMID- 26739156 TI - Performance and Verification of a Real-Time PCR Assay Targeting the gyrA Gene for Prediction of Ciprofloxacin Resistance in Neisseria gonorrhoeae. AB - In the United States, 19.2% of Neisseria gonorrhoeae isolates are resistant to ciprofloxacin. We evaluated a real-time PCR assay to predict ciprofloxacin susceptibility using residual DNA from the Roche Cobas 4800 CT/NG assay. The results of the assay were 100% concordant with agar dilution susceptibility test results for 100 clinical isolates. Among 76 clinical urine and swab specimens positive for N. gonorrhoeae by the Cobas assay, 71% could be genotyped. The test took 1.5 h to perform, allowing the physician to receive results in time to make informed clinical decisions. PMID- 26739157 TI - Comparison of Performance Characteristics of Aspergillus PCR in Testing a Range of Blood-Based Samples in Accordance with International Methodological Recommendations. AB - Standardized methodologies for the molecular detection of invasive aspergillosis (IA) have been established by the European Aspergillus PCR Initiative for the testing of whole blood, serum, and plasma. While some comparison of the performance of Aspergillus PCR when testing these different sample types has been performed, no single study has evaluated all three using the recommended protocols. Standardized Aspergillus PCR was performed on 423 whole-blood pellets (WBP), 583 plasma samples, and 419 serum samples obtained from hematology patients according to the recommendations. This analysis formed a bicenter retrospective anonymous case-control study, with diagnosis according to the revised European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus definitions (11 probable cases and 36 controls). Values for clinical performance using individual and combined samples were calculated. For all samples, PCR positivity was significantly associated with cases of IA (for plasma, P = 0.0019; for serum, P = 0.0049; and for WBP, P = 0.0089). Plasma PCR generated the highest sensitivity (91%); the sensitivities for serum and WBP PCR were 80% and 55%, respectively. The highest specificity was achieved when testing WBP (96%), which was significantly superior to the specificities achieved when testing serum (69%, P = 0.0238) and plasma (53%, P = 0.0002). No cases were PCR negative in all specimen types, and no controls were PCR positive in all specimens. This study confirms that Aspergillus PCR testing of plasma provides robust performance while utilizing commercial automated DNA extraction processes. Combining PCR testing of different blood fractions allows IA to be both confidently diagnosed and excluded. A requirement for multiple PCR-positive plasma samples provides similar diagnostic utility and is technically less demanding. Time to diagnosis may be enhanced by testing multiple contemporaneously obtained sample types. PMID- 26739158 TI - Evaluation of the FilmArray Blood Culture Identification Panel: Results of a Multicenter Controlled Trial. AB - Sepsis is a major cause of morbidity, mortality, and increased medical expense. Rapid diagnosis improves outcomes and reduces costs. The FilmArray blood culture identification panel (BioFire Diagnostics LLC, Salt Lake City, UT), a highly multiplexed PCR assay, can identify 24 etiologic agents of sepsis (8 Gram positive, 11 Gram-negative, and 5 yeast species) and three antimicrobial resistance genes (mecA, vanA/B, and blaKPC) from positive blood culture bottles. It provides results in about 1 h with 2 min for assay setup. We present the results of an eight-center trial comparing the sensitivity and specificity of the panel with those of the laboratories' standard phenotypic identification techniques, as well as with molecular methods used to distinguish Acinetobacter baumannii from other members of the A. calcoaceticus-A. baumannii complex and to detect antimicrobial resistance genes. Testing included 2,207 positive aerobic blood culture samples, 1,568 clinical and 639 seeded. Samples were tested fresh or were frozen for later testing within 8 h after the bottles were flagged as positive by an automated blood culture system. At least one organism was detected by the panel in 1,382 (88.1%) of the positive clinical specimens. The others contained primarily off-panel organisms. The panel reported multiple organisms in 81 (5.86%) positive clinical specimens. The unresolved blood culture identification sensitivity for all target detections exceeded 96%, except for Klebsiella oxytoca (92.2%), which achieved 98.3% sensitivity after resolution of an unavoidable phenotypic error. The sensitivity and specificity for vanA/B and blaKPC were 100%; those for mecA were 98.4 and 98.3%, respectively. PMID- 26739159 TI - Cost-Effectiveness Analysis of Multiplex PCR with Magnetic Resonance Detection versus Empiric or Blood Culture-Directed Therapy for Management of Suspected Candidemia. AB - Candida bloodstream infections (BSI) are associated with significant morbidity, mortality, and increased health care costs. Early treatment is essential, because delayed therapy detrimentally impacts clinical outcomes. The FDA recently approved the first culture-independent direct molecular detection method for Candida BSIs (T2Candida). The speed and sensitivity of this assay give it the potential to improve patient care, but the reagents and instrumentation are expensive. We used an analytic decision tree model to compare the cost effectiveness of T2Candida-directed antifungal therapy (T2DT) to that of either empirical therapy (ET) or blood culture-directed therapy (BCDT). The costs included those of T2Candida testing, antifungal treatment, and hospital length of stay. The effectiveness measure was survival status at hospital discharge. T2DT was less costly and more effective than BCDT but was less costly and less effective than ET with an echinocandin (incremental cost-effectiveness ratio, $111,084 per additional survivor). One-way sensitivity analyses demonstrated that the cost-effectiveness of T2DT was highly dependent on Candida BSI prevalence and the cost of antifungal therapy and T2Candida test reagents. The use of T2DT reduced the number of unnecessarily treated patients by 98% relative to that with ET. Reduced drug exposure might lessen the possibility of drug-related adverse events and may also prevent the development of antifungal resistance or emergence of drug-resistant Candida species. The greatest benefit of T2Candida appears to be the ability to confidently withhold or stop empirical antifungal therapy in low-to-moderate-risk patients who are unlikely to benefit from treatment. PMID- 26739161 TI - Pseudoclavibacter endophyticus sp. nov., isolated from roots of Glycyrrhiza uralensis. AB - A Gram-stain-positive, aerobic, rod-shaped, non-motile actinomycete strain, designated EGI 60007T, was isolated from healthy roots of Glycyrrhiza uralensis F. collected from Yili County, Xinjiang Province, north-west China. A polyphasic approach was applied to study the taxonomic position of the new isolate. The 16S rRNA gene sequence of strain EGI 60007T had highest similarities with members of the genus Pseudoclavibacter, including Pseudoclavibacter chungangensis CAU 59T (96.98 % 16S rRNA gene sequence similarity), Pseudoclavibacter helvolus DSM 20419T (96.43 %) and Pseudoclavibacter terrae THG-MD12T (96.14 %). The neighbour joining phylogenetic tree based on 16S rRNA gene sequences showed that strain EGI 60007T clustered with members of the genus Pseudoclavibacter, and formed a distinct clade with P. chungangensis CAU 59T. The polar lipids detected for strain EGI 60007T were phosphatidylglycerol, diphosphatidylglycerol, one unidentified glycolipid and one unidentified lipid. The DNA G+C content was determined to be 63.3 mol%. The chemotaxonomic features of strain EGI 60007T showed typical characteristics of the genus Pseudoclavibacter, with MK-9 as the respiratory quinone, 2,4-diaminobutyric acid as the diamino acid in the peptidoglycan, and anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0 as the major fatty acids. The sugars of whole-cell hydrolysates were mainly mannose, rhamnose, ribose and glucose, and a minor amount of xylose. Based on the results of the phylogentic analysis supported by morphological, physiological, chemotaxonomic and other differentiating phenotypic characteristics, strain EGI 60007T is considered to represent a novel species of the genus Pseudoclavibacter, for which the name Pseudoclavibacter endophyticus sp. nov. is proposed. The type strain is EGI 60007T ( = CGMCC 1.15081T = KCTC 39112T = DSM 29943T). PMID- 26739162 TI - Confirming the candidacy of THOC6 in the etiology of intellectual disability. PMID- 26739160 TI - Detection of Atypical H-Type Bovine Spongiform Encephalopathy and Discrimination of Bovine Prion Strains by Real-Time Quaking-Induced Conversion. AB - Prion diseases of cattle include the classical bovine spongiform encephalopathy (C-BSE) and the atypical H-type BSE (H-BSE) and L-type BSE (L-BSE) strains. Although the C- and L-BSE strains can be detected and discriminated by ultrasensitive real-time quaking-induced conversion (RT-QuIC) assays, no such test has yet been described for the detection of H-BSE or the discrimination of each of the major bovine prion strains. Here, we demonstrate an RT-QuIC assay for H-BSE that can detect as little as 10(-9) dilutions of brain tissue and neat cerebrospinal fluid samples from clinically affected cattle. Moreover, comparisons of the reactivities with different recombinant prion protein substrates and/or immunoblot band profiles of proteinase K-treated RT-QuIC reaction products indicated that H-, L-, and C-BSE have distinctive prion seeding activities and can be discriminated by RT-QuIC on this basis. PMID- 26739163 TI - Catheter Ablation of Recurrent Lone Atrial Fibrillation in Teenagers with a Structurally Normal Heart. AB - BACKGROUND: Atrial fibrillation (AF) is rare in teenagers. There are few reports and no clear guidelines on the management of AF with catheter ablation in teenagers. METHODS: A case series of teenagers (<18 years) with paroxysmal AF and a structurally normal heart who underwent catheter ablation was undertaken. RESULTS: Four teenage boys aged 15-17 years underwent catheter ablation of AF. All but one had failed antiarrhythmic medical therapy. Two had focal triggers and underwent culprit vein isolation (one recurred and so underwent isolation of an additional vein), and two had no focal triggers identified and so underwent isolation of all four pulmonary veins (PVs). At follow-up ranging from 2-6 years, one patient who underwent isolation of all four veins had recurrence of paroxysmal AF. All others have had medium and long-term success with complete absence of AF. None are on long-term antiarrhythmic therapy. No patient had a procedural or postprocedure complication. CONCLUSIONS: A cautious attempt at catheter ablation may be appropriate in teenagers with paroxysmal AF and a structurally normal heart who fail pharmacologic therapy. Culprit vein(s) isolation should be preferred if possible but if no focal triggers are identified, isolation of all PVs appears to be beneficial. PMID- 26739165 TI - Not a typical case of bilateral knee osteoarthritis. PMID- 26739166 TI - Unrecognized circulation of SAT 1 foot-and-mouth disease virus in cattle herds around Queen Elizabeth National Park in Uganda. AB - BACKGROUND: Foot-and-mouth disease (FMD) is endemic in Uganda in spite of the control measures used. Various aspects of the maintenance and circulation of FMD viruses (FMDV) in Uganda are not well understood; these include the role of the African buffalo (Syncerus caffer) as a reservoir for FMDV. To better understand the epidemiology of FMD at the livestock-wildlife-interface, samples were collected from young, unvaccinated cattle from 24 pastoral herds that closely interact with wildlife around Queen Elizabeth National Park in Uganda, and analysed for evidence of FMDV infection. RESULTS: In total, 37 (15%) of 247 serum samples had detectable antibodies against FMDV non-structural proteins (NSPs) using a pan-serotypic assay. Within these 37 sera, antibody titres >= 80 against the structural proteins of serotypes O, SAT 1, SAT 2 and SAT 3 were detected by ELISA in 5, 7, 4 and 3 samples, respectively, while neutralizing antibodies were only detected against serotype O in 3 samples. Two FMDV isolates, with identical VP1 coding sequences, were obtained from probang samples from clinically healthy calves from the same herd and are serotype SAT 1 (topotype IV (EA-I)). Based on the VP1 coding sequences, these viruses are distinct from previous cattle and buffalo SAT 1 FMDV isolates obtained from the same area (19-30% nucleotide difference) and from the vaccine strain (TAN/155/71) used within Uganda (26% nucleotide difference). Eight herds had only one or a few animals with antibodies against FMDV NSPs while six herds had more substantial evidence of prior infection with FMDV. There was no evidence for exposure to FMDV in the other ten herds. CONCLUSIONS: The two identical SAT 1 FMDV VP1 sequences are distinct from former buffalo and cattle isolates from the same area, thus, transmission between buffalo and cattle was not demonstrated. These new SAT 1 FMDV isolates differed significantly from the vaccine strain used to control Ugandan FMD outbreaks, indicating a need for vaccine matching studies. Only six herds had clear serological evidence for exposure to O and SAT 1 FMDV. Scattered presence of antibodies against FMDV in other herds may be due to the occasional introduction of animals to the area or maternal antibodies from past infection and/or vaccination. The evidence for asymptomatic FMDV infection has implications for disease control strategies in the area since this obstructs early disease detection that is based on clinical signs in FMDV infected animals. PMID- 26739169 TI - Hospice Admission Assessment. AB - Hospice admission assessment is a pivotal encounter for patient/family and hospice representative. For patient/family, the admission is the threshold by which a particular level of care can commence and, symbolically, a certain marker in health status trajectory is reached. For hospice representative, the admission episode is an occasion to inaugurate an ambience that can serve to frame future hospice care experiences for the patient/family. Through a narrative lens, hospice admission assessment can be seen as experiential time and space, where patient's and family's stories are mindfully and deliberately witnessed and explored. Through the practice of narrative mining, the hospice representative can better understand others' offered stories of reality, which will better inform the plan of palliation and hospice care. PMID- 26739167 TI - Detecting and Characterizing the Highly Divergent Plastid Genome of the Nonphotosynthetic Parasitic Plant Hydnora visseri (Hydnoraceae). AB - Plastid genomes of photosynthetic flowering plants are usually highly conserved in both structure and gene content. However, the plastomes of parasitic and mycoheterotrophic plants may be released from selective constraint due to the reduction or loss of photosynthetic ability. Here we present the greatly reduced and highly divergent, yet functional, plastome of the nonphotosynthetic holoparasite Hydnora visseri (Hydnoraceae, Piperales). The plastome is 27 kb in length, with 24 genes encoding ribosomal proteins, ribosomal RNAs, tRNAs, and a few nonbioenergetic genes, but no genes related to photosynthesis. The inverted repeat and the small single copy region are only approximately 1.5 kb, and intergenic regions have been drastically reduced. Despite extreme reduction, gene order and orientation are highly similar to the plastome of Piper cenocladum, a related photosynthetic plant in Piperales. Gene sequences in Hydnora are highly divergent and several complementary approaches using the highest possible sensitivity were required for identification and annotation of this plastome. Active transcription is detected for all of the protein-coding genes in the plastid genome, and one of two introns is appropriately spliced out of rps12 transcripts. The whole-genome shotgun read depth is 1,400* coverage for the plastome, whereas the mitochondrial genome is covered at 40* and the nuclear genome at 2*. Despite the extreme reduction of the genome and high sequence divergence, the presence of syntenic, long transcriptionally active open-reading frames with distant similarity to other plastid genomes and a high plastome stoichiometry relative to the mitochondrial and nuclear genomes suggests that the plastome remains functional in H. visseri. A four-stage model of gene reduction, including the potential for complete plastome loss, is proposed to account for the range of plastid genomes in nonphotosynthetic plants. PMID- 26739168 TI - Mobile Element Evolution Playing Jigsaw - SINEs in Gastropod and Bivalve Mollusks. AB - SINEs (Short INterspersed Elements) are widely distributed among eukaryotes. Some SINE families are organized in superfamilies characterized by a shared central domain. These central domains are conserved across species, classes, and even phyla. Here we report the identification of two novel such superfamilies in the genomes of gastropod and bivalve mollusks. The central conserved domain of the first superfamily is present in SINEs in Caenogastropoda and Vetigastropoda as well as in all four subclasses of Bivalvia. We designated the domain MESC (Romanian for MElc-snail and SCoica-mussel) because it appears to be restricted to snails and mussels. The second superfamily is restricted to Caenogastropoda. Its central conserved domain-Snail-is related to the Nin-DC domain. Furthermore, we provide evidence that a 40-bp subdomain of the SINE V-domain is conserved in SINEs in mollusks and arthropods. It is predicted to form a stable stem-loop structure that is preserved in the context of the overall SINE RNA secondary structure in invertebrates. Our analysis also recovered short retrotransposons with a Long INterspersed Element (LINE)-derived 5' end. These share the body and/or the tail with transfer RNA (tRNA)-derived SINEs within and across species. Finally, we identified CORE SINEs in gastropods and bivalves-extending the distribution range of this superfamily. PMID- 26739171 TI - The Effect of Providing Life Support on Nurses' Decision Making Regarding Life Support for Themselves and Family Members in Japan. AB - Decision making in terminal illness has recently received increased attention. In Japan, patients and their families typically make decisions without understanding either the severity of illness or the efficacy of life-supporting treatments at the end of life. Japanese culture traditionally directs the family to make decisions for the patient. This descriptive study examined the influence of the experiences of 391 Japanese nurses caring for dying patients and family members and how that experience changed their decision making for themselves and their family members. The results were mixed but generally supported the idea that the more experience nurses have in caring for the dying, the less likely they would choose to institute lifesupport measures for themselves and family members. The results have implications for discussions on end-of-life care. PMID- 26739170 TI - Validation of an Arabic Questionnaire for Symptom Assessment. AB - BACKGROUND: Impeccable assessment of symptoms is central to palliative care (PC) practice. OBJECTIVES: The study objectives are (1) to test the validity of the Arabic Questionnaire for Symptom Assessment (AQSA) as a self-administered (SA) tool for assessing the severity of the listed symptoms among PC patients and (2) to test the validity of AQSA when completed by a proxy. METHODS: The AQSA is a tool for assessing the severity of 11 symptoms in addition to the overall suffering experience on a 0 to 10 numeric scale. Symptom scores on the SA AQSA were compared to scores obtained through interviews with patients. The same procedure was repeated with patients' sitters to explore the validity of using the tool for symptom assessment by proxy. RESULTS: The study involved 107 pairs (a patient and a sitter, each) with a mean age of 46.3 years (females 59.8%) for patients and 35.9 years (females 65.7%) for sitters. The correlation coefficient ( r) for agreement between SA and interview-based (IB) scores for patients ranged from .65 ( P < .0001) for drowsiness to .86 ( P < .0001) for pain. The SA AQSA showed positive correlation between sitters' and patients' scores, with r ranging from .28 ( P = .004) for depression to .62 ( P <= .0001) for vomiting. CONCLUSIONS: The strong positive correlation between SA and IB AQSA indicates that the former is a valid tool. When the SA AQSA is used by proxy, it showed moderate to strong positive correlation with patients' actual scores for most of the symptoms. PMID- 26739174 TI - The Role of OnabotulinumtoxinA in Urology: What Is the Next Step? PMID- 26739172 TI - A human macrophage-hepatocyte co-culture model for comparative studies of infection and replication of Francisella tularensis LVS strain and subspecies holarctica and mediasiatica. AB - BACKGROUND: Francisella tularensis, a gram-negative bacterium replicates intracellularly within macrophages and efficiently evades the innate immune response. It is able to infect and replicate within Kupffer cells, specialized tissue macrophages of the liver, and to modulate the immune response upon infection to its own advantage. Studies on Francisella tularensis liver infection were mostly performed in animal models and difficult to extrapolate to the human situation, since human infections and clinical observations are rare. RESULTS: Using a human co-culture model of macrophages and hepatocytes we investigated the course of infection of three Francisella tularensis strains (subspecies holarctica--wildtype and live vaccine strain, and mediasiatica--wildtype) and analyzed the immune response triggered upon infection. We observed that hepatocytes support the intracellular replication of Franciscella species in macrophages accompanied by a specific immune response inducing TNFalpha, IL 1beta, IL-6 and fractalkine (CX3CL1) secretion and the induction of apoptosis. CONCLUSIONS: We could demonstrate that this human macrophage/hepatocyte co culture model reflects strain-specific virulence of Francisella tularensis. We developed a suitable tool for more detailed in vitro studies on the immune response upon liver cell infection by F. tularensis. PMID- 26739175 TI - Practical Aspects of Botulinum Toxin-A Treatment in Patients With Overactive Bladder Syndrome. AB - Intravesical onabotulinumtoxinA (BoNT-A) injection is an effective treatment for overactive bladder syndrome (OAB) that is refractory to antimuscarinics. An injectable dose of 100 U has been suggested to achieve the optimal balance of benefit and safety in patients with OAB. BoNT-A (total volume of 10 mL) was administered as evenly distributed intradetrusor injections (5 U) across 20 sites approximately 1 cm apart (0.5 mL per site) using a flexible or rigid cystoscope. Treatment with BoNT-A was generally well tolerated by most patients, and most treatment-related adverse events were localized to the urinary tract. The prevalence of OAB increases with age, and elderly patients are more vulnerable to complications. The short-term efficacy of intravesical BoNT-A injection for refractory OAB with no treatment-related complications in the elderly population has been documented. Frail elderly patients can experience the same treatment results, such as significantly improved urgent urinary incontinence and quality of life, as young and nonfrail elderly patients with 100-U BoNT-A injections. However, increased risk of larger postvoid residual (PVR) urine and lower long term success rates were noted in frail elderly patients; around 11% had acute urinary retention, while 60% had PVR urine volume >150 mL after treatment. In addition, intravesical injection of BoNT-A effectively decreased urgency symptoms in elderly patients with OAB and central nervous system lesions. The adverse effects were acceptable, while the long-term effects were comparable to those in patients with OAB without central nervous system lesions. Nonetheless, the possibility of longstanding urinary retention and chronic catheterization in this vulnerable population requires careful evaluation before treatment with intravesical BoNT-A. In conclusion, the current findings indicate that intravesical BoNT-A is an effective and safe treatment for OAB in elderly patients. PMID- 26739176 TI - Effects of Modafinil on Behavioral Learning and Hippocampal Synaptic Transmission in Rats. AB - PURPOSE: Modafinil is a wake-promoting agent that has been proposed to improve cognitive performance at the preclinical and clinical levels. Since there is insufficient evidence for modafinil to be regarded as a cognitive enhancer, the aim of this study was to investigate the effects of chronic modafinil administration on behavioral learning in healthy adult rats. METHODS: Y-maze training was used to assess learning performance, and the whole-cell patch clamp technique was used to assess synaptic transmission in pyramidal neurons of the hippocampal CA1 region of rats. RESULTS: Intraperitoneal administration of modafinil at 200 mg/kg or 300 mg/kg significantly improved learning performance. Furthermore, perfusion with 1mM modafinil enhanced the frequency and amplitude of spontaneous postsynaptic currents and spontaneous excitatory postsynaptic currents in CA1 pyramidal neurons in hippocampal slices. However, the frequency and amplitude of spontaneous inhibitory postsynaptic currents in CA1 pyramidal neurons were inhibited by treatment with 1mM modafinil. CONCLUSIONS: These results indicate that modafinil improves learning and memory in rats possibly by enhancing glutamatergic excitatory synaptic transmission and inhibiting GABAergic (gamma-aminobutyric acid-ergic) inhibitory synaptic transmission. PMID- 26739177 TI - Alpha1-Adrenoceptor Antagonists Improve Memory by Activating N-methyl-D-Aspartate Induced Ion Currents in the Rat Hippocampus. AB - PURPOSE: Alpha1 (alpha1)-adrenoceptor antagonists are widely used to treat lower urinary tract symptoms. These drugs not only act on peripheral tissues, but also cross the blood-brain barrier and affect the central nervous system. Therefore, alpha1-adrenoceptor antagonists may enhance brain functions. In the present study, we investigated the effects of tamsulosin, an alpha1-adrenoceptor antagonist, on short-term memory, as well as spatial learning and memory, in rats. METHODS: The step-down avoidance test was used to evaluate short-term memory, and an eight-arm radial maze test was used to evaluate spatial learning and memory. TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling) staining was performed in order to evaluate the effect of tamsulosin on apoptosis in the hippocampal dentate gyrus. Patch clamp recordings were used to evaluate the effect of tamsulosin on ionotropic glutamate receptors, such as N methyl-D-aspartate (NMDA), amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainate receptors, in hippocampal CA1 neurons. RESULTS: Tamsulosin treatment improved short-term memory, as well as spatial learning and memory, without altering apoptosis. The amplitudes of NMDA-induced ion currents were dose dependently increased by tamsulosin. However, the amplitudes of AMPA- and kainate induced ion currents were not affected by tamsulosin. CONCLUSIONS: Tamsulosin enhanced memory function by activating NMDA receptor-mediated ion currents in the hippocampus without initiating apoptosis. The present study suggests the possibility of using tamsulosin to enhance memory under normal conditions, in addition to its use in treating overactive bladder. PMID- 26739178 TI - A Meta-Analysis of Long- Versus Short-Acting Phosphodiesterase 5 Inhibitors: Comparing Combination Use With alpha-Blockers and alpha-Blocker Monotherapy for Lower Urinary Tract Symptoms and Erectile Dysfunction. AB - PURPOSE: Combination therapy with an alpha-1-adrenergic blocker and phosphodiesterase type 5 inhibitors (PDE5Is) has shown improvements in lower urinary tract symptoms (LUTS) with negligible side effects. Nonetheless, decisive advantages in symptom improvement were insufficient, and there were no clinical differences between long- or short-acting PDE5Is in combination with combination medication. METHODS: To review the studies on alpha-1-adrenergic blocker monotherapy and combination therapy with long vs. short-acting PDE5Is in their use in LUTS and erectile dysfunction (ED). A search of the MEDLINE, Embase, Cochrane Library, and KoreaMed databases was conducted from 2000 to 2014 using combinations of the relevant terms. Among the 323 relevant references discovered, 10 were selected for meta-analysis. The data showed that 616 men received combination therapy (PDE5Is with alpha-1-adrenergic blockers) or alpha-1 adrenergic blocker monotherapy. RESULTS: Meta-analysis of the combination therapy showed it was more effective than alpha-blockers in improving symptoms, with a mean International Prostrate Symptom Score change difference of -1.93 while those of the long- vs. short-acting PDE5I were -2.12 vs. -1.70. Compared to maximum flow rate (Qmax) value with monotherapy, the Qmax increased more with the combination therapy (mean difference of 0.71) while change values were 0.14 and 1.13 for the long- and short-acting PDE5Is, respectively. Residual urine decreased more with the combination therapy than it did with alpha-1-adrenergic blocker monotherapy with a mean difference of -7.09 while the mean residual urine change values for long- vs. short-acting PDE5Is were -18.83 vs. -5.93. The International Index of Erectile Function value increased by 3.99, 2.85, and 4.85 following combination therapy, and therapy with long- and short-acting PDE5Is. CONCLUSIONS: Our meta-analysis suggests that PDE5Is can significantly improve LUTS in men with benign prostatic hyperplasia/ED. Furthermore, combination PDE5I and alpha-1-adrenergic blocker could be a more effective treatment than alpha-1 adrenergic blocker monotherapy, and the differences between long and short-acting agents were minimal. PMID- 26739179 TI - Efficacy and Safety of Tension-Free Vaginal Tape-Secur Mini-Sling Versus Standard Midurethral Slings for Female Stress Urinary Incontinence: A Systematic Review and Meta-Analysis. AB - PURPOSE: To assess the efficacy and safety of tension-free vaginal tape (TVT) Secur for stress urinary incontinence (SUI). METHODS: A literature review was performed to identify all published trials of TVT-Secur. The search included the following databases: MEDLINE, Embase, and the Cochrane Controlled Trial Register. RESULTS: Seventeen publications involving a total of 1,879 patients were used to compare TVT-Secur with tension-free obturator tape (TVT-O) and TVT. We found that TVT-Secur had significant reductions in operative time, visual analog score for pain, and postoperative complications compared with TVT-O. Even though TVT-Secur had a significantly lower subjective cure rate (P<0.00001), lower objective cure rate (P<0.00001), and higher intraoperative complication rate, compared with TVT O at 1 to 3 years, there was no significant difference between TVT-Secur and TVT O in the subjective cure rate (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.22-1.08; P=0.08), objective cure rate (OR, 0.49; 95% CI, 0.22-1.09; P=0.08), or complications at 3 to 5 years. Moreover, TVT-Secur had significantly lower subjective and objective cure rates compared with TVT. CONCLUSIONS: This meta-analysis indicates that TVT-Secur did not show an inferior efficacy and safety compared with TVT-O for SUI in 3 to 5 years, even though displaying a clear tread toward a lower efficacy in 1 to 3 years. Considering that the safety is similar, there are no advantages in using TVT-Secur. PMID- 26739180 TI - Knowledge and Practice Behaviors Regarding Urinary Incontinence Among Korean Healthcare Providers in Long-term Care Hospitals. AB - PURPOSE: The purpose of this study was to assess the current management status of patients with urological issues and to examine the level of knowledge and practice behaviors regarding urinary incontinence (UI) among Korean healthcare providers in long-term care hospitals. METHODS: This study used a cross-sectional descriptive design with a written questionnaire to assess knowledge and practice behaviors of 756 healthcare providers in 11 long-term care hospitals in Korean metropolitan areas. RESULTS: A total 42.6% of participants reported that more than 50% of patients had urologic issues, and that 68.1% of patients were regularly sent to urologists; no participants reported an on-site urologist in their facility. Participants identified collaboration with other hospitals and regular consultations by urologists as important factors in improving urologic care. Although the overall UI knowledge score was upper intermediate, a knowledge deficit was found for risk factors of UI. The knowledge level of physicians was significantly higher than that of other healthcare providers. Practice behaviors of nurses seemed to be better than those of other healthcare providers. CONCLUSIONS: Systematic collaboration between healthcare providers and urologic specialists, enhancing staff competence, and patient-tailored intervention should be recommended to improve quality of care for patients with urologic issues in long-term care hospitals. PMID- 26739181 TI - Comparison Between Ambulatory and Conventional Urodynamics of the Modified Orthotopic Hautmann Neobladder. AB - PURPOSE: The aim of the present study was to determine the diagnostic accuracy of conventional and ambulatory urodynamic studies (UDS) in estimating neobladder function. METHODS: We evaluated 32 patients who underwent radical cystectomy and orthotopic Hautmann W neobladder with Abol-Enein-Ghoneim uretero-intestinal anastomosis for bladder cancer. The patients were initially examined by using both conventional and ambulatory UDS. RESULTS: Conventional UDS detected a very high mean intravesical pressure at maximum capacity (53.7+/-17.5 cm H2O). By contrast, the mean intravesical pressure detected by using ambulatory UDS (which reflects the dominant pattern of pressure variation during filling) was significantly lower (34.4+/-5.2 cm H2O, P<0.001). The comparison between intravesical pressure at half of maximum capacity in conventional UDS and the mean value in ambulatory UDS did not show significant difference (P=0.152). The mean voided volume in conventional UDS was greater than both the mean voided volume (P<0.001) and the mean maximum voided volume in ambulatory UDS (P=0.001). However, this difference did not affect the postvoid residual urine volume measured in both studies (P=0.207). Moreover, incontinence episodes recorded in ambulatory UDS were more frequent but not statistically significantly different from those recorded in conventional UDS (P=0.332). CONCLUSIONS: The estimation of neobladder function by means of ambulatory UDS seems to provide interesting research data for the mode of lower urinary tract function in patients with orthotopic substitution after radical cystectomy. The great high value in ambulatory UDS, in cases in which conventional UDS had failed, is due to the exposure of daily and nocturnal incontinence episodes, confirming our patients' complaints. PMID- 26739182 TI - Association Between the Neurogenic Bladder Symptom Score and Urodynamic Examination in Multiple Sclerosis Patients With Lower Urinary Tract Dysfunction. AB - PURPOSE: To determine the relationship between the neurogenic bladder symptoms score (NBSS) and urodynamic examination in patients affected by multiple sclerosis (MS) and related lower urinary tract dysfunction (LUTD). METHODS: We recruited 122 consecutive patients with MS in remission and LUTD from January 2011 to September 2013 who underwent their first urodynamic examination. Neurological impairment was assessed using the Expanded Disability Status Scale (EDSS) and bladder symptoms were studied with the NBSS. RESULTS: Median NBSS was 20.0 (interquartile range, 12.75-31.0). Neurogenic detrusor overactivity (NDO) was discovered in 69 patients (56.6%). The concordance between patients with NDO and maximum detrusor pressure during involuntary detrusor contraction (PdetmaxIDC)>=20.0 cm H2O was 0.89 (kappa-Cohen; P<0.05). Patients with EDSS scores of >=4.5 had a greater NBSS (25.41 vs. 20.19, P<0.05), NBSS-incontinence (8.73 vs. 4.71, P<0.05), NBSS-consequence (4.51 vs. 3.13, P<0.05) and NBSS quality of life (2.14 vs. 1.65, P<0.05). The NBSS was not associated with PdetmaxIDC>=20 cm H2O (P=0.77) but with maximum cystometric capacity<212 mL (odds ratio, 0.95; P<0.05). CONCLUSIONS: The NBSS cannot give adequate information the way urodynamic studies can, in patients with MS and LUTD. PMID- 26739183 TI - Efficacy of Holmium Laser Enucleation of the Prostate Based on Patient Preoperative Characteristics. AB - PURPOSE: To evaluate the efficacy of holmium laser enucleation of the prostate (HoLEP) in relation to prostate size and urodynamic parameters, including bladder outlet obstruction index (BOOI), presence of detrusor overactivity, and detrusor contractility, and to investigate factors predictive of HoLEP success. METHODS: This retrospective analysis of prospective data included 174 consecutive patients treated with HoLEP at Samsung Medical Center from 2009 to 2013. Prostate-specific antigen, prostate size, urodynamic parameters, and International Prostate Symptom Score (IPSS)/quality of life (QoL) were evaluated preoperatively, while prostate specific antigen, uroflowmetry/postvoid residual (PVR) urine, and IPSS were measured six months after HoLEP. Two definitions of treatment success were established based on the following three variables: IPSS, maximum flow rate (Qmax), and QoL index. Factors predictive of HoLEP success were identified using multiple logistic regression analysis. RESULTS: IPSS/QoL, Qmax, and PVR improved significantly following HoLEP. Improvements in IPSS and PVR were more significant in the BOOI>=40 group compared to the BOOI<40 group, with overall success rates of 93.7% and 73.6%, respectively. Thus, the BOOI>=40 group had a significantly higher success rate, and BOOI>=40 was a significant predictor of HoLEP success based on the multivariate analyses. CONCLUSIONS: We found good surgical outcomes after HoLEP, and specifically patients with a higher BOOI had a greater chance of surgical success. PMID- 26739185 TI - Origin of Urgency Symptom in Underactive Bladder: Commentary on "Underactive Bladder: Clinical Features, Urodynamic Parameters, and Treatment" (Int Neurourol J 2015;19:185-9). PMID- 26739184 TI - Men With Severe Lower Urinary Tract Symptoms Are at Increased Risk of Depression. AB - PURPOSE: Lower urinary tract symptoms (LUTS) comprise a set of common, bothersome symptoms in middle-aged and elderly men. Recent research suggests that depressive symptoms may influence the symptoms of benign prostatic hyperplasia (BPH). We performed a community-based cross-sectional study to evaluate the correlation between LUTS and depression. METHODS: The survey was conducted in a rural community during four periods in August 2009, 2010, 2011, and 2012. Two validated questionnaires were used to examine LUTS and depressive symptoms. These included the International Prostate Symptom Score/quality of life (IPSS/QoL) and the Korean version of the Center for Epidemiological Studies-Depression scale (CES-D K). Patients were categorized in the depressive symptom group if their CES-D-K score was >16 points. RESULTS: A total of 711 men were included in this study. Thirty-five participants (4.92%) were found to have depressive symptoms. There was a positive correlation between depressive symptoms and LUTS severity (P<0.001). As compared to the mild LUTS group, the odds ratio (OR) of depression was 2.868 (95% confidence interval [CI], 1.293-6.362; P for trend<0.001) in the moderate LUTS group, and 4.133 (95% CI, 1.510-11.313; P for trend<0.001) in the severe LUTS group. In a model considering multiple variables such as age, education level, smoking, and exercise, the OR in the moderate LUTS group was 2.534 (1.125-5.708, 95% CI, P for trend=0.005), while that in the severe LUTS group was 3.910 (95% CI, 5.708-11.154; P for trend=0.005). In addition, depression was related to voiding symptoms. CONCLUSIONS: Men with severe LUTS are at higher risk of depression than those with less severe urinary symptoms. The severity of voiding symptoms worsens depression. More aggressive urological diagnosis and treatment is needed in patients with severe LUTS, due to the impact on depressive symptoms and QoL. PMID- 26739186 TI - Textbook of the Neurogenic Bladder. 3rd ed. PMID- 26739187 TI - Electroacupuncture at the Baihui acupoint alleviates cognitive impairment and exerts neuroprotective effects by modulating the expression and processing of brain-derived neurotrophic factor in APP/PS1 transgenic mice. AB - Alzheimer's disease (AD) is a common human neurodegenerative disorder characterized by progressive deterioration of cognition and memory. Acupuncture at the Baihui (DU20) acupoint has long been used in China to clinically treat cognitive impairment. However, the precise mechanism underlying its neuroprotective effects remains to be elucidated. In the present study, electroacupuncture (EA) at the Baihui (DU20) acupoint was observed to markedly ameliorate cognitive impairments, reduce the aberrant overexpression of beta amyloid(1-42), and inhibit neuronal apoptosis in APP/PS1 mice. As brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of AD, the expression and processing of BDNF in APP/PS1 mice was investigated. EA at the Baihui (DU20) acupoint was indicated to significantly enhance the expression levels of mature BDNF and proBDNF in APP/PS1 mice. Furthermore, an increase in the BDNF/proBDNF ratio, upregulation of the expression levels of phosphorylated tropomyosin receptor kinase B and a decrease in the expression level of p75 neurotrophin receptor were also observed in the APP/PS1 mice. The present study demonstrates the efficacy of EA at the Baihui (DU20) acupoint in the treatment of cognitive impairments in APP/PS1 transgenic mice. The present study hypothesized that modulation of BDNF expression and processing may be the underlying mechanism by which stimulation of the Baihui (DU20) acupoint exerts its neuroprotective effect. PMID- 26739189 TI - Hypercholesterolemia Impairs Nonstenotic Kidney Outcomes After Reversal of Experimental Renovascular Hypertension. AB - BACKGROUND: Revascularization of a stenotic renal artery improves kidney function only in select patients with renovascular hypertension (HT) secondary to atherosclerosis. However, the effects of reversal of renovascular HT (RRHT) on the nonstenotic kidney are unclear. We hypothesized that concurrent hypercholesterolemia (HC) attenuates nonstenotic kidney recovery. METHODS: Female domestic pigs were randomized as Normal, renovascular HT, HT+RRHT, HTC (renovascular HT and HC), and HTC+RHT (n = 7 each). RRHT or sham was performed after 6 weeks of HT. Nonstenotic renal blood flow, glomerular filtration rate, and injurious pathways were studied 4 weeks later. RESULTS: Mean arterial pressure increased similarly in HT and HTC and decreased after RRHT. Oxidative stress increased in HT and HTC kidneys, and decreased in HT+RRHT, but remained elevated in HTC+RRHT. Renal interstitial fibrosis, glomerulosclerosis, and tubular injury were all attenuated in HT+RRHT, but not HTC+RRHT. Endothelin-1 signaling and PGF2alpha isoprostane levels were elevated in both HTC and HTC+RRHT pigs. CONCLUSIONS: RRHT reverses nonstenotic kidney injury in experimental renovascular HT, but concurrent HC blunts regression of kidney injury, possibly due to predominant vasoconstrictors and oxidative stress. These findings reinforce the contribution of the nonstenotic kidney and of prevailing cardiovascular risk factors to irreversibility of kidney dysfunction after revascularization. PMID- 26739193 TI - Envisioning a Global Health Partnership Movement. PMID- 26739190 TI - Therapeutic drug monitoring of voriconazole helps to decrease the percentage of patients with off-target trough serum levels. AB - We monitored trough voriconazole serum concentrations from 107 patients (n = 258 samples) at 6 hospitals in Madrid. Most of the patients were male (67%) and had the following underlying conditions: hematological cancer (42%), solid organ transplantation (15%), chronic obstructive pulmonary disease (14%), human immunodeficiency virus infection (8.4%), solid cancer (5.6%), and other (29%). The indication for voriconazole administration was aspergillosis treatment (74.6%) and prophylaxis (14%). The main reasons for voriconazole trough drug monitoring were initiation of treatment/prophylaxis (33%), patient monitoring (47%), and suspected toxicity (3.5%). Levels (MUg/ml) were subtherapeutic (<1; 18.2%), on-target (1-5.5; 71.3%), and high (>5.5; 10.5%). The samples percentage with on-target levels was significantly lower for the first sample than for subsequent samples (62.6% vs. 77.5%). "Subsequent samples," "admission in nonpediatric wards," "voriconazole used for treatment of invasive aspergillosis," and "use of proton pump inhibitors" were predictors of voriconazole therapeutic levels (>=1 MUg/ml). PMID- 26739194 TI - Thermal fluctuations of vesicles and nonlinear curvature elasticity--implications for size-dependent renormalized bending rigidity and vesicle size distribution. AB - Both closed and open biological membranes noticeably undulate at physiological temperatures. These thermal fluctuations influence a broad range of biophysical phenomena, ranging from self-assembly to adhesion. In particular, the experimentally measured thermal fluctuation spectra also provide a facile route to the assessment of mechanical and certain other physical properties of biological membranes. The theoretical assessment of thermal fluctuations, be it for closed vesicles or the simpler case of flat open lipid bilayers, is predicated upon assuming that the elastic curvature energy is a quadratic functional of the curvature tensor. However, a qualitatively correct description of several phenomena such as binding-unbinding transition, vesicle-to-bicelle transition, appearance of hats and saddles among others, appears to require consideration of constitutively nonlinear elasticity that includes fourth order curvature contributions rather than just quadratic. In particular, such nonlinear considerations are relevant in the context of large-curvature or small-sized vesicles. In this work we discuss the statistical mechanics of closed membranes (vesicles) incorporating both constitutive and geometrical nonlinearities. We derive results for the renormalized bending rigidity of small vesicles and show that significant stiffening may occur for sub-20 nm vesicle sizes. Our closed form results may also be used to determine nonlinear curvature elasticity properties from either experimentally measured fluctuation spectra or microscopic calculations such as molecular dynamics. Finally, in the context of our results on thermal fluctuations of vesicles and nonlinear curvature elasticity, we reexamine the problem of determining the size distribution of vesicles and obtain results that reconcile well with experimental observations. However, our results are somewhat paradoxical. Specifically, the molecular dynamics predictions for the thermo-mechanical behavior of small vesicles of prior studies appear to be inconsistent with the nonlinear elastic properties that we estimate by fitting to the experimentally determined vesicle size-distribution trends and data. PMID- 26739197 TI - Arginine vasotocin neuronal development and its projection in the adult brain of the medaka. AB - The neurohypophysial peptide arginine vasotocin (AVT) and its mammalian ortholog arginine vasopressin function in a wide range of physiological and behavioral events. Here, we generated a new line of transgenic medaka (Oryzias latipes), which allowed us to monitor AVT neurons by enhanced green fluorescent protein (EGFP) and demonstrate AVT neuronal development in the embryo and the projection of AVT neurons in the adult brain of avt-egfp transgenic medaka. The onset of AVT expression manifested at 2 days postfertilization (dpf) as a pair of signals in the telencephalon of the brain. The telencephalic AVT neurons migrated and converged on the preoptic area (POA) by 4dpf. At the same stage, another onset of AVT expression manifested in the central optic tectum (OT), and they migrated to the ventral part of the hypothalamus (VH) by 6dpf. In the adult brain, the AVT somata with EGFP signals existed in the gigantocellular POA (gPOA), magnocellular POA (mPOA), and parvocellular POA (pPOA) and in the VH. Whereas the major projection of AVT fibers was found from the pPOA and VH to the posterior pituitary, it was also found that AVT neurons in the three POAs send their fibers into wide regions of the brain such as the telencephalon, mesencephalon and diencephalon. This study suggests that the avt-egfp transgenic medaka is a useful model to explore AVT neuronal development and function. PMID- 26739196 TI - Longitudinal in vivo tracking of adverse effects following topical steroid treatment. AB - Topical steroids are known for their anti-inflammatory properties and are commonly prescribed to treat many adverse skin conditions such as eczema and psoriasis. While these treatments are known to be effective, adverse effects including skin atrophy are common. In this study, the progression of these effects is investigated in an in vivo mouse model using multimodal optical microscopy. Utilizing a system capable of performing two-photon excitation fluorescence microscopy (TPEF) of reduced nicotinamide adenine dinucleotide (NADH) to visualize the epidermal cell layers and second harmonic generation (SHG) microscopy to identify collagen in the dermis, these processes can be studied at the cellular level. Fluorescence lifetime imaging microscopy (FLIM) is also utilized to image intracellular NADH levels to obtain molecular information regarding metabolic activity following steroid treatment. In this study, fluticasone propionate (FP)-treated, mometasone furoate (MF)-treated and untreated animals were imaged longitudinally using a custom-built multimodal optical microscope. Prolonged steroid treatment over the course of 21 days is shown to result in a significant increase in mean fluorescence lifetime of NADH, suggesting a faster rate of maturation of epidermal keratinocytes. Alterations to collagen organization and the structural microenvironment are also observed. These results give insight into the structural and biochemical processes of skin atrophy associated with prolonged steroid treatment. PMID- 26739201 TI - Propofol versus traditional sedative methods for colonoscopy in a low-resource setting. AB - AIMS AND OBJECTIVES: We set out to determine the safety and efficacy of the use of three sedative regimens, namely propofol alone, propofol with benzodiazepine and/or opioids and benzodiazepine with opioids in Nigerian patients undergoing diagnostic colonoscopy at a Nigerian tertiary hospital. PATIENTS AND METHODS: A total of 120 patients undergoing outpatient colonoscopy were assigned prospectively to one of the three treatment regimens. Patients in Group A (n = 40) received propofol alone (PRO), Group B (n = 40) received propofol with midazolam and/or fentanyl and Group C (n = 40) received opioids and midazolam (fentanyl and midazolam - conscious sedation). Study outcome measures include the level of sedation, length of the procedure, sedation/recovery time, patient satisfaction and adverse events. RESULTS: Patients receiving PRO alone received higher doses of PRO compared with PRO and additives (P = 0.043). The overall procedure and sedation duration were similar in both PRO containing groups but statistically significantly shorter than the conscious sedation group (P < 0.0001, P < 0.006). The recovery time was statistically shorter in the PRO additives group compared to the other two groups (P < 0.0001). While the drop in blood pressure was similar in all the groups (P = 0.227), the occurrence of hypoxaemia was higher in the PRO containing groups (P < 0.0001). Overall physicians and patients pain assessment scores were statistically different in the three groups (both P < 0.0001). CONCLUSION: Our data suggest that PRO sedation is safe when used for outpatient diagnostic colonoscopy in low-resource settings with better patients and physician satisfaction. The synergistic sedative effect of midazolam and/or opioids combined with PRO help reducing the dose of PRO used with better recovery. PMID- 26739198 TI - Epigenetic modulation of gene expression governs the brain's response to injury. AB - Mild stress from ischemia, seizure, hypothermia, or infection can produce a transient neuroprotected state in the brain. In the neuroprotected state, the brain responds differently to a severe stress and sustains less injury. At the genomic level, the response of the neuroprotected brain to a severe stress is characterized by widespread differential regulation of genes with diverse functions. This reprogramming of gene expression observed in the neuroprotected brain in response to a stress is consistent with an epigenetic model of regulation mediated by changes in DNA methylation and histone modification. Here, we summarize our evolving understanding of the molecular basis for endogenous neuroprotection and review recent findings that implicate DNA methylation and protein mediators of histone modification as epigenetic regulators of the brain's response to injury. PMID- 26739202 TI - Neonatal Jaundice: Knowledge, Attitude and practices of mothers in Mosan-Okunola community, Lagos, Nigeria. AB - BACKGROUND: A community-based survey was conducted amongst mothers aged 15-49 years living in Mosan-Okunola, Lagos, Nigeria to determine the knowledge of, attitudes to, preventive and treatment practices towards neonatal jaundice (NNJ). MATERIALS AND METHODS: The mothers were selected using a multi-stage sampling technique. A pre-tested interviewer-administered structured questionnaire was used to obtain data. The knowledge of the mothers was scored and scores lower than 50% were graded as poor, 50-74% as fair and >=75% as good. The practice was also categorised as appropriate if one correct option was identified and was categorised as inappropriate where an incorrect option(s) was identified singly or in combination with a correct option. RESULTS: Three hundred and fifty-eight mothers were recruited. The mean age was 34.8 +/- 9.05 years. Two hundred and seventy (75.4%) mothers had ever heard about the condition. Two hundred and forty seven (91.4%) mothers correctly identified the condition and infection was the only most common known cause (47%). Only 34% of the mothers knew that NNJ could cause brain damage, and 40% identified refusal of feeds as a danger sign. Up to 64% of the mothers believed attending antenatal care could prevent the condition, and 58% were of the opinion that exposing babies to sunlight could prevent the condition. Sixty-eight percent (68.9%) of the mothers had a poor level of knowledge. Age and educational qualification did not show any statistically significant relationship with knowledge about NNJ (P < 0.05) but increasing maternal age had a significant association with an appropriate treatment practice (P < 0.05), the association was negative (r = -0.32). CONCLUSION: Knowledge about NNJ was low in this community and ineffective preventive practices were utilised. Efforts should be made to increase it, and health workers should play a leading role. PMID- 26739203 TI - Impact of basic life support training on the knowledge of basic life support in a group of Nigerian Dental Students. AB - Aim and Objetive: The burden of cardiac arrest remains enormous globally. Early recognition and prompt and effective cardiopulmonary resuscitation are crucial to successful outcome following a cardiac arrest. This study assessed the impact of basic life support (BLS) training on the knowledge of a group of dental students. MATERIALS AND METHODS: Sixty-eight dental students participated in this interventional study. Using convenience sampling, pre- and post-BLS training assessment were conducted with a questionnaire. RESULTS: The mean score (standard deviation) for pretest was 4.7 (+/-1.47) with a range of 2-8 out a total of 10, while the mean posttest score was 8.04 +/- 1.47 with a range of 3-10. The differences were statistically significant (P < 0.01). There was a marked improvement in the knowledge of the respondents with 88.2% of them having a posttest score of >=7. CONCLUSION: The results of this study suggest that the group of dental students' knowledge of BLS was very poor prior to the BLS training. The study also showed that the BLS training had a positive influence on the BLS knowledge of the participants. PMID- 26739204 TI - Willingness to support antenatal blood donation among married men in a Metropolitan City in North-central Nigeria. AB - AIMS AND OBJECTIVES: Improving blood availability through voluntary or compulsory antenatal blood donation is pivotal to reducing maternal morbidity and mortality in developing countries. Willingness to donate blood is adjudged to be an important step to the actual practice of donating blood. This study aimed to determine the knowledge, attitude and willingness of men towards antenatal blood donation. PATIENTS AND METHODS: This was a descriptive cross-sectional study. A multi-stage sampling technique was used to recruit 500 married men into the study using interviewer-administered questionnaire. Data analysis was done using SPSS version 16 software package. Pearson's Chi-squared test was used to test for significant associations between variables. A P < 0.05 was considered as statistically significant. RESULTS: More than half 300 (60%) of the respondents had good knowledge of antenatal blood donation in general. Majority (85.8%) of the respondents were willing to support voluntary blood donation. The overall attitude to blood donation was positive in 77.8% of the respondents. A significantly higher proportion 268 (89.3%) of respondents with good knowledge of antenatal blood donation were willing to donate blood (P = 0.0006). CONCLUSIONS: The majority have good knowledge and positive attitude towards antenatal blood donation. However, there is need to urgently transform this positive attitude to action through continual public enlightenment to reduce maternal morbidity and mortality. PMID- 26739205 TI - Foetal congenital anomalies: An experience from a tertiary health institution in north-west nigeria (2011-2013). AB - BACKGROUND: Structural or functional defects present at birth may lead to physical or mental disabilities. They contribute significantly to perinatal morbidity and mortality. AIMS AND OBJECTIVES: The study aimed to determine the prevalence of congenital anomalies among women delivering in the labour room suites of a tertiary health institution in North-Western Nigeria. Various maternal risk factors were also correlated and analysed. SUBJECTS AND METHODS: This was a 3-year hospital-based prospective study carried out in the Department of Obstetrics and Gynaecology in association with the Department of Paediatrics in a tertiary health care centre in North-Western Nigeria. All neonates delivered in the labour rooms were examined for congenital abnormalities (CAs) soon after birth. The study group included all live births along with stillbirths delivered after the 28th week of gestation. Those diagnosed with congenital anomaly were admitted to the special care baby unit for observation and documentation. RESULTS: A total of 72 congenital anomalies were documented among 10,163 deliveries. Central nervous system (CNS) anomalies had the highest prevalence 34.7% (25/72) and were followed by those of the musculoskeletal system 22.2% (16/72). Spina bifida/meningocoele were the most common anomalies of the CNS 44% (11/25) followed by hydrocephaly 28% (7/25). Most of the anomalies involved single organs 59/72 (81.9%). Majority of the CA 84.7% (61/72) were prevalent within the maternal age range of 16-35 years, while 12.5% were seen in teenage pregnancy. Diagnosis of most of the anomalies was made after delivery 69.4% (50/72). History of maternal febrile illness during pregnancy was present in 75% (54/72) and in 50% (27/54) of cases with CNS anomaly. CONCLUSION: Central nervous system anomalies were the most prevalent congenital anomalies observed. Improved maternal health, pre-conception care, folic acid supplementation and routine foetal anomaly scan may help to reduce these anomalies. PMID- 26739206 TI - Electrophysiological and functional evaluation of peroneal nerve regeneration in rabbit following topical hyaluronic acid or tacrolimus application after nerve repair. AB - AIMS AND OBJECTIVES: To investigate and compare the effects of hyaluronic acid (HA), tacrolimus (FK-506) and saline on peripheral nerve regeneration in vivo after topical application at the site of nerve repair. MATERIALS AND METHODS: In the present study, 48 adult male European rabbits (Oryctolagus cuniculus), ranging in weight from 2.5 to 3 kg, were randomly assigned to three experimental groups: Group I (saline), Group II (HA) and Group III (FK-506). After transection and immediate repair of the right sciatic nerve of each rabbit, the nerve repair sites were wrapped with an absorbable gelatin sponge soaked that contained saline, HA and FK-506 in Groups I, II and III, respectively. The left hind leg was used as a control. To evaluate the effects of HA and FK-506 on nerve regeneration, electrophysiological measurements were acquired at 6 and 12 weeks after nerve repair and toe-spreading index (TSI) experiments were conducted at 4, 8 and 12 weeks after nerve repair. RESULTS: Motor nerve conduction velocity (MNCV) was improved in Groups II and III compared to Group I, but no differences between Groups II and III were observed. After 12 weeks, however, the MNCV in Groups I, II and III was 40.04%, 51.16% and 50.42%, respectively, of that in the control group (100%). In addition, at 12 weeks, Grade 4 TSI scores were observed in Groups II and III. CONCLUSION: Electrophysiological analyses and functional evaluations based on the TSI indicate that HA and FK-506 exert similar, positive effects on nerve regeneration that are superior to those observed in response to saline treatment. PMID- 26739207 TI - Primary ovarian pregnancy mimicking abdominal pregnancy. AB - The objectives of this study were to emphasise that ectopic pregnancy (EP) can occasionally occur in rare sites such as the ovary, and to show that it may be difficult making the diagnosis clinically and radiologically. It also highlighted the benefit of early surgical intervention in reducing mortality and morbidity from this condition. The case was a 31-year-old nulliparous woman who presented with amenorrhoea of 20 weeks and a 2-month history of lower abdominal pain. Radiological studies suggested abdominal pregnancy coexisting with uterine fibroids for which she had an exploratory laparotomy, which revealed a primary right ovarian pregnancy necessitating the performance of right ovariectomy. Locating the sites of EP may still pose a diagnostic challenge. Despite the benefits and reliability of ultrasound scanning, there will still be situations where the definitive diagnosis can only be confirmed at surgery. PMID- 26739208 TI - Condyloma acuminata of the bladder in benign prostatic obstruction: Case report and review of literature. AB - Condyloma acuminata (CA) is a warty lesion caused by the sexually transmitted human papillomavirus that most commonly affects external genitalia and mucocutaneous junctions. Involvement of the urinary tract (UT) is rare. Anogenital CA is considered a predisposition for urethral and subsequently bladder involvement. Isolated urinary bladder involvement is thought to be due to immunosuppression. A 60-year-old man presented with progressively worsening lower UT symptoms, which culminated in acute urinary retention due to histologically proven benign prostatic obstruction (BPO). He had neither cutaneous nor anogenital CA, and viral markers were unremarkable. He had failed a trial of voiding without catheter and had simple prostatectomy 2 years later. Findings at surgery included an enlarged prostate with prominent median lobe and a sessile, warty lesion of 1.2 cm in the widest diameter found incidentally at the dome of the bladder, which turned out to be CA after histopathological analysis of excisional biopsy specimen. CA of the urethra is uncommon while that of the bladder is rare. CA of the bladder without preceding anorectal CA or immunosuppression is uncommon. There is no report of CA of the bladder in BPO till date. Complete surgical excision is the preferred option of management except when not practicable. PMID- 26739209 TI - SuccinSite: a computational tool for the prediction of protein succinylation sites by exploiting the amino acid patterns and properties. AB - Lysine succinylation is an emerging protein post-translational modification, which plays an important role in regulating the cellular processes in both eukaryotic and prokaryotic cells. However, the succinylation modification site is particularly difficult to detect because the experimental technologies used are often time-consuming and costly. Thus, an accurate computational method for predicting succinylation sites may help researchers towards designing their experiments and to understand the molecular mechanism of succinylation. In this study, a novel computational tool termed SuccinSite has been developed to predict protein succinylation sites by incorporating three sequence encodings, i.e., k spaced amino acid pairs, binary and amino acid index properties. Then, the random forest classifier was trained with these encodings to build the predictor. The SuccinSite predictor achieves an AUC score of 0.802 in the 5-fold cross validation set and performs significantly better than existing predictors on a comprehensive independent test set. Furthermore, informative features and predominant rules (i.e. feature combinations) were extracted from the trained random forest model for an improved interpretation of the predictor. Finally, we also compiled a database covering 4411 experimentally verified succinylation proteins with 12 456 lysine succinylation sites. Taken together, these results suggest that SuccinSite would be a helpful computational resource for succinylation sites prediction. The web-server, datasets, source code and database are freely available at http://systbio.cau.edu.cn/SuccinSite/. PMID- 26739210 TI - If it ain't broke, don't fix it: Depressive traits are part and parcel of neuroticism revisited. PMID- 26739211 TI - Clinical impact of myocardial mTORC1 activation in nonischemic dilated cardiomyopathy. AB - BACKGROUND: Activity of mTOR complex 1 (mTORC1) has been shown to be up-regulated in animal models of heart failure. Here, we investigated the change and role of mTORC1 in human nonischemic dilated cardiomyopathy (NICM). METHODS: Endomyocardial biopsy specimens were obtained from patients with NICM (n=52) and from Brugada syndrome patients with normal LVEF as controls (n=10). The specimens were stained for phospho-ribosomal protein S6 (p-Rps6) and phospho-p70S6K (p p70S6K), and the area with p-Rps6 signal was used as an index of mTORC1 activity. Using median mTORC1 activity, patients were divided into a high mTORC1 activity (H-mTOR) group and a low mTORC1 activity (L-mTOR) group. RESULTS: The ratio of p Rps6-positive area in biopsy samples was 10-fold larger in patients with NICM than in controls (2.0+/-2.2% vs. 0.2+/-0.2%, p<0.01). p-p70S6K signal level was higher in the H-mTOR group than in the L-mTOR group. The proportion of patients with a family history of cardiomyopathy was higher and the proportion of patients on ACE inhibitors or angiotensin receptor blockers was lower in the H-mTOR group than in the L-mTOR group. The p-Rps6-positive area was correlated with extent of myocardial fibrosis (r=0.46, p<0.01). The cardiac event-free survival rate during a 5-year follow-up period tended to be lower in the H-mTOR group than in the L mTOR group (52.9% vs. 81.6%, P=0.10). CONCLUSION: Aberrant activation of mTORC1 in cardiomyocytes was associated with myocardial fibrosis and a trend for worse prognosis in patients with NICM, indicating that persistently activated mTORC1 contributes to progression of human heart failure. PMID- 26739212 TI - LRP5: A novel anti-inflammatory macrophage marker that positively regulates migration and phagocytosis. PMID- 26739213 TI - DPP-4 inhibition has beneficial effects on the heart after myocardial infarction. AB - AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors are reported to have protective effects on various cells but it is unclear how DPP-4 inhibitors have cardioprotective effects. Our aim was to study the mechanisms of cardioprotective effects by DPP-4 inhibition. METHODS AND RESULTS: C57BL/6 mice and DPP-4 knockout (DPP-4KO) mice were subjected to left coronary artery ligation to produce acute myocardial infarction (MI). C57BL/6 mice were then treated with vehicle or DPP-4 inhibitor. Left ventricular function, infarct size, the number of vessels, and myocardial ischemia were assessed at 5days after MI. The treatment with DPP-4 inhibitor significantly improved cardiac function and decreased the infarct size. DPP-4 inhibitor increased the ratio of endothelial cell numbers to a cardiomyocyte. The extent of myocardial ischemia and the number of TUNEL-positive cells in the border area were significantly decreased by DPP-4 inhibitor. Stromal cell-derived factor-1alpha (SDF-1alpha) level in myocardium was significantly increased by DPP-4 inhibitor. Those cardioprotective effects after MI were also recognized in DPP-4KO mice. DPP-4 protein was expressed on rat neonatal cardiomyocytes and DPP-4 inhibitor significantly reduced hypoxia-induced apoptosis in the cardiomyocytes. However, this effect was abolished by the pretreatment with a CXCR4 antagonist or a signal transducer and activator of transcription 3 (STAT3) inhibitor. The beneficial effects of DPP-4 inhibitor on heart failure after MI were abolished by cardiomyocyte-specific deletion of STAT3. CONCLUSIONS: DPP-4 inhibition may have direct protective effects on the post-MI heart by inducing an antiapoptotic effect and inhibiting a decrease in vessel number through the SDF-1alpha/CXCR4-mediated STAT3 signaling pathway. PMID- 26739214 TI - The crossroads of inflammation, fibrosis, and arrhythmia following myocardial infarction. AB - Optimal healing of damaged tissue following myocardial infarction (MI) requires a coordinated cellular response that can be divided into three phases: inflammatory, proliferative/reparative, and maturation. The inflammatory phase, characterized by rapid influx of cytokines, chemokines, and immune cells, is critical to the removal of damaged tissue. The onset of the proliferative/reparative phase is marked by increased proliferation of myofibroblasts and secretion of collagen to replace dead tissue. Lastly, crosslinking of collagen fibers and apoptosis of immune cells marks the maturation phase. Excessive inflammation or fibrosis has been linked to increased incidence of arrhythmia and other MI-related pathologies. This review describes the roles of inflammation and fibrosis in arrhythmogenesis and prospective therapies for anti-arrhythmic treatment. PMID- 26739218 TI - A novel feline norovirus in diarrheic cats. AB - By screening a collection of fecal samples from young cats housed in three different shelters in South Italy, noroviruses (NoVs) were found in 3/48 (6.2%) specimens of animals with enteritis signs while they were not detected in samples collected from healthy cats (0/57). Upon sequence analysis of the short RNA dependent RNA polymerase (RdRp) region, the three strains displayed the highest nucleotide (nt) and amino acid (aa) identities to the prototype GIV.2 strain lion/Pistoia/387/06/ITA (91.0-93.0% nt and 97.0-98.0% aa). The sequence of ~3.4 kb portion at the 3' end of the genome of a NoV strain, TE/77-13/ITA, was determined. In the full-length ORF2, encoding the VP1 capsid protein, the virus was genetically closest to the canine GVI.2 NoV strains C33/Viseu/2007/PRT and FD53/2007/ITA (81.0-84.0% nt and 93.0-94.0% aa identities), suggesting a recombination nature, with the cross-over site being mapped to the ORF1-ORF2 junction. Based on the full-length VP1 amino acid sequence, we classified the novel feline NoV, together with the canine strains Viseu and FD53, as a genotype 2, within the genogroup GVI. These findings indicate that, as observed for GIV NoV, GVI strains may infect both the canine and feline host. Unrestricted circulation of NoV strains in small carnivores may provide the basis for quick genetic diversification of these viruses by recombination. Interspecies circulation of NoVs in pets must also be considered when facing outbreaks of enteric diseases in these animals. PMID- 26739221 TI - Mismatch repair and homeologous recombination. AB - DNA mismatch repair influences the outcome of recombination events between diverging DNA sequences. Here we discuss how mismatch repair proteins are active in different homologous recombination subpathways and specific reaction steps, resulting in differential modulation of these recombination events, with a focus on the mechanism of heteroduplex rejection during the inhibition of recombination between slightly diverged (homeologous) DNA sequences. PMID- 26739222 TI - Chronic lymphocytic thyroiditis is associated with invasive characteristics of differentiated thyroid carcinoma in children and adolescents. PMID- 26739215 TI - Mitochondrial quality control in the diabetic heart. AB - Diabetes is a well-known risk factor for heart failure. Diabetic heart damage is closely related to mitochondrial dysfunction and increased ROS generation. However, clinical trials have shown no effects of antioxidant therapies on heart failure in diabetic patients, suggesting that simply antagonizing existing ROS by antioxidants is not sufficient to reduce diabetic cardiac injury. A potentially more effective treatment strategy may be to enhance the overall capacity of mitochondrial quality control to maintain a pool of healthy mitochondria that are needed for supporting cardiac contractile function in diabetic patients. Mitochondrial quality is controlled by a number of coordinated mechanisms including mitochondrial fission and fusion, mitophagy and biogenesis. The mitochondrial damage consistently observed in the diabetic hearts indicates a failure of the mitochondrial quality control mechanisms. Recent studies have demonstrated a crucial role for each of these mechanisms in cardiac homeostasis and have begun to interrogate the relative contribution of insufficient mitochondrial quality control to diabetic cardiac injury. In this review, we will present currently available literature that links diabetic heart disease to the dysregulation of major mitochondrial quality control mechanisms. We will discuss the functional roles of these mechanisms in the pathogenesis of diabetic heart disease and their potentials for targeted therapeutical manipulation. PMID- 26739224 TI - Epidemiology of malaria in the Taabo health and demographic surveillance system, south-central Cote d'Ivoire. AB - BACKGROUND: A deep understanding of the local epidemiology of malaria is essential for the design and implementation of setting-specific control and elimination efforts. In Cote d'Ivoire, new initiatives are underway to reduce the burden of malaria, which requires high-quality longitudinal data. The epidemiology of malaria was studied in the Taabo health and demographic surveillance system (HDSS) in south-central Cote d'Ivoire and implications for control are discussed. METHODS: Two cross-sectional surveys were carried out in the rainy season of June/July in 2010 and 2011. Inhabitants of approximately 7% of randomly selected households in the Taabo HDSS were invited to participate. People were clinically examined, ear temperature was measured and spleen size determined. Finger-prick blood samples were collected and subjected to a rapid diagnostic test (RDT). Additionally, thick and thin blood films were prepared on microscope slides and diagnosed under a microscope for Plasmodium infection and parasitaemia. Haemoglobin (Hb) level was determined using a HemoCue device. RESULTS: A total of 1187 and 1264 people in 2010 and 2011, respectively, had complete data records. The prevalence of Plasmodium infection was 46.0% in 2010 and 56.6% in 2011, owing to a statistically significant difference (p < 0.05). Males showed a higher Plasmodium infection prevalence than females (49.6 and 62.8% versus 42.6 and 51.2%; respectively, in 2010 and 2011; both p < 0.05). The highest malaria prevalence was observed among infants and young children (aged <=9 years). The risk of Plasmodium infection was significantly higher in villages compared to small hamlets and urban settings (p < 0.05). Fever, Hb level and splenomegaly were associated with parasitaemia. CONCLUSION: Malaria is highly endemic in the Taabo HDSS in south-central Cote d'Ivoire with considerable spatial heterogeneity of Plasmodium infection. There is a pressing need to scale up control interventions against malaria. PMID- 26739225 TI - Apramycin treatment affects selection and spread of a multidrug-resistant Escherichia coli strain able to colonize the human gut in the intestinal microbiota of pigs. AB - The effect of apramycin treatment on transfer and selection of an Escherichia coli strain (E. coli 912) in the intestine of pigs was analyzed through an in vivo experiment. The strain was sequenced and assigned to the sequence type ST101 and serotype O11. It carried resistance genes to apramycin/gentamicin, sulphonamide, tetracycline, hygromycin B, beta-lactams and streptomycin [aac(3) IV, sul2, tet(X), aph(4), bla TEM-1 and strA/B], with all but tet(X) located on the same conjugative plasmid. Nineteen pigs were randomly allocated into two inoculation groups, one treated with apramycin (pen 2) and one non-treated (pen 3), along with a non-inoculated control group (pen 1). Two pigs of pen 2 and 3 were inoculated intragastrically with a rifampicin resistant variant of the strain. Apramycin treatment in pen 2 was initiated immediately after inoculation. Strain colonization was assessed in the feces from all pigs. E. coli 912 was shown to spread to non-inoculated pigs in both groups. The selective effect did not persist beyond 3 days post-treatment, and the strain was not detected from this time point in pen 2. We demonstrated that E. coli 912 was able to spread between pigs in the same pen irrespective of treatment, and apramycin treatment resulted in significantly higher counts compared to the non-treated group. This represents the first demonstration of how antimicrobial treatment affects spread of resistant bacteria in pig production. The use of apramycin may lead to enhanced spread of gentamicin-resistant E. coli. Since gentamicin is a first choice drug for human bacteremia, this is of concern. PMID- 26739226 TI - Reward value enhances post-decision error-related activity in the cingulate cortex. AB - By saying "Anyone who has never made a mistake has never tried anything new", Albert Einstein himself allegedly implied that the making and processing of errors are essential for behavioral adaption to a new or changing environment. These essential error-related cognitive and neural processes are likely influenced by reward value. However, previous studies have not dissociated accuracy and value and so the distinct effect of reward on error processing in the brain remained unknown. Therefore, we set out to investigate this at various points in decision-making. We used functional magnetic resonance imaging to scan participants while they completed a random dot motion discrimination task where reward and non-reward were associated with stimuli via classical conditioning. Pre-error activity was found in the medial frontal cortex prior to response but this was not related to reward value. At response time, error-related activity was found to be significantly greater in reward than non-reward trials in the midcingulate cortex. Finally at outcome time, error-related activity was found in the anterior cingulate cortex in non-reward trials. These results show that reward value enhances post-decision but not pre-decision error-related activities and these results therefore have implications for theories of error correction and confidence. PMID- 26739227 TI - Repetitive trigeminal nociceptive stimulation in rats increases their susceptibility to cortical spreading depression. AB - We examined the ability of trigeminal nerve activation to induce cortical spreading depression in rats. Capsaicin was injected into the bilateral plantar or whisker pad for either 4 or 6 days in rats. The number and duration of cortical spreading depressions induced by potassium were significantly increased in animals injected with capsaicin in the bilateral whisker pad compared with animals injected in the bilateral plantar or in controls, while administration of a GABAA receptor agonist decreased these effects. Repetitive nociceptive stimulation of the trigeminal nerve lowers the threshold for the induction of cortical spreading depression by altering GABAergic neuronal activity. PMID- 26739229 TI - Urinary profiling of cis-diol-containing metabolites in rats with bisphenol A exposure by liquid chromatography-mass spectrometry and isotope labeling. AB - Exposure to bisphenol A (BPA), an environmental contaminant, has been linked to metabolic disorders. However, there are no reports describing the effects of BPA on the profiling of cis-diol metabolites. It is challenge to detect these metabolites in biological samples because of their low abundance, high polarity and serious matrix interference. In this study, a chemical isotope-labeling method was applied to solve these problems. Acetone and deuterated acetone (acetone-d6) were used as chemical tags to label the rat urine samples, respectively. The light and heavy labeling products were recognized using the ShiftedIonsFinder software. The selected cis-diol metabolite signals were used to build a data set. The data set was applied to evaluate the changes in the urinary profiling of cis-diol-containing metabolites in rats with BPA exposure. The results showed that chromatographic separation and mass spectrometry detection of cis-diol metabolites were improved after acetone labeling. Using this method, the cis-diol metabolites were recognized easily from the urine samples. By comparing different dose administration on rats, the influence of BPA exposure on cis-diol metabolites was investigated. The analytes showing noticeable differences were identified. It was found that high-dose BPA exposure had strong effects on the cis-diol compound metabolism. The influences were mostly related to the metabolism of galactose and nucleoside and its analogues. The disturbance of the galactose metabolism by BPA is reported for the first time, to the best of our knowledge. This may have some implications for exploring the toxic effects of BPA exposure. PMID- 26739230 TI - Experimental demonstration of plasmon enhanced energy transfer rate in NaYF4:Yb(3+),Er(3+) upconversion nanoparticles. AB - Energy transfer upconversion (ETU) is known to be the most efficient frequency upconversion mechanism. Surface plasmon can further enhance the upconversion process, opening doors to many applications. However, ETU is a complex process involving competing transitions between multiple energy levels and it has been difficult to precisely determine the enhancement mechanisms. In this paper, we report a systematic study on the dynamics of the ETU process in NaYF4:Yb(3+),Er(3+) nanoparticles deposited on plasmonic nanograting structure. From the transient near-infrared photoluminescence under various excitation power densities, we observed faster energy transfer rates under stronger excitation conditions until it reached saturation where the highest internal upconversion efficiency was achieved. The experimental data were analyzed using the complete set of rate equations. The internal upconversion efficiency was found to be 56% and 36%, respectively, with and without the plasmonic nanograting. We also analyzed the transient green emission and found that it is determined by the infrared transition rate. To our knowledge, this is the first report of experimentally measured internal upconversion efficiency in plasmon enhanced upconversion material. Our work decouples the internal upconversion efficiency from the overall upconverted luminescence efficiency, allowing more targeted engineering for efficiency improvement. PMID- 26739233 TI - Cis-Regulatory Elements Determine Germline Specificity and Expression Level of an Isopentenyltransferase Gene in Sperm Cells of Arabidopsis. AB - Flowering plant sperm cells transcribe a divergent and complex complement of genes. To examine promoter function, we chose an isopentenyltransferase gene known as PzIPT1. This gene is highly selectively transcribed in one sperm cell morphotype of Plumbago zeylanica, which preferentially fuses with the central cell during fertilization and is thus a founding cell of the primary endosperm. In transgenic Arabidopsis (Arabidopsis thaliana), PzIPT1 promoter displays activity in both sperm cells and upon progressive promoter truncation from the 5' end results in a progressive decrease in reporter production, consistent with occurrence of multiple enhancer sites. Cytokinin-dependent protein binding motifs are identified in the promoter sequence, which respond with stimulation by cytokinin. Expression of PzIPT1 promoter in sperm cells confers specificity independently of previously reported Germline Restrictive Silencer Factor binding sequence. Instead, a cis-acting regulatory region consisting of two duplicated 6 bp Male Gamete Selective Activation (MGSA) motifs occurs near the site of transcription initiation. Disruption of this sequence-specific site inactivates expression of a GFP reporter gene in sperm cells. Multiple copies of the MGSA motif fused with the minimal CaMV35S promoter elements confer reporter gene expression in sperm cells. Similar duplicated MGSA motifs are also identified from promoter sequences of sperm cell-expressed genes in Arabidopsis, suggesting selective activation is possibly a common mechanism for regulation of gene expression in sperm cells of flowering plants. PMID- 26739232 TI - Phosphatidylinositol 3-Kinase Promotes Activation and Vacuolar Acidification and Delays Methyl Jasmonate-Induced Leaf Senescence. AB - PI3K and its product PI3P are both involved in plant development and stress responses. In this study, the down-regulation of PI3K activity accelerated leaf senescence induced by methyl jasmonate (MeJA) and suppressed the activation of vacuolar H(+)-ATPase (V-ATPase). Yeast two-hybrid analyses indicated that PI3K bound to the V-ATPase B subunit (VHA-B). Analysis of bimolecular fluorescence complementation in tobacco guard cells showed that PI3K interacted with VHA-B2 in the tonoplasts. Through the use of pharmacological and genetic tools, we found that PI3K and V-ATPase promoted vacuolar acidification and stomatal closure during leaf senescence. Vacuolar acidification was suppressed by the PIKfyve inhibitor in 35S:AtVPS34-YFP Arabidopsis during MeJA-induced leaf senescence, but the decrease was lower than that in YFP-labeled Arabidopsis. These results suggest that PI3K promotes V-ATPase activation and consequently induces vacuolar acidification and stomatal closure, thereby delaying MeJA-induced leaf senescence. PMID- 26739235 TI - Evaluation of the ease of taking mini-tablets compared with other tablet formulations in healthy volunteers. AB - "Mini-tablets" (MTs) are tablets of diameter<=3mm and have been widely studied and developed. However, reports comparing MTs with other tablet formulations are few. We wished to evaluate the ease of taking a MT quantitatively in comparison with an orally disintegrating mini-tablet (ODMT), conventional tablet (CT) and conventional orally disintegrating tablet (ODT). Four types of tablets were prepared. We prepared tablets of two diameters (3mm for MTs and ODMTs vs. 8mm for CTs and ODTs) and two formulations (MTs and CTs vs. ODMTs and ODTs). Our randomized crossover trial in 18 healthy volunteers (8 men and 10 women; mean age, 22.5years) indicated that the visual analog scale (VAS) score for the ease and amount of water required for intake of MTs was significantly lower than those of CTs. An ODMT required the least amount of water and smallest VAS score for the ease of taking a tablet. Our results showed that the advantage of MTs with regard to the ease of taking and decreased amount of water required was exerted for a unit of dosing comprising <5 tablets. These data suggested the usefulness of MTs and the importance of the number of MTs for comfortable consumption by patients. PMID- 26739234 TI - Comprehensive Profiling of Ethylene Response Factor Expression Identifies Ripening-Associated ERF Genes and Their Link to Key Regulators of Fruit Ripening in Tomato. AB - Our knowledge of the factors mediating ethylene-dependent ripening of climacteric fruit remains limited. The transcription of ethylene-regulated genes is mediated by ethylene response factors (ERFs), but mutants providing information on the specific role of the ERFs in fruit ripening are still lacking, likely due to functional redundancy among this large multigene family of transcription factors. We present here a comprehensive expression profiling of tomato (Solanum lycopersicum) ERFs in wild-type and tomato ripening-impaired tomato mutants (Never-ripe [Nr], ripening-inhibitor [rin], and non-ripening [nor]), indicating that out of the 77 ERFs present in the tomato genome, 27 show enhanced expression at the onset of ripening while 28 display a ripening-associated decrease in expression, suggesting that different ERFs may have contrasting roles in fruit ripening. Among the 19 ERFs exhibiting the most consistent up-regulation during ripening, the expression of 11 ERFs is strongly down-regulated in rin, nor, and Nr tomato ripening mutants, while only three are consistently up-regulated. Members of subclass E, SlERF.E1, SlERF.E2, and SlERF.E4, show dramatic down regulation in the ripening mutants, suggesting that their expression might be instrumental in fruit ripening. This study illustrates the high complexity of the regulatory network connecting RIN and ERFs and identifies subclass E members as the most active ERFs in ethylene- and RIN/NOR-dependent ripening. PMID- 26739236 TI - BAP1/ASXL1 recruitment and activation for H2A deubiquitination. AB - The deubiquitinating enzyme BAP1 is an important tumor suppressor that has drawn attention in the clinic since its loss leads to a variety of cancers. BAP1 is activated by ASXL1 to deubiquitinate mono-ubiquitinated H2A at K119 in Polycomb gene repression, but the mechanism of this reaction remains poorly defined. Here we show that the BAP1 C-terminal extension is important for H2A deubiquitination by auto-recruiting BAP1 to nucleosomes in a process that does not require the nucleosome acidic patch. This initial encounter-like complex is unproductive and needs to be activated by the DEUBAD domains of ASXL1, ASXL2 or ASXL3 to increase BAP1's affinity for ubiquitin on H2A, to drive the deubiquitination reaction. The reaction is specific for Polycomb modifications of H2A as the complex cannot deubiquitinate the DNA damage-dependent ubiquitination at H2A K13/15. Our results contribute to the molecular understanding of this important tumor suppressor. PMID- 26739239 TI - Supported lipid bilayer repair mediated by AH peptide. AB - The adsorption and fusion of small unilamellar lipid vesicles on silica-based substrates such as glass is a common method used to fabricate supported lipid bilayers. Successful bilayer formation depends on a number of experimental conditions as well as on the quality of the vesicle preparation. Inevitably, a small fraction of unruptured vesicles always remains in a supported bilayer, and this kind of defect can have devastating influences on the morphological and electrical properties of the supported bilayer when used as a biosensing platform. In this paper, a simple method is reported to improve the completeness of supported bilayers by adding a vesicle rupturing peptide as a final step in the fabrication process. Peptide treatment reduces the fraction of unruptured vesicles to less than 1%, as determined by epifluorescence microscopy and quartz crystal microbalance-dissipation experiments. This step can easily be incorporated into existing procedures for preparing high-quality supported lipid bilayers. PMID- 26739240 TI - Correlates of Domestic Violence Victimization Among North Korean Refugee Women in South Korea. AB - Although many North Korean (NK) refugee women are victims of domestic violence (DV) in North Korea, face sexual exploitation during migration, and remain at risk of DV while adapting to life in South Korea, there is no empirical evidence about risk factors for DV in this population. To fill this gap, this study examined whether gender role beliefs, child abuse history, and sociocultural adaptation were associated with past-year physical, emotional, sexual, and economic abuse, and whether they were associated with multiple forms of abuse. We also explored whether these associations were similar or different across different types of DV among NK refugee women. A sample of 180 ever-married NK refugee women in South Korea from the 2010 National Survey on Family Violence was used for analysis. Physical abuse was associated with more traditional gender role beliefs; emotional abuse and multiple forms of abuse were associated with lower levels of sociocultural adaptation; and sexual and economic abuse were associated with an increased likelihood of childhood abuse and poor sociocultural adaptation. Our study findings underscore the importance of assisting NK refugee women to be better adapted to the new culture in a practical way, because better sociocultural adaptation might protect them from experiencing various types of abuse. At the same time, findings of this study highlight the need for empowering NK refugee women who report physical abuse by educating their rights and altering their traditional beliefs of gender roles, and screening of childhood abuse and providing culturally sensitive psychotherapy to those who report sexual or economic abuse. Moreover, we suggest future studies to examine correlates of different forms of abuse separately because they can inform culturally tailored interventions for abused NK refugee women. To prevent further victimization, educational programs should be provided to NK refugee women at an early stage of resettlement in South Korea. PMID- 26739241 TI - Definitions of Violence: Narratives of Survivors From the War in Bosnia and Herzegovina. AB - Previous research on violence during the war in Bosnia and Herzegovina has resulted in a one-sided presentation of the phenomenon of "war violence." Researchers have emphasized the importance of narratives in general but have not analyzed stories on war violence that were the product of interpersonal interaction and meaning-making activity. The aim of this article is to fill this knowledge gap by analyzing survivor narratives of the 1990s war in northwestern Bosnia. The focus is on analyzing interviewees' descriptions of wartime violence and the discursive patterns that contribute to constructing the phenomenon of "war violence." My analysis reveals an intimate relationship between how an interviewee interprets the biographical consequences of war violence and the individual's own war experiences. All interviewees described war violence as something that is morally reprehensible. These narratives, from both perpetrators of violence and those subjected to violence, recount violent situations that not only exist as mental constructions but also live on even after the war; thus, they have real consequences for the individuals and their society. PMID- 26739237 TI - Analysis of advanced glycation end products in the DHS Mind Study. AB - AIMS: Human studies of links between advanced glycation end-products (AGEs) and disease phenotypes are less common than studies of animal and cell models. Here, we examined the association of total AGEs with diabetes risk factors in a predominately type 2 diabetes (T2D) affected cohort. METHODS: AGEs were measured using an enzyme linked immunosorbant assay in 816 individuals from the DHS Mind Study (n=709 T2D affected), and association analyses were completed. RESULTS: Total AGEs were associated with estimated glomerular filtration rate (p=0.0054; beta=-0.1291) and coronary artery calcification (p=0.0352; beta=1.1489) in the entire cohort. No significant associations were observed when individuals with T2D were analyzed separately. In individuals without T2D, increased circulating AGEs were associated with increased BMI (p=0.02, beta=0.138), low density lipoproteins (p=0.046, beta=17.07) and triglycerides (p=0.0004, beta=0.125), and decreased carotid artery calcification (p=0.0004, beta=-1.2632) and estimated glomerular filtration rate (p=0.0018, beta=-0.1405). Strong trends were also observed for an association between AGEs and poorer cognitive performance on the digit symbol substitution test (p=0.046, beta=-6.64) and decreased grey matter volume (p=0.037, beta=-14.87). CONCLUSIONS: AGEs may play an important role in a number of phenotypes and diseases, although not necessarily in interindividual variation in people with T2D. Further evaluation of specific AGE molecules may shed more light on these relationships. PMID- 26739242 TI - Exploring Kenyan Women's Perceptions of Intimate Partner Violence. AB - Intimate partner violence (IPV) is a major public health problem and global human rights violation. Effective interventions can only be created upon conducting qualitative studies that explore the cultural context of an affected population and how they interpret the phenomenon. This qualitative study investigated Kenyan women's perceptions of IPV. Two community-based focus groups ( n = 19) were conducted with Kenyan women in Nairobi. Conventional content analysis identified seven primary themes that emerged from focus group data: snapshot of violence; poverty; cultural context; masculinity; women taking action; resources; and, prevention strategies. Themes are described and implications for further research and intervention are presented. PMID- 26739243 TI - Referred orofacial pain from the cervical region. PMID- 26739244 TI - High-calorie diet inflates steatogenic effects of valproic acid in mice. AB - Valproic acid (VPA) is an anti-epileptic drug used in patients with convulsive seizures and psychic disorders. Despite its therapeutic use, VPA administration is associated with several side effects of which hepatosteatosis (lipid deposition in liver >10% of organ weight) is of concern. Recently, the consumption of western-type diet rich in fat and simple sugar has increased, the pathological consequences of which has been linked to the escalating incidence of metabolic disorders. The hypothesis of the study is that the metabolic stress induced by high-calorie diet may potentiate VPA-induced hepatosteatosis. Two groups of Swiss Mus musculus male mice weighing 25-35 g were fed either normal chow or high fat and high fructose diet (HFFD) and maintained for 30 days. On the 16th day of the experiment, VPA (100 mg/kg bw) administration was initiated in one set of animals from each group and the other set was left without VPA treatment. Assays were done in the hemolysate, plasma and liver tissue of mice after the experimental period. Deregulated lipid metabolism, loss of insulin sensitivity, enhanced CYP2E1 activity and oxidative damage, and diminution of cellular antioxidants were observed in animals that received HFFD and VPA. HFFD fed mice are sensitized to VPA toxicity than the normal chow-fed counterparts. The results of this study show that preformed metabolic derangements due to high energy diet may infuriate VPA-induced hepatosteatosis and insulin resistance. PMID- 26739245 TI - Autophosphorylation at Thr279 of Entamoeba histolytica atypical kinase EhAK1 is required for activity and regulation of erythrophagocytosis. AB - Phagocytosis plays a key role in survival and pathogenicity of Entamoeba histolytica. We have recently demonstrated that an atypical kinase EhAK1 is involved in phagocytosis in this parasite. It is recruited to the phagocytic cups through interaction with EhCaBP1. EhAK1 manipulates actin dynamics by multiple mechanisms including phosphorylation of G-actin. Biochemical analysis showed that EhAK1 is a serine/threonine kinase with broad ion specificity and undergoes multiple trans-autophosphorylation. Three autophosphorylation sites were identified by mass spectrometry. Out of these Thr279 appears to be involved in both autophosphorylation as well as substrate phosphorylation. Over expression of the mutant Thr279A inhibited erythrophagocytosis showing dominant negative phenotype. Multiple alignments of different kinases including alpha kinases displayed conserved binding sites that are thought to be important for function of the protein. Mutation studies demonstrated the importance of some of these binding sites in kinase activity. Binding studies with fluorescent-ATP analogs supported our prediction regarding ATP binding site based on sequence alignment. In conclusion, EhAK1 has multiple regulatory features and enrichment of EhAK1 at the site of phagocytosis stimulates trans-autophosphorylation reaction that increases kinase activity resulting in enhanced actin dynamics and phagocytosis. Some of the properties of EhAK1 are similar to that seen in alpha kinases. PMID- 26739246 TI - Environmental risk factors and Parkinson's disease: An umbrella review of meta analyses. AB - BACKGROUND: Parkinson's disease is a neurological disorder with complex pathogenesis implicating both environmental and genetic factors. We aimed to summarise the environmental risk factors that have been studied for potential association with Parkinson's disease, assess the presence of diverse biases, and identify the risk factors with the strongest support. METHODS: We searched PubMed from inception to September 18, 2015, to identify systematic reviews and meta analyses of observational studies that examined associations between environmental factors and Parkinson's disease. For each meta-analysis we estimated the summary effect size by random-effects and fixed-effects models, the 95% confidence interval and the 95% prediction interval. We estimated the between study heterogeneity expressed by I(2), evidence of small-study effects and evidence of excess significance bias. RESULTS: Overall, 75 unique meta-analyses on different risk factors for Parkinson's disease were examined, covering diverse biomarkers, dietary factors, drugs, medical history or comorbid diseases, exposure to toxic environmental agents and habits. 21 of 75 meta-analyses had results that were significant at p < 0.001 by random-effects. Evidence for an association was convincing (more than 1000 cases, p < 10(-6) by random-effects, not large heterogeneity, 95% prediction interval excluding the null value and absence of hints for small-study effects and excess significance bias) for constipation, and physical activity. CONCLUSION: Many environmental factors have substantial evidence of association with Parkinson's disease, but several, perhaps most, of them may reflect reverse causation, residual confounding, information bias, sponsor conflicts or other caveats. PMID- 26739247 TI - RAB39B mutations are a rare finding in Parkinson disease patients. PMID- 26739248 TI - Trajectories of recovery in depressed Parkinson's disease patients treated with paroxetine or venlafaxine. AB - INTRODUCTION: Depression is considered a syndrome with a constellation of symptoms that are frequently categorized into 3 domains including affective, somatic and cognitive. There has been limited research into the domain specific magnitude or relative timing of treatment response in patients with Parkinson's disease (PD). In addition, antidepressant trials involving patients with PD have demonstrated a similar robust placebo response to that seen in other populations. However, the timing of the placebo response has not been carefully studied. METHODS: We studied differential responses to antidepressant treatment in affective, somatic and cognitive domains of depression. Patients were treated for twelve weeks with placebo, venlafaxine or paroxetine as part of the Study of Antidepressants in Parkinson's Disease (SAD-PD) randomized controlled trial. Depressive symptoms were evaluated with three commonly used rating scales. RESULTS: All symptom domains improved during the study period, There was a significant placebo effect, especially in the first two weeks that had diminished by week 12. Compared to placebo, the affective symptoms significantly improved during treatment as early as week 4, followed by the somatic symptoms of depression in week 6 and cognitive symptoms in week 8. The largest response was seen in the affective domain. CONCLUSION: In depressed PD patients treated with venlafaxine or paroxetine, affective symptoms improved first, followed by somatic symptoms and cognitive symptoms. These findings could guide patient counselling and increase patient compliance by informing about the expected treatment responses. The substantial placebo effect underlines the importance of a sufficiently long study period in future studies. PMID- 26739249 TI - Anti-atherosclerotic effects of garlic preparation in freeze injury model of atherosclerosis in cholesterol-fed rabbits. AB - BACKGROUND: Garlic (Allium sativum L.) is one of the most popular substances used to reduce various risks associated with cardiovascular disease. However, little is known on the direct effects of garlic on atherosclerosis. PURPOSE: In the present study we have examined the effect of per oral administration of the time released garlic herbal preparation on serum atherogenicity and formation of intimal thickening after freeze injury in cholesterol-fed rabbits. METHODS: Group 1 rabbits maintained on the standard cholesterol-rich diet served as the control. Group 2 rabbits were fed the cholesterol-rich diet and treated with garlic preparation containing 300 mg garlic powder. RESULTS: Local thickening of the aortic media (i.e., the neointima formation) in the freeze injury zone was observed in all the rabbits. Regular garlic preparation therapy prevented the neointima formation and the accumulation of free and esterified cholesterol, triglycerides, phospholipids and collagen in the neointima, the effects being statistically significant. Garlic preparation also decreased serum lipid content by 1.5-fold and lowered atherogenic activity of blood serum (ability to induce lipid accumulation in cultured cells) induced by cholesterol-rich diet. CONCLUSION: The results obtained indicate that garlic preparation prevents the development of cholesterol-induced experimental atherosclerosis and possesses the direct anti-atherogenic activity. PMID- 26739251 TI - The nature of Ordovician limestone-marl alternations in the Oslo-Asker District (Norway): witnesses of primary glacio-eustasy or diagenetic rhythms? AB - Ordovician limestone-marl alternations in the Oslo-Asker District have been interpreted as signaling glacio-eustatic lowstands, which would support a prolonged "Early Palaeozoic Icehouse". However, these rhythmites could alternatively reflect differential diagenesis, without sedimentary trigger. Here, we test both hypotheses through one Darriwilian and three Katian sections. Our methodology consists of a bed-by-bed analysis of palynological (chitinozoan) and geochemical (XRF) data, to evaluate whether the limestone/marl couplets reflect an original cyclic signal. The results reveal similar palynomorph assemblages in limestones and marls. Exceptions, which could be interpreted as reflecting palaeoclimatological fluctuations, exist at the species level: Ancyrochitina bornholmensis seems to be more abundant in the marl samples from the lower Frognerkilen Formation on Nakkholmen Island. However, these rare cases where chitinozoans differ between limestone/marl facies are deemed insufficient for the identification of original cyclicity. The geochemical data show a near-perfect correlation between insoluble elements in the limestone and the marls, which indicates a similar composition of the potential precursor sediment, also in the Frognerkilen Formation. This is consistent with the palynological data. Although an original cyclic pattern could still be recorded by other, uninvestigated parameters, our palaeontological and geochemical data combined do not support the presence of such a signal. PMID- 26739252 TI - Flexible Endoscopic Spray Application of Respiratory Epithelial Cells as Platform Technology to Apply Cells in Tubular Organs. AB - INTRODUCTION: Inoperable airway stenoses are currently treated by placing stents. A major problem of covered stents is missing mucociliary clearance, which is caused by covering the native respiratory epithelium. By coating a stent with respiratory epithelium, this problem can be overcome. However, no methods are available for efficient endoscopic cell seeding. METHODS: We designed a flexible endoscopic spraying device based on a bronchoscope and tested it with respiratory epithelial cells. With this device cells can also be applied in a thin layer of fibrin glue. We evaluated the survival rate directly after spray application with a live-dead staining and the long-term differentiation capacity with histology and electron microscopy. Furthermore, the random distribution of cells when applied in a tube was analyzed and the macroscopic and microscopic characteristics of the endoscopic spray were investigated using high-speed visualization. RESULTS: Spray visualization revealed a polydisperse character of the spray with the majority of droplets larger than epithelial cells. Spray application does not influence the survival rate and differentiation of respiratory epithelial cells. After 4 weeks, cells built up a pseudostratified epithelial layer with cilia and goblet cells. When cells are applied in a thin layer of fibrin gel into a tube, a nearest neighbor index of 1.2 is obtained, which suggests a random distribution of the cells. CONCLUSIONS: This spraying device is a promising tool for application of various cell types onto stents or implants with high survival rates and homogeneous distribution as shown in this study for ovine respiratory epithelial cells. The system could also be used for cell therapy to locally apply cells to the diseased parts of hollow organs. For the first time, the fluid dynamics of a spray device for cells were examined to validate in vitro results. PMID- 26739253 TI - A Comprehensive Lifestyle Intervention to Prevent Type 2 Diabetes and Cardiovascular Diseases: the German CHIP Trial. AB - The prevalence of type 2 diabetes is continuously increasing. This chronic metabolic disorder is difficult to treat and imposes a considerable economic burden on the healthcare system. In view of the fact that type 2 diabetes is primarily caused by behavioral factors, effective preventive strategies are urgently needed. We examined the effects of a holistic lifestyle intervention on clinical and laboratory parameters as well as on the long-term diabetes risk in patients at risk to develop diabetes. We conducted a randomized controlled trial in a primary care setting in Hannover, Germany, with 83 patients diagnosed as (pre)diabetic or at risk for diabetes. CHIP Germany is a 40-hour coaching lifestyle intervention program for the primary and secondary prevention of type 2 diabetes and cardiovascular diseases. The intervention included a comprehensive nutrition and health educational program based on the American CHIP approach. The primary outcome parameter was the body mass index (BMI). Secondary outcome parameters included body weight, blood pressure, fasting glucose, HbA1c, blood lipids, and the FINDRISK score, which assesses long-term diabetes risk. At the final measurement after 12 months, in the intervention group the BMI was reduced by 1.4 versus 0.2 kg/m(2) in controls (p = .119). The mean sustained weight loss after 12 months was -4.1 kg in the intervention group versus -0.8 kg in controls. Furthermore, we found a trend toward a stronger reduction in blood pressure, fasting glucose, and HbA1c as well as an improved FINDRISK score in the intervention group, compared to controls. Although failing to reach statistical significance at the final assessment, this comprehensive lifestyle intervention showed a noticeable reduction in several cardiometabolic risk factors which may facilitate the prevention of diabetes. PMID- 26739254 TI - Hyperstabilization of Tetrameric Bacillus sp. TB-90 Urate Oxidase by Introducing Disulfide Bonds through Structural Plasticity. AB - Bacillus sp. TB-90 urate oxidase (BTUO) is one of the most thermostable homotetrameric enzymes. We previously reported [Hibi, T., et al. (2014) Biochemistry 53, 3879-3888] that specific binding of a sulfate anion induced thermostabilization of the enzyme, because the bound sulfate formed a salt bridge with two Arg298 residues, which stabilized the packing between two beta-barrel dimers. To extensively characterize the sulfate-binding site, Arg298 was substituted with cysteine by site-directed mutagenesis. This substitution markedly increased the protein melting temperature by ~ 20 degrees C compared with that of the wild-type enzyme, which was canceled by reduction with dithiothreitol. Calorimetric analysis of the thermal denaturation suggested that the hyperstabilization resulted from suppression of the dissociation of the tetramer into the two homodimers. The crystal structure of R298C at 2.05 A resolution revealed distinct disulfide bond formation between the symmetrically related subunits via Cys298, although the Cbeta distance between Arg298 residues of the wild-type enzyme (5.4 A apart) was too large to predict stable formation of an engineered disulfide cross-link. Disulfide bonding was associated with local disordering of interface loop II (residues 277-300), which suggested that the structural plasticity of the loop allowed hyperstabilization by disulfide formation. Another conformational change in the C-terminal region led to intersubunit hydrogen bonding between Arg7 and Asp312, which probably promoted mutant thermostability. Knowledge of the disulfide linkage of flexible loops at the subunit interface will help in the development of new strategies for enhancing the thermostabilization of multimeric proteins. PMID- 26739256 TI - Tetraphenylphosphonium Tetrafluoroborate/1,1,1,3,3,3-Hexafluoroisopropanol (Ph4PBF4/HFIP) Effecting Epoxide-Initiated Cation-Olefin Polycyclizations. AB - The use of an excess amount of tetraphenylphosphonium tetrafluoroborate in 1,1,1,3,3,3-hexafluoroisopropanol, which can stabilize the intermediate cation in the reaction, efficiently promoted epoxide-initiated cation-olefin polycyclization reactions with broad functional group tolerance and water and oxygen tolerance. PMID- 26739255 TI - Arsenic exposure and the seroprevalence of total hepatitis A antibodies in the US population: NHANES, 2003-2012. AB - We evaluated the association between urinary arsenic and the seroprevalence of total hepatitis A antibodies (total anti-HAV: IgG and IgM) in 11 092 participants aged ?6 years using information collected in the US National Health and Nutrition Examination Survey (2003-2012). Multivariate logistic regression models evaluated associations between total anti-HAV and total urinary arsenic defined as the sum of arsenite, arsenate, monomethylarsonate and dimethylarsinate (TUA1). Effect modification by self-reported HAV immunization status was evaluated. Total anti HAV seroprevalence was 35.1% [95% confidence interval (CI) 33.3-36.9]. Seropositive status was associated with higher arsenic levels and this association was modified by immunization status (P = 0.03). For participants that received ?2 vaccine doses or did not know if they had received any doses, a positive dose-response association was observed between increasing TUA1 and odds of total anti-HAV [odds ratio (OR) 1.42, 95% CI 1.11-1.81; and OR 1.75, 95% CI 1.22-2.52], respectively. A positive but not statistically significant association was observed in those who received <2 doses (OR 1.46, 95% CI 0.83 2.59) or no dose (OR 1.12, 95% CI 0.98-1.30). Our analysis indicates that prevalent arsenic exposure was associated with positive total anti-HAV seroprevalence. Further studies are needed to determine if arsenic increases the risk for incident hepatitis A infection or HAV seroconversion. PMID- 26739257 TI - Molecular hydrogen regulates gene expression by modifying the free radical chain reaction-dependent generation of oxidized phospholipid mediators. AB - We previously showed that H2 acts as a novel antioxidant to protect cells against oxidative stress. Subsequently, numerous studies have indicated the potential applications of H2 in therapeutic and preventive medicine. Moreover, H2 regulates various signal transduction pathways and the expression of many genes. However, the primary targets of H2 in the signal transduction pathways are unknown. Here, we attempted to determine how H2 regulates gene expression. In a pure chemical system, H2 gas (approximately 1%, v/v) suppressed the autoxidation of linoleic acid that proceeds by a free radical chain reaction, and pure 1-palmitoyl-2 arachidonyl-sn-glycero-3-phosphocholine (PAPC), one of the major phospholipids, was autoxidized in the presence or absence of H2. H2 modified the chemical production of the autoxidized phospholipid species in the cell-free system. Exposure of cultured cells to the H2-dependently autoxidized phospholipid species reduced Ca(2+) signal transduction and mediated the expression of various genes as revealed by comprehensive microarray analysis. In the cultured cells, H2 suppressed free radical chain reaction-dependent peroxidation and recovered the increased cellular Ca(2+), resulting in the regulation of Ca(2+)-dependent gene expression. Thus, H2 might regulate gene expression via the Ca(2+) signal transduction pathway by modifying the free radical-dependent generation of oxidized phospholipid mediators. PMID- 26739258 TI - The time course of cognitive control implementation. AB - Optimally recruiting cognitive control is a key factor in efficient task performance. In line with influential cognitive control theories, earlier work assumed that control is relatively slow. We challenge this notion and test whether control also can be implemented more rapidly by investigating the time course of cognitive control. In two experiments, a visual discrimination paradigm was applied. A reward cue was presented with variable intervals to target onset. The results showed that reward cues can rapidly improve performance. Importantly, the reward manipulation was orthogonal to the response, ensuring that the reward effect was due to fast cognitive control implementation rather than to automatic activation of rewarded S-R associations. We also empirically specify the temporal limits of cognitive control, because the reward cue had no effect when it was presented shortly after target onset, during task execution. PMID- 26739259 TI - Mind wandering minimizes mind numbing: Reducing semantic-satiation effects through absorptive lapses of attention. AB - Mind wandering is associated with perceptual decoupling: the disengagement of attention from perception. This decoupling is deleterious to performance in many situations; however, we sought to determine whether it might occur in the service of performance in certain circumstances. In two studies, we examined the role of mind wandering in a test of "semantic satiation," a phenomenon in which the repeated presentation of a word reduces semantic priming for a subsequently presented semantic associate. We posited that the attentional and perceptual decoupling associated with mind wandering would reduce the amount of satiation in the semantic representations of repeatedly presented words, thus leading to a reduced semantic-satiation effect. Our results supported this hypothesis: Self reported mind-wandering episodes (Study 1) and behavioral indices of decoupled attention (Study 2) were both predictive of maintained semantic priming in situations predicted to induce semantic satiation. Additionally, our results suggest that moderate inattention to repetitive stimuli is not sufficient to enable "dishabituation": the refreshment of cognitive performance that results from diverting attention away from the task at hand. Rather, full decoupling is necessary to reap the benefits of mind wandering and to minimize mind numbing. PMID- 26739260 TI - Probing Intersubunit Interfaces in AMPA-subtype Ionotropic Glutamate Receptors. AB - AMPA subtype ionotropic glutamate receptors (iGluRs) mediate the majority of fast neurotransmission across excitatory synapses in the central nervous system. Each AMPA receptor is composed of four multi-domain subunits that are organized into layers of two amino-terminal domain (ATD) dimers, two ligand-binding domain (LBD) dimers, transmembrane domains and carboxy-terminal domains. We introduced cysteine substitutions at the intersubunit interfaces of AMPA receptor subunit GluA2 and confirmed substituted cysteine crosslink formation by SDS-PAGE. The functional consequence of intersubunit crosslinks was assessed by recording GluA2 mediated currents in reducing and non-reducing conditions. Strong redox-dependent changes in GluA2-mediated currents were observed for cysteine substitutions at the LBD dimer-dimer interface but not at the ATD dimer-dimer interface. We conclude that during gating, LBD dimers undergo significant relative displacement, while ATD dimers either maintain their relative positioning, or their relative displacement has no appreciable effect on AMPA receptor function. PMID- 26739261 TI - Reduction of a marker of oxidative stress with enhancement of iron utilization by erythropoiesis activation following epoetin beta pegol administration in iron loaded db/db mice. AB - Iron, an essential element for various biological processes, can induce oxidative stress. We hypothesized that iron utilization for erythropoiesis, stimulated by epoetin beta pegol (C.E.R.A.), a long-acting erythropoiesis-stimulating agent, contributes to the reduction of iron-induced oxidative stress. We first investigated the sensitivity of several biomarkers to detect oxidative stress in mice by altering the amount of total body iron; we then investigated whether C.E.R.A. ameliorated oxidative stress through enhanced iron utilization. We treated db/db mice with intravenous iron-dextran and evaluated several biomarkers of iron-induced oxidative stress. In mice loaded with 5 mg/head iron, hepatic iron content was elevated and the oxidative stress marker d-ROMs (serum derivatives of reactive oxygen metabolites) was increased, whereas urinary 8 hydroxy-2'-deoxyguanosine and serum malondialdehyde were not, indicating that d ROMs is a sensitive marker of iron-induced oxidative stress. To investigate whether C.E.R.A. ameliorated oxidative stress, db/db mice were intravenously administered iron-dextran or dextran only, followed by C.E.R.A. Hemoglobin level increased, while hepatic iron content decreased after C.E.R.A. TREATMENT: Serum d ROMs decreased after C.E.R.A. treatment in the iron-dextran-treated group. Our results suggest that C.E.R.A. promotes iron utilization for erythropoiesis through mobilization of hepatic iron storage, leading to a decrease in serum oxidative stress markers in iron-loaded db/db mice. PMID- 26739262 TI - Quality of Life in Survivors of Pediatric Cancer and Their Siblings: The Consensus Between Parent-Proxy and Self-Reports. AB - OBJECTIVES: To examine the discrepancy between survivor-parent and sibling-parent reports of health-related quality of life (HRQL) and the level of agreement (i.e., correlation) between child reports (i.e., survivor and sibling) and parent proxy reports of HRQL. METHODS: Fifty-one families participated. Pediatric cancer survivors (49% male; 6-18 years of age) and one sibling (47% male; 9-18 years of age) completed a measure of their HRQL. As well, one parent (14% male; 27-65 years of age) from each family completed a proxy report of their children's (i.e., survivor and sibling) HRQL. Consensus was determined through discrepancy and agreement scores, between parent-proxy and children's (i.e., survivors and siblings) self-reports of total HRQL, and physical, emotional, social, and school functioning subscales. RESULTS: Repeated-measures analysis of variance (ANOVA) revealed significant group differences for total HRQL (F = 6.79, P <= 0.01). Repeated-measure ANOVAs of subscale discrepancy scores revealed significant group differences for physical functioning scores (F = 6.39, P < 0.01). A significant interaction was also found for social functioning when age at diagnosis was considered as a covariate (F = 10.30, P < 0.01). Zero-order and intraclass correlation coefficients revealed different levels of agreement between parent and child reports. Specifically, there was poorer agreement between parent-proxy and sibling's self-reports, particularly on social and emotional subscales. CONCLUSIONS: Discrepancy and agreement are both important indices to consider when examining consensus between parent-proxy and child self-reports. The findings from this study have important implications for future research and suggest that the impact of cancer on siblings should be further investigated. PMID- 26739263 TI - Investigating the state-of-the-art in whole-body MR-based attenuation correction: an intra-individual, inter-system, inventory study on three clinical PET/MR systems. AB - OBJECTIVE: We assess inter- and intra-subject variability of magnetic resonance (MR)-based attenuation maps (MRMUMaps) of human subjects for state-of-the-art positron emission tomography (PET)/MR imaging systems. MATERIALS AND METHODS: Four healthy male subjects underwent repeated MR imaging with a Siemens Biograph mMR, Philips Ingenuity TF and GE SIGNA PET/MR system using product-specific MR sequences and image processing algorithms for generating MRMUMaps. Total lung volumes and mean attenuation values in nine thoracic reference regions were calculated. Linear regression was used for comparing lung volumes on MRMUMaps. Intra- and inter-system variability was investigated using a mixed effects model. RESULTS: Intra-system variability was seen for the lung volume of some subjects, (p = 0.29). Mean attenuation values across subjects were significantly different (p < 0.001) due to different segmentations of the trachea. Differences in the attenuation values caused noticeable intra-individual and inter-system differences that translated into a subsequent bias of the corrected PET activity values, as verified by independent simulations. CONCLUSION: Significant differences of MRMUMaps generated for the same subjects but different PET/MR systems resulted in differences in attenuation correction factors, particularly in the thorax. These differences currently limit the quantitative use of PET/MR in multi-center imaging studies. PMID- 26739265 TI - Natural Killer T cell subsets in eutopic and ectopic endometrium: a fresh look to a busy corner. AB - PURPOSE: Invariant Natural Killer T cells (iNKT) are a specialized subset of T cells that use their T cell receptor to recognize self and foreign lipids presented by CD1d as cognate antigens. iNKT have been shown to have either protective or harmful roles in many pathological states, including microbial infection, autoimmune disease, allergic disease and cancer. Accumulating evidence seems to suggest that this unique T cell subset combines both classically innate and adaptive immunologic characteristic. Considering these recent data, the aim of work was to review the current knowledge about iNKT in eutopic and ectopic endometrium. METHODS: Narrative overview, synthesizing the findings of literature retrieved from searches of computerized databases. RESULTS: Currently, the immune paradigm of reproduction is gradually changing shape: recent data confirmed that cytokine milieu influences the development and plasticity of different subtype of mononuclear cells, and in turn it can be influenced by the cytokine production of the latter. Among the different NKT cell populations, the recently characterized iNKT seems to share actions typical both of innate and adaptive immunity, being capable of secreting Th1 as well as Th2 cytokine pattern. Moreover, several subtypes of iNKT were identified, who partially express the same master transcription factors of the corresponding T cells counterpart. CONCLUSIONS: Although the data about iNKT's actions in eutopic and ectopic endometrium are still scarce, it is possible to hypothesize that future investigation can shed light on this point, thus allowing a better knowledge about the regulation of these two microenvironments. PMID- 26739264 TI - Segmentation of human brain using structural MRI. AB - Segmentation of human brain using structural MRI is a key step of processing in imaging neuroscience. The methods have undergone a rapid development in the past two decades and are now widely available. This non-technical review aims at providing an overview and basic understanding of the most common software. Starting with the basis of structural MRI contrast in brain and imaging protocols, the concepts of voxel-based and surface-based segmentation are discussed. Special emphasis is given to the typical contrast features and morphological constraints of cortical and sub-cortical grey matter. In addition to the use for voxel-based morphometry, basic applications in quantitative MRI, cortical thickness estimations, and atrophy measurements as well as assignment of cortical regions and deep brain nuclei are briefly discussed. Finally, some fields for clinical applications are given. PMID- 26739267 TI - Visitors' perception of thermal comfort during extreme heat events at the Royal Botanic Garden Melbourne. AB - Outdoor thermal comfort studies have mainly examined the perception of local residents, and there has been little work on how those conditions are perceived differently by tourists, especially tourists of diverse origins. This issue is important because it will improve the application of thermal indices in predicting the thermal perception of tourists. This study aims to compare the differences in thermal perception and preferences between local and overseas visitors to the Royal Botanic Garden (RBG) in Melbourne during summer. An 8-day survey was conducted in February 2014 at four sites in the garden (n = 2198), including 2 days with maximum temperature exceeding 40 degrees C. The survey results were compared with data from four weather stations adjacent to the survey locations. One survey location, 'Fern Gully', has a misting system and visitors perceived the Fern Gully to be cooler than other survey locations. As the apparent temperature exceeded 32.4 degrees C, visitors perceived the environment as being 'warm' or 'hot'. At 'hot' conditions, 36.8 % of European visitors voted for no change to the thermal conditions, which is considerably higher than the response from Australian visitors (12.2 %) and Chinese visitors (7.5 %). Study results suggest that overseas tourists have different comfort perception and preferences compared to local Australians in hot weather based at least in part on expectations. Understanding the differences in visitors' thermal perception is important to improve the garden design. It can also lead to better tour planning and marketing to potential visitors from different countries. PMID- 26739266 TI - Male endocrine response to seasonally varying environmental and social factors in a neotropical primate, Cebus capucinus. AB - OBJECTIVE: Circannual variation in reproduction is pervasive in birds and mammals. In primates, breeding seasonality is variable, with seasonal birth peaks occurring even in year-round breeders. Environmental seasonality is reportedly an important contributor to the observed variation in reproductive seasonality. Given that food availability is the primary factor constraining female reproduction, predictions concerning responsiveness to environmental seasonality focus on females, with studies of males focusing primarily on social factors. We examined the influence of both environmental and social factors on male fecal testosterone (fT) and glucocorticoids (fGC) in moderately seasonally breeding white-faced capuchin monkeys (Cebus capucinus) in Costa Rica. METHODS: Over 17 months, we collected 993 fecal samples from 14 males in three groups. We used LMM to simultaneously examine the relative effects of photoperiod, fruit biomass, rainfall, temperature, female reproductive status (i.e., number of periovulatory periods, POPs), and male age and dominance rank on monthly fT and fGC levels. RESULTS: Male age and rank had large effects on fT and fGC. Additionally, some hormone variation was explained by environmental factors: photoperiod in the previous month (i.e., lagged photoperiod) was the best environmental predictor of monthly fT levels, whereas fGC levels were best explained by lagged photoperiod, fruit biomass, and rainfall. POPs predicted monthly fT and fGC, but this effect was reduced when all variables were considered simultaneously, possibly because lagged photoperiod and POP were highly correlated. CONCLUSIONS: Males may use photoperiod as a cue predicting circannual trends in the temporal distribution of fertile females, while also fine-tuning short-term hormone increases to the actual presence of ovulatory females, which may occur at any time during the year. PMID- 26739269 TI - Bifidobacterium aquikefiri sp. nov., isolated from water kefir. AB - A novel Bifidobacterium, strain LMG 28769T, was isolated from a household water kefir fermentation process. Cells were Gram-stain-positive, non-motile, non-spore forming, catalase-negative, oxidase-negative and facultatively anaerobic short rods. Analysis of its 16S rRNA gene sequence revealed Bifidobacterium crudilactis and Bifidobacterium psychraerophilum (97.4 and 97.1 % similarity towards the respective type strain sequences) as nearest phylogenetic neighbours. Its assignment to the genus Bifidobacterium was confirmed by the presence of fructose 6-phosphate phosphoketolase activity. Analysis of the hsp60 gene sequence revealed very low similarity with nucleotide sequences in the NCBI nucleotide database. The genotypic and phenotypic analyses allowed the differentiation of strain LMG 28769T from all recognized Bifidobacterium species. Strain LMG 28769T ( = CCUG 67145T = R 54638T) therefore represents a novel species, for which the name Bifidobacterium aquikefiri sp. nov. is proposed. PMID- 26739271 TI - Editorial: Advancing Debates in Health Care Analysis. PMID- 26739268 TI - Family-led rehabilitation after stroke in India: the ATTEND trial, study protocol for a randomized controlled trial. AB - BACKGROUND: Globally, most strokes occur in low- and middle-income countries, such as India, with many affected people having no or limited access to rehabilitation services. Western models of stroke rehabilitation are often unaffordable in many populations but evidence from systematic reviews of stroke unit care and early supported discharge rehabilitation trials suggest that some components might form the basis of affordable interventions in low-resource settings. We describe the background, history and design of the ATTEND trial, a complex intervention centred on family-led stroke rehabilitation in India. METHODS/DESIGN: The ATTEND trial aims to test the hypothesis that a family-led caregiver-delivered home-based rehabilitation intervention, designed for the Indian context, will reduce the composite poor outcome of death or dependency at 6 months after stroke, in a multicentre, individually randomized controlled trial with blinded outcome assessment, involving 1200 patients across 14 hospital sites in India. DISCUSSION: The ATTEND trial is testing the effectiveness of a low-cost rehabilitation intervention that could be widely generalizable to other low- and middle-income countries. TRIAL REGISTRATION: Clinical Trials Registry-India CTRI/2013/04/003557 . Australian New Zealand Clinical Trials Registry ACTRN12613000078752 . Universal Trial Number U1111-1138-6707. PMID- 26739272 TI - Formative evaluation of a participatory women's group intervention to improve reproductive and women's health outcomes in rural Bangladesh: a controlled before and after study. AB - BACKGROUND: Women's groups using participatory methods reduced newborn mortality in rural areas of low income countries. Our study assessed a participatory women's group intervention that focused on women's health, nutrition and family planning. METHODS: The study was conducted in three districts in Bangladesh between October 2011 and March 2013, covering a population of around 230 000. On the basis of allocation for the preceding cluster randomised trials, three unions per district were randomly allocated to receive a women's group intervention and three per district were control clusters. Outcomes included unmet need for family planning, morbidity, dietary diversity, night blindness, healthcare decision making and knowledge of sexual and reproductive health, nutrition and anaemia. A difference-in-difference analysis was used to adjust for secular trends and baseline differences between women taking part in the intervention and a random sample from control clusters. RESULTS: We interviewed 5355 (91% response rate) women before the intervention and 5128 after (96% response rate). There were significant improvements in women's dietary diversity score (increase of 0.2 (95% CI 0.1 to 0.3)) and participation in healthcare decision-making (proportion increase (95% CI) 14.0% (10.6% to 17.4%)). There were also increases in knowledge about: contraception (4.2% (2.0% to 6.3%)), ways to treat (55.4% (52.2% to 58.5%)) and prevent (71.0% (68.0% to 74.1%)) sexually transmitted infections, nutrition (46.6% (43.6% to 49.6%)) and anaemia prevention (62.8% (60.9% to 64.6%)). There were no significant differences in unmet need for family planning, morbidity or night blindness. CONCLUSIONS: Participatory women's groups have considerable potential to improve women's health knowledge, but evidence of impact on certain outcomes is lacking. Further formative work and intervention development is needed to optimise the impact of this approach for women's health. PMID- 26739273 TI - The Link Between Inflammatory Disorders and Coronary Heart Disease: a Look at Recent Studies and Novel Drugs in Development. AB - Inflammation is a critical component in the development of coronary heart disease (CHD), specifically in the process of atherogenesis. Human translational and preclinical studies have demonstrated that inflammation contributes to the development, sustainment, and progression of atherosclerosis, and epidemiological studies demonstrate that human diseases associated with increased systemic inflammation increase the risk of CHD-related events. Therefore, over the last decade, multiple clinical studies were designed to target the inflammatory cascade in order to reduce the risk of CHD and to identify which populations may benefit from these preventative treatment strategies. This review briefly summarizes inflammation as a risk factor in atherosclerosis, human disease states associated with accelerated atherosclerosis, and current treatment strategies for CHD targeting the inflammatory cascade. PMID- 26739274 TI - Assessment of the main plasma parameters included in a metabolic profile of dairy cow based on Fourier Transform mid-infrared spectroscopy: preliminary results. AB - BACKGROUND: Although a metabolic profile represents a valid tool utilized in dairy herds to determine abnormalities in blood chemistry related to an increased risk of production diseases, there are no studies on application of Fourier Transform mid-infrared (FT-MIR) spectroscopy. This study assesses the potential application of FT-MIR to analyze the main blood biochemical parameters included in the metabolic profile of dairy cows. Infrared transmission spectra were acquired for 35 plasma samples (two replicates on each sample) of Italian Friesian dairy cows (14 primiparous and 21 pluriparous), all without clinical events, and at different stages of lactation, although mainly in the transition phase. Each sample was also analyzed independently using accepted reference clinical chemical methods and these results were used as calibrating values to perform predictive models by PLS method using cross validation. RESULTS: Measured blood parameters concentrations were all within the reference ranges reported for healthy dairy cows. The number of extracted factors with the PLS procedure for each prediction model ranged between 3 and 7. The coefficient of determination (R(2)) of the prediction models ranged between 0.1 to values close to 1. R(2) values greater than 0.9 were observed for the prediction models of total cholesterol, total protein, globulin, and albumin; values between 0.75 and 0.9 were observed for urea, NEFA, and total bilirubin, while values of R(2) lower than 0.6 were observed for all minerals and for enzyme activity. The range error ratio (RER) and prediction to deviation (RPD) ranged from 5.1 to 43.8 and from 1 to 13.8 for RER and RPD, respectively. Values of RPD greater than 5 were observed for total cholesterol, total protein, albumin, and globulin. RPD ranged between 2 and 5 for the prediction models of urea, NEFA, and total bilirubin, while RPD and RER were low for minerals and enzyme activities. CONCLUSIONS: Although the results of this study require further validation, the use of FT-MIR spectroscopy was possible and provides fairly accurate measurement of various parameters of great importance in the evaluation of the metabolic and inflammatory status in dairy cows. PMID- 26739275 TI - A modest proposal on gun control--and a real one. PMID- 26739277 TI - Opioid Pharmacokinetics-Pharmacodynamics: Clinical Implications in Acute Pain Management in Trauma. AB - OBJECTIVE: To evaluate acute traumatic pain protocols and to suggest optimization by characterizing opioid pharmacokinetics and pharmacodynamics (PK-PD). DATA SOURCES: MEDLINE (1946 to November 2015), EMBASE (1974 to November 2015), International Pharmaceutical Abstracts (1970 to December 2014), and Cochrane Database of Systematic Reviews (2005 to November 2015). KEYWORDS: morphine, hydromorphone, fentanyl, trauma, acute pain, intravenous, opioid, pharmacokinetics, and pharmacodynamics. STUDY SELECTION AND DATA EXTRACTION: Literature characterizing opioid PK-PD was included. Additionally, studies evaluatingoutcomes of opioids for acute severe pain in adult trauma patients were selected. DATA SYNTHESIS: PK-PD literature suggests that morphine exhibits an effect delay of 1.6 to 4.8 hours; however, clinical significance is doubtful. The relative onset of morphine is approximately 6 minutes, and duration, 96 minutes. Morphine 0.1 mg/kg IV then 0.05 mg/kg every 5 minutes achieved pain control in 40% of patients at 10 minutes and 76% at 60 minutes. The effect delay of hydromorphone (orally) is 18 to 38 minutes; its relative onset (IV), 5 minutes; and duration, 120 minutes. Hydromorphone every 15 minutes achieved variable success in clinical trials. The effect delay of fentanyl IV is 16.4 minutes; relative onset, 2 minutes; and duration, 7 minutes. One randomized controlled trial used fentanyl 0.1 ug/kg IV every 5 minutes. CONCLUSIONS: Further integration of opioid PK-PD into acutepain protocols is possible. One opioid should not be deemed more effective but rather titrated to effect. Morphine and hydromorphone can be titrated IV every 5 minutes until adequate pain control. Fentanyl can be titrated every 3 minutes. PMID- 26739276 TI - Hairy Canola (Brasssica napus) re-visited: Down-regulating TTG1 in an AtGL3 enhanced hairy leaf background improves growth, leaf trichome coverage, and metabolite gene expression diversity. AB - BACKGROUND: Through evolution, some plants have developed natural resistance to insects by having hairs (trichomes) on leaves and other tissues. The hairy trait has been neglected in Brassica breeding programs, which mainly focus on disease resistance, yield, and overall crop productivity. In Arabidopsis, a network of three classes of proteins consisting of TTG1 (a WD40 repeat protein), GL3 (a bHLH factor) and GL1 (a MYB transcription factor), activates trichome initiation and patterning. Introduction of a trichome regulatory gene AtGL3 from Arabidopsis into semi-glabrous Brassica napus resulted in hairy canola plants which showed tolerance to flea beetles and diamondback moths; however plant growth was negatively affected. In addition, the role of BnTTG1 transcription in the new germplasm was not understood. RESULTS: Here, we show that two ultra-hairy lines (K-5-8 and K-6-3) with BnTTG1 knock-down in the hairy AtGL3+ B. napus background showed stable enhancement of trichome coverage, density, and length and restored wild type growth similar to growth of the semi-glabrous Westar plant. In contrast, over-expression of BnTTG1 in the hairy AtGL3+ B. napus background gave consistently glabrous plants of very low fertility and poor stability, with only one glabrous plant (O-3-7) surviving to the T3 generation. Q-PCR trichome gene expression data in leaf samples combining several leaf stages for these lines suggested that BnGL2 controlled B. napus trichome length and out-growth and that strong BnTTG1 transcription together with strong GL3 expression inhibited this process. Weak expression of BnTRY in both glabrous and trichome-bearing leaves of B. napus in the latter Q-PCR experiment suggested that TRY may have functions other than as an inhibitor of trichome initiation in the Brassicas. A role for BnTTG1 in the lateral inhibition of trichome formation in neighbouring cells was also proposed for B. napus. RNA sequencing of first leaves identified a much larger array of genes with altered expression patterns in the K-5-8 line compared to the hairy AtGL3(+) B. napus background (relative to the Westar control plant). These genes particularly included transcription factors, protein degradation and modification genes, but also included pathways that coded for anthocyanins, flavonols, terpenes, glucosinolates, alkaloids, shikimates, cell wall biosynthesis, and hormones. A 2nd Q-PCR experiment was conducted on redox, cell wall carbohydrate, lignin, and trichome genes using young first leaves, including T4 O-3-7-5 plants that had partially reverted to yield two linked growth and trichome phenotypes. Most of the trichome genes tested showed to be consistant with leaf trichome phenotypes and with RNA sequencing data in three of the lines. Two redox genes showed highest overall expression in K-5-8 leaves and lowest in O 3-7-5 leaves, while one redox gene and three cell wall genes were consistently higher in the two less robust lines compared with the two robust lines. CONCLUSION: The data support the strong impact of BnTTG1 knockdown (in the presence of strong AtGL3 expression) at restoring growth, enhancing trichome coverage and length, and enhancing expression and diversity of growth, metabolic, and anti-oxidant genes important for stress tolerance and plant health in B. napus. Our data also suggests that the combination of strong (up-regulated) BnTTG1 expression in concert with strong AtGL3 expression is unstable and lethal to the plant. PMID- 26739278 TI - A proto-object based saliency model in three-dimensional space. AB - Most models of visual saliency operate on two-dimensional images, using elementary image features such as intensity, color, or orientation. The human visual system, however, needs to function in complex three-dimensional environments, where depth information is often available and may be used to guide the bottom-up attentional selection process. In this report we extend a model of proto-object based saliency to include depth information and evaluate its performance on three separate three-dimensional eye tracking datasets. Our results show that the additional depth information provides a small, but statistically significant, improvement in the model's ability to predict perceptual saliency (eye fixations) in natural scenes. The computational mechanisms of our model have direct neural correlates, and our results provide further evidence that proto-objects help to establish perceptual organization of the scene. PMID- 26739280 TI - Comparative ethnobotany of the Wakhi agropastoralist and the Kyrgyz nomads of Afghanistan. AB - BACKGROUND: The mountainous Wakhan and Pamir in northeastern Afghanistan is one of the most isolated yet inhabited places in Asia. It is home to the agropastoralist Wakhi and the last Afghan semi-nomadic Kyrgyz. We present a study of plant names and uses, along with comparisons of plant name etymology, origins of plant resources, intra- and intercultural exchanges and relations, and the relative availability of the known and used plants. METHODS: The fieldwork was conducted as an expedition in the summer of 2010, and visited settlements and pastures in Upper Wakhan and Big and Little Pamir. Semi-structured group interviews, talks and observations gave initial data on names, uses and the relative availability of used plants, and provided foundation for individual interviews using an interview-herbarium containing vouchers of the 72 most frequently used plants or plant groups. RESULTS: Wakhi and Kyrgyz plant names are recorded in western transcription, the new Wakhi alphabet, phonetically and in Cyrillic. The present study documents a large body of endemic, indigenous plant knowledge; on crops, fuel, fodder, cosmetics, dyes, vegetables, veterinary medicine, traditional medicines and other plant uses which sustain life in Wakhan and Pamir. Overall, the Wakhi use considerably more plants than the Kyrgyz, and their materia medica and use thereof is more complex. Although the Wakhi and Kyrgyz are close neighbours, there are few indications of direct knowledge transfer between them. Most shared plant uses are strictly necessary for survival in the mountains. While there are few differences between genders and cultural subgroups within the two cultures, the Wakhi and Kyrgyz exhibit great differences both in their total number of use-plants and the distance from which they obtain them. The agropastoralist Wakhi appear to have their basic needs for wild natural resources covered within half a days travel, while the relatively plant-derived environment of the high Pamir appears to have necessitated the nomadic Kyrgyz to adapt by developing uses and obtaining plants that are comparatively remote. CONCLUSION: The comparative differences in plant uses between the agropastoralist Wakhi and nomadic Kyrgyz appear to be accentuated by an environment at the extreme of what is humanly possible. PMID- 26739281 TI - Misled about lead: an assessment of online public health education material from Australia's lead mining and smelting towns. AB - BACKGROUND: This study assesses the accuracy and comprehensiveness of online public health education materials from the three Australian cities with active lead mines and or smelters: Broken Hill, Mount Isa and Port Pirie. METHODS: Qualitative content analysis of online Australian material with comparison to international best practice where possible. RESULTS: All materials provided incomplete information about the health effects of lead and pathways of exposure compared to best practice materials. Inconsistent strategies to reduce exposure to lead were identified among the Australian cities, and some evidence-based best practices were not included. The materials normalised environmental lead and neglected to identify that there is no safe level of lead, or that primary prevention is the best strategy for protecting children's health. CONCLUSIONS: Health education materials need to clearly state health risks from lead across developmental stages and for sensitive populations, integrate a primary prevention perspective, and provide comprehensive evidence-based recommendations for reducing lead exposure in and around the home. Families who rely on information provided by these online public education materials are likely to be inadequately informed about the importance of protecting their children from exposure to lead and strategies for doing so. PMID- 26739283 TI - Evidence map of studies evaluating methods for conducting, interpreting and reporting overviews of systematic reviews of interventions: rationale and design. AB - BACKGROUND: Overviews of systematic reviews attempt to systematically retrieve and summarise the results of multiple systematic reviews into a single document. Methods for conducting, interpreting and reporting overviews of reviews are in their infancy. To date, there has been no systematic review or evidence map examining the range of methods for overviews nor of the evidence for using these methods. The objectives of the study are to develop and populate a framework of methods that have or may be used in conducting, interpreting and reporting overviews of systematic reviews of interventions (stage I); create an evidence map of studies that have evaluated these methods (stage II); and identify and describe unique methodological challenges of overviews. METHODS: The research will be undertaken in two stages. For both stages, we plan to search methods collections (e.g. Cochrane Methodology Register, Meth4ReSyn library, AHRQ Effective Health Care Program) to identify eligible studies. These searches will be supplemented by searching reference lists and citation searching. Stage I: Methods used in overviews will be identified from articles describing methods for overviews, methods studies examining a cross section/cohort of overviews, guidance documents and commentaries. The identified methods will populate a framework of available methods for conducting an overview. Two reviewers will independently code included studies to develop the framework. Thematic analysis of the coded data will be used to categorise and describe methods. Stage II: Evaluations of the performance of methods will be identified from systematic reviews of methods studies and methods studies. Evaluations will be described and mapped to the framework of methods identified in stage I. DISCUSSION: The results of this process will be useful for mapping of methods for overviews of systematic reviews, informing guidance and identifying and prioritising method research in this field. PMID- 26739285 TI - Description of Serpentirhabdias atroxi n. sp. (Nematoda: Rhabdiasidae), a parasite of Bothrops atrox (Linnaeus) (Reptilia: Serpentes: Viperidae) in Brazilian Amazonia. AB - A new lung-dwelling nematode species is described from the common lancehead Bothrops atrox (Linnaeus) in the Brazilian Amazon Region. The species is assigned to the genus Serpentirhabdias Tkach, Kuzmin & Snyder, 2014 based on the presence of six lips arranged in two lateral groups, the absence of prominent cuticular inflations, and lung parasitism in snakes. Serpentirhabdias atroxi n. sp. differs from other species of the genus mainly by details of the morphology of the anterior end: cuticularised ring surrounding the anterior part of the buccal cavity and six minute onchia present in the oesophastome. Serpentirhabdias atroxi n. sp. is the seventh species of the genus known from the Neotropical Realm and the second species described from viperid snakes. PMID- 26739284 TI - An annotated catalogue of the ascaridoid nematode parasites of Chinese vertebrates. AB - A catalogue, based on both examined specimens and the published literature, of all the ascaridoid nematodes recorded in China is presented. A total of 95 recognised species, representing 26 genera in five families, are reported. Detailed information on the type-host, type-locality, original reference, synonyms, annotated subsequent references of taxonomic importance, other host records, site of infection, location of type-specimens and distribution are listed for each recognised species. Additional comments on the taxonomic status of some species are also given. Moreover, some nomenclatural changes are proposed: (i) Toxascaris selenarctis Wang, 1965 and T. ailuri Wu, He & Hu, 1987 are placed in synonymy with Baylisascaris transfuga (Rudolphi, 1819); (ii) Raphidascaris lophii Wang & Wu, 1991 is a secondary homonym of R. lophii (Wu, 1949) and a replacement name, R. wangi nom. nov., is proposed for the former species; (iii) Aliascaris aetoplatea Luo, 2001 is transferred to Terranova Leiper & Atkinson, 1914, as T. aetoplatea (Luo, 2001) n. comb., and should be considered a species inquirenda; (iv) Ophidascaris orientalis (Wang, 1965) is resurrected as a valid species; (v) Phocascaris longispiculum Wang & Wu, 1991 and Ophidascaris agkistrodontis Wang, 1979 are treated as incertae sedis; and (vi) Hysterothylacium sauridae Li, Xu & Zhang, 2008 is listed as a nomen nudum. PMID- 26739286 TI - Does Alella Leigh-Sharpe, 1925 (Siphonostomatoida: Lernaeopodidae) really consist of seven species? AB - Alella Leigh-Sharpe, 1925 (Lernaeopodidae) consists of seven species, namely A. pagelli (Kroyer, 1863), A. canthari (Heller, 1865), A. macrotrachelus (Brian, 1906), A. ditrematis (Yamaguti, 1939), A. pterobrachiata (Kabata, 1968), A. tarakihi Hewitt & Blackwell, 1987 and A. gibbosa van Niekerk & Olivier, 1995. Specimens of Alella collected from Rhabdosargus sarba (Forsskal), R. holubi (Steindachner), R. globiceps (Valenciennes) and Acanthopagrus berda (Forsskal) (Sparidae) from South African waters were examined. The specimens from R. sarba are from the same host individuals that A. gibbosa were described. However, comparing the armature of the appendages, no consistent and conclusive differences were found between the examined specimens and the other congeners. Additionally, a comparison of the morphology of the appendages and their armature of the examined specimens and those described and illustrated for the known species also revealed limited differences which may be due to regional or intraspecific variation and inconsistent observations rather than distinguishing characteristics of different species. Therefore it is proposed that Alella only has one valid species namely A. pagelli. PMID- 26739287 TI - Descriptions of two new species of Rhizorhina Hansen, 1892 (Copepoda: Siphonostomatoida: Nicothoidae) parasitic on tanaidacean crustaceans, with a note on their phylogenetic position. AB - Two new species of nicothoid copepod are described. Rhizorhina ohtsukai n. sp. found on a leptocheliid (Leptochelia sp.) collected at depths of 151-136 m in the North Pacific Ocean is most similar to Rhizorhina aesthetes Boxshall & Harrison, 1988 but can be distinguished by the possession of a narrower body with a rounded anterior end, and in the position of the gonopores. Rhizorhina soyoae n. sp. found on an apseudid (Fageapseudes sp.) collected at depths of 1,595-1,557 m in East China Sea most closely resembles Rhizorhina tanaidaceae Gotto, 1984 but differs in having a narrower body with a rounded anterior end. Partial nucleotide sequences of the cytochrome c oxidase subunit I (COI) gene were obtained from the two copepods in order to enable future barcoding. A phylogenetic reconstruction based on the 18S rRNA gene placed the copepods within the Siphonostomatoida Burmeister, 1835, with the nicothoid Choniosphaera maenadis (Bloch & Gallien, 1933), and separate from the Rhizorhina spp. clade, suggesting that the family Nicothoidae Dana, 1849 is not monophyletic. This is the third report of copepods parasitic on tanaidacean crustaceans. PMID- 26739288 TI - Morphological study of Ophidascaris excavata Hsu & Hoeppli, 1931 (Ascaridida: Ascarididae) from Gloydius brevicaudus (Stejneger) (Reptilia: Viperidae). AB - Ophidascaris excavata Hsu & Hoeppli, 1931 is a poorly known ascaridid parasite reported from the short-tailed pit viper Gloydius brevicaudus (Stejneger) (Reptilia: Viperidae) in China. In the present paper, the detailed morphology of this nematode was studied using light and scanning electron microscopy (SEM) based on newly collected material. The results revealed several important, but previously unreported, morphological features, including the presence of one pair of small, finger-like prolongations on each lip, narrow cervical alae beginning well posterior to the base of the ventrolateral lips and the second pair of postcloacal ventro-lateral papillae being double; in addition, there is no intestinal caecum. These supplementary morphological and morphometric data, especially the detailed morphological features obtained herein under SEM, would help us to understand the relationships of O. excavata with its congeners and enable us to diagnose this species more accurately. PMID- 26739289 TI - A new coccidian (Apicomplexa: Eimeriidae), from midland brown snake, Storeria dekayi wrightorum Trapido (Ophidia: Colubridae) from Arkansas, USA. AB - A new species of coccidian (Protista: Apicomplexa: Eimeriidae) collected from the faeces of a midland brown snake Storeria dekayi wrightorum Trapido (Ophidia: Colubridae) in Arkansas, USA, is described. Oocysts of Isospora holbrooki n. sp. are subspherical to ovoidal with a smooth, colourless, bi-layered wall, measure on average 27.1 * 24.0 um, and have a length/width (L/W) ratio of 1.1; both micropyle and oocyst residuum are absent, but a polar granule is present. Sporocysts are ovoidal, 14.8 * 10.0 um on average (L/W 1.5); the Stieda body is nipple-like, the sub-Stieda body is ellipsoidal and the sporocyst residuum is composed of coarse granules in a cluster. Sporozoites have a spheroidal anterior refractile body, a subspheroidal posterior refractile body, and one centrally located nucleus. This is the first description of an isosporan from the snake genus Storeria Baird & Girard as well as the largest oocysts and sporocysts of any previous snake isosporan to date. PMID- 26739290 TI - A new feather mite of the genus Pteronyssoides Hull, 1931 (Astigmata: Pteronyssidae) from thrushes (Passeriformes: Turdidae) in the New World. AB - A new feather mite species, Pteronyssoides turdinus n. sp. (Acariformes: Pteronyssidae), is described from two species of thrushes, Turdus amaurochalinus Cabanis (type-host) and T. leucomelas Vieillot (Passeriformes: Turdidae) in Minas Gerais, Brazil. The new species belongs to the parinus species group and most clearly differs from previously known species of this group by the following features: in both sexes of P. turdinus, setae c2 are anterior to the level of the sejugal furrow; in males, the anterior margin of the hysteronotal shield has a deep trapezoidal concavity, setae d1 are situated on the striated tegument, the adanal shield is represented by a narrow longitudinal sclerite, and tarsus and tibia of legs IV are subequal in length; in females, the opisthosomal sclerites are split into proper opisthosomal sclerites and pygidial fragments encompassing the bases of setae h2 and h3. This is the first description of a feather mite of the genus Pteronyssoides Hull, 1931 from birds of the family Turdidae. PMID- 26739291 TI - Euryphorus suarezi n. sp. (Copepoda: Caligidae) parasitic on an elasmobranch from the Gulf of Mexico. AB - Currently, the caligid genus Euryphorus Milne Edwards, 1840 contains two valid species. A new species, Euryphorus suarezi, is described based on adult females and males collected from the spotted eagle ray Aetobatus narinari (Euphrasen) (Elasmobranchii: Myliobatidae), captured off Campeche and Tabasco, Mexico (southern coast of the Gulf of Mexico). The new species is mainly distinguished from its congeners by the absence of dorsal plates, the presence of postantennal process, bifurcated maxillule, maxilliped with slender corpus, and leg 4 with 3 segmented endopod. Leg 6 is conspicuous in the male. Additional differences are described. This is the first record of a species of Euryphorus from an elasmobranch host, which may provide insight into the evolutionary relationships within the Caligidae. PMID- 26739292 TI - Reusable nanoengineered surfaces for bacterial recruitment and decontamination. AB - Biofouling, or accumulation of unwanted biofilms, on surfaces is a major concern for public health and human industry. Materials either avoiding contamination (fouling resistant) and/or directly killing attached microbes (biocidal) have thus far failed to achieve the goal of eliminating biofouling; fouling resistant surfaces eventually foul and biocidal surfaces accumulate debris that eventually decrease their efficacy. Combined biocidal and fouling release materials offer the potential for both killing and removing debris and are promising candidates for reducing biofouling on manufactured materials. Interference lithography was used to create nanopatterns of initiators, which were then used to initiate atom transfer radical polymerization of the temperature-responsive polymer, poly(N isopropylacrylamide) (PNIPAAm) as a fouling release component. Biocidal activity was conferred by subsequent layer-by-layer deposition of cationic and anionic poly(phenylene ethynylenes) into the valleys between the PNIPAAm. For both Gram positive and Gram negative model bacteria, dark-regime biocidal activity was observed that did not increase upon exposure to light, suggesting that the mode of antimicrobial activity is due to ionic disruption of the cell wall. Subsequent to killing, bacteria and cellular debris were removed upon a temperature-induced phase transition of the PNIPAAm. These materials exhibited capture, killing, and release activity over multiple cycles of use. PMID- 26739293 TI - Correlation and crowding measures: the fundamental lesson behind complex statistics. PMID- 26739294 TI - Comparison of the International Crowding Measure in Emergency Departments (ICMED) and the National Emergency Department Overcrowding Score (NEDOCS) to measure emergency department crowding: pilot study. AB - INTRODUCTION: There is uncertainty about the best way to measure emergency department crowding. We have previously developed a consensus-based measure of crowding, the International Crowding Measure in Emergency Departments (ICMED). We aimed to obtain pilot data to evaluate the ability of a shortened form of the ICMED, the sICMED, to predict senior emergency department clinicians' concerns about crowding and danger compared with a very well-studied measure of emergency department crowding, the National Emergency Department Overcrowding Score (NEDOCS). METHODS: We collected real-time observations of the sICMED and NEDOCS and compared these with clinicians' perceptions of crowding and danger on a visual analogue scale. Data were collected in four emergency departments in the East of England. Associations were explored using simple regression, random intercept models and models accounting for correlation between adjacent time points. RESULTS: We conducted 82 h of observation in 10 observation sets. Naive modelling suggested strong associations between sICMED and NEDOCS and clinician perceptions of crowding and danger. Further modelling showed that, due to clustering, the association between sICMED and danger persisted, but the association between these two measures and perception of crowding was no longer statistically significant. CONCLUSIONS: Both sICMED and NEDOCS can be collected easily in a variety of English hospitals. Further studies are required but initial results suggest both scores may have potential use for assessing crowding variation at long timescales, but are less sensitive to hour-by-hour variation. Correlation in time is an important methodological consideration which, if ignored, may lead to erroneous conclusions. Future studies should account for such correlation in both design and analysis. PMID- 26739295 TI - Condom Use, Sexual Risk, and Self-Reported STI in a Sample of Older Male Clients of Heterosexual Prostitution in the United States. AB - While there is evidence of increasing rates of sexually transmitted infections (STIs) among older men in the United States, there has been little research on older male clients of female sex providers. The purpose of the current study was to understand the sexual risk behaviors and psychosocial correlates among older men hiring sex providers through provider review websites and discussion boards. A convenience sample of 208 male clients ages 60 to 84 completed online surveys about their sexual behavior and psychosocial factors. Participants indicated the most common sexual activities with providers in the past 12 months were receiving condomless fellatio (33.7%) and having penile-vaginal intercourse with a condom (31.7%). Although condomless penile-vaginal sex with a provider in the past 12 months was only reported by 2.9%, about half (51%) of the respondents indicated that they had experienced this at least once during their lifetime. This was associated with a preference for providers who do not require condoms, having been previously diagnosed with an STI, and perceiving one's HIV risk to be higher, as well as advancing age and having more emotional relationships with providers. Findings demonstrate the need for general and sexual health care practitioners to openly discuss protective measures and strategies for avoiding STIs among their older-to-elderly male patients. PMID- 26739297 TI - Impact of fasting on (18)F-fluorocholine gastrointestinal uptake and detection of lymph node metastases in patients with prostate cancer. AB - BACKGROUND: (18)F-fluorocholine PET/CT is used to detect lymph node metastases in prostate cancer patients. Physiological (18)F-fluorocholine in the gastrointestinal tract, especially in the intestines, may interfere with the detection of malignant lymph nodes. Fasting is frequently proposed in literature; however, scientific support is lacking. This study aims to determine the impact of fasting on (18)F-fluorocholine uptake in the gastrointestinal tract. METHODS: Eighty patients were studied, 40 fasted for at least 6 h prior to (18)F fluorocholine administration while the other 40 did not fast. (18)F-fluorocholine uptake pattern and intensity were evaluated in the intestine near the abdominal aorta and four regions near the iliac arteries. (18)F-fluorocholine intensity was also measured in the liver, pancreas, stomach and spleen. FINDINGS: No statistically significant differences were found in (18)F-fluorocholine uptake in the gastrointestinal tract between the fasting and non-fasting group. CONCLUSIONS: Fasting for 6 h has no effect on (18)F-fluorocholine uptake in the gastrointestinal tract. Therefore, no effects on the detection of malignant lymph nodes are expected, and fasting is not recommended in our opinion. PMID- 26739296 TI - Expression of connective tissue growth factor in the livers of non-viral hepatocellular carcinoma patients with metabolic risk factors. AB - BACKGROUND: The incidence of hepatocellular carcinoma (HCC) associated with metabolic risk factors, such as diabetes and obesity, has been increasing. However, the underlying mechanism that links these diseases remains unclear. METHODS: We performed genome-wide expression analysis of human liver tissues of non-viral HCC patients with or without metabolic risk factors. The upregulated genes that associated with diabetes and obesity were investigated by in vitro and in vivo experiments, and immunohistochemistry of human liver tissues was performed. RESULTS: Among the upregulated genes, connective tissue growth factor (CTGF) expression was induced to a greater extent by combined glucose and insulin administration to human hepatoma cells. Genome-wide expression analysis revealed upregulation of a chemokine network in CTGF-overexpressing hepatoma cells, which displayed an increased ability to induce in vitro activation of macrophages, and in vivo infiltration of liver macrophages. Immunohistochemistry of human liver tissues validated the correlations between CTGF expression and diabetes or obesity as well as activation of liver macrophages in patients with non-viral HCC. Recurrence-free survival was significantly poorer in the CTGF-positive patients compared with the CTGF-negative patients (p = 0.002). Multivariate analysis determined that CTGF expression (HR 2.361; 95 % CI 1.195-4.665; p = 0.013) and vascular invasion (HR 2.367; 95 % CI 1.270-4.410; p = 0.007) were independent prognostic factors for recurrence of non-viral HCC. CONCLUSIONS: Our data suggest that CTGF could be involved in oncogenic pathways promoting non viral HCC associated with metabolic risk factors via induction of liver inflammation and is expected to be a novel HCC risk biomarker and potential therapeutic target. PMID- 26739298 TI - Chronic thromboembolic pulmonary hypertension: detection, medical and surgical treatment approach, and current outcomes. AB - Pulmonary hypertension due to chronic thromboembolic disease is potentially curable with pulmonary thromboendarterectomy surgery. As a result, it is important for clinicians to recognize and appropriately diagnose this form of pulmonary hypertension. Advances in this field with changes in surgical technique, the availability of PH-targeted medical therapy for select patient subgroups, and the development of balloon pulmonary angioplasty have broadened therapeutic options for patients. This review will examine what is known about the epidemiology and medical conditions placing patients at risk of developing this disease, will present an approach to evaluation of patients with suspected chronic thromboembolic disease, and will describe the surgical and non-surgical management of this unique patient population. PMID- 26739299 TI - Liver acquisition with volume acceleration flex on 70-cm wide-bore and 60-cm conventional-bore 3.0-T MRI. AB - This study aimed to compare the uniformity of fat suppression and image quality between liver acquisition with volume acceleration flex (LAVA-Flex) and LAVA on 60-cm conventional-bore and 70-cm wide-bore 3.0-T magnetic resonance imaging (MRI). The uniformity of fat suppression by LAVA-Flex and LAVA was assessed as the efficiency of suppression of superficial fat at the levels of the liver dome, porta, and renal hilum. Percentage standard deviation (%SD) was calculated using the following equation: %SD (%) = 100 * SD of the regions of interest (ROIs)/mean value of the signal intensity (SI) in the ROIs. Signal-to-noise ratio (SNR) and contrast ratio (CR) were calculated. In the LAVA sequence, the %SD in all slices on wide-bore 3.0-T MRI was significantly higher than that on conventional-bore 3.0-T MRI (P < 0.01). However, there was no significant difference in fat signal uniformity between the conventional and wide-bore scanners when LAVA-Flex was used. In the liver, there were no significant differences in SNR between the two sequences. However, the SNR in the pancreas was lower for the wide-bore scanner than for the conventional-bore scanner for both sequences (P < 0.05). There were no significant differences in CR for the liver and fat between LAVA-Flex and LAVA in both scanners. The CR in the LAVA-Flex images obtained by wide-bore MRI was significantly higher than that in the LAVA-Flex images recorded by conventional bore MRI (P < 0.001). LAVA-Flex offers more homogenous fat suppression in the upper abdomen than LAVA for both conventional and wide-bore 3.0-T MRI. PMID- 26739300 TI - Normative values for volume and fat content of the hip abductor muscles and their dependence on side, age and gender in a healthy population. AB - OBJECTIVE: To determine normative values for volume and fat content of the gluteus medius (GMed) and minimus (GMin) muscle in healthy volunteers and to evaluate their dependence on age, gender and leg dominance. MATERIALS AND METHODS: The IRB approval was obtained for this study. 80 healthy volunteers (females, 40; males, 40; age range 20-62 years), divided into four age groups, were included. Fat- and water-signal-separated MR images of the pelvis were acquired on a 3.0 T MR with a 3-point mDIXON sequence. Normalized volume and fat signal fraction (FSF) of the GMed (ViGMed, FSFGMed) and GMin (ViGMin, FSFGMin) muscles were determined. RESULTS: The overall mean volumes (normalized) and FSF +/- SD: ViGMed 105.13 +/- 16.30 cm(3); ViGMin 30.24 +/- 5.15 cm(3); FSFGMed 8.13 +/- 1.70 % and FSFGMin 9.89 +/- 2.72 %. Comparing different age subgroups within each gender no significant differences were found concerning the volumes and FSFs (except FSFGMin in male subgroup aged 20-29 versus 50-62 years, P = 0.014). Comparing FSFs differences between the two genders, only in 20-29 years subgroup, FSFGMed (P =0.003) and FSFGMin (P =0.002) were greater in female. Volume differences between the two legs were not significant (P > 0.077); FSFGMed and FSFGMin (P =0.005 for both) were significantly lower in the dominant leg in female but not in male group (P = 0.454 for FSFGMed and P = 0.643 for FSFMin). CONCLUSION: No age dependency was evident for volume normative data for GMed and GMin and normative data for FSF values showed no age- or gender dependency. PMID- 26739301 TI - Suture slippage in knotless suture anchors resulting in subacromial-subdeltoid bursitis. AB - Rotator cuff repair using a suture bridge and knotless suture anchors is a relatively new, but increasingly used technique. The suture bridge technique creates an anatomically similar and more secure rotator cuff repair compared with conventional arthroscopic techniques and the use of knotless anchors eliminates the challenges associated with knot tying during arthroscopic surgery. However, previous in vitro biomechanical tests have shown that the hold of the suture in a knotless suture anchor is far lower than the pullout strength of the anchor from bone. Up until now slippage has been a theoretical concern. We present a prospectively diagnosed case of in vivo suture loosening after rotator cuff repair using a knotless bridge technique resulting in subacromial-subdeltoid bursitis. PMID- 26739302 TI - Evaluation of resident's training for endoscopic sinus surgery using a sheep's head. AB - Training in functional endoscopic sinus surgery (FESS) is an essential part of each ENT resident and it takes place on a very fragile area. This study focus on showing the learning curve of FESS, using an anatomical model such as the sheep's head. Four residents in our centre performed dissections. Each of these residents operated eight sheep's head. They performed an endoscopic septoplasty followed by maxillary antrostomy, total ethmoidectomy and frontal sinusotomy on every head. A staff member guided all procedures and checked for the appropriate dissection and complications occurred. Analysis was made upon the residents' performance of their first four septoplasties and eight nasal sides against their subsequent performance of the same. Final procedures presented better outcomes than the initial ones on every step of them. Results were measured by means of decrease of time (P < 0.0001) and complications, showing no major complications on the latest ones. Sheep's head is a suitable substitute for the cadaveric human head, to obtain the surgical skills needed for FESS procedures. Sheep's nasal cavity allows gaining dexterity and it is an easy model to obtain. PMID- 26739303 TI - Erratum to: A Prospective Randomized Trial of Enteral Nutrition After Thoracoscopic Esophagectomy for Esophageal Cancer. PMID- 26739304 TI - High Resectability Rate of Initially Unresectable Colorectal Liver Metastases After UGT1A1-Adapted High-Dose Irinotecan Combined with LV5FU2 and Cetuximab: A Multicenter Phase II Study (ERBIFORT). AB - BACKGROUND: The purpose of this study was to assess the efficacy and tolerance of induction chemotherapy combining LV5FU2 with increased doses of irinotecan adapted to UGT1A1 genotyping and cetuximab in untreated potentially resectable liver metastases of colorectal cancer. METHODS: Twenty-six patients, PS 0-1, with class II hepatic metastases received chemotherapy combining irinotecan 260 mg/m(2) on day 1 for UGT1A1 6/6 and 6/7 genotypes and 220 mg/m(2) for UGT1A1 7/7 genotypes, with leucovorin on day 1, 5FU 400 mg/m(2) bolus on day 1 and continuous 5FU infusion for 46 h, and cetuximab on day 1 (day 1 = day 14). Primary prevention with lenograstim (day 5-9) was given to UGT1A1 6/7 and 7/7 genotypes. The primary endpoint was the response rate (RECIST1.1), and the secondary endpoints were tolerance (NCI-CTC criteria) and R0 resection rate. RESULTS: The average number of cycles per patient was 6 (+/-1.9). The UGT1A1 genotype was 6/6 in 34.6 %, 6/7 in 53.9 %, and 7/7 in 11.5 % of patients. At 6 cycles, 18 patients (69.2 %) presented a partial response, 5 patients (19.2 %) had stable disease, 2 patients (7.7 %) died independently of chemotherapy, and 1 patient (3.9 %) refused the treatment after 3 cycles. Four patients received 2 more cycles and the cumulative response rate at 8 cycles was 76.9 % (20/26). There was no progression. Among assessable patients (n = 23), the overall response rate was 82.6 % and 21 patients (80.7 %) had a metastasis resection. The most frequent grade 3-4 toxicities were neutropenia (31 %), diarrhea (20.8 %), and anorexia (16.4 %). There were no deaths due to toxicity. CONCLUSIONS: High dose FOLFIRI combined with cetuximab yielded high response rates and enabled complete resection of class II hepatic metastases in most patients. It seemed to be well-tolerated among healthy selected patients thanks to irinotecan dose adaptation according to UGT1A1 pharmacogenomics status. This intensified chemotherapy regimen needs to be confirmed in a randomized, phase III study. PMID- 26739305 TI - Accuracy of Sentinel Lymph Node Mapping After Previous Hysterectomy in Patients with Occult Cervical Cancer. AB - BACKGROUND: In patients with a diagnosis of occult cervical cancer made on a hysterectomy specimen after surgery for a benign indication, lymph node assessment is crucial to determine treatment. We aimed to compare sentinel lymph node (SLN) mapping between patients with postoperative diagnosis of occult cervical carcinoma and patients with cervical cancer and uterus in situ. METHODS: A retrospective analysis of cervical cancer patients International Federation of Gynecology and Obstetrics (FIGO) stage IA-IIA disease undergoing laparoscopic SLN mapping was performed. Patients were divided into two groups: those with a diagnosis of occult cervical cancer made on a hysterectomy specimen (group 1) and those with a diagnosis of cervical cancer and uterus in situ (group 2). Tracers used for SLN mapping included technetium-99m ((99m)Tc), blue dye, and indocyanine green. After detection and excision, the SLN was sent for frozen section analysis, and the planned surgical procedure was aborted in case of metastatic disease in favor of a chemoradiotherapeutic treatment. RESULTS: Groups 1 and 2 included 9 and 62 patients, respectively. Clinicopathologic characteristics were similar among the two groups. Overall and bilateral detection rates were 66.6 and 33.3 and 95.1 and 87 % in groups 1 and 2, respectively (p < 0.05). No false negative SLNs were identified in either group, with a negative predictive value of 100 %. CONCLUSIONS: SLN mapping in occult cervical cancer patients has lower detection rates compared to patients with uterus in situ. In these patients, proper management of their disease has already failed before diagnosis, and additional mistakes may definitely compromise attempts at cure. PMID- 26739306 TI - Sedimentibacter acidaminivorans sp. nov., an anaerobic, amino-acid-utilizing bacterium isolated from marine subsurface sediment. AB - A novel, anaerobic bacterium, strain MO-SEDIT, was isolated from a methanogenic microbial community, which was originally obtained from marine subsurface sediments collected from off the Shimokita Peninsula of Japan. Cells were Gram stain-negative, non-motile, non-spore-forming rods, 0.4-1.4 MUm long by 0.4-0.6 MUm wide. The cells also formed long filaments of up to about 11 MUm. The strain grew on amino acids (i.e. valine, leucine, isoleucine, methionine, glycine, phenylalanine, tryptophan, lysine and arginine), pyruvate and melezitose in the presence of yeast extract. Growth was observed at 4-37 degrees C (optimally at 30 degrees C), at pH 6.0 and 8.5 (optimally at 7.0-7.5) and in 0-60 g l- 1 NaCl (optimally 20 g NaCl l- 1). The G+C content of the DNA was 32.0 mol%. The polar lipids of strain MO-SEDIT were phosphatidylglycerol, phosphatidyl lipids and unknown lipids. The major cellular fatty acids (>10 % of the total) were C14 : 0, C16 : 1omega9 and C16 : 0 dimethyl aldehyde. Comparative sequence analysis of the 16S rRNA gene showed that strain MO-SEDIT was affiliated with the genus Sedimentibacter within the phylum Firmicutes. It was related most closely to the type strain of Sedimentibacter saalensis (94 % sequence similarity). Based on the phenotypic and genetic characteristics, strain MO-SEDIT is considered to represent a novel species of the genus Sedimentibacter, for which the name Sedimentibacter acidaminivorans sp. nov. is proposed. The type strain is MO-SEDIT ( = JCM 17293T = DSM 24004T). PMID- 26739307 TI - The ethics of future trials: qualitative analysis of physicians' decision making. AB - BACKGROUND: The decision to conduct a randomized controlled trial (RCT) in a field raises ethical as well as scientific issues. From the clinical equipoise literature, future trials are justifiable if there is "honest, professional disagreement in the community of expert practitioners as to the preferred treatment". Empirical data are sparse about how clinicians apply the principles of equipoise to the justification of future RCTs. For example, selective decontamination of the digestive tract (SDD) is not widely used in critical care practice despite the strength of the evidence base and therefore provides a unique opportunity to learn how clinicians think about the ethics of further RCTs in critical care. METHODS: In an international interview study of views of healthcare professionals about SDD, we undertook a secondary analysis of qualitative data collected using a Theoretical Domains Framework of clinical behaviour. We adopted a general descriptive approach to explore how physicians determined whether another RCT of SDD is ethical. Following a constant comparison approach, three investigators reviewed 54 purposively chosen transcripts from three international regions. We interpreted the data using thematic analysis. RESULTS: We grouped participants' responses into four inter-related themes: 1) cultural norms about evidence and practice within healthcare; 2) personal views about what evidence is current or applicable; 3) the interpersonal and relational nature of professional decision making locally; and 4) an a priori commitment to future trials. The analysis also identified several unresolved tensions regarding when a future RCT should be pursued. These tensions focused on a clash between potential benefits to current individual patients and potential future harms to patients more broadly. CONCLUSIONS: Our study suggests that ethical decision making about future RCTs in the field of SDD does not rely strongly on appeals to evidence, even when the quality of the evidence is reasonably high. Rather, "extra-evidential" reasons, including social, professional, and relational factors, seem to influence opinions regarding the ethics of future trials. Further work is required to see if these conclusions are applicable to other clinical topics and settings. PMID- 26739308 TI - The Effect of Application Rate of GF-120 (Spinosad) and Malathion on the Mortality of Apis mellifera (Hymenoptera: Apidae) Foragers. AB - Beneficial organisms like the honey bee, Apis mellifera L. (Hymenoptera: Apidae), are heavily affected by pest control practices that incorporate insecticides. Safer alternatives as the spinosad-based formulation GF-120 have been developed to overcome this issue. Though both the low concentration of spinosad and the ultra-low-volume application rate of GF-120 are supposed to have a low acute toxicity in honey bee foragers, to our knowledge such claims have not been explicitly proven. We thus carried out a series of experiments to assess the effect of GF-120, malathion, and Spintor (spinosad) on honey bee foragers when applied at two concentrations (80 and 1,500 ppm) and two application rates (low density rate [LDR]-80 drops of 5 mm diameter per square meter; high density rate [HDR]-thousands of 200 -um-diameter droplets per square meter). Interestingly, the three pesticides caused low mortality on foragers when applied at LDR-80, LDR 1,500, or HDR-80. However, HDR-1,500 caused a very high mortality. Based upon these results, we developed a computer program to estimate the average number of foragers that are exposed at LDR and HDR. We found that more foragers receive a lethal dose when exposed at HDR than at the other rates. Our results support the hypothesis that the impact of GF-120 and malathion upon honey bees is minimal when applied at LDR and that computer simulation can help greatly in understanding the effects of pesticides upon nontarget species. PMID- 26739310 TI - Anonymisation of geographical distance matrices via Lipschitz embedding. AB - BACKGROUND: Anonymisation of spatially referenced data has received increasing attention in recent years. Whereas the research focus has been on the anonymisation of point locations, the disclosure risk arising from the publishing of inter-point distances and corresponding anonymisation methods have not been studied systematically. METHODS: We propose a new anonymisation method for the release of geographical distances between records of a microdata file--for example patients in a medical database. We discuss a data release scheme in which microdata without coordinates and an additional distance matrix between the corresponding rows of the microdata set are released. In contrast to most other approaches this method preserves small distances better than larger distances. The distances are modified by a variant of Lipschitz embedding. RESULTS: The effects of the embedding parameters on the risk of data disclosure are evaluated by linkage experiments using simulated data. The results indicate small disclosure risks for appropriate embedding parameters. CONCLUSION: The proposed method is useful if published distance information might be misused for the re identification of records. The method can be used for publishing scientific-use files and as an additional tool for record-linkage studies. PMID- 26739311 TI - It could be a 'Golden Goose': a qualitative study of views in primary care on an emergency admission risk prediction tool prior to implementation. AB - BACKGROUND: Rising demand for health care has prompted interest in new technologies to support a shift of care from hospital to community and primary care, which may require clinicians to undertake new working practices. A predictive risk stratification tool (Prism) was developed for use in primary care to estimate patients' risk of an emergency hospital admission. As part of an evaluation of Prism, we aimed to understand what might be needed to bring Prism into effective use by exploring clinicians and practice managers' attitudes and expectations about using it. We were informed by Normalisation Process Theory (NPT) which examines the work needed to bring an innovation into use. METHODS: We conducted 4 focus groups and 10 interviews with a total of 43 primary care doctors and colleagues from 32 general practices. All were recorded and transcribed. Analysis focussed in particular on the construct of 'coherence' within NPT, which examines how people understand an innovation and its purpose. RESULTS: Respondents were in agreement that Prism was a technological formalisation of existing practice, and that it would function as a support to clinical judgment, rather than replacing it. There was broad consensus about the role it might have in delivering new models of care based on active management, but there were doubts about the scope for making a difference to some patients and about whether Prism could identify at-risk patients not already known to the clinical team. Respondents did not expect using the tool to be onerous, but were concerned about the work which might follow in delivering care. Any potential value would not be of the tool in isolation, but would depend on the availability of support services. CONCLUSIONS: Policy imperatives and the pressure of rising demand meant respondents were open to trying out Prism, despite underlying uncertainty about what difference it could make. TRIAL REGISTRATION: Controlled Clinical Trials no. ISRCTN55538212 . PMID- 26739312 TI - Foodways in transition: food plants, diet and local perceptions of change in a Costa Rican Ngabe community. AB - BACKGROUND: Indigenous populations are undergoing rapid ethnobiological, nutritional and socioeconomic transitions while being increasingly integrated into modernizing societies. To better understand the dynamics of these transitions, this article aims to characterize the cultural domain of food plants and analyze its relation with current day diets, and the local perceptions of changes given amongst the Ngabe people of Southern Conte-Burica, Costa Rica, as production of food plants by its residents is hypothesized to be drastically in recession with an decreased local production in the area and new conservation and development paradigms being implemented. METHODS: Extensive freelisting, interviews and workshops were used to collect the data from 72 participants on their knowledge of food plants, their current dietary practices and their perceptions of change in local foodways, while cultural domain analysis, descriptive statistical analyses and development of fundamental explanatory themes were employed to analyze the data. RESULTS: Results show a food plants domain composed of 140 species, of which 85 % grow in the area, with a medium level of cultural consensus, and some age-based variation. Although many plants still grow in the area, in many key species a decrease on local production-even abandonment-was found, with much reduced cultivation areas. Yet, the domain appears to be largely theoretical, with little evidence of use; and the diet today is predominantly dependent on foods bought from the store (more than 50 % of basic ingredients), many of which were not salient or not even recognized as 'food plants' in freelists exercises. While changes in the importance of food plants were largely deemed a result of changes in cultural preferences for store bought processed food stuffs and changing values associated with farming and being food self-sufficient, Ngabe were also aware of how changing household livelihood activities, and the subsequent loss of knowledge and use of food plants, were in fact being driven by changes in social and political policies, despite increases in forest cover and biodiversity. CONCLUSIONS: Ngabe foodways are changing in different and somewhat disconnected ways: knowledge of food plants is varied, reflecting most relevant changes in dietary practices such as lower cultivation areas and greater dependence on food from stores by all families. We attribute dietary shifts to socioeconomic and political changes in recent decades, in particular to a reduction of local production of food, new economic structures and agents related to the State and globalization. PMID- 26739313 TI - Aspirin dosing frequency in the primary and secondary prevention of cardiovascular events. AB - Aspirin has been a cornerstone of cardiovascular disease prevention since the late 1980s. Despite the popularity of aspirin and its wide use, the proper dosing and frequency of aspirin has yet to be determined. Early aspirin trials focused on its utility in broad target populations, but this strategy did not magnify the benefit of aspirin, and rather increased the complication rate. We have learned from previous studies that laboratory and clinical response to aspirin therapy in patients with different conditions and settings are diverse. This difference in aspirin response necessitates a personalized, tailored aspirin therapy. We aim to perform a comprehensive review of the current evidence surrounding aspirin responsiveness in several distinct patient populations and the rationale of different aspirin frequency and dosing strategies. Our conclusions call for future studies to determine individualized aspirin strategies to maximize the benefit and minimize the risk of aspirin. PMID- 26739314 TI - Evaluation of brush cytology and DNA image cytometry for the detection of cancer of the oral cavity. AB - BACKGROUND: Cancer of the oral cavity is the sixth most common malignancy reported worldwide. This study was undertaken to evaluate the efficacy of brush cytology and the adjunctive role of DNA image cytometry (ICM) in the diagnosis of oral cancer. METHOD: Oral brush smears and biopsy were obtained from 100 consecutive patients presenting with suspicious oral lesions. DNA-ICM was performed on 96 cytology smears which had adequate cellularity. RESULTS: On cytology, 54 cases were benign, 36 were malignant, 6 were suspicious for malignancy, and 4 were inadequate due to scanty cellularity. On histopathologic examination, 49 cases were diagnosed as squamous cell carcinoma and 51 cases as benign. The sensitivity of brush cytology for the detection of cancer was 83.3% and the specificity was 95.8%. The positive and negative predictive values were 95.2% and 85.2%, respectively, with a diagnostic accuracy of 86%. Out of 96 cases analyzed by image analysis to assess DNA ploidy, 33 cases were aneuploid and 63 were diploid. The sensitivity, specificity, positive predictive value, and negative predictive value of DNA-ICM were 68.7%, 100%, 100%, and 76.1%, respectively, giving a diagnostic accuracy of 81%. The combination of cytology and DNA cytometry increased the sensitivity to 92% and specificity to 100%. CONCLUSION: The study demonstrates the usefulness of DNA-ICM as an adjunct to brush cytology to diagnose oral cancer. It reduces the false negative cases on cytology and also adds to objectivity in cytologically doubtful cases. PMID- 26739315 TI - Intra-arterial versus intra venous contrast-enhanced computed tomography of the equine head. AB - BACKGROUND: The anatomical complexity of the horse's head limits the abilities of radiography. Computed tomography (CT) in combination with contrast enhanced CT is used more often for diagnosing various head pathology in horses. The objective of this study was to compare intravenous and intra-arterial contrast-enhancement techniques and describe normal and abnormal contrast enhancement in the horse's head. RESULTS: All 24 horses included in the study recovered without complication from the procedures. Compared to the pre-contrast studies, post-contrast studies showed significant contrast enhancement in the pituitary gland (IA: p < 0.0001; IV: p < 0.0001), IA nose septum (p = 0.002), nose mucosa (IA: p < 0.0001; IV: p = 0.02), parotid salivary gland (IA: p < 0.0001; IV p < 0.0001), cerebrum (IA: p < 0.0001; IV: p < 0.0001), rectus capitis muscle (IA: p < 0.0001; IV p = 0.001), IA temporal muscle (p < 0.0001), IA masseter muscle (p <0.0001) and IV brainstem (p = 0.01). No significant contrast enhancement was seen in the eye (IA: p = 0.23; IV p = 0.33), tongue (IA p = 0.2; IV p = 0.57), IA brainstem (p = 0.88), IV nose septum (p = 0.26), IV temporal muscle (p = 0.09) and IV masseter muscle (p = 0.46). Three different categories of abnormal enhancement were detected: a strong vascularised mass, an enhanced rim surrounding an unenhanced structure and an inflamed anatomical structure with abnormal contrast enhancement. CONCLUSION: Using the intra-arterial technique, similar contrast enhancement is achieved using less contrast medium compared to the intravenous technique. And a potential major advantage of the IA technique is the ability to evaluate lesions that are characterized by increased blood flow. Using the intravenous technique, a symmetrical and homogenous enhancement is achieved, however timing is more crucial and the contrast dosage is more of influence in the IV protocol. And a potential major advantage of the IV technique is the ability to evaluate lesions that are characterized by increased vascular permeability. Knowing the different normal contrast enhancement patterns will facilitate the recognition of abnormal contrast enhancements. PMID- 26739316 TI - Quantitative Coronary Physiology for Clinical Management: the Imaging Standard. AB - Pressure derived FFR and coronary flow capacity by PET define a physiologic severity-risk-benefit continuum wherein probability of benefit from revascularization over risk of the procedure and risk of residual global diffuse disease guides personalized, informed, evidenced based, interventional decisions. For the many variations in PET or MRI protocols for quantifying myocardial perfusion to define physiologic severity, the simple standard performance test combining measurement accuracy and clinical coronary pathophysiology to assure correct clinical decisions is the capacity to measure (i) rest perfusion of 0.2 cm(3)/min/gm in transmural scar in at least five patients to test low perfusion accuracy (ii) regional and global CFR of 4.0 or stress perfusion of 2.9 cm(3)/min/gm on two sequential rest-stress PET perfusion studies in the same subject with +/-15 % variability for at least 15 young healthy volunteers with no risk factors, no smoking, no obesity, and no measureable blood caffeine levels. PMID- 26739318 TI - New mechanistic approach of inorganic palladium toxicity: impairment in mitochondrial electron transfer. AB - Human activities have increased the levels of palladium (Pd) that are progressively accumulating in the environment. The growing evidence of Pd toxicity has become the focus of serious concern for the environment, organisms and humans, with little data on the mechanism of Pd toxicity. Recent studies have suggested that mitochondria have a key role in Pd toxicity via mitochondrial membrane potential collapse and depletion of the cellular glutathione (GSH) level. Therefore, it was decided to determine the mechanistic toxicity of Pd towards isolated mitochondria via new and reliable methods. Isolated liver and kidney mitochondria were obtained by differential ultracentrifugation and incubated with different concentrations of Pd (100-400 MUM). Our results showed that Pd induced mitochondrial dysfunction via an increase in mitochondrial ROS production and membrane potential collapse, which correlated to cytochrome c release. Also, increased disturbance in oxidative phosphorylation was also shown by the increase in ADP/ATP ratio in Pd-treated mitochondria, which indicates mitochondrial dysfunction in isolated liver and kidney mitochondria. Our results suggest that Pd-induced toxicity is the result of a disruptive effect on the mitochondrial respiratory chain, increasing the chance of cell death signaling. In addition, it is supposed that kidney tissue is more susceptible to Pd exposure than liver tissue. PMID- 26739319 TI - Assessment of palpitations. PMID- 26739320 TI - Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes. PMID- 26739321 TI - Circulating Endothelial Progenitor Cells: Potential Biomarkers for Idiopathic Dilated Cardiomyopathy. AB - Dilated cardiomyopathy (DCM) remains the most frequent cause of cardiac transplant and thus results in an enormous cost burden for health care systems worldwide. Although DCM is thought to be induced mainly by genetic and/or environmental factors, the cause is unknown in the majority of cases, giving rise to the term idiopathic DCM. Marked cardiac endothelial changes are associated with disease progression and outcome, and there are ongoing efforts to identify biomarkers that have diagnostic and prognostic value. Here, we discuss the potential and the limitations of circulating endothelial progenitor cells (EPCs) as minimally invasive serological biomarkers for DCM. In this context, it is essential to further evaluate their clinical utility independently of other variable factors that can also affect EPC levels such as age, gender, lifestyles, and treatments. To that end, large multicenter studies and standardized instrument settings, reagents, and sample preparation protocols are needed to confirm this. PMID- 26739322 TI - Human milk microbiota profiles in relation to birthing method, gestation and infant gender. AB - BACKGROUND: Human milk is an important source of bacteria for the developing infant and has been shown to influence the bacterial composition of the neonate, which in turn can affect disease risk later in life. Very little is known about what factors shape the human milk microbiome. The goal of the present study was to examine the milk microbiota from a range of women who delivered vaginally or by caesarean (C) section, who gave birth to males or females, at term or preterm. METHODS: Milk was collected from 39 Caucasian Canadian women, and microbial profiles were analyzed by 16S ribosomal RNA (rRNA) sequencing using the Illumina platform. RESULTS: A diverse community of milk bacteria was found with the most dominant phyla being Proteobacteria and Firmicutes and at the genus level, Staphylococcus, Pseudomonas, Streptococcus and Lactobacillus. Comparison of bacterial profiles between preterm and term births, C section (elective and non elective) and vaginal deliveries, and male and female infants showed no statistically significant differences. CONCLUSIONS: The study revealed the diverse bacterial types transferred to newborns. We postulate that there may be a fail-safe mechanism whereby the mother is "ready" to pass along her bacterial imprint irrespective of when and how the baby is born. PMID- 26739323 TI - The effect of cannabis on regular cannabis consumers' ability to ride a bicycle. AB - To assess the effects of cannabis on the ability required to ride a bicycle, repetitive practical cycling tests and medical examinations were carried out before and after inhalative consumption of cannabis. A maximum of three joints with body weight-adapted THC content (300 MUg THC per kg body weight) could be consumed by each test subject. Fourteen regular cannabis-consuming test subjects were studied (12 males, 2 females). In summary, only a few driving faults were observed even under the influence of very high THC concentrations. A defined THC concentration that leads to an inability to ride a bicycle cannot be presented. The test subjects showed only slight distinctive features that can be documented using a medical test routinely run for persons under suspicion of driving under the influence of alcohol or drugs. PMID- 26739324 TI - Hepatic Failure After Pig Heart Transplantation Into a Baboon: No Involvement of Porcine Hepatitis E Virus. AB - BACKGROUND: After transplantation of pig hearts into baboons, a particularly high increase of liver parameters was observed in 1 animal. To evaluate whether porcine hepatitis E virus (HEV) was involved in the pathological changes, the donor pig and the recipient baboon were screened for the presence of HEV. MATERIAL AND METHODS: Screening for HEV was performed using highly sensitive and specific PCR methods as well as immunological screening for HEV-specific antibodies. RESULTS: HEV was not detected in the donor pig or the baboon recipient. At necropsy, histopathological examination of liver sections showed acute coagulative necrosis of hepatocytes and hemorrhage, but minimal inflammatory cell activity. CONCLUSIONS: The liver failure observed in the recipient animal was not due to transmission of porcine HEV. Liver failure could have been caused by the onset of cardiac failure related to delayed transplant rejection. PMID- 26739325 TI - Trade-offs between acquired and innate immune defenses in humans. AB - Immune defenses provide resistance against infectious disease that is critical to survival. But immune defenses are costly, and limited resources allocated to immunity are not available for other physiological or developmental processes. We propose a framework for explaining variation in patterns of investment in two important subsystems of anti-pathogen defense: innate (non-specific) and acquired (specific) immunity. The developmental costs of acquired immunity are high, but the costs of maintenance and activation are relatively low. Innate immunity imposes lower upfront developmental costs, but higher operating costs. Innate defenses are mobilized quickly and are effective against novel pathogens. Acquired responses are less effective against novel exposures, but more effective against secondary exposures due to immunological memory. Based on their distinct profiles of costs and effectiveness, we propose that the balance of investment in innate versus acquired immunity is variable, and that this balance is optimized in response to local ecological conditions early in development. Nutritional abundance, high pathogen exposure and low signals of extrinsic mortality risk during sensitive periods of immune development should all favor relatively higher levels of investment in acquired immunity. Undernutrition, low pathogen exposure, and high mortality risk should favor innate immune defenses. The hypothesis provides a framework for organizing prior empirical research on the impact of developmental environments on innate and acquired immunity, and suggests promising directions for future research in human ecological immunology. PMID- 26739326 TI - Activity-dependent regulation of calcium and ribosomes in the chick cochlear nucleus. AB - Cochlea removal results in the death of 20-30% of neurons in the chick cochlear nucleus, nucleus magnocellularis (NM). Two potentially cytotoxic events, a dramatic rise in intracellular calcium concentration ([Ca(2+)]i) and a decline in the integrity of ribosomes are observed within 1h of deafferentation. Glutamatergic input from the auditory nerve has been shown to preserve NM neuron health by activating metabotropic glutamate receptors (mGluRs), maintaining both normal [Ca(2+)]i and ribosomal integrity. One interpretation of these results is that a common mGluR-activated signaling cascade is required for the maintenance of both [Ca(2+)]i and ribosomal integrity. This could happen if both responses are influenced directly by a common messenger, or if the loss of mGluR activation causes changes in one component that secondarily causes changes in the other. The present studies tested this common-mediator hypothesis in slice preparations by examining activity-dependent regulation of [Ca(2+)]i and ribosomes in the same tissue after selectively blocking group I mGluRs (1-Aminoindan-1,5-dicarboxylic acid (AIDA)) or group II mGluRs (LY 341495) during unilateral auditory nerve stimulation. Changes in [Ca(2+)]i of NM neurons were measured using fura-2 ratiometric calcium imaging and the tissue was subsequently processed for Y10B immunoreactivity (Y10B-ir), an antibody that recognizes a ribosomal epitope. The group I mGluR antagonist blocked the activity-dependent regulation of both [Ca(2+)]i and Y10B-ir, but the group II antagonist blocked only the activity dependent regulation of Y10B-ir. That is, even when group II receptors were blocked, stimulation continued to maintain low [Ca(2+)]i, but it did not maintain Y10B-ir. These results suggest a dissociation in how calcium and ribosomes are regulated in NM neurons and that ribosomes can be regulated through a mechanism that is independent of calcium regulation. PMID- 26739327 TI - White matter apoptosis is increased by delayed hypothermia and rewarming in a neonatal piglet model of hypoxic ischemic encephalopathy. AB - Therapeutic hypothermia is widely used to treat neonatal hypoxic ischemic (HI) brain injuries. However, potentially deleterious effects of delaying the induction of hypothermia and of rewarming on white matter injury remain unclear. We used a piglet model of HI to assess the effects of delayed hypothermia and rewarming on white matter apoptosis. Piglets underwent HI injury or sham surgery followed by normothermic or hypothermic recovery at 2h. Hypothermic groups were divided into those with no rewarming, slow rewarming at 0.5 degrees C/h, or rapid rewarming at 4 degrees C/h. Apoptotic cells in the subcortical white matter of the motor gyrus, corpus callosum, lateral olfactory tract, and internal capsule at 29h were identified morphologically and counted by hematoxylin & eosin staining. Cell death was verified by terminal deoxynucleotidyl transferase (TdT) dUTP nick end labeling (TUNEL) assay. White matter neurons were also counted, and apoptotic cells were immunophenotyped with the oligodendrocyte marker 2',3' cyclic-nucleotide 3'-phosphodiesterase (CNPase). Hypothermia, slow rewarming, and rapid rewarming increased apoptosis in the subcortical white matter relative to normothermia (p<0.05). The number of white matter neurons was not lower in groups with more apoptosis after hypothermia or rapid rewarming, indicating that the apoptosis occurred among glial cells. Hypothermic piglets had more apoptosis in the lateral olfactory tract than those that were rewarmed (p<0.05). The promotion of apoptosis by hypothermia and rewarming in these regions was independent of HI. In the corpus callosum, HI piglets had more apoptosis than shams after normothermia, slow rewarming, and rapid rewarming (p<0.05). Many apoptotic cells were myelinating oligodendrocytes identified by CNPase positivity. Our results indicate that delaying the induction of hypothermia and rewarming are associated with white matter apoptosis in a piglet model of HI; in some regions these temperature effects are independent of HI. Vulnerable cells include myelinating oligodendrocytes. This study identifies a deleterious effect of therapeutic hypothermia in the developing brain. PMID- 26739328 TI - Evaluation of software tools for automated identification of neuroanatomical structures in quantitative beta-amyloid PET imaging to diagnose Alzheimer's disease. AB - INTRODUCTION: For regional quantification of nuclear brain imaging data, defining volumes of interest (VOIs) by hand is still the gold standard. As this procedure is time-consuming and operator-dependent, a variety of software tools for automated identification of neuroanatomical structures were developed. As the quality and performance of those tools are poorly investigated so far in analyzing amyloid PET data, we compared in this project four algorithms for automated VOI definition (HERMES Brass, two PMOD approaches, and FreeSurfer) against the conventional method. We systematically analyzed florbetaben brain PET and MRI data of ten patients with probable Alzheimer's dementia (AD) and ten age matched healthy controls (HCs) collected in a previous clinical study. METHODS: VOIs were manually defined on the data as well as through the four automated workflows. Standardized uptake value ratios (SUVRs) with the cerebellar cortex as a reference region were obtained for each VOI. SUVR comparisons between ADs and HCs were carried out using Mann-Whitney-U tests, and effect sizes (Cohen's d) were calculated. SUVRs of automatically generated VOIs were correlated with SUVRs of conventionally derived VOIs (Pearson's tests). RESULTS: The composite neocortex SUVRs obtained by manually defined VOIs were significantly higher for ADs vs. HCs (p=0.010, d=1.53). This was also the case for the four tested automated approaches which achieved effect sizes of d=1.38 to d=1.62. SUVRs of automatically generated VOIs correlated significantly with those of the hand drawn VOIs in a number of brain regions, with regional differences in the degree of these correlations. Best overall correlation was observed in the lateral temporal VOI for all tested software tools (r=0.82 to r=0.95, p<0.001). CONCLUSION: Automated VOI definition by the software tools tested has a great potential to substitute for the current standard procedure to manually define VOIs in beta-amyloid PET data analysis. PMID- 26739329 TI - Beta-amyloid deposition and cognitive function in patients with major depressive disorder with different subtypes of mild cognitive impairment: (18)F-florbetapir (AV-45/Amyvid) PET study. AB - PURPOSE: The objective of this study was to evaluate the amyloid burden, as assessed by (18)F-florbetapir (AV-45/Amyvid) positron emission tomography PET, in patients with major depressive disorder (MDD) with different subtypes of mild cognitive impairment (MCI) and the relationship between amyloid burden and cognition in MDD patients. METHODS: The study included 55 MDD patients without dementia and 21 healthy control subjects (HCs) who were assessed using a comprehensive cognitive test battery and (18)F-florbetapir PET imaging. The standardized uptake value ratios (SUVR) in eight cortical regions using the whole cerebellum as reference region were determined and voxel-wise comparisons between the HC and MDD groups were performed. Vascular risk factors, serum homocysteine level and the apolipoprotein E (ApoE) genotype were also determined. RESULTS: Among the 55 MDD patients, 22 (40.0 %) had MCI, 12 (21.8 %) non-amnestic MCI (naMCI) and 10 (18.2 %) amnestic MCI (aMCI). The MDD patients with aMCI had the highest relative (18)F-florbetapir uptake in all cortical regions, and a significant difference in relative (18)F-florbetapir uptake was found in the parietal region as compared with that in naMCI subjects (P < 0.05) and HCs (P < 0.01). Voxel-wise analyses revealed significantly increased relative (18)F florbetapir uptake in the MDD patients with aMCI and naMCI in the frontal, parietal, temporal and occipital areas (P < 0.005). The global cortical SUVR was significantly negatively correlated with MMSE score (r = -0.342, P = 0.010) and memory function (r = -0.328, P = 0.015). The negative correlation between the global SUVR and memory in the MDD patients remained significant in multiple regression analyses that included age, educational level, ApoE genotype, and depression severity (beta = -3.607, t = -2.874, P = 0.006). CONCLUSION: We found preliminary evidence of brain beta-amyloid deposition in MDD patients with different subtypes of MCI. Our findings in MDD patients support the hypothesis that a higher amyloid burden is associated with a poorer memory performance. We also observed a high prevalence of MCI among elderly depressed patients, and depressed patients with MCI exhibited heterogeneously elevated (18)F-florbetapir retention as compared with depressed patients without MCI. The higher amyloid burden in the aMCI patients suggests that these patients may also be more likely to develop Alzheimer's disease than other patients diagnosed with major depression. PMID- 26739330 TI - Association of liprin beta-1 with kank proteins in melanoma. PMID- 26739331 TI - Sequential learning of psychomotor and visuospatial skills for laparoscopic suturing and knot tying - study protocol for a randomized controlled trial "The shoebox study". AB - BACKGROUND: Laparoscopy training has become an integral part of surgical education. Suturing and knot tying is a basic, yet inherent part of many laparoscopic operations, and should be mastered prior to operating on patients. One common and standardized suturing technique is the C-loop technique. In the standard training setting, on a box trainer, the trainee learns the psychomotor movements of the task and the laparoscopic visuospatial orientation simultaneously. Learning the psychomotor and visuospatial skills separately and sequentially may offer a more time-efficient alternative to the current standard of training. METHODS: This is a monocentric, two-arm randomized controlled trial. The participants are medical students in their clinical years (third to sixth year) at Heidelberg University who have not previously partaken in a laparoscopic training course lasting more than 2 hours. A total of 54 students are randomized into one of two arms in a 1:1 ratio to sequential learning (group 1) or control (group 2). Both groups receive a standardized introduction to the training center, laparoscopic instruments, and C-loop technique. Group 1 learn the C-loop using a transparent shoebox, thus only learning the psychomotor skills. Once they reach proficiency, they then perform the same knot tying procedure on a box trainer with standard laparoscopic view, where they combine their psychomotor skills with the visuospatial orientation inherent to laparoscopy. Group 2 learn the C-loop using solely a box trainer with standard laparoscopic view until they reach proficiency. Trainees work in pairs and time is recorded for each attempt. The primary outcome is mean total training time for each group. Secondary endpoints include procedural and knot quality subscore differences. Tertiary endpoints include studying the influence of gender and video game experience on performance. DISCUSSION: This study addresses whether the learning of the psychomotor and visuospatial aspects of laparoscopic suturing and knot tying is optimal sequentially or simultaneously, by assessing total training time, procedural, and knot quality differences between the two groups. It will improve the efficiency of future laparoscopic suturing courses and may serve as an indicator for laparoscopic training in a broader context, i.e., not only for suturing and knot tying. TRIAL REGISTRATION: This trial was registered on 12 August 2015 with the trial registration number DRKS00008668 . PMID- 26739332 TI - Identification of potential therapeutic targets for lung cancer by bioinformatics analysis. AB - The aim of the present study was to identify potential therapeutic targets for lung cancer and explore underlying molecular mechanisms of its development and progression. The gene expression profile datasets no. GSE3268 and GSE19804, which included five and 60 pairs of tumor and normal lung tissue specimens, respectively, were downloaded from Gene Expression Omnibus. Differentially expressed genes (DEGs) between lung cancer and normal tissues were identified, and gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis of the DEGs was performed. Furthermore, protein-protein interaction (PPI) networks and a transcription factor (TF) regulatory network were constructed and key target genes were screened. A total of 466 DEGs were identified, and the PPI network indicated that IL-6 and MMP9 had key roles in lung cancer. A PPI module containing 34 nodes and 547 edges was obtained, including PTTG1. The TF regulatory network indicated that TFs of FOSB and LMO2 had a key role. Furthermore, MMP9 was indicated to be the target of FOSB, while PTTG1 was the target of LMO2. In conclusion, the bioinformatics analysis of the present study indicated that IL-6, MMP9 and PTTG1 may have key roles in the progression and development of lung cancer and may potentially be used as biomarkers or specific therapeutic targets for lung cancer. PMID- 26739335 TI - G protein-coupled receptors: signalling and regulation by lipid agonists for improved glucose homoeostasis. AB - G protein-coupled receptors (GPCRs) play a pivotal role in cell signalling, controlling many processes such as immunity, growth, cellular differentiation, neurological pathways and hormone secretions. Fatty acid agonists are increasingly recognised as having a key role in the regulation of glucose homoeostasis via stimulation of islet and gastrointestinal GPCRs. Downstream cell signalling results in modulation of the biosynthesis, secretion, proliferation and anti-apoptotic pathways of islet and enteroendocrine cells. GPR40 and GPR120 are activated by long-chain fatty acids (>C12) with both receptors coupling to the Galphaq subunit that activates the Ca(2+)-dependent pathway. GPR41 and GPR43 are stimulated by short-chain fatty acids (C2-C5), and activation results in binding to Galphai that inhibits the adenylyl cyclase pathway attenuating cAMP production. In addition, GPR43 also couples to the Galphaq subunit augmenting intracellular Ca(2+) and activating phospholipase C. GPR55 is specific for cannabinoid endogenous agonists (endocannabinoids) and non-cannabinoid fatty acids, which couples to Galpha12/13 and Galphaq proteins, leading to enhancing intracellular Ca(2+), extracellular signal-regulated kinase 1/2 (ERK) phosphorylation and Rho kinase. GPR119 is activated by fatty acid ethanolamides and binds to Galphas utilising the adenylate cyclase pathway, which is dependent upon protein kinase A. Current research indicates that GPCR therapies may be approved for clinical use in the near future. This review focuses on the recent advances in preclinical diabetes research in the signalling and regulation of GPCRs on islet and enteroendocrine cells involved in glucose homoeostasis. PMID- 26739333 TI - Imaging metabolic heterogeneity in cancer. AB - As our knowledge of cancer metabolism has increased, it has become apparent that cancer metabolic processes are extremely heterogeneous. The reasons behind this heterogeneity include genetic diversity, the existence of multiple and redundant metabolic pathways, altered microenvironmental conditions, and so on. As a result, methods in the clinic and beyond have been developed in order to image and study tumor metabolism in the in vivo and in vitro regimes. Both regimes provide unique advantages and challenges, and may be used to provide a picture of tumor metabolic heterogeneity that is spatially and temporally comprehensive. Taken together, these methods may hold the key to appropriate cancer diagnoses and treatments in the future. PMID- 26739336 TI - The advantages of incorporating liquid-based cytology (TACASTM) in mass screening for cervical cancer. AB - We incorporated liquid-based cytology (LBC) in population-based screening for cervical cancer. The usefulness of using LBC in mass screening for cervical cancer was examined. From 2009 to 2014, 157,061 individuals underwent mass screening for cervical cancer in Aomori Prefecture. From 2009 to 2011, cells were collected from 82,218 individuals and the specimens were conventionally prepared (CP). From 2012 to 2014, cells were collected from 74,843 individuals and the specimens were prepared using LBC (TACASTM). Cytology results for the 2 sets of specimens were compared and differences in cytologic features were examined. ASC US and more severe lesions were detected at a rate of 1.13 % by CP and 1.44 % by LBC, so LBC had a 1.3-fold higher rate of detection. LBC had a 1.6-fold higher rate of LSIL detection and a 1.2-fold higher rate of HSIL detection. CP detected cancer in 20 cases at a rate of 0.024 % while LBC detected cancer in 18 cases at a rate of 0.024 %. Cytodiagnosis of the 18 cases of SCC that LBC identified revealed that 7 were SCC, 8 were HSIL, and 3 were ASC-H. Atypical cells tended to be smaller with TACASTM. LBC reduced the time needed for microscopic examination of a single specimen by 42 % in comparison to CP. LBC using TACASTM allowed the detection of slight lesions and slight changes in cells. LBC can lessen the burden on medical personnel and may lead to improved accuracy. PMID- 26739337 TI - Free fatty acid production in the cyanobacterium Synechocystis sp. PCC 6803 is enhanced by deletion of the cyAbrB2 transcriptional regulator. AB - The cyAbrB2 (Sll0822) transcriptional regulator in Synechocystis sp. PCC 6803 is involved in coordination of carbon and nitrogen metabolism and its deletion causes distinct phenotypes such as decreased expression levels of nitrogen regulated genes and high accumulation of glycogen granules. From the viewpoint of metabolic engineering, the highly accumulated glycogen granules in the DeltacyabrB2 mutant could be a valuable source for the production of biofuels. Here, by disruption of the aas gene (slr1609) encoding acyl-acyl carrier protein synthetase and introduction of a gene encoding thioesterase from Umbellularia californica (UcTE), we conferred the ability of production and secretion of free fatty acids on the DeltacyabrB2 mutant. Notable features of the resulting DeltacyabrB2Deltaaas::UcTE strain compared with DeltacyabrB2 by RNA-seq analysis were decrease in expression levels of genes related to uptake and subsequent metabolism of nitrogen and carbon and increase in the expression level of sigE encoding a group 2 sigma factor. These changes in gene expression profile were not observed when the same genetic modification was introduced in the wild-type background. The DeltacyabrB2Deltaaas::UcTE strain showed two-folds higher free fatty acid productivity on a per OD730 basis compared with the Deltaaas::UcTE strain, without expense of the accumulated glycogen granules. This shows the potential of the DeltacyabrB2 mutant as the platform of biofuel production. The effective utilization of the accumulated glycogen must be the next task to be pursued. PMID- 26739338 TI - Editorial overview: Innate immunity. PMID- 26739339 TI - Effectiveness of a home-based cognitive behavioral program to manage concerns about falls in community-dwelling, frail older people: results of a randomized controlled trial. AB - BACKGROUND: Concerns about falls are common among older people. These concerns, also referred to as fear of falling, can have serious physical and psychosocial consequences, such as functional decline, increased risk of falls, activity restriction, and lower social participation. Although cognitive behavioral group programs to reduce concerns about falls are available, no home-based approaches for older people with health problems, who may not be able to attend such group programs are available yet. The aim of this study was to assess the effectiveness of a home-based cognitive behavioral program on concerns about falls, in frail, older people living in the community. METHODS: In a randomized controlled trial in the Netherlands, 389 people aged 70 years and older, in fair or poor perceived health, who reported at least some concerns about falls and related activity avoidance were allocated to a control (n = 195) or intervention group (n = 194). The intervention was a home-based, cognitive behavioral program consisting of seven sessions including three home visits and four telephone contacts. The program aims to instill adaptive and realistic views about fall risks via cognitive restructuring and to increase activity and safe behavior using goal setting and action planning and was facilitated by community nurses. Control group participants received usual care. Outcomes at 5 and 12 months follow-up were concerns about falls, activity avoidance due to concerns about falls, disability and falls. RESULTS: At 12 months, the intervention group showed significant lower levels of concerns about falls compared to the control group. Furthermore, significant reductions in activity avoidance, disability and indoor falls were identified in the intervention group compared with the control group. Effect sizes were small to medium. No significant difference in total number of falls was noted between the groups. CONCLUSIONS: The home-based, cognitive behavioral program significantly reduces concerns about falls, related activity avoidance, disability and indoor falls in community-living, frail older people. The program may prolong independent living and provides an alternative for those people who are not able or willing to attend group programs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01358032. Registered 17 May 2011. PMID- 26739340 TI - Virtual addictions: An examination of problematic social casino game use among at risk gamblers. AB - The overlap of gaming and gambling activities within online digital technologies is of growing relevance to the study of technological addictions. Social casino games are immensely popular 'free to play' games that offer realistic emulation of financial gambling activities. Their structural similarities might suggest that engagement in social casino games may be particularly risky for people with existing gambling problems. Currently it is not known whether social casino games are used problematically by individuals who also experience problematic gambling, the extent of this overlap, the characteristics of those who experience problems with both activities, and the symptoms of problematic social casino game use they experience. An online survey was administered to Internet users (N=1554) to assess social casino game use and associated problems. This study examined a subsample of 176 adults who played social casino games and reported self identified gambling problems. The results indicated that a greater frequency and diversity of social casino game playing and more frequent and larger expenditure on social casino games was significantly positively associated with symptom severity of problematic social casino game use. Gamblers who were younger, less educated, spoke a non-English language, and with higher psychological distress, were more likely to report greater problems. Playing social casino games to escape or relieve a negative mood was the most commonly reported symptom. These findings suggest that some problem gamblers may also be at risk of problematic engagement in online gambling activities that lack financial incentives. Gamblers' concurrent engagement in social casino games therefore warrants further consideration in gambling research studies and clinical practice settings. PMID- 26739341 TI - Liver metabolic and histopathological profile in finishing lambs fed licuri (Syagrus coronata(Mart.)Becc.) cake. AB - The objective of this study was to determine the impact of including licuri cake in the diet of Santa Ines crossbred finishing lambs by examining their liver metabolic and histopathological profile. Forty-four uncastrated lambs with an average age of 6 months and an average weight of 21.2 kg +/- 2.7 kg. The animals were fed diets with 40 % Tifton 85 hay and 60 % of a mixture consisting of corn and soybean meal, 1 % urea, a mineral-vitamin premix, and an inclusion of licuri cake at a level of 0, 8, 16, and 24 % of the dietary dry matter (DM), which composed the treatments. The experimental design was completely randomized, and the data were analyzed by variance and regression analyses. The animals were confined in individual stalls for 70 days. Blood was collected on the last day of the experimental period, and metabolite, protein, energy, and enzyme profiles of the liver were determined for these samples. Histopathological evaluations of the liver parenchyma were also undertaken. The increase in the level of the licuri cake in the diet caused a linear increase (P < 0.05) in the serum urea content. The protein metabolism was not affected by the licuri cake inclusion levels in the diet. Regarding energy metabolism, a linear increase (P < 0.01) was observed in the serum triglyceride concentrations, but there were no effects on serum cholesterol levels. Regarding the functioning of the liver and muscle, the inclusion of the licuri cake had no effect on the enzymatic activities, except on gamma-glutamyltransferase, which decreased linearly (P < 0.05). The values found for the evaluated parameters varied within a range considered normal for this species. In the postmortem examination at slaughter, no macroscopic alterations in the liver were observed. Histopathological analysis revealed the presence of discrete and nonspecific alterations common to all treatments, suggesting no effect of the level of inclusion of the licuri cake. The use of the licuri cake in composing up to 24 % of the diet did not cause metabolic or liver disorders in the lambs. PMID- 26739342 TI - Genetic analysis and the estimates of genetic and phenotypic correlation of growth rates, Kleiber ratios, and fat-tail dimensions with birth to yearling live body weight traits in Makuie sheep. AB - Genetic parameter estimates of growth rates, Kleiber ratios, and fat-tail dimensions were aimed using 22, 253 records at the present study. The studied traits were average daily gain from birth to weaning, average daily gain from 9 months of age to yearling, Kleiber ratio from birth to weaning, Kleiber ratio from 9 months of age to yearling, fat-tail length, fat-tail width, and fat-tail thickness. Each trait was fitted by four different animal models, which are differentiated by including or excluding maternal effects. Beside the estimates of genetic and phenotypic correlation among the studied traits, the association of them with birth to yearling live body weights using series of bivariate animal models was investigated. The direct heritabilities were ranged from 0.04 to 0.20, which indicated a wide range of additive genetic variances of the traits. Genetic and phenotypic correlations between the main traits were ranged from -0.11 to 0.99 and -0.08 to 0.95, respectively. The results indicated that the traits could be improved by including them in the selection index due to their moderate to high heritability estimation. PMID- 26739343 TI - Efficiency of different hormonal treatments for estrus synchronization in tropical Santa Ines sheep. AB - The aim of this study was to evaluate the effect of (i) the duration of hormone treatment with progestogen sponges during the seasonal anestrus and (ii) the administration of two doses of prostaglandin at 7 days apart during the breeding season on reproductive parameters of Santa Ines ewes. In experiment 1, 32 ewes received intravaginal MAP sponges for 6 (G6 days), 9 (G9 days), or 12 (G12days) days and 75 MUg D-cloprostenol i.m. and 300 IU eCG i.m. 1 day before sponge removal. In experiment 2, 23 ewes received two doses of 0.48-mg sodium cloprostenol i.m. 7 days apart. Ovarian follicular dynamic was assessed through transrectal ultrasonography. Blood samples were collected daily to determine progesterone concentrations. In experiment 1, estrus and ovulation rates did not differ (P > 0.05) among protocols and between cyclic and acyclic ewes at the beginning of the experiment. The G9 days treatment showed a lower dispersion of ovulations in relation to onset of estrus when compared to G6 days and G12 days. In experiment 2, all ewes exhibit estrus and ovulated after the second dose of prostaglandin, although ewes that were in diestrus at D0 showed subluteal concentrations of progesterone during the follicle development stage of the treatment. In conclusion, the use of progestogen device during 9 days promotes lower dispersion of ovulation when compared to its use for 6 or 12 days, and the protocol of two doses of prostaglandin 7 days apart synchronizes estrus efficiently but results in follicular development under low progesterone concentrations. PMID- 26739344 TI - Effect of water hyacinth (Eichhornia crassipes) hay inclusion in the diets of sheep. AB - The aim of this study was to evaluate the effects of replacing Tifton-85 hay (0, 20, 40, 60 and 80 % on a dry matter basis) with water hyacinth hay (Eichhornia crassipes) on intake and digestibility of nutrients, feeding behaviour, rumen and blood parameters of sheep. Five uncastrated male sheep, cannulated in the rumen, with an average body weight of 40 kg were assigned in a 5 * 5 Latin square design. The water hyacinth hay contained 870 g/kg dry matter (DM), 159 g/kg crude protein (CP), 547 g/kg neutral detergent fibre (NDF) and 461 g/kg total digestible nutrients (TDN). The DM intake and digestibility of NDF and non-fibre carbohydrates (NFC) were linearly reduced by replacing the Tifton-85 hay with water hyacinth hay. Similarly, there was a linear reduction of rumination time and efficiencies of feeding and rumination of DM and NDF. The concentrations of urea, glucose, AST and GGT in blood plasma were not changed by replacing the Tifton-85 hay with water hyacinth hay. Although water hyacinth hay reduced the intake and digestibility of some nutrients, the Tifton-85 hay replacement could be economically advantageous for sheep feeding. PMID- 26739345 TI - Are IQ and educational outcomes in teenagers related to their cannabis use? A prospective cohort study. AB - There is much debate about the impact of adolescent cannabis use on intellectual and educational outcomes. We investigated associations between adolescent cannabis use and IQ and educational attainment in a sample of 2235 teenagers from the Avon Longitudinal Study of Parents and Children. By the age of 15, 24% reported having tried cannabis at least once. A series of nested linear regressions was employed, adjusted hierarchically by pre-exposure ability and potential confounds (e.g. cigarette and alcohol use, childhood mental-health symptoms and behavioural problems), to test the relationships between cumulative cannabis use and IQ at the age of 15 and educational performance at the age of 16. After full adjustment, those who had used cannabis ? 50 times did not differ from never-users on either IQ or educational performance. Adjusting for group differences in cigarette smoking dramatically attenuated the associations between cannabis use and both outcomes, and further analyses demonstrated robust associations between cigarette use and educational outcomes, even with cannabis users excluded. These findings suggest that adolescent cannabis use is not associated with IQ or educational performance once adjustment is made for potential confounds, in particular adolescent cigarette use. Modest cannabis use in teenagers may have less cognitive impact than epidemiological surveys of older cohorts have previously suggested. PMID- 26739346 TI - Ethnoichthyology of the indigenous Truka people, Northeast Brazil. AB - BACKGROUND: Historically, fishing is an important activity for riverine communities established along the Sao Francisco River, including indigenous communities. In the present study, we researched fishing activities in two villages of the Truka ethnic group, both located in the State of Pernambuco along the sub-middle section of the Sao Francisco River, Northeast Brazil. We recorded the richness and uses of the fished species and the ecological knowledge on these species, the fishing techniques employed and the perception of the indigenous people regarding current environmental impacts on the Sao Francisco River that influence local fishing. METHOD: The information was obtained through interviews with 33 Truka fishers (27 men and six women), including 17 interviewees from Central Village (Cabrobo) and 16 from Tapera Village (Oroco). RESULTS: Using five fishing techniques, the interviewees caught 25 fish species, including 21 native and four exotic species. All species are used as food, and two species are used in traditional Truka medicine. The interviewees revealed that fishing currently has less importance in their subsistence. They indicated that this situation is occurring because of several factors, such as the introduction of exotic species, pollution and urbanization, that have impacted the Sao Francisco River, resulting in a decline of fishing resources. Nevertheless, we found that the indigenous people who are still fishing have a broad knowledge of the habitat and ecology of the target fishing. CONCLUSION: Although fishing is declining in importance among the Truka, we found that the individuals who are still practicing this activity have a broad knowledge about the habitat and ecology of the target species and apply that knowledge to fishing methods. Knowledge about the ecology of the species and the environmental impacts that have affected them can support basic research on local fish populations and research investigating the environmental impacts, resource management and sustainable exploitation of fisheries resources. PMID- 26739347 TI - Is There a Role for HbA1c in Pregnancy? AB - Outside pregnancy, HbA1c analysis is used for monitoring, screening for and diagnosing diabetes and prediabetes. During pregnancy, the role for HbA1c analysis is not yet established. Physiological changes lower HbA1c levels, and pregnancy-specific reference ranges may need to be recognised. Other factors that influence HbA1c are also important to consider, particularly since emerging data suggest that, in early pregnancy, HbA1c elevations close to the reference range may both identify women with underlying hyperglycaemia and be associated with adverse pregnancy outcomes. In later pregnancy, HbA1c analysis is less useful than an oral glucose tolerance test (OGTT) at detecting gestational diabetes. Postpartum, HbA1c analysis detects fewer women with abnormal glucose tolerance than an OGTT, but the ease of testing may improve follow-up rates and combining HbA1c analysis with fasting plasma glucose or waist circumference may improve detection rates. This article discusses the relevance of HbA1c testing at different stages of pregnancy. PMID- 26739348 TI - Pseudofulvibacter marinus sp. nov., isolated from seawater. AB - A novel Gram-stain-negative, rod-shaped, non-spore-forming, non-flagellated, strictly aerobic strain, designated RZW2-1T, was isolated from coastal seawater of the Yellow Sea in China (35.475 degrees N 119.613 degrees E). The organism grew optimally at 24 degrees C, at pH 7.0 and in the presence of 3.0 % (w/v) NaCl. The strain requires seawater or artificial seawater for growth and NaCl alone does not support growth. Strain RZW2-1T contained MK-6 as the only respiratory quinone and iso-C15 : 0, iso-C15 : 1 G and 10-methyl C16 : 0 and/or iso-C17 : 1omega9c as the dominant fatty acids. The polar lipids of strain RZW2 1T were four unidentified phospholipids (PL1-PL4), two unknown lipids (L1, L2) and one unidentified aminolipid (AL1). The DNA G+C content of strain RZW2-1T was 32 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that the novel strain was most closely related to the type strain of the only described species of genus Pseudofulvibacter, Pseudofulvibacter geojedonensis YCS-9T, with 95.1 % 16S rRNA gene sequence similarity. On the basis of polyphasic analyses, strain RZW2-1T represents a novel species of the genus Pseudofulvibacter, for which the name Pseudofulvibacter marinus sp. nov. is proposed. The type strain is RZW2-1T ( = JCM 30826T = MCCC 1K00695T). PMID- 26739349 TI - Budesonide and fluticasone propionate differentially affect the airway epithelial barrier. AB - BACKGROUND: COPD patients have a higher risk of pneumonia when treated with fluticasone propionate (FP) than with placebo, and a lower risk with budesonide (BUD). We hypothesized that BUD and FP differentially affect the mucosal barrier in response to viral infection and/or cigarette smoke. METHODS: We assessed protective effects of equivalent concentrations of BUD and FP on cytokine production and barrier function (electrical resistance) in human bronchial epithelial 16HBE cells and primary bronchial epithelial cells (PBECs) upon exposure to viral mimetic poly-(I:C) and/or cigarette smoke extract (CSE) or epidermal growth factor (EGF). RESULTS: BUD and FP were equally effective in suppressing poly-(I:C)- and/or CSE-induced IL-8 secretion in 16HBE and PBECs. Poly-(I:C) substantially decreased electrical resistance in 16HBE cells and both BUD and FP fully counteracted this effect. However, FP hardly affected 16HBE barrier dysfunction induced by CSE with/without poly-(I:C), whereas BUD (16 nM) provided full protection, an effect likely mediated by affecting EGFR-downstream target GSK-3beta. Similarly, BUD, but not FP, significantly improved CSE-induced barrier dysfunction in PBECs. Finally, BUD, but not FP, exerted a modest but significant protective effect against Streptococcus Pneumoniae-induced barrier dysfunction, and BUD, but not FP, prevented cellular adhesion and/or internalization of these bacteria induced by poly-(I:C) in 16HBE. CONCLUSIONS: Collectively, both BUD and FP efficiently control epithelial pro-inflammatory responses and barrier function upon mimicry of viral infection. Of potential clinical relevance, BUD more effectively counteracted CSE-induced barrier dysfunction, reinforcing the epithelial barrier and potentially limiting access of pathogens upon smoking in vivo. PMID- 26739350 TI - Two-year outcomes after diagnostic and therapeutic fetal cystoscopy for lower urinary tract obstruction. AB - OBJECTIVES: Our objective is to report long-term outcome after fetal cystoscopy for lower urinary tract obstruction (LUTO), as well as to investigate the accuracy of fetal cystoscopy in diagnosing the cause of bladder outlet obstruction. METHODS: This is a retrospective cohort study of all fetuses who underwent cystoscopy for prenatal diagnosis of LUTO in three tertiary referral centers. Fetal diagnostic cystoscopy was performed to determine prenatally the cause of LUTO and to ablate the posterior urethral valves (PUV). RESULTS: A total of 50 fetal cystoscopies were performed, revealing PUV in 31 (62%) fetuses, urethral atresia (UA) in 14 (28%) fetuses, and urethral stenosis (US) in 5 (10%) fetuses. Two fetuses had trisomy 18 diagnosed after fetal cystoscopy and were excluded from the present analysis. Fetal cystoscopy was accurate in the diagnosis of the etiology of LUTO in 32/35 (91.4%). There were no survivors in the UA group. One fetus with US underwent urethral stenting and survived with normal renal function at 2 years of life. Among the infants with PUV, 17/30 (56.7%) infants survived, and 13/17 (76.5%) had normal renal function at 1 year of life; 15/28 (53.6%) infants survived, and 11/15 (73.3%) had normal renal function at 2 years. CONCLUSIONS: Fetal cystoscopy is accurate in the diagnosis of the etiology of LUTO and serves as a guide to the specific prenatal treatment. This procedure is associated with modest long-term survival (54%) but with adequate preserved normal renal function in two thirds of the infants among fetuses with PUV. PMID- 26739352 TI - Confining energy migration in upconversion nanoparticles towards deep ultraviolet lasing. AB - Manipulating particle size is a powerful means of creating unprecedented optical properties in metals and semiconductors. Here we report an insulator system composed of NaYbF4:Tm in which size effect can be harnessed to enhance multiphoton upconversion. Our mechanistic investigations suggest that the phenomenon stems from spatial confinement of energy migration in nanosized structures. We show that confining energy migration constitutes a general and versatile strategy to manipulating multiphoton upconversion, demonstrating an efficient five-photon upconversion emission of Tm(3+) in a stoichiometric Yb lattice without suffering from concentration quenching. The high emission intensity is unambiguously substantiated by realizing room-temperature lasing emission at around 311 nm after 980-nm pumping, recording an optical gain two orders of magnitude larger than that of a conventional Yb/Tm-based system operating at 650 nm. Our findings thus highlight the viability of realizing diode pumped lasing in deep ultraviolet regime for various practical applications. PMID- 26739353 TI - Two COX-2 inhibitors induce apoptosis in human erythroleukemia K562cells by modulating NF-kappaB and FHC pathways. AB - BACKGROUND: Leukemia is distinguished by abnormal proliferation of leukocytes. Although there has been some progress in developing novel cancer therapies, no significant improvement was observed in the overall survival rate over the last decade. Selective cyclooxygenase-2 (COX-2) inhibitors are known to inhibit tumor growth by exerting antimetastatic and antiangiogenic effects through inhibition of COX -dependent and independent pathways. The ability of two new triaryl oxadiazole derivatives, compounds A (3-(4-chlorophenyl) -5-(4-flurophenyl)-4 Phenyl-4,5-dihydro-1,2,4-oxadiazole) and B (3,5-bis(4-chlorophenyl)-4-Phenyl-4,5 dihydro-1,2,4-oxadiazole), to induce apoptosis in human erythroleukemia K562 cells was evaluated and the upstream mechanism was investigated. METHODS: K562 cells were treated with compounds A and B at their IC50 concentrations and analyzed by DAPI staining and Annexin-V-FLUOS labelling solution. Nuclear factor kappa-B (NF-kappaB) activation was evaluated by TransAM kit. Cyclooxygenase-2 (COX-2), Caspase-3, Bax, Bcl-2, ferritin heavy chain (FHC), extra cellular signal regulated kinase (ERK), p-ERK and early growth response protein-1 (Egr1) levels were determined using Western blotting, while c-Myc mRNA level was investigated by RT-PCR. RESULTS: Changes in nuclear morphology and the increased annexin-V/PI staining revealed the apoptotic cell death in compounds A- and B-treated K562 cells. A significant reduction in NF-kappaB activity as well as FHC and p-ERK levels were detected in these cells. No change was observed in the levels of Bax, Bcl-2, Caspase-3, COX-2, c-Myc and Egr1, following treatment with the two compounds. Collectively, compounds A and B potentiate apoptosis as shown by DAPI staining, flowcytometry, FHC and p-ERK downregulation and NF-kappaB inactivation. CONCLUSION: Two compounds induce apoptosis in a COX-2-independent manner which also appears to be independent from mitochondria, caspase and c-Myc/Egr1 pathways. PMID- 26739351 TI - Viewing the Personality Traits Through a Cerebellar Lens: a Focus on the Constructs of Novelty Seeking, Harm Avoidance, and Alexithymia. AB - The variance in the range of personality trait expression appears to be linked to structural variance in specific brain regions. In evidencing associations between personality factors and neurobiological measures, it seems evident that the cerebellum has not been up to now thought as having a key role in personality. This paper will review the most recent structural and functional neuroimaging literature that engages the cerebellum in personality traits, as novelty seeking and harm avoidance, and it will discuss the findings in the context of contemporary theories of affective and cognitive cerebellar function. By using region of interest (ROI)- and voxel-based approaches, we recently evidenced that the cerebellar volumes correlate positively with novelty seeking scores and negatively with harm avoidance scores. Subjects who search for new situations as a novelty seeker does (and a harm avoiding does not do) show a different engagement of their cerebellar circuitries in order to rapidly adapt to changing environments. The emerging model of cerebellar functionality may explain how the cerebellar abilities in planning, controlling, and putting into action the behavior are associated to normal or abnormal personality constructs. In this framework, it is worth reporting that increased cerebellar volumes are even associated with high scores in alexithymia, construct of personality characterized by impairment in cognitive, emotional, and affective processing. On such a basis, it seems necessary to go over the traditional cortico-centric view of personality constructs and to address the function of the cerebellar system in sustaining aspects of motivational network that characterizes the different temperamental traits. PMID- 26739355 TI - Otitis Media and Related Complications Among Children with Autism Spectrum Disorders. AB - Acute otitis media (AOM) symptoms can be masked by communication deficits, common to children with autism spectrum disorders (ASD). We sought to evaluate the association between ASD and otitis media. Using ICD-9-CM diagnostic codes, we performed a retrospective case-cohort study comparing AOM, and otitis-related diagnoses among children with and without ASD. Children with ASD had a significantly increased rate of AOM, otitis media with effusion, otorrhea, and PE tube placement. Children with ASD were more than twice as likely to develop mastoiditis, and to undergo mastoidectomy and tympanoplasty. Children with ASD are more likely to have middle ear infections and otitis-related complications, highlighting the importance of routine middle ear examinations and close attention to hearing impairment in this population. PMID- 26739356 TI - Erratum to: Discourse/Conversation Analysis and Autism Spectrum Disorder. PMID- 26739354 TI - Ocular Fixation Abnormality in Patients with Autism Spectrum Disorder. AB - We examined the factors that influence ocular fixation control in adults with autism spectrum disorder (ASD) including sensory information, individuals' motor characteristics, and inhibitory control. The ASD group showed difficulty in maintaining fixation especially when there was no fixation target. The fixational eye movement characteristics of individuals were consistent regardless of the presence or absence of a fixation target in the controls, but not in the ASD group. Additionally, fixation stability did not correlate with an ability to suppress reflexive saccades measured by an antisaccade task. These findings suggest that ASD adults have deficits in converting alternative sensory information, such as retinal signals in the peripheral visual field or extraretinal signals, to motor commands when the foveal information is unavailable. PMID- 26739357 TI - Autism Spectrum Disorder in Children Adopted After Early Care Breakdown. AB - Syndromic autism has been described in children adopted after orphanage rearing. We investigated whether the same existed in children adopted after family breakdown. Families of 54/60 adopted children aged 6-11 years (mean 102 months; SD 20; 45% male) returned screening questionnaires for autism spectrum disorder (ASD); 21/54 (39%) screened positive. Detailed in-person phenotyping of screen positive cases showed ASD in 6/54 (11%), Broad ASD (sub threshold traits) in 10/54 (18.5%); 5/54 (9%) screened false positive. The ASD group showed impairments across both social communication and restrictive repetitive behaviour domains, Broad ASD was more mixed. These rates, much higher than population prevalence, are comparable with institutionalised samples. There are implications for developmental science, and assessment, treatment and policy for adopted children. PMID- 26739358 TI - Molecular aging of the mammalian vestibular system. AB - Dizziness and imbalance frequently affect the elderly and contribute to falls and frailty. In many geriatric patients, clinical testing uncovers a dysfunction of the vestibular system, but no specific etiology can be identified. Neuropathological studies have demonstrated age-related degeneration of peripheral and central vestibular neurons, but the molecular mechanisms are poorly understood. In contrast, recent studies into age-related hearing loss strongly implicate mitochondrial dysfunction, oxidative stress and apoptotic cell death of cochlear hair cells. While some data suggest that analogous biological pathomechanisms may underlie vestibular dysfunction, actual proof is missing. In this review, we summarize the available data on the molecular causes of vestibular dysfunction. PMID- 26739359 TI - Mathematical modelling of transcriptional heterogeneity identifies novel markers and subpopulations in complex tissues. AB - Tissue heterogeneity is both a major confounding factor and an underexploited information source. While a handful of reports have demonstrated the potential of supervised computational methods to deconvolute tissue heterogeneity, these approaches require a priori information on the marker genes or composition of known subpopulations. To address the critical problem of the absence of validated marker genes for many (including novel) subpopulations, we describe convex analysis of mixtures (CAM), a fully unsupervised in silico method, for identifying subpopulation marker genes directly from the original mixed gene expressions in scatter space that can improve molecular analyses in many biological contexts. Validated with predesigned mixtures, CAM on the gene expression data from peripheral leukocytes, brain tissue, and yeast cell cycle, revealed novel marker genes that were otherwise undetectable using existing methods. Importantly, CAM requires no a priori information on the number, identity, or composition of the subpopulations present in mixed samples, and does not require the presence of pure subpopulations in sample space. This advantage is significant in that CAM can achieve all of its goals using only a small number of heterogeneous samples, and is more powerful to distinguish between phenotypically similar subpopulations. PMID- 26739360 TI - Socially Desirable Responding in Web-Based Questionnaires: A Meta-Analytic Review of the Candor Hypothesis. AB - Unproctored, web-based assessments supposedly reduce social desirability distortions in self-report questionnaires because of an increased sense of privacy among participants. Three random-effects meta-analyses focusing either on social desirability ( k = 30, total N = 3,746), the Big Five of personality ( k = 66, total N = 2,951), or psychopathology ( k = 96, total N = 16,034) compared social desirability distortions of self-reports across computerized and paper-and pencil administration modes. Overall, a near-zero effect, Delta = 0.01, was obtained that did not indicate less socially desirable responding in computerized assessments. Moreover, moderator analyses did not identify differential effects for proctored and unproctored procedures. Thus, paper-and-pencil and computerized administrations of self-report scales yield comparable mean scores. Unproctored web-based surveys do not offer an advantage with regard to socially desirable responding in self-report questionnaires. PMID- 26739361 TI - Does the KABC-II Display Ethnic Bias in the Prediction of Reading, Math, and Writing in Elementary School Through High School? AB - This study explored whether the Kaufman Assessment Battery for Children-Second Edition (KABC-II) predicted academic achievement outcomes of the Kaufman Test of Educational Achievement-Second Edition (KTEA-II) equally well across a representative sample of African American, Hispanic, and Caucasian school-aged children ( N = 2,001) in three grade groups (1-4, 5-8, 9-12). It was of interest to study possible prediction bias in the slope and intercept of the five underlying Cattell-Horn-Carroll (CHC) cognitive factors of the KABC-II Sequential/Gsm (Short-Term Memory), Learning/Glr (Long-Term Storage and Retrieval), Simultaneous/Gv (Visual Processing), Planning/Gf (Fluid Reasoning), and Knowledge/Gc (Crystallized Ability)-in estimating reading, writing, and math. Structural equation modeling techniques demonstrated a lack of bias in the slopes; however, four of the five CHC indexes showed a persistent overprediction of the minority groups' achievement in the intercept. The overprediction is likely attributable to institutional or societal contributions, which limit the students' ability to achieve to their fullest potential. PMID- 26739363 TI - Experimental evidence for the influence of charge on the adsorption capacity of carbon dioxide on charged fullerenes. AB - We show, both experimentally and theoretically, that the adsorption of CO2 is sensitive to charge on a capturing model carbonaceous surface. In the experiment we doped superfluid helium droplets with C60 and CO2 and exposed them to ionising free electrons. Both positively and negatively charged C60(CO2)n(+/-) cluster ion distributions are observed using a high-resolution mass spectrometer and they show remarkable and reproducible anomalies in intensities that are strongly dependent on the charge. The highest adsorption capacity is seen with C60(+). Complementary density functional theory calculations and molecular dynamics simulations provided insight into the nature of the interaction of charged C60 with CO2 as well as trends in the packing of C60(+) and C60(-). The quadrupole moment of CO2 itself was found to be decisive in determining the charge dependence of the observed adsorption features. Our findings are expected to be applied for the adsorption of CO2 on charged surfaces in general. PMID- 26739364 TI - Is costly punishment altruistic? Exploring rejection of unfair offers in the Ultimatum Game in real-world altruists. AB - In the Ultimatum Game (UG), incurring a cost to punish inequity is commonly termed altruistic punishment. This behaviour is thought to benefit others if the defector becomes more equitable in future interactions. However, clear connections between punishment in the UG and altruistic behaviours outside the laboratory are lacking. We tested the altruistic punishment hypothesis in a sample of extraordinarily altruistic adults, predicting that if punishing inequity is predictive of altruism more broadly, extraordinary altruists should punish more frequently. Results showed that punishment was not more prevalent in extraordinary altruists than controls. However, a self-reported altruism measure previously linked to peer evaluations but not behaviour, and on which extraordinary altruists and controls did not differ, did predict punishment. These findings support suggestions that altruistic punishment in the UG is better termed costly punishment and may be motivated by social, but not necessarily prosocial, concerns. Results also support prior suggestions that self-reported altruism may not reliably predict altruistic behaviour. PMID- 26739366 TI - High Electron Mobility in Epitaxial Trilayer Graphene on Off-axis SiC(0001). AB - The van de Waals heterostructure formed by an epitaxial trilayer graphene is of particular interest due to its unique tunable electronic band structure and stacking sequence. However, to date, there has been a lack in the fundamental understanding of the electronic properties of epitaxial trilayer graphene. Here, we investigate the electronic properties of large-area epitaxial trilayer graphene on a 4 degrees off-axis SiC(0001) substrate. Micro-Raman mappings and atomic force microscopy (AFM) confirmed predominantly trilayer on the sample obtained under optimized conditions. We used angle-resolved photoemission spectroscopy (ARPES) and Density Functional Theory (DFT) calculations to study in detail the structure of valence electronic states, in particular the dispersion of pi bands in reciprocal space and the exact determination of the number of graphene layers. Using far-infrared magneto-transmission (FIR-MT), we demonstrate, that the electron cyclotron resonance (CR) occurs between Landau levels with a (B)(1/2) dependence. The CR line-width is consistent with a high Dirac fermions mobility of ~3000 cm(2).V(-1).s(-1) at 4 K. PMID- 26739369 TI - Simultaneous determination of capsaicin and dihydrocapsaicin for vegetable oil adulteration by immunoaffinity chromatography cleanup coupled with LC-MS/MS. AB - Capsaicin and dihydrocapsaicin were selected as adulteration markers to authenticate vegetable oils. In this study, a method of immunoaffinity chromatography (IAC) combined with liquid chromatography-tandem mass spectrometry was established for the determination of capsaicin and dihydrocapsaicin in vegetable oils. In this method, immunosorbents were obtained by covalently coupling highly specific capsaicinoid polyclonal antibodieswith CNBr-activated Sepharose 4B, and then packed into a polyethylene column. In this paper, the major parameters affecting IAC extraction efficiency, including loading, washing and eluting conditions, were also investigated. The IAC column displayed high selectivity for capsaicin and dihydrocapsaicin with the maximum capacity of 240ng. The limit of detection (LOD) and limit of quantification (LOQ) for capsaicin were calculated as 0.02 and 0.08MUgkg(-1), and for dihydrocapsaicin were 0.03 and 0.10MUgkg(-1). The recoveries of capsaicin and dihydrocapsaicin in oil samples were in the range of 87.3-95.2% with the relative standard deviation (RSD) of less than 6.1%. The results indicated that capsaicinoid compounds could not be found in edible vegetable oils. Therefore, the proposed method is simple, reliable and adequate for routine monitoring of capsaicinoid compounds in vegetable oils and has an excellent potential for detection of adulteration with inedible waste oil. PMID- 26739370 TI - Identification of dityrosine cross-linked sites in oxidized human serum albumin. AB - Reactive oxygen species (ROS) can oxidize virtually all cellular components. In proteins cysteine, methionine, tryptophan, and tyrosine residues are most prone to oxidation and their oxidized forms are thus considered as biomarkers of oxidative protein damages. Ultraviolet radiation and some endogenous ROS can produce tyrosine radicals reacting with other tyrosine residues yielding intra- or intermolecular cross-links in proteins. These 3,3'-dityrosines can be quantified by their characteristic fluorescence, but analytical methods to identify the modification sites in proteins are still missing. Although mass spectrometry (MS) is routinely used to map other post-translational modifications, the analysis of dityrosines is challenged by simultaneous fragmentations of both cross-linked peptide chains producing complex tandem mass spectra. Additionally, the fragmentation patterns differ from linear peptides. Here, we studied the fragmentation behavior of dityrosine cross-linked peptides obtained by incubating three peptides (AAVYHHFISDGVR, TEVSSNHVLIYLDK, and LVAYYTLIGASGQR) with horseradish peroxidase in the presence of hydrogen peroxide. Homo- and hetero-dimerization via dityrosine was monitored by fluorescence spectroscopy and MS. The fragmentation characteristics of dityrosine-linked peptides were studied on an ESI-LTQ-Orbitrap-MS using collision induced dissociation, which allowed localizing the cross-linked positions and provided generic rules to identify this oxidative modification. When human serum albumin oxidized with 50-fold molar excess of HOCl in phosphate buffer saline was analyzed by nanoRPC-ESI-MS/MS, an automatic database search considering all possible (in-silico generated) tyrosine-containing peptides as dynamic modifications revealed four different types of oxidatively modified tyrosine residues including dityrosines linking ten different Tyr residues. The automatic database search was confirmed by manual interpretation of each tandem mass spectrum. PMID- 26739371 TI - From imprinting to microcontact imprinting-A new tool to increase selectivity in analytical devices. AB - Molecular imprinting technology has been successfully applied to small molecular templates but a slow progress has been made in macromolecular imprinting owing to the challenges in natural properties of macromolecules, especially proteins. In this review, the macromolecular imprinting approaches are discussed with examples from recent publications. A new molecular imprinting strategy, microcontact imprinting is highlighted with its recent applications. PMID- 26739372 TI - Credit risk evaluation based on social media. AB - Social media has been playing an increasingly important role in the sharing of individuals' opinions on many financial issues, including credit risk in investment decisions. This paper analyzes whether these opinions, which are transmitted through social media, can accurately predict enterprises' future credit risk. We consider financial statements oriented evaluation results based on logit and probit approaches as the benchmarks. We then conduct textual analysis to retrieve both posts and their corresponding commentaries published on two of the most popular social media platforms for financial investors in China. Professional advice from financial analysts is also investigated in this paper. We surprisingly find that the opinions extracted from both posts and commentaries surpass opinions of analysts in terms of credit risk prediction. PMID- 26739373 TI - Front waves in the early RNA world: The Schlogl model and the logistic growth model. AB - Front wave solutions of nonlinear reaction-diffusion models describing the spatio temporal growth of RNA populations in the early RNA world are discussed. A two variable model for RNA enzymes and enzyme complex molecules as well as single variable models obtained via adiabatic elimination of the complex molecules are considered. In both models, the focus is on enzyme diffusion in one spatial dimension, assuming that the diffusion of complex molecules can be neglected. It is shown that one of the single-variable models corresponds to a Schlogl model of front propagation. In general, for the single-variable models it is found that front speed corresponds to the minimal speed of traveling fronts. In contrast, the two-variable model exhibits even slower front propagation. Front propagation might be an important factor in competitive evolutionary processes in the early RNA world. PMID- 26739374 TI - A 3D numerical study of antimicrobial persistence in heterogeneous multi-species biofilms. AB - We develop a 3D hydrodynamic model to investigate the mechanism of antimicrobial persistence in a multi-species oral biofilm and its recovery after being treated by bisbiguanide chlorhexidine gluconate (CHX). In addition to the hydrodynamic transport in the spatially heterogeneous biofilm, the model also includes mechanisms of solvent-biomass interaction, bacterial phenotype conversion, and bacteria-drug interaction. A numerical solver for the model is developed using a second order numerical scheme in 3D space and time and implemented on GPUs for high-performance computing. The model is calibrated against a set of experimental data obtained using confocal laser scan microscopy (CLSM) on multi-species oral biofilms, where a quantitative agreement is reached. Our numerical results reveal that quorum sensing molecules and growth factors in this model are instrumental in biofilm formation and recovery after the antimicrobial treatment. In particular, we show that (i) young biofilms are more susceptible to the antimicrobial treatment than the mature ones, (ii) this phenomenon is strongly correlated with volume fractions of the persister and EPS in the biofilm being treated. This suggests that antimicrobial treatment should be best administered to biofilms earlier before they mature to produce a thick protective EPS layer. In addition, the numerical study also indicates that an antimicrobial effect can be achieved should a proper mechanism be devised to minimize the conversion of susceptible bacteria to persisters during and even after the treatment. PMID- 26739375 TI - Dispersal polymorphism in stable habitats. AB - In fragmented but temporally stable landscapes, kin competition selects for dispersal when habitat patches are small, whereas the loss of dispersal is favoured when dispersal is costly and local populations are large enough for kin interactions to be negligible. In heterogeneous landscapes with both small and large patches, contrasting levels of kin competition facilitate the coexistence of low-dispersal and high-dispersal strategies. In this paper, I use both adaptive dynamics and inclusive fitness to analyse the evolution of dispersal in a simple model assuming that each patch supports either a single individual or a large population. With this assumption, many results can be obtained analytically. If the fraction of individuals living in small patches is below a threshold, then evolutionary branching yields two coexisting dispersal strategies. An attracting and evolutionarily stable dimorphism always exists (also when the monomorphic population does not have a branching point), and contains a strategy with zero dispersal and a strategy with dispersal probability between one half and the ESS of the classic Hamilton-May model. The present model features surprisingly rich population dynamics with multiple equilibria and unprotected dimorphisms, but the evolutionarily stable dimorphism is always protected. PMID- 26739376 TI - Analysis of mating system, fecundity, hatching and survival rates in two Schistosoma mansoni intermediate hosts (Biomphalaria pfeifferi and Biomphalaria camerunensis) in Cameroon. AB - BACKGROUND: Biomphalaria pfeifferi and Biomphalaria camerunensis are intermediate hosts of the trematode Schistosoma mansoni. Up till now, very scanty data report the life history traits of these freshwater snails. This study was therefore conducted to provide further knowledge on the mating system of these two S. mansoni intermediate hosts in Cameroon. The study was performed following a three step experimental design as follows: (i) for each species, a sample of young snails (G1), virgin and sexually mature was constituted and divided into two groups; (ii) in the first group, individuals were maintained isolated for the evaluation of the impact of self-fertilization on life history traits while in the second group, individuals were paired for few hours for the evaluation of cross-fertilization impact; (iii) in each group, fitness parameters (fecundity of G1 snails and survival of G2 offspring) were monitored during one month. RESULTS: The sexual maturity (age at first egg-laying) was reached, on average, at 63.9 (sd: 3.0) and 103.7 (sd: 36.6) days for B. pfeifferi and B. camerunensis, respectively. Copulation was observed in all paired individuals in both species. In B. pfeifferi, the fecundity (number of egg capsules and eggs) of young G1 individuals and survival of G2 offspring on D0 and D8 were similar between selfing and outcrossing individuals, and a very low inbreeding depression (0.063) was observed. In B. camerunensis, the fecundity of outcrossed individuals was significantly higher than that of selfed individuals. The hatching rate was significantly higher and the incubation time significantly shorter for cross fertilized eggs as compared with self-fertilized eggs, and a high inbreeding depression (0.71) was observed. CONCLUSION: These findings may explain the high adaptability to more diverse and inconstant habitats, as well as the better compatibility of B. pfeifferi to S. mansoni compared with B. camerunensis, and may support the sustainability of S. mansoni life cycle where this intermediate host prevails. PMID- 26739378 TI - The first major primate extinction: An evaluation of paleoecological dynamics of North American stem primates using a homology free measure of tooth shape. AB - OBJECTIVES: The disappearance of the North American plesiadapoids (stem primates, or plesiadapiforms) in the latest Paleocene has been attributed to competition with rodents over dietary resources. This study compares molar morphology of plesiadapoids and early rodents to assess whether all taxa were adapted to consuming foods of the same structural properties with similar mechanical efficacy. MATERIALS AND METHODS: Micro-CT scans of second mandibular molars (M2 s) of plesiadapoids (n = 181) and ischyromyid (early fossil) rodents (n = 13) were evaluated using Dirichlet normal energy (DNE), a dental topographic metric that quantifies the curvature of a tooth's occlusal surface, independent of the orientation of the occlusal plane; this metric can be used to infer diet. RESULTS: Comparisons of DNE values for plesiadapoids and rodents show that rodents shared functionally similar dental morphology with at least some plesiadapid plesiadapoids and thus were likely adapted to processing foods with similar physical properties. However, the DNE values for rodents contrast markedly with those for the other two plesiadapoid families, the Carpolestidae and Saxonellidae. CONCLUSIONS: It is unlikely that direct competition over food resources with rodents played a major role in the extinction of carpolestids and saxonellids, as members of these families were capable of consuming a range of foods that were not accessible to rodents. Although several plesiadapid species overlap with rodents in their range of DNE values, only three overlap in time. One of these (Plesiadapis cookei) may have been too large to be in direct competition with rodents, another (Plesiadapis dubius) has DNE values substantially different (higher) than those of rodents, whereas the third, Chiromyoides, has teeth of both a similar size and DNE value to those of Clarkforkian rodents. If dietary niche overlap with rodents played a direct role in the decline of plesiadapiforms, it can only have potentially done so for Chiromyoides. PMID- 26739379 TI - Professional discipline and support recommendations for family caregivers of persons with dementia. AB - BACKGROUND: Family caregivers of persons with dementia often require support services to help ease the challenges of providing care. Although the efficacy of some dementia caregiver interventions seems apparent, evidence indicating which types of protocols can best meet the diverse needs of individual families is not yet available. Because of this gap, families must often turn to professionals for such guidance, but it remains unknown whether professionals from different disciplines are more inclined to recommend particular types of services than others. This study assessed whether recommendations of supportive interventions to hypothetical dementia family caregivers differed by professional discipline. METHODS: In a cross-sectional survey design, a convenience sample of 422 dementia care professionals across the USA viewed up to 24 randomly selected, hypothetical scenarios that systematically varied characteristics of persons with dementia and their caregivers. For each scenario, 7 possible intervention recommendations were rated. A total of 6,890 scenarios were rated and served as the unit of analysis. RESULTS: General linear models revealed that discipline was often a stronger predictor of how likely professionals were to recommend dementia caregiver interventions than caregiver, care recipient, or other professional characteristics. Psychotherapists tended to recommend psychoeducation more than other professionals, while those in medicine were more likely to recommend training of the person with dementia and psychotherapy. CONCLUSIONS: The heterogeneity in recommendations suggests that the professional source of information influences the types of support families are directed toward. Empirical evidence should inform these professional judgments to better achieve person-centered care for families. PMID- 26739380 TI - Erratum to: Neurogenic muscle cramps. PMID- 26739381 TI - Lyme disease-related intracranial hypertension in children: clinical and imaging findings. AB - Lyme disease (LD) is a tick-borne infection that is endemic to multiple areas of the United States. Patients with LD may present with sign and symptoms of intracranial hypertension (IH). The objective of this study is to evaluate the history, clinical findings, CSF analysis, and brain imaging results in pediatric patients with increased intracranial pressure secondary to LD. A retrospective database search was performed using the International Classification of Diseases (ICD) 9/10 codes to identify patients diagnosed with LD and IH between 2004 and 2014 at a tertiary referral pediatric hospital. Clinical, laboratory and neuroimaging data for each patient were reviewed. Seven patients met inclusion criteria; mean age was 9.6 years (standard deviation 4.0 years); 4/7 patients were male. Average body mass index was 18.8 kg/m(2) (standard deviation 3.0 kg/m(2)). Fever was present in four patients. Four had a history of LD related erythema migrans. All had elevated CSF opening pressure with leukocytosis and lymphocytic predominance. MRI obtained in six patients showed contrast enhancement of various cranial nerves. Tentorial enhancement was noted in all patients. In addition, patients had widening of the optic nerve sheath (ONS), optic nerve protrusion, and flattening of the posterior globe consistent with increased intracranial pressure. All patients had resolution of their symptoms after initiation of antibiotic therapy. In endemic areas, LD should be included in the differential of IH. MRI can help distinguish IH due to LD from its idiopathic form due to the presence of tentorial and cranial nerve enhancement in the former in addition to abnormal CSF showing leukocytosis with lymphocyte predominance. PMID- 26739382 TI - Increased risk of tumor in DM1 is not related to exposure to common lifestyle risk factors. AB - Recent studies documented an increased risk of neoplasm in patients with myotonic dystrophies (DM). Yet, none of these studies evaluated the contribution of common cancer risk factors in such observation. In this study, we included a cohort of patients (n = 255) with an established molecular diagnosis of DM type 1 (DM1), and who receives their treatment in one of the four centers with recognized expertise in neuromuscular disorders in Rome. We estimated the prevalence of benign and malignant tumors, and assessed if lifestyle factors and/or specific disease features would be associated to their occurrence. Overall, 59 benign tumors in 54 patients and 19 malignant tumors in 17 patients were diagnosed. The most common malignant neoplasms were cancers of the skin (31.6%), thyroid (21.0%), ovary (10.5%), and breast (10.5%). Uterine fibroid was the most common benign tumor (37.6%) in women, while pilomatricoma was the most common in men (28.6%). Age at enrollment (OR = 1.02, 95% CI 1.00-1.05), and female gender (OR = 5.71, 95% CI 2.90-11.22) were associated with tumor development in DM1 patients, while thyroid disorders was associated with malignant tumors only in women (OR = 5.12, 95% CI 1.35-19.37). There was no association between tumor development and evaluated lifestyle factors. In conclusion, the lack of association between common cancer risk factors and tumor development in DM1 support a pathogenic link between tumors and DM1 itself, emphasizing the need for a systematic surveillance. Our observation of an association between thyroid diseases in women and cancer development needs confirmation. PMID- 26739384 TI - Visualization: A Mind-Machine Interface for Discovery. AB - Computation is critical for enabling us to process data volumes and model data complexities that are unthinkable by manual means. However, we are far from automating the sense-making process. Human knowledge and reasoning are critical for discovery. Visualization offers a powerful interface between mind and machine that should be further exploited in future genome analysis tools. PMID- 26739383 TI - Hybrid Approaches to Structural Characterization of Conformational Ensembles of Complex Macromolecular Systems Combining NMR Residual Dipolar Couplings and Solution X-ray Scattering. AB - Solving structures or structural ensembles of large macromolecular systems in solution poses a challenging problem. While NMR provides structural information at atomic resolution, increased spectral complexity, chemical shift overlap, and short transverse relaxation times (associated with slow tumbling) render application of the usual techniques that have been so successful for medium sized systems (<50 kDa) difficult. Solution X-ray scattering, on the other hand, is not limited by molecular weight but only provides low resolution structural information related to the overall shape and size of the system under investigation. Here we review how combining atomic resolution structures of smaller domains with sparse experimental data afforded by NMR residual dipolar couplings (which yield both orientational and shape information) and solution X ray scattering data in rigid-body simulated annealing calculations provides a powerful approach for investigating the structural aspects of conformational dynamics in large multidomain proteins. The application of this hybrid methodology is illustrated for the 128 kDa dimer of bacterial Enzyme I which exists in a variety of open and closed states that are sampled at various points in the catalytic cycles, and for the capsid protein of the human immunodeficiency virus. PMID- 26739385 TI - Obscurumines H-P, new Lycopodium alkaloids from the club moss Lycopodium obscurum. AB - Seven new fawcettimine-type (1-7) and two new lycopodine-type (8 and 9) Lycopodium alkaloids, as well as 10 known compounds, were isolated from the club moss, Lycopodium obscurum L. The structures of obscurumines H-P (1-9) were determined based on high-resolution MS and 1D and 2D NMR data. Compounds 1 and 2 include a new skeleton that is formed via the linkage of C-9-N-2', which is rarely present in Lycopodium alkaloids. The in vitro acetylcholinesterase (AChE) inhibitory activity assay showed that 5 exhibited weak anti-AChE activity with an IC50 value of 81.0 MUM. Compound 8 exhibited inhibition of the secretion of IL-2 in phytohemagglutinin (PHA) and phorbol myristate acetate (PMA) stimulated Jurkat cells, and the IC50 value was 17.2 MUM. PMID- 26739386 TI - Hepatoprotective triterpenes from the gum resin of Boswellia carterii. AB - Ten tirucallane-type triterpenes named boscartene A-J and a nor-tetracyclic triterpene boscartene K, together with ten known compounds were isolated from the gum resin of Boswellia carterii Birdw. Their structures and absolute configurations were elucidated by extensive spectroscopic analysis. In vitro assay, some of these compounds (10 MUM) showed moderate hepatoprotective activities against d-galactosamine-induced HL-7702 cell damage. PMID- 26739387 TI - PKM2 promotes tumor angiogenesis by regulating HIF-1alpha through NF-kappaB activation. AB - BACKGROUND: Initially identified as a molecule that regulates the final step of glycolysis, the M2 isoform of pyruvate kinase (PKM2) was recently reported to have a central role in the metabolic reprogramming of cancer cells as well as participating in cell cycle progression and gene transcription. Despite intensive efforts, the intricate molecular mechanisms through which PKM2 regulates tumor progression remain elusive. METHODS: The proliferation and apoptosis of various pancreatic cancer cells using lentiviral-mediated PKM2 abrogation were assessed in vitro via Western blot and flow cytometric assay while the in vivo experiments involved tumor xenograft on chicken chorionallantoic membranes and immunohistochemistry on human tissue specimens. In order to decipher the molecular mechanism of HIF-1alpha and p65/RelA regulation by PKM2 in cancer cells cultivated in hypoxic atmosphere or normoxia we involved various biochemical assays such as Western blotting, immunoprecipitation, reporter gene assay and ELISA. RESULTS: Strong expression of PKM2 was observed in 68 % of human pancreatic adenocarcinoma specimens and almost all analyzed pancreatic cancer cell lines. Abrogation of PKM2 resulted in impaired proliferation and augmented apoptosis in vitro as well as impaired tumor growth and decreased blood vessel formation in vivo. Furthermore, deletion of PKM2 negatively impacted hypoxia induced HIF-1alpha accumulation and promoter activity ultimately resulting in impaired secretion of VEGF. CONCLUSIONS: Our study suggests that in hypoxic pancreatic tumors PKM2 interferes both with NF-kappaB/p65 and HIF-1alpha activation that ultimately triggers VEGF-A secretion and subsequent blood vessel formation. PMID- 26739388 TI - Exosomes as nanocarriers for systemic delivery of the Helicobacter pylori virulence factor CagA. AB - CagA, encoded by cytotoxin-associated gene A (cagA), is a major virulence factor of Helicobacter pylori, a gastric pathogen involved in the development of upper gastrointestinal diseases. Infection with cagA-positive H. pylori may also be associated with diseases outside the stomach, although the mechanisms through which H. pylori infection promotes extragastric diseases remain unknown. Here, we report that CagA is present in serum-derived extracellular vesicles, known as exosomes, in patients infected with cagA-positive H. pylori (n = 4). We also found that gastric epithelial cells inducibly expressing CagA secrete exosomes containing CagA. Addition of purified CagA-containing exosomes to gastric epithelial cells induced an elongated cell shape, indicating that the exosomes deliver functional CagA into cells. These findings indicated that exosomes secreted from CagA-expressing gastric epithelial cells may enter into circulation, delivering CagA to distant organs and tissues. Thus, CagA-containing exosomes may be involved in the development of extragastric disorders associated with cagA-positive H. pylori infection. PMID- 26739390 TI - Junior doctors' contract talks will resume on Friday. PMID- 26739391 TI - PPARgamma-induced upregulation of CD36 enhances hematoma resolution and attenuates long-term neurological deficits after germinal matrix hemorrhage in neonatal rats. AB - Germinal matrix hemorrhage remains the leading cause of morbidity and mortality in preterm infants in the United States with little progress made in its clinical management. Survivors are often afflicted with long-term neurological sequelae, including cerebral palsy, mental retardation, hydrocephalus, and psychiatric disorders. Blood clots disrupting normal cerebrospinal fluid circulation and absorption after germinal matrix hemorrhage are thought to be important contributors towards post-hemorrhagic hydrocephalus development. We evaluated if upregulating CD36 scavenger receptor expression in microglia and macrophages through PPARgamma stimulation, which was effective in experimental adult cerebral hemorrhage models and is being evaluated clinically, will enhance hematoma resolution and ameliorate long-term brain sequelae using a neonatal rat germinal matrix hemorrhage model. PPARgamma stimulation (15d-PGJ2) increased short-term PPARgamma and CD36 expression levels as well as enhanced hematoma resolution, which was reversed by a PPARgamma antagonist (GW9662) and CD36 siRNA. PPARgamma stimulation (15d-PGJ2) also reduced long-term white matter loss and post hemorrhagic ventricular dilation as well as improved neurofunctional outcomes, which were reversed by a PPARgamma antagonist (GW9662). PPARgamma-induced upregulation of CD36 in macrophages and microglia is, therefore, critical for enhancing hematoma resolution and ameliorating long-term brain sequelae. PMID- 26739392 TI - Usefulness of Highly Sensitive Troponin as a Predictor of Short-Term Outcome in Patients With Diabetes Mellitus and Stable Coronary Artery Disease (from the ARTEMIS Study). AB - The aim of this study was to test the hypothesis that novel biomarkers may predict cardiac events in diabetic patients with stable coronary artery disease (CAD). Serum levels of highly sensitive troponin T (hs-TnT), B-type natriuretic peptide, highly sensitive C-reactive protein (hs-CRP), galectin-3, and soluble suppressor of tumorigenicity-2 (sST2) were analyzed in 1,137 patients with CAD and with type 2 diabetes, impaired glucose tolerance, or fasting glycaemia (diabetic group) and in 649 patients with normal glucose state. Cardiac death or hospitalization for congestive heart failure was the major end point during the follow-up of 2 years. Forty patients in the diabetic group (3.5%) and 9 patients in the nondiabetic group (1.4%) reached the primary end point. High hs-TnT level (>=14 ng/l) was the strongest predictor of the primary end point with hazard ratio of 24.5 (95% confidence interval 8.7 to 69.0; p <0.001) and remained so when adjusted for clinical variables, ejection fraction, renal, lipid, and glycemic status and other biomarkers (hazard ratio 9.9, 95% confidence interval 3.2 to 30.8; p <0.001). In the multivariate model, hs-CRP, B-type natriuretic peptide, and sST2 also predicted the primary end point in the diabetic group (p <0.01 for all). Only sST2 (p <0.001) and hs-CRP (p = 0.02) predicted the primary end point in nondiabetic group. The inclusion of hs-TnT in the model significantly improved discrimination (integrated discrimination improvement 0.050) and reclassification of the patients (net reclassification index 0.21). In conclusion, hs-TnT is a strong predictor of cardiac death or hospitalization for heart failure independently from traditional risk markers or other biomarkers in diabetic patients with stable CAD. PMID- 26739394 TI - Frequency of Angina Pectoris After Percutaneous Coronary Intervention and the Effect of Metallic Stent Type. AB - Although metallic coronary stents significantly reduce angina pectoris compared with optimal medical therapy, angina after percutaneous coronary intervention (PCI) remains frequent. We, therefore, sought to compare the incidence of any angina during the 1 year after PCI among the spectrum of commercially available metallic stents. Metallic stent type was classified as bare metal stent, Cypher, Taxus Express, Xience V, Promus Element, and Resolute. The primary end point was patient-reported angina within 1 year of PCI. Multivariable logistic regression was performed to assess the independent association of stent type with any angina at 1 year. Overall, 8,804 patients were queried in regard to angina symptoms; 32.3% experienced angina at some point in the first year after PCI. Major adverse cardiovascular events, a composite of all-cause mortality, target vessel revascularization, and Q-wave myocardial infarction, increased with angina severity: 6.8% for patients without angina, 10.0% for patients with class 1 or 2 angina, and 19.7% for patients with class 3 or 4 angina (p <0.001 for trend). After multivariable adjustment, there was no significant association between stent type and angina at 1 year after PCI. Baseline Canadian Cardiovascular Society class 3 or 4 angina, history of coronary artery bypass grafting, and history of PCI were associated with a higher likelihood of angina at 1 year; increasing age, male gender, presentation with acute coronary syndrome, and higher stented length were associated with less angina. In conclusion, metallic stent type is not associated with the occurrence of angina at up to 1 year after PCI. PMID- 26739393 TI - Impact of Modifiable Risk Factors on B-type Natriuretic Peptide and Cardiac Troponin T Concentrations. AB - Alcohol use, physical activity, diet, and cigarette smoking are modifiable cardiovascular risk factors that have a substantial impact on the risk of myocardial infarction, stroke, and cardiovascular death. We hypothesized that these behaviors may alter concentrations of cardiac troponin, a marker of myocyte injury, and B-type natriuretic peptide, a marker of myocyte stress. Both markers have shown strong association with adverse cardiovascular outcomes. In 519 women with no evidence of cardiovascular disease, we measured circulating concentrations of cardiac troponin T, using a high-sensitivity assay (hsTnT), and the N-terminal fragment of B-type natriuretic peptide (NT-proBNP). We used logistic regression to determine if these behaviors were associated with hsTnT >= 3 ng/l or with NT-proBNP in the highest quartile (>= 127.3 ng/l). The median (Q1 to Q3) NT-proBNP of the cohort was 68.8 ng/l (40.3 to 127.3 ng/l), and 30.8% (160 of 519) of the cohort had circulating hsTnT >= 3 ng/l. In adjusted models, women who drank 1 to 6 drinks/week had lower odds of having a hsTnT >= 3 ng/l (odds ratio 0.58, 95% confidence interval 0.34 to 0.96) and lower odds of having an elevated NT-proBNP (odds ratio 0.55, 95% confidence interval 0.32 to 0.96). We were subsequently able to validate the results for B-type natriuretic peptide in a large independent cohort. In conclusion, our results suggest that regular alcohol consumption is associated with lower concentrations of hsTnT and NT proBNP, 2 cardiovascular biomarkers associated with cardiovascular risk, and raise the hypothesis that the beneficial effects of alcohol consumption may be mediated by direct effects on the myocardium. PMID- 26739395 TI - Computed Tomography-Derived Parameters of Myocardial Morphology and Function in Black and White Patients With Acute Chest Pain. AB - Blacks have higher mortality and hospitalization rates because of congestive heart failure compared with white counterparts. Differences in cardiac structure and function may contribute to the racial disparity in cardiovascular outcomes. Our aim was to compare computed tomography (CT)-derived cardiac measurements between black patients with acute chest pain and age- and gender-matched white patients. We performed a retrospective analysis under an institutional review board waiver and in Health Insurance Portability and Accountability Act compliance. We investigated patients who underwent cardiac dual-source CT for acute chest pain. Myocardial mass, left ventricular (LV) ejection fraction, LV end-systolic volume, and LV end-diastolic volume were quantified using an automated analysis algorithm. Septal wall thickness and cardiac chamber diameters were manually measured. Measurements were compared by independent t test and linear regression. The study population consisted of 300 patients (150 black-mean age 54 +/- 12 years; 46% men; 150 white-mean age 55 +/- 11 years; 46% men). Myocardial mass was larger for blacks compared with white (176.1 +/- 58.4 vs 155.9 +/- 51.7 g, p = 0.002), which remained significant after adjusting for age, gender, body mass index, and hypertension. Septal wall thickness was slightly greater (11.9 +/- 2.7 vs 11.2 +/- 3.1 mm, p = 0.036). The LV inner diameter was moderately larger in black patients in systole (32.3 +/- 9.0 vs 30.1 +/- 5.4 ml, p = 0.010) and in diastole (50.1 +/- 7.8 vs 48.9 +/- 5.2 ml, p = 0.137), as well as LV end-diastolic volume (134.5 +/- 42.7 vs 128.2 +/- 30.6 ml, p = 0.143). Ejection fraction was nonsignificantly lower in blacks (67.1 +/- 13.5% vs 69.0 +/ 9.6%, p = 0.169). In conclusion, CT-derived myocardial mass was larger in blacks compared with whites, whereas LV functional parameters were generally not statistically different, suggesting that LV mass might be a possible contributing factor to the higher rate of cardiac events in blacks. PMID- 26739396 TI - Effect of Remote Ischemic Preconditioning on Platelet Activation Induced by Coronary Procedures. AB - In this study, we aim to assess whether remote ischemic preconditioning (RIPC) reduces platelet activation during coronary angiography (CA) and/or percutaneous coronary interventions. We studied 30 patients who underwent CA because of a suspect of stable angina. Patients were randomized to RIPC (3 short episodes of forearm ischemia) or sham RIPC (controls) before the procedure. Blood samples were collected at baseline, at the end of the procedure, and 24 hours later. Monocyte-platelet aggregate (MPA) formation and platelet CD41 in the MPA gate and CD41 and CD62 expression in the platelet gate were assessed by flow cytometry, in the absence and in the presence of adenosine diphosphate (ADP) stimulation. A significant increase in platelet activation occurred during the invasive procedure in controls, which persisted at 24 hours. However, compared with controls, RIPC group showed no or a lower increase in platelet variables, including MPA formation (p <0.0001) and CD41 (p = 0.002) in the MPA gate and CD41 (p <0.0001) and CD62 (p = 0.002) in the platelet gate. ADP increased platelet activation at baseline, but did not further increase platelet reactivity during the invasive procedure in either groups. Percutaneous coronary interventions, performed in 10 patients (6 in the RIPC group and 4 in controls), did not have any further significant effect on platelet activation and reactivity compared with CA alone. In conclusion, RIPC reduces platelet activation occurring during CA. In contrast, no effects were observed on platelet response to ADP stimulation, probably related to the administration of an ADP antagonist in all patients. PMID- 26739399 TI - Reduction of Factor VIII Inhibitor Titers During Immune Tolerance Induction With Recombinant Factor VIII-Fc Fusion Protein. AB - The development of inhibitors toward factor VIII (FVIII) is a common and serious complication of hemophilia A (HA) therapy. Patients with hemophilia who develop inhibitors often undergo time- and resource-intensive immune tolerance induction (ITI) protocols. We report a 15-month-old male with severe HA and a high-titer inhibitor that occurred while receiving prophylactic treatment with recombinant FVIII (rFVIII), in whom significant inhibitor titer reduction was achieved with thrice weekly infusions of a new, prolonged half-life rFVIII-Fc fusion protein product (trade name Eloctate). Further studies are warranted to explore the potential of Eloctate in ITI protocols. PMID- 26739400 TI - Associations of Atopic Dermatitis With Obesity and Unmarried Status in Young Adults: Evidence for Atopic Dermatitis as a Life-Style Disorder With High Social Impact. PMID- 26739401 TI - Environmental Exposure and Genetic Predisposition as Risk Factors for Asthma in China. AB - Asthma is the most common chronic pulmonary disease worldwide and places a considerable economic burden on society. China is the world's largest developing country and has the largest population. China has undergone dramatic changes in the past few decades. The traditional lifestyle and living environment have changed in ways that directly affect the prevalence of asthma. The prevalence of asthma is lower in Chinese children and adults than in developed countries, but the prevalence has been on the rise during the past 30 years. The prevalence significantly varies among different parts of China. Polymorphisms of multiple genes, outdoor air pollution caused by PM2.5, PM10, SO2, NO2, environmental tobacco smoke, and coal, indoor pollution, and inhaled allergens, such as house dust mites, pollen, and cockroach particles, are risk factors for asthma. PMID- 26739402 TI - Shellfish and House Dust Mite Allergies: Is the Link Tropomyosin? AB - Crustacean shellfish allergy is an important cause of food allergy and anaphylaxis in Asia. The major allergen in shellfish allergy is tropomyosin, a pan-allergen that is also found in house dust mites and cockroaches. Tropomyosins from house dust mites (HDMs) have a high sequence homology to shellfish tropomyosins, and cross-reactivity between HDM and shrimp tropomyosins has been demonstrated. Exposure to inhaled tropomyosins from house dust mites has been postulated to be the primary sensitizer for shellfish allergy, in a reaction analogous to the oral allergy (inhalant-food) syndrome. This notion is supported by indirect data from the effects of HDM immunotherapy on shellfish allergy, and strong correlations of shellfish and HDM sensitization. HDM immunotherapy has been reported to induce both shrimp allergy in non-allergic patients and shrimp tolerance in shrimp-allergic patients. Epidemiological surveys have also demonstrated a strong correlation between shellfish and HDM sensitization in both hospital-based and community-based studies. Unexposed populations have also been shown to develop sensitization-shellfish sensitization in orthodox Jews with no history of shellfish consumption was associated with HDM sensitization. Reciprocally, HDM sensitization in an Icelandic population living in a HDM-free environment was associated with shrimp sensitization. In vitro IgE inhibition studies on sera in shrimp-allergic Spanish patients indicate that mites are the primary sensitizer in shrimp-allergic patients living in humid and warm climates. Current data supports the hypothesis that tropomyosin is the link between HDM and shellfish allergies. The role of tropomyosin in HDM and shellfish allergies is a fertile field for investigation as it may provide novel immunotherapeutic strategies for shellfish allergy. PMID- 26739403 TI - Association Between Obesity, Abdominal Obesity, and Adiposity and the Prevalence of Atopic Dermatitis in Young Korean Adults: the Korea National Health and Nutrition Examination Survey 2008-2010. AB - PURPOSE: Whether obesity is a risk factor for atopic dermatitis (AD) remains unclear. The aim of the present study was to investigate the association between obesity and AD in Korean young adults. METHODS: We included nationally representative data of 5,202 Korean adults aged 19-40 years, obtained from the cross-sectional Korea National Health and Nutrition Examination Survey 2008-2010. RESULTS: Single (unmarried) status was more frequently observed in AD patients (male, [P=0.0002] and female, [P<0.0001]). AD prevalence exhibited a U-shape trend in relation to body mass index (BMI), waist circumference (WC), and total body fat (BF) percentage, especially in young adult women. Women with BMI >=25 kg/m2, WC >=80 cm, and highest quartile (Q4) of total BF percentage had the highest prevalence of AD. The odds ratio (OR) for participants with both BMI >=25 kg/m2 and WC >=80 cm was 3.29 (95% confidence interval [CI] 1.71-3.55); therefore, having both general and abdominal obesity was considered a prominent risk factor for AD in young women. After adjustment for confounding factors, including age, smoking, alcohol drinking, exercise, vitamin D, income level, and single status, high BMI (>=30 kg/m2) (OR=4.08, 95% CI: 1.53-10.93), high WC (>=80 cm) (OR=2.05, 95% CI: 1.07-3.94), and high BF percentage (Q4) (OR=2.10, 95% CI: 1.24-3.57) were shown to be significantly associated with AD in young adult women. CONCLUSIONS: In this large-scale nation-wide study of Korean adults, obesity was positively related to the presence of AD in women. Our findings suggest that weight management may help prevent AD. PMID- 26739404 TI - Prognostic Factors for Chronic Spontaneous Urticaria: A 6-Month Prospective Observational Study. AB - PURPOSE: Chronic urticaria (CU) has a substantial impact on the quality of life. Little clinical data on the prognosis of CU has been reported. This study aimed to investigate the control status and remission rate of CU and to explore potential predictors of good responses to the treatment during a 6-month treatment period. METHODS: A total of 75 patients with chronic spontaneous urticaria (CSU) were enrolled from 3 university hospitals in Korea. Urticaria control state was classified into 2 groups: group I (remission and well controlled) and group II (partly and uncontrolled). CU-specific quality of life (CU-QoL) and the urticaria activity score (UAS) were measured before and after the treatment. Autologous serum skin test (ASST), and anti-nuclear and anti thyroid antibodies were measured at the enrollment into the study. Aspirin intolerance was confirmed by an oral provocation test. RESULTS: Of 59 patients completing the study, 21 (35.6%) arrived at well-controlled status and only 2 (3.4%) achieved remission, whereas 26 (44.1%) remained at partly controlled status and 10 (16.9%) were at uncontrolled status. Mean changes in CU-QoL (36.5+/ 2.7 vs 20.6+/-4.3, P=0.017) and UAS (-7.9+/-0.8 vs -3.0+/-1.0, P=0.001) were significantly different between groups I and II. The presence of serum autoantibodies and aspirin intolerance had no influence on the control of urticaria in this study. However, ASST positivity was identified as a significant predictor of CU control in multivariate analysis (OR=6.106, P=0.017). CONCLUSIONS: The proportion of CSU patients that achieved remission or a well controlled state was 39% for the 6 months of stepwise treatment. Longer observations are necessary to assess the exact prognosis of CSU. ASST results may be a useful parameter for predicting a better response to treatment and both UAS and CU-QoL are helpful to monitor therapeutic response. PMID- 26739405 TI - Mimotopes for Api g 5, a Relevant Cross-reactive Allergen, in the Celery-Mugwort Birch-Spice Syndrome. AB - PURPOSE: In the celery-mugwort-birch-spice syndrome, a significant proportion of IgE is directed against high molecular weight (HMW) glycoproteins, including the celery allergen Api g 5. BIP3, a monoclonal antibody originally raised against birch pollen, recognizes HMW allergens in birch and mugwort pollens, celery, and Apiaceae spices. Our aim was to generate mimotopes using BIP3 for immunization against the HMW allergens relevant in the celery-mugwort-birch-spice cross reactivity syndrome. METHODS: Mimotopes were selected from a random-peptide display library by BIP3 and applied in IgE inhibition assays. The 3 phage clones with the highest inhibitory capacity were chosen for immunization of BALB/c mice. Mouse immune sera were tested for IgG binding to blotted birch pollen extract and used for inhibiting patients' IgE binding. Furthermore, sera were tested for binding to Api g 5, to horseradish peroxidase (HRP) as a second glycoprotein, or to non-glycosylated control allergen Phl p 5 in ELISA, and the specific Api g 5 specific IgG titers were determined. RESULTS: Three rounds of biopanning resulted in phage clones exhibiting 7 different sequences including 1 dominant, 1-6-cyclo CHKLRCDKAIA. Three phage clones had the capacity to inhibit human IgE binding and induced IgG to the HMW antigen when used for immunizing BALB/c mice. The induced BIP3-mimotope IgG reached titers of 1:500 specifically to Api g 5, but hardly reacted to glycoprotein HRP, revealing a minor role of carbohydrates in their epitope. CONCLUSIONS: The mimotopes characterized in this study mimic the epitope of BIP3 relevant for Api g 5, one of the cross-reactive HMW allergens relevant in the celery-mugwort-birch-spice syndrome. BIP3 mimotopes may be used in the future for hyposensitization in this clinical syndrome by virtue of good and specific immunogenicity. PMID- 26739406 TI - Increased Expression of miR-146a in Children With Allergic Rhinitis After Allergen-Specific Immunotherapy. AB - PURPOSE: MicroRNAs (miRs) were recently recognized to be important for immune cell differentiation and immune regulation. However, whether miRs were involved in allergen-specific immunotherapy (SIT) remains largely unknown. This study sought to examine changes in miR-146a and T regulatory cells in children with persistent allergic rhinitis (AR) after 3 months of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). METHODS: Twenty-four HDM-sensitized children with persistent AR were enrolled and treated with SCIT (n=13) or SLIT (n=11) for 3 months. Relative miR-146a and Foxp3 mRNA expression, the TRAF6 protein level, and the ratio of post-treatment to baseline IL-10+CD4+ T cells between the SCIT and SLIT groups were examined in the peripheral blood mononuclear cells (PBMCs) of AR patients using quantitative reverse transcription polymerase chain reaction (qRT-PCR), flow cytometry, and Western blot analysis, respectively. Serum levels of IL-5 and IL-10 were determined using ELISA. RESULTS: After 3 months of SIT, both the TNSS and INSS scores were significantly decreased compared to the baseline value (P<0.01). The relative expression of miR 146a and Foxp3 mRNA was significantly increased after both SCIT and SLIT (P<0.01). The ratio of post-treatment to baseline IL-10+CD4+ T cells and the serum IL-10 level were significantly increased in both the SCIT and SLIT groups (P<0.01), whereas the TRAF6 protein level and serum IL-5 level were significantly decreased (P<0.01). No significant differences in these biomarkers were observed between the SCIT and SLIT groups. CONCLUSIONS: Our findings suggest that miR-146a and its related biomarkers may be comparably modulated after both SCIT and SLIT, highlighting miR-146a as a potential therapeutic target for the improved management of AR. PMID- 26739407 TI - The Potential for Poverty to Lower the Self-Efficacy of Adults With Asthma: An Australian Longitudinal Study. AB - PURPOSE: It is known that strong feelings of self-efficacy are linked with better management of asthma. However, it is not known whether the experience of poverty can detrimentally impact the self-efficacy feelings of asthma patients. This paper aims to determine whether falling into income or multidimensional poverty lowers self-efficacy among people diagnosed with asthma. METHODS: Longitudinal analysis of Waves 7 to 11 (2007 to 2011) of the nationally representative Household, Income and Labour Dynamics in Australia (HILDA) survey using generalized linear models. The analysis was limited to those who had been diagnosed with asthma. The Freedom Poverty Measure was used to identify those in multidimensional poverty. RESULTS: People with asthma who fell into income poverty had significantly lower self-efficacy scores-23% lower (95% CI: -35.1 to 9.1), after falling into income poverty for 3 or 4 years between 2007 and 2011 compared to those who were never in income poverty. Those who fell into multidimensional poverty also had significantly lower self-efficacy scores-25% lower (95% CI: -42.8 to -2.0), after being in multidimensional poverty for 3 or 4 years between 2007 and 2011 compared to those who were never in poverty. CONCLUSIONS: Asthmatics who fall into poverty are likely to experience a decline in their feelings of self-efficacy. The findings of this study show that experiencing poverty should be a flag to identify those who may need extra assistance in managing their condition. PMID- 26739409 TI - Diagnostic Value of Specific IgE to Peanut and Ara h 2 in Korean Children with Peanut Allergy. AB - PURPOSE: The purpose of this study was to establish the diagnostic decision point (DDP) of peanut specific IgE (sIgE) for predicting the outcome of oral food challenge (OFC). We also evaluated the usefulness of sIgE to peanut components (Ara h 1, 2, 3, 8, and 9) in diagnosing peanut allergy. METHODS: Korean children aged over 12 months with a suspected peanut allergy were enrolled. Diagnosis of peanut allergy was confirmed by an open OFC or through the convincing history of anaphylaxis. Cutoff levels of sIgE to peanut and peanut components were determined by analyzing receiver operating characteristic curves. RESULTS: Forty eight children (22 boys and 26 girls) with a suspected peanut allergy were enrolled. The previously established DDP for peanut-sIgE antibodies (14 kU/L) showed a sensitivity of 22.7%, specificity of 100%, positive predictive value (PPV) of 100%, and negative predictive value of 60.4% in our study population. The median levels of peanut-sIgE (5.4 kU/L vs 1.1 kU/L, P<0.001) and Ara h 2-sIgE (0.8 kU/L vs 0 kU/L, P<0.001) were significantly higher in the peanut allergy group than in the peanut tolerance group. The peanut-sIgE concentration indicating a PPV of 100% was 10.3 kU/L. The Ara h 2-sIgE level of 4.0 kU/L had a PPV of 100%. CONCLUSIONS: Our results showed that the cutoff levels for peanut (10.3 kU/L) and Ara h 2 (4.0 kU/L) established in this study is useful for the diagnosis of peanut allergy in Korean children. PMID- 26739410 TI - Administration of Pigment Epithelium-Derived Factor Inhibits Airway Inflammation and Remodeling in Chronic OVA-Induced Mice via VEGF Suppression. AB - PURPOSE: Pigment epithelium-derived factor (PEDF) is a recently discovered antiangiogenesis protein. PEDF possesses powerful anti-inflammatory, antioxidative, antiangiogenic, and antifibrosis properties. It has been reported that PEDF can regulate vascular endothelial growth factor (VEGF) expression. This study aimed to evaluate whether recombinant PEDF protein could attenuate allergic airway inflammation and airway remodeling via the negative regulation of VEGF using a murine model of chronic ovalbumin (OVA)-induced asthma and BEAS-2B human bronchial epithelial cells. METHODS: In an in vivo experiment, mice sensitized with OVA were chronically airway challenged with aerosolized 1% OVA solution for 8 weeks. Treated mice were given injections of recombinant PEDF protein (50 or 100 MUg/kg body weight) via the tail vein. In an in vitro experiment, we investigated the effects of recombinant PEDF protein on VEGF release levels in BEAS-2B cells stimulated with IL-1beta. RESULTS: Recombinant PEDF protein significantly inhibited eosinophilic airway inflammation, airway hyperresponsiveness, and airway remodeling, including goblet cell hyperplasia, subepithelial collagen deposition, and airway smooth muscle hypertrophy. In addition, recombinant PEDF protein suppressed the enhanced expression of VEGF protein in lung tissue and bronchoalveolar lavage fluid (BALF) in OVA-challenged chronically allergic mice. In the in vitro experiment, VEGF expression was increased after IL-1beta stimulation. Pretreatment with 50 and 100 ng/mL of recombinant PEDF protein significantly attenuated the increase in VEGF release levels in a concentration-dependent manner in BEAS-2B cells stimulated by IL 1beta. CONCLUSIONS: These results suggest that recombinant PEDF protein may abolish the development of characteristic features of chronic allergic asthma via VEGF suppression, providing a potential treatment option for chronic airway inflammation diseases such as asthma. PMID- 26739408 TI - Defining Chronic Cough: A Systematic Review of the Epidemiological Literature. AB - PURPOSE: Recent evidence suggests a global burden of chronic cough in general populations. However, the definitions vary greatly among epidemiological studies, and none have been validated for clinical relevance. We aimed to examine previous epidemiological definitions in detail and explore the operational characteristics. METHODS: A systematic review was conducted for epidemiological surveys that reported the prevalence of chronic cough in general adult populations during the years 1980 to 2013. A literature search was performed on Pubmed and Embase without language restriction. Epidemiological definitions for chronic cough were classified according to their components, such as cutoff duration. Meta-analyses were performed for the male-to-female ratio of chronic cough prevalence to explore operational characteristics of epidemiological definitions. RESULTS: A total of 70 studies were included in the systematic review. The most common epidemiological definition was identified as 'cough >=3 months' duration without specification of phlegm (n=50); however, it conflicted with the cutoff duration in current clinical guidelines (cough >=8 weeks). Meta analyses were performed for the male-to-female ratio of chronic cough among 28 studies that reported sex-specific prevalence using the most common definition. The pooled male-to-female odds ratio was 1.26 (95% confidence interval 0.92-1.73) with significant heterogeneity (I2=96%, P<0.001), which was in contrast to clinical observations of female predominance from specialist clinics. Subgroup analyses did not reverse the ratio or reduce the heterogeneity. CONCLUSIONS: This study identified major issues in defining chronic cough in future epidemiological studies. The conflict between epidemiological and clinical diagnostic criteria needs to be resolved. The unexpected difference in the gender predominance between the community and clinics warrants further studies. Clinical validation of the existing definition is required. PMID- 26739411 TI - Papain Induced Occupational Asthma with Kiwi and Fig Allergy. AB - Papain is a proteolytic enzyme which is widely used in food industry, pharmaceuticals, and cosmetics. Occupational and non-occupational papain allergies have previously been documented; however, there are limited publications about papain allergy with its relative fruit allergy. Here, we present a case of occupational, IgE-mediated papain allergy with kiwi fruit and fig fruit allergy. A 53-year-old man suffered from rhinitis for several years, with the onset of his symptoms coinciding with the time he started to work at a sausage processing plant where papain is often used as a meat tenderizer. He began to experience symptoms of chest tightness, shortness of breath and wheezing shortly after starting work 5 years ago. Furthermore, he experienced several episodes of oral itching, and tongue and oropharyngeal angioedema after injestion of kiwi fruit and fig fruit. The patient had a lifelong history of allergic conjunctivitis, allergic rhinitis, and childhood asthma. Specific IgE was positive to kiwi fruit, papain and chymopapain (2.95 kUA/L, >100 kUA/L, and 95.0 kUA/L, respectively). Similar bands at 10-15 kDa in blotting with papain and kiwi fruit extracts were found. This patient showed a potential association between papain allergy and sensitization to kiwi fruit. We also reviewed 13 patients with papain allergy published in the literature, with 85% (11/13) of the patients sensitized through the respiratory tract, and 40% (4/11) having atopy. Further studies should focus on the determination of cross-reactive allergens between papain and its fruit relatives, and the prevalence of food allergy in patients with papain allergy should be investigated in a relatively large cohort. PMID- 26739412 TI - The Hidden Culprit: A Case of Repeated Anaphylaxis to Cremophor. AB - Drug-induced anaphylaxis is a big pitfall in patients receiving antineoplastic chemotherapy. We report a case of lung cancer patient who experienced two near fatal anaphylactic reactions that resulted from paclitaxel and multivitamin, seperately. Recurrent severe reactions to different agents led to further investigation to which material the patient was hypersensitive. The skin prick test revealed sensitization to cremophor, which is a commonly used emulsifying agent. This case emphasizes the importance of correctly identifying the culprit drug of anaphylaxis to avoid potentially fatal reaction. PMID- 26739413 TI - Erratum: Butter Tolerance in Children Allergic to Cow's Milk. AB - [This corrects the article DOI: 10.4168/aair.2015.7.2.186.]. PMID- 26739414 TI - Asthma as a risk factor for zoster in adults: A population-based case-control study. AB - BACKGROUND: We recently reported an increased risk of herpes zoster (shingles or zoster) in children with asthma, but little is known about whether the same is true for adults with asthma. OBJECTIVE: We determined whether asthma is associated with an increased risk of zoster in adults. METHODS: This study was designed as a population-based case-control study. Zoster cases during the study period were identified among adults (aged >=50 years) who resided in Olmsted County, Minnesota. We compared the frequency of asthma between zoster cases and birthday- and sex-matched control subjects (1:2 matching) without a history of zoster. Asthma status was ascertained based on predetermined criteria. A conditional logistic regression model was used to assess the association of asthma with risk of zoster. RESULTS: A total of 371 zoster cases and their 742 matched control subjects were enrolled. Of the 371 cases, 246 (66%) were female, 348 (94%) were white, and the mean +/- SD age was 66.8 +/- 10.7 years. Twenty three percent (n = 87) of zoster cases had a history of asthma compared with 15% (n = 114) of control subjects. Controlling for pertinent covariates and confounders, there was a significant association between a history of asthma and risk of zoster (adjusted odds ratio, 1.70; 95% CI, 1.20-2.42; P = .003). The population attributable risk percentage for asthma was about 10%. CONCLUSIONS: Asthma is an unrecognized risk factor for zoster in adults. Consideration should be given to immunizing adults with asthma aged more than 50 years as a target group. PMID- 26739415 TI - Search for the potential "second-hit" mechanism underlying the onset of familial hemophagocytic lymphohistiocytosis type 2 by whole-exome sequencing analysis. AB - Familial hemophagocytic lymphohistiocytosis type 2 (FHL2), caused by perforin 1 (PRF1), is a genetic disorder of lymphocyte cytotoxicity that usually presents in the first 2 years of life and has a poor prognosis. Late onset of FHL2 has been sporadically reported, and the mechanism is largely unknown. A newly diagnosed FHL2 patient was detected to have compound mutations in both PRF1 alleles and positive Epstein-Barr virus (EBV) infection. Her brother carried the same mutations and EBV infection status but kept healthy. To search the potential unknown mechanisms, we performed whole-exome sequencing analysis. The patient and her asymptomatic brother carried the same heterozygous missense (c.916G>A) and frameshift mutation (c.65delC) in PRF1. Germline mutation analysis demonstrated that only the proband was exclusively detected with a homozygous missense mutation (S1006L) in the PCDH18 gene, whereas others were found to have a heterozygous mutation (S1006L) of PCDH18. The calculated stability (free energy) changes showed that the mutation of PCDH18 mainly destabilized the protein structure. Furthermore, the mutation (S1006L) could lessen the PCDH18-induced inhibition of target cell activation and reduce the apoptosis of T lymphocytes. This study is the first to perform whole-exome sequencing analysis to search the potential "second-hit" mechanism that underlies the onset of FHL2. A novel type of compound heterozygous mutation has been found in PRF1. The detection of the homozygous germline mutation in PCDH18 strongly argues that the presence of a "second" germline mutation besides the PRF1 gene might be potentially an important mechanism for triggering the onset of FHL2. PMID- 26739421 TI - Plant Growth Beyond Limits. AB - Growth processes, governed by complex genetic networks in a coordinated manner, are determining factors for numerous crop traits. Many components of these networks, described in Arabidopsis and to a lesser extent in crops, enhance organ growth when perturbed. However, translating our understanding of plant growth into crop improvement has been very limited. We argue here that this lack of success is due to the fact that modifying the expression of single genes in a complex growth regulatory network might be buffered by other components of the network. We discuss the observation that simultaneous perturbations of multiple genes have more pronounced effects, and present novel perspectives to use knowledge of growth regulatory networks to enhance crop yield in a targeted manner. PMID- 26739424 TI - Abundance, composition and activity of denitrifier communities in metal polluted paddy soils. AB - Denitrification is one of the most important soil microbial processes leading to the production of nitrous oxide (N2O). The potential changes with metal pollution in soil microbial community for N2O production and reduction are not well addressed. In this study, topsoil samples were collected both from polluted and non-polluted rice paddy fields and denitrifier communities were characterized with molecular fingerprinting procedures. All the retrieved nirK sequences could be grouped into neither alpha- nor beta- proteobacteria, while most of the nosZ sequences were affiliated with alpha-proteobacteria. The abundances of the nirK and nosZ genes were reduced significantly in the two polluted soils. Thus, metal pollution markedly affected composition of both nirK and nosZ denitrifiers. While the total denitrifying activity and N2O production rate were both reduced under heavy metal pollution of the two sites, the N2O reduction rate showed no significant change. These findings suggest that N2O production activity could be sensitive to heavy metal pollution, which could potentially lead to a decrease in N2O emission in polluted paddies. Therefore, metal pollution could have potential impacts on soil N transformation and thus on N2O emission from paddy soils. PMID- 26739425 TI - Specific neutralizing response in plasma from convalescent patients of Ebola Virus Disease against the West Africa Makona variant of Ebola virus. AB - BACKGROUND: The current outbreak of Ebola Virus Disease in West Africa is caused by a new variant of Ebola virus (EBOV) named Makona 2014, whose sequence differs 3% from isolates from Central Africa such as Mayinga 1976 EBOV. The specificity and kinetics of the neutralizing antibody response induced by the circulating Makona EBOV has not been thoroughly studied. METHODS: We have used a lentiviral EBOV-glycoprotein (GP)-pseudotyped infection assay to measure Makona-GP and Mayinga-GP specific neutralizing activity of plasma from three convalescent Ebola Virus Disease patients from the current EBOV outbreak at 2, 3, 4 and 9 months post-infection. Total anti-EBOV GP IgG was measured by a commercial ELISA assay. FINDINGS: In convalescent Ebola Virus Disease patients, Makona-GP-specific neutralizing titers increased from 2 months (mean IC50 1/59), 3 months (IC50 1/212), 4 months (IC50 1/239) and up to 9 months (IC50 1/268) post-infection. Neutralizing activity of plasma from the three convalescent Ebola Virus Disease patients was more vigorous against the current Makona-GP pseudotyped EBOV variant than against Mayinga-GP pseudotyped EBOV and this difference was observed at each time point tested: Mayinga vs Makona mean IC50 fold=4.92 at 2 months post infection, 2.89 fold at 3 months post-infection, 2.23 at 4 months post-infection and 2.98 at 9 months post-infection (all differences p<0.01). Total level of IgG against EBOV-GP did not evolve significantly during the follow up. DISCUSSION: In convalescent Ebola Virus Disease patients, EBOV-GP specific neutralizing activity increases over time, at least up to 9 months post-infection, which suggests that active affinity maturation of antibodies takes place long after clinical recovery. EBOV-GP specific neutralizing response is significantly higher against Makona EBOV circulating in West Africa than against the variants included in the currently approved vaccines. Correlates of protection for EBOV vaccines have not been completely established and the relevance of a lower neutralizing activity in convalescent plasma from the current outbreak against one of the EBOV-GPs contained in the vaccines in terms of its potential efficacy does not necessarily preclude its efficacy. However, this observation highlights the concern regarding the natural diversity of EBOV and its subsequent challenge for diagnosis, therapy and vaccine design. EBOV-GP neutralizing activity varies considerably over time in convalescent Ebola Virus Disease patients. Titering of convalescent blood products would be desirable to standardize and evaluate their potential therapeutic value. PMID- 26739426 TI - Establishment and characterization of duck embryo epithelial (DEE) cell line and its use as a new approach toward DHAV-1 propagation and vaccine development. AB - The primary cell culture was derived from duck embryonic tissue, digested with collagenase type I. The existence of cell colonies with epithelial-like morphology, named duck embryo epithelial (DEE), were purified and optimally maintained at 37 degrees C in M199 medium supplemented with 5% fetal bovine serum. The purified cells were identified as epithelial cell line by detecting Keratin-18 expression using immunofluorescence assay. Our findings demonstrated that DEE cell line can be propagated in culture with (i) a great capacity to adhere, (ii) a great proliferation activity, and (iii) a population doubling time of approximately 18h. Chromosomal features of the DEE cell line were remained constant after the 50th passage. Further characterizations of DEE cell line showed that cell line can normally be grown even after several passages and never converted to tumorigenic cells either in vitro or in vivo study. Susceptibility of DEE cell line was determined for transfection and duck hepatitis A type 1 virus (DHAV-1)-infection. Interestingly, the 50% egg lethal dose (ELD50) of the propagated virus in DEE cell line was higher than ELD50 of the propagated virus in embryonated eggs. Finally, DEE cell line was evaluated to be used as a candidate for DHAV-1 vaccine development. Our results showed that the propagated DHAV-1 vaccine strain SDE in DEE cell line was able to protect ducklings against DHAV-1 challenge. Taken together, our findings suggest that the DEE cell line can serve as a valuable tool for DHAV-1 propagation and vaccine production. PMID- 26739427 TI - Canine parvovirus NS1 protein exhibits anti-tumor activity in a mouse mammary tumor model. AB - Many viral proteins have the ability to kill tumor cells specifically without harming the normal cells. These proteins, on ectopic expression, cause lysis or induction of apoptosis in the target tumor cells. Parvovirus NS1 is one of such proteins, which is known to kill high proliferating tumor cells. In the present study, we assessed the apoptosis inducing ability of canine parvovirus type 2 NS1 protein (CPV2.NS1) in vitro in 4T1 cells, and found it to cause significant cell death due to induction of apoptosis through intrinsic or mitochondrial pathway. Further, we also evaluated the oncolytic activity of CPV2.NS1 protein in a mouse mammary tumor model. The results suggested that CPV2.NS1 was able to inhibit the growth of 4T1 induced mouse mammary tumor as indicated by significantly reduced tumor volume, mitotic, AgNOR and PCNA indices. Further, inhibition of tumor growth was found to be because of induction of apoptosis in the tumor cells, which was evident by a significant increase in the number of TUNEL positive cells. Further, CPV2.NS1 was also able to stimulate the immune cells against the tumor antigens as indicated by the increased CD4+ and CD8+ counts in the blood of CVP2.NS1 treated mice. Further optimization of the delivery of NS1 protein and use of an adjuvant may further enhance its anti-tumor activity. PMID- 26739428 TI - Generation of a reliable full-length cDNA of infectiousTembusu virus using a PCR based protocol. AB - Full-length cDNA of Tembusu virus (TMUV) cloned in a plasmid has been found instable in bacterial hosts. Using a PCR-based protocol, we generated a stable full-length cDNA of TMUV. Different cDNA fragments of TMUV were amplified by reverse transcription (RT)-PCR, and cloned into plasmids. Fragmented cDNAs were amplified and assembled by fusion PCR to produce a full-length cDNA using the recombinant plasmids as templates. Subsequently, a full-length RNA was transcribed from the full-length cDNA in vitro and transfected into BHK-21 cells; infectious viral particles were rescued successfully. Following several passages in BKH-21 cells, the rescued virus was compared with the parental virus by genetic marker checks, growth curve determinations and animal experiments. These assays clearly demonstrated the genetic and biological stabilities of the rescued virus. The present work will be useful for future investigations on the molecular mechanisms involved in replication and pathogenesis of TMUV. PMID- 26739429 TI - Genetic polymorphisms of the drug-metabolizing enzyme cytochrome P450 3A5 in a Uyghur Chinese population. AB - 1. Detection of CYP3A5 variant alleles, and knowledge about their allelic frequency in Uyghur ethnic groups, is important to establish the clinical relevance of screening for these polymorphisms to optimize pharmacotherapy. 2. We used DNA sequencing to investigate the promoter, exons and surrounding introns, and 3'-untranslated region of the CYP3A5 gene in 96 unrelated healthy Uyghur individuals. We also used SIFT and PolyPhen-2 to predict the protein function of the novel non-synonymous mutation in CYP3A5 coding regions. 3. We found 24 different CYP3A5 polymorphisms in the Uyghur population, three of which were novel: the synonymous mutation 43C > T in exon 1, two mutations 32120C > G and 32245T > C in 3'-untranslated region, and we detected the allele frequencies of CYP3A5*1 and *3 as 64.58% and 35.42%, respectively. While no subjects with CYP3A5*6 were identified. Other identified genotypes included the heterozygous genotype 1A/3A (59.38%) and 1A/3E (11.46%), which lead to decreased enzyme activity. In addition, the frequency of haplotype "TTAGGT" was the most prevalent with 0.781. 4. Our data provide new information regarding CYP3A5 genetic polymorphisms in Uyghur individuals, which may help to improve individualization of drug therapy and offer a preliminary basis for more rational use of drugs. PMID- 26739431 TI - Interleukin-6 receptor alpha blockade improves skin lesions in a murine model of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by antinuclear autoantibodies (ANA) and immunocomplexes, commonly affecting kidneys, skin, heart, lung or even the brain. We have shown that JunB(Deltaep) mice develop a SLE phenotype linked to increased epidermal Interleukin (IL)-6 secretion. Blocking of IL-6 receptor alpha (IL-6Ralpha) is considered as therapeutic strategy for the treatment of SLE. JunB(Deltaep) and wild-type mice were treated for short (5 weeks) or long term (21 weeks) with the IL-6Ralpha blocking antibody MR16-1. Skin and kidney of mice were investigated by histology and immunofluorescence, and in addition, kidneys were analysed by electron microscopy. Furthermore, soluble IL-6R (sIL-6R), antihistone and antinucleosome antibodies levels were measured and associated with disease parameters. Treatment with MR16-1 resulted in significant improvement of SLE-like skin lesions in JunB(Deltaep) mice, compared to untreated mice. The sIL-6R amount upon long-term treatment with MR16-1 was significantly higher in JunB(Deltaep) versus untreated JunB(Deltaep) (P = 0.034) or wild-type mice (P = 0.034). MR16-1 treatment over these time spans did not significantly improve kidney pathology of immunoglobulin deposits causing impaired function. Significantly higher antihistone (P = 0.028) and antinucleosome antibody levels (P = 0.028) were measured in MR16-1-treated JunB(Deltaep) mice after treatment compared to levels before therapy. In conclusion, blockade of IL-6Ralpha improves skin lesions in a murine SLE model, but does not have a beneficial effect on autoimmune-mediated kidney pathology. Inhibition of IL-6R signalling might be helpful in lupus cases with predominant skin involvement, but combinatorial treatment might be required to restrain autoantibodies. PMID- 26739434 TI - Beyond simple models of adolescence to an integrated circuit-based account: A commentary. PMID- 26739433 TI - Structure of deaths associated with heavy alcohol use and their contribution to general mortality in Northwest Slovakia. AB - OBJECTIVES: The article analyses death cases with detected blood alcohol level >=2 g/kg. Their contribution to general mortality is calculated. METHODS: Death cases from 2005 to 2012 with detected blood alcohol concentration >=2 g/kg (975 cases) were selected from autopsy records at the Department of Forensic Medicine and Medical Expertises of the Jessenius Faculty of Medicine in Martin. The selected cases were analysed by age and causes of death (pathological, fatal alcohol intoxication, other external causes). Their contribution to general mortality was calculated using official demographic data. RESULTS: Deaths associated with heavy alcohol use comprised 2.2 % of general mortality in males and 0.3 % in females and showed declining trend. The proportion was highest in males aged up to 39 years (10.3 %). External causes dominated among death cases associated with heavy alcohol use (90.8 % in males, 83.7 % in females). CONCLUSIONS: Deaths associated with heavy alcohol use significantly contribute to general mortality, particularly in younger males. In spite of the trend indicating slight improvement of the situation, this specific part of alcohol related problems still constitutes a significant public health issue. PMID- 26739435 TI - Longitudinal outcome and recovery of social problems after pediatric traumatic brain injury (TBI): Contribution of brain insult and family environment. AB - Pediatric traumatic brain injury (TBI) can result in a range of social impairments, however longitudinal recovery is not well characterized, and clinicians are poorly equipped to identify children at risk for persisting difficulties. Using a longitudinal prospective design, this study aimed to evaluate the contribution of injury and non-injury related risk and resilience factors to longitudinal outcome and recovery of social problems from 12- to 24 months post-TBI. 78 children with TBI (injury age: 5.0-15.0 years) and 40 age and gender-matched typically developing (TD) children underwent magnetic resonance imaging including a susceptibility-weighted imaging (SWI) sequence 2-8 weeks post injury (M=39.25, SD=27.64 days). At 12 and 24-months post- injury, parents completed questionnaires rating their child's social functioning, and environmental factors including socioeconomic status, caregiver mental health and family functioning. Results revealed that longitudinal recovery profiles differed as a function of injury severity, such that among children with severe TBI, social problems significantly increased from 12- to 24-months post-injury, and were found to be significantly worse than TD controls and children with mild and moderate TBI. In contrast, children with mild and moderate injuries showed few problems at 12-months post-injury and little change over time. Pre-injury environment and SWI did not significantly contribute to outcome at 24-months, however concurrent caregiver mental health and family functioning explained a large and significant proportion of variance in these outcomes. Overall, this study shows that longitudinal recovery profiles differ as a function of injury severity, with evidence for late-emerging social problems among children with severe TBI. Poorer long-term social outcomes were associated with family dysfunction and poorer caregiver mental health at 24-months post injury, suggesting that efforts to optimize the child's environment and bolster family coping resources may enhance recovery of social problems following pediatric TBI. PMID- 26739436 TI - Does route of methamphetamine exposure during pregnancy have an impact on neonatal development and behaviour in rat offspring? AB - Many preclinical studies have aimed to elucidate the effects of methamphetamine (MA) exposure during pregnancy on the offspring in recent years. However, the severity of effects on the neonate may be related to the subcutaneous (sc) route of administration of the drug that is often employed (88% of preclinical studies) and consequently the delivered dose that the foetus is exposed to. To date there is a paucity of comparative studies investigating different routes of administration for MA during pregnancy and it is not known how these different routes compare when it comes to neonatal outcome. Thus, the aim of this study was to determine if the route of administration of MA (oral gavage or sc injection) during pregnancy at a pharmacological dose affects the magnitude of neurodevelopmental and behavioural effects in the resultant rat offspring. Pregnant Sprague-Dawley dams (n=10 dams/group) received MA (3.75 mg/kg) or control (distilled water) via oral gavage or sc injection from gestation day 7 21. A range of well-recognised neurodevelopmental parameters were examined in the offspring. When administered sc, MA significantly reduced maternal weight gain and altered maternal behaviour; mothers spent less time in the nest with pups and spent less time nursing compared to controls. Significant impairments in neurodevelopmental parameters were evident in both MA treatment groups. Somatic development such as pinna unfolding, fur appearance and eye opening were all delayed after MA exposure but these impairments were more pronounced in the MA sc group. Other somatic parameters such as ano-genital distance and body length were only impeded by sc MA. Behavioural development in the surface righting, inclined plane and forelimb grip tests were also altered for both MA treatment groups. This study demonstrates that prenatal MA can have a profound effect on neonatal outcome, but this can be exacerbated if given via the subcutaneous route, as well as producing additional effects not seen with the oral gavage route. Consequently, the route of administration should be considered when interpreting preclinical studies investigating prenatal MA exposure. PMID- 26739438 TI - A direct assay of carboxyl-containing small molecules by SALDI-MS on a AgNP/rGO based nanoporous hybrid film. AB - Silver nanoparticles (AgNPs) and reduced graphene oxide (rGO) hybrid nanoporous structures fabricated by the layer-by-layer (LBL) electrostatic self-assembly have been applied as a simple platform for the rapid analysis of carboxyl containing small molecules by surface-assisted laser desorption/ionization (D/I) mass spectrometry (SALDI-MS). By the simple one-step deposition of analytes onto the (AgNP/rGO)9 multilayer film, the MS measurements of various carboxyl containing small molecules (including amino acids, fatty acids and organic dicarboxylic acids) can be done. In contrast to other energy transfer materials relative to AgNPs, the signal interferences of a Ag cluster (Agn(+) or Agn(-)) and a C cluster (Cn(+) or Cn(-)) have been effectively reduced or eliminated. The effects of various factors, such as the pore structure and composition of the substrates, on the efficiency of D/I have been investigated by comparing with the (AgNP)9 LBL nanoporous structure, (AgNP/rGO)9/(SiO2NP)6 LBL multilayer film and AgNP/prGO nanocomposites. PMID- 26739439 TI - Short Communication: Diagnosis of Pneumocystis jirovecii Pneumonia by Detection of DNA in Blood and Oropharyngeal Wash, Compared with Sputum. AB - Molecular diagnostic methods on lower respiratory specimens for Pneumocystis pneumonia (PCP) are recommended, but specimens can be difficult to obtain. This study examined the diagnostic use of PCP polymerase chain reaction (PCR) on oropharyngeal wash (OPW) and blood versus sputum (spontaneous and induced) to find faster, simpler, and less invasive diagnostic methods. We prospectively recruited consenting adults with symptoms consistent with PCP. Real-time PCR targeted the Pneumocystis mitochondrial large subunit ribosomal RNA gene, using the aforementioned specimens. Clinical data were collected from routine records. Forty-five participants provided 45 sputa, 31 OPW, and 41 blood samples. Median age was 39 years and 41 (91%) were male, with median CD4 count being 64 cells/MUL. Sputum PCR was positive in 27/45 (60%) participants. Comparative sensitivity of OPW was 9/19 (47%, 95% confidence interval [CI] 23-71) and blood 12/24 (50%, 95% CI 29-71) participants, both with specificity 100%. Including only samples obtained <=2 days after start of treatment, sensitivity of OPW was 80% (8/10, 95% CI 51-100), that of blood was 57% (8/14, 95% CI 29-86), and that of combined tests was 88% (14/16, 95% CI 70-100). In 14/16 individuals with PCP and specimens obtained <=2 days after start of treatment, diagnosis was possible using nonrespiratory samples. Despite moderate sensitivity of individual tests, combined PCP PCR on early blood and OPW specimens had high sensitivity and could reduce the need for invasive procedures. There were no false-positive results on nonrespiratory samples. Sampling and laboratory methods use routine technology and so require few additional resources. PMID- 26739441 TI - Abdominal aortic aneurysm mimicking L2-L3 disc herniation. PMID- 26739442 TI - Non-Langerhans cell histiocytosis. PMID- 26739444 TI - Drug resistance characteristics and cluster analysis of M. tuberculosis in Chinese patients with multiple episodes of anti-tuberculosis treatment. AB - BACKGROUND: Tuberculosis (TB) patients with multiple episodes of anti-TB treatment represent an important source of TB transmission, as well as a serious threat to the control of drug resistant TB, due to the high risk of multidrug and extensively drug resistance (MDR/XDR) and elongating infectiousness of this patient group. In this study we analyzed the possible risk of development and transmission of MDR and XDR in TB patients with multiple episodes of previous treatment history. METHODS: The study subjects were pulmonary TB patients who had at least two episodes of previous anti-TB treatment. A total of 166 eligible patients were identified from 10 counties/districts distributed in east, west, north, south and central China. Drug susceptibility test (DST) was performed by proportion method on LJ-media for the 1st line anti-TB drugs and a line probe assay was used to detect mutations related to resistance of the key 2nd-line drugs. Genotyping of M. tuberculosis (Mtb) was performed with MIRU-VNTR and Spoligotyping. RESULTS: Resistances to 1st-line drugs was observed in 122 (73.5%) of the 166 Mtb isolates with 97 (58.4%) being MDR-TB. Mutations relevant to 2nd line drug resistance was seen in 63 isolates, including 35 MDR-TB isolates (30 pre-XDR, 5 XDR-TB). The Spoligotyping revealed 83.1% Mtb isolates belonged to the Beijing family. The MIRU-VNTR based genotyping revealed 32 (19.3%) of patients were infected with more than one strain. The number of previous TB treatment episode was found being significantly associated with the risk of MDR-TB and XDR TB. Among the remaining 134 patients infected with a single Mtb strain, MIRU-VNTR revealed a high homogeneity of strain especially within Beijing family despite the polymorphic variations along with geographic locations. CONCLUSIONS: The high genetic relatedness and risk of MDR-TB and subsequent pre-XDR and XDR-TB among repeatedly treated patients suggest the establishment of M/XDR Mtb in this specific patient population. It highlights the urgent needs of providing DST of both 1st- and 2nd-line drugs before and during the medication in China's MDR-TB control program. Furthermore, the possibility of infection with multiple strains should also be considered to be associated with the drug resistance, which calls for the modification of treatment regimen. PMID- 26739445 TI - Why so many deep brain stimulation targets in Tourette's syndrome? Toward a broadening of the definition of the syndrome. PMID- 26739446 TI - Serum uric acid is associated with apathy in early, drug-naive Parkinson's disease. AB - Both low serum uric acid (UA) levels and apathy are considered biomarkers of cognitive decline and dementia in Parkinson's disease (PD). There is an urgent need to combine different biomarkers to predict disease course in PD. Data on the relationship between serum UA levels and apathy in PD are lacking. The aim of this study is to evaluate the relationship between serum UA levels and pure apathy in early, drug-naive PD patients. Forty-nine early, drug-naive PD patients were enrolled and stratified into two groups using the median serum UA levels at diagnosis (Group 1 serum UA <= 4.8 mg/dl; Group 2 serum UA > 4.8 mg/dl). The cohort was followed for the first 2 years of disease. Apathy was evaluated with the Apathy Evaluation Scale (AES). Patients with lower serum UA levels presented significant higher AES score compared to patients with higher serum UA levels. Regression analysis showed that baseline serum UA levels were significant determinants of AES scores at both baseline and 2-year follow up, irrespective of gender, age, attention/executive functions and dopamine replacement therapy when applicable. This is the first study showing a link between serum UA levels and apathy in non-demented, non-depressed, early, drug-naive PD, being lower serum UA levels associated with greater apathy. Further follow up of our patients and replication of this observation in independent cohorts are needed to establish if this combination of biomarkers may help in characterizing a subgroup of PD patients at diagnosis. PMID- 26739447 TI - Monitoring cytosolic and ER Zn(2+) in stimulated breast cancer cells using genetically encoded FRET sensors. AB - The Zn(2+)-specific ion channel ZIP7 has been implicated to play an important role in releasing Zn(2+) from the ER. External stimulation of breast cancer cells has been proposed to induce phosphorylation of ZIP7 by CK2alpha, resulting in ZIP7-mediated Zn(2+) release from the ER into the cytosol. Here, we examined whether changes in cytosolic and ER Zn(2+) concentrations can be detected upon such external stimuli. Two previously developed FRET sensors for Zn(2+), eZinCh-2 (Kd = 1 nM at pH 7.1) and eCALWY-4 (Kd = 0.63 nM at pH 7.1), were expressed in both the cytosol and the ER of wild-type MCF-7 and TamR cells. Treatment of MCF-7 and TamR cells with external Zn(2+) and pyrithione, one of the previously used triggers, resulted in an immediate increase in free Zn(2+) in both cytosol and ER, suggesting that Zn(2+) was directly transferred across the cellular membranes by pyrithione. Cells treated with a second trigger, EGF/ionomycin, showed no changes in intracellular Zn(2+) levels, neither in multicolor imaging experiments that allowed simultaneous imaging of cytosolic and ER Zn(2+), nor in experiments in which cytosolic and ER Zn(2+) were monitored separately. In contrast to previous work using small-molecule fluorescent dyes, these results indicate that EGF-ionomycin treatment does not result in significant changes in cytosolic Zn(2+) levels as a result from Zn(2+) release from the ER. These results underline the importance of using genetically encoded fluorescent sensors to complement and verify intracellular imaging experiments with synthetic fluorescent Zn(2+) dyes. PMID- 26739449 TI - Serum Brain-Derived Neurotrophic Factor is Related to Platelet Reactivity but not to Genetic Polymorphisms within BDNF Encoding Gene in Patients with Type 2 Diabetes. AB - BACKGROUND: The aim of this study was to investigate the association between serum concentrations of the brain-derived neurotrophic factor (BDNF), platelet reactivity and inflammatory markers, as well as its association with BDNF encoding gene variants in type 2 diabetic patients (T2DM) during acetylsalicylic acid (ASA) therapy. MATERIAL/METHODS: This retrospective, open-label study enrolled 91 patients. Serum BDNF, genotype variants, hematological, biochemical, and inflammatory markers were measured. Blood samples were taken in the morning 2 3 h after the last ASA dose. The BDNF genotypes for selected variants were analyzed by use of the iPLEX Sequenom assay. RESULTS: In multivariate linear regression analysis, CADP-CT >74 sec (p<0.001) and sP-selectin concentration (p=0.03) were predictive of high serum BDNF. In multivariate logistic regression analysis, CADP-CT >74 sec (p=0.02) and IL-6 concentration (p=0.03) were risk factors for serum BDNF above the median. Non-significant differences were observed between intronic SNP rs925946, missense SNP rs6265, and intronic SNP rs4923463 allelic groups and BDNF concentrations in the investigated cohort. CONCLUSIONS: Chronic inflammatory condition and enhanced immune system are associated with the production of BDNF, which may be why the serum BDNF level in T2DM patients with high platelet reactivity was higher compared to subjects with normal platelet reactivity in this study. PMID- 26739450 TI - On the Identifiability of Transmission Dynamic Models for Infectious Diseases. AB - Understanding the transmission dynamics of infectious diseases is important for both biological research and public health applications. It has been widely demonstrated that statistical modeling provides a firm basis for inferring relevant epidemiological quantities from incidence and molecular data. However, the complexity of transmission dynamic models presents two challenges: (1) the likelihood function of the models is generally not computable, and computationally intensive simulation-based inference methods need to be employed, and (2) the model may not be fully identifiable from the available data. While the first difficulty can be tackled by computational and algorithmic advances, the second obstacle is more fundamental. Identifiability issues may lead to inferences that are driven more by prior assumptions than by the data themselves. We consider a popular and relatively simple yet analytically intractable model for the spread of tuberculosis based on classical IS6110 fingerprinting data. We report on the identifiability of the model, also presenting some methodological advances regarding the inference. Using likelihood approximations, we show that the reproductive value cannot be identified from the data available and that the posterior distributions obtained in previous work have likely been substantially dominated by the assumed prior distribution. Further, we show that the inferences are influenced by the assumed infectious population size, which generally has been kept fixed in previous work. We demonstrate that the infectious population size can be inferred if the remaining epidemiological parameters are already known with sufficient precision. PMID- 26739451 TI - Functional Interplay of Two Paralogs Encoding SWI/SNF Chromatin-Remodeling Accessory Subunits During Caenorhabditis elegans Development. AB - SWI/SNF ATP-dependent chromatin-remodeling complexes have been related to several cellular processes such as transcription, regulation of chromosomal stability, and DNA repair. The Caenorhabditis elegans gene ham-3 (also known as swsn-2.1) and its paralog swsn-2.2 encode accessory subunits of SWI/SNF complexes. Using RNA interference (RNAi) assays and diverse alleles we investigated whether ham-3 and swsn-2.2 have different functions during C. elegans development since they encode proteins that are probably mutually exclusive in a given SWI/SNF complex. We found that ham-3 and swsn-2.2 display similar functions in vulva specification, germline development, and intestinal cell proliferation, but have distinct roles in embryonic development. Accordingly, we detected functional redundancy in some developmental processes and demonstrated by RNA sequencing of RNAi-treated L4 animals that ham-3 and swsn-2.2 regulate the expression of a common subset of genes but also have specific targets. Cell lineage analyses in the embryo revealed hyper-proliferation of intestinal cells in ham-3 null mutants whereas swsn-2.2 is required for proper cell divisions. Using a proteomic approach, we identified SWSN-2.2-interacting proteins needed for early cell divisions, such as SAO-1 and ATX-2, and also nuclear envelope proteins such as MEL-28. swsn-2.2 mutants phenocopy mel-28 loss-of-function, and we observed that SWSN-2.2 and MEL-28 colocalize in mitotic and meiotic chromosomes. Moreover, we demonstrated that SWSN-2.2 is required for correct chromosome segregation and nuclear reassembly after mitosis including recruitment of MEL-28 to the nuclear periphery. PMID- 26739453 TI - Converting solid wastes into liquid fuel using a novel methanolysis process. AB - Biomass fast pyrolysis followed by hydrodeoxygenation upgrading is the most popular way to produce upgraded bio-oil from biomass. This process requires large quantities of expensive hydrogen and operates under high pressure condition (70 140 atm). Therefore, a novel methanolysis (i.e., biomass pyrolysis under methane environment) process is developed in this study, which is effective in upgraded bio-oil formation at atmospheric pressure and at about 400-600 degrees C. Instead of using pure methane, simulated biogas (60% CH4+40% CO2) was used to test the feasibility of this novel methanolysis process for the conversion of different solid wastes. The bio-oil obtained from canola straw is slightly less than that from sawdust in term of quantity, but the oil quality from canola straw is better in terms of lower acidity, lower Bromine Number, higher H/C atomic ratio and lower O/C atomic ratio. The municipal solid waste and newspaper can also obtain relatively high oil yields, but the oil qualities of them are both lower than those from sawdust and canola straw. Compared with catalysts of 5%Zn/ZSM-5 and 1%Ag/ZSM-5, the 5%Zn-1%Ag/ZSM-5 catalyst performed much better in terms of upgraded bio-oil yield as well as oil quality. During the methanolysis process, the metal silver may be used to reduce the total acid number of the oil while the metal zinc might act to decrease the bromine number of the oil. The highly dispersed Zn and Ag species on/in the catalyst benefit the achievement of better upgrading performance and make it be a very promising catalyst for bio-oil upgrading by biogas. PMID- 26739452 TI - Signaling Cascades Governing Cdc42-Mediated Chondrogenic Differentiation and Mensenchymal Condensation. AB - Endochondral ossification consists of successive steps of chondrocyte differentiation, including mesenchymal condensation, differentiation of chondrocytes, and hypertrophy followed by mineralization and ossification. Loss of-function studies have revealed that abnormal growth plate cartilage of the Cdc42 mutant contributes to the defects in endochondral bone formation. Here, we have investigated the roles of Cdc42 in osteogenesis and signaling cascades governing Cdc42-mediated chondrogenic differentiation. Though deletion of Cdc42 in limb mesenchymal progenitors led to severe defects in endochondral ossification, either ablation of Cdc42 in limb preosteoblasts or knockdown of Cdc42 in vitro had no obvious effects on bone formation and osteoblast differentiation. However, in Cdc42 mutant limb buds, loss of Cdc42 in mesenchymal progenitors led to marked inactivation of p38 and Smad1/5, and in micromass cultures, Cdc42 lay on the upstream of p38 to activate Smad1/5 in bone morphogenetic protein-2-induced mesenchymal condensation. Finally, Cdc42 also lay on the upstream of protein kinase B to transactivate Sox9 and subsequently induced the expression of chondrocyte differential marker in transforming growth factor-beta1-induced chondrogenesis. Taken together, by using biochemical and genetic approaches, we have demonstrated that Cdc42 is involved not in osteogenesis but in chondrogenesis in which the BMP2/Cdc42/Pak/p38/Smad signaling module promotes mesenchymal condensation and the TGF-beta/Cdc42/Pak/Akt/Sox9 signaling module facilitates chondrogenic differentiation. PMID- 26739454 TI - Monetizing the social benefits of landfill mining: Evidence from a Contingent Valuation survey in a rural area in Greece. AB - Despite the emerging global attention towards promoting waste management policies that reduce environmental impacts and conserve natural resources, landfilling still remains the dominant waste management practice in many parts of the world. Owing to this situation, environmental burdens are bequeathed to and large amounts of potentially valuable materials are lost for future generations. As a means to undo these adverse effects a process known as landfill mining (LFM) could be implemented provided that economic feasibility is ensured. So far, only a few studies have focused on the economic feasibility of LFM from a private point of view and even less studies have attempted to economically justify the need for LMF projects from a social point of view. This paper, aiming to add to the limited literature in the field, presents the results of a survey conducted in a rural district in Greece, by means of the Contingent Valuation method (CVM) in order to estimate society's willingness to pay for LFM programs. According to the empirical survey, more than 95% of the respondents recognize the need for LFM programs. Nevertheless, only one-fourth of the respondents are willing to pay through increased taxes for LFM, owing mainly to economic depression and unemployment. Those who accept the increased tax are willing to pay about ?50 per household per year, on average, which results in a mean willingness to pay (WTP) for the entire population under investigation of around ?12 per household per year. The findings of this research work provide useful insights about the 'dollar-based' benefits of LFM in the context of social cost-benefit analysis of LFM projects. Yet, it is evident that further research is necessary. PMID- 26739455 TI - Pilot plant experience on anaerobic codigestion of source selected OFMSW and sewage sludge. AB - Anaerobic codigestion of source selected organic fraction of municipal solid waste (SS-OFMSW) and sewage sludge may be one of the most viable solutions to optimize oversized digesters efficiency in wastewater treatment plants. Based on results of BMP tests obtained for sewage sludge and SS-OFMSW, pilot plant tests were carried out by 3.4 m(3) CSTR reactor at mesophilic temperature. A mix of fruit and vegetable waste from wholesale market and canteen waste was used as SS OFMSW substrate. Tests were conducted applying an OLR (organic loading rate) ramp with 6 different phases until a value of 3.2 kgVS/m(3) d. Feedstock and digestate characteristics, efficiency and process parameters were monitored. The anaerobic codigestion development was stable in each phase: early indicators like VFA (volatile fatty acids) and FOS/TAC ratio were always below instability threshold values. The maximum OLR tested determined a GPR (gas production rate) of 0.95 N m(3)/m(3) d and SGP (specific gas production) of 0.49 N m(3)/kgVS with a VS abatement of 67.3%. PMID- 26739456 TI - Enhancing recovery of ammonia from swine manure anaerobic digester effluent using gas-permeable membrane technology. AB - Gas-permeable membrane technology is useful to recover ammonia from manure. In this study, the technology was enhanced using aeration instead of alkali chemicals to increase pH and the ammonium (NH4(+)) recovery rate. Digested effluents from covered anaerobic swine lagoons containing 1465-2097 mg NH4(+)-N L(-1) were treated using submerged membranes (0.13 cm(2) cm(-3)), low-rate aeration (120 mL air L-manure(-1) min(-1)) and nitrification inhibitor (22 mg L( 1)) to prevent nitrification. The experiment included a control without aeration. The pH of the manure with aeration rose from 8.6 to 9.2 while the manure without aeration decreased from 8.6 to 8.1. With aeration, 97-99% of the NH4(+) was removed in about 5 days of operation with 96-98% recovery efficiency. In contrast, without aeration it took 25 days to treat the NH4(+). Therefore, the recovery of NH4(+) was five times faster with the low-rate aeration treatment. This enhancement could reduce costs by 70%. PMID- 26739457 TI - Molecular characterization of a distinct bipartite Begomovirus species infecting ivy gourd (Coccinia grandis L.) in Tamil Nadu, India. AB - A distinct bipartite begomovirus was found to be associated with the mosaic disease on ivy gourd (Coccinia grandis L.) in Tamil Nadu, India. The complete DNA A and DNA B components were cloned by rolling circle amplification. Genome organization of this virus is found to be typical of Old World bipartite begomovirus. The association of betasatellite component with this virus is absent. The closest nucleotide identity of 73.4 % was seen with the Loofa yellow mosaic virus (LYMV-[VN]-AF509739) suggesting that it is a new virus species Coccinia mosaic virus (CoMoV-Ivy gourd [TN TDV Coc1]) and distantly related to the other known begomoviruses. The DNA B component shared a maximum identity of 55 % with that of Tomato leaf curl New Delhi virus (ToLCNDV). In the phylogenetic analysis, CoMoV-Ivy gourd form cluster separate from other begomoviruses. Recombination analysis showed that there was no recombination event in the genome. This is the distinct begomovirus infecting ivy gourd. PMID- 26739458 TI - Horses naturally infected with EIAV harbor 2 distinct SU populations but are monophyletic with respect to IN. AB - Equine infectious anemia virus (EIAV) causes lifelong infections ranging from acutely fatal, to chronic, to asymptomatic. Within infected animals, EIAV is found as a quasispecies. Many experimental studies on EIAV, carried out in the U.S. over the past 70 years, have used either the highly virulent Wyoming (EIAVWYO) field strain or various derivatives of that strain. These infections have provided insights into the variety of genetic changes that accumulate in the env gene and LTR in experimentally infected horses. In the current study, we obtained EIAV sequences from blood samples collected from naturally infected Texas horses between 2000 and 2002. We found surface (SU) and long terminal repeat (LTR) sequences clearly related to EIAVWYO and its cell culture-adapted derivatives. Some blood samples yielded SU or LTR sequences belonging to 2 discrete clusters. In these cases, SU and LTR variation between animals was no greater than sequence variation within animals. In contrast, a portion of integrase (IN) was more homogeneous within animals than between animals. These results suggest that specific selective pressures are applied to SU and LTR sequences, potentially driving generation of two distinct sequence clusters within a horse. We speculate that viruses in one cluster may be more highly expressed and easily transmitted while those in the second cluster support long term inapparent infection. The presence of homogeneous IN sequences within a horse supports the hypothesis that SU and LTR sequences diverged after the initial infection. PMID- 26739459 TI - Human T-cell leukemia virus type 1 (HTLV-1) Tax1 oncoprotein but not HTLV-2 Tax2 induces the expression of OX40 ligand by interacting with p52/p100 and RelB. AB - Human T-cell leukemia virus type 1 (HTLV-1) is a causative retrovirus of adult T cell leukemia and HTLV-1-associated myelopathy. Unlike HTLV-1, the same group of retrovirus HTLV-2 has not been found to be associated with these diseases. HTLV-1 and HTLV-2 encode transforming proteins Tax1 and Tax2, and a few distinct activities of Tax1 from those of Tax2 have been proposed to contribute to the HTLV-1-specific pathogenesis of disease. One significant difference of Tax1 from Tax2 is the activation of transcription factor NF-kappaB2/p100/p52. We found that Tax1 but not Tax2 induces the expression of OX40 ligand (OX40L) in a human T-cell line. To induce the OX40L expression, Tax1 but not Tax2 was observed to interact with NF-kappaB2/p100/p52 and RelB and the distinct interaction activity was mediated by the Tax1 amino acid region of 225-232. In addition, Tax1 but not Tax2 or Tax1/225-232 interacted with p65, p50, and c-Rel; however, the interactions were much less than those noted with NF-kappaB2/p100/p52 and RelB. OX40L is a T cell costimulatory molecule of the tumor necrosis factor family, and its signal plays a critical role in establishing adaptive immunity by inducing the polarized differentiation of T-cells to cells such as T helper type 2 and T follicular helper cells. Therefore, the present findings suggest that Tax1 might alter the immune response to HTLV-1 and/or differentiation of HTLV-1-infected T-cells via OX40L induction, thereby acting as a factor mediating the distinct phenotypes and pathogenesis of HTLV-1 from that of HTLV-2. PMID- 26739460 TI - Artesunate, an anti-malarial drug, has a potential to inhibit HCV replication. AB - Hepatitis C virus (HCV) infection is a major global health issue. Although the search for HCV treatments has resulted in great achievements, the current treatment methods have limitations, and new methods and drugs for hepatitis C treatment are still required. The aim of the present study was to investigate the effects of artesunate (ART) on HCV replication and compared these effects with those of ribavirin (RBV) and interferon-2b (IFN). The study was performed in HCV infection cell models (JFH1-infected Huh7.5.1 and OR6 cell lines). Our results showed that the antimalarial drug ART inhibited HCV replicon replication in a dose- and time-dependent manner at a concentration that had no effect on the proliferation of exponentially growing host cells, and the inhibitory effect on HCV replication was stronger than RBV but weaker than IFN, as determined by qPCR, luciferase assays, and Western blot analysis. Furthermore, the combination of ART and IFN resulted in a greater inhibition of HCV replication. These findings demonstrated that ART had an inhibitive effect on HCV replication and may be a novel supplemental co-therapy with IFN and RBV for HCV and as an alternative strategy to combat resistance mechanisms that have emerged in the presence of DAA agents. PMID- 26739461 TI - Process evaluation of the implementation of the Unplugged Program for drug use prevention in Brazilian schools. AB - BACKGROUND: Most Brazilian schools do not have a continuous program for drug use prevention. To address this gap, the Ministry of Health adapted the European evidence-based program Unplugged to improve the drug use prevention efforts of Brazilian public schools. The aim of this study was to evaluate the process of program implementation in three Brazilian cities among middle school students between 6(th) and 9(th) grade (11 to 14 years old). METHODS: Mixed methods were used in this process evaluation study, including focus groups, fidelity forms, and satisfaction questionnaires. Study participants included 36 teachers, 11 school administrators, 6 coaches, 16 stakeholders, and 1267 students from 62 classes in 8 schools. RESULTS: The 12 Unplugged lessons were all implemented in 94 % of the classes. However, only 57 % of the classes were completed as described in the program's manual. The decision to exclude activities because of time constraints was made without a common rationale. Teachers reported difficulties due to the amount of time necessary to plan the lessons and implement the activities. In addition, they mentioned that the lack of support from school administrators was an obstacle to proper program implementation. The majority of students and teachers responded positively to the program, reporting changes in the classroom environment and in personal skills or knowledge. CONCLUSIONS: The Unplugged program can be feasibly implemented in Brazilian public schools. However, it is necessary to reduce the number of activities per class and to restructure the format of the standard teaching schedule to ensure that the normal academic content is still taught while Unplugged is being implemented. PMID- 26739462 TI - Pediatric Rectal Exam: Why, When, and How. AB - The digital rectal examination (DRE) is performed in children less often than is indicated. Indications for the pediatric DRE include diarrhea, constipation, fecal incontinence, abdominal pain, gastrointestinal bleeding, and anemia. Less well-recognized indications may include abdominal mass, urinary symptoms, neurologic symptoms, urogenital or gynecologic symptoms, and anemia. Indeed, we believe that it should be considered part of a complete physical examination in children presenting with many different complaints. Physicians avoid this part of the physical examination in both children and adults for a number of reasons: discomfort on the part of the health care provider; belief that no useful information will be provided; lack of adequate training and experience in the performance of the DRE; conviction that planned "orders" or testing can obviate the need for the DRE; worry about "assaulting" a patient, particularly one who is small, young, and subordinate; anticipation that the exam will be refused by patient or parent; and concern regarding the time involved in the exam. The rationale and clinical utility of the DRE will be summarized in this article. In addition, the components of a complete pediatric DRE, along with suggestions for efficiently obtaining the child's consent and cooperation, will be presented. PMID- 26739463 TI - [Chinese recommendations for clinical practice guideline development]. PMID- 26739464 TI - [The guideline of prevention and treatment for chronic hepatitis B: a 2015 update]. PMID- 26739465 TI - [The guideline of prevention and treatment for hepatitis C: a 2015 update]. PMID- 26739466 TI - [Consensus on the diagnosis and treatment of cholestasis liver diseases]. PMID- 26739467 TI - [Effect of the cytoplasmic DNA sensor DAI on replication of hepatitis B virus]. AB - OBJECTIVE: To explore the effect of the cytoplasmic DNA sensor DAI on replication of hepatitis B virus (HBV) and its possible mechanism. METHODS: The hepatocyte derived cell line HepG2 was co-transfected with DAI siRNA and the HBV1.3 replicative plasmid PHY106, and the cells were divided into two experimental groups. Six hours later, total RNA was extracted from the first group of cells and expression of IFIT1 and IL-6 were detected by real-time RT-PCR. The second group of cells was incubated for 4 days, after which the cell supernatant was collected and the HBV surface antigen (HBsAg) and envelope antigen (HBeAg) were detected by ELISA. In addition, HBV core particles were extracted and applied to southern blot assay to detect the intracellular HBV replication intermediates (rcDNA, dlDNA and ssDNA). Next, the HepG2 cells were triple transfected with siRNA targeting the type I interferon pathway molecule TBK1 and DAI simultaneously and HBV1.3, after which HBV viral proteins were detected. Two group comparisons were made using the independent sample t-test, and more-than-2 group comparisons were made using ANOVA. RESULTS: DAI gene expression was down regulated in response to DAI siRNA transfection. Cells with down-regulated DAI showed inhibited HBV replication (in a dose-dependent manner), accompanied by reduced levels of HBsAg (0.0195+/-0.0050 vs. CONTROL: 0.3150+/-0.0200, P less than 0.05, t = 14.77) and HBeAg (0.0140+/-0.0040 vs. CONTROL: 0.01235+/-0.0135, P less than 0.05, t = 7.777). No effect of down-regulated DAI was observed for the expression of IFIT1 of IL-6. siRNA-mediated down-regulation of TBK1 and DAI simultaneously led to reduced expression of HBsAg and HBeAg. CONCLUSION: Down regulation of DAI gene expression inhibited HBV replication and HBV protein expression, but the underlying mechanism was not related to the type I interferon or NF-kB signaling pathway. PMID- 26739468 TI - [Reversal of liver fibrosis through AG490 inhibitor-mediated inhibition of the TGFbeta1-STAT3 pathway]. AB - OBJECTIVE: To investigate the role of TGF-beta1 and STAT3 signaling in liver fibrosis using a rat model system and to determine the therapeutic mechanism of AG490 in relation to this signaling pathway. METHODS: Rats were randomly divided into a control group and DENA-induced liver fibrosis model group, and then subdivided into AG490 treatment groups. During fibrosis development, liver tissue samples were collected at different time points (0, 4 and 8 weeks) and evaluated according to the Scheuer scoring system. Expression of STAT3, TGFbeta1, alpha SMA, E-cadherin, MMP2 and TIMP1 was measured by PCR (mRNA) and immunohistochemistry and western blotting (protein). RESULTS: Increasing degrees of inflammation and fibrosis were observed in liver tissues of DENA-treated rats throughout model establishment. The mRNA expression of TGFbeta1 and STAT3 was significantly increased in DENA-induced rats with advanced fibrosis (AF) compared to those with early fibrosis (EF) (P = 0.034 and P = 0.012 respectively). The protein expression of TGF-beta1, phospho-Smad2, alpha-SMA, E-cadherin, STAT3 and phospho-STAT3 was significantly increased in DENA-induced rats with AF compared to the unmodeled control group (P = 0.048, P = 0.003, P = 0.002, P = 0.028, P = 0.009 and P = 0.039). The protein expression of E-cadherin was lower in the DENA induced rats with AF than in those with EF (P = 0.026). STAT3 and TGF-beta1 co expression was detected in AF tissues. DENA-induced AG490-treated rats with AF showed substantially lower protein expression of STAT3, TGF-beta1, MMP2 and TIMP1 compared to DENA-induced untreated rats with AF (P = 0.006, P = 0.018, P = 0.010 and P = 0.005); in addition, the degrees of fibrosis and inflammation were also greatly reduced in the DENA-induced AG490-treated rats with AF compared to DENA induced untreated rats with AF (P = 0.042 and P = 0.021). Conclusions STAT3 signal transduction may regulate the TGF-beta1 pathway and affect liver fibrosis, especially in the advanced phase. AG490 can inhibit TGFbeta1-STAT3 signaling, resulting in reversal of liver fibrosis. PMID- 26739469 TI - [Clinical significance of cysteinyl leukotriene receptor expression in primary hepatocellular carcinoma]. AB - OBJECTIVE: To investigate expression of the cysteinyl leukotriene receptor (CysLT1R) in hepatocellular carcinoma (HCC) tissues and determine its clinical significance. METHODS: Cancerous and paraneoplastic liver tissues were collected from 30 patients with HCC and from 12 patients with liver hemangioma patients (controls). Real-time PCR and immunohistochemistry were used to evaluate the expression of CysLT1R in these tissues and assess the relationship with clinical pathological features. T-test,?Fisher's exact test and Kaplan-Meier survival analysis were used for statistical analysis. RESULTS: The expression of CysLT1R in adjacent liver tissues (100%) was higher than that in the HCC (43.33%, P = 0.000) and normal liver tissues (41.67%, P = 0.000). The level of CysLT1R mRNA was also higher in paraneoplastic liver tissues (0.0339+/-0.0221) than in the paired HCC tissues (0.0127+/-0.0116, t = 2.911, P = 0.008) and normal liver tissues (0.0154+/-0.0123, t = -2.310, P = 0.033). There was no difference between the levels in HCC and normal liver tissues (P more than 0.05). Higher level of CysLT1R mRNA, higher level of serum alpha-fetoprotein, and higher tumor stage (III-IV) were associated with poor prognosis (respectively 4.372, P = 0.037; 24.187, P = 0.000; 8.75, P = 0.003). However, no evident relationship between the expression of CysLT1R and other clinical features was observed. Conclusions Overexpression of CysLT1R may contribute to the occurrence and progression of HCC. PMID- 26739470 TI - [Effects of JAZF1 overexpression on proinflammatory cytokines in hepatocytes induced by palmitic acid]. AB - OBJECTIVE: To investigate the effects of JAZF1 overexpression on the pro inflammatory cytokines in hepatic steatosis. METHODS: The model of hepatic steatosis was established by incubating hepatocytes with palmitic acid (PA) at 0, 0.125, 0.25, 0.5 and 1 mM dose and for 0, 6, 12, 24 and 48 hours, after which recombinant adenovirus expressing JAZF1 (Ad-JAZF1) was introduced to up-regulate expression. Triglyceride level was measured by GOD. Cell viability was detected by CCK-8. The mRNA and protein expression of TNF-alpha, MCP-1, IL-8 and JAZF1 was examined by RT-PCR, ELISA, and western blotting. RESULTS: The PA-treated hepatocytes showed dose-dependent significant increases in TNF-alpha, MCP-1 and IL-8 mRNA expression for doses up to 0.25 mM; there were no significant increases for the highest doses of 0.5 and 1 mM. The 0.25 mM PA-treated hepatocytes showed time-dependent significant increases in TNF-alpha, MCP-1 and IL-8 mRNA expressions (FTNF-alpha = 26.51, FMCP-1 = 57.20, FIL-8 = 353.85, P less than 0.01), with the maximum level reached at 12 h and followed by a gradual decrease with longer treatment times. JAZF1 mRNA and protein expression was markedly increased in hepatocytes infected with Ad-JAZF1 (P less than 0.01). However, the AP-treated hepatocytes with JAZF1 overexpression showed down-regulation of TNF alpha, MCP-1 and IL-8 mRNA expression (decreased by 89.69%, 77.68%, and 83.21%, respectively) and secretion (37%, 37% and 41%, respectively, P less than 0.01). CONCLUSION: Stimulation of hepatocytes by the PA fatty acid in vitro promotes mRNA expression of TNF-alpha, MCP-1 and IL-8, but overexpression of JAZF1 inhibits the PA-induced expression and secretion of these factors. PMID- 26739471 TI - [Hepatopulmonary syndrome-related changes in D-dimer, prothrombin time, fibrinogen, CD4 and CD8 in a rat model system]. AB - OBJECTIVE: To determine the changes in levels of D-dimer, prothrombin time (PT), fibrinogen (Fib), CD4 and CD8 in relation to hepatopulmonary syndrome (HPS) by using a rat model system and to assess the association with pathologic changes in lung. METHODS: Forty male Sprague-Dawley rats were divided into equal groups for modeling of cirrhosis and HPS. The two groups were assessed by blood gas analysis, standard biochemical tests to measure D-dimer, PT, Fib, CD4 and CD8, and pathological examination of lung tissues. RESULTS: The HPS rats showed significantly lower PaO2 than the cirrhosis rats (58.20+/-3.19 mmHg vs. 85.00+/ 2.53 mmHg, P = 0.000). The HPS rats showed significantly higher levels of D dimer, Fib and CD8 than the cirrhosis rats (0.39+/-0.09 mg/ml vs. 0.25+/-0.05 mg/ml, P = 0.000; 1.77+/-0.10 g/L vs. and 1.49+/-0.09 g/L, P = 0.010; 32.32+/ 4.45/mm3 vs. 20.13+/-6.09/mm3, P = 0.014). The HPS rats showed significantly lower levels of PT, CD4 and CD4/CD8 than the cirrhosis rats (14.86+/-1.04 s vs. 16.23+/-0.75 s, P = 0.036; 20.45+/-3.86/mm3 vs. 26.75+/-5.32/mm3, P = 0.000; 0.64+/-0.09 vs. 1.32+/-0.13, P = 0.000). The lung tissues of the HPS rats showed microthrombosis in pulmonary vessels, which were not observed in lung tissues of the cirrhosis rats. CONCLUSION: HPS-related differential levels of D-dimer, PT, Fib, CD4, CD8 and CD4/CD8 may represent a biomarker profile suggestive of incidence of thromboembolism in lung. PMID- 26739472 TI - [Case report of aspergillus infection in a patient with drug-induced liver injury]. PMID- 26739473 TI - [Case report of hepatic malignant fibrous histiocytoma combined with renal malignant tumor]. PMID- 26739474 TI - Taxonomic evaluation of putative Streptomyces scabiei strains held in the ARS Culture Collection (NRRL) using multi-locus sequence analysis. AB - Multi-locus sequence analysis has been demonstrated to be a useful tool for identification of Streptomyces species and was previously applied to phylogenetically differentiate the type strains of species pathogenic on potatoes (Solanum tuberosum L.). The ARS Culture Collection (NRRL) contains 43 strains identified as Streptomyces scabiei deposited at various times since the 1950s and these were subjected to multi-locus sequence analysis utilising partial sequences of the house-keeping genes atpD, gyrB, recA, rpoB and trpB. Phylogenetic analyses confirmed the identity of 17 of these strains as Streptomyces scabiei, 9 of the strains as the potato-pathogenic species Streptomyces europaeiscabiei and 6 strains as potentially new phytopathogenic species. Of the 16 other strains, 12 were identified as members of previously described non-pathogenic Streptomyces species while the remaining 4 strains may represent heretofore unrecognised non pathogenic species. This study demonstrated the value of this technique for the relatively rapid, simple and sensitive molecular identification of Streptomyces strains held in culture collections. PMID- 26739475 TI - Genes from pUM505 plasmid contribute to Pseudomonas aeruginosa virulence. AB - The pUM505 plasmid was isolated from a clinical strain of Pseudomonas aeruginosa. This plasmid contains a genomic island with sequence similar to islands found in chromosomes of virulent P. aeruginosa clinical isolates. The objective of this work was to determine whether pUM505 increases the virulence of P. aeruginosa and to identify the genes responsible for this property. First, using the lettuce leaf model, we found that pUM505 significantly increases the virulence of P. aeruginosa reference strain PAO1. pUM505 also increased the PAO1 virulence in a murine model and increased cytotoxicity of this strain toward HeLa cells. Thus, we generated a pUM505 gene library of 103 clones in the pUCP20 binary vector. The library was transferred to Escherichia coli TOP10 and P. aeruginosa PAO1 to identify genes. The lettuce-leaf model allowed us to identify three recombinant plasmids that increased the virulence of both E. coli and P. aeruginosa strains. These recombinant plasmids also increased the virulence of the PAO1 strain in mice and induced a cytotoxic effect in HeLa cells. Eleven genes were identified in the virulent transformants. Of these genes, only the pUM505 ORF 2 has homology with a gene previously implicated in virulence. These results indicate that pUM505 contains several genes that encode virulence factors, suggesting that the plasmid may contribute directly to bacterial virulence. PMID- 26739477 TI - Anomalous coronary arteries: What we know and what we do not know. PMID- 26739476 TI - Utilization due to chronic obstructive pulmonary disease and its predictors: a study using the U.S. National Emergency Department Sample (NEDS). AB - BACKGROUND: Previous studies of healthcare utilization for chronic obstructive pulmonary disease (COPD) have focused on time-trends in COPD visits or COPD treatments, or the effect of hospital volume on mortality. Few data are available regarding outcomes after an ED visit (and subsequent hospitalization) for COPD, which are both very common in patients with COPD. Our objective was to assess time-trends and predictors of emergency department and subsequent inpatient health care utilization and charges associated with COPD in the U.S. METHOD: We used the 2009-12 U.S. Nationwide Emergency Department Sample (NEDS) to study the incidence of ED visits and subsequent hospitalizations with COPD as the primary diagnosis. We used the 2012 NEDS data to study key patient/hospital factors associated with outcomes, including charges, hospitalization and dischage from hospital to home. RESULTS: ED visits for COPD as the primary diagnosis increased from 1.02 million in 2009 to 1.04 in 2010 to 1.10 million in 2012 (0.79-0.82 % of all ED visits); respective charges were $2.13, $2.32, and $3.09 billion. In 2012, mean ED charges/visit were $2,812, hospitalization charges/visit were $29,043 and the length of hospital stay was 4.3 days. 49 % were hospitalized after an ED visit. Older age, higher median income, metropolitan residence and comorbidities (diabetes, hypertension, HF, hyperlipidemia, CHD, renal failure and osteoarthritis) were associated with higher risk whereas male sex, Medicaid or self pay insurance status, hospital location in Midwest, South or West U.S. were associated with lower risk of hospitalization. 65.4 % of all patients hospitalized for COPD from ED were discharged home. Older age, comorbidities (diabetes, HF, CHD, renal failure, osteoarthritis) and metropolitan residence were associated with lower odds of discharge to home, whereas male sex, payer other than Medicare, Midwest, South or West U.S. hospital location were associated with higher odds. CONCLUSION: Health care utilization and costs in patients with COPD are significant and increasing. COPD constitutes a major public health burden in the U.S. We identified risk factors for hospitalization, costs, and home discharge in patients with COPD that will allow future studies to investigate interventions to potentially reduce COPD-associated utilization. PMID- 26739478 TI - Tympanoplasty--conchal cavum approach. AB - The three well recognized tympanoplasty approaches: permeatal, postaural, and endaural, each have advantages and disadvantages. The permeatal approach is suitable only for ears with adequate canal size. The postaural approach limits visualization of the posterior eardrum margin. The endaural approach limits the view of the eardrum's anterior margin. This study describes a modified endaural approach, developed to overcome these limitations. A retrospective case series review and collection of a prospective cohort of patient reported outcome data were undertaken to assess the technique. METHOD: Standard incisions as used in an endaural approach are placed within the ear canal. The novel incision extends from the superior canal incision into the conchal cavum. This allows a flap of the thick, hairbearing skin from both the bony and cartilaginous portions of the canal to be raised, and everted, to provide an excellent view of the entire drum. Perichondrium can be harvested for grafting from the conchal cavum. The clinical charts of all patients operated on by the first author using this technique from 2010-2012 were retrospectively reviewed. The size and position of the perforation, size of the canal, whether primary or revision surgery, graft take rate, hearing results and the occurrence of chondritis/perichondritis were recorded. To investigate the morbidities and the acceptance by the patients of the incision/scar in the conchal cavum, all patients undergoing the procedure in the 8 months up to the end of August 2013 were prospectively recruited to complete a self-assessment Likert scale questionnaire recording postoperative pain, and satisfaction with the cosmesis of the operative site. The clinician recorded if there was any evidence of chondritis/perichondritis. RESULTS: A 100% graft take rate was achieved in the 75 adults treated by the first author from 2010 to 2012 regardless of the size and position of the perforation, configuration of the canal, primary or revision surgery. Preoperative Pure Tone Audiometric (PTA) Air Bone Gap (ABG) averaged over 3 frequencies (0.5, 1 and 2 K Hz) was 19.4dB (standard deviation = 9.6, range 2 to 50). Postoperative PTA ABG average was 6.2 dB (standard deviation = 8.3, range -7 to 37), demonstrating a statistically significant post-surgery mean improvement of 13.2 dB (paired T test, p < 0.001). Twenty-one patients who underwent the procedure in 2013, reported minimal postoperative analgesic use, and scored the acceptability of the incision scar highly (4.8 out of a maximum of 5). There was no case of chondritis/perichondritis in the 96 cases. CONCLUSION: Whilst it is the surgeon's decision to use a permeatal, postaural or endaural approach, the endaural approach with the conchal cavum modification is an excellent alternative to the traditionally described approaches. TRIAL REGISTRATION: CLINICAL TRIAL NUMBER: NCT02000843 at ClinicalTrials.gov. PMID- 26739479 TI - A Case of Severe, Prolonged, Refractory Hypophosphatemia After Zoledronic Acid Administration. AB - Zoledronic acid (ZA) administration has been associated with electrolyte abnormalities, including hypocalcemia, hypomagnesemia, hypokalemia, and hypophosphatemia. We describe a case of severe, refractory hypophosphatemia in a patient who received ZA for hypercalcemia of malignancy (HCM). Little data are available that describe the incidence or degree of severity of hypophosphatemia that can occur following ZA administration. In addition, no formal recommendations exist to guide monitoring for or management of electrolyte derangements in the setting of bisphosphonate use. Our patient required daily, high-dose phosphorus replacement beginning day 4 following ZA administration. The average daily dose of phosphorus, including both intravenous and enteral administration, was highest in the first 2 weeks after ZA, averaging 77 mmol/d days 4 through 15, and does not include sources of phosphorus from the patient's nutrition support. Despite this high amount of supplementation, which was well beyond what meets normal daily requirements and the amount expected to treat "usual" hypophosphatemia, the patient did not achieve sustained normal serum phosphorus levels for over 30 days after ZA. ZA is a favorable option for treating HCM because of its longer duration of action, potent serum calcium lowering effects, and favorable safety profile. The risk of hypophosphatemia with ZA use is reviewed. PMID- 26739480 TI - Hypothermia Associated With Thioridazine Use in an Intellectually Disabled Patient. AB - PURPOSE: To report a case of hypothermia in a patient with intellectual disability treated with thioridazine. SUMMARY: A 59-year-old female presented to the emergency department with altered mental status, generalized weakness, chills, and fatigue and was diagnosed with a urinary tract infection. Upon completion of a history and physical examination, the patient was found to be hypothermic with a temperature of 91 F. A Bair Hugger protocol was initiated to manage hypothermia, and a taper schedule for thioridazine was initiated as it was identified as a possible culprit for the patient's hypothermia. According to the Naranjo probability scale, thioridazine was a possible cause of this adverse effect. Other patient-specific risk factors for hypothermia were evaluated and ruled out. CONCLUSION: This case indicates a possible correlation between hypothermia and the use of phenothiazine antipsychotics such as thioridazine. Appropriate measures, including early detection and identification of possible causative agents, should be taken to prevent and treat this adverse event in patients taking these medications, specifically in patients with the inability to participate in self-care. PMID- 26739481 TI - Mechanisms for the Specific Properties of gamma-Hydroxybutyrate in Brain. AB - gamma-Hydroxybutyrate (GHB) is both a natural brain compound with neuromodulatory properties at central GABAergic synapses (micromolar concentration range) and also a drug (Xyrem(R) ) clinically used for the treatment of various neurological symptoms (millimolar dose range). However, this drug has abuse potential and can be addictive for some patients. Here, we review the basic mechanistic role of endogenous GHB in brain as well as the properties and mechanisms of action for therapeutic clinical doses of exogenous GHB. Several hypotheses are discussed with a preference for a molecular mechanism that conciliates most of the findings available. This conciliatory model may help for the design of GHB-like drugs active at lower doses and devoid of major side effects. PMID- 26739482 TI - Performance of an ICD algorithm to detect lead noise and reduce inappropriate shocks. AB - BACKGROUND: Implantable cardioverter-defibrillators (ICD) provide treatment for life-threatening ventricular tachyarrhythmias. Failure of the pace/sense conductor of an ICD lead can cause noise on the sensing electrogram (EGM) that may be misinterpreted as ventricular activity, triggering inappropriate therapy. An algorithm based upon the confirmation of ventricular activity from a far-field EGM has been developed to reduce inappropriate therapies resulting from this type of lead failure, while ensuring that appropriate therapy is delivered. The objectives of this study were to evaluate the algorithm's ability to discriminate lead noise from ventricular tachycardia/ventricular fibrillation (VT/VF) and to determine whether it inhibits inappropriate shocks without delaying appropriate shocks. METHODS: The algorithm was prospectively tested using near- and far-field EGM recordings from patients in three conditions: normal sinus rhythm with sustained and non-sustained lead noise via manipulation of the ICD pocket or lead system, and VT/VF induced during defibrillation threshold testing. The recordings were played through a bench-top device running the algorithm with the diagnosis, time to diagnosis, and inhibition of therapy documented. RESULTS: The algorithm detected noise and withheld inappropriate therapy in 231 of 238 recordings of sustained lead noise that would otherwise have been diagnosed as VT/VF (97.1%). Non-sustained lead noise was correctly diagnosed in 47 of the 52 recordings (90.4%). The device appropriately identified all 853 recordings of VT/VF (100%), without an increase in the time to detection (0.01 +/- 0.14 s). CONCLUSIONS: The SecureSense(TM) algorithm correctly diagnosed sustained and non-sustained lead noise recordings without compromising detection of VT/VF. Use of the algorithm may reduce inappropriate shocks and alert clinicians to lead noise indicative of lead failure. PMID- 26739483 TI - Cardioprotective effects of low-level carotid baroreceptor stimulation against myocardial ischemia-reperfusion injury in canine model. AB - PURPOSE: The modulation of the autonomic nervous system (ANS) has been shown to prevent myocardial ischemia-reperfusion injury (MIRI). Carotid baroreceptor stimulation modulates the ANS by sympathetic withdrawal and vagal activation. The aim of this study was to assess whether low-level carotid baroreceptor stimulation (LL-CBS) attenuated MIRI and test its underlying molecular mechanisms. METHODS: Forty adult healthy mongrel dogs were randomly assigned to three groups as follows: (1) I/R group (n = 15): left anterior descending artery (LAD) was occluded for 1 h and allowed for 1 h reperfusion; (2) LL-CBS group (n = 15): I/R plus LL-CBS; and (3) sham group (n = 10): sham surgery without stimulation. The voltage-reducing blood pressure by 5% was defined as the threshold. LL-CBS was performed at a voltage that is 80% below the threshold. Infarct size was assessed with Evans blue and TTC staining. The inflammatory cytokines, biomarker of oxidative stress and apoptosis, and connexin 43 (Cx43) expression were measured to assess the injury. RESULTS: The number of ventricular tachycardia/ventricular fibrillation (VT/VF) episodes was significantly decreased in the LL-CBS group compared with the I/R group (2.8 +/- 0.8 vs. 7.0 +/- 2.6, P < 0.05). LL-CBS reduced tumor necrosis factor alpha, interleukin (IL)-1, IL-6, and malondialdehyde levels but increased superoxide dismutase level compared with the I/R group (P < 0.05). Meanwhile, LL-CBS significantly decreased the percentage of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL)-positive cardiomyocytes (20 +/- 8 vs. 47 +/- 12, P < 0.05). Western blotting and real-time polymerase chain reaction (RT-PCR) in Cx43 revealed that LL-CBS caused an increase, respectively, compared with the I/R group (0.75 +/- 0.3 vs. 0.3 +/- 0.2 and 1.0 +/- 0.3 vs. 0.4 +/- 0.1, respectively, both P < 0.05). CONCLUSIONS: LL-CBS exerted cardioprotective effects during ischemic reperfusion period potentially by inhibiting inflammation, oxidative stress, and apoptosis and modulating the Cx43 expression. PMID- 26739484 TI - Immediate post-procedure bridging with unfractioned heparin versus low molecular weight heparin in patients undergoing radiofrequency ablation for atrial fibrillation with an interrupted oral anticoagulation strategy. AB - PURPOSE: Many centers perform catheter ablation for atrial fibrillation (AF) with periprocedural interruption of oral vitamin K antagonists. In this scenario, the optimal post-procedural anticoagulation strategy is still under debate. We sought to compare the incidence of major complications associated with post-procedural use of low molecular weight heparin (LMWH) versus unfractioned heparin (UFH) as a bridge to reinitiation of oral anticoagulation after an AF ablation procedure. METHODS: We retrospectively reviewed medical history data of all patients undergoing catheter ablation for AF at three Spanish referral centers between January 2009 and January 2014. A total of 702 patients were included in the analysis. We compared the incidence of major complications (a combination of major bleeding and thromboembolic events) between patients receiving UFH (291) and those receiving LMWH (411) after the procedure. RESULTS: The overall incidence of major complications was 4.1%, including five thromboembolic events (0.7%) and 24 major bleeding events (3.4%), with no significant differences in patients treated with LMWH vs. UFH (2.9 vs. 4.1%; P = NS). The presence of peripheral vascular disease emerged as the only independent predictor of major complications (adjusted odds ratio (OR) 9.1; confidence interval (CI) 95% 1.7 49.3; P < 0.01). CONCLUSIONS: Immediate post-procedural bridging with UFH or with LMWH are equally safe strategies in patients undergoing catheter ablation for AF in whom oral anticoagulation is interrupted for the procedure. Due to its greater simplicity of use, LMWH may be the preferred option. The presence of peripheral vascular disease is a potent predictor of major post-procedural complications. PMID- 26739485 TI - Catheter ablation of ventricular arrhythmias arising from the basal septum of the right ventricle: characteristics and significance of junctional rhythm appearing during ablation. AB - BACKGROUND: Most right ventricular arrhythmias (VA) originate from the outflow tract. Experiences of VA arising from the basal septum of the right ventricle (RV) are limited. We aimed to describe the ablation procedure and results, focusing on the characteristics and clinical significance of junctional rhythm (JR) appearing during radiofrequency application. METHODS AND RESULTS: Among 86 consecutive patients undergoing radiofrequency ablation for VA from the RV, 12 (14%) (mean age, 71 +/- 7 years) had their origin in the basal septum of the RV defined as the region from 1 to 5 o'clock of the tricuspid annulus (TA) in the left anterior oblique view and extending anteriorly from the TA to 2 cm. A mean QRS duration of VA was 137 +/- 8 msec with normal (10/12, 83%) or left-deviated axis (2/12, 17%). Five patients (41%) had structural heart diseases including three dilated cardiomyopathies. Radiofrequency energy was applied to the sites showing the earliest activation during VA and/or best pacemap. Complete elimination of VA was achieved in 11 (92%) patients. The successful ablation site was 12 +/- 4 mm away from the His-bundle electrogram recording site. Among 11 patients with successful ablation, 10 (91 %) exhibited JR (mean cycle length, 638 +/- 172 ms) during ablation without subsequent atrioventricular conduction disturbance (AVCD) except for one showing high-rate JR (181 beats/min) and transient AVCD. All these patients were free from VA during 32 +/- 21 months. CONCLUSIONS: VA originating from the basal septum of the RV can be ablated effectively. JR appears in most cases without causing AVCD, unless the rate is high. PMID- 26739486 TI - Interrogation of individual intratumoral B lymphocytes from lung cancer patients for molecular target discovery. AB - Intratumoral B lymphocytes are an integral part of the lung tumor microenvironment. Interrogation of the antibodies they express may improve our understanding of the host response to cancer and could be useful in elucidating novel molecular targets. We used two strategies to explore the repertoire of intratumoral B cell antibodies. First, we cloned VH and VL genes from single intratumoral B lymphocytes isolated from one lung tumor, expressed the genes as recombinant mAbs, and used the mAbs to identify the cognate tumor antigens. The Igs derived from intratumoral B cells demonstrated class switching, with a mean VH mutation frequency of 4%. Although there was no evidence for clonal expansion, these data are consistent with antigen-driven somatic hypermutation. Individual recombinant antibodies were polyreactive, although one clone demonstrated preferential immunoreactivity with tropomyosin 4 (TPM4). We found that higher levels of TPM4 antibodies were more common in cancer patients, but measurement of TPM4 antibody levels was not a sensitive test for detecting cancer. Second, in an effort to focus our recombinant antibody expression efforts on those B cells that displayed evidence of clonal expansion driven by antigen stimulation, we performed deep sequencing of the Ig genes of B cells collected from seven different tumors. Deep sequencing demonstrated somatic hypermutation but no dominant clones. These strategies may be useful for the study of B cell antibody expression, although identification of a dominant clone and unique therapeutic targets may require extensive investigation. PMID- 26739487 TI - EGF-modified mPEG-PLGA-PLL nanoparticle for delivering doxorubicin combined with Bcl-2 siRNA as a potential treatment strategy for lung cancer. AB - CONTEXT: Nanoparticles (NPs) have been widely used as carriers to deliver siRNA and chemotherapeutic agents. Bcl-2 siRNA has been widely used to induce cancer cell apoptosis, and doxorubicin (Dox) can destroy cancer cells by binding with cancer cell DNA. OBJECTIVE: To investigate the therapeutic effect on lung cancer of simultaneously delivering Dox and Bcl-2-siRNA using epidermal growth factor (EGF) modified monomethoxy (polyethylene glycol)-poly (D, L-lactide-co-glycolide) poly(L-lysine) (mPEG-PLGA-PLL, PEAL) NPs (EGF-PEAL). METHODS: EGF-PEAL NPs were characterized with respect to size, zeta potential and morphology. Cytotoxicity and drug (or siRNA) loading capacity of EGF-PEAL NPs were analyzed. Cellular uptake, drug release profile, cell killing effects of Dox and Bcl-2-siRNA-loaded EGF-PEAL NPs were assessed. Biodistribution and therapeutic effects of Dox and Bcl-2-siRNA EGF-PEAL NPs were evaluated in H1299 tumor-bearing mice. RESULTS AND DISCUSSION: EGF-PEAL NPs or PEAL NPs had nearly negligible cytotoxicity toward H1299 cells. Dox and Bcl-2-siRNA gradually released from EGF-PEAL NPs and exhibited sustained release patterns. Dox and Bcl-2-siRNA-loaded NPs were taken up by cells and induced the apoptosis of H1299 cells more effectively than using Dox or Bcl-2 siRNA alone. With the intravenous injection of PEAL NPs into H1299 xenografted mice, we found that combination treatment suppressed lung cancer growth and reduced Bcl-2 expression in tumor tissue, and EGF-PEAL NPs concentrated in lung tumor much more than non-targeted PEAL NPs. CONCLUSION: We conclude that co-delivery of Dox and Bcl-2-siRNA by tumor-targeted EGF-PEAL NPs could significantly inhibit lung cancer growth. PMID- 26739488 TI - Altered expression of uncoupling protein 2 in GLP-1-producing cells after chronic high glucose exposure: implications for the pathogenesis of diabetes mellitus. AB - Glucagon-like peptide-1 (GLP-1) is a gut L-cell hormone that enhances glucose stimulated insulin secretion. Several approaches that prevent GLP-1 degradation or activate the GLP-1 receptor are being used to treat type 2 diabetes mellitus (T2DM) patients. In T2DM, GLP-1 secretion has been suggested to be impaired, and this defect appears to be a consequence rather than a cause of impaired glucose homeostasis. However, although defective GLP-1 secretion has been correlated with insulin resistance, little is known about the direct effects of chronic high glucose concentrations, which are typical in diabetes patients, on GLP-1 secreting cell function. In the present study, we demonstrate that glucotoxicity directly affects GLP-1 secretion in GLUTag cells chronically exposed to high glucose. Our results indicate that this abnormality is associated with a decrease in ATP production due to the elevated expression of mitochondrial uncoupling protein 2 (UCP2). Furthermore, UCP2 inhibition using small interfering RNA (siRNA) and the application of glibenclamide, an ATP-sensitive potassium (KATP(+)) channel blocker, reverse the GLP-1 secretion defect induced by chronic high-glucose treatment. These results show that glucotoxicity diminishes the secretory responsiveness of GLP-1-secreting cells to acute glucose stimulation. We conclude that the loss of the incretin effect, as observed in T2DM patients, could at least partially depend on hyperglycemia, which is typical in diabetes patients. Such an understanding may not only provide new insight into diabetes complications but also ultimately contribute to the identification of novel molecular targets within intestinal L-cells for controlling and improving endogenous GLP-1 secretion. PMID- 26739489 TI - Endothelial mitochondria regulate the intracellular Ca2+ response to fluid shear stress. AB - Shear stress is known to stimulate an intracellular free calcium concentration ([Ca(2+)]i) response in vascular endothelial cells (ECs). [Ca(2+)]i is a key second messenger for signaling that leads to vasodilation and EC survival. Although it is accepted that the shear-induced [Ca(2+)]i response is, in part, due to Ca(2+) release from the endoplasmic reticulum (ER), the role of mitochondria (second largest Ca(2+) store) is unknown. We hypothesized that the mitochondria play a role in regulating [Ca(2+)]i in sheared ECs. Cultured ECs, loaded with a Ca(2+)-sensitive fluorophore, were exposed to physiological levels of shear stress. Shear stress elicited [Ca(2+)]i transients in a percentage of cells with a fraction of them displaying oscillations. Peak magnitudes, percentage of oscillating ECs, and oscillation frequencies depended on the shear level. [Ca(2+)]i transients/oscillations were present when experiments were conducted in Ca(2+)-free solution (plus lanthanum) but absent when ECs were treated with a phospholipase C inhibitor, suggesting that the ER inositol 1,4,5 trisphosphate receptor is responsible for the [Ca(2+)]i response. Either a mitochondrial uncoupler or an electron transport chain inhibitor, but not a mitochondrial ATP synthase inhibitor, prevented the occurrence of transients and especially inhibited the oscillations. Knockdown of the mitochondrial Ca(2+) uniporter also inhibited the shear-induced [Ca(2+)]i transients/oscillations compared with controls. Hence, EC mitochondria, through Ca(2+) uptake/release, regulate the temporal profile of shear-induced ER Ca(2+) release. [Ca(2+)]i oscillation frequencies detected were within the range for activation of mechanoresponsive kinases and transcription factors, suggesting that dysfunctional EC mitochondria may contribute to cardiovascular disease by deregulating the shear-induced [Ca(2+)]i response. PMID- 26739491 TI - Role of protein phosphatases in the run down of guinea pig cardiac Cav1.2 Ca2+ channels. AB - This study aimed to investigate protein phosphatases involved in the run down of Cav1.2 Ca(2+) channels. Single ventricular myocytes obtained from adult guinea pig hearts were used to record Ca(2+) channel currents with the patch-clamp technique. Calmodulin (CaM) and ATP were used to restore channel activity in inside-out patches. Inhibitors of protein phosphatases were applied to investigate the role of phosphatases. The specific protein phosphatase type 1 (PP1) inhibitor (PP1 inhibitor-2) and protein phosphatase type 2A (PP2A) inhibitor (fostriecin) abolished the slow run down of Cav1.2 Ca(2+) channels, which was evident as the time-dependent attenuation of the reversing effect of CaM/ATP on the run down. However, protein phosphatase type 2B (PP2B, calcineurin) inhibitor cyclosporine A together with cyclophilin A had no effect on the channel run down. Furthermore, PP1 inhibitor-2 mainly prolonged the open time constants of the channel, specifically, the slow open time. Fostriecin primarily shortened the slow close time constants. Our data suggest that PP1 and PP2A were involved in the slow phase of Cav1.2 Ca(2+) channel run down. In addition, they exerted different effects on the open-close kinetics of the channel. All above support the view that PP1 and PP2A may dephosphorylate distinct phosphorylation sites on the Cav1.2 Ca(2+) channel. PMID- 26739490 TI - Exendin-4 induces myocardial protection through MKK3 and Akt-1 in infarcted hearts. AB - We have demonstrated that glucagon like peptide-1 (GLP-1) protects the heart against ischemic injury. However, the physiological mechanism by which GLP-1 receptor (GLP-1R) initiates cardioprotection remains to be determined. The objective of this study is to elucidate the functional roles of MAPK kinase 3 (MKK3) and Akt-1 in mediating exendin-4-elicited protection in the infarcted hearts. Adult mouse myocardial infarction (MI) was created by ligation of the left descending artery. Wild-type, MKK3(-/-), Akt-1(-/-), and Akt-1(-/-);MKK3(-/ ) mice were divided into one of several groups: 1) sham: animals underwent thoracotomy without ligation; 2) MI: animals underwent MI and received a daily dose of intraperitoneal injection of vehicle (saline); 3) MI + exendin-4: infarcted mice received daily injections of exendin-4, a GLP-1R agonist (0.1 mg/kg, ip). Echocardiographic measurements indicate that exendin-4 treatment resulted in the preservation of ventricular function and increases in the survival rate, but these effects were diminished in MKK3(-/-), Akt-1(-/-), and Akt-1(-/-);MKK3(-/-) mice. Exendin-4 treatments suppressed cardiac hypotrophy and reduced scar size and cardiac interstitial fibrosis, respectively, but these beneficial effects were lost in genetic elimination of MKK3, Akt-1, or Akt-1(-/ );MKK3(-/-) mice. GLP-1R stimulation stimulated angiogenic responses, which were also mitigated by deletion of MKK3 and Akt-1. Exendin-4 treatment increased phosphorylation of MKK3, p38, and Akt-1 at Ser129 but decreased levels of active caspase-3 and cleaved poly (ADP-ribose) polymerase; these proteins were diminished in MKK3(-/-), Akt-1(-/-), and Akt-1(-/-);MKK3(-/-) mice. These results reveal that exendin-4 treatment improves cardiac function, attenuates cardiac remodeling, and promotes angiogenesis in the infarcted myocardium through MKK3 and Akt-1 pathway. PMID- 26739492 TI - Intermittent hypoxia induces NF-kappaB-dependent endothelial activation via adipocyte-derived mediators. AB - Aberrant release of adipocytokines from adipose tissues dysregulates cardiometabolic functions. The present study hypothesizes that chronic intermittent hypoxia (IH) present in obstructive sleep apnea leads to adipose tissue dysfunction, which in turn contributes to vascular pathogenesis. The effect of IH was evaluated in adipose depots and aortic tissues in lean rats in vivo. Furthermore, the cellular and molecular mechanisms underlying pathophysiological interactions between adipocytes and endothelial cells were investigated in vitro. The in vivo results showed that IH induced upregulation of IL-6 and monocyte chemoattractant protein-1 (MCP-1) in subcutaneous and periaortic adipose tissues and downregulated phosphorylation of endothelial nitric oxide synthase [eNOS (ser1177)] in the aorta with activation of Erk and p38 MAPK. In support, cultured adipocytes demonstrated IH-induced elevations of NADPH oxidase 4, phosphorylation of Erk, NF-kappaBp65, and inducible NOS (iNOS) and increased expression of IL-6 and MCP-1. Likewise, endothelial EA.hy926 (EA) cells exposed to IH showed eNOS (ser1177) and intracellular cGMP reduction, whereas MCP-1 and iNOS expression were upregulated. Treatment of EA cells with conditioned media derived from IH-exposed cultured adipocytes caused nuclear translocation of NF-kappaBp65 and elevation of MCP-1, which were prevented by addition of neutralizing IL-6 antibodies to the conditioned media. Recombinant IL 6 in addition to IH induced further MCP-1 release and iNOS protein expression in EA cells, which were prevented by pharmacological inhibition of Erk, p38, and NF kappaB. These findings suggest that IH could induce adipose tissue inflammation, which may cross talk with endothelial cells via adipocyte-derived mediators such as IL-6, and promote NF-kappaB-dependent endothelial dysfunction. PMID- 26739493 TI - Hydrophobic motif site-phosphorylated protein kinase CbetaII between mTORC2 and Akt regulates high glucose-induced mesangial cell hypertrophy. AB - PKCbetaII controls the pathologic features of diabetic nephropathy, including glomerular mesangial cell hypertrophy. PKCbetaII contains the COOH-terminal hydrophobic motif site Ser-660. Whether this hydrophobic motif phosphorylation contributes to high glucose-induced mesangial cell hypertrophy has not been determined. Here we show that, in mesangial cells, high glucose increased phosphorylation of PKCbetaII at Ser-660 in a phosphatidylinositol 3-kinase (PI3 kinase)-dependent manner. Using siRNAs to downregulate PKCbetaII, dominant negative PKCbetaII, and PKCbetaII hydrophobic motif phosphorylation-deficient mutant, we found that PKCbetaII regulates activation of mechanistic target of rapamycin complex 1 (mTORC1) and mesangial cell hypertrophy by high glucose. PKCbetaII via its phosphorylation at Ser-660 regulated phosphorylation of Akt at both catalytic loop and hydrophobic motif sites, resulting in phosphorylation and inactivation of its substrate PRAS40. Specific inhibition of mTORC2 increased mTORC1 activity and induced mesangial cell hypertrophy. In contrast, inhibition of mTORC2 decreased the phosphorylation of PKCbetaII and Akt, leading to inhibition of PRAS40 phosphorylation and mTORC1 activity and prevented mesangial cell hypertrophy in response to high glucose; expression of constitutively active Akt or mTORC1 restored mesangial cell hypertrophy. Moreover, constitutively active PKCbetaII reversed the inhibition of high glucose-stimulated Akt phosphorylation and mesangial cell hypertrophy induced by suppression of mTORC2. Finally, using renal cortexes from type 1 diabetic mice, we found that increased phosphorylation of PKCbetaII at Ser-660 was associated with enhanced Akt phosphorylation and mTORC1 activation. Collectively, our findings identify a signaling route connecting PI3-kinase to mTORC2 to phosphorylate PKCbetaII at the hydrophobic motif site necessary for Akt phosphorylation and mTORC1 activation, leading to mesangial cell hypertrophy. PMID- 26739494 TI - Positive cross talk between protein kinase D and beta-catenin in intestinal epithelial cells: impact on beta-catenin nuclear localization and phosphorylation at Ser552. AB - Given the fundamental role of beta-catenin signaling in intestinal epithelial cell proliferation and the growth-promoting function of protein kinase D1 (PKD1) in these cells, we hypothesized that PKDs mediate cross talk with beta-catenin signaling. The results presented here provide several lines of evidence supporting this hypothesis. We found that stimulation of intestinal epithelial IEC-18 cells with the G protein-coupled receptor (GPCR) agonist angiotensin II (ANG II), a potent inducer of PKD activation, promoted endogenous beta-catenin nuclear localization in a time-dependent manner. A significant increase was evident within 1 h of ANG II stimulation (P< 0.01), peaked at 4 h (P< 0.001), and declined afterwards. GPCR stimulation also induced a marked increase in beta catenin-regulated genes and phosphorylation at Ser(552) in intestinal epithelial cells. Exposure to preferential inhibitors of the PKD family (CRT006610 or kb NB 142-70) or knockdown of the isoforms of the PKD family prevented the increase in beta-catenin nuclear localization and phosphorylation at Ser(552) in response to ANG II. GPCR stimulation also induced the formation of a complex between PKD1 and beta-catenin, as shown by coimmunoprecipitation that depended on PKD1 catalytic activation, as it was abrogated by cell treatment with PKD family inhibitors. Using transgenic mice that express elevated PKD1 protein in the intestinal epithelium, we detected a marked increase in the localization of beta-catenin in the nucleus of crypt epithelial cells in the ileum of PKD1 transgenic mice, compared with nontransgenic littermates. Collectively, our results identify a novel cross talk between PKD and beta-catenin in intestinal epithelial cells, both in vitro and in vivo. PMID- 26739496 TI - Cold atmospheric plasma inhibits the growth of Candida albicans by affecting ergosterol biosynthesis and suppresses the fungal virulence factors in vitro. AB - BACKGROUND: The pathogenic yeast Candida albicans is the most common opportunistic fungal pathogen that is responsible for a wide array of infections in susceptible individuals. Despite recent progress in developing novel antifungal drugs which combat Candida-related disorders, this fungus is still a major cause of life-threatening infections all over the world. In the present study, the effect of cold atmospheric plasma (CAP) was evaluated on the growth of C. albicans with special attention to the ability of the CAP-treated fungus for biofilm formation, ergosterol biosynthesis and phospholipase and proteinase secretory production. METHODS: C. albicans cell suspensions were irradiated over time-scales ranging of 90, 120, 150 and 180s under cold atmospheric plasma contained He/O2 (2%). Treated and untreated yeast cells were analyzed for the growth, biofilm formation, ergosterol content, and activities of phospholipase and proteinase. RESULTS: Our results showed that CAP remarkably suppressed the growth of C. albicans by 31-82% at the given times. Likewise, CAP strongly inhibited the ergosterol biosynthesis by the fungus in the range of 40-91%, biofilm formation by 43-57% and the activities of phospholipase and proteinase enzymes by 4-45%, dose-dependently. CONCLUSION: CAP strongly inhibits the growth and virulence factors of C. albicans and thus, it could be a potential candidate to treat Candida-related superficial and cutaneous infections in practice. PMID- 26739497 TI - Ice-sheet-driven methane storage and release in the Arctic. AB - It is established that late-twentieth and twenty-first century ocean warming has forced dissociation of gas hydrates with concomitant seabed methane release. However, recent dating of methane expulsion sites suggests that gas release has been ongoing over many millennia. Here we synthesize observations of ~1,900 fluid escape features--pockmarks and active gas flares--across a previously glaciated Arctic margin with ice-sheet thermomechanical and gas hydrate stability zone modelling. Our results indicate that even under conservative estimates of ice thickness with temperate subglacial conditions, a 500-m thick gas hydrate stability zone--which could serve as a methane sink--existed beneath the ice sheet. Moreover, we reveal that in water depths 150-520 m methane release also persisted through a 20-km-wide window between the subsea and subglacial gas hydrate stability zone. This window expanded in response to post-glacial climate warming and deglaciation thereby opening the Arctic shelf for methane release. PMID- 26739495 TI - Orai1 and STIM1 in ER/PM junctions: roles in pancreatic cell function and dysfunction. AB - Membrane contact sites (MCS) are critical junctions that form between the endoplasmic reticulum (ER) and membranes of various organelles, including the plasma membrane (PM). Signaling complexes, including mediators of Ca(2+) signaling, are assembled within MCS, such as the ER/PM junction. This is most evident in polarized epithelial cells, such as pancreatic cells. Core Ca(2+) signaling proteins cluster at the apical pole, the site of inositol 1,4,5 trisphosphate-mediated Ca(2+) release and Orai1/transient receptor potential canonical-mediated store-dependent Ca(2+) entry. Recent advances have characterized the proteins that tether the membranes at MCS and the role of these proteins in modulating physiological and pathological intracellular signaling. This review discusses recent advances in the characterization of Ca(2+) signaling at ER/PM junctions and the relation of these junctions to physiological and pathological Ca(2+) signaling in pancreatic acini. PMID- 26739498 TI - Investigation of sodium insertion into tetracyanoquinodimethane (TCNQ): results for a TCNQ thin film obtained by a surface science approach. AB - In this contribution, we investigate the insertion of sodium into tetracyanoquinodimethane (TCNQ) and its effect on the electronic structure by means of a surface science experiment. We exposed a TCNQ thin film stepwise to sodium vapour and monitored the electronic structure by X-ray photoelectron spectroscopy (XPS) and ultra-violet photoelectron spectroscopy (UPS). During the insertion experiment three stages were observed, which can be related to three different phases, predominantly consisting of TCNQ(0), TCNQ(1-) and TCNQ(2-). With increasing sodium content the Fermi level shifts upwards and new electronic states appear in the band gap. For phases with high sodium content the sodium diffusion seems to be inhibited which we attribute to closed diffusion pathways in the molecular structure of TCNQ(1-). PMID- 26739499 TI - Acute gastric obstruction following cardiopulmonary bypass in a patient with an adjustable gastric band. PMID- 26739500 TI - Morphological changes in the spiracles of Anopheles gambiae s.l (Diptera) as a response to the dry season conditions in Burkina Faso (West Africa). AB - BACKGROUND: Survival to dry season conditions of sub-Saharan savannahs is a major challenge for insects inhabiting such environments, especially regarding the desiccation threat they are exposed to. While extensive literature about insect seasonality has revealed morphologic, metabolic and physiological changes in many species, only a few studies have explored the responses following exposure to the stressful dry season conditions in major malaria vectors. Here, we explored morphological changes triggered by exposure to dry season conditions in An. gambiae s.l. mosquitoes by comparing females reared in climatic chambers reflecting environmental conditions found in mosquito habitats during the rainy and dry seasons in a savannah area of Burkina Faso (West Africa). RESULTS: Using scanning electron microscopy (SEM) and confocal imaging, we revealed significant changes in morphological features of the spiracles in females An. gambiae s.l. exposed to contrasted environmental conditions. Hence, the hairs surrounding the spiracles were thicker in the three species when raised under dry season environmental conditions. The thicker hairs were in some cases totally obstructing spiracular openings. Specific staining provided evidence against contamination by external microorganisms such as bacteria and fungi. However, only further analysis would unequivocally rule out the hypothesis of experimental artifact. CONCLUSION: Morphological changes in spiracular features probably help to limit body water loss during desiccating conditions, therefore contributing to insect survival. Differences between species within the An. gambiae complex might therefore reflect different survival strategies used by these species to overcome the detrimental dry season conditions in the wild. PMID- 26739502 TI - MicroRNAs in Honey Bee Caste Determination. AB - The cellular mechanisms employed by some organisms to produce contrasting morphological and reproductive phenotypes from the same genome remains one of the key unresolved issues in biology. Honeybees (Apis mellifera) use differential feeding and a haplodiploid sex determination system to generate three distinct organismal outcomes from the same genome. Here we investigate the honeybee female and male caste-specific microRNA and transcriptomic molecular signatures during a critical time of larval development. Both previously undetected and novel miRNAs have been discovered, expanding the inventory of these genomic regulators in invertebrates. We show significant differences in the microRNA and transcriptional profiles of diploid females relative to haploid drone males as well as between reproductively distinct females (queens and workers). Queens and drones show gene enrichment in physio-metabolic pathways, whereas workers show enrichment in processes associated with neuronal development, cell signalling and caste biased structural differences. Interestingly, predicted miRNA targets are primarily associated with non-physio-metabolic genes, especially neuronal targets, suggesting a mechanistic disjunction from DNA methylation that regulates physio-metabolic processes. Accordingly, miRNA targets are under-represented in methylated genes. Our data show how a common set of genetic elements are differentially harnessed by an organism, which may provide the remarkable level of developmental flexibility required. PMID- 26739503 TI - The effects of thoracic load carriage on maximal ambulatory work tolerance and acceptable work durations. AB - PURPOSE: Torso loads restrict chest-wall movement and ventilation, particularly during heavy exercise. Therefore, the differential impact of load carriage and chest-wall restriction was investigated during progressive treadmill exercise. In addition, acceptable work durations were derived across a wide range of submaximal, loaded exercise intensities. METHODS: Twelve males participated in two research phases. Phase 1: Three incremental treadmill tests until exhaustion [control (clothing only), load carriage (clothing plus 22-kg vest), and clothing with chest strapping]. Phase 2: Five steady-state exercise trials (clothing plus 22-kg vest) at intensities from 30 to 80 % of peak aerobic power to determine maximal acceptable work durations. RESULTS: Maximal work tolerance [control 17.21 min (+/-0.93); loaded 13.44 min (+/-0.68); strapped 17.00 min (+/-0.83)] and the mass-specific peak aerobic power [control 61.61 mL kg(-1) min(-1) (+/-2.28); loaded 45.42 mL kg(-1) min(-1) (+/-1.41); strapped 59.99 mL kg(-1) min(-1) (+/ 1.61)] were reduced only when loaded (P < 0.05). Peak minute ventilation was retained, although loading and chest strapping reduced the breathing reserve. The lower and upper acceptable work duration derivations when working at the 30 % intensity were 133.40 min (+/-23.77) and 220.10 min (+/-48.69), but at 80 % intensity, both durations were reduced to <7 min. CONCLUSION: Thoracic loading significantly reduced exercise tolerance and the breathing reserve, but did not modify peak minute ventilation or the absolute peak aerobic power. Chest strapping, as used herein, exerted minimal impact. However, the projected maximal acceptable work durations were much less than derived using previously published methods. PMID- 26739504 TI - Acoustic dispersive prism. AB - The optical dispersive prism is a well-studied element, which allows separating white light into its constituent spectral colors, and stands in nature as water droplets. In analogy to this definition, the acoustic dispersive prism should be an acoustic device with capability of splitting a broadband acoustic wave into its constituent Fourier components. However, due to the acoustical nature of materials as well as the design and fabrication difficulties, there is neither any natural acoustic counterpart of the optical prism, nor any artificial design reported so far exhibiting an equivalent acoustic behaviour. Here, based on exotic properties of the acoustic transmission-line metamaterials and exploiting unique physical behaviour of acoustic leaky-wave radiation, we report the first acoustic dispersive prism, effective within the audible frequency range 800 Hz 1300 Hz. The dispersive nature, and consequently the frequency-dependent refractive index of the metamaterial are exploited to split the sound waves towards different and frequency-dependent directions. Meanwhile, the leaky-wave nature of the structure facilitates the sound wave radiation into the ambient medium. PMID- 26739506 TI - Adipose triglyceride lipase (Atgl) mediates the antibiotic jinggangmycin stimulated reproduction in the brown planthopper, Nilaparvata lugens Stal. AB - The antibiotic jinggangmycin (JGM) is an agrochemical product widely used in China for controlling rice sheath blight, Rhizoctonia solani. Unexpectedly, it stimulates reproduction in the brown planthopper (BPH), Nilaparvata lugens (Stal). However, the underlying molecular mechanisms of the stimulation are unclear. The present investigation demonstrates that adipose triglyceride lipase (Atgl) is one of the enzymes involved in the JGM-stimulated reproduction in BPH. Silence of Atgl in JGM-treated (JGM + dsAtgl) females eliminated JGM-stimulated fecundity of BPH females. In addition, Atgl knockdown significantly reduced the protein and glycerin contents in the ovaries and fat bodies of JGM + dsAtgl females required for reproduction. We conclude that Atgl is one of the key enzymes responsible for JGM-stimulated reproduction in BPH. PMID- 26739511 TI - Elderly male smokers with right lung tumors are viable candidates for KRAS mutation screening. AB - Genetic aberrations in tumor driver genes provide specific molecular targets for therapeutic intervention, which can greatly improve therapeutic outcomes. Here, we analyzed the mutational frequency of EGFR and KRAS gene, as well as EML4-ALK rearrangement, and summarized the clinicopathological characters of Chinese lung cancer patients. We detected the mutation spectrum of 1033 primary lung cancer patients. The analyzed clinicopathological parameters included gender, age at diagnosis, smoking status, pathological TNM stage, tumor morphology and location, visceral pleural invasion, and histological type. A total of 618 patients had mutations in EGFR or KRAS gene as well as rearrangement of EML4-ALK. Exon 19 deletions and L858R in the EGFR gene were the most frequent mutations. Left-side lung cancer was more common in female patients carrying the KRAS mutation. Rearrangement of EML4-ALK was more common in non-tobacco-using male patients, who also exhibited a higher likelihood of visceral pleura invasion. Elderly females who never smoked and possessed 1-20 mm stage I adenocarcinomas in the right side exhibited a higher frequency of EGFR mutations. Elderly male smokers with right lung tumors were viable candidates for KRAS mutation screening. PMID- 26739509 TI - Testosterone production by a Leydig tumor cell line is suppressed by hyperthermia induced endoplasmic reticulum stress in mice. AB - AIMS: Leydig cells are characterized by their ability to produce testosterone. When the Leydig cells are unable to produce enough testosterone, spermatogenesis fails completely. Considering this, it is of great interest to investigate whether the expressions of steroidogenic enzymes are affected by testicular heat stress. This study aimed to demonstrate that heat induced ER-stress significantly influences steroidogenic enzyme expression and testosterone production in the Leydig cells. MAIN METHODS: C57BL/6 mice were subjected to repetitive testicular heat-treatment at 42 degrees C for 15 min per day, and heat-treated mLTC-1 cells following hCG treatment for 1h. The protein and RNA expressions were measured by Western blot, RT-PCR. The testosterone and progesterone levels were detected by EIA. The histological and pathological characteristics using hematoxylin and eosin (H&E) and antibody stains. KEY FINDINGS: The 3beta-HSD expression was decreased by heat-stress and hCG treatment. While the GRP78/BiP and CHOP levels were increased by ER-stress inducers, those of the steroidogenic enzyme and progesterone were decreased. In contrast, an ER-stress inhibitor rescued the testosterone levels, even under heat-stress conditions. Moreover, the Leydig cells were randomly scattered, and severely damaged upon repetitive testicular heat-treatment. Additionally, immunohistochemical analyses revealed that cleaved caspase-3 was elevated in the testicular Leydig cells, and rescued by TUDCA. Thus, repetitive testicular heat-treatment in mice promotes excessive ER-stress, thereby leading to apoptosis of the Leydig cells and thus, decreased testosterone production. SIGNIFICANCE: Our findings help to provide an ER-stress mediate mechanistic explanation to the impairment of spermatogenesis upon elevation of the testicular temperature. PMID- 26739507 TI - Receptor tyrosine kinase gene expression profiles of Ewing sarcomas reveal ROR1 as a potential therapeutic target in metastatic disease. AB - Receptor tyrosine kinases (RTKs) have provided molecular targets for the development of novel, prognosis-improving agents in many cancers; however, resistances to these therapies occur. On the cellular level, one resistance mechanism is attributed to functional RTK redundancies and compensatory cross signaling, leading to perception of RTKs as signaling and target networks. To provide a basis for better exploitation of this network in Ewing sarcoma, we generated comprehensive qPCR gene expression profiles of RTKs in Ewing sarcoma cell lines and 21 untreated primary tumors. Key findings confirm broad-spectrum RTK expressions with potential for signaling redundancy. Profile analyses with regard to patient risk-group further revealed several individual RTKs of interest. Among them, VEGFR3 and TIE1 showed high-level expressions and also were suggestive of poor prognosis in localized tumors; underscoring the relevance of angiogenic signaling pathways and tumor-stroma interactions in Ewing sarcoma. Of note, compared to localized disease, tumors derived from metastatic disease were marked by global high-level RTK expressions. Nine individual RTKs were significantly over-expressed, suggesting contributions to molecular mechanisms of metastasis. Of these, ROR1 is being pursued as therapeutic target in leukemias and carcinomas, but un-characterized in sarcomas. We demonstrate expression of ROR1 and its putative ligand Wnt5a in Ewing sarcomas, and of an active ROR1 protein variant in cell lines. ROR1 silencing impaired cell migration in vitro. Therefore, ROR1 calls for further evaluation as a therapeutic target in metastatic Ewing sarcoma; and described as a pseudo-kinase with several isoforms, underlines these additional complexities arising in our understanding of RTK signaling networks. PMID- 26739512 TI - Construct validity and internal consistency of the neuropsychiatric inventory - nursing home (NPI-NH) in German nursing homes. AB - BACKGROUND: The Neuropsychiatric Inventory (NPI) is one of the most popular and frequently used instruments for assessing so-called challenging behavior in individuals with dementia in research practice. However, no information is available regarding the factor structure of the German version of the Neuropsychiatric Inventory - Nursing Home (NPI-NH). The aim of this study was to evaluate the factor structure (an aspect of construct validity) and internal consistency of the NPI-NH for two different stages of dementia severity in a large German nursing home population. METHODS: A total of 784 residents with dementia from 40 nursing homes in three studies was included in a secondary data analysis. Principal component analysis (PCA) using an orthogonal rotational procedure (with varimax rotation) was used to evaluate the factor structure of the NPI. Cronbach's alpha was used to assess the stability of the scale. RESULTS: The factors agitation & restless behavior, psychosis, and mood were identified (with factor loading > 0.4 explaining 50% of the variance). The factors showed a moderate internal consistency of 0.55 and 0.68 (Cronbach's alpha). CONCLUSIONS: The results show the acceptable factor structure of the NPI for a German population in nursing homes and confirm the results of studies from other countries. The three identified factors appear to be robust over the various stages of dementia severity. The results also support the hypothesis that the NPI NH can be subdivided into multiple domains. PMID- 26739513 TI - Coming of age in Roman Britain: Osteological evidence for pubertal timing. AB - OBJECTIVES: Puberty is a key transitional phase of the human life course, with important biological and social connotations. Novel methods for the identification of the pubertal growth spurt and menarche in skeletal remains have recently been proposed (Shapland and Lewis, 2013, 2014). In this study we applied the methods to two Romano-British cemetery samples (1st-early 5th centuries AD) in order to investigate the timing of puberty during this period and further assess the veracity of the methods. MATERIALS AND METHODS: Shapland and Lewis' methods (2013, 2014) were applied to 38 adolescents (aged 8-20 years) from the British cemetery sites of Roman London (1st-early 5th centuries AD) and Queenford Farm, Oxfordshire (4th-early 5th centuries AD). RESULTS: Overall, the Romano British males and females experienced the onset of puberty at similar ages to modern European adolescents, but subsequently experienced a longer period of pubertal development. Menarche occurred between the ages of 15 and 17 years for these Romano-British females, around 2 to 4 years later than for present-day European females. DISCUSSION: The observed Romano-British pattern of pubertal timing has various possible explanations, including exposure to environmental stressors in early urban environments. The pattern of pubertal timing is largely congruent with social age transitions alluded to in ancient texts and funerary evidence for this period. While there are limitations to the application of these techniques to archaeological samples, they were successfully applied in this study, and may have important implications for understandings of past life courses, as well as providing a long-term perspective on pubertal timing and biocultural interactions. PMID- 26739514 TI - Investigating attentional processes in depressive-like domestic horses (Equus caballus). AB - Some captive/domestic animals respond to confinement by becoming inactive and unresponsive to external stimuli. Human inactivity is one of the behavioural markers of clinical depression, a mental disorder diagnosed by the co-occurrence of symptoms including deficit in selective attention. Some riding horses display 'withdrawn' states of inactivity and low responsiveness to stimuli that resemble the reduced engagement with their environment of some depressed patients. We hypothesized that 'withdrawn' horses experience a depressive-like state and evaluated their level of attention by confronting them with auditory stimuli. Five novel auditory stimuli were broadcasted to 27 horses, including 12 'withdrawn' horses, for 5 days. The horses' reactions and durations of attention were recorded. Non-withdrawn horses reacted more and their attention lasted longer than that of withdrawn horses on the first day, but their durations of attention decreased over days, but those of withdrawn horses remained stable. These results suggest that the withdrawn horses' selective attention is altered, adding to already evidenced common features between this horses' state and human depression. PMID- 26739516 TI - Risk of gastrointestinal complications associated to NSAIDs, low-dose aspirin and their combinations: Results of a pharmacovigilance reporting system. AB - Gastrointestinal (GI) complications are one of the most limiting cause of use of NSAIDs. Beyond others well defined factors, history of peptic ulcer, older age, Helicobacter pylori infection and use of gastrotoxic drugs may affect their GI safety profile. In particular, the risk of GI complications associated to the use of antiplatelet drugs, especially low-dose acetylsalicylic acid (LDA) should deserve much attention. However, only few studies have focused on the effect of combination LDA/NSAIDs on the GI tract compared with the monotherapy and much less studies assessed this effect with multiple NSAIDs use. We aimed to characterize the GI safety profile of NSAIDs and LDA as monotherapy or their combinations in real-life conditions by analysing spontaneous adverse drug reactions (ADRs) reporting system in a Southern Italy. We used the case/non-case method in the Italian Pharmacovigilance Network (RNF). Cases were reports of GI events in the RNF between January 2007 and December 2011. Non-cases were all other reports during the same period. The association between NSAID and suspected GI ADRs was calculated using the reporting odds ratio (ROR) with 95% confidence intervals as a measure of disproportionality while adjusting for age, and concomitant use of antineoplastic agents or drugs for cardiovascular diseases. Sub-analysis were performed within the NSAID class. Among the 2816 adverse drug reactions recorded, we identified 374 (13.3%) cases of GI complications. Upper GI complications were the most frequently reported type of events. The highest associations were found for the combined use of NSAIDs and/or LDA, whilst the lowest associations were for their respective monotherapy. Looking at individual NSAIDs the highest association with GI events was observed for ketorolac exposure followed by nimesulide, diclofenac, aspirin, ketoprofen, and ibuprofen. This study highlights the primary role of the national spontaneous reporting system to bring out potential signals, such as the inappropriate drug use pattern, which however, have to be furtherly studied in-depth with ad hoc population-based studies. PMID- 26739518 TI - Clinicopathological characteristics of unicentric retroperitoneal Castleman's disease: a study of 14 cases. AB - BACKGROUND: The objectives of this study are to investigate the clinicopathological characteristics and prognosis analysis of unicentric retroperitoneal Castleman's disease (CD), and to improve the level of diagnosis and treatment of unicentric retroperitoneal CD. METHODS: The clinical data of 14 patients with unicentric retroperitoneal CD undergoing surgery from September 2007 to March 2014 were retrospectively reviewed. RESULTS: There were six males and eight females with a median age of 39 years old (range 15-58). Only three patients had a clinical manifestation of abdominal pain, and one patient associated with myasthenia gravis. All patients underwent surgical resection. The mean operation time was 137 min with a range of 72-472 min. The mean blood loss was 143 ml (range 50-500 ml). The CD was confirmed by histopathology. There were hyaline vascular (HV) type of CD in 13 cases, and mixed type of CD in one case. The mean hospital stay was 17.9 days with a mean postoperation hospital stay of 9.2 days. The duration of follow-up ranged from 21 to 99 months for 14 cases. All the 14 patients were alive without recurrence. CONCLUSIONS: Unicentric retroperitoneal CD is a rare disease that is often misdiagnosed due to the absence of specific clinical manifestations. The final diagnosis depends on pathologic examination. Complete surgical resection of the tumor is the best therapeutic alternative for unicentric CD. PMID- 26739520 TI - Newborn Screening for Sickle Cell Disease in Liberia: A Pilot Study. AB - BACKGROUND: In malaria-endemic countries in West Africa, sickle cell disease (SCD) contributes to childhood mortality. Historically, Liberia had regions wherein hemoglobin S and beta-thalassemia trait were mutually exclusive. Data on hemoglobinopathies in the Monrovia, the capital, are outdated and do not reflect urban migration. Updating the epidemiology of SCD is necessary to plan a public health and clinical agenda. Neither newborn screening (NBS) nor screening tools were available in country. This pilot study aimed to determine the feasibility of NBS using a South-South partnership and define the incidence of sickle cell trait (SCT) and SCD in Monrovia. PROCEDURE: This descriptive epidemiologic feasibility study collected dried blood spots from 2,785 consecutive newborns delivered at a hospital in Monrovia. Samples were analyzed by isoelectric focusing at a regional reference laboratory. Infants with SCD were referred for preventive care. RESULTS: SCT occurred in 10.31% of infants screened. SCD occurred in 33 infants screened [1.19% (95% confidence interval [CI]: 0.79-1.59%)] (FS: 28/33, FSB: 2/33, FSA: 2/33, FSX: 1/33). There were no infants with FSC phenotype observed. Nonsickling hemoglobin phenotypes "FC" and "F" were each present in three infants screened. Seventy-six percent of infants with SCD were brought to care, demonstrating the feasibility of our approach. CONCLUSIONS: The incidence of SCD and other hemoglobinopathies remains high in Liberia. Additional studies are needed to clarify sickle genotypes and identify the contribution of silent beta thalassemia alleles. By developing regional partnerships, countries similar to Liberia can acquire current data to inform NBS as an important public health initiative toward improving child health. PMID- 26739521 TI - Nerve growth factor and diarrhea-predominant irritable bowel syndrome (IBS-D): a potential therapeutic target? AB - Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by recurrent abdominal pain or discomfort associated with abnormal bowel habits. Diarrhea-predominant IBS (IBS-D) is a major subtype of IBS, the predominant manifestations of which are abdominal pain and diarrhea. The pathogenesis of IBS-D remained unknown until recently. The effects of psychosocial stress, central hypervigilance, neuroendocrine abnormality, disturbed gastrointestinal motility, mucosal immune activation, intestinal barrier dysfunction, visceral hypersensitivity (VH), altered gut flora, and genetic susceptibility may be involved in its development. Recently, increased attention has been placed on the neural-immune-endocrine network mechanism in IBS D, especially the role of various neuroendocrine mediators. As a member of the neurotrophin family, nerve growth factor (NGF) has diverse biological effects, and participates in the pathogenesis of many diseases. Basic studies have demonstrated that NGF is associated with inflammatory- and stress-related VH, as well as stress-related intestinal barrier dysfunction. The aim of this study is to summarize recent literature and discuss the role of NGF in the pathophysiology of IBS-D, especially in VH and intestinal barrier dysfunction, as well as its potential as a therapeutic target in IBS-D. PMID- 26739522 TI - Impact of DNA mismatch repair system alterations on human fertility and related treatments. AB - DNA mismatch repair (MMR) is one of the biological pathways, which plays a critical role in DNA homeostasis, primarily by repairing base-pair mismatches and insertion/deletion loops that occur during DNA replication. MMR also takes part in other metabolic pathways and regulates cell cycle arrest. Defects in MMR are associated with genomic instability, predisposition to certain types of cancers and resistance to certain therapeutic drugs. Moreover, genetic and epigenetic alterations in the MMR system demonstrate a significant relationship with human fertility and related treatments, which helps us to understand the etiology and susceptibility of human infertility. Alterations in the MMR system may also influence the health of offspring conceived by assisted reproductive technology in humans. However, further studies are needed to explore the specific mechanisms by which the MMR system may affect human infertility. This review addresses the physiological mechanisms of the MMR system and associations between alterations of the MMR system and human fertility and related treatments, and potential effects on the next generation. PMID- 26739523 TI - Changes of testicular phosphorylated proteins in response to restraint stress in male rats. AB - OBJECTIVE: To investigate male reproductive parameters via changes of potential testicular protein markers in restraint-stress rats. METHODS: Male Sprague-Dawley rats were divided into two groups (non-immobilized control and restraint immobilized/stress groups, n=8 each group). The stress animals were immobilized (12 h/d) by a restraint cage for 7 consecutive days. All reproductive parameters, morphology and histology were observed and compared between groups. In addition, the expression of steroidogenic acute regulatory (StAR) and phosphotyrosine proteins (previously localized in Sertoli and late spermatid cells) in testicular lysate was assayed by immuno-Western blotting. RESULTS: Testosterone level, sperm concentration and sperm head normality of stress rats were significantly decreased while the corticosterone level was increased as compared with the control (P<0.05). Histologically, stress rats showed low sperm mass in epididymal lumen and some atrophy of seminiferous tubules. Although the expression of testicular StAR protein was not significantly different between groups, changed patterns of the 131, 95, and 75 kDa testicular phosphorylated proteins were observed in the stress group compared with the control group. The intensity of a testicular 95-kDa phosphorylated protein was significantly decreased in stress rats. CONCLUSIONS: This study has demonstrated the alteration of testicular phosphorylated protein patterns, associated with adverse male reproductive parameters in stress rats. It could be an explanation of some infertility in stress males. PMID- 26739524 TI - Adenovirus-mediated GDF-5 promotes the extracellular matrix expression in degenerative nucleus pulposus cells. AB - OBJECTIVE: To construct a recombinant adenovirus vector-carrying human growth and differentiation factor-5 (GDF-5) gene, investigate the biological effects of adenovirus-mediated GDF-5 (Ad-GDF-5) on extracellular matrix (ECM) expression in human degenerative disc nucleus pulposus (NP) cells, and explore a candidate gene therapy method for intervertebral disc degeneration (IDD). METHODS: Human NP cells of a degenerative disc were isolated, cultured, and infected with Ad-GDF-5 using the AdEasy-1 adenovirus vector system. On Days 3, 7, 14, and 21, the contents of the sulfated glycosaminoglycan (sGAG), deoxyribonucleic acid (DNA) and hydroxyproline (Hyp), synthesis of proteoglycan and collagen II, gene expression of collagen II and aggrecan, and NP cell proliferation were assessed. RESULTS: The adenovirus was an effective vehicle for gene delivery with prolonged expression of GDF-5. Biochemical analysis revealed increased sGAG and Hyp contents in human NP cells infected by Ad-GDF-5 whereas there was no conspicuous change in basal medium (BM) or Ad-green fluorescent protein (GFP) groups. Only cells in the Ad-GDF-5 group promoted the production of ECM, as demonstrated by the secretion of proteoglycan and up-regulation of collagen II and aggrecan at both protein and mRNA levels. The NP cell proliferation was significantly promoted. CONCLUSIONS: The data suggest that Ad-GDF-5 gene therapy is a potential treatment for IDD, which restores the functions of degenerative intervertebral disc through enhancing the ECM production of human NP cells. PMID- 26739525 TI - L-Carnitine, but not coenzyme Q10, enhances the anti-osteoporotic effect of atorvastatin in ovariectomized rats. AB - OBJECTIVE: Statins' therapy in osteoporosis can aggravate muscle damage. This study was designed to assess which agent, L-carnitine or coenzyme Q10, could enhance the anti-osteoporotic effect of atorvastatin while antagonizing myopathy in ovariectomized rats. METHODS: Forty-eight female Sprague Dawley rats were used; forty rats were ovariectomized while eight were sham-operated. Eight weeks post-ovariectomy, rats were divided into ovariectomized-untreated group and four ovariectomized-treated groups (n=8) which received by gavage (mg/(kg?d), for 8 weeks) 17beta-estradiol (0.1), atorvastatin (50), atorvastatin (50)+L-carnitine (100), or atorvastatin (50)+coenzyme Q10 (20). At the end of therapy, bone mineral density (BMD), bone mineral content (BMC), and serum levels of bone metabolic markers (BMMs) and creatine kinase (CK) were measured. Femurs were used for studying the breaking strength and histopathological changes. RESULTS: Treatment with atorvastatin+L-carnitine restored BMD, BMC, and bone strength to near normal levels. Estrogen therapy restored BMD and BMC to near normal levels, but failed to increase bone strength. Although atorvastatin and atorvastatin+coenzyme Q10 improved BMD, BMC, and bone strength, they failed to restore levels to normal. All treatments decreased BMMs and improved histopathological changes maximally with atorvastatin+L-carnitine which restored levels to near normal. Atorvastatin aggravated the ovariectomy-induced increase in CK level while estrogen, atorvastatin+L-carnitine, and atorvastatin+coenzyme Q10 decreased its level mainly with atorvastatin+L-carnitine which restored the level to near normal. CONCLUSIONS: Co-administration of L-carnitine, but not coenzyme Q10, enhances the anti-osteoporotic effect of atorvastatin while antagonizing myopathy in ovariectomized rats. This could be valuable in treatment of osteoporotic patients. However, further confirmatory studies are needed. PMID- 26739526 TI - Trends in the prevalence of heart diseases over a ten-year period from single center observations based on a large echocardiographic database. AB - There is a paucity of data regarding trends in the incidence of heart disease in China during recent years. Using a large echocardiography database in our center, we analyzed trends in the prevalence of several common heart diseases from Dec. 2003. This study retrospectively analyzed the echocardiographic database in our Department from 2003 to 2012. A total of 385 682 cases were included in the study. The prevalence of rheumatic heart disease decreased over the 10-year period, from 4.04% in 2003 to 3.06% in 2012 (P<0.01). Infective endocarditis also decreased, from a mean prevalence of 0.37% in July 2003 to 0.27% in Dec. 2008 (P<0.001). The prevalence of hypertrophic cardiomyopathy, which includes 20% apical hypertrophic cardiomyopathy and 20% hypertrophic obstructive cardiomyopathy, was about 1.8%. The prevalence of the three most common adult congenital heart diseases (CHDs) decreased by about 10% from July 2003 to Dec. 2008 (all P<0.001). The prevalence of moderate pulmonary arterial hypertension (PAH) or left ventricular systolic dysfunction (LVSD) decreased during the 10 year period (P<0.001), but there was no change in the prevalence of severe PAH or LVSD (P>0.05). The present study indirectly demonstrates that the prevalence of several common heart diseases in China has declined in recent years. PMID- 26739527 TI - Impact of misplaced subclavian vein catheter into jugular vein on transpulmonary thermodilution measurement variables. AB - OBJECTIVE: The subclavian vein (SCV) is usually used to inject the indicator of cold saline for a transpulmonary thermodilution (TPTD) measurement. The SCV catheter being misplaced into the internal jugular (IJV) vein is a common occurrence. The present study explores the influence of a misplaced SCV catheter on TPTD variables. METHODS: Thirteen severe acute pancreatitis (SAP) patients with malposition of the SCV catheter were enrolled in this study. TPTD variables including cardiac index (CI), global end-diastolic volume index (GEDVI), intrathoracic blood volume index (ITBVI), and extravascular lung water index (EVLWI) were obtained after injection of cold saline via the misplaced SCV catheter. Then, the misplaced SCV catheter was removed and IJV access was constructed for a further set of TPTD variables. Comparisons were made between the TPTD results measured through the IJV and misplaced SCV accesses. RESULTS: A total of 104 measurements were made from TPTD curves after injection of cold saline via the IJV and misplaced SCV accesses. Bland-Altman analysis demonstrated an overestimation of +111.40 ml/m(2) (limits of agreement: 6.13 and 216.70 ml/m(2)) for GEDVI and ITBVI after a misplaced SCV injection. There were no significant influences on CI and EVLWI. The biases of +0.17 L/(min.m(2)) for CI and +0.17 ml/kg for EVLWI were revealed by Bland-Altman analysis. CONCLUSIONS: The malposition of an SCV catheter does influence the accuracy of TPTD variables, especially GEDVI and ITBVI. The position of the SCV catheter should be confirmed by chest X-ray in order to make good use of the TPTD measurements. PMID- 26739529 TI - Association between SMN2 methylation and disease severity in Chinese children with spinal muscular atrophy. AB - The homozygous loss of the survival motor neuron 1 (SMN1) gene is the primary cause of spinal muscular atrophy (SMA), a neuromuscular degenerative disease. A genetically similar gene, SMN2, which is not functionally equivalent in all SMA patients, modifies the clinical SMA phenotypes. We analyzed the methylation levels of 4 CpG islands (CGIs) in SMN2 in 35 Chinese children with SMA by MassARRAY. We found that three CpG units located in CGI 1 (nucleotides (nt) -871, -735) and CGI 4 (nt +999) are significantly hypomethylated in SMA type III compared with type I or II children after receiving Bonferroni correction. In addition to the differentially methylated CpG unit of nt -871, the methylation level of the nt -290/-288/-285 unit was negatively correlated with the expression of SMN2 full-length transcripts (SMN2-fl). In addition, the methylation level at nt +938 was inversely proportional to the ratio of SMN2-fl and lacking exon 7 transcripts (SMN2-Delta7, fl/Delta7), and was not associated with the SMN2 transcript levels. Thus, we can conclude that SMN2 methylation may regulate the SMA disease phenotype by modulating its transcription. PMID- 26739528 TI - Concomitant coronary and renal revascularization improves left ventricular hypertrophy more than coronary stenting alone in patients with ischemic heart and renal disease. AB - Percutaneous transluminal renal artery stenting (PTRAS) has been proved to have no more benefit than medication alone in treating atherosclerotic renal artery stenosis (ARAS). Whether PTRAS could improve left ventricular hypertrophy (LVH) and reduce adverse events when based on percutaneous coronary intervention (PCI) for patients with coronary artery disease (CAD) and ARAS is still unclear. A retrospective study was conducted, which explored the effect of concomitant PCI and PTRAS versus PCI alone for patients with CAD and ARAS complicated by heart failure with preserved ejection fraction (HFpEF). A total of 228 patients meeting inclusion criteria were divided into two groups: (1) the HFpEF-I group, with PCI and PTRAS; (2) the HFpEF-II group, with PCI alone. Both groups had a two-year follow-up. The left ventricular mass index (LVMI) and other clinical characteristics were compared between groups. During the follow-up period, a substantial decrease in systolic blood pressure (SBP) was observed in the HFpEF-I group, but not in the HFpEF-II group. There was marked decrease in LVMI in both groups, but the HFpEF-I group showed a greater decrease than the HFpEF-II group. Regression analysis demonstrated that PTRAS was significantly associated with LVMI reduction and fewer adverse events after adjusting for other factors. In HFpEF patients with both CAD and ARAS, concomitant PCI and PTRAS can improve LVH and decrease the incidence of adverse events more than PCI alone. This study highlights the beneficial effect of ARAS revascularization, as a new and more aggressive revascularization strategy for such high-risk patients. PMID- 26739530 TI - Ovarian characteristics and timed artificial insemination pregnancy risk after presynchronization with gonadotropin-releasing hormone 7 days before PGF2alpha in dairy cows. AB - The objective was to determine the benefit of including GnRH and PGF2alpha (PG) as a part of a presynchronization option before enrolling cows in a timed artificial insemination (AI) program. Holstein cows in one herd were assigned weekly at calving from January 2012 to August 2014 to a completely randomized design consisting of two presynchronization treatments. Cows in the Presynch-11 (n = 290) control were administered two PGF2alpha injections (Presynch PG-1 and Presynch PG-2) 14 days apart starting at 39 +/- 4 days postpartum (study Days 0 and 14). Cows receiving the experimental presynchronization treatment (Gsynch-11, n = 287) were treated with GnRH (pre-GnRH) on study Day 7 and PG (pre-PG) on study Day 14. On study Day 25, all cows were enrolled in the Ovsynch-56 timed AI program: GnRH-1 on study Day 25, PG on study Day 32, GnRH-2 on study Day 34, 56 hours after PG, and timed AI on study Day 35, 16 hours after GnRH-2. In a subsample of 255 cows, ovarian structures were monitored for size and ovulation, and blood samples were collected on study Days 7, 14, 25, 32, 34, and 41 to measure progesterone. Concentrations of progesterone were greater (P < 0.05) in Gsynch-11 than Presynch-11 cows before pre-GnRH was administered (3.3 +/- 0.3 vs. 2.1 +/- 0.3 ng/mL), respectively, and ovulatory response to the pre-GnRH treatment also was greater (P = 0.008) in Gsynch-11 than Presynch-11 cows (53.2 vs. 35.0%), respectively. One week later, the dominant follicle was larger (P = 0.045) in Presynch-11 than Gsynch-11 cows. Eleven days after completing the presynchronization treatments, ovulatory response to the Ovsynch GnRH-1 treatment was greater (P = 0.016) in Presynch-11 than Gsynch-11 cows (62.2% vs. 45.6%), respectively. At the time of the Ovsynch-PG treatment, more (P = 0.019) Presynch 11 than Gsynch-11 cows had at least one CL. Subsequent luteal regression (>96%), ovulation to GnRH-2 (>90%), and synchronization risk (>88%) did not differ between treatments, but incidence of multiple ovulation after GnRH-2 was larger (P = 0.036) in Presynch-11 than Gsynch-11 cows (28.4% vs. 15.9%), respectively. Pregnancy per AI at 32 days (36.4% vs. 35.1%) and 60 days (30.0% vs. 29.0%) after AI did not differ between Gsynch-11 and Presynch-11 cows, respectively, but was suppressed during summer months in both treatments to less than 70% of the pregnancy per AI of nonsummer months. Because more than 90% of the cows were ovular as treatments were applied, the GnRH treatment of Gsynch-11 could not be assessed for its benefit in anovular cows. The Gsynch-11 presynchronization treatment performed comparably with the standard Presynch-11 program and provides a viable presynchronization option for use before first AI in dairy herds. PMID- 26739531 TI - Effect of inhibin gene immunization on antibody production and reproductive performance in Partridge Shank hens. AB - To investigate the effect of inhibin gene immunization on antibody production and reproductive performance in broiler breeder females, Partridge Shank hens aged 380 days were immunized with inhibin recombinant plasmid pcISI. One hundred and twenty hens were randomly assigned to four groups and treated intramuscularly with 25, 75, or 125 MUg/300-MUL inhibin recombinant plasmid pcISI (T1~T3) or 300 MUL saline as control (C), respectively. Booster immunization was given with the same dosage 20 days later. Blood and egg samples were collected to detect the antibody against inhibin by enzyme-linked immunosorbent assay and to evaluate egg performance. The ovaries were collected to classify the follicles and detect the FSH receptor (FSHR) messenger RNA (mRNA) expression by reverse transcription-PCR. The results showed that immunization against pcISI could elicit antibody against inhibin in both plasma and egg yolk compared with the control (P < 0.05), whereas booster immunization did not increase the antibody level in plasma. Vaccination promoted egg lay during the first 30 days after primary vaccination (P < 0.05) with no effect on egg quality and hatching rate. Immunization increased the amounts of dominant, small yellow and large white follicles in the ovary (P < 0.05). Reverse transcription-PCR results showed that immunization increased the FSHR mRNA in the large white follicles, whereas decreased the FSHR mRNA in the small yellow follicles (P < 0.05). In conclusion, inhibin vaccine pcISI can stimulate the production of antibody against inhibin as well as the follicle development and egg laying performance in Partridge Shank hens, which provides a good foundation for the application of inhibin DNA vaccine in avian production. PMID- 26739533 TI - A new direct transfer protocol for cryopreserved IVF embryos. AB - The global demand for in vitro-produced (IVP) embryos of determined sex has greatly increased over the last decade. Efficient protocols for the direct transfer of IVP embryos are lacking. This study aimed to compare the pregnancy rates for fresh, vitrified, or frozen/directly transferred IVP dairy cow embryos. Oocytes (n = 3171) recovered by ovum pickup (n = 112) from Girolando (Holstein Gir) females (n = 36) were selected and submitted to IVM for 24 hours at 38.5 degrees C with 5% CO2 in air with saturated humidity. In vitro fertilization was performed with the thawed, sexed semen from 5 Holstein bulls. After IVF, presumptive zygotes were denuded and cultured for 7 days under the same IVM and IVF conditions of temperature and humidity, except with 5% CO2 and 5% O2. Grade I blastocysts were randomly assigned for either the transferred fresh, vitrified/thawing, or frozen/directly embryo transfer into previously synchronized recipient females. Conception rates were analyzed by binomial logistic regression, and a probability level of P < 0.05 was considered significant. The conception rates were 51.35 +/- 1.87% (133/259) for the fresh embryos, 35.89 +/- 3.87% (84/234) for the vitrified embryos, and 40.19 +/- 4.65% (125/311) for the frozen directly transferred embryos. These data demonstrate that IVP embryos with sexed semen could be directly transferred into recipient cows with similar conception rates to vitrified embryos. The comparison found that the use of frozen embryos in direct transfer provides easier logistics and a more practical approach for the transfer of IVP embryos on dairy farms. PMID- 26739532 TI - Doppler sonographic examination of uterine and placental perfusion in cows in the last month of gestation and effects of epidural anesthesia and isoxsuprine. AB - The massive increase in size of the fetus and uterus in the last trimester is accompanied by an increasing demand for nutrients and oxygen, and it is assumed that this demand is met by increasing uterine and fetal perfusion. The goals of this study were to measure the perfusion of the uterine arteries and the placentomes in the last month of gestation and to investigate the effect of epidural anesthesia and isoxsuprine on perfusion. During the last month of gestation, eight Braunvieh cows underwent nine color Doppler sonographic examinations of the uterine arteries to determine diameter (DM), pulse rate (PR), resistance index, time-averaged maximum blood flow velocity (TAMV), and blood flow volume (BFV), and power-mode Doppler sonography was used to determine perfusion of placentomes. The PR increased (P < 0.001), and the BFV and TAMV of the ipsilateral uterine artery decreased between 4.5 and 0.5 weeks prepartum (BFV, 236.8 +/- 65.80 and 208 +/- 41.52 cm(3)/s, P < 0.01; TAMV, 140.0 +/- 26.53 cm/s and 125.2 +/- 18.46 cm/s, P < 0.05). After sonographic examination, the cows received epidural administration of local anesthetic (100-mg lidocaine) in the sacrococcygeal space or isoxsuprine (200 mg/cow, iv), and the sonographic measurements were repeated 30 minutes later. After epidural anesthesia, the TAMV and BFV of the contralateral uterine artery increased by 5.4% (P < 0.05) and 7.9% (P < 0.01). In the placentomes of the gravid uterine horn, the relative placentome perfusion and the color pixel grading (Cp) increased by 10.1% (P < 0.05) and 11.5% (P < 0.01) after epidural anesthesia. After isoxsuprine, the DM, PR, and BFV increased by 4.7%, 49.3%, and 16.9% in the ipsilateral uterine artery and by 10.8%, 48.7%, and 22.8%, respectively in the contralateral uterine artery. The TAMV of the ipsilateral uterine artery increased by 7.1% (P < 0.01), and the resistance index decreased in both uterine arteries (ipsilateral 24.2%, contralateral 14.9%, both P < 0.00001). Isoxsuprine increased the relative placentome perfusion and the Cp of the placentomes by 18.1% and 18.3% in the gravid horn and by 10.2% and 24.2% in the nongravid horn. Blood flow variables changed little in the last month of gestation. However, epidural anesthesia and isoxsuprine caused changes in uterine and placentome perfusion that suggest improvement of placental nutrient and oxygen supply to the fetus. PMID- 26739534 TI - Obama issues executive orders to curtail gun violence. PMID- 26739539 TI - See for Yourself: Perception Is Attuned to Morality. PMID- 26739542 TI - Assessment of the Quality of Chronic Anticoagulation Control With Time in Therapeutic Range in Atrial Fibrillation Patients Treated With Vitamin K Antagonists by Hemostasis Specialists: The TERRA Registry: Tiempo en rango en la Republica Argentina. AB - BACKGROUND: Oral anticoagulation therapy with vitamin K antagonists (VKA) such as warfarin and acenocoumarol is recommended in patients with atrial fibrillation (AF) and risk factors for embolism. The quality of anticoagulation control with VKA may be assessed by the time in therapeutic range (TTR). In our country, there are no data available about the quality of anticoagulation in patients with AF. The primary goal of our study was to assess the level of effective anticoagulation in a multicenter network of anticoagulation clinics in Argentina, which included patients with nonvalvular AF (NVAF) treated with VKA oral anticoagulants. METHODS: The TERRA trial is a multicenter, cross-sectional study involving 14 anticoagulation clinics that were invited to participate and recruit 100 consecutive patients with NVAF treated with VKA for more than 1 year. The international normalized ratio (INR) values were retrospectively obtained from patient charts, and TTR was calculated using the Rosendaal method. RESULTS: A total of 1190 patients were included in the analysis. Mean age was 74.9 +/- 9.9 years, and 52.5% of the patients were male. Median TTR was 67.5% (interquartile interval 54-80). During 55% of the TTR, INR was >3. Interinstitution variability was substantial, with a range of 57.7% +/- 17% to 87.7% +/- 17%, P < .001. The 10th percentile of TTR was 41%, the 20th percentile was 50%, the 30th was 58%, and the 35th percentile was 60%. In 40% of patients, TTR was <70%. CONCLUSION: In this multicenter study, mean TTR values in patients with AF under VKA were similar to those in international therapeutic clinical trials (55%-65%). Marked variations among institutions were observed and, although average results obtained were high, one third of the patients exhibited a TTR below 60%. This cutoff value is conservative according to current recommendations, and guidelines suggest that when management with VKA cannot be improved, patients should be switched to direct oral anticoagulants. The addition of TTR calculation to clinical practice may help improve the quality of oral anticoagulation in patients with AF, thus improving anticoagulation outcomes. PMID- 26739543 TI - Enoxaparin Treatment Followed by Rivaroxaban for the Treatment of Acute Lower Limb Venous Thromboembolism: Initial Experience in a Single Center. AB - Rivaroxaban is a target-specific oral anticoagulant approved for the treatment of venous thromboembolism (VTE). On its major clinical trials, treatment was initiated directly with a 3-week dose of oral 15 mg twice daily followed by 20 mg every day for at least 3 months. We retrospectively evaluated an initial therapy for confirmed VTE with 1 to 18 days of enoxaparin (1 mg/kg twice daily parenteral) followed by oral rivaroxaban 20 mg every day. Of 49 patients, we found no symptomatic recurrence, no major bleeding, and only 1 clinically relevant nonmajor bleeding. We concluded in this pilot study that it is safe and effective to treat patients with enoxaparin course followed directly by a dose of 20 mg of rivaroxaban. PMID- 26739544 TI - Rs5918ITGB3 Polymorphism, Smoking, and BMI as Risk Factors for Early Onset and Recurrence of DVT in Young Women. AB - OBJECTIVE: To evaluate the contribution of rs5918ITGB3 on the incidence and recurrence of deep venous thrombosis (DVT) in women and the relationship with body mass index (BMI) and smoking and to compare with data in men. RESULTS: Rs5918(C) polymorphism in ITGB3 gene was assessed in 224 patients diagnosed with DVT and 216 controls. Thrombophilic genetic variant rs5918(C) was significantly pronounced in women (chi2 =7.565, P = .008) and total patients (chi2 = 9.266, P = .002) but not in men. Women patients (<45 years) who were carriers of rs5918ITGB3 polymorphism had an early onset of DVT (34.5 vs 39.4 years, chi2 = 7.027, P = .008) as analyzed by Kaplan-Meier and a higher risk of the recurrent event (chi2 = 3.405, odds ratio = 2.581, P = .044). The period before recurrent venous thromboembolism event was related to smoking status and BMI in young female who were carriers of rs5918 polymorphism but not in the males. CONCLUSIONS: Carriage of genetic variant rs5918(C) polymorphism in ITGB3 gene in women contributes to higher risk of single and recurrent DVT events at younger age. PMID- 26739546 TI - Efficient OPSL-pumped mode-locked Yb:Lu2O3 laser with 67% optical-to-optical efficiency. AB - We present a mode-locked Yb:Lu2O3 laser with up to 67% of optical-to-optical efficiency. By utilizing a high brightness optically pumped semiconductor laser (OPSL) as a pump source and using a semiconductor saturable absorber mirror (SESAM) we obtained self-starting mode locking. A pulse duration of 571 fs at 4.73 W of average output power with an optical-to-optical efficiency of 67% was achieved. In a slightly different cavity configuration the pulse duration was reduced to 313 fs at 2.16 W of average output power. In both cases the pulse duration was longer than the Fourier limit and the spectrum supports significantly shorter pulse durations. The laser wavelength is centered at 1034 nm and the repetition rate is 100.76 MHz in both cases. In continuous wave fundamental mode operation the optical-to-optical efficiency was as high as 78% with output powers exceeding 5 W. PMID- 26739547 TI - Oral nanomedicine approaches for the treatment of psychiatric illnesses. AB - Psychiatric illnesses are a leading cause of disability and morbidity globally. However, the preferred orally dosed pharmacological treatment options available for depression, anxiety and schizophrenia are often limited by factors such as low drug aqueous solubility, food effects, high hepatic first-pass metabolism effects and short half-lives. Furthermore, the discovery and development of more effective psychotropic agents has stalled in recent times, with the majority of new drugs reaching the market offering similar efficacy, but suffering from the same oral delivery concerns. As such, the application of nanomedicine formulation approaches to currently available drugs is a viable option for optimizing oral drug delivery and maximizing treatment efficacy. This review focuses on the various delivery challenges encountered by psychotropic drugs, and the ability of nanomedicine formulation strategies to overcome these. Specifically, we critically review proof of concept in vitro and in vivo studies of nanoemulsions/microemulsions, solid lipid nanoparticles, dendrimers, polymeric micelles, nanoparticles of biodegradable polymers and nanosuspensions, and provide new insight into the various mechanisms for improved drug performance. The advantages and limitations of current oral nanomedicine approaches for psychotropic drugs are discussed, which will provide guidance for future research directions and assist in fostering the translation of such delivery systems to the clinical setting. Accordingly, emphasis has been placed on correlating the in vitro/in vivo performance of these nanomedicine approaches with their potential clinical outcomes and benefits for patients. PMID- 26739548 TI - Microneedle delivery of autoantigen for immunotherapy in type 1 diabetes. AB - Antigen specific immunotherapy mediated via the sustained generation of regulatory T cells arguably represents the ideal therapeutic approach to preventing beta cell destruction in type 1 diabetes. However, there is a need to enhance the efficacy of this approach to achieve disease modification in man. Previous studies suggest that prolonged expression of self-antigen in skin in a non-inflammatory context is beneficial for tolerance induction. We therefore sought to develop a dry-coated microneedle (MN) delivery system and combine it with topical steroid to minimise local inflammation and promote prolonged antigen presentation in the skin. Here we show that a combination of surface-modified MNs coated with appropriate solvent systems can deliver therapeutically relevant quantities of peptide to mouse and human skin even with hydrophobic peptides. Compared to conventional "wet" intradermal (ID) administration, "dry" peptide delivered via MNs was retained for longer in the skin and whilst topical hydration of the skin with vehicle or steroid accelerated loss of ID-delivered peptide from the skin, MN delivery of peptide was unaffected. Furthermore, MN delivery resulted in enhanced presentation of antigen to T cells in skin draining lymph nodes (LNs) both 3 and 10days after administration. Repeated administration of islet antigen peptide via MN was effective at reducing antigen-specific T cell proliferation in the pancreatic LN, although topical steroid therapy did not enhance this. Taken together, these data show auto-antigenic peptide delivery into skin using coated MNs results in prolonged retention and enhanced antigen presentation compared to conventional ID delivery and this approach may have potential in individuals identified as being at a high risk of developing type 1 diabetes and other autoimmune diseases. PMID- 26739549 TI - Theranostic gas-generating nanoparticles for targeted ultrasound imaging and treatment of neuroblastoma. AB - The development of safe and efficient diagnostic/therapeutic agents for treating cancer in clinics remains challenging due to the potential toxicity of conventional agents. Although the annual incidence of neuroblastoma is not that high, the disease mainly occurs in children, a population vulnerable to toxic contrast agents and therapeutics. We demonstrate here that cancer-targeting, gas generating polymeric nanoparticles are useful as a theranostic tool for ultrasound (US) imaging and treating neuroblastoma. We encapsulated calcium carbonate using poly(d,l-lactide-co-glycolide) and created gas-generating polymer nanoparticles (GNPs). These nanoparticles release carbon dioxide bubbles under acidic conditions and enhance US signals. When GNPs are modified using rabies virus glycoprotein (RVG) peptide, a targeting moiety to neuroblastoma, RVG-GNPs effectively accumulate at the tumor site and substantially enhance US signals in a tumor-bearing mouse model. Intravenous administration of RVG-GNPs also reduces tumor growth in the mouse model without the use of conventional therapeutic agents. This approach to developing theranostic agents with disease-targeting ability may provide useful strategy for the detection and treatment of cancers, allowing safe and efficient clinical applications with fewer side effects than may occur with conventional agents. PMID- 26739550 TI - Water soluble PEG-conjugate of xanthine oxidase inhibitor, PEG-AHPP micelles, as a novel therapeutic for ROS related inflammatory bowel diseases. AB - Xanthine oxidase (XO) is one of the major enzymes to generate superoxide anion (O2(-)), that is frequently associated with various diseases involving reactive oxygen species (ROS). 4-Amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP) is a potent XO inhibitor showing therapeutic potential for oxidative inflammatory diseases. However its very poor aqueous solubility makes pharmaceutical application difficult. To overcome this drawback, we have successfully synthesized a water soluble polyethylene glycol (PEG) conjugate of AHPP (PEG AHPP) that exhibited good water solubility, forming micelles in aqueous solution. In the present study, the in vivo pharmacokinetics of this PEG-AHPP was examined. Further its therapeutic potential was investigated in dextran sulfate sodium (DSS) induced mouse colitis model. Compared to parental AHPP, the plasma t1/2 of PEG-AHPP was increased remarkably from 3h to 14h, indicating macromolecular nature of AHPP in circulation. In the DSS induced colitis model, oral administration of 2% DSS in drinking water resulted in the progression of the colitis with diarrhea and hematochezia as well as shortening of the large bowel. Administration of PEG-AHPP intravenously (10mg/kg) or orally (20mg/kg) suppressed pathogenesis significantly; namely diarrhea was reduced markedly, and the length of large bowel returned to almost normal level. Pathological examination clearly revealed improvement of colonic ulcer or necrosis. Production of inflammatory cytokines, i.e., interleukin-6 and tumor necrosis factor (TNF)-alpha, was significantly increased in DSS-induced colitis mice. However, it was markedly suppressed by PEG-AHPP administration. Similar results were found when serum 8 hydroxydeoxyguanosine (8-OHdG) and thiobarbituric acid reactive substances (TBARS), that are the index of oxidative injury, were measured. PEG-AHPP thus may be a potential candidate drug for ROS-related diseases including inflammatory bowel disease. PMID- 26739551 TI - Molecular imaging-guided photothermal/photodynamic therapy against tumor by iRGD modified indocyanine green nanoparticles. AB - Multifunctional near-infrared (NIR) nanoparticles demonstrate great potential in tumor theranostic applications. To achieve the sensitive detection and effective phototherapy in the early stage of tumor genesis, it is highly desirable to improve the targeting of NIR theranostic agents to biomarkers and to enhance their accumulation in tumor. Here we report a novel targeted multifunctional theranostic nanoparticle, internalized RGD (iRGD)-modified indocyanine green (ICG) liposomes (iRGD-ICG-LPs), for molecular imaging-guided photothermal therapy (PTT) and photodynamic therapy (PDT) therapy against breast tumor. The iRGD peptides with high affinity to alphavbeta3 integrin and effective tumor internalized property were firstly used to synthesize iRGD-PEG2000-DSPE lipopeptides, which were further utilized to fabricate the targeted ICG liposomes. The results indicated that iRGD-ICG-LPs exhibited excellent stability and could provide an accurate and sensitive detection of breast tumor through NIR fluorescence molecular imaging. We further employed this nanoparticle for tumor theranostic application, demonstrating significantly higher tumor accumulation and tumor inhibition efficacy through PTT/PDT effects. Histological analysis further revealed much more apoptotic cells, confirming the advantageous anti tumor effect of iRGD-ICG-LPs over non-targeted ICG-LPs. Notably, the targeting therapy mediated by iRGD provides almost equivalent anti-tumor efficacy at a 12.5 fold lower drug dose than that by monoclonal antibody, and no tumor recurrence and obvious treatment-induced toxicity were observed in our study. Our study provides a promising strategy to realize the sensitive detection and effective treatment of tumors by integrating molecular imaging into PTT/PDT therapy. PMID- 26739552 TI - Serum 25-Hydroxyvitamin D Level Does Not Affect the Aggressiveness and Prognosis of Papillary Thyroid Cancer. AB - BACKGROUND: Vitamin D deficiency has been known to be associated with the aggressiveness and prognosis of several cancers. This study evaluated the effect of preoperative serum vitamin D levels on the aggressiveness and prognosis of papillary thyroid cancer (PTC). METHODS: In total, 820 patients with PTC were enrolled. 25-hydroxyvitamin D levels were measured in blood samples before surgery. Clinical, pathologic, and recurrence data were accessed to examine the prognostic effects of vitamin D. Patients were categorized into four quartiles by preoperative serum vitamin D levels. RESULTS: Of the enrolled patients, 795 (97%) had insufficient vitamin D levels (<30 ng/mL). Vitamin D levels showed positive correlations with age and body mass index (BMI), and negative correlations with serum thyrotropin levels and antithyroid peroxidase antibody titers. The association between vitamin D quartile and the risks of extrathyroidal invasion, lymph node metastasis, advanced cancer stages (III or IV), and risk of recurrence were not significant after adjusting for age, sex, BMI, preoperative ionized calcium, and parathyroid hormone. Additionally, serum vitamin D was not associated with recurrent or persistent PTC. CONCLUSION: Serum vitamin D levels are not associated with either disease aggressiveness or poor outcomes among patients with PTC and vitamin D insufficiency. PMID- 26739558 TI - Connecting the new with the old: modifying the combined application of Procrustes superimposition and principal component analysis, to allow for comparison with traditional lateral cephalometric variables. AB - OBJECTIVE: The combination of generalized Procrustes superimposition (GPS) and principal component analysis (PCA) has been hypothesized to solve some of the problems plaguing traditional cephalometry. This study demonstrates how to establish the currently unclear relationship between the shape space defined by the first two principal components to the ANB angle, Wits appraisal, and GoGnSN angle, and to elucidate possible clinical applications thereof. METHODS: Digitized landmarks of 200 lateral cephalograms were subjected to GPS and PCA, after which the sample mean shape was deformed along/parallel to principal components (PC) 1 and 2, recording the ANB, Wits, and GoGnSN value at each location. Trajectories were then calculated through the PC1-PC2 space connecting locations with the same values. These were finally utilized to renormalize the PC1-PC2 space. RESULTS: The trajectories for the Wits appraisal were almost straight and parallel to PC1.Those for the ANB angle were angled approximately 20degrees downward relative to PC1, with a more accentuated curvature. The GoGnSN curves were mildly angled relative to the PC2 axis, their curvature increasing slightly with increasing PC1 scores. By combining the aforementioned trajectories, it was possible to delineate the region of the PC1-PC2 shape space which would be regarded as normodivergent and skeletal Class I in traditional cephalometry. Geometric distortion could be avoided by assigning patients the ANB, Wits, or GoGnSN value of the sample mean shape, deformed to the patient's position within the PC1-PC2 plot. CONCLUSION: The methodology successfully relates the shape space resulting from the GPS-PCA results with traditional cephalometric variables. PMID- 26739557 TI - Comparing comorbidity scales: Attending physician score versus the Cumulative Illness Rating Scale for Geriatrics. AB - OBJECTIVES: Assessing comorbidity using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) and its comprehensive manual is time consuming. We investigated if similar information could be obtained by a simpler assessment based on the original CIRS. MATERIALS AND METHODS: Data from a randomized chemotherapy trial (RCT) on advanced NSCLC (non-small cell lung cancer) were analyzed. Baseline comorbidity was assessed by 1) trained oncologists using hospital records and the CIRS-G manual (CIRS-G), 2) by patients' oncologists/pulmonologists (local investigators=LI-score) using a brief set of instructions. By both methods, the severity of comorbidity in 14 organ systems was graded 0 (no problem) to 4 (extremely severe). The agreement between methods was assessed using Bland-Altman analysis and weighted kappa statistics. The impact of comorbidity on survival was analyzed by Cox regression. RESULTS: Complete data were available for 375/446 (84%) patients enrolled in the RCT. Median age was 65years (25-85). Overall, more comorbidities and higher severity were registered by the CIRS-G compared to the LI-score. Severe comorbidity was registered for 184 (49%) and 94 (25%) patients according to the CIRS-G and LI scores, respectively. Mean total score was 7.0 (0-17) (CIRS-G) versus 4.2 (0-16) (LI-score), and mean severity index (total score/number of categories with score >0) was 1.73 (SD 0.46) versus 1.43 (SD 0.78). Neither the CIRS-G scores nor the LI-scores were prognostic for survival. CONCLUSION: The CIRS-G scores and LI scores had poor agreement, indicating that assessment method affects the registration of comorbidity. Thorough descriptions of comorbidity registrations in trials are paramount due to lack of a standardized assessment. PMID- 26739556 TI - Are itch and scratching the nausea and vomiting of skin? AB - The physiologic similarities between itch and nausea may not be evident initially, but they share the role of repelling irritants and toxins from the body by inducting scratching and vomiting, respectively. In addition, itch and nausea frequently occur together in certain conditions such as uraemia. Here we show that the mechanisms underlying itch and nausea overlap and that advances in either field may influence the identification of novel drug targets, particularly for itch. PMID- 26739559 TI - Transcriptional profiles of supragranular-enriched genes associate with corticocortical network architecture in the human brain. AB - The human brain is patterned with disproportionately large, distributed cerebral networks that connect multiple association zones in the frontal, temporal, and parietal lobes. The expansion of the cortical surface, along with the emergence of long-range connectivity networks, may be reflected in changes to the underlying molecular architecture. Using the Allen Institute's human brain transcriptional atlas, we demonstrate that genes particularly enriched in supragranular layers of the human cerebral cortex relative to mouse distinguish major cortical classes. The topography of transcriptional expression reflects large-scale brain network organization consistent with estimates from functional connectivity MRI and anatomical tracing in nonhuman primates. Microarray expression data for genes preferentially expressed in human upper layers (II/III), but enriched only in lower layers (V/VI) of mouse, were cross correlated to identify molecular profiles across the cerebral cortex of postmortem human brains (n = 6). Unimodal sensory and motor zones have similar molecular profiles, despite being distributed across the cortical mantle. Sensory/motor profiles were anticorrelated with paralimbic and certain distributed association network profiles. Tests of alternative gene sets did not consistently distinguish sensory and motor regions from paralimbic and association regions: (i) genes enriched in supragranular layers in both humans and mice, (ii) genes cortically enriched in humans relative to nonhuman primates, (iii) genes related to connectivity in rodents, (iv) genes associated with human and mouse connectivity, and (v) 1,454 gene sets curated from known gene ontologies. Molecular innovations of upper cortical layers may be an important component in the evolution of long-range corticocortical projections. PMID- 26739560 TI - Cytokine Diedel and a viral homologue suppress the IMD pathway in Drosophila. AB - Viruses are obligatory intracellular parasites that suffer strong evolutionary pressure from the host immune system. Rapidly evolving viral genomes can adapt to this pressure by acquiring genes that counteract host defense mechanisms. For example, many vertebrate DNA viruses have hijacked cellular genes encoding cytokines or cytokine receptors to disrupt host cell communication. Insect viruses express suppressors of RNA interference or apoptosis, highlighting the importance of these cell intrinsic antiviral mechanisms in invertebrates. Here, we report the identification and characterization of a family of proteins encoded by insect DNA viruses that are homologous to a 12-kDa circulating protein encoded by the virus-induced Drosophila gene diedel (die). We show that die mutant flies have shortened lifespan and succumb more rapidly than controls when infected with Sindbis virus. This reduced viability is associated with deregulated activation of the immune deficiency (IMD) pathway of host defense and can be rescued by mutations in the genes encoding the homolog of IKKgamma or IMD itself. Our results reveal an endogenous pathway that is exploited by insect viruses to modulate NF-kappaB signaling and promote fly survival during the antiviral response. PMID- 26739561 TI - Marine biogenic source of atmospheric organic nitrogen in the subtropical North Atlantic. AB - Global models estimate that the anthropogenic component of atmospheric nitrogen (N) deposition to the ocean accounts for up to a third of the ocean's external N supply and 10% of anthropogenic CO2 uptake. However, there are few observational constraints from the marine atmospheric environment to validate these findings. Due to the paucity of atmospheric organic N data, the largest uncertainties related to atmospheric N deposition are the sources and cycling of organic N, which is 20-80% of total N deposition. We studied the concentration and chemical composition of rainwater and aerosol organic N collected on the island of Bermuda in the western North Atlantic Ocean over 18 mo. Here, we show that the water soluble organic N concentration ([WSON]) in marine aerosol is strongly correlated with surface ocean primary productivity and wind speed, suggesting a marine biogenic source for aerosol WSON. The chemical composition of high-[WSON] aerosols also indicates a primary marine source. We find that the WSON in marine rain is compositionally different from that in concurrently collected aerosols, suggesting that in-cloud scavenging (as opposed to below-cloud "washout") is the main contributor to rain WSON. We conclude that anthropogenic activity is not a significant source of organic N to the marine atmosphere over the North Atlantic, despite downwind transport from large pollution sources in North America. This, in conjunction with previous work on ammonium and nitrate, leads to the conclusion that only 27% of total N deposition to the global ocean is anthropogenic, in contrast to the 80% estimated previously. PMID- 26739562 TI - Reversal of morphine-induced cell-type-specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement. AB - Drug-evoked plasticity at excitatory synapses on medium spiny neurons (MSNs) of the nucleus accumbens (NAc) drives behavioral adaptations in addiction. MSNs expressing dopamine D1 (D1R-MSN) vs. D2 receptors (D2R-MSN) can exert antagonistic effects in drug-related behaviors, and display distinct alterations in glutamate signaling following repeated exposure to psychostimulants; however, little is known of cell-type-specific plasticity induced by opiates. Here, we find that repeated morphine potentiates excitatory transmission and increases GluA2-lacking AMPA receptor expression in D1R-MSNs, while reducing signaling in D2-MSNs following 10-14 d of forced abstinence. In vivo reversal of this pathophysiology with optogenetic stimulation of infralimbic cortex-accumbens shell (ILC-NAc shell) inputs or treatment with the antibiotic, ceftriaxone, blocked reinstatement of morphine-evoked conditioned place preference. These findings confirm the presence of overlapping and distinct plasticity produced by classes of abused drugs within subpopulations of MSNs that may provide targetable molecular mechanisms for future pharmacotherapies. PMID- 26739563 TI - Novel cystine transporter in renal proximal tubule identified as a missing partner of cystinuria-related plasma membrane protein rBAT/SLC3A1. AB - Heterodimeric amino acid transporters play crucial roles in epithelial transport, as well as in cellular nutrition. Among them, the heterodimer of a membrane protein b(0,+)AT/SLC7A9 and its auxiliary subunit rBAT/SLC3A1 is responsible for cystine reabsorption in renal proximal tubules. The mutations in either subunit cause cystinuria, an inherited amino aciduria with impaired renal reabsorption of cystine and dibasic amino acids. However, an unsolved paradox is that rBAT is highly expressed in the S3 segment, the late proximal tubules, whereas b(0,+)AT expression is highest in the S1 segment, the early proximal tubules, so that the presence of an unknown partner of rBAT in the S3 segment has been proposed. In this study, by means of coimmunoprecipitation followed by mass spectrometry, we have found that a membrane protein AGT1/SLC7A13 is the second partner of rBAT. AGT1 is localized in the apical membrane of the S3 segment, where it forms a heterodimer with rBAT. Depletion of rBAT in mice eliminates the expression of AGT1 in the renal apical membrane. We have reconstituted the purified AGT1-rBAT heterodimer into proteoliposomes and showed that AGT1 transports cystine, aspartate, and glutamate. In the apical membrane of the S3 segment, AGT1 is suggested to locate itself in close proximity to sodium-dependent acidic amino acid transporter EAAC1 for efficient functional coupling. EAAC1 is proposed to take up aspartate and glutamate released into luminal fluid by AGT1 due to its countertransport so that preventing the urinary loss of aspartate and glutamate. Taken all together, AGT1 is the long-postulated second cystine transporter in the S3 segment of proximal tubules and a possible candidate to be involved in isolated cystinuria. PMID- 26739564 TI - SDPR functions as a metastasis suppressor in breast cancer by promoting apoptosis. AB - Metastatic dissemination of breast cancer cells represents a significant clinical obstacle to curative therapy. The loss of function of metastasis suppressor genes is a major rate-limiting step in breast cancer progression that prevents the formation of new colonies at distal sites. However, the discovery of new metastasis suppressor genes in breast cancer using genomic efforts has been slow, potentially due to their primary regulation by epigenetic mechanisms. Here, we report the use of model cell lines with the same genetic lineage for the identification of a novel metastasis suppressor gene, serum deprivation response (SDPR), localized to 2q32-33, a region reported to be associated with significant loss of heterozygosity in breast cancer. In silico metaanalysis of publicly available gene expression datasets suggests that the loss of expression of SDPR correlates with significantly reduced distant-metastasis-free and relapse-free survival of breast cancer patients who underwent therapy. Furthermore, we found that stable SDPR overexpression in highly metastatic breast cancer model cell lines inhibited prosurvival pathways, shifted the balance of Bcl-2 family proteins in favor of apoptosis, and decreased migration and intravasation/extravasation potential, with a corresponding drastic suppression of metastatic nodule formation in the lungs of NOD/SCID mice. Moreover, SDPR expression is silenced by promoter DNA methylation, and as such it exemplifies epigenetic regulation of metastatic breast cancer progression. These observations highlight SDPR as a potential prognostic biomarker and a target for future therapeutic applications. PMID- 26739565 TI - Extracardiac septum transversum/proepicardial endothelial cells pattern embryonic coronary arterio-venous connections. AB - Recent reports suggest that mammalian embryonic coronary endothelium (CoE) originates from the sinus venosus and ventricular endocardium. However, the contribution of extracardiac cells to CoE is thought to be minor and nonsignificant for coronary formation. Using classic (Wt1(Cre)) and previously undescribed (G2-Gata4(Cre)) transgenic mouse models for the study of coronary vascular development, we show that extracardiac septum transversum/proepicardium (ST/PE)-derived endothelial cells are required for the formation of ventricular coronary arterio-venous vascular connections. Our results indicate that at least 20% of embryonic coronary arterial and capillary endothelial cells derive from the ST/PE compartment. Moreover, we show that conditional deletion of the ST/PE lineage-specific Wilms' tumor suppressor gene (Wt1) in the ST/PE of G2-Gata4(Cre) mice and in the endothelium of Tie2(Cre) mice disrupts embryonic coronary transmural patterning, leading to embryonic death. Taken together, our results demonstrate that ST/PE-derived endothelial cells contribute significantly to and are required for proper coronary vascular morphogenesis. PMID- 26739566 TI - Geometry-induced protein pattern formation. AB - Protein patterns are known to adapt to cell shape and serve as spatial templates that choreograph downstream processes like cell polarity or cell division. However, how can pattern-forming proteins sense and respond to the geometry of a cell, and what mechanistic principles underlie pattern formation? Current models invoke mechanisms based on dynamic instabilities arising from nonlinear interactions between proteins but neglect the influence of the spatial geometry itself. Here, we show that patterns can emerge as a direct result of adaptation to cell geometry, in the absence of dynamical instability. We present a generic reaction module that allows protein densities robustly to adapt to the symmetry of the spatial geometry. The key component is an NTPase protein that cycles between nucleotide-dependent membrane-bound and cytosolic states. For elongated cells, we find that the protein dynamics generically leads to a bipolar pattern, which vanishes as the geometry becomes spherically symmetrical. We show that such a reaction module facilitates universal adaptation to cell geometry by sensing the local ratio of membrane area to cytosolic volume. This sensing mechanism is controlled by the membrane affinities of the different states. We apply the theory to explain AtMinD bipolar patterns in [Formula: see text] EcMinDE Escherichia coli. Due to its generic nature, the mechanism could also serve as a hitherto-unrecognized spatial template in many other bacterial systems. Moreover, the robustness of the mechanism enables self-organized optimization of protein patterns by evolutionary processes. Finally, the proposed module can be used to establish geometry-sensitive protein gradients in synthetic biological systems. PMID- 26739567 TI - A rigorous comparison of sexual selection indexes via simulations of diverse mating systems. AB - Sexual selection is a cornerstone of evolutionary theory, but measuring it has proved surprisingly difficult and controversial. Various proxy measures--e.g., the Bateman gradient and the opportunity for sexual selection--are widely used in empirical studies. However, we do not know how reliably these measures predict the strength of sexual selection across natural systems, and most perform poorly in theoretical worst-case scenarios. Here we provide a rigorous comparison of eight commonly used indexes of sexual selection. We simulated 500 biologically plausible mating systems, based on the templates of five well-studied species that cover a diverse range of reproductive life histories. We compared putative indexes to the actual strength of premating sexual selection, measured as the strength of selection on a simulated "mating trait." This method sidesteps a key weakness of empirical studies, which lack an appropriate yardstick against which proxy measures can be assessed. Our model predicts that, far from being useless, the best proxy measures reliably track the strength of sexual selection across biologically realistic scenarios. The maximum intensity of precopulatory sexual selection s'max (the Jones index) outperformed all other indexes and was highly correlated with the strength of sexual selection. In contrast, the Bateman gradient and the opportunity for sexual selection were poor predictors of sexual selection, despite their continuing popularity. PMID- 26739569 TI - The use of the short communication article format. PMID- 26739570 TI - Cyclopropenation of internal alkynylsilanes and diazoacetates catalyzed by copper(i) N-heterocyclic carbene complexes. AB - Copper(i) N-heterocyclic carbene (CuNHC) complexes are more catalytically active than traditional transition metal salts for the cyclopropenation of internal alkynylsilanes and diazoacetate compounds. A series of 1,2,3-trisubstituted and 1,2,3,3-tetrasubstituted cyclopropenylsilane compounds were isolated in good overall yields. An interesting regioselective and chemodivergent reaction pathway was also observed to furnish a tetra-substituted furan for an electron-rich donor/acceptor diazoacetate. Finally, a practical synthesis of a cyclopropenyl containing starting material that is useful for bioorthogonal chemistry is also described. PMID- 26739568 TI - Sex-specific silencing of X-linked genes by Xist RNA. AB - X-inactive specific transcript (Xist) long noncoding RNA (lncRNA) is thought to catalyze silencing of X-linked genes in cis during X-chromosome inactivation, which equalizes X-linked gene dosage between male and female mammals. To test the impact of Xist RNA on X-linked gene silencing, we ectopically induced endogenous Xist by ablating the antisense repressor Tsix in mice. We find that ectopic Xist RNA induction and subsequent X-linked gene silencing is sex specific in embryos and in differentiating embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs). A higher frequency of X(DeltaTsix)Y male cells displayed ectopic Xist RNA coating compared with X(DeltaTsix)X female cells. This increase reflected the inability of X(DeltaTsix)Y cells to efficiently silence X-linked genes compared with X(DeltaTsix)X cells, despite equivalent Xist RNA induction and coating. Silencing of genes on both Xs resulted in significantly reduced proliferation and increased cell death in X(DeltaTsix)X female cells relative to X(DeltaTsix)Y male cells. Thus, whereas Xist RNA can inactivate the X chromosome in females it may not do so in males. We further found comparable silencing in differentiating X(DeltaTsix)Y and 39,X(DeltaTsix) (X(DeltaTsix)O) ESCs, excluding the Y chromosome and instead implicating the X-chromosome dose as the source of the sex specific differences. Because X(DeltaTsix)X female embryonic epiblast cells and EpiSCs harbor an inactivated X chromosome prior to ectopic inactivation of the active X(DeltaTsix) X chromosome, we propose that the increased expression of one or more X-inactivation escapees activates Xist and, separately, helps trigger X linked gene silencing. PMID- 26739571 TI - Thiazolium carbene catalysts for the fixation of CO2 onto amines. AB - The catalytic N-formylation and N-methylation of amines using CO2 as the carbon source represents a facile and sustainable approach for the synthesis of pharmaceuticals and natural products. Herein, we describe highly effective and inexpensive thiazolium carbene-based catalysts derived from vitamin B1 for the N formylation and N-methylation of amines, using polymethylhydrosiloxane (PMHS) as a reducing agent, which operate under ambient conditions. PMID- 26739573 TI - Improvement of lipid profiles when switching from efavirenz to rilpivirine in HIV infected patients with dyslipidemia. AB - Rilpivirine (RPV) is a non-nucleoside reverse transcriptase inhibitor, which has better lipid profiles than efavirenz (EFV) in treatment naive patients. However, the data on treatment experience are limited especially in dyslipidemic HIV patients; thus, we aimed to assess the change of lipid profiles after switching from EFV to RPV in these patients. In this prospective, open-label, cohort study, we enrolled HIV-1 infected adults who had received at least 6 months of EFV-based regimen, with HIV RNA <50 copies/mL for >=6 months prior to switching. The objectives of this study were to analyze lipid changes and to evaluate the efficacy, safety, tolerability at 24 weeks after switching therapy. Fifty-three patients were enrolled and completed the study. At week 24, a significant decrease in the mean (95% confident interval, CI) total cholesterol (-28.06 mg/dL, 95%CI -35.20 to -20.91, p < 0.0001), LDL-cholesterol (-20.96 mg/dL, 95%CI 28.12 to -13.80, p < 0.0001), high-density lipoprotein (HDL)-cholesterol (-5.11 mg/dL, 95%CI -7.79 to -2.44, p < 0.0001), and triglyceride (-29.79 mg/dL. 95%CI 52.39 to -7.19, p = 0.011) levels were observed. One patient had virologic rebound with HIV RNA of 114 copies/mL at week 24. Three (5.7%) patients had grade 2 elevations of liver enzymes. None of the patients discontinued RPV during the study. Switching from EFV-based therapy to RPV-based regimen improved lipid profiles in fully suppressed HIV patients with dyslipidemia. This treatment should be considered in these patients. PMID- 26739575 TI - Cellular uptake of metallated cobalamins. AB - Cellular uptake of vitamin B12-cisplatin conjugates was estimated via detection of their metal constituents (Co, Pt, and Re) by inductively coupled plasma mass spectrometry (ICP-MS). Vitamin B12 (cyano-cob(iii)alamin) and aquo-cob(iii)alamin [Cbl-OH2](+), which differ in the beta-axial ligands (CN(-) and H2O, respectively), were included as control samples. The results indicated that B12 derivatives delivered cisplatin to both cellular cytosol and nuclei with an efficiency of one third compared to the uptake of free cisplatin cis [Pt(II)Cl2(NH3)2]. In addition, uptake of charged B12 derivatives including [Cbl OH2](+), [{Co}-CN-{cis-PtCl(NH3)2}](+), [{Re}-{Co}-CN-{cis-PtCl(NH3)2}](+), and [{Co}-CN-{trans-Pt(Cyt)(NH3)2}](2+) (Cyt = cytarabin) was high compared to neutral B12, which implied the existence of an additional internalization pathway for charged B12 vitamin analogs. The affinities of the charged B12 derivatives to the B12 transporters HC, IF and TC were similar to that of native vitamin B12. PMID- 26739577 TI - Analysis of motion during the breast clamping phase of mammography. AB - OBJECTIVE: To measure paddle motion during the clamping phase of a breast phantom for a range of machine/paddle combinations. METHODS: A deformable breast phantom was used to simulate a female breast. 12 mammography machines from three manufacturers with 22 flexible and 20 fixed paddles were evaluated. Vertical motion at the paddle was measured using two calibrated linear potentiometers. For each paddle, the motion in millimetres was recorded every 0.5 s for 40 s, while the phantom was compressed with 80 N. Independent t-tests were used to determine differences in paddle motion between flexible and fixed, small and large, GE Senographe Essential (General Electric Medical Systems, Milwaukee, WI) and Hologic Selenia Dimensions paddles (Hologic, Bedford, MA). Paddle tilt in the medial-lateral plane for each machine/paddle combination was calculated. RESULTS: All machine/paddle combinations demonstrate highest levels of motion during the first 10 s of the clamping phase. The least motion is 0.17 +/- 0.05 mm/10 s (n = 20) and the most motion is 0.51 +/- 0.15 mm/10 s (n = 80). There is a statistical difference in paddle motion between fixed and flexible (p < 0.001), GE Senographe Essential and Hologic Selenia Dimensions paddles (p < 0.001). Paddle tilt in the medial-lateral plane is independent of time and varied from 0.04 degrees to 0.69 degrees . CONCLUSION: All machine/paddle combinations exhibited motion and tilting, and the extent varied with machine and paddle sizes and types. ADVANCES IN KNOWLEDGE: This research suggests that image blurring will likely be clinically insignificant 4 s or more after the clamping phase commences. PMID- 26739579 TI - Current Clinical Trials on the Use of Direct Oral Anticoagulants in the Pediatric Population. AB - Common treatment options for deep vein thrombosis and venous thromboembolism in the pediatric population include unfractionated heparin, low molecular weight heparin, and warfarin. Other alternatives are bivalirudin, argatroban, and fondaparinux. Warfarin is the only approved oral option, but an oral agent without frequent monitoring would be optimal for pediatric patients. Thus, there is an increasing need for new anticoagulation options in this population. None of the current direct oral anticoagulants have FDA-approved indications and dosing in children. The two classes of DOACs and the drugs they are comprised of are factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) and direct thrombin inhibitor (dabigatran). Off-label usage of these agents is largely based on adult doses. By far, rivaroxaban and dabigatran have the most published data and ongoing trials in pediatric patients compared to edoxaban and apixaban. After evaluating the current literature available on these agents, it is, however, still too early to make any definitive recommendations on their usage in this special population. PMID- 26739580 TI - Small datasets to develop and validate prognostic models may be a necessary evil to study rare tumours. PMID- 26739581 TI - Acute kidney injury induced by thrombotic microangiopathy in a patient with hemophagocytic lymphohistiocytosis. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a fatal clinical syndrome characterized by excessive immune activation and inflammation. It is frequently complicated by acute kidney injury (AKI) that often develops as acute tubular necrosis (ATN). Meanwhile, renal thrombotic microangiopathy (TMA) is a rare pathologic finding that mostly occurs in hemolytic uremic syndrome or thrombotic thrombocytopenic purpura. There are only few reports on TMA developing in patients with HLH. We present here a rare case of TMA associated HLH. CASE PRESENTATION: A 60-year-old woman was admitted for a fever of unknown origin that had persisted for several weeks. She presented with AKI and pancytopenia. Clinical, laboratory and bone marrow biopsy findings met the criteria of HLH. Kidney biopsy showed TMA and minimal ATN, which suggested that the primary cause of AKI was TMA in this case. Because of sustained oliguria, we initiated hemodialysis (HD) and also decided to use chemotherapy composed of dexamethasone, etoposide and cyclosporine for treatment of HLH. Six months after the initiation of chemotherapy, pancytopenia was completely resolved, indicating the resolution of HLH. At the same time, serum creatinine decreased to a normal range without the need for HD, suggesting the resolution of TMA. CONCLUSION: We report a case of renal TMA associated HLH. This case suggests that renal TMA should be considered as a primary cause of AKI in patients with underlying HLH. PMID- 26739582 TI - Conserved arginine residues in the carboxyl terminus of the equine arteritis virus E protein may play a role in heparin binding but may not affect viral infectivity in equine endothelial cells. AB - Equine arteritis virus (EAV), the causative agent of equine viral arteritis, has relatively broad cell tropism in vitro. In horses, EAV primarily replicates in macrophages and endothelial cells of small blood vessels. Until now, neither the cellular receptor(s) nor the mechanism(s) of virus attachment and entry have been determined for this virus. In this study, we investigated the effect of heparin on EAV infection in equine endothelial cells (EECs). Heparin, but not other glycosaminoglycans, could reduce EAV infection up to 93 %. Sequence analysis of the EAV E minor envelope protein revealed a conserved amino acid sequence (52 RSLVARCSRGARYR 65) at the carboxy terminus of the E protein, which was predicted to be the heparin-binding domain. The basic arginine (R) amino acid residues were subsequently mutated to glycine by site-directed mutagenesis of ORF2a in an E protein expression vector and an infectious cDNA clone of EAV. Two single mutations in E (R52G and R57G) did not affect the heparin-binding capability, whereas the E double mutation (R52,60G) completely eliminated the interaction between the E protein and heparin. Although the mutant R52,60G EAV did not bind heparin, the mutations did not completely abolish infectivity, indicating that heparin is not the only critical factor for EAV infection. This also suggested that other viral envelope protein(s) might be involved in attachment through heparin or other cell-surface molecules, and this warrants further investigation. PMID- 26739583 TI - Cryopreservation in fish: current status and pathways to quality assurance and quality control in repository development. AB - Cryopreservation in aquatic species in general has been constrained to research activities for more than 60 years. Although the need for application and commercialisation pathways has become clear, the lack of comprehensive quality assurance and quality control programs has impeded the progress of the field, delaying the establishment of germplasm repositories and commercial-scale applications. In this review we focus on the opportunities for standardisation in the practices involved in the four main stages of the cryopreservation process: (1) source, housing and conditioning of fish; (2) sample collection and preparation; (3) freezing and cryogenic storage of samples; and (4) egg collection and use of thawed sperm samples. In addition, we introduce some key factors that would assist the transition to commercial-scale, high-throughput application. PMID- 26739584 TI - Bone marrow stem cell dysfunction in radiation-induced abscopal bone loss. AB - BACKGROUND: Bone-related complications are commonly reported in cancer patients receiving radiotherapy and are collectively referred to as the abscopal effect of irradiation, the mechanism of which remains poorly understood. When patients receive targeted radiotherapy to a tumor, the local skeleton is exposed to radiation, particularly within the bone marrow. We therefore investigated the hypothesis that single bone irradiation can induce deterioration of the skeleton outside the radiation field and is mediated by the bone marrow. METHODS: Using 4 month-old male Sprague-Dawley rats, the effects of irradiation (20 Gy, right distal femur and proximal tibia) on bone quality, microarchitecture and bone marrow, were evaluated prospectively by microcomputed tomography, histomorphometry, real-time polymerase chain reaction, and Western blot analysis. RESULTS: At 12 weeks post-irradiation, bone loss of the non-irradiated bone was induced and marrow adiposity was increased. Expression of runt-related transcription factor-2 by bone mesenchymal stem cells (BMSCs) decreased after irradiation by 88.0 % (P < 0.01) at the contralateral and 82.3 % (P < 0.01) at the irradiation site 2 weeks post-irradiation and decreased by 94.5 % (P < 0.001) at the contralateral and 44.1 % (P < 0.05) at the irradiation site 12 weeks post irradiation. Interestingly, peroxisome proliferator-activated receptor gamma expression decreased by 61.8 % (P < 0.05) at the contralateral and by 48.3 % (P < 0.05) at the irradiation site 2 weeks post-irradiation but increased by 9-fold at the contralateral (P < 0.001) and by 13-fold (P < 0.001) at the irradiation site 12 weeks post-irradiation. CONCLUSIONS: These data highlight that radiation induced bone complications are partly BMSC-mediated, with important implications for bone health maintenance in patients receiving radiotherapy. PMID- 26739585 TI - Re: Pediatric Hypertension and Cardiac Hypertrophy. PMID- 26739587 TI - Democratizing Implementation and Innovation in Mental Health Care. AB - Improvements in the quality of mental health care in the United States depend on the successful implementation of evidence-based treatments (EBT's) in typical settings of care. Unfortunately, there is little evidence that EBT's are used in ways that would approximate their established fidelity standards in such settings. This article describes an approach to more successful implementation of EBT's via a collaborative process between intervention developers and intervention users (e.g. providers, administrators, consumers) called Lead-user Innovation. Lead-user Innovation democratizes the implementation process by integrating the expertise of lead-users in the delivery, adaptation, innovation and evaluation of EBT's. PMID- 26739586 TI - Renal Denervation for Treatment of Hypertension: a Second Start and New Challenges. AB - Following the publication of the randomized controlled but open-label trial Symplicity HTN-2, catheter-based renal sympathetic denervation was proposed as a novel treatment for drug-resistant hypertension. Thousands of procedures were routinely performed in Europe, Australia and Asia, and many observational studies were published. A sudden shift from overoptimistic views to radical scepticism occurred later, when the large US randomized sham-controlled trial Symplicity HTN 3 failed to meet its primary blood pressure lowering efficacy endpoint. Experts are divided on the reasons accounting for the large discrepancy between the results of initial studies and those of Symplicity HTN-3. Indeed, the blood pressure lowering effect associated with renal denervation was overestimated in initial trials due to various patient and physician-related biases, whereas it could have been underestimated in Symplicity HTN-3, which was well designed but not rigorously executed. Still, there is a large consensus on the need to further study catheter-based renal denervation in more controlled conditions, with particular emphasis on identification of predictors of blood pressure response. US and European experts have recently issued very similar recommendations on design of upcoming trials, procedural aspects, drug treatment, patient population and inclusion-exclusion criteria. Application of these new standards may represent a second chance for renal denervation to demonstrate--or not--its efficacy and safety in various patient populations. With its highly standardized treatment regimen, the French trial DENERHTN paved the way for this new approach and may inspire upcoming studies testing novel renal denervation systems in different populations. PMID- 26739588 TI - Gestational Age, Birthweight for Gestational Age, and Childhood Hospitalisations for Asthma and Other Wheezing Disorders. AB - BACKGROUND: Preterm birth, early term birth, and low birthweight are associated with childhood wheezing disorders in developed Western settings, but observed associations could be confounded by socio-economic position. This study aims to clarify such associations in a developed non-Western setting with a different confounding structure. METHODS: Using Cox regression, we examined the adjusted associations of gestational age and birthweight for gestational age with time to first public hospital admission for asthma, bronchitis, and bronchiolitis (International Classification of Diseases, Ninth Version Clinical Modification 466, 490, and 493) from 9 days to 12 years in a population-representative birth cohort of 8327 Chinese children in Hong Kong, a developed setting with less clear social patterning of prematurity or birthweight. Analyses were adjusted for infant and parental characteristics and socio-economic position. RESULTS: Children born late preterm (34 to <37 weeks) had higher risk of hospitalisation for asthma and other wheezing disorders [hazard ratio (HR) 1.99, 95% confidence interval (CI) 1.48, 2.67] than children born full term (39 to <41 weeks). Early term births (37 to <39 weeks) had HR 1.01 (95% CI 0.84, 1.22), late term births (41 to <42 weeks) had HR 0.77 (95% 0.59, 1.01), and post-term births (>=42 weeks) had HR 0.56 (95% CI 0.32, 0.98). Large for gestational age was associated with lower risk of hospitalisation (HR 0.76, 95% CI 0.57, 0.99). CONCLUSION: The association of preterm birth with childhood wheezing could be biologically mediated. We cannot rule out an association for early term births. PMID- 26739589 TI - Coronary artery bypass surgery compared with percutaneous coronary interventions in patients with insulin-treated type 2 diabetes mellitus: a systematic review and meta-analysis of 6 randomized controlled trials. AB - BACKGROUND: Data regarding the long-term clinical outcomes in patients with insulin-treated type 2 diabetes mellitus (ITDM) revascularized by either coronary artery bypass surgery (CABG) or percutaneous coronary intervention (PCI) are still controversial. We sought to compare the long-term (>=1 year) adverse clinical outcomes in patients with ITDM who underwent revascularization by either CABG or PCI. METHODS: Randomized Controlled Trials (RCTs) comparing the long-term clinical outcomes in patients with ITDM and non-ITDM revascularized by either CABG or PCI were searched from electronic databases. Data for patients with ITDM were carefully retrieved. Odd Ratio (OR) with 95 % confidence interval (CI) was used to express the pooled effect on discontinuous variables and the pooled analyses were performed with RevMan 5.3. RESULTS: Six RCTs involving 10 studies, with a total of 1297 patients with ITDM were analyzed (639 patients from the CABG group and 658 patients from the PCI group). CABG was associated with a significantly lower mortality rate compared to PCI with OR: 0.59, 95 % CI 0.42 0.85; P = 0.004. Major adverse cardiovascular and cerebrovascular events as well as repeated revascularization were also significantly lower in the CABG group with OR: 0.51, 95 % CI 0.27-0.99; P = 0.03 and OR 0.34, 95 % CI 0.24-0.49; P < 0.00001 respectively. However, compared to PCI, the rate of stroke was higher in the CABG group with OR: 1.41, 95 % CI 0.64-3.09; P = 0.40, but this result was not statistically significant. CONCLUSION: CABG was associated with significantly lower long-term adverse clinical outcomes compared to PCI in patients with ITDM. However, due to an insignificantly higher rate of stroke in the CABG group, further researches with a larger number of randomized patients are required to completely solve this issue. PMID- 26739592 TI - Synthesis and in vivo diuretic activity of some new benzothiazole sulfonamides containing quinoxaline ring system. AB - A series of new 6-substituted-N-[3-{2-(substituted phenyl)-ethenyl} quinoxaline 2(1H)-ylidene]-1,3-benzothiazole-2-amine (4a-f) were designed and synthesized by condensing 2-amino-benzothiazole-6-sulfonic acid amide (1) with chalcones of quinoxaline-2-one (3a-f) in a hope to obtain promising and a new class of diuretic agents. Structures of all the newly synthesized compounds were characterized by spectral data and elemental analysis. The pharmacological studies in experimental rats indicates that compound 4c possesses excellent in vivo diuretic activity of 1.13 and appears to be a better diuretic agent than the reference drugs, acetazolamide (1.0) and urea (0.88). Insight of the binding mode of the synthesized compounds (ligand) into the binding sites of carbonic anhydrase enzyme (PDF code: 4KUV) was provided by docking studies, performed with the help of Maestro 9.0 docking software. Further pharmacokinetic and toxicological studies are needed to confirm the safety of compound 4c which emerged as a lead diuretic compound. PMID- 26739591 TI - Can widely used cell type markers predict the suitability of immortalized or primary mammary epithelial cell models? AB - BACKGROUND: Mammary cell cultures are convenient tools for in vitro studies of mammary gland biology. However, the heterogeneity of mammary cell types, e.g., glandular milk secretory epithelial or myoepithelial cells, often complicates the interpretation of cell-based data. The present study was undertaken to determine the relevance of bovine primary mammary epithelial cells isolated from American Holstein (bMECUS) or Swiss Holstein-Friesian (bMECCH) cows, and of primary bovine mammary alveolar epithelial cells stably transfected with simian virus-40 (SV-40) large T-antigen (MAC-T) for in vitro analyses. This was evaluated by testing their expression pattern of cytokeratin (CK) 7, 18, 19, vimentin, and alpha smooth muscle actin (alpha-SMA). RESULTS: The expression of the listed markers was assessed using real-time quantitative PCR, flow cytometry and immunofluorescence microscopy. Characteristic markers of the mesenchymal (vimentin), myoepithelial (alpha-SMA) and glandular secretory cells (CKs) showed differential expression among the studied cell cultures, partly depending on the analytical method used. The relative mRNA expression of vimentin, CK7 and CK19, respectively, was lower (P < 0.05) in immortalized than in primary mammary cell cultures. The stain index (based on flow cytometry) of CK7 and CK19 protein was lower (P < 0.05) in MAC-T than in bMECs, while the expression of alpha-SMA and CK18 showed an inverse pattern. Immunofluorescence microscopy analysis mostly confirmed the mRNA data, while partly disagreed with flow cytometry data (e.g., vimentin level in MAC-T). The differential expression of CK7 and CK19 allowed discriminating between immortal and primary mammary cultures. CONCLUSIONS: The expression of the selected widely used cell type markers in primary and immortalized MEC cells did not allow a clear preference between these two cell models for in vitro analyses studying aspects of milk composition. All tested cell models exhibited to a variable degree epithelial and mesenchymal features. Thus, based on their characterization with widely used cell markers, none of these cultures represent an unequivocal alveolar mammary epithelial cell model. For choosing the appropriate in vitro model additional properties such as the expression profile of specific proteins of interest (e.g., transporter proteins) should equally be taken into account. PMID- 26739593 TI - 2015 Reviewers. PMID- 26739594 TI - Achieving Adherence to Evidence-Based Practices: Are Health IT and Hospital Physician Integration Complementary or Substitutive Strategies? AB - In response to evolving policies and conditions, hospitals have increased health information technology (HIT) adoption and strived to improve hospital-physician integration. While evidence suggests that both HIT and integration confer independent benefits, when combined, they may provide complementary means to achieve high performance or overlap to offset each other's contribution. We explore this relationship in the context of hospital adherence to evidence-based practices (EBPs). Using the American Hospital Association's Annual and IT Supplement surveys, and Centers for Medicare and Medicaid Services's Hospital Compare, we estimate the independent relationships and interactions between HIT and hospital-physician integration with respect to EBP adherence. HIT adoption and tight (but not loose) integration are independently associated with greater adherence to EBPs. The interaction between HIT adoption and tight integration is negative, consistent with an offsetting association between HIT adoption and integration in their relationship to EBP adherence. This finding reveals the need to be aware of potential substitutive effects from simultaneous pursuit of multiple approaches to performance improvement. PMID- 26739595 TI - Reconstruction of complex soft-tissue defects in the extremities with chimeric anterolateral thigh perforator flap. AB - INTRODUCTION: The reconstruction of extensive three-dimensional defects in the extremities is a difficult challenge. Many attempts have been made to reconstruct such defects using the chimeric flap concept, enabling flaps with larger surface areas to be used while maintaining economical tissue use. The anterolateral thigh (ALT) chimeric flap is one of the most useful tools for the reconstruction of complex three-dimensional defects in the extremities. METHODS: From January 2010 to March 2012, Twenty-two patients underwent extremity reconstruction using chimeric ALT perforator flaps, which consists of a skin component on its isolated perforator and a portion of the fascia and muscle flaps on the same pedicle from the descending branch of the lateral circumflex femoral artery (LCFA). The defects were in either a lower (n = 10) or an upper extremity (n = 12). The area of the soft tissue defects ranged from 43 * 35 cm to 19 * 9 cm (mean, 25 * 18 cm), containing extensive, irregular, ring-like soft tissue defects or degloving injuries. RESULTS: The mean dimension of skin flap was 19.8 * 11.2 cm. The mean dimension of fascia flap was 8.9 * 7.1 cm. The mean dimension of muscle flap was 11.1 * 7.5 cm. No total flap loss occurred. One patient presented with venous thrombosis, and re-anastomosis and vein grafting were performed. Two cases exhibiting partial skin graft loss at the site at which the fascia flap was inset were treated via secondary skin grafts. During a follow-up period of 18 months-30 months, patients were satisfied with the functional and aesthetic outcome. No serious donor-site complications occurred. DISCUSSION: Chimeric anterolateral thigh perforator flap can be one of the best choice for reconstruction of complex soft-tissue defects in the extremities. CONCLUSIONS: The various tissue components and maximal freedom offered by chimeric tissue flaps associated with the same descending branch of the LCFA provide versatile coverage of large, complex, and irregular soft-tissue defects in the extremities. PMID- 26739596 TI - Retrospective analysis of survival after resection of pancreatic renal cell carcinoma metastases. AB - INTRODUCTION: Previous reports showed an excellent survival for patients after resection of pancreatic metastases from renal cell cancer (pRCC) and reported several predictive factors. This study aims to give more evidence to reported risk factors by analyzing a large cohort of patients with pancreatic resection due to pRCC. PATIENTS AND METHODS: We retrospectively analyzed all pancreatic resections due to pRCC between January 1993 and October 2014 in two German pancreatic surgery centers. Predictive factors were analyzed using the chi square test. RESULTS: Surgery was performed in 40 patients. Mean survival after resection was 147.9 months (SD 25.6 months). No predictive factors for survival were identified. Pathological examination showed that five out of 21 patients with examined peripancreatic lymph nodes had lymph node metastases. CONCLUSIONS: Although our analysis comprised the biggest cohort of patients with pRCC it rendered no significant predictor for survival. This might be due to the overall excellent prognosis of study patients and the relatively rare condition with a limited number of patients. Several patients had lymph node metastases. Therefore lymphadenectomy should be considered in pRCC resection if the health condition of the patient permits this. By this more aggressive approach to pRCC, a better prognosis after resection might be achieved. PMID- 26739597 TI - The effect of atp-dependent potassium uptake on mitochondrial functions under acute hypoxia. AB - The opening of mitochondrial K(+) ATR-channel (mtK(+) ATR-channel) is supposed to be important in the modulation of mitochondrial functions under hypoxia, but the underlying mechanisms have not been clarified yet. The aim of this work was to study the effect of acute hypoxia on mtK(+) ATR-channel activity and to estimate the contribution of the channel in the modulation of mitochondrial functions. MtK(+) ATR-channel activity was assessed polarographically from the rate of State 4 respiration and by potentiometric monitoring of potassium efflux from deenergized mitochondria. It was shown that hypoxia reliably increased mtK(+) ATR channel activity, which resulted in the changes of respiration rates (increase of State 4 and suppression of State 3 respiration), uncoupling (the decrease of respiratory control ratio) and suppression of phosphorylation. These effects were well mimicked by mtK(+) ATR-channel opener diazoxide (DZ) in isolated rat liver mitochondria. MtK(+) ATR-channel opening in vitro suppressed phosphorylation too, but increased phosphorylation efficiency, while mtK(+) ATR-channel blockers reduced it dramatically. The correlation was established between mtK(+) ATR channel activity and the endurance of the rats to physical training under hypoxia. Hypoxia improved physical endurance, but treatment by mtK(+) ATR-channel blockers glibenklamide and 5-hydroxydecanoate (5-HD) prior to hypoxia strongly reduced both the channel activity and the endurance limits. This was in accord with the observation that under glibenklamide and 5-HD administration hypoxia failed to restore mtK(+) ATR-channel activity. Based on the experiments, we came to the conclusion that mtK(+) ATR-channel opening played a decisive role in the regulation of energy metabolism under acute hypoxia via the modulation of phosphorylation system in mitochondria. PMID- 26739598 TI - Antineoplastic copper coordinated complexes (Casiopeinas) uncouple oxidative phosphorylation and induce mitochondrial permeability transition in cardiac mitochondria and cardiomyocytes. AB - Copper-based drugs, Casiopeinas (Cas), exhibit antiproliferative and antineoplastic activities in vitro and in vivo, respectively. Unfortunately, the clinical use of these novel chemotherapeutics could be limited by the development of dose-dependent cardiotoxicity. In addition, the molecular mechanisms underlying Cas cardiotoxicity and anticancer activity are not completely understood. Here, we explore the potential impact of Cas on the cardiac mitochondria energetics as the molecular mechanisms underlying Cas-induced cardiotoxicity. To explore the properties on mitochondrial metabolism, we determined Cas effects on respiration, membrane potential, membrane permeability, and redox state in isolated cardiac mitochondria. The effect of Cas on the mitochondrial membrane potential (Deltapsim) was also evaluated in isolated cardiomyocytes by confocal microscopy and flow cytometry. Cas IIIEa, IIgly, and IIIia predominately inhibited maximal NADH- and succinate-linked mitochondrial respiration, increased the state-4 respiration rate and reduced membrane potential, suggesting that Cas also act as mitochondrial uncouplers. Interestingly, cyclosporine A inhibited Cas-induced mitochondrial depolarization, suggesting the involvement of mitochondrial permeability transition pore (mPTP). Similarly to isolated mitochondria, in isolated cardiomyocytes, Cas treatment decreased the Deltapsim and cyclosporine A treatment prevented mitochondrial depolarization. The production of H2O2 increased in Cas-treated mitochondria, which might also increase the oxidation of mitochondrial proteins such as adenine nucleotide translocase. In accordance, an antioxidant scavenger (Tiron) significantly diminished Cas IIIia mitochondrial depolarization. Cas induces a prominent loss of membrane potential, associated with alterations in redox state, which increases mPTP opening, potentially due to thiol-dependent modifications of the pore, suggesting that direct or indirect inhibition of mPTP opening might reduce Cas-induced cardiotoxicity. PMID- 26739599 TI - Early failures of porous tantalum osteonecrosis implants: a case series with retrieval analysis. AB - BACKGROUNDS: Porous tantalum osteonecrosis implants have been used in femoral head necrosis for several years, while the clinical outcomes were mixed. As a joint-preserving surgery, early necrosis deterioration and conversion to total hip arthroplasy failed our expectation. We hence investigate an observational study with retrieval analysis to find out the underlying reasons. METHODS: Thirteen patients were treated with core decompression and implantation of a tantalum rod. The cases were evaluated both functionally and radiologically. We retrieved and analyzed the micro-structural changes and the histopathologic features of four early failed femoral heads with scanning electron microscopy, histopathologic examination, and micro-CT scaning. RESULTS: All implants were placed in proper positions. One-year survival rate was 64.29 % with a HSS score of 81.11 +/- 15.62. Four patients converted to arthroplasty in a mean time of 305 days (0.84 years), with a HSS score of 43.75 +/- 7.5 at the last follow-up. A liquid layer surrounded the tantalum implant was noted on MRI in all four failed cases. Volume render CT remodeling revealed interspace between the metal and bone. Scanning electron microscopy and histopathologic examination indicated sparse and isolated bone ingrowth into the implants. The remodeled trabecular bone and the increased density around the peri-implant area were illustrated with micro-CT scaning. CONCLUSIONS: The deterioration of early failed tantalum implant exceeds the nature of osteonecrosis progression. Rather than insufficient mechanical support resulting in improper position and invalid bone ingrowth, nullification of core decompression and consequential intra-osseous pressurization probably led to early failure of porous tantalum osteonecrosis implants. PMID- 26739600 TI - Molar tooth carbonates and benthic methane fluxes in Proterozoic oceans. AB - Molar tooth structures are ptygmatically folded and microspar-filled structures common in early- and mid-Proterozoic (~2,500-750 million years ago, Ma) subtidal successions, but extremely rare in rocks <750 Ma. Here, on the basis of Mg and S isotopes, we show that molar tooth structures may have formed within sediments where microbial sulphate reduction and methanogenesis converged. The convergence was driven by the abundant production of methyl sulphides (dimethyl sulphide and methanethiol) in euxinic or H2S-rich seawaters that were widespread in Proterozoic continental margins. In this convergence zone, methyl sulphides served as a non-competitive substrate supporting methane generation and methanethiol inhibited anaerobic oxidation of methane, resulting in the buildup of CH4, formation of degassing cracks in sediments and an increase in the benthic methane flux from sediments. Precipitation of crack-filling microspar was driven by methanogenesis-related alkalinity accumulation. Deep ocean ventilation and oxygenation around 750 Ma brought molar tooth structures to an end. PMID- 26739602 TI - Relationship between vesicle size and steric hindrance influences vesicle rupture on solid supports. AB - Phospholipid assemblies on solid supports mimic the cell membrane, and provide a platform to study membrane biology. Among the different types of model membranes, the planar bilayer is a two-dimensional lipid bilayer sheet that can be formed by the adsorption and spontaneous rupture of vesicles. The formation process is influenced by the interactions between vesicles and the solid support as well as between vesicles. On silicon oxide, which is a commonly used solid support, vesicles typically adsorb until reaching a critical coverage and then spontaneous rupture begins. Although it is generally understood that spontaneous rupture leads to planar bilayer formation, oversaturation of vesicles at the critical coverage can hinder the whole process due to a steric factor. To date, the role of this factor has been scrutinized only in relation to temperature, and the influence of additional parameters remains to be elucidated. In this work, we have investigated how vesicle size and corresponding steric constraints influence the kinetics of vesicle adsorption and rupture and, more specifically, how the state of adsorbed vesicles after fusion depends on the vesicle size. Using quartz crystal microbalance-dissipation (QCM-D) and fluorescence recovery after photobleaching (FRAP), we characterized the adsorption kinetics of vesicles onto silicon oxide and the lateral mobility of solid-supported lipid assemblies. While the vesicle adsorption kinetics were diffusion-limited up to the onset of vesicle rupture, the extent of rupture depended on vesicle size and it was observed that larger vesicles are more prone to steric effects than smaller vesicles. We discuss this finding in terms of the structural transformation from adsorbed vesicles to a planar bilayer, including how the interplay of thermodynamic, kinetic and steric factors can affect vesicle rupture on solid supports. PMID- 26739604 TI - The Global Burden of Fungal Diseases. AB - Fungal diseases require greater attention today than ever before, given the expanding population of immunosuppressed patients who are at higher risk for these diseases. This article reports on distribution, incidence, and prevalence of various fungal diseases and points out gaps in knowledge where such data are not available. Fungal diseases that contribute substantially to global morbidity and mortality are highlighted. Long-term, sustainable surveillance programs for fungal diseases and better noninvasive and reliable diagnostic tools are needed to estimate the burden of these diseases more accurately. PMID- 26739605 TI - Update from the Laboratory: Clinical Identification and Susceptibility Testing of Fungi and Trends in Antifungal Resistance. AB - Despite the availability of new diagnostic assays and broad-spectrum antifungal agents, invasive fungal infections remain a significant challenge to clinicians and are associated with marked morbidity and mortality. In addition, the number of etiologic agents of invasive mycoses has increased accompanied by an expansion in the immunocompromised patient populations, and the use of molecular tools for fungal identification and characterization has resulted in the discovery of several cryptic species. This article reviews various methods used to identify fungi and perform antifungal susceptibility testing in the clinical laboratory. Recent developments in antifungal resistance are also discussed. PMID- 26739606 TI - Contemporary Strategies in the Prevention and Management of Fungal Infections. AB - Major patient groups at risk for invasive fungal infection are found in hematology, intensive care, and abdominal surgery units. The vast majority of invasive fungal infections are candidemia, pulmonary aspergillosis, and pulmonary or sinunasal mucormycosis, the latter typically in the context of diabetes. Clinical presentation is highly variable and depends on host, fungus, and organs involved. Symptoms are unspecific and, outside of fungemia, diagnosis is established by radiographic imaging combined with microbiological, serologic, and histopathological workup. Complex prevention and management strategies have been developed, and it is recommended to follow institutional pathways to standardize diagnostic and therapeutic strategies. PMID- 26739603 TI - Approach to the Solid Organ Transplant Patient with Suspected Fungal Infection. AB - In solid organ transplant (SOT) recipients, invasive fungal infections (IFIs) are associated with significant morbidity and mortality. Detection of IFIs can be difficult because the signs and symptoms are similar to those of viral or bacterial infections, and diagnostic techniques have limited sensitivity and specificity. Clinicians must rely on knowledge of the patient's risk factors for fungal infection to make a diagnosis. The authors describe their approach to the SOT recipient with suspected fungal infection. The epidemiology of IFIs in the SOT population is reviewed, and a syndromic approach to suspected IFI in SOT recipients is described. PMID- 26739607 TI - Blastomycosis. AB - Blastomycosis is an endemic fungal infection due to Blastomyces dermatitidis that most commonly causes pneumonia; but the organism can disseminate to any organ system, most commonly the skin, bones/joints, and genitourinary tract. Both immunocompetent and immunocompromised persons can be infected, but more severe disease occurs in the immunocompromised. Blastomycosis can be diagnosed by culture, direct visualization of the yeast in affected tissue, and/or antigen testing. Treatment course and duration depend on severity of illness. For mild to moderate pulmonary disease the treatment is itraconazole. For severe blastomycosis, lipid formulation amphotericin B is given, followed by step-down therapy with itraconazole. PMID- 26739608 TI - Antifungal Agents: Spectrum of Activity, Pharmacology, and Clinical Indications. AB - The currently available antifungal therapies vary significantly in terms of spectrum of activity, pharmacologic properties, toxicity, and potential for drug drug interactions. This article provides a history of antifungal development and discusses the characteristics of individual drugs and drug classes, including the amphotericin B formulations, the triazoles, the echinocandins, and flucytosine. For each drug, the clinically relevant pharmacokinetics are reviewed, the spectrum of activity described, and the Food and Drug Administration-approved clinical indications examined. Antifungal side-effects, therapeutic drug monitoring, and drug-drug interactions are summarized. The variations among different formulations are highlighted. PMID- 26739609 TI - Coccidioidomycosis. AB - Coccidioides immitis and C posadasii are pathogenic dimorphic fungi responsible for causing coccidioidomycosis in the Southwestern United States and Central and South America. Antifungal therapy is beneficial and entails careful periodic assessment with therapies ranging from none or short courses of therapy to prolonged antifungal therapy. Factors that influence the decision to treat are the duration or severity of infection, radiographic findings, anticomplementary titers, presence of underlying immunosuppression, and comorbidities. Cure for disseminated infection is infrequent with current treatment regimens. This review summarizes the management guidelines for various disease manifestations and reviews data on challenging cases with newer agents. PMID- 26739610 TI - Invasive Candidiasis. AB - Invasive candidiasis is a collective term that refers to a group of infectious syndromes caused by a variety of species of Candida, 5 of which cause most cases. Candidemia is the most commonly recognized syndrome associated with invasive candidiasis. Certain conditions may influence the likelihood for one species versus another in a specific clinical scenario, and this can have important implications for selection of antifungal therapy and the duration of treatment. Molecular diagnostic technology plays an ever-increasing role as an adjunct to traditional culture-based diagnostics, offering significant potential toward improvement in patient care. PMID- 26739613 TI - Simulation of synaptic short-term plasticity using Ba(CF3SO3)2-doped polyethylene oxide electrolyte film. AB - The simulation of synaptic plasticity using new materials is critical in the study of brain-inspired computing. Devices composed of Ba(CF3SO3)2-doped polyethylene oxide (PEO) electrolyte film were fabricated and with pulse responses found to resemble the synaptic short-term plasticity (STP) of both short-term depression (STD) and short-term facilitation (STF) synapses. The values of the charge and discharge peaks of the pulse responses did not vary with input number when the pulse frequency was sufficiently low(~1 Hz). However, when the frequency was increased, the charge and discharge peaks decreased and increased, respectively, in gradual trends and approached stable values with respect to the input number. These stable values varied with the input frequency, which resulted in the depressed and potentiated weight modifications of the charge and discharge peaks, respectively. These electrical properties simulated the high and low band-pass filtering effects of STD and STF, respectively. The simulations were consistent with biological results and the corresponding biological parameters were successfully extracted. The study verified the feasibility of using organic electrolytes to mimic STP. PMID- 26739611 TI - Potential Dual Role of Eugenol in Inhibiting Advanced Glycation End Products in Diabetes: Proteomic and Mechanistic Insights. AB - Medicinally important genus Ocimum harbors a vast pool of chemically diverse metabolites. Current study aims at identifying anti-diabetic candidate compounds from Ocimum species. Major metabolites in O. kilimandscharicum, O. tenuiflorum, O. gratissimum were purified, characterized and evaluated for anti-glycation activity. In vitro inhibition of advanced glycation end products (AGEs) by eugenol was found to be highest. Preliminary biophysical analysis and blind docking studies to understand eugenol-albumin interaction indicated eugenol to possess strong binding affinity for surface exposed lysines. However, binding of eugenol to bovine serum albumin (BSA) did not result in significant change in secondary structure of protein. In vivo diabetic mice model studies with eugenol showed reduction in blood glucose levels by 38% likely due to inhibition of alpha glucosidase while insulin and glycated hemoglobin levels remain unchanged. Western blotting using anti-AGE antibody and mass spectrometry detected notably fewer AGE modified peptides upon eugenol treatment both in vivo and in vitro. Histopathological examination revealed comparatively lesser lesions in eugenol treated mice. Thus, we propose eugenol has dual mode of action in combating diabetes; it lowers blood glucose by inhibiting alpha-glucosidase and prevents AGE formation by binding to epsilon-amine group on lysine, protecting it from glycation, offering potential use in diabetic management. PMID- 26739616 TI - Genome-wide identification of DNA methylation provides insights into the association of gene expression in rice exposed to pesticide atrazine. AB - Atrazine (ATR) is a pesticide widely used for controlling weeds for crop production. Crop contamination with ATR negatively affects crop growth and development. This study presents the first genome-wide single-base-resolution maps of DNA methylation in ATR-exposed rice. Widespread differences were identified in CG and non-CG methylation marks between the ATR-exposed and ATR free (control) rice. Most of DNA methyltransferases, histone methyltransferases and DNA demethylase were differentially regulated by ATR. We found more genes hypermethylated than those hypomethylated in the regions of upstream, genebody and downstream under ATR exposure. A stringent group of 674 genes (p < 0.05, two fold change) with a strong preference of differential expression in ATR-exposed rice was identified. Some of the genes were identified in a subset of loss of function mutants defective in DNA methylation/demethylation. Provision of 5 azacytidine (AZA, inhibitor of DNA methylation) promoted the rice growth and reduced ATR content. By UPLC/Q-TOF-MS/MS, 8 degraded products and 9 conjugates of ATR in AZA-treated rice were characterized. Two of them has been newly identified in this study. Our data show that ATR-induced changes in DNA methylation marks are possibly involved in an epigenetic mechanism associated with activation of specific genes responsible for ATR degradation and detoxification. PMID- 26739619 TI - Surgical strategies for restoring liver arterial perfusion in pancreatic resections. AB - BACKGROUND: Hepatic perfusion failure represents an important risk factor for severe complications and death after pancreatic resections. Arterial reconstruction could be required during pancreatic surgery because of tumor infiltration, benign strictures, or as a consequence of accidental arterial injury during dissection. All these situations can be faced with a certain frequency in high-volume pancreatic centers, where surgeons must be aware of the different alternatives to deal with these intricate scenarios. PURPOSE: We herein describe the preoperative surgical planning as well as different surgical strategies for the restoration of arterial perfusion of the liver in pancreatic resections. CONCLUSION: A thorough preoperative evaluation is essential for planning pancreatic surgery and preparing the surgeon and patient for potentially high complex procedures. The various therapeutic alternatives presented in this technical report might represent a good solution for selected patients with no other potentially curative option than surgery. PMID- 26739617 TI - Predictors of advanced colorectal neoplasia at initial and surveillance colonoscopy after positive screening immunochemical faecal occult blood test. AB - BACKGROUND: Characteristics such as gender and lifestyle are not taken in account in colorectal cancer screening and surveillance recommendations. AIMS: To identify factors associated with advanced neoplasia at initial and surveillance colonoscopy. METHODS: In this observational study, 750 individuals with positive faecal occult blood test, aged 50-74 years, underwent a first screening colonoscopy in 2007-2009. We collected anthropometric data as well as data on physical activity, smoking and drinking habits, fruit and vegetable consumption and low-dose aspirin use through a questionnaire. RESULTS: At initial colonoscopy advanced neoplasia (n=399, 53.2%) was positively associated with age, male gender, smoking and alcohol drinking, and inversely associated with physical activity, fruit and vegetables consumption and long-term use of aspirin. These 7 factors were used to calculate a risk score, ranging from 0 (no unfavourable characteristics) to 7 (all unfavourable characteristics present), which was significantly associated with advanced neoplasia (odds ratio 1.55 for one point increase, P<0.01). Among the 372 adenoma patients who returned for follow-up surveillance colonoscopy, the score remained associated with advanced neoplasia (odds ratio 1.28 for one point increase, P=0.01). CONCLUSION: Besides age and gender, modifiable factors such as lifestyle and aspirin use were associated with the risk of advanced neoplasia at initial and surveillance colonoscopy. PMID- 26739615 TI - POGZ truncating alleles cause syndromic intellectual disability. AB - BACKGROUND: Large-scale cohort-based whole exome sequencing of individuals with neurodevelopmental disorders (NDDs) has identified numerous novel candidate disease genes; however, detailed phenotypic information is often lacking in such studies. De novo mutations in pogo transposable element with zinc finger domain (POGZ) have been identified in six independent and diverse cohorts of individuals with NDDs ranging from autism spectrum disorder to developmental delay. METHODS: Whole exome sequencing was performed on five unrelated individuals. Sanger sequencing was used to validate variants and segregate mutations with the phenotype in available family members. RESULTS: We identified heterozygous truncating mutations in POGZ in five unrelated individuals, which were confirmed to be de novo or not present in available parental samples. Careful review of the phenotypes revealed shared features that included developmental delay, intellectual disability, hypotonia, behavioral abnormalities, and similar facial characteristics. Variable features included short stature, microcephaly, strabismus and hearing loss. CONCLUSIONS: While POGZ has been associated with neurodevelopmental disorders in large cohort studies, our data suggest that loss of function variants in POGZ lead to an identifiable syndrome of NDD with specific phenotypic traits. This study exemplifies the era of human reverse clinical genomics ushered in by large disease-directed cohort studies; first defining a new syndrome molecularly and, only subsequently, phenotypically. PMID- 26739620 TI - Prognostic factors after pancreatoduodenectomy with en bloc portal venous resection for pancreatic cancer. AB - PURPOSE: Pancreatoduodenectomy (PD) with superior mesenteric/portal venous resection (PVR) for pancreatic ductal adenocarcinoma (PDAC) is performed routinely in case of tumor adhesion to the superior mesenteric or portal vein. True histopathological portal vein invasion (PVI) is found in a subgroup of patients. Even though this procedure has become routine in most centers for pancreatic surgery, data on prognostic factors in this situation is limited. The aim of this study was to identify prognostic factors after PD with PVR for PDAC. METHODS: Retrospective analysis was performed on the basis of a prospectively maintained database, and paraffin-embedded formalin-fixed tissue slides stained for hematoxylin-eosin were re-evaluated by two independent pathologists. Statistical analysis was conducted using MedCalc software. RESULTS: From 2001 to 2012, 86 cases of PD with PVR for PDAC with long-term follow-up and sufficient tissue for re-assessment were identified. Histopathological re-review disclosed PVI in 39 resection specimens and adhesion without infiltration in 47. Overall median survival in all patients was 22 months. Patients with PVI versus no PVI showed comparable baseline demographic and standard histopathological parameters; however, PVI was associated with microscopic hemangiosis (p = 0.001) and positive margin status (p = 0.001). Median survival in patients with PVI was 14 months versus 25 months in patients without PVI (p = 0.042). Only lymph node ratio and PVI were independent predictors of survival after resection. CONCLUSION: The only independent factors influencing overall survival after PD with PVR for PDAC were lymph node ratio and PVI. PVI might indicate aggressive tumor biology, but the available data remains controversial. PMID- 26739621 TI - PTP1B confers liver fibrosis by regulating the activation of hepatic stellate cells. AB - Liver fibrosis is a reversible wound-healing response to chronic hepatic injuries. Activation of hepatic stellate cells (HSCs) plays a pivotal role in the development of hepatic fibrosis. The currently accepted mechanism for the resolution of liver fibrosis is the apoptosis and inactivation of activated HSCs. Protein tyrosine phosphatase 1B (PTP1B), a prototype of non-receptor protein tyrosine phosphatase, is proved to be a vital modulator in cardiac fibrogenesis. However, the precise role of PTP1B on liver fibrosis and HSC activation is still unclear. Our study showed that the expression of PTP1B was elevated in fibrotic liver but reduced after spontaneous recovery. Moreover, stimulation of HSC-T6 cells with transforming growth factor-beta1 (TGF-beta1) resulted in a dose/time dependent increase of PTP1B mRNA and protein. Co-incubation of HSC-T6 cells with PTP1B-siRNA inhibited the cell proliferation and activation induced by TGF-beta1. Additionally, both mRNA and protein of PTP1B were dramatically decreased in inactivated HSCs after treated with adipogenic differentiation mixture (MDI). Over-expression of PTP1B hindered the inactivation of HSC-T6 cells induced by MDI. These observations revealed a regulatory role of PTP1B in liver fibrosis and implied PTP1B as a potential therapeutic target. PMID- 26739623 TI - Lovastatin prevents cisplatin-induced activation of pro-apoptotic DNA damage response (DDR) of renal tubular epithelial cells. AB - The platinating agent cisplatin (CisPt) is commonly used in the therapy of various types of solid tumors. The anticancer efficacy of CisPt largely depends on the formation of bivalent DNA intrastrand crosslinks, which stimulate mechanisms of the DNA damage response (DDR), thereby triggering checkpoint activation, gene expression and cell death. The clinically most relevant adverse effect associated with CisPt treatment is nephrotoxicity that results from damage to renal tubular epithelial cells. Here, we addressed the question whether the HMG-CoA-reductase inhibitor lovastatin affects the DDR of renal cells by employing rat renal proximal tubular epithelial (NRK-52E) cells as in vitro model. The data show that lovastatin has extensive inhibitory effects on CisPt stimulated DDR of NRK-52E cells as reflected on the levels of phosphorylated ATM, Chk1, Chk2, p53 and Kap1. Mitigation of CisPt-induced DDR by lovastatin was independent of the formation of DNA damage as demonstrated by (i) the analysis of Pt-(GpG) intrastrand crosslink formation by Southwestern blot analyses and (ii) the generation of DNA strand breaks as analyzed on the level of nuclear gammaH2AX foci and employing the alkaline comet assay. Lovastatin protected NRK-52E cells from the cytotoxicity of high CisPt doses as shown by measuring cell viability, cellular impedance and flow cytometry-based analyses of cell death. Importantly, the statin also reduced the level of kidney DNA damage and apoptosis triggered by CisPt treatment of mice. The data show that the lipid-lowering drug lovastatin extensively counteracts pro-apoptotic signal mechanisms of the DDR of tubular epithelial cells following CisPt injury. PMID- 26739626 TI - Employing Forbidden Transitions as Qubits in a Nuclear Spin-Free Chromium Complex. AB - The implementation of quantum computation (QC) would revolutionize scientific fields ranging from encryption to quantum simulation. One intuitive candidate for the smallest unit of a quantum computer, a qubit, is electronic spin. A prominent proposal for QC relies on high-spin magnetic molecules, where multiple transitions between the many MS levels are employed as qubits. Yet, over a decade after the original notion, the exploitation of multiple transitions within a single manifold for QC remains unrealized in these high-spin species due to the challenge of accessing forbidden transitions. To create a proof-of-concept system, we synthesized the novel nuclear spin-free complex [Cr(C3S5)3](3-) with precisely tuned zero-field splitting parameters that create two spectroscopically addressable transitions, with one being a forbidden transition. Pulsed electron paramagnetic resonance (EPR) measurements enabled the investigation of the coherent lifetimes (T2) and quantum control (Rabi oscillations) for two transitions, one allowed and one forbidden, within the S = (3)/2 spin manifold. This investigation represents a step forward in the development of high-spin species as a pathway to scalable QC systems within magnetic molecules. PMID- 26739622 TI - Current understanding of interactions between nanoparticles and the immune system. AB - The delivery of drugs, antigens, and imaging agents benefits from using nanotechnology-based carriers. The successful translation of nanoformulations to the clinic involves thorough assessment of their safety profiles, which, among other end-points, includes evaluation of immunotoxicity. The past decade of research focusing on nanoparticle interaction with the immune system has been fruitful in terms of understanding the basics of nanoparticle immunocompatibility, developing a bioanalytical infrastructure to screen for nanoparticle-mediated immune reactions, beginning to uncover the mechanisms of nanoparticle immunotoxicity, and utilizing current knowledge about the structure activity relationship between nanoparticles' physicochemical properties and their effects on the immune system to guide safe drug delivery. In the present review, we focus on the most prominent pieces of the nanoparticle-immune system puzzle and discuss the achievements, disappointments, and lessons learned over the past 15years of research on the immunotoxicity of engineered nanomaterials. PMID- 26739628 TI - Fast water channeling across carbon nanotubes in far infrared terahertz electric fields. AB - Using molecular dynamics simulations, we investigate systematically the water permeation properties across single-walled carbon nanotubes (SWCNT) in the presence of the terahertz electric field (TEF). With the TEF normal to the nanotube, the fracture of the hydrogen bonds results in the giant peak of net fluxes across the SWCNT with a three-fold enhancement centered around 14 THz. The phenomenon is attributed to the resonant mechanisms, characterized by librational, rotational, and rotation-induced responses of in-tube polar water molecules to the TEF. For the TEF along the symmetry axis of the nanotube, the vortical modes for resonances and consequently the enhancement of net fluxes are greatly suppressed by the alignment of polar water along the symmetry axis, which characterizes the quasi one-dimensional feature of the SWCNT nicely. The resonances of water molecules in the TEF can have potential applications in the high-flux device designs used for various purposes. PMID- 26739624 TI - A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen. AB - Obesity and nonalcoholic fatty liver disease (NAFLD) can increase susceptibility to hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are poorly understood. For acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during NAFLD. The first aim of our study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, human HepaRG cells were incubated for one week with stearic acid or oleic acid, in the presence of different concentrations of insulin. Although cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids, CYP2E1 activity was significantly increased only by stearic acid. CYP2E1 activity was reduced by insulin and this effect was reproduced in cultured primary human hepatocytes. Next, APAP cytotoxicity was assessed in HepaRG cells with or without lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations showed that the loss of ATP and glutathione was almost always greater in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole, recovery of ATP was significantly higher in the presence of stearate with low (2.5mM) or high (20mM) concentrations of APAP. Levels of APAP-glucuronide were significantly enhanced by insulin. Hence, HepaRG cells can be used as a valuable model of NAFLD to unveil important metabolic and hormonal factors which can increase susceptibility to drug-induced hepatotoxicity. PMID- 26739627 TI - Ozone-induced IL-17A and neutrophilic airway inflammation is orchestrated by the caspase-1-IL-1 cascade. AB - Ozone is a common environmental air pollutant leading to respiratory illness. The mechanisms regulating ozone-induced airway inflammation remain poorly understood. We hypothesize that ozone-triggered inflammasome activation and interleukin (IL) 1 production regulate neutrophilic airway inflammation through IL-17A. Pulmonary neutrophilic inflammation was induced by extended (72 h) low-dose (0.7 ppm) exposure to ozone. IL-1 receptor 1 (Il1r1)(-/-), Il17a(-/-) mice and the caspase 1 inhibitor acetyl-YVAD-chloromethylketone (Ac-YVAD-cmk) were used for in vivo studies. Cellular inflammation and protein levels in bronchial alveolar lavage fluid (BALF), cytokines, and IL-17A-producing gammadeltaT-cells, as well as mitochondrial reactive oxygen species (ROS), mitochondrial DNA (mtDNA) release, and inflammasome activation in lung macrophages were analyzed. Ozone-induced neutrophilic airway inflammation, accompanied an increased production of IL 1beta, IL-18, IL-17A, Granulocyte-colony stimulating factor (G-CSF), Interferon gamma inducible protein 10 (IP-10) and BALF protein in the lung. Ozone-induced IL 17A production was predominantly in gammadeltaT-cells, and Il17a-knockout mice exhibited reduced airway inflammation. Lung macrophages from ozone-exposed mice exhibited higher levels of mitochondrial ROS, enhanced cytosolic mtDNA, increased caspase-1 activation, and higher production of IL-1beta. Il1r1-knockout mice or treatment with Ac-YVAD-cmk decreased the IL-17A production and subsequent airway inflammation. Taken together, we demonstrate that ozone-induced IL-17A and neutrophilic airway inflammation is orchestrated by the caspase-1-IL-1 cascade. PMID- 26739630 TI - Introduction. PMID- 26739629 TI - Comparison of Aortic Collagen Fiber Angle Distribution in Mouse Models of Atherosclerosis Using Second-Harmonic Generation (SHG) Microscopy. AB - Characterization of collagen fiber angle distribution throughout the blood vessel wall provides insight into the mechanical behavior of healthy and diseased arteries and their capacity to remodel. Atherosclerotic plaque contributes to the overall mechanical behavior, yet little is known experimentally about how collagen fiber orientation is influenced by atherogenesis. We hypothesized that atherosclerotic lesion development, and the factors contributing to lesion development, leads to a shift in collagen fiber angles within the aorta. Second harmonic generation microscopy was used to visualize the three-dimensional organization of collagen throughout the aortic wall and to examine structural differences in mice maintained on high-fat Western diet versus age-matched chow diet mice in a model of atherosclerosis. Image analysis was performed on thoracic and abdominal sections of the aorta from each mouse to determine fiber orientation, with the circumferential (0 degrees ) and blood flow directions (axial +/-90 degrees ) as the two reference points. All measurements were used in a multiple regression analysis to determine the factors having a significant influence on mean collagen fiber angle. We found that mean absolute angle of collagen fibers is 43 degrees lower in Western diet mice compared with chow diet mice. Mice on a chow diet have a mean collagen fiber angle of +/-63 degrees , whereas mice on a Western diet have a more circumferential fiber orientation (~20 degrees ). This apparent shift in absolute angle coincides with the development of extensive aortic atherosclerosis, suggesting that atherosclerotic factors contribute to collagen fiber angle orientation. PMID- 26739631 TI - Familiar and unfamiliar pseudoneoplastic lesions of the head and neck. AB - Pseudoneoplastic lesions in the head and neck are numerous. Familiarity with the sites of predilection and demographics of these lesions is particularly useful if the differential diagnosis for a minimal biopsy sample includes benign and malignant entities. This article is a brief overview of some common and unusual pseudo neoplasms specific to this region. PMID- 26739632 TI - Immunohistochemical expression of cytokeratin 15, cytokeratin 19, follistatin, and Bmi-1 in basal cell carcinoma. AB - BACKGROUNDS: Basal cell carcinoma (BCC) is the most common cutaneous neoplasm. Despite numerous previous studies, the origin of BCC is still controversial. OBJECTIVE: The aim of this study is to evaluate whether BCC arises from the hair follicle rather than the epidermal basal cell. METHODS: The labeling index and differences of expression of the immunohistochemical (IHC) stainings of CK15, CK19, follistatin, and Bmi-1 were evaluated in 20 cases of BCC, 13 cases of trichoblastoma, 21 cases of actinic keratosis (AK), and 19 cases of squamous cell carcinoma (SCC) which were biopsied in the department of dermatology of the Yeungnam University Medical Center. RESULTS: For CK15, labeling indexes of BCC (83.0%) and trichoblastoma (84.4%) were significantly higher than those of AK (15.9%) and SCC (15.8%). For CK19, labeling indexes of BCC (8.1%), trichoblastoma (6.6%), AK (3.5%), and SCC (14.8%) revealed no difference. For follistatin, labeling indexes of BCC (51.1%) and trichoblastoma (70.1%) were significantly higher than those of AK (0.9%) and SCC (8.5%). For Bmi-1, labeling indexes of BCC (74.4%) and trichoblastoma (84.7%) were significantly higher than those of AK (24.7%) and SCC (18.6%). CONCLUSION: In this study, strong positivity of CK15, follistatin, and Bmi-1 was more frequently observed in BCC and trichoblastoma than in SCC and AK. These findings suggest that BCC and trichoblastoma share the same differentiation toward the hair follicle. Furthermore, CK15, follistatin, and Bmi-1 can be useful as markers to differentiate BCC from SCC. PMID- 26739633 TI - About case reports and the perverse application of reasonable principles. PMID- 26739634 TI - About case reports and the perverse application of reasonable principles. PMID- 26739635 TI - A baleful weed and the king of fruits: tolerance, immunity, and the microbiome. PMID- 26739636 TI - Crosstalk-eliminated quantitative determination of aflatoxin B1-induced hepatocellular cancer stem cells based on concurrent monitoring of CD133, CD44, and aldehyde dehydrogenase1. AB - Cancer stem cells (CSCs), known as tumor initiating cells, have become a critically important issue for cancer therapy. Although much research has demonstrated the induction of hepato cellular carcinoma by aflatoxin B1, the formation of hepatocellular CSCs and their quantitative determination is hardly reported. In this work, it was found that hepatocellular CSCs were produced from HepG2 cells by aflatoxin B1-induced mutation, and their amount was quantitatively determined using crosstalk-eliminated multicolor cellular imaging based on quantum dot (Qdot) nanoprobes and an acousto-optical tunable filter (AOTF). Hepatocellular CSCs were acquired via magnetic bead-based sorting and observed using concurrent detection of three different markers: CD133, CD44, and aldehyde dehydrogenase1 (ALDH1). The DNA mutation of HepG2 cells caused by aflatoxin B1 was quantitatively observed via absorbance spectra of aflatoxin B1-8, 9-epoxide DNA adducts. The percentages of hepatocellular CSCs formed in the entire HepG2 cells were determined to be 9.77+/-0.65%, 10.9+/-1.39%, 11.4+/-1.32%, and 12.8+/ 0.7%, respectively, at 0 MUM, 5 MUM, 10 MUM, and 20 MUM of aflatoxin B1. The results matched well with those obtained utilizing flow cytometry. This study demonstrates that aflatoxin mediated mutation induced the conversion of hepatic cancer cell to hepatic CSCs by using a Qdot based constructed multicolor cellular imaging system. PMID- 26739638 TI - Role of a multimodal educational strategy on health care workers' handwashing. AB - BACKGROUND: Good hand hygiene is the single most important strategy used to prevent health care-associated infections (HAIs); however, health care workers' (HCWs') hand hygiene compliance rates range between 25% and 51%. This study aims to determine if a multimodal strategy using the World Health Organization's (WHO's) My 5 Moments for Hand Hygiene methodology increases HCWs' compliance with handwashing and awareness of the importance of good hand hygiene in the prevention of HAIs. METHODS: A quasi-experimental, 1-group pre-post survey design was used to test awareness and knowledge. A simple interrupted time series methodology at baseline and 3 months was used to monitor hand hygiene compliance. RESULTS: Overall, HCWs' hand hygiene compliance increased from 51.3% to 98.6%, with an odds ratio of 71.10. The pre-post survey demonstrated HCWs were aware and knowledgeable of the importance of good hand hygiene. Eight postsurvey questions focusing on the strategies used to promote hand hygiene demonstrated statistical significance using a 1-sample t test, with P values ranging from .000-.024. CONCLUSION: A multimodal approach using the WHO's My 5 Moments for Hand Hygiene does increase HCWs' hand hygiene compliance and awareness and knowledge of the importance of hand hygiene in the prevention of HAIs. Using this approach can produce a positive social change by reducing preventable disease and decreasing HAIs not only within a facility but also in the community. PMID- 26739637 TI - Progenitor-derived hepatocyte-like (B-13/H) cells metabolise 1'-hydroxyestragole to a genotoxic species via a SULT2B1-dependent mechanism. AB - Rat B-13 progenitor cells are readily converted into functional hepatocyte-like B 13/H cells capable of phase I cytochrome P450-dependent activation of pro carcinogens and induction of DNA damage. The aim of the present study was to investigate whether the cells are also capable of Phase II sulphotransferase (SULT)-dependent activation of a pro-carcinogen to an ultimate carcinogen. To this end we therefore examined the bioactivation of the model hepatic (hepato- and cholangio-) carcinogen estragole and its proximate SULT1A1-activated genotoxic metabolite 1'-hydroxyestragole. Exposing B-13 or B-13/H cells to estragole (at concentrations up to 1mM) resulted in the production of low levels of 1'-hydroxyestragole, but did not result in detectable DNA damage. Exposing B 13/H cells - but not B-13 cells - to 1'-hydroxyestragole resulted in a dose dependent increase in DNA damage in comet assays, confirmed by detection of N(2) (trans-isoestragol-3'-yl)-2'-deoxyguanosine adducts. Genotoxicity was inhibited by general SULT inhibitors, supporting a role for SULTS in the activation of 1 hydroxyestragole in B-13/H cells. However, B-13 and B-13/H cells did not express biologically significant levels of SULT1A1 as determined by qRT-PCR, Western blotting and its associated 7-hydroxycoumarin sulphation activity. B-13 and B 13/H cells expressed - relative to intact rat liver - high levels of SULT2B1 (primarily the b isoform) and SULT4A1 mRNAs and proteins. B-13 and B-13/H cells also expressed the 3'-phosphoadenosine 5'-phosphosulphate synthase 1 required for the generation of activated sulphate cofactor 3'-phosphoadenosine 5' phosphosulphate. However, only B-13/H cells expressed functional SULT activities towards SULT2B1 substrates DHEA, pregnenolone and 4 methylumbelliferone. Since liver progenitor cells are bi-potential and also form cholangiocytes, we therefore hypothesised that B-13 cells express a cholangiocyte-like SULT profile. To test this hypothesis, the expression of SULTs was examined in liver by RT-PCR and immunohistochemistry. SULT2B1 - but not SULT1A1 - was determined to be expressed in both rat and human cholangiocytes. Since 1'-hydroxyestragole exposure readily produced DNA injury in B-13/H cells, these data suggest that cholangiocarcinomas generated in rats fed estragole may be dependent, in part, on SULT2B1 activation of the 1'-hydroxyestragole metabolite. PMID- 26739639 TI - Recovery of resistant bacteria from mattresses of patients under contact precautions. AB - BACKGROUND: Microorganisms may contaminate hospital mattresses even after terminal cleaning. We investigated the recovery of resistant bacteria from the mattresses of patients under contact precautions at a university hospital. METHODS: We conducted a cross-sectional study. Samples were obtained from the surface of mattresses, spread on replicate organism detection and counting plates, and cultivated at 37 degrees C for 48 hours. After collecting samples, we identified microorganisms and tested for antimicrobial susceptibility using the Vitek 2 (bioMerieux SA, Marcy-l'Etoile, France) automation system. RESULTS: We evaluated 51 mattresses. A total of 26 had resistant bacteria on the surface; the predominant species were Acinetobacter baumannii (69.2%), Klebsiella pneumoniae (11.5%), and Pseudomonas aeruginosa (11.5%). The median length of hospital stay was 41 days; the bed occupancy for patients under contact precautions and the time at which the patient was diagnosed as a carrier of resistant bacteria was 18 days. CONCLUSIONS: The phenotypic similarity of A baumannii in inpatient units (mattresses) suggests circulation of the same strain. These results highlight the importance of controlling the potential spread of microorganisms through hospital mattresses. PMID- 26739640 TI - Risk factors for measles in children younger than age 8 months: A case-control study during an outbreak in Guangxi, China, 2013. AB - BACKGROUND: Following a period (2009-2012) during which zero measles cases were reported, a measles outbreak occurred in 2013 in Bama County, Guangxi, China, that involved more than 100 children younger than age 8 months. We aimed to identify the pitfalls and risk factors while implementing the control measures. METHODS: An outbreak investigation and a case-control study was conducted among children younger than age 8 months. The serum specimens of the study subjects and their mothers were tested for measles immunoglobulin M and immunoglobulin G. RESULTS: The attack rate was 2.3/1,000 population. The median (interquartile range) age was 18.6 months (7.9-52.8 months). The coverage of 2-dose measles containing vaccine was only 34%. The case-control study revealed 2 independent risk factors: low education level of main caregiver (odds ratio [OR], 2.86; 95% confidence interval [CI], 1.31-6.22) and visiting a hospital 7-21 days before the date of symptoms onset (OR, 9.84; 95% CI, 4.27-22.67). The population attributable fraction of the latter was 52.8%. The mothers of the cases had nonsignificantly higher levels of immunoglobulin M and were significantly more likely to have protective levels of immunoglobulin G than those of the controls. This suggests a reactive rather than protective role of the antibody to the child's infection. CONCLUSIONS: In a near-elimination but low measles-containing vaccine coverage community, supplementary immunization activities should be emphasized for children and women who are potential future mothers. The minimum age of measles-containing vaccine should be further reduced. Hospital measles transmission must also be strictly prevented. PMID- 26739641 TI - Antiretroviral therapy among pregnant and postpartum women in China: A systematic review and meta-analysis. AB - BACKGROUND: The objectives of this study were to estimate the antiretroviral therapy (ART) rate and the proportion of women with adequate ART adherence (100%), and to identify the reasons for not initiating ART in HIV-infected pregnant women in China. METHODS: We searched MEDLINE, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and Wanfang (Chinese) to identify research studies published from 1990-2015. Only descriptive epidemiologic studies were eligible for this study. RESULTS: A total of 58 eligible studies were included in this meta-analysis. The eligible articles were published from 2006-2015 and covered all Chinese provinces. The estimated ART rate in HIV-positive pregnant women was continually increased, and the mean estimated ART rate increased from 47.1% (95% confidence interval [CI], 22.4-71.8) in 2006 to 95.0% (95% CI, 93.2-96.0) in 2013. In the meta-regression model, study year, study region, and income level were statistically significantly associated with ART rate estimates. During the last 10 years, the pooled ART adherence proportions for all studies yielded an estimate of 76.7% (95% CI, 61.0-92.5) of patients with adequate ART adherence (100%). Emergency cesarean delivery (57.9%; 95% CI, 9.9-100) and not knowing their HIV-infection status before starting (45.7%; 95% CI, 24.4-67.0) account for the dominant reasons for not initiating ART. CONCLUSIONS: The geographic variation in ART rate of HIV-infected pregnant women was significant in China, and >25% of pregnant women did not achieved optimal ART adherence. It is crucial to investigate specific barriers for lower ART rates in the high-income regions and to develop interventions to maintain the adequate ART adherence. PMID- 26739644 TI - Performance of Seven Tree Breeding Strategies Under Conditions of Inbreeding Depression. AB - In the domestication and breeding of tree species that suffer from inbreeding depression (ID), the long-term performance of different breeding strategies is poorly known. Therefore, seven tree breeding strategies including single population, subline, selfing, and nucleus breeding were simulated using a multi locus model with additive, partial, and complete dominance allele effects, and with intermediate, U-shaped, and major allele distributions. The strategies were compared for genetic gain, inbreeding accumulation, capacity to show ID, the frequencies and fixations of unfavorable alleles, and genetic variances in breeding and production populations. Measured by genetic gain of production population, the nucleus breeding and the single breeding population with mass selection strategies were equal or superior to subline and single breeding population with within-family selection strategies in all simulated scenarios, in spite of their higher inbreeding coefficients. Inbreeding and cross-breeding effectively decreased ID and could in some scenarios produce genetic gains during the first few generations. However, in all scenarios, considerable fixation of unfavorable alleles rendered the purging performance of selfing and cross breeding strategies ineffective, and resulted in substantial inferiority in comparison to the other strategies in the long-term. PMID- 26739645 TI - Genetic Correlates of Individual Differences in Sleep Behavior of Free-Living Great Tits (Parus major). AB - Within populations, free-living birds display considerable variation in observable sleep behaviors, reflecting dynamic interactions between individuals and their environment. Genes are expected to contribute to repeatable between individual differences in sleep behaviors, which may be associated with individual fitness. We identified and genotyped polymorphisms in nine candidate genes for sleep, and measured five repeatable sleep behaviors in free-living great tits (Parus major), partly replicating a previous study in blue tits (Cyanistes caeruleus). Microsatellites in the CLOCK and NPAS2 clock genes exhibited an association with sleep duration relative to night length, and morning latency to exit the nest box, respectively. Furthermore, microsatellites in the NPSR1 and PCSK2 genes associated with relative sleep duration and proportion of time spent awake at night, respectively. Given the detection rate of associations in the same models run with random markers instead of candidate genes, we expected two associations to arise by chance. The detection of four associations between candidate genes and sleep, however, suggests that clock genes, a clock-related gene, or a gene involved in the melanocortin system, could play key roles in maintaining phenotypic variation in sleep behavior in avian populations. Knowledge of the genetic architecture underlying sleep behavior in the wild is important because it will enable ecologists to assess the evolution of sleep in response to selection. PMID- 26739648 TI - Is Erwinase Necessary for all Children With ALL and Allergic Reactions to E. coli Asparaginase? PMID- 26739646 TI - Vesicular Trafficking Systems Impact TORC1-Controlled Transcriptional Programs in Saccharomyces cerevisiae. AB - The Target of Rapamycin Complex I (TORC1) orchestrates global reprogramming of transcriptional programs in response to myriad environmental conditions, yet, despite the commonality of the TORC1 complex components, different TORC1 inhibitory conditions do not elicit a uniform transcriptional response. In Saccharomyces cerevisiae, TORC1 regulates the expression of nitrogen catabolite repressed (NCR) genes by controlling the nuclear translocation of the NCR transactivator Gln3. Moreover, Golgi-to-endosome trafficking was shown to be required for nuclear translocation of Gln3 upon a shift from rich medium to the poor nitrogen source proline, but not upon rapamycin treatment. Here, we employed microarray profiling to survey the full impact of the vesicular trafficking system on yeast TORC1-orchestrated transcriptional programs. In addition to the NCR genes, we found that ribosomal protein, ribosome biogenesis, phosphate responsive, and sulfur-containing amino acid metabolism genes are perturbed by disruption of Golgi-to-endosome trafficking following a nutritional shift from rich to poor nitrogen source medium, but not upon rapamycin treatment. Similar to Gln3, defects in Golgi-to-endosome trafficking significantly delayed cytoplasmic nuclear translocation of Sfp1, but did not detectably affect the cytoplasmic nuclear or nuclear-cytoplasmic translocation of Met4, which are the transactivators of these genes. Thus, Golgi-to-endosome trafficking defects perturb TORC1 transcriptional programs via multiple mechanisms. Our findings further delineate the downstream transcriptional responses of TORC1 inhibition by rapamycin compared with a nitrogen quality downshift. Given the conservation of both TORC1 and endomembrane networks throughout eukaryotes, our findings may also have implications for TORC1-mediated responses to nutritional cues in mammals and other eukaryotes. PMID- 26739649 TI - Glucose delays the insulin-induced increase in thyroid hormone-mediated signaling in adipose of prolong-fasted elephant seal pups. AB - Prolonged food deprivation in mammals typically reduces glucose, insulin, and thyroid hormone (TH) concentrations, as well as tissue deiodinase (DI) content and activity, which, collectively, suppress metabolism. However, in elephant seal pups, prolonged fasting does not suppress TH levels; it is associated with upregulation of adipose TH-mediated cellular mechanisms and adipose-specific insulin resistance. The functional relevance of this apparent paradox and the effects of glucose and insulin on TH-mediated signaling in an insulin-resistant tissue are not well defined. To address our hypothesis that insulin increases adipose TH signaling in pups during extended fasting, we assessed the changes in TH-associated genes in response to an insulin infusion in early- and late-fasted pups. In late fasting, insulin increased DI1, DI2, and THrbeta-1 mRNA expression by 566%, 44%, and 267% at 60 min postinfusion, respectively, with levels decreasing by 120 min. Additionally, we performed a glucose challenge in late fasted pups to differentiate between insulin- and glucose-mediated effects on TH signaling. In contrast to the insulin-induced effects, glucose infusion did not increase the expressions of DI1, DI2, and THrbeta-1 until 120 min, suggesting that glucose delays the onset of the insulin-induced effects. The data also suggest that fasting duration increases the sensitivity of adipose TH-mediated mechanisms to insulin, some of which may be mediated by increased glucose. These responses appear to be unique among mammals and to have evolved in elephant seals to facilitate their adaptation to tolerate an extreme physiological condition. PMID- 26739650 TI - Calorie restriction leads to greater Akt2 activity and glucose uptake by insulin stimulated skeletal muscle from old rats. AB - Skeletal muscle insulin resistance is associated with many common age-related diseases, but moderate calorie restriction (CR) can substantially elevate glucose uptake by insulin-stimulated skeletal muscle from both young and old rats. The current study evaluated the isolated epitrochlearis muscle from ~24.5-mo-old rats that were either fed ad libitum (AL) or subjected to CR (consuming ~65% of ad libitum, AL, intake beginning at ~22.5 mo old). Some muscles were also incubated with MK-2206, a potent and selective Akt inhibitor. The most important results were that in isolated muscles, CR vs. AL resulted in 1) greater insulin stimulated glucose uptake 2) that was accompanied by significantly increased insulin-mediated activation of Akt2, as indicated by greater phosphorylation on both Thr(309) and Ser(474) along with greater Akt2 activity, 3) concomitant with enhanced phosphorylation of several Akt substrates, including an Akt substrate of 160 kDa on Thr(642) and Ser(588), filamin C on Ser(2213) and proline-rich Akt substrate of 40 kDa on Thr(246), but not TBC1D1 on Thr(596); and 4) each of the CR effects was eliminated by MK-2206. These data provide compelling new evidence linking greater Akt2 activation to the CR-induced elevation of insulin-stimulated glucose uptake by muscle from old animals. PMID- 26739652 TI - Survivorship and fecundity of Culex pipiens pallens feeding on flowering plants and seed pods with differential preferences. AB - Adult mosquitoes rely on ingestion of sugar from plants to survive, swarm and mate. Culex pipiens pallens Coguillett is the primary vector of lymphatic filariasis and epidemic encephalitis. Little is known about the effect of feeding on different sugar sources on the survivorship and fecundity of Cx. pipiens pallens. In the present study, newly emerged mosquitoes were exposed to several flowering plant and seed pod species with different olfactory preferences, and the survival times of mosquitoes exposed to these sugar sources were determined. The proportions of mosquitoes that ingested sugar from host plants were investigated by cold anthrone tests. The numbers of eggs per egg raft laid by mosquitoes were compared when they were provided with different sugar sources and one blood meal. The results revealed that feeding on different kinds of sugar sources significantly affected female and male mosquitoes' survival times. Cold anthrone tests indicated that the proportions of sugar-positive mosquitoes from different nutritional regimes within 24h corresponded to the preference rankings of Cx. pipiens pallens to these sugar sources, and rapid declines in the proportions of surviving individuals might be attributed to their insufficient ingestion of sugar from nutritional regimes. Feeding on different sugar sources strongly affected the proportions of engorged mosquitoes, and females that had fed on their preferred sugar sources laid more eggs than mosquitoes provided with less preferred sugar sources. The results would provide insights in developing mosquito control strategies that target the sugar feeding behavior of mosquitoes. PMID- 26739651 TI - Adropin acts in brain to inhibit water drinking: potential interaction with the orphan G protein-coupled receptor, GPR19. AB - Adropin, a recently described peptide hormone produced in the brain and liver, has been reported to have physiologically relevant actions on glucose homeostasis and lipogenesis, and to exert significant effect on endothelial function. We describe a central nervous system action of adropin to inhibit water drinking and identify a potential adropin receptor, the orphan G protein-coupled receptor, GPR19. Reduction in GPR19 mRNA levels in medial basal hypothalamus of male rats resulted in the loss of the inhibitory effect of adropin on water deprivation induced thirst. The identification of a novel brain action of adropin and a candidate receptor for the peptide should extend and accelerate the study of the potential therapeutic value of adropin or its mimetics for the treatment of metabolic disorders. PMID- 26739653 TI - Seroprevalence of antibodies against dengue virus among pregnant women in the Democratic Republic of Sao Tome and Principe. AB - Dengue fever has become a worldwide public health concern, threatening an estimated 40% of the world's population. However, most resources and attention are still focused on malaria, while dengue statuses are poorly recognized in many African countries. In this serological survey, dengue virus (DENV) transmission was demonstrated by using serum samples collected from 78 pregnant women in the Democratic Republic of Sao Tome and Principe (DRSTP) during 2003 to 2004. Immunofluorescence assay was performed and 31 samples (39.74%) were found positive for DENV antibodies. Indirect enzyme-linked immunosorbent assay (ELISA) showed that 53 samples (67.95%) were positive for dengue E IgG, and 38 samples (48.72%) were positive for NS1 IgG. A prevalence of 35.90% was therefore determined for dengue IgG by considering samples that yielded positive results by all three tests. Cross-reactions with other flaviviruses were examined by indirect ELISA against Japanese encephalitis virus, West Nile virus, and yellow fever virus. Only one sample exhibited stronger absorbance against Japanese encephalitis virus and West Nile virus. Moreover, one sample was positive for dengue IgM. These results agreed with the previous researches in neighboring countries and suggested DENV exposure. The study contributes to raising public awareness of dengue and supporting future control strategies. PMID- 26739654 TI - Prevalence and associated factors of malaria among febrile children in Ethiopia: A cross-sectional health facility-based study. AB - Malaria is one of the most important public health problems in Ethiopia. The objective of this study was to identify the prevalence and associated factors of malaria among children who presented for investigation. A cross-sectional health facility-based study was conducted between October and November 2012 in East Shewa Zone of Oromia Regional Sate in Ethiopia. Blood samples by finger pricks were collected for microscopic diagnosis of malaria from children under the age of 16 years with symptoms suggestive of malaria attending five health centers. An interview was conducted with the parents/guardians of the children using a pre tested structured questionnaire. Bivariate and multivariate logistic regression was employed to study associations between malaria infection and associated factors. Of 830 children who provided blood samples, 170/830 (20.5%) were microscopically confirmed for malaria parasites. The predominant Plasmodium species were Plasmodium vivax (11.7%) and Plasmodium falciparum (8.4%), whilst mixed infections of both species were identified in 0.4% of patients (relative proportion: 57.1%, 41.2%, and 1.8%, respectively). Household's ownership of insecticide treated nets (ITNs) was significantly associated with decreased odds of malaria infection (adjusted odds ratio [aOR]: 0.69, 95% confidence interval [CI]: 0.56-0.85). However, an increased odds of malaria infection was observed among children between 10 and 15 years old (aOR: 2.19, 95% CI: 1.25-3.83) compared to children under the age of 2 years. The strong association reported here between household's ownership of ITNs and malaria infection among children in this part of Ethiopia call for continued efforts of net distribution and use to control malaria, which in turn might improve children's health and development. PMID- 26739655 TI - Innate immune response against an oomycete pathogen Aphanomyces invadans in common carp (Cyprinus carpio), a fish resistant to epizootic ulcerative syndrome. AB - Infection with Aphanomyces invadans, also known as epizootic ulcerative syndrome, is a destructive disease of freshwater and brackishwater fishes. Although more than 130 species of fish have been confirmed to be susceptible to this disease, some of the commercially important fish species like common carp, milk fish and tilapia are reported to be resistant. Species that are naturally resistant to a particular disease, provide a potential model to study the mechanisms of resistance against that disease. In the present study, following experimental infection with A. invadans in common carp Cyprinus carpio, sequential changes in various innate immune parameters and histopathological alterations were monitored. Some of the studied innate immunity parameters viz. respiratory burst, alternative complement and total antiproteases activities of the infected common carp were higher compared to control fish, particularly at early stages of infection. On the other hand, some parameters such as myeloperoxidase, lysozyme and alpha-2 macroglobulin activities were not altered. Histopathological examination of the muscle at the site of injection revealed well developed granulomas at 12 days post infection, with subsequent regeneration of muscle fibers. From the results, it could be inferred that innate defense mechanisms of common carp are able to neutralize the virulence factors secreted by A. invadans, thereby, preventing its invasive spread and containing the infection. The results obtained here will help to better understand the mechanisms underlying resistance against A. invadans infection. PMID- 26739656 TI - Live pig markets in eastern Indonesia: Trader characteristics, biosecurity and implications for disease spread. AB - Classical swine fever has been negatively impacting pig production in Nusa Tenggara Timur province in eastern Indonesia since its introduction in the 1990s, with live market trade contributing to disease spread. To understand market trader knowledge and practices regarding pig management, biosecurity, pig movements and pig health (specifically CSF), a repeated survey was conducted with pig sellers and pig buyers at 9 market sites across West Timor and the islands of Flores and Sumba. A total of 292 sellers and 281 buyers were interviewed in 2009 during two periods (rounds), a high-demand month (September) and a low-demand month (November). Information was collected via questionnaire. The majority of traders were male (sellers: 89%; buyers: 87%) with the highest level of completed education being primary school (sellers: 48%; buyers: 41%). The primary occupation of most respondents was farming: 90% of sellers and 87% of buyers were smallholder pig farmers and tended to sell their own home-raised pigs at market (52%). Pigs were sold for monetary gain either for primary (52%) or extra income (44%). Markets tended to be selected based on a good reputation (62%), a location close to residence (62%) and having the desired pig type (59%). Pig sales through markets were reported to be highest from August to October with 31% of sellers trading pigs at two or more markets. Prices at market were significantly higher on Sumba compared to West Timor and cross-bred pigs were significantly more expensive than indigenous pigs. Understanding of CSF and biosecurity was limited: 85% of sellers and 83% of buyers had no prior knowledge of CSF. Fifty-four percent of sellers reported no use of any biosecurity practices at market. Most respondents (88%) were able to recognise at least one clinical sign of a sick pig. Informal pig movements were also identified: 18% of pig buyers purchased pigs directly from other farmers. This study has provided baseline information on market trader activities at live pig markets in NTT that can contribute to the formation of sustainable strategies for improving pig health. Since NTT is the poorest province in Indonesia and pigs play a vital socioeconomic role in this province, market management and farmer education is needed to improve the pig market chain and contribute to socioeconomic development. PMID- 26739657 TI - Evaluation of gastrointestinal transit after infection with different loads of Strongyloides venezuelensis in rats. AB - The aim was to correlate the gastrointestinal transit profile in rats, evaluated by a biomagnetic technique, in response to infection with different loads of Strongyloides venezuelensis. Eggs per gram, intestinal number of worms and fecundity, and also gastric emptying time, cecum arrival time, small intestinal transit time and stool weight were determined. Assessments occurred at 0 (control), 3, 6, 9, 12, 15, 18 and 21 days post infection (dpi) with three infective loads (400, 2000, and 10,000 L). Gastric emptying was faster (p=0.0001) and the intestinal transit was significantly slower (p=0.001) during the infection time course. Also, linear mixed-effects models showed significantly changes in small intestinal transit after three parasite load over time. Cecum arrival was not influenced by infection time course or parasite load. As indirect effect, stool weight decreased accompanied a strong oviposition peak at 9 dpi in 400 L and 2000 L. In several motor function instances, neuromuscular dysfunction persists after mucosal inflammation has decreased. Our approach could be very helpful to evaluate gastrointestinal motor abnormalities in vivo after parasite infection. Despite parasitological data progressively decreased after 15 dpi, small intestinal transit worse over time and according to burden. PMID- 26739658 TI - Governmental supervision and rapid detection on dengue vectors: An important role for dengue control in China. AB - BACKGROUND: China experienced an unprecedented outbreak of dengue fever in 2014, the National Health and Family Planning Commission of the People's Republic of China (NHFPC) carried out a series of supervision work on integrated vector management (IVM), and Chinese Center for Disease Control and Prevention (China CDC) conducted a rapid detection on vector density in some areas with high dengue incidence. The goal of this study was to explain the effect of these actions, which play an important role for dengue control, and we wish to give a good example for dengue control in China, even in the world. METHODS: Compare mosquito vector density with Breteau Index (BI) and dengue incidence after or along with control work vs. before. Data was entered and analyzed by Microsoft Excel 2007 and SPSS19.0. RESULTS: Average value of BI from 22.82 in September dropped to 3.93 along with supervision and rapid detection. BI showed a significant decrease (paired sample t-test, t=3.061, P=0.018?0.05). Dengue incidence decreased gradually along with supervision and rapid detection. CONCLUSIONS: Supervised work on IVM by NHFPC and the rapid detection on dengue vector Aedes by China CDC promoted to cut down the dengue vector density, then reduced dengue incidence; both played an important role for dengue control throughout China in 2014. PMID- 26739659 TI - Evaluation of aminotransferase abnormality in dengue patients: A meta analysis. AB - Dengue virus is a type of flavivirus transmitted by Aedes mosquitoes. The symptoms of infection by this virus range from asymptomatic or mild symptomatic dengue fever (DF) to dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS). Significant abnormality in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) has been shown in a large number of dengue infection cases and to be indicator for liver injury provided that there are no other combined infections or liver injury. This study aims to assess the abnormal levels of liver aminotransferase in dengue patients. The related literature was searched in multiple databases, including PubMed, Embase, Google Scholar and Cochrane Library. The literature was selected through strict inclusion and exclusion criteria, and the quantitative synthesis of the liver aminotransferase abnormality was performed with R software. The fixed or random effects model was employed based on the results of the statistical test for homogeneity. In total, 15 studies were included. The proportion of AST abnormality with 95% confidence interval (95% CI) was 0.80 (95% CI: 0.56-0.92) in DHF patients and 0.75 (95% CI: 0.63-0.84) in DF patients; the proportion of ALT abnormality was 0.54 (95% CI: 0.34-0.73) in DHF patients and 0.52 (95% CI: 0.41-0.63) in DF patients. Serum ALT and AST levels may be indicators for evaluating liver injury in dengue infection and for diagnosis and treatment effect. PMID- 26739664 TI - WHO analgesic ladder: a good concept gone astray. PMID- 26739660 TI - Postoperation of cervical cancer with intestine metastasis: a case report and literature review. AB - BACKGROUND: Cervical cancer can infiltrate locally and directly spread to adjacent organs including the vagina, peritoneum, urinary bladder, ureters, rectum, and paracervical tissue, but the intestine metastasis from cervical cancer is extremely rare, which can easily be misdiagnosed. CASE PRESENTATION: Here, we report a case about a 45-year-old postoperative cervical cancer patient with metastases to small intestine and sigmoid colon who presented abdominal distention and dull pain due to intestinal obstruction. The patient underwent exploratory laparotomy, and two intestinal segments including the tumors were resected. The postoperative pathological diagnosis illustrated sigmoid colon and terminal ileum metastatic squamous cell carcinoma. CONCLUSIONS: This case demonstrates that intestine metastasis must be considered in the differential diagnosis of acute abdomen in patients with cervical cancer even at an early tumor stage. PMID- 26739665 TI - Editorial overview: Omics: The maturation of chemical biology. PMID- 26739667 TI - Corrigendum: Plant-microbe rhizosphere interactions mediated by Rehmannia glutinosa root exudates under consecutive monoculture. PMID- 26739669 TI - Core Competencies of the Certified Pediatric Doctor of Chiropractic: Results of a Delphi Consensus Process. AB - An outline of the minimum core competencies expected from a certified pediatric doctor of chiropractic was developed using a Delphi consensus process. The initial set of seed statements and substatements was modeled on competency documents used by organizations that oversee chiropractic and medical education. These statements were distributed to the Delphi panel, reaching consensus when 80% of the panelists approved each segment. The panel consisted of 23 specialists in chiropractic pediatrics (14 females) from across the broad spectrum of the chiropractic profession. Sixty-one percent of panelists had postgraduate pediatric certifications or degrees, 39% had additional graduate degrees, and 74% were faculty at a chiropractic institution and/or in a postgraduate pediatrics program. The panel were initially given 10 statements with related substatements formulated by the study's steering committee. On all 3 rounds of the Delphi process the panelists reached consensus; however, multiple rounds occurred to incorporate the valuable qualitative feedback received. PMID- 26739671 TI - Local salvage therapy for late (>=2 years) metastatic and local relapse of renal cell cancer is a potentially curative treatment irrespective of the site of recurrence. AB - OBJECTIVE: The primary treatment approach to locoregional renal cell carcinoma (RCC) is surgical resection. Most relapses occur within the first 2 years but some patients experience late recurrences. Surgical resection of oligometastatic disease may be considered a curative option for relapsed RCC. However, limited data are available of long-term follow-up of late relapse regarding treatment choice. PATIENTS AND METHODS: We identified 104 patients with RCC from our database, who relapsed after>=2 years from resection of their primary tumor. Median age at primary diagnosis was 61 years and sex distribution was F:M = 40:64. Histology was clear cell, n = 103 and papillary, n = 1. Sites of relapse were local, n = 14 (13.4%); lung only, n = 25 (24.0%); or extrapulmonary, n = 65 (62.5%). Treatment at first relapse was local therapy (LT) in n = 60 (57.7%) patients, of these, n = 55 patients had surgery done and n = 5 patients had underwent radiotherapy. Systemic therapy was used in n = 9 (8.7%) patients. Overall, 35 patients received best supportive care (33.7%). RESULTS: We found a median overall survival (OS) of 49.8 months (95% CI: 29.3-70.2) and a progression free survival (PFS) of 21.6 months (95% CI: 12.6-30.5) for all patients. Patients receiving LT had a median OS of 99.9 months (95% CI: 77.2-122.6) and a PFS of 31.1 months (95% CI: 21.5-40.7). Patients treated with systemic therapy, in turn, had an OS of 21.1 months (95% CI: 8.4-33.8) and a PFS of 4 months (95% CI: 1.0 6.2). Patients who received best supportive care had an OS of 10 months (95% CI: 1.3-18.7). This difference was highly significant (log rank for PFS: P<0.001; log rank for OS: P<0.003). Subgroup analysis of the LT group showed a superior outcome for local relapses (OS: not reached, PFS: 61.4mo [95% CI: 28.5-9.2]) compared to visceral relapses (OS: 35.5mo [95% CI: 17.9-53.1], PFS: 21.1mo [95% CI: 19.2-22.9]). CONCLUSION: Local salvage therapy should be considered the first therapeutic option in late relapse of RCC irrespective of the site of relapse. PMID- 26739673 TI - Evaluation of vitamin D levels in allergic and non-allergic asthma. AB - BACKGROUND AND OBJECTIVE: Some researches show that low vitamin D may play a role in asthma pathogenesis. The aim of this study was to evaluate the serum vitamin D level in asthmatics with different phenotypes and to determine its associations with lung function, IgE, eosinophil count and body mass index (BMI). MATERIALS AND METHODS: The study population comprised 85 patients with asthma and 73 healthy persons. Patients with asthma were divided into groups according to phenotypes. Allergy was assessed using a skin prick test and measuring eosinophil count in peripheral blood and total IgE in serum. Lung function was evaluated by spirometry. Concentration of vitamin D (25(OH)D3) was measured using a commercial ELISA kit. Smoking history was assessed and BMI was calculated for all individuals. RESULTS: The vitamin D level was lower in asthmatics than in the control group (14.36+/-0.57 vs. 22.13+/-0.84 ng/mL, P<0.01). There were no significant differences in the vitamin D level between the groups with allergic and non-allergic asthma (14.36+/-0.77 vs. 14.35+/-0.74 ng/mL). The low vitamin D level increased the risk of asthma 1.2 times (OR, 1.194; 95% CI, 1.109-1.286, P<0.01). The vitamin D level did not correlate with lung function and markers of allergy in asthmatic patients. The vitamin D level correlated with FEV1/FVC (rs=0.72, P<0.05) in smoking patients with asthma. Correlation between the vitamin D level and BMI was found in all studied subjects (rs=-0.18, P<0.05). CONCLUSIONS: The vitamin D level was lower in asthmatic patients than in healthy individuals despite their hypersensitivity and increase risk of asthma. There was no relation between the vitamin D level and lung function, eosinophil count and total IgE level, whereas the lower vitamin D level was associated with higher BMI. PMID- 26739672 TI - Primary genitourinary melanoma: Epidemiology and disease-specific survival in a large population-based cohort. AB - BACKGROUND: Primary genitourinary (GU) melanoma is a rare disease, which is poorly characterized. OBJECTIVE: To examine clinical characteristics and survival outcomes of primary GU melanoma among men and women. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study using the Surveillance, Epidemiology, and End Results database (1973-2010) was used to identify primary GU melanoma cases by tumor site and histology codes. We examined associations of GU melanoma with demographic, clinical, and pathologic characteristics, as well as disease specific survival (DSS). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: DSS was calculated using the Kaplan-Meier method. Cox-proportional hazard models were used to calculate hazard ratios and 95% CI for factors associated with worse DSS. RESULTS AND LIMITATIONS: A total of 1,586 histologically confirmed cases of primary GU melanoma were identified with a median age of 66.1 years (IQR: 55-80). Incidence of primary GU melanoma was 0.2cases/million among men and 1.80cases/million among women. Overall, 60.1% of patients had localized disease at presentation and 90.5% of patients had cancer-directed surgery. Patients with urothelial melanoma had the worst 5- and 10-year DSS (39% and 29%, respectively). Women with vulvar/vaginal melanoma had worse 5- and 10-year DSS compared to men with penile/scrotal melanoma. In multivariate analysis, decreased survival was associated with increasing age, distant stage, and lymph node involvement. Results are limited by the lack of standardized staging for primary GU melanoma and the retrospective design of our study. CONCLUSIONS: Patients with primary GU melanoma present with advanced stage and have a poor prognosis. Women have worse DSS compared to men. DSS is negatively associated with advanced age at diagnosis, higher stage, and lymph node involvement. PATIENT SUMMARY: Clinicians and patients must be aware of the poor disease-specific outcomes associated with primary GU melanoma. Most importantly, women fare worse than men and mucosal melanomas have worse outcomes compared to cutaneous melanomas. PMID- 26739674 TI - Distribution of human papillomavirus type 16 variants in Lithuanian women with cervical cancer. AB - BACKGROUND AND OBJECTIVE: Cervical cancer usually is caused by HPV 16. However, HPV 16 varies within type; different genotypes are described as prototype or variants. Prevalence of different variants differ according the geographic regions and has an unequal impact for cervical cancer development. Our study aimed to identify which variant of HPV 16 was most prevalent in biological samples taken from Lithuanian women with cervical cancer. MATERIALS AND METHODS: A total of 122 HPV 16 positive cervical samples (invasive cancer and cervical intraepithelial neoplasia) were investigated and sequenced to identify different variants. HPV 16 was detected using type specific PCR, exact sequence of the virus was obtained by viral DNA sequencing. RESULTS: Adequate HPV sequence was detected in 106 cases from 122 (86.9% of all cases). After histological confirmation, 96 cases were included in the final analysis. In 33 cases (34.4%) HPV 16 prototype was detected; in 50 cases (52.1%), L83V variant; and in remaining 13 cases (13.5%), multivariant of HPV 16. The frequency of L83V variant in invasive cancer and carcinoma in situ samples was the same (66.7% and 62.0%, respectively; P=0.696). Of analyzed multivariants, 10 were attributed to the European phylogenetic line; 1, to the North American, and 1, to the Asian American. One sample was not attributed to any of the known phylogenetic lines. CONCLUSIONS: The European HPV 16 L83V variant is usually associated with high risk of cervical cancer among women. However, statistically significant difference was not achieved when comparing difference of L83V variants between investigated groups and in HPV 16 L83V variant and prototype distribution in CIN3/Ca in situ and cancer. PMID- 26739675 TI - Early sport practice is related to lower prevalence of cardiovascular and metabolic outcomes in adults independently of overweight and current physical activity. AB - BACKGROUND AND OBJECTIVE: Early sport practice prevents development of diseases in children/adolescents, but still unclear its effect over health in adulthood. Therefore, the purpose of this study was to analyze the association between sport practice in early life and chronic diseases in adulthood. MATERIALS AND METHODS: A retrospective population-based survey carried out in eight Brazilian cities with adults of both genders. Throughout a multistage random process 2720 adults (1096 male and 1624 female) were selected and interviewed. Type 2 diabetes mellitus and arterial hypertension were assessed in a face-to-face interview through a self-report, which was necessarily based on previous medical diagnosis. Early sport practice was assessed in childhood (7-10 years old) and adolescence (11-17 years old). Current physical activity and body mass index were assessed in adulthood throughout a face-to-face interview. RESULTS: Type 2 diabetes mellitus and arterial hypertension were identified in 8.1% (95% CI, 7.1-9.2) and 23.5% (95% CI, 21.9-25.1) of the sample, respectively. Early sport practice during childhood and adolescence was associated with lower occurrence of arterial hypertension (OR, 0.49; 95% CI, 0.33-0.73) and type 2 diabetes (OR, 0.46; 95% CI, 0.24-0.88) in adulthood. CONCLUSIONS: Independently of obesity and current physical activity, early sport practice in early life was positively associated with lower occurrence of chronic diseases in adulthood. PMID- 26739676 TI - Effect of physical training on indices of platelet aggregation and fibrinogen concentration in patients with chronic heart failure. AB - OBJECTIVE: The aim of this study was to determine the effect of long-term physical load on the changes in the fibrinogen concentration and platelet aggregation. MATERIAL AND METHODS: Platelet aggregation was investigated in 144 patients while fibrinogen concentration in 138 patients with CHF. The patients were divided into the groups of the trained patients and the controls and were investigated as follows: on admission to the hospital (stage 1); after treatment in the hospital (stage 2); after 3 months (stage 3); after 6 months (stage 4); and after 1 year (stage 5). The indices were investigated before and after physical load. RESULTS: It was determined that fibrinogen concentration significantly increased after physical load in all the treatment stages in both groups of the patients (P=0.045). In the course of the treatment, fibrinogen concentration gradually decreased in the group of the trained patients (P=0.02). Platelet aggregation investigated with ADP significantly increased after physical load in all the stages in both groups of the patients and decreased during the different investigation stages in the groups of the untrained (P=0.02) and trained patients. Platelet aggregation investigated with ADR consistently decreased before physical load during the different investigation stages in the groups of the trained (difference is not significant) and untrained patients (P=0.02). CONCLUSIONS: Physical training reduces fibrinogen concentration in patients with CHF. It remains unclear whether physical training can have an effect on the decrease in platelet aggregation in patients who have long-term physical training applied. PMID- 26739677 TI - Nutritional habits among high-performance endurance athletes. AB - BACKGROUND AND OBJECTIVE: For athletes, the main purpose of nutrition is to ensure the compensation of increased energy consumption and the need for nutrients in the athlete's body, thereby enabling maximum adaptation to physical loads. The aim of this study was to determine the habits of highly trained endurance athletes depending on sports type, sex and age in order to improve the planning and management of the training of athletes using targeted measures. MATERIALS AND METHODS: In 2009-2012, the dietary habits of 146 endurance athletes were analyzed. The actual diet of Lithuania endurance athletes was investigated using a 24-h dietary survey method. Data on the athletes' actual diet were collected for the previous day. RESULTS: It was found that 80.8% of endurance athletes used lower-than-recommended amounts of carbohydrates in their diet, and more than 70% of athletes used higher-than-recommended levels of fat, saturated fatty acids, and cholesterol. The diet of female athletes was low in carbohydrates, dietary fiber, protein, omega-3 fatty acids, B vitamins, potassium, calcium, phosphorus, iron, manganese, and zinc. Athletes aged 14-18 years tended to consume quantities of protein that were either lower than recommended or excessive. CONCLUSIONS: The diet of highly trained endurance athletes does not fully meet their requirements and in this situation cannot ensure maximum adaptation to very intense and/or long-duration physical loads. The diet of highly trained endurance athletes must be optimized, adjusted and individualized. Particular attention should be focused on female athletes. PMID- 26739678 TI - Correlation between suicide and meteorological parameters. AB - OBJECTIVE: The aim of this study was to investigate the link between suicide and meteorological parameters in the 23 wards of Tokyo, Japan. MATERIALS AND METHODS: Monthly data (from January 2008 to December 2012) of suicide stratified by the type of suicide, i.e. hanging, drowning and jumping, were obtained from the Tokyo Medical Examiner's Office official web site. Monthly meteorological parameters (atmospheric pressure, air temperature, humidity and daylight hours) in the 23 wards of Tokyo were also used for the required period. The effects of meteorological parameters on suicide were explored. RESULTS: The number of suicides was 110.4+/-14.7 (80-149) for men and 55.6+/-9.1 (41-87) for women in the 23 wards of Tokyo, Japan. The mean air temperature was 16.6 degrees C+/-7.7 degrees C (4.8-29.6 degrees C). The number of suicides by drowning for men was significantly and positively correlated with air temperature, and weakly and positively correlated with humidity. In addition, the number of suicides by drowning for men was significantly and negatively correlated with atmospheric pressure. CONCLUSIONS: The number of suicides by drowning was associated with meteorological parameters, especially in men, in the 23 wards of Tokyo, Japan. PMID- 26739680 TI - Risks and Targeted Interventions: Firearms in Intimate Partner Violence. AB - The use of firearms in intimate partner violence (IPV) is widely recognized as an important public health threat. However, what we know about the risks of firearm access on IPV outcomes is limited. Therefore, we conducted a systematic review to determine the state of knowledge on 1) the risks of firearm access and use in IPV and 2) the effectiveness of interventions designed specifically to reduce firearm violence in intimate relationships. Only studies published in English in peer reviewed journals from 1990 through 2014 were included. Results of the review suggest that, when violent intimates have access to firearms, IPV increases in severity and deadliness; however, increases in severity may not be due to firearm use. Additionally, statutes prohibiting persons under domestic violence restraining orders from accessing firearms are associated with reductions in intimate partner homicide, but certain provisions of these laws and their enforcement may impact their effectiveness. Future research should focus on elucidating the link between firearm access and increased IPV severity and on investigating whether and which specific provisions of domestic violence restraining order laws impact the laws' effectiveness. Additionally, more evaluations of initiatives designed to improve the enforcement of domestic violence restraining order firearm prohibitions are needed. PMID- 26739679 TI - Anti-inflammatory and anti-oxidative effects of herbal preparation EM 1201 in adjuvant arthritic rats. AB - BACKGROUND AND OBJECTIVE: The purpose of the present study was to examine the anti-arthritic and antioxidant effects of herbal and active organic ingredient complex (EM 1201) in rats with experimental adjuvant arthritis (AA). MATERIALS AND METHODS: AA was induced in 30 male Wistar rats by intradermal injection of complete Freund's adjuvant into the left hind paw. The course of disease in 30 rats in response to the treatment with EM 1201 and diclofenac, the parameters including body weight, joint swelling, blood indices pro-/antioxidant status of blood serum, and histology of joints and the liver, were investigated. RESULTS: Preparation EM 1201 showed anti-inflammatory effect analogous to diclofenac, improved blood indices, significantly decreased joint swelling and histological changes in them. Joint swelling was suppressed by 29%-42.8% and 9.3%-34.4% in response to administration of EM 1201 and diclofenac during the entire experiment. Both preparations significantly suppressed pannus formation, general inflammatory reaction and edema in soft periarticular tissues and synovium, diminished MDA level and elevated AOA in the blood serum. Significantly lower absolute and relative weight of the liver and lower dystrophic processes in it, and general inflammatory infiltration of hepatic stroma proved the positive effect of treatment with EM 1201. CONCLUSIONS: The present study suggests that EM 1201 has protective activity against arthritis and demonstrated its potential beneficiary effect analogical to diclofenac. Anti-inflammatory and anti-oxidative effect of EM 1201 in rats with AA support the need of further investigations by using it as supplementary agent alone or together with other anti-arthritic drugs in the treatment of rheumatoid arthritis. PMID- 26739683 TI - Effects of CYP3A4 Inhibitors Ketoconazole and Verapamil and the CYP3A4 Inducer Rifampicin on the Pharmacokinetic Parameters of Fostamatinib: Results from In Vitro and Phase I Clinical Studies. AB - BACKGROUND: Fostamatinib (R788) is a spleen tyrosine kinase (SYK) inhibitor. The active metabolite of fostamatinib, R406, is primarily metabolized by CYP3A4. OBJECTIVES: The aim of this study was to characterize hepatic microsomal metabolism of R406 and confirm the role of CYP3A4 in R406 metabolism, determining whether co-administration of CYP3A4 inhibitors (ketoconazole, verapamil) or inducers (rifampicin) affects R406 pharmacokinetics. METHODS: R406 stability was determined using human hepatic microsomes. The CYP450 isoforms responsible for R406 metabolism in humans were identified using expressed CYP450 isoforms and specific chemical inhibitors. The ketoconazole interaction study (double-blind, randomized, placebo-controlled, two-period crossover) involved fostamatinib administration (single 80-mg dose), alone and with ketoconazole (200 mg twice daily). The verapamil and rifampicin interaction studies (open-label, two-period, fixed-sequence) involved fostamatinib administration (single 150-mg dose), alone and with immediate-release verapamil (80 mg three times daily) or rifampicin (600 mg once daily). Standard pharmacokinetic parameters were calculated in all studies. RESULTS/DISCUSSION: Hepatic microsomes showed time-dependent loss of R406 and formation of para-O-demethylated R406. Microsomal metabolism of R406 was markedly inhibited by CYP3A4 inhibitors and, in the expressed CYP450 studies, the rate of R406 disappearance was greatest with CYP3A4. In the clinical studies, co administration of ketoconazole caused a 2-fold (CI 1.77-2.30) increase in R406 exposure. Verapamil increased R406 exposure (39% increase, CI 8-80), whereas rifampicin co-administration decreased exposure by 75% (CI 68-81). Fostamatinib was well tolerated. CONCLUSION: The oxidative metabolism of R406 is predominantly catalyzed by CYP3A4. In clinical studies, exposure to R406 is affected by concomitant administration of CYP3A4 inducers/inhibitors. These findings should be taken into account when considering co-prescription of fostamatinib with such agents. PMID- 26739684 TI - Jennifer Hobbs wins the 2015 JEB Outstanding Paper Prize. PMID- 26739685 TI - Behavioural effects of juvenile hormone and their influence on division of labour in leaf-cutting ant societies. AB - Division of labour in social insects represents a major evolutionary transition, but the physiological mechanisms that regulate this are still little understood. Experimental work with honey bees, and correlational analyses in other social insects, have implicated juvenile hormone (JH) as a regulatory factor, but direct experimental evidence of behavioural effects of JH in social insects is generally lacking. Here, we used experimental manipulation of JH to show that raised JH levels in leaf-cutting ants results in workers becoming more active, phototactic and threat responsive, and engaging in more extranidal activity - behavioural changes that we show are all characteristic of the transition from intranidal work to foraging. These behavioural effects on division of labour suggest that the JH mediation of behaviour occurs across multiple independent evolutions of eusociality, and may be a key endocrine regulator of the division of labour which has produced the remarkable ecological and evolutionary success of social insects. PMID- 26739686 TI - Gait kinetics of above- and below-branch quadrupedal locomotion in lemurid primates. AB - For primates and other mammals moving on relatively thin branches, the ability to effectively adopt both above- and below-branch locomotion is seen as critical for successful arboreal locomotion, and has been considered an important step prior to the evolution of specialized suspensory locomotion within our Order. Yet, little information exists on the ways in which limb mechanics change when animals shift from above- to below-branch quadrupedal locomotion. This study tested the hypothesis that vertical force magnitude and distribution do not vary between locomotor modes, but that the propulsive and braking roles of the forelimb change when animals shift from above- to below-branch quadrupedal locomotion. We collected kinetic data on two lemur species (Varecia variegata and Lemur catta) walking above and below an instrumented arboreal runway. Values for peak vertical, braking and propulsive forces as well as horizontal impulses were collected for each limb. When walking below branch, both species demonstrated a significant shift in limb kinetics compared with above-branch movement. The forelimb became both the primary weight-bearing limb and propulsive organ, while the hindlimb reduced its weight-bearing role and became the primary braking limb. This shift in force distribution represents a shift toward mechanics associated with bimanual suspensory locomotion, a locomotor mode unusual to primates and central to human evolution. The ability to make this change is not accompanied by significant anatomical changes, and thus likely represents an underlying mechanical flexibility present in most primates. PMID- 26739687 TI - Ambient CO2, fish behaviour and altered GABAergic neurotransmission: exploring the mechanism of CO2-altered behaviour by taking a hypercapnia dweller down to low CO2 levels. AB - Recent studies suggest that projected rises of aquatic CO2 levels cause acid-base regulatory responses in fishes that lead to altered GABAergic neurotransmission and disrupted behaviour, threatening fitness and population survival. It is thought that changes in Cl(-) and HCO3 (-) gradients across neural membranes interfere with the function of GABA-gated anion channels (GABAA receptors). So far, such alterations have been revealed experimentally by exposing species living in low-CO2 environments, like many oceanic habitats, to high levels of CO2 (hypercapnia). To examine the generality of this phenomenon, we set out to study the opposite situation, hypothesizing that fishes living in typically hypercapnic environments also display behavioural alterations if exposed to low CO2 levels. This would indicate that ion regulation in the fish brain is fine-tuned to the prevailing CO2 conditions. We quantified pH regulatory variables and behavioural responses of Pangasianodon hypophthalmus, a fish native to the hypercapnic Mekong River, acclimated to high-CO2 (3.1 kPa) or low-CO2 (0.04 kPa) water. We found that brain and blood pH was actively regulated and that the low-CO2 fish displayed significantly higher activity levels, which were reduced after treatment with gabazine, a GABAA receptor blocker. This indicates an involvement of the GABAA receptor and altered Cl(-) and HCO3 (-) ion gradients. Indeed, Goldman calculations suggest that low levels of environmental CO2 may cause significant changes in neural ion gradients in P. hypophthalmus. Taken together, the results suggest that brain ion regulation in fishes is fine-tuned to the prevailing ambient CO2 conditions and is prone to disruption if these conditions change. PMID- 26739689 TI - Secondary analysis of large databases for hepatology research. AB - Secondary analysis of large datasets involves the utilization of existing data that has typically been collected for other purposes to advance scientific knowledge. This is an established methodology applied in health services research with the unique advantage of efficiently identifying relationships between predictor and outcome variables but which has been underutilized for hepatology research. Our review of 1431 abstracts published in the 2013 European Association for the Study of Liver (EASL) abstract book showed that less than 0.5% of published abstracts utilized secondary analysis of large database methodologies. This review paper describes existing large datasets that can be exploited for secondary analyses in liver disease research. It also suggests potential questions that could be addressed using these data warehouses and highlights the strengths and limitations of each dataset as described by authors that have previously used them. The overall goal is to bring these datasets to the attention of readers and ultimately encourage the consideration of secondary analysis of large database methodologies for the advancement of hepatology. PMID- 26739688 TI - Peginterferon lambda for the treatment of HBeAg-positive chronic hepatitis B: A randomized phase 2b study (LIRA-B). AB - BACKGROUND & AIMS: Peginterferon lambda-1a (lambda) is a Type-III interferon, which, like alfa interferons, has antiviral activity in vitro against hepatitis B virus (HBV) and hepatitis C virus (HCV); however, lambda has a more limited extra hepatic receptor distribution. This phase 2b study (LIRA-B) evaluated lambda in patients with chronic HBV infection. METHODS: Adult HBeAg+ interferon-naive patients were randomized (1:1) to weekly lambda (180 MUg) or peginterferon alfa 2a (alfa) for 48 weeks. The primary efficacy endpoint was HBeAg seroconversion at week 24 post-treatment; lambda non-inferiority was demonstrated if the 80% confidence interval (80% CI) lower bound was >-15%. RESULTS: Baseline characteristics were balanced across groups (lambda N=80; alfa N=83). Early on treatment declines in HBV-DNA and qHBsAg through week 24 were greater with lambda. HBeAg seroconversion rates were comparable for lambda and alfa at week 48 (17.5% vs. 16.9%, respectively); however lambda non-inferiority was not met at week 24 post-treatment (13.8% vs. 30.1%, respectively; lambda vs. alfa 80% CI lower bound -24%). Results for other key secondary endpoints (virologic, serologic, biochemical) and post hoc combined endpoints (HBV-DNA <2000 IU/ml plus HBeAg seroconversion or ALT normalization) mostly favored alfa. Overall adverse events (AE), serious AE, and AE-discontinuation rates were comparable between arms but AE-spectra differed (more cytopenias, flu-like, and musculoskeletal symptoms observed with alfa, more ALT flares and bilirubin elevations seen with lambda). Most on-treatment flares occurred early (weeks 4-12), associated with HBV-DNA decline; all post-treatment flares were preceded by HBV-DNA rise. CONCLUSIONS: On-treatment, lambda showed greater early effects on HBV-DNA and qHBsAg, and comparable serologic/virologic responses at end-of-treatment. However, post-treatment, alfa-associated HBeAg seroconversion rates were higher, and key secondary results mostly favored alfa. ClinicalTrials.gov number: NCT01204762. PMID- 26739690 TI - Association between lower serum bicarbonate and renal hyperfiltration in the general population with preserved renal function: a cross-sectional study. AB - BACKGROUND: Lower serum bicarbonate, mainly due to the modern Western-style diet, and renal hyperfiltration (RHF) are both independently associated with higher mortality in the general population with preserved renal function. The objective of this study was to evaluate the association between serum bicarbonate and RHF. METHODS: The health data of 41,886 adults with an estimated glomerular filtration rate (eGFR) >=60 mL/min per 1.73 m(2) were analyzed. The eGFR was calculated with the Chronic Kidney Disease Epidemiology Collaboration creatinine equation and RHF was defined as eGFR with adjusted residuals > sex-specific 95(th) percentile. RESULTS: The adjusted mean of eGFR was lower in the highest quintile of serum bicarbonate than in other quintiles, after adjusting for confounders. A lower percentile rank of serum bicarbonate was associated with higher odds of RHF. The odds ratio (OR) for RHF in the lowest quintile of serum bicarbonate was 1.39 (95 % confidence interval, 95 % CI, 1.11-1.75) compared to the highest, after adjusting for confounders. With subgroup analysis, the association was prominent in participants with a body mass index >25 kg/m(2) (OR 1.98, 95 % CI 1.32-2.95 in the lowest quintile compared to the highest), compared to those with a body mass index <=25 kg/m(2) (OR 1.18, 95 % CI 0.89-1.56 in the lowest quintile compared to the highest). CONCLUSIONS: This study observed an association between lower serum bicarbonate and higher odds of RHF and the possible differential effect of obesity in this association. It is necessary to confirm the association between lower serum bicarbonate and RHF and its causality. PMID- 26739691 TI - Morphometric analysis of young petiole galls on the narrow-leaf cottonwood, Populus angustifolia, by the sugarbeet root aphid, Pemphigus betae. AB - An insect-induced gall is a highly specialized structure resulting from atypical development of plant tissue induced by a reaction to the presence and activity of an insect. The insect induces a differentiation of tissues with features and functions of an ectopic organ, providing nutrition and protection to the galling insect from natural enemies and environmental stresses. In this anatomical and cytological study, we characterized how the gall-inducing aphid Pemphigus betae reshapes the leaf morphology of the narrow-leaf cottonwood Populus angustifolia to form a leaf fold gall. Young galls displayed a bend on one side of the midvein toward the center of the leaf and back to create a fold on the abaxial side of the leaf. This fold was formed abaxially by periclinal and anticlinal divisions, effectively eliminating intercellular spaces from the spongy parenchyma. Galls at this stage exhibited both cell hypertrophy and tissue hyperplasia. Cells on the adaxial surface were more numerous and smaller than cells near the abaxial surface were, creating the large fold that surrounds the insect. Mesophyll cells exhibited some features typical of nutritive cells induced by other galling insects, including conspicuous nucleolus, reduced and fragmented vacuole, smaller and degraded chloroplasts, and dense cytoplasm compared to ungalled tissue. Even though aphids feed on the contents of phloem and do not directly consume the gall tissue, they induce changes in the plant vascular system, which lead to nutrient accumulation to support the growing aphid numbers in mature galls. PMID- 26739692 TI - An Overview of Alternating Electric Fields Therapy (NovoTTF Therapy) for the Treatment of Malignant Glioma. AB - As with many cancer treatments, tumor treating fields (TTFields) target rapidly dividing tumor cells. During mitosis, TTFields-exposed cells exhibit uncontrolled membrane blebbing at the onset of anaphase, resulting in aberrant mitotic exit. Based on these criteria, at least two protein complexes have been proposed as TTFields' molecular targets, including alpha/beta-tubulin and the septin 2, 6, 7 heterotrimer. After aberrant mitotic exit, cells exhibited abnormal nuclei and signs of cellular stress, including decreased cellular proliferation and p53 dependence, and exhibit the hallmarks of immunogenic cell death, suggesting that TTFields treatment may induce an antitumor immune response. Clinical trials lead to Food and Drug Administration approval for their treatment of recurrent glioblastoma. Detailed modeling of TTFields within the brain suggests that the location of the tumor may affect treatment efficacy. These observations have a profound impact on the use of TTFields in the clinic, including what co-therapies may be best applied to boost its efficacy. PMID- 26739695 TI - Physician-assisted death in Canada: an imminent reality. PMID- 26739694 TI - Temporal fluctuations in oribatid mites indicate that density-independent factors favour parthenogenetic reproduction. AB - We investigated the oribatid mite density, community structure and the percentage of parthenogenetic individuals in four different forest types across three regions in Germany in 2008 and once again in 2011. We compared temporal (inter annual) fluctuations in population densities between sexually and parthenogenetically reproducing species of oribatid mites. We hypothesized that population densities in parthenogenetic oribatid mite species fluctuate more than in sexual ones. Further, we expected species composition and dominance of parthenogenetic species to differ between forest types and regions. Oribatid mite community structure did not differ between years but varied with forest type and region, indicating low species turnover in time. As hypothesized, temporal fluctuations were more pronounced in parthenogenetic as compared to sexual species. The percentage of parthenogenetic individuals was significantly higher in coniferous than in beech forests and significantly higher in Schorfheide Chorin than in Hainich-Dun and Schwabische Alb. The results indicate that parthenogenetic species flourish if populations are controlled by density independent factors and dominate at sites were resources are plentiful and easily available, such as coniferous forests, and in regions with more acidic soils and thick organic layers, such as Schorfheide-Chorin. However, historical factors also may have contributed to the increased dominance of parthenogenetic species in the Schorfheide-Chorin, as this region was more heavily glaciated and this may have favoured parthenogenetic species. Overall, our study supports the hypothesis that parthenogenetic species benefit from the lack of density-dependent population control whereas the opposite is true for sexual species. PMID- 26739693 TI - Neurodegeneration with Brain Iron Accumulation. AB - Syndromes with neurodegeneration with brain iron accumulation (NBIA) are a group of neurodegenerative disorders characterized by abnormalities in brain iron metabolism with excess iron accumulation in the globus pallidus and to a lesser degree in the substantia nigra and sometimes adjacent areas. They clinically present as neurodegenerative diseases with progressive hypo- and/or hyperkinetic movement disorders and a variable degree of pyramidal, cerebellar, peripheral nerve, autonomic, cognitive and psychiatric involvement, and visual dysfunction. Several causative genes underlying NBIA have been identified which explain about 65% of cases. Pathophysiologically, many of the NBIA syndromes map into related biochemical pathways and gene networks including mitochondrial pathways, lipid metabolism, and autophagy. Treatment for NBIA disorders remains symptomatic but a placebo-controlled double-blind study is underway. Rapid developments prompted the review of this interesting field. PMID- 26739696 TI - Lessons learned from physician participation in lethal injection: Is Carter v. Canada a death knell for medical self-regulation? PMID- 26739697 TI - Physician-assisted death and the anesthesiologist. AB - Although physician-assisted death (PAD) is established in certain countries, the legality and ethics of this issue have been debated for decades in Canada. The Supreme Court of Canada has now settled the issue of legality nationally, and as a result of the decision in Carter v. Canada, PAD (which includes both physician assisted suicide and euthanasia) will become legal on February 6, 2016. It is difficult to predict the potential demand for PAD in Canada. This paper highlights other countries' experiences with PAD in order to shed light on this question and to forecast issues that Canadian physicians will face once the change to the law comes into effect. At present, there is no legislative scheme in place to regulate the conduct of PAD. Physicians and their provincial colleges may find themselves acting as the de facto regulators of PAD if a regulatory vacuum persists. With their specialized knowledge of pharmacology and interdisciplinary leadership, anesthesiologists may be called upon to develop protocols for the administration of PAD as well as to administer euthanasia. Canadian anesthesiologists currently have a unique opportunity to consider the complex ethical issues they will face when PAD becomes legal and to contribute to the creation of a regulatory structure that will govern PAD in Canada. PMID- 26739698 TI - Cervical spine tuberculosis and airway compromise. PMID- 26739699 TI - Parent satisfaction with neuropsychological consultation after pediatric mild traumatic brain injury. AB - Few studies have focused on consumer satisfaction following neuropsychological evaluation. We sought to examine parent satisfaction with neuropsychological consultation following a mild traumatic brain injury (TBI) in school-age children. We surveyed 71 parents of 8- to 17-year-olds participating in a prospective longitudinal study examining neuropsychological consultation as an intervention for persistent postconcussive symptoms. Children had sustained injuries between 2 and 12 months prior to enrollment. Neuropsychological consultation occurred on average 5 months post-injury. Parent satisfaction data were collected via telephone approximately 4 months after the neuropsychological consultation. The vast majority of parents were quite satisfied with the service (e.g., 94% overall satisfaction rate; 96% rated the service as good or excellent). Satisfaction rates were associated positively with time since injury and negatively with parental education. No other child, parent, or provider variable correlated with satisfaction. The results add to the relatively sparse literature on parent satisfaction with neuropsychological evaluation. A pressing future need in pediatric neuropsychology is to examine the satisfaction of other consumers of the service, including healthcare personnel, educators, and the child patients themselves. PMID- 26739701 TI - ABCG2 deficiency in skin impairs re-epithelialization in cutaneous wound healing. AB - The ATP-binding cassette transporter ABCG2 is expressed in the interfollicular epidermis and mediates the side-population phenotype in skin cells. However, the role of ABCG2 in skin is unclear. Increased expression levels of ABCG2 were found at the basal layer of transitional epidermis adjacent to cutaneous wounds in human patients, indicating that ABCG2 may be involved in regulating the wound healing process. To investigate the role of ABCG2 in cutaneous wound healing, full-thickness skin wounds were created in ABCG2 knockout (ABCG2-KO) and wild type mice. The healing process was analysed and revealed that ABCG2 deficiency in skin results in delays in wound closure and impairments in re-epithelialization, as evidenced by reductions in both suprabasal differentiation and in p63 expressing keratinocytes migrating from transitional epidermis to epithelial tongues. The reduction in p63-expressing cells may be due to elevated levels of reactive oxygen species in ABCG2-KO epidermis, which can cause DNA damage and lead to proliferation arrest. To determine whether ABCG2 deficiency affects the potency of epidermal stem/progenitor cells (EPCs), transplantation studies were carried out, which demonstrated that ABCG2-KO EPCs display higher levels of gammaH2AX and lose the capacity to differentiate into suprabasal keratinocytes. A competitive repopulation assay confirmed that ABCG2 expression is critical for the proper expansion and differentiation of EPCs in cutaneous wounds. As EPCs are known to contribute to the healing of larger wounds, the current findings imply a functional role for ABCG2 in the expansion and differentiation of p63-expressing EPCs. Thus, ABCG2 deficiency in skin impairs re-epithelialization in cutaneous wound healing. PMID- 26739702 TI - P2X ion channel receptors and inflammation. AB - Neuroinflammation limits tissue damage in response to pathogens or injury and promotes repair. There are two stages of inflammation, initiation and resolution. P2X receptors are gaining attention in relation to immunology and inflammation. The P2X7 receptor in particular appears to be an essential immunomodulatory receptor, although P2X1 and P2X4 receptors also appear to be involved. ATP released from damaged or infected cells causes inflammation by release of inflammatory cytokines via P2X7 receptors and acts as a danger signal by occupying upregulated P2X receptors on immune cells to increase immune responses. The purinergic involvement in inflammation is being explored for the development of novel therapeutic strategies. PMID- 26739703 TI - Saffron reduces ATP-induced retinal cytotoxicity by targeting P2X7 receptors. AB - P2X7-type purinergic receptors are distributed throughout the nervous system where they contribute to physiological and pathological functions. In the retina, this receptor is found in both inner and outer cells including microglia modulating signaling and health of retinal cells. It is involved in retinal neurodegenerative disorders such as retinitis pigmentosa and age-related macular degeneration (AMD). Experimental studies demonstrated that saffron protects photoreceptors from light-induced damage preserving both retinal morphology and visual function and improves retinal flicker sensitivity in AMD patients. To evaluate a possible interaction between saffron and P2X7 receptors (P2X7Rs), different cellular models and experimental approaches were used. We found that saffron positively influences the viability of mouse primary retinal cells and photoreceptor-derived 661W cells exposed to ATP, and reduced the ATP-induced intracellular calcium increase in 661W cells. Similar results were obtained on HEK cells transfected with recombinant rat P2X7R but not on cells transfected with rat P2X2R. Finally, patch-clamp experiments showed that saffron inhibited cationic currents in HEK-P2X7R cells. These results point out a novel mechanism through which saffron may exert its protective role in neurodegeneration and support the idea that P2X7-mediated calcium signaling may be a crucial therapeutic target in the treatment of neurodegenerative diseases. PMID- 26739707 TI - The expression of heterologous MAM-7 in Lactobacillus rhamnosus reduces its intrinsic capacity to inhibit colonization of pathogen Vibrio parahaemolyticus in vitro. AB - BACKGROUND: Vibrio parahaemolyticus (V. parahaemolyticus) is a Gram-negative, halophilic bacterium recognized as one of the most important foodborne pathogen. When ingested, V. parahaemolyticus causes a self-limiting illness (Vibriosis), characterized mainly by watery diarrhoea. Treatment is usually oral rehydration and/or antibiotics in complicated cases. Since 1996, the pathogenic and pandemic V. parahaemolyticus O3:K6 serotype has spread worldwide, increasing the reported number of vibriosis cases. Thus, the design of new strategies for pathogen control and illness prevention is necessary. Lactobacillus sp. grouped Gram positive innocuous bacteria, part of normal intestinal microbiota and usually used as oral vaccines for several diarrheic diseases. Recombinants strains of Lactobacillus (RL) expressing pathogen antigens can be used as part of an anti adhesion strategy where RL block the pathogen union sites in host cells. Thus, we aimed to express MAM-7 V. parahaemolyticus adhesion protein in Lactobacillus sp. to generate an RL that prevents pathogen colonization. RESULTS: We cloned the MAM 7 gene from V. parahaemolyticus RIMD 2210633 in Lactobacillus expression vectors. Recombinant strains (Lactobacillus rhamnosus pSEC-MAM7 and L. rhamnosus pCWA MAM7) adhered to CaCo-2 cells and competed with the pathogen. However, the L. rhamnosus wild type strain showed the best capacity to inhibit pathogen colonization in vitro. In addition, LDH-assay showed that recombinant strains were cytotoxic compared with the wild type isogenic strain. CONCLUSIONS: MAM-7 expression in lactobacilli reduces the intrinsic inhibitory capacity of L. rhamnosus against V. parahaemolyticus. PMID- 26739709 TI - Sensory loss and its consequences for couples' psychosocial and relational wellbeing: an integrative review. AB - OBJECTIVES: Previous research has shown that marital communication is key to couples' successful illness adjustment. However, little is known about couples' experiences of health conditions characterised by communication difficulties such as acquired hearing, vision, and dual-sensory loss. The aim of this review was to identify the effect of sensory loss, and associated communication difficulties, on couples' relational and psychosocial adjustment. METHOD: A systematic search was conducted to identify studies investigating the social, psychological, and relational impact of sensory loss on couples. RESULTS: Twenty-four articles met the criteria for inclusion in the review. Significant heterogeneity in the measurements and design of the quantitative studies prevented statistical data synthesis. All but two studies reported some effect of sensory loss on couples' psychosocial or relational wellbeing. Higher levels of marital satisfaction were found to buffer against adverse psychological outcomes. Results of quantitative and qualitative studies were synthesised to form an integrative model illustrating the associations between sensory loss and couples' relational and psychosocial wellbeing. CONCLUSIONS: Although this review reports an association between sensory loss and couples' relational and psychosocial wellbeing, the results should be viewed with caution given that relatively few studies on couples' experiences of acquired sensory loss exist, and many have methodological limitations. PMID- 26739706 TI - Circulating angiopoietin-like protein 8 (ANGPTL8) and ANGPTL3 concentrations in relation to anthropometric and metabolic profiles in Korean children: a prospective cohort study. AB - BACKGROUND: Previous studies have shown that angiopoietin-like protein 8 (ANGPTL8), also called as betatrophin, acts together with ANGPTL3 to regulate lipid metabolism, glucose metabolism, and energy homeostasis. Moreover, ANGPTL8 promotes proliferation of pancreatic beta-cells and induces insulin secretion. However, there are no previous longitudinal studies in humans. METHODS: We analyzed the age- and sex-matched data of 240 normal weight and overweight Korean children from the Korean Metabolic disorders and Obesity Study in Elementary School children (K-MOSES), a prospective observational cohort study. RESULTS: At baseline, ANGPTL8 concentrations were positively associated with triglycerides (TG) (r = 0.168, P = 0.010), whereas ANGPTL3 levels were associated with fasting insulin (r = 0.248, P < 0.001) and the homeostasis model assessment of insulin resistance (HOMA-IR) (r = 0.197, P = 0.002). Although both ANGPTL8 and ANGPTL3 levels did not differ between children with normal weight and children with overweight, ANGPTL8 levels were increased in males compared to females (341.2 [267.4-436.5] vs. 270.2 [213.9-378.8] pg/ml, P = 0.001). In particular, there was no significant inter-relationship between circulating ANGPTL8 and ANGPTL3 concentrations in Korean boys and girls (r = -0.073, P = 0.265). Multivariate analysis showed that baseline ANGPTL8 concentrations were independently associated with future changes of serum TG levels in Korean children after adjusting for confounding factors after a 3 year follow-up period (r = -0.165, P = 0.016). CONCLUSIONS: This longitudinal study demonstrated for the first time that baseline ANGPTL8 levels were associated with baseline and future changes in TG levels in Korean children. PMID- 26739710 TI - Biophysics and Physiology of the Volume-Regulated Anion Channel (VRAC)/Volume Sensitive Outwardly Rectifying Anion Channel (VSOR). AB - The volume-regulated anion channel (VRAC), also known as the volume-sensitive outwardly rectifying (VSOR) anion channel or the volume-sensitive organic osmolyte/anion channel (VSOAC), is essential for cell volume regulation after swelling in most vertebrate cell types studied to date. In addition to its role in cell volume homeostasis, VRAC has been implicated in numerous other physiological and pathophysiological processes, including cancer, ischemic brain edema, cell motility, proliferation, angiogenesis, programmed cell death, and excitotoxic glutamate release. Although VRAC has been extensively biophysically, pharmacologically, and functionally characterized, its molecular identity was highly controversial until the recent identification of the leucine-rich repeats containing 8A (LRRC8A) protein as essential for the VRAC current in multiple cell types and a likely pore-forming subunit of VRAC. Members of this distantly pannexin-1-related protein family form heteromers, and in addition to LRRC8A, at least another LRRC8 family member is required for the formation of a functional VRAC. This review summarizes the biophysical and pharmacological properties of VRAC, highlights its main physiological functions and pathophysiological implications, and outlines the search for its molecular identity. PMID- 26739712 TI - Physiological impact of CB1 receptor expression by hippocampal GABAergic interneurons. AB - A subset of hippocampal GABAergic neurons, which are cholecystokinin-positive, highly express cannabinoid type 1 (CB1) receptors. Activation of these receptors inhibits GABA release and thereby limits inhibitory control. While genetic deletion of CB1 receptors from GABAergic neurons led to behavioural alterations and neuroinflammatory reactions, it remained unclear whether these changes in the knockout animals were a direct consequence of the enhanced transmitter release or reflected developmental deficits. The hippocampus is vital for the generation of spatial, declarative and working memory. Here, we addressed the question how CB1 receptors in GABAergic neurons influence hippocampal function. Patch clamp and field potential recordings in mice devoid of CB1 receptors in GABAergic neurons revealed an enhanced frequency and faster kinetics of spontaneous inhibitory postsynaptic currents in CA1 pyramidal neurons while tonic inhibition, paired pulse facilitation and long-term potentiation in the hippocampus were not affected. Evaluation of cognitive functions demonstrated impaired acquisition of spatial memory and deficits in novel object recognition and partner recognition in the knockout mice, while working memory and spatial memory remained intact. The density of GABAergic neurons was also similar in knockout mice and their littermates, which argues against global deficits in hippocampal development. Together, these results suggest that CB1 receptors in GABAergic neurons influence specific aspects of neuronal excitability and hippocampal learning. PMID- 26739714 TI - Analysis of Surface Water Pollution Accidents in China: Characteristics and Lessons for Risk Management. AB - Understanding historical accidents is important for accident prevention and risk mitigation; however, there are no public databases of pollution accidents in China, and no detailed information regarding such incidents is readily available. Thus, 653 representative cases of surface water pollution accidents in China were identified and described as a function of time, location, materials involved, origin, and causes. The severity and other features of the accidents, frequency and quantities of chemicals involved, frequency and number of people poisoned, frequency and number of people affected, frequency and time for which pollution lasted, and frequency and length of pollution zone were effectively used to value and estimate the accumulated probabilities. The probabilities of occurrences of various types based on origin and causes were also summarized based on these observations. The following conclusions can be drawn from these analyses: (1) There was a high proportion of accidents involving multi-district boundary regions and drinking water crises, indicating that more attention should be paid to environmental risk prevention and the mitigation of such incidents. (2) A high proportion of accidents originated from small-sized chemical plants, indicating that these types of enterprises should be considered during policy making. (3) The most common cause (49.8% of the total) was intentional acts (illegal discharge); accordingly, efforts to increase environmental consciousness in China should be enhanced. PMID- 26739713 TI - Risk of Infections Among 2100 Individuals with IgA Deficiency: a Nationwide Cohort Study. AB - PURPOSE: To explore the risk of infections in individuals with IgA deficiency compared to general population controls. METHODS: In this nationwide prospective population-based cohort study, we used data on IgA levels (<0.07 g/L) from six university hospitals in Sweden to identify 2100 individuals with IgA deficiency. Individuals were diagnosed between 1980 and 2010. For each patient with IgA deficiency we identified 10 controls from the general population, matched on age, sex, and place of residence (n = 18,653). Data on infections were obtained from the Swedish National Patient Register (including inpatient and hospital-based outpatient care) between 2001 and 2010. We defined infections as having a record of a relevant international classification of disease (ICD) code. Prevalences and prevalence ratios (PRs) were calculated. RESULTS: Individuals with IgA deficiency were more likely to have a record of any infection (36.1 vs. 18.8% in controls) corresponding to a PR of 2.4 (95%CI 2.2-2.6). We also noted statistically significant associations with IgA deficiency (all P-values <0.05) and respiratory tract infections (17.8 vs. 6.3% in controls; PR = 3.2), gastrointestinal infections (6.0 vs. 1.8% in controls; PR = 3.5), skin infections (4.1 vs. 2.2% in controls; PR = 1.9), joint infections (0.48 vs. 0.24% in controls; PR = 2.0; P = 0.052), sepsis (1.5 vs. 0.45% in controls; PR = 3.4), meningitis (0.38 vs. 0.12%, PR = 3.2), mastoiditis/otitis (2.1 vs. 1.1% in controls; PR = 2.0), and urinary tract infections (6.1 vs. 3.4% in controls; PR = 1.8). CONCLUSIONS: Individuals with IgA deficiency are at an increased risk of infections requiring hospital care. PMID- 26739715 TI - Effects of economic crises on population health outcomes in Latin America, 1981 2010: an ecological study. AB - OBJECTIVES: The relative health effects of changes in unemployment, inflation and gross domestic product (GDP) per capita on population health have not been assessed. We aimed to determine the effect of changes in these economic measures on mortality metrics across Latin America. DESIGN: Ecological study. SETTING: Latin America (21 countries), 1981-2010. OUTCOME MEASURES: Uses multivariate regression analysis to assess the effects of changes in unemployment, inflation and GDP per capita on 5 mortality indicators across 21 countries in Latin America, 1981-2010. Country-specific differences in healthcare infrastructure, population structure and population size were controlled for. RESULTS: Between 1981 and 2010, a 1% rise in unemployment was associated with statistically significant deteriorations (p<0.05) in 5 population health outcomes, with largest deteriorations in 1-5 years of age and male adult mortality rates (1.14 and 0.53 rises per 1000 deaths respectively). A 1% rise in inflation rate was associated with significant deteriorations (p<0.05) in 4 population health outcomes, with the largest deterioration in male adult mortality rate (0.0033 rise per 1000 deaths). Lag analysis showed that 5 years after rises in unemployment and inflation, significant deteriorations (p<0.05) occurred in 3 and 5 mortality metrics, respectively. A 1% rise in GDP per capita was associated with no significant deteriorations in population health outcomes either in the short or long term. beta coefficient comparisons indicated that the effect of unemployment increases was substantially greater than that of changes in GDP per capita or inflation. CONCLUSIONS: Rises in unemployment and inflation are associated with long-lasting deteriorations in several population health outcomes. Unemployment exerted much larger effects on health than inflation. In contrast, changes in GDP per capita had almost no association with the explored health outcomes. Contrary to neoclassical development economics, policymakers should prioritise amelioration of unemployment if population health outcomes are to be optimised. PMID- 26739711 TI - A Pore Idea: the ion conduction pathway of TMEM16/ANO proteins is composed partly of lipid. AB - Since their first descriptions, ion channels have been conceived as proteinaceous conduits that facilitate the passage of ionic cargo between segregated environments. This concept is reinforced by crystallographic structures of cation channels depicting ion conductance pathways completely lined by protein. Although lipids are sometimes present in fenestrations near the pore or may be involved in channel gating, there is little or no evidence that lipids inhabit the ion conduction pathway. Indeed, the presence of lipid acyl chains in the conductance pathway would curse the design of the channel's aqueous pore. Here, we make a speculative proposal that anion channels in the TMEM16/ANO superfamily have ion conductance pathways composed partly of lipids. Our reasoning is based on the idea that TMEM16 ion channels evolved from a kind of lipid transporter that scrambles lipids between leaflets of the membrane bilayer and the modeled structural similarity between TMEM16 lipid scramblases and TMEM16 anion channels. This novel view of the TMEM16 pore offers explanation for the biophysical and pharmacological oddness of TMEM16A. We build upon the recent X-ray structure of nhTMEM16 and develop models of both TMEM16 ion channels and lipid scramblases to bolster our proposal. It is our hope that this model of the TMEM16 pore will foster innovative investigation into TMEM16 function. PMID- 26739717 TI - Phase 2, randomised placebo-controlled trial to evaluate the efficacy and safety of an anti-GM-CSF antibody (KB003) in patients with inadequately controlled asthma. AB - OBJECTIVES: We wished to evaluate the effects of an antigranulocyte-macrophage colony-stimulating factor monoclonal antibody (KB003) on forced expiratory volume in 1 s (FEV1), asthma control and asthma exacerbations in adult asthmatics inadequately controlled by long-acting bronchodilators and inhaled/oral corticosteroids. SETTINGS: 47 ambulatory asthma care centres globally. PRIMARY OUTCOME MEASURES: Change in FEV1 at week 24. PARTICIPANTS: 311 were screened, 160 were randomised and 129 completed the study. INTERVENTIONS: 7 intravenous infusions of either 400 mg KB003 or placebo at baseline and weeks 2, 4, 8, 12, 16 and 20. PRIMARY AND SECONDARY OUTCOME MEASURES: FEV1 at week 24, asthma control, exacerbation rates and safety in all participants as well as prespecified subgroups. MAIN RESULTS: In the KB003 treated group, FEV1 at week 24 improved to 118 mL compared with 54 mL in the placebo group (p=0.224). However, FEV1 improved to 253 vs 26 mL at week 24 (p=0.02) in eosinophilic asthmatics (defined as >300 peripheral blood eosinophils/mL at baseline) and comparable improvements were seen at weeks 20 (p=0.034) and 24 (p=0.077) in patients with FEV1 reversibility >= 20% at baseline and at weeks 4 (p=0.029), 16 (p=0.018) and 20 (p=0.006) in patients with prebronchodilator FEV1 <= 50% predicted at baseline. There were no effects on asthma control or exacerbation rates. The most frequent adverse events in the KB003 group were rhinosinusitis and headache. There was no significant difference in antidrug antibody response between placebo and treated groups. There were no excess infections or changes in biomarkers known to be associated with the development of pulmonary alveolar proteinosis. CONCLUSIONS: Higher doses and/or further asthma phenotyping may be required in future studies with KB003. TRIAL REGISTRATION NUMBER: NCT01603277; Results. PMID- 26739716 TI - Prognostic factors for disability and sick leave in patients with subacute non malignant pain: a systematic review of cohort studies. AB - OBJECTIVE: This systematic review aims to identify generic prognostic factors for disability and sick leave in subacute pain patients. SETTING: General practice and other primary care facilities. PARTICIPANTS: Adults (>18 years) with a subacute (<= 3-month) non-malignant pain condition. Eligibility criteria were cohort studies investigating the prediction of disability or long-term sick leave in adults with a subacute pain condition in a primary care setting. 19 studies were included, referring to a total of 6266 patients suffering from pain in the head, neck, back and shoulders. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was long-term disability (>3 months) due to a pain condition. The secondary outcome was sick leave, defined as 'absence from work' or 'return-to work'. RESULTS: PubMed, EMBASE, CINAHL and PEDro databases were searched from 16 January 2003 to 16 January 2014. The quality of evidence was presented according to the GRADE WG recommendations. Several factors were found to be associated with disability at follow-up for at least two different pain symptoms. However, owing to insufficient studies, no generic risk factors for sick leave were identified. CONCLUSIONS: Multiple site pain, high pain severity, older age, baseline disability and longer pain duration were identified as potential prognostic factors for disability across pain sites. There was limited evidence that anxiety and depression were associated with disability in patients with subacute pain, indicating that these factors may not play as large a role as expected in developing disability due to a pain condition. Quality of evidence was moderate, low or very low, implying that confidence in the results is limited. Large prospective prognostic factor studies are needed with sufficient study populations and transparent reporting of all factors examined. TRIAL REGISTRATION NUMBER: CRD42014008914. PMID- 26739718 TI - Poor housing conditions in association with child health in a disadvantaged immigrant population: a cross-sectional study in Rosengard, Malmo, Sweden. AB - OBJECTIVES: To describe the home environment in terms of housing conditions and their association with child health in a disadvantaged immigrant population. DESIGN: A cross-sectional observational study. SETTING: Enrolment took place during 2010-2011 in Rosengard, Malmo, Sweden. PARTICIPANTS: Children aged 0-13 years in 2 study neighbourhoods were recruited from local health records and from schools. 359 children participated, with a participation rate of 40%. Data on health, lifestyle and apartment characteristics from questionnaire-led interviews with the mothers of the children were obtained together with data from home inspections carried out by trained health communicators. OUTCOME MEASURES: Logistic regression analysis was used to estimate ORs for various health outcomes, adjusted for demographic information and lifestyle factors. RESULTS: The housing conditions were very poor, especially in one of the study neighbourhoods where 67% of the apartments had been sanitised of cockroaches, 27% were infested with cockroaches and 40% had a visible mould. The association between housing conditions and health was mostly inconclusive, but there were statistically significant associations between current asthma and dampness (OR=4.1, 95% CI 1.7 to 9.9), between asthma medication and dampness (OR=2.8, 95% CI 1.2 to 6.4), and between mould and headache (OR=4.2, 95% CI 1.2 to 14.8). The presence of cockroaches was associated with emergency care visits, with colds, with headache and with difficulty falling asleep, and worse general health was associated with mould and presence of cockroaches. CONCLUSIONS: The associations between dampness and asthma, and the association between mould and headache, are in line with current knowledge. The presence of cockroaches seemed to be associated with various outcomes, including those related to mental well-being, which is less described in the literature. The results of the present study are hypothesis generating and provide strong incentives for future studies in this study population. PMID- 26739719 TI - High prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae infections in anal and pharyngeal sites among a community-based sample of men who have sex with men and transgender women in Lima, Peru. AB - OBJECTIVES: This study aimed to characterise the epidemiology of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections among men who have sex with men (MSM) and transgender women (TW) in Lima, Peru. SETTING: Cross-sectional study in Lima, Peru. PARTICIPANTS: We recruited a group of 510 MSM and 208 TW for a subsequent community-based randomised controlled trial. The presence of CT and NG were evaluated using Aptima Combo2 in pharyngeal and anal swabs. We also explored correlates of these infections. PRIMARY AND SECONDARY OUTCOME MEASURES: Study end points included overall prevalence of C. trachomatis and N. gonorrhoeae in anal and pharyngeal sites. RESULTS: Overall prevalence of CT was 19% (95% CI 16.1% to 22.1%) and 4.8% (95% CI 3.3% to 6.6%) in anal and pharyngeal sites, respectively, while prevalence of NG was 9.6% (95% CI 7.5% to 12.0%) and 6.5% (95% CI 4.8% to 8.5%) in anal and pharyngeal sites, respectively. CONCLUSIONS: The prevalence of each infection declined significantly among participants older than 34 years (p<0.05). Efforts towards prevention and treatment of extraurogenital chlamydial and gonococcal infections in high-risk populations like MSM and TW in Lima, Peru, are warranted. TRIAL REGISTRATION NUMBER: NCT00670163; Results. PMID- 26739720 TI - 'Please don't call me Mister': patient preferences of how they are addressed and their knowledge of their treating medical team in an Australian hospital. AB - OBJECTIVES: To investigate how patients prefer to be addressed by healthcare providers and to assess their knowledge of their attending medical team's identity in an Australian Hospital. SETTING: Single-centre, large tertiary hospital in Australia. PARTICIPANTS: 300 inpatients were included in the survey. Patients were selected in a sequential, systematic and whole-ward manner. Participants were excluded with significant cognitive impairment, non-English speaking, under the age of 18 years or were too acutely unwell to participate. The sample demographic was predominately an older population of Anglo-Saxon background. PRIMARY AND SECONDARY OUTCOME MEASURES: Patients preferred mode of address from healthcare providers including first name, title and second name, abbreviated first name or another name. Whether patients disliked formal address of title and second name. Secondarily, patient knowledge of their attending medical team members name and role and if correct, what position within the medical hierarchy they held. RESULTS: Over 99% of patients prefer informal address with greater than one-third having a preference to being called a name other than their legal first name. 57% of patients were unable to correctly name a single member of their attending medical team. CONCLUSIONS: These findings support patient preference of informal address; however, healthcare providers cannot assume that a documented legal first name is preferred by the patient. Patient knowledge of their attending medical team is poor and suggests current introduction practices are insufficient. PMID- 26739721 TI - Efficacy and safety of nesiritide in patients with decompensated heart failure: a meta-analysis of randomised trials. AB - OBJECTIVES: Current evidence suggests that nesiritide may have effects on renal function and decrease the incidence of mortality. However, a clear superiority using nesiritide in terms of renal toxicity and mortality in patients with heart failure was not consistently proven by previous studies. We performed a meta analysis of all randomised trials to obtain the best estimates of efficacy and safety of nesiritide for the initial treatment of decompensated heart failure. METHOD: We performed a meta-analysis of randomised trials of nesiritide in patients with decompensated heart failure (n=38,064 patients, in 22 trials). Two reviewers independently extracted data. Data on efficacy and safety outcomes were collected. We calculated pooled relatives risk (RRs), weighted mean difference and associated 95% CIs. RESULTS: Compared with placebo, dobutamine and nitroglycerin, nesiritide indicated no increasing risk of total mortality. Compared with the combined control therapy, nesiritide was associated with non significant differences in short-term mortality (RR 1.24; 95% CI 0.85 to 1.80; p=0.27), mid-term mortality (RR 0.86; 95% CI 0.60 to 1.24; p=0.42) and long-term mortality (RR 0.94; 95% CI 0.75 to 1.18; p=0.61). Nesiritide therapy increased the risk of hypotension (p<0.00 001) and bradycardia (p=0.02) when compared with control therapy. Compared with dobutamine or placebo therapy, no differences in serum creatinine, blood urea nitrogen and creatinine clearance, and no risk of the need for dialysis was observed in nesiritide therapy. CONCLUSIONS: Our findings indicated that, in patients with heart failure, nesiritide was not associated with the risk of mortality. However, it increased the risk of cardiovascular adverse events. The change of serum creatinine and creatinine clearance had no significant difference, and no risk of the need for dialysis was observed after low-dose nesiritide treatment. PMID- 26739722 TI - Temporal trends in death causes in adults attending an urban HIV clinic in Uganda: a retrospective chart review. AB - OBJECTIVE: To study temporal trends of mortality in HIV-infected adults who attended an HIV clinic in Kampala, Uganda, between 2002 and 2012. DESIGN: Descriptive retrospective study. METHODS: Two doctors independently reviewed the clinic database that contained information derived from the clinic files and assigned one or more causes of death to each patient >18 years of age with a known date of death. Four cause-of-death categories were defined: 'communicable conditions and AIDS-defining malignancies', 'chronic non-communicable conditions', 'other non-communicable conditions' and 'unknown'. Trends in cause of-death categories over time were evaluated using multinomial logistic regression with year of death as an independent continuous variable. RESULTS: 1028 deaths were included; 38% of these individuals were on antiretroviral therapy (ART). The estimated mortality rate dropped from 21.86 deaths/100 person years of follow-up (PYFU) in 2002 to 1.75/100 PYFU in 2012. There was a significant change in causes of death over time (p<0.01). Between 2002 and 2012, the proportion of deaths due to 'communicable conditions and AIDS-defining malignancies' decreased from 84% (95% CI 74% to 90%) to 64% (95% CI 53% to 74%) and the proportion of deaths due to 'chronic non-communicable conditions', 'other non-communicable conditions' and a combination of 'communicable and non communicable conditions' increased. Tuberculosis (TB) was the main cause of death (34%). Death from TB decreased over time, from 43% (95% CI 32% to 53%) in 2002 to a steady proportion of approximately 25% from 2006 onwards (p<0.01). CONCLUSIONS: Mortality rate decreased over time. The proportion of deaths from communicable conditions and AIDS-defining malignancies decreased and from non-communicable diseases, both chronic and non-chronic, increased. Nevertheless, communicable conditions and AIDS-defining malignancies continued to cause the majority of deaths, with TB as the main cause. Ongoing monitoring of cause of death is warranted and strategies to decrease mortality from TB and other common opportunistic infections are essential. PMID- 26739724 TI - Experiences of food abstinence in patients with type 2 diabetes: a qualitative study. AB - OBJECTIVE: People with type 2 diabetes often report pressure to abstain from many of life's pleasures. We tried to reconstruct these patients' sense of pressure to better understand how people with diabetes make sense of, and integrate, these feelings into their life. DESIGN, SETTING AND PARTICIPANTS: A secondary analysis of narrative interviews with 14 patients with type 2 diabetes who are part of a website project. MAIN OUTCOME MEASURES: Grounded theory-based analysis of narrative interviews, consisting of open, axial and selective coding. RESULTS: People with type 2 diabetes felt obliged to give up many pleasures and live a life of abstinence. They perceived a pressure to display a modest culinary lifestyle via improved laboratory test results and weight. Their verbal efforts to reassure and distance themselves from excessiveness indicate a high moral pressure. With regard to the question of how to abstain, food and behaviour were classified into healthy and unhealthy. Personal rules sometimes led to surprising experiences of freedom. CONCLUSIONS: People with diabetes have internalised that their behaviour is a barrier to successful treatment. They experience an intensive pressure to show abstinence and feel misjudged when their efforts have no visible effect. Taking into account this moral pressure, and listening to patients' personal efforts and strategies to establish healthy behaviours, might help to build a trusting relationship with healthcare providers. PMID- 26739723 TI - Feasibility study of an integrated stroke self-management programme: a cluster randomised controlled trial. AB - OBJECTIVES: To test the feasibility of conducting a controlled trial into the effectiveness of a self-management programme integrated into stroke rehabilitation. DESIGN: A feasibility cluster-randomised design was utilised with stroke rehabilitation teams as units of randomisation. SETTING: Community-based stroke rehabilitation teams in London. PARTICIPANTS: 78 patients with a diagnosis of stroke requiring community based rehabilitation. INTERVENTION: The intervention consisted of an individualised approach to self-management based on self-efficacy. Clinicians were trained to integrate defined self-management principles into scheduled rehabilitation sessions, supported by a patient-held workbook. MAIN OUTCOMES MEASURES: Patient measures of quality of life, mood, self efficacy and functional capacity, and health and social care utilisation, were carried out by blinded assessors at baseline, 6 weeks and 12 weeks. Fidelity and acceptability of the delivery were evaluated by observation and interviews. RESULTS: 4 community stroke rehabilitation teams were recruited, and received a total of 317 stroke referrals over 14 months. Of these, 138 met trial eligibility criteria and 78 participants were finally recruited (56.5%). Demographic and baseline outcome measures were similar between intervention and control arms, with the exception of age. All outcome measures were feasible to use and clinical data at 12 weeks were completed for 66/78 participants (85%; 95% CI 75% to 92%). There was no significant difference in any of the outcomes between the arms of the trial, but measures of functional capacity and self-efficacy showed responsiveness to the intervention. Observation and interview data confirmed acceptability and fidelity of delivery according to predetermined criteria. Costs varied by site. CONCLUSIONS: It was feasible to integrate a stroke self management programme into community rehabilitation, using key principles. Some data were lost to follow-up, but overall results support the need for conducting further research in this area and provide data to support the design of a definitive trial. TRIAL REGISTRATION NUMBER: ISRCTN42534180. PMID- 26739725 TI - Patient-centred care, health behaviours and cardiovascular risk factor levels in people with recently diagnosed type 2 diabetes: 5-year follow-up of the ADDITION Plus trial cohort. AB - OBJECTIVE: To examine the association between the experience of patient-centred care (PCC), health behaviours and cardiovascular disease (CVD) risk factor levels among people with type 2 diabetes. DESIGN: Population-based prospective cohort study. SETTING: 34 general practices in East Anglia, UK, delivering organised diabetes care. PARTICIPANTS: 478 patients recently diagnosed with type 2 diabetes aged between 40 and 69 years enrolled in the ADDITION-Plus trial. MAIN OUTCOME MEASURES: Self-reported and objectively measured health behaviours (diet, physical activity, smoking status), CVD risk factor levels (blood pressure, lipid levels, glycated haemoglobin, body mass index, waist circumference) and modelled 10-year CVD risk. RESULTS: Better experiences of PCC early in the course of living with diabetes were not associated with meaningful differences in self reported physical activity levels including total activity energy expenditure (beta-coefficient: 0.080 MET h/day (95% CI 0.017 to 0.143; p=0.01)), moderate-to vigorous physical activity (beta-coefficient: 5.328 min/day (95% CI 0.796 to 9.859; p=0.01)) and reduced sedentary time (beta-coefficient: -1.633 min/day (95% CI -2.897 to -0.368; p=0.01)). PCC was not associated with clinically meaningful differences in levels of high-density lipoprotein cholesterol (beta-coefficient: 0.002 mmol/L (95% CI 0.001 to 0.004; p=0.03)), systolic blood pressure (beta coefficient: -0.561 mm Hg (95% CI -0.653 to -0.468; p=0.01)) or diastolic blood pressure (beta-coefficient: -0.565 mm Hg (95% CI -0.654 to -0.476; p=0.01)). Over an extended follow-up of 5 years, we observed no clear evidence that PCC was associated with self-reported, clinical or biochemical outcomes, except for waist circumference (beta-coefficient: 0.085 cm (95% CI 0.015 to 0.155; p=0.02)). CONCLUSIONS: We found little evidence that experience of PCC early in the course of diabetes was associated with clinically important changes in health-related behaviours or CVD risk factors. TRIAL REGISTRATION NUMBER: ISRCTN99175498; Post results. PMID- 26739727 TI - Research protocol for a diagnostic study of non-invasive exhaled breath analysis for the prediction of oesophago-gastric cancer. AB - INTRODUCTION: Despite improvements in a range of chemo, radio and surgical therapies, the overall survival at 5 years from oesophago-gastric cancer remains poor and ranges from 10% to 30%. Early diagnosis is a key strategy to improve survival but early disease stage has non-specific symptoms that are very common while the warning clinical picture often indicates advanced disease. The aim of this research is to validate a breath test to predict oesophago-gastric cancer therefore allowing earlier diagnosis and introduction of treatment. METHODS AND ANALYSIS: The study will include 325 patients and be conducted across four major oesophago-gastric cancer centres in London, UK. This research will utilise selected ion flow-tube mass spectrometry (SIFT-MS) exhaled breath analysis, for comparison of predicted cancer risk based on the previously developed volatile organic compound exhaled breath model, with endoscopic findings and histology biopsies. This will determine the overall diagnostic accuracy for non-invasive breath testing for the diagnosis of oesophago-gastric cancer. ETHICS AND DISSEMINATION: Approval was gained from NRES Committee London, on 16 July 2014 (REC reference 14/LO/1136) for the completion of this study. Different methods of dissemination will be employed including international clinical and patient group presentations, and publication of research outputs in a high-impact clinical journal. This is to ensure that the findings from this research will reach patients, primary care practitioners, scientists, hospital specialists in gastroenterology, oncology and surgery, health policymakers and commissioners as well as NHS regulatory bodies. TRIALS REGISTRATION NUMBER: UKCRN18063; Pre results. PMID- 26739726 TI - Migration to the Downtown Eastside neighbourhood of Vancouver and changes in service use in a cohort of mentally ill homeless adults: a 10-year retrospective study. AB - OBJECTIVES: Little research has investigated the role of migration as a potential contributor to the spatial concentration of homeless people with complex health and social needs. In addition, little is known concerning the relationship between possible migration and changes in levels of service use over time. We hypothesised that homeless, mentally ill individuals living in a concentrated urban setting had migrated from elsewhere over a 10-year period, in association with significant increases in the use of public services. SETTING: Recruitment was concentrated in the Downtown Eastside neighbourhood of Vancouver, Canada. PARTICIPANTS: Participants (n=433) met criteria for chronic homelessness and serious mental illness, and provided consent to access administrative data. METHODS: Linked administrative data were used to retrospectively examine geographic relocation as well as rates of health, justice, and social welfare service utilisation in each of the 10 years prior to recruitment. Generalised estimating equations were used to estimate the effect of migration on service use. RESULTS: Over a 10-year period there was significant movement into Vancouver's Downtown Eastside neighbourhood (from 17% to 52% of the cohort). During the same period, there were significant annual increases in community medical services (adjusted rate ratio (ARR) per year=1.08; 95% CI 1.06 to 1.10), hospital admissions (ARR=1.08; 95% CI 1.04 to 1.11), criminal convictions (ARR=1.08; 95% CI 1.03 to 1.13), and financial assistance payments (ARR=1.04; 95% CI 1.03 to 1.06). Migration was significantly associated with financial assistance, but not with other types of services. CONCLUSIONS: Significant increases in service use over a 10-year period coincided with significant migration into an urban area where relevant services were concentrated. These results highlight opportunities for early intervention in spatially diverse neighbourhoods to interrupt trajectories marked by worsening health and extremely high service involvement. Further research is urgently needed to investigate the causal relationships between physical migration, health and social welfare, and escalating use of public services. TRIAL REGISTRATION NUMBERS: ISRCTN57595077 and ISRCTN66721740; Post-results. PMID- 26739728 TI - Understanding stroke survivors' and informal carers' experiences of and need for primary care and community health services--a systematic review of the qualitative literature: protocol. AB - INTRODUCTION: Despite the rising prevalence of stroke, no comprehensive model of postacute stroke care exists. Research on stroke has focused on acute care and early supported discharge, with less attention dedicated to longer term support in the community. Likewise, relatively little research has focused on long-term support for informal carers. This review aims to synthesise and appraise extant qualitative evidence on: (1) long-term healthcare needs of stroke survivors and informal carers, and (2) their experiences of primary care and community health services. The review will inform the development of a primary care model for stroke survivors and informal carers. METHODS AND ANALYSIS: We will systematically search 4 databases: MEDLINE, EMBASE, PsycINFO and CINAHL for published qualitative evidence on the needs and experiences of stroke survivors and informal carers of postacute care delivered by primary care and community health services. Additional searches of reference lists and citation indices will be conducted. The quality of articles will be assessed by 2 independent reviewers using a Critical Appraisal Skills Programme (CASP) checklist. Disagreements will be resolved through discussion or third party adjudication. Meta-ethnography will be used to synthesise the literature based on first-order, second-order and third order constructs. We will construct a theoretical model of stroke survivors' and informal carers' experiences of primary care and community health services. ETHICS AND DISSEMINATION: The results of the systematic review will be disseminated via publication in a peer-reviewed journal and presented at a relevant conference. The study does not require ethical approval as no patient identifiable data will be used. PMID- 26739729 TI - Clustered randomised controlled trial of two education interventions designed to increase physical activity and well-being of secondary school students: the MOVE Project. AB - OBJECTIVE: To assess the effectiveness of 2 interventions in improving the physical activity and well-being of secondary school children. DESIGN: A clustered randomised controlled trial; classes, 1 per school, were assigned to 1 of 3 intervention arms or a control group based on a 2*2 factorial design. The interventions were peer-mentoring and participative learning. Year 7 children (aged 11-12) in the peer-mentoring intervention were paired with year 9 children for 6 weekly mentoring meetings. Year 7 children in the participative learning arm took part in 6 weekly geography lessons using personalised physical activity and Global Positioning System (GPS) data. Year 7 children in the combined intervention received both interventions, with the year 9 children only participating in the mentoring sessions. PARTICIPANTS: 1494 year 7 students from 60 schools in the North of England took part in the trial. Of these, 43 students opted out of taking part in the evaluation measurements, 2 moved teaching group and 58 changed school. Valid accelerometry outcome data were collected for 892 students from 53 schools; and well-being outcome data were available for 927 students from 52 schools. MAIN OUTCOME MEASURES: The primary outcomes were mean minutes of accelerometer-measured moderate-to-vigorous intensity physical activity per day, and well-being as evaluated by the KIDSCREEN-27 questionnaire. These data were collected 6 weeks after the intervention; a 12-month follow-up is planned. RESULTS: No significant effects (main or interaction) were observed for the outcomes. However, small positive differences were found for both outcomes for the participative learning intervention. CONCLUSIONS: These findings suggest that the 2 school-based interventions did not modify levels of physical activity or well-being within the period monitored. Change in physical activity may require more comprehensive individual behavioural intervention, and/or more system-based efforts to address wider environmental influences such as family, peers, physical environment, transport and educational policy. TRIAL REGISTRATION NUMBER: ISRCTN82956355. PMID- 26739731 TI - Infant outcomes after exposure to Tdap vaccine in pregnancy: an observational study. AB - OBJECTIVE: Pertussis vaccination during pregnancy has recently been recommended in both the USA and UK to prevent pertussis infection in infants. While there are no apparent safety concerns about the administration of Tdap vaccine during pregnancy, there is only limited safety data available. We aimed to closely monitor infants exposed to Tdap during pregnancy to look for any adverse outcomes that may be attributable to the vaccine. DESIGN: This was a prospective observational study, collecting information to evaluate the safety of Tdap vaccine for infants exposed during pregnancy. Infants were followed for between 6 and 12 months after birth, with 84% completing 12 months of follow-up. Information was obtained from objective sources including routine health visits and vaccination records wherever possible, as well as frequent parental reports. SETTING: The Canterbury region of New Zealand. PATIENTS: A cohort of 403 infants whose mothers had received Tdap vaccine. MAIN OUTCOME MEASURES: Gestational age at birth, growth parameters, congenital anomalies, immunisation status and timeliness of immunisation, development of pertussis infection. RESULTS: There were no significant differences in birth weight, gestational age at birth, congenital anomalies or infant growth as compared with baseline population data. Infants of mothers who had received the vaccine were more likely to receive their vaccinations on time during infancy. No cases of pertussis occurred in this cohort despite high rates of disease in the community. We have not found any adverse events attributable to vaccine exposure. CONCLUSIONS: These data add to the growing pool of evidence that the administration of Tdap vaccine during pregnancy is an appropriate strategy for reducing the burden of pertussis in infants. CLINICAL TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12613001045707. PMID- 26739730 TI - Effectiveness of varenicline and counselling for smoking cessation in an observational cohort study in China. AB - OBJECTIVES: To evaluate the effectiveness of varenicline for smoking cessation in Chinese smokers in a real world cessation clinic practice. DESIGN: A prospective observational study. SETTING: Beijing, China. PARTICIPANTS: A total of 924 smokers (883 men and 41 women) who attended a smoking cessation clinic of a large general hospital were assessed with data from structured questionnaires at baseline and follow-up at 1, 3 and 6 months. Trained physician counsellors provided free individual counselling for all subjects and follow-up interviews with brief counselling. 332 subjects additionally prescribed varenicline according to their own choice were compared with those without varenicline. MAIN OUTCOME MEASURES: Primary outcomes were self-reported 7-day point prevalence abstinence rate and 3-month continuous abstinence rate at 6-month follow-up. Secondary outcomes were 7-day point prevalence abstinence rates at 1 and 3-month follow-up, and 1-month continuous abstinence rate at 3-month follow-up. RESULTS: By intention-to-treat, the 7-day point prevalence abstinence rate with varenicline and counselling at 6 months was significantly higher than counselling only (37.0% vs 23.1%; OR, 1.75; 95% CI 1.46 to 2.62; p=0.001). The 3-month continuous abstinence rate at 6 months was higher with varenicline (33.1% vs 18.4%; OR, 2.04; 95% CI 1.61 to 2.99; p<0.001). Varenicline also showed better secondary outcomes. CONCLUSIONS: Varenicline prescription in the smoking cessation clinic appeared to be effective with doubling of quit rates in Chinese smokers in a real world cessation clinic practice. CLINICAL TRIAL REGISTRATION: NCT01935505; Results. PMID- 26739733 TI - Chlamydia trachomatis genotypes in a cross-sectional study of urogenital samples from remote Northern and Central Australia. AB - OBJECTIVES: The objective was to determine the frequency of trachoma genotypes of Chlamydia trachomatis-positive urogenital tract (UGT) specimens from remote areas of the Australian Northern Territory (NT). SETTING: The setting was analysis of remnants of C. trachomatis positive primarily UGT specimens obtained in the course of clinical practice. The specimens were obtained from two pathology service providers. PARTICIPANTS: From 3356 C. trachomatis specimens collected during May 2012-April 2013, 439 were selected for genotyping, with a focus on specimens from postpubescent patients, in remote Aboriginal communities where ocular trachoma is potentially present. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was the proportion of successfully genotyped UGT specimens that were trachoma genotypes. The secondary outcome measures were the distribution of genotypes, and the frequencies of different classes of specimens able to be genotyped. RESULTS: Zero of 217 successfully genotyped UGT specimens yielded trachoma genotypes (95% CI for frequency=0-0.017). For UGT specimens, the genotypes were E (41%), F (22%), D (21%) and K (7%), with J, H and G and mixed genotypes each at 1-4%. Four of the five genotyped eye swabs yielded trachoma genotype Ba, and the other genotype J. Two hundred twenty-two specimens (50.6%) were successfully genotyped. Urine specimens were less likely to be typable than vaginal swabs (p<0.0001). CONCLUSIONS: Unlike in some other studies, in the remote NT, trachoma genotypes of C. trachomatis were not found circulating in UGT specimens from 2012 to 2013. Therefore, C. trachomatis genotypes in UGT specimens from young children can be informative as to whether the organism has been acquired through sexual contact. We suggest inclusion of C. trachomatis genotyping in guidelines examining the source of sexually transmitted infections in young children in areas where trachoma genotypes may continue to circulate, and continued surveillance of UGT C. trachomatis genotypes. PMID- 26739732 TI - Preoperative therapy with pazopanib in high-risk soft tissue sarcoma: a phase II window-of-opportunity study by the German Interdisciplinary Sarcoma Group (GISG 04/NOPASS). AB - INTRODUCTION: For resectable soft tissue sarcoma (STS), radical surgery, usually combined with radiotherapy, is the mainstay of treatment and the only potentially curative modality. Since surgery is often complicated by large tumour size and extensive tumour vasculature, preoperative treatment strategies with the aim of devitalising the tumour are being explored. One option is treatment with antiangiogenic drugs. The multikinase inhibitor pazopanib, which possesses pronounced antiangiogenic effects, has shown activity in metastatic and unresectable STS, but has so far not been tested in the preoperative setting. METHODS AND ANALYSIS: This open-label, multicentre phase II window-of-opportunity trial assesses pazopanib as preoperative treatment of resectable STS. Participants receive a 21-day course of pazopanib 800 mg daily during wait time for surgery. Major eligibility criteria are resectable, high-risk adult STS of any location, or metachronous solitary STS metastasis for which resection is planned, and adequate organ function and performance status. The trial uses an exact single-stage design. The primary end point is metabolic response rate (MRR), that is, the proportion of patients with >50% reduction of the mean standardised uptake value (SUVmean) in post-treatment compared to pre-treatment fluorodeoxyglucose positron emission tomography CT. The MRR below which the treatment is considered ineffective is 0.2. The MRR above which the treatment warrants further exploration is 0.4. With a type I error of 5% and a power of 80%, the sample size is 35 evaluable patients, with 12 or more responders as threshold. Main secondary end points are histopathological and MRI response, resectability, toxicity, recurrence-free and overall survival. In a translational substudy, endothelial progenitor cells and vascular epithelial growth factor receptor are analysed as potential prognostic and predictive markers. ETHICS AND DISSEMINATION: Approval by the ethics committee II, University of Heidelberg, Germany (2012-019F-MA), German Federal Institute for Drugs and Medical Devices (61-3910-4038155) and German Federal Institute for Radiation Protection (Z5 22463/2-2012-007). TRIAL REGISTRATION NUMBER: NCT01543802, EudraCT: 2011-003745 18; Pre-results. PMID- 26739734 TI - The impact of self-harm by young people on parents and families: a qualitative study. AB - OBJECTIVES: Little research has explored the full extent of the impact of self harm on the family. This study aimed to explore the emotional, physical and practical effects of a young person's self-harm on parents and family. DESIGN AND PARTICIPANTS: We used qualitative methods to explore the emotional, physical and practical effects of a young person's self-harm on their parents and family. We conducted a thematic analysis of thirty-seven semistructured narrative interviews with parents of young people who had self-harmed. RESULTS: After the discovery of self-harm, parents described initial feelings of shock, anger and disbelief. Later reactions included stress, anxiety, feelings of guilt and in some cases the onset or worsening of clinical depression. Social isolation was reported, as parents withdrew from social contact due to the perceived stigma associated with self-harm. Parents also described significant impacts on siblings, ranging from upset and stress to feelings of responsibility and worries about stigma at school. Siblings had mixed responses, but were often supportive. Practically speaking, parents found the necessity of being available to their child often conflicted with the demands of full-time work. This, along with costs of, for example, travel and private care, affected family finances. However, parents generally viewed the future as positive and hoped that with help, their child would develop better coping mechanisms. CONCLUSIONS: Self-harm by young people has major impacts on parents and other family members. Clinicians and staff who work with young people who self-harm should be sensitive to these issues and offer appropriate support and guidance for families. PMID- 26739735 TI - Understanding influences and decisions of households with children with asthma regarding temperature and humidity in the home in winter: a qualitative study. AB - OBJECTIVES: This study aimed to understand the influences and decisions of households with children with asthma regarding keeping warm and well at home in winter. SETTING: Community settings in Rotherham and Doncaster, South Yorkshire, UK. PARTICIPANTS: Individuals from 35 families and 25 health, education and social care staff underwent interview. 5 group interviews were held, 1 with parents (n=20) and 4 with staff (n=25). OUTCOME MEASURES: This qualitative study incorporated in-depth, semistructured individual and group interviews, framework analysis and social marketing segmentation techniques. RESULTS: The research identifies a range of psychological and contextual influences on parents that may inadvertently place a child with asthma at risk of cold, damp and worsening health in a home. Parents have to balance a range of factors to manage fluctuating temperatures, damp conditions and mould. Participants were constantly assessing their family's needs against the resources available to them. Influences, barriers and needs interacted in ways that meant they made 'trade offs' that drove their behaviour regarding the temperature and humidity of the home, including partial self-disconnection from their energy supply. Evidence was also seen of parents lacking knowledge and understanding while working their way through conflicting and confusing information or advice from a range of professionals including health, social care and housing. Pressure on parents was increased when they had to provide help and support for extended family and friends. CONCLUSIONS: The findings illustrate how and why a child with asthma may be at risk of a cold home. A 'trade-off model' has been developed as an output of the research to explain the competing demands on families. Messages emerge about the importance of tailored advice and information to families vulnerable to cold related harm. PMID- 26739736 TI - Leisure time physical activity and subsequent physical and mental health functioning among midlife Finnish, British and Japanese employees: a follow-up study in three occupational cohorts. AB - OBJECTIVES: The aim of this study was to examine whether leisure time physical activity contributes to subsequent physical and mental health functioning among midlife employees. The associations were tested in three occupational cohorts from Finland, Britain and Japan. DESIGN: Cohort study. SETTING: Finland, Britain and Japan. PARTICIPANTS: Prospective employee cohorts from the Finnish Helsinki Health Study (2000-2002 and 2007, n=5958), British Whitehall II study (1997-1999 and 2003-2004, n=4142) and Japanese Civil Servants Study (1998-1999 and 2003, n=1768) were used. Leisure time physical activity was classified into three groups: inactive, moderately active and vigorously active. PRIMARY OUTCOME MEASURE: Mean scores of physical and mental health functioning (SF-36) at follow up were examined. RESULTS: Physical activity was associated with better subsequent physical health functioning in all three cohorts, however, with varying magnitude and some gender differences. Differences were the clearest among Finnish women (inactive: 46.0, vigorously active: 49.5) and men (inactive: 47.8, active vigorous: 51.1) and British women (inactive: 47.3, active vigorous: 50.4). In mental health functioning, the differences were generally smaller and not that clearly related to the intensity of physical activity. Emerging differences in health functioning were relatively small. CONCLUSIONS: Vigorous physical activity was associated with better subsequent physical health functioning in all three cohorts with varying magnitude. For mental health functioning, the intensity of physical activity was less important. Promoting leisure time physical activity may prove useful for the maintenance of health functioning among midlife employees. PMID- 26739737 TI - Preovulatory uterine flushing with saline as a treatment for unexplained infertility: a randomised controlled trial protocol. AB - INTRODUCTION: In vitro fertilisation (IVF) is the treatment of choice for unexplained infertility. Preovulatory uterine flushing could reduce intrauterine debris and inflammatory factors preventing pregnancy and constitute an alternative to IVF. Our objective is to assess the efficacy of preovulatory uterine flushing with physiological saline for the treatment of unexplained infertility. METHODS AND ANALYSIS: We will perform a randomised controlled trial based on consecutive women aged between 18 and 37 years consulting for unexplained infertility for at least 1 year. On the day of their luteinising hormone surge, 192 participants will be randomised in two equal groups to either receive 20 mL of physiological saline by an intrauterine catheter or 10 mL of saline intravaginally. We will assess relative risk of live birth (primary outcome), as well as pregnancy (secondary outcome) over one cycle of treatment. We will report the side effects, complications and acceptability of the intervention. ETHICS AND DISSEMINATION: This project was approved by the Ethics committee of the Centre Hospitatlier Universitaire de Quebec (no 2015-1146). Uterine flushing is usually well tolerated by women and would constitute a simple, affordable and minimally invasive treatment for unexplained infertility. We plan to communicate the results of the review by presenting research abstracts at conferences and by publishing the results in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02539290; Pre-results. PMID- 26739738 TI - Non-response in a cross-sectional study of respiratory health in Norway. AB - OBJECTIVES: Declining participation in epidemiological studies has been reported in recent decades and may lead to biased prevalence estimates and selection bias. The aim of the study was to identify possible causes and effects of non-response in a population-based study of respiratory health in Norway. DESIGN: The Telemark study is a longitudinal study that began with a cross-sectional survey in 2013. SETTING: In 2013, a random sample of 50,000 inhabitants aged 16-50 years, living in Telemark county, received a validated postal questionnaire. The response rate was 33%. In this study, a random sample of 700 non-responders was contacted first by telephone and then by mail. OUTCOME MEASURES: Response rates, prevalence and OR of asthma and respiratory symptoms based on exposure to vapours, gas, dust or fumes (VGDF) and smoking. Causes of non-response. RESULTS: A total of 260 non responders (37%) participated. Non-response was associated with younger age, male sex, living in a rural area and past smoking. The prevalence was similar for responders and non-responders for physician-diagnosed asthma and several respiratory symptoms. The prevalence of chronic cough and use of asthma medication was overestimated in the Telemark study, and adjusted prevalence estimates were 17.4% and 5%, respectively. Current smoking was identified as a risk factor for respiratory symptoms among responders and non-responders, while occupational VGDF exposure was a risk factor only among responders. The Breslow Day test detected heterogeneity between productive cough and occupational VGDF exposure among responders. CONCLUSIONS: The Telemark study provided valid estimates for physician-diagnosed asthma and several respiratory symptoms, while it was necessary to adjust prevalence estimates for chronic cough and use of asthma medication. Reminder letters had little effect on risk factor associations. Selection bias should be considered in future investigations of the relationship between respiratory outcomes and exposures. PMID- 26739739 TI - Sex differences in body anthropometry and composition in individuals with and without diabetes in the UK Biobank. AB - OBJECTIVE: Type I and II diabetes are associated with a greater relative risk of cardiovascular diseases (CVD) in women than in men. Sex differences in adiposity storage may explain these findings. METHODS: A cross-sectional study of 480,813 participants from the UK Biobank without history of CVD was conducted to assess whether the difference in body size in people with and without diabetes was greater in women than in men. Age-adjusted linear regression analyses were used to obtain the mean difference in women minus men in the difference in body size measures, separately for type I and II diabetes. RESULTS: Body size was higher in individuals with diabetes than in individuals without diabetes, particularly in type II diabetes. Differences in body size between individuals with and without type II diabetes were more extreme in women than in men; compared to those without type II diabetes, body mass index and waist circumference were 1.94 (95% CI 1.82 to 2.07) and 4.84 (4.53 to 5.16) higher in women than in men, respectively. In type I diabetes, body size differed to a similar extent between those with and without diabetes in women as in men. This pattern was observed across all prespecified subgroups. CONCLUSIONS: Differences in body size associated with diabetes were significantly greater in women than in men in type II diabetes but not in type I diabetes. Prospective studies can determine whether sex differences in body size associated with diabetes underpin some of the excess risk for CVD in women with type II diabetes. PMID- 26739740 TI - Endoscopic totally extraperitoneal (TEP) hernia repair for inguinal disruption (Sportsman's hernia): rationale and design of a prospective observational cohort study (TEP-ID-study). AB - INTRODUCTION: Chronic inguinal pain is a frequently occurring problem in athletes. A diagnosis of inguinal disruption is performed by exclusion of other conditions causing groin pain. Up to now, conservative medical management is considered to be the primary treatment for this condition. Relevant large and prospective clinical studies regarding the treatment of inguinal disruption are limited; however, recent studies have shown the benefits of the totally extraperitoneal patch (TEP) technique.This study provides a complete assessment of the inguinal area in athletes with chronic inguinal pain before and after treatment with the TEP hernia repair technique. METHODS AND ANALYSIS: We describe the rationale and design of an observational cohort study for surgical treatment with the endoscopic TEP hernia repair technique in athletes with a painful groin (inguinal disruption).The study is being conducted in a high-volume, single centre hospital with specialty in TEP hernia repair. Patients over 18 years, suffering from inguinal pain for at least 3 months during or after playing sports, and whom have not undergone previous inguinal surgery and have received no benefit from physiotherapy are eligible for inclusion. Patients with any another cause of inguinal pain, proven by physical examination, inguinal ultrasound, X-pelvis/hip or MRI are excluded.Primary outcome is reduction in pain after 3 months. Secondary outcomes are pain reduction, physical functioning, and resumption of sport (in frequency and intensity). ETHICS AND DISSEMINATION: An unrestricted research grant for general study purposes was assigned to the Hernia Centre. This study itself is not directly subject to the above mentioned research grant or any other financial sponsorship. We intend to publish the outcome of the study, regardless of the findings. All authors will give final approval of the manuscript version to be published. PMID- 26739741 TI - Association between APOE polymorphism and metabolic syndrome in Uyghur ethnic men. AB - OBJECTIVES: This study aimed to examine the association between apolipoprotein E (APOE) polymorphism and metabolic syndrome (MetS) among Uyghur ethnic men in Xinjiang, China. PARTICIPANTS: A total of 482 patients with MetS and 510 healthy sex-matched and age-matched controls were recruited from the Xinjiang Uyghur Autonomous Region of China. The participants were subjected to routine physical and blood biochemical tests, and APOE genotyping was performed. RESULTS: The APOE epsilon3/3 was the predominant type, with a frequency of 71.8%, while epsilon2/2 was less common than epsilon4/4 in Uyghur males. The frequencies of the APOE2, E3 and E4 alleles in Uyghur males were 8.5%, 80.0% and 11.5%, respectively. However, the distribution of APOE genotypes was significantly different between the MetS and control groups (p<0.001). In the MetS group, the frequencies of the epsilon2 and epsilon4 alleles and the frequencies of the epsilon2/2, epsilon2/3 and epsilon2/4 genotypes were significantly lower than those of the control group. Those individuals without the epsilon2 and epsilon4 alleles had higher MetS prevalence than the other gene carriers, and the ORs of these individuals developing MetS were 1.5 and 1.27 compared to the gene carriers. Triglyceride, serum total cholesterol and low-density lipoprotein cholesterol levels were lower and serum high-density lipoprotein was higher in the epsilon2 carriers than the epsilon3 carriers, and the prevalence of MetS, central obesity, high blood pressure, hypercholesterolaemia and hypertriglyceridaemia was lower in the APOE2 group than in the APOE4 group. The risks of these individuals with epsilon4 allele carriers getting these changes were 1.327, 1.780, 1.888, 1.428 and 2.571 times greater than those of epsilon2 allele carriers. CONCLUSIONS: APOE4 is associated with many individual components of MetS, whereas APOE2 was associated with a reduced risk of MetS at the univariate level in Uyghur ethnic men. PMID- 26739743 TI - Efficacy and safety of second-generation antipsychotic long-acting injections (SGA LAIs) in maintenance treatment of bipolar disorder: protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Bipolar disorder requires long-term treatment but non-adherence is a common problem. Antipsychotic long-acting injections (LAIs) have been suggested to improve adherence but none are licensed in the UK for bipolar. However, the use of second-generation antipsychotics (SGA) LAIs in bipolar is not uncommon albeit there is a lack of systematic review in this area. This study aims to systematically review safety and efficacy of SGA LAIs in the maintenance treatment of bipolar disorder. METHODS AND ANALYSIS: The protocol is based on Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) and will include only randomised controlled trials comparing SGA LAIs in bipolar. PubMed, EMBASE, CINAHL, Cochrane Library (CENTRAL), PsychINFO, LiLACS, http://www.clinicaltrials.gov will be searched, with no language restriction, from 2000 to January 2016 as first SGA LAIs came to the market after 2000. Manufacturers of SGA LAIs will also be contacted. Primary efficacy outcome is relapse rate or delayed time to relapse or reduction in hospitalisation and primary safety outcomes are drop-out rates, all-cause discontinuation and discontinuation due to adverse events. Qualitative reporting of evidence will be based on 21 items listed on standards for reporting qualitative research (SRQR) focusing on study quality (assessed using the Jadad score, allocation concealment and data analysis), risk of bias and effect size. Publication bias will be assessed using funnel plots. If sufficient data are available meta-analysis will be performed with primary effect size as relative risk presented with 95% CI. Sensitivity analysis, conditional on number of studies and sample size, will be carried out on manic versus depressive symptoms and monotherapy versus adjunctive therapy. ETHICS AND DISSEMINATION: Ethical approval is not required as primary data will not be collected. The results will be disseminated through a peer reviewed publication, conference presentation and the press. STUDY REGISTRATION NUMBER: PROSPERO CRD42015023948. PMID- 26739742 TI - Acupuncture treatment for ischaemic stroke in young adults: protocol for a randomised, sham-controlled clinical trial. AB - INTRODUCTION: Stroke in young adults is not uncommon. Although the overall incidence of stroke has been recently declining, the incidence of stroke in young adults is increasing. Traditional vascular risk factors are the main cause of young ischaemic stroke. Acupuncture has been shown to benefit stroke rehabilitation and ameliorate the risk factors for stroke. The aims of this study were to determine whether acupuncture treatment will be effective in improving the activities of daily living (ADL), motor function and quality of life (QOL) in patients of young ischaemic stroke, and in preventing stroke recurrence by controlling blood pressure, lipids and body weight. METHODS AND ANALYSIS: In this randomised, sham-controlled, participant-blinded and assessor-blinded clinical trial, 120 patients between 18 and 45 years of age with a recent (within 1 month) ischaemic stroke will be randomised for an 8-week acupuncture or sham acupuncture treatment. The primary outcome will be the Barthel Index for ADL. The secondary outcomes will include the Fugl-Meyer Assessment for motor function; the World Health Organization Quality of Life BREF (WHOQOL-BREF) for QOL; and risk factors that are measured by ambulatory blood pressure, the fasting serum lipid, body mass index and waist circumference. Incidence of adverse events and long-term mortality and recurrence rate during a 10-year and 30-year follow-up will also be investigated. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of The Third Affiliated Hospital of Zhejiang Chinese Medical University. Protocol V.3 was approved in June 2013. The results will be disseminated in a peer-reviewed journal and presented at international congresses. The results will also be disseminated to patients by telephone during follow-up calls enquiring on the patient's post-study health status. TRIAL REGISTRATION NUMBER: ChiCTR-TRC- 13003317; Pre-results. PMID- 26739744 TI - Impact of health insurance for tertiary care on postoperative outcomes and seeking care for symptoms: quasi-experimental evidence from Karnataka, India. AB - OBJECTIVES: To evaluate the effects of a government insurance programme covering tertiary care for the poor in Karnataka, India--Vajpayee Arogyashree Scheme (VAS) -on treatment seeking and postoperative outcomes. DESIGN: Geographic regression discontinuity. SETTING: 572 villages in Karnataka, India. PARTICIPANTS: 3478 households in 300 villages where VAS was implemented and 3486 households in 272 neighbouring matched villages ineligible for VAS. INTERVENTION: A government insurance programme that provided free tertiary care to households below the poverty line in half of villages in Karnataka from February 2010 to August 2012. MAIN OUTCOME MEASURE: Seeking treatment for symptoms, posthospitalisation well being, occurrence of infections during hospitalisation and need for rehospitalisation. RESULTS: The prevalence of symptoms was nearly identical for households in VAS-eligible villages compared with households in VAS-ineligible villages. However, households eligible for VAS were 4.96 percentage points (95% CI 1 to 8.9; p=0.014) more likely to seek treatment for their symptoms. The increase in treatment seeking was more pronounced for symptoms of cardiac conditions, the condition most frequently covered by VAS. Respondents from VAS eligible villages reported greater improvements in well-being after a hospitalisation in all categories assessed and they were statistically significant in 3 of the 6 categories (walking ability, pain and anxiety). Respondents eligible for VAS were 9.4 percentage points less likely to report any infection after their hospitalisation (95% CI -20.2 to 1.4; p=0.087) and 16.5 percentage points less likely to have to be rehospitalised after the initial hospitalisation (95% CI -28.7 to -4.3; p<0.01). CONCLUSIONS: Insurance for tertiary care increased treatment seeking among eligible households. Moreover, insured patients experienced better posthospitalisation outcomes, suggesting better quality of care received. These results suggest that there are several pathways through which tertiary care insurance could improve health, aside from increasing utilisation of the services that the programme directly subsidises. PMID- 26739745 TI - Aggregation of binary colloidal suspensions on attractive walls. AB - The adsorption of colloidal particles from a suspension on a solid surface is of fundamental importance to many physical and biological systems. In this work, Brownian Dynamics simulations are performed to study the aggregation in a suspension of oppositely charged colloidal particles in the presence of an attractive wall. For sufficiently strong attractions, the wall alters the microstructure of the aggregates so that B2 (CsCl-type) structures are more likely obtained instead of B1 (NaCl-type) structures. The probability of forming either B1 or B2 crystallites depends also on the inverse interaction range kappaa. Suspensions with small kappaa are more likely to form B2 crystals than suspensions with larger kappaa, even if the energetic stability of the B2 phase decreases with decreasing kappaa. The mechanisms underlying this aggregation and crystallization behaviour are analyzed in detail. PMID- 26739746 TI - A multi-factorial analysis of response to warfarin in a UK prospective cohort. AB - BACKGROUND: Warfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors explaining variance in stable dose, but have not explored the initial patient response to warfarin, and a wider range of clinical and biochemical factors affecting both initial and stable dosing with warfarin. METHODS: A prospective cohort of 711 patients starting warfarin was followed up for 6 months with analyses focusing on both non-genetic and genetic factors. The outcome measures used were mean weekly warfarin dose (MWD), stable mean weekly dose (SMWD) and international normalised ratio (INR) > 4 during the first week. Samples were genotyped on the Illumina Human610-Quad chip. Statistical analyses were performed using Plink and R. RESULTS: VKORC1 and CYP2C9 were the major genetic determinants of warfarin MWD and SMWD, with CYP4F2 having a smaller effect. Age, height, weight, cigarette smoking and interacting medications accounted for less than 20 % of the variance. Our multifactorial analysis explained 57.89 % and 56.97 % of the variation for MWD and SMWD, respectively. Genotypes for VKORC1 and CYP2C9*3, age, height and weight, as well as other clinical factors such as alcohol consumption, loading dose and concomitant drugs were important for the initial INR response to warfarin. In a small subset of patients for whom data were available, levels of the coagulation factors VII and IX (highly correlated) also played a role. CONCLUSION: Our multifactorial analysis in a prospectively recruited cohort has shown that multiple factors, genetic and clinical, are important in determining the response to warfarin. VKORC1 and CYP2C9 genetic polymorphisms are the most important determinants of warfarin dosing, and it is highly unlikely that other common variants of clinical importance influencing warfarin dosage will be found. Both VKORC1 and CYP2C9*3 are important determinants of the initial INR response to warfarin. Other novel variants, which did not reach genome-wide significance, were identified for the different outcome measures, but need replication. PMID- 26739749 TI - The use of isolated natural products as scaffolds for the generation of chemically diverse screening libraries for drug discovery. AB - A diverse range of strategies leading to natural product derived or inspired screening libraries aims to increase the number of new chemical entities emerging per year. However, the use of isolated natural products as scaffolds for the semi synthesis of larger biological screening libraries remains rare. This particular method avoids the time-consuming and resource intensive de novo synthetic strategy for scaffold production, and has become more feasible through improvements to synthetic and isolation methodologies. This Highlight examines the increasing popularity of small- to large-sized screening libraries generated directly from isolated natural products. Several of the examples detailed herein show how this strategy can lead to improvements in not only potency but also other important (and often forgotten) drug discovery parameters such as toxicity, selectivity, lipophilicity and bioavailability. However, there are still improvements to be made to this method, particularly in the choice of the natural product scaffold and the derivatising reagents used. Avoidance of known nuisance compounds or structural alert motifs (e.g. PAINS) that interfere with bioactivity screens, and impact downstream drug development will play a significant role in the future success of this methodology. Incorporation of rational design strategies that take into account the physicochemical parameters (e.g. log P, MW, HBA, HBD) of the final semi-synthetic library analogues will also facilitate the discovery and development of leads and drugs. A multi-pronged approach to drug discovery that incorporates the use of isolated natural product scaffolds for library generation will surely be beneficial. PMID- 26739750 TI - FIB Plan View Preparation and Electron Tomography of Ga-Containing Droplets Induced by Melt-Back Etching in Si. AB - Melt-back etching is an effect that can occur for gallium (Ga) containing III/V semiconductors grown on Si. Since this effect influences interfaces between the two compounds and therefore the physical characteristics of the material composition, it is desirable to understand its driving forces. Therefore, we investigated Ga grown on Si (001) via metal organic chemical vapor deposition using trimethyl Ga as a precursor. As a result of the melt-back etching, Ga containing droplets formed on the Si surface which reach into the Si wafer. The shape of these structures was analyzed by plan view investigation and cross sectional tomography in a (scanning) transmission electron microscope. For plan view preparation a focused ion beam was used to avoid damage to the Ga-containing structures, which are sensitive to the chemicals normally used during conventional plan view preparation. Combining the results of both investigation methods confirms that the Ga-containing structure within the Si exhibits a pyramid shape with facets along the Si {111} lattice planes. PMID- 26739751 TI - Iron-catalyzed direct alpha-arylation of alpha-amino carbonyl compounds with indoles. AB - A mild and general alpha-arylation of alpha-amino carbonyls with indoles catalyzed by Fe(ClO4)3 has been developed. C-H activation is smoothly fulfilled by using TBHP as the oxidant with good yields. Two hydrogen dissociations make this transformation more environmentally benign because of high atom efficiency. PMID- 26739748 TI - A comprehensive characterization of simple sequence repeats in pepper genomes provides valuable resources for marker development in Capsicum. AB - The sequences of the full set of pepper genomes including nuclear, mitochondrial and chloroplast are now available for use. However, the overall of simple sequence repeats (SSR) distribution in these genomes and their practical implications for molecular marker development in Capsicum have not yet been described. Here, an average of 868,047.50, 45.50 and 30.00 SSR loci were identified in the nuclear, mitochondrial and chloroplast genomes of pepper, respectively. Subsequently, systematic comparisons of various species, genome types, motif lengths, repeat numbers and classified types were executed and discussed. In addition, a local database composed of 113,500 in silico unique SSR primer pairs was built using a homemade bioinformatics workflow. As a pilot study, 65 polymorphic markers were validated among a wide collection of 21 Capsicum genotypes with allele number and polymorphic information content value per marker raging from 2 to 6 and 0.05 to 0.64, respectively. Finally, a comparison of the clustering results with those of a previous study indicated the usability of the newly developed SSR markers. In summary, this first report on the comprehensive characterization of SSR motifs in pepper genomes and the very large set of SSR primer pairs will benefit various genetic studies in Capsicum. PMID- 26739753 TI - Inhibition of the histone demethylase Kdm5b promotes neurogenesis and derepresses Reln (reelin) in neural stem cells from the adult subventricular zone of mice. AB - The role of epigenetic regulators in the control of adult neurogenesis is largely undefined. We show that the histone demethylase enzyme Kdm5b (Jarid1b) negatively regulates neurogenesis from adult subventricular zone (SVZ) neural stem cells (NSCs) in culture. shRNA-mediated depletion of Kdm5b in proliferating adult NSCs decreased proliferation rates and reduced neurosphere formation in culture. When transferred to differentiation culture conditions, Kdm5b-depleted adult NSCs migrated from neurospheres with increased velocity. Whole-genome expression screening revealed widespread transcriptional changes with Kdm5b depletion, notably the up-regulation of reelin (Reln), the inhibition of steroid biosynthetic pathway component genes and the activation of genes with intracellular transport functions in cultured adult NSCs. Kdm5b depletion increased extracellular reelin concentration in the culture medium and increased phosphorylation of the downstream reelin signaling target Disabled-1 (Dab1). Sequestration of extracellular reelin with CR-50 reelin-blocking antibodies suppressed the increase in migratory velocity of Kdm5b-depleted adult NSCs. Chromatin immunoprecipitation revealed that Kdm5b is present at the proximal promoter of Reln, and H3K4me3 methylation was increased at this locus with Kdm5b depletion in differentiating adult NSCs. Combined the data suggest Kdm5b negatively regulates neurogenesis and represses Reln in neural stem cells from the adult SVZ. PMID- 26739755 TI - MicroRNA-induced cascaded and catalytic self-assembly of DNA nanostructures for enzyme-free and sensitive fluorescence detection of microRNA from tumor cells. AB - The presence of target microRNA triggers cascaded and catalytic self-assembly of two DNA motifs into DNA nanostructures, which serves as a remarkable signal amplification means for the highly sensitive monitoring of the target microRNA and the detection of low numbers of tumor cells. PMID- 26739752 TI - Differential regulation of translation and endocytosis of alternatively spliced forms of the type II bone morphogenetic protein (BMP) receptor. AB - The expression and function of transforming growth factor-beta superfamily receptors are regulated by multiple molecular mechanisms. The type II BMP receptor (BMPRII) is expressed as two alternatively spliced forms, a long and a short form (BMPRII-LF and -SF, respectively), which differ by an ~500 amino acid C-terminal extension, unique among TGF-beta superfamily receptors. Whereas this extension was proposed to modulate BMPRII signaling output, its contribution to the regulation of receptor expression was not addressed. To map regulatory determinants of BMPRII expression, we compared synthesis, degradation, distribution, and endocytic trafficking of BMPRII isoforms and mutants. We identified translational regulation of BMPRII expression and the contribution of a 3' terminal coding sequence to this process. BMPRII-LF and -SF differed also in their steady-state levels, kinetics of degradation, intracellular distribution, and internalization rates. A single dileucine signal in the C-terminal extension of BMPRII-LF accounted for its faster clathrin-mediated endocytosis relative to BMPRII-SF, accompanied by mildly faster degradation. Higher expression of BMPRII SF at the plasma membrane resulted in enhanced activation of Smad signaling, stressing the potential importance of the multilayered regulation of BMPRII expression at the plasma membrane. PMID- 26739754 TI - Evidence for new C-terminally truncated variants of alpha- and beta-tubulins. AB - Cellular alpha-tubulin can bear various carboxy-terminal sequences: full-length tubulin arising from gene neosynthesis is tyrosinated, and two truncated variants, corresponding to detyrosinated and Delta2 alpha-tubulin, result from the sequential cleavage of one or two C-terminal residues, respectively. Here, by using a novel antibody named 3EG that is highly specific to the -EEEG C-terminal sequence, we demonstrate the occurrence in neuronal tissues of a new alphaDelta3 tubulin variant corresponding to alpha1A/B-tubulin deleted of its last three residues (EEY). alphaDelta3-tubulin has a specific distribution pattern: its quantity in the brain is similar to that of alphaDelta2-tubulin around birth but is much lower in adult tissue. This truncated alpha1A/B-tubulin variant can be generated from alphaDelta2-tubulin by the deglutamylases CCP1, CCP4, CCP5, and CCP6 but not by CCP2 and CCP3. Moreover, using 3EG antibody, we identify a C terminally truncated beta-tubulin form with the same -EEEG C-terminal sequence. Using mass spectrometry, we demonstrate that beta2A/B-tubulin is modified by truncation of the four C-terminal residues (EDEA). We show that this newly identified betaDelta4-tubulin is ubiquitously present in cells and tissues and that its level is constant throughout the cell cycle. These new C-terminally truncated alpha- and beta-tubulin variants, both ending with -EEEG sequence, are expected to regulate microtubule physiology. Of interest, the alphaDelta3-tubulin seems to be related to dynamic microtubules, resembling tyrosinated-tubulin rather than the other truncated variants, and may have critical function(s) in neuronal development. PMID- 26739756 TI - A Conventional Multiplex PCR Assay for the Detection of Toxic Gemfish Species (Ruvettus pretiosus and Lepidocybium flavobrunneum): A Simple Method To Combat Health Frauds. AB - The meat of Ruvettus pretiosus and Lepidocybium flavobrunneum (gemfishes) contains high amounts of indigestible wax esters that provoke gastrointestinal disorders. Although some countries have banned the sale of these species, mislabeling cases have been reported in sushi catering. This work developed a simple conventional multiplex PCR, which discriminates the two toxic gemfishes from other potentially replaced species, such as tunas, cod, and sablefish. A common degenerate forward primer and three species-specific reverse primers were designed to amplify cytochrome oxidase subunit I (COI) gene regions of different lengths (479, 403, and 291 bp) of gemfishes, tunas, and sablefish, respectively. A primer pair was designed to amplify a fragment (193 bp) of the cytb gene of cod species. Furthermore, a primer pair targeting the 16S rRNA gene was intended as common positive control (115 bp). The method developed in this study, by producing the expected amplicon for all of the DNA samples tested (reference and commercial), provides a rapid and reliable response in identifying the two toxic species to combat health frauds. PMID- 26739758 TI - The descriptive epidemiology of accelerometer-measured physical activity in older adults. AB - BACKGROUND: Objectively measured physical activity between older individuals and between populations has been poorly described. We aimed to describe and compare the variation in accelerometry data in older UK (EPIC-Norfolk) and American (NHANES) adults. METHODS: Physical activity was measured by uniaxial accelerometry in 4,052 UK (49-91 years) and 3459 US older adults (49-85 years). We summarized physical activity as volume (average counts/minute), its underlying intensity distribution, and as time spent <100counts/minute, >=809counts/minute and >=2020counts/minute both for total activity and that undertaken in >=10-min bouts. RESULTS: In EPIC-Norfolk 65% of wear-time was spent at <100 counts/minute and 20% spent in the range 100-500 counts/minute. Only 4.1% of this cohort accumulated more than 30 min/day of activity above 2020 counts/minute in 10-min bouts. If a cut-point of >809 counts/minute is used 18.7% of people reached the 30 min/day threshold. By comparison, 2.5% and 9.5% of American older adults accumulated activity at these levels, respectively. CONCLUSION: As assessed by objectively measured physical activity, the majority of older adults in this UK study did not meet current activity guidelines. Older adults in the UK were more active overall, but also spent more time being sedentary than US adults. PMID- 26739759 TI - Toxicokinetics and tissue distribution of nivalenol in broiler chickens. AB - Nivalenol (NIV), a type B trichothecene mycotoxin, is mainly produced by the fungi of Fusarium genus, which naturally occurs in agricultural commodities. Consumers are particularly concerned over the toxicity and safety of NIV in food animal products. To evaluate the toxicokinetics and persistence of residues of NIV, NIV was administered intravenously (iv) or orally (po) to broiler chickens at a dosage of 0.8 mg/kg body weight. The concentration of NIV in the plasma and various tissues was detected using liquid chromatography tandem-mass spectrometry. The plasma concentration of NIV in broilers could be measured up to 24 h and 12 h after iv and po administration, respectively. The value of elimination half-life of NIV was 5.27 +/- 0.82 h and 2.51 +/- 0.88 h after iv and po administration, respectively. The absolute oral bioavailability was 3.98 +/- 0.08%. NIV was detected in the intestine, kidney, muscle, heart and liver after po administration. Regarding tissue residues, largest quantities of NIV were found in the small intestine. These results suggest that NIV is absorbed from the gastrointestinal tract with low bioavailability and it has the ability to diffuse into various tissues of broilers. PMID- 26739761 TI - Severe summer heatwave and drought strongly reduced carbon uptake in Southern China. AB - Increasing heatwave and drought events can potentially alter the carbon cycle. Few studies have investigated the impacts of hundred-year return heatwaves and droughts, as those events are rare. In the summer of 2013, southern China experienced its strongest drought and heatwave on record for the past 113 years. We show that the record-breaking heatwave and drought lasted two months (from July to August), significantly reduced the satellite-based vegetation index and gross primary production, substantially altered the regional carbon cycle, and produced the largest negative crop yield anomaly since 1960. The event resulted in a net reduction of 101.54 Tg C in carbon sequestration in the region during these two months, which was 39-53% of the annual net carbon sink of China's terrestrial ecosystems (190-260 Tg C yr(-1)). Moreover, model experiments showed that heatwaves and droughts consistently decreased ecosystem vegetation primary production but had opposite impacts on ecosystem respiration (TER), with increased TER by 6.78 +/- 2.15% and decreased TER by 15.34 +/- 3.57% assuming only changed temperature and precipitation, respectively. In light of increasing frequency and severity of future heatwaves and droughts, our study highlights the importance of accounting for the impacts of heatwaves and droughts in assessing the carbon sequestration in terrestrial ecosystems. PMID- 26739763 TI - Triple SILAC quantitative proteomic analysis reveals differential abundance of cell signaling proteins between normal and lung cancer-derived exosomes. AB - Exosomes are 30-100 nm sized membrane vesicles released by cells into the extracellular space that mediate intercellular communication via transfer of proteins and other biological molecules. To better understand the role of these microvesicles in lung carcinogenesis, we employed a Triple SILAC quantitative proteomic strategy to examine the differential protein abundance between exosomes derived from an immortalized normal bronchial epithelial cell line and two non small cell lung cancer (NSCLC) cell lines harboring distinct activating mutations in the cell signaling molecules: Kirsten rat sarcoma viral oncogene homolog (KRAS) or epidermal growth factor receptor (EGFR). In total, we were able to quantify 721 exosomal proteins derived from the three cell lines. Proteins associated with signal transduction, including EGFR, GRB2 and SRC, were enriched in NSCLC exosomes, and could actively regulate cell proliferation in recipient cells. This study's investigation of the NSCLC exosomal proteome has identified enriched protein cargo that can contribute to lung cancer progression, which may have potential clinical implications in biomarker development for patients with NSCLC. BIOLOGICAL SIGNIFICANCE: The high mortality associated with lung cancer is a result of late-stage diagnosis of the disease. Current screening techniques used for early detection of lung cancer lack the specificity for accurate diagnosis. Exosomes are nano-sized extracellular vesicles, and the increased abundance of select protein cargo in exosomes derived from cancer cells may be used for diagnostic purposes. In this paper, we applied quantitative proteomic analysis to elucidate abundance differences in exosomal protein cargo between two NSCLC cell lines with distinctive oncogene mutations and an immortalized normal bronchial epithelial cell line. This study revealed proteins associated with cell adhesion, the extracellular matrix, and a variety of signaling molecules were enriched in NSCLC exosomes. The present data reveals a protein profile associated with NSCLC exosomes that suggests a role these vesicles have in the progression of lung carcinogenesis, as well as identifies several promising candidates that could be utilized as a multi-marker protein panel in a diagnostic platform for NSCLC. PMID- 26739764 TI - The iron-responsive microsomal proteome of Aspergillus fumigatus. AB - Aspergillus fumigatus is an opportunistic fungal pathogen. Siderophore biosynthesis and iron acquisition are essential for virulence. Yet, limited data exist with respect to the adaptive nature of the fungal microsomal proteome under iron-limiting growth conditions, as encountered during host infection. Here, we demonstrate that under siderophore biosynthetic conditions--significantly elevated fusarinine C (FSC) and triacetylfusarinine C (TAFC) production (p<0.0001), extensive microsomal proteome remodelling occurs. Specifically, a four-fold enrichment of transmembrane-containing proteins was observed with respect to whole cell lysates following ultracentrifugation-based microsomal extraction. Comparative label-free proteomic analysis of microsomal extracts, isolated following iron-replete and -deplete growth, identified 710 unique proteins. Scatterplot analysis (MaxQuant) demonstrated high correlation amongst biological replicates from each growth condition (Pearson correlation >0.96 within groups; biological replicates (n=4)). Quantitative and qualitative comparison revealed 231 proteins with a significant change in abundance between the iron-replete and iron-deplete conditions (p<0.05, fold change >= 2), with 96 proteins showing increased abundance and 135 with decreased abundance following iron limitation, including predicted siderophore transporters. Fluorescently labelled FSC was only sequestered following A. fumigatus growth under iron limiting conditions. Interestingly, human sera exhibited significantly increased reactivity (p<0.0001) against microsomal protein extracts obtained following iron deplete growth. BIOLOGICAL SIGNIFICANCE: The opportunistic fungal pathogen Aspergillus fumigatus must acquire iron to facilitate growth and pathogenicity. Iron-chelating non-ribosomal peptides, termed siderophores, mediate iron uptake via membrane-localised transporter proteins. Here we demonstrate for the first time that growth of A. fumigatus under iron-deplete conditions, concomitant with siderophore biosynthesis, leads to an extensive remodelling of the microsomal proteome which includes significantly altered levels of 231 constituent proteins (96 increased and 135 decreased in abundance), many of which have not previously been localised to the microsome. We also demonstrate the first synthesis of a fluorescent version of fusarinine C, an extracellular A. fumigatus siderophore, and its uptake and localization under iron-restricted conditions. This infers the use of an A. fumigatus siderophore as a 'Trojan horse' to potentiate the efficacy of anti-fungal drugs. Finally, in addition to revealing the Aspergillus-specific IgG reactivity in normal human sera against microsomal proteins, there appears to be a significantly increased reactivity against microsomal proteins obtained following iron-restricted growth. We hypothesise that iron-limiting environment in humans, which has evolved to nutritionally limit pathogen growth in vivo, may also alter the fungal microsomal proteome. PMID- 26739767 TI - Operational implementation and lessons learned from Haiti's first helicopter air ambulance. AB - Critical-care helicopter transport has demonstrated improvements in morbidity and mortality to those patients who utilise the service, but this has largely excluded developing country populations due to set up costs. Haiti Air Ambulance is the first completely publicly-available helicopter ambulance service in a developing country. US standards were adopted for both aviation and aeromedical care in Haiti due to proximity and relationships. In order to implement properly, standards for aviation, critical care, and insurance reimbursement had to be put in place with local authorities. Haiti Air Ambulance worked with the Ministry of Health to author standards for medical procedures, medication usage, and staff training for aeromedical programs in the country. Utilisation criteria for the helicopter were drafted, edited, and constantly updated to ensure the program adapted to the clinical situation while maintaining US standard of care. During the first year, 76 patients were transferred; 13 of whom were children and 3 pregnant women. Three patients were intubated and two required bi-level mask ventilation. Traumatic injury and non-emergency interfacility transfers were the two most common indications for service. More than half of the transfers (54%) originated at one of six hospitals, mostly as a result of highly-involved staff. The program was limited by weather and the lack of weather reporting, radar, visual flight recognition, thus also causing an inability to fly at night. In partnership with the government and other non-governmental organisations, we seek to implement a more robust pre-hospital system in Haiti over the next 12-24 months, including more scene call capabilities. PMID- 26739768 TI - [Usefulness of procalcitonin in the elderly patient with a suspected infection]. PMID- 26739766 TI - Functional inhibition of urea transporter UT-B enhances endothelial-dependent vasodilatation and lowers blood pressure via L-arginine-endothelial nitric oxide synthase-nitric oxide pathway. AB - Mammalian urea transporters (UTs), UT-A and UT-B, are best known for their role in urine concentration. UT-B is especially distributed in multiple extrarenal tissues with abundant expression in vascular endothelium, but little is known about its role in vascular function. The present study investigated the physiological significance of UT-B in regulating vasorelaxations and blood pressure. UT-B deletion in mice or treatment with UT-B inhibitor PU-14 in Wistar Kyoto rats (WKYs) and spontaneous hypertensive rats (SHRs) reduced blood pressure. Acetylcholine-induced vasorelaxation was significantly augmented in aortas from UT-B null mice. PU-14 concentration-dependently produced endothelium dependent relaxations in thoracic aortas and mesenteric arteries from both mice and rats and the relaxations were abolished by N(omega)-nitro-L-arginine methyl ester. Both expression and phosphorylation of endothelial nitric oxide synthase (eNOS) were up-regulated and expression of arginase I was down-regulated when UT B was inhibited both in vivo and in vitro. PU-14 induced endothelium-dependent relaxations to a similar degree in aortas from 12 weeks old SHRs or WKYs. In summary, here we report for the first time that inhibition of UT-B plays an important role in regulating vasorelaxations and blood pressure via up-regulation of L-arginine-eNOS-NO pathway, and it may become another potential therapeutic target for the treatment of hypertension. PMID- 26739769 TI - In the superobese, weight loss and resolution of obesity comorbidities after biliopancreatic bypass and/or duodenal switch vary according to health insurance carrier: Medicaid vs Medicare vs Private insurance vs Self-Pay in 1681 Bariatric Outcomes Longitudinal Database patients. AB - BACKGROUND: Differences in Medicaid vs Medicare vs Private vs Self-Pay duodenal switch (DS) results are unknown. This study identified DS outcomes variations by health insurance. METHODS: Data from 1,681 DS patients were analyzed retrospectively: Medicaid (n = 138), Medicare (n = 313), Private insurance (n = 1,171), and Self-Pay (n = 59). General linear models included baseline and postoperative data and were modified for dichotomous variables. RESULTS: Hypertension, obstructive sleep apnea, abdominal hernia, diabetes, and 9 other hepatobiliary, and somatic conditions were lowest in Private (P < .05). Self-Pay cholelithiasis, gastroesophageal reflux disease, back and/or musculoskeletal pain, and 3 others were lowest; asthma, angina, congestive heart failure, alcohol use, liver disease, and 3 others were highest (P < .05). Medicare had highest abdominal hernia and musculoskeletal pain, pseudotumor cerebri; lowest asthma, and polycystic ovarian syndrome (P < .05). Medicaid hypertension, sleep apnea, cholelithiasis, gastroesophageal reflux disease, diabetes, back pain, and 5 others were highest (P < .05); dyslipidemia and alcohol use were lowest. CONCLUSIONS: Outcomes after DS vary by health insurance. These findings may facilitate management of DS patients. PMID- 26739771 TI - Gestational Age at Term, Delivery Circumstance, and Their Association with Childhood Attention Deficit Hyperactivity Disorder Symptoms. AB - BACKGROUND: Perinatal characteristics may identify subgroups of term-born children at risk for academic and behavioural difficulties. Using follow-up data from the Pregnancy Outcomes and Community Health Study, we subdivided term births according to two potential markers of perinatal risk (gestational age, delivery circumstance) and evaluated their association with attention deficit hyperactivity disorder (ADHD) symptoms. METHODS: We included children born at term whose mothers completed the Conners' Parent Rating Scales-Revised-Short Form (CPRS-R-S) (n = 610; ages: 3-9 years). The CPRS-R-S yields age and sex-referenced T-scores for the two primary dimensions of ADHD (inattention, hyperactivity) and an ADHD Index that reflects both dimensions. Using general linear models, we evaluated whether: (1) term delivery defined by gestational week (reference: 39 40 weeks), or (2) term delivery circumstance defined by labour onset type and mode of delivery (reference: spontaneous labour, vaginal delivery) was associated with these problems. RESULTS: Following adjustment for parity, sociodemographics, and maternal mental health both during pregnancy and at the child follow-up survey, the induced labour plus caesarean group exhibited higher inattention and ADHD Index scores relative to the spontaneous labour, vaginal delivery group (inattention: mean difference = 5.1, 95% CI 0.6, 9.7; ADHD Index: mean difference = 4.1, 95% CI 0.5, 7.8). Findings were primarily driven by male children. CONCLUSIONS: Among term-born children, only those whose mothers experienced induction of labour that culminated in caesarean delivery exhibited higher levels of ADHD symptoms. Prenatal, antepartum, and/or postnatal factors associated with this delivery profile may reflect increased risk for such problems. PMID- 26739773 TI - Evolutionary biology and the question of teleology. AB - Teleology-what Aristotle called "final cause"-is trying to understand things in terms of the future, as when we ask about the plates on the back of the dinosaur, stegosaurus, and suggest that they might sometime be used to control the internal temperature of the brute. Recently the philosopher Thomas Nagel has argued for a wholesale embrace of teleological thinking in the sciences, particularly the life sciences. I argue that Nagel's thinking is shoddy and ill-informed, but that in some sense biologists do (with reason) seem drawn to teleological understanding, and so the correct response is not outright rejection of the very idea but a more informed and sympathetic approach to those aspects of nature that seem to call for final cause thinking. PMID- 26739770 TI - Adapted physical exercise enhances activation and differentiation potential of satellite cells in the skeletal muscle of old mice. AB - During ageing, a progressive loss of skeletal muscle mass and a decrease in muscle strength and endurance take place, in the condition termed sarcopenia. The mechanisms of sarcopenia are complex and still unclear; however, it is known that muscle atrophy is associated with a decline in the number and/or efficiency of satellite cells, the main contributors to muscle regeneration. Physical exercise proved beneficial in sarcopenia; however, knowledge of the effect of adapted physical exercise on the myogenic properties of satellite cells in aged muscles is limited. In this study the amount and activation state of satellite cells as well as their proliferation and differentiation potential were assessed in situ by morphology, morphometry and immunocytochemistry at light and transmission electron microscopy on 28-month-old mice submitted to adapted aerobic physical exercise on a treadmill. Sedentary age-matched mice served as controls, and sedentary adult mice were used as a reference for an unperturbed control at an age when the capability of muscle regeneration is still high. The effect of physical exercise in aged muscles was further analysed by comparing the myogenic potential of satellite cells isolated from old running and old sedentary mice using an in vitro system that allows observation of the differentiation process under controlled experimental conditions. The results of this ex vivo and in vitro study demonstrated that adapted physical exercise increases the number and activation of satellite cells as well as their capability to differentiate into structurally and functionally correct myotubes (even though the age-related impairment in myotube formation is not fully reversed): this evidence further supports adapted physical exercise as a powerful, non-pharmacological approach to counteract sarcopenia and the age-related deterioration of satellite cell capabilities even at very advanced age. PMID- 26739774 TI - Glycine: A potential coupling agent to bond to helium plasma treated PEEK? AB - OBJECTIVES: To test the tensile bond strength (TBS) between two self-adhesive resin composite cements and PEEK after helium plasma treatment and used glycine as a potential coupling agent incorporated in different adhesives. METHODS: In summary, 896 air-abraded PEEK specimens were fabricated. Half of the specimens were treated with cold active inert helium plasma and the other half were left non-treated. Both groups were then split in two groups: In group 1 (n=256), 64 specimens were pre-treated with: (a) soft-liner liquid, (b) visio.link, (c) Ambarino P60 and (d) no pre-treatment (control), respectively. In group 2 (n=192), specimens were conditioned accordingly, but the adhesive materials were modified by including a commercially available glycine (Air-Flow PERIO). PEEK specimens were then luted using either RelyX Unicem or Clearfil SA Cement and TBS was measured initially and after 14 days water storage combined with 10'000 thermal cycles (16 specimens/subgroup). Fracture type analysis was performed. For statistical analyses Kolmogorov-Smirnov, Shapiro-Wilk tests, 1-, 4-way ANOVA (post hoc: Scheffe), and t-test were used (p<0.001). RESULTS: Helium plasma pre treatment without glycine showed no impact on initial TBS (p>0.348). In contrast, a combination between glycine application and Softline/Ambarino P60 allowed for significantly higher initial TBS was measured after helium plasma treatment (p=0.001). However, this effect was no evident after thermo-cycling. All groups conditioned with visio.link showed the highest TBS values. SIGNIFICANCE: The introduction of amine groups by simple provision of amino acids in the form of glycine can improve the bond strength after helium plasma treatment using different adhesive materials. However, using this simple approach, the method cannot withstand thermal challenge yet. PMID- 26739776 TI - In vitro synergistic anticancer activity of the combination of T-type calcium channel blocker and chemotherapeutic agent in A549 cells. AB - As a result of our continuous research, new 3,4-dihydroquinazoline derivative containing ureido group, KCP10043F was synthesized and evaluated for T-type Ca(2+) channel (Cav3.1) blockade, cytotoxicity, and cell cycle arrest against human non-small cell lung (A549) cells. KCP10043F showed both weaker T-type Ca(2+) channel blocking activity and less cytotoxicity against A549 cells than parent compound KYS05090S [4-(benzylcarbamoylmethyl)-3-(4-biphenylyl)-2-(N,N',N' trimethyl-1,5-pentanediamino)-3,4-dihydroquinazoline 2 hydrochloride], but it exhibited more potent G1-phase arrest than KYS05090S in A549 cells. This was found to be accompanied by the downregulations of cyclin-dependent kinase (CDK) 2, CDK4, CDK6, cyclin D2, cyclin D3, and cyclin E at the protein levels. However, p27(KIP1) as a CDK inhibitor was gradually upregulated at the protein levels and increased recruitment to CDK2, CDK4 and CDK6 after KCP10043F treatment. Based on the strong G1-phase cell cycle arrest of KCP10043F in A549 cells, the combination of KCP10043F with etoposide (or cisplatin) resulted in a synergistic cell death (combination index=0.2-0.8) via the induction of apoptosis compared with either agent alone. Taken together with these overall results and the favorable in vitro ADME (absorption, distribution, metabolism, and excretion) profiles of KCP10043F, therefore, it could be used as a potential agent for the combination therapy on human lung cancer. PMID- 26739775 TI - Effect of carbodiimide on the fatigue crack growth resistance of resin-dentin bonds. AB - Recent studies have shown that ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) inactivates endogenous dentin proteases, thereby preventing collagen degradation and improving the durability of adhesive bonds to dentin. Bond durability is routinely assessed by monotonic microtensile testing, which does not consider the cyclic nature of mastication. OBJECTIVE: To characterize the effect of an EDC pretreatment on the fatigue crack growth behavior of resin-dentin bonds. METHODS: Bonded interface Compact Tension (CT) specimens were prepared using a three-step etch-and-rinse adhesive and hybrid resin-composite. Adhesive bonding of the treated groups included a 1 min application of an experimental EDC conditioner to the acid-etched dentin. The control groups did not receive EDC treatment. The fatigue crack growth resistance was examined after storage in artificial saliva for 0, 3 and 6 months. RESULTS: There was no significant difference in the immediate fatigue crack growth resistance of the EDC-treated and control groups at 0 months. However, after the 3 and 6 months storage periods the EDC-treated groups exhibited significantly greater (p<=0.05) fatigue crack growth resistance than the control specimens. SIGNIFICANCE: Although the EDC treatment maintained the fatigue crack growth resistance of the dentin bonds through 6 months of storage, additional studies are needed to assess its effectiveness over longer periods and in relation to other cross-linking agents. PMID- 26739777 TI - Development of curcumin-cyclodextrin/cellulose nanocrystals complexes: New anticancer drug delivery systems. AB - The synthesis of curcumin-cyclodextrin/cellulose nanocrystals (CNCx) nano complexes was performed. CNCx were functionalized by ionic association with cationic beta-cyclodextrin (CD) and CD/CNCx complexes were used to encapsulate curcumin. Preliminary in vitro results showed that the resulting curcumin-CD/CNCx complexes exerted antiproliferative effect on colorectal and prostatic cancer cell lines, with IC50s lower than that of curcumin alone. PMID- 26739778 TI - A one pot, two-step synthesis of 5-arylpyrrolo[2,3-d]pyrimidines and screening of their preliminary antibacterial properties. AB - A one pot two step methodology for the synthesis of ten derivatives of 5 arylpyrrolo[2,3-d]pyrimidine has been reported. The methodology exploits the strong reducing nature of alkaline Na2S2O4 solution coupled with favorability of Michael type addition reaction in alkaline medium. The methodology demands attraction as it is non-catalytic, quite general for wide range of nitrostyrenes and possesses comprehensive advantages over most of the earlier methods in terms of reaction time as well as yield. The methodology enjoys additional advantage of utilizing cheaper and easily available chemicals as reagent for the purpose. Some of the synthesized compounds are found to possess remarkable activity against some of the tested bacterial strains. PMID- 26739780 TI - Synthesis, structure and in vitro cytostatic activity of ferrocene-Cinchona hybrids. AB - Exploring copper(I)- and ruthenium(II)-catalyzed azide-alkyne cycloadditions and a Sonogashira protocol, novel cytostatic ferrocene-cinchona hybrids were synthetized displaying significant in vitro activity on HepG-2 and HT-29 cells. Preliminary SAR studies disclosed that compounds incorporating linkers with 1,2,3 triazole and chalchone residues can be considered as promising lead structures. According to the best of our knowledge this is the first letter on the incorporation of ferrocene nucleus in the reputed cinchona family via triazole and chalcone linkers with established pharmaceutical profile. PMID- 26739779 TI - Discovery of EBI-907: A highly potent and orally active B-Raf(V600E) inhibitor for the treatment of melanoma and associated cancers. AB - A novel series of pyrazolo[3,4-c]isoquinoline derivatives was discovered as B Raf(V600E) inhibitors through scaffold hopping based on a literature lead PLX4720. Further SAR exploration and optimization led to the discovery of potent B-Raf(V600E) inhibitors with good oral bioavailability in rats and dogs. One of the compounds EBI-907 (13g) demonstrated excellent in vivo efficacy in B Raf(V600E) dependent Colo-205 tumor xenograft models in mouse and is under preclinical studies for the treatment of melanoma and B-Raf(V600E) associated cancers. PMID- 26739781 TI - Receptor binding profiles and quantitative structure-affinity relationships of some 5-substituted-N,N-diallyltryptamines. AB - N,N-Diallyltryptamine (DALT) and 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT) are two tryptamines synthesized and tested by Alexander Shulgin. In self-experiments, 5-MeO-DALT was reported to be psychoactive in the 12-20mg range, while the unsubstituted compound DALT had few discernible effects in the 42-80 mg range. Recently, 5-MeO-DALT has been used in nonmedical settings for its psychoactive effects, but these effects have been poorly characterized and little is known of its pharmacological properties. We extended the work of Shulgin by synthesizing additional 5-substituted-DALTs. We then compared them to DALT and 5-MeO-DALT for their binding affinities at 45 cloned receptors and transporter proteins. Based on in vitro binding affinity, we identified 27 potential receptor targets for the 5-substituted-DALT compounds. Five of the DALT compounds had affinity in the 10 80 nM range for serotonin 5-HT1A and 5-HT2B receptors, while the affinity of DALT itself at 5-HT1A receptors was slightly lower at 100 nM. Among the 5-HT2 subtypes, the weakest affinity was at 5-HT2A receptors, spanning 250-730 nM. Five of the DALT compounds had affinity in the 50-400 nM range for serotonin 5-HT1D, 5 HT6, and 5-HT7 receptors; again, it was the unsubstituted DALT that had the weakest affinity at all three subtypes. The test drugs had even weaker affinity for 5-HT1B, 5-HT1E, and 5-HT5A subtypes and little or no affinity for the 5-HT3 subtype. These compounds also had generally nanomolar affinities for adrenergic alpha2A, alpha2B, and alpha2C receptors, sigma receptors sigma1 and sigma2, histamine H1 receptors, and norepinephrine and serotonin uptake transporters. They also bound to other targets in the nanomolar-to-low micromolar range. Based on these binding results, it is likely that multiple serotonin receptors, as well as several nonserotonergic sites are important for the psychoactive effects of DALT drugs. To learn whether any quantitative structure-affinity relationships existed, we evaluated correlations among physicochemical properties of the congeneric 5-substituted-DALT compounds. The descriptors included electronic (sigmap), hydrophobic (pi), and steric (CMR) parameters. The binding affinity at 5-HT1A, 5-HT1D, 5-HT7, and kappa opioid receptors was positively correlated with the steric volume parameter CMR. At alpha2A, alpha2B, and alpha2C receptors, and at the histamine H1 receptor, binding affinity was correlated with the Hammett substituent parameter sigmap; higher affinity was associated with larger sigmap values. At the sigma2 receptor, higher affinity was correlated with increasing pi. These correlations should aid in the development of more potent and selective drugs within this family of compounds. PMID- 26739782 TI - Synthesis and biological activity of benzamide DNA minor groove binders. AB - A range of di- and triaryl benzamides were synthesised to investigate the effect of the presence and nature of a polar sidechain, bonding and substitution patterns and functionalisation of benzylic substituents. These compounds were tested for their antiproliferative activity as well as their DNA binding activity. The most active compounds in all assays were unsymmetrical triaryl benzamides with a bulky or alkylating benzylic substituent and a polar amino sidechain. PMID- 26739783 TI - Conforming to partnership values: a qualitative case study of public-private mix for TB control in Ghana. AB - BACKGROUND: Public-private mix (PPM) can supplement public sector initiatives, including public health. As National Tuberculosis Control Programmes around the world embrace PPM, conforming to the four key principles of partnership values of beneficence, non-maleficence, autonomy, and equity as espoused by the World Health Organization can provide a useful framework to guide successful implementation. DESIGN: This is a qualitative case study of PPM in tuberculosis (TB) control, which utilised a purposive sample of 30 key stakeholders involved in TB control in Ghana. Respondents comprised an equal number of respondents from both the public and private sectors. Semi-structured in-depth interviews (IDI) were conducted with respondents. Data emanating from the IDIs were analysed deductively. RESULTS: Although the respondents' perceptions about beneficence were unanimous, their views about non-maleficence, autonomy, and equity appeared incongruous with the underlying meanings of the PPM values. Underlying the unfavourable perceptions were disruptions in funding, project implementers' failure to follow-up on promised incentives, and private providers lost interest. This was perceived to have negatively affected the smooth implementation of PPM in the country. CONCLUSIONS: Going forward, it is imperative that future partnerships are built around utilitarian principles and also adhere to the dictates of agreements, whether they are 'soft' or standard contracts. PMID- 26739785 TI - A dual affinity-tag strategy for the expression and purification of human linker histone H1.4 in Escherichia coli. AB - Linker histones are an abundant and critical component of the eukaryotic chromatin landscape. They play key roles in regulating the higher order structure of chromatin and many genetic processes. Higher eukaryotes possess a number of different linker histone subtypes and new data are consistently emerging that indicate these subtypes are functionally distinct. We were interested in studying one of the most abundant human linker histone subtypes, H1.4. We have produced recombinant full-length H1.4 in Escherichia coli. An N-terminal Glutathione-S Transferase tag was used to promote soluble expression and was combined with a C terminal hexahistidine tag to facilitate a simple non-denaturing two-step affinity chromatography procedure that results in highly pure full-length H1.4. The purified H1.4 was shown to be functional via in vitro chromatin assembly experiments and remains active after extended storage at -80 degrees C. PMID- 26739784 TI - Health worker preferences for performance-based payment schemes in a rural health district in Burkina Faso. AB - BACKGROUND: One promising way to improve the motivation of healthcare providers and the quality of healthcare services is performance-based incentives (PBIs) also referred as performance-based financing. Our study aims to explore healthcare providers' preferences for an incentive scheme based on local resources, which aimed at improving the quality of maternal and child health care in the Nouna Health District. DESIGN: A qualitative and quantitative survey was carried out in 2010 involving 94 healthcare providers within 34 health facilities. In addition, in-depth interviews involving a total of 33 key informants were conducted at health facility levels. RESULTS: Overall, 85% of health workers were in favour of an incentive scheme based on the health district's own financial resources (95% CI: [71.91; 88.08]). Most health workers (95 and 96%) expressed a preference for financial incentives (95% CI: [66.64; 85.36]) and team-based incentives (95% CI: [67.78; 86.22]), respectively. The suggested performance indicators were those linked to antenatal care services, prevention of mother-to-child human immunodeficiency virus transmission, neonatal care, and immunization. CONCLUSIONS: The early involvement of health workers and other stakeholders in designing an incentive scheme proved to be valuable. It ensured their effective participation in the process and overall acceptance of the scheme at the end. This study is an important contribution towards the designing of effective PBI schemes. PMID- 26739786 TI - Elimination of truncated recombinant protein expressed in Escherichia coli by removing cryptic translation initiation site. AB - Undesirable truncated recombinant protein products pose a special expression and purification challenge because such products often share similar chromatographic properties as the desired full length protein. We describe here our observation of both full length and a truncated form of a yeast protein (Gcn5) expressed in Escherichia coli, and the reduction or elimination of the truncated form by mutating a cryptic Shine-Dalgarno or START codon within the Gcn5 coding region. Unsuccessful attempts to engineer in a cryptic translation initiation site into other recombinant proteins suggest that cryptic Shine-Dalgarno or START codon sequences are necessary but not sufficient for cryptic translation in E. coli. PMID- 26739790 TI - Delayed low frequency hearing loss caused by cochlear implantation interventions via the round window but not cochleostomy. AB - Cochlear implant recipients show improved speech perception and music appreciation when residual acoustic hearing is combined with the cochlear implant. However, up to one third of patients lose their pre-operative residual hearing weeks to months after implantation, for reasons that are not well understood. This study tested whether this "delayed" hearing loss was influenced by the route of electrode array insertion and/or position of the electrode array within scala tympani in a guinea pig model of cochlear implantation. Five treatment groups were monitored over 12 weeks: (1) round window implant; (2) round window incised with no implant; (3) cochleostomy with medially-oriented implant; (4) cochleostomy with laterally-oriented implant; and (5) cochleostomy with no implant. Hearing was measured at selected time points by the auditory brainstem response. Cochlear condition was assessed histologically, with cochleae three-dimensionally reconstructed to plot electrode paths and estimate tissue response. Electrode array trajectories matched their intended paths. Arrays inserted via the round window were situated nearer to the basilar membrane and organ of Corti over the majority of their intrascalar path compared with arrays inserted via cochleostomy. Round window interventions exhibited delayed, low frequency hearing loss that was not seen after cochleostomy. This hearing loss appeared unrelated to the extent of tissue reaction or injury within scala tympani, although round window insertion was histologically the most traumatic mode of implantation. We speculate that delayed hearing loss was related not to the electrode position as postulated, but rather to the muscle graft used to seal the round window post-intervention, by altering cochlear mechanics via round window fibrosis. PMID- 26739791 TI - Tinnitus: Research supported by the Tinnitus Research Consortium. PMID- 26739792 TI - CRN Message From the Chairperson: Happy 2016! PMID- 26739793 TI - Heart-Healthy Nutrition Approach for Chronic Kidney Disease Patients. PMID- 26739795 TI - Hypertension in pregnancy and long-term cardiovascular mortality: a retrospective cohort study. AB - BACKGROUND: There is growing evidence that hypertensive disorders of pregnancy are associated with increased long-term cardiovascular mortality in the mother. Hypertension in pregnancy, until recently, however, has been ignored largely as a risk factor for future cardiovascular disease and mortality because the link between the 2 is not fully understood. OBJECTIVE: To determine the association between women with hypertension in pregnancy and long-term cardiovascular disease mortality. STUDY DESIGN: All women who delivered at a metropolitan hospital between the periods of January 1, 1980, and December 31, 1989, were identified by use of the International Statistical Classification of Diseases and Related Health Problems, 9th Revision, Australian Modification. RESULTS: The total number of deliveries in the given time period was 31,656, with 4387 (14%) of the women identified as having had hypertension in their pregnancy. Using information from the New South Wales Births, Deaths and Marriages Registry and the Australian Bureau of Statistics Death Registry, we identified a total of 651 deaths from this cohort (n = 31,656). There were 521 deaths among the women who remained normotensive in their pregnancy and 129 deaths for women who had hypertension during their pregnancy. Overall, the women with hypertensive disorders of pregnancy were at greater risk of death than the women who remained normotensive in their pregnancy (odds ratio 1.56; 95% confidence interval 1.28-1.89; P < .001). CONCLUSION: Women with a history of hypertension in their pregnancy are at an increased risk of future cardiovascular mortality, and this work identifies a group of women who may benefit from early screening and intervention strategies to help decrease their risk of future cardiovascular disease. PMID- 26739796 TI - A systematic review and metaanalysis of energy intake and weight gain in pregnancy. AB - BACKGROUND: Gestational weight gain within the recommended range produces optimal pregnancy outcomes, yet many women exceed the guidelines. Official recommendations to increase energy intake by ~ 1000 kJ/day in pregnancy may be excessive. OBJECTIVE: To determine by metaanalysis of relevant studies whether greater increments in energy intake from early to late pregnancy corresponded to greater or excessive gestational weight gain. DATA SOURCES: We systematically searched electronic databases for observational and intervention studies published from 1990 to the present. The databases included Ovid Medline, Cochrane Library, Excerpta Medica DataBASE (EMBASE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Science Direct. In addition we hand searched reference lists of all identified articles. STUDY ELIGIBILITY CRITERIA: Studies were included if they reported gestational weight gain and energy intake in early and late gestation in women of any age with a singleton pregnancy. Search also encompassed journals emerging from both developed and developing countries. STUDY APPRAISAL AND SYNTHESIS METHODS: Studies were individually assessed for quality based on the Quality Criteria Checklist obtained from the Evidence Analysis Manual: Steps in the academy evidence analysis process. Publication bias was plotted by the use of a funnel plot with standard mean difference against standard error. Identified studies were meta-analyzed and stratified by body mass index, study design, dietary methodology, and country status (developed/developing) by the use of a random-effects model. RESULTS: Of 2487 articles screened, 18 studies met inclusion criteria. On average, women gained 12.0 (2.8) kg (standardized mean difference = 1.306, P < .0005) yet reported only a small increment in energy intake that did not reach statistical significance (~475 kJ/day, standard mean difference = 0.266, P = .016). Irrespective of baseline body mass index, study design, dietary methodology, or country status, changes in energy intake were not significantly correlated to the amount of gestational weight gain (r = 0.321, P = .11). CONCLUSION: Despite rapid physiologic weight gain, women report little or no change in energy intake during pregnancy. Current recommendations to increase energy intake by ~ 1000 kJ/day may, therefore, encourage excessive weight gain and adverse pregnancy outcomes. PMID- 26739797 TI - Computational multiqubit tunnelling in programmable quantum annealers. AB - Quantum tunnelling is a phenomenon in which a quantum state traverses energy barriers higher than the energy of the state itself. Quantum tunnelling has been hypothesized as an advantageous physical resource for optimization in quantum annealing. However, computational multiqubit tunnelling has not yet been observed, and a theory of co-tunnelling under high- and low-frequency noises is lacking. Here we show that 8-qubit tunnelling plays a computational role in a currently available programmable quantum annealer. We devise a probe for tunnelling, a computational primitive where classical paths are trapped in a false minimum. In support of the design of quantum annealers we develop a nonperturbative theory of open quantum dynamics under realistic noise characteristics. This theory accurately predicts the rate of many-body dissipative quantum tunnelling subject to the polaron effect. Furthermore, we experimentally demonstrate that quantum tunnelling outperforms thermal hopping along classical paths for problems with up to 200 qubits containing the computational primitive. PMID- 26739799 TI - Full disclosure about cancer screening. PMID- 26739801 TI - Reply To: Sleep Disturbances in Childhood Cancer Survivors. PMID- 26739803 TI - Prevalence of Non-thrombotic Iliac Vein Lesions in Patients with Unilateral Primary Varicose Veins. AB - OBJECTIVES: A role of non-thrombotic iliac vein lesions (NIVLs) in the development of primary varicose veins (PVVs) has not been studied. It seems that intravascular ultrasound (IVUS) is the most accurate method to diagnose these lesions. The aim of the study was to investigate the association between the presence of NIVLs and PVVs and the frequency of NIVLs in asymptomatic and PVV limbs. DESIGN: This was an observational study. MATERIALS: Thirty-three patients with unilateral PVV and great saphenous vein incompetence who were qualified for surgical treatment were analyzed. Nineteen patients (57%) presented with varicose veins on the right side. METHODS: During varicose vein surgery, IVUS of the iliac veins and the inferior vena cava was performed. In all patients the iliocaval outflow was interrogated by IVUS in both the limb with and without PVVs. The PVV side was accessed through the surgically exposed sapheno-femoral junction and the non-PVV side was accessed by an ultrasound guided percutaneous puncture of the common femoral vein. In both the common iliac (CIVs) and the external iliac veins (EIVs) the minimal and reference lumen area were measured and the percentage stenosis calculated. RESULTS: There were no intra- or post-procedural complications. The minimal lumen area (MLA) was smaller and the stenosis of the CIV was greater on the left side than the right: median 57 and 108 mm(2) (p = 0.001) and 69 and 34% (p < 0.001), respectively. However when the PVV and non-PVV sides were compared, no statistically significant differences of MLA or stenosis of the CIV were found: 88 and 67 mm(2) (p = 0.38) and 44% and 51% (p = 0.40), respectively. With regard to EIVs, no statistically significant differences in either MLA or stenosis between the left and right and PVV and non-PVV sides were found. The frequency of >=50% stenosis of CIV and EIV in the PVV limbs and the non-PVV limbs was 42% and 48% and 51% and 39%, respectively. CONCLUSIONS: NIVLs are common in patients with PVV but do not seem to be associated with the presence of ipsilateral PVV. PMID- 26739804 TI - Laser Generated In situ Fenestrations in Dacron Stent Grafts. AB - OBJECTIVE/BACKGROUND: To evaluate if the creation of laser generated in situ fenestrations in polyester/Dacron stent grafts causes embolization. METHODS: In seven pigs, Dacron stent grafts were implanted from the infrarenal aorta to the right iliac artery. Prior to placing the stent graft, a carotid artery protection filter, with a pore size of 70-200 MUm, was placed in the proximal left common iliac artery. An excimer laser catheter was then advanced antegradely through the stent graft and positioned at the level of origin of the left iliac artery. A fenestration was then created with the laser probe. The carotid filter was retrieved and inspected macroscopically with magnifying glasses, for emboli and clot. RESULTS: Seven pigs with a median weight of 90 kg (range 78-98 kg) were tested. The median operating time was 170 minutes. All laser fenestrations were successfully completed. No emboli or clot could be detected in the protection filters. CONCLUSION: Creation of laser generated, in situ fenestrations do not produce macroscopically visible emboli/clot. This might indicate safe usage of laser created fenestrations for endovascular arch repair and left subclavian artery revascularization. PMID- 26739805 TI - Surgical Treatment of a Thrombosed Proximal Great Saphenous Vein Aneurysm. PMID- 26739806 TI - High-frequency chaotic dynamics enabled by optical phase-conjugation. AB - Wideband chaos is of interest for applications such as random number generation or encrypted communications, which typically use optical feedback in a semiconductor laser. Here, we show that replacing conventional optical feedback with phase-conjugate feedback improves the chaos bandwidth. In the range of achievable phase-conjugate mirror reflectivities, the bandwidth increase reaches 27% when compared with feedback from a conventional mirror. Experimental measurements of the time-resolved frequency dynamics on nanosecond time-scales show that the bandwidth enhancement is related to the onset of self-pulsing solutions at harmonics of the external-cavity frequency. In the observed regime, the system follows a chaotic itinerancy among these destabilized high-frequency external-cavity modes. The recorded features are unique to phase-conjugate feedback and distinguish it from the long-standing problem of time-delayed feedback dynamics. PMID- 26739809 TI - Extracellular ATP mediates inflammatory responses in colitis via P2 * 7 receptor signaling. AB - Extracellular purinergic products, particularly ATP, have recently been implicated to regulate immune cell functions and contribute to aberrant inflammatory responses of immune diseases. However, regulation of immune responses of colitis by extracellular ATP and its main receptor, P2 * 7, remains to be elucidated. In the study, we induced murine colitis by feeding mice with 4% dextran sulfate sodium (DSS), and noted dramatically heightened extracellular ATP levels in colon tissues during the progression of experimental colitis. Blockade of ATP release by carbenoxolone (CBX) treatment, or promoting ATP degradation by ATP diphosphohydrolase (apyrase), decreased extracellular ATP levels in colon tissues, attenuated DSS-induced colitis, whereas inhibition of extracellular ATP degradation by sodium metatungstate (POM-1) exacerbated tissue damage in the mice with colitis. Moreover, treatment with inhibitor of P2 * 7 receptor, A438079, decreased NFkappaB activation and active caspase-1 expression in lamina propria immune cells, downregulated proinflammatory cytokine production in colon tissues, and attenuated murine colitis. Collectively, these data suggest extracellular ATP participates in regulation of inflammatory responses of experimental colitis, through P2 * 7 receptor and inflammasome and NFkappaB signaling, which provides potential alternatives to the current clinical approaches to suppress extracellular ATP-mediated immune responsiveness. PMID- 26739812 TI - Tobacco alkaloids reduction by casings added/enzymatic hydrolysis treatments assessed through PLSR analysis. AB - Based on encouraged development of potential reduced-exposure products (PREPs) by the US Institute of Medicine, casings (glucose and peptides) added treatments (CAT) and enzymatic (protease and xylanase) hydrolysis treatments (EHT) were developed to study their effect on alkaloids reduction in tobacco and cigarette mainstream smoke (MS) and further investigate the correlation between sensory attributes and alkaloids. Results showed that the developed treatments reduced nicotine by 14.5% and 24.4% in tobacco and cigarette MS, respectively, indicating that both CAT and EHT are potentially effective for developing lower-risk cigarettes. Sensory and electronic nose analysis confirmed the significant influence of treatments on sensory and cigarette MS components. PLSR analysis demonstrated that tobacco alkaloids were positively correlated to the off-taste, irritation and impact attributes, and negatively correlated to the aroma and softness attributes. Additionally, nicotine and anabasine from tobacco leaves positively contributed to the impact attribute, while they negatively contributed to the aroma attribute (P<0.05). Meanwhile, most alkaloids in cigarette MS positively contributed to the impact and irritation attributes (P<0.05). Hence, this study paved a way to better understand the correlation between tobacco alkaloids and sensory attributes. PMID- 26739813 TI - Thiazolidine: A Potent Candidate for Central Nervous Systems Diseases. AB - Thiazolidines are multifaceted molecules and exhibit varied types of biological activities, and also showed anticonvulsants and antidepressants activity. It is the diversified class of heterocyclic compounds. Thiazolidinediones (TZD) has been shown beneficial action in various CNS diseases. The significant mechanism of TZD-induced neuroprotection useful in prevention of microglial activation and cytokine that is responsible for inflammatory condition and chemokine expression. At the molecular level TZDs were also responsible to prevent the activation of pro-inflammatory transcription factors as well as promoting the anti-oxidant mechanisms in the injured CNS. Important SAR, molecular mechanism and potent biological activities with special references to central nervous system are discussed in this article. Various investigations suggest that this moiety pave the way for design and discovery of new drug candidates. PMID- 26739814 TI - Glucose-dependent downregulation of glucagon gene expression mediated by selective interactions between ALX3 and PAX6 in mouse alpha cells. AB - AIMS/HYPOTHESIS: The stimulation of glucagon secretion in response to decreased glucose levels has been studied extensively. In contrast, little is known about the regulation of glucagon gene expression in response to fluctuations in glucose concentration. Paired box 6 (PAX6) is a key transcription factor that regulates the glucagon promoter by binding to the G1 and G3 elements. Here, we investigated the role of the transcription factor aristaless-like homeobox 3 (ALX3) as a glucose-dependent modulator of PAX6 activity in alpha cells. METHODS: Experiments were performed in wild-type or Alx3-deficient islets and alphaTC1 cells. We used chromatin immunoprecipitations and electrophoretic mobility shift assays for DNA binding, immunoprecipitations and pull-down assays for protein interactions, transfected cells for promoter activity, and small interfering RNA and quantitative RT-PCR for gene expression. RESULTS: Elevated glucose concentration resulted in stimulated expression of Alx3 and decreased glucagon gene expression in wild-type islets. In ALX3-deficient islets, basal glucagon levels were non responsive to changes in glucose concentration. In basal conditions ALX3 bound to the glucagon promoter at G3, but not at G1. ALX3 could form heterodimers with PAX6 that were permissive for binding to G3 but not to G1. Thus, increasing the levels of ALX3 in response to glucose resulted in the sequestration of PAX6 by ALX3 for binding to G1, thus reducing glucagon promoter activation and glucagon gene expression. CONCLUSIONS/INTERPRETATION: Glucose-stimulated expression of ALX3 in alpha cells provides a regulatory mechanism for the downregulation of glucagon gene expression by interfering with PAX6-mediated transactivation on the glucagon G1 promoter element. PMID- 26739815 TI - Muscle sphingolipids during rest and exercise: a C18:0 signature for insulin resistance in humans. AB - AIMS/HYPOTHESES: Ceramides and other sphingolipids comprise a family of lipid molecules that accumulate in skeletal muscle and promote insulin resistance. Chronic endurance exercise training decreases muscle ceramides and other sphingolipids, but less is known about the effects of a single bout of exercise. METHODS: We measured basal relationships and the effect of acute exercise (1.5 h at 50% [Formula: see text]) and recovery on muscle sphingolipid content in obese volunteers, endurance trained athletes and individuals with type 2 diabetes. RESULTS: Muscle C18:0 ceramide (p = 0.029), dihydroceramide (p = 0.06) and glucosylceramide (p = 0.03) species were inversely related to insulin sensitivity without differences in total ceramide, dihydroceramide, and glucosylceramide concentration. Muscle C18:0 dihydroceramide correlated with markers of muscle inflammation (p = 0.04). Transcription of genes encoding sphingolipid synthesis enzymes was higher in athletes, suggesting an increased capacity for sphingolipid synthesis. The total concentration of muscle ceramides and sphingolipids increased during exercise and then decreased after recovery, during which time ceramide levels reduced to significantly below basal levels. CONCLUSIONS/INTERPRETATION: These data suggest ceramide and other sphingolipids containing stearate (18:0) are uniquely related to insulin resistance in skeletal muscle. Recovery from an exercise bout decreased muscle ceramide concentration; this may represent a mechanism promoting the insulin-sensitising effects of acute exercise. PMID- 26739816 TI - Metabolic and hormonal response to intermittent high-intensity and continuous moderate intensity exercise in individuals with type 1 diabetes: a randomised crossover study. AB - AIMS/HYPOTHESIS: To investigate exercise-related fuel metabolism in intermittent high-intensity (IHE) and continuous moderate intensity (CONT) exercise in individuals with type 1 diabetes mellitus. METHODS: In a prospective randomised open-label cross-over trial twelve male individuals with well-controlled type 1 diabetes underwent a 90 min iso-energetic cycling session at 50% maximal oxygen consumption ([Formula: see text]), with (IHE) or without (CONT) interspersed 10 s sprints every 10 min without insulin adaptation. Euglycaemia was maintained using oral (13)C-labelled glucose. (13)C Magnetic resonance spectroscopy (MRS) served to quantify hepatocellular and intramyocellular glycogen. Measurements of glucose kinetics (stable isotopes), hormones and metabolites complemented the investigation. RESULTS: Glucose and insulin levels were comparable between interventions. Exogenous glucose requirements during the last 30 min of exercise were significantly lower in IHE (p = 0.02). Hepatic glucose output did not differ significantly between interventions, but glucose disposal was significantly lower in IHE (p < 0.05). There was no significant difference in glycogen consumption. Growth hormone, catecholamine and lactate levels were significantly higher in IHE (p < 0.05). CONCLUSIONS/INTERPRETATION: IHE in individuals with type 1 diabetes without insulin adaptation reduced exogenous glucose requirements compared with CONT. The difference was not related to increased hepatic glucose output, nor to enhanced muscle glycogen utilisation, but to decreased glucose uptake. The lower glucose disposal in IHE implies a shift towards consumption of alternative substrates. These findings indicate a high flexibility of exercise-related fuel metabolism in type 1 diabetes, and point towards a novel and potentially beneficial role of IHE in these individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT02068638 FUNDING: Swiss National Science Foundation (grant number 320030_149321/) and R&A Scherbarth Foundation (Switzerland). PMID- 26739817 TI - Understanding the Experience of Age-Related Vestibular Loss in Older Individuals: A Qualitative Study. AB - BACKGROUND: Inner ear balance (or vestibular) function declines with age and is associated with decreased mobility and an increased risk of falls in older individuals. We sought to understand the lived experience of older adults with vestibular loss in order to improve care in this population. METHODS: Qualitative data were derived from semi-structured interviews of individuals aged 65 years or older presenting to the Balance and Falls Prevention Clinic from February 1, 2014 to March 30, 2015 for evaluation of age-related vestibular loss. Transcripts were analyzed using interpretive phenomenological analysis. We created a taxonomy of overarching superordinate themes based on the World Health Organization's International Classification of Functioning, Disability, and Health (ICF) Framework, and classified key dimensions within each of these themes. RESULTS: Sixteen interviews were conducted with individuals (mean age 76.0 years, 75 % female) with age-related vestibular loss. The three superordinate themes and associated key dimensions were (1) body impairment (including depression, fatigue, fear/anxiety, and problems with concentrating and memory); (2) activity limitation and participation restriction (isolation, needing to stop in the middle of activities, reduced participation relative to expectations, reduced ability to drive or travel, and problems with bending/looking up, standing, and walking); and (3) environmental influences (needing help with daily activities). All participants reported difficulty walking. CONCLUSIONS: Older adults report that vestibular loss impacts their body functioning and restricts their participation in activities. The specific key dimensions uncovered by this qualitative study can be used to evaluate care from the patient's perspective. PMID- 26739818 TI - Successful en bloc venous resection with reconstruction and subsequent radiotherapy for 2 consecutive recurrences of intravenous leiomyoma--a case report. AB - BACKGROUND: Intravenous leiomyomas are a rare variant of uterine leiomyoma. Although histologically benign, these tumors are associated with a poor prognosis due to propensity for metastasis, high recurrence rate, difficulty of obtaining complete resection, and frequent extension into and along major veins. CASE PRESENTATION: We describe a 43-year-old patient initially presenting with lower abdominal pain. Clinical examination revealed a large right pelvic mass that was shown by computed tomography (CT) to surround the right external iliac vein, right common iliac vein and distal inferior vena cava. The patient had a history of total abdominal hysterectomy with bilateral ovarian cystectomies for uterine leiomyoma approximately 3 years prior to her presentation. Her past surgical history also included removal of an ovarian endometriosis cyst and right hydrosalpinx. The patient underwent an exploratory laparotomy. Operative findings included complete occlusion of the right iliac vessels and distal vena cava by a large tumor that filled the pelvis and extended to the level of the right kidney. The mass was resected en bloc with the involved veins and synthetic vascular grafts were placed. This highly technical procedure was complicated by hemorrhage requiring a total of 32 units of red blood cells and 2.0 L of plasma. Pathologic examination confirmed intravenous leiomyoma. On Immunohistochemical staining, the tumor cells were positive for CD32, CD34, Vimentin and smooth muscle actin. Eight months after this procedure, the patient again presented with an abdominal mass. She was diagnosed with a pelvic recurrence and noted to have intravascular extension into the left iliac vein and inferior vena cava. For this tumor she underwent radiation treatment with three-dimensional conformal radiation therapy (total dose 4500 cGy). The tumor gradually decreased in size during follow-up and became undetectable by CT. CONCLUSIONS: Surgical excision is the mainstay of treatment of intravenous leiomyoma. Radiation therapy may be an effective alternative in patients with unresectable disease or poor surgical candidates. PMID- 26739819 TI - Noncontact Rotational Head Injury Produces Transient Cognitive Deficits but Lasting Neuropathological Changes. AB - Traumatic brain injury (TBI) caused by improvised explosive devices (IEDs) is a growing problem in military settings, but modeling this disease in rodents to pre clinically evaluate potential therapeutics has been challenging because of inconsistency between models. Although the effects of primary blast wave injury have been extensively studied, little is known regarding the effects of noncontact rotational TBIs independent of the blast wave. To model this type of injury, we generated an air cannon system that does not produce a blast wave, but generates enough air pressure to cause rotational TBI. Mice exposed to this type of injury showed deficits in cognitive and motor task acquisition within 1-2 weeks post-injury, but mice tested 7-8 weeks post-injury did not retain any deficits. This suggests that the effects of a single, noncontact rotational TBI are not long lasting. Despite the transient nature of the behavioral deficits, increased levels of phosphorylated tau were observed at 2 and 8 weeks post injury; however, this tau did not adopt typical pathological structures that have been observed in other TBI models that incorporate blast waves. This was possibly attributed to the fact that this injury was insufficient to induce changes in microglial activation, which was not affected at 2 or 8 weeks post-injury. Taken together, these data suggest that exposure to noncontact, rotational head injury only produces transient cognitive anomalies, but elicits some minor lasting neuropathological changes. PMID- 26739821 TI - Biological processes in solar lentigo: insights brought by experimental models. AB - Common in ageing patient, the solar lentigo is a macular hyperpigmented skin lesion that results from chronic exposure to ultraviolet irradiations. Despite sharing numerous features with other pigmented spots, the diagnostic of this benign lesion is well characterized at the tissue level. Recent studies shed lights on several factors and their pathogenic mechanisms involved in the development of the solar lentigo. This review summarizes how diverse experimental approaches allowed the identification of several biomarkers, which contribute to a better understanding on the initiation and the maintenance of this pigmentary disorder. PMID- 26739820 TI - Enzyme promiscuity in earthworm serine protease: substrate versatility and therapeutic potential. AB - Enzymes are the most versatile molecules in the biological world. These amazing molecules play an integral role in the regulation of various metabolic pathways and physiology subsequently. Promiscuity of an enzyme is the capacity to catalyze additional biochemical reactions besides their native one. Catalytic promiscuity has shown great impact in enzyme engineering for commercial enzyme and therapeutics with natural or engineered catalytic promiscuity. The earthworm serine protease (ESP) is a classic example of enzyme promiscuity and studied for its therapeutic potential over the last few decades. The ESP was reported for several therapeutic properties and fibrinolytic activity has been much explored. ESP, a complex enzyme exists as several isoforms of molecular weight ranging from 14 to 33 kDa. The fibrinolytic capacity of the enzyme has been studied in different species of earthworm and molecular mechanism is quite different from conventional thrombolytics. Cytotoxic and anti-tumor activities of ESP were evaluated using several cancer cell lines. Enzyme had shown tremendous scope in fighting against plant viruses and microbes. ESP is also reported for anti inflammatory activity and anti-oxidant property. Apart from these, recently, ESP is reported for DNase activity. The daunting challenge for researchers is to understand the molecular mechanism for such diverse properties and possibility of enzyme promiscuity. This review emphasizes molecular mechanism of ESP governing various biochemical reactions. Further, the concept of enzyme promiscuity in ESP towards development of novel enzyme based drugs has been reviewed in this study. PMID- 26739823 TI - Talking About Sex When Sex Is Painful: Dyadic Sexual Communication Is Associated With Women's Pain, and Couples' Sexual and Psychological Outcomes in Provoked Vestibulodynia. AB - Provoked vestibulodynia (PVD) is a recurrent vulvovaginal pain condition associated with psychological and sexual consequences for affected women and their partners, including lower quality of dyadic sexual communication compared to pain-free couples. Although greater sexual communication is associated with positive sexual and relational outcomes for both pain-free couples and couples experiencing painful sex, little is known about its role in women's pain and psychological outcomes, especially in a relational context. The present study examined associations between dyadic sexual communication and pain, sexual satisfaction, sexual functioning, and depressive symptoms in a sample of 107 couples in which the woman was diagnosed with PVD via a standardized gynecological assessment. Women completed a measure of pain intensity, and both members of the couple completed measures of their dyadic sexual communication, sexual satisfaction, sexual functioning, and depressive symptoms. Analyses were guided by the actor-partner interdependence model. Women and partners' own perceptions of greater dyadic sexual communication were associated with their own greater sexual satisfaction and sexual functioning, and lower depressive symptoms. Partners' perceptions of greater dyadic sexual communication were also associated with women's lower pain and greater sexual satisfaction. Results point to the importance of dyadic coping conceptualizations for both individual and interpersonal outcomes in PVD. Dyadic sexual communication may be a key treatment target for interventions aimed at improving the pain and psychological and sexual impairments of women with PVD and their partners. PMID- 26739822 TI - Robotic Surgery for Colon and Rectal Cancer. AB - Robotic surgery, used generally for colorectal cancer, has the advantages of a three-dimensional surgical view, steadiness, and seven degrees of robotic arms. However, there are disadvantages, such as a decreased sense of touch, extra time needed to dock the robotic cart, and high cost. Robotic surgery is performed using various techniques, with or without laparoscopic surgery. Because the results of this approach are reported to be similar to or less favorable than those of laparoscopic surgery, the learning curve for robotic colorectal surgery remains controversial. However, according to short- and long-term oncologic outcomes, robotic colorectal surgery is feasible and safe compared with conventional surgery. Advanced technologies in robotic surgery have resulted in favorable intraoperative and perioperative clinical outcomes as well as functional outcomes. As the technical advances in robotic surgery improve surgical performance as well as outcomes, it increasingly is being regarded as a treatment option for colorectal surgery. However, a multicenter, randomized clinical trial is needed to validate this approach. PMID- 26739826 TI - Transapical Off-pump Neochord Implantation for Mitral Regurgitation Recurrence. PMID- 26739825 TI - Pituitary Adenylate Cyclase Activating Polypeptide, A Potential Therapeutic Agent for Diabetic Retinopathy in Rats: Focus on the Vertical Information Processing Pathway. AB - Pituitary adenylate cyclase activating polypeptide (PACAP) is a neurotrophic and neuroprotective peptide that has been shown to exert protective effects in different neuronal injuries, such as retinal degenerations. Diabetic retinopathy (DR), the most common complication of diabetes, affects the microvasculature and neuronal architecture of the retina. We have proven earlier that PACAP is also protective in a rat model of DR. In this study, streptozotocin-induced DR was treated with intravitreal PACAP administration in order to further analyze the synaptic structure and proteins of PACAP-treated diabetic retinas, primarily in the vertical information processing pathway. Streptozotocin-treated Wistar rats received intravitreal PACAP injection three times into the right eye 2 weeks after the induction of diabetes. Morphological and molecular biological (qRT-PCR; Western blot) methods were used to analyze retinal synapses (ribbons, conventional) and related structures. Electron microscopic analysis revealed that retinal pigment epithelium, the ribbon synapses and other synaptic profiles suffered alterations in diabetes. However, in PACAP-treated diabetic retinas more bipolar ribbon synapses were found intact in the inner plexiform layer than in DR animals. The ribbon synapse was marked with C-terminal binding protein 2/Bassoon and formed horseshoe-shape ribbons, which were more retained in PACAP-treated diabetic retinas than in DR rats. These results are supported by molecular biological data. The selective degeneration of related structures such as bipolar and ganglion cells could be ameliorated by PACAP treatment. In summary, intravitreal administration of PACAP may have therapeutic potential in streptozotocin-induced DR through maintaining synapse integrity in the vertical pathway. PMID- 26739827 TI - Self-expanding Portico Valve Versus Balloon-expandable SAPIEN XT Valve in Patients With Small Aortic Annuli: Comparison of Hemodynamic Performance. AB - INTRODUCTION AND OBJECTIVES: The self-expanding Portico valve is a new transcatheter aortic valve system yielding promising preliminary results, yet there are no comparative data against earlier generation transcatheter aortic valve systems. The aim of this study was to compare the hemodynamic performance of the Portico and balloon-expandable SAPIEN XT valves in a case-matched study with echocardiographic core laboratory analysis. METHODS: Twenty-two patients underwent transcatheter aortic valve implantation with the Portico 23-mm valve and were matched for aortic annulus area and mean diameter measured by multidetector computed tomography, left ventricular ejection fraction, body surface area, and body mass index with 40 patients treated with the 23-mm SAPIEN XT. Mean aortic annulus diameters were 19.6+/-1.3mm by transthoracic echocardiography and 21.4+/-1.2mm by computed tomography, with no significant between-group differences. Doppler echocardiographic images were collected at baseline and at 1-month of follow-up and were analyzed in a central echocardiography core laboratory. RESULTS: There were no significant between group differences in residual mean transaortic gradients (SAPIEN XT: 10.4+/ 3.7mmHg; Portico: 9.8+/-1.1mmHg; P=.49) and effective orifice areas (SAPIEN XT: 1.36+/-0.27cm(2); Portico, 1.37+/-.29cm(2); P=.54). Rates of severe prosthesis patient mismatch (effective orifice area<0.65cm(2)/m(2)) were similar (SAPIEN XT: 13.5%; Portico: 10.0%; P=.56). No between-group differences were found in the occurrence of moderate-severe paravalvular leaks (5.0% vs 4.8% of SAPIEN XT and Portico respectively; P=.90). CONCLUSIONS: Transcatheter aortic valve implantation with the self-expanding Portico system yielded similar short-term hemodynamic performance compared with the balloon-expandable SAPIEN XT system for treating patients with severe aortic stenosis and small annuli. Further prospective studies with longer-term follow-up and in patients with larger aortic annuli are required. PMID- 26739828 TI - Impact of the Everolimus-eluting Bioresorbable Scaffold in Coronary Atherosclerosis. AB - INTRODUCTION AND OBJECTIVES: The Absorb bioresorbable vascular scaffold has been shown to decrease total plaque areas in the treated segment. However, it is unknown whether plaque size is modified in scaffolded segments only or whether the modification extends to other coronary segments. METHODS: Absorb Cohort A is a single-arm, prospective study, with safety and imaging endpoints, in which 30 patients underwent percutaneous coronary intervention with the first generation Absorb bioresorbable vascular scaffold. Noninvasive multislice computed tomography imaging was performed in 18 patients at 18 months and 5 years of follow-up. The present study was an intrapatient comparison of matched segments (normalized by the segment length) of the scaffolded region with nonintervened segments for lumen volume, vessel volume, plaque volume, plaque burden, and percent change in plaque atheroma volume. RESULTS: All 18 scaffolded segments could be analyzed. In the nonintervened segments, 1 of 72 segments had a motion artifact and was excluded. Serial comparison showed that the scaffolded segments showed no significant change in the mean plaque burden, total atheroma volume, total lumen volume, or vessel volume between 18 months and 5 years. Conversely, the untreated segments showed a significant increase in plaque burden (2.7 +/- 6.5%; P < .01) and normalized plaque volumes (8.0 +/- 22.8mm(3); P < .01). This resulted in a significant difference in plaque burden between scaffolded and nonintervened segments (P = .03). CONCLUSIONS: In this small series, the Absorb bioresorbable vascular scaffold showed the potential to provide an additional benefit to pharmacological therapy in locally reducing progression of percent plaque burden. These findings need to be confirmed in larger studies. PMID- 26739829 TI - Seroprevalence and "Knowledge, Attitudes and Practices" (KAPs) survey of endemic ovine brucellosis in Egypt. AB - BACKGROUND: Between February and July 2014, a cross-sectional study to estimate the seroprevalence of brucellosis in sheep in the Kafrelsheikh district of Egypt was carried out, together with a survey of knowledge, attitudes and practices (KAPs) among local shepherds. A total of 273 serum samples were collected from 28 sheep flocks in 10 villages within the study area. These samples were analysed by the Rose Bengal Plate test (RBPT) test, with all positive samples being confirmed by complement fixation test (CFT). RESULTS: True seroprevalence was 20 % (95 % CI 15.3-24.7 %) with the prevalence of villages with at least one seropositive sheep estimated at 95.5 % (95 % CI 92.2-100 %); village flock seroprevalence ranged from 0 to 46.8 %. Results of the KAPs survey demonstrated that despite good knowledge regarding brucellosis being potentially present within their flocks, shepherds lacked knowledge regarding routes of livestock to humans disease transmission and the symptoms of brucellosis in humans. This lack of knowledge regarding disease transmission resulted in high-risk practices being widespread practices such as assisting parturition without protective measures, throwing aborted material into water canals and a reluctance to remove animals that had aborted from the flock. CONCLUSIONS: This study proposes potential measures to reduce seroprevalence of brucellosis in sheep and reduce public health risks from brucellosis such as culling aborted livestock and educational campaigns among shepherds regarding disease risks and modes of transmission. PMID- 26739832 TI - Bilateral adrenalectomy in the 21st century: when to use it for hypercortisolism? AB - Therapeutic options available for the treatment of Cushing's syndrome (CS) have expanded over the last 5 years. For instance, the efficient management of severe hypercortisolism using a combination of fast-acting steroidogenesis inhibitors has been reported. Recent publications on the long-term efficacy of drugs or radiation techniques have also demonstrated low toxicity. These data should encourage endocrinologists to reconsider the place of bilateral adrenalectomy in patients with ACTH-dependent aetiologies of CS; similarly, the indication of bilateral adrenalectomy is reassessed in primary bilateral macronodular adrenal hyperplasia. The objective of this review is to compare the efficacy and side effects of the various therapeutic options of hypercortisolism with those of bilateral adrenalectomy, in order to better define its indications in the 21st century. PMID- 26739833 TI - Somatic arousal and sleepiness/fatigue among patients with sleep-disordered breathing. AB - OBJECTIVES: In a large clinical sample, we tested the hypothesis that levels of sleepiness and fatigue among upper airway resistance syndrome (UARS) patients are correlated with levels of somatic arousal (SA; reflecting the sympathetic nervous system component of the stress response). We also tested the correlations of post treatment change in these three parameters, and we extended the investigation to obstructive sleep apnea/hypopnea (OSA/H) patients. METHODS: From 5 years of patient data, we obtained scores on the body sensation questionnaire (BSQ), measuring the level of SA, the fatigue severity scale (FSS), and Epworth sleepiness scale (ESS) for 152 consecutive UARS patients and 150 consecutive OSA/H patients. For each group, we correlated the FSS and ESS scores with the BSQ scores. Among the 45 UARS patients and 49 OSA/H patients treated with nasal CPAP who provided post-treatment data, we correlated change in FSS and ESS scores with change in BSQ scores. RESULTS: Scores on the BSQ, FSS, and ESS for UARS patients and OSA/H patients were comparable. In both UARS and OSA/H patients, both the FSS and ESS scores were positively correlated with the BSQ score. Nasal CPAP use decreased all three questionnaire scores in both patient groups. In the pooled data, changes in FSS were significantly correlated with changes in BSQ. CONCLUSIONS: Our findings confirm our preliminary observations that sleepiness and fatigue among UARS patients are correlated with their level of SA and suggest that the same is true for OSA/H patients. The decrease of SA following treatment suggests that SDB is a cause of SA among patients with UARS and OSA/H. PMID- 26739834 TI - Changes in depressive symptoms during widowhood among older Mexican Americans: the role of financial strain, social support, and church attendance. AB - OBJECTIVES: This study examines how depressive symptoms change during the widowhood process among older adults of Mexican descent. This research also investigates whether financial strain, social support, and church attendance moderate changes in depressive symptoms in the context of widowhood. METHOD: This study uses seven waves of data from the Hispanic Established Population for the Epidemiologic Study of the Elderly collected at approximately two-year intervals. This research applies multiphase growth models to examine changes in depressive symptomatology before, during, and after the transition to widowhood (the measurement wave at which spousal bereavement was first reported) among 385 older adults of Mexican descent who experienced the death of a spouse during the survey. RESULTS: This study demonstrates that older adults of Mexican descent experienced a significant increase in depressive symptoms pre-widowhood and in particular, during the transition to widowhood. The levels and rates of changes in depressive symptoms post-widowhood did not differ from the pre-widowhood ones. Greater social support was related to more depressive symptoms during the transition to widowhood. More frequent church attendance was a protective factor against increases in depressive symptoms pre-widowhood. CONCLUSION: This study highlights the multiphase pattern in the effects of the widowhood process on depressive symptomatology among older adults of Mexican descent. The findings also suggest that social support and church attendance can have implications for the interplay between widowhood and depressive symptoms. PMID- 26739836 TI - Higher serum betatrophin level in type 2 diabetes subjects is associated with urinary albumin excretion and renal function. AB - BACKGROUND: Betatrophin is a newly identified liver-derived hormone that is associated with glucose homeostasis and lipid metabolism. Although dysregulated lipid metabolism results in diabetic nephropathy (DN) development in patients with type 2 diabetes mellitus (T2DM), it is not understood whether betatrophin is associated with urinary albumin excretion and renal function. METHODS: Based on albumin/creatinine ratio (ACR), 109 T2DM patients were divided into normoalbuminuria (ACR <30 mg/g), microalbuminuria (ACR between 30 and 300 mg/g), and macroalbuminuria (ACR > 300 mg/g). Serum betatrophin levels of 109 T2DM patients and 32 healthy subjects were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum level of betatrophin was significantly increased in T2DM patients with normoalbuminuria, microalbuminuria, and macroalbuminuria as compared with healthy subjects (P < 0.001). Serum betatrophin level was positively correlated with sex, duration of diabetes, systolic blood pressure (SBP), body mass index (BMI), ACR, and triglyceride, whereas it was inversely correlated with estimated glomerular filtration rate (eGFR), total cholesterol, and high-density lipoprotein cholesterol (HDL-C) (P < 0.001). Furthermore, multivariate regression analysis showed the betatrophin was significantly and positively independent with triglyceride and low-density lipoprotein cholesterol (LDL-C) (P < 0.05), whereas it was inversely independent with eGFR, total cholesterol, and low-density lipoprotein cholesterol (HDL-C) (P < 0.05). In addition, the betatrophin had higher odds of having DN [odds ratio (OR) = 5.65, 95 % confidence interval (CI) 2.17-14.57, P < 0.001]. CONCLUSION: Betatrophin is significantly increased in T2DM patients with different stages of albuminuria. Betatrophin may be a novel endocrine regulator involved in DN development. PMID- 26739837 TI - Reduced Plasma Levels of sCD14 and I-FABP in HIV-infected Patients with Mesalazine-treated Ulcerative Colitis. AB - BACKGROUND: Microbial translocation (MT) is a shared feature of HIV infection and inflammatory bowel disease (IBD). AIMS: This study was conducted to assess the impact of IBD (and particularly ulcerative colitis, UC) on plasma markers of MT and immune activation in HIV+ subjects. METHODS: A cross-sectional study was conducted in 3 groups of patients: HIV+/UC+(group HIV/UC); HIV+/UC- (group HIV); HIV-/UC+(group UC). Plasma levels of soluble CD14 (sCD14), intestinal fatty acid binding protein (I-FABP), and endotoxin core antibodies (endoCAB) were measured as plasma markers of MT. Inflammation and immune activation were evaluated by measuring plasma levels of IL-6, IL-21, TNF-alpha, and high-sensitivity C reactive protein (hs-CRP). T- and B-cells subpopulations were characterized by FACS analysis. RESULTS: Seven patients were enrolled in group HIV/UC, 9 in HIV, and 10 in UC. All HIV-positive patients had plasma values of HIV-1 RNA<37 copies/mL for at least 12 months and good immunological recovery. All patients with UC were treated with oral mesalazine. Markers of MT, immune activation, and inflammation were not increased in subjects with HIV/UC. In fact, they had lower levels of I-FABP (p=0.001) and sCD14 (p=0.007) when compared to other patients groups. Positive correlations were found between I-FABP and sCD14 (r=.355, p=0.076). Frequency of T- and B-cell subsets did not differ among groups. CONCLUSIONS: Our results suggest that UC does not worsen MT, inflammation, or immune activation in HIV-infected subjects. The anti-inflammatory activity of chronic mesalazine administration on intestinal mucosa may contribute to this finding. PMID- 26739838 TI - Differentiation therapy: a promising strategy for cancer treatment. AB - Poor differentiation is an important hallmark of cancer cells, and differentiation therapy holds great promise for cancer treatment. The restoration of IkB kinase alpha (IKKalpha) leads to the differentiation of nasopharyngeal carcinoma cells with reduced tumorigenicity. The findings by Yan et al. validate the polycomb protein enhancer of zeste homologue 2 (EZH2) as a target for intervention. PMID- 26739839 TI - Developing a Model of Advanced Training to Promote Career Advancement for Certified Genetic Counselors: An Investigation of Expanded Skills, Advanced Training Paths, and Professional Opportunities. AB - There are currently multiple paths through which genetic counselors can acquire advanced knowledge and skills. However, outside of continuing education opportunities, there are few formal training programs designed specifically for the advanced training of genetic counselors. In the genetic counseling profession, there is currently considerable debate about the paths that should be available to attain advanced skills, as well as the skills that might be needed for practice in the future. The Association of Genetic Counseling Program Directors (AGCPD) convened a national committee, the Committee on Advanced Training for Certified Genetic Counselors (CATCGC), to investigate varied paths to post-master's training and career development. The committee began its work by developing three related grids that view career advancement from the viewpoints of the skills needed to advance (skills), ways to obtain these skills (paths), and existing genetic counselor positions that offer career change or advancement (positions). Here we describe previous work related to genetic counselor career advancement, the charge of the CATCGC, our preliminary work in developing a model through which to view genetic counselor advanced training and career advancement opportunities, and our next steps in further developing and disseminating the model. PMID- 26739841 TI - A Comparison of Laparoscopy and Laparotomy for the Management of Abdominal Trauma: A Systematic Review and Meta-Analysis: Reply. PMID- 26739840 TI - Spanish- and English-Speaking Pregnant Women's Views on cfDNA and Other Prenatal Screening: Practical and Ethical Reflections. AB - The rapid clinical implementation of cell-free DNA (cfDNA) screening, a non invasive method of prenatal genetic screening, has outpaced research on its social and ethical implications. This study is the first to compare the ethical and practical views of Spanish- and English-speaking pregnant women in the United States about cfDNA screening. Semi-structured interviews were conducted with diverse Spanish- and English-speaking women who had received prenatal care at a large academic medical center. Of the 24 interviewees, ten were Latinas who were interviewed in Spanish; English-language interviews were conducted with seven non Hispanic Asian and seven non-Hispanic White women. Participants held positive opinions concerning the accuracy of cfDNA screening and often noted that it would enhance preparedness. Participants also expressed concerns about the possibility of inaccurate results and the potentially negative effects of cfDNA screening on the experience of pregnancy. Differences emerged between Spanish and English speakers in their portrayals of their relationships with prenatal health care providers, the extent to which they questioned providers' advice, their ethical concerns, and their informational needs. We emphasize the importance of customizing prenatal test counseling to the needs of the individual patient, providing educationally appropriate counseling and literature, and mitigating potential language barriers. PMID- 26739843 TI - Out-of-hospital cardiac arrest: should everyone go to the cath lab? PMID- 26739842 TI - Arabinogalactan proteins and arabinan pectins abound in the specialized matrices surrounding female gametes of the fern Ceratopteris richardii. AB - MAIN CONCLUSION: Both male and female gametes of archegoniates are highly specialized cells surrounded by an extraprotoplasmic matrix rich in AGPs, which are speculated to facilitate development and gamete fusion through Ca 2+) oscillations. An additional layer, the egg envelope, forms around the egg periphery, except at the fertilization pore, and contains arabinose-rich polymers that presumably impart flexibility for the rapidly growing zygote and embryo. The abundant AGPs and arabinan pectins associated with the eggs of C. richardii not only are integral to development, fertilization, and early embryogenesis, but also may be involved in desiccation tolerance important to the survival of the reproductive gametophyte. A defining feature of gametogenesis in archegoniates is the deposition of a special matrix outside of the plasmalemma of both egg and sperm cells that displaces the primary cell wall away from the protoplasm. It is within this matrix that gamete differentiation occurs. In leptosporangiate ferns, maturation of the egg cell involves the deposition of a second specialized wall, the so-called egg envelope that surrounds the cell except at the fertilization pore, a narrow site where gamete fusion takes place. We provide the first conclusive evidence of the macromolecular constituents in the unique structures surrounding fern egg cells before and after fertilization. To test the hypotheses that the egg extracellular matrix contains arabinogalactan proteins (AGPs) as does the sperm cell matrix, and that cell wall polysaccharides, especially pectins, are components of the egg envelope, we examined the expression patterns of AGPs and cell wall constituents during oogenesis in Ceratopteris richardii. Utilizing histochemical stains for callose, cellulose and AGPs coupled with immunogold localizations employing a suite of monoclonal antibodies to cell wall components (JIM13, JIM8, LM2, LM5, LM6, LM19, LM20 and anticallose), we demonstrate that AGPs, but not pectins, are abundant in the matrix around egg cells and degrading neck canal and ventral canal cells during archegonial development. A striking finding is that both AGPs and (1,5)-alpha-L-arabinan pectin epitopes are principle components of the egg envelope before and after fertilization, suggesting that they are important in both egg maturation and gamete fusion. PMID- 26739844 TI - Residents' narrative feedback on teaching performance of clinical teachers: analysis of the content and phrasing of suggestions for improvement. AB - OBJECTIVES: High-quality teaching performance is important to ensure patient safety and encourage residents' learning. This study aims to explore the content and phrasing of suggestions for improvement that residents provide to support excellent teaching performance of their supervisors. METHODS: From February 2010 to November 2011, 577 residents were invited to evaluate 501 teachers from both surgical and medical residency training programmes from 20 hospitals. Feedback was collected through a validated formative feedback system named System for Evaluation of Teaching Qualities. Two researchers independently coded the suggestions for improvement with literature-based coding schemes on (1) content and (2) linguistic characteristics. Besides these qualitative outcomes, descriptive statistics were calculated using SPSS. RESULTS: In total, 422 residents (73%) evaluated 488 teachers (97%), yielding 4184 evaluations. Of all teachers, 385 (79%) received suggestions for improvement focusing on teaching skills (TS), 390 (80%) on teaching attitude (TA) and 151 (31%) on personal characteristics. For 13%-47% of the suggestions for improvement, residents added (1) the location or situation where the observed TS or TA had taken place, (2) concrete examples of what teachers could do to improve or (3) (expected) effects of what the change in TS or TA would mean for residents. CONCLUSIONS: Residents provide mainly relevant suggestions for improvement that mirror important aspects of teaching performance. However, these comments often lack specific phrasing limiting their value for performance improvement. Therefore, residents are recommended to increase the specificity of the suggestions for improvement. The paper provides directions to phrase narrative feedback. PMID- 26739845 TI - Predictors of inhospital mortality following out-of-hospital cardiac arrest: Insights from a single-centre consecutive case series. AB - PURPOSE OF THE STUDY: Out-of-hospital cardiac arrest (OHCA) has a poor prognosis despite bystander resuscitation and rapid transfer to hospital. Optimal management of patients after arrival to hospital continues to be contentious, especially the timing of emergency coronary angiography+/-revascularisation. Robust predictors of inhospital outcome would be of clinical value for initial decision-making. STUDY DESIGN: A retrospective analysis of consecutive patients who presented to a university hospital following OHCA over a 70-month period (2008-2013). Patients were identified from the emergency department electronic patient registration and coding system. For those patients who underwent emergency percutaneous coronary intervention, details were crosschecked with national databases. RESULTS: We identified 350 consecutive patients who were brought to our hospital following OHCA. Return of spontaneous circulation (ROSC) for >20 min was achieved either before arrival or inhospital in 196 individuals. From the 350 subjects, 114 (32.6%) survived to hospital discharge. When sustained ROSC was achieved, either before or inhospital, survival to discharge was 58.2% (114 of 196). Non-shockable rhythm, absence of bystander cardiopulmonary resuscitation, 'downtime' >15 min and initial pH <=7.11 were predictors of inhospital death. 12% patients who underwent angiography in the presence of ST elevation had no acute coronary occlusion. 21% patients with acute coronary occlusion at angiography did not have ST elevation. CONCLUSIONS: In our cohort of patients with OHCA, those who achieve ROSC had a survival-to-discharge rate of 58.2%. We identified four predictors of inhospital death, which are readily available at the time of patient presentation. Reliance on ST elevation to decide about coronary angiography and revascularisation may be flawed. More data are required. PMID- 26739846 TI - Use of spaced education to deliver a curriculum in quality, safety and value for postgraduate medical trainees: trainee satisfaction and knowledge. AB - PURPOSE: Quality, patient safety and value are important topics for graduate medical education (GME). Spaced education delivers case-based content in a structured longitudinal experience. Use of spaced education to deliver quality and safety education in GME at an institutional level has not been previously evaluated. OBJECTIVES: To implement a spaced education course in quality, safety and value; to assess learner satisfaction; and to describe trainee knowledge in these areas. METHODS: We developed a case-based spaced education course addressing learning objectives related to quality, safety and value. This course was offered to residents and fellows about two-thirds into the academic year (March 2014) and new trainees during orientation (June 2014). We assessed learner satisfaction by reviewing the course completion rate and a postcourse survey, and trainee knowledge by the per cent of correct responses. RESULTS: The course was offered to 1950 trainees. A total of 305 (15.6%) enrolled in the course; 265/305 (86.9%) answered at least one question, and 106/305 (34.8%) completed the course. Fewer participants completed the March programme compared with the orientation programme (42/177 (23.7%) vs 64/128 (50.0%), p<0.001). Completion rates differed by specialty, 80/199 (40.2%) in non-surgical specialties compared with 16/106 (24.5%) in surgical specialties (p=0.008). The proportion of questions answered correctly on the first attempt was 53.2% (95% CI 49.4% to 56.9%). Satisfaction among those completing the programme was high. CONCLUSIONS: Spaced education can help deliver and assess learners' understanding of quality, safety and value principles. Offering a voluntary course may result in low completion. Learners were satisfied with their experience and were introduced to new concepts. PMID- 26739847 TI - It is time to relax. PMID- 26739848 TI - Cutaneous manifestations of familial hypercholesterolaemia. PMID- 26739851 TI - Novel in situ gelling ocular inserts for voriconazole-loaded niosomes: design, in vitro characterisation and in vivo evaluation of the ocular irritation and drug pharmacokinetics. AB - This work aimed to develop voriconazole in situ gelling ocular inserts loaded with niosomal suspension. Niosomes and mixed niosomes were prepared using span 40 and span 60 with pluronic L64 and pluronic F127. The entrapment efficiency percentages (EE%), mean vesicle size, polydispersity index (PI), zeta potential and in vitro drug release of these niosomes were evaluated. F3-mixed niosomes prepared with span 60 and pluronic L64 was selected, due to its highest EE; optimum vesicle size with smallest PdI and suitable release pattern of the drug (63% after 8 h). In situ ocular inserts were prepared using sodium carboxymethylcellulose (CMC Na) and sodium alginate (ALG) and characterised for surface morphology, surface pH, water uptake, mucoadhesion and in vitro release. ALG in situ ocular insert (S2) was selected for further in vivo evaluation of the ocular irritation and drug pharmacokinetics in the aqueous humour of rabbit's eyes. S2 in situ gelling ocular insert was non-irritant and showed significantly (p < 0.01) higher Cmax, delayed Tmax and increased bioavailability. PMID- 26739849 TI - The utility of heart failure registries: a descriptive and comparative study of two heart failure registries. AB - BACKGROUND AND AIM: Registries are useful to address questions that are difficult to answer in clinical trials. The objective of this study was to describe and compare two heart failure (HF) cohorts from two Spanish HF registries. METHODS: We compared the RICA and EAHFE registries, both of which are prospective multicentre cohort studies including patients with decompensated HF consecutively admitted to internal medicine wards (RICA) or attending the emergency department (EAHFE). From the latter registry we only included patients who were admitted to internal medicine wards. RESULTS: A total of 5137 patients admitted to internal medicine wards were analysed (RICA: 3287 patients; EAHFE: 1850 patients). Both registries included elderly patients (RICA: mean (SD) age 79 (9) years; EAHFE: mean (SD) age 81 (9) years), with a slight predominance of female gender (52% and 58%, respectively, in the RICA and EAHFE registries) and with a high proportion of patients with preserved ejection fraction (58% and 62%, respectively). Some differences in comorbidities were noted, with diabetes mellitus, dyslipidaemia, chronic renal failure and atrial fibrillation being more frequent in the RICA registry while cognitive and functional impairment predominated in the EAHFE registry. The 30-day mortality after discharge was 3.4% in the RICA registry and 4.8% in the EAHFE registry (p<0.05) and the 30-day readmission rate was 7.5% in the RICA registry (readmission to hospital) and 24.0% in the EAHFE registry (readmission to emergency department) (p<0.001). CONCLUSIONS: We found differences in the clinical characteristics of patients admitted to Spanish internal medicine wards for decompensated HF depending on inclusion in either the RICA or EAHFE registry. PMID- 26739853 TI - Unique Static Magnetic and Dynamic Electromagnetic Behaviors in Titanium Nitride/Carbon Composites Driven by Defect Engineering. AB - Recently, the defect-induced static magnetic behaviours of nanomaterials have been a cutting-edge issue in diluted magnetic semiconductor materials. However, the dynamic magnetic properties of nanomaterials are commonly ignored if their bulk counterparts are non-magnetic. In the present research, titanium nitride carbon (TiN/C) nanocomposites were found to exhibit both static and dynamic magnetic properties that vary in the opposite trend. Moreover, novel unconventional electromagnetic resonance behaviour was demonstrated in TiN/C systems, and their permeability and permittivity show similar trend. This is challenging for the traditional understanding of electromagnetism and makes it possible to achieve an appropriate balance between the permeability and permittivity simultaneously in a simple system. Hopefully, the results could provide some valuable clues to revealing the magnetism and electromagnetism of nanostructures. PMID- 26739852 TI - High-mobility group box 1 potentiates antineutrophil cytoplasmic antibody inducing neutrophil extracellular traps formation. AB - BACKGROUND: Recent studies found that the circulating high-mobility group box 1 (HMGB1) levels could reflect the disease activity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). HMGB1 could prime neutrophils by increasing ANCA antigens translocation for ANCA-mediated respiratory burst and degranulation. The current study aimed to investigate whether HMGB1 participates in ANCA-induced neutrophil extracellular traps (NETs) formation, which is one of the most important pathogenic aspects in the development of AAV. METHODS: NETs were induced by treating neutrophils with HMGB1 and ANCA-positive IgG in vitro. NETs formation was assessed using immunofluorescence microscopy and fluorescence probe. Antagonist for relevant receptors Toll-like receptor (TLR)2, TLR4 and the receptor for advanced glycation end products (RAGE), as well as NADPH oxidase molecules were employed. RESULTS: The percentage of NETs formation was significantly higher in neutrophils stimulated with HMGB1 plus ANCA-positive IgG than that in neutrophils incubated with HMGB1 or ANCA-positive IgG alone. Consistently, compared with the nonstimulated neutrophils, the cell-free DNA (cfDNA) concentration of NETs was significantly increased from 334.09 +/- 46.89 ng/ml to 563.32 +/- 122.07 ng/ml in the neutrophils incubated with HMGB1 plus MPO ANCA-positive IgG (P < 0.001), and from 303.44 +/- 37.14 ng/ml to 563.79 +/- 145.94 ng/ml in the neutrophils incubated with HMGB1 plus PR3-ANCA-positive IgG (P < 0.001). The aforementioned effect was significantly attenuated by antagonist for relevant receptors TLR2, TLR4 and RAGE, as well as blocking NADPH oxidase. CONCLUSIONS: HMGB1 can potentiate ANCA-inducing NETs formation and may be involved in the pathogenesis of AAV. HMGB1 exerts effects on NETs formation through interaction with TLR2, TLR4 and RAGE, and the process is NADPH oxidase dependent. PMID- 26739854 TI - High Prevalence of Laryngopharyngeal Reflux Disease in Patients With Lumbar Kyphosis. AB - OBJECTIVE: To evaluate the relationship between laryngopharyngeal reflux disease and presence of lumbar kyphosis. STUDY DESIGN: A cross-sectional study. METHODS: We included 20 patients with lumbar kyphosis and 31 control subjects. A diagnosis of laryngopharyngeal reflux disease and gastroesophageal reflux disease was made if the Reflux Symptom Index score was >=13 and if the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease was >=8, respectively. We compared the prevalence of the two reflux diseases, frequent reflux symptoms, and demographic factors between the two groups. RESULTS: There was no significant difference in demographic factors between the two groups. Five (25%) of 20 patients with lumbar kyphosis had a Reflux Symptom Index >=13 compared with one (3.2%) of 31 controls. Seven (35.0%) of 20 patients had a Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease >=8 compared with three (9.7%) of 31 controls. A comparison of the prevalence of laryngopharyngeal reflux disease and gastroesophageal reflux disease showed a significant difference between patients with kyphosis and controls (P value = 0.029 and 0.036, respectively). In Reflux Symptom Index, heartburn, hoarseness, and a swallowing problem were significantly frequent symptoms in the kyphosis group compared with the control group. CONCLUSIONS: The prevalence of laryngopharyngeal reflux disease and gastroesophageal reflux disease was significantly higher in patients with lumbar kyphosis than in controls. Therefore, otolaryngologists and orthopedic surgeons should be aware that patients with lumbar kyphosis are likely to have gastroesophageal reflux disease and also laryngopharyngeal reflux disease. PMID- 26739855 TI - Adaptation and Validation of the Voice-Related Quality of Life Measure Into Polish. AB - OBJECTIVES: The purpose of the study was to translate and adapt the original V RQOL (Voice-Related Quality of Life) instrument into Polish and to evaluate the psychometric properties of the Polish version of the V-RQOL Measure such as internal consistency, reliability, and construct validity in different groups of dysphonic patients. METHODS: A total of 214 patients with voice disorders were assessed using the V-RQOL Measure, the Voice Handicap Index, and the World Health Organization Quality of Life, short version. RESULTS: The Polish version of the V RQOL Measure showed strong internal consistency with the Cronbach alpha coefficient: 0.92 for the total score, 0.90 for the social-emotional domain, and 0.86 for the physical functioning domain, and a good test-retest reliability (r Spearman correlation coefficient: r = 0.8852 for the total score of the V-RQOL Measure). Construct validity was demonstrated with a strong correlation to the Voice Handicap Index (r = -0.843, P = 0.000*) and a weak positive, statistically significant correlation between the V-RQOL-physical functioning domain, V-RQOL social-emotional domain, and the Q1, Q2, and Domain 1-Domain 4 of the World Health Organization Quality of Life, short version (0.2 < r < 0.4). CONCLUSIONS: The Polish version of the V-RQOL Measure is a valid and reliable instrument to evaluate the patient's perception of his or her own voice disorders and the impact it can have on the patient's life. The V-RQOL Measure is easy to perform in clinical practice. PMID- 26739856 TI - Teachers' Perception of Vocal Quality Compared With Professional Perception. AB - PURPOSE: The purpose of this study was to investigate the difference in teachers' self-perception of their own voices compared with a voice clinician's perceptual assessment. METHODS: Participants included 45 elementary school (grades 1-8) teachers (34 females, 11 males) in public and private schools, with a mean age of 38.9 and age ranging from 24 to 65 years. The procedures included a demographic questionnaire, a self-assessment scale, and perceptual analysis. RESULTS: We found no difference when comparing overall vocal deviation of connected speech perceived by the teachers and the voice clinician (P = 0.509). However, the sustained vowel samples were perceived differently (P = 0.015). When comparing the teachers' and the voice clinician's perception of vocal qualities in both the vowel and the connected speech samples, we observed that they perceive roughness (P < 0.001 for both samples) and strain (P = 0.005 for vowel and P = 0.019 for connected speech) differently; however, breathiness is perceived similarly for both the vowel and the connected speech samples (P = 0.591 for vowel and P = 0.134 for connected speech). Increase in the numbers of years teaching showed a significant correlation with increase in teachers' perception of frequency of overall deviation (r = .870; P < 0.001). Additionally, increase in number of students in class was associated with increase in teachers' perception of frequency of strain (r = .819) (P < 0.001). CONCLUSION: The findings indicate that the teachers' perception corresponds partially with the clinician's perceptual analysis. A similar impression about the voice deviation was found only when comparing the perceptual analysis of connected speech. PMID- 26739857 TI - A Measure of the Auditory-perceptual Quality of Strain from Electroglottographic Analysis of Continuous Dysphonic Speech: Application to Adductor Spasmodic Dysphonia. AB - OBJECTIVES: (1) To develop an automated algorithm to analyze electroglottographic (EGG) signal in continuous dysphonic speech, and (2) to identify EGG waveform parameters that correlate with the auditory-perceptual quality of strain in the speech of patients with adductor spasmodic dysphonia (ADSD). STUDY DESIGN: Software development with application in a prospective controlled study. METHODS: EGG was recorded from 12 normal speakers and 12 subjects with ADSD reading excerpts from the Rainbow Passage. Data were processed by a new algorithm developed with the specific goal of analyzing continuous dysphonic speech. The contact quotient, pulse width, a new parameter peak skew, and various contact closing slope quotient and contact opening slope quotient measures were extracted. EGG parameters were compared between normal and ADSD speech. Within the ADSD group, intra-subject comparison was also made between perceptually strained syllables and unstrained syllables. RESULTS: The opening slope quotient SO7525 distinguished strained syllables from unstrained syllables in continuous speech within individual subjects with ADSD. The standard deviations, but not the means, of contact quotient, EGGW50, peak skew, and SO7525 were different between normal and ADSD speakers. The strain-stress pattern in continuous speech can be visualized as color gradients based on the variation of EGG parameter values. CONCLUSIONS: EGG parameters may provide a within-subject measure of vocal strain and serve as a marker for treatment response. The addition of EGG to multidimensional assessment may lead to improved characterization of the voice disturbance in ADSD. PMID- 26739858 TI - Investigating the Effects of Glottal Stop Productions on Voice in Children With Cleft Palate Using Multidimensional Voice Assessment Methods. AB - OBJECTIVES: The aim was to investigate the effects of glottal stop productions (GS) on voice in children with cleft palate using multidimensional voice assessment methods. STUDY DESIGN: This is a prospective case-control study. METHODS: Children with repaired cleft palate (n = 34) who did not have any vocal fold lesions were separated into two groups based on the results of the articulation test. The glottal stop group (GSG) consisted of 17 children who had GS. The control group (CG) consisted of an equal number of age- and gender matched children who did not have GS. The voice evaluation protocol included acoustic analysis, Pediatric Voice Handicap Index (pVHI), and perceptual analysis (Grade, Roughness, Breathiness, Asthenia, Strain method). The velopharyngeal statuses of the groups were compared using the nasopharyngoscopy and the nasometer. RESULTS: The total pVHI score and the subscales of the pVHI were found to be significantly higher in the GSG. The F0, jitter, and shimmer were found to be numerically higher in the GSG with the difference being statistically significant in jitter (P < 0.05). Audioperceptual analysis revealed a difference in overall voice quality and roughness between the groups. Greater incidence of significant velopharyngeal insufficiency and higher nasalance scores were found in the GSG (P < 0.05). CONCLUSIONS: These results may indicate that the vocal quality characteristics of children with GS differ from children who do not have this type of production. It is suggested that children with cleft palate who have GS should receive a comprehensive speech and language pathology intervention including voice therapy techniques. PMID- 26739859 TI - Measurement Reliability of Phonation Quotient Derived From Three Aerodynamic Instruments. AB - OBJECTIVE: The purpose of this study was to examine parallel forms reliability between two hand-held spirometers and a pneumotachograph-based system for vital capacity and derived phonation quotient measurements. STUDY DESIGN: This is a prospective, repeated measures design. METHODS: A total of 20 adult males were tested using three aerodynamic instruments-Baseline windmill-type spirometer, Contec SP10 digital spirometer and the Pentax Medical Phonatory Aerodynamic System (PAS), Model 6600 for measures of vital capacity. Phonation quotient was calculated using vital capacity from each instrument along with maximum phonation time. Repeated measures analyses of covariance (ANCOVAs) were performed to test for main effects of the instruments on vital capacity and phonation quotient, with age as a covariate. Pearson Product Moment correlation was performed to assess measurement reliability between the instruments. RESULTS: Statistically significant differences on ANCOVA were seen in vital capacity measures for the digital spirometer compared with the windmill spirometer and PAS. No differences were found between any of the instruments for phonation quotient. Large and positive correlations were present between all three instruments for both vital capacity and phonation quotient measurements. CONCLUSIONS: Strong parallel forms reliability in measures of vital capacity and derived phonation quotient was seen among the three instrument systems, although measurement precision was different when comparing the digital spirometer to two other instrument types. PMID- 26739861 TI - Image-based modelling of nutrient movement in and around the rhizosphere. AB - In this study, we developed a spatially explicit model for nutrient uptake by root hairs based on X-ray computed tomography images of the rhizosphere soil structure. This work extends our previous work to larger domains and hence is valid for longer times. Unlike the model used previously, which considered only a small region of soil about the root, we considered an effectively infinite volume of bulk soil about the rhizosphere. We asked the question: At what distance away from root surfaces do the specific structural features of root-hair and soil aggregate morphology not matter because average properties start dominating the nutrient transport? The resulting model was used to capture bulk and rhizosphere soil properties by considering representative volumes of soil far from the root and adjacent to the root, respectively. By increasing the size of the volumes that we considered, the diffusive impedance of the bulk soil and root uptake were seen to converge. We did this for two different values of water content. We found that the size of region for which the nutrient uptake properties converged to a fixed value was dependent on the water saturation. In the fully saturated case, the region of soil we needed to consider was only of radius 1.1mm for poorly soil mobile species such as phosphate. However, in the case of a partially saturated medium (relative saturation 0.3), we found that a radius of 1.4mm was necessary. This suggests that, in addition to the geometrical properties of the rhizosphere, there is an additional effect of soil moisture properties, which extends further from the root and may relate to other chemical changes in the rhizosphere. The latter were not explicitly included in our model. PMID- 26739860 TI - Vocal and Neural Responses to Unexpected Changes in Voice Pitch Auditory Feedback During Register Transitions. AB - OBJECTIVE/HYPOTHESIS: It is known that singers are able to control their voice to maintain a relatively constant vocal quality while transitioning between vocal registers; however, the neural mechanisms underlying this effect are not understood. It was hypothesized that greater attention to the acoustical feedback of the voice and increased control of the vocal musculature during register transitions compared with singing within a register would be represented as neurological differences in event-related potentials. STUDY DESIGN/METHODS: Nine singers sang musical notes at the high end of the modal register (the boundary between the modal and the head/falsetto registers) and at the low end (the boundary between the modal and the fry/pulse registers). While singing, the pitch of the voice auditory feedback was unexpectedly shifted either into the adjacent register ("toward" the register boundary) or within the modal register ("away from" the boundary). Singers were instructed to maintain a constant pitch and ignore any changes to their voice feedback. RESULTS: Vocal response latencies and magnitude of the accompanying N1 and P2 event-related potentials were greatest at the lower (modal-to-fry) boundary when the pitch shift carried the subjects' voices into the fry register as opposed to remaining within the modal register. CONCLUSIONS: These findings suggest that when a singer lowers the pitch of his or her voice such that it enters the fry register from the modal register, there is increased sensory-motor control of the voice, reflected as increased magnitude of the neural potentials to help minimize qualitative changes in the voice. PMID- 26739863 TI - Establishing a herbicide-metabolizing enzyme library in Beckmannia syzigachne to identify genes associated with metabolic resistance. AB - Non-target site resistance (NTSR) to herbicides is an increasing concern for weed control. Metabolic herbicide resistance is an important mechanism for NTSR. However, little is known about metabolic resistance at the genetic level. In this study, we have identified three fenoxaprop-P-ethyl-resistant American sloughgrass (Beckmannia syzigachne Steud.) populations, in which the molecular basis for NTSR remains unclear. To reveal the mechanisms of metabolic resistance, the genes likely to be involved in herbicide metabolism (e.g. for cytochrome P450s, esterases, hydrolases, oxidases, peroxidases, glutathione S-transferases, glycosyltransferases, and transporter proteins) were isolated using transcriptome sequencing, in combination with RT-PCR (reverse transcription-PCR) and RACE (rapid amplification of cDNA ends). Consequently, we established a herbicide metabolizing enzyme library containing at least 332 genes, and each of these genes was cloned and the sequence and the expression level compared between the fenoxaprop-P-ethyl-resistant and susceptible populations. Fifteen metabolic enzyme genes were found to be possibly involved in fenoxaprop-P-ethyl resistance. In addition, we found five metabolizing enzyme genes that have a different gene sequence in plants of susceptible versus resistant B. syzigachne populations. These genes may be major candidates for herbicide metabolic resistance. This established metabolic enzyme library represents an important step forward towards a better understanding of herbicide metabolism and metabolic resistance in this and possibly other closely related weed species. This new information may help to understand weed metabolic resistance and to develop novel strategies of weed management. PMID- 26739862 TI - Water-deficiency conditions differently modulate the methylome of roots and leaves in barley (Hordeum vulgare L.). AB - One of the strategies of plant adaptation to stress is the modulation of gene expression, which may result from the regulation of DNA methylation. This study attempted to characterize and compare the barley methylome of leaves and roots under water-deficiency treatment and in the subsequent rewatering phase. Our results, obtained using methylation-sensitive amplification polymorphism sequencing analysis, indicated that the overall DNA methylation level in the barley genome was high and in general stable under water-deficiency conditions. Nevertheless, numerous differentially methylated sites (DMSs) were induced by stress in the leaves and roots. Equal proportions of novel stress-induced methylation and demethylation events were observed within the genes in the leaves, but new methylations dominated in the roots. Repetitive elements preferentially underwent demethylation in the leaves and novel methylations in the roots. Importantly, rewatering and plant recovery resulted in the reversibility of the majority of stress-induced methylation events, but this process was more efficient in the leaves than in the roots. Different biological processes were enriched within the subsets of the DMSs that were identified in the genic regions of leaves and roots. We assume that the organ specificity of the methylome changes in response to water deficiency might be an important regulatory mechanism that leads to multi-level mechanisms of stress tolerance in barley. PMID- 26739864 TI - Scanning Electron Microscope-Cathodoluminescence Analysis of Rare-Earth Elements in Magnets. AB - Scanning electron microscope-cathodoluminescence (SEM-CL) analysis was performed for neodymium-iron-boron (NdFeB) and samarium-cobalt (Sm-Co) magnets to analyze the rare-earth elements present in the magnets. We examined the advantages of SEM CL analysis over conventional analytical methods such as SEM-energy-dispersive X ray (EDX) spectroscopy and SEM-wavelength-dispersive X-ray (WDX) spectroscopy for elemental analysis of rare-earth elements in NdFeB magnets. Luminescence spectra of chloride compounds of elements in the magnets were measured by the SEM-CL method. Chloride compounds were obtained by the dropwise addition of hydrochloric acid on the magnets followed by drying in vacuum. Neodymium, praseodymium, terbium, and dysprosium were separately detected in the NdFeB magnets, and samarium was detected in the Sm-Co magnet by the SEM-CL method. In contrast, it was difficult to distinguish terbium and dysprosium in the NdFeB magnet with a dysprosium concentration of 1.05 wt% by conventional SEM-EDX analysis. Terbium with a concentration of 0.02 wt% in an NdFeB magnet was detected by SEM-CL analysis, but not by conventional SEM-WDX analysis. SEM-CL analysis is advantageous over conventional SEM-EDX and SEM-WDX analyses for detecting trace rare-earth elements in NdFeB magnets, particularly dysprosium and terbium. PMID- 26739865 TI - Expedient synthesis of new cinnoline diones by Ru-catalyzed regioselective unexpected deoxygenation-oxidative annulation of propargyl alcohols with phthalazinones and pyridazinones. AB - Ruthenium-catalyzed simple, cascade and one-pot synthesis of cinnoline-fused diones has been carried out by the C-H activation of phthalazinones/pyridazinones accomplished by the unusual deoxygenation of propargyl alcohols. The bond selectivity is accredited to the traceless directing nature of the hydroxyl group of propargyl alcohol. A sequential C-H activation, insertion and deoxy-oxidative annulation has been proposed based on the preliminary mechanistic study. PMID- 26739866 TI - Wavelength-selective light-triggered strand exchange reaction. AB - We prepared an oligodeoxynucleotide (ODN) bearing two 4-hydroxy-2 mercaptobenzimidazole nucleobase analogues (SB(NV) and SB(NB)) modified with different photolabile groups. This ODN enabled a light-triggered strand exchange reaction in a wavelength-selective manner. PMID- 26739867 TI - HRMS Profile of a Hazelnut Skin Proanthocyanidin-rich Fraction with Antioxidant and Anti-Candida albicans Activities. AB - Roasted hazelnut skins (RHS) represent a byproduct of kernel industrial processing. In this research, a RHS extract (RHS-M) and its fraction RHS-M-F3 enriched in proanthocyanidins (PAs), with antioxidant activity, were characterized in terms of total phenolic compound and PA contents. RHS-M and RHS M-F3 showed antifungal properties against Candida albicans SC5314 (MIC2 = 3.00 and 0.10 MUg/mL and MIC0 = 5.00 and 0.50 MUg/mL, respectively), determined by the microbroth dilution method and Candida albicans morphological analysis. No cytotoxic effect on HEKa and HDFa cell lines was exhibited by RHS-M and RHS-M-F3. The metabolite profiling of RHS-M and RHS-M-F3 was performed by thiolysis followed by HPLC-UV-HRMS analysis and a combination of HRMS-FIA and HPLC-HRMS(n). Extract and fraction contain oligomeric PAs (mDP of 7.3 and 6.0, respectively, and DP up to 10) mainly constituted by B-type oligomers of (epi)-catechin. Also, (epi)-gallocatechin and gallate derivatives were identified as monomer units, and A-type PAs were detected as minor compounds. PMID- 26739868 TI - Association of age and admission mean arterial blood pressure in patients with stroke-data from a national stroke registry. AB - Elevated blood pressure (BP) upon admission is common in patients with ischemic stroke (IS) and intracerebral hemorrhage (ICH). Older patients have a higher prevalence of stroke, but data on admission mean arterial pressure (MAP) patterns in older patients with stroke are scarce. All 6060 patients with IS (72%), ICH (8%) and transient ischemic attack (TIA; 20%) with data on BP and hypertension status on admission in the National Acute Stroke Israeli Registry were included. Admission MAP in the emergency department was studied by age group (<60, 60-74 and ?75 years) and stroke type. Linear regression models for admission MAP were produced, including age group, gender, hypertension status and stroke severity as covariates. Interactions between hypertension and age were assessed. Lower MAP (s.d.) was associated with older ages in hypertensive patients (113 (18) mm Hg for age <60 years, 109 (17) for age 60-74 years and 108 (19) for age ?75 years, P<0.0001) but not in non-hypertensive IS patients. Among patients with ICH and TIA, a significant negative association of MAP with age was observed for hypertensive patients (P=0.015 and P=0.023, respectively), whereas a significant positive association with age was found in non-hypertensive patients (P=0.023 and P=0.038, respectively). In adjusted regression models, MAP was significantly associated with hypertension in IS, ICH and TIA patients. The interaction between hypertension and age was significantly associated with MAP in IS and ICH patients. In hypertensive patients, the average admission MAP was lower in persons at older ages. PMID- 26739870 TI - Which has the stronger impact on coronary artery disease, eicosapentaenoic acid or docosahexaenoic acid? AB - It has been suggested that n-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), protect against cardiovascular diseases, and EPA/arachidonic acid (AA) and DHA/AA ratios in serum are potential risk markers for coronary artery disease (CAD). The purpose of this study was to clarify the clinical significance of the difference in the EPA/AA ratio and the DHA/AA ratio in patients with CAD. In 369 patients with confirmed or suspected CAD who underwent diagnostic coronary angiography, we measured serum levels of EPA, DHA and AA and calculated the EPA/AA and DHA/AA ratios. The EPA/AA ratio was significantly lower in patients with acute coronary syndrome (ACS) than in patients with chronic CAD or chest pain syndrome (0.27+/-0.19 vs. 0.44+/-0.20, respectively; P<0.01), whereas the DHA/AA ratio was similar in the two groups (0.78+/-0.27 vs. 0.79+/-0.37). Multiple logistic regression analyses using various biomarkers related to coronary risk discriminated ACS from other disease entities and demonstrated that the EPA/AA ratio (odds ratio: 0.0012, 95% confidence interval: 0.00-0.16, P<0.01) but not the DHA/AA ratio (odds ratio: 1.05, 95% confidence interval: 0.98-1.12) was a significant independent predictive factor. Our findings suggest that the EPA/AA ratio might be more closely associated with the pathophysiology of CAD, especially with that of ACS, than the DHA/AA ratio. Our findings suggest that interventions with EPA agents or supplemental EPA intake, compared with DHA agents or supplemental DHA, may confer greater benefit for plaque stabilization to prevent the onset of ACS in patients with CAD. PMID- 26739869 TI - The association between the prevalence, treatment and control of hypertension and the risk of mild cognitive impairment in an elderly urban population in China. AB - It remains unclear whether lowering the blood pressure effectively prevents cognitive impairment. The aim of the current study was to explore the association between the prevalence, treatment and control of hypertension and the risk of mild cognitive impairment (MCI) among elderly Chinese people. This is a cross sectional study conducted in Beijing, China. A two-stage stratified clustering sampling method was used, and 2065 participants, aged ?60 years, were included in the analysis. The Mini-Mental State Examination was used to assess participants' cognitive function. The prevalence of MCI was higher in hypertensive (16.5%) than in normotensive individuals (13.1%; P=0.043). Furthermore, in those hypertensive patients, the prevalence of MCI was lower in those treated (14.9%) than in those not treated (19.9%; P=0.019) and lower in those controlled (13.4%) than in those uncontrolled (17.9%; P=0.042). The adjusted odds ratio (OR; 95% confidence interval (CI)) of having MCI was 1.59 (1.07-2.35) in those with hypertension compared with those normotensive individuals. The assessment of the hypertensive patients revealed the adjusted OR (95% CI) of having MCI in those with treated hypertension was 0.60 (0.42-0.86) compared with those untreated hypertension, and in those with controlled hypertension was 0.64 (0.43-0.93) compared with those non-controlled hypertension (regardless of treatment). However, among the treated hypertensive patients, there was no difference in the prevalence of MCI between the patients who reached and those who did not reach their treatment goal. We suggest that improved diagnoses and optimal therapeutics are needed to achieve the aim of cognitive decline prevention. PMID- 26739871 TI - Persistent olmesartan-based blood pressure-lowering effects on morning hypertension in Asians: the HONEST study. AB - Using data from the large-scale HONEST (Home blood pressure measurement with Olmesartan Naive patients to Establish Standard Target blood pressure) study, we investigated the characteristics of the effects of olmesartan-based treatment on morning hypertension in Asian hypertensive patients. Specifically, we investigated the relationship between baseline blood pressure (BP) and BP reduction after 16 weeks by linear regression analyses; determinants of BP reduction were also investigated. For both morning home BP (MHBP) and clinic BP (CBP), reduced systolic BP (SBP) after 16 weeks was associated with baseline SBP (P<0.001). The slope of the regression lines was similar for morning home SBP (MHSBP) (-0.744) and clinic SBP (-0.735). Although sex, concomitant diabetes mellitus and concomitant hepatic disease significantly influence the relationship between BP reduction and baseline BP for MHSBP, none were deemed clinically relevant. In conclusion, olmesartan-based treatment robustly reduced baseline high MHBP, similar to CBP, and the effect was associated with baseline BP but unaffected by patient background factors. PMID- 26739872 TI - Augmented circadian rhythm of the intrarenal renin-angiotensin systems in anti thymocyte serum nephritis rats. AB - We report that disturbance to the circadian rhythm of urinary angiotensinogen (AGT) excretion may lead to renal damage, hypertension and diurnal blood pressure (BP) variations. We aim to clarify the circadian rhythm of the intrarenal renin angiotensin system (RAS) and its contribution to renal damage, hypertension and BP variations, and to evaluate whether the administration of RAS blockers influences the circadian rhythms of intrarenal RAS components. Anti-thymocyte serum (ATS) nephritis rats were used as a chronic progressive glomerulonephritis model (group A) and compared with control rats (group C). Other rats with ATS nephritis received olmesartan medoxomil (an angiotensin II (AngII) type 1 receptor (AT1R) blocker; group AO) or hydralazine (a vasodilator; group AH). The levels of intrarenal RAS components were evaluated every 6 h. The expression levels of intrarenal AGT, AngII and AT1R were increased in group A and peaked at the same time as BP and urinary protein excretion during the rest phase. The amplitude of the circadian fluctuation of these proteins was more increased in group A than in group C. The circadian fluctuation of these proteins was reduced in groups AO and AH. However, renal function, proteinuria and augmentation of intrarenal RAS components were reduced only in group AO. Intrarenal RAS components, such as AGT, AngII and AT1R proteins, were increased and the amplitude of the oscillations of these proteins was augmented in ATS nephritis rats. Interestingly, renal damage may be linked to the activation of the intrarenal RAS independent of the amplitude of its oscillations and BP. PMID- 26739873 TI - Individualized real-time clinical decision support to monitor cardiac loading during venoarterial ECMO. AB - Veno-arterial extracoporeal membrane oxygenation (VA ECMO) is increasingly used for acute and refractory cardiogenic shock. Yet, in clinical practice, monitoring of cardiac loading conditions during VA ECMO can be cumbersome. To this end, we illustrate the validity and clinical applicability of a real-time cardiovascular computer simulation, which allows to integrate hemodynamics, cardiac dimensions and the corresponding degree of VA ECMO support and ventricular loading in individual patients over time. PMID- 26739881 TI - Selection on Mitochondrial Variants Occurs between and within Individuals in an Expanding Invasion. AB - Mitochondria are critical for life, yet their underlying evolutionary biology is poorly understood. In particular, little is known about interaction between two levels of evolution: between individuals and within individuals (competition between cells, mitochondria or mitochondrial DNA molecules). Rapid evolution is suspected to occur frequently in mitochondrial DNA, whose maternal inheritance predisposes advantageous mutations to sweep rapidly though populations. Rapid evolution is also predicted in response to changed selection regimes after species invasion or removal of pathogens or competitors. Here, using empirical and simulated data from a model invasive bird species, we provide the first demonstration of rapid selection on the mitochondrial genome within individuals in the wild. Further, we show differences in mitochondrial DNA copy number associated with competing genetic variants, which may provide a mechanism for selection. We provide evidence for three rarely documented phenomena: selection associated with mitochondrial DNA abundance, selection on the mitochondrial control region, and contemporary selection during invasion. PMID- 26739883 TI - Midostaurin + Chemo Ups AML Survival. AB - In a phase III clinical trial, previously untreated patients with acute myeloid leukemia and FLT3 mutations received either the FLT3 inhibitor midostaurin or a placebo during chemotherapy. Patients who received midostaurin had a 5-year survival rate of 50.9% compared with 43.9% for the placebo group, as well as remissions that lasted nearly a year longer. PMID- 26739880 TI - Euarchontan Opsin Variation Brings New Focus to Primate Origins. AB - Debate on the adaptive origins of primates has long focused on the functional ecology of the primate visual system. For example, it is hypothesized that variable expression of short- (SWS1) and middle-to-long-wavelength sensitive (M/LWS) opsins, which confer color vision, can be used to infer ancestral activity patterns and therefore selective ecological pressures. A problem with this approach is that opsin gene variation is incompletely known in the grandorder Euarchonta, that is, the orders Scandentia (treeshrews), Dermoptera (colugos), and Primates. The ancestral state of primate color vision is therefore uncertain. Here, we report on the genes (OPN1SW and OPN1LW) that encode SWS1 and M/LWS opsins in seven species of treeshrew, including the sole nocturnal scandentian Ptilocercus lowii. In addition, we examined the opsin genes of the Central American woolly opossum (Caluromys derbianus), an enduring ecological analogue in the debate on primate origins. Our results indicate: 1) retention of ultraviolet (UV) visual sensitivity in C. derbianus and a shift from UV to blue spectral sensitivities at the base of Euarchonta; 2) ancient pseudogenization of OPN1SW in the ancestors of P. lowii, but a signature of purifying selection in those of C. derbianus; and, 3) the absence of OPN1LW polymorphism among diurnal treeshrews. These findings suggest functional variation in the color vision of nocturnal mammals and a distinctive visual ecology of early primates, perhaps one that demanded greater spatial resolution under light levels that could support cone-mediated color discrimination. PMID- 26739882 TI - Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. AB - KRAS gain-of-function mutations occur in approximately 30% of all human cancers. Despite more than 30 years of KRAS-focused research and development efforts, no targeted therapy has been discovered for cancers with KRAS mutations. Here, we describe ARS-853, a selective, covalent inhibitor of KRAS(G12C) that inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation. Based on the rates of engagement and inhibition observed for ARS-853, along with a mutant-specific mass spectrometry-based assay for assessing KRAS activation status, we show that the nucleotide state of KRAS(G12C) is in a state of dynamic flux that can be modulated by upstream signaling factors. These studies provide convincing evidence that the KRAS(G12C) mutation generates a "hyperexcitable" rather than a "statically active" state and that targeting the inactive, GDP-bound form is a promising approach for generating novel anti-RAS therapeutics. SIGNIFICANCE: A cell-active, mutant-specific, covalent inhibitor of KRAS(G12C) is described that targets the GDP-bound, inactive state and prevents subsequent activation. Using this novel compound, we demonstrate that KRAS(G12C) oncoprotein rapidly cycles bound nucleotide and responds to upstream signaling inputs to maintain a highly active state. PMID- 26739884 TI - Alectinib Approved for ALK+ Lung Cancer. AB - The FDA has approved a third ALK inhibitor, alectinib, for advanced ALK-positive non-small cell lung cancer. Two phase II studies show that patients who have become resistant to crizotinib respond well to alectinib; the drug is also effective against brain metastases, which are common in this disease subtype. PMID- 26739885 TI - Facile synthesis of N-rich carbon quantum dots by spontaneous polymerization and incision of solvents as efficient bioimaging probes and advanced electrocatalysts for oxygen reduction reaction. AB - In this study, uniform nitrogen-doped carbon quantum dots (N-CDs) were synthesized through a one-step solvothermal process of cyclic and nitrogen-rich solvents, such as N-methyl-2-pyrrolidone (NMP) and dimethyl-imidazolidinone (DMEU), under mild conditions. The products exhibited strong light blue fluorescence, good cell permeability and low cytotoxicity. Moreover, after a facile post-thermal treatment, it developed a lotus seedpod surface-like structure of seed-like N-CDs decorating on the surface of carbon layers with a high proportion of quaternary nitrogen moieties that exhibited excellent electrocatalytic activity and long-term durability towards the oxygen reduction reaction (ORR). The peak potential was -160 mV, which was comparable to or even lower than commercial Pt/C catalysts. Therefore, this study provides an alternative facile approach to the synthesis of versatile carbon quantum dots (CDs) with widespread commercial application prospects, not only as bioimaging probes but also as promising electrocatalysts for the metal-free ORR. PMID- 26739887 TI - Maintaining K+ balance on the low-Na+, high-K+ diet. AB - A low-Na+, high-K+ diet (LNaHK) is considered a healthier alternative to the "Western" high-Na+ diet. Because the mechanism for K+ secretion involves Na+ reabsorptive exchange for secreted K+ in the distal nephron, it is not understood how K+ is eliminated with such low Na+ intake. Animals on a LNaHK diet produce an alkaline load, high urinary flows, and markedly elevated plasma ANG II and aldosterone levels to maintain their K+ balance. Recent studies have revealed a potential mechanism involving the actions of alkalosis, urinary flow, elevated ANG II, and aldosterone on two types of K+ channels, renal outer medullary K+ and large-conductance K+ channels, located in principal and intercalated cells. Here, we review these recent advances. PMID- 26739889 TI - Deleting the TGF-beta receptor in proximal tubules impairs HGF signaling. AB - Transforming growth factor-beta (TGF-beta) and hepatocyte growth factor (HGF) play key roles in regulating the response to renal injury but are thought to mediate divergent effects on cell behavior. However, how TGF-beta signaling alters the response to HGF in epithelia, the key site of HGF signaling in the injured kidney, is not well studied. Contrary to our expectation, we showed that deletion of the TGF-beta type II receptor in conditionally immortalized proximal tubule (PT) cells impaired HGF-dependent signaling. This reduced signaling was due to decreased transcription of c-Met, the HGF receptor, and the TGF-beta dependent c-Met transcription and increased response to HGF in PT cells were mediated by the Notch pathway. The interactions of TGF-beta, HGF, and Notch pathways had biologically significant effects on branching morphogenesis, cell morphology, migration, and proliferation. In conclusion, epithelial TGF-beta signaling promotes HGF signaling in a Notch-dependent pathway. These findings suggest that TGF-beta modulates PT responses not only by direct effects, but also by affecting other growth factor signaling pathways. PMID- 26739890 TI - Effect of chronic uremia on the transcriptional profile of the calcified aorta analyzed by RNA sequencing. AB - The development of vascular calcification (VC) in chronic uremia (CU) is a tightly regulated process controlled by factors promoting and inhibiting mineralization. Next-generation high-throughput RNA sequencing (RNA-seq) is a powerful and sensitive tool for quantitative gene expression profiling and the detection of differentially expressed genes. In the present study, we, for the first time, used RNA-seq to examine rat aorta transcriptomes from CU rats compared with control rats. Severe VC was induced in CU rats, which lead to extensive changes in the transcriptional profile. Among the 10,153 genes with an expression level of >1 reads/kilobase transcript/million mapped reads, 2,663 genes were differentially expressed with 47% upregulated genes and 53% downregulated genes in uremic rats. Significantly deregulated genes were enriched for ontologies related to the extracellular matrix, response to wounding, organic substance, and ossification. The individually affected genes were of relevance to osteogenic transformation, tissue calcification, and Wnt modulation. Downregulation of the Klotho gene in uremia is believed to be involved in the development of VC, but it is debated whether the effect is caused by circulating Klotho only or if Klotho is produced locally in the vasculature. We found that Klotho was neither expressed in the normal aorta nor calcified aorta by RNA-seq. In conclusion, we demonstrated extensive changes in the transcriptional profile of the uremic calcified aorta, which were consistent with a shift in phenotype from vascular tissue toward an osteochondrocytic transcriptome profile. Moreover, neither the normal vasculature nor calcified vasculature in CU expresses Klotho. PMID- 26739888 TI - TGF-beta signaling in the kidney: profibrotic and protective effects. AB - Transforming growth factor-beta (TGF-beta) is generally considered as a central mediator of fibrotic diseases. Indeed, much focus has been placed on inhibiting TGF-beta and its downstream targets as ideal therapeutic strategies. However, pharmacological blockade of TGF-beta has not yet translated into successful therapy for humans, which may be due to pleiotropic effects of TGF-beta signaling. Equally, TGF-beta signaling as a protective response in kidney injury has been relatively underexplored. An emerging body of evidence from experimental kidney disease models indicates multifunctionality of TGF-beta capable of inducing profibrotic and protective effects. This review discusses recent advances highlighting the diverse roles of TGF-beta in promoting not only renal fibrosis but also protective responses of TGF-beta signaling. We review, in particular, growing evidence that supports protective effects of TGF-beta by mechanisms which include inhibiting inflammation and induction of autophagy. Additional detailed studies are required to fully understand the diverse mechanisms of TGF-beta actions in renal fibrosis and inflammation that will likely direct toward effective antifibrotic therapies. PMID- 26739891 TI - Knockdown of RTN1A attenuates ER stress and kidney injury in albumin overload induced nephropathy. AB - Our previous studies have suggested a critical role of reticulon (RTN)1A in mediating endoplasmic reticulum (ER) stress in kidney cells of animal models and humans with kidney diseases. A large body of evidence suggests that proteinuria itself can cause tubular cell injury leading to the progression of kidney disease. In the present study, we determined whether RTN1A mediates proteinuria induced tubular cell injury through increased ER stress. We found that incubation of HK2 cells with human serum albumin induced the expression of RTN1A and ER stress markers, whereas knockdown of RTN1A expression attenuated human serum albumin-induced ER stress and tubular cell apoptosis in vitro. In vivo, we found that tubular cell-specific RTN1 knockdown resulted in a significant attenuation of tubular cell ER stress, apoptosis, and renal fibrosis in a model of albumin overload nephropathy. Based on these findings, we conclude that RTN1A is a key mediator for proteinuria-induced tubular cell toxicity and renal fibrosis. PMID- 26739892 TI - mPGES-1-derived PGE2 contributes to adriamycin-induced podocyte injury. AB - Podocyte damage is a common pathological feature in many types of glomerular diseases and is involved in the occurrence and progression of kidney disease. However, the pathogenic mechanisms leading to podocyte injury are still uncertain. The present study was undertaken to investigate the role of microsomal PGE synthase (mPGES)-1 in adriamycin (ADR)-induced podocyte injury as well as the underlying mechanism. In both mouse kidneys and in vitro podocytes, application of ADR remarkably enhanced mPGES-1 expression in line with a stimulation of cyclooxygenase-2. Interestingly, inhibition of mPGES-1 with a small interfering RNA approach significantly attenuated ADR-induced downregualtion of podocin and nephrin. Moreover, ADR-induced podocyte apoptosis was also markedly blocked in parallel with blunted caspase-3 induction. In agreement with the improvement of cell phenotypic alteration and apoptosis, the enhanced inflammatory markers of IL 1beta and TNF-alpha were also significantly suppressed by mPGES-1 silencing. More importantly, in mPGES-1-deficient mice, albuminuria induced by ADR showed a remarkable attenuation in line with decreased urinary output of PGE2 and TNF alpha, highly suggesting an in vivo role of mPGES-1 in mediating podocyte injury. In summary, findings from the present study offered the first evidence demonstrating a pathogenic role of mPGES-1 in mediating ADR-induced podocyte injury possibly via triggering an inflammatory response. PMID- 26739893 TI - Repeated administration of low-dose cisplatin in mice induces fibrosis. AB - Cisplatin, a chemotherapeutic used for the treatment of solid cancers, has nephrotoxic side effects leading to acute kidney injury (AKI). Cisplatin cannot be given to patients that have comorbidities that predispose them to an increased risk for AKI. Even without these comorbidities, 30% of patients administered cisplatin will develop kidney injury, requiring the oncologist to withhold or reduce the next dose, leading to a less effective therapeutic regimen. Although recovery can occur after one episode of cisplatin-induced AKI, longitudinal studies have indicated that multiple episodes of AKI lead to the development of chronic kidney disease, an irreversible disease with no current treatment. The standard mouse model of cisplatin-induced AKI consists of one high dose of cisplatin (>20 mg/kg) that is lethal to the animal 3 days later. This model does not accurately reflect the dosing regimen patients receive nor does it allow for the long-term study of kidney function and biology. We have developed a repeated dosing model whereby cisplatin is given once a week for 4 wk. Comparison of the repeated dosing model with the standard dosing model demonstrated that inflammatory cytokines and chemokines were induced in the repeated dosing model, but levels of cell death were lower in the repeated dosing model. The repeated dosing model had increased levels of fibrotic markers (fibronectin, transforming growth factor-beta, and alpha-smooth muscle actin) and interstitial fibrosis. These data indicate that the repeated dosing model can be used to study the AKI to chronic kidney disease progression as well as the mechanisms of this progression. PMID- 26739896 TI - Nine new cytochalasan alkaloids from Chaetomium globosum TW1-1 (Ascomycota, Sordariales). AB - Chemical investigation on the methanol extract of Chaetomium globosum TW1-1, a fungus isolated from the common pillbug (Armadillidium vulgare), has resulted in the isolation of nine new highly oxygenated cytochalasan alkaloids, armochaetoglobins S-Z (1 and 3-9) and 7-O-acetylarmochaetoglobin S (2), together with eight structurally related known analogues (10-17). Their structures and absolute configurations were elucidated by spectroscopic analyses. Among them, compound 2 presents to be the first member of chaetoglobosin family with an acetyl group, and compounds 3 represents the first chaetoglobosin characterized by an 2',3'-epoxy-indole moiety. The discovery of these new compounds revealed the largely untapped chemical diversity of cytochalasans and enriched their chemical research. Compounds 1-9 were evaluated for their cytotoxic activities against five human cancer cell lines, and compounds 8 and 9 exhibited significant cytotoxic activities with IC50 values ranging from 10.45 to 30.42 MUM. PMID- 26739894 TI - Muc1 enhances the beta-catenin protective pathway during ischemia-reperfusion injury. AB - The hypoxia-inducible factor (HIF)-1 and beta-catenin protective pathways represent the two most significant cellular responses that are activated in response to acute kidney injury. We previously reported that murine mucin (Muc)1 protects kidney function and morphology in a mouse model of ischemia-reperfusion injury (IRI) by stabilizing HIF-1alpha, enhancing HIF-1 downstream signaling, and thereby preventing metabolic stress (Pastor-Soler et al. Muc1 is protective during kidney ischemia-reperfusion injury. Am J Physiol Renal Physiol 308: F1452 F1462, 2015). We asked if Muc1 regulates the beta-catenin protective pathway during IRI as 1) beta-catenin nuclear targeting is MUC1 dependent in cultured human cells, 2) beta-catenin is found in coimmunoprecipitates with human MUC1 in extracts of both cultured cells and tissues, and 3) MUC1 prevents beta-catenin phosphorylation by glycogen synthase kinase (GSK)3beta and thereby beta-catenin degradation. Using the same mouse model of IRI, we found that levels of active GSK3beta were significantly lower in kidneys of control mice compared with Muc1 knockout (KO) mice. Consequently, beta-catenin was significantly upregulated at 24 and 72 h of recovery and appeared in the nuclear fraction at 72 h in control mouse kidneys. Both beta-catenin induction and nuclear targeting were absent in Muc1 KO mice. We also found downstream induction of beta-catenin prosurvival factors (activated Akt, survivin, transcription factor T cell factor 4 (TCF4), and its downstream target cyclin D1) and repression of proapoptotic factors (p53, active Bax, and cleaved caspase-3) in control mouse kidneys that were absent or aberrant in kidneys of Muc1 KO mice. Altogether, the data clearly indicate that Muc1 protection during acute kidney injury proceeds by enhancing both the HIF-1 and beta-catenin protective pathways. PMID- 26739899 TI - Taxing sugar. PMID- 26739898 TI - High mobility group box 1-induced epithelial mesenchymal transition in human airway epithelial cells. AB - Epithelial-mesenchymal transition (EMT) is implicated in bronchial remodeling and loss of lung function in chronic inflammatory airway diseases. Previous studies showed the involvement of the high mobility group box 1 (HMGB1) protein in the pathology of chronic pulmonary inflammatory diseases. However, the role of HMGB1 in EMT of human airway epithelial cells is still unclear. In this study, we used RNA sequencing to show that HMGB1 treatment regulated EMT-related gene expression in human primary-airway epithelial cells. The top five upregulated genes were SNAI2, FGFBP1, VIM, SPARC (osteonectin), and SERPINE1, while the downregulated genes included OCLN, TJP1 (ZO-1), FZD7, CDH1 (E-cadherin), and LAMA5. We found that HMGB1 induced downregulation of E-cadherin and ZO-1, and upregulation of vimentin mRNA transcription and protein translation in a dose-dependent manner. Additionally, we observed that HMGB1 induced AKT phosphorylation, resulting in GSK3beta inactivation, cytoplasmic accumulation, and nuclear translocation of beta-catenin to induce EMT in human airway epithelial cells. Treatment with PI3K inhibitor (LY294006) and beta-catenin shRNA reversed HMGB1-induced EMT. Moreover, HMGB1 induced expression of receptor for advanced glycation products (RAGE), but not that of Toll-like receptor (TLR) 2 or TLR4, and RAGE shRNA inhibited HMGB1 induced EMT in human airway epithelial cells. In conclusion, we found that HMGB1 induced EMT through RAGE and the PI3K/AKT/GSK3beta/beta-catenin signaling pathway. PMID- 26739900 TI - [Large cell carcinoma, lymphoepithelioma-like carcinoma, NUT carcinoma]. AB - The diagnosis of large cell carcinoma can only be made on a sampled resected tumor and should not be applied to biopsies or cytology. In the 2015 WHO classification, the definition of large cell carcinoma is restricted to carcinomas both lacking morphological signs of glandular, squamous or neuroendocrine differentiation and exhibiting a null or unclear phenotype (TTF1 /p40 ou p63 ou CK5/6+ focally). These carcinomas have an adenocarcinoma molecular profile because they harbor a significant number of KRAS and BRAF mutations, a profile that is more similar to adenocarcinoma than squamous cell carcinoma. They also have a worse prognosis than the other types of non-small cell lung carcinoma. Many large cell carcinomas previously classified on morphological data alone are now reclassified in the adenocarcinoma and squamous cell carcinoma types, including immunohistochemical features. The other large cell carcinoma subtypes from the 2004 WHO classification, i.e. large cell neuroendocrine carcinoma and basaloid carcinoma, are grouped respectively with the other neuroendocrine tumors and squamous cell carcinomas. Clear cell and rhabdoid features are now considered as cytological variants that can occur in any histopathological subtype and not as distinct subtypes. Lymphoepithelioma-like carcinoma is moved to the group of other and unclassified carcinomas as NUT carcinoma. PMID- 26739903 TI - Neuroendovascular Interventions for Acute Ischemic Strokes in Patients Supported with Left Ventricular Assist Devices: A Single-Center Case Series and Review of the Literature. AB - BACKGROUND: With the shortage of donor hearts, increasingly more patients with end-stage heart failure are implanted with left ventricular assist devices (LVADs). LVADs are associated with a significant risk of developing acute ischemic strokes (AISs). Very little is known on about the management of AIS in patients with LVAD, especially with regard to the safety and efficacy of neuroendovascular techniques. METHODS: We identified 5 patients with heart failure and LVAD implants who developed AIS and underwent neuroendovascular interventions at Columbia University Medical Center. Their cases were reviewed for the safety, efficacy of the interventions, and potential complications. RESULTS: There were no significant complications from the interventions. In all 5 cases, there was at least a 4-point improvement in the National Institutes of Health Stroke scale and none of the cases developed symptomatic hemorrhage. Two patients had substantial improvement and received cardiac transplantations. CONCLUSIONS: Neuroendovascular intervention is safe and feasible in patients with LVAD and may potentially contribute to improving the outcome of a disease that has a poor natural history. Further study is recommended. PMID- 26739904 TI - In-Hospital Mortality and Complication Rates in Surgically and Conservatively Treated Patients with Spontaneous Intracerebral Hemorrhage in Central Europe: A Population-Based Study. AB - OBJECTIVE: Secondary complications (SC) after intracerebral hemorrhage (ICH) can worsen outcome and are associated with early death. The purpose of the present study was to determine in-hospital mortality rates and SC after spontaneous ICH during acute care stay in a population-based cohort in central Europe. METHODS: A prospective database of the State of Hesse, Germany, was screened for all patients with the primary diagnosis of spontaneous ICH (International statistical classification-10: I61.0-I61.9) between January 2007 and December 2012. RESULTS: In the examined time period 10,029 patients with spontaneous ICH were identified. The cumulative rate of SC was 39.9% (1, 2, or >=3 SC were documented in 25.0%, 10.1%, and 4.7%, respectively). The most common SC were pneumonia (15.1%), brain edema (6.5%), cardiac decompensation (5.9%), urogenital infection (5.5%), hydrocephalus (4.6%), epilepsy (3.4%), and rebleeding (3.4%). One, 2, or >=3 SC were found in 2512 patients (25.0%), 1012 (10.1%), 473 (4.7%) patients, respectively. One SC was only a predictor of in-hospital mortality in conservatively treated patients (odds ratio [OR], 1.3; 95% confidence interval [CI] 1.2-1.5, P< 0.001). With an accumulation of SC to >=3 the chance of in hospital death increases for surgically (OR, 3.7, 95% CI 2.3-5.9; P< 0.001) and conservatively (OR, 3.0, 95% CI 2.3-3.9; P< 0.001) treated patients. CONCLUSIONS: Surgical treatment of hematomas is associated with an increased rate of SC, but not with higher mortality rates compared with conservatively treated patients. The prevention of an accumulation of SC could lead to a decrease of in-hospital mortality after spontaneous ICH. PMID- 26739905 TI - Surgical Outcomes of the Ossification of the Posterior Longitudinal Ligament According to the Involvement of the C2 Segment. AB - OBJECTIVE: The complex structure around the upper cervical spine makes surgical treatment difficult. the present study aimed to analyze how patients with ossification of the longitudinal ligament (OPLL) involving the C2 were managed and to compare the surgical outcomes according to the C2 involvement. METHODS: Ninety-five patients with cervical OPLL who underwent surgical treatment were divided into C2 involvement (C2+ group, 40 patients) or none (C2- group, 55 patients). In the C2+ group, subanalysis was conducted to according to the C2 surgery (C2 surgery+ group, 14 patients). RESULTS: All patients had a minimum of 1 year of follow-up with a mean of 51.36 months. The most common location of the narrowest space available for the spinal cord was C2 and C5 in the C2+ and C2- groups, respectively. In the C2+ group, a longer OPLL with thickened diameter was radiographically demonstrated, but clinical outcomes were not different from the C2- group. In the C2 surgery+ group, the narrowest spinal cord was common in the C2 (50.0%), and an extension of the signal change of spinal cord to the C2 was observed in 4 patients, showing a statistical difference. C2 surgery was performed in all patients using the posterior approach and it did not result in different clinical outcomes or surgery-related complications. An anterior surgical approach was deemed risky given the chance of the development of complications. CONCLUSIONS: Both of C2 involvement from OPLL and surgery including the C2 did not affect clinical outcomes. The posterior decompressive surgery is safer and more effective than the anterior approach regarding the development of surgery-related complications. PMID- 26739906 TI - Presentation of Cerebral Arteriovenous Malformations. PMID- 26739907 TI - Steroid Therapy for Spinal Cord Trauma: Where's the Evidence? PMID- 26739908 TI - [Democracy, compromise and consensus in collective movements of baboons]. PMID- 26739909 TI - Erratum: A biomimetic hybrid nanoplatform for encapsulation and precisely controlled delivery of theranostic agents. PMID- 26739910 TI - Reverse Genetics in Zebrafish: Mutants, Morphants, and Moving Forward. AB - Gene editing in zebrafish has begun to reveal discordance between mutant phenotypes and those associated with knockdown via morpholino oligonucleotides (MOs). These studies suggest that MOs should not be used as a standalone tool and underscore the need for guidelines that require defined mutants to assess gene function in zebrafish. PMID- 26739911 TI - Septic arthritis by Streptococcus equi. PMID- 26739912 TI - Development, validation and application of an ultra high performance liquid chromatographic-tandem mass spectrometric method for the simultaneous detection and quantification of five different classes of veterinary antibiotics in swine manure. AB - In this study, a fast, simple and selective ultra high performance liquid chromatographic-tandem mass spectrometric (UHPLC-MS/MS) method for the simultaneous detection and quantification of colistin, sulfadiazine, trimethoprim, doxycycline, oxytetracycline and ceftiofur and for the detection of tylosin A in swine manure was developed and validated. First, a simple extraction procedure with acetonitrile and 6% trichloroacetic acid was carried out. Second, the supernatant was evaporated and the pellet was reconstituted in 1 ml of water/acetonitrile (80/20) and 0.1% formic acid. Extracts were filtered and analyzed by UHPLC-MS/MS on a Kinetex C18 column using gradient elution. The method developed was validated according to the criteria of Commission Decision 2002/657/EC. Recovery percentages varied between 94% and 106%, repeatability percentages were within the range of 1.7-9.2% and the intralaboratory reproducibility varied between 2.8% and 9.3% for all compounds, except for tylosin A for which more variation was observed resulting in a higher measurement uncertainty. The limit of detection and limit of quantification varied between 1.1 and 20.2 and between 3.5 and 67.3 MUg/kg, respectively. This method was used to determine the presence and concentration of the seven antibiotic residues in swine manure sampled from ten different manure pits on farms where the selected antibiotics were used. A link was found between the antibiotics used and detected, except for ceftiofur which is injected at low doses and degraded readily in swine manure and was therefore not recovered in any of the samples. To the best of our knowledge, this is the first method available for the simultaneous extraction and quantification of colistin with other antibiotic classes. Additionally, colistin was never extracted from swine manure before. Another innovative aspect of this method is the simultaneous detection and quantification of five different classes of antibiotic residues in swine manure. PMID- 26739913 TI - A capillary electrophoretic-mass spectrometric method for the assessment of octreotide stability under stress conditions. AB - A capillary zone electrophoretic-electrospray ion trap mass spectrometric method has been developed to assess the stability and pathways of degradation of the cancer therapeutic octapeptide, octreotide. As a somatostatin analogue, octreotide contains a single disulphide bond linking Cys(2)-Cys(7) with the structure of NH2-D-Phe-[Formula: see text]-Thr-OH. Resolution of octreotide from its degradation products was achieved using a capillary zone electrophoretic method with bare fused silica capillaries, a 10mM ammonium formate buffer, pH 3.20, at 25 degrees C and an applied voltage of 25 kV. An ion trap low energy collision induced dissociation procedure was applied for the characterization of the chemical structures of the degradation products derived from an acidic, alkaline, neutral and thermal solution treatment of octreotide. The results so obtained indicated that linear octreotide degradation products were formed under acidic and alkaline conditions, due to the hydrolysis of a ring amide bond and a hitherto unknown desulfurization of the Cys-Cys disulfide bond, respectively. Degradation under neutral conditions occurred via cleavage of the exocyclic N ((2R,3R)-1,3-dihydroxybutan-2-yl) amide bond which also preceded the ring amide hydrolysis under acidic conditions. The developed method was further successfully applied to assess the kinetics of these octreotide degradations. Overall, this method is suitable for the rapid and precise assessment of the stability and quality control of octreotide as a synthetic peptide-based pharmaceutical product, and has led to the discovery of a new Cys-Cys disulfide degradation pathway. PMID- 26739914 TI - Editorial on "Sample normalization methods in quantitative metabolomics" by Yiman Wu and Liang Li. PMID- 26739915 TI - Improving washing strategies of human mesenchymal stem cells using negative mode expanded bed chromatography. AB - The use of human mesenchymal stem cells (hMSC) in clinical applications has been increasing over the last decade. However, to be applied in a clinical setting hMSC need to comply with specific requirements in terms of identity, potency and purity. This study reports the improvement of established tangential flow filtration (TFF)-based washing strategies, further increasing hMSC purity, using negative mode expanded bed adsorption (EBA) chromatography with a new multimodal prototype matrix based on core-shell bead technology. The matrix was characterized and a stable, expanded bed could be obtained using standard equipment adapted from what is used for conventional packed bed chromatography processes. The effect of different expansion rates on cell recovery yield and protein removal capacity was assessed. The best trade-off between cell recovery (89%) and protein clearance (67%) was achieved using an intermediate expansion bed rate (1.4). Furthermore, we also showed that EBA chromatography can be efficiently integrated on the already established process for the downstream processing (DSP) of hMSC, where it improved the washing efficiency more than 10 fold, recovering approximately 70% of cells after global processing. This strategy showed not to impact cell viability (>95%), neither hMSC's characteristics in terms of morphology, immunophenotype, proliferation, adhesion capacity and multipotent differentiation potential. PMID- 26739916 TI - Simultaneous determination of alpha-, beta- and gamma-hexabromocyclododecane diastereoisomers in water samples by isotope dilution mass spectrometry using (81)Br-labeled analogs. AB - This work describes the synthesis, characterization and application of three (81)Br-labeled diastereosiomers of hexabromocyclododecane (HBCD) for the accurate and precise determination of alpha-, beta- and gamma-HBCD in water samples by isotope dilution mass spectrometry. The synthesis of the labeled analogs was carried out by bromination of cis, trans, trans-1,5,9-cyclododecatriene with (81)Br-enriched bromine. After isolation and purification by semipreparative HPLC, each diastereoisomer was characterized in terms of concentration and isotopic enrichment. Then, they were added to the samples to simultaneously quantify the three HBCD diastereoisomers in a single LC-MS/MS injection without resorting to a methodological calibration graph. The results obtained here demonstrate that the use of (81)Br-labeled analogs provides accurate and precise determinations of alpha-, beta- and gamma-HBCD in real water samples. The limits of quantification obtained in real samples for alpha-, beta- and gamma-HBCD were 0.022, 0.073 and 0.015 ng L(-1), respectively, significantly lower than those required by the European Directive 2013/39/EC. PMID- 26739917 TI - Habituation of visual adaptation. AB - Our sensory system adjusts its function driven by both shorter-term (e.g. adaptation) and longer-term (e.g. learning) experiences. Most past adaptation literature focuses on short-term adaptation. Only recently researchers have begun to investigate how adaptation changes over a span of days. This question is important, since in real life many environmental changes stretch over multiple days or longer. However, the answer to the question remains largely unclear. Here we addressed this issue by tracking perceptual bias (also known as aftereffect) induced by motion or contrast adaptation across multiple daily adaptation sessions. Aftereffects were measured every day after adaptation, which corresponded to the degree of adaptation on each day. For passively viewed adapters, repeated adaptation attenuated aftereffects. Once adapters were presented with an attentional task, aftereffects could either reduce for easy tasks, or initially show an increase followed by a later decrease for demanding tasks. Quantitative analysis of the decay rates in contrast adaptation showed that repeated exposure of the adapter appeared to be equivalent to adaptation to a weaker stimulus. These results suggest that both attention and a non attentional habituation-like mechanism jointly determine how adaptation develops across multiple daily sessions. PMID- 26739918 TI - [Assessment of perception about medication reconciliation among healthcare professionals at Saint-Justine hospital]. AB - OBJECTIVES: Our main objective is to assess nurses and doctors perception about medication reconciliation. METHODS: This is a descriptive and cross-sectional study. We have created three surveys, one for each health worker (nurses, doctors, resident, pharmacists). Each survey consists of single or multi-choice closed questions. A four-point Likert scale was used to collect the perception. Descriptive statistics have been calculated. RESULTS: A total of 114 nurses, 98 doctors and residents and 26 pharmacists from all care services, replied to the survey. The majority of doctors (58%), pharmacists (60%) and nurses (52%) recognized the relevance and utility of medication reconciliation in healthcare safety. However, few healthcare professionals (6% of doctors, 13% of nurses et 46% of pharmacists) know that medication reconciliation is a required organizational practice. Only 25% of doctors always consult the best possible medication history after a patient admission while the majority do not use it because of unreliability issues. So, there have been some major changes to optimize medication reconciliation process in our hospital. CONCLUSION: This study shows a increasing interest to medication reconciliation by healthcare professionals. However, the use of medication reconciliation remains marginal. PMID- 26739922 TI - Multilocus resolution of Mugilidae phylogeny (Teleostei: Mugiliformes): Implications for the family's taxonomy. AB - The interrelationships among mugilids (Mugiliformes: Mugilidae) remain highly debated. Using a mitochondrial gene-based phylogeny as criterion, a revised classification with 25 genera in the Mugilidae has recently been proposed. However, phylogenetic relationships of major mitochondrial lineages remain unresolved and to gain a general acceptance the classification requires confirmation based on multilocus evidence and diagnostic morphological characters. Here, we construct a species-tree using twelve nuclear and three mitochondrial loci and infer the evolution of 71 morphological characters. Our multilocus phylogeny does not agree with previous morphology-based hypotheses for the relationships within Mugilidae, confirms the revised classification with 25 genera and further resolves their phylogenetic relationships. Using the well resolved multilocus phylogeny as the criterion, we reclassify Mugilidae genera into three new subfamilies (Myxinae, Rhinomugilinae, and Cheloninae) and one new, recombined, subfamily (Mugilinae). The Rhinomugilinae subfamily is further divided into four tribes. The revised classification of Mugilidae is supported by morpho-anatomical synapomorphies or a combination of characters. These characters are used to erect a key to the subfamilies and genera. PMID- 26739921 TI - Deletion of collapsin response mediator protein 4 results in abnormal layer thickness and elongation of mitral cell apical dendrites in the neonatal olfactory bulb. AB - Collapsin response mediator protein 4 (CRMP4), a member of the CRMP family, is involved in the pathogenesis of neurodevelopmental disorders such as schizophrenia and autism. Here, we first compared layer thickness of the olfactory bulb between wild-type (WT) and CRMP4-knockout (KO) mice. The mitral cell layer (MCL) was significantly thinner, whereas the external plexiform layer (EPL) was significantly thicker in CRMP4-KO mice at postnatal day 0 (PD0) compared with WTs. However, differences in layer thickness disappeared by PD14. No apoptotic cells were found in the MCL, and the number of mitral cells (MCs) identified with a specific marker (i.e. Tbx21 antibody) did not change in CRMP4 KO neonates. However, DiI-tracing showed that the length of mitral cell apical dendrites was greater in CRMP4-KO neonates than in WTs. In addition, expression of CRMP4 mRNA in WT mice was most abundant in the MCL at PD0 and decreased afterward. These results suggest that CRMP4 contributes to dendritic elongation. Our in vitro studies showed that deletion or knockdown of CRMP4 resulted in enhanced growth of MAP2-positive neurites, whereas overexpression of CRMP4 reduced their growth, suggesting a new role for CRMP4 as a suppressor of dendritic elongation. Overall, our data suggest that disruption of CRMP4 produces a temporary alteration in EPL thickness, which is constituted mainly of mitral cell apical dendrites, through the enhanced growth of these dendrites. PMID- 26739923 TI - Eastward colonization of the Mediterranean Basin by two geographically structured clades: The case of Odontites Ludw. (Orobanchaceae). AB - The biogeography of Mediterranean groups is very heterogeneous, because of the complex geologic and climatic history of the region. Our goal was to reconstruct the spatio-temporal history of the genus Odontites. In particular, we aimed to infer its area of origin and colonization routes, investigate its timing of diversification, and examine possible correlations with major environmental events. Based on sequencing of three chloroplast markers (psbA-trnH, trnL-trnF and trnC-ycf6), we reconstructed phylogenetic relationships among species. We performed molecular dating analyses (based on a large-scale rbcL dataset), ancestral areas reconstructions, and interpreted the observed patterns in the light of the complex geologic and climatic histories of the region. Our results suggested that Bartsiella and Bornmuellerantha should be reintegrated into Odontites s.l. The genus originated in the Iberian Peninsula ca. 18.9Ma and diverged into two main clades 16.2Ma, but species diversification was most intense <5-6Ma. The two clades showed a clear geographic pattern: one clade originated in the Iberian Peninsula and Morocco, and extended its range to Eastern North Africa and the central Mediterranean Basin; the other clade originated in Europe and Western Asia, and mostly diversified within this ancestral area. The eastward colonization of the Mediterranean Basin contrasts with many other plant groups. Nevertheless, the burst of diversification in the Plio-Pleistocene agrees with what has been reported for other groups, and is concomitant with the end of the Messinian Salinity Crisis, onset of the Mediterranean climate and Quaternary glaciations. The link between phylogeny and geography suggests limited dispersal, and most dispersal events may have occurred overland rather than overseas. PMID- 26739924 TI - Investigation of traditional medicinal floral knowledge of Sarban Hills, Abbottabad, KP, Pakistan. AB - ETHNO PHARMACOLOGICAL RELEVANCE: Ethno medicinal traditional knowledge regarding the uses of indigenous medicinal plants for treating various human infectious diseases is totally in hold of the elder community members. The young generation is not much aware about such vital traditional medicinal practices. AIM OF STUDY: To document, accumulate and widely disseminate the massive indigenous knowledge of century's practiced therapeutic uses of medicinal plants by the local people living in this area. MATERIALS AND METHODS: A total of 134 local inhabitants (78 male and 56 female) were interviewed through questionnaire method. The data obtained were quantitatively analyzed through the use value, fidelity level index and relative frequency citation. Plants specimen were preserved and mounted on herbarium sheets and labeled, cataloged and deposited with voucher numbers in Hazara University Herbarium, Mansehra, Pakistan (HUP). RESULTS: 74 plant species belonging to 70 genera and 42 families were documented in the current study. These medicinal plant species are used commonly as an ethno medicine against 56 various diseases such as digestive disorder, cough, pain and skin diseases etc. Herbaceous plant species were the dominant among plants studied which were 57% of the total plants, followed by shrubs (23%) and trees (20%). Asteraceae was the leading family among collected medicinal plant species (10.81%). Maximum medicinal plant species were used for treatment of digestive disorders (9.09%) and cough (7.44%). Most widely part used is leaf (27.9%), followed by fruit (13.5%) and seed (13.5%) for the treatment of different ailments by the traditional healers. The medicinal plant species with greater use values were Berberis lycium (0.91) and Cannabis sativa (0.81). The medicinal plant species with maximum fidelity level were Ziziphus jujuba (100%) and Lonicera caprifolium (92.31%) whereas the medicinal with most relative frequency citation were B. lycium (0.313), Ziziphus nummularia (0.276). The comparative result reveals that 36% of medicinal plant species were reported for the first time from Abbottabad regarding their uses, whereas 26% of plant species were reported with different medicinal uses. Brugmansia suaveolens and Allium griffithianum were recorded for the first time from Pakistan as well as from other countries across the globe for currently reported medicinal uses. CONCLUSION: The current study revealed the importance to document and launch list of all possible plants that are used in ethno medicinal practices in the study area. Future antimicrobial, antivirals, and pharmacological studies are required to ratify the efficacy and safety of the medicinal plants species. PMID- 26739925 TI - Xerostomia among older home care clients. AB - OBJECTIVES: The purpose of this study was to examine drug use and other factors associated with xerostomia in home care clients aged 75 years or older. METHODS: The study sample included 270 home care clients aged >=75 years living in Eastern and Central Finland. The home care clients underwent in-home interviews carried out by trained home care nurses, nutritionists, dental hygienists and pharmacists. The collected data contained information on sociodemographic factors, health and oral health status, drug use, depressive symptoms (GDS-15), cognitive functioning (MMSE), functional ability (Barthel Index, IADL) and nutrition (MNA). The primary outcome was xerostomia status (never, occasionally or continuously). RESULTS: Among the home care clients, 56% (n = 150) suffered from xerostomia. Persons with continuous xerostomia used more drugs and had more depressive symptoms and a higher number of comorbidities than other home care clients. In multivariate analyses, excessive polypharmacy (OR = 1.83, 95% Cl 1.08 3.10) and depressive symptoms (OR = 1.12, 95% Cl 1.03-1.22) were associated with xerostomia. CONCLUSIONS: Xerostomia is a common problem among old home care clients. Excessive polypharmacy, use of particular drug groups and depressive symptoms were associated with xerostomia. The findings support the importance of a multidisciplinary approach in the care of older home care clients. PMID- 26739927 TI - Reply to Comment on: Treatment of EBV-Associated Nodular Sclerosing Hodgkin Lymphoma in a Patient With Ataxia Telangiectasia With Brentuximab Vedotin and Reduced COPP Plus Rituximab. PMID- 26739928 TI - It's You, the School Nurse. PMID- 26739929 TI - The Making of a Clinical Resource Journal. PMID- 26739930 TI - Epinephrine Policies and Protocols Guidance for Schools: Equipping School Nurses to Save Lives. AB - In response to limited direction given by legislative bodies to school nurses about how to implement state-mandated or recommended stock epinephrine programs in their schools, NASN convened a workgroup of invested stakeholders. This workgroup was challenged to equip school nurses with the necessary tools to develop policies and protocols regarding stock epinephrine in their school districts. The dynamic workgroup subcommittees focused on policies, procedures, and reporting tools. This article reviews the results of the subcommittees' work and the overall collaboration within the workgroup. This article provides clear, nationally recognized guidance on the best practice for establishing stock epinephrine policies and protocols with reporting tools at the local school district level. PMID- 26739931 TI - Psychosocial Aspects of Obesity. AB - This article is the sixth in a series of the comorbidities of childhood obesity and reviews psychosocial aspects with a focus on weight-based victimization and discrimination stemming from weight bias and stigma. Outcomes from these bullying and discriminatory experiences are pervasive and impact youth across all settings, including school. Lastly, this article provides recommendations on how to reduce bias and stigma to better serve these students in the school environment. PMID- 26739932 TI - What's Up With "Step Up"? Step Up and Be Counted: The National Uniform School Nurse Data Set. AB - The health and well-being of children who attend school is not collected in any national data sets. To effectively advocate for the health needs of children where they live, learn, and play, it is essential to build a National Uniform School Nurse Data Set. In 2014, school nurses nationwide were invited to join the Step Up and Be Counted! initiative. To prepare nurses for data collection and reporting, an informational website was established, a marketing campaign was launched, and a data collection tool was developed. Trainings were held at the national conferences of both the National Association of School Nurses and the National Association of State School Nurse Consultants, and locally by state school nurse consultants and champions. The goal of the 2014-2015 academic year was to establish the processes for such a large-scale effort. In Year 1, only three initial data sets were collected from participating school nurses from 37 states. The first year yielded much data, and challenges have been identified and addressed. PMID- 26739933 TI - Motivational Interviewing: A Practical Intervention for School Nurses to Engage in Trauma Informed Care. AB - This article provides an overview of motivational interviewing (MI) as an effective intervention for trauma informed care. It offers a description of trauma and its most commonly associated negative side effects in the school setting. Within this context, basic theoretical concepts of MI are discussed. The article closes by examining the need for future research regarding MI as an effective, school-based intervention for adolescents. PMID- 26739934 TI - Framework for 21st Century School Nursing Practice: National Association of School Nurses. AB - The National Association of School Nurses (NASN) developed the Framework for 21st Century School Nursing Practice to reflect current school nurse practice. The Framework of practice was introduced in June 2015, and feedback was requested and obtained from practicing school nurses in a variety of ways. The final version of the Framework is introduced in this article. This article updates (and replaces) the articles in the July 2015 NASN School Nurse related to the Framework. Central to the Framework is student-centered nursing care that occurs within the context of the students' family and school community. Surrounding the student, family, and school community are the nonhierarchical, overlapping key principles of Care Coordination, Leadership, Quality Improvement, and Community/Public Health.These principles are surrounded by the fifth principle, Standards of Practice, which is foundational for evidence-based and clinically competent quality care. Each of these principles is further defined by practice components. Suggestions are provided regarding how the Framework can be used in a variety of settings to articulate and prioritize school nursing practice. The ultimate goal is to provide a resource to guide school nurses in their practice to help students be healthy, safe, and ready to learn. PMID- 26739936 TI - Corrigendum. AB - Jakubowski, T.L., Perron, T.J., and Teixeira, E. (2015). Rashes in school: Can they stay, or should they go? NASN School Nurse, 30(5): 274-282. (Original DOI: 10.1177/1942602X15596815)In the September 2015 issue of NASN School Nurse, the images for Lyme Disease and Spider bites were reversed. The correct order appears below.spnas;31/1/61/TABLE11942602X15621761T1table1-1942602X15621761Table 5.Bites/Stings in ChildrenDiagnosis(Bites, Stings, cutaneous infestations)Rash DescriptionSigns and SymptomsStay in School or Go Home?PhotoLyme Disease (Borrelia burgdorferi)Transmitted by deer tickErythema rash when present, "Bull's eye rash" distinct red borders with central clearing.Rash at site of bite but can have multiple rashesFever, joint pain, malaise, headache, single swollen joint usually knee usually accompany the rash.Not Contagious: Can stay at school.Incubation: 1-32 days median is 11 days. PREVALENCE: April through October with more than 50% of the cases presenting in June and July.Rocky Mountain Spotted Fever (RMSF) Rickettial infection transmitted by wood ticks.Characteristic spotted rash, maculopapular and sometimes petechial rash.Triad of fever, rash, and history of tick exposure, headache, vomiting, sore throatNot Contagious: Can stay at school.Rash initially appears on wrists and ankles and spreads to trunk within hours. Palms of hands and soles of feet are also involved.Incubation: Average time frame one week. Can range 2-14 days. PREVALENCE: August through September highest prevalence.Scabies(Mites)Papules and burrows, excoriation secondary to scratching.Intense itching especially at night. Commonly seen between the fingers and toes.Is Contagious: Should go home.Skin-to skin contact. Mites can remain alive for > 2 days on clothing and bedding.Incubation: 4-6 weeksIf the child had it previously 1-4 days.*Can return to school with medical clearance.Bee stingsLocalized swelling, redness. If allergic can spread rapidly. Raised pink wheel.Pain, redness, swelling, hives if allergic, respiratory distress if highly allergic.Not Contagious: Can stay at school.Spider bitesLocalized redness, swelling, can spread if infection - cellulitis can occur.Pain, redness, swelling. Bites are commonly seen on thighs, buttocks and abdomen.Not Contagious: Can stay at school.Bed Bugs(Cimex Lectularius)Red itchy welts that appear in a row. Numerous bites appear as a red itchy wide spread rash. Often mistaken for mosquito bites.Red, itchy, swellingAppear on face neck and extremities, areas exposed during sleep.Not Contagious: Can stay at school.Incubation: Bites may not appear for several days after exposure.Flea BitesRed spots surrounded by reddened haloes.Red, itchy.Commonly seen on the feet and ankles.Not Contagious: Can stay at school. PMID- 26739937 TI - Design of a PKCdelta-specific small peptide as a theragnostic agent for glioblastoma. AB - Glioblastoma is an aggressive malignant brain tumor that starts in the brain or spine and frequently recurs after anticancer treatment. The development of an accurate diagnostic system combined with effective cancer therapy is essential to improve prognosis of glioma patients. Peptides, produced from phage display, are attractive biomolecules for glioma treatment because of their biostability, nontoxicity, and small size. In this study, we employed phage display methodology to screen for peptides that specifically recognize the target PKCdelta as a novel biomarker for glioma. The phage library screening yielded four different peptides displayed on phages with a 20- to 200-pM Kd value for the recombinant PKCdelta catalytic domain. Among these four phage peptides, we selected one to synthesize and tagged it with fluorescein isothiocyanate (FITC) based on the sequence of the PKCdelta-binding phage clone. The synthetic peptide showed a relative binding affinity for antibody and localization in the U373 glioma cell. The kinase activity of PKCdelta was inhibited by FITC-labeled peptide with an IC50 of 1.4 MUM in vitro. Consequently, the peptide found in this study might be a promising therapeutic agent against malignant brain tumor. PMID- 26739943 TI - Effect of different oxide thickness on the bending Young's modulus of SiO2@SiC nanowires. AB - The surface or sheath effect on core-shell nanowires plays an important role in the nanomechanical test. In the past few years, SiC nanowires have been synthesized using various methods with an uneven and uncontrollable amorphous silicon dioxide sheath. The bending Young's modulus of the SiC nanowires has scarcely been measured, and the effect of the oxide sheath has not been taken into account. In this paper, SiO2-coated SiC (SiO2@SiC) nanowires were synthesized using the chemical vapor deposition method, followed by thermal reduction. Scanning electron microscopy and transmission electron microscopy show that the SiO2@SiC nanowires in this paper have diameters ranging from 130 ~ 150 nm, with the average thickness of SiO2 layer approximately 14 nm. After different processing times with 1 mol/L NaOH, approximately 5 nm, 9 nm, 14 nm silicon dioxide layers were obtained. The results of the three-point-bending test show that the modulus of SiO2@SiC nanowires is found to clearly decrease with the increase in oxide thickness and the influence of the oxide sheath should not be ignored when the layer thickness is above 5 nm. Young's modulus of the SiO2@SiC nanowires calculated in this study by the core-shell structure model is in good agreement with the theoretical value. PMID- 26739938 TI - On the acquisition and analysis of microscale thermophoresis data. AB - A comprehensive understanding of the molecular mechanisms underpinning cellular functions is dependent on a detailed characterization of the energetics of macromolecular binding, often quantified by the equilibrium dissociation constant, KD. While many biophysical methods may be used to obtain KD, the focus of this report is a relatively new method called microscale thermophoresis (MST). In an MST experiment, a capillary tube filled with a solution containing a dye labeled solute is illuminated with an infrared laser, rapidly creating a temperature gradient. Molecules will migrate along this gradient, causing changes in the observed fluorescence. Because the net migration of the labeled molecules will depend on their liganded state, a binding curve as a function of ligand concentration can be constructed from MST data and analyzed to determine KD. Herein, simulations demonstrate the limits of KD that can be measured in current instrumentation. They also show that binding kinetics is a major concern in planning and executing MST experiments. Additionally, studies of two protein protein interactions illustrate challenges encountered in acquiring and analyzing MST data. Combined, these approaches indicate a set of best practices for performing and analyzing MST experiments. Software for rigorous data analysis is also introduced. PMID- 26739945 TI - Delayed restoration of maximum speech discrimination scores in patients with idiopathic sudden sensorineural hearing loss. AB - OBJECTIVE: To assess possible delayed recovery of the maximum speech discrimination score (SDS) when the audiometric threshold ceases to change. METHODS: We retrospectively examined 20 patients with idiopathic sudden sensorineural hearing loss (ISSNHL) (gender: 9 males and 11 females, age: 24-71 years). The findings of pure-tone average (PTA), maximum SDS, auditory brainstem responses (ABRs), and tinnitus handicap inventory (THI) were compared among the three periods of 1-3 months, 6-8 months, and 11-13 months after ISSNHL onset. RESULTS: No significant differences were noted in PTA, whereas an increase of greater than or equal to 10% in maximum SDS was recognized in 9 patients (45%) from the period of 1-3 months to the period of 11-13 months. Four of the 9 patients showed 20% or more recovery of maximum SDS. No significant differences were observed in the interpeak latency difference between waves I and V and the interaural latency difference of wave V in ABRs, whereas an improvement in the THI grade was recognized in 11 patients (55%) from the period of 1-3 months to the period of 11-13 months. CONCLUSION: The present study suggested the incidence of maximum SDS restoration over 1 year after ISSNHL onset. These findings may be because of the effects of auditory plasticity via the central auditory pathway. PMID- 26739946 TI - Immunohistochemical localization of alpha and beta adrenergic receptors in the human nasal turbinate. AB - OBJECTIVE: Adrenergic receptors (ARs) include four general types (alpha1, alpha2, beta1 and beta2), which are found in different target tissues. alpha-AR agonists are commonly used for decongestant therapy of upper airway diseases. In order to clarify the roles of AR subtypes in the upper airways, we investigated the localization of these receptors by immunohistochemistry. METHODS: Human turbinates were obtained after turbinectomy from 12 patients with nasal obstruction refractory to medical therapy. The specific cells expressing alpha- and beta-AR proteins were identified by immunostaining using an anti-human AR subtype-specific antibodies (alpha1A-, alpha1D-, alpha2C- and beta2-ARs) antibody. RESULTS: Immunohistochemical analysis revealed that immunoreactivities for alpha1D- and beta2-ARs were densely distributed in submucosal glands. In contrast, immunoreactivities for alpha1A- and 2C-ARs were densely distributed in vascular smooth muscle. CONCLUSION: Our results suggested that adrenergic receptor (AR) subtypes had different roles in upper airway diseases, such as allergic rhinitis and nonallergic rhinitis. PMID- 26739947 TI - Topical application of timolol decreases the severity and frequency of epistaxis in patients who have previously undergone nasal dermoplasty for hereditary hemorrhagic telangiectasia. AB - OBJECTIVE: Hereditary hemorrhagic telangiectasia (HHT) is widely known to cause bleeding that is difficult to control because of the associated vascular wall fragility. Although nasal dermoplasty results in decreased severity and frequency of nasal bleeding in patients with HHT, it does not eradicate epistaxis because this procedure cannot cover the entire nasal cavity. Residual bleeding warrants additional effective therapy. Preliminary reports on the use of beta-adrenergic blockers for treating epistaxis in patients with HHT encouraged us to examine their effects in HHT patients who had previously undergone nasal dermoplasty but still complained of epistaxis. METHODS: We performed a prospective topical timolol, a nonselective beta blocker, application study involving 12 HHT patients who had undergone nasal dermoplasty. The observation period lasted for 3 months. RESULTS: There was one improperly enrolled case in which timolol administration was discontinued. The mean score of bleeding intensity and that of bleeding frequency were markedly reduced after treatment. Two patients who had required transfusions before treatment did not need them afterward, and patients were generally satisfied with the treatment. CONCLUSION: Topical timolol application was effective in decreasing epistaxis. Although no adverse effects were observed in the properly selected patients, there are contraindications to timolol application that should be kept in mind when applying this treatment. PMID- 26739948 TI - Prognostic impact of salvage treatment on hearing recovery in patients with sudden sensorineural hearing loss refractory to systemic corticosteroids: A retrospective observational study. AB - OBJECTIVE: To determine the prognostic factors for hearing recovery in patients with sudden sensorineural hearing loss (SSHL) refractory to systemic corticosteroids following salvage treatment. METHODS: This is a retrospective observational study at nine tertiary referral hospitals. A total of 120 patients with sudden deafness refractory to systemic corticosteroids were enrolled. The patients were randomly assigned to receive topical application of recombinant human IGF-1 or intratympanic injection of dexamethasone as salvage treatment. Multiple regression analysis was performed to identify determinants of hearing recovery using pure tone audiometry results at 8 weeks after treatment. Clinical predictors that were evaluated included age, sex, pretreatment hearing level, presence of vertiginous symptoms, days to study entry from symptom onset and salvage treatment assignment (IGF-1 vs. dexamethasone). RESULTS: The linear regression model identified age (P=0.001), pretreatment hearing level (P<0.001), days to study entry from symptom onset (P=0.011) and treatment assignment (P=0.033) at 8 weeks after treatment as significant variables influencing the recovery of pure tone audiometry average thresholds. Younger age (<60 years), early initiation of salvage treatment and treatment with topical IGF-1 therapy had significant effects on hearing recovery. CONCLUSION: The results indicate that early initiation and choice of treatment modalities for salvage treatment may be important for the prognosis of patients with refractory SSHL. The positive effect of topical IGF-1 therapy on hearing recovery indicates its utility as salvage treatment. PMID- 26739949 TI - The value of insulin-like growth factor-1 receptor for predicting early glottic carcinoma response to radiotherapy. AB - OBJECTIVE: The optimal management of laryngeal carcinoma requires tumor treatment and preservation of laryngeal functions, such as swallowing and voice quality. Radiotherapy (RT) can fulfill both criteria, although it remains important to identify predictors of radioresistance and reduce unnecessary irradiation. Insulin-like growth factor-1 receptor (IGF-1R) is a transmembrane receptor that plays a key role in cancer development, although its prognostic value after RT remains unknown. We evaluated the predictive value of IGF-1R expression for RT response in patients with early glottic squamous cell carcinoma. METHODS: We retrospectively reviewed 43 patients with T1N0 and T2N0 glottic squamous cell carcinoma who were treated with RT alone. Biopsy specimens were stained using an anti-IGF-1R antibody, and we evaluated the relationships between IGF-1R expression and T classification or tumor recurrence. We also evaluated the loco regional control (LRC) rate and the prognostic value of various clinical factors. RESULTS: All cases achieved complete response after the initial RT, and 10 (23.3%) patients experienced local tumor recurrence. Twenty-five patients (58.1%) exhibited high IGF-1R expression, although the level of IGF-1R expression was not correlated with T classification. Local recurrence was observed in 36% (9/25) of patients with high IGF-1R expression and in only 5% (1/18) of patients with low IGF-1R expression (p<0.05). The 2-year LRC rate was 94.1% for the low IGF-1R expression group, compared to 49.8% for the high IGF-1R expression group (p=0.04). Anterior commissure involvement and IGF-1R expression were independent adverse factors for LRC. CONCLUSION: High IGF-1R expression was more common among patients with recurrent early glottic carcinoma, which suggests that there is a biological relationship between IGF-1R expression and RT response. Thus, IGF-1R may be a useful screening parameter for RT response in laryngeal carcinoma. PMID- 26739950 TI - 5-HT2C receptors in psychiatric disorders: A review. AB - 5-HT2Rs have a different genomic organization from other 5-HT2Rs. 5HT2CR undergoes post-transcriptional pre-mRNA editing generating diversity among RNA transcripts. Selective post-transcriptional editing could be involved in the pathophysiology of psychiatric disorders through impairment in G-protein interactions. Moreover, it may influence the therapeutic response to agents such as atypical antipsychotic drugs. Additionally, 5-HT2CR exhibits alternative splicing. Central serotonergic and dopaminergic systems interact to modulate normal and abnormal behaviors. Thus, 5HT2CR plays a crucial role in psychiatric disorders. 5HT2CR could be a relevant pharmacological target in the treatment of neuropsychiatric disorders. The development of drugs that specifically target 5 HT2C receptors will allow for better understanding of their involvement in the pathophysiology of psychiatric disorders including schizophrenia, anxiety, and depression. Among therapeutic means currently available, most drugs used to treat highly morbid psychiatric diseases interact at least partly with 5-HT2CRs. Pharmacologically, 5HT2CRs, have the ability to generate differentially distinct response signal transduction pathways depending on the type of 5HT2CR agonist. Although this receptor property has been clearly demonstrated, in vitro, the eventual beneficial impact of this property opens new perspectives in the development of agonists that could activate signal transduction pathways leading to better therapeutic efficiency with fewer adverse effects. PMID- 26739952 TI - Genotoxicity of Water Contaminants from the Basin of Lake Sevan, Armenia Evaluated by the Comet Assay in Gibel Carp (Carassius auratus gibelio) and Tradescantia Bioassays. AB - Combination of bioassays and chemical analysis was applied to determine the genotoxic/mutagenic contamination in four different sites of the basin of Lake Sevan in Armenia. Water genotoxicity was evaluated using the single cell gel electrophoresis technique (comet assay) in erythrocytes of gibel carp (Carassius auratus gibelio), Tradescantia micronucleus (Trad-MCN) and Tradescantia stamen hair mutation (Trad-SHM) assays. Significant inter-site differences in the levels of water genotoxicity according to fish and Trad-MCN bioassays have been revealed. Two groups of locations with lower (south-southwest of the village Shorzha and Peninsula of Lake Sevan) and higher (estuaries of Gavaraget and Dzknaget rivers) levels of water genotoxicity were distinguished. Correlation analysis support the hypothesis that the observed genetic alterations in fish and plant may be a manifestation of the effects of water contamination by nitrate ions, Si, Al, Fe, Mn and Cu. Increase of DNA damage in fish also correlated with content of total phosphorus. PMID- 26739953 TI - A decade of occupational accidents due to direct or indirect electrical contact in the primary, secondary and tertiary sectors in Spain (2003-2012). AB - Occupational accidents caused by electrical contact are a major concern worldwide due to their severe consequences. The study conducted is based on an analysis of the evolution of incidence rates and dependence between variables for 14,022 electrical accidents occurring in Spain between 2003 and 2012. The results show that electrical accidents as a whole are 3.6 times more likely to have severe consequences than the rest of the accidents in the country. This proportion is even nine times greater in the case of fatal accidents. They also confirm a significant relationship between the severity of this type of accidents and the economic sector in which they occur. On the other hand, there is a positive trend in the reduction of the incidence rate, especially in relation to direct contact, although unexpectedly the rate of accidents due to indirect contact is on the rise. Thus, preventing electrical occupational accidents requires efforts to guarantee adequate training adapted to the needs of workers in the various economic sectors. Furthermore, those responsible for safety should work to implement mechanisms to monitor and control compliance with efficient protective measures against electrical contact. PMID- 26739955 TI - Value-Based Assessment of New Medical Technologies: Towards a Robust Methodological Framework for the Application of Multiple Criteria Decision Analysis in the Context of Health Technology Assessment. AB - In recent years, multiple criteria decision analysis (MCDA) has emerged as a likely alternative to address shortcomings in health technology assessment (HTA) by offering a more holistic perspective to value assessment and acting as an alternative priority setting tool. In this paper, we argue that MCDA needs to subscribe to robust methodological processes related to the selection of objectives, criteria and attributes in order to be meaningful in the context of healthcare decision making and fulfil its role in value-based assessment (VBA). We propose a methodological process, based on multi-attribute value theory (MAVT) methods comprising five distinct phases, outline the stages involved in each phase and discuss their relevance in the HTA process. Importantly, criteria and attributes need to satisfy a set of desired properties, otherwise the outcome of the analysis can produce spurious results and misleading recommendations. Assuming the methodological process we propose is adhered to, the application of MCDA presents three very distinct advantages to decision makers in the context of HTA and VBA: first, it acts as an instrument for eliciting preferences on the performance of alternative options across a wider set of explicit criteria, leading to a more complete assessment of value; second, it allows the elicitation of preferences across the criteria themselves to reflect differences in their relative importance; and, third, the entire process of preference elicitation can be informed by direct stakeholder engagement, and can therefore reflect their own preferences. All features are fully transparent and facilitate decision making. PMID- 26739954 TI - Identification of two rare and novel large deletions in ITGB4 gene causing epidermolysis bullosa with pyloric atresia. AB - Epidermolysis bullosa with pyloric atresia (EB-PA) is a rare autosomal recessive hereditary disease with a variable prognosis from lethal to very mild. EB-PA is classified into Simplex form (EBS-PA: OMIM #612138) and Junctional form (JEB-PA: OMIM #226730), and it is caused by mutations in ITGA6, ITGB4 and PLEC genes. We report the analysis of six patients with EB-PA, including two dizygotic twins. Skin immunofluorescence epitope mapping was performed followed by PCR and direct sequencing of the ITGB4 gene. Two of the patients presented with non-lethal EB-PA associated with missense ITGB4 gene mutations. For the other four, early postnatal demise was associated with complete lack of beta4 integrin due to a variety of ITGB4 novel mutations (2 large deletions, 1 splice-site mutation and 3 missense mutations). One of the deletions spanned 278 bp, being one of the largest reported to date for this gene. Remarkably, we also found for the first time a founder effect for one novel mutation in the ITGB4 gene. We have identified 6 novel mutations in the ITGB4 gene to be added to the mutation database. Our results reveal genotype-phenotype correlations that contribute to the molecular understanding of this heterogeneous disease, a pivotal issue for prognosis and for the development of novel evidence-based therapeutic options for EB management. PMID- 26739956 TI - Economic Burden and Quality-of-Life Effects of Chronic Lymphocytic Leukemia: A Systematic Review of the Literature. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most prevalent type of leukemia in the Western hemisphere. The disease affects quality of life (QOL) and poses an economic burden on patients, payers, and society. The objective of this review was to quantify the economic burden and quality-of-life effects and identify the gaps that should be addressed by future research. METHODS: Free-text and subject heading searches in MEDLINE, EMBASE, the Cochrane Library, the University of York Centre for Reviews and Dissemination Database, and the Web of Science Core Collection database were conducted to identify observational and interventional studies reporting costs and/or quality-of-life effects published up to 2 October 2015. Studies were included irrespective of whether they were conducted prospectively or retrospectively. The focus population consisted of adult patients aged 18 years or older affected by any stage of CLL. Studies were included regardless of whether the underlying population was treated at baseline or not. Risk of bias was assessed using a quality checklist developed by the Effective Public Health Practice Project for (randomized) controlled trials, cohort studies, and cross-sectional studies. Economic evaluations were rated using a checklist developed by Stuhldreher et al. (Int J Eat Disord 45:476-91, 2012). RESULTS: From 2451 records identified, 27 studies were found to be eligible for inclusion. Studies were heterogeneous with respect to methodology, perspective, and data used. Annual direct costs per person ranged from US$4491 in Germany to US$43,913 in the USA. The share of costs attributable to drug treatment varied between 26.2 and 79 %. Indirect costs amounted to US$4208. Severity of disease was a predictor for quality of life, whereas differences by age and sex were mainly present in subdomains. Comparisons of treated and untreated populations resulted in an increase of quality of life in favor of treated populations in the long-term perspective. Differences between treatments were small. Consequently, cost effectiveness in decision-analytic models did not depend on whether quality of life or survival are used to describe the benefits of treatment. CONCLUSIONS: Although the quantity and the quality of health economic and quality-of-life evidence have substantially increased, there is still a need for studies that take a patient or societal perspective. Factors that influence costs and the quality of life of patients seem to be well established, while longitudinal lifetime cost studies at the population level are still scarce. PMID- 26739959 TI - The Gender Bender effect in Periodontal Immune Response. AB - BACKGROUND: The gender and sex of an individual is known to have a significant bearing on the immune system, responsible for protection against infections and disease. Contemporary evidence suggests there exists a sexual dimorphism in the hetero immune as well as autoimmune responses in human beings and females show stronger and more vigorous immune responses to antigenic stimulations, e.g infectious diseases and vaccination. The evidence supportive to gender based heterogeneity in immune responses specifically in context of periodontal disease, is mounting in contemporary literature. METHOD: A thorough and methodical search for related scientific publications have been accomplished by using different key words and terms like sex or gender based immune differences in periodontal disease, both by manual methods and on various electronic databases. Primary research articles, narrative and systematic reviews of good quality, relevant to the subject were included. RESULTS: The aggregate effects of the factors related to gender such as the steroid hormones as well as gene based differences in both sexes as supported by published literature are in line with the observed variation in susceptibility for chronic periodontitis in both genders , with males showing more risk for disease than women. CONCLUSION: Gender as a risk factor for periodontal disease needs to identified, its underlying mechanisms to contribute needs to be revealed, so that novel strategies for risk assessment, disease identification and individualized therapeutic approaches can be developed for optimized patient care. PMID- 26739957 TI - Cost Effectiveness of First-Line Oral Therapies for Pulmonary Arterial Hypertension: A Modelling Study. AB - BACKGROUND: In recent years, a significant number of costly oral therapies have become available for the treatment of pulmonary arterial hypertension (PAH). Funding decisions for these therapies requires weighing up their effectiveness and costs. OBJECTIVE: The aim of this study was to assess the cost effectiveness of monotherapy with oral PAH-specific therapies versus supportive care as initial therapy for patients with functional class (FC) II and III PAH in Canada. METHODS: A cost-utility analysis, from the perspective of a healthcare system and based on a Markov model, was designed to estimate the costs and quality-adjusted life-years (QALYs) associated with bosentan, ambrisentan, riociguat, tadalafil, sildenafil and supportive care for PAH in treatment-naive patients. Separate analyses were conducted for cohorts of patients commencing therapy at FC II and III PAH. Transition probabilities, based on the relative risk of improving and worsening in FC with treatment versus placebo, were derived from a recent network meta-analysis. Utility values and costs were obtained from published data and clinical expert opinion. Extensive sensitivity analyses were conducted. RESULTS: Analysis suggests that sildenafil is the most cost-effective therapy for PAH in patients with FC II or III. Sildenafil was both the least costly and most effective therapy, thereby dominating all other treatments. Tadalafil was also less costly and more effective than supportive care in FC II and III; however, sildenafil was dominant over tadalafil. Even given the uncertainty within the clinical inputs, the probabilistic sensitivity analysis showed that apart from sildenafil and tadalafil, the other PAH therapies had negligible probability of being the most cost effective. CONCLUSION: The results show that initiation of therapy with sildenafil is likely the most cost-effective strategy in PAH patients with either FC II or III disease. PMID- 26739960 TI - The effectiveness of interventions targeting the stigma of mental illness at the workplace: a systematic review. AB - BACKGROUND: The majority of people experiencing mental-health problems do not seek help, and the stigma of mental illness is considered a major barrier to seeking appropriate treatment. More targeted interventions (e.g. at the workplace) seem to be a promising and necessary supplement to public campaigns, but little is known about their effectiveness. The aim of this systematic review is to provide an overview of the evidence on the effectiveness of interventions targeting the stigma of mental illness at the workplace. METHODS: Sixteen studies were included after the literature review. The effectiveness of anti-stigma interventions at the workplace was assessed by examining changes in: (1) knowledge of mental disorders and their treatment and recognition of signs/symptoms of mental illness, (2) attitudes towards people with mental-health problems, and (3) supportive behavior. RESULTS: The results indicate that anti stigma interventions at the workplace can lead to improved employee knowledge and supportive behavior towards people with mental-health problems. The effects of interventions on employees' attitudes were mixed, but generally positive. The quality of evidence varied across studies. CONCLUSIONS: This highlights the need for more rigorous, higher-quality evaluations conducted with more diverse samples of the working population. Future research should explore to what extent changes in employees' knowledge, attitudes, and supportive behavior lead to affected individuals seeking help earlier. Such investigations are likely to inform important stakeholders about the potential benefits of current workplace anti stigma interventions and provide guidance for the development and implementation of effective future interventions. PMID- 26739961 TI - Form and Function of Exosome-Associated Long Non-coding RNAs in Cancer. AB - The recent discovery that long non-coding RNAs (lncRNAs) are functional and are not merely "transcriptional noise" has spawned an entirely new arena of investigation. LncRNAs have been found to be functional in the regulation of a wide variety of genes, including those involved in cancer. Studies have identified that lncRNAs play a role in the development and regulation of cancer and can also act as prognostic markers. Meanwhile, exosomes , which are extracellular particles generated endogenously by cells, have been observed to act as transport vesicles for a variety of biological components, particularly proteins and RNAs. This transportation of biological components has been shown to impact a variety of biological processes including the development of cancer. Collectively, these observations, along with those of several recent studies, suggest that lncRNAs and exosomes may function together to disseminate cell signals that alter and/or control local cellular microenvironments. This review will identify the various roles that lncRNAs and exosomes play in cancer development, as well as the possibility that exosomes may transfer functional lncRNAs between cells as a means of cell-to-cell communication. PMID- 26739962 TI - Heterologous biosynthesis of triterpenoid dammarenediol-II in engineered Escherichia coli. AB - OBJECTIVES: To achieve heterologous biosynthesis of dammarenediol-II, which is the precursor of dammarane-type tetracyclic ginsenosides, by reconstituting the 2,3-oxidosqualene-derived triterpenoid biosynthetic pathway in Escherichia coli. RESULTS: By the strategy of synthetic biology, dammarenediol-II biosynthetic pathway was reconstituted in E. coli by co-expression of squalene synthase (SS), squalene epoxidase (SE), NADPH-cytochrome P450 reductase (CPR) from Saccharomyces cerevisiae, and SE from Methylococcus capsulatus (McSE), NADPH-cytochrome P450 reductase (CPR) from Arabidopsis thaliana. Sequences of transmembrane domains were truncated if necessary in each of the genes. Different sources of SE/CPR combinations were tested, during which two CPRs were detected to be new reductase partners of McSE. When the gene encoding dammarenediol-II synthase was co expressed with the 2,3-oxidosqualene expression modules, dammarenediol-II was detected and the production was 8.63 mg l(-1) in E. coli under the shake-flask conditions. CONCLUSIONS: Two E. coli chassis for production of dammarenediol-II were established which could be potentially applied in other triterpenoid production in E. coli when different oxidosqualene cyclases (OSCs) introduced into the system. PMID- 26739963 TI - The Obesity Epidemic and Consequences for Rheumatoid Arthritis Care. AB - With the prevalence of obesity increasing dramatically worldwide over the past several decades, an increasing body of literature has examined the impact of obesity in the context of rheumatoid arthritis (RA). Epidemiologic studies suggest that obesity may be associated with a modestly increased risk for the development of RA, although these studies have shown conflicting results. Among patients with established RA, obesity has been observed to be associated with greater subjective measures of disease activity and poor treatment response, but also with a decreased risk of joint damage and lower mortality. A comprehensive evaluation of the influence of obesity on the measurement of disease, response to therapies, and long-term prognosis is critical in order to understand these observations. This review therefore focuses on recent observations, potential explanations for these findings, and implications for clinicians and investigators caring for and studying patients with RA. PMID- 26739964 TI - Extending the Time Window for Endovascular and Pharmacological Reperfusion. AB - Pharmacological and device-induced reperfusion therapies have demonstrated increasingly positive outcomes regarding both reperfusion efficacy and 90-day functional outcomes after acute ischemic stroke. However, presently, only a minority of patients are eligible for these treatments. Less than 10 % of all ischemic stroke patients receive intravenous thrombolysis in most centers and it has been projected that only approximately 7-15 % of ischemic stroke patients are eligible for acute endovascular intervention. Making these effective therapies safely available to a much larger number of patients is critical for expanding the benefits of acute ischemic stroke treatment. In this article, we summarize the key results from the clinical trials, challenges, and exciting novel opportunities to increase patient eligibility for these therapies as well as for better outcomes for stroke patients. PMID- 26739965 TI - [How does sleep deprivation during 24 hours on call duty affect the cognitive performance orthopaedic residents?]. AB - INTRODUCTION: Sleep deprivation is usually present in residents during their training program. The purpose of our study was to analyze the cognitive performance of a group of orthopaedic residents before and after 24 hours on call duty. METHODS: We include orthopaedic residents and their cognitive functions were evaluated by the following tests: Continuous Performance Test (CPT 2), Digit Spam (Version 5), 1 letter Fonologic Fluence y Pasat Test. All the tests were done after a sleeping period at home of at least 6 hours and after being on call (sleeping less than 3 hours). RESULTS: Nineteen residents were included in the study. The median age was 27 +/- 1.89 and 15 were male. The mean hours of sleeping at home was 6.5 (range 6-8) and after on call duty was 1.5 (range 0.5 3). Statistical difference were found in CPT 2 test en terms of correct answers (p=0.007), omissions (p=0.004) and perseverations (p=0.036). No significant differences were found in the other tests. CONCLUSION: Sleep deprivation after 24 hours on call duty affects cognitive performance of orthopaedic residents, increasing the number of errors and omissions. PMID- 26739967 TI - Saudi Medical Journal reforms 2015. PMID- 26739968 TI - Will the Eastern Mediterranean Region be the first to prevent all of folic acid preventable spina bifida and anencephaly? PMID- 26739966 TI - Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation. AB - BACKGROUND: Rasd1 is a member of the Ras family of monomeric G proteins that was first identified as a dexamethasone inducible gene in the pituitary corticotroph cell line AtT20. Using microarrays we previously identified increased Rasd1 mRNA expression in the rat supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus in response to increased plasma osmolality provoked by fluid deprivation and salt loading. RASD1 has been shown to inhibit adenylyl cyclase activity in vitro resulting in the inhibition of the cAMP-PKA-CREB signaling pathway. Therefore, we tested the hypothesis that RASD1 may inhibit cAMP stimulated gene expression in the brain. RESULTS: We show that Rasd1 is expressed in vasopressin neurons of the PVN and SON, within which mRNA levels are induced by hyperosmotic cues. Dexamethasone treatment of AtT20 cells decreased forskolin stimulation of c-Fos, Nr4a1 and phosphorylated CREB expression, effects that were mimicked by overexpression of Rasd1, and inhibited by knockdown of Rasd1. These effects were dependent upon isoprenylation, as both farnesyltransferase inhibitor FTI-277 and CAAX box deletion prevented Rasd1 inhibition of cAMP-induced gene expression. Injection of lentiviral vector into rat SON expressing Rasd1 diminished, whereas CAAX mutant increased, cAMP inducible genes in response to osmotic stress. CONCLUSIONS: We have identified two mechanisms of Rasd1 induction in the hypothalamus, one by elevated glucocorticoids in response to stress, and one in response to increased plasma osmolality resulting from osmotic stress. We propose that the abundance of RASD1 in vasopressin expressing neurons, based on its inhibitory actions on CREB phosphorylation, is an important mechanism for controlling the transcriptional responses to stressors in both the PVN and SON. These effects likely occur through modulation of cAMP-PKA-CREB signaling pathway in the brain. PMID- 26739970 TI - Kleine-Levin syndrome. Familial cases and comparison with sporadic cases. AB - OBJECTIVES: To highlight the occurrence of familial cases and addresses, whether familial Kleine-Levine syndrome (KLS) presents the same spectrum of disease, as that seen in sporadic KLS. METHODS: Between September and December 2014, reports of familial cases of KLS were identified by searching the Library of Congress, PubMed, and Web of Science databases restricted to the English language, with no restriction on date of publication. All cases were reviewed to identify familial cases consistent with current diagnostic criteria for sporadic KLS. RESULTS: Six reviews and 11 case reports describing cases of familial KLS were identified. In 17 of the 29 familial cases identified, sufficient clinical details were described to be confident that these cases were familial and consistent with the description of KLS in the International Classification of Sleep Disorders 3rd edition (ICSD-3), and recent detailed reviews of sporadic KLS. CONCLUSION: A significant number of familial cases of KLS have been described that are consistent with the ICSD-3 description of KLS, and indistinguishable from sporadic KLS. This suggests that study of familial KLS using modern genetic techniques may be useful in elucidating the pathogenesis of this rare condition. PMID- 26739969 TI - Assessment of the environmental and genetic factors influencing prevalence of metabolic syndrome in Saudi Arabia. AB - Metabolic syndrome (MS) is a combination of factors that increases the risk of cardiovascular atherosclerotic diseases including diabetes, obesity, dyslipidemia, and high blood pressure. Cardiovascular diseases are one of the leading causes of death in the adult Saudi population where the increase in cardiovascular-related mortality is augmented by the rise in the prevalence of MS. Metabolic syndrome is a multi-factorial disorder influenced by interactions between genetic and environmental components. This review aims to provide a comprehensive assessment of studied environmental and genetic factors explaining the prevalence of MS in the Kingdom of Saudi Arabia. Additionally, this review aims to illustrate factors related to the population genetics of Saudi Arabia, which might explain a proportion of the prevalence of MS. PMID- 26739971 TI - Low oxytocin and melatonin levels and their possible role in the diagnosis and prognosis in Iraqi autistic children. AB - OBJECTIVES: To test the possible association between oxytocin and melatonin levels with the severity of social and cognitive dysfunctions, and to study the correlation between these parameters in children with autism. METHODS: A case control study was carried out in the Department of Chemistry and Biochemistry, College of Medicine, Al-Nahrain University, Baghdad, Iraq. The study was performed on 60 male autistic patients recruited from the Pediatric Department of Al-Sader General Hospital, Baghdad, Iraq between November 2014 and April 2015. The levels of oxytocin and melatonin were measured in the serum of these autistic male patients, and categorized as mild, moderate, and severe (20 patients each), and was compared with 26 age- and gender-matched control subjects. RESULTS: The data indicated that the levels of oxytocin (44.72 +/- 36.1 MUIU/mL) and melatonin in patients (23.08 +/- 10.41 pg/mL) were significantly lower (p less than 0.05) than that of age-matched (102.1 +/- 34.31 MUIU/mL) and gender-matched controls (53.05 +/- 38.38 pg/mL). These parameters were remarkably associated with the severity of the disease that was indicated by the significant decrease in the levels of oxytocin (47 +/- 25.47 MUIU/mL) and melatonin in moderate (20 +/- 6.14 pg/mL), and patients with severe oxytocin (27.92 +/- 10.23 MUIU/mL) and patients with severe melatonin (21.69 +/- 7.02 pg/mL) when compared with mild autistic patients with oxytocin (59.22 +/- 27.32 MUIU/mL) and melatonin (27.55 +/- 14.71 pg/mL). These 2 parameters showed a significant positive correlation with each other in moderate (r=0.513; p=0.021), and severe patients (r=0.598; p=0.005). CONCLUSION: Receiver operating characteristic analysis revealed that oxytocin can be considered as a good diagnostic marker in severe autistic patients while melatonin can be considered as a good diagnostic marker in all autistic subgroups. This study proves the possibility of using oxytocin and melatonin in the diagnosis, and as markers of autism severity. PMID- 26739972 TI - Correlation between hormone receptor status and age, and its prognostic implications in breast cancer patients in Bahrain. AB - OBJECTIVES: To assess the correlation between hormone receptor status (HRS) and age, and its significance as a predictor of outcome in patients with breast cancer (BC). METHODS: This retrospective review was conducted on 109 patients diagnosed with BC at Salmaniya Medical Complex, Manama, Bahrain from 2010-2013. Patients were divided into 2 age groups; under and over 40 years, and were analyzed for tumor histology, lymph node status, stage, and HRS. RESULTS: Younger patients with BC were more likely to be of higher stage, grade, and of larger size. Older women were more likely to be estrogen receptor (ER) positive (72.6% versus 55.3%), and progesterone receptor (PR) positive (71% versus 53.2%) (p=0.03). The human epidermal growth factor receptor (HER)-2 over-expression was seen more in younger women (51% versus 40%) (p=0.2). Younger patients had higher lymph node metastases (88.6% versus 56.1%) (p=0.0004), and higher distant metastases (26.7% versus 6.8%) (p=0.005). The HER-2 over-expression strongly correlated with lymph node status. A total of 63.4% of lymph node positive patients had HER-2 over-expression compared with only 13.3% of lymph node negative patients (p less than 0.00001). CONCLUSION: Breast cancer is more aggressive and advanced in younger women, a fact that can be significantly attributed to under expression of ER and PR, and over expression of HER-2, which also correlates well with lymph node status, as a measure of aggressiveness. Further studies should evaluate the genetic profile of BC in such population to improve their outcomes. PMID- 26739973 TI - Association of doripenem resistance with OXA-type carbapenemases in Acinetobacter baumannii isolates. AB - OBJECTIVES: To evaluate the in vitro activity of doripenem in Acinetobacter baumannii (A. baumannii) clinical isolates that possess different OXA-type carbapenemases, and to evaluate the roles of these enzymes in the development of carbapenem resistance. METHODS: This retrospective study was conducted with 25 A. baumannii isolates at Sakarya University Training and Research Hospital, Sakarya, Turkey from June to October 2014. Antibiotic susceptibility testing was carried out using the Vitek-2 automated system (bioMerieux, Marcy l'Etoile, France). Minimum inhibitory concentrations (MICs) were determined using Etest strips (bioMerieux, Marcy l'Etoile, France). Quantitative polymerase chain reaction was performed in a Fluorion Instrument (Iontek, Istanbul, Turkey). RESULTS: Isolates were divided into 5 groups based on their susceptibility profiles and OXA-type carbapenemase positivity. Group 2 isolates whose MIC of both meropenem and doripenem are in the range of 4-32 ug/mL were negative for both blaOXA-23 and blaOXA-58. Group 3 isolates whose MIC of meropenem and doripenem is in the range of 4-32 ug/mL, blaOXA-23 is positive, and blaOXA-58 is negative. Group 5 isolates whose MIC of meropenem is more than 32 ug/mL, and that of doripenem is in the range of 16-32 ug/mL were positive for both blaOXA-23 and blaOXA-58. CONCLUSION: The blaOXA-23 and blaOXA-58 gene combinations may confer resistance with a much greater MIC of both meropenem and doripenem. But the blaOXA-58 presence alone was not correlated with doripenem resistance. PMID- 26739974 TI - Impaired secretion of glucagon-like peptide 1 during oral glucose tolerance test in patients with newly diagnosed type 2 diabetes mellitus. AB - OBJECTIVES: To assess glucagon-like peptide 1 (GLP-1) secretion after oral glucose tolerance tests (OGTTs) in subjects with newly diagnosed type 2 diabetes mellitus (T2DM), impaired glucose tolerance (IGT), and normal glucose tolerance (NGT) to clarify changes in GLP-1 secretion during the course of T2DM. METHODS: In this cross sectional study, 80 subjects were divided into the NGT, IGT, and T2DM groups after undergoing a 75 g OGTT from March to December 2014 at the School of Medicine, First Affiliated Hospital, Shihezi University, Xinjiang, China. Plasma total GLP-1 was measured at 0, 30, 60, 120, and 180 minutes. Homeostasis model assessment of insulin resistance (HOMA-IR), islet beta-cell function (HOMA-beta), Gutt index, Matsuda index, incremental GLP-1 (DeltaGLP-1), and areas under the curves of GLP-1 (AUCglp-1), glucose (AUCg), and insulin (AUCins) were calculated. RESULTS: Plasma total GLP-1 at 30-120 minutes and DeltaGLP-1 at 30-120 minutes were lower in the T2DM group than in the IGT and NGT groups (p less than 0.05). Peak GLP-1 levels were 35% lower in the T2DM group than in the NGT group. Plasma total GLP-1, DeltaGLP-1, and AUCglp-1 correlated negatively with HOMA-IR and AUCg, and positively with HOMA-beta, Gutt index, Matsuda index, and AUCins (p less than 0.05). CONCLUSION: The GLP-1 secretion after 75 g OGTT was impaired in newly diagnosed T2DM patients, inversely proportional to IR and hyperglycemia, and positively correlated with beta-cell function and insulin sensitivity. PMID- 26739975 TI - Comparison of efficacy of prophylactic ketamine and dexmedetomidine on postoperative bladder catheter-related discomfort. AB - OBJECTIVES: To compare the effects of prophylactic ketamine and dexmedetomidine on postoperative bladder catheter-related discomfort/pain in patients undergoing cystoscopy. METHODS: This prospective study was conducted on 75 American Society of Anesthesiologists (ASA) I-II patients between 18-75 years of age and undergoing cystoscopy between November 2011 and June 2012 at Hacettepe University Hospital, Ankara, Turkey. Patients were randomly assigned to one of the 3 groups to receive 1 MU/kg dexmedetomidine, 250 MU/kg intravenous ketamine, or normal saline. All patients were questioned regarding probe-related discomfort, patient satisfaction, and pain at the end of the operation 0 (t0) and 15 (t1), 60 (t2), 120 (t3), and 360 (t4) minutes postoperatively. Evaluations were performed in person at the post-anesthesia care unit, or in ambulatory surgery rooms, or by phone calls. RESULTS: Pain incidence in the dexmedetomidine and ketamine groups (p=0.042) was significantly lower than that in the control group (p=0.044).The sedation scores recorded at t0 in the dexmedetomidine and ketamine groups (p=0.004) were significantly higher than that of the control group (p=0.017).Patient groups were similar regarding the rate of hallucinations experienced at t1, no patients experienced hallucinations at t2, t3, or t4. Significantly more patients experienced hallucinations at t0 in the ketamine group than in the dexmedetomidine group (p=0.034) and the control group (p=0.005). CONCLUSION: Dexmedetomidine and ketamine had similar analgesic effects in preventing catheter-related pain; however, dexmedetomidine had a more acceptable side effect profile. To identify the optimal doses of dexmedetomidine and ketamine, more large-scale interventional studies are needed. PMID- 26739976 TI - Comparison of the effect of rocuronium dosing based on corrected or lean body weight on rapid sequence induction and neuromuscular blockade duration in obese female patients. AB - OBJECTIVES: To compare onset time, duration of action, and tracheal intubation conditions in obese patients when the intubation dose of rocuronium was based on corrected body weight (CBW) versus lean body weight (LBW) for rapid sequence induction. METHODS: This prospective study was carried out at Numune Education and Research Hospital, Ankara, Turkey between August 2013 and May 2014. Forty female obese patients scheduled for laparoscopic surgery under general anesthesia were randomized into 2 groups. Group CBW (n=20) received 1.2 mg/kg rocuronium based on CBW, and group LBW (n=20) received 1.2 mg/kg rocuronium based on LBW. Endotracheal intubation was performed 60 seconds after injection of muscle relaxant, and intubating conditions were evaluated. Neuromuscular transmission was monitored using acceleromyography of the adductor pollicis. Onset time, defined as time to depression of the twitch tension to 95% of its control value, and duration of action, defined as time to achieve one response to train-of-four stimulation (T1) were recorded. RESULTS: No significant differences were observed between the groups in intubation conditions or onset time (50-60 seconds median, 30-30 interquartile range [IQR]). Duration of action was significantly longer in the CBW group (60 minutes median, 12 IQR) than the LBW group (35 minutes median, 16 IQR; p less than 0.01). CONCLUSION: In obese patients, dosing of 1.2 mg/kg rocuronium based on LBW provides excellent or good tracheal intubating conditions within 60 seconds after administration and does not lead to prolonged duration of action. PMID- 26739977 TI - The effect of different types of abdominal binders on intra-abdominal pressure. AB - OBJECTIVES: To investigate the effect of non-elastic/elastic abdominal binders on intra-vesical pressure (IVP), physiological functions, and clinical outcomes in laparotomy patients at the perioperative stage. METHODS: This prospective study was conducted from May to October 2014 at the Trauma Surgery Department, Daping Hospital, Chongqing, China. Laparotomy patients were randomly divided into non elastic abdominal binder group (28 patients), and elastic abdominal binder group (29 patients). Binders were applied for 14 days following the operation, or until discharge. Demographic information, Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation II (APACHE-II) scores (prior to the operation, on the first day after operation, the day IVP measurement was stopped, and one day before discharge), and outcomes were recorded. The IVP was measured before the operation to postoperative day 7. RESULTS: There were no significant differences in the demographic information, outcomes, SOFA or APACHE II scores between the 2 groups. Initial out-of-bed mobilization occurred earlier in the elastic binder group (3.2 +/- 2.0 versus 5.0 +/- 3.7 days, p=0.028). A greater increase in IVP was observed in the non-elastic binder group than in the elastic binder group (2.9 +/- 1.1 versus 1.1 +/- 0.7 mm Hg, p=0.000). CONCLUSION: Elastic binders have relatively little effect on IVP and are more helpful at promoting postoperative recovery than non-elastic binders. Therefore, elastic binders are more suitable for clinical use. PMID- 26739978 TI - Validation of an Arabic version of Fatigue Severity Scale. AB - OBJECTIVES: To develop and test the psychometric properties of an Arabic version of Fatigue Severity Scale (FSS-Ar) that can be used to measure fatigue in Arabic patients with disorders where fatigue is a major symptom. METHODS: Forward and backward translations of FSS were undertaken to develop an Arabic version. The validity and reliability of the FSS-Ar was then tested on 28 patients with systemic lupus erythematosus (SLE), 24 patients with multiple sclerosis (MS), and 31 healthy subjects. Exploratory factor analysis and hypothesis testing methods were used to examine construct validity. The correlation between FSS-Ar and the vitality domain of the RAND 36-Item Health was examined to test construct validity. The study was conducted at the King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia between February and June 2012. RESULTS: Using a score of >=4.05 to define fatigue, 39 of 52 (75%) participants were fatigued compared with 10 out of 31 (32%) healthy participants. The correlation between the FSS-Ar and the vitality domain of the RAND-36 was acceptable (r = -0.46). Factor analysis showed that items of the FSS-Ar measured one underlying construct, namely, fatigue. Test-retest reliability and internal consistency of the FSS-Ar was acceptable (intraclass correlation coefficient model 2,1 = 0.80; Cronbach's alpha = 0.84). CONCLUSION: The Arabic version of the FSS demonstrated acceptable psychometric properties and was able to differentiate between patients with SLE or MS, and healthy subjects. PMID- 26739979 TI - The impact on bone tissues of immediate implant-supported mandibular overdentures with cusped and cuspless teeth. AB - OBJECTIVES: To examine the effects on bone tissues of immediate implant-supported mandibular overdentures with cusped or cuspless teeth. METHODS: A randomized controlled trial was conducted at the Dental Clinic, Faculty of Dentistry, Al Azhar University, Assiut Branch, Egypt, over a 12-month period from September 2013 to September 2014. Twenty patients were treated with immediate implant supported overdentures: one group received overdentures with cusped teeth, and the other group received overdentures with cuspless teeth. The rate of implant success was assessed clinically and radiographically at 3, 6, 9, and 12 months. The data were collected by a questionnaire, an observation checklist, and radiography. The data were then analyzed using computerized methods. RESULTS: Overdentures with cusped teeth showed a significant improvement in the clinical criteria, including the absence of clinical implant mobility, pain, and bone resorption, while the clinical criteria for the absence of peri-implant radiolucency were insignificantly different between the 2 groups (p more than 0.05). There were no significant differences in the clinical evaluations for bone levels at the time of insertion or 3 months after insertions, while significant differences were found at 6, 9, and 12 months after insertion. CONCLUSION: Overdentures with cusped teeth supported by immediate implants were found superior regarding many clinical criteria than those cuspless counterparts. PMID- 26739980 TI - Failure rate of inferior alveolar nerve block among dental students and interns. AB - OBJECTIVES: To report the failure rate of inferior alveolar nerve block (IANB) among dental students and interns, causes of failure, investigate awareness of different IANB techniques, and to report IANB-associated complications. METHODS: A 3-page questionnaire containing 13 questions was distributed to a random sample of 350 third to fifth years students and interns at the College of Dentistry, King Saud University, Riyadh, Saudi Arabia on January 2011. It included demographic questions (age, gender, and academic level) and questions on IANB failure frequency and reasons, actions taken to overcome the failure, and awareness of different anesthetic techniques, supplementary techniques, and complications. RESULTS: Of the 250 distributed questionnaires, 238 were returned (68% response rate). Most (85.7%) of surveyed sample had experienced IANB failure once or twice. The participants attributed the failures most commonly (66.45%) to anatomical variations. The most common alternative technique used was intraligamentary injection (57.1%), although 42.8% of the sample never attempted any alternatives. Large portion of the samples stated that they either lacked both knowledge of and training for other techniques (44.9%), or that they had knowledge of them but not enough training to perform them (45.8%). CONCLUSION: To decrease IANB failure rates for dental students and interns, knowledge of landmarks, anatomical variation and their training in alternatives to IANB, such as the Gow-Gates and Akinosi techniques, both theoretically and clinically in the dental curriculum should be enhanced. PMID- 26739981 TI - Cardiac lymphangioma presenting as intrapericardial cystic mass. AB - Cystic lymphangioma usually confined to head and neck is a well-recognized tumor that occurs during childhood. However, a cardiac lymphangioma is exceptionally uncommon and a particularly rare form of disease. We report a case of cystic lymphangioma arising from the right ventricular wall, and presenting as pericardial mass in a young female, who presented with a history of exercise intolerance in the form of breathlessness on exertion and palpitations. The management of such a case was a difficult task; however, she underwent near total resection of the mass, and is doing well for the last 2 years. PMID- 26739982 TI - Acute hepatitis C virus infection related to capillary blood glucose meter. AB - Hepatitis C virus (HCV) infects an estimated 130-150 million people worldwide, becoming the major cause of chronic liver disease, cirrhosis, hepatocellular carcinoma, and liver transplantation. There are various preventable modes of transmission of HCV infection, including needlestick and sharps injuries. However, HCV infection secondary to needlestick injury by a capillary blood glucose meter (CBGM) lancet has not been previously well reported. We describe an unusual case of a 25-year-old male medical student, acquiring acute HCV infection with a lancing device of CBGM. The source patient was a 54-year-old diabetic male with positive anti-HCV test results. In our patient, after 3 months of initial exposure, a standard set of investigations confirmed the diagnosis of acute HCV infection with the same genotype (3a) as the source. The CBGM, as in our case, may have a role in the transmission of HCV infection warranting radical advancements in diabetes screening and monitoring technology. PMID- 26739983 TI - Prevalence of intimate partner violence and its associated risk factors among Saudi female patients attending the primary healthcare centers in Western Saudi Arabia. AB - OBJECTIVES: To estimate the prevalence of intimate partner violence (IPV) among female patients, age 18-60 years, attending primary health care centers (PHCCs) and to measure its determinants, and reporting behavior. METHODS: A cross sectional study design using validated, translated, and self-administered questionnaire among 497 Saudi female patients attending PHCCs in Taif, Kingdom of Saudi Arabia (KSA) from January to February 2015 was employed. A 2-stage probability sampling was adopted for selection of PHCCs in the first stage, and then participants in the second stage. RESULTS: The estimated prevalence of IPV during the last year was 11.9%. Predictors of IPV related to abused women included divorced status and divorced parents; while those related to abusers (husbands) included widowed parents, exposure to violence in childhood, and alcohol or drugs addiction. Most of the abused wives (56%) talked regarding their IPV to their families, their husbands' families (15.2%), or their friends (11.8%); while only a minority (3.3%) complained to the police or to a judge, and no one reported this to a family physician, or to women protection agency. CONCLUSION: One out of 10 women is a victim of IPV in Taif, KSA. Intimate partner violence is significantly associated with a number of victims and abuser-related psychosocial factors, the detection of which might help screening for individuals at risk. PMID- 26739984 TI - Indomethacin for treatment of prolapsed amniotic sac "hourglass membranes" presented at late mid-trimester. PMID- 26739985 TI - Evaluation of health care services provided for older adults in primary health care centers and its internal environments. PMID- 26739986 TI - The association between the CC chemokine ligand 5-28>G and tuberculosis susceptibility. PMID- 26739987 TI - Non-target effects of pretilachlor on microbial properties in tropical rice soil. AB - The use of herbicides has been questioned in recent past for their non-target effects. Therefore, we planned to study the effect of pretilachlor on growth and activities of microbes in tropical rice soil under controlled condition at National Rice Research Institute, Cuttack, India. Three pretilachlor treatments, namely, recommended dose at 600 g a.i. ha(-1) (RD), double the recommended dose at 1200 g a.i. ha(-1) (2RD), and ten times of the recommended dose at 6000 g a.i. ha(-1) (10RD) along with control, were imposed. The initial residue (after 2 h of spray) deposits in soil were 0.174, 0.968, and 3.35 MUg g(-1) for recommended, double the recommended, and ten times of the recommended doses, respectively. No residue in soil was detected in RD treatment on day 45. The half life values were 16.90, 17.76, and 36.47 days for RD, 2RD, and 10RD treatments, respectively. Application of pretilachlor at 10RD, in general, had significantly reduced the number of bacteria, actinomycetes, fungi, nitrogen fixers, and microbial biomass carbon. Pretilachlor at RD did not record any significant changes in microbial properties compared to control. The results of the present study thus indicated that pretilachlor at RD can be safely used for controlling grassy weeds in rice fields. PMID- 26739988 TI - Monitoring cryptic amphibians and reptiles in a Florida state park. AB - We monitored cryptic herpetofauna at Savannas Preserve State Park, Florida, by combining artificial cover counts with a quantitative paradigm for constructing and calculating population indices. Weekly indices were calculated from two consecutive days of data collection each week for 7 months from mid-winter to mid summer in three habitats. Seventeen species were observed at least once, and time trends using index values were followed for six species. Among these, abundance and seasonal pattern information were obtained for an exotic species (greenhouse frog) and a species identified by the Florida Committee on Rare and Endangered Plants and Animals as threatened (Florida scrub lizard). We identified winter as the optimal time in this area to monitor populations for conducting annual assessments. This combined observation and indexing approach could provide managers or researchers with an economical means to quantitatively index population trends for multiple cryptic herpetofauna species simultaneously. Using artificial cover to sample within a population indexing design can be generalized beyond monitoring herpetofauna. Other forms of artificial cover that can be used as observation stations include aquatic artificial substrates, artificial tree cavities, artificial reefs, and other artificial aquatic structures and artificial sea grass units, among many others, and a wide range of taxa are suitable for population monitoring using artificial cover as observation stations in the approach we present, including insects, soil invertebrates, micro and macro aquatic invertebrates, fish, crustaceans, and small mammals. PMID- 26739989 TI - Spatial and temporal assessment of metal pollution in the sediments of the Qaraoun reservoir, Lebanon. AB - This study reports on metal (Cd, Cr, Cu, Ni, Pb, and Zn) pollution in the sediments of the Qaraoun reservoir over a span period of 9 years (2004, 2008, and 2013) along with key major environmental indicators. This time period corresponds with the onset of the rapid economic and industrial development of the reservoir region. For the first time, this study assessed the degree of environmental pollution by using indices such as enrichment factors (EF), contamination factors (CF), pollution load index (PLI), and geoaccumulation index (I geo). Moreover, sequential extraction was used to study the operationally determined chemical forms of the metals and their spatial and temporal distribution in the sediments. Correlation coefficients were also calculated to delineate the origin and association of the metals. Total metal concentrations and the environmental indices indicated increased pollution with time. Total organic carbon data showed a remarkable and significant increase in the organic fraction in 2013 relative to previous years. The increase in the organic fraction in the sediments was accompanied with a shift in cadmium [Cd] and lead [Pb] fractionation from the carbonate fraction to the organic fraction. The enrichment of the metal in the sediments along with the increased organic content is expected to exacerbate the metal bioavailability in the reservoir. PMID- 26739990 TI - Symbiotic relationship analysis of predominant bacteria in a lab-scale anammox UASB bioreactor. AB - In order to provide the comprehensive insight into the key microbial groups in anaerobic ammonium oxidation (anammox) process, high-throughput sequencing analysis has been used for the investigation of the bacterial communities of a lab-scale upflow anaerobic sludge bed (UASB) anammox bioreactor. Results revealed that 109 operational taxonomic units (OTUs; out of 14,820 reads) were identified and a domination of anammox bacteria of Candidatus Kuenenia stuttgartiensis (OTU474, 35.42 %), along with heterotrophs of Limnobacter sp. MED105 (OTU951, 14.98 %), Anerolinea thermophila UNI-1 (OTU465 and OTU833, 6.60 and 3.93 %), Azoarcus sp. B72 (OTU26, 9.47 %), and Ignavibacterium sp. JCM 16511 (OTU459, 8.33 %) were detected. Metabolic pathway analysis showed that Candidatus K. stuttgartiensis encountered gene defect in synthesizing a series of metabolic cofactors for growth, implying that K. stuttgartiensis is auxotrophic. Coincidentally, the other dominant species severally showed complete metabolic pathways with full set gene encoding to corresponding cofactors presented in the surrounding environment. Furthermore, it was likely that the survival of heterotrophs in the autotrophic system indicates the existence of a symbiotic and mutual relationship in anammox system. PMID- 26739991 TI - Integrative evaluation of data derived from biomonitoring and models indicating atmospheric deposition of heavy metals. AB - Atmospheric deposition of heavy metals (HM) can be determined by use of numeric models, technical devices and biomonitors. Mainly focussing on Germany, this paper aims at evaluating data from deposition modelling and biomonitoring programmes. The model LOTOS-EUROS (LE) yielded data on HM deposition at a spatial resolution of 25 km by 25 km throughout Europe. The European Monitoring and Evaluation Programme (EMEP) provided model calculations on 50 km by 50 km grids. Corresponding data on HM concentration in moss, leaves and needles and soil were derived from the European Moss Survey (EMS), the German Environmental Specimen Bank (ESB) and the International Co-operative Programme on Assessment and Monitoring of Air Pollution Effects on Forests (iCP Forests). The modelled HM deposition and respective concentrations in moss (EMS), leaves and needles (ESB, iCP Forests) and soil (iCP Forests) were investigated for their statistical relationships. Regression equations were applied on geostatistical surface estimations of HM concentration in moss and then the residuals were interpolated by use of kriging interpolation. Both maps were summed up to a map of cadmium (Cd) and lead (Pb) deposition across Germany. Biomonitoring data were strongly correlated to LE than to EMEP. For HM concentrations in moss, the highest correlations were found for the association between geostatistical surface estimations of HM concentration in moss and deposition (LE). PMID- 26739992 TI - A comparative study of cambium histology of Ceiba speciosa (A. St.-Hil.) Ravenna (Malvaceae) under urban pollution. AB - Air pollution is considered to be one of the main causes of forest decline. The cambium is responsible for increase in tree girth, and its functioning is determined by environmental pressures. This study compared cambium histology of Ceiba speciosa (A. St.-Hil.) Ravenna (Malvaceae) in polluted and preserved sites in the Atlantic Rainforest domain. Samples were obtained during periods of cambial activity and dormancy and were processed and examined according to standard light microscopy techniques. In addition to differences typically observed in cambium during periods of activity and dormancy, the fusiform initials were shorter in trees of the polluted site. Furthermore, cambial rays were shorter, but larger, in the polluted site. It should be noted that all parameters related to cambial rays showed significant differences between the study sites. This is the first report of the effects of pollution on cambial activity in a South American species. The results suggest a tolerance of C. speciosa to pollution and reveal this species to be an important biomarker for environmental monitoring studies. PMID- 26739993 TI - Biorecovery of gold as nanoparticles and its catalytic activities for p nitrophenol degradation. AB - Recovery of gold from aqueous solution using simple and economical methodologies is highly desirable. In this work, recovery of gold as gold nanoparticles (AuNPs) by Shewanella haliotis with sodium lactate as electron donor was explored. The results showed that the process was affected by the concentration of biomass, sodium lactate, and initial gold ions as well as pH value. Specifically, the presence of sodium lactate determines the formation of nanoparticles, biomass, and AuCl4 (-) concentration mainly affected the size and dispersity of the products, reaction pH greatly affected the recovery efficiency, and morphology of the products in the recovery process. Under appropriate conditions (5.25 g/L biomass, 40 mM sodium lactate, 0.5 mM AuCl4 (-), and pH of 5), the recovery efficiency was almost 99 %, and the recovered AuNPs were mainly spherical with size range of 10-30 nm (~85 %). Meanwhile, Fourier transforms infrared spectroscopy and X-ray photoelectron spectroscopy demonstrated that carboxyl and amine groups might play an important role in the process. In addition, the catalytic activity of the AuNPs recovered under various conditions was testified by analyzing the reduction rate of p-nitrophenol by borohydride. The biorecovered AuNPs exhibited interesting size and shape-dependent catalytic activity, of which the spherical particle with smaller size showed the highest catalytic reduction activity with rate constant of 0.665 min(-1). PMID- 26739995 TI - Improving clinical outcomes through centralization of rectal cancer surgery and clinical audit: a mixed-methods assessment. AB - BACKGROUND: The aim of centralizing rectal cancer surgery in Catalonia (Spain) was to improve the quality of patient care. We evaluated the impact of this policy by assessing patterns of care, comparing the clinical audits carried out and analysing the implications of the healthcare reform from an organizational perspective. METHODS: A mixed methods approach based on a convergent parallel design was used. Quality of rectal cancer care was assessed by means of a clinical audit for all patients receiving radical surgery for rectal cancer in two time periods (2005-2007 and 2011-2012). The qualitative study consisted of 18 semi-structured interviews in September-December 2014, with healthcare professionals, managers and experts. RESULTS: From 2005-2007 to 2011-2012, hospitals performing rectal cancer surgery decreased from 51 to 32. The proportion of patients undergoing surgery in high volume centres increased from 37.5% to 52.8%. Improved report of total mesorectal excision (36.2 vs. 85.7), less emergency surgery (5.6% vs. 3.6%) and more lymph node examinations (median: 14.1 vs. 16) were observed (P < 0.001). However, centralizing highly complex cancers using different critical masses and healthcare frameworks prompted the need for rearticulating partnerships at a hospital, rather than disease, level. CONCLUSION: The centralization of rectal cancer surgery has been associated with better quality of care and conformity with clinical guidelines. However, a more integrated model of care delivery is needed to strengthen the centralization strategy. PMID- 26739997 TI - Concentration-QT analysis of the randomized, placebo- and moxifloxacin-controlled thorough QT study of umeclidinium monotherapy and umeclidinium/vilanterol combination in healthy subjects. AB - The long-acting muscarinic antagonist umeclidinium (UMEC) is approved as a once daily monotherapy and in combination with the long-acting beta2 agonist vilanterol (VI) for chronic obstructive pulmonary disease. The objective of this analysis was to assess the relationship between observed plasma UMEC and/or VI concentrations and QT interval corrected using Fridericia's correction (QTcF). 103 subjects were enrolled and 86 (83 %) completed the study. Subjects were randomized to 4 of 5 repeat-dose treatments (days 1-10: n = 77 subjects received placebo, n = 76 UMEC 500 ug, n = 78 UMEC/VI 125/25 ug, or n = 76 UMEC/VI 500/100 ug; day 10: n = 74 oral tablet moxifloxacin 400 mg [positive control]). The concentration-QTcF interval relationship was examined using nonlinear mixed effects methods. For UMEC, predicted QTcF interval prolongation (at observed geometric mean of maximum plasma concentrations) was -2.38 ms (90 % prediction interval [PI] -3.82, -0.85) with UMEC 500 ug and -0.50 ms (90 % PI -0.80, -0.18) and -2.01 ms (90 % PI -3.22, -0.72) with UMEC/VI 125/25 ug and 500/100 ug, respectively. For VI, estimates were 5.89 ms (90 % PI 4.89, 6.91) and 7.23 ms (90 % PI 5.88, 8.55) with UMEC/VI 125/25 ug and 500/100 ug, respectively. Combined additive mean effects were estimated for UMEC/VI 125/25 ug (5.39 ms [90 % PI 4.40, 6.47]) and 500/100 ug (5.22 ms [90 % PI 3.72, 6.80]). The model-predicted decrease with UMEC and increase with UMEC/VI combination in QTcF interval suggest that the QT effect is likely attributable to VI. These model-predicted results support those of previously-published traditional statistical analyses. PMID- 26739996 TI - CLOCK gene variation is associated with incidence of type-2 diabetes and cardiovascular diseases in type-2 diabetic subjects: dietary modulation in the PREDIMED randomized trial. AB - BACKGROUND: Circadian rhythms regulate key biological processes influencing metabolic pathways. Disregulation is associated with type 2 diabetes (T2D) and cardiovascular diseases (CVD). Circadian rhythms are generated by a transcriptional autoregulatory feedback loop involving core clock genes. CLOCK (circadian locomotor output cycles protein kaput), one of those core genes, is known to regulate glucose metabolism in rodent models. Cross-sectional studies in humans have reported associations between this locus and obesity, plasma glucose, hypertension and T2D prevalence, supporting its role in cardiovascular risk. However, no longitudinal study has investigated the association between CLOCK gene variation and T2D or CVD incidence. Moreover, although in a previous work we detected a gene-diet interaction between the CLOCK-rs4580704 (C > G) single nucleotide polymorphism (SNP) and monounsaturated (MUFA) intake on insulin resistance, no interventional study has analyzed gene-diet interactions on T2D or CVD outcomes. METHODS: We analyzed the association between the CLOCK-rs4580704 SNP and incidence of T2D and CVD longitudinally in 7098 PREDIMED trial (ISRCTN35739639) participants after a median 4.8-year follow-up. We also examined modulation by Mediterranean diet (MedDiet) intervention (high in MUFA) on these associations. RESULTS: We observed a significant association between the CLOCK rs4580704 SNP and T2D incidence in n = 3671 non-T2D PREDIMED participants, with variant allele (G) carriers showing decreased incidence (dominant model) compared with CC homozygotes (HR: 0.69; 95 % CI 0.54-0.87; P = 0.002). This protection was more significant in the MedDiet intervention group (HR: 0.58; 95 % CI 0.43-0.78; P < 0.001) than in the control group (HR: 0.95; 95 % CI 0.63-1.44; P = 0.818). Moreover, we detected a statistically significant interaction (P = 0.018) between CLOCK-rs4580704 SNP and T2D status on stroke. Thus, only in T2D subjects was CLOCK-rs4580704 SNP associated with stroke risk, G-carriers having decreased risk (HR: 0.61; 95 % CI 0.40-0.94; P = 0.024 versus CC) in the multivariable-adjusted model. CONCLUSIONS: In agreement with our previous results showing a protective effect of the G-allele against hyperglycemia, we extended our findings by reporting a novel association with lower T2D incidence and also suggesting a dietary modulation. Moreover, we report for the first time an association between a CLOCK polymorphism and stroke in T2D subjects, suggesting that core clock genes may significantly contribute to increased CVD risk in T2D. PMID- 26739999 TI - A Tribolium castaneum whole-embryo culture protocol for studying the molecular mechanisms and morphogenetic movements involved in insect development. AB - The development of the red flour beetle Tribolium castaneum is more representative of arthropods than the evolutionarily derived fly, Drosophila melanogaster. Thus, Tribolium is becoming an emerging organism model for studying the evolution of the mechanisms that control embryonic development in arthropods. In this regard, diverse genetic and molecular tools are currently available for Tribolium, as well as imaging and embryonic techniques. Recently, we developed a method for culturing embryos in order to study specific stages during Tribolium development. In this report, we present a detailed and "easy-to-follow" protocol for embryo handling and dissection, extending the use of whole-embryo culture to functional analysis by performing in vivo pharmacological manipulations. This experimental accessibility allowed us to study the relevance of microtubules in axis elongation, using nocodazole and taxol drugs to interfere with microtubule networks, followed by length measurement analysis. Additionally, we demonstrated that embryo handling had no effect on the development of Tribolium embryos, and we checked viability after dissection and bisection and during incubation using propidium iodide. The embryo culture protocol we describe here can be applied to study diverse developmental processes in Tribolium. We expect that this protocol can be adapted and applied to other arthropods. PMID- 26740000 TI - A unilateral septal flap based on the anterior ethmoidal artery (Castelnuovo's flap): CT cadaver study. AB - OBJECTIVE: We describe our experience for repair septal perforation with a septal flap and we analyse the route of the septal branch of the anterior ethmoidal artery (AEA) in the septum area with a radiological anatomy study in order to perform this flap. STUDY DESIGN: We carry out a prospective analysis with computed tomography scan in the cadaver heads and we perform an endoscopic technique in the patients. METHODS: Ten nasal cavities were analysed in five adult cadaveric heads and two patients diagnosed with anterior septal perforation were surgically treated. Measurements in the cadaveric heads were obtained from a sagittal plane of the nasal septum. The anterior point corresponds to the projection of the anterior insertion of the middle turbinate in the frontal process of the maxilla over the nasal septum. The posterior point was obtained with a vertical line passing through the entrance of the AEA in the nasal septum. RESULTS: The mean distance between the anterior point and the posterior point was 7.35 mm with a standard deviation of 0.95 mm. The lowest value was 5.5 mm and the highest value was 8.7 mm. We observed good epithelialisation and closure of the perforation in all patients. CONCLUSION: The unilateral septal flap pedicle by anterior ethmoidal artery may be used for small and medium perforations with a pedicle smaller than 1 cm posterior to the axilla. PMID- 26739998 TI - Phase II study of oxaliplatin combined with S-1 and leucovorin (SOL) for Chinese patients with metastatic colorectal cancer. AB - BACKGROUND: Fluoropyrimidine and oxaliplatin are widely used for patients with colorectal cancer. This phase II study was conducted to evaluate the efficacy and safety of the combination of S-1, oxaliplatin, and leucovorin (SOL) in the treatment of Chinese patients with metastatic colorectal cancer (mCRC). METHODS: Eligible patients with untreated mCRC from four hospitals in China received intravenous oxaliplatin (85 mg/m(2)) on day 1, oral S-1 twice daily (80-120 mg per day) on day 1-7, and leucovorin twice daily (50 mg per day) simultaneously with S-1, every 2 weeks. RESULTS AND DISCUSSION: Forty patients were enrolled in our study. In total, 296 cycles of SOL were administered. The overall response rate was 50.0%. At a median follow-up of 27 months, progression-free survival and overall survival were 7.0 months (95% confidence interval [CI] 6.0-10.6 months) and 22.2 months (95% CI 15.1-29.3 months), respectively. The most common grade 3/4 non-hematological adverse events were diarrhea (n = 8, 20.0%), nausea (n = 3, 7.5%), and vomiting (n = 3, 7.5%). The most common grade 3/4 hematological toxicities were thrombocytopenia (n = 3, 7.5%), neutropenia (n = 1, 2.5%), and abnormal alanine transaminase/aspartate transaminase levels (n = 1, 2.5%). There was one treatment-related death. CONCLUSIONS: The data indicate that the SOL regimen is effective and moderately tolerated in Chinese patients with mCRC. TRIAL REGISTRATION: CLINICAL TRIAL INFORMATION: ChiCTR-TNRC-100000838. PMID- 26740001 TI - Analysis of the position of the branches of the ulnar nerve in Guyon's canal using high-resolution MRI in positions adopted by cyclists. AB - PURPOSE: To study variations in the anatomical relationships of the branches of the ulnar nerve in Guyon's canal relative to the hamulus of hamate (HH) in a grip encountered among cyclists. MATERIALS AND METHODS: Forty-seven wrist examinations were performed on a 3-T MRI (soft antenna, 16 channels) in propeller sequence in the plane perpendicular to the carpus in 28 healthy volunteers in three cycling positions (neutral, hyperextension and ulnar deviation). The positions and distance between the superficial (SB) and deep (DB) branches of the ulnar nerve with respect to the HH were determined on the section passing through the HH. RESULTS: The mean distances between the SB (d s) and DP (d p) and HH were 2.4 and 0.6 mm, respectively. The d s in hyperextension and ulnar deviation were 2.2 mm (P = 0.3) and 3 mm (P = 0.07), respectively. The d p in hyperextension and ulnar deviation were 0.3 mm (P = 0.02) and 0.5 mm (P = 0.15), respectively. Hyperextended, 60 % of SB and 40 % of DB were close to the HH, and 26 % of DB came directly in contact with it. In ulnar deviation, 30 % of SB and 29 % of DB approached HH, and 47 % of DB were in contact with it. CONCLUSION: This study shows that SB and DB positions of the ulnar nerve vary with respect to the HH depending on the position of the wrist, and such differences may promote Guyon's canal syndrome in cyclists. PMID- 26740003 TI - Mediation and moderation of the effects of watching the angiography screen on patients. AB - It has been reported that allowing patients to watch the coronary angiography screen during the procedure results in psychological benefits. This study aimed to investigate the roles of illness perceptions as mediators of this outcome and to examine whether individual differences in monitoring coping style moderated these effects. The experiment compared patients who were instructed to watch the monitor screen (n = 57) with those who were not (n = 51). Questionnaires were used to measure the research variables at one day and one month after the procedure. Results showed that watching the angiography screen increased patients' personal and treatment control perceptions that mediated changes in self-assessed health, risk perceptions, negative affect, general and diet outcome expectancies, and diet and physical activity intentions. The behavior-related outcomes were moderated by monitoring coping style. These findings illustrate the significance of illness perceptions, perceived control and monitoring coping style in achieving desirable outcomes among patients undergoing coronary angiography, and reveal opportunities for interventions using medical imaging technologies. PMID- 26740004 TI - Word balloon catheter for Bartholin's cyst and abscess as an office procedure: clinical time gained. AB - BACKGROUND: Around 2% of women develop a Bartholin's cyst or abscess at least once in their life time. The use of Word balloon catheter as an office procedure for the management of Bartholin's cyst and abscess has been well described and indicates high patient acceptance, low short-term recurrence rates and reduced cost. In most of the reported studies, the reduced costs are attributed to savings from equipment cost, operating theatre costs and health personnel costs. An evaluation of the actual clinical time gained with this office procedure has not been reported and hence the rationale for this study. This study was conducted from December 2011 to January 2014 on 35 patients. An initial retrospective clinical audit of 14 cases of marsupialization under general anesthetic between December 2011 and December 2012 was performed. The findings were compared with a subsequent prospective observational service evaluation of 21 consecutive patients between December 2012 and January 2014. RESULTS: Compared to marsupialization under general anesthetic, the mean clinical time gained from admission to insertion of Word balloon catheter as an office procedure is 15 h and 40 min and the mean clinical time gained from admission to discharge is at least 24 h. There were very few minor complications and no major complications in the Word catheter group compared to the marsupialization group. CONCLUSIONS: There is a clinically significant time gained with the use of Word balloon catheter as an office procedure compared to marsupialization under general anesthetic for Bartholin's cyst and abscess. The findings from our study could assist other units that want to adopt this procedure justify the efficiency savings in terms of clinical time gained when a business case is submitted. Further studies are needed to investigate and address the underlying causes for the delays encountered when marsupialization under general anesthetic is chosen by patients. PMID- 26740006 TI - All-metal electride molecules CuAg@Ca7M (M = Be, Mg, and Ca) with multi-excess electrons and all-metal polyanions: molecular structures and bonding modes as well as large infrared nonlinear optical responses. AB - All-metal electride molecules, CuAg@Ca7M (M = Be, Mg and Ca), have been designed and researched in theory for the first time. In these molecules, a pull-push electron relay occurs. Unusually, the all-metal polyanions of fourfold negatively charged [Cu-Ag-Be/Mg](4-) and [Cu-Ag](4-) with 4 extra electrons gained from Ca atoms push the remaining valence electrons of the Ca atoms forming the multi excess electrons (Ne = 10/12). Therefore, these molecules can be described as salt-like [(Ca(2+))7(CuAgM)(4-)] + 10e(-) (M = Be and Mg) and [(Ca(2+))8(CuAg)(4 )] + 12e(-). In these salt-like molecules, there are extraordinary covalent bonding modes, which include 2c-2e/3c-2e sigma-bonding in the polyanions and the Ca(2+) cations sharing the diffuse multi-excess electrons. For an intriguing nonlinear optical (NLO) response, these all-metal electride molecules display large electronic first hyperpolarizabilities (beta0), thus a new class of NLO molecules, all-metal electride NLO molecules, emerge. Moreover, it is also found that manipulating the atomic number and position of M is a new strategy to enhance beta0. As a result, CuAg@Ca7Mg(1) exhibits a considerable beta0 (1.43 * 10(4) au), which is 16 times the beta0 sum of two isolated CuAg and Ca7Mg(1) subunits, and this deeply reveals the fundamental origin of the considerable beta0, namely, the multi-excess electrons generated by the subunit interaction. These all-metal electride molecules have the infrared (IR) transparent region of 1.3-6 MUm, and hence are new IR NLO molecules. In addition the electronic contribution, beta0, the large effects of vibrations on the static first hyperpolarizabilities of these all-metal electride molecules are also estimated. Thus, this study opens the new research field of all-metal electride IR NLO molecules. PMID- 26740007 TI - Feasibility of Active Machine Learning for Multiclass Compound Classification. AB - A common task in the hit-to-lead process is classifying sets of compounds into multiple, usually structural classes, which build the groundwork for subsequent SAR studies. Machine learning techniques can be used to automate this process by learning classification models from training compounds of each class. Gathering class information for compounds can be cost-intensive as the required data needs to be provided by human experts or experiments. This paper studies whether active machine learning can be used to reduce the required number of training compounds. Active learning is a machine learning method which processes class label data in an iterative fashion. It has gained much attention in a broad range of application areas. In this paper, an active learning method for multiclass compound classification is proposed. This method selects informative training compounds so as to optimally support the learning progress. The combination with human feedback leads to a semiautomated interactive multiclass classification procedure. This method was investigated empirically on 15 compound classification tasks containing 86-2870 compounds in 3-38 classes. The empirical results show that active learning can solve these classification tasks using 10-80% of the data which would be necessary for standard learning techniques. PMID- 26740008 TI - Drug-conjugated PLA-PEG-PLA copolymers: a novel approach for controlled delivery of hydrophilic drugs by micelle formation. AB - A conjugate of the antihypertensive drug, lisinopril, with triblock poly(lactic acid)-poly(ethylene glycol)-poly(lactic acid) (PLA-PEG-PLA) copolymer was synthesized by the reaction of PLA-PEG-PLA copolymer with lisinopril in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine. The conjugated copolymer was characterized in vitro by hydrogen nuclear magnetic resonance (HNMR), Fourier transform infrared (FTIR), differential scanning calorimetry (DSC) and gel permeation chromatography (GPC) techniques. Then, the lisinopril conjugated PLA-PEG-PLA were self-assembled into micelles in aqueous solution. The resulting micelles were characterized further by various techniques such as dynamic light scattering (DLS) and atomic force microscopy (AFM). The results revealed that the micelles formed by the lisinopril-conjugated PLA-PEG-PLA have spherical structure with the average size of 162 nm. The release behavior of conjugated copolymer, micelles and micelles physically loaded by lisinopril were compared in different media. In vitro release study showed that in contrast to physically loaded micelles, the release rate of micelles consisted of the conjugated copolymer was dependent on pH of media where it was higher at lower pH compared to the neutral medium. Another feature of the conjugated micelles was their more sustained release profile compared to the lisinopril-conjugated copolymer and physically loaded micelles. PMID- 26740010 TI - Divergent reactivity of an indole glucosinolate yields Lossen or Neber rearrangement products: the phytoalexin rapalexin A or a unique beta-d glucopyranose fused heterocycle. AB - Transformation of 1-t-Boc-4-methoxyindole-3-glucosinolate under acidic conditions yielded the potent phytoalexin rapalexin A, providing its first biomimetic synthesis via Lossen type rearrangement, while a novel 1-thioimidocarbonyl-beta-d glucopyranose heterocyclic system was obtained under basic conditions via Neber type rearrangement. PMID- 26740009 TI - PI3Kdelta promotes CD4(+) T-cell interactions with antigen-presenting cells by increasing LFA-1 binding to ICAM-1. AB - Activation of T lymphocytes by peptide/major histocompatibility complex on antigen-presenting cells (APCs) involves dynamic contacts between the two cells, during which T cells undergo marked morphological changes. These interactions are facilitated by integrins. Activation of the T cells increases the binding of the integrin lymphocyte function-associated antigen 1 (LFA-1) expressed by T cells to intercellular adhesion molecule (ICAM)-1 and ICAM-2 expressed by APCs. The signalling pathways that control integrin affinities are incompletely defined. The phosphoinositide 3-kinases (PI3Ks) generate second-messenger signalling molecules that control cell growth, proliferation, differentiation and trafficking. Here we show that in T cells, PI3Kdelta attenuates the activation of Rac1, but sustains the activation of Rap1. Consequently, PI3Kdelta increases LFA 1-dependent adhesion to form stable conjugates with APCs. Increased Rap1 activity and LFA-1 adhesion were only in part mediated by the downstream kinase Akt, suggesting the involvement of additional phosphatidylinositol(3,4,5)P3-binding proteins. These results establish a link between PI3K activity, cytoskeletal changes and integrin binding and help explain the impaired T-cell-dependent immune responses in PI3Kdelta-deficient mice. PMID- 26740012 TI - Effect of caponisation on physicochemical and sensory characteristics of chickens. AB - The meat fats content associated to nutritional and sensory characteristics are the most important concerns of consumers. To study the effect of caponisation on the meat quality of two different breed chickens, slaughtered at 18 weeks of age, raised under the same conditions, the physicochemical and sensory characteristics of capons (castrated males at 8 weeks of age) and roosters??? meat of native Amarela Portuguesa and native Pedr??s Portuguesa breeds were evaluated. Forty Amarela (20 roosters and 20 capons), 40 Pedr??s (20 roosters and 20 capons) chickens, and also, six free-range chicken and six broilers were evaluated. The pH, water-holding capacity, Warner-Bratzler shear force, moisture content, ash, myoglobin, collagen, CP, total fat and fatty acids profile were evaluated in breast and leg meat, according to standard procedures. Leg meat capon showed greater intramuscular fat content (P???0.05), monounsaturated fatty acids (MUFA) and CP (P???0.001) than leg roosters. Caponisation increased the content of myoglobin and MUFA (P???0.05) and reduced the moisture content in the leg (P???0.05). The main fatty acids found were oleic acid (C18:1), palmitic acid (C16:0) and linoleic acid (C18:2). The greatest value of C18:1 was observed in capon???s breast (P???0.01). Sensory analysis was made to compare the Amarela and Pedr??s meat with a free-range chicken and a broiler. The sensory taste panel classified the capon???s meat (Amarela and Pedr??s) as juicier, less fibrous and tougher than rooster???s meat. The broiler was in general juicier, tenderer and less fibrous than the other birds. The results of sensory analysis complement those obtained in physicochemical analysis, suggesting that caponisation promotes an overall improvement in meat quality. PMID- 26740011 TI - Oxidative Dimerization of PHD2 is Responsible for its Inactivation and Contributes to Metabolic Reprogramming via HIF-1alpha Activation. AB - Prolyl hydroxylase domain protein 2 (PHD2) belongs to an evolutionarily conserved superfamily of 2-oxoglutarate and Fe(II)-dependent dioxygenases that mediates homeostatic responses to oxygen deprivation by mediating hypoxia-inducible factor 1alpha (HIF-1alpha) hydroxylation and degradation. Although oxidative stress contributes to the inactivation of PHD2, the precise molecular mechanism of PHD2 inactivation independent of the levels of co-factors is not understood. Here, we identified disulfide bond-mediated PHD2 homo-dimer formation in response to oxidative stress caused by oxidizing agents and oncogenic H-ras(V12) signalling. Cysteine residues in the double-stranded beta-helix fold that constitutes the catalytic site of PHD isoforms appeared responsible for the oxidative dimerization. Furthermore, we demonstrated that disulfide bond-mediated PHD2 dimerization is associated with the stabilization and activation of HIF-1alpha under oxidative stress. Oncogenic H-ras(V12) signalling facilitates the accumulation of HIF-1alpha in the nucleus and promotes aerobic glycolysis and lactate production. Moreover, oncogenic H-ras(V12) does not trigger aerobic glycolysis in antioxidant-treated or PHD2 knocked-down cells, suggesting the participation of the ROS-mediated PHD2 inactivation in the oncogenic H-ras(V12) mediated metabolic reprogramming. We provide here a better understanding of the mechanism by which disulfide bond-mediated PHD2 dimerization and inactivation result in the activation of HIF-1alpha and aerobic glycolysis in response to oxidative stress. PMID- 26740014 TI - A metal-free yne-addition/1,4-aryl migration/decarboxylation cascade reaction of alkynoates with Csp(3)-H centers. AB - A metal-free cascade reaction of aryl alkynoates with five different types of radical precursors (R-H) through an yne-addition/1,4-aryl migration/decarboxylation process was reported, which allowed facile and convenient access to functionalized vinyl products with "R" and protons located at the identical carbon of the formed double bond. PMID- 26740015 TI - Modeling our understanding of the His-Purkinje system. AB - The His-Purkinje System (HPS) is responsible for the rapid electric conduction in the ventricles. It relays electrical impulses from the atrioventricular node to the muscle cells and, thus, coordinates the contraction of ventricles in order to ensure proper cardiac pump function. The HPS has been implicated in the genesis of ventricular tachycardia and fibrillation as a source of ectopic beats, as well as forming distinct portions of reentry circuitry. Despite its importance, it remains much less well characterized, structurally and functionally, than the myocardium. Notably, important differences exist with regard to cell structure and electrophysiology, including ion channels, intracellular calcium handling, and gap junctions. Very few computational models address the HPS, and the majority of organ level modeling studies omit it. This review will provide an overview of our current knowledge of structure and function (including electrophysiology) of the HPS. We will review the most recent advances in modeling of the system from the single cell to the organ level, with considerations for relevant interspecies distinctions. PMID- 26740017 TI - Endothelium-targeted human Delta-like 1 enhances the regeneration and homing of human cord blood stem and progenitor cells. AB - BACKGROUND: Umbilical cord blood (UCB) is becoming an alternative cell source for hematopoietic stem cell transplantation (HSCT). However, umbilical cord blood transplantation (UCBT) has been severely limited by low and finite numbers of hematopoietic stem cells and their delayed engraftment. New strategies are needed to improve ex vivo expansion efficiency and in vivo haematopoietic recovery. METHODS: We produced an endothelium-targeted soluble Notch ligand, the Delta Serrate-Lag-2 (DSL) domain of human Delta-like 1 fused with a RGD motif (hD1R), and tested the effects of this protein on human umbilical cord blood hematopoietic stem and progenitor cell (UCB-HSPC) ex vivo and in vivo. RESULTS: hD1R-mediated ex vivo expansion system was able to significantly increase the absolute number of UCB-HSPCs. The hD1R-expanded cells had the enhanced homing and maintained long-term hematopoietic stem cell repopulation capacity in the bone marrow of immunodeficient nonobese diabetic-severe combined immunodeficient (NOD/SCID) mice. Moreover, systemic administration of hD1R promoted the in vivo regeneration of donor cells in recipient mice and accelerated hematopoietic recovery, particularly in settings wherein the HSPCs dose was limiting. CONCLUSIONS: Our results indicated that hD1R might be applied in improving hematopoietic recovery and HSC engraftment in human UCBT. PMID- 26740019 TI - Coral mucus fuels the sponge loop in warm- and cold-water coral reef ecosystems. AB - Shallow warm-water and deep-sea cold-water corals engineer the coral reef framework and fertilize reef communities by releasing coral mucus, a source of reef dissolved organic matter (DOM). By transforming DOM into particulate detritus, sponges play a key role in transferring the energy and nutrients in DOM to higher trophic levels on Caribbean reefs via the so-called sponge loop. Coral mucus may be a major DOM source for the sponge loop, but mucus uptake by sponges has not been demonstrated. Here we used laboratory stable isotope tracer experiments to show the transfer of coral mucus into the bulk tissue and phospholipid fatty acids of the warm-water sponge Mycale fistulifera and cold water sponge Hymedesmia coriacea, demonstrating a direct trophic link between corals and reef sponges. Furthermore, 21-40% of the mucus carbon and 32-39% of the nitrogen assimilated by the sponges was subsequently released as detritus, confirming a sponge loop on Red Sea warm-water and north Atlantic cold-water coral reefs. The presence of a sponge loop in two vastly different reef environments suggests it is a ubiquitous feature of reef ecosystems contributing to the high biogeochemical cycling that may enable coral reefs to thrive in nutrient-limited (warm-water) and energy-limited (cold-water) environments. PMID- 26740021 TI - Disseminated Mycobacterium avium Complex With Cutaneous Lesions. AB - BACKGROUND: Although most commonly encountered in patients with human immunodeficiency virus infection, disseminated Mycobacterium avium complex (MAC) is becoming more common in patients receiving immunosuppressive medications. Disseminated MAC with skin lesions may occur, and several presentations have been reported, including panniculitis, cutaneous granulomas, pustules, ulcerations, and erythematous skin lesions. OBJECTIVES: The objective of this report is to describe an unusual presentation of MAC that is unlikely to be encountered frequently in the outpatient dermatology setting, especially in a patient without human immunodeficiency virus infection. METHODS: The authors present a case of disseminated MAC infection with cutaneous manifestations in an iatrogenically immunocompromised patient. CONCLUSIONS: Diagnosis of MAC infection is challenging given the varied clinical presentations and the difficulty in culturing MAC. In addition, the acid-fast stain is nonspecific. Clinicians should remember to consider MAC infection in patients with acid-fast-positive skin lesions, as the selection of appropriate antibiotic therapy is species specific. PMID- 26740022 TI - MicroRNA profiles in colorectal carcinomas, adenomas and normal colonic mucosa: variations in miRNA expression and disease progression. AB - MiRNAs are small, non-protein-coding RNA molecules that regulate gene expression either by post-transcriptionally suppressing mRNA translation or by mRNA degradation. We examine differentially expressed miRNAs in colorectal carcinomas, adenomas and normal colonic mucosa. Data come from population-based studies of colorectal cancer conducted in Utah and the Kaiser Permanente Medical Care Program. A total of 1893 carcinoma/normal-paired samples and 290 adenoma tissue samples were run on the Agilent Human miRNA Microarray V19.0 which contained 2006 miRNAs. We tested for significant differences in miRNA expression between paired carcinoma/adenoma/normal colonic tissue samples. Fewer than 600 miRNAs were expressed in >80% of people for colonic tissue; of these 86.5% were statistically differentially expressed between carcinoma and normal colonic mucosa using a false discovery rate of 0.05. Roughly half of these differentially expressed miRNAs showed a progression in levels of expression from normal to adenoma to carcinoma tissue. Other miRNAs appeared to be altered at the normal to adenoma stage, while others were only altered at the adenoma to carcinoma stage or only at the normal to carcinoma stage. Evaluation of the Agilent platform showed a high degree of repeatability (r = 0.98) and reasonable agreement with the NanoString platform. Our data suggest that miRNAs are highly dysregulated in colorectal tissue among individuals with colorectal cancer; the pattern of disruption varies by miRNA as tissue progresses from normal to adenoma to carcinoma. PMID- 26740023 TI - Synthesis and DFT investigation of new bismuth-containing MAX phases. AB - The Mn + 1AXn phases (M = early transition metal; A = group A element and X = C and N) are materials exhibiting many important metallic and ceramic properties. In the present study powder processing experiments and density functional theory calculations are employed in parallel to examine formation of Zr2(Al1-xBix)C (0 <= x <= 1). Here we show that Zr2(Al1-xBix)C, and particularly with x ~ 0.58, can be formed from powders even though the end members Zr2BiC and Zr2AlC seemingly cannot. This represents a significant extension of the MAX phase family, as this is the first report of a bismuth-based MAX phase. PMID- 26740024 TI - Defining antibiotic effectiveness and resistance: how a private party may soon rule judgments over susceptibility testing. PMID- 26740025 TI - Depression After First Hospital Admission for Acute Coronary Syndrome: A Study of Time of Onset and Impact on Survival. AB - We examined incidence of depression after acute coronary syndrome (ACS) and whether the timing of depression onset influenced survival. All first-time hospitalizations for ACS (n = 97,793) identified in the Danish Patient Registry during 2001-2009 and a reference population were followed for depression and mortality via linkage to patient, prescription, and cause-of-death registries until the end of 2012. Incidence of depression (as defined by hospital discharge or antidepressant medication use) and the relationship between depression and mortality were examined using time-to-event models. In total, 19,520 (20.0%) ACS patients experienced depression within 2 years after the event. The adjusted rate ratio for depression in ACS patients compared with the reference population was 1.28 (95% confidence interval (CI): 1.25, 1.30). During 12 years of follow-up, 39,523 (40.4%) ACS patients and 27,931 (28.6%) of the reference population died. ACS patients with recurrent (hazard ratio (HR) = 1.62, 95% CI: 1.57, 1.67) or new onset (HR = 1.66, 95% CI: 1.60, 1.72) depression had higher mortality rates than patients with no depression. In the reference population, the corresponding relative estimates for recurrent (HR =1.98, 95% CI: 1.92, 2.05) and new-onset (HR = 2.42, 95% CI: 2.31, 2.54) depression were stronger. Depression is common in ACS patients and is associated with increased mortality independently of time of onset, but here the excess mortality associated with depression seemed to be lower in ACS patients than in the reference population. PMID- 26740026 TI - Maternal Consumption of Seafood in Pregnancy and Child Neuropsychological Development: A Longitudinal Study Based on a Population With High Consumption Levels. AB - Seafood consumption during pregnancy is thought to be beneficial for child neuropsychological development, but to our knowledge no large cohort studies with high fatty fish consumption have analyzed the association by seafood subtype. We evaluated 1,892 and 1,589 mother-child pairs at the ages of 14 months and 5 years, respectively, in a population-based Spanish birth cohort established during 2004-2008. Bayley and McCarthy scales and the Childhood Asperger Syndrome Test were used to assess neuropsychological development. Results from multivariate linear regression models were adjusted for sociodemographic characteristics and further adjusted for umbilical cord blood mercury or long chain polyunsaturated fatty acid concentrations. Overall, consumption of seafood above the recommended limit of 340 g/week was associated with 10-g/week increments in neuropsychological scores. By subtype, in addition to lean fish, consumption of large fatty fish showed a positive association; offspring of persons within the highest quantile (>238 g/week) had an adjusted increase of 2.29 points in McCarthy general cognitive score (95% confidence interval: 0.42, 4.16). Similar findings were observed for the Childhood Asperger Syndrome Test. Beta coefficients diminished 15%-30% after adjustment for mercury or long-chain polyunsaturated fatty acid concentrations. Consumption of large fatty fish during pregnancy presents moderate child neuropsychological benefits, including improvements in cognitive functioning and some protection from autism-spectrum traits. PMID- 26740028 TI - Exploring changes in nursing students' attitudes towards the use of technology: A four-wave longitudinal panel study. AB - BACKGROUND: It is essential for nursing students to be equipped with the necessary technology skills throughout and after their study period. Their acceptance of this technology depends largely on their attitudes towards technology. OBJECTIVES: To explore the evolution in nursing students' attitudes towards technology, and to determine whether there was a change in participants' formal education in technology over their four years of study. METHODS: A longitudinal panel study was conducted in a single school of nursing in Jordan. A total of 140 students were followed over their four years of undergraduate study. They completed the same tool (the Technology Attitude Scale) each year, to capture any changes in their attitudes towards technology across the years. RESULTS: In all four waves of data collection, students showed positive attitudes towards technology, with the highest attitude scores being in their final year (M=6.19, SD=0.72). As the students spent more time on their nursing education, they were found to have a more positive attitude. Thus, a strong positive relationship existed between this formal education in technology and attitudes: as the students' education in technology increased, their attitudes were more positive. CONCLUSION: A remarkable development in students' attitudes towards technology is reported in this study. The positive attitudes displayed by the students should be enhanced by providing technology-related subjects during their studies in nursing schools at a very early stage. PMID- 26740029 TI - Clinical case in digital technology for nursing students' learning: An integrative review. AB - OBJECTIVES: This review aimed to analyze the available evidences in literature about clinical case studies inserted in digital technologies for nursing education, characterizing the technology resources and cognitive, procedural and attitudinal learnings. DESIGN: Integrative review of literature with the following steps: development of the research problem, data collection, data extraction and critic evaluation, data analysis and interpretation and presentation of results. The research question was: how does the clinical case study inserted in educational digital technology collaborate for cognitive, attitudinal and procedural learning of nursing students? DATA SOURCES: data bases LILACS, PUBMED, CINAHL and Scopus. REVIEW METHODS: the search resulted in 437 studies: 136 from LILACS, 122 from PUBMED, 104 from Scopus and 75 from CINAHL. Of these, 143 did not meet the including criteria, 93 were duplicated and four studies were unavailable. After analyzing all abstracts based on inclusion and exclusion criteria, there were selected 197 studies and after full text analysis the final sample resulted in 21 primary studies. RESULTS: Case study use in educational digital technologies allowed the students to build different types of learning: cognitive learning (n 16 studies), attitudinal learning (n=12 studies) and procedural learning (n=8 studies). CONCLUSION: It is possible to conclude that case studies can collaborate with the students to develop different learnings which can be built integrate, continuous, informative and formative, aiming integral formation and aligned to policies of formation in nursing, both national and international. PMID- 26740030 TI - Effects of team-based learning on problem-solving, knowledge and clinical performance of Korean nursing students. AB - BACKGROUND: Team-based learning (TBL) has been used as a learner-centered teaching strategy in efforts to improve students' problem-solving, knowledge and practice performance. Although TBL has been used in nursing education in Korea for a decade, few studies have studied its effects on Korean nursing students' learning outcomes. OBJECTIVES: To examine the effects of TBL on problem-solving ability and learning outcomes (knowledge and clinical performance) of Korean nursing students. DESIGN: Randomized controlled trial. PARTICIPANTS: 63 third year undergraduate nursing students attending a single university were randomly assigned to the TBL group (n=32), or a control group (n=31). METHODS: The TBL and control groups attended 2h of class weekly for 3weeks. Three scenarios with pulmonary disease content were employed in both groups. However, the control group received lectures and traditional case study teaching/learning strategies instead of TBL. A questionnaire of problem-solving ability was administered at baseline, prior to students' exposure to the teaching strategies. Students' problem-solving ability, knowledge of pulmonary nursing care, and clinical performance were assessed following completion of the three-week pulmonary unit. RESULTS: After the three-week educational interventions, the scores on problem solving ability in the TBL group were significantly improved relative to that of the control group (t=10.89, p<.001). In addition, there were significant differences in knowledge, and in clinical performance with standardized patients between the two groups (t=2.48, p=.016, t=12.22, p<.001). CONCLUSION: This study demonstrated that TBL is an effective teaching strategy to enhance problem solving ability, knowledge and clinical performance. More research on other specific learning outcomes of TBL for nursing students is recommended. PMID- 26740031 TI - Plastic with personality: Increasing student engagement with manikins. AB - BACKGROUND: Simulation allows students to practice key psychomotor skills and gain technical proficiency, fostering the development of clinical reasoning and student confidence in a low risk environment. Manikins are a valuable learning tool; yet there is a distinct lack of empirical research investigating how to enhance engagement between nursing students and manikins. OBJECTIVE: To describe student perspectives of a layered, technology enhanced approach to improve the simulation learning experience. EDUCATIONAL FRAMEWORK: Tanner's Model of Clinical Judgment underpins the entire curriculum. This study additionally drew on the principles of narrative pedagogy. INTERVENTION: Across ten teaching weeks, five separate case studies were introduced to students through short vignettes. Students viewed the vignettes prior to their laboratory class. In the labs, manikins were dressed in the props used in the vignettes. SETTING: The innovation was trialed in a second year core subject of a Bachelor of Nursing program in a large urban university in the autumn semester of 2014. DATA COLLECTION AND ANALYSIS: Following ethics approval, students were emailed a participant information sheet. A focus group of nine students was held. The discussion was digitally recorded and transcribed verbatim prior to being subject to thematic analysis. Students' comments (143) about the vignettes in their standard subject specific student feedback surveys were also considered as data. RESULTS: Four themes were identified: Getting past the plastic; knowing what to say; connecting and caring; and, embracing diversity. The feedback indicated that these measures increased students ability to suspend disbelief, feel connected to, and approach the manikins in a more understanding and empathetic fashion. CONCLUSIONS: In addition to achieving increased engagement with manikins, other advantages such as students reflecting on their own values and pre-conceived notions of people from diverse backgrounds were realized. PMID- 26740032 TI - The Society of Thoracic Surgeons Mitral Repair/Replacement Composite Score: A Report of The Society of Thoracic Surgeons Quality Measurement Task Force. AB - BACKGROUND: The Society of Thoracic Surgeons (STS) Quality Measurement Task Force is developing a portfolio of composite performance measures for the most commonly performed procedures in adult cardiac surgery. We now describe the fourth in this series, the STS composite measure for mitral valve repair/replacement (MVRR). METHODS: We examined all patients undergoing isolated MVRR, with or without concomitant performance of tricuspid valve repair, surgical arrhythmia ablation, or repair of atrial septal defect, between July 1, 2011, and June 30, 2014. In this two-domain model, risk-adjusted mortality and any-or-none major morbidity were combined into a composite score using 3 years of STS data and 95% Bayesian credible intervals to estimate composite scores and star ratings. RESULTS: There were 61,201 MVRR patients studied at 867 participant sites. Mitral valve repair was performed in 57.4% (35,114 of 61,201) and mitral valve replacement in 42.6% (26,087 of 61,201). Mortality was 2.9% (1,773 of 61,201), and occurrence of any major morbidity was 17.0% (10,381 of 61,201). The median composite score was 93.2% (interquartile range, 92.3% to 94.2%). Star rating classifications included 23 of 867 (2.6%) 1-star programs (lower-than-expected performance), 795 of 867 (91.7%) 2-star programs (as-expected or average performance), and 49 of 867 (5.7%) 3-star programs (higher-than-expected performance). CONCLUSIONS: STS has developed an MVRR composite performance measure that will be used for participant feedback, quality performance assessment and improvement, and voluntary public reporting. PMID- 26740034 TI - Stereotactic radiosurgery for deep intracranial arteriovenous malformations, part 1: Brainstem arteriovenous malformations. AB - The management of brainstem arteriovenous malformations (AVM) are one of the greatest challenges encountered by neurosurgeons. Brainstem AVM have a higher risk of hemorrhage compared to AVM in other locations, and rupture of these lesions commonly results in devastating neurological morbidity and mortality. The potential morbidity associated with currently available treatment modalities further compounds the complexity of decision making for affected patients. Stereotactic radiosurgery (SRS) has an important role in the management of brainstem AVM. SRS offers acceptable obliteration rates with lower risks of hemorrhage occurring during the latency period. Complex nidal architecture requires a multi-disciplinary treatment approach. Nidi partly involving subpial/epipial regions of the dorsal midbrain or cerebellopontine angle should be considered for a combination of endovascular embolization, micro-surgical resection and SRS. Considering the fact that incompletely obliterated lesions (even when reduced in size) could still cause lethal hemorrhages, additional treatment, including repeat SRS and surgical resection should be considered when complete obliteration is not achieved by first SRS. Patients with brainstem AVM require continued clinical and radiological observation and follow-up after SRS, well after angiographic obliteration has been confirmed. PMID- 26740035 TI - The golden perfection of the aortic valve. PMID- 26740036 TI - Where now for plasmonics? PMID- 26740037 TI - Less is Moore. PMID- 26740039 TI - Atomic-scale photonic hybrids for mid-infrared and terahertz nanophotonics. AB - The field of nanophotonics focuses on the ability to confine light to nanoscale dimensions, typically much smaller than the wavelength of light. The goal is to develop light-based technologies that are impossible with traditional optics. Subdiffractional confinement can be achieved using either surface plasmon polaritons (SPPs) or surface phonon polaritons (SPhPs). SPPs can provide a gate tunable, broad-bandwidth response, but suffer from high optical losses; whereas SPhPs offer a relatively low-loss, crystal-dependent optical response, but only over a narrow spectral range, with limited opportunities for active tunability. Here, motivated by the recent results from monolayer graphene and multilayer hexagonal boron nitride heterostructures, we discuss the potential of electromagnetic hybrids--materials incorporating mixtures of SPPs and SPhPs--for overcoming the limitations of the individual polaritons. Furthermore, we also propose a new type of atomic-scale hybrid--the crystalline hybrid--where mixtures of two or more atomic-scale (~3 nm or less) polar dielectric materials lead to the creation of a new material resulting from hybridized optic phonon behaviour of the constituents, potentially allowing direct control over the dielectric function. These atomic-scale hybrids expand the toolkit of materials for mid infrared to terahertz nanophotonics and could enable the creation of novel actively tunable, yet low-loss optics at the nanoscale. PMID- 26740040 TI - Reconfigurable nanomechanical photonic metamaterials. AB - The changing balance of forces at the nanoscale offers the opportunity to develop a new generation of spatially reconfigurable nanomembrane metamaterials in which electromagnetic Coulomb, Lorentz and Ampere forces, as well as thermal stimulation and optical signals, can be engaged to dynamically change their optical properties. Individual building blocks of such metamaterials, the metamolecules, and their arrays fabricated on elastic dielectric membranes can be reconfigured to achieve optical modulation at high frequencies, potentially reaching the gigahertz range. Mechanical and optical resonances enhance the magnitude of actuation and optical response within these nanostructures, which can be driven by electric signals of only a few volts or optical signals with power of only a few milliwatts. We envisage switchable, electro-optical, magneto optical and nonlinear metamaterials that are compact and silicon-nanofabrication technology compatible with functionalities surpassing those of natural media by orders of magnitude in some key design parameters. PMID- 26740042 TI - Correction. PMID- 26740041 TI - All-dielectric metamaterials. AB - The ideal material for nanophotonic applications will have a large refractive index at optical frequencies, respond to both the electric and magnetic fields of light, support large optical chirality and anisotropy, confine and guide light at the nanoscale, and be able to modify the phase and amplitude of incoming radiation in a fraction of a wavelength. Artificial electromagnetic media, or metamaterials, based on metallic or polar dielectric nanostructures can provide many of these properties by coupling light to free electrons (plasmons) or phonons (phonon polaritons), respectively, but at the inevitable cost of significant energy dissipation and reduced device efficiency. Recently, however, there has been a shift in the approach to nanophotonics. Low-loss electromagnetic responses covering all four quadrants of possible permittivities and permeabilities have been achieved using completely transparent and high refractive-index dielectric building blocks. Moreover, an emerging class of all dielectric metamaterials consisting of anisotropic crystals has been shown to support large refractive index contrast between orthogonal polarizations of light. These advances have revived the exciting prospect of integrating exotic electromagnetic effects in practical photonic devices, to achieve, for example, ultrathin and efficient optical elements, and realize the long-standing goal of subdiffraction confinement and guiding of light without metals. In this Review, we present a broad outline of the whole range of electromagnetic effects observed using all-dielectric metamaterials: high-refractive-index nanoresonators, metasurfaces, zero-index metamaterials and anisotropic metamaterials. Finally, we discuss current challenges and future goals for the field at the intersection with quantum, thermal and silicon photonics, as well as biomimetic metasurfaces. PMID- 26740043 TI - Physicist meets chemist. PMID- 26740046 TI - The influence of cardiovascular autonomic neuropathy on mortality in type 1 diabetic patients; 10-year follow-up. AB - AIM: The aim of our retrospective study was to answer the question if the presence of cardiovascular autonomic neuropathy (CAN) affects mortality in type 1 diabetic patients during a 10-year follow-up. METHODS: Patients with type 1 diabetes mellitus examined for CAN in 2003 were enrolled in this retrospective study. A total of 278 patients were included and divided into two groups according to the presence or absence of CAN (111 CAN+, 167 CAN-). The group characteristics and outcomes were compared at baseline and after ten years (in 2013). RESULTS: In the follow-up period, a total of 18 patients died; CAN+ (14/111; 12.6%) and CAN- (4/167; 2.4%) (P < 0.001). At baseline, the CAN+ patients were older (47 vs. 33 years; P < 0.001), had longer duration of diabetes (20 vs. 12 years; P < 0.05), had worse glycemic control assessed by HbA1c (73 vs. 68 mmol/mol; P < 0.05), higher systolic (130 vs. 120 mmHg; P < 0.001) and diastolic (80 vs. 70 mmHg; P < 0.01) blood pressure and had more diabetic complications. In our analysis we found the strongest predictor of mortality to be the presence of CAN (P < 0.01) and the blood pressure value at baseline (P < 0.05). Other baseline characteristics, including the duration of diabetes, age and the presence of micro- and macrovascular complications were not significant. The statistical analysis was performed using logistic regression step-wise analysis. CONCLUSIONS: During the 10-year follow-up, CAN+ patients had a 5-fold higher mortality rate than CAN- patients. The strongest predictor of mortality was the presence of CAN. PMID- 26740047 TI - Synapse alterations in autism: Review of animal model findings. AB - BACKGROUND: Recent research has produced an explosion of experimental data on the complex neurobiological mechanisms of developmental disorders including autism. Animal models are one approach to studying the phenotypic features and molecular basis of autism. In this review, we describe progress in understanding synaptogenesis and alterations to this process with special emphasis on the cell adhesion molecules and scaffolding proteins implicated in autism. Genetic mouse model experiments are discussed in relation to alterations to selected synaptic proteins and consequent behavioral deficits measured in animal experiments. METHODS: Pubmed databases were used to search for original and review articles on animal and human clinical studies on autism. RESULTS: The cell adhesion molecules, neurexin, neurolignin and the Shank family of proteins are important molecular targets associated with autism. CONCLUSION: The heterogeneity of the autism spectrum of disorders limits interpretation of information acquired from any single animal model or animal test. We showed synapse-specific/ model specific defects associated with a given genotype in these models. Characterization of mouse models with genetic variations may help study the mechanisms of autism in humans. However, it will be necessary to apply new analytic paradigms in using genetically modified mice for understanding autism etiology in humans. Further studies are needed to create animal models with mutations that match the molecular and neural bases of autism. PMID- 26740045 TI - Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes. AB - The nucleoporin Nup98 is frequently rearranged to form leukemogenic Nup98-fusion proteins with various partners. However, their function remains largely elusive. Here, we show that Nup98-HoxA9, a fusion between Nup98 and the homeobox transcription factor HoxA9, forms nuclear aggregates that frequently associate with facultative heterochromatin. We demonstrate that stable expression of Nup98 HoxA9 in mouse embryonic stem cells selectively induces the expression of Hox cluster genes. Genome-wide binding site analysis revealed that Nup98-HoxA9 is preferentially targeted and accumulated at Hox cluster regions where the export factor Crm1 is originally prebound. In addition, leptomycin B, an inhibitor of Crm1, disassembled nuclear Nup98-HoxA9 dots, resulting in the loss of chromatin binding of Nup98-HoxA9 and Nup98-HoxA9-mediated activation of Hox genes. Collectively, our results indicate that highly selective targeting of Nup98 fusion proteins to Hox cluster regions via prebound Crm1 induces the formation of higher order chromatin structures that causes aberrant Hox gene regulation. PMID- 26740048 TI - Prospective comparison of conventional radiography, low-dose computed tomography and magnetic resonance imaging in monoclonal gammopathies. AB - AIMS: We carried out a prospective study in order to identify the best imaging approach for patients with newly diagnosed multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). METHODS: We assessed the extent of myeloma bone disease (MBD) in 112 individuals - 84 patients with MM and 28 individuals with MGUS. For the detection of osteolytic involvement we used whole body magnetic resonance imaging (WB-MRI), low-dose computed tomography (LD-CT) and conventional radiography (CR). Each method assessed the presence of osteolytic involvement, compressive fractures and extramedullary involvement in the following regions: skull, spine and chest, pelvis and humerus and femur. We compared the difference in the number and extent of osteolytic involvement, especially the findings in CR negative patients. RESULTS: Conventional radiography showed no superiority in any of the evaluated regions, and failed in the detection of extramedullary massess and spine involvement. WB-MRI was best at imaging the spine including extramedullary involvement, however, detection of osteolytic lesions of the skull was limited in comparison with both CR and LD-CT. Both WB-MRI and LD-CT were comparable in imaging of lesions of pelvis, humerus, femur and the presence of extramedullary masses. LD-CT showed superiority in detection of skull lesions but lower sensitivity in spine compared to WB-MRI. CONCLUSIONS: Our results confirm that relying solely on CR in the diagnostics of MM is insufficient. We suggest that the most suitable method for primary assessment of osteolytic involvement in monoclonal gammopathies should include either whole-body MRI together with CR of the skull or, with an equivalent sensitivity, whole body LD-CT. PMID- 26740049 TI - Off-pump versus on-pump coronary artery bypass grafting surgery in high-risk patients: PRAGUE-6 trial at 30 days and 1 year. AB - AIMS: Off-pump coronary artery bypass graft surgery (OPCAB) is an established alternative to on-pump surgical revascularization. Previous studies in patients with low or intermediate risk showed no significant differences between off-pump and on-pump surgical revascularization. The aim of this study was to compare the two techniques in patients with high operative risk. METHODS: PRAGUE-6 is a prospective randomized single-center study of 206 patients, with an additive EuroSCORE >= 6, scheduled for isolated coronary surgery: Group A - on-pump (n = 108) versus Group B - off-pump (n = 98). The primary outcome was a combined endpoint of all-cause deaths, stroke, myocardial infarction, or renal failure requiring new hemodialysis, within 30 days and 1 year after randomization. All data were analyzed using the "intention-to-treat" principle. RESULTS: Early postoperative myocardial infarction was detected in 12.1% (A) vs. 4.1% (B) of patients (P = 0.048, hazard ratio 0.32, 95% CI 0.11-0.99). There was a significantly higher incidence of primary combined end-point in group A (20.6% vs. 9.2%, P = 0.028, HR 0.41, 95% CI 0.19-0.91) in the first 30 days, but not after 1 year (30.8% vs. 21.4%, P = 0.117, HR 0.65, CI 0.37-1.12). CONCLUSION: Off pump surgical revascularization in patients with high operative risks can significantly reduce the incidence of major postoperative complications during the first 30 days. There was no statistically significant difference in the incidence of these complications after 1 year. PMID- 26740050 TI - Clinical manifestations of infective endocarditis in relation to infectious agents: An 8-year retrospective study. AB - AIM: To compare clinical complications and outcomes of infective endocarditis (IE) episodes caused by Staphylococcus aureus (S. aureus) and other most frequent aetiological agents (streptococci, enterococci, coagulase-negative staphylococci, and culture-negative IE). METHODS: A total of 117 IE episodes assessed by all internal medicine services of a major teaching institution in the Czech Republic over an eight-year period were identified. RESULTS: We found that S. aureus IE episodes (n = 36) were significantly more associated with systemic embolism (41.7% vs 18.5%, P = 0.01), severe sepsis/septic shock (33.3% vs 3.7%, P < 0.0001), and in-hospital mortality (33% vs 12.3%, P = 0.01). No differences in local, structural, and/or functional complications (cardiac abscess formation, impaired integrity of the valvular apparatus, conduction disturbances, or incidence of heart failure) were observed between studied groups. Long-term survival estimates were significantly improved in patients with IE caused by agents other than S. aureus (13.78 median years vs 5.48 median years, P=0.03). CONCLUSIONS: IE episodes caused by S. aureus are associated with both increased short-term and long-term mortality. Of all the studied parameters, only systemic embolism and severe sepsis/septic shock predicted in-hospital mortality. PMID- 26740052 TI - Swing time ratio, a new parameter of gait disturbance, for the evaluation of the severity of neuropathic pain in a rat model of partial sciatic nerve ligation. AB - INTRODUCTION: Dynamic weight bearing tests are used to evaluate the chronic pain severity in animal models of nociceptive pain (such as osteoarthritis); however, common tests frequently fail to collect the characteristics of neuropathic pain such as allodynia, because surgical intervention which is sometimes required to establish the models causes both nociceptive and neuropathic pain. METHODS: In this study, we used rats with partial sciatic nerve ligation (PSL) as the neuropathic and chronic pain model. To assess the severity of pain by gait disturbance, we applied automatic analysis on walking function using the GAIT(r) system. The system employs a novel index of abnormal step cycles, the swing time ratio (STR), of laboratory animals. Data were compared to those obtained with conventional tests, including a von Frey test and a hot plate test. Finally, we analyzed recovery of walking function after single or repeated administration of pregabalin. RESULTS: By using rats with PSL, we confirmed that results obtained by the GAIT(r) system were comparable to those obtained by both von Frey tests and hot plate tests. Single administration of pregabalin transiently improved STR, on the other hand, repeated pregabalin treatment showed lasting STR recovery. DISCUSSION: STR is sensitive to claudication of rats with PSL, providing a new scale to evaluate neuropathic pain in addition to conventional tests. Moreover, STR analysis enables us to evaluate walking function of animal models after neuropathic injury, which is quite important to judge the effectiveness of new treatments and analgesics. PMID- 26740053 TI - CD123 redirected multiple virus-specific T cells for acute myeloid leukemia. AB - Hematopoietic stem cell transplantation (HSCT) has been increasingly used as a curative treatment for acute myeloid leukemia (AML). However, relapse rates after HSCT in complete remission (CR) are reported between 30% and 70%. In addition, numerous studies suggested that secondary viral infection from a variety of viruses including Epstein-Barr virus (EBV), adenovirus (Adv), and cytomegalovirus (CMV) are among the most common causes of death post-HSCT. Currently, chimeric antigen receptor (CAR)-based T cells have been developed to treat AML in clinical studies, while virus-specific cytotoxic T cells (VST) have been proven to be able to effectively prevent or treat viral infection after HSCT. Thus it would be desirable to develop T cells with the ability of simultaneously targeting AML relapse and viral infection. In this article, we now describe the generation of VST cells that are engineered to express CAR for a specific AML cell-surface antigen CD123 (CD123-CAR-VST). Using Dendritic cells (DCs) pulsed with EBV, Adv, and CMV peptides as sources of viral antigens, we generated VST from A2 donor peripheral mononuclear cells (PBMC). VST were then transduced with retroviral vector encoding CD123-CAR to generate CD123-CAR-VST. We demonstrated that CD123 CAR-VST recognized EBV, Adv, and CMV epitopes and had HLA-restricted virus specific cytotoxic effector function against EBV target. In addition, CD123-CAR VST retained the specificity against CD123-positive AML cell lines such as MOLM13 and THP-1 in vitro. Thus our results suggested that CD123-CAR-VST might be a valuable candidate to simultaneously prevent or treat relapse and viral infection in AML HSCT recipients. PMID- 26740054 TI - Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells. AB - Bortezomib, a clinical drug for multiple myeloma (MM) and mantle cell lymphoma, exhibits complex mechanisms of action, which vary depending on the cancer type and the critical genetic alterations of each cancer. Here we investigated the signaling mechanisms of bortezomib in mouse B lymphoma and human MM cells deficient in a new tumor suppressor gene, TRAF3. We found that bortezomib consistently induced up-regulation of the cell cycle inhibitor p21(WAF1) and the pro-apoptotic protein Noxa as well as cleavage of the anti-apoptotic protein Mcl 1. Interestingly, bortezomib induced the activation of NF-kappaB1 and the accumulation of the oncoprotein c-Myc, but inhibited the activation of NF kappaB2. Furthermore, we demonstrated that oridonin (an inhibitor of NF-kappaB1 and NF-kappaB2) or AD 198 (a drug targeting c-Myc) drastically potentiated the anti-cancer effects of bortezomib in TRAF3-deficient malignant B cells. Taken together, our findings increase the understanding of the mechanisms of action of bortezomib, which would aid the design of novel bortezomib-based combination therapies. Our results also provide a rationale for clinical evaluation of the combinations of bortezomib and oridonin (or other inhibitors of NF-kappaB1/2) or AD 198 (or other drugs targeting c-Myc) in the treatment of lymphoma and MM, especially in patients containing TRAF3 deletions or relevant mutations. PMID- 26740055 TI - The RNA binding proteins RBM38 and DND1 are repressed in AML and have a novel function in APL differentiation. AB - The RNA binding proteins RBM binding motif protein 38 (RBM38) and DEAD END 1 (DND1) selectively stabilize mRNAs by attenuating RNAse activity or protecting them from micro(mi)RNA-mediated cleavage. Furthermore, both proteins can efficiently stabilize the mRNA of the cell cycle inhibitor p21(CIP1). Since acute myeloid leukemia (AML) differentiation requires cell cycle arrest and RBM38 as well as DND1 have antiproliferative functions, we hypothesized that decreased RBM38 and DND1 expression may contribute to the differentiation block seen in this disease. We first quantified RBM38 and DND1 mRNA expression in clinical AML patient samples and CD34(+) progenitor cells and mature granulocytes from healthy donors. We found significantly lower RBM38 and DND1 mRNA levels in AML blasts and CD34(+) progenitor cells as compared to mature neutrophils from healthy donors. Furthermore, the lowest expression of both RBM38 and DND1 mRNA correlated with t(8;21). In addition, neutrophil differentiation of CD34(+) cells in vitro with G CSF (granulocyte colony stimulating factor) resulted in a significant increase of RBM38 and DND1 mRNA levels. Similarly, neutrophil differentiation of NB4 acute promyelocytic leukemia (APL) cells was associated with a significant induction of RBM38 and DND1 expression. To address the function of RBM38 and DND1 in neutrophil differentiation, we generated two independent NB4RBM38 as well as DND1 knockdown cell lines. Inhibition of both RBM38 and DND1 mRNA significantly attenuated NB4 differentiation and resulted in decreased p21(CIP1) mRNA expression. Our results clearly indicate that expression of the RNA binding proteins RBM38 and DND1 is repressed in primary AML patients, that neutrophil differentiation is dependent on increased expression of both proteins, and that these proteins have a critical role in regulating p21(CIP1) expression during APL differentiation. PMID- 26740056 TI - Anatomy, morphology and evolution of the patella in squamate lizards and tuatara (Sphenodon punctatus). AB - The patella (kneecap) is the largest and best-known of the sesamoid bones, postulated to confer biomechanical advantages including increasing joint leverage and reinforcing the tendon against compression. It has evolved several times independently in amniotes, but despite apparently widespread occurrence in lizards, the patella remains poorly characterised in this group and is, as yet, completely undescribed in their nearest extant relative Sphenodon (Rhynchocephalia). Through radiography, osteological and fossil studies we examined patellar presence in diverse lizard and lepidosauromorph taxa, and using computed tomography, dissection and histology we investigated in greater depth the anatomy and morphology of the patella in 16 lizard species and 19 Sphenodon specimens. We have found the first unambiguous evidence of a mineralised patella in Sphenodon, which appears similar to the patella of lizards and shares several gross and microscopic anatomical features. Although there may be a common mature morphology, the squamate patella exhibits a great deal of variability in development (whether from a cartilage anlage or not, and in the number of mineralised centres) and composition (bone, mineralised cartilage or fibrotendinous tissue). Unlike in mammals and birds, the patella in certain lizards and Sphenodon appears to be a polymorphic trait. We have also explored the evolution of the patella through ancestral state reconstruction, finding that the patella is ancestral for lizards and possibly Lepidosauria as a whole. Clear evidence of the patella in rhynchocephalian or stem lepidosaurian fossil taxa would clarify the evolutionary origin(s) of the patella, but due to the small size of this bone and the opportunity for degradation or loss we could not definitively conclude presence or absence in the fossils examined. The pattern of evolution in lepidosaurs is unclear but our data suggest that the emergence of this sesamoid may be related to the evolution of secondary ossification centres and/or changes in knee joint conformation, where enhancement of extensor muscle leverage would be more beneficial. PMID- 26740057 TI - Distance regularized two level sets for segmentation of left and right ventricles from cine-MRI. AB - This paper presents a new level set method for segmentation of cardiac left and right ventricles. We extend the edge based distance regularized level set evolution (DRLSE) model in Li et al. (2010) to a two-level-set formulation, with the 0-level set and k-level set representing the endocardium and epicardium, respectively. The extraction of endocardium and epicardium is obtained as a result of the interactive curve evolution of the 0 and k level sets derived from the proposed variational level set formulation. The initialization of the level set function in the proposed two-level-set DRLSE model is generated from roughly located endocardium, which can be performed by applying the original DRLSE model. Experimental results have demonstrated the effectiveness of the proposed two level-set DRLSE model. PMID- 26740058 TI - Performance of simultaneous high temporal resolution quantitative perfusion imaging of bladder tumors and conventional multi-phase urography using a novel free-breathing continuously acquired radial compressed-sensing MRI sequence. AB - PURPOSE: To investigate the feasibility of high temporal resolution quantitative perfusion imaging of bladder tumors performed simultaneously with conventional multi-phase MR urography (MRU) using a novel free-breathing continuously acquired radial MRI sequence with compressed-sensing reconstruction. METHODS: 22 patients with bladder lesions underwent MRU using GRASP (Golden-angle RAdial Sparse Parallel) acquisition. Multi-phase contrast-enhanced abdominopelvic GRASP was performed during free-breathing (1.4*1.4*3.0mm(3) voxel size; 3:44min acquisition). Two dynamic datasets were retrospectively reconstructed by combining different numbers of sequentially acquired spokes into each dynamic frame: 110 spokes per frame for 25-s temporal resolution (serving as conventional MRU for clinical interpretation) and 8 spokes per frame for 1.7-s resolution. Using 1.7-s resolution images, ROIs were placed within bladder lesions and normal bladder wall, a femoral artery arterial input function was generated, and the Generalized Kinetic Model was applied. RESULTS: Biopsy/cystectomy demonstrated 16 bladder tumors (13 stage>=T2, 3 stage<=T1) and 6 benign lesions. All lesions were well visualized using 25-s clinical multi-phase images. Using 1.7-s resolution images, K(trans) was significantly higher in tumors (0.38+/-0.24) than normal bladder (0.12+/-0.02=8, p<0.001) or benign lesions (0.15+/-0.04, p=0.033). Ratio between K(trans) of lesions and normal bladder was nearly double for tumors than benign lesions (4.3+/-3.4 vs. 2.2+/-1.6), and K(trans) was nearly double in stage>=T2 than stage<=T1 tumors (0.44+/-0.24 vs. 0.24+/-0.24), although these did not approach significance (p=0.180-0.209), possibly related to small sample size. CONCLUSION: GRASP allows simultaneous quantitative high temporal resolution perfusion of bladder lesions during clinical MRU examinations using only one contrast injection and without additional scan time. PMID- 26740060 TI - Differences in the vascular tree of the femoral trochlear growth cartilage at osteochondrosis-susceptible sites in foals revealed by SWI 3T MRI. AB - Focal ischemic chondronecrosis of epiphyseal growth cartilage (EGC) during endochondral ossification is believed to be a key early event on the pathway to osteochondrosis (OC) in both animals and humans. The lateral ridge of the equine trochlea is a site where severe osteochondritis dissecans lesions frequently arise and is a model for the study of naturally occurring disease. Non-invasive imaging to investigate EGC vascularity may help elucidate why focal ischemia occurs. 3T MRI susceptibility-weighted imaging (SWI) of femoral trochlea of OC predisposed (n = 10) and control (n = 6) day-old foals, with minimal joint loading after birth, was performed. SWI and 3D images revealed the EGC vascular architecture without a contrast agent, and matched histologic observations. No vascular lesions were identified. There was no difference in the vascular density and architecture between control and OC specimens, but a striking difference in vascular pattern was seen at the OC-predilected site in the lateral ridge of the trochlea in all specimens, when compared to the medial ridge of the trochlea, where OC lesions are rarely observed. This site was less ossified with more perichondrial vessels not yet bridging with the subchondral bone. Furthermore, the mean vascular density of all specimens was significantly higher at this site. We speculate that joint morphology and focal internal trauma on this site with a unique vascular architecture may trigger ischemic events at this site. SWI permitted visualization of EGC in young foals with a clinical 3T MRI and paves the way for non-destructive longitudinal studies to improve understanding of OC in all species. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1539-1546, 2016. PMID- 26740061 TI - The Highs and Lows of Measuring Thrombopoietin in Aplastic Anemia. PMID- 26740062 TI - Evaluating Individual Change With the Quality of Life in Neurological Disorders (Neuro-QoL) Short Forms. AB - OBJECTIVE: To provide a clinically useful means of interpreting change for individual patients on the Quality of Life in Neurological Disorders (Neuro-QoL) adult short forms (SFs) by applying a classical test theory concept for interpreting individual change. DESIGN: Secondary analysis of existing data. SETTING: Community. PARTICIPANTS: Persons with neurologic conditions including stroke, epilepsy, amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson disease residing in community settings. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Neuro-QoL SFs for Applied Cognition-General Concerns, Applied Cognition-Executive Function, Applied Cognition-Combined, Ability to Participate in Social Roles and Activities, Satisfaction With Social Roles and Activities, Positive Affect and Well-Being, Depression, Stigma, Upper Extremity Function (Fine Motor, Activities of Daily Living), Lower Extremity Function (Mobility), Anxiety, Sleep Disturbance, Fatigue, and Emotional and Behavioral Dyscontrol. We estimated conditional minimal detectable change (cMDC) indices from the pooled SEs adjusted for a 95% confidence interval using the average of the SEs for any given pair of scores multiplied by the z score, or ([SE(Score1) + SE(Score2)]/2) * (1.96) * (SQRT(2)). RESULTS: The cMDC indices are generally smallest in the midrange of all scales, ranging from 3.6 to 11.2 T-score points, and higher on the outer quartiles ranging from 3.7 to 21.6 T-score points. The lowest midrange cMDCs were for Satisfaction With Social Roles and Activities (3.6 4.7 T-score points), and the largest were for Sleep Disturbance (9.4-11.2 T-score points). CONCLUSIONS: Change indices can help clinicians and investigators identify differences for individual patients or subjects that are large enough to motivate treatment change. cMDCs can reduce misclassification of magnitudes of change that are near the margins of error across the range of the Neuro-QoL SFs. PMID- 26740063 TI - Utility of Ultrasound for Imaging Osteophytes in Patients With Insertional Achilles Tendinopathy. AB - OBJECTIVES: To examine (1) the validity of ultrasound imaging to measure osteophytes and (2) the association between osteophytes and insertional Achilles tendinopathy (IAT). DESIGN: Case-control study. SETTING: Academic medical center. PARTICIPANTS: Persons with chronic unilateral IAT (n=20; mean age, 58.7+/-8.3y; 10 [50%] women) and age- and sex-matched controls (n=20; mean age, 57.4+/-9.8y; 10 [50%] women) participated in this case-control study (N=40). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Symptom severity was assessed using the Foot and Ankle Ability Measure, the Victorian Institute of Sport Assessment Achilles questionnaire, and the numerical rating scale. Length of osteophytes was measured bilaterally in both groups using ultrasound imaging, as well as on the symptomatic side of the IAT group using radiography. The intraclass correlation coefficient was used to examine the agreement between ultrasound and radiograph measures. McNemar, Wilcoxon signed-rank, and Fisher exact tests were used to compare the frequency and length of osteophytes between sides and groups. Pearson correlation was used to examine the association between osteophyte length and symptom severity. RESULTS: There was good agreement (intraclass correlation coefficient, >=.75) between ultrasound and radiograph osteophyte measures. There were no statistically significant differences (P>.05) in the frequency of osteophytes between sides or groups. Osteophytes were larger on the symptomatic side of the IAT group than on the asymptomatic side (P=.01) and on the left side of controls (P=.03). There was no association between osteophyte length and symptom severity. CONCLUSIONS: Ultrasound imaging is a valid measure of osteophyte length, which is associated with IAT. Although a larger osteophyte indicates tendinopathy, it does not indicate more severe IAT symptoms. PMID- 26740064 TI - Social Cognitive Correlates of Physical Activity in Black Individuals With Multiple Sclerosis. AB - OBJECTIVE: To examine variables from social cognitive theory as correlates of physical activity in black and white individuals with multiple sclerosis (MS). DESIGN: Cross-sectional. SETTING: National survey. PARTICIPANTS: Black (n=151) and white (n=185) individuals with MS were recruited through the North American Research Committee on Multiple Sclerosis Registry. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: The battery of questionnaires included information on demographic and clinical characteristics, physical activity, exercise self efficacy, function, social support, exercise outcome expectations, and exercise goal setting and planning. RESULTS: Black individuals with MS reported significantly lower levels of physical activity compared with white individuals with MS. Physical activity levels were significantly correlated with self efficacy, outcome expectations, functional limitations as impediments, and goal setting in black participants with MS. The pattern and magnitude of correlations were comparable with those observed in white participants based on Fisher z tests. CONCLUSIONS: Researchers should consider applying behavioral interventions that target social cognitive theory variables for increasing physical activity levels among black individuals with MS. PMID- 26740066 TI - Does mouse embryo primordial germ cell activation start before implantation as suggested by single-cell transcriptomics dynamics? AB - STUDY HYPOTHESIS: Does primordial germ cell (PGC) activation start before mouse embryo implantation, and does the possible regulation of the DNA (cytosine-5-) methyltransferase 3-like (Dnmt3l) by transcription factor AP-2, gamma (TCFAP2C) have a role in this activation and in the primitive endoderm (PE)-epiblast (EPI) lineage specification? STUDY FINDING: A burst of expression of PGC markers, such as Dppa3/Stella, Ifitm2/Fragilis, Fkbp6 and Prdm4, is observed from embryonic day (E) 3.25, and some of them, together with the late germ cell markers Zp3, Mcf2 and Morc1, become restricted to the EPI subpopulation at E4.5, while the dynamics analysis of the PE-EPI transitions in the single-cell data suggests that TCFAP2C transitorily represses Dnmt3l in EPI cells at E3.5 and such repression is withdrawn with reactivation of Dnmt3l expression in PE and EPI cells at E4.5. WHAT IS KNOWN ALREADY: In the mouse preimplantation embryo, cells with the same phenotype take different fates based on the orchestration between topological clues (cell polarity, positional history and division orientation) and gene regulatory rules (at transcriptomics and epigenomics level), prompting the proposal of positional, stochastic and combined models explaining the specification mechanism. PGC specification starts at E6.0-6.5 post-implantation. In view of the important role of DNA methylation in developmental events, the cross-talk between some transcription factors and DNA methyltransferases is of particular relevance. TCFAP2C has a CpG DNA methylation motif that is not methylated in pluripotent cells and that could potentially bind on DNMT3L, the stimulatory DNA methyltransferase co-factor that assists in the process of de novo DNA methylation. Chromatin-immunoprecipitation analysis has demonstrated that Dnmt3l is indeed a target of TCFAP2C. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: We aimed to assess the timing of early preimplantation events and to understand better the segregation of the inner cell mass (ICM) into PE and EPI. We designed a single-cell transcriptomics dynamics computational study to identify markers of the PE-EPI bifurcation in ICM cells through searching for statistically significant (using the Student's t-test method) differently expressed genes (DEGs) between PE and EPI cells from E3.5 to E4.5. The DEGs common for E3.5 and E4.5 were used as the markers defining the steady states. We collected microarray and next-generation sequencing transcriptomics data from public databases from bulk populations and single cells from mice at E3.25, E3.5 and E4.5. The results are based on three independent single-cell transcriptomics data sets, with a fold change of 3 and P-value <0.01 for the DEG selection. MAIN RESULTS AND THE ROLE OF CHANCE: The dynamics analysis revealed new transitory E3.5 and steady PE and EPI markers. Among the transitory E3.5 PE markers (Dnmt3l, Dusp4, Cpne8, Akap13, Dcaf12l1, Aaed1, B4galt6, BC100530, Rnpc3, Tfpi, Lgalsl, Ckap4 and Fbxl20), several (Dusp4, Akap13, Cpn8, Dcaf12l1 and Tfpi) are related to the extracellular regulated kinase pathway. We also identified new transitory E3.5 EPI markers (Sgk1, Mal, Ubxn2a, Atg16l2, Gm13102, Tcfap2c, Hexb, Slc1a1, Svip, Liph and Mier3), six new stable PE markers (Sdc4, Cpn1, Dkk1, Havcr1, F2r/Par1 and Slc7a6os) as well as three new stable EPI markers (Zp3, Mcf2 and Hexb), which are known to be late stage germ cell markers. We found that mouse PGC marker activation starts at least at E3.25 preimplantation. The transcriptomics dynamics analyses support the regulation of Dnmt3l expression by TCFAP2C. LIMITATIONS, REASONS FOR CAUTION: Since the regulation of Dnmt3l by TCFAP2C is based on computational prediction of DNA methylation motifs, Chip-Seq and transcriptomics data, functional studies are required to validate this result. WIDER IMPLICATIONS OF THE FINDINGS: We identified a collection of previously undescribed E3.5-specific PE and EPI markers, and new steady PE and EPI markers. Identification of these genes, many of which encode cell membrane proteins, will facilitate the isolation and characterization of early PE and EPI populations. Since it is so well established in the literature that mouse PGC specification is a post-implantation event, it was surprising for us to see activation of PGC markers as early as E3.25 preimplantation, and identify the newly found steady EPI markers as late germ cell markers. The discovery of such early activation of PGC markers has important implications in the derivation of germ cells from pluripotent cells (embryonic stem cells or induced pluripotent stem cells), since the initial stages of such derivation resemble early development. The early activation of PGC markers points out the difficulty of separating PGC cells from pluripotent populations. Collectively, our results suggest that the combining of the precision of single-cell omics data with dynamic analysis of time-series data can establish the timing of some developmental stages as earlier than previously thought. LARGE-SCALE DATA: Not applicable. STUDY FUNDING AND COMPETING INTERESTS: This work was supported by grants DFG15/14 and DFG15/020 from Diputacion Foral de Gipuzkoa (Spain), and grant II14/00016 from I + D + I National Plan 2013-2016 (Spain) and FEDER funds. The authors declare no conflict of interest. PMID- 26740065 TI - Dimensionality and Item-Difficulty Hierarchy of the Lower Extremity Fugl-Meyer Assessment in Individuals With Subacute and Chronic Stroke. AB - OBJECTIVE: To investigate the dimensionality and item-difficulty hierarchy of the Fugl-Meyer Assessment of the lower extremity (FMA-LE). DESIGN: Secondary analyses of data pooled from 4 existing datasets: a phase III randomized controlled trial investigating the effectiveness of body weight support and a treadmill for rehabilitation of walking poststroke, and 3 cross-sectional studies investigating the link between impaired motor performance poststroke and walking. SETTING: University research centers and rehabilitation centers. PARTICIPANTS: A pooled sample of individuals with a stroke (N=535, men=313; mean age +/- SD, 61.91+/ 12.42y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Confirmatory factor analyses (CFA) and Rasch residual principal component analysis (PCA) investigated the dimensionality of the FMA-LE. The Rasch analysis rating scale model investigated item-difficulty hierarchy of the FMA-LE. RESULTS: The CFA showed adequate fit of a 3-factor model, with 2 out of 3 indices (CFA=.95; Tucker Lewis Index=.94; root mean square error of approximation=.124) showing good model fit. Rasch PCA showed that removal of the reflex and coordination items explained 90.8% of variance in the data, suggesting that the abnormal synergy items contributed to the measurement of a unidimensional construct. However, rating scale model results revealed deviations in the item-difficulty hierarchy of the unidimensional abnormal synergy items from the originally proposed stepwise sequence of motor recovery. CONCLUSIONS: Our findings suggest that the FMA-LE might represent a multidimensional construct, challenging the use of a total score of the FMA-LE to predict lower extremity motor recovery. Removal of the misfit items resulted in creation of a unidimensional scale composed of the abnormal synergy items. However, this unidimensional scale deviates from the originally proposed hierarchical ordering. PMID- 26740073 TI - ENT and airways in the emergency department: national survey of junior doctors' knowledge and skills. AB - BACKGROUND: Given the urgent nature of ENT emergencies, appropriate knowledge is required amongst front-line staff. Junior doctors account for almost one quarter of emergency department doctors. It has been shown that undergraduate coverage of ENT is variable. This study therefore aimed to determine whether emergency department junior doctors were confident in dealing with ENT emergencies, with special focus on the airway. METHOD: An online survey was circulated to junior doctors working in emergency medicine, at the discretion of their training co ordinators. RESULTS: A total of 104 responses were received. Junior doctors were not confident in managing patients who have undergone tracheostomy or laryngectomy. Management of stridor varied, with 51 per cent giving oxygen and only 77 per cent referring such patients as an emergency to ENT. Most training on the management of airway emergencies was not provided through hospital induction. CONCLUSION: Training should be provided to junior doctors starting work in the emergency department. We suggest mandatory multidisciplinary induction training for such staff. PMID- 26740072 TI - Transverse electron momentum distribution in tunneling and over the barrier ionization by laser pulses with varying ellipticity. AB - We study transverse electron momentum distribution in strong field atomic ionization driven by laser pulses with varying ellipticity. We show, both experimentally and theoretically, that the transverse electron momentum distribution in the tunneling and over the barrier ionization regimes evolves in a qualitatively different way when the ellipticity parameter describing polarization state of the driving laser pulse increases. PMID- 26740067 TI - The mouse endometrium contains epithelial, endothelial and leucocyte populations expressing the stem cell marker telomerase reverse transcriptase. AB - STUDY HYPOTHESIS: The mouse endometrium harbours stem/progenitor cells that express the stem cell marker mouse telomerase reverse transcriptase (mTert). STUDY FINDING: We used a mouse carrying a transgenic reporter for mTert promoter activity to identify rare endometrial populations of epithelial and endothelial cells that express mTert. WHAT IS KNOWN ALREADY: Stem/progenitor cells are hypothesized to be responsible for the remarkable regenerative capacity of the endometrium, but the lack of convenient endometrial stem/progenitor markers in the mouse has hampered investigations into the identity of these cells. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: A mouse containing a green fluorescent protein (GFP) reporter under the control of the telomerase reverse transcriptase promoter (mTert-GFP) was used to identify potential stem/progenitor cells in the endometrium. mTert promoter activity was determined using fluorescence microscopy and flow cytometry to identify GFP(+) cells. GFP(+) cells were examined for epithelial, stromal, endothelial, leucocyte and proliferation markers and bromodeoxyuridine retention to determine their identity. The endometrium of ovariectomized mice was compared to that of intact cycling mice to establish the role of ovarian hormones in maintaining mTert-expressing cells. MAIN RESULTS AND THE ROLE OF CHANCE: We found that mTert-GFP is expressed by rare luminal and glandular epithelial cells (0.3% of epithelial cells by flow cytometry), rare CD45(-) cells in the stromal compartment (0.028 +/- 0.010% of stromal cells by microscopy) and many CD45(+) leucocytes. Ovariectomy resulted in significant decrease of mTert-GFP(+) epithelial cells (P = 0.029 for luminal epithelium; P = 0.034 for glandular epithelium) and a decrease in the percentage of mTert-GFP(+) CD45(+) leucocytes in the stromal compartment (P = 0.015). However, CD45(-) mTert GFP(+) cells in the stromal compartment were maintained in ovariectomized mice. This population is enriched for cells bearing the endothelial marker CD31 (10.3% of CD90(-) CD45(-) and 97.8% CD90(+) CD45(-) by flow cytometry). CD45(-) mTert GFP(+) cells also immunostained for the endothelial marker von Willebrand factor. These results suggest that the endometrial epithelium and vasculature are foci of stem/progenitor activity and provide a system to investigate molecular mechanisms involved in endometrial regeneration and repair. LIMITATIONS, REASONS FOR CAUTION: The stem/progenitor activity of endometrial mTert-GFP(+) cells needs to be experimentally verified. WIDER IMPLICATIONS OF THE FINDINGS: The identification and characterization of mTert-expressing progenitor cells in the mouse will facilitate the identification of equivalent populations in the human endometrium that are likely to be involved in endometrial function, fertility and disease. LARGE-SCALE DATA: Not applicable. STUDY FUNDING AND COMPETING INTERESTS: This study was funded by National Health and Medical Research Council (NHMRC) of Australia grants (1085435, C.E.G., J.A.D.), 1021127 (C.E.G.), NHMRC Senior Research Fellowship (1042298, C.E.G.), the Victorian Infrastructure Support Program, U.S. National Institutes of Health grant R01 DK084056 (D.T.B.) and the Harvard Stem Cell Institute (D.T.B.). The authors have no conflicts of interest to declare. PMID- 26740075 TI - Pathological crying and emotional vasovagal syncope as symptoms of a dorsally exophytic medullary tumor. AB - A 3-year-old boy with a dorsally exophytic tumor arising from the rostral medulla presented with a chief complaint of a change in his emotional behavior, most notably anxiety and paroxysmal crying often followed by syncope. Magnetic resonance imaging revealed that the tumor pushed on the dorsal surface of the medulla and displaced the medulla anteriorly, and also displaced the cerebellar vermis upward and slightly posteriorly. Tissue from a partial resection was diagnosed as a pilocytic astrocytoma. The symptoms did not improved after surgery, but did improve clinically after chemotherapy with vincristine and carboplatin, at which time MR showed a reduction in tumor size. We diagnosed the paroxysmal crying as 'pathological crying' and the syncope with increased anxiety as 'emotional vasovagal syncope'. This case stresses the importance of recognition of this rare presentation as an indication of a medullary tumor. PMID- 26740076 TI - Sleep health, messaging, headaches, and academic performance in high school students. AB - AIM: We tested for associations of bedtime, sleep duration, instant messaging, and chronic headaches with hypersomnolence and academic performance in a sample of high school students in New Jersey, USA. METHODS: Students were surveyed anonymously and asked to report their sleep and messaging habits, headache status, and overall grades. RESULTS: We found that greater hypersomnolence was associated with later bedtimes, shorter sleep durations, and the presence of chronic headaches, but not with messaging after lights out. Also, we found that academic performance was lower in students who messaged after lights out, but it was not affected by headache status, bedtime, or sleep duration. CONCLUSIONS: These results are consistent with other studies that have demonstrated associations between headaches and hypersomnolence and between instant messaging habits and academic performance. They also add to a growing literature on the relationships among use of electronic devices, sleep health, and academic performance by adolescents. PMID- 26740077 TI - Autoimmune autonomic ganglionopathy in a pediatric patient presenting with acute encephalitis. AB - Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to systemic autonomic failure. Autoantibodies to the ganglionic nicotinic acetylcholine receptor (gAChR) are detected in 50% of AAG patients. We report the first pediatric case of AAG presenting with acute encephalitis. The patient was a 13-year-old boy who presented with orthostatic hypotension, followed by rapidly progressing disturbance of consciousness. Cerebrospinal fluid analysis revealed significant pleocytosis and increased neopterin concentration. Head MRI showed hyperintensities in bilateral caudate nuclei, putamen, hippocampus, and insula cortex. Severe autonomic dysfunctions such as severe orthostatic hypotension, bradycardia, dysuria, prolonged constipation and vomiting appeared. These symptoms were successfully controlled by repeated immunomodulating therapy with intravenous methylprednisolone pulse therapy and intravenous immunoglobulin. Autoantibodies to the alpha3 subunit of gAChR were detected at neurological onset, but were undetectable five months later. This observation indicates that AAG should be suspected in patients manifesting acute encephalitis characterized by preceding and prolonged autonomic symptoms, and immunomodulating therapy from an early stage can be effective. PMID- 26740078 TI - Toxicological assessment of nattokinase derived from Bacillus subtilis var. natto. AB - Subtilisin NAT, commonly known as "nattokinase," is a fibrinolytic enzyme produced by the bacterial strain B. subtilis var. natto, which plays a central role in the fermentation of soybeans into the popular Japanese food natto. Recent studies have reported on the potential anticoagulatory and antihypertensive effects of nattokinase administration in humans, with no indication of adverse effects. To evaluate the safety of nattokinase in a more comprehensive manner, several GLP-compliant studies in rodents and human volunteers have been conducted with the enzyme product, NSK-SD (Japan Bio Science Laboratory Co., Ltd., Japan). Nattokinase was non-mutagenic and non-clastogenic in vitro, and no adverse effects were observed in 28-day and 90-day subchronic toxicity studies conducted in Sprague-Dawley rats at doses up to 167 mg/kg-day and 1000 mg/kg-day, respectively. Mice inoculated with 7.55 * 10(8) CFU of the enzyme-producing bacterial strain showed no signs of toxicity or residual tissue concentrations of viable bacteria. Additionally consumption of 10 mg/kg-day nattokinase for 4 weeks was well tolerated in healthy human volunteers. These findings suggest that the oral consumption of nattokinase is of low toxicological concern. The 90-day oral subchronic NOAEL for nattokinase in male and female Sprague-Dawley rats is 1000 mg/kg-day, the highest dose tested. PMID- 26740080 TI - Hemidesmosomes: how much plakins do they need? PMID- 26740081 TI - LRRK2 at the Crossroad Between Autophagy and Microtubule Trafficking: Insights into Parkinson's Disease. AB - Mutations in leucine-rich repeat kinase 2 ( lrrk2) gene cause inherited Parkinson's disease (PD), and common variants in lrrk2 are a risk factor for sporadic PD. The neuropathology associated with LRRK2-linked PD is extremely pleomorphic involving inclusions of alpha-synuclein (SNCA), tau or neither, therefore suggesting that LRRK2 may be central in the pathogenic pathways of PD. This large protein localizes in the cytosol, as well as, in specific membrane domains, including mitochondria and autophagosomes and interacts with a wide range of proteins such as SNCA, tau, alpha- and beta-tubulin. For this reason LRRK2 has been associated with a variety of cellular functions, including autophagy, mitochondrial function/dynamics and microtubule/cytoskeletal dynamics. LRRK2 has been shown to interact with microtubules as well as with mitochondria interfering with their network and dynamics. Moreover, LRRK2 knock-out or mutations affect autophagic efficiency. Here, we review and discuss the literature on how LRRK2 affects mitochondrial function, autophagy, and microtubule dynamics and how this is implicated in the PD etiology. PMID- 26740082 TI - Corrigendum. AB - Corrigendum for 'Relearning to See in Cortical Blindness' by Michael D. Melnick, Duje Tadin, Krystel R. Huxlin. The Neuroscientist 2015, 10.1177/1073858415621035.The Corresponding Author as listed in the original published version of this article was incorrect. It should have read:Krystel R. Huxlin, University of Rochester Flaum Eye Institute, Rochester, NY 14642Email: huxlin@mail.cvs.rochester.edu. PMID- 26740084 TI - Tubercular infection after arthroscopic rotator cuff repair. AB - Tubercular septic arthritis after shoulder arthroscopy has not been reported in the English literature to our knowledge. A case of Tubercular septic arthritis of the shoulder following arthroscopic rotator cuff repair is presented. The sinus and the wound healed well, and laboratory parameters returned to normal, which suggests that the infection was well controlled with the treatment follow-up of 1 year. But the functional score was poor due to repeated surgeries; long-standing infection and the arthritic changes developed. Tubercular infection can occur after arthroscopic shoulder surgery especially in healthcare workers in zones endemic for Tuberculosis. Level of evidence V. PMID- 26740085 TI - A cadaveric assessment of the risk of nerve injury during open subpectoral biceps tenodesis using a bicortical guidewire. AB - PURPOSE: To evaluate the risk of neurological injury from the placement of a bicortical guidewire during subpectoral biceps tenodesis. METHODS: Ten forequarter cadaver specimens were evaluated. A bicortical guidewire was placed, and measurements to important local neurological structures were made with digital calipers at open dissection. RESULTS: The mean (range, SD) distances from the guidewire to the respective nerves was as follows: axillary nerve posteriorly, 15.7 mm (10-22 mm, 3.4); axillary nerve laterally, 18.7 mm (12-27 mm, 4.3); radial nerve posteriorly, 26.2 mm (16-35 mm, 7.0); radial nerve medially, 25 mm (16-33 mm, 4.4); and musculocutaneous nerve, 20.1 mm (12-26 mm, 5.2). CONCLUSIONS: There has been some disagreement in the literature regarding the proximity of a bicortical guidewire to the axillary nerve posteriorly. The results of this study concur with reports from several other authors and demonstrate that this nerve is at risk of iatrogenic injury when using this technique. The clinical relevance of this work is to allow surgeons to better understand the proximity of the nerve to a bicortical guidewire and to highlight that this risk is avoided with a unicortical technique. PMID- 26740086 TI - Evaluation of the size and position of the insertion of the anterior medial meniscus root in varus osteoarthritic knees. AB - PURPOSE: Recent studies have suggested radial displacement of the medial meniscus as a cause of varus knee osteoarthritis (OA). Two anatomical studies reported that such displacement may be associated with anterior insertion of the medial meniscus anterior horn. It was aimed to evaluate the location and area of this insertion in patients with advanced knee OA. METHODS: Medial meniscus anterior horn insertions were classified into four types, as described in a previously reported classification during 225 total knee arthroplasty (TKA) in 184 patients. The incidence rates of insertion type were compared with previously reported rates in nearly normal or non-arthritic knees. The insertion surface area was also measured during 158 TKAs. RESULTS: Of the 225 knees, 82 (36.4 %), 93 (41.3 %), 35 (15.6 %), and 15 (6.7 %) were classified as I, II, III, and IV, respectively. An anteriorly inserted anterior horn was not more frequent in advanced varus OA knees than in previously reported nearly normal or non arthritic knees. The insertion surface areas were 57.5 +/- 18.9, 56.1 +/- 16.0, and 56.4 +/- 14.4 mm2 for types I, II, and III, respectively; these areas did not differ significantly. CONCLUSION: Since the incidence of an anteriorly inserted medial meniscus anterior horn was not higher in advanced varus OA knees than in normal or non-arthritic knees, an anteriorly inserted anterior horn may have little or no effect on the aetiology of varus OA knees. This study provides some information for clarifying the aetiology of knee OA. LEVEL OF EVIDENCE: IV. PMID- 26740087 TI - Cross-cultural adaptation and validation of Persian Achilles tendon Total Rupture Score. AB - PURPOSE: To cross-culturally adapt the Achilles tendon Total Rupture Score (ATRS) to Persian language and to preliminary evaluate the reliability and validity of a Persian ATRS. METHODS: A cross-sectional and prospective cohort study was conducted to translate and cross-culturally adapt the ATRS to Persian language (ATRS-Persian) following steps described in guidelines. Thirty patients with total Achilles tendon rupture and 30 healthy subjects participated in this study. Psychometric properties of floor/ceiling effects (responsiveness), internal consistency reliability, test-retest reliability, standard error of measurement (SEM), smallest detectable change (SDC), construct validity, and discriminant validity were tested. Factor analysis was performed to determine the ATRS-Persian structure. RESULTS: There were no floor or ceiling effects that indicate the content and responsiveness of ATRS-Persian. Internal consistency was high (Cronbach's alpha 0.95). Item-total correlations exceeded acceptable standard of 0.3 for the all items (0.58-0.95). The test-retest reliability was excellent [(ICC)agreement 0.98]. SEM and SDC were 3.57 and 9.9, respectively. Construct validity was supported by a significant correlation between the ATRS-Persian total score and the Persian Foot and Ankle Outcome Score (PFAOS) total score and PFAOS subscales (r = 0.55-0.83). The ATRS-Persian significantly discriminated between patients and healthy subjects. Explanatory factor analysis revealed 1 component. CONCLUSION: The ATRS was cross-culturally adapted to Persian and demonstrated to be a reliable and valid instrument to measure functional outcomes in Persian patients with Achilles tendon rupture. LEVEL OF EVIDENCE: II. PMID- 26740088 TI - Joint awareness in osteoarthritis of the hip and knee evaluated with the 'Forgotten Joint' Score before and after joint replacement. AB - PURPOSE: To utilize the 'Forgotten Joint' Score (FJS), a 12-item questionnaire analysing the ability to forget the joint, for comparing preoperative status in osteoarthritic patients scheduled for total hip arthroplasty (THA) or total knee arthroplasty (TKA). Higher scores represent a better result with a maximum of 100. The hypothesis of this study was that a preoperative difference in favour of hip arthritis could eventually explain why THA is cited more often as a forgotten joint than TKA. METHODS: A prospective cohort study was conducted in 150 patients with either tricompartmental knee (n = 75) or hip osteoarthritis (n = 75). Patients completed FJS-12 scores preoperatively and 1 year postoperatively. RESULTS: A similar preoperative FJS-12 was observed for hip (22 (15)) and knee osteoarthritis (24 (17)) (n.s.). The postoperative FJS-12 score was significantly higher for THA (80 (24)) than for TKA (70 (27)) (p < 0.05). High reliability after 6 weeks was observed for the preoperative FJS-12 test-retest reliability (ICC = 0.87) in TKA. A preoperative floor effect of 15 % in THA and 0 % in TKA was found as well as a postoperative ceiling effect of 33 % in THA and 9 % in TKA. CONCLUSIONS: The clinical relevance of utilizing the FJS-12 as an instrument to evaluate outcome is strongly proposed for knee arthroplasty. In general, one is not aware of a healthy joint during the ADL, and it can therefore be regarded as 'forgotten'. The preoperative FJS-12 Score is a powerful tool to provide patients with clearer insights into their positive evolution after surgery. The use of the FJS-12 in THA is a topic for further research, as this study found that floor and ceiling effects limit its usefulness in studies evaluating clinical outcome in this area. LEVEL OF EVIDENCE: II. PMID- 26740090 TI - Targeted Therapy Management in NSCLC Patients Using Cytology: Experience from a Tertiary Care Cancer Center. AB - BACKGROUND: Although biopsy is the gold standard for diagnosis, cytological material has often been used to assist in making a pathologic diagnosis as well as for molecular testing in certain cancers such as in the lung, cervix, and head/neck. OBJECTIVE: Our objective is to share experience from our institution in the use of cytological material in screening for epidermal growth factor receptor (EGFR) mutations in a subset of patients with non-small cell lung cancer (NSCLC). METHODS: Fine needle aspirates, pleural effusion, cell blocks of 223 NSCLC patients, where cytology suggested malignancy were screened for EGFR mutation in exons 18-21 using Scorpion((r)) ARMS real-time polymerase chain reaction (PCR) technology. RESULTS: Overall, EGFR mutation was seen in 43.5 % of study samples. Deletions were highest in exon 19 (27.2 %), followed by exon 21 (15.5 %), exon 18 (5.3 %), and exon 20 (1.9 %). Chi-squared analysis revealed a significant correlation for mutation status in women compared with men (chi (2) = 5.88, p = 0.02), with exon 19 mutation predominating (chi (2) = 5.66, p = 0.02). CONCLUSION: Our results demonstrate the successful use of cytology material for molecular testing in a subset of NSCLC patients to direct their treatment. PMID- 26740089 TI - Peroneal tendons well vascularized: results from a cadaveric study. AB - PURPOSE: Peroneal tendon tears are relatively common injuries that seem to have a poor healing tendency. The discussion goes that peroneal tendons have avascular zones, contributing to the poor healing of those tears. The purpose of this study was to provide evidence on the vascularization pattern of the peroneal tendons. METHODS: Ten adult fresh-frozen cadavers were obtained from a university affiliated body donation programme. The femoral artery was injected with natural coloured latex at the level of the knee. Macroscopic and microscopic dissections were performed to visualize the vascularization towards the peroneal tendons. To expose intratendinous vascularity, the tendons were cleared using a modified Spalteholz technique. RESULTS: In all specimens, blood was mainly supplied by the peroneal artery through a posterolateral vincula connecting both tendons. Branches were bifurcated every 3.9 +/- 1.8 cm, starting 24 +/- 5.3 cm proximal to the tip of the fibula. Eight out of 10 (80%) specimens had poor vascularized zones in the peroneus longus tendon. No avascular zones were found in the peroneus brevis tendon. CONCLUSION: The peroneal tendons are well vascularized by the peroneal artery, via vessels running through a common vincula for both tendons. In the peroneus brevis, no avascular zones were found. To keep the tendons well vascularized and therefore improve tendon healing, surgeons should be careful leaving the vincula intact during surgical procedures. PMID- 26740091 TI - Biallelic FANCD1/BRCA2 mutations predisposing to glioblastoma multiforme with multiple oncogenic amplifications. AB - Fanconi anaemia (FA) caused by biallelic mutation in FANCD1/BRCA2 is rare but carries a high risk of early onset cancer. Medulloblastoma is well described in this cohort but reports of other brain tumours are uncommon. The molecular profile of tumours from FA patients is not well reported. A glioblastoma multiforme (GBM) from a 3-year-old patient with FA and confirmed biallelic BRCA2 mutations was submitted for methylation analysis. This revealed strong clustering with the K27 mutation subgroup and copy number analysis showed gains of chromosomes 1q, 4q, part of 7q, part of 8q and 17q with resultant amplifications of MDM4, CDK6, MET, MYC and PPM1D (WIP1). We also describe for the first time the germline mutation in BRCA2 c.8057T > C resulting in p.Leu2686Pro in our patient with confirmed FA. Biallelic BRCA2 mutations have predisposed to an aggressive and universally fatal subtype of childhood GBM in our patient. Copy number alterations and multiple oncogenic amplifications may be secondary to inherent chromosomal instability and this raises the question of what role BRCA2 may play in the development of GBM in children without FA. PMID- 26740093 TI - Editorial: "Infectious Diseases in Asia-Pacific: Historical and Contemporary Perspectives". PMID- 26740092 TI - An Internet-supported Physical Activity Intervention Delivered in Secondary Schools Located in Low Socio-economic Status Communities: Study Protocol for the Activity and Motivation in Physical Education (AMPED) Cluster Randomized Controlled Trial. AB - BACKGROUND: School-based physical education is an important public health initiative as it has the potential to provide students with regular opportunities to participate in moderate-to-vigorous physical activity (MVPA). Unfortunately, in many physical education lessons students do not engage in sufficient MVPA to achieve health benefits. In this trial we will test the efficacy of a teacher professional development intervention, delivered partially via the Internet, on secondary school students' MVPA during physical education lessons. Teaching strategies covered in this training are designed to (i) maximize opportunities for students to be physically active during lessons and (ii) enhance students' autonomous motivation towards physical activity. METHOD: A two-arm cluster randomized controlled trial with allocation at the school level (intervention vs. usual care control). Teachers and Year 8 students in government-funded secondary schools in low socio-economic areas of the Western Sydney region of Australia will be eligible to participate. During the main portion of the intervention (6 months), teachers will participate in two workshops and complete two implementation tasks at their school. Implementation tasks will involve video based self-reflection via the project's Web 2.0 platform and an individualized feedback meeting with a project mentor. Each intervention school will also complete two group peer-mentoring sessions at their school (one per term) in which they will discuss implementation with members of their school physical education staff. In the booster period (3 months), teachers will complete a half day workshop at their school, plus one online implementation task, and a group mentoring session at their school. Throughout the entire intervention period (main intervention plus booster period), teachers will have access to online resources. Data collection will include baseline, post-intervention (7-8 months after baseline) and maintenance phase (14-15 months after baseline) assessments. Research assistants blinded to group allocation will collect all data. The primary outcome will be the proportion of physical education lesson time that students spend in MVPA. Secondary outcomes will include leisure-time physical activity, subjective well-being, and motivation towards physical activity. DISCUSSION: The provision of an online training platform for teachers could help facilitate more widespread dissemination of evidence-based interventions compared with programs that rely exclusively on face-to-face training. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry- ACTRN12614000184673 . Registration date: February 19, 2014. PMID- 26740094 TI - Disseminated Cutaneous Leishmaniasis, a Patient with 178 Lesions Cured with Fluconazole. PMID- 26740097 TI - Empirical correction for PM7 band gaps of transition-metal oxides. AB - A post-calculation correction is established for PM7 band gaps of transition metal oxides. The correction is based on the charge on the metal cation of interest, as obtained from MOPAC PM7 calculations. Application of the correction reduces the average error in the PM7 band gap from ~3 eV to ~1 eV. The residual error after correction is shown to be uncorrelated to the Hartree-Fock method upon which PM7 is based. Graphical Abstract Comparison between calculated band gaps and experimental band gaps for binary oxides. The orange crosses are for corrected PM7 band gaps. Blue squares are uncorrected values. The orange crosses fall closer to the diagonal dashed line, showing an overall improvement of the accuracy of calculated values. PMID- 26740098 TI - [Susceptibility status of Anopheles gambiae sensu lato to insecticides commonly used for malaria control in Mali]. AB - The objective of this work was to monitor the susceptibility of malaria vectors to insecticides in nine sentinel sites of the National Malaria Control Program in Mali. The study was performed during the rainy seasons of 2010 and 2011. WHO bioassays were conducted using F0 and/or F1 from wild collected females. The insecticides used were lambda-cyhalothrin 0.05%, DDT 4%, permethrin 0.75%, deltamethrin 0.05%, bendiocarb 0.1% and fenitrothion 1.0%. Results showed suspicion of resistance to pyrethroids and organochlorine in An. gambiae s.l. at almost all the sites except Yanfolila where the vector was susceptible to lambda cyhalothrin (98.0%) [CI 95%, 98-99.8] and to DDT (100%). An. gambiae s.l. was susceptible to bendiocarb in five of the sites (Gao, Bougouni, Djenne, Yanfolila, Tombouctou) while there was a suspicion of resistance at the other sites (Kati, Niono, Bandiagara, Kita). Fenitrothion remains efficient except in the rice area of Niono, where there was a suspicion of resistance with a mortality rate of 92% [IC 95% 88.3-94.8]. Thus, it could be used as an alternative insecticide for IRS in Mali. These results show resistance to pyrethroids, the main insecticide family used in public health (and to some extent in agriculture). This could compromise the malaria vector control efforts in Mali where pyrethroids are used for both in bed nets and in IRS. PMID- 26740099 TI - Gone with the Wind: Conceiving of Moral Responsibility in the Case of GMO Contamination. AB - Genetically modified organisms are a technology now used with increasing frequency in agriculture. Genetically modified seeds have the special characteristic of being living artefacts that can reproduce and spread; thus it is difficult to control where they end up. In addition, genetically modified seeds may also bring about uncertainties for environmental and human health. Where they will go and what effect they will have is therefore very hard to predict: this creates a puzzle for regulators. In this paper, I use the problem of contamination to complicate my ascription of forward-looking moral responsibility to owners of genetically modified organisms. Indeed, how can owners act responsibly if they cannot know that contamination has occurred? Also, because contamination creates new and unintended ownership, it challenges the ascription of forward-looking moral responsibility based on ownership. From a broader perspective, the question this paper aims to answer is as follows: how can we ascribe forward-looking moral responsibility when the effects of the technologies in question are difficult to know or unknown? To solve this problem, I look at the epistemic conditions for moral responsibility and connect them to the normative notion of the social experiment. Indeed, examining conditions for morally responsible experimentation helps to define a range of actions and to establish the related epistemic virtues that owners should develop in order to act responsibly where genetically modified organisms are concerned. PMID- 26740101 TI - Combined deletion of Xrcc4 and Trp53 in mouse germinal center B cells leads to novel B cell lymphomas with clonal heterogeneity. AB - BACKGROUND: Activated B lymphocytes harbor programmed DNA double-strand breaks (DSBs) initiated by activation-induced deaminase (AID) and repaired by non homologous end-joining (NHEJ). While it has been proposed that these DSBs during secondary antibody gene diversification are the primary source of chromosomal translocations in germinal center (GC)-derived B cell lymphomas, this point has not been directly addressed due to the lack of proper mouse models. METHODS: In the current study, we establish a unique mouse model by specifically deleting a NHEJ gene, Xrcc4, and a cell cycle checkpoint gene, Trp53, in GC B cells, which results in the spontaneous development of B cell lymphomas that possess features of GC B cells. RESULTS: We show that these NHEJ deficient lymphomas harbor translocations frequently targeting immunoglobulin (Ig) loci. Furthermore, we found that Ig translocations were associated with distinct mechanisms, probably caused by AID- or RAG-induced DSBs. Intriguingly, the AID-associated Ig loci translocations target either c-myc or Pvt-1 locus whereas the partners of RAG associated Ig translocations scattered randomly in the genome. Lastly, these NHEJ deficient lymphomas harbor complicated genomes including segmental translocations and exhibit a high level of ongoing DNA damage and clonal heterogeneity. CONCLUSIONS: We propose that combined NHEJ and p53 defects may serve as an underlying mechanism for a high level of genomic complexity and clonal heterogeneity in cancers. PMID- 26740102 TI - A family with pheochromocytoma-paraganglioma inherited tumour syndrome. Serial 18F-DOPA PET/CT investigations. AB - AIM: Hereditary pheochromocytoma-paraganglioma syndromes are characterized by multiple pheochromocytomas (PCC) and paragangliomas (PGLs), inherited in an autosomal dominant manner. Early detection and removal of tumours may prevent or minimize complications related to mass effects and malignant transformation. Having confirmed the diagnosis, it is important to localize the tumours and reveal their extent preoperatively. This study aimed to introduce 18F-DOPA PET/CT as a highly sensitive non-invasive diagnostic tool for early detection of mass lesions in patients with pheochromocytoma-paraganglioma inherited tumour syndrome and to report about its impact on patient management. PATIENTS, METHODS: We are currently supervising one of the largest documented families in Germany with genetically determined SDHD gene mutation. We performed 18F-DOPA PET/CT in order to detect tumours in asymptomatic gene carriers and enable subsequent surgical therapy. RESULTS: In seven patients undergoing 12 18F-DOPA PET/CT scans 17 lesions have been detected. Three of these lesions, located in the head and neck region, have had no morphologic correlate in CT and one had also no morphologic correlate in MRI. Of the six histologically analyzed lesions five have been tumors (PGL or PCC) and one has been a nodular hyperplasia. This means the 18F DOPA PET/CT scan in our study group had a sensitivity of 83%. 18F-DOPA PET/CT investigations lead to change in the management in 5/7 studied patients (70%). CONCLUSION: The benefits of PET/CT in detection of pheochromocytoma and paraganglioma are well documented, but we are the first to use this technique for screening of a rare hereditary disease (estimated prevalence 0.3/100 000). PMID- 26740103 TI - Dynamic modulation of innate immunity programming and memory. AB - Recent progress harkens back to the old theme of immune memory, except this time in the area of innate immunity, to which traditional paradigm only prescribes a rudimentary first-line defense function with no memory. However, both in vitro and in vivo studies reveal that innate leukocytes may adopt distinct activation states such as priming, tolerance, and exhaustion, depending upon the history of prior challenges. The dynamic programming and potential memory of innate leukocytes may have far-reaching consequences in health and disease. This review aims to provide some salient features of innate programing and memory, patho physiological consequences, underlying mechanisms, and current pressing issues. PMID- 26740104 TI - Genome reduction of Borrelia burgdorferi: two TCS signaling pathways for two distinct host habitats. PMID- 26740105 TI - RNA-seq reveals the critical role of CspA in regulating Brucella melitensis metabolism and virulence. AB - Brucella melitensis is a facultative intracellular bacterium that replicates within macrophages. The ability of Brucella to survive and multiply in the hostile environment of host macrophages is essential for its virulence. The cold shock protein CspA plays an important role in the virulence of B. melitensis. To analyze the genes regulated by CspA, the whole transcriptomes of B. melitensis NIDeltacspA and its parental wild-type strain, B. melitensis NI, were sequenced and analyzed using the Solexa/Illumina sequencing platform. A total of 446 differentially expressed genes were identified, including 324 up-regulated and 122 down-regulated genes. Numerous genes identified are involved in amino acid, fatty acid, nitrogen, and energy metabolism. Interestingly, all genes involved in the type IV secretion system and LuxR-type regulatory protein VjbR were significantly down-regulated in NIDeltacspA. In addition, an effector translocation assay confirmed that the function of T4SS in NIDeltacspA is influenced by deletion of the cspA gene. These results revealed the differential phenomena associated with virulence and metabolism in NIDeltacspA and NI, providing important information for understanding detailed CspA-regulated interaction networks and Brucella pathogenesis. PMID- 26740108 TI - The Forgotten: Identification and Functional Characterization of MHC Class II Molecules H2-Eb2 and RT1-Db2. AB - In this article, we report the complete coding sequence and to our knowledge, the first functional analysis of two homologous nonclassical MHC class II genes: RT1 Db2 of rat and H2-Eb2 of mouse. They differ in important aspects compared with the classical class II beta1 molecules: their mRNA expression by APCs is much lower, they show minimal polymorphism in the Ag-binding domain, and they lack N glycosylation and the highly conserved histidine 81. Also, their cytoplasmic region is completely different and longer. To study and compare them with their classical counterparts, we transduced them in different cell lines. These studies show that they can pair with the classical alpha-chains (RT1-Da and H2-Ea) and are expressed at the cell surface where they can present superantigens. Interestingly, compared with the classical molecules, they have an extraordinary capacity to present the superantigen Yersinia pseudotuberculosis mitogen. Taken together, our findings suggest that the b2 genes, together with the respective alpha-chain genes, encode for H2-E2 or RT1-D2 molecules, which could function as Ag-presenting molecules for a particular class of Ags, as modulators of Ag presentation like nonclassical nonpolymorphic class II molecules DM and DO do, or even as players outside the immune system. PMID- 26740106 TI - Human Head and Neck Squamous Cell Carcinoma-Associated Semaphorin 4D Induces Expansion of Myeloid-Derived Suppressor Cells. AB - One of the mechanisms by which malignancies can induce immune suppression is through the production of cytokines that affect the maturation and differentiation of inflammatory cells in the tumor microenvironment. Semaphorin 4D (Sema4D) is a proangiogenic cytokine produced by several malignancies, which has been described in the regulation of the immune system. In the present study, we examined the role of human head and neck squamous cell carcinoma (HNSCC) secreted Sema4D on myeloid cell differentiation. CD33(+) cells cultured in HNSCC cell line-derived conditioned medium differentiated into myeloid derived suppressor cells (MDSC) (CD33(+)CD11b(+)HLA-DR(-/low)). The addition of anti Sema4D Ab to HNSCC conditioned medium significantly reduced the expansion of the MDSC population. Similarly, knockdown of Sema4D in an HNSCC cell line resulted in a loss of MDSC function as shown by a decrease in the production of the immune suppressive cytokines arginase-1, TGF-beta, and IL-10 by MDSC, concomitant with recovery of T cell proliferation and IFN-gamma production following stimulation of CD3/CD28. Importantly, CD33(+) myeloid and T cells cultured in conditioned medium of HNSCC cells in which Sema4D was knocked down promoted antitumor inflammatory profile, through recovery of the effector T cells (CD4(+)T-bet(+) and CD8(+)T-bet(+)), as well as a decrease in regulatory T cells (CD4(+)CD25(+)FOXP3(+)). We also showed that Sema4D was comparable to GM-CSF in its induction of MDSC. Collectively, this study describes a novel immunosuppressive role for Sema4D in HNSCC through induction of MDSC, and it highlights Sema4D as a therapeutic target for future studies to enhance the antitumorigenic inflammatory response in HNSCC and other epithelial malignancies. PMID- 26740107 TI - Distinctions among Circulating Antibody-Secreting Cell Populations, Including B-1 Cells, in Human Adult Peripheral Blood. AB - Human Ab-secreting cell (ASC) populations in circulation are not well studied. In addition to B-1 (CD20(+)CD27(+)CD38(lo/int)CD43(+)) cell and conventional plasmablast (PB) (CD20-CD27(hi)CD38(hi)) cell populations, in this study, we identified a novel B cell population termed 20(+)38(hi) B cells (CD20(+)CD27(hi)CD38(hi)) that spontaneously secretes Ab. At steady-state, 20(+)38(hi) B cells are distinct from PBs on the basis of CD20 expression, amount of Ab production, frequency of mutation, and diversity of BCR repertoire. However, cytokine treatment of 20(+)38(hi) B cells induces loss of CD20 and acquisition of CD138, suggesting that 20(+)38(hi) B cells are precursors to PBs or pre-PBs. We then evaluated similarities and differences among CD20(+)CD27(+)CD38(lo/int)CD43(+) B-1 cells, CD20(+)CD27(hi)CD38(hi) 20(+)38(hi) B cells, CD20(-)CD27(hi)CD38(hi) PBs, and CD20(+)CD27(+)CD38(lo/int)CD43(-) memory B cells. We found that B-1 cells differ from 20(+)38(hi) B cells and PBs in a number of ways, including Ag expression, morphological appearance, transcriptional profiling, Ab skewing, Ab repertoire, and secretory response to stimulation. In terms of gene expression, B-1 cells align more closely with memory B cells than with 20(+)38(hi) B cells or PBs, but differ in that memory B cells do not express Ab secretion-related genes. We found that B-1 cell Abs use Vh4-34, which is often associated with autoreactivity, 3- to 6-fold more often than other B cell populations. Along with selective production of IgM anti phosphoryl choline, these data suggest that human B-1 cells might be preferentially selected for autoreactivity/natural specificity. In summary, our results indicate that human healthy adult peripheral blood at steady-state consists of three distinct ASC populations. PMID- 26740109 TI - Cryptococcus gattii Capsule Blocks Surface Recognition Required for Dendritic Cell Maturation Independent of Internalization and Antigen Processing. AB - Cryptococcus gattii is an emerging fungal pathogen on the west coast of Canada and the United States that causes a potentially fatal infection in otherwise healthy individuals. In previous investigations of the mechanisms by which C. gattii might subvert cell-mediated immunity, we found that C. gattii failed to induce dendritic cell (DC) maturation, leading to defective T cell responses. However, the virulence factor and the mechanisms of evasion of DC maturation remain unknown. The cryptococcal polysaccharide capsule is a leading candidate because of its antiphagocytic properties. Consequently, we asked if the capsule of C. gattii was involved in evasion of DC maturation. We constructed an acapsular strain of C. gattii through CAP59 gene deletion by homologous integration. Encapsulated C. gattii failed to induce human monocyte-derived DC maturation and T cell proliferation, whereas the acapsular mutant induced both processes. Surprisingly, encapsulation impaired DC maturation independent of its effect on phagocytosis. Indeed, DC maturation required extracellular receptor signaling that was dependent on TNF-alpha and p38 MAPK, but not ERK activation, and the cryptococcal capsule blocked this extracellular recognition. Although the capsule impaired phagocytosis that led to pH-dependent serine-, threonine-, and cysteine-sensitive protease-dependent Ag processing, it was insufficient to impair T cell responses. In summary, C. gattii affects two independent processes, leading to DC maturation and Ag processing. The polysaccharide capsule masked extracellular detection and reduced phagocytosis that was required for DC maturation and Ag processing, respectively. However, the T cell response was fully restored by inducing DC maturation. PMID- 26740110 TI - Phosphatidylinositol 3-Kinase p110delta Isoform Regulates CD8+ T Cell Responses during Acute Viral and Intracellular Bacterial Infections. AB - The p110delta isoform of PI3K is known to play an important role in immunity, yet its contribution to CTL responses has not been fully elucidated. Using murine p110delta-deficient CD8(+) T cells, we demonstrated a critical role for the p110delta subunit in the generation of optimal primary and memory CD8(+) T cell responses. This was demonstrated in both acute viral and intracellular bacterial infections in mice. We show that p110delta signaling is required for CD8(+) T cell activation, proliferation and effector cytokine production. We provide evidence that the effects of p110delta signaling are mediated via Akt activation and through the regulation of TCR-activated oxidative phosphorylation and aerobic glycolysis. In light of recent clinical trials that employ drugs targeting p110delta in certain cancers and other diseases, our study suggests caution in using these drugs in patients, as they could potentially increase susceptibility to infectious diseases. These studies therefore reveal a novel and direct role for p110delta signaling in in vivo CD8(+) T cell immunity to microbial pathogens. PMID- 26740112 TI - Rab12 Regulates Retrograde Transport of Mast Cell Secretory Granules by Interacting with the RILP-Dynein Complex. AB - Secretory granule (SG) transport is a critical step in regulated exocytosis including degranulation of activated mast cells. The latter process results in the release of multiple inflammatory mediators that play key roles in innate immunity, as well as in allergic responses. In this study, we identified the small GTPase Rab12 as a novel regulator of mast cell SG transport, and we provide mechanistic insights into its mode of action. We show that Rab12 is activated in a stimulus-dependent fashion and promotes microtubule-dependent retrograde transport of the SGs in the activated cells. We also show that this minus end transport of the SGs is mediated by the RILP-dynein complex and identify RILP as a novel effector of Rab12. Finally, we show that Rab12 negatively regulates mast cell degranulation. Taken together, our results identify Rab12 as a novel regulator of mast cell responses and disclose for the first time, to our knowledge, the mechanism of retrograde transport of the mast cell SGs. PMID- 26740113 TI - They Just Respect You for Who You Are: Contributors to Educator Positive Youth Development Promotion for Somali, Latino, and Hmong Students. AB - Youth from immigrant communities may experience barriers to connecting with schools and teachers, potentially undermining academic achievement and healthy youth development. This qualitative study aimed to understand how educators serving Somali, Latino, and Hmong (SLH) youth can best promote educator-student connectedness and positive youth development, by exploring the perspectives of teachers, youth workers, and SLH youth, using a community based participatory research approach. We conducted four focus groups with teachers, 18 key informant interviews with adults working with SLH youth, and nine focus groups with SLH middle and high school students. Four themes emerged regarding facilitators to educators promoting positive youth development in schools: (1) an authoritative teaching approach where teachers hold high expectations for student behavior and achievement, (2) building trusting educator-student relationships, (3) conveying respect for students as individuals, and (4) a school infrastructure characterized by a supportive and inclusive environment. Findings suggest a set of skills and educator-student interactions that may promote positive youth development and increase student-educator connectedness for SLH youth in public schools. PMID- 26740115 TI - Months dispensed and oral contraceptive discontinuation. PMID- 26740111 TI - Invariant NKT Cell Activation Induces Late Preterm Birth That Is Attenuated by Rosiglitazone. AB - Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. Although intra-amniotic infection is a recognized cause of spontaneous preterm labor, the noninfection-related etiologies are poorly understood. In this article, we demonstrated that the expansion of activated CD1d-restricted invariant NKT (iNKT) cells in the third trimester by administration of alpha galactosylceramide (alpha-GalCer) induced late PTB and neonatal mortality. In vivo imaging revealed that fetuses from mice that underwent alpha-GalCer-induced late PTB had bradycardia and died shortly after delivery. Yet, administration of alpha-GalCer in the second trimester did not cause pregnancy loss. Peroxisome proliferator-activated receptor (PPAR)gamma activation, through rosiglitazone treatment, reduced the rate of alpha-GalCer-induced late PTB and improved neonatal survival. Administration of alpha-GalCer in the third trimester suppressed PPARgamma activation, as shown by the downregulation of Fabp4 and Fatp4 in myometrial and decidual tissues, respectively; this suppression was rescued by rosiglitazone treatment. Administration of alpha-GalCer in the third trimester induced an increase in the activation of conventional CD4(+) T cells in myometrial tissues and the infiltration of activated macrophages, neutrophils, and mature dendritic cells to myometrial and/or decidual tissues. All of these effects were blunted after rosiglitazone treatment. Administration of alpha GalCer also upregulated the expression of inflammatory genes at the maternal fetal interface and systemically, and rosiglitazone treatment partially attenuated these responses. Finally, an increased infiltration of activated iNKT like cells in human decidual tissues is associated with noninfection-related preterm labor/birth. Collectively, these results demonstrate that iNKT cell activation in vivo leads to late PTB by initiating innate and adaptive immune responses and suggest that the PPARgamma pathway has potential as a target for prevention of this syndrome. PMID- 26740116 TI - Prognostic significance of the pre-chemotherapy lymphocyte-to-monocyte ratio in patients with previously untreated metastatic colorectal cancer receiving FOLFOX chemotherapy. AB - BACKGROUND: As a surrogate marker of systemic inflammation, the lymphocyte-to monocyte ratio (LMR) is an independent prognostic factor for various malignancies. This study investigated the prognostic significance of the pre chemotherapy LMR in patients with previously untreated metastatic colorectal cancer (mCRC) receiving chemotherapy. METHODS: The present study included newly diagnosed mCRC patients treated between January 2005 and December 2013 with FOLFOX chemotherapy, specifically oxaliplatin 180 mg/m(2) on day 1, with leucovorin 400 mg/m(2) administered as a 2-hour infusion before the administration of 5-fluorouracil 400 mg/m(2) as an intravenous bolus injection, and 5-fluorouracil 2400 mg/m(2) as a 46-h infusion immediately after 5 fluorouracil bolus injection. The LMR was calculated as the absolute count of lymphocytes divided by the absolute count of monocytes. COX proportional hazards analysis was performed to evaluate the association of LMR with survival outcomes. RESULTS: A total of 488 patients were included. Patients with high pre chemotherapy LMR experienced significant improvements in progression-free survival (PFS, 9.2 vs. 7.6 months, P < 0.001) and overall survival (OS, 19.4 vs. 16.6 months, P < 0.001) compared with patients with low pre-chemotherapy LMR. Subsequent COX multivariate analysis showed that high pre-chemotherapy LMR (>=3.11) was an independent favorable prognostic factor for PFS and OS. Additionally, patients whose LMR remained high (high-high subgroup), increased (low-high subgroup), or decreased (high-low subgroup) following chemotherapy showed better results in terms of PFS and OS than patients whose LMR remained low (low-low subgroup) after chemotherapy. CONCLUSIONS: For patients with previously untreated mCRC receiving FOLFOX chemotherapy, an elevated pre-chemotherapy LMR is an independent favorable prognostic factor for PFS and OS, and changes in the LMR before and after chemotherapy seem to predict the benefit of chemotherapy. PMID- 26740120 TI - Metformin and pancreatic cancer: Is there a role? AB - Pancreatic cancer is the fourth leading cause of cancer-related deaths in the USA, with a 5-year survival rate of 6 %. Anti-hyperglycemic treatments for type 2 diabetes mellitus that induce hyperinsulinemia (i.e., sulfonylureas) are thought to increase cancer risk, whereas treatments that lower insulin resistance and hyperinsulinemia (i.e., metformin) are considered cancer prevention strategies. Metformin is a cornerstone in the treatment of diabetes mellitus type 2. Retrospective studies have shown a survival benefit in diabetic patients with many solid tumors including pancreatic cancer that have been treated with metformin compared with patients treated with insulin or sulfonylureas. Metformin influences various cellular pathways, including activation of the LKB1/AMPK pathway, inhibition of cell division, promotion of apoptosis and autophagy, down regulation of circulating insulin, and activation of the immune system. Ongoing research is redefining our understanding about how metformin modulates the molecular pathways implicated in pancreatic cancer. The authors review the topic critically and also give their opinion. Further studies investigating the effect of metformin in combination with chemotherapy, targeted agents, or radiation therapy are undergoing. In addition, the role of metabolic and other biomarkers is needed. PMID- 26740121 TI - Halogen-bridged metal-organic frameworks constructed from bipyridinium-based ligand: structures, photochromism and non-destructive readout luminescence switching. AB - Two isomorphous halogen-bridged metal-organic frameworks have been solvothermally synthesized based on the bipyridinium ligand and structurally characterized. The two compounds show an eye-detectable color development upon light irradiation, but different coloration degrees. The relationship between the structure and photosensitivity has been studied in detail. The photochromic properties of the bipyridinium unit have been used to modulate the luminescence under light illumination. Compound 1 is the first example showing photo-modulated luminescence switching featuring a non-destructive readout capability based on transition metals. PMID- 26740122 TI - Unified biogenesis of ambiguine, fischerindole, hapalindole and welwitindolinone: identification of a monogeranylated indolenine as a cryptic common biosynthetic intermediate by an unusual magnesium-dependent aromatic prenyltransferase. AB - Biochemical characterization of aromatic prenyltransferase AmbP1 and its close homologs WelP1/FidP1 in hapalindole-type alkaloid biosynthetic pathways is reported. These enzymes mediate the magnesium-dependent selective formation of 3 geranyl 3-isocyanovinyl indolenine (2) from cis-indolyl vinyl isonitrile and geranyl pyrophosphate. The role of the magnesium cofactor in AmbP1/WelP1/FidP1 catalysis is unusual for a microbial aromatic prenyltransferase, as it not only facilitates the formation of 2 but also prevents its rearrangement to an isomeric 2-geranyl 3-isocyanovinyl indole (3). The discovery of 2 as a cryptically conserved common biosynthetic intermediate to all hapalindole-type alkaloids suggests an enzyme-mediated Cope rearrangement and aza-Prins-type cyclization cascade is required to transform 2 to a polycyclic hapalindole-like scaffold. PMID- 26740124 TI - Synthesis and activity of a novel inhibitor of nonsense-mediated mRNA decay. AB - During efforts to prepare the known compound , a new tetracyclic compound, called VG1, was prepared in six steps. This compound was found to have good activity as an inhibitor of nonsense-mediated mRNA decay. PMID- 26740123 TI - Autophagic dysfunction is improved by intermittent administration of osteocalcin in obese mice. AB - BACKGROUND: Osteoblast-specific secreted osteocalcin has been considered as an important regulator of energy and glucose metabolism, however, the causative role and clinical potential of osteocalcin implicated in insulin resistance remains not fully understood. METHODS: Osteocalcin was administered intermittently in vivo and in vitro, and metabolic parameters, autophagy and insulin signaling were assessed. RESULTS: The intermittent injections of osteocalcin in mice fed high fat diet resulted in decreased body weight gain, fat-pad weight gain, serum triglycerides, serum-free fatty acid, blood glucose, insulin level and partial normalization of glucose tolerance relative to the mice fed high-fat diet and received vehicle injections. Meanwhile, the intermittent administration of osteocalcin not only led to the alleviation of autophagic dysfunction and endoplasmic reticulum (ER) stress, but also contributed to the restoration of the impaired insulin signaling in adipose tissue and skeleton muscle of mice consumed the high-fat diet. In accordance with these findings in vivo, osteocalcin treatment also displayed a protective impact on adipocytes and myocytes against tunicamycin- or palmitate-induced ER stress and autophagy dysfunction in an XBP-1 independent manner, with these effects of osteocalcin being reversed by inhibition of mammalian target of rapamycin (mTOR) or nuclear factor-kappaB (NF kappaB). CONCLUSIONS: Intermittent administration of osteocalcin efficiently reversed the attenuated autophagy and ER stress, and restored the impaired insulin sensitivity in cellular and mice models of insulin resistance. Our findings provide new insights into the clinical potential of osteocalcin in metabolic homeostasis, and suggest an innovative strategy for the treatment against diabetes, obesity and metabolic syndrome. PMID- 26740126 TI - Development of a fast dissolving film of epinephrine hydrochloride as a potential anaphylactic treatment for pediatrics. AB - OBJECTIVE: To develop a fast dissolving film strip containing epinephrine HCl for the potential treatment of pediatric anaphylaxis. METHODS: Four different films have been prepared by solvent casting technique where the percentages of the polymer (Lycoat RS720) were optimized. The polymer percentages were (20%, 25%, 27% and 30%) of the total formulation weighs. The thickness and elastic modulus of the optimized film was evaluated using dynamic mechanical analyzer. Epinephrine content uniformity was assessed using UV at wavelength 280 nm. For the dissolution test, fast dissolving films (FDFs) were evaluated in 500 Simulated Saliva, with 50 rpm. In vivo taste and disintegration evaluation was performed on six healthy volunteers. RESULTS: Films formed by formulations 1, 2 and 3 were too sticky after drying, while formulation 4 that has 30% polymer content formed smooth, transparent, flexible and uniform film, and therefore, it was selected for further testing. The value of elastic modulus was determined at 1.325 MPa. The thickness of the film at different locations was measured at 0.29 mm. Drug content in film was measured at 93% +/-10. More than 90% of epinephrine was released from the film within 7.2 min. Bitterness of epinephrine was masked efficiently according to volunteer's comments with average disintegration time of 20 s. CONCLUSION: This study presents potential proof for using FDFs as a replacement therapy of epinephrine injections for pediatrics. PMID- 26740125 TI - HIV-1 gp120 induces type-1 programmed cell death through ER stress employing IRE1alpha, JNK and AP-1 pathway. AB - The ER stress-mediated apoptosis has been implicated in several neurodegenerative diseases; however, its role in HIV/neuroAIDS remains largely unexplored. The present study was undertaken to assess the involvement and detailed mechanism of IRE1alpha pathway in HIV-1 gp120-mediated ER stress and its possible involvement in cell death. Various signaling molecules for IRE1alpha pathway were assessed using SVGA cells, primary astrocytes and gp120 transgenic mice, which demonstrated gp120-mediated increase in phosphorylated JNK, XBP-1 and AP-1 leading to upregulation of CHOP. Furthermore, HIV-1 gp120-mediated activation of IRE1alpha also increased XBP-1 splicing. The functional consequence of gp120 mediated ER stress was determined via assessment of gp120-mediated cell death using PI staining and MTT assay. The gp120-mediated cell death also involved caspase-9/caspase-3-mediated apoptosis. These findings were confirmed with the help of specific siRNA for IRE1alpha, JNK, AP-1, BiP and CHOP showing significant reduction in gp120-mediated CHOP expression. Additionally, silencing all the intermediates also reduced the gp120-mediated cell death and caspase-9/caspase-3 activation at differential levels. This study provides ER-stress as a novel therapeutic target in the management of gp120-mediated cell death and possibly in the treatment of neuroAIDS. PMID- 26740127 TI - Potential head of Food Standards Agency would treat antimicrobial resistance as priority. PMID- 26740129 TI - Bio-transformation of agri-food wastes by newly isolated Neurospora crassa and Lactobacillus plantarum for egg production. AB - Using bio-transferred feedstuff was a cost-effective approach to improve egg quality and production; particularly, the nutritive diet came from agri-food wastes. In this study, optimization of fermentation conditions and co-cultivation of Neurospora crassa with Lactobacillus plantarum was performed in a simple bioreactor. The optimized fermentation of beer lees substrates through N. crassa led to the hydrolysis rates of crude fiber increasing to 43.27%. Compared to that of using N. crassa alone, the combination of N. crassa and L. plantarum enhanced the content of amino acids (13,120 to 18,032 mg/100 g) on oil-tea seed cake substrates particularly. When hens were fed 10% fermented oil-tea seedcake substrate, the ratio of feed to egg decreased from 3.1 to 2.6, egg production ratio increased from 65.71 to 80.10%, and color of vitelline (Roche) increased from 8.20 to 10.20. Fifteen kinds of carotenoids were identified by HPLC in fermented oil-tea seed cake substrates. The results of this study highlighted that the mixed-fermentation by N. crassa and L. plantarum may be an effective way to convert agri-food wastes into high-valued biomass products, which could have a positive effect on hens and their eggs. PMID- 26740130 TI - Effect of yeast-derived products and distillers dried grains with solubles (DDGS) on growth performance, gut morphology, and gene expression of pattern recognition receptors and cytokines in broiler chickens. AB - An experiment was carried out to investigate the effect of yeast-derived products and distillers' dried grains with solubles (DDGS) on growth performance, small intestinal morphology, and innate immune response in broiler chickens from 1 to 21 d of age. Nine replicates of 5 birds each were assigned to dietary treatments consisting of a control diet without antibiotic (C), and diets containing 11 mg/kg of virginiamycin, 0.25% of yeast cell wall (YCW), 0.2% of a commercial product Maxi-Gen Plus, 0.025% of nucleotides, 0.05% of nucleotides, or a diet containing 10% of DDGS. On d 21, 5 birds per treatment were euthanized and approximately 5-cm long duodenum, jejunum, and ileum segments were collected for intestinal morphology measurements. Cecal tonsils and spleen were collected to measure the gene expression of toll-like receptors TLR2b, TLR4, and TLR21, macrophage mannose receptor (MMR), and cytokines IFN-gamma, IL-12, IL-10, and IL 4. No significant difference was observed for growth performance parameters. However, diets containing 0.05% of nucleotides and YCW significantly increased (P < 0.05) villus height in the jejunum. Furthermore, the number of the goblet cells per unit area in the ileum was increased (P < 0.05) in diets supplemented with yeast-derived products. The expression of TLR2b in the spleen was down-regulated for diets supplemented with nucleotides and antibiotic. In addition, lower expression of TLR21 and MMR was observed in the spleen of birds receiving yeast derived products and antibiotic. However, expression of TLR4 in the spleen was up regulated in diets supplemented with YCW and nucleotides. The expression of IFN gamma and IL-12 was down-regulated in the spleen of birds fed diets supplemented with yeast-derived products. In addition, inclusion of YCW, Maxi-Gen Plus, or 0.05% of nucleotides down-regulated the expression of IL-10 and IL-4 in the cecal tonsils. In conclusion, down-regulation of receptors and cytokines in spleen and cecal tonsils of birds fed diets supplemented with yeast-derived products may suggest that yeast products do not exert immune stimulating effect under normal health conditions. PMID- 26740131 TI - Impacts of dietary calcium, phytate, and nonphytate phosphorus concentrations in the presence or absence of phytase on inositol hexakisphosphate (IP6) degradation in different segments of broilers digestive tract. AB - A total of 1,440 straight-run Heritage 56M * fast-feathering Cobb 500F broiler birds were fed from 11 to 13 d of age to determine the impacts of calcium (Ca), phytate phosphorus (PP), nonphytate P (NPP) and phytase concentrations on the myo inositol hexakisphosphate (IP6) flow through the different parts of gastrointestinal tract (GIT). The experiment was a 2*2*2*3 randomized block design with 2 Ca (0.7 and 1.0%), 2 PP (0.23 and 0.34%), 2 nPP (0.28 and 0.45%) and 3 phytase (0-, 500-, and 1,000-phytase unit (FTU)/kg) concentrations. The experiment was replicated twice (block) with 3 replicates per treatment (TRT) of 10 birds per block. Concentration of IP6 in crop, proventriculus (PROV) plus (+) gizzard (GIZ) and distal ileum digesta as well as the ileal IP6 disappearance was determined at 13 d of age. In crop, higher IP6 concentration was seen with increased Ca (P < 0.05). Despite the interaction between PP and phytase, higher dietary PP led to greater IP6 concentration (P < 0.05). Similar main effects of PP and phytase were also seen in Prov+Giz and ileum (P < 0.05) without interactions. Interaction between Ca and nPP on IP6 concentration was seen in Prov+Giz (P < 0.05). Decreased ileal IP6 disappearance was found at higher Ca (62.3% at 0.7% Ca vs. 57.5% at 1.0% Ca; P < 0.05). In general, adding phytase improved IP6 degradation but the degree of impact was dependent on nPP and PP (P < 0.05). In conclusion, phytase inclusion significantly reduced IP6 concentration and IP6 disappearance in distal ileum regardless of GIT segments or diet composition, but impacts of dietary Ca, nPP, and PP differed depending on GIT segment examined. PMID- 26740132 TI - Functional assessment of encapsulated citral for controlling necrotic enteritis in broiler chickens. AB - Development of viable alternatives to antibiotics to control necrotic enteritis (NE) caused by Clostridium perfringensis becoming urgent for chicken production due to pessures on poultry producers to limit or stop the use of antibiotics in feed. We have previously identified citral as a potential alternative to antibiotics. Citral has strong antimicrobial activity and can be encasupsulated in a powder form for protection from loss during feed processing, storage, and intestinal delivery. In the present study, encapsulated citral was evaluated both in vitro and in vivo for its antimicrobial activity against C. perfringens Encapsulation did not adversely affect the antimicrobial activity of citral. In addition, encapsulated citral was superior to the unencapsulated form in retaining its antimicrobial activity after treatment with simulated gastrointestinal fluids and in the presence of chicken intestinal digesta. In addition, the higher antimicrobial activity of encapsulated citral was confirmed in digesta samples from broilers that had been gavaged with encapsulated or unencapsulated citral. In broilers infected with C. perfringens, the diets supplemented with encapsualted citral at both 250 and 650 MUg/g significantly reduced intestinal NE lesions, which was comparable to the effect of bacitracin- and salinomycin-containing diets. However, supplementation with the encapsulated citral appeared to have no significant impact on the intestinal burden of Lactobacillus These data indicate that citral can be used to control NE in chickens after proper protection by encapsulation. PMID- 26740133 TI - Organic trace mineral supplementation enhances local and systemic innate immune responses and modulates oxidative stress in broiler chickens. AB - The effect of organic trace mineral supplementation on performance, intestinal morphology, immune organ weights (bursa of Fabricius and spleen), expression of innate immune response related genes, blood heterophils/lymphocytes ratio, chemical metabolic panel, natural antibodies (IgG), and oxidative stress of broiler chickens was studied. A total of 1,080 day-old male broilers were assigned to 1 of 3 dietary treatments, which included basal diet with Monensin (control), control diet supplemented with bacitracin methylene disalicylate (BMD), and BMD diet supplemented with organic trace minerals (OTM). No difference in feed conversion ratio was observed among treatments; ileum histomorphological analysis showed a lower crypt depth, higher villi height/crypt depth ratio, and lower villi width in the OTM treatment compared to control. Furthermore, OTM treatment resulted in higher uric acid and lower plasma malondehaldehyde (MDA), indicating lower oxidative stress. Gene expression analysis showed that OTM treatment resulted in up-regulations of TLR2 bin the ileum, and TLR2b, TLR4, and IL-12p35 in the bursa of Fabricius, and down-regulation of TLR2b and TLR4 in the cecal tonsils. In the spleen, OTM treatment resulted in up-regulation of IL-10. In conclusion, OTM supplementation to broiler diets may have beneficial effects on intestinal development, immune system status, and survival by improving ileum histomorphological parameters, modulation of Toll-like receptors and anti inflammatory cytokines, and decreasing level of MDA, which in conjunction could enhance health status. PMID- 26740134 TI - Heterogeneous size datasets of broiler intestinal microbial communities can be analyzed without normalization. AB - Next-generation sequencing technologies have become a powerful tool for the analysis of microbial communities. Sequencing of the hypervariable regions of the 16S ribosomal RNA gene following the amplitag amplification process has allowed the study of the diversity of samples of diverse origin. According to previous reports, the number of sequences required for the correct determination of the composition of a given sample may vary with the degree of diversity of that sample. In this paper, we investigate the correctness of comparing heterogeneous size datasets of bird intestinal microbial communities obtained from pyrosequencing data (Roche 454 technology) without prior normalization. We conclude that the differences observed between samples are due mainly to individual differences, not to differences in the number of readings in each sample, which makes data normalization unnecessary with the conditions described here. PMID- 26740136 TI - Inferring relationships between Phosphorus utilization, feed per gain, and bodyweight gain in an F2 cross of Japanese quail using recursive models. AB - Phosphorus utilization (PU) has received considerable attention in poultry nutrition. However, reliable estimates of genetic parameters for PU and related traits have largely not been reported until now; however, these are needed to assess whether selection for an improved PU would result in selection response. A large Japanese quail F2 cross was generated and 888 F2 individuals were phenotyped for PU, bodyweight gain (BWG), and feed per gain (F:G). Because it can reasonably be assumed that the interrelationships between these traits are complex, structural equation models were used. The structural coefficient lambdaij describes the rate of change of trait I with respect to trait j for a model with a recursive effect of trait j on trait i Three recursive structural coefficients (lambdaF:G,PU,lambdaBWG,PU,lambdaBWG,F:G) were selected a priori based on biological knowledge. The model was fitted using ASReml software. Standard errors of estimated variance components and genetic parameters were approximated using the delta method. The heritability of PU, F:G, and BWG were 0.136, 0.118, and 0.092. The structural coefficient[Formula: see text]indicates that an increase in PU leads to reduced and thus improved F:G. The estimate[Formula: see text]indicates that improved F:G leads to an increase in BWG. The overall effect of PU on BWG was[Formula: see text]i.e. an increase in PU of 1% leads to an increase of BWG of 0.374 g in the data collection period, which spanned five days. The phenotypic and genetic correlations were negative between PU and F:G as well as between BWG and F:G and were positive between PU and BWG. These correlations are driven by direct genetic effects (pleiotropic genes or genes being in linkage disequilibrium) as well as by indirect genetic effects (genes affecting trait j affected indirectly trait i). The application of structural equation models contributed to our understanding of the complex biological relationship between PU, F:G, and BWG in quails. PU shows a heritability that is sufficient to achieve a selection response when breeding for this very-hard-to-measure trait. PMID- 26740138 TI - Effects of dietary protein concentration on performance and nutrient digestibility in Pekin ducks during aflatoxicosis. AB - A 14-d study was conducted to determine the impact of dietary crude protein concentration on performance, serum biochemistry, and nutrient digestive functions in Pekin ducklings during aflatoxicosis. A total of 144 male Pekin ducklings were randomly allotted to 4 dietary treatments arranged in a 2*2 factorial with 2 crude protein (CP) (20 and 24% on an analyzed basis) with or without 0.2 mg/kg aflatoxin B1 (AFB1) (0.21 mg/kg analyzed). The AFB1 reduced BW gain, feed intake, and breast muscle weight by 33 to 43% (P<0.0001). Serum concentration of protein, glucose, and Ca were also decreased by AFB1 (P<=0.0015), while pancreatic activities of amylase and lipase were increased by AFB1 (P<0.005). Apparent N digestibility was not affected by dietary treatment, whereas apparent ileal digestible energy was reduced 7.6% by AFB1 (P=0.0003). Higher dietary CP improved BW gain, gain:feed ratio, and breast muscle weight (P<=0.021), and tended to improve feed intake (P=0.094), but did not improve serum measures, digestive enzyme activity, or nutrient digestibility. No statistical interaction of AFB1 by CP was observed for any measures. Results from the current study suggest that AFB1 at low concentration can significantly impair performance of Pekin ducklings primarily through inhibited feed intake, as well as influence nutrient digestion processes (jejunum morphology, digestive enzyme activity, and apparent energy digestibility). Higher dietary CP can improve growth performance of ducklings regardless of AF exposure, but did not interact with dietary AFB1 on performance, serum biochemistry, or nutrient digestion in Pekin ducklings from hatch to 14 d. PMID- 26740137 TI - Effect of different doses of coated butyric acid on growth performance and energy utilization in broilers. AB - We recently applied four dietary treatments in experiments I and II to determine the effect of protected calcium butyrate (BP) on growth performance and nutrient digestibility in broiler chickens. A group of one-day-old male Ross 308 broiler chicks (total 960, 480 per trial) were used in the study. In experiment I, the basal diets were fed with protected BP inclusion (0.2, 0.3, or 0.4 g/kg of finished feed) (BP) or without (C). In experiment II, 4 different diets were tested: 1) basal diet with no supplementation (C), 2) basal diet supplemented with protected BP (0.3 g/kg) (BP), 3) basal diet supplemented with avilamycin (6 mg/kg, active substance) a common antibiotic growth promoter (AGP) (Av), and 4) basal diet supplemented with the combination of both avilaymicin and BP. In experiment I, considering the entire study period, the use of BP improved feed conversion ratio (P<0.05) irrespective of the dose. Apparent total tract crude fat digestibility and apparent metabolizable energy corrected for nitrogen (AMEN) were improved after BP supplementation (P<0.05). In experiment II, A or AB diets improved (P<0.05) body weight gain compared to the control treatment. The diets Av, BP, and AvB improved (P<0.05) feed conversion ratio compared to the control treatment. Birds from the treatment diet were characterized by having the thickest mucosa (P<0.05). On days 14, 35, and 42, the use of AB diets improved AMENcontent compared to the control treatment (P<0.05). The apparent ileal digestibility of amino acid data showed that Av or AvB treated birds were characterized by higher Asp, Glu, Cys, Gly, and Ala ileal digestibility than the control animals (P<0.05). The use of Av, BP, or AvB increased ileal digestibility of Thr, Ser, and Pro (P<0.05). There is an indication that BP, alone or in combination with avilamycin, improve the digestion and absorptive processes and consequently birds performance results. PMID- 26740135 TI - Brief review of the chicken Major Histocompatibility Complex: the genes, their distribution on chromosome 16, and their contributions to disease resistance. AB - Nearly all genes presently mapped to chicken chromosome 16 (GGA 16) have either a demonstrated role in immune responses or are considered to serve in immunity by reason of sequence homology with immune system genes defined in other species. The genes are best described in regional units. Among these, the best known is the polymorphic major histocompatibility complex-B (MHC-B) region containing genes for classical peptide antigen presentation. Nearby MHC-B is a small region containing two CD1 genes, which encode molecules known to bind lipid antigens and which will likely be found in chickens to present lipids to specialized T cells, as occurs with CD1 molecules in other species. Another region is the MHC-Y region, separated from MHC-B by an intervening region of tandem repeats. Like MHC B, MHC-Y is polymorphic. It contains specialized class I and class II genes and c type lectin-like genes. Yet another region, separated from MHC-Y by the single nucleolar organizing region (NOR) in the chicken genome, contains olfactory receptor genes and scavenger receptor genes, which are also thought to contribute to immunity. The structure, distribution, linkages and patterns of polymorphism in these regions, suggest GGA 16 evolves as a microchromosome devoted to immune defense. Many GGA 16 genes are polymorphic and polygenic. At the moment most disease associations are at the haplotype level. Roles of individual MHC genes in disease resistance are documented in only a very few instances. Provided suitable experimental stocks persist, the availability of increasingly detailed maps of GGA 16 genes combined with new means for detecting genetic variability will lead to investigations defining the contributions of individual loci and more applications for immunogenetics in breeding healthy poultry. PMID- 26740139 TI - Metabolic and clinical response to Escherichia coli lipopolysaccharide in layer pullets of different genetic backgrounds supplied with graded dietary L-arginine. AB - L-arginine (Arg) is an essential amino acid in birds that plays a decisive role in avian protein synthesis and immune response. Effects of graded dietary Arg supply on metabolic and clinical response to Escherichia coli lipopolysaccharide (LPS) were studied over 48 hours after a single intramuscular LPS injection in 18 week-old genetically diverse purebred pullets. LPS induced a genotype-specific fever response within 4 hours post injectionem. Whereas brown genotypes showed an initial hypothermia followed by longer-lasting moderate hyperthermia, white genotypes exhibited a biphasic hyperthermia without initial hypothermia. Furthermore, within 2 hours after LPS injection, sickness behavior characterized by lethargy, anorexia, intensified respiration, and ruffled feathers appeared, persisted for 3 to 5 hours and recovered 12 hours post injectionem. The varying grades of Arg did not alter the examined traits named above, whereas insufficient Arg reduced body growth and increased relative weights of liver and pancreas significantly. At 48 hours post injectionem, increased relative weights of liver and spleen were also found in LPS treated pullets, whereas LPS decreased those of pancreas, bursa, thymus, and cecal tonsils. Moreover, LPS lowered the sum of plasma amino acids and decreased plasma concentrations of Arg, citrulline, glutamate, methionine, ornithine, phenylalanine, proline, tryptophan, and tyrosine, and increased those of aspartate, glutamine, lysine, 1- and 3-methyl histidine. Elevating concentrations of dietary Arg led to increasing plasma concentrations of Arg, citrulline, ornithine, and 3-methyl-histidine subsequently. As quantitative expression of LPS-induced anorexia, proteolysis, and the following changes in plasma amino acids, pullets showed a significant decrease of feed and nitrogen intake and catabolic metabolism characterized by negative nitrogen balance and body weight loss in the first 24 hours post injectionem. Pullets recovered from the challenge within the second 24 hours post injectionem and changed to anabolism with re-increased feed and nitrogen intake, positive nitrogen retention, and weight gain. To conclude, present results confirmed that LPS induced numerous metabolic and physiological changes in pullet's genotypes, whereas dietary Arg affected the examined traits only slightly. PMID- 26740140 TI - Mechanistic Insights into the Enhanced Activity and Stability of Agglomerated Cu Nanocrystals for the Electrochemical Reduction of Carbon Dioxide to n-Propanol. AB - The reduction of carbon dioxide (CO2) to n-propanol (CH3CH2CH2OH) using renewable electricity is a potentially sustainable route to the production of this valuable engine fuel. In this study, we report that agglomerates of ~15 nm sized copper nanocrystals exhibited unprecedented catalytic activity for this electrochemical reaction in aqueous 0.1 M KHCO3. The onset potential for the formation of n propanol was 200-300 mV more positive than for an electropolished Cu surface or Cu(0) nanoparticles. At -0.95 V (vs RHE), n-propanol was formed on the Cu nanocrystals with a high current density (jn-propanol) of -1.74 mA/cm(2), which is ~25* larger than that found on Cu(0) nanoparticles at the same applied potential. The Cu nanocrystals were also catalytically stable for at least 6 h, and only 14% deactivation was observed after 12 h of CO2 reduction. Mechanistic studies suggest that n-propanol could be formed through the C-C coupling of carbon monoxide and ethylene precursors. The enhanced activity of the Cu nanocrystals toward n-propanol formation was correlated to their surface population of defect sites. PMID- 26740141 TI - Mutant of a Light-Driven Sodium Ion Pump Can Transport Cesium Ions. AB - Krokinobacter eikastus rhodopsin 2 (KR2) is a light-driven Na(+) pump found in marine bacterium. KR2 pumps Li(+) and Na(+), but it becomes an H(+) pump in the presence of K(+), Rb(+), and Cs(+). Site-directed mutagenesis of the cytoplasmic surface successfully converted KR2 into a light-driven K(+) pump, suggesting that ion selectivity is determined at the cytoplasmic surface. Here we extended this research and successfully created a light-driven Cs(+) pump. KR2 N61L/G263F pumps Cs(+) as well as other monovalent cations in the presence of a protonophore. Ion transport activities correlated with the additive volume of the residues at 61 and 263. The result suggests that an ion-selectivity filter is affected by these two residues and functions by strict exclusion of K(+) and larger cations in the wild type (N61/G263). In contrast, introduction of large residues possibly destroys local structures of the ion-selectivity filter, leading to the permeation of K(+) (P61/W263) and Cs(+) (L61/F263). PMID- 26740142 TI - Reaching Out with Physical Chemistry. PMID- 26740143 TI - Crossbreeding effects on rabbit reproduction from four maternal lines of rabbits. AB - Litter size is essential for an efficient production of rabbit meat. A diallel cross between four maternal lines was carried out and the analysis of the components of litter size has been already done. This paper presents the analysis of litter size traits themselves (total born (TB), number born alive (NBA), number weaned (NW)) and kindling interval (KI), that complete the analysis of the reproductive performance. The 16 genetic groups were distributed in four Spanish farms. The V line was present in all farms in order to be used as reference group. A total of 34 546 parities from 7111 does, were analysed. The crossbreeding parameters were estimated according to Dickerson model. The differences between lines performance were of low magnitude and not significant for litter size traits. The LP line showed the shortest KI followed by H respect to lines A and V. These differences reflected the differences between direct and maternal genetic effects. The differences between the average of all crosses and line V were found to be significant and seemed to be important, being 0.46 for TB, 0.56 for NBA, 0.75 for NW and -2.21 days for KI. The differences between reciprocal crosses for litter size were of low magnitude and non-significant, which indicate that the maternal effects are not important between these lines. In general, the lines did not show significant differences in direct and maternal genetic effects for TB, NBA and NW but there were some significant differences for KI, which ranged from 1.54 to 6.85 days in direct effects and from 0.63 to 3.38 days for maternal effects. A positive and, in some cases, relevant heterosis was found. The largest heterosis was for TB in the HV cross (1.05 rabbits), followed by the AH (0.74 rabbits), AV (0.57 rabbits) and LH (0.55 rabbits) crosses. For NBA, significant heterosis was found in HV (1.11 rabbits) and AV (0.49 rabbits) and for NW in AV (0.90 rabbits), LH (0.70 rabbits) and LV (0.58 rabbits). Favourable and significant heterosis for KI was found in AV and LV crosses, whereas it was unfavourable in AL and in LH. The more recommended crosses were AV and LH, showing the greatest performances on NW, while the cross HV, which shows the greatest performances an NBA, could be highly recommended when cross-fostering is practised to equalise litter sizes after birth, in this situation the lower NW performance observed could be improved. PMID- 26740144 TI - Insect stereopsis demonstrated using a 3D insect cinema. AB - Stereopsis - 3D vision - has become widely used as a model of perception. However, all our knowledge of possible underlying mechanisms comes almost exclusively from vertebrates. While stereopsis has been demonstrated for one invertebrate, the praying mantis, a lack of techniques to probe invertebrate stereopsis has prevented any further progress for three decades. We therefore developed a stereoscopic display system for insects, using miniature 3D glasses to present separate images to each eye, and tested our ability to deliver stereoscopic illusions to praying mantises. We find that while filtering by circular polarization failed due to excessive crosstalk, "anaglyph" filtering by spectral content clearly succeeded in giving the mantis the illusion of 3D depth. We thus definitively demonstrate stereopsis in mantises and also demonstrate that the anaglyph technique can be effectively used to deliver virtual 3D stimuli to insects. This method opens up broad avenues of research into the parallel evolution of stereoscopic computations and possible new algorithms for depth perception. PMID- 26740145 TI - Re: Sighinolfi et al.: Chemical and Mineralogical Analysis of Ureteral Stent Encrustation and Associated Risk Factors (Urology 2015;86:703-706). PMID- 26740148 TI - Health Advice from Internet Discussion Forums: How Bad Is Dangerous? AB - BACKGROUND: Concerns over online health information-seeking behavior point to the potential harm incorrect, incomplete, or biased information may cause. However, systematic reviews of health information have found few examples of documented harm that can be directly attributed to poor quality information found online. OBJECTIVE: The aim of this study was to improve our understanding of the quality and quality characteristics of information found in online discussion forum websites so that their likely value as a peer-to-peer health information-sharing platform could be assessed. METHODS: A total of 25 health discussion threads were selected across 3 websites (Reddit, Mumsnet, and Patient) covering 3 health conditions (human immunodeficiency virus [HIV], diabetes, and chickenpox). Assessors were asked to rate information found in the discussion threads according to 5 criteria: accuracy, completeness, how sensible the replies were, how they thought the questioner would act, and how useful they thought the questioner would find the replies. RESULTS: In all, 78 fully completed assessments were returned by 17 individuals (8 were qualified medical doctors, 9 were not). When the ratings awarded in the assessments were analyzed, 25 of the assessments placed the discussion threads in the highest possible score band rating them between 5 and 10 overall, 38 rated them between 11 and 15, 12 rated them between 16 and 20, and 3 placed the discussion thread they assessed in the lowest rating band (21-25). This suggests that health threads on Internet discussion forum websites are more likely than not (by a factor of 4:1) to contain information of high or reasonably high quality. Extremely poor information is rare; the lowest available assessment rating was awarded only 11 times out of a possible 353, whereas the highest was awarded 54 times. Only 3 of 78 fully completed assessments rated a discussion thread in the lowest possible overall band of 21 to 25, whereas 25 of 78 rated it in the highest of 5 to 10. Quality assessments differed depending on the health condition (chickenpox appeared 17 times in the 20 lowest-rated threads, HIV twice, and diabetes once). Although assessors tended to agree on which discussion threads contained good quality information, what constituted poor quality information appeared to be more subjective. CONCLUSIONS: Most of the information assessed in this study was considered by qualified medical doctors and nonmedically qualified respondents to be of reasonably good quality. Although a small amount of information was assessed as poor, not all respondents agreed that the original questioner would have been led to act inappropriately based on the information presented. This suggests that discussion forum websites may be a useful platform through which people can ask health-related questions and receive answers of acceptable quality. PMID- 26740150 TI - The First Two Clostridium difficile Ribotype 027/ST1 Isolates Identified in Beijing, China-an Emerging Problem or a Neglected Threat? AB - Clostridium difficile hyper-virulent ribotype 027 strain has become a significant concern globally, but has rarely been reported in Asian countries including China. Recently, a retrospective single-center study in Beijing, China, detected two ribotype 027 C. difficile isolates from two patients coming for outpatient visits in 2012 and 2013. We performed a systematic investigation of the two isolates (and patients). Both C. difficile isolates had the typical PCR ribotype 027 profile; were positive for tcdA, tcdB and binary toxin genes; belonged to multilocus sequence type 1 (ST1); had typical ribotype 027 deletions in the tcdC gene; and were highly-resistant to fluoroquinolones; but had a different MLVA profile and were not genetically related to any previously reported international ribotype 027 clones. A review of the patients' medical records showed that neither received appropriate antimicrobial treatment and were lost to follow-up after outpatient visits. We propose that C. difficile infections caused by ribotype 027 are probably a neglected problem in China, and the subsequent impact of unawareness of this problem is worrying. Appropriate testing assays and multi center or national level surveillance for C. difficile infections and specifically for ribotype 027 should be introduced to provide essential data and guide future clinical practice. PMID- 26740152 TI - N-(3,4-Dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4 [(11)C]methylphenyl)thiazol-2-yl]-1-carboxamide: A promising positron emission tomography ligand for fatty acid amide hydrolase. AB - To visualize fatty acid amide hydrolase (FAAH) in brain in vivo, we developed a novel positron emission tomography (PET) ligand N-(3,4-dimethylisoxazol-5 yl)piperazine-4-[4-(2-fluoro-4-[(11)C]methylphenyl)thiazol-2-yl]-1-carboxamide ([(11)C]DFMC, [(11)C]1). DFMC (1) was shown to have high binding affinity (IC50: 6.1nM) for FAAH. [(11)C]1 was synthesized by C-(11)C coupling reaction of arylboronic ester 2 with [(11)C]methyl iodide in the presence of Pd catalyst. At the end of synthesis, [(11)C]1 was obtained with a radiochemical yield of 20+/ 10% (based on [(11)C]CO2, decay-corrected, n=5) and specific activity of 48 166GBq/MUmol. After the injection of [(11)C]1 in mice, high uptake of radioactivity (>2% ID/g) was distributed in the lung, liver, kidney, and brain, organs with high FAAH expression. PET images of rat brains for [(11)C]1 revealed high uptakes in the cerebellar nucleus (SUV=2.4) and frontal cortex (SUV=2.0), two known brain regions with high FAAH expression. Pretreatment with the FAAH selective inhibitor URB597 reduced the brain uptake. Higher than 90% of the total radioactivity in the rat brain was irreversible at 30min after the radioligand injection. The present results indicate that [(11)C]1 is a promising PET ligand for imaging of FAAH in living brain. PMID- 26740153 TI - Identification of B. anthracis N(5)-carboxyaminoimidazole ribonucleotide mutase (PurE) active site binding compounds via fragment library screening. AB - The de novo purine biosynthesis pathway is an attractive target for antibacterial drug design, and PurE from this pathway has been identified to be crucial for Bacillus anthracis survival in serum. In this study we adopted a fragment-based hit discovery approach, using three screening methods-saturation transfer difference nucleus magnetic resonance (STD-NMR), water-ligand observed via gradient spectroscopy (WaterLOGSY) NMR, and surface plasmon resonance (SPR), against B. anthracis PurE (BaPurE) to identify active site binding fragments by initially testing 352 compounds in a Zenobia fragment library. Competition STD NMR with the BaPurE product effectively eliminated non-active site binding hits from the primary hits, selecting active site binders only. Binding affinities (dissociation constant, KD) of these compounds varied between 234 and 301MUM. Based on test results from the Zenobia compounds, we subsequently developed and applied a streamlined fragment screening strategy to screen a much larger library consisting of 3000 computationally pre-selected fragments. Thirteen final fragment hits were confirmed to exhibit binding affinities varying from 14MUM to 700MUM, which were categorized into five different basic scaffolds. All thirteen fragment hits have ligand efficiencies higher than 0.30. We demonstrated that at least two fragments from two different scaffolds exhibit inhibitory activity against the BaPurE enzyme. PMID- 26740154 TI - Illuminating the binding interactions of galactonoamidines during the inhibition of beta-galactosidase (E. coli). AB - Several galactonoamidines were previously identified as very potent competitive inhibitors that exhibit stabilizing hydrophobic interactions of the aglycon in the active site of beta-galactosidase (Aspergillus oryzae). To elucidate the contributions of the glycon to the overall inhibition ability of the compounds, three glyconoamidine derivatives with alteration in the glycon at C-2 and C-4 were synthesized and evaluated herein. All amidines are competitive inhibitors of beta-galactosidase (Escherichia coli) and show significantly reduced inhibition ability when compared to the parent. The results highlight strong hydrogen bonding interactions between the hydroxyl group at C-2 of the amidine glycon and the active site of the enzyme. Slightly weaker H-bonds are promoted through the hydroxyl group at C-4. The inhibition constants were determined to be picomolar for the parent galactonoamidine, and nanomolar for the designed derivatives rendering all glyconoamidines very potent inhibitors of glycosidases albeit the derivatized amidines show up to 700-fold lower inhibition activity than the parent. PMID- 26740155 TI - Synthesis and biological activity of ferrocenyl indeno[1,2-c]isoquinolines as topoisomerase II inhibitors. AB - Three series of indeno[1,2-c]isoquinolines bearing a ferrocenyl entity were synthesized and evaluated for DNA interaction, topoisomerase I and II inhibition, and cytotoxicity against breast human cancer cell lines. In the first and second series, the ferrocenyl scaffold was inserted as a linker between the two nitrogen atoms. In the last series, it was introduced at the end of the carbon chain. The present study showed that the ferrocenyl entity enhanced the topoisomerase II inhibition. Most compounds showed a potent growth inhibitory effect on MDA-MB-231 cell line with the IC50 in MUM range. PMID- 26740156 TI - Synthesis and biological evaluation of disubstituted amidoxanthones as potential telomeric G-quadruplex DNA-binding and apoptosis-inducing agents. AB - A series of disubstituted xanthones was obtained by cationic modification of xanthone's C2 and C7 with amine groups of different pKa values. Modified structures by using moieties with high pKa values had good antitumor activity according to the MTT assay, AO/EB staining and flow cytometry assay, especially bis-dimethylamine derivative (5a). Further study indicated that compound 5a had good binding activity to telomeric G-quadruplex DNA, as detected by using spectroscopy methods, melting profiles, polymerase chain reaction stop assay and molecular modeling study. The results suggested that the antitumor activity of 5a might be associated with its stabilization of G-quadruplex DNA, which could be developed as new G-quadruplex DNA stabilizer and potent antitumor agents. PMID- 26740157 TI - Synthesis, characterization and antimicrobial activities of novel silver(I) complexes with coumarin substituted N-heterocyclic carbene ligands. AB - Eight new coumarin substituted silver(I) N-heterocyclic carbene (NHC) complexes were synthesized by the interaction of the corresponding imidazolium or benzimidazolium chlorides and Ag2O in dichloromethane at room temperature. Structures of these complexes were established on the basis of elemental analysis, (1)H NMR, (13)C NMR, IR and mass spectroscopic techniques. The antimicrobial activities of carbene precursors and silver NHC complexes were tested against standard strains: Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and the fungi Candida albicans and Candida tropicalis. Results showed that all the compounds inhibited the growth of the all bacteria and fungi strains and some complexes performed good activities against different microorganisms. Among all the compounds, the most lipophilic complex bis[1-(4-methylene-6,8-dimethyl-2H-chromen-2-one)-3-(naphthalene-2 ylmethyl)benzimidazol-2-ylidene]silver(I) dichloro argentate (5e) was found out as the most active one. PMID- 26740158 TI - Assessment of aflatoxin exposure using serum and urinary biomarkers in Sao Paulo, Brazil: A pilot study. AB - The aim of this study was to evaluate the human exposure of individuals from Pirassununga, Brazil, to dietary aflatoxins B1 (AFB1) and M1 (AFM1) by determination of serum AFB1-lysine and urinary aflatoxin biomarkers (AFM1 and AFB1-N(7)-guanine). The participants were recruited among employees from a Campus of the University of Sao Paulo, which provided food samples from their homes, as well as serum and urine samples four times every three months, from June 2011 until March 2012. The probable daily intake (PDI) of aflatoxin was estimated by using the results from analysis of food products collected by the time of samples collection, and data from a 24-hour dietary recall questionnaire. Analyses of AFB1 and AFM1 in food samples were conducted by high-performance liquid chromatography with fluorescence detection. Biomarkers in serum and urine were determined by tandem mass spectrometry. AFB1 and AFM1 were detected in 38 samples of cereals (28%, N=136) and 31 milk products (36%, N=86), respectively. AFB1 lysine and AFB1-N(7)-guanine and were not detected in serum or urine samples, respectively. However, AFM1 was found in 74 urine samples (65%), at mean levels in the 4 sampling times ranging from 0.37+/-0.23 to 1.70+/-2.88pg/mg creatinine. The mean PDI varied among different sampling times, ranging from 0.09+/-0.09 to 1.35+/-5.98ng/kg body weight/day. A modest though significant correlation (r=0.45; p=0.03; N=23) was found for the first time in Brazil between the AFM1 concentration in urine and the PDI for total aflatoxins (AFB1+AFM1) in sampling 1 (June 2011). Urinary AFM1 was confirmed as very sensitive for monitoring the human exposure to dietary aflatoxin. Further studies using serum and urinary biomarkers are needed to estimate the aflatoxin exposure of populations in higher risk areas in Brazil. PMID- 26740161 TI - Acquisition of specific response-outcome associations requires NMDA receptor activation in the basolateral amygdala but not in the insular cortex. AB - The basolateral amygdala (BLA) and the gustatory region of the insular cortex (IC) are required for the encoding and retrieval of outcome value. Here, we examined if these regions are also necessary to learn associations between actions and their outcomes. Hungry rats were first trained to press two levers for a common outcome. Next, specific response-outcome (R-O) associations were introduced such that each response now earned a distinct food outcome. Prior to each specific R-O training session, rats received a bilateral infusion of the N methyl-D-aspartate (NMDA) receptor antagonist, DL-APV, into either the BLA or the IC. One of the two outcomes was then devalued immediately prior to a choice test. Inhibition of NMDA receptor activity in the BLA, but not the IC, during the acquisition of specific R-O associations abolished selective devaluation. These results indicate that the BLA is critical for learning the association between actions and their specific consequences. PMID- 26740162 TI - High level evidence does not support first wave behavioural approaches to parent infant sleep. PMID- 26740163 TI - Response to SMRV-D-15-564: Not yet time to throw the baby out with the bathwater, a paradigm shift is premature. PMID- 26740164 TI - Infant sleep interventions - Methodological and conceptual issues. PMID- 26740165 TI - Is Sport Activity Possible After Arthroscopic Meniscal Allograft Transplantation? Midterm Results in Active Patients. AB - BACKGROUND: Meniscal allograft transplantation (MAT) has produced good to excellent results in the general population; however, few investigations have examined MAT in athletes and sport-related outcomes. PURPOSE: To report midterm clinical outcomes of MAT and the rate of return to sport in a physically active population. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The study included all physically active patients who underwent arthroscopic MAT without bone plugs and had a minimum of 2 years of follow-up at a single institution. Clinical evaluation was performed with the Knee injury and Osteoarthritis Outcome Score (KOOS), the Tegner activity scale, and a 0- to 100-point subjective scale for knee function and satisfaction. Outcomes evaluated included ability to return to sport, time to return to sport, level of sport activity upon return compared with preinjury level, and level of decrease in sport participation or reasons for not returning to sport participation. Comparisons were made between patients who did or did not return to sport and between patients who returned to the same level or a decreased level. Regression analysis was performed to determine the variables affecting the outcomes. RESULTS: Eighty-nine patients, whose mean +/- SD age at surgery was 38.5 +/- 11.2 years, were evaluated to a mean follow-up of 4.2 +/- 1.9 years. Total KOOS improved from a mean +/- SD of 39.5 +/- 18.5 preoperatively to 84.7 +/- 14.8 at the latest follow-up (P < .001). The Tegner score improved significantly from a median of 2 (interquartile range [IQR], 1-4) preoperatively to a median of 4 (IQR, 3-6) at the latest follow-up (P < .001), although it did not reach the preinjury level of 6 (IQR, 5-7) (P < .001). Older age at surgery was correlated with the worst clinical results. Sixty-six patients (74%) were able to return to sport after 8.6 +/- 4.1 months. Forty-four (49%) returned to the same level as preinjury. Patients who did not return to sport activity and those who reduced their activity level at follow-up had inferior subjective outcomes compared with those who returned to sport and those who returned to their preinjury levels, respectively. Only 11 patients (12%) underwent a surgical procedure during the follow-up period. CONCLUSION: Arthroscopic MAT without bone plugs improved knee function and reduced pain, allowing sport resumption in 74% of patients and return to the preinjury activity level in 49% of patients at midterm follow-up. Of all the demographic and surgical variables, only age at surgery seemed to affect outcomes. PMID- 26740166 TI - Global burden of prematurity. AB - The global burden of preterm birth (PTB) includes the morbidity and mortality of babies born before 37 completed weeks of gestation. Prematurity has been the leading worldwide cause of neonatal mortality for at least a decade, but has now also become the leading cause of childhood mortality through age five years. Globally, each year, 15 million babies are born preterm, which is estimated to be about 11% of all deliveries. Preterm birth appears to be increasing in most countries. This review will address the epidemiology, rates, and etiology of PTB around the globe as well as survival by gestational age and interventions and preventative measures known to improve outcomes in high-burden countries. PMID- 26740168 TI - Reducing the risk of venous thromboembolism in pregnancy--The safe motherhood initiative thromboembolism bundle. AB - Maternal mortality from venous thromboembolism (VTE) remains a significant cause of direct maternal death, and one that is largely preventable. The incidence of VTE in pregnancy and the postnatal period is, however, rising in the United States, likely reflecting increasing obesity and operative delivery rates. There is a clear need to establish and implement risk assessment tools and thromboprophylaxis guidelines in an effort to curb these rising rates and reverse this current trend. In this article, Friedman and D'Alton introduce a thromboembolism bundle of recommendations from the Safe Motherhood Initiative, which aim to do just that. In this article, we review the recommendations made, and compare to established guidelines, such as those from the Royal College of Obstetricians and Gynaecologists, which have successfully reduced maternal mortality from VTE following publication. PMID- 26740170 TI - Repeated exposure to whole cigarette smoke promotes primary human gingival epithelial cell growth and modulates keratin expression. AB - BACKGROUND AND OBJECTIVE: The gingiva is the first oral tissue directly exposed to cigarette smoke (CS). Exposure to CS compromises the structure and function of gingival tissue. Damaging or altering the gingival epithelium leads to a compromised protective barrier of the periodontium, resulting in several diseases. The aim of this study was to assess the effect of repeated exposure to CS on gingival epithelial cell growth and on expression of apoptotic protein and keratin. MATERIAL AND METHODS: Primary human gingival epithelial cells were seeded on a collagen scaffold for 5 d to allow growth and stratification. The cells were then exposed for 5 min to whole CS for 3, 6 and 9 d. At the end of each exposure period, cell proliferation [using (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide) (MTT) and 5-bromo-2'-deoxyuridine (BrdU) assays], gene expression [by quantitative reverse transcription polymerase chain reaction (qRT-PCR)] and protein production (by western blot analysis) were investigated. RESULTS: Higher metabolic activity was found in the CS-exposed cells than in the nonexposed cells, specifically after 3 and 6 d of exposure to CS. At 9 d there was no significant difference between CS-exposed and nonexposed cells. Metabolic activity was supported by the BrdU cell-proliferation analyses, which showed increased cell growth at 3 d compared with the control. However, at 6 and 9 d, cell proliferation in the CS-exposed culture was comparable to that in the nonexposed culture. Interestingly, the Bax/Bcl-2 protein ratios decreased with increased CS exposure, suggesting cell resistance. Moreover, protein analyses showed that CS decreased expression of keratin(K) 5 at 3, 6 and 9 d, and increased expression of K14 at 6 and 9 d. Finally, mRNA analyses showed significant decreases of K1, K6, K10 and K16 in CS-exposed cultures, correlating, at times, with a decrease of protein production. CONCLUSION: CS was shown to increase epithelial cell proliferation, which may involve cell resistance to apoptosis. This is supported by the modulation of expression of different keratin genes and proteins. Altogether, these data may explain the hyperplasia reported in gingival tissue, as well as periodontal disease, in smokers. PMID- 26740169 TI - Evolution of an ancient protein function involved in organized multicellularity in animals. AB - To form and maintain organized tissues, multicellular organisms orient their mitotic spindles relative to neighboring cells. A molecular complex scaffolded by the GK protein-interaction domain (GKPID) mediates spindle orientation in diverse animal taxa by linking microtubule motor proteins to a marker protein on the cell cortex localized by external cues. Here we illuminate how this complex evolved and commandeered control of spindle orientation from a more ancient mechanism. The complex was assembled through a series of molecular exploitation events, one of which - the evolution of GKPID's capacity to bind the cortical marker protein can be recapitulated by reintroducing a single historical substitution into the reconstructed ancestral GKPID. This change revealed and repurposed an ancient molecular surface that previously had a radically different function. We show how the physical simplicity of this binding interface enabled the evolution of a new protein function now essential to the biological complexity of many animals. PMID- 26740171 TI - Quercetin and the mitochondria: A mechanistic view. AB - Quercetin is an important flavonoid that is ubiquitously present in the diet in a variety of fruits and vegetables. It has been traditionally viewed as a potent antioxidant and anti-inflammatory molecule. However, recent studies have suggested that quercetin may exert its beneficial effects independent of its free radical-scavenging properties. Attention has been placed on the effect of quercetin on an array of mitochondrial processes. Quercetin is now recognized as a phytochemical that can modulate pathways associated with mitochondrial biogenesis, mitochondrial membrane potential, oxidative respiration and ATP anabolism, intra-mitochondrial redox status, and subsequently, mitochondria induced apoptosis. The present review evaluates recent evidence on the ability of quercetin to interact with the abovementioned pathways, and critically analyses how, such interactions can exert protection against mitochondrial damage in response to toxicity induced by several exogenously and endogenously-produced cellular stressors, and oxidative stress in particular. PMID- 26740172 TI - When Life Expectancy is Not Short Enough: A Perspective on the National Institute for Health and Care Excellence (NICE) Preliminary Guidance for Dinutuximab. PMID- 26740174 TI - Breed Distribution and Clinical Characteristics of B Cell Chronic Lymphocytic Leukemia in Dogs. AB - BACKGROUND: B-cell chronic lymphocytic leukemia (B-CLL) is the most common hematopoietic malignancy in humans in the developed world and the primary risk factor is genetic. Dogs also develop B-CLL, but there is no systematic description of the disease in dogs. Understanding the epidemiology of B-CLL in dogs may help practitioners recognize the disease and position the dog as a model for future genetic studies. OBJECTIVES: To describe B-CLL presentation in dogs, its clinicopathologic findings, and breed predisposition. ANIMALS: Four hundred and ninety-one dogs with B-CLL and 5,673 control dogs with suspicion of a lymphoproliferative disorder (LPD). METHODS: Retrospective cross-sectional study of dogs for which samples were submitted to the Colorado State University Clinical Immunology Laboratory for immunophenotyping between 2010 and 2014. To assess breed predilection, dogs with B-CLL were compared to those with suspicion of other LPDs using logistic regression. RESULTS: The median age was 11 years with no sex predilection. Half of the dogs presented with peripheral lymphadenopathy or splenomegaly and 26% had anemia. Eleven small-breed dogs had significantly increased odds of B-CLL. In addition, English Bulldogs had an increased risk and a unique presentation: these dogs were diagnosed at a median of 6 years and expressed lower class II MHC and CD25. CONCLUSIONS: B-cell chronic lymphocytic leukemia is overrepresented in small-breed dogs. Future genetic studies of these breeds may identify genetic risk factors. The unique presentation of English Bulldogs provides evidence of multiple forms of this disease. Additional studies are necessary to determine whether presenting signs are associated with survival. PMID- 26740175 TI - Over-expression of CHAF1A promotes cell proliferation and apoptosis resistance in glioblastoma cells via AKT/FOXO3a/Bim pathway. AB - Chromatinassembly factor 1 subunit A (CHAF1A) has been reported to be involved in several human diseases including cancer. However, the biological and clinical significance of CHAF1A in glioblastoma progression remains largely unknown. In this study, we found that up-regulation of CHAF1A happens frequently in glioblastoma tissues and is associated with glioblastoma prognosis. Knockout of CHAF1A by CRISPR/CAS9 technology induce G1 phase arrest and apoptosis in glioblastoma cell U251 and U87. In addition, inhibition of CHAF1A influenced the signal transduction of the AKT/FOXO3a/Bim axis, which is required for glioblastoma cell proliferation. Taken together, these results show that CHAF1A contributes to the proliferation of glioblastoma cells and may be developed as a de novo drug target and prognosis biomarker of glioblastoma. PMID- 26740176 TI - House dust mite extract induces growth factor expression in nasal mucosa by activating the PI3K/Akt/HIF-1alpha pathway. AB - Growing evidence suggests that hypoxia-inducible factor-alpha (HIF-1alpha) plays an important role in the progression of allergic airway inflammation and remodeling. However, the biochemical mechanisms leading to the activation of HIF 1alpha and the effects of HIF-1alpha on the expression of growth factors, including vascular endothelial growth factor (VEGF), transforming growth factor beta1 (TGF-beta1), and fibroblast growth factor-2 (FGF-2), in allergic nasal inflammation are not clear. We examined the relationship between HIF-1alpha activation and production of VEGF, TGF-beta1, and FGF-2 in primary cultured nasal epithelial cells (NECs) after stimulation with house dust mite (HDM) extract. Moreover, we evaluated the importance of phosphoinositide3-kinase(PI3K)/Akt signaling in HDM-induced production of these growth factors in vitro and in the nasal mucosa of a murine model of allergic rhinitis (AR). Our results indicate HDM extract induced the expression of VEGF, TGF-beta1, and FGF-2 by activating the PI3K/Akt/HIF-1alpha pathway in human primary cultured NECs and in the nasal mucosa of a murine model. HIF-1alpha regulated the expression of VEGF, TGF-beta1, and FGF-2 in the nasal mucosa through direct and indirect pathways, which suggested that targeting the HIF-1alpha pathway could be a novel therapeutic approach for reducing nasal airway inflammation and remodeling in AR. PMID- 26740177 TI - CED-4 is an mRNA-binding protein that delivers ced-3 mRNA to ribosomes. AB - Cell death abnormal (ced)-3 and ced-4 genes regulate apoptosis to maintain tissue homeostasis in Caenorhabditis elegans. Apoptosome formation and CED-4 translocation drive CED-3 activation. However, the precise role of CED-4 translocation is not yet fully understood. In this study, using a combination of immunoprecipitation and reverse transcription-polymerase chain reaction methods in cells and a glutathione-S-transferase pull down assay in a cell-free system, we show that CED-4 binds ced-3 mRNA. In the presence of ced-3 mRNA, CED-4 protein is enriched in the microsomal fraction and interacts with ribosomal protein L10a in mammalian cells, increasing the levels of CED-3. These results suggest that CED-4 forms a complex with ced-3 mRNA and delivers it to ribosomes for translation. PMID- 26740178 TI - Enhancement of cisplatin-induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in vivo. AB - Cisplatin-based therapy is one of the most important chemotherapy treatments for cancers. However, its efficacy is greatly limited by drug resistance and undesirable side effects. Therefore, it is of great importance to develop effective chemosensitization agents to cisplatin. In the present study, we demonstrated the strategy to use shikonin, a natural product from the root of Lithospermum erythrorhizon, as a synergistic agent of cisplatin and elucidated their action mechanisms. The combination of shikonin and cisplatin exhibited synergistic anticancer efficacy and achieved greater selectivity between cancer cells and normal cells. By inducing intracellular oxidative stress, shikonin potentiated cisplatin-induced DNA damage, followed by increased activation of mitochondrial pathway. In addition, inhibition of ROS reversed the apoptosis induced by shikonin and cisplatin, and recovered the depletion of mitochondrial membrane potential, which revealed the vital role of ROS in the synergism. Moreover, HCT116 xenograft tumor growth in nude mice was more effectively inhibited by combined treatment with shikonin and cisplatin. Our findings suggest that the strategy to apply shikonin as a synergistic agent to cisplatin could be a highly efficient way to achieve anticancer synergism by inducing intracellular oxidative stress. Shikonin may be a promising candidate as a chemosensitizer to cisplatin-based therapy for cancer treatments. PMID- 26740179 TI - Inflammation increases pyruvate dehydrogenase kinase 4 (PDK4) expression via the Jun N-Terminal Kinase (JNK) pathway in C2C12 cells. AB - Chronic inflammation augments the deleterious effects of several diseases, particularly diabetes, cancer, and sepsis. It is also involved in the process of metabolic shift from glucose oxidation to lactate production. Although several studies suggest that the change in activity of the pyruvate dehydrogenase complex (PDC) is a major factor causing this metabolic change, the exact mechanism of the inflammatory state remains unclear. In this study, we investigated the effect of lipopolysaccharide (LPS) on the expression of pyruvate dehydrogenase kinase 4 (PDK4), which is strongly associated with inactivation of the PDC in C2C12 myoblasts. In C2C12 myoblasts, LPS exposure led to increased PDK4 mRNA and protein expression levels as well as lactate production in culture medium. However, the expression levels of other PDK isoenzymes (PDK1 - 3) remained unchanged. Additionally, we observed that LPS treatment induced phosphorylation of Jun N-Terminal Kinases (JNK). To confirm the role of JNK, we inhibited the JNK pathway and observed that PDK4 expression and lactate production were decreased, but p38 and ERK were not significantly changed. Taken together, our results suggest that LPS induces PDK4 expression and alters glucose metabolism via the JNK pathway. PMID- 26740180 TI - Salicortin inhibits osteoclast differentiation and bone resorption by down regulating JNK and NF-kappaB/NFATc1 signaling pathways. AB - Receptor activator of nuclear factor (NF)-kappaB ligand (RANKL)-activated signaling is essential for osteoclast differentiation, activation, and survival. Salicortin is a phenolic glycoside that has been isolated from many plants such as Populus and Salix species, and has been shown to have anti-amnesic and anti adipogenic effects. In this study, we investigated the effect of salicortin on RANKL-induced osteoclasts formation, bone resorption, and activation of osteoclast-related signaling pathways. Salicortin suppressed RANKL-induced osteoclastogenesis in bone marrow macrophage cultures in a dose-dependent manner, and inhibited osteoclastic bone resorption activity without any cytotoxicity. Salicortin inhibited RANKL-induced c-Jun N-terminal kinase and NF-kappaB activation, concomitant with retarded IkappaBalpha phosphorylation and inhibition of p65 nuclear translocation, leading to impaired transcription of nuclear factor of activated T cells c1 (NFATc1) and expression of osteoclastic-specific genes. Taken together, our findings demonstrate that salicortin inhibits NF-kappaB and NFATc1 activation, leading to attenuation of osteoclastogenesis and bone resorption. Thus, salicortin may be of interest in developments of treatment for osteoclast related diseases. PMID- 26740181 TI - Chlorogenic acid ameliorates endotoxin-induced liver injury by promoting mitochondrial oxidative phosphorylation. AB - Acute or chronic hepatic injury is a common pathology worldwide. Mitochondrial dysfunction and the depletion of adenosine triphosphate (ATP) play important roles in liver injury. Chlorogenic acids (CGA) are some of the most abundant phenolic acids in human diet. This study was designed to test the hypothesis that CGA may protect against chronic lipopolysaccharide (LPS)-induced liver injury by modulating mitochondrial energy generation. CGA decreased the activities of serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. The contents of ATP and adenosine monophosphate (AMP), as well as the ratio of AMP/ATP, were increased after CGA supplementation. The activities of enzymes that are involved in glycolysis were reduced, while those of enzymes involved in oxidative phosphorylation were increased. Moreover, phosphorylated AMP-activated protein kinase (AMPK), and mRNA levels of AMPK-alpha, peroxisome proliferator activated receptor-gamma coactivator 1alpha (PGC-1alpha), nuclear respiratory factor 1, and mitochondrial DNA transcription factor A were increased after CGA supplementation. Collectively, these findings suggest that the hepatoprotective effect of CGA might be associated with enhanced ATP production, the stimulation of mitochondrial oxidative phosphorylation and the inhibition of glycolysis. PMID- 26740182 TI - Serum immunoglobulin G Fc region N-glycosylation profiling by matrix-assisted laser desorption/ionization mass spectrometry can distinguish breast cancer patients from cancer-free controls. AB - Herein, we report that breast cancer (BC) patients can be distinguished from cancer-free (NC) controls by serum immunoglobulin G (IgG) crystallizable fragment (Fc) region N-glycosylation profiling using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). Recently, there has been much progress in the field of tumor immunology. However, to date, the role and biomarker potential of IgG Fc region N-glycosylation, which affects the function of antibodies, have not been examined in BC. In the present study, we profiled serum IgG Fc region N-glycans in BC patients (N = 90) and NC controls (N = 54) using MALDI-MS. An IgG Fc region N-glycan-based multiple logistic regression model was produced which could distinguish BC patients from NC controls (area under the receiver operative characteristic curve = 0.874). Furthermore, stage 0 patients could also be distinguished using this model. These results suggest that an unknown humoral factor or soluble mediator affects IgGs from the earliest stage of breast cancer, and also suggests that IgG Fc region N-glycosylation may play a role in tumor biology. Although further investigation is required, our findings are the evidence that IgG N-glycan profiling has the potential to be used as a breast cancer biomarker and may provide the insights into tumor immunology. PMID- 26740183 TI - Remote Ischemic Conditioning: Its Benefits and Limitations. AB - This editorial describes benefits and limitations of remote ischemic conditioning. Remote ischemic conditioning was shown to reduce myocardial intact size in at least 4 sizeable clinical trials of acute myocardial infarction. It was not effective in recent studies of cardiac surgery. Reasons for these differences are discussed. PMID- 26740184 TI - The Potential Role of Catheter-Based Renal Sympathetic Denervation in Chronic and End-Stage Kidney Disease. AB - Sympathetic activation is a hallmark of chronic and end-stage renal disease and adversely affects cardiovascular prognosis. Hypertension is present in the vast majority of these patients and plays a key role in the progressive deterioration of renal function and the high rate of cardiovascular events in this patient cohort. Augmentation of renin release, tubular sodium reabsorption, and renal vascular resistance are direct consequences of efferent renal sympathetic nerve stimulation and the major components of neural regulation of renal function. Renal afferent nerve activity directly influences sympathetic outflow to the kidneys and other highly innervated organs involved in blood pressure control via hypothalamic integration. Renal denervation of the kidney has been shown to reduce blood pressure in many experimental models of hypertension. Targeting the renal nerves directly may therefore be specifically useful in patients with chronic and end-stage renal disease. In this review, we will discuss the potential role of catheter-based renal denervation in patients with impaired kidney function and also reflect on the potential impact on other cardiovascular conditions commonly associated with chronic kidney disease such as heart failure and arrhythmias. PMID- 26740187 TI - Insights on FXR selective modulation. Speculation on bile acid chemical space in the discovery of potent and selective agonists. AB - Bile acids are the endogenous modulators of the nuclear receptor FXR and the membrane receptor GPBAR1. FXR represents a promising pharmacological target for the treatment of cholestatic liver disorders. Currently available semisynthetic bile acid derivatives cover the same chemical space of bile acids and therefore they are poorly selective toward BA receptors, increasing patient risk for adverse side effects. In this report, we have investigated around the structure of CDCA describing the synthesis and the in vitro and in vivo pharmacological characterization of a novel family of compounds modified on the steroidal tetracyclic core and on the side chain. Pharmacological characterization resulted in the identification of several potent and selective FXR agonists. These novel agents might add utility in the treatment of cholestatic disorders by potentially mitigating side effects linked to unwanted activation of GPBAR1. PMID- 26740192 TI - Mercury toxicokinetics of the healthy human term placenta involve amino acid transporters and ABC transporters. AB - BACKGROUND: The capacity of the human placenta to handle exogenous stressors is poorly understood. The heavy metal mercury is well-known to pass the placenta and to affect brain development. An active transport across the placenta has been assumed. The underlying mechanisms however are virtually unknown. OBJECTIVES: Uptake and efflux transporters (17 candidate proteins) assumed to play a key role in placental mercury transfer were examined for expression, localization and function in human primary trophoblast cells and the trophoblast-derived choriocarcinoma cell line BeWo. METHODS: To prove involvement of the transporters, we used small interfering RNA (siRNA) and exposed cells to methylmercury (MeHg). Total mercury contents of cells were analyzed by Cold vapor atomic fluorescence spectrometry (CV-AFS). Localization of the proteins in human term placenta sections was determined via immunofluorescence microscopy. RESULTS: We found the amino acid transporter subunits L-type amino acid transporter (LAT)1 and rBAT (related to b(0,+) type amino acid transporter) as well as the efflux transporter multidrug resistance associated protein (MRP)1 to be involved in mercury kinetics of trophoblast cells (t-test P<0.05). CONCLUSION: The amino acid transporters located at the apical side of the syncytiotrophoblast (STB) manage uptake of MeHg. Mercury conjugated to glutathione (GSH) is effluxed via MRP1 localized to the basal side of the STB. The findings can well explain why mercury is transported primarily towards the fetal side. PMID- 26740194 TI - Effect of intranasal steroids on rhinosinusitis after radiotherapy for nasopharyngeal carcinoma: clinical study. AB - OBJECTIVE: Post-irradiation rhinosinusitis is one of the most common untoward side effects in patients with nasopharyngeal carcinoma. This study aimed to evaluate the effect of fluticasone propionate aqueous nasal spray on post irradiation rhinosinusitis. METHODS: Nasopharyngeal carcinoma patients who had undergone radiotherapy and subsequently developed chronic rhinosinusitis were randomised to receive either fluticasone propionate aqueous nasal spray 200 ug plus nasal irrigation or a single nasal irrigation, for six months. A questionnaire, nasal endoscopy and computed tomography were used to evaluate rhinosinusitis severity, at the beginning of treatment, and at three and six months after treatment. RESULTS: The group who received fluticasone propionate aqueous nasal spray combined with irrigation had fewer nasal complaints (overall symptoms, blocked nose and headache were reduced), a better quality of life and less severe endoscopic findings than those who only received nasal irrigation at three and six months after treatment. CONCLUSION: Nasal steroids are a safe and effective therapy for patients with post-irradiation rhinosinusitis. PMID- 26740195 TI - Vaccination coverage of adolescents: Results of a Defense and Citizenship Day based survey. AB - INTRODUCTION: Vaccination coverage among French young adults is not routinely measured. Every French adolescent aged between 16 and 18years must take part in the Defense and Citizenship Day (French acronym JDC). We aimed to assess vaccination coverage among young adults for hepatitis B, group C meningococcus meningitis, human papillomavirus (HPV), and measles. We also aimed to assess the proportion of adolescents who received the pertussis booster between the age of 11 and 13years. METHODS: The survey took place from January 19th to 26th, 2015 at the JDC center of Rennes, France. Vaccination coverage data was collected on site from the adolescents' health records. We collected the number of doses received and the dates of administration for each type of vaccine. A properly vaccinated adolescent was defined as having received the right number of doses according to the vaccination schedule. RESULTS: A total of 467 adolescents attended the JDC Day: 408 (87.4%) had brought their health record or an equivalent document. Vaccination coverage was 92.6% [90.1-95.1] for measles, 34.6% [30-39.2] for group C meningococcus meningitis, 40.7% [35.9-45.5] for hepatitis B, and 30.1% [23.9 36.3] of girls had been vaccinated against HPV. Of all adolescents, 60.1% [55.7 64.9] received a dose of the pertussis vaccine between 11 and 13years of age. CONCLUSION: Our results are similar to those of other data sources. With regard to the difficulty of assessing vaccination coverage in that age group, we believe recruitment bias was minimized due to our study location. PMID- 26740196 TI - The effect of pelvic organ prolapse repair on vaginal sensation. AB - INTRODUCTION AND HYPOTHESIS: The objective was to evaluate vaginal and clitoral sensation before and after robotic sacrocolpopexy for the repair of pelvic organ prolapse. METHODS: Twenty-two women, mean age 63 years (range 41-77), were admitted for robotic sacrocolpopexy repair of pelvic organ prolapse; 4 were lost to follow-up. Quantitative sensory thresholds for warm, cold, and vibratory sensations were measured at the vagina (anterior and posterior areas) and clitoris 1 day before and a mean of 12 +/- 4 months following surgery. Student's paired t test was used to compare sensory thresholds before and after surgery. RESULTS: For the 18 women who completed follow-up, sensitivity was significantly higher after surgery (sensory threshold decreased) at the clitoral and vaginal regions, to cold and warm stimuli. In contrast, the vaginal and clitoral vibratory sensory thresholds did not change significantly following surgery. CONCLUSION: The repair of pelvic organ prolapse by robotic sacrocolpopexy could potentially play a role in restoring clitoral and vaginal wall sensation. The effects of these sensory changes on sexual function and the quality of sexual life need further investigation. PMID- 26740197 TI - Vaginal prolapse repair with or without a midurethral sling in women with genital prolapse and occult stress urinary incontinence: a randomized trial. AB - INTRODUCTION AND HYPOTHESIS: We compared pelvic organ prolapse (POP) repair with and without midurethral sling (MUS) in women with occult stress urinary incontinence (SUI). METHODS: This was a randomized trial conducted by a consortium of 13 teaching hospitals assessing a parallel cohort of continent women with symptomatic stage II or greater POP. Women with occult SUI were randomly assigned to vaginal prolapse repair with or without MUS. Women without occult SUI received POP surgery. Main outcomes were the absence of SUI at the 12 month follow-up based on the Urogenital Distress Inventory and the need for additional treatment for SUI. RESULTS: We evaluated 231 women, of whom 91 randomized as follows: 43 to POP surgery with and 47 without MUS. A greater number of women in the MUS group reported absence of SUI [86 % vs. 48 %; relative risk (RR) 1.79; 95 % confidence interval (CI) 1.29-2.48]. No women in the MUS group received additional treatment for postoperative SUI; six (13 %) in the control group had a secondary MUS. Women with occult SUI reported more urinary symptoms after POP surgery and more often underwent treatment for postoperative SUI than women without occult SUI. CONCLUSIONS: Women with occult SUI had a higher risk of reporting SUI after POP surgery compared with women without occult SUI. Adding a MUS to POP surgery reduced the risk of postoperative SUI and the need for its treatment in women with occult SUI. Of women with occult SUI undergoing POP-only surgery, 13 % needed additional MUS. We found no differences in global impression of improvement and quality of life. PMID- 26740198 TI - Endoscopic lithotripsy and vaginal excision of a calcified bladder-mesh extrusion. AB - INTRODUCTION AND HYPOTHESIS: Synthetic meshes have proven to increase efficacy of pelvic organ prolapse (POP) repair, but associated complications are not rare. Bladder mesh extrusion is one of the most serious adverse events following POP surgery with mesh. The aim of this video was to describe endoscopic and vaginal approaches for treating a bladder-mesh extrusion. METHODS: A 52-year-old female patient with a history of vaginal POP surgery with mesh was referred for severe pelvic and perineal pain, dyspareunia, and dysuria. She was found to have a bladder calculus on a mesh extrusion. The calculus was removed by endoscopic lithotripsy before vaginal mesh excision was performed. CONCLUSIONS: With the use of synthetic vaginal mesh, the incidence of bladder-mesh extrusion could increase. This didactic video will be helpful to surgeons required to manage such cases using a minimally invasive treatment. PMID- 26740199 TI - The role of acupuncture in managing overactive bladder; a review of the literature. AB - INTRODUCTION AND HYPOTHESIS: Overactive bladder (OAB) affects a considerable proportion of men and women in the United States and is associated with significant costs and quality of life (QoL) reduction. While medication remains a mainstay of treatment, there is increasing interest in the use of alternative medicine in the form of acupuncture. We reviewed the literature on the role of acupuncture in managing OAB. METHODS: A narrative review was compiled after searching electronic databases (PubMed, MEDLINE, Scopus, and EMBASE) for clinical studies involving acupuncture in treating OAB. Databases were searched from the time of inception through September 2015 by a clinician for articles reporting the results related to the use of acupuncture in OAB. Key search terms were acupuncture, overactive bladder, bladder instability, urgency, urinary incontinence. Articles in English or translated into English were included. RESULTS: Initial animal studies suggest several biochemical mechanisms of action underlying the effect of acupuncture on OAB suppression. The experience in humans includes two case series and six comparative trials. All studies demonstrated subjective improvement in OAB symptoms, and some reported objective improvement in urodynamic studies. Notably, some comparative trials showed the benefit of acupuncture to be comparable with antimuscarinic treatment. CONCLUSION: Despite their limitations, existing studies serve as a promising foundation for suggesting a role for acupuncture as an alternative therapy for OAB. Further well designed studies are required to investigate optimal technique and their outcomes. PMID- 26740200 TI - Cultural adaptation and validation of the Wexner scale in patients with anal incontinence in a Brazilian population. AB - INTRODUCTION AND HYPOTHESIS: Jorge and Wexner devised a questionnaire for anal incontinence (AI), known as the Wexner scale (WS). Specific validated questionnaires are essential for the assessment of symptom severity. The objective was to accomplish the cultural adaptation and validation of the Portuguese version of the WS. METHODS: The WS was validated according to the international criteria. A Brazilian version was tested, including the item "I do not understand" at the end of each question. If this answer was reported at a rate higher than 15 %, the item would be considered difficult to understand and would thus be modified. The final version of the WS and the Fecal Incontinence Quality of Life (FIQL) were completed by 50 women. Convergent validity was assessed by comparing the data from the first interview of the WS with the FIQL using Spearman's test. Reproducibility was assessed by means of a 2-week test retest procedure using Cronbach's alpha coefficient. RESULTS: In the initial version of the questionnaire, we did not obtain a response of "I do not understand" at a rate greater than 15 % and this version was considered definitive. A significant negative relationship (r = -0.63) was found between the FIQL total score and the WS. The answers obtained on the "test-re-est" questionnaires showed a significant correlation according to the intraclass correlation coefficient (ICC). A high level of internal consistency was found, as demonstrated by a Cronbach's alpha of 0.932. CONCLUSION: The Brazilian Portuguese version of the WS is a reliable, consistent, and valid instrument. PMID- 26740201 TI - [Techniques to enhance the accuracy and efficiency of injections of the face in aesthetic medicine]. AB - The common principle of injections in esthetic medicine is to treat and to prevent the signs of aging with minimal doses and with more precision and efficiency. This relies on functional, histological, ultrasound or electromyographic analysis of the soft tissues and of the mechanisms of facial skin aging (fine lines, wrinkles, hollows). These injections may be done with hyaluronic acid (HA) and botulinum toxin. The aim of this technical note was to present four delivery techniques allowing for more precision and low doses of product. The techniques of "vacuum", "interpores" and "blanching" will be addressed for HA injection and the concept of "Face Recurve" for botulinum toxin injection. PMID- 26740202 TI - Facial features in Harlequin ichthyosis: Clinical findings about 4 cases. AB - We report 4 cases of Harlequin ichthyosis, which is a rare and severe congenital ichthyosis involving the face. Facial appearance consists in severe ectropion, conjonctival edema, eclabium, flattened ears, broadened nose and large, thick, plate-like skin scales. Recent advances in neonatal care have been made, such as retinoid therapy, and have led to an increased survival rate. Early surgical correction of ectropion may be required because of ocular complications. PMID- 26740203 TI - [Paranasal sinus mucoceles: About 32 cases]. AB - INTRODUCTION: Mucocele is a pseudo-cystic tumor of the paranasal sinuses. Despite its benign histological nature, it is aggressive towards neighboring structures (orbit and brain). Our aim was to study the epidemiological, clinical, therapeutic, and evolution aspects of this pathology. PATIENT AND METHODS: We conducted a retrospective study over a period of 9 years on 32 patients operated on and followed for mucocele in our department. RESULTS: Mean age was 43.28 years with a sex ratio to 1. Mucoceles were located in the fronto-ethmoid sinus (27 cases), the maxillary sinus (3 cases) and the sphenoid sinus (2 cases). The most common symptoms were periorbital swelling and exophthalmia. CT scan confirmed the diagnosis in the majority of cases. MRI was performed in 3 patients. Surgery consisted in a large marsupialization by endonasal approach in 30 cases, and by a combined approach in two cases. A recurrence was observed in two patients after a mean period of 18 months. DISCUSSION: Mucocele is a benign and expansive pseudo cystic tumor, affecting mostly adults and developing in the paranasal sinuses. Clinical symptoms are not specific. It may reveal itself by ophthalmic or intracranial complications. Diagnosis is based on imaging (CT and MRI). Endonasal surgery has become the gold standard for the treatment of mucoceles and is endowed with low morbidity. PMID- 26740205 TI - Competitive Interaction Between Plasma Omega-3 Fatty Acids and Arachidonic Acid is Related to Down-Regulation of A Signaling Mediator. AB - Autism spectrum disorders (ASD) may be attributed to altered composition of polyunsaturated fatty acids. We examined the relationships between the plasma ratios of docosahexaenoic acid (DHA)/arachidonic acid (AA) and eicosapentaenoic acid (EPA)/AA, and biomarkers of AA-related signaling mediators, i.e., ceruloplasmin, transferrin and superoxide dismutase, with the behavioral symptoms of 30 individuals with ASD (mean age, 13.0 years old) and 20 age- and gender matched normal controls (mean age, 13.6 years old). Behavioral symptoms were assessed using the Aberrant Behavior Checklists (ABC). The ASD group had significantly higher plasma DHA/AA and EPA/AA ratios, as well as ABC scores, compared to the control group. The plasma ceruloplasmin levels in the ASD group were significantly reduced compared to those in the control group. Multiple linear regression demonstrated that plasma DHA/AA ratio was a fitting model for distinguishing the ASD group from the control group. These findings suggested that increased plasma DHA/AA ratio may be related to lower plasma levels of ceruloplasmin, which may contribute to the pathophysiology of behavioral symptoms in 30 individuals with ASD. PMID- 26740206 TI - Synthesis, Biological Evaluation and Pharmacokinetic Studies of Mefenamic Acid - N-Hydroxymethylsuccinimide Ester Prodrug as Safer NSAID. AB - BACKGROUND: Non steroidal anti-inflammatory drugs are the most widely prescribed drugs to manage pain and inflammatory conditions, but their long term use is associated with gastrointestinal toxicity. OBJECTIVES: The study aimed to synthesize an ester-based prodrug of a non steroidal anti-inflammatory agent, mefenamic acid in order to improve the therapeutic index vis a vis to overcome the side effects such as gastrointestinal irritation and bleeding associated with the use of mefenamic acid. METHODS: The ester prodrug (MA-NH) was prepared by condensing mefenamic acid with N-hydroxymethylsuccinimide in the presence of Phosphorus oxychloride. The pharmacokinetic profile, including stability and release of mefenamic acid and N-hydroxymethylsuccinimide from the ester prodrug (MA-NH) was studied by RP- HPLC in acidic medium (pH 1.2), basic medium (pH 7.4), 80 % v/v human plasma, 10 % w/v rat intestinal homogenate and 10 % w/v rat liver homogenate (pH 7.4). RESULTS: The chemical structure of the title compound was characterized by using modern spectroscopic techniques. The prodrug was found to be stable in acid medium, but it hydrolyzed and released sufficient quantities of the drug in alkaline medium. The prodrug produced lesser number of ulcers and showed improved analgesic and anti-inflammatory activity as compared to the parent drug. CONCLUSION: The results indicate that the synthesized prodrug (MA NH) is better in terms of analgesic and antiinflammatory activities and with less GI toxicity than the parent drug. PMID- 26740207 TI - Design, Synthesis and Antiproliferative Activity of Novel Benzothiazole Derivatives Conjugated with Semicarbazone Scaffold. AB - Two series of novel benzothiazole derivatives conjugated with semicarbazone scaffold were designed and synthesized through a structure-based molecular hybridization strategy. All the target compounds were evaluated for their cytotoxicity in vitro against three cancer cell lines (HT-29, MKN-45 and H460) by standard MTT assay. The pharmacological results indicated that seven compounds (17h-n) exhibited comparable or even better antiproliferative activity in comparison with reference drugs Sorafenib and PAC-1. Particularly, compound 17i displayed remarkable cytotoxicity against tested three cancer cell lines with IC50 values of 0.84, 0.06 and 0.52 uM, which were 4.3-, 36.6-, 4.2-folds more potent than Sorafenib and 1.2-, 13.7-, 6.9-times more active than PAC-1, respectively. PMID- 26740208 TI - Facing Chagas' disease: trypanocidal properties of new coumarin-chalcone scaffolds. AB - With the aim of finding new chemical entities based on coumarin and chalcone scaffolds, new hybrid compounds 2-5 were designed and synthesized. The trypanocidal activity of these compounds was tested against the epimastigote, trypomastigote and amastigote stages of the Trypanosoma cruzi parasite. Cytotoxicity assays were also performed in RAW 264.7 and VERO cells. Compound 5 presented the highest trypanocidal activity of the series, with trypanocidal values higher than nifurtimox for the trypomastigote and epimastigote stages., but presenting cytotoxic effects in the mammalian cells. A SAR study suggested that methoxy substitution at positions 2 and 5 in the designed scaffold seemed to be a key feature for the trypanocidal activity. Therefore, the coumarin-chalcone scaffold can be taken into account for further lead optimization and design new and more effective trypanocidal compounds. PMID- 26740209 TI - Identification of New Inhibitors for Human SIRT1: An in-silico Approach. AB - BACKGROUND: Human SIRT1 is a class III histone deacetylase (HDAC) family protein. As the overexpression of hSIRT1 leads to cancer, inhibiting its HDAC function may be a better strategy for the treatment of cancer. Till now, only a few reported inhibitor compounds have reached the stage of animal studies; hence, identifying high efficacy inhibitors of hSIRT1 is essential. OBJECTIVE: The main objective of the study is to obtain a new class of inhibitor compounds of hSIRT1 by the rational structure-based method. METHODOLOGY: We performed virtual screening using AutoDock Vina for the HDAC domain of hSIRT1 against the Drug- Bank library containing 1,716 compounds. The recently determined crystal structure of the HDAC domain of hSIRT1 (PDB Id: 4KXQ) was used for docking studies. Subsequently, we performed molecular dynamics simulations and an invitro deacetylase assay for selected compounds. RESULTS: Virtual screening studies yielded seven compounds from two chemical classes, namely diphenyl and oxycoumarin derivatives. Molecular dynamic simulations confirmed that the predicted seven compounds bind well to their respective complex structures. Moreover, four commercially available drugs containing the predicted compounds showed significant inhibition of hSIRT1 deacetylase activity in comparison to the known hSIRT1 inhibitor (sirtinol). CONCLUSION: Our results indicate that the compounds of the diphenyl and oxycoumarin series may serve as useful scaffolds in the development of new chemical libraries of hSIRT1 inhibitory activity. PMID- 26740210 TI - Atherosclerosis at arterial bifurcations: evidence for the role of haemodynamics and geometry. AB - Atherosclerotic plaques are found at distinct locations in the arterial system, despite the exposure to systemic risk factors of the entire vascular tree. From the study of arterial bifurcation regions, emerges ample evidence that haemodynamics are involved in the local onset and progression of the atherosclerotic disease. This observed co-localisation of disturbed flow regions and lesion prevalence at geometrically predisposed districts such as arterial bifurcations has led to the formulation of a 'haemodynamic hypothesis', that in this review is grounded to the most current research concerning localising factors of vascular disease. In particular, this review focuses on carotid and coronary bifurcations because of their primary relevance to stroke and heart attack. We highlight reported relationships between atherosclerotic plaque location, progression and composition, and fluid forces at vessel's wall, in particular shear stress and its 'easier-to-measure' surrogates, i.e. vascular geometric attributes (because geometry shapes the flow) and intravascular flow features (because they mediate disturbed shear stress), in order to give more insight in plaque initiation and destabilisation. Analogous to Virchow's triad for thrombosis, atherosclerosis must be thought of as subject to a triad of, and especially interactions among, haemodynamic forces, systemic risk factors, and the biological response of the wall. PMID- 26740211 TI - Successful left ventricular assist device re-implantation with omental covering for MDRP device infection. AB - We present a case of paracorporeal left ventricular assist device (p-LVAD) related infection, caused by multi-drug resistant Pseudomonas aeruginosae (MDRP), and successfully treated by p-LVAD re-implantation with omental covering. A 59 year-old man underwent p-LVAD implantation and coronary artery bypass grafting after percutaneous cardiopulmonary support and intra-aortic balloon pumping for cardiogenic shock due to acute myocardial infarction. Then, he was registered for heart transplantation. He suffered from blood stream infection causative organism of Pseudomonas aeruginosa, 2 months after that operation. He underwent re-median sternotomy and open drainage, 15 months after the p-LVAD implantation. However, he suffered from septic shock due to MDRP. He underwent p-LVAD re-implantation under hypothermic circulatory arrest and iodine gauze packing, followed by omental covering of the all artificial materials in his body 10 days after that operation. Soon after that, the infection was well controlled and the intravenous antibiotics could be discontinued 2 months after that operation. He successfully underwent heart transplantation, 17 months after that procedure. We concluded that p-LVAD re-implantation with omental covering is seemed to be useful in the treatment of massive device infection. This procedure might be a novel treatment for severe VAD-related infection until heart transplantation. PMID- 26740212 TI - Silencing overexpression of FXYD3 protein in breast cancer cells amplifies effects of doxorubicin and gamma-radiation on Na(+)/K(+)-ATPase and cell survival. AB - FXYD3, also known as mammary tumor protein 8, is overexpressed in several common cancers, including in many breast cancers. We examined if such overexpression might protect Na(+)/K(+)-ATPase and cancer cells against the high levels of oxidative stress characteristic of many tumors and often induced by cancer treatments. We measured FXYD3 expression, Na(+)/K(+)-ATPase activity and glutathionylation of the beta1 subunit of Na(+)/K(+)-ATPase, a reversible oxidative modification that inhibits the ATPase, in MCF-7 and MDA-MB-468 cells. Expression of FXYD3 was suppressed by transfection with FXYD3 siRNA. A colorimetric end-point assay was used to estimate cell viability. Apoptosis was estimated by caspase 3/7 (DEVDase) activation using a Caspase fluorogenic substrate kit. Expression of FXYD3 in MCF-7 breast cancer cells was ~eightfold and ~twofold higher than in non-cancer MCF-10A cells and MDA-MB-468 cancer cells, respectively. A ~50 % reduction in FXYD3 expression increased glutathionylation of the beta1 Na(+)/K(+)-ATPase subunit and reduced Na(+)/K(+)-ATPase activity by ~50 %, consistent with the role of FXYD3 to facilitate reversal of glutathionylation of the beta1 subunit of Na(+)/K(+)-ATPase and glutathionylation induced inhibition of Na(+)/K(+)-ATPase. Treatment of MCF-7 and MDA-MB- 468 cells with doxorubicin or gamma-radiation decreased cell viability and induced apoptosis. The treatments upregulated FXYD3 expression in MCF-7 but not in MDA-MB 468 cells and suppression of FXYD3 in MCF-7 but not in MDA-MB-468 cells amplified effects of treatments on Na(+)/K(+)-ATPase activity and treatment-induced cell death and apoptosis. Overexpression of FXYD3 may be a marker of resistance to cancer treatments and a potentially important therapeutic target. PMID- 26740213 TI - Pre-diagnostic high-sensitive C-reactive protein and breast cancer risk, recurrence, and survival. AB - Inflammation may initiate and promote breast cancer development, and be associated with elevated circulating levels of inflammation markers. A total of eight 130 initially healthy women, participated in the population-based Tromso study (1994-2008). Pre-diagnostic high-sensitivity C-reactive protein (hs-CRP) was assessed. During 14.6 years of follow-up, a total of 192 women developed invasive breast cancer. These cases were followed for additional 7.2 years. Detailed medical records were obtained. We observed an overall positive dose response relationship between pre-diagnostic hs-CRP and breast cancer risk (hazard ratio (HR) = 1.06, 95 % CI 1.01-1.11). Postmenopausal women with above median levels of hs-CRP (>1.2 mg/l) had a 1.42 (95 % CI 1.01-2.00) higher breast cancer risk compared to postmenopausal women with hs-CRP below median. Postmenopausal women, who were hormone replacement therapy non-users, and were in the middle tertile (0.8-1.9 mg/l), or highest tertile of hs-CRP (>1.9 mg/l), had a 2.31 (95 % CI 1.31-4.03) and 2.08 (95 % CI 1.16-3.76) higher breast cancer risk, respectively, compared with women in the lowest tertile. For each unit increase in pre-diagnostic hs-CRP levels (mg/l), we observed an 18 % increase in disease-free interval (95 % CI 0.70-0.97), and a 22 % reduction in overall mortality (95 % CI 0.62-0.98). Our study supports a positive association between pre-diagnostic hs-CRP and breast cancer risk. In contrast, increased pre diagnostic hs-CRP was associated with improved overall mortality, but our findings are based on a small sample size, and should be interpreted with caution. PMID- 26740214 TI - Identification of six pathogenic RAD51C mutations via mutational screening of 1228 Danish individuals with increased risk of hereditary breast and/or ovarian cancer. AB - Germ-line mutations in the RAD51C gene have recently been identified in families with breast and ovarian cancer and have been associated with an increased risk of ovarian cancer. In this study, we describe the frequency of pathogenic RAD51C mutations identified in Danish breast and/or ovarian cancer families. We screened the RAD51C gene in 1228 Danish hereditary breast and/or ovarian cancer families by next-generation sequencing analysis. The frequency of the identified variants was examined in the exome sequencing project database and in data from 2000 Danish exomes and the presumed significance of missense and intronic variants was predicted by in silico analysis. We identified six families with a pathogenic mutation in RAD51C, including three frameshift mutations, one nonsense mutation, and 2 missense mutations. Overall, pathogenic RAD51C mutations were identified in 0.5 % of Danish families with increased risk of hereditary breast and/or ovarian cancer. Moreover, we identified 24 additional RAD51C variants of which 14 have not been previously reported in the literature. In this study, we determine the prevalence of RAD51C mutations in Danish breast and/or ovarian cancer families. We identified six pathogenic RAD51C mutations as well as 23 variants of uncertain clinical significance and one benign variant. Together, the study extends our knowledge of the RAD51C mutation spectrum and supports that RAD51C should be included in gene panel testing of individuals with high risk of breast and ovarian cancer. PMID- 26740215 TI - Erratum to: Evaluation of an Interdisciplinary Curriculum Teaching Team-Based Care Integration in Oncology. PMID- 26740216 TI - Erratum to: Oral Cancer Knowledge and Diagnostic Ability Among Dental Students. PMID- 26740217 TI - Excessive Selenium Supplementation Induced Oxidative Stress and Endoplasmic Reticulum Stress in Chicken Spleen. AB - Excessive selenium (Se) intake is harmful for animals and humans. The aim of the present study was to examine the effect of long-term excessive Se supplementation on oxidative stress and endoplasmic reticulum (ER) stress-related injuries in chicken spleen. A total of 180 1-day-old chickens were randomly divided into four groups with different Se dietary contents (0.2 mg/kg Se, 5 mg/kg Se, 10 mg/kg Se, or 15 mg/kg Se) for 45 days. Then, the levels of antioxidative enzymes, GPx, SOD, and MDA as well as the expression levels of GRP78, ARF6, caspase 3, caspase 12, and Bcl 2 in the spleen were determined at days 15, 30, and 45, respectively. The results showed that excessive Se treatment decreased the activities of GPx and SOD (P < 0.05) but increased the levels of MDA (P < 0.05) in a dose- and time dependent manner. In addition, the ER stress genes GRP78 and ATF6 were highly expressed (P < 0.05), and the apoptosis genes caspase 3 and caspase 12 were increased, but Bcl 2 was decreased by Se treatment (P < 0.05). Correlation analysis showed that there was a high correlation between these biomarkers, which indicated that ER stress and ER stress-related apoptosis were correlated with oxidative stress. These results showed the important role of oxidative stress and ER stress in Se-related immune injuries in chicken. PMID- 26740218 TI - Effect of Different Selenium Supplementation Levels on Oxidative Stress, Cytokines, and Immunotoxicity in Chicken Thymus. AB - This study assessed the effects of different selenium (Se) supplementation levels on oxidative stress, cytokines, and immunotoxicity in chicken thymus. A total of 180 laying hens (1 day old; Mianyang, China) were randomly divided into 4 groups (n = 45). The chickens were maintained either on a basic diet (control group) containing 0.2 mg/kg Se, a low-supplemented diet containing 5 mg/kg Se, a medium supplemented diet containing 10 mg/kg Se, or a high-supplemented diet containing 15 mg/kg Se for 15, 30, and 45 days, respectively. Over the entire experimental period, serum and thymus samples were collected and used for the detection of the experimental index. The results indicated that the antioxidative enzyme activities and messenger RNA (mRNA) levels of antioxidative enzymes, IFN-gamma and IL-2 in the thymus, and the content of IFN-gamma and IL-2 in the serum of excessive-Se-treated chickens at all time points (except for the 5 mg/kg Se supplement group at 15 days) were significantly decreased (P < 0.05) compared to the corresponding control groups. Interestingly, a significantly increase (P < 0.05) in the content of IFN-gamma was observed in the serum and thymus in the 5 mg/kg Se supplement group at 15 and 30 days compared to the corresponding control groups. In histopathological examination, the thymus tissue from excessive-Se treated chickens revealed different degrees of cortex drop, incrassation of the medulla, and degeneration of the reticular cells. These results suggested that the excessive Se could result in a decrease in immunity, an increase in oxidative damage, and a series of clinical pathology changes, such as cortex drop, incrassation of the medulla, and degeneration of the reticular cells. PMID- 26740219 TI - Influence of Long-Term Zinc Administration on Spatial Learning and Exploratory Activity in Rats. AB - Animal brain contains a significant amount of zinc, which is a cofactor for more than 300 enzymes. Moreover, it provides the basis for functioning of more than 2000 transcription factors, and it is necessary for memory formation and learning processes in the brain. The aim of this study was to investigate the effect of zinc supplementation on behavior in 3-month-old rats. For this purpose, the Morris water maze paradigm, hole-board, and T-maze were used. Wistar rats received a solution of ZnSO4 in drinking water at the doses of 16 mg/kg (Zn16 group) and 32 mg/kg (Zn32 group). In rats pretreated with the lower dose of zinc, the improvement of the mean escape latency was observed in comparison to the control group and Zn32 group. During memory task, both ZnSO4-supplemented groups showed an increase in crossings over the previous platform position. Furthermore, the exploratory activity in Zn16 group was improved in comparison to Zn32 and control group. In the brains of zinc-supplemented rats, we observed the higher content of zinc, both in the hippocampus and the prefrontal cortex. Hippocampal zinc level correlated positively with the mean annulus crossings of the Zn16 group during the probe trial. These findings show that the long-term administration of ZnS04 can improve learning, spatial memory, and exploratory activity in rats. Graphical Abstract Improvement of spatial learning, memory, and exploratory behavior. PMID- 26740221 TI - Shugan Liangxue Decoction () Down-Regulates Estrogen Receptor alpha Expression in Breast Cancer Cells. AB - OBJECTIVE: To observe the effect of Shugan Liangxue Decoction (, SGLXD) on estrogen receptor alpha (ERalpha) in human breast cancer cells. METHODS: The effect of SGLXD (0.85-5.10 mg/mL) on the proliferation of breast cancer cells were evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The nuclear ERalpha protein levels in MCF-7, T47D and ZR-75 1 cells which treated by SGLXD for 24 h were examined by western blot and immunofluorescence assay. MCF-7 and MDA-MB-231 cells were treated by 17beta estradiol (E2) with or without SGLXD, for 24 h, and the E2 targeted genes c-myc and bcl-2 protein product was evaluated by western blot. RESULTS: SGLXD showed dose-dependent inhibition on the proliferation of MCF-7, T47D and ZR-75-1 cells, but did not inhibit the proliferation of MDA-MB-231 cells. Furthermore, the promotive effect on cell growth induced by E2 was also significantly inhibited by SGLXD treatment. With the treatment of 1.70, 3.40, 5.10 mg/mL SGLXD, the nuclear ERalpha protein level was reduced to 88.1%, 70.4% and 60.9% in MCF-7 cells, and was decreased to 43.0%, 38.4% and 5.9% in ZR-75-1 cells as compared with the control group. In T47D cells, the nuclear ERalpha protein was down-regulated to 51.3% and 4.3% by 3.40 and 5.10 mg/mL SGLXD treatment. The down-regulative effect of SGLXD on nuclear ERalpha was confirmed by immunofluorescence assay. SGLXD decreased the protein product of c-myc and bcl-2. CONCLUSIONS: SGLXD may exhibit selective inhibition effect on the proliferation of ER positive breast cancer cells. SGLXD reduced the nuclear ERalpha expression and the protein product of E2 target gene c-myc and bcl-2. PMID- 26740222 TI - Cardioprotection of ginsenoside Rb1 against ischemia/reperfusion injury is associated with mitochondrial permeability transition pore opening inhibition. AB - OBJECTIVE: To investigate the role of ginsenoside Rb1 (Gs-Rb1) in cardioprotection against ischemia/reperfusion (I/R) or hypoxia/reoxygenation (H/R) injury and to explore whether the cardioprotective action is mediated via attenuating the formation of mitochondrial permeability transition pore (mPTP). METHODS: A Langendorff-perfused model of rat heart was employed. I/R injury was induced by breaking off perfusion for 40 min then reperfusion for 60 min. Gs-Rb1 (100 MUmol/L) were administrated for 10 min before I/R. Infarct size was estimated by the 2,3,5-triphenyl tetrazolium chloride (TTC) staining. Lactate dehydrogenase (LDH) and creatine kinase (CK) released from effluents were measured. Transmission electron microscopy was performed to assess morphological difference between cardiac mitochondrial isolated from I/R rats and Gs-Rb1 pretreated rats. Western blot analysis was used to determine phosphorylation of protein kinase B/Akt, and its downstream target glycogen synthase kinase 3beta (GSK-3beta). Incubation isolated cardiac mitochondria with Gs-Rb1, Ca2+-induced opening of the mPTP was assessed by the reduction of absorbance at 520 nm (A520). Neonatal rat cardiomyocytes were subjected to hypoxia 9 h followed by reoxygenation 4 h to induce H/R injury. After pretreated with different concentration of Gs-Rb1 (6.25, 25, 100 MUmol/L ), cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) method. The membrane potential was estimated by Rh123 fluorescence. mPTP opening was measured using the probe calcein-AM. RESULTS: Gs-Rb1 100 MUmol/L significantly reduced the infarct size of hearts (26.39%+/-11.67% vs. I/R group 56.68%+/-5.88%, P<0.01). Compared with the I/R group, Gs-Rb1 pretreatment decreased LDH and CK levels in the coronary effluent (P<0.05 or P<0.01) as well as attenuated destructive ultrastructure induced by I/R. The protective effect of Gs-Rb1 involved in phosphorylating protein kinase B/PKB (Akt) and GSK-3beta. In mitochondria isolated from rat hearts, significant inhibition of Ca2+-induced swelling was observed in samples that were pretreated with Gs-Rb1 (6.25, 25, 100, 400 MUmol/L) for 10 min. When cardiomyocytes were isolated from neonatal rat and subjected to H/R, cell viability was increased with treatment of Gs-Rb1 (6.25, 25, 100 MUmol/L ). Gs-Rb1 inhibited mPTP opening and restored subsequent loss of mitochondrial membrane potential. CONCLUSION: Gs-Rb1 presents cardioprotective effect against I/R or H/R injury which involves in activating Akt, phosphorylating GSK-3beta and inhibiting mPTP opening. PMID- 26740223 TI - Herbal medicines prevent the development of atopic dermatitis by multiple mechanisms. AB - Atopic dermatitis (AD) is among the most common skin disorders in humans. Although a variety of regimens are available for the treatment of AD, preventive approaches are limited. Recent studies have demonstrated that certain naturally occurring herbal medicines are effective in preventing the development of AD via divergent mechanisms, such as inhibiting cytokine and chemokine expression, IgE production, inflammatory cell infiltration, histamine release, and/or enhancement of epidermal permeability barrier function. Yet, they exhibit few adverse effects. Since herbal medicines are widely available, inexpensive and generally safe, they could represent an ideal approach for preventing the development of AD, in both highly developed and developing countries. PMID- 26740224 TI - Somato stimulation and acupuncture therapy. AB - Acupuncture is an oldest somato stimulus medical technique. As the most representative peripheral nerve stimulation therapy, it has a complete system of theory and application and is applicable to a large population. This paper expounds the bionic origins of acupuncture and analyzes the physiological mechanism by which acupuncture works. For living creatures, functionally sound viscera and effective endurance of pain are essential for survival. This paper discusses the way in which acupuncture increases the pain threshold of living creatures and the underlying mechanism from the perspective of bionics. Acupuncture can also help to adjust visceral functions and works most effectively in facilitating the process of digestion and restraining visceral pain. This paper makes an in-depth overview of peripheral nerve stimulation therapy represented by acupuncture. We look forward to the revival of acupuncture, a long standing somato stimulus medicine, in the modern medical systems. PMID- 26740225 TI - Diagnosis of retrodiscal tissue in painful temporomandibular joint (TMJ) by fluid attenuated inversion recovery (FLAIR) signal intensity. AB - AIMS: The purpose of the present study is to analyze the fluid-attenuated inversion recovery (FLAIR) signal intensity of the retrodiscal tissue in a painful temporomandibular joint (TMJ), and to develop a diagnostic system based on FLAIR data. METHODOLOGY: The study was based on 33 joints of 17 patients referred for MR imaging of the TMJ. Regions of interest were placed over retrodiscal tissue and gray matter (GM) on FLAIR images. Using signal intensities of GM as reference points, signal intensity ratios (SIR) of retrodiscal tissue were calculated. SIRs in painful TMJ were compared with those in painless TMJ. Wilcoxon's Rank Sum Test was used to analyze the difference in SIRs between the painful and painless groups (P<0.05). RESULTS: The SIRs of retrodiscal tissue were significantly higher in painful joints than in painless joints. CONCLUSION: FLAIR sequences provide a high signal in patients having painful TMJ, and it suggests that retrodiscal tissue in painful TMJ contains elements such as protein. PMID- 26740226 TI - Catalyzing a Reproductive Health and Social Justice Movement. AB - OBJECTIVES: The maternal and child health (MCH) community, partnering with women and their families, has the potential to play a critical role in advancing a new multi-sector social movement focused on creating a women's reproductive and economic justice agenda. Since the turn of the twenty-first century, the MCH field has been planting seeds for change. The time has come for this work to bear fruit as many states are facing stagnant or slow progress in reducing infant mortality, increasing maternal death rates, and growing health inequities. METHODS: This paper synthesizes three current, interrelated approaches to addressing MCH challenges-life course theory, preconception health, and social justice/reproductive equity. CONCLUSION: Based on these core constructs, the authors offer four directions for advancing efforts to improve MCH outcomes. The first is to ensure access to quality health care for all. The second is to facilitate change through critical conversations about challenging issues such as poverty, racism, sexism, and immigration; the relevance of evidence-based practice in disenfranchised communities; and how we might be perpetuating inequities in our institutions. The third is to develop collaborative spaces in which leaders across diverse sectors can see their roles in creating equitable neighborhood conditions that ensure optimal reproductive choices and outcomes for women and their families. Last, the authors suggest that leaders engage the MCH workforce and its consumers in dialogue and action about local and national policies that address the social determinants of health and how these policies influence reproductive and early childhood outcomes. PMID- 26740227 TI - Hospital Utilization and Costs Among Preterm Infants by Payer: Nationwide Inpatient Sample, 2009. AB - OBJECTIVES: To describe hospital utilization and costs associated with preterm or low birth weight births (preterm/LBW) by payer prior to implementation of the Affordable Care Act and to identify areas for improvement in the quality of care received among preterm/LBW infants. METHODS: Hospital utilization-defined as mean length of stay (LOS, days), secondary diagnoses for birth hospitalizations, primary diagnoses for rehospitalizations, and transfer status-and costs were described among preterm/LBW infants using the 2009 Nationwide Inpatient Sample. RESULTS: Approximately 9.1 % of included hospitalizations (n = 4,167,900) were births among preterm/LBW infants; however, these birth hospitalizations accounted for 43.4 % of total costs. Rehospitalizations of all infants occurred at a rate of 5.9 % overall, but accounted for 22.6 % of total costs. This pattern was observed across all payer types. The prevalence of rehospitalizations was nearly twice as high among preterm/LBW infants covered by Medicaid (7.6 %) compared to commercially-insured infants (4.3 %). Neonatal transfers were more common among preterm/LBW infants whose deliveries and hospitalizations were covered by Medicaid (7.3 %) versus commercial insurance (6.5 %). Uninsured/self-pay preterm and LBW infants died in-hospital during the first year of life at a rate of 91 per 1000 discharges-nearly three times higher than preterm and LBW infants covered by either Medicaid (37 per 1000) or commercial insurance (32 per 1000). CONCLUSIONS: When comparing preterm/LBW infants whose births were covered by Medicaid and commercial insurance, there were few differences in length of hospital stays and costs. However, opportunities for improvement within Medicaid and CHIP exist with regard to reducing rehospitalizations and neonatal transfers. PMID- 26740229 TI - Tyrosine hydroxylase localization in the nucleus accumbens in schizophrenia. AB - The nucleus accumbens (NAcc) has been implicated in schizophrenia (SZ) pathology, based on antipsychotic action therein. However, recent imaging studies suggest that the NAcc may not be a locus of dopamine dysregulation in SZ. This study examined postmortem human tissue to determine if abnormalities are present in dopamine synthesis in the NAcc in SZ. We compared the immunohistochemical localization of tyrosine hydroxylase (TH), the rate-limiting synthesizing enzyme of dopamine, in postmortem tissue from SZ subjects and demographically matched controls. To study the effects of chronic antipsychotic drug (APD) treatment on TH immunolabeling in the NAcc, rats were treated for 6 months with haloperidol or olanzapine. In the NAcc, TH immunolabeling was similar in control and SZ subjects, in both the core and shell. Rats had similar TH optical density levels across treatment groups in both the core and shell. Similar levels of TH suggest DA synthesis may be normal. These findings provide further insight into the role of the NAcc in SZ. PMID- 26740231 TI - Structural variation in cation-assisted assembly of high-nuclearity Mn arsonate and phosphonate wheels. AB - Comproportionation reactions between MnCl2 and KMnO4 in the presence of arsonate or phosphonate ligands promote the cation-assisted assembly of high-nuclearity, wheel-shaped or toroidal {Mn8} () and {Mn24} () complexes; the closely corresponding reaction systems provide insights into the complexation behaviour of homologous phosphonate/arsonate ligand species. PMID- 26740230 TI - Ascending serotonin neuron diversity under two umbrellas. AB - Forebrain serotonin relevant for many psychological disorders arises in the hindbrain, primarily within the dorsal and median raphe nuclei (DR and MR). These nuclei are heterogeneous, containing several distinct groups of serotonin neurons. Here, new insight into the afferent and efferent connectivity of these areas is reviewed in correlation with their developmental origin. These data suggest that the caudal third of the DR, the area originally designated B6, may be misidentified as part of the DR as it shares many features of connectivity with the MR. By considering the rostral DR independently and affiliating the B6 to the MR, the diverse subgroups of serotonin neurons can be arranged with more coherence into two umbrella groups, each with distinctive domains of influence. Serotonin neurons within the rostral DR are uniquely interconnected with brain areas associated with emotion and motivation such as the amygdala, accumbens and ventral pallidum. In contrast serotonin neurons in the B6 and MR are characterized by their dominion over the septum and hippocampus. This distinction between the DR and B6/MR parallels their developmental origin and likely impacts their role in both behavior and psychopathology. Implications and further subdivisions within these areas are discussed. PMID- 26740232 TI - Mechanisms and energetics for N-glycosidic bond cleavage of protonated 2' deoxyguanosine and guanosine. AB - Experimental and theoretical investigations suggest that hydrolysis of N glycosidic bonds generally involves a concerted SN2 or a stepwise SN1 mechanism. While theoretical investigations have provided estimates for the intrinsic activation energies associated with N-glycosidic bond cleavage reactions, experimental measurements to validate the theoretical studies remain elusive. Here we report experimental investigations for N-glycosidic bond cleavage of the protonated guanine nucleosides, [dGuo+H](+) and [Guo+H](+), using threshold collision-induced dissociation (TCID) techniques. Two major dissociation pathways involving N-glycosidic bond cleavage, resulting in production of protonated guanine or the elimination of neutral guanine are observed in competition for both [dGuo+H](+) and [Guo+H](+). The detailed mechanistic pathways for the N glycosidic bond cleavage reactions observed are mapped via electronic structure calculations. Excellent agreement between the measured and B3LYP calculated activation energies and reaction enthalpies for N-glycosidic bond cleavage of [dGuo+H](+) and [Guo+H](+) in the gas phase is found indicating that these dissociation pathways involve stepwise E1 mechanisms in analogy to the SN1 mechanisms that occur in the condensed phase. In contrast, MP2 is found to significantly overestimate the activation energies and slightly overestimate the reaction enthalpies. The 2'-hydroxyl substituent is found to stabilize the N glycosidic bond such that [Guo+H](+) requires ~25 kJ mol(-1) more than [dGuo+H](+) to activate the glycosidic bond. PMID- 26740233 TI - Erratum to: Bowel perforations in a patient affected by Churg-Strauss syndrome under high-dose steroid treatment: will alternative drugs reduce risk of surgery? PMID- 26740234 TI - SNP array screening of cryptic genomic imbalances in 450 Japanese subjects with intellectual disability and multiple congenital anomalies previously negative for large rearrangements. AB - Intellectual disability (ID) is a heterogeneous condition affecting 2-3% of the population, often associated with multiple congenital anomalies (MCA). The genetic cause remains largely unexplained for most cases. To investigate the causes of ID/MCA of unknown etiology in the Japanese population, 645 subjects have been recruited for the screening of pathogenic copy-number variants (CNVs). Two screenings using bacterial artificial chromosome (BAC) arrays were previously performed, which identified pathogenic CNVs in 133 cases (20.6%; Hayashi et al., J. Hum. Genet., 2011). Here, we present the findings of the third screening using a single-nucleotide polymorphism (SNP) array, performed in 450 negative cases from our previous report. Pathogenic CNVs were found in 22 subjects (4.9%), in which 19 CNVs were located in regions where clinical significance had been previously established. Among the 22 cases, we identified PPFIA2 as a novel candidate gene for ID. Analysis of copy-neutral loss of heterozygosity (CNLOH) detected one case in which the CNLOH regions seem to be significant. The SNP array detected a modest fraction of small causative CNVs, which is explained by the fact that the majority of causative CNVs have larger sizes, and those had been mostly identified in the two previous screenings. PMID- 26740235 TI - Next-generation sequencing discloses a nonsense mutation in the dystrophin gene from long preserved dried umbilical cord and low-level somatic mosaicism in the proband mother. AB - Duchene muscular dystrophy (DMD) is a progressive muscle wasting disease, caused by mutations in the dystrophin (DMD) on the X chromosome. One-third of patients are estimated to have de novo mutations. To provide in-depth genetic counseling, the comprehensive identification of mutations is mandatory. However, many DMD patients did not undergo genetic diagnosis because detailed genetic diagnosis was not available or their mutational types were difficult to identify. Here we report the genetic testing of a sporadic DMD boy, who died >20 years previously. Dried umbilical cord preserved for 38 years was the only available source of genomic DNA. Although the genomic DNA was severely degraded, multiplex ligation dependent probe amplification analysis was performed but no gross mutations found. Sanger sequencing was attempted but not conclusive. Next-generation sequencing (NGS) was performed by controlling the tagmentation during library preparation. A nonsense mutation in DMD (p.Arg2095*) was clearly identified in the proband. Consequently, the identical mutation was detected as an 11% mosaic mutation from his healthy mother. Finally, the proband's sister was diagnosed as a non-carrier of the mutation. Thus using NGS we have identified a pathogenic DMD mutation from degraded DNA and low-level somatic mosaicism, which would have been overlooked using Sanger sequencing. PMID- 26740236 TI - Investigation of associations between ten polymorphisms and the risk of coronary artery disease in Southern Han Chinese. AB - A large-scale meta-analysis of 14 genome-wide association studies has identified and replicated a series of susceptibility polymorphisms for coronary artery disease (CAD) in European ancestry populations, but evidences for the associations of these loci with CAD in other ethnicities remain lacking. Herein we investigated the associations between ten (rs579459, rs12413409, rs964184, rs4773144, rs2895811, rs3825807, rs216172, rs12936587, rs46522 and rs3798220) of these loci and CAD in Southern Han Chinese (CHS). Genotyping was performed in 1716 CAD patients and 1572 controls using mass spectrography. Both allelic and genotypic associations of rs964184, rs2895811 and rs3798220 with CAD were significant, regardless of adjustment for covariates of gender, age, hypertension, type 2 diabetes, blood lipid profiles and smoking. Significant association of rs12413409 was initially not observed, but after the adjustment for the covariates, both allelic and genotypic associations were identified as significant. Neither allelic nor genotypic association of the other six polymorphisms with CAD was significant regardless of the adjustment. Our results indicated that four loci of the total 10 were associated with CAD in CHS. Therefore, some of the CAD-related loci in European ancestry populations are indeed susceptibility loci for the risk of CAD in Han Chinese. PMID- 26740237 TI - Global trends on fears and concerns of genetic discrimination: a systematic literature review. AB - Since the 1990s, developments in the field of genetics have led to many questions on the use and possible misuse of genetic information. 'Genetic discrimination' has been defined as the differential treatment of asymptomatic individuals or their relatives on the basis of their real or assumed genetic characteristics. Despite the public policy attention around genetic discrimination, there is currently still much confusion surrounding this phenomenon. On the one hand, there is little evidence of the occurrence of genetic discrimination. On the other hand, it appears that people remain concerned about this theme, and this fear influences their health and life choices. This article makes use of a systematic literature review to investigate what is already known about the nature, extent and background of these fears and concerns. The 42 included studies have found considerable levels of concerns about genetic discrimination. Concerns dominate in insurance contexts and within personal interactions. The extent of concerns appears to vary depending on the type of genetic illness. Furthermore, installed laws prohibiting genetic discrimination do not seem to alleviate existing fears. This raises important questions as to the origins of these fears. Based on the findings, recommendations for future research are made. First, research on the background of fears is needed. Second, future research needs to assess more fully all different forms (for example, direct and indirect) of genetic discrimination. Thirdly, it has to be studied whether genetic discrimination is a form of discrimination that is distinguishable from discrimination based on an illness or disability. Finally, a last element that should be addressed in future research is the most recent developments in research on genomics, such as next-generation sequencing or genome-wide association studies. PMID- 26740238 TI - Demographic characteristics and distribution of lysosomal storage disorder subtypes in Eastern China. AB - Lysosomal storage disorders (LSDs) are a group of >50 different types of inherited metabolic disorders that result from defects in the lysosome. The aim of this study was to investigate the distribution and demographic characteristics of the different subtypes of LSDs in Eastern China. From 2006 to 2012, 376 out of 1331 clinically suspected patients were diagnosed with 17 different subtypes of LSDs at our hospital. Mucopolysaccharidoses (MPS) were the most common group of LSDs (50.5%), followed by sphingolipidoses (25.4%) and Pompe disease (19.8%). Mucolipidosis type II/III accounted for the remaining 4% of diagnosed LSDs. MPS II was the most common form of MPS, comprising 47.4% of all MPS cases diagnosed, followed by MPS IVA (26.8%) and MPS I (16.3%). Gaucher disease and Niemann-Pick disease type A/B were the two most common forms of sphingolipidoses. There was a large variation in the time between disease onset and eventual diagnosis, from 0.3 years in infantile-onset Pompe disease to 30 years in Fabry disease, highlighting timely and accurate diagnosis of LSDs as the main challenge in China. PMID- 26740239 TI - A patient with a novel homozygous missense mutation in FTO and concomitant nonsense mutation in CETP. AB - The fat mass and obesity associated (FTO) gene has previously been associated with a variety of diseases and conditions, notably obesity, acute coronary syndrome and metabolic syndrome. Reports describing mutations in FTO as well as in FTO animal models have further demonstrated a role for FTO in the development of the brain and other organs. Here, we describe a patient born of consanguineous union who presented with microcephaly, developmental delay, behavioral abnormalities, dysmorphic facial features, hypotonia and other various phenotypic abnormalities. Whole-exome sequencing revealed a novel homozygous missense mutation in FTO and a nonsense mutation in the cholesteryl ester transfer protein (CETP). Exome copy number variation analysis revealed no disease-causing large duplications or deletions within coding regions. Patient's, her parents' and non related control' fibroblasts were analyzed for morphologic defects, abnormal proliferation, apoptosis and transcriptome profile. We have shown that FTO is located in the nucleus of cells from each tested sample. Western blot analysis demonstrated no changes in patient FTO. Quantitative (qPCR) analysis revealed slightly decreased levels of FTO expression in patient cells compared with controls. No morphological or proliferation differences between the patient and control fibroblasts were observed. There is still much to be learned about the molecular mechanisms by which mutations in FTO contribute to such severe phenotypes. PMID- 26740241 TI - Asymmetric dearomatization of phenols. AB - This review summarizes the recent advances in the field of asymmetric dearomatization of phenols and their applications in the total synthesis of some complex natural products. The dearomatization discussed here includes metal catalysed direct dearomatization, organocatalytic dearomatization and hypervalent iodine mediated dearomatization. PMID- 26740242 TI - Formulation and process considerations for the design of sildenafil-loaded polymeric microparticles by vibrational spray-drying. AB - CONTEXT AND OBJECTIVE: The current study reports the preparation and characterization of sildenafil-loaded poly(lactide-co-glycolide) (PLGA)-based microparticles (MPs) by means of vibrational spray-drying. Emphasis was placed on relevant formulation and process parameters with influence on the properties of obtained powders. Materials and methods, results and discussion: The solid state solubility of sildenafil in spray-dried PLGA-MPs amounted to 17 wt.%. Thus, a drug loading below and above the determined solubility limit resulted in solid solutions and phase separation (i.e. solid dispersions), respectively. Furthermore, interactions between sildenafil and the PLGA matrix were observed for the spray-dried MPs. Optimization of spray-drying conditions allowed for a fabrication of defined MPs (size range of ~4-8 MUm) displaying a high sildenafil encapsulation efficiency (>90%) and sustained sildenafil release (from ~4 to >12 h). The individual drug release rates from the spray-dried formulations were mainly a function of the drug loading, applied polymer and MP size. Finally, a scale-up of the preparation process did not result in a relevant change of the physicochemical and in vitro drug release properties of the prepared powders. CONCLUSION: Identification of relevant formulation and spray-drying parameters enabled the fabrication of tailored sildenafil-loaded PLGA-based MPs, which meet the needs of the individual application (e.g. controlled drug delivery to the lungs). PMID- 26740240 TI - Inhibition of Canonical NF-kappaB Signaling by a Small Molecule Targeting NEMO Ubiquitin Interaction. AB - The IkappaB kinase (IKK) complex acts as the gatekeeper of canonical NF-kappaB signaling, thereby regulating immunity, inflammation and cancer. It consists of the catalytic subunits IKKalpha and IKKbeta and the regulatory subunit NEMO/IKKgamma. Here, we show that the ubiquitin binding domain (UBAN) in NEMO is essential for IKK/NF-kappaB activation in response to TNFalpha, but not IL-1beta stimulation. By screening a natural compound library we identified an anthraquinone derivative that acts as an inhibitor of NEMO-ubiquitin binding (iNUB). Using biochemical and NMR experiments we demonstrate that iNUB binds to NEMOUBAN and competes for interaction with methionine-1-linked linear ubiquitin chains. iNUB inhibited NF-kappaB activation upon UBAN-dependent TNFalpha and TCR/CD28, but not UBAN-independent IL-1beta stimulation. Moreover, iNUB was selectively killing lymphoma cells that are addicted to chronic B-cell receptor triggered IKK/NF-kappaB activation. Thus, iNUB disrupts the NEMO-ubiquitin protein-protein interaction interface and thereby inhibits physiological and pathological NF-kappaB signaling. PMID- 26740244 TI - Should patients pay to see the GP? PMID- 26740245 TI - Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles. AB - Drug dose, high local target tissue concentration, and prolonged duration of exposure are essential criteria in achieving optimal drug performance. However, systemically delivered drugs often fail to effectively address these factors with only fractions of the injected dose reaching the target tissue. This is especially evident in the treatment of peritoneal cancers, including mesothelioma, ovarian, and pancreatic cancer, which regularly employ regimens of intravenous and/or intraperitoneal chemotherapy (e.g., gemcitabine, cisplatin, pemetrexed, and paclitaxel) with limited results. Here, we show that a "two-step" nanoparticle (NP) delivery system may address this limitation. This two-step approach involves the separate administration of NP and drug where, first, the NP localizes to tumor. Second, subsequent administration of drug then rapidly concentrates into the NP already stationed within the target tissue. This two step method results in a greater than 5-fold increase in intratumoral drug concentrations compared to conventional "drug-alone" administration. These results suggest that this unique two-step delivery may provide a novel method for increasing drug concentrations in target tissues. PMID- 26740246 TI - Concentration and distribution of contaminants in lake trout and walleye from the Laurentian Great Lakes (2008-2012). AB - Biomonitoring programs for persistent, bioaccumulative, and/or toxic chemicals of concern in fish tissues have been operated by the governments of Canada and the United States in the Great Lakes since the 1970's. The objectives of these programs are to assess concentrations of harmful chemicals in whole body top predator fish as an indicator of ecosystem health and to infer potential harm to fish and fish consuming wildlife in the Great Lakes Basin. Chemicals of interest are selected based upon national and binational commitments, risk assessment, and regulation, and include a wide range of compounds. This review summarizes all available data generated by Environment Canada and the United States Environmental Protection Agency for chemicals measured in whole body homogenates of Lake Trout (Salvelinus namaycush) and Walleye (Sander vitreus) for the time period spanning 2008 to 2012 from each of the five Great Lakes. The summary shows that concentrations of legacy compounds, such as, POPs listed in the Stockholm Convention and mercury continue to dominate the chemical burden of Great Lakes fish. This assessment, and others like it, can guide the creation of environmental quality targets where they are lacking, optimize chemical lists for monitoring, and prioritize chemicals of concern under agreements such as the Great Lakes Water Quality Agreement and the Stockholm Convention. PMID- 26740247 TI - Niosomes as Drug Nanovectors: Multiscale pH-Dependent Structural Response. AB - The use of nanocarriers, which respond to different stimuli controlling their physicochemical properties and biological responsivness, shows a growing interest in pharmaceutical science. The stimuli are activated by targeting tissues and biological compartments, e.g., pH modification, temperature, redox condition, enzymatic activity, or can be physically applied, e.g., a magnetic field and ultrasound. pH modification represents the easiest method of passive targeting, which is actually used to accumulate nanocarriers in cells and tissues. The aim of this paper was to physicochemically characterize pH-sensitive niosomes using different experimental conditions and demonstrate the effect of surfactant composition on the supramolecular structure of niosomes. In this attempt, niosomes, made from commercial (Tween21) and synthetic surfactants (Tween20 derivatives), were physicochemically characterized by using different techniques, e.g., transmission electron microscopy, Raman spectroscopy, and small-angle X-ray scattering. The changes of niosome structure at different pHs depend on surfactants, which can affect the supramolecular structure of colloidal nanocarriers and their potential use both in vitro and in vivo. At pH 7.4, the shape and structure of niosomes have been maintained; however, niosomes show some differences in terms of bilayer thicknesses, water penetration, membrane coupling, and cholesterol dispersion. The acid pH (5.5) can increase the bilayer fluidity, and affect the cholesterol depletion. In fact, Tween21 niosomes form large vesicles with lower curvature radius at acid pH; while Tween20-derivative niosomes increase the intrachain mobility within a more interchain correlated membrane. These results demonstrate that the use of multiple physicochemical procedures provides more information about supramolecular structures of niosomes and improves the opportunity to deeply investigate the effect of stimuli responsiveness on the niosome structure. PMID- 26740248 TI - Prehospital Indicators for Disaster Preparedness and Response: New York City Emergency Medical Services in Hurricane Sandy. AB - OBJECTIVE: We aimed to evaluate emergency medical services (EMS) data as disaster metrics and to assess stress in surrounding hospitals and a municipal network after the closure of Bellevue Hospital during Hurricane Sandy in 2012. METHODS: We retrospectively reviewed EMS activity and call types within New York City's 911 computer-assisted dispatch database from January 1, 2011, to December 31, 2013. We evaluated EMS ambulance transports to individual hospitals during Bellevue's closure and incremental recovery from urgent care capacity, to freestanding emergency department (ED) capability, freestanding ED with 911 receiving designation, and return of inpatient services. RESULTS: A total of 2,877,087 patient transports were available for analysis; a total of 707,593 involved Manhattan hospitals. The 911 ambulance transports disproportionately increased at the 3 closest hospitals by 63.6%, 60.7%, and 37.2%. When Bellevue closed, transports to specific hospitals increased by 45% or more for the following call types: blunt traumatic injury, drugs and alcohol, cardiac conditions, difficulty breathing, "pedestrian struck," unconsciousness, altered mental status, and emotionally disturbed persons. CONCLUSIONS: EMS data identified hospitals with disproportionately increased patient loads after Hurricane Sandy. Loss of Bellevue, a public, safety net medical center, produced statistically significant increases in specific types of medical and trauma transports at surrounding hospitals. Focused redeployment of human, economic, and social capital across hospital systems may be required to expedite regional health care systems recovery. (Disaster Med Public Health Preparedness. 2016;10:333-343). PMID- 26740249 TI - Adolescent, parent and societal preferences and willingness to pay for meningococcal B vaccine: A Discrete Choice Experiment. AB - OBJECTIVE: Meningococcal B (MenB) vaccines have been licensed in many countries with private purchase the only option until recently, when a funded programme was introduced in the UK. The aim of this study was to explore adolescent/parental values for a variety of salient vaccine attributes (cost, effectiveness, side effect profile) to assess preferences and willingness-to-pay (WTP) for a MenB vaccine. METHODOLOGY: A national cross-sectional population study was conducted in Australia using Discrete Choice Experiment methodology to assess adolescent/parent/adult preferences for attributes related to MenB vaccine. RESULTS: 2003 adults and 502 adolescents completed the survey in 2013. The majority of participants were willing to be vaccinated with MenB vaccine with vaccination opt-out chosen by 11.9% of adolescents and parents, and 18.2% of non parent adults. A mixed logit regression model examining adolescent/adult preferences indicated consistent findings; the higher the effectiveness, the longer the duration of protection, the less chance of adverse events and the lower the cost, the more likely respondents were to agree to vaccination. For an ideal MenB vaccine, including the most favoured level of each attribute summed together (90% effectiveness, 10 year duration, 1 injection, no adverse events) adolescents would pay AU$251.60 and parents AU$295.10. Adolescents and parents would pay AU$90.70 or AU$127.20 for 90% vaccine effectiveness vs AU$18.50 or AU$16.70 for 70% effectiveness and would want to be financially compensated for 50% effectiveness; pay AU$63.30 or AU$76.40 for 10 years protection; and pay AU$48.50 or AU$49.20 for no vaccine related adverse events. A slight fever post vaccination was a preferred choice with parents and adolescents willing to pay AU$9.60 or AU$12.30 for this attribute. CONCLUSIONS: Vaccine effectiveness, adverse events and duration of immunity are important drivers for parental and adolescent decisions about WTP for MenB vaccine and should be included in discussions on the benefits, risks and cost. PMID- 26740250 TI - A systematic review and meta-analysis on the safety of newly adjuvanted vaccines among children. AB - INTRODUCTION: New adjuvants such as the AS- or the MF59-adjuvants improve vaccine efficacy and facilitate dose-sparing. Their use in influenza and malaria vaccines has resulted in a large body of evidence on their clinical safety in children. METHODS: We carried out a systematic search for safety data from published clinical trials on newly adjuvanted vaccines in children <=10 years of age. Serious adverse events (SAEs), solicited AEs, unsolicited AEs and AEs of special interest were evaluated for four new adjuvants: the immuno-stimulants containing adjuvant systems AS01 and AS02, and the squalene containing oil-in-water emulsions AS03 and MF59. Relative risks (RR) were calculated, comparing children receiving newly adjuvanted vaccines to children receiving other vaccines with a variety of antigens, both adjuvanted and unadjuvanted. RESULTS: Twenty-nine trials were included in the meta-analysis, encompassing 25,056 children who received at least one dose of the newly adjuvanted vaccines. SAEs did not occur more frequently in adjuvanted groups (RR 0.85, 95%CI 0.75-0.96). Our meta analyses showed higher reactogenicity following administration of newly adjuvanted vaccines, however, no consistent pattern of solicited AEs was observed across adjuvant systems. Pain was the most prevalent AE, but often mild and of short duration. No increased risks were found for unsolicited AEs, febrile convulsions, potential immune mediated diseases and new onset of chronic diseases. CONCLUSIONS: Our meta-analysis did not show any safety concerns in clinical trials of the newly adjuvanted vaccines in children <=10 years of age. An unexplained increase of meningitis in one Phase III AS01-adjuvanted malaria trial and the link between narcolepsy and the AS03-adjuvanted pandemic vaccine illustrate that continued safety monitoring is warranted. PMID- 26740251 TI - Future pandemics and vaccination: Public opinion and attitudes across three European countries. AB - BACKGROUND: Understanding public opinion and attitudes regarding vaccination is crucial for successful outbreak management and effective communication at the European level. METHODS: We explored national differences by conducting focus group discussions in The Netherlands, Poland and Sweden. Discussions were structured using concepts from behavioural models. RESULTS: Thematic analysis revealed that participants would base their vaccination decision on trade-offs between perceived benefits and barriers of the vaccine also taking into account the seriousness of the new outbreak. Except for those having chronic diseases, participants expected a low infection risk, resulting in a low willingness to get vaccinated. Information about the health status of cases was considered important since this might change perceived susceptibility. Participants displayed concerns about vaccine safety due to the limited available time to produce and test vaccines in the acute situation of a new pandemic. Swedish participants mentioned their tendency of doing the right thing and following the rules, as well as to get vaccinated because of solidarity with other citizens and social influences. This appeared much less prominent for the Dutch and Polish participants. However, Swedish participants indicated that their negative experiences during the Influenza A/H1N1 2009 pandemic decreases their acceptance of future vaccinations. Polish participants lacked trust in their national (public) health system and government, and were therefore sceptical about the availability and quality of vaccines in Poland. CONCLUSIONS: Although participants overall expressed similar considerations, important differences between countries stand out, such as previous vaccination experiences, the degree of adherence to social norms, and the degree of trust in health authorities. PMID- 26740252 TI - The effect of 3-bromopyruvate on human colorectal cancer cells is dependent on glucose concentration but not hexokinase II expression. AB - Cancer cells heavily rely on the glycolytic pathway regardless of oxygen tension. Hexokinase II (HKII) catalyses the first irreversible step of glycolysis and is often overexpressed in cancer cells. 3-Bromopyruvate (3BP) has been shown to primarily target HKII, and is a promising anti-cancer compound capable of altering critical metabolic pathways in cancer cells. Abnormal vasculature within tumours leads to heterogeneous microenvironments, including glucose availability, which may affect drug sensitivity. The aim of the present study was to elucidate the mechanisms by which 3BP acts on colorectal cancer (CRC) cells with focus on the HKII/Akt signalling axis. High HKII-expressing cell lines were more sensitive to 3BP than low HKII-expressing cells. 3BP-induced rapid Akt phosphorylation at site Thr-308 and cell death via both apoptotic and necrotic mechanisms. Cells grown under lower glucose concentrations showed greater resistance towards 3BP. Cells with HKII knockdown showed no changes in 3BP sensitivity, suggesting the effects of 3BP are independent of HKII expression. These results emphasize the importance of the tumour microenvironment and glucose availability when considering therapeutic approaches involving metabolic modulation. PMID- 26740253 TI - Soluble arabinoxylan enhances large intestinal microbial health biomarkers in pigs fed a red meat-containing diet. AB - OBJECTIVES: The aim of this study was to investigate how moderately increased dietary red meat combined with a soluble fiber (wheat arabinoxylan [AX]) alters the large intestinal microbiota in terms of fermentative end products and microbial community profiles in pigs. METHODS: Four groups of 10 pigs were fed Western-type diets containing two amounts of red meat, with or without a solubilized wheat AX-rich fraction for 4 wk. After euthanasia, fermentative end products (short-chain fatty acids, ammonia) of digesta from four sections of large intestine were measured. Di-amino-pimelic acid was a measure of total microbial biomass, and bacterial profiles were determined using a phylogenetic microarray. A factorial model determined effects of AX and meat content. RESULTS: Arabinoxylan was highly fermentable in the cecum, as indicated by increased concentrations of short-chain fatty acids (particularly propionate). Protein fermentation end products were decreased, as indicated by the reduced ammonia and branched-chain ratio although this effect was less prominent distally. Microbial profiles in the distal large intestine differed in the presence of AX (including promotion of Faecalibacterium prausnitzii), consistent with an increase in carbohydrate versus protein fermentation. Increased di-amino-pimelic acid (P < 0.0001) suggested increased microbial biomass for animals fed AX. CONCLUSIONS: Solubilized wheat AX has the potential to counteract the effects of dietary red meat by reducing protein fermentation and its resultant toxic end products such as ammonia, as well as leading to a positive shift in fermentation end products and microbial profiles in the large intestine. PMID- 26740254 TI - Effects of Rubus occidentalis extract on blood pressure in patients with prehypertension: Randomized, double-blinded, placebo-controlled clinical trial. AB - OBJECTIVE: Black raspberry (Rubus occidentalis) is known for improving vascular function. However, there has been no study evaluating its effects on 24-h systolic and diastolic blood pressure in prehypertensive patients. The aim of this study was to examine those effects. METHODS: Patients with prehypertension (N = 45) were prospectively randomized into a moderate-dose black raspberry group (n = 15, 1500 mg/d), a high-dose black raspberry group (n = 15, 2500 mg/d), or a placebo group (n = 15) during an 8-wk follow-up period. Raspberries were consumed in the form of a dried powder extract that was fashioned into capsules. The capsules contained 187.5 and 312.5 mg of raspberry powder, which was equivalent to 1500 and 2500 mg raspberries. Ambulatory 24-h blood pressure (BP); central BP; pulse-wave velocity; abdominal visceral fat; serum renin; angiotensin-converting enzyme; and inflammatory cytokines such as interleukin-6, tumor necrosis factor alpha, C-reactive protein, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and plasminogen activator inhibitor-1 were measured at baseline and at 8-wk follow-up. RESULTS: High-dose black raspberry significantly reduced 24-h systolic blood pressure (SBP; 3.3 +/- 10 mm Hg versus 6.7 +/- 11.8 mm Hg; P < 0.05) and nighttime SBP (5.4 +/- 10.6 mm Hg versus -4.5 +/- 11.3 mm Hg; P < 0.05) compared with controls during the 8-wk follow-up. Black raspberry powder did not produce any significant changes in most of the parameters other than BP. CONCLUSION: The use of black raspberry significantly lowered 24-h BP in prehypertensive patients during the 8-wk follow-up. Black raspberry used as a dietary supplement could be beneficial in reducing SBP in prehypertensive patients. PMID- 26740255 TI - Estimation of body fat in adults using a portable A-mode ultrasound. AB - OBJECTIVE: This study aimed to develop and validate equations to estimate body fat based on anthropometric measurements of subcutaneous fat thickness (SFT) and muscle thickness (MT) measured by A-mode ultrasound (BodyMetrix) in Brazilian adults. METHODS: Individuals (n = 206) underwent air-displacement plethysmography for body composition assessment. Arm, thigh, and calf circumferences were also obtained. SFT from triceps, biceps, subscapular, abdominal, thigh, and calf regions and MT from triceps, biceps, thigh, and calf regions were measured by BodyMetrix. Prediction equations were developed by stepwise multiple linear regression using the circumferences, weight, height, SFT, and MT. Lin's concordance correlation coefficient, mean difference, and 95% limits of agreement (95% LOA) were assessed in apparent and internal validity. RESULTS: The prediction equation for whole-body fat for men included thigh circumference, triceps and thigh SFT, biceps MT, weight, and height. The equation for women included age, calf circumference, abdominal and calf SFT, weight, and height. The prediction equation overestimated men's whole-body fat by 0.5 percentual points, in average, and the lower and upper 95% LOA were -6.8% and 7.7%, respectively. For women, the prediction equation overestimated whole-body fat by 0.1 percentual points, in average. Lower and upper 95% LOA were -6.5% and 6.7%, respectively. Optimism-adjusted results using 500 repetitions with same size samples have shown similar results. Body fat extremes did not influence the whole-body fat estimation. CONCLUSIONS: BodyMetrix A-mode ultrasound, in association with selected conventional anthropometric measurements, proved to be a reliable tool for the estimation of body fat percentage. PMID- 26740256 TI - Body composition and lung function in cystic fibrosis and their association with adiposity and normal-weight obesity. AB - OBJECTIVES: This study aimed to evaluate the relationship between lung function and body composition in cystic fibrosis (CF) and examine the presence of normal weight obesity (NWO), a high body fat percentage with a normal body mass index (BMI), in this population. METHODS: In a pilot, cross-sectional study, 32 subjects with CF and a reference group of 20 adults without CF underwent body composition analysis with air displacement plethysmography. NWO was defined as a BMI <25 kg/m(2) and body fat >30% (for women) or >23% (for men). Lung function in subjects with CF was determined by the percentage of predicted forced expiratory volume in 1 s (FEV1% predicted). RESULTS: Despite lower BMI and fat-free mass index (P < 0.01), fat mass index and percent body fat did not differ between subjects with CF and the reference group. Among subjects with CF, FEV1% predicted was positively associated with fat-free mass index (beta = 6.31 +/- 2.93, P = 0.04) and inversely associated with fat mass index (beta = -6.44 +/- 2.93, P = 0.04), after adjusting for age, sex, and BMI. Ten subjects with CF (31%) had NWO, which corresponded with lower fat-free mass index and FEV1% predicted compared with overweight subjects (P = 0.006 and 0.004, respectively). CONCLUSIONS: Excess adiposity, particularly in the form of NWO, was inversely associated with lung function in CF. Larger prospective studies should be undertaken to confirm these findings and determine the long-term metabolic and clinical consequences of excess adiposity in CF. As the lifespan of individuals with CF increases, nutrition screening protocols, which primarily rely on BMI, may require reassessment. PMID- 26740257 TI - The development, application, and validation of a Healthy eating index for Australian Adults (HEIFA-2013). AB - OBJECTIVE: Diet quality indices are used to assess dietary behavior and adherence to dietary guideline recommendations. The aim of this study was to develop, apply, and validate a Healthy Eating Index for Australian Adults (HEIFA-2013) based on the updated Dietary Guidelines for Australians 2013. METHODS: The HEIFA 2013 used an 11-component system of 5 food groups, 4 nutrients, water intake, and a measure of dietary variety. The total possible index score was 100. The HEIFA 2013 was applied to weighed food record (WFR) and food frequency questionnaire (FFQ) data of a sample (n = 100) of young adults. The HEIFA-2013 was assessed using principal components analysis (PCA), Cronbach's coefficient, and correlation coefficient with nutrient intakes. Scores for HEIFA-2013 components were compared between methods using means, frequencies, 95% limits of agreement, Bland and Altman methods, and weighted kappa. RESULTS: PCA indicated that multiple underlying dimensions compose the index, and Cronbach's coefficient alpha was 0.41. A higher HEIFA-2013 was associated with higher dietary quality, including a low intake of saturated fat and sodium and a high intake of selected vitamins and minerals. Low correlations with energy were observed. The mean HEIFA 2013 score +/- standard error (SE) for the WFR was 53.84 +/- 1 and for the FFQ was 54.82 +/- 0.9. The total mean scores were 54.33 +/- 0.1. Young adults had the lowest mean scores for sodium (2.9 +/- 0.2), fat (3.0 +/- 0.0), vegetables (4.7 +/- 0.1), and grains (5.1 +/- 0.1). The WFR and FFQ scored individual components differently, but at the group level the differences were not significant. CONCLUSIONS: The HEIFA-2013 will need to be catered for different diet collection methods. It is a useful index of overall diet quality and can be used to monitor changes in dietary intake of adults over time. The findings infer that even a highly educated affluent group of young adults fails to meet recommended dietary guidelines. PMID- 26740258 TI - New compartment model analysis of lean-mass and fat-mass growth with overfeeding. AB - OBJECTIVES: Mathematical models of lean- and fat-mass growth with diet are useful to help describe and potentially predict the fat- and lean-mass change with different diets as a function of consumed protein and fat calories. Most of the existing models do not explicitly account for interdependence of fat-mass on the lean-mass and vice versa. The aim of this study was to develop a new compartmental model to describe the growth of lean and fat mass depending on the input of dietary protein and fat, and accounting for the interdependence of adipose tissue and muscle growth. METHODS: The model was fitted to existing clinical data of an overfeeding trial for 23 participants (with a high-protein diet, a normal-protein diet, and a low-protein diet) and compared with the existing Forbes model. RESULTS: Qualitatively and quantitatively, the compartment model data fit was smoother with less overall error than the Forbes model. The root means square error were 0.39, 0.93 and 0.72 kg for the new model, the Forbes model, and the modified Forbes model, respectively. Additionally, for the present model, the differences between some of the coefficients (on the cross dependence of fat and lean mass as well as on the intake diet dependence) across different diets were statistically significant (P < 0.05). CONCLUSIONS: Our new Dey-model showed excellent fit to overfeeding data for 23 normal participants with some significant differences of model coefficients across diets, enabling further studies of the model coefficients for larger groups of participants with obesity or other diseases. PMID- 26740259 TI - BRCA1/2 mutations associated with progression-free survival in ovarian cancer patients in the AGO-OVAR 16 study. AB - OBJECTIVE: AGO-OVAR 16 demonstrated that pazopanib maintenance therapy significantly increased progression-free survival (PFS) in patients with ovarian cancer whose disease had not progressed after first-line therapy. In a sub-study, we evaluated the effect of clinically important germline BRCA1 and BRCA2 mutations on PFS. METHODS: Of 940 AGO-OVAR 16 participants, 664 had BRCA1/2 exon sequencing data (pazopanib, n=335; placebo, n=329). A Cox model was used to test the association between genetic variants and PFS. RESULTS: Ninety-seven of 664 patients (15%) carried clinically important BRCA1/2 mutations (BRCA1/2 carriers: pazopanib 14%, placebo 16%). Median PFS was longer in BRCA1/2 mutation carriers than in BRCA1/2 non-carriers in the placebo arm (30.3 vs 14.1 months, hazard ratio, 0.48; 95% confidence interval [CI]: 0.29-0.78; P=0.0031); a similar non significant trend was noted with pazopanib (30.2 vs 17.7 months, hazard ratio, 0.64; 95% CI: 0.40-1.03; P=0.069). Among BRCA1/2 non-carriers, PFS was longer for pazopanib-treated patients than placebo-treated patients (17.7 vs 14.1 months, hazard ratio, 0.77; 95% CI: 0.62-0.97; P=0.024). Among BRCA1/2 carriers, there was no significant PFS difference between treatments, although numbers were small (pazopanib, 46; placebo, 51), resulting in a wide CI (hazard ratio, 1.36; 95% CI: 0.66-2.82). CONCLUSIONS: Patients with clinically important BRCA1/2 mutations had better prognosis. BRCA1/2 mutation status might be added as strata in future trials in primary ovarian cancer. PMID- 26740262 TI - Determination of the substrate repertoire of ADAMTS2, 3, and 14 significantly broadens their functions and identifies extracellular matrix organization and TGF beta signaling as primary targets. AB - A disintegrin and metalloproteinase with thrombospondin type I motif (ADAMTS)2, 3, and 14 are collectively named procollagen N-proteinases (pNPs) because of their specific ability to cleave the aminopropeptide of fibrillar procollagens. Several reports also indicate that they could be involved in other biological processes, such as blood coagulation, development, and male fertility, but the potential substrates associated with these activities remain unknown. Using the recently described N-terminal amine isotopic labeling of substrate approach, we analyzed the secretomes of human fibroblasts and identified 8, 17, and 22 candidate substrates for ADAMTS2, 3, and 14, respectively. Among these newly identified substrates, many are components of the extracellular matrix and/or proteins related to cell signaling such as latent TGF-beta binding protein 1, TGF beta RIII, and dickkopf-related protein 3. Candidate substrates for the 3 ADAMTS have been biochemically validated in different contexts, and the implication of ADAMTS2 in the control of TGF-beta activity has been further demonstrated in human fibroblasts. Finally, the cleavage site specificity was assessed showing a clear and unique preference for nonpolar or slightly hydrophobic amino acids. This work shows that the activities of the pNPs extend far beyond the classically reported processing of the aminopropeptide of fibrillar collagens and that they should now be considered as multilevel regulators of matrix deposition and remodeling.-Bekhouche, M., Leduc, C., Dupont, L., Janssen, L., Delolme, F., Vadon Le Goff, S., Smargiasso, N., Baiwir, D., Mazzucchelli, G., Zanella-Cleon, I., Dubail, J., De Pauw, E., Nusgens, B., Hulmes, D. J. S., Moali, C., Colige, A. Determination of the substrate repertoire of ADAMTS2, 3, and 14 significantly broadens their functions and identifies extracellular matrix organization and TGF beta signaling as primary targets. PMID- 26740263 TI - Distinct roles of T-cell lymphopenia and the microbial flora for gastrointestinal and CNS autoimmunity. AB - T-cell lymphopenia is a major risk factor for autoimmunity. Here we describe congenic Lewis (LEW) rats with a loss-of-function mutation in the Gimap5 gene, leading to a 92% reduction in peripheral T-cell numbers. Gimap5-deficient LEW rats developed eosinophilic autoimmune gastroenteritis accompanied by a 40-fold increase in IgE serum levels. This phenotype was ameliorated by antibiotic treatment, indicating a critical role of the microbial flora in the development of inflammatory bowel disease. Interestingly, Gimap5-deficient LEW rats showed strongly aggravated experimental autoimmune encephalomyelitis (EAE) after immunization with guinea pig myelin basic protein. This phenotype, however, persisted after antibiosis, confirming that the enhanced CNS autoimmune response in T-cell lymphopenic Gimap5-deficient LEW rats was unrelated to the composition of the microbial flora. Rather, it seems that it was caused by the 7-fold increase in the percentage of activated T cells producing IL-17 and IFN-gamma, and the skewed T-cell receptor (TCR) repertoire, both of which were the result of T-cell lymphopenia and not affected by antibiosis. This notion was supported by the observation that adoptive T-cell transfer corrected the TCR repertoire and improved EAE. Collectively, our findings confirm a critical albeit differential role of T-cell lymphopenia in the susceptibility to organ-specific autoimmune responses.-Fischer, H. J., Witte, A.-K., Walter, L., Grone, H.-J., van den Brandt, J., Reichardt, H. M. Distinct roles of T-cell lymphopenia and the microbial flora for gastrointestinal and CNS autoimmunity. PMID- 26740264 TI - Web-Based Cognitive Behavioral Relapse Prevention Program With Tailored Feedback for People With Methamphetamine and Other Drug Use Problems: Development and Usability Study. AB - BACKGROUND: Although drug abuse has been a serious public health concern, there have been problems with implementation of treatment for drug users in Japan because of poor accessibility to treatment, concerns about stigma and confidentiality, and costs. Therapeutic interventions using the Internet and computer technologies could improve this situation and provide more feasible and acceptable approaches. OBJECTIVE: The objective of the study was to show how we developed a pilot version of a new Web-based cognitive behavioral relapse prevention program with tailored feedback to assist people with drug problems and assessed its acceptance and usability. METHODS: We developed the pilot program based on existing face-to-face relapse prevention approaches using an open source Web application to build an e-learning website, including relapse prevention sessions with videos, exercises, a diary function, and self-monitoring. When users submitted exercise answers and their diary, researchers provided them with personalized feedback comments using motivational interviewing skills. People diagnosed with drug dependence were recruited in this pilot study from a psychiatric outpatient ward and nonprofit rehabilitation facilities and usability was evaluated using Internet questionnaires. Overall, website usability was assessed by the Web Usability Scale. The adequacy of procedures in the program, ease of use, helpfulness of content, and adverse effects, for example, drug craving, mental distress, were assessed by original structured questionnaires and descriptive form questions. RESULTS: In total, 10 people participated in the study and completed the baseline assessment, 60% completed all relapse prevention sessions within the expected period. The time needed to complete one session was about 60 minutes and most of the participants took 2 days to complete the session. Overall website usability was good, with reasonable scores on subscales of the Web Usability Scale. The participants felt that the relapse prevention sessions were easy to use and helpful, but that the length of the videos was too long. The participant who until recently used drugs was satisfied with the self monitoring, but others that had already maintained abstinence for more than a year felt this activity was unhelpful and were bored tracking and recording information on daily drug use. Feedback comments from researchers enhanced participants' motivation and further insight into the disease. Serious adverse effects caused by the intervention were not observed. Some possible improvements to the program were suggested. CONCLUSIONS: The Web-based relapse prevention program was easy to use and acceptable to drug users in this study. This program will be helpful for drug users who do not receive behavioral therapy. After the pilot program is revised, further large-scale research is needed to assess its efficacy among drug users who have recently used drugs. PMID- 26740266 TI - Leptomeningeal carcinomatosis from oesophageal cancer, presenting as meningitis. AB - A 47-year-old woman presented with headache, neck pain, dizziness, nausea and vomiting for 4-5 days. She also had a history of weight loss and difficulty in swallowing. On physical examination, she had nuchal rigidity with a positive Kernig's sign. Cerebrospinal fluid analysis revealed mild pleocytosis but some atypical cells were also noted. Cytopathological analysis of the atypical cells showed high nuclear/cytoplasmic ratios and eccentric nuclei with prominent nucleoli, consistent with malignancy. A CT scan of the head and neck showed multiple lytic lesions involving the left calvarium, and diffuse thickening and enhancement of meninges over the left cerebral area. Extensive osteolytic lesions were also noted on the vertebral bodies, pedicles and lamina, at multiple levels of the cervical spine. An endoscopy revealed a mass at the gastro-oesophageal junction, and biopsy confirmed moderately differentiated adenocarcinoma of the oesophagus. The patient was started on chemotherapy along with radiation therapy. PMID- 26740267 TI - Noma in a child with acute leukaemia: when the 'face of poverty' finds an ally. AB - A 2-year-6-month old, appropriately immunised, well-thriving boy, symptomatic for the past 6 months, presented with recurrent fever, progressive pallor, lymphadenopathy and a raw area on the right cheek, with discharging sinus. The necrotising infection of the face developed after one and half months of febrile illness. This febrile illness with bicytopaenia was diagnosed as enteric fever and treated with antibiotics. Skin grafting was performed for the full-thickness defect of the face. The patient continued to have a non-healing oral ulcer with progressive pallor and was finally diagnosed as having acute lymphoblastic leukaemia. Immunodeficiency was ruled out by appropriate investigations. Noma is an indirect measure of extreme poverty, but malignancy is known to predispose to this debilitating condition. The worldwide incidence of Noma is reported to be 30,000-140,000, with a preponderance in sub-Saharan Africa. This case emphasises the need for a thorough search for the underlying illness predisposing to a rare opportunistic infection such as Noma in a well-thriving child. PMID- 26740268 TI - A rare case of Behcet disease with generalised myositis, cardiomyositis and necrotising fasciitis. AB - Behcet disease (BD) is a rare relapsing, multisystem vasculitis characterised by recurrent oral and genital ulcers, and uveitis. As an autoimmune small vessel vasculitis, BD can involve other organs including the skin, joints, nervous system, kidney and the gastrointestinal tract. This report describes a 40-year old woman who presented with an uncommon feature of BD, namely myositis, and who went on to develop myocarditis and polymicrobial necrotising fasciitis. To the best of our knowledge, this is the first reported case of an immunocompromised associated infection occurring in BD without concurrent immunosuppressive therapy. PMID- 26740269 TI - Pelvic paraganglioma: a rare and unusual clinical presentation of paraganglioma. AB - Paraganglioma of the urinary bladder is a rare tumour of the urinary bladder causing palpitation, headache, paroxysmal hypertension, tachycardia, blurring of vision and haematuria. Patients may present with these exaggerated symptoms during or just after micturition. We present a case of a 15-year-old girl who presented to us with accelerated hypertension, headache, palpitation and blurring of vision. On the basis of a positive family history, laboratory investigations and imaging studies, she was diagnosed to have an extra-adrenal paraganglioma. Complete enucleation of the tumour with preservation of the bladder was done. This case is reported because of the rarity of the disease in urology. PMID- 26740270 TI - Resolution of norfloxacin-induced acute liver failure after N-acetylcysteine therapy: further support for the use of NAC in drug-induced ALF? AB - Liver injury due to idiosyncratic drug reactions can be difficult to diagnose and may lead to acute liver failure (ALF), which has a high mortality rate. N acetylcysteine (NAC) is effective treatment for paracetamol toxicity, but its role in non-paracetamol drug-induced ALF is controversial. We report on the use of a validated bedside tool to establish causality for drug-induced liver injury (DILI) and describe the first case of resolution of norfloxacin-induced ALF after NAC therapy. NAC is easy to administer and generally has a good safety profile. We discuss the evidence to support the use of NAC in ALF secondary to DILI and possibilities for further clinical research in this field. PMID- 26740271 TI - Simultaneous occurrence of Hodgkin's disease and tubercular lymphadenitis in the same cervical lymph node: a rare presentation. AB - Concomitant presentation of tuberculosis (TB) and lymphoma is a rare entity. A primary malignancy such as Hodgkin's disease (HD) may cause suppression of the cell-mediated immunity, which predisposes to a concomitant TB infection. We report a case of an 18-year-old man, who presented with fever and was found to have pallor, generalised lymphadenopathy, hepatosplenomegaly, ascites and pedal oedema. Ultrasound of the abdomen revealed enlarged lymph nodes in the para aortic and peripancreatic region. On chest contrast-enhanced CT, calcified mediastinal lymph nodes were seen. A surgical biopsy of a cervical lymph node was performed, which revealed caseous necrosis surrounded by epithelioid cells along with diffuse nodal architectural effacement by large atypical lymphoid cells. Numerous Reed Sternberg cells were also seen. Immunohistochemistry confirmed diagnosis of Hodgkin's lymphoma. The same lymph node came out to be positive for mycobacterium TB on polymerised chain reaction. The patient was given antitubercular therapy concomitantly with chemotherapy for HD, and improved with treatment. PMID- 26740272 TI - Uncommon benign tumour of the skin: infraorbital pilomatricoma. AB - Pilomatricoma is a relatively rare tumour of the skin derived from primitive basal cells of epidermis that differentiate into hair matrix cells. It comprises approximately 1% of all benign skin tumours. The most common sites for pilomatricomas are the head, neck and upper extremities. A 44-year-old woman, admitted to our department, underwent an orthopantomography examination, which revealed a well-circumscribed 1.6*1.4 mm radiopaque mass superimposed between the medial wall of the right maxillary sinus and lateral wall of the nasal cavity. Clinically, it was firm and mobile, and remained attached to the underlying skin when palpated. A cone beam CT scan was performed to ascertain its location and anatomic relations. Subsequently, it was totally excised under local anaesthesia. Histopathological evaluation of the lesion reported it to be a pilomatricoma. PMID- 26740273 TI - Severe rhinovirus pneumonia in a young woman taking performance-enhancing drugs. AB - A 22-year-old woman presented to the emergency room of a local hospital with pleuritic chest pain. She regularly worked out and admitted to taking performance enhancing drugs (PEDs). Clinical findings and further diagnostic work up revealed a diagnosis of perimyocarditis, and adequate therapy was initiated. During the course of the first day, the patient had to be intubated and mechanically ventilated. A diagnosis of bilateral pneumonia and acute respiratory distress syndrome (ARDS) due to an infection by rhinovirus spp was made. A smoking habit, the intense physical training and the use of PED's may have exacerbated the course of the viral pneumonia. After 12 days the patient could be extubated. The length of stay in the intensive care unit was 16 days. After hospital discharge, the patient went to a pulmonary rehabilitation facility for 2 weeks. The outcome was favourable and the patient resumed her strength and endurance training. PMID- 26740274 TI - Low Prolactin and High 20-alpha-Hydroxysteroid Dehydrogenase Levels Contribute to Lower Progesterone Levels in HIV-Infected Pregnant Women Exposed to Protease Inhibitor-Based Combination Antiretroviral Therapy. AB - BACKGROUND: It has been reported that pregnant women receiving protease inhibitor (PI)-based combination antiretroviral therapy (cART) have lower levels of progesterone, which put them at risk of adverse birth outcomes, such as low birth weight. We sought to understand the mechanisms involved in this decline in progesterone level. METHODS: We assessed plasma levels of progesterone, prolactin, and lipids and placental expression of genes involved in progesterone metabolism in 42 human immunodeficiency virus (HIV)-infected and 31 HIV uninfected pregnant women. In vitro studies and a mouse pregnancy model were used to delineate the effect of HIV from that of PI-based cART on progesterone metabolism. RESULTS: HIV-infected pregnant women receiving PI-based cART showed a reduction in plasma progesterone levels (P= .026) and an elevation in placental expression of the progesterone inactivating enzyme 20-alpha-hydroxysteroid dehydrogenase (20alpha-HSD; median, 2.5 arbitrary units [AU]; interquartile range [IQR], 1.00-4.10 AU), compared with controls (median, 0.89 AU; IQR, 0.66-1.26 AU;P= .002). Prolactin, a key regulator of 20alpha-HSD, was lower (P= .012) in HIV-infected pregnant women. We observed similar data in pregnant mice exposed to PI-based cART. In vitro inhibition of 20alpha-HSD activity in trophoblast cells reversed PI-based cART-induced decreases in progesterone levels. CONCLUSIONS: Our data suggest that the decrease in progesterone levels observed in HIV-infected pregnant women exposed to PI-based cART is caused, at least in part, by an increase in placental expression of 20alpha-HSD, which may be due to lower prolactin levels observed in these women. PMID- 26740275 TI - Flow-Tolerant Adhesion of a Bacterial Pathogen to Human Endothelial Cells Through Interaction With Biglycan. AB - BACKGROUND: Bacterial pathogens causing systemic infections disseminate from the initial infection focus to the target organs usually through the blood vasculature. To be able to colonize various organs, bacteria need to adhere to the endothelial cells of the vascular wall, and the adhesion must be strong enough to resist the shear force of the blood flow.Borrelia burgdorferi sensu lato spirochetes, the causative agents of the tick-borne disease Lyme borreliosis, disseminate hematogenously from the tick bite site to the joints, the heart, and the central nervous system of the patient. METHODS: We used both wild-type and genetically modified B. burgdorferi s. l. bacteria, recombinant borrelia adhesins, and an array of adhesion assays carried out both under stationary and flow conditions to investigate the molecular mechanisms of borrelial adhesion to human endothelial cells. RESULTS: Borrelia garinii, a member of the B. burgdorferi s. l. complex, adhered to biglycan expressed by human endothelial cells in a flow-tolerant manner. The adhesion was mediated by the decorin-binding protein A (DbpA) and DbpB surface molecules of B. garinii. CONCLUSIONS: The proteoglycan biglycan is a receptor molecule for flow-resistant adhesion of the bacterial pathogen B. garinii on human endothelial cells. PMID- 26740276 TI - Effectiveness of Residential Acaricides to Prevent Lyme and Other Tick-borne Diseases in Humans. AB - BACKGROUND: In the northeastern United States, tick-borne diseases are a major public health concern. In controlled studies, a single springtime application of acaricide has been shown to kill 68%-100% of ticks. Although public health authorities recommend use of acaricides to control tick populations in yards, the effectiveness of these pesticides to prevent tick bites or human tick-borne diseases is unknown. METHODS: We conducted a 2-year, randomized, double-blinded, placebo-controlled trial among 2727 households in 3 northeastern states. Households received a single springtime barrier application of bifenthrin or water according to recommended practices. Tick drags were conducted 3-4 weeks after treatment on 10% of properties. Information on human-tick encounters and tick-borne diseases was collected through monthly surveys; reports of illness were validated by medical record review. RESULTS: Although the abundance of questing ticks was significantly lower (63%) on acaricide-treated properties, there was no difference between treatment groups in human-tick encounters, self reported tick-borne diseases, or medical-record-validated tick-borne diseases. CONCLUSIONS: Used as recommended, acaricide barrier sprays do not significantly reduce the household risk of tick exposure or incidence of tick-borne disease. Measures for preventing tick-borne diseases should be evaluated against human outcomes to confirm effectiveness. PMID- 26740277 TI - Tick-borne Disease Prevention: Still No Silver Bullet. PMID- 26740279 TI - Fatigue-induced Orosomucoid 1 Acts on C-C Chemokine Receptor Type 5 to Enhance Muscle Endurance. AB - Understanding and managing fatigue is a significant challenge in clinic and society. In attempting to explore how the body responds to and regulates fatigue, we found in rodent fatigue models that orosomucoid 1 (ORM1) was significantly increased in multiple tissues, including blood and muscle. Interestingly, administration of exogenous ORM1 increased muscle glycogen and enhanced muscle endurance, whereas ORM1 deficiency resulted in a significant decrease of muscle endurance both in vivo and in vitro, which could largely be restored by exogenous ORM1. Further studies demonstrated that ORM1 can bind to C-C chemokine receptor type 5 (CCR5) on muscle cells and deletion of the receptor abolished the effect of ORM1. Thus, fatigue upregulates the level of ORM1, which in turn functions as an anti-fatigue protein to enhance muscle endurance via the CCR5 pathway. Modulation of the level of ORM1 and CCR5 signaling could be a novel strategy for the management of fatigue. PMID- 26740280 TI - Mesenchymoangioblast-derived mesenchymal stromal cells inhibit cell damage, tissue damage and improve peripheral blood flow following hindlimb ischemic injury in mice. AB - BACKGROUND AIMS: Existing treatments have limited success in modifying the course of peripheral artery disease, which may eventually lead to limb-threatening ulcers and amputation. Cellular therapies have the potential to provide a new treatment option for this condition, but isolation of cells by conventional means has limitations with respect to reproducibility and scalability. METHODS: Induced pluripotent stem cells (iPSCs) were differentiated into precursor cells known as mesenchymoangioblasts (MCAs) and subsequently into mesenchymal stromal cells (MSCs). Hindlimb ischemia in mice was created by ligating both the iliac and femoral arteries of one hindlimb. Immediately after surgery, each animal received intramuscular injections of 5 * 10(6) cells or media in the ischemic limb. Toe necrosis was assessed visually, and hindlimb blood flow was measured by laser Doppler using a set region of interest (ROI) and by tracing the entire foot. Myofiber heterogeneity, nuclear centralization, fatty degeneration, fibrosis and capillary angiogenesis in the gastrocnemius muscle were assessed histologically. RESULTS: Blood flow in the MCA-derived MSC-treated animals was higher at each day (P <0.006), and these mice recovered faster than control animals (3.6 vs. 2.5 for set ROI; 7.5 vs. 4.1 foot tracing; slope; P <0.001). There was significantly less myofiber heterogeneity, nuclear centralization, fatty degeneration and fibrosis in MCA-derived MSC-treated animals, indicating less tissue damage. DISCUSSION: MCA-derived MSCs improved limb blood flow, reduced necrosis and maintained muscle mass and gross muscle appearance. We conclude that MCA-derived MSCs have a significant and protective effect against ischemic insults. PMID- 26740281 TI - The Predictive Role of Serum Cystatin C Levels in Polycystic Ovary Syndrome in Adolescents. AB - STUDY OBJECTIVE: To evaluate the correlation between serum cystatin levels and clinical parameters in adolescents with polycystic ovary syndrome (PCOS). DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: This prospective case-control study included 89 adolescents with PCOS. Demographic characteristics and hormonal and biochemical parameters were compared between study (89 patients with PCOS) and control (84 subjects without PCOS) groups. Risk factors recorded were age, body mass index (BMI), waist to hip ratio (WHR), Ferriman-Gallwey score, triglyceride, total cholesterol, high-density lipoprotein, low-density lipoprotein (LDL), high-sensitivity C-reactive protein, cystatin C, follicle stimulating hormone, luteinizing hormone, estradiol, dehydroepiandrosterone sulfate, homeostatic model assessment insulin resistance index, free testosterone, and progesterone levels. RESULTS: BMI, WHR, Ferriman-Gallwey score, and triglyceride, LDL, total cholesterol, estradiol, dehydroepiandrosterone sulfate, free testosterone, luteinizing hormone, high-sensitivity C-reactive protein, and cystatin C levels, and homeostatic model assessment insulin resistance index scores were significantly higher, and high-density lipoprotein levels were lower in the PCOS patients compared with healthy subjects (P < .05). We also found positive correlations between the cystatin C levels and BMI, WHR, estradiol, high-sensitivity C-reactive protein, and LDL levels in the study group. CONCLUSION: The serum cystatin C level is a promising marker for diagnosing adolescent patients with PCOS and suggests an inflammatory etiology for these patients. Further studies with more participants should examine this potential association with inflammation. PMID- 26740282 TI - Teen Pregnancy and Contraceptive Methods: The Situation in an Underdeveloped Country. PMID- 26740285 TI - Corrigendum: Migraine and possible etiologic heterogeneity for hormone-receptor negative breast cancer. PMID- 26740286 TI - [Endovascular treatment of giant intracranial aneurysms]. AB - Giant aneurysms are defined as having a maximal diameter higher than 25mm. The dynamic aspect of giant aneurysms, in particular, is its growth, which was responsible for parenchyma sequellae either due to haemorrhagic complications or a compression of cranial nerves. The treatment of these giant aneurysms was challenging because of its size, the mass effect and the neck diameter. These morphologic conditions required complex endovascular procedures such as remodelling, stenting, using flow diverters. Subsequently, the complex procedures increased the risk of morbidity because of ischemic complications. Despite these procedures, the risk of recurrence was high. PMID- 26740287 TI - Cytokeratin 17 immunoexpression in actinic keratosis (bowenoid and nonbowenoid) and in Bowen disease. AB - Cytokeratin (CK) 17 immunoexpression has been investigated in nonmelanoma skin cancer as well as in many preinvasive epithelial malignancies. However, there is not any previous study of CK17 immunoexpression in actinic keratosis (AK) or Bowen disease in nonimmunocompromised patients. We evaluated CK17 immunoexpression in 20 cases of AK (10 nonbowenoid and 10 bowenoid) as well as in 10 cases of Bowen disease. We identified expression of CK17 in the superficial layers above the atypical foci. In some cases, there were foci of expression by the full thickness of the epidermis, which was the predominant pattern in very few cases (1 Bowen disease and 1 bowenoid AK). In addition, 1 case of bowenoid AK showed CK17 expression in a "skyline" pattern in the basal layer of the epidermis. Cytokeratin 17 immunostaining did not allow us to distinguish between the 3 entities studied. However, the immunostaining allowed us to distinguish atypical foci in the biopsies, even if atypicality was minimal. In addition, CK17 was useful in identifying surgical borders involved by disease in cases in which the hematoxylin-eosin was difficult to evaluate. Cytokeratin 17 immunoexpression might have a role in evaluating surgical borders in some cases of AK and Bowen disease. PMID- 26740290 TI - Restless Legs Symptoms and Pregnancy and Neonatal Outcomes. AB - PURPOSE: Restless legs syndrome (RLS) is a commonly occurring neurologic disorder that affects up to one third of women during pregnancy. RLS has been associated with increased sympathetic tone in the nonpregnant population. We examined whether a RLS surrogate is associated with a higher prevalence of pregnancy and neonatal outcomes. METHODS: Data were analyzed from a cross-sectional survey of 1000 women interviewed soon after delivery by using an RLS surrogate question. Women were asked how frequently (0 = none, 1 = rarely [<1 time/week], 2 = sometimes [1-2 times/week], 3 = frequently [3-4 times/week], and 4 = always [5-7 times/week]) they had "experienced jumpy or jerky leg movements" in the last 3 months of pregnancy. Clinical charts were reviewed to obtain relevant demographic and clinical data, including the presence of gestational hypertensive disorders and neonatal outcomes at birth. Subjects who "always" experienced RLS were compared with subjects experiencing symptoms less frequently or not at all with respect to prevalence of gestational hypertensive disorder. FINDINGS: The mean ([SD]) age, prepregnancy body mass index (BMI), and BMI at delivery were 29.0 (6.1) years, 26.1 (6.2) kg/m(2), and 32.0 (6.3) kg/m(2), respectively. The overall prevalence of the RLS surrogate (jumpy or jerky leg movements) was 35.5% with the following distribution on a Likert scale: score 1 = 6.4%; score 2 = 10.2%; score 3 = 8.1%; and score 4 = 10.8%. Chronic hypertension was present in 2.1%, pregnancy-induced hypertension in 9.5%, and preeclampsia in 4.5% of respondents. Subjects who reported "always" having sensations of jumpy or jerky legs were more likely to have gestational hypertensive disorders compared with those who reported less frequent occurrence of the symptoms. Adjusted odds ratios were 3.74 (95% CI, 1.31-10.72; P = 0.014) for chronic hypertension; 1.26 (95% CI, 0.65-2.46; P = 0.487) for pregnancy-induced hypertension; and 2.15 (95% CI, 0.97 4.75; P = 0.060) for preeclampsia. There was a significant association between leg movement score and neonatal birth weight (coefficient, -149.5 g [95% CI, 276.9 to -22.5]; P = 0.005) and gestational age at birth (-0.7 week [95% CI, -1.1 to -0.2]; P = 0.021) that persisted after adjusting for preeclampsia, diabetes, and smoking. IMPLICATIONS: A higher frequency of jumpy or jerky leg symptoms, a proxy for RLS during pregnancy, was associated with a higher likelihood of gestational hypertensive disorders and neonatal outcomes such as gestational age at birth and birth weight. These findings may affect RLS treatment decisions during pregnancy. PMID- 26740288 TI - The BREAST-Q in surgical research: A review of the literature 2009-2015. AB - BACKGROUND: Health outcomes research has gained considerable traction over the past decade as the medical community attempts to move beyond traditional outcome measures such as morbidity and mortality. Since its inception in 2009, the BREAST Q has provided meaningful and reliable information regarding health-related quality of life (HRQOL) and patient satisfaction for use in both clinical practice and research. In this study, we review how researchers have used the BREAST-Q and how it has enhanced our understanding and practice of plastic and reconstructive breast surgery. METHODS: An electronic literature review was performed to identify publications that used the BREAST-Q to assess patient outcomes. Studies developing and/or validating the BREAST-Q or an alternate patient-reported outcome measure (PROM), review papers, conference abstracts, discussions, comments and/or responses to previously published papers, studies that modified a version of BREAST-Q, and studies not published in English were excluded. RESULTS: Our literature review yielded 214 unique articles, 49 of which met our inclusion criteria. Important trends and highlights were further examined. DISCUSSION: The BREAST-Q has provided important insights into breast surgery highlighted by literature concerning autologous reconstruction, implant type, fat grafting, and patient education. The BREAST-Q has increased the use of PROMs in breast surgery and provided numerous important insights in its brief existence. The increased interest in PROMs as well as the underutilized potential of the BREAST-Q should permit its continued use and ability to foster innovations and improve quality of care. PMID- 26740291 TI - Correlation of Mast Cell Density With Angiogenic Cytokines in Patients With Active Multiple Myeloma. AB - PURPOSE: The aim of the study is to estimate whether bone marrow mast cell density (MCD) in multiple myeloma (MM) correlates with circulating levels of various angiogenic factors. METHODS: In 70 patients with newly diagnosed active MM, we measured MCD using immunohistochemical stain for tryptase and serum levels of matrix metalloproteinase 9 (MMP-9), angiopoietin 2 (ANGIOP-2), and angiogenin (ANG) with ELISA. FINDINGS: Levels of MCD, ANGIOP-2, and ANG were significantly higher in MM patients compared with the control group. The MMP-9 level was higher in MM patients compared with the control group but without statistical significance. All values were increasing in parallel with clinical stages. Furthermore, MCD correlated positively with MMP-9, ANGIOP-2, and ANG. IMPLICATIONS: MCs participate in the angiogenic processes of MM, with complex implicated mechanisms. This interplay between MCs and the other participants favors angiogenesis and MM growth. PMID- 26740292 TI - The effect of an inhibitor of gut serotonin (LP533401) during the induction of periodontal disease. AB - BACKGROUND AND OBJECTIVE: LP533401 is an inhibitor of tryptophan hydroxylase 1, which regulates serotonin production in the gut. Previous work indicates that LP533401 has an anabolic effect in bone. Thus, we hypothesized that inhibition of gut serotonin production may modulate the host response in periodontal disease. In this study, we aimed to analyze the effects of LP533401 in a rat periodontitis model to evaluate the role of gut serotonin in periodontitis pathophysiology. MATERIAL AND METHODS: Twenty-four rats were divided into three groups: treated group (T: ligature-induced periodontal disease and LP533401, 25 mg/kg/d) by gavage; ligature group (L: ligature-induced periodontal disease only); and control group (C: without ligature-induced periodontal disease). After 28 d, radiographic alveolar bone support was measured on digital radiographs, and alveolar bone volume fraction, tissue mineral density and trabeculae characteristics were quantified by microcomputed tomography in the right hemi mandible. Left hemi-mandibles were decalcified and alveolar bone loss, attachment loss and area of collagen in the gingiva were histologically analyzed. RESULTS: Significant difference between the L and C groups was found, confirming that periodontal disease was induced. We observed no difference between the T and L groups regarding alveolar bone destruction and area of collagen. CONCLUSION: LP533401 (25 mg/kg/d) for 28 d does not prevent bone loss and does not modulate host response in a rat model of induced periodontal disease. PMID- 26740293 TI - Is a prenatal diagnosis detrimental to the survival of a fetus with trisomy 18? AB - As trisomy 18 is so rare any individual study is unlikely to have a sufficient number of cases to examine whether a prenatal diagnosis is advantageous or detrimental to the survival of these infants. Estimates of survival in prenatally diagnosed live births have been obtained by combining data from individual hospitals, whereas estimates of survival in postnatally diagnosed live births have been obtained from large population studies linking cytogenetic registers to national mortality registers. The estimates of survival are often lower in the prenatally diagnosed series. However, comparing estimates from these two different sources is not valid; both sources are subject to different biases. At present, there is insufficient information available to indicate that receiving a prenatal diagnosis of trisomy 18 is detrimental to the survival of a foetus with trisomy 18. A prenatal diagnosis does enable the parents and clinicians time to reach a consensus on how best to care for the baby. PMID- 26740297 TI - Anaphylaxis--two stories not covered by the current guidelines. PMID- 26740296 TI - Microbiota-induced obesity requires farnesoid X receptor. AB - OBJECTIVE: The gut microbiota has been implicated as an environmental factor that modulates obesity, and recent evidence suggests that microbiota-mediated changes in bile acid profiles and signalling through the bile acid nuclear receptor farnesoid X receptor (FXR) contribute to impaired host metabolism. Here we investigated if the gut microbiota modulates obesity and associated phenotypes through FXR. DESIGN: We fed germ-free (GF) and conventionally raised (CONV-R) wild-type and Fxr-/- mice a high-fat diet (HFD) for 10 weeks. We monitored weight gain and glucose metabolism and analysed the gut microbiota and bile acid composition, beta-cell mass, accumulation of macrophages in adipose tissue, liver steatosis, and expression of target genes in adipose tissue and liver. We also transferred the microbiota of wild-type and Fxr-deficient mice to GF wild-type mice. RESULTS: The gut microbiota promoted weight gain and hepatic steatosis in an FXR-dependent manner, and the bile acid profiles and composition of faecal microbiota differed between Fxr-/- and wild-type mice. The obese phenotype in colonised wild-type mice was associated with increased beta-cell mass, increased adipose inflammation, increased steatosis and expression of genes involved in lipid uptake. By transferring the caecal microbiota from HFD-fed Fxr-/- and wild type mice into GF mice, we showed that the obesity phenotype was transferable. CONCLUSIONS: Our results indicate that the gut microbiota promotes diet-induced obesity and associated phenotypes through FXR, and that FXR may contribute to increased adiposity by altering the microbiota composition. PMID- 26740298 TI - Serological diagnosis of allergic bronchopulmonary mycosis: Progress and challenges. AB - Prompt diagnosis of allergic bronchopulmonary mycosis (ABPM) is an important clinical issue in preventing irreversible lung damage. Therefore, a good serological marker for the diagnosis of ABPM is desired in clinical practice. The measurement of IgE antibody to crude Aspergillus fumigatus allergen is considered the first step in screening asthmatic patients for allergic bronchopulmonary aspergillosis (ABPA). However, presence of IgE to A. fumigatus does not always indicate genuine sensitization to A. fumigatus because of cross-reactivity between crude extracts from different fungal sources. The application of molecular-based allergy diagnosis can solve this problem. The specificity of testing can be greatly improved by measuring the IgE antibody to Asp f 1 and f 2, specific allergen components for genuine A. fumigatus allergy. The problem of cross-reactivity between crude fungal extracts is also true for the identification of genuine causal fungi in each ABPM patient. Some patients with ABPM induced by fungi other than Aspergillus may be consistent with ABPA diagnostic criteria because current criteria depend on IgE/IgG reactivity to crude extracts. Accurate identification of genuine causal fungi for ABPM is of clinical importance, considering that clinical presentation, anti-fungal treatment strategies and disease prognosis can be influenced by different causal fungi. The diagnosis of causal fungi can be robustly validated by the confirmation of genuine sensitization to fungi after measuring IgE to specific allergen components, as well as repeated microbiological isolation of the fungi from their airway. PMID- 26740299 TI - Oral challenge tests for soybean allergies in Japan: A summary of 142 cases. AB - BACKGROUND: Soybeans are one of causative foods for infantile onset allergies in Japan. This study aimed to analyze the results of soybean challenge tests that were conducted over approximately 7 years at our institution. Using the test data, we sought to identify the responses and clinical profiles of patients with soybean allergies, and to investigate the relationship between the responses and soybean sensitization status. METHODS: Between July 2004 and May 2010, 142 cases (125 patients) underwent food challenge tests (100 g of silken tofu) for the diagnosis of soybean allergy or confirmation of their tolerance. The patients' characteristics, soybean sensitization status, and responses to the challenge tests were retrospectively evaluated. RESULTS: Among the subjects who underwent the soybean challenge test, the male/female ratio was 1.6 (87/55), and the mean age at the test was 2.8 +/- 1.7 years. The positive rate for the challenge test was 38.7%. Induced symptoms were observed in the skin (81.8%), respiratory system (50.9%), and gastrointestinal system/mucosal membrane/anaphylaxis (12.7%). Intramuscular epinephrine was administered to all 7 patients who experienced an anaphylactic reaction. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic efficiency of soybean-specific IgE titers were low for predicting the responses to the challenge test. CONCLUSIONS: Soybean allergies were diagnosed in only 18% of the subjects with positive sensitization to soybeans. Therefore, soybean-specific IgE titers are not an effective predictor of a positive response to the challenge test. PMID- 26740303 TI - Unveiling laser diode "fossil" and the dynamic analysis for heliotropic growth of catastrophic optical damage in high power laser diodes. AB - Taking advantage of robust facet passivation, we unveil a laser "fossil" buried within a broad area laser diode (LD) cavity when the LD was damaged by applying a high current. For the first time, novel physical phenomena have been observed at these dramatically elevated energy densities within the nanoscale LD waveguide. The observation of the laser "fossil" is interpreted with different mechanisms, including: the origination of bulk catastrophic optical damage (COD) due to locally high energy densities, heliotropic COD growth, solid-liquid-gas phase transformations, strong longitudinal phonon cooling effect on the molten COD wave front, and the formation of patterns due to laser lateral modes. For the first time the COD propagation is analyzed temporally by an acoustic phonon bouncing model and the COD velocity is extrapolated to be exponentially decreasing from more than 800 MUm/MUs to a few MUm/MUs within a 20 MUs time period as the energy density dissipates. PMID- 26740304 TI - Serum- and glucocorticoid-inducible kinase SGK2 regulates human organic anion transporters 4 via ubiquitin ligase Nedd4-2. AB - Human organic anion transporter 4 (hOAT4) belongs to a family of organic anion transporters that play critical roles in the body disposition of clinically important drugs, including anti-viral therapeutics, anti-cancer drugs, antibiotics, antihypertensives, and anti-inflammatories. hOAT4 is abundantly expressed in the kidney and placenta. In the current study, we examined the regulation of hOAT4 by serum- and glucocorticoid-inducible kinase 2 (sgk2) in the kidney COS-7 cells. We showed that sgk2 stimulated hOAT4 transport activity. Such stimulation mainly resulted from an increased cell surface expression of the transporter, kinetically revealed as an increased maximal transport velocity Vmax without significant change in substrate-binding affinity Km. We further showed that regulation of hOAT4 activity by sgk2 was mediated by ubiquitin ligase Nedd4 2. Overexpression of Nedd4-2 enhanced hOAT4 ubiquitination, and inhibited hOAT4 transport activity, whereas overexpression of ubiquitin ligase-dead mutant Nedd4 2/C821A or siRNA knockdown of endogenous Nedd4-2 had opposite effects on hOAT4. Our co-immunoprecipitation experiment revealed that sgk2 weakened the association between hOAT4 and Nedd4-2. In conclusion, our study demonstrated for the first time that sgk2 stimulated hOAT4 transport activity by abrogating the inhibitory effect of Nedd4-2 on the transporter. PMID- 26740305 TI - PTSD SYMPTOMS ACROSS PREGNANCY AND EARLY POSTPARTUM AMONG WOMEN WITH LIFETIME PTSD DIAGNOSIS. AB - BACKGROUND: Little is known about trajectories of PTSD symptoms across the peripartum period in women with trauma histories, specifically those who met lifetime PTSD diagnoses prior to pregnancy. The present study seeks to identify factors that influence PTSD symptom load across pregnancy and early postpartum, and study its impact on postpartum adaptation. METHOD: The current study is a secondary analysis on pregnant women with a Lifetime PTSD diagnosis (N = 319) derived from a larger community sample who were interviewed twice across pregnancy (28 and 35 weeks) and again at 6 weeks postpartum, assessing socioeconomic risks, mental health, past and ongoing trauma exposure, and adaptation to postpartum. RESULTS: Using trajectory analysis, first we examined the natural course of PTSD symptoms based on patterns across peripartum, and found four distinct trajectory groups. Second, we explored factors (demographic, historical, and gestational) that shape the PTSD symptom trajectories, and examined the impact of trajectory membership on maternal postpartum adaptation. We found that child abuse history, demographic risk, and lifetime PTSD symptom count increased pregnancy-onset PTSD risk, whereas gestational PTSD symptom trajectory was best predicted by interim trauma and labor anxiety. Women with the greatest PTSD symptom rise during pregnancy were most likely to suffer postpartum depression and reported greatest bonding impairment with their infants at 6 weeks postpartum. CONCLUSIONS: Screening for modifiable risks (interpersonal trauma exposure and labor anxiety) and /or PTSD symptom load during pregnancy appears critical to promote maternal wellbeing. PMID- 26740306 TI - Minimally Invasive Versus Open Distal Fibular Plating for AO/OTA 44-B Ankle Fractures. AB - BACKGROUND: Open reduction and internal fixation (ORIF), the standard treatment for unstable ankle fractures, has well-known wound complications. Minimally invasive surgery (MIS) has been proposed to decrease these complications. The objectives of this study were to describe an algorithm of MIS for fibular plating and compare the radiographic restoration of fibular anatomy, functional outcomes, and complications between ORIF and MIS for ankle fractures. METHODS: This retrospective study included 71 patients with AO/OTA 44-B ankle fractures treated by a single surgeon. ORIF group consisted of 34 patients (54.5-month follow-up) and MIS group was composed of 37 patients (55.9-month follow-up). Among 37 MIS patients, 13 patients were treated with minimally invasive percutaneous plate osteosynthesis and 24 patients with minimally invasive trans-fracture approach according to our MIS algorithm. Operative outcomes were evaluated and compared between the 2 groups by radiographic measurements, functional assessment, and complications. RESULTS: The MIS group had less blood loss but longer operative time and greater exposure to fluoroscopy. Radiographic measurements revealed similar union time, fibular length, talocrural angle, medial clear space, and tibiofibular clear space in both groups. Lower visual analogue pain score was observed in the MIS group in the early postoperative period. At last follow-up, there were no significant differences regarding pain score, American Orthopaedic Foot & Ankle Society ankle-hindfoot score, and range of motion between the 2 groups. Total complication rate was significantly higher in the ORIF group. CONCLUSION: Patients with AO/OTA 44-B fractures treated with MIS fibular plating achieved similar radiographic and functional outcomes but had less pain in the early postoperative period and fewer wound complications compared with those treated with ORIF. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 26740309 TI - From infancy to aging: Biological and behavioral modifiers of Fetuin-A. AB - Fetuin-A is a multifunctional protein which inhibits ectopic calcification and insulin receptor phosphorylation. It may also promote insulin resistance by activation of toll-like receptor 4 pro-inflammatory cascade. Increased levels of Fetuin-A have been associated with obesity and related comorbidities such as type 2 diabetes and cardiovascular disease, therefore, it has been suggested as a potential therapeutic target for intervention. However, in addition to its role in disease pathophysiology, Fetuin-A is also important for growth and development. Thus, before evaluating Fetuin-A as a biomarker or pharmacological target, an understanding of Fetuin-A variability throughout the life cycle is essential. This manuscript reviews the current body of knowledge surrounding Fetuin-A throughout the life cycle and discuss challenges to studying Fetuin-A. PMID- 26740310 TI - Is painful knee an independent predictor of mortality in middle-aged women? PMID- 26740311 TI - Tracheal agenesis, a frightening scenario. AB - OBJECTIVE: This paper discusses three cases of tracheal agenesis that presented within a six-week period to the Norfolk and Norwich University Hospital. By reviewing the available literature on tracheal agenesis, the report aims to outline a protocol for future prenatal and postnatal management. METHODS: A case series and a literature review. RESULTS: Three cases of tracheal agenesis presented in the classical manner, with respiratory distress and unsuccessful intubation following delivery. A literature review confirmed that prenatal diagnosis requires future innovation; survival is rare and is predominately reliant on intubation of the oesophagus when a patent tracheoesophageal fistula is present. In most cases, tracheal agenesis represents part of the 'VATER' association: vertebral defects, anal atresia, tracheoesophageal fistula with oesophageal atresia, and radial or renal dysplasia. Complex, multiple-stage surgical procedures have been described; however, no survival to adolescence is documented. CONCLUSION: There is a call for improved prenatal diagnosis to allow both adequate counselling of parents and preparation for multi-specialty management at delivery. In addition, these cases highlight the ongoing need for improved congenital anomaly data within the UK, with currently only 49 per cent of England's births being registered. PMID- 26740313 TI - Coexistence of blaOXA-23 with armA in quinolone-resistant Acinetobacter baumannii from a Chinese university hospital. AB - A total of 101 Acinetobacter baumannii isolates were collected to determine the mechanisms of quinolone resistance and investigate the occurrence of carbapenem and high-level aminoglycoside resistance genes among quinolone-resistant strains. Among 77 quinolone-resistant A. baumannii harbored mutations of gyrA and parC, 41 isolates, which belonged to European clone II, had resistance to aminoglycosides and carbapenems due to the expression of armA and acquisition of blaOXA-23. Most of sequence type belonged to clonal complex 92. These results suggested hospital dissemination of multidrug-resistant A. baumannii carrying blaOXA-23, armA, and mutations of quinolone resistance-determining regions in western China. PMID- 26740314 TI - Paraneoplastic pemphigus as a first sign of metastatic retroperitoneal inflammatory myofibroblastic tumor: (18)F-FDG PET/CT findings. AB - A 30-year-old female presented with a 3-month history of erosive stomatitis and bullous lesions, along with recurrent episodes of abdominal pain. She was found to have a retroperitoneal lump in left lumbar region. Skin biopsy revealed bullous disorder. CT guided biopsy of the retroperitoneal mass was suggestive of inflammatory myofibroblastic tumor (IMT). She was started on oral steroids and supportive care, and surgery was being planned when she developed respiratory failure. CT chest revealed vertebral metastases. PET/CT for whole body work up revealed a left para-aortic mass along with multiple skeletal metastases. The patient was kept on conservative management. After 3 months, the patient has shown clinical improvement, and an exploratory laparotomy is now being planned for the excision of the tumor, followed by chemotherapy. This case of retroperitoneal IMT is rare in terms of skeletal metastases with paraneoplastic pemphigus. PMID- 26740316 TI - Ankle-Brachial Index and cardiovascular events in atrial fibrillation. The ARAPACIS Study. AB - Atrial fibrillation (AF) patients are at high risk for thrombotic and vascular events related to their cardiac arrhythmia and underlying systemic atherosclerosis. Ankle-Brachial Index (ABI) is a non-invasive tool in evaluating systemic atherosclerosis, useful in predicting cardiovascular events in general population; no data are available in AF patients. ARAPACIS is a prospective multicentre observational study performed by the Italian Society of Internal Medicine, analysing association between low ABI (<= 0.90) and vascular events in NVAF out- or in-patients, enrolled in 136 Italian centres. A total of 2,027 non valvular AF (NVAF) patients aged > 18 years from both sexes followed for a median time of 34.7 (interquartile range: 22.0-36.0) months, yielding a total of 4,614 patient-years of observation. Mean age was 73 +/- 10 years old with 55 % male patients. A total of 176 patients (8.7 %) experienced a vascular event, with a cumulative incidence of 3.81 %/patient-year. ABI<= 0.90 was more prevalent in patients with a vascular event compared with patients free of vascular events (32.2 vs 20.2 %, p< 0.05). On Cox proportional hazard analysis, ABI<= 0.90 was an independent predictor of vascular events (hazard ratio (HR): 1.394, 95 % confidence interval (CI): 1.042-1.866; p=0.02), vascular death (HR: 2.047, 95 % CI: 1.255-3.338; p=0.004) and MI (HR: 2.709, 95 % CI: 1.485-5.083; p=0.001). This latter association was also confirmed after excluding patients with previous MI (HR: 2.901, 95 % CI: 1.408-5.990, p=0.004). No association was observed between low ABI and stroke/transient ischaemic attack (p=0.91). In conclusion, low ABI is useful to predict MI and vascular death in NVAF patients and may independently facilitate cardiovascular risk assessment in NVAF patients. PMID- 26740317 TI - Stereochemistry of the Brivaracetam Diastereoisomers. AB - The stereochemistry of all four stereoisomers of brivaracetam was determined using vibrational circular dichroism (VCD) spectroscopy. By comparing experimentally obtained VCD spectra and computationally simulated ones, the absolute configurations can be confidently assigned without prior knowledge of their relative stereochemistry. Neither the corrected mean absolute errors analysis of the nuclear magnetic resonance (NMR) data, nor the matching of experimental and calculated infrared spectra allowed the diastereoisomers to be distinguished. VCD spectroscopy itself suffices to establish the absolute configurations of all diastereoisomers. The relative stereochemistry could also be statistically confirmed by matching experimental and computed NMR spectra using the CP3 algorithm. The combination of VCD and NMR is recommended for molecules bearing more than one chiral center, as the relative configurations obtained from NMR serve as an independent check for those established with VCD. Analysis of the calculated VCD spectra reveals that the localized NH2 scissoring mode at around 1600 cm(-1) is characteristic for intramolecular hydrogen bonding, while the orientation of the ethyl group is reflected by the delocalized modes between 1150 and 1050 cm(-1). PMID- 26740321 TI - Characterization of carbapenem-resistant Escherichia coli and Klebsiella pneumoniae from a healthcare region in Hong Kong. AB - Carbapenem-resistant Enterobacteriaceae represents a major public health issue. This study investigated the clonality and resistance mechanisms of 92 carbapenem resistant E. coli (n = 21) and K. pneumoniae (n = 71) isolates collected consecutively from clinical specimens and patients at high risk of carriage between 2010 and 2012 in a healthcare region in Hong Kong. Combined disk tests (CDTs) and the Carba NP test were used for phenotypic detection of carbapenemases. PCR assays were used to detect carbapenemase genes. All isolates were intermediate or resistant to at least one carbapenem. Nine (9.8 %) isolates were genotypic carbapenemase producers and included six K. pneumoniae (one ST1306/bla IMP-4, one ST889/bla IMP-4, two ST11/bla KPC-2, one ST258/bla KPC-2, one ST483/bla NDM-1) and three E. coli (one ST131/bla IMP-4, two ST744/ bla NDM 1) isolates. All nine isolates carrying carbapenemase genes could be detected by the CDTs and the Carba NP test. PCR identified bla CTX-M and bla AmpC alone or in combination in 77.8 % (7/9) and 96.4 % (80/83) of the carbapenemase-producers and non-producers, respectively. Porin loss was detected in 22.2 % (2/9) and 59.0 % (49/83) of the carbapenemase-producers and non-producers, respectively. Overall, the E. coli clones were diverse (14 different STs), but 36.6 % (26/71) of the K. pneumoniae isolates belonged to ST11. In conclusion, the prevalence of carbapenemases among carbapenem-nonsusceptible E. coli and K. pneumoniae remained low in Hong Kong. Porin loss combined with AmpC and/or CTX-M type ESBL was the major mechanism of carbapenem resistance in the study population. PMID- 26740318 TI - Escitalopram reversed the traumatic stress-induced depressed and anxiety-like symptoms but not the deficits of fear memory. AB - RATIONALE: Posttraumatic stress disorder (PTSD) is a trauma-induced mental disorder characterised by fear extinction dysfunction in which fear circuit monoamines are possibly associated. PTSD often coexists with depressive/anxiety symptoms, and selective serotonin reuptake inhibitors (SSRIs) are recommended to treat PTSD. However, therapeutic mechanisms of SSRIs underlying the PTSD fear symptoms remain unclear. OBJECTIVES: Using a rodent PTSD model, we examined the effects of early SSRI intervention in mood and fear dysfunctions with associated changes of monoamines within the fear circuit areas. METHODS: A 14-day escitalopram (ESC) regimen (5 mg/kg/day) was undertaken in two separate experiments in rats which previously received a protocol of single prolonged stress (SPS). In experiment 1, sucrose preference and elevated T-maze were used to index anhedonia depression and avoidance/escape anxiety profiles. In experiment 2, the percentage of freezing time was measured in a 3-day fear conditioning paradigm. At the end of our study, tissue levels of serotonin (5-HT) in the medial prefrontal cortex, amygdala, hippocampus, and striatum were measured in experiment 1, and the efflux levels of infralimbic (IL) monoamines were measured in experiment 2. RESULTS: In experiment 1, ESC corrected both behavioural (depression/anxiety) and neurochemical (reduced 5-HT tissue levels in amygdala/hippocampus) abnormalities. In experiment 2, ESC was unable to correct the SPS-impaired retrieval of fear extinction. In IL, ESC increased the efflux level of 5-HT but failed to reverse SPS-reduced dopamine (DA) and noradrenaline (NA). CONCLUSIONS: PTSD-induced mood dysfunction is psychopathologically different from PTSD-induced fear disruption in terms of disequilibrium of monoamines within the fear circuit areas. PMID- 26740322 TI - Comprehensive real-time epidemiological data from respiratory infections in Finland between 2010 and 2014 obtained from an automated and multianalyte mariPOC(r) respiratory pathogen test. AB - Respiratory viruses cause seasonal epidemics every year. Several respiratory pathogens are circulating simultaneously and typical symptoms of different respiratory infections are alike, meaning it is challenging to identify and diagnose different respiratory pathogens based on symptoms alone. mariPOC(r) is an automated, multianalyte antigen test which allows the rapid detection of nine respiratory infection pathogens [influenza A and B viruses, respiratory syncytial virus (RSV), human metapneumovirus, adenovirus, parainfluenza 1-3 viruses and pneumococci] from a single nasopharyngeal swab or aspirate samples, and, in addition, can be linked to laboratory information systems. During the study period from November 2010 to June 2014, a total of 22,485 multianalyte respi tests were performed in the 14 participating laboratories in Finland and, in total, 6897 positive analyte results were recorded. Of the tested samples, 25 % were positive for one respiratory pathogen, with RSV (9.8 %) and influenza A virus (7.2 %) being the most common findings, and 0.65 % of the samples were multivirus-positive. Only small geographical variations in seasonal epidemics occurred. Our results show that the mariPOC(r) multianalyte respi test allows simultaneous detection of several respiratory pathogens in real time. The results are reliable and give the clinician a picture of the current epidemiological situation, thus minimising guesswork. PMID- 26740324 TI - Epidemiology of urinary tract infections, bacterial species and resistances in primary care in France. AB - General practitioners often have to manage urinary tract infections (UTI) with probabilistic treatments, although bacterial resistances are increasing. Therefore, the French Society of Infectious Diseases published new guidelines in 2014. The aim of this study was to investigate the bacterial epidemiology of UTI in the general population in primary care and analyse risk factors for Escherichia coli resistance to antibiotics. A cross-sectional study was conducted in 12 ambulatory laboratories. Patients over 18 years of age coming for urinalysis were included. Risk factors for UTI were collected using a questionnaire and the laboratory records. Bacteria meeting criteria for UTI were analysed. A positive urinalysis was found in 1119 patients, corresponding to 1125 bacterial isolates. The bacterial species were: E. coli (73 %), Enterococcus spp. (7 %), Klebsiella spp. (6 %), Proteus spp. (4 %), Staphylococcus spp. (3 %) and Pseudomonas spp. (2 %). Regardless of the bacteria, the most common resistance was that to co-trimoxazole: 27 % (95 % confidence interval [CI] = [0.24; 0.30]), followed by ofloxacin resistance: 16 % [0.14; 0.18]. Escherichia coli resistances to co-trimoxazole, ofloxacin, cefixime, nitrofurantoin and fosfomycin were, respectively, 25.5 % [0.23; 0.28], 17 % [0.14; 0.20], 5.6 % [0.04; 0.07], 2.2 % [0.01; 0.03] and 1.2 % [0.005; 0.02]. Independent risk factors for E. coli resistance to ofloxacin were age over 85 years (odds ratio [OR] = 3.08; [1.61; 5.87]) and a history of UTI in the last 6 months (OR = 2.34; [1.54; 3.52]). Our findings support the guidelines recommending fluoroquinolone sparing. The scarcity of E. coli resistance to fosfomycin justifies its use as a first-line treatment in acute cystitis. These results should be reassessed in a few years to identify changes in the bacterial epidemiology of UTI. PMID- 26740323 TI - Long-term efficacy of microbiology-driven periodontal laser-assisted therapy. AB - Periodontitis represents a highly prevalent health problem, causing severe functional impairment, reduced quality of life and increased risk of systemic disorders, including respiratory, cardiovascular and osteoarticular diseases, diabetes and fertility problems. It is a typical example of a multifactorial disease, where a polymicrobial infection inducing chronic inflammation of periodontal tissues is favoured by environmental factors, life style and genetic background. Since periodontal pathogens can colonise poorly vascularised niches, antiseptics and antibiotics are typically associated with local treatments to manage the defects, with unstable outcomes especially in early-onset cases. Here, the results of a retrospective study are reported, evaluating the efficacy of a protocol (Periodontal Biological Laser-Assisted Therapy, PerioblastTM) by which microbial profiling of periodontal pockets is used to determine the extent and duration of local neodymium-doped yttrium aluminium garnet (Nd:YAG) laser irradiation plus conventional treatment. The protocol was applied multicentrically on 2683 patients, and found to produce a significant and enduring improvement of all clinical and bacteriological parameters, even in aggressive cases. Microbiome sequencing of selected pockets revealed major population shifts after treatment, as well as strains potentially associated with periodontitis in the absence of known pathogens. This study, conducted for the first time on such a large series, clearly demonstrates long-term efficacy of microbiology-driven non-invasive treatment of periodontal disease. PMID- 26740325 TI - Acute Bartholin's abscess: microbial spectrum, patient characteristics, clinical manifestation, and surgical outcomes. AB - The purpose of this investigation was to evaluate the patient characteristics, clinical manifestations, microbiology, and modes of treatment of a large cohort of women with acute Bartholin's abscess, from a single medical center. A retrospective study was undertaken of all women diagnosed with acute Bartholin's gland abscess who were admitted to the gynecology department in a university affiliated tertiary hospital in central Israel from January 2004 to December 2013. A total of 267 women were included in the study. The mean age at diagnosis was 33.5 +/- 12.1 years and the mean hospitalization period was 1.4 +/- 0.9 days. Pain presented in 152 (56.9 %), swelling in 81 (30.3 %), and fever in 34 (12.7 %). Leukocytosis was detected in 149 (55.8 %). The three main treatment modalities were: antibiotics (75.7 %), abscess drainage (19.1 %), and marsupialization (80.9 %). Bacterial infections were detected in 154 (57.7 %) cultures, Escherichia coli presented in 59 (22.1 %), and Streptococcus species in 27 (10.1 %). The clinical and patient characteristics were similar between women with bacterial and sterile Bartholin's abscesses, though leukocytosis was more prevalent among women with bacterial infections. E. coli was the single most frequent pathogen in cultures of acute Bartholin's abscess. Respiratory tract associated organisms were also common. This study indicates the polymicrobial spectrum of acute Bartholin's abscess. PMID- 26740326 TI - UV-Visible Absorption Spectroscopy Enhanced X-ray Crystallography at Synchrotron and X-ray Free Electron Laser Sources. AB - This review describes the use of single crystal UV-Visible Absorption micro Spectrophotometry (UV-Vis AS) to enhance the design and execution of X-ray crystallography experiments for structural investigations of reaction intermediates of redox active and photosensitive proteins. Considerations for UV Vis AS measurements at the synchrotron and associated instrumentation are described. UV-Vis AS is useful to verify the intermediate state of an enzyme and to monitor the progression of reactions within crystals. Radiation induced redox changes within protein crystals may be monitored to devise effective diffraction data collection strategies. An overview of the specific effects of radiation damage on macromolecular crystals is presented along with data collection strategies that minimize these effects by combining data from multiple crystals used at the synchrotron and with the X-ray free electron laser. PMID- 26740327 TI - Applications of "Tender" Energy (1-5 keV) X-ray Absorption Spectroscopy in Life Sciences. AB - The "tender" energy range of 1 to 5 keV, between the energy ranges of most "hard" (>5 keV) and "soft" (<1 keV) synchrotron X-ray facilities, offers some unique opportunities for synchrotron- based X-ray absorption fine structure spectroscopy in life sciences. In particular the K absorption edges of Na through Ca offer opportunities to study local structure, speciation, and chemistry of many important biological compounds, structures and processes. This is an area of largely untapped science, in part due to a scarcity of optimized facilities. Such measurements also entail unique experimental challenges. This brief review describes the technique, its experimental challenges, recent progress in development of microbeam measurement capabilities, and several highlights illustrating applications in life sciences. PMID- 26740328 TI - MBL2 genetic polymorphisms and HIV-1 mother-to-child transmission in Zambia. AB - Since antiretroviral drugs have been introduced to prevent mother-to-child transmission, the risk of HIV-1 infection in infants has decreased considerably worldwide. Nevertheless, many factors are involved in viral transmission and host susceptibility to infection. The immune system and its components, including mannose binding protein C (encoding by MBL2 gene), are already known to play an important role in this scenario. In the present study, 313 children and 98 of their mothers from Zambia were genotyped for the MBL2 promoter HL (rs11003125) and XY (rs7096206) polymorphisms and exon 1 D (rs5030737, at codon 52) B (rs1800450, at codon 54) and C (rs1800451, at codon 57) polymorphisms in order to investigate the potential role of these genetic variants in HIV-1 mother-to-child transmission. No statistical significant association was observed comparing transmitter and non-transmitter mothers and also confronting HIV-positive and HIV negative children. The findings of the current study obtained on mother and children from Zambia evidence lack of association between MBL2 functional polymorphisms and HIV-1 mother-to-child transmission. PMID- 26740329 TI - Cloning and characterizing of the murine IRF-3 gene promoter region. AB - The interferon regulatory factor 3 (IRF-3) plays essential roles in inflammation and immune response. Here, we cloned the nucleotide sequence of the 5'-flanking region of the murine IRF-3 gene (mIRF-3) and characterized the molecular mechanisms controlling the mIRF-3 transcriptional activity in NIH3T3 cells. Analyses of a series of 5' deletion constructs demonstrated that a 301 bp region (-255/+46) of the mIRF-3 gene is sufficient for full promoter activity. This region contains IK1, Egr2, Cmyb, E2F1 and YY1 putative transcription factor binding sites. Mutation of Egr2 or YY1 site led to 52-68 % decrease of the mIRF-3 promoter activity, and double Egr2 and YY1 mutation reduced the promoter activity to 20 % of the wild-type promoter activity. Furthermore, knockingdown of endogenous Egr2 or YY1 by a siRNA strategy markedly inhibited the mIRF-3 promoter activity. Chromatin immunoprecipitation assays showed that Egr2 and YY1 interact with the mIRF-3 promoter in vivo. These results suggested that the basal promoter activity of the mIRF-3 gene is regulated by transcription factors Egr2 and YY1 in NIH3T3 cells. PMID- 26740332 TI - Fluorescent DNA probes at liquid/liquid interfaces studied by surface second harmonic generation. AB - The properties of a series of oxazole yellow dyes, including the dicationic YOPRO 1 and its homodimeric parent YOYO-1 and two monocationic dyes (YOSAC-1 and YOSAC 3), have been investigated at the dodecane/water interface using stationary and time-resolved surface second harmonic generation (SSHG) combined with quantum chemical calculations. Whereas YOYO-1 exists predominantly as a H-dimer in aqueous solution, the stationary SSHG spectra reveal that such dimers are not formed at the interface. No significant H-aggregation was observed with YOPRO-1, neither in solution nor at the interface. In the case of the monocationic YOSAC dyes, a distinct SSHG band due to H-aggregates was measured at the interface, whereas only weak aggregation was found in solution. These distinct aggregation behaviors can be explained by the different orientations of the dyes at the interface, as revealed from the analysis of polarization-resolved experiments, the doubly-charged dyes lying more flat on the interface than the singly charged ones. Although YOYO-1 and YOPRO-1 do not form H-dimer/aggregates at the interface, time-resolved SSHG measurements point to the occurrence of intra- and intermolecular interactions, respectively, which inhibit the ultrafast non radiative decay of the excited dyes via large amplitude motion, and lead to a nanosecond excited-state lifetime. The distinct behavior evidenced here for YOYO 1 and YOSAC dyes points to their potential use as fluorescent or SHG interfacial probes. PMID- 26740330 TI - Tumoral NKG2D alters cell cycle of acute myeloid leukemic cells and reduces NK cell-mediated immune surveillance. AB - The stimulatory natural killer group 2 member D (NKG2D) lymphocyte receptor, initially discovered and expressed mostly on natural killer (NK) cells, T cells and natural killer T cells, can promote tumor immune surveillance. However, with increasing tumor grade, tumors themselves express NKG2D to self-stimulate oncogenic pathways. To confirm that cancer cells themselves express NKG2D, we have now investigated the role of the tumoral NKG2D in NK cell-mediated immune surveillance. Both anti-NKG2D and shRNA to that down-regulated tumoral NKG2D increased the number of cells in G1 phase and S phase, increased the expression of cyclin E-CDK2 and decreased P21. In addition, CD107a, IFN-gamma and TNF-alpha increased when the cells were treated with anti-NKG2D which suggests that blocking tumoral NKG2D could augment tumor surveillance of NK cells. Altogether, tumoral NKG2D stimulates cell propagation and immune escape in acute myeloid leukemia cells. PMID- 26740333 TI - Fluorescent PET probes based on perylene-3,4,9,10-tetracarboxylic tetraesters. AB - Perylene-3,4,9,10-tetracarboxylic tetraester-based fluorescent PET probes with aniline receptors attached either at the peri- or the bay-positions have been synthesized. By attaching aniline receptors at the bay position, pH-sensitive "light-up" probes, with fluorescence quantum yields PhiF > 0.75 and fluorescent enhancements FE > 500 in ethanol, have been obtained. PMID- 26740335 TI - Light scattering of rectangular slot antennas: parallel magnetic vector vs perpendicular electric vector. AB - We study light scattering off rectangular slot nano antennas on a metal film varying incident polarization and incident angle, to examine which field vector of light is more important: electric vector perpendicular to, versus magnetic vector parallel to the long axis of the rectangle. While vector Babinet's principle would prefer magnetic field along the long axis for optimizing slot antenna function, convention and intuition most often refer to the electric field perpendicular to it. Here, we demonstrate experimentally that in accordance with vector Babinet's principle, the incident magnetic vector parallel to the long axis is the dominant component, with the perpendicular incident electric field making a small contribution of the factor of 1/|epsilon|, the reciprocal of the absolute value of the dielectric constant of the metal, owing to the non perfectness of metals at optical frequencies. PMID- 26740336 TI - Combination therapy of renin-angiotensin system inhibitors plus calcium channel blockers versus other two-drug combinations for hypertension: a systematic review and meta-analysis. AB - Many randomized clinical trials (RCTs) have investigated the efficacy and safety of renin-angiotensin system inhibitors (RASIs) plus calcium channel blockers (CCBs), compared with other two-drug combinations, but systematic assessment in this aspect is still lacking. We carried out the present meta-analysis of randomized controlled trials to evaluate the long-term effect and safety of RASIs plus CCBs. Literatures were searched in MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials in September 2014. A fixed-effect model was used to estimate the pooled effect of trials identified. Thirty-four trials with 41 694 patients were included. Compared with RASIs plus diuretics, RASIs plus CCBs decreased total cardiovascular (CV) events (relative risk (RR) 0.82, 95% confidence interval (CI): 0.75, 0.91, adjusted RR (ARR) 1.7%) and withdrawals due to adverse effect (WDAE) (RR 0.87, 95% CI: 0.80, 0.94, ARR 1.3%). Compared with CCBs plus diuretics, RASIs plus CCBs decreased WDAE (RR 0.63, 95% CI: 0.45, 0.90, ARR 1.1%). Our meta-analysis indicates that RASIs plus CCBs provide a superior safety and prevention of CV events to RASIs plus diuretics, whereas this combination is also safer than CCBs plus diuretics. We also raise a new hypothesis. More high-quality RCTs focused on hard end points with CV, cerebrovascular and renal events are needed to confirm the hypothesis we have brought out. PMID- 26740337 TI - Renal and cardiovascular risk predictive value of two different microalbuminuria screening methods in patients with hypertension with/without diabetes in Portugal. AB - MicRoAlbuminuria sCreening survEy (RACE) was a multicentre, observational, cross sectional study conducted in primary health-care settings of Portugal. Here, we present a post-hoc analysis from the RACE study, assessing the renal and cardiovascular (CV) risk predictive value of two different microalbuminuria (MA) screening methods, nephelometry with 24-h urine (MA-24 h) and Micral test with occasional urine (MicralA) in patients with hypertension (HTN) with/without type 2 diabetes mellitus (T2DM). Out of 3065 patients, 1173 (38.3%) were in the HTN group without T2DM (HTN) and 1892 (61.7%) in the HTN group with T2DM (HTN+T2DM). The overall prevalence of MA was 50.6% determined by MicralA and 22.1% with MA-24 h. Urinary albumin excretion data obtained by both techniques correlated significantly (rs=0.586; P<0.001). In all subjects, MicralA showed a sensitivity of 93%, specificity of 62% for detection of MA, with a positive predictive value of 41% and negative predictive value of 97%. With both methods, the presence of MA was independently associated with a higher risk (1.5- to 2.9-fold) of CV and renal organ damage in both HTN and HTN+T2DM groups. MicralA, due to its high sensitivity and negative predictive value, can be considered as a valid and reliable method for MA screening in patients with HTN with/without T2DM. PMID- 26740338 TI - Cardiac autonomic neuropathy risk estimated by sudomotor function and arterial stiffness in Chinese subjects. AB - The SUDOSCAN test was recently developed to detect diabetic autonomic neuropathy early and screen for cardiac autonomic neuropathy (CAN) through assessment of sudomotor function. The aim of this study was to investigate the relationship of cardiac autonomic dysfunction estimated by the SUDOSCAN test with arterial stiffness. A total of 4019 subjects without diabetes or established cardiovascular disease were tested with SUDOSCAN, central systolic blood pressure (cSBP) and brachial-ankle pulse wave velocity (baPWV). Hands mean electrochemical skin conductance (ESC) measured by SUDOSCAN was 70+/-17 MUS, feet mean ESC was 71+/-16 MUS and the CAN risk score was 21+/-10%. The levels of cSBP and baPWV increased across quartiles of CAN risk score (P for trend <0.001 for all). In spearman correlation analyses, the CAN risk score was positively correlated with cSBP (r=0.391, P<0.001) and baPWV (r=0.305, P<0.001). In multivariable analyses, the values of cSBP and baPWV increased 0.17 mm Hg (P=0.002) and 2.01 cm per second (P=0.010), respectively, when CAN risk score increased 1%. The results were unchanged when stratified by glucose tolerance status. In conclusion, cardiac autonomic dysfunction estimated by sudomotor function was correlated with arterial stiffness independent of conventional factors and glucose tolerance status. PMID- 26740339 TI - Parenteral dosage form development and testing of dimethyl trisulfide, as an antidote candidate to combat cyanide intoxication. AB - This study focused on the solubility enhancement and the in vivo antidotal efficacy testing of a new potential cyanide (CN) countermeasure, dimethyl trisulfide (DMTS). Various FDA approved cyclodextrins (HPbetaCD, RMbetaCD, HPgammaCD), cosolvents (ethanol, polyethylene glycols, propylene glycol), surfactants (cremophor EL, cremophor RH 40, sodium cholate, sodium deoxycholate, polysorbate 80) and their combinations were applied. Based on the solubility enhancing potential of the tested systems, polysorbate 80 was chosen for further in vivo efficacy studies. A composition comprising 15% polysorbate 80 and 50 mg/ml DMTS with the applied DMTS dose of 100 mg/kg provided a therapeutic antidotal protection of 3.4 * LD50. For comparison, the present therapy of sodium thiosulfate (TS) with the dose of 100 mg/kg provided only 1.1 * LD50 protection, and at the dose of 200 mg/kg, the LD50 was enhanced by 1.3 times. No difference in the therapeutic protection by DMTS was detected when the concentration of polysorbate 80 was increased to 20% (3.2 * LD50 protection). These data demonstrate the potential importance of DMTS as a CN countermeasure, and the formulation comprising polysorbate 80 provides the base of an injectable intramuscular dosage form that can later serve as a CN antidotal kit suitable for mass scenario. PMID- 26740341 TI - Improving the MR Imaging Sensitivity of Upconversion Nanoparticles by an Internal and External Incorporation of the Gd(3+) Strategy for in Vivo Tumor-Targeted Imaging. AB - Gd(3+)-ion-doped upconversion nanoparticles (UCNPs), integrating the advantages of upconversion luminescence and magnetic resonance imaging (MRI) modalities, are capturing increasing attention because they are promising to improve the accuracy of diagnosis. The embedded Gd(3+) ions in UCNPs, however, have an indistinct MRI enhancement owing to the inefficient exchange of magnetic fields with the surrounding water protons. In this study, a novel approach is developed to improve the MR imaging sensitivity of Gd(3+)-ion-doped UCNPs. Bovine serum albumin (BSA) bundled with DTPA-Gd(3+) (DTPA(Gd)) is synthesized both as the MR imaging sensitivity synergist and phase-transfer ligand for the surface engineering of UCNPs. The external Gd(3+) ion attachment strategy is found to significant improve the MR imaging sensitivity of Gd(3+)-ion-doped UCNPs. The relaxivity analysis shows that UCNPs@BSA.DTPA(Gd) exhibit higher relaxivity values than do UCNPs@BSA without DTPA(Gd) moieties. Another relaxivity study discloses a striking message that the relaxivity value does not always reflect the realistic MRI enhancement capability. The high concentration of Gd(3+)-ion containing UCNPs with further surface-engineered BSA.DTPA(Gd) (denoted as UCNPs H@BSA.DTPA(Gd)) exhibits a more pronounced MRI enhancement capability compared to the other two counterparts [UCNPs-N@BSA.DTPA(Gd) and UCNPs-L@BSA.DTPA(Gd) (-N and -L are denoted as zero and low concentrations of Gd(3+) ion doping, respectively)], even though it holds the lowest r1 of 1.56 s(-1) per mmol L(-1) of Gd(3+). The physicochemical properties of UCNPs are essentially maintained after BSA.DTPA(Gd) surface decoration with good colloidal stability, in addition to improving the MR imaging sensitivity. In vivo T1-weighted MRI shows potent tumor-enhanced MRI with UCNPs-H@BSA.DTPA(Gd). An in vivo biodistribution study indicates that it is gradually excreted from the body via hepatobiliary and renal processing with no obvious toxicity. It could therefore be concluded, with improved MR imaging sensitivity by an internal and external incorporation of Gd(3+) strategy, that UCNPs-H@BSA.DTPA(Gd) presents great potential as an alternative in tumor-targeted MR imaging. PMID- 26740342 TI - Can peer support be effective online? PMID- 26740340 TI - An authenticity survey of herbal medicines from markets in China using DNA barcoding. AB - Adulterant herbal materials are a threat to consumer safety. In this study, we used DNA barcoding to investigate the proportions and varieties of adulterant species in traditional Chinese medicine (TCM) markets. We used a DNA barcode database of TCM (TCMD) that was established by our group to investigate 1436 samples representing 295 medicinal species from 7 primary TCM markets in China. The results indicate that ITS2 barcodes could be generated for most of the samples (87.7%) using a standard protocol. Of the 1260 samples, approximately 4.2% were identified as adulterants. The adulterant focused on medicinal species such as Ginseng Radix et Rhizoma (Renshen), Radix Rubi Parvifolii (Maomeigen), Dalbergiae odoriferae Lignum (Jiangxiang), Acori Tatarinowii Rhizoma (Shichangpu), Inulae Flos (Xuanfuhua), Lonicerae Japonicae Flos (Jinyinhua), Acanthopanacis Cortex (Wujiapi) and Bupleuri Radix (Chaihu). The survey revealed that adulterant species are present in the Chinese market, and these adulterants pose a risk to consumer health. Thus, regulatory measures should be adopted immediately. We suggest that a traceable platform based on DNA barcode sequences be established for TCM market supervision. PMID- 26740343 TI - Why cancer screening has never been shown to "save lives"--and what we can do about it. PMID- 26740344 TI - Longitudinal associations of active commuting with wellbeing and sickness absence. AB - OBJECTIVE: Our aim was to explore longitudinal associations of active commuting (cycling to work and walking to work) with physical wellbeing (PCS-8), mental wellbeing (MCS-8) and sickness absence. METHOD: We used data from the Commuting and Health in Cambridge study (2009 to 2012; n=801) to test associations between: a) maintenance of cycling (or walking) to work over a one year period and indices of wellbeing at the end of that one year period; and b) associations between change in cycling (or walking) to work and change in indices of wellbeing. Linear regression was used for testing associations with PCS-8 and MCS-8, and negative binomial regression for sickness absence. RESULTS: After adjusting for sociodemographic variables, physical activity and physical limitation, those who maintained cycle commuting reported lower sickness absence (0.46, 95% CI: 0.14 0.80; equivalent to one less day per year) and higher MCS-8 scores (1.50, 0.10 2.10) than those who did not cycle to work. The association for sickness absence persisted after adjustment for baseline sickness absence. No significant associations were observed for PCS-8. Associations between change in cycle commuting and change in indices of wellbeing were not significant. No significant associations were observed for walking. CONCLUSIONS: This work provides some evidence of the value of cycle commuting in improving or maintaining the health and wellbeing of adults of working age. This may be important in engaging employers in the promotion of active travel and communicating the benefits of active travel to employees. PMID- 26740345 TI - Concurrent lifestyle risk factors: Clusters and determinants in an Australian sample. AB - OBJECTIVE: To examine clustering among three major lifestyle risk factors for chronic disease (smoking, alcohol, and physical inactivity) and define sociodemographic subgroups with elevated risks of multiple lifestyle risk factors. METHOD: Data on 6052 adults aged 28-32, 48-52, and 68-72 from wave 3 (2007-2010) of the PATH Through Life Cohort Study, Australia, were used to estimate prevalence of individual and combinations of risk factors, and multinomial regression analysis undertaken to examine demographic factors associated with number of risks. RESULTS: Clustering of risks varied by age and gender, with more people than expected having none or all of the risk factors. Smoking clustered with harmful alcohol use, as well as physical inactivity. No relationship was observed between physical inactivity and alcohol use. Several sociodemographic characteristics were associated with the number of lifestyle risk factors including partner status, gender, age, education, and physical and mental health related quality of life. CONCLUSIONS: The tendency for lifestyle risk factors to aggregate in different subgroups has meaningful implications for health promotion strategies. Better insight in the more vulnerable subpopulations that are at higher risk of displaying multiple lifestyle risk factors is of importance if we wish to reduce the population propensity for chronic disease. PMID- 26740346 TI - A community based primary prevention programme for type 2 diabetes integrating identification and lifestyle intervention for prevention: the Let's Prevent Diabetes cluster randomised controlled trial. AB - OBJECTIVES: Prevention of type 2 diabetes (T2DM) is a priority in healthcare, but there is a lack of evidence investigating how to effectively translate prevention research into a UK primary care setting. We assessed whether a structured education programme targeting lifestyle and behaviour change was effective at preventing progression to T2DM in people with pre-diabetes. MATERIALS AND METHODS: Forty-four general practices were randomised to receive either standard care or a 6hour group structured education programme with an annual refresher course, and regular phone contact. Participants were followed up for 3years. The primary outcome was progression to T2DM. RESULTS: Eight hundred and eighty participants were included (36% female, mean age 64years, 16% ethnic minority group); 131 participants developed T2DM. There was a non-significant 26% reduced risk of developing T2DM in the intervention arm compared to standard care (HR 0.74, 95% CI 0.48, 1.14, p=0.18). The reduction in T2DM risk when excluding those who did not attend the initial education session was also non-significant (HR 0.65, 0.41, 1.03, p=0.07). There were statistically significant improvements in HbA1c (-0.06, -0.11, -0.01), LDL cholesterol (-0.08, -0.15, -0.01), sedentary time (-26.29, -45.26, -7.32) and step count (498.15, 162.10, 834.20) when data were analysed across all time points. CONCLUSIONS: This study suggests that a relatively low resource, pragmatic diabetes prevention programme resulted in modest benefits to biomedical, lifestyle and psychosocial outcomes, however the reduction to the risk of T2DM did not reach significance. The findings have important implications for future research and primary care. PMID- 26740347 TI - The association between participation in a pay-for-performance program and macrovascular complications in patients with type 2 diabetes in Taiwan: A nationwide population-based cohort study. AB - OBJECTIVE: Diabetes and diabetes-related complications are major causes of morbidity and mortality worldwide and contribute substantially to health care costs. Proper care can prevent or delay vascular complications in people with type 2 diabetes. We sought to examine whether a diabetes pay-for-performance (P4P) program under Taiwan's National Health Insurance program decreased risk of macrovascular complications in type 2 diabetes patients, and associated risk factors. RESEARCH DESIGN AND METHOD: We conducted a longitudinal observational case and control cohort study using two nationwide population-based databases in Taiwan, 2007-2012. Type 2 diabetes patients with a primary diabetes diagnosis in year 2007 and 2008 were included. We excluded patients with any diabetes complications within 2years before the index date. A propensity score matching approach was used to determine comparable P4P and non-P4P groups. We followed each P4P and non-P4P patient until December 31, 2012. Complication incidence rates per 1000 person-years for each complication were calculated. RESULTS: Overall, our results indicated that P4P patients had lower risk of macrovascular complications than non-P4P patients. Specifically, hazard ratios (95% confidence intervals) were 0.84 (0.80-0.88) for stroke, 0.83 (0.75-0.92) for myocardial infarction, 0.72 (0.60-0.85) for atrial fibrillation, 0.93 (0.87-0.98) for heart failure, 0.61 (0.50-0.73) for gangrene, and 0.83 (0.74-0.93) for ulcer of lower limbs. CONCLUSIONS: Compared with patients not enrolled in the P4P program, P4P patients had lower risk of developing serious vascular complications. Our empirical findings provide evidence for the potential long-term benefit of P4P programs in reducing risks of macrovascular complications. PMID- 26740348 TI - Educational attainment and the clustering of health-related behavior among U.S. young adults. AB - OBJECTIVE: We documented health-related behavior clustering among US young adults and assessed the extent to which educational attainment was associated with the identified clusters. METHODS: Using data from Wave IV of the National Longitudinal Study of Adolescent to Adult Health (Add Health), we performed latent class analysis on 8 health-related behaviors (n=14,338), documenting clustering of behavior separately by gender. Subsequently, we used multinomial logistic regression and estimated associations between educational attainment and the health-related behavior clusters. RESULTS: Twenty-eight percent of young women grouped into the most favorable health behavior cluster, while 22% grouped into a very high-risk cluster. A larger percentage of young men (40%) grouped into the highest risk cluster. Individuals with educational attainment at the college and advanced degree levels exhibited much lower risk of being in the unhealthy behavioral clusters than individuals with lower educational attainment, net of a range of confounders. CONCLUSION: Substantial fractions of US young adults, particularly those with less than college degrees, exhibit unhealthy behavior profiles. Efforts to improve health among young adults should focus particular attention on the clustering of poor health-related behavior, especially among individuals who have less than a college degree. PMID- 26740349 TI - The factors associated with toddlers' screen time change in the STEPS Study: A two-year follow-up. AB - BACKGROUND AND OBJECTIVES: Early childhood screen time seems to persist into later childhood. This study examined the factors affecting the screen time change during the first two years of toddler's lives in Finland. We hypothesized that parents' sedentary behaviour and physical activity habits correlate significantly with children's screen time change. METHODS: The data consists of 1797 mothers, 1658 fathers and their 1827 children from the STEPS Study (Steps to the healthy development) in Southwest Finland. Screen time change during the two-year follow up was calculated for those (n=634) who had both 13 and 36months screen time measures (13months, n=940; 36months, n=845). Demographic correlates and parental behavioural correlates were measured with questionnaires, and anthropometric measurements in study visits. RESULTS: The mean change in the children's screen time was a 55min increase from 13 to 36months. A linear mixed model analysis showed that the father's longer duration of sitting time was statistically significantly associated with a smaller increase in screen time of the child. Parents' physical activity was not associated with children's screen time change. The mother's advanced education, a younger age, and a lower screen time, the child attending day care and the child's lower body mass index were associated with children's smaller increase in screen time. CONCLUSION: The mother's advanced education as well as the father's sitting time, including sitting at the office, implied that children of higher educated parents have a smaller increase in screen time. Future studies should focus on studying why parental education has a greater influence on children's screen time change than parents' behaviour. PMID- 26740350 TI - Immediate loading of implants inserted in edentulous arches using multiple mucosa supported stereolithographic surgical templates: a 10-year prospective cohort study. AB - The purpose of this prospective study was to evaluate survival and marginal bone loss at 10-year follow-up of implants inserted in completely edentulous arches and immediately loaded using multiple mucosa-supported stereolithographic surgical templates. The influence on marginal bone loss of the following variables was evaluated: sex, smoking habit, arch, implant position, implant diameter, and implant length. Prosthesis survival and success were also determined. STROBE guidelines were followed. One hundred and eighty-eight implants were inserted in 16 consecutively selected patients using a prefabricated metal-reinforced full-arch provisional acrylic restoration. The definitive metal-ceramic full-arch prosthesis was delivered within 2 weeks. Kappa statistics, two-way analysis of variance (ANOVA) with Bonferroni adjusted post hoc test, one-way ANOVA with Tukey's range test, and unpaired Student t-tests were used for the analysis. Four implants failed during the first year of function (maxilla 3, mandible 1), leading to a 10-year survival rate of 97.9%. The mean marginal bone loss after 10 years was 0.76 mm. The marginal bone changes were found not to be influenced significantly by the variables evaluated (P > 0.05). The prosthetic success rate was 66.7%; no prosthesis failures occurred. In conclusion the technique described is a predictable treatment option with high survival in the long-term follow-up. PMID- 26740351 TI - Juvenile ossifying fibroma of the jaw: a retrospective study of 15 cases. AB - The management of patients with juvenile ossifying fibroma (JOF) remains controversial. To explore the correlations between different treatments and the patient prognosis, 15 cases of JOF of the jaw were reviewed. Five patients were male and 10 were female. Patient age at the time of disease onset ranged from 7 to 18 years (mean 10.9 years). Nine tumours were located in mandible and six in the maxilla. These cases typically manifested clinically as painless swelling of the jaw (9/15, 60%); 40% (6/15) of the cases were associated with pain, diplopia, stuffy nose, and/or rapid growth. Images of JOF can show a radiolucent, mixed, or ground glass-like appearance. Pathological examinations revealed 10 cases of juvenile trabecular ossifying fibroma (JTOF) and five cases of juvenile psammomatoid ossifying fibroma (JPOF). In terms of the treatment plan, six patients initially received radical surgery; nine patients underwent conservative treatment, among whom six (6/9, 66.7%) had one or more recurrence. At the end of the follow-up period, 12 patients had no evidence of tumour recurrence and three cases were alive with a tumour. In summary, surgeons should develop the surgical plan according to the extent of the lesion, relapse status, growth rate, and family choice, and these patients should be followed up closely. PMID- 26740354 TI - Using Smartphones to Monitor Bipolar Disorder Symptoms: A Pilot Study. AB - BACKGROUND: Relapse prevention in bipolar disorder can be improved by monitoring symptoms in patients' daily life. Smartphone apps are easy-to-use, low-cost tools that can be used to assess this information. To date, few studies have examined the usefulness of smartphone data for monitoring symptoms in bipolar disorder. OBJECTIVE: We present results from a pilot test of a smartphone-based monitoring system, Social Information Monitoring for Patients with Bipolar Affective Disorder (SIMBA), that tracked daily mood, physical activity, and social communication in 13 patients. The objective of this study was to investigate whether smartphone measurements predicted clinical symptoms levels and clinical symptom change. The hypotheses that smartphone measurements are (1) negatively related to clinical depressive symptoms and (2) positively related to clinical manic symptoms were tested. METHODS: Clinical rating scales were administered to assess clinical depressive and manic symptoms. Patients used a smartphone with the monitoring app for up to 12 months. Random-coefficient multilevel models were computed to analyze the relationship between smartphone data and externally rated manic and depressive symptoms. Overall clinical symptom levels and clinical symptom changes were predicted by separating between-patient and within-patient effects. Using established clinical thresholds from the literature, marginal effect plots displayed clinical relevance of smartphone data. RESULTS: Overall symptom levels and change in clinical symptoms were related to smartphone measures. Higher overall levels of clinical depressive symptoms were predicted by lower self-reported mood measured by the smartphone (beta=-.56, P<.001). An increase in clinical depressive symptoms was predicted by a decline in social communication (ie, outgoing text messages: beta=-.28, P<.001) and a decline in physical activity as measured by the smartphone (ie, cell tower movements: beta= .11, P=.03). Higher overall levels of clinical manic symptoms were predicted by lower physical activity on the smartphone (ie, distance travelled: beta=-.37, P<.001), and higher social communication (beta=.48, P=.03). An increase in clinical manic symptoms was predicted by a decrease in physical activity on the smartphone (beta=-.17, P<.001). CONCLUSIONS: Clinical symptoms were related to some objective and subjective smartphone measurements, but not all smartphone measures predicted the occurrence of bipolar symptoms above clinical thresholds. Thus, smartphones have the potential to monitor bipolar disorder symptoms in patients' daily life. Further validation of monitoring tools in a larger sample is needed. Conclusions are limited by the low prevalence of manic and depressive symptoms in the study sample. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 05663421; http://www.controlled trials.com/ISRCTN05663421 (Archived by WebCite at http://www.webcitation.org/6d9wsibJB). PMID- 26740355 TI - Foodborne trematodes: a diverse and challenging group of neglected parasites. PMID- 26740356 TI - The importance of recognising parasite cryptic diversity for research programmes on foodborne trematodiases. AB - The development of molecular tools in the last two decades enhanced our capacity to accurately describe biodiversity on Earth. Analysis of molecular data may lead to the discovery of cryptic species (morphologically indistinguishable, genetically distinct species lineages). As cryptic species are discovered with increasing frequency among parasites, we must consider their potential implications, especially for the epidemiology, diagnostics and control of parasitic diseases that affect humans. Investigators that conduct research on different aspects of infectious diseases, for example, on foodborne trematodiases, must remain aware of the possibility for undiscovered cryptic species and how this could impact their conclusions. PMID- 26740357 TI - Gene diversity and genetic variation in lung flukes (genus Paragonimus). AB - Paragonimiasis caused by lung flukes (genus Paragonimus) is a neglected disease occurring in Asia, Africa and the Americas. The genus is species-rich, ancient and widespread. Genetic diversity is likely to be considerable, but investigation of this remains confined to a few populations of a few species. In recent years, studies of genetic diversity have moved from isoenzyme analysis to molecular phylogenetic analysis based on selected DNA sequences. The former offered better resolution of questions relating to allelic diversity and gene flow, whereas the latter is more suitable for questions relating to molecular taxonomy and phylogeny. A picture is emerging of a highly diverse taxon of parasites, with the greatest diversity found in eastern and southern Asia where ongoing speciation might be indicated by the presence of several species complexes. Diversity of lung flukes in Africa and the Americas is very poorly sampled. Functional molecules that might be of value for immunodiagnosis, or as targets for medical intervention, are of great interest. Characterisation of these from Paragonimus species has been ongoing for a number of years. However, the imminent release of genomic and transcriptomic data for several species of Paragonimus will dramatically increase the rate of discovery of such molecules, and illuminate their diversity within and between species. PMID- 26740358 TI - Clonorchis sinensis and Opisthorchis spp. in Vietnam: current status and prospects. AB - Clonorchis sinensis and Opisthorchis viverrini are clinically important small liver flukes because of their known association with development of cholangiocarcinoma. In Vietnam, high prevalence of C. sinensis infection in humans was previously reported in northern provinces, and O. viverrini infection has been detected in several central provinces. However, diagnosis of C. sinensis and O. viverrini infections in the past was merely based on faecal egg examination. This method alone can lead to misidentification at the species level because of morphological similarity between the eggs of these liver flukes and minute intestinal trematodes of the family Heterophyidae. In fact, recent surveys in Vietnam revealed that infection with several minute intestinal flukes, such as Haplorchis pumilio and H. taichui, are much more common than infection with C. sinensis or O. viverrini, and they often co-infect humans. Thus, previously reported prevalence of small liver fluke infection in Vietnam was likely over estimated due to mis identification of parasites in copro-parasitological examinations. In addition, there is some confusion about identification of cercariae, metacercariae and also adults of C. sinensis and O. viverrini in intermediate and definitive hosts. The aim of this review is, therefore, to draw realistic pictures of the past and present scientific reports on the epidemiology and biology of C. sinensis and Opisthorchis spp. infection in Vietnam. PMID- 26740360 TI - The liver fluke Opisthorchis felineus: biology, epidemiology and carcinogenic potential. AB - The liver fluke Opisthorchis felineus is a member of the triad of epidemiologically important liver fluke species belonging to the family Opisthorchiidae and the major agent causing opisthorchiasis over a vast territory, covering Russia, Kazakhstan and several European countries. The similarity between the diseases caused by O. felineus and other liver flukes, O. viverrini and Clonorchis sinensis, in clinical manifestations and course suggests that the scenarios of their development and, possibly, complications have much in common. The International Agency for Research on Cancer classified O. viverrini and C. sinensis as group 1 agents and the major factors inducing cholangiocarcinoma in endemic regions. However, a carcinogenic potential of O. felineus is poorly studied. This review characterizes O. felineus, briefs the epidemiological situation in Western Siberia, the world's largest opisthorchiasis focus, and assesses the carcinogenic potential of this liver fluke. The review is based on a comprehensive analysis of the published medical data on opisthorchiasis and its complications in Western Siberia. Results of performed analysis reflect the actual epidemiological situation in opisthorchiasis focus and suggest an association of this disease with bile duct cancer. PMID- 26740359 TI - Current status of Clonorchis sinensis and clonorchiasis in China. AB - The oriental liver fluke, Clonorchis sinensis, a pathogen causing clonorchiasis, is of major socio-economic importance in East Asia, including China, Korea and Vietnam. This parasite is now recognized as a biocarcinogen strongly linked to cholangiocarcinoma in humans. Here, we describe the status of clonorchiasis in China, where it has been estimated that more than 15 million patients are affected. This paper also summarizes the major advances in the field of clonorchiasis research during last decade, including diagnosis techniques, pathogenesis and genome/transcriptome/proteome studies in the last years. We strongly hope that our work can stimulate the governments of the countries or regions where clonorchiasis is endemic to pay more attention to this disease and establish related guidelines to prevent and control it. PMID- 26740361 TI - An update on human echinostomiasis. AB - Echinostomiasis, caused by trematodes belonging to the family Echinostomatidae, is an important intestinal foodborne parasitic disease. Humans become infected after ingestion of raw or insufficiently cooked molluscs, fish, crustaceans and amphibians, thus, understanding eating habits is essential to determine the distribution of the disease. Despite the public health impact of echinostomiasis, it has been neglected for years. Traditionally, echinostomiasis has been considered as a minor disease confined to low-income areas, mainly in Asia. However, the geographical boundaries and the population at risk are currently expanding and changing in relation to factors such as growing international markets, improved transportation systems, new eating habits in developed countries and demographic changes. These factors make it necessary to improve our understanding of intestinal trematode infections. Herein, we review the main features of human echinostomiasis in relation to their biology, epidemiology, host-parasite relationships, pathogenicity, clinical aspects, diagnosis, treatment and control. PMID- 26740362 TI - Comparison of infectivity, metacercarial burden and host mortality induced by Opisthorchis viverrini sensu lato cercariae from Lao PDR compared with Thailand in cyprinid fish, Barbonymus gonionotus. AB - BACKGROUND: Previous studies indicate that Opisthorchis viverrini sensu lato (s.l.) is a species complex with strong associations to geographical regions, i.e., specific wetlands. The present study was conducted to compare the infectivity, establishment and metacercarial burden and survival of the fish host following exposure to O. viverrini s.l. cercariae isolates from two different river wetlands. METHODS: Experimental infections were performed by exposing fish (silver barb, Barbonymus gonionotus) individually to 0 (control) and 100 O. viverrini s.l. cercariae originating from the Songkram River wetland in Thailand and the Nam Ngum River wetland, Lao PDR. Metacercarial burden and fish survivals were monitored after infection. RESULTS: Fish exposed to O. viverrini s.l. cercariae from the Nam Ngum River wetland had significantly greater metacercarial burden and more active motility at 28 and 35 days post infection than those from the Songkram River wetland. The mortality of fish infected with O. viverrini s.l. from the Nam Ngum River wetland was greater than that from the Songkram River wetland (log-rank test, p<0.01). CONCLUSIONS: The findings in this study provided additional evidence supporting the importance of cryptic species of O. viverrini s.l. and it has implications for parasite transmission dynamics, life cycle success and disease ecology. PMID- 26740363 TI - Higher physiopathogenicity by Fasciola gigantica than by the genetically close F. hepatica: experimental long-term follow-up of biochemical markers. AB - BACKGROUND: Fascioliasis is caused by Fasciola hepatica and F. gigantica. The latter, always considered secondary in human infection, nowadays appears increasingly involved in Africa and Asia. Unfortunately, little is known about its pathogenicity, mainly due to difficulties in assessing the moment a patient first becomes infected and the differential diagnosis with F. hepatica. METHODS: A long-term, 24-week, experimental study comparing F. hepatica and F. gigantica was made for the first time in the same animal model host, Guirra sheep. Serum biochemical parameters of liver damage, serum electrolytes, protein metabolism, plasma proteins, carbohydrate metabolism, hepatic lipid metabolism and inflammation were analysed on a biweekly basis as morbidity indicators. Serum anti-Fasciola IgG, coproantigen and egg shedding were simultaneously followed up. RESULTS: rDNA and mtDNA sequencing and the morphometric study by computer image analysis system (CIAS) showed that fasciolids used fitted standard species characteristics. Results demonstrated that F. gigantica is more pathogenic, given its bigger size and biomass but not due to genetic differences which are few. Fasciola gigantica shows a delayed development of 1-2 weeks regarding both the biliary phase and the beginning of egg shedding, with respective consequences for biochemical modifications in the acute and chronic periods. CONCLUSIONS: The higher F. gigantica pathogenicity contrasts with previous studies which only reflected the faster development of F. hepatica observed in short-term experiments. PMID- 26740364 TI - Intron sequence of the taurocyamine kinase gene as a marker to investigate genetic variation of Paragonimus species in Japan and the origins of triploidy in P. westermani. AB - BACKGROUND: Paragonimiasis is a foodborne parasitic infection caused by lung flukes of the genus Paragonimus. Several species of Paragonimus are endemic in Japan: P. westermani (diploid and triploid) P. miyazakii, P. ohirai and P. iloktsuenensis. The taxonomic status and genetic variability of these lung flukes remains poorly understood. METHODS: The second intron of domain 1 of the taurocyamine kinase gene (TKD1int2) region was used to explore genetic variation and differentiation of diploid and triploid P. westermani, as well as P. miyazakii, P. ohirai and P. iloktsuenensis originating from Japan. RESULTS: We found high levels of intraspecific variation in P. westermani, but only low levels of variation within the other species studied. Haplotype network and phylogenetic tree analyses demonstrated the sister-group relationship of P. ohirai and P. iloktsuenensis and the phylogenetically distant relationship of P. westermani with the other species. All individuals except for triploid P. westermani were homozygous. Each triploid contained at least one allele similar to that seen in most diploids from Chiba and one allele resembling that seen in diploids from Oita. One triploid contained three different sequences. CONCLUSIONS: Our findings suggested that the TKD1int2 region is a suitable marker for use in studying the genetic variation and phylogenetics of Paragonimus species, as well as providing clues to the origins of triploidy in P. westermani. PMID- 26740365 TI - A singleplex real-time fluorescence resonance energy transfer PCR with melting curve analysis for the differential detection of Paragonimus heterotremus, Echinostoma malayanum and Fasciola gigantica eggs in faeces. AB - BACKGROUND: Because the eggs of Paragonimus, Echinostoma and Fasciola are very similar in size and shape, it is difficult to distinguish and accurately identify species by the morphology of their eggs, which is a standard diagnostic method. METHODS: In this study, a novel assay combining a real-time fluorescence resonance energy transfer PCR and melting curve analysis using one set of primers and fluorophore-labelled hybridization probes specific for the 28S rDNA region was developed for the molecular detection of Paragonimus heterotremus, Echinostoma malayanum and Fasciola gigantica eggs. RESULTS: This assay could detect and distinguish P. heterotremus, E. malayanum and F. gigantica DNA with the distinct melting temperature (Tm) values of 57.99+/-0.08, 62.12+/-0.15 and 74.10+/-0.18, respectively. The assay can also be used to detect and distinguish DNA from P. bangkokensis, P. harinasutai, P. machorchis, E. revolutum, Hypodereum conoideum and F. hepatica, which have different Tm values. The sensitivity of this assay enabled the detection of one egg of P. heterotremus, E. malayanum or F. gigantica per 100 mg of faeces. In addition, the specificity testing showed no fluorescence signal for other parasites. CONCLUSIONS: Due to the sensitivity and specificity of our assay in detecting P. heterotremus, E. malayanum and F. gigantica, our method could be used to accurately diagnose these three medically important parasitic groups and has potential implications for molecular epidemiological investigations of human and/or animal infections. PMID- 26740367 TI - Associations Between Self-Reported and Objectively Recorded Early Life Stress, FKBP5 Polymorphisms, and Depressive Symptoms in Midlife. AB - BACKGROUND: FK506-binding protein 51 is involved in hypothalamic-pituitary adrenal axis regulation. Single nucleotide polymorphisms (SNPs) in the FKBP5 gene have been shown to interact with retrospectively self-reported early life stress (ELS) in patients with psychiatric disorders. We examined interactions between three selected FKBP5 SNPs and self-reported and objectively recorded ELS in relation to depressive symptoms in midlife. METHODS: This study comprised 1431 Helsinki Birth Cohort Study participants genotyped for FKBP5 SNPs shown to alter cortisol metabolism (rs1360780, rs9470080, and rs9394309). Participants completed the Beck Depression Inventory (BDI) at ages 61.5 years (time 1) and 63.4 years (time 2); 165 and 181 participants were separated from their parents in childhood as a result of evacuations during World War II as indicated by self-reports and the Finnish National Archives registry, respectively. RESULTS: Associations between self-reported and objectively recorded ELS, but not stressful events in midlife, and the mean BDI score (average of time 1 and time 2) or mild to severe BDI scores (10-63 points at time 1 and time 2), or both, were moderated by the FKBP5 variants (p values for interactions < .05; p values between self-reported and objectively recorded ELS in these interactions > .18). Mean BDI scores or odds for having mild to severe BDI scores, or both, increased according to number of minor alleles and haplotypes derived from these alleles in the separated groups, but not in the nonseparated groups. CONCLUSIONS: FKBP5 variations in combination with self-reported and objectively recorded ELS predict more pronounced depressive symptoms in midlife. Our findings confirm previous retrospective findings in a prospective epidemiologic study setting. PMID- 26740368 TI - Nonsurgical management of condylar fractures in children: A 15-year clinical retrospective study. AB - PURPOSE: To present the 15 years of experience after closed treatment of condylar fractures in children, by evaluating the short- and long-term results and propose treatment modalities. MATERIAL AND METHODS: Data were retrieved for all young patients with condylar fractures who were treated from 2000 to 2014. Gender, age of patient, date of injury, type of fracture, treatment provided, and follow-up were registered. RESULTS: A total of 84 patients (mean age: 8.9 years) with 106 condylar fracture sites were included in the study. In 80 cases (95.2%), treatment was nonsurgical, with or without intermaxillary fixation, followed by kinesiotherapy. An intraocclusal block was additionally placed in 19 cases. Open reduction was selected in 4 cases. All condylar fractures healed without functional or esthetic complications, with the exception of 2 patients (2/80, 2.5%). Therefore, in late follow-up, no subjective symptoms were recorded, and a functional well-contoured condylar process was observed in all X-rays. Slight asymptomatic mandibular deviation was recorded in wide mouth opening in 29.1% of the patients. CONCLUSIONS: Conservative treatment of condylar fractures is the treatment of choice in children. However, the child's age, adequacy of function of the mandible, degree of displacement or dislocation of the condylar fragment, and need for active kinesiotherapy should be considered in all cases. PMID- 26740369 TI - GeNN: a code generation framework for accelerated brain simulations. AB - Large-scale numerical simulations of detailed brain circuit models are important for identifying hypotheses on brain functions and testing their consistency and plausibility. An ongoing challenge for simulating realistic models is, however, computational speed. In this paper, we present the GeNN (GPU-enhanced Neuronal Networks) framework, which aims to facilitate the use of graphics accelerators for computational models of large-scale neuronal networks to address this challenge. GeNN is an open source library that generates code to accelerate the execution of network simulations on NVIDIA GPUs, through a flexible and extensible interface, which does not require in-depth technical knowledge from the users. We present performance benchmarks showing that 200-fold speedup compared to a single core of a CPU can be achieved for a network of one million conductance based Hodgkin-Huxley neurons but that for other models the speedup can differ. GeNN is available for Linux, Mac OS X and Windows platforms. The source code, user manual, tutorials, Wiki, in-depth example projects and all other related information can be found on the project website http://genn team.github.io/genn/. PMID- 26740370 TI - Editorial overview: Neurosciences: Brain and immunity: new targets for neuroprotection. PMID- 26740371 TI - A Pilot Study of Continuous Infusion of Mycophenolate Mofetil for Prophylaxis of Graft-versus-Host-Disease in Pediatric Patients. AB - Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is used increasingly for graft-versus-host disease (GVHD) prophylaxis. Empiric fixed-dose escalation strategies in pediatric hematopoietic cell transplantation (HCT) recipients have failed to achieve target MPA exposure. We evaluated the safety and feasibility of a pharmacokinetics-based dosing approach using a novel continuous infusion (CI) method of administration of MMF in pediatric HCT recipients. All patients received a myeloablative conditioning with cyclosporine A and MMF for GVHD prophylaxis. MMF was initiated on day 0 at a dose of 15 mg/kg every 8 hours. Based on steady-state pharmacokinetics, MMF was converted to CI to target a total MPA AUC(0-24) of 40 to 80 MUg.hour/mL. The MMF dose was adjusted to maintain a total MPA steady-state concentration (Css) of 1.7 to 3.3 MUg/mL. During the CI schedule, MPA AUC(0-24) was maintained at a mean of 40.1 MUg.hour/mL (range, 20.6 to 63.8), and 17 of 19 patients (89%) achieved MPA Css within target of 1.7 to 3.3 MUg/mL. Eighteen of 19 patients (95%) achieved neutrophil engraftment at a median of 13 days (range, 8 to 41) post-transplant and platelet engraftment at 39 days (range, 17 to 298) days post-transplant. Six of 18 assessable patients (33%) developed stages II to IV acute GVHD and 2 of 15 (13%) developed chronic GVHD. The MMF dose was reduced in 9 patients due to gastrointestinal symptoms (n = 6), low blood counts (n = 4), and viral infection (n = 3). Five patients with acute lymphoblastic leukemia relapsed, of whom 4 have died. Fifteen of 19 patients are alive with a median follow-up of 2.4 years (range, .4 to 4.9), with 3-year event-free and overall survival rates of 68% and 79%, respectively. In this pilot study of pharmacokinetically directed MMF dosing, we observed no toxic deaths, excellent engraftment, and low rates of grades III to IV acute and chronic GVHD. We found significantly lower half-life and higher drug clearance in pediatric HCT recipients compared with stable pediatric renal transplant patients or adult transplant patients. This regimen deserves further validation in a larger cohort of pediatric patients undergoing myeloablative transplantation. PMID- 26740372 TI - Adult Nephrotic Syndrome after Hematopoietic Stem Cell Transplantation: Renal Pathology is the Best Predictor of Response to Therapy. AB - Nephrotic syndrome (NS) after allogeneic hematopoietic stem cell transplantation (HSCT) is a rare phenomenon usually associated with graft-versus-host disease (GVHD). This systematic review of post-HSCT NS cases reported in the literature aimed to identify risk factors and unique features of the disease in this clinical setting. One hundred sixteen cases of post-HSCT NS published in the English literature between 1988 and 2015 were revealed and analyzed. The median onset of NS was 20.5 months (range, 3 to 174) post-HSCT. NS development was associated with acute or chronic GVHD in 87.2% of cases. Membranous nephropathy (MGN) was the most frequent pathology (65.5%), followed by minimal change disease (MCD) (19%). Complete remission of the NS was achieved in 63.5% of patients (59.1% of MGN cases and 81.3% of MCD cases; P = .15). Patients presenting with MCD recovered at a median of 1.75 months (range, 1 to 12) and with MGN a median of 7 months (range, 1 to 53) (P = .001). NS was treated with corticosteroids alone in 16.8% of patients and with a combination of corticosteroids and other immunosuppressive agents in 73.5% of patients. Univariate analysis failed to identify a single predictive factor of response to therapy. In conclusion, post HSCT NS usually develops concomitant to GVHD and is associated with high rates of response to therapy. Although most patients were treated with a combination of immunosuppressive drugs, single-agent therapy with steroids may be sufficient in some cases. PMID- 26740373 TI - Cytokine Profile of Engraftment Syndrome in Pediatric Hematopoietic Stem Cell Transplant Recipients. AB - The biology of engraftment syndrome is poorly understood, and the degree of overlap with acute graft-versus-host disease (GVHD) is unclear. To understand engraftment syndrome better, plasma cytokine profiles were evaluated in 56 pediatric allogeneic bone marrow transplant recipients before transplant, on the day of stem cell infusion, and weekly until day +100. Patients were divided into 4 groups: those with isolated engraftment syndrome (n = 8), acute GVHD (n = 12), both engraftment syndrome and acute GVHD (n = 4), and neither engraftment syndrome nor acute GVHD (n = 32). Engraftment syndrome was observed a median of 13.5 days (range, 10 to 28) after transplant, whereas acute GVHD was diagnosed a median of 55 days (range, 19 to 95) after transplant. Four patients developed both engraftment syndrome at a median of 10.5 days (range, 10 to 11) and acute GVHD at a median of 35 days (range, 23 to 56) after stem cell infusion. Median plasma levels of IL-1beta, IL-6, IL-12, IL-4, and IL-13 were significantly elevated in patients with isolated engraftment syndrome when compared with isolated acute GVHD. A rise of proinflammatory cytokines (IL-1beta, IL-6, and IL 12) was followed by surge in anti-inflammatory cytokines (IL-4 and IL-13) in patients with isolated engraftment syndrome. The observation of elevated IL-1beta suggests that engraftment syndrome could be an inflammasome mediated phenomenon. PMID- 26740374 TI - Cytosine-Phosphorothionate-Guanine Oligodeoxynucleotides Exacerbates Hemophagocytosis by Inducing Tumor Necrosis Factor-Alpha Production in Mice after Bone Marrow Transplantation. AB - Hemophagocytic syndrome (HPS) is frequently associated with hematopoietic stem cell transplantation and is treated with some benefit derived from TNF-alpha inhibitors. However, the mechanisms of how HPS occurs and how a TNF-alpha inhibitor exerts some benefit to HPS management have remained unclear. We evaluated the effect of toll-like receptor (TLR) ligands, especially focusing on cytosine-phosphorothionate-guanine oligodeoxynucleotide (CpG), a TLR9 ligand, on HPS in mice that underwent transplantation with syngeneic or allogeneic bone marrow (BM) cells (Syn-BMT, Allo-BMT), or with allogeneic BM cells plus splenocytes to promote graft-versus-host disease (GVHD mice). Hemophagocytosis was a common feature early after all BMT, but it subsided in Syn-BMT and Allo-BMT mice. In GVHD mice, however, hemophagocytosis persisted and was accompanied by upregulated production of IFN-gamma but not TNF-alpha, and it was suppressed by blockade of IFN-gamma but not TNF-alpha. A single injection of the TLR9 ligand CpG promoted HPS in all BMT mice and was lethal in GVHD mice, accompanied by greatly upregulated production of TNF-alpha, IL-6, and IFN-gamma. Blocking of TNF alpha, but not IL-6 or IFN-gamma, suppressed CpG-induced HPS in all BMT mice and rescued GVHD mice from CpG-induced mortality. Thus, TLR9 signaling mediates TNF alpha-driven HPS in BMT mice and is effectively treated through TNF-alpha inhibition. PMID- 26740378 TI - Corrigendum: Three Dimensional Hybrids of Vertical Graphene-nanosheet Sandwiched by Ag-nanoparticles for Enhanced Surface Selectively Catalytic Reactions. PMID- 26740375 TI - Long-Term Follow-Up of Allogeneic Hematopoietic Stem Cell Transplantation for Solid Cancer. AB - We wanted to determine whether allogeneic hematopoietic stem cell transplantation (HSCT) may result in long-term survival in patients with solid cancer. HSCT was performed in 61 patients with solid cancer: metastatic renal carcinoma (n = 22), cholangiocarcinoma (n = 17), colon carcinoma (n = 15), prostate cancer (n = 3), pancreatic adenocarcinoma (n = 3), or breast cancer (n = 1). Liver transplantation was performed for tumor debulking in 18 patients. Median age was 56 years (range, 28 to 77). Donors were either HLA-identical siblings (n = 29) or unrelated (n = 32). Conditioning was nonmyeloablative (n = 23), reduced (n = 36), or myeloablative (n = 2). Graft failure occurred in 13 patients (21%). The cumulative incidence of acute graft-versus-host disease (GVHD) of grades II to IV was 47%, and that of chronic GVHD was 32%. Treatment-related mortality was 21%. At 5 years cancer-related mortality was 63%. Currently, 6 patients are alive, 2 with renal cell carcinoma, 1 with cholangiocarcinoma, and 3 with pancreatic carcinoma. Eight-year survival was 12%. Risk factors for mortality were nonmyeloablative conditioning (HR, 2.95; P < .001), absence of chronic GVHD (HR, 3.57; P < .001), acute GVHD of grades II to IV (HR, 2.90; P = .002), and HLA identical transplant (HR, 5.00; P = .03). With none of these risk factors, survival at 6 years was 50% (n = 6). Long-term survival can be achieved in some patients with solid cancer after HSCT. PMID- 26740379 TI - The Guillain-Mollaret triangle in action. AB - The Guillain-Mollaret triangle comprises the ipsilateral red nucleus in the midbrain, the inferior olive in the medulla and the contralateral dentate nucleus in the cerebellum: together, these form the dentato-rubro-olivary pathway. Pathology in this triangle disinhibits (and so activates) the inferior olivary nucleus. The olivary nucleus then hypertrophies and its rhythmical discharges may manifest clinically as oculopalatal tremor. We describe three cases with either oculopalatal tremor or MRI evidence of olivary hypertrophy caused by vascular insults to this triangle. It is not clear why only some patients have the oculopalatal tremor. Olivary hypertrophy can be confused with demyelination if the imaging is not put into clinical context. Oculopalatal tremor may occur without olivary hypertrophy since the nucleus atrophies with time. Oculopalatal tremor does not respond to medical treatment. A better understanding of the mechanism of the discharge at a cellular level may lead to more targeted medical treatments. PMID- 26740380 TI - Intracranial bleeding from collaterals following carotid artery occlusion. PMID- 26740381 TI - Overview and potential unifying themes of the atypical chemokine receptor family. AB - Chemokines modulate immune responses through their ability to orchestrate the migration of target cells. Chemokines directly induce cell migration through a distinct set of 7 transmembrane domain G protein-coupled receptors but are also recognized by a small subfamily of atypical chemokine receptors, characterized by their inability to support chemotactic activity. Atypical chemokine receptors are now emerging as crucial regulatory components of chemokine networks in a wide range of physiologic and pathologic contexts. Although a new nomenclature has been approved recently to reflect their functional distinction from their conventional counterparts, a systematic view of this subfamily is still missing. This review discusses their biochemical and immunologic properties to identify potential unifying themes in this emerging family. PMID- 26740384 TI - Longitudinal relationship of severe periodontitis with cognitive decline in older Japanese. AB - BACKGROUND AND OBJECTIVE: Epidemiologic data examining the longitudinal relationship between periodontitis and cognitive status are very limited, especially in Asian populations. The present study examined the longitudinal relationship of periodontitis with cognitive decline in 85 Japanese community dwelling individuals (average age: 79.3 years) for whom data were available from comprehensive health examinations conducted in 2010 and 2013. MATERIAL AND METHODS: Based on a baseline full-mouth periodontal examination, severe periodontitis was defined using a Centers for Disease Control and Prevention/American Academy of Periodontology definition. Cognitive decline during the 3-year study period was defined using the results of the Mini-Mental State Examination (MMSE). Information on age, gender, education, depression, body mass index, smoking status, alcohol use, exercise, hypertension, diabetes, history of cardiovascular disease and stroke, and baseline MMSE scores were obtained and tested as potential confounders in the statistical models. RESULTS: Among 85 study participants, 21 (24.7%) were defined as having severe periodontitis. Multivariable Poisson regression analyses revealed that severe periodontitis was significantly associated with an increased risk of cognitive decline [adjusted relative risk = 2.2; 95% confidence interval (95% CI): 1.1 4.5]. Furthermore, multivariable linear regression analyses revealed that participants with severe periodontitis had a 1.8-point greater decrease (95% CI: 3.3 to -0.2) in MMSE score than those without severe periodontitis. CONCLUSION: Within the limitations related to its small sample size, the findings of the present study suggest that severe periodontitis is significantly associated with future decline in cognitive function among community-dwelling older Japanese subjects. PMID- 26740382 TI - Recapitulation of metabolic defects in a model of propionic acidemia using patient-derived primary hepatocytes. AB - BACKGROUND: Propionic acidemia (PA) is a disorder of intermediary metabolism with defects in the alpha or beta subunits of propionyl CoA carboxylase (PCCA and PCCB respectively) enzyme. We previously described a liver culture system that uses liver-derived hemodynamic blood flow and transport parameters to restore and maintain primary human hepatocyte biology and metabolism utilizing physiologically relevant milieu concentrations. METHODS: In this study, primary hepatocytes isolated from the explanted liver of an 8-year-old PA patient were cultured in the liver system for 10 days and evaluated for retention of differentiated polarized morphology. The expression of PCCA and PCCB was assessed at a gene and protein level relative to healthy donor controls. Ammonia and urea levels were measured in the presence and absence of amino acid supplements to assess the metabolic consequences of branched-chain amino acid metabolism in this disease. RESULTS: Primary hepatocytes from the PA patient maintained a differentiated polarized morphology (peripheral actin staining) over 10 days of culture in the system. We noted lower levels of PCCA and PCCB relative to normal healthy controls at the mRNA and protein level. Supplementation of branched-chain amino acids, isoleucine (5mM) and valine (5mM) in the medium, resulted in increased ammonia and decreased urea in the PA patient hepatocyte system, but no such response was seen in healthy hepatocytes or patient-derived fibroblasts. CONCLUSIONS: We demonstrate for the first time the successful culture of PA patient-derived primary hepatocytes in a differentiated state, that stably retain the PCCA and PCCB enzyme defects at a gene and protein level. Phenotypic response of the system to an increased load of branched-chain amino acids, not possible with fibroblasts, underscores the utility of this system in the better understanding of the molecular pathophysiology of PA and examining the effectiveness of potential therapeutic agents in the most relevant tissue. PMID- 26740385 TI - Is there an association between leukoaraiosis volume and diabetes? AB - OBJECTIVES: The relation between white matter loss (WML) and diabetes is still debated. The aim of this study was to investigate the correlation between typical WML- and diabetes-related magnetic resonance imaging (MRI) findings in a cohort of patients scheduled for carotid endarterectomy (CEA). MATERIALS AND METHODS: Ninety-three consecutive patients (mean age 71+/-9years; male 71) were included in a single-centre retrospective study. All the patients underwent MRI as baseline evaluation prior to CEA. A neuroradiologist blinded to the presence of risk factors calculated WML volume and number of lesions on FLAIR images using a semi-automated segmentation technique. Receiver operating characteristics analysis was performed to search for any association between WML volume and the number of WML lesions. The Mann-Whitney tests were used to determine significant WML differences between diabetic and non-diabetic patients. Logistic regression analysis was performed to evaluate the potential association of other variables. RESULTS: The prevalence of diabetes was 20.4% (n=19). WML volume and number of WML lesions were significantly associated with diabetes (P=0.001). A statistically significant difference in WML volume was found between diabetic and non-diabetic patients (P<0.0001). Only diabetes, among all the investigated variables (WML volume, CAD status, age, smoking status, gender, hypertension, hyperlipidemia, diabetes) was significantly associated with WML (P=0.0001). CONCLUSION: Our results demonstrate a strong statistical correlation between diabetes and WML. Future scientific challenges could include the identification of potential therapeutic targets and the creation of dedicated screening protocols for WML in diabetic patients other than the simple measurement of leukoaraiosis total burden. PMID- 26740386 TI - Radiological features of cerebellar glioblastoma. AB - BACKGROUND AND PROPOSE: Glioblastoma (GBM) is the most common type of malignant primary central nervous system tumor in adults; however, the prevalence of GBM arising in the cerebellum is extremely low. This study aimed to demonstrate the radiological features of cerebellar GBMs, including computed tomography (CT), magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and (18)F fluorodeoxyglucose (FDG)- and (11)C methionine (MET)-positron emission tomography (PET) findings. MATERIALS AND METHODS: We retrospectively reviewed seven patients with cerebellar GBM (six men and one woman: mean age: 56 years, range: 18-73 years). We reviewed medical records and radiological data, including preoperative CT, MRI and PET. All patients underwent CT and MRI. DWI data were acquired in four patients. Three patients underwent FDG- and MET-PET examinations. All patients underwent total or subtotal tumor resection and received pathological diagnoses. RESULTS: Four patients had imaging findings consistent with GBM and received preoperative cerebellar GBM diagnoses. Two patients exhibited homogeneous patchy and nodular enhancement without necrosis on MRI, which resembled malignant lymphoma and metastasis. One case exhibited Lhermitte-Duclos disease-like parallel linear striations (i.e.,"tiger-striped" appearance). Although the imaging findings of these three patients were inconsistent with GBM, pathological diagnosis confirmed cerebellar GMB. CONCLUSIONS: Some evaluated cases of cerebellar GBM did not exhibit the common CT, MRI, and PET findings of supratentrial GBM, leading to considerable difficulty with preoperative differential diagnosis. PMID- 26740387 TI - Disparities Between Clinician and Patient Perception of Breakthrough Pain Control. AB - CONTEXT: There are disparities in the level of symptom severity as perceived by patients and health professionals. There is limited information about patients' and clinicians' global assessment of breakthrough pain control, the need to change analgesics, and change in breakthrough pain over time. OBJECTIVES: To establish whether patients and clinicians independently agree on adequacy of breakthrough pain control, management strategy, and impression of change over time. METHODS: One hundred patients with breakthrough cancer pain were assessed and followed up one week later by a palliative medicine specialist. The patient and clinician independently answered the same questions about the adequacy of the patient's breakthrough pain control and breakthrough pain management. The results were compared with items on the Breakthrough Pain Assessment Tool (BAT). RESULTS: At initial consultation, 35% of patients rated their breakthrough cancer pain as inadequately controlled compared with 72% of clinicians. Breakthrough pain analgesics were changed in 68% of cases. At one-week follow-up consultation, 62% of patients considered their breakthrough cancer pain to be better, and in 57% of cases, the clinicians also categorized the pain this way. CONCLUSION: There are significant differences in global impressions of breakthrough pain between patients and pain clinicians that become less disparate as a therapeutic relationship evolves. Therapeutic decisions were based on clinical rather than patient perceptions. PMID- 26740388 TI - Muenke syndrome: An international multicenter natural history study. AB - Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal, and calcaneal fusions, and behavioral differences. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings. Muenke syndrome constitutes the most common syndromic form of craniosynostosis, with an incidence of 1 in 30,000 births and is defined by the presence of the p.Pro250Arg mutation in FGFR3. Participants were recruited from international craniofacial surgery and genetic clinics. Affected individuals, parents, and their siblings, if available, were enrolled in the study if they had a p.Pro250Arg mutation in FGFR3. One hundred and six patients from 71 families participated in this study. In 51 informative probands, 33 cases (64.7%) were inherited. Eighty-five percent of the participants had craniosynostosis (16 of 103 did not have craniosynostosis), with 47.5% having bilateral and 28.2% with unilateral synostosis. Females and males were similarly affected with bicoronal craniosynostosis, 50% versus 44.4% (P = 0.84), respectively. Clefting was rare (1.1%). Hearing loss was identified in 70.8%, developmental delay in 66.3%, intellectual disability in 35.6%, attention deficit/hyperactivity disorder in 23.7%, and seizures in 20.2%. In patients with complete skeletal surveys (upper and lower extremity x-rays), 75% of individuals were found to have at least a single abnormal radiographical finding in addition to skull findings. This is the largest study of the natural history of Muenke syndrome, adding valuable clinical information to the care of these individuals including behavioral and cognitive impairment data, vision changes, and hearing loss. PMID- 26740390 TI - Adenoviral Expression of a Bispecific VHH-Based Neutralizing Agent That Targets Protective Antigen Provides Prophylactic Protection from Anthrax in Mice. AB - Bacillus anthracis, the causative agent of anthrax, secretes three polypeptides, which form the bipartite lethal and edema toxins (LT and ET, respectively). The common component in these toxins, protective antigen (PA), is responsible for binding to cellular receptors and translocating the lethal factor (LF) and edema factor (EF) enzymatic moieties to the cytosol. Antibodies against PA protect against anthrax. We previously isolated toxin-neutralizing variable domains of camelid heavy-chain-only antibodies (VHHs) and demonstrated their in vivo efficacy. In this work, gene therapy with an adenoviral (Ad) vector (Ad/VNA2-PA) (VNA, VHH-based neutralizing agents) promoting the expression of a bispecific VHH based neutralizing agent (VNA2-PA), consisting of two linked VHHs targeting different PA-neutralizing epitopes, was tested in two inbred mouse strains, BALB/cJ and C57BL/6J, and found to protect mice against anthrax toxin challenge and anthrax spore infection. Two weeks after a single treatment with Ad/VNA2-PA, serum VNA2-PA levels remained above 1 MUg/ml, with some as high as 10 mg/ml. The levels were 10- to 100-fold higher and persisted longer in C57BL/6J than in BALB/cJ mice. Mice were challenged with a lethal dose of LT or spores at various times after Ad/VNA2-PA administration. The majority of BALB/cJ mice having serum VNA2-PA levels of >0.1 MUg/ml survived LT challenge, and 9 of 10 C57BL/6J mice with serum levels of >1 MUg/ml survived spore challenge. Our findings demonstrate the potential for genetic delivery of VNAs as an effective method for providing prophylactic protection from anthrax. We also extend prior findings of mouse strain-based differences in transgene expression and persistence by adenoviral vectors. PMID- 26740394 TI - Small Incisions for Small Children: Is Right Lateral Thoracotomy a Right Approach in Open Heart Surgery in Infants? PMID- 26740391 TI - Vitamin Supplementation at the Time of Immunization with a Cold-Adapted Influenza Virus Vaccine Corrects Poor Mucosal Antibody Responses in Mice Deficient for Vitamins A and D. AB - Vitamin A and D deficiencies and insufficiencies are prevalent worldwide in developed and developing countries. Vitamin metabolites are functionally intertwined in that they are high-affinity ligands for related receptors of the nuclear receptor superfamily. The effects of vitamin A deficiencies (VAD) on antibody responses to respiratory virus vaccines have already been demonstrated. Of particular concern was the reduction in IgA, a first line of defense against pathogens in the respiratory tract. Here, we describe the individual and combined effects of vitamin A and D deficiencies in mice immunized with an attenuated influenza virus vaccine. Relative to VAD, vitamin D deficiency (VDD) had a limited effect, but double deficiencies for vitamins A and D (VAD+VDD) further reduced antibody responses in the respiratory tract. The administration of supplemental vitamins A and D to VAD+VDD mice at the time of vaccination restored responses in a dose-dependent manner. Results suggest that vitamin supplementation programs may be beneficial in a clinical setting to promote healthy immune responses to respiratory virus vaccines in vitamin-deficient individuals. PMID- 26740396 TI - Coralline algal physiology is more adversely affected by elevated temperature than reduced pH. AB - In this study we analyzed the physiological responses of coralline algae to ocean acidification (OA) and global warming, by exposing algal thalli of three species with contrasting photobiology and growth-form to reduced pH and elevated temperature. The analysis aimed to discern between direct and combined effects, while elucidating the role of light and photosynthesis inhibition in this response. We demonstrate the high sensitivity of coralline algae to photodamage under elevated temperature and its severe consequences on thallus photosynthesis and calcification rates. Moderate levels of light-stress, however, were maintained under reduced pH, resulting in no impact on algal photosynthesis, although moderate adverse effects on calcification rates were still observed. Accordingly, our results support the conclusion that global warming is a stronger threat to algal performance than OA, in particular in highly illuminated habitats such as coral reefs. We provide in this study a quantitative physiological model for the estimation of the impact of thermal-stress on coralline carbonate production, useful to foresee the impact of global warming on coralline contribution to reef carbon budgets, reef cementation, coral recruitment and the maintenance of reef biodiversity. This model, however, cannot yet account for the moderate physiological impact of low pH on coralline calcification. PMID- 26740397 TI - From the 90's to now: A brief historical perspective on more than two decades of estrogen neuroprotection. AB - Historical perspective abstract:From the 90's to now: a historical perspective on more than two decades of estrogen neuroprotection: In the early 90's, estrogens were known to exert organizational and activational effects on reproductive tissues and sexual behavior. As well, the role of sex and gonadal hormones in altering the risk for developing Alzheimer's Disease (AD) was only beginning to be elucidated. Preliminary investigations suggested that estrogen-containing therapies typically given for the management of disruptive menopausal symptoms could reduce AD risk, attenuate disease-associated cognitive deficits, and modulate brain substrates known to be dysregulated by the condition, such as the cholingeric system. The findings from our seminal paper demonstrating cognitive benefits and cholinergic impacts with exogenous estrogen treatment in a rodent model of surgical hormone depletion provided initial support for use of estrogen containing therapies as a treatment for age-related brain disorders. We then went on to demonstrate neuroprotective actions of estrogen in several other in vivo and in vitro models of neurological challenge, including stroke and AD. Further, our findings of the chemical structure requirements for estrogen's neuroprotective effects identified a novel approach for optimizing future estrogen-containing hormone therapy options. These early efforts laid the groundwork for later, large-scale clinical investigations into the potential of estrogen-based menopausal hormone therapies for the prevention of a variety of age-related disorders. Although findings of these studies were equivocal, the neuroprotective actions of estrogen, and specifically 17beta-estradiol, identified by early investigations, remain well-documented. Future development of interventions that optimize cognitive aging are crucial and, with proper understanding of the factors that influence the realization of beneficial impacts, estrogen-containing treatments may still be among these. ORIGINAL ARTICLE ABSTRACT: Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague-Dawley rats: We hypothesized that estradiol (E2) serves as a neurotrophomodulatory substance for basal forebrain cholinergic neurons thought to be involved in learning and memory. Learning/memory was assessed using the two-way active avoidance paradigm and the Morris water task. Female Sprague-Dawley rats were either ovariectomized (OVX) or OVX for 3 weeks, followed by s.c. implantation of a Silastic pellet containing 17-betaE2 (E2 pellet), resulting in a replacement of E2 to physiological levels. Ovary-intact (INTACT) animals served as our positive control. Active avoidance behavior and choline acetyltransferase (ChAT) activity in the frontal cortex and hippocampus were assessed at 5 and 28 weeks postovariectomy while performance on the Morris water task and high-affinity choline uptake (HACU) were measured only at the 5-week time point. At the 5-week time point, E2 replacement caused a significant elevation in the level of active avoidance performance relative to OVX animals. At the 28-week time point, OVX animals demonstrated a significantly lower number of avoidances relative to controls (61%) whereas E2-pellet animals not only demonstrated superior performance relative to OVX animals but also showed an accelerated rate of learning. Morris water task performance, on the other hand, was not significantly affected by estrogenic milieu despite a trend towards better performance in the E2-pellet group. Neurochemical analyses revealed that 5 weeks of ovariectomy was sufficient to reduce HACU in both the frontal cortex and hippocampus by 24 and 34%, respectively, while E2 replacement was successful in elevating HACU relative to OVX animals in both regions. ChAT activity was decreased in the hippocampus but not the frontal cortex of 5-week OVX animals. E2 replacement resulted in a reversal of this effect. At the 28-week time period, an unexpected decrease in ChAT activity was observed across all treatment groups. Interestingly, E2-pellet animals demonstrated the least severe decline in ChAT. This phenomenon was most evident in the frontal cortex where ChAT decreased by 61 and 56% in INTACT and OVX animals, respectively, whereas the decline in E2-pellet animals was only 16% over the same time period, suggesting a previously unreported cytoprotective effect of E2. Taken together, these findings demonstrate important effects of estrogens on cholinergic neurons and support the potential use of estrogen therapy in treatment of dementias in postmenopausal women. (c) 1994. This article is part of a Special Issue entitled SI:50th Anniversary Issue. PMID- 26740398 TI - Reflections on: "A general role for adaptations in G-Proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function". AB - In 1991 we demonstrated that chronic morphine exposure increased levels of adenylyl cyclase and protein kinase A (PKA) in several regions of the rat central nervous system as inferred from measures of enzyme activity in crude extracts (Terwilliger et al., 1991). These findings led us to hypothesize that a concerted upregulation of the cAMP pathway is a general mechanism of opiate tolerance and dependence. Moreover, in the same study we showed similar induction of adenylyl cyclase and PKA activity in nucleus accumbens (NAc) in response to chronic administration of cocaine, but not of several non-abused psychoactive drugs. Morphine and cocaine also induced equivalent changes in inhibitory G protein subunits in this brain region. We thus extended our hypothesis to suggest that, particularly within brain reward regions such as NAc, cAMP pathway upregulation represents a common mechanism of reward tolerance and dependence shared by several classes of drugs of abuse. Research since that time, by many laboratories, has provided substantial support for these hypotheses. Specifically, opiates in several CNS regions including NAc, and cocaine more selectively in NAc, induce expression of certain adenylyl cyclase isoforms and PKA subunits via the transcription factor, CREB, and these transcriptional adaptations serve a homeostatic function to oppose drug action. In certain brain regions, such as locus coeruleus, these adaptations mediate aspects of physical opiate dependence and withdrawal, whereas in NAc they mediate reward tolerance and dependence that drives increased drug self-administration. This work has had important implications for understanding the molecular basis of addiction. ORIGINAL ARTICLE ABSTRACT: "A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function". Previous studies have shown that chronic morphine increases levels of the G-protein subunits Gialpha and Goalpha, adenylate cyclase, cyclic AMP-dependent protein kinase, and certain phosphoproteins in the rat locus coeruleus, but not in several other brain regions studied, and that chronic morphine decreases levels of Gialpha and increases levels of adenylate cyclase in dorsal root ganglion/spinal cord (DRG-SC) co-cultures. These findings led us to survey the effects of chronic morphine on the G-protein/cyclic AMP system in a large number of brain regions to determine how widespread such regulation might be. We found that while most regions showed no regulation in response to chronic morphine, nucleus accumbens (NAc) and amygdala did show increases in adenylate cyclase and cyclic AMP-dependent protein kinase activity, and thalamus showed an increase in cyclic AMP-dependent protein kinase activity only. An increase in cyclic AMP-dependent protein kinase activity was also observed in DRG-SC co cultures. Morphine regulation of G-proteins was variable, with decreased levels of Gialpha seen in the NAc, increased levels of Gialpha and Goalpha amygdala, and no change in thalamus or the other brain regions studied. Interestingly, chronic treatment of rats with cocaine, but not with several non-abused drugs, produced similar changes compared to morphine in G-proteins, adenylate cyclase, and cyclic AMP-dependent protein kinase in the NAc, but not in the other brain regions studied. These results indicate that regulation of the G-protein/cyclic AMP system represents a mechanism by which a number of opiate-sensitive neurons adapt to chronic morphine and thereby develop aspects of opiate tolerance and/or dependence. The findings that chronic morphine and cocaine produce similar adaptations in the NAc, a brain region important for the reinforcing actions of many types of abused substances, suggest further that common mechanisms may underlie psychological aspects of drug addiction mediated by this brain region. (c) 1991. This article is part of a Special Issue entitled SI:50th Anniversary Issue. PMID- 26740399 TI - Stress-induced remodeling of hippocampal CA3 pyramidal neurons. AB - The discovery of steroid hormone receptors in brain regions that mediate virtually every aspect of brain function has broadened the definition of 'neuroendocrinology' to include the reciprocal communication between the brain and the body via hormonal and neural pathways. The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as determining the behavioral and physiological responses to the stressor. The adult and developing brain possess remarkable structural and functional plasticity in response to stress, including neurogenesis leading to neuronal replacement, dendritic remodeling, and synapse turnover. Stress causes an imbalance of neural circuitry subserving cognition, decision-making, anxiety and mood that can alter expression of those behaviors and behavioral states. The two Brain Research papers noted in this review played an important role in triggering these advances. This article is part of a Special Issue entitled SI:50th Anniversary Issue. PMID- 26740400 TI - Neuroprotection of inositol hexaphosphate and changes of mitochondrion mediated apoptotic pathway and alpha-synuclein aggregation in 6-OHDA induced parkinson's disease cell model. AB - Animal and cell experiments showed that inositol hexaphosphate (IP6) was protective on neurons in parkinson's disease (PD) model, but the underlying mechanism of this action was not extensively elucidated. To address this question, we established 6-hydroxydopamine (6-OHDA) induced human dopaminergic cell line SH-SY5Y as PD cell model and testified the neuroprotection of IP6. Through hoechst nuclear stain method and flow cytometric analysis, apoptosis induced by 6-OHDA was blocked by IP6 pretreatment. Significant protection against reactive oxygen species (ROS) and lipid peroxidation product malondialdehyde (MDA) was observed in 6-OHDA induced cells pretreated with IP6. To further investigate the mechanism of anti-apoptotic effect of IP6, expression of mediators in mitochondrion dependent apoptotic pathway was detected. Results indicated that loss of mitochondrial membrane potential, cytochrome c releasing, upregulation of Bcl-2-associated X protein (Bax), downregulation of B-cell CLL/lymphoma 2 (Bcl-2) and caspases activation were reversed by IP6. In addition, using flow cytometric method and western blot approach, our data showed that IP6 attenuated the rise of calcium and alpha-synuclein aggregation in cytosol. Collectively, IP6 exerted its neuroprotection on dopaminergic cells in PD cell model and the mechanism may be associated with changes of mitochondrion mediated apoptotic pathway and alpha-synuclein aggregation. PMID- 26740401 TI - Preattentive and attentive responses to changes in small numerosities of tones in adult humans. AB - The brain hosts a primitive number sense to non-symbolically represent numerosities of objects or events. Small exact numerosities (~4 or less) can be individuated in parallel. In contrast, large numerosities (more than ~4) can only be approximated. However, whether small numerosities can be approximated without their parallel individuation remains unclear. Parallel individuation is suggested to be an attentive process and numerical approximation an automatic process. We, therefore, tested whether small numerosities can be represented preattentively. We recorded adult humans' event-related potentials (ERPs) and behavioral responses to 300-ms sequences of six tones (each of either 440 Hz or 660 Hz in frequency). Mostly, a sequence was of 3 tones of each frequency. Occasionally (P=0.1), the numerosities were 4 and 2 (minor changes) or 5 and 1 (major changes). Mismatch negativity (MMN), but no later attention-related positive polarity ERPs, was observed to the major but not to the minor changes during a visual non-numerical task. In a following attentive task, behavioral responses even to major changes resulted in a very low hit rates (0.11 for major and 0.023 for minor changes) and yet an above-zero false-alarm rate (0.052). The findings support a view that small numerosities of objects can be automatically approximated independently of their attentive individuation. PMID- 26740402 TI - Neural mechanisms of sentence comprehension based on predictive processes and decision certainty: Electrophysiological evidence from non-canonical linearizations in a flexible word order language. AB - The specificity or generality of language-related event-related brain potentials (ERPs) has been a point of continuing debate in the cognitive neuroscience of language. The present study measured ERPs to (preferred) subject-before-object (SO) and (dispreferred) object-before-subject (OS) word orders in German while manipulating morphosyntactic and semantic cues to correct sentence interpretation. We presented sentence pairs as connected speech (context and target sentences) and examined ERPs at the position of the first argument (noun phrase) in the target sentence. At this position, word order was determinable by either (a) case marking (morphosyntactic cue); (b) animacy (semantic cue); or (c) the preceding context sentence (local ambiguity; contextual cue). Following each sentence pair, participants judged the acceptability of the second sentence in the context of the first and performed a probe word recognition task. Results showed a biphasic N400-P600 pattern at the first noun phrase in the OS conditions irrespectively of which cues (syntactic or semantic) were available to the parser for disambiguation. N400 latency varied as a function of temporal cue availability and P600 amplitude increased for unambiguous object-initial conditions even though these were rated acceptable in the judgment task. These findings support an interpretation of ERP components in terms of general cognitive mechanisms such as predictive processes (N400) and decision certainty (P600 as an instance of the P300) rather than a domain-specific view of a semantic N400 and a syntactic P600. PMID- 26740403 TI - Individual vulnerabilities relative for potential pathological conditions. AB - It is not a usual venture to review experiments conducted decades ago in the context of interests of that time and replace them in a long-term historical perspective. These investigations were the product of a long-standing interest for individual differences in vulnerabilities relative to coping with stressful situations and for potential pathological conditions such as drug abuse. The rationale was, and still is, to decipher the psychobiological characteristics of these complex traits. ORIGINAL ARTICLE ABSTRACT: STRESS- AND PHARMACOLOGICALLY INDUCED BEHAVIORAL SENSITIZATION INCREASES VULNERABILITY TO ACQUISITION OF AMPHETAMINE SELF-ADMINISTRATION: Individual vulnerability to drug addiction may be an important factor in the prognosis of pathological behavior in man. However, experimental investigations have largely neglected the psychobiological substrate of predisposition to addiction. In this study, we use a self-administration (SA) acquisition paradigm showing that previous repeated exposure to a stressful experience (tail-pinch) or to amphetamine increases the locomotor response to this drug (behavioral sensitization) and enhances vulnerability to amphetamine SA. These results show that vulnerability to developing amphetamine SA may be influenced by stressful experiences, and that previous contact with the drug may also enhance a predisposition to amphetamine-taking behavior. As tail-pinch and amphetamine sensitization affect both the dopamine (DA) neural system and the propensity to self-administer amphetamine (a behavior also modulated by DA activity), stress may influence SA via an action on the DA system. (c) 1990. This article is part of a Special Issue entitled SI:50th Anniversary Issue. PMID- 26740404 TI - Bimodal bilingualism as multisensory training?: Evidence for improved audiovisual speech perception after sign language exposure. AB - The aim of the present study was to characterize effects of learning a sign language on the processing of a spoken language. Specifically, audiovisual phoneme comprehension was assessed before and after 13 weeks of sign language exposure. L2 ASL learners performed this task in the fMRI scanner. Results indicated that L2 American Sign Language (ASL) learners' behavioral classification of the speech sounds improved with time compared to hearing nonsigners. Results indicated increased activation in the supramarginal gyrus (SMG) after sign language exposure, which suggests concomitant increased phonological processing of speech. A multiple regression analysis indicated that learner's rating on co-sign speech use and lipreading ability was correlated with SMG activation. This pattern of results indicates that the increased use of mouthing and possibly lipreading during sign language acquisition may concurrently improve audiovisual speech processing in budding hearing bimodal bilinguals. PMID- 26740405 TI - Therapies negating neuroinflammation after brain trauma. AB - Traumatic brain injury (TBI) elicits a complex secondary injury response, with neuroinflammation as a crucial central component. Long thought to be solely a deleterious factor, the neuroinflammatory response has recently been shown to be far more intricate, with both beneficial and detrimental consequences depending on the timing, magnitude and specific immune composition of the response post injury. Despite extensive preclinical and clinical research into mechanisms of secondary injury after TBI, no effective neuroprotective therapy has been identified, with potential candidates repeatedly proving disappointing in the clinic. The neuroinflammatory response offers a promising avenue for therapeutic targeting, aiming to quell the deleterious consequences without influencing its function in providing a neurotrophic environment supportive of repair. The present review firstly describes the findings of recent clinical trials that aimed to modulate inflammation as a means of neuroprotection. Secondly, we discuss promising multifunctional and single-target anti-inflammatory candidates either currently in trial, or with ample experimental evidence supporting clinical application. This article is part of a Special Issue entitled SI:Brain injury and recovery. PMID- 26740406 TI - Serotonin receptors in brain revisited. AB - In the early 1980's, the dispute on the existence of a multiplicity of receptors for neurotransmitter was at its height. Several subtypes of serotonin (5-HT) receptors were proposed on the basis of radioligand binding assays. In order to provide further support to the existence of these receptors we performed quantitative autoradiographic mapping of the binding of several ligands for the 5 HT1 receptor labeling the subtypes 5-HT1A, 5-HT1B and 5-HT1C, and characterized pharmacologically these different receptors. The results demonstrated differential localization of the subtypes of 5-HT1 receptors indicating that they were expressed by different cell populations, probably neurons, in the brain and further supporting their reality. Shortly afterwards, the cloning of the genes coding for these 5-HT receptors, and many others, ended the dispute by demonstrating that they were different proteins. The advent of Molecular Biology provided new methodologies for the study of the chemical and molecular anatomy of 5-HT receptors in brain, by visualizing cells expressing their mRNA by in situ hybridization and showed that the family of mammalian 5-HT receptors has 14 members, a figure much larger than ever suspected at that time. ORIGINAL ARTICLE ABSTRACT: QUANTITATIVE AUTORADIOGRAPHIC MAPPING OF SEROTONIN RECEPTORS IN THE RAT BRAIN. I. SEROTONIN-1 RECEPTORS: The distribution of serotonin-1 (5-HT1) receptors in the rat brain was studied by light microscopic quantitative autoradiography. Receptors were labeled with [(3)H]serotonin (5-[(3)H]HT), 8 hydroxy-2-[H-dipropylamino-(3)H]tetralin (8-OH-[(3)H]DPAT), [(3)H]LSD and [(3)H]mesulergine, and the densities quantified by microdensitometry with the aid of a computer-assisted image-analysis system. Competition experiments for 5 [(3)H]HT binding by several serotonin-1 agonizts led to the identification of brain areas enriched in each one of the three subtypes of 5-HT1 recognition sites already described (5-HT1A, 5-HT1B, 5-HT1C). The existence of these'selective' areas allowed a detailed pharmacological characterization of these sites to be made in a more precise manner than has been attained in membrane-binding studies. While 5-[(3)H]HT labeled with nanomolar affinity all the 5-HT1 subtypes, the other (3)H-labeled ligands labeled selectively 5-HT1A (8-OH-[(3)H]DPAT), 5-HT1C ([(3)H]mesulergine) and both of them ([(3)H]LSD). Very high concentrations of 5 HT1 receptors were localized in the choroid plexus, lateroseptal nucleus, globus pallidus and ventral pallidum, dentate gyrus, dorsal subiculum, olivary pretectal nucleus, substantia nigra, reticular and external layer of the entorhinal cortex. The different fields of the hippocampus (CA1-CA4), some nuclei of the amygdaloid complex, the hypothalamic nuclei and the dorsal raphe, among others, also presented high concentrations of sites. Areas containing intermediate densities of 5-HT1 receptors included the claustrum, olfactory tubercle, accumbens, central gray and lateral cerebellar nucleus. The nucleus caudate-putamen and the cortex, at the different levels studied, presented receptor densities ranging from intermediate to low. Finally, in other brain areas-pons, medulla, and spinal cord only low or very low concentrations of 5-HT1 receptors were found. From the areas strongly enriched in 5-HT1 sites, dentate gyrus and septal nucleus contained 5 HT1A sites, while globus pallidus, dorsal subiculum, substantia nigra and olivary pretectal nucleus were enriched in 5-HT1B. The sites in the choroid plexus, which presented the highest density of receptors in the rat brain, were of the 5-HT1C subtype. The distribution of 5-HT1 receptors reported here is discussed in correlation with the distribution of serotoninergic neurons and fibers, the related anatomical pathways and the effects which appear to be mediated by these sites. (c) 1985.This article is part of a Special Issue entitled SI:50th Anniversary Issue. This article is part of a Special Issue entitled SI:50th Anniversary Issue. PMID- 26740407 TI - Chronic low-dose melatonin treatment maintains nigrostriatal integrity in an intrastriatal rotenone model of Parkinson's disease. AB - Parkinson's disease is a major neurodegenerative disorder which primarily involves the loss of dopaminergic neurons in the substantia nigra and related projections in the striatum. The pesticide/neurotoxin, rotenone, has been shown to cause systemic inhibition of mitochondrial complex I activity in nigral dopaminergic neurons, with consequent degeneration of the nigrostriatal pathway, as observed in Parkinson's disease. A novel intrastriatal rotenone model of Parkinson's disease was used to examine the neuroprotective effects of chronic low-dose treatment with the antioxidant indoleamine, melatonin, which can upregulate neurotrophic factors and other protective proteins in the brain. Sham or lesioned rats were treated with either vehicle (0.04% ethanol in drinking water) or melatonin at a dose of 4 ug/mL in drinking water. The right striatum was lesioned by stereotactic injection of rotenone at three sites (4 MUg/site) along its rostrocaudal axis. Apomorphine administration to lesioned animals resulted in a significant (p<0.001) increase in ipsilateral rotations, which was suppressed by melatonin. Nine weeks post-surgery, animals were sacrificed by transcardial perfusion. Subsequent immunohistochemical examination revealed a decrease in tyrosine hydroxylase immunoreactivity within the striatum and substantia nigra of rotenone-lesioned animals. Melatonin treatment attenuated the decrease in tyrosine hydroxylase in the striatum and abolished it in the substantia nigra. Stereological cell counts indicated a significant (p<0.05) decrease in dopamine neurons in the substantia nigra of rotenone-lesioned animals, which was confirmed by Nissl staining. Importantly, chronic melatonin treatment blocked the loss of dopamine neurons in rotenone-lesioned animals. These findings strongly support the therapeutic potential of long-term and low dose melatonin treatment in Parkinson's disease. PMID- 26740408 TI - Tension pneumothorax during flexible bronchoscopy in a nonintubated infant. AB - We describe the case of a tension pneumothorax occurring during flexible bronchoscopy in a nonintubated infant. The pneumothorax likely occurred secondary to wall source oxygen insufflation via the bronchoscope without sufficient gas egress. The use of wall source oxygen via the bronchoscope working channel is inherently dangerous and should be avoided. PMID- 26740411 TI - Topical nitroglycerin ointment to aid umbilical artery cannulation in neonates. PMID- 26740412 TI - Conversation prior to resuscitation: The new CPR. PMID- 26740413 TI - Corticosteroids and inflammation after cardiac arrest. PMID- 26740414 TI - Reply to Letter: 'Corticosteroids and inflammation after cardiac arrest'. PMID- 26740415 TI - Epithelioid Schwannoma of a Spinal Nerve Root. PMID- 26740416 TI - Hallucinations, loneliness, and social isolation in Alzheimer's disease. AB - INTRODUCTION: Cognitive and functional compromise, as frequently observed in Alzheimer's disease (AD), hinders communication and social interactions. One consequence of this hindrance may be a feeling of loneliness. Moreover, emptiness and boredom, as observed in social isolation and loneliness, may thus be compensated for by creating imagined stimuli. Conditions of loneliness may be viewed as potentially generating hallucinatory experiences. To assess this assumption, the present study explored the relationship between social isolation, loneliness, and hallucinations in a sample of 22 mild AD participants and 24 elderly, healthy controls. METHODS: Participants were assessed using the Launay Slade Hallucination Scale, the UCLA Loneliness Scale, and a scale exploring contact with others and social participation. RESULTS: More hallucinatory experiences, social isolation, and loneliness were found in the AD group than in the healthy control group. Moreover, significant correlations were observed between hallucinations and loneliness and between hallucinations and social isolation in both groups. Finally, hallucinations were predicted by social isolation. DISCUSSION: Hallucinations may constitute a compensatory mechanism that aims to fulfil communication needs in lonely, elderly participants. Hallucinations may also be regarded as experiences that allow certain participants to escape the cycle of boredom, emptiness, and affective deprivation caused by social isolation. PMID- 26740417 TI - Inflammatory biomarkers predicting prognosis in patients with acute dyspnea. AB - OBJECTIVE/PURPOSE: The objective was to identify inflammatory biomarkers that predict risk of 90-day mortality in patients with acute dyspnea. METHOD: We analyzed 25 inflammatory biomarkers, in plasma, in 407 adult patients admitted to the emergency department (ED) with acute dyspnea and related them to risk of 90 day mortality using Cox proportional hazard models adjusted for age, sex, oxygen saturation, respiratory rate, C-reactive protein, and Medical Emergency Triage and Treatment System-Adult score. RESULTS: Fifty patients (12%) died within 90 day from admission. Two strong and independent biomarker signals were detected: The hazard ratio (95% confidence interval) for 90-day mortality per 1-SD increment of interleukin-8 (IL-8) was 2.20 (1.67-2.90) (P = 2.5 * 10(-8)) and for growth differentiation factor-15 (GDF-15) was 3.45 (2.18-5.45) (P = 1.3 * 10(-7)) A Biomarker Mortality Risk Score (BMRS) summing standardized and weighted values of IL-8 and GDF-15 revealed that of patients belonging to quartile 1 (Q1) of the BMRS, only 1 patient died, whereas 32 patients died among those belonging to quartile 4. Each 1-SD increment of the BMRS was associated with a hazard ratio of 3.79 (2.50-5.73) (P = 2 * 10(-10)) for 90-day mortality, and the point estimate was 13 times higher in Q4 as compared with Q1 of the BMRS (P(trend) over quartiles = 2 * 10(-6)). CONCLUSION: Interleukin-8 and GDF-15 are strongly and independently related to risk of 90-day mortality in unselected patients admitted to the ED because of acute dyspnea, suggesting that they may guide first-line physicians at the ED in risk assessment which in turn could lead to more accurate level of care and treatment intensity. PMID- 26740418 TI - Mitigating hyperventilation during cardiopulmonary resuscitation. AB - Although multiple airway management and ventilation strategies have been proposed during cardiac arrest, the ideal strategy is unknown. Current strategies call for advanced airways, such as endotracheal intubation and supraglottic airways. These may facilitate hyperventilation which is known to adversely affect cardiopulmonary physiology. We provide a summary of conceptual models linking hyperventilation to patient outcomes and identify methods for mitigating hyperventilation during cardiac arrest. PMID- 26740419 TI - A suspected case of IgG4-related bilateral arthritis of the knee. PMID- 26740420 TI - The effect of rhBMP-2 in a novel, non-instrumented extremity nonunion model. AB - BACKGROUND: Pre-clinical models of bony nonunion typically employ critical-length defects. However, these models may not accurately reflect clinical practice since many nonunions are diagnosed without bone loss. We developed a non-displaced rat ulna fracture model in order to examine the efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2) with an absorbable collagen sponge (ACS) for nonunion treatment. METHODS: Transverse diaphyseal ulna fractures were created in 24 Sprague-Dawley rats. Eight animals (Group 1: Nonunion) received no further intervention. The remaining 16 animals were treated with 5 MUg rhBMP-2/ACS at 8 weeks after the original intervention (Group 2: Nonunion + BMP) or at the time of initial injury (Group 3: Fresh fracture + BMP). RESULTS: In Group 1, 7 of 8 fractures demonstrated gross motion and a persistent radiographic gap (12.5% healing rate). In Groups 2 and 3, fractures healed at a rate of 75% (6 of 8 in each group) as determined by manual and radiographic evaluation. Biomechanical testing for torque load-to-failure and torsional stiffness demonstrated no significant difference between healed specimens treated with rhBMP-2. CONCLUSIONS: To our knowledge, this is the first description of a physiologic, non-stabilized, non-defect fracture nonunion model in a rodent. Furthermore, unlike previous nonunion models, the healing rates after treatment with rhBMP-2 are comparable to that of clinical data, suggesting that this model may provide an environment more representative of nonunions in humans. PMID- 26740421 TI - Treatment of perimedullary arteriovenous fistula of the spinal cord by superselective neuroendovascular therapy: A case report and literature review. PMID- 26740422 TI - Tissue-engineered cartilage implantation for the chondral lesion in a patient with multiple epiphyseal dysplasia. PMID- 26740423 TI - Functional evaluation and DASH scores of a patient treated with second toe-to thumb transfers for bilateral thumb amputations: A case report. PMID- 26740425 TI - The Asian size Exeter femoral stem fracture. PMID- 26740424 TI - Malignant peripheral nerve sheath tumor in the cervical spine with multiple nevus cell nevi. PMID- 26740426 TI - Pyogenic spondylodiscitis following anti-interleukin-6 therapy in a patient with rheumatoid arthritis (implication of hematogenous infection risk in degenerative intervertebral discs): A case report and review of the literature. PMID- 26740427 TI - Chronic expanding hematoma resulting from osteoporotic insufficiency fracture of the pubis. PMID- 26740428 TI - Locking plate fixation with femoral head allograft for treatment of nonunion of the surgical neck of the humerus: A case report. PMID- 26740429 TI - Arthroscopic fixation of iatrogenic glenoid rim fracture caused by brisement manipulation: Two case reports. PMID- 26740430 TI - Spinal nerve root transection caused by spinal instability after osteoporotic vertebral collapse: A case report. PMID- 26740431 TI - A case of femoral pseudoaneurysm after surgery for intertrochanteric fracture. PMID- 26740433 TI - Three-year follow-up study of health related QOL and lifestyle indicators for Japanese patients after total hip arthroplasty. AB - BACKGROUND: In non-Western countries including Japan, activities requiring deep flexion of the hip joint, such as seiza (kneeling with calves tucked under the thighs and buttocks resting on the heels) and using squat toilets are commonly practiced. The purpose of this study was to assess longitudinal changes in traditional health-related quality of life measures and measures of physical functions associated with lifestyle for Japanese patients pre-surgery and after total hip arthroplasty. METHODS: Consecutive primary total hip arthroplasty patients between July 2003 and November 2006 were eligible. Patients were measured preoperatively and at 6 weeks, 1 year and 3 years postoperatively. Patients completed the EuroQol 5D, the Western Ontario and McMaster Universities Osteoarthritis Index and items related to Japanese lifestyle activities such as squatting. Changes in these scale scores across the four time points were tested, and we examined predictive factors of EuroQol 5D score at 3-year follow-up using multiple linear regression. RESULTS: Of 1103 eligible patients, 576 completed questionnaires at all four time points. By 6 weeks post-surgery, reductions in pain and improvements in physical function and stiffness became highly significant, and improvements continued to 3 years postoperative. In contrast, improvements were far more limited for items related to Japanese lifestyle functions such as seiza and use of a Japanese squat toilet, even 3 years after surgery. Predictive factors of EQ5D at 3-year post THA were WOMAC pain and physical function, seiza, age and comorbidity measured at 3-year post THA. CONCLUSION: The rate of improvement in QOL requiring deep flexion of the hip joint was much slower than that in QOL related to Western lifestyle. Our study suggests a need for lifestyle modification for THA patients in the other countries where kneeling and squatting are commonly performed. PMID- 26740434 TI - A foreign body granuloma after the usage of polyglycolic acid mesh and fibrin glue for dural repair. A case report. PMID- 26740432 TI - Reconstruction using frozen tumour-bearing vertebra en bloc after total spondylectomy. PMID- 26740435 TI - A case report on a very rare variant of popliteal artery entrapment syndrome due to an enlarged fabella associated with severe knee osteoarthritis. PMID- 26740436 TI - Delayed esophageal perforation 17 years after anterior cervical fusion surgery with plating. PMID- 26740437 TI - Reverse total shoulder arthroplasty in the treatment of chronic anterior fracture dislocation complicated by a chronic full thickness retracted rotator cuff tear in an elderly patient. PMID- 26740439 TI - Two-stage surgery on pregnant woman with a giant cell tumor of bone who refused blood transfusion: A case report. PMID- 26740438 TI - Plantar fibromatosis with flexion contracture and valgus deformity of the great toe. PMID- 26740440 TI - Posterior approach using a proximal humeral internal locking system long plate for open fractures of the distal tibia: A report of three cases. PMID- 26740441 TI - Metallosis and cobalt - chrome intoxication after hip resurfacing arthroplasty. PMID- 26740442 TI - Avulsion fracture of the calcaneal tuberosity treated using a side-locking loop suture (SLLS) technique through bone tunnels. PMID- 26740443 TI - Arthroscopic treatment of an osteoid osteoma at the base of the coracoid process: A case report. PMID- 26740444 TI - A cervical myelopathy associated with an anomaly of the axis: Two case reports of invaginated spinous process of the axis with spina bifida into the spinal canal. PMID- 26740445 TI - Longitudinal stress fracture of the patella in a female weightlifter. PMID- 26740446 TI - Midshaft clavicle fracture with ipsilateral acromioclavicular joint separation found during serial follow-up. PMID- 26740447 TI - Reconstruction of right thumb with duplicated left thumb: A case report with 7 year follow-up. PMID- 26740448 TI - Alcohol-associated osteonecrosis of the femoral head with subsequent development in the contralateral hip: A report of two cases. PMID- 26740451 TI - Corrective osteotomy for malunited small finger proximal phalangeal fracture using linkage simulation: A case report. PMID- 26740450 TI - A novel nerve root anomaly with unpredictable morphology on diffusion tensor imaging in the lumbar spine: A case report. PMID- 26740449 TI - Once-weekly teriparatide administration for an Anderson type II odontoid fracture in an elderly patient: A case report. PMID- 26740452 TI - Severe toxicity of chemotherapy against advanced soft tissue sarcoma in Werner's syndrome: Ifosfamide-induced encephalopathy with central diabetes insipidus. PMID- 26740453 TI - Clinical features and surgical management of rare cases of thoracic intraspinal cysts: Report of 3 cases. PMID- 26740454 TI - Delayed detection of testicular dislocation with pelvic ring fracture: A case report. PMID- 26740455 TI - Orbito-frontal cortex and thalamus volumes in the patients with obsessive compulsive disorder before and after cognitive behavioral therapy. AB - Background The effect of a variety of treatment modalities including psychopharmacological and cognitive behavioral therapy on the brain volumes and neurochemicals have not been investigated enough in the patients with obsessive compulsive disorder. Therefore, in the present study, we aimed to investigate the effect of cognitive behavioral therapy on the volumes of the orbito-frontal cortex and thalamus regions which seem to be abnormal in the patients with obsessive-compulsive disorder. We hypothesized that there would be change in the volumes of the orbito-frontal cortex and thalamus. Methods Twelve patients with obsessive-compulsive disorder and same number of healthy controls were included into the study. At the beginning of the study, the volumes of the orbito-frontal cortex and thalamus were compared by using magnetic resonance imaging. In addition, volumes of these regions were measured before and after the cognitive behavioral therapy treatment in the patient group. Results The patients with obsessive-compulsive disorder had greater left and right thalamus volumes and smaller left and right orbito-frontal cortex volumes compared to those of healthy control subjects at the beginning of the study. When we compared baseline volumes of the patients with posttreatment ones, we detected that thalamus volumes significantly decreased throughout the period for both sides and that the orbito frontal cortex volumes significantly increased throughout the period for only left side. Conclusions In summary, we found that cognitive behavioral therapy might volumetrically affect the key brain regions involved in the neuroanatomy of obsessive-compulsive disorder. However, future studies with larger sample are required. PMID- 26740456 TI - An inquiry into the causes and effects of the variolae (or Cow-pox. 1798). AB - Few papers have had a greater impact on the health of the human species than the simple, yet elegant, observations and clinical trials of Edward Jenner with what was at the time called the Cow Pox. In fact, this was a naturally attenuated rodent (probably rat) pox that could infect horses and, through farriers and farm hands, dairy cattle. While commonly called the Cow Pox at the time, Jenner's transmission studies between humans used infectious materials from horses. His methods provided protection from the serious effects of smallpox infections. In 1977, smallpox was considered to be eradicated, although people continue to be infected by pox viruses from other mammalian species. We consider this to be our 'favorite historical paper' because it emphasizes careful clinical observation followed by relatively simple clinical testing can have a profound influence on human health, even when almost nothing is known about the underlying molecular mechanisms. Continued follow-up with strict attention to detail resulted in a crude but effective way to deal with an epidemic, methods still used today for containing infectious diseases. PMID- 26740458 TI - A novel semi-supervised algorithm for the taxonomic assignment of metagenomic reads. AB - BACKGROUND: Taxonomic assignment is a crucial step in a metagenomic project which aims to identify the origin of sequences in an environmental sample. Among the existing methods, since composition-based algorithms are not sufficient for classifying short reads, recent algorithms use only the feature of similarity, or similarity-based combined features. However, those algorithms suffer from the computational expense because the task of similarity search is very time consuming. Besides, the lack of similarity information between reads and reference sequences due to the length of short reads reduces significantly the classification quality. RESULTS: This paper presents a novel taxonomic assignment algorithm, called SeMeta, which is based on semi-supervised learning to produce a fast and highly accurate classification of short-length reads with sufficient mutual overlap. The proposed algorithm firstly separates reads into clusters using their composition feature. It then labels the clusters with the support of an efficient filtering technique on results of the similarity search between their reads and reference databases. Furthermore, instead of performing the similarity search for all reads in the clusters, SeMeta only does for reads in their subgroups by utilizing the information of sequence overlapping. The experimental results demonstrate that SeMeta outperforms two other similarity based algorithms on different aspects. CONCLUSIONS: By using a semi-supervised method as well as taking the advantages of various features, the proposed algorithm is able not only to achieve high classification quality, but also to reduce much computational cost. The source codes of the algorithm can be downloaded at http://it.hcmute.edu.vn/bioinfo/metapro/SeMeta.html. PMID- 26740457 TI - The expanding repertoire of receptor activity modifying protein (RAMP) function. AB - Receptor activity modifying proteins (RAMPs) associate with G-protein-coupled receptors (GPCRs) at the plasma membrane and together bind a variety of peptide ligands, serving as a communication interface between the extracellular and intracellular environments. The collection of RAMP-interacting GPCRs continues to expand and now consists of GPCRs from families A, B and C, suggesting that RAMP activity is extremely prevalent. RAMP association with GPCRs can regulate GPCR function by altering ligand binding, receptor trafficking and desensitization, and downstream signaling pathways. Here, we elaborate on these RAMP-dependent mechanisms of GPCR regulation, which provide opportunities for pharmacological intervention. PMID- 26740459 TI - Flexibility and conformation of the cocaine aptamer studied by PELDOR. AB - The cocaine aptamer is a DNA three-way junction that binds cocaine at its helical junction. We studied the global conformation and overall flexibility of the aptamer in the absence and presence of cocaine by pulsed electron-electron double resonance (PELDOR) spectroscopy, also called double electron-electron resonance (DEER). The rigid nitroxide spin label C was incorporated pairwise into two helices of the aptamer. Multi-frequency 2D PELDOR experiments allow the determination of the mutual orientation and the distances between two Cs. Since C is rigidly attached to double-stranded DNA, it directly reports on the aptamer dynamics. The cocaine-bound and the non-bound states could be differentiated by their conformational flexibility, which decreases upon binding to cocaine. We observed a small change in the width and mean value of the distance distribution between the two spin labels upon cocaine binding. Further structural insights were obtained by investigating the relative orientation between the two spin labeled stems of the aptamer. We determined the bend angle between this two stems. By combining the orientation information with a priori knowledge about the secondary structure of the aptamer, we obtained a molecular model describing the global folding and flexibility of the cocaine aptamer. PMID- 26740461 TI - Multi-hierarchical profiling: an emerging and quantitative approach to characterizing diverse biological networks. AB - Multi-hierarchical profiling may offer valuable insights into the structural stability and functional direction of biological networks in cellular development, pathological process and disease variation. Owing to the emergence of several new techniques, such as bioinformatics for omics data, structural biology and structural bioinformatics, the pace of network hierarchical research has accelerated a lot in recent years. Here, we discuss and compare the techniques available for quantifying multilevel hierarchies, with a focus on their features, capabilities and drawbacks when used for different applications. Then, we classify these methods into three types: topological spatial-scales, multilevel hierarchical control and feature ordering. We observe that challenges and limitations do exist in functional hierarchical identification. And, we also provide useful suggestions on how to analyze the dynamic data of complex network studies. PMID- 26740460 TI - A proteogenomic approach to understand splice isoform functions through sequence and expression-based computational modeling. AB - The products of multi-exon genes are a mixture of alternatively spliced isoforms, from which the translated proteins can have similar, different or even opposing functions. It is therefore essential to differentiate and annotate functions for individual isoforms. Computational approaches provide an efficient complement to expensive and time-consuming experimental studies. The input data of these methods range from DNA sequence, to RNA selection pressure, to expressed sequence tags, to full-length complementary DNA, to exon array, to RNA-seq expression, to proteomic data. Notably, RNA-seq technology generates quantitative profiling of transcript expression at the genome scale, with an unprecedented amount of expression data available for developing isoform function prediction methods. Integrative analysis of these data at different molecular levels enables a proteogenomic approach to systematically interrogate isoform functions. Here, we briefly review the state-of-the-art methods according to their input data sources, discuss their advantages and limitations and point out potential ways to improve prediction accuracies. PMID- 26740462 TI - [Tattooing of the nipple-areola complex in breast reconstruction: Technical note]. AB - The reconstruction of the nipple-areola complex is an essential step in breast reconstruction. It announces the end of the reconstruction process, which is often long and sometimes difficult to live for the patient and will significantly improve the perception of body image. Concerning the reconstruction of the areola, tattooing is one of the preferred techniques. It's a simple, quick and safe procedure with a high satisfaction rate. This technique is still perfectible in our opinion, because the random lifetime of pigmentation is a recognized disadvantage of this procedure. We propose a modification of the conventional technique for improving the quality of dermopigmentation while reducing its completion time. Our method is to perform a dermabrasion before starting the tattoo. Indeed, dermabrasion allows better penetration of the pigments inside the dermis and thus offers two advantages: a more durable result over time and reduced operation time by reducing the number of passing of the machine tattoo. Finally, our tattooing technique seems relevant and totally appropriate: its realization is simple, reproducible, does not increase the overall cost of reconstruction, provides timesavings and gives a better long-term result. PMID- 26740463 TI - Regression of left ventricular hypertrabeculation is associated with improvement in systolic function and favorable prognosis in adult patients with non-ischemic cardiomyopathy. AB - BACKGROUND: We sometimes experience regression of left ventricular hypertrabeculation (LVHT), which is compatible with the diagnosis of LV non compaction cardiomyopathy (LVNC) in adult patients. However, little is known about the association between LVHT regression and LV systolic function in adult patients. METHODS: We prospectively examined 23 consecutive adult patients who fulfilled the echocardiographic criteria for LVNC. LV reverse remodeling (RR) was defined as an absolute increase in LV ejection fraction of >10% at 6 months follow-up. LVHT area was calculated by subtraction from the outer edge to the inner edge of the LVHT at end-systole. RESULTS: The mean follow-up period was 61 months. LVRR was observed in 9 patients (39%). The changes in the mean LVHT area showed significant correlation with the changes in LV ejection fraction (r=-0.78, p<0.0001). Cardiac death occurred in 7 patients (50%) without LVRR, but no patients with LVRR died (log-rank, p=0.003). Furthermore, composite of cardiac death and hospitalization for heart failure occurred in 10 patients (71%) without LVRR, whereas there was one patient with LVRR (log-rank, p<0.001). CONCLUSIONS: Regression of LVHT is associated with improvement in LV systolic function. LVRR might be associated with a favorable prognosis in patients with LVHT. PMID- 26740464 TI - Probing the binding of procyanidin B3 to trypsin and pepsin: A multi-technique approach. AB - Proanthocyanidins are a mixture of monomers, oligomers, and polymers of flavan-3 ols that are widely distributed in the plant kingdom. One of the most widely studied proanthocyanidins is procyanidin B3. In this study, the binding of procyanidin B3 to trypsin and pepsin was investigated using spectrofluorimetry, equilibrium microdialysis, circular dichroism (CD) spectroscopy and molecular modeling. Fluorescence experiments indicate procyanidin B3 quenches the fluorescence of trypsin/pepsin through a static process. Thermodynamic analysis reveals that procyanidin B3 binds to trypsin/pepsin is synergistically driven by enthalpy and entropy, and the major driving forces are hydrophobic, hydrogen bonding, and electrostatic interactions. Procyanidin B3 binds trypsin in a more firmly way than pepsin, and one molecule of procyanidin B3 combines with one molecule of trypsin/pepsin. The binding parameters obtained from equilibrium microdialysis are consistent with the results obtained from fluorescence spectroscopy. Synchronous fluorescence spectroscopy and CD spectroscopy show that procyanidin B3 may induce microenvironmental and conformational changes of trypsin and pepsin. Molecular modeling displays the specific binding site of procyanidin B3 on trypsin and pepsin. The study provides an accurate and full basic data for clarifying the binding mechanisms of procyanidin B3 with trypsin and pepsin and is helpful for understanding its biological activity in vivo. PMID- 26740465 TI - Structural and catalytic properties of immobilized alpha-amylase from Laceyella sacchari TSI-2. AB - One of the approaches to address the issues of the cost of production, recovery and reusability of the extremozymes can be immobilization. In this report, we describe immobilization of an alpha-amylase from Laceyella sacchari TSI-2 and characterization of the immobilized enzyme. The enzyme was immobilized on 6 different matrices using entrapment, ionic binding and surface adsorption. The DEAE cellulose with glutaraldehyde crosslinking appeared most effective for the immobilization with high operational stability. While the temperature optima and thermal stability of the immobilized alpha-amylase shifted from 60 to 70 degrees C with increased half-life, the pH optima remain unaltered while pH stability was shifted from 6 to 7. The stability of the immobilized enzyme improved in solvents. The enzyme catalysis in surfactants enhanced, while the Km and Vmax were reduced after immobilization. The structural features of the immobilized enzyme as probed by FT-IR established the role of aliphatic amines, esters and alkenes in immobilization. The starch hydrolysis efficiency of the immobilized enzyme was 15.55%. The immobilized enzyme in various detergents was highly efficient in removing the starch stain from cotton cloth. Taken together, the alpha-amylase turned more stable after immobilization and can be a favored choice for applications. PMID- 26740466 TI - Application of Box-Behnken design for preparation of levofloxacin-loaded stearic acid solid lipid nanoparticles for ocular delivery: Optimization, in vitro release, ocular tolerance, and antibacterial activity. AB - The aim of the present study was to develop and optimize levofloxacin loaded solid lipid nanoparticles for the treatment of conjunctivitis. Box-Behnken experimental design was applied for optimization of solid lipid nanoparticles. The independent variables were stearic acid as lipid (X1), Tween 80 as surfactant (X2) and sodium deoxycholate as co-surfactant (X3) while particle size (Y1) and entrapment efficiency (Y2) were the dependent variables. Further in vitro release and antibacterial activity in vitro were also performed. The optimized formulation of levofloxacin provides particle size of 237.82 nm and showed 78.71% entrapment efficiency and achieved flux 0.2,493 MUg/cm(2)/h across excised goat cornea. In vitro release study showed prolonged drug release from the optimized formulation following Korsmeyer-Peppas model. Antimicrobial study revealed that the developed formulation possesses antibacterial activity against Staphylococcus aureus, and Escherichia coli equivalent to marketed eye drops. HET-CAM test demonstrated that optimized formulation was found to be non-irritant and safe for topical ophthalmic use. Our results concluded that solid lipid nanoparticles are an efficient carrier for ocular delivery of levofloxacin and other drugs. PMID- 26740467 TI - Antibiotic loaded carboxymethylcellulose/MCM-41 nanocomposite hydrogel films as potential wound dressing. AB - Existing wound dressings have disadvantages such as lack of antibacterial activity, insufficient oxygen and water vapor permeability, and poor mechanical properties. Hydrogel-based wound dressings swell several times their dry volume and would be helpful to absorb wound exudates and afford a cooling sensation and a moisture environment. To overcome these hassles, a novel antibiotic-eluting nanocomposite hydrogel was designed via incorporation of mesoporous silica MCM-41 as a nano drug carrier into carboxymethylcellulose hydrogel. Tetracycline and methylene blue as antibacterial agents were loaded to the system and showed different release profiles. The prepared nanocomposite hydrogel was characterized using Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry (XRD), UV-vis spectroscopy, and scanning electron microscopy (SEM). The prepared nanocomposite hydrogels exhibited an enhanced in vitro swelling, erosion, water vapor and oxygen permeability, and antimicrobial activity. This could effectively increase the time intervals needed to exchange the bandage. The obtained data strongly encourage the use of these nanocomposite hydrogels as wound dressing material. PMID- 26740468 TI - Online Tobacco Cessation Training and Competency Assessment for Complementary and Alternative Medicine (CAM) Practitioners: Protocol for the CAM Reach Web Study. AB - BACKGROUND: Complementary and alternative medicine (CAM) practitioners, such as chiropractors, acupuncturists, and massage therapists, are a growing presence in the US health care landscape and already provide health and wellness care to significant numbers of patients who use tobacco. For decades, conventional biomedical practitioners have received training to provide evidence-based tobacco cessation brief interventions (BIs) and referrals to cessation services as part of routine clinical care, whereas CAM practitioners have been largely overlooked for BI training. Web-based training has clear potential to meet large-scale training dissemination needs. However, despite the exploding use of Web-based training for health professionals, Web-based evaluation of clinical skills competency remains underdeveloped. OBJECTIVE: In pursuit of a long-term goal of helping CAM practitioners integrate evidence-based practices from US Public Health Service Tobacco Dependence Treatment Guideline into routine clinical care, this pilot protocol aims to develop and test a Web-based tobacco cessation training program tailored for CAM practitioners. METHODS: In preparation for a larger trial to examine the effect of training on CAM practitioner clinical practice behaviors around tobacco cessation, this developmental study will (1) adapt an existing in-person tobacco cessation BI training program that is specifically tailored for CAM therapists for delivery via the Internet; (2) develop a novel, Web-based tool to assess CAM practitioner competence in tobacco cessation BI skills, and conduct a pilot validation study comparing the competency assessment tool to live video role plays with a standardized patient; (3) pilot test the Web-based training with 120 CAM practitioners (40 acupuncturists, 40 chiropractors, 40 massage therapists) for usability, accessibility, acceptability, and effects on practitioner knowledge, self efficacy, and competency with tobacco cessation; and (4) conduct qualitative and quantitative formative research on factors influencing practitioner tobacco cessation clinical behaviors (eg, practice environment, peer social influence, and insurance reimbursement). RESULTS: Web-training and competency assessment tool development and study enrollment and training activities are complete (N=203 practitioners enrolled). Training completion rates were lower than expected (36.9%, 75/203), necessitating over enrollment to ensure a sufficient number of training completers. Follow-up data collection is in progress. Data analysis will begin immediately after data collection is complete. CONCLUSIONS: To realize CAM practitioners' potential to promote tobacco cessation and use of evidence-based treatments, there is a need to know more about the facilitative and inhibitory factors influencing CAM practitioner tobacco intervention behaviors (eg, social influence and insurance reimbursement). Given marked differences between conventional and CAM practitioners, extant knowledge about factors influencing conventional practitioner adoption of tobacco cessation behaviors cannot be confidently extrapolated to CAM practitioners. The potential impact of this study is to expand tobacco cessation and health promotion infrastructure in a new group of health practitioners who can help combat the continuing epidemic of tobacco use. PMID- 26740469 TI - Exciting Times for Pancreatic Islets: Glutamate Signaling in Endocrine Cells. AB - Glutamate represents a key excitatory neurotransmitter in the central nervous system, and also modulates the function and viability of endocrine cells in pancreatic islets. In insulin-secreting beta cells, glutamate acts as an intracellular messenger, and its transport into secretory granules promotes glucose- and incretin-stimulated insulin secretion. Mitochondrial degradation of glutamate also contributes to insulin release when glutamate dehydrogenase is allosterically activated. It also signals extracellularly via glutamate receptors (AMPA and NMDA receptors) to modulate glucagon, insulin and somatostatin secretion, and islet cell survival. Its degradation products, GABA and gamma hydroxybutyrate, are released and also influence islet cell behavior. Thus, islet glutamate receptors, such as the NMDA receptors, might serve as possible drug targets to develop new medications for adjunct treatment of diabetes. PMID- 26740470 TI - Gastropod-Borne Helminths: A Look at the Snail-Parasite Interplay. AB - More than 300 million people suffer from a range of diseases caused by gastropod borne helminths, predominantly flatworms and roundworms, whose life cycles are characterized by a diversified ecology and epidemiology. Despite the plethora of data on these parasites, very little is known of the fundamental biology of their gastropod intermediate hosts, or of the interactions occurring at the snail helminth interface. In this article, we focus on schistosomes and metastrongylids of human and animal significance, and review current knowledge of snail-parasite interplay. Future efforts aimed at elucidating key elements of the biology and ecology of the snail intermediate hosts, together with an improved understanding of snail-parasite interactions, will aid to identify, plan, and develop new strategies for disease control focused on gastropod intermediate hosts. PMID- 26740473 TI - A review on possible therapeutic targets to contain obesity: The role of phytochemicals. AB - The prevalence and severity of obesity has increased markedly in recent decades making it a global public health concern. Since obesity is a potential risk factor in the development of hypertension, type-2 diabetes, cardiovascular diseases, infertility, etc., it is no more viewed as a cosmetic issue. Currently, only a few FDA-approved anti-obesity drugs like Orlistat, Lorcaserin and Phentermine-topiramate are available in the market, but they have considerable side effects. On the other hand, bariatric surgery as an alternative is associated with high risk and expensive. In view of these there is a growing trend towards natural product-based drug intervention as one of the crucial strategies for management of obesity and related ailments. In Asian traditional medicine and Ayurvedic literature a good number of plant species have been used and quoted for possible lipid-lowering and anti-obesity effects; however, many of them have not been evaluated rigorously for a definite recommendation and also lack adequate scientific validation. This review explores and updates on various plant species, their used parts, bioactive components and focuses multiple targets/pathways to contain obesity which may pave the way to develop novel and effective drugs. We also summarised different drugs in use to treat obesity and their current status. Nature is future promise of our wellbeing. PMID- 26740474 TI - Use of a control film piece in radiochromic film dosimetry. AB - PURPOSE: Radiochromic films change their color upon irradiation due to polymerization of the sensitive component embedded within the sensitive layer. However, agents, other than monitored radiation, can lead to a change in the color of the sensitive layer (temperature, humidity, UV light) that can be considered as a background signal and can be removed from the actual measurement by using a control film piece. In this work, we investigate the impact of the use of control film pieces on both accuracy and uncertainty of dose measured using radiochromic film based reference dosimetry protocol. METHODS: We irradiated "control" film pieces (EBT3 GafChromic(TM) film model) to known doses in a range of 0.05-1 Gy, and five film pieces of the same size to 2, 5, 10, 15 and 20 Gy, considered to be "unknown" doses. Depending on a dose range, two approaches to incorporating control film piece were investigated: signal and dose corrected method. RESULTS: For dose values greater than 10 Gy, the increase in accuracy of 3% led to uncertainty loss of 5% by using dose corrected approach. At lower doses and signals of the order of 5%, we observed an increase in accuracy of 10% with a loss of uncertainty lower than 1% by using the corrected signal approach. CONCLUSIONS: Incorporation of the signal registered by the control film piece into dose measurement analysis should be a judgment call of the user based on a tradeoff between deemed accuracy and acceptable uncertainty for a given dose measurement. PMID- 26740471 TI - Connexins in the skeleton. AB - Shaping of the skeleton (modeling) and its maintenance throughout life (remodeling) require coordinated activity among bone forming (osteoblasts) and resorbing cells (osteoclasts) and osteocytes (bone embedded cells). The gap junction protein connexin43 (Cx43) has emerged as a key modulator of skeletal growth and homeostasis. The skeletal developmental abnormalities present in oculodentodigital and craniometaphyseal dysplasias, both linked to Cx43 gene (GJA1) mutations, demonstrate that the skeleton is a major site of Cx43 action. Via direct action on osteolineage cells, including altering production of pro osteoclastogenic factors, Cx43 contributes to peak bone mass acquisition, cortical modeling of long bones, and maintenance of bone quality. Cx43 also contributes in diverse ways to bone responsiveness to hormonal and mechanical signals. Skeletal biology research has revealed the complexity of Cx43 function; in addition to forming gap junctions and "hemichannels", Cx43 provides a scaffold for signaling molecules. Hence, Cx43 actively participates in generation and modulation of cellular signals driving skeletal development and homeostasis. Pharmacological interference with Cx43 may in the future help remedy deterioration of bone quality occurring with aging, disuse and hormonal imbalances. PMID- 26740475 TI - Low-tube-voltage selection for non-contrast-enhanced CT: Comparison of the radiation dose in pediatric and adult phantoms. AB - PURPOSE: We used pediatric and adult anthropomorphic phantoms to compare the radiation dose of low- and standard tube voltage chest and abdominal non-contrast enhanced computed tomography (CT) scans. We also discuss the optimal low tube voltage for non-contrast-enhanced CT. METHODS: Using a female adult- and three differently-sized pediatric anthropomorphic phantoms we acquired chest and abdominal non-contrast-enhanced scans on a 320-multidetector CT volume scanner. The tube voltage was set at 80-, 100-, and 120 kVp. The tube current was automatically assigned on the CT scanner in response to the set image noise level. On each phantom and at each tube voltage we measured the surface and center dose using high-sensitivity metal-oxide-semiconductor field-effect transistor detectors. RESULTS: The mean surface dose of chest and abdominal CT scans in 5-year olds was 4.4 and 5.3 mGy at 80 kVp, 4.5 and 5.4 mGy at 100 kV, and 4.0 and 5.0 mGy at 120 kVp, respectively. These values were similar in our 3 pediatric phantoms (p > 0.05). The mean surface dose in the adult phantom increased from 14.7 to 19.4 mGy for chest- and from 18.7 to 24.8 mGy for abdominal CT as the tube voltage decreased from 120 to 80 kVp (p < 0.01). CONCLUSION: Compared to adults, the surface and center dose for pediatric patients is almost the same despite a decrease in the tube voltage and the low tube voltage technique can be used for non-contrast-enhanced chest- and abdominal scanning. PMID- 26740476 TI - Glutathione levels in plasma, saliva and gingival crevicular fluid after periodontal therapy in obese and normal weight individuals. AB - BACKGROUND AND OBJECTIVE: The purpose of this study was to investigate the effects of obesity on reduced and oxidized glutathione (GSH and GSSG) levels in the gingival crevicular fluid, plasma and saliva of patients with chronic periodontitis and to evaluate the changes after nonsurgical periodontal therapy. MATERIAL AND METHODS: The study included 60 patients: 30 patients with chronic periodontitis (15 obese patients and 15 normal weight patients) and 30 healthy control subjects (15 obese patients and 15 normal weight patients). Gingival crevicular fluid, plasma and saliva samples were collected, and clinical periodontal measurements were recorded at baseline and at the first month after periodontal therapy from patients with chronic periodontitis. GSH and GSSG levels were analyzed with spectrophotometry. RESULTS: The GSH levels in the plasma, saliva and gingival crevicular fluid in obese individuals with chronic periodontitis were lower than in normal weight individuals at baseline (p < 0.01). There was a significant difference in the GSH/GSSG ratio in plasma and gingival crevicular fluid between the obese and normal weight groups at baseline (p < 0.01). The GSH levels in plasma, gingival crevicular fluid and saliva were significantly increased in both chronic periodontitis groups after nonsurgical periodontal therapy (p < 0.01). A significant positive correlation was found between GSH levels in saliva, plasma and gingival crevicular fluid in all groups (p < 0.001). CONCLUSIONS: The study revealed that obesity in patients with chronic periodontitis is associated with decreased GSH levels and the GSH/GSSG ratio. Moreover, nonsurgical periodontal therapy may be helpful for improvement in glutathione values in obese and normal weight individuals with chronic periodontitis. PMID- 26740477 TI - Association of Myianoetus muscarum (Acari: Histiostomatidae) With Synthesiomyia nudiseta (Wulp) (Diptera: Muscidae) on Human Remains. AB - Synthesiomyia nudiseta (Wulp) (Diptera: Muscidae) was identified during the course of three indoor medicolegal forensic entomology investigations in the state of Texas, one in 2011 from Hayes County, TX, and two in 2015 from Harris County, TX. In all cases, mites were found in association with the sample and subsequently identified as Myianoetus muscarum (L., 1758) (Acariformes: Histiostomatidae). This report represents the first records of a mite associated with S. nudiseta in the continental United States. In particular, this association is believed to be of potential future value in forensic investigations, as it lends new insight into the community structure of colonizers on human remains in indoor environments. PMID- 26740478 TI - The effects of water sample treatment, preparation, and storage prior to cyanotoxin analysis for cylindrospermopsin, microcystin and saxitoxin. AB - Cyanobacterial harmful algal blooms occur in freshwater lakes, ponds, rivers, and reservoirs, and in brackish waters throughout the world. The wide variety of cyanotoxins and their congeners can lead to frequent exposure of humans through consumption of meat, fish, seafood, blue-green algal products and water, accidental ingestion of contaminated water and cyanobacterial scum during recreational activities, and inhalation of cyanobacterial aerosols. Cyanotoxins can also occur in the drinking water supply. In order to monitor human exposure, sensitive analytical methods such as enzyme linked immunosorbent assay and liquid chromatography-mass spectrometry are often used. Regardless of the analytical method of choice, some problems regularly occur during sample collection, treatment, storage, and preparation which cause toxin loss and therefore underestimation of the true concentration. To evaluate the potential influence of sample treatment, storage and preparation materials on surface and drinking water samples, the effects of different types of materials on toxin recovery were compared. Collection and storage materials included glass and various types of plastics. It was found that microcystin congeners LA and LF adsorbed to polystyrene, polypropylene, high density polyethylene and polycarbonate storage containers, leading to low recoveries (<70%), cylindrospermopsin and saxitoxin did not adsorb to the containers tested. Therefore, this study shows that glass or polyethylene terephthalate glycol containers are the materials of choice for collection and storage of samples containing the cyanotoxins cylindrospermopsin, microcystins, and saxitoxin. This study also demonstrated that after 15 min chlorine decreased the concentration of microcystin LR to <40%, microcystin LA and saxitoxin to <15%, therefore quenching of drinking water samples immediately upon sample collection is critical for accurate analysis. In addition, the effect of various drinking water treatment chemicals on toxin recovery and the behavior of those chemicals in the enzyme linked immunosorbent assays were also studied and are summarized. PMID- 26740479 TI - The clinical impact of contemporary stress echocardiography in morbid obesity for the assessment of coronary artery disease. AB - OBJECTIVE: Non-invasive cardiac imaging may suffer from poor image quality in morbidly obese individuals. This study aimed to determine the clinical value of contemporary stress echocardiography (SE) in morbidly obese patients referred for assessment of suspected coronary artery disease (CAD). METHODS: This prospective, multicentre observational study was conducted in two district hospitals and one tertiary centre in London, UK. Individuals with body mass index >=35 kg/m(2) referred for SE were evaluated. The percentage of patients with obstructive CAD on coronary angiography, following abnormal SE, was assessed. Patient outcomes were determined with follow-up for the composite end-point of all-cause mortality, myocardial infarction and late revascularisation. RESULTS: Over a 13 month period, 209 morbidly obese patients underwent SE, and contrast agent was used in 96% of patients. A diagnostic result was obtained in 200/209 (96%) patients. Of 32 (15%) patients with inducible ischaemia, 25 underwent angiography, 22 (88%) had corresponding significant CAD and, of these, 16 (77%) underwent revascularisation. Conversely, only 2/157 patients (1.3%) with normal SE underwent angiography, and none underwent revascularisation. Over a mean follow-up period of 17.8+/-5.4 months, there were nine events. The annualised cardiac event rate after a normal SE was 0.95%. Events were more frequent in patients with inducible ischaemia versus those without ischaemia (5/32 (15.6%) vs 4/153 (2.6%); p=0.002). Ejection fraction <50% (HR 9.5; 95% CI 2.4 to 38.0; p=0.002) and inducible ischaemia (HR 9.4; 95% CI 2.5 to 35.8; p=0.001) were predictors of outcome on univariable Cox regression analysis. CONCLUSIONS: Contemporary SE has excellent feasibility and positive predictive value and resulted in appropriate risk stratification of symptomatic patients with significant obesity. A normal SE portends an excellent outcome over the short intermediate term in this high-risk patient population. PMID- 26740480 TI - Ischaemic cardiomyopathy: pathophysiology, assessment and the role of revascularisation. PMID- 26740481 TI - Unexpectedly low left ventricular voltage on ECG in hypertrophic cardiomyopathy. AB - OBJECTIVE: While late gadolinium enhancement (LGE) in paediatric patients with hypertrophic cardiomyopathy (HCM) is reported as similar to adults, the relationship between LGE and ECG findings in paediatric patients is unknown. We sought to evaluate the relationship between LGE on cardiac MRI and LV precordial voltage on ECG. METHODS: This was a retrospective analysis of paediatric patients with HCM aged 9-21 years with cardiac MRI and ECG completed within 60 days of each other. Demographic, MRI and ECG data were compared between patients with and without LGE. Maximal diastolic septal thickness, septal to free wall ratio and LGE presence were compared with LV precordial voltage (SV1, RV6 and SV1+RV6). RESULTS: This study included 37 patients (33 male). Mean age was 15.8+/-2.8 years. Mean maximal LV diastolic septal thickness was 22.1+/-7.9 mm. Mean septal to free wall ratio was 2.4+/-1.6 mm. LGE was present in 18 patients, with 16 isolated to the ventricular septum. Comparing patients with and without LGE, there was no difference in age (p=0.2) or body surface area (p=0.9). However, the presence of LGE was associated with significantly increased septal thickness (p=0.03), yet decreased voltages in SV1 (p=0.005), RV6 (p=0.005) and SV1+RV6 (p=0.002) despite increased septal dimensions. CONCLUSIONS: A significant inverse relationship exists between LGE presence and LV precordial voltage in this population. Unexpectedly low LV precordial voltages in patients with HCM may serve as a clinical surrogate marker for myocardial fibrosis and potential loss of viable myocardial tissue. PMID- 26740482 TI - Clinical characterisation and long-term prognosis of women with Brugada syndrome. AB - OBJECTIVES: Brugada syndrome (BS) in women is considered an infrequent condition with a more favourable prognosis than in men. Nevertheless, arrhythmic events and sudden cardiac death (SCD) also occur in this population. Long-term follow-up data of this group are sparse. The purpose of the present study was to investigate the clinical characteristics and long-term prognosis of women with BS. METHODS: A consecutive cohort of 228 women presenting with spontaneous or drug-induced Brugada type I ECG at our institution were included and compared with 314 men with the same diagnosis. RESULTS: Mean age was 41.5+/-17.3 years. Clinical presentation was SCD in 6 (2.6%), syncope in 51 (22.4%) and the remaining 171 (75.0%) were asymptomatic. As compared with men, spontaneous type I ECG was less common (7.9% vs 23.2%, p<0.01) and less ventricular arrhythmias were induced during programmed electrical stimulation (5.5% vs 22.3%, p<0.01). An implantable cardioverter defibrillator (ICD) was implanted in 64 women (28.1%). During a mean follow-up of 73.2+/-56.2 months, seven patients developed arrhythmic events, constituting an event rate of 0.7% per year (as compared with 1.9% per year in men, p=0.02). Presentation as SCD or sinus node dysfunction (SND) was risk factor significantly associated with arrhythmic events (hazard risk (HR) 25.4 and 9.1). CONCLUSION: BS is common in women, representing 42% of patients in our database. Clinical presentation is less severe than men, with more asymptomatic status and less spontaneous type I ECG and prognosis is more favourable, with an event rate of 0.7% year. However, women with SCD or previous SND are at higher risk of arrhythmic events. PMID- 26740483 TI - Coronary revascularisation in older patients with non-ST elevation acute coronary syndromes. AB - With an ageing population, older patients with non-ST elevation acute coronary syndrome are at higher risk of adverse outcomes but are far less likely to receive invasive revascularisation, contemporary antiplatelet therapy or drug eluting stents than their younger counterparts. Accurate risk stratification in the older age groups may aid individualised decision-making with respect to identifying which patients will benefit most from invasive revascularisation, but more research is needed in this field. Based on current knowledge in this field, it would be appropriate following risk stratification to offer optimal medical therapy plus invasive care to older patients at high risk of future cardiovascular events but at low risk of complications and to offer optimal medical therapy alone to those who are deemed low risk of future events with high risk of developing procedural complications and severely frail patients. PMID- 26740484 TI - Effect of supplemental oxygen exposure on myocardial injury in ST-elevation myocardial infarction. AB - OBJECTIVE: Supplemental oxygen therapy may increase myocardial injury following ST-elevation myocardial infarction (STEMI). In this study, we aimed to evaluate the effect of the dose and duration of oxygen exposure on myocardial injury after STEMI. METHODS: Descriptive analysis of data from a multicentre, prospective, randomised, controlled trial of 441 patients with STEMI randomised to supplemental oxygen therapy or room air breathing. The primary endpoint was myocardial infarct size as assessed by cardiac biomarkers, troponin (cTnI) and creatine kinase (CK). Oxygen therapy was commenced by paramedics, and continued for up to 12 h postintervention in hospital. Supplemental oxygen exposure was calculated as the area under the dose*time curve for oxygen administration over the first 12 h, and then assessed for its association with cTnI/CK release using multivariable linear regression. RESULTS: The median supplemental oxygen exposure was 1746 L (IQR: 960-2858). After adjustment for potential confounders, every 100 L increase in oxygen exposure in the first 12 h was associated with a 1.4% (95% CI 0.6% to 2.2%, p<0.001) and 1.2% (95% CI 0.7% to 1.8%, p<0.001) increase in the mean peak cTnI and CK, respectively. Excluding patients who developed cardiogenic shock, recurrent myocardial infarction or desaturations (SpO2<94%) during admission, every 100 L increase in oxygen exposure was associated with a 1.2% (95% CI 0.2% to 2.1%, p=0.01) and 1.0% (95% CI 0.3% to 1.7%, p=0.003) increase in the mean peak cTnI and CK, respectively. The median supplemental oxygen exposure of 1746 L would result in a 21% (95% CI 3% to 37%) increase in infarct size according to the cTnI profile. CONCLUSIONS: Supplemental oxygen exposure in the first 12 h after STEMI was associated with a clinically significant increase in cTnI and CK release. PMID- 26740485 TI - Disease-modifying medical therapy in phenotypically overt hypertrophic cardiomyopathy: a case of too little, too late? PMID- 26740487 TI - Mechanical stress and the development of pseudo-comedones and tunnels in Hidradenitis suppurativa/Acne inversa. PMID- 26740488 TI - Impaired Valuation Leads to Increased Apathy Following Ventromedial Prefrontal Cortex Damage. AB - Apathy is defined by reduced goal-directed behavior, and is common in patients with damage to the ventromedial prefrontal cortex (vmPFC). Separately, in neuroeconomics research, the vmPFC has been shown to play a role in reward processing-namely, in "stimulus valuation," or the computation of the subjective reward value of a stimulus. Here, we used a sample of patients with focal brain lesions (N = 93) and matched healthy controls (N = 21) to determine whether the association between vmPFC damage and increased apathy is driven by impaired valuation. An auction task was used to measure valuation, and apathy was assessed via caregiver ratings of patients' day-to-day behavior. Lesion-symptom mapping identified the locus of impaired valuation in the vmPFC, and patients with damage to this region demonstrated increased apathy relative to patients with damage to dorsomedial prefrontal cortex (dmPFC), patients with damage to other brain regions, and healthy controls. Critically, the association between vmPFC damage and apathy was mediated by impaired valuation, with no effect as a function of dmPFC damage. Our results implicate a valuation-based mechanism underlying the relationship between vmPFC integrity and apathy, bridging findings from both the clinical literature and neuroeconomics research. PMID- 26740486 TI - The Challenge of Cancer Genomics in Rare Nervous System Neoplasms: Malignant Peripheral Nerve Sheath Tumors as a Paradigm for Cross-Species Comparative Oncogenomics. AB - Comprehensive genomic analyses of common nervous system cancers provide new insights into their pathogenesis, diagnosis, and treatment. Although analogous studies of rare nervous system tumors are needed, there are major barriers to performing such studies. Cross-species comparative oncogenomics, identifying driver mutations in mouse cancer models and validating them in human tumors, is a promising alternative. Although still in its infancy, this approach is being applied to malignant peripheral nerve sheath tumors (MPNSTs), rare Schwann cell derived malignancies that occur sporadically, after radiotherapy, and in neurofibromatosis type 1. Studies of human neurofibromatosis type 1-associated tumors suggest that NF1 tumor suppressor loss in Schwann cells triggers cell autonomous and intercellular changes, resulting in development of benign neurofibromas; subsequent neurofibroma-MPNST progression is caused by aberrant growth factor signaling and mutations affecting the p16(INK4A)-cyclin D1-CDK4-Rb and p19(ARF)-Mdm2-p53 cell cycle pathways. Mice with Nf1, Trp53, and/or Cdkn2a mutations that overexpress the Schwann cell mitogen neuregulin-1 or overexpress the epidermal growth factor receptor validate observations in human tumors and, to various degrees, model human tumorigenesis. Genomic analyses of MPNSTs arising in neuregulin-1 and epidermal growth factor receptor-overexpressing mice and forward genetic screens with Sleeping Beauty transposons implicate additional signaling cascades in MPNST pathogenesis. These studies confirm the utility of mouse models for MPNST driver gene discovery and provide new insights into the complexity of MPNST pathogenesis. PMID- 26740490 TI - Ultrasound-Guided Lower Cervical Nerve Root Injectate Volumes Associated With Dorsal Root Ganglion and Epidural Spread. AB - OBJECTIVES: We aimed to estimate the spread of injections for ultrasound-guided cervical nerve root blocks and to determine the optimal injectate volume required in this procedure. METHODS: A total of 32 ultrasound-guided injections (C5-C8) were made in 4 fresh cadavers. The target on each cervical root was the space between the posterior tubercle and the cervical root at the most proximal location possible on the sonogram. After ultrasound-guided needle insertion, 0.5 mL of a contrast medium was injected 4 times. The dye flow patterns were confirmed with fluoroscopy each time, and we recorded whether the contrast medium reached the dorsal root ganglion level or the epidural space. After the injections, the needle tip location was determined by computed tomography and image reconstruction. RESULTS: All injections produced typical neurograms. The contrast medium reached the dorsal root ganglion in 29 of 32 (90.6%) injections (mean +/- SD, 0.84 +/- 0.42 mL of contrast medium) and the epidural space in 10 of 32 (31.3%) injections (1.30 +/- 0.54 mL of contrast medium). The mean distance between the needle tip and neural foramen was 9.64 +/- 3.68 mm, and this distance correlated positively with the volume of contrast medium necessary to reach the dorsal root ganglion or the epidural space. CONCLUSIONS: Ultrasound-guided cervical nerve root blocks show potential utility for targeting an anesthetic into the cervical root area. This study may be helpful for deciding the most appropriate volume for the procedure. PMID- 26740489 TI - Caspr Controls the Temporal Specification of Neural Progenitor Cells through Notch Signaling in the Developing Mouse Cerebral Cortex. AB - The generation of layer-specific neurons and astrocytes by radial glial cells during development of the cerebral cortex follows a precise temporal sequence, which is regulated by intrinsic and extrinsic factors. The molecular mechanisms controlling the timely generation of layer-specific neurons and astrocytes remain not fully understood. In this study, we show that the adhesion molecule contactin associated protein (Caspr), which is involved in the maintenance of the polarized domains of myelinated axons, is essential for the timing of generation of neurons and astrocytes in the developing mouse cerebral cortex. Caspr is expressed by radial glial cells, which are neural progenitor cells that generate both neurons and astrocytes. Absence of Caspr in neural progenitor cells delays the production cortical neurons and induces precocious formation of cortical astrocytes, without affecting the numbers of progenitor cells. At the molecular level, Caspr cooperates with the intracellular domain of Notch to repress transcription of the Notch effector Hes1. Suppression of Notch signaling via a Hes1 shRNA rescues the abnormal neurogenesis and astrogenesis in Caspr-deficient mice. These findings establish Caspr as a novel key regulator that controls the temporal specification of cell fate in radial glial cells of the developing cerebral cortex through Notch signaling. PMID- 26740491 TI - Sonographically Identified Echogenic Renal Masses Up to 1 cm in Size Are So Rarely Malignant They Can Be Safely Ignored. AB - OBJECTIVES: The purpose of this study was to determine whether small echogenic renal masses up to 1 cm in size incidentally detected by sonography are rarely malignant and thus do not need further workup. METHODS: We reviewed approximately 13,600 reports of all abdominal sonographic examinations performed between November 2001 and October 2007 that identified a small echogenic mass in a kidney. Patients with known malignancy of any kind, tuberous sclerosis, lesions larger than 1.0 cm, lesions with heterogeneous echogenicity, and lesions with posterior ring-down artifacts or posterior acoustic shadowing were excluded. All patients without magnetic resonance imaging or computed tomographic scans that completely characterized the lesions were excluded unless a follow-up study (sonography, magnetic resonance imaging, or contrast-enhanced computed tomography) at least 5 years later was available for comparison to prove that the lesion was benign. RESULTS: A total of 120 lesions in 111 patients satisfied the inclusion criteria. Lesion sizes were 0 to 5 mm (n = 16) and 6 to 10 mm (n = 104). Of these, 54 lesions were characterized as definitely benign (47 angiomyolipomas and 7 other benign entities: calcifications in stones or within a cyst or calyx and cysts that were either simple on follow-up studies or complicated with hemorrhagic or proteinaceous content). For the remaining 66 lesions, follow-up results after at least 5 years were normal in 24 cases (which meant that the lesion was no longer visible), and the remaining 42 lesions were stable in size. The mean duration of follow-up for these 66 lesions was 7.4 years. CONCLUSIONS: Small echogenic renal masses up to 1 cm in size that fulfill our study criteria are so likely to be benign that they can be safely ignored. PMID- 26740492 TI - A New Reliable Method for Evaluating Gallbladder Dynamics: The 3-Dimensional Sonographic Examination. AB - OBJECTIVES: The purpose of this study was to compare conventional 2-dimensional (2D) B-mode sonography with 3-dimensional (3D) sonography for assessing gallbladder volume and contractility. METHODS: Gallbladder volume and contractility were evaluated in 32 healthy volunteers after fasting and abstinence from smoking for 8 hours and after a standardized balanced liquid meal. The gallbladder was evaluated with 2D sonography (with the use of the ellipsoid method) and with 3D sonography using a volumetric matrix probe. Both measurements were made by an operator who was skilled in sonography and an unskilled operator. The group of volunteers was subdivided into 2 subgroups including 16 participants, which represented the "2 moments" of acquisition by the techniques, particularly for the unskilled operator. RESULTS: The postprandial volumes obtained with 3D sonography were significantly lower in comparison to the volumes obtained with 2D sonography (P= .013), and there was a significant difference between the measurements made by the skilled and unskilled operators only for 2D sonography (P< .001), whereas between the 2 moments of acquisition by the 3D technique, there was no significant difference. The reproducibility of the technique for evaluation of gallbladder volumes was higher for 3D sonography than 2D sonography, particularly for the postprandial evaluation. CONCLUSIONS: The new 3D sonographic method using a volumetric matrix probe is a simple, reliable, and more reproducible technique than conventional 2D sonography, even if performed by an unskilled operator, and it allows a reliable stimulation test for a gallbladder dynamic study. PMID- 26740493 TI - Renal Cell Carcinomas: Sonographic Appearance Depending on Size and Histologic Type. AB - OBJECTIVES: Prior studies have demonstrated that approximately 10% of malignant renal cell carcinomas are as echogenic as angiomyolipomas on sonography. However, a recent presentation suggested that small (<1-cm) echogenic renal masses are always angiomyolipomas or other benign entities. We therefore examined our own cases of renal cell carcinoma, with corresponding sonography, to confirm that some renal cell carcinomas may also be detected as hyperechoic masses on sonography. METHODS: Institutional Review Board approval and Health Insurance Portability and Accountability Act compliance were maintained for this retrospective review of 91 pathologically proven cases of renal cell carcinoma, with corresponding sonography. Tumors were first differentiated by histologic cell type (clear cell, papillary, and chromophobe). Tumors were then stratified according to 2 size group parameters, falling into those that were 3 cm or larger and those that were smaller than 3 cm in diameter, with the less than 3-cm group further subdivided into 2 cm or smaller and greater than 2 cm. Tumor echogenicity was graded on a 5-point scale with respect to the renal parenchyma. RESULTS: Forty-six tumors (51%) were 3 cm in diameter or smaller, and most were found to be either isoechoic (35%) or mildly hyperechoic (26%) to the surrounding renal parenchyma. Of tumors smaller than 2 cm, most were either mildly hyperechoic (29%) or as hyperechoic as renal sinus fat (very hyperechoic; 29%). Tumors larger than 3 cm were found most often to be either isoechoic (49%) or mildly hyperechoic (33%), with only 4% found to be very hyperechoic. CONCLUSIONS: The sonographic appearances of renal cell carcinomas include a small population that are very hyperechoic on sonography and thus could potentially be misdiagnosed as angiomyolipomas. PMID- 26740494 TI - Displaying radiation exposure and cost information at order entry for outpatient diagnostic imaging: a strategy to inform clinician ordering. AB - BACKGROUND: Displaying radiation exposure and cost information at electronic order entry may encourage clinicians to consider the value of diagnostic imaging. METHODS: An urban safety-net health system displayed radiation exposure information for CT and cost information for CT, MRI and ultrasound on an electronic referral system for outpatient ordering. We assessed whether there were differences in numbers of outpatient CT scans and MRIs per month relative to ultrasounds before and after the intervention, and evaluated primary care clinicians' responses to the intervention. RESULTS: There were 23 171 outpatient CTs, 15 052 MRIs and 43 266 ultrasounds from 2011 to 2014. The ratio of CTs to ultrasounds decreased by 15% (95% CI 9% to 21%), from 58.2 to 49.6 CTs per 100 ultrasounds; the ratio of MRIs to ultrasounds declined by 13% (95% CI 7% to 19%), from 37.5 to 32.5 per 100. Of 300 invited, 190 (63%) completed the web-based survey in 17 clinics. 154 (81%) noticed the radiation exposure information and 158 (83.2%) noticed the cost information. Clinicians believed radiation exposure information was more influential than cost information: when unsure clinically about ordering a test (radiation=69.7%; cost=46.4%), when a patient wanted a test not clinically indicated (radiation=77.5%; cost=54.8%), when they had a choice between imaging modalities (radiation=77.9%; cost=66.6%), in patient care discussions (radiation=71.9%; cost=43.2%) and in trainee discussions (radiation=56.5%; cost=53.7%). Resident physicians and nurse practitioners were more likely to report that the cost information influenced them (p<0.05). CONCLUSIONS: Displaying radiation exposure and cost information at order entry may improve clinician awareness about diagnostic imaging safety risks and costs. More clinicians reported the radiation information influenced their clinical practice. PMID- 26740495 TI - Why do we still page each other? Examining the frequency, types and senders of pages in academic medical services. AB - BACKGROUND: Paging still represents an important form of communication within hospitals, but it results in interruptions, and other more modern approaches could be superior. This study aims to describe how paging is currently used in an academic medical centre, including the frequency, type, urgency and sender of pages, so that improvements in communication can be better informed. STUDY SAMPLE: In order to understand what communication needs paging fulfils in a modern academic medical centre, we analysed a database of 1252 pages sent to internal medicine residents within an academic medical centre. We assessed all pages from 3 separate general medicine rotations over a total of 56 days encompassing 602 h. RESULTS: Residents were paged an average of 22.4 times per day, with a maximum of 50 pages per day. Most pages were deemed clinically relevant (76%) and important (76%) to patient care. Overall, 59% of pages required a response. A mean of 7.7 pages were sent per patient, up to a maximum of 70 pages for one patient. Nurses (28%), consultants (16%) and the clinical laboratory (15%) were responsible for the majority of pages. Almost all pages from nurses (82%) and consultants (82%) required a response. Regionalised services had significantly fewer pages per day than non-regionalised services (19 vs 37, p<=0.00001). CONCLUSIONS: Paging remains widely used for communications within hospitals about patient care. Although the majority of pages were judged to be clinically relevant and important, they frequently required a response potentially leading to interruptions in workflow, and communication waste. Paging rate and volume has not decreased in 25 years despite significant penetration of newer technologies. For the majority of current uses of pages, we believe other approaches may now be more appropriate. Regionalisation significantly reduces the number and urgency of the pages. PMID- 26740496 TI - The Healthcare Complaints Analysis Tool: development and reliability testing of a method for service monitoring and organisational learning. AB - BACKGROUND: Letters of complaint written by patients and their advocates reporting poor healthcare experiences represent an under-used data source. The lack of a method for extracting reliable data from these heterogeneous letters hinders their use for monitoring and learning. To address this gap, we report on the development and reliability testing of the Healthcare Complaints Analysis Tool (HCAT). METHODS: HCAT was developed from a taxonomy of healthcare complaints reported in a previously published systematic review. It introduces the novel idea that complaints should be analysed in terms of severity. Recruiting three groups of educated lay participants (n=58, n=58, n=55), we refined the taxonomy through three iterations of discriminant content validity testing. We then supplemented this refined taxonomy with explicit coding procedures for seven problem categories (each with four levels of severity), stage of care and harm. These combined elements were further refined through iterative coding of a UK national sample of healthcare complaints (n= 25, n=80, n=137, n=839). To assess reliability and accuracy for the resultant tool, 14 educated lay participants coded a referent sample of 125 healthcare complaints. RESULTS: The seven HCAT problem categories (quality, safety, environment, institutional processes, listening, communication, and respect and patient rights) were found to be conceptually distinct. On average, raters identified 1.94 problems (SD=0.26) per complaint letter. Coders exhibited substantial reliability in identifying problems at four levels of severity; moderate and substantial reliability in identifying stages of care (except for 'discharge/transfer' that was only fairly reliable) and substantial reliability in identifying overall harm. CONCLUSIONS: HCAT is not only the first reliable tool for coding complaints, it is the first tool to measure the severity of complaints. It facilitates service monitoring and organisational learning and it enables future research examining whether healthcare complaints are a leading indicator of poor service outcomes. HCAT is freely available to download and use. PMID- 26740497 TI - High-value care programmes from the bottom-up... and the top-down. PMID- 26740499 TI - Missed diagnosis of oesophageal perforation in ankylosing spondylitis cervical fracture: Two case reports and literature review. AB - Oesophageal perforation after blunt injury cervical fracture in patients with ankylosing spondylitis (AS) is rarely reported. The early diagnosis of oesophageal perforation is extremely important. We present two cases of patients with AS who sustained cervical fracture dislocation and spinal cord injury. The ossified sharp fragments caused oesophageal perforation, and the delayed diagnoses had serious consequences. Oesophageal perforation should be suspected in patients with AS and cervical fracture if bone fragments are pressing against the oesophagus and a gas shadow is visible around the fracture site on computed tomography imaging. PMID- 26740501 TI - Monocular distance estimation with optical flow maneuvers and efference copies: a stability-based strategy. AB - The visual cue of optical flow plays an important role in the navigation of flying insects, and is increasingly studied for use by small flying robots as well. A major problem is that successful optical flow control seems to require distance estimates, while optical flow is known to provide only the ratio of velocity to distance. In this article, a novel, stability-based strategy is proposed for monocular distance estimation, relying on optical flow maneuvers and knowledge of the control inputs (efference copies). It is shown analytically that given a fixed control gain, the stability of a constant divergence control loop only depends on the distance to the approached surface. At close distances, the control loop starts to exhibit self-induced oscillations. The robot can detect these oscillations and hence be aware of the distance to the surface. The proposed stability-based strategy for estimating distances has two main attractive characteristics. First, self-induced oscillations can be detected robustly by the robot and are hardly influenced by wind. Second, the distance can be estimated during a zero divergence maneuver, i.e., around hover. The stability based strategy is implemented and tested both in simulation and on board a Parrot AR drone 2.0. It is shown that the strategy can be used to: (1) trigger a final approach response during a constant divergence landing with fixed gain, (2) estimate the distance in hover, and (3) estimate distances during an entire landing if the robot uses adaptive gain control to continuously stay on the 'edge of oscillation.' PMID- 26740498 TI - Poor response to platinum-based chemotherapy is associated with KRAS mutation and concomitant low expression of BRAC1 and TYMS in NSCLC. AB - OBJECTIVE: To evaluate treatment response, survival, and the associations between KRAS mutation status and tumour expression levels of BRCA1, TYMS and SRC retrospectively in a cohort of patients with non-small cell lung cancer (NSCLC), treated exclusively with conjunctive platinum-based doublet chemotherapy. METHODS: KRAS mutation status was determined via amplification refractory mutation and multiple quantitative polymerase chain reaction (PCR) analysis. Tumour expression levels of BRCA1, TYMS and SRC were determined via real time quantitative PCR. RESULTS: Patients with KRAS mutations (n = 3) had significantly shorter survival duration than patients with wild type KRAS (n = 42). Tumour expression levels of BRCA1 and TYMS, but not SRC, were significantly lower in patients with, than in those without, KRAS mutations. Tumour expression level of BRCA1 was positively correlated with survival duration. CONCLUSIONS: KRAS mutation status and BRCA1 tumour expression are potential biomarkers for tailoring chemotherapy and predicting clinical outcome. PMID- 26740502 TI - Glass transition of two-dimensional 80-20 Kob-Andersen model at constant pressure. AB - We reconsider numerically the two-dimensional version of the Kob-Andersen model (KA2d) with a fraction of 80% of large spheres. A constant moderate pressure is imposed while the temperature T is systematically quenched from the liquid limit through the glass transition at [Formula: see text] down to very low temperatures. Monodisperse Lennard-Jones (mdLJ) bead systems, forming a crystal phase at low temperatures, are used to highlight several features of the KA2d model. As can be seen, e.g. from the elastic shear modulus G(T), determined using the stress-fluctuation formalism, our KA2d model is a good glass-former. A continuous cusp-singularity, [Formula: see text] with [Formula: see text], is observed in qualitative agreement with other recent numerical and theoretical work, however in striking conflict with the additive jump discontinuity predicted by mode-coupling theory. PMID- 26740500 TI - Apolipoprotein E E2/E3/E4 variant in association with obstructive sleep apnoea and lipid profile: A meta-analysis. AB - OBJECTIVE: A meta-analysis of the association between haplotypical variants of the apolipoprotein E (APOE) gene (E2/E3/E4) and obstructive sleep apnoea (OSA) risk and changes in lipid profile. METHODS: Electronic databases were searched to retrieve articles that provided data on APOE gene E2/E3/E4 variants in patients with OSA and healthy controls. Data were extracted from eligible articles and statistical analyses were performed. RESULTS: The meta-analysis included 14 articles involving 19 study populations (3198 patients and 6031 controls). There was no significant association between the presence of the E4 allele and OSA risk. The presence of E4 was associated with significantly increased total cholesterol and decreased high-density lipoprotein cholesterol, compared with E4 allele negative individuals. There was a low probability of publication bias but significant heterogeneity. CONCLUSIONS: There was no association between APOE E2/E3/E4 and OSA susceptibility. The presence of APOE E4 was associated with changes in lipid profile. PMID- 26740503 TI - Effect of biphasic calcium phosphate scaffold porosities on odontogenic differentiation of human dental pulp cells. AB - Calcium phosphates (CaP) of different porosities have been widely and successfully used as scaffolds with osteoblast cells for bone tissue regeneration. However, the effects of scaffold porosities on cell viability and differentiation of human dental pulp cells for dentin tissue regeneration are not well known. In this study, biphasic calcium phosphate (BCP) scaffolds of 20/80 hydroxyapatite to beta tricalcium phosphate ratio with a mean pore size of 300 MUm were prepared into BCP1, BCP2, BCP3, and BCP4 of 25%, 50%, 65%, and 75% of total porosities, respectively. The extracts of these scaffolds were assessed with regard to cell viability, proliferation, and differentiation of human dental pulp cells. The high alkalinity, and more calcium and phosphate ions release that were exhibited by BCP3 and BCP4 decreased the viability and proliferation of human dental pulp cells as compared to BCP1 and BCP2. BCP2 significantly increased both cell viability and cell proliferation. However, the cells cultured with BCP3 extract revealed high alkaline phosphatase (ALP) activity and high expression of odontoblast related genes, collagen type I alpha 1, dentin matrix protein-1, and dentin sialophosphoprotein as compared to that cultured with BCP1, BCP2, and BCP4 extracts. The results highlight the effect of different scaffold porosities on the cell microenvironment and demonstrate that BCP3 scaffold of 65% porosity can support human dental pulp cells differentiation for dentin tissue regeneration. PMID- 26740504 TI - Medical treatment of left ventricular pseudoaneurysms. PMID- 26740505 TI - Lung mass and tularaemia. PMID- 26740506 TI - Current needs for human and medical genomics research infrastructure in low and middle income countries. PMID- 26740507 TI - KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects. AB - Mutations in the sodium-gated potassium channel subunit gene KCNT1 have recently emerged as a cause of several different epileptic disorders. This review describes the mutational and phenotypic spectrum associated with the gene and discusses the comorbidities found in patients, which include intellectual disability and psychiatric features. The gene may also be linked with cardiac disorders. KCNT1 missense mutations have been found in 39% of patients with the epileptic encephalopathy malignant migrating focal seizures of infancy (MMFSI), making it the most significant MMFSI disease-causing gene identified to date. Mutations in KCNT1 have also been described in eight unrelated cases of sporadic and familial autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE). These patients have a high frequency of associated intellectual disability and psychiatric features. Two mutations in KCNT1 have been associated with both ADNFLE and MMFSI, suggesting that the genotype-phenotype relationship for KCNT1 mutations is not straightforward. Mutations have also been described in several patients with infantile epileptic encephalopathies other than MMFSI. Notably, all mutations in KCNT1 described to date are missense mutations, and electrophysiological studies have shown that they result in increased potassium current. Together, these genetic and electrophysiological studies raise the possibility of delivering precision medicine by treating patients with KCNT1 mutations using drugs that alter the action of potassium channels to specifically target the biological effects of their disease-causing mutation. Such trials are now in progress. Better understanding of the mechanisms underlying KCNT1-related disease will produce further improvements in treatment of the associated severe seizure disorders. PMID- 26740509 TI - Confinement and inhomogeneous broadening effects in the quantum oscillatory magnetization of quantum dot ensembles. AB - We report on the magnetization of ensembles of etched quantum dots with a lateral diameter of 460 nm, which we prepared from InGaAs/InP heterostructures. The quantum dots exhibit 1/B-periodic de-Haas-van-Alphen-type oscillations in the magnetization M(B) for external magnetic fields B > 2 T, measured by torque magnetometry at 0.3 K. We compare the experimental data to model calculations assuming different confinement potentials and including ensemble broadening effects. The comparison shows that a hard wall potential with an edge depletion width of 100 nm explains the magnetic behavior. Beating patterns induced by Rashba spin-orbit interaction (SOI) as measured in unpatterned and nanopatterned InGaAs/InP heterostructures are not observed for the quantum dots. From our model we predict that signatures of SOI in the magnetization could be observed in larger dots in tilted magnetic fields. PMID- 26740508 TI - Identification of novel genetic causes of Rett syndrome-like phenotypes. AB - BACKGROUND: The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach. METHODS AND RESULTS: We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT. CONCLUSIONS: Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT like clinical presentations and identify new candidate genes for RTT-like phenotypes. PMID- 26740510 TI - Structure and magnetism in Cr-embedded Co nanoparticles. AB - We present the results of an investigation into the atomic structure and magnetism of 2 nm diameter Co nanoparticles embedded in an antiferromagnetic Cr matrix. The nanocomposite films used in this study were prepared by co-deposition directly from the gas phase, using a gas aggregation source for the Co nanoparticles and a molecular beam epitaxy (MBE) source for the Cr matrix material. Co K and Cr K edge extended x-ray absorption fine structure (EXAFS) experiments were performed in order to investigate atomic structure in the embedded nanoparticles and matrix respectively, while magnetism was investigated by means of a vibrating sample magnetometer. The atomic structure type of the Co nanoparticles is the same as that of the Cr matrix (bcc) although with a degree of disorder. The net Co moment per atom in the Co/Cr nanocomposite films is significantly reduced from the value for bulk Co, and decreases as the proportion of Co nanoparticles in the film is decreased; for the sample with the most dilute concentration of Co nanoparticles (4.9% by volume), the net Co moment was 0.25 MU B/atom. After field cooling to below 30 K all samples showed an exchange bias, which was largest for the most dilute sample. Both the structural and magnetic results point towards a degree of alloying at the nanoparticle/matrix interface, leading to a core/shell structure in the embedded nanoparticles consisting of an antiferromagnetic CoCr alloy shell surrounding a reduced ferromagnetic Co core. PMID- 26740511 TI - Validation of non-rigid point-set registration methods using a porcine bladder pelvic phantom. AB - The problem of accurate dose accumulation in fractionated radiotherapy treatment for highly deformable organs, such as bladder, has garnered increasing interest over the past few years. However, more research is required in order to find a robust and efficient solution and to increase the accuracy over the current methods. The purpose of this study was to evaluate the feasibility and accuracy of utilizing non-rigid (affine or deformable) point-set registration in accumulating dose in bladder of different sizes and shapes. A pelvic phantom was built to house an ex vivo porcine bladder with fiducial landmarks adhered onto its surface. Four different volume fillings of the bladder were used (90, 180, 360 and 480 cc). The performance of MATLAB implementations of five different methods were compared, in aligning the bladder contour point-sets. The approaches evaluated were coherent point drift (CPD), gaussian mixture model, shape context, thin-plate spline robust point matching (TPS-RPM) and finite iterative closest point (ICP-finite). The evaluation metrics included registration runtime, target registration error (TRE), root-mean-square error (RMS) and Hausdorff distance (HD). The reference (source) dataset was alternated through all four points-sets, in order to study the effect of reference volume on the registration outcomes. While all deformable algorithms provided reasonable registration results, CPD provided the best TRE values (6.4 mm), and TPS-RPM yielded the best mean RMS and HD values (1.4 and 6.8 mm, respectively). ICP-finite was the fastest technique and TPS-RPM, the slowest. PMID- 26740512 TI - Detection of mixed-range proton pencil beams with a prompt gamma slit camera. AB - With increasing availability of proton and particle therapy centers for tumor treatment, the need for in vivo range verification methods comes more into the focus. Imaging of prompt gamma rays emitted during the treatment is one of the possibilities currently under investigation. A knife-edge shaped slit camera was recently proposed for this task and measurements proved the feasibility of range deviation detection in homogeneous and inhomogeneous targets. In the present paper, we concentrate on laterally inhomogeneous materials, which lead to range mixing situations when crossed by one pencil beam: different sections of the beam have different ranges. We chose exemplative cases from clinical irradiation and assembled idealized tissue equivalent targets. One-dimensional emission profiles were obtained by measuring the prompt gamma emission with the slit camera. It could be shown that the resulting range deviations can be detected by evaluation of the measured data with a previously developed range deviation detection algorithm. The retrieved value, however, strongly depends on the target composition, and is not necessarily in direct relation to the ranges of both parts of the beam. By combining the range deviation detection with an analysis of the slope of the distal edge of the measured prompt gamma profile, the origin of the detected range deviation, i.e. the mixed range of the beam, is also identified. It could be demonstrated that range mixed prompt gamma profiles exhibit less steep distal slopes than profiles from beams traversing laterally homogeneous material. For future application of the slit camera to patient irradiation with double scattered proton beams, situations similar to the range mixing cases are present and results could possibly apply. PMID- 26740513 TI - Evaluation of Drug-Drug Interactions Between Hepatitis C Antiviral Agents Ombitasvir, Paritaprevir/Ritonavir, and Dasabuvir and HIV-1 Protease Inhibitors. AB - BACKGROUND: Guidelines for the treatment of human immunodeficiency virus (HIV) infection consistently recommend initiation of antiretroviral therapy in patients with hepatitis C virus (HCV)/HIV-1 coinfection. Therefore, potential drug interactions between antiretroviral drugs and HCV direct-acting antiviral agents (DAAs) must be carefully considered. The objective of this investigation was to evaluate the compatibility of a novel combination of DAAs (the 3D regimen) with commonly prescribed HIV-1 protease inhibitors (PIs). METHODS: Five phase 1, multiple-dose, open-label pharmacokinetic studies were performed in 144 healthy volunteers. Participants in each study were randomly assigned 1:1 into cohorts assessing the effects of the steady-state 3D regimen on steady-state HIV-1 PIs or vice versa. The 3D regimen comprised ombitasvir (25 mg once daily), paritaprevir/ritonavir (150/100 mg once daily), and dasabuvir (250 or 400 mg twice daily). The HIV-1 PIs assessed included atazanavir, darunavir, and lopinavir (administered with ritonavir). Safety, tolerability, and pharmacokinetic parameters were assessed to evaluate the compatibility of the drug regimens. RESULTS: Coadministration of the 3D regimen with the evaluated HIV 1 PIs was generally well tolerated in healthy volunteers. Morning administration of atazanavir (300 mg once daily) and darunavir regimens exhibited no clinically meaningful drug interactions with the 3D regimen. However, owing to higher paritaprevir and/or ritonavir exposures, evening administration of atazanavir (300 mg) plus ritonavir (100 mg) or lopinavir/ritonavir (800/200 mg) with the 3D regimen is not recommended. CONCLUSIONS: The 3D regimen can be coadministered with morning atazanavir and darunavir regimens. However, evening atazanavir plus ritonavir and lopinavir/ritonavir regimens are not recommended in combination with the 3D regimen. PMID- 26740514 TI - First Real Life Evidence of New Direct-acting Antivirals (DAA) in Co-infected HIV HCV Patients: Better than Ever. PMID- 26740516 TI - Reply to Menard et al. PMID- 26740517 TI - Motion prediction in MRI-guided radiotherapy based on interleaved orthogonal cine MRI. AB - In-room cine-MRI guidance can provide non-invasive target localization during radiotherapy treatment. However, in order to cope with finite imaging frequency and system latencies between target localization and dose delivery, tumour motion prediction is required. This work proposes a framework for motion prediction dedicated to cine-MRI guidance, aiming at quantifying the geometric uncertainties introduced by this process for both tumour tracking and beam gating. The tumour position, identified through scale invariant features detected in cine-MRI slices, is estimated at high-frequency (25 Hz) using three independent predictors, one for each anatomical coordinate. Linear extrapolation, auto regressive and support vector machine algorithms are compared against systems that use no prediction or surrogate-based motion estimation. Geometric uncertainties are reported as a function of image acquisition period and system latency. Average results show that the tracking error RMS can be decreased down to a [0.2; 1.2] mm range, for acquisition periods between 250 and 750 ms and system latencies between 50 and 300 ms. Except for the linear extrapolator, tracking and gating prediction errors were, on average, lower than those measured for surrogate-based motion estimation. This finding suggests that cine-MRI guidance, combined with appropriate prediction algorithms, could relevantly decrease geometric uncertainties in motion compensated treatments. PMID- 26740515 TI - Persistent Infections by Nontyphoidal Salmonella in Humans: Epidemiology and Genetics. AB - BACKGROUND: Although chronic infections by typhoidal Salmonella are well-known, prolonged human infections by nontyphoidal Salmonella (NTS) are poorly characterized. METHODS: We retrospectively analyzed 48 345 culture-confirmed NTS infections that occurred in Israel 1995-2012. A case-control study was performed to identify risk factors associated with persistent infections. Whole-genome sequencing, pulsed-field gel electrophoresis (PFGE), and a mouse infection model were used to study genetic and phenotypic differences between same-patient persistent, recurring isolates. RESULTS: In total, 1047 cases of persistent NTS infections, comprising 2.2% of all reported cases of salmonellosis, were identified. The persistence periods ranged between 30 days to 8.3 years. The majority (93%) of the persistently infected patients were immunocompetent, and 65% were symptomatic with relapsing diarrhea, indicating a distinct clinical manifestation from the asymptomatic carriage of typhoidal Salmonella. Four NTS serovars (Mbandaka, Bredeney, Infantis and Virchow) were found to be significantly more frequently associated with persistence than others. Comparative genomics between early and later isolates obtained from the same patients confirmed clonal infection and showed 0 to 10 SNPs between persistent isolates. A different composition of mobile genetic elements (plasmids and phages) or amino acid substitutions in global regulators was identified in multiple cases. These changes resulted in differences in phenotype and virulence between early and later same-patient isolates. CONCLUSIONS: These results illuminate the overlooked clinical manifestation of persistent salmonellosis that can serve as a human reservoir for NTS infections. Additionally, we demonstrate mechanisms of in-host microevolution and exhibit their potential to shape Salmonella pathogenicity, antimicrobial resistance and host-pathogen interactions. PMID- 26740518 TI - Data-driven RBE parameterization for helium ion beams. AB - Helium ion beams are expected to be available again in the near future for clinical use. A suitable formalism to obtain relative biological effectiveness (RBE) values for treatment planning (TP) studies is needed. In this work we developed a data-driven RBE parameterization based on published in vitro experimental values. The RBE parameterization has been developed within the framework of the linear-quadratic (LQ) model as a function of the helium linear energy transfer (LET), dose and the tissue specific parameter (alpha/beta)ph of the LQ model for the reference radiation. Analytic expressions are provided, derived from the collected database, describing the RBEalpha = alphaHe/alphaph and Rbeta = betaHe/betaph ratios as a function of LET. Calculated RBE values at 2 Gy photon dose and at 10% survival (RBE10) are compared with the experimental ones. Pearson's correlation coefficients were, respectively, 0.85 and 0.84 confirming the soundness of the introduced approach. Moreover, due to the lack of experimental data at low LET, clonogenic experiments have been performed irradiating A549 cell line with (alpha/beta)ph = 5.4 Gy at the entrance of a 56.4 MeV u(-1)He beam at the Heidelberg Ion Beam Therapy Center. The proposed parameterization reproduces the measured cell survival within the experimental uncertainties. A RBE formula, which depends only on dose, LET and (alpha/beta)ph as input parameters is proposed, allowing a straightforward implementation in a TP system. PMID- 26740522 TI - Efficacy of Maxillomandibular Advancement Examined with Drug-Induced Sleep Endoscopy and Computational Fluid Dynamics Airflow Modeling. AB - OBJECTIVES: To use drug-induced sedation endoscopy (DISE) and computational fluid dynamics (CFD) modeling to study dynamic airway and airflow changes after maxillomandibular advancement (MMA), and how the changes correlate with surgical success based on polysomnography parameters. STUDY DESIGN: Retrospective cohort study. SETTING: University medical center. METHODS: DISE was rated with the VOTE (velum, oropharynx, tongue, epiglottis) classification, and CFD was used to model airflow velocity and negative pressure exerted on pharyngeal wall. Changes in VOTE score by site and CFD measurements were correlated with perioperative polysomnography outcomes of apnea-hypopnea index (AHI), apnea index (AI), oxygenation desaturation index (ODI), and lowest oxygen saturation. RESULTS: After MMA, 20 subjects (17 males, 3 females) with a mean age of 44 +/- 12 years and body mass index of 27.4 +/- 4.6 kg/m(2) showed mean decreases in AHI (53.6 +/ 26.6 to 9.5 +/- 7.4 events/h) and ODI (38.7 +/- 30.3 to 8.1 +/- 9.2 events/h; P < .001). Improvement in lateral pharyngeal wall collapse during DISE based on VOTE score correlated with the most decrease in AHI (60.0 +/- 25.6 to 7.5 +/- 3.4 events/h) and ODI (46.7 +/- 29.8 to 5.3 +/- 2 events/h; P = .002). CFD modeling showed significant positive Pearson correlations between reduction of retropalatal airflow velocity and AHI (r = 0.617, P = .04) and ODI (r = 0.773, P = .005). CONCLUSION: AHI and ODI improvement after MMA is best correlated with (1) decreased retropalatal airflow velocity modeled by CFD and (2) increased lateral pharyngeal wall stability based on VOTE scoring from DISE. PMID- 26740523 TI - SV-Bay: structural variant detection in cancer genomes using a Bayesian approach with correction for GC-content and read mappability. AB - MOTIVATION: Whole genome sequencing of paired-end reads can be applied to characterize the landscape of large somatic rearrangements of cancer genomes. Several methods for detecting structural variants with whole genome sequencing data have been developed. So far, none of these methods has combined information about abnormally mapped read pairs connecting rearranged regions and associated global copy number changes automatically inferred from the same sequencing data file. Our aim was to create a computational method that could use both types of information, i.e. normal and abnormal reads, and demonstrate that by doing so we can highly improve both sensitivity and specificity rates of structural variant prediction. RESULTS: We developed a computational method, SV-Bay, to detect structural variants from whole genome sequencing mate-pair or paired-end data using a probabilistic Bayesian approach. This approach takes into account depth of coverage by normal reads and abnormalities in read pair mappings. To estimate the model likelihood, SV-Bay considers GC-content and read mappability of the genome, thus making important corrections to the expected read count. For the detection of somatic variants, SV-Bay makes use of a matched normal sample when it is available. We validated SV-Bay on simulated datasets and an experimental mate-pair dataset for the CLB-GA neuroblastoma cell line. The comparison of SV Bay with several other methods for structural variant detection demonstrated that SV-Bay has better prediction accuracy both in terms of sensitivity and false positive detection rate. AVAILABILITY AND IMPLEMENTATION: https://github.com/InstitutCurie/SV-Bay CONTACT: valentina.boeva@inserm.fr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26740524 TI - Bayesian variable selection for binary outcomes in high-dimensional genomic studies using non-local priors. AB - MOTIVATION: The advent of new genomic technologies has resulted in the production of massive data sets. Analyses of these data require new statistical and computational methods. In this article, we propose one such method that is useful in selecting explanatory variables for prediction of a binary response. Although this problem has recently been addressed using penalized likelihood methods, we adopt a Bayesian approach that utilizes a mixture of non-local prior densities and point masses on the binary regression coefficient vectors. RESULTS: The resulting method, which we call iMOMLogit, provides improved performance in identifying true models and reducing estimation and prediction error in a number of simulation studies. More importantly, its application to several genomic datasets produces predictions that have high accuracy using far fewer explanatory variables than competing methods. We also describe a novel approach for setting prior hyperparameters by examining the total variation distance between the prior distributions on the regression parameters and the distribution of the maximum likelihood estimator under the null distribution. Finally, we describe a computational algorithm that can be used to implement iMOMLogit in ultrahigh dimensional settings ([Formula: see text]) and provide diagnostics to assess the probability that this algorithm has identified the highest posterior probability model. AVAILABILITY AND IMPLEMENTATION: Software to implement this method can be downloaded at: http://www.stat.tamu.edu/~amir/code.html CONTACT: wwang7@mdanderson.org or vjohnson@stat.tamu.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26740525 TI - PINCAGE: probabilistic integration of cancer genomics data for perturbed gene identification and sample classification. AB - MOTIVATION: Cancer development and progression is driven by a complex pattern of genomic and epigenomic perturbations. Both types of perturbations can affect gene expression levels and disease outcome. Integrative analysis of cancer genomics data may therefore improve detection of perturbed genes and prediction of disease state. As different data types are usually dependent, analysis based on independence assumptions will make inefficient use of the data and potentially lead to false conclusions. MODEL: Here, we present PINCAGE (Probabilistic INtegration of CAncer GEnomics data), a method that uses probabilistic integration of cancer genomics data for combined evaluation of RNA-seq gene expression and 450k array DNA methylation measurements of promoters as well as gene bodies. It models the dependence between expression and methylation using modular graphical models, which also allows future inclusion of additional data types. RESULTS: We apply our approach to a Breast Invasive Carcinoma dataset from The Cancer Genome Atlas consortium, which includes 82 adjacent normal and 730 cancer samples. We identify new biomarker candidates of breast cancer development (PTF1A, RABIF, RAG1AP1, TIMM17A, LOC148145) and progression (SERPINE3, ZNF706). PINCAGE discriminates better between normal and tumour tissue and between progressing and non-progressing tumours in comparison with established methods that assume independence between tested data types, especially when using evidence from multiple genes. Our method can be applied to any type of cancer or, more generally, to any genomic disease for which sufficient amount of molecular data is available. AVAILABILITY AND IMPLEMENTATION: R scripts available at http://moma.ki.au.dk/prj/pincage/ CONTACT: : michal.switnicki@clin.au.dk or jakob.skou@clin.au.dk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26740526 TI - Modelling-based experiment retrieval: a case study with gene expression clustering. AB - MOTIVATION: Public and private repositories of experimental data are growing to sizes that require dedicated methods for finding relevant data. To improve on the state of the art of keyword searches from annotations, methods for content-based retrieval have been proposed. In the context of gene expression experiments, most methods retrieve gene expression profiles, requiring each experiment to be expressed as a single profile, typically of case versus control. A more general, recently suggested alternative is to retrieve experiments whose models are good for modelling the query dataset. However, for very noisy and high-dimensional query data, this retrieval criterion turns out to be very noisy as well. RESULTS: We propose doing retrieval using a denoised model of the query dataset, instead of the original noisy dataset itself. To this end, we introduce a general probabilistic framework, where each experiment is modelled separately and the retrieval is done by finding related models. For retrieval of gene expression experiments, we use a probabilistic model called product partition model, which induces a clustering of genes that show similar expression patterns across a number of samples. The suggested metric for retrieval using clusterings is the normalized information distance. Empirical results finally suggest that inference for the full probabilistic model can be approximated with good performance using computationally faster heuristic clustering approaches (e.g. k-means). The method is highly scalable and straightforward to apply to construct a general-purpose gene expression experiment retrieval method. AVAILABILITY AND IMPLEMENTATION: The method can be implemented using standard clustering algorithms and normalized information distance, available in many statistical software packages. CONTACT: paul.blomstedt@aalto.fi or samuel.kaski@aalto.fi SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26740527 TI - UCSC Data Integrator and Variant Annotation Integrator. AB - Two new tools on the UCSC Genome Browser web site provide improved ways of combining information from multiple datasets, optionally including the user's own custom track data and/or data from track hubs. The Data Integrator combines columns from multiple data tracks, showing all items from the first track along with overlapping items from the other tracks. The Variant Annotation Integrator is tailored to adding functional annotations to variant calls; it offers a more restricted set of underlying data tracks but adds predictions of each variant's consequences for any overlapping or nearby gene transcript. When available, it optionally adds additional annotations including effect prediction scores from dbNSFP for missense mutations, ENCODE regulatory summary tracks and conservation scores. AVAILABILITY AND IMPLEMENTATION: The web tools are freely available at http://genome.ucsc.edu/ and the underlying database is available for download at http://hgdownload.cse.ucsc.edu/ The software (written in C and Javascript) is available from https://genome-store.ucsc.edu/ and is freely available for academic and non-profit usage; commercial users must obtain a license. CONTACT: angie@soe.ucsc.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26740528 TI - Wearing a Bicycle Helmet Can Increase Risk Taking and Sensation Seeking in Adults. AB - Humans adapt their risk-taking behavior on the basis of perceptions of safety; this risk-compensation phenomenon is typified by people taking increased risks when using protective equipment. Existing studies have looked at people who know they are using safety equipment and have specifically focused on changes in behaviors for which that equipment might reduce risk. Here, we demonstrated that risk taking increases in people who are not explicitly aware they are wearing protective equipment; furthermore, this happens for behaviors that could not be made safer by that equipment. In a controlled study in which a helmet, compared with a baseball cap, was used as the head mount for an eye tracker, participants scored significantly higher on laboratory measures of both risk taking and sensation seeking. This happened despite there being no risk for the helmet to ameliorate and despite it being introduced purely as an eye tracker. The results suggest that unconscious activation of safety-related concepts primes globally increased risk propensity. PMID- 26740529 TI - Neural correlates of heat-evoked pain memory in humans. AB - The neural processes underlying pain memory are not well understood. To explore these processes, contact heat-evoked potentials (CHEPs) were recorded in humans with electroencephalography (EEG) technique during a delayed matching-to-sample task, a working memory task involving presentations of two successive painful heat stimuli (S-1 and S-2) with different intensities separated by a 2-s interval (the memorization period). At the end of the task, the subject was required to discriminate the stimuli by indicating which (S-1 or S-2) induced more pain. A control task was used, in which no active discrimination was required between stimuli. All event-related potential (ERP) analysis was aligned to the onset of S 1. EEG activity exhibited two successive CHEPs: an N2-P2 complex (~400 ms after onset of S-1) and an ultralate component (ULC, ~900 ms). The amplitude of the N2 P2 at vertex, but not the ULC, was significantly correlated with stimulus intensity in these two tasks, suggesting that the N2-P2 represents neural coding of pain intensity. A late negative component (LNC) in the frontal recording region was observed only in the memory task during a 500-ms period before onset of S-2. LNC amplitude differed between stimulus intensities and exhibited significant correlations with the N2-P2 complex. These indicate that the frontal LNC is involved in maintenance of intensity of pain in working memory. Furthermore, alpha-band oscillations observed in parietal recording regions during the late delay displayed significant power differences between tasks. This study provides in the temporal domain previously unidentified neural evidence showing the neural processes involved in working memory of painful stimuli. PMID- 26740531 TI - Inhibitory stabilization and visual coding in cortical circuits with multiple interneuron subtypes. AB - Recent anatomical and functional characterization of cortical inhibitory interneurons has highlighted the diverse computations supported by different subtypes of interneurons. However, most theoretical models of cortex do not feature multiple classes of interneurons and rather assume a single homogeneous population. We study the dynamics of recurrent excitatory-inhibitory model cortical networks with parvalbumin (PV)-, somatostatin (SOM)-, and vasointestinal peptide-expressing (VIP) interneurons, with connectivity properties motivated by experimental recordings from mouse primary visual cortex. Our theory describes conditions under which the activity of such networks is stable and how perturbations of distinct neuronal subtypes recruit changes in activity through recurrent synaptic projections. We apply these conclusions to study the roles of each interneuron subtype in disinhibition, surround suppression, and subtractive or divisive modulation of orientation tuning curves. Our calculations and simulations determine the architectural and stimulus tuning conditions under which cortical activity consistent with experiment is possible. They also lead to novel predictions concerning connectivity and network dynamics that can be tested via optogenetic manipulations. Our work demonstrates that recurrent inhibitory dynamics must be taken into account to fully understand many properties of cortical dynamics observed in experiments. PMID- 26740533 TI - Habit formation coincides with shifts in reinforcement representations in the sensorimotor striatum. AB - Evaluating outcomes of behavior is a central function of the striatum. In circuits engaging the dorsomedial striatum, sensitivity to goal value is accentuated during learning, whereas outcome sensitivity is thought to be minimal in the dorsolateral striatum and its habit-related corticostriatal circuits. However, a distinct population of projection neurons in the dorsolateral striatum exhibits selective sensitivity to rewards. Here, we evaluated the outcome-related signaling in such neurons as rats performed an instructional T-maze task for two rewards. As the rats formed maze-running habits and then changed behavior after reward devaluation, we detected outcome-related spike activity in 116 units out of 1,479 recorded units. During initial training, nearly equal numbers of these units fired preferentially either after rewarded runs or after unrewarded runs, and the majority were responsive at only one of two reward locations. With overtraining, as habits formed, firing in nonrewarded trials almost disappeared, and reward-specific firing declined. Thus error-related signaling was lost, and reward signaling became generalized. Following reward devaluation, in an extinction test, postgoal activity was nearly undetectable, despite accurate running. Strikingly, when rewards were then returned, postgoal activity reappeared and recapitulated the original early response pattern, with nearly equal numbers responding to rewarded and unrewarded runs and to single rewards. These findings demonstrate that outcome evaluation in the dorsolateral striatum is highly plastic and tracks stages of behavioral exploration and exploitation. These signals could be a new target for understanding compulsive behaviors that involve changes to dorsal striatum function. PMID- 26740534 TI - Conduction block of mammalian myelinated nerve by local cooling to 15-30 degrees C after a brief heating. AB - This study aimed at understanding thermal effects on nerve conduction and developing new methods to produce a reversible thermal block of axonal conduction in mammalian myelinated nerves. In 13 cats under alpha-chloralose anesthesia, conduction block of pudendal nerves (n = 20) by cooling (5-30 degrees C) or heating (42-54 degrees C) a small segment (9 mm) of the nerve was monitored by the urethral striated muscle contractions and increases in intraurethral pressure induced by intermittent (5 s on and 20 s off) electrical stimulation (50 Hz, 0.2 ms) of the nerve. Cold block was observed at 5-15 degrees C while heat block occurred at 50-54 degrees C. A complete cold block up to 10 min was fully reversible, but a complete heat block was only reversible when the heating duration was less than 1.3 +/- 0.1 min. A brief (<1 min) reversible complete heat block at 50-54 degrees C or 15 min of nonblock mild heating at 46-48 degrees C significantly increased the cold block temperature to 15-30 degrees C. The effect of heating on cold block fully reversed within ~40 min. This study discovered a novel method to block mammalian myelinated nerves at 15-30 degrees C, providing the possibility to develop an implantable device to block axonal conduction and treat many chronic disorders. The effect of heating on cold block is of considerable interest because it raises many basic scientific questions that may help reveal the mechanisms underlying cold or heat block of axonal conduction. PMID- 26740532 TI - Systems-level neurophysiological state characteristics for drug evaluation in an animal model of levodopa-induced dyskinesia. AB - Disorders affecting the central nervous system have proven particularly hard to treat, and disappointingly few novel therapies have reached the clinics in recent decades. A better understanding of the physiological processes in the brain underlying various symptoms could therefore greatly improve the rate of progress in this field. We here show how systems-level descriptions of different brain states reliably can be obtained through a newly developed method based on large scale recordings in distributed neural networks encompassing several different brain structures. Using this technology, we characterize the neurophysiological states associated with parkinsonism and levodopa-induced dyskinesia in a rodent model of Parkinson's disease together with pharmacological interventions aimed at reducing dyskinetic symptoms. Our results show that the obtained electrophysiological data add significant information to conventional behavioral evaluations and hereby elucidate the underlying effects of treatments in greater detail. Taken together, these results potentially open up for studies of neurophysiological mechanisms underlying symptoms in a wide range of neurological and psychiatric conditions that until now have been very hard to investigate in animal models of disease. PMID- 26740536 TI - The genus Retiboletus in China. AB - Species of the genus Retiboletus (Boletaceae, Boletales) in China are investigated based on morphology and phylogenetic analyses of DNA sequences from nuc rDNA internal transcribed spacer (ITS) and partial 28S regions and sequences from the translation elongation factor 1-a gene (tef1a). Six lineages are recovered among the collections studied. Five of these are documented and presented in the present paper, including three new species and two new combinations. The remaining species is not described due to the paucity of material. The specimens from China identified as "R. ornatipes" or "R. retipes" are in fact R. sinensis or R. kauffmanii, those labeled "R. griseus" are either R. fuscus or R. pseudogriseus A key to all known taxa of the genus is provided. Phylogenetic relationships of taxa within Retiboletus are partially resolved. A preliminary biogeographical analysis shows that allied species of Retiboletus between eastern Asia and North/Central America are common but there are no Retiboletus species common to both continents. Species of Retiboletus in Japan and southern China are conspecific or closely related. PMID- 26740535 TI - Shape-independent object category responses revealed by MEG and fMRI decoding. AB - Neuroimaging research has identified category-specific neural response patterns to a limited set of object categories. For example, faces, bodies, and scenes evoke activity patterns in visual cortex that are uniquely traceable in space and time. It is currently debated whether these apparently categorical responses truly reflect selectivity for categories or instead reflect selectivity for category-associated shape properties. In the present study, we used a cross classification approach on functional MRI (fMRI) and magnetoencephalographic (MEG) data to reveal both category-independent shape responses and shape independent category responses. Participants viewed human body parts (hands and torsos) and pieces of clothing that were closely shape-matched to the body parts (gloves and shirts). Category-independent shape responses were revealed by training multivariate classifiers on discriminating shape within one category (e.g., hands versus torsos) and testing these classifiers on discriminating shape within the other category (e.g., gloves versus shirts). This analysis revealed significant decoding in large clusters in visual cortex (fMRI) starting from 90 ms after stimulus onset (MEG). Shape-independent category responses were revealed by training classifiers on discriminating object category (bodies and clothes) within one shape (e.g., hands versus gloves) and testing these classifiers on discriminating category within the other shape (e.g., torsos versus shirts). This analysis revealed significant decoding in bilateral occipitotemporal cortex (fMRI) and from 130 to 200 ms after stimulus onset (MEG). Together, these findings provide evidence for concurrent shape and category selectivity in high level visual cortex, including category-level responses that are not fully explicable by two-dimensional shape properties. PMID- 26740530 TI - Using fMRI to study reward processing in humans: past, present, and future. AB - Functional magnetic resonance imaging (fMRI) is a noninvasive tool used to probe cognitive and affective processes. Although fMRI provides indirect measures of neural activity, the advent of fMRI has allowed for1) the corroboration of significant animal findings in the human brain, and2) the expansion of models to include more common human attributes that inform behavior. In this review, we briefly consider the neural basis of the blood oxygenation level dependent signal to set up a discussion of how fMRI studies have applied it in examining cognitive models in humans and the promise of using fMRI to advance such models. Specifically, we illustrate the contribution that fMRI has made to the study of reward processing, focusing on the role of the striatum in encoding reward related learning signals that drive anticipatory and consummatory behaviors. For instance, we discuss how fMRI can be used to link neural signals (e.g., striatal responses to rewards) to individual differences in behavior and traits. While this functional segregation approach has been constructive to our understanding of reward-related functions, many fMRI studies have also benefitted from a functional integration approach that takes into account how interconnected regions (e.g., corticostriatal circuits) contribute to reward processing. We contend that future work using fMRI will profit from using a multimodal approach, such as combining fMRI with noninvasive brain stimulation tools (e.g., transcranial electrical stimulation), that can identify causal mechanisms underlying reward processing. Consequently, advancements in implementing fMRI will promise new translational opportunities to inform our understanding of psychopathologies. PMID- 26740537 TI - Ancestral state reconstruction infers phytopathogenic origins of sooty blotch and flyspeck fungi on apple. AB - Members of the sooty blotch and flyspeck (SBFS) complex are epiphytic fungi in the Ascomycota that cause economically damaging blemishes of apples worldwide. SBFS fungi are polyphyletic, but approx. 96% of SBFS species are in the Capnodiales. Evolutionary origins of SBFS fungi remain unclear, so we attempted to infer their origins by means of ancestral state reconstruction on a phylogenetic tree built utilizing genes for the nuc 28S rDNA (approx. 830 bp from near the 59 end) and the second largest subunit of RNA polymerase II (RPB2). The analyzed taxa included the well-known genera of SBFS as well as non-SBFS fungi from seven families within the Capnodiales. The non-SBFS taxa were selected based on their distinct ecological niches, including plant-parasitic and saprophytic species. The phylogenetic analyses revealed that most SBFS species in the Capnodiales are closely related to plant-parasitic fungi. Ancestral state reconstruction provided strong evidence that plant-parasitic fungi were the ancestors of the major SBFS lineages. Knowledge gained from this study may help to better understand the ecology and evolution of epiphytic fungi. PMID- 26740538 TI - Phylogenetic overview of the genus Genea (Pezizales, Ascomycota) with an emphasis on European taxa. AB - We constructed a comprehensive phylogeny of the genus Genea, with new molecular data from samples collected in several countries in temperate and Mediterranean Europe, as well as North America. Type specimens and authentic material of most species were examined to support identifications. The molecular identity of the most common species in Genea was compared with nuc rDNA internal transcribed spacer (ITS), D1-D2 domains of 28S nuc rDNA (28S rDNA) and translation elongation factor 1-alpha ene (TEF1) profiles of 10 recently proposed taxa, G. brunneocarpa, G. compressa, G. dentata, G. fageticola, G. lobulata, G. oxygala, G. pinicola, G. pseudobalsleyi, G. pseudoverrucosa and G. tuberculata, supporting their status as distinct species. Genea mexicana and G. thaxteri on the one hand and G. sphaerica and G. lespiaultii on the other are closely related. Multiple lineages were recorded for G. verrucosa and G. fragrans, but we found no morphological traits to discriminate among them, so we tentatively interpreted them as cryptic species. A key to species of the genus Genea is provided to facilitate identification. We provide macroscopic images of fresh specimens and of representative spores of most species. Finally, we conducted a molecular analysis of the divergence time for Genea and discuss the implications of our results. PMID- 26740539 TI - Systematics of the ectomycorrhizal genus Lactarius in the Rocky Mountain alpine zone. AB - Lactarius (Russulales) is an important component of ectomycorrhizal fungal communities in cold-dominated contiguous arctic and disjunct alpine habitats where it associates primarily with Betula, Dryas and Salix However, little is known of this genus in the central and southern Rocky Mountain alpine zone (3000 3900 m) of North America. Molecular phylogenetic analyses of nuc rDNA ITS1-5.8S ITS2 (ITS barcode) and the second largest subunit of the RNA polymerase II gene (RPB2) partial sequences in conjunction with detailed morphological examination confirm at least six species occurring above treeline. Most have intercontinental distributions in North America and Eurasia according to molecular comparison with type material and collections from Europe, Fennoscandia, Svalbard and Alaska. Rocky Mountain collections of L. lanceolatus (subgenus Russularia), along with the type from Alaska are paraphyletic with respect to L. aurantiacus and North American taxa L. luculentus and L. luculentus v. laetus Rocky Mountain collections of L. nanus, L. glyciosmus, L. repraesentaneus and L. salicis reticulatae (subgenus Piperites) all form clades with European material from type localities and other arctic-alpine habitats. The arctic-alpine L. pseudouvidus/L. brunneoviolaceus group appears to be a complex containing additional taxa. North American material originally described as part of this group is well-separated phylogenetically and is described here as L. pallidomarginatus sp. nov. Lactarius lanceolatus, L. nanus and L. salicis-reticulatae appear largely restricted to arctic-alpine habitats with Salix Lactarius glyciosmus and L. repraesentaneus occur in arctic-alpine, subalpine and boreal habitats with Betula and also Picea and possibly Salix for the latter. Species distributions are hypothesized to be shaped by host ranges, glaciation and long distance dispersal. PMID- 26740540 TI - Russulaceae in American Samoa: new species and further support for an Australasian origin for Samoan ectomycorrhizal fungi. AB - Two new species from the Russulaceae, Lactifluus aurantiotinctus and Russula pallidirosea, are described from American Samoa. Based on analyses of nuc rDNA internal transcribed spacer region barcodes (ITS), L. aurantiotinctus has an affinity to subgenus Lactariopsis and strong phylogeographic ties to Papua New Guinea. The ITS data indicate that Russula pallidirosea has an affinity to subgenus Heterophyllidia and suggest that it also has phylogeographic ties to Australasia. Both species were associated with the ectomycorrhizal tree Intsia bijuga. PMID- 26740541 TI - Botrytis californica, a new cryptic species in the B. cinerea species complex causing gray mold in blueberries and table grapes. AB - The Botrytis cinerea species complex comprises two cryptic species, originally referred to Group I and Group II based on Bc-hch gene RFLP haplotyping. Group I was described as a new cryptic species B. pseudocinerea During a survey of Botrytis spp. causing gray mold in blueberries and table grapes in the Central Valley of California, six isolates, three from blueberries and three from table grapes, were placed in Group I but had a distinct morphological character with conidiophores significantly longer than those of B. cinerea and B. pseudocinerea We compared these with B. cinerea and B. pseudocinerea by examining morphological and physiological characters, sensitivity to fenhexamid and phylogenetic analysis inferred from sequences of three nuclear genes. Phylogenetic analysis with the three partial gene sequences encoding glyceraldehyde-3-phosate dehydrogenase (G3PDH), heat-shock protein 60 (HSP60) and DNA-dependent RNA polymerase subunit II (RPB2) supported the proposal of a new Botrytis species, B. californica, which is closely related genetically to B. cinerea, B. pseudocinerea and B. sinoviticola, all known as causal agents of gray mold of grapes. Botrytis californica caused decay on blueberry and table grape fruit inoculated with the fungus. This study suggests that B. californica is a cryptic species sympatric with B. cinerea on blueberries and table grapes in California. PMID- 26740542 TI - Diversity and distribution patterns of root-associated fungi on herbaceous plants in alpine meadows of southwestern China. AB - The diversity of root-associated fungi associated with four ectomycorrhizal herbaceous species, Kobresia capillifolia, Carex parva, Polygonum macrophyllum and Potentilla fallens, collected in three sites of alpine meadows in southwestern China, was estimated based on internal transcribed spacer (ITS) rDNA sequence analysis of root tips. Three hundred seventy-seven fungal sequences sorted to 154 operational taxonomical units (sequence similarity of >= 97% across the ITS) were obtained from the four plant species across all three sites. Similar taxa (in GenBank with >= 97% similarity) were not found in GenBank and/or UNITE for most of the OTUs. Ectomycorrhiz a made up 64% of the fungi operational taxonomic units (OTUs), endophytes constituted 4% and the other 33% were unidentified root-associated fungi. Fungal OTUs were represented by 57% basidiomycetes and 43% ascomycetes. Inocybe, Tomentella/Thelophora, Sebacina, Hebeloma, Pezizomycotina, Cenococcum geophilum complex, Cortinarius, Lactarius and Helotiales were OTU-rich fungal lineages. Across the sites and host species the root-associated fungal communities generally exhibited low host and site specificity but high host and sampling site preference. Collectively our study revealed noteworthy diversity and endemism of root-associated fungi of alpine plants in this global biodiversity hotspot. PMID- 26740543 TI - An enigmatic fossil fungus from the 410 Ma Rhynie chert that resembles Macrochytrium (Chytridiomycota) and Blastocladiella (Blastocladiomycota). AB - Litter layers in the Lower Devonian (~ 410 Ma) Rhynie chert were inhabited by a wide variety of saprotrophic fungi, however, only a few of these organisms have been described formally. A new microfungus, Trewinomyces annulifer gen. et sp. nov., occurs as tufts on decaying land plant axes from the Rhynie chert. The fungus consists of an intramatrical rhizoidal system and an erect extramatrical hypha (stalk) that bears a single, terminal sporangium. One or two successive rings often are present in the stalk immediately below the sporangium base. Overall morphology of T. annulifer resembles the extant genera Macrochytrium (Chytridiomycota) and Blastocladiella (Blastocladiomycota). However, the rhizoids are septate or pseudoseptate, a feature not known in extant zoosporic fungi, and thus render the systematic affinities of T. annulifer unresolved. Trewinomyces annulifer offers a rare view of the morphology of a distinctive Early Devonian saprotrophic microfungus. PMID- 26740544 TI - Identification, pathogenicity and abundance of Paracremonium pembeum sp. nov. and Graphium euwallaceae sp. nov.--two newly discovered mycangial associates of the polyphagous shot hole borer (Euwallacea sp.) in California. AB - Fusarium euwallaceae is a well-characterized fungal symbiont of the exotic ambrosia beetle Euwallacea sp. (polyphagous shot hole borer [PSHB]), together inciting Fusarium dieback on many host plants in Israel and California. Recent discoveries of additional fungal symbionts within ambrosia beetle mycangia suggest these fungi occur as communities. Colony-forming units of Graphium euwallaceae sp. nov. and Paracremonium pembeum sp. nov., two novel fungal associates of PSHB from California, grew from 36 macerated female heads and 36 gallery walls collected from Platanus racemosa, Acer negundo, Persea americana and Ricinus communis. Fungi were identified based on micromorphology and phylogenetic analyses of the combined internal transcribed spacer region (nuc rDNA ITS1-5.8S-ITS2 [ITS barcode]), elongation factor (EF 1-alpha), small subunit (18S rDNA) sequences for Graphium spp., ITS, EF 1-alpha, calmodulin (cmdA), large subunit of the ATP citrate lyase (acl1), beta-tubulin (tub2), RNA polymerase II second largest subunit (rpb2) and large subunit (28S rDNA) sequences for Paracremonium spp. Other Graphium spp. recovered from PSHB in Vietnam, Euwallacea fornicatus in Thailand, E. validus in Pennsylvania and Paracremonium sp. recovered from PSHB in Vietnam were identified. F. euwallaceae was recovered from mycangia at higher frequencies and abundances in all hosts except R. communis, in which those of F. euwallaceae and P. pembeum were equal. P. pembeum was relatively more abundant within gallery walls of A. negundo and R. communis. In all hosts combined F. euwallaceae was relatively more abundant within PSHB heads than gallery walls. All three fungi grew at different rates and colonized inoculated excised stems of P. americana and A. negundo. P. pembeum produced longer lesions than F. euwallaceae and G. euwallaceae on inoculated avocado shoots. Results indicate PSHB is associated with a dynamic assemblage of mycangial fungal associates that pose additional risk to native and nonnative hosts in California. PMID- 26740545 TI - Sexual and asexual states of some endophytic Phialocephala species of Picea. AB - Unidentified DNA sequences in isolation-based or culture-free studies of conifer endophytes are a persistent problem that requires a field approach to resolve. An investigation of foliar endophytes of Picea glauca, P. mariana, P. rubens and Pinus strobus in eastern Canada, using a combined field, morphological, cultural and DNA sequencing approach, resulted in the frequent isolation of Phialocephala spp. and the first verified discovery of their mollisia-like sexual states in the field. Phialocephala scopiformis and Ph. piceae were the most frequent species isolated as endophytes from healthy conifer needles. Corresponding Mollisia or mollisioid sexual states for Ph. scopiformis, Ph. piceae and several undescribed species in a clade containing Ph. dimorphospora were collected in the sampling area and characterized by analysis of the nuc internal transcribed spacer rDNA (ITS) and gene for the largest subunit of RNA polymerase II (RPB1) loci. Four novel species and one new combination in a clade containing Ph. dimorphospora, the type of Phialocephala, are presented, accompanied by descriptions of apothecia and previously undocumented synanamorphs. An epitype culture and corresponding reference sequences for Phialocephala dimorphospora are proposed. The resulting ITS barcodes linked with robust taxonomic species concepts are an important resource for future research on forest ecosystems and endophytes. PMID- 26740546 TI - Phylogenetic analyses of Chinese Tuber species that resemble T. borchii reveal the existence of the new species T. hubeiense and T. wumengense. AB - In phylogenetic analyses based on the internal transcribed spacers and 28S nuc rDNA and translation elongation factor 1-alpha to compare Chinese white truffle specimens that have ascomata resembling the European Tuber borchii, the sequences of Chinese species resembling T. borchii in morphology grouped into seven distinct clusters among three clades: Puberulum, Maculatum and Latisporum No sequences from these Chinese species matched those of the European T. borchii and the occurrence of the European T. borchii in China could not be supported by our study. Three unknown species are recognized from the seven Chinese clusters; two are described here as T. hubeiense and T. wumengense based on molecular and morphological evidence. PMID- 26740547 TI - Gendered use of experts in the media: Analysis of the gender gap in Finnish news journalism. AB - Several studies conducted in Western democracies have indicated that men continue to be overrepresented and women underrepresented as experts in the media. This article explores the situation in Finland, a progressive and 'female-friendly' Nordic country with highly educated women who are widely present in the job market. The analysis is based on three sets of research data featuring a wide set of media data, a survey and interviews. This study reveals that public expertise continues to be male dominated in Finland: less than 30% of the experts interviewed in the news media are women. While the distribution of work and power in the labour market may explain some of the observed gender gap, journalistic practices and a masculine tradition of public expertise are likely to play a role as well. PMID- 26740549 TI - Loss of HCN1 enhances disease progression in mouse models of CNG channel-linked retinitis pigmentosa and achromatopsia. AB - Most inherited blinding diseases are characterized by compromised retinal function and progressive degeneration of photoreceptors. However, the factors that affect the life span of photoreceptors in such degenerative retinal diseases are rather poorly understood. Here, we explore the role of hyperpolarization activated cyclic nucleotide-gated channel 1 (HCN1) in this context. HCN1 is known to adjust retinal function under mesopic conditions, and although it is expressed at high levels in rod and cone photoreceptor inner segments, no association with any retinal disorder has yet been found. We investigated the effects of an additional genetic deletion of HCN1 on the function and survival of photoreceptors in a mouse model of CNGB1-linked retinitis pigmentosa (RP). We found that the absence of HCN1 in Cngb1 knockout (KO) mice exacerbated photoreceptor degeneration. The deleterious effect was reduced by expression of HCN1 using a viral vector. Moreover, pharmacological inhibition of HCN1 also enhanced rod degeneration in Cngb1 KO mice. Patch-clamp recordings revealed that the membrane potentials of Cngb1 KO and Cngb1/Hcn1 double-KO rods were both significantly depolarized. We also found evidence for altered calcium homeostasis and increased activation of the protease calpain in Cngb1/Hcn1 double-KO mice. Finally, the deletion of HCN1 also exacerbated degeneration of cone photoreceptors in a mouse model of CNGA3-linked achromatopsia. Our results identify HCN1 as a major modifier of photoreceptor degeneration and suggest that pharmacological inhibition of HCN channels may enhance disease progression in RP and achromatopsia patients. PMID- 26740548 TI - Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation. AB - Persons with neurofibromatosis type 1 (NF1) have a predisposition for premature and severe arterial stenosis. Mutations in the NF1 gene result in decreased expression of neurofibromin, a negative regulator of p21(Ras), and increases Ras signaling. Heterozygous Nf1 (Nf1(+/-)) mice develop a marked arterial stenosis characterized by proliferating smooth muscle cells (SMCs) and a predominance of infiltrating macrophages, which closely resembles arterial lesions from NF1 patients. Interestingly, lineage-restricted inactivation of a single Nf1 allele in monocytes/macrophages is sufficient to recapitulate the phenotype observed in Nf1(+/-) mice and to mobilize proinflammatory CCR2+ monocytes into the peripheral blood. Therefore, we hypothesized that CCR2 receptor activation by its primary ligand monocyte chemotactic protein-1 (MCP-1) is critical for monocyte infiltration into the arterial wall and neointima formation in Nf1(+/-) mice. MCP 1 induces a dose-responsive increase in Nf1(+/-) macrophage migration and proliferation that corresponds with activation of multiple Ras kinases. In addition, Nf1(+/-) SMCs, which express CCR2, demonstrate an enhanced proliferative response to MCP-1 when compared with WT SMCs. To interrogate the role of CCR2 activation on Nf1(+/-) neointima formation, we induced neointima formation by carotid artery ligation in Nf1(+/-) and WT mice with genetic deletion of either MCP1 or CCR2. Loss of MCP-1 or CCR2 expression effectively inhibited Nf1(+/-) neointima formation and reduced macrophage content in the arterial wall. Finally, administration of a CCR2 antagonist significantly reduced Nf1(+/-) neointima formation. These studies identify MCP-1 as a potent chemokine for Nf1(+/-) monocytes/macrophages and CCR2 as a viable therapeutic target for NF1 arterial stenosis. PMID- 26740550 TI - Assessing similarity to primary tissue and cortical layer identity in induced pluripotent stem cell-derived cortical neurons through single-cell transcriptomics. AB - Induced pluripotent stem cell (iPSC)-derived cortical neurons potentially present a powerful new model to understand corticogenesis and neurological disease. Previous work has established that differentiation protocols can produce cortical neurons, but little has been done to characterize these at cellular resolution. In particular, it is unclear to what extent in vitro two-dimensional, relatively disordered culture conditions recapitulate the development of in vivo cortical layer identity. Single-cell multiplex reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) was used to interrogate the expression of genes previously implicated in cortical layer or phenotypic identity in individual cells. Totally, 93.6% of single cells derived from iPSCs expressed genes indicative of neuronal identity. High proportions of single neurons derived from iPSCs expressed glutamatergic receptors and synaptic genes. And, 68.4% of iPSC-derived neurons expressing at least one layer marker could be assigned to a laminar identity using canonical cortical layer marker genes. We compared single cell RNA-seq of our iPSC-derived neurons to available single-cell RNA-seq data from human fetal and adult brain and found that iPSC-derived cortical neurons closely resembled primary fetal brain cells. Unexpectedly, a subpopulation of iPSC-derived neurons co-expressed canonical fetal deep and upper cortical layer markers. However, this appeared to be concordant with data from primary cells. Our results therefore provide reassurance that iPSC-derived cortical neurons are highly similar to primary cortical neurons at the level of single cells but suggest that current layer markers, although effective, may not be able to disambiguate cortical layer identity in all cells. PMID- 26740551 TI - Three-layered proteomic characterization of a novel ACTN4 mutation unravels its pathogenic potential in FSGS. AB - Genetic diseases constitute the most important cause for end-stage renal disease in children and adolescents. Mutations in the ACTN4 gene, encoding the actin binding protein alpha-actinin-4, are a rare cause of autosomal dominant familial focal segmental glomerulosclerosis (FSGS). Here, we report the identification of a novel, disease-causing ACTN4 mutation (p.G195D, de novo) in a sporadic case of childhood FSGS using next generation sequencing. Proteome analysis by quantitative mass spectrometry (MS) of patient-derived urinary epithelial cells indicated that ACTN4 levels were significantly decreased when compared with healthy controls. By resolving the peptide bearing the mutated residue, we could proof that the mutant protein is less abundant when compared with the wild-type protein. Further analyses revealed that the decreased stability of p.G195D is associated with increased ubiquitylation in the vicinity of the mutation site. We next defined the ACTN4 interactome, which was predominantly composed of cytoskeletal modulators and LIM domain-containing proteins. Interestingly, this entire group of proteins, including several highly specific ACTN4 interactors, was globally decreased in the patient-derived cells. Taken together, these data suggest a mechanistic link between ACTN4 instability and proteome perturbations of the ACTN4 interactome. Our findings advance the understanding of dominant effects exerted by ACTN4 mutations in FSGS. This study illustrates the potential of genomics and complementary, high-resolution proteomics analyses to study the pathogenicity of rare gene variants. PMID- 26740553 TI - Integrating population variation and protein structural analysis to improve clinical interpretation of missense variation: application to the WD40 domain. AB - We present a generic, multidisciplinary approach for improving our understanding of novel missense variants in recently discovered disease genes exhibiting genetic heterogeneity, by combining clinical and population genetics with protein structural analysis. Using six new de novo missense diagnoses in TBL1XR1 from the Deciphering Developmental Disorders study, together with population variation data, we show that the beta-propeller structure of the ubiquitous WD40 domain provides a convincing way to discriminate between pathogenic and benign variation. Children with likely pathogenic mutations in this gene have severely delayed language development, often accompanied by intellectual disability, autism, dysmorphology and gastrointestinal problems. Amino acids affected by likely pathogenic missense mutations are either crucial for the stability of the fold, forming part of a highly conserved symmetrically repeating hydrogen-bonded tetrad, or located at the top face of the beta-propeller, where 'hotspot' residues affect the binding of beta-catenin to the TBLR1 protein. In contrast, those altered by population variation are significantly less likely to be spatially clustered towards the top face or to be at buried or highly conserved residues. This result is useful not only for interpreting benign and pathogenic missense variants in this gene, but also in other WD40 domains, many of which are associated with disease. PMID- 26740554 TI - Familial prion protein mutants inhibit Hrd1-mediated retrotranslocation of misfolded proteins by depleting misfolded protein sensor BiP. AB - Similar to many proteins trafficking through the secretory pathway, cellular prion protein (PrP) partly retrotranslocates from the endoplasmic reticulum to the cytosol through the endoplasmic reticulum-associated degradation (ERAD) pathway in an attempt to alleviate accumulation of cellular misfolded PrP. Surprisingly, familial PrP mutants fail to retrotranslocate and simultaneously block normal cellular PrP retrotranslocation. That impairments in retrotranslocation of misfolded proteins could lead to global disruptions in cellular homeostasis prompted further investigations into PrP mutant retrotranslocation defects. A gain- and loss-of-function approach identified human E3 ubiquitin ligase, Hrd1, as a critical regulator of PrP retrotranslocation in mammalian cells. Expression of familial human PrP mutants, V210I(129V) and M232R(129V), not only abolished PrP retrotranslocation, but also that of Hrd1-dependent ERAD substrates, transthyretin TTR(D18G) and alpha1-anti trypsin A1AT(NHK). Mutant PrP expression decreased binding immunoglobulin protein (BiP) levels by 50% and attenuated ER stress-induced BiP by increasing BiP turnover 6-fold. Overexpression of BiP with PrP mutants rescued retrotranslocation of PrP, TTR(D18G) and A1AT(NHK). PrP mutants-induced cell death was also rescued by co-expression of BiP. These results show that PrP mutants highjack the Hrd1-dependent ERAD pathway, an action that would result in misfolded protein accumulation especially in terminally differentiated neurons. This could explain the age-dependent neuronal degeneration in familial prion diseases. PMID- 26740552 TI - Mitochondrial DNA sequence characteristics modulate the size of the genetic bottleneck. AB - With a combined carrier frequency of 1:200, heteroplasmic mitochondrial DNA (mtDNA) mutations cause human disease in ~1:5000 of the population. Rapid shifts in the level of heteroplasmy seen within a single generation contribute to the wide range in the severity of clinical phenotypes seen in families transmitting mtDNA disease, consistent with a genetic bottleneck during transmission. Although preliminary evidence from human pedigrees points towards a random drift process underlying the shifting heteroplasmy, some reports describe differences in segregation pattern between different mtDNA mutations. However, based on limited observations and with no direct comparisons, it is not clear whether these observations simply reflect pedigree ascertainment and publication bias. To address this issue, we studied 577 mother-child pairs transmitting the m.11778G>A, m.3460G>A, m.8344A>G, m.8993T>G/C and m.3243A>G mtDNA mutations. Our analysis controlled for inter-assay differences, inter-laboratory variation and ascertainment bias. We found no evidence of selection during transmission but show that different mtDNA mutations segregate at different rates in human pedigrees. m.8993T>G/C segregated significantly faster than m.11778G>A, m.8344A>G and m.3243A>G, consistent with a tighter mtDNA genetic bottleneck in m.8993T>G/C pedigrees. Our observations support the existence of different genetic bottlenecks primarily determined by the underlying mtDNA mutation, explaining the different inheritance patterns observed in human pedigrees transmitting pathogenic mtDNA mutations. PMID- 26740555 TI - Exome arrays capture polygenic rare variant contributions to schizophrenia. AB - Schizophrenia is a highly heritable disorder. Genome-wide association studies based largely on common alleles have identified over 100 schizophrenia risk loci, but it is also evident from studies of copy number variants (CNVs) and from exome sequencing studies that rare alleles are also involved. Full characterization of the contribution of rare alleles to the disorder awaits the deployment of sequencing technology in very large sample sizes, meanwhile, as an interim measure, exome arrays allow rare non-synonymous variants to be sampled at a fraction of the cost. In an analysis of exome array data from 13 688 individuals (5585 cases and 8103 controls) from the UK, we found that rare (minor allele frequency < 0.1%) variant association signal was enriched among genes that map to autosomal loci that are genome-wide significant (GWS) in common variant studies of schizophrenia genome-wide association study (PGWAS = 0.01) as well as gene sets known to be enriched for rare variants in sequencing studies (PRARE = 0.026). We also identified the gene-wise equivalent of GWS support for WDR88 (WD repeat-containing protein 88), a gene of unknown function (P = 6.5 * 10(-7)). Rare alleles represented on exome chip arrays contribute to the genetic architecture of schizophrenia, but as is the case for GWAS, very large studies are required to reveal additional susceptibility alleles for the disorder. PMID- 26740558 TI - Testing and Empiric Treatment for Neonatal Herpes Simplex Virus: Challenges and Opportunities for Improving the Value of Care. PMID- 26740556 TI - Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer. AB - Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 * 10(-6)]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and prostate tumours and in corresponding normal tissues. Investigation of rs700635[C] carriers revealed that they have a human specific short interspersed element-variable number of tandem repeat-Alu (SINE VNTR-Alu), subfamily-E retrotransposon (SVA-E) inserted into CASP8 intron 8. The SVA-E shows evidence of prior activity, because it has transduced some CASP8 sequences during subsequent retrotransposition events. Whole-genome sequence (WGS) data were used to tag the SVA-E with a surrogate SNP rs1035142[T] (r(2) = 0.999), which showed associations with both the splicing anomalies (P = 6.5 * 10( 32)) and with protection against prostate cancer (OR = 0.91, P = 3.8 * 10(-7)). PMID- 26740559 TI - Photoautotrophic microorganisms as a carbon source for temperate soil invertebrates. AB - We tested experimentally if photoautotrophic microorganisms are a carbon source for invertebrates in temperate soils. We exposed forest or arable soils to a (13)CO2-enriched atmosphere and quantified (13)C assimilation by three common animal groups: earthworms (Oligochaeta), springtails (Hexapoda) and slugs (Gastropoda). Endogeic earthworms (Allolobophora chlorotica) and hemiedaphic springtails (Ceratophysella denticulata) were highly (13)C enriched when incubated under light, deriving up to 3.0 and 17.0%, respectively, of their body carbon from the microbial source in 7 days. Earthworms assimilated more (13)C in undisturbed soil than when the microbial material was mixed into the soil, presumably reflecting selective surface grazing. By contrast, neither adult nor newly hatched terrestrial slugs (Deroceras reticulatum) grazed on algal mats. Non photosynthetic (13)CO2 fixation in the dark was negligible. We conclude from these preliminary laboratory experiments that, in addition to litter and root derived carbon from vascular plants, photoautotrophic soil surface microorganisms (cyanobacteria, algae) may be an ecologically important carbon input route for temperate soil animals that are traditionally assigned to the decomposer channel in soil food web models and carbon cycling studies. PMID- 26740557 TI - alpha-Synuclein interferes with the ESCRT-III complex contributing to the pathogenesis of Lewy body disease. AB - alpha-Synuclein (alpha-syn) has been implicated in neurological disorders with parkinsonism, including Parkinson's disease and Dementia with Lewy body. Recent studies have shown alpha-syn oligomers released from neurons can propagate from cell-to-cell in a prion-like fashion exacerbating neurodegeneration. In this study, we examined the role of the endosomal sorting complex required for transport (ESCRT) pathway on the propagation of alpha-syn. alpha-syn, which is transported via the ESCRT pathway through multivesicular bodies for degradation, can also target the degradation of the ESCRT protein-charged multivesicular body protein (CHMP2B), thus generating a roadblock of endocytosed alpha-syn. Disruption of the ESCRT transport system also resulted in increased exocytosis of alpha-syn thus potentially increasing cell-to-cell propagation of synuclein. Conversely, delivery of a lentiviral vector overexpressing CHMP2B rescued the neurodegeneration in alpha-syn transgenic mice. Better understanding of the mechanisms of intracellular trafficking of alpha-syn might be important for understanding the pathogenesis and developing new treatments for synucleinopathies. PMID- 26740560 TI - Flexibility and control of thorax deformation during hawkmoth flight. AB - The interaction between neuromuscular systems and body mechanics plays an important role in the production of coordinated movements in animals. Lepidopteran insects move their wings by distortion of the thorax structure via the indirect flight muscles (IFMs), which are activated by neural signals at every stroke. However, how the action of these muscles affects thorax deformation and wing kinematics is poorly understood. We measured the deformation of the dorsal thorax (mesonotum) of tethered flying hawkmoths, Agrius convolvuli, using a high-speed laser profilometer combined with simultaneous recordings of electromyograms and wing kinematics. We observed that locally amplified mesonotum deformation near the wing hinges ensures sufficient wing movement. Furthermore, phase asymmetry in IFM activity leads to phase asymmetry in mesonotum oscillations and wingbeats. Our results revealed the flexibility and controllability of the single structure of the mesonotum by neurogenic action of the IFMs. PMID- 26740561 TI - Individual variation in whole-animal hypoxia tolerance is associated with cardiac hypoxia tolerance in a marine teleost. AB - Hypoxia is a pervasive problem in coastal environments and is predicted to have enduring impacts on aquatic ecosystems. Intraspecific variation in hypoxia tolerance is well documented in fish; however, the factors underlying this variation remain unknown. Here, we investigate the role of the heart in individual hypoxia tolerance of the European sea bass (Dicentrarchus labrax). We found individual whole-animal hypoxia tolerance is a stable trait in sea bass for more than 18 months (duration of study). We next examined in vitro cardiac performance and found myocardial muscle from hypoxia-tolerant individuals generated greater force, with higher rates of contraction and relaxation, than hypoxic-sensitive individuals during hypoxic exposure. Thus, whole-animal hypoxia tolerance is associated with cardiac hypoxia tolerance. As the occurrence of aquatic hypoxia is expected to increase in marine ecosystems, our experimental data suggest that cardiac performance may influence fish survival and distribution. PMID- 26740562 TI - Energetics of stress: linking plasma cortisol levels to metabolic rate in mammals. AB - Physiological stress may result in short-term benefits to organismal performance, but also long-term costs to health or longevity. Yet, we lack an understanding of the variation in stress hormone levels (i.e. glucocorticoids) that exist within and across species. Here, we present comparative analyses that link the primary stress hormone in most mammals (i.e. cortisol) to metabolic rate. We show that baseline concentrations of plasma cortisol vary with mass-specific metabolic rate among cortisol-dominant mammals, and both baseline and elevated concentrations scale predictably with body mass. The results quantitatively link a classical measure of physiological stress to whole-organism energetics, providing a point of departure for cross-species comparisons of stress levels among mammals. PMID- 26740563 TI - Weak rappers rock more: hermit crabs assess their own agonistic behaviour. AB - Fighting animals use a variety of information sources to make strategic decisions. A neglected potential source of information is an individual's own performance during a fight. Surprisingly, this possibility has yet to be incorporated into the large body of theory concerning the evolution of aggressive behaviour. Here, by experimentally dampening the impact of their shell rapping behaviour, we test for the possibility that attacking hermit crabs monitor their own fight performance. Attackers with dampened raps did not show a reduction in the number of raps used. By contrast, they showed an increased frequency of a less intense agonistic behaviour, shell rocking. This change in behaviour, in attackers that are forced to rap weakly, indicates that they assess their own agonistic behaviour. PMID- 26740564 TI - Adaptations to squid-style high-speed swimming in Jurassic belemnitids. AB - Although the calcitic hard parts of belemnites (extinct Coleoidea) are very abundant fossils, their soft parts are hardly known and their mode of life is debated. New fossils of the Jurassic belemnitid Acanthoteuthis provided supplementary anatomical data on the fins, nuchal cartilage, collar complex, statoliths, hyponome and radula. These data yielded evidence of their pelagic habitat, their nektonic habit and high swimming velocities. The new morphological characters were included in a cladistic analysis, which confirms the position of the Belemnitida in the stem of Decabrachia (Decapodiformes). PMID- 26740565 TI - Ecological immunization: in situ training of free-ranging predatory lizards reduces their vulnerability to invasive toxic prey. AB - In Australia, large native predators are fatally poisoned when they ingest invasive cane toads (Rhinella marina). As a result, the spread of cane toads has caused catastrophic population declines in these predators. Immediately prior to the arrival of toads at a floodplain in the Kimberley region, we induced conditioned taste aversion in free-ranging varanid lizards (Varanus panoptes), by offering them small cane toads. By the end of the 18-month study, only one of 31 untrained lizards had survived longer than 110 days, compared to more than half (nine of 16) of trained lizards; the maximum known survival of a trained lizard in the presence of toads was 482 days. In situ aversion training (releasing small toads in advance of the main invasion front) offers a logistically simple and feasible way to buffer the impact of invasive toads on apex predators. PMID- 26740567 TI - Heterozygosity increases microsatellite mutation rate. AB - Whole genome sequencing of families of Arabidopsis has recently lent strong support to the heterozygote instability (HI) hypothesis that heterozygosity locally increases mutation rate. However, there is an important theoretical difference between the impact on base substitutions, where mutation rate increases in regions surrounding a heterozygous site, and the impact of HI on sequences such as microsatellites, where mutations are likely to occur at the heterozygous site itself. At microsatellite loci, HI should create a positive feedback loop, with heterozygosity and mutation rate mutually increasing each other. Direct support for HI acting on microsatellites is limited and contradictory. I therefore analysed AC microsatellites in 1163 genome sequences from the 1000 genomes project. I used the presence of rare alleles, which are likely to be very recent in origin, as a surrogate measure of mutation rate. I show that rare alleles are more likely to occur at locus-population combinations with higher heterozygosity even when all populations carry exactly the same number of alleles. PMID- 26740566 TI - Stress and the microbiome: linking glucocorticoids to bacterial community dynamics in wild red squirrels. AB - Bacterial diversity within animals is emerging as an essential component of health, but it is unknown how stress may influence the microbiome. We quantify a proximate link between the oral microbiome and hypothalamic-pituitary-adrenal (HPA) axis activity using faecal glucocorticoid metabolites (FGM) in wild red squirrels (Tamiasciurus hudsonicus). Not only was bacterial diversity lower at higher levels of FGM, but also between capture periods a change in bacterial relative abundance was related to an increase in FGM. These linkages between the HPA axis and microbiome communities represent a powerful capacity for stress to have multi-dimensional effects on health. PMID- 26740568 TI - Deviation from niche optima affects the nature of plant-plant interactions along a soil acidity gradient. AB - There is increasing recognition of the importance of niche optima in the shift of plant-plant interactions along environmental stress gradients. Here, we investigate whether deviation from niche optima would affect the outcome of plant plant interactions along a soil acidity gradient (pH = 3.1, 4.1, 5.5 and 6.1) in a pot experiment. We used the acid-tolerant species Lespedeza formosa Koehne as the neighbouring plant and the acid-tolerant species Indigofera pseudotinctoria Mats. or acid-sensitive species Medicago sativa L. as the target plants. Biomass was used to determine the optimal pH and to calculate the relative interaction index (RII). We found that the relationships between RII and the deviation of soil pH from the target's optimal pH were linear for both target species. Both targets were increasingly promoted by the neighbour as pH values deviated from their optima; neighbours benefitted target plants by promoting soil symbiotic arbuscular mycorrhizal fungi, increasing soil organic matter or reducing soil exchangeable aluminium. Our results suggest that the shape of the curve describing the relationship between soil pH and facilitation/competition depends on the soil pH optima of the particular species. PMID- 26740569 TI - BRE facilitates skeletal muscle regeneration by promoting satellite cell motility and differentiation. AB - The function of the Bre gene in satellite cells was investigated during skeletal muscle regeneration. The tibialis anterior leg muscle was experimentally injured in Bre knockout mutant (BRE-KO) mice. It was established that the accompanying muscle regeneration was impaired as compared with their normal wild-type counterparts (BRE-WT). There were significantly fewer pax7(+) satellite cells and smaller newly formed myofibers present in the injury sites of BRE-KO mice. Bre was required for satellite cell fusion and myofiber formation. The cell fusion index and average length of newly-formed BRE-KO myofibers were found to be significantly reduced as compared with BRE-WT myofibers. It is well established that satellite cells are highly invasive which confers on them the homing ability to reach the muscle injury sites. Hence, we tracked the migratory behavior of these cells using time-lapse microscopy. Image analysis revealed no difference in directionality of movement between BRE-KO and BRE-WT satellite cells but there was a significant decrease in the velocity of BRE-KO cell movement. Moreover, chemotactic migration assays indicated that BRE-KO satellite cells were significantly less responsive to chemoattractant SDF-1alpha than BRE-WT satellite cells. We also established that BRE normally protects CXCR4 from SDF-1alpha induced degradation. In sum, BRE facilitates skeletal muscle regeneration by enhancing satellite cell motility, homing and fusion. PMID- 26740570 TI - Biosignature for airway inflammation in a house dust mite-challenged murine model of allergic asthma. AB - House dust mite (HDM) challenge is commonly used in murine models of allergic asthma for preclinical pathophysiological studies. However, few studies define objective readouts or biomarkers in this model. In this study we characterized immune responses and defined molecular markers that are specifically altered after HDM challenge. In this murine model, we used repeated HDM challenge for two weeks which induced hallmarks of allergic asthma seen in humans, including airway hyper-responsiveness (AHR) and elevated levels of circulating total and HDM specific IgE and IgG1. Kinetic studies showed that at least 24 h after last HDM challenge results in significant AHR along with eosinophil infiltration in the lungs. Histologic assessment of lung revealed increased epithelial thickness and goblet cell hyperplasia, in the absence of airway wall collagen deposition, suggesting ongoing tissue repair concomitant with acute allergic lung inflammation. Thus, this model may be suitable to delineate airway inflammation processes that precede airway remodeling and development of fixed airway obstruction. We observed that a panel of cytokines e.g. IFN-gamma, IL-1beta, IL 4, IL-5, IL-6, KC, TNF-alpha, IL-13, IL-33, MDC and TARC were elevated in lung tissue and bronchoalveolar fluid, indicating local lung inflammation. However, levels of these cytokines remained unchanged in serum, reflecting lack of systemic inflammation in this model. Based on these findings, we further monitored the expression of 84 selected genes in lung tissues by quantitative real-time PCR array, and identified 31 mRNAs that were significantly up-regulated in lung tissue from HDM-challenged mice. These included genes associated with human asthma (e.g. clca3, ear11, il-13, il-13ra2, il-10, il-21, arg1 and chia1) and leukocyte recruitment in the lungs (e.g. ccl11, ccl12 and ccl24). This study describes a biosignature to enable broad and systematic interrogation of molecular mechanisms and intervention strategies for airway inflammation pertinent to allergic asthma that precedes and possibly potentiates airway remodeling and fibrosis. PMID- 26740571 TI - METACASPASE9 modulates autophagy to confine cell death to the target cells during Arabidopsis vascular xylem differentiation. AB - We uncovered that the level of autophagy in plant cells undergoing programmed cell death determines the fate of the surrounding cells. Our approach consisted of using Arabidopsis thaliana cell cultures capable of differentiating into two different cell types: vascular tracheary elements (TEs) that undergo programmed cell death (PCD) and protoplast autolysis, and parenchymatic non-TEs that remain alive. The TE cell type displayed higher levels of autophagy when expression of the TE-specific METACASPASE9 (MC9) was reduced using RNAi (MC9-RNAi). Misregulation of autophagy in the MC9-RNAi TEs coincided with ectopic death of the non-TEs, implying the existence of an autophagy-dependent intercellular signalling from within the TEs towards the non-TEs. Viability of the non-TEs was restored when AUTOPHAGY2 (ATG2) was downregulated specifically in MC9-RNAi TEs, demonstrating the importance of autophagy in the spatial confinement of cell death. Our results suggest that other eukaryotic cells undergoing PCD might also need to tightly regulate their level of autophagy to avoid detrimental consequences for the surrounding cells. PMID- 26740572 TI - Foraging at wastewater treatment works affects brown adipose tissue fatty acid profiles in banana bats. AB - In this study we tested the hypothesis that the decrease in habitat quality at wastewater treatment works (WWTW), such as limited prey diversity and exposure to the toxic cocktail of pollutants, affect fatty acid profiles of interscapular brown adipose tissue (iBrAT) in bats. Further, the antioxidant capacity of oxidative tissues such as pectoral and cardiac muscle may not be adequate to protect those tissues against reactive molecules resulting from polyunsaturated fatty acid auto-oxidation in the WWTW bats. Bats were sampled at two urban WWTW, and two unpolluted reference sites in KwaZulu-Natal, South Africa. Brown adipose tissue (BrAT) mass was lower in WWTW bats than in reference site bats. We found lower levels of saturated phospholipid fatty acids and higher levels of mono- and polyunsaturated fatty acids in WWTW bats than in reference site bats, while C18 desaturation and n-6 to n-3 ratios were higher in the WWTW bats. This was not associated with high lipid peroxidation levels in pectoral and cardiac muscle. Combined, these results indicate that WWTW bats rely on iBrAT as an energy source, and opportunistic foraging on abundant, pollutant-tolerant prey may change fatty acid profiles in their tissue, with possible effects on mitochondrial functioning, torpor and energy usage. PMID- 26740573 TI - Direct lateral maneuvers in hawkmoths. AB - We used videography to investigate direct lateral maneuvers, i.e. 'sideslips', of the hawkmoth Manduca sexta. M. sexta sideslip by rolling their entire body and wings to reorient their net force vector. During sideslip they increase net aerodynamic force by flapping with greater amplitude, (in both wing elevation and sweep), allowing them to continue to support body weight while rolled. To execute the roll maneuver we observed in sideslips, they use an asymmetric wing stroke; increasing the pitch of the roll-contralateral wing pair, while decreasing that of the roll-ipsilateral pair. They also increase the wing sweep amplitude of, and decrease the elevation amplitude of, the contralateral wing pair relative to the ipsilateral pair. The roll maneuver unfolds in a stairstep manner, with orientation changing more during downstroke than upstroke. This is due to smaller upstroke wing pitch angle asymmetries as well as increased upstroke flapping counter-torque from left-right differences in global reference frame wing velocity about the moth's roll axis. Rolls are also opposed by stabilizing aerodynamic moments from lateral motion, such that rightward roll velocity will be opposed by rightward motion. Computational modeling using blade-element approaches confirm the plausibility of a causal linkage between the previously mentioned wing kinematics and roll/sideslip. Model results also predict high degrees of axial and lateral damping. On the time scale of whole and half wing strokes, left-right wing pair asymmetries directly relate to the first, but not second, derivative of roll. Collectively, these results strongly support a roll based sideslip with a high degree of roll damping in M. sexta. PMID- 26740574 TI - Stable atrogin-1 (Fbxo32) and MuRF1 (Trim63) gene expression is involved in the protective mechanism in soleus muscle of hibernating Daurian ground squirrels (Spermophilus dauricus). AB - Understanding the mechanisms that protect against or limit muscle atrophy in hibernators during prolonged inactivity has important implications for its treatment. We examined whether external factors influence the pathways regulating protein synthesis and degradation, leading to muscle atrophy prevention in Daurian ground squirrels (Spermophilus dauricus). We investigated the effects of 14-day hindlimb-unloading (HU) in different seasons and two-month hibernation on the soleus (SOL) muscle wet mass, muscle-to-body mass ratio, fiber cross sectional area (CSA), fiber distribution and muscle ultrastructure. We also measured changes in the protein expression and activation states of Akt, mTOR and FoxO1 and the mRNA expression of atrogin-1 and MuRF1. Compared with the control groups, autumn and winter HU significantly lowered SOL muscle wet mass and muscle to-body mass ratio, decreased type I and II fiber CSA and induced ultrastructural anomalies. However, these measured indices were unchanged between Pre-hibernation and Hibernation groups. Furthermore, phosphorylation levels of Akt and mTOR significantly decreased, while the phosphorylation level of FoxO1 and mRNA expression of atrogin-1 and MuRF1 increased after HU. During hibernation, the phosphorylation levels of Akt and mTOR significantly decreased, but the phosphorylation level of FoxO1 and mRNA expression of atrogin-1 and MuRF1 remained unchanged. Overall, our findings suggest that disuse and seasonality may not be sufficient to initiate the innate protective mechanism that prevents SOL atrophy during prolonged periods of hibernation inactivity. The stable expression of atrogin-1 and MuRF1 may facilitate to prevent SOL atrophy via controlling ubiquitination of muscle proteins during hibernation. PMID- 26740575 TI - Probability of atrial fibrillation after ablation: Using a parametric nonlinear temporal decomposition mixed effects model. AB - Atrial fibrillation is an arrhythmic disorder where the electrical signals of the heart become irregular. The probability of atrial fibrillation (binary response) is often time varying in a structured fashion, as is the influence of associated risk factors. A generalized nonlinear mixed effects model is presented to estimate the time-related probability of atrial fibrillation using a temporal decomposition approach to reveal the pattern of the probability of atrial fibrillation and their determinants. This methodology generalizes to patient specific analysis of longitudinal binary data with possibly time-varying effects of covariates and with different patient-specific random effects influencing different temporal phases. The motivation and application of this model is illustrated using longitudinally measured atrial fibrillation data obtained through weekly trans-telephonic monitoring from an NIH sponsored clinical trial being conducted by the Cardiothoracic Surgery Clinical Trials Network. PMID- 26740576 TI - Global cropland and greenhouse gas impacts of UK food supply are increasingly located overseas. AB - Producing sufficient, healthy food for a growing world population amid a changing climate is a major challenge for the twenty-first century. Agricultural trade could help alleviate this challenge by using comparative productivity advantages between countries. However, agricultural trade has implications for national food security and could displace environmental impacts from developed to developing countries. This study illustrates the global effects resulting from the agricultural trade of a single country, by analysing the global cropland and greenhouse gas impacts of the UK's food and feed supply. The global cropland footprint associated with the UK food and feed supply increased by 2022 kha (+23%) from 1986 to 2009. Greenhouse gas emissions (GHGE) associated with fertilizer and manure application, and rice cultivation remained relatively constant at 7.9 Mt CO2e between 1987 and 2008. Including GHGE from land-use change, however, leads to an increase from 19.1 in 1987 to 21.9 Mt CO2e in 2008. The UK is currently importing over 50% of its food and feed, whereas 70% and 64% of the associated cropland and GHGE impacts, respectively, are located abroad. These results imply that the UK is increasingly reliant on external resources and that the environmental impact of its food supply is increasingly displaced overseas. PMID- 26740577 TI - Prostaglandin E2 and vascular endothelial growth factor A mediate angiogenesis of human ovarian follicular endothelial cells. AB - STUDY QUESTION: Which receptors for prostaglandin E2 (PGE2) and vascular endothelial growth factor A (VEGFA) mediate angiogenesis in the human follicle around the time of ovulation? SUMMARY ANSWER: PGE2 and VEGFA act via multiple PGE2 receptors (PTGERs) and VEGF receptors (VEGFRs) to play complementary roles in follicular angiogenesis. WHAT IS KNOWN ALREADY: Production of PGE2 and VEGFA by the follicle are prerequisites for ovulation. PGE2 is an emerging regulator of angiogenesis and has not been examined in the context of the human ovulatory follicle. VEGFA is an established regulator of follicular angiogenesis. STUDY DESIGN, SIZE, DURATION: Ovarian biopsies containing the ovulatory follicle were obtained from 11 women of reproductive age (30-45 years) undergoing surgery for laparoscopic sterilization. In some cases, women received hCG to substitute for the ovulatory LH surge before ovarian biopsy. In addition, aspirates from four women of reproductive age (18-31 years) undergoing gonadotrophin stimulation for oocyte donation were obtained for isolation of human ovarian microvascular endothelial cells (hOMECs). PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian biopsies were utilized for immunocytochemical detection of von Willebrand factor to identify endothelial cells. hOMECs were cultured with PGE2, PTGER receptor selective agonists, VEGFA, or VEGFR selective agonists. hOMECs were assessed for proliferation by Ki67 immunocytochemistry. hOMEC migration was determined by counting cells which migrated through a porous membrane in vitro. Sprout formation was quantified by determining sprout number and length from photographs take after culture of hOMECs in a 3-dimensional matrix. MAIN RESULTS AND THE ROLE OF CHANCE: Endothelial cells were not observed within the granulosa cell layer of human ovulatory follicles prior to an ovulatory dose of hCG and were first seen amongst granulosa cells 18-34 h after hCG. In vitro, PGE2 enhanced migration and sprout formation but did not alter hOMEC proliferation. Agonists selective for each PTGER increased migration with no change in proliferation. PTGER1 and PTGER2 agonists increased the number of sprouts, while only PTGER1 affected sprout length. VEGFA increased hOMEC proliferation, migration, and formation of structures resembling capillary sprouts. Signaling through VEGFR1 promoted hOMEC migration, proliferation, and the formation of few, long endothelial cell sprouts, while VEGFR2 stimulation promoted hOMEC migration and the formation of many, short sprouts. All effects of treatments in vitro were considered significant at P < 0.05. LIMITATIONS, REASONS FOR CAUTION: While primary cultures of hOMECs respond to PGE2 and VEGFA differently than other cultured endothelial cells, hOMECs may not respond to PGE2 and VEGFA in vivo as they do in vitro. WIDER IMPLICATIONS OF THE FINDINGS: Agonists and antagonists selective for PTGER1, PTGER2, VEGFR1, or VEGFR2 may have therapeutic value to promote or prevent ovulation in women. STUDY FUNDING/COMPETING INTERESTS: This research was supported by grant funding from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development (HD071875 to D.M.D., T.E.C., M.B.). The authors have no conflicts of interest to disclose. PMID- 26740578 TI - Assisted reproductive technology in Europe, 2011: results generated from European registers by ESHRE. AB - STUDY QUESTION: The 15th European IVF-monitoring (EIM) report presents the results of treatments involving assisted reproductive technology (ART) initiated in Europe during 2011: are there any changes in the trends compared with previous years? SUMMARY ANSWER: Despite some fluctuations in the number of countries reporting data, while the overall number of ART cycles has continued to increase year by year, the pregnancy rates in 2011 decreased slightly to those reported in 2010, and the number of transfers with multiple embryos (3+) and the multiple delivery rates declined. WHAT IS KNOWN ALREADY: Since 1997, ART data in Europe have been collected and reported in 14 manuscripts, published in Human Reproduction. STUDY DESIGN, SIZE, DURATION: Retrospective data collection of European ART data by the EIM Consortium for the European Society of Human Reproduction and Embryology (ESHRE); cycles started between 1 January and 31 December 2011 are collected on a yearly basis. The data are collected by National Registers, when existing, or on a voluntary basis by personal information. PARTICIPANTS/MATERIALS SETTING, METHODS: From 33 countries (+2 compared with 2010), 1064 clinics reported 609 973 treatment cycles including: IVF 138 592, ICSI 298 918, frozen embryo replacement (FER) 129 693, egg donation (ED) 30 198, in vitro maturation 511, preimplantation genetic diagnosis/screening 6824 and frozen oocyte replacements 5237. European data on intrauterine insemination (IUI) using husband/partner's semen (IUI-H) and donor semen (IUI-D) were reported from 861 IUI laboratories in 24 countries. A total of 174 390 IUI-H and 41 151 IUI-D cycles were included. MAIN RESULTS AND THE ROLE OF CHANCE: In 17 countries where all clinics reported to the ART register, a total of 361 972 ART cycles were performed in a population of 285 million inhabitants, corresponding to 1269 cycles per million inhabitants. For all IVF cycles, the clinical pregnancy rates per aspiration and per transfer were stable with 29.1 and 33.2%, respectively, and for ICSI, the corresponding rates also were stable with 27.9 and 31.8%, respectively. In FER cycles, the pregnancy rate per thawing increased to 21.3% if compared with previous years. In ED cycles, the pregnancy rate per fresh transfer decreased to 45.8% (47.4% in 2010) and increased to 33.6% (33.3% in 2010) per thawed transfer. The delivery rate after IUI-H decreased to 8.3 (8.9 in 2010), and to 12.2% (13.8% in 2010) after IUI-D. In IVF and ICSI cycles, 1, 2, 3 and 4+ embryos were transferred in 27.5, 56.7, 14.5 and 1.3% of cycles, respectively. The proportions of singleton, twin and triplet deliveries after IVF and ICSI (added together) were 80.8, 18.6 and 0.6%, respectively, resulting in a total multiple delivery rate of 19.2% compared with 20.6% in 2010, 20.2% in 2009, 21.7% in 2008, 22.3% in 2007 and 20.8% in 2006. In FER cycles, the multiple delivery rate was 13.2% (12.8% twins and 0.4% triplets). Twin and triplet delivery rates associated with IUI cycles were 9.7/0.6% and 7.3/0.3%, following IUI-H and IUI-D treatment, respectively. LIMITATIONS, REASONS FOR CAUTION: The method of reporting varies among countries, and registers from a number of countries have been unable to provide some of the relevant data such as initiated cycles and deliveries. As long as data are incomplete and generated through different methods of collection, results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: The 15th ESHRE report on ART shows a continuing expansion of the number of treatment cycles in Europe, with more than 600 000 cycles reported in 2011. Since 2006, the proportion of IVF to ICSI cycles has reached a plateau after a small decrease in 2009. Pregnancy and delivery rates after IVF remained relatively stable compared with 2010 and 2009. The pregnancy rate per aspiration in ICSI cycles declined for the first time by 0.9%. The multiple delivery rate is lower than ever before. STUDY FUNDING/COMPETING INTERESTS: The study had no external funding; all costs are covered by ESHRE. There are no competing interests. PMID- 26740579 TI - Semen quality improves marginally during young adulthood: a longitudinal follow up study. AB - STUDY QUESTION: Does semen quality improve during early adulthood? SUMMARY ANSWER: Semen variables change little during the third decade of life, however some improvement in sperm morphology and motility may occur. WHAT IS KNOWN ALREADY: A suspicion of deteriorating semen quality has been raised in several studies. The longitudinal development of semen quality in early adulthood is insufficiently understood. STUDY DESIGN, SIZE, DURATION: A longitudinal follow-up of two cohorts of volunteer young adult Finnish men representing the general population was carried out. Cohorts A (discovery cohort, born 1979-1981, n = 336) and B (validation cohort, born 1983, n = 197) were followed up from the age of 19 years onward for 10 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria included that both the men and their mothers were born in Finland. Semen analysis was performed in cohorts A and B at 2-4 year intervals over a period of 10 years. Semen volume, sperm concentration, total sperm count, motility, total motile count and morphology were the variables assessed in the analysis. A physical examination was carried out at each visit to detect any significant andrological abnormalities. The overall participation rate was 13.4%. MAIN RESULTS AND THE ROLE OF CHANCE: During the follow-up, the percentage of sperm with normal morphology and the percentage of motile sperm increased significantly both in the discovery (A) (P < 0.001 at 19 versus 29 years for both) and validation (B) (P < 0.001 and P = 0.03 at 19 versus 29 years, respectively) cohort. Sperm concentration and total sperm count showed a significant increase with age only in cohort B (P = 0.03 at 21 versus 29 years, P = 0.009 at 19 versus 29 years, respectively). LIMITATIONS, REASONS FOR CAUTION: A limited number of men participated both in the first round and in the final fourth round (cohort A, n = 111 and cohort B, n = 90 men) and in all four rounds (cohort A, n = 61 and cohort B, n = 52). WIDER IMPLICATIONS OF THE FINDINGS: Almost full spermatogenic capacity is reached by the age of 19 years. However, the improvement in sperm motility and morphology during early adulthood may slightly improve male fecundity. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the European Commission (QLK4-CT-1999-01422, QLK4-CT-2001-00269, QLK4-2002-0063, FP7/2008-2012: DEER 212844), The Danish Medical Research Council (9700833, 9700909), Danish Agency for Science (Technology and Innovation 09-067180), the Svend Andersen's Foundation, Velux Foundation, and Novo Nordisk Foundation, the Turku University Hospital, Sigrid Juselius Foundation and the Academy of Finland. There are no conflicts of interest. PMID- 26740580 TI - Robust detection of alternative splicing in a population of single cells. AB - Single cell RNA-seq experiments provide valuable insight into cellular heterogeneity but suffer from low coverage, 3' bias and technical noise. These unique properties of single cell RNA-seq data make study of alternative splicing difficult, and thus most single cell studies have restricted analysis of transcriptome variation to the gene level. To address these limitations, we developed SingleSplice, which uses a statistical model to detect genes whose isoform usage shows biological variation significantly exceeding technical noise in a population of single cells. Importantly, SingleSplice is tailored to the unique demands of single cell analysis, detecting isoform usage differences without attempting to infer expression levels for full-length transcripts. Using data from spike-in transcripts, we found that our approach detects variation in isoform usage among single cells with high sensitivity and specificity. We also applied SingleSplice to data from mouse embryonic stem cells and discovered a set of genes that show significant biological variation in isoform usage across the set of cells. A subset of these isoform differences are linked to cell cycle stage, suggesting a novel connection between alternative splicing and the cell cycle. PMID- 26740581 TI - Expanding the CRISPR imaging toolset with Staphylococcus aureus Cas9 for simultaneous imaging of multiple genomic loci. AB - In order to elucidate the functional organization of the genome, it is vital to directly visualize the interactions between genomic elements in living cells. For this purpose, we engineered the Cas9 protein from Staphylococcus aureus (SaCas9) for the imaging of endogenous genomic loci, which showed a similar robustness and efficiency as previously reported for Streptococcus pyogenes Cas9 (SpCas9). Imaging readouts allowed us to characterize the DNA-binding activity of SaCas9 and to optimize its sgRNA scaffold. Combining SaCas9 and SpCas9, we demonstrated two-color CRISPR imaging with the capability to resolve genomic loci spaced by <300 kb. Combinatorial color-mixing further enabled us to code multiple genomic elements in the same cell. Our results highlight the potential of combining SpCas9 and SaCas9 for multiplexed CRISPR-Cas9 applications, such as imaging and genome engineering. PMID- 26740582 TI - An integrated systems biology approach identifies positive cofactor 4 as a factor that increases reprogramming efficiency. AB - Spermatogonial stem cells (SSCs) can spontaneously dedifferentiate into embryonic stem cell (ESC)-like cells, which are designated as multipotent SSCs (mSSCs), without ectopic expression of reprogramming factors. Interestingly, SSCs express key pluripotency genes such as Oct4, Sox2, Klf4 and Myc. Therefore, molecular dissection of mSSC reprogramming may provide clues about novel endogenous reprogramming or pluripotency regulatory factors. Our comparative transcriptome analysis of mSSCs and induced pluripotent stem cells (iPSCs) suggests that they have similar pluripotency states but are reprogrammed via different transcriptional pathways. We identified 53 genes as putative pluripotency regulatory factors using an integrated systems biology approach. We demonstrated a selected candidate, Positive cofactor 4 (Pc4), can enhance the efficiency of somatic cell reprogramming by promoting and maintaining transcriptional activity of the key reprograming factors. These results suggest that Pc4 has an important role in inducing spontaneous somatic cell reprogramming via up-regulation of key pluripotency genes. PMID- 26740583 TI - tRNA is a new target for cleavage by a MazF toxin. AB - Toxin-antitoxin (TA) systems play key roles in bacterial persistence, biofilm formation and stress responses. The MazF toxin from the Escherichia coli mazEF TA system is a sequence- and single-strand-specific endoribonuclease, and many studies have led to the proposal that MazF family members exclusively target mRNA. However, recent data indicate some MazF toxins can cleave specific sites within rRNA in concert with mRNA. In this report, we identified the repertoire of RNAs cleaved by Mycobacterium tuberculosis toxin MazF-mt9 using an RNA-seq-based approach. This analysis revealed that two tRNAs were the principal targets of MazF-mt9, and each was cleaved at a single site in either the tRNA(Pro14) D-loop or within the tRNA(Lys43) anticodon. This highly selective target discrimination occurs through recognition of not only sequence but also structural determinants. Thus, MazF-mt9 represents the only MazF family member known to target tRNA and to require RNA structure for recognition and cleavage. Interestingly, the tRNase activity of MazF-mt9 mirrors basic features of eukaryotic tRNases that also generate stable tRNA-derived fragments that can inhibit translation in response to stress. Our data also suggest a role for tRNA distinct from its canonical adapter function in translation, as cleavage of tRNAs by MazF-mt9 downregulates bacterial growth. PMID- 26740584 TI - Human nonsense-mediated mRNA decay factor UPF2 interacts directly with eRF3 and the SURF complex. AB - Nonsense-mediated mRNA decay (NMD) is an mRNA degradation pathway that regulates gene expression and mRNA quality. A complex network of macromolecular interactions regulates NMD initiation, which is only partially understood. According to prevailing models, NMD begins by the assembly of the SURF (SMG1-UPF1 eRF1-eRF3) complex at the ribosome, followed by UPF1 activation by additional factors such as UPF2 and UPF3. Elucidating the interactions between NMD factors is essential to comprehend NMD, and here we demonstrate biochemically and structurally the interaction between human UPF2 and eukaryotic release factor 3 (eRF3). In addition, we find that UPF2 associates with SURF and ribosomes in cells, in an UPF3-independent manner. Binding assays using a collection of UPF2 truncated variants reveal that eRF3 binds to the C-terminal part of UPF2. This region of UPF2 is partially coincident with the UPF3-binding site as revealed by electron microscopy of the UPF2-eRF3 complex. Accordingly, we find that the interaction of UPF2 with UPF3b interferes with the assembly of the UPF2-eRF3 complex, and that UPF2 binds UPF3b more strongly than eRF3. Together, our results highlight the role of UPF2 as a platform for the transient interactions of several NMD factors, including several components of SURF. PMID- 26740585 TI - Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics. AB - BACKGROUND: Endometriosis, the growth of endometrial tissue outside the uterine cavity, is associated with chronic pelvic pain, subfertility and an increased risk of ovarian cancer. Current treatments include the surgical removal of the lesions or the induction of a hypoestrogenic state. However, a reappearance of the lesion after surgery is common and a hypoestrogenic state is less than optimal for women of reproductive age. Additional approaches are required. Endometriosis lesions exist in a unique microenvironment characterized by increased concentrations of hormones, inflammation, oxidative stress and iron. This environment influences cell survival through the binding of membrane receptors and a subsequent cascading activation of intracellular kinases that stimulate a cellular response. Many of these kinase signalling pathways are constitutively activated in endometriosis. These pathways are being investigated as therapeutic targets in other diseases and thus may also represent a target for endometriosis treatment. METHODS: To identify relevant English language studies published up to 2015 on kinase signalling pathways in endometriosis, we searched the Pubmed database using the following search terms in various combinations; 'endometriosis', 'inflammation', 'oxidative stress', 'iron', 'kinase', 'NF kappa', 'mTOR', 'MAPK' 'p38', 'JNK', 'ERK' 'estrogen' and progesterone'. Further citing references were identified using the Scopus database and finally current clinical trials were searched on the clinicaltrials.gov trial registry. RESULTS: The current literature on intracellular kinases activated by the endometriotic environment can be summarized into three main pathways that could be targeted for treatments: the canonical IKKbeta/NFkappaB pathway, the MAPK pathways (ERK1/2, p38 and JNK) and the PI3K/AKT/mTOR pathway. A number of pharmaceutical compounds that target these pathways have been successfully trialled in in vitro and animal models of endometriosis, although they have not yet proceeded to clinical trials. The current generation of kinase inhibitors carry a potential for adverse side effects. CONCLUSIONS: Kinase signalling pathways represent viable targets for endometriosis treatment. At present, however, further improvements in clinical efficacy and the profile of adverse effects are required before these compounds can be useful for long-term endometriosis treatment. A better understanding of the molecular activity of these kinases, including the specific extracellular compounds that lead to their activation in endometriotic cells specifically should facilitate their improvement and could potentially lead to new, non hormonal treatments of endometriosis. PMID- 26740588 TI - Editorial bring in the new! PMID- 26740586 TI - The DyP-type peroxidase DtpA is a Tat-substrate required for GlxA maturation and morphogenesis in Streptomyces. AB - The filamentous bacterium Streptomyces lividans depends on the radical copper oxidase GlxA for the formation of reproductive aerial structures and, in liquid environments, for the formation of pellets. Incorporation of copper into the active site is essential for the formation of a cross-linked tyrosyl-cysteine cofactor, which is needed for enzymatic activity. In this study, we show a crucial link between GlxA maturation and a group of copper-related proteins including the chaperone Sco and a novel DyP-type peroxidase hereinafter called DtpA. Under copper-limiting conditions, the sco and dtpA deletion mutants are blocked in aerial growth and pellet formation, similarly to a glxA mutant. Western blot analysis showed that GlxA maturation is perturbed in the sco and dtpA mutants, but both maturation and morphology can by rescued by increasing the bioavailability of copper. DtpA acts as a peroxidase in the presence of GlxA and is a substrate for the twin-arginine translocation (Tat) translocation pathway. In agreement, the maturation status of GlxA is also perturbed in tat mutants, which can be compensated for by the addition of copper, thereby partially restoring their morphological defects. Our data support a model wherein a copper trafficking pathway and Tat-dependent secretion of DtpA link to the GlxA dependent morphogenesis pathway. PMID- 26740587 TI - Dr Jekyll and Mr Hyde: a strange case of 5-ethynyl-2'-deoxyuridine and 5-ethynyl 2'-deoxycytidine. AB - 5-Ethynyl-2'-deoxyuridine (EdU) and 5-ethynyl-2'-deoxycytidine (EdC) are mainly used as markers of cellular replicational activity. Although EdU is employed as a replicational marker more frequently than EdC, its cytotoxicity is commonly much higher than the toxicity of EdC. To reveal the reason of the lower cytotoxicity of EdC, we performed a DNA analysis of five EdC-treated human cell lines. Surprisingly, not a single one of the tested cell lines contained a detectable amount of EdC in their DNA. Instead, the DNA of all the cell lines contained EdU. The content of incorporated EdU differed in particular cells and EdC-related cytotoxicity was directly proportional to the content of EdU. The results of experiments with the targeted inhibition of the cytidine deaminase (CDD) and dCMP deaminase activities indicated that the dominant role in the conversion pathway of EdC to EdUTP is played by CDD in HeLa cells. Our results also showed that the deamination itself was not able to effectively prevent the conversion of EdC to EdCTP, the conversion of EdC to EdCTP occurs with much lesser effectivity than the conversion of EdU to EdUTP and the EdCTP is not effectively recognized by the replication complex as a substrate for the synthesis of nuclear DNA. PMID- 26740589 TI - A meta-analysis of computerized tomography scan for reducing complications following repeat sternotomy for cardiac surgery. AB - Cardiac reoperation carries additional risks compared with surgery in patients who are sternotomy-naive. To identify if preoperative computerized tomography (CT) can reduce this risk, we performed a systematic review of the literature and meta-analysis. Literature search identified 178 studies of which 4 retrospective cohort studies incorporating 900 patients met inclusion criteria. There were no statistically significant differences in the risk of death, re-entry injury, renal failure or perfusion/ischaemic times. CT scan reduced the risk of stroke by 0.42 [95% confidence interval (CI): 0.19-0.93, P = 0.03] and a composite of major complications by 0.65 (95% CI: 0.47-0.88, P = 0.006). The use of preoperative cross-sectional imaging to reduce the risk of complications following cardiac reoperation is advocated. PMID- 26740590 TI - Nonclassical Testosterone Signaling: A New Pathway Controlling Spermatogenesis? PMID- 26740591 TI - DNA Methylation and Expression Patterns of Selected Genes in First-Trimester Placental Tissue from Pregnancies with Small-for-Gestational-Age Infants at Birth. AB - Variations in DNA methylation levels in the placenta are thought to influence gene expression and are associated with complications of pregnancy, like fetal growth restriction (FGR). The most important cause for FGR is placental dysfunction. Here, we examined whether changes in DNA methylation, followed by gene expression changes, are mechanistically involved in the etiology of FGR. In this retrospective case-control study, we examined the association between small for-gestational-age (SGA) children and both DNA methylation and gene expression levels of the genes WNT2, IGF2/H19, SERPINA3, HERVWE1, and PPARG in first trimester placental tissue. We also examined the repetitive element LINE-1. These candidate genes have been reported in the literature to be associated with SGA. We used first-trimester placental tissue from chorionic villus biopsies. A total of 35 SGA children (with a birth weight below the 10th percentile) were matched to 70 controls based on their gestational age. DNA methylation levels were analyzed by pyrosequencing and mRNA levels were analyzed by real-time PCR. None of the average DNA methylation levels, measured for each gene, showed a significant difference between SGA placental tissue compared to control tissue. However, hypermethylation of WNT2 was detected on two CpG positions in SGA. This was not associated with changes in gene expression. Apart from two CpG positions of the WNT2 gene, in early placenta samples, no evident changes in DNA methylation or expression were found. This indicates that the already reported changes in term placenta are not present in the early placenta, and therefore must arise after the first trimester. PMID- 26740592 TI - A Novel Female-Specific and Sexual Reproduction-Associated Dmrt Gene Discovered in the Stony Coral, Euphyllia ancora. AB - Transcription factors encoded by the Dmrt gene family regulate multiple aspects of animal reproduction. Most studies investigating the Dmrt gene family were conducted in model organisms from bilateral species, with a particular emphasis on gene function in male sex determination. It is still unclear whether the E. ancora Dmrt (EaDmrt) genes found in basal metazoans such as cnidarians share similar characteristics with orthologs in other metazoans. In this study, seven full Dmrt gene transcript sequences for a gonochoric coral, Euphyllia ancora (phylum: Cnidaria; class: Anthozoa), were obtained through transcriptome data mining, RT-PCR analysis, rapid amplification of cDNA ends, and sequencing. These EaDmrts were subjected to quantitative assays measuring temporal and tissue specific expression. Results demonstrated a unique gene expression pattern for EaDmrtE, which is enriched in female germ cells during the spawning season. Based on the phylogenetic analyses performed across the homologous Dmrt genes in metazoans, we found that the female-specific EaDmrtE gene is not related to the DM1 gene of Acropora spp. coral nor to Dmrt1 of vertebrates, which are involved in sexual reproduction, especially in sex determination (vertebrate Dmrt1). Additionally, high levels of EaDmrtE transcripts detected in unfertilized mature eggs are retained in newly formed zygotes but decrease during embryonic development. We suggest that the newly discovered gene may play a role in oogenesis and early embryogenesis as a maternal factor in corals. Therefore, the sexual reproduction-associated Dmrt gene(s) should have arisen in cnidarians and might have evolved multiple times in metazoans. PMID- 26740593 TI - The Equine Embryo Influences Immune-Related Gene Expression in the Oviduct. AB - Although the equine oviduct clearly affects early embryo development and the selective transport of equine embryos through the oviduct indicates a reciprocal interaction, the influence of the embryo on gene expression in the oviduct remains to be determined in the horse. The aim of this study was to examine this by means of RNA sequencing. Four days after ovulation, epithelial cells ipsilateral and contralateral to the ovulation side from five cyclic and five pregnant mares were collected from the oviduct. RNA was extracted, samples were sequenced, and data analysis was performed to determine differentially expressed genes (DEGs) (P value <=0.05 and absolute fold change >=2) and to provide functional interpretation. A total of 10 743 transcripts were identified and 253 genes were found to be upregulated and 108 to be downregulated in the pregnant ipsilateral oviduct when compared to the cyclic ipsilateral oviduct. Comparison of the ipsilateral and the contralateral oviduct indicated 164 DEGs in pregnant mares and 77 DEGs in cyclic mares. Enriched functional categories were detected only in the comparison of pregnant and cyclic ipsilateral oviducts and showed that the equine embryo affects the expression of immune response-related genes in the oviduct, with marked upregulation of interferon-associated genes. This research represents the foundation for further assessment of the role of specific genes in the early embryo-maternal dialogue of the horse. PMID- 26740594 TI - Growth Arrest Specific-1 (GAS1) Is a C/EBP Target Gene That Functions in Ovulation and Corpus Luteum Formation in Mice. AB - Ovulation and luteinization are initiated in preovulatory follicles by the luteinizing hormone (LH) surge; however, the signaling events that mediate LH actions in these follicles remain incompletely defined. Two key transcription factors that are targets of LH surge are C/EBPalpha and C/EBPbeta, and their depletion in granulosa cells results in complete infertility. Microarray analyses of these mutant mice revealed altered expression of a number of genes, including growth arrest specific-1 (Gas1). To investigate functions of Gas1 in ovulation- and luteinization-related processes, we crossed Cyp19a1-Cre and Gas1(flox/flox) mice to conditionally delete Gas1 in granulosa and cumulus cells. While expression of Gas1 is dramatically increased in granulosa and cumulus cells around 12-16 h post-human chorionic gonadotropin (hCG) stimulation in wild-type mice, this increase is abolished in Cebpa/b double mutant and in Gas1 mutant mice. GAS1 is also dynamically expressed in stromal cells of the ovary independent of C/EBPalpha/beta. Female Gas1 mutant mice are fertile, exhibit enhanced rates of ovulation, increased fertility, and higher levels of Areg and Lhcgr mRNA in granulosa cells. The morphological appearance and vascularization of corpora lutea appeared normal in these mutant females. Interestingly, levels of mRNA for a number of genes (Cyp11a1, Star, Wnt4, Prlr, Cd52, and Sema3a) associated with luteinization are decreased in corpora lutea of Gas1 mutant mice as compared with controls at 24 h post-hCG; these differences were no longer detectable by 48 h post-hCG. The C/EBP target Gas1 is induced in granulosa cells and is associated with ovulation and luteinization. PMID- 26740596 TI - Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance. AB - Adiponectin, an insulin-sensitizing hormone, and resistin, known to promote insulin resistance, constitute a potential link between obesity and type 2 diabetes. In addition, fibroblast growth factor (FGF)21 has effects similar to those of adiponectin in regulating glucose and lipid metabolism and insulin sensitivity. However, the interplay between adiponectin, FGF21, and resistin signaling pathways during the onset of insulin resistance is unknown. Here, we investigated whether central resistin promotes insulin resistance through the impairment of adiponectin and FGF21 signaling. We show that chronic intracerebroventricular resistin infusion downregulated both hypothalamic and hepatic APPL1, a key protein in adiponectin signaling, associated with decreased Akt-APPL1 interaction and an increased Akt association with its endogenous inhibitor tribbles homolog 3. Resistin treatment also decreased plasma adiponectin levels and reduced both hypothalamic and peripheral expression of adiponectin receptors. Additionally, we report that intracerebroventricular resistin increased plasma FGF21 levels and downregulated its receptor components in the hypothalamus and peripheral tissues, promoting FGF21 resistance. Interestingly, we also show that resistin effects were abolished in TLR4 knockout mice and in neuronal cells expressing TLR4 siRNAs. Our study reveals a novel mechanism of insulin resistance onset orchestrated by a central resistin-TLR4 pathway that impairs adiponectin signaling and promotes FGF21 resistance. PMID- 26740595 TI - Functional Deficits Precede Structural Lesions in Mice With High-Fat Diet-Induced Diabetic Retinopathy. AB - Obesity predisposes to human type 2 diabetes, the most common cause of diabetic retinopathy. To determine if high-fat diet-induced diabetes in mice can model retinal disease, we weaned mice to chow or a high-fat diet and tested the hypothesis that diet-induced metabolic disease promotes retinopathy. Compared with controls, mice fed a diet providing 42% of energy as fat developed obesity related glucose intolerance by 6 months. There was no evidence of microvascular disease until 12 months, when trypsin digests and dye leakage assays showed high fat-fed mice had greater atrophic capillaries, pericyte ghosts, and permeability than controls. However, electroretinographic dysfunction began at 6 months in high fat-fed mice, manifested by increased latencies and reduced amplitudes of oscillatory potentials compared with controls. These electroretinographic abnormalities were correlated with glucose intolerance. Unexpectedly, retinas from high fat-fed mice manifested striking induction of stress kinase and neural inflammasome activation at 3 months, before the development of systemic glucose intolerance, electroretinographic defects, or microvascular disease. These results suggest that retinal disease in the diabetic milieu may progress through inflammatory and neuroretinal stages long before the development of vascular lesions representing the classic hallmark of diabetic retinopathy, establishing a model for assessing novel interventions to treat eye disease. PMID- 26740597 TI - Relative Contribution of Intramyocellular Lipid to Whole-Body Fat Oxidation Is Reduced With Age but Subsarcolemmal Lipid Accumulation and Insulin Resistance Are Only Associated With Overweight Individuals. AB - Insulin resistance is closely related to intramyocellular lipid (IMCL) accumulation, and both are associated with increasing age. It remains to be determined to what extent perturbations in IMCL metabolism are related to the aging process per se. On two separate occasions, whole-body and muscle insulin sensitivity (euglycemic-hyperinsulinemic clamp with 2-deoxyglucose) and fat utilization during 1 h of exercise at 50% VO2max ([U-(13)C]palmitate infusion combined with electron microscopy of IMCL) were determined in young lean (YL), old lean (OL), and old overweight (OO) males. OL displayed IMCL content and insulin sensitivity comparable with those in YL, whereas OO were markedly insulin resistant and had more than twofold greater IMCL in the subsarcolemmal (SSL) region. Indeed, whereas the plasma free fatty acid Ra and Rd were twice those of YL in both OL and OO, SSL area only increased during exercise in OO. Thus, skeletal muscle insulin resistance and lipid accumulation often observed in older individuals are likely due to lifestyle factors rather than inherent aging of skeletal muscle as usually reported. However, age per se appears to cause exacerbated adipose tissue lipolysis, suggesting that strategies to reduce muscle lipid delivery and improve adipose tissue function may be warranted in older overweight individuals. PMID- 26740598 TI - NETosis Delays Diabetic Wound Healing in Mice and Humans. AB - Upon activation, neutrophils undergo histone citrullination by protein arginine deiminase (PAD)4, exocytosis of chromatin and enzymes as neutrophil extracellular traps (NETs), and death. In diabetes, neutrophils are primed to release NETs and die by NETosis. Although this process is a defense against infection, NETosis can damage tissue. Therefore, we examined the effect of NETosis on the healing of diabetic foot ulcers (DFUs). Using proteomics, we found that NET components were enriched in nonhealing human DFUs. In an independent validation cohort, a high concentration of neutrophil elastase in the wound was associated with infection and a subsequent worsening of the ulcer. NET components (elastase, histones, neutrophil gelatinase-associated lipocalin, and proteinase-3) were elevated in the blood of patients with DFUs. Circulating elastase and proteinase-3 were associated with infection, and serum elastase predicted delayed healing. Neutrophils isolated from the blood of DFU patients showed an increased spontaneous NETosis but an impaired inducible NETosis. In mice, skin PAD4 activity was increased by diabetes, and FACS detection of histone citrullination, together with intravital microscopy, showed that NETosis occurred in the bed of excisional wounds. PAD4 inhibition by Cl-amidine reduced NETting neutrophils and rescued wound healing in diabetic mice. Cumulatively, these data suggest that NETosis delays DFU healing. PMID- 26740599 TI - PPARgamma Antagonist Gleevec Improves Insulin Sensitivity and Promotes the Browning of White Adipose Tissue. AB - Blocking phosphorylation of peroxisome proliferator-activated receptor (PPAR)gamma at Ser(273) is one of the key mechanisms for antidiabetes drugs to target PPARgamma. Using high-throughput phosphorylation screening, we here describe that Gleevec blocks cyclin-dependent kinase 5-mediated PPARgamma phosphorylation devoid of classical agonism as a PPARgamma antagonist ligand. In high fat-fed mice, Gleevec improved insulin sensitivity without causing severe side effects associated with other PPARgamma-targeting drugs. Furthermore, Gleevec reduces lipogenic and gluconeogenic gene expression in liver and ameliorates inflammation in adipose tissues. Interestingly, Gleevec increases browning of white adipose tissue and energy expenditure. Taken together, the results indicate that Gleevec exhibits greater beneficial effects on both glucose/lipid metabolism and energy homeostasis by blocking PPARgamma phosphorylation. These data illustrate that Gleevec could be a novel therapeutic agent for use in insulin resistance and type 2 diabetes. PMID- 26740600 TI - Next-Generation Sequencing Reveals That HLA-DRB3, -DRB4, and -DRB5 May Be Associated With Islet Autoantibodies and Risk for Childhood Type 1 Diabetes. AB - The possible contribution of HLA-DRB3, -DRB4, and -DRB5 alleles to type 1 diabetes risk and to insulin autoantibody (IAA), GAD65 (GAD autoantibody [GADA]), IA-2 antigen (IA-2A), or ZnT8 against either of the three amino acid variants R, W, or Q at position 325 (ZnT8RA, ZnT8WA, and ZnT8QA, respectively) at clinical diagnosis is unclear. Next-generation sequencing (NGS) was used to determine all DRB alleles in consecutively diagnosed patients ages 1-18 years with islet autoantibody-positive type 1 diabetes (n = 970) and control subjects (n = 448). DRB3, DRB4, or DRB5 alleles were tested for an association with the risk of DRB1 for autoantibodies, type 1 diabetes, or both. The association between type 1 diabetes and DRB1*03:01:01 was affected by DRB3*01:01:02 and DRB3*02:02:01. These DRB3 alleles were associated positively with GADA but negatively with ZnT8WA, IA 2A, and IAA. The negative association between type 1 diabetes and DRB1*13:01:01 was affected by DRB3*01:01:02 to increase the risk and by DRB3*02:02:01 to maintain a negative association. DRB4*01:03:01 was strongly associated with type 1 diabetes (P = 10(-36)), yet its association was extensively affected by DRB1 alleles from protective (DRB1*04:03:01) to high (DRB1*04:01:01) risk, but its association with DRB1*04:05:01 decreased the risk. HLA-DRB3, -DRB4, and -DRB5 affect type 1 diabetes risk and islet autoantibodies. HLA typing with NGS should prove useful to select participants for prevention or intervention trials. PMID- 26740601 TI - Glucose Induces Mouse beta-Cell Proliferation via IRS2, MTOR, and Cyclin D2 but Not the Insulin Receptor. AB - An important goal in diabetes research is to understand the processes that trigger endogenous beta-cell proliferation. Hyperglycemia induces beta-cell replication, but the mechanism remains debated. A prime candidate is insulin, which acts locally through the insulin receptor. Having previously developed an in vivo mouse hyperglycemia model, we tested whether glucose induces beta-cell proliferation through insulin signaling. By using mice lacking insulin signaling intermediate insulin receptor substrate 2 (IRS2), we confirmed that hyperglycemia induced beta-cell proliferation requires IRS2 both in vivo and ex vivo. Of note, insulin receptor activation was not required for glucose-induced proliferation, and insulin itself was not sufficient to drive replication. Glucose and insulin caused similar acute signaling in mouse islets, but chronic signaling differed markedly, with mammalian target of rapamycin (MTOR) and extracellular signal related kinase (ERK) activation by glucose and AKT activation by insulin. MTOR but not ERK activation was required for glucose-induced proliferation. Cyclin D2 was necessary for glucose-induced beta-cell proliferation. Cyclin D2 expression was reduced when either IRS2 or MTOR signaling was lost, and restoring cyclin D2 expression rescued the proliferation defect. Human islets shared many of these regulatory pathways. Taken together, these results support a model in which IRS2, MTOR, and cyclin D2, but not the insulin receptor, mediate glucose-induced proliferation. PMID- 26740602 TI - Proximity to Delivery Alters Insulin Sensitivity and Glucose Metabolism in Pregnant Mice. AB - In late pregnancy, maternal insulin resistance occurs to support fetal growth, but little is known about insulin-glucose dynamics close to delivery. This study measured insulin sensitivity in mice in late pregnancy at day 16 (D16) and near term at D19. Nonpregnant (NP) and pregnant mice were assessed for metabolite and hormone concentrations, body composition by DEXA, tissue insulin signaling protein abundance by Western blotting, glucose tolerance and utilization, and insulin sensitivity using acute insulin administration and hyperinsulinemic euglycemic clamps with [(3)H]glucose infusion. Whole-body insulin resistance occurred in D16 pregnant dams in association with basal hyperinsulinemia, insulin resistant endogenous glucose production, and downregulation of several proteins in hepatic and skeletal muscle insulin signaling pathways relative to NP and D19 values. Insulin resistance was less pronounced at D19, with restoration of NP insulin concentrations, improved hepatic insulin sensitivity, and increased abundance of hepatic insulin signaling proteins. At D16, insulin resistance at whole-body, tissue, and molecular levels will favor fetal glucose acquisition, while improved D19 hepatic insulin sensitivity will conserve glucose for maternal use in anticipation of lactation. Tissue sensitivity to insulin, therefore, alters differentially with proximity to delivery in pregnant mice, with implications for human and other species. PMID- 26740603 TI - Hypothyroidism Impairs Human Stem Cell-Derived Pancreatic Progenitor Cell Maturation in Mice. AB - Pancreatic progenitors derived from human embryonic stem cells (hESCs) are a potential source of transplantable cells for treating diabetes and are currently being tested in clinical trials. Yet, how the milieu of pancreatic progenitor cells, including exposure to different factors after transplant, may influence their maturation remains unclear. Here, we examined the effect of thyroid dysregulation on the development of hESC-derived progenitor cells in vivo. Hypothyroidism was generated in SCID-beige mice using an iodine-deficient diet containing 0.15% propyl-2-thiouracil, and hyperthyroidism was generated by addition of L-thyroxine (T4) to drinking water. All mice received macroencapsulated hESC-derived progenitor cells, and thyroid dysfunction was maintained for the duration of the study ("chronic") or for 4 weeks posttransplant ("acute"). Acute hyperthyroidism did not affect graft function, but acute hypothyroidism transiently impaired human C-peptide secretion at 16 weeks posttransplant. Chronic hypothyroidism resulted in severely blunted basal human C-peptide secretion, impaired glucose-stimulated insulin secretion, and elevated plasma glucagon levels. Grafts from chronic hypothyroid mice contained fewer beta-cells, heterogenous MAFA expression, and increased glucagon(+) and ghrelin(+) cells compared to grafts from euthyroid mice. Taken together, these data suggest that long-term thyroid hormone deficiency may drive the differentiation of human pancreatic progenitor cells toward alpha- and epsilon cell lineages at the expense of beta-cell formation. PMID- 26740605 TI - Unfashionable tales: narratives about what is (still) great in NHS general practice. AB - BACKGROUND: There is clear evidence that general practice has become a less popular career choice and among GPs there are high levels of dissatisfaction and demotivation. Little empirical evidence has emerged to indicate which factors contribute intrinsic value to the working lives of GPs and sustain their ongoing commitment. AIM: To understand which aspects of work continue to motivate and engage senior GPs by exploring their narrative accounts. DESIGN AND SETTING: This was part of a qualitative study in which senior GPs and hospital specialists contributed narratives in which they reflected on their working lives. METHOD: Individual, open interviews were conducted with eight GPs who had graduated in the early 1980s. Thematic analysis and situational analysis mapping were used to identify and connect related themes. RESULTS: During interviews in which doctors drew on a wide range of encounters and experiences, they revealed which aspects of work were associated with greater intrinsic rewards and contributed to their continuing motivation. Having chosen careers that suited their preferred settings and working practices, they recounted adjustments made in response to new challenges and confirmed experiencing greater enjoyment when performing roles affirming their sense of providing valued health care. CONCLUSION: This study's findings offer an alternative angle from which to consider the current unpopularity of general practice careers. The article proposes that long-term engagement of practitioners may be achieved through provision of adequate supportive resources to allow them to enact a sense of medical identity that matches with their acquired expectations of their role in the NHS. PMID- 26740604 TI - Unrecognised bipolar disorder among UK primary care patients prescribed antidepressants: an observational study. AB - BACKGROUND: Bipolar disorder is not uncommon, is associated with high disability and risk of suicide, often presents with depression, and can go unrecognised. AIM: To determine the prevalence of unrecognised bipolar disorder among those prescribed antidepressants for depressive or anxiety disorder in UK primary care; whether those with unrecognised bipolar disorder have more severe depression than those who do not; and the accuracy of a screening questionnaire for bipolar disorder, the Mood Disorder Questionnaire (MDQ), in this setting. DESIGN AND SETTING: Observational primary care study of patients on the lists of 21 general practices in West Yorkshire aged 16-40 years and prescribed antidepressant medication. METHOD: Participants were recruited using primary care databases, interviewed using a diagnostic interview, and completed the screening questionnaire and rating scales of symptoms and quality of life. RESULTS: The prevalence of unrecognised bipolar disorder was 7.3%. Adjusting for differences between the sample and a national database gives a prevalence of 10.0%. Those with unrecognised bipolar disorder were younger and had greater lifetime depression. The predictive value of the MDQ was poor. CONCLUSION: Among people aged 16-40 years prescribed antidepressants in primary care for depression or anxiety, there is a substantial proportion with unrecognised bipolar disorder. When seeing patients with depression or anxiety disorder, particularly when they are young or not doing well, clinicians should review the life history for evidence of unrecognised bipolar disorder. Some clinicians might find the MDQ to be a useful supplement to non-standardised questioning. PMID- 26740606 TI - Lost to the NHS: a mixed methods study of why GPs leave practice early in England. AB - BACKGROUND: The loss of GPs in the early stages of their careers is contributing to the GP workforce crisis. Recruitment in the UK remains below the numbers needed to support the demand for GP care. AIM: To explore the reasons why GPs leave general practice early. DESIGN AND SETTING: A mixed methods study using online survey data triangulated with qualitative interviews. METHOD: Participants were GPs aged <50 years who had left the English Medical Performers List in the last 5 years (2009-2014). A total of 143 early GP leavers participated in an online survey, of which 21 took part in recorded telephone interviews. Survey data were analysed using descriptive statistics, and qualitative data using thematic analysis techniques. RESULTS: Reasons for leaving were cumulative and multifactorial. Organisational changes to the NHS have led to an increase in administrative tasks and overall workload that is perceived by GP participants to have fundamentally changed the doctor-patient relationship. Lack of time with patients has compromised the ability to practise more patient-centred care, and, with it, GPs' sense of professional autonomy and values, resulting in diminished job satisfaction. In this context, the additional pressures of increased patient demand and the negative media portrayal left many feeling unsupported and vulnerable to burnout and ill health, and, ultimately, to the decision to leave general practice. CONCLUSION: To improve retention of young GPs, the pace of administrative change needs to be minimised and the time spent by GPs on work that is not face-to-face patient care reduced. PMID- 26740607 TI - International variation in adherence to referral guidelines for suspected cancer: a secondary analysis of survey data. AB - BACKGROUND: Variation in cancer survival persists between comparable nations and appears to be due, in part, to primary care practitioners (PCPs) having different thresholds for acting definitively in response to cancer-related symptoms. AIM: To explore whether cancer guidelines, and adherence to them, differ between jurisdictions and impacts on PCPs' propensity to take definitive action on cancer related symptoms. DESIGN AND SETTING: A secondary analysis of survey data from six countries (10 jurisdictions) participating in the International Cancer Benchmarking Partnership. METHOD: PCPs' responses to five clinical vignettes presenting symptoms and signs of lung (n = 2), colorectal (n = 2), and ovarian cancer (n = 1) were compared with investigation and referral recommendations in cancer guidelines. RESULTS: Nine jurisdictions had guidelines covering the two colorectal vignettes. For the lung vignettes, although eight jurisdictions had guidelines for the first, the second was covered by a Swedish guideline alone. Only the UK and Denmark had an ovarian cancer guideline. Survey responses of 2795 PCPs (crude response rate: 12%) were analysed. Guideline adherence ranged from 20 82%. UK adherence was lower than other jurisdictions for the lung vignette covered by the guidance (47% versus 58%; P <0.01) but similar (45% versus 46%) or higher (67% versus 38%; P <0.01) for the two colorectal vignettes. PCPs took definitive action least often when a guideline recommended a non-definitive action or made no recommendation. UK PCPs adhered to recommendations for definitive action less than their counterparts (P <0.01). There wasno association between jurisdictional guideline adherence and 1-year survival. CONCLUSION: Cancer guideline content is variable between similarly developed nations and poor guideline adherence does not explain differential survival. Guidelines that fail to cover high-risk presentations or that recommend non-definitive action may reduce definitive diagnostic action. PMID- 26740608 TI - Saccadic vector optokinetic perimetry in children with neurodisability or isolated visual pathway lesions: observational cohort study. AB - BACKGROUND/AIMS: Children and adults with neurological impairments are often not able to access conventional perimetry; however, information about the visual field is valuable. A new technology, saccadic vector optokinetic perimetry (SVOP), may have improved accessibility, but its accuracy has not been evaluated. We aimed to explore accessibility, testability and accuracy of SVOP in children with neurodisability or isolated visual pathway deficits. METHODS: Cohort study; recruitment October 2013-May 2014, at children's eye clinics at a tertiary referral centre and a regional Child Development Centre; full orthoptic assessment, SVOP (central 30 degrees of the visual field) and confrontation visual fields (CVF). Group 1: age 1-16 years, neurodisability (n=16), group 2: age 10-16 years, confirmed or suspected visual field defect (n=21); group 2 also completed Goldmann visual field testing (GVFT). RESULTS: Group 1: testability with a full 40-point test protocol is 12.5%; with reduced test protocols, testability is 100%, but plots may be clinically meaningless. Children (44%) and parents/carers (62.5%) find the test easy. SVOP and CVF agree in 50%. Group 2: testability is 62% for the 40-point protocol, and 90.5% for reduced protocols. Corneal changes in childhood glaucoma interfere with SVOP testing. All children and parents/carers find SVOP easy. Overall agreement with GVFT is 64.7%. CONCLUSIONS: While SVOP is highly accessible to children, many cannot complete a full 40-point test. Agreement with current standard tests is moderate to poor. Abnormal saccades cause an apparent non-specific visual field defect. In children with glaucoma or nystagmus SVOP calibration often fails. PMID- 26740609 TI - Global cell-by-cell evaluation of endothelial viability after two methods of graft preparation in Descemet membrane endothelial keratoplasty. AB - PURPOSE: To describe a novel method of global cell viability assessment for Descemet membrane endothelial keratoplasty (DMEK) and the comparison of two contemporary methods of donor tissue preparation. METHODS: DMEK transplants were prepared using two different methods: liquid bubble separation and manual peeling (n=8 each group). Samples were incubated with Hoechst, calcein-AM and ethidium homodimer prior to mounting on a curved imaging chamber. Z-stacked fluorescence microscopy images were combined to produce an in-focus global image capable of resolving all cell nuclei. Image processing software was used to define a calcein positive live cell area, count all cell nuclei within this area and subtract ethidium-positive dead cells to derive the total viable endothelial cell count. Corrected global cell density was calculated by dividing the number of viable cells by the graft area, which had been corrected for imaging a curved surface. RESULTS: Corrected global cell density was lower than the central endothelial cell density in both groups: 85.5% of the pre-preparation central endothelial cell density in the peel group and 75.8% in the bubble group. Corrected global cell density was significantly lower in the liquid bubble separation group than in the peel group (p=0.04). CONCLUSIONS: Eye bank estimations of central endothelial cell density overestimate true cell density after graft preparation in DMEK. A peel method is less damaging and more consistent than a liquid bubble method. Cell loss correlated strongly with the degree of stromal hydration prior to bubble separation in the liquid bubble group. PMID- 26740610 TI - Overseas seed dispersal by migratory birds. AB - Long-distance dispersal (LDD) promotes the colonization of isolated and remote habitats, and thus it has been proposed as a mechanism for explaining the distributions of many species. Birds are key LDD vectors for many sessile organisms such as plants, yet LDD beyond local and regional scales has never been directly observed nor quantified. By sampling birds caught while in migratory flight by GPS-tracked wild falcons, we show that migratory birds transport seeds over hundreds of kilometres and mediate dispersal from mainland to oceanic islands. Up to 1.2% of birds that reached a small island of the Canary Archipelago (Alegranza) during their migration from Europe to Sub-Saharan Africa carried seeds in their guts. The billions of birds making seasonal migrations each year may then transport millions of seeds. None of the plant species transported by the birds occurs in Alegranza and most do not occur on nearby Canary Islands, providing a direct example of the importance of environmental filters in hampering successful colonization by immigrant species. The constant propagule pressure generated by these LDD events might, nevertheless, explain the colonization of some islands. Hence, migratory birds can mediate rapid range expansion or shifts of many plant taxa and determine their distribution. PMID- 26740611 TI - Robustness of norm-driven cooperation in the commons. AB - Sustainable use of common-pool resources such as fish, water or forests depends on the cooperation of resource users that restrain their individual extraction to socially optimal levels. Empirical evidence has shown that under certain social and biophysical conditions, self-organized cooperation in the commons can evolve. Global change, however, may drastically alter these conditions. We assess the robustness of cooperation to environmental variability in a stylized model of a community that harvests a shared resource. Community members follow a norm of socially optimal resource extraction, which is enforced through social sanctioning. Our results indicate that both resource abundance and a small increase in resource variability can lead to collapse of cooperation observed in the no-variability case, while either scarcity or large variability have the potential to stabilize it. The combined effects of changes in amount and variability can reinforce or counteract each other depending on their size and the initial level of cooperation in the community. If two socially separate groups are ecologically connected through resource leakage, cooperation in one can destabilize the other. These findings provide insights into possible effects of global change and spatial connectivity, indicating that there is no simple answer as to their effects on cooperation and sustainable resource use. PMID- 26740612 TI - Fatness and fitness: exposing the logic of evolutionary explanations for obesity. AB - To explore the logic of evolutionary explanations of obesity we modelled food consumption in an animal that minimizes mortality (starvation plus predation) by switching between activities that differ in energy gain and predation. We show that if switching does not incur extra predation risk, the animal should have a single threshold level of reserves above which it performs the safe activity and below which it performs the dangerous activity. The value of the threshold is determined by the environmental conditions, implying that animals should have variable 'set points'. Selection pressure to prevent energy stores exceeding the optimal level is usually weak, suggesting that immediate rewards might easily overcome the controls against becoming overweight. The risk of starvation can have a strong influence on the strategy even when starvation is extremely uncommon, so the incidence of mortality during famine in human history may be unimportant for explanations for obesity. If there is an extra risk of switching between activities, the animal should have two distinct thresholds: one to initiate weight gain and one to initiate weight loss. Contrary to the dual intervention point model, these thresholds will be inter-dependent, such that altering the predation risk alters the location of both thresholds; a result that undermines the evolutionary basis of the drifty genes hypothesis. Our work implies that understanding the causes of obesity can benefit from a better understanding of how evolution shapes the mechanisms that control body weight. PMID- 26740613 TI - Host discrimination in modular mutualisms: a theoretical framework for meta populations of mutualists and exploiters. AB - Plants in multiple symbioses are exploited by symbionts that consume their resources without providing services. Discriminating hosts are thought to stabilize mutualism by preferentially allocating resources into anatomical structures (modules) where services are generated, with examples of modules including the entire inflorescences of figs and the root nodules of legumes. Modules are often colonized by multiple symbiotic partners, such that exploiters that co-occur with mutualists within mixed modules can share rewards generated by their mutualist competitors. We developed a meta-population model to answer how the population dynamics of mutualists and exploiters change when they interact with hosts with different module occupancies (number of colonists per module) and functionally different patterns of allocation into mixed modules. We find that as module occupancy increases, hosts must increase the magnitude of preferentially allocated resources in order to sustain comparable populations of mutualists. Further, we find that mixed colonization can result in the coexistence of mutualist and exploiter partners, but only when preferential allocation follows a saturating function of the number of mutualists in a module. Finally, using published data from the fig-wasp mutualism as an illustrative example, we derive model predictions that approximate the proportion of exploiter, non-pollinating wasps observed in the field. PMID- 26740614 TI - Lifespan behavioural and neural resilience in a social insect. AB - Analyses of senescence in social species are important to understanding how group living influences the evolution of ageing in society members. Social insects exhibit remarkable lifespan polyphenisms and division of labour, presenting excellent opportunities to test hypotheses concerning ageing and behaviour. Senescence patterns in other taxa suggest that behavioural performance in ageing workers would decrease in association with declining brain functions. Using the ant Pheidole dentata as a model, we found that 120-day-old minor workers, having completed 86% of their laboratory lifespan, showed no decrease in sensorimotor functions underscoring complex tasks such as alloparenting and foraging. Collaterally, we found no age-associated increases in apoptosis in functionally specialized brain compartments or decreases in synaptic densities in the mushroom bodies, regions associated with integrative processing. Furthermore, brain titres of serotonin and dopamine--neuromodulators that could negatively impact behaviour through age-related declines--increased in old workers. Unimpaired task performance appears to be based on the maintenance of brain functions supporting olfaction and motor coordination independent of age. Our study is the first to comprehensively assess lifespan task performance and its neurobiological correlates and identify constancy in behavioural performance and the absence of significant age-related neural declines. PMID- 26740615 TI - Re-evaluating the health of coral reef communities: baselines and evidence for human impacts across the central Pacific. AB - Numerous studies have documented declines in the abundance of reef-building corals over the last several decades and in some but not all cases, phase shifts to dominance by macroalgae have occurred. These assessments, however, often ignore the remainder of the benthos and thus provide limited information on the present-day structure and function of coral reef communities. Here, using an unprecedentedly large dataset collected within the last 10 years across 56 islands spanning five archipelagos in the central Pacific, we examine how benthic reef communities differ in the presence and absence of human populations. Using islands as replicates, we examine whether benthic community structure is associated with human habitation within and among archipelagos and across latitude. While there was no evidence for coral to macroalgal phase shifts across our dataset we did find that the majority of reefs on inhabited islands were dominated by fleshy non-reef-building organisms (turf algae, fleshy macroalgae and non-calcifying invertebrates). By contrast, benthic communities from uninhabited islands were more variable but in general supported more calcifiers and active reef builders (stony corals and crustose coralline algae). Our results suggest that cumulative human impacts across the central Pacific may be causing a reduction in the abundance of reef builders resulting in island scale phase shifts to dominance by fleshy organisms. PMID- 26740616 TI - Functional traits reveal the expansion and packing of ecological niche space underlying an elevational diversity gradient in passerine birds. AB - Variation in species richness across environmental gradients may be associated with an expanded volume or increased packing of ecological niche space. However, the relative importance of these alternative scenarios remains unknown, largely because standardized information on functional traits and their ecological relevance is lacking for major diversity gradients. Here, we combine data on morphological and ecological traits for 523 species of passerine birds distributed across an Andes-to-Amazon elevation gradient. We show that morphological traits capture substantial variation in species dietary (75%) and foraging niches (60%) when multiple independent trait dimensions are considered. Having established these relationships, we show that the 14-fold increase in species richness towards the lowlands is associated with both an increased volume and density of functional trait space. However, we find that increases in volume contribute little to changes in richness, with most (78%) lowland species occurring within the range of trait space occupied at high elevations. Taken together, our results suggest that high species richness is mainly associated with a denser occupation of functional trait space, implying an increased specialization or overlap of ecological niches, and supporting the view that niche packing is the dominant trend underlying gradients of increasing biodiversity towards the lowland tropics. PMID- 26740617 TI - Time in tortoiseshell: a bomb radiocarbon-validated chronology in sea turtle scutes. AB - Some of the most basic questions of sea turtle life history are also the most elusive. Many uncertainties surround lifespan, growth rates, maturity and spatial structure, yet these are critical factors in assessing population status. Here we examine the keratinized hard tissues of the hawksbill (Eretmochelys imbricata) carapace and use bomb radiocarbon dating to estimate growth and maturity. Scutes have an established dietary record, yet the large keratin deposits of hawksbills evoke a reliable chronology. We sectioned, polished and imaged posterior marginal scutes from 36 individual hawksbills representing all life stages, several Pacific populations and spanning eight decades. We counted the apparent growth lines, microsampled along growth contours and calibrated Delta(14)C values to reference coral series. We fit von Bertalanffy growth function (VBGF) models to the results, producing a range of age estimates for each turtle. We find Hawaii hawksbills deposit eight growth lines annually (range 5-14), with model ensembles producing a somatic growth parameter (k) of 0.13 (range 0.1-0.2) and first breeding at 29 years (range 23-36). Recent bomb radiocarbon values also suggest declining trophic status. Together, our results may reflect long-term changes in the benthic community structure of Hawaii reefs, and possibly shed light on the critical population status for Hawaii hawksbills. PMID- 26740618 TI - Monitoring chicken flock behaviour provides early warning of infection by human pathogen Campylobacter. AB - Campylobacter is the commonest bacterial cause of gastrointestinal infection in humans, and chicken meat is the major source of infection throughout the world. Strict and expensive on-farm biosecurity measures have been largely unsuccessful in controlling infection and are hampered by the time needed to analyse faecal samples, with the result that Campylobacter status is often known only after a flock has been processed. Our data demonstrate an alternative approach that monitors the behaviour of live chickens with cameras and analyses the 'optical flow' patterns made by flock movements. Campylobacter-free chicken flocks have higher mean and lower kurtosis of optical flow than those testing positive for Campylobacter by microbiological methods. We show that by monitoring behaviour in this way, flocks likely to become positive can be identified within the first 7 10 days of life, much earlier than conventional on-farm microbiological methods. This early warning has the potential to lead to a more targeted approach to Campylobacter control and also provides new insights into possible sources of infection that could transform the control of this globally important food-borne pathogen. PMID- 26740619 TI - The social and ecological costs of an 'over-extended' phenotype. AB - Extended phenotypes offer a unique opportunity to experimentally manipulate and identify sources of selection acting on traits under natural conditions. The social cichlid fish Neolamprologus multifasciatus builds nests by digging up aquatic snail shells, creating an extended sexual phenotype that is highly amenable to experimental manipulation through addition of extra shells. Here, we find sources of both positive sexual selection and opposing natural selection acting on this trait; augmenting shell nests increases access to mates, but also increases social aggression and predation risk. Increasing the attractiveness of one male also changed social interactions throughout the social network and altered the entire community structure. Manipulated males produced and received more displays from neighbouring females, who also joined augmented male territories at higher rates than unmanipulated groups. However, males in more attractive territories received more aggression from neighbouring males, potentially as a form of social policing. We also detected a significant ecological cost of the 'over-extended' phenotype; heterospecific predators usurped augmented nests at higher rates, using them as breeding sites and displacing residents. Using these natural experiments, we find that both social and ecological interactions generate clear sources of selection mediating the expression of an extended phenotype in the wild. PMID- 26740620 TI - High-throughput Functional Genomics Identifies Regulators of Primary Human Beta Cell Proliferation. AB - The expansion of cells for regenerative therapy will require the genetic dissection of complex regulatory mechanisms governing the proliferation of non transformed human cells. Here, we report the development of a high-throughput RNAi screening strategy specifically for use in primary cells and demonstrate that silencing the cell cycle-dependent kinase inhibitors CDKN2C/p18 or CDKN1A/p21 facilitates cell cycle entry of quiescent adult human pancreatic beta cells. This work identifies p18 and p21 as novel targets for promoting proliferation of human beta cells and demonstrates the promise of functional genetic screens for dissecting therapeutically relevant state changes in primary human cells. PMID- 26740621 TI - Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling. AB - Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cellular metabolism, growth, and proliferation. mTORC1 has been implicated in many diseases such as cancer, diabetes, and neurodegeneration, and is a target to prolong lifespan. Here we report a small molecule inhibitor (Cbz-B3A) of mTORC1 signaling. Cbz-B3A inhibits the phosphorylation of eIF4E-binding protein 1 (4EBP1) and blocks 68% of translation. In contrast, rapamycin preferentially inhibits the phosphorylation of p70(S6k) and blocks 35% of translation. Cbz-B3A does not appear to bind directly to mTORC1, but instead binds to ubiquilins 1, 2, and 4. Knockdown of ubiquilin 2, but not ubiquilins 1 and 4, decreases the phosphorylation of 4EBP1, suggesting that ubiquilin 2 activates mTORC1. The knockdown of ubiquilins 2 and 4 decreases the effect of Cbz-B3A on 4EBP1 phosphorylation. Cbz-B3A slows cellular growth of some human leukemia cell lines, but is not cytotoxic. Thus Cbz-B3A exemplifies a novel strategy to inhibit mTORC1 signaling that might be exploited for treating many human diseases. We propose that Cbz-B3A reveals a previously unappreciated regulatory pathway coordinating cytosolic protein quality control and mTORC1 signaling. PMID- 26740623 TI - Identification of the Zinc Finger Protein ZRANB2 as a Novel Maternal Lipopolysaccharide-binding Protein That Protects Embryos of Zebrafish against Gram-negative Bacterial Infections. AB - Zinc finger ZRANB2 proteins are widespread in animals, but their functions and mechanisms remain poorly defined. Here we clearly demonstrate that ZRANB2 is a newly identified LPS-binding protein present abundantly in the eggs/embryos of zebrafish. We also show that recombinant ZRANB2 (rZRANB2) acts as a pattern recognition receptor capable of identifying the bacterial signature molecule LPS as well as binding the Gram-negative bacteria Escherichia coli, Vibrio anguilarum, and Aeromonas hydrophila and functions as an antibacterial effector molecule capable of directly killing the bacteria. Furthermore, we reveal that N terminal residues 11-37 consisting of the first ZnF_RBZ domain are indispensable for ZRANB2 antimicrobial activity. Importantly, microinjection of rZRANB2 into early embryos significantly enhanced the resistance of the embryos against pathogenic A. hydrophila challenge, and this enhanced bacterial resistance was markedly reduced by co-injection of anti-ZRANB2 antibody. Moreover, precipitation of ZRANB2 in the embryo extracts by preincubation with anti-ZRANB2 antibody caused a marked decrease in the antibacterial activity of the extracts against the bacteria tested. In addition, the N-terminal peptide Z1/37 or Z11/37 with in vitro antibacterial activity also promoted the resistance of embryos against A. hydrophila, but the peptide Z38/198 without in vitro antibacterial activity did not. Collectively, these results indicate that ZRANB2 is a maternal LPS-binding protein that can protect the early embryos of zebrafish against pathogenic attacks, a novel role ever assigned to ZRANB2 proteins. This work also provides new insights into the immunological function of the zinc finger proteins that are widely distributed in various animals. PMID- 26740622 TI - Rapid Remodeling of Invadosomes by Gi-coupled Receptors: DISSECTING THE ROLE OF Rho GTPases. AB - Invadosomes are actin-rich membrane protrusions that degrade the extracellular matrix to drive tumor cell invasion. Key players in invadosome formation are c Src and Rho family GTPases. Invadosomes can reassemble into circular rosette-like superstructures, but the underlying signaling mechanisms remain obscure. Here we show that Src-induced invadosomes in human melanoma cells (A375M and MDA-MB-435) undergo rapid remodeling into dynamic extracellular matrix-degrading rosettes by distinct G protein-coupled receptor agonists, notably lysophosphatidic acid (LPA; acting through the LPA1 receptor) and endothelin. Agonist-induced rosette formation is blocked by pertussis toxin, dependent on PI3K activity and accompanied by localized production of phosphatidylinositol 3,4,5-trisphosphate, whereas MAPK and Ca(2+) signaling are dispensable. Using FRET-based biosensors, we show that LPA and endothelin transiently activate Cdc42 through Gi, concurrent with a biphasic decrease in Rac activity and differential effects on RhoA. Cdc42 activity is essential for rosette formation, whereas G12/13-mediated RhoA-ROCK signaling suppresses the remodeling process. Our results reveal a Gi-mediated Cdc42 signaling axis by which G protein-coupled receptors trigger invadosome remodeling, the degree of which is dictated by the Cdc42-RhoA activity balance. PMID- 26740624 TI - Identification of a Natural Green Light Absorbing Chloride Conducting Channelrhodopsin from Proteomonas sulcata. AB - Chloride conducting channelrhodopsins (ChloCs) are new members of the optogenetic toolbox that enable neuronal inhibition in target cells. Originally, ChloCs have been engineered from cation conducting channelrhodopsins (ChRs), and later identified in a cryptophyte alga genome. We noticed that the sequence of a previously described Proteomonas sulcata ChR (PsChR1) was highly homologous to the naturally occurring and previously reported ChloCs GtACR1/2, but was not recognized as an anion conducting channel. Based on electrophysiological measurements obtained under various ionic conditions, we concluded that the PsChR1 photocurrent at physiological conditions is strongly inward rectifying and predominantly carried by chloride. The maximum activation was noted at excitation with light of 540 nm. An initial spectroscopic characterization of purified protein revealed that the photocycle and the transport mechanism of PsChR1 differ significantly from cation conducting ChRs. Hence, we concluded that PsChR1 is an anion conducting ChR, now renamed PsACR1, with a red-shifted absorption suited for multicolor optogenetic experiments in combination with blue light absorbing cation conducting ChRs. PMID- 26740626 TI - Use of Cysteine Trapping to Map Spatial Approximations between Residues Contributing to the Helix N-capping Motif of Secretin and Distinct Residues within Each of the Extracellular Loops of Its Receptor. AB - Amino-terminal regions of secretin-family peptides contain key determinants for biological activity and binding specificity, although the nature of interactions with receptors is unclear. A helix N-capping motif within this region has been postulated to directly contribute to agonist activity while also stabilizing formation of a helix extending toward the peptide carboxyl terminus and docking within the receptor amino terminus. We used cysteine trapping to systematically explore spatial approximations between cysteines replacing each residue in this motif of secretin (sec), Phe(6), Thr(7), and Leu(10), and cysteines incorporated into the extracellular face of the receptor. Each peptide was a full agonist for cAMP, but had a lower binding affinity than natural hormone. These bound to COS cells expressing 61 receptor constructs incorporating cysteines in every position along each extracellular loop (ECL) and adjacent parts of transmembrane (TM) segments. Patterns of covalent labeling were distinct for each probe, with Cys(6) sec labeling multiple residues in the carboxyl-terminal half of ECL2 and throughout ECL3, Cys(7)-sec predominantly labeling only single residues in the carboxyl-terminal end of ECL2 and the amino-terminal end of ECL3, and Cys(10)-sec not efficiently labeling any of these residues. These spatial constraints were used to refine our model of secretin bound to its receptor, now bringing ECL3 above the amino terminus of the ligand and revealing possible charge-charge interactions between this part of secretin and receptor residues in TM5, TM6, ECL2, and ECL3, which can orient and stabilize the peptide-receptor complex. This was validated by testing predicted approximations by mutagenesis and residue residue complementation studies. PMID- 26740625 TI - The Dendritic Cell Major Histocompatibility Complex II (MHC II) Peptidome Derives from a Variety of Processing Pathways and Includes Peptides with a Broad Spectrum of HLA-DM Sensitivity. AB - The repertoire of peptides displayed in vivo by MHC II molecules derives from a wide spectrum of proteins produced by different cell types. Although intracellular endosomal processing in dendritic cells and B cells has been characterized for a few antigens, the overall range of processing pathways responsible for generating the MHC II peptidome are currently unclear. To determine the contribution of non-endosomal processing pathways, we eluted and sequenced over 3000 HLA-DR1-bound peptides presented in vivo by dendritic cells. The processing enzymes were identified by reference to a database of experimentally determined cleavage sites and experimentally validated for four epitopes derived from complement 3, collagen II, thymosin beta4, and gelsolin. We determined that self-antigens processed by tissue-specific proteases, including complement, matrix metalloproteases, caspases, and granzymes, and carried by lymph, contribute significantly to the MHC II self-peptidome presented by conventional dendritic cells in vivo. Additionally, the presented peptides exhibited a wide spectrum of binding affinity and HLA-DM susceptibility. The results indicate that the HLA-DR1-restricted self-peptidome presented under physiological conditions derives from a variety of processing pathways. Non endosomal processing enzymes add to the number of epitopes cleaved by cathepsins, altogether generating a wider peptide repertoire. Taken together with HLA-DM dependent and-independent loading pathways, this ensures that a broad self peptidome is presented by dendritic cells. This work brings attention to the role of "self-recognition" as a dynamic interaction between dendritic cells and the metabolic/catabolic activities ongoing in every parenchymal organ as part of tissue growth, remodeling, and physiological apoptosis. PMID- 26740627 TI - VAMP-associated Proteins (VAP) as Receptors That Couple Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Proteostasis with Lipid Homeostasis. AB - Unesterified cholesterol accumulates in late endosomes in cells expressing the misfolded cystic fibrosis transmembrane conductance regulator (CFTR). CFTR misfolding in the endoplasmic reticulum (ER) or general activation of ER stress led to dynein-mediated clustering of cholesterol-loaded late endosomes at the Golgi region, a process regulated by ER-localized VAMP-associated proteins (VAPs). We hypothesized that VAPs serve as intracellular receptors that couple lipid homeostasis through interactions with two phenylalanines in an acidic track (FFAT) binding signals (found in lipid sorting and sensing proteins, LSS) with proteostasis regulation. VAPB inhibited the degradation of DeltaF508-CFTR. The activity was mapped to the ligand-binding major sperm protein (MSP) domain, which was sufficient in regulating CFTR biogenesis. We identified mutations in an unstructured loop within the MSP that uncoupled VAPB-regulated CFTR biogenesis from basic interactions with FFAT. Using this information, we defined functional and physical interactions between VAPB and proteostasis regulators (ligands), including the unfolded protein response sensor ATF6 and the ER degradation cluster that included FAF1, VCP, BAP31, and Derlin-1. VAPB inhibited the degradation of DeltaF508-CFTR in the ER through interactions with the RMA1-Derlin BAP31-VCP pathway. Analysis of pseudoligands containing tandem FFAT signals supports a competitive model for VAP interactions that direct CFTR biogenesis. The results suggest a model in which VAP-ligand binding couples proteostasis and lipid homeostasis leading to observed phenotypes of lipid abnormalities in protein folding diseases. PMID- 26740629 TI - Mechanism of Ribonucleotide Incorporation by Human DNA Polymerase eta. AB - Ribonucleotides and 2'-deoxyribonucleotides are the basic units for RNA and DNA, respectively, and the only difference is the extra 2'-OH group on the ribonucleotide sugar. Cellular rNTP concentrations are much higher than those of dNTP. When copying DNA, DNA polymerases not only select the base of the incoming dNTP to form a Watson-Crick pair with the template base but also distinguish the sugar moiety. Some DNA polymerases use a steric gate residue to prevent rNTP incorporation by creating a clash with the 2'-OH group. Y-family human DNA polymerase eta (hpol eta) is of interest because of its spacious active site (especially in the major groove) and tolerance of DNA lesions. Here, we show that hpol eta maintains base selectivity when incorporating rNTPs opposite undamaged DNA and the DNA lesions 7,8-dihydro-8-oxo-2'-deoxyguanosine and cyclobutane pyrimidine dimer but with rates that are 10(3)-fold lower than for inserting the corresponding dNTPs. X-ray crystal structures show that the hpol eta scaffolds the incoming rNTP to pair with the template base (dG) or 7,8-dihydro-8-oxo-2' deoxyguanosine with a significant propeller twist. As a result, the 2'-OH group avoids a clash with the steric gate, Phe-18, but the distance between primer end and Palpha of the incoming rNTP increases by 1 A, elevating the energy barrier and slowing polymerization compared with dNTP. In addition, Tyr-92 was identified as a second line of defense to maintain the position of Phe-18. This is the first crystal structure of a DNA polymerase with an incoming rNTP opposite a DNA lesion. PMID- 26740630 TI - Pin1-mediated Modification Prolongs the Nuclear Retention of beta-Catenin in Wnt3a-induced Osteoblast Differentiation. AB - The canonical Wnt signaling pathway, in which beta-catenin nuclear localization is a crucial step, plays an important role in osteoblast differentiation. Pin1, a prolyl isomerase, is also known as a key enzyme in osteogenesis. However, the role of Pin1 in canonical Wnt signal-induced osteoblast differentiation is poorly understood. We found that Pin1 deficiency caused osteopenia and reduction of beta catenin in bone lining cells. Similarly, Pin1 knockdown or treatment with Pin1 inhibitors strongly decreased the nuclear beta-catenin level, TOP flash activity, and expression of bone marker genes induced by canonical Wnt activation and vice versa in Pin1 overexpression. Pin1 interacts directly with and isomerizes beta catenin in the nucleus. The isomerized beta-catenin could not bind to nuclear adenomatous polyposis coli, which drives beta-catenin out of the nucleus for proteasomal degradation, which consequently increases the retention of beta catenin in the nucleus and might explain the decrease of beta-catenin ubiquitination. These results indicate that Pin1 could be a critical target to modulate beta-catenin-mediated osteogenesis. PMID- 26740628 TI - The Budding Yeast Ubiquitin Protease Ubp7 Is a Novel Component Involved in S Phase Progression. AB - DNA damage must be repaired in an accurate and timely fashion to preserve genome stability. Cellular mechanisms preventing genome instability are crucial to human health because genome instability is considered a hallmark of cancer. Collectively referred to as the DNA damage response, conserved pathways ensure proper DNA damage recognition and repair. The function of numerous DNA damage response components is fine-tuned by posttranslational modifications, including ubiquitination. This not only involves the enzyme cascade responsible for conjugating ubiquitin to substrates but also requires enzymes that mediate directed removal of ubiquitin. Deubiquitinases remove ubiquitin from substrates to prevent degradation or to mediate signaling functions. The Saccharomyces cerevisiae deubiquitinase Ubp7 has been characterized previously as an endocytic factor. However, here we identify Ubp7 as a novel factor affecting S phase progression after hydroxyurea treatment and demonstrate an evolutionary and genetic interaction of Ubp7 with DNA damage repair pathways of homologous recombination and nucleotide excision repair. We find that deletion of UBP7 sensitizes cells to hydroxyurea and cisplatin and demonstrate that factors that stabilize replication forks are critical under these conditions. Furthermore, ubp7Delta cells exhibit an S phase progression defect upon checkpoint activation by hydroxyurea treatment. ubp7Delta mutants are epistatic to factors involved in histone maintenance and modification, and we find that a subset of Ubp7 is chromatin-associated. In summary, our results suggest that Ubp7 contributes to S phase progression by affecting the chromatin state at replication forks, and we propose histone H2B ubiquitination as a potential substrate of Ubp7. PMID- 26740631 TI - Macro Domain from Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Is an Efficient ADP-ribose Binding Module: CRYSTAL STRUCTURE AND BIOCHEMICAL STUDIES. AB - The newly emerging Middle East respiratory syndrome coronavirus (MERS-CoV) encodes the conserved macro domain within non-structural protein 3. However, the precise biochemical function and structure of the macro domain is unclear. Using differential scanning fluorimetry and isothermal titration calorimetry, we characterized the MERS-CoV macro domain as a more efficient adenosine diphosphate (ADP)-ribose binding module than macro domains from other CoVs. Furthermore, the crystal structure of the MERS-CoV macro domain was determined at 1.43-A resolution in complex with ADP-ribose. Comparison of macro domains from MERS-CoV and other human CoVs revealed structural differences in the alpha1 helix alters how the conserved Asp-20 interacts with ADP-ribose and may explain the efficient binding of the MERS-CoV macro domain to ADP-ribose. This study provides structural and biophysical bases to further evaluate the role of the MERS-CoV macro domain in the host response via ADP-ribose binding but also as a potential target for drug design. PMID- 26740632 TI - RNA Helicase Associated with AU-rich Element (RHAU/DHX36) Interacts with the 3' Tail of the Long Non-coding RNA BC200 (BCYRN1). AB - RNA helicase associated with AU-rich element (RHAU) is an ATP-dependent RNA helicase that demonstrates high affinity for quadruplex structures in DNA and RNA. To elucidate the significance of these quadruplex-RHAU interactions, we have performed RNA co-immunoprecipitation screens to identify novel RNAs bound to RHAU and characterize their function. In the course of this study, we have identified the non-coding RNA BC200 (BCYRN1) as specifically enriched upon RHAU immunoprecipitation. Although BC200 does not adopt a quadruplex structure and does not bind the quadruplex-interacting motif of RHAU, it has direct affinity for RHAU in vitro. Specifically designed BC200 truncations and RNase footprinting assays demonstrate that RHAU binds to an adenosine-rich region near the 3'-end of the RNA. RHAU truncations support binding that is dependent upon a region within the C terminus and is specific to RHAU isoform 1. Tests performed to assess whether BC200 interferes with RHAU helicase activity have demonstrated the ability of BC200 to act as an acceptor of unwound quadruplexes via a cytosine rich region near the 3'-end of the RNA. Furthermore, an interaction between BC200 and the quadruplex-containing telomerase RNA was confirmed by pull-down assays of the endogenous RNAs. This leads to the possibility that RHAU may direct BC200 to bind and exert regulatory functions at quadruplex-containing RNA or DNA sequences. PMID- 26740633 TI - Effect of Long-Acting Insulin Analogs on the Risk of Cancer: A Systematic Review of Observational Studies. AB - OBJECTIVE: Observational studies examining the association between long-acting insulin analogs and cancer incidence have produced inconsistent results. We conducted a systematic review of these studies, focusing on their methodological strengths and weaknesses. RESEARCH DESIGN AND METHODS: We systematically searched MEDLINE and EMBASE from 2000 to 2014 to identify all observational studies evaluating the relationship between the long-acting insulin analogs and the risk of any and site-specific cancers (breast, colorectal, prostate). We included cohort and case-control studies published in English on insulin glargine and detemir and any cancer incidence among patients with type 1 or 2 diabetes. The methodological assessment involved the inclusion of prevalent users, inclusion of lag periods, time-related biases, and duration of follow-up between insulin initiation and cancer incidence. RESULTS: A total of 16 cohort and 3 case-control studies met our inclusion criteria. All studies evaluated insulin glargine, and four studies also examined insulin detemir. Follow-up ranged from 0.9 to 7.0 years. Thirteen of 15 studies reported no association between insulin glargine and detemir and any cancer. Four of 13 studies reported an increased risk of breast cancer with insulin glargine. In the quality assessment, 7 studies included prevalent users, 11 did not consider a lag period, 6 had time-related biases, and 16 had short (<5 years) follow-up. CONCLUSIONS: The observational studies examining the risk of cancer associated with long-acting insulin analogs have important methodological shortcomings that limit the conclusions that can be drawn. Thus, uncertainty remains, particularly for breast cancer risk. PMID- 26740634 TI - Day-and-Night Hybrid Closed-Loop Insulin Delivery in Adolescents With Type 1 Diabetes: A Free-Living, Randomized Clinical Trial. AB - OBJECTIVE: To evaluate feasibility, safety, and efficacy of day-and-night hybrid closed-loop insulin delivery in adolescents with type 1 diabetes under free living conditions without remote monitoring or supervision. RESEARCH DESIGN AND METHODS: In an open-label, randomized, free-living, crossover study design, 12 adolescents receiving insulin pump therapy (mean [+/-SD] age 15.4 +/- 2.6 years; HbA1c 8.3 +/- 0.9%; duration of diabetes 8.2 +/- 3.4 years) underwent two 7-day periods of sensor-augmented insulin pump therapy or hybrid closed-loop insulin delivery without supervision or remote monitoring. During the closed-loop insulin delivery, a model predictive algorithm automatically directed insulin delivery between meals and overnight; prandial boluses were administered by participants using a bolus calculator. RESULTS: The proportion of time when the sensor glucose level was in the target range (3.9-10 mmol/L) was increased during closed-loop insulin delivery compared with sensor-augmented pump therapy (72 vs. 53%, P < 0.001; primary end point), the mean glucose concentration was lowered (8.7 vs. 10.1 mmol/L, P = 0.028), and the time spent above the target level was reduced (P = 0.005) without changing the total daily insulin amount (P = 0.55). The time spent in the hypoglycemic range was low and comparable between interventions. CONCLUSIONS: Unsupervised day-and-night hybrid closed-loop insulin delivery at home is feasible and safe in young people with type 1 diabetes. Compared with sensor-augmented insulin pump therapy, closed-loop insulin delivery may improve glucose control without increasing the risk of hypoglycemia in adolescents with suboptimally controlled type 1 diabetes. PMID- 26740636 TI - Association Between Hospitalization for Heart Failure and Dipeptidyl Peptidase 4 Inhibitors in Patients With Type 2 Diabetes: An Observational Study. AB - OBJECTIVE: To examine, among patients with type 2 diabetes, the association between hospitalization for heart failure (hHF) and treatment with dipeptidyl peptidase 4 inhibitors (DPP-4is) versus sulfonylureas (SUs), and treatment with saxagliptin versus sitagliptin. RESEARCH DESIGN AND METHODS: This was a retrospective, observational study using a U.S. insurance claims database. Patients initiated treatment between 1 August 2010 and 30 August 2013, and had no use of the comparator treatments in the prior 12 months (baseline). Each comparison consisted of patients matched 1:1 on a propensity score. Time to each outcome was compared between matched groups using Cox models. Analyses were stratified by the presence of baseline cardiovascular disease (CVD). Secondary analyses examined associations between comparator treatments and other selected cardiovascular events. RESULTS: After matching, the study included 218,556 patients in comparisons of DPP-4i and SU, and 112,888 in comparisons of saxagliptin and sitagliptin. The hazard ratios (HRs) of hHF were as follows: DPP 4i versus SU (reference): HR 0.95 (95% CI 0.78-1.15), P = 0.580 for patients with baseline CVD; HR 0.59 (95% CI 0.38-0.89), P = 0.013 for patients without baseline CVD; saxagliptin versus sitagliptin (reference): HR 0.95 (95% CI 0.70-1.28), P = 0.712 for patients with baseline CVD; HR 0.99 (95% CI 0.56-1.75), P = 0.972 for patients without baseline CVD. Comparisons of the individual secondary and composite cardiovascular outcomes followed a similar pattern. CONCLUSIONS: In patients with type 2 diabetes, there was no association between hHF, or other selected cardiovascular outcomes, and treatment with a DPP-4i relative to SU or treatment with saxagliptin relative to sitagliptin. PMID- 26740635 TI - Natriuretic Peptide and High-Sensitivity Troponin for Cardiovascular Risk Prediction in Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study. AB - OBJECTIVE: Cardiovascular disease (CVD) is the major cause of morbidity and mortality in diabetes; yet, heterogeneity in CVD risk has been suggested in diabetes, providing a compelling rationale for improving diabetes risk stratification. We hypothesized that N-terminal prohormone brain natriuretic peptide (NTproBNP) and high-sensitivity troponin T may enhance CVD risk stratification beyond commonly used markers of risk and that CVD risk is heterogeneous in diabetes. RESEARCH DESIGN AND METHODS: Among 8,402 participants without prevalent CVD at visit 4 (1996-1998) of the Atherosclerosis Risk in Communities (ARIC) study there were 1,510 subjects with diabetes (mean age 63 years, 52% women, 31% African American, and 60% hypertensive). RESULTS: Over a median follow-up of 13.1 years, there were 540 incident fatal/nonfatal CVD events (coronary heart disease, heart failure, and stroke). Both troponin T >=14 ng/L (hazard ratio [HR] 1.96 [95% CI 1.57-2.46]) and NTproBNP >125 pg/mL (1.61 [1.29 1.99]) were independent predictors of incident CVD events at multivariable Cox proportional hazard models. Addition of circulating cardiac biomarkers to traditional risk factors, abnormal electrocardiogram (ECG), and conventional markers of diabetes complications including retinopathy, nephropathy, and peripheral arterial disease significantly improved CVD risk prediction (net reclassification index 0.16 [95% CI 0.07-0.22]). Compared with individuals without diabetes, subjects with diabetes had 1.6-fold higher adjusted risk of incident CVD. However, participants with diabetes with normal cardiac biomarkers and no conventional complications/abnormal ECG (n = 725 [48%]) were at low risk (HR 1.12 [95% CI 0.95-1.31]), while those with abnormal cardiac biomarkers, alone (n = 186 [12%]) or in combination with conventional complications/abnormal ECG (n = 243 [16%]), were at greater risk (1.99 [1.59-2.50] and 2.80 [2.34-3.35], respectively). CONCLUSIONS: Abnormal levels of NTproBNP and troponin T may help to distinguish individuals with high diabetes risk from those with low diabetes risk, providing incremental risk prediction beyond commonly used markers of risk. PMID- 26740638 TI - Anti-inflammatory Effect of Mediterranean Diet in Type 2 Diabetes Is Durable: 8 Year Follow-up of a Controlled Trial. PMID- 26740637 TI - Association of Gestational Diabetes Mellitus With Left Ventricular Structure and Function: The CARDIA Study. AB - OBJECTIVE: Gestational diabetes mellitus (GDM) predicts incident cardiovascular disease (CVD). However, mechanisms linking GDM to CVD beyond intervening incident diabetes are not well understood. We examined the relation of GDM with echocardiographic parameters of left ventricular (LV) structure and function, which are important predictors of future CVD risk. RESEARCH DESIGN AND METHODS: We studied 609 women (43% black) from the Coronary Artery Risk Development in Young Adults (CARDIA) study who delivered one or more births during follow-up and had echocardiograms in 1990-1991 (mean age 28.8 years) and 2010-2011. RESULTS: During the 20-year follow-up, 965 births were reported, with GDM developing in 64 women (10.5%). In linear regression models adjusted for sociodemographic factors, BMI, physical activity, parity, smoking, use of oral contraceptives, alcohol intake, family history of coronary heart disease, systolic blood pressure, and lipid levels, women with GDM had impaired longitudinal peak strain (-15.0 vs. 15.7%, P = 0.025), circumferential peak strain (-14.8 vs. -15.6%, P = 0.028), lateral e' wave velocity (11.0 vs. 11.8 cm/s, P = 0.012), and septal e' wave velocity (8.6 vs. 9.3 cm/s, P = 0.015) in 2010-2011 and a greater 20-year increase in LV mass indexed to body surface area (14.3 vs. 6.0 g/m(2), P = 0.006) compared with women with non-GDM pregnancies. Further adjustment for incident type 2 diabetes after pregnancy did not attenuate these associations. CONCLUSIONS: Pregnancy complicated by GDM is independently associated with increased LV mass and impaired LV relaxation and systolic function. Implementation of postpartum cardiovascular health interventions in women with a history of GDM may offer an additional opportunity to reduce future CVD risk. PMID- 26740639 TI - Hyperbaric Oxygen Therapy Does Not Reduce Indications for Amputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: A Prospective, Double Blind, Randomized Controlled Clinical Trial. AB - OBJECTIVE: Hyperbaric oxygen therapy (HBOT) is used for the treatment of chronic diabetic foot ulcers (DFUs). The controlled evidence for the efficacy of this treatment is limited. The goal of this study was to assess the efficacy of HBOT in reducing the need for major amputation and improving wound healing in patients with diabetes and chronic DFUs. RESEARCH DESIGN AND METHODS: Patients with diabetes and foot lesions (Wagner grade 2-4) of at least 4 weeks' duration participated in this study. In addition to comprehensive wound care, participants were randomly assigned to receive 30 daily sessions of 90 min of HBOT (breathing oxygen at 244 kPa) or sham (breathing air at 125 kPa). Patients, physicians, and researchers were blinded to group assignment. At 12 weeks postrandomization, the primary outcome was freedom from meeting the criteria for amputation as assessed by a vascular surgeon. Secondary outcomes were measures of wound healing. RESULTS: One hundred fifty-seven patients were assessed for eligibility, with 107 randomly assigned and 103 available for end point adjudication. Criteria for major amputation were met in 13 of 54 patients in the sham group and 11 of 49 in the HBOT group (odds ratio 0.91 [95% CI 0.37, 2.28], P = 0.846). Twelve (22%) patients in the sham group and 10 (20%) in the HBOT group were healed (0.90 [0.35, 2.31], P = 0.823). All other indices of wound healing were also not statistically significantly different between groups. CONCLUSIONS: HBOT does not offer an additional advantage to comprehensive wound care in reducing the indication for amputation or facilitating wound healing in patients with chronic DFUs. PMID- 26740640 TI - Little Change in Diet After Onset of Type 2 Diabetes, Metabolic Syndrome, and Obesity in Middle-Aged Adults: 11-Year Follow-up Study. PMID- 26740641 TI - Reduced Lower-Limb Muscle Strength and Volume in Patients With Type 2 Diabetes in Relation to Neuropathy, Intramuscular Fat, and Vitamin D Levels. AB - OBJECTIVE: Muscle weakness and atrophy of the lower limbs may develop in patients with diabetes, increasing their risk of falls. The underlying basis of these abnormalities has not been fully explained. The aim of this study was to objectively quantify muscle strength and size in patients with type 2 diabetes mellitus (T2DM) in relation to the severity of neuropathy, intramuscular noncontractile tissue (IMNCT), and vitamin D deficiency. RESEARCH DESIGN AND METHODS: Twenty patients with T2DM and 20 healthy control subjects were matched by age, sex, and BMI. Strength and size of knee extensor, flexor, and ankle plantar and dorsiflexor muscles were assessed in relation to the severity of diabetic sensorimotor polyneuropathy (DSPN), amount of IMNCT, and serum 25 hydroxyvitamin D (25OHD) levels. RESULTS: Compared with control subjects, patients with T2DM had significantly reduced knee extensor strength (P = 0.003) and reduced muscle volume of both knee extensors (P = 0.045) and flexors (P = 0.019). Ankle plantar flexor strength was also significantly reduced (P = 0.001) but without a reduction in ankle plantar flexor (P = 0.23) and dorsiflexor (P = 0.45) muscle volumes. IMNCT was significantly increased in the ankle plantar (P = 0.006) and dorsiflexors (P = 0.005). Patients with DSPN had significantly less knee extensor strength than those without (P = 0.02) but showed no difference in knee extensor volume (P = 0.38) and ankle plantar flexor strength (P = 0.21) or volume (P = 0.96). In patients with <25 nmol/L versus >25 nmol/L 25OHD, no significant differences were found for knee extensor strength and volume (P = 0.32 vs. 0.18) and ankle plantar flexors (P = 0.58 vs. 0.12). CONCLUSIONS: Patients with T2DM have a significant reduction in proximal and distal leg muscle strength and a proximal but not distal reduction in muscle volume possibly due to greater intramuscular fat accumulation in distal muscles. Proximal but not distal muscle strength is related to the severity of peripheral neuropathy but not IMNCT or 25OHD level. PMID- 26740642 TI - Highly sensitive and ultrafast read mapping for RNA-seq analysis. AB - As sequencing technologies progress, the amount of data produced grows exponentially, shifting the bottleneck of discovery towards the data analysis phase. In particular, currently available mapping solutions for RNA-seq leave room for improvement in terms of sensitivity and performance, hindering an efficient analysis of transcriptomes by massive sequencing. Here, we present an innovative approach that combines re-engineering, optimization and parallelization. This solution results in a significant increase of mapping sensitivity over a wide range of read lengths and substantial shorter runtimes when compared with current RNA-seq mapping methods available. PMID- 26740643 TI - Combining Computational Models of Cognition and Neural Data to Learn about Mixed Task Strategies. PMID- 26740644 TI - Late EEG Responses Are Absent for Conscious But Task-Irrelevant Stimuli. PMID- 26740645 TI - Optogenetic Activation of Dorsal Raphe Serotonin Neurons Rapidly Inhibits Spontaneous But Not Odor-Evoked Activity in Olfactory Cortex. AB - Serotonin (5-hydroxytriptamine; 5-HT) is implicated in a variety of brain functions including not only the regulation of mood and control of behavior but also the modulation of perception. 5-HT neurons in the dorsal raphe nucleus (DRN) often fire locked to sensory stimuli, but little is known about how 5-HT affects sensory processing, especially on this timescale. Here, we used an optogenetic approach to study the effect of 5-HT on single-unit activity in the mouse primary olfactory (anterior piriform) cortex. We show that activation of DRN 5-HT neurons rapidly inhibits the spontaneous firing of olfactory cortical neurons, acting in a divisive manner, but entirely spares sensory-driven firing. These results identify a new role for serotonergic modulation in dynamically regulating the balance between different sources of neural activity in sensory systems, suggesting a possible role for 5-HT in perceptual inference. SIGNIFICANCE STATEMENT: Serotonin is implicated in a wide variety of (pato)physiological functions including perception, but its precise role has remained elusive. Here, using optogenetic tools in vivo, we show that serotonergic neuromodulation prominently inhibits the spontaneous electrical activity of neurons in the primary olfactory cortex on a rapid (<1 s) timescale but leaves sensory responses unaffected. These results identify a new role for serotonergic modulation in rapidly changing the balance between different sources of neural activity in sensory systems. PMID- 26740648 TI - Mild Perceptual Categorization Deficits Follow Bilateral Removal of Anterior Inferior Temporal Cortex in Rhesus Monkeys. AB - In primates, visual recognition of complex objects depends on the inferior temporal lobe. By extension, categorizing visual stimuli based on similarity ought to depend on the integrity of the same area. We tested three monkeys before and after bilateral anterior inferior temporal cortex (area TE) removal. Although mildly impaired after the removals, they retained the ability to assign stimuli to previously learned categories, e.g., cats versus dogs, and human versus monkey faces, even with trial-unique exemplars. After the TE removals, they learned in one session to classify members from a new pair of categories, cars versus trucks, as quickly as they had learned the cats versus dogs before the removals. As with the dogs and cats, they generalized across trial-unique exemplars of cars and trucks. However, as seen in earlier studies, these monkeys with TE removals had difficulty learning to discriminate between two simple black and white stimuli. These results raise the possibility that TE is needed for memory of simple conjunctions of basic features, but that it plays only a small role in generalizing overall configural similarity across a large set of stimuli, such as would be needed for perceptual categorical assignment. SIGNIFICANCE STATEMENT: The process of seeing and recognizing objects is attributed to a set of sequentially connected brain regions stretching forward from the primary visual cortex through the temporal lobe to the anterior inferior temporal cortex, a region designated area TE. Area TE is considered the final stage for recognizing complex visual objects, e.g., faces. It has been assumed, but not tested directly, that this area would be critical for visual generalization, i.e., the ability to place objects such as cats and dogs into their correct categories. Here, we demonstrate that monkeys rapidly and seemingly effortlessly categorize large sets of complex images (cats vs dogs, cars vs trucks), surprisingly, even after removal of area TE, leaving a puzzle about how this generalization is done. PMID- 26740646 TI - Dual Modulation of Nociception and Cardiovascular Reflexes during Peripheral Ischemia through P2Y1 Receptor-Dependent Sensitization of Muscle Afferents. AB - Numerous musculoskeletal pain disorders are based in dysfunction of peripheral perfusion and are often comorbid with altered cardiovascular responses to muscle contraction/exercise. We have recently found in mice that 24 h peripheral ischemia induced by a surgical occlusion of the brachial artery (BAO) induces increased paw-guarding behaviors, mechanical hypersensitivity, and decreased grip strength. These behavioral changes corresponded to increased heat sensitivity as well as an increase in the numbers of chemosensitive group III/IV muscle afferents as assessed by an ex vivo forepaw muscles/median and ulnar nerves/dorsal root ganglion (DRG)/spinal cord (SC) recording preparation. Behaviors also corresponded to specific upregulation of the ADP-responsive P2Y1 receptor in the DRGs. Since group III/IV muscle afferents have separately been associated with regulating muscle nociception and exercise pressor reflexes (EPRs), and P2Y1 has been linked to heat responsiveness and phenotypic switching in cutaneous afferents, we sought to determine whether upregulation of P2Y1 was responsible for the observed alterations in muscle afferent function, leading to modulation of muscle pain-related behaviors and EPRs after BAO. Using an afferent specific siRNA knockdown strategy, we found that inhibition of P2Y1 during BAO not only prevented the increased mean blood pressure after forced exercise, but also significantly reduced alterations in pain-related behaviors. Selective P2Y1 knockdown also prevented the increased firing to heat stimuli and the BAO-induced phenotypic switch in chemosensitive muscle afferents, potentially through regulating membrane expression of acid sensing ion channel 3. These results suggest that enhanced P2Y1 in muscle afferents during ischemic-like conditions may dually regulate muscle nociception and cardiovascular reflexes. SIGNIFICANCE STATEMENT: Our current results suggest that P2Y1 modulates heat responsiveness and chemosensation in muscle afferents to play a key role in the development of pain-related behaviors during ischemia. At the same time, under these pathological conditions, the changes in muscle sensory neurons appear to modulate an increase in mean systemic blood pressure after exercise. This is the first report of the potential peripheral mechanisms by which group III/IV muscle afferents can dually regulate muscle nociception and the exercise pressor reflex. These data provide evidence related to the potential underlying reasons for the comorbidity of muscle pain and altered sympathetic reflexes in disease states that are based in problems with peripheral perfusion and may indicate a potential target for therapeutic intervention. PMID- 26740647 TI - Saccadic Corollary Discharge Underlies Stable Visual Perception. AB - Saccadic eye movements direct the high-resolution foveae of our retinas toward objects of interest. With each saccade, the image jumps on the retina, causing a discontinuity in visual input. Our visual perception, however, remains stable. Philosophers and scientists over centuries have proposed that visual stability depends upon an internal neuronal signal that is a copy of the neuronal signal driving the eye movement, now referred to as a corollary discharge (CD) or efference copy. In the old world monkey, such a CD circuit for saccades has been identified extending from superior colliculus through MD thalamus to frontal cortex, but there is little evidence that this circuit actually contributes to visual perception. We tested the influence of this CD circuit on visual perception by first training macaque monkeys to report their perceived eye direction, and then reversibly inactivating the CD as it passes through the thalamus. We found that the monkey's perception changed; during CD inactivation, there was a difference between where the monkey perceived its eyes to be directed and where they were actually directed. Perception and saccade were decoupled. We established that the perceived eye direction at the end of the saccade was not derived from proprioceptive input from eye muscles, and was not altered by contextual visual information. We conclude that the CD provides internal information contributing to the brain's creation of perceived visual stability. More specifically, the CD might provide the internal saccade vector used to unite separate retinal images into a stable visual scene. SIGNIFICANCE STATEMENT: Visual stability is one of the most remarkable aspects of human vision. The eyes move rapidly several times per second, displacing the retinal image each time. The brain compensates for this disruption, keeping our visual perception stable. A major hypothesis explaining this stability invokes a signal within the brain, a corollary discharge, that informs visual regions of the brain when and where the eyes are about to move. Such a corollary discharge circuit for eye movements has been identified in macaque monkey. We now show that selectively inactivating this brain circuit alters the monkey's visual perception. We conclude that this corollary discharge provides a critical signal that can be used to unite jumping retinal images into a consistent visual scene. PMID- 26740649 TI - Cochlear Implant Stimulation of a Hearing Ear Generates Separate Electrophonic and Electroneural Responses. AB - Electroacoustic stimulation in subjects with residual hearing is becoming more widely used in clinical practice. However, little is known about the properties of electrically induced responses in the hearing cochlea. In the present study, normal-hearing guinea pig cochleae underwent cochlear implantation through a cochleostomy without significant loss of hearing. Using recordings of unit activity in the midbrain, we were able to investigate the excitation patterns throughout the tonotopic field determined by acoustic stimulation. With the cochlear implant and the midbrain multielectrode arrays left in place, the ears were pharmacologically deafened and electrical stimulation was repeated in the deafened condition. The results demonstrate that, in addition to direct neuronal (electroneuronal) stimulation, in the hearing cochlea excitation of the hair cells occurs ("electrophonic responses") at the cochlear site corresponding to the dominant temporal frequency components of the electrical stimulus, provided these are < 12 kHz. The slope of the rate-level functions of the neurons in the deafened condition was steeper and the firing rate was higher than in the hearing condition at those sites that were activated in the two conditions. Finally, in a monopolar stimulation configuration, the differences between hearing status conditions were smaller than in the narrower (bipolar) configurations. SIGNIFICANCE STATEMENT: Stimulation with cochlear implants and hearing aids is becoming more widely clinically used in subjects with residual hearing. The neurophysiological characteristics underlying electroacoustic stimulation and the mechanism of its benefit remain unclear. The present study directly demonstrates that cochlear implantation does not interfere with the normal mechanical and physiological function of the cochlea. For the first time, it double-dissociates the electrical responses of hair cells (electrophonic responses) from responses of the auditory nerve fibers (electroneural responses), with separate excited cochlear locations in the same animals. We describe the condition in which these two responses spatially overlap. Finally, the study implicates that using the clinical characteristics of stimulation makes electrophonic responses unlikely in implanted subjects. PMID- 26740651 TI - Glycinergic Neurotransmission: A Potent Regulator of Embryonic Motor Neuron Dendritic Morphology and Synaptic Plasticity. AB - Emerging evidence suggests that central synaptic inputs onto motor neurons (MNs) play an important role in developmental regulation of the final number of MNs and their muscle innervation for a particular motor pool. Here, we describe the effect of genetic deletion of glycinergic neurotransmission on single MN structure and on functional excitatory and inhibitory inputs to MNs. We measured synaptic currents in E18.5 hypoglossal MNs from brain slices using whole-cell patch-clamp recording, followed by dye-filling these same cells with Neurobiotin, to define their morphology by high-resolution confocal imaging and 3D reconstruction. We show that hypoglossal MNs of mice lacking gephyrin display increased dendritic arbor length and branching, increased spiny processes, decreased inhibitory neurotransmission, and increased excitatory neurotransmission. These findings suggest that central glycinergic synaptic activity plays a vital role in regulating MN morphology and glutamatergic central synaptic inputs during late embryonic development. SIGNIFICANCE STATEMENT: MNs within the brainstem and spinal cord are responsible for integrating a diverse array of synaptic inputs into discrete contractions of skeletal muscle to achieve coordinated behaviors, such as breathing, vocalization, and locomotion. The last trimester in utero is critical in neuromotor development, as this is when central and peripheral synaptic connections are made onto and from MNs. At this time point, using transgenic mice with negligible glycinergic postsynaptic responses, we show that this deficiency leads to abnormally high excitatory neurotransmission and alters the dendritic architecture responsible for coherently integrating these inputs. This study compliments the emerging concept that neurodevelopmental disorders (including autism, epilepsy, and amyotrophic lateral sclerosis) are underpinned by synaptic dysfunction and therefore will be useful to neuroscientists and neurologists alike. PMID- 26740650 TI - Smoking-Relevant Nicotine Concentration Attenuates the Unfolded Protein Response in Dopaminergic Neurons. AB - Retrospective epidemiological studies show an inverse correlation between susceptibility to Parkinson's disease and a person's history of tobacco use. Animal model studies suggest nicotine as a neuroprotective agent and nicotinic acetylcholine (ACh) receptors (nAChRs) as targets for neuroprotection, but the underlying neuroprotective mechanism(s) are unknown. We cultured mouse ventral midbrain neurons for 3 weeks. Ten to 20% of neurons were dopaminergic (DA), revealed by tyrosine hydroxylase (TH) immunoreactivity. We evoked mild endoplasmic reticulum (ER) stress with tunicamycin (Tu), producing modest increases in the level of nuclear ATF6, phosphorylated eukaryotic initiation factor 2alpha, nuclear XBP1, and the downstream proapoptotic effector nuclear C/EBP homologous protein. We incubated cultures for 2 weeks with 200 nm nicotine, the approximate steady-state concentration between cigarette smoking or vaping, or during nicotine patch use. Nicotine incubation suppressed Tu-induced ER stress and the unfolded protein response (UPR). Study of mice with fluorescent nAChR subunits showed that the cultured TH+ neurons displayed alpha4, alpha6, and beta3 nAChR subunit expression and ACh-evoked currents. Gene expression profile in cultures from TH-eGFP mice showed that the TH+ neurons also express several other genes associated with DA release. Nicotine also upregulated ACh-induced currents in DA neurons by ~2.5-fold. Thus, nicotine, at a concentration too low to activate an appreciable fraction of plasma membrane nAChRs, induces two sequelae of pharmacological chaperoning in the ER: UPR suppression and nAChR upregulation. Therefore, one mechanism of neuroprotection by nicotine is pharmacological chaperoning, leading to UPR suppression. Measuring this pathway may help in assessing neuroprotection. SIGNIFICANCE STATEMENT: Parkinson's disease (PD) cannot yet be cured or prevented. However, many retrospective epidemiological studies reveal that PD is diagnosed less frequently in tobacco users. Existing programs attempting to develop nicotinic drugs that might exert this apparent neuroprotective effect are asking whether agonists, antagonists, partial agonists, or channel blockers show the most promise. The underlying logic resembles the previous development of varenicline for smoking cessation. We studied whether, and how, nicotine produces neuroprotective effects in cultured dopaminergic neurons, an experimentally tractable, mechanistically revealing neuronal system. We show that nicotine, operating via nicotinic receptors, does protect these neurons against endoplasmic reticulum stress. However, the mechanism is probably "inside-out": pharmacological chaperoning in the endoplasmic reticulum. This cellular-level insight could help to guide neuroprotective strategies. PMID- 26740652 TI - Neuroimaging Evidence of a Bilateral Representation for Visually Presented Numbers. AB - The clustered architecture of the brain for different visual stimulus categories is one of the most fascinating topics in the cognitive neurosciences. Interestingly, recent research suggests the existence of additional regions for newly acquired stimuli such as letters (letter form area; LFA; Thesen et al., 2012) and numbers (visual number form area; NFA; Shum et al., 2013). However, neuroimaging methods thus far have failed to visualize the NFA in healthy participants, likely due to fMRI signal dropout caused by the air/bone interface of the petrous bone (Shum et al., 2013). In the current study, we combined a 64 channel head coil with high spatial resolution, localized shimming, and liberal smoothing, thereby decreasing the signal dropout and increasing the temporal signal-to-noise ratio in the neighborhood of the NFA. We presented subjects with numbers, letters, false numbers, false letters, objects and their Fourier randomized versions. A group analysis showed significant activations in the inferior temporal gyrus at the previously proposed location of the NFA. Crucially, we found the NFA to be present in both hemispheres. Further, we could identify the NFA on the single-subject level in most of our participants. A detailed analysis of the response profile of the NFA in two separate experiments confirmed the whole-brain results since responses to numbers were significantly higher than to any other presented stimulus in both hemispheres. Our results show for the first time the existence and stimulus selectivity of the NFA in the healthy human brain. SIGNIFICANCE STATEMENT: This fMRI study shows for the first time a cluster of neurons selective for visually presented numbers in healthy human adults. This visual number form area (NFA) was found in both hemispheres. Crucially, numbers have gained importance for humans too recently for neuronal specialization to be established by evolution. Therefore, investigations of this region will greatly advance our understanding of learning and plasticity in the brain. In addition, these results will aid our knowledge regarding related neurological illnesses (e.g., dyscalculia). To overcome the fMRI signal dropout in the neighborhood of the NFA, we combined high spatial resolution with liberal smoothing. We believe that this approach will be useful to the broad neuroimaging community. PMID- 26740653 TI - Functionally Distinct Dopamine Signals in Nucleus Accumbens Core and Shell in the Freely Moving Rat. AB - Dynamic signaling of mesolimbic dopamine (DA) neurons has been implicated in reward learning, drug abuse, and motivation. However, this system is complex because firing patterns of these neurons are heterogeneous; subpopulations receive distinct synaptic inputs, and project to anatomically and functionally distinct downstream targets, including the nucleus accumbens (NAc) shell and core. The functional roles of these cell populations and their real-time signaling properties in freely moving animals are unknown. Resolving the real time DA signal requires simultaneous knowledge of the synchronized activity of DA cell subpopulations and assessment of the down-stream functional effect of DA release. Because this is not yet possible solely by experimentation in vivo, we combine computational modeling and fast-scan cyclic voltammetry data to reconstruct the functionally relevant DA signal in DA neuron subpopulations projecting to the NAc core and shell in freely moving rats. The approach provides a novel perspective on real-time DA neuron firing and concurrent activation of presynaptic autoreceptors and postsynaptic targets. We first show that individual differences in DA release arise from differences in autoreceptor feedback. The model predicts that extracellular DA concentrations in NAc core result from constant baseline DA firing, whereas DA concentrations in NAc shell reflect highly dynamic firing patters, including synchronized burst firing and pauses. Our models also predict that this anatomical difference in DA signaling is exaggerated by intravenous infusion of cocaine. SIGNIFICANCE STATEMENT: Orchestrated signaling from mesolimbic dopamine (DA) neurons is important for initiating appropriate behavior in response to salient stimuli. Thus, subpopulations of mesolimbic DA neurons show different in vitro properties and synaptic inputs depending on their specific projections to the core and shell subterritories of the nucleus accumbens (NAc). However, the functional consequence of these differences is unknown. Here we analyze and model DA dynamics in different areas of the NAc to establish the real-time DA signal. In freely behaving animals, we find that the DA signal from mesencephalic neurons projecting to the NAc shell is dominated by synchronized bursts and pauses, whereas signaling is uniform for core-projecting neurons; this difference is amplified by cocaine. PMID- 26740654 TI - Behavioral Evidence for More than One Taste Signaling Pathway for Sugars in Rats. AB - By conventional behavioral measures, rodents respond to natural sugars, such as glucose and fructose, as though they elicit an identical perceptual taste quality. Beyond that, the metabolic and sensory effects of these two sugars are quite different. Considering the capacity to immediately respond to the more metabolically expedient sugar, glucose, would seem advantageous for energy intake, the present experiment assessed whether experience consuming these two sugars would modify taste-guided ingestive responses to their yet unknown distinguishing orosensory properties. One group (GvF) had randomized access to three concentrations of glucose and fructose (0.316, 0.56, 1.1 m) in separate 30 min single access training sessions, whereas control groups received equivalent exposure to the three glucose or fructose concentrations only, or remained sugar naive. Comparison of the microstructural licking patterns for the two sugars revealed that GvF responded more positively to glucose (increased total intake, increased burst size, decreased number of pauses), relative to fructose, across training. As training progressed, GvF rats began to respond more positively to glucose in the first minute of the session when intake is principally taste driven. During post-training brief-access taste tests, GvF rats licked more for glucose than for fructose, whereas the other training groups did not respond differentially to the two sugars. Additional brief access testing showed that this did not generalize to Na-saccharin or galactose. Thus, in addition to eliciting a common taste signal, glucose and fructose produce distinct signals that are apparently rendered behaviorally relevant and hedonically distinct through experience. The taste pathway(s) underlying this remain to be identified. SIGNIFICANCE STATEMENT: The T1R2+T1R3 heterodimer is thought by many to be the only taste receptor for sugars. Although most sugars have been conventionally shown to correspondingly produce a unitary taste percept (sweet), there is reason to question this model. Here, we demonstrate that rats that repeatedly consumed two metabolically distinct sugars (glucose and fructose), and thus have had the opportunity to associate the tastes of these sugars with their differential postoral consequences, initially respond identically to the orosensory properties of the two sugars but eventually respond more positively to glucose. Thus, in addition to the previously identified common taste pathway, glucose and fructose must engage distinct orosensory pathways, the underlying molecular and neural mechanisms of which now await discovery. PMID- 26740655 TI - Enhanced Store-Operated Calcium Entry Leads to Striatal Synaptic Loss in a Huntington's Disease Mouse Model. AB - In Huntington's disease (HD), mutant Huntingtin (mHtt) protein causes striatal neuron dysfunction, synaptic loss, and eventual neurodegeneration. To understand the mechanisms responsible for synaptic loss in HD, we developed a corticostriatal coculture model that features age-dependent dendritic spine loss in striatal medium spiny neurons (MSNs) from YAC128 transgenic HD mice. Age dependent spine loss was also observed in vivo in YAC128 MSNs. To understand the causes of spine loss in YAC128 MSNs, we performed a series of mechanistic studies. We previously discovered that mHtt protein binds to type 1 inositol (1,4,5)-trisphosphate receptor (InsP3R1) and increases its sensitivity to activation by InsP3. We now report that the resulting increase in steady-state InsP3R1 activity reduces endoplasmic reticulum (ER) Ca(2+) levels. Depletion of ER Ca(2+) leads to overactivation of the neuronal store-operated Ca(2+) entry (nSOC) pathway in YAC128 MSN spines. The synaptic nSOC pathway is controlled by the ER resident protein STIM2. We discovered that STIM2 expression is elevated in aged YAC128 striatal cultures and in YAC128 mouse striatum. Knock-down of InsP3R1 expression by antisense oligonucleotides or knock-down or knock-out of STIM2 resulted in normalization of nSOC and rescue of spine loss in YAC128 MSNs. The selective nSOC inhibitor EVP4593 was identified in our previous studies. We now demonstrate that EVP4593 reduces synaptic nSOC and rescues spine loss in YAC128 MSNs. Intraventricular delivery of EVP4593 in YAC128 mice rescued age-dependent striatal spine loss in vivo. Our results suggest EVP4593 and other inhibitors of the STIM2-dependent nSOC pathway as promising leads for HD therapeutic development. SIGNIFICANCE STATEMENT: In Huntington's disease (HD) mutant Huntingtin (mHtt) causes early corticostriatal synaptic dysfunction and eventual neurodegeneration of medium spine neurons (MSNs) through poorly understood mechanisms. We report here that corticostriatal cocultures prepared from YAC128 HD mice feature age-dependent MSN spine loss, mirroring YAC128 MSN spine loss in vivo. This finding establishes a system for mechanistic studies of synaptic instability in HD. We use it to demonstrate that sensitization of type 1 inositol (1,4,5)-trisphosphate receptors by mHtt, which depletes endoplasmic reticulum calcium, contributes to synaptotoxic enhancement of STIM2-dependent store operated calcium (SOC) entry. Treatment with EVP4593, a neuroprotective inhibitor of neuronal SOC channels, rescues YAC128 MSN spine loss both in vitro and in vivo. These results suggest that enhanced neuronal SOC causes synaptic loss in HD afflicted MSNs. PMID- 26740656 TI - Human iPS Cell-Derived Neurons Uncover the Impact of Increased Ras Signaling in Costello Syndrome. AB - Increasing evidence implicates abnormal Ras signaling as a major contributor in neurodevelopmental disorders, yet how such signaling causes cortical pathogenesis is unknown. We examined the consequences of aberrant Ras signaling in the developing mouse brain and uncovered several critical phenotypes, including increased production of cortical neurons and morphological deficits. To determine whether these phenotypes are recapitulated in humans, we generated induced pluripotent stem (iPS) cell lines from patients with Costello syndrome (CS), a developmental disorder caused by abnormal Ras signaling and characterized by neurodevelopmental abnormalities, such as cognitive impairment and autism. Directed differentiation toward a neuroectodermal fate revealed an extended progenitor phase and subsequent increased production of cortical neurons. Morphological analysis of mature neurons revealed significantly altered neurite length and soma size in CS patients. This study demonstrates the synergy between mouse and human models and validates the use of iPS cells as a platform to study the underlying cellular pathologies resulting from signaling deficits. SIGNIFICANCE STATEMENT: Increasing evidence implicates Ras signaling dysfunction as a major contributor in psychiatric and neurodevelopmental disorders, such as cognitive impairment and autism, but the underlying cortical cellular pathogenesis remains unclear. This study is the first to reveal human neuronal pathogenesis resulting from abnormal Ras signaling and provides insights into how these phenotypic abnormalities likely contribute to neurodevelopmental disorders. We also demonstrate the synergy between mouse and human models, thereby validating the use of iPS cells as a platform to study underlying cellular pathologies resulting from signaling deficits. Recapitulating human cellular pathologies in vitro facilitates the future high throughput screening of potential therapeutic agents that may reverse phenotypic and behavioral deficits. PMID- 26740657 TI - Previous Ketamine Produces an Enduring Blockade of Neurochemical and Behavioral Effects of Uncontrollable Stress. AB - Recent interest in the antidepressant and anti-stress effects of subanesthetic doses of ketamine, an NMDA receptor antagonist, has identified mechanisms whereby ketamine reverses the effect of stress, but little is known regarding the prophylactic effect ketamine might have on future stressors. Here we investigate the prophylactic effect of ketamine against neurochemical and behavioral changes that follow inescapable, uncontrollable tail shocks (ISs) in Sprague Dawley rats. IS induces increased anxiety, which is dependent on activation of serotonergic (5 HT) dorsal raphe nucleus (DRN) neurons that project to the basolateral amygdala (BLA). Ketamine (10 mg/kg, i.p.) administered 2 h, 1 week, or 2 weeks before IS prevented the increased extracellular levels of 5-HT in the BLA typically produced by IS. In addition, ketamine administered at these time points blocked the decreased juvenile social investigation produced by IS. Microinjection of ketamine into the prelimbic (PL) region of the medial prefrontal cortex duplicated the effects of systemic ketamine, and, conversely, systemic ketamine effects were prevented by pharmacological inhibition of the PL. Although IS does not activate DRN-projecting neurons from the PL, IS did so after ketamine, suggesting that the prophylactic effect of ketamine is a result of altered functioning of this projection. SIGNIFICANCE STATEMENT: The reported data show that systemic ketamine, given up to 2 weeks before a stressor, blunts behavioral and neurochemical effects of the stressor. The study also advances understanding of the mechanisms involved and suggests that ketamine acts at the prelimbic cortex to sensitize neurons that project to and inhibit the DRN. PMID- 26740658 TI - Hippocampal Respiration-Driven Rhythm Distinct from Theta Oscillations in Awake Mice. AB - We have recently described a slow oscillation in the hippocampus of urethane anesthetized mice, which couples to nasal respiration and is clearly distinct from co-occurring theta oscillations. Here we set out to investigate whether such type of patterned network activity, which we named "hippocampal respiration rhythm" (HRR), also occurs in awake mice. In freely moving mice, instantaneous respiration rate is extremely variable, and respiration is superimposed by bouts of sniffing. To reduce this variability, we clamped the behavior of the animal to either awake immobility or treadmill running by using a head-fixed setup while simultaneously recording respiration and field potentials from the olfactory bulb (OB) and hippocampus. Head-fixed animals often exhibited long periods of steady respiration rate during either immobility or running, which allowed for spectral and coherence analyses with a sufficient frequency resolution to sort apart respiration and theta activities. We could thus demonstrate the existence of HRR in awake animals, namely, a respiration-entrained slow rhythm with highest amplitude at the dentate gyrus. HRR was most prominent during immobility and running with respiration rates slower than theta oscillations. Nevertheless, HRR could also be faster than theta. Discharges of juxtacellularly recorded cells in CA1 and dentate gyrus were modulated by HRR and theta oscillations. Granger directionality analysis revealed that HRR is caused by the OB and that theta oscillations in OB are caused by the hippocampus. Our results suggest that respiration-coupled oscillations aid the exchange of information between olfactory and memory networks. SIGNIFICANCE STATEMENT: Olfaction is a major sense in rodents. In consequence, the olfactory bulb (OB) should be able to transmit information to downstream regions. Here we report potential mechanisms underlying such information transfer. We demonstrate the existence of a respiration entrained rhythm in the hippocampus of awake mice. Frequencies of the hippocampal respiration rhythm (HRR) overlap with classical theta oscillations, but both rhythms are clearly distinct. HRR is most prominent in the dentate gyrus, especially when respiration is slower than theta frequency. Discharges of neurons in CA1 and dentate gyrus are modulated by both HRR and theta. Directionality analysis shows that HRR is caused by the OB. Our results suggest that respiration coupled oscillations aid the exchange of information between olfactory and memory networks. PMID- 26740659 TI - Direct Evidence for Daily Plasticity of Electrical Coupling between Rod Photoreceptors in the Mammalian Retina. AB - Rod photoreceptors are electrically coupled through gap junctions. Coupling is a key determinant of their light response properties, but whether rod electrical coupling is dynamically regulated remains elusive and controversial. Here, we have obtained direct measurements of the conductance between adjacent rods in mouse retina and present evidence that rod electrical coupling strength is dependent on the time of day, the lighting conditions, and the mouse strain. Specifically, we show in CBA/Ca mice that under circadian conditions, the rod junctional conductance has a median value of 98 pS during the subjective day and of 493 pS during the subjective night. In C57BL/6 mice, the median junctional conductance between dark-adapted rods is ~140 pS, regardless of the time in the circadian cycle. Adaptation to bright light decreases the rod junctional conductance to ~0 pS, regardless of the time of day or the mouse strain. Together, these results establish the high degree of plasticity of rod electrical coupling over the course of the day. Estimates of the rod coupling strength will provide a foundation for further investigations of rod interactions and the role of rod coupling in the ability of the visual system to anticipate, assimilate, and respond to the daily changes in ambient light intensity. SIGNIFICANCE STATEMENT: Many cells in the CNS communicate via gap junctions, or electrical synapses, the regulation of which remains largely unknown. Here, we show that the strength of electrical coupling between rod photoreceptors of the retina is regulated by the time of day and the lighting conditions. This mechanism may help us understand some key aspects of day and night vision as well as some visual malfunctions. PMID- 26740660 TI - Recurrent Processing in the Formation of Shape Percepts. AB - The human visual system must extract reliable object information from cluttered visual scenes several times per second, and this temporal constraint has been taken as evidence that the underlying cortical processing must be strictly feedforward. Here we use a novel rapid reinforcement paradigm to probe the temporal dynamics of the neural circuit underlying rapid object shape perception and thus test this feedforward assumption. Our results show that two shape stimuli are optimally reinforcing when separated in time by ~60 ms, suggesting an underlying recurrent circuit with a time constant (feedforward + feedback) of 60 ms. A control experiment demonstrates that this is not an attentional cueing effect. Instead, it appears to reflect the time course of feedback processing underlying the rapid perceptual organization of shape. SIGNIFICANCE STATEMENT: Human and nonhuman primates can spot an animal shape in complex natural scenes with striking speed, and this has been taken as evidence that the underlying cortical mechanisms are strictly feedforward. Using a novel paradigm to probe the dynamics of shape perception, we find that two shape stimuli are optimally reinforcing when separated in time by 60 ms, suggesting a fast but recurrent neural circuit. This work (1) introduces a novel method for probing the temporal dynamics of cortical circuits underlying perception, (2) provides direct evidence against the feedforward assumption for rapid shape perception, and (3) yields insight into the role of feedback connections in the object pathway. PMID- 26740661 TI - Competition with Primary Sensory Afferents Drives Remodeling of Corticospinal Axons in Mature Spinal Motor Circuits. AB - Injury to the mature motor system drives significant spontaneous axonal sprouting instead of axon regeneration. Knowing the circuit-level determinants of axonal sprouting is important for repairing motor circuits after injury to achieve functional rehabilitation. Competitive interactions are known to shape corticospinal tract axon outgrowth and withdrawal during development. Whether and how competition contributes to reorganization of mature spinal motor circuits is unclear. To study this question, we examined plastic changes in corticospinal axons in response to two complementary proprioceptive afferent manipulations: (1) enhancing proprioceptive afferents activity by electrical stimulation; or (2) diminishing their input by dorsal rootlet rhizotomy. Experiments were conducted in adult rats. Electrical stimulation produced proprioceptive afferent sprouting that was accompanied by significant corticospinal axon withdrawal and a decrease in corticospinal connections on cholinergic interneurons in the medial intermediate zone and C boutons on motoneurons. In contrast, dorsal rootlet rhizotomy led to a significant increase in corticospinal connections, including those on cholinergic interneurons; C bouton density increased correspondingly. Motor cortex-evoked muscle potentials showed parallel changes to those of corticospinal axons, suggesting that reciprocal corticospinal axon changes are functional. Using the two complementary models, we showed that competitive interactions between proprioceptive and corticospinal axons are an important determinant in the organization of mature corticospinal axons and spinal motor circuits. The activity- and synaptic space-dependent properties of the competition enables prediction of the remodeling of spared corticospinal connection and spinal motor circuits after injury and informs the target-specific control of corticospinal connections to promote functional recovery. SIGNIFICANCE STATEMENT: Neuroplasticity is limited in maturity, but it is promoted after injury. Axons of the major descending motor pathway for motor skills, the corticospinal tract (CST), sprout after brain or spinal cord injury. This contributes to spontaneous spinal motor circuit repair and partial motor recovery. Knowing the determinants that enhance this plasticity is critical for functional rehabilitation. Here we examine the remodeling of CST axons directed by sensory fibers. We found that the CST projection is regulated dynamically in maturity by the competitive, activity-dependent actions of sensory fibers. Knowledge of the properties of this competition enables prediction of the remodeling of CST connections and spinal circuits after injury and informs ways to engineer target-specific control of CST connections to promote recovery. PMID- 26740663 TI - Absence of Neuroplastin-65 Affects Synaptogenesis in Mouse Inner Hair Cells and Causes Profound Hearing Loss. AB - The Neuroplastin gene encodes two synapse-enriched protein isoforms, Np55 and Np65, which are transmembrane glycoproteins that regulate several cellular processes, including the genesis, maintenance, and plasticity of synapses. We found that an absence of Np65 causes early-onset sensorineural hearing loss and prevented the normal synaptogenesis in inner hair cells (IHCs) in the newly identified mouse mutant pitch. In wild-type mice, Np65 is strongly upregulated in the cochlea from around postnatal day 12 (P12), which corresponds to the onset of hearing. Np65 was specifically localized at the presynaptic region of IHCs. We found that the colocalization of presynaptic IHC ribbons and postsynaptic afferent terminals is greatly reduced in pitch mutants. Moreover, IHC exocytosis is also reduced with mutant mice showing lower rates of vesicle release. Np65 appears to have a nonessential role in vision. We propose that Np65, by regulating IHC synaptogenesis, is critical for auditory function in mammals. SIGNIFICANCE STATEMENT: In the mammalian cochlea, the sensory inner hair cells (IHCs) encode auditory information. They do this by converting sound wave-induced mechanical motion of their hair bundles into an electrical current. This current generates a receptor potential that controls release of glutamate neurotransmitter from their ribbon synapses onto the auditory afferent fiber. We show that the synapse-enriched protein Np65, encoded by the Neuroplastin gene, is localized at the IHC presynaptic region. In mutant mice, absence of Np65 causes early-onset sensorineural hearing loss and prevents normal neurotransmitter release in IHCs and colocalization of presynaptic ribbons with postsynaptic afferents. We identified Neuroplastin as a novel deafness gene required for ribbon synapse formation and function, which is critical for sound perception in mammals. PMID- 26740662 TI - Sustained Suppression of Hyperalgesia during Latent Sensitization by MU-, delta-, and kappa-opioid receptors and alpha2A Adrenergic Receptors: Role of Constitutive Activity. AB - Many chronic pain disorders alternate between bouts of pain and periods of remission. The latent sensitization model reproduces this in rodents by showing that the apparent recovery ("remission") from inflammatory or neuropathic pain can be reversed by opioid antagonists. Therefore, this remission represents an opioid receptor-mediated suppression of a sustained hyperalgesic state. To identify the receptors involved, we induced latent sensitization in mice and rats by injecting complete Freund's adjuvant (CFA) in the hindpaw. In WT mice, responses to mechanical stimulation returned to baseline 3 weeks after CFA. In MU opioid receptor (MOR) knock-out (KO) mice, responses did not return to baseline but partially recovered from peak hyperalgesia. Antagonists of alpha2A-adrenergic and delta-opioid receptors reinstated hyperalgesia in WT mice and abolished the partial recovery from hyperalgesia in MOR KO mice. In rats, antagonists of alpha2A adrenergic and MU-, delta-, and kappa-opioid receptors reinstated hyperalgesia during remission from CFA-induced hyperalgesia. Therefore, these four receptors suppress hyperalgesia in latent sensitization. We further demonstrated that suppression of hyperalgesia by MORs was due to their constitutive activity because of the following: (1) CFA-induced hyperalgesia was reinstated by the MOR inverse agonist naltrexone (NTX), but not by its neutral antagonist 6beta-naltrexol; (2) pro-enkephalin, pro-opiomelanocortin, and pro dynorphin KO mice showed recovery from hyperalgesia and reinstatement by NTX; (3) there was no MOR internalization during remission; (4) MORs immunoprecipitated from the spinal cord during remission had increased Ser(375) phosphorylation; and (5) electrophysiology recordings from dorsal root ganglion neurons collected during remission showed constitutive MOR inhibition of calcium channels. SIGNIFICANCE STATEMENT: Chronic pain causes extreme suffering to millions of people, but its mechanisms remain to be unraveled. Latent sensitization is a phenomenon studied in rodents that has many key features of chronic pain: it is initiated by a variety of noxious stimuli, has indefinite duration, and pain appears in episodes that can be triggered by stress. Here, we show that, during latent sensitization, there is a sustained state of pain hypersensitivity that is continuously suppressed by the activation of MU-, delta-, and kappa-opioid receptors and by adrenergic alpha2A receptors in the spinal cord. Furthermore, we show that the activation of MU-opioid receptors is not due to the release of endogenous opioids, but rather to its ligand-independent constitutive activity. PMID- 26740665 TI - Episodic Memory Retrieval Functionally Relies on Very Rapid Reactivation of Sensory Information. AB - Episodic memory retrieval is assumed to rely on the rapid reactivation of sensory information that was present during encoding, a process termed "ecphory." We investigated the functional relevance of this scarcely understood process in two experiments in human participants. We presented stimuli to the left or right of fixation at encoding, followed by an episodic memory test with centrally presented retrieval cues. This allowed us to track the reactivation of lateralized sensory memory traces during retrieval. Successful episodic retrieval led to a very early (~100-200 ms) reactivation of lateralized alpha/beta (10-25 Hz) electroencephalographic (EEG) power decreases in the visual cortex contralateral to the visual field at encoding. Applying rhythmic transcranial magnetic stimulation to interfere with early retrieval processing in the visual cortex led to decreased episodic memory performance specifically for items encoded in the visual field contralateral to the site of stimulation. These results demonstrate, for the first time, that episodic memory functionally relies on very rapid reactivation of sensory information. SIGNIFICANCE STATEMENT: Remembering personal experiences requires a "mental time travel" to revisit sensory information perceived in the past. This process is typically described as a controlled, relatively slow process. However, by using electroencephalography to measure neural activity with a high time resolution, we show that such episodic retrieval entails a very rapid reactivation of sensory brain areas. Using transcranial magnetic stimulation to alter brain function during retrieval revealed that this early sensory reactivation is causally relevant for conscious remembering. These results give first neural evidence for a functional, preconscious component of episodic remembering. This provides new insight into the nature of human memory and may help in the understanding of psychiatric conditions that involve the automatic intrusion of unwanted memories. PMID- 26740664 TI - Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats. AB - Chronic exposure to drugs of abuse is linked to long-lasting alterations in the function of limbic system structures, including the nucleus accumbens (NAc). Although cocaine acts via dopaminergic mechanisms within the NAc, less is known about whether phasic dopamine (DA) signaling in the NAc is altered in animals with cocaine self-administration experience or if these animals learn and interact normally with stimuli in their environment. Here, separate groups of rats self-administered either intravenous cocaine or water to a receptacle (controls), followed by 30 d of enforced abstinence. Next, all rats learned an appetitive Pavlovian discrimination and voltammetric recordings of real-time DA release were taken in either the NAc core or shell of cocaine and control subjects. Cocaine experience differentially impaired DA signaling in the core and shell relative to controls. Although phasic DA signals in the shell were essentially abolished for all stimuli, in the core, DA did not distinguish between cues and was abnormally biased toward reward delivery. Further, cocaine rats were unable to learn higher-order associations and even altered simple conditioned approach behaviors, displaying enhanced preoccupation with cue associated stimuli (sign-tracking; ST) but diminished time at the food cup awaiting reward delivery (goal-tracking). Critically, whereas control DA signaling correlated with ST behaviors, cocaine experience abolished this relationship. These findings show that cocaine has persistent, differential, and pathological effects on both DA signaling and DA-dependent behaviors and suggest that psychostimulant experience may remodel the very circuits that bias organisms toward repeated relapse. SIGNIFICANCE STATEMENT: Relapsing to drug abuse despite periods of abstinence and sincere attempts to quit is one of the most pernicious facets of addiction. Unfortunately, little is known about how the dopamine (DA) system functions after periods of drug abstinence, particularly its role in behavior in nondrug situations. Here, rats learned about food-paired stimuli after prolonged abstinence from cocaine self-administration. Using voltammetry, we found that real-time DA signals in cocaine-experienced rats were strikingly altered relative to controls. Further, cocaine-experienced animals found reward predictive stimuli abnormally salient and spent more time interacting with cues. Therefore, cocaine induces neuroplastic changes in the DA system that biases animals toward salient stimuli (including reward-associated cues), putting addicts at increasing risk to relapse as addiction increases in severity. PMID- 26740666 TI - NHS Health Checks: time for a reality check? PMID- 26740667 TI - Systematic Review: Issues in Measuring Clinically Meaningful Change in Self Reported Chronic Pediatric Pain Intensity. AB - OBJECTIVE: This report examined limitations in our ability to assess clinically significant change (CSC) in randomized controlled trials of treatments of self reported pediatric chronic pain intensity. METHODS: The following were reviewed: (a) approaches to assessing CSC; (b) approaches to assessing CSC used in psychological treatment studies of self-reported pediatric chronic pain intensity included in a recent systematic review; (c) the role of test-retest reliability in distribution-based CSC measures; (d) the test-retest reliability of recommended chronic pain measures. RESULTS AND CONCLUSIONS: Existing studies do not assess whether a CSC occurred or use procedures that did not account for measurement error and true score fluctuations unrelated to treatment, possibly resulting in overestimating CSCs. Distribution-based approaches to assessing CSCs that address these problems require knowing test-retest reliability of the chronic pain measure at appropriate intervals. Available information raises concern about our ability to estimate CSC reliably. Recommendations are made for future research. PMID- 26740668 TI - Identification and Characterization of Novel Microsomal Prostaglandin E Synthase 1 Inhibitors for Analgesia. AB - Prostaglandin (PG) E2 plays a critical role in eliciting inflammation. Nonsteroidal anti-inflammatory drugs and selective inhibitors of cyclooxygenase, which block PGE2 production, have been used as key agents in treating inflammation and pain associated with arthritis and other conditions. However, these agents have significant side effects such as gastrointestinal bleeding and myocardial infarction, since they also block the production of prostanoids that are critical for other normal physiologic functions. Microsomal prostaglandin E2 synthase-1 is a membrane-bound terminal enzyme in the prostanoid pathway, which acts downstream of cyclooxygenase 2 and is responsible for PGE2 production during inflammation. Thus, inhibition of this enzyme would be expected to block PGE2 production without inhibiting other prostanoids and would provide analgesic efficacy without the side effects. In this report, we describe novel microsomal prostaglandin E2 synthase-1 inhibitors that are potent in blocking PGE2 production and are efficacious in a guinea pig monoiodoacetate model of arthralgia. These molecules may be useful in treating the signs and symptoms associated with arthritis. PMID- 26740671 TI - Overall and cardiovascular mortality in Norwegian kidney donors compared to the background population. PMID- 26740669 TI - The 2016 database issue of Nucleic Acids Research and an updated molecular biology database collection. AB - The 2016 Database Issue of Nucleic Acids Research starts with overviews of the resources provided by three major bioinformatics centers, the U.S. National Center for Biotechnology Information (NCBI), the European Bioinformatics Institute (EMBL-EBI) and Swiss Institute for Bioinformatics (SIB). Also included are descriptions of 62 new databases and updates on 95 databases that have been previously featured in NAR plus 17 previously described elsewhere. A number of papers in this issue deal with resources on nucleic acids, including various kinds of non-coding RNAs and their interactions, molecular dynamics simulations of nucleic acid structure, and two databases of super-enhancers. The protein database section features important updates on the EBI's Pfam, PDBe and PRIDE databases, as well as a variety of resources on pathways, metabolomics and metabolic modeling. This issue also includes updates on popular metagenomics resources, such as MG-RAST, EBI Metagenomics, and probeBASE, as well as a newly compiled Human Pan-Microbe Communities database. A significant fraction of the new and updated databases are dedicated to the genetic basis of disease, primarily cancer, and various aspects of drug research, including resources for patented drugs, their side effects, withdrawn drugs, and potential drug targets. A further six papers present updated databases of various antimicrobial and anticancer peptides. The entire Database Issue is freely available online on the Nucleic Acids Research website (http://nar.oxfordjournals.org/). The NAR online Molecular Biology Database Collection, http://www.oxfordjournals.org/nar/database/c/, has been updated with the addition of 88 new resources and removal of 23 obsolete websites, which brought the current listing to 1685 databases. PMID- 26740672 TI - Cardiorespiratory fitness and cognition in the elderly: Can you outrun cognitive impairment? PMID- 26740673 TI - Bevacizumab in late-onset radiation-induced myelopathy. AB - OBJECTIVE: To investigate the efficacy of bevacizumab for treatment of late radiation-induced myelopathy. METHODS: We studied all patients diagnosed with radiation-induced myelopathy presenting to 2 neuro-oncology centers between 2008 and 2012. All patients were treated with bevacizumab, after no clinical or radiologic improvement was achieved with conventional (in particular steroid) treatment. RESULT: This was a retrospective case study of 4 patients (2 women) with late-onset radiation-induced myelopathy who were each treated with 4 cycles of bevacizumab. The median delay from radiotherapy to myelopathy was 19 months (range 14-22 months). Initial treatment with steroids was unsuccessful in all 4 patients. Bevacizumab was introduced after a median of 4.8 months (range 4-5 months) from the onset of the neurologic symptoms. We observed stabilization of clinical outcome in 3 patients. Radiologic findings improved in all 4 patients. CONCLUSION: The use of bevacizumab resulted in radiologic improvement, but had only a modest effect on clinical outcome. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with late radiation-induced myelopathy unresponsive to steroids, bevacizumab improves radiologic but not clinical outcomes. PMID- 26740674 TI - Fitness and cognition in the elderly: The Austrian Stroke Prevention Study. AB - OBJECTIVE: To investigate whether greater cardiorespiratory fitness is associated with better global and domain-specific cognitive function. METHODS: We investigated 877 participants (aged 65 +/- 7 years, 55% women) of the Austrian Stroke Prevention Study. For cardiorespiratory fitness, the maximum oxygen consumption (Vo2max) was calculated based on weight and maximum and resting heart rate on a treadmill test (mL.kg(-1).min(-1)). A test battery assessing memory (Baumler's Lern-und Gedachtnistest), executive function (Wisconsin Card Sorting Test, Trail Making Test-Part B, Digit Span Backward, Alters Konzentrationstest, a computerized complex reaction time task) and motor skills (Purdue Pegboard Test) was administered. Summary measures for cognitive domains and for global cognition were calculated. White matter lesions, lacunes, and brain atrophy were assessed using MRI. RESULTS: Higher Vo2max was associated with better global (B = 0.024; p = 0.000) and domain-specific cognitive function (memory B = 0.026, p = 0.000; executive function B = 0.009, p = 0.003; motor skills B = 0.012, p = 0.018) after adjustment for age, sex, education years, and Ca(2+) channel antagonists or beta blockers. White matter lesions, lacunes, or brain atrophy did not mediate the effect (p > 0.05 for all mediators). The interactions of Vo2max with age, overweight, and APOE epsilon4 on cognition were not statistically significant (p > 0.05 for all interaction terms) with the exception of a modulating effect of body mass index on Vo2max in the memory domain. CONCLUSIONS: Higher Vo2max is associated with better global cognitive function and with better performance in the cognitive domains of memory, executive function, and motor skills in the middle-aged and elderly. The association is not mediated by the presence of white matter lesions, lacunes, and brain atrophy. PMID- 26740676 TI - The cerebellar channelopathy of multiple sclerosis. PMID- 26740675 TI - Channelopathy-related SCN10A gene variants predict cerebellar dysfunction in multiple sclerosis. AB - OBJECTIVE: To determine the motor-behavioral and neural correlates of putative functional common variants in the sodium-channel NaV1.8 encoding gene (SCN10A) in vivo in patients with multiple sclerosis (MS). METHODS: We recruited 161 patients with relapsing-onset MS and 94 demographically comparable healthy participants. All patients with MS underwent structural MRI and clinical examinations (Expanded Disability Status Scale [EDSS] and Multiple Sclerosis Functional Composite [MSFC]). Whole-brain voxel-wise and cerebellar volumetry were performed to assess differences in regional brain volumes between genotype groups. Resting-state fMRI was acquired from 62 patients with MS to evaluate differences in cerebellar functional connectivity. All participants were genotyped for 4 potentially functional SCN10A polymorphisms. RESULTS: Two SCN10A polymorphisms in high linkage disequilibrium (r(2) = 0.95) showed significant association with MSFC performance in patients with MS (rs6795970: p = 6.2 * 10(-4); rs6801957: p = 0.0025). Patients with MS with rs6795970(AA) genotype performed significantly worse than rs6795970(G) carriers in MSFC (p = 1.8 * 10(-4)) and all of its subscores. This association was independent of EDSS and cerebellar atrophy. Although the genotype groups showed no difference in regional brain volumes, rs6795970(AA) carriers demonstrated significantly diminished cerebellar functional connectivity with the thalami and midbrain. No significant SCN10A genotype effect was observed on MSFC performance in healthy participants. CONCLUSIONS: Our data suggest that SCN10A variation substantially influences functional status, including prominent effects on motor coordination in patients with MS. These findings were supported by the effects of this variant on a neural system important for motor coordination, namely cerebello-thalamic circuitry. Overall, our findings add to the emerging evidence that suggests that sodium channel NaV1.8 could serve as a target for future drug-based interventions to treat cerebellar dysfunction in MS. PMID- 26740677 TI - Incidence, short-term outcome, and spatial distribution of stroke patients in Ludhiana, India. AB - OBJECTIVE: To estimate the incidence, short-term outcome, and spatial distribution of stroke patients and to evaluate the completeness of case ascertainment in Ludhiana. METHODS: This population-based prospective cohort study was conducted in Ludhiana, Punjab, Northwest India. All first-ever stroke patients (>=18 years) were included between March 2010 and March 2013 using WHO Stepwise Approach Surveillance methodology from the city. Stroke patient data were obtained from hospitals, scan centers, and general practitioners, and details of deaths from the Municipal Corporation. RESULTS: Out of 7,199 stroke patients recruited, 3,441 were included in final analysis. The mean age was 59 +/ 15 years. The annual incidence rate was 140/100,000 (95% confidence interval [CI] 133-147) and age-adjusted incidence rate was 130/100,000 (95% CI 123-137). The annual incidence rate for stroke in the young (18-49 years) was 46/100,000 (95% CI 41-51). The case fatality at 28 days was 22%. Patients above 60 years of age (p = 0.03) and patients who were managed in public hospitals had poor survival (p = 0.01). Hot spots for cumulative incidence were seen in central and southern parts of the city, and hot spots for poor outcome were seen in the outskirts of the city. CONCLUSIONS: The incidence rates are similar to other studies from India. Stroke patient survival is poor in public hospitals. The finding of spatial analysis is of public health significance for stroke prevention and strengthening of stroke services. PMID- 26740679 TI - Natalizumab-related PML 2 weeks after negative anti-JCV antibody assay. PMID- 26740678 TI - OPTN 691_692insAG is a founder mutation causing recessive ALS and increased risk in heterozygotes. AB - OBJECTIVE: To detect genetic variants underlying familial and sporadic amyotrophic lateral sclerosis (ALS). METHODS: We analyzed 2 founder Jewish populations of Moroccan and Ashkenazi origins and ethnic matched controls. Exome sequencing of 2 sisters with ALS from Morocco was followed by genotyping the identified causative null mutation in 379 unrelated patients with ALS and 1,000 controls. The shared risk haplotype was characterized using whole-genome single nucleotide polymorphism array. RESULTS: We identified 5 unrelated patients with ALS homozygous for the null 691_692insAG mutation in the optineurin gene (OPTN), accounting for 5.8% of ALS of Moroccan origin and 0.3% of Ashkenazi. We also identified a high frequency of heterozygous carriers among patients with ALS, 8.7% and 2.9%, respectively, compared to 0.75% and 1.0% in controls. The risk of carriers for ALS was significantly increased, with odds ratio of 13.46 and 2.97 in Moroccan and Ashkenazi Jews, respectively. We determined that 691_692insAG is a founder mutation in the tested populations with a minimal risk haplotype of 58.5 Kb, encompassing the entire OPTN gene. CONCLUSIONS: Our data show that OPTN 691_692insAG mutation is a founder mutation in Moroccan and Ashkenazi Jews. This mutation causes autosomal recessive ALS and significantly increases the risk to develop the disease in heterozygous carriers, suggesting both a recessive mode of inheritance and a dominant with incomplete penetrance. These data emphasize the important role of OPTN in ALS pathogenesis, and demonstrate the complex genetics of ALS, as the same mutation leads to different phenotypes and appears in 2 patterns of inheritance. PMID- 26740680 TI - Two- and 6-minute walk tests assess walking capability equally in neuromuscular diseases. AB - OBJECTIVE: This methodologic study investigates if the 2-minute walk test (2MWT) can be a valid alternative to the 6-minute walk test (6MWT) to describe walking capability in patients with neuromuscular diseases. METHODS: Patients (n = 115) with different neuromuscular diseases were invited to participate on 2 test days, each consisting of 1 2MWT and 1 6MWT separated by a minimum 30-minute period of rest. The order of the walk tests was randomly assigned via sealed envelopes. A group of 38 healthy controls completed 1 6MWT. RESULTS: The mean walking distance for the 2MWT was 142.8 meters and for the 6MWT 405.3 meters. The distance walked in the 2MWT was highly correlated to the distance walked in the 6MWT (r = 0.99, p < 0.001). There was a significant decrease in walking speed from the first to last minute in the 6MWT, both among patients and healthy controls, which was not evident in the 2MWT. Results were consistent across diagnoses and levels of disease severity. CONCLUSION: The 2MWT is a potential alternative to the 6MWT to describe walking capability among patients with neuromuscular diseases during clinical trials. PMID- 26740681 TI - How temporal evolution of intracranial collaterals in acute stroke affects clinical outcomes. AB - OBJECTIVE: We compared intracranial collaterals on pretreatment and day 2 brain CT angiograms (CTA) to assess their evolution and relationship with functional outcomes in acute ischemic stroke (AIS) patients treated with IV tissue plasminogen activator (tPA). METHODS: Consecutive AIS patients who underwent pretreatment and day 2 CTA and received IV tPA during 2010-2013 were included. Collaterals were evaluated by 2 independent neuroradiologists using 3 predefined criteria: the Miteff system, the Maas system, and 20-point collateral scale by the Alberta Stroke Program Early CT Score methodology. We stratified our cohort by baseline pre-tPA state of their collaterals and by recanalization status of the primary vessel for analysis. Good outcomes at 3 months were defined by a modified Rankin Scale score of 0-1. RESULTS: This study included 209 patients. Delayed collateral recruitment by any grading system was not associated with good outcomes. All 3 scoring systems showed that collateral recruitment on the follow up CTA from a baseline poor collateral state was significantly associated with poor outcome and increased bleeding risk. When the primary vessel remained persistently occluded, collateral recruitment was significantly associated with worse outcomes. Interestingly, collateral recruitment was significantly associated with increased mortality in 2 of the 3 grading systems. CONCLUSIONS: Not all collateral recruitment is beneficial; delayed collateral recruitment may be different from early recruitment and can result in worse outcomes and higher mortality. Prethrombolysis collateral status and recanalization are determinants of how intracranial collateral evolution affects functional outcomes. PMID- 26740682 TI - Lipid-Based Nutrient Supplements Providing Approximately the Recommended Daily Intake of Vitamin A Do Not Increase Breast Milk Retinol Concentrations among Ghanaian Women. AB - BACKGROUND: Vitamin A deficiency remains a global public health problem. Daily supplementation with a lipid-based nutrient supplement (LNS) has potential for increasing milk vitamin A concentrations. OBJECTIVE: The objective of this study was to determine whether daily supplementation with approximately the recommended daily intake of vitamin A in an LNS or a multiple-micronutrient supplement (MMN) during pregnancy and the first 6 mo postpartum has an effect on breast milk retinol concentration at 6 mo postpartum. METHODS: Women <=20 wk pregnant (n = 1320) were randomly assigned to receive either the MMN providing 18 micronutrients, including 800 MUg retinol equivalents of vitamin A, or the LNS with the same nutrients as the MMN group, plus 4 minerals and macronutrients, until 6 mo postpartum; a control group received iron and folic acid during pregnancy and a placebo (calcium tablet) during the first 6 mo postpartum. Breast milk samples collected at 6 mo postpartum were analyzed for retinol and fat concentrations by HPLC and creamatocrit, respectively, in a subsample of 756 women. RESULTS: The breast milk retinol concentration was (mean +/- SD) 56.3 +/- 2.1 nmol/g fat, with no significant differences between groups [iron and folic acid (n = 243): 59.1 +/- 2.8; MMN (n = 260): 55.4 +/- 2.5; LNS (n = 253): 54.7 +/ 2.5 nmol/g fat; P = 0.45], regardless of whether the woman had or had not received a high-dose vitamin A supplement (200,000 IU) soon after childbirth. Around 17% of participants had low milk retinol (<=28 nmol/g fat). We estimated that 41% of infants were potentially receiving vitamin A at amounts above the Tolerable Upper Intake Level (600 MUg retinol activity equivalents/d), with no group differences in percentages with low or high milk retinol concentration. CONCLUSION: Daily consumption of approximately the recommended intake of vitamin A did not increase breast milk retinol concentrations in this sample of Ghanaian women. This trial was registered at clinicaltrials.gov as NCT00970866. PMID- 26740683 TI - Altered Appetite-Mediating Hormone Concentrations Precede Compensatory Overeating After Severe, Short-Term Energy Deprivation in Healthy Adults. AB - BACKGROUND: Adaptive responses of appetite-mediating hormones to negative energy balance are thought to contribute to a counterregulatory response that drives weight regain, but they have not been studied while controlling for reduced diet volume. OBJECTIVE: In this secondary analysis, we aimed to determine the effects of short-term, severe energy deprivation (ED) on appetite and appetite-mediating hormone concentrations. METHODS: Twenty-one adults with a mean +/- SD age of 21 +/- 3 y and body mass index of 25 +/- 3 kg/m(2) consumed isovolumetric diets provided over separate 48-h periods while increasing habitual energy expenditure by 1683 +/- 329 kcal/d through light- and moderate-intensity exercise. Energy intake was matched to energy expenditure to maintain energy balance (EB) (-44 +/- 92 kcal/d) or was <10% of energy expenditure to generate a -3696 +/- 742-kcal/d energy deficit. Postprandial appetite, glucose, insulin, acyl ghrelin, peptide YY, pancreatic polypeptide (PP), and glucagon-like peptide-1 (GLP-1) responses and ad libitum energy intake were measured as secondary outcomes after both experimental periods. RESULTS: Fasting insulin (-56% +/- 42%) and acyl ghrelin ( 60% +/- 17%) concentrations decreased during ED but not during EB (condition-by time interaction; P-interaction <= 0.01), whereas fasting leptin concentrations decreased more during ED compared with during EB (-47% +/- 27% compared with -20% +/- 27%; P-interaction = 0.05). Postprandial insulin (57% +/- 63%; P < 0.001), GLP-1 (14% +/- 28%; P = 0.04), and PP (54% +/- 52%; P < 0.001) areas under the curve (AUCs) were higher, whereas the acyl ghrelin AUC was lower (-56% +/- 13%; P < 0.001) after ED compared with after EB. After ED, self-rated appetite was greater, and ad libitum energy intake was 811 kcal/36 h (95% CI: 184, 1439 kcal/36 h) higher relative to after EB (P = 0.01). CONCLUSIONS: Short-term, severe ED suppressed acyl ghrelin concentrations and increased postprandial anorexigenic hormone concentrations. These effects preceded compensatory overeating, suggesting that in adults without obesity, altered sensitivity to appetite-mediating hormones may contribute to an adaptive counterregulatory response during the initial stages of negative EB. This trial was registered at clinicaltrials.gov as NCT01603550. PMID- 26740684 TI - Lipid-Based Nutrient Supplements Increase Energy and Macronutrient Intakes from Complementary Food among Malawian Infants. AB - BACKGROUND: Low intakes of good-quality complementary foods (CFs) contribute to undernutrition and consequently negatively affect health, growth, and development. Lipid-based nutrient supplements (LNSs) are designed to ensure dietary adequacy in micronutrients and essential fatty acids and to provide some energy and high-quality protein. In populations in which acute energy deficiency is rare, the dose-dependent effect of LNSs on CF intakes is unknown. OBJECTIVE: The objective of this study was to evaluate the difference in energy and macronutrient intakes from CF between a control (no supplement) group and 3 groups that received 10, 20, or 40 g LNS/d. METHODS: We collected repeated interactive 24-h dietary recalls from caregivers of rural Malawian 9- to 10-mo old infants (n = 748) to estimate dietary intakes (LNS and all non-breast-milk foods) of energy and macronutrients and their dietary patterns. All infants were participating in a 12-mo randomized controlled trial to investigate the efficacy of various doses of LNS for preventing undernutrition. RESULTS: Dietary energy intakes were significantly higher among infants in the LNS intervention groups than in the control group (396, 406, and 388 kcal/d in the 10-, 20-, and 40-g LNS/d groups, respectively, compared with 345 kcal/d; each pairwise P < 0.05), but no significant differences were found in energy intakes between groups who were administered the different LNS doses (10 g LNS/d compared with 20 g LNS/d: P = 0.72; 10 g LNS/d compared with 40 g LNS/d: P >= 0.67; 20 g LNS/d compared with 40 g LNS/d: P = 0.94). Intakes of protein and fat were significantly higher in the LNS intervention groups than in the control group. No significant intergroup differences were found in median intakes of energy from non-LNS CFs (357, 347, and 296 kcal/d in the 10-, 20-, and 40-g LNS/d groups, respectively, compared with 345 kcal/d in the control group; P = 0.11). CONCLUSION: LNSs in doses of 10 40 g/d increase intakes of energy and macronutrients among 9- to 10-mo-old Malawian infants, without displacing locally available CFs. This trial was registered at clinicaltrials.gov as NCT00945698. PMID- 26740687 TI - Work as treatment? The effectiveness of re-employment programmes for unemployed persons with severe mental health problems on health and quality of life: a systematic review and meta-analysis. AB - Given the importance of unemployment in health inequalities, re-employment of unemployed persons into paid employment may be a powerful intervention to increase population health. It is suggested that integrated programmes of vocational reintegration with health promotion may improve the likelihood of entering paid employment of long-term unemployed persons with severe mental health problems. However, the current evidence regarding whether entering paid employment of this population will contribute to a reduction in health problems remains unambiguous. This systematic review and meta-analysis aimed to assess the effects of re-employment programmes with regard to health and quality of life. Three electronic databases were searched (up to March 2015). Two reviewers independently selected articles and assessed the risk of bias on prespecified criteria. Measures of effects were pooled and random effect meta-analysis of randomised controlled trials was conducted, where possible. Sixteen studies were included. Nine studies described functioning as an outcome measure. Five studies with six comparisons provided enough information to calculate a pooled effect size of -0.01 (95% CI -0.13 to 0.11). Fifteen studies presented mental health as an outcome measure of which six with comparable psychiatric symptoms resulted in a pooled effect size of 0.20 (95% CI -0.23 to 0.62). Thirteen studies described quality of life as an outcome measure. Seven of these studies, describing eight comparisons, provided enough information to calculate a pooled effect size of 0.28 (95% CI 0.04 to 0.52). Re-employment programmes have a modest positive effect on the quality of life. No evidence was found for any effect of these re employment programmes on functioning and mental health. PMID- 26740686 TI - Stability of symptom patterns in Australian Gulf War veterans: 10-year longitudinal study. AB - OBJECTIVES: Previously we established that symptoms reported by 1990-1991 Gulf War veterans were correlated and exhibited a pattern with 3 factors (psychophysiological distress, somatic distress and arthroneuromuscular distress), and this pattern was similar to that observed in a military comparison group. In this follow-up study, we examined whether the patterns of symptomatology have changed over time. METHODS: Using data on 56 symptoms that was collected in 2000-2003 (wave 1) and 2011-2012 (wave 2) from an Australian cohort of Gulf War veterans (veterans) and a military comparison group, exploratory factor analysis was conducted and Tucker's Congruence Coefficient (TCC) was used to determine factor structure similarity across study groups and waves. RESULTS: The results showed that the 3 factors observed at wave 1 were still present at wave 2, and factor structures across study groups and study waves were fairly similar, with TCC ranging 0.86-0.92. Veterans consistently reported more symptoms across all 3 factors. Veterans' symptomatology specific to psychophysiological distress increased between waves 1 and 2 (ratio of means 1.15; 95% CI 1.07 to 1.25) but psychophysiological distress symptomatology was constant in the comparison group (ratio of means 0.97; 95% CI 0.89 to 1.06). Somatic and arthroneuromuscular distress symptomatology significantly increased over time for both study groups, although at a similar rate. CONCLUSIONS: While the symptom groupings (measured by the 3 factors) remained unchanged at 10 years of follow-up, and remained comparable between Gulf War and comparison group, symptomatology continued to be elevated in Gulf War veterans than in the comparison group, and was most evident for psychophysiological distress. PMID- 26740688 TI - Physical workload and risk of long-term sickness absence in the general working population and among blue-collar workers: prospective cohort study with register follow-up. AB - OBJECTIVE: To determine the prospective association between physical workload--in terms of specific physical exposures and the number of exposures--and long-term sickness absence (LTSA). METHODS: Using cox-regression analyses, we estimated the risk of register-based incident LTSA (at least 3 consecutive weeks) from self reported exposure to different physical workloads among 11,908 wage earners from the general working population (Danish Work Environment Cohort Study year 2000 and 2005). RESULTS: The incidence of LTSA was 8.9% during two-year follow-up. Spending 25% or more of the total work time with a bent or twisted back (HR 1.59 (95% CI 1.39 to 1.83)), arms above shoulder height (HR 1.35 (95% CI 1.14 to 1.59)), squatting or kneeling (HR 1.30 (95% CI 1.09 to 1.54)), pushing/pulling or lifting/carrying (HR 1.40 (95% CI 1.22 to 1.62)) and standing in the same place for 50% or more of total work time (HR 1.19 (95% CI 1.00 to 1.42), were risk factors for LTSA when adjusted for baseline age, gender, psychosocial work environment, lifestyle, musculoskeletal and mental disorders, and socioeconomic status. HR increased from 1.25 (95% CI 1.04 to 1.51) for one to 1.94 (95% CI 1.56 to 2.41) for four combined physical workloads. Results largely remained stable in subgroup analyses including only blue-collar workers (n=5055). Population attributable risks for LTSA from one or more physical workloads were 26% and 40% in the general working population and among blue-collar workers, respectively. CONCLUSIONS: Several of the investigated types of physical workload were risk factors for LTSA when exceeding 25% of the work time. A higher number of combined physical workloads was associated with progressively increased risk. Our study underscores the importance of physical workload as risk factors for LTSA in the general working population as well as among blue-collar workers. PMID- 26740685 TI - Dietary Patterns High in Red Meat, Potato, Gravy, and Butter Are Associated with Poor Cognitive Functioning but Not with Rate of Cognitive Decline in Very Old Adults. AB - BACKGROUND: Healthy dietary patterns (DPs) have been linked to better cognition and reduced risk of dementia in older adults, but their role in cognitive functioning and decline in the very old (aged >=85 y) is unknown. OBJECTIVE: We investigated the association between previously established DPs from the Newcastle 85+ Study and global and attention-specific cognition over 5 y. METHODS: We followed up with 302 men and 489 women (1921 birth cohort from Northeast United Kingdom) for change in global cognition [measured by the Standardized Mini-Mental State Examination (SMMSE)] over 5 y and attention (assessed by the cognitive drug research attention battery) over 3 y. We used 2 step clustering to derive DPs and mixed models to determine the relation between DPs and cognition in the presence of the dementia susceptibility gene. RESULTS: Previously, we characterized 3 DPs that differed in intake of red meat, potato, gravy, and butter and varied with key health measures. When compared with participants in DP1 (high red meat) and DP3 (high butter), participants in DP2 (low meat) had higher SMMSE scores at baseline (P < 0.001) and follow-ups, and better initial attention (P < 0.05). Membership in DP1 and DP3 was associated with overall worse SMMSE scores (beta = 0.09, P = 0.01 and beta = 0.08, P = 0.02, respectively) than membership in DP2 after adjustment for sociodemographic factors, lifestyle, multimorbidity, and body mass index (BMI). Additional adjustment for apolipoprotein (apoE) epsilon4 genotype attenuated the association to nonsignificant in women but not in men in DP1 (beta = 0.13, P = 0.02). Participants in DP1 and DP3 also had overall worse concentration (beta = 0.04, P = 0.002 and beta = 0.028, P = 0.03, respectively) and focused attention (beta = 0.02, P = 0.01 and beta = 0.02, P = 0.03, respectively), irrespective of apoE epsilon4 genotype, but similar rate of decline in all cognitive measures over time. CONCLUSION: DPs high in red meat, potato, gravy (DP1), or butter (DP3) were associated with poor cognition but not with the rate of cognitive decline in very old adults. PMID- 26740689 TI - Persistent musculoskeletal pain and productive employment; a systematic review of interventions. AB - A systematic analysis of the literature was undertaken to determine which characteristics of workplace interventions are most effective in assisting people with persistent musculoskeletal pain (PMP) to remain productively employed. Databases of Medline, PsychINFO, CINAHL and Embase were searched using MeSH and other relevant terms. Studies that reported on interventions at, or involving, the workplace were included. Interventions were considered as either focused on the individual or multilevel. Outcome measures assessed included: job loss, productivity, sick leave, pain and cost benefit. A quality assessment was undertaken using GRADE criteria with development of impact statements to synthesise the results. Eighteen relevant articles (14 studies) were identified for inclusion in the review. No high-level evidence for workplace interventions to assist people with PMP were identified. Low numbers of participants and limited studies resulted in downgrading of evidence. However, individually focused interventions will probably reduce job loss and sick leave, but are unlikely to reduce pain. Multilevel focused interventions will probably result in decreased sick leave and provide some cost benefit. The evidence on productivity was limited and of poor quality. Further research is required because sustainable employment for individuals with PMP is important and understanding what works is necessary to ensure effective workplace interventions are developed. PMID- 26740690 TI - Diastereocontrolled Synthesis of Carbon Glycosides of N-Acetylneuraminic Acid via Glycosyl Samarium(III) Intermediates. PMID- 26740691 TI - Diagnostic Ophthalmology. PMID- 26740692 TI - Antibiotic use: Let's be ready for the change! PMID- 26740693 TI - An ethicist's commentary on treatment of fish. PMID- 26740694 TI - Canine parvovirus type 2b is the most prevalent genomic variant strain found in parvovirus antigen positive diarrheic dog feces samples across Canada. PMID- 26740695 TI - Together we build: The OVC Student Wives' Auxiliary. PMID- 26740696 TI - An observational study of mortality on bison farms in Saskatchewan with special emphasis on malignant catarrhal fever. AB - In December 2011, the Malignant Catarrhal Fever (MCF) Task Force in Saskatchewan recommended that research be conducted on the relationship between the proximity of bison and sheep under typical commercial production settings and bison deaths due to MCF. The objective of this study was to evaluate all causes of death in bison herds and compare the incidence of MCF in herds at varying distances of exposure from sheep operations. Necropsies were completed on 76 of 133 bison reported to have died during the 18-month study period. A total of 7 MCF deaths was reported from 2 large herds within 1.0 km of sheep operations. Although there was a greater risk of MCF deaths in bison herds within 1.0 km of sheep operations than in herds more than 1.0 km away, the overall incidence of MCF deaths within the study period was very low. Most deaths were attributed to non-infectious causes, including copper deficiency. PMID- 26740697 TI - Factors associated with development of Canine Infectious Respiratory Disease Complex (CIRDC) in dogs in 5 Canadian small animal clinics. AB - This study investigated the association between presence of respiratory pathogens and development of Canine Infectious Respiratory Disease Complex (CIRDC) in dogs in 5 Canadian small animal clinics. In total, 86 dogs were tested using a commercial PCR respiratory panel; 64 dogs were considered as cases and 22 were control dogs matched by veterinary clinic. No control animals (0/22) were positive for canine parainfluenza virus (CPIV), whereas 27/64 (42%) CIRDC cases were positive. Furthermore, 81% of case dogs tested positive for Mycoplasma cynos, compared with 73% of control dogs. Canine respiratory corona virus (CRCoV) was detected in no control dogs compared with 9.4% of clinical dogs. No animals were positive for any influenza virus type A present in the diagnostic panel. Presence of CPIV was associated (P < 0.01) with the occurrence of CIRDC after adjustment for demographic factors and presence of CRCoV (P = 0.09). PMID- 26740698 TI - Characterizing 1341 cases of veterinary toxicoses confirmed in western Canada: A 16-year retrospective study. AB - Veterinary toxicoses are frequently observed in western Canada. This study reports the frequency and characteristics of intoxications in animals reported between January 1, 1998 and December 31, 2013. Information was obtained from toxicological case records from the Prairie Diagnostic Services, Saskatoon, Saskatchewan. There were 1341 animal poisonings with 19 compounds over the investigational period. Lead poisoning was the most common toxicity (43.7%). Poisoning with acetylcholinesterase inhibitors and strychnine were also common events. Poisonings were most common in 2001, 2009, and 2012. Intoxications occurred most frequently during the months of May through July. Cattle were the most commonly poisoned species (n = 696), followed by dogs and eagles. PMID- 26740700 TI - Erratum. PMID- 26740701 TI - Antimicrobial susceptibility of Staphylococcus pseudintermedius colonizing healthy dogs in Saskatoon, Canada. AB - This study reports antimicrobial susceptibility of Staphylococcus pseudintermedius carried by healthy dogs in Saskatoon, and describes changes in antimicrobial resistance since a 2008 study. One hundred healthy dogs presenting to the wellness service at the Western College of Veterinary Medicine were screened for S. pseudintermedius by culturing rectal and pharyngeal swabs. Staphylococcus pseudintermedius was identified biochemically and antimicrobial minimum inhibitory concentrations were determined by broth microdilution. Methicillin resistance was confirmed by polymerase chain reaction (PCR) and sequencing of the mecA gene. Of 221 S. pseudintermedius isolates from 78 dogs, 7 were methicillin resistant. No resistance to the fluoroquinolones, nitrofurantoin, tigecycline, vancomycin, quinupristin-dalfopristin, linezolid, or daptomycin was identified. Of the 78 positive dogs, isolates resistant to penicillin were found in 78%, to ampicillin in 61% and to tetracycline in 26%; resistance to oxacillin, erythromycin, clindamycin, trimethoprim + sulfamethoxazole, chloramphenicol, and gentamicin was found in < 10% of dogs. Compared to the 2008 study, the frequency of resistance to all drugs increased, and the frequency of colonization with pan-susceptible isolates decreased from 46% to 30%. PMID- 26740699 TI - Evaluation of surgical outcome, complications, and mortality in dogs undergoing preoperative computed tomography angiography for diagnosis of an extrahepatic portosystemic shunt: 124 cases (2005-2014). AB - This study evaluated the safety of preoperative computed tomography angiography (CTA) and its effect on surgical time and clinical outcomes in dogs that underwent surgical correction of a single congenital extrahepatic portosystemic shunt (CEPSS). Patient data were retrospectively collected from medical records and owner communications for 124 dogs with single CEPSS, undergoing preoperative CTA (n = 43) or not (n = 81) which were surgically treated from 2005 to 2014. The frequency of major postoperative complications was 4.7% and 9.9% for the CTA and no CTA groups, respectively (P = 0.49). Mean +/- standard deviation (SD) surgical time for the preoperative CTA group was 84 +/- 40 min and 81 +/- 31 min for the no CTA group (P = 0.28). We conclude that anesthetized preoperative CTA appears to be a safe method for diagnosis and surgical planning in dogs with single CEPSS, and does not appear to affect surgical procedure time, complication rate, or clinical outcome. PMID- 26740702 TI - The use of dexmedetomidine continuous rate infusion for horses undergoing transvenous electrical cardioversion--A case series. AB - Five horses were presented for treatment of atrial fibrillation by transvenous electrical cardioversion (TVEC). A dexmedetomidine infusion was administered for sedation during positioning of the cardioversion catheters, and continued during general anesthesia. Shocks were applied until return to sinus rhythm. Dexmedetomidine infusion provided excellent conditions for TVEC catheter placement and procedure. PMID- 26740703 TI - Aberrant heartworm migration to the abdominal aorta and systemic arteriolitis in a dog presenting with vomiting and hemorrhagic diarrhea. AB - A 2-year-old Dachshund was presented for vomiting and diarrhea. Abdominal ultrasound revealed Dirofilaria immitis in the abdominal aorta and an avascular segment of small intestine. The dog was euthanized. Necropsy revealed D. immitis in the abdominal aorta and widespread necrotizing arteriolitis. This is a unique presentation of aberrant migration of D. immitis. PMID- 26740704 TI - Poorly differentiated cutaneous carcinoma of non-sebaceous origin in a 3-year-old Mongolian gerbil (Meriones unguiculatus). AB - A 3-year-old female gerbil developed a non-healing skin wound due to a malignant neoplasm. Histology, immunohistochemistry (cytokeratin 19 positive; vimentin, estrogen, and progesterone receptor negative), and electron microscopy (no desmosomes or melanosomes) revealed an undifferentiated carcinoma with pulmonary metastasis. Unlike in previous reports, it did not arise from the abdominal pad's sebaceous gland. PMID- 26740706 TI - Minimizing the cost of your veterinary education: Saving through expedited student debt repayment. PMID- 26740705 TI - Outbreak investigation of porcine epidemic diarrhea in swine in Ontario. AB - Porcine epidemic diarrhea virus was first diagnosed in Ontario in January of 2014. An outbreak investigation was conducted and it was hypothesized that feed containing spray-dried porcine plasma contaminated with the virus was a risk factor in the introduction and spread of the disease in Ontario. PMID- 26740726 TI - Theoretical foundation, methods, and criteria for calibrating human vibration models using frequency response functions. AB - While simulations of the measured biodynamic responses of the whole human body or body segments to vibration are conventionally interpreted as summaries of biodynamic measurements, and the resulting models are considered quantitative, this study looked at these simulations from a different angle: model calibration. The specific aims of this study are to review and clarify the theoretical basis for model calibration, to help formulate the criteria for calibration validation, and to help appropriately select and apply calibration methods. In addition to established vibration theory, a novel theorem of mechanical vibration is also used to enhance the understanding of the mathematical and physical principles of the calibration. Based on this enhanced understanding, a set of criteria was proposed and used to systematically examine the calibration methods. Besides theoretical analyses, a numerical testing method is also used in the examination. This study identified the basic requirements for each calibration method to obtain a unique calibration solution. This study also confirmed that the solution becomes more robust if more than sufficient calibration references are provided. Practically, however, as more references are used, more inconsistencies can arise among the measured data for representing the biodynamic properties. To help account for the relative reliabilities of the references, a baseline weighting scheme is proposed. The analyses suggest that the best choice of calibration method depends on the modeling purpose, the model structure, and the availability and reliability of representative reference data. PMID- 26740727 TI - HOW DOES PEER PRESSURE AFFECT EDUCATIONAL INVESTMENTS? AB - When effort is observable to peers, students may try to avoid social penalties by conforming to prevailing norms. To test this hypothesis, we first consider a natural experiment that introduced a performance leaderboard into computer-based high school courses. The result was a 24 percent performance decline. The decline appears to be driven by a desire to avoid the leaderboard; top performing students prior to the change, those most at risk of appearing on the leaderboard, had a 40 percent performance decline, while poor performing students improved slightly. We next consider a field experiment that offered students complimentary access to an online SAT preparatory course. Sign-up forms differed randomly across students only in whether they said the decision would be kept private from classmates. In nonhonors classes, sign-up was 11 percentage points lower when decisions were public rather than private. Honors class sign-up was unaffected. For students taking honors and nonhonors classes, the response depended on which peers they were with at the time of the offer, and thus to whom their decision would be revealed. When offered the course in a nonhonors class (where peer sign up rates are low), they were 15 percentage points less likely to sign up if the decision was public. But when offered the course in an honors class (where peer sign-up rates are high), they were 8 percentage points more likely to sign up if the decision was public. Thus, students are highly responsive to their peers are the prevailing norm when they make decisions. PMID- 26740707 TI - Positive Action for Today's Health (PATH): Sex differences in walking and perceptions of the physical and social environment. AB - Research indicates that people from low socioeconomic and ethnic minority backgrounds disproportionately fail to meet the weekly national recommendations for physical activity. Perceptions of environmental factors may be significant barriers to walking in communities experiencing high rates of crime and poverty and may impact women and men differently. The present study investigated sex differences in the impact of perceptions of the environment and overall neighborhood quality on walking in an underserved population. Participants were 195 African American women and 95 African American men. Baseline data indicated that women reported greater concerns about safety, poorer perceptions of aesthetics, and lower neighborhood satisfaction than men. Regression analyses showed that perceptions of access to places for walking significantly predicted walking for both women and men and that sex moderated the effect of neighborhood satisfaction. These results suggest that interventions focused on building accessibility to places for walking while also addressing social environmental concerns are needed in high crime communities. PMID- 26740728 TI - 'Lonesome Town'? Is Loneliness Associated with the Residential Environment, including Housing and Neighbourhood Factors? AB - This article considers whether feelings of loneliness are associated with aspects of the home and neighbourhood of residence. Multinominal logistic regression models were used to explore associations between residential environment and loneliness in 4,000 residents across deprived areas of Glasgow. People who rated their neighbourhood environment of higher quality, and who used more local amenities, were less likely to report loneliness. Respondents who knew more people within the local area were less likely to report loneliness. Those who reported more antisocial behaviour problems, who had a weak perception of collective efficacy, and who felt unsafe walking alone at night-time were more likely to report loneliness. Length of residence and dwelling type were not associated with reported loneliness. The findings indicate the potential importance of several dimensions of the neighbourhood physical, service and social environment, including aspects of both quality and trust, in protecting against or reducing loneliness in deprived areas. PMID- 26740729 TI - Varying kernel density estimation on R. AB - In this article a new nonparametric density estimator based on the sequence of asymmetric kernels is proposed. This method is natural when estimating an unknown density function of a positive random variable. The rates of Mean Squared Error, Mean Integrated Squared Error, and the L1-consistency are investigated. Simulation studies are conducted to compare a new estimator and its modified version with traditional kernel density construction. PMID- 26740730 TI - U.S. Correctional Officers Killed or Injured on the Job. PMID- 26740731 TI - Preventing domestic abuse for children and young people: A review of school-based interventions. AB - Schools provide the setting in which interventions aimed at preventing intimate partner violence and abuse (IPVA) are delivered to young people in the general population and a range of programmes have been designed and evaluated. To date, most rigorous studies have been undertaken in North America and the extent to which programmes are transferable to other settings and cultures is uncertain. This paper reports on a mixed methods review, aimed at informing UK practise and policy, which included a systematic review of the international literature, a review of the UK grey literature and consultation with young people as well as experts to address the question of what works for whom in what circumstances. The context in which an intervention was delivered was found to be crucial. Context included: the wider policy setting; the national or regional level, where the local culture shaped understandings of IPVA, and the readiness of an individual school. The programmes included in the systematic review provided stronger evidence for changing knowledge and attitudes than for behavioural change and those young people who were at higher risk at baseline may have exerted a strong influence on study outcomes. Shifting social norms in the peer group emerged as a key mechanism of change and the young people consulted emphasised the importance of authenticity which could be achieved through the use of drama and which required those delivering programmes to have relevant expertise. While the consultation identified increasing interest in targeting interventions on boys, there was an identified lack of materials designed for minority groups of young people, especially Lesbian, Gay, Bisexual and Transgender young people. Increased responsivity to the local context can be achieved by involving those who will deliver and receive these preventive programmes in their development. Schools need to be better prepared and supported in the task of delivering these interventions and this is particularly relevant for the management of disclosures of IPVA. Outcomes measured by evaluations should include those relevant to education. PMID- 26740732 TI - Structural Biology: A Century-long Journey into an Unseen World. AB - When the first atomic structures of salt crystals were determined by the Braggs in 1912-1913, the analytical power of X-ray crystallography was immediately evident. Within a few decades the technique was being applied to the more complex molecules of chemistry and biology and is rightly regarded as the foundation stone of structural biology, a field that emerged in the 1950s when X-ray diffraction analysis revealed the atomic architecture of DNA and protein molecules. Since then the toolbox of structural biology has been augmented by other physical techniques, including nuclear magnetic resonance spectroscopy, electron microscopy, and solution scattering of X-rays and neutrons. Together these have transformed our understanding of the molecular basis of life. Here I review the major and most recent developments in structural biology that have brought us to the threshold of a landscape of astonishing molecular complexity. PMID- 26740734 TI - Usefulness of Preoperative Assessment of Perigastric Vascular Anatomy by Dynamic Computed Tomography for Laparoscopic Gastrectomy. AB - BACKGROUND: Laparoscopic surgery requires a more detailed understanding of local anatomy than does conventional open surgery. The aim of this study was to examine the usefulness of dynamic computed tomography (D-CT) for identification of the location of the left gastric vein (LGV) and existence of the aberrant left hepatic artery (ALHA) compared with conventional enhanced computed tomography (E CT). METHODS: Sixty-eight patients underwent laparoscopic-assisted gastrectomy (LAG). E-CT and D-CT were performed in 32 and 36 patients, respectively, and three-dimensional computed tomographic angiography (3D-CTA) was performed in addition to D-CT. The location of the LGV and existence of the ALHA were confirmed during LAG, and these results were compared with those determined preoperatively by CT imaging. RESULTS: The location of the LGV as detected by preoperative E-CT and D-CT was consistent with that identified during LAG in 28 (87.5%) and 31 (88.9%) patients, respectively, with no statistical differences. The existence of the ALHA as detected by preoperative E-CT and D-CT was consistent with that identified during gastrectomy in 24 (75%) and 36 (100%) patients, respectively, with a statistical difference (P = 0.005). Furthermore, the type of ALHA could be identified in 10 of 12 patients (83.3%) by D-CT. CONCLUSION: D-CT can produce excellent images of the vascular supply, and thus undoubtedly contributes to the preoperative planning of LAG. Preoperative D-CT might be an informative tool with which to help overcome the disadvantages of LAG. PMID- 26740733 TI - Cytoplasmic Maspin Expression Correlates with Poor Prognosis of Patients with Adenocarcinoma of the Uterine Cervix. AB - BACKGROUND: Maspin is known to be a tumor suppressor protein and its prognostic significance in patients with several types of cancer has been reported. To date, however, no study has focused on the association between maspin expression and the prognosis of patients with adenocarcinoma of the uterine cervix. We explored the prognostic value of maspin expression with particular reference to its subcellular localization in patients with adenocarcinoma of the uterine cervix. METHODS: Paraffin-embedded tissue samples from 46 patients diagnosed as adenocarcinoma of the uterine cervix were immunohistochemically analyzed using an antibody for maspin. The patients were followed up for 3 to 165 months (median: 64.2 months) and the prognostic value was evaluated by the log-rank test and the Cox regression hazard model. RESULTS: A sample was considered maspin-positive if maspin was expressed in only the cytoplasm; 69.6% (32 cases) of the specimens were maspin-positive, and there was significant correlation between positivity and recurrence (P = 0.022). Maspin-positive patients had both shorter disease free survival and shorter overall survival by the log-rank test (P = 0.023, P = 0.043, respectively). By Cox's multivariate analysis, the International Federation of Obstetrics and Gynecology (FIGO) status was the only independent prognostic factor for disease free survival and overall survival in patients with adenocarcinoma of the uterine cervix. CONCLUSION: This is the first report to reveal an association between cytoplasmic maspin expression and the prognosis of patients with adenocarcinoma of the uterine cervix. Although further studies with a larger series of patients and a longer follow up period are necessary, the present results suggest that cytoplasmic maspin expression could be an indicator of unfavorable prognosis in patients with adenocarcinoma of the uterine cervix. PMID- 26740735 TI - Frequent Isolations of Influenza A Viruses (H1N1)pdm09 with Identical Hemagglutinin Sequences for More Than Three Months in Japan. AB - BACKGROUND: Although it has been suggested that antigenic drift does not occur in a single epidemic season in temperate countries, there is not enough evidence on the circulation period of influenza virus with identical nucleotide sequences. Therefore, strains of influenza virus were isolated sequentially during five consecutive epidemic seasons in Japan and their nucleotide sequences were determined. METHODS: Nasal swabs or aspirated nasal discharges were collected from influenza A virus antigen-positive individuals living in Tottori Prefecture, Japan for five consecutive winters starting in 2009-2010, and subjected to viral isolation, determination of hemagglutinin nucleotide sequence and phylogenic analyses. The nucleotide sequences were compared with each other and also with those of foreign strains in the International Nucleotide Sequence Database. RESULTS: Totally 288 A(H1N1)pdm09 strains were tested and those composed 38 clusters with identical ones displaying 100% nucleotide homology. One strain showed sequential infections more than three months without any detectable mutation, and a maximum interval of two detection timings of strains was 94 days. This implies that influenza viruses mutate rarely in an epidemic season in Japan if they can be hypothesized, mutation frequency of influenza viruses being mostly the same among strains. Among these identical strains, two strains were not only identical to other Japanese isolates, but also to those isolated in Mongolia and Thailand in the same epidemic season. CONCLUSION: These results suggest that genetic drift has occurred infrequently in Japan as shown in some other countries. The drifted strains may have generated somewhere else and entered into Japan. These results support the proposed 'sink-source' model of viral ecology in which new lineages are seeded from a persistent influenza reservoir in tropical countries to 'sink' populations in temperate regions including Japan. PMID- 26740736 TI - An Exploratory Analysis of Linguistic Acculturation, Neighborhood, and Risk Behaviors among Children of Southeast Asian Immigrants. PMID- 26740737 TI - Application of a wide-field phantom eye for optical coherence tomography and reflectance imaging. AB - Optical coherence tomography (OCT) and reflectance imaging are used in clinical practice to measure the thickness and transverse dimensions of retinal features. The recent trend towards increasing the field of view (FOV) of these devices has led to an increasing significance of the optical aberrations of both the human eye and the device. We report the design, manufacture and application of the first phantom eye that reproduces the off-axis optical characteristics of the human eye, and allows the performance assessment of wide-field ophthalmic devices. We base our design and manufacture on the wide-field schematic eye, [Navarro, R. J. Opt. Soc. Am. A, 1985,2.] as an accurate proxy to the human eye and enable assessment of ophthalmic imaging performance for a [Formula: see text] external FOV. We used multi-material 3D-printed retinal targets to assess imaging performance of the following ophthalmic instruments: the Optos 200Tx, Heidelberg Spectralis, Zeiss FF4 fundus camera and Optos OCT SLO and use the phantom to provide an insight into some of the challenges of wide-field OCT. PMID- 26740738 TI - Competing for ideal bodies: a study of exergames used as teaching aids in schools. AB - Since the development of the welfare state, the Swedish school subject Health and Physical Education (HPE) has been regarded as an important site for public health work, and still assumes a central role in promoting the health of the coming generation. A specific type of health intervention, promoted by researchers in recent years, is the use of so-called exergames. In some countries, these fitness games are used as teaching aids in physical education classes and can be seen as examples of how public health issues and popular culture are shaping HPE in schools. The aim of the study reported in this paper is to examine which messages about health and body are offered, and how these are expressed in some of the fitness games used as teaching aids in school. The results of the study highlight the dangers of using exergames in the teaching of HPE in schools. The messages communicated by the games have a number of potentially harmful consequences, particularly with regard to the creation of specific health and bodily norms based on a measurable ideal. The use of this tool in education is thus far from value free, and the problems that might be solved when using the games are not necessarily the ones that education should privilege. PMID- 26740739 TI - Why do Sequence Signatures Predict Enzyme Mechanism? Homology versus Chemistry. AB - First, we identify InterPro sequence signatures representing evolutionary relatedness and, second, signatures identifying specific chemical machinery. Thus, we predict the chemical mechanisms of enzyme-catalyzed reactions from catalytic and non-catalytic subsets of InterPro signatures. We first scanned our 249 sequences using InterProScan and then used the MACiE database to identify those amino acid residues that are important for catalysis. The sequences were mutated in silico to replace these catalytic residues with glycine and then again scanned using InterProScan. Those signature matches from the original scan that disappeared on mutation were called catalytic. Mechanism was predicted using all signatures, only the 78 "catalytic" signatures, or only the 519 "non-catalytic" signatures. The non-catalytic signatures gave indistinguishable results from those for the whole feature set, with precision of 0.991 and sensitivity of 0.970. The catalytic signatures alone gave less impressive predictivity, with precision and sensitivity of 0.791 and 0.735, respectively. These results show that our successful prediction of enzyme mechanism is mostly by homology rather than by identifying catalytic machinery. PMID- 26740740 TI - Modeling Kidney Disease with iPS Cells. AB - Induced pluripotent stem cells (iPSCs) are somatic cells that have been transcriptionally reprogrammed to an embryonic stem cell (ESC)-like state. iPSCs are a renewable source of diverse somatic cell types and tissues matching the original patient, including nephron-like kidney organoids. iPSCs have been derived representing several kidney disorders, such as ADPKD, ARPKD, Alport syndrome, and lupus nephritis, with the goals of generating replacement tissue and 'disease in a dish' laboratory models. Cellular defects in iPSCs and derived kidney organoids provide functional, personalized biomarkers, which can be correlated with genetic and clinical information. In proof of principle, disease specific phenotypes have been described in iPSCs and ESCs with mutations linked to polycystic kidney disease or focal segmental glomerulosclerosis. In addition, these cells can be used to model nephrotoxic chemical injury. Recent advances in directed differentiation and CRISPR genome editing enable more specific iPSC models and present new possibilities for diagnostics, disease modeling, therapeutic screens, and tissue regeneration using human cells. This review outlines growth opportunities and design strategies for this rapidly expanding and evolving field. PMID- 26740742 TI - Homology-Based Prediction of Potential Protein-Protein Interactions between Human Erythrocytes and Plasmodium falciparum. AB - Plasmodium falciparum, a causative agent of malaria, is a well-characterized obligate intracellular parasite known for its ability to remodel host cells, particularly erythrocytes, to successfully persist in the host environment. However, the current levels of understanding from the laboratory experiments on the host-parasite interactions and the strategies pursued by the parasite to remodel host erythrocytes are modest. Several computational means developed in the recent past to predict host-parasite/pathogen interactions have generated testable hypotheses on feasible protein-protein interactions. We demonstrate the utility of protein structure-based protocol in the recognition of potential interacting proteins across P. falciparum and host erythrocytes. In concert with the information on the expression and subcellular localization of host and parasite proteins, we have identified 208 biologically feasible interactions potentially brought about by 59 P. falciparum and 30 host erythrocyte proteins. For selected cases, we have evaluated the physicochemical viability of the predicted interactions in terms of surface complementarity, electrostatic complementarity, and interaction energies at protein interface regions. Such careful inspection of molecular and mechanistic details generates high confidence on the predicted host-parasite protein-protein interactions. The predicted host parasite interactions generate many experimentally testable hypotheses that can contribute to the understanding of possible mechanisms undertaken by the parasite in host erythrocyte remodeling. Thus, the key protein players recognized in P. falciparum can be explored for their usefulness as targets for chemotherapeutic intervention. PMID- 26740743 TI - Effect of Prepregnancy Alcohol Consumption on Postpartum Relationship Satisfaction and Divorce among Norwegian Mothers. AB - This study assessed the effect of prepregnancy level of alcohol use among mothers on relationship breakups with young children at 36 months after birth and the extent to which relationship satisfaction (RS) throughout the postpartum period could mediate any association between alcohol use and divorce. The data were part of the Norwegian Mother and Child Cohort Study, and analyses of the present article were based on a total of 69,117 mothers divided into low-, medium-, and high-risk consumption groups. All the three groups experienced a decrease in RS, but the largest effect was observed for the high-risk group. Mothers in this group had 55% higher odds for divorce as compared to the low-risk group. The findings supported a conceptual model whereby the effects of alcohol use on divorce were mediated through lowered RS. PMID- 26740744 TI - The Pediatric Home Care/Expenditure Classification Model (P/ECM): A Home Care Case-Mix Model for Children Facing Special Health Care Challenges. AB - Case-mix classification and payment systems help assure that persons with similar needs receive similar amounts of care resources, which is a major equity concern for consumers, providers, and programs. Although health service programs for adults regularly use case-mix payment systems, programs providing health services to children and youth rarely use such models. This research utilized Medicaid home care expenditures and assessment data on 2,578 children receiving home care in one large state in the USA. Using classification and regression tree analyses, a case-mix model for long-term pediatric home care was developed. The Pediatric Home Care/Expenditure Classification Model (P/ECM) grouped children and youth in the study sample into 24 groups, explaining 41% of the variance in annual home care expenditures. The P/ECM creates the possibility of a more equitable, and potentially more effective, allocation of home care resources among children and youth facing serious health care challenges. PMID- 26740745 TI - Alkaline Phosphatase-Positive Immortal Mouse Embryo Fibroblasts Are Cells in a Transitional Reprogramming State Induced to Face Environmental Stresses. AB - In this study, we report that immortal mouse embryonic fibroblasts (I-MEFs) have a baseline level of cells positive for alkaline phosphatase (AP(+)) staining. Environmental stresses, including long-lasting growth in the absence of expansion and treatment with drugs, enhance the frequency of AP(+) I-MEFs. By adapting fast red AP staining to the sorting procedure, we separated AP(+) and AP(-) I-MEFs and demonstrated that the differentially expressed genes are consistent with a reprogrammed phenotype. In particular, we found that sestrin 1 is upregulated in AP(+) I-MEFs. We focused on this gene and demonstrated that increased sestrin 1 expression is accompanied by the growth of I-MEFs in the absence of expansion and occurs before the formation of AP(+) I-MEFs. Together with sestrin 1 upregulation, we found that AP(+) I-MEFs accumulated in the G1 phase of the cell cycle, suggesting that the two events are causally related. Accordingly, we found that silencing sestrin 1 expression reduced the frequency and G1 accumulation of AP(+) I-MEFs. Taken together, our data suggested that I-MEFs stressed by environmental changes acquire the AP(+) phenotype and achieve a quiescent state characterized by a new transcriptional network. PMID- 26740748 TI - Big Data for Cancer Research. PMID- 26740746 TI - Cardiac Magnetic Resonance Imaging Might Complement Two-Dimensional Echocardiography in the Detection of a Reversible Nonischemic Cardiomyopathy. AB - We report a case of reversible nonischemic dilated cardiomyopathy in a male in his 60s who presented with an acute heart failure syndrome. Both conventional two dimensional echocardiography and cardiac magnetic resonance imaging (cMRI) demonstrated severe left ventricular systolic dysfunction; however, both modalities were devoid of significant valvular heart disease as well as the presence of fibrosis, infiltration, inflammation, and scar. After six months of aggressive neurohumoral modulation, there was complete reverse remodeling and normalization of left ventricular function, which highlights the role of cMRI as an adjunct to two-dimensional echocardiography in the detection of a potentially reversible nonischemic cardiomyopathy. PMID- 26740747 TI - Myriad Functions of Stanniocalcin-1 (STC1) Cover Multiple Therapeutic Targets in the Complicated Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). AB - Idiopathic pulmonary fibrosis (IPF) is an intractable disease for which the pathological findings are characterized by temporal and spatial heterogeneity. The pathogenesis is composed of myriad factors, including repetitive injuries to epithelial cells, alterations in immunity, the formation of vascular leakage and coagulation, abnormal wound healing, fibrogenesis, and collagen accumulation. Therefore, the molecular target drugs that are used or attempted for treatment or clinical trials may not cover the myriad therapeutic targets of IPF. In addition, the complicated pathogenesis results in a lack of informative biomarkers to diagnose accurately the status of IPF. These facts point out the necessity of using a combination of drugs, that is, each single drug with molecular targets or a single drug with multiple therapeutic targets. In this review, we introduce a humoral factor, stanniocalcin-1 (STC1), which has myriad functions, including the maintenance of calcium homeostasis, the promotion of early wound healing, uncoupling respiration (aerobic glycolysis), reepithelialization in damaged tissues, the inhibition of vascular leakage, and the regulation of macrophage functions to keep epithelial and endothelial homeostasis, which may adequately cover the myriad therapeutic targets of IPF. PMID- 26740741 TI - Interplay Between Metabolism and Oncogenic Process: Role of microRNAs. AB - Cancer is a complex disease that arises from the alterations in the composition and regulation of several genes leading to the disturbances in signaling pathways, resulting in the dysregulation of cell proliferation and death as well as the ability of transformed cells to invade the host tissue and metastasize. It is increasingly becoming clear that metabolic reprograming plays a critical role in tumorigenesis and metastasis. Therefore, targeting this phenotype is considered as a promising approach for the development of therapeutics and adjuvants. The process of metabolic reprograming is linked to the activation of oncogenes and/or suppression of tumor suppressor genes, which are further regulated by microRNAs (miRNAs) that play important roles in the interplay between oncogenic process and metabolic reprograming. Looking at the advances made in the recent past, it appears that the translation of knowledge from research in the areas of metabolism, miRNA, and therapeutic response will lead to paradigm shift in the management of this disease. PMID- 26740749 TI - Diversity of Breast Carcinoma: Histological Subtypes and Clinical Relevance. AB - Mammary carcinoma is the most common malignant tumor in women, and it is the leading cause of mortality, with an incidence of >1,000,000 cases occurring worldwide annually. It is one of the most common human neoplasms, accounting for approximately one-quarter of all cancers in females worldwide and 27% of cancers in developed countries with a Western lifestyle. They exhibit a wide scope of morphological features, different immunohistochemical profiles, and unique histopathological subtypes that have specific clinical course and outcome. Breast cancers can be classified into distinct subgroups based on similarities in the gene expression profiles and molecular classification. PMID- 26740750 TI - Cryptorchidism and Fertility. AB - Cryptorchidism, the failure of one or both testes to descend into the scrotum prenatally, occurs in 2.4%-5% of newborns. Many of these testes will descend spontaneously shortly after birth, but ~23% will remain undescended unless surgery is performed. Bilaterally cryptorchid men have a six times greater risk of being infertile when compared with unilaterally cryptorchid men and the general male population. Approximately 10% of infertile men have a history of cryptorchidism and orchidopexy. The main reasons for infertility in men with a history of cryptorchidism treated by orchidopexy are maldevelopment of the testes and an improper environment for the normal development of the testes, hyperthermia, and antisperm antibodies. PMID- 26740751 TI - Monensin ameliorates cadmium-induced hepatic injury in mice, subjected to subacute cadmium intoxication. AB - This study was designed to evaluate the potential application of monensin as an oral drug for the treatment of cadmium-induced hepatic dysfunction. The study was performed using ICR mouse model. Twenty-seven adult ICR male mice were divided into three groups of nine animals each: control (received distilled water and food ad libitum for 28 days); Cd-intoxicated (treated orally with 20 mg/kg b.w. Cd(II) acetate from the 1st to the 14th day of the experimental protocol); and monensin treated group (intoxicated with Cd(II) acetate as described for the Cd intoxicated group followed by an oral treatment with 16 mg/kg b.w. tetraethylammonium salt of monensic acid for two weeks). The obtained results demonstrated that the treatment of Cd-intoxicated animals with monensin restored the liver weight/body weight index to normal values, decreased the concentration of the toxic metal ion by 50% compared to the Cd-treated controls, and recovered the homeostasis of Cu and Zn. Monensin reduced the activity of aspartate aminotransferase, alanine aminotrasnferase and alkaline phosphatase in the plasma of Cd-treated animals to the normal control levels and ameliorated the Cd-induced inflammation in the liver. Taken together, these data demonstrated that monensin could be an effective chelating agent for the treatment of Cd-induced hepatotoxicity. PMID- 26740752 TI - Uptake and trans-membrane transport of petroleum hydrocarbons by microorganisms. AB - Petroleum-based products are a primary energy source in the industry and daily life. During the exploration, processing, transport and storage of petroleum and petroleum products, water or soil pollution occurs regularly. Biodegradation of the hydrocarbon pollutants by indigenous microorganisms is one of the primary mechanisms of removal of petroleum compounds from the environment. However, the physical contact between microorganisms and hydrophobic hydrocarbons limits the biodegradation rate. This paper presents an updated review of the petroleum hydrocarbon uptake and transport across the outer membrane of microorganisms with the help of outer membrane proteins. PMID- 26740753 TI - Identification of activation-tag Arabidopsis mutants with altered production of germination stimulants for Phelipanche ramosa (L.). AB - Germination of seeds of root parasites like broomrapes (Orobanchaceae) is tightly regulated by chemical products exuded from the roots of the host plant, known as germination stimulants (GSs). Changes in the levels of synthesis and emission of GS can allow the development of practical measures for control of the crops harming parasitic species. However, the genes encoding enzymes responsible for GS biosynthesis are still unknown. We performed a large-scale screening of 62,000 Arabidopsis activation-tag mutants for alteration in susceptibility to Phelipanche ramosa and to identify lines with altered GS production among them. After five successive screenings we identified 36 lines with altered susceptibility to P. ramosa. Seven of them displayed altered levels of GS production. By using a combination of Southern blot and thermal asymmetric interlaced polymerase chain reaction (TAIL-PCR), we pinpointed the location of activation-tag constructs in these lines. A combination of differential display and quantitative real-time PCR (qRT-PCR) allowed us to identify several affected genes. Two of them are directly involved in isoprenoid biosynthetic pathway in chloroplasts, and we believe that their activation led to increased levels of GS production. We believe that these genes are responsible for increased GS production in five of the Arabidopsis lines resistant to P. ramosa. PMID- 26740754 TI - Investigation of single nucleotide polymorphisms based on the intronic sequences of the propylene alcohol dehydrogenase gene in Chinese tobacco genotypes. AB - A pair of primers was designed to amplify the propylene alcohol dehydrogenase gene sequence based on the cDNA sequence of the tobacco allyl-alcohol dehydrogenase gene. All introns were sequenced using traditional polymerase chain reaction (PCR) methods and T-A cloning. The sequences from common tobacco (Nicotiana tabaccum L.) and rustica tobacco (Nicotiana rustica L.) were analysed between the third intron and the fourth intron of the propylene alcohol dehydrogenase gene. The results showed that the alcohol dehydrogenase gene is a low-copy nuclear gene. The intron sequences have a combination of single nucleotide polymorphisms and length polymorphisms between common tobacco and rustica tobacco, which are suitable to identify the different germplasms. Furthermore, there are some single nucleotide polymorphism sites in the target sequence within common tobacco that can be used to distinguish intraspecific varieties. PMID- 26740755 TI - Optimization of medium components for production of chitin deacetylase by Bacillus amyloliquefaciens Z7, using response surface methodology. AB - Plackett-Burman design and Box-Behnken response surface methodology (RSM) was employed to optimize the medium components for the chitin deacetylase (CDA) activity from Bacillus amyloliquefaciens Z7. Plackett-Burman design was applied to determine the specific medium components affecting CDA activity and found that starch, chitin and MgSO4 were critical in augmenting CDA activity. These significant parameters were further optimized using Box-Behnken RSM and the optimum concentrations of starch, chitin and MgSO4 were found to be 24.4, 8.8 and 0.19 g/L, respectively. The optimum medium composition was chitin 8.8 g/L, starch 24.4 g/L, yeast extract 10g/L, MgSO4 0.19 g/L, K2HPO4 0.3 g/L and NaCl 5 g/L. Under these optimal conditions, the CDA activity of Bacillus amyloliquefaciens Z7 increased distinctly from 18.75 to 27.48 U/mL (46.6% increase in total yield). PMID- 26740756 TI - Influence of Ni2+ on urease activity produced by biofilms of Arthrobacter oxydans 1388. AB - New TiO2-based hybrid materials composed of an organic polymer, cellulose acetate butyrate and copolymer of acrylonitrile acrylamide (AN + AA) were prepared. The effectiveness of immobilization of microbial strain Arthrobacter oxydans 1388 on the newly synthesized hybrid membranes was investigated by biochemical methods. The obtained results revealed that the matrix more suitable for biofilm formation was composed of organic polymers without a metal component in the membrane composition. The influence of Ni2+ on urease activity produced by biofilms was investigated. The experimental results demonstrated that 2 mg L-1 concentration of Ni2+ in the nutrient medium is more appropriate for biofilm proliferation. PMID- 26740757 TI - New Paenibacillus larvae bacterial isolates from honey bee colonies infected with American foulbrood disease in Egypt. AB - The American foulbrood disease is widely distributed all over the world and causes a serious problem for the honeybee industry. Different infected larvae were collected from different apiaries, ground in phosphate saline buffer (PSB) and bacterial isolation was carried out on nutrient agar medium. Different colonies were observed and were characterized biologically. Two bacterial isolates (SH11 and SH33) were subjected to molecular identification using 16S rRNA gene and the sequence analysis revealed that the two isolates are Paenibacillus larvae with identity not exceeding 83%. The DNA sequence alignment between the other P. larvae bacterial strains and the two identified bacterial isolates showed that all the examined bacterial strains have the same ancestor, i.e. they have the same origin. The SH33 isolate was closely related to the P. larvae isolated from Germany, whereas the isolate SH11 was close to the P. larvae isolated from India. The phylogenetic tree constructed for 20 different Bacillus sp. and the two isolates SH11 and SH33 demonstrated that the two isolates are Bacillus sp. and they are new isolates. The bacterial isolates will be subjected to more tests for more confirmations. PMID- 26740758 TI - Long-term effect of radiofrequency turbinoplasty in nasal obstruction. AB - The aim of this retrospective study is to investigate long term (two years) effect of radiofrequency tissue volume reduction (RFVTR) on nasal obstruction associated with inferior turbinate hypertrophy, which is not respond to medical treatment. This retrospective study carried out on 98 patients with nasal obstruction treated by RFVTR (56 males, 42 females, from 17 to 70 years of age). Visual analogue scales (VAS) and nasal endoscopic view score (NES) were used for nasal obstruction to evaluate the efficacy of the treatment. Results of one, three, six, twelve and twenty four months after RFVTR treatment were compared with pre-exposure values. Turbinate edema and nasal obstruction in the treated patients were recovered after one month of treatment (p < 0.01). Maximum improvement were determined at the end of third month (p < 0.01). However, eficacy of RFVTR declined twelve months after treatment. Final percentage of imrovement was found as 51 % at the end of second year of treatment because of co factors was not eliminated by some patients. On the other hand, no statistical significant difference was observed between the right and left nasal cavity (p < 0.001). In conclusion, the result of this study indicated that patients who have not eliminate co-factors such as smoking, obesity and allergic rhinitis may need re-application of RFTVR. However, further studies on radiofrequecy energy level and elimination of other co-factors are necessary to illuminate the eficacy of RFVTR. PMID- 26740759 TI - Antibacterial and antitumour activities of some plants grown in Turkey. AB - Screening of antibacterial and antitumour activities of 33 different extracts prepared with three types of solvents (water, ethanol and methanol) was conducted. The extracts were obtained from 11 different plant species grown in Turkey: Eryngium campestre L., Alchemilla mollis (Buser) Rothm., Dorycnium pentaphyllum Scop., Coronilla varia L., Onobrychis oxyodonta Boiss., Fritillaria pontica Wahlenb., Asarum europaeum L., Rhinanthus angustifolius C. C. Gmelin, Doronicum orientale Hoffm., Campanula glomerata L. and Campanula olympica Boiss. Antibacterial activity against six bacteria was evaluated: Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pyogenes, Staphylococcus aureus and Staphylococcus epidermidis by using disc diffusion and well diffusion methods. S. aureus and S. epidermidis were most sensitive to the methanolic extract from A. europaeum. S. pyogenes was vulnerable to all used extracts of D. orientale. In addition, ethanolic or methanolic extracts of E. campestre, A. mollis, D. pentaphyllum, C. varia, R. angustifolius, C. glomerata and C. olympica displayed strong antibacterial activity against at least one of the tested gram-negative bacteria. The methanolic extract from R. angustifolius showed a broad-spectrum activity against both gram-positive and gram-negative bacteria. Antitumour activity was evaluated with Agrobacterium-tumefaciens induced potato disc tumour assay. Best antitumour activity was obtained with the aqueous extract from A. europaeum and methanolic extract from E. campestre (100% and 86% tumour inhibition, respectively). PMID- 26740760 TI - Advances in the development of an imaging device for plaque measurement in the area of the carotid artery. AB - This paper describes the advances in the development and subsequent testing of an imaging device for three-dimensional ultrasound measurement of atherosclerotic plaque in the carotid artery. The embolization from the atherosclerotic carotid plaque is one of the most common causes of ischemic stroke and, therefore, we consider the measurement of the plaque as extremely important. The paper describes the proposed hardware for enhancing the standard ultrasonic probe to provide a possibility of accurate probe positioning and synchronization with the cardiac activity, allowing the precise plaque measurements that were impossible with the standard equipment. The synchronization signal is derived from the output signal of the patient monitor (electrocardiogram (ECG)), processed by a microcontroller-based system, generating the control commands for the linear motion moving the probe. The controlling algorithm synchronizes the movement with the ECG waveform to obtain clear images not disturbed by the heart activity. PMID- 26740761 TI - The expression of CBF genes at Fr-2 locus is associated with the level of frost tolerance in Bulgarian winter wheat cultivars. AB - The regulation of the majority of cold-regulated genes in plants is mediated by CBF (C-repeat binding factors) transcription factor family. Natural differences in frost tolerance (FT) of wheat have been mapped to the Fr-2 (Frost Resistance 2) locus on chromosome group 5 and are associated with variation in threshold induction temperatures and/or transcript levels of CBF genes. This study used real-time reverse-transcription polymerase chain reaction (qRT-PCR) to compare the relative expression levels of four T. aestivum CBF genes (TaCBF15.2, TaCBFA19, TaCBFA2 and TaCBFD21) in crown tissue of two Bulgarian hexaploid winter wheat cultivars (Milena and Russalka) with distinct levels of low-temperature (LT) tolerance but same vernalization requirement, and the spring cultivar Chinese Spring. The transcription profiles of the selected TaCBF genes showed that they are induced by cold treatment at 2 degrees C. Analysis of transcript abundance revealed that the four TaCBF genes were expressed at higher levels in the frost tolerant Milena than in the susceptible Russalka. Largest differences (fivefold and fourfold) in expression levels between both winter cultivars were observed in two of the analysed genes, TaCBF15.2 and TaCBFA19, respectively. The higher steady-state expression levels of TaCBF genes before the onset of the LT treatment in Milena, combined with stronger induction by cold treatment, suggest that these molecular responses to LT are associated with superior FT development capacity. The results expand our understanding of the molecular mechanisms underlying LT acclimation in Bulgarian wheat and can be used for development of functional markers for improvement of FT wheat-breeding programmes. PMID- 26740762 TI - Isolation and characterization of NBS-LRR resistance gene analogues from mango. AB - The nucleotide-binding site (NBS)-leucine-rich repeat (LRR) gene family is a class of R genes in plants. NBS genes play a very important role in disease defence. To further study the variation and homology of mango NBS-LRR genes, 16 resistance gene analogues (RGAs) (GenBank accession number HM446507-22) were isolated from the polymerase chain reaction fragments and sequenced by using two degenerate primer sets. The total nucleotide diversity index Pi was 0.362, and 236 variation sites were found among 16 RGAs. The degree of homology between the RGAs varied from 44.4% to 98.5%. Sixteen RGAs could be translated into amino sequences. The high level of this homology in the protein sequences of the P-loop and kinase-2 of the NBS domain between the RGAs isolated in this study and previously characterized R genes indicated that these cloned sequences belonged to the NBS-LRR gene family. Moreover, these 16 RGAs could be classified into the non-TIR-NBS-LRR gene family because only tryptophan (W) could be claimed as the final residual of the kinase-2 domain of all RGAs isolated here. From our results, we concluded that our mango NBS-LRR genes possessed a high level of variation from the mango genome, which may allow mango to recognize many different pathogenic virulence factors. PMID- 26740763 TI - Tomato (Solanum lycopersicum) variety discrimination and hybridization analysis based on the 5S rRNA region. AB - The tomato (Solanum lycopersicum) is a major vegetable crop worldwide. To satisfy popular demand, more than 500 tomato varieties have been bred. However, a clear variety identification has not been found. Thorough understanding of the phylogenetic relationship and hybridization information of tomato varieties is very important for further variety breeding. Thus, in this study, we collected 26 tomato varieties and attempted to distinguish them based on the 5S rRNA region, which is widely used in the determination of phylogenetic relations. Sequence analysis of the 5S rRNA region suggested that a large number of nucleotide variations exist among tomato varieties. These variable nucleotide sites were also informative regarding hybridization. Chromas sequencing of Yellow Mountain View and Seuwiteuking varieties indicated three and one variable nucleotide sites in the non-transcribed spacer (NTS) of the 5S rRNA region showing hybridization, respectively. Based on a phylogenetic tree constructed using the 5S rRNA sequences, we observed that 16 tomato varieties were divided into three groups at 95% similarity. Rubiking and Sseommeoking, Lang Selection Procedure and Seuwiteuking, and Acorn Gold and Yellow Mountain View exhibited very high identity with their partners. This work will aid variety authentication and provides a basis for further tomato variety breeding. PMID- 26740764 TI - Factors influencing the trans-membrane transport of n-octadecane by Pseudomonas sp. DG17. AB - In soil bioremediation techniques, the trans-membrane transport of hydrocarbons across the cell membrane is a new and complex point of understanding the process of hydrocarbons biodegradation. In this study, the effect of different environmental factors, including substrate concentration, bacterial inoculums, pH, salinity, substrate analogues and nutrients, on the transport of [14C]n octadecane by Pseudomonas sp. DG17 was investigated. The results showed that cellular [14C]n-octadecane levels increased along with the increase in the substrate concentration. However, the trans-membrane transport of [14C]n octadecane was a saturable process in the case of equal amounts of inoculum (biomass). The highest concentration of accumulated [14C]n-octadecane was 0.51 MUmol mg-1 +/- 0.028 MUmol mg-1 after incubation for 20 min. Meanwhile, the cellular n-octadecane concentration decreased along with the biomass increase, and reached a stable level. Acidic/alkaline conditions, high salinity, and supplement of substrate analogues could inhibit the transport of [14C]n octadecane by Pseudomonas sp. DG17, whereas nitrogen or phosphorus deficiency did not influence this transport. The results suggested that trans-membrane transport of octadecane depends on both the substrate concentration and the microorganism biomass, and extreme environmental conditions could influence the biodegradation ability of microorganisms through inhibiting the transport of extracellular octadecane. PMID- 26740765 TI - Study on anti-inflammatory and immunomodulatory effects of clomipramine in carrageenan- and lipopolysaccharide-induced rat models of inflammation. AB - The aim of the present study was to evaluate the anti-inflammatory effect of clomipramine in carrageenan- and lipopolysaccharide-induced (LPS-induced) models of inflammation by investigating the changes in serum levels of the pro inflammatory cytokine TNF-alpha and the anti-inflammatory cytokines IL-10 and TGF beta after single and repeated administration of the drug. In order to study the effect of single and repeated doses of clomipramine on carrageenan-induced paw oedema, male Wistar rats were divided in five groups (n = 8): control, positive control group and three experimental groups treated with 5, 10 and 20 mg/kg bw clomipramine, respectively. The effect of single and repeated doses of clomipramine on serum cytokine levels was studied as animals were divided in four groups: two control groups treated with saline and two experimental groups treated with clomipramine 20 mg/kg bw. Carrageenan and LPS were injected immediately after clomipramine or saline injection. Serum cytokine concentrations were tested by enzyme immunoassay. Following acute administration only the highest dose that was used inhibited the carrageenan-induced inflammation. Oedema inhibition was observed with 5, 10 and 20 mg/kg bw clomipramine after repeated administration. Single and repeated administration of clomipramine at a dose of 20 mg/kg bw did not significantly change the serum levels of TGF-1beta, IL-10 and TNF-alpha when compared to the controls in carrageenan-induced inflammation. Following LPS-induced inflammation clomipramine significantly increased the serum levels of TGF-1beta after repeated administration and decreased TNF-alpha in rats after single-dose and repeated pretreatment with 20 mg/kg bw clomipramine. A significant increase in the levels of IL-10 in relation to this inflammatory model was observed only in single dose treated animals. Clomipramine possesses an anti-inflammatory effect in the carrageenan-induced model of exudative inflammation. In LPS-induced inflammation, clomipramine showed an immunomodulatory effect, decreasing TNF-alpha and increasing TGF-1beta after repeated administration, and increasing IL-10 after a single dose. PMID- 26740766 TI - SRAP analysis on genetic relationships of genotypes in the genus Malus Mill. AB - Thirteen sequence-related amplified polymorphism (SRAP) primers combined with polymerase chain reaction (PCR) were used to evaluate the genetic relationships among 24 genotypes of the genus Malus Mill. including Sect. Malus, Baccatus, Sorbomalus and Chloromeles. Out of 115 surveyed fragments, 107 (93.04%) were polymorphic. Coefficients of genetic similarity ranged from 0.538 to 0.868, with an average value of 0.720 between pairs of materials, which indicated the high degree of polymorphism within this species. Cluster analysis showed that all genotypes were divided into six groups. A dendrogram showed that some of the clustered genotypes were largely congruent for geographical distribution. The species in Sect. Malus, Sorbomalus and Chloromeles were separated to a great extent. However, the DNA patterns for some genotype groups did not demonstrate relative agreement in their pedigrees. In Sect. Sorbomalus, M. yunnanesis was independently separated, while M. prattii were clustered in group III with M. bhutanica, M. platycarpa and M. fusca classified into Ser. Kansuenses. Five species originated from the American region were dispersed into two groups within the dendrogram. The conflicts were reflecting their complex genetic backgrounds. PMID- 26740767 TI - Insights into the stereospecificity of the d-specific dehalogenase from Rhizobium sp. RC1 toward d- and l-2-chloropropionate. AB - Halogenated compounds are recalcitrant environmental pollutants prevalent in agricultural fields, waste waters and industrial by-products, but they can be degraded by dehalogenase-containing microbes. Notably, 2-haloalkanoic acid dehalogenases are employed to resolve optically active chloropropionates, as exemplified by the d-specific dehalogenase from Rhizobium sp. RCI (DehD), which acts on d-2-chloropropionate but not on its l-enantiomer. The catalytic residues of this dehalogenase responsible for its affinity toward d-2-chloropropionate have not been experimentally determined, although its three-dimensional crystal structure has been solved. For this study, we performed in silico docking and molecular dynamic simulations of complexes formed by this dehalogenase and d- or l-2-chloropropionate. Arg134 of the enzyme plays the key role in the stereospecific binding and Arg16 is in a position that would allow it to activate a water molecule for hydrolytic attack on the d-2-chloropropionate chiral carbon for release of the halide ion to yield l-2-hydroxypropionate. We propose that within the DehD active site, the NH group of Arg134 can form a hydrogen bond with the carboxylate of d-2-chloropropionate with a strength of ~4 kcal/mol that may act as an acid-base catalyst, whereas, when l-2-chloropropionate is present, this bond cannot be formed. The significance of the present work is vital for rational design of this dehalogenase in order to confirm the involvement of Arg16 and Arg134 residues implicated in hydrolysis and binding of d-2-chloropropionate in the active site of d-specific dehalogenase from Rhizobium sp. RC1. PMID- 26740768 TI - Modelling of risk effect of mercury on nutrient transformation in lake sediments. AB - The influence of mercury on the transformation processes in the waters and the sediments in the reservoir of a small hydroelectric power plant (SHPP) Lakatnik was simulated in laboratory conditions. SHPP Lakatnik is the first (of nine similar) SHPPs put into exploitation in the middle part of the Iskar River (Bulgaria). In previous studies of the sediments in the reservoir of SHPP Lakatnik, our team found high concentrations of mercury, sometimes exceeding maximum concentration limit (MCL). In model bioreactors we studied the effect of mercury on the dynamics of the following hydrochemical and microbiological indicators: NH4+, NO3-, NO2-, PO43-, chemical oxygen demand (COD), total organic carbon (TOC); aerobic and anaerobic heterotrophs (AH and AnH), Pseudomonas spp. (Ps.), Acinetobacter spp. (Ac.), sulphate-reducing bacteria (SR), denitrifying microorganisms (Dn). We looked for linear correlations among the studied indicators in order to find quick, mutual replaceability among them. The extent to which mercury affects the amount of key microbial groups and the rate of transformation of biogenic elements was calculated in percentages. The microorganism dynamics showed that AH, AnH and Ps. adapt more quickly and their number increased more in the presence of mercury, whereas SR, Dn and Ac. were inhibited to a greater extent by the presence of mercury. Mercury had a marked stimulating effect on Ps., which showed a 312% increase in number at the 192nd hour. The obtained results can be used when decisions have to be taken in risky situations related to increased concentrations of mercury in the sediments. PMID- 26740769 TI - Hexavalent chromium reduction by chromate-resistant haloalkaliphilic Halomonas sp. M-Cr newly isolated from tannery effluent. AB - The current study aimed to isolate and characterize a chromate-resistant bacterium from tannery effluent, able to reduce Cr(VI) aerobically at high pH and salinity. Environmental contamination by hexavalent chromium, Cr(VI), presents a serious public health problem. Enrichment led to the isolation of 12 bacteria displaying different degrees of chromate reduction. Phenotypic characterization and phylogenetic analysis based on 16S rDNA sequence comparison indicated that the most potent strain belonged to the genus Halomonas. The new strain designated as Halomonas sp. M-Cr was able to reduce 82% of 50 mg L-1 Cr(VI) in 48 h, concomitant with discolouring of yellow colour of the medium and formation of white insoluble precipitate of Cr(III). It exhibited growth up to 3500 mg L-1 Cr(VI), 20% NaCl and showed strong Cr(VI) reduction under alkaline condition, pH 10. Scanning electron microscopy revealed precipitation of chromium hydroxide on bacterial cell surfaces, which showed characteristic peak of chromium in energy dispersive X-ray analysis. Plackett-Burman design was used to evaluate the influence of related parameters for enhancing Cr(VI) reduction. Glucose, yeast extract and KH2PO 4 were confirmed as significant variables in the medium. Data suggest Halomonas sp. M-Cr as a promising candidate for bioremediation of Cr(VI) contaminated effluents particularly in saline and alkaline environments. Up to our knowledge, this is the first report on isolation of haloalkaliphilic Halomonas sp. from tannery effluent. PMID- 26740771 TI - Histological investigation of the impact of streptozotocin-induced experimental diabetes on the healthy gingivae of rats. AB - This study was aimed at the histological investigation of the impact of experimental diabetes on the healthy gingiva of rats. Thirty male Wistar rats were used in this study. The animals were randomly divided into two groups (n = 15) prior to the experiment. Group 1 experimental diabetes was created by streptozotocin injection in 15 rats. Group 2 comprised the control group (15 rats). On the 7th, 14th and 21st days after the induction of diabetes by streptozotocin, five animals from each group were euthanized by cardiac puncture. The gingiva of the maxillary left first molar tooth of the sacrificed animals was extracted for histological examination. Histological examination demonstrated that, when compared to the control group, the diabetes group displayed marked hyperkeratosis and parakeratosis of the gingival epithelium on day 21 post induction. Furthermore, the diabetes group presented with an increased number of inflammatory cells and vasodilatation of the capillaries, in comparison to the controls. The overall evaluation of the findings obtained in this study suggested that diabetes alone could cause changes in the periodontium and affect periodontal health. PMID- 26740770 TI - New X-chromosomal interactors of dFMRP regulate axonal and synaptic morphology of brain neurons in Drosophila melanogaster. AB - Fragile X syndrome is a neuro-developmental disease caused by transcriptional inactivation of the gene FMR1 (fragile X mental retardation 1) and loss of its protein product FMRP. FMRP has multiple neuronal functions which are implemented together with other proteins. To better understand these functions, the aim of this study was to reveal new protein interactors of dFMRP. In a forward genetic screen, we isolated ethyl-metanesulphonate-induced X-chromosomal modifier mutations of dfmr1. Four of them were identified and belong to the genes: peb/hindsight, rok, shaggy and ras. They are dominant suppressors of the dfmr1 overexpression wing phenotype 'notched wings'. These mutations dominantly affected the axonal and synaptic morphology of the lateral ventral neurons (LNv's) in adult Drosophila brains. Heterozygotes for each of them displayed effects in the axonal growth, pathfinding, branching and in the synapse formation of these neurons. Double heterozygotes for both dfmr1-null mutation and for each of the suppressor mutations showed robust genetic interactions in the fly central nervous system. The mutations displayed severe defects in the axonal growth and synapse formation of the LNv's in adult brains. Our biochemical studies showed that neither of the proteins - Rok, Shaggy, Peb/Hnt or Ras - encoded by the four mutated genes regulates the protein level of dFMRP, but dFMRP negatively regulates the protein expression level of Rok in the brain. Altogether, these data suggest that Rok, Shaggy, Peb/Hnt and Ras are functional partners of dFMRP, which are required for correct wing development and for neuronal connectivity in Drosophila brain. PMID- 26740772 TI - Protein analysis of boar seminal plasma proteins with protective effect during low-temperature storage of spermatozoa. AB - The present study aimed to investigate the effect of different seminal plasma proteins (SPPs) on boar spermatozoa functional characteristics. We investigated the putative protective effect of SSPs on sperm cells motility and velocity, as well as on the integrity of the plasma membrane (PM) during low-temperature storage at 4 degrees C. SPPs fractions were obtained and purified by gel permeation chromatography (GPC). Nine fractions of SPPs were obtained and further characterized by 12% sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). Sperm computer analysis (SCA) after incubation of spermatozoa with separated proteins revealed that fraction 6 consisting of low molecular weight (MW) proteins could preserve spermatozoa motility and velocity better when compared to those with higher MW. Two-dimensional (2D) elecrtophoretic analysis showed that fraction 6 contained proteins with the following MW and isoelectric point (pI): 16 kDa and pI 7.35, 18 kDa and pI 5.20, 19 kDa and pI 7.35, 26 kDa and pI 4.50, 26 kDa and pI 4.30, 29 kDa and pI 5.85. PMID- 26740773 TI - Sol-gel immobilization as a suitable technique for enhancement of alpha-amylase activity of Aspergillus oryzae PP. AB - Bioencapsulation of microbial cells in silica-based matrices has proved to be a good strategy to enhance the biosynthetic capabilities and viability of bioproducers. In the present study, mycelium and pellet cultures of strain Aspergillus oryzae PP were successfully immobilized in sol-gel hybrid matrices composed of tetraethylorthosilicate as an inorganic precursor, 5% (w/v) starch and 10 or 15% (w/v) polyethylene oxide, or 10% (w/v) calcium alginate as organic compounds. Biosynthetic activity of immobilized cultures was investigated by batch and fed-batch cultivation and the obtained results of 3042.04 IU cm-3 were comparable with the enzyme activity of the free cell culture. Immobilized cultures retained their viability and biosynthetic capabilities up to the 744th h during fed-batch fermentation processes. Consequently, sol-gel encapsulation in hybrid matrices could be considered as a promising technique for immobilization of Aspergillus oryzae PP in order to increase the alpha-amylase production. PMID- 26740774 TI - Synthesis, characterization and antibacterial assessment of SiO2 hydroxypropylmethyl cellulose hybrid materials with embedded silver nanoparticles. AB - Antibacterial SiO2 hybrid materials based on tetraethyl orthosilicate (TEOS), hydroxypropylmethylcellulose (HPMC) and silver were prepared by the sol-gel method. The content of cellulose derivate was 5 wt% and the silver concentration varied from 0.5 wt% to 2.5 wt%. The amorphous nature, morphology and antibacterial behaviour were studied. Fourier transform infrared (FTIR) spectra of the hybrids showed characteristic peaks for SiO2 network. Scanning electron microscope (SEM) analysis confirmed the formation of spherically shaped silver nanoparticles with a size of 30 nm on the matrix surfaces. Bacillus subtilis and Escherichia coli K12 were used as model microorganisms. The hybrid materials demonstrated bacteriostatic and bactericidal effect on the tested bacteria. Highest sensitivity to the obtained hybrids was observed in B. subtilis with significant lag-phase delay and biggest inhibition zone sizes. PMID- 26740775 TI - Plant pathogen nanodiagnostic techniques: forthcoming changes? AB - Plant diseases are among the major factors limiting crop productivity. A first step towards managing a plant disease under greenhouse and field conditions is to correctly identify the pathogen. Current technologies, such as quantitative polymerase chain reaction (Q-PCR), require a relatively large amount of target tissue and rely on multiple assays to accurately identify distinct plant pathogens. The common disadvantage of the traditional diagnostic methods is that they are time consuming and lack high sensitivity. Consequently, developing low cost methods to improve the accuracy and rapidity of plant pathogens diagnosis is needed. Nanotechnology, nano particles and quantum dots (QDs) have emerged as essential tools for fast detection of a particular biological marker with extreme accuracy. Biosensor, QDs, nanostructured platforms, nanoimaging and nanopore DNA sequencing tools have the potential to raise sensitivity, specificity and speed of the pathogen detection, facilitate high-throughput analysis, and to be used for high-quality monitoring and crop protection. Furthermore, nanodiagnostic kit equipment can easily and quickly detect potential serious plant pathogens, allowing experts to help farmers in the prevention of epidemic diseases. The current review deals with the application of nanotechnology for quicker, more cost-effective and precise diagnostic procedures of plant diseases. Such an accurate technology may help to design a proper integrated disease management system which may modify crop environments to adversely affect crop pathogens. PMID- 26740776 TI - Sequencing and comparative genomics analysis in Senecio scandens Buch.-Ham. Ex D. Don, based on full-length cDNA library. AB - Senecio scandens Buch.-Ham. ex D. Don, an important antibacterial source of Chinese traditional medicine, has a widespread distribution in a few ecological habitats of China. We generated a full-length complementary DNA (cDNA) library from a sample of elite individuals with superior antibacterial properties, with satisfactory parameters such as library storage (4.30 * 106 CFU), efficiency of titre (1.30 * 106 CFU/mL), transformation efficiency (96.35%), full-length ratio (64.00%) and redundancy ratio (3.28%). The BLASTN search revealed the facile formation of counterparts between the experimental sample and Arabidopsis thaliana in view of high-homology cDNA sequence (90.79%) with e-values <1e - 50. Sequence similarities to known proteins indicate that the entire sequences of the full-length cDNA clones consist of the major of functional genes identified by a large set of microarray data from the present experimental material. For other Compositae species, a large set of full-length cDNA clones reported in the present article will serve as a useful resource to facilitate further research on the transferability of expressed sequence tag-derived simple sequence repeats (EST-SSR) development, comparative genomics and novel transcript profiles. PMID- 26740777 TI - Influence of cryopreservation on the antioxidative activity of in vitro cultivated Hypericum species. AB - Antioxidative activity of two in vitro cultivated Hypericum species - H. rumeliacum Boiss. and H. tetrapterum Fr. - was estimated after cryopreservation. Both species were successfully regenerated after a cryopreservation procedure performed by the vitrification method. H. tetrapterum did not manifest any significant oxidative stress-induced changes caused by low-temperature treatment. Conversely, a decrease in green pigments' content of H. rumeliacum was measured, particularly pronounced in chlorophyll b, which was accompanied by an increase of carotenoids in the regenerated plants. A strong increase of malone dialdehyde and H2O2 levels in H. rumeliacum tissues was detected. Superoxide dismutase activity was enhanced by 170%, as well as the catalase activity, which was 220% above the control. The same trend was observed in H. tetrapterum, although less pronounced 143% increase of superoxide dismutase and 112% of catalase. Cryopreservation did not influence the phenol content in the examined plants, but it led to an increase of flavonoid content, especially in H. tetrapterum, by 237%. Total antioxidant activity in regenerated H. tetrapterum varied around the control level, but it was increased in H. rumeliacum. The free proline content in H. tetrapterum remained almost unaffected after freezing, as opposed to H. rumeliacum, where a strong increase of proline content (208% above the control) occurred. An electrolyte leakage from the cells of H. rumeliacum regenerated after cryopreservation was also registered, albeit not significant. PMID- 26740778 TI - Functional state modelling approach validation for yeast and bacteria cultivations. AB - In this paper, the functional state modelling approach is validated for modelling of the cultivation of two different microorganisms: yeast (Saccharomyces cerevisiae) and bacteria (Escherichia coli). Based on the available experimental data for these fed-batch cultivation processes, three different functional states are distinguished, namely primary product synthesis state, mixed oxidative state and secondary product synthesis state. Parameter identification procedures for different local models are performed using genetic algorithms. The simulation results show high degree of adequacy of the models describing these functional states for both S. cerevisiae and E. coli cultivations. Thus, the local models are validated for the cultivation of both microorganisms. This fact is a strong structure model verification of the functional state modelling theory not only for a set of yeast cultivations, but also for bacteria cultivation. As such, the obtained results demonstrate the efficiency and efficacy of the functional state modelling approach. PMID- 26740779 TI - Mapping QTLs for cold tolerance at germination and the early seedling stage in rice (Oryza sativa L.). AB - Cold tolerance is an important breeding target in rice production. We studied quantitative trait loci (QTLs) controlling cold tolerance at germination (CTG) and early seedling (CTS) stages, using recombinant inbred lines derived from a japonica * indica cross. CTG was evaluated based on the percentage rate of germination at 15 degrees C for 12 days after pre-incubation of imbibed seeds at 20 degrees C for 2 days. For CTS, seven-day-old seedlings grown at 25 degrees C were subjected to two consecutive periods of three-day cold stress at 4 degrees C with an intervening eight-day recovery at 25 degrees C. CTS evaluation was according to an arbitrary five-point rating system at the fifth day of recovery after each stress period. No correlations were found between CTG and CTS, while a weak correlation was detected between CTS after the first and second stress. By the composite interval mapping, five QTLs for CTG explaining 5.7%-9.3% of the total phenotypic variance (PVE) and nine for CTS with PVE of 5.8%-35.6% were detected. Only one of these QTLs was common, indicating growth-stage specificity of cold tolerance. Four of the five QTLs after the second cold stress were different from the ones after the first cold stress. Analysis of variance test showed significant interactions between alleles at the QTL sites and the two stress conditions with respect to the mean CTS scores. A possible involvement of cold acclimation and usefulness of japonica germplasms in breeding for cold tolerance in indica rice was discussed. PMID- 26740780 TI - Expression analysis of innate immunity related genes in the true/field blast resistance gene-mediated defence response. AB - Rice blast resistance (R) genes-mediated resistance response depends on various resistance-related genes involved in incompatible interactions. In this work, the expression profiles of innate rice immunity related genes were examined in the mediated resistance response of true/field resistance genes. Three sets of rice near-isogenic lines (NILs) were used: the resistant NILs carrying true resistance genes in the genetic background of the susceptible cultivar Nipponbare (NB), NB Pib, NB-Pizt, NB-Pik and NB-Pita2; NILs bearing field resistance genes pi21 in the susceptible cultivar Aichiasahi (AA) AA-pi21, Kahei (KHR). The marker gene OsWRKY45 of salicylic acid (SA) signalling was upregulated in all tested cultivars. And, JAmyb (marker gene of jasmonic acid signalling) showed higher upregulation in the resistance lines with nucleotide-binding sites and leucine rich repeat (NBS-LRR) R genes Pib, Pizt, Pik, Pita2 and Pikahei than in NB and KHS. SalT of abscisic acid (ABA) signalling may be involved in the R/Avr interaction, including Pizt, Pik, pi21 and Pikahei. However, SalT was shown to negatively regulate Pib/AvrPib interaction. OsPR1b and PBZ1 were differentially expressed and strongly activated at a later stage by 48 h post-inoculation. Interestingly, there was evidence that OsPR1b and PBZ1 played an important role in the pi21-mediated response. It was shown that OsRAR1 could be upregulated in the true resistance line NB-Pita2 and the field resistance line KHR, while OsSGT1 and OsHSP90 could be upregulated in all tested lines. The involvement of these genes illustrated the complexity of the downstream signalling pathways in the mediated resistance response of true/field resistance genes. PMID- 26740781 TI - Heterologous expression of glutamyl-tRNA reductase gene in Rhodobacter sphaeroides O.U.001 to enhance 5-aminolevulinic acid production. AB - The pathways for synthesis of 5-aminolevulinic acid (5-ALA) use either succinyl CoA and glycine (C-4 pathway), or glutamate (C-5 pathway). Although Rhodobacter sphaeroides synthesizes 5-ALA through the C-4 pathway, it also has the genes coding for the enzymes of the C-5 pathway, except for glutamyl-tRNA reductase. The glutamyl-tRNA reductase gene was cloned from Rhodospirillum rubrum and expressed in R. sphaeroides; thus, the C-5 pathway was enabled to function upon assembling all the required genes. Consequently, a new and unique bacterial strain producing more 5-ALA was developed. Biohydrogen was also produced in the same bioprocess within a biorefinery approach using sugar beet molasses as substrate. The amount of 5-ALA produced by the modified strain was 25.9 mg/g dry cell weight (DCW), whereas the wild-type strain produced 12.4 mg/g DCW. In addition, the amount of H2 generated by the modified and wild-type cells, respectively, was 0.92 L/L culture and 1.05 L/L culture. PMID- 26740782 TI - Enzymatic production of a solvent-free menthyl butyrate via response surface methodology catalyzed by a novel thermostable lipase from Geobacillus zalihae. AB - Most substrate for esterification has the inherent problem of low miscibility which requires addition of solvents into the reaction media. In this contribution, we would like to present an alternative and feasible option for an efficient solvent-free synthesis of menthyl butyrate using a novel thermostable crude T1 lipase. We investigated the effects of incubation time, temperature, enzyme loading and substrate molar ratio and determined the optimum conditions. The high conversion of menthyl butyrate catalyzed by crude T1 lipase in a solvent free system is greatly affected by temperature and time of the reaction media. The highest yield of menthyl butyrate was 99.3% under optimized conditions of 60 degrees C, incubation time of 13.15 h, 2.53 mg, 0.43% (w/w) enzyme to substrate ratio and at molar ratio of butyric anhydride/menthol 2.7:1. Hence, the investigation revealed that the thermostable crude T1 lipase successfully catalyzed the high-yield production of menthyl butyrate in a solvent-free system. The finding suggests that the crude T1 lipase was a promising alternative to overcome shortcomings associated with solvent-assisted enzymatic reactions. PMID- 26740783 TI - Rifoligotyping assay: an alternative method for rapid detection of rifampicin resistance in Mycobacterium tuberculosis isolates from Morocco. AB - One of the greatest threats to global tuberculosis (TB) control is the growing prevalence of drug resistant strains. In the past decades, considerable efforts have been made upon the development of new molecular technologies and methodologies for detection of drug resistance in Mycobacterium tuberculosis (MTB). A sensitive, specific reverse line blot assay, called rifoligotyping (RIFO), for the detection of genotypic resistance to rifampicin (RIF), was designed and evaluated. RIFO includes oligonucleotide probes specific for wild type and mutant sequences, allowing specific and sensitive detection of both genotypes in a single assay. The RIFO was applied on 500 MTB isolates from Morocco. The results of the RIFO showed a good sensitivity (90.9%) and high specificity (100%); the positive and negative predictive values were 100% and 96.1%, respectively. This rapid, simple, economical assay provides a practical alternative for RIF genotyping, especially in low-income countries, to improve TB control and management. PMID- 26740784 TI - In vitro screening for anti-acetylcholiesterase, anti-oxidant, anti-glucosidase, anti-inflammatory and anti-bacterial effect of three traditional medicinal plants. AB - In this study we investigated the phytoconstituents Calluna vulgaris, Ferula hermonis and Tribulus terrestris, and then assessed their possible biological activities by using standard methods. A preliminary phytochemical investigation of the three extracts revealed the presence of alkaloids, flavonoids, proteins, lipids, phenolic compounds, saponins, sterols and amino acids. Three extracts showed anti-oxidant effect as they inhibited the 1,1-diphenyl-2-picryl hydrazyl (DPPH) oxidation and production of thiobarbituric acid reactive substances (TBARS). Moreover, three extracts showed anti-acetylcholiesterase (AChE) and this effect was concentration dependent. C. vulgaris was the most potent inhibitor of AChE. Furthermore, the three plant extracts had an inhibitory effect toward alpha glucosidase. The inhibitory effect was concentration dependent and the most potent inhibitor for alpha-glucosidase was the extract from T. terrestris. Calluna vulgaris showed anti-inflammatory effect at tested concentrations while the other two extracts exhibited this effect only at concentration of 25 MUg/mL. Finally, C. vulgaris had a significant effect against pathogenic bacteria (Agrobacterium tumefaciens, Erwinia sp., Klebsiella pneumonia and Pseudomonas aeruginosa) in comparison to other extracts from Ferula sp., or Tribulus sp. In conclusion, all tested extracts could be promising sources for the treatment of diabetes, Alzheimer's disease, infectious diseases and oxidative stress related disorders because they are rich in phenols and flavonoids that give anti-oxidant molecules and produce an inhibitory effect against the tested enzymes. PMID- 26740785 TI - Measurement of bio-physical signals for posture movement on the transformation system. AB - A signal transformation system of posture movement for the stable state was designed in order to measure the bio-physical signal. To estimate the subject in a stable state on the basis of the bio-physical signal in the posture movement, the conditions of vision, vestibular, somatosensory apparatus and the central nervous system (CNS) were detected. Based on the vision condition, there was a greater average variation (Vi-alphaAVG-MAX and Vi-alphaAVG-MIN) in position with eyes closed and eyes opened (PC and PO), which was 27.11 +/- 6.36 units. The vestibular condition showed a slightly larger average variation (Ve-alphaAVG-MAX and Ve-alphaAVG-MIN) in the body position with PC and PO, which was 6.60 +/- 1.65 units. The somatosensory condition demonstrated a lower average variation (So alphaAVG-MAX and So-alphaAVG-MIN) in position with PC and PO that amounted to 3.653 +/- 2.424 units. The CNS condition was confirmed to indicate very little average variation (C-alphaAVG-MAX and C-alphaAVG-MIN) in body position with PC and PO that was at 0.401 +/- 0.56 units. As the model depends on the bio-physical transformation system of posture movement, the average values of these perturbations were computed (0.01-2 Hz, range of Fourier frequency). The system consists of a data algorithm, an acquisition system, a data signal processing unit and a network system for the evaluated stability. PMID- 26740786 TI - Effect of cyprodinil and fludioxonil pesticides on bovine liver catalase activity. AB - This study investigated if the use of the pesticides cyprodinil and fludioxonil produced an inhibitory effect on the bovine liver catalase (CAT) activity. It was documented that the activity of the enzyme decreased with increasing concentrations of cyprodinil and fludioxonil from 0 to 500 ppm. At pesticide concentrations of 250 and 500 ppm, the activity of CAT remained unchanged and passed to a steady state. The exposure to cyprodinil in concentrations of 10, 50, 100, 250 and 500 ppm, led to a decrease in the per cent of the CAT enzyme activity calculated as 45.4, 68.0, 73.0, 77.8 and 77.4, respectively. Similarly, the exposure to fludioxonil in concentrations of 10, 50, 100, 250 and 500 ppm, produced the following percentage decrease in the CAT enzyme activity: 20.0, 30.8, 42.8, 46.3 and 45.9, respectively. Cyprodinil inhibited CAT competitively, whereas the mechanism of fludioxonil inhibition over the enzyme was non competitive. PMID- 26740787 TI - Degradation kinetics and pathway of phenol by Pseudomonas and Bacillus species. AB - This article elucidates that strain Pseudomonas aeruginosa (IES-Ps-1) is a versatile toxic organic compound degrader. With the degradation of malathion and cypermethrin (studied by other researchers previously), this strain was able to degrade phenol. Two other indigenous soil flora (i.e., Pseudomonas sp. (IES-S) and Bacillus subtilis (IES-B)) were also found to be potential phenol degraders. Phenol was degraded with Monod kinetics during growth in nutrient broth and mineral salts medium. Before entering into the growth inhibition phase, strains IES-Ps-1, IES-S and IES-B could tolerate up to 400, 700 and 500 mg/L phenol, respectively, when contained in nutrient broth. However, according to the Luong Levenspiel model, the growth of strains IES-Ps-1, IES-S and IES-B would cease at 2000, 2174 and 2190 mg/L phenol, respectively. Strain IES-Ps-1 degraded 700, 900 and 1050 mg/L phenol contained in mineral salts medium with the specific rates of 0.034, 0.075 and 0.021 h-1, respectively. All these strains grew by making clusters when exposed to phenol in order to prevent damages due to high substrate concentration. These strains transformed phenol into catechol, which was then degraded via ortho-cleavage pathway. PMID- 26740788 TI - Bacillus safensis LAU 13: a new source of keratinase and its multi-functional biocatalytic applications. AB - A newly isolated bacterium identified as Bacillus safensis based on biochemical tests and 16S rRNA analysis and its mutant variant created by exposure to ultraviolet radiation at 254 nm were investigated for keratinolytic activity. The wild-type strain produced 35.4-50.4 U/mL keratinase over a period of 120 h, while the mutant one yielded 64.4-108.5 U/mL keratinase for the same period of 120 h. The optimal conditions for the enzyme activities were pH 7.5 and 40 degrees C. The mutant and wild-type strain keratinases retained 59% and 54% of their activity after 12 h pretreatment at 40 degrees C, and 64% and 60% of their activity after 12 h at pH 7.5, respectively. The keratinases showed high substrate specificity for feathers, but low specificity for human and bovine hairs. The enzymes were activated by Na+, Ca2+, Fe2+ and Mg2+. However, while Mn2+ activated the enzyme from the mutant strain, it inhibited that of the wild type. The mutant and wild-type strain completely degraded whole chicken feathers after 6 and 9 days at 30 +/- 2 degrees C, and also completely dehaired goat skin within 12 and 16 h, respectively, without damage to the skin. Similarly, remarkable destaining of blood-stained cloth occurred within 2-3 h. The obtained results showed an improvement in the properties of the mutant strain for use of the micro-organism or its enzyme as biocatalysts. PMID- 26740790 TI - Complementary annealing mediated by exonuclease: a method for seamless cloning and conditioning site-directed mutagenesis. AB - Traditional cut-paste DNA cloning is often limited by the availability of restriction enzyme sites. Here, we described the complementary annealing mediated by exonuclease (CAME), in which the insert or vector fragment is amplified to carry sequences complementary to the other, and both fragments are modified by exonuleases to create directional single-stranded overhangs. The two recessed DNA fragments are joined through complementary strand annealing. The CAME is highly efficient for cloning the DNA of at least 12 kb and single DNA fragment out of a complex DNA sample. Moreover, the application of CAME greatly improved the efficiency of site-directed mutagenesis. PMID- 26740789 TI - Optimization of lipase production on agro-industrial residue medium by Pseudomonas fluorescens (NRLL B-2641) using response surface methodology. AB - The aim of our research was to explore the most cost-efficient and optimal medium composition for the production of lipase from Pseudomonas fluorescens (NRLL B 2641) culture grown on sunflower oil cake (SuOC) by applying response surface methodology (RSM). The oil cake was used instead of carbon sources. Peptone, ammonium sulphate and the carbon source (SuOC) were the most important factors as it is obligatory for microbial growth. Subsequently, the optimum values for the carbon source, peptone and ammonium sulphate were found to be 11.10% (w/v), 1.18% (w/v) and 0.83% (w/v), respectively. Experiments carried out under optimum conditions revealed a maximum lipase activity of 10.8 U mL-1, which was achieved after 48 h of fermentation. The obtained results were finally verified with batch experiments carried out under the optimum conditions evaluated and it was demonstrated that the SuOC from agro-industrial residue as substrates can be used as an inexpensive base (carbon source) for the production of lipase by P. fluorescens (NRLL B-2641). PMID- 26740791 TI - Subclinical hypothyroidism: association with cardiovascular risk factors and components of metabolic syndrome. AB - The aim of this cross-sectional study was to evaluate the cardiovascular risk in patients with subclinical hypothyroidism (SH) and metabolic syndrome (MetS) components. The study included 60 patients with SH and a control group of 60 healthy volunteers, gender and age matched, with normal thyroid-stimulating hormone (TSH) and free thyroxin (FT4) concentration. The following measurements were made in all participants: TSH, FT4, thyroid peroxidase antibodies, anti thyroglobulin antibodies, body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose, total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), TC/HDL cholesterol and LDL/HDL cholesterol ratio, basal insulin level and homeostatic model assessment insulin resistance (HOMA-IR) index. MetS was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III criteria. The results showed that the following indices were statistically significantly higher in the SH group: BMI (p < 0.05), diastolic blood pressure (p < 0.001), TC (p < 0.05), TG (p < 0.05) and basal insulin level (p < 0.05). Although MetS parameters were present in a higher per cent in the SH group, there was a significantly higher number of patients with hypertension and decreased HDL cholesterol (p < 0.05). More frequently, MetS was diagnosed in SH patients (46.67%) than in the control group (33.33%), although the difference was not statistically significant. These results indicated that the traditional cardiovascular risk factors were more frequently present in SH patients as compared to euthyroid participants. Our results did not confirm significantly higher presence of MetS in SH patients in comparison with euthyroid respondents. PMID- 26740792 TI - Increasing plasmid-based DNA vaccine construct (16 kb pSVK-HBVA) production in Escherichia coli XL10-Gold through optimization of media component. AB - At present, there are production processes to produce protein by Escherichia coli (E. coli) fermentation. Research on the design and optimization of the plasmid fermentation medium, however, is less advanced. The fermentation medium that is optimized for plasmid DNA production is different from the medium that is optimized for protein production. So, establishing a scientific and rational method to optimize the fermentation medium used for plasmid production is very important. Previously, our laboratory developed a novel therapeutic DNA vaccine (named pSVK-HBVA) for hepatitis B based on the alphavirus replicon, and found that E. coli XL10-Gold was the optimal host strain for the production of plasmid pSVK-HBVA. The aim of this study was to establish a scientific and rational method to optimize the fermentation medium used for plasmid production, and investigate the effect of growth medium composition on the production of plasmid pSVK-HBVA harboured in E. coli XL10-Gold, as well as to optimize the medium composition. The one-factor-at-a-time experiments demonstrated that Luria-Bertani (LB) was the optimal basic medium. The optimal carbon source and nitrogen source were glycerol and home-made proteose peptone, respectively. Based on the Plackett Burman (PB) design, proteose peptone, glycerol and NH4Cl were identified as the significant variables, which were further optimized by the steepest ascent (descent) method and central composite design. Growth medium optimization in 500 mL shake flasks by response surface methodology resulted in a maximum volumetric yield of 13.61 mg/L, which was approximately 2.5 times higher than that obtained from the basic medium (LB). PMID- 26740793 TI - Closure of a human tissue biobank: individual, institutional, and field expectations during cycles of promise and disappointment. AB - Biobanks are increasingly being established to act as mediators between patient donors and researchers. In practice, some of these will close. This paper details the experiences of one such bank. We report interviews with the bank's staff and oversight group during the period when the bank ceased biobanking activity, reconfigured as a disseminator of best practice, before then closing altogether. The paper makes three distinct contributions: (i) to provide a detailed account of the establishment, operational challenges, and eventual closure of the bank, which makes clear the rapid turnover in a cycle of promise and disappointment; (ii) to explore this in terms of a novel analytical focus upon field, institutional, and individual expectations; and (iii) to use this typology to demonstrate how, even after the bank's closure, aspects of its work were reconfigured and reused in new contexts. This provides a unique empirical analysis of the under-reported issue of biobank closure. PMID- 26740794 TI - Introduction: Young Fatherhood: Lived experiences and policy challenges. AB - The entry of young people into early parenthood has long been regarded as an issue for social policy and for professional practice in the UK and internationally. Despite a steadily falling trend, most notably since 1998, the UK still has one of the highest rates of teenage pregnancy in Europe, concentrated in the most socially disadvantaged areas of the country (Office for National Statistics, 2015). The majority of these pregnancies are unplanned, with about half resulting in the birth of a child, although the extent to which this should be a cause for concern is a contested issue (Duncan et al., 2010). Considerable research evidence exists on the experiences of young mothers, with a range of interventions designed to meet their needs. However, young fathers (defined as those under the age of 25, a quarter of whom are estimated to be in their teens) have, until recently, been neglected in both research and policy. Over the past decade, small pockets of research evidence on the circumstances, practices and values of young fathers have begun to coalesce into a fledgling evidence base. However, the notion of 'feckless' young men, who are assumed to be absent, or disinterested in 'being there', or, worse, regarded as a potential risk to their children, continues to hold sway, particularly in popular media and some political discourses (Neale and Davies, 2015). PMID- 26740795 TI - Becoming a Young Breadwinner? The Education, Employment and Training Trajectories of Young Fathers. AB - The entry into fatherhood is a major life course transition involving the acquisition of new adult roles and responsibilities. This transition is rarely planned for young fathers, and may involve a range of challenges, not least their capacity to provide materially and financially for their child. Drawing on a Qualitative Longitudinal study of young fathers in the UK, this article charts their very different pathways through education, training and employment, showing how these are shaped by a constellation of life circumstances. The implications for policy are considered in the light of a shifting landscape of welfare reform and 'austerity' measures. PMID- 26740796 TI - Patterns of Engagement and Non-Engagement of Young Fathers in Early Intervention and Safeguarding Work. AB - This article is based on research into early intervention and safeguarding work with young fathers. It draws on a study of the Family Nurse Partnership (FNP), a home visitation service in the UK that is offered to vulnerable teenage mothers. The research investigated whether and how such early intervention work was done with the fathers of these babies. Three broad patterns of engagement emerged from the research: (1) where fathers were fully engaged with the service straightaway and the relationship with the family nurse deepened over time; (2) where fathers were partially engaged with the service; and (3) where fathers were resentful at the outset and never stopped being resistant and sometimes hostile towards intervention. Within these broad patterns several nuanced aspects of professional father relationships are identified, which are the product of the interaction of several factors. Some general implications for early intervention and safeguarding work with fathers and their babies are drawn out. PMID- 26740797 TI - Risk, Resource, Redemption? The Parenting and Custodial Experiences of Young Offender Fathers. AB - Drawing on an ESRC funded qualitative longitudinal study of young fatherhood, this article explores the experiences of young offender fathers, the complex intersection of offender and fatherhood pathways for young men and the impact of professional support and tailored intervention programmes on these processes. The article challenges the axiom of young offender fathers as inherently 'risky', and suggests the utility of a dynamic, life course approach to criminal policy and practice that recognises the fluidity of their life journeys, and brings ideas of redemption more centrally into the picture. PMID- 26740798 TI - The Lives of Young Fathers: A Review of Selected Evidence. AB - While young fathers have been neglected in social research in the UK, over the past fifteen years a small but growing body of empirical evidence has emerged across a range of studies. This review article draws selectively on this literature to document the characteristics of young fathers in the UK and their lived experiences. It presents compelling evidence for the desire of young fathers to be engaged as parents, despite the sometimes multiple challenges that they face. The article begins with a demographic profile of young fathers and documents what is known of young fathers' relationships with their children, the child's mother and wider kin. It goes on to consider a range of practical issues facing young fathers. The article concludes with a consideration of young fathers' support needs and experiences of professional support, drawing out the implications for policy and professional practice. PMID- 26740799 TI - Supporting Young Dads' Journeys through Fatherhood. AB - While the recent Coalition government committed to some initiatives supporting the role of parents, relationships and the early years, there remains a lack of focus on fathers as a distinct policy area. This is reflected at local government level, as lead professionals for young fathers are rare and data on the number of young fathers in each local area are not routinely collected. Barnardo's was funded by the Department for Education in 2012, as part of the Family Strategic Partnership, to highlight the needs and experiences of young fathers in England, and the joint role of statutory and voluntary services in supporting them (fully reported by Barnardo's in Cundy, 2012). Based on selected case studies drawn from research and a range of practice organisations, this article presents the journeys of five young fathers and their experience of maternity services, children's centres, schools, housing services and the secure estate. PMID- 26740800 TI - Evaluation of local trace element status and 8-Iso-prostaglandin F2alpha concentrations in patients with Tinea pedis. AB - BACKGROUND: Tinea pedis (TP) is an infection of the feet caused by fungi. The infectious diseases caused by dermatophytes are mainly related to the enzymes produced by these fungi. Up to the now, the local 8-iso-prostaglandin F2alpha (8 iso-PGF2alpha), concentration as oxidative stress biomarker and trace elements status have not been published in patients with TP. The aim of this study is to evaluate the relationship between oxidative stress and trace elements (Cu, Zn, Se), and to evaluate the ratios of Cu/Zn and Cu/Se in this disorder. METHODS: Forty-three consecutive patients with a diagnosis of unilateral interdigital TP were enrolled in this study. The samples were obtained by scraping the skin surface. 8-iso-PGF2alpha concentrations in scraping samples were determined by ELISA. In addition, the levels of Se, Zn and Cu in scraping samples were determined on flame and furnace atomic absorption spectrophotometer using Zeeman background correction. RESULTS: Oxidative stress was confirmed by the significant elevation in 8-iso-PGF2alpha concentrations (p < 0.05). When compared to non lesional area, Zn and Se levels were significantly lower on lesional area, whereas Cu levels was higher on the lesional area than the non-lesional area (p < 0.05). In addition, the correlation results of this study were firstly shown that there were significant and positive correlations between Cu and 8-iso-PGF2alpha parameters, but negative correlations between Se-Cu; Se-8-iso-PGF2alpha parameters in lesional area. Furthermore, the ratios of Cu/Zn and Cu/Se were significantly higher on the lesional area than the non-lesional area (p < 0.05). According to sex and fungal subtypes, there was no significant difference in the concentrations of 8-iso-PGF2alpha and trace elements in patients with TP (p > 0.05). CONCLUSIONS: Our results showed that there is a possible link between oxidative stress (increased 8-iso-PGF2alpha concentrations) and imbalanced of trace elements status in lesional area of TP patients. The use of antifungal agents together with both Zn and Se drugs could be helpful in the both regression of disease and in shortening the duration of disease. PMID- 26740802 TI - Retraction. AB - [This retracts the article on p. 170 in vol. 15, PMID: 26130980.]. PMID- 26740801 TI - Angina treatments and prevention of cardiac events: an appraisal of the evidence. AB - Angina pectoris is the symptomatic manifestation of transient myocardial ischaemia. At the most fundamental level, angina arises when myocardial oxygen demand exceeds the ability of the coronary circulation to provide adequate oxygen delivery to maintain normal myocardial metabolic function. In vivo, the balance of oxygen demand and delivery is a complex physiological process that can be altered by a variety of interventions. Lifestyle modification is a cornerstone of cardiovascular disease management, with or without angina. Additional pharmaceutical and physical interventions are usually applied to patients with angina. Mechanisms of action for these interventions include heart rate modulation, vascular smooth muscle relaxation, metabolic manipulation, revascularization, and others. A number of these interventions have overlapping mechanisms that target angina. Additionally, some interventions may directly or indirectly prevent or delay adverse outcomes such as myocardial infarction or death. This review summarizes current evidence for many applied ischaemia treatments documented to modify angina and comments on available evidence relating to improvement in cardiovascular outcomes. PMID- 26740803 TI - The Utility of Fisher's Geometric Model in Evolutionary Genetics. AB - The accumulation of data on the genomic bases of adaptation has triggered renewed interest in theoretical models of adaptation. Among these models, Fisher Geometric Model (FGM) has received a lot of attention over the last two decades. FGM is based on a continuous multidimensional phenotypic landscape, but it is for the emerging properties of individual mutation effects that it is mostly used. Despite an apparent simplicity and a limited number of parameters, FGM integrates a full model of mutation and epistatic interactions that allows the study of both beneficial and deleterious mutations, and subsequently the fate of evolving populations. In this review, I present the different properties of FGM and the qualitative and quantitative support they have received from experimental evolution data. I later discuss how to estimate the different parameters of the model and outline some future directions to connect FGM and the molecular determinants of adaptation. PMID- 26740805 TI - Nonlinearity in MCF7 Cell Survival Following Exposure to Modulated 6 MV Radiation Fields: Focus on the Dose Gradient Zone. AB - The study of cell survival following exposure to nonuniform radiation fields is taking on particular interest because of the increasing evidence of a nonlinear relationship at low doses. We conducted in vitro experiments using the MCF7 breast cancer cell line. A 2.4 * 2.4 cm(2) square area of a T25 flask was irradiated by a Varian Novalis accelerator delivering 6 MV photons. Cell survival inside the irradiation field, in the dose gradient zone and in the peripheral zone, was determined using a clonogenic assay for different radiation doses at the isocenter. Increased cell survival was observed inside the irradiation area for doses of 2, 10, and 20 Gy when nonirradiated cells were present at the periphery, while the cells at the periphery showed decreased survival compared to controls. Increased survival was also observed at the edge of the dose gradient zone for cells receiving 0.02 to 0.01 Gy when compared with cells at the periphery of the same flask, whatever the isocenter dose. These data are the first to report cell survival in the dose gradient zone. Radiotherapists must be aware of this nonlinearity in dose response. PMID- 26740804 TI - Molecular Mechanisms of Action of BPA. AB - Bisphenol A (BPA) exposure has been associated with serious endocrine-disrupting effects in humans and wildlife. Toxicological and epidemiological studies evidenced that BPA increases body mass index and disrupts normal cardiovascular physiology by interfering with endogenous hormones in rodents, nonhuman primates, and cell culture test systems. The BPA concentration derived from these experiments were used by government regulatory agencies to determine the safe exposure levels of BPA in humans. However, accumulating literature in vivo and in vitro indicate that at concentrations lower than that reported in toxicological studies, BPA could elicit a different endocrine-disrupting capacity. To further complicate this picture, BPA effects rely on several and diverse mechanisms that converge upon endocrine and reproductive systems. If all or just few of these mechanisms concur to the endocrine-disrupting potential of low doses of BPA is at present still unclear. Thus, taking into account that the incidence and/or prevalence of health problems associated with endocrine disruption have increased worldwide, the goal of the present review is to give an overview of the many mechanisms of BPA action in order to decipher whether different mechanisms are at the root of the effect of low dose of BPA on endocrine system. PMID- 26740806 TI - Risk Evaluation of Endocrine-Disrupting Chemicals: Effects of Developmental Exposure to Low Doses of Bisphenol A on Behavior and Physiology in Mice (Mus musculus). AB - We review here our studies on early exposure to low doses of the estrogenic endocrine-disrupting chemical bisphenol A (BPA) on behavior and metabolism in CD 1 mice. Mice were exposed in utero from gestation day (GD) 11 to delivery (prenatal exposure) or via maternal milk from birth to postnatal day 7 (postnatal exposure) to 10 ug/kg body weight/d of BPA or no BPA (controls). Bisphenol A exposure resulted in long-term disruption of sexually dimorphic behaviors. Females exposed to BPA pre- and postnatally showed increased anxiety and behavioral profiles similar to control males. We also evaluated metabolic effects in prenatally exposed adult male offspring of dams fed (from GD 9 to 18) with BPA at doses ranging from 5 to 50 000 ug/kg/d. The males showed an age-related significant change in a number of metabolic indexes ranging from food intake to glucose regulation at BPA doses below the no observed adverse effect level (5000 ug/kg/d). Consistent with prior findings, low but not high BPA doses produced significant effects for many outcomes. These findings provide further evidence of the potential risks that developmental exposure to low doses of the endocrine disrupter BPA may pose to human health, with fetuses and infants being highly vulnerable. PMID- 26740807 TI - Assessment of Some Immune Parameters in Occupationally Exposed Nuclear Power Plant Workers: Flow Cytometry Measurements of T Lymphocyte Subpopulations and Immunoglobulin Determination. AB - A 10-year survey of immune status of nuclear power plant (NPP) workers was assessed by cellular and humoral immune parameters. The cumulative doses of NPP workers were in the range of 0.06 to 766.36 mSv. The results did not show significant deviations in the studied parameters of cellular and humoral immunity, but a tendency of elevated values in CD3+4+ helper inducers cells, especially its CD4+62L+ subpopulation, regulatory CD4+25+ cells, CD8+28+ cytotoxic subpopulation, and immunoglobulin M, was established. The observed trend of the above-mentioned parameters could be interpreted by assumption that while the adaptation processes are dominated with low prevalence of T-helper (Th) 1 immune response to cumulative doses less than 100 mSv, a switch to Th-2 response occurred at doses above 100 mSv. The impact of a number of other confounding factors on the immune system does not allow definitive conclusions about the direct radiation-induced changes in immune parameters. PMID- 26740809 TI - Endocrine Disruptors: Improving Regulatory Science Policy. AB - Law and science combine in the estimation of risks from endocrine disruptors (EDs) and actions for their regulation. For both, dose-response models are the causal link between exposure and probability (or percentage change) of adverse response. The evidence that leads to either regulations or judicial decrees is affected by uncertainty and limited knowledge, raising difficult policy issues that we enumerate and discuss. In the United States, some courts have dealt with EDs, but causation based on animal studies has been a stumbling block for plaintiffs seeking compensation, principally because those courts opt for epidemiological evidence. The European Union (EU) has several regulatory tools and ongoing research on the risks associated with bisphenol A, under the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Regulation and other regulations or directives. The integration of a vast (in kind and in scope) number of research papers into a statement of causation for either policy or to satisfy legal requirements, in both the United States and the EU, relies on experts. We outline the discursive dilemma and issues that may affect consensus-based results and a Bayesian causal approach that accounts for the evolution of information, yielding both value of information and flexibility associated with public choices. PMID- 26740808 TI - Biological Tools to Study the Effects of Environmental Contaminants at the Feto Maternal Interface. AB - The identification of reproductive toxicants is a major scientific challenge for human health. Prenatal life is the most vulnerable and important time span of human development. For obvious ethical reasons, in vivo models cannot be used in human pregnancy, and animal models do not perfectly reflect human physiology. This review describes the in vitro test models representative of the human feto maternal interface and the effects of environmental chemicals with estrogen-like activity, mainly bisphenol A and para-nonylphenol, with a particular emphasis on the effects at low, nontoxic doses similar to concentrations commonly detected in the population. PMID- 26740810 TI - Biological Response of Positron Emission Tomography Scan Exposure and Adaptive Response in Humans. AB - The biological effects of exposure to radioactive fluorodeoxyglucose ((18)F-FDG) were investigated in the lymphocytes of patients undergoing positron emission tomography (PET) procedures. Low-dose, radiation-induced cellular responses were measured using 3 different end points: (1) apoptosis; (2) chromosome aberrations; and (3) gammaH2AX foci formation. The results showed no significant change in lymphocyte apoptosis, or chromosome aberrations, as a result of in vivo (18)F-FDG exposure, and there was no evidence the PET scan modified the apoptotic response of lymphocytes to a subsequent 2 Gy in vitro challenge irradiation. However, lymphocytes sampled from patients following a PET scan showed an average of 22.86% fewer chromosome breaks and 39.16% fewer dicentrics after a subsequent 2 Gy in vitro challenge irradiation. The effect of (18)F-FDG exposure on phosphorylation of histone H2AX (gammaH2AX) in lymphocytes of patients showed a varied response between individuals. The relationship between gammaH2AX foci formation and increasing activity of (18)F-FDG was not directly proportional to dose. This variation is most likely attributed to differences in the factors that combine to constitute an individual's radiation response. In summary, the results of this study indicate(18)F-FDG PET scans may not be detrimental but can elicit variable responses between individuals and can modify cellular response to subsequent radiation exposures. PMID- 26740811 TI - Chromosome Damage Caused by Accidental Chronic Whole-Body Gamma Radiation Exposure in Thailand. AB - In February 2000, a radiation incident involving a medical (60)Co source occurred in a metal scrapyard in Thailand. Several individuals were suspected to have received chronic or fractionated exposures ranging from a few mGy to a several Gy. Using fluorescence in situ hybridization to paint chromosomes, we determined the frequencies of chromosome aberrations in peripheral blood lymphocytes of 13 people who entered the scrapyard, 3 people who involved in recovering the source, and 9 nearby residents. Aberration frequencies greater than controls were observed in 13 of the donors at 3 months postexposure. The predominant form of aberration observed was simple, complete, symmetrical translocations. An approximate 50% decrease in these aberrations and in total color junctions was observed in 7 donors resampled at 16 months postexposure. Although high, acute exposures are known to have detrimental effects, the biological consequences of chronic, low dose-rate radiation exposures are unclear. Thirteen of the donors had elevated aberration frequencies, and 6 also had symptoms of acute radiation syndrome. If there are any long-term health consequences of this incident, it will most likely occur among this group of individuals. The consequences for the remaining donors, who presumably received lower total doses delivered at lower dose rates, are less clear. PMID- 26740812 TI - Threshold for Radon-Induced Lung Cancer From Inhaled Plutonium Data. AB - Cohen's lung cancer mortality data, from his test of the LNT theory, do not extend to the no observed adverse effects level (NOAEL) above which inhaled radon decay products begin to induce excess lung cancer mortality. Since there is concern about the level of radon in homes, it is important to set the radon limit near the NOAEL to avoid the risk of losing a health benefit. Assuming that dogs model humans, data from a study on inhaled plutonium dioxide particulates in dogs were assessed, and the NOAEL for radon-induced lung tumors was estimated to be about 2100 Bq/m(3). The US Environmental Protection Agency should consider raising its radon action level from 150 to at least 1000 Bq/m(3). PMID- 26740813 TI - Serotonin and Histamine Therapy Increases Tetanic Forces of Myoblasts, Reduces Muscle Injury, and Improves Grip Strength Performance of Dmd(mdx) Mice. AB - Duchenne muscular dystrophy (DMD) is a recessive X-linked fatal disorder caused by a mutation in the dystrophin gene. Although several therapeutic approaches have been studied, none has led to substantial long-term effects in patients. The aim of this study was to test a serotonin and histamine (S&H) combination on human skeletal myoblasts and Dmd(mdx) mice for its effects on muscle strength and injury. Normal human bioartificial muscles (BAMs) were treated, and muscle tetanic forces and muscle injury tests were performed using the MyoForce Analysis System. Dmd(mdx) mice, the murine model of DMD, were administered serotonin, histamine, or S&H combination twice daily for 6 weeks, and functional performance tests were conducted once a week. The S&H combination treatment caused significant increases in tetanic forces at all time points and concentrations tested as compared to the saline controls. Dose response of the BAMs to the treatment demonstrated a significant increase in force generation at all concentrations compared to the controls after 3 to 4 days of drug treatment. The highest 3 concentrations had a significant effect on lowering contractile-induced injury as measured by a reduction in the release of adenylate kinase. Histamine only and S&H treatments improved grip strength of Dmd(mdx) mice, whereas serotonin-only treatment resulted in no significant improvement in muscle strength. The results of this study indicate that S&H therapy might be a promising new strategy for muscular dystrophies and that the mechanism should be further investigated. PMID- 26740814 TI - Acute Metabolic Effects of Olanzapine Depend on Dose and Injection Site. AB - Atypical antipsychotics (AAPs), such as olanzapine (OLZ), are associated with metabolic side effects, including hyperglycemia. Although a central mechanism of action for the acute effects on glycemia has been suggested, evidence for peripheral versus central effects of AAPs has been mixed and has not been explored for an effect of OLZ on the respiratory exchange ratio (RER). Here, we tested the hypothesis that some inconsistencies in the glycemic responses are likely a result of different doses and central sites of injection. We also compared the effects of central versus peripherally administered OLZ on the RER of unsedated rats. Third ventricle infusion of OLZ at 0.3 mg/kg caused hyperglycemia within 30 minutes, with a higher dose (1.8 mg/kg) needed to elicit a similar response in the lateral ventricles. In contrast, 3 mg/kg of OLZ was needed to raise blood glucose within 30 minutes when given intragastrically, and 10 mg/kg resulted in a prolonged hyperglycemia lasting at least 60 minutes. Third ventricle injection of OLZ significantly decreased RER after 75 minutes, whereas intragastric OLZ resulted in a faster drop in RER after 30 minutes. Since changes in glycemia were most sensitive when OLZ was infused into the third ventricle, but effects on RER were more rapidly and efficaciously observed when the drug was given peripherally, these results raise the likelihood of a dual mechanism of action involving hypothalamic and peripheral mechanisms. Some discrepancies in the literature arising from central administration appear to result from the injection site and dose. PMID- 26740815 TI - Model Uncertainty via the Integration of Hormesis and LNT as the Default in Cancer Risk Assessment. AB - On June 23, 2015, the US Nuclear Regulatory Commission (NRC) issued a formal notice in the Federal Register that it would consider whether "it should amend its 'Standards for Protection Against Radiation' regulations from the linear non threshold (LNT) model of radiation protection to the hormesis model." The present commentary supports this recommendation based on the (1) flawed and deceptive history of the adoption of LNT by the US National Academy of Sciences (NAS) in 1956; (2) the documented capacity of hormesis to make more accurate predictions of biological responses for diverse biological end points in the low-dose zone; (3) the occurrence of extensive hormetic data from the peer-reviewed biomedical literature that revealed hormetic responses are highly generalizable, being independent of biological model, end point measured, inducing agent, level of biological organization, and mechanism; and (4) the integration of hormesis and LNT models via a model uncertainty methodology that optimizes public health responses at 10(-4). Thus, both LNT and hormesis can be integratively used for risk assessment purposes, and this integration defines the so-called "regulatory sweet spot." PMID- 26740816 TI - Health Care providers and Teen Driving Safety: Topics Discussed and Educational Resources Used in Practice. AB - Traffic crashes are the leading cause of death among teens. Health care providers have an opportunity to address what works to keep teens safe on the road during the patient visit. An online survey was conducted of 1088 health care providers who saw patients at or near driving age. The survey assessed which road safety topics were discussed and which types of educational products were used most often. Family and general practice physicians represented 44.3% of the sample, followed by pediatricians (22.5%), nurse practitioners (17.6%), and internists (15.5%). Nearly all respondents (92.9%) reported addressing one or more driving safety factors (seat belt use, nighttime driving, fatigue, teen passengers, alcohol/drug use, speeding/reckless driving, and cell phone use/texting) with adolescent patients and/or their parents. Seat belt use was reported more often (83.7%) than other topics. The use of parent-teen driving agreements, a known effective intervention, was reported by less than 10% of respondents. Since health care providers expressed interest in receiving written resource materials, distribution of parent-teen driving agreements to health care providers might encourage greater uptake and use of this effective intervention. PMID- 26740817 TI - Gesture-speech integration in narrative: Are children less redundant than adults? AB - Speakers sometimes express information in gestures that they do not express in speech. In this research, we developed a system that could be used to assess the redundancy of gesture and speech in a narrative task. We then applied this system to examine whether children and adults produce non-redundant gesture-speech combinations at similar rates. The coding system was developed based on a sample of 30 children. A crucial feature of the system is that gesture meanings can be assessed based on form alone; thus, the meanings speakers express in gesture and speech can be assessed independently and compared. We then collected narrative data from a new sample of 17 children (ages 5-10), as well as a sample of 20 adults, and we determined the average proportion of non-redundant gesture-speech combinations produced by individuals in each group. Children produced more non redundant gesture-speech combinations than adults, both at the clause level and at the word level. These findings suggest that gesture-speech integration is not constant over the life span, but instead appears to change with development. PMID- 26740818 TI - Comparison of the results of laparoscopic appendectomies with application of different techniques for closure of the appendicular stump. AB - BACKGROUND: Nowadays laparoscopy is used frequently not only in elective surgery but also in abdominal emergencies, including acute appendicitis. There are several techniques used to close the appendicular stump during laparoscopic appendectomy. The aim of the study was to present and compare the results of minimally invasive appendectomies performed with the use of endoscopic staplers (group A), titanium endoclips (group B) and invaginating sutures (group C). METHODS: Three hundred seven patients (mean age = 35.6; SD = 15.9; 178 males,129 females) operated on laparoscopically for acute appendicitis from January 2010 to December 2014 at our department were included in the study. We reviewed retrospectively patients' data including: age, sex, duration of the surgical procedure and hospital stay, mortality, intraoperative and postoperative complication rates in all analyzed groups. RESULTS: There were 102 patients in group A (mean age = 35.8;SD = 15.4; 57 males, 45 females). The average hospital stay in this group was 4.3 days (SD = 1.7), average operation time was 62.0 min (SD = 15), postoperative complication rate was 5.9 %. There were 160 patients in group B (mean age = 35.0; SD = 16.3; 96 males, 64 females). The average hospital stay in this group was 3.6 days (SD = 1.4), average operation time was 62.9 min (SD = 13.5), postoperative complication rate was 5.6 %. There were 45 patients in group C (mean age =37.3; SD = 15.8; 25 males, 20 females). The average hospital stay in this group was 4.6 days (SD = 2.0), average operation time was 73.9 min (SD = 20.8), postoperative complication rate was 6.7 %. There were no intraoperative complications and no mortality in all compared groups of patients operated on laparoscopically for acute appendicitis. CONCLUSIONS: Laparoscopic appendectomies with application of different techniques for closure of the appendicular stump are useful and safe. In our study the shortest hospital stay and lowest complication rate were observed in patients operated with the use of titanium endoclips. The longest hospital stay and operation time and the highest complication rate was associated with the use of invaginating sutures. PMID- 26740819 TI - Polygenic analysis and targeted improvement of the complex trait of high acetic acid tolerance in the yeast Saccharomyces cerevisiae. AB - BACKGROUND: Acetic acid is one of the major inhibitors in lignocellulose hydrolysates used for the production of second-generation bioethanol. Although several genes have been identified in laboratory yeast strains that are required for tolerance to acetic acid, the genetic basis of the high acetic acid tolerance naturally present in some Saccharomyces cerevisiae strains is unknown. Identification of its polygenic basis may allow improvement of acetic acid tolerance in yeast strains used for second-generation bioethanol production by precise genome editing, minimizing the risk of negatively affecting other industrially important properties of the yeast. RESULTS: Haploid segregants of a strain with unusually high acetic acid tolerance and a reference industrial strain were used as superior and inferior parent strain, respectively. After crossing of the parent strains, QTL mapping using the SNP variant frequency determined by pooled-segregant whole-genome sequence analysis revealed two major QTLs. All F1 segregants were then submitted to multiple rounds of random inbreeding and the superior F7 segregants were submitted to the same analysis, further refined by sequencing of individual segregants and bioinformatics analysis taking into account the relative acetic acid tolerance of the segregants. This resulted in disappearance in the QTL mapping with the F7 segregants of a major F1 QTL, in which we identified HAA1, a known regulator of high acetic acid tolerance, as a true causative allele. Novel genes determining high acetic acid tolerance, GLO1, DOT5, CUP2, and a previously identified component, VMA7, were identified as causative alleles in the second major F1 QTL and in three newly appearing F7 QTLs, respectively. The superior HAA1 allele contained a unique single point mutation that significantly improved acetic acid tolerance under industrially relevant conditions when inserted into an industrial yeast strain for second-generation bioethanol production. CONCLUSIONS: This work reveals the polygenic basis of high acetic acid tolerance in S. cerevisiae in unprecedented detail. It also shows for the first time that a single strain can harbor different sets of causative genes able to establish the same polygenic trait. The superior alleles identified can be used successfully for improvement of acetic acid tolerance in industrial yeast strains. PMID- 26740820 TI - Monoallelic and biallelic deletions of 13q14 in a group of CLL/SLL patients investigated by CGH Haematological Cancer and SNP array (8x60K). AB - BACKGROUND: Deletion of 13q14 is the most common cytogenetic change in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and is detected in about 50 % of patients by fluorescence in situ hybridization (FISH), which can reveal presence of del(13)(q14) and mono- or biallelic deletion status without information about the size of the lost region. Array-comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) can detect submicroscopic copy number changes, loss of heterozygosity (LOH) and uniparental disomy (UPD) regions. The purpose of this study was detection of the size of del(13)(q14) deletion in our group of patients, comparing the size of the monoallelic and biallelic deletions, detection of LOH and UPD regions. RESULTS: We have investigated 40 CLL/SLL patients by karyotype, FISH and CGH and SNP array. Mutational status was of immunoglobulin heavy-chain variable-region (IGVH) was also examined. The size of deletion ranged from 348,12 Kb to 38.97 Mb. Detected minimal deleted region comprised genes: TRIM13, miR-3613, KCNRG, DLEU2, miR-16-1, miR-15a, DLEU1. The RB1 deletions were detected in 41 % of cases. The average size in monoallelic 13q14 deletion group was 7,2 Mb while in biallelic group was 4,8 Mb. In two cases 13q14 deletions were located in the bigger UPD regions. CONCLUSIONS: Our results indicate that bigger deletion including RB1 or presence of biallelic 13q14 deletion is not sufficient to be considered as adverse prognostic factor in CLL/SLL. CytoSure Haematological Cancer and SNP array (8x60k) can precisely detect recurrent copy number changes with known prognostic significance in CLL/SLL as well as other chromosomal imbalances. The big advantage of this array is simultaneous detection of LOH and UPD regions during the same test. PMID- 26740821 TI - Patient and clinician views on the quality of foot health care for rheumatoid arthritis outpatients: a mixed methods service evaluation. AB - BACKGROUND: Feet are often the first site of joint involvement in rheumatoid arthritis (RA) and get progressively worse if unmanaged, leading to permanent disability and negatively impacting patients' quality of life. Podiatrists are specialists in the assessment, diagnosis and management of foot and ankle problems, however, RA outpatients often rely on referral from rheumatology clinicians to gain access to musculoskeletal podiatry services on the UK National Health Service (NHS). Therefore, the aim of this evaluation was to identify the foot health needs of rheumatoid arthritis patients and if they are being met by rheumatology clinicians. METHODS: A mixed methods approach was used: collecting qualitative data from patients and quantitative data from clinicians. Two focus groups were conducted with nine RA patients from a tertiary rheumatology outpatient clinic in the UK and the data were thematically analysed to inform a clinician survey. Thirteen rheumatology clinicians, from the same centre, completed the online survey. Resultant data were analysed to produce descriptive statistics. RESULTS: Patient focus group data generated four main themes: (1) need for foot health information, (2) feet ignored during routine consultations, (3) frequency of foot examination and (4) access to podiatry. Survey data highlighted that (i) 69-85 % of clinicians provided patients with foot health information sometimes, (ii) feet were examined in 47 % of routine consultations, (iii) 54 % of clinicians did not examine feet routinely because they are not included in the disease activity score with 28 joints (DAS-28), (iv) 31 % of clinicians referred patients to podiatry upon RA diagnosis, (v) 0 % of clinicians referred patients to podiatry for periodic review, (vi) 54 % of clinicians believed patients will self-report foot problems and (vii) 62 % of clinicians felt competent in foot examination. CONCLUSIONS: RA patients' foot health needs were not being fully met by rheumatology clinicians. Patients want foot health information and easy access to podiatry services. Rheumatology outpatient consultations need to have a wider focus than the DAS-28 and incorporate foot examination as standard. Clinicians need to ensure they have sufficient training and follow current national foot health guidance to provide optimal foot health care and outcomes for their RA patients. PMID- 26740822 TI - Concepts and clinical use of ultra-long basal insulin. AB - Diabetes mellitus (DM) is a public health issue, affecting around 382 million people worldwide. In order to achieve glycemic goals, insulin therapy is the frontline therapy for type 1 DM patients; for patients with type 2 DM, use of insulin therapy is an option as initial or add-on therapy for those not achieving glycemic control. Despite insulin therapy developments seen in the last decades, several barriers remain for insulin initiation and optimal maintenance in clinical practice. Fear of hypoglycemia, weight gain, pain associated with blood testing and injection-related pain are the most cited reasons for not starting insulin therapy. However, new generation of basal insulin formulations, with longer length of action, have shown the capability of providing adequate glycemic control with lower risk of hypoglycemia. PMID- 26740824 TI - Therapeutic Targeting of Circulating Tumor Cells: An Important Problem That Deserves Careful Study. PMID- 26740823 TI - Low Power Laser Irradiation Stimulates the Proliferation of Adult Human Retinal Pigment Epithelial Cells in Culture. AB - We investigated the effects of low power laser irradiation on the proliferation of retinal pigment epithelial (RPE) cells. Adult human RPE cells were artificially pigmented by preincubation with sepia melanin, and exposed to a single sublethal laser pulse (590 nm, 1 us, <200 mJ/cm2). DNA synthesis, cell number, and growth factor activity in irradiated RPE cells were subsequently monitored. The effect of sublethal laser irradiation on the "wound" healing response of an RPE monolayer in an in vitro scratch assay was also investigated. Single pulsed laser irradiation increased DNA synthesis in pigmented RPE cells measured 6 h post-treatment. In the scratch assay, laser irradiation increased the rates of cell proliferation and wound closure. Conditioned medium, collected 48 h following laser treatment, increased cell proliferation of unirradiated cells. Irradiation increased RPE cell secretion of platelet-derived growth factor (PDGF)-B chain, and increased mRNA levels of several growth factors and their receptors, including PDGF, transforming growth factor-beta1, basic fibroblast growth factor, epidermal growth factor, insulin-like growth factor, as well as heat shock proteins. This demonstrates, for the first time, that low power single pulsed laser irradiation stimulates the proliferation of RPE cells, and upregulates growth factors that are mitogenic for RPE cells. PMID- 26740825 TI - Microvascular Obstruction Evaluation Using Cardiovascular Magnetic Resonance (CMR) in ST-Elevated Myocardial Infarction (STEMI) Patients. AB - BACKROUND: Restoration of blood flow in epicardial coronary artery in patients with acute myocardial infarction can, but does not have to restore efficient blood flow in coronary circulation. The aim of the study was a direct comparison of microvascular obstruction (MVO) detected by rest and stress perfusion imaging and gadolinium enhancement obtained 2 min. (early MVO) and 15 min. (delayed MVO) post contrast. MATERIAL/METHODS: 106 patients with first anterior myocardial infarction were studied. Cardiovascular magnetic resonance (CMR) was performed 5+/-2 days after primary percutaneous coronary intervention (pPCI). Stress and rest perfusion imaging was performed as well as early and delayed gadolinium enhancement and systolic function assessment. Scoring of segmental function, perfusion defect, MVO and scar transmurality was performed in 16 segment left ventricular model. RESULTS: The prevalence of MVO varies significantly between imaging techniques ranging from 48.8% for delayed MVO to 94% with stress perfusion. Median sum of scores was significantly different for each technique: stress perfusion 13 (7; 18), rest perfusion 3 (0.5; 6), early MVO 3 (0; 8), delayed MVO 0 (0; 4); p<0.05. Infarct size, stress and rest perfusion defects were independent predictors of LV EF at discharge from hospital. CONCLUSIONS: Imaging protocol has a significant impact on MVO results. The study is the first to describe a stress-induced MVO in STEMI patients. Further research is needed to evaluate its impact on a long term prognosis. PMID- 26740826 TI - Importance of Diffusion Weighted Magnetic Resonance Imaging in Evaluation of the Treatment Efficacy in Multiple Sclerosis Patients with Acute Attacks. AB - BACKGROUND: We planned to investigate contribution of DWMR to the treatment efficacy with ADC values which were measured in acute and chronic plaque before and after MS treatment. ADC changes in normal appearing white matter (NAWM) in patients with MS and healthy volunteers were also evaluated in this study. MATERIAL/METHODS: 25 patients with MS and 30 healthy subjects with normal brain MR findings were included to our study. Contrast enhancement in plaque was evaluated as an acute, and non-contrast enhancement in plaque was evaluated as a chronic. Also, ADC measurements were performed using the same parameters in NAWM in plaque neighborhood and volunteers. Results were compared with appropriate statistical methods. RESULTS: ADC values in acute and chronic plaques were decreased after the treatment, and these reductions were statistically significant for acute plaqus in b500 and for chronic plaques in b500 and b1000. The mean ADC values were measured as 1.53+/-0.49*10(-3) and 1.43+/-0.58*10(-3) in acute plaques and 1.40+/-0.35*10(-3) and 1.34+/-0.36*10(-3) mm(2)/sec in chronic plaques before and after the treatment. CONCLUSIONS: We think that DWMR have important role due to quantitative measurement ability in the evaluation of the treatment efficacy of the MS patients with acute attack in addition to contrast enhanced MR sequence. PMID- 26740827 TI - Effectiveness of CT Computed Tomography Perfusion in Diagnostics of Acute Ischemic Stroke. AB - BACKGROUND: Stroke is the third most common death reason after the cardiovascular disorders and cancer. Cerebral ischemia is a pathology that stems from a decrease in cerebral perfusion. Computed Tomography Perfusion (CTP) is an additional method to the conventional Computed Tomography (CT) that could be performed by using developed softwares, in a short period of time and with a low risk of complications. CTP not only allows early detection of cerebral ischemia but also gives valuable information on the ischemic penumbra which are very important in early diagnosis and treatment. Acute Ischemic Stroke (AIS) can be cured by trombolytic treapy within 3-6 hours after symptom onset. Since rapid screening and accurate diagnosis increase the success of the treatment, the role of neuroradiology in acute ischemia diagnostics and treatment has become more important. Our aim was to define CT skills in early diagnosis of AIS, to define its contribution to patient's diagnosis and treatment and to define its importance regarding patient's prognosis. MATERIAL/METHODS: We included 42 patients that presented to the emergency service and neurology outpatient clinic with the symptoms of acute cerebral incidence. RESULTS: In our study, we found that Cerebral Blood Flow (CBF) is 90.91% sensitive and 100% specific in examining ischemia. CONCLUSIONS: Tissue hemodynamic data, especially sensitivity and specificity rates, which cannot be acquired by conventional CT and MRI methods, can be acquired by the CTP method. PMID- 26740828 TI - Winter Issue 2015. PMID- 26740829 TI - Risk of Pre-and Post-Operative Delirium and the Delirium Elderly At Risk (DEAR) Tool in Hip Fracture Patients. AB - BACKGROUND AND PURPOSE: Delirium is common after hip fracture. Previous work has shown that a simple delirium risk factor tool, the Delirium Elderly At Risk instrument (DEAR), has a high inter-rater reliability in this population. Little research has looked at the ability of risk factor screening tools to identify patients at high risk of pre-operative delirium. This study investigates the ability of the DEAR to identify patients at high risk of pre-operative delirium, as well as reporting its performance in a post-operative validation sample. Associations between delirium risk factors and pre-operative delirium are explored. METHODS: This prospective cohort study took place on an orthopedic in patient service at a University-affiliated tertiary care hospital. Patients aged 65 and older who were admitted for surgical repair of hip fracture (N = 283) were assessed pre-operatively for 5 delirium risk factors (cognitive impairment, sensory impairment, functional dependence, substance use, age) using the DEAR. Patients were assessed for delirium using the Mini-Mental State Examination and the Confusion Assessment Method pre-operatively and on post-operative days 1, 3 and 5. Characteristics of patients who developed delirium were compared with the characteristics of those who did not. RESULTS: Delirium was present in 58% (95% CI = 52-63%) of patients pre-operatively and 42% (95% CI = 36-48%) post operatively. Individually, sensory impairment (chi(2) = 21.7, p = .0001), functional dependence (chi(2) = 24.1, p = .0001), cognitive impairment (chi(2) = 55.5, p = .0001) and substance use (chi(2) = 7.5, p = .007) were significantly associated with pre-operative delirium, as was wait-time for surgery (t = 3.1, p = .003) and length of stay (t = 2.8, p =.03). In multivariate modeling, the strongest association with pre-operative delirium was cognitive impairment. CONCLUSIONS: The DEAR, a simple, delirium risk factor screening tool, can be used to identify hip fracture patients at risk of both pre-operative and post operative delirium, which may allow targeted implementation of delirium prevention strategies. PMID- 26740830 TI - The Fountain of Health: Bringing Seniors' Mental Health Promotion into Clinical Practice. AB - BACKGROUND: The Fountain of Health (FoH) initiative offers valuable evidence based mental health knowledge and provides clinicians with evaluated tools for translating knowledge into practice, in order to reduce seniors' risks of mental disorders, including dementia. METHODS: A presentation on mental health promotion and educational materials were disseminated to mental health clinicians including physicians and other allied health professionals either in-person or via tele education through a provincial seniors' mental health network. Measures included: 1) a tele-education quality evaluation form, 2) a knowledge transfer questionnaire, 3) a knowledge translation-to-practice evaluation tool, and 4) a quality assurance questionnaire. RESULTS: A total of 74 mental health clinicians received the FoH education session. There was a highly significant (p < .0001) difference in clinicians' knowledge transfer questionnaire scores pre- and post educational session. At a two-month follow-up, 19 (25.7%) participants completed a quality assurance questionnaire, with all 19 (100%) of respondents stating they would positively recommend the FoH information to colleagues and patients. Eleven (20.4%) translation-to-practice forms were also collected at this interval, tracking clinician use of the educational materials. CONCLUSIONS: The use of a formalized network for knowledge transfer allows for education and evaluation of health-care practitioners in both acquisition of practical knowledge and subsequent clinical behavior change. PMID- 26740831 TI - Pre-Clerkship Observerships to Increase Early Exposure to Geriatric Medicine. AB - BACKGROUND AND PURPOSE: To foster interest in geriatric care, the Queen's Geriatrics Interest Group (QGIG) collaborated with the Division of Geriatric Medicine to arrange a Geriatrics Pre-Clerkship Observership Program. METHODS: Forty-two pre-clerkship medical students participated in the program between October 2013 and May 2014. Participants were paired with a resident and/or attending physician for a four-hour weekend observership on an inpatient geriatric rehabilitation unit. The program was assessed using: (1) internally developed Likert scales assessing student's experiences and interest in geriatric medicine before and after the observership; (2) University of California Los Angeles-Geriatric Attitudes Scale (UCLA-GAS); and (3) narrative feedback. RESULTS: All participants found the process of setting up the observership easy. Some 72.7% described the observership experience as leading to positive changes in their attitude toward geriatric medicine and 54.5% felt that it stimulated their interest in the specialty. No statistically significant change in UCLA-GAS scores was detected (mean score pre- versus post-observership: 3.5 +/- 0.5 versus 3.7 +/- 0.4; p=.35). All participants agreed that the program should continue, and 90% stated that they would participate again. CONCLUSIONS: The observership program was positively received by students. Structured pre-clerkship observerships may be a feasible method for increasing exposure to geriatric medicine. PMID- 26740833 TI - Ebola in West Africa. Before, now and then. PMID- 26740834 TI - West African Ebola epidemic: lessons and a call to action. AB - The current Ebola epidemic in West Africa is unprecedented in terms of magnitude and spread. A year after the index case had been identified in a remote village in Guinea, over 17,000 cases and 6,000 deaths were reported in Africa and beyond. Many interventions have been implemented but the outbreak rages on. This paper examines key gaps in the interventions and calls for evidence-based actions to reverse the trend and prevent future epidemics of this proportion. PMID- 26740832 TI - Effect of Nutrients, Dietary Supplements and Vitamins on Cognition: a Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Observational studies have suggested that various nutrients, dietary supplements, and vitamins may delay the onset of age-associated cognitive decline and dementia. We systematically reviewed recent randomized controlled trials investigating the effect of nutritional interventions on cognitive performance in older non-demented adults. METHODS: We searched MEDLINE, CINAHL, Embase, and the Cochrane Library for articles published between 2003 and 2013. We included randomized trials of >= 3 months' duration that examined the cognitive effects of a nutritional intervention in non-demented adults > 40 years of age. Meta analyses were done when sufficient trials were available. RESULTS: Twenty-four trials met inclusion criteria (six omega-3 fatty acids, seven B vitamins, three vitamin E, eight other interventions). In the meta-analyses, omega-3 fatty acids showed no significant effect on Mini-Mental State Examination (MMSE) scores (four trials, mean difference 0.06, 95% CI -0.08 - 0.19) or digit span forward (three trials, mean difference -0.02, 95% CI -0.30 - 0.25), while B vitamins showed no significant effect on MMSE scores (three trials, mean difference 0.02, 95% CI 0.22 - 0.25). None of the vitamin E studies reported significant effects on cognitive outcomes. Among the other nutritional interventions, statistically significant differences between the intervention and control groups on at least one cognitive domain were found in single studies of green tea extract, Concord grape juice, chromium picolinate, beta-carotene, two different combinations of multiple vitamins, and a dietary approach developed for the control of hypertension. CONCLUSIONS: Omega-3 fatty acids, B vitamins, and vitamin E supplementation did not affect cognition in non-demented middle-aged and older adults. Other nutritional interventions require further evaluation before their use can be advocated for the prevention of age-associated cognitive decline and dementia. PMID- 26740835 TI - Beyond Ebola: surveillance for all hemorrhagic fever in West Africa should be enhanced. PMID- 26740836 TI - Experience on the management of the first imported Ebola virus disease case in Senegal. AB - The Ebola virus disease, as a first epidemic in West Africa, stands as the most deadly one throughout history. Guinea, the source of the epidemic, Sierra Leone and Liberia remain the most strongly affected. That epidemic thoroughly destabilized the health system of those countries. Following Nigeria, Senegal received its first imported case from the neighboring Republic of Guinea. In that sub regional psychotic context, such a situation has been handled and managed starting from the potential of a health system that is already suitably structured. The organization of the response, the management of the communication system and the rigorous monitoring of contacts have been decisive in the control of the epidemic. Our countries have to be prepared in order to face health threats, and that is the reason why the need to empower our health systems is important. PMID- 26740837 TI - Ethical considerations in the conduct of research on therapies for the prevention and treatment of Ebola virus disease in developing countries. AB - The devastating toll of the Ebola epidemic in West Africa necessitates considerations of new approaches to research into new prevention technologies and treatments for Ebola Virus Disease (EVD). Research must be planned and delivered in consultation with civil society from the epicentre to prevent mistrust and misunderstanding. Ethical considerations include development of local research and regulatory capacity; negotiating the standard of prevention packages for research participants, including healthcare workers; and strengthening health systems in developing countries to ensure effective response to future EVD outbreaks in the region. Also, strategic consultation with local communities is an ethical imperative for EVD research, particularly where there is potential for differential access to prevention and care packages between trial staff and local hospital staff. PMID- 26740838 TI - Ethics, emergencies and Ebola clinical trials: the role of governments and communities in offshored research. AB - The Ebola Virus Disease (EVD) in West Africa has stimulated investments in EVD research. While these research efforts are most welcome, we are concerned about the potential to ignore effective community ethics engagement programmes and critical government regulatory agencies in light of the urgency to conduct clinical trials for EVD therapies and vaccines. We discuss the reasons why community engagement with various research stakeholders is essential, how community engagement should be conducted, and the potential consequences of failing to engage both communities and regulatory agencies by drawing on past experiences in the field of HIV research. We highlight the importance of a) capacity building to enable local researchers design and implement EVD research for future epidemics, b) the need to support community research literacy, and c) the need to build the competency of research regulatory agencies on the continent to address EVD therapy and vaccine research. PMID- 26740840 TI - Preparing for Ebola, the experiences of a national training team (Ghana). PMID- 26740839 TI - Misconceptions about Ebola seriously affect the prevention efforts: KAP related to Ebola prevention and treatment in Kouroussa Prefecture, Guinea. AB - INTRODUCTION: Guinea is the third hardest hit country in the region with 2,806 cases and 1,814 deaths as of January 11, 2015 after Sierra Leone and Liberia respectively. This KAP study was conducted in three sub-prefectures of Kouroussa in the Kankan region of Guinea from 15 December 2014 to 15 January 2015. It was conducted with the general objective of examining the knowledge, attitude and practice related to Ebola prevention and care among the public of Kouroussa Prefecture. METHODS: A cross-sectional study design was employed to collect quantitative data to examine knowledge, attitude and practice related to Ebola. Structured questionnaire was administered by trained data collectors who were supervised by doctors and epidemiologists from WHO and Africa Union. Data were collected from 358 individuals (93% response rate) and analyzed in STATA 13 while tables and graphs are used to display results. RESULTS: Over 96% of the respondents have ever heard about Ebola while only 76.2% believed the disease existed in Kouroussa. Avoiding physical contacts including hand shaking and contacts with body fluids, and early treatment of persons sick from Ebola were the two important prevention methods frequently mentioned (96.8% and 93.9%). Only 35.7% of respondents were found to have comprehensive knowledge about Ebola (composite of correctly accepting three methods of prevention (85%) and rejecting misconceptions (55.7%)). CONCLUSION: The high level of knowledge about modes of transmission and prevention methods has not positively affected the level of comprehensive knowledge about Ebola. In contrast, the prevailing high level of misconceptions surrounding Ebola was found to be responsible for a low comprehensive knowledge. PMID- 26740841 TI - Nigerian response to the 2014 Ebola viral disease outbreak: lessons and cautions. AB - The Ebola virus disease outbreak that initially hit Guinea, Liberia and Senegal in 2014 was projected to affect Nigeria very badly when the first case was reported in July 2014. However, the outbreak was effectively and swiftly contained with only eight deaths out of 20 cases, confounding even the most optimistic predictions of the disease modelers. A combination of health worker and public education, a coordinated field epidemiology and laboratory training program (with prior experience in disease outbreak control in other diseases) and effective set-up of emergency operations centers were some of the measures that helped to confound the critics and contain what would have been an otherwise deadly outbreak in a densely populated country with a highly mobile population. This article highlights the measures taken in Nigeria and looks to the translatable lessons learnt for future disease outbreaks, whether that be from the Ebola virus or other infectious agents. PMID- 26740842 TI - Community Care Centre (CCC) as adjunct in the management of Ebola Virus Disease (EVD) cases during outbreaks: experience from Sierra Leone. AB - Community Care Centres (CCCs) represent an innovative response to the containment of infection and the care of those infected in the context of an an Ebola Virus Disease (EVD) outbreak of unprecedented scale. This paper describes the implementation of this response in the Port Loko district of Sierra Leone in the last quarter of 2014. CCCs were effective in encouraging EVD patients to come forward, thus removing risk of transmission to their families and communities however there is significant scope for improvement in care for patients in the centres if the model is applied in future outbreaks of infectious disease. Changes in lay out of the centres, in staff training and support, in logistics and patient education are recommended. PMID- 26740843 TI - Ebola impact on African health systems entails a quest for more international and local resilience: the case of African Portuguese speaking countries. AB - INTRODUCTION: Ebola epidemics have shown to have significant impacts on many aspects of healthcare systems. African countries have been facing many difficulties while addressing Ebola epidemics, moreover due to both lack of resources and fragmented involvement of national and international entities. The participation of multiple organizations has created serious problems of coordination of aid and the operation of that aid on the ground. This paper aims at addressing the impact of Ebola epidemics on African health systems, with a special focus on the definition of impact mitigation guidelines and the role of resilience. The example of Portuguese speaking countries is presented. METHODS: A combination of literature review and case study methods are used. A literature review on Ebola outbreak impact on health systems will provide information to define a set of guidelines for healthcare services response to Ebola. The role of cooperation in providing additional resilience is described. Finally a case study focusing on the Portuguese collaboration and intervention in African Portuguese Speaking Countries (PALOP) is presented, as an example how the international community can provide additional resilience. RESULTS: The existing knowledge is very helpful to guide both the preparation and the coordination of Ebola preparedness interventions. Additional resilience can be provided by international cooperation. CONCLUSION: In addition to international concrete support in times of crisis, to have a regional strategy of creating (multi national) teams to rapidly implement an intervention while establishing better regional capacity to have sufficient resources to support the "resilience" required of the health system. PMID- 26740844 TI - Implications of Ebola virus disease on wildlife conservation in Nigeria. AB - The recent Ebola Virus Disease outbreak in some West African countries spanning from late 2013 and currently on as of 13th March, 2015 is the most widespread and fatal with human mortality that has surpassed all previous outbreaks. The outbreak has had its toll on conservation of endangered species. This portends danger for the wild fauna of the country if proactive measures are not taken to prepare grounds for evidence-based assertions concerning the involvement of wild species. To this end, there is an urgent need for sweeping census of reserves, national parks and wetlands. As well as the creation of a system involving reportage by sectors like the industries (extractive and construction) including persons and organisations involved with wildlife related activities. This documentation of die offs and unusual events to collaborating institutions, will help in monitoring trends which hitherto would have gone unnoticed. The importance of bats and primates in agriculture and public health via consumption of vermin insects and seed dispersal cannot be over-emphasized. There is the need for caution on the tendencies to destroy indicator species which could be silent pointers to emerging or re-emerging health and environmental issues. Wildlife resources are still reliably useful and caution is advised in the use of blanket destructive policies like fumigation of caves, indiscriminate culling and poisoned baits to destroy supposedly Ebola Disease Virus wildlife reservoirs. This paper highlights the immediate conservation problems and likely future implications of Ebola saga in Nigeria. It tries to identify the gaps in wildlife researches and makes recommendations for probable workable conservation strategies. PMID- 26740845 TI - Ebola epidemic--the Nigerian experience. AB - The current West African ebola epidemic has been described as the most unprecedented in the history of the disease. Nigeria reported its first case of the disease in July, 2014, at the end of the epidemic 20 people were infected and eight of them died. The epidemic resulted in increased knowledge of the disease as well as some misconceptions, increase in household and community hygiene practice and change in social interaction between affected individuals and the community. Prompt response by the government, with the support of international partners and proactive engagement of public health measures resulted in the rapid control of the epidemic; an experience the country hopes to leverage upon in subsequent epidemics. PMID- 26740846 TI - Ebola Virus Diseases in Africa: a commentary on its history, local and global context. AB - Ebola Virus Disease (EVD) started as a minor infection in Uganda in 1974 and has been frequent in Central Africa Region for the past 40 years. For over 40 years, Ebola was treated as an African disease, called a fever and known by other names where occurrences have been frequent. EVD has become a global public health threat following the most recent outbreak in West Africa. By December 31, 2014, Ebola has infected more than 23,500 people in West Africa and killed over 9,500, nearly all in the three worst-affected countries of Guinea, Liberia and Sierra Leone. It is transmitted through blood, vomit, diarrhea and other bodily fluids but cultural attributes associate its etiology to man-made and supernatural causes, hence stemming public health approaches to contain EVD difficult. Distrust and conflict between two healing systems are rife necessitating an African Model of EVD care and prevention. The African model remains indispensable to understand EVD and developing appropriate EVD containing approaches. PMID- 26740847 TI - Comparing the knowledge, attitude and practices of health care workers in public and private primary care facilities in Lagos State on Ebola virus disease. AB - INTRODUCTION: The West African sub-region is currently witnessing an outbreak of EVD that began in December 2013. The first case in Nigeria was diagnosed in Lagos, at a private medical facility in July 2014. Health care workers are known amplifiers of the disease. The study aimed to determine and compare EVD knowledge, attitude and practices among HCWs in public and private primary care facilities in Lagos, Nigeria. METHODS: This was a comparative cross-sectional study. Seventeen public and private primary care facilities were selected from the 3 senatorial districts that make up Lagos State. 388 respondents from these facilities were selected at random and interviewed using a structured questionnaire. RESULTS: Proportion of respondents with good knowledge and practice among public HCWs was 98.5% and 93.8%; and among private HCW, 95.9% and 89.7%. Proportion of respondents with positive attitude was 67% (public) and 72.7% (private). Overall, there were no statistically significant differences between the knowledge, attitude and preventive practices of public HCWs and that of private HCWs, (p<=0.05). CONCLUSION: Timely and intense social mobilization and awareness campaigns are the best tools to educate all segments of the community about public health emergencies. There exists significant surmountable gaps in EVD knowledge, negative attitude and sub-standard preventive practices that can be eliminated through continued training of HCW and provision of adequate material resources. PMID- 26740848 TI - Preventive and social cost implications of Ebola Virus Disease (EVD) outbreak on selected organizations in Lagos state, Nigeria. AB - INTRODUCTION: As Ebola virus disease (EVD) continues to pose public health challenge in West Africa, with attending fears and socio-economic implications in the current epidemic challenges. It is compelling to estimate the social and preventive costs of EVD containment in a Nigerian city. Hence, this study was to determine the social and preventive cost implications of EVD among selected public institutions in Lagos, Nigeria, from July to December, 2014. METHODS: Questionnaires and key-informants interview were administered to respondents and administrators of selected hospitals, hotels and schools in Eti-Osa Local Government Area of Lagos State. Knowledge of disease transmission, mortality and protocols for prevention, including cost of specific preventive measures adopted against EVD were elicited from respondents. Descriptive statistics and categorical analysis were used to summarize and estimate social and preventive costs incurred by respective institutions. RESULTS: An estimated five million, nineteen thousand, three hundred and seventy-nine Naira and eighty kobo (N5,019,379.80) only was observed as direct and social cost implication of EVD prevention. This amount translated into a conservative estimate of one billion, twenty-seven million, ninety-four thousand, seven hundred and fifty-six Naira (N1,027,094,756.10) for a total of four thousand schools, two hundred and fifty three hospitals and one thousand, four hundred and fifty one hotels in Lagos during the period (July 20-November 20, 2014). CONCLUSION: The high cost of prevention of EVD within the short time-frame indicated high importance attached to a preventive policy against highly pathogenic zoonotic disease in Nigeria. PMID- 26740849 TI - Learning from the challenges of Ebola Virus Disease contact tracers in Sierra Leone, February, 2015. AB - INTRODUCTION: Sierra Leone was in the process of strengthening tracing of Ebola Virus Disease (EVD) contact with training of contact tracers, continuous mentoring and monitoring, supervision and continuous support. This was through various national and international organizations. This study aimed at identifying the challenges of contact tracers with a view of improving contact tracing activities in Tonkolili District, Sierra Leone. METHODS: In-depth interview was conducted among contact tracers who were actively involved in contact tracing within the 4 weeks preceding the interview. In-depth interview guide was used to interview the contact tracers. Questions were asked about the state of EVD outbreak, challenges of contact tracing, ways to improving contact tracers activities and ways to ensure community participation and follow up action. RESULTS: A total of 12 Contact tracers were interviewed. Most of the contact tracers saw the lifting of ban by the Government on movement as a delay to stopping the outbreak. Some of them were being threatened by their communities and insulted. Some communities with EVD cases felt it was no longer in Sierra Leone and that the contact tracers were the ones infecting the people with Ebola. More than 80% of the participants indicated that retraining of contact tracers and re-orientation of community members would help in putting a stop to the outbreak. CONCLUSION: All participants indicated interest in improving their activities and performance. They suggested that more social mobilization is needed to ensure the cooperation of their communities. PMID- 26740850 TI - Challenges in controlling the Ebola outbreak in two prefectures in Guinea: why did communities continue to resist? AB - INTRODUCTION: The Ebola outbreak emerged in a remote corner of Guinea in December 2013, and spread into Liberia and Sierra Leone in the context of weak health systems. In this paper, we report on the main challenges faced by frontline health services and by communities including their perceptions and views on the current Ebola response in the Prefectures of Coyah and Forecariah in Guinea. METHODS: A cross-sectional study was conducted in December 2014 using mixed approaches: (i) Desk review; (ii) Interviews; and (iii) Direct observation. RESULTS: Almost one year after the beginning of the Ebola virus disease outbreak in West Africa, the perceptions of stakeholders and the observed reality were that the level of preparedness in the two health districts was low. The study identified poor coordination mechanisms, inadequate training of human resources and lack of equipment and supplies to field teams and health facilities as key elements that affected the response. The situation was worsened by the inadequate communication strategy, misconceptions around the disease, ignorance of local culture and customs and lack of involvement of local communities in the control strategies, within the context of poor socioeconomic development. As a result distrust developed between communities and those seeking to control the epidemic and largely contributed to the reluctance of the communities to participate and contribute to the effort. CONCLUSION: There is a need to rethink the way disease control interventions in the context of an emergency such as Ebola virus disease are designed, planned and implemented in low income countries. PMID- 26740851 TI - Ebola: is the response justified? AB - Ebola virus disease is a viral hemorrhagic fever, first discovered in 1976 in Sudan, where the outbreak infected over 284 people with a 53% case fatality ratio. There have been 34 further epidemics, the current major incident in West Africa having recorded more cases and deaths than all previous outbreaks combined. To date there have been over 27, 000 confirmed, probable and suspected cases and 11,000 reported deaths in Liberia, Guinea and Sierra Leone. With total funding and pledges to help control the outbreak amounting to more than US $2.4 billion, many question how the disease has continued to spread in Sierra Leone and Guinea Conakry, and whether the response to the outbreak has been justified. This article aims to analyze the effectiveness of the responses to the outbreak in terms of economic, social, cultural and, to an extent, political impact. We argue that the response has been justified due to the awareness raised, the infrastructure and staffing improvements, the success in receiving financial aid and the minimal spread to other countries outside the main transmission zone. Despite this, some failures in communication and a slow early response were noted. PMID- 26740852 TI - The effect of Ebola Virus Disease outbreak on hand washing among secondary school students in Ondo State Nigeria, October, 2014. AB - INTRODUCTION: Hand washing with soap and water is one of the cheapest, most effective ways of limiting the spread of Ebola Virus Disease (EVD). Despite its importance the prevalence of hand washing was low before the EVD outbreak in Nigeria. This study aimed at determining the factors associated with improved hand washing practices following the EVD outbreak. METHODS: A descriptive cross sectional study of 440 students from a secondary school in Owo, Ondo State was done. Data was collected in October 2014 when Nigeria was yet to be declared EVD free. Systematic random sampling was used. A semi-structured, interviewer administered questionnaire was used. Data was analysed with epi info version 7, descriptive statistics were done, Chi square test was used for the assessment of significant associations between proportions. Determinants of good hand washing practices was identified using logistics regression analysis at 5% level of significance. RESULTS: Of 440 respondents, mean age was 13.7+/-1.9 years. Females were 48.2%. Only 4.6% have never heard of Ebola Virus Disease.Level of hand washing with soap and water improved by62.6%. Significant improvement in hand washing was in 75.8% of those who heard through social media (p < 0.001), 70.5% of Newspaper readers(p < 0.001), 65.6% of radio listeners (p = 0.001), 75.4% of family members p < 0.001, 76.3% talk in church p < 0.001, 77.6% peers p = 0.02, 72.4% TV p < 0.001. Change in hand washing practices was associated with watching television (AOR: 2.2; CI 95%: 1.1-4.3) and listening to health education in church (AOR: 2.4; CI 95%: 1.2-4.7).Major reason for change in hand washing practices was because of EVD deadly nature, 170(40.5%). CONCLUSION: Watching health education messages on television and listening to it in church are the determinants of change in hand washing practices. Promotion of hand washing with soap and water needs to be sustained to prevent other diseases. Training of students on prevention of EVD was conducted in selected schools. PMID- 26740853 TI - Rare variant testing across methods and thresholds using the multi-kernel sequence kernel association test (MK-SKAT). AB - Analysis of rare genetic variants has focused on region-based analysis wherein a subset of the variants within a genomic region is tested for association with a complex trait. Two important practical challenges have emerged. First, it is difficult to choose which test to use. Second, it is unclear which group of variants within a region should be tested. Both depend on the unknown true state of nature. Therefore, we develop the Multi-Kernel SKAT (MK-SKAT) which tests across a range of rare variant tests and groupings. Specifically, we demonstrate that several popular rare variant tests are special cases of the sequence kernel association test which compares pair-wise similarity in trait value to similarity in the rare variant genotypes between subjects as measured through a kernel function. Choosing a particular test is equivalent to choosing a kernel. Similarly, choosing which group of variants to test also reduces to choosing a kernel. Thus, MK-SKAT uses perturbation to test across a range of kernels. Simulations and real data analyses show that our framework controls type I error while maintaining high power across settings: MK-SKAT loses power when compared to the kernel for a particular scenario but has much greater power than poor choices. PMID- 26740854 TI - Vasospasm Risk in Surgical ICU Patients With Grade I Subarachnoid Hemorrhage. AB - Aneurysmal subarachnoid hemorrhage (SAH) is associated with high mortality. The initial hemorrhage causes death in approximately 25% of patients, with most subsequent mortality being attributable to delayed cerebral ischemia (DCI). Delayed cerebral ischemia generally occurs on post-bleed days 4 through 20, with the incidence peaking at day 8. Because of the risks of DCI, patients with SAH are usually monitored in an intensive care unit (ICU) for 14 to 21 days. Unfortunately, prolonged ICU admissions are expensive and are associated with well-documented risks to patients. We hypothesized that a subset of patients who are at low risk of DCI should be safe to transfer out of the ICU early. All patients admitted to Montefiore Medical Center from 2008 to 2013 with grade I SAH who had their aneurysms successfully protected, had an uncomplicated postoperative course, and had no clinical or ultrasonographic evidence of DCI after day 8 were retrospectively studied. The primary outcome was clinical or ultrasonographic evidence of the development of DCI after day 8. Secondary outcomes included length of ICU and hospital stay and hospital mortality. Forty patients who met the above-mentioned criteria were identified. Of these, only 1 (2.5%) developed ultrasonographic evidence of DCI after day 8 but required no intervention. The mean length of stay in the ICU was until post-bleed day 13, and the mean hospital length of stay was until post-bleed day 14. The in-hospital mortality was 0 of 40. Thus, we identified a low-risk subset of patients with grade I SAH who may be candidates for early transfer out of the ICU. PMID- 26740855 TI - Eastern Equine Encephalitis Treated With Intravenous Immunoglobulins. AB - We report the case of a 68-year-old man from southeastern Massachusetts presenting with encephalitis due to eastern equine encephalitis (EEE) virus. Despite the high morbidity and mortality rate of EEE, the patient made a near complete recovery in the setting of receiving early intravenous immunoglobulins. PMID- 26740856 TI - Morvan Syndrome: A Case Report With Patient Narrative and Video. AB - A 74-year-old gentleman was admitted to the regional neurosciences center with encephalopathy, myokymia, and dysautonomia. Chest imaging had previously identified an incidental mass in the anterior mediastinum, consistent with a primary thymic tumor. Antivoltage-gated potassium channel (anti-VGKC) antibodies were positive (titer 1273 pmol/L) and he was hypokalemic. Electromyogram and nerve conduction studies were in keeping with peripheral nerve hyperexcitability syndrome, and an electroencephalogram was consistent with encephalopathy. A diagnosis of Morvan syndrome was made, for which he was initially treated with high-dose steroids, followed by a 5-day course of intravenous immunoglobulin (IVIG) therapy. He also underwent thymectomy, followed by a postexcision flare of his symptoms requiring intensive care management. Further steroids, plasmapheresis, and IVIG achieved stabilization of his clinical condition, enabling transfer for inpatient neurorehabilitation. He was commenced on azathioprine and a prolonged oral steroid taper. A subsequent presumed incipient relapse responded well to further IVIG treatment. This case report documents a thymoma-associated presentation of anti-VGKC-positive Morvan syndrome supplemented by patient and carer narrative and video, both of which provide valuable further insights into this rare disorder. There are a limited number of publications surrounding this rare condition available in the English literature. This, combined with the heterogenous presentation, association with underlying malignancy, response to treatment, and prognosis, provides a diagnostic challenge. However, the association with anti-VGKC antibody-associated complexes and 2 recent case series have provided some scope for both accurate diagnosis and management. PMID- 26740857 TI - Monocular Blindness as Presentation Manifestation of Neuroblastoma. PMID- 26740858 TI - Horner Syndrome and Thoracic Disc Herniation. PMID- 26740859 TI - Episodic Aphasia Associated With Cortical Spreading Depression After Subdural Hemorrhage Evacuation. AB - Cortical spreading depression (CSD) has been associated with many pathological entities including migraine, trauma, hemorrhage, and mitochondrial disease. The clinical diagnosis remains challenging without the other concomitant features such as headache because CSD can mimic seizure or acute stroke. Wereport of a 77 year-old right handed man with a left subdural hematoma evacuation that subsequently developed episodic aphasia, slurred speech, right nasolabial fold flattening, and right pronator drift. In this case report, we discuss our multimodal diagnostic approach and treatment in a patient with episodic aphasia and neurological deficits in order to propose the diagnosis of cortical spreading depression. CSD should be considered when focal deficits in brief episodes occur after stroke and seizures have been ruled out. Treatment choices as illustrated by this case report can have an impact on outcome and resolution of episodes. PMID- 26740860 TI - Swiss Cheese Striatum. PMID- 26740861 TI - Survey on Neural Networks Used for Medical Image Processing. AB - This paper aims to present a review of neural networks used in medical image processing. We classify neural networks by its processing goals and the nature of medical images. Main contributions, advantages, and drawbacks of the methods are mentioned in the paper. Problematic issues of neural network application for medical image processing and an outlook for the future research are also discussed. By this survey, we try to answer the following two important questions: (1) What are the major applications of neural networks in medical image processing now and in the nearby future? (2) What are the major strengths and weakness of applying neural networks for solving medical image processing tasks? We believe that this would be very helpful researchers who are involved in medical image processing with neural network techniques. PMID- 26740863 TI - Coexistence of p190 BCR/ABL Transcript and CALR 52-bp Deletion in Chronic Myeloid Leukemia Blast Crisis: A Case Report. AB - We introduce a 78-year-old woman presented with thrombocytosis and high blast count who had a history of splenectomy. Her cytogenetic analysis revealed aberrant chromosomal rearrangements in different clonal populations harboring 46XX karyotype with t(9;22) (q34;q11). RT-PCR assay detected the e1a2 BCR-ABL translocation resulting from rearrangement of the minor breakpoint cluster region (m-bcr) in BCR gene. Subsequent evaluation of the disease showed calreticulin (CALR) 52-bp deletion as well as the absence of JAK2 (V617F) heterozygous mutation in granulocyte population of peripheral blood using allele-specific PCR and bi-directional DNA sequencing. To our knowledge, this is the first case of a patient initially diagnosed as p190 BCR-ABL transcript positive CML in blast crisis characterized by a 52-bp deletion in CALR gene. PMID- 26740862 TI - Acquired Hypogonadotropic Hypogonadism (AHH) in Thalassaemia Major Patients: An Underdiagnosed Condition? AB - INTRODUCTION: In males, acquired hypogonadotropic hypogonadism (AHH) includes all disorders that damage or alter the function of gonadotropin-releasing hormone (GnRH) neurons and/or pituitary gonadotroph cells. The clinical characteristics of AHH are androgen deficiency and lack, delay or halt of pubertal sexual maturation. AHH lead to decreased libido, impaired erectile function, and strength, a worsened sense of well-being and degraded quality of life (QOL). PATIENTS AND METHODS: We studied 11 adult men with thalassemia major (TM) aged between 26 to 54 years (mean +/- SD: 34.3 +/- 8.8 years) with AHH. Twelve age- and sex-matched TM patients with normal pubertal development were used as a control group. All patients were on regular transfusions and iron chelation therapy. Fasting venous blood samples were collected two weeks after transfusion to measure serum concentrations of IGF-1, free thyroxine (FT4), thyrotropin (TSH), cortisol, luteinizing hormone (LH), follicle stimulating hormone (FSH), total testosterone (TT), prolactin and estradiol (E2), glucose, urea, creatinine and electrolytes (including calcium and phosphate). Liver functions and screening for hepatitis C virus seropositivity (HCVab and HCV-RNA) were performed. Iron status was assessed by measuring serum ferritin levels, and evaluation of iron concentrations in the liver (LIC) and heart using MRI- T2*. Bone mineral density was measured at the lumbar spine (L1-L4) for all patients with AHH by dual energy X-ray absorptiometry (DXA) using Hologic QDR 4000 machine. RESULTS: The mean basal serum LH and FSH concentrations in AHH patients were 2.4 +/- 2.2 IU/L and 1.2 +/- 0.9 IU/L respectively; these, values were significantly lower compared to the control group. Semen analysis in 5 patients with AHH showed azoospermia in 3 and oligoasthenozoospermia in 2. The percentage of patients with serum ferritin level >2000 ng/ml (severe iron load) was significantly higher in AHH patients compared to controls, 5/11 (45.4 %) versus1/12 (8.3%), p=0.043. Heart iron concentrations (T2* values) were significantly lower in AHH patients compared to controls (p=0.004). Magnetic resonance imaging in the 3 azoospermic patients revealed volume loss and reduction of pituitary signal intensity. Heart T2* values were significantly reduced in the AHH group vs. the controls (p=0.004). On the other hand, liver iron concentration (mg/g dry weight) was not different between the two groups of TM patients. Using DXA, 63.6 % (7/11) of patients with AHH were osteoporotic, and 36.3 % (4/11) were osteopenic. CONCLUSIONS: In this cohort of thalassemic patients iron overload and chronic liver disease appear to play a role in the development of AHH. Treatment of AHH in TM patients is a vital and dynamic field for improving their health and QOL. Early identification and management of AHH are very crucial to avoid long-term morbidity, including sexual dysfunction and infertility. Therapy aims to restore serum testosterone levels to the mid-normal range. Many exciting opportunities remain for further research and therapeutic development. PMID- 26740864 TI - Cytokine Response Associated with Hepatitis C Virus Clearance in HIV Coinfected Patients Initiating Peg Interferon-alpha Based Therapy. AB - BACKGROUND: Treatment of hepatitis C virus (HCV) infection based on peginterferon alpha (pegIFNalpha) and ribavirin induces important changes in cytokine release and T cell activation. OBJECTIVE: Immune response to pegIFNalpha-ribavirin therapy was explored in patients coinfected by HCV and HIV. METHODS: Concentrations of 25 cytokines and CD8(+) T cell activation were monitored in HCV/HIV coinfected patients classified as sustained virological responders (SVR, n=19) and non-responders (NR, n=11). RESULTS: High pretreatment concentrations of IP-10 (CXCL-10) and MCP-1 (CCL-2) were associated with a poor anti-HCV response. PegIFNalpha-ribavirin therapy increased CD8(+) T cell activation and induced significant changes in levels of eleven cytokines related to both Th1 and Th2 responses in SVR (IL-1beta, IL-1RA, IL-4, IL-5, IL-6, IL-7, IL-12p40/70, IL-13, IP-10, eotaxin, MCP-1) but of only six cytokines in NR (IL-1beta, IL-2, IL-5, IL 12p40/70, IL-13, eotaxin). The highest rise in MIP-1beta and MCP-1 levels was observed four weeks after anti-HCV treatment initiation in SVR compared to NR (p=0.002 and p=0.03, respectively), whereas a decrease in IL-8 concentration was associated with treatment failure (p= 0.052). CONCLUSIONS: Higher and broader cytokine responses to pegIFNalpha-ribavirin therapy were observed in SVR patients compared to NR. Changes in IL-8, MIP-1beta, and MCP-1 serum concentrations may be associated with efficacy of pegIFNalpha- and ribavirin-based therapies in patients coinfected by HCV and HIV. PMID- 26740865 TI - Evaluation of Glutathione-S-Transferase P1 Polymorphism and its Relation to Bone Mineral Density in Egyptian Children and Adolescents with Beta-Thalassemia Major. AB - BACKGROUND: Osteoporosis is a major complication of beta thalassemia major (TM). Increased oxidative stress and its controlling genes were linked to osteoporosis. Ile105 Val variant is a functional polymorphism of Glutathione S-transferase P1 (GSTP1), with reduced anti-oxidative property. No data are available about this variant or its association with osteoporosis among thalassemia patients yet. OBJECTIVES: To investigate Ile105Val polymorphism and its possible association with bone mineral density (BMD) values in a group of TM children. METHODS: Thirty five TM children and 30 age and sex matched healthy controls were included. Liver and renal functions, serum ferritin, calcium, phosphorous, alkaline phosphatase and osteocalcin were assayed. BMD was determined by DXA with calculation of Z scores at lumbar spine (LS) and femoral neck (FN). Height for age Z- score (HAZ) adjusted BMD Z-scores were calculated. GSTP1 Ile105Val polymorphism was studied by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The relative frequency of 105 Val allele was significantly higher in TM patients than the controls (p<0.0001). Significant association between genotype subgroups and BMD parameters was detected. Compared to wild homozygotes, polymorphic homozygotes had lower LS-BMD (p =0.029), LS-BMD Z -score (p=0.008 ), LS- BMD haz Z-score (p=0.011), FN- BMD (p= 0.001), FN- BMD Z -score (p=0.02) and FN-BMD haz Z-score (p=0.001). They exhibited higher osteocalcin levels compared to heterozygotes and wild homozygotes (p=0.012, p=0.013, respectively). CONCLUSION: Ile105Val polymorphism was frequent among TM patients and could increase their susceptibility to reduced BMD. Large sample studies are required to confirm these findings. PMID- 26740866 TI - Features of Adolescents Tuberculosis at a Referral TB's Hospital in Tehran, Iran. AB - OBJECTIVE: To identify the pattern of the clinical, radiological, diagnostic procedures and loss to follow-up of the diagnosed cases of active tuberculosis (TB) adolescents. METHODS: This study was a retrospective analysis of the medical records of 143 adolescents aged 10 to 18 years with tuberculosis who were admitted TB wards of National Research Institute of Tuberculosis and Lung Disease (NRITLD) in Tehran, Iran, between March 2006 and March 2011. RESULTS: Of the 143 patients identified, 62.9% were females. Median age of the patients was 16 years. The contact source was identified in 47.5%. The most common presenting symptom was cough (86%). Isolated pulmonary TB (PTB) was detected in 113 patients (79%), 21 patients (14.7%) had extrapulmonary TB(EPTB), and 9 patients (6.3%) had PTB and EPTB. The most common site of EPTB was pleural (14%). The most common radiographic finding was infiltration (61%). Positive acid fast smears were seen in 67.6%. Positive cultures for Mycobacterium tuberculosis (M. TB) were seen in 44.7%. Positive Polymerase chain reaction (PCR) results were seen in 60%. The adolescents aged 15 to 18 years were more likely to lose weight (p=0.001), smear positive (p=0.001), culture positive (p<0.001) and have positive PCR results (p=0.009). The type of TB (p=0.017) was a significant factor influencing loss to follow-up. CONCLUSIONS: The study has revealed that the clinical and radiological findings of TB in adolescents are combination as identified in children and adults. The TB control programs should pay more attention to prevention and treatment of TB in adolescents. PMID- 26740868 TI - Prevalence of Hepatitis C among Egyptian Children with Sickle Cell Disease and the Role of IL28b Gene Polymorphisms in Spontaneous Viral Clearance. AB - BACKGROUND AND OBJECTIVES: Hepatitis C virus (HCV) is a major health problem in Egypt with its prevalence estimated to be 14.7% among the general population in 2008. Patients receiving frequent blood transfusions like those with sickle cell disease (SCD) are more exposed to the risk of acquiring HCV. IL28B gene polymorphisms have been associated with spontaneous HCV clearance. This study aims to determine the prevalence of HCV infection among children with SCD and to investigate the relation between IL28B gene polymorphisms and spontaneous HCV clearance. METHODS: Seventy SCD patients were screened for HCV antibody. HCV positive patients were tested for the level of HCV RNA using quantitative real time PCR. IL28B polymorphisms (rs 12979860 SNP and rs 12980275 SNP) were detected using TaqMan QRT-PCR and sequence-specific primers PCR respectively. RESULTS: Sixteen patients (23%) were HCV antibody positive, 9 of them (56.3%) had undetectable HCV RNA in serum, and 7 (43.7%) had persistent viremia. Genotypes CC/CT/TT of rs12979860 were found in 30 (42.9%), 29 (41.4%) and 11 (15.7%) patients and rs12980275 AA/AG/GG were found in 8 (11.4%), 59 (84.3%) and 3 (4.3%) patients. There was no significant difference in the frequency of IL28B (rs 12979860 and rs12980275) genotypes among HCV patients who cleared the virus and those with persistent viremia (p=0.308 and 0.724 respectively). CONCLUSION: Egyptian SCD patients have a high prevalence of HCV. Multi-transfused patients still exposed to the risk of transmission of HCV. IL28B gene polymorphismsare not associated with spontaneous clearance of HCV in this cohort of Egyptian children with SCD. PMID- 26740869 TI - Prognostic Impact of WT-1 Gene Expression in Egyptian Children with Acute Lymphoblastic Leukemia. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer representing 23% of pediatric cancers. Wilms' tumor -1 gene is a novel prognostic factor, minimal residual disease marker and therapeutic target in acute leukemia. AIM OF THE WORK: The aim of this work was to study the impact of WT-1 gene expression in the prognosis of ALL. PATIENTS AND METHODS: This study was conducted on 40 Egyptian children with newly diagnosed ALL who were subjected to full history taking, thorough clinical examination and laboratory investigations including; complete blood count, LDH, BM aspiration, cytochemistry, immunophenotyping, FISH technique for detection of t(12;21) and t(9;22) and assessment of WT-1 Gene by real-time PCR in BM samples at time of diagnosis. RESULTS: Positive WT-1 gene expression was found in 22 cases (55%) and negative expression in 18 cases (45%). Positive WT-1 gene expression group (n=22) includes 14 males and 8 females with mean age at presentation of 5.261 +/- 0.811 while negative WT-1 gene expression group (n=18) includes 12 males and 6 females with mean age at diagnosis of 9.669 +/- 3.731 with significantly older age in negative WT-1 gene expression group but no significant differences between positive and negative WT-1 gene expression groups regarding sex and clinical presentations. There were no significant differences in platelets and WBCs counts, hemoglobin and LDH levels and the number of peripheral blood and BM blast cells at diagnosis between positive and negative WT-1 gene expression groups but after induction therapy there were significantly lower BM blast cells in positive WT-1 gene expression group. There were no statistically significant differences between positive and negative WT-1 gene expression groups regarding immunophenotyping and chromosomal translocations including t(12;21) and t(9;22). There were a significantly higher relapse and death rate and a lower rate of CR, DFS, and OAS in negative WT-1 gene expression group. MRD at end of induction therapy was found in 14 cases out of 40 patients. There were significantly higher number of patients with MRD+ in negative WT-1 gene expression group (After the therapy 20 out of 22 (89%) patients with positive WT-1 gene expression attained a negative MRD, while only 6 out of 18 (33%) with negative WT-1 attained a negative MRD) (p-value = 0.006). CONCLUSIONS AND RECOMMENDATION: WT-1 gene expression is an important prognostic factor in patients with ALL, being able to prognosticate a negative MRD. Therefore, we can recommend its incorporation into novel risk adapted therapeutic strategies in patients with ALL. PMID- 26740867 TI - Infectious Aetiology of Marginal Zone Lymphoma and Role of Anti-Infective Therapy. AB - Marginal zone lymphomas have been associated with several infectious agents covering both viral and bacterial pathogens and in some cases a clear aetiological role has been established. Pathogenetic mechanisms are currently not completely understood. However, the role of chronic stimulation of the host immune response with persistent lymphocyte activation represents the most convincing explanation for lymphoproliferation. Gastric MALT lymphoma is strictly associated with Helicobacter pylori infection and various eradicating protocols, developed due to increasing antibiotic resistance, represent the first line therapy for gastric MALT. The response rate to eradication is good with 80% of response at 1 year; this finding is also noteworthy because it recapitulates cancer cured only by the antibacterial approach and it satisfies the Koch postulates of causation, establishing a causative relationship between Hp and gastric MALT lymphoma. Patients with chronic HCV infection have 5 times higher risk to develop MZL, in particular, an association with splenic and nodal MZL has been shown in several studies. Moreover, there is evidence of lymphoma regression after antiviral therapy with interferon+ribavirin, thus raising hope that newly available drugs, extremely efficient against HCV replication, could improve outcome also in HCV-driven lymphomas. Another case-study are represented by those rare cases of MZL localized to orbital fat and eye conjunctivas that have been associated with Chlamydophila psittaci infection carried by birds. Efficacy of antibacterial therapy against C. psittaci are conflicting and generally poorer than gastric MALT. Finally, some case reports will cover the relationship between primary cutaneous B-cell Lymphomas and Borrelia Burgdorferi. PMID- 26740870 TI - Treatment with Low-Dose Cytarabine in Elderly Patients (Age 70 Years or Older) with Acute Myeloid Leukemia: A Single Institution Experience. AB - OBJECTIVES: Low-dose cytarabine (LD-AraC) is still regarded as the standard of care in elderly patients with acute myeloid leukemia (AML) 'unfit' for intensive chemotherapy. In this study, we reported our experience with LD-AraC in patients >= 70 years old and compared the results to those of intensive chemotherapy, best supportive care (BSC), or hypomethylating agents in the same age population. METHODS: Between 2000 and 2014, 60 patients received LD-AraC at 20 mg once or twice daily by subcutaneous injection for 10 consecutive days every 4-6 weeks. RESULTS: Complete remission rate with LD-AraC was 7% versus 56% with intensive chemotherapy and 21% with hypomethylating agents. Median overall survival (OS) of patients treated with LD-AraC was 9.6 months with 3-year OS of 12%. Survival with LD-AraC was better than with BSC only (P = 0.001). Although not statistically significant, intensive chemotherapy and hypomethylating agents tended to be better than LD-AraC in terms of OS (median: 12.4 months and 16.1 months, respectively). There was no clear evidence that a beneficial effect of LD-AraC was restricted to any particular subtype of patients, except for cytogenetics. There was a trend for a better OS in LD-AraC treated patients in the setting of clinical trials as compared with those treated outside of a clinical trial. CONCLUSIONS: Despite a trend in favor of intensive chemotherapy and hypomethylating agents over LD-AraC, no real significant advantage could be demonstrated, while LD-AraC showed a significant advantage comparatively to BSC. All this tends to confirm that LD-AraC can still represent a baseline against which new promising agents may be compared either alone or in combination. PMID- 26740871 TI - Refractory Immune Thrombocytopenic Purpura and Cytomegalovirus Infection: A Call for a Change in the Current Guidelines. AB - Immune thrombocytopenic purpura (ITP) is characterized by a decreased platelet count caused by excess destruction of platelets and inadequate platelet production. In many cases, the etiology is not known, but the viral illness is thought to play a role in the development of some cases of ITP. The current (2011) American Society of Hematology ITP guidelines recommend initial diagnostic studies to include testing for HIV and Hepatitis C. The guidelines suggest that initial treatment consist of observation, therapy with corticosteroids, IVIG or anti D. Most cases respond to the standard therapy such that the steroids may be tapered and the platelet counts remain at a hemostatically safe level. Some patients with ITP are dependent on long-term steroid maintenance, and the thrombocytopenia persists with the tapering of the steroids. Recent case reports demonstrate that ITP related to cytomegalovirus (CMV) can persist in spite of standard therapy and that antiviral therapy may be indicated. Herein we report a case of a 26-year-old female with persistent ITP that resolved after the delivery of a CMV-infected infant and placenta. Furthermore, we review the current literature on CMV-associated ITP and propose that the current ITP guidelines be amended to include assessment for CMV, even in the absence of signs and symptoms, as part of the work-up for severe and refractory ITP, especially prior to undergoing an invasive procedure such as splenectomy. PMID- 26740872 TI - Ubiquitin phosphorylation in Parkinson's disease: Implications for pathogenesis and treatment. AB - Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized primarily by the loss of dopaminergic neurons in substantia nigra. The pathogenic mechanisms of PD remain unclear, and no effective therapy currently exists to stop neurodegeneration in this debilitating disease. The identification of mutations in mitochondrial serine/threonine kinase PINK1 or E3 ubiquitin-protein ligase parkin as the cause of autosomal recessive PD opens up new avenues for uncovering neuroprotective pathways and PD pathogenic mechanisms. Recent studies reveal that PINK1 translocates to the outer mitochondrial membrane in response to mitochondrial depolarization and phosphorylates ubiquitin at the residue Ser65. The phosphorylated ubiquitin serves as a signal for activating parkin and recruiting autophagy receptors to promote clearance of damaged mitochondria via mitophagy. Emerging evidence has begun to indicate a link between impaired ubiquitin phosphorylation-dependent mitophagy and PD pathogenesis and supports the potential of Ser65-phosphorylated ubiquitin as a biomarker for PD. The new mechanistic insights and phenotypic screens have identified multiple potential therapeutic targets for PD drug discovery. This review highlights recent advances in understanding ubiquitin phosphorylation in mitochondrial quality control and PD pathogenesis and discusses how these findings can be translated into novel approaches for PD diagnostic and therapeutic development. PMID- 26740874 TI - First report of co-morbidity of pantothenate kinase-associated neurodegeneration and three types of chronic hemolytic anemias. AB - BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN), sickle cell anemia, and thalassemia are autosomal recessive disorders that can cause iron deposition in tissues during childhood. PKAN is characterized by accumulation of iron in the basal ganglia causing progressive extrapyramidal manifestations. Thalassemia and sickle cell disease can cause iron overload and deposition in tissues, including central nervous system. PRESENTATION OF CASE: we herein report the first report of comorbidity of PKAN, beta-thalassemia-major, sickle cell and glucose-6-phosphate dehydrogenase deficiency (G6PD) anemias in a 9 years old Saudi female patient who presented with gait disturbance, speech difficulty, and progressive movement disorders of the neck, upper and lower limbs. CONCLUSION: Although extremely rare, beta-thalassemia-major, sickle cell and G6PD anemias can be associated with PKAN. It is unknown whether this association is random or due to an unknown factor that may have caused several mutations. PMID- 26740873 TI - 7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders. AB - Brain-derived neurotrophic factor (BDNF) regulates a variety of biological processes predominantly via binding to the transmembrane receptor tyrosine kinase TrkB. It is a potential therapeutic target in numerous neurological, mental and metabolic disorders. However, the lack of efficient means to deliver BDNF into the body imposes an insurmountable hurdle to its clinical application. To address this challenge, we initiated a cell-based drug screening to search for small molecules that act as the TrkB agonist. 7,8-Dihydroxyflavone (7,8-DHF) is our first reported small molecular TrkB agonist, which has now been extensively validated in various biochemical and cellular systems. Though binding to the extracellular domain of TrkB, 7,8-DHF triggers TrkB dimerization to induce the downstream signaling. Notably, 7,8-DHF is orally bioactive that can penetrate the brain blood barrier (BBB) to exert its neurotrophic activities in the central nervous system. Numerous reports suggest 7,8-DHF processes promising therapeutic efficacy in various animal disease models that are related to deficient BDNF signaling. In this review, we summarize our current knowledge on the binding activity and specificity, structure-activity relationship, pharmacokinetic and metabolism, and the pre-clinical efficacy of 7,8-DHF against some human diseases. PMID- 26740875 TI - A diagnostic approach and natural course of a patient with asthma-COPD overlap syndrome. AB - The diagnostic criteria of asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) advocated by the Global Initiative for Asthma (GINA)/Global Initiative for Chronic Obstructive Lung Disease (GOLD) are somewhat complicated, and limited data are available regarding how ACOS patients respond to current medications. We present a case of a 64-year-old man with ACOS. With features favoring asthma including childhood asthma history with intermittent episodes of dyspnea at night, elevated blood eosinophil count and total IgE, increased forced expiratory volume in 1 s (FEV 1) after bronchodilator (>200 mL and >12% from baseline), and positive skin prick tests, he also had features favoring COPD such as heavy smoker, persistent exertional dyspnea, and airflow limitation after inhaled therapy. Over 5-year follow up, our patient experienced a single episode of moderate exacerbation. However, post-bronchodilator FEV 1 decreased by 240 mL for 4 years (-60 mL/year) after 1.5 years of treatment, indicating rapid lung function decline. Longitudinal studies are necessary to assess optimal interventions and natural course of ACOS. PMID- 26740876 TI - Organizing pneumonia associated with myeloperoxidase anti-neutrophil cytoplasmic antibody. AB - Organizing pneumonia (OP) is a clinicopathological entity that occurs idiopathically or in association with several conditions, but there are few reports about myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) associated OP. We describe a patient with OP whose clinical conditions improved spontaneously. Moreover, serum MPO-ANCA titers paralleled the clinical activity of the disease, which disappeared in association with disease quiescence. Based on these findings, a subset of patients may have OP related to MPO-ANCA. ANCA testing should be considered in the work-up of patients with suspected OP. PMID- 26740877 TI - Organizing pneumonia associated with multicentric reticulohistiocytosis. AB - Organizing pneumonia (OP) is a clinicopathological entity that occurs idiopathically or in association with several conditions such as connective tissue diseases. Multicentric reticulohistiocytosis (MRH) is a systemic disease characterized by polyarthritis and mucocutaneous lesions, but lung involvement is uncommon. We report a patient with MRH associated with OP. This case may be of interest when considering the pathophysiological mechanisms of both diseases. PMID- 26740878 TI - Required thoracic drainage through the respiratory tract during transbronchial biopsy using EBUS-GS. AB - A 71-year-old woman was referred to our department due to an abnormal chest shadow. Imaging revealed a pulmonary nodule shadow in the left S6 segment, multiple small nodule shadows in the left pleura, and left pleural effusion. Transbronchial biopsy using endobronchial ultrasonography (EBUS) with a guide sheath was conducted. EBUS showed the probe of the sheath located in the lesion and biopsy was performed in this area. A yellow turbid fluid appeared in the sheath and vacuum aspiration resulted in collection of 200 mL of this fluid. We suspected that drainage occurred because the sheath tip had ruptured the pleural cavity. The pathological diagnosis was adenocarcinoma. It is likely that the EBUS images reflected pleural effusion adjacent to the lesion, and that the complication occurred because the biopsy was performed without awareness of these findings. This complication may be prevented by closer examination of echo findings and rotation of the X-ray source to ensure performance of the biopsy directly under the pleura. PMID- 26740879 TI - Tuberculous pericarditis leading to cardiac tamponade: importance of screening prior to immunosuppression. AB - Mycobacterium tuberculosis (TB) presenting with pericardial disease complicated by cardiac tamponade is rare in the developed world, although it occurs more frequently in the context of immunosuppression. In this report, a 74-year-old man on methotrexate for rheumatoid arthritis presented with fever, productive cough and cough-induced syncope. During his admission, he developed clinical signs of cardiac tamponade confirmed on an echocardiogram, which showed a massive pericardial effusion. He was treated with an urgent pericardiocentesis and a pericardial window. Subsequently, TB polymerase chain reaction of pericardial fluid unexpectedly returned positive, and he was commenced on standard quadruple therapy for TB, as well as high-dose prednisolone. Notably, the patient did not have a history suggestive of previous TB exposure, and no screening investigations had been performed prior to initiation of methotrexate. This case highlights the importance of TB screening prior to immunosuppressive therapy, even in populations considered low risk for latent disease. PMID- 26740880 TI - ECMO-dependent respiratory failure after snorting speed associated with anti-GBM antibodies. AB - A previously well 20-year-old man with a history of nasal inhalation of "speed" was retrieved on extracorporeal membrane oxygenation for respiratory failure. Anti-glomerular basement membrane (anti-GBM) antibody was positive in the absence of renal disease. We postulate a hitherto unreported causal link between snorting "speed" and lung disease associated with anti-GBM antibody formation. PMID- 26740881 TI - Endobronchial ultrasound: beyond nodes and masses. AB - Pulmonary embolism (PE) is a life-threatening condition with varied presentation and, therefore, poses clinical challenge for early diagnosis and proper management without which it carries high mortality. Previous studies on the role of endobronchial ultrasound (EBUS) in diagnosis of PE were carried out after PE was already diagnosed by computed tomography pulmonary angiography. We report a case of massive PE with shock, promptly diagnosed with bed side EBUS - Doppler study, as patient's clinical condition did not allow conventionally proposed diagnostic algorithm. PMID- 26740882 TI - Transbronchial lung biopsy (TBLB) in diagnosing pulmonary alveolar proteinosis (PAP): forgotten role in Australia? AB - Transbronchial lung biopsy (TBLB) is uncommonly performed in non-malignant conditions because of its low sensitivity and small tissue samples. It is not routinely performed in Australia to investigate idiopathic pulmonary fibrosis, although it can be a useful adjunct in obtaining tissue diagnosis in selected conditions in interstitial lung disease (ILD). A 52-year-old non-smoker received a living unrelated renal transplant in January 2014 but developed insidious onset of dyspnea on exertion 1 year later. Computed tomography of the thorax showed bilateral persistent ground glass opacifications with a characteristic crazy paving pattern, although P neumocystis jirovecii pneumonia was more concerning. He was treated as P neumocystis jirovecii pneumonia but his initial bronchoscopy failed to confirm either diagnoses. He then went on to TBLB that showed the presence of periodic acid-Schiff staining material. We conclude that TBLB is a useful adjunct to obtain histological diagnosis of ILD in carefully selected patients with appropriate radiological indications. PMID- 26740883 TI - Pleural vasculitides of microscopic polyangiitis with asbestos-related plaques. AB - A 69-year-old man who had been exposed to asbestos for approximately 40 years presented with the complaint of fever and pleuritic chest pain on the right side on deep inspiration. Chest X-ray films showed pleural effusion in the right side. Initial antibiotic treatment was ineffective. The hyaluronic acid level was high in the pleural effusion but no malignant mesotheliomal cells were seen with blind pleural biopsy. Blood chemistry showed a remarkable high titer of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) and open renal biopsy suggested crescentic glomerulonephritis. The precise pathological examination on the pleura obtained by the open pleural biopsy showed vasculitides and plaque leading to diagnosis of microscopic polyangiitis (MPA). This is a rare case of MPA seen in the pleural arteries. PMID- 26740884 TI - Primary tracheobronchial amyloidosis associated with tracheobronchomegaly evaluated by novel four-dimensional functional CT. AB - Amyloid is a heterogeneous family of extracellular proteinaceous deposits characterized by apple-green birefringence on polarized light microscopy. There are rare case reports of these extracellular deposits accumulating in the upper and central airways. Progressive infiltration may impair glottic and airway function with some cases requiring intervention to improve flow. Bronchoscopy and lung function testing provide dynamic information to monitor for disease progression; however, the recent development of 320 multislice computed tomography (320 CT) enables dynamic, four-dimensional (4-D) evaluation of laryngeal and tracheal structure and function and presents as a noninvasive, low radiation dose surveillance tool. We reviewed a 43-year-old man with primary amyloidosis of the larynx and central airways who presented with an 18-year history of progressive dysphonia without breathlessness and preserved lung function. 4-D CT demonstrated marked thickening of supraglottic folds and trachea with marked tracheal dilatation. Despite gross structural abnormalities, dynamic function assessed throughout inspiration and expiration was normal, demonstrating neither rigidity nor dynamic collapse. This combination of structural and functional assessment of the proximal airway by 4-D CT is a novel application to surveillance for laryngeal and tracheal amyloid. PMID- 26740885 TI - Trilogy of sequential infections in a diabetic male. AB - Uncontrolled diabetes is a known immunosuppressive state. It predisposes individuals to bacterial and fungal infections. The present case report demonstrates sequential infections by Klebsiella followed by tuberculosis and later development of mucormycosis in a poorly controlled diabetic patient. Timing of diagnosis is of essence because of high mortality seen with such pulmonary infections. High index of suspicion needs to be maintained as the same individual may harbor multiple infections as highlighted in this case. PMID- 26740886 TI - Effect of enzyme replacement therapy (ERT) added to Home Mechanical Ventilation (HMV) in Adult Pompe disease. AB - Adult Pompe disease/acid maltase deficiency is an autosomal recessive disorder resulting in accumulation of glycogen in skeletal muscles, leading to myopathy frequently involving respiratory muscles. This involvement can cause respiratory insufficiency that may present as acute hypercapnic respiratory failure. Enzyme replacement therapy (ERT) with alpha - glucosidase alfa, the only disease specific treatment, has been available as treatment option since 2006. ERT has shown efficacy concerning muscle strength and pulmonary function in adult patients as well as positive association with survival. We present two cases where addition of ERT to Home Mechanical Ventilation (HMV) showed improvements in lung function and gas exchange that may not be entirely attributable to nocturnal HMV and therefore may further indicate the beneficial role of ERT in conjunction with HMV in Adult Pompe disease. PMID- 26740887 TI - Serologic evidence of exposure to Rift Valley fever virus detected in Tunisia. AB - Rift Valley fever virus (RVFv) is capable of causing dramatic outbreaks amongst economically important animal species and is capable of causing severe symptoms and mortality in humans. RVFv is known to circulate widely throughout East Africa; serologic evidence of exposure has also been found in some northern African countries, including Mauritania. This study aimed to ascertain whether RVFv is circulating in regions beyond its known geographic range. Samples from febrile patients (n = 181) and nonfebrile healthy agricultural and slaughterhouse workers (n = 38) were collected during the summer of 2014 and surveyed for exposure to RVFv by both serologic tests and PCR. Of the 219 samples tested, 7.8% of nonfebrile participants showed immunoglobulin G reactivity to RVFv nucleoprotein and 8.3% of febrile patients showed immunoglobulin M reactivity, with the latter samples indicating recent exposure to the virus. Our results suggest an active circulation of RVFv and evidence of human exposure in the population of Tunisia. PMID- 26740888 TI - Comparison of three boosting methods in parent-offspring trios for genotype imputation using simulation study. AB - BACKGROUND: Genotype imputation is an important process of predicting unknown genotypes, which uses reference population with dense genotypes to predict missing genotypes for both human and animal genetic variations at a low cost. Machine learning methods specially boosting methods have been used in genetic studies to explore the underlying genetic profile of disease and build models capable of predicting missing values of a marker. METHODS: In this study strategies and factors affecting the imputation accuracy of parent-offspring trios compared from lower-density SNP panels (5 K) to high density (10 K) SNP panel using three different Boosting methods namely TotalBoost (TB), LogitBoost (LB) and AdaBoost (AB). The methods employed using simulated data to impute the un-typed SNPs in parent-offspring trios. Four different datasets of G1 (100 trios with 5 k SNPs), G2 (100 trios with 10 k SNPs), G3 (500 trios with 5 k SNPs), and G4 (500 trio with 10 k SNPs) were simulated. In four datasets all parents were genotyped completely, and offspring genotyped with a lower density panel. RESULTS: Comparison of the three methods for imputation showed that the LB outperformed AB and TB for imputation accuracy. The time of computation were different between methods. The AB was the fastest algorithm. The higher SNP densities resulted the increase of the accuracy of imputation. Larger trios (i.e. 500) was better for performance of LB and TB. CONCLUSIONS: The conclusion is that the three methods do well in terms of imputation accuracy also the dense chip is recommended for imputation of parent-offspring trios. PMID- 26740889 TI - Effect of misting and wallowing cooling systems on milk yield, blood and physiological variables during heat stress in lactating Murrah buffalo. AB - BACKGROUND: Heat stress adversely affects the physiological and metabolic status, and the productive performance of buffalo. METHODS: The present study was conducted to explicate the effect of misting and wallowing cooling strategies during heat stress in lactating Murrah buffalo. The study was conducted for three months (May-July) of which first two months were hot dry and last month was hot humid. Eighteen lactating buffaloes, offered the same basal diet, were blocked by days in milk, milk yield and parity, and then randomly allocated to three treatments: negative control (no cooling), cooling by misting, and cooling by wallowing. RESULTS: The results showed higher (P < 0.05) milk yield in buffaloes of misting and wallowing group compared to control during the experimental period however wallowing was found more (P < 0.05) effective during July (hot humid period). Both the treatments resulted into significant (P < 0.05) reduction in rectal temperature (RT) and respiratory rate (RR) compared to control animals during study period whereas wallowing was found to be effective on pulse rate (PR) only during July. Both treatments were resulted in mitigating the heat stress mediated decrease in packed cell volume (PCV), lymphocytopnoea and neutrophilia whereas decrease in total erythrocyte count (TEC) and monocytes was only mitigated by wallowing. Heat load induced alteration in serum creatinine and sodium concentration was significantly (P < 0.05) ameliorated by misting and wallowing whereas aspartate aminotransferase, alkaline phosphatase and superoxide dismutase activity, and reactive oxygen species concentration could be normalized neither by misting nor by wallowing. The significant (P < 0.05) increment in serum cortisol and prolactin levels observed in June and July period in control animals was significantly (P < 0.05) prevented by misting and wallowing. CONCLUSIONS: It can be concluded that misting and wallowing were equally effective in May and June (hot dry period) whereas wallowing was more effective during hot humid period in preventing a decline in milk production and maintaining physiological, metabolic, endocrine and redox homeostasis. PMID- 26740891 TI - Checklists in Neurosurgery to Decrease Preventable Medical Errors: A Review. AB - Neurosurgery represents a zero tolerance environment for medical errors, especially preventable ones like all types of wrong site surgery, complications due to the incorrect positioning of patients for neurosurgical interventions and complications due to failure of the devices required for the specific procedure. Following the excellent and encouraging results of the safety checklists in intensive care medicine and in other surgical areas, the checklist was naturally introduced in neurosurgery. To date, the reported world experience with neurosurgical checklists is limited to 15 series with fewer than 20,000 cases in various neurosurgical areas. The purpose of this review was to study the reported neurosurgical checklists according to the following parameters: year of publication; country of origin; area of neurosurgery; type of neurosurgical procedure-elective or emergency; person in charge of the checklist completion; participants involved in completion; whether they prevented incorrect site surgery; whether they prevented complications due to incorrect positioning of the patients for neurosurgical interventions; whether they prevented complications due to failure of the devices required for the specific procedure; their specific aims; educational preparation and training; the time needed for checklist completion; study duration and phases; number of cases included; barriers to implementation; efforts to implementation; team appreciation; and safety outcomes. Based on this analysis, it could be concluded that neurosurgical checklists represent an efficient, reliable, cost-effective and time-saving tool for increasing patient safety and elevating the neurosurgeons' self-confidence. Every neurosurgical department must develop its own neurosurgical checklist or adopt and modify an existing one according to its specific features and needs in an attempt to establish or develop its safety culture. The world, continental, regional and national neurosurgical societies could promote safety checklists and their benefits. PMID- 26740890 TI - Magnetogenetics: remote non-invasive magnetic activation of neuronal activity with a magnetoreceptor. AB - Current neuromodulation techniques such as optogenetics and deep-brain stimulation are transforming basic and translational neuroscience. These two neuromodulation approaches are, however, invasive since surgical implantation of an optical fiber or wire electrode is required. Here, we have invented a non invasive magnetogenetics that combines the genetic targeting of a magnetoreceptor with remote magnetic stimulation. The non-invasive activation of neurons was achieved by neuronal expression of an exogenous magnetoreceptor, an iron-sulfur cluster assembly protein 1 (Isca1). In HEK-293 cells and cultured hippocampal neurons expressing this magnetoreceptor, application of an external magnetic field resulted in membrane depolarization and calcium influx in a reproducible and reversible manner, as indicated by the ultrasensitive fluorescent calcium indicator GCaMP6s. Moreover, the magnetogenetic control of neuronal activity might be dependent on the direction of the magnetic field and exhibits on response and off-response patterns for the external magnetic field applied. The activation of this magnetoreceptor can depolarize neurons and elicit trains of action potentials, which can be triggered repetitively with a remote magnetic field in whole-cell patch-clamp recording. In transgenic Caenorhabditis elegans expressing this magnetoreceptor in myo-3-specific muscle cells or mec-4-specific neurons, application of the external magnetic field triggered muscle contraction and withdrawal behavior of the worms, indicative of magnet-dependent activation of muscle cells and touch receptor neurons, respectively. The advantages of magnetogenetics over optogenetics are its exclusive non-invasive, deep penetration, long-term continuous dosing, unlimited accessibility, spatial uniformity and relative safety. Like optogenetics that has gone through decade long improvements, magnetogenetics, with continuous modification and maturation, will reshape the current landscape of neuromodulation toolboxes and will have a broad range of applications to basic and translational neuroscience as well as other biological sciences. We envision a new age of magnetogenetics is coming. PMID- 26740892 TI - Seasonal Association of Immune Thrombocytopenia in Adults. AB - BACKGROUND: Immune thrombocytopenia (ITP) is an autoimmune disorder. It is characterized by thrombocytopenia due to thrombocyte destruction mediated by autoantibodies; however, cytotoxic and defective regulatory T-lymphocytes play an important role in its pathogenesis. While childhood ITP is usually acute, self limiting and generally seasonal in nature, ITP in adults is usually chronic; its relation with seasons has not been studied. AIMS: We investigated whether months and/or seasons have triggering roles in adults with ITP. STUDY DESIGN: Descriptive study. METHODS: A retrospective case review of adult patients with primary ITP diagnosed at various University Hospitals in cities where Mediterranean climate is seen was performed. Demographic data, date of referral and treatments were recorded. Corticosteroid-resistant, chronic and refractory cases were determined. Relation between sex, corticosteroid-resistant, chronic and refractory ITP with the seasons was also investigated. RESULTS: The study included 165 patients (124 female, mean age=42.8+/-16.6). Most cases of primary ITP were diagnosed in the spring (p=0.015). Rates of patients diagnosed according to the seasons were as follows: 35.8% in spring, 23% in summer, 20.6% in fall, and 20.6% in winter. With respect to months, the majority of cases occurred in May (18.2%). Time of diagnosis according to the seasons did not differ between genders (p=0.699). First-line treatment was corticosteroids in 97.3%, but 35% of the cases were corticosteroid-resistant. Steroid-resistant patients were mostly diagnosed in the spring (52.1%) (p=0.001). ITP was chronic in 52.7% of the patients and they were also diagnosed mostly in the spring (62.7%) (p=0.149). CONCLUSION: This is the first study showing seasonal association of ITP in adults and we have observed that ITP in adults is mostly diagnosed in the spring. The reason why more patients are diagnosed in the spring may be due to the existence of atmospheric pollens reaching maximum levels in the spring in places where a Mediterranean climate is seen. PMID- 26740893 TI - In Vivo Anti-Inflammatory Effect of H1 Antihistamines in Allergic Rhinitis: A Randomized Clinical Trial. AB - BACKGROUND: Allergic rhinitis is characterized by a chronic inflammation of nasal mucosa and represents a risk factor for asthma occurrence. H1 antihistamines reduce the symptoms of rhinitis, but some compounds may have anti-inflammatory properties. AIMS: We evaluated the plasma level of some cytokines in patients with persistent allergic rhinitis (PAR) and their evolution after a 4-week treatment with H1 anti-histamines, as well as the risk of asthma after 1.5 years. STUDY DESIGN: Randomized clinical trial. METHODS: Eighty-five patients with PAR and 30 healthy volunteers were included in the study. The patients with PAR were randomly divided into 2 groups: 41 patients treated with 5 mg/day desloratadine and 44 patients under 5 mg/day levocetirizine for 4 weeks. The clinical and biological evaluations were performed before and after treatment and included rhinitis symptoms and total symptoms score, type of sensitization, and plasmatic levels of total IgE, IL-1beta, IL-6, IL-8 and TNF-alpha. RESULTS: IL-8 and TNF alpha were significantly increased in patients with PAR compared to healthy volunteers (5.85 vs 3.12, p<0.001 and 2.32 vs 1.06, p<0.001, respectively). Both H1 antihistamines reduce all symptoms of allergic rhinitis, including nasal congestion and the plasmatic level of IL-1beta, IL-6, IL-8 and TNF-alpha, after 4 weeks of treatment. The reduction of cytokine levels was not influenced by patients' age, sex, duration or severity of rhinitis, or type of sensitization. Levocetirizine has a superior effect compared to desloratadine in reducing the rhinitis symptoms and cytokines' level. Twenty eight (32.9%) of the patients presented asthma symptoms after 1.5 years. The occurrence of asthma was influenced by house dust sensitization (OR-14.6; CI 95% 1.8-116.3; p=0.01), but baseline values of cytokines were not predictive factors for its appearance. CONCLUSION: Levocetirizine and desloratadine as a prolonged therapy reduce plasmatic levels of some pro-inflammatory cytokines in patients with PAR. Levocetirizine has a better effect on decreasing the symptoms and plasmatic levels of IL-1beta and IL-8. (ClinicalTrials. gov Identifier: NCT02507635). FOUNDING: POSDRU and University of Medicine and Pharmacy, Iuliu Hatieganu, Cluj Napoca. PMID- 26740894 TI - Severe Preeclampsia versus HELLP Syndrome: Maternal and Perinatal Outcomes at <34 and >=34 Weeks' Gestation. AB - BACKGROUND: Preeclampsia and Hemolysis, Elevated Liver enzymes, Low Platelet (HELLP) syndrome are important disorders affecting the health of both the mother and fetus. Prediction of the maternal and perinatal outcomes at early and late gestational age is important for the management of both disorders. AIMS: The purpose of the study was to investigate adverse maternal and perinatal outcomes in severe preeclampsia and HELLP syndrome cases according to gestational age. STUDY DESIGN: Retrospective cross-sectional study. METHODS: One hundred and ninety-seven pregnancies with severe preeclampsia and 56 pregnancies with HELLP syndrome were included the study. Clinical characteristics and adverse maternal and perinatal outcomes were noted from medical records. Participants were divided into two groups at <34 and >=34 weeks' gestation: the severe preeclampsia group and the HELLP syndrome group. The differences between the outcomes in the groups were investigated. Statistical analysis was performed using the Student t test, Fisher Exact test and Yates' Chi-square test. RESULTS: Eclampsia was more common in HELLP syndrome cases at <34 weeks' gestation (p 0.028). However, eclampsia rates were statistically similar between groups at >=34 weeks' gestation. The requirement for blood products transfusion was higher in the HELLP group at all gestational weeks. No statistical difference was found in perinatal outcomes between severe preeclampsia and HELLP groups at less than and more than 34 weeks' gestation. CONCLUSION: Eclampsia risk increases in HELLP syndrome, especially at gestations less than 34 weeks. Perinatal morbidity at less than 34 weeks' gestation and mortality were similar in severe preeclampsia and HELLP syndrome cases at the same gestational age. PMID- 26740895 TI - Local Effect of Neurotrophin-3 in Neuronal Inflammation of Allergic Rhinitis: Preliminary Report. AB - BACKGROUND: Allergic rhinitis is a common inflammatory nasal mucosal disease characterized by sneezing, watery nasal discharge, nasal obstruction and itching. Although allergen-specific antibodies play a main role in the allergic airway inflammation, neuronal inflammation may also contribute to the symptoms of allergic rhinitis. Neuronal inflammation is primarily caused by the stimulation of sensory nerve endings with histamine. It has been shown that neurotrophins may also have a role in allergic reactions and neuronal inflammation. Nerve growth factor, neurotrophin 3 (NT-3), neurotrophin 4/5 and brain-derived neurotrophic factor are members of the neurotrophin family. Although nerve growth factor and brain-derived neurotrophic factor are well studied in allergic rhinitis patients, the exact role of Neurotrophin-3 is not known. AIMS: To investigate the possible roles of neurotrophin-3 in allergic rhinitis patients. STUDY DESIGN: Case-control study. METHODS: Neurotrophin-3 levels were studied in the inferior turbinate and serum samples of 20 allergic rhinitis and 13 control patients. Neurotrophin-3 staining of nasal tissues was evaluated by immunohistochemistry and ELISA was used for the determination of serum Neurotrophin-3 levels. RESULTS: Neurotrophin 3 staining scores were statistically higher in the study group than in the control patients (p=0.001). Regarding serum Neurotrophin-3 levels, no statistically significant difference could be determined between allergic rhinitis and control patients (p=0.156). When comparing the serum NT-3 levels with tissue staining scores, there were no statistically significant differences in the allergic rhinitis and control groups (p=0.254 for allergic rhinitis and p=0.624 for control groups). CONCLUSION: We suggest that Neurotrophin-3 might affect the nasal mucosa locally without being released into the systemic circulation in allergic rhinitis patients. PMID- 26740896 TI - Usefulness of Neutrophil to Lymphocyte Ratio in Prediction of Coronary Artery Lesions in Patients with Kawasaki Disease. AB - BACKGROUND: Kawasaki disease is an inflammatory condition. Neutrophil to lymphocyte ratio is a marker reflecting inflammation. AIMS: The aim of the study is to evaluate usefulness of neutrophil to lymphocyte ratio in diagnosis of Kawasaki disease and in prediction of coronary artery lesions. STUDY DESIGN: Retrospective cross-sectional study. METHODS: Seventy-five children with Kawasaki disease and 66 controls were retrospectively enrolled. Their leukocyte, neutrophil, and lymphocyte counts were recorded. Abnormally distributed data were shown as median (interquartile range). Cases having coronary artery diameter two standard deviation above mean were diagnosed to have coronary artery lesions. RESULTS: Median age of Kawasaki disease patients was 34 months. Twentyfive of those (33.33%) had incomplete Kawasaki disease and twenty-six (34.66%) had coronary artery lesions. Leukocyte [12.61 (6.09)*10(3)/uL vs. 8.48 (5.58)*10(3)/uL], neutrophil [6.73 (4.10) *10(3)/uL vs. 4.62 (5.47)*10(3)/uL], and lymphocyte [4.04 (2.91)*10(3)/uL vs. 3.02 (2.57) *10(3)/uL] counts were significantly higher in Kawasaki disease patients compared to controls (all p values <0.01). However, there was not significant difference between patients and controls regarding neutrophil to lymphocyte ratio [1.72 (1.22) vs. 1.71 (1.88)]. Findings of Kawasaki disease and incomplete Kawasaki disease cases did not differ, while comparison of patients with and without coronary artery lesions revealed significantly higher neutrophil to lymphocyte ratio values in former group [2.02 (1.63) vs. 1.50 (1.28), p=0.01]. The cut-off neutrophil to lymphocyte ratio value for prediction of coronary artery lesions was determined as 1.32. CONCLUSION: Neutrophil to lymphocyte ratio values in Kawasaki patients with coronary lesions were significantly higher than the ones without and values greater than 1.32 were useful in prediction of coronary lesions. PMID- 26740897 TI - The Relationship between Proliferative Scars and Endothelial Function in Surgically Revascularized Patients. AB - BACKGROUND: Proliferative scars are benign fibrotic proliferations which demonstrate abnormal wound healing in response to skin injuries. As postulated in the "response to injury hypothesis", atherosclerosis is also triggered by an endothelial injury. Keloid and atherosclerotic processes have many pathophysiological and cytological features in common. AIMS: In this study, we investigated the relationship between proliferative scars and endothelial function in surgically revascularized patients. We aimed to test the hypothesis that atherosclerosis is a wound healing abnormality. STUDY DESIGN: Cross sectional study. METHODS: Consecutive patients who were admitted to the cardiology outpatient clinic with a history of coronary artery bypass grafting operation were evaluated. Thirty-three patients with proliferative scars at the median sternotomy site formed the keloid group, and 36 age- and sex-matched patients with no proliferative scar at the median sternotomy site formed the control group. Endothelial function was evaluated by flow-mediated vasodilatation of the brachial artery via ultrasonograhic examination. RESULTS: There is no signicant difference according to the demographic data, biochemical parameters, clinical parameters and number of grafts between keloid and control groups. Endothelial-dependent vasodila-tory response was lower in the keloid group than the control group (9.30+/-3.5 and 18.68+/-8.2, respectively; p=0.001). CONCLUSION: This study showed that endothalial dysfunction, which is strongly correlated with atherosclerosis, was more prominent in patients with proliferative scars. As proliferative scars and atherosclerosis have many features in common, we might conclude that atherosclerosis is a wound healing abnormality. PMID- 26740898 TI - Neutrophil-to-Lymphocyte Ratio as a Marker in Patients with Non-arteritic Anterior Ischemic Optic Neuropathy. AB - BACKGROUND: Non-arteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic neuropathy in patients over the age of 50 and is the second most common cause of permanent optic nerve-related visual loss in adults after glaucoma. Although the precise cause of NAION remains elusive, the etiology of NAION is believed to be multifactorial. AIMS: To evaluate the utility of neutrophil-to-lymphocyte ratio (NLR) as a simple and readily available prognostic factor for clinical disease activity in patients with NAION. STUDY DESIGN: Case control study. METHODS: Forty-five patients with the diagnosis of NAION and 50 age- and sex-matched controls with/without any systemic or ocular diseases except cataract were retrospectively enrolled in the study. Demographic characteristics and laboratory findings including complete blood count of all patients and control subjects were obtained from the electronic medical record. The neutrophil and lymphocyte counts were recorded and the NLR was calculated. RESULTS: White blood cell, neutrophil, NLR and platelet values of the NAION patients were significantly higher than those of the controls (p<0.001, p<0.001, p=0.004, p=0.037, respectively). Initial NLR values were negatively correlated with initial and the third month best corrected visual acuity levels in the study group. The optimum NLR cut-off point for NAION was 1.94. CONCLUSION: NLR could be considered as a new inflammatory marker for assessment of the severity of inflammation in NAION patients with its quick, cheap, easily measurable property with routine complete blood count analysis. PMID- 26740899 TI - Histopathological Features of Gastrointestinal Stromal Tumors and the Contribution of DOG1 Expression to the Diagnosis. AB - BACKGROUND: Gastrointestinal stromal tumors (GIST) have KIT or platelet-derived growth factor receptor alpha (PDGFRalpha) mutations affecting receptor tyrosine kinase activity and do not benefit from classic treatment regimens. AIMS: The aim of this study was to review the algorithm that may be followed for the diagnosis and differential diagnosis in GISTs by investigating the histomorphological parameters and expression characteristics of classical immunohistochemical antibodies used in routine tests in addition to DOG1 expression. STUDY DESIGN: Diagnostic accuracy study. METHODS: We reevaluated the histological and immunohistochemical parameters of 37 GISTs. The standard immunohistochemical diagnosis and differential diagnosis panel antibodies (CD117, PDGFRalpha, CD34, vimentin, desmin, SMA, S-100, and Ki67) were studied on the tumor sections. We also used the popular marker DOG1 antibody with accepted sensitivity for GISTs in recent years and the PDGFRalpha immune marker for which the benefit in routine practice is discussed. RESULTS: Classification according to progressive disease risk groups of the 37 cases revealed that 54% were in the high risk, 19% in the moderate risk, 16% in the low risk, 8% in the very low risk and 8% in the no risk group. Cytological atypia, necrosis, mucosal invasion and the Ki67 index were found to be related to the progressive disease risk groups of the tumors (p<0.05). Positive immunoreaction was observed with CD117 and PDGFRalpha in all GISTs in the study (100%). Positivity with the DOG1 antibody was found in 33 (89%) cases. CD34 was positive in 62% (23) of the cases. CONCLUSION: The CD117 antibody still plays a key role in GIST diagnosis. However, the use of DOG1 and PDGFRalpha antibodies combined with CD117 as sensitive markers can be beneficial. PMID- 26740900 TI - Analyses of C-Reactive Protein, Endothelial Nitric Oxide Synthase and Interleukin 6 Gene Polymorphisms in Adolescents with a Family History of Premature Coronary Artery Disease: A Pilot Study. AB - BACKGROUND: Family history of premature atherosclerosis imposes a high risk to people. The relationship between atherosclerosis and gene polymorphisms of various biomarkers such as Endothelial Nitric Oxide Synthase (eNOS), C-Reactive Protein (CRP), and Interleukin-6 (IL-6) has shown in previous studies. AIMS: The major aim of the study was to evaluate the CRP, eNOS, and IL-6 gene polymorphisms in a group of adolescents who have a parental history of early coronary artery disease (CAD). STUDY DESIGN: Case-control study. METHODS: Thirty-six volunteers with a father with obstructive CAD during the first four decades and 46 subjects with a father with normal coronary arteries documented with coronary angiography were included in the study. Polymerase chain reaction-restriction fragment length polymorphism techniques were used to analyze CRP, eNOS, and IL-6 polymorphisms. RESULTS: We did not find any differences between the two groups with regard to age, sex, body mass index, renal functions, systolic and diastolic blood pressures, lipid profile, and fasting glucose, hemoglobin, and high sensitivity CRP. A significant difference was only observed in IL-6-572 G/C genotype distribution and allele frequency between two groups (Pc=0.036 OR=3.48 CI (95%) 1.17-10.32). CONCLUSION: The present study showed a significant association between the IL-6-572 G/C gene polymorphism (presence of C allele) and adolescents with a parental history of premature CAD. PMID- 26740901 TI - Diffusion Weighted Magnetic Resonance Imaging for the Characterization of Solitary Pulmonary Lesions. AB - BACKGROUND: We evaluated the differential diagnosis of solitary pulmonary lesions on magnetic resonance imaging. AIMS: To investigate the value of diffusion weighted imaging on the differential diagnosis of solitary pulmonary lesions. STUDY DESIGN: Randomized prospective study. METHODS: This prospective study included 48 solitary pulmonary nodules and masses (18 benign, 30 malignant). Single shot echo planar spin echo diffusion weighted imaging (DWI) was performed with two b factors (0 and 1000 s/mm(2)). Apparent diffusion coefficients (ADCs) were calculated. On diffusion weighted (DW) trace images, the signal intensities (SI) of the lesions were visually compared to the SI of the thoracic spinal cord using a 5-point scale: 1: hypointense, 2: moderately hypointense, 3: isointense, 4: moderately hyperintense, 5: significantly hyperintense. For the quantitative evaluation, the lesion to thoracic spinal signal intensity ratios and the ADCs of the lesions were compared between groups. RESULTS: On visual evaluation, taking the density of the spinal cord as a reference, most benign lesions were found to be hypointense, while most of the malignant lesions were evaluated as hyperintense on DWI with a b factor of 1000 s/mm(2). In contrast, on T2 weighted images, it was seen that the distinction of malignant lesions from benign lesions was not statistically significant. The ADCs of the malignant lesions were significantly lower than those of benign lesions (mean ADC was 2.02*10(-3) mm(2)/s for malignant lesions, and 1.195*10(-3)+/-0.3 mm(2)/s for benign lesions). Setting the cut-off value at 1.5*10(-3), ADC had a sensitivity of 86.7% and a specificity of 88.9% for the differentiation of benign lesions from malignant lesions. CONCLUSION: DWI may aid in the differential diagnosis of solitary pulmonary lesions. (ClinicalTrials.gov Identifier: NCT02482181). PMID- 26740902 TI - Mean Platelet Volume in Early Diagnosis of Adnexal Torsion. AB - BACKGROUND: Adnexal torsion (AT) is among the gynecological emergencies; more common in reproductive age, if diagnosed late, this can cause ovarian failure and infertility, but rarely thrombophlebitis and peritonitis. Despite these severe complications, preoperative diagnostic tests are not enough for early diagnosis. There are certain pieces of literature on the subject that reveal changes in mean platelet volume (MPV) values occur in inflammatory and ischemic diseases and that these changes have diagnostic and prognostic significance. However, there are no studies investigating this relationship with adnexal torsion. AIMS: The aim of the study is to investigate the diagnostic and prognostic significance of the mean platelet volume value in the early diagnosis of patients with adnexal torsion. STUDY DESIGN: Case-control study. METHODS: Pre-operative demographic data, MPV, leukocyte count and neutrophils to lymphocytes (N/L) ratio in the blood samples of 51 patients, who were operated on preliminary adnexal torsion and diagnosed as adnexal torsion with a benign ovarian cyst (AT group) were retrospectively compared with those of 50 patients who were operated upon because of benign ovarian cysts and without torsion (control group) at this hospital between 2006 and 2014. RESULTS: The mean MPV level was found to be 8.1 (7.1-10.7) fL in the AT group and 7.9 (6.6-10.2) fL in the control group; no statistically significant difference was found between the groups (p>0.05). Leukocyte count and N/L ratio in the AT group were, on average, 12*10(3)/mm(3) and 82% respectively and in control group; they were, on average, 7.2*10(3)/mm(3) and 59%, respectively. A statistically significant increase was found in the leukocyte count and N/L ratio of the AT group compared to the control group (p<0.001). The platelet count in the AT group was, on average, 253*10(3)/mm(3) and in the control group it was, on average, 280*10(3)/mm(3); no statistically significant difference was detected between these two groups (p>0.05). No correlation was detected between the MPV, platelet and leukocyte counts. The sensitivity of the leukocytosis to the AT cases was found to be 66.7%, and selectivity was 94%. CONCLUSION: The AT diagnostic and prognostic importance of MPV value has not been determined in this study. PMID- 26740903 TI - Indices of Central and Peripheral Obesity; Anthropometric Measurements and Laboratory Parameters of Metabolic Syndrome and Thyroid Function. AB - BACKGROUND: Metabolic syndrome (MetS) and obesity are serious health problems in the World, including Turkey. Contemporary studies have suggested a meaningful association between insulin resistance (IR), MetS parameters, and thyroid function tests. AIMS: We aimed to elucidate the impact of fat distribution on the anthropometric and laboratory parameters, especially indices of MetS, IR and thyroid function, in obese women. STUDY DESIGN: Cross-sectional study. METHODS: Anthropometric measurements of all participants and biochemical tests in their serum samples were performed. RESULTS: Weight, waist circumference (WC), body mass index (BMI), and other parameters of fat distribution were significantly increased in all obese compared to control subjects; but there was no significant difference between central and peripheral obese groups. The central obese group had significantly higher insulin levels, components of MetS, the ratio free triiodothyronine (fT3) to free thyroxin fT4, and fT4 than those of peripheral obese and control groups. CONCLUSION: Elevated triglyceride, glucose and insulin levels may be associated with increased IR, which in turn is related to MetS. Body fat composition may affect thyroid tests in the obese; the changes in fT3/fT4 could be the consequence of fat distribution. PMID- 26740904 TI - Reversible Posterior Leukoencephalopathy Syndrome Due to Carboplatin and Paclitaxel Therapy. AB - BACKGROUND: Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinicoradiologic syndrome characterized by headache, decreased alertness, seizures, visual abnormalities, and white matter changes indicative of cerebral edema. Although the pathogenesis remains poorly understood, several etiological causes have been described. RPLS is a common complication of chemotherapeutics because of its toxic effect on the central nervous system. This syndrome is frequently associated with seizures but rarely seen with status epilepticus and periodic lateralized epileptiform discharges (PLEDs). CASE REPORT: We present a case with metastatic lung cancer that developed RPLS after carboplatin and paclitaxel therapy. Our case was admitted to the hospital with status epilepticus and her electroencephalography showed PLEDs. CONCLUSION: It is important to closely monitor blood pressure and electrolyte levels in patients who take chemotherapeutic agents, especially when there is no previous history of hypertension. It should be kept in mind that RPLS is a causative factor of status epilepticus and PLEDs. PMID- 26740905 TI - Utero-cutaneous Fistula after Multiple Abdominal Myomectomies: A Case Report. AB - BACKGROUND: Utero-cutaneous fistula (UCF) is an extremely rare entity and only a few case reports have been published. Most UCFs develop secondary to post-partum or postoperative complications. CASE REPORT: A 42 year-old woman began to complain from bleeding and malodorous discharge through her abdominal incision scar. The fistula tract with a thickness of 8 mm was observed between the uterus and wound using magnetic resonance imaging (MRI). The risks and benefits of conservative treatment have been discussed; the patient demanded definitive treatment, so hysterectomy and excision of the fistulous tract was performed. Histopathology of the fistulous tract showed endometrial epithelization of the tract lined by granulation. CONCLUSION: There are many causes of such an extremely rare entity. Patients should be counseled for medical or surgical treatment considering their age, accompanied uterine pathologies such as fibroids and fertility expectations. PMID- 26740906 TI - A Threat to Autonomy? The Intrusion of Predictive Brain Implants. AB - The world's first-in-human clinical trial using invasive intelligent brain devices-devices that predict specific neuronal events directly to the implanted person-has been completed with significant success. Predicting brain activity before specific outcomes occur brings a raft of unprecedented applications, especially when implants offer advice on how to respond to the neuronal events forecasted. Although these novel predictive and advisory implantable devices offer great potential to positively affect patients following surgery by enhancing quality of life (e.g., provide control over symptoms), substantial ethical concerns remain. The invasive nature of these novel devices is not unique; however, the inclusion of predictive and advisory functionalities within the implants, involving permanent monitoring of brain activity in real time, raises new ethical issues to explore, especially in relation to concerns for patient autonomy. What might be the effects of ongoing monitoring of predictive and advisory brain technologies on a patient's postoperative sense of autonomy? The role played by predictive and advisory implantable brain devices on patient's feelings of autonomy following surgery is completely unknown. The first section of this article addresses this shortcoming by reporting on a pilot study that we conducted with one of the patients implanted with one of these novel brain devices. The second section examines how overreliance on predictive and advisory brain technologies may threaten patients' autonomy. The third section looks into ethical problems concerning how devices delivering automated therapeutic responses might, hypothetically speaking, be used to monitor and control individual's autonomy through inhibition of undesirable behaviors. PMID- 26740907 TI - Arsenic-induced Histological Alterations in Various Organs of Mice. AB - Deposition of arsenic in mice through groundwater is well documented but little is known about the histological changes of organs by the metalloid. Present study was designed to evaluate arsenic-induced histological alterations in kidney, liver, thoracic artery and brain of mice which are not well documented yet. Swiss albino male mice were divided into 2 groups and treated as follows: Group 1: control, 2: arsenic (sodium arsenite at 10 mg/kg b.w. orally for 8 wks). Group 2 showed marked degenerative changes in kidney, liver, thoracic artery, and brain whereas Group 1 did not reveal any abnormalities on histopathology. We therefore concluded that arsenic induces histological alterations in the tested organs. PMID- 26740908 TI - Extranodal diffuse large B-cell lymphoma with monoclonal gammopathy: an aggressive and primary refractory disease responding to an immunomodulatory agent. AB - BACKGROUND: Although the clinical outcome of patients with diffuse large B cell lymphoma (DLBCL) has been improved by the addition of rituximab to standard chemotherapy, almost one-third fails or relapses after first line treatment. The presence of monoclonal gammopathy (MG) is a known adverse prognostic factor for DLBCL. Because this subset of patients does not benefit from R-CHOP, new therapeutic options are required. Herein, we report the first case of extranodal DBCL of the lung with a concomitant MG who achieved a long lasting complete remission with lenalidomide. CASE PRESENTATION: The 73-year-old male patient presented with lateral cervical lymphadenopathy, B symptoms, lactate dehydrogenase and beta2-microglobulin elevation. Computed tomography (CT) showed mediastinal lymphadenopathy and bilateral lung involvement. Biopsy of both disease locations revealed the presence of DLBCL. Successive bone marrow trephine biopsy proved the presence of concordant DLBCL involvement. At the time of diagnosis, a MG was present as well. The patient did not respond to the standard treatments, and subsequently underwent lenalidomide 25 mg/m(2) days 1-21 q28 plus dexamethasone 40 mg days 1-4, 9-12 e 17-20. This therapeutic regimen was efficacious and safe as salvage therapy in extranodal DBCL with a MG. Furthermore, we observed a close association between DLBCL response to therapy and MG levels, suggesting that the amount of M-protein might be a surrogate marker of disease response. CONCLUSION: Although DLBCL associated with MG does not respond properly to the standard treatments, it is highly sensitive to lenalidomide, which is why we endorse its role as treatment of choice in this subset of patients. In addition, MG levels appear to correlate with tumor burden, suggesting that it might be a useful marker of disease response. Prospective trials to validate these observations are warranted. PMID- 26740910 TI - Tunnel Vision Prismatic Field Expansion: Challenges and Requirements. AB - PURPOSE: No prismatic solution for peripheral field loss (PFL) has gained widespread acceptance. Field extended by prisms has a corresponding optical scotoma at the prism apices. True expansion can be achieved when each eye is given a different view (through visual confusion). We analyze the effects of apical scotomas and binocular visual confusion in different designs to identify constraints on any solution that is likely to meet acceptance. METHODS: Calculated perimetry diagrams were compared to perimetry with PFL patients wearing InWave channel prisms and Trifield spectacles. Percept diagrams illustrate the binocular visual confusion. RESULTS: Channel prisms provide no benefit at primary gaze. Inconsequential extension was provided by InWave prisms, although accessible with moderate gaze shifts. Higher-power prisms provide greater extension, with greater paracentral scotoma loss, but require uncomfortable gaze shifts. Head turns, not eye scans, are needed to see regions lost to the apical scotomas. Trifield prisms provide field expansion at all gaze positions, but acceptance was limited by disturbing effects of central binocular visual confusion. CONCLUSIONS: Field expansion when at primary gaze (where most time is spent) is needed while still providing unobstructed central vision. Paracentral multiplexing prisms we are developing that superimpose shifted and see-through views may accomplish that. TRANSLATIONAL RELEVANCE: Use of the analyses and diagramming techniques presented here will be of value when considering prismatic aids for PFL, and could have prevented many unsuccessful designs and the improbable reports we cited from the literature. New designs must likely address the challenges identified here. PMID- 26740909 TI - Suicide Attempt Characteristics Among Veterans and Active-Duty Service Members Receiving Mental Health Services: A Pooled Data Analysis. AB - Past suicidal behaviors are among the strongest and most consistent predictors of eventual suicide and may be particularly salient in military suicide. The current study compared characteristics of suicide attempts in veterans (N = 746) and active-duty service members (N = 1,013) receiving treatment for acute suicide risk. Baseline data from six randomized controlled trials were pooled and analyzed using robust regression. Service members had greater odds of having attempted suicide relative to veterans, though there were no differences in number of attempts made. Service members also had higher rates of premilitary suicide attempts and nonsuicidal self-injury (NSSI). Veterans disproportionately attempted suicide by means of overdose. In veterans, combat deployment was associated with lower odds of lifetime suicide attempt, while history of NSSI was associated with greater attempt odds. Neither was significantly associated with lifetime suicide attempt in service members. Implications for suicide assessment and treatment are discussed. PMID- 26740911 TI - Electronic Cigarette and Electronic Hookah: A Pilot Study Comparing Two Vaping Products. AB - INTRODUCTION: Since the introduction of e-cigarettes into the U.S. market, the number and variety of vaping products has proliferated. E-hookahs are long, pen like vaping devices that debuted in U.S. markets in 2014. By applying the Host, Agent, Vector, Environment (HAVE) Model, the objective of this exploratory study was to assess differences between e-cigarettes and e-hookahs to help inform tobacco regulatory science and practice. METHODS: In June-August 2014, a total of 54 unique manufactured e-cigarette and e-hookah products were identified at point of sales (POS) around three college campuses in Southeast U.S. Documented characteristics included brand name, disposable, rechargeable, nicotine containing, packaging, and flavor type. Statistical analyses were conducted October to November 2014 to assess frequency and percent of product type across POS and specific characteristics. RESULTS: Among 54 products, 70.4% were e cigarettes and 29.6% were e-hookahs. Across POS, drug stores and grocery stores carried e-cigarettes exclusively, while gas stations carried the greatest proportion of e-hookahs. Compared to e-hookahs, a greater proportion of e cigarettes were non-disposable and contained nicotine; a greater proportion of e hookahs came in fruit and other types of flavors compared to e-cigarettes. CONCLUSIONS: The present study suggests that e-cigarettes and e-hookahs differ by specific product characteristics and by places where they are sold. Despite these differences, the products are used for similar purposes warranting careful monitoring of industry manufacturing and marketing, because the safety of both products is still undetermined. Additional research is needed to understand the uptake and continued use of these products. PMID- 26740913 TI - Relationship between chronic pain and brain reorganization after deafferentation: A systematic review of functional MRI findings. AB - BACKGROUND: Mechanisms underlying the development of phantom limb pain and neuropathic pain after limb amputation and spinal cord injury, respectively, are poorly understood. The goal of this systematic review was to assess the robustness of evidence in support of "maladaptive plasticity" emerging from applications of advanced functional magnetic resonance imaging (MRI). METHODS: Using MeSH heading search terms in PubMed and SCOPUS, a systematic review was performed querying published manuscripts. RESULTS: From 146 candidate publications, 10 were identified as meeting the inclusion criteria. Results from fMRI investigations provided some level of support for maladaptive cortical plasticity, including longitudinal studies that demonstrated a change in functional organization related to decreases in pain. However, a number of studies have reported no relationship between reorganization, pain and deafferentation, and emerging evidence has also suggested the opposite - that is, chronic pain is associated with preserved cortical function. CONCLUSION: Based solely on advanced functional neuroimaging results, there is only limited evidence for a relationship between chronic pain intensity and reorganization after deafferentation. The review demonstrates the need for additional neuroimaging studies to clarify the relationship between chronic pain and reorganization. PMID- 26740912 TI - Automatic segmentation of the hippocampus for preterm neonates from early-in-life to term-equivalent age. AB - INTRODUCTION: The hippocampus, a medial temporal lobe structure central to learning and memory, is particularly vulnerable in preterm-born neonates. To date, segmentation of the hippocampus for preterm-born neonates has not yet been performed early-in-life (shortly after birth when clinically stable). The present study focuses on the development and validation of an automatic segmentation protocol that is based on the MAGeT-Brain (Multiple Automatically Generated Templates) algorithm to delineate the hippocampi of preterm neonates on their brain MRIs acquired at not only term-equivalent age but also early-in-life. METHODS: First, we present a three-step manual segmentation protocol to delineate the hippocampus for preterm neonates and apply this protocol on 22 early-in-life and 22 term images. These manual segmentations are considered the gold standard in assessing the automatic segmentations. MAGeT-Brain, automatic hippocampal segmentation pipeline, requires only a small number of input atlases and reduces the registration and resampling errors by employing an intermediate template library. We assess the segmentation accuracy of MAGeT-Brain in three validation studies, evaluate the hippocampal growth from early-in-life to term-equivalent age, and study the effect of preterm birth on the hippocampal volume. The first experiment thoroughly validates MAGeT-Brain segmentation in three sets of 10-fold Monte Carlo cross-validation (MCCV) analyses with 187 different groups of input atlases and templates. The second experiment segments the neonatal hippocampi on 168 early-in-life and 154 term images and evaluates the hippocampal growth rate of 125 infants from early-in-life to term-equivalent age. The third experiment analyzes the effect of gestational age (GA) at birth on the average hippocampal volume at early-in-life and term-equivalent age using linear regression. RESULTS: The final segmentations demonstrate that MAGeT-Brain consistently provides accurate segmentations in comparison to manually derived gold standards (mean Dice's Kappa > 0.79 and Euclidean distance <1.3 mm between centroids). Using this method, we demonstrate that the average volume of the hippocampus is significantly different (p < 0.0001) in early-in-life (621.8 mm(3)) and term equivalent age (958.8 mm(3)). Using these differences, we generalize the hippocampal growth rate to 38.3 +/- 11.7 mm(3)/week and 40.5 +/- 12.9 mm(3)/week for the left and right hippocampi respectively. Not surprisingly, younger gestational age at birth is associated with smaller volumes of the hippocampi (p = 0.001). CONCLUSIONS: MAGeT-Brain is capable of segmenting hippocampi accurately in preterm neonates, even at early-in-life. Hippocampal asymmetry with a larger right side is demonstrated on early-in-life images, suggesting that this phenomenon has its onset in the 3rd trimester of gestation. Hippocampal volume assessed at the time of early-in-life and term-equivalent age is linearly associated with GA at birth, whereby smaller volumes are associated with earlier birth. PMID- 26740914 TI - Semi-metric analysis of the functional brain network: Relationship with familial risk for psychotic disorder. AB - BACKGROUND: Dysconnectivity in schizophrenia can be understood in terms of dysfunctional integration of a distributed network of brain regions. Here we propose a new methodology to analyze complex networks based on semi-metric behavior, whereby higher levels of semi-metricity may represent a higher level of redundancy and dispersed communication. It was hypothesized that individuals with (increased risk for) psychotic disorder would have more semi-metric paths compared to controls and that this would be associated with symptoms. METHODS: Resting-state functional MRI scans were obtained from 73 patients with psychotic disorder, 83 unaffected siblings and 72 controls. Semi-metric percentages (SMP) at the whole brain, hemispheric and lobar level were the dependent variables in a multilevel random regression analysis to investigate group differences. SMP was further examined in relation to symptomatology (i.e., psychotic/cognitive symptoms). RESULTS: At the whole brain and hemispheric level, patients had a significantly higher SMP compared to siblings and controls, with no difference between the latter. In the combined sibling and control group, individuals with high schizotypy had intermediate SMP values in the left hemisphere with respect to patients and individuals with low schizotypy. Exploratory analyses in patients revealed higher SMP in 12 out of 42 lobar divisions compared to controls, of which some were associated with worse PANSS symptomatology (i.e., positive symptoms, excitement and emotional distress) and worse cognitive performance on attention and emotion processing tasks. In the combined group of patients and controls, working memory, attention and social cognition were associated with higher SMP. DISCUSSION: The results are suggestive of more dispersed network communication in patients with psychotic disorder, with some evidence for trait based network alterations in high-schizotypy individuals. Dispersed communication may contribute to the clinical phenotype in psychotic disorder. In addition, higher SMP may contribute to neuro- and social cognition, independent of psychosis risk. PMID- 26740915 TI - Association between lesion location and language function in adult glioma using voxel-based lesion-symptom mapping. AB - BACKGROUND: Management of language difficulties is an important aspect of clinical care for glioma patients, and accurately identifying the possible language deficits in patients based on lesion location would be beneficial to clinicians. To that end, we examined the relationship between lesion presence and language performance on tests of receptive language and expressive language using a highly specific voxel-based lesion-symptom mapping (VLSM) approach in glioma patients. METHODS: 98 adults with primary glioma, who were pre-surgical candidates, were administered seven neurocognitive tests within the domains of receptive language and expressive language. The association between language performance and lesion presence was examined using VLSM. Statistical parametric maps were created for each test, and composite maps for both receptive language and expressive language were created to display the significant voxels common to all tests within these language domains. RESULTS: We identified clusters of voxels with a significant relationship between lesion presence and language performance. All tasks were associated with several white matter pathways. The receptive language tasks were additionally all associated with regions primarily within the lateral temporal lobe and medial temporal lobe. In contrast, the expressive language tasks shared little overlap, despite each task being independently associated with large anatomic areas. CONCLUSIONS: Our findings identify the key anatomic structures involved in language functioning in adult glioma patients using an innovative lesion analysis technique and suggest that expressive language abilities may be more task-dependent and distributed than receptive language abilities. PMID- 26740917 TI - Quantifying brain tissue volume in multiple sclerosis with automated lesion segmentation and filling. AB - Lesion filling has been successfully applied to reduce the effect of hypo-intense T1-w Multiple Sclerosis (MS) lesions on automatic brain tissue segmentation. However, a study of fully automated pipelines incorporating lesion segmentation and lesion filling on tissue volume analysis has not yet been performed. Here, we analyzed the % of error introduced by automating the lesion segmentation and filling processes in the tissue segmentation of 70 clinically isolated syndrome patient images. First of all, images were processed using the LST and SLS toolkits with different pipeline combinations that differed in either automated or manual lesion segmentation, and lesion filling or masking out lesions. Then, images processed following each of the pipelines were segmented into gray matter (GM) and white matter (WM) using SPM8, and compared with the same images where expert lesion annotations were filled before segmentation. Our results showed that fully automated lesion segmentation and filling pipelines reduced significantly the % of error in GM and WM volume on images of MS patients, and performed similarly to the images where expert lesion annotations were masked before segmentation. In all the pipelines, the amount of misclassified lesion voxels was the main cause in the observed error in GM and WM volume. However, the % of error was significantly lower when automatically estimated lesions were filled and not masked before segmentation. These results are relevant and suggest that LST and SLS toolboxes allow the performance of accurate brain tissue volume measurements without any kind of manual intervention, which can be convenient not only in terms of time and economic costs, but also to avoid the inherent intra/inter variability between manual annotations. PMID- 26740918 TI - Abnormal white matter properties in adolescent girls with anorexia nervosa. AB - Anorexia nervosa (AN) is a serious eating disorder that typically emerges during adolescence and occurs most frequently in females. To date, very few studies have investigated the possible impact of AN on white matter tissue properties during adolescence, when white matter is still developing. The present study evaluated white matter tissue properties in adolescent girls with AN using diffusion MRI with tractography and T1 relaxometry to measure R1 (1/T1), an index of myelin content. Fifteen adolescent girls with AN (mean age = 16.6 years +/- 1.4) were compared to fifteen age-matched girls with normal weight and eating behaviors (mean age = 17.1 years +/- 1.3). We identified and segmented 9 bilateral cerebral tracts (18) and 8 callosal fiber tracts in each participant's brain (26 total). Tract profiles were generated by computing measures for fractional anisotropy (FA) and R1 along the trajectory of each tract. Compared to controls, FA in the AN group was significantly decreased in 4 of 26 white matter tracts and significantly increased in 2 of 26 white matter tracts. R1 was significantly decreased in the AN group compared to controls in 11 of 26 white matter tracts. Reduced FA in combination with reduced R1 suggests that the observed white matter differences in AN are likely due to reductions in myelin content. For the majority of tracts, group differences in FA and R1 did not occur within the same tract. The present findings have important implications for understanding the neurobiological factors underlying white matter changes associated with AN and invite further investigations examining associations between white matter properties and specific physiological, cognitive, social, or emotional functions affected in AN. PMID- 26740919 TI - Scene unseen: Disrupted neuronal adaptation in melancholia during emotional film viewing. AB - Impairments in attention and concentration are distinctive features of melancholic depression, and may diminish the ability to shift focus away from internal dysphoric states. Disrupted brain networks may underlie the inability to effectively disengage from interoceptive signals in this disorder. This study investigates changes in effective connectivity between cortical systems supporting attention, interoception, and perception in those with melancholic depression when shifting attention from rest to viewing dynamic film stimuli. We hypothesised that those with melancholia would show impaired attentional shifting from rest to emotional film viewing, captured in neuronal states that differed little across conditions. Functional magnetic resonance imaging (fMRI) data were acquired from 48 participants (16 melancholic depressed, 16 non-melancholic depressed, and 16 healthy controls) at rest and whilst viewing emotionally salient movies. Using independent component analysis, we identified 8 cortical modes (default mode, executive control, left/right frontoparietal attention, left/right insula, visual and auditory) and studied their dynamics using dynamic causal modelling. Engagement with dynamic emotional material diminished in melancholia and was associated with network-wide increases in effective connectivity. Melancholia was also characterised by an increase in effective connectivity amongst cortical regions involved in attention and interoception when shifting from rest to negative film viewing, with the converse pattern in control participants. The observed involvement of attention- and insula-based cortical systems highlights a potential neurobiological mechanism for disrupted attentional resource allocation, particularly in switching between interoceptive and exteroceptive signals, in melancholia. PMID- 26740921 TI - Corrigendum to "Cardio-metabolic risk factors and cortical thickness in a neurologically healthy male population: Results from the psychological, social and biological determinants of ill health (pSoBid) study" [Neuroimage Clin. 2 (2013) 646-57]. AB - [This corrects the article DOI: 10.1016/j.nicl.2013.04.012.]. PMID- 26740920 TI - White matter and reading deficits after pediatric traumatic brain injury: A diffusion tensor imaging study. AB - Pediatric traumatic brain injury often results in significant long-term deficits in mastery of reading ability. This study aimed to identify white matter pathways that, when damaged, predicted reading deficits in children. Based on the dual route model of word reading, we predicted that integrity of the inferior fronto occipital fasciculus would be related to performance in sight word identification while integrity of the superior longitudinal fasciculus would be related to performance in phonemic decoding. Reading fluency and comprehension were hypothesized to relate to the superior longitudinal fasciculus, inferior fronto occipital fasciculus, and cingulum bundle. The connectivity of white matter pathways was used to predict reading deficits in children aged 6 to 16 years with traumatic brain injury (n = 29) and those with orthopedic injury (n = 27) using tract-based spatial statistics. Results showed that children with traumatic brain injury and reduced microstructural integrity of the superior longitudinal fasciculus demonstrated reduced word-reading ability on sight word and phonemic decoding tasks. Additionally, children with traumatic brain injury and microstructural changes involving the cingulum bundle demonstrated reduced reading fluency. Results support the association of a dorsal pathway via the superior longitudinal fasciculus with both sight word reading and phonemic decoding. No association was identified between the inferior fronto-occipital fasciculus and sight word reading or phonemic decoding. Reading fluency was associated with the integrity of the cingulum bundle. These findings support dissociable pathways predicting word reading and fluency using Diffusion Tensor Imaging and provide additional information for developing models of acquired reading deficits by specifying areas of brain damage which may predict reading deficits following recovery from the acute phase of TBI. PMID- 26740922 TI - The tracking of active travel and its relationship with body composition in UK adolescents. AB - BACKGROUND: To examine the tracking of active travel through adolescence, and its association with body mass index (BMI) and fat mass at age 17 in a UK cohort. METHODS: We analysed data collected from the Avon Longitudinal Study of Parents and Children (ALSPAC). The analyses include all participants with self-reported travel mode to school at ages 12, 14 and 16 years, and measured height, weight and body composition at age 17 (n=2,026). Tracking coefficients were calculated for individual travel behaviours (including walking and cycling) through adolescence using Generalised Estimating Equations. Linear regression analyses examined associations between travel pattern (consistently passive, consistently active, active at two time points or active at one time point), BMI, and DXA measured fat mass (expressed as internally derived standard deviation scores) at 17 years. Analyses were adjusted for height (where appropriate), sex, age, parental social class, and maternal education with interaction terms to assess sex differences. RESULTS: There was substantial tracking in active travel through adolescence, with 38.5% of males and 32.3% of females consistently walking or cycling to school. In males, a consistently or predominantly active travel pattern was associated with a lower BMI SD score at age 17 (consistently active: adjusted beta=-0.23; 95% CI -0.40, -0.06; active at two time points: adjusted beta-0.30; 95% CI -0.50, -0.10) compared to those with a consistently passive pattern. No associations were seen in females. CONCLUSIONS: Maintenance of active travel behaviours throughout adolescence may help to protect against the development of excess BMI in males. In addition to encouraging the adoption of active travel to school, public health messages should aim to prevent drop out from active travel to promote good health in youth. PMID- 26740923 TI - Optimized method for methylated DNA immuno-precipitation. AB - Methylated DNA immunoprecipitation (MeDIP) is one of the most widely used methods to evaluate DNA methylation on a whole genome scale, and involves the capture of the methylated fraction of the DNA by an antibody specific to methyl-cytosine. MeDIP was initially coupled with microarray hybridization to detect local DNA methylation enrichments along the genome. More recently, MeDIP has been coupled with next generation sequencing, which highlights its current and future applicability. In previous studies in which MeDIP was applied, the protocol took around 3 days to be performed. Given the importance of MeDIP for studies involving DNA methylation, it was important to optimize the method in order to deliver faster turnouts. The present article describes optimization steps of the MeDIP method. The length of the procedure was reduced in half without compromising the quality of the results. This was achieved by:*Reduction of the number of washes in different stages of the protocol, after a careful evaluation of the number of indispensable washes.*Reduction of reaction times for detaching methylated DNA fragments from the complex agarose beads:antibody.*Modification of the methods to purify methylated DNA, which incorporates new devices and procedures, and eliminates a lengthy phenol and chloroform:isoamyl alcohol extraction. PMID- 26740924 TI - Sequential fractionation and isolation of subcellular proteins from tissue or cultured cells. AB - Many types of studies require the localization of a protein to, or isolation of enriched protein from a specific cellular compartment. Many protocols in the literature and from commercially available kits claim to yield pure cellular fractions. However, in our hands, the former often do not work effectively and the latter may be prohibitively expensive if a large number of fractionations are required. Furthermore, the largely proprietary composition of reagents in commercial kits means that the user is not able to make adjustments if, for example, a particular component affects the activity of a protein of interest. The method described here allows the isolation of purified proteins from three cellular fractions: the cytosol, membrane-bound organelles, and the nucleus. It uses gentle buffers with increasing detergent strength that sequentially lyse the cell membrane, organelle membranes and finally the nuclear membrane.*Quick, simple to replicate or adjust; this method does not require expensive reagents or use of commercial kits*The protocol can be applied to tissue samples or cultured cells without changing buffer components*Yields purified fractions of cytosolic, membrane bound and nuclear proteins, with the proper distribution of the appropriate subcellular markers: GAPDH, VDAC, SERCA2 and lamin A/C. PMID- 26740925 TI - Legionella spp. isolation and quantification from greywater. AB - Legionella, an opportunistic human pathogen whose natural environment is water, is transmitted to humans through inhalation of contaminated aerosols. Legionella has been isolated from a high diversity of water types. Due its importance as a pathogen, two ISO protocols have been developed for its monitoring. However, these two protocols are not suitable for analyzing Legionella in greywater (GW). GW is domestic wastewater excluding the inputs from toilets and kitchen. It can serve as an alternative water source, mainly for toilet flushing and garden irrigation; both producing aerosols that can cause a risk for Legionella infection. Hence, before reuse, GW has to be treated and its quality needs to be monitored. The difficulty of Legionella isolation from GW strives in the very high load of contaminant bacteria. Here we describe a modification of the ISO protocol 11731:1998 that enables the isolation and quantification of Legionella from GW samples. The following modifications were made:*To enable isolation of Legionella from greywater, a pre-filtration step that removes coarse matter is recommended.*Legionella can be isolated after a combined acid-thermic treatment that eliminates the high load of contaminant bacteria in the sample. PMID- 26740927 TI - Early psychological interventions for psychosis. AB - The manuscript correspond to an editorial in order to assess the most important and effective interventions for people with psychosis in the early stages. PMID- 26740916 TI - Highly adaptive tests for group differences in brain functional connectivity. AB - Resting-state functional magnetic resonance imaging (rs-fMRI) and other technologies have been offering evidence and insights showing that altered brain functional networks are associated with neurological illnesses such as Alzheimer's disease. Exploring brain networks of clinical populations compared to those of controls would be a key inquiry to reveal underlying neurological processes related to such illnesses. For such a purpose, group-level inference is a necessary first step in order to establish whether there are any genuinely disrupted brain subnetworks. Such an analysis is also challenging due to the high dimensionality of the parameters in a network model and high noise levels in neuroimaging data. We are still in the early stage of method development as highlighted by Varoquaux and Craddock (2013) that "there is currently no unique solution, but a spectrum of related methods and analytical strategies" to learn and compare brain connectivity. In practice the important issue of how to choose several critical parameters in estimating a network, such as what association measure to use and what is the sparsity of the estimated network, has not been carefully addressed, largely because the answers are unknown yet. For example, even though the choice of tuning parameters in model estimation has been extensively discussed in the literature, as to be shown here, an optimal choice of a parameter for network estimation may not be optimal in the current context of hypothesis testing. Arbitrarily choosing or mis-specifying such parameters may lead to extremely low-powered tests. Here we develop highly adaptive tests to detect group differences in brain connectivity while accounting for unknown optimal choices of some tuning parameters. The proposed tests combine statistical evidence against a null hypothesis from multiple sources across a range of plausible tuning parameter values reflecting uncertainty with the unknown truth. These highly adaptive tests are not only easy to use, but also high-powered robustly across various scenarios. The usage and advantages of these novel tests are demonstrated on an Alzheimer's disease dataset and simulated data. PMID- 26740926 TI - Conceptualization and treatment of negative symptoms in schizophrenia. AB - Negative symptoms of schizophrenia including social withdrawal, diminished affective response, lack of interest, poor social drive, and decreased sense of purpose or goal directed activity predict poor functional outcomes for patients with schizophrenia. They may develop and be maintained as a result of structural and functional brain abnormalities, particularly associated with dopamine reward pathways and by environmental and psychosocial factors such as self-defeating cognitions and the relief from overstimulation that accompanies withdrawal from social and role functioning. Negative symptoms are more difficult to treat than the positive symptoms of schizophrenia and represent an unmet therapeutic need for large numbers of patients with schizophrenia. While antipsychotic medications to treat the symptoms of schizophrenia have been around for decades, they have done little to address the significant functional impairments in the disorder that are associated with negative symptoms. Negative symptoms and the resulting loss in productivity are responsible for much of the world-wide personal and economic burden of schizophrenia. Pharmacologic treatments may be somewhat successful in treating secondary causes of negative symptoms, such as antipsychotic side effects and depression. However, in the United States there are no currently approved treatments for severe and persistent negative symptoms (PNS) that are not responsive to treatments for secondary causes. Pharmacotherapy and psychosocial treatments are currently being developed and tested with severe and PNS as their primary targets. Academia, clinicians, the pharmaceutical industry, research funders, payers and regulators will need to work together to pursue novel treatments to address this major public health issue. PMID- 26740928 TI - Treating comorbid anxiety and depression: Psychosocial and pharmacological approaches. AB - Comorbid anxiety with depression predicts poor outcomes with a higher percentage of treatment resistance than either disorder occurring alone. Overlap of anxiety and depression complicates diagnosis and renders treatment challenging. A vital step in treatment of such comorbidity is careful and comprehensive diagnostic assessment. We attempt to explain various psychosocial and pharmacological approaches for treatment of comorbid anxiety and depression. For the psychosocial component, we focus only on generalized anxiety disorder based on the following theoretical models: (1) "the avoidance model"; (2) "the intolerance of uncertainty model"; (3) "the meta-cognitive model"; (4) "the emotion dysregulation model"; and (5) "the acceptance based model". For depression, the following theoretical models are explicated: (1) "the cognitive model"; (2) "the behavioral activation model"; and (3) "the interpersonal model". Integration of these approaches is suggested. The treatment of comorbid anxiety and depression necessitates specific psychopharmacological adjustments as compared to treating either condition alone. Serotonin reuptake inhibitors are considered first-line treatment in uncomplicated depression comorbid with a spectrum of anxiety disorders. Short-acting benzodiazepines (BZDs) are an important "bridging strategy" to address an acute anxiety component. In patients with comorbid substance abuse, avoidance of BZDs is recommended and we advise using an atypical antipsychotic in lieu of BZDs. For mixed anxiety and depression comorbid with bipolar disorder, we recommend augmentation of an antidepressant with either lamotrigine or an atypical agent. Combination and augmentation therapies in the treatment of comorbid conditions vis-a-vis monotherapy may be necessary for positive outcomes. Combination therapy with tricyclic antidepressants, gabapentin and selective serotonin/norepinephrine reuptake inhibitors (e.g., duloxetine) are specifically useful for comorbid chronic pain syndromes. Aripiprazole, quetiapine, risperidone and other novel atypical agents may be effective as augmentations. For treatment-resistant patients, we recommend a "stacking approach" not dissimilar from treatment of hypertension In conclusion, we delineate a comprehensive approach comprising integration of various psychosocial approaches and incremental pharmacological interventions entailing bridging strategies, augmentation therapies and ultimately stacking approaches towards effectively treating comorbid anxiety and depression. PMID- 26740929 TI - Who says this is a modern disorder? The early history of attention deficit hyperactivity disorder. AB - Attention-deficit hyperactivity disorder (ADHD) is a complex, heterogeneous and multifactorial neurodevelopmental disorder characterized by persistent symptoms of inattention, hyperactivity and impulsivity. Although the first clinical description of a constellation of symptoms highly resembling to what currently could be diagnosed as ADHD is generally attributed to George F Still in 1902, there are scattered but significant published historical medical, scientific and non-scientific reports, much prior to Still's lectures, of what is currently conceptualized as ADHD. The present report aimed at exploring the early history of ADHD, prior to the 20(th) century in the medical literature and in other historical sources, to provide clinicians, researchers and other professionals with a better understanding of the roots and current conceptualization of this disorder. It is possible to find clues and highly suggestive descriptions of individuals presenting symptoms resembling what is currently defined as ADHD in the literature, in paintings or in the Bible. However, the earliest medical reports of individuals with abnormal degrees of inattention, distractibility and overactivity date from the last quarter of the 18(th) century, included in two of the first textbooks specifically on the subject of mental diseases, published by the German Melchior Adam Weikard and the Scottish Sir Alexander Crichton. During the 19(th) century some eminent physicians from Germany, France or Great Britain, such as Charles West, Thomas C Albutt, Thomas S Clouston, William W, Ireland, John Haslam, Heinrich Neumann, or Desire-Magloire Bourneville, among others provided clinical depictions of patients that most likely presently would be diagnosed as having ADHD. Whilst some of the children described by Still and his predecessors may have suffered from a variety of neurological and psychiatric disorders, many of these patients showed clear symptoms of ADHD and may present with comorbid disorders, as it is commonly the case in clinical practice. PMID- 26740931 TI - Does mindfulness meditation improve attention in attention deficit hyperactivity disorder? AB - Attention deficit hyperactivity disorder (ADHD) manifests by high levels of inattention, impulsiveness and hyperactivity. ADHD starts in childhood and results in impairments that continue into adulthood. While hyperactivity declines over time, inattention and executive function difficulties persist, leading to functional deficits. Adolescents and adults with ADHD have pervasive impairment in interpersonal and family relationships. They may develop addiction, delinquent behavior and comorbid psychiatric disorders. Despite advances in diagnosis and treatment, persistent residual symptoms are common, highlighting the need for novel treatment strategies. Mindfulness training, derived from Eastern meditation practices, may improve self-regulation of attention. It may also be a useful strategy to augment standard ADHD treatments and may be used as a potential tool to reduce impairments in patients with residual symptoms of ADHD. Clinically, this would manifest by an increased ability to suppress task-unrelated thoughts and distractions resulting in improved attention, completion of tasks and potential improvement in occupational and social function. PMID- 26740930 TI - Animal models for posttraumatic stress disorder: An overview of what is used in research. AB - Posttraumatic stress disorder (PTSD) is a common anxiety disorder characterised by its persistence of symptoms after a traumatic experience. Although some patients can be cured, many do not benefit enough from the psychological therapies or medication strategies used. Many researchers use animal models to learn more about the disorder and several models are available. The most-used physical stressor models are single-prolonged stress, restraint stress, foot shock, stress-enhanced fear learning, and underwater trauma. Common social stressors are housing instability, social instability, early-life stress, and social defeat. Psychological models are not as diverse and rely on controlled exposure to the test animal's natural predator. While validation of these models has been resolved with replicated symptoms using analogous stressors, translating new findings to human patients remains essential for their impact on the field. Choosing a model to experiment with can be challenging; this overview of what is possible with individual models may aid in making a decision. PMID- 26740932 TI - Comprehensive neurocognitive assessment of patients with anorexia nervosa. AB - AIM: To utilise a comprehensive cognitive battery to gain a better understanding of cognitive performance in anorexia nervosa (AN). METHODS: Twenty-six individuals with AN and 27 healthy control participants matched for age, gender and premorbid intelligence, participated in the study. A standard cognitive battery, the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery, was used to investigate performance on seven cognitive domains with the use of 10 different tasks: speed of processing [Brief Assessment Of Cognition In Schizophrenia: Symbol Coding, Category Fluency: Animal Naming (Fluency) and Trail Making Test: Part A], attention/vigilance [Continuous Performance Test - Identical Pairs (CPT-IP)], working memory [Wechsler Memory Scale (WMS((r))-III): Spatial Span, and Letter-Number Span (LNS)], verbal learning [Hopkins Verbal Learning Test - Revised], visual learning [Brief Visuospatial Memory Test - Revised], reasoning and problem solving [Neuropsychological Assessment Battery: Mazes], and social cognition [Mayer Salovey-Caruso Emotional Intelligence Test: Managing Emotions]. Statistical analyses involved the use of multivariate and univariate analyses of variance. RESULTS: Analyses conducted on the cognitive domain scores revealed no overall significant difference between groups nor any interaction between group and domain score [F(1,45) = 0.73, P = 0.649]. Analyses conducted on each of the specific tasks within the cognitive domains revealed significantly slower reaction times for false alarm responses on the CPT-IP task in AN [F(1,51) = 12.80, P < 0.01, Cohen's d = 0.982] and a trend towards poorer performance in AN on the backward component of the WMS((r))-III Spatial Span task [F(1,51) = 5.88, P = 0.02, Cohen's d = -0.665]. The finding of slower reaction times of false alarm responses is, however, limited due to the small number of false alarm responses for either group. CONCLUSION: The findings are discussed in terms of poorer capacity to manipulate and process visuospatial material in AN. PMID- 26740933 TI - Risk for emerging bipolar disorder, variants, and symptoms in children with attention deficit hyperactivity disorder, now grown up. AB - AIM: To determine the prevalence of bipolar disorder (BD) and sub-threshold symptoms in children with attention deficit hyperactivity disorder (ADHD) through 14 years' follow-up, when participants were between 21-24 years old. METHODS: First, we examined rates of BD type I and II diagnoses in youth participating in the NIMH-funded Multimodal Treatment Study of ADHD (MTA). We used the diagnostic interview schedule for children (DISC), administered to both parents (DISC-P) and youth (DISCY). We compared the MTA study subjects with ADHD (n = 579) to a local normative comparison group (LNCG, n = 289) at 4 different assessment points: 6, 8, 12, and 14 years of follow-ups. To evaluate the bipolar variants, we compared total symptom counts (TSC) of DSM manic and hypomanic symptoms that were generated by DISC in ADHD and LNCG subjects. Then we sub-divided the TSC into pathognomonic manic (PM) and non-specific manic (NSM) symptoms. We compared the PM and NSM in ADHD and LNCG at each assessment point and over time. We also evaluated the irritability as category A2 manic symptom in both groups and over time. Finally, we studied the irritability symptom in correlation with PM and NSM in ADHD and LNCG subjects. RESULTS: DISC-generated BD diagnosis did not differ significantly in rates between ADHD (1.89%) and LNCG 1.38%). Interestingly, no participant met BD diagnosis more than once in the 4 assessment points in 14 years. However, on the symptom level, ADHD subjects reported significantly higher mean TSC scores: ADHD 3.0; LNCG 1.7; P < 0.001. ADHD status was associated with higher mean NSM: ADHD 2.0 vs LNCG 1.1; P < 0.0001. Also, ADHD subjects had higher PM symptoms than LNCG, with PM means over all time points of 1.3 ADHD; 0.9 LNCG; P = 0.0001. Examining both NSM and PM, ADHD status associated with greater NSM than PM. However, Over 14 years, the NSM symptoms declined and changed to PM over time (df 3, 2523; F = 20.1; P < 0.0001). Finally, Irritability (BD DSM criterion A2) rates were significantly higher in ADHD than LNCG (chi(2) = 122.2, P < 0.0001), but irritability was associated more strongly with NSM than PM (df 3, 2538; F = 43.2; P < 0.0001). CONCLUSION: Individuals with ADHD do not appear to be at significantly greater risk for developing BD, but do show higher rates of BD symptoms, especially NSM. The greater linkage of irritability to NSM than to PM suggests caution when making BD diagnoses based on irritability alone as one of 2 (A-level) symptoms for BD diagnosis, particularly in view of its frequent presentation with other psychopathologies. PMID- 26740934 TI - Prevalence of substance use among moroccan adolescents and association with academic achievement. AB - AIM: To investigate rates of drug and alcohol use and their association with academic performance in Moroccan youth. METHODS: An adapted version of the European School Project on Alcohol and Other Drugs survey was administered to 2139 10(th)-12(th) graders in 36 Moroccan public high schools. Two multiple logistic regressions were completed, one for male and one for female subjects. Grade average was used as a two-part outcome variable, and drug use was used as a four-level categorical independent variable. Parents' education levels and socioeconomic status were included as covariates. RESULTS: Of the subjects, 181 girls (16%) and 390 boys (40%) reported ever having used alcohol, hashish, or psychotropic drugs. Girls who had used any of those substances in the past 30 d demonstrated an adjusted odds ratio (AOR) of 2.62 (95%CI: 1.31-5.22) of having average or below-average grades, and those with any lifetime use showed an AOR of 1.72 (95%CI: 1.07-2.77). Among the boys, use in the past 30 d was associated with an AOR of 2.08 (95%CI: 1.33-3.24) of average or below average grades, and use in the last 12 mo with an AOR of 1.74 (95%CI: 1.00-3.05). Any lifetime use among male and previous 12 mo use among female subjects were not significantly associated with academic achievement. CONCLUSION: Among Moroccan adolescents, drug use is substantially different between boys and girls. In both genders, lower academic achievement was associated with alcohol, hashish, or psychotropic drug use in the last 30 d. PMID- 26740935 TI - Impact of social isolation on behavioral health in elderly: Systematic review. AB - AIM: To examine and compare the effects of subjective and objective social isolation on behavioral health in elderly adults. METHODS: A systematic search of PubMed was performed for original research articles from peer-reviewed journals examining one of the following topics: "Social isolation and sleep disturbance", "social isolation and depression", or "social isolation and fatigue in older adults". Studies were selected following the criteria established based on the aim of this review. Data were extracted from the articles by two independent reviewers. Due to the heterogeneity in study designs and outcome measures of the included studies, qualitative and narrative analyses were conducted. RESULTS: The set criteria were used to select a total of 16 studies for the review. Of the 16, 13 were cross-sectional studies. The characteristics of study populations were identified as follows. A total of 12 studies randomly selected subjects irrespective of pre-existing health conditions. Consequently, an unspecified number of the study subjects had chronic diseases in the studies compared. In addition, cultural and ethnic backgrounds of studies in this review were diverse, and included subjects living in North America, South America, Asia, Europe, and Oceania. Both subjective and objective types of social isolation increased behavioral symptoms, such as sleep disturbance, depressive symptoms, and fatigue in older adults. Furthermore, a few recent studies reported stronger effects of subjective social isolation than objective social isolation on sleep disturbance and depressive symptoms. CONCLUSION: Social isolation affects behavioral health in older adults. Compared to the objective social isolation, subjective social isolation contributes more significantly to sleep disturbance and depression. PMID- 26740936 TI - Bilateral Retrobulbar Optic Neuritis Caused by Varicella Zoster Virus in a Patient with AIDS. AB - AIMS: To report on a case of bilateral retrobulbar optic neuritis in a patient with acquired immune deficiency syndrome (AIDS) caused by varicella-zoster virus (VZV); and to review the literature focusing on: cases reported, epidemiology, pathophysiology, diagnosis and treatment. PRESENTATION OF CASE: A 38-year-old woman with AIDS presented with a 10-day history of progressive bilateral visual loss and ocular pain. She had bilateral dilated pupils with no light perception; the fundoscopic examination was normal. Facial herpes zoster lesions appeared on the second day of hospitalization Magnetic resonance imaging (MRI) findings were compatible with a bilateral optic neuritis; the cerebrospinal fluid (CSF) showed pleocytosis, increased proteins and a positive VZV-DNA PCR. She was treated with intravenous acyclovir and corticosteroids and was able, when discharged 2 weeks after admission, to carry out activities of daily living. DISCUSSION: VZV retrobulbar optic neuritis has previously been reported in 12 patients with AIDS, more than half of the cases had concomitant herpes zoster and an associated retinopathy. A positive VZV-DNA in the CSF is indicative of VZV infection, initial use of intravenous acyclovir is recommended, and the concomitant use of corticosteroids would be a prudent choice; the duration of antiviral therapy remains undefined. CONCLUSION: VZV retrobulbar optic neuritis in AIDS patients can occur with or without herpes zoster. It is a sight-threatening infectious and inflammatory process requiring the advice of specialists in infectious diseases, ophthalmology, neurology and viral microbiology. PMID- 26740937 TI - Forging a morphological system out of two dimensions: Agentivity and number. AB - Languages have diverse strategies for marking agentivity and number. These strategies are negotiated to create combinatorial systems. We consider the emergence of these strategies by studying features of movement in a young sign language in Nicaragua (NSL). We compare two age cohorts of Nicaraguan signers (NSL1 and NSL2), adult homesigners in Nicaragua (deaf individuals creating a gestural system without linguistic input), signers of American and Italian Sign Languages (ASL and LIS), and hearing individuals asked to gesture silently. We find that all groups use movement axis and repetition to encode agentivity and number, suggesting that these properties are grounded in action experiences common to all participants. We find another feature - unpunctuated repetition - in the sign systems (ASL, LIS, NSL, Homesign) but not in silent gesture. Homesigners and NSL1 signers use the unpunctuated form, but limit its use to No Agent contexts; NSL2 signers use the form across No-Agent and Agent contexts. A single individual can thus construct a marker for number without benefit of a linguistic community (homesign), but generalizing this form across agentive conditions requires an additional step. This step does not appear to be achieved when a linguistic community is first formed (NSL1), but requires transmission across generations of learners (NSL2). PMID- 26740938 TI - Foreword to volume 3, issue 6. AB - As 2015 draws to a close so too do the many celebrations of the 150th anniversary of Mendel's presentation of his work entitled "Experiments in Plant Hybridization" to the Natural History Society of Brno. PMID- 26740939 TI - Remembering Johann Gregor Mendel: a human, a Catholic priest, an Augustinian monk, and abbot. AB - Johann Mendel (Gregor was the name given to him only later by his Augustinian order, Fig. 1) was born on July 20, 1822 to an ethnic German family, Anton and Rosina Mendel (Fig. 2), in Heinzendorf in the Austrian Empire at the Moravian Silesian border (now Hyncice, Czech Republic). PMID- 26740940 TI - Medical genetics and genomic medicine in Rwanda. PMID- 26740941 TI - Identification of an Alu-repeat-mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype. AB - Genetic causes of ocular conditions remain largely unknown. To reveal the molecular basis for a congenital ocular phenotype associated with glaucoma we performed whole-exome sequencing (WES) and whole-genome copy number analyses of patient DNA. WES did not identify a causative variant. Copy number variation analysis identified a deletion of 10p13 in the patient and his unaffected father; the deletion breakpoint contained a single 37-bp sequence that is normally present in two distinct Alu repeats separated by ~181 kb. The deletion removed part of the upstream region of optineurin (OPTN) as well as the upstream sequence and two coding exons of coiled-coil domain containing 3 (CCDC3); analysis of the patient's second allele showed normal OPTN and CCDC3 sequences. Studies of zebrafish orthologs identified expression in the developing eye for both genes. OPTN is a known factor in dominant adult-onset glaucoma and Amyotrophic Lateral Sclerosis (ALS). The deletion eliminates 98 kb of the OPTN upstream sequence leaving only ~1 kb of the proximal promoter region. Comparison of transcriptional activation capability of the 3 kb normal and the rearranged del(10)(p13) OPTN promoter sequences demonstrated a statistically significant decrease for the deleted allele; sequence analysis of the entire deleted region identified multiple conserved elements with possible cis-regulatory activity. Additional screening of CCDC3 indicated that heterozygous loss-of-function alleles are unlikely to cause congenital ocular disease. In summary, we report the first regulatory region deletion involving OPTN, caused by Alu-mediated nonallelic homologous recombination and possibly contributing to the patient's ocular phenotype. In addition, our data indicate that Alu-mediated rearrangements of the OPTN upstream region may represent a new source of affected alleles in human conditions. Evaluation of the upstream OPTN sequences in additional ocular and ALS patients may help to determine the role of this region, if any, in human disease. PMID- 26740942 TI - Identification of point mutations and large intragenic deletions in Fanconi anemia using next-generation sequencing technology. AB - Fanconi anemia (FA) is a rare bone marrow failure disorder characterized by clinical and genetic heterogeneity with at least 17 genes involved, which make molecular diagnosis complex and time-consuming. Since next-generation sequencing technologies could greatly improve the genetic testing in FA, we sequenced DNA samples with known and unknown mutant alleles using the Ion PGM (TM) system (IPGM). The molecular target of 74.2 kb in size covered 96% of the FA-coding exons and their flanking regions. Quality control testing revealed high coverage. Comparing the IPGM and Sanger sequencing output of FANCA,FANCC, and FANCG we found no false-positive and a few false-negative variants, which led to high sensitivity (95.58%) and specificity (100%) at least for these two most frequently mutated genes. The analysis also identified novel mutant alleles, including those in rare complementation groups FANCF and FANCL. Moreover, quantitative evaluation allowed us to characterize large intragenic deletions of FANCA and FANCD2, suggesting that IPGM is suitable for identification of not only point mutations but also copy number variations. PMID- 26740943 TI - 126 novel mutations in Italian patients with neurofibromatosis type 1. AB - Genetic analysis of Neurofibromatosis type 1 (NF1) may facilitate the identification of patients in early phases of the disease. Here, we present an overview of our diagnostic research spanning the last 11 years, with a focus on the description of 225 NF1 mutations, 126 of which are novel, found in a series of 607 patients (513 unrelated) in Italy. Between 2003 and 2013, 443 unrelated patients were profiled by denaturing high pressure liquid chromatography (DHPLC) analysis of 60 amplicons derived from genomic NF1 DNA and subsequent sequencing of heterozygotic PCR products. In addition, a subset of patients was studied by multiplex ligation-dependent probe amplification (MLPA) to identify any duplications, large deletions or microdeletions present at the locus. Over the last year, 70 unrelated patients were investigated by MLPA and sequencing of 22 amplicons spanning the entire NF1 cDNA. Mutations were found in 70% of the 293 patients studied by DHPLC, thereby fulfilling the NIH criterion for the clinical diagnosis of NF1 (detection rate: 70%); furthermore, 87% of the patients studied by RNA sequencing were genetically characterized. Mutations were also found in 36 of the 159 patients not fulfilling the NIH clinical criteria. We confirmed a higher incidence of intellectual disability in patients harboring microdeletion type 1 and observed a correlation between a mild phenotype and the small deletion c.2970_2972delAAT or the missense alteration in amino acid residue 1809 (p.Arg1809Cys). These data support the use of RNA-based methods for genetic analysis and provide novel information for improving the management of symptoms in oligosymptomatic patients. PMID- 26740944 TI - Uncovering the molecular pathogenesis of congenital hyperinsulinism by panel gene sequencing in 32 Chinese patients. AB - Congenital hyperinsulinism (CHI) has been mostly associated with mutations in seven major genes. We retrospectively reviewed a cohort of 32 patients with CHI. Extensive mutational analysis (ABCC8,KCNJ11,GCK,GLUD1,HADH,HNF4A, and UCP2) was performed on Ion torrent platform, which could analyze hundreds of genes simultaneously with ultrahigh-multiplex PCR using up to 6144 primer pairs in a single primer pool and address time-sensitive samples with single-day assays, from samples to annotated variants, to identify the genetic etiology of this disease. Thirty-seven sequence changes were identified, including in ABCC8/KCNJ11 (n = 25, 65.7%), GCK (n = 2), HNF4A (n = 3), GLUD1 (n = 2), HADH (n = 4), and UCP2 (n = 1); these mutations included 14 disease-causing mutations, eight rare SNPs, 14 common SNPs, and one novel mutation. Mutations were identified in 21 of 32 patients (65.6%). Among the patients with an identified mutation, 14 had mutations in ABCC8, one of which was combined with a GLUD1 mutation. Four patients had mutations in KCNJ11, 1 had a GCK mutation, 1 had a mutation in HADH, and two had a mutation in HNF4A. Among the 32 patients, the age at the onset of hyperinsulinemia ranged from the neonatal period to 1 year of age; five patients underwent a pancreatectomy due to intractable hyperinsulinemia. This study describes novel and previously identified mutations in patients with CHI. The spectrum of mutations in CHI patients represents an important tool for the diagnosis and prognosis of CHI patients in the Chinese population as well as for the genetic counseling of CHI families. PMID- 26740945 TI - The rs3737964 single-nucleotide polymorphism of the chloride channel-6 gene as a risk factor for coronary heart disease. AB - The present study investigates the association of single-nucleotide polymorphisms (SNPs) on the chloride channel-6 (CLC-6) gene with coronary heart disease (CHD) in China. We carried out a large case-control study among 1193 CHD patients and 1200 unrelated healthy control subjects. Information on the participants' health status was collected through the modified Inter-heart questionnaire. Genomic DNA from peripheral blood samples was analyzed for the genotypes of rs3737964 and rs3737965 SNPs on the CLC-6 gene using Taqman probe-based quantitative real-time PCR (qPCR). We compared the collected data between the case group and the control group by chi-square test and t/nonparametric test. Furthermore, we performed logistic regression to evaluate factors associated with CHD. The frequency of TT genotypes in rs3737964 was significantly higher in CHD patients compared to the control group, with an odds ratio (OR) of 2.32 (95% confidence interval, CI: 1.17 4.06, P = 0.016). The association of CHD with TT genotype was even stronger in smoking population after adjusting for confounders (OR = 3.19, 95% CI: 1.04-9.79, P = 0.043). Multivariate logistic regression showed the CHD risk associated with TT genotype in rs3737964 was particularly among population who were more than 60 years old, smoking, and male (P = 0.023, 0.008 and 0.043, respectively). The present study has revealed that rs3737964 SNP of CLC-6 was associated with CHD. In particular, subjects with TT genotype who were 60-plus years old, with smoking habit or were male were more susceptible to CHD. PMID- 26740946 TI - A distinctive oral phenotype points to FAM20A mutations not identified by Sanger sequencing. AB - Biallelic FAM20A mutations cause two conditions where Amelogenesis Imperfecta (AI) is the presenting feature: Amelogenesis Imperfecta and Gingival Fibromatosis Syndrome; and Enamel Renal Syndrome. A distinctive oral phenotype is shared in both conditions. On Sanger sequencing of FAM20A in cases with that phenotype, we identified two probands with single, likely pathogenic heterozygous mutations. Given the recessive inheritance pattern seen in all previous FAM20A mutation positive families and the potential for renal disease, further screening was carried out to look for a second pathogenic allele. Reverse transcriptase-PCR on cDNA was used to determine transcript levels. CNVseq was used to screen for genomic insertions and deletions. In one family, FAM20A cDNA screening revealed only a single mutated FAM20A allele with the wild-type allele not transcribed. In the second family, CNV detection by whole genome sequencing (CNVseq) revealed a heterozygous 54.7 kb duplication encompassing exons 1 to 4 of FAM20A. This study confirms the link between biallelic FAM20A mutations and the characteristic oral phenotype. It highlights for the first time examples of FAM20A mutations missed by the most commonly used mutation screening techniques. This information informed renal assessment and ongoing clinical care. PMID- 26740947 TI - Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9. AB - SOX9 haploinsufficiency underlies campomelic dysplasia (CD) with or without testicular dysgenesis. Current understanding of the phenotypic variability and mutation spectrum of SOX9 abnormalities remains fragmentary. Here, we report three patients with hitherto unreported SOX9 abnormalities. These patients were identified through molecular analysis of 33 patients with 46,XY disorders of sex development (DSD). Patients 1-3 manifested testicular dysgenesis or regression without CD. Patients 1 and 2 carried probable damaging mutations p.Arg394Gly and p.Arg437Cys, respectively, in the SOX9 C-terminal domain but not in other known 46,XY DSD causative genes. These substitutions were absent from ~120,000 alleles in the exome database. These mutations retained normal transactivating activity for the Col2a1 enhancer, but showed impaired activity for the Amh promoter. Patient 3 harbored a maternally inherited ~491 kb SOX9 upstream deletion that encompassed the known 32.5 kb XY sex reversal region. Breakpoints of the deletion resided within nonrepeat sequences and were accompanied by a short-nucleotide insertion. The results imply that testicular dysgenesis and regression without skeletal dysplasia may be rare manifestations of SOX9 abnormalities. Furthermore, our data broaden pathogenic SOX9 abnormalities to include C-terminal missense substitutions which lead to target-gene-specific protein dysfunction, and enhancer-containing upstream microdeletions mediated by nonhomologous end joining. PMID- 26740949 TI - Injuries to Professional and Amateur Kickboxing Contestants: A 15-Year Retrospective Cohort Study. AB - BACKGROUND: Kickboxing is a group of full-contact combat sports that allows both kicking and punching from a standing position. Despite its popularity, there is a scarcity of published data elucidating the injury epidemiology in kickboxing. PURPOSE: To determine the injury incidence, describe the injury pattern, and identify potential risk factors for injury in kickboxing. STUDY DESIGN: Descriptive epidemiology study. METHODS: Data describing fight outcomes and injuries sustained during professional and amateur kickboxing contests over a 15 year period were obtained from the official records of the Nevada Athletic Commission, United States. Injury incidence rates and rate ratios were calculated with 95% confidence intervals (95% CIs) per 1000 athlete-exposures (AEs) and per 1000 minutes of exposure. The injury pattern was described using frequencies and proportions of injuries by anatomic region and type of injury. In addition, Poisson mixed-effects generalized linear modeling was used to examine the multivariate relationships between injury incidence rates and potential risk factors. RESULTS: The sample consisted of 481 unique fighters competing across 57 events, 976 AEs, 9562 minutes of exposure, and 380 injuries. The mean +/- SD age of the fighters was 29.0 +/- 5.3 years (range, 15-48 years). The overall injury incidence rates were 390.1 injuries (95% CI, 351.9-431.4) per 1000 AEs and 39.7 injuries (95% CI, 35.8-43.9) per 1000 minutes of exposure. The most commonly injured anatomic regions were the head (57.8%) and lower extremity (26.1%), while the most common types of injury were laceration (70.6%) and fracture (20.6%). Professional fighters were 2.5 times more likely to get injured compared with amateurs (rate ratio, 2.51; 95% CI, 1.39-4.55), while defeated fighters were 3.5 times more likely to get injured compared with winners (rate ratio, 3.48; 95% CI, 2.73-4.44). CONCLUSION: Injuries are frequent and often significant in kickboxing, and better injury surveillance is strongly recommended. The scarcity of good-quality epidemiological data in kickboxing, especially pertaining to the severity of injuries, underscores the urgent need for further research, whereupon evidence-informed sport safety and injury prevention policies can be developed. PMID- 26740950 TI - Electromyographic Analysis of the Shoulder Girdle Musculature During External Rotation Exercises. AB - BACKGROUND: Implementation of overhead activity, a key component of many professional sports, requires an effective and balanced activation of the shoulder girdle muscles, particularly during forceful external rotation (ER) motions. PURPOSE: To identify activation strategies of 16 shoulder girdle muscles/muscle segments during common shoulder ER exercises. STUDY DESIGN: Descriptive laboratory study. METHOD: Thirty healthy subjects were included in this study, and 16 shoulder girdle muscles/muscle segments were investigated (surface electrode: anterior, middle, and posterior deltoid; upper, middle, and lower trapezius; serratus anterior; teres major; upper and lower latissimus dorsi; and upper and lower pectoralis major; fine wire electrodes: supraspinatus, infraspinatus, subscapularis, and rhomboid major) using a telemetric electromyography (EMG) system. Five ER exercises (standing ER at 0 degrees and 90 degrees of abduction, with underarm towel roll, prone ER at 90 degrees of abduction, side-lying ER with underarm towel) were studied. Exercise EMG amplitudes were normalized to EMG at maximum ER force in a standard position. Univariate analysis of variance and post hoc analysis applied on EMG activity of each muscle were used to assess the main effect of the exercise condition. RESULTS: Muscular activity differed significantly among the ER exercises (P < .05 to P < .001). The greatest activation for anterior and middle deltoid, supraspinatus, upper trapezius, and serratus anterior occurred during standing ER at 90 degrees of abduction; for posterior deltoid, middle trapezius, and rhomboid during side-lying ER with underarm towel; for lower trapezius, upper and lower latissimus dorsi, subscapularis, and teres major during prone ER at 90 degrees of abduction; and for the clavicular and sternal part of the pectoralis major during standing ER with underarm towel. CONCLUSION: Key glenohumeral and scapular muscles can be optimally activated during specific ER exercises, particularly in positions that stimulate athletic overhead motions. CLINICAL RELEVANCE: These results enable sports medicine professionals to target specific muscles during shoulder rehabilitation protocols while minimizing the effect of others, providing a foundation for optimal evidence-based exercise prescription. They also provide information for tailored muscle training and injury prevention in overhead sports. PMID- 26740951 TI - Injury Risk Estimation Expertise: Interdisciplinary Differences in Performance on the ACL Injury Risk Estimation Quiz. AB - BACKGROUND: Simple observational assessment of movement is a potentially low-cost method for anterior cruciate ligament (ACL) injury screening and prevention. Although many individuals utilize some form of observational assessment of movement, there are currently no substantial data on group skill differences in observational screening of ACL injury risk. PURPOSE/HYPOTHESIS: The purpose of this study was to compare various groups' abilities to visually assess ACL injury risk as well as the associated strategies and ACL knowledge levels. The hypothesis was that sports medicine professionals would perform better than coaches and exercise science academics/students and that these subgroups would all perform better than parents and other general population members. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A total of 428 individuals, including physicians, physical therapists, athletic trainers, strength and conditioning coaches, exercise science researchers/students, athletes, parents, and members of the general public participated in the study. Participants completed the ACL Injury Risk Estimation Quiz (ACL-IQ) and answered questions related to assessment strategy and ACL knowledge. RESULTS: Strength and conditioning coaches, athletic trainers, physical therapists, and exercise science students exhibited consistently superior ACL injury risk estimation ability (+2 SD) as compared with sport coaches, parents of athletes, and members of the general public. The performance of a substantial number of individuals in the exercise sciences/sports medicines (approximately 40%) was similar to or exceeded clinical instrument-based biomechanical assessment methods (eg, ACL nomogram). Parents, sport coaches, and the general public had lower ACL-IQ, likely due to their lower ACL knowledge and to rating the importance of knee/thigh motion lower and weight and jump height higher. CONCLUSION: Substantial cross-professional/group differences in visual ACL injury risk estimation exist. The relatively profound differences in injury risk estimation accuracy and their potential implications for risk screening suggest the need for additional training and outreach (see http://www.ACL-IQ.org). CLINICAL RELEVANCE: Parents and sport coaches would likely benefit from training or use of decision support tools such as the ACL nomogram to assess ACL injury risk. In addition, physicians and other sports medicine professionals may also benefit from improving risk estimation performance to reach clinical biomechanical standards. PMID- 26740952 TI - Residual Impact of Previous Injury on Musculoskeletal Characteristics in Special Forces Operators. AB - BACKGROUND: Musculoskeletal injuries are a significant burden to United States Army Special Operations Forces. The advanced tactical skill level and physical training required of Army Special Operators highlights the need to optimize musculoskeletal characteristics to reduce the likelihood of suffering a recurrent injury. PURPOSE: To identify the residual impact of previous injury on musculoskeletal characteristics. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Isokinetic strength of the knee, shoulder, and back and flexibility of the shoulder and hamstrings were assessed as part of a comprehensive human performance protocol, and self-reported musculoskeletal injury history was obtained. Subjects were stratified based on previous history of low back, knee, or shoulder injury, and within-group and between-group comparisons were made for musculoskeletal variables. RESULTS: Knee injury analysis showed no significant strength or flexibility differences. Shoulder injury analysis found internal rotation strength of the healthy subjects (H) was significantly higher compared with injured (I) and uninjured (U) limbs of the injured group (H, 60.8 +/- 11.5 percent body weight [%BW]; I, 54.5 +/- 10.5 %BW; U, 55.5 +/- 11.3 %BW) (P = .014 [H vs I] and P = .05 [H vs U]). The external rotation/internal rotation strength ratio was significantly lower in the healthy subjects compared with injured and uninjured limbs of the injured group (H, 0.653 +/- 0.122; I, 0.724 +/- 0.121; U, 0.724 +/- 0.124) (P = .026 [H vs I] and P = .018 [H vs U]). Posterior shoulder tightness was significantly different between the injured and uninjured limb of the injured group (I, 111.6 degrees +/- 9.4 degrees ; U, 114.4 degrees +/- 9.3 degrees ; P = .008). The back injury analysis found no significant strength differences between the healthy and injured groups. CONCLUSION: Few physical differences existed between operators with prior knee or back injury. However, operators with a previous history of shoulder injury demonstrated significantly less shoulder strength than uninjured operators as well as decreased shoulder flexibility on the injured side. All operators, regardless of prior injury, must perform the same tasks; therefore, a targeted injury rehabilitation/human performance training specifically focused on internal rotation strength and tightness of the posterior capsule may help reduce the risk for recurrence of injury. Operators presenting with musculoskeletal asymmetries and/or insufficient strength ratios may be predisposed to musculoskeletal injury. CLINICAL RELEVANCE: Specific fitness programs to compensate for deficiencies in strength and flexibility need to be designed that may reduce the risk of injuries in Special Forces Operators. PMID- 26740948 TI - Genetic analysis of nonalcoholic fatty liver disease within a Caribbean-Hispanic population. AB - We explored potential genetic risk factors implicated in nonalcoholic fatty liver disease (NAFLD) within a Caribbean-Hispanic population in New York City. A total of 316 individuals including 40 subjects with biopsy-proven NAFLD, 24 ethnically matched non-NAFLD controls, and a 252 ethnically mixed random sampling of Bronx County, New York were analyzed. Genotype analysis was performed to determine allelic frequencies of 74 known single-nucleotide polymorphisms (SNPs) associated with NAFLD risk based on previous genome-wide association study (GWAS) and candidate gene studies. Additionally, the entire coding region of PNPLA3, a gene showing the strongest association to NAFLD was subjected to Sanger sequencing. Results suggest that both rare and common DNA variations in PNPLA3 and SAMM50 may be correlated with NAFLD in this small population study, while common DNA variations in CHUK and ERLIN1, may have a protective interaction. Common SNPs in ENPP1 and ABCC2 have suggestive association with fatty liver, but with less compelling significance. In conclusion, Hispanic patients of Caribbean ancestry may have different interactions with NAFLD genetic modifiers; therefore, further investigation with a larger sample size, into this Caribbean-Hispanic population is warranted. PMID- 26740953 TI - Does Geographic Location Matter on the Prevalence of Ulnar Collateral Ligament Reconstruction in Collegiate Baseball Pitchers? AB - BACKGROUND: There has been a significant amount of research in the prevention of throwing injuries. However, one area of research that is lacking is geographic location of play. Warm climates may permit year-round play and increased exposure to throwing arm injury risk. HYPOTHESES: (1) Pitchers from southern institutions would have greater rates of ulnar collateral ligament reconstruction (UCL-R) compared with pitchers from northern institutions. (2) Pitchers originating from high school teams in warm weather states would have a greater risk of undergoing UCL-R while in college. STUDY DESIGN: Descriptive epidemiological study. METHODS: This study was completed by reviewing publicly obtained records of male collegiate baseball players during the 2008 through 2014 seasons. Data were accessed through online search engines, online baseball media guides, and school websites. RESULTS: A total of 5315 player-years and 2575 pitcher-years were identified. Fifty-eight UCL-R cases were found in collegiate pitchers, 40 of which occurred in the Southeastern Conference (SEC) and 18 in the Big Ten. More injuries (36/58) occurred in pitchers who participated in high school baseball in southern states as compared with northern states (22/58), regardless of location of collegiate participation (chi(2) = 28.8, P < .05). The injury rate for pitchers who participated in high school baseball in southern states was 25.3 per 1000 player-years versus 19.1 per 1000 player-years in northern states, with a risk ratio of 1.32 (chi(2) = 0.89, P = .35). The injury rate for the SEC versus Big Ten pitchers was 13.3 per 1000 player-years versus 7.8 per 1000 player-years, with a risk ratio of 1.71 (chi(2) = 1.45, P = .23). CONCLUSION: There is a greater likelihood of undergoing UCL-R in the SEC compared with the Big Ten. There is also an increased risk for UCL-R for pitchers who played high school baseball in southern states versus northern states, irrespective of collegiate play location. CLINICAL RELEVANCE: Pitchers originating from high schools in a warm weather climate may be more likely to undergo UCL-R. PMID- 26740954 TI - Anterior Cruciate Ligament Rupture: A Family Affair. PMID- 26740955 TI - Isolated Chronic Exertional Compartment Syndrome of the Lateral Lower Leg: A Case Series. AB - BACKGROUND: Exercise-induced lower leg pain may be caused by chronic exertional compartment syndrome (CECS). The anterior (ant-CECS) or deep posterior compartment (dp-CECS) is usually affected. Knowledge regarding CECS of the lateral compartment (lat-CECS) is limited. PURPOSE: To describe demographic characteristics and symptoms in a consecutive series of patients with isolated CECS of the lateral compartment of the leg. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Since 2001, patients undergoing dynamic intracompartmental pressure (ICP) measurements for suspected CECS in a single institution were prospectively monitored. Individuals with a history possibly associated with lat CECS and elevated ICP measurements (Pedowitz criteria) were identified. Exclusion criteria were concomitant ipsilateral ant-CECS/dp-CECS, acute compartment syndrome, recent significant trauma, peroneal nerve entrapment, or vascular claudication. RESULTS: During an 11-year time period, a total of 26 patients with isolated lat-CECS fulfilled study criteria (15 females; median age, 21 years; range, 14-48 years). Frequently identified provocative sports were running (n = 4), walking (n = 4), field hockey (n = 3), soccer (n = 3), and volleyball (n = 2). Exercise-induced lateral lower leg pain (92%) and tightness (42%) were often reported. The syndrome was bilateral in almost two-thirds (62%, n = 16). Delay in diagnosis averaged 24 months (range, 2 months to 10 years). CONCLUSION: Young patients with exercise-induced pain in the lateral portions of the lower leg may suffer from isolated CECS of the lateral compartment. ICP measurements in the lateral compartment in these patients are recommended. PMID- 26740956 TI - Ulnar Collateral Ligament Reconstruction of the Elbow: A Systematic Review of the Literature. AB - BACKGROUND: Ulnar collateral ligament reconstruction (UCLR) is a common procedure in both professional and high-level athletes. PURPOSE: To determine the effect of technique and level of play with UCLR on return to sport (RTS). HYPOTHESIS: When comparing different surgical techniques or preoperative level of sports participation, there is no difference in rate of RTS after UCLR. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A systematic review was registered with PROSPERO and performed following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines using 3 publicly available free databases. Therapeutic clinical outcome investigations reporting UCLR outcomes with level of evidence 1 through 4 were eligible for inclusion. All study, subject, and surgical technique demographics were analyzed and compared between continents and countries. Descriptive statistics were calculated, and 2 proportion 2-sample z-test calculators with alpha = .05 were used to compare RTS between level of play and technique. RESULTS: Twenty studies (2019 patients/elbows; mean age, 22.13 +/- 4 years; 97% male; mean follow-up, 39.9 +/- 16.2 months) were included. The majority of patients were baseball players (94.5%), specifically pitchers (80%). The most common level of play was collegiate (44.6%). Palmaris longus (71.2%) and the American Sports Medicine Institute (ASMI) technique (65.6%) were the most common graft choice and surgical technique, respectively. There was a pooled 86.2% RTS rate, and 90% of players scored excellent/good on the Conway-Jobe scale. RTS rates were higher among collegiate athletes (95.5%) than either high school (89.4%, P = .023) or professional athletes (86.4%, P < .0001). RTS rates were higher for the docking technique (97.0%, P = .001) and the ASMI technique (93.3%, P = .0034) than the Jobe technique (66.7%). CONCLUSION: UCLR is performed most commonly in collegiate athletes. Collegiate athletes have the highest RTS rate after UCLR of all levels of competition. The docking and ASMI techniques had higher RTS rates than the Jobe technique. PMID- 26740957 TI - Style of Play and Rate of Concussions in the National Football League. AB - BACKGROUND: The majority of studies on concussion in the National Football League (NFL) focus on testing, evaluation, and outcomes. Meanwhile, there is a paucity of research on how a team's style of play influences the risk of concussion. HYPOTHESIS: Style of play, such as offensive and defensive strategies, is associated with the rate of concussions in the NFL. STUDY DESIGN: Descriptive epidemiology study. METHODS: The current study retrospectively analyzed data from the 2012 to 2014 NFL regular seasons. Reported numbers of concussions were stratified by each team and each position and were compared based on style of play, including offensive scheme (West Coast offense, Air Coryell offense, or other offensive schemes) and defensive alignment (3-4 or 4-3), attempts statistics, per-drive statistics, and offensive and defensive productions, along with strength of schedule (SoS) and team quality measured by simple rating system (SRS). Data analyses included descriptive statistics, 1-way analysis of variance, correlation analysis, and regression analysis. RESULTS: There were 437 documented concussions during the 2012 to 2014 NFL regular seasons, with a mean 4.6 concussions per season per team. In general, players most involved in pass plays reported more concussions. The number of concussions sustained by offensive players was significantly higher among the teams adopting the West Coast offense (mean, 3.0) than among those utilizing the Air Coryell offense (mean, 1.6; P = .006) or those with non-West Coast offenses combined (mean, 1.9; P = .004). The multiple regression analysis revealed that the West Coast offense or not, SoS, and SRS explained 25.3% of the variance in the number of concussions by offensive players. After accounting for SRS, the West Coast offense was found to be a significant predictor of the number of concussions (P = .007), while there was a tendency for SoS to be inversely associated with the number of concussions (P = .105). None of the variables for attempts statistics, per-drive statistics, and offensive production were significantly associated with the number of concussions in the regression analysis. CONCLUSION: In the NFL, players most involved in pass plays appear to be at increased risk for concussions. The West Coast offense may be associated with a greater risk of concussion. Furthermore, teams with easier schedules may have more players sustaining concussions. PMID- 26740958 TI - Increased Compliance With Supervised Rehabilitation Improves Functional Outcome and Return to Sport After Anterior Cruciate Ligament Reconstruction in Recreational Athletes. AB - BACKGROUND: Successful return to sport is an important outcome measure after anterior cruciate ligament (ACL) reconstruction and a reason for patients' decisions to elect surgery. Rehabilitation programs supervised by physical therapists are routinely prescribed after ACL reconstruction surgery. However, the added advantage of supervised physical therapy after ACL reconstruction is still debatable. HYPOTHESIS: Attending more supervised physical therapy sessions after arthroscopic ACL reconstruction in recreational athletes increases their chance of successful return to sport. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: The authors analyzed 93 recreational athletes who underwent arthroscopic ACL reconstruction. After arthroscopic single-bundle ACL reconstruction, patients were advised to attend 20 supervised physical therapy sessions. Patients' demographics, surgical details, and outcome measures (Knee injury and Osteoarthritis Outcome Score [KOOS], Lysholm scale, and Short Form-36 Health Survey [SF-36]) were recorded presurgery and at 1-year follow-up. Ability to return to sports was documented through patients' self-report. The attendance at physical therapy by each patient was obtained by examining database records and assessed as fully compliant (>15 sessions), moderately compliant (6-15 sessions), or noncompliant (<6 sessions). RESULTS: Patients in the fully compliant group had significantly greater odds (odds ratio [OR], 18.5; 95% CI, 1.9-184.5; P = .013) of a successful return to sport as compared with the noncompliant group. Patients in the moderately compliant group also had greater odds of returning to sport as compared with the noncompliant group (OR, 4.2; 95% CI, 1.0-16.6; P = .043). Patients in the fully compliant group had significantly greater scores on the Lysholm (P < .001), KOOS Sports and Recreation subscale (P = .021), KOOS Symptoms subscale (P = .040), and SF-36 physical component summary (PCS) (P = .012) as compared with the noncompliant group. Moderately compliant patients had significantly greater scores on the Lysholm (P = .004), KOOS Sports and Recreation (P = .026), KOOS Symptoms (P = .041), KOOS Quality of Life (P = .022), and SF-36 PCS (P = .004) as compared with noncompliant patients. CONCLUSION: In recreational athletes, moderate to full compliance with a supervised physical therapy program predicts improved knee function and a greater chance of returning to sport 1 year after ACL reconstruction. PMID- 26740959 TI - Does Screening or Providing Information on Resources for Intimate Partner Violence Increase Women's Knowledge? Findings from a Randomized Controlled Trial. AB - BACKGROUND: Screening for IPV in health care settings might increase women's knowledge or awareness around its frequency and its impact on health. When IPV is disclosed, assuring women it is not their fault should improve their knowledge that IPV is the perpetrator's responsibility. Providing information about IPV resources may also increase women's knowledge about the availability of solutions. METHODS: Women (n=2708) were randomly assigned to one of three groups: (1) partner violence screen plus video referral and list of local partner violence resources if screening was positive (n=909); (2) partner violence resource list only without screen (n=893); and (3) a no-screen, no-partner violence resource list control group (n=898). One year later, 2364 women (87%) were re-contacted and asked questions assessing their knowledge of the frequency of partner violence, its impact on physical and mental health, the availability of resources to help women experiencing partner violence, and that it is the perpetrator's fault. RESULTS: There were no differences between women screened and provided with a partner violence resource list compared to a control group as to women's knowledge of the frequency of IPV, its impact on physical or mental health, or the availability of IPV services in their community. However, among women who experienced IPV in the year before or year after enrolling in the trial, those who were provided a list of IPV resources without screening were significantly less likely to know that IPV is not the victim's fault than those in the control or list plus screening conditions. CONCLUSIONS: The results of this study suggest that providing information on partner violence resources, with or without asking questions about partner violence, did not result in improved knowledge. PMID- 26740962 TI - A Pharmaceutical Bioethics Consultation Service: Six-Year Descriptive Characteristics and Results of a Feedback Survey. AB - Background: Bioethics consultations are conducted in varied settings, including hospitals, universities, and other research institutions, but there is sparse information about bioethics consultations conducted in corporate settings such as pharmaceutical companies. The purpose of this article is to describe a bioethics consultation service at a pharmaceutical company, to report characteristics of consultations completed by the service over a 6-year period, and to share results of a consultation feedback survey. Methods: Data on the descriptive characteristics of bioethics consultations were collected from 2008 to 2013 and analyzed in Excel 2007. Categorical data were analyzed via the pivot table function, and time-based variables were analyzed via formulas. The feedback survey was administered to consultation requesters from 2009 to 2012 and also analyzed in Excel 2007. Results: Over the 6-year period, 189 bioethics consultations were conducted. The number of consultations increased from five per year in 2008 to approximately one per week in 2013. During this time, the format of the consultation service was changed from a committee-only approach to a tiered approach (tailored to the needs of the case). The five most frequent topics were informed consent, early termination of a clinical trial, benefits and risks, human biological samples, and patient rights. The feedback survey results suggest the consultation service is well regarded overall and viewed as approachable, helpful, and responsive. Conclusions: Pharmaceutical bioethics consultation is a unique category of bioethics consultation that primarily focuses on pharmaceutical research and development but also touches on aspects of clinical ethics, business ethics, and organizational ethics. Results indicate there is a demand for a tiered bioethics consultation service within this pharmaceutical company and that advice was valued. This company's experience indicates that a bioethics consultation service raises awareness about bioethics, empowers employees to raise bioethical concerns, and helps them reason through challenging issues. PMID- 26740961 TI - Review on photoacoustic imaging of the brain using nanoprobes. AB - Photoacoustic (PA) tomography (PAT) is a hybrid imaging modality that integrates rich optical contrasts with a high-ultrasonic spatial resolution in deep tissue. Among various imaging applications, PA neuroimaging is becoming increasingly important as it nicely complements the limitations of conventional neuroimaging modalities, such as the low-temporal resolution in magnetic resonance imaging and the low depth-to-resolution ratio in optical microscopy/tomography. In addition, the intrinsic hemoglobin contrast PA neuroimaging has also been greatly improved by recent developments in nanoparticles (NPs). For instance, near-infrared absorbing NPs greatly enhanced the vascular contrast in deep-brain PAT; tumor targeting NPs allowed highly sensitive and highly specific delineation of brain tumors; and multifunctional NPs enabled comprehensive examination of the brain through multimodal imaging. We aim to give an overview of NPs used in PA neuroimaging. Classifications of various NPs used in PAT will be introduced at the beginning, followed by an overview of PA neuroimaging systems, and finally we will discuss major applications of NPs in PA neuroimaging and highlight representative studies. PMID- 26740963 TI - Untapped Potential: Animal care and use programs adopt alternative training and recruitment strategies for individuals with intellectual and developmental disabilities. PMID- 26740960 TI - Prediction, Bayesian inference and feedback in speech recognition. AB - Speech perception involves prediction, but how is that prediction implemented? In cognitive models prediction has often been taken to imply that there is feedback of activation from lexical to pre-lexical processes as implemented in interactive activation models (IAMs). We show that simple activation feedback does not actually improve speech recognition. However, other forms of feedback can be beneficial. In particular, feedback can enable the listener to adapt to changing input, and can potentially help the listener to recognise unusual input, or recognise speech in the presence of competing sounds. The common feature of these helpful forms of feedback is that they are all ways of optimising the performance of speech recognition using Bayesian inference. That is, listeners make predictions about speech because speech recognition is optimal in the sense captured in Bayesian models. PMID- 26740964 TI - (1)H-NMR analysis provides a metabolomic profile of patients with multiple sclerosis. AB - OBJECTIVE: To investigate the metabolomic profiles of patients with multiple sclerosis (MS) and to define the metabolic pathways potentially related to MS pathogenesis. METHODS: Plasma samples from 73 patients with MS (therapy-free for at least 90 days) and 88 healthy controls (HC) were analyzed by (1)H-NMR spectroscopy. Data analysis was conducted with principal components analysis followed by a supervised analysis (orthogonal partial least squares discriminant analysis [OPLS-DA]). The metabolites were identified and quantified using Chenomx software, and the receiver operating characteristic (ROC) curves were calculated. RESULTS: The model obtained with the OPLS-DA identified predictive metabolic differences between the patients with MS and HC (R2X = 0.615, R2Y = 0.619, Q2 = 0.476; p < 0.001). The differential metabolites included glucose, 5-OH tryptophan, and tryptophan, which were lower in the MS group, and 3-OH-butyrate, acetoacetate, acetone, alanine, and choline, which were higher in the MS group. The suitability of the model was evaluated using an external set of samples. The values returned by the model were used to build the corresponding ROC curve (area under the curve of 0.98). CONCLUSION: NMR metabolomic analysis was able to discriminate different metabolic profiles in patients with MS compared with HC. With the exception of choline, the main metabolic changes could be connected to 2 different metabolic pathways: tryptophan metabolism and energy metabolism. Metabolomics appears to represent a promising noninvasive approach for the study of MS. PMID- 26740966 TI - Influence of retinoic acid on mesenchymal stem cell differentiation in amyloid hydrogels. AB - This paper presents data related to the research article "Self healing hydrogels composed of amyloid nano fibrils for cell culture and stem cell differentiation" [1]. Here we probed the collective influence of all-trans retinoic acid (RA) and substrate properties (amyloid hydrogel) on human mesenchymal stem cell (hMSC) differentiation. Stem cells were cultured on soft amyloid hydrogels [1], [2] in the presence and absence of matrix encapsulated RA. The cell morphology was imaged and assessed via quantification of circularity. Further immunostaining and quantitative real time PCR was used to quantify various markers of differentiation in the neuronal lineage. PMID- 26740965 TI - HLA-DRB1*14 is a protective allele for multiple sclerosis in an admixed Colombian population. AB - OBJECTIVE: The aim of this study was to determine ancestry informative markers, mitochondrial DNA haplogroups, and the association between HLA-DRB1 alleles and multiple sclerosis (MS) in a group of patients from Bogota, Colombia. METHODS: In this case-control study, genomic DNA was isolated and purified from blood samples. HLA-DRB1 allele genotyping was done using PCR. Mitochondrial hypervariable region 1 was amplified and haplogroups were determined using HaploGrep software. Genomic ancestry was estimated by genotyping a panel of ancestry informative markers. To test the association of HLA polymorphisms and MS, we ran separate multivariate logistic regression models. Bonferroni correction was used to account for multiple regression tests. RESULTS: A total of 100 patients with MS (mean age 40.4 +/- 12 years; 70% females) and 200 healthy controls (mean age 37.6 +/- 11 years; 83.5% females) were included in the analysis. Ancestry proportions and haplogroup frequencies did not differ between patients and controls. HLA-DRB1*15 was present in 31% of cases and 13.5% of controls, whereas HLA-DRB1*14 was present in 5% of cases and 15.5% of controls. In the multivariate model, HLA-DRB1*15 was significantly associated with MS (odds ratio [OR] = 3.05, p < 0.001), whereas HLA-DRB1*14 was confirmed as a protective factor in our population (OR = 0.16, p = 0.001). CONCLUSIONS: This study provides evidence indicating that HLA-DRB1*15 allele confers susceptibility to MS and HLA DRB1*14 allele exerts resistance to MS in a highly admixed population. This latter finding could partially explain the low prevalence of MS in Bogota, Colombia. PMID- 26740967 TI - NFATc1 regulates the transcription of DNA damage-induced apoptosis suppressor. AB - DNA damage induced apoptosis suppressor (DDIAS), or human Noxin (hNoxin), is strongly expressed in lung cancers. DDIAS knockdown induced apoptosis in non small cell lung carcinoma A549 cells in response to DNA damage, indicating DDIAS as a potential therapeutic target in lung cancer. To understand the transcriptional regulation of DDIAS, we determined the transcription start site, promoter region, and transcription factor. We found that DDIAS transcription begins at nucleotide 212 upstream of the DDIAS translation start site. We cloned the DDIAS promoter region and identified NFAT2 as a major transcription factor (Im et al., 2016 [1]). We demonstrated that NFATc1 regulates DDIAS expression in both pancreatic cancer Panc-1 cells and lung cancer cells. PMID- 26740968 TI - Data supporting the structural and functional characterization of Thrombin Activatable Fibrinolysis Inhibitor in breast cancer. AB - The data in this paper is related to the research article entitled "Thrombin activatable fibrinolysis inhibitor Thr325Ile polymorphism and plasma level in breast cancer: A pilot study" (Fawzy et al., 2015) [1]. Many emerging studies have begun to unravel the pathophysiologic role of the fibrinolytic system in breast cancer (BC) progression (Zorio et al., 2008) [2]. Activation of the fibrinolytic plasminogen/plasmin system results in degradation of protein barriers, thereby mediating cell migration essential for tumor growth, angiogenesis, and dissemination (Castellino and Ploplis, 2005) [3]. In the current study, in silico data analysis of Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) gene and protein has been done. Data have been retrieved from several databases mentioned in details in the text. Determination and analysis of the structural and functional impact of TAFI and its expression could help elucidate the contribution of the TAFI pathway to acquired hemostatic dysfunction and will form the basis of potential therapeutic strategies to manipulate this pathway. An inhibition of TAFI (e.g. by FXI inhibitors) will offer the therapeutic possibilities to improve the decreased fibrinolysis and increase the efficiency of fibrinolytic therapy in thrombotic disorders including cancer. PMID- 26740969 TI - Enzyme-based lignocellulose hydrolyzation - Brief data survey for cellulase performance characterization on behalf of the Sauter mean diameter of raw material particles. AB - The data presented here supports the informational background of enzyme-based lignocellulose hydrolyzation, cellulase characterization, and sugar yield prediction for the work "Enzyme-based lignocellulose hydrolyzation - Sauter mean diameter of raw materials as a basis for cellulase performance characterization and yield prediction" by Glaser [1]. Glucose yields from the enzymatic hydrolysis of the raw materials were shown as a function of cellulase enzyme loading as well as of particle size with different solid loading. The data for the proposed methods of the determination of enzyme activity in inhomogeneous samples of lignocellulosic raw materials are presented. The data of the empirical model that was developed for the prediction of hydrolysis yields for different enzyme concentrations, substrate specific particle size, and solid loadings, are given. Data are also given in relation of terms of scale-up opportunities. PMID- 26740971 TI - Diffusion MR Characteristics Following Concurrent Radiochemotherapy Predicts Progression-Free and Overall Survival in Newly Diagnosed Glioblastoma. AB - The standard of care for newly diagnosed glioblastoma (GBM) is surgery, then radiotherapy (RT) with concurrent temozolomide (TMZ), followed by adjuvant TMZ. We hypothesized patients with low diffusivity measured using apparent diffusion coefficient (ADC) histogram analysis evaluated after RT+TMZ, prior to adjuvant TMZ, would have a significantly shorter progression-free (PFS) and overall survival (OS). To test this hypothesis we evaluated 120 patients with newly diagnosed GBM receiving RT+TMZ followed by adjuvant TMZ. MRI was performed after completion of RT+TMZ, prior to initiation of adjuvant TMZ. A double Gaussian mixed model was used to describe the ADC histograms within the enhancing tumor, where ADCL and ADCH were defined as the mean ADC value of the lower and higher Gaussian distribution, respectively. An ADCL value of 1.0 um2/ms and ADCH value of 1.6 um2/ms were used to stratify patients into high and low risk categories. Results suggest patients with low ADCL had significantly shorter PFS (Cox Hazard Ratio = 0.12, P = 0.0006). OS was significantly shorter with low ADCL tumors, showing a median OS of 407 vs. 644 days (Cox Hazard Ratio = 0.31, P = 0.047). ADCH was not predictive of PFS or OS when accounting for age and ADCL. In summary, newly diagnosed glioblastoma patients with low ADCL after completion of RT+TMZ are likely to progress and die earlier than patients with higher ADCL. Results suggest ADC histogram analysis may be useful for patient risk stratification following completion of RT+TMZ. PMID- 26740970 TI - Spontaneous Pancreatitis Caused by Tissue-Specific Gene Ablation of Hhex in Mice. AB - BACKGROUND & AIMS: Perturbations in pancreatic ductal bicarbonate secretion cause chronic pancreatitis. The physiologic mechanism of ductal secretion is known, but its transcriptional control is not. We determine the role of the transcription factor hematopoietically expressed homeobox protein (Hhex) in ductal secretion and pancreatitis. METHODS: We derived mice with pancreas-specific, Cremediated Hhex gene ablation to determine the requirement of Hhex in the pancreatic duct in early life and in adult stages. Histologic and immunostaining analyses were used to detect the presence of pathology. Pancreatic primary ductal cells were isolated to discover differentially expressed transcripts upon acute Hhex ablation on a cell autonomous level. RESULTS: Hhex protein was detected throughout the embryonic and adult ductal trees. Ablation of Hhex in pancreatic progenitors resulted in postnatal ductal ectasia associated with acinar-to-ductal metaplasia, a progressive phenotype that ultimately resulted in chronic pancreatitis. Hhex ablation in adult mice, however, did not cause any detectable pathology. Ductal ectasia in young mice did not result from perturbation of expression of Hnf6, Hnf1beta, or the primary cilia genes. RNA-seq analysis of Hhex-ablated pancreatic primary ductal cells showed mRNA levels of the G-protein coupled receptor natriuretic peptide receptor 3 (Npr3), implicated in paracrine signaling, up-regulated by 4.70-fold. CONCLUSIONS: Although Hhex is dispensable for ductal cell function in the adult, ablation of Hhex in pancreatic progenitors results in pancreatitis. Our data highlight the critical role of Hhex in maintaining ductal homeostasis in early life and support ductal hypersecretion as a novel etiology of pediatric chronic pancreatitis. PMID- 26740972 TI - Quantitative "Hot Spot" Imaging of Transplanted Stem Cells using Superparamagnetic Tracers and Magnetic Particle Imaging (MPI). AB - Magnetic labeling of stem cells enables their non-invasive detection by magnetic resonance imaging (MRI). Practically, most MRI studies have been limited to visualization of local engraftment as other sources of endogenous hypointense contrast complicate the interpretation of systemic (whole body) cell distribution. In addition, MRI cell tracking is inherently non-quantitative in nature. We report here on the potential of magnetic particle imaging (MPI) as a novel tomographic technique for non-invasive hot spot imaging and quantification of stem cells using superparamagnetic iron oxide (SPIO) tracers. Neural and mesenchymal stem cells, representing small and larger cell bodies, were labeled with three different SPIO tracer formulations, including two preparations that have previously been used in clinical MRI cell tracking studies (Feridex(r) and Resovist(r)). Magnetic particle spectroscopy (MPS) measurements demonstrated a linear correlation between MPI signal and iron content, for both homogeneous solutions of free particles in solution and for internalized and aggregated particles in labeled cells over a wide range of concentrations. The overall MP signal ranged from 1*10-3 - 3*10-4 Am2/g Fe, which was equivalent to 2*10-14 - 1*10-15 Am2 per cell, indicating that cell numbers can be quantified with MPI analogous to the use of radiotracers in nuclear medicine or fluorine tracers in 19F MRI. When SPIO-labeled cells were transplanted in mouse brain, they could be readily detected by MPI at a detection threshold of about 5*104 cells, with MPI/MRI overlays showing an excellent agreement between the hypointense MRI areas and MPI hot spots. The calculated tissue MPI signal ratio for 100,000 vs. 50,000 implanted cells was 2.08. Hence, MPI has potential to be further developed for quantitative and easy-to-interpret, tracer-based non-invasive imaging of cells, preferably with MRI as an adjunct anatomical imaging modality. PMID- 26740973 TI - Genomic Medicine: Why Do "Similar" Patients Have Different Outcomes? AB - Genomic variation is an important factor in why supposedly "similar" patients react differently to drugs, have different disease course(s), and varying clinical outcomes. This review provides an update on concepts in modern genomic medicine with an emphasis on clinically relevant study approaches, disease/drug pathway analysis, and recent pharmacogenomic findings. The application of genomic medicine and its importance for rapid diagnosis of disease-causing agents, as well as its clinical application in human disease diagnosis/treatment and in cardiovascular disease are discussed. In addition to direct clinical applications, modern genomic approaches also play an important role in elucidating new mechanisms of disease. Finally, the role of the National Institutes of Health national pharmacogenomics research network in codifying "bench to bedside" translation of genetic results that impact drug therapy will also be discussed. PMID- 26740974 TI - APDT Research Spotlight: Project ROVER's Survey of Assistance Dog Providers. PMID- 26740975 TI - Selecting Quality Service Dogs: Part 1: Morphological and Health Considerations. PMID- 26740976 TI - [Not Available]. PMID- 26740977 TI - [Not Available]. PMID- 26740978 TI - Obituary. PMID- 26740979 TI - Looking beyond the crystal ball: An ethical dilemma in advance directive implementation in multidisciplinary patient care. PMID- 26740980 TI - Retraction notice to "Glutathione peroxidase's reaction intermediate selenenic acid is stabilized by the protein microenvironment". PMID- 26740981 TI - Commentary on 'Nurse-led clinics can manage faecal incontinence effectively: results from a tertiary referral centre'. PMID- 26740983 TI - Appropriate Preparation for Healthcare Executive Management Positions for all New Entrants to the Field. PMID- 26740982 TI - Top Issues Confronting Hospitals: 2014. PMID- 26740984 TI - The Role of the Healthcare Executive in Change in Organizational Ownership or Control. PMID- 26740985 TI - Novel combined candidate--new hopes for COPD maintenance therapy!? PMID- 26741022 TI - A Digital-Analog Microfluidic Platform for Patient-Centric Multiplexed Biomarker Diagnostics of Ultralow Volume Samples. AB - Microfluidic diagnostic devices have the potential to transform the practice of medicine. We engineered a multiplexed digital-analog microfluidic platform for the rapid and highly sensitive detection of 3-4 biomarkers in quadruplicate in 16 independent and isolated microfluidic unit cells requiring only a single 5 MUL sample. We comprehensively characterized the platform by performing single enzyme and digital immunoassays, achieving single molecule detection and measured as low as ~10 fM (330 fg/mL) GFP in buffer and ~12 fM GFP in human serum. We applied our integrated digital detection mechanism to multiplexed detection of 1pM anti-Ebola IgG in human serum and were able to differentiate three common Ebola strains. To ascertain that the device can be applied in environments beyond clinical point-of care settings, we developed a low-cost, portable hardware system to control and read out the microfluidic device and detected anti-Ebola IgG in ultralow volume whole blood samples to levels of 100 pM in a multiplexed assay format. PMID- 26740986 TI - Pollution and respiratory consequences--Have we done enough? AB - Pollution is the second major cause for many respiratory diseases, after smoking. For every country it is a challenging problem to diminish the exposure of their citizens. The authors are discussing the history of progressing of pollution in different countries, the interactions with some respiratory diseases, the influence on mortality and morbidity and the strategies in developing and developed countries for diminishing the level of the polluted particles. PMID- 26741023 TI - General Deposition of Metal-Organic Frameworks on Highly Adaptive Organic Inorganic Hybrid Electrospun Fibrous Substrates. AB - Electrospun nanofibrous mats are ideal substrates for metal-organic frameworks (MOFs) crystal deposition because of their specific structural parameters and chemical tenability. In this work, we utilized organic-inorganic hybrid electrospun fibrous mats as support material to study the deposition of various MOF particles. HKUST-1 and MIL-53(Al) were produced through solvothermal method, while ZIF-8 and MIL-88B(Fe) were prepared using microwave-induced heating method. The synthesis procedure for both methods were simple and effective because the hybrid nanofibrous mats showed considerable affinity to MOF particles and could be used without additional modifications. The obtained MOF composites exhibited effective incorporation between MOF particles and the porous substrates. MIL 53(Al) composite was applied as fibrous sorbent and showed enhanced adsorption capacity and removal rate, as well as easier operation, compared with thepowdered sample. Moreover, MIL-53(Al) composite was easier to be regenerated compared with powder form. PMID- 26741024 TI - Surface Organometallic and Coordination Chemistry toward Single-Site Heterogeneous Catalysts: Strategies, Methods, Structures, and Activities. PMID- 26741025 TI - Source of Molecular Hydrogen in High-Temperature Water Radiolysis. AB - Molecular hydrogen is a primary product of the interaction of low-LET (gamma, beta) radiation with water, and previous measurements have shown that its initial yield increases at elevated temperature. This has been the subject of controversy because more atomic H and (e(-))aq free radicals escape recombination at elevated temperature, and the corresponding production of H2 should decrease. Room temperature experiments have demonstrated that a large fraction of H2 also comes from early physicochemical processes (presumably electron-hole charge recombination and/or dissociative electron attachment), which can be suppressed by scavenging presolvated electrons. In the present work we extend these scavenging measurements up to 350 degrees C to investigate why the H2 yield increases. We find that most of the H2 yield increase is due to the "presolvation" processes. Relatively small changes in the scavenging efficiency vs LET, and a significant effect of temperature depending on the (positive or negative) charge of the scavenger, indicate that the presolvation H2 is dominated by electron-hole charge recombination rather than dissociative electron attachment at all temperatures. PMID- 26741026 TI - Drug Distribution to Retinal Pigment Epithelium: Studies on Melanin Binding, Cellular Kinetics, and Single Photon Emission Computed Tomography/Computed Tomography Imaging. AB - Melanin binding is known to affect the distribution and elimination of ocular drugs. The purpose of this study was to evaluate if the extent of drug uptake to primary retinal pigment epithelial (RPE) cells could be estimated based on in vitro binding studies with isolated melanin and evaluate the suitability of single photon emission computed tomography/computed tomography (SPECT/CT) in studying pigment binding in vivo with pigmented and albino rats. Binding of five compounds, basic molecules timolol, chloroquine, and nadolol and acidic molecules methotrexate and 5(6)-carboxy-2',7'-dichlorofluorescein (CDCF), was studied using isolated melanin from porcine choroid-RPE at pH 5.0 and 7.4. The uptake to primary porcine RPE cells was studied with timolol, chloroquine, methotrexate, and CDCF. The cell study setting was modeled using parameters from the in vitro binding study. In vivo kinetics of 3-[I-123]-iodochloroquine was studied by the SPECT/CT method in albino and pigmented rats. All basic compounds bound to melanin at both pH values, whereas the acidic compounds bound more at pH 5.0 than at pH 7.4. The basic compounds (chloroquine, timolol) showed significant cellular uptake, unlike the acidic compounds (methotrexate, CDCF). On the basis of the modeling, melanin binding was a major factor governing the overall drug distribution to the RPE cells. Likewise, melanin binding explained distribution of 3-[I-123]-iodochloroquine in the pigmented RPE, whereas drug accumulation was not seen in the albino rat. This study demonstrates the suitability of noninvasive SPECT/CT imaging in monitoring ocular melanin binding in vivo. These studies are a useful step toward understanding the pharmacokinetic impact of melanin binding. PMID- 26741027 TI - Smart Grafting of Lanthanides onto Silica via N,N-Dialkylcarbamato Complexes. AB - The grafting and the postgrafting functionalization of lanthanide ions on commercial amorphous silica have been herein carried out by using as a precursor the terbium N,N-dibutylcarbamato derivative [Tb(O2CNBu2)3]. The reaction of the complex with the surface silanols involved only a fraction of the carbamato ligands. The following protolytic substitution of the residual carbamato ligands was carried out by exploiting the Bronsted's acidity of the beta-diketone dibenzoylmethane (Hdbm), in view of the antenna effect of the beta-diketonato groups, which are commonly used in lanthanide photoluminescence studies. The reaction proceeded at room temperature in a clean and easy way affording the introduction of the chosen functionality in the lanthanide coordination sphere. The same procedure has been followed by using as a precursor the X-ray characterized heterometallic N,N-dibutylcarbamato complex [NH2Bu2]2[Ln4(CO3)(O2CNBu2)12] (Ln = Eu, Tb, Tm). In both cases, X-ray photoelectron spectroscopy evidenced the chemical implantation of the lanthanide ions on the silica surface, and photoluminescence studies pointed out the potentiality of the proposed synthetic approach in the preparation of highly luminescent materials. PMID- 26741029 TI - Synthesis and Molecular Properties of Two Isomeric Dialkylated Tetrathienonaphthalenes. AB - Isomeric 2,8-distannyl 5,11-didodecyl alphabeta-TTN (1, tetrathienonaphthalene = TTN) and 2,8-didodecyl 5,11-distannyl alphabeta-TTN (2) have been designed and successfully synthesized. The naphthalene core structures in alphabeta-TTNs were constructed by a systematic protocol using PtCl2-catalyzed cyclization followed by oxidative Scholl annulation in good yields. Compared to the one-dimensional naphthodithiophene derivatives, the two-dimensional alphabeta-TTN molecules showed good solubility, extended conjugation, strong absorptivity, and highly coplanar structures. Compounds 1 and 2 were polymerized with a 5,5'-dibromo-2,2' bithiophene-based monomer to afford 2,8-alphabeta-PTTNTT and 5,11-alphabeta PTTNTT copolymers. 2,8-alphabeta-PTTNTT with the alpha-aNDT moiety in the main chain exhibited a higher hole mobility of 1.26 * 10(-2) cm(2) V(-1) s(-1). PMID- 26741028 TI - 4-Arylbenzenesulfonamides as Human Carbonic Anhydrase Inhibitors (hCAIs): Synthesis by Pd Nanocatalyst-Mediated Suzuki-Miyaura Reaction, Enzyme Inhibition, and X-ray Crystallographic Studies. AB - Benzenesulfonamides bearing various substituted (hetero)aryl rings in the para position were prepared by palladium nanoparticle-catalyzed Suzuki-Miyaura cross coupling reactions and evaluated as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors against isoforms hCA I, II, IX, and XII. Most of the prepared sulfonamides showed low inhibition against hCA I isoform, whereas the other cytosolic isoenzyme, hCA II, was strongly affected. The major part of these new derivatives acted as potent inhibitors of the tumor-associated isoform hCA XII. An opposite trend was observed for phenyl, naphthyl, and various heteroaryl substituted benzenesulfonamides which displayed subnanomolar hCA IX inhibition while poorly inhibiting the other tumor-associated isoform hCA XII. The inhibition potency and influence of the partially restricted aryl-aryl bond rotation on the activity/selectivity were rationalized by means of X-ray crystallography of the adducts of hCA II with several 4-arylbenzenesulfonamides. PMID- 26741045 TI - Accounting for intrusive thoughts in PTSD: Contributions of cognitive control and deliberate regulation strategies. AB - BACKGROUND: Persistent, trauma-related intrusive thoughts are common in individuals with posttraumatic stress disorder (PTSD). Automatic aspects of cognitive functioning (including executive functioning) and maladaptive deliberate attempts at cognitive regulation have been proposed as individual difference factors that may perpetuate intrusive thoughts. The current study sought to examine the joint contribution of these two factors on intrusive thoughts in PTSD. METHOD: Forty-two women with PTSD completed an executive functioning assessment followed by a thought suppression task. Intrusive thoughts (frequency and duration), as well as participants' use of specific cognitive regulation strategies (avoidance-based thought regulation strategies; TRS), were measured during the task. Hierarchical linear regression was used to examine the interaction of executive functioning and TRS on intrusive thoughts. RESULTS: Greater use of TRS was associated with greater intrusive thought persistence for those with low executive functioning, but not those with high executive functioning. LIMITATIONS: Data was collected cross-sectionally and the laboratory thought suppression task may not correspond to naturalistic thought regulation. CONCLUSIONS: Results are consistent with prior literature suggesting that certain responses deployed by individuals to control intrusive thoughts may be unhelpful, but that a higher level of cognitive capacity may mitigate this effect. Implications of these findings for recent models of cognition in PTSD are discussed. PMID- 26741047 TI - Synthesis of 2,3-Dihydrothieno(2,3-b)quinolines and Thieno(2,3-b)- quinolines via an Unexpected Domino Aza-MBH/Alkylation/Aldol Reaction. AB - An efficient, mild, and convenient method for the preparation of 2,3 dihydrothieno(2,3-b)quinolines and thieno(2,3-b)-quinolines via an unexpected domino aza-Morita-Baylis-Hillman/alkylation/aldol reaction has been developed. The plausible mechanisms for the unexpected reaction are also given. PMID- 26741048 TI - Excess-Electron Transfer in DNA by a Fluctuation-Assisted Hopping Mechanism. AB - The dynamics of excess-electron transfer in DNA has attracted the attention of scientists from all kinds of research fields because of its importance in biological processes. To date, several studies on excess-electron transfer in consecutive adenine (A):thymine (T) sequences in donor-DNA-acceptor systems have been published. However, the reported excess-electron transfer rate constants for consecutive T's are in the range of 10(10)-10(11) s(-1) depending on the photosensitizing electron donor, which provides various driving forces for excess electron injection into DNA. In this study, we employed a strongly electron donating photosensitizer, a dimer of 3,4-ethylenedioxythiophene (2E), and an electron acceptor, diphenylacetylene (DPA), to synthesize a series of modified DNA oligomers (2-Tn, n = 3-6) in order to investigate the excess-electron transfer dynamics in these donor-DNA-acceptor systems using femtosecond laser flash photolysis. The relation between the free energy change for charge injection and the excess-electron transfer rate among consecutive T's provided an intrinsic excess-electron hopping rate constant of (3.8 +/- 1.5) * 10(10) s(-1) in the DNA, which is consistent with the fluctuation frequency of the DNA sugar backbone and bases (3.3 * 10(10) s(-1)). Thus, we discuss the effect of structural fluctuations on the excess-electron hopping in DNA. PMID- 26741046 TI - Neurophenotypes in Airway Diseases. Insights from Translational Cough Studies. AB - RATIONALE: Most airway diseases, including chronic obstructive pulmonary disease (COPD), are associated with excessive coughing. The extent to which this may be a consequence of increased activation of vagal afferents by pathology in the airways (e.g., inflammatory mediators, excessive mucus) or an altered neuronal phenotype is unknown. Understanding whether respiratory diseases are associated with dysfunction of airway sensory nerves has the potential to identify novel therapeutic targets. OBJECTIVES: To assess the changes in cough responses to a range of inhaled irritants in COPD and model these in animals to investigate the underlying mechanisms. METHODS: Cough responses to inhaled stimuli in patients with COPD, healthy smokers, refractory chronic cough, asthma, and healthy volunteers were assessed and compared with vagus/airway nerve and cough responses in a cigarette smoke (CS) exposure guinea pig model. MEASUREMENTS AND MAIN RESULTS: Patients with COPD had heightened cough responses to capsaicin but reduced responses to prostaglandin E2 compared with healthy volunteers. Furthermore, the different patient groups all exhibited different patterns of modulation of cough responses. Consistent with these findings, capsaicin caused a greater number of coughs in CS-exposed guinea pigs than in control animals; similar increased responses were observed in ex vivo vagus nerve and neuron cell bodies in the vagal ganglia. However, responses to prostaglandin E2 were decreased by CS exposure. CONCLUSIONS: CS exposure is capable of inducing responses consistent with phenotypic switching in airway sensory nerves comparable with the cough responses observed in patients with COPD. Moreover, the differing profiles of cough responses support the concept of disease-specific neurophenotypes in airway disease. Clinical trial registered with www.clinicaltrials.gov (NCT 01297790). PMID- 26741050 TI - Tunable and Diastereoselective Bronsted Acid Catalyzed Synthesis of beta Enaminones. AB - The Bronsted acid catalyzed Meyer-Schuster reaction of hemiaminals was studied for the stereoselective synthesis of beta-enaminones. Hemiaminals were formed from propargyl aldehydes (or the oxidation of propargyl alcohols) and amines in the presence of Bronsted acids. A critical step to control the stereochemistry of the products is the protonation of the corresponding allenol intermediate, which is dictated by the Bronsted acid used, the steric effect of the amine, and the electronic effect of the propargyl aldehyde. PMID- 26741049 TI - Characterization of the Life Cycle of a Fish Eye Fluke, Austrodiplostomum ostrowskiae (Digenea: Diplostomidae), with Notes on Two Other Diplostomids Infecting Biomphalaria havanensis (Mollusca: Planorbidae) from Catfish Aquaculture Ponds in Mississippi, USA. AB - Ocular diplostomiasis is caused by trematode species in the family Diplostomidae, specifically those in the genera Austrodiplostomum, Diplostomum, and Tylodelphys. Diplostomid trematodes are globally distributed parasites of fish. Heavy infections of diplostomids that parasitize the eyes of fish can result in acute mortality while chronic infections are often characterized by impaired vision or blindness. In the southeastern United States, commercial catfish production is threatened by piscivorous birds and the many trematode species that parasitize them. The life cycles typically involve a piscivorous avian definitive host, a mollusk first intermediate host, and a fish second intermediate host. A survey of parasites infecting the snail host Biomphalaria havanensis (= B. obstructa ) in catfish production ponds was undertaken. Snails were collected from 2 separate ponds during the summer of 2014 and observed for the release of trematode cercariae. A total of 1,740 snails were collected. Three distinct longifurcate pharyngeate cercariae were observed and these cercariae were characterized morphologically and molecularly. Sequencing of ~4,200 base pairs (bp) of the nuclear ribosomal genes and ~450 bp of the mitochondrial cytochrome c oxidase gene revealed 3 genetically distinct species. One morphotype shared 99-100% sequence identity with metacercariae from the aqueous and vitreous humors of gizzard shad Dorosoma cepedianum and channel catfish Ictalurus punctatus as well as an adult trematode, Austrodiplostomum ostrowskiae, a parasite of the double crested cormorant Nannopterum auritus. The remaining 2 cercariae morphotypes shared 99-100% sequence identity with an unidentified Tylodelphys sp. and Austrodiplostomum sp. metacercaria from the brain and eyes of several freshwater fish. Herein we molecularly link the cercaria, metacercaria, and adult stage of the life cycle of A. ostrowskiae, identifying the snail host for this parasite, in addition to providing notes on 2 cercariae representing 2 other diplostomids. PMID- 26741052 TI - Topical Application of Naltrexone to the Ocular Surface of Healthy Volunteers: A Tolerability Study. AB - PURPOSE: A short-term, randomized double-masked study was conducted to test the tolerability of topical application of naltrexone to the corneal surface. METHODS: Healthy human volunteers were recruited at the Penn State Hershey Medical Center between 2010 and 2013. Study groups of 4 subjects were established to receive escalating dosages of naltrexone; within each group, 1 subject received placebo. Four drops of 4 different dosages of naltrexone dissolved in commercial moxifloxacin solution were administered over a 24-h period of time; 1 group of subjects received only 1 drop. The naltrexone dosages tested were 1 * 10(-6) M (1 drop), 1 * 10(-6) M (4 drops), 5 * 10(-6) M (4 drops), 1 * 10(-5) M (4 drops), and 5 * 10(-5) M (4 drops). Drops were administered over a 24-h period. Consenting subjects had complete eye examinations, including visual acuity (ETDRS), external and slit-lamp examinations, corneal sensitivity, pachymetry, corneal topography, endothelial specular microscopy, Schirmer testing with anesthetic, and fundus photography, before receiving naltrexone. Individuals were reexamined at 24 h and 7 days following naltrexone or placebo application. RESULTS: Twenty subjects were recruited for the study; 62% were male, 90% were Caucasian; and 19 subjects completed the study. No significant differences were noted in ocular health between left (treated) and right (untreated) eyes of subjects receiving naltrexone or placebo. No significant adverse events were reported. CONCLUSIONS: Topical naltrexone was well tolerated in healthy human subjects after 1 or 4 eye drops of naltrexone at dosages up to 50 MUM administered over a 24-h treatment period and observed for 1 week. PMID- 26741053 TI - Pigmentation and Macular Degeneration: Is There a Role for GPR143? PMID- 26741055 TI - Flexibility at a glycosidic linkage revealed by molecular dynamics, stochastic modeling, and (13)C NMR spin relaxation: conformational preferences of alpha-L Rhap-alpha-(1 -> 2)-alpha-L-Rhap-OMe in water and dimethyl sulfoxide solutions. AB - The monosaccharide L-rhamnose is common in bacterial polysaccharides and the disaccharide alpha-L-Rhap-alpha-(1 -> 2)-alpha-L-Rhap-OMe represents a structural model for a part of Shigella flexneri O-antigen polysaccharides. Utilization of [1'-(13)C]-site-specific labeling in the anomeric position at the glycosidic linkage between the two sugar residues facilitated the determination of transglycosidic NMR (3)JCH and (3)JCC coupling constants. Based on these spin spin couplings the major state and the conformational distribution could be determined with respect to the psi torsion angle, which changed between water and dimethyl sulfoxide (DMSO) as solvents, a finding mirrored by molecular dynamics (MD) simulations with explicit solvent molecules. The (13)C NMR spin relaxation parameters T1, T2, and heteronuclear NOE of the probe were measured for the disaccharide in DMSO-d6 at two magnetic field strengths, with standard deviations <=1%. The combination of MD simulation and a stochastic description based on the diffusive chain model resulted in excellent agreement between calculated and experimentally observed (13)C relaxation parameters, with an average error of <2%. The coupling between the global reorientation of the molecule and the local motion of the spin probe is deemed essential if reproduction of NMR relaxation parameters should succeed, since decoupling of the two modes of motion results in significantly worse agreement. Calculation of (13)C relaxation parameters based on the correlation functions obtained directly from the MD simulation of the solute molecule in DMSO as solvent showed satisfactory agreement with errors on the order of 10% or less. PMID- 26741056 TI - On Latent Growth Models for Composites and Their Constituents. AB - Over the last decade and a half, latent growth modeling has become an extremely popular and versatile technique for evaluating longitudinal change and its determinants. Most common among the models applied are those for a single measured variable over time. This model has been extended in a variety of ways, most relevant for the current work being the multidomain and the second-order latent growth models. Whereas the former allows for growth function characteristics to be modeled for multiple outcomes simultaneously, with the degree of growth characteristics' relations assessed within the model (e.g., cross-domain slope factor correlations), the latter models growth in latent outcomes, each of which has effect indicators repeated over time. But what if one has an outcome that is believed to be formative relative to its indicator variables rather than latent? In this case, where the outcome is a composite of multiple constituents, modeling change over time is less straightforward. This article provides analytical and applied details for simultaneously modeling growth in composites and their constituent elements, including a real data example using a general computer self-efficacy questionnaire. PMID- 26741054 TI - Habitability: A Review. AB - Habitability is a widely used word in the geoscience, planetary science, and astrobiology literature, but what does it mean? In this review on habitability, we define it as the ability of an environment to support the activity of at least one known organism. We adopt a binary definition of "habitability" and a "habitable environment." An environment either can or cannot sustain a given organism. However, environments such as entire planets might be capable of supporting more or less species diversity or biomass compared with that of Earth. A clarity in understanding habitability can be obtained by defining instantaneous habitability as the conditions at any given time in a given environment required to sustain the activity of at least one known organism, and continuous planetary habitability as the capacity of a planetary body to sustain habitable conditions on some areas of its surface or within its interior over geological timescales. We also distinguish between surface liquid water worlds (such as Earth) that can sustain liquid water on their surfaces and interior liquid water worlds, such as icy moons and terrestrial-type rocky planets with liquid water only in their interiors. This distinction is important since, while the former can potentially sustain habitable conditions for oxygenic photosynthesis that leads to the rise of atmospheric oxygen and potentially complex multicellularity and intelligence over geological timescales, the latter are unlikely to. Habitable environments do not need to contain life. Although the decoupling of habitability and the presence of life may be rare on Earth, it may be important for understanding the habitability of other planetary bodies. PMID- 26741057 TI - Bifactor Modeling and the Estimation of Model-Based Reliability in the WAIS-IV. AB - Previous confirmatory factor analytic research that has examined the factor structure of the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) has endorsed either higher order models or oblique factor models that tend to amalgamate both general factor and index factor sources of systematic variance. An alternative model that has not yet been examined for the WAIS-IV is the bifactor model. Bifactor models allow all subtests to load onto both the general factor and their respective index factor directly. Bifactor models are also particularly amenable to the estimation of model-based reliabilities for both global composite scores (omega h ) and subscale/index scores (omega s ). Based on the WAIS-IV normative sample correlation matrices, a bifactor model that did not include any index factor cross loadings or correlated residuals was found to be better fitting than the conventional higher order and oblique factor models. Although the omega h estimate associated with the full scale intelligence quotient (FSIQ) scores was respectably high (.86), the omega s estimates associated with the WAIS-IV index scores were very low (.13 to .47). The results are interpreted in the context of the benefits of a bifactor modeling approach. Additionally, in light of the very low levels of unique internal consistency reliabilities associated with the index scores, it is contended that clinical index score interpretations are probably not justifiable. PMID- 26741058 TI - A New Procedure to Test Mediation With Missing Data Through Nonparametric Bootstrapping and Multiple Imputation. AB - This article proposes a new procedure to test mediation with the presence of missing data by combining nonparametric bootstrapping with multiple imputation (MI). This procedure performs MI first and then bootstrapping for each imputed data set. The proposed procedure is more computationally efficient than the procedure that performs bootstrapping first and then MI for each bootstrap sample. The validity of the procedure is evaluated using a simulation study under different sample size, missing data mechanism, missing data proportion, and shape of distribution conditions. The result suggests that the proposed procedure performs comparably to the procedure that combines bootstrapping with full information maximum likelihood under most conditions. However, caution needs to be taken when using this procedure to handle missing not-at-random or nonnormal data. PMID- 26741059 TI - Explanatory, Multilevel Person-Fit Analysis of Response Consistency on the Spielberger State-Trait Anxiety Inventory. AB - Self-report measures are vulnerable to concentration and motivation problems, leading to responses that may be inconsistent with the respondent's latent trait value. We investigated response consistency in a sample (N = 860) of cardiac patients with an implantable cardioverter defibrillator and their partners who completed the Spielberger State-Trait Anxiety Inventory on five measurement occasions. For each occasion and for both the state and trait subscales, we used the l (p) z person-fit statistic to assess response consistency. We used multilevel analysis to model the between-person and within-person differences in the repeated observations of response consistency using time-dependent (e.g., mood states) and time-invariant explanatory variables (e.g., demographic characteristics). Respondents with lower education, undergoing psychological treatment, and with more post-traumatic stress disorder symptoms tended to respond less consistently. The percentages of explained variance in response consistency were small. Hence, we conclude that the results give insight into the causes of response inconsistency but that the identified explanatory variables are of limited practical value for identifying respondents at risk of producing invalid test results. We discuss explanations for the small percentage of explained variance and suggest alternative methods for studying causes of response inconsistency. PMID- 26741060 TI - The Three-Level Synthesis of Standardized Single-Subject Experimental Data: A Monte Carlo Simulation Study. AB - Previous research indicates that three-level modeling is a valid statistical method to make inferences from unstandardized data from a set of single-subject experimental studies, especially when a homogeneous set of at least 30 studies are included ( Moeyaert, Ugille, Ferron, Beretvas, & Van den Noortgate, 2013a ). When single-subject data from multiple studies are combined, however, it often occurs that the dependent variable is measured on a different scale, requiring standardization of the data before combining them over studies. One approach is to divide the dependent variable by the residual standard deviation. In this study we use Monte Carlo methods to evaluate this approach. We examine how well the fixed effects (e.g., immediate treatment effect and treatment effect on the time trend) and the variance components (the between- and within-subject variance) are estimated under a number of realistic conditions. The three-level synthesis of standardized single-subject data is found appropriate for the estimation of the treatment effects, especially when many studies (30 or more) and many measurement occasions within subjects (20 or more) are included and when the studies are rather homogeneous (with small between-study variance). The estimates of the variance components are less accurate. PMID- 26741061 TI - A Meta-View of Multivariate Statistical Inference Methods in European Psychology Journals. AB - We investigated the extent and nature of multivariate statistical inferential procedures used in eight European psychology journals covering a range of content (i.e., clinical, social, health, personality, organizational, developmental, educational, and cognitive). Multivariate methods included those found in popular texts that focused on prediction, group difference, and advanced modeling: multiple regression, logistic regression, analysis of covariance, multivariate analysis of variance, factor or principal component analysis, structural equation modeling, multilevel modeling, and other methods. Results revealed that an average of 57% of the articles from these eight journals involved multivariate analyses with a third using multiple regression, 17% using structural modeling, and the remaining methods collectively comprising about 50% of the analyses. The most frequently occurring inferential procedures involved prediction weights, dichotomous p values, figures with data, and significance tests with very few articles involving confidence intervals, statistical mediation, longitudinal analyses, power analysis, or meta-analysis. Contributions, limitations and future directions are discussed. PMID- 26741062 TI - Chondrocyte-Specific Ablation of AMPKalpha1 Does Not Affect Bone Development or Pathogenesis of Osteoarthritis in Mice. AB - AMP-activated protein kinase (AMPK) acts as an intracellular sensor that modulates the energy balance within the cell. AMPKalpha1 is the dominant catalytic isoform expressed in the bone, but the significance of AMPKalpha1 in articular cartilage has not been well studied. In this study, we aimed to assess the in vivo function of AMPKalpha1 in chondrocytes. We created chondrocyte specific AMPKalpha1 conditional knockout (KO) mice using Col2alpha1-Cre and analyzed and compared growth characteristics, HE staining, and AMPKalpha gene expression between wild-type (WT) mice and AMPKalpha1 conditional KO mice under normal physiological conditions or following activation of AMPK by metformin intake or treadmill exercise. Microcomputed tomography and safranin O-fast green staining were compared between WT and KO mice after induction of experimental osteoarthritis (OA). Our data showed that there was no somatic difference between WT mice and KO mice of the same age. Metformin intake and treadmill exercise did not alter the phenotype of KO mice, and no difference in cartilage degradation was observed in WT mice or in KO mice after induction of traumatic arthritis. We thought that chondrocyte-specific ablation of AMPKalpha1 had no effect on bone growth or on pathogenesis of OA in mice, probably because the feedback overexpression of AMPKalpha2 compensated for loss of AMPKalpha1 and maintained the combination of AMPKalpha subunits. PMID- 26741063 TI - A modern conceptualization of phobia in al-Balkhi's 9th century treatise: Sustenance of the Body and Soul. AB - Morbid fears and phobias have been mentioned in religious, philosophical and medical manuscripts since ancient times. Despite early insights by the Greeks, phobias did not appear as a separate clinical phenomenon in Western medicine until the 17th century and has evolved substantially since. However, robust investigations attempting to decipher the clinical nature of phobias emerged in pre-modern times during the oft-overlooked Islamic Golden Era (9th-12th centuries); which overlapped with Europe's medieval period. An innovative attempt was made by the 9th century Muslim scholar, Abu Zayd al-Balkhi, in his medical manuscript "Sustenance of the Body and Soul," to define phobias as a separate diagnostic entity. Al-Balkhi was one of the earliest to cluster psychological and physical symptoms of phobias under one category, "al-Fazaa", and outline a specific management plan. We analyze al-Balkhi's description of phobias, according to the modern understanding of psychiatric classifications and symptomatology as described in the DSM-5. PMID- 26741066 TI - Value of the Lost Art of a Good History and Physical Exam. PMID- 26741065 TI - Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management. AB - Tumor necrosis factor-alpha (TNFalpha) antagonists have advanced the management of inflammatory bowel diseases patients leading to an improvement of patient's quality of life with the reduction of number of surgeries and hospitalizations. Despite these advances, many patients do not respond to the induction therapy (primary non-response-PNR) or lose response during the treatment (secondary loss of response-LOR). In this paper we will provide an overview of the definition, epidemiology and risk factors for PNR and LOR, as well as discuss the therapeutic options for managing LOR. PMID- 26741064 TI - Germline Mutation of the CCK Receptor: A Novel Biomarker for Pancreas Cancer. AB - OBJECTIVES: Today, genetic biomarkers have been demonstrated to play an important role in identifying at-risk subjects for familial or inherited cancers. We have identified a single-nucleotide polymorphism (SNP) that results in missplicing of the cholecystokinin (CCK) receptor gene and expressing a larger mutated receptor in pancreatic cancer. The purpose of this study was to evaluate the significance and specificity of this SNP as a potential biomarker in patients with pancreatic cancer compared with other gastrointestinal (GI) cancers that also have CCK receptors. METHODS: DNA was isolated and genotyped for the CCK receptor SNP from frozen tumor tissue from banked specimens of patients with pancreas, gastric, or colon cancer and from human cancer cell lines. Genotype and allelic frequencies were compared between the cancer cohort and two normal control databases using Fisher's exact test and odds ratio (OR). The Kaplan-Meier method was used to estimate the survival for patients with the CCK-B receptor SNP compared with those with the wild-type genotype. Immunohistochemical staining of cancer cells was done to detect the mutated receptor. RESULTS: Colon and gastric cancer patients had similar genotype frequencies for the CCK receptor SNP as that reported in the normal population. In contrast, the prevalence of the SNP in subjects with pancreatic cancer was twice that of controls and other GI cancers. Survival was adversely affected by the presence of the SNP only in those with pancreatic cancer. Immunoreactivity for the mutated receptor was positive in pancreatic cancer tissues with the SNP but absent in other GI cancers. CONCLUSIONS: A SNP of the CCK receptor is significantly increased in patients with pancreatic cancer but not in those with other GI malignancies. Therefore, this SNP may be a potential biomarker for pancreatic cancer. PMID- 26741068 TI - Iterative Majorizing Rotation to Orthogonal Simple Structure Solution. AB - An iterative process is proposed for obtaining an orthogonal simple structure solution. At each iteration step a target matrix is constructed, such that the relative contributions of the target majorize the original ones, factor by factor. The convergence of the procedure is proven. The algorithm is illustrated with several standard numerical examples. Simple structure solution is achieved for the Thurstone's 26-variable box problem. PMID- 26741067 TI - Bullying and victimisation are common in four-year-old children and are associated with somatic symptoms and conduct and peer problems. AB - AIM: There are few population-based studies on bullying behaviour among preschool children. The aims of the study were to investigate the prevalence of bullying behaviour among four-year-old children, as reported by their parents, the prevalence of types of bullying behaviour and the associations between bullying behaviour and psychosocial factors. METHODS: This study was based on a population based study sample of 931 children who attended their check-up at a child health clinic at four years of age. Parents completed the questionnaire about their child's bullying behaviour and risk factors during the check-up. RESULTS: Bullying behaviour, especially being both a bully and a victim, was a common phenomenon among four-year-old children. Being a bully or both a bully and victim were most strongly associated with conduct problems, while being a victim was associated with somatic symptoms and peer problems. CONCLUSION: Bullying behaviour was frequently found in preschool children and associated with a wide range of other problems, which indicate that routine checking of bullying behaviour should be included in child health clinic check-ups. Bullying prevention programmes are usually targeted at school-aged children, but this study highlights the importance of focusing already on preschool children. PMID- 26741069 TI - Covariance Structure Analysis of Partially Additive Ipsative Data Using Restricted Maximum Likelihood Estimation. AB - A data matrix is said to be ipsative when the sum of the scores obtained over the variables for each subject is a constant. In this article, a general type of ipsative data known as partially additive ipsative data (PAID) is defined. Ordinary additive ipsative data (All311 is a special case. Due to the specific nature of the research design or measurement process, the observed vector is X PAID with an underlying nonipsative vector y. It is shown that if the underlying distribution of y is multivariate normal with structured covariance matrix Sigma = Sigma(Theta), the observed X will have a degenerate normal distribution. As a result, ordinary maximum likelihood estimation of Theta cannot be carried out directly. A transformation of X is suggested so that the transformed vector X* = BX will have a nonsingular density and restricted maximum likelihood (REML) estimation can be applied. A simulation study is conducted to investigate the effect of sample size and other model characteristics on the performance of the ML estimators and the sampling behavior of the goodness of fit statistic. It is found that REML estimates are in general close to the true parameter values, but they have larger dard errors as compared with the ordinary MLE based on y. The test statistic is well behaved when sample size is large enough. Moreover, the likelihood of obtaining a convergent solution depends on a number of factors such as sample size, number of indicators per latent factor, and degree of ipsativity. Finally, statistical decisions (reject or not reject the hypothesized model) based on X* are in general consistent with that based on y. PMID- 26741070 TI - A Latent Trait-State Model of Adolescent Depression Using the Center for Epidemiologic Studies-Depression Scale. AB - This study utilized the latent trait-state model for estimating stable and changing components of depressive symptomology in adolescents. The factorial structure of the CES-D was assessed separately for males and females at four measurement occasions, at six-month intervals. The variance decomposition of general trait, state, specific trait, and random error parameters for the CES-D scores was estimated simultaneously and tested statistically. Parameter estimates indicated that the CES-D measured both trait- and state-depression about equally well, and that the trait-specific variance parameter was statistically significant, but substantially smaller than those associated with general trait- and state-depression. Findings are discussed with regard to depressive mood fluctuations among adolescents and the potential usefulness of the latent trait state model to capture such dynamic features of development. PMID- 26741071 TI - Answering Ordinal Questions with Ordinal Data Using Ordinal Statistics. AB - It is argued that ordinal statistical methods are often more appropriate than their more common counterparts for three types of reasons: Conclusions from them will be unaffected by monotonic transformation of the variables, they are statistically more robust when used appropriately, and they often correspond more closely to the goals of the investigator. Kendall's tau (Kendall, 1970) and its counterpart delta are recommended as having wide I applicability and good statistical behavior. It is recommended that they be estimated as population parameters and their standard errors estimated form the data. Ways in which they can then substitute for Pearson correlations and mean comparisons in a number of research contexts are suggested. PMID- 26741072 TI - Application of AIC to Wald and Lagrange Multiplier Tests in Covariance Structure Analysis. AB - The Akaike Information Criterion (AIC) has been proposed as an alternative to the conventional chi(2) goodness-of-fit test. In this article some efficient procedures for the use of AIC in covariance structure analysis are proposed, based on the backward search via the Wald test to impose constraints and the forward search via the Lagrange Multiplier rest to release constraints. An Approximated AIC, AAIC, is developed that is considerably more efficient computationally in providing information on AIC than the conventional approach based on the likelihood ratio test. AAIC can be effectively computed with a stepwise procedure for more general and for more restricted models that do not need to be explicitly estimated. The necessity of a given restriction is shown within the AIC theory not to depend on an a-level cut off in the chi(2) distribution, but on the absolute cutoff value of 2.0. As a consequence, the AIC based procedure did not yield the simplest model in an example examined in this study. Results also showed that the univariate increment tests, which are products of stepwise procedures in both backward and forward searches, generated the same modifications as the AIC. PMID- 26741073 TI - Mixed-effects Models in the Study of Individual Differences with Repeated Measures Data. AB - Nonlinear mixed-effects models are used to describe each person's set of scores from a longitudinal design or repeated measures study by a function that includes an overall group effect plus an effect for the individual. The model is ideal for many kinds of behavioral data. Some characteristics of mixed models are reviewed in this article and illustrated by a series of examples. PMID- 26741109 TI - Histological Assessment of a Combined Low-Level Laser/Light-Emitting Diode Therapy (685 nm/470 nm) for Sutured Skin Incisions in a Porcine Model: A Short Report. AB - OBJECTIVE: The aim of our study was to evaluate, from a histological point of view, the effect of photobiomodulation (PBM) with combined low-level laser therapy (LLLT)/light- emitting diode (LED) on porcine skin wound healing. BACKGROUND DATA: Most LLLT/LED wound healing studies have been performed on various types of rat models, with their inherent limitations. Minipigs are evolutionary and physiologically closer to humans than rats. MATERIALS AND METHODS: With the animals under general anesthesia, one full-thickness skin incision was performed on the back of each minipig (n = 10) and immediately closed using simple interrupted percutaneous sutures. The minipigs were randomly allocated into two groups: a PBM-treated group (LLLT lambda = 685 nm, LED lambda = 470 nm, both light sources producing power densities at 0.008 W/cm2; each light source delivering total daily doses of 3.36 J/cm2) and a sham-irradiated control group. Half of the animals in each group were killed on postoperative day 3, and the other half were killed on the postoperative day 7, and samples were removed for histological examination. RESULTS: Combined red and blue PBM accelerated the process of re-epithelization and formation of cross-linked collagen fibers compared with sham irradiated control wounds. CONCLUSIONS: Our results demonstrate that the current dose of combined red and blue PBM improves the healing of sutured skin incisions in minipigs. PMID- 26741110 TI - Low-Level Laser Therapy to the Bone Marrow Reduces Scarring and Improves Heart Function Post-Acute Myocardial Infarction in the Pig. AB - OBJECTIVE: Cell therapy for myocardial repair is one of the most intensely investigated strategies for treating acute myocardial infarction (MI). The aim of the present study was to determine whether low-level laser therapy (LLLT) application to stem cells in the bone marrow (BM) could affect the infarcted porcine heart and reduce scarring following MI. METHODS: MI was induced in farm pigs by percutaneous balloon inflation in the left coronary artery for 90 min. Laser was applied to the tibia and iliac bones 30 min, and 2 and 7 days post induction of MI. Pigs were euthanized 90 days post-MI. The extent of scarring was analyzed by histology and MRI, and heart function was analyzed by echocardiography. RESULTS: The number of c-kit+ cells (stem cells) in the circulating blood of the laser-treated (LT) pigs was 2.62- and 2.4-fold higher than in the non-laser-treated (NLT) pigs 24 and 48 h post-MI, respectively. The infarct size [% of scar tissue out of the left ventricle (LV) volume as measured from histology] in the LT pigs was 3.2 +/- 0.82%, significantly lower, 68% (p < 0.05), than that (16.6 +/- 3.7%) in the NLT pigs. The mean density of small blood vessels in the infarcted area was significantly higher [6.5-fold (p < 0.025)], in the LT pigs than in the NLT ones. Echocardiography (ECHO) analysis for heart function revealed the left ventricular ejection fraction in the LT pigs to be significantly higher than in the NLT ones. CONCLUSIONS: LLLT application to BM in the porcine model for MI caused a significant reduction in scarring, enhanced angiogenesis and functional improvement both in the acute and long term phase post-MI. PMID- 26741111 TI - Advances in allograft monitoring after intestinal transplantation. AB - PURPOSE OF REVIEW: The intestinal allograft, with an enormous lymphoid load, is a highly immunogenic organ which elicits a strong alloimmune response. In the early posttransplant period, a robust graft biopsy protocol via a temporary ileostomy is utilized for surveillance to detect rejection. In the later posttransplant period, after enteral continuity is reestablished, graft biopsies via a colonoscopy become more cumbersome. Alternative methods for intestinal allograft monitoring other than graft biopsy are of particular interest. RECENT FINDINGS: Biomarkers and diagnostic tools, such as granzyme B, perforin, fecal calprotectin, citrulline, donor-specific antibody, and zoom video endoscopy have all been studied for application as reliable methods of performing intestinal allograft surveillance. Each modality has the capability to monitor a separate and unique process in the host-allograft immune response. SUMMARY: The goal to find a reliable, reproducible, and noninvasive method for intestinal graft monitoring remains an elusive one. Many of the current modalities available only serve to act as complementary tests in conjunction with astute clinical observations. Graft biopsy remains the gold standard for monitoring the intestinal allograft. PMID- 26741112 TI - Lipid management in pediatric intestinal failure. AB - PURPOSE OF REVIEW: Lipids are a crucial component in parenteral nutrition but their prolonged use can be associated with parenteral nutrition-associated liver disease (PNALD), which may lead to significant morbidity and mortality. The purpose of this review is to discuss the current state of lipid management in pediatric intestinal failure, especially as it relates to the prevention of PNALD. RECENT FINDINGS: Lipid restriction has emerged as a successful strategy in both the treatment and prevention of PNALD in parenteral nutrition-dependent children. There is concern, however, that lipid restriction can lead to essential fatty acid deficiency. This, in turn, may affect neurodevelopmental outcomes. A wide variety of lipid emulsion formulations is available throughout the world although only one, a soybean-based product, is Food and Drug Administration approved for use in the pediatric population. To date, there are no definitive data favoring one lipid emulsion composition over another. SUMMARY: Pediatric intestinal failure patients are at high risk for the development of PNALD. Although this may be managed, and even prevented, with lipid restrictive strategies, the development of essential fatty acid deficiency in this setting remains a concern. Further studies are needed to determine the ideal lipid emulsion and dose to be used in parenteral nutrition-dependent children. PMID- 26741113 TI - Macro- and micro-designed chitosan-alginate scaffold architecture by three dimensional printing and directional freezing. AB - While many tissue-engineered constructs aim to treat cartilage defects, most involve chondrocyte or stem cell seeding on scaffolds. The clinical application of cell-based techniques is limited due to the cost of maintaining cellular constructs on the shelf, potential immune response to allogeneic cell lines, and autologous chondrocyte sources requiring biopsy from already diseased or injured, scarce tissue. An acellular scaffold that can induce endogenous influx and homogeneous distribution of native stem cells from bone marrow holds great promise for cartilage regeneration. This study aims to develop such an acellular scaffold using designed, channeled architecture that simultaneously models the native zones of articular cartilage and subchondral bone. Highly porous, hydrophilic chitosan-alginate (Ch-Al) scaffolds were fabricated in three dimensionally printed (3DP) molds designed to create millimeter scale macro channels. Different polymer preform casting techniques were employed to produce scaffolds from both negative and positive 3DP molds. Macro-channeled scaffolds improved cell suspension distribution and uptake overly randomly porous scaffolds, with a wicking volumetric flow rate of 445.6 +/- 30.3 mm(3) s(-1) for aqueous solutions and 177 +/- 16 mm(3) s(-1) for blood. Additionally, directional freezing was applied to Ch-Al scaffolds, resulting in lamellar pores measuring 300 MUm and 50 MUm on the long and short axes, thus creating micrometer scale micro-channels. After directionally freezing Ch-Al solution cast in 3DP molds, the combined macro- and micro-channeled scaffold architecture enhanced cell suspension uptake beyond either macro- or micro-channels alone, reaching a volumetric flow rate of 1782.1 +/- 48 mm(3) s(-1) for aqueous solutions and 440.9 +/- 0.5 mm(3) s(-1) for blood. By combining 3DP and directional freezing, we can control the micro- and macro-architecture of Ch-Al to drastically improve cell influx into and distribution within the scaffold, while achieving porous zones that mimic articular cartilage zonal architecture. In future applications, precisely controlled micro- and macro-channels have the potential to assist immediate endogenous bone marrow uptake, stimulate chondrogenesis, and encourage vascularization of bone in an osteochondral scaffold. PMID- 26741114 TI - Lessons learnt from a primary care asthma improvement project. AB - Asthma is a very common disease that can occur at any age. In the UK and in many other countries it is mainly managed in primary care. The published evidence suggests that the key to improving diagnosis and management lies in better training and education rather than in the discovery of new medications. An asthma improvement project managed through the British Lung Foundation is attempting to do this. The project has three pilot sites: two in England supported by the Department of Health and one in Scotland supported by the Scottish Government. If the project is successful it will be rolled out to other health areas within the UK. The results of this project are not yet available. This article highlights the challenges encountered in setting up the project and may well be applicable to other areas in the UK and to other countries where similar healthcare systems exist. The encountered challenges reflect the complex nature of healthcare systems and electronic data capture in primary care. We discuss the differences between general practices in their ability and willingness to support the project, the training and education of their staff on asthma management, governance issues in relation to information technology systems, and the quality of data capture. Virtually all the challenges have now been overcome, but discussing them should ensure that others become aware of them at an early stage should they wish to undertake similar projects in the future. PMID- 26741115 TI - Design and synthesis of dihydroisoquinolones for fragment-based drug discovery (FBDD). AB - This study describes general synthesis aspects of fragments for FBDD, as illustrated by the dihydroisoquinolones 1-3. Previous Rh(III) methodology is extended to incorporate amines, heteroatoms (N and S), and substituents (halogen, ester) as potential binding groups and/or synthetic growth points for fragment-to lead elaboration. PMID- 26741116 TI - Expression of Tim4 in Glioma and its Regulatory Role in LN-18 Glioma Cells. AB - BACKGROUND: Tim4 is a transmembrane protein known as T cell immunoglobulin and mucin domain containing protein-4. We speculated that Tim4 might be associated with glioma. This study aimed to investigate the expression level of Tim4 in gliomas and the regulatory role of Tim4 on the growth and apoptosis of LN-18 glioma cells. MATERIAL/METHODS: Tumor tissues and adjacent normal tissues were collected from patients with glioma. The expression level of Tim4 mRNA and protein was determined by RT-PCR and Western blot analyses, respectively to evaluate their association with glioma. Tim4 was overexpressed or silenced by siRNA interference in cultured human glioma cells LN-18. The growth and apoptosis of LN-18 cells was detected by MTT assay and flow cytometry. The colony-forming ability of LN-18 cells was assessed by the colony formation assay. The collection of human tissues was approved by the Research Ethics Committee at the Harbin Medical University Cancer Hospital and performed in strict accordance with international standards. All patients were required to sign the informed consent. RESULTS: The expression level of Tim4 mRNA and protein in tumor tissues was significantly higher compared with adjacent normal tissues. Antisense miRNA targeting Tim4 inhibited the growth of LN-18 cells, induced their apoptosis, and reduced their clonogenic capacity. In contrast, overexpression of Tim4 promoted the growth of LN-18 cells, inhibited their apoptosis, and enhanced their clonogenic potential. CONCLUSIONS: The expression level of Tim-4 is closely associated with glioma. Decreased expression of Tim4 inhibited the growth and colony-forming ability of LN-18 cells and induced their apoptosis, whereas increased expression of Tim4 stimulated the growth and clonogenic potential of LN 18 cells and suppressed their apoptosis. PMID- 26741117 TI - Prevalence of Physical Activity Is Lower among Individuals with Chronic Disease. AB - INTRODUCTION: Physical inactivity is associated with increased risk for morbidity and mortality and contributes to health care costs. Although data supporting the secondary preventive benefits of being physically active continues to grow, there is limited data on the prevalence of sufficient volume of leisure-time physical activity among individuals diagnosed with chronic disease. PURPOSE: To describe the association between select chronic diseases and the prevalence of sufficient volume of aerobic leisure-time physical activity to achieve substantial health benefits (i.e., >=150 min.wk) among adults in the United States. METHODS: Self reported leisure-time physical activity (LTPA) and history of select chronic diseases were obtained from a nationally representative sample of noninstitutionalized civilian adults 18 yr or older in the United States who participated in the 2014 National Health Interview Survey (n = 36,697). RESULTS: Among all adults, the prevalence of sufficient volume of aerobic LTPA was 50.1% +/- 0.5% (mean +/- standard error). This prevalence was inversely related to age and was lower in women (47.1% +/- 0.6%) compared with men (53.4% +/- 0.6%; P < 0.001). Prevalence of sufficient volume of aerobic LTPA was lower for each chronic disease (prevalence range = 26.1%-48.6%) compared with apparently healthy adults (53.6% +/- 0.7%). Relative to no chronic disease, each additional chronic disease was associated with an odds ratio of 0.83 (95% confidence interval, 0.81 0.85; P < 0.001) for sufficient volume of aerobic LTPA. CONCLUSIONS: The prevalence of sufficient volume of aerobic LTPA to achieve substantial health benefits is inversely related to age and is lower among women and individuals with a chronic disease. Systems to regularly assess physical activity are needed as well as programs to help individuals be more active. PMID- 26741118 TI - Hypoventilation Training at Supramaximal Intensity Improves Swimming Performance. AB - PURPOSE: This study aimed to determine whether hypoventilation training at supramaximal intensity could improve swimming performance more than the same training conducted under normal breathing conditions. METHODS: For a 5-wk period, 16 triathletes (12 men and 4 women) were asked to include one supramaximal set of 12 to 20 * 25-m front crawl swimming twice a week into their usual swimming session, performed either with hypoventilation at low lung volume (VHL group) or with normal breathing (CONT group). Before (Pre) and after (Post) training, all triathletes performed all-out front crawl trials for 100, 200, and 400 m. RESULTS: Time performance was significantly improved in VHL in all trials (100 m: -3.7 +/- 3.7 s [-4.4% +/- 4.0%]; 200 m: -6.9 +/- 5.0 s [-3.6% +/- 2.3%]; 400 m: 13.6 +/- 6.1 s [-3.5% +/- 1.5%]) but did not change in CONT. In VHL, the maximal lactate concentration (+2.35 +/- 1.3 mmol.L on average) and the rate of lactate accumulation in blood (+41.7% +/- 39.4%) were higher at Post than at Pre in the three trials, whereas they remained unchanged in CONT. Arterial oxygen saturation, heart rate, breathing frequency, and stroke length were not altered in both groups at the end of the training period. On the other hand, stroke rate was higher at Post compared with Pre in VHL but not different in CONT. The measurements of gas exchange for the 400-m trial revealed no change in peak oxygen consumption as well as in any pulmonary variable in both groups. CONCLUSION: This study demonstrated that VHL training, when performed at supramaximal intensity, represents an effective method for improving swimming performance, partly through an increase in the anaerobic glycolysis activity. PMID- 26741119 TI - Enhanced Endurance Performance by Periodization of Carbohydrate Intake: "Sleep Low" Strategy. AB - PURPOSE: We investigated the effect of a chronic dietary periodization strategy on endurance performance in trained athletes. METHODS: Twenty-one triathletes (VO2max: 58.7 +/- 5.7 mL.min(-1).kg(-1)) were divided into two groups: a "sleep low" (SL) (n = 11) and a control (CON) group (n = 10) consumed the same daily carbohydrate (CHO) intake (6 g.kg(-1).d(-1)) but with different timing over the day to manipulate CHO availability before and after training sessions. The SL strategy consisted of a 3-wk training-diet intervention comprising three blocks of diet-exercise manipulations: 1) "train-high" interval training sessions in the evening with high-CHO availability, 2) overnight CHO restriction ("sleeping low"), and 3) "train-low" sessions with low endogenous and exogenous CHO availability. The CON group followed the same training program but with high CHO availability throughout training sessions (no CHO restriction overnight, training sessions with exogenous CHO provision). RESULTS: There was a significant improvement in delta efficiency during submaximal cycling for SL versus CON (CON, +1.4% +/- 9.3%; SL, +11% +/- 15%, P < 0.05). SL also improved supramaximal cycling to exhaustion at 150% of peak aerobic power (CON, +1.63% +/- 12.4%; SL, +12.5% +/- 19.0%; P = 0.06) and 10-km running performance (CON, -0.10% +/- 2.03%; SL, -2.9% +/- 2.15%; P < 0.05). Fat mass was decreased in SL (CON, -2.6 +/- 7.4; SL, -8.5% +/- 7.4% before; P < 0.01), but not lean mass (CON, -0.22 +/- 1.0; SL, 0.16% +/- 1.7% PRE). CONCLUSION: Short-term periodization of dietary CHO availability around selected training sessions promoted significant improvements in submaximal cycling economy, as well as supramaximal cycling capacity and 10-km running time in trained endurance athletes. PMID- 26741120 TI - Acute Exercise Improves Mood and Motivation in Young Men with ADHD Symptoms. AB - PURPOSE: Little is known about whether acute exercise affects signs or symptoms of attention deficit/hyperactivity disorder (ADHD) in adults. This experiment sought to determine the effects of a single bout of moderate-intensity leg cycling exercise on measures of attention, hyperactivity, mood, and motivation to complete mental work in adult men reporting elevated ADHD symptoms. METHODS: A repeated-measures crossover experiment was conducted with 32 adult men (18-33 yr) with symptoms consistent with adult ADHD assessed by the Adult Self-Report Scale V1.1. Measures of attention (continuous performance task and Bakan vigilance task), motivation to perform the mental work (visual analog scale), lower leg physical activity (accelerometry), and mood (Profile of Mood States and Addiction Research Center Inventory amphetamine scale) were measured before and twice after a 20-min seated rest control or exercise condition involving cycling at 65% VO2peak. Condition (exercise vs rest) * time (baseline, post 1, and post 2) ANOVA was used to test the hypothesized exercise-induced improvements in all outcomes. RESULTS: Statistically significant condition-time interactions were observed for vigor (P < 0.001), amphetamine (P < 0.001), motivation (P = 0.027), and Profile of Mood States depression (P = 0.027), fatigue (P = 0.030), and confusion (P = 0.046) scales. No significant interaction effects were observed for leg hyperactivity, simple reaction time, or vigilance task performance (accuracy, errors, or reaction time). CONCLUSION: In young men reporting elevated symptoms of ADHD, a 20-min bout of moderate-intensity cycle exercise transiently enhances motivation for cognitive tasks, increases feelings of energy, and reduces feelings of confusion, fatigue, and depression, but this has no effect on the behavioral measures of attention or hyperactivity used. PMID- 26741121 TI - Leisure Time Physical Activity and Gestational Diabetes Mellitus in the Omega Study. AB - PURPOSE: Findings of studies investigating associations of leisure time physical activity (LTPA) with gestational diabetes mellitus (GDM) risk have been inconsistent. We investigated associations of LTPA with GDM and whether these associations differ by prepregnancy overweight/obese status or gestational weight gain category. METHODS: Participants (N = 3209) of the Omega study, a pregnancy cohort study in Washington State (1996-2008), reported LTPA duration (h.wk) and energy expenditure (MET.h.wk) in the year before pregnancy and in early pregnancy. Diagnoses of GDM were abstracted from medical records. Poisson regression models were used to determine relative risks of GDM across tertiles of prepregnancy or early pregnancy LTPA duration and energy expenditure. Stratified analyses and interaction terms were used to assess effect modification by prepregnancy overweight/obese status (BMI >=25 kg.m) or gestational weight gain category (adequate or excessive). RESULTS: Each tertile increase in prepregnancy LTPA duration or energy expenditure was associated with 15% (95% CI = 0.72-1.00) and 19% (95% CI = 0.69-0.96) lower risk of GDM, respectively. Each tertile increase in early pregnancy LTPA duration or energy expenditure was associated with 16% (95% CI = 0.72-0.97) and 17% (95% CI = 0.72-0.95) lower risk of GDM, respectively. LTPA during both prepregnancy and early pregnancy was associated with a 46% reduced risk of GDM (95% CI = 0.32-0.89) compared with inactivity during both periods. LTPA-GDM associations were similar by prepregnancy BMI and gestational weight gain. CONCLUSION: Our results support a role for the promotion of physical activity before and during pregnancy in the prevention of GDM. PMID- 26741122 TI - Accuracy of Posture Allocation Algorithms for Thigh- and Waist-Worn Accelerometers. AB - PURPOSE: The objective of this study is to compare the accuracy of the activPAL and ActiGraph GT3X+ (waist and thigh) proprietary postural allocation algorithms and an open-source postural allocation algorithm applied to GENEActiv (thigh) and ActiGraph GT3X+ (thigh) data. METHODS: Thirty-four adults (>=18 yr) wore the activPAL3, GENEActiv, and ActiGraph GT3X+ on the right thigh and an ActiGraph on the right hip while performing four lying, seven sitting, and five upright activities in the laboratory. Lying and sitting tasks incorporated a range of leg angles (e.g., lying with legs bent and sitting with legs crossed). Each activity was performed for 5 min while being directly observed. The percentage of the time the posture was correctly classified was calculated. RESULTS: Participants consisted of 14 males and 20 females (mean age, 27.2 +/- 5.9 yr; mean body mass index, 23.8 +/- 3.7 kg.m). All postural allocation algorithms applied to monitors worn on the thigh correctly classified >=93% of the time lying, >=91% of the time sitting, and >=93% of the time upright. The ActiGraph waist proprietary algorithm correctly classified 72% of the time lying, 58% of the time sitting, and 74% of the time upright. Both the activPAL and ActiGraph thigh proprietary algorithms misclassified sitting on a chair with legs stretched out (58% and 5% classified incorrectly, respectively). The ActiGraph thigh proprietary and open-source algorithm applied to the thigh-worn ActiGraph misclassified participants lying on their back with their legs bent 27% and 9% of the time, respectively. CONCLUSION: All postural allocation algorithms when applied to devices worn on the thigh were highly accurate in identifying lying, sitting, and upright postures. Given the poor accuracy of the waist algorithm for detecting sitting, caution should be taken if inferring sitting time from a waist-worn device. PMID- 26741123 TI - Central Regulation and Neuromuscular Fatigue during Exercise of Different Durations. AB - PURPOSE: The aim of this study was to determine if exercise time trials (TT) of different durations would cause different levels of peripheral and central fatigue during exercise. METHODS: Twelve trained subjects (11 men, one woman) performed TT lasting 3, 10, and 40 min with repetitive self-paced concentric right knee extension at 60 degrees .s on an isokinetic dynamometer. Neuromuscular function was assessed before, during, and immediately after the TT using voluntary and electrically evoked forces. RESULTS: Maximal voluntary contraction force, evoked peak force for single stimulus, and rating of perceived exertion reached similar levels at termination of all TT. Evoked peak force for paired stimuli of 100 Hz decreased more for the 40-min TT compared with the 3-min TT ( 42% +/- 15% vs -37% +/- 13%, P < 0.05), and central fatigue was significant for the 40-min TT and 10-min TT but not for the 3-min TT. Single stimulus and paired stimuli of 100 Hz decreased, whereas voluntary electromyography normalized to M wave for self-paced contractions increased during the end-spurt in all TT. CONCLUSIONS: These data demonstrate that the extent of peripheral and central fatigue that contribute to reductions in force of single-limb dynamic contractions depend on the duration and intensity of self-paced exercise. There was no evidence for a critical threshold in peripheral fatigue that was common to all TT. PMID- 26741125 TI - An efficient level set method for simultaneous intensity inhomogeneity correction and segmentation of MR images. AB - Intensity inhomogeneity (bias field) is a common artefact in magnetic resonance (MR) images, which hinders successful automatic segmentation. In this work, a novel algorithm for simultaneous segmentation and bias field correction is presented. The proposed energy functional allows for explicit regularization of the bias field term, making the model more flexible, which is crucial in presence of strong inhomogeneities. An efficient minimization procedure, attempting to find the global minimum, is applied to the energy functional. The algorithm is evaluated qualitatively and quantitatively using a synthetic example and real MR images of different organs. Comparisons with several state-of-the-art methods demonstrate the superior performance of the proposed technique. Desirable results are obtained even for images with strong and complicated inhomogeneity fields and sparse tissue structures. PMID- 26741124 TI - The Physiological Capacity of the World's Highest Ranked Female Cross-country Skiers. AB - PURPOSE: The objective of this study is to compare the physiological capacity and training characteristics of the world's six highest ranked female cross-country skiers (world class (WC)) with those of six competitors of national class (NC). METHODS: Immediately before the start of the competition season, all skiers performed three 5-min submaximal stages of roller skiing on a treadmill for measurement of oxygen cost, as well as a 3-min self-paced performance test using both the double poling (DP) and diagonal stride (DIA) techniques. During the 3 min performance tests, the total distance covered, peak oxygen uptake (VO2peak), and accumulated oxygen deficit were determined. Each skier documented the intensity and mode of their training during the preceding 6 months in a diary. RESULTS: There were no differences between the groups with respect to oxygen cost or gross efficiency at the submaximal speeds. The WC skiers covered 6%-7% longer distances during the 3-min tests and exhibited average VO2peak values of ~70 and ~65 mL.min.kg with DIA and DP, respectively, which were 10% and 7% higher than the NC skiers (all P < 0.05). However, the accumulated oxygen deficit did not differ between groups. From May to October, the WC skiers trained a total of 532 +/- 73 h (270 +/- 26 sessions) versus 411 +/- 62 h (240 +/- 27 sessions) for the NC skiers. In addition, the WC skiers performed 26% more low-intensity and almost twice as much moderate-intensity endurance and speed training (all P < 0.05). CONCLUSIONS: This study highlights the importance of a high oxygen uptake and the ability to use this while performing the different skiing techniques on varying terrains for female cross-country skiers to win international races. In addition, the training data documented here provide benchmark values for female endurance athletes aiming for medals. PMID- 26741126 TI - One-pot peptide and protein conjugation: a combination of enzymatic transamidation and click chemistry. AB - Enzymatic transamidation and copper-catalyzed azide-alkyne cycloaddition (CuAAC) were combined to yield covalently conjugated peptides and proteins. The addition of glutathione preserved enzymatic activity in the presence of copper. Tuning the reaction kinetics was key to success, providing up to 95% conversion. This one pot reaction allowed for targeted fluorescent protein labeling. PMID- 26741127 TI - Effects of the inverse alpha-agonist doxazosin in allergic rhinitis. AB - BACKGROUND: We examined the paradoxical hypothesis that the alpha-receptor inverse agonist doxazosin might produce beneficial effects in allergic rhinitis. OBJECTIVES: To evaluate single and chronic dosing effects of doxazosin on nasal airflow and symptoms in allergic rhinitis. METHODS: Fifteen patients randomized to receive 3-5 weeks of oral doxazosin 4 mg daily or placebo in crossover fashion. Measurements were taken at baseline and after first and last doses. RESULTS: There was a fall in peak nasal inspiratory flow (PNIF) between baseline vs. first dose of doxazosin: mean difference -19 L/min (95% CI -35 to -2) P = 0.03, with recovery between first and last doses: 21 L/min (95% CI 7-34) P = 0.006. Nasal visual analogue scale (VAS) and blockage scores were worse between baseline vs. first dose of doxazosin: mean difference VAS -10 mm (95% CI -18 to 2) P = 0.02, blockage -0.7 (95% CI -1.3 to -0.1) P = 0.02, with recovery between first and last doses: VAS 15 mm (95% CI 4-25) P = 0.009, blockage 1.1 (95% CI 0.5 1.6) P = 0.001. The oxymetazoline dose-response for PNIF was blunted after single vs chronic dosing with doxazosin: mean difference -17 L/min (95% CI -30 to -4) P = 0.01. Heart rate and diastolic blood pressure showed the same pattern. There was a significant difference between doxazosin and placebo for nasal blockage score and heart rate after single but not chronic dosing. CONCLUSIONS: There was a disconnect between single and chronic dosing effects of doxazosin for nasal symptoms, oxymetazoline response and cardiovascular outcomes, in turn suggesting alpha-1 receptor up-regulation. PMID- 26741128 TI - Testicular cancer: germ cell tumours. AB - INTRODUCTION: More than half of painless solid swellings of the body of the testis are malignant, with a peak incidence in men aged 30 to 34 years. Most testicular cancers are germ cell tumours and half of these are seminomas, which tend to affect older men and have a good prognosis. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of treatments following orchidectomy in men diagnosed with stage 1 germ cell tumours (confined to testis)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: At this update, 76 records were screened for inclusion. Appraisal of titles and abstracts led to the exclusion of 47 studies and the further review of 29 full publications. Of the 29 full articles evaluated, two systematic reviews and one RCT, were added at this update. Data from long-term follow-up of an already reported study were also added. We performed a GRADE evaluation for seven PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for seven interventions based on information about the effectiveness and safety of adjuvant chemotherapy (including different drugs and the number of cycles), adjuvant radiotherapy (including different regimens), adjuvant surgery, and surveillance/observation. PMID- 26741129 TI - MicroRNA-320a Regulates the Osteogenic Differentiation of Human Bone Marrow Derived Mesenchymal Stem Cells by Targeting HOXA10. AB - BACKGROUND/AIMS: Human bone marrow-derived mesenchymal stem cells (hMSCs) are a promising cell source for bone engineering owing to their high potential to differentiate into osteoblasts. The bone morphogenetic protein-inducible gene homeobox a10 (HOXA10) is a critical regulator of osteogenesis. The objective of the present study was to identify microR-NAs (miRNAs) targeting HOXA10 and examine the effects on the osteogenic differentiation of hMSCs. METHODS: Based on in silico analysis, HOXA10-targeting miRNAs were selected and their regulatory roles in osteoblast differentiation were investigated. RESULTS: Six HOXA10 targeting miRNAs were identifIed by computational analysis, of which miR-320a was selected for further analysis because it was downregulated during osteogenic induction. Overexpression of miR-320a downregulated HOXA10 and significantly inhibited osteogenesis in hMSCs, as determined by the downregulation of the osteogenic markers Runx2, ALP, and OC and the inhibition of ALP activity and matrix mineralization, whereas miR-320a inhibition had the opposite effects. Furthermore, ectopic expression of HOXA10 (not including 3'-UTR) rescued the effects of miR-320a on osteogenic differentiation. CONCLUSION: These results suggest that miR-320a acts as a critical regulator of osteogenic differentiation of hMSCs by repressing its target HOXA10. PMID- 26741130 TI - Smallpox and Dracunculiasis: The Scientific Value of Infectious Diseases That Have Been Eradicated or Targeted for Eradication. Is Schistosomiasis Next? PMID- 26741131 TI - Model-Based Analysis of Cell Cycle Responses to Dynamically Changing Environments. AB - Cell cycle progression is carefully coordinated with a cell's intra- and extracellular environment. While some pathways have been identified that communicate information from the environment to the cell cycle, a systematic understanding of how this information is dynamically processed is lacking. We address this by performing dynamic sensitivity analysis of three mathematical models of the cell cycle in Saccharomyces cerevisiae. We demonstrate that these models make broadly consistent qualitative predictions about cell cycle progression under dynamically changing conditions. For example, it is shown that the models predict anticorrelated changes in cell size and cell cycle duration under different environments independently of the growth rate. This prediction is validated by comparison to available literature data. Other consistent patterns emerge, such as widespread nonmonotonic changes in cell size down generations in response to parameter changes. We extend our analysis by investigating glucose signalling to the cell cycle, showing that known regulation of Cln3 translation and Cln1,2 transcription by glucose is sufficient to explain the experimentally observed changes in cell cycle dynamics at different glucose concentrations. Together, these results provide a framework for understanding the complex responses the cell cycle is capable of producing in response to dynamic environments. PMID- 26741132 TI - Honey Bee Allatostatins Target Galanin/Somatostatin-Like Receptors and Modulate Learning: A Conserved Function? AB - Sequencing of the honeybee genome revealed many neuropeptides and putative neuropeptide receptors, yet functional characterization of these peptidic systems is scarce. In this study, we focus on allatostatins, which were first identified as inhibitors of juvenile hormone synthesis, but whose role in the adult honey bee (Apis mellifera) brain remains to be determined. We characterize the bee allatostatin system, represented by two families: allatostatin A (Apime-ASTA) and its receptor (Apime-ASTA-R); and C-type allatostatins (Apime-ASTC and Apime ASTCC) and their common receptor (Apime-ASTC-R). Apime-ASTA-R and Apime-ASTC-R are the receptors in bees most closely related to vertebrate galanin and somatostatin receptors, respectively. We examine the functional properties of the two honeybee receptors and show that they are transcriptionally expressed in the adult brain, including in brain centers known to be important for learning and memory processes. Thus we investigated the effects of exogenously applied allatostatins on appetitive olfactory learning in the bee. Our results show that allatostatins modulate learning in this insect, and provide important insights into the evolution of somatostatin/allatostatin signaling. PMID- 26741134 TI - DNA Barcode Analysis of Thrips (Thysanoptera) Diversity in Pakistan Reveals Cryptic Species Complexes. AB - Although thrips are globally important crop pests and vectors of viral disease, species identifications are difficult because of their small size and inconspicuous morphological differences. Sequence variation in the mitochondrial COI-5' (DNA barcode) region has proven effective for the identification of species in many groups of insect pests. We analyzed barcode sequence variation among 471 thrips from various plant hosts in north-central Pakistan. The Barcode Index Number (BIN) system assigned these sequences to 55 BINs, while the Automatic Barcode Gap Discovery detected 56 partitions, a count that coincided with the number of monophyletic lineages recognized by Neighbor-Joining analysis and Bayesian inference. Congeneric species showed an average of 19% sequence divergence (range = 5.6% - 27%) at COI, while intraspecific distances averaged 0.6% (range = 0.0% - 7.6%). BIN analysis suggested that all intraspecific divergence >3.0% actually involved a species complex. In fact, sequences for three major pest species (Haplothrips reuteri, Thrips palmi, Thrips tabaci), and one predatory thrips (Aeolothrips intermedius) showed deep intraspecific divergences, providing evidence that each is a cryptic species complex. The study compiles the first barcode reference library for the thrips of Pakistan, and examines global haplotype diversity in four important pest thrips. PMID- 26741133 TI - Gene Polymorphism of Toll-Like Receptors and Lung Function at Five to Seven Years of Age after Infant Bronchiolitis. AB - AIM: Toll-like receptors (TLR) play a crucial role in innate immunity, protecting the host from pathogens such as viruses. Genetic variations in TLRs have been associated with the severity of viral bronchiolitis in infancy and with the later occurrence of post-bronchiolitis asthma. The aim of the present study was to evaluate if there are any exploratory associations between TLR gene polymorphisms and lung function at 5 to 7 years of age in former bronchiolitis patients. METHODS: We performed impulse oscillometry (IOS) at the median age of 6.3 years for 103 children who had been hospitalized for bronchiolitis at less than six months of age. The main parameters evaluated were airway resistance and reactance at 5Hz in baseline and post-exercise measurements. Data on single nucleotide polymorphisms (SNP) of TLR1 rs5743618, TLR2 rs5743708, TLR6 rs5743810 and TLR10 rs4129009 (TLR2 subfamily) and TLR3 rs3775291, TLR4 rs4986790, TLR7 rs179008, TLR8 rs2407992 and TLR 9 rs187084 were available for analyses. RESULTS: The TLR4 rs4986790 wild genotype A/A was associated with a greater Rrs5 response (0.72 vs. -0.42, p = 0.03) to exercise. In TLR6 rs5743810, the minor allele T was associated with greater Rrs5 response (0.80 vs. -0.03, p = 0.04) to exercise. In TLR7 rs179008, the major allele A was associated with baseline decline in dRrs/df (-1.03 vs 0.61, p = 0.01) and increased Fres (2.28 vs. 0.89, p = 0.01) in girls. CONCLUSION: Among the nine studied TLRs, only TLR7 rs179008 showed some exploratory associations with post-bronchiolitis lung function deficiency, and polymorphisms of TLR4 rs4986790, and TLR6 rs5743810 in particular, with airway reactivity. These findings call for further confirmatory studies. PMID- 26741135 TI - Global Consensus Recommendations on Prevention and Management of Nutritional Rickets. AB - BACKGROUND: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. EVIDENCE: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence. PROCESS: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. RESULTS: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. CONCLUSION: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required. PMID- 26741136 TI - Spinal Motion and Muscle Activity during Active Trunk Movements - Comparing Sheep and Humans Adopting Upright and Quadrupedal Postures. AB - Sheep are used as models for the human spine, yet comparative in vivo data necessary for validation is limited. The purpose of this study was therefore to compare spinal motion and trunk muscle activity during active trunk movements in sheep and humans. Three-dimensional kinematic data as well as surface electromyography (sEMG) of spinal flexion and extension was compared in twenty four humans in upright (UR) and 4-point kneeling (KN) postures and in 17 Austrian mountain sheep. Kinematic markers were attached over the sacrum, posterior iliac spines, and spinous and transverse processes of T5, T8, T11, L2 and L5 in humans and over the sacrum, tuber sacrale, T5, T8, T12, L3 and L7 in sheep. The activity of erector spinae (ES), rectus abdominis (RA), obliquus externus (OE), and obliquus internus (OI) were collected. Maximum sEMG (MOE) was identified for each muscle and trial, and reported as a percentage (MOE%) of the overall maximally observed sEMG from all trials. Spinal range of motion was significantly smaller in sheep compared to humans (UR / KN) during flexion (sheep: 6-11 degrees ; humans 12-34 degrees ) and extension (sheep: 4 degrees ; humans: 11-17 degrees ). During extension, MOE% of ES was greater in sheep (median: 77.37%) than UR humans (24.89%), and MOE% of OE and OI was greater in sheep (OE 76.20%; OI 67.31%) than KN humans (OE 21.45%; OI 19.34%), while MOE% of RA was lower in sheep (21.71%) than UR humans (82.69%). During flexion, MOE% of RA was greater in sheep (83.09%) than humans (KN 47.42%; UR 41.38%), and MOE% of ES in sheep (45.73%) was greater than KN humans (14.45%), but smaller than UR humans (72.36%). The differences in human and sheep spinal motion and muscle activity suggest that caution is warranted when ovine data are used to infer human spine biomechanics. PMID- 26741137 TI - Mechanistic Modeling of Dose and Dose Rate Dependences of Radiation-Induced DNA Double Strand Break Rejoining Kinetics in Saccharomyces cerevisiae. AB - Mechanistic modeling of DNA double strand break (DSB) rejoining is important for quantifying and medically exploiting radiation-induced cytotoxicity (e.g. in cancer radiotherapy). Most radiation-induced DSBs are quickly-rejoinable and are rejoined within the first 1-2 hours after irradiation. Others are slowly rejoinable (persist for several hours), and yet others are essentially unrejoinable (persist for >24 hours). The dependences of DSB rejoining kinetics on radiation dose and dose rate remain incompletely understood. We hypothesize that the fraction of slowly-rejoinable and/or unrejoinable DSBs increases with increasing dose/dose rate. This radiation-dependent (RD) model was implemented using differential equations for three DSB classes: quickly-rejoinable, slowly rejoinable and unrejoinable. Radiation converts quickly-rejoinable to slowly rejoinable, and slowly-rejoinable to unrejoinable DSBs. We used large published data sets on DSB rejoining in yeast exposed to sparsely-ionizing (electrons and gamma-rays, single or split-doses, high or low dose rates) and densely-ionizing (alpha-particles) radiation to compare the performances of the proposed RD formalism and the established two-lesion kinetic (TLK) model. These yeast DSB rejoining data were measured within the radiation dose range relevant for clonogenic cell survival, whereas in mammalian cells DSB rejoining is usually measured only at supra-lethal doses for technical reasons. The RD model described both sparsely-ionizing and densely-ionizing radiation data much better than the TLK model: by 217 and 14 sample-size-adjusted Akaike information criterion units, respectively. This occurred because: the RD (but not the TLK) model reproduced the observed upwardly-curving dose responses for slowly-rejoinable/unrejoinable DSBs at long times after irradiation; the RD model adequately described DSB yields at both high and low dose rates using one parameter set, whereas the TLK model overestimated low dose rate data. These results support the hypothesis that DSB rejoining is progressively impeded at increasing radiation doses/dose rates. PMID- 26741138 TI - Discovery and Characterization of a Thermostable and Highly Halotolerant GH5 Cellulase from an Icelandic Hot Spring Isolate. AB - With the ultimate goal of identifying robust cellulases for industrial biocatalytic conversions, we have isolated and characterized a new thermostable and very halotolerant GH5 cellulase. This new enzyme, termed CelDZ1, was identified by bioinformatic analysis from the genome of a polysaccharide enrichment culture isolate, initiated from material collected from an Icelandic hot spring. Biochemical characterization of CelDZ1 revealed that it is a glycoside hydrolase with optimal activity at 70 degrees C and pH 5.0 that exhibits good thermostability, high halotolerance at near-saturating salt concentrations, and resistance towards metal ions and other denaturing agents. X ray crystallography of the new enzyme showed that CelDZ1 is the first reported cellulase structure that lacks the defined sugar-binding 2 subsite and revealed structural features which provide potential explanations of its biochemical characteristics. PMID- 26741139 TI - Comparative MD Simulations Indicate a Dual Role for Arg1323.50 in Dopamine Dependent D2R Activation. AB - Residue Arg3.50 belongs to the highly conserved DRY-motif of class A GPCRs, which is located at the bottom of TM3. On the one hand, Arg3.50 has been reported to help stabilize the inactive state of GPCRs, but on the other hand has also been shown to be crucial for stabilizing active receptor conformations and mediating receptor-G protein coupling. The combined results of these studies suggest that the exact function of Arg3.50 is likely to be receptor-dependent and must be characterized independently for every GPCR. Consequently, we now present comparative molecular-dynamics simulations that use our recently described inactive-state and Galpha-bound active-state homology models of the dopamine D2 receptor (D2R), which are either bound to dopamine or ligand-free, performed to identify the function of Arg1323.50 in D2R. Our results are consistent with a dynamic model of D2R activation in which Arg1323.50 adopts a dual role, both by stabilizing the inactive-state receptor conformation and enhancing dopamine dependent D2R-G protein coupling. PMID- 26741141 TI - Erratum. PMID- 26741140 TI - Telomere Length as a Prognostic Factor for Overall Survival in Colorectal Cancer Patients. AB - BACKGROUND/AIMS: The stabilization of telomere length has important roles in the carcinogenesis of colorectal cancer. A systemic review and meta-analysis of published studies was performed to assess the prognostic role of telomere length in colorectal cancer. METHODS: Pubmed and Embase were searched for eligible studies on the association between telomere length and overall survival in colorectal cancer patients. The pooled hazard ratio (HR) and corresponding 95% confidence intervals (95%CI) was calculated using fixed-effects or random-effects model according to the magnitude of between-study heterogeneity. RESULTS: Seven individual studies with a total of 956 colorectal cancer patients were included. Long telomere length in cancer tissues was marginally associated with poorer overall survival (Random-effects HR = 1.85, 95% 0.90 to 3.83, P = 0.09). When using studies with adjusted estimates, long telomere length in cancer tissues was independently and significantly associated with poorer overall survival (Fixed effects HR = 2.70, 95% 1.51 to 4.84, P = 0.001). However, short telomere length in peripheral blood leukocytes was independently and significantly associated with poorer overall survival (Fixed-effects HR = 2.01, 95% 1.46 to 2.77, P < 0.001). CONCLUSIONS: There is some evidence for telomere length as a prognostic factor for overall survival in colorectal cancer patients. More studies with large number of participants are needed to further assess the prognostic significance of telomere length in colorectal cancer patients. PMID- 26741143 TI - Willingness to Act upon Beliefs about 'Treatment as Prevention' among Australian Gay and Bisexual Men. AB - HIV 'treatment as prevention' (TasP) is highly effective in reducing HIV transmission in serodiscordant couples. There has been little examination of gay and bisexual men's attitudes towards TasP, particularly regarding men's willingness to act on beliefs about TasP. We conducted an online cross-sectional survey of Australian men in late 2012 to investigate knowledge and beliefs about new developments in HIV prevention. Amongst 839 men (mean age 39.5 years), men tended to disagree that TasP was sufficiently effective to justify reduced condom use, although HIV-positive men had more favourable attitudes. Only a minority of men were aware of any evidence for TasP; and one-quarter incorrectly believed that evidence for the effectiveness of TasP already existed for the homosexual population. One-fifth (20.5%) of men reported that they would be willing to have condomless anal intercourse with an opposite-status sexual partner when the HIV positive partner was taking HIV treatments. Factors independently associated with such willingness were: HIV-positive serostatus, reporting any serodiscordant or serononconcordant condomless anal intercourse with a regular male partner in the previous six months, reporting any condomless anal intercourse with a casual male partner in the previous six months, and having greater beliefs in the effectiveness of TasP. This indicated that the men most willing to rely on TasP to prevent transmission were already engaging in higher risk practices. Biomedical HIV prevention represents a rapidly changing environment with new research as well as community and policy responses emerging at a fast pace. For men with serodiscordant sexual partners to successfully apply TasP to reducing transmission risk, more support and education is needed to enable better utilisation of TasP in specific relational and sexual contexts. PMID- 26741142 TI - Sodium-Glucose Linked Cotransporter-2 Inhibition Does Not Attenuate Disease Progression in the Rat Remnant Kidney Model of Chronic Kidney Disease. AB - Pharmacological inhibition of the proximal tubular sodium-glucose linked cotransporter-2 (SGLT2) leads to glycosuria in both diabetic and non-diabetic settings. As a consequence of their ability to modulate tubuloglomerular feedback, SGLT2 inhibitors, like agents that block the renin-angiotensin system, reduce intraglomerular pressure and single nephron GFR, potentially affording renoprotection. To examine this further we administered the SGLT2 inhibitor, dapagliflozin, to 5/6 (subtotally) nephrectomised rats, a model of progressive chronic kidney disease (CKD) that like CKD in humans is characterised by single nephron hyperfiltration and intraglomerular hypertension and where angiotensin converting enzyme inhibitors and angiotensin receptor blockers are demonstrably beneficial. When compared with untreated rats, both sham surgery and 5/6 nephrectomised rats that had received dapagliflozin experienced substantial glycosuria. Nephrectomised rats developed hypertension, heavy proteinuria and declining GFR that was unaffected by the administration of dapagliflozin. Similarly, SGLT2 inhibition did not attenuate the extent of glomerulosclerosis, tubulointerstitial fibrosis or overexpression of the profibrotic cytokine, transforming growth factor-beta1 mRNA in the kidneys of 5/6 nephrectomised rats. While not precluding beneficial effects in the diabetic setting, these findings indicate that SGLT2 inhibition does not have renoprotective effects in this classical model of progressive non-diabetic CKD. PMID- 26741145 TI - Extremely Stable Polypyrrole Achieved via Molecular Ordering for Highly Flexible Supercapacitors. AB - The cycling stability of flexible supercapacitors with conducting polymers as electrodes is limited by the structural breakdown arising from repetitive counterion flow during charging/discharging. Supercapacitors made of facilely electropolymerized polypyrrole (e-PPy) have ultrahigh capacitance retentions of more than 97, 91, and 86% after 15000, 50000, and 100000 charging/discharging cycles, respectively, and can sustain more than 230000 charging/discharging cycles with still approximately half of the initial capacitance retained. To the best of our knowledge, such excellent long-term cycling stability was never reported. The fully controllable electropolymerization shows superiority in molecular ordering, favoring uniform stress distribution and charge transfer. Being left at ambient conditions for even 8 months, e-PPy supercapacitors completely retain the good electrochemical performance. The extremely stable supercapacitors with excellent flexibility and scalability hold considerable promise for the commerical application of flexible and wearable electronics. PMID- 26741144 TI - Modeling analysis of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ mobilization under the control of glucagon-like peptide-1 in mouse pancreatic beta-cells. AB - Glucagon-like peptide-1 (GLP-1) is an intestinally derived blood glucose-lowering hormone that potentiates glucose-stimulated insulin secretion from pancreatic beta-cells. The secretagogue action of GLP-1 is explained, at least in part, by its ability to stimulate cAMP production so that cAMP may facilitate the release of Ca(2+) from inositol trisphosphate receptor (IP3R)-regulated Ca(2+) stores. However, a quantitative model has yet to be provided that explains the molecular mechanisms and dynamic processes linking GLP-1-stimulated cAMP production to Ca(2+) mobilization. Here, we performed simulation studies to investigate how GLP 1 alters the abilities of Ca(2+) and IP3 to act as coagonists at IP3R Ca(2+) release channels. A new dynamic model was constructed based on the Kaftan model, which demonstrates dual steady-state allosteric regulation of the IP3R by Ca(2+) and IP3. Data obtained from beta-cells were then analyzed to understand how GLP-1 facilitates IP3R-mediated Ca(2+) mobilization when UV flash photolysis is used to uncage Ca(2+) and IP3 intracellularly. When the dynamic model for IP3R activation was incorporated into a minimal cell model, the Ca(2+) transients and oscillations induced by GLP-1 were successfully reconstructed. Simulation studies indicated that transient and oscillatory responses to GLP-1 were produced by sequential positive and negative feedback regulation due to fast activation and slow inhibition of the IP3R by Ca(2+). The slow rate of Ca(2+)-dependent inhibition was revealed to provide a remarkable contribution to the time course of the decay of cytosolic Ca(2+) transients. It also served to drive and pace Ca(2+) oscillations that are significant when evaluating how GLP-1 stimulates insulin secretion. PMID- 26741146 TI - Medicinal Chemistry, Pharmacology, and Potential Therapeutic Benefits of Cannabinoid CB2 Receptor Agonists. PMID- 26741147 TI - Engineering Chimeric Receptors To Investigate the Size- and Rigidity-Dependent Interaction of PEGylated Nanoparticles with Cells. AB - Attachment of ligands to the surface of nanoparticles (NPs) is an attractive approach to target specific cells and increase intracellular delivery of nanocargos. To expedite investigation of targeted NPs, we engineered human cancer cells to express chimeric receptors that bind polyethylene glycol (PEG) and internalize stealth NPs in a fashion similar to ligand-targeted liposomes against epidermal growth factor receptor 1 or 2 (HER1 or HER2), which are validated targets for cancer therapy. Measurement of the rate of endocytosis and lysosomal accumulation of small (80-94 nm) or large (180-220 nm) flexible liposomes or more rigid lipid-coated mesoporous silica particles in human HT29 colon cancer and SKBR3 breast cancer cells that express chimeric receptors revealed that larger and more rigid NPs were internalized more slowly than smaller and more flexible NPs. An exception is when both the small and large liposomes underwent endocytosis via HER2. HER1 mediated faster and greater uptake of NPs into cells but retained NPs less well as compared to HER2. Lysosomal accumulation of NPs internalized via HER1 was unaffected by NP rigidity but was inversely related to NP size, whereas large rigid NPs internalized by HER2 displayed increased lysosomal accumulation. Our results provide insight into the effects of NP properties on receptor-mediated endocytosis and suggest that anti-PEG chimeric receptors may help accelerate investigation of targeted stealth NPs. PMID- 26741148 TI - Sequence-Selective Synthesis of Rotacatenane Isomers. AB - Rotacatenane is an interlocked compound composed of two mechanically interlocked macrocyclic components, i.e., a [2]catenane, and one axle component. In this paper we describe the selective synthesis of isomeric rotacatenanes. Two [2]rotaxanes with different phenanthroline moieties were synthesized by the oxidative coupling of an alkyne with a bulky blocking group, which proceeded in the cavity of the macrocyclic phenanthroline-Cu complex. The metal template method was used to install another cyclic component: the tetrahedral Cu(I) complex, which was composed of a [2]rotaxane and an acyclic phenanthroline derivative, was synthesized, and the cyclization of the phenanthroline derivative gave the rotacatenane. The sequential isomers of rotacatenanes were distinguished by (1)H and (13)C NMR spectroscopy. PMID- 26741150 TI - Structures and Properties of the Products of the Reaction of Lanthanide Atoms with H2O: Dominance of the +II Oxidation State. AB - The reactions of lanthanides with H2O have been studied using density functional theory with the B3LYP functional. H2O forms an initial Lewis acid-base complex with the lanthanides exothermically with interaction energies from -2 to -20 kcal/mol. For most of the Ln, formation of HLnOH is more exothermic than formation of H2LnO, HLnO + H, and LnOH + H. The reactions to produce HLnOH are exothermic from -25 to -75 kcal/mol. The formation of LnO + H2 for La and Ce is slightly more exothermic than formation of HLnOH and is less or equally exothermic for the rest of the lanthanides. The Ln in HLnOH and LnOH are in the formal +II and +I oxidation states, respectively. The Ln in H2LnO is mostly in the +III formal oxidation state with either Ln-O(-)/Ln-H(-) or Ln-(H2)(-)/Ln=O(2 ) bonding interactions. A few of the H2LnO have the Ln in the +IV or mixed +III/+IV formal oxidation states with Ln=O(2-)/Ln-H(-) bonding interactions. The Ln in HLnO are generally in the +III oxidation state with the exception of Yb in the +II state. The orbital populations calculated within the natural bond orbital (NBO) analysis are consistent with the oxidation states and reaction energies. The more exothermic reactions to produce HLnOH are always associated with more backbonding from the O(H) and H characterized by more population in the 6s and 5d in Ln and the formation of a stronger Ln-O(H) bond. Overall, the calculations are consistent with the experiments in terms of reaction energies and vibrational frequencies. PMID- 26741149 TI - Two-Dimensional SiS Layers with Promising Electronic and Optoelectronic Properties: Theoretical Prediction. AB - Two-dimensional (2D) semiconductors can be very useful for novel electronic and optoelectronic applications because of their good material properties. However, all current 2D materials have shortcomings that limit their performance. As a result, new 2D materials are highly desirable. Using atomic transmutation and differential evolution global optimization methods, we identified two group IV-VI 2D materials, Pma2-SiS and silicene sulfide. Pma2-SiS is found to be both chemically, energetically, and thermally stable. Most importantly, Pma2-SiS has shown good electronic and optoelectronic properties, including direct bandgaps suitable for solar cells, good mobility for nanoelectronics, good flexibility of property tuning by layer control and applied strain, and good air stability as well. Therefore, Pma2-SiS is expected to be a promising 2D material in the field of 2D electronics and optoelectronics. The designing principles demonstrated in identifying these two tantalizing examples have great potential to accelerate the finding of new functional 2D materials. PMID- 26741151 TI - Small-Molecule-Triggered and Light-Controlled Reversible Regulation of Enzymatic Activity. AB - The fine control of enzyme activity is essential for the regulation of many important cellular and organismal functions. The light-regulation of proteins serves as an important method for the spatiotemporal control over the production and degradation of an enzyme product. This area is of intense interest for researchers. To the best of our knowledge, the use of small molecules as light triggered molecular switches to reversibly control enzyme activity at the protein level has not yet been studied. In the present study, we demonstrate the light controlled reversible regulation of the enzyme using a small-molecule-triggered switch, which is based on molecular recognition between an azobenzene derivative and telomere DNA. This molecule interconverts between the trans and cis states under alternate 365 nm UV and visible light irradiation, which consequently triggers the compaction and extension of telomere DNA. We further provide direct evidence for this structural switch using a circular dichroism study. Furthermore, our strategy has been successfully used to effectively control blood clotting in human plasma. PMID- 26741152 TI - [Nine-valent HPV vaccine - new generation of HPV vaccine]. AB - OBJECTIVE: To evaluate current knowledge about new generation of HPV vaccine - nine-valent vaccine Gardasil9. DESIGN: Review article. RESULTS: The nine-valent vaccine against HPV 6/11/16/18/31/33/45/52/58 could improve efficacy of quadrivalent vaccine from 70 to 90 percent for cervical cancer. In addition this vaccine has covered around85-90% of HPV-related vulvar, vaginal and anal cancers. Efficacy and immunogenicity against HPV 6/11/16/18 is the same as for quadrivalent vaccine. Efficacy against HPV 31/33/45/52/58 associated lesions is 97%. PMID- 26741153 TI - [Spontaneous antepartal RhD alloimmunization]. AB - AIM OF THE STUDY: Assess the incidence of spontaneous antepartal RhD alloimmunization in RhD negative pregnant women with an RhD positive fetus. DESIGN: Clinical study. SETTING: Department of Obstetrics and Gynecology, Medical School and University Hospital Olomouc. METHODS: A total of 906 RhD negative women with an RhD positive fetus and without the presence of anti-Dalloantibodies at the beginning of pregnancy were examined. Always it was a singleton pregnancy, RhD blood group of the pregnant women was assessed in the 1st trimester of pregnancy, RhD status of the fetus was determined after delivery. Screening for irregular antierythrocyte antibodies was performed in all women in the 1st trimester of pregnancy, at 28-32 weeks gestation and immediately prior to delivery at 38-42 weeks gestation. Screening for irregular antierythrocyte antibodies was performed also at 6 months following delivery in all cases of positive antibodies before delivery. Antibody screening was performed using the indirect antiglobulin (LISS/NAT) and enzyme (papain) test with their subsequent identification using a panel of reference erythrocytes by column agglutination method Dia-Med. After delivery, the volume of fetomaternal hemorrhage was assesed in all RhD negative women and RhD alloimmunization prophylaxis was performed by administering the necessary IgG anti-D dose; none of the women were administered IgG anti-D antepartally. RESULTS: During screening for irregular antierythrocyte antibodies at 28-32 weeks gestation, anti-D alloantibodies were diagnosed in 0.2% of the women (2/906); immediately prior to the delivery at 38-42 weeks gestation, anti-D alloantibodies were diagnosed in 2.3% of the women (21/906) and repeatedly even at 6 months following delivery (21/157). In 82.7% of the women (749/906), examination at 6 months following delivery was not performed, therefore in these women spontaneous antepartal RhD alloimmunization cannot reliably be ruled out. Alloimmunization may not be diagnosed yet at term of delivery. If anti-D alloantibodies were not present prior to the delivery, these women were all administered IgG anti-D in a dose of at least 125 MUg after delivery. CONCLUSION: In RhD negative women with an RhD positive fetus, the incidence of spontaneous antepartal RhD alloimmunization was at least 2.3%. Most cases may theoretically be prevented by prophylactic administration of 250 MUg of IgG anti-D to all RhD negative women at 28 weeks gestation. PMID- 26741154 TI - [Prognostic significance of Pgp, MRP1, and MRP3 in ovarian cancer patients]. AB - OBJECTIVE: To evaluate the correlation of resistance proteins Pgp (P glycoprotein), MRP1 (Multidrug Related Protein, Multidrug Resistance-Associated Protein) and MRP3 with clinical - pathological factors and to find the clinical outcome of these data in ovarian cancer patients. DESIGN: Prospective study. SETTING: Department of Gynecology and Obstetrics, Charles University in Prague, Faculty of Medicine in Hradec Kralove, University Hospital Hradec Kralove. METHODS: 133 patients with epithelial ovarian cancer who underwent primary surgery from 2006-2010 had specimens stained with imunohistochemistry for Pgp, MRP1, MRP3. RESULTS: The histological subtype of epithelial ovarian cancer correlated with the expression of PgP, MRP1, and MRP3. The lowest incidence of Pgp and MRP1 expression was documented in endometrioid ovarian cancers (P = 0.151, P = 0.013). Patients with advanced ovarian cancer (FIGO III+IV) had higher MRP1 expression than those with early stage ovarian cancer (Med MRP1 FIGO I+II 80%; CI: 60-100; FIGO III+IV 100%; CI: 90-100; P = 0.100). An association was observed between MRP1 and tumor grade (Med MRP1 G1 80% (CI: 0-100), G2 80% (CI: 30-100), G3 100% (CI: 90-100); P < 0.001). There was no relationship between the size of the residual tumor after primary surgery and any resistance proteins. Patients with complete response after primary treatment had lower levels of LRP, Pgp, and MRP1 expression than other patients. Patients with higher Pgp and MRP1 expression had relapse of disease during the following 24 months more often than patients with lower Pgp and MRP1 expression. FIGO stage, histological type, debulking efficiency, and Pgp and MRP1 expression correlated with poor patient survival (P < 0.001, P < 0.001, P < 0.001, P = 0.040, P = 0.026). CONCLUSION: We found prognostic significance of Pgp, MRP1 and MRP3 expression in ovarian cancer patients. MRP1 have some additional prognostic value for the clinical outcome of patients with ovarian carcinoma. PMID- 26741155 TI - [Cytological-energetic principle of the amniotic fluid examination on female patients with diagnosis of preterm premature rupture of membranes - up to now experiences and perspectives]. AB - In our study we have dealt with the amniotic fluid examination on female patients with diagnosis of preterm premature rupture of membranes (PPROM). For one of the most important task in the feto-maternal medicine we consider the discovered method of amniotic fluid examination which is capable of the earliest possible detection in an intraamniotic inflammatory response. Unnoticed could harm or in the most serious cases threat the life of fetus or its mother. This was also the main reason why we chose this topic for our study. We have not been interested only in already known interleu-kin-6 (IL-6), but we have approached the examination comprehensively. We used the cytological-energetic principle supplemented by the examination of aspartate-amino-transferase (AST), in which already are long-term experiences in investigating other extracellular fluids. We have monitored values of C-reactive protein (CRP) and leucocytes in maternal serum, IL-6, AST and energetic score ratio (KEB) in amniotic fluid. Further we have investigated which imunocompetent cells have been dominant in amniotic fluid at different types of inflamantory reaction. According to the results of the examination of the control groups, it was necessary to correct the KEB limit in comparison to KEB limits of other extracellular fluids. Although our study includes untill now only 44 patients - 21 controls and 23 investigated persons, we have been already able to find out some trends of changes in observed parametres. As a very impotant discovery we consider the fact, that KEB, AST and cytological examination of amniotic fluid seem to be the methods for prediction of chorioamnionitis as reliable as the examination of IL-6. These methods are besides less expensive and therefore more suitable for the use in the small hospitals and developing countries. We continue in our study to confirm the previously found trends on the larger numbers of patients. PMID- 26741156 TI - [Thrombophilia in pregnacy]. AB - OBJECTIVE: Bring a comprehensive overview of the available knowledge about thrombophilia in pregnat women. DESIGN: Overview study. SETTING: Departmentof Haematology and Transfusion Medicine, National Centre for Haemostasis and Thrombosis, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia. METHODS: Analysis of literary sources. CONCLUSION: Anticoagulation may provide benefit for women both as prophylaxis and as treatment for venous thrombosis during pregnancy. The use of anticoagulants in women with inherited thrombophilia and history of miscarriage remains controversial. In contrast, pregnant women with acquired thrombophilia should be anticoagulated. PMID- 26741157 TI - [Satisfaction with perinatal care in Vysocina region in the period between October 2013 and September 2014]. AB - OBJECTIVE: To assess women's satisfaction with perinatal care provided in maternity hospitals in Vysocina region, to identify the areas with high satisfaction scores as well as those requiring improvement, and to describe the factors influencing women's satisfaction, i. e. dissatisfaction with the care provided during labor and birth and the early postpartal period. DESIGN: Original study. SETTING: Department of Psychology, Faculty of Philo-sophy, Charles University, Prague. METHODS: The satisfaction survey was conducted in all maternity hospitals in Vysocina region (Jihlava, Havlickuv Brod, Trebic, Pelhrimov, Nove mesto na Morave) during the period between October 2013 and September 2014. All women who had given birth in those hospitals during the period were approached and asked to participate in this survey. The women evaluated the perinatal care not before 58 days after birth, so that the evaluation of perinatal care did not take place directly during their stay at maternity hospital. In total, 1366 women took part in the study. The original Czech questionnaire KLI-P was used for the data collection. The KLI-P measures psychosocial climate of maternity hospitals on the following six scales: helpfulness and empathy of caregivers; control and involvement in decision making; communication of information and availability of caregivers; dismissive attitude and lack of interest; physical comfort and services. The satisfaction rates with component dimensions of intrapartal and postpartal care at the maternity hospitals in Vysocina region were compared to the satisfaction rates for the Czech Republic as a whole as obtained in our previous study. We used the Kruskal-Wallis test for this comparison. The ordinal logistical regression (cumulative logit model) was used to identify predictors of women's satisfaction with intrapartum and postpartum care in Vysocina region. RESULTS: The women who delivered at maternity hospitals in Vysocina region were significantly more satisfied with all dimensions of care received both at delivery (DU) and after birth unit (ABU) as compared to the average parturient's satisfaction in the Czech Republic as specified in our previous study. The best rated scale at DU in Vysocina region was Physical comfort and services (93% vs. 85% for the whole country; P < 0,0001), while the worst evaluation score received the scale Control and involvement in decision-making (75% vs. 58% for the whole country; P < 0,0001). At ABU, the best rated scale was Control and involvement in decision making (95% vs. 89% for the whole country; P < 0,0001), while the lowest evaluation score was found for the scale Physical comfort and services (85% vs. 76% for the whole Republic; P < 0,0001). The women perceived generally the caregivers as helpful and kind but they often missed sufficient emotional support. They considered the information received easy to understand, but they would welcome more information in general. Among the most important determinants of parturients satisfaction with care at DU were kind and helpful attitude of midwives (P < 0,0001), confidence in physicians (P < 0,0001), sufficient provision of information (P = 0,0016), pleasant appearance of the delivery room (P = 0,0010), kind and helpful attitude of physicians (P = 0,018). Among the most important determinants of satisfaction with care at ABU were sufficient provision of information (P = 0,0007), equipment of the room (P = 0,0014), informations regarding the care for the newborn (P = 0,0013), emotional support (P = 0,0039) and confidence in staff employed in newborn care (P = 0,025). CONCLUSION: Satisfaction with care received at maternity hospitals in Vysocina region was rated very high. However, despite its high quality, the perinatal care in Vysocina region suffers from several shortcomings. Regarding the significance of the individual determinants of parturient's satisfaction, improving the quality of care requires first of all better provision of information both during the labor and postpartal period. It would be beneficial to provide the health care professionals with the opportunities of attending a training in breastfeeding support and communication and of taking part in clinical supervision. PMID- 26741158 TI - [Utilization of self-sampling kits for HPV testing in cervical cancer screening - pilot study]. AB - OBJECTIVE: To get initial experience with alternative sampling (self-sampling) for HPV testing as the means of cervical cancer screening program. DESIGN: Original work. SETTING: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc. METHODS: Based on expression of interest, 215 self-sampling kits were posted to women. Evalyn((r)) Brush Vaginal swabs obtained by self-sampling were analyzed for the presence of HPV infection by Cobas 4800 HPV (Roche) followed by genotyping using PapilloCheck((r)) HPV-Screening (Greiner Bio-One). Sixty women randomly chosen from our sample were sent a questionnaire focused on their experience with self sampling. RESULTS: One hundred seventy-four of 215 (81%) distributed self sampling devices have been delivered to analysis. All cervicovaginal swabs were sampled correctly and it was possible to analyze them by Cobas 4800 HPV test. Similarly, 98% (171/174) samples were analyzable by PapilloCheck((r)) HPV Screening.One hundred twenty-five (72%) of 174 tested samples were HPV negative. Low risk HPV infection was detected only in 7 samples (4%), and high risk HPV (hrHPV) infection was present in 42 samples (24%). The most frequently detected hrHPV genotypes were HPV16 (11/42; 26%) and HPV53 (6/42; 14%). HrHPV co-infection was detected in 10 cases, in 5 of them lrHPV infection was find also.Of the 60 questionnaires, 48 (80%) were returned. From this group, 47 (98%) women rated their experience with self-sampling device as good to excellent. User manual of self-sampling device was considered good to excellent by all women (100%). All women also rated the convenience of self-sampling device using as good to excellent. As expected, most of the women (n = 42 [88%]) preferred self-sampling to physician sampling. CONCLUSION: Cervicovaginal self-sampling leads to valid results of HPV screening using two molecular genetics methods and was accepted by Czech women very well. The self-sampling as an opportunity to participate in cervical cancer screening could increase the attendance of the screening program and would help to reduce the incidence and mortality for this disease in the Czech population. PMID- 26741159 TI - [Hyperthyroidism in pregnancy, less common disorder of the thyroid gland complicating the pregnancy]. AB - The case report focuses on the case of heavy Graves - Basedow thyreotoxicosis in 33 years old secundipara who was transferred to our departement from regional hospital for decompensation of gestational hypertension, oligohydramnios and the suspition on intrauterine growth restriction (IUGR). In our clinical praxis the problems of thyroid gland in terms of its reduced function in pregnant women are getting more frequent. The goal of this article is to describe the less often situation, the hyperthyroidism in the third trimestr of the pregnancy. Thyretoxicosis in pregnancy is associated with higher risk of preterm labour, preeclampsia, IUGR, heart failure and stillbirth. Some of these complications confirmes our case report. PMID- 26741160 TI - [Severe ovarian hyperstimulation syndrome - case study]. AB - OBJECTIVE: To draw attention to the issue and the need of interdisciplinary cooperation in treating severe ovarian hyperstimulation syndrome (OHSS). DESIGN: Case study. SETTING: Department of Obstetrics and Gynecology, Hospital Kolin. CASE REPORT: We report a case of a patient after embryotransfer that is hospitalized with a diagnosis of late severe OHSS. During the treatment when her condition is accompained by voluminous ascites, disseminated intravascular coagulation and elevated liver enzymes, it is necessary to cooperate with doctors of different specialization - anestetist, hematologist, internist. CONCLUSION: Severe OHSS is a rare but serious complication of IVF treatment that due to a high number of IVF cycles is a diagnosis which every gynecologist could be confronted with. Event that numerous methods on how to prevent this condition are known these days, it is necessary not to underestimate it and to treat it thoroughly and in interdisciplinary cooperation. PMID- 26741161 TI - [Medical termination of pregnancy by mifepristone and misoprostol - evaluation of succes rate, complications and satisfaction of patients]. AB - OBJECTIVE: The purpose of this study was to evaluate the success rate and complications of medical termination of pregnancy up to 49 days of amenorrhea and present the outcome of our phone questionaire of satisfaction of patients. DESIGN: Retrospective analysis. SETTING: Department of Obstetrics and Gynecology Masaryk University and University Hospital Brno. METHODS: The analysis of 111 patients, who underwent medical termination of pregnancy at the Department of Obstetrics and Gynecology Masaryk University and University Hospital Brno from 1. 6. 2014 to 30. 6. 2015 using 600 mg of mifepristone (Mifegyne) and 400 ug of misoprostol (Mispregnol). In our set of patients we monitored subjective perception of medical termination of pregnancy (pain, nausea, vomiting, satisfaction with this method) and objective process (hospitalisation, surgical intervention). The view of patients was found out by the phone questionnaire RESULTS: Complete abortion without a surgical intervention underwent 103 patients. Nausea, pelvic pain, and intensity of bleeding were evaluated as suitable. Only 1 patient (0.9%) was hospitalised for nausea and 1 patient (0.9%) was hospitalised in case of need for an emergency curretage and transfusions. Some kind of contraception after the medical termination of pregnancy started using 98.0% of women. The satisfaction rate of this method was high - 101 patients declared themselves satisfied - 66.7% very satisfied, 24.3% rather satisfied. CONCLUSION: Medical termination of pregnancy has good efficiency, we consider it safe with minimum side-effects and is well evaluated by patients. PMID- 26741162 TI - Lipid Nanoparticles Composed of Quaternary Amine-Tertiary Amine Cationic Lipid Combination (QTsome) for Therapeutic Delivery of AntimiR-21 for Lung Cancer. AB - MicroRNA-21 (miR-21) is an oncomiR that is frequently upregulated in human cancers. AntimiR-21 (AM-21) is an oligonucleotide complementary to miR-21 that is designed to inhibit its gene silencing activities. To facilitate efficient delivery of AM-21, a novel lipid nanoparticle formulation called QTsome, based on a combination of quaternary amine and tertiary amine cationic lipids, with a distinctive pH-responsive profile, was developed. QTsome/AM-21 comprising DODMA/DOTAP/DOPC/CHOL/mPEG-DPPE and AM-21 oligonucleotide exhibited a mean particle diameter of below 150 nm, moderate zeta potential (+13.2 mV), excellent colloidal stability, and high drug loading efficiency (above 80%). In vitro study showed QTsome/AM-21 induced upregulation of miR-21 targets, including PTEN and DDAH1, in A549 cells while increasing their sensitivity toward paclitaxel (PTX). Finally, tumor regression, prolonged survival, and miR-21 target upregulation were demonstrated in an A549 xenograft mouse model. These data suggest that QTsome/AM-21 warrants further evaluation as an anticancer agent. PMID- 26741164 TI - Synthesis, Structure, and Magnetic Properties of A2Cu5(TeO3)(SO4)3(OH)4 (A = Na, K): The First Compounds with a 1D Kagome Strip Lattice. AB - Two new tellurite-sulfates A2Cu5(TeO3)(SO4)3(OH)4 (A = Na, K) have been synthesized by a conventional hydrothermal method. Both compounds feature 1D kagome strip structure built by distorted CuO6 octahedra, which can be regarded as the dimensional reduction of kagome lattice. Magnetic measurements confirmed that the titled compounds possess antiferromagnetic ordering at low temperature, while a field-induced magnetic transition can be observed at critical field. To the best of our knowledge, this is the first time to obtain distorted kagome strip compounds. PMID- 26741163 TI - Stable Colloidal Drug Aggregates Catch and Release Active Enzymes. AB - Small molecule aggregates are considered nuisance compounds in drug discovery, but their unusual properties as colloids could be exploited to form stable vehicles to preserve protein activity. We investigated the coaggregation of seven molecules chosen because they had been previously intensely studied as colloidal aggregators, coformulating them with bis-azo dyes. The coformulation reduced colloid sizes to <100 nm and improved uniformity of the particle size distribution. The new colloid formulations are more stable than previous aggregator particles. Specifically, coaggregation of Congo Red with sorafenib, tetraiodophenolphthalein (TIPT), or vemurafenib produced particles that are stable in solutions of high ionic strength and high protein concentrations. Like traditional, single compound colloidal aggregates, the stabilized colloids adsorbed and inhibited enzymes like beta-lactamase, malate dehydrogenase, and trypsin. Unlike traditional aggregates, the coformulated colloid-protein particles could be centrifuged and resuspended multiple times, and from resuspended particles, active trypsin could be released up to 72 h after adsorption. Unexpectedly, the stable colloidal formulations can sequester, stabilize, and isolate enzymes by spin-down, resuspension, and release. PMID- 26741165 TI - Identification of Transient Radical Anions (LiClO4)(n)(-) (n = 1-3) in THF Solutions: Experimental and Theoretical Investigation on Electron Localization in Oligomers. AB - Picosecond pulse radiolysis measurements of tetrahydrofuran (THF) solutions containing LiClO4 over a wide range of concentration are performed to investigate the formation of transient species. The (35)Cl NMR measurements of these solutions prior to irradiation show that the salt is in the form of (LiClO4)n oligomers. Kinetics and transient absorption spectra of intermediates in each solution are obtained on the time scale from 10 to 3800 ps. A global spectro kinetic matrix of the data is analyzed by the multicurve resolution alternated least-squares (MCR-ALS) method. It shows the presence of 3 transient species induced by electron pulse, in addition to the solvated electron. A hybrid Monte Carlo/DFT molecular simulation method is elaborated, using the MPW1K functional for the configuration sampling and B3LYP for the spectra calculations. The maximum of the absorption band of the monomer (LiClO4)(-), dimer (LiClO4)2(-), trimer (LiClO4)3(-), and tetramer (LiClO4)4(-) anions are deduced from the simulations. They enable one to label the MCR-ALS spectra (differences are below 0.1 eV) and to interpret the kinetic data. The simulations show also that Li(I) ion catalyzes the reduction of perchlorate by excess electrons. Only the dimer anion, due to its unique structure with a stable Li2(+) core and two nonbridging perchlorates, presents higher stability toward ClO4(-) reduction into ClO3(-). It corresponds to the long-lived species observed in the experiments. PMID- 26741166 TI - Discovery of (3-(4-(2-Oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidin-1 yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone (AZD1979), a Melanin Concentrating Hormone Receptor 1 (MCHr1) Antagonist with Favorable Physicochemical Properties. AB - A novel series of melanin concentrating hormone receptor 1 (MCHr1) antagonists were the starting point for a drug discovery program that culminated in the discovery of 103 (AZD1979). The lead optimization program was conducted with a focus on reducing lipophilicity and understanding the physicochemical properties governing CNS exposure and undesired off-target pharmacology such as hERG interactions. An integrated approach was taken where the key assay was ex vivo receptor occupancy in mice. The candidate compound 103 displayed appropriate lipophilicity for a CNS indication and showed excellent permeability with no efflux. Preclinical GLP toxicology and safety pharmacology studies were without major findings and 103 was taken into clinical trials. PMID- 26741167 TI - Debromination of PBDEs in Arkansas Water Bodies Analyzed by Positive Matrix Factorization. AB - A previously generated data set for polybrominated diphenyl ethers (PBDEs) in dated sediment cores of West Lake of El Dorado (AED), Calion Lake (ACL), and the lagoon of Magnolia Wastewater Treatment Facility (AMW) from Southern Arkansas is examined by a weighted chemical mass balance (CMB) model and positive matrix factorization (PMF) in order to quantify PBDE sources and debromination. DNA extraction and pyrosequencing were done on several core sections in order to investigate microbial debromination. CMB and PMF analyses indicate that deca technical mixtures are the dominant PBDE input (>99% in mole fraction in AED and ACL, and 94.7% in AMW). Minor contributions of penta and octa technical mixtures were found in all three water bodies (<1% in AED and ACL; and 1.1% and 4.1% in AMW, respectively). Results suggest that debromination takes place in all three lakes, but is more intense in AMW. In-situ microbial debromination was supported by the microorganism analysis. The PMF results are validated by PBDE manufacturing records, and the operating history of AMW. Despite the high PBDE concentrations in these sediments near former manufacturing facilities, the extent of debromination is limited, possibly due to sorption to natural organic matter of the sediment. PMID- 26741170 TI - Immobilization of Active Bacteriophages on Polyhydroxyalkanoate Surfaces. AB - A rapid, efficient technique for the attachment of bacteriophages (phages) onto polyhydroxyalkanoate (PHA) surfaces has been developed and compared to three reported methods for phage immobilization. Polymer surfaces were modified to facilitate phage attachment using (1) plasma treatment alone, (2) plasma treatment followed by activation by 1-ethyl-3-(3 (dimethylamino)propyl)carbodiimide hydrochloride (EDC) and N hydroxysulfosuccinimide (sulfo-NHS), (3) plasma-initiated acrylic acid grafting, or (4) plasma-initiated acrylic acid grafting with activation by EDC and sulfo NHS. The impact of each method on the surface chemistry of PHA was investigated using contact angle analysis and X-ray photoelectron spectroscopy. Each of the four treatments was shown to result in both increased hydrophilicity and in the modification of the surface functional groups. Modified surfaces were immersed in suspensions of phage T4 for immobilization. The highest level of phage binding was observed for the surfaces modified by plasma treatment alone. The change in chemical bond states observed for surfaces that underwent plasma treatment is suspected to be the cause of the increased binding of active phages. Plasma treated surfaces were further analyzed through phage-staining and fluorescence microscopy to assess the surface density of immobilized phages and their capacity to capture hosts. The infective capability of attached phages was confirmed by exposing the phage-immobilized surfaces to the host bacteria Escherichia coli in both plaque and infection dynamic assays. Plasma-treated surfaces with immobilized phages displayed higher infectivity than surfaces treated with other methods; in fact, the equivalent initial multiplicity of infection was 2 orders of magnitude greater than with other methods. Control samples - prepared by immersing polymer surfaces in phage suspensions (without prior plasma treatment) did not show any bacterial growth inhibition, suggesting they did not bind phages from the suspension. PMID- 26741171 TI - Structural Equation Modeling Approaches for Analyzing Partially Nested Data. AB - Study designs involving clustering in some study arms, but not all study arms, are common in clinical treatment-outcome and educational settings. For instance, in a treatment arm, persons may be nested in therapy groups, whereas in a control arm there are no groups. Methodological approaches for handling such partially nested designs have recently been developed in a multilevel modeling framework (MLM-PN) and have proved very useful. We introduce two alternative structural equation modeling (SEM) approaches for analyzing partially nested data: a multivariate single-level SEM (SSEM-PN) and a multiple-arm multilevel SEM (MSEM PN). We show how SSEM-PN and MSEM-PN can produce results equivalent to existing MLM-PNs and can be extended to flexibly accommodate several modeling features that are difficult or impossible to handle in MLM-PNs. For instance, using an SSEM-PN or MSEM-PN, it is possible to specify complex structural models involving cluster-level outcomes, obtain absolute model fit, decompose person-level predictor effects in the treatment arm using latent cluster means, and include traditional factors as predictors/outcomes. Importantly, implementation of such features for partially nested designs differs from that for fully nested designs. An empirical example involving a partially nested depression intervention combines several of these features in an analysis of interest for treatment outcome studies. PMID- 26741169 TI - Access to 3-Acyl-(2H)-indazoles via Rh(III)-Catalyzed C-H Addition and Cyclization of Azobenzenes with alpha-Keto Aldehydes. AB - The rhodium(III)-catalyzed direct C-H functionalization of azobenzenes with ethyl glyoxalate and aryl glyoxals is described. This protocol provides the facile and efficient formation of various C3-acylated-(2H)-indazoles in moderate to high yields. PMID- 26741172 TI - A Computationally Efficient State Space Approach to Estimating Multilevel Regression Models and Multilevel Confirmatory Factor Models. AB - Although the state space approach for estimating multilevel regression models has been well established for decades in the time series literature, it does not receive much attention from educational and psychological researchers. In this article, we (a) introduce the state space approach for estimating multilevel regression models and (b) extend the state space approach for estimating multilevel factor models. A brief outline of the state space formulation is provided and then state space forms for univariate and multivariate multilevel regression models, and a multilevel confirmatory factor model, are illustrated. The utility of the state space approach is demonstrated with either a simulated or real example for each multilevel model. It is concluded that the results from the state space approach are essentially identical to those from specialized multilevel regression modeling and structural equation modeling software. More importantly, the state space approach offers researchers a computationally more efficient alternative to fit multilevel regression models with a large number of Level 1 units within each Level 2 unit or a large number of observations on each subject in a longitudinal study. PMID- 26741173 TI - Aggregating and Testing Intra-Individual Correlations: Methods and Comparisons. AB - From a longitudinal study, we have repeatedly measured data from multiple individuals at multiple occasions. For each individual, the relation between 2 variables can be measured by the Pearson's correlation. The question is how to aggregate the multiple correlations and conduct statistical inference on the aggregated intra-individual correlation. Several methods are proposed to aggregate and test intra-individual correlations: (a) a meta-analysis method based on Fisher's Z transformed correlations, (b) a meta-analysis method based on the Pearson's correlations, and (c) a multilevel modeling method using data standardized within each individual. The performance of the methods after bias corrections was compared using simulations with considering factors including numbers of individuals, numbers of time points, population effect sizes, and their distribution forms (homogeneous vs heterogeneous). The results from the simulation studies show that estimation biases were found using the meta-analytic methods and suggestions on when and how to correct biases were provided based on the simulation results. Furthermore, the performance of the 3 methods after necessary bias corrections was found to be comparable and reasonably good, indicating that all 3 methods worked for aggregating and testing intra-individual correlations. An empirical daily diary data set was then used to illustrate the applications of the 3 methods. The assumptions, advantages and disadvantages, and possible extensions of the 3 methods were discussed. PMID- 26741168 TI - 8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors. AB - We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay. PMID- 26741174 TI - The Consequences of Ignoring Variability in Measurement Occasions Within Data Collection Waves in Latent Growth Models. AB - In longitudinal data collection, it is common that each wave of collection spans several months. However, researchers using latent growth models commonly ignore variability in data collection occasions within a wave. In this study, we investigated the consequences of ignoring within-wave variability in measurement occasions using a Monte Carlo simulation and an empirical study. The results of the simulation study showed that ignoring heterogeneity resulted in biased estimates for some parameters, especially when heterogeneity was large and assessment dates had a skewed distribution. Models constructed on person-specific time points yielded precise estimates and more adequate model fit. In the empirical study, we demonstrated different time coding strategies with a subsample taken from Early Childhood Longitudinal Study Kindergarten Cohort. PMID- 26741175 TI - Measuring Response Styles Across the Big Five: A Multiscale Extension of an Approach Using Multinomial Processing Trees. AB - This study shows how to address the problem of trait-unrelated response styles (RS) in rating scales using multidimensional item response theory. The aim is to test and correct data for RS in order to provide fair assessments of personality. Expanding on an approach presented by Bockenholt (2012), observed rating data are decomposed into multiple response processes based on a multinomial processing tree. The data come from a questionnaire consisting of 50 items of the International Personality Item Pool measuring the Big Five dimensions administered to 2,026 U.S. students with a 5-point rating scale. It is shown that this approach can be used to test if RS exist in the data and that RS can be differentiated from trait-related responses. Although the extreme RS appear to be unidimensional after exclusion of only 1 item, a unidimensional measure for the midpoint RS is obtained only after exclusion of 10 items. Both RS measurements show high cross-scale correlations and item response theory-based (marginal) reliabilities. Cultural differences could be found in giving extreme responses. Moreover, it is shown how to score rating data to correct for RS after being proved to exist in the data. PMID- 26741176 TI - Analytical Problems and Suggestions in the Analysis of Behavioral Economic Demand Curves. AB - Behavioral economic demand curves (Hursh, Raslear, Shurtleff, Bauman, & Simmons, 1988) are innovative approaches to characterize the relationships between consumption of a substance and its price. In this article, we investigate common analytical issues in the use of behavioral economic demand curves, which can cause inconsistent interpretations of demand curves, and then we provide methodological suggestions to address those analytical issues. We first demonstrate that log transformation with different added values for handling zeros changes model parameter estimates dramatically. Second, demand curves are often analyzed using an overparameterized model that results in an inefficient use of the available data and a lack of assessment of the variability among individuals. To address these issues, we apply a nonlinear mixed effects model based on multivariate error structures that has not been used previously to analyze behavioral economic demand curves in the literature. We also propose analytical formulas for the relevant standard errors of derived values such as P max, O max, and elasticity. The proposed model stabilizes the derived values regardless of using different added increments and provides substantially smaller standard errors. We illustrate the data analysis procedure using data from a relative reinforcement efficacy study of simulated marijuana purchasing. PMID- 26741190 TI - Acceptability Study of "Ascenso": An Online Program for Monitoring and Supporting Patients with Depression in Chile. AB - BACKGROUND: Major depression is a highly prevalent and severe mental disease. Despite the effective treatment options available, the risk of relapse is high. Interventions based on information and communication technologies generate innovative opportunities to provide support to patients after they completed treatment for depression. MATERIALS AND METHODS: This acceptability study evaluated the Internet-based program Apoyo, Seguimiento y Cuidado de Enfermedades a partir de Sistemas Operativos (ASCENSO) in terms of its feasibility and acceptability in a sample of 35 patients in Chile. RESULTS: The study reveals high rates of acceptance and satisfaction among patients who actively used the program. As obstacles, patients mentioned technical problems, a lack of contact with other participants, and an insufficient connection between the program and the health service professionals. CONCLUSIONS: ASCENSO appears to be a promising complement to regular care for depression. Following improvements of the program based on participants' feedback, future research should evaluate its efficacy and cost-effectiveness. PMID- 26741191 TI - Teleoperated Echograph and Probe Transducer for Remote Ultrasound Investigation on Isolated Patients (Study of 100 Cases). AB - PURPOSE: The objective of this study was to design and validate a "Tele-Operated UltRasound System" ("TOURS") to perform ultrasound examinations on patients located in isolated areas. MATERIALS AND METHODS: A commercially available portable echograph was modified to allow functions (Doppler, two-dimensional, three-dimensional, elastography, etc.) and settings (gain, depth, freeze, record, etc.) to be teleoperated through an Internet connection. Specialized probes were developed that contained motorized transducers that could be teleoperated to change the transducer orientation. The system was installed and tested in four medical centers 50 km, 60 km, 1,800 km, and 7,000 km away from the university hospital. RESULTS: Using the teleoperated system, 100 examinations were performed on the abdomen and pelvis (36%), vascular structures (42%), and small parts (thyroid and muscle, 22%), and 15 were performed on fetuses. During these examinations the expert sonographer was able to teleoperate the echograph and motorized probe to obtain images of sufficient quality for diagnoses in 97% of the cases. The average time for one examination was 17 +/- 4 min. This new system (dimensions of 400 cm(3) and weighing 430 g) was found to be more ergonomic that a robotic arm previously developed by us for tele-echography (dimensions of 35 * 40 * 40 cm(3) and weighing 3-4 kg). In addition, the teleoperation of the echograph settings and functions allowed for greater ease in acquiring images, resulting in faster examinations with improved quality images. CONCLUSIONS: The results of this study demonstrate that the teleoperated echograph and probe system developed by our research group can be successfully used for ultrasound examinations in areas isolated from trained sonographers. PMID- 26741192 TI - Projecting Critical Care Beyond the ICU: An Analysis of Tele-ICU Support for Rapid Response Teams. AB - BACKGROUND: The rapid response team (RRT) concept was developed to improve care for decompensating patients outside of the intensive care unit (ICU) setting. The tele-ICU service (eICU((r))) at Health First Hospitals (Brevard County, FL) has provided tele-critical care support for patients outside the ICU using a mobile platform (the eMobile platform) since 2012. In this study we sought to evaluate the ability of eMobile to support care administered by RRTs. MATERIALS AND METHODS: A retrospective review evaluating mobile cart activations for RRT calls was performed. Data on mobile cart deployments were recorded over a 33-month period from January 2012 through September 2014. RESULTS: Five hundred eighty mobile cart activations for critical care support were initiated by RRTs, and 577 were completed (>99%). For recorded gender, 223 patients (47%) were male, and 248 (53%) patients were female. Mean recorded age was 70 +/- 16 years (median, 72 years). The most common patient conditions were respiratory distress (n = 190, 33%), altered mental status (n = 137, 24%) and hypotension (n = 59, 10%). The most common interventions were medication orders (n = 231, 40%) and laboratory studies (n = 92, 29%). For 566 eMobile calls with documented dispositions, 189 patients (33%) were managed without ICU upgrade. No adverse patient outcomes were recorded involving eMobile. Compared with the RRT program in 2009, the last year before testing of eMobile began (2010-2011), addition of tele-critical care support for calendar years 2012 and 2013 increased projected cost avoidance from unnecessary ICU transfers by a mean of 66% above the 2009 baseline. For Fiscal Year 2014, a projected cost avoidance analysis for unnecessary ICU transfers including costs of information technology (IT) support demonstrated a return on investment up to $1.66 for every $1 invested in IT support. CONCLUSIONS: Mobile critical care coupled with RRT is clinically effective and can generate meaningful cost avoidance. PMID- 26741177 TI - Matrix Remodeling in Pulmonary Fibrosis and Emphysema. AB - Pulmonary fibrosis and emphysema are chronic lung diseases characterized by a progressive decline in lung function, resulting in significant morbidity and mortality. A hallmark of these diseases is recurrent or persistent alveolar epithelial injury, typically caused by common environmental exposures such as cigarette smoke. We propose that critical determinants of the outcome of the injury-repair processes that result in fibrosis versus emphysema are mesenchymal cell fate and associated extracellular matrix dynamics. In this review, we explore the concept that regulation of mesenchymal cells under the influence of soluble factors, in particular transforming growth factor-beta1, and the extracellular matrix determine the divergent tissue remodeling responses seen in pulmonary fibrosis and emphysema. PMID- 26741193 TI - Regulating Telemedicine: Are State Medical Boards Violating Physicians' Constitutional Rights? PMID- 26741194 TI - Reducing Emergency Department Utilization Through Engagement in Telemedicine by Senior Living Communities. AB - BACKGROUND: High-intensity telemedicine has been shown to reduce the need for emergency department (ED) care for older adult senior living community (SLC) residents with acute illnesses. We evaluated the effect of SLC engagement in the telemedicine program on ED use rates. MATERIALS AND METHODS: We performed a secondary analysis of data from a prospective cohort study evaluating the effectiveness of high-intensity telemedicine for SLC residents. We compared the annual rate of change in ED use among subjects who resided in SLC units that were more engaged in telemedicine services with that among subjects who resided in SLC units that were less engaged in telemedicine and control subjects who lived at facilities without access to telemedicine services. RESULTS: During the study, subjects had 503 telemedicine visits, with 362 (72.0%) in the more engaged SLCs and 141 (28.0%) in the less engaged SLCs. For subjects residing in more engaged SLCs, ED use decreased at an annualized rate of 28% (rate ratio [RR] = 0.72; 95% confidence interval [CI], 0.58-0.89), whereas in the less engaged (RR = 0.962; 95% CI, 0.776-1.19) and control (RR = 0.909, 95% CI, 0.822-1.07) groups there was no significant change in ED use (p = 0.036 for group * time interaction). CONCLUSIONS: Individuals residing in more engaged SLCs experienced a greater decrease in ED use compared with subjects residing in less engaged SLCs or those without access to high-intensity telemedicine for acute illnesses. We identified potential factors associated with more engaged SLCs, but further research is needed to understand resident and staff engagement and how to increase it. PMID- 26741197 TI - A New Era in Cervical Cancer Screening: Balancing the Risks and Benefits of Screening. PMID- 26741195 TI - Maternal Vitamin D Deficiency Programs Reproductive Dysfunction in Female Mice Offspring Through Adverse Effects on the Neuroendocrine Axis. AB - Vitamin D (VitD) deficiency affects more than 1 billion people worldwide with a higher prevalence in reproductive-aged women and children. The physiological effects of maternal VitD deficiency on the reproductive health of the offspring has not been studied. To determine whether maternal VitD deficiency affects reproductive physiology in female offspring, we monitored the reproductive physiology of C57BL/6J female offspring exposed to diet-induced maternal VitD deficiency at three specific developmental stages: 1) in utero, 2) preweaning, or 3) in utero and preweaning. We hypothesized that exposure to maternal VitD deficiency disrupts reproductive function in exposed female offspring. To test this hypothesis, we assessed vaginal opening and cytology and ovary and pituitary function as well as gonadotropin and gonadal steroid levels in female offspring. The in utero, preweaning, and in utero and preweaning VitD deficiency did not affect puberty. However, all female mice exposed to maternal VitD deficiency developed prolonged and irregular estrous cycles characterized by oligoovulation and extended periods of diestrus. Despite similar gonadal steroid levels and GnRH neuron density, females exposed to maternal VitD deficiency released less LH on the evening of proestrus. When compared with control female offspring, there was no significant difference in the ability of females exposed to maternal VitD deficiency to respond robustly to exogenous GnRH peptide or controlled ovarian hyperstimulation. These findings suggest that maternal VitD deficiency programs reproductive dysfunction in adult female offspring through adverse effects on hypothalamic function. PMID- 26741198 TI - Adequacy of Prenatal Care and Gestational Weight Gain. AB - BACKGROUND: The goal of prenatal care is to maximize health outcomes for a woman and her fetus. We examined how prenatal care is associated with meeting the 2009 Institute of Medicine (IOM) guidelines for gestational weight gain. SAMPLE: The study used deidentified birth certificate data supplied by the North Carolina State Center for Health Statistics. The sample included 197,354 women (>=18 years) who delivered singleton full-term infants in 2011 and 2012. METHODS: A generalized multinomial model was used to identify how adequate prenatal care was associated with the odds of gaining excessive or insufficient weight during pregnancy according to the 2009 IOM guidelines. The model adjusted for prepregnancy body size, sociodemographic factors, and birth weight. RESULTS: A total of 197,354 women (>=18 years) delivered singleton full-term infants. The odds ratio (OR) for excessive weight gain was 2.44 (95% CI 2.37-2.50) in overweight and 2.33 (95% CI 2.27-2.40) in obese women compared with normal weight women. The OR for insufficient weight gain was 1.15 (95% CI 1.09-1.22) for underweight and 1.34 (95% CI 1.30-1.39) for obese women compared with normal weight women. Prenatal care at the inadequate or intermediate levels was associated with insufficient weight gain (OR: 1.32, 95% CI 1.27-1.38; OR: 1.15, 95% CI 1.09-1.21, respectively) compared with adequate prenatal care. Women with inadequate care were less likely to gain excessive weight (OR: 0.88, 95% CI 0.86 0.91). CONCLUSIONS: Whereas prenatal care was effective for preventing insufficient weight gain regardless of prepregnancy body size, educational background, and racial/ethnic group, there were no indications that adequate prenatal care was associated with reduced risk for excessive gestational weight gain. Further research is needed to improve prenatal care programs for preventing excess weight gain. PMID- 26741200 TI - Elective Oophorectomy: Primum Non Nocere. PMID- 26741196 TI - Translocator Protein (TSPO) Affects Mitochondrial Fatty Acid Oxidation in Steroidogenic Cells. AB - Translocator protein (TSPO), also known as the peripheral benzodiazepine receptor, is a highly conserved outer mitochondrial membrane protein present in specific subpopulations of cells within different tissues. In recent studies, the presumptive model depicting mammalian TSPO as a critical cholesterol transporter for steroidogenesis has been refuted by studies examining effects of Tspo gene deletion in vivo and in vitro, biochemical testing of TSPO cholesterol transport function, and specificity of TSPO-mediated pharmacological responses. Nevertheless, high TSPO expression in steroid-producing cells seemed to indicate an alternate function for this protein in steroidogenic mitochondria. To seek an explanation, we used CRISPR/Cas9-mediated TSPO knockout steroidogenic MA-10 Leydig cell (MA-10:TspoDelta/Delta) clones to examine changes to core mitochondrial functions resulting from TSPO deficiency. We observed that 1) MA 10:TspoDelta/Delta cells had a shift in substrate utilization for energy production from glucose to fatty acids with significantly higher mitochondrial fatty acid oxidation (FAO), and increased reactive oxygen species production; and 2) oxygen consumption rate, mitochondrial membrane potential, and proton leak were not different between MA-10:TspoDelta/Delta and MA-10:Tspo+/+ control cells. Consistent with this finding, TSPO-deficient adrenal glands from global TSPO knockout (Tspo(-/-)) mice also showed up-regulation of genes involved in FAO compared with the TSPO floxed (Tspo(fl/fl)) controls. These results demonstrate the first experimental evidence that TSPO can affect mitochondrial energy homeostasis through modulation of FAO, a function that appears to be consistent with high levels of TSPO expression observed in cell types active in lipid storage/metabolism. PMID- 26741201 TI - Simulating Multivariate Nonnormal Data Using an Iterative Algorithm. AB - Simulating multivariate nonnormal data with specified correlation matrices is difficult. One especially popular method is Vale and Maurelli's (1983) extension of Fleishman's (1978) polynomial transformation technique to multivariate applications. This requires the specification of distributional moments and the calculation of an intermediate correlation matrix such that when data are transformed, the target correlation matrix is reproduced. We present an alternative technique that involves sampling data from specified population distributions and identifying the intermediate correlation matrix through an iterative, trial-and-error process. We provide R program code to implement this technique and show that it can generate data under a wide range of conditions (e.g., with empirical samples, with discrete rather than continuous data, when distributional moments are undefined or outside the boundary conditions of other techniques). This approach could be useful in many contexts, especially Monte Carlo studies of multivariate statistics. PMID- 26741199 TI - Bladder Symptoms in the Early Menopausal Transition. AB - PURPOSE: Bladder symptoms are common in women and result in use of healthcare resources and poor quality of life. Bladder symptoms have been linked to age and menopause, but debate exists in the literature. This article examines factors associated with bladder symptoms and compares women in late reproductive stage with those in menopausal transition. MATERIALS AND METHODS: We analyzed cross sectional data from a prospective cohort study of midlife women (mean age, 48; range, 44-54 years) in northern California. The sample consisted of 158 women in late reproductive stage or menopause transition. Assessments included anthropometrics, menstrual cycle lengths and symptoms, urine samples for follicle stimulating hormone level, and self-reported health perception and depressive symptoms. Analyses included descriptive bivariate statistics, group comparisons, and regression models. RESULTS: The most common bladder symptoms were nocturia (72%) at least once per night and urinary incontinence (50%) at least once per week. Incontinence was less prevalent in African American women compared to European Americans and Latinas (p = 0.001) and more prevalent in late reproductive stage than in menopause transition (p = 0.024). Controlling for age, women in late reproductive stage were more likely to report nocturia compared to those in menopause transition. Reproductive stage (p = 0.016), higher body mass index (p = 0.007), and race (p = 0.017) contributed to the variance in weekly nighttime urinary frequency. CONCLUSION: Bladder symptoms were associated with reproductive stage. Women in late reproductive stage were more likely to experience nocturia and incontinence than those in menopause transition. The higher rates of nocturia and incontinence in late reproductive stage are intriguing. Future studies should include analysis of pelvic organ prolapse degree and other structural differences. PMID- 26741202 TI - Sample Size Calculation for Estimating or Testing a Nonzero Squared Multiple Correlation Coefficient. AB - The problems of hypothesis testing and interval estimation of the squared multiple correlation coefficient of a multivariate normal distribution are considered. It is shown that available one-sided tests are uniformly most powerful, and the one-sided confidence intervals are uniformly most accurate. An exact method of calculating sample size to carry out one-sided tests (null hypothesis may involve a nonzero value for the multiple correlation coefficient) to attain a specified power is given. Sample size calculation for computing confidence intervals for the squared multiple correlation coefficient with a specified expected width is also provided. Sample sizes for powers and confidence intervals are tabulated for a wide range of parameter configurations and dimensions. The results are illustrated using the empirical data from Timm (1975) that related scores from the Peabody Picture Vocabulary Test to four proficiency measures. PMID- 26741203 TI - Item Selection for the Development of Short Forms of Scales Using an Ant Colony Optimization Algorithm. AB - This article presents the use of an ant colony optimization (ACO) algorithm for the development of short forms of scales. An example 22-item short form is developed for the Diabetes-39 scale, a quality-of-life scale for diabetes patients, using a sample of 265 diabetes patients. A simulation study comparing the performance of the ACO algorithm and traditionally used methods of item selection is also presented. It is shown that the ACO algorithm outperforms the largest factor loadings and maximum test information item selection methods. The results demonstrate the capabilities of using ACO for creating short-form scales. PMID- 26741204 TI - Postmodeling Sensitivity Analysis to Detect the Effect of Missing Data Mechanisms. AB - Incomplete or missing data is a common problem in almost all areas of empirical research. It is well known that simple and ad hoc methods such as complete case analysis or mean imputation can lead to biased and/or inefficient estimates. The method of maximum likelihood works well; however, when the missing data mechanism is not one of missing completely at random (MCAR) or missing at random (MAR), it too can result in incorrect inference. Statistical tests for MCAR have been proposed, but these are restricted to a certain class of problems. The idea of sensitivity analysis as a means to detect the missing data mechanism has been proposed in the statistics literature in conjunction with selection models where conjointly the data and missing data mechanism are modeled. Our approach is different here in that we do not model the missing data mechanism but use the data at hand to examine the sensitivity of a given model to the missing data mechanism. Our methodology is meant to raise a flag for researchers when the assumptions of MCAR (or MAR) do not hold. To our knowledge, no specific proposal for sensitivity analysis has been set forth in the area of structural equation models (SEM). This article gives a specific method for performing postmodeling sensitivity analysis using a statistical test and graphs. A simulation study is performed to assess the methodology in the context of structural equation models. This study shows success of the method, especially when the sample size is 300 or more and the percentage of missing data is 20% or more. The method is also used to study a set of real data measuring physical and social self-concepts in 463 Nigerian adolescents using a factor analysis model. PMID- 26741205 TI - Detecting Outliers in Factor Analysis Using the Forward Search Algorithm. AB - In this article we extend and implement the forward search algorithm for identifying atypical subjects/observations in factor analysis models. The forward search has been mainly developed for detecting aberrant observations in regression models ( Atkinson, 1994 ) and in multivariate methods such as cluster and discriminant analysis ( Atkinson, Riani, & Cerioli, 2004 ). Three data sets and a simulation study are used to illustrate the performance of the forward search algorithm in detecting atypical and influential cases in factor analysis models. The first data set has been discussed in the literature for the detection of outliers and influential cases and refers to the grades of students on 5 exams. The second data set is artificially constructed to include a cluster of contaminated observations. The third data set measures car's characteristics and is used to illustrate the performance of the forward search when the wrong model is specified. Finally, a simulation study is conducted to assess various aspects of the forward search algorithm. PMID- 26741236 TI - Introduction of Bovine-Based Nutrient Fortifier and Gastrointestinal Inflammation in Very Low Birth Weight Infants as Measured by Fecal Calprotectin. AB - BACKGROUND: Fecal calprotectin (fCP) is a biomarker of gastrointestinal tract (GIT) inflammation that is currently being used investigationally among very low birth weight (VLBW) infants. MATERIALS AND METHODS: Stool was collected weekly from 20 breastmilk-fed VLBW infants for up to 8 weeks after birth during the establishment and fortification of feeds, and fCP concentrations were measured. RESULTS: Mean fCP levels increased significantly in stools collected immediately following bovine-based nutrient fortification of feeds (p = 0.005). CONCLUSIONS: Addition of bovine fortifier to breastmilk feeds appeared to be associated with an acute increase in GIT inflammation. PMID- 26741237 TI - Novel method to improve vascularization of tissue engineered constructs with biodegradable fibers. AB - Tissue engineered grafts lack adequate vascularization and suffer from poor perfusion in vivo curtailing clinical application. Improving vascularization in any tissue implants would hence increase their survivability and treatment efficacy. Many prevascularization strategies established to date involves the angiogenic induction of endothelial progenitor cells in thick tissue engineered scaffolds to obtain vascularization. These 3D scaffolds typically require a dynamic cell culturing system involving/needful of bioreactors to obtain vascularization in thick tissue engineered scaffolds. Herein, we developed a novel method to engineer a vessel network without bioreactor, where 3D blood vessels could be simply obtained in a 2D static cell culturing system. This network could be used to augment the prevascularization of tissue engineered grafts. Endothelial cells (HUVECs) were confluently cultured on resorbable electrospun poly (D, L-lactide-co-glycolide) microfibers of capillary dimensions. These cell encapsulated capillary fibers were further embedded in collagen with HUVECs and vascular endothelial growth factor. Green fluorescent protein and red fluorescent protein expressing HUVECs were used to label cells on fiber and in collagen respectively for visualization and monitoring of capillary network formation. Seeded HUVECs in the hybrid construct were subsequently cultured for 30 days before implantation. Vessel density was measured by the total tubule length per unit area at different time points. In vitro results indicated that the fibers provide contact guidance to form primary networks to direct more vessels branching of HUVECs in hybrid constructs and the vessel integrity of microvasculature was retained after fiber degradation. In addition, these preformed engineered capillaries could capably inosculate with de novo capillaries in collagen when combined, giving rise to a hybrid pre-vascularized scaffold of more extensive vessel network and interconnections, thereby markedly improved prevascularization. When implanted onto the dorsal skin of immune deficient mice, vessels of hybrid pre-vascularized scaffold also rapidly anastomosed with mice vasculature within a day as confirmed with the immunostaining of endothelial cell markers CD31 and von Willebrand factor. This proof of concept study showed that artificial capillaries formed through contact guidance of endothelial cells on resorbable capillary sized microfibers can significantly enhance prevascularization in tissue engineered constructs intended for surgical implantation. PMID- 26741238 TI - Prevalence of Excess Sodium Intake in the United States - NHANES, 2009-2012. AB - Hypertension, a major risk factor for cardiovascular diseases, occurs among 29% of U.S. adults, and lowering excess sodium intake can reduce blood pressure (1 3). The 2015-2020 Dietary Guidelines for Americans recommend consuming less than 2,300 mg dietary sodium per day for persons aged >=14 years and less for persons aged 2-13 years.* To examine the current prevalence of excess sodium intake among Americans overall, and among hypertensive adults, CDC analyzed data from 14,728 participants aged >=2 years in the 2009-2012 National Health and Nutrition Examination Survey (NHANES). Eighty-nine percent of adults and over 90% of children exceeded recommendations for sodium intake. Among hypertensive adults, 86% exceeded 2,300 mg dietary sodium per day. To address the high prevalence of excess sodium consumption in the U.S. population, the Institute of Medicine (IOM) recommended reducing sodium in the food supply, as excess sodium added to foods during commercial processing and preparation represents the main source of sodium intake in U.S. diets (4). PMID- 26741239 TI - Experimental infection of Holstein cows and calves with EHDV-7 and preliminary evaluation of different inoculation methods. AB - Infection of cattle with epizootic haemorrhagic disease (EHD) virus (EHDV) is frequently subclinical, yet reports of disease have increased in recent years. In 2006, a widespread EHDV-7 epidemic caused disease and economic loss in the Israeli dairy industry. In this study, the main objective was to infect cattle with EHDV-7 and replicate disease observed in Israel during 2006. Two infection studies were performed. Experiment 1, 4 cows inoculated with intradermal (ID) and subcutaneous (SC) injections with an EHDV-7 blood inoculum. Experiment 2, 6 calves inoculated using 1 of the following 3 methods (2 calves/method): (1) mammalian cell culture supernatant by ID and SC injection; (2) culture supernatant by ID, SC, and intravenous injection; and (3) bite transmission from Culicoides sonorensis. Further, during experiment 2, C. sonorensis were fed on 4 infected calves (18 days post-inoculation) and processed for virus isolation 10 days later in order to evaluate infectivity of low-titer viraemia. Three cows had detectable viraemia and all 4 seroconverted. No clinical signs were observed. All 6 calves developed viraemia, peaking 7-10 dpi and all calves seroconverted. No differences in virus kinetics were observed between the inoculation groups. Calves in group 2 had transiently elevated rectal temperatures but no other clinical abnormalities were observed. The 124 midge pools processed after feeding on calves with low-titer viraemia were virus isolation negative. Detectable viraemia was more consistent in calves than adult cows. This study demonstrates US-origin cattle are susceptible to EHDV-7 infection by multiple inoculation methods; however, as reported in other studies, the disease was not replicated experimentally. PMID- 26741240 TI - Bluetongue: a disease that does not speak 'one tongue' only. PMID- 26741241 TI - Bluetongue and other orbiviruses in South America: gaps and challenges. AB - South America (SA) has the ideal climatic conditions for occurrence of Bluetongue virus (BTV) and other orbiviruses. Based on serological evidence of BTV circulation, the virus is widespread across SA. However, little knowledge has been acquired about BTV origin and distribution, and circulation of specific serotypes is almost non-existent. The first barrier to a better understanding of Bluetongue (BT) in SA concerns its recognition in the field, as most infections of seropositive ruminants are unapparent in endemic areas. There are few reports on BTV isolation in SA, many of them from viraemic asymptomatic animals. Among the known competent BTV vectors, Culicoides insignis is the most abundant species in SA. However, information about biological characteristics and competence of various other Culicoides species described in SA is missing. The few reports on BT outbreaks lead to an underestimation of the disease impact on the continent economy. To overcome these major gaps, it is necessary to: improve diagnostic structure and disease recognition in the field; identify BTV serotypes and their distribution in different SA areas; and to study the biology and epidemiology of Culicoides. Furthermore, it is important to have a surveillance system for BT, as well as contingency plans for possible outbreaks in SA. PMID- 26741242 TI - Forty years continous monitoring for bluetongue virus at an Australian site of high arbovirus activity. What have we achieved? AB - Beatrice Hill Farm (BHF) near Darwin, Australia was identified in the early 1970's as a site of high arbovirus activity. The first isolation of Bluetongue virus (BTV) in Australia was made on BHF in 1975. Since then, there has been continuous monitoring for BTV at BHF, the virus has been isolated on a yearly basis, with the only exception of 1990. All 10 serotypes known in Australia have been isolated at this site and an assessment of their biological behaviour made. Over the years, the methods and intensity of monitoring have been changed. In recent years molecular techniques have permitted more detailed examination of the origins of the viruses and their natural behaviour in field situations. Data collected at BHF have allowed modelling to detect likely origins of the BTVs that regularly enter Australia through wind borne infected Culicoides from South East Asia. Concurrent vector monitoring led to assess the Culicoides species more likely to be involved with transmission of these viruses. PMID- 26741243 TI - Molecular evolution of American field strains of bluetongue and epizootic haemorrhagic disease viruses. AB - Recent Orbivirus occurrences in the Americas have been investigated using whole genome amplification and sequencing followed by phylogenetic analysis. The bluetongue virus (BTV) and epizootic haemorrhagic disease virus (EHDV) whole genomes were amplified without prior sequence knowledge and deep sequenced. This technology was applied to evaluate BTV-3 isolates spanning 4 decades from Florida, Arkansas, Mississippi, South Dakota, Central America, and the Caribbean basin. The results of the dataset analysis are consistent with the hypothesis that these viruses were introduced into the United States from Central America and the Caribbean basin. A similar analysis has been performed on a recent BTV-2 isolate from California. It indicates that the BTV-2 strain was likely introduced into Florida and then moved South to the Caribbean and West to California. A historical (1955-2012) molecular characterisation of EHDV strains was also completed, and subsequently used as reference sequence for comparison of genomes from recent 2012 cattle isolates associated with clinical disease. Finally, this analysis was performed on BTV-11 isolated from 2 canine cases and demonstrated that the genome sequences of the virus isolates from these cases were almost identical. These studies indicate the value of this technology in understanding virus epidemiology and ecology. PMID- 26741244 TI - Cytokine release and endothelial dysfunction: a perfect storm in orbivirus pathogenesis. AB - Although bluetongue viruses (BTV) and epizootic haemorrhagic disease viruses (EHDV) are closely related, there are differences in susceptibility to these viruses both between and within a species. White-tailed deer are susceptible to disease by both BTV and EHDV, sheep are susceptible to BTV, but resistant to EHDV, and cattle can be infected with both viruses but disease is usually subclinical. Host genetics probably play a role in the disease outcome, but cytokine and endothelial responses are likely to determine if subclinical or clinical disease develops. Dendritic macrophages deliver virus to lymph nodes following the bite of an infected Culicoides. The virus then disseminates to many organs replicating in mononuclear phagocytes and endothelium. Initially, an interferon-1 response probably determines if the disease develops. Replication in mononuclear cells and endothelium results in the release of cytokines and vasoactive mediators, and may result in endothelial cell death leading to the clinical features of fever, hyperaemia, exudation of fluid, and haemorrhage. Disease outcome may also be linked to virus binding Toll-like receptor-3 and upregulation of endothelial surface receptors potentiating cytokine release and allowing transmigration of inflammatory cells, respectively. Despite a wealth of information, host genetics involved in resistance to BTV and EHDV and how variations in cytokines and endothelial responses determine clinical outcome still need further elucidation. PMID- 26741245 TI - Expression of interleukin-1 beta and interleukin-6 in white-tailed deer infected with Epizootic Hemorrhagic Disease virus. AB - The pathogenesis of epizootic haemorrhagic disease (EHD) in white-tailed deer (WTD) may be related to factors other than direct viral damage caused by replication in endothelium, such as the release of cytokines. This study focused on interleukin-1 beta (IL-1) and interleukin-6 (IL-6), which have been shown to be variably upregulated in Bluetongue virus (BTV) infected cattle and sheep endothelial cultures possibly explaining species susceptibility to BTV. We evaluated circulating and tissue levels of IL-1 and IL-6 in WTD experimentally infected with EHD virus serotype 2 (EHDV-2). Circulating levels of IL-1 were assayed by ELISA. RT-PCR and immunohistochemistry (IHC) were used to detect upregulation of IL-1 and IL-6 mRNA as well as protein expression, respectively. RT-PCR was also used to determine whether IL-1 and IL-6 were upregulated in WTD peripheral blood mononuclear cells (PBMC) infected with EHDV-2 in vitro. We found increased circulating levels of IL-1 and upregulation of IL-1 mRNA and protein expression and upregulation of IL-6 mRNA in tissues of WTD infected with EHDV. Upregulation of mRNA levels of IL-1 and IL-6 in EHDV infected PBMCs was also observed. Findings suggest a role for IL-1 and IL-6 in the pathogenesis of EHD in WTD. PMID- 26741246 TI - Recent advances in knowledge of BTV-host-vector interaction. AB - Bluetongue virus (BTV) has since 1998 extended its distribution further North than where it has previously been encountered. Changes in the epidemiology of Bluetongue (BT), as well as novel features of recent outbreaks of BTV in Europe, have stimulated research on BTV-vector-host interaction. The outbreak of BTV-8 in Northern Europe from 2006-2008 is particular noteworthy in this regard, as the European strain of BTV-8 demonstrated novel properties, including high virulence especially for cattle - and the capability to cross the ruminant placenta. The virus was in addition transmitted by indigenous European Culicoides species that had not previously been implicated in the widespread transmission of BTV. Recent advances in the scientific understanding of BTV-vector-host interaction include increased knowledge of the virus' replication cycle, the role of biotic factors in influencing viral infection of the insect vector, increased knowledge of BTV immunology and pathogenesis in the mammalian host, and increased knowledge of virulence and pathogenicity features of newly discovered serotypes/strains of the virus. New research on aspects of BTV-vector-host interaction has been driven in part by developments in molecular biology and experimental infection biology, of which next generation sequencing, the expression of individual viral proteins in cell culture, the establishment of a reverse genetics system for the virus, the development of novel in vitro and in vivo infection models, and refinement of existing BTV experimental infection methodologies have proven instrumental. Moreover, these developments have also provided the opportunity for the development of novel vaccine strategies. This article provides a synopsis of selected recent advances that have been made in the understanding of BTV-vector host interaction, with a particular focus on research that has been conducted in Europe over the last 5 years. PMID- 26741247 TI - Culicoides spp. (Diptera: Ceratopogonidae) as vectors of bluetongue virus in South Africa - a review. AB - The aim of this paper is to consolidate vector competence studies on Culicoides midges (Diptera: Ceratopogonidae) as vectors of bluetongue virus (BTV) done over a period 25 years at the ARC-Onderstepoort Veterinary Institute in South Africa. In 1944, it was demonstrated for the first time in South Africa that Culicoides midges transmit BTV. In 1991, field-collected Culicoides imicola were fed on blood containing BTV-3 or -6 and the infection rates were established as being 31% and 24%, respectively. In 1998, Culicoides bolitinos was shown to have a higher infection prevalence and virus titre/midge than C. imicola. This species was then shown to have a higher transmission potential for BTV-1 over a range of incubation temperatures wider than the one showed by C. imicola. Attenuation of BTV also does not reduce its ability to infect competent Culicoides species. Oral susceptibility studies, involving 29 BTV isolates of various serotypes, indicated differences between various geographic virus isolates and Culicoides populations evaluated. While low recovery rates of European BTV strains from South African Culicoides species suggest co-adaptation between orbiviruses and vectors in a given locality, co-adaption was shown not to be essential for virus transmission. Cumulative results since 1991 provide evidence that at least 13 livestock associated Culicoides species are susceptible to BTV. Susceptibility results are supported by field isolations from 5 of these species. This implies that multi vector potential for the transmission of BTV will complicate the epidemiology of BT. It must be emphasised that neither oral susceptibility nor virus isolation/detection from field-collected specimens is proof that a species is a confirmed field vector. PMID- 26741248 TI - Evaluation of in vitro methods for assessment of infection of Australian Culicoides spp. with bluetongue viruses. AB - Biting midges from the genus Culicoides (Diptera: Ceratopogonidae) are the vectors of several globally important arboviruses that affect livestock. These include orbiviruses from the bluetongue virus (BTV) and African horse sickness virus (AHSV) groups and members of the Simbu serogroup of orthobunyaviruses, such as the recently emerged Schmallenberg virus. In this article, the authors evaluate several methods for feeding wild-caught Australian Culicoides on BTV infected preparations of blood and sucrose. Feeding Culicoides on the membrane of embryonated chicken eggs was identified as the preferred feeding method. Although, cotton wool pads soaked in either virus-infected blood or virus-sucrose mixtures were also successful. A non-destructive nucleic acid extraction technique for the detection of viral RNA in Culicoides was also evaluated as it allows for readily differentiating infected from non-infected Culicoides. PMID- 26741249 TI - Integrative taxonomy to investigate species boundaries within Culicoides (Diptera: Ceratopogonidae): a case study using subgenus Avaritia from Australasia and Eastern Asia. AB - In this study, species boundaries were examined for 15 described and 2 undescribed species within the economically important Culicoides subg. Avaritia Fox from Australasia and Eastern Asia. We used an integrative taxonomic approach incorporating DNA barcoding, nuclear gene sequencing, and retrospective morphological analyses. Some arbovirus vector species such as Culicoides fulvus Sen and Das Gupta and Culicoides wadai Kitaoka were genetically and morphologically uniform across sampled distributions, but others including Culicoides actoni Smith and Culicoides brevipalpis Delfinado contained 2 or more genetically independent populations of 'cryptic species' that in some cases were sympatric. Some of these 'cryptic species' exhibited consistent morphological differences, while differences are yet to be found for others species. Additionally, an undescribed species, C. Avaritia sp. No. 3, was found to be synonymous with C. fulvus. These results refine our understanding of the distribution of individual species of C. subg. Avaritia and demonstrate that species descriptions and distribution records need revision for part of the Culicoides fauna. Furthermore, because vector competence studies for most of these species are based entirely on Australian populations, the competence of the putative cryptic species identified elsewhere will require independent assessment. Finally, integrative taxonomic assessment requires genetic and morphological assessment of material from the type localities in order to clarify the status and distribution of species, especially for clades containing cryptic species. International collaboration is needed to facilitate this research. PMID- 26741250 TI - Effect of Culicoides sonorensis salivary proteins on clinical disease outcome in experimental bluetongue virus serotype 8 infection of Dorset sheep. AB - The severity of bluetongue clinical disease in ruminants varies greatly depending on the outbreak serotype/strain, animal species/breed, and immune status of the herd. To predict disease risk from any of the 26 bluetongue virus (BTV) serotypes identified to date, experimental animal susceptibility studies are often conducted. Although sheep are the most susceptible livestock species in the US, infection of domestic breeds by injection of field isolates rarely produces the level of clinical disease observed in natural Culicoides midge-transmitted outbreaks. Thus, outbreak risk assessments based on experimental animal infections can underestimate the severity posed by a potential outbreak with a given virus serotype or strain. The aim of this study was to determine whether secreted Culicoides salivary proteins injected simultaneously with virus, to more closely mimic midge-delivered virus, would affect clinical disease outcome in a BTV-8 sheep susceptibility study. Eight sheep were intradermally inoculated with BTV-8; 4 received virus mixed with secreted Culicoides salivary proteins (BTV-8 + Cu SP), 4 received virus alone. Clinical signs were monitored daily for type, severity and duration. In sheep receiving the BTV-8 + Cu SP inoculum, clinical signs were more varied, more severe, and duration was three times longer compared to sheep receiving virus alone. These results suggest that Culicoides salivary proteins may play a contributing role in BTV pathology and that use of these proteins in experimental animal infections may allow development of a more robust target-host animal model. PMID- 26741251 TI - Impact of the blood meal on humoral immunity and microbiota in the gut of female Culicoides sonorensis. AB - Although Culicoides sonorensis is an important vector of orbiviruses causing significant disease in domestic and wild ruminants in the USA, little is known about factors contributing to midge vector competence. In other vectors such as mosquitoes, interactions among the humoral immune response, microbiota, and ingested pathogens within the vector gut directly impact pathogen survival and therefore vectoring potential. We recently described components of the humoral immune response in the reference transcriptome for adult female C. sonorensis and analysed their temporal expression profiles across several dietary states (unfed, blood, or sugar fed). Blood feeding altered the transcription of several humoral immune components of the Immune deficiency (Imd), dual-oxidase (DUOX), and Janus Kinase and Signal Transducer and Activator of Transcription (JAK/STAT) pathways. Genes for immune effectors, such as antimicrobial peptides, were in particular highly induced. Since blood feeding also stimulated proliferation and diversification of bacterial populations colonising the gut of female midges, we infer that changes in immune gene expression were a result of fluctuations in gut microbiota. Thus, diet can indirectly (via microbiota) impact gut immune status and therefore should be carefully considered in subsequent studies assessing vector competence in biting midges. PMID- 26741252 TI - Economic impact of Bluetongue: a review of the effects on production. AB - Bluetongue (BT) is often said to be a disease of severe economic consequence with a global estimate of US$ 3 billion. This review describes the most relevant contribution in the extant literature on production related losses due to BT. In summary, the impact of the endemic situations appears to be relatively small and surrounds the impacts on flock and herd fertility. The largest and most serious impact with BT in the epidemic situations has been in the reactions to the presence and risk of the disease. Such a reaction, in hindsight, has been far greater than the production losses caused by the disease. More data are required with more careful analysis to provide better impact assessment for BT. This would offer the ground for research prioritisation and the rebalancing of resource allocation. Such an economic impact assessment should follow scientific methods mirroring the careful and thorough biological work on BT. PMID- 26741253 TI - Immunity to malaria in an era of declining malaria transmission. AB - With increasing malaria control and goals of malaria elimination, many endemic areas are transitioning from high-to-low-to-no malaria transmission. Reductions in transmission will impact on the development of naturally acquired immunity to malaria, which develops after repeated exposure to Plasmodium spp. However, it is currently unclear how declining transmission and malaria exposure will affect the development and maintenance of naturally acquired immunity. Here we review the key processes which underpin this knowledge; the amount of Plasmodium spp. exposure required to generate effective immune responses, the longevity of antibody responses and the ability to mount an effective response upon re exposure through memory responses. Lastly we identify research priorities which will increase our understanding of how changing transmission will impact on malarial immunity. PMID- 26741254 TI - Falls in young adults: Perceived causes and environmental factors assessed with a daily online survey. AB - Falls are the third leading cause of unintentional injuries for ages 18-35years (CDC), but the causes and circumstances of falls in this age group are understudied. The purpose of this study was to document the frequency and circumstances of falls in young adults with a daily online survey. Ninety-four undergraduate students (19.9+/-0.9years) received a daily email for 16weeks regarding slips, trips and falls in the past 24h (93% response rate). More than half of the participants (52%) fell in the 16-week interval. Injuries were reported in 16% of falls, and medical treatment was received in 4% of all falls. The majority of falls occurred while walking (58%), and the main cause of the fall was a slip (48%) or trip (25%). On average, participants fell once out of every 18 perceived slips and trips. Physical activity level did not distinguish fallers from non-fallers (p=0.45), but for those who did fall, falls were more frequent as physical activity level increased (p=0.007). The high fall and injury rate in a short interval reflects the inherent instability of bipedal locomotion and indicates that falls are not a trivial problem for young adults. PMID- 26741255 TI - Effects of disease severity and medication state on postural control asymmetry during challenging postural tasks in individuals with Parkinson's disease. AB - The aim of this study was to investigate the effects of disease severity and medication state on postural control asymmetry during challenging tasks in individuals with Parkinson's disease (PD). Nineteen people with PD and 11 neurologically healthy individuals performed three standing task conditions: bipedal standing, tandem and unipedal adapted standing; the individuals with PD performed the tasks in ON and OFF medication state. The participants with PD were distributed into 2 groups according to disease severity: unilateral group (n=8) and bilateral group (n=11). The two PD groups performed the evaluations both under and without the medication. Two force plates were used to analyze the posture. The symmetric index was calculated for various of center of pressure. ANOVA one-way (groups) and two-way (PD groups*medication), with repeated measures for medication, were calculated. For main effects of group, the bilateral group was more asymmetric than CG. For main effects of medication, only unipedal adapted standing presented effects of PD medication. There was PD groups*medication interaction. Under the effects of medication, the unilateral group presented lower asymmetry of RMS in anterior-posterior direction and area than the bilateral group in unipedal adapted standing. In addition, the unilateral group presented lower asymmetry of mean velocity, RMS in anterior posterior direction and area in unipedal standing and area in tandem adapted standing after a medication dose. Postural control asymmetry during challenging postural tasks was dependent on disease severity and medication state in people with PD. The bilateral group presented higher postural control asymmetry than the control and unilateral groups in challenging postural tasks. Finally, the medication dose was able to reduce postural control asymmetry in the unilateral group during challenging postural tasks. PMID- 26741256 TI - Changes in motor synergies for tracking movement and responses to perturbations depend on task-irrelevant dimension constraints. AB - We investigated the changes in the motor synergies of target-tracking movements of hands and the responses to perturbation when the dimensionalities of target positions were changed. We used uncontrolled manifold (UCM) analyses to quantify the motor synergies. The target was changed from one to two dimensions, and the direction orthogonal to the movement direction was switched from task-irrelevant directions to task-relevant directions. The movement direction was task-relevant in both task conditions. Hence, we evaluated the effects of constraints on the redundant dimensions on movement tracking. Moreover, we could compare the two types of responses to the same directional perturbations in one- and two dimensional target tasks. In the one-dimensional target task, the perturbation along the movement direction and the orthogonal direction were task-relevant and irrelevant perturbations, respectively. In the two-dimensional target task, the both perturbations were task-relevant perturbations. The results of the experiments showed that the variabilities of the hand positions in the two dimensional target-tracking task decreased, but the variances of the joint angles did not significantly change. For the task-irrelevant perturbations, the variances of the joint angles within the UCM that did not affect hand position (UCM component) increased. For the task-relevant perturbations, the UCM component tended to increase when the available UCM was large. These results suggest that humans discriminate whether the perturbations were task-relevant or -irrelevant and then adjust the responses of the joints by utilizing the available UCM. PMID- 26741257 TI - The acquisition of socio-motor improvisation in the mirror game. AB - Socio-motor improvisation is defined as the creative action of two or more people without a script or anticipated preparation. It is evaluated through two main parameters: movement synchronization and movement richness. Experts in art (e.g., dance, theater or music) are known to exhibit higher synchronization and to perform richer movements during interpersonal improvisation, but how these competences evolve over time is largely unknown. In the present study, we investigated whether performing more synchronized and richer movements over time can promote the acquisition of improvisation. Pairs of novice participants were instructed to play an improvisation mirror game in three different sessions. Between sessions, they performed an unintended interpersonal coordination task in which synchronization and richness were manipulated, resulting in four different groups of dyads. Our results demonstrate that synchronization during improvisation improved for all groups whereas movement richness only enhanced for dyads that performed synchronized movements during unintended coordination tasks. Our findings suggest that movement synchrony contributes more than movement richness to the acquisition of socio-motor improvisation in the mirror game. PMID- 26741259 TI - Implicit out-group preference is associated with eating disorders symptoms amongst Emirati females. AB - Studies exploring the relationship between acculturation and eating disorders symptoms have proven equivocal. Socially desirable responding associated with the use of explicit measures may account for these mixed findings. This study explores the relationship between in-group identity, acculturation and eating disorders symptoms using both implicit and explicit assessments. Emirati female college students (N=94) completed an affective priming task (APT) designed to implicitly assess Emirati in-group evaluations. Participants also completed explicit measures, including the Westernization Survey and the Multicomponent In group Identification Scale. Eating disorders symptoms were assessed using the Eating Attitudes Test. Only implicit in-group evaluations were correlated with eating disorders symptoms. Specifically, increases in in-group preference were associated with lower levels of eating disorders symptomatology. Furthermore, participants with an actual out-group preference had significantly higher levels of eating disorders symptomatology compared with those demonstrating an in-group preference. These findings support the acculturative stress hypothesis, and suggest that the relationship between eating disorders and acculturation may be better understood with reference to implicit rather than explicit in-group evaluations. PMID- 26741258 TI - Food cravings, binge eating, and eating disorder psychopathology: Exploring the moderating roles of gender and race. AB - OBJECTIVE: To examine the moderating effects of gender and race on the relationships among food cravings, binge eating, and eating disorder psychopathology in a community sample. METHODS: Data were collected from a convenience sample of 320 adults (53% male; mean age 28.5+/-8.2years; mean BMI 27.1+/-5.2kg/m(2); mean education 15.1+/-2.2years; 64% white, 24% black, and 13% other race) participating in a cross-sectional study examining the interactions between stress, self-control and addiction. Participants completed a comprehensive assessment panel including a demographic questionnaire, the Food Craving Inventory, and Eating Disorder Examination Questionnaire. Data were analyzed using multiple logistic regression for binge eating behavior and multiple linear regression for eating disorder psychopathology. RESULTS: Overall, food cravings demonstrated significant main effects for binge eating behavior (adjusted OR=2.65, p<.001) and global eating disorder psychopathology (B=.47+/ .09, p<.001). Females had a stronger relationship between food cravings and eating disorder psychopathology than males; there were no statistically significant differences by race. CONCLUSION: These findings, based on a diverse sample recruited from the community, suggest that food cravings are associated with binge eating and eating disorder psychopathology and may represent an important target for interventions. PMID- 26741260 TI - Smoking status and psychosocial factors in binge eating disorder and bulimia nervosa. AB - OBJECTIVE: To examine eating-disorder psychopathology and depressive symptoms by smoking status (never, former, or current smoker) in persons with binge eating disorder (BED) and bulimia nervosa (BN). METHODS: Participants were 575 adult volunteers from the community (mean age=36.0+/-12years and BMI=32.9+/-9.5kg/m(2); 80% white; 88% female) who were classified with BED (n=410) or BN (n=165). Participants completed a battery of questionnaires, including items about current and historical cigarette smoking, the Eating Disorder Examination -Questionnaire, and the Beck Depression Inventory. RESULTS: Among those with BED, depressive symptoms were significantly higher in current smokers than former or never smokers (p=.001). There were no significant differences in depressive symptoms by smoking status in participants with BN and no differences in eating-disorder psychopathology by smoking status in either the BED or BN groups. DISCUSSION: In this non-clinical group of community volunteers, we found that smoking history or status was not associated with eating disorder psychopathology in participants classified with BED and BN but was significantly associated with depressive symptoms in participants with BED. PMID- 26741261 TI - End-of-life decision-making for children with severe developmental disabilities: The parental perspective. AB - BACKGROUND AND AIMS: The objectives of this integrative review were to understand how parents of children with severe developmental disorders experience their involvement in end-of-life decision-making, how they prefer to be involved and what factors influence their decisions. METHODS AND PROCEDURES: We searched MEDLINE, EMBASE, CINAHL and PsycINFO. The search was limited to articles in English or Dutch published between January 2004 and August 2014. We included qualitative and quantitative original studies that directly investigated the experiences of parents of children aged 0-18 years with severe developmental disorders for whom an end-of-life decision had been considered or made. OUTCOMES AND RESULTS: We identified nine studies that met all inclusion criteria. Reportedly, parental involvement in end-of-life decision-making varied widely, ranging from having no involvement to being the sole decision-maker. Most parents preferred to actively share in the decision-making process regardless of their child's specific diagnosis or comorbidity. The main factors that influenced parents in their decision-making were: their strong urge to advocate for their child's best interests and to make the best (possible) decision. In addition, parents felt influenced by their child's visible suffering, remaining quality of life and the will they perceived in their child to survive. CONCLUSIONS AND IMPLICATIONS: Most parents of children with severe developmental disorders wish to actively share in the end-of-life decision-making process. An important emerging factor in this process is the parents' feeling that they have to stand up for their child's interests in conversations with the medical team. PMID- 26741262 TI - Spilling over: Partner parenting stress as a predictor of family cohesion in parents of adolescents with developmental disabilities. AB - Family cohesion relates to positive outcomes for both parents and children. Maintaining cohesion may be especially challenging for families of adolescents with developmental disabilities, yet this has been studied infrequently in this group. We investigated cohesion in these families, particularly with respect to partner stress, using the notion of the 'spillover effect' as a model. Adolescents with disabilities and their parents participated. Parents reported on teen adaptive and problem behaviours and on marital satisfaction, parenting stress, and family cohesion. The stress of one partner was tested as a predictor of the quality of family cohesion reported by the other. Adolescent behaviour problems were negative predictors of family cohesion in mothers, and marital satisfaction positively predicted cohesion for both parents. Above other factors, greater partner stress predicted poorer family cohesion for both fathers and mothers. Marital satisfaction acted as a suppressor of this relation. To improve the overall climate of families, care providers should take into consideration individual relationships, including the marital relationship. In addition, the possibility of spillover from one individual to another should be recognized as a factor in family functioning. Family-centred practices are likely to lead to greater feelings of cohesion and overall better individual and family well-being. PMID- 26741263 TI - Comparing participation in physical recreation activities between children with disability and children with typical development: A secondary analysis of matched data. AB - BACKGROUND: Facilitating participation in physical recreation among children with disability is an increasingly important aim of paediatric rehabilitation. AIM: To compare the extent (diversity and frequency), context (where and companionship), experience (enjoyment) and preference for participation in physical recreation activities outside-of-school between children with disability and children with typical development. METHODS AND PROCEDURES: One hundred and sixty-three children with physical, intellectual, sensory or multiple disabilities (67 girls; mean age 10.8 yr) were matched with 163 children with typical development for age, sex, geographical location and socioeconomic status. Participation in 16 physical recreation activities (including walking, cycling, team sports) was compared between these two groups using non-parametric statistics and relative risk ratios. OUTCOMES AND RESULTS: There were significant differences between the groups in 14 activities. A lower percentage of children with disability reported participating in 5 physical recreation activities. A higher percentage of children with disability reported not participating in their preferred activities. Children with disability were less likely to participate on their own in some day-to-day physical recreation activities such as walking and cycling. CONCLUSIONS AND IMPLICATIONS: Differences between the groups related to the context (companionship) and preference for participation. Understanding and addressing these differences may enhance participation among children with disability. PMID- 26741264 TI - Angelica sinensis polysaccharide attenuates concanavalin A-induced liver injury in mice. AB - Angelica sinensis polysaccharide (ASP), extracted from the roots of A. sinensis (Oliv.) Diels, is a beta-D-pyranoid polysaccharide with an average molecular weight of 72,900 Da. In this study, we investigated the protective effects of ASP against concanavalin A-induced liver failure and the underlying mechanisms. Concentrations of ASP ranging from 5 to 125 MUg/mL could inhibit concanavalin A (ConA)-induced lymphoproliferative response. The potential hepatoprotective activity of ASP was demonstrated by the significant decrease in serum transaminase (ALT and AST) levels and the attenuation of liver inflammation damage exhibited by H&E stain of the liver. Furthermore, ASP pretreatment significantly decreased proinflammatory cytokines (TNF-alpha, IFN-gamma, IL-2 and IL-6) and alleviated oxidative stress by reducing MDA and ROS levels and by enhancing SOD activity after ConA administration in mice. Results of Western blot analysis indicated that ASP attenuated Caspase-3-dependent apoptosis by Caspase-8 and JNK-mediated pathway and inhibited the activation of IL-6/STAT3 and NF-kappaB signaling pathways in ConA-induced liver damage in mice. In conclusion, ASP pretreatment could attenuate concanavalin A-induced liver injury through its anti inflammatory and anti-oxidant actions in mice. PMID- 26741265 TI - Rosiglitazone attenuates angiotensin II-induced C-reactive protein expression in hepatocytes via inhibiting AT1/ROS/MAPK signal pathway. AB - Inflammation is a commonly pathological change in liver diseases, and promotes the development of acute and chronic liver diseases by excessive production of inflammatory cytokines. C-reactive protein (CRP) is primarily synthesized in the liver and participates in many chronic diseases. Our previous study confirmed that Ang II stimulates CRP generation in hepatocytes. This study investigated the effect of rosiglitazone (RSG) on Ang II-stimulated CRP expression and the molecular mechanism in hepatocytes. The results showed that the subcutaneous infusion of Ang II to rats for 7days through the osmotic minipumps increased CRP expression in the liver and serum CRP level. The simultaneous treatment of rats with RSG reduced CRP generation in the liver and CRP concentration in serum. Further study showed that RSG down-regulated Ang II-induced mRNA and protein expression of CRP and AT1 as well as phosphorylation of ERK1/2 and JNK, enhanced mRNA and protein expression of PPARgamma in hepatocytes in vivo and in vitro. In addition, RSG increased superoxide dismutase activity in the liver of Ang II infused rats in vivo, and decreased Ang II-stimulated reactive oxygen species (ROS) production in hepatocytes in vitro. In conclusion, the present study demonstrates that RSG is able to inhibit Ang II-induced CRP generation by interfering with AT1-ROS-ERK1/2/JNK signal pathway and up-regulating PPARgamma expression in hepatocytes, which provides the new evidence and mechanisms for the beneficial effect of RSG to relieve hepatic inflammation and suggests the possibility that RSG is used for the inflammatory hepatic diseases. PMID- 26741266 TI - Structural and electronic properties of ZnO/GaN heterostructured nanowires from first-principles study. AB - ZnO/GaN alloys have exceptional photocatalytic applications owing to their suitable band gaps corresponding to the range of visible light wavelength and thus have attracted extensive attention over the past few years. In this study, the structural stabilities and electronic properties of core/shell, biaxial, and super-lattice ZnO/GaN heterostructured nanowires have been investigated by means of first-principles calculations based on the density functional theory. The effects of the nanowire size, the GaN ratio, and strain have been explored. It is found that all studied heterostructured nanowires are less stable than pure ZnO nanowires, exhibiting larger sized wires with better structural stabilities and inversely proportional relationship between structural stability and the GaN ratio. Electronic band structures imply that all heterostructured nanowires are semiconductors with the band gaps strongly depending on the GaN ratios as well as mechanical strain. Particularly, for the biaxial and the super-lattice nanowires, their band gaps decrease firstly and then increase with the increasing GaN ratios. Electronic contributions to the valence band maximum (VBM) and the conduction band minimum (CBM) are discussed for exploiting the potential photocatalytic applications. PMID- 26741267 TI - Baicalin loaded in folate-PEG modified liposomes for enhanced stability and tumor targeting. AB - Bioavailability of baicalin (BAI), an example of traditional Chinese medicine, has been modified by loading into liposome. Several liposome systems of different composition i.e., lipid/cholesterol (L), long-circulating stealth liposome (L PEG) and folate receptor (FR)-targeted liposome (L-FA) have been used as the drug carrier for BAI. The obtained liposomes were around 80 nm in diameter with proper zeta potentials about -25 mV and sufficient physical stability in 3 months. The entrapment efficiency and loading efficiency of BAI in the liposomes were 41.0 46.4% and 8.8-10.0%, respectively. The morphology details of BAI lipsosome systems i.e., formation of small unilamellar vesicles, have been determined by cryogenic transmission electron microscopy (cryo-TEM) and small angle X-ray scattering (SAXS). In vitro cytotoxicity of BAI liposomes against HeLa cells was evaluated by MTT assay. BAI loaded FR-targeted liposomes showed higher cytotoxicity and cellular uptake compared with non-targeted liposomes. The results suggested that L-FA-BAI could enhance anti-tumor efficiency and should be an effective FR-targeted carrier system for BAI delivery. PMID- 26741268 TI - Factors influencing the transfection efficiency and cellular uptake mechanisms of Pluronic P123-modified polypropyleneimine/pDNA polyplexes in multidrug resistant breast cancer cells. AB - Generally, the major obstacles for efficient gene delivery are cellular internalization and endosomal escape of nucleic acid such as plasmid DNA (pDNA) or small interfering RNA (siRNA). We previously developed Pluronic P123 modified polypropyleneimine (PPI)/pDNA (P123-PPI/pDNA) polyplexes as a gene delivery system. The results showed that P123-PPI/pDNA polyplexes revealed higher transfection efficiency than PPI/pDNA polyplexes in multidrug resistant breast cancer cells. As a continued effort, the present investigation on the factors influencing the transfection efficiency, cellular uptake mechanisms, and intracellular fate of P123-PPI/pDNA polyplexes is reported. The presence of P123 was the main factor influencing the transfection efficiency of P123-PPI/pDNA polyplexes in MCF-7/ADR cells, but other parameters, such as N/P ratio, FBS concentration, incubation time and temperature were important as well. The endocytic inhibitors against clathrin-mediated endocytosis (CME), caveolae mediated endocytosis (CvME), and macropinocytosis were involved in the internalization to investigate their effects on the cellular uptake and transfection efficiency of P123-PPI/pDNA polyplexes in vitro. The data showed that the internalization of P123-PPI/pDNA polyplexes was obtained from both CME and CvME. Colocalization experiments with TRITC-transferrin (CME indicator), Alexa Fluor 555-CTB (CvME indicator), monoclonal anti-alpha-tubulin (microtubule indicator), and LysoTracker Green (Endosome/lysosome indicator) were carried out to confirm the internalization routes. The results showed that both CME and CvME played vital roles in the effective transfection of P123-PPI/pDNA polyplexes. Endosome/lysosome system and skeleton, including actin filament and microtubule, were necessary for the transportation after internalization. PMID- 26741269 TI - Antimicrobial films obtained from latex particles functionalized with quaternized block copolymers. AB - New amphiphilic block copolymers with antimicrobial properties were obtained by atom transfer radical polymerization (ATRP) and copper catalyzed cycloaddition following two approaches, a simultaneous strategy or a two-step synthesis, which were proven to be very effective methods. These copolymers were subsequently quaternized using two alkyl chains, methyl and butyl, to amplify their antimicrobial properties and to investigate the effect of alkyl length. Antimicrobial experiments in solution were performed with three types of bacteria, two gram-positive and one gram-negative, and a fungus. Those copolymers quaternized with methyl iodide showed better selectivities on gram-positive bacteria, Staphylococcus aureus and Staphylococcus epidermidis, against red blood cells, demonstrating the importance of the quaternizing agent chosen. Once the solution studies were performed, we prepared poly(butyl methacrylate) latex particles functionalized with the antimicrobial copolymers by emulsion polymerization of butyl methacrylate using such copolymers as surfactants. The characterization by various techniques served to test their effectiveness as surfactants. Finally, films were prepared from these emulsions, and their antimicrobial activity was studied against the gram-positive bacteria. The results indicate that the antimicrobial efficiency of the films depends not only on the copolymer activity but also on other factors such as the surface segregation of the antimicrobial agent to the interface. PMID- 26741270 TI - Nano-biointeractions of PEGylated and bare reduced graphene oxide on lung alveolar epithelial cells: A comparative in vitro study. AB - Graphene and its derivatives have garnered significant scientific interest and have potential use in nano-electronics as well as biomedicine. However the undesirable biological consequence, especially upon inhalation of the particle, requires further investigations. This study aimed to elucidate the nano biointeractions of PEGylated reduced graphene oxide (PrGO) and reduced graphene oxide (rGO) with that of lung alveolar epithelial cells (A549). Both nanomaterials showed dose dependent decrease in cell viability and alteration of cell morphology after 24h. Upon intracellular uptake of PrGO, it elicited oxidative stress mediated apoptosis in the cells by inducing ROS, loss of mitochondrial membrane potential (MMP) and inflammatory response by NF-kappaB activation. Conversely, rGO was found to scavenge ROS efficiently except at high dose after 24h. It was found that ROS at high dose of rGO prompted loss of MMP. rGO was found to adhere to the cell membrane, where it is assumed to bind to cell surface Toll like receptors (TLRs) thereby activating NF-kappaB mediated inflammatory response. All these events culminated in an increase in apoptosis of A549 cells after 24h of rGO exposure. It was also noticed that both the nanomaterials did not initiate lysosomal pathway but instead activated mitochondria mediated apoptosis. This study highlights the possible adverse toxic effect of PrGO and rGO upon inhalation and persistence of these particles in the lungs. Further research is required to comprehend the biological response of PrGO and rGO so as to advance its biomedical application and safety. PMID- 26741271 TI - The effect of living alone on the costs and benefits of surgery amongst older people. AB - Older people who live alone are a growing, high-cost group for health and social services. The literature on how living alone affects health and the costs and benefits of healthcare has focused on crude measures of health and utilisation and gives little consideration to other cost determinants and aspects of patient experience. We study the effect of living alone at each stage along an entire treatment pathway using a large dataset which provides information on pre treatment experience, treatment benefits and costs of surgery for 105,843 patients receiving elective hip and knee replacements in England in 2009 and 2010. We find that patients who live alone are healthier prior to treatment and experience the same gains from treatment. However, living alone is associated with a 9.2% longer length of in-hospital stay and increased probabilities of readmission and discharge to expensive destinations. These increase the costs per patient by L179.88 (3.12%) and amount to an additional L4.9 million per annum. A lack of post-discharge support for those living alone is likely to be a key driver of these additional costs. PMID- 26741272 TI - Gossypiboma revisited: A never ending issue. AB - INTRODUCTION: Leaving a surgical item inside the patient at the end of surgery, is one of the most dreadful complications. The item is frequently a surgical sponge and the resultant morbidity is usually severe. Additionally, the event poses considerable psychic strain to the operating team, notably the surgeon. PRESENTATION OF CASES: Here we describe the clinical course of three patients in whom a surgical sponge was missed, despite a seemingly correct count at the end of difficult caesarean sections. In two patients, who presented shortly after surgery, the pad was extracted with no bowel resection. In the third patient, who presented several years after surgery, colectomy was performed. DISCUSSION: Gossypiboma is under reported and the true incidence is largely unknown. Depending on the body reaction and the characters of the retained sponge, the patient may present within months to years after surgery. Risk factors for retained foreign objects include emergency surgery, an unplanned change in the surgical procedure, higher body mass index, multiple surgical teams, greater number of major procedures done at the same time and incorrect count recording. The surgical procedure needed to extract the retained sponge may be a simple one, as in the first case, or it may be more complex, as seen in the other two cases. Although holding the correct count at the end of surgery is the gold standard safeguard against this mishap, human errors continue to occur, as happened in our patients. For that reason, the correct count should be supplemented by employing one of the several new technologies currently available. CONCLUSION: Gossypiboma continues to occur, despite precautionary measures. As its consequences might cost the patient his life and the surgeon his professional reputation, extra preventive measures should be sought and implemented. New advances in technology should be incorporated in the theatre protocol as additional safeguard against human error. When encountered, a direct incision over the encapsulated swelling, in contrast to a formal laparotomy incision, might simplify the surgical procedure. PMID- 26741273 TI - An extremely rare case of thyroid malignancy from the non-Alpine region: Angiosarcoma. AB - INTRODUCTION: Thyroid angiosarcoma is a rather rare malignancy featuring a poor prognosis, and which may interfere with other aggressive thyroid tumors; it is usually seen in the Alpine region. CASE PRESENTATION: A 74-year-old male was referred to our center with complaints of progressive neck swelling and dyspnea. He had multiple nodules featuring cystic degeneration and calcifications in the thyroid gland, together with multiple lymphadenopathies of the neck region. Fine needle aspiration cytology (FNAC) confirmed the presence of anaplastic carcinoma. A total thyroidectomy was performed. During the postoperative period, multiple drainage were performed for recurrent hematomas, but hematoma development could not be prevented. On postoperative day 7, the patient died due to multiple-system failure. Histopathological investigation of the thyroidectomy specimen indicated that the lesion was an angiosarcoma. DISCUSSION: The cytological diagnosis of thyroid angiosarcoma is quite difficult. Extracapsular invasion and distant organ metastasis during surgery are known as strong and negative prognostic factors for thyroid angiosarcoma. Treatment is quite difficult, since this tumor is locally aggressive, destructive, and features a high recurrence rate. In this case, since extracapsular invasion, as well as lymph node and lung metastasis were present at the time of surgery; the expected survival time was quite short. CONCLUSION: This case shows that during differential diagnosis, patients initially diagnosed with anaplastic carcinoma via FNAC may actually present with angiosarcoma. It may be helpful to review the treatment modalities for this cancer type, which has a rather poor prognosis and features severe bleeding, as well as local and distant metastasis. PMID- 26741274 TI - Spontaneous aortoenteric fistula involving the sigmoid: A case report and review of literature. AB - INTRODUCTION: Primary aortoenteric fistula (PAEF) is a pathological communication between the aorta and any portion of the gastrointestinal tract. The pathology is very rare and easily overlooked during the diagnostic process. PRESENTATION OF CASE: We report the exceptional case of an 86-year-old man with episodes of abdominal pain and rectal bleeding of unknown cause over a period of 1,5 months due to a PAEF to the sigmoid. A sigmoidectomy was performed and a rifampicin soaked aortic graft was placed. The patient had an uneventful post-operative recovery. The duration of symptoms, the anatomic location of the fistula and the outcome after surgery makes this case unique. DISCUSSION: With an incidence of 0.04-0.07% in all patients with aortic aneurysms a PAEF is very rare. Only 2% of PAEF's involves the sigmoid. The most common cause is an atherosclerotic aortic aneurysm. Patients with PAEF can present with a triad of symptoms including gastrointestinal bleeding, abdominal pain and a pulsating mass. A contrast enhanced computer-tomography scan (CTa) is the most accurate tool to demonstrate a PAEF. Without a strong clinical suspicion, diagnosing a PAEF is hard and frequently delayed. The overall PAEF-related mortality is high (61-100%) and decreases after surgery (30-40%). CONCLUSION: A primary aortoenteric fistula involving the sigmoid is very rare. Clinical presentation can vary, diagnosis can be difficult and surgical options may differ. Even with low suspicion of PAEF, we recommend performing a CTa. With a high overall mortality of more than 60% due to exsanguinating, surgical treatment is always indicated. PMID- 26741275 TI - A huge ependymoma of the cervical spinal cord with subtle atypical manifestations and hyperhidrosis: Case report. AB - INTRODUCTION: Ependymomas are the most common neuroepithelial tumors of the spinal cord, accounting for 50-60% of spinal cord gliomas. The nonspecific clinical presentation of a spinal cord tumor frequently results in delay of diagnosis with opposing outcomes. PRESENTATION OF CASE: We report a 34-year-old man presented with abnormally enhanced sweating on the left side of his neck, upper extremity, and chest that had been occurring for 1 year. In the sagittal MRI there were a centrally localized mass lesion extending from medulla and C1 to T2 vertebra level and expanding the cord. Surgical elimination of the tumor was performed with posterior midline approach and near total resection of tumor was achieved. CONCLUSION: Cervical intramedullary ependymal is a rare, slow growing spinal cord tumor. Attention to uncommon characteristics like hyperhidrosis might be an important key to early diagnosis of this rare spinal tumor. Surgical resection is the choice of treatment with infrequent recurrence. PMID- 26741276 TI - Hydrogenated CeO(2-x)S(x) mesoporous hollow spheres for enhanced solar driven water oxidation. AB - A facile route for the fabrication of hydrogenated sulfur-doped CeO2 (H-CeO(2 x)S(x)) mesoporous hollow spheres is reported. The spheres exhibited excellent photocatalytic activity due to the synergistic effect of the higher sulfur doping level and hydrogen post-treatment. PMID- 26741277 TI - History of childhood maltreatment augments dorsolateral prefrontal processing of emotional valence in PTSD. AB - Posttraumatic stress disorder (PTSD) is characterized by conflicting findings of both increased and decreased amygdala and prefrontal reactivity to threat or trauma stimuli. Childhood maltreatment (CM), a potent risk factor for PTSD, exerts long-lasting influences on threat processing and prefrontal-amygdala function. This suggests that CM history may influence PTSD neural phenotypes related to threat processing. Here, we adapt a well-characterized emotional conflict paradigm to investigate CM effects on both emotional conflict and emotional valence processing within PTSD stratified by task relevance. Forty-two individuals with PTSD (22 reporting extensive CM history (PTSD-CM)) and 20 trauma exposed healthy controls (TEHCs) underwent functional magnetic resonance imaging while identifying affect of emotional faces (fear and happy) overlaid with a goal irrelevant emotional distractor word ("FEAR" or "HAPPY"). We examined effects of CM on conflict, conflict adaptation, valence-related activation (fear vs. happy) for goal-relevant (face) and goal-irrelevant stimuli (word), and valence effects in interaction with goal-relevancy (face vs. word). Though no activation differences between groups were observed for conflict contrasts nor for valence effects in the amygdala, CM status interacted with valence processing differences as a function of goal relevance in the left dorsolateral prefrontal cortex (dlPFC). Here, PTSD-CM displayed greater activation relative to PTSD to negative valence when stimuli were goal-irrelevant. CM history also moderated relationships between activation abnormalities and PTSD re-experiencing symptoms. These findings provide initial evidence that CM history augments dorsolateral prefrontal bias to implicitly processed stimulus valence in PTSD. PMID- 26741278 TI - Problem-gambling severity and psychiatric disorders among American-Indian/Alaska native adults. AB - INTRODUCTION: Little is known about the association between problem-gambling severity and psychiatric disorders among American-Indian/Alaska-Native (AI/AN) individuals. Thus, we examined these factors among a nationally representative sample of AI/AN and other American adults in the USA. METHOD: Using the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) data, we conducted separate Wald tests and multinomial logistic regression analyses comparing AI/AN to black/African American, white/Caucasian, and all other racial/ethnic groups, respectively. RESULTS: Relative to other American adults, AI/AN adults were least likely to report non-/low-frequency gambling (NG: AI/AN 66.5%, white/Caucasian 70.5%, black/African American 72.8%, other racial/ethnic group 72.3%) and most likely to report low-risk gambling (LRG: AI/AN 30.1%, white/Caucasian 26.5%, black/African American 23.4%, other racial/ethnic group 24.7%). The association between at-risk/problem-gambling (ARPG) and any past-year Axis-I disorder was stronger among AI/AN versus other American adults. Although ARPG and LRG were associated with multiple past-year Axis-I and lifetime Axis-II psychiatric disorders in both AI/AN and other American adults, LRG was more strongly associated with both Axis-I disorders (particularly major depression, generalized anxiety disorder and nicotine dependence) and Cluster-B Axis-II (particularly antisocial personality disorder) disorders in AI/AN versus other American adults. DISCUSSION: A stronger association between problem-gambling severity and past-year psychiatric disorders among AI/AN relative to other American adults suggests the importance of enhancing mental health and problem gambling prevention and treatment strategies that may help AI/AN individuals. PMID- 26741281 TI - Synthesis of 8-Phenylphenalenones: 2-Hydroxy-8-(4-hydroxyphenyl)-1H-phenalen-1 one from Eichhornia crassipes. AB - 2-Hydroxy-8-(4-hydroxyphenyl)-1H-phenalen-1-one (1), the first reported 8 phenylphenalenone from the roots of Eichhornia crassipes (water hyacinth), was synthesized starting from 2-methoxynaphthalene in 11 steps and with an overall yield of 2%. A cascade Friedel-Crafts/Michael annulation reaction between acryloyl chloride and 2-methoxynaphthalene afforded 9-methoxyperinaphthanone that, after transformation to 9-methoxy-2-(4-methoxyphenyl)-1H-phenalen-1-one by means of standard Suzuki-Miyaura methodology, was subjected to a reductive carbonyl transposition to afford 8-(4-methoxyphenyl)perinaphthanone. Dehydrogenation, epoxidation, and demethylation of the latter afforded 1. PMID- 26741279 TI - Native Oxide Transport and Removal During Atomic Layer Deposition of TiO2 Films on GaAs(100) Surfaces. AB - In this work, we studied the evolution and transport of the native oxides during the atomic layer deposition (ALD) of TiO2 on GaAs(100) from tetrakis dimethyl amino titanium and H2O. Arsenic oxide transport through the TiO2 film and removal during the ALD process was investigated using transmission Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). Experiments were designed to decouple these processes by utilizing their temperature dependence. A 4 nm TiO2 layer was initially deposited on a native oxide surface at 100 degrees C. Ex situ XPS confirmed that this step disturbed the interface minimally. An additional 3 nm TiO2 film was subsequently deposited at 150 to 250 degrees C with and without an intermediate thermal treatment step at 250 degrees C. Arsenic and gallium oxide removal was confirmed during this second deposition, leading to the inevitable conclusion that these oxides traversed at least 4 nm of film so as to react with the precursor and its surface reaction/decomposition byproducts. XPS measurements confirmed the relocation of both arsenic and gallium oxides from the interface to the bulk of the TiO2 film under normal processing conditions. These results explain the continuous native oxide removal observed for alkyl-amine precursor-based ALD processes on III-V surfaces and provide further insight into the mechanisms of film growth. PMID- 26741282 TI - Strain Rate Dependent Shear Plasticity in Graphite Oxide. AB - Graphene oxide film is made of stacked graphene layers with chemical functionalities, and we report that plasticity in the film can be engineered by strain rate tuning. The deformation behavior and plasticity of such functionalized layered systems is dominated by shear slip between individual layers and interaction between functional groups. Stress-strain behavior and theoretical models suggest that the deformation is strongly strain rate dependent and undergoes brittle to ductile transition with decreasing strain rate. PMID- 26741283 TI - Intermolecular Energy Transfer Dynamics at a Hot-Spot Interface in RDX Crystals. AB - The phonon mediated vibrational up-pumping mechanisms assume an intact lattice and climbing of a vibrational ladder using strongly correlated multiphonon dynamics under equilibrium or near-equilibrium conditions. Important dynamic processes far from-equilibrium in regions of large temperature gradient after the onset of decomposition reactions in energetic solids are relatively unknown. In this work, we present a classical molecular dynamics (MD) simulation-based study of such processes using a nonreactive and a reactive potential to study a fully reacted and unreacted zone in RDX (1,3,5-trinitro-1,3,5-triazocyclohexane) crystal under nonequilibrium conditions. The energy transfer rate is evaluated as a function of temperature difference between the reacted and unreacted regions, and for different widths and cross-sectional area of unreacted RDX layers. Vibrational up-pumping processes probed using velocity autocorrelation functions indicate that the mechanisms at high-temperature interfaces are quite different from the standard phonon-based models proposed in current literature. In particular, the up-pumping of high-frequency vibrations are seen in the presence of small molecule collisions at the hot-spot interface with strong contributions from bending modes. It also explains some major difference in the order of decomposition of C-N and N-N bonds as seen in recent literature on initiation chemistry. PMID- 26741284 TI - Label-Free, In-Solution Screening of Peptide Libraries for Binding to Protein Targets Using Hydrogen Exchange Mass Spectrometry. AB - There is considerable interest in the discovery of peptide ligands that bind to protein targets. Discovery of such ligands is usually approached by screening large peptide libraries. However, the individual peptides must be tethered to a tag that preserves their individual identities (e.g., phage display or one-bead one-compound). To overcome this limitation, we have developed a method for screening libraries of label-free peptides for binding to a protein target in solution as a single batch. The screening is based on decreased amide hydrogen exchange by peptides that bind to the target. Hydrogen exchange is measured by mass spectrometry. We demonstrate the approach using a peptide library derived from the Escherichia coli proteome that contained 6664 identifiable features. The library was spiked separately with a peptide spanning the calmodulin binding domain of endothelial nitric oxide synthase (eNOS, 494-513) and a peptide spanning the N-terminal 20 residues of bovine ribonuclease A (S peptide). Human calmodulin and bovine ribonuclease S (RNase S) were screened against the library. Using a novel data analysis workflow, we identified the eNOS peptide as the only calmodulin binding peptide and S peptide as the only ribonuclease S binding peptide in the library. PMID- 26741285 TI - An mGlu5-Positive Allosteric Modulator Rescues the Neuroplasticity Deficits in a Genetic Model of NMDA Receptor Hypofunction in Schizophrenia. AB - There is substantial evidence that NMDA receptor (NMDAR) hypofunction contributes to the pathophysiology of schizophrenia (SCZ). A recent large-scale genome-wide association study identified serine racemase (SR), the enzyme that produces the NMDAR co-agonist D-serine, as a risk gene for SCZ. Serine racemase knockout (SR-/ ) mice, which lack D-serine, exhibit many of the neurochemical and behavioral abnormalities observed in SCZ. Metabotropic glutamate receptor 5 (mGlu5)-positive allosteric modulators (PAMs) are currently being developed to treat cognitive dysfunction. We used in vitro electrophysiology to determine whether the mGlu5 PAM VU0409551 directly enhances NMDAR function in hippocampal slices from adult male SR-/- mice. We administered VU0409551 systemically for 5 days to adult male wild-type C57BL/6 animals to determine the optimal dose to test in SR-/- mice. We used western blot analyses and trace-fear conditioning to determine whether 5 days of VU0409551 treatment could reverse the neuroplasticity and learning deficits, respectively, in SR-/- mice. We show that VU0409551 enhances NMDAR function and rescues long-term potentiation in hippocampal slices obtained from SR-/- mice. Systemic treatment with VU0409551 (10 and 30 mg/kg) to wild-type mice causes a dose-dependent increase in the Akt/GS3Kalpha/beta signaling pathway, which is reduced in SR-/- mice and in SCZ. Furthermore, the administration of VU0409551 to SR-/- mice reverses their deficits in several neuroplasticity signaling pathways and improves their contextual fear memory. These results support positive allosteric modulation of mGlu5, particularly with VU0409551, as a viable mechanism to reverse the deficits in NMDAR function, synaptic plasticity, and memory that are known to be impaired in SCZ. PMID- 26741286 TI - Intranasal Oxytocin Normalizes Amygdala Functional Connectivity in Posttraumatic Stress Disorder. AB - The neuropeptide oxytocin (OT) has been suggested as a promising pharmacological agent for medication-enhanced psychotherapy in posttraumatic stress disorder (PTSD) because of its anxiolytic and prosocial properties. We therefore investigated the behavioral and neurobiological effects of a single intranasal OT administration (40 IU) in PTSD patients. We conducted a randomized, placebo controlled, cross-over resting-state fMRI study in male and female police officers with (n=37, 21 males) and without PTSD (n=40, 20 males). We investigated OT administration effects on subjective anxiety and functional connectivity of basolateral (BLA) and centromedial (CeM) amygdala subregions with prefrontal and salience processing areas. In PTSD patients, OT administration resulted in decreased subjective anxiety and nervousness. Under placebo, male PTSD patients showed diminished right CeM to left ventromedial prefrontal cortex (vmPFC) connectivity compared with male trauma-exposed controls, which was reinstated after OT administration. Additionally, female PTSD patients showed enhanced right BLA to bilateral dorsal anterior cingulate cortex (dACC) connectivity compared with female trauma-exposed controls, which was dampened after OT administration. Although caution is warranted, our findings tentatively suggest that OT has the potential to diminish anxiety and fear expression of the amygdala in PTSD, either via increased control of the vmPFC over the CeM (males) or via decreased salience processing of the dACC and BLA (females). Our findings add to accumulating evidence that OT administration could potentially enhance treatment response in PTSD. PMID- 26741288 TI - Identification of critical variants within SLC44A4, an ulcerative colitis susceptibility gene identified in a GWAS in north Indians. AB - SLC44A4 is one of the seven novel susceptibility genes that were discovered in the first ever genome-wide association study (GWAS) on ulcerative colitis (UC) in the genetically distinct north Indians. This gene seems to be functionally relevant to disease biology as it may contribute to the associated phenotype of Vitamin B1 deficiency among UC patients, hence playing a role in disease pathogenesis. A large number of single-nucleotide polymorphisms (SNPs) are known to be distributed throughout this gene, but the functional status of most are not known. Thus, an extensive investigation of structural and regulatory variants within this gene was undertaken in this study to identify the critical variants amongst them using a combination of fine mapping, in silico and in vitro approaches. A few intronic SNPs were predicted to have regulatory roles on the basis of in silico analysis, suggesting that they may be the critical variants within SLC44A4. This highlights the importance of this gene in UC biology, thus confirming the finding of the GWAS and also warranting additional studies. PMID- 26741289 TI - Occurrence of typical perfusion defects attributed to jailed or occluded side branch after ramus descendens anterior stenting in a patient cohort referred for 13NH3 myocardial PET/CT. AB - AIM: Coronary stenting is frequently accompanied by occlusion or jailing of side branches. This can cause small reversible or persistent perfusion defects on myocardial perfusion single photon emission computed tomography studies, but data from NH3 myocardial perfusion PET/computed tomography (CT) are lacking. This study aimed to describe the occurrence of perfusion defects in patients with ramus descendes anterior (RDA) stents on myocardial perfusion imaging as measured by NH3 PET/CT. METHODS: From 10 September 2013 till 29 August 2014, 53 consecutive RDA-stented patients, who were referred for NH3 PET/CT, were entered into a database. All scans were evaluated for the occurrence of reversible or persisting perfusion defects within the RDA flow territory, which was categorized as normal, infarction, ischemia, or as a small persisting defect after stent placement or small area of ischemia after stent placement, attributable to side branch occlusion (SBO). RESULTS: Of the 53 patients [65+/-10 years, male : female 33 (62%) : 20 (38%)] with an RDA stent, 29 had received a stent in the proximal RDA, 18 in the mid-RDA, and six in both the proximal and the mid-RDA.NH3-measured myocardial perfusion was scored as normal in 26 (49%), as infarction in 5 (9%), and as ischemia in 2 patients (4%). Six patients (11%) showed a small persisting defect within the RDA flow territory, whereas 14 patients (26%) showed a small area of ischemia in the RDA territory. CONCLUSION: myocardial perfusion abnormalities attributed to SBO are frequently observed on NH3 PET/CTs of patients with RDA stents. In the present cohort, 38% of patients showed such small defects in the RDA territory, which proved to be reversible in 70% of the cases. Recognizing and reporting SBO-related perfusion abnormalities will help clinicians to interpret NH3 myocardial PET/CT properly. PMID- 26741287 TI - Genome-wide association study of antibody responses to Plasmodium falciparum candidate vaccine antigens. AB - We conducted a genome-wide association study (GWAS) of antibody responses directed to three Plasmodium falciparum vaccine candidate antigens (MSP1, MSP2 and GLURP) previously associated with different patterns of protection against malaria infection in Senegalese children. A total of 174 950 single-nucleotide polymorphisms (SNPs) were tested for association with immunoglobulin G1 (IgG1) responses directed to MSP1 and to GLURP and with IgG3 responses to MSP2 FC27 and to MSP2 3D7. We first performed a single-trait analysis with each antibody response and then a multiple-trait analysis in which we analyzed simultaneously the three immune responses associated with the control of clinical malaria episodes. Suggestive associations (P<1 * 10(-4)) were observed for 25 SNPs in MSP1 antibody response analysis or in multiple-trait analysis. According to the strength of their observed associations and their functional role, the following genes are of particular interest: RASGRP3 (2p22.3, P=7.6 * 10(-6)), RIMS1 (6q13, P=2.0 * 10(-5)), MVB12B (9q33.3, P=8.9 * 10(-5)) and GNPTAB (12q23.2, P=7.4 * 10( 5)). Future studies will be required to replicate these findings in other African populations. This work will contribute to the elucidation of the host genetic factors underlying variable immune responses to P. falciparum. PMID- 26741290 TI - The role of fluorine-18 fluorodeoxyglucose PET in prognosis evaluation for stem cell transplantation of lymphoma: a systematic review and meta-analysis. AB - The role of fluorine-18 fluorodeoxyglucose PET (F-FDG PET) in prognostic evaluation of pre-stem cell transplantation (SCT) and post-SCT is still uncertain. A systematic review and meta-analysis were carried out to detect the prognostic power of F-FDG PET. 'PubMed', EMBASE, and Springer were searched for relevant articles. Subgroup analysis was carried out to evaluate the F-FDG PET in predicting the prognosis between Hodgkin lymphoma (HL) and non-Hodgkin lymphoma. Finally, 17 studies that included 1192 patients were eligible, 16 studies for progression-free survival (PFS) and 12 studies for overall survival (OS). For the pre-SCT PET or PET/computed tomography scan, the combined hazard ratios (HRs) of PET for PFS and OS were 2.32 and 2.64, respectively. Subgroup analysis showed that the HRs of PFS for HL and non-Hodgkin lymphoma were 3.28 and 2.00, respectively. For the post-SCT PET scan, the combined HR for PFS was 4.61. The sensitivity analysis showed that exlcusion of any single study had no significant effect on HR. We found that F-FDG PET was especially effective in predicting pre STC and post-STC prognosis. The patients with a negative PET scan had a better prognosis compared with those with a positive scan in PFS and OS. In the subgroup analysis, F-FDG PET had a higher value in predicting prognosis before SCT for HL patients. PMID- 26741291 TI - Utility of 18F-FDG PET/CT in the assessment of lymphoepithelioma-like carcinoma. AB - Lymphoepithelioma-like carcinoma (LELC) is a rare Epstein-Barr virus (EBV) related disease, which commonly originates from the lung and is associated with more favourable treatment outcomes compared with other non-LELC thoracic carcinomas. Radiological assessment utilizing fluorine-18 fluorodeoxyglucose PET combined with computed tomography (F-FDG PET/CT) is important for initial disease staging to tailor the treatment strategy, evaluation of treatment response and detection of disease recurrence. The aim of this article was to highlight the utility of F-FDG PET/CT in different stages of disease evaluation of LELC. We reviewed seven patients with histologically proven LELC who underwent F-FDG PET/CT for disease evaluation. We described the F-FDG-avidity of LELC (ranged from maximum standardized uptake value 7.6 to maximum standardized uptake value 14.5 in our series) and highlighted the clinical values of F-FDG PET/CT in different stages of disease evaluation. F-FDG PET/CT enables accurate evaluation of the primary tumour, its relationship with the surrounding structures and accurate staging. It is also useful in treatment response assessment to monitor the efficacy of the treatment and to decide upon treatment strategy. Given the F FDG-avidity of LELC, F-FDG PET/CT is advantageous in detecting tumour recurrence of LELC. LELC is a rare disease entity associated with EBV and is more prevalent in Asia, where EBV is endemic. LELC is an F-FDG-avid tumour. Although the features on F-FDG PET/CT are not specific, F-FDG PET/CT provides valuable information for disease management of LELC. PMID- 26741292 TI - Dispersing Zwitterions into Comb Polymers for Nonviral Transfection: Experiments and Molecular Simulation. AB - Polymer-based gene delivery vehicles benefit from the presence of hydrophilic groups that mitigate the inherent toxicity of polycations and that provide tunable polymer-DNA binding strength and stable complexes (polyplexes). However, hydrophilic groups screen charge, and as such can reduce cell uptake and transfection efficiency. We report the effect of embedding zwitterionic sulfobetaine (SB) groups in cationic comb polymers, using a combination of experiments and molecular simulations. Ring-opening metathesis polymerization (ROMP) produced comb polymers with tetralysine (K4) and SB pendent groups. Dynamic light scattering, zeta potential measurements, and fluorescence-based experiments, together with coarse-grained molecular dynamics simulations, described the effect of SB groups on the size, shape, surface charge, composition, and DNA binding strength of polyplexes formed using these comb polymers. Experiments and simulations showed that increasing SB composition in the comb polymers decreased polymer-DNA binding strength, while simulations indicated that the SB groups distributed throughout the polyplex. This allows polyplexes to maintain a positive surface charge and provide high levels of gene expression in live cells. Notably, comb polymers with nearly 50 mol % SB form polyplexes that exhibit positive surface charge similarly as polyplexes formed from purely cationic comb polymers, indicating the ability to introduce an appreciable amount of SB functionality without screening surface charge. This integrated simulation-experimental study demonstrates the effectiveness of incorporating zwitterions in polyplexes, while guiding the design of new and effective gene delivery vectors. PMID- 26741293 TI - Visual, Ocular Motor, and Cochleo-Vestibular Loss in Patients With Heteroplasmic, Maternally-Inherited Diabetes Mellitus and Deafness (MIDD), 3243 Transfer RNA Mutation. AB - BACKGROUND: Mitochondrial encephalopathy, lactic acidosis, and stroke-like symptoms (MELAS) and MIDD (maternally-inherited diabetes mellitus and deafness) are caused by A3243G transfer RNA mutations that affect mitochondrial function. Hearing loss and early onset diabetes mellitus constitute the main MIDD phenotype. Regarding the ophthalmologic manifestations of MIDD, we hypothesized that decreased vestibulo-ocular reflex (VOR) gain in patients with MIDD may contribute to impaired dynamic visual acuity. METHODS: Neuro-ophthalmologic, neuroimaging, and neuro-otologic evaluations were performed in 2 nonrelated patients with MIDD who complained of oscillopsia with head movement. We obtained quantitative recording of the horizontal and the vertical VOR, using the video head impulse test device. RESULTS: In the 2 patients, we detected visual, ocular motor, and vestibular abnormalities. Decreased VOR gain in the planes of all 3 semicircular canals and impaired dynamic visual acuity was demonstrated in both cases. CONCLUSIONS: MIDD patients are primarily recognized by their advanced hearing loss or deafness, early onset diabetes mellitus, and lactic acidosis. Decreased vision in these patients relates primarily to peri-macular retinal atrophy. In addition, loss of vestibular function causes poor dynamic visual acuity. Both patients, in their late fifties, had evidence of progressive central and peripheral nervous system dysfunction. PMID- 26741294 TI - Design, Synthesis, Assembly, and Engineering of Peptoid Nanosheets. AB - Two-dimensional (2D) atomically defined organic nanomaterials are an important material class with broad applications. However, few general synthetic methods exist to produce such materials in high yields and to precisely functionalize them. One strategy to form ordered 2D organic nanomaterials is through the supramolecular assembly of sequence-defined synthetic polymers. Peptoids, one such class of polymer, are designable bioinspired heteropolymers whose main-chain length and monomer sequence can be precisely controlled. We have recently discovered that individual peptoid polymers with a simple sequence of alternating hydrophobic and ionic monomers can self-assemble into highly ordered, free floating nanosheets. A detailed understanding of their molecular structure and supramolecular assembly dynamics provides a robust platform for the discovery of new classes of nanosheets with tunable properties and novel applications. In this Account, we discuss the discovery, characterization, assembly, molecular modeling, and functionalization of peptoid nanosheets. The fundamental properties of peptoid nanosheets, their mechanism of formation, and their application as robust scaffolds for molecular recognition and as templates for the growth of inorganic minerals have been probed by an arsenal of experimental characterization techniques (e.g., scanning probe, electron, and optical microscopy, X-ray diffraction, surface-selective vibrational spectroscopy, and surface tensiometry) and computational techniques (coarse-grained and atomistic modeling). Peptoid nanosheets are supramolecular assemblies of 16-42-mer chains that form molecular bilayers. They span tens of microns in lateral dimensions and freely float in water. Their component chains are highly ordered, with chains nearly fully extended and packed parallel to one another as a result of hydrophobic and electrostatic interactions. Nanosheets form via a novel interface catalyzed monolayer collapse mechanism. Peptoid chains first assemble into a monolayer at either an air-water or oil-water interface, on which peptoid chains extend, order, and pack into a brick-like pattern. Upon mechanical compression of the interface, the monolayer buckles into stable bilayer structures. Recent work has focused on the design of nanosheets with tunable properties and functionality. They are readily engineerable, as functional monomers can be readily incorporated onto the nanosheet surface or into the interior. For example, functional hydrophilic "loops" have been displayed on the surfaces of nanosheets. These loops can interact with specific protein targets, serving as a potentially general platform for molecular recognition. Nanosheets can also bind metal ions and serve as 2D templates for mineral growth. Through our understanding of the formation mechanism, along with predicted features ascertained from molecular modeling, we aim to further design and synthesize nanosheets as robust protein mimetics with the potential for unprecedented functionality and stability. PMID- 26741295 TI - Effect of Defect Distribution on the Optical Storage Properties of Strontium Gallates with a Low-Dimensional Chain Structure. AB - The low-dimensional structure of the SrGa2O4 host exhibits a self-activated long persistent luminescence related to the creation of the oxygen vacancies. Because of the unique structure of the SrGa2O4 with a chain of cations along the a crystal direction, the emission and trapping centers could be introduced easily when the metal ions of Bi(3+) are doped. Both the photoluminescence and long persistent luminescence are related to two efficient emission centers of Bi(3+) in the two different crystallographic Sr sites, while the photostimulated luminescence spectra exhibit only one emission center of Bi1 ions under excitation at 980 or 808 nm. The results indicate that the distribution of defects in the low-chain structure of the SrGa2O4 host plays a vital role in the capture and transfer processes of carriers, which has a profound influence on the luminescence performance of SrGa2O4:Bi(3+) as one of the electron-trapping materials. PMID- 26741296 TI - Solvation of Esters and Ketones in Supercritical CO2. AB - Vibrational Raman spectra for the C?O stretching modes of three esters with different functional groups (methyl, a single phenyl, and two phenyl groups) were measured in supercritical carbon dioxide (scCO2). The results were compared with Raman spectra for three ketones involving the same functional groups, measured at the same thermodynamic states in scCO2. The peak frequencies of the Raman spectra of these six solute molecules were analyzed by decomposition into the attractive and repulsive energy components, based on the perturbed hard-sphere theory. For all solute molecules, the attractive energy is greater than the repulsive energy. In particular, a significant difference in the attractive energies of the ester CO2 and ketone-CO2 systems was observed when the methyl group is attached to the ester or ketone. This difference was significantly reduced in the solute systems with a single phenyl group and was completely absent in those with two phenyl groups. The optimized structures among the solutes and CO2 molecules based on quantum chemical calculations indicate that greater attractive energy is obtained for a system where the oxygen atom of the ester is solvated by CO2 molecules. PMID- 26741298 TI - Receptor-Mediated Endocytosis of Two-Dimensional Nanomaterials Undergoes Flat Vesiculation and Occurs by Revolution and Self-Rotation. AB - Two-dimensional nanomaterials, such as graphene and transitional metal dichalcogenide nanosheets, are promising materials for the development of antimicrobial surfaces and the nanocarriers for intracellular therapy. Understanding cell interaction with these emerging materials is an urgently important issue to promoting their wide applications. Experimental studies suggest that two-dimensional nanomaterials enter cells mainly through receptor mediated endocytosis. However, the detailed molecular mechanisms and kinetic pathways of such processes remain unknown. Here, we combine computer simulations and theoretical derivation of the energy within the system to show that the receptor-mediated transport of two-dimensional nanomaterials, such as graphene nanosheet across model lipid membrane, experiences a flat vesiculation event governed by the receptor density and membrane tension. The graphene nanosheet is found to undergo revolution relative to the membrane and, particularly, unique self-rotation around its normal during membrane wrapping. We derive explicit expressions for the formation of the flat vesiculation, which reveals that the flat vesiculation event can be fundamentally dominated by a dimensionless parameter and a defined relationship determined by complicated energy contributions. The mechanism offers an essential understanding on the cellular internalization and cytotoxicity of the emerging two-dimensional nanomaterials. PMID- 26741297 TI - N16, a Nacreous Protein, Inhibits Osteoclast Differentiation and Enhances Osteogenesis. AB - N16 is a protein from the nacreous layer of Pinctada fucata, a pearl oyster. It has been found to promote biomineralization, and we hypothesized that it also plays a role in bone metabolism. The cDNA of N16 was cloned and expressed in Escherichia coli to produce N16 protein, which was purified to high homogeneity by ion-exchange and gel filtration columns. The effects of N16 on osteoclast differentiation and osteogenesis were clarified using the murine preosteoclast cell line RAW 264.7 and the preosteoblast cell line MC3T3-E1. Results on preosteoclasts showed that N16 only slightly inhibited cell survival but significantly inhibited differentiation induced by receptor activator of nuclear factor kappa-B ligand (RANKL). Apart from reduced formation of multinucleated osteoclasts, N16-treated cells exhibited lower gene expression and enzymatic activity typical of mature osteoclasts. Actin ring formation and intracellular acidification essential for osteoclastic function were also impaired upon N16 treatment. At concentrations nontoxic to preosteoblasts, N16 strongly up regulated alkaline phosphatase activity and increased mineralized nodule formation, which are indicative of differentiation into osteoblasts. These effects coincided with an increase in mRNA expression of osteoblast markers osteopotin and osteocalcin. The present study demonstrated that N16 has both anabolic and antiresorptive effects on bone, which makes it potentially useful for treating osteoporosis. PMID- 26741299 TI - Predicting Polycyclic Aromatic Hydrocarbon Bioavailability to Mammals from Incidentally Ingested Soils Using Partitioning and Fugacity. AB - Soil and dust ingestion is one of the major human exposure pathways to contaminated soil; however, pollutant transfer from ingested substances to humans cannot currently be confidently predicted. Soil polycyclic aromatic hydrocarbon (PAH) bioavailability is likely dependent upon properties linked to chemical potential and partitioning such as fugacity, fugacity capacity, soil organic carbon, and partitioning to simulated intestinal fluids. We estimated the oral PAH bioavailability of 19 historically contaminated soils fed to juvenile swine. Between soils, PAH blood content, with the exception of benzo(a)pyrene, was not linked to fugacity. In contrast, between individual PAHs, using partitioning explained PAH blood content (area under the curve = 0.47 log fugacity + 0.34, r(2) = 0.68, p < 0.005, n = 14). Soil fugacity capacity predicts PAH soil concentration with an average slope of 0.30 (MUg PAH g(-1) soil) Pa(-1) and r(2)'s of 0.61-0.73. Because PAH blood content was independent of soil concentration, soil fugacity correlated to PAH bioavailability via soil fugacity's link to soil concentration. In conclusion, we can use fugacity to explain PAH uptake from a soil into blood. However, something other than partitioning is critical to explain the differences in PAH uptake into blood between soils. PMID- 26741300 TI - Visible-Light-Promoted and Yb(OTf)3-Catalyzed Constructions of Coumarin-Pyrrole (Iso)quinoline-Fused Pentacycles: Synthesis of Lamellarin Core, Lamellarin D Trimethyl Ether, and Lamellarin H. AB - The efficient construction of a coumarin-pyrrole-isoquinoline-fused pentacycle via the visible-light-promoted cyclization of 4-(isoquinolin-1-ylmethyl)-3 nitrocoumarin or Yb(OTf)3-catalyzed coupling of 4-chloro-3-nitrocoumarin and 1 methylisoquinoline is reported. This methodology has further led to the development of the concise synthesis of the lamellarin core in one, two, and three steps, as well as of lamellarin D trimethyl ether in three steps. PMID- 26741301 TI - The Influence of Nebulized Drugs on Nasal Ciliary Activity. AB - INTRODUCTION: Nebulized drugs are used in the treatment of cystic fibrosis (CF) lung disease, asthma, and COPD, and increasingly also in other chronic lung diseases. Their use in CF is reasonably evidence based, but this is not so for use in other orphan diseases. Potential side effects often have not been studied. Therefore, we evaluated the influence of nebulized drugs on ciliary activity in an in vitro model. METHODS: We constructed an in vitro nebulization model to examine the effect of drugs on ciliary activity. The model was validated by testing solutions with known neutral, positive, or negative effect on ciliary beat frequency (CBF). Next, the influence on CBF of other inhaled drugs was tested. RESULTS: Nebulization of NaCl 0.9% had no influence on CBF, and was used as paired neutral control in further experiments. Salbutamol (Ventolin((r))) had a ciliostimulatory effect (CBF +18%, CBF at t0-t10-t60 7.1-8.5-8.6 Hz, p = 0.002), while hypertonic saline (CBF - 11%, CBF at t0-t10-t60 6.5-5.1-5.9 Hz, p = 0.018) and dry air (CBF -10%, CBF at t0-t10-t60 6.8-5.8-6.1 Hz, p = 0.008) had a cilioinhibitory effect. Nebulization of tobramycin inhaled solution (TOBI((r))) (p = 0.662), colistimethate (Colistineb((r))) (p = 0.369), rhDNAse (Pulmozyme((r))) (p = 0.069), ceftazidim (Glazidim((r))) (p = 0.875), and aztreonam (Cayston((r))) (p = 0.435) did not affect CBF. Obracin((r)), a tobramycin containing solution manufactured for intravenous use, had a negative effect on CBF (CBF - 21%, CBF at t0-t10-t60 6.9-5.2-4.5 Hz, p = 0.004). CONCLUSION: Inhaled drugs that are used off-label might have an influence on ciliary activity. This must be taken into account when prescribing these drugs for non-CF indications. PMID- 26741302 TI - Rheological Properties of Cystic Fibrosis Bronchial Secretion and in Vitro Drug Permeation Study: The Effect of Sodium Bicarbonate. AB - BACKGROUND: Cystic fibrosis (CF) is characterized by a thick, sticky mucus responsible for both airway obstruction and resistance to drug diffusion, reducing the effectiveness of drug delivery to the lung. Studies of drug-mucus interaction may be a crucial step in therapeutic management of CF. In the present research, the effect of a saline solution of sodium bicarbonate (100 mM) on sputum viscosity and the permeation properties of ketoprofen lysinate (Klys) from a previously developed dry powder inhaler were evaluated. METHODS: Rheological measurements were performed using an ARES rotational rheometer (Rheometrics, Inc.) with a parallel plate geometry. The gel fraction, separated from the liquid phase of various sputum samples from CF patients was loaded onto the plate. The elastic (G') and the viscous (G") moduli, tan delta (ratio of G" to G') and eta* (complex viscosity) were evaluated as frequency-dependent parameters. Drug permeation across CF sputum from dry powders was studied by means of Franz-type vertical diffusion cells. The experiments were conducted on untreated sputum and on sputum treated with bicarbonate. RESULTS: Rheological studies showed that the elastic modulus (G') was always greater than the viscous modulus (G") and the viscosity decreased with increasing frequency, as for pseudo-plastic fluids. Bicarbonate caused a downward shift of both the elastic and viscous moduli, with a reduction in complex viscosity. As to drug permeation, the untreated sputum slowed down drug dissolution and permeation compared to buffer permeability (control). Permeation studies across CF sputum treated with bicarbonate showed higher Klys dissolution/permeation than untreated sputum. CONCLUSIONS: The interesting results confirm the previously reported bicarbonate. effectiveness in CF; this weak base seems to act by decreasing high viscosity of the CF bronchial secretion and, potentially, resulting in better mucus clearance and in fighting pulmonary infections. PMID- 26741303 TI - Effects of Emulsion Composition on Pulmonary Tobramycin Delivery During Antibacterial Perfluorocarbon Ventilation. AB - BACKGROUND: The effectiveness of inhaled aerosolized antibiotics is limited by poor ventilation of infected airways. Pulmonary delivery of antibiotics emulsified within liquid perfluorocarbon [antibacterial perfluorocarbon ventilation (APV)] may solve this problem through better airway penetration and improved spatial uniformity. However, little work has been done to explore emulsion formulation and the corresponding effects on drug delivery during APV. This study investigated the effects of emulsion formulation on emulsion stability and the pharmacokinetics of antibiotic delivery via APV. METHODS: Gravity-driven phase separation was examined in vitro by measuring emulsion tobramycin concentrations at varying heights within a column of emulsion over 4 hours for varying values of fluorosurfactant concentration (Cfs = 5-48 mg/mL H2O). Serum and pulmonary tobramycin concentrations in rats were then evaluated following pulmonary tobramycin delivery via aerosol or APV utilizing sufficiently stable emulsions of varying aqueous volume percentage (Vaq = 1%-5%), aqueous tobramycin concentration (Ct = 20-100 mg/mL), and Cfs (15 and 48 mg/mL H2O). RESULTS: In vitro assessment showed sufficient spatial and temporal uniformity of tobramycin dispersion within emulsion for Cfs >=15 mg/mL H2O, while lower Cfs values showed insufficient emulsification even immediately following preparation. APV with stable emulsion formulations resulted in 5-22 times greater pulmonary tobramycin concentrations at 4 hours post-delivery relative to aerosolized delivery. Concentrations increased with emulsion formulations utilizing increased Vaq (with decreased Ct) and, to a lesser extent, increased Cfs. CONCLUSIONS: The emulsion stability necessary for effective delivery is retained at Cfs values as low as 15 mg/mL H2O. Additionally, the pulmonary retention of antibiotic delivered via APV is significantly greater than that of aerosolized delivery and can be most effectively increased by increasing Vaq and decreasing Ct. APV has been further proven as an effective means of pulmonary drug delivery with the potential to significantly improve antibiotic therapy for lung disease patients. PMID- 26741305 TI - The effect of mechanical vibration on orthodontically induced root resorption. AB - OBJECTIVE: To investigate the effect of low-frequency mechanical vibration (LFMV) on orthodontically induced root resorption. MATERIALS AND METHODS: Forty male CD1, 12-week-old mice were used for the study. The mice were randomly divided into five groups: group 1 (baseline)-no spring and no mechanical vibration, group 2-orthodontic spring but no vibration, group 3-orthodontic spring and 5 Hz of vibration applied to the maxillary first molar, group 4-orthodontic spring and 10 Hz of vibration applied to maxillary first molar, and group 5-orthodontic spring and 20 Hz of vibration applied to maxillary first molar. In the different experimental groups, the first molar was moved mesially for 2 weeks using a nickel-titanium coil spring delivering 10 g of force. LFMVs were applied at 5 Hz, 10 Hz, and 20 Hz. Microfocus X-ray computed tomography imaging was used to analyze root resorption. Additionally, to understand the mechanism, we applied LFMV to MC3T3 cells, and gene expression analyses were done for receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG). RESULTS: Orthodontic tooth movement leads to decreased root volume (increased root resorption craters). Our in vivo experiments showed a trend toward increase in root volume with different frequencies of mechanical vibration. In vitro gene expression analyses showed that with 20 Hz of mechanical vibration, there was a significant decrease in RANKL and a significant increase in OPG expression. CONCLUSION: There was a trend toward decreased root resorption with different LFMVs (5 Hz, 10 Hz, and 20 Hz); however, it was not more statistically significant than the orthodontic-spring-only group. PMID- 26741304 TI - Force decay and dimensional changes of thermoplastic and novel thermoset elastomeric ligatures. AB - OBJECTIVES: To compare over a period of 8 weeks (1) the force decay and (2) the dimensional changes between thermoplastic (TP) and thermoset (TS) elastomeric ligatures. MATERIALS AND METHODS: TP and TS elastomeric ligatures were obtained from Rocky Mountain OrthodonticsTM. The TS ligatures were custom made specifically for this study. The sample included 72 clear TP and 72 clear TS elastomeric ligatures. The experiment was performed in a simulated oral environment (pH of 6.75) at 37 degrees C. The remaining forces and the dimensional changes were measured at different time points over a period of 8 weeks. RESULTS: Student's t-tests revealed significant differences in percent force loss, percent change in outer diameter, percent change in inner diameter, and percent change in wall thickness between TP and TS elastomeric ligatures across all time points (P < .001). The difference in percent change in width between TP and TS elastomeric ligatures was not significant at all time points (P > .05). The mean difference in force loss between TP and TS across all time points was 22.91%. The TP and TS specimens exhibited 93.04% and 77.41% force loss, respectively, at the 28th day. CONCLUSIONS: This novel TS elastomeric ligature showed significantly less force decay and dimensional changes over time; therefore, it might be superior during initial leveling and aligning and during finishing stages. Using a transfer jig to prevent relaxation of the specimens before force measurement showed that force decay of commercially available elastomeric ligatures was greater than that described in previous publications. PMID- 26741306 TI - Comparison of anterior and posterior mini-implant-assisted maxillary incisor intrusion: Root resorption and treatment efficiency. AB - OBJECTIVE: To compare, through cone-beam computed tomography (CBCT), the root resorption and treatment efficiency of two different mini-implant-assisted modalities in intruding the maxillary incisors. MATERIALS AND METHODS: Thirty-two adults who had deep bite and elongated maxillary incisors were randomly allocated to two groups: anterior mini-implant group (AMG) and posterior mini-implant group (PMG). In the AMG, approximately 40 g of force was applied per side with elastic chains from mini-implants placed between the lateral incisors and canines and in the PMG, with beta-titanium wires from mini-implants placed between the second premolars and first molars. This study was conducted on CBCT scans taken before intrusion and after 4 months of intrusion. Data were analyzed by means of a paired t-test, independent t-test, and Pearson's correlation test. RESULTS: One patient was excluded from the AMG due to mini-implant loosening. While the incisors showed a significant reduction in length and volume, this amount was greater in the AMG, especially in the central incisors (P < .05). Together with the mean intrusion rates of 0.62 and 0.39 mm/mo in the AMG and PMG respectively, the center of resistance of the incisors showed distal movement with labial tipping; these changes were greater in the PMG (P < .001). Volumetric root resorption was correlated with the amount of intrusion (P < .05). CONCLUSIONS: Intrusion anchoring from posterior mini-implants is preferred in cases of upright incisors, as the use of such mechanics directs the roots into the spongiosa where they undergo less root resorption and more labial tipping. PMID- 26741321 TI - Utility of ATRX immunohistochemistry in diagnosis of adult diffuse gliomas. AB - AIMS: We performed an immunohistochemical analysis of alpha-thalassaemia/mental retardation syndrome X-linked (ATRX) expression in adult diffuse gliomas, with reference to clinicopathological and genetic features, to determine the utility of this analysis in diagnostic practice. METHODS AND RESULTS: A total of 193 adult diffuse gliomas underwent immunohistochemical analysis. In areas in which internal controls, neurones, glia and blood vessels were properly stained, the ATRX immunoreactivity of tumour cells was either almost totally absent or completely retained in all cases. There was perfect concordance between the immunohistochemical results and ATRX mutation status, which was known in 19 cases. ATRX loss was observed in 54.5, 30.8 and 0.0% of grades II/III astrocytomas, oligoastrocytomas and oligodendrogliomas, respectively, and 12.7% of glioblastomas. In grades II/III gliomas, most ATRX-loss cases (92.3%) had IDH1/2 mutations. ATRX loss was associated significantly with TP53 mutation and p53 overexpression (P < 0.001), but was never accompanied by 1p/19q co-deletion. IDH1/2 mutation in ATRX-loss tumours was less frequent in glioblastomas than in grades II/III gliomas (P < 0.001). Further, there was no significant association between ATRX loss and p53 overexpression in glioblastomas. ATRX-loss glioblastomas affected younger patients (P < 0.001) and occurred more frequently in locations other than the cerebral hemispheres (P = 0.006). Most grades II/III gliomas (93.3%) were categorized into three molecular subtypes based on the status of IDH1/2 mutation, ATRX immunohistochemistry and 1p/19q co-deletion. CONCLUSIONS: Distinct histological and molecular characteristics of adult diffuse gliomas with and without ATRX immunoreactivity indicate the utility of ATRX immunohistochemistry in diagnostic practice. PMID- 26741322 TI - Cannabinoid receptor-2 agonist inhibits macrophage induced EMT in non-small cell lung cancer by downregulation of EGFR pathway. AB - JWH-015, a cannabinoid receptor 2 (CB2) agonist has tumor regressive property in various cancer types. However, the underlying mechanism by which it acts in lung cancer is still unknown. Tumor associated macrophage (TAM) intensity has positive correlation with tumor progression. Also, macrophages recruited at the tumor site promote tumor growth by enhancing epithelial to mesenchymal (EMT) progression. In this study, we analyzed the role of JWH-015 on EMT and macrophage infiltration by regulation of EGFR signaling. JWH-015 inhibited EMT in NSCLC cells A549 and also reversed the mesenchymal nature of CALU-1 cells by downregulation of EGFR signaling targets like ERK and STAT3. Also, in vitro co-culture experiments of A549 with M2 polarized macrophages provided evidence that JWH-015 decreased migratory and invasive abilities which was proved by reduced expression of FAK, VCAM1, and MMP2. Furthermore, it decreased macrophage induced EMT in A549 by attenuating the mesenchymal character by downregulating EGFR and its targets. These results were confirmed in an in vivo subcutaneous syngenic mouse model where JWH-015 blocks tumor growth and also inhibits macrophage recruitment and EMT at the tumor site which was regulated by EGFR pathway. Finally, JWH-015 reduced lung tumor lesions in an in vivo tumorigenicity mouse model. These data confer the impact of this cannabinoid on anti-proliferative and anti-tumorigenic effects, thus enhancing our understanding of its therapeutic efficacy in NSCLC. Our findings open new avenues for cannabinoid receptor CB2 agonist-JWH-015 as a novel and potential therapeutic target based on EGFR downregulation mechanisms in NSCLC. (c) 2016 Wiley Periodicals, Inc. PMID- 26741323 TI - Detection of Aedes aegypti, Aedes albopictus, and Aedes koreicus in the Area of Sochi, Russia. AB - Following the identification of Aedes (Ae.) aegypti in the Sochi area in Russia at the beginning of 2000, entomological surveys were conducted during the summers of 2007, 2011, and 2012, leading to the identification of Ae. albopictus and Ae. koreicus. These findings highlight Russia as being the only country in the World Health Organization European Region with a documented presence of both Ae. aegypti and Ae. albopictus mosquitoes. Both mosquito species are found on the coasts of the Black Sea. Control measures are needed to reduce the possible risks of importing exotic vector-borne infections, such as dengue and chikungunya. PMID- 26741324 TI - Molecular Investigation of Francisella-Like Endosymbiont in Ticks and Francisella tularensis in Ixodid Ticks and Mosquitoes in Turkey. AB - This study was carried out to investigate the molecular prevalence of Francisella like endosymbionts (FLEs) and Francisella tularensis in ticks (Acari: Ixodidae) and mosquitoes in Turkey. Genomic DNA pools were constructed from a total of 1477 adult hard ticks of Rhipicephalus (Rh.) annulatus, Rh. turanicus, Rh. sanguineus, Rh. bursa, Haemaphysalis (Hae.) parva, Hae. sulcata, Hyalomma marginatum marginatum, H. anatolicum anatolicum, H. anatolicum excavatum, H. detritum detritum, H. dromedarii, Dermacentor marginatus, and Ixodes ricinus species, which were collected from several barns, cattle, and people. Genomic DNA was also extracted from pools consisting of 6203 adult female mosquito species belonging to Aedes vexans, Culex (Cx.) pipiens, Cx. hortensis, Cx. theileri, Culiseta annulata, and Anopheles maculipennis species. Conventional PCR and TaqMan probe based real- time PCR targeting the 16S rRNA gene for FLEs and the lpnA gene for F. tularensis, respectively, were performed on the DNA isolates obtained. FLEs and F. tularensis were not found in any genomic DNA pools constructed from ixodid ticks and mosquitos. This study represents the first investigation of F. tularensis and FLEs in potential vector ticks and mosquitoes by molecular methods in Turkey. The present study provides useful insights into the molecular epidemiology of F. tularensis and FLEs. One of the major conclusions of the study is that tularemia outbreaks may be essentially due to direct transmission from the environment (especially from water) in Turkey and not to vector-borne transmission. PMID- 26741325 TI - Avian Chlamydiosis Zoonotic Disease. AB - This review presents recent data about avian chlamydiosis. Chlamydia psittaci has been considered to be the main causative agent of chlamydiosis in birds; however, two new Chlamydia species have been detected recently-C. gallinacea in breeding birds and C. avium in wild birds. We discuss the zoonotic potential of avian Chlamydia species. PMID- 26741327 TI - The Longitudinal Interplay of Adolescents' Self-Esteem and Body Image: A Conditional Autoregressive Latent Trajectory Analysis. AB - Self-esteem and body image are central to coping successfully with the developmental challenges of adolescence. However, the current knowledge surrounding self-esteem and body image is fraught with controversy. This study attempts to clarify some of them by addressing three questions: (1) Are the intraindividual developmental trajectories of self-esteem and body image stable across adolescence? (2) What is the direction of the relations between body image and self-esteem over time? (3) What is the role of gender, ethnicity, and pubertal development on those trajectories? This study relies on Autoregressive Latent Trajectory analyses based on data from a 4-year, 6-wave, prospective longitudinal study of 1,001 adolescents. Self-esteem and body image levels remained high and stable over time, although body image levels also tended to increase slightly. The results show that levels of self-esteem were positively influenced by levels of body image. However, these effects remained small and most of the observed associations were cross-sectional. Finally, the effects of pubertal development on body image and self-esteem levels were mostly limited to non-Caucasian females who appeared to benefit from more advanced pubertal development. Conversely, Caucasian females presented the lowest self-esteem and body image levels of all, although for them more advanced pubertal development levels were associated with a slight rise in body image over time. PMID- 26741328 TI - Sensitivity Analysis in Structural Equation Models: Cases and Their Influence. AB - The detection of outliers and influential observations is routine practice in linear regression. Despite ongoing extensions and development of case diagnostics in structural equation models (SEM), their application has received limited attention and understanding in practice. The use of case diagnostics informs analysts of the uncertainty of model estimates under different subsets of the data and highlights unusual and important characteristics of certain cases. We present several measures of case influence applicable in SEM and illustrate their implementation, presentation, and interpretation with two empirical examples: (a) a common factor model on verbal and visual ability ( Holzinger & Swineford, 1939 ) and (b) a general structural equation model assessing the effect of industrialization on democracy in a mediating model using country-level data ( Bollen, 1989 ; Bollen & Arminger, 1991 ). Throughout these examples, three issues are emphasized. First, cases may impact different aspects of results as identified by different measures of influence. Second, the important distinction between outliers and influential cases is highlighted. Third, the concept of good and bad cases is introduced-these are influential cases that improve/worsen overall model fit based on their presence in the sample. We conclude with a discussion on the utility of detecting influential cases in SEM and present recommendations for the use of measures of case influence. PMID- 26741329 TI - Bias and Efficiency in Structural Equation Modeling: Maximum Likelihood Versus Robust Methods. AB - In the structural equation modeling literature, the normal-distribution-based maximum likelihood (ML) method is most widely used, partly because the resulting estimator is claimed to be asymptotically unbiased and most efficient. However, this may not hold when data deviate from normal distribution. Outlying cases or nonnormally distributed data, in practice, can make the ML estimator (MLE) biased and inefficient. In addition to ML, robust methods have also been developed, which are designed to minimize the effects of outlying cases. But the properties of robust estimates and their standard errors (SEs) have never been systematically studied. This article studies two robust methods and compares them against the ML method with respect to bias and efficiency using a confirmatory factor model. Simulation results show that robust methods lead to results comparable with ML when data are normally distributed. When data have heavy tails or outlying cases, robust methods lead to less biased and more efficient estimators than MLEs. A formula to obtain consistent SEs for one of the robust methods is also developed. The formula-based SEs for both robust estimators match the empirical SEs very well with medium-size samples. A sample of the Cross Racial Identity Scale with a 6-factor model is used for illustration. Results also confirm conclusions of the simulation study. PMID- 26741330 TI - Dynamic Factor Analysis Models With Time-Varying Parameters. AB - Dynamic factor analysis models with time-varying parameters offer a valuable tool for evaluating multivariate time series data with time-varying dynamics and/or measurement properties. We use the Dynamic Model of Activation proposed by Zautra and colleagues (Zautra, Potter, & Reich, 1997) as a motivating example to construct a dynamic factor model with vector autoregressive relations and time varying cross-regression parameters at the factor level. Using techniques drawn from the state-space literature, the model was fitted to a set of daily affect data (over 71 days) from 10 participants who had been diagnosed with Parkinson's disease. Our empirical results lend partial support and some potential refinement to the Dynamic Model of Activation with regard to how the time dependencies between positive and negative affects change over time. A simulation study is conducted to examine the performance of the proposed techniques when (a) changes in the time-varying parameters are represented using the true model of change, (b) supposedly time-invariant parameters are represented as time-varying, and PMID- 26741331 TI - The Hull Method for Selecting the Number of Common Factors. AB - A common problem in exploratory factor analysis is how many factors need to be extracted from a particular data set. We propose a new method for selecting the number of major common factors: the Hull method, which aims to find a model with an optimal balance between model fit and number of parameters. We examine the performance of the method in an extensive simulation study in which the simulated data are based on major and minor factors. The study compares the method with four other methods such as parallel analysis and the minimum average partial test, which were selected because they have been proven to perform well and/or they are frequently used in applied research. The Hull method outperformed all four methods at recovering the correct number of major factors. Its usefulness was further illustrated by its assessment of the dimensionality of the Five Factor Personality Inventory ( Hendriks, Hofstee, & De Raad, 1999 ). This inventory has 100 items, and the typical methods for assessing dimensionality prove to be useless: the large number of factors they suggest has no theoretical justification. The Hull method, however, suggested retaining the number of factors that the theoretical background to the inventory actually proposes. PMID- 26741332 TI - On the Usefulness of a Multilevel Logistic Regression Approach to Person-Fit Analysis. AB - The logistic person response function (PRF) models the probability of a correct response as a function of the item locations. Reise (2000) proposed to use the slope parameter of the logistic PRF as a person-fit measure. He reformulated the logistic PRF model as a multilevel logistic regression model and estimated the PRF parameters from this multilevel framework. An advantage of the multilevel framework is that it allows relating person fit to explanatory variables for person misfit/fit. We critically discuss Reise's approach. First, we argue that often the interpretation of the PRF slope as an indicator of person misfit is incorrect. Second, we show that the multilevel logistic regression model and the logistic PRF model are incompatible, resulting in a multilevel person-fit framework, which grossly violates the bivariate normality assumption for residuals in the multilevel model. Third, we use a Monte Carlo study to show that in the multilevel logistic regression framework estimates of distribution parameters of PRF intercepts and slopes are biased. Finally, we discuss the implications of these results and suggest an alternative multilevel regression approach to explanatory person-fit analysis. We illustrate the alternative approach using empirical data on repeated anxiety measurements of cardiac arrhythmia patients who had a cardioverter-defibrillator implanted. PMID- 26741344 TI - Analytical estimation of ultrasound properties, thermal diffusivity, and perfusion using magnetic resonance-guided focused ultrasound temperature data. AB - For thermal modeling to play a significant role in treatment planning, monitoring, and control of magnetic resonance-guided focused ultrasound (MRgFUS) thermal therapies, accurate knowledge of ultrasound and thermal properties is essential. This study develops a new analytical solution for the temperature change observed in MRgFUS which can be used with experimental MR temperature data to provide estimates of the ultrasound initial heating rate, Gaussian beam variance, tissue thermal diffusivity, and Pennes perfusion parameter. Simulations demonstrate that this technique provides accurate and robust property estimates that are independent of the beam size, thermal diffusivity, and perfusion levels in the presence of realistic MR noise. The technique is also demonstrated in vivo using MRgFUS heating data in rabbit back muscle. Errors in property estimates are kept less than 5% by applying a third order Taylor series approximation of the perfusion term and ensuring the ratio of the fitting time (the duration of experimental data utilized for optimization) to the perfusion time constant remains less than one. PMID- 26741346 TI - SOX17 promoter methylation in plasma circulating tumor DNA of patients with non small cell lung cancer. AB - BACKGROUND: SOX17 belongs to the high-mobility group-box transcription factor superfamily and down-regulates the Wnt pathway. The aim of our study was to evaluate the prognostic significance of SOX17 promoter methylation in circulating tumor DNA (ctDNA) in plasma of non-small cell lung cancer (NSCLC) patients. METHODS: We examined the methylation status of SOX17 promoter in 57 operable NSCLC primary tumors and paired adjacent non-cancerous tissues and in ctDNA isolated from 48 corresponding plasma samples as well as in plasma from 74 patients with advanced NSCLC and 49 healthy individuals. SOX17 promoter methylation was examined by Methylation Specific PCR (MSP). RESULTS: In operable NSCLC, SOX17 promoter was fully methylated in primary tumors (57/57, 100%), and in corresponding ctDNA (27/48, 56.2%) while it was detected in only 1/49 (2.0%) healthy individuals. In advanced NSCLC, SOX17 promoter was methylated in ctDNA in 27/74 (36.4%) patients and OS was significantly different in favor of patients with non-methylated SOX17 promoter (p=0.012). Multivariate analysis revealed that SOX17 promoter methylation in ctDNA was an independent prognostic factor associated with OS in patients with advanced but not operable NSCLC. CONCLUSIONS: Our results show that SOX17 promoter is highly methylated in primary tumors and in corresponding plasma samples both in operable and advanced NSCLC. In the advanced setting, SOX17 promoter methylation in plasma ctDNA has a statistical significant influence on NSCLC patient's survival time. Detection of SOX17 promoter methylation in plasma provides prognostic information and merits to be further evaluated as a circulating tumor biomarker in patients with operable and advanced NSCLC. PMID- 26741345 TI - Analytical and clinical evaluation of the new Fujirebio Lumipulse(r)G non competitive assay for 25(OH)-vitamin D and three immunoassays for 25(OH)D in healthy subjects, osteoporotic patients, third trimester pregnant women, healthy African subjects, hemodialyzed and intensive care patients. AB - BACKGROUND: In this study, we provide a short analytical evaluation of the new Fujirebio Lumipulse(r)G non-competitive immunoassay for 25(OH)D. Clinical performance was compared with three commercial competitive automated immunoassays against a Vitamin D Standardization Program (VDSP)-traceable liquid chromatography-tandem mass spectrometry (LC-MS/MS) in six different clinically relevant populations. METHODS: Lumipulse(r)G 25(OH)D precision, measurement uncertainty, recovery, limit of quantification were assessed, as well as 25(OH)D2 and C3-epimer recovery. For method comparison, 250 serum samples obtained in healthy Caucasians and Africans, osteoporotic, hemodialyzed and intensive care patients and 3rd trimester pregnant women were analyzed by all methods. Correlation was studied using Passing-Bablok and Bland-Altman analysis. Concordance correlation coefficient (CCC) was calculated to evaluate agreement between immunoassays and the LC-MS/MS. RESULTS: The Lumipulse(r)G 25(OH)D assay presented interesting analytical features and showed excellent correlation to the LC-MS/MS results (y=1.00*-1.35 ng/mL), as obtained in healthy Caucasian individuals. In the other special populations, Lumipulse(r)G presented a concordance with LC-MS/MS which was generally higher than competitors, even if all methods significantly under-recovered 25(OH)D in hemodialyzed patients. Intra assay CV ranged from 12.1% at 9.6 ng/mL to 2.1% at 103.7 ng/mL and inter-assay CV ranged from 16.2 to 3.7% at the same concentrations, respectively. Measurement uncertainty, with a probability of 95%, were respectively 33.1 and 7.6% at these concentrations. LOQ was found to be at 4.6 ng/mL. Mean (95% CI) 25(OH)D2 revovery was 77% (74-81) and no cross-reactivity was observed with C3-epimer. CONCLUSIONS: Fujirebio Lumipulse(r)G 25-OH Vitamin D Total assay is therefore considered suitable for assessment of vitamin D status in clinical routine. PMID- 26741347 TI - Mother's instinct - a rare case of multiple test interferences due to heterophile antibodies. PMID- 26741348 TI - A national survey of preanalytical handling of oral glucose tolerance tests in pregnancy. PMID- 26741349 TI - The way of prostate cancer diagnostics. PMID- 26741350 TI - Low serum bilirubin values are associated with pulmonary embolism in a case control study. PMID- 26741351 TI - Intramyocellular fat storage in metabolic diseases. AB - Over the past decades, obesity and its metabolic co-morbidities such as type 2 diabetes (T2D) developed to reach an endemic scale. However, the mechanisms leading to the development of T2D are still poorly understood. One main predictor for T2D seems to be lipid accumulation in "non-adipose" tissues, best known as ectopic lipid storage. A growing body of data suggests that these lipids may play a role in impairing insulin action in metabolic tissues, such as liver and skeletal muscle. This review aims to discuss recent literature linking ectopic lipid storage and insulin resistance, with emphasis on lipid deposition in skeletal muscle. The link between skeletal muscle lipid content and insulin sensitivity, as well as the mechanisms of lipid-induced insulin resistance and potential therapeutic strategies to alleviate lipotoxic lipid pressure in skeletal muscle will be discussed. PMID- 26741352 TI - Practical prospects for boosting hepatic production of the "pro-longevity" hormone FGF21. AB - Fibroblast growth factor-21 (FGF21), produced mainly in hepatocytes and adipocytes, promotes leanness, insulin sensitivity, and vascular health while down-regulating hepatic IGF-I production. Transgenic mice overexpressing FGF21 enjoy a marked increase in median and maximal longevity comparable to that evoked by calorie restriction - but without a reduction in food intake. Transcriptional factors which promote hepatic FGF21 expression include PPARalpha, ATF4, STAT5, and FXR; hence, fibrate drugs, elevated lipolysis, moderate-protein vegan diets, growth hormone, and bile acids may have potential to increase FGF21 synthesis. Sirt1 activity is required for optimal responsiveness of FGF21 to PPARalpha, and Sirt1 activators can boost FGF21 transcription. Conversely, histone deacetylase 3 (HDAC3) inhibits PPARalpha's transcriptional impact on FGF21, and type 1 deacetylase inhibitors such as butyrate therefore increase FGF21 expression. Glucagon-like peptide-1 (GLP-1) increases hepatic expression of both PPARalpha and Sirt1; acarbose, which increases intestinal GLP-1 secretion, also increases FGF21 and lifespan in mice. Glucagon stimulates hepatic production of FGF21 by increasing the expression of the Nur77 transcription factor; increased glucagon secretion can be evoked by supplemental glycine administered during post absorptive metabolism. The aryl hydrocarbon receptor (AhR) has also been reported recently to promote FGF21 transcription. Bilirubin is known to be an agonist for this receptor, and this may rationalize a recent report that heme oxygenase-1 induction in the liver boosts FGF21 expression. There is reason to suspect that phycocyanorubin, a bilirubin homolog that is a metabolite of the major phycobilin in spirulina, may share bilirubin's agonist activity for AhR, and perhaps likewise promote FGF21 induction. In the future, regimens featuring a plant-based diet, nutraceuticals, and safe drugs may make it feasible to achieve physiologically significant increases in FGF21 that promote metabolic health, leanness, and longevity. PMID- 26741353 TI - Ingestion of a natural mineral-rich water in an animal model of metabolic syndrome: effects in insulin signalling and endoplasmic reticulum stress. AB - BACKGROUND: High-fructose and/or low-mineral diets are relevant in metabolic syndrome (MS) development. Insulin resistance (IR) represents a central mechanism in MS development. Glucocorticoid signalling dysfunction and endoplasmic reticulum (ER) and oxidative stresses strongly contribute to IR and associate with MS. We have described that natural mineral-rich water ingestion delays fructose-induced MS development, modulates fructose effects on the redox state and glucocorticoid signalling and increases sirtuin 1 expression. Here, we investigated mineral-rich water ingestion effects on insulin signalling and ER homeostasis of fructose-fed rats. MATERIALS AND METHODS: Adult male Sprague Dawley rats had free access to standard-chow diet and different drinking solutions (8 weeks): tap water (CONT), 10%-fructose/tap water (FRUCT) or 10% fructose/mineral-rich water (FRUCTMIN). Hepatic and adipose (visceral, VAT) insulin signalling and hepatic ER homeostasis (Western blot or PCR) as well as hepatic lipid accumulation were evaluated. RESULTS: Hepatic p-IRS1Ser307/IRS1 (tendency), p-IRS1Ser307, total JNK and (activated IRE1alpha)/(activated JNK) decreased with fructose ingestion, while p-JNK tended to increase; mineral-rich water ingestion, totally or partially, reverted all these effects. Total PERK, p eIF2alpha (tendency) and total IRS1 (tendency) decreased in both fructose-fed groups. p-ERK/ERK and total IRE1alpha increasing tendencies in FRUCT became significant in FRUCTMIN (similar pattern for lipid area). Additionally, unspliced XBP1 increased with mineral-rich water. In VAT, total ERK fructose-induced increase was partially prevented in FRUCTMIN. CONCLUSIONS: Mineral-rich water modulation of fructose-induced effects on insulin signalling and ER homeostasis matches the better metabolic profile previously reported. Increased p-ERK/ERK, adding to decreased IRE1alpha activation, and increased unspliced-XBP1 and lipid area may protect against oxidative stress and IR development in FRUCTMIN. PMID- 26741354 TI - The dendritic cell side of the immunological synapse. AB - Immune responses are initiated by the interactions between antigen-presenting cells (APCs), such as dendritic cells (DCs), with responder cells, such as T cells, via a tight cellular contact interface called the immunological synapse. The immunological synapse is a highly organized subcellular structure that provides a platform for the presentation of antigen in major histocompatibility class I and II complexes (MHC class I and II) on the surface of the APC to receptors on the surface of the responder cells. In T cells, these contacts lead to highly polarized membrane trafficking that results in the local release of lytic granules and in the delivery and recycling of T cell receptors at the immunological synapse. Localized trafficking also occurs at the APC side of the immunological synapse, especially in DCs where antigen loaded in MHC class I and II is presented and cytokines are released specifically at the synapse. Whereas the molecular mechanisms underlying polarized membrane trafficking at the T cell side of the immunological synapse are increasingly well understood, these are still very unclear at the APC side. In this review, we discuss the organization of the APC side of the immunological synapse. We focus on the directional trafficking and release of membrane vesicles carrying MHC molecules and cytokines at the immunological synapses of DCs. We hypothesize that the specific delivery of MHC and the release of cytokines at the immunological synapse mechanistically resemble that of lytic granule release from T cells. PMID- 26741355 TI - Diagnosis of Tuberculosis in Three Zoo Elephants and a Human Contact - Oregon, 2013. AB - In 2013, public health officials in Multnomah County, Oregon, started an investigation of a tuberculosis (TB) outbreak among elephants and humans at a local zoo. The investigation ultimately identified three bull elephants with active TB and 118 human contacts of the elephants. Ninety-six (81%) contacts were evaluated, and seven close contacts were found to have latent TB infection. The three bulls were isolated and treated (elephants with TB typically are not euthanized) to prevent infection of other animals and humans, and persons with latent infection were offered treatment. Improved TB screening methods for elephants are needed to prevent exposure of human contacts. PMID- 26741356 TI - Peer counseling to improve shared decision making in surplus embryo disposition. PMID- 26741357 TI - WITHDRAWN: Orthodontics for treating temporomandibular joint (TMJ) disorders. PMID- 26741358 TI - Design, synthesis and biological evaluation of N-phenylquinazolin-4-amine hybrids as dual inhibitors of VEGFR-2 and HDAC. AB - A single agent that simultaneously inhibits multiple targets may offer greater therapeutic benefits in cancer than single-acting agents through interference with multiple pathways and potential synergistic action. In this work, a series of hybrids bearing N-phenylquinazolin-4-amine and hydroxamic acid moieties were designed and identified as dual VEGFR-2/HDAC inhibitors. Compound 6fd exhibited the most potent inhibitory activity against HDAC with IC50 of 2.2 nM and strong inhibitory effect against VEGFR-2 with IC50 of 74 nM. It also showed the most potent inhibitory activity against a human breast cancer cell line MCF-7 with IC50 of 0.85 MUM. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the active binding sites of VEGFR-2 and HDLP ((Histone Deacetylase-Like Protein), which demonstrates that compound 6fd is a potential agent for cancer therapy deserving further researching. PMID- 26741359 TI - Faster Adaptation in Smaller Populations: Counterintuitive Evolution of HIV during Childhood Infection. AB - Analysis of HIV-1 gene sequences sampled longitudinally from infected individuals can reveal the evolutionary dynamics that underlie associations between disease outcome and viral genetic diversity and divergence. Here we extend a statistical framework to estimate rates of viral molecular adaptation by considering sampling error when computing nucleotide site-frequencies. This is particularly beneficial when analyzing viral sequences from within-host viral infections if the number of sequences per time point is limited. To demonstrate the utility of this approach, we apply our method to a cohort of 24 patients infected with HIV-1 at birth. Our approach finds that viral adaptation arising from recurrent positive natural selection is associated with the rate of HIV-1 disease progression, in contrast to previous analyses of these data that found no significant association. Most surprisingly, we discover a strong negative correlation between viral population size and the rate of viral adaptation, the opposite of that predicted by standard molecular evolutionary theory. We argue that this observation is most likely due to the existence of a confounding third variable, namely variation in selective pressure among hosts. A conceptual non-linear model of virus adaptation that incorporates the two opposing effects of host immunity on the virus population can explain this counterintuitive result. PMID- 26741360 TI - A Trypanosomatid Iron Transporter that Regulates Mitochondrial Function Is Required for Leishmania amazonensis Virulence. AB - Iron, an essential co-factor of respiratory chain proteins, is critical for mitochondrial function and maintenance of its redox balance. We previously reported a role for iron uptake in differentiation of Leishmania amazonensis into virulent amastigotes, by a mechanism that involves reactive oxygen species (ROS) production and is independent of the classical pH and temperature cues. Iron import into mitochondria was proposed to be essential for this process, but evidence supporting this hypothesis was lacking because the Leishmania mitochondrial iron transporter was unknown. Here we describe MIT1, a homolog of the mitochondrial iron importer genes mrs3 (yeast) and mitoferrin-1 (human) that is highly conserved among trypanosomatids. MIT1 expression was essential for the survival of Trypanosoma brucei procyclic but not bloodstream forms, which lack functional respiratory complexes. L. amazonensis LMIT1 null mutants could not be generated, suggesting that this mitochondrial iron importer is essential for promastigote viability. Promastigotes lacking one LMIT1 allele (LMIT1/Deltalmit1) showed growth defects and were more susceptible to ROS toxicity, consistent with the role of iron as the essential co-factor of trypanosomatid mitochondrial superoxide dismutases. LMIT1/Deltalmit1 metacyclic promastigotes were unable to replicate as intracellular amastigotes after infecting macrophages or cause cutaneous lesions in mice. When induced to differentiate axenically into amastigotes, LMIT1/Deltalmit1 showed strong defects in iron content and function of mitochondria, were unable to upregulate the ROS-regulatory enzyme FeSOD, and showed mitochondrial changes suggestive of redox imbalance. Our results demonstrate the importance of mitochondrial iron uptake in trypanosomatid parasites, and highlight the role of LMIT1 in the iron-regulated process that orchestrates differentiation of L. amazonensis into infective amastigotes. PMID- 26741361 TI - Inhaled Methane Limits the Mitochondrial Electron Transport Chain Dysfunction during Experimental Liver Ischemia-Reperfusion Injury. AB - BACKGROUND: Methanogenesis can indicate the fermentation activity of the gastrointestinal anaerobic flora. Methane also has a demonstrated anti inflammatory potential. We hypothesized that enriched methane inhalation can influence the respiratory activity of the liver mitochondria after an ischemia reperfusion (IR) challenge. METHODS: The activity of oxidative phosphorylation system complexes was determined after in vitro methane treatment of intact liver mitochondria. Anesthetized Sprague-Dawley rats subjected to standardized 60-min warm hepatic ischemia inhaled normoxic air (n = 6) or normoxic air containing 2.2% methane, from 50 min of ischemia and throughout the 60-min reperfusion period (n = 6). Measurement data were compared with those on sham-operated animals (n = 6 each). Liver biopsy samples were subjected to high-resolution respirometry; whole-blood superoxide and hydrogen peroxide production was measured; hepatocyte apoptosis was detected with TUNEL staining and in vivo fluorescence laser scanning microscopy. RESULTS: Significantly decreased complex II-linked basal respiration was found in the normoxic IR group at 55 min of ischemia and a lower respiratory capacity (~60%) and after 5 min of reperfusion. Methane inhalation preserved the maximal respiratory capacity at 55 min of ischemia and significantly improved the basal respiration during the first 30 min of reperfusion. The IR-induced cytochrome c activity, reactive oxygen species (ROS) production and hepatocyte apoptosis were also significantly reduced. CONCLUSIONS: The normoxic IR injury was accompanied by significant functional damage of the inner mitochondrial membrane, increased cytochrome c activity, enhanced ROS production and apoptosis. An elevated methane intake confers significant protection against mitochondrial dysfunction and reduces the oxidative damage of the hepatocytes. PMID- 26741362 TI - Association with Spontaneous Hepatitis C Viral Clearance and Genetic Differentiation of IL28B/IFNL4 Haplotypes in Populations from Mexico. AB - AIM: To analyze the genetic heterogeneity of the Amerindian and admixed population (Mestizos) based on the IL28B (rs12979860, rs8099917) and IFNL4 (rs368234815) haplotypes, and their association with spontaneous clearance (SC) and liver damage in patients with hepatitis C infection from West Mexico. METHODS: A total of 711 subjects from West Mexico (181 Amerindians and 530 Mestizos) were studied for the prevalence of IL28B (rs12979860C/T, rs8099917G/T) and IFNL4 (rs368234815?G/TT) genotypes. A case-control study was performed in 234 treatment-naive HCV Mestizos (149 chronic hepatitis C and 85 with SC) for the association of haplotypes with SC and liver damage. A real-time PCR assay was used for genotyping, and transitional elastography staged liver damage. RESULTS: Significant Fst-values indicated differentiation between the studied populations. The frequencies of the protective C, T, TT alleles were significantly lower in the Amerindians than in Mestizos (p<0.05). The r2 measure of linkage disequilibrium was significant for all variants and the T/G/DeltaG risk haplotype predominated in Amerindians and secondly in Mestizos. The protective C/T/TT haplotype was associated with SC (OR = 0.46, 95% IC 0.22-0.95, p = 0.03) and less liver damage (OR = 0.32, 95% IC 0.10-0.97, p = 0.04) in chronic patients. The Structure software analysis demonstrated no significant differences in ancestry among SC and chronic patients. CONCLUSIONS: West Mexico's population is genetically heterogeneous at the IL28B/IFNL4 polymorphisms. The T/G/DeltaG high risk haplotype predominated in Amerindians and the beneficial alternative haplotype in Mestizos. The C/T/TT haplotype was associated with SC and less liver damage in chronically infected Mestizo patients. PMID- 26741363 TI - Cataract Surgery Visual Outcomes and Associated Risk Factors in Secondary Level Eye Care Centers of L V Prasad Eye Institute, India. AB - PURPOSE: To evaluate cataract surgery visual outcomes and associated risk factors in rural secondary level eye care centers of L V Prasad Eye Institute (LVPEI), India. METHODS: The Eye Health pyramid of LVPEI has a network of rural secondary care centres (SCs) and attached vision centres (VCs) that provide high quality comprehensive eye care with permanent infrastructure to the most disadvantaged sections of society. The most common procedure performed at SCs is cataract surgery. We audited the outcome of a random sample of 2,049 cataract surgeries done from October 2009-March 2010 at eight rural SCs. All patients received a comprehensive ophthalmic examination, both before and after surgery. The World Health Organization recommended cataract surgical record was used for data entry. Visual outcomes were measured at discharge, 1-3 weeks and 4-11 weeks follow up visits. Poor outcome was defined as best corrected visual acuity <6/18. RESULTS: Mean age was 61.8 years (SD: 8.9 years) and 1,133 (55.3%) surgeries were performed on female patients. Pre-existing ocular co-morbidity was present in 165 patients (8.1%). The most common procedure was small incision cataract surgery (SICS) with intraocular lens (IOL) implantation (91.8%). Intraoperative complications were seen in 29 eyes (1.4%). At the 4-11 weeks follow-up visit, based on presenting visual acuity (PVA), 61.8% had a good outcome and based on best-corrected visual acuity (BCVA), 91.7% had a good outcome. Based on PVA and BCVA, those with less than 6/60 were only 2.9% and 1.6% respectively. Using multivariable analysis, poor visual outcomes were significantly higher in patients aged >=70 (OR 4.63; 95% CI 1.61, 13.30), in females (OR 1.58; 95% CI 1.04, 2.41), those with preoperative comorbidities (odds ratio 4.68; 95% CI 2.90, 7.57), with intraoperative complications (OR 8.01; 95% CI 2.91, 22.04), eyes that underwent no IOL or anterior chamber-IOL (OR 12.63; 95% CI 2.65, 60.25) and those undergoing extracapsular cataract extraction (OR 9.39; 95% CI 1.18, 74.78). CONCLUSIONS: This study demonstrates that quality cataract surgeries can be achieved at rural SCs. The concept of the LVPEI SCs can be applied to other developing countries, allowing rural patients to attain better vision through cataract surgery. Despite improvements in quality of cataract surgery, gender discrimination in terms of outcome continues to be an issue and needs further investigation. PMID- 26741364 TI - Morphostructural investigation of the female reproductive system and molecular evidence for Wolbachia in Balclutha brevis Lindberg 1954 (Hemiptera, Cicadellidae). AB - Balclutha brevis Lindberg 1954 (Homoptera, Cicadellidae) is an allochthonous species that is rapidly spreading in Sicily and in mainland Europe due to the wide spread of its host plant and therefore could also compete with populations of native species. Considering these ecological implications, based on the lacking ultrastructural data about the reproductive systems of the Auchenorrhyncha and since previous investigations on the male reproductive system of B. brevis have shown some interesting features, we carried out morphostructural investigations on the female reproductive system of this alien leafhopper. Moreover, given the high interest in literature on Wolbachia entomoparasite and based on our previous studies, we provided a contribution to further investigations in applied sciences. For this aim we performed a molecular analysis on males and females of B. brevis to detect the possible presence of strains of the bacterium known to alter host reproductive biology. The female reproductive system has a morphological organization comparable to the general anatomical features of most of the Auchenorrhyncha species; however, comparing our data with the literature, some considerations are discussed. As for the histological and ultrastructural investigations, our results show a secretory activity of the various examined structures. In the spermatheca of B. brevis, in particular, the secretory activity is more marked in the sac-shaped tract, where histochemical investigations showed a lipid component of the secretion; possible origin of this component is discussed. Moreover, mainly free spermatozoa are found in the sac-shaped tract of the spermatheca and in the common oviduct. As for the latter, an interesting findings is the lack of cuticular intima on the epithelial surface of the common oviduct; furthermore, the observed features and the literature in this regards led us to review the significance of the structure called as spermatheca. The molecular screening study (PCR) with three Wolbachia specific genes (16SrRNA, ftsZ,wsp) strongly supports Wolbachia infections in both males and females of the host species. This is the first study demonstrating the presence of Wolbachia in Balclutha genus, though no morphostructural alteration commonly related to the presence of the bacterium has been found in all the examined specimens. PMID- 26741366 TI - The Chloride Anion Acts as a Second Messenger in Mammalian Cells - Modifying the Expression of Specific Genes. AB - BACKGROUND/AIMS: Cystic Fibrosis (CF) is caused by mutations in the CFTR gene, encoding a cAMP-activated chloride (Cl-) channel. We have previously demonstrated that the expression of several genes can be modulated by the CFTR activity; among them, SRC, MTND4, CISD1, and IL1B. However, the CFTR signalling mechanism involved in the expression of CFTR-dependent genes is unknown. The aim of this work was to determine if intracellular chloride (Cl-)i might function as a second messenger modulating the expression of specific genes. METHODS: Differential display (DD) was applied to IB3-1 cells (CF cells), cultured under conditions that produce different intracellular Cl- concentrations ([Cl-]i), to analyse their expression profile. RESULTS: Several differentially expressed gene products were observed by using DD, suggesting the presence of chloride-dependent gene expression. Two cDNA fragments, derived from differentially expressed mRNAs and showing opposed response to Cl-' were isolated, cloned, sequenced and its Cl- dependency validated by reverse transcription quantitative-PCR (RT-qPCR). We identified the gene RPS27, which encodes the multifunctional ribosomal protein RPS27, also known as metallopanstimulin-1 (MPS-1), and the gene GLRX5, encoding glutaredoxin-related protein 5, as chloride-dependent genes. RPS27 was negatively regulated with increased [Cl-]i, approximately from 25-75 mM Cl- (EC50 = 46 +/- 7 mM), and positively regulated from 75-125 mM Cl- (EC50 = 110 +/- 11 mM) (biphasic response). In contrast, GLRX5 was positively modulated by [Cl-]i, showing a typical sigmoidal dose-response curve from 0-50 mM Cl-, reaching a plateau after 50 mM Cl- (EC50 ~ 34 mM). CONCLUSION: The results suggest the existence of chloride-dependent genes. The Cl- anion, therefore, might act as a second messenger for channels or receptors able to modulate the intracellular Cl- concentration, regulating in turn the expression of specific genes. PMID- 26741365 TI - The Sphingosine-1-Phosphate Lyase (LegS2) Contributes to the Restriction of Legionella pneumophila in Murine Macrophages. AB - L. pneumophila is the causative agent of Legionnaires' disease, a human illness characterized by severe pneumonia. In contrast to those derived from humans, macrophages derived from most mouse strains restrict L. pneumophila replication. The restriction of L. pneumophila replication has been shown to require bacterial flagellin, a component of the type IV secretion system as well as the cytosolic NOD-like receptor (NLR) Nlrc4/ Ipaf. These events lead to caspase-1 activation which, in turn, activates caspase-7. Following caspase-7 activation, the phagosome-containing L. pneumophila fuses with the lysosome, resulting in the restriction of L. pneumophila growth. The LegS2 effector is injected by the type IV secretion system and functions as a sphingosine 1-phosphate lyase. It is homologous to the eukaryotic sphingosine lyase (SPL), an enzyme required in the terminal steps of sphingolipid metabolism. Herein, we show that mice Bone Marrow Derived Macrophages (BMDMs) and human Monocyte-Derived Macrophages (hMDMs) are more permissive to L. pneumophila legS2 mutants than wild-type (WT) strains. This permissiveness to L. pneumophila legS2 is neither attributed to abolished caspase 1, caspase-7 or caspase-3 activation, nor due to the impairment of phagosome lysosome fusion. Instead, an infection with the legS2 mutant resulted in the reduction of some inflammatory cytokines and their corresponding mRNA; this effect is mediated by the inhibition of the nuclear transcription factor kappa-B (NF-kappaB). Moreover, BMDMs infected with L. pneumophila legS2 mutant showed elongated mitochondria that resembles mitochondrial fusion. Therefore, the absence of LegS2 effector is associated with reduced NF-kappaB activation and atypical morphology of mitochondria. PMID- 26741368 TI - Effect of Methamphetamine on Spectral Binding, Ligand Docking and Metabolism of Anti-HIV Drugs with CYP3A4. AB - Cytochrome P450 3A4 (CYP3A4) is the major drug metabolic enzyme, and is involved in the metabolism of antiretroviral drugs, especially protease inhibitors (PIs). This study was undertaken to examine the effect of methamphetamine on the binding and metabolism of PIs with CYP3A4. We showed that methamphetamine exhibits a type I spectral change upon binding to CYP3A4 with deltaAmax and KD of 0.016+/-0.001 and 204+/-18 MUM, respectively. Methamphetamine-CYP3A4 docking showed that methamphetamine binds to the heme of CYP3A4 in two modes, both leading to N demethylation. We then studied the effect of methamphetamine binding on PIs with CYP3A4. Our results showed that methamphetamine alters spectral binding of nelfinavir but not the other type I PIs (lopinavir, atazanavir, tipranavir). The change in spectral binding for nelfinavir was observed at both deltaAmax (0.004+/ 0.0003 vs. 0.0068+/-0.0001) and KD (1.42+/-0.36 vs.2.93+/-0.08 MUM) levels. We further tested effect of methamphetamine on binding of 2 type II PIs; ritonavir and indinavir. Our results showed that methamphetamine alters the ritonavir binding to CYP3A4 by decreasing both the deltaAmax (0.0038+/-0.0003 vs. 0.0055+/ 0.0003) and KD (0.043+/-0.0001 vs. 0.065+/-0.001 nM), while indinavir showed only reduced KD in presence of methamphetamine (0.086+/-0.01 vs. 0.174+/-0.03 nM). Furthermore, LC-MS/MS studies in high CYP3A4 human liver microsomes showed a decrease in the formation of hydroxy ritonavir in the presence of methamphetamine. Finally, CYP3A4 docking with lopinavir and ritonavir in the absence and presence of methamphetamine showed that methamphetamine alters the docking of ritonavir, which is consistent with the results obtained from spectral binding and metabolism studies. Overall, our results demonstrated differential effects of methamphetamine on the binding and metabolism of PIs with CYP3A4. These findings have clinical implication in terms of drug dose adjustment of antiretroviral medication, especially with ritonavir-boosted antiretroviral therapy, in HIV-1-infected individuals who abuse methamphetamine. PMID- 26741367 TI - Comparing Residue Clusters from Thermophilic and Mesophilic Enzymes Reveals Adaptive Mechanisms. AB - Understanding how proteins adapt to function at high temperatures is important for deciphering the energetics that dictate protein stability and folding. While multiple principles important for thermostability have been identified, we lack a unified understanding of how internal protein structural and chemical environment determine qualitative or quantitative impact of evolutionary mutations. In this work we compare equivalent clusters of spatially neighboring residues between paired thermophilic and mesophilic homologues to evaluate adaptations under the selective pressure of high temperature. We find the residue clusters in thermophilic enzymes generally display improved atomic packing compared to mesophilic enzymes, in agreement with previous research. Unlike residue clusters from mesophilic enzymes, however, thermophilic residue clusters do not have significant cavities. In addition, anchor residues found in many clusters are highly conserved with respect to atomic packing between both thermophilic and mesophilic enzymes. Thus the improvements in atomic packing observed in thermophilic homologues are not derived from these anchor residues but from neighboring positions, which may serve to expand optimized protein core regions. PMID- 26741369 TI - Contribution of Underlying Connective Tissue Cells to Taste Buds in Mouse Tongue and Soft Palate. AB - Taste buds, the sensory organs for taste, have been described as arising solely from the surrounding epithelium, which is in distinction from other sensory receptors that are known to originate from neural precursors, i.e., neural ectoderm that includes neural crest (NC). Our previous study suggested a potential contribution of NC derived cells to early immature fungiform taste buds in late embryonic (E18.5) and young postnatal (P1-10) mice. In the present study we demonstrated the contribution of the underlying connective tissue (CT) to mature taste buds in mouse tongue and soft palate. Three independent mouse models were used for fate mapping of NC and NC derived connective tissue cells: (1) P0 Cre/R26-tdTomato (RFP) to label NC, NC derived Schwann cells and derivatives; (2) Dermo1-Cre/RFP to label mesenchymal cells and derivatives; and (3) Vimentin CreER/mGFP to label Vimentin-expressing CT cells and derivatives upon tamoxifen treatment. Both P0-Cre/RFP and Dermo1-Cre/RFP labeled cells were abundant in mature taste buds in lingual taste papillae and soft palate, but not in the surrounding epithelial cells. Concurrently, labeled cells were extensively distributed in the underlying CT. RFP signals were seen in the majority of taste buds and all three types (I, II, III) of differentiated taste bud cells, with the neuronal-like type III cells labeled at a greater proportion. Further, Vimentin CreER labeled cells were found in the taste buds of 3-month-old mice whereas Vimentin immunoreactivity was only seen in the CT. Taken together, our data demonstrate a previously unrecognized origin of taste bud cells from the underlying CT, a conceptually new finding in our knowledge of taste bud cell derivation, i.e., from both the surrounding epithelium and the underlying CT that is primarily derived from NC. PMID- 26741372 TI - Paraxial Nodal Expression Reveals a Novel Conserved Structure of the Left-Right Organizer in Four Mammalian Species. AB - Nodal activity in the left lateral plate mesoderm is a conserved sign of irreversible left-right asymmetry at early somite stages of the vertebrate embryo. An earlier, paraxial nodal domain accompanies the emergence and initial extension of the notochord and is either left-sided, as in the chick and pig, or symmetrical, as in the mouse and rabbit; intriguingly, this interspecific dichotomy is mirrored by divergent morphological features of the posterior notochord (also known as the left-right organizer), which is ventrally exposed to the yolk sac cavity and carries motile cilia in the latter 2 species only. By introducing the cattle embryo as a new model organism for early left-right patterning, we present data to establish 2 groups of mammals characterized by both the morphology of the left-right organizer and the dynamics of paraxial nodal expression: presence and absence of a ventrally open surface of the early (plate-like) posterior notochord correlates with a symmetrical (in mice and rabbits) versus an asymmetrical (in pigs and cattle) paraxial nodal expression domain next to the notochordal plate. High-resolution histological analysis reveals that the latter domain defines in all 4 mammals a novel 'parachordal' axial mesoderm compartment, the topography of which changes according to the specific regression of the similarly novel subchordal mesoderm during the initial phases of notochord development. In conclusion, the mammalian axial mesoderm compartment (1) shares critical conserved features despite the marked differences in early notochord morphology and early left-right patterning and (2) provides a dynamic topographical framework for nodal activity as part of the mammalian left right organizer. PMID- 26741371 TI - Circadian Clock Genes Modulate Human Bone Marrow Mesenchymal Stem Cell Differentiation, Migration and Cell Cycle. AB - Many of the components that regulate the circadian clock have been identified in organisms and humans. The influence of circadian rhythm (CR) on the regulation of stem cells biology began to be evaluated. However, little is known on the role of CR on human mesenchymal stem cell (hMSCs) properties. The objective of this study was to investigate the influence of CR on the differentiation capacities of bone marrow hMSCs, as well as the regulation of cell cycle and migration capabilities. To that, we used both a chemical approach with a GSK-3beta specific inhibitor (2'E,3'Z-6-bromoindirubin-3'-oxime, BIO) and a knockdown of CLOCK and PER2, two of the main genes involved in CR regulation. In these experimental conditions, a dramatic inhibition of adipocyte differentiation was observed, while osteoblastic differentiation capacities were not modified. In addition, cell migration was decreased in PER2-/- cells. Lastly, downregulation of circadian clock genes induced a modification of the hMSCs cell cycle phase distribution, which was shown to be related to a change of the cyclin expression profile. Taken together, these data showed that CR plays a role in the regulation of hMSCs differentiation and division, and likely represent key factor in maintaining hMSCs properties. PMID- 26741373 TI - Expanding the CHARGE Geno-Phenotype: A Girl with Novel CHD7 Deletion, Hypogonadotropic Hypogonadism, and Agenesis of Uterus and Ovaries. AB - BACKGROUND: CHARGE syndrome is a variable entity. Clinical diagnosis is based on the Blake-Verloes criteria and can be confirmed by identifying a mutation or deletion in the CHD7 gene. Hypoplasia of the male genitalia and lack or incomplete secondary sexual development in both sexes is a common feature, and is most often attributable to hypogonadotropic hypogonadism which is described in >80% of the CHARGE patients. Other genital anomalies in CHARGE patients are rare. METHODS AND RESULTS: We describe the case of a girl with a novel heterozygous deletion in exon 15 of the CHD7 gene and combined agenesis of uterus and ovaries, besides gonadotropin deficiency, thus expanding the geno-phenotype of CHARGE syndrome. CONCLUSION: In case of persistent primary amenorrhea, despite estrogen replacement, this unusual combination should be considered in girls with CHARGE syndrome. PMID- 26741374 TI - Visual Receptive Field Properties of Neurons in the Mouse Lateral Geniculate Nucleus. AB - The lateral geniculate nucleus (LGN) is increasingly regarded as a "smart-gating" operator for processing visual information. Therefore, characterizing the response properties of LGN neurons will enable us to better understand how neurons encode and transfer visual signals. Efforts have been devoted to study its anatomical and functional features, and recent advances have highlighted the existence in rodents of complex features such as direction/orientation selectivity. However, unlike well-researched higher-order mammals such as primates, the full array of response characteristics vis-a-vis its morphological features have remained relatively unexplored in the mouse LGN. To address the issue, we recorded from mouse LGN neurons using multisite-electrode-arrays (MEAs) and analysed their discharge patterns in relation to their location under a series of visual stimulation paradigms. Several response properties paralleled results from earlier studies in the field and these include centre-surround organization, size of receptive field, spontaneous firing rate and linearity of spatial summation. However, our results also revealed "high-pass" and "low-pass" features in the temporal frequency tuning of some cells, and greater average contrast gain than reported by earlier studies. In addition, a small proportion of cells had direction/orientation selectivity. Both "high-pass" and "low-pass" cells, as well as direction and orientation selective cells, were found only in small numbers, supporting the notion that these properties emerge in the cortex. ON- and OFF-cells showed distinct contrast sensitivity and temporal frequency tuning properties, suggesting parallel projections from the retina. Incorporating a novel histological technique, we created a 3-D LGN volume model explicitly capturing the morphological features of mouse LGN and localising individual cells into anterior/middle/posterior LGN. Based on this categorization, we show that the ON/OFF, DS/OS and linear response properties are not regionally restricted. Our study confirms earlier findings of spatial pattern selectivity in the LGN, and builds on it to demonstrate that relatively elaborate features are computed early in the visual pathway. PMID- 26741375 TI - Morphological and mechanical characterization of composite bone cement containing polymethylmethacrylate matrix functionalized with trimethoxysilyl and bioactive glass. AB - Medical polymers of biostable nature (e.g. polymethylmetacrylate, PMMA) are widely used in various clinical applications. In this study, novel PMMA-based composite bone cement was prepared. Bioactive glass (BAG) particulate filler (30wt%) was added to enhance potentially the integration of bone to the cement. The polymer matrix was functionalized with trimethoxysilyl to achieve an interfacial bond between the matrix and the fillers of BAG. The amount of trimethoxysilyl in the monomer system varied from 0 to 75wt%. The effects of dry and wet (simulated body fluid, SBF at +37 degrees C for 5 weeks) conditions were investigated. In total, 20 groups of specimens were prepared. The specimens were subjected to a destructive mechanical test in compression. Scanning electron microscopy (SEM) and micro-computed tomography (micro-CT) were used to study the surface and the three-dimensional morphology of the specimens. The results of the study indicated that the addition of trimethoxysilyl groups led to the formation of a hybrid polymer matrix which, in lower amounts (<10wt% of total weight), did not significantly affect the compression properties. However, when the specimens stored in dry and wet conditions were compared, the water sorption increased the compression strength (~5-10MPa per test group). At the same time, the water sorption also caused an evident porous structure formation for the specimens containing BAG and siloxane formation in the hybrid polymer matrix. PMID- 26741376 TI - Influence of platelet aspect ratio on the mechanical behaviour of bio-inspired nanocomposites using molecular dynamics. AB - Superior mechanical properties of biocomposites such as nacre and bone are attributed to their basic building blocks. These basic building blocks have nanoscale features and play a major role in achieving combined stiffening, strengthening and toughening mechanisms. Bioinspired nanocomposites based on these basic building blocks, regularly and stairwise staggered arrangements of hard platelets in soft matrix, have huge potential for developing advanced materials. The study of applicability of mechanical principles of biological materials to engineered materials will guide designing advanced materials. To probe the generic mechanical characteristics of these bioinspired nanocomposites, the model material concept in molecular dynamics (MD) is used. In this paper, the effect of platelets aspect ratio (AR) on the mechanical behaviour of bioinspired nanocomposites is investigated. The obtained Young's moduli of both the models and the strengths of the regularly staggered models agree with the available theories. However, the strengths of the stairwise staggered models show significant difference. For the stairwise staggered model, we demonstrate the existence of two critical ARs, a smaller critical AR above which platelet fracture occurs and a higher critical AR above which composite strength remains constant. Our MD study also shows the existence of mechanisms of platelet pull out and breakage for lower and higher ARs. Pullout mechanism acts as a major source of plasticity. Further, we find that the regularly staggered model can achieve an optimal combination of high Young's modulus, flow strength and toughness, and the stairwise staggered model is efficient in obtaining high Young's modulus and tensile strength. PMID- 26741377 TI - Anti-Aging Effects of Probiotics. AB - The body of evidence demonstrating the beneficial effects of probiotics on the skin continues to grow in the published literature. Insights into their effects at the molecular level, in animal models, and in human clinical trials build the case for their role in slowing the skin manifestations of both intrinsic and extrinsic aging. The reports reviewed in this manuscript demonstrate that probiotics can restore acidic skin pH, alleviate oxidative stress, attenuate photoaging, improve skin barrier function, and enhance hair quality. PMID- 26741378 TI - Fractional Ablative Laser Followed by Transdermal Acoustic Pressure Wave Device to Enhance the Drug Delivery of Aminolevulinic Acid: In Vivo Fluorescence Microscopy Study. AB - BACKGROUND: Topical drug delivery is the foundation of all dermatological therapy. Laser-assisted drug delivery (LAD) using fractional ablative laser is an evolving modality that may allow for a greater precise depth of penetration by existing topical medications, as well as more efficient transcutaneous delivery of large drug molecules. Additional studies need to be performed using energy driven methods that may enhance drug delivery in a synergistic manner. Processes such as iontophoresis, electroporation, sonophoresis, and the use of photomechanical waves aid in penetration. This study evaluated in vivo if there is increased efficacy of fractional CO2 ablative laser with immediate acoustic pressure wave device. METHODS: Five patients were treated and biopsied at 4 treatment sites: 1) topically applied aminolevulinic acid (ALA) alone; 2) fractional ablative CO2 laser and topical ALA alone; 3) fractional ablative CO2 laser and transdermal acoustic pressure wave device delivery system; and 4) topical ALA with transdermal delivery system. The comparison of the difference in the magnitude of diffusion with both lateral spread of ALA and depth diffusion of ALA was measured by fluorescence microscopy. RESULTS: For fractional ablative CO2 laser, ALA, and transdermal acoustic pressure wave device, the protoporphyrin IX lateral fluorescence was 0.024 mm on average vs 0.0084 mm for fractional ablative CO2 laser and ALA alone. The diffusion for the acoustic pressure wave device was an order of magnitude greater. CONCLUSION: We found that our combined approach of fractional ablative CO2 laser paired with the transdermal acoustic pressure wave device increased the depth of penetration of ALA. PMID- 26741379 TI - Natural Cosmeceutical Ingredients for Hyperpigmentation. AB - As Dermatologists caring for patients with hyperpigmentation problems, we are always looking for more alternative therapies. Hydroquinone (HQ) is still the standard of care. However, traditional depigmenting agents such as HQ and corticosteroids, although highly effective, can raise safety concerns including exogenous ochronosis, atrophy, carcinogenesis and local and systemic untoward effects with long term use. Therefore, we need to investigate non-prescription natural alternatives. This manuscript presents many of the natural ingredients found in cosmeceuticals for the treatment of hyperpigmentation and their mechanisms of action. It will also describe the melanocyte activation pathways and how each of these ingredients interferes with it. PMID- 26741380 TI - Comparative Study of Professional vs Mass Market Topical Products for Treatment of Facial Photodamage. AB - BACKGROUND: Many over the counter topical products claim to reverse the signs of cutaneous photo-damage. To date, the two most studied ingredients for improving the texture, tone, and pigmentation of the skin are topical retinoids and hydroquinone. OBJECTIVE: This split face study compares a mass market skincare regimen with a prescription skin care regimen for improvement in photo damaged skin. METHODS: Twenty-seven subjects with moderate photo damaged facial skin were enrolled. Each subject was consented and assigned with the mass market anti-aging system (Treatment A) to one side of the face and the prescription anti-aging system (Treatment B or Treatment C) to the other side of the face. Treatment B contained 13 subjects whom did not use 0.025% Retinol cream. Treatment C contained 14 subjects who used a 0.025% Retinol Cream. Subjects had 4 visits over 12 weeks for digital photography and surveys. Photographs were evaluated by blinded physicians. RESULTS: Physician objective analysis showed all three systems to have a statistically significant clinical improvement in photoaged skin seen in as little as 4 weeks of use. Participant's surveys rated the mass market system higher than both of the professional systems for visible skin changes, ease of use, and likelihood to recommend to a friend. Twelve of twenty seven subjects preferred the mass market system for overall improvement while twelve thought each system gave the same improvement. CONCLUSION: This study demonstrates that a mass marketed skin care system can give similar clinical improvements in photo-aged skin as a professionally dispensed prescription system and the majority of participants preferred the mass-marketed system. PMID- 26741381 TI - A Firming Neck Cream Containing N-Acetyl Glucosamine Significantly Improves Signs of Aging on the Challenging Neck and Decolletage. AB - BACKGROUND: Noninvasive antiaging neck and decolletage treatments are highly sought after by aging patients. A topical cosmetic antiaging cream was formulated with skin matrix building and smoothing ingredients to help reverse visible signs of aging on the neck and decolletage, including laxity, crepiness, deep lines, and hyperpigmentation. OBJECTIVE: A clinical study was conducted to evaluate the efficacy and safety of the antiaging neck/decolletage cream over a 16-week treatment period. METHOD: Caucasian women with moderate texture (including wrinkles, fine lines, laxity, and/or crepiness) on the neck and hyperpigmentation on the decolletage used the test cream for 16 weeks. At weeks 0, 8, 12 and 16, the dermatologist investigator graded neck texture, decolletage texture and decolletage pigmentation using a 0-5 scale, and irritation/tolerability using a 0 4 scale. Subjects were photographed and provided self-assessment of their aging parameters as well as product tolerability. Chromameter measurements were collected in triplicate on the chest at weeks 0, 8, and 16 to quantitatively and objectively assess pigmentation. RESULTS: Forty-two women completed the study. All dermatologist-graded aging parameters were significantly improved at each time point, P<0.001. Chromameter measurements demonstrated significant improvements in brightness (L*) and redness (a*), P<0.05. Self-assessed aging parameters were significantly improved on the decolletage and neck, P<0.05. Digital photography demonstrated obvious antiaging effects including improved texture of neck and decolletage areas, reduced appearance of lines and wrinkles, reduced mottled hyperpigmentation, and a more youthful, firm appearance. The test cream was well-tolerated with no significant changes in irritation parameters throughout the study. CONCLUSION: The antiaging neck/decolletage cream delivered significant firming and smoothing effects with reduced appearance of hyperpigmentation and can be considered an effective topical homecare treatment option for patients seeking rejuvenation of this challenging area PMID- 26741382 TI - Effects of Subdermal Monopolar RF Energy on Abdominoplasty Flaps. AB - BACKGROUND: Radiofrequency has long been successfully employed for medical and, more recently, aesthetic indications due to its ability to cause tissue contraction by thermal induction of neocollagenesis and the subsequent wound healing cascade, leading to collagen remodeling and a tightening effect. Percutaneous RF treatment provides therapeutically relevant thermal stimulation directly to the tissue target in a minimally invasive manner, which is therapeutically ideal because of limitations inherent in transcutaneous RF heating. A novel device combines percutaneous RF with thermistor-controlled temperature regulation and external tissue temperature monitoring, providing the ability to safely deliver RF energy. METHODS: Percutaneous subdermal RF treatment was performed on 48 samples of abdominoplasty tissue; samples were marked to standardize measurement of surface area in the treatment zones, and a subdermal temperature target of 51 degrees C was preprogrammed into the treatment device. The treatment cannula was inserted parallel to the dermal plane at four points with a single pass per insertion. Surface area was then re-measured. RESULTS: Approximate average reduction in surface area was 91.23+/-19.33 mm2, ranging between 124.45 mm2 and 35.39 mm2 (median 96.83 mm2). Results were statistically significant (P<0.0001). Statistical analysis via analysis of variance (ANOVA) plus Tukey post-hoc testing revealed no statistically significant difference between the sides in all comparisons, demonstrating symmetry in contracture. CONCLUSION: Percutaneous subdermal monopolar RF creates dramatic, immediate tissue contraction in vitro and is a viable technology for tissue tightening. PMID- 26741383 TI - Assessing Improvement of Facial Appearance and Quality of Life after Minimally Invasive Cosmetic Dermatology Procedures Using the FACE-Q Scales. AB - BACKGROUND: Detecting clinically meaningful change from the patients' perspective is critical to evaluating a successful cosmetic procedure. FACE-Q is a patient reported outcome instrument for use in patients undergoing cosmetic procedures. OBJECTIVE: We sought to determine the impact of laser resurfacing and injectable treatment (neurotoxin or fillers) on patient perceived improvement in facial appearance. METHODS AND MATERIALS: Patients were asked to complete FACE-Q scales (Satisfaction with Facial Appearance, Satisfaction with Facial Skin, and Appraisal of Facial Lines) at their pre-procedure consultation and/or at post procedural follow-up. Item means (range 1-4) and Rasch transformed scores (range 0-100) were compared pre to post-procedure using two sample t-tests. Higher FACE Q scores indicated greater satisfaction. RESULTS: Overall, patients experienced a statistically significant improvement in all three scales pre- to post-procedure (P <0.05). Sub-group analysis showed statistically significant improvement in Satisfaction with Facial Appearance and Satisfaction with Facial Skin for both the laser resurfacing group and injectables group with moderate effect sizes. Improvement on Appraisal of Facial Lines trended toward improvement but did not reach statistical significance. CONCLUSION: Our results support the ability to directly measure and quantify meaningful improvement in appearance among facial cosmetic dermatology patients using FACE-Q scales. Reporting this data is important, as this is the first step towards evidence-based cosmetic procedures in dermatology. PMID- 26741384 TI - Safety and Effectiveness of Hyaluronic Acid Injectable Gel in Correcting Moderate Nasolabial Folds in Chinese Subjects. AB - BACKGROUND: The hyaluronic acid (HA) dermal filler, Juvederm(r) Ultra, which employs Hylacross(r) technology, produces a gel with a smooth consistency and has demonstrated effectiveness in correcting nasolabial folds (NLFs) in Caucasian populations. OBJECTIVE: To evaluate the safety and effectiveness of Juvederm Ultra vs Restylane(r) for the correction of moderate NLFs in Chinese subjects. METHODS: In this double-blind randomized study, adult Chinese subjects with moderate NLFs received Juvederm Ultra (24 mg/mL) in 1 NLF and Restylane injectable gel (20 mg/mL) in the other NLF. NLFs were evaluated using the validated 5-point photonumeric Allergan NLF Severity Scale (NLFSS); scores ranged from 0 ("no wrinkle") to 4 ("very deep wrinkle"). Response was defined as >=1 point improvement at 6 months. Investigator-assessed responder rate (primary outcome), NLF mean improvement, and subject-assessed responder rate and preference were assessed. RESULTS: Among the 104 subjects who completed the study, median initial volumes (mL) were 0.8 (range, 0.2-1.4) for Juvederm Ultra and 0.8 (0.3-1.5) for Restylane; median touch-up volumes were 0.3 (0.1-0.5) and 0.3 (0.1-0.5), respectively. At 6 months, investigator-assessed responder rates were 87.3% for both products, indicating that Juvederm Ultra was noninferior to Restylane; mean improvement in NLFSS scores from baseline was 1.0 for both products. At 6 months, Juvederm Ultra and Restylane subject-assessed responder rates were 86.3% and 79.4%, respectively, and mean improvement in NLFSS scores from baseline was 1.2 and 1.0, respectively. Among subjects who expressed a preference, 57.9% preferred Juvederm Ultra. For both products, the most commonly reported treatment site responses were swelling, firmness, and tenderness; treatment site responses were generally mild or moderate in severity. Juvederm Ultra had fewer severe responses than Restylane. CONCLUSIONS: Juvederm Ultra is noninferior to Restylane and is a safe and effective treatment for correcting moderate NLFs in Chinese subjects. PMID- 26741385 TI - Evolution of Acne Assessments and Impact on Acne Medications: An Evolving, Imperfect Paradigm. AB - BACKGROUND: Outcomes for success in acne interventional trials include statistically significant differences from baseline between treatment arms in lesion counts (comedonal, inflammatory and/or total) and in thresholds of categorical improvement in investigator global assessments (IGA). OBJECTIVES: We evaluated differences in outcome measures and definition of success in acne trials; and their impact on FDA approval and indications for acne medications. METHODS: Review of acne clinical trial literature, prescribing information and regulatory guidelines for currently approved acne medications in the United States. RESULTS: Numerous IGA scales exist with variations in specific categorical definitions. There are also differences in definitions of global success. Outcome success may not be accurately translated into corresponding terminology for indications. CONCLUSIONS: Variability in IGA scales and definitions of success confound comparison of trial results for acne treatments. Harmonization and standardization of these factors will facilitate meta-analytics and treatment selection in patient care. Outcome measure success has not consistently been incorporated into acne medication indications. PMID- 26741386 TI - Evaluation of the Appearance of Nail Polish Following Daily Treatment of Ex Vivo Human Fingernails With Topical Solutions of Tavaborole or Efinaconazole. AB - INTRODUCTION: Patients with onychomycosis may mask infected nails with polish. Tavaborole topical solution, 5% is a boron-based, small-molecule pharmaceutical approved for the treatment of toenail onychomycosis caused by Trichophyton rubrum and Trichophyton mentagrophytes; efinaconazole topical solution, 10% is approved for the same indication. Nail polish appearance after application of tavaborole (dropper) or efinaconazole (brush); respective applicator appearance; presence of color transfer from respective applicators; and color transfer to remaining solutions after dosing of polished nails were evaluated. METHODS: Twelve ex vivo human cadaver fingernails were cleaned, polished with two coats of L'Oreal(r) Nail Color, Devil Wears Red #420, and mounted on floral foam. Nails were treated with tavaborole or efinaconazole solutions once daily for 7 days. Dropper and brush applicators were applied to white watercolor paper immediately after dosing to evaluate color transfer from polished nails. On day 7, remaining solutions were transferred to clear glass vials to evaluate color transfer from applicators to solutions. Nails, applicators, and papers were photographed daily following application; remaining solutions were photographed after 7 days of dosing. RESULTS: Tavaborole-treated polished nails showed no polish discoloration, and tavaborole applicators did not change in appearance during treatment. No color transfer from polished nails was evident to applicator, paper, or remaining solution. Efinaconazole-treated polished nails showed substantial polish changes after the first day of treatment, with polish appearance and discoloration progressively worsening over 7 days of treatment. Color transfer from nails was evident to applicator, paper, and remaining solution. CONCLUSIONS: Daily dropper application of tavaborole to ex vivo polished nails did not alter polish appearance. Brush application of efinaconazole produced visible changes in polish appearance and color transfer to applicators, paper, and remaining solution. Tavaborole topical solution, 5% may not alter nail polish appearance; the impact of nail polish on tavaborole clinical efficacy has not been evaluated. PMID- 26741388 TI - Luliconazole Retention in Stratum Corneum and Prevention of Fungal Infection in a Guinea Pig Tinea Pedis Model. AB - OBJECTIVE: To compare drug concentrations in the stratum corneum following daily application of luliconazole and terbinafine cream in a guinea pig tinea pedis model. METHODS: Luliconazole 1% cream or terbinafine 1% cream were topically applied once daily to hind limbs of guinea pigs for 14 days. Drug concentration in stratum corneum of plantar skin was measured by HPLC-UV on days 1, 3, 7, 10, and 14. Separately, creams were applied daily for 5 days to the hind limbs of guinea pigs and skin drug release determined. In addition, drug retention in the stratum corneum was assessed by infecting guinea pigs with Trichophyton mentagrophytes, 14 and 21 days after a single application of luliconazole or terbinafine creams. RESULTS: Luliconazole stratum corneum concentrations were higher than those of terbinafine throughout the study. Concentrations of luliconazole and terbinafine were 71.6MUg/g and 36.6MUg/g, respectively, after a single application (P<.05), reaching steady state after 10 days. Cumulative release of luliconazole from the stratum corneum was 4.5 times greater than with terbinafine. Unlike terbinafine, no fungal invasion of the stratum corneum was seen 14 days post-treatment with luliconazole. CONCLUSIONS: Drug concentrations of luliconazole in the stratum corneum and subsequent release are greater than those achieved with terbinafine and may contribute to clinical efficacy. Luliconazole may also provide greater protection against disease recurrence. PMID- 26741387 TI - iPLEDGE Weaknesses: Is It Time to Address the Flaws? AB - BACKGROUND: The observance during acne follow-ups that information stored within iPLEDGE was discordant with medical charts prompted this study. OBJECTIVE: To evaluate the information acquired and stored within iPLEDGE as it compares to medical charts with a goal of assessing the efficacy of iPLEDGE as a database. METHODS: This is a multicenter retrospective chart review analyzing congruence and discrepancies between medical chart documentation and iPLEDGE data for all patients who received at least a single dose of isotretinoin from the primary investigators between January 2006 and November 2010. RESULTS: A total of 357 charts were analyzed. Overall congruence between medical chart documentation and iPLEDGE data was observed in only 73.1% of cases. The discrepancy (N=96) was due to a missed dose (prescription recorded in chart but not in iPLEDGE) in 81.4% of cases, or an addition (medication dispensed per iPLEDGE without corresponding chart documentation) in the remainder of cases. Of note, several charts had multiple discrepancies (N=249 total discrepancies). LIMITATIONS: Retrospective chart review study. CONCLUSION: Given the large percentage of discordant data, our findings question the efficacy of the iPLEDGE system, which is designed to monitor every dispensed isotretinoin dose. PMID- 26741389 TI - A Combination Approach to Perioral Rejuvenation. AB - Fine lines and wrinkles, loss of volume, texture changes, and solar lentigines around the mouth are the result of both extrinsic and intrinsic factors, and are common concerns seen in cosmetic practice. Perioral rejuvenation can be addressed using a variety of noninvasive means including botulinum toxin, fillers, and laser resurfacing. In clinical practice, a multifaceted treatment plan utilizing a variety of noninvasive means to address the multiple tissue changes is often undertaken. Combining botulinum toxin with fillers or laser resurfacing has previously been shown to produce more desirable and longer lasting results. Here we report the results of using a sequential approach with all three modalities. PMID- 26741390 TI - Horrendous, Treatment-resistant Pediatric Atopic Dermatitis Solved With a Change in Vehicle. AB - Severe atopic dermatitis can have an enormous impact on a child and the child's caregivers. Topical corticosteroids can be highly effective, but not all patients respond. If atopic dermatitis does not improve with a topical corticosteroid, poor adherence should be strongly considered as the cause of treatment failure. We report a child with horrendous atopic dermatitis whose disease resolved rapidly in the hospital when therapy was changed to a product that was easier to apply. PMID- 26741391 TI - Inflammatory Acne Treatment: Review of Current and New Topical Therapeutic Options. AB - Acne vulgaris (AV) is an inflammatory skin disease characterized by the presence of comedones, papules, pustules, and nodules. Consensus guidelines recommend the use of combination therapy using different drugs with complementary mechanisms of action to best address as many acne pathogenic factors as possible at the same time. Topical acne medications exist as individual agents that may be combined in physician-recommended regimens or as pre-formulated fixed-dose combination products. In addition, there are several new and promising topical therapies currently being developed that work by different mechanisms of action from traditionally used acne therapies. The following review will cover commonly used drugs, newcomers to the market, and what the future holds for the topical treatment of AV. PMID- 26741393 TI - Understanding and Addressing the Acne Vulgaris Paradigm Shift. PMID- 26741392 TI - Rejuvenating Hydrator: Restoring Epidermal Hyaluronic Acid Homeostasis With Instant Benefits. AB - Skin aging is a combination of multifactorial mechanisms that are not fully understood. Intrinsic and extrinsic factors modulate skin aging, activating distinctive processes that share similar molecular pathways. One of the main characteristics of youthful skin is its large capacity to retain water, and this decreases significantly as we age. A key molecule involved in maintaining skin hydration is hyaluronic acid (HA). Concentration of HA in the skin is determined by the complex balance between its synthesis, deposition, association with cellular structures, and degradation. HA bio-equivalency and bio-compatibility have been fundamental in keeping this macromolecule as the favorite of the skincare industry for decades. Scientific evidence now shows that topically applied HA is unable to penetrate the skin and is rapidly degraded on the skin surface. SkinMedica's HA5 Rejuvenating Hydrator (SkinMedica Inc., an Allergan company, Irvine, CA) promotes restoration of endogenous epidermal HA homeostasis and provides instant smoothing and hydration of the skin. These dual benefits are accomplished through the combination of 2 breakthrough technologies: 1) a unique blend of actives powered by SkinMedica proprietary flower-derived stem cell extract that restores the endogenous production of HA; and 2) a proprietary mix of 5 HA forms that plump the skin, decreasing the appearance of fine lines/wrinkles. Pre-clinical studies demonstrated that HA5 induces expression of key epidermal differentiation and barrier markers as well as epidermal HA synthases. A decrease expression of hyaluronidases was also observed upon HA5 application. Initial clinical studies showed that within 15 minutes of application, HA5 instantly improves the appearance of fine lines/wrinkles and skin hydration. Subjects that continue using HA5 (for 8 weeks) demonstrated significant improvements in fine lines/wrinkles, tactile roughness, and skin hydration. In summary, the blend of these 2 key technologies present in HA5 promotes restoration of endogenous epidermal HA while delivering instant smoothing effects. PMID- 26741394 TI - Advances in the Understanding of the Pathogenesis of Inflammatory Acne. AB - Acne vulgaris (AV) is the most common skin disorder. It was traditionally thought that AV lesions developed after abnormal desquamation of the keratinocytes that line the sebaceous follicle, leading to hyperkeratinization and microcomedone formation. However, in recent years there has been a paradigm shift with regard to understanding the pathogenesis of AV, and it is now viewed as a primary inflammatory skin disorder. Research has implicated the presence of subclinical inflammation in the normal skin of acne patients, even before microcomedone formation. This article will review the novel concepts that play a role in the new pathogenesis of acne vulgaris. PMID- 26741395 TI - The new insight into the structure-activity relation of Pd/CeO2-ZrO2-Nd2O3 catalysts by Raman, in situ DRIFTS and XRD Rietveld analysis. AB - Pd/CeO2-ZrO2-Nd2O3 (CZN) catalysts with different CeO2/ZrO2 molar ratios were synthesized and have been characterized by multiple techniques, e.g. XRD in combination with Rietveld refinement, UV-Raman, XPS and in situ DRIFTS. The XRD pattern of CZN with CeO2/ZrO2 molar ratios >=1/2 can be indexed satisfactorily to the fluorite structure with a space group Fm3m, while the XRD patterns of CZ12 only display diffraction peaks of the tetragonal phase (S.G. P42/nmc). Nd addition can effectively stabilize the cubic structure of the CZN support and increase the enrichment of defect sites on the surface, which may be related to the better catalytic activity of Pd/CZN12 catalysts compared with Pd/CZ12. The presence of moderate ZrO2 can increase the concentration of O* active species, leading to accelerate the formation of nitrate species and thus enhance the catalytic activity of NOx and HC elimination. The Pd-dispersion decreases with the increasing Zr content, leading to the decreased CO catalytic activity, especially for the aged catalysts. The change regularity of the OSC value is almost the same with the in situ dynamic operational window, demonstrating that the in situ dynamic operational window is basically affected by the OSC value. PMID- 26741396 TI - Transport, retention, and long-term release behavior of ZnO nanoparticle aggregates in saturated quartz sand: Role of solution pH and biofilm coating. AB - The transport, retention, and long-term release of zinc oxide nanoparticle aggregates (denoted below as ZnO-NPs) were investigated in saturated, bare and biofilm (Pseudomonas putida) coated sand packed columns. Almost complete retention of ZnO-NPs occurred in bare and biofilm coated sand when the influent solution pH was 9 and the ionic strength (IS) was 0.1 or 10 mM NaCl, and the retention profiles were always hyper-exponential. Increasing the solution IS and biofilm coating produced enhanced retention of ZnO-NPs near the column inlet. The enhanced NPs retention at high IS was attributed to more favorable NP-silica and NP-NP interactions; this was consistent with the interaction energy calculations. Meanwhile, the greater NPs retention in the presence of biofilm was attributed to larger roughness heights which alter the mass transfer rate, the interaction energy profile, and lever arms associated with the torque balance; e.g., scanning electron and atomic force microscopy was used to determine roughness heights of 33.4 nm and 97.8 nm for bare sand and biofilm-coated sand, respectively. Interactions between NPs and extracellular polymeric substances may have also contributed to enhanced NP retention in biofilm-coated sand at low IS. The long term release of retained ZnO-NPs was subsequently investigated by continuously injecting NP-free solution at pH 6, 9, or 10 and keeping the IS constant at 10 mM. The amount and rate of retained ZnO-NP removal was strongly dependent on the solution pH. Specifically, almost complete removal of retained ZnO-NPs was observed after 627 pore volumes when the solution pH was 6, whereas much less Zn was recovered when the eluting solution pH was buffered to pH = 9 and especially 10. This long-term removal was attributed to pH-dependent dissolution of retained ZnO-NPs because: (i) the solubility of ZnO-NPs increases with decreasing pH; and (ii) ZnO-NPs were not detected in the effluent. The presence of biofilm also decreased the initial rate and amount of dissolution and the subsequent transport of Zn(2+) due to the strong Zn(2+) re-adsorption to the biofilm. Our study indicates that dissolution will eventually lead to the complete removal of retained ZnO-NPs and the transport of toxic Zn(2+) ions in groundwater environments with pH ranges of 5-9. PMID- 26741397 TI - Tracking legacy radionuclides in St. Louis, Missouri, via unsupported (210)Pb. AB - Analysis of 287 soil, sediment and house dust samples collected in a 200 km(2) zone in northern St. Louis County, Missouri, establish that offsite migration of radiological contaminants from Manhattan Project-era uranium processing wastes has occurred in this populated area. Specifically, 48% of samples (111 of a subset of 229 soils and sediments tested) had (210)Pb concentrations above the risk-based soil cleanup limits for residential farming established by the US Department of Energy at the Fernald, OH, uranium plant, which handled and stored the same concentrated Manhattan Project-era wastes; the geographical distribution of the exceedances are consistent with water and radon gas releases from a landfill and related sites used to store and dispose of legacy uranium wastes; and offsite soil and house dust samples proximal to the landfill showed distinctive secular disequilibrium among uranium and its progeny indicative of uranium ore processing wastes. The secular disequilibrium of uranium progeny in the environment provides an important method for distinguishing natural uranium from industrial uranium wastes. In this study, the detection of unsupported (210)Pb beyond expected atmospheric deposition rates is examined as a possible indicator of excessive radon emissions from buried uranium and radium-containing wastes. PMID- 26741398 TI - Chemically-modified cellulose paper as smart sensor device for colorimetric and optical detection of hydrogen sulfate in water. AB - A portable, recyclable and highly selective paper-based sensor device for the colorimetric and optical detection of hydrogen sulfate anions in water was developed. The detection system features a rhodamine-based sensor covalently grafted onto the highly hydrophilic surface of cellulose paper. PMID- 26741400 TI - Epichlorohydrin-Cross-linked Hydroxyethyl Cellulose/Soy Protein Isolate Composite Films as Biocompatible and Biodegradable Implants for Tissue Engineering. AB - A series of epichlorohydrin-cross-linked hydroxyethyl cellulose/soy protein isolate composite films (EHSF) was fabricated from hydroxyethyl cellulose (HEC) and soy protein isolate (SPI) using a process involving blending, cross-linking, solution casting, and evaporation. The films were characterized with FTIR, solid state (13)C NMR, UV-vis spectroscopy, and mechanical testing. The results indicated that cross-linking interactions occurred in the inter- and intramolecules of HEC and SPI during the fabrication process. The EHSF films exhibited homogeneous structure and relative high light transmittance, indicating there was a certain degree of miscibility between HEC and SPI. The EHSF films exhibited a relative high mechanical strength in humid state and an adjustable water uptake ratio and moisture absorption ratio. Cytocompatibility, hemocompatibility and biodegradability were evaluated by a series of in vitro and in vivo experiments. These results showed that the EHSF films had good biocompatibility, hemocompatibility, and anticoagulant effect. Furthermore, EHSF films could be degraded in vitro and in vivo, and the degradation rate could be controlled by adjusting the SPI content. Hence, EHSF films might have a great potential for use in the biomedical field. PMID- 26741404 TI - Ab Initio Investigation of O-H Dissociation from the Al-OH2 Complex Using Molecular Dynamics and Neural Network Fitting. AB - The dissociation dynamics of the O-H bond in Al-OH2 is investigated on an approximated ab initio potential energy surface (PES). By adopting a dynamic sampling method, we obtain a database of 92 834 configurations. The potential energy for each point is calculated using MP2/6-311G (3df, 2p) calculations; then, a 60-neuron feed-forward neural network is utilized to fit the data to construct an analytic PES. The root-mean-square error (rmse) for the training set is reported as 0.0036 eV, while the rmse for the independent testing set is 0.0034 eV. Such excellent fitting accuracy indeed confirms the reliability of the constructed PES. Subsequently, quasi-classical molecular dynamics (MD) trajectories are performed on the constructed PES at various levels of vibrational excitation in the range of 1.03 to 2.23 eV to investigate the probability of O-H bond dissociation. The results indicate a linear relationship between reaction probability and internal energy, from which we can determine the minimum activation internal energy required for the dissociation as 0.62 eV. Moreover, the O-H bond rupture is shown to be highly correlated with the formation of Al-O bond. PMID- 26741402 TI - Laser-Assisted Field Evaporation and Three-Dimensional Atom-by-Atom Mapping of Diamond Isotopic Homojunctions. AB - It addition to its high evaporation field, diamond is also known for its limited photoabsorption, strong covalent bonding, and wide bandgap. These characteristics have been thought for long to also complicate the field evaporation of diamond and make its control hardly achievable on the atomistic-level. Herein, we demonstrate that the unique behavior of nanoscale diamond and its interaction with pulsed laser lead to a controlled field evaporation thus enabling three dimensional atom-by-atom mapping of diamond (12)C/(13)C homojunctions. We also show that one key element in this process is to operate the pulsed laser at high energy without letting the dc bias increase out of bounds for diamond nanotip to withstand. Herein, the role of the dc bias in evaporation of diamond is essentially to generate free charge carriers within the nanotip via impact ionization. The mobile free charges screen the internal electric field, eventually creating a hole rich surface where the pulsed laser is effectively absorbed leading to an increase in the nanotip surface temperature. The effect of this temperature on the uncertainty in the time-of-flight of an ion, the diffusion of atoms on the surface of the nanotip, is also discussed. In addition to paving the way toward a precise manipulation of isotopes in diamond-based nanoscale and quantum structures, this result also elucidates some of the basic properties of dielectric nanostructures under high electric field. PMID- 26741405 TI - Vapochromic Behavior of a Chair-Shaped Supramolecular Metallacycle with Ultra Stability. AB - A new discrete supramolecular metallacycle functionalized with an alkynylplatinum(II) bzimpy moiety was successfully prepared via coordination driven self-assembly, and it displayed a reversible color change in the solid state between yellow and red, triggered by CH2Cl2 vapor or mechanical grinding. Notably, unlike many known vapochromic systems, the obtained vapochromic metallacycle exhibits ultra-stability, with the red color remaining unchanged in air for several months at room temperature or even under vacuum for >1 week. Further investigation revealed that the chair conformation of the metallacyclic scaffold, which was thought to prevent intermolecular steric repulsion between the alkyl chain and triethylphosphine, favored close molecular stacking through intermolecular Pt...Pt and pi-pi stacking interactions, thus allowing such vapochromic behavior with ultra-stability. PMID- 26741401 TI - The role of PfEMP1 as targets of naturally acquired immunity to childhood malaria: prospects for a vaccine. AB - The Plasmodium falciparum erythrocyte membrane protein 1 antigens that are inserted onto the surface of P. falciparum infected erythrocytes play a key role both in the pathology of severe malaria and as targets of naturally acquired immunity. They might be considered unlikely vaccine targets because they are extremely diverse. However, several lines of evidence suggest that underneath this molecular diversity there are a restricted set of epitopes which may act as effective targets for a vaccine against severe malaria. Here we review some of the recent developments in this area of research, focusing on work that has assessed the potential of these molecules as possible vaccine targets. PMID- 26741406 TI - In vitro reconstitution of B cell receptor-antigen interactions to evaluate potential vaccine candidates. AB - Predicting immune responses before vaccination is challenging because of the complexity of the governing parameters. Nevertheless, recent work has shown that B cell receptor (BCR)-antigen engagement in vitro can prove a powerful means of informing the design of antibody-based vaccines. We have developed this principle into a two-phased immunogen evaluation pipeline to rank-order vaccine candidates. In phase 1, recombinant antigens are screened for reactivity to the germline precursors that produce the antibody responses of interest. To both mimic the architecture of initial antigen engagement and facilitate rapid immunogen screening, these antibodies are expressed as membrane-anchored IgM (mIgM) in 293F indicator cells. In phase 2, the binding hits are multimerized by nanoparticle or proteoliposome display, and they are evaluated for BCR triggering in an engineered B cell line displaying the IgM sequences of interest. Key developments that complement existing methodology in this area include the following: (i) introduction of a high-throughput screening step before evaluation of more time intensive BCR-triggering analyses; (ii) generalizable multivalent antigen-display platforms needed for BCR activation; and (iii) engineered use of a human B cell line that does not display endogenous antibody, but only ectopically expressed BCR sequences of interest. Through this pipeline, the capacity to initiate favorable antibody responses is evaluated. The entire protocol can be completed within 2.5 months. PMID- 26741407 TI - Highly multiplexed targeted DNA sequencing from single nuclei. AB - Single-cell DNA sequencing methods are challenged by poor physical coverage, high technical error rates and low throughput. To address these issues, we developed a single-cell DNA sequencing protocol that combines flow-sorting of single nuclei, time-limited multiple-displacement amplification (MDA), low-input library preparation, DNA barcoding, targeted capture and next-generation sequencing (NGS). This approach represents a major improvement over our previous single nucleus sequencing (SNS) Nature Protocols paper in terms of generating higher coverage data (>90%), thereby enabling the detection of genome-wide variants in single mammalian cells at base-pair resolution. Furthermore, by pooling 48-96 single-cell libraries together for targeted capture, this approach can be used to sequence many single-cell libraries in parallel in a single reaction. This protocol greatly reduces the cost of single-cell DNA sequencing, and it can be completed in 5-6 d by advanced users. This single-cell DNA sequencing protocol has broad applications for studying rare cells and complex populations in diverse fields of biological research and medicine. PMID- 26741399 TI - Interplay between oxidant species and energy metabolism. AB - It has long been recognized that energy metabolism is linked to the production of reactive oxygen species (ROS) and critical enzymes allied to metabolic pathways can be affected by redox reactions. This interplay between energy metabolism and ROS becomes most apparent during the aging process and in the onset and progression of many age-related diseases (i.e. diabetes, metabolic syndrome, atherosclerosis, neurodegenerative diseases). As such, the capacity to identify metabolic pathways involved in ROS formation, as well as specific targets and oxidative modifications is crucial to our understanding of the molecular basis of age-related diseases and for the design of novel therapeutic strategies. Herein we review oxidant formation associated with the cell's energetic metabolism, key antioxidants involved in ROS detoxification, and the principal targets of oxidant species in metabolic routes and discuss their relevance in cell signaling and age related diseases. PMID- 26741409 TI - Molecular mechanisms of protein aggregation from global fitting of kinetic models. AB - The elucidation of the molecular mechanisms by which soluble proteins convert into their amyloid forms is a fundamental prerequisite for understanding and controlling disorders that are linked to protein aggregation, such as Alzheimer's and Parkinson's diseases. However, because of the complexity associated with aggregation reaction networks, the analysis of kinetic data of protein aggregation to obtain the underlying mechanisms represents a complex task. Here we describe a framework, using quantitative kinetic assays and global fitting, to determine and to verify a molecular mechanism for aggregation reactions that is compatible with experimental kinetic data. We implement this approach in a web based software, AmyloFit. Our procedure starts from the results of kinetic experiments that measure the concentration of aggregate mass as a function of time. We illustrate the approach with results from the aggregation of the beta amyloid (Abeta) peptides measured using thioflavin T, but the method is suitable for data from any similar kinetic experiment measuring the accumulation of aggregate mass as a function of time; the input data are in the form of a tab separated text file. We also outline general experimental strategies and practical considerations for obtaining kinetic data of sufficient quality to draw detailed mechanistic conclusions, and the procedure starts with instructions for extensive data quality control. For the core part of the analysis, we provide an online platform (http://www.amylofit.ch.cam.ac.uk) that enables robust global analysis of kinetic data without the need for extensive programming or detailed mathematical knowledge. The software automates repetitive tasks and guides users through the key steps of kinetic analysis: determination of constraints to be placed on the aggregation mechanism based on the concentration dependence of the aggregation reaction, choosing from several fundamental models describing assembly into linear aggregates and fitting the chosen models using an advanced minimization algorithm to yield the reaction orders and rate constants. Finally, we outline how to use this approach to investigate which targets potential inhibitors of amyloid formation bind to and where in the reaction mechanism they act. The protocol, from processing data to determining mechanisms, can be completed in <1 d. PMID- 26741408 TI - Preparation of pyrenyl-based multifunctional nanocomposites for biomedical applications. AB - Nanocomposites are widely used to obtain an accurate diagnosis of, and to provide effective therapy for, a number of diseases, because they can be easily formulated by introducing therapeutic agents (e.g., drugs and genes) and imaging agents (e.g., magnetic nanocrystals). Furthermore, nanocomposites can be developed as all-in-one systems, which enable cancer diagnosis and therapy, as well as the simultaneous monitoring of drug behavior. In this protocol, we describe the synthesis of four pyrenyl-based polymers (pyrenyl polyethylene glycol (Py-PEG), pyrenyl dextran (Py-DEX), pyrenyl hyaluronan (Py-HA) and pyrenyl conjugated heterofunctional PEG (pyrenyl PEG)) and their subsequent use in the preparation of multifunctional nanocomposites for different applications including multimodal imaging, targeted cancer detection and pH-sensitive drug delivery. Notably, these nanocomposites can be used to simultaneously perform multiple tasks--for example, delivering magnetic particles for early cancer detection by MRI, efficient cataloging of patient groups for personalized therapy and real-time monitoring of disease progress. Starting from the synthesis of pyrenyl-based polymers, this protocol can be completed in ~15 d. PMID- 26741410 TI - Expanding the genetic counseling workforce: program directors' views on increasing the size of genetic counseling graduate programs. AB - PURPOSE: Although there is an anticipated need for more genetic counselors, little is known about limitations at the graduate training level. We evaluated opportunities for growth of the genetic counseling (GC) workforce by exploring program directors' perspectives on increasing number of graduate trainees. METHODS: Thirty US-based GC program directors (PDs) were recruited through the Association of Genetic Counseling Program Directors' listserv. Online surveys and semistructured phone interviews were used to explore factors impacting the expansion of the GC workforce. RESULTS: Twenty-five PDs completed the survey; 18 interviews were conducted. Seventy-three percent said they believe that the workforce is growing too slowly and the number of graduates should increase. Attitudes were mixed regarding whether the job market should be the main factor driving workforce expansion. Thematic analysis of transcripts identified barriers to program expansion in six categories: funding, accreditation requirements, clinical sites, faculty availability, applicant pool, and physical space. CONCLUSION: General consensus among participants indicates the importance of increasing the capacity of the GC workforce pipeline. Addressing funding issues, examining current accreditation requirements, and reevaluating current education models may be effective strategies to expanding GC program size. Future research on increasing the number of GC programs and a needs assessment for GC services are suggested.Genet Med 18 8, 842-849. PMID- 26741411 TI - The psychological impact of genetic information on children: a systematic review. AB - PURPOSE: This review assessed the psychological impact that acquiring personal and familial genetic information has on children. We also examined the concordance between the available empirical data and clinical guidance/perspectives articles. METHODS: We screened 591 abstracts and identified 13 studies, representing 966 children. Ten studies assessed 386 children tested for familial adenomatous polyposis (n = 171), hereditary cardiac disease (n = 134), and other conditions (n = 81). Three studies addressed the impact of BRCA1/2 testing of a family member on 580 children. RESULTS: Serious adverse psychological outcomes were uncommon. Most studies reported no significant increase in mean anxiety, depression, and distress scores (n = 8, 61.5%); however, some children experienced intrafamilial distress, discrimination, and guilt/regret. Some children were more concerned about their own health or their family members' health. There was limited consistency between anticipated adverse impact and empirical data. CONCLUSIONS: The review identified little conclusive evidence of deleterious psychological consequences for children acquiring genetic information. However, there is a lack of data regarding genetic testing for conditions that may not be treatable/modifiable, as well as a dearth of longitudinal studies. Therefore, clinical caution remains essential for the ethical integration of genetic testing into pediatrics. Further research assessing the potential positive and negative effects of genetic testing in childhood is warranted.Genet Med 18 8, 755-762. PMID- 26741412 TI - Identification of microsatellite markers <1 Mb from the FMR1 CGG repeat and development of a single-tube tetradecaplex PCR panel of highly polymorphic markers for preimplantation genetic diagnosis of fragile X syndrome. AB - PURPOSE: To develop a single-tube polymerase chain reaction (PCR) panel of highly polymorphic markers for preimplantation genetic diagnosis (PGD) of fragile X syndrome (FXS). METHODS: An in silico search was performed to identify all markers within 1 Mb flanking the FMR1 gene. Selected markers were optimized into a single-tube PCR panel and their polymorphism indices were determined from 272 female samples from three populations. The single-tube assay was also validated on 30 single cells to evaluate its applicability to FXS PGD. RESULTS: Thirteen markers with potentially high polymorphism information content (PIC) and heterozygosity values were selected and optimized into a single-tube PCR panel together with AMELX/Y for gender determination. Analysis of 272 female samples confirmed the high polymorphism (PIC > 0.5) of most markers, with expected and observed heterozygosities ranging from 0.31 to 0.87. More than 99% of individuals were heterozygous for at least three markers, with 95.8% of individuals heterozygous for at least two markers on either side of the FMR1 CGG repeat. CONCLUSION: The tetradecaplex marker assay can be performed directly on single cells or after whole-genome amplification, thus supporting its use in FXS PGD either as a standalone linkage-based assay or as a complement to FMR1 mutation detection.Genet Med 18 9, 869-875. PMID- 26741413 TI - Propofol Use in Israeli PICUs. AB - OBJECTIVES: In Israel, the recommendation for the use of propofol is age limited. Furthermore, procedural sedations involving propofol must be performed only by anesthesiologists. Propofol is frequently used in the PICUs in Israel. DESIGN: Questionnaire survey. SETTING: PICUs in Israel. SUBJECTS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Physicians from 13 PICUs (86.6%) responded to the questionnaire. Propofol was used for induction, procedural sedation, and ongoing ICU sedation in 100%, 70%, and 12% of cases, respectively. Eighty-eight percent of the participants limited the duration of propofol infusion to 24 hours at a dose of less than or equal to 4 mg/kg/1 hr, but 40% administered propofol as needed without specifying an upper dose limit. Twenty-five percent encountered adverse effects such as apnea, desaturation, and bradycardia, but only two of the participants suspected propofol infusion syndrome, each in one patient. All the participants agreed to expand the indications for propofol use in the pediatric age group. Ketamine was the drug mostly used instead of propofol (50%), followed by fentanyl (30%), midazolam (30%), and remifentanil (5%). Apart from anesthesiologists, PICU physicians support the use of propofol by physicians who have the technical skills for rapid-sequence intubation and advanced airway management. CONCLUSIONS: Off-label use of propofol is an accepted practice in Israeli PICUs. Propofol has a unique profile that makes it an attractive sedative agent in many clinical settings. PICU physicians may want to prescribe it, at least for short periods and at low doses. PMID- 26741414 TI - Preferential Protection of Cerebral Autoregulation and Reduction of Hippocampal Necrosis With Norepinephrine After Traumatic Brain Injury in Female Piglets. AB - OBJECTIVES: Traumatic brain injury contributes to morbidity in children and boys is disproportionately represented. Cerebral autoregulation is impaired after traumatic brain injury, contributing to poor outcome. Cerebral perfusion pressure is often normalized by the use of vasopressors to increase mean arterial pressure. In prior studies, we observed that phenylephrine prevented impairment of autoregulation in female but exacerbated in male piglets after fluid percussion injury. In contrast, dopamine prevented impairment of autoregulation in both sexes after fluid percussion injury, suggesting that pressor choice impacts outcome. The extracellular signal-regulated kinase isoform of mitogen activated protein kinase produces hemodynamic impairment after fluid percussion injury, but the role of the cytokine interleukin-6 is unknown. We investigated whether norepinephrine sex-dependently protects autoregulation and limits histopathology after fluid percussion injury and the role of extracellular signal regulated kinase and interleukin-6 in that outcome. DESIGN: Prospective, randomized animal study. SETTING: University laboratory. SUBJECTS: Newborn (1-5 d old) pigs. INTERVENTIONS: Cerebral perfusion pressure, cerebral blood flow, and pial artery diameter were determined before and after fluid percussion injury in piglets equipped with a closed cranial window and post-treated with norepinephrine. Cerebrospinal fluid extracellular-signal-regulated kinase mitogen activated protein kinase was determined by enzyme-linked immunosorbent assay. MEASUREMENTS AND MAIN RESULTS: Norepinephrine does not protect autoregulation or prevent reduction in cerebral blood flow in male but fully protects autoregulation in female piglets after fluid percussion injury. Papaverine induced dilation was unchanged by fluid percussion injury and norepinephrine. Norepinephrine increased extracellular signal-regulated kinase mitogen-activated protein kinase up-regulation in male but blocked such up-regulation in female piglets after fluid percussion injury. Norepinephrine aggravated interleukin-6 upregulation in males in an extracellular signal-regulated kinase mitogen activated protein kinase-dependent mechanism but blocked interleukin-6 up regulation in females after fluid percussion injury. Norepinephrine augments loss of neurons in CA1 and CA3 hippocampus of male piglets after fluid percussion injury in an extracellular signal-regulated kinase mitogen-activated protein kinase-dependent and interleukin-6-dependent manner but prevents loss of neurons in females after fluid percussion injury. CONCLUSION: Norepinephrine protects autoregulation and limits hippocampal neuronal cell necrosis via modulation of extracellular signal-regulated kinase mitogen-activated protein kinase and interleukin-6 after fluid percussion injury in a sex-dependent manner. PMID- 26741415 TI - Comparison of stethoscope bell and diaphragm, and of stethoscope tube length, for clinical blood pressure measurement. AB - OBJECTIVE: This study investigated the effect of stethoscope side and tube length on auscultatory blood pressure (BP) measurement. METHODS: Thirty-two healthy participants were studied. For each participant, four measurements with different combinations of stethoscope characteristics (bell or diaphragm side, standard or short tube length) were each recorded at two repeat sessions, and eight Korotkoff sound recordings were played twice on separate days to one experienced listener to determine the systolic and diastolic BPs (SBP and DBP). Analysis of variance was carried out to study the measurement repeatability between the two repeat sessions and between the two BP determinations on separate days, as well as the effects of stethoscope side and tube length. RESULTS: There was no significant paired difference between the repeat sessions and between the repeat determinations for both SBP and DBP (all P-values>0.10, except the repeat session for SBP using short tube and diaphragm). The key result was that there was a small but significantly higher DBP on using the bell in comparison with the diaphragm (0.66 mmHg, P=0.007), and a significantly higher SBP on using the short tube in comparison with the standard length (0.77 mmHg, P=0.008). CONCLUSION: This study shows that stethoscope characteristics have only a small, although statistically significant, influence on clinical BP measurement. Although this helps understand the measurement technique and resolves questions in the published literature, the influence is not clinically significant. PMID- 26741459 TI - Two-Center/Three-Electron Sigma Half-Bonds in Main Group and Transition Metal Chemistry. AB - First proposed in a classic Linus Pauling paper, the two-center/three-electron (2c/3e) sigma half-bond challenges the extremes of what may or may not be considered a chemical bond. Two electrons occupying a sigma bonding orbital and one electron occupying the antibonding sigma* orbital results in bond orders of ~0.5 that are characteristic of metastable and exotic species, epitomized in the fleetingly stable He2(+) ion. In this Account, I describe the use of coordination chemistry to stabilize such fugacious three-electron bonded species at disparate ends of the periodic table. A recent emphasis in the chemistry of metal-metal bonds has been to prepare compounds with extremely short metal-metal distances and high metal-metal bond orders. But similar chemistry can be used to explore metal-metal bond orders less than one, including 2c/3e half-bonds. Bimetallic compounds in the Ni2(II,III) and Pd2(II,III) oxidation states were originally examined in the 1980s, but the evidence collected at that time suggested that they did not contain 2c/3e sigma bonds. Both classes of compounds have been re examined using EPR spectroscopy and modern computational methods that show the unpaired electron of each compound to occupy a M-M sigma* orbital, consistent with 2c/3e Ni-Ni and Pd-Pd sigma half-bonds. Elsewhere on the periodic table, a seemingly unrelated compound containing a trigonal bipyramidal Cu3S2 core caused a stir, leaving prominent theorists at odds with one another as to whether the compound contains a S-S bond. Due to my previous experience with 2c/3e metal metal bonds, I suggested that the Cu3S2 compound could contain a 2c/3e S-S sigma half-bond in the previously unknown oxidation state of S2(3-). By use of the Cambridge Database, a number of other known compounds were identified as potentially containing S2(3-) ligands, including a noteworthy set of cyclopentadienyl-supported compounds possessing diamond-shaped Ni2E2 units with E = S, Se, and Te. These compounds were subjected to extensive studies using X-ray absorption spectroscopy, X-ray photoelectron spectroscopy, density functional theory, and wave function-based computational methods, as well as chemical oxidation and reduction. The compounds contain E-E 2c/3e sigma half-bonds and unprecedented E2(3-) "subchalcogenide" ligands, ushering in a new oxidation state paradigm for transition metal-chalcogen chemistry. PMID- 26741458 TI - Mixed alpha/beta-Peptides as a Class of Short Amphipathic Peptide Hydrogelators with Enhanced Proteolytic Stability. AB - Peptide hydrogels are a highly promising class of materials for biomedical application, albeit facing many challenges with regard to stability and tunability. Here, we report a new class of amphipathic peptide hydrogelators, namely mixed alpha/beta-peptide hydrogelators. These mixed alpha/beta-gelators possess good rheological properties (high storage moduli) and form transparent self-supporting gels with shear-thinning behavior. Infrared spectroscopy indicates the presence of beta-sheets as the underlying secondary structure. Interestingly, self-assembled nanofibers of the mixed alpha/beta-peptides display unique structural morphologies with alteration of the C-terminus (acid vs amide) playing a key role in the fiber formation and gelation properties of the resulting hydrogels. The incorporation of beta3-homoamino acid residues within the mixed alpha/beta-peptide gelators led to an increase in proteolytic stability of the peptides under nongelating conditions (in solution) as well as gelating conditions (as hydrogel). Under diluted conditions, degradation of mixed alpha/beta-peptides in the presence of elastase was slowed down 120-fold compared to that of an alpha-peptide, thereby demonstrating beneficial enzymatic resistance for hydrogel applications in vivo. In addition, increased half-life values were obtained for the mixed alpha/beta-peptides in human blood plasma, as compared to corresponding alpha-peptides. It was also found that the mixed alpha/beta-peptides were amenable to injection via needles used for subcutaneous administrations. The preformed peptide gels could be sheared upon injection and were found to quickly reform to a state close to that of the original hydrogel. The shown properties of enhanced proteolytic stability and injectability hold great promise for the use of these novel mixed alpha/beta-peptide hydrogels for applications in the areas of tissue engineering and drug delivery. PMID- 26741460 TI - Upper airway trauma during general anaesthesia for major surgery: incidence and trends: A retrospective study. PMID- 26741461 TI - Peritonsillar morphine infiltration to prevent early postoperative pain after tonsillectomy: A randomised controlled trial. PMID- 26741462 TI - Reply to: blind intubation through Air-Q SP laryngeal mask in morbidly obese patients. PMID- 26741463 TI - Tuning the Gas Separation Performance of CuBTC by Ionic Liquid Incorporation. AB - The efficient separation of gases has industrial, economic, and environmental importance. Here, the gas separation performance of a metal organic framework (MOF) is enhanced by ionic liquid (IL) incorporation. One of the most commonly used ILs, 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]), was incorporated into a commercially available MOF, CuBTC. Detailed characterization by combining spectroscopy with diffraction, electron microscopy, and thermal analysis confirmed that the structures were intact after incorporation. Adsorption isotherms of CH4, H2, N2, and CO2 in IL-incorporated CuBTC were experimentally measured and compared with those of pristine CuBTC. Consequently, ideal selectivities for CO2/CH4, CO2/N2, CO2/H2, CH4/N2, CH4/H2, and N2/H2 separations were calculated. The results showed that the CH4 selectivity of CuBTC over CO2, H2, and N2 gases becomes at least 1.5 times higher than that of pristine CuBTC upon the incorporation of IL. For example, the CH4/H2 selectivity of CuBTC increased from 26 to 56 at 0.2 bar when the IL loading was 30 wt %. These results show that the incorporation of ILs into MOFs can lead to unprecedented improvements in the gas separation performance of MOFs. The tunable physicochemical properties of ILs combined with a large number of possible MOF structures open up opportunities for the rational design of novel materials for meeting future energy challenges. PMID- 26741464 TI - Facial Emotion Recognition in Bipolar Disorder and Healthy Aging. AB - Emotional face recognition is impaired in bipolar disorder, but it is not clear whether this is specific for the illness. Here, we investigated how aging and bipolar disorder influence dynamic emotional face recognition. Twenty older adults, 16 bipolar patients, and 20 control subjects performed a dynamic affective facial recognition task and a subsequent rating task. Participants pressed a key as soon as they were able to discriminate whether the neutral face was assuming a happy or angry facial expression and then rated the intensity of each facial expression. Results showed that older adults recognized happy expressions faster, whereas bipolar patients recognized angry expressions faster. Furthermore, both groups rated emotional faces more intensely than did the control subjects. This study is one of the first to compare how aging and clinical conditions influence emotional facial recognition and underlines the need to consider the role of specific and common factors in emotional face recognition. PMID- 26741465 TI - Mononuclear, Dinuclear, and Trinuclear Iron Complexes Featuring a New Monoanionic SNS Thiolate Ligand. AB - The new tridentate ligand, S(Me)N(H)S = 2-(2-methylthiophenyl)benzothiazolidine, prepared in a single step from commercial precursors in excellent yield, undergoes ring-opening on treatment with Fe(OTf)2 in the presence of base affording a trinuclear iron complex, [Fe3(MU2-S(Me)NS(-))4](OTf)2 (1) which is fully characterized by structural and spectroscopic methods. X-ray structural data reveal that 1 contains four S(Me)NS(-) ligands meridionally bound to two pseudooctahedral iron centers each bridged by two thiolates to a distorted tetrahedral central iron. The combined spectroscopic (UV-vis, Mossbauer, NMR), magnetic (solution and solid state), and computational (DFT) studies indicate that 1 includes a central, high-spin Fe(II) (S = 2) with two low-spin (S = 0) peripheral Fe(II) centers. Complex 1 reacts with excess PMePh2, CNxylyl (2,6 dimethylphenyl isocyanide), and P(OMe)3 in CH3CN to form diamagnetic, thiolate bridged, dinuclear Fe(II) complexes {[Fe(MU-S(Me)NS(-))L2]2}(OTf)2 (2-4). These complexes are characterized by elemental analysis; (1)H NMR, IR, UV-vis, and Mossbauer spectroscopy; and single crystal X-ray diffraction. Interestingly, addition of excess P(OMe)3 to complex 1 in CH2Cl2 produces primarily the diamagnetic, mononuclear Fe(II) complex, {Fe(S(Me)NS(-))[P(OMe)3]3}(OTf) (5). PMID- 26741466 TI - The Missing Link in Military Global Health Engagement. PMID- 26741467 TI - The American Ambulance in Paris, 1914-1917 Part II: The University Surgical Service. PMID- 26741468 TI - 16-Year-Old With Chest Pain. PMID- 26741469 TI - Should Military Doctors Help Patients When Doing So Could Increase Risks to Others? PMID- 26741470 TI - Guiding Appropriate Laboratory Test Utilization: 1,25-OH-Vitamin D. PMID- 26741471 TI - Strengthening the U.S. Public Health Service Commissioned Corps: A View From The Assistant Secretary for Health. AB - OBJECTIVE: To summarize the results of the major management review of the U.S. Public Health Service Commissioned Corps (2009-2010) and note related outcomes. METHOD: Narrative from the U.S. Assistant Secretary for Health, who directed and oversaw the management review. RESULTS: The management review led to 46 recommendations, all of which have since been implemented. The subsequent organizational and operational changes have unified reporting structures, streamlined the administrative Corps organizational structure, and transferred support services to providers with expertise in uniformed services to create a new integrated personnel and payroll system. Related processes have also prompted a systematic billet review as well as establishment of explicit criteria for eligibility to become a Corps officer. Corps leaders report improvements in recruiting talented officers, increased selectivity from the candidate pool, and enhanced matching of incoming officers with agency assignments. Furthermore, Corps activity has grown in both traditional and innovative ways. CONCLUSION: The Corps has enjoyed heightened activity and outcomes in the era of health reform. The management review and its implementation have strengthened the Corps, helping officers to do their job and achieve their mission. PMID- 26741472 TI - The Impact of Unit Membership on Smoking Among Soldiers. AB - Cultural, organizational, and dyadic influences have been found to be associated with smoking in the military while group-level influences have been identified in the general population. However, there are few studies examining group-level influences in the military and none using group-level analyses. Such studies are essential for understanding how to optimally forestall or cease smoking. This study, using mixed effects modelling, examined whether unit membership influenced smoking behavior in soldiers from brigade combat teams. Unit membership was assessed in 2008 to 2009 at the company level (n = 2204) and in 2012 at the platoon level (n = 452). Smoking was assessed by the number of daily cigarettes smoked (range: 0-99) with smoking status (nonsmoker vs. smoker) and smoking level (none, smoker, and heavy [20 + cigarettes/day]) as the outcomes. For both samples, unit membership was not significantly associated with a soldier's propensity to smoke when comparing either all smokers to nonsmokers or heavy smokers to smokers. These results suggest typical military unit-level training programs are unlikely to be the most effective mode of intervention for smoking prevention or cessation. Smoking rates in the military may be influenced instead by small group or individual relationships or by overall military culture. PMID- 26741473 TI - A Retrospective Case Series of Surgical Implant Generation Network (SIGN) Placement at the Afghan National Police Hospital, Kabul, Afghanistan. AB - In Afghanistan, adequate and cost-effective medical care for even routine conditions is lacking; especially for complex injuries like long-bone fractures. The Surgical Implant Generation Network (SIGN) intramedullary nail is used for treatment of long-bone fractures from blunt injuries and does not require imaging. We are reporting for the first time results of the SIGN intramedullary nail at the Afghan National Police Hospital, a tertiary care facility in Kabul. 71 records from the SIGN Online Surgical Database were reviewed for gender, age, date of injury, implant date, patient's home of record, and type/ mechanism of injury. Mean age was 26.7 years, all but one being male; time from injury to implant ranged 1 to 401 days, with mean of 40.6 days. Long-bone fractures from motor vehicle accidents remained constant, and war injuries peaked in summer. Follow-up is limited because of security and financial burdens of travel. However, personal communication with Afghan National Police Hospital surgeons suggests that patients included in the current study have not experienced any adverse outcomes. While it remains to be seen if the SIGN Online Surgical Database will facilitate more comprehensive outcome studies, our results provide support for the efficacy of SIGN nails in treating long-bone fractures from war injuries. PMID- 26741474 TI - Free-Tissue Transfer for the Reconstruction of War-Related Extremity Injuries: A Systematic Review of Current Practice. AB - OBJECTIVES: Extremity injuries in combat zones have devastating sequelae. The increasing survival of war-zone casualties, combined with rapid advances in microsurgery, means that there is a growing role for free-tissue reconstruction. We systematically reviewed the current practices in microsurgical reconstruction of combat-related extremity injuries, focusing on free-flap types, timing of surgery, and outcomes. METHODS: We conducted a PubMed search of the terms "War" and "Reconstruction," identifying 21st century studies on subacute/delayed free flap repair, to reflect the idiosyncrasies of modern warfare. Case reports and studies exclusively describing craniofacial and thoracoabdominal injuries were excluded. RESULTS: A total of 11 studies fulfilled our inclusion criteria. In 9 studies, patients were repatriated/transferred to specialist facilities for treatment; in 2 studies, reconstruction was performed within combat/austere environments. The number of free-flaps described per study ranged from 6 to 233 (Total = 501). Latissimus dorsi flaps were most commonly used (43.7%). The average time to definitive reconstruction ranged from 9.6 days to 3 years, being delayed to address life-threatening injuries. The average free-flap success rate was 95.5% (range = 88.9%-100%). CONCLUSION: Combat-associated extremity injuries are characterized by extensive tissue loss and gross contamination. Despite this, microsurgical reconstruction results in minimal morbidity and successful outcomes. Large, multicenter studies are necessary to corroborate these findings and establish definitive management guidelines. PMID- 26741475 TI - Integrative Literature Review: U.S. Military Women's Genitourinary and Reproductive Health. AB - OBJECTIVES: This integrated literature review evaluated research on genitourinary and reproductive health care needs and gender-specific health care delivery for active duty U.S. military women, a growing population in the armed forces. METHODS: A literature search was conducted for publications on genitourinary and reproductive health published between 2008 and 2014 using keywords and terms utilized in previous systematic literature reviews in similar military populations. RESULTS: Previous literature reviews concentrated on broader health care issues of military women. This review updates and expands the literature identified in three previous reviews. Publications were evaluated for relevancy to U.S. military women's health and a sample of 82 publications was included. Five broad categories were addressed across the literature: (1) pregnancy health, (2) deployment and preventive health, (3) sexually transmitted infections, (4) family planning and contraceptive services, and (5) sexual violations. DISCUSSION: Health care challenges are evolving within a changing military environment that includes a greater integration of women. Contraceptive, genitourinary-reproductive health care access, and self-diagnostic tools for easily treatable vulvovaginal conditions can empower military women and improve quality of life. CONCLUSIONS: Studies examining military gender-specific health care delivery are limited. Research to understand factors important for women in a changing military environment can improve health care delivery and outcomes, and military readiness. PMID- 26741476 TI - Factors Affecting Health Care Utilization in OEF/OIF Veterans: The Impact of PTSD and Pain. AB - OBJECTIVES: Returning Operation Enduring Freedom and Operation Iraqi Freedom veterans are at a high risk for physical and mental health symptoms including pain (90%) and post-traumatic stress disorder (PTSD) (58%). These often present concurrently and result in many health problems, functional impairments, and overall poor rehabilitation. To address postdeployment health, effective and efficient allocation of health care resources is needed. METHODS: Retrospective study of 144 veterans who completed a second-level screening in the Polytrauma clinic. Veterans completed the PTSD Checklist-Civilian Version. Their pain rating and health care utilization (sum of visits during 12 months, categorized as medical or mental health) was extracted through chart review. RESULTS: The majority of veterans reported significant PTSD (72%) and pain (87%) symptoms; 45% received adequate mental health treatment, defined as >=8 sessions in 12 months. PTSD and the interaction with pain predicted medical utilization; at high pain levels veterans' PTSD severity predicted utilization. PTSD alone predicted mental health utilization. CONCLUSIONS: The results show the increased influence of PTSD symptoms on medical health care services when pain ratings are high and suggest the need for interdisciplinary pain clinics that are able to address the overlapping symptoms of pain and common mental health conditions. Implication of results for VA planning are discussed. PMID- 26741477 TI - Impact of Transcendental Meditation on Psychotropic Medication Use Among Active Duty Military Service Members With Anxiety and PTSD. AB - The purpose of the study was to determine whether the regular practice of Transcendental Meditation (TM) decreased the need for psychotropic medications required for anxiety and post-traumatic stress disorder (PTSD) management and increased psychological wellbeing. The sample included 74 military Service Members with documented PTSD or anxiety disorder not otherwise specified (ADNOS), 37 that practiced TM and 37 that did not. At 1 month, 83.7% of the TM group stabilized, decreased, or ceased medications and 10.8% increased medication dosage; compared with 59.4% of controls that showed stabilizations, decreases, or cessations; and 40.5% that increased medications (p < 0.03). A similar pattern was observed after 2 (p < 0.27), 3 (p < 0.002), and 6 months (p < 0.34). Notably, there was a 20.5% difference between groups in severity of psychological symptoms after 6 months, that is, the control group experienced an increase in symptom severity compared with the group practicing TM. These findings provide insight into the benefits of TM as a viable treatment modality in military treatment facilities for reducing PTSD and ADNOS psychological symptoms and associated medication use. PMID- 26741478 TI - Descriptive Epidemiology of Musculoskeletal Injuries in Naval Special Warfare Sea, Air, and Land Operators. AB - The purpose of this analysis was to describe medical chart reviewed musculoskeletal injuries among Naval Special Warfare Sea, Air, and Land Operators. 210 Operators volunteered (age: 28.1 +/- 6.0 years, height: 1.8 +/- 0.1 m, weight: 85.4 +/- 9.3 kg). Musculoskeletal injury data were extracted from subjects' medical charts, and injuries that occurred during 1 year were described. Anatomic location of injury, cause of injury, activity when injury occurred, and injury type were described. The frequency of injuries was 0.025 per Operator per month. Most injuries involved the upper extremity (38.1% of injuries). Frequent anatomic sublocations for injuries were the shoulder (23.8%) and lumbopelvic region of the spine (12.7%). Lifting was the cause of 7.9% of injuries. Subjects were participating in training when 38.1% of injuries occurred and recreational activity/sports when 12.7% of injuries occurred. Frequent injury types were strain (20.6%), pain/spasm/ache (19.0%), fracture (11.1%), and sprain (11.1%). The results of this analysis underscore the need to investigate the risk factors, especially of upper extremity and physical activity related injuries, in this population of Operators. There is a scope for development of a focused, customized injury prevention program, targeting the unique injury profile of this population. PMID- 26741479 TI - Multi-Injury Casualty Stream Simulation in a Shipboard Combat Environment. AB - Accurate forecasts of casualty streams are essential for estimating personnel and materiel requirements for future naval combat engagements. The scarcity of recent naval combat data makes accurate forecasting difficult. Furthermore, current forecasts are based on single injuries only, even though empirical evidence indicates most battle casualties suffer multiple injuries. These anticipated single-injury casualty streams underestimate the needed medical resources. This article describes a method of simulating realistic multi-injury casualty streams in a maritime environment by combining available shipboard data with ground combat blast data. The simulations, based on the Military Combat Injury Scale, are expected to provide a better tool for medical logistics planning. PMID- 26741480 TI - Characteristics of Highly Rated Internal Medicine Attendings Before and After the 2004 Work-Hour Restrictions. AB - OBJECTIVES: To describe the characteristics of top-rated Internal Medicine attendings and whether they changed after implementation of the 2004 work-hour restrictions. METHODS: Mixed methods study of resident ratings of medicine attendings (Period 1: 1994-1996, n = 250 and Period 2: 2007-2009, n = 152). Residents evaluated 17 attending characteristics. The top 25% of "overall" ratings were classified as "highly rated." Two free-text questions included "What was your attending's best characteristic?" and "How could your attending best improve?" and were coded in duplicate, using grounded qualitative methods. RESULTS: There were no differences in the characteristics of highly rated attendings in the two time periods. Characteristics associated with being a top rated attending included enthusiasm (odds ratio [OR]: 5.69, 2.78-11.67), balanced teaching style (OR: 3.63, 1.64-8.02), promoting independent thinking (OR: 2.90, 0.96-8.74), fund of knowledge (OR: 2.73, 1.13-6.58), and time management (OR: 1.78, 1.14-2.80). Among the 1,410 utterances, valued attending attributes included helpfulness, promoting independent thinking, and having strong medical knowledge. CONCLUSIONS: The characteristics valued by residents in attendings did not change over time despite a major structural change in work hours and patterns of teaching. These valued characteristics continue to be a strong general fund of knowledge, enthusiasm for teaching, and balance between didactic and bedside approaches. PMID- 26741482 TI - Walter Reed, Yellow Fever, and Informed Consent. PMID- 26741481 TI - Effectiveness of Healthy Menu Changes in a Nontrainee Military Dining Facility. AB - The purpose of this study was to evaluate the impact of implementing the Initial Military Training (IMT) menu standards in nontrainee dining facilities (DFAC) on food selection, nutrient intake, and satisfaction of soldiers. Participants were recruited during lunch before and 3 weeks after the menu changes. Direct observations, digital photography, and plate waste methods were used to assess soldiers' food selection and consumption, along with a survey assessing soldiers' meal satisfaction under the two menu standards. Descriptive statistics and independent sample t-tests were used to summarize and compare the data. A total of 172 and 140 soldiers participated before and after menu changes, respectively. Soldiers consumed 886 kcals (38.6% from total fat and 11.2% from saturated fat) and 1,784 mg of sodium before the menu change. Three weeks after the change, all figures improved (p < 0.01). The percentage of healthier food selections mirrored food items served at the DFAC and improved after the intervention (p < 0.001). There were no differences observed in overall satisfaction and meal acceptability after the intervention. Our findings suggest implementing the Initial Military Training menu standards in nontrainee Army DFACs is feasible and has the potential to improve the overall healthfulness of soldiers' food selection and consumption. PMID- 26741483 TI - Nitric Oxide Inhibitory Activity and Absolute Configurations of Arylalkenyl alpha,beta-Unsaturated delta/gamma-Lactones from Cryptocarya concinna. AB - During an ongoing exploration of potential anti-inflammatory agents from medicinal plants, eight new arylalkenyl alpha,beta-unsaturated delta-lactones, cryptoconcatones A-H (1-8), and two unusual arylalkenyl alpha,beta-unsaturated gamma-lactones, cryptoconcatones I and J (9 and 10), were identified from the leaves and twigs of Cryptocarya concinna. The structures of these compounds were established based on spectroscopic data (MS, 1D/2D NMR), and their absolute configurations were determined with Riguera's method, the modified Mosher's method, chemical derivatization, and the Snatzke chirality rule. Compounds 4-6 and 8-10 showed inhibitory activity toward nitric oxide (NO) production in lipopolysaccharide-induced RAW 264.7 macrophages, particularly compounds 4 and 8 10, with IC50 values of 3.2, 4.2, 3.4, and 7.5 MUM, respectively. PMID- 26741484 TI - Relative Penetration of Zinc Oxide and Zinc Ions into Human Skin after Application of Different Zinc Oxide Formulations. AB - Zinc oxide (ZnO) is frequently used in commercial sunscreen formulations to deliver their broad range of UV protection properties. Concern has been raised about the extent to which these ZnO particles (both micronized and nanoparticulate) penetrate the skin and their resultant toxicity. This work has explored the human epidermal skin penetration of zinc oxide and its labile zinc ion dissolution product that may potentially be formed after application of ZnO nanoparticles to human epidermis. Three ZnO nanoparticle formulations were used: a suspension in the oil, capric caprylic triglycerides (CCT), the base formulation commonly used in commercially available sunscreen products; an aqueous ZnO suspension at pH 6, similar to the natural skin surface pH; and an aqueous ZnO suspension at pH 9, a pH at which ZnO is stable and there is minimal pH-induced impairment of epidermal integrity. In each case, the ZnO in the formulations did not penetrate into the intact viable epidermis for any of the formulations but was associated with an enhanced increase in zinc ion fluorescence signal in both the stratum corneum and the viable epidermis. The highest labile zinc fluorescence was found for the ZnO suspension at pH 6. It is concluded that, while topically applied ZnO does not penetrate into the viable epidermis, these applications are associated with hydrolysis of ZnO on the skin surface, leading to an increase in zinc ion levels in the stratum corneum, thence in the viable epidermis and subsequently in the systemic circulation and the urine. PMID- 26741485 TI - Emissions of Ultrafine Particles and Volatile Organic Compounds from Commercially Available Desktop Three-Dimensional Printers with Multiple Filaments. AB - Previous research has shown that desktop 3D printers can emit large numbers of ultrafine particles (UFPs, particles less than 100 nm) and some hazardous volatile organic compounds (VOCs) during printing, although very few filament and 3D printer combinations have been tested to date. Here we quantify emissions of UFPs and speciated VOCs from five commercially available filament extrusion desktop 3D printers utilizing up to nine different filaments by controlled experiments in a test chamber. Median estimates of time-varying UFP emission rates ranged from ~10(8) to ~10(11) min(-1) across all tested combinations, varying primarily by filament material and, to a lesser extent, bed temperature. The individual VOCs emitted in the largest quantities included caprolactam from nylon-based and imitation wood and brick filaments (ranging from ~2 to ~180 MUg/min), styrene from acrylonitrile butadiene styrene (ABS) and high-impact polystyrene (HIPS) filaments (ranging from ~10 to ~110 MUg/min), and lactide from polylactic acid (PLA) filaments (ranging from ~4 to ~5 MUg/min). Results from a screening analysis of potential exposure to these products in a typical small office environment suggest caution should be used when operating many of the printer and filament combinations in poorly ventilated spaces or without the aid of combined gas and particle filtration systems. PMID- 26741486 TI - Silaborative Carbocyclizations of 1,7-Enynes. Diastereoselective Preparation of Chromane Derivatives. AB - Palladium(0)-catalyzed carbocyclization of 1,7-enynes mediated by (chlorodimethylsilyl)pinacolborane proceeds with 1,8-addition of the silicon and boron functions to give functionalized cyclohexane derivatives with boron attached to the exocyclic olefin. A variety of chromane dervatives are accessible by this method. In contrast to the analogous reactions with 1,6-enynes, the configuration of the newly formed stereogenic center is controlled by a stereogenic center present in the substrate. PMID- 26741487 TI - The impact of pontine disease on lower urinary tract symptoms in patients with multiple sclerosis. AB - AIMS: To investigate the relationship between pontine lesion characteristics on MRI and lower urinary tract symptoms (LUTS) in patients with multiple sclerosis (MS). METHODS: We performed a prospective cohort study of patients with MS and LUTS who were undergoing brain/spine MRI. Patients were administered the American Urological Association Symptom Score (AUA-SS), Medical, Epidemiologic, and Social Aspects of Aging questionnaire (MESA), and Urogenital Distress Inventory questionnaire (UDI-6), underwent Kurtzke Expanded Disability Status Scale (EDSS) scoring by a neurologist, and had their MRIs reviewed by a neuroradiologist. The relationships between symptom scores and lesion number, size, and location were analyzed. RESULTS: There were 42 patients that completed the study and 20 (48%) had one or more pontine lesions. Total AUA-SS and UDI-6 were related to multiple Short Form Health Survey (SF-36) scales and not EDSS scoring. Weak urinary stream measured on the AUA-SS (P = 0.028), and urgency incontinence measured on the MESA questionnaire (P = 0.034) were related to pontine lesion diameter. There was no difference in urinary symptoms according to the presence or absence of a pontine lesion, or according to lesion location within the pons. CONCLUSIONS: Pontine lesion size appears to be related to lower urinary tract symptoms (weak stream and urgency incontinence) in patients with MS. Therefore, CNS lesion characteristics may be able to phenotype voiding symptoms in patients with MS. Neurourol. Urodynam. 36:453-456, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26741488 TI - Geographic Variation and Factors Associated with Female Genital Mutilation among Reproductive Age Women in Ethiopia: A National Population Based Survey. AB - BACKGROUND: Female genital mutilation (FGM) is a common traditional practice in developing nations including Ethiopia. It poses complex and serious long-term health risks for women and girls and can lead to death. In Ethiopia, the geographic distribution and factors associated with FGM practices are poorly understood. Therefore, we assessed the spatial distribution and factors associated with FGM among reproductive age women in the country. METHOD: We used population based national representative surveys. Data from two (2000 and 2005) Ethiopian demographic and health surveys (EDHS) were used in this analysis. Briefly, EDHS used a stratified, two-stage cluster sampling design. A total of 15,367 (from EDHS 2000) and 14,070 (from EDHS 2005) women of reproductive age (15 49 years) were included in the analysis. Three outcome variables were used (prevalence of FGM among women, prevalence of FGM among daughters and support for the continuation of FGM). The data were weighted and descriptive statistics (percentage change), bivariate and multivariable logistic regression analyses were carried out. Multicollinearity of variables was assessed using variance inflation factors (VIF) with a reference value of 10 before interpreting the final output. The geographic variation and clustering of weighted FGM prevalence were analyzed and visualized on maps using ArcGIS. Z-scores were used to assess the statistical difference of geographic clustering of FGM prevalence spots. RESULT: The trend of FGM weighted prevalence has been decreasing. Being wealthy, Muslim and in higher age categories are associated with increased odds of FGM among women. Similarly, daughters from Muslim women have increased odds of experiencing FGM. Women in the higher age categories have increased odds of having daughters who experience FGM. The odds of FGM among daughters decrease with increased maternal education. Mass media exposure, being wealthy and higher paternal and maternal education are associated with decreased odds of women's support of FGM continuation. FGM prevalence and geographic clustering showed variation across regions in Ethiopia. CONCLUSION: Individual, economic, socio demographic, religious and cultural factors played major roles in the existing practice and continuation of FGM. The significant geographic clustering of FGM was observed across regions in Ethiopia. Therefore, targeted and integrated interventions involving religious leaders in high FGM prevalence spot clusters and addressing the socio-economic and geographic inequalities are recommended to eliminate FGM. PMID- 26741489 TI - Downregulation of AKT3 Increases Migration and Metastasis in Triple Negative Breast Cancer Cells by Upregulating S100A4. AB - BACKGROUND: Treatment of breast cancer patients with distant metastases represents one of the biggest challenges in today's gynecological oncology. Therefore, a better understanding of mechanisms promoting the development of metastases is of paramount importance. The serine/threonine kinase AKT was shown to drive cancer progression and metastasis. However, there is emerging data that single AKT isoforms (i.e. AKT1, AKT2 and AKT3) have different or even opposing functions in the regulation of cancer cell migration in vitro, giving rise to the hypothesis that inhibition of distinct AKT isoforms might have undesirable effects on cancer dissemination in vivo. METHODS: The triple negative breast cancer cell line MDA-MB-231 was used to investigate the functional roles of AKT in migration and metastasis. AKT single and double knockdown cells were generated using isoform specific shRNAs. Migration was analyzed using live cell imaging, chemotaxis and transwell assays. The metastatic potential of AKT isoform knockdown cells was evaluated in a subcutaneous xenograft mouse model in vivo. RESULTS: Depletion of AKT3, but not AKT1 or AKT2, resulted in increased migration in vitro. This effect was even more prominent in AKT2,3 double knockdown cells. Furthermore, combined downregulation of AKT2 and AKT3, as well as AKT1 and AKT3 significantly increased metastasis formation in vivo. Screening for promigratory proteins revealed that downregulation of AKT3 increases the expression of S100A4 protein. In accordance, depletion of S100A4 by siRNA approach reverses the increased migration induced by knockdown of AKT3. CONCLUSIONS: We demonstrated that knockdown of AKT3 can increase the metastatic potential of triple negative breast cancer cells. Therefore, our results provide a rationale for the development of AKT isoform specific inhibitors. PMID- 26741491 TI - Influence of Sub-Daily Variation on Multi-Fractal Detrended Fluctuation Analysis of Wind Speed Time Series. AB - Using multi-fractal detrended fluctuation analysis (MF-DFA), the scaling features of wind speed time series (WSTS) could be explored. In this paper, we discuss the influence of sub-daily variation, which is a natural feature of wind, in MF-DFA of WSTS. First, the choice of the lower bound of the segment length, a significant parameter of MF-DFA, was studied. The results of expanding the lower bound into sub-daily scope shows that an abrupt declination and discrepancy of scaling exponents is caused by the inability to keep the whole diel process of wind in one single segment. Additionally, the specific value, which is effected by the sub-daily feature of local meteo-climatic, might be different. Second, the intra-day temporal order of wind was shuffled to determine the impact of diel variation on scaling exponents of MF-DFA. The results illustrate that disregarding diel variation leads to errors in scaling. We propose that during the MF-DFA of WSTS, the segment length should be longer than 1 day and the diel variation of wind should be maintained to avoid abnormal phenomena and discrepancy in scaling exponents. PMID- 26741490 TI - TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection. AB - HIV infection induces phenotypic and functional changes to CD8+ T cells defined by the coordinated upregulation of a series of negative checkpoint receptors that eventually result in T cell exhaustion and failure to control viral replication. We report that effector CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue exhibit higher levels of the negative checkpoint receptor TIGIT. Increased frequencies of TIGIT+ and TIGIT+ PD-1+ CD8+ T cells correlated with parameters of HIV and SIV disease progression. TIGIT remained elevated despite viral suppression in those with either pharmacological antiretroviral control or immunologically in elite controllers. HIV and SIV specific CD8+ T cells were dysfunctional and expressed high levels of TIGIT and PD-1. Ex-vivo single or combinational antibody blockade of TIGIT and/or PD-L1 restored viral-specific CD8+ T cell effector responses. The frequency of TIGIT+ CD4+ T cells correlated with the CD4+ T cell total HIV DNA. These findings identify TIGIT as a novel marker of dysfunctional HIV-specific T cells and suggest TIGIT along with other checkpoint receptors may be novel curative HIV targets to reverse T cell exhaustion. PMID- 26741493 TI - Hippocampal Fast Glutamatergic Transmission Is Transiently Regulated by Corticosterone Pulsatility. AB - In recent years it has become clear that corticosteroid hormones (such as corticosterone) are released in ultradian pulses as a natural consequence of pituitary-adrenal interactions. All organs, including the brain, are thus exposed to pulsatile changes in corticosteroid hormone level, important to ensure full genomic responsiveness to stress-induced surges. However, corticosterone also changes neuronal excitability through rapid non-genomic pathways, particularly in the hippocampus. Potentially, background excitability of hippocampal neurons could thus be changed by pulsatile exposure to corticosteroids. It is currently unknown, though, how neuronal activity alters during a sequence of corticosterone pulses. To test this, hippocampal cells were exposed in vitro to four consecutive corticosterone pulses with a 60 min inter-pulse interval. During the pulses we examined four features of hippocampal signal transfer by the main excitatory transmitter glutamate-i.e., postsynaptic responses to spontaneous release of presynaptic vesicles, postsynaptic GluA2-AMPA receptor dynamics, basal (evoked) field responses, and synaptic plasticity, using a set of high resolution imaging and electrophysiological approaches. We show that the first pulse of corticosterone causes a transient increase in miniature EPSC frequency, AMPA receptor trafficking and synaptic plasticity, while basal evoked field responses are unaffected. This pattern is not maintained during subsequent applications: responses become more variable, attenuate or even reverse over time, albeit with different kinetics for the various experimental endpoints. This may indicate that the beneficial effect of ultradian pulses on transcriptional regulation in the hippocampus is not consistently accompanied by short-term perturbations in background excitability. In general, this could be interpreted as a means to keep hippocampal neurons responsive to incoming signals related to environmental challenges. PMID- 26741494 TI - Ecological Distribution and CQ11 Genetic Structure of Culex pipiens Complex (Diptera: Culicidae) in Italy. AB - Mosquitoes in the Culex pipiens complex are considered to be involved in the transmission of a range of pathogens, including West Nile virus (WNV). Although its taxonomic status is still debated, the complex includes species, both globally distributed or with a more limited distribution, morphologically similar and characterised by different physiological and behavioural traits, which affect their ability as vectors. In many European countries, Cx. pipiens and its sibling species Culex torrentium occur in sympatry, exhibiting similar bionomic and morphological characters, but only Cx. pipiens appears to play a vector role in WNV transmission. This species consists of two biotypes, pipiens and molestus, which can interbreed when in sympatry, and their hybrids can act as WNV-bridge vectors, due to intermediate ecological features. Considering the yearly WNV outbreaks since 2008 and given the morphological difficulties in recognising species and biotypes, our aim was to molecularly identify and characterised Cx. pipiens and Cx. torrentium in Italy, using recently developed molecular assays. Culex torrentium was not detected; as in other European countries, the pipiens and molestus biotypes were widely found in sympatry with hybrids in most environments. The UPGMA cluster analysis applied to CQ11 genotypic frequencies mainly revealed two groups of Cx. pipiens populations that differed in ecological features. The high propensity of the molestus biotype to exist in hypogean environments, where the habitat's physical characteristics hinder and preclude the gene flow, was shown. These results confirmed the CQ11 assay as a reliable diagnostic method, consistent with the ecological and physiological aspects of the populations analysed. Since the assessment of the actual role of three biotypes in the WNV circulation remains a crucial point to be elucidated, this extensive molecular screening of Cx. pipiens populations can provide new insights into the ecology of the species and may give useful indications to plan and implement WNV surveillance activities in Italy. PMID- 26741492 TI - A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. AB - Mitochondrial disorders have the highest incidence among congenital metabolic disorders characterized by biochemical respiratory chain complex deficiencies. It occurs at a rate of 1 in 5,000 births, and has phenotypic and genetic heterogeneity. Mutations in about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial dysfunction of energy production and mitochondrial disorders. More than 250 genes that cause mitochondrial disorders have been reported to date. However exact genetic diagnosis for patients still remained largely unknown. To reveal this heterogeneity, we performed comprehensive genomic analyses for 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies. The approach includes whole mtDNA and exome analyses using high-throughput sequencing, and chromosomal aberration analyses using high density oligonucleotide arrays. We identified 37 novel mutations in known mitochondrial disease genes and 3 mitochondria-related genes (MRPS23, QRSL1, and PNPLA4) as novel causative genes. We also identified 2 genes known to cause monogenic diseases (MECP2 and TNNI3) and 3 chromosomal aberrations (6q24.3-q25.1, 17p12, and 22q11.21) as causes in this cohort. Our approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically defined mitochondrial respiratory chain complex deficiencies in clinical settings. They also underscore clinical and genetic heterogeneity and will improve patient care of this complex disorder. PMID- 26741495 TI - Assessing Bacterial Diversity in the Rhizosphere of Thymus zygis Growing in the Sierra Nevada National Park (Spain) through Culture-Dependent and Independent Approaches. AB - Little is known of the bacterial communities associated with the rhizosphere of wild plant species found in natural settings. The rhizosphere bacterial community associated with wild thyme, Thymus zygis L., plants was analyzed using cultivation, the creation of a near-full length 16S rRNA gene clone library and 454 amplicon pyrosequencing. The bacterial community was dominated by Proteobacteria (mostly Alphaproteobacteria and Betaproteobacteria), Actinobacteria, Acidobacteria, and Gemmatimonadetes. Although each approach gave a different perspective of the bacterial community, all classes/subclasses detected in the clone library and the cultured bacteria could be found in the pyrosequencing datasets. However, an exception caused by inconclusive taxonomic identification as a consequence of the short read length of pyrotags together with the detection of singleton sequences which corresponded to bacterial strains cultivated from the same sample highlight limitations and considerations which should be taken into account when analysing and interpreting amplicon datasets. Amplicon pyrosequencing of replicate rhizosphere soil samples taken a year later permit the definition of the core microbiome associated with Thymus zygis plants. Abundant bacterial families and predicted functional profiles of the core microbiome suggest that the main drivers of the bacterial community in the Thymus zygis rhizosphere are related to the nutrients originating from the plant root and to their participation in biogeochemical cycles thereby creating an intricate relationship with this aromatic plant to allow for a feedback ecological benefit. PMID- 26741498 TI - Manganese Oxide Nanoarchitectures as Broad-Spectrum Sorbents for Toxic Gases. AB - We demonstrate that sol-gel-derived manganese oxide (MnOx) nanoarchitectures exhibit broad-spectrum filtration activity for three chemically diverse toxic gases: NH3, SO2, and H2S. Manganese oxides are synthesized via the reaction of NaMnO4 and fumaric acid to form monolithic gels of disordered, mixed-valent Na MnOx; incorporated Na(+) is readily exchanged for H(+) by subsequent acid rinsing to form a more crystalline H-MnOx phase. For both Na-MnOx and H-MnOx forms, controlled pore-fluid removal yields either densified, yet still mesoporous, xerogels or low-density aerogels (prepared by drying from supercritical CO2). The performance of these MnOx nanoarchitectures as filtration media is assessed using dynamic-challenge microbreakthrough protocols. We observe technologically relevant sorption capacities under both dry conditions and wet (80% relative humidity) for each of the three toxic industrial chemicals investigated. The Na MnOx xerogels and aerogels provide optimal performance with the aerogel exhibiting maximum sorption capacities of 39, 200, and 680 mg g(-1) for NH3, SO2, and H2S, respectively. Postbreakthrough characterization using X-ray photoelectron spectroscopy (XPS) and diffuse-reflectance infrared Fourier transform spectroscopy (DRIFTS) confirms that NH3 is captured and partially protonated within the MnOx structure, while SO2 undergoes oxidation by the redox active oxide to form adsorbed sulfate at the MnOx surface. Hydrogen sulfide is also oxidized to form a combination of sulfate and sulfur/polysulfide products, concomitant with a decrease in the average Mn oxidation state from 3.43 to 2.94 and generation of a MnOOH phase. PMID- 26741496 TI - Preserved Pressure Autoregulation but Disturbed Cyclo-Oxygenase and Nitric Oxide Effects on Retinal Arterioles during Acute Hypoxia in Diabetic Patients without Retinopathy. AB - BACKGROUND: Acute hypoxia induces retinal vasodilatation, which depends on cyclooxygenase (COX) products and nitric oxide (NO) in vitro. However, it is unknown whether these mechanisms are active in diabetic patients and may contribute to the development of diabetic retinopathy. METHODS: The Dynamic Vessel Analyzer was used to study the diameter regulation in retinal vessels during hypoxia in type 1 diabetic patients without retinopathy. The influence of NO and COX synthesis inhibition on the diameter of larger retinal vessels was studied during hypoxia, during isometric exercise and during flicker stimulation. RESULTS: Increased arterial blood pressure during L-NMMA infusion and isometric exercise were paralleled by constriction of the retinal arterioles suggesting normal pressure autoregulation. Hypoxia significantly reduced the diameter responses during isometric exercise and during flicker stimulation as compared to normal persons. CONCLUSION: The findings support that changes in metabolic autoregulation develop before changes in pressure autoregulation in diabetic patients. PMID- 26741497 TI - Effect of Different Levels of Pressure Relieving Air-Mattress Firmness on Cough Strength. AB - Cough is an important host-defense mechanism. The elderly and patients who are severely ill cannot cough effectively when lying in the supine position. Furthermore, pressure relieving air-mattresses are recommended for preventing the development of pressure ulcers. In this study, we clarified whether or not the cough peak flow (CPF), an index of cough strength, is affected by different firmness levels of a pressure relieving air-mattress in healthy volunteers in the supine position. Fifty-two healthy young men participated. All the measurements were carried out on each participant in the supine position on a pressure relieving air-mattress. The participants were assessed at two firmness levels, a "hard" and "soft" mode. The CPF, forced vital capacity (FVC), maximal expiratory pressure (PEmax), and maximal inspiratory pressure (PImax) were determined for each mode. The sinking distance of the body into the mattress was measured without any activity and the difference between the sinking distances of the two firmness levels was determined. The CPF, FVC, PEmax, and PImax were determined for each mode. The sinking distance of the body into the mattress was measured and the difference between the sinking distances of the two firmness levels was determined. The CPF, FVC, PEmax and PImax values of the participants coughing on the mattress were significantly lower when the mattress was in "soft" than in "hard" mode. The differences between the sinking distances of the mattress in "soft" and "hard" modes were larger for the anterior superior iliac spine. A harder mattress may lead to increased CPF in healthy young men lying in the supine position, and increased CPF may be important for host defense. PMID- 26741499 TI - When a Little Knowledge Can Be Dangerous: False-Positive Diagnosis of Behavioral Variant Frontotemporal Dementia among Community Clinicians. AB - BACKGROUND: Accurate diagnosis of behavioral variant frontotemporal dementia (bvFTD) is important as patients' behavioral symptoms have profound implications for their families and communities. Since the diagnosis of bvFTD derives from behavioral features, accurate identification of patients can be difficult for non specialists. Concrete rates of diagnostic accuracy among non-specialists are unavailable. METHODS: To examine the accuracy of community clinicians' diagnoses of bvFTD and to identify patient characteristics leading to misdiagnosis, we reviewed the charts and referral letters of 3,578 patients who were seen at our specialized center. Referral diagnosis and reasons, manifesting symptoms, demographic data, Mini-Mental State Examination score, Clinical Dementia Rating score and Neuropsychiatric Inventory score were extracted. RESULTS: 60% of patients assigned a single diagnosis of bvFTD by community clinicians did not have bvFTD according to specialists. Compared to specialist-confirmed bvFTD patients, false bvFTD patients were more likely to be depressed and to be non Caucasian, showed less euphoria, apathy, disinhibition and abnormal eating behaviors, had milder disease severity and better overall cognition. bvFTD was mentioned by referring clinicians in 86% of specialist-confirmed bvFTD cases, but missed cases were called Alzheimer's, Parkinson's or Huntington's disease, or progressive aphasia. CONCLUSION: These results revealed a widespread lack of familiarity with core diagnostic symptoms among non-specialists and suggest that community clinicians require specialized diagnostic support before providing a definitive diagnosis of bvFTD. PMID- 26741500 TI - Diffuse Cystic Lung Disease as the Presenting Manifestation of Sjogren Syndrome. AB - Interstitial lung diseases, especially lymphoproliferative disorders such as follicular bronchiolitis and lymphoid interstitial pneumonia, are commonly seen in association with Sjogren syndrome. Although the predominant computed tomographic (CT) findings in patients with lymphoid interstitial pneumonia/follicular bronchiolitis include poorly defined centrilobular nodules and ground-glass attenuation, cystic changes can be seen in approximately two thirds of these patients. The objective of this study was to define the clinical, radiological, and histopathological features of cyst-predominant lymphoid interstitial pneumonia/follicular bronchiolitis in patients with Sjogren syndrome. We present four patients who were referred to our institution with diffuse cystic changes on chest CT imaging. All four had a presumptive diagnosis of lymphangioleiomyomatosis but were subsequently found to have Sjogren syndrome. The diagnosis was established based on the clinical symptoms of xerostomia and xerophthalmia along with serologic detection of antinuclear antibodies, rheumatoid factor, anti-Sjogren's syndrome-related antigen A (SSA)/Ro antibodies, and anti-Sjogren's syndrome-related antigen B (SSB)/La antibodies. The cystic pattern associated with Sjogren syndrome had a characteristic appearance on chest CT images. Typical features included a wide variation in cyst size, internal structure within cysts, geographic simplification of parenchymal architecture producing a "dissolving lung appearance," perivascular and often basilar predominant distribution, and frequent association with ground-glass opacities and nodules. In a compatible clinical context, we submit that these findings can be sufficiently distinctive to obviate the need for lung biopsy, even in the absence of confirmatory serological studies or lip biopsy. Clinicians should consider occult Sjogren syndrome in the differential diagnosis of patients presenting with idiopathic diffuse cystic lung disease. PMID- 26741501 TI - Oroxylin A inhibits invasion and migration through suppressing ERK/GSK-3beta signaling in snail-expressing non-small-cell lung cancer cells. AB - Snail is closely linked to tumor invasion, metastasis, and recurrence and indicates prognosis of patients suffering from cancer. Overexpression of Snail increases motility and invasiveness of cancer cells, which has become target for anti-metastatic treatment. Oroxylin A, a natural compound extracted from Scutellaria radix, has been reported to inhibit invasion and migration in breast cancer. In this study, we investigated the anti-invasive effect of oroxylin A on lung cells and uncovered its underlying mechanism. The results suggested that oroxylin A could inhibit migration and invasion in Snail-expressing 95-D, and A549 cells whereas it had little effect on non-expressing GLC-82 cells. Furthermore, enhanced Snail expression after transfection of Snail vector in GLC 82 cells is decreased by oroxylin A. Snail can also induce epithelial-mesenchymal transition. We found oroxylin A could reverse TGFbeta1-induced epithelial mesenchymal transition by inhibiting Snail expression. As a result, oroxylin A up regulated E-cadherin expression and down-regulated vimentin, MMP-9, and CD44v6 expression, which could lead to the inhibition of tumor migration and invasion. Mechanically, we demonstrated that oroxylin A suppressed activation of ERK instead of AKT pathway and then promoted activation of GSK-3beta to reduce Snail protein content. Finally, we established transplanted, metastatic, and orthotopic models of A549 cells, and found that oroxylin A inhibited the growth and lung metastasis of A549 cells in vivo. Taken together, we proposed that oroxylin A might be a promising candidate targeting tumor metastasis. (c) 2016 Wiley Periodicals, Inc. PMID- 26741502 TI - A Single Neonatal Injection of Ethinyl Estradiol Impairs Passive Avoidance Learning and Reduces Expression of Estrogen Receptor alpha in the Hippocampus and Cortex of Adult Female Rats. AB - Although perinatal exposure of female rats to estrogenic compounds produces irreversible changes in brain function, it is still unclear how the amount and timing of exposure to those substances affect learning function, or if exposure alters estrogen receptor alpha (ERalpha) expression in the hippocampus and cortex. In adult female rats, we investigated the effects of neonatal exposure to a model estrogenic compound, ethinyl estradiol (EE), on passive avoidance learning and ERalpha expression. Female Wistar-Imamichi rats were subcutaneously injected with oil, 0.02 mg/kg EE, 2 mg/kg EE, or 20 mg/kg 17beta-estradiol within 24 h after birth. All females were tested for passive avoidance learning at the age of 6 weeks. Neonatal 0.02 mg/kg EE administration significantly disrupted passive avoidance compared with oil treatment in gonadally intact females. In a second experiment, another set of experimental females, treated as described above, was ovariectomized under pentobarbital anesthesia at 10 weeks of age. At 15-17 weeks of age, half of each group received a subcutaneous injection of 5 MUg estradiol benzoate a day before the passive avoidance learning test. Passive avoidance learning behavior was impaired by the 0.02 mg/kg EE dose, but notably only in the estradiol benzoate-injected group. At 17-19 weeks of age, hippocampal and cortical samples were collected from rats with or without the 5 MUg estradiol benzoate injection, and western blots used to determine ERalpha expression. A significant decrease in ERalpha expression was observed in the hippocampus of the estradiol-injected, neonatal EE-treated females. The results demonstrated that exposure to EE immediately after birth decreased learning ability in adult female rats, and that this may be at least partly mediated by the decreased expression of ERalpha in the hippocampus. PMID- 26741503 TI - Tracking Foodborne Pathogenic Bacteria in Raw and Ready-to-Eat Food Illegally Sold at the Eastern EU Border. AB - Food illegally brought into the European Union, mainly in the personal luggage of travelers, represents a potential threat to consumers' health. The aim of this study was to investigate the presence of five pathogens in food brought into the European Union by Moldavian citizens as personal goods and illegally sold in Romania in the vicinity of the border. The occurrence of Staphylococcus aureus and Listeria monocytogenes was 7.5% and 8%, while Campylobacter spp., Escherichia coli O157:H7, and Salmonella spp. were absent in all samples. L. monocytogenes sequence type 2, 9, 121, and 155, highly prevalent among foodstuffs worldwide, was also present among isolates from ready-to-eat food illegally sold in Romania, even at the same date of sampling, indicating cross-contamination during food handling. S. aureus spa types t449, t304, and t524 were most often isolated from raw-milk cheeses contaminated with 10(3)-10(5) colony-forming units per gram, evidencing a contamination at herd level or unhygienic conditions during processing. S. aureus t011 and t3625, both included in the livestock-associated CC398, were isolated from pork lard and poultry meat. This study shows that cross border trade from nonmember states represents a neglected route of transmission of foodborne pathogens into the European Union that could lead to sporadic or family-associated cases of disease. PMID- 26741504 TI - Locus- and Site-Specific DNA Methylation of 19 kDa Zein Genes in Maize. AB - An interesting question in maize development is why only a single zein gene is highly expressed in each of the 19-kDa zein gene clusters (A and B types), z1A2-1 and z1B4, in the immature endosperm. For instance, epigenetic marks could provide a structural difference. Therefore, we investigated the DNA methylation of the arrays of gene copies in both promoter and gene body regions of leaf (non expressing tissue as a control), normal endosperm, and cultured endosperm. Although we could show that expressed genes have much lower methylation levels in promoter regions than silent ones in both leaf and normal endosperm, there was surprisingly also a difference in the pattern of the z1A and z1B gene clusters. The expression of z1B gene is suppressed by increased DNA methylation and activated with reduced DNA methylation, whereas z1A gene expression is not. DNA methylation in gene coding regions is higher in leaf than in endosperm, whereas no significant difference is observed in gene bodies between expressed and non expressed gene copies. A median CHG methylation (25-30%) appears to be optimal for gene expression. Moreover, tissue-cultured endosperm can reset the DNA methylation pattern and tissue-specific gene expression. These results reveal that DNA methylation changes of the 19-kDa zein genes is subject to plant development and tissue culture treatment, but varies in different chromosomal locations, indicating that DNA methylation changes do not apply to gene expression in a uniform fashion. Because tissue culture is used to produce transgenic plants, these studies provide new insights into variation of gene expression of integrated sequences. PMID- 26741505 TI - Aldehyde dehydrogenase 2 activation in aged heart improves the autophagy by reducing the carbonyl modification on SIRT1. AB - Cardiac aging is characterized by accumulation of damaged proteins and decline of autophagic efficiency. Here, by forestalling SIRT1 carbonylated inactivation in aged heart, we determined the benefits of activation of aldehyde dehydrogenase 2 (ALDH2) on the autophagy. In this study, the ALDH2 KO mice progressively developed age-related heart dysfunction and showed reduction in the life span, which strongly suggests that ALDH2 ablation leads to cardiac aging. What's more, aged hearts displayed a significant decrease ALDH2 activity, resulting in accumulation of 4-HNE-protein adducts and protein carbonyls, impairment in the autophagy flux, and, consequently, deteriorated cardiac function after starvation. Sustained Alda-1 (selective ALDH2 activator) treatment increased cardiac ALDH2 activity and abrogated these effects. Using SIRT1 deficient heterozygous (Sirt1+/-) mice, we found that SIRT1 was necessary for ALDH2 activation-induced autophagy. We further demonstrated that ALDH2 activation attenuated SIRT1 carbonylation and improved SIRT1 activity, thereby increasing the deacetylation of nuclear LC3 and FoxO1. Sequentially, ALDH2 enhanced SIRT1 regulates LC3-Atg7 interaction and FoxO1 increased Rab7 expression, which were both necessary and sufficient for restoring autophagy flux. These results highlight that both accumulation of proteotoxic carbonyl stress linkage with autophagy decline contribute to heart senescence. ALDH2 activation is adequate to improve the autophagy flux by reducing the carbonyl modification on SIRT1, which in turn plays an important role in maintaining cardiac health during aging. PMID- 26741506 TI - Epithelial but not stromal expression of collagen alpha-1(III) is a diagnostic and prognostic indicator of colorectal carcinoma. AB - Colorectal cancer (CRC) is the third most common cancer in males and the second in females worldwide with very poor prognosis. Collagen alpha-1(III) (COL3A1) gene, encoding an extracellular matrix protein, is upregulated in human cancers. Here, we revealed that COL3A1 was increased in CRC by analysis of five Oncomine gene expression datasets (n = 496). Immunohistochemistry analysis of a tissue microarray (n = 90) demonstrated that cancer epithelial but not stromal COL3A1 was significantly upregulated comparing with the normal counterparts. High COL3A1 mRNA and/or protein expression was accompanied with high stage, T stage, Dukes stage, grade and older age, as well as smoking and recurrence status. Upregulated COL3A1 predicted poor overall (p = 0.003) and disease-free (p = 0.025) survival. Increased epithelial but not stromal COL3A1 protein predicted worse outcome (p = 0.03). Older patients (age>65) with high COL3A1 had worse survival than younger (age<=65) with high COL3A1. Plasma COL3A1 was increased in CRC patients (n = 86) by 5.4 fold comparing with healthy individuals, enteritis and polyps patients. Plasma COL3A1 had an area under curve (AUC) of 0.92 and the best sensitivity/specificity of 98.8%/69.1%. While plasma CEA had a poorer prediction power (AUC = 0.791, sensitivity/selectivity = 70.2%/73.0%). Older patients (age>=60) had higher plasma COL3A1 than younger patients. The epithelial COL3A1 protein had an AUC of 0.975 and the best sensitivity/specificity of 95.2%/91.1%. Silencing of COL3A1 suppressed CRC cell proliferation in in vitro MTT assay and in in vivo Zebra fish xenograft model by downregulation of PI3K/AKT and WNT signaling. COL3A1 was a novel diagnosis and prognosis marker of CRC. PMID- 26741507 TI - Control of glioma cell migration and invasiveness by GDF-15. AB - Growth and differentiation factor (GDF)-15 is a member of the transforming growth factor (TGF)-beta family of proteins. GDF-15 levels are increased in the blood and cerebrospinal fluid of glioblastoma patients. Using a TCGA database interrogation, we demonstrate that high GDF-15 expression levels are associated with poor survival of glioblastoma patients. To elucidate the role of GDF-15 in glioblastoma in detail, we confirmed that glioma cells express GDF-15 mRNA and protein in vitro. To allow for a detailed functional characterization, GDF-15 expression was silenced using RNA interference in LNT-229 and LN-308 glioma cells. Depletion of GDF-15 had no effect on cell viability. In contrast, GDF-15 deficient cells displayed reduced migration and invasion, in the absence of changes in Smad2 or Smad1/5/8 phosphorylation. Conversely, exogenous GDF-15 stimulated migration and invasiveness. Large-scale expression profiling revealed that GDF-15 gene silencing resulted in minor changes in the miRNA profile whereas several genes, including members of the plasminogen activator/inhibitor complex, were deregulated at the mRNA level. One of the newly identified genes induced by GDF-15 gene silencing was the serpin peptidase inhibitor, clade E nexin group 1 (serpine1) which is induced by TGF-beta and known to inhibit migration and invasiveness. However, serpine1 down-regulation alone did not mediate GDF-15 induced promotion of migration and invasiveness. Our findings highlight the complex contributions of GDF-15 to the invasive phenotype of glioma cells and suggest anti-GDF-15 approaches as a promising therapeutic strategy. PMID- 26741509 TI - Alleviation of Lipopolysaccharides-Induced Acute Lung Injury by MiR-454. AB - BACKGROUND/AIMS: Although acute lung injury (ALI) is an important and common disease in humans, its pathogenesis is poorly understood and its therapeutic outcome has not been significantly improved in the past years. Here, we examined whether application of microRNAs might inhibit the ALI-associated lung inflammatory, and subsequently reduce the injury. METHODS: In vitro, we performed bioinformatics analyses to identify the miRNAs that target the most important chemo-attractive factor CXCL12, and confirmed that the binding was functional by luciferase reporter assay. We prepared adeno-associated virus (AAV) carrying miRNA mimics or null control. We expressed miRNA in mouse lung through i.v. injection of AAV and then we used Lipopolysaccharides (LPS) to induce ALI in mice. We analyzed the changes in permeability index and production of inflammatory cytokines in mouse lung, and we also verified the effects of virus mediated gene expression by examining the levels of miRNAs and CXCL12 in lung by RT-qPCR and ELISA, and by quantifying the recruited inflammatory cells in mouse lung by flow cytometry. RESULTS: We found that miR-454 targeted the 3'-UTR of CXCL12 mRNA to inhibit its protein translation in human lung epithelial cells. Overexpression of miR-454 in mouse lung significantly reduced the LPS-induced increases in permeability index and production of inflammatory cytokines CXCL1, CXCL2, IL6 and TNFalpha, possibly through suppression of CXCL12/CXCR4-mediated recruitment of inflammatory cells. CONCLUSION: Overexpression of miR-454 in lung may be a promising therapeutic approach to reduce the severity of ALI. PMID- 26741508 TI - Tumor sialylation impedes T cell mediated anti-tumor responses while promoting tumor associated-regulatory T cells. AB - The increased presence of sialylated glycans on the tumor surface has been linked to poor prognosis, yet the effects on tumor-specific T cell immunity are hardly studied. We here show that hypersialylation of B16 melanoma substantially influences tumor growth by preventing the formation of effector T cells and facilitating the presence of high regulatory T cell (Treg) frequencies. Knock down of the sialic acid transporter created "sialic acid low" tumors, that grew slower in-vivo than hypersialylated tumors, altered the Treg/Teffector balance, favoring immunological tumor control. The enhanced effector T cell response in developing "sialic acid low" tumors was preceded by and dependent on an increased influx and activity of Natural Killer (NK) cells. Thus, tumor hypersialylation orchestrates immune escape at the level of NK and Teff/Treg balance within the tumor microenvironment, herewith dampening tumor-specific T cell control. Reducing sialylation provides a therapeutic option to render tumors permissive to immune attack. PMID- 26741510 TI - Emergence of Carbapenemase-Producing Escherichia coli Isolated from Companion Animals in Algeria. AB - The emergence and worldwide spread of carbapenemase-producing Enterobacteriaceae is of great concern to public health. The aim of this study was to investigate the occurrence of carbapenemase-producing Escherichia coli in companion animals in Algeria. Two hundred fecal samples were obtained from healthy and diseased dogs and cats in one veterinary office and private owners in Bejaia city, Algeria, during November 2014 to March 2015. Isolates were screened by polymerase chain reaction for the presence of carbapenemase, acquired plasmidic AmpC (pAmpC) and extended-spectrum beta-lactamase genes. Five carbapenemase-producing E. coli isolates were detected including four OXA-48-producing isolates and one isolate producing NDM-5. Coexpression of ESBL and pAmpC genes was observed in these isolates. Phylogenetic grouping revealed that these isolates belonged to A and D phylogroups. The results of this study show that carbapenemase-producing E. coli spread to the companion animals in Algeria. PMID- 26741511 TI - What gets lost. PMID- 26741512 TI - Pre-emptive correction for haemodialysis arteriovenous access stenosis. AB - BACKGROUND: Guidelines recommend routine arteriovenous (AV) graft and fistula surveillance (technology-based screening) in addition to clinical monitoring (physical examination) for early identification and pre-emptive correction of a stenosis before the access becomes dysfunctional. However, consequences on patient-relevant outcomes of pre-emptive correction of a stenosis in a functioning access as opposed to deferred correction, i.e. correction postponed to when the access becomes dysfunctional, are uncertain. OBJECTIVES: We aimed to evaluate 1) whether pre-emptive correction of an AV access stenosis improves clinically relevant outcomes; 2) whether the effects of pre-emptive correction of an AV access stenosis differ by access type (fistula versus graft), aim (primary and secondary prophylaxis), and surveillance method for primary prophylaxis (Doppler ultrasound for the screening of functional and anatomical changes versus measurement of the flow in the access); and 3) whether other factors (dialysis duration, access location, configuration or materials, algorithm for referral for intervention, intervention strategies (surgical versus radiological or other), or study design) explain the heterogeneity that might exist in the effect estimates. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register to 30 November 2015 using search terms relevant to this review. SELECTION CRITERIA: We included all studies of any access surveillance method for early identification and pre-emptive treatment of an AV access stenosis. DATA COLLECTION AND ANALYSIS: We extracted data on potentially remediable and irremediable failure of the access (i.e. thrombosis and access loss respectively); infection and mortality; and resource use (hospitalisation, diagnostic and intervention procedures). Analysis was by a random effects model and results expressed as risk ratio (RR), hazard ratio (HR) or incidence rate ratio (IRR) with 95% confidence intervals (CI). MAIN RESULTS: We identified 14 studies (1390 participants), nine enrolled adults without a known access stenosis (primary prophylaxis; three studies including people using fistulas) and five enrolled adults with a documented stenosis in a non-dysfunctional access (secondary prophylaxis; three studies in people using fistulas). Study follow-up ranged from 6 to 38 months, and study size ranged from 58 to 189 participants. In low- to moderate-quality evidence (based on GRADE criteria) in adults treated with haemodialysis, relative to no surveillance and deferred correction, surveillance with pre-emptive correction of an AV stenosis reduced the risk of thrombosis (RR 0.79, 95% CI 0.65 to 0.97; I2 = 30%; 18 study comparisons, 1212 participants), but had imprecise effect on the risk of access loss (RR 0.81, 95% CI 0.65 to 1.02; I2 = 0%; 11 study comparisons, 972 participants). In analyses subgrouped by access type, pre-emptive stenosis correction did not reduce the risk of thrombosis (RR 0.95, 95% CI 0.8 to 1.12; I2 = 0%; 11 study comparisons, 697 participants) or access loss in grafts (RR 0.9, 95% CI 0.71 to 1.15; I2 = 0%; 7 study comparisons; 662 participants), but did reduce the risk of thrombosis (RR 0.5, 95% CI 0.35 to 0.71; I2 = 0%; 7 study comparisons, 515 participants) and the risk of access loss in fistulas (RR 0.5, 95% CI 0.29 to 0.86; I2 = 0%; 4 studies; 310 participants). Three of the four studies reporting access loss data in fistulas (199 participants) were conducted in the same centre. Insufficient data were available to assess whether benefits vary by prophylaxis aim in fistulas (i.e. primary and secondary prophylaxis). Although the magnitude of the effects of pre-emptive stenosis correction was considerable for patient-centred outcomes, results were either heterogeneous or imprecise. While pre-emptive stenosis correction may reduce the rates of hospitalisation (IRR 0.54, 95% CI 0.31 to 0.93; I2 = 67%; 4 study comparisons, 219 participants) and use of catheters (IRR 0.58, 95% CI 0.35 to 0.98; I2 = 53%; 6 study comparisons, 394 participants), it may also increase the rates of diagnostic procedures (IRR 1.78, 95% CI 1.18 to 2.67; I2 = 62%; 7 study comparisons, 539 participants), infection (IRR 1.74, 95% CI 0.78 to 3.91; I2 = 0%; 3 studies, 248 participants) and mortality (RR 1.38, 95% CI 0.91 to 2.11; I2 = 0%; 5 studies, 386 participants).In general, risk of bias was high or unclear in most studies for many domains we assessed. Four studies were published after 2005 and only one had evidence of registration within a trial registry. No study reported information on authorship and/or involvement of the study sponsor in data collection, analysis, and interpretation. AUTHORS' CONCLUSIONS: Pre-emptive correction of a newly identified or known stenosis in a functional AV access does not improve access longevity. Although pre-emptive stenosis correction may be promising in fistulas existing evidence is insufficient to guide clinical practice and health policy. While pre-emptive stenosis correction may reduce the risk of hospitalisation, this benefit is uncertain whereas there may be a substantial increase (i.e. 80%) in the use of access-related procedures and procedure-related adverse events (e.g. infection, mortality). The net effects of pre-emptive correction on harms and resource use are thus unclear. PMID- 26741513 TI - Vitamin A Influence on B Cell Class Switch Recombination. PMID- 26741522 TI - Vital Signs: Exposure to Electronic Cigarette Advertising Among Middle School and High School Students - United States, 2014. AB - INTRODUCTION: Electronic cigarette (e-cigarette) use has increased considerably among U.S. youths since 2011. Tobacco use among youths in any form, including e cigarettes, is unsafe. Tobacco product advertising can persuade youths to start using tobacco. CDC analyzed data from the 2014 National Youth Tobacco Survey to estimate the prevalence of e-cigarette advertisement exposure among U.S. middle school and high school students. METHODS: The 2014 National Youth Tobacco Survey, a school-based survey of middle school and high school students in grades 6-12, included 22,007 participants. Exposure to e-cigarette advertisements (categorized as "sometimes," "most of the time," or "always") was assessed for four sources: retail stores, Internet, TV and movies, and newspapers and magazines. Weighted exposure estimates were assessed overall and by school type, sex, race/ethnicity, and grade. RESULTS: In 2014, 68.9% of middle and high school students (18.3 million) were exposed to e-cigarette advertisements from at least one source. Among middle school students, exposure was highest for retail stores (52.8%), followed by Internet (35.8%), TV and movies (34.1%), and newspapers and magazines (25.0%). Among high school students, exposure was highest for retail stores (56.3%), followed by Internet (42.9%), TV and movies (38.4%), and newspapers and magazines (34.6%). Among middle school students, 23.4% reported exposure to e cigarette advertising from one source, 17.4% from two sources, 13.7% from three sources, and 11.9% from four sources. Among high school students, 21.1% reported exposure to e-cigarette advertising from one source, 17.0% from two sources, 14.5% from three sources, and 18.2% from four sources. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Approximately seven in 10 U.S. middle and high school students were exposed to e-cigarette advertisements in 2014. Exposure to e-cigarette advertisements might contribute to increased use of e cigarettes among youths. Multiple approaches are warranted to reduce youth e cigarette use and exposure to e-cigarette advertisements, including efforts to reduce youth access to settings where tobacco products, such as e-cigarettes, are sold, and regulation of youth-oriented e-cigarette marketing. PMID- 26741523 TI - Model Selection with the Linear Mixed Model for Longitudinal Data. AB - Model building or model selection with linear mixed models (LMMs) is complicated by the presence of both fixed effects and random effects. The fixed effects structure and random effects structure are codependent, so selection of one influences the other. Most presentations of LMM in psychology and education are based on a multilevel or hierarchical approach in which the variance-covariance matrix of the random effects is assumed to be positive definite with nonzero values for the variances. When the number of fixed effects and random effects is unknown, the predominant approach to model building is a step-up method in which one starts with a limited model (e.g., few fixed and random intercepts) and then additional fixed effects and random effects are added based on statistical tests. A model building approach that has received less attention in psychology and education is a top-down method. In the top-down method, the initial model has a single random intercept but is loaded with fixed effects (also known as an "overelaborate" model). Based on the overelaborate fixed effects model, the need for additional random effects is determined. There has been little if any examination of the ability of these methods to identify a true population model (i.e., identifying the model that generated the data). The purpose of this article is to examine the performance of the step-up and top-down model building approaches for exploratory longitudinal data analysis. Student achievement data sets from the Chicago longitudinal study serve as the populations in the simulations. PMID- 26741524 TI - Investigating the Nature of Method Factors Through Multiple Informants: Evidence for a Specific Factor? AB - When a self-report instrument includes a balanced number of positively and negatively worded items, factor analysts often use method factors to aid model fitting. The nature of these factors, often referred to as acquiescence, is still debated. Relying upon previous results ( Alessandri et al., 2010 ; DiStefano & Motl, 2006 , 2008 ; Rauch, Schweizer, & Moosbrugger, 2007 ), we submit that the so-called method factors, instead, represent substantive specific factors. This study investigates the convergence of method effects across different observers. The revised Life Orientation Test ( Scheier, Carver, & Bridges, 1994 ) was administered to a sample of 372 adults (57% females), with 372 acquaintances serving as informants. Results showed that a specific factor was detectable both with self- and other-ratings. A significant correlation across informants provided evidence for the convergence of this specific factor. Construct validity was examined by locating this specific factor within a nomological net of personality variables. Theoretical and practical implications of the findings are discussed. PMID- 26741514 TI - Hotspots for Vitamin-Steroid-Thyroid Hormone Response Elements Within Switch Regions of Immunoglobulin Heavy Chain Loci Predict a Direct Influence of Vitamins and Hormones on B Cell Class Switch Recombination. AB - Vitamin A deficiencies are common throughout the world and have a significant negative influence on immune protection against viral infections. Mouse models demonstrate that the production of IgA, a first line of defense against viruses at mucosal sites, is inhibited in the context of vitamin A deficiency. In vitro, the addition of vitamin A to activated B cells can enhance IgA expression, but downregulate IgE. Previous reports have demonstrated that vitamin A modifies cytokine patterns, and in so doing may influence antibody isotype expression by an indirect mechanism. However, we have now discovered hundreds of potential response elements among SMU, SE, and Salpha switch sites within immunoglobulin heavy chain loci. These hotspots appear in both mouse and human loci and include targets for vitamin receptors and related proteins (e.g., estrogen receptors) in the nuclear receptor superfamily. Full response elements with direct repeats are relatively infrequent or absent in Sgamma regions although half-sites are present. Based on these results, we pose a hypothesis that nuclear receptors have a direct effect on the immunoglobulin heavy chain class switch recombination event. We propose that vitamin A may alter S site accessibility to activation induced deaminase and nonhomologous end-joining machinery, thereby influencing the isotype switch, antibody production, and protection against viral infections at mucosal sites. PMID- 26741515 TI - Procalcitonin Levels in Acute Respiratory Infection. AB - Procalcitonin (PCT) is a biomarker of inflammation that is used to help make clinical decisions, like starting antibiotics or admitting a patient to the hospital. While PCT levels have been widely studied in pneumonia, levels in less severe acute respiratory infections (ARI) have not been well studied. To measure PCT levels in otherwise healthy adults during ARI, we followed 99 healthy adults during the cold and flu season, collecting blood specimens for PCT testing at baseline, and when participants presented with ARI. Ninety-six percent of the ARI samples had PCT levels <0.05 ng/mL. The remaining 4% were <0.25 ng/mL. These data suggest that PCT is not a useful test in ARI of mild-to-moderate severity. PMID- 26741525 TI - Formulation and Application of the Hierarchical Generalized Random-Situation Random-Weight MIRID. AB - The process-component approach has become quite popular for examining many psychological concepts. A typical example is the model with internal restrictions on item difficulty (MIRID) described by Butter (1994) and Butter, De Boeck, and Verhelst (1998). This study proposes a hierarchical generalized random-situation random-weight MIRID. The proposed model is more flexible for formulating endogenous latent variables within a multilevel framework, allowing the analysis of polytomous data with complex models (e.g., including item discriminations, random situations, random weights, and heteroskedasticity). The parameters in the proposed model can be estimated using the computer program WinBUGS, which adopts Markov Chain Monte Carlo algorithms. To illustrate the application of the proposed model, a real data set about guilt is analyzed and a comparison of MIRIDs for various conditions is conducted. PMID- 26741526 TI - Analyzing Longitudinal Item Response Data via the Pairwise Fitting Method. AB - Multidimensional item response theory (MIRT) models can be applied to longitudinal educational surveys where a group of individuals are administered different tests over time with some common items. However, computational problems typically arise as the dimension of the latent variables increases. This is especially true when the latent variable distribution cannot be integrated out analytically, as with MIRT models for binary data. In this article, based on the pseudolikelihood theory, we propose a pairwise modeling strategy to estimate item and population parameters in longitudinal studies. Our pairwise method effectively reduces the dimensionality of the problem and hence is applicable to longitudinal IRT data with high-dimensional latent variables, which are challenging for classical methods. And in the low-dimensional case, our simulation study shows that it performs comparably with the classical methods. We further illustrate the implementation of the pairwise method using a development study of mathematics levels of junior high school students in which the response data are collected from 65 classes of 8 schools from 4 different school districts in China. PMID- 26741527 TI - Multilevel SEM Strategies for Evaluating Mediation in Three-Level Data. AB - Strategies for modeling mediation effects in multilevel data have proliferated over the past decade, keeping pace with the demands of applied research. Approaches for testing mediation hypotheses with 2-level clustered data were first proposed using multilevel modeling (MLM) and subsequently using multilevel structural equation modeling (MSEM) to overcome several limitations of MLM. Because 3-level clustered data are becoming increasingly common, it is necessary to develop methods to assess mediation in such data. Whereas MLM easily accommodates 3-level data, MSEM does not. However, it is possible to specify and estimate some 3-level mediation models using both single- and multilevel SEM. Three new alternative approaches are proposed for fitting 3-level mediation models using single- and multilevel SEM, and each method is demonstrated with simulated data. Discussion focuses on the advantages and disadvantages of these approaches as well as directions for future research. PMID- 26741528 TI - Red alert: labile heme is an alarmin. AB - Alarmins are a heterogeneous group of endogenous molecules that signal cellular damage when sensed extracellularly. Heme is an endogenous molecule that acts as a prosthetic group of hemoproteins, such as hemoglobin and myoglobin. When released from damaged red blood cells or muscle cells, oxidized hemoglobin and myoglobin release their prosthetic heme groups, respectively. This generates labile heme, which is sensed by pattern recognition receptors (PRR) expressed by innate immune cells and possibly regulatory T cells (TREG). The ensuing adaptive response, which alerts for the occurrence of red blood cell or muscle cell damage, regulates the pathologic outcome of hemolysis or rhabdomyolysis, respectively. In conclusion, we propose that labile heme is an alarmin. PMID- 26741530 TI - Rapid dry-reagent immunomagnetic biosensing platform based on volumetric detection of nanoparticles on 3D structures. AB - A dry-reagent immunomagnetic (DRIM) biosensing platform is developed for rapid high-precision quantitative analyses for in vitro diagnostics. The platform combines the advantages of immunochromatography with highly sensitive quantification of 200-nm magnetic nanoparticles (MP) from the entire volume of lateral flow membranes. The MP are registered by their non-linear magnetization at combinatorial frequencies by a portable reader that offers the detection limit of 60 zeptomoles or 0.4 ng of magnetic nanolabels and extremely wide linear dynamic range of 7 orders. The efficient combination of small MP with large reaction surface of the 3D membranes has permitted the detection in human serum of as low as 25 pg/ml total prostate specific antigen (PSA) during 30-min assay. The featured 3-fold signal increase per every order of concentration within 3.5 orders of magnitude allows precise analysis of antigen concentrations in a wide range. The system also provides the first tool for quantitative MP mapping along the lateral flow strip for easy development and optimization of assays. The DRIM detection can be used for simple, rapid and sensitive quantification of protein biomarkers for in vitro diagnostics both in laboratory and near-patient conditions, for food analysis, environmental monitoring, security, and safety applications. PMID- 26741529 TI - Label-free hairpin DNA-scaffolded silver nanoclusters for fluorescent detection of Hg2+ using exonuclease III-assisted target recycling amplification. AB - A new label-free DNA sensing protocol was designed for fluorescent detection of mercury(II) (Hg(2+)), coupling hairpin DNA-scaffolded silver nanocluster (DNA AgNC) with exonuclease III-assisted target recycling amplification. The assay was carried out through target-induced conformational change of hairpin DNA, while the signal derived from the formed silver nanoclusters on hairpin DNA probes. Initially, target Hg(2+) was specifically coordinated with thymine-thymine (T-T) mismatches to form an intact hairpin DNA. Then, the newly formed hairpin DNA was digested through exonuclease III from blunt 3' termini and restrained at 3' protruding terminus, thus resulting in the release of target Hg(2+) from hairpin DNA. The liberated target Hg(2+) initiated the next cycling, thereby causing the conformational change of numerous hairpin probes from the stem-loop DNA structure to single-stranded DNA. Under the optimal conditions, the fluorescent intensity of the as-produced DNA-AgNCs decreased with the increasing Hg(2+) concentration within a dynamic range from 0.1 nM to 10nM with a detection limit (LOD) of 24 pM. Moreover, the low-cost fluorescent sensing system exhibited high reproducibility and good specificity, thus representing an optional sensing platform for rapid screening of Hg(2+) in environmental water samples. PMID- 26741532 TI - Development and evaluation of a RT-LAMP assay for rapid detection of hepatitis E virus from shellfish. AB - Hepatitis E virus (HEV) has becoming a well known zoonotic enteric pathogen and circulated widely inter human-animal-water-food. Generally, detection of the virus has relied on conventional reverse transcription-PCR (RT-PCR) and TaqMan/SYBR quantitative real-time RT-PCR (RT-qPCR), but these tools are usually disadvantages in time-consuming and expensive instruments required. In the present study, we report here on the development of a one-step single-tube reverse transcription-loop-mediated isothermal amplification (RT-LAMP) assay for rapid detection of HEV contamination in shellfish. The amplification is completed under the isothermal condition (63 degrees C) for 60 min, and can be visually evaluated by staining at a time in about 1h. In addition, a total of 315 shellfish (80 Anadara granosa, 115 Scapharca subcrenata and 120 Ruditapes philippinarum) collected monthly from the Jinzhou coastal estuary of China Bohai gulf were investigated for HEV contamination by the RT-LAMP compared with a standard RT-qPCR. It was found that genotype 4 HEV was detected in all three species of shellfish sampled using the RT-LAMP assay and was in accordance with RT-qPCR detection of HEV in shellfish. Summarily, our results indicate that the RT-LAMP is a rapid, specific, sensitive and reliable method. This method offers a new tool for the routine monitoring of HEV contamination in shellfish or its harvesting waters in field. PMID- 26741531 TI - Near-infrared fluorescence-based multiplex lateral flow immunoassay for the simultaneous detection of four antibiotic residue families in milk. AB - In this study, we developed a novel near-infrared fluorescence based multiplex lateral flow immunoassay by conjugating a near-infrared label to broad specificity monoclonal antibody/receptor as detection complexes. Different antigens were dispensed onto separate test zones of nitrocellulose membrane to serve as capture reagents. This assay format allowed the simultaneous detection of four families of antibiotics (beta-lactams, tetracyclines, quinolones and sulfonamides) in milk within 20 min. Qualitative and quantitative analysis of target antibiotics were realized by imaging the fluorescence intensity of the near-infrared label captured on respective test lines. For qualitative analysis, the cut-off values of beta-lactams, tetracyclines, quinolones and sulfonamides were determined to be 8 ng/mL, 2 ng/mL, 4 ng/mL and 8 ng/mL respectively, which were much lower than the conventional gold nanoparticle based lateral flow immunoassay. For quantitative analysis, the detection ranges were 0.26-3.56 ng/mL for beta-lactams, 0.04-0.98 ng/mL for tetracyclines, 0.08-2.0 ng/mL for quinolones, and 0.1-3.98 ng/mL for sulfonamides, with linear correlation coefficients higher than 0.97. The mean spiked recoveries ranged from 93.7% to 108.2% with coefficient of variations less than 16.3%. These results demonstrated that this novel immunoassay is a promising approach for rapidly screening the four families of antibiotic residues in milk. PMID- 26741534 TI - Spatial resolution and measurement uncertainty of strains in bone and bone-cement interface using digital volume correlation. AB - The measurement uncertainty of strains has been assessed in a bone analogue (sawbone), bovine trabecular bone and bone-cement interface specimens under zero load using the Digital Volume Correlation (DVC) method. The effects of sub-volume size, sample constraint and preload on the measured strain uncertainty have been examined. There is generally a trade-off between the measurement uncertainty and the spatial resolution. Suitable sub-volume sizes have been be selected based on a compromise between the measurement uncertainty and the spatial resolution of the cases considered. A ratio of sub-volume size to a microstructure characteristic (Tb.Sp) was introduced to reflect a suitable spatial resolution, and the measurement uncertainty associated was assessed. Specifically, ratios between 1.6 and 4 appear to give rise to standard deviations in the measured strains between 166 and 620 MUepsilon in all the cases considered, which would seem to suffice for strain analysis in pre as well as post yield loading regimes. A microscale finite element (MUFE) model was built from the CT images of the sawbone, and the results from the MUFE model and a continuum FE model were compared with those from the DVC. The strain results were found to differ significantly between the two methods at tissue level, consistent in trend with the results found in human bones, indicating mainly a limitation of the current DVC method in mapping strains at this level. PMID- 26741533 TI - A comparison of stress in cracked fibrous tissue specimens with varied crack location, loading, and orientation using finite element analysis. AB - Cracks in fibrous soft tissue, such as intervertebral disc annulus fibrosus and knee meniscus, cause pain and compromise joint mechanics. A crack concentrates stress at its tip, making further failure and crack extension (fracture) more likely. Ex vivo mechanical testing is an important tool for studying the loading conditions required for crack extension, but prior work has shown that it is difficult to reproduce crack extension. Most prior work used edge crack specimens in uniaxial tension, with the crack 90 degrees to the edge of the specimen. This configuration does not necessarily represent the loading conditions that cause in vivo crack extension. To find a potentially better choice for experiments aiming to reproduce crack extension, we used finite element analysis to compare, in factorial combination, (1) center crack vs. edge crack location, (2) biaxial vs. uniaxial loading, and (3) crack-fiber angles ranging from 0 degrees to 90 degrees . The simulated material was annulus fibrosus fibrocartilage with a single fiber family. We hypothesized that one of the simulated test cases would produce a stronger stress concentration than the commonly used uniaxially loaded 90 degrees crack-fiber angle edge crack case. Stress concentrations were compared between cases in terms of fiber-parallel stress (representing risk of fiber rupture), fiber-perpendicular stress (representing risk of matrix rupture), and fiber shear stress (representing risk of fiber sliding). Fiber-perpendicular stress and fiber shear stress concentrations were greatest in edge crack specimens (of any crack-fiber angle) and center crack specimens with a 90 degrees crack-fiber angle. However, unless the crack is parallel to the fiber direction, these stress components alone are insufficient to cause crack opening and extension. Fiber-parallel stress concentrations were greatest in center crack specimens with a 45 degrees crack-fiber angle, either biaxially or uniaxially loaded. We therefore recommend that the 45 degrees center crack case be tried in future experiments intended to study crack extension by fiber rupture. PMID- 26741535 TI - Interpretation bias for uncertain threat: A replication and extension. AB - BACKGROUND: Intolerance of uncertainty (IU) has been proposed as an important transdiagnostic variable within various anxiety-related disorders. Research has suggested that individuals high in IU may interpret ambiguous information in a more threatening manner, suggesting a negative interpretation bias for uncertain information. However, interpretation biases within IU have not been adequately tested in the literature. METHODS: The current study evaluated negative interpretation biases for uncertain information by directly measuring an individual's interpretations of ambiguous information across two samples. Participants consisted of 76 (Study 1; 72.4% female) and 31 (Study 2; 81% female) undergraduate students. RESULTS: Results indicated that individuals high in IU interpret ambiguous scenarios as more threatening compared to negative and/or positive scenarios (beta = .45, p = .02). In addition, individuals high in IU showed a negative interpretation bias for ambiguous information, but not benign information (Study 1: beta = -.40, p < .001; Study 2: beta = -.57, p = .002). LIMITATIONS: Future research should attempt to replicate these findings within clinical populations. In addition, future work would benefit from the inclusion of behavioral assessments of IU. CONCLUSIONS: These findings are the first to detect the presence of a negative interpretation bias for uncertain information among individuals high in IU utilizing a task designed to directly measure an individual's interpretation of information. Given the efficacy and low economic burden associated with interpretation bias modification protocols, and the transdiagnostic nature of IU, targeting IU within these protocols could have a tremendous public health impact. PMID- 26741536 TI - New strategies for the use of Linum usitatissimum cell factories for the production of bioactive compounds. AB - In this work, suspension-cultured cells of Linum usitatissimum L. were used to evaluate the effect of two types of cyclodextrins, beta-glucan and (Z)-3-hexenol separately or in combination on phytosterol and tocopherol production. Suspension cultured cells of L. usitatissimum were able to produce high levels of phytosterols in the presence of 50 mM methylated-beta-cyclodextrins (1325.96 +/- 107.06 MUg g dry weight(-1)) separately or in combination with beta-glucan (1278.57 +/- 190.10 MUg g dry weight(-1)) or (Z)-3-hexenol (1507.88 +/- 173.02 MUg g dry weight(-1)), being cyclodextrins able to increase both the secretion and accumulation of phytosterols in the spent medium, whereas beta-glucan and (Z) 3-hexenol themselves only increased its intracellular accumulation. Moreover, the phytosterol values found in the presence of hydroxypropylated-beta-cyclodextrins were lower than those found in the presence of methylated-beta-cyclodextrins in all cases studied. However, the results showed that the presence of methylated beta-cyclodextrins did not increase the tocopherols production and only an increase in tocopherol levels was observed when cells were elicited with 50 mM hydroxypropylated-beta-cyclodextrins in combination with beta-glucan (174 MUg g dry weight(-1)) or (Z)-3-hexenol (257 MUg g dry weight(-1)). Since the levels of tocopherol produced in the combined treatment were higher than the sum of the individual treatments, a synergistic effect between both elicitors was assumed. To sum up, flax cell cultures elicited with cyclodextrins alone or in combination with beta-glucan or (Z)-3-hexenol were able produce phytosterols and tocopherols, and therefore, these elicited suspension-cultured cells of L. usitatissimum can provide an alternative system, which is at the same time more sustainable, economical and ecological for their production. PMID- 26741537 TI - Structural basis of the lack of endo-glucanase inhibitory activity of Lupinus albus gamma-conglutin. AB - Lupin gamma-conglutin and soybean BG7S are two legume seed proteins strongly similar to plant endo-beta-glucanases inhibitors acting against fungal GH11 and GH12 glycoside hydrolase. However these proteins lack inhibitory activity. Here we describe the conversion of lupin gamma-conglutin to an active inhibitor of endo-beta-glucanases belonging to GH11 family. A set of gamma-conglutin mutants was designed and expressed in Pichia pastoris, along with the wild-type protein. Unexpectedly, this latter was able to inhibit a GH11 enzyme, but not GH12, whereas the mutants were able to modulate the inhibition capacity. In lupin, gamma-conglutin is naturally cleaved in two subunits, whereas in P. pastoris it is not. The lack of proteolytic cleavage is one of the reasons at the basis of the inhibitory activity of recombinant gamma-conglutin. The results provide new insights about structural features at the basis of the lack of inhibitory activity of wild-type gamma-conglutin and its legume homologues. PMID- 26741538 TI - Reduced arsenic accumulation in rice (Oryza sativa L.) shoot involves sulfur mediated improved thiol metabolism, antioxidant system and altered arsenic transporters. AB - Arsenic (As) contamination in rice is at alarming level as majority of rice growing regions are As contaminated such as South East Asia. Restricting the As in aerial parts of rice plant may be an effective strategy to reduce As contamination in food chain. Sulfur (S), an essential element for plant growth and development, plays a crucial role in diminishing heavy metal toxicity. Current study is designed to investigate the role of S to mitigate As toxicity in rice under different S regimes. High S (5 mM) treatment resulted in enhanced root As accumulation as well as prevented its entry in to shoot. Results of thiol metabolism indicate that As was complexed in plant roots through enhanced synthesis of phytochelatins. High S treatment also reduced the expression of OsLsi1 and OsLsi2, the potent transporters of As in rice. High S treatment enhanced the activities of antioxidant enzymes and mitigated the As induced oxidative stress. Thus from present study it is evident that proper supply of S nutrition may be helpful in prevention of As accumulation in aerial parts of plant as well as As induced toxicity. PMID- 26741539 TI - Resident Rounds: Part III--Case Report: Metastatic Multiple Myeloma. AB - We report a case of cutaneous plasmacytomas developing in a patient with a 7 month history of progressive multiple myeloma refractory to bortezomib and combination chemotherapy. When involving the skin, plasmacytomas typically arise in the setting of multiple myeloma as contiguous extensions from underlying bony disease. More rarely, cutaneous plasmacytomas develop from hematologic metastases in patients with a high systemic plasma cell tumor burden. In our patient, the presence of cutaneous plasmacytomas involving two distinct sites, and malignant plasma cells within the dermis without infiltration into the subcutaneous fat, suggest a diagnosis of metastatic multiple myeloma to the skin. Metastatic multiple myeloma to the skin portends a poor prognosis, and treatment should be aimed at the underlying systemic disease. PMID- 26741540 TI - Deionization of Dopants in Silicon Nanofilms Even with Donor Concentration of Greater than 10(19) cm(-3). AB - Understanding the dopant properties in heavily doped nanoscale semiconductors is essential to design nanoscale devices. We report the deionization or finite ionization energy of dopants in silicon (Si) nanofilms with dopant concentration (ND) of greater than 10(19) cm(-3), which is in contrast to the zero ionization energy (ED) in bulk Si at the same ND. From the comparison of experimentally observed and theoretically calculated ED, we attribute the deionization to the suppression of metal-insulator transition in highly doped nanoscale semiconductors in addition to the quantum confinement and the dielectric mismatch, which greatly increase ED in low-doped nanoscale semiconductors. Thus, for nanoscale transistors, ND should be higher than that estimated from bulk Si dopant properties in order to reduce their resistivity by the metal-insulator transition. PMID- 26741541 TI - Continuous-flow leaching in a rotating coiled column for studies on the mobility of toxic elements in dust samples collected near a metallurgic plant. AB - Continuous-flow (dynamic) leaching in a rotating coiled column has been applied to studies on the mobility of Zn, Cd, Cu, Pb, Ni, Sb, As, S, and other potentially toxic elements in atmospherically deposited dust samples collected near a large copper smelter (Chelyabinsk region, Russia). Water and simulated "acid rain" (pH 4) were used as eluents. The technique enables not only the fast and efficient leaching of elements but as well time-resolved studies on the mobilization of heavy metals, sulphur, and arsenic in environmentally relevant forms to be made. It is shown that up to 1.5, 4.1, 1.9, 11.1, and 46.1% of Pb, As, Cu, Zn, and S, correspondingly, can be easily mobilized by water. Taking into consideration that the total concentrations of these elements in the samples under investigation are surprisingly high and vary in the range from 2.7 g/kg (for arsenic) to 15.5 g/kg (for sulphur), the environmental impact of the dust may be dramatic. The simulated acid rain results in somewhat higher recoveries of elements, except Cu and Pb. The proposed approach and the data obtained can very useful for the risk assessment related to the mobility of potentially toxic elements and their inclusion in the biogeochemical cycle. PMID- 26741542 TI - Ceramic membrane defouling (cleaning) by air Nano Bubbles. AB - Ceramic membranes are among the most promising technologies for membrane applications, owing to their excellent resistance to mechanical, chemical, and thermal stresses. However, membrane fouling is still an issue that hampers the applications at large scales. Air Nano Bubbles (NBs), due to high mass transfer efficiency, could potentially prevent fouling of ceramic membrane filtration processes. In this study, bench and pilot scale ceramic membrane filtration was performed with air NBs to resist fouling. To simulate fouling, humic acid, as an organic foulant, was applied to the membrane flat sheet surface. Complete membrane clogging was achieved in less than 6 h. Membrane defouling (cleaning) was performed by directly feeding of air NBs to the membrane cells. The surface of the ceramic membrane was superbly cleaned by air NBs, as revealed by atomic force microscope (AFM) images before and after the treatment. The permeate flux recovered to its initial level (e.g., 26.7 * 10(-9) m(3)/m(2)/s at applied pressure of 275.8 kPa), which indicated that NBs successfully unclogged the pores of the membrane. The integrated ceramic membrane and air NBs system holds potential as an innovative sustainable technology. PMID- 26741543 TI - The major parameters on biomass pyrolysis for hyperaccumulative plants--A review. AB - Phytoextraction is one of the main phytoremediation techniques and it has often been described as a potentially feasible in situ soil decontamination method of large amounts of heavy metals, organic pollutants and explosive compounds. As this remediation technique is approaching extensive on-field experimentation and commercialization, research focus is on investigating new ways to achieve the valorisation of its by-products. Biomass pyrolysis represents a key step to numerous valorisation options and it is characterized by differential output products that are determined by the operating conditions of the process and the characteristics of the input. However, when used to valorise plants that have undergone significant metal uptake, this strategy involves some new aspects related to harvest, procedure and final product reutilization. This paper reviews the studies made on biomass pyrolysis of plants with emphasis on the differential quality and distribution of pyrolysis products in relation with the variables of the process and the metal-rich phytoextraction feedstock properties. By investigating these parameters, this survey provides indications on ways to optimize the valorisation of phytoremediation by-products through biomass pyrolysis. PMID- 26741544 TI - Chemical and toxicological effects of medicinal Baccharis trimera extract from coal burning area. AB - The entire process of power generation, extraction, processing and use of coal strongly impact water resources, soil, air quality and biota leads to changes in the fauna and flora. Pollutants generated by coal burning have been contaminating plants that grow in area impacted by airborne pollution with high metal contents. Baccharis trimera is popularly consumed as tea, and is widely developed in Candiota (Brazil), one of the most important coal burning regions of the Brazil. This study aims to investigate the phytochemical profile, in vivo genotoxic and mutagenic potential of extracts of B. trimera collected from an exposed region to pollutants generated by coal burning (Candiota City) and other unexposed region (Bage City), using the Comet assay and micronucleus test in mice and the Salmonella/microsome short-term assay. The HPLC analyses indicated higher levels of flavonoids and phenolic acids for B. trimera aqueous extract from Bage and absence of polycyclic aromatic hydrocarbons for both extracts. The presence of toxic elements such as cobalt, nickel and manganese was statistically superior in the extract from Candiota. For the Comet assay and micronucleus test, the mice were treated with Candiota and Bage B. trimera aqueous extracts (500-2000 mg/kg). Significant genotoxicity was observed at higher doses treated with B. trimera aqueous extract from Candiota in liver and peripheral blood cells. Micronuclei were not observed but the results of the Salmonella/microsome short-term assay showed a significant increase in TA98 revertants for B. trimera aqueous extract from Candiota. The extract of B. trimera from Candiota bioacumulated higher levels of trace elements which were associated with the genotoxic effects detected in liver and peripheral blood cells. PMID- 26741545 TI - Dynamic energy-based modeling of uranium and cadmium joint toxicity to Caenorhabditis elegans. AB - Toxicokinetic - toxicodynamic energy-based models offer new alternatives to the commonly used approaches for the analysis of mixture toxicity data. Based on the Dynamic Energy Budget theory, DEBtox models enable the description of several endpoints over time simultaneously under the same framework. However, such model still has to be faced with experimental data in a multi-contamination context. In this study, the predictive capacities of a DEBtox model to describe the uranium and cadmium joint toxicity over the entire growth and reproduction period of the soil nematode Caenorhabditis elegans was examined. The two reference additivity approaches, Concentration Addition and Response addition, implemented in the DEBtox model were tested. Assuming no interaction between the two toxicants through Response addition, the DEBtox model allowed a rather accurate fit of the U and Cd joint effects on the growth and reproduction of C. elegans: an interaction between the two metals at the toxicokinetic or toxicodynamic level seems thus unlikely or has only minor consequences. Interestingly, this study underlines that even if the compounds of a mixture share the same DEBtox physiological mode of action (in this case a decrease in assimilation), the Response addition approach may provide a better fit of joint toxicity data than the Concentration addition approach. Moreover, the present work highlighted limitations in the model predictions which are related to the simplifications of the DEBtox framework and its adaptations to the physiology of C. elegans and which lead to an overestimation of the U and Cd joint toxicity in some cases. PMID- 26741546 TI - Degradation of methyl orange by ozone in the presence of ferrous and persulfate ions in a rotating packed bed. AB - This work investigated the degradation of methyl orange by ozone in the presence of ferrous and persulfate ions (O3/Fe(2+)/S2O8(2-)) in a rotating packed bed. The effects of various operating parameters such as initial pH, rotational speed, gas liquid ratio, ozone inlet concentration and reaction temperature on the degradation rate of methyl orange were studied with an aim to optimize the operation conditions. Results reveal that the degradation rate increased with an increase in rotational speed, gas-liquid ratio and ozone inlet concentration, and reached a maximum at 25 degrees C and initial pH 4. Contrast experiments involving ozone and ferrous ions (O3/Fe(2+)) were also carried out, and the results show approximately 10% higher degradation rate and COD removal in the O3/Fe(2+)/S2O8(2-) process than in the O3/Fe(2+) process. Additionally, the intermediates of the degradation process were analyzed to ascertain the degradation products. PMID- 26741547 TI - Estimated dietary intake and risk assessment of polychlorinated dibenzo-p-dioxins and dibenzofurans and dioxin-like polychlorinated biphenyls from fish consumption in the Korean general population. AB - We analyzed 17 polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), and 12 dioxin-like polychlorinated biphenyls (DL-PCBs) in samples from various fish species available at food markets in nine Korean cities. The estimated dietary intake of these chemicals was calculated from the raw concentrations of PCDD/Fs and DL-PCBs in each sample and from the food consumption of the Korean general population, and a comparison was made with the provisional tolerable monthly intake (PTMI). The average daily dietary exposure and the 95th percentile of intake of PCDD/Fs and DL-PCBs were 0.21 and 0.49 pg WHO05-toxic equivalents (TEQ) kg(-1) body weight d(-1) representing 5.27% and 12.26%, respectively, of the Korean tolerable daily intake (TDI). We applied the monthly fish consumption limits to the evaluation of improved risk assessment and concluded that unlimited consumption of most fish species does not contribute to the elevated cancer risk. This investigation was the first such large-scale study in Korea, and incorporated 37 species, including a species of whale, and 480 samples. The major aims of this study were to demonstrate the health risks associated with fish intake and to ensure food safety through total analysis of PCDD/Fs and DL-PCBs using gas chromatography/high-resolution mass spectrometry (GC-HRMS). PMID- 26741548 TI - Dynamic flux chamber measurements of hydrogen sulfide emission rate from a quiescent surface--A computational evaluation. AB - Enclosure devices have been studied and used for research purposes and practical applications in order to measure the emission rate of odorous pollutants from quiescent liquid surfaces to atmosphere. However, important questions remain about the interference of these measuring devices on the actual emission rate. The main concern regarding the use of a flux chamber is the fact that odorous compounds can accumulate into the chamber and yield gas-phase concentration increase inside the equipment, which causes a reduction of the emission rate during the measurement and thus gives an inaccurate local emission rate. Furthermore, the fluid flow inside the chamber does not reproduce the atmospheric boundary layer flow. This study applied the Computational Fluid Dynamics (CFD) technique in order to investigate the influence of the fluid flow features inside a flux chamber on the measured hydrogen sulfide emission rate at quiescent liquid surfaces. The flux chamber design and operational conditions are those supported by the United States Environmental Protection Agency (US EPA). The results show that the US EPA flux chamber presents a fairly well mixed air phase. However, a trend to stagnation and hydrogen sulfide accumulation near chamber walls was detected in the computational simulation, which also indicated that the positioning of the sampling tube in relation to the inlet orifices may lead to deviations in the measurement results. CFD results showed that the wall shear and concentration gradients spatially vary at the gas-liquid interface, and friction velocity inside the chamber does not match typical values of atmospheric flow. PMID- 26741549 TI - Emerging pollutants and plants--Metabolic activation of diclofenac by peroxidases. AB - Human pharmaceuticals and their residues are constantly detected in our waterbodies, due to poor elimination rates, even in the most advanced waste water treatment plants. Their impact on the environment and human health still remains unclear. When phytoremediation is applied to aid water treatment, plants may transform and degrade xenobiotic contaminants through phase I and phase II metabolism to more water soluble and less toxic intermediates. In this context, peroxidases play a major role in activating compounds during phase I via oxidation. In the present work, the ability of a plant peroxidase to oxidize the human painkiller diclofenac was confirmed using stopped flow spectroscopy in combination with LC-MS analysis. Analysis of an orange colored product revealed the structure of the highly reactive Diclofenac-2,5-Iminoquinone, which may be the precursor of several biological conjugates and breakdown products in planta. PMID- 26741550 TI - Removal of refractory organics in nanofiltration concentrates of municipal solid waste leachate treatment plants by combined Fenton oxidative-coagulation with photo--Fenton processes. AB - Removal of the refractory organic matters in leachate brines generated from nanofiltration unit in two full-scale municipal solid waste landfill leachate treatment plants was investigated by Fenton oxidative-coagulation and ultraviolet photo - Fenton processes in this study. Fenton oxidative-coagulation was performed under the condition of an initial pH of 5.0 and low H2O2/Fe(2+) ratios. After precipitate separation, the remaining organic constituents were further oxidized by photo - Fenton process. For both leachate brines with varying pollution strength, more than 90% COD and TOC reductions were achieved at H2O2/Fe(2+) dosages of 35 mM/8 mM and 90 mM/10 mM, respectively. The effluent COD ranged 120-160 mg/L under the optimal operating conditions, and the biodegradability was increased significantly. Fenton oxidative-coagulation was demonstrated to contribute nearly 70% overall removal of organic matters. In the combined processes, the efficiency of hydrogen peroxide varied from 216 to 228%, which may significantly reduce the operating cost of conventional Fenton method. Six phthalic acid esters and thirteen polycyclic aromatic hydrocarbons were found in leachate brines, and, on the average, around 80% phthalic acid esters and 90% polycyclic aromatic hydrocarbons were removed by the combined treatments. PMID- 26741551 TI - Fate and transport of agriculturally applied fungicidal compounds, azoxystrobin and propiconazole. AB - Fungicidal active ingredients azoxystrobin and propiconazole, individually and in combination, have been marketed worldwide in a range of fungicide treatment products for preventative and curative purposes, respectively. Their presence in streams located throughout the midwestern and southeastern United States warrant the need for research into the potential routes of transport of these fungicides in an agricultural field setting. Potential canopy penetration and drift effects of these fungicides during aerial and ground applications were studied in the current project. Canopy penetration was observed for both application types, however drift was associated only with the aerial application of these fungicides. Azoxystrobin and propiconazole persisted in the soil up to 301 d, with peak concentrations occurring approximately 30 d after application. The predominant mode of transport for these compounds was agricultural runoff water, with the majority of the fungicidal active ingredients leaving the target area during the first rain event following application. The timing of application in relation to the first rain event significantly affected the amount of loss that occurred, implying application practices should follow manufacturer recommended guidelines. PMID- 26741552 TI - Influence of milling on the adsorption ability of eggshell waste. AB - Eggshell waste was successfully used for the removal of heavy metal ions from model solutions. The effect of ball milling on the structure and adsorption ability of eggshell (ES) and its membrane (ESM) was investigated, with the conclusion that milling is benefitial only for the ES. The adsorption experiments showed that the ESM is a selective adsorbent, as the adsorption ability toward different ions decreased in the following order: Ag(I) > Cd(II) > Zn(II). The obtained Qm values for Ag(I) adsorption on the ESM and ES were 52.9 and 55.7 mg g(-1), respectively. The potential industrial application of ES was also demonstrated by successful removal of Ag(I) from the technological waste. PMID- 26741553 TI - Investigation of the impact of organic solvent type and solution pH on the extraction efficiency of naphthenic acids from oil sands process-affected water. AB - Naphthenic acids (NAs) from oil sand process-affected water (OSPW) were liquid liquid extracted using six organic solvents (n-pentane, n-hexane, cyclohexane, dichloromethane, ethyl ether, and ethyl acetate) at three pHs (2.0, 8.5, and 12.0). The NAs exist in ionic (ions) and non-ionic (molecules) forms in the water phase depending on their dissociation constants and the solution pH. Results showed the extractability of NA molecules depends on the solvent polarity and the extractability of NA ions on the water solubility in solvent. The organic solvent type and solution pH were found to not only impact the extracted amounts of each NA species, but also the NAs distribution in terms of molecule carbon number and hydrogen deficiency. Overall, it is concluded that ethyl ether can be used as an alternative to dichloromethane (DCM) given their similar extraction efficiencies and extracted NA profiles. This is important since DCM is known to have metabolic toxicity and transitioning to the safer ethyl ether would eliminate laboratory DCM exposures and risk to human health. Despite the higher extraction efficiency of NAs at pH 2.0, extraction at pH 12.0 could be useful for targeted extraction of low-concentration nonpolar organic compounds in OSPW. This knowledge may assist in the determination of the specific NAs species that are known to have chronic, sub-chronic and acute toxicity to various organisms, and the potential targeting of treatment to these NAs species. PMID- 26741554 TI - Effects of phoxim on nutrient metabolism and insulin signaling pathway in silkworm midgut. AB - Silkworm (Bombyx mori) is an important economic insect. Each year, poisoning caused by phoxim pesticide leads to huge economic losses in sericulture in China. Silkworm midgut is the major organ for food digestion and nutrient absorption. In this study, we found that the activity and expression of nutrition metabolism related enzymes were dysregulated in midgut by phoxim exposure. DGE analysis revealed that 40 nutrition metabolism-related genes were differentially expressed. qRT-PCR results indicated that the expression levels of insulin/insulin growth factor signaling (IIS) pathway genes Akt, PI3K, PI3K60, PI3K110, IRS and PDK were reduced, whereas PTEN's expression was significantly increased in the midgut at 24 h after phoxim treatment. However, the transcription levels of Akt, PI3K60, PI3K110, IRS, InR and PDK were elevated and reached the peaks at 48 h, which were 1.48-, 1.35-, 1.21-, 2.24-, 2.89-, and 1.44 fold of those of the control, respectively. At 72 h, the transcription of these genes was reduced. Akt phosphorylation level was increasing along with the growth of silkworms in the control group. However, phoxim treatment led to increased Akt phosphorylation that surged at 24 h but gradually decreased at 48 h and 72 h. The results indicated that phoxim dysregulated the expression of IIS pathway genes and induced abnormal nutrient metabolism in silkworm midgut, which may be the reason of the slow growth of silkworms. PMID- 26741555 TI - Bioaccumulation of pharmaceuticals and personal care products in the unionid mussel Lasmigona costata in a river receiving wastewater effluent. AB - Freshwater mussels are frequently found in rivers receiving effluent from wastewater treatment plants (WWTP), and there is strong evidence that poor water quality is deleterious to freshwater mussel populations. WWTPs are among the main sources of pharmaceuticals and personal care products (PPCPs) in surface waters. We monitored 145 PPCPs in wild and caged mussels both upstream and downstream of the Kitchener WWTP in the Grand River, Ontario, as well as 118 PPCPs in water samples. Our objectives were to characterize the seasonal changes in PPCP concentrations in water, to calculate bioaccumulation factors (BAFs) of PPCPs in mussels, and to determine the chemical and physical properties of PPCPs driving the bioaccumulation. Seventy PPCPs were detected in water, and concentrations were highest in the summer or early fall, which corresponded to low river flow. Forty-three PPCPs from many pharmaceutical classes were detected in mussel tissues, including stimulants, a contrasting agent, anti-inflammatory drugs, anti bacterial agents, antibiotics, antidepressants, antihistamines, progestins, and illicit drugs such as cocaine and amphetamines. The BAFs ranged from 0.66 for metformin to 32,022 for sertraline. Using partial least squares to predict BAFs based upon chemical properties, log KOC, Log KOW, and fugacity ratio (sediment) all had similar and positive loadings with BAFs (R(2)X = 0.70; caged mussels). BAFs of PPCPs in mussels were predictable from fugacity models that estimate bioconcentration factors using log KOW. Our study demonstrated that mussels readily bioaccumulate PPCPs, in a manner consistent with expectations based upon BCF models and the chemical characteristics of each compound. PMID- 26741556 TI - Estrogenic activities of diuron metabolites in female Nile tilapia (Oreochromis niloticus). AB - Some endocrine disrupting chemicals (EDCs) can alter the estrogenic activities of the organism by directly interacting with estrogen receptors (ER) or indirectly through the hypothalamus-pituitary-gonadal axis. Recent studies in male Nile tilapia (Oreochromis niloticus) indicated that diuron may have anti-androgenic activity augmented by biotransformation. In this study, the effects of diuron and three of its metabolites were evaluated in female tilapia. Sexually mature female fish were exposed for 25 days to diuron, as well as to its metabolites 3,4 dichloroaniline (DCA), 3,4-dichlorophenylurea (DCPU) and 3,4-dichlorophenyl-N methylurea (DCPMU), at concentrations of 100 ng/L. Diuron metabolites caused increases in E2 plasma levels, gonadosomatic indices and in the percentage of final vitellogenic oocytes. Moreover, diuron and its metabolites caused a decrease in germinative cells. Significant differences in plasma concentrations of the estrogen precursor and gonadal regulator17alpha-hydroxyprogesterone (17alpha-OHP) were not observed. These results show that diuron metabolites had estrogenic effects potentially mediated through enhanced estradiol biosynthesis and accelerated the ovarian development of O. niloticus females. PMID- 26741557 TI - Catalytic thermolysis in treating Cibacron Blue in aqueous solution: Kinetics and degradation pathway. AB - A thermal degradation pathway of the decolourisation of Reactive Cibacron Blue F3GA (RCB) in aqueous solution through catalytic thermolysis is established. Catalytic thermolysis is suitable for the removal of dyes from wastewater as it breaks down the complex dye molecules instead of only transferring them into another phase. RCB is a reactive dye that consists of three main groups, namely anthraquinone, benzene and triazine groups. Through catalytic thermolysis, the bonds that hold the three groups together were effectively broken and at the same time, the complex molecules degraded to form simple molecules of lower molecular weight. The degradation pathway and products were characterized and determined through UV-Vis, FT-IR and GCMS analysis. RCB dye molecule was successfully broken down into simpler molecules, namely, benzene derivatives, amines and triazine. The addition of copper sulphate, CuSO4, as a catalyst, hastens the thermal degradation of RCB by aiding in the breakdown of large, complex molecules. At pH 2 and catalyst mass loading of 5 g/L, an optimum colour removal of 66.14% was observed. The degradation rate of RCB is well explained by first order kinetics model. PMID- 26741559 TI - Theoretical analysis of NMR shieldings in XSe and XTe (X = Si, Ge, Sn and Pb): the spin-rotation constant saga. AB - The nuclear spin-rotation (NSR) and absolute nuclear magnetic resonance (NMR) shielding tensors of the nuclei in the series of X(77)Se and X(125)Te (X = (29)Si, (73)Ge, (119)Sn and (207)Pb) are calculated using four-component relativistic density functional theory (DFT) and coupled-cluster singles-doubles with a perturbative triples correction (CCSD(T)). The results for the NSR constants are compared to available experimental data. The best theoretical estimates are obtained when relativistic corrections from DFT are added to the accurate non-relativistic CCSD(T) results. All the calculated NSR constants are in excellent agreement with the corresponding experimental values. Even though there are previously estimated absolute shielding constants and spans from experimental NSR tensors, new accurate values are reported following the same approach used to calculate the NSR constants in this study. The main reasons for the discrepancy between the previously reported NMR properties and the accurate results obtained in this study are also discussed. PMID- 26741558 TI - Proteolytic bacterial dominance in a full-scale municipal solid waste anaerobic reactor assessed by 454 pyrosequencing technology. AB - Biomethanization entails a good means to reduce the organic fraction (OF) derived from municipal solid wastes (MSW). The bacterial diversity of a full scale MSW anaerobic reactor located in Madrid (Spain) was investigated using high throughput 454 pyrosequencing. Even though the proteolytic bacteria prevailed throughout all of the process, community shifts were observed from the start-up to the steady-state conditions, with an increasing biodiversity displayed over time. The Bacteroidetes and the Firmicutes were the majority phyla: 55.1 and 40.2% (start-up) and 18.7 and 78.7 (steady-state) of the total reads. The system's lack of evenness remains noteworthy as the sequences affiliated to the proteolytic non-saccharolytic Proteiniphylum, Gallicola and Fastidiosipila genera, together with the saccharolytic Saccharofermentans, were predominant on the system and this predominance appears to correlate with the presence of a high ammonium concentration. The 454 pyrosequencing revealed a great diversity of rare organisms which seemingly do not sustain any metabolic roles in the course of the OF-MSW degradation. However, this scarce and unique microbiota can confer great resilience to the system as a buffer against nutritional and environmental changing conditions, thus opening the door to increase the current knowledge about the bacterial community dynamics taking place during MSW treatment processes. PMID- 26741560 TI - Elemental composition of Usnea sp lichen from Potter Peninsula, 25 de Mayo (King George) Island, Antarctica. AB - Several pollutants, which include metals, are present in the Antarctic atmosphere, snow, marine and terrestrial organisms. This work reports the elements incorporated by Usnea sp thalli in Potter Peninsula, 25 de Mayo (King George) Island, South Shetlands, Antarctica. Geological origin was analyzed as possible sources of elements. For this purpose, correlations were done using a geochemical tracer, principal component analysis and enrichment factors were computed. Lithophile elements from particulate matter were present in most of the sampling sites. Bromine, Se and Hg showed the highest enrichment factors suggesting other sources than the particulate matter. Mercury values found in Usnea sp were in the same range as those reported for Deception Island (South Shetlands) and remote areas from the Patagonia Andes. PMID- 26741561 TI - Chemical composition of scales generated from oil industry and correlation to radionuclide contents and gamma-ray measurements of (210)Pb. AB - Scale generated from the maintenance of equipment contaminated by naturally occurring radioactive materials may contain also chemical components that cause hazardous pollution to human health and the environment. This study spotlights the characterisation of chemical pollutants in scales in relation to home-made comparison samples as no reference material for such waste exists. Analysis by energy dispersive x-ray fluorescence, with accuracy and precision better than 90%, revealed that barium was the most abundant element in scale samples, ranging from 1.4 to 38.2%. The concentrations of the toxic elements such as lead and chromium were as high as 2.5 and 1.2% respectively. Statistically, high correlation was observed between the concentration of Ba and Sr, sample density, radionuclide contents ((210)Pb and (226)Ra) and self-attenuation factor used for the radio-measurements. However, iron showed a reverse correlation. Interpretation of data with regards to the mineralogical components indicated that (226)Ra and (210)Pb co-precipitated with the insoluble salt Ba0.75Sr0.25SO4. Since both Ba and Sr have high Z, samples of high density (rho) were accompanied with high values of self-attenuation correction factors (Cf) for the emitted radiation; correlation matrix of Pearson reached 0.935 between rho and Cf. An attempt to eliminate the effect of the elemental composition and improve gamma measurements of (210)Pb activity concentration in scale samples was made, which showed no correction for self-attenuation was needed when sample densities were in the range 1.0-1.4 g cm(-3). For denser samples, a mathematical model was developed. Accurate determinations of radionuclide and chemical contents of scale would facilitate future Environmental Impact Assessment for the petroleum industry. PMID- 26741562 TI - Significance of antifouling paint flakes to the distribution of dichlorodiphenyltrichloroethanes (DDTs) in estuarine sediment. AB - Recently published literature indicated that dichlorodiphenyltrichloroethane (DDT)-containing antifouling paint flakes were heterogeneously distributed within estuarine sediments. However, the significance of antifouling paint flakes in the fate and transport of DDT compounds and other organic pollutants in estuarine sediment is yet to be adequately addressed. To fill this knowledge gap, estuarine sediment and paint flakes from cabin and boat surfaces were collected from a fishery base in Guangdong Province of South China and analyzed for DDT compounds. Coarse fractioned samples collected from the vicinity of boat maintenance facilities contained appreciable amounts of colorful particles, which were identified as paint flakes by Fourier transform infrared spectroscopy. The highest concentrations of DDXs (sum of DDTs and its metabolites) occurred in the heavy-density (>1.7 g cm(-3)) fraction of coarse-size (200-2000 MUm) sediments from near the boat maintenance facilities, suggesting the importance of paint flakes in the distribution pattern of "hot spots" in estuarine sediment. Moreover, the desorption rates of DDT compounds from paint flakes and the heavy density fraction of coarse-size sediment were both extremely slow. Apparently, unevenly distributed paint flakes in sediment can artificially inflate the sorption capacity of heavy-density sediment for DDT compounds, and therefore can substantially change the environmental fate and behavior of hydrophobic organic chemicals in estuarine sediment. Finally, commonly used source diagnostic indices of DDT compounds were mostly grain-size and density dependent in sediment, as a result of the occurrence of paint flakes, which may strongly compromise the outcome of any source diagnostics efforts. PMID- 26741563 TI - Shaping the role of 'fast' and 'slow' drivers of change in forest-shrubland socio ecological systems. AB - The temporal speeds and spatial scales at which ecosystem processes operate are often at odds with the scale and speed at which natural resources such as soil, water and vegetation are managed those. Scale mismatches often occur as a result of the time-lag between policy development, implementation and observable changes in natural capital in particular. In this study, we analyse some of the transformations that can occur in complex forest-shrubland socio-ecological systems undergoing biophysical and socioeconomic change. We use a Multiway Factor Analysis (MFA) applied to a representative set of variables to assess changes in components of natural, economic and social capitals over time. Our results indicate similarities among variables and spatial units (i.e. municipalities) which allows us to rank the variables used to describe the SES according to their rapidity of change. The novelty of the proposed framework lies in the fact that the assessment of rapidity-to-change, based on the MFA, takes into account the multivariate relationships among the system's variables, identifying the net rate of change for the whole system, and the relative impact that individual variables exert on the system itself. The aim of this study was to assess the influence of fast and slow variables on the evolution of socio-economic systems based on simplified multivariate procedures applicable to vastly different socio-economic contexts and conditions. This study also contributes to quantitative analysis methods for long-established socio-ecological systems, which may help in designing more effective, and sustainable land management strategies in environmentally sensitive areas. PMID- 26741564 TI - Cytotoxic Effects of Phosphonate-Functionalized Mesoporous Silica Nanoparticles. AB - In this work, we synthesized pristine mesoporous silica nanoparticles (MSN) and functionalized these with phosphonate groups (MSN-Phos). We report, for the first time, cell death in MCF-7 cells (human breast adenocarcinoma cell line) when exposed to the empty MSN and MSN-Phos nanoparticles. In comparison, the same nanoparticles were found to elicit few deleterious effects on normal human foreskin fibroblast cells (BJ cells). MCF-7 cells were found to exhibit a concentration-dependent uptake, whereas no detectable nanoparticle uptake was observed in the BJ cells, irrespective of treatment dosage. A disruption of the cell cycle in the MCF-7 cells was determined to be the cause of cell death from the nanoparticle exposure, thereby suggesting the role of nondrug loaded MSN and MSN-Phos as effective anticancer drugs. PMID- 26741565 TI - Collision Cross Sections for O + Ar(+) Collisions in the Energy Range 0.03-500 eV. AB - The interatomic potentials of the a(2)Pi and b(2)Pi states of the OAr(+) molecule are calculated using the relativistic complete-active space Hartree-Fock method followed by a multireference configuration interaction calculation with an aug-cc pwCVNZ-DK basis sets where N is 4 and 5. The calculations were followed by an extrapolation to the complete basis set limit. An avoided crossing between the two potential energy curves is found at an internuclear separation of 5.75 bohr (3.04 A). As the transition probability between the curves is negligible in the relative collision energy range 0.03-500 eV of interest here, collisions on the lower adiabatic a(2)Pi potential may be treated without reference to the upper state. For low energies and orbital angular momentum quantum numbers, the one dimensional radial Schrodinger equation is solved numerically using a Numerov algorithm method to determine the phase shift. The semiclassical JWKB approximation was employed for relative energies greater than 5 eV and orbital angular quantum numbers higher than 500. Differential, integral, transport (diffusion), and viscosity cross sections for elastic collisions of oxygen atoms with argon ions are calculated for the first time for the range of relative collision energies studied. The calculated cross sections are expected to be of utility in the fields of nanotechnology and arc welding. The combination of an Ar(+)((2)P) ion and a O((3)P) atom gives rise to a total of 12 different molecular electronic states that are all coupled by spin-orbit interactions. Potential energy curves for all 12 states are computed at the complete active space self-consistent field (CASSCF) level and scattering calculations performed. The results are compared with those obtained using just the lowest potential energy curve. PMID- 26741566 TI - Highly diastereoselective approach to methylenecyclopropanes via boron homologation/allylboration sequences. AB - A simple and efficient diastereoselective synthesis of methylenecyclopropanes is described, in which boron-homologation and allylboration are merged into a one pot process, starting from in situ generated cyclopropenyllithium species. This unprecedented methodology opens a new route to strained alkylidenecycloalkanes containing a quaternary stereocenter, in high yields and excellent diastereomeric ratios. PMID- 26741567 TI - Theropod courtship: large scale physical evidence of display arenas and avian like scrape ceremony behaviour by Cretaceous dinosaurs. AB - Relationships between non-avian theropod dinosaurs and extant and fossil birds are a major focus of current paleobiological research. Despite extensive phylogenetic and morphological support, behavioural evidence is mostly ambiguous and does not usually fossilize. Thus, inferences that dinosaurs, especially theropods displayed behaviour analogous to modern birds are intriguing but speculative. Here we present extensive and geographically widespread physical evidence of substrate scraping behavior by large theropods considered as compelling evidence of "display arenas" or leks, and consistent with "nest scrape display" behaviour among many extant ground-nesting birds. Large scrapes, up to 2 m in diameter, occur abundantly at several Cretaceous sites in Colorado. They constitute a previously unknown category of large dinosaurian trace fossil, inferred to fill gaps in our understanding of early phases in the breeding cycle of theropods. The trace makers were probably lekking species that were seasonally active at large display arena sites. Such scrapes indicate stereotypical avian behaviour hitherto unknown among Cretaceous theropods, and most likely associated with terrirorial activity in the breeding season. The scrapes most probably occur near nesting colonies, as yet unknown or no longer preserved in the immediate study areas. Thus, they provide clues to paleoenvironments where such nesting sites occurred. PMID- 26741568 TI - Human parasites in the Roman World: health consequences of conquering an empire. AB - The archaeological evidence for parasites in the Roman era is presented in order to demonstrate the species present at that time, and highlight the health consequences for people living under Roman rule. Despite their large multi-seat public latrines with washing facilities, sewer systems, sanitation legislation, fountains and piped drinking water from aqueducts, we see the widespread presence of whipworm (Trichuris trichiura), roundworm (Ascaris lumbricoides) and Entamoeba histolytica that causes dysentery. This would suggest that the public sanitation measures were insufficient to protect the population from parasites spread by fecal contamination. Ectoparasites such as fleas, head lice, body lice, pubic lice and bed bugs were also present, and delousing combs have been found. The evidence fails to demonstrate that the Roman culture of regular bathing in the public baths reduced the prevalence of these parasites. Fish tapeworm was noted to be widely present, and was more common than in Bronze and Iron Age Europe. It is possible that the Roman enthusiasm for fermented, uncooked fish sauce (garum) may have facilitated the spread of this helminth. Roman medical practitioners such as Galen were aware of intestinal worms, explaining their existence and planning treatment using the humoural theory of the period. PMID- 26741569 TI - EEG maturation and stability of cerebral oxygen extraction in very low birth weight infants. AB - OBJECTIVE: Fractional cerebral tissue oxygen extraction (FTOE) can be continuously monitored by simultaneous near-infrared spectroscopy (NIRS) and pulse oximetry. The objective of this study is to test the hypothesis that in very low birth weight (VLBW) infants, the more mature EEG activity is, the less variable FTOE is. STUDY DESIGN: A prospective study was conducted on VLBW infants (< 1500 g and ? 34 weeks gestation) without significant brain injury. Simultaneous continuous two-channel electroencephalography (EEG), NIRS and pulse oximetry were recorded. Absolute and relative powers of EEG in the delta, theta, alpha, beta and total frequency bands have been calculated. FTOE variability was calculated on two scales: short scales (3 to 20 s) and long scales (20 to 150 s). FTOE variability was examined against changes in relative spectral power of different EEG bands. RESULT: We evaluated 67 studies performed on 46 VLBW infants. Average study duration was 21.3 +/- 5.5 h. Relative power of delta band positively correlated with FTOE short- and long-scale variability (r=0.45, P<0.001; r=0.44, P<0.001, respectively). Relative power of alpha bands negatively correlated with FTOE short- and long-scale variability (r=-0.38, P=0.002; r= 0.42, P<0.001, respectively). These correlations continued to be significant when controlling for sex, small for gestational age, postmenstrual age, being on respiratory support, hemoglobin concentration, systemic oxygen saturation and transcutaneous carbon dioxide tension. CONCLUSION: Increased maturation of EEG activity is associated with decreased variability in cerebral oxygen extraction. The implications of increased variability in FTOE on brain injury in premature infants need further exploration. PMID- 26741570 TI - Safety of donor milk: a brief report. AB - OBJECTIVE: To review the standard processing and testing of human donors and donor milk and to report the frequency of detected markers of potential harm. STUDY DESIGN: This was a retrospective analysis of the data gathered by a donor and human milk screening and monitoring process over a period of 3 years. RESULTS: Screening results from 2011 to the end of 2015 demonstrated that careful history taking resulted in rejection or hold of 29.7% of willing donor candidates. Individual infection screening tests rejected an additional 0.3-2.9 per 1000 donations. DNA fingerprinting of donations eliminated 2 out of 13 491. Drug testing rejected 42 out of 12 408 and dilution or adulteration eliminated 73 out of 4935 donations. Only the dilution rejection rate was significantly higher in the remunerated donors. The details of these results are presented. CONCLUSIONS: There are significant risks involved in the collection, processing and distribution of donor milk-based products. The behaviors of the donors, biochemical and genetic screening and milk processing are critical to mitigation of these recognized risks. Testing at this level of rigor appears to be justified. PMID- 26741572 TI - Primary cesarean section and adverse delivery outcomes among women of very advanced maternal age. AB - OBJECTIVE: To assess associations between primary cesarean delivery and adverse delivery outcomes with very advanced maternal age. STUDY DESIGN: We conducted a population-based cohort study including 78,880 births to mothers 25 years and older with singleton births from 2003 to 2012 using Washington State birth certificates and hospital discharge data, excluding births to women with a prior cesarean section. The primary outcome was mode of delivery. Secondary outcomes included maternal transfusion, chorioamnionitis, severe perineal lacerations and prolonged length of stay. Outcomes of births to women of advanced maternal age (35 to 39, 40 to 44) and very advanced maternal age (45 to 49, ?50) were compared with referent births among women aged 25 to 34 years. General linear models with a log-link function were used to calculate unadjusted and adjusted relative risks and 95% confidence intervals (CIs). RESULT: Proportions and risks of primary cesarean section increased with age (25 to 34 years, referent: 20.0%; 35 to 39 years: 25.9%, relative risk (RR)=1.25 (95% CI=1.20 to 1.29); 40 to 44 years: 30.9%, RR=1.45 (95% CI=1.40 to 1.50); 45 to 49 years: 35.7%, RR=1.59 (95% CI=1.45 to 1.75); and ?50 years: 60.7%, RR=2.44 (95% CI=1.95 to 3.05); P-trend <0.001). Associations did not differ between primiparous and multiparous women. No differences were noted for measures of maternal morbidity, except there was a trend of increasing risk of prolonged length of stay among births to older women (P-trend <0.001). CONCLUSION: Primary cesarean delivery risk continues to increase above age 35 regardless of prior vaginal birth, with the highest risk among women aged 50 years and older. PMID- 26741573 TI - Complications of percutaneous thoracostomy in neonates and infants. AB - OBJECTIVE: Percutaneous thoracostomy tubes are widely used in neonates, infants and children. The technique has a low complication rate. Lung perforation by a pigtail catheter is described in a single case report. STUDY DESIGN: This is a multi-center case series of neonates and infants who experienced thoracic organ injury following percutaneous chest tube placement between 2006 and 2015. RESULT: Eleven patients had chest tube-related thoracic organ injury. In six, tubes were placed during resuscitation. Gestational ages ranged from 24+6 weeks to term. Most of the chest tubes were pigtail catheters, and the most common injury was lung lobe perforation. Pericardium and mediastinum were also sites of injury. Some patients had small pleural effusions, with no other complications identified. CONCLUSION: Thoracic organ injury by percutaneous catheters may be more common than previously appreciated. Clinical and radiological findings are non-specific, and the diagnosis may not be apparent until autopsy. PMID- 26741571 TI - Breastmilk from obese mothers has pro-inflammatory properties and decreased neuroprotective factors. AB - OBJECTIVE: To determine the impact of maternal obesity on breastmilk composition. STUDY DESIGN: Breastmilk and food records from 21 lean and 21 obese women who delivered full-term infants were analyzed at 2 months post-partum. Infant growth and adiposity were measured at birth and 2 months of age. RESULT: Breastmilk from obese mothers had higher omega-6 to omega-3 fatty acid ratio and lower concentrations of docosahexaenoic acid, eicosapentaenoic acid, docasapentaenoic acid and lutein compared with lean mothers (P<0.05), which were strongly associated with maternal body mass index. Breastmilk saturated fatty acid and monounsaturated fatty acid concentrations were positively associated with maternal dietary inflammation, as measured by dietary inflammatory index. There were no differences in infant growth measurements. CONCLUSION: Breastmilk from obese mothers has a pro-inflammatory fatty acid profile and decreased concentrations of fatty acids and carotenoids that have been shown to have a critical role in early visual and neurodevelopment. Studies are needed to determine the link between these early-life influences and subsequent cardiometabolic and neurodevelopmental outcomes. PMID- 26741574 TI - Maternal and neonatal outcomes in obese women who lose weight during pregnancy. AB - OBJECTIVE: To evaluate neonatal and maternal outcomes in obese pregnant women whose weight gain differed from the Institute of Medicine (IOM) recommendations. STUDY DESIGN: Maternal and neonatal outcomes associated with weight change in pregnancy were retrospectively investigated in women with obesity (body mass index (BMI) ?30 kg m(-2); N=10734) who gave birth at 12 hospitals. Using a 1:1:1:1 design (n=778 matched groups), we matched women with obesity who lost, maintained, gained appropriate (IOM recommended) and gained excessive weight during pregnancy by gestational age at delivery, maternal age, race/ethnicity, prepregnancy BMI, chronic hypertension, pregestational diabetes and smoking status. Regression techniques were used to adjust for confounders and compare outcomes across weight change categories. RESULT: Compared with IOM recommendations, weight loss was associated with twofold greater odds of low birth weight infants and a mean decrease in estimated blood loss of 30 ml; excessive weight gain was associated with doubled odds of gestational hypertension or preeclampsia, fourfold greater odds of macrosomia and a mean decrease in 5-min APGAR of 0.09. From lost to excessively gained weight, the odds of cesarean delivery increased 1.4 times and mean infant birth weight increased by 197 g. In contrast, the odds of small-for-gestational age were 1.8 times greater for women who lost than gained excessive weight. CONCLUSION: Weight loss in obese pregnant women is associated with increased risk for low birth weight neonates but significantly decreased or maintained risk for other maternal and neonatal morbidities, as compared with appropriate or excessive weight gain. This study supports re-evaluation of the current IOM guidelines for women with obesity. PMID- 26741575 TI - Using very high frequencies with very low lung volumes during high-frequency oscillatory ventilation to protect the immature lung. A pilot study. AB - OBJECTIVE: High-frequency oscillatory ventilation (HFOV) has been described as a rescue therapy in severe respiratory distress syndrome (RDS) with a potential protective effect in immature lungs. In recent times, HFOV combined with the use of volume guarantee (VG) strategy has demonstrated an independent effect of the frequency on tidal volume to increase carbon-dioxide (CO2) elimination. The aim of this study was to demonstrate the feasibility of using the lowest tidal volume on HFOV+VG to prevent lung damage, maintaining a constant CO2 elimination by increasing the frequency. STUDY DESIGN: Newborn infants with RDS on HFOV were prospectively included. After adequate and stable ventilation using a standard HFOV strategy, the tidal volume was fixed using VG and decreased while the frequency was increased to the highest possible to maintain a constant CO2 elimination. Pre- and post-PCO2, delta pressure and tidal volume obtained in each situation were compared. RESULT: Twenty-three newborn infants were included. It was possible to increase the frequency while decreasing the tidal volume in all patients, maintaining a similar CO2 elimination, with a tendency to a lower mean PCO2 after reaching the highest frequency. High-frequency tidal volume was significantly lower, 2.20 ml kg(-1) before vs 1.59 ml kg(-1) at the highest frequency. CONCLUSION: It is possible to use lower delivered tidal volumes during HFOV combined with VG and higher frequencies with adequate ventilation to allow minimizing lung injury. PMID- 26741576 TI - Comparison of non-invasive vs invasive blood pressure measurement in neonates undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy. AB - OBJECTIVE: To evaluate the accuracy of blood pressure (BP) measured non invasively (NIBP) compared with invasive arterial BP (IABP) measured by umbilical arterial catheter in neonates undergoing therapeutic hypothermia (TH) for hypoxic ischemic encephalopathy (HIE). STUDY DESIGN: We conducted a retrospective study of neonates with gestational age (GA)?35 weeks with HIE who received TH. Paired NIBP and IABP measurements were obtained during TH and during normothermia. RESULT: We collected 897 paired measurements from 40 infants, which included 623 pairs during TH and 274 pairs during normothermia. The mean+/-s.d. differences in BP measured by NIBP compared with IABP in mmHg were -0.2+/-8.8 (P=0.505) for systolic BP (SBP), -4.5+/-8.3 (P<0.001) for diastolic BP (DBP) and -5.1+/-7.5 (P<0.001) for mean BP (MBP) during TH; and -1.3+/-9.2 (P=0.016) for SBP, -7.5+/ 7.8 (P<0.001) for DBP and -7.3+/-6.8 (P<0.001) for MBP during normothermia. Overall 466/623 (74.8%), 324/623 (52.0%) and 363/623 (58.3%) of NIBP measurements of SBP, DBP and MBP, respectively, were clinically acceptable (defined as difference ?15% of IABP reading) during TH; and 202/274 (73.7%), 118/274 (43.1%) and 148/274 (54.0%), were clinically acceptable during normothermia. CONCLUSION: In term or near-term neonates with HIE, NIBP measurements are a robust method to determine SBP; however, DBP and MBP are underestimated. Determination of hypotension using the MBP measured non-invasively should be interpreted with caution. PMID- 26741577 TI - Low-Dose Acetylsalicylic Acid Treatment and Impact on Short-Term Mortality in Staphylococcus aureus Bloodstream Infection: A Propensity Score-Matched Cohort Study. AB - OBJECTIVES: Staphylococcus aureus bloodstream infection is associated with considerable mortality. Experimental models suggest a direct antistaphylococcal effect of acetylsalicylic acid, but evidence from human studies is scarce. We aimed to estimate the effect of low-dose acetylsalicylic acid therapy on mortality in bloodstream infections caused by S. aureus compared with Escherichia coli. DESIGN: Retrospective cohort study based on observational data from 838 and 602 episodes of S. aureus and E. coli bloodstream infection, respectively. SETTING: Swiss tertiary referral center. PATIENTS: Adult patients with S. aureus and E. coli bloodstream infection, respectively, categorized according to low dose acetylsalicylic acid therapy as outpatient or inpatient before bacteremia. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty-day all-cause mortality was analyzed in a total of 314 propensity score-matched S. aureus bloodstream infection and in 268 E. coli bloodstream infection patients, respectively (1:1 match of low-dose acetylsalicylic acid users and nonusers). S. aureus bloodstream infection cases and controls were equally matched for relevant confounders except treatment with statins, which was strongly associated with a low-dose acetylsalicylic acid use (p < 0.001). At day 30, 12.1% of cases and 27.4% of controls had died (hazard ratio, 0.40; p < 0.001). Low-dose acetylsalicylic acid use was associated with a reduced 30-day all-cause mortality in multivariate analysis (hazard ratio, 0.38; 95% CI, 0.21-0.69; p = 0.001) of matched patients and also of the entire cohort (n = 689) after adjustment for the propensity score (hazard ratio, 0.58, 95% CI, 0.34-0.98; p = 0.04). In contrast, low-dose acetylsalicylic acid use was not associated with the primary endpoint in patients with E. coli bloodstream infection (hazard ratio, 0.78; 95% CI, 0.40 1.55; p = 0.8). CONCLUSIONS: Low-dose acetylsalicylic acid at the time of bloodstream infection was strongly associated with a reduced short-term mortality in patients with S. aureus bloodstream infection. Future studies are required to investigate if early low-dose acetylsalicylic acid is a suitable treatment in patients with S. aureus bloodstream infection. PMID- 26741578 TI - The Efficacy of Earplugs as a Sleep Hygiene Strategy for Reducing Delirium in the ICU: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: A systematic review and meta-analysis to assess the efficacy of earplugs as an ICU strategy for reducing delirium. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Central Register of controlled trials were searched using the terms "intensive care," "critical care," "earplugs," "sleep," "sleep disorders," and "delirium." STUDY SELECTION: Intervention studies (randomized or nonrandomized) assessing the efficacy of earplugs as a sleep hygiene strategy in patients admitted to a critical care environment were included. Studies were excluded if they included only healthy volunteers, did not report any outcomes of interest, did not contain an intervention group of interest, were crossover studies, or were only published in abstract form. DATA EXTRACTION: Nine studies published between 2009 and 2015, including 1,455 participants, fulfilled the eligibility criteria and were included in the systematic review. Studies included earplugs as an isolated intervention (n = 3), or as part of a bundle with eye shades (n = 2), or earplugs, eye shades, and additional sleep noise abatement strategies (n = 4). The risk of bias was high for all studies. DATA SYNTHESIS: Five studies comprising 832 participants reported incident delirium. Earplug placement was associated with a relative risk of delirium of 0.59 (95% CI, 0.44 0.78) and no significant heterogeneity between the studies (I, 39%; p = 0.16). Hospital mortality was reported in four studies (n = 481) and was associated with a relative risk of 0.77 (95% CI, 0.54-1.11; I, 0%; p < 0.001). Compliance with the placement of earplugs was reported in six studies (n = 681). The mean per patient noncompliance was 13.1% (95% CI, 7.8-25.4) of those assigned to receive earplugs. CONCLUSIONS: Placement of earplugs in patients admitted to the ICU, either in isolation or as part of a bundle of sleep hygiene improvement, is associated with a significant reduction in risk of delirium. The potential effect of cointerventions and the optimal strategy for improving sleep hygiene and associated effect on patient-centered outcomes remains uncertain. PMID- 26741579 TI - Predicting Fluid Responsiveness by Passive Leg Raising: A Systematic Review and Meta-Analysis of 23 Clinical Trials. AB - OBJECTIVE: Passive leg raising creates a reversible increase in venous return allowing for the prediction of fluid responsiveness. However, the amount of venous return may vary in various clinical settings potentially affecting the diagnostic performance of passive leg raising. Therefore we performed a systematic meta-analysis determining the diagnostic performance of passive leg raising in different clinical settings with exploration of patient characteristics, measurement techniques, and outcome variables. DATA SOURCES: PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and citation tracking of relevant articles. STUDY SELECTION: Clinical trials were selected when passive leg raising was performed in combination with a fluid challenge as gold standard to define fluid responders and non-responders. DATA EXTRACTION: Trials were included if data were reported allowing the extraction of sensitivity, specificity, and area under the receiver operating characteristic curve. DATA SYNTHESIS: Twenty-three studies with a total of 1,013 patients and 1,034 fluid challenges were included. The analysis demonstrated a pooled sensitivity of 86% (95% CI, 79-92), pooled specificity of 92% (95% CI, 88-96), and a summary area under the receiver operating characteristic curve of 0.95 (95% CI, 0.92-0.98). Mode of ventilation, type of fluid used, passive leg raising starting position, and measurement technique did not affect the diagnostic performance of passive leg raising. The use of changes in pulse pressure on passive leg raising showed a lower diagnostic performance when compared with passive leg raising-induced changes in flow variables, such as cardiac output or its direct derivatives (sensitivity of 58% [95% CI, 44-70] and specificity of 83% [95% CI, 68-92] vs sensitivity of 85% [95% CI, 78-90] and specificity of 92% [95% CI, 87-94], respectively; p < 0.001). CONCLUSIONS: Passive leg raising retains a high diagnostic performance in various clinical settings and patient groups. The predictive value of a change in pulse pressure on passive leg raising is inferior to a passive leg raising-induced change in a flow variable. PMID- 26741581 TI - Acute Disseminated Encephalomyelitis After Human Parechovirus Infection. AB - BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is an inflammatory, demyelinating disease occurring several weeks after viral infection. Enteroviruses have been described as potential triggers of ADEM, but the closely related parechoviruses have not. The objective of the study is to assess the prevalence and disease presentation of ADEM after parechovirus infection in a syndromic surveillance program for pediatric infection/inflammation of the central nervous system (CNS). METHODS: The surveillance was conducted at the Charite Department of Pediatrics in Berlin, Germany, from November 2010 to November 2014. All hospitalized children meeting predefined case criteria underwent highly standardized prospective clinical assessments based on the published case definitions, including for ADEM. Stool samples were independently analyzed by enterovirus and parechovirus real-time polymerase chain reaction at the Robert Koch Institute. RESULTS: Of 105,557 patients screened, 774 (0.7%) fulfilled entry criteria for CNS infection/inflammation, with 114 cases ascertained as ADEM. Parechoviruses were detected in 2.5% of patients with CNS infection/inflammation, including 1 case fulfilling ADEM case criteria with the highest level of diagnostic certainty. CONCLUSIONS: We report a first case of ADEM after parechovirus infection in a 5-year-old female presenting with acute hemiparesis 2 weeks after a respiratory illness. Parechovirus disease should be included in the differential diagnosis of ADEM. PMID- 26741580 TI - Impact of Initial Central Venous Pressure on Outcomes of Conservative Versus Liberal Fluid Management in Acute Respiratory Distress Syndrome. AB - OBJECTIVES: In acute respiratory distress syndrome, conservative fluid management increases ventilator-free days without affecting mortality. Response to fluid management may differ based on patients' initial central venous pressure. We hypothesized that initial central venous pressure would modify the effect of fluid management on outcomes. DESIGN: Retrospective analysis of the Fluid and Catheter Treatment Trial, a multicenter randomized trial comparing conservative with liberal fluid management in acute respiratory distress syndrome. We examined the relationship between initial central venous pressure, fluid strategy, and 60 day mortality in univariate and multivariable analysis. SETTING: Twenty acute care hospitals. PATIENTS: Nine hundred thirty-four ventilated acute respiratory distress syndrome patients with a central venous pressure available at enrollment, 609 without baseline shock (for whom fluid balance was managed by the study protocol). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among patients without baseline shock, those with initial central venous pressure greater than 8 mm Hg experienced similar mortality with conservative and liberal fluid management (18% vs 18%; p = 0.928), whereas those with central venous pressure of 8 mm Hg or less experienced lower mortality with a conservative strategy (17% vs 36%; p = 0.005). Multivariable analysis demonstrated an interaction between initial central venous pressure and the effect of fluid strategy on mortality (p = 0.031). At higher initial central venous pressures, the difference in treatment between arms was predominantly furosemide administration, which was not associated with mortality (p = 0.122). At lower initial central venous pressures, the difference between arms was predominantly fluid administration, with additional fluid associated with increased mortality (p = 0.013). CONCLUSIONS: Conservative fluid management decreases mortality for acute respiratory distress syndrome patients with a low initial central venous pressure. In this population, the administration of IV fluids seems to increase mortality. PMID- 26741582 TI - Respiratory Infections by Enterovirus D68 in Outpatients and Inpatients Spanish Children. AB - BACKGROUND: The incidence of enterovirus D68 (EV-D68) and the spectrum of clinical disease in children are not well known in European countries. We have designed a study with the objective of describing the clinical impact of EV-D68 detected in children with respiratory tract infections. METHODS: As a part of a prospective study to identify the etiology and clinical characteristics of viral respiratory infections in children in Spain, we performed the analysis of the cases of EV infections in all children hospitalized in a secondary hospital in Madrid, during the epidemic respiratory season 2012-2013. A second group of samples was corresponded to infants of the same area, with ambulatory respiratory infection or asymptomatic. Phylogenetic EV-D68 analysis was made using the viral protein 1 gene (VP1). Clinical data of EV-D68 patients were compared with those infected by rhinovirus in the same period and population. RESULTS: The study population consisted of 720 patients corresponding to 399 episodes of hospitalization for respiratory causes, 44 episodes of ambulatory respiratory infections and 277 children determined as a healthy control group. A total of 22 patients were positive for EVs (3.05%), and 12 of them were specifically typed as EV-D68 (11/443 respiratory infections, 2.5%). The most frequent diagnosis in the 10 hospitalized children with EV-D68 detection was recurrent wheezing. Hypoxia was present in 70% of cases, but admission in the intensive care unit was not required. No neurological signs or symptoms were observed. One patient had an ambulatory mild bronchiolitis and another was asymptomatic. No differences were found with rhinovirus infections except less duration of hypoxia and fever in EV D68 group. CONCLUSIONS: EV-D68 infections were detected in 3.05% of respiratory studied samples (2.5% of admissions). The infection was associated with wheezing episodes with hypoxia. No admissions to intensive care unit or neurological symptoms were found. PMID- 26741584 TI - Blood Cultures in Cellulitis are not Cost Effective and Should Prompt Investigation for an Alternative Focus. PMID- 26741583 TI - In Utero Exposure to Antiretroviral Drugs: Effect on Birth Weight and Growth Among HIV-exposed Uninfected Children in Brazil. AB - BACKGROUND: There are concerns about the effects of in utero exposure to antiretroviral drugs (ARVs) on the development of HIV-exposed but uninfected (HEU) children. The aim of this study was to evaluate whether in utero exposure to ARVs is associated with lower birth weight/height and reduced growth during the first 2 years of life. METHODS: This cohort study was conducted among HEU infants born between 1996 and 2010 in Tertiary children's hospital in Rio de Janeiro, Brazil. Weight was measured by mechanical scale, and height was measured by measuring board. Z-scores for weight-for-age (WAZ), length-for-age (LAZ) and weight-for-length were calculated. We modeled trajectories by mixed-effects models and adjusted for mother's age, CD4 cell count, viral load, year of birth and family income. RESULTS: A total of 588 HEU infants were included of whom 155 (26%) were not exposed to ARVs, 114 (19%) were exposed early (first trimester) and 319 (54%) later. WAZ were lower among infants exposed early compared with infants exposed later: adjusted differences were -0.52 (95% confidence interval [CI]: -0.99 to -0.04, P = 0.02) at birth and -0.22 (95% CI: -0.47 to 0.04, P = 0.10) during follow-up. LAZ were lower during follow-up: -0.35 (95% CI: -0.63 to 0.08, P = 0.01). There were no differences in weight-for-length scores. Z-scores of infants exposed late during pregnancy were similar to unexposed infants. CONCLUSIONS: In HEU children, early exposure to ARVs was associated with lower WAZ at birth and lower LAZ up to 2 years of life. Growth of HEU children needs to be monitored closely. PMID- 26741585 TI - Aeromonas Associated With Swimming Pool Folliculitis. PMID- 26741586 TI - Parental Reasons for Acceptance or Refusal of Human Papillomavirus Vaccine in a Southern California Pediatric Practice. PMID- 26741587 TI - Saksenaeae Subcutaneous Abscess in an Immunocompetent Child. PMID- 26741588 TI - Helicobacter pylori Associated With Pulmonary Hemosiderosis. PMID- 26741636 TI - Role of Acid Sphingomyelinase-Induced Signaling in Melanoma Cells for Hematogenous Tumor Metastasis. AB - BACKGROUND: Hematogenous metastasis of malignant tumor cells is a multistep process that requires release of tumor cells from the local tumor mass, interaction of the tumor cells with platelets in the blood, and adhesion of either the activated tumor cells or the complexes of platelets and tumor cells to the endothelial cells of the target organ. We have previously shown that the interaction of melanoma cells with platelets results in the release of acid sphingomyelinase (Asm) from activated platelets. Secreted platelet-derived Asm acts on malignant tumor cells to cluster and activate integrins; such clustering and activation are necessary for tumor cell adhesion to endothelial cells and for metastasis. METHODS: We examined the response of tumor cells to treatment with extracellular sphingomyelinase or co-incubation with wild-type and Asm-deficient platelets. We determined the phosphorylation and activation of several intracellular signaling molecules, in particular p38 kinase (p38K), phospholipase Cx03B3; (PLCx03B3;), ezrin, and extracellular signal-regulated kinases. RESULTS: Incubation of B16F10 melanoma cells with Asm activates p38 MAP kinase (p38K), phospholipase Cx03B3; (PLCx03B3;), ezrin, and extracellular signal-regulated kinases. Co-incubation of B16F10 melanoma cells with wild-type or Asm-deficient platelets showed that the phosphorylation/activation of p38K is dependent on Asm. Pharmacological blockade of p38K prevents activation of beta1 integrin and adhesion in vitro. Most importantly, inhibition of p38K activity in B16F10 melanoma cells prevents tumor cell adhesion and metastasis to the lung in vivo, a finding indicating the importance of p38K for metastasis. CONCLUSIONS: Asm, secreted from activated platelets after tumor cell-platelet contact, induces p38K phosphorylation in tumor cells. This in turn stimulates beta1 integrin activation that is necessary for adhesion and subsequent metastasis of tumor cells. Thus, inhibition of p38K might be a novel target to prevent tumor metastasis. PMID- 26741589 TI - Stimulant Medications and Cognition, Behavior and Quality of Life in Children and Youth with HIV. AB - BACKGROUND: Limited empirical investigation exists into longitudinal changes in cognition, behavior or quality of life (QOL) in children with perinatal HIV who are prescribed stimulants. METHODS: This study was an analysis of longitudinal data from children age 3-19 years, with perinatal HIV infection, with and without prescriptions for stimulant medications [prescription (PG) and comparison (CG) groups, respectively], matched on age, availability of CD4% and outcome measures of cognition, behavior and QOL. Generalized estimating equation models were used to evaluate effects of stimulant exposure on change in measured outcomes over 3 years of follow-up, adjusting for baseline levels of outcomes and relevant covariates. RESULTS: Children in both the PG (n = 132) and the CG (n = 392) obtained mean verbal and performance (nonverbal) intelligence quotients (VIQ and PIQ, respectively) in the low-average range for age. At baseline, those in PG demonstrated more frequent signs of hyperactivity, impulsivity and conduct and learning problems than those in CG (P <= 0.003 in unadjusted analyses). At follow up, after adjustment for baseline functioning and other relevant covariates, there were no significant changes from baseline in VIQ or PIQ. Stimulant prescription use, however, was associated with worsening symptoms of hyperactivity (P = 0.01), impulsivity (P = 0.04), learning problems (P < 0.001) and worsening of perceived health status (P < 0.001). CONCLUSIONS: The results suggest expectations for behavioral improvement may not align well with long-term effects of stimulant prescription use on behavior and QOL in children with HIV. Further research is necessary to determine if there are subsets of children who may benefit from stimulant therapy. PMID- 26741637 TI - Could serotonin be a potential marker for hepatocellular carcinoma? A prospective single-center observational study. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality among men worldwide. Serotonin is a biogenic amine, which may be involved in the tumorigenesis of HCC. AIM: We aimed to determine whether serotonin is a dependable marker for the diagnosis of HCC in cirrhotic patients in comparison with alpha-fetoprotein protein (AFP) and prothrombin induced by vitamin K absence-II (PIVKA-II). PATIENTS AND METHODS: Serum serotonin, AFP, and PIVKA-II were measured in 262 patients with chronic hepatitis C (CHC): 82 cirrhotic patients with HCC (group I), 80 cirrhotic patients without HCC (group II), and 100 CHC-infected patients without cirrhosis (group III); in addition, 60 healthy controls were studied (group IV). RESULTS: AFP showed significant statistical differences among the groups studied (P<0.001). PIVKA-II and serotonin levels showed no statistically significant differences between the patients with CHC group and the healthy controls (P1=0.614 and P1=0.13, respectively), whereas their levels were statistically higher in cirrhotic patients than patients with CHC (all P values <0.001) and in the cirrhotic patients with HCC group than the cirrhotic patients without HCC (P<0.001). A significant positive correlation was found between serum serotonin and AFP (rho=0.794; P<0.001) and serum serotonin and PIVKA-II (rho=0.889; P<0.001) among the patient groups. The receiver operator characteristic curve showed a higher area under the curve for serotonin than AFP and PIVKA-II (0.942, 0.824, and 0.921, respectively). CONCLUSION: Serotonin may be used together with PIVKA-II to screen for HCC in cirrhotic patients with CHC. PMID- 26741638 TI - Patterned Thermoresponsive Microgel Surfaces to Control Cell Detachment. AB - The aim of this work is to examine how adhered individual cells could detach from the patterned, discontinuous thermoresponsive coating substrate and how different patterns in the form of thermoresponsive squares and gaps would affect cell detachment. Microgels prepared from copolymerization of N-isopropylacrylamide and styrene (pNIPAAmSt) were spin-coated on polyethylenimine (PEI) precoated glass coverslips to form a uniform microgel monolayer; then a surface-moisturized PMDS stamp was used to contact the microgel monolayer at room temperature. The thin layer of water on the PDMS stamp surface worked as an ink to penetrate the microgels so that any microgels in direct contact with the wet stamp surface became swollen and could be peeled away, while uncontacted microgels formed patterns. Using this method, various patterns with different thermo-island diameters and gaps could be fabricated. NIH3T3 fibroblast cells were then cultured on these patterns to study their detachment behavior. It was found that cells could detach not only from these discontinuous thermoresponsive coatings, but also from the patterned surfaces with the thermoresponsive area being as low as 20% of the cell spread area. PMID- 26741639 TI - Gaining Control over Radiolytic Synthesis of Uniform Sub-3-nanometer Palladium Nanoparticles: Use of Aromatic Liquids in the Electron Microscope. AB - Synthesizing nanomaterials of uniform shape and size is of critical importance to access and manipulate the novel structure-property relationships arising at the nanoscale, such as catalytic activity. In this work, we synthesize Pd nanoparticles with well-controlled size in the sub-3 nm range using scanning transmission electron microscopy (STEM) in combination with an in situ liquid stage. We use an aromatic hydrocarbon (toluene) as a solvent that is very resistant to high-energy electron irradiation, which creates a net reducing environment without the need for additives to scavenge oxidizing radicals. The primary reducing species is molecular hydrogen, which is a widely used reductant in the synthesis of supported metal catalysts. We propose a mechanism of particle formation based on the effect of tri-n-octylphosphine (TOP) on size stabilization, relatively low production of radicals, and autocatalytic reduction of Pd(II) compounds. We combine in situ STEM results with insights from in situ small-angle X-ray scattering (SAXS) from alcohol-based synthesis, having similar reduction potential, in a customized microfluidic device as well as ex situ bulk experiments. This has allowed us to develop a fundamental growth model for the synthesis of size-stabilized Pd nanoparticles and demonstrate the utility of correlating different in situ and ex situ characterization techniques to understand, and ultimately control, metal nanostructure synthesis. PMID- 26741640 TI - Sequencing of DNA Lesions Facilitated by Site-Specific Excision via Base Excision Repair DNA Glycosylases Yielding Ligatable Gaps. AB - Modifications to nucleotides in the genome can lead to mutations or are involved in regulation of gene expression, and therefore, finding the site of modification is a worthy goal. Robust methods for sequencing modification sites on commercial sequencers have not been developed beyond the epigenetic marks on cytosine. Herein, a method to sequence DNA modification sites was developed that utilizes DNA glycosylases found in the base excision repair pathway to excise the modification. This approach yields a gap at the modification site that is sealed by T4-DNA ligase, yielding a product strand missing the modification. Upon sequencing, the modified nucleotide is reported as a deletion mutation, identifying its location. This approach was used to detect a uracil (U) or 8-oxo 7,8-dihydroguanine (OG) in codon 12 of the KRAS gene in synthetic oligodeoxynucleotides. Additionally, an OG modification site was placed in the VEGF promoter in a plasmid and sequenced. This method requires only commercially available materials and can be put into practice on any sequencing platform, allowing this method to have broad potential for finding modifications in DNA. PMID- 26741641 TI - Combined Percutaneous Iliosacral Screw Fixation With Sacroplasty Using Resorbable Calcium Phosphate Cement for Osteoporotic Pelvic Fractures Requiring Surgery. AB - Osteoporotic sacral fractures, including acute and chronic insufficiency fractures, are increasing in frequency and present a number of management problem. Many of these patients are treated nonoperatively with relative immobility (eg, bedrest, wheelchair, or weight-bearing restrictions) and analgesics, which likely make the osteoporotic component worse. Surgery in this patient population may be desirable in some cases with the goals of improving mobility, relieving pain, and healing in an aligned position while minimizing deformity progression. However, internal fixation of the osteoporotic pelvis can be difficult. Large unicortical lag screws are the workhorse of posterior pelvic fixation, and yet fixation in cancellous bone corridors of an osteoporotic sacrum seems unlikely to achieve optimal fixation. As a result, the operative management and clinical results of these difficult injuries may not be uniformly successful. The authors present a technique for treating osteoporotic patients with a sacral fracture when operative treatment is indicated using percutaneous screw fixation combined with screw augmentation using a resorbable calcium phosphate bone substitute or "cement." The guide wire for a 7.3-mm or other large cannulated lag screw is fully inserted along the desired bony sacral corridor as is standard. The lag screw is then inserted over the wire to the depth where cement is desired. The guide wire is removed, and the aqueous calcium phosphate is injected through the screw's cannulation. For acute fractures, cement was applied to the areas distant to the fracture; whereas in insufficiency fractures, the cement was inserted along most of the screw path. The guide wire then can be reinserted and the lag screw fully inserted. The rationale for using these 2 modalities is their synergistic effect: the cannulated screw provides typical screw fixation and also a conduit for cement application. The cement augments the lag screw's purchase in osteoporotic bone, enhancing fixation strength. The authors propose that combining percutaneous screw fixation with calcium phosphate augmentation may provide an improved biomechanical environment for healing of these difficult fractures that might translate into earlier mobility, better pain control, and improved outcomes. PMID- 26741642 TI - Can Thrombelastography Predict Venous Thromboembolic Events in Patients With Severe Extremity Trauma? AB - OBJECTIVES: An elevated maximal amplitude (mA) value with rapid thrombelastography on admission can identify general trauma patients with an increased risk of venous thromboembolic events (VTEs). We hypothesized that (1) the risk of VTE traditionally assigned to injury lies specifically in those who sustain major orthopaedic trauma and (2) an elevated admission mA value could be used to identify patients with major orthopaedic injuries at risk for VTE during initial hospital admission. DESIGN: Retrospective. SETTING: University level 1 trauma center. PATIENTS/PARTICIPANTS: Consecutive trauma patients admitted to an urban level 1 trauma center between September 2009 and February 2011 who met the criteria for level 1 trauma activation and who were between 18 and 85 years of age were included in our study group. Two groups were created, one whose extremity abbreviated injury severity score was 2 or greater (ORTHO) and the other whose extremity abbreviated injury severity score was <2 (non-ORTHO). MAIN OUTCOME MEASUREMENTS: Pulmonary emboli were confirmed by computed tomography angiography, and deep vein thromboses were confirmed by venous duplex. Univariate analyses were conducted and followed by purposeful regression analysis. RESULTS: Of note, 1818 patients met the inclusion criteria (310 ORTHO and 1508 non-ORTHO). Despite more hypocoagulable r-TEG values on arrival (alpha angle 71 vs. 73 and mA 62 vs. 64, both P < 0.05), ORTHO patients had higher rates of VTE (6.5% vs. 2.7%, P < 0.001). Stepwise regression generated 4 values to predict development of VTE (age, male gender, white race, and ORTHO). After controlling for these variables, admission mA values >=65 (odds ratio 3.66) and >=72 (odds ratio 6.70) were independent predictors of VTEs during hospitalization. CONCLUSIONS: Admission rapid thrombelastography mA values can identify patients with major orthopaedic trauma injuries who present with an increased risk of in-hospital deep vein thromboses and pulmonary embolism with a 3.6-fold and 6.7-fold increased risk for mA values >=65 and >=72, respectively. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 26741643 TI - Early Appropriate Care: A Protocol to Standardize Resuscitation Assessment and to Expedite Fracture Care Reduces Hospital Stay and Enhances Revenue. AB - OBJECTIVES: We hypothesized that a standardized protocol for fracture care would enhance revenue by reducing complications and length of stay. DESIGN: Prospective consecutive series. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Two hundread and fifty-three adult patients with a mean age of 40.7 years and mean Injury Severity Score of 26.0. INTERVENTION: Femur, pelvis, or spine fractures treated surgically. MAIN OUTCOME MEASUREMENTS: Hospital and professional charges and collections were analyzed. Fixation was defined as early (<36 hours) or delayed. Complications and hospital stay were recorded. RESULTS: Mean charges were US $180,145 with a mean of US $66,871 collected (37%). The revenue multiplier was US $59,882/$6989 (8.57), indicating hospital collection of US $8.57 for every professional dollar, less than half of which went to orthopaedic surgeons. Delayed fracture care was associated with more intensive care unit (4.5 vs. 9.4) and total hospital days (9.4 vs. 15.3), with mean loss of actual revenue US $6380/patient delayed (n = 47), because of the costs of longer length of stay. Complications were associated with the highest expenses: mean of US $291,846 charges and US $101,005 collections, with facility collections decreased by 5.1%. An uncomplicated course of care was associated with the most favorable total collections: (US $60,017/$158,454 = 38%) and the shortest mean stay (8.7 days). CONCLUSIONS: Facility collections were nearly 9 times more than professional collections. Delayed fixation was associated with more complications, and facility collections decreased 5% with a complication. Furthermore, delayed fixation was associated with longer hospital stay, accounting for US $300K more in actual costs during the study. A standardized protocol to expedite definitive fixation enhances the profitability of the trauma service line. LEVEL OF EVIDENCE: Economic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26741645 TI - Activating "Invisible" Glue: Using Electron Beam for Enhancement of Interfacial Properties of Graphene-Metal Contact. AB - Interfacial contact of two-dimensional graphene with three-dimensional metal electrodes is crucial to engineering high-performance graphene-based nanodevices with superior performance. Here, we report on the development of a rapid "nanowelding" method for enhancing properties of interface to graphene buried under metal electrodes using a focused electron beam induced deposition (FEBID). High energy electron irradiation activates two-dimensional graphene structure by generation of structural defects at the interface to metal contacts with subsequent strong bonding via FEBID of an atomically thin graphitic interlayer formed by low energy secondary electron-assisted dissociation of entrapped hydrocarbon contaminants. Comprehensive investigation is conducted to demonstrate formation of the FEBID graphitic interlayer and its impact on contact properties of graphene devices achieved via strong electromechanical coupling at graphene metal interfaces. Reduction of the device electrical resistance by ~50% at a Dirac point and by ~30% at the gate voltage far from the Dirac point is obtained with concurrent improvement in thermomechanical reliability of the contact interface. Importantly, the process is rapid and has an excellent insertion potential into a conventional fabrication workflow of graphene-based nanodevices through single-step postprocessing modification of interfacial properties at the buried heterogeneous contact. PMID- 26741646 TI - Interacting Superparamagnetic Iron(II) Oxide Nanoparticles: Synthesis and Characterization in Ionic Liquids. AB - Interacting superparamagnetic iron(II) oxide nanoparticles (NPs) with sizes of 5.3 +/- 1.6 nm were prepared by simple decomposition of [Fe(COT)2] (COT = 1,3,5,7 cyclooctatetraene) with 5 bar of H2 in 1-n-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide (BMI.NTf2) ionic liquid (IL). The static and dynamic magnetic characterization revealed a superparamagnetic behavior with weak dipolar interactions of these NPs. In situ structural studies by X-ray absorption spectroscopy demonstrated that they consist of nanostructured FeO. This approach is an appropriate method to prepare and stabilize nanostructured FeO particles, where the presence of an IL proved to be fundamental to suppress the aggregation and usual overoxidation of the FeO NPs. PMID- 26741647 TI - The efficacy of acupuncture in managing patients with chronic prostatitis/chronic pelvic pain syndrome: A systemic review and meta-analysis. AB - OBJECTIVES: This study aimed to systemically review published randomized control trials that compared the efficacy of acupuncture with sham acupuncture or standard medical treatment as management for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: A systemic search of the PubMED(r), Embase, Airiti Library, and China Journal Net was done for all randomized controlled trials that compared the efficacy of acupuncture with sham acupuncture, alpha blockers, antibiotics, or anti-inflammatory drugs in patients with CP/CPPS. Two investigators conducted the literature search, quality assessment, and data extraction. The data were then analyzed using the Cochrane Collaboration Review Manager (RevMan(r), version 5.3). The study endpoints were response rate, the National Institute of Health-Chronic Prostatitis Index (NIH-CPSI), and the International Prostate symptom score (IPSS) reduction. RESULTS: Three and four randomized controlled trials compared acupuncture with sham acupuncture (n = 101 vs. 103) and medical treatment (n = 156 vs. 138), respectively. The results revealed that acupuncture was superior to sham acupuncture as regards response rate (OR: 5.15, 95%CI: 2.72-9.75; P < 0.01), NIH-CPSI (WMD: -6.09, 95%CI: -7.85 to -4.33), and IPSS (WMD: -2.44, 95%CI: -4.86 to -0.03; P = 0.05) reductions, therefore, excluding the placebo effect. Compared to standard medical treatments, acupuncture had a significantly higher response rate (OR: 3.57, 95%CI: 1.78-7.15; P < 0.01). CONCLUSIONS: Acupuncture has promising efficacy for patients with CP/CPPS. Compared to standard medical treatment, it has better efficacy. Thus, it may also serve as a standard treatment option when available. Neurourol. Urodynam. 36:474-481, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26741648 TI - An Improved Quantitative Real-Time PCR Assay for the Enumeration of Heterosigma akashiwo (Raphidophyceae) Cysts Using a DNA Debris Removal Method and a Cyst Based Standard Curve. AB - The identification and quantification of Heterosigma akashiwo cysts in sediments by light microscopy can be difficult due to the small size and morphology of the cysts, which are often indistinguishable from those of other types of algae. Quantitative real-time PCR (qPCR) based assays represent a potentially efficient method for quantifying the abundance of H. akashiwo cysts, although standard curves must be based on cyst DNA rather than on vegetative cell DNA due to differences in gene copy number and DNA extraction yield between these two cell types. Furthermore, qPCR on sediment samples can be complicated by the presence of extracellular DNA debris. To solve these problems, we constructed a cyst-based standard curve and developed a simple method for removing DNA debris from sediment samples. This cyst-based standard curve was compared with a standard curve based on vegetative cells, as vegetative cells may have twice the gene copy number of cysts. To remove DNA debris from the sediment, we developed a simple method involving dilution with distilled water and heating at 75 degrees C. A total of 18 sediment samples were used to evaluate this method. Cyst abundance determined using the qPCR assay without DNA debris removal yielded results up to 51-fold greater than with direct counting. By contrast, a highly significant correlation was observed between cyst abundance determined by direct counting and the qPCR assay in conjunction with DNA debris removal (r2 = 0.72, slope = 1.07, p < 0.001). Therefore, this improved qPCR method should be a powerful tool for the accurate quantification of H. akashiwo cysts in sediment samples. PMID- 26741649 TI - Complete Preoperative Evaluation of Pulmonary Atresia with Ventricular Septal Defect with Multi-Detector Computed Tomography. AB - OBJECTIVE: To compare multi-detector computed tomography (MDCT) with cardiac catheterization and transthoracic echocardiography (TTE) in comprehensive evaluation of the global cardiovascular anatomy in patients with pulmonary atresia with ventricular septal defect (PA-VSD). METHODS: The clinical and imaging data of 116 patients with PA-VSD confirmed by surgery were reviewed. Using findings at surgery as the reference standard, data from MDCT, TTE and catheterization were reviewed for assessment of native pulmonary vasculature and intracardiac defects. RESULTS: MDCT was more accurate than catheterization and TTE in identification of native pulmonary arteries. MDCT is also the most accurate test for delineation of the major aortopulmonary collateral arteries. The inter-modality agreement for evaluation of overriding aorta and VSD were both excellent. In the subgroup with surgical correlation, excellent agreement was found between TTE and surgery, and substantial agreement was also found at MDCT. CONCLUSION: MDCT can correctly delineate the native pulmonary vasculatures and intracardiac defects and may be a reliable method for noninvasive assessment of global cardiovascular abnormalities in patients with PA-VSD. PMID- 26741650 TI - Discrete Molecular Recognition Induced Higher-Order Structures: Fibrous Formation Triggered by Melamine Recognition with a Cationic Ethynylpyridine Macrocyclic Host. AB - A tricationic shape-persistent macrocycle was obtained by methylation on the nitrogen atoms of the three 3,5-pyridylene groups of an alternating 2,6-/3,5 substituted ethynylpyridine macrocycle. The tricationic macrocycle recognized melamine in polar solvents such as DMSO and water, and the host-guest association in water induced a higher-order aggregate confirmed by UV-vis titration and dynamic light scattering experiments. Scanning electron microscopy, transmission electron microscopy, and atomic force microscopy indicated that fibrous network structures resulted from the stacking of the macrocycle and melamine complex. PMID- 26741651 TI - Viral Reservoirs in Lymph Nodes of FIV-Infected Progressor and Long-Term Non Progressor Cats during the Asymptomatic Phase. AB - BACKGROUND: Examination of a cohort of cats experimentally infected with feline immunodeficiency virus (FIV) for 5.75 years revealed detectable proviral DNA in peripheral blood mononuclear cells (PBMCs) harvested during the asymptomatic phase, undetectable plasma viral RNA (FIV gag), and rarely detectable cell associated viral RNA. Despite apparent viral latency in peripheral CD4+ T cells, circulating CD4+ T cell numbers progressively declined in progressor animals. The aim of this study was to explore this dichotomy of peripheral blood viral latency in the face of progressive immunopathology. The viral replication status, cellular immunophenotypes, and histopathologic features were compared between popliteal lymph nodes (PLNs) and peripheral blood. Also, we identified and further characterized one of the FIV-infected cats identified as a long-term non progressor (LTNP). RESULTS: PLN-derived leukocytes from FIV-infected cats during the chronic asymptomatic phase demonstrated active viral gag transcription and FIV protein translation as determined by real-time RT-PCR, Western blot and in situ immunohistochemistry, whereas viral RNA in blood leukocytes was either undetectable or intermittently detectable and viral protein was not detected. Active transcription of viral RNA was detectable in PLN-derived CD4+ and CD21+ leukocytes. Replication competent provirus was reactivated ex vivo from PLN derived leukocytes from three of four FIV-infected cats. Progressor cats showed a persistent and dramatically decreased proportion and absolute count of CD4+ T cells in blood, and a decreased proportion of CD4+ T cells in PLNs. A single long term non-progressor (LTNP) cat persistently demonstrated an absolute peripheral blood CD4+ T cell count indistinguishable from uninfected animals, a lower proviral load in unfractionated blood and PLN leukocytes, and very low amounts of viral RNA in the PLN. CONCLUSION: Collectively our data indicates that PLNs harbor important reservoirs of ongoing viral replication during the asymptomatic phase of infection, in spite of undetectable viral activity in peripheral blood. A thorough understanding of tissue-based lentiviral reservoirs is fundamental to medical interventions to eliminate virus or prolong the asymptomatic phase of FIV infection. PMID- 26741653 TI - H2 Photogeneration Using a Phosphonate-Anchored Ni-PNP Catalyst on a Band-Edge Modified p-Si(111)|AZO Construct. AB - We report the fabrication of a {semiconductor}|{metal oxide}|{molecular catalyst} construct for the photogeneration of dihydrogen (H2) under illumination, including band-edge modulation of the semiconductor electrode depending on the identity of Si(111)-R and the metal oxide. Briefly, a synergistic band-edge modulation is observed upon (i) the introduction of a p-Si|n-AZO heterojunction and (ii) introduction of an organic dimethoxyphenyl (diMeOPh) group at the heterojunction interface; the AZO also serves as a transparent and conductive conduit, which was capped with an ultrathin layer (20 A) of amorphous TiO2 for stability. A phosphonate-appended PNP ligand and its Ni complex were then adsorbed to the p/n heterojunction for photoelectrochemical H2 generation (figures of merit: Vonset ~ + 0.03 V vs NHE, Jmax ~ 8 mA cm(-2) at 60 mM TsOH). PMID- 26741654 TI - Fisetin-Rich Extracts of Rhus verniciflua Stokes Improve Blood Flow Rates in Mice Fed Both Normal and High-Fat Diets. AB - Although it has been previously reported that Rhus verniciflua Stokes (RVS) possesses in vitro anti-inflammatory activity, the precise in vivo mechanisms of RVS extracts and a main active component called fisetin have not been well elucidated. In this study, using newly developed protocols, we prepared urushiol free but fisetin-enriched RVS extracts and investigated their effects on the vascular immune system. We found that the water-soluble fractions of detoxified RVS with the flavonoid fisetin can inhibit lipopolysaccharide-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2). Furthermore, RVS can reduce inducible nitric oxide synthase and COX2 gene expression levels, which are responsible for NO and PGE2 production, respectively, in RAW264.7 macrophage cells. Because inflammation is linked to the activation of the coagulation system, we hypothesized that RVS and its active component fisetin possess anticoagulatory activities. As expected, we found that both RVS and fisetin could inhibit the coagulation of human peripheral blood cells. Moreover, in vivo RVS treatment could return the retarded blood flow elicited by a high-fat diet (HFD) back to the normal level in mice. In addition, RVS treatment has significantly reduced body weight gained by HFD in mice. Taken together, the fisetin-rich RVS extracts have potential antiplatelet and antiobesity activities and could be used as a functional food ingredient to improve blood circulation. PMID- 26741652 TI - Seroepidemiological Studies of Crimean-Congo Hemorrhagic Fever Virus in Domestic and Wild Animals. AB - Crimean-Congo hemorrhagic fever (CCHF) is a widely distributed, tick-borne viral disease. Humans are the only species known to develop illness after CCHF virus (CCHFV) infection, characterized by a nonspecific febrile illness that can progress to severe, often fatal, hemorrhagic disease. A variety of animals may serve as asymptomatic reservoirs of CCHFV in an endemic cycle of transmission. Seroepidemiological studies have been instrumental in elucidating CCHFV reservoirs and in determining endemic foci of viral transmission. Herein, we review over 50 years of CCHFV seroepidemiological studies in domestic and wild animals. This review highlights the role of livestock in the maintenance and transmission of CCHFV, and provides a detailed summary of seroepidemiological studies of wild animal species, reflecting their relative roles in CCHFV ecology. PMID- 26741655 TI - Artemisia annua Leaf Extract Attenuates Hepatic Steatosis and Inflammation in High-Fat Diet-Fed Mice. AB - Artemisia annua L. (AA) is a well-known source of the antimalarial drug artemisinin. AA also has an antibacterial and antioxidant activity. However, the effect of AA extract on hepatic steatosis induced by obesity is unclear. We investigated whether AA extract prevents obesity-induced insulin resistance and hepatic steatosis in high-fat diet (HFD)-fed mice. Mice were randomly divided into groups that received a normal chow diet or HFD with or without AA for 12 weeks. We found that AA extract reduced insulin resistance and hepatic steatosis in HFD-fed mice. Western blot analysis showed that HFD-induced expression of nuclear sterol regulatory element-binding protein 1 and carbohydrate-responsive element-binding protein in the livers was decreased by AA extract. In particular, dietary administration of AA extract decreased hepatic high-mobility group box 1 and cyclooxygenase-2 expression in HFD-fed mice. AA extract also attenuated HFD induced collagen deposition and fibrosis-related transforming growth factor-beta1 and connective tissue growth factor. These data indicate that dietary AA extract has beneficial effects on hepatic steatosis and inflammation in HFD-fed mice. PMID- 26741657 TI - Attitudes to contralateral risk reducing mastectomy among breast and plastic surgeons in England. AB - INTRODUCTION: Rates of contralateral risk reducing mastectomy (CRRM) are rising despite a paucity of data to support this practice. Surgeons work as part of the multidisciplinary team (MDT). They may counsel women on these requests without the benefit of established guidelines or agreed protocol. This study assessed the practices and perceptions of breast and plastic surgeons in England on CRRM. METHODS: A postal questionnaire was sent to 455 breast and 364 plastic surgeons practising in England. Basic demographics, trends in CRRM, risk assessment, role of the MDT and knowledge base were assessed. RESULTS: The response rate among breast surgeons was 48.3% (220/455) and 12.6% (46/364) among plastic surgeons. Nearly half (44%) of the respondents felt there had been an increase in rates of CRRM over the last three years. Seventy-one per cent of those surveyed performed 1-5 CRRMs annually while sixteen per cent did not perform this procedure at all. A third (32%) of respondents correctly quoted their patients an annual risk of 0.5-0.7%. Funding was refused in 4% of cases and 43% of the surgeons felt that in the future they would have to apply to relevant clinical commissioning groups. Over half (58%) of all respondents reported that decisions for CRRM are always discussed in the MDT meeting but 6% stated that these cases are never discussed by the MDT. BRCA mutation was perceived as the main risk factor for contralateral breast cancer by 81% of respondents. Surgeons felt that women requested CRRM mainly to alleviate anxiety. The next most common reasons were carriage of BRCA mutation and a desire to have reconstructions match. CONCLUSIONS: A wide variation of surgical practices and perceptions exist in assessing women for CRRM. Guidelines to standardise practices are required. PMID- 26741659 TI - The utility of repeat ultrasound imaging in the follow-up of metal-on-metal hip arthroplasty patients. AB - INTRODUCTION: We assessed changes in metal-on-metal hip arthroplasties (MoMHAs) after repeat ultrasound examination. METHODS: This retrospective, single-centre cohort study involved all patients undergoing two ultrasound examinations of the same MoMHA. Between 2010 and 2014, 96 ultrasound examinations were performed in 48 MoMHAs (mean time between scans = 1.1 years). A radiologist assigned each scan to one of four grades and measured volumes of any solid/cystic masses. Changes in grade and lesion volume between scans were analysed. RESULTS: Change in grade between scans was significant (p=0.012); 27% (n=13) of MoMHAs increased in grade, 67% (n=32) had no grade change, and 6% (n=3) decreased in grade. The mean increase in lesion volume was 24.2cm(3) by the second scan, and was significant (p=0.023). Evidence of progression in findings was observed in 54% (26/48) of MoMHAs. Of patients with normal scans initially, 44% (8/18) developed abnormalities. No factors (including blood metal ion concentrations and cup position) were associated significantly with progression of ultrasound findings. CONCLUSIONS: Repeat ultrasound in MoMHA patients demonstrated that findings frequently progress in the short-term. Therefore, regular surveillance of MoMHA patients is important, with ultrasound representing an effective investigation for identifying the development and progression of lesions. PMID- 26741658 TI - The provision of total hip replacement for displaced intracapsular hip fractures. AB - INTRODUCTION: The National Institute for Health and Care Excellence (NICE) currently recommends the use of total hip replacement (THR) for displaced intracapsular hip fractures in patients who meet certain mobility, cognitive and health criteria. METHODS: A multicentre prospective audit was conducted within a defined geographic region to assess current practice and variation in provision of THR for displaced intracapsular hip fractures. RESULTS: A total of 879 patients with hip fractures, admitted to 8 acute trauma units, were included in this study. Of 462 patients with displaced intracapsular hip fractures, 169 fulfilled the NICE criteria for THR. THR was performed for only 49 of (29%) the eligible patients. There was significant variation in THR provision between the eight units (0% to 50% THR usage, p<0.001). There were statistically significant differences in age, ASA (American Society of Anesthesiologists) grade, abbreviated mental test score and walking ability prior to the injury between patients who underwent fixation, THR or hemiarthroplasty (all p<=0.05). There was a significantly increased chance of not undergoing THR if a patient was older than 77 years (median age for the THR eligible cohort; relative risk [RR]: 7.9, 95% confidence interval [CI]: 2.8-22.0, p<0.001). There was also a trend for this with patients who were ASA grade 3 compared with ASA grade 1 or 2 (RR: 2.7, 95% CI: 1.0-7.3, p=0.06). The surgeons gave multifactorial reasons for not performing THR in eligible patients. CONCLUSIONS: There is significant variation in the provision of THR for eligible hip fracture patients, which is influenced by both patient demographics and the unit to which a patient is admitted. PMID- 26741660 TI - A report of three cases and review of the literature on rectal disruption following abdominal seatbelt trauma. AB - Seatbelt associated blunt trauma to the rectum is a rare but well recognised injury. The exact mechanism of hollow visceral injury in blunt trauma is unclear. Stress and shear waves generated by abdominal compression may in part account for injury to gas containing structures. A 'seatbelt sign' (linear ecchymosis across the abdomen in the distribution of the lap belt) should raise the suspicion of hollow visceral injuries and can be more severe with disruption of the abdominal wall musculature. Three consecutive cases of rectal injury following blunt abdominal trauma, requiring emergency laparotomy and resection, are described. Lumbar spine injury occurred in one case and in the other two cases, there was injury to the iliac wing of the pelvis; all three cases sustained significant abdominal wall contusion or muscle disruption. Abdominal wall reconstruction and closure posed a particular challenge, requiring a multidisciplinary approach. The literature on this topic is reviewed and potential mechanisms of injury are discussed. PMID- 26741661 TI - Technique to test flexor hallucis longus after Akin osteotomy. PMID- 26741662 TI - A bladder syringe both as a spigot and for joint drainage during ACL reconstruction. PMID- 26741663 TI - A review of the surgical conversion rate and independent management of spinal extended scope practitioners in a secondary care setting. AB - INTRODUCTION: Spinal orthopaedic triage aims to reduce unnecessary referrals to surgical consultants, thereby reducing waiting times to be seen by a surgeon and to surgical intervention. This paper presents an evaluation of a spinal orthopaedic triage service in the third largest spinal unit in the UK. METHODS: A retrospective service evaluation spanning 2012 to 2014 was undertaken by members of the extended scope practitioner (ESP) team to evaluate the ESPs' ability to manage patient care independently and triage surgical referrals appropriately. Data collected included rates of independent management, referral rates for surgical consideration and conversion to surgery. Patient satisfaction rates were evaluated retrospectively from questionnaires given to 5% of discharged patients. RESULTS: A total of 2,651 patients were seen. The vast majority (92%) of all referrals seen by ESPs were managed independently. Only 8% required either a discussion with a surgeon to confirm management or for surgical review. Of the latter, 81% were considered to be suitable surgical referrals. A 99% satisfaction rate was reported by discharged patients. CONCLUSIONS: ESP services in a specialist spinal service are effective in managing spinal conditions conservatively and identifying surgical candidates appropriately. Further research is needed to confirm ESPs' diagnostic accuracy, patient outcomes and cost effectiveness. PMID- 26741664 TI - Insertion of thermoexpandable metallic ureteric stents can be aided by ureteric predilation. PMID- 26741666 TI - An easy technique for removal of a light bulb from the vagina. PMID- 26741665 TI - High rate of common bile duct stones and postoperative abscess following percutaneous cholecystostomy. AB - INTRODUCTION: The short and long-term outcomes in patients managed with percutaneous cholecystostomy (PCY) at a single institution are described. METHODS: A retrospective study was conducted for patients treated between February 2000 and November 2012. Patient charts, imaging and biochemical data were reviewed. Patient demographics, presenting clinical features and treatment variables were noted. Outcome variables were length of admission, 30-day mortality, 30-day unplanned readmission, tube dislodgement, abscess formation, subsequent endoscopic retrograde cholangiography and surgery, complications after surgery and median overall survival. RESULTS: PCY was performed for 55 patients for acute cholecystitis where surgical risk was very high. The 30-day readmission rate was 20% (n=11), the 30-day mortality rate was 9% (n=5) and median survival was 59 months (95% confidence interval: 30-88 months). The median follow-up duration was 68 months. Tubes were dislodged in 15 patients (27%) and an abscess occurred after PCY in 5 patients (9%). Subsequent endoscopic common bile duct stone extraction was required in 20 patients (36%). Cholecystectomy was planned in 22 patients and an abscess occurred following the cholecystectomy in 5 (23%). CONCLUSIONS: Although a PCY is lifesaving, significant morbidity can arise during recovery. This study demonstrates a high rate of choledocholithiasis (44%), tube dislodgement (27%) and postoperative abscess (23%) compared with previous reports. PMID- 26741667 TI - The nylon-tape retraction technique for laparoscopic appendicectomy. PMID- 26741668 TI - Needlescopic insertion of a Tenckhoff catheter. PMID- 26741669 TI - Ivor-Lewis oesophagogastrectomy with Roux-en-Y duodenal bypass. AB - Oesophagectomies and gastrectomies are performed predominantly for the treatment of malignant disease. However, in this case series, we describe three patients with benign disease who had a laparoscopic oesophagogastrectomy with gastroduodenal detachment and Roux-en-Y biliary diversion, and discuss the operative feasibility and consequent patient outcomes. Our aim was to modify the procedure using an established reconstruction already practised in gastric and bariatric surgery, thereby preventing operative sequelae that lead to a poor quality of life (eg reflux oesophagitis and vomiting). During the first postoperative year, our first two patients experienced weight loss, indigestion and lower bowel symptoms with no apparent improvement in gastric function compared with a standard gastric tube pull-up reconstruction. In the longer term, in both patients, the gastric tube interpositions appeared to function well and there was no evidence of gastro-oesophageal reflux disease, delayed gastric emptying or troublesome indigestion. Our third patient, who had lifelong severe reflux symptoms, was eating normally three months after the operation with no need for antacid medication. We therefore conclude that laparoscopic Ivor-Lewis oesophagogastrectomy with Roux-en-Y bypass is a more complex reconstruction with added risks but may in the long term result in better overall outcomes and satisfaction for patients, particularly those with benign disease. PMID- 26741670 TI - A simple and safe method for creating closed pneumoperitoneum in slim patients with firm abdominal skin. PMID- 26741671 TI - Syringe-pressurised bone wax to stop bleeding from vertebral body pin sites during anterior cervical discectomy and fusion (ACDF). PMID- 26741672 TI - Accurate insertion of a guide pin for acute correction of bone deformity using a locked intramedullary nail. PMID- 26741673 TI - Protection of soft tissue and avoidance of inadvertent neurovascular injury in repair of the distal biceps. PMID- 26741675 TI - Novel method for retrieval of a well-fixed fractured femoral component after total hip replacement. PMID- 26741674 TI - Systematic review and meta-analysis of the association between frailty and outcome in surgical patients. AB - INTRODUCTION: Frailty is becoming increasingly prevalent in the elderly population although a lack of consensus regarding a clinical definition hampers comparison of clinical studies. More elderly patients are being assessed for surgical intervention but the effect of frailty on surgical related outcomes is still not clear. METHODS: A systematic literature search for studies prospectively reporting frailty and postoperative outcomes in patients undergoing surgical intervention was performed with data collated from a total of 12 studies. Random effects meta-analysis modelling was undertaken to estimate the association between frailty and mortality rates (in-hospital and one-year), length of hospital stay and the need for step-down care for further rehabilitation/nursing home placement. RESULTS: Frailty was associated with a higher in-hospital mortality rate (pooled odds ratio [OR]: 2.77, 95% confidence interval [CI]: 1.62-4.73), a higher one-year mortality rate (pooled OR: 1.99, 95% CI: 1.49-2.66), a longer hospital stay (pooled mean difference: 1.05 days, 95% CI: 0.02-2.07 days) and a higher discharge rate to further rehabilitation/step down care (pooled OR: 5.71, 95% CI: 3.41-9.55). CONCLUSIONS: The presence of frailty in patients undergoing surgical intervention is associated with poorer outcomes with regard to mortality and return to independence. Further in-depth studies are required to identify factors that can be optimised to reduce the burden of frailty in surgical patients. PMID- 26741676 TI - Temporal variation in major trauma admissions. AB - INTRODUCTION: Trauma is a significant cause of morbidity and mortality in the UK. Since the inception of the trauma networks, little is known of the temporal pattern of trauma admissions. METHODS: Trauma Audit and Research Network data for 1 April 2011 to 31 March 2013 were collated from two large major trauma centres (MTCs) in the South East of England: Brighton and Sussex University Hospitals NHS Trust (BSUH) and St George's University Hospitals NHS Foundation Trust (SGU). The number of admissions and the injury severity score by time of admission, by weekdays versus weekend and by month/season were analysed. RESULTS: There were 1,223 admissions at BSUH and 1,241 at SGU. There was significant variation by time of admission; there were more admissions in the afternoons (BSUH p<0.001) and evenings (SGU p<0.001). There were proportionally more admissions at the weekends than on weekdays (BSUH p<0.001, SGU p=0.028). There was significant seasonal variation in admissions at BSUH (p<0.001) with more admissions in summer and autumn. No significant seasonal variation was observed at SGU (p=0.543). CONCLUSIONS: The temporal patterns observed were different for each MTC with important implications for resource planning of trauma care. This study identified differing needs for different MTCs and resource planning should be individualised to the network. PMID- 26741677 TI - Metachronous small bowel metastasis from a mixed Mullerian mesodermal tumour. AB - A mixed Mullerian mesodermal tumour (MMMT) is a rare aggressive carcinosarcoma. Metastatic progression is uncommon, and occurs via haematological, lymphatic and intraperitoneal spread. Although the latter is seen most frequently, the small intestine seems to be relatively preserved from disease progression with only one reported case of synchronous involvement. We report a case of metachronous MMMT involvement of the small bowel presenting with subacute obstruction that was successfully resected at operation. PMID- 26741678 TI - Gastric perforation secondary to ingestion of a plastic bag. AB - Foreign body ingestion is a common presentation in clinical practice, seen predominantly in children. Most foreign bodies pass through the gastrointestinal tract without any additional morbidity. We present a case of gastric perforation secondary to the ingestion of a small plastic bag. We discuss the likely pathophysiological process underlying perforation secondary to plastic bag ingestion, which is most commonly associated with the concealment of narcotics. PMID- 26741679 TI - Delayed surgical management of an isolated trochlear fracture of the elbow. AB - We present a rare case of a 23-year-old man with an isolated trochlear fracture following an injury to the left elbow. To our knowledge, there are only a few cases previously reported in the literature. The relevant literature is reviewed. PMID- 26741680 TI - Ureteric obstruction secondary to a paraperitoneal inguinal hernia. AB - Ureteric obstruction is a rare consequence of inguinoscrotal hernias. We report the case of a 71-year-old man who presented with a left hemiscrotal swelling and ipsilateral hydronephrosis. Following investigations, he was found to have a sliding inguinal hernia involving the left ureter. His left inguinal hernia was repaired electively and without complication. Follow-up imaging revealed resolution of the hydronephrosis and a more conventional course of the left ureter. PMID- 26741682 TI - Parkinson Disease Hospitalizations and Mortality in Louisiana, 1999-2012. AB - This study describes Parkinson Disease hospitalizations and deaths in the Louisiana population during the years 1999-2012. Data from the Louisiana Hospitalization Discharge Database (LAHIDD) were collected and analyzed by age, race, and gender and also compared to length of hospital stay and daily hospitalization cost. PMID- 26741683 TI - Cutaneous Granular Cell Tumor on the Arm in a Middle-Aged Man. AB - Granular Cell Tumors are uncommon, often benign neoplasms that occur primarily in the oral cavity. Granular Cell Tumors have also been reported in breast, gastrointestinal tissues, and less commonly in the dermis of the upper extremities. This is a case presentation of a 44-year-old Caucasian male with an asymptomatic Granular Cell Tumor on his right arm. PMID- 26741681 TI - Differential Killing of Salmonella enterica Serovar Typhi by Antibodies Targeting Vi and Lipopolysaccharide O:9 Antigen. AB - Salmonella enterica serovar Typhi expresses a capsule of Vi polysaccharide, while most Salmonella serovars, including S. Enteritidis and S. Typhimurium, do not. Both S. Typhi and S. Enteritidis express the lipopolysaccharide O:9 antigen, yet there is little evidence of cross-protection from anti-O:9 antibodies. Vaccines based on Vi polysaccharide have efficacy against typhoid fever, indicating that antibodies against Vi confer protection. Here we investigate the role of Vi capsule and antibodies against Vi and O:9 in antibody-dependent complement- and phagocyte-mediated killing of Salmonella. Using isogenic Vi-expressing and non-Vi expressing derivatives of S. Typhi and S. Typhimurium, we show that S. Typhi is inherently more sensitive to serum and blood than S. Typhimurium. Vi expression confers increased resistance to both complement- and phagocyte-mediated modalities of antibody-dependent killing in human blood. The Vi capsule is associated with reduced C3 and C5b-9 deposition, and decreased overall antibody binding to S. Typhi. However, purified human anti-Vi antibodies in the presence of complement are able to kill Vi-expressing Salmonella, while killing by anti O:9 antibodies is inversely related to Vi expression. Human serum depleted of antibodies to antigens other than Vi retains the ability to kill Vi-expressing bacteria. Our findings support a protective role for Vi capsule in preventing complement and phagocyte killing of Salmonella that can be overcome by specific anti-Vi antibodies, but only to a limited extent by anti-O:9 antibodies. PMID- 26741684 TI - Nephrologic Impact of Hurricanes Katrina and Rita in Areas Not Directly Affected. AB - Hurricanes Katrina and Rita resulted in enormous loss of life and disrupted the delivery of health care in areas affected by them. In causing mass movements of patients, natural disasters can overwhelm the resources of nephrology communities in areas not suffering direct damage. The following largely personal account evaluates the impact these hurricanes had upon the nephrology community, patients and health care providers alike, in areas not directly affected by the storms. Mass evacuation of hundreds of dialysis patients to surrounding areas overwhelmed the capacity of local hemodialysis centers. Non-availability of medical records in patients arriving without a supply of their routine medications led to confusion and sub-optimal treatment of conditions such as hypertension and congestive heart failure. Availability of cadaveric organs for transplantation was reduced in the surrounding areas, as the usual lines of communication and transportation were severed for several weeks. All of these issues led to prolong waiting times for patients on the transplant list. The hurricanes severely disrupted usual supply lines of medications to hospitals; certain rare conditions may be seen in higher numbers as a result of the shortages induced. We present the interesting surge in cases of acute kidney injury secondary to use of intravenous immune globulin. PMID- 26741686 TI - Using Simulation-Based Training to Incorporate Thoracic Ultrasound into Physical Examination. AB - BACKGROUND: Thoracic ultrasound examination has become increasingly used as a valuable diagnostic tool for the bedside assessment of patients with respiratory distress. We implemented a thoracic ultrasonography curriculum for third year medical students with the goal of developing a model for teaching thoracic ultrasound skills to undergraduate medical students. METHODS: Seventy medical students completed a program comprised of a didactic and hands-on session in fundamental and thoracic ultrasonography. Knowledge assessment and students' questionnaire (on Likert scale 1-5) prior to and following the program were done to assess ultrasonography knowledge and perception of training effectiveness. An image acquisition skills assessment checklist was performed by the instructors after completing the program on all of the participants. RESULTS: The pre intervention knowledge score was 52.05 percent. Post-intervention demonstrated significant improvement: 87.31 percent, p less than 0.001. There was a significant increase in comfort level, basic ultrasound knowledge, self assurance, and motivation by students' self-assessments. The clinical relevance and course evaluation were rated high on Likert scale 4.41/5 and 4.47/5 respectively. Skills assessment checklist demonstrated students' ability to understand anatomic structures shown in ultrasonographic images and fundamental ultrasound skills. CONCLUSIONS: The knowledge of 70 medical students regarding thoracic ultrasound improved significantly after a short dedicated course. The evaluation of the program affirmed the value and clinical relevance of the curriculum to undergraduate medical education. PMID- 26741685 TI - Prescribing Patterns of Metformin in High-risk Patients with Prediabetes. AB - AIMS: The primary objective of this study is to examine the rates of metformin prescribing in patients with prediabetes who are either less than 60 years of age, have a BMI greater than 35 kg/m2, or women with a history of gestational diabetes mellitus (GDM). Secondary objectives include: 1) examination of the time from diagnosis of prediabetes to the initiation of metformin and 2) if metformin initiation status and length of time correlates to the patient having any other additional diabetes mellitus (DM) risk factors. METHODS: This was a single center, retrospective cohort study. This study included all patients with prediabetes, defined as having hemoglobin A1c (HbA1c) of 39 through 46 mmol/mol (5.7-6.4 percent), who were patients at the Interim LSU Hospital and Clinics from January 2012-September 2013. RESULTS: There were a total of 13 patients out of 160 patients in the study population who were prescribed metformin for an overall metformin initiation rate of 8.1 percent. The metformin initiation rate for the three individual groups; history of GDM, aged less than 60 years, and BMI greater than 35 kg/m2 were 0 percent, 9.0 percent, and 17.5 percent respectively. CONCLUSION: Metformin initiation rates in patients with prediabetes are not in accordance with current recommendations, and provider education is necessary to increase rates to delay or prevent the progression of prediabetes to type 2 Diabetes Mellitus. PMID- 26741687 TI - A Cross-Sectional Survey of Hemodialysis Patients on Their Preference for Arm vs. Thigh Grafts. AB - AIM: Recent studies have shown that survival and complication rates of thigh grafts are similar to those of arm grafts and fistulas. However, there is little information in the literature regarding patients' preference for thigh grafts. METHODS: This cross-sectional survey was conducted on patients currently on hemodialysis (n=196), who were queried regarding their preference for location of their next access (arm graft v. thigh graft). Data on their age, race, gender, educational level, and dialysis access history was collected. RESULTS: 93 percent of patients were African American and 64 percent male; 96 percent had been on dialysis >=1 year. 81 percent patients had completed high school or higher education. Current access was arm fistula (55 percent), catheter (29 percent), arm graft (13 percent) and thigh graft (3 percent). Seven percent of patients had thigh grafts at some point in their access history. Overall, 90 percent patients preferred an arm graft and 10 percent a thigh graft. Patients' age, gender, level of education, particular dialysis unit, and dialysis vintage did not influence patient preference. Those patients with a current or prior thigh graft were more likely to prefer a thigh graft for their next access, when compared to those who never had a thigh graft, 36 percent v. 8 percent (P=0.001). CONCLUSIONS: The likelihood of patient preference for placement of a thigh graft is increased by the existence of a current or prior thigh graft. Other demographic factors and dialysis history seem not to influence patient preference. PMID- 26741688 TI - ECG of the Month: ECG in an 81-Year-Old Woman. AB - DIAGNOSIS: Sinus bradycardia (48 beats/min), long P-R interval (0.29 s), long QT interval (0.53 s with QTc of 0.47 s), and prominent J waves suggest hypothermia; non-specific ST abnormality. PMID- 26741689 TI - Pathology Image of the Month: Prolonged Fever in a Traveler. AB - A 23 year old Russian male cargo ship crew member arrived in the port of New Orleans after a one month voyage originating in central Africa. During the month at sea, he developed fever up to 103 degrees Fahrenheit which was unsuccessfully managed with the antipyretic, dipyrone. He subsequently developed back and stomach pain, along with diarrhea. Upon the ship's arrival to New Orleans, he was transported to a local hospital where his axillary temperature was 104 degrees Fahrenheit. He was unresponsive, tachycardic and tachypneic with a plasma bicarbonate of 16mmol/L (24-32mmol/L). PMID- 26741690 TI - Radiology Case of the Month: Rising Creatinine in an Elderly Woman. AB - To assess an elevated creatinine, a 67-year old woman underwent renal ultrasound which incidentally revealed an abdominal aortic aneurysm (AAA). PMID- 26741691 TI - Clinical Case of the Month: A 49-Year-Old Man with Fever, Headache and Leg Weakness. AB - A 49-year-old man with an unremarkable past medical history presented to an outside hospital with a five-day history of fever, left leg weakness, myalgia and headache. The patient reported that the illness started as a fever and sore throat and he was originally diagnosed with streptococcal pharyngitis and prescribed antibiotics. The day after his initial diagnosis, his fever had progressed to include a headache, myalgia, a rash on his upper torso and right shoulder and sudden-onset left leg weakness with preserved sensation. With progressively worsening symptoms, he eventually presented to a local emergency department (ED), five days after his symptoms first started. He was experiencing continued left leg weakness, an inability to ambulate, persistent fevers to 103oF, muscle aches, an intense band-like headache and confusion. The patient denied neck stiffness, photophobia, loss of sensation or any additional muscle weakness. He denied any recent travel aside from work, any sick contacts, recent tick/insect bites, history of sexually transmitted diseases or contact with animals. He reported no history of illicit drug use as well as no recent weight loss, trauma or radiation exposure. The patient had approximately a 10-pack-year tobacco smoking history. For the last ten years he drank about a six-pack of beer daily while onshore (roughly two weeks out of every month). He works on an offshore oil platform. He was not taking any home medications besides his recently prescribed antibiotics. He lived alone at home in a moderately rural area of South Louisiana. His family history was non-contributory. PMID- 26741692 TI - Effects of Synthetic Diets Enriched in Specific Nutrients on Drosophila Development, Body Fat, and Lifespan. AB - Gene-diet interactions play a crucial but poorly understood role in susceptibility to obesity. Accordingly, the development of genetically tractable model systems to study the influence of diets in obesity-prone genetic backgrounds is a focus of current research. Here I present a modified synthetic Drosophila diet optimized for timely larval development, a stage dedicated to energy storage. Specifically increasing the levels of individual macronutrients carbohydrate, lipid, or protein-resulted in markedly different organismal effects. A high-carbohydrate diet adversely affected the timing of development, size, early lifespan and body fat. Strikingly, quadrupling the amount of dietary lipids had none of these effects. Diets rich in protein appeared to be the most beneficial, as larvae developed faster, with no change in size, into long-lived adults. I believe this synthetic diet will significantly facilitate the study of gene-diet interactions in organismal energy balance. PMID- 26741693 TI - Macrophage Migration Inhibitory Factor Secretion Is Induced by Ionizing Radiation and Oxidative Stress in Cancer Cells. AB - The macrophage migration inhibitory factor (MIF) has been increasingly implicated in cancer development and progression by promoting inflammation, angiogenesis, tumor cell survival and immune suppression. MIF is overexpressed in a variety of solid tumor types in part due to its responsiveness to hypoxia inducible factor (HIF) driven transcriptional activation. MIF secretion, however, is a poorly understood process owing to the fact that MIF is a leaderless polypeptide that follows a non-classical secretory pathway. Better understanding of MIF processing and release could have therapeutic implications. Here, we have discovered that ionizing radiation (IR) and other DNA damaging stresses can induce robust MIF secretion in several cancer cell lines. MIF secretion by IR appears independent of ABCA1, a cholesterol efflux pump that has been implicated previously in MIF secretion. However, MIF secretion is robustly induced by oxidative stress. Importantly, MIF secretion can be observed both in cell culture models as well as in tumors in mice in vivo. Rapid depletion of MIF from tumor cells observed immunohistochemically is coincident with elevated circulating MIF detected in the blood sera of irradiated mice. Given the robust tumor promoting activities of MIF, our results suggest that an innate host response to genotoxic stress may mitigate the beneficial effects of cancer therapy, and that MIF inhibition may improve therapeutic responses. PMID- 26741695 TI - Efficiency of Attentional Components in Elderly with Mild Neurocognitive Disorders Shown by the Attention Network Test. AB - AIMS: Complex attention, serving as a main diagnostic item of mild neurocognitive disorders (NCD), has been reported to be susceptible to pathological ageing. This study aimed to evaluate the attention network functions in older adults with subtypes of NCD. METHODS: 36 adults with NCD due to Alzheimer's disease (NCD-AD), 31 adults with NCD due to vascular disease (NCD-vascular) and 137 healthy controls were recruited. Attention Network Test (ANT) was conducted to assess the efficiency of alerting, orienting and executive control. RESULTS: Significant between-group differences were found in executive control (conventional score: F = 11.472, p < 0.001; ratio score: F = 8.430, p < 0.001) and processing speed (F = 4.958, p = 0.008). NCD subgroups demonstrated poorer performance on the ANT, particularly on executive control (healthy 59.9 +/- 45.9, NCD-vascular 88.9 +/- 44.8, NCD-AD 97.0 +/- 53.9). Moreover, the NCD-AD group showed both less efficient executive control and prominent slowing processing speed (reaction time: healthy 687.5 +/- 106.0 ms, NCD-vascular 685.3 +/- 97.1 ms, NCD-AD 750.6 +/ 132.6 ms). CONCLUSIONS: The NCD-vascular group appeared to be less efficient in executive control, while the NCD-AD group demonstrated less effective executive control and also slower processing speed. These results suggest that the characterized performance of ANT, processing speed and executive control in particular, might help differentiate adults at risk of different forms of cognitive impairment. PMID- 26741694 TI - Toll-Like Receptor 4 Is Essential in the Development of Abdominal Aortic Aneurysm. AB - Toll-like receptor (TLR) family plays a key role in innate immunity and various inflammatory responses. TLR4, one of the well-characterized pattern-recognition receptors, can be activated by endogenous damage-associated molecular pattern molecules such as high mobility group box 1 (HMGB1) to sustain sterile inflammation. Evidence suggested that blockade of TLR4 signaling may confer protection against abdominal aortic aneurysm (AAA). Herein we aimed to obtain further insight into the mechanism by which TLR4 might promote aneurysm formation. Characterization of the CaCl2-induced AAA model in mice revealed that upregulation of TLR4 expression, localized predominantly to vascular smooth muscle cells (VSMCs), was followed by a late decline during a 28-day period of AAA development. In vitro, TLR4 expression was increased in VSMCs treated with HMGB1. Knockdown of TLR4 by siRNA attenuated HMGB1-enhanced production of proinflammatory cytokines, specifically interleukin-6 and monocyte chemoattractant protein-1 (MCP-1), and matrix-degrading matrix metalloproteinase (MMP)-2 from VSMCs. In vivo, two different strains of TLR4-deficient (C57BL/10ScNJ and C3H/HeJ) mice were resistant to CaCl2-induced AAA formation compared to their respective controls (C57BL/10ScSnJ and C3H/HeN). Knockout of TLR4 reduced interleukin-6 and MCP-1 levels and HMGB1 expression, attenuated macrophage accumulation, and eventually suppressed MMP production, elastin destruction and VSMC loss. Finally, human AAA exhibited higher TLR4 expression that was localized to VSMCs. These data suggest that TLR4 signaling contributes to AAA formation by promoting a proinflammatory status of VSMCs and by inducing proteinase release from VSMCs during aneurysm initiation and development. PMID- 26741696 TI - Grey matter changes of the pain matrix in patients with burning mouth syndrome. AB - Burning mouth syndrome (BMS) is characterized by a burning sensation in the mouth, usually in the absence of clinical and laboratory findings. Latest findings indicate that BMS could result from neuropathic trigeminal conditions. While many investigations have focused on the periphery, very few have examined possible central dysfunctions. To highlight changes of the central system of subjects with BMS, we analysed the grey matter concentration in 12 subjects using voxel-based morphometry. Data were compared with a control group (Ct). To better understand the brain mechanisms underlying BMS, the grey matter concentration of patients was also compared with those of dysgeusic patients (Dys). Dysgeusia is another oral dysfunction condition, characterized by a distorted sense of taste and accompanied by a reduced taste function. We found that a major part of the 'pain matrix' presented modifications of the grey matter concentration in subjects with BMS. Six regions out of eight were affected [anterior and posterior cingulate gyrus, lobules of the cerebellum, insula/frontal operculum, inferior temporal area, primary motor cortex, dorsolateral pre-frontal cortex (DLPFC)]. In the anterior cingulate gyrus, the lobules of the cerebellum, the inferior temporal lobe and the DLPFC, pain intensity correlated with grey matter concentration. Dys also presented changes in grey matter concentration but in different areas of the brain. Our results suggest that a deficiency in the control of pain could in part be a cause of BMS and that BMS and dysgeusia conditions are not linked to similar structural changes in the brain. PMID- 26741697 TI - A Rehabilitation First-Tournament Between Teams of Nursing Home Residents with Chronic Stroke. AB - PURPOSE: This study describes the BrightArmTM Duo virtual reality system (Bright Cloud International Corp., Highland Park, NJ) and determines its clinical benefit for maintenance of upper extremity function in nursing home residents who are chronic poststroke. MATERIALS AND METHODS: Participants sat at a low-friction robotic table with tilt and lift capability and interacted with serious games through computerized supports that measured forearm movement and grasp. The rehabilitation simulations were designed to improve arm and hand function, increase range of motion, and improve emotional well-being and cognition (attention, memory, and executive functioning). After 8 weeks of initial intensive therapy, there were three booster periods at 8-week intervals, each consisting of four sessions over 2 weeks. The last booster was a tournament competition, where pairs of residents played games collaboratively from remote nursing homes. Participants were evaluated before and after each booster period using standardized clinical measures. RESULTS: Range of motion improved for 18 out of 23 upper extremity movement variables (P = 0.01) between pre- and post tournament assessment, and the residents self-reported that they enjoyed playing with a partner (score of 4.7 out of 5.0). Participants were able to reduce game completion time through cooperative play (teamwork), and the times improved with successive sessions of the tournament. Affected hand and arm function and depression levels were maintained (no decline) after the tournament. CONCLUSIONS: A rehabilitation tournament using virtual reality between teams of nursing home residents chronic poststroke is the first of its kind in clinical practice. This study demonstrates its effectiveness in improving range of motion of the upper extremity while engaging residents in the maintenance program at their nursing home. PMID- 26741698 TI - Protection against lethal vaccinia virus infection in mice using an siRNA targeting the A5R gene. AB - BACKGROUND: Although the World Health Organization has declared the eradication of smallpox in 1980, the fear of its potential use in bioterrorism has become a reality. Since the effectiveness of current vaccines and antiviral drugs is limited, development of new therapeutic strategies is needed. In this study, we investigated small interfering RNA (siRNA) as a therapeutic approach for preventing and treating smallpox infection. METHODS: Eight siRNA sequences were designed and evaluated for antiviral activity against vaccinia virus (VACV) in vitro and in vivo. RESULTS: Of eight siRNAs, A5R1 siRNA targeted the A5R gene and reduced VACV replication in cell culture by up to 85% at 100 nM concentration without inducing cytotoxicity. A prolonged prophylactic as well as therapeutic effect of siRNA was observed. In addition, real-time PCR analysis showed that A5R1 siRNA can especially reduce the target mRNA. Finally, intraperitoneal delivery of A5R1 siRNA in Balb/c mice significantly protected these animals from lethal challenge with VACV. CONCLUSIONS: This study suggests the potential of A5R1 siRNA as a therapeutic antiviral agent against smallpox. PMID- 26741700 TI - Association of rs9939609 Polymorphism with Metabolic Parameters and FTO Risk Haplotype Among Tunisian Metabolic Syndrome. AB - BACKGROUND: Variants in the fat mass and obesity-associated (FTO) gene are associated with obesity and type 2 diabetes mellitus. AIM OF THE STUDY: This study aims to assess the association of the rs9939609 variant and haplotypes in FTO gene with metabolic syndrome (MetS) components in a Tunisian population sample. METHODS: A total of 685 Tunisian subjects were genotyped for the rs9939609T>A using TaqMan allelic discrimination assay. Two variants rs1421085T>C and rs8057044A>G already genotyped in a previous study were used to test haplotype association of the FTO gene. RESULTS: Genotype distribution of the variant rs9939609 was different between MetS and controls (P = 0.017). Individuals carrying TA genotypes had a significantly increased risk independently of body mass index or age (P = 0.009). The variant rs9939609 was also associated with impaired fasting glucose (IFG) (P = 0.002). Among the eight haplotypes in the population, the haplotype GCA was significantly associated with a higher risk of developing the MetS, higher systolic blood pressure, and higher levels of fasting glucose and triglycerides (TGs) in the total sample and females, separately. Separate analysis by gender revealed a protective haplotype TGT among women (P = 0.023). CONCLUSIONS: FTO haplotypes have a strong influence on blood pressures and TG and IFG levels. These findings provide evidence that FTO gene may play a critical role in leading to MetS in Tunisian population. PMID- 26741699 TI - Vitamin D Status Is Associated with Metabolic Syndrome in a Clinic-Based Sample of Hispanic Adults. AB - BACKGROUND: Vitamin D status has been associated with metabolic syndrome (MetSyn) and its components in different populations, but few studies have assessed this among Hispanics. The objective of this analysis was to assess such association in a clinic-based sample of Hispanic adults. METHODS: Medical records were reviewed retrospectively for the years 2005-2013. MetSyn was assessed using the revised NCEP-ATP III criteria. Vitamin D status was evaluated from reported serum 25(OH)D levels. A multivariable logistic regression model was used to assess the association between MetSyn risk and vitamin D status, controlling for important confounders. RESULTS: From 1379 medical records evaluated, 712 met the inclusion criteria. Most were females (62.6%), with a mean age of 53.8 +/- 14.1 years, mean body mass index (BMI) of 30.1 +/- 6.4 kg/m(2), and mean serum 25(OH)D levels of 24.4 +/- 8.3 ng/mL. MetSyn was identified in 40.5% of the participants. Serum 25(OH)D levels in those with MetSyn (22.7 +/- 8.0 ng/mL) were significantly lower compared to those without MetSyn (25.5 +/- 8.4 ng/mL; P < 0.001). Serum 25(OH)D levels were inversely correlated to triglycerides, waist circumference, and fasting blood glucose (P < 0.05). In the multivariable logistic regression model, decreased serum 25(OH)D levels were associated with higher odds of MetSyn, even after adjusting for age, gender, BMI, and seasonality. CONCLUSION: In this clinic based sample, the odds of MetSyn increased as serum 25(OH)D levels decreased. These results have important public health implications for developing recommendations directed to increase vitamin D status in this sample. PMID- 26741701 TI - Association Between HbA1c Level and Hearing Impairment in a Nondiabetic Adult Population. AB - BACKGROUND: The aim of this study was to investigate whether glycosylated hemoglobin (HbA1c) level in nondiabetic patients is associated with hearing impairment in the general Korean population. PATIENTS AND METHODS: Data from the Korean National Health and Nutrition Examination Survey 2011-2013 were used in the analyses. Participants were excluded from this study for the following reasons: they could not provide data regarding pure tone audiometry, they had ear disease, they had brain disorders, asymmetric sensory neural hearing loss (HL), or they were younger than 40 years or had diabetes mellitus. Finally, 7449 participants were included in this study. RESULTS: The mean HbA1c levels in the low, middle, and high tertiles were 5.3% +/- 0.2%, 5.7% +/- 0.1%, and 6.1% +/- 0.2%, respectively. The numbers of participants in the low, middle, and high tertiles were 2808, 2509, and 2132, respectively. The low-frequency, mid frequency, high-frequency, and average hearing thresholds were significantly increased with increasing HbA1c tertile. Linear regression analyses showed that HbA1c level in the nondiabetic participants was associated with components of metabolic syndrome. The mean numbers of metabolic syndrome components in the low, middle, and high HbA1c tertiles were 1.22, 1.53, and 2.02, respectively. The participants in the middle and high HbA1c tertiles had a 1.239- and 1.253-fold increased risk of HL, respectively, compared with those in the low HbA1c tertile. CONCLUSION: HbA1c level was associated with hearing impairment in the nondiabetic participants of this study. Therefore, the participants with high HbA1c levels should be closely monitored for hearing impairment. PMID- 26741702 TI - Interface Management between General Practitioners and Rheumatologists-Results of a Survey Defining a Concept for Future Joint Recommendations. AB - OBJECTIVE: To measure the views of general practitioners (GPs) and rheumatologists in a nationwide evaluation, so as to optimise their cooperation in managing patients with inflammatory rheumatic diseases. METHODS: A questionnaire covering aspects of collaboration was sent, both by mail and/or by email, to all GPs and rheumatologists in Austria. Topics covered were (i) examinations and interventions to be performed before referral, (ii) the spectrum of diseases to be referred, and (iii) the role of GPs in follow-up and continuous management of patients. RESULTS: 1,229 GPs of the 4,016 GPs (31%) and 110 of the 180 rheumatologists (61%) responded to the questionnaire. In cases of suspected arthritis, 99% of the GPs and 92% of the rheumatologists recommended specific laboratory tests, and 92% and 70%, respectively, recommended X-rays of affected joints before referral. Rheumatoid arthritis and spondyloarthritis, psoriatic arthritis and connective tissue disease were unanimously seen as indications for referral to a rheumatologist. Only 12% of rheumatologists felt responsible for the treatment of hand osteoarthritis and fibromyalgia. 80% of GPs and 85% of rheumatologists were of the opinion that treatment with disease-modifying drugs should be initiated by a specialist. Subsequent drug prescription and administration by GPs was supported by a majority of GPs and rheumatologists, with a concomitant rheumatologist follow-up every three to six months. CONCLUSION: The considerable consensus between the two professional groups constitutes a solid base for future joint recommendations, with the aim to accelerate the diagnostic process and the initiation of adequate therapy. PMID- 26741703 TI - Associations between attending physician workload, teaching effectiveness, and patient safety. AB - BACKGROUND: Prior studies suggest that high workload among attending physicians may be associated with reduced teaching effectiveness and poor patient outcomes, but these relationships have not been investigated using objective measures of workload and safety. OBJECTIVE: To examine associations between attending workload, teaching effectiveness, and patient safety, hypothesizing that higher workload would be associated with lower teaching effectiveness and negative patient outcomes. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective study of 69,386 teaching evaluation items submitted by 543 internal medicine residents for 107 attending physicians who supervised inpatient teaching services from July 2, 2005 to July 1, 2011. MEASUREMENTS: Attending workload measures included hospital service census, patient length of stay, daily admissions, daily discharges, and concurrent outpatient duties. Teaching effectiveness was measured using residents' evaluations of attendings. Patient outcomes considered were applicable patient safety indicators (PSIs), intensive care unit transfers, cardiopulmonary resuscitation/rapid response team calls, and patient deaths. Mixed linear models and generalized linear regression models were used for statistical analysis. RESULTS: Workload measures of midnight census and daily discharges were associated with lower teaching evaluation scores (both beta = 0.026, P < 0.0001). The number of daily admissions was associated with higher teaching scores (beta = 0.021, P = 0.001) and increased PSIs (odds ratio = 1.81, P = 0.0001). CONCLUSION: Several measures of attending physician workload were associated with slightly lower teaching effectiveness, and patient safety may be compromised when teams are managing new admissions. Ongoing efforts by residency programs to optimize the learning environment should include strategies to manage the workload of supervising attendings. PMID- 26741705 TI - Inhibiting HIF-1alpha Decreases Expression of TNF-alpha and Caspase-3 in Specific Brain Regions Exposed Kainic Acid-Induced Status Epilepticus. AB - BACKGROUND/AIMS: A recent study demonstrates that pro-inflammatory cytokines (PICs, i.e., IL-1beta, IL-6 and TNF-alpha) in specific brain regions of rats play a role in regulating kainic acid (KA)-induced status epilepticus (SE) via a GABAergic mechanism. The purposes of this report were to examine contributions of hypoxia inducible factor subtype 1alpha (HIF-1alpha) to expression of PICs in these specific brain regions in epileptic rats. Particularly, we investigated the parietal cortex, hippocampus and amygdala. In addition, we further examined expression of Caspase-3 indicating cell apoptosis in those brain regions of epileptic rats after infusing 2-methoxyestradiol (2-MET, inhibitor of HIF-1alpha) and etanercept (TNF-alpha receptor antagonist). METHODS: ELISA was used to determine the levels of HIF-1alpha and PICs and western blot analysis was used to examine Caspase-3 expression. RESULTS: Our data show that HIF-1alpha was significantly increased in the parietal cortex, hippocampus and amygdala 1, 3 and 7 days after induction of SE (P<0.05 vs. control rats). Our results also show that inhibiting HIF-1alpha by central infusion of 2-MET significantly decreased the amplified TNF-alpha expression in these brain regions evoked by SE (P<0.05 vs. vehicle control), but did not modify IL-1beta and IL-6. Our results demonstrate that 2-MET and etanercept attenuated an increase in Caspase-3 evoked by SE. CONCLUSION: Overall, we suggest that HIF-1alpha activated by SE is likely to contribute to epileptic activity via a TNF-alpha pathway, which has pharmacological implications to target specific HIF-1alpha and TNF-alpha pathways for neuronal dysfunction and vulnerability related to epilepsy. PMID- 26741704 TI - New Insights into Asian Prunus Viruses in the Light of NGS-Based Full Genome Sequencing. AB - Double stranded RNAs were purified from five Prunus sources of Asian origin and submitted to 454 pyrosequencing after a random, whole genome amplification. Four complete genomes of Asian prunus virus 1 (APV1), APV2 and APV3 were reconstructed from the sequencing reads, as well as four additional, near-complete genome sequences. Phylogenetic analyses confirmed the close relationships of these three viruses and the taxonomical position previously proposed for APV1, the only APV so far completely sequenced. The genetic distances in the respective polymerase and coat protein genes as well as their gene products suggest that APV2 should be considered as a distinct viral species in the genus Foveavirus, even if the amino acid identity levels in the polymerase are very close to the species demarcation criteria for the family Betaflexiviridae. However, the situation is more complex for APV1 and APV3, for which opposite conclusions are obtained depending on the gene (polymerase or coat protein) analyzed. Phylogenetic and recombination analyses suggest that recombination events may have been involved in the evolution of APV. Moreover, genome comparisons show that the unusually long 3' non-coding region (3' NCR) is highly variable and a hot spot for indel polymorphisms. In particular, two APV3 variants differing only in their 3' NCR were identified in a single Prunus source, with 3' NCRs of 214-312 nt, a size similar to that observed in other foveaviruses, but 567-850 nt smaller than in other APV3 isolates. Overall, this study provides critical genome information of these viruses, frequently associated with Prunus materials, even though their precise role as pathogens remains to be elucidated. PMID- 26741706 TI - Body Image and Anti-Fat Attitudes: An Experimental Study Using a Haptic Virtual Reality Environment to Replicate Human Touch. AB - It is well documented that anti-fat attitudes influence the interactions individuals have with overweight people. However, testing attitudes through self report measures is challenging. In the present study, we explore the use of a haptic virtual reality environment to physically interact with overweight virtual human (VH). We verify the hypothesis that duration and strength of virtual touch vary according to the characteristics of VH in ways similar to those encountered from interaction with real people in anti-fat attitude studies. A group of 61 participants were randomly assigned to one of the experimental conditions involving giving a virtual hug to a female or a male VH of either normal or overweight. We found significant associations between body image satisfaction and anti-fat attitudes and sex differences on these measures. We also found a significant interaction effect of the sex of the participants, sex of the VH, and the body size of the VH. Female participants hugged longer the overweight female VH than overweight male VH. Male participants hugged longer the normal-weight VH than the overweight VH. We conclude that virtual touch is a promising method of measuring attitudes, emotion and social interactions. PMID- 26741723 TI - Erratum: Vol. 64, No. 37. PMID- 26741725 TI - Generalizations and Extensions of the Probability of Superiority Effect Size Estimator. AB - Researchers are strongly encouraged to accompany the results of statistical tests with appropriate estimates of effect size. For 2-group comparisons, a probability based effect size estimator (A) has many appealing properties (e.g., it is easy to understand, robust to violations of parametric assumptions, insensitive to outliers). We review generalizations of the A statistic to extend its use to applications with discrete data, with weighted data, with k > 2 groups, and with correlated samples. These generalizations are illustrated through reanalyses of data from published studies on sex differences in the acceptance of hypothetical offers of casual sex and in scores on a measure of economic enlightenment, on age differences in reported levels of Authentic Pride, and in differences between the numbers of promises made and kept in romantic relationships. Drawing from research on the construction of confidence intervals for the A statistic, we recommend a bootstrap method that can be used for each generalization of A. We provide a suite of programs that should make it easy to use the A statistic and accompany it with a confidence interval in a wide variety of research contexts. PMID- 26741724 TI - Comparison of Nomothetic Versus Idiographic-Oriented Methods for Making Predictions About Distal Outcomes From Time Series Data. AB - We illustrate the idiographic/nomothetic debate by comparing 3 approaches to using daily self-report data on affect for predicting relationship quality and breakup. The 3 approaches included (a) the first day in the series of daily data; (b) the mean and variability of the daily series; and (c) parameters from dynamic factor analysis, a statistical model that uses all measurement occasions to estimate the structure and dynamics of the data. Our results indicated that data from the first measurement occasion does not provide information about the couples' relationship quality or breakup 1 to 2 years later. The mean and variability of the time series, however, were more informative: females' average positive and negative affect across time was related to relationship quality, whereas males' variability in negative affect across time was predictive of breakup. The dynamic factor analysis, in turn, allowed us to extract information central to the dyadic dynamics. This information proved useful to predict relationship quality but not breakup. The importance of examining intraindividual variability and couple dynamics is highlighted. PMID- 26741726 TI - Testing 40 Predictions From the Transtheoretical Model Again, With Confidence. AB - Testing Theory-based Quantitative Predictions (TTQP) represents an alternative to traditional Null Hypothesis Significance Testing (NHST) procedures and is more appropriate for theory testing. The theory generates explicit effect size predictions and these effect size estimates, with related confidence intervals, are used to test the predictions. The focus of a study is shifted to a quantitative approach in contrast to the NHST dyadic decision centered on testing a prediction not based on the theory. This article describes the TTQP as an alternative approach by replicating and extending a test of 40 a priori predictions based on the Transtheoretical Model (TTM). Specific quantitative predictions were made about the magnitude of the effect size (omega(2)). The predictions involved movement from 1 of 3 initial stages (Precontemplation, Contemplation, and Preparation) to stage membership 12 months later. In the initial study, 36 of the 40 predictions were confirmed. The same 40 predictions are evaluated on a sample (N = 3,923) of smokers recruited from a large New England HMO for a smoking cessation study. The predictions were recalibrated based on the first study and 99% confidence intervals were employed to test the predictions. Thirty-two of the 40 predictions were confirmed. Of the 8 failures, 4 were judged to reflect a need for further recalibration, 1 was attributed to sampling fluctuation, and 3 suggested revisions of the theory are needed. The results provide overall support for the TTM. The study also illustrates some of the challenges of testing quantitative predictions. PMID- 26741707 TI - Disease-Specific Trends of Comorbidity Coding and Implications for Risk Adjustment in Hospital Administrative Data. AB - OBJECTIVE: To investigate changes in comorbidity coding after the introduction of diagnosis related groups (DRGs) based prospective payment and whether trends differ regarding specific comorbidities. DATA SOURCES: Nationwide administrative data (DRG statistics) from German acute care hospitals from 2005 to 2012. STUDY DESIGN: Observational study to analyze trends in comorbidity coding in patients hospitalized for common primary diseases and the effects on comorbidity-related risk of in-hospital death. EXTRACTION METHODS: Comorbidity coding was operationalized by Elixhauser diagnosis groups. The analyses focused on adult patients hospitalized for the primary diseases of heart failure, stroke, and pneumonia, as well as hip fracture. PRINCIPAL FINDINGS: When focusing the total frequency of diagnosis groups per record, an increase in depth of coding was observed. Between-hospital variations in depth of coding were present throughout the observation period. Specific comorbidity increases were observed in 15 of the 31 diagnosis groups, and decreases in comorbidity were observed for 11 groups. In patients hospitalized for heart failure, shifts of comorbidity-related risk of in hospital death occurred in nine diagnosis groups, in which eight groups were directed toward the null. CONCLUSIONS: Comorbidity-adjusted outcomes in longitudinal administrative data analyses may be biased by nonconstant risk over time, changes in completeness of coding, and between-hospital variations in coding. Accounting for such issues is important when the respective observation period coincides with changes in the reimbursement system or other conditions that are likely to alter clinical coding practice. PMID- 26741727 TI - Extensions of the Johnson-Neyman Technique to Linear Models With Curvilinear Effects: Derivations and Analytical Tools. AB - The past decade has witnessed renewed interest in the use of the Johnson-Neyman (J-N) technique for calculating the regions of significance for the simple slope of a focal predictor on an outcome variable across the range of a second, continuous independent variable. Although tools have been developed to apply this technique to probe 2- and 3-way interactions in several types of linear models, this method has not been extended to include quadratic terms or more complicated models involving quadratic terms and interactions. Curvilinear relations of this type are incorporated in several theories in the social sciences. This article extends the J-N method to such linear models along with presenting freely available online tools that implement this technique as well as the traditional pick-a-point approach. Algebraic and graphical representations of the proposed J N extension are provided. An example is presented to illustrate the use of these tools and the interpretation of findings. Issues of reliability as well as "spurious moderator" effects are discussed along with recommendations for future research. PMID- 26741728 TI - Getting the party started--Alone: Solitary predrinking mediates the effect of social anxiety on alcohol-related problems. AB - Predrinking (or pregaming) is common among undergraduates and has been linked with problem alcohol use. While many students predrink to save money, evidence suggests that some students predrink to cope with social anxiety (SA). Tension reduction and cognitive theories predict that those high in SA may predrink to reduce anticipatory anxiety before attending social events and their predrinking may be done alone rather than in normative social contexts. Available data suggest that, relative to social drinking, solitary drinking elevates risk for alcohol use and related problems. Informed by this evidence, we speculated that context for predrinking may be an important mechanism by which SA-risk for alcohol use unfolds. Specifically, we offered the novel hypothesis that those high in SA would engage frequently in solitary predrinking and this in turn would be associated with elevated alcohol use and related problems. Undergraduate drinkers (N=293; 70% women) completed self-reports of social anxiety, predrinking context (social, solitary), alcohol use, and alcohol-related problems. In partial support of our hypotheses, SA was a positive predictor of solitary predrinking, which in turn predicted elevated alcohol-related problems, but not alcohol use. While not hypothesized, we also found that SA was a negative predictor of social predrinking, which in turn reduced risk for alcohol use and related problems. Our study is the first in the literature to show that solitary predrinking helps explain the well-documented association between SA and alcohol-related problems. These findings may inform etiological models and clinical interventions, suggesting that SA-risk for problem drinking begins even before the party starts. PMID- 26741729 TI - Clinical outcome of elderly patients with unresectable pancreatic cancer treated with gemcitabine plus S-1, S-1 alone, or gemcitabine alone: Subgroup analysis of a randomised phase III trial, GEST study. AB - BACKGROUND: In the GEST study of unresectable pancreatic cancer, S-1 demonstrated non-inferiority compared to gemcitabine, but gemcitabine plus S-1 (GS) did not show superiority over gemcitabine for overall survival (OS). We performed subgroup analysis of these data focused on the efficacy and safety of these regimens as a first-line treatment for elderly patients. METHODS: Elderly patients (>= 70 years, n = 261) treated for unresectable pancreatic cancer (GS: n = 90, S-1: n = 85 and gemcitabine: n = 86) were analysed. RESULTS: No significant differences between the GS, S-1, or gemcitabine groups in OS (median: 10.2, 8.0 and 8.5 months, respectively) or objective response rates (27.6%, 25.3% and 14.3%, respectively) were noted. Grade >= III adverse haematological events were observed more frequently in GS-treated than in S-1- or gemcitabine-treated elderly patients (p < 0.001 and p = 0.016, respectively). Four of 8 patients aged >= 80 years experienced serious adverse events. CONCLUSIONS: S-1 and gemcitabine are both efficacious options for treatment of elderly patients with unresectable pancreatic cancer. Conversely, first-line treatment of elderly patients with GS should only be used after careful consideration. PMID- 26741732 TI - Reducing the V2O3(0001) surface through electron bombardment--a quantitative structure determination with I/V-LEED. AB - The (0001) surface of vanadium sesquioxide, V2O3, is terminated by vanadyl groups under standard ultra high vacuum preparation conditions. Reduction with electrons results in a chemically highly active surface with a well-defined LEED pattern indicating a high degree of order. In this work we report the first quantitative structure determination of a reduced V2O3(0001) surface. We identify two distinct surface phases by STM, one well ordered and one less well ordered. I/V-LEED shows the ordered phase to be terminated by a single vanadium atom per surface unit cell on a quasi-hexagonal oxygen layer with three atoms per two-dimensional unit cell. Furthermore we compare the method of surface reduction via electron bombardment with the deposition of V onto a vanadyl terminated film. The latter procedure was previously proposed to result in a structure with three surface vanadium atoms in the 2D unit cell and we confirm this with simulated STM images. PMID- 26741730 TI - Diastereoselective Synthesis of the Aminocyclitol Core of Jogyamycin via an Allene Aziridination Strategy. AB - Oxidative allene amination provides rapid access to densely functionalized amine containing stereotriads through highly reactive bicyclic methyleneaziridine intermediates. This strategy has been demonstrated as a viable approach for the construction of the densely functionalized aminocyclitol core of jogyamycin, a natural product with potent antiprotozoal activity. Importantly, the flexibility of oxidative allene amination will enable the syntheses of modified aminocyclitol analogues of the jogyamycin core. PMID- 26741731 TI - Controlled Fabrication of Bioactive Microfibers for Creating Tissue Constructs Using Microfluidic Techniques. AB - The fabrication of heterogeneous microstructures, which exert precise control over the distribution of different cell types within biocompatible constructs, is important for many tissue engineering applications. Here, bioactive microfibers with tunable morphologies, structures, and components are generated and employed for creating different tissue constructs. Multibarrel capillary microfluidics with multiple laminar flows are used for continuously spinning these microfibers. With an immediate gelation reaction of the cell dispersed alginate solutions, the cell-laden alginate microfibers with the tunable morphologies and structures as the designed multiple laminar flows can be generated. The performances of the microfibers in cell culture are improved by incorporating bioactive polymers, such as extracellular matrix (ECM) or methacrylated gelatin (GelMA), into the alginate. It is demonstrated that a series of complex three-dimensional (3D) architectural cellular buildings, including biomimic vessels and scaffolds, can be created using these bioactive microfibers. PMID- 26741734 TI - Creasable Batteries: Understanding Failure Modes through Dynamic Electrochemical Mechanical Testing. AB - Thin-film batteries that can be folded, bent, and even repeatedly creased with minimal or no loss in electrochemical performance have been demonstrated and systematically evaluated using two dynamic mechanical testing approaches for either controlled bending or creasing of flexible devices. The results show that mechanically robust and flexible Li-ion batteries (Li4Ti5O12//LiFePO4) based on the use of a nonwoven multiwalled carbon nanotube (MWNT) mat as a current collector (CC) exhibited a 14-fold decrease in voltage fluctuation at a bending strain of 4.2%, as compared to cells using traditional metal foil CCs. More importantly, MWNT-based full-cells exhibited excellent mechanical integrity through 288 crease cycles, whereas the foil full-cell exhibited continuously degraded performance with each fold and catastrophic fracture after only 94 folds. The enhancements due to MWNT CCs can be attributed to excellent interfacial properties as well as high mechanical strength coupled with compliancy, which allow the batteries to easily conform during mechanical abuse. These results quantitatively demonstrate the substantial enhancement offered in both mechanical and electrochemical stability which can be realized with traditional processing approaches when an appropriate choice of a flexible and robust CC is utilized. PMID- 26741735 TI - Application of Black Silicon for Nanostructure-Initiator Mass Spectrometry. AB - Nanostructure-initiator mass spectrometry (NIMS) is a matrix-free desorption/ionization technique with high sensitivity for small molecules. Surface preparation has relied on hydrofluoric acid (HF) electrochemical etching which is undesirable given the significant safety controls required in this specialized process. In this study, we examine a conventional and widely used process for producing black silicon based on sulfur hexafluoride/oxygen (SF6/O2) inductively coupled plasma (ICP) etching at cryogenic temperatures and we find it to be suitable for NIMS. A systematic study varying parameters in the plasma etching process was performed to understand the relationship of black silicon morphology and its sensitivity as a NIMS substrate. The results suggest that a combination of higher silicon temperature and oxygen flow rate gives rise to the formation of black silicon with fine pillar structures, whose aspect ratio are ~ 8.7 and depth are <1 MUm resulting in higher NIMS sensitivity which is attributed to surface restructuring caused by their low melting point upon laser irradiation. Interestingly, we find selectivity of these black silicon substrates to different analytes depending on the etching parameters. Though, the sensitivity of the dry etching process is lower than the traditional "wet" electrochemical etching process, it is suitable for many applications and is prepared using conventional equipment without the use of HF. PMID- 26741736 TI - Are combined AOPs effective for toxicity reduction in receiving marine environment? Suitability of battery of bioassays for wastewater treatment plant (WWTP) effluent as an ecotoxicological assessment. AB - Ecotoxicological assessment of three different wastewater treatment plant (WWTP) effluents D1, D2 and D3 was performed before and after tertiary treatment using combination of advanced oxidation processes (AOPs). A multibarrier treatment (MBT) consisting of microfiltration (MF), hydrogen peroxide photolysis (H2O2/UVC) and catalytic wet peroxide oxidation (CWPO) was applied for all effluents. Sparus aurata, Paracentrotus lividus, Isochrysis galbana and Vibrio fischeri, representing different trophic levels, constituted the battery of bioassays. Different acute toxicity effects were observed in each WWTP effluents tested. The percentage of sea urchin larval development and mortality fish larvae were the most sensitive endpoints. Significant reduction (p < 0.05) of effluent's toxicity was observed using a classification pT-method after MBT process. Base on obtained results, tested battery of bioassays in pT-method framework can be recommended for acute toxicity preliminary evaluation of WWTP effluents for the marine environment. PMID- 26741737 TI - Limited differences in fish and benthic communities and possible cascading effects inside and outside a protected marine area in Sagres (SW Portugal). AB - Marine protected areas (MPAs) are a relatively recent fisheries management and conservation tool for conservation of marine ecosystems and serve as experimental grounds to assess trophic cascade effects in areas were fishing is restricted to some extent. A series of descriptive field studies were performed to assess fish and benthic communities between two areas within a newly established MPA in SW Portugal. We characterized benthic macroalgal composition and determined the size, density and biomass of the main benthic predatory and herbivorous fish species as well as the main benthic herbivorous invertebrates to assess indications of top-down control on the phytobenthic assemblages. Fish species were identical inside and outside the MPA, in both cases Sarpa salpa was the most abundant fish herbivore and Diplodus spp. accounted for the great majority of the benthic predators. However, size and biomass of D. spp. were higher inside than outside the MPA. The main herbivorous invertebrate was the sea urchin Paracentrotus lividus, which was smaller and predominantly showing a crevice dwelling behaviour in the MPA. In addition, P. lividus size frequency distribution showed a unimodal pattern outside and a bimodal pattern inside the MPA. We found significant differences in the algal assemblages between inside and outside the MPA, with higher abundance of turf and foliose algae inside, and articulated calcareous and corticated macrophytes outside the MPA, but no differences in the invasive Asparagopsis spp. The obtained results show differences in predatory fish and benthic community structure, but not in species richness, inside and outside the MPA. We hypothesize these differences lead to variation in species interactions: directly through predation and indirectly via affecting sea urchins behavioural patterns, predators might drive changes in macroalgal assemblages via trophic cascade in the study area. However due to non biological differences between the two areas it is difficult to suggest that the MPA causes increased biological parameters of targeted species and to assess predatory control and trophic cascade effects in areas where fishing pressure is reduced. It is therefor advisable to design MPAs so that their impacts can be scientifically evaluated in a proper fashion. PMID- 26741738 TI - A photoelectrochemical methanol fuel cell based on aligned TiO2 nanorods decorated graphene photoanode. AB - We report the photoelectrochemical (PEC) oxidation of methanol on a rationally designed graphene-TiO2 nanorod array (G-TNR) photoanode. A PEC methanol fuel cell was constructed by coupling the G-TNR photoanode with a cathode. This study raises a conceptual fuel cell that realizes the synergistic energy conversion of chemical energy and solar energy. PMID- 26741739 TI - The practicalities of living with oxygen: a perspective from a person living with COPD. AB - Although I welcomed oxygen into my life, it required a degree of adjustment and perseverance. The concentrator told all visitors that this was the home of a 'patient', and using ambulatory oxygen in public takes a lot of getting used to. Safe use of oxygen entailed some changes in routine activities, and travel needs to be planned ahead to ensure that I don't run out of oxygen. Despite its drawbacks, oxygen has enabled me to have a full and active life once again. PMID- 26741741 TI - Conditioned Pain Modulation in Patients With Acute and Chronic Low Back Pain. AB - OBJECTIVES: Disturbed endogenous pain modulation is likely one of the mechanisms underlying central hypersensitivity and might be a contributing factor for the development and maintenance of chronic pain. To our knowledge, no study has investigated endogenous pain modulation in both acute and chronic low back pain (LBP). We tested the hypothesis that endogenous pain inhibition is impaired in patients with acute and chronic LBP. MATERIALS AND METHODS: We evaluated 40 patients with acute LBP, 34 patients with chronic LBP and 30 pain-free controls for their conditioned pain modulation (CPM), with pressure pain tolerance and cold pressor as test and conditioning stimulus, respectively. Measurements were repeated up to 10 minutes after cold pressor test. RESULTS: There was no difference in CPM among the groups immediately after cold pressor test. However, the decline in CPM effect was significantly faster in chronic and acute LBP patients than in controls, with no evidence for differences between pain groups. DISCUSSION: The present study provides evidence for some alterations of endogenous modulation in both acute and chronic LBP. CPM was still detected in both patient groups, indicating that endogenous modulation, although effective for a shorter duration, is partially functioning in patients with LBP. PMID- 26741740 TI - Oocyte Polarization Is Coupled to the Chromosomal Bouquet, a Conserved Polarized Nuclear Configuration in Meiosis. AB - The source of symmetry breaking in vertebrate oocytes is unknown. Animal-vegetal oocyte polarity is established by the Balbiani body (Bb), a conserved structure found in all animals examined that contains an aggregate of specific mRNAs, proteins, and organelles. The Bb specifies the oocyte vegetal pole, which is key to forming the embryonic body axes as well as the germline in most vertebrates. How Bb formation is regulated and how its asymmetric position is established are unknown. Using quantitative image analysis, we trace oocyte symmetry breaking in zebrafish to a nuclear asymmetry at the onset of meiosis called the chromosomal bouquet. The bouquet is a universal feature of meiosis where all telomeres cluster to one pole on the nuclear envelope, facilitating chromosomal pairing and meiotic recombination. We show that Bb precursor components first localize with the centrosome to the cytoplasm adjacent to the telomere cluster of the bouquet. They then aggregate around the centrosome in a specialized nuclear cleft that we identified, assembling the early Bb. We show that the bouquet nuclear events and the cytoplasmic Bb precursor localization are mechanistically coordinated by microtubules. Thus the animal-vegetal axis of the oocyte is aligned to the nuclear axis of the bouquet. We further show that the symmetry breaking events lay upstream to the only known regulator of Bb formation, the Bucky ball protein. Our findings link two universal features of oogenesis, the Bb and the chromosomal bouquet, to oocyte polarization. We propose that a meiotic-vegetal center couples meiosis and oocyte patterning. Our findings reveal a novel mode of cellular polarization in meiotic cells whereby cellular and nuclear polarity are aligned. We further reveal that in zygotene nests, intercellular cytoplasmic bridges remain between oocytes and that the position of the cytoplasmic bridge coincides with the location of the centrosome meiotic-vegetal organizing center. These results suggest that centrosome positioning is set by the last mitotic oogonial division plane. Thus, oocytes are polarized in two steps: first, mitotic divisions preset the centrosome with no obvious polarization yet, then the meiotic-vegetal center forms at zygotene bouquet stages, when symmetry is, in effect, broken. PMID- 26741742 TI - An Empirical Investigation of a Biopsychosocial Model of Pain in Multiple Sclerosis. AB - OBJECTIVES: Pain is a significant problem for many individuals with multiple sclerosis (MS). Pain is often associated with other MS symptoms (eg, physical, sensorimotor, cognitive declines), and both pain and MS symptoms are hypothesized to contribute to psychosocial problems (eg, depression), other symptoms (eg, fatigue, sleep disturbance), and functional impairments (eg, pain interference). On the basis of a biopsychosocial model, we sought to: (1) examine the associations between pain, MS symptoms, depression, psychosocial, and functional variables and (2) identify possible risk and protective factors associated with pain in MS. MATERIALS AND METHODS: A cross-sectional survey was completed by 424 individuals with MS. Pain, MS symptoms, demographics, MS diagnostic factors, and psychosocial and functional variables were assessed. Data were analyzed by structural equation models. RESULTS: Participants were predominantly white (92%), middle-aged (mean=50.7 y), and female (80%). Results indicated that pain severity and depression accounted for >50% of the variance in pain interference. Although pain contributed minimally to fatigue and sleep quality, depression and MS symptoms predicted 49% of the variance in fatigue, and depression was largely responsible for the 40% of predicted variance in sleep quality. Identified risk factors for pain were low educational attainment and lack of a committed/marital relationship, even while controlling for diagnostic and other key demographic variables. DISCUSSION: Results highlight the importance of targeting interventions toward improving coping skills and social support within the context of pain and MS. Research is needed to determine whether effectively targeting depression in MS results in improvements of other critical psychosocial and physical functioning domains. PMID- 26741743 TI - Clinical Outcome of Hydroxyapatite Coated, Bioactive Glass Coated, and Machined Ti6Al4V Threaded Dental Implant in Human Jaws: A Short-Term Comparative Study. AB - INTRODUCTION: Growing aspect of endosseous implant research is focused on surface modification of dental implants for the purpose of improving osseointegration. The aim of this study was to evaluate and compare the clinical outcome (ie, osseointegration) of hydroxyapatite coated, bioactive glass coated and machined titanium alloy threaded dental implants in human jaw bone after implantation. MATERIALS AND METHODS: One hundred twenty-six implants (45 hydroxyapatite coated, 41 bioactive glass coated, and 40 machined titanium implants) have been placed in incisor areas of 62 adult patients. Outcome was assessed up to 12 months after prosthetic rehabilitation using different clinical and radiological parameters. Surface roughness of failed implants was analyzed by laser profilometer. DISCUSSION: Hydroxyapatite and bioactive glass coating materials were nontoxic and biocompatible. Least marginal bone loss in radiograph, significantly higher (P < 0.05) interface radiodensity, and less interfacial gaps were observed in computed tomography with bioactive glass coated implants at anterior maxilla compared to other 2 types. CONCLUSION: Bioactive glass coated implants are equally safe and effective as hydroxyapatite coated and machined titanium implants in achieving osseointegration; therefore, can be effectively used as an alternative coating material for dental implants. PMID- 26741744 TI - Enhanced Mechanical Properties in Cellulose Nanocrystal-Poly(oligoethylene glycol methacrylate) Injectable Nanocomposite Hydrogels through Control of Physical and Chemical Cross-Linking. AB - While injectable hydrogels have several advantages in the context of biomedical use, their generally weak mechanical properties often limit their applications. Herein, we describe in situ-gelling nanocomposite hydrogels based on poly(oligoethylene glycol methacrylate) (POEGMA) and rigid rod-like cellulose nanocrystals (CNCs) that can overcome this challenge. By physically incorporating CNCs into hydrazone cross-linked POEGMA hydrogels, macroscopic properties including gelation rate, swelling kinetics, mechanical properties, and hydrogel stability can be readily tailored. Strong adsorption of aldehyde- and hydrazide modified POEGMA precursor polymers onto the surface of CNCs promotes uniform dispersion of CNCs within the hydrogel, imparts physical cross-links throughout the network, and significantly improves mechanical strength overall, as demonstrated by quartz crystal microbalance gravimetry and rheometry. When POEGMA hydrogels containing mixtures of long and short ethylene oxide side chain precursor polymers were prepared, transmission electron microscopy reveals that phase segregation occurs with CNCs hypothesized to preferentially locate within the stronger adsorbing short side chain polymer domains. Incorporating as little as 5 wt % CNCs results in dramatic enhancements in mechanical properties (up to 35-fold increases in storage modulus) coupled with faster gelation rates, decreased swelling ratios, and increased stability versus hydrolysis. Furthermore, cell viability can be maintained within 3D culture using these hydrogels independent of the CNC content. These properties collectively make POEGMA-CNC nanocomposite hydrogels of potential interest for various biomedical applications including tissue engineering scaffolds for stiffer tissues or platforms for cell growth. PMID- 26741745 TI - Anti-Allergic Drugs Tranilast and Ketotifen Dose-Dependently Exert Mast Cell Stabilizing Properties. AB - BACKGROUND: Anti-allergic drugs, such as tranilast and ketotifen, inhibit the release of chemokines from mast cells. However, we know little about their direct effects on the exocytotic process of mast cells. Since exocytosis in mast cells can be monitored electrophysiologically by changes in the whole-cell membrane capacitance (Cm), the absence of such changes by these drugs indicates their mast cell-stabilizing properties. METHODS: Employing the standard patch-clamp whole cell recording technique in rat peritoneal mast cells, we examined the effects of tranilast and ketotifen on the Cm during exocytosis. Using confocal imaging of a water-soluble fluorescent dye, lucifer yellow, we also examined their effects on the deformation of the plasma membrane. RESULTS: Relatively lower concentrations of tranilast (100, 250 uM) and ketotifen (1, 10 uM) did not significantly affect the GTP-x03B3;-S-induced increase in the Cm. However, higher concentrations of tranilast (500 uM, 1 mM) and ketotifen (50, 100 uM) almost totally suppressed the increase in the Cm, and washed out the trapping of the dye on the surface of the mast cells. Compared to tranilast, ketotifen required much lower doses to similarly inhibit the degranulation of mast cells or the increase in the Cm. CONCLUSIONS: This study provides electrophysiological evidence for the first time that tranilast and ketotifen dose-dependently inhibit the process of exocytosis, and that ketotifen is more potent than tranilast in stabilizing mast cells. The mast cell-stabilizing properties of these drugs may be attributed to their ability to counteract the plasma membrane deformation in degranulating mast cells. PMID- 26741746 TI - Anticonvulsants Based on the alpha-Substituted Amide Group Pharmacophore Bind to and Inhibit Function of Neuronal Nicotinic Acetylcholine Receptors. AB - Although the antiepileptic properties of alpha-substituted lactams, acetamides, and cyclic imides have been known for over 60 years, the mechanism by which they act remains unclear. I report here that these compounds bind to the nicotinic acetylcholine receptor (nAChR) and inhibit its function. Using transient kinetic measurements with functionally active, nondesensitized receptors, I have discovered that (i) alpha-substituted lactams and cyclic imides are noncompetitive inhibitors of heteromeric subtypes (such as alpha4beta2 and alpha3beta4) of neuronal nAChRs and (ii) the binding affinity of these compounds toward the nAChR correlates with their potency in preventing maximal electroshock (MES)-induced convulsions in mice. Based on the hypothesis that alpha-substituted amide group is the essential pharmacophore of these drugs, I found and tested a simple compound, 2-phenylbutyramide. This compound indeed inhibits nAChR and shows good anticonvulsant activity in mice. Molecular docking simulations suggest that alpha-substituted lactams, acetamides, and cyclic imides bind to the same sites on the extracellular domain of the receptor. These new findings indicate that inhibition of brain nAChRs may play an important role in the action of these antiepileptic drugs, a role that has not been previously recognized. PMID- 26741783 TI - Evaluation development for a physical activity positive youth development program for girls. AB - Girls on the Run (GOTR) is an after school program for girls in third through fifth grade which utilizes a physical activity based positive youth development curriculum that culminates with completing a 5K run. Unfortunately, there is little empirical data documenting GOTR participant changes that align with the curriculum and describe the evaluation process. Therefore, this study presents an evaluation of GOTR consisting of three main processes: curriculum content analysis and stakeholder focus groups (N=11) to identify key outcomes of the program; community-based participatory research to collaborate with program personnel to further identify important outcomes; and the design and pilot testing of an instrument (N=104) for assessing changes in the theoretically grounded outcomes over time. Findings demonstrated a positive collaborative process that led to important information to be used for an impact evaluation of Girls on the Run and for future evaluation development efforts for physical activity based positive youth development. PMID- 26741784 TI - Ab Initio Determined Phase Diagram of Clean and Solvated Muscovite Mica Surfaces. AB - Focusing on muscovite mica, the most significant phyllosilicate in the mica series, we determine its surface phase diagram employing density functional theory. Surfaces in vacuum and in more realistic environmental conditions, that is, the surface in contact with water or an ionic liquid, are considered. These results naturally explain experimental observations such as the swelling of mica when it comes into contact with water. PMID- 26741785 TI - (99m)Tc-Cyclopentadienyl Tricarbonyl Chelate-Labeled Compounds as Selective Sigma 2 Receptor Ligands for Tumor Imaging. AB - We have designed and synthesized a series of cyclopentadienyl tricarbonyl rhenium complexes containing a 5,6-dimethoxyisoindoline or a 6,7-dimethoxy-1,2,3,4 tetrahydroisoquinoline pharmacophore as sigma2 receptor ligands. Rhenium compound 20a possessed low nanomolar sigma2 receptor affinity (K(i) = 2.97 nM) and moderate subtype selectivity (10-fold). Moreover, it showed high selectivity toward vesicular acetylcholine transporter (2374-fold), dopamine D2L receptor, NMDA receptor, opiate receptor, dopamine transporter, norepinephrine transporter, and serotonin transporter. Its corresponding radiotracer [(99m)Tc]20b showed high uptake in a time- and dose-dependent manner in DU145 prostate cells and C6 glioma cells. In addition, this tracer exhibited high tumor uptake (5.92% ID/g at 240 min) and high tumor/blood and tumor/muscle ratios (21 and 16 at 240 min, respectively) as well as specific binding to sigma receptors in nude mice bearing C6 glioma xenografts. Small animal SPECT/CT imaging of [(99m)Tc]20b in the C6 glioma xenograft model demonstrated a clear visualization of the tumor at 180 min after injection. PMID- 26741786 TI - Emerging Frontiers in Drug Delivery. AB - Medicine relies on the use of pharmacologically active agents (drugs) to manage and treat disease. However, drugs are not inherently effective; the benefit of a drug is directly related to the manner by which it is administered or delivered. Drug delivery can affect drug pharmacokinetics, absorption, distribution, metabolism, duration of therapeutic effect, excretion, and toxicity. As new therapeutics (e.g., biologics) are being developed, there is an accompanying need for improved chemistries and materials to deliver them to the target site in the body, at a therapeutic concentration, and for the required period of time. In this Perspective, we provide an historical overview of drug delivery and controlled release followed by highlights of four emerging areas in the field of drug delivery: systemic RNA delivery, drug delivery for localized therapy, oral drug delivery systems, and biologic drug delivery systems. In each case, we present the barriers to effective drug delivery as well as chemical and materials advances that are enabling the field to overcome these hurdles for clinical impact. PMID- 26741787 TI - Measuring Patients' Knowledge About Adverse Effects of Angiotensin-Converting Enzyme Inhibitors. AB - BACKGROUND: Knowledge about adverse effects of medications is an important part of proper medication use and prerequisite for good treatment adherence. OBJECTIVE: The aim of our study was to construct, develop, and test a new questionnaire for the measurement of patients' knowledge about adverse drug reactions of angiotensin-converting enzyme (ACE) inhibitors. METHODS: The 8-item questionnaire was constructed to measure adverse reactions to ACE inhibitors. The questions were closed, with 7 offered answers, in the form of a Likert scale. It was tested for psychometric properties on patients who visited their general practitioners at state-owned health facilities in 5 Serbian cities: Belgrade, Kragujevac, Banja Luka, Gracanica, and Despotovac. RESULTS: The questionnaire was tested on 259 patients from general practice, taking an ACE inhibitor for more than 3 months. Experience with at least 1 adverse effect of ACE inhibitor was reported in 64 patients (24.7%), only 94 patients (36.3%) previously received any form of information about at least 1 adverse effect of ACE inhibitors from health workers, and only 42% expressed knowledge of any adverse events. The patients who were informed knew about the following adverse events as phrased in the official patient information leaflets: severe dizziness or light-headedness (44%); cough (37%); swelling of the hands, face, lips, or tongue (32%); indigestion (22%); headache (51%); and difficulty in breathing (15%). The questionnaire showed satisfactory internal consistency, with Cronbach alpha of 0.767, and individual scores correlated with general education of the patients. Factorial analysis revealed 2 domains (subscales): the first one with 5 questions is directed to adverse effects the patients may physically experience directly, whereas the second with 3 questions measures knowledge about adverse effects that could be experienced only indirectly, through conditions caused by the adverse effects. CONCLUSIONS: The questionnaire about knowledge of ACE inhibitors' adverse effects is a reliable and probably valid instrument for measuring patients' knowledge about adverse effects of ACE inhibitors. PMID- 26741788 TI - Perceptions of Emergency Department Triage Nurses About Prehospital Emergency Rescuers in Italy: A Latent Threat to Clinical Handover. AB - OBJECTIVES: In Italy, volunteer rescuers respond to most prehospital emergency calls. These rescuers provide the majority of patient information during handover at the emergency department triage. Standardized terminology between rescuers and triage nurses is lacking in Italy, and miscommunication may cause a poor handover. Even though rescuers are professional health providers, their qualification is not legally recognized, and triage nurses have a pervasive sense of inadequacy about the rescuers' competences.This work explored triage nurses' perceptions of rescuers and the causes of these perceptions to verify whether difficult interprofessional relationships negatively influence the clinical handover process. METHODS: We performed a survey among 402 triage nurses for 3 main areas of rescuers' competency: communication, knowledge, and decision making. For each area, we identified communications, decision making, and knowledge indicators. A scale score of 6 or higher was considered not sufficient. RESULTS: We found that 75.5% (n = 302/400) of triage nurses regard rescuers' ability to recognize life-threatening situations as not sufficient (communication ability indicator). Approximately 66% (n = 264/401) of triage nurses regard rescuers' ability to administer oxygen as not sufficient (decision-making indicator), and approximately 58% (n = 232/402) of nurses regard rescuers' ability to report the reason for the emergency call as not sufficient (knowledge indicator). CONCLUSIONS: The results of this survey show that the overall perception of triage nurses about prehospital rescuers is slightly below sufficiency. This perception could cause errors during the prehospital or hospital handover at the triage and could lead to delayed decisions and incorrect treatment. PMID- 26741789 TI - Information Transfer at Hospital Discharge: A Systematic Review. AB - BACKGROUND: Prompt, complete, and accurate information transfer at the time of discharge between hospital-based and primary care providers (PCPs) is needed for the provision of safe and effective care. PURPOSE OF THE STUDY: To evaluate timeliness, quality, and interventions to improve timeliness and quality of hospital discharge summaries. DATA SOURCES: PubMed, MEDLINE, EMBASE, CINAHL, Web of Science, and Scopus database published in English between January 2007 and February 2014 were searched. We also hand-searched bibliographies of relevant articles. STUDY SELECTION: Observational studies investigating transfer of information at hospital discharge (n = 7) and controlled studies evaluating interventions to improve timeliness and quality of discharge information (n = 12) were included. DATA EXTRACTION: We extracted data on availability, timeliness, and content of hospital discharge summaries and on the effectiveness of interventions targeting discharge summaries. Results of studies are presented narratively and using descriptive statistics. DATA SYNTHESIS: Across the studies, discharge summaries were completed within 48 hours in a median of 67% and were available to PCPs within 48 hours only 55% of the time. Most of the time, discharge summaries included demographics, primary diagnosis, hospital course, and discharge instructions. However, information was limited to pending test results (25%), diagnostic tests performed (60%), and postdischarge medications (78%). In 6 interventional studies, implementation of electronic discharge summaries was associated with improvement in timeliness but not quality. CONCLUSIONS: Delayed or insufficient transfer of discharge information between hospital-based providers and PCPs remains common. Creation of electronic discharge summaries seems to improve timeliness and availability but does not consistently improve quality. PMID- 26741790 TI - Improved Safety Culture and Teamwork Climate Are Associated With Decreases in Patient Harm and Hospital Mortality Across a Hospital System. AB - OBJECTIVES: Improved safety and teamwork culture has been associated with decreased patient harm within specific units in hospitals or hospital groups. Most studies have focused on a specific harm type. This study's objective was to document such an association across an entire hospital system and across multiple harm types. METHODS: The Safety Attitudes Questionnaire (SAQ) was administered to all clinical personnel (including physicians) before, 2 years after, and 4 years after establishing a comprehensive patient safety/high-reliability program at a major children's hospital. Resultant data were analyzed hospital-wide as well as by individual units, medical sections, and professional groups. RESULTS: Safety attitude scores improved over the 3 surveys (P < 0.05) as did teamwork attitude scores (P = nonsignificant). These increases were accompanied by contemporaneous statistically significant decreases in all-hospital harm (P < 0.01), serious safety events (P < 0.001), and severity-adjusted hospital mortality (P < 0.001). Differences were noted between physicians' and nurses' views on specific safety and teamwork items within individual units, with nursing scores often lower. These discipline-specific differences decreased with time. CONCLUSIONS: Improved safety and teamwork climate as measured by SAQ are associated with decreased patient harm and severity-adjusted mortality. Discrepancies in SAQ scores exist between different professional groups but decreased over time. PMID- 26741792 TI - Homoleptic Tris-Cyclometalated Iridium Complexes with Substituted o-Carboranes: Green Phosphorescent Emitters for Highly Efficient Solution-Processed Organic Light-Emitting Diodes. AB - Homoleptic tris-cyclometalated iridium complexes, fac-Ir[5-(2-RCB)ppy]3 (3a-3c; CB = o-carboran-1-yl; ppy = 2-phenylpyridinato-C(2),N; R = H (3a), Me (3b), (i)Bu (3c)) with 2-R-substituted o-carboranes at the 5-position of the ppy ligand, were prepared and characterized. X-ray diffraction analysis of 3a and 3c revealed that the three C^N ligands adopt a fac-arrangement around the Ir atom and that the carboranyl C-C bond distance increases with increasing steric effects of the 2-R substituent. The phosphorescence wavelengths of the complexes were apparently blue-shifted by ca. 20 nm (lambdaem = 487-493 nm) compared to that of the parent fac-Ir(ppy)3 (4; lambdaem = 508 nm). In particular, 3a-3c were highly emissive in toluene, and the phosphorescence quantum efficiencies of 3a and 3b (PhiPL = 0.95 0.98) were comparable to that of 4. Solution-processed electroluminescent devices incorporating 3a-3c as emitters displayed green light with high performance, and devices based on the 3c dopant showed the highest performance. In particular, the devices based on 3c exhibited performance more than double of that of the device based on 4 in terms of current efficiency (29.6 cd/A for 3c vs 15.8 cd/A for 4 at 4 wt % Ir and 1000 cd/m(2)), power efficiency (11.0 lm/W for 3c vs 6.3 lm/W for 4), and external quantum efficiency (10.2% for 3c vs 4.7% for 4) over a wide range of luminance. The higher PL quantum yields of doped host films with 3c than those with 4 at high dopant concentrations above 8 wt % suggested that along with high phosphorescence quantum efficiency, the steric bulkiness of the 2-(i)Bu substituted o-carborane in 3c plays a crucial role in improving device performance. PMID- 26741793 TI - Gram Scale Conversion of R-BINAM to R-NOBIN. AB - A mild, operationally simple, and single-step transition-metal-free protocol for the synthesis of enantiomerically pure (R)-(+)-2'-amino-1,1'-binaphthalen-2-ol (R NOBIN) from (R)-(+)-1,1'-binaphthyl-2,2'-diamine (R-BINAM) is reported. The one pot conversion proceeds with good yield and shows no racemization. The hydroxyl on the R-NOBIN product was shown to have come from water in the reaction medium via an H2(18)O study. The correct value of the specific rotation of R-NOBIN was reported. PMID- 26741791 TI - Ultrahigh (19)F Loaded Cu1.75S Nanoprobes for Simultaneous (19)F Magnetic Resonance Imaging and Photothermal Therapy. AB - (19)F magnetic resonance imaging (MRI) is a powerful noninvasive, sensitive, and accurate molecular imaging technique for early diagnosis of diseases. The major challenge of (19)F MRI is signal attenuation caused by the reduced solubility of probes with increased number of fluorine atoms and the restriction of molecular mobility. Herein, we present a versatile one-pot strategy for the fabrication of a multifunctional nanoprobe with high (19)F loading (~2.0 * 10(8 19)F atoms per Cu1.75S nanoparticle). Due to the high (19)F loading and good molecular mobility that results from the small particle size (20.8 +/- 2.0 nm) and ultrathin polymer coating, this nanoprobe demonstrates ultrahigh (19)F MRI signal. In vivo tests show that this multifunctional nanoprobe is suitable for (19)F MRI and photothermal therapy. This versatile fabrication strategy has also been readily extended to other single-particle nanoprobes for ablation and sensitive multimodal imaging. PMID- 26741795 TI - Metal-exchangeable macrocycles: from a bismetallo-Ru2/Zn triangle to a Ru2/Fe triangular assembly. AB - Bismetallic triangles T4 (Ru2/Fe) and T5 (Ru2/Zn) were effectively prepared via a stepwise method from a 60 degrees -bent bisterpyridne. Compared with obtaining T4 by mixing metallo-organic ligand L2 with Fe(2+) directly and refluxing at a higher temperature (85 degrees C), the site to site metallo-transformation from T5 to T4 was employed at RT by simply adding Fe(2+) to T5. The structures were fully confirmed by the NMR, ESI-mass, UV-vis absorption and emission spectroscopies. PMID- 26741794 TI - Vocal activity of lesser galagos (Galago spp.) at zoos. AB - Almost nothing is known about the natural vocal behavior of lesser galagos living in zoos. This is perhaps because they are usually kept in nocturnal exhibits separated from the visitors by a transparent and acoustically insulating glass barrier. The aim of the present study was therefore to fill this gap in knowledge of the vocal behavior of lesser galagos from zoos. This knowledge might be beneficial because the vocalizations of these small primates can be used for species determination. We performed a 10-day-long acoustic monitoring of vocal activity in each of seven various groups of Galago senegalensis and G. moholi living at four zoos. We quantitatively evaluated the occurrence of four loud vocalization types present in both species, including the most species-specific advertisement call. We found that qualitative as well as quantitative differences exist in the vocal behavior of the studied groups. We confirmed that the observed vocalization types can be collected from lesser galagos living at zoos, and the success can be increased by selecting larger and more diverse groups. We found two distinct patterns of diel vocal activity in the most vocally active groups. G. senegalensis groups were most vocally active at the beginning and at the end of their activity period, whereas one G. moholi group showed an opposite pattern. The latter is surprising, as it is generally accepted that lesser galagos emit advertisement calls especially at dawn and dusk, i.e., at the beginning and at the end of their diel activity. PMID- 26741796 TI - Manganese- and Borane-Mediated Synthesis of Isobenzofuranones from Aromatic Esters and Oxiranes via C-H Bond Activation. AB - A manganese- and borane-mediated synthesis of isobenzofuranones from esters and oxiranes is developed. The reaction proceeded at aromatic, heteroaromatic, and olefinic C-H bonds with high functional group tolerance. This is the first example of a manganese-catalyzed C-H transformation using an oxygen-directing group. Triphenylborane played an important role in this reaction to cooperatively promote the annulation reaction. Kinetic isotope effect experiments revealed that C-H bond activation of the aromatic rings was the rate-determining step. PMID- 26741797 TI - APOBEC3G Variants and Protection against HIV-1 Infection in Burkina Faso. AB - Studies on host factors, particularly the APOBEC3G gene, have previously found an association with AIDS progression in some populations and against some HIV-1 strains but not others. Our study had two main objectives: firstly, to screen a population from Burkina Faso for three variants of APOBEC3G previously described, and secondly to analyze the effect of these three variants and their haplotypes on HIV-1 infection with Circulating Recombinant Forms (CRFs) present in Burkina Faso. This case control study involved 708 seropositive and seronegative individuals. Genotyping was done by the TaqMan allelic discrimination method. Minor allele frequencies of rs6001417 (p<0.05), rs8177832 (P<0.05), and rs35228531 (P<0.001) were higher in seronegative subjects. The rs6001417 and rs8177832 SNPs were associated with HIV-1 infection in an additive model (P<0.01). Furthermore the SNP rs35228531 was also associated with HIV-1 infection in a dominant model (P<0.001). Odds ratio analysis of genotypes and alleles of the different APOBEC3G variants showed that there is a strong association between the minor genetic variants, genotype of the three SNPs, and HIV-1 status. Haplotype analysis demonstrated that rs6001417, rs8177832, and rs35228531 are in linkage disequilibrium. The haplotype GGT from the rs6001417, rs8177832 and rs35228531 respectively has a protective effect OR = 0.54 [0.43-0.68] with P<0.001. There was also associations between the haplotypes GGC OR = 1.6 [1.1; 2.3] P<0.05, and CGC OR = 5.21 [2.4-11.3] P<0.001, which increase the risk of infection by HIV-1 from almost two (2) to five (5) fold. This study demonstrates an association of rs6001417, rs8177832, and rs35228531 of APOBEC3G with HIV-1 infection in a population from Burkina Faso. PMID- 26741800 TI - The Rapid Capture of Attention by Rewarded Objects. AB - When a stimulus is associated with a reward, it becomes prioritized, and the allocation of attention to that stimulus increases. For low-level features, such as color, this reward-based allocation of attention can manifest early in time and as a faster and stronger shift of attention to targets with that color, as reflected by the N2pc (a parieto-occipital electrophysiological component peaking at ~250 msec). It is unknown, however, if reward associations can similarly modulate attentional shifts to complex objects or object categories, or if reward related modulation of attentional allocation to such stimuli would occur later in time or through a different mechanism. Here, we used magnetoencephalographic recordings in 24 participants to investigate how object categories with a reward association would modulate the shift of attention. On each trial, two colored squares were presented, one in a target color and the other in a distractor color, each with an embedded object. Participants searched for the target-colored square and performed a corner discrimination task. The embedded objects were from either a rewarded or non-rewarded category, and if a rewarded-category object were present within the target-colored square, participants could earn extra money for correct performance. We observed that when the target color contained an object from a rewarded versus a non-rewarded category, the neural shift of attention to the target was faster and of greater magnitude, although the rewarded objects were not relevant for correct task performance. These results suggest that reward associations of complex objects can rapidly modulate attentional allocation to a target. PMID- 26741801 TI - Near-optimal Integration of Magnitude in the Human Parietal Cortex. AB - Humans are often observed to make optimal sensorimotor decisions but to be poor judges of situations involving explicit estimation of magnitudes or numerical quantities. For example, when drawing conclusions from data, humans tend to neglect the size of the sample from which it was collected. Here, we asked whether this sample size neglect is a general property of human decisions and investigated its neural implementation. Participants viewed eight discrete visual arrays (samples) depicting variable numbers of blue and pink balls. They then judged whether the samples were being drawn from an urn in which blue or pink predominated. A participant who neglects the sample size will integrate the ratio of balls on each array, giving equal weight to each sample. However, we found that human behavior resembled that of an optimal observer, giving more credence to larger sample sizes. Recording scalp EEG signals while participants performed the task allowed us to assess the decision information that was computed during integration. We found that neural signals over the posterior cortex after each sample correlated first with the sample size and then with the difference in the number of balls in either category. Moreover, lateralized beta-band activity over motor cortex was predicted by the cumulative difference in number of balls in each category. Together, these findings suggest that humans achieve statistically near-optimal decisions by adding up the difference in evidence on each sample, and imply that sample size neglect may not be a general feature of human decision making. PMID- 26741798 TI - Detection of Alpha-Toxin and Other Virulence Factors in Biofilms of Staphylococcus aureus on Polystyrene and a Human Epidermal Model. AB - BACKGROUND & AIM: The ability of Staphylococcus aureus to successfully colonize (a)biotic surfaces may be explained by biofilm formation and the actions of virulence factors. The aim of the present study was to establish the presence of 52 proteins, including virulence factors such as alpha-toxin, during biofilm formation of five different (methicillin resistant) S. aureus strains on Leiden human epidermal models (LEMs) and polystyrene surfaces (PS) using a competitive Luminex-based assay. RESULTS: All five S. aureus strains formed biofilms on PS, whereas only three out of five strains formed biofilms on LEMs. Out of the 52 tested proteins, six functionally diverse proteins (ClfB, glucosaminidase, IsdA, IsaA, SACOL0688 and nuclease) were detected in biofilms of all strains on both PS and LEMs. At the same time, four toxins (alpha-toxin, gamma-hemolysin B and leukocidins D and E), two immune modulators (formyl peptide receptor-like inhibitory protein and Staphylococcal superantigen-like protein 1), and two other proteins (lipase and LytM) were detectable in biofilms by all five S. aureus strains on LEMs, but not on PS. In contrast, fibronectin-binding protein B (FnbpB) was detectable in biofilms by all S. aureus biofilms on PS, but not on LEMs. These data were largely confirmed by the results from proteomic and transcriptomic analyses and in case of alpha-toxin additionally by GFP-reporter technology. CONCLUSION: Functionally diverse virulence factors of (methicillin resistant) S. aureus are present during biofilm formation on LEMs and PS. These results could aid in identifying novel targets for future treatment strategies against biofilm-associated infections. PMID- 26741799 TI - Intensive Working Memory Training Produces Functional Changes in Large-scale Frontoparietal Networks. AB - Working memory is central to human cognition, and intensive cognitive training has been shown to expand working memory capacity in a given domain. It remains unknown, however, how the neural systems that support working memory are altered through intensive training to enable the expansion of working memory capacity. We used fMRI to measure plasticity in activations associated with complex working memory before and after 20 days of training. Healthy young adults were randomly assigned to train on either a dual n-back working memory task or a demanding visuospatial attention task. Training resulted in substantial and task-specific expansion of dual n-back abilities accompanied by changes in the relationship between working memory load and activation. Training differentially affected activations in two large-scale frontoparietal networks thought to underlie working memory: the executive control network and the dorsal attention network. Activations in both networks linearly scaled with working memory load before training, but training dissociated the role of the two networks and eliminated this relationship in the executive control network. Load-dependent functional connectivity both within and between these two networks increased following training, and the magnitudes of increased connectivity were positively correlated with improvements in task performance. These results provide insight into the adaptive neural systems that underlie large gains in working memory capacity through training. PMID- 26741802 TI - Are Face and Object Recognition Independent? A Neurocomputational Modeling Exploration. AB - Are face and object recognition abilities independent? Although it is commonly believed that they are, Gauthier et al. [Gauthier, I., McGugin, R. W., Richler, J. J., Herzmann, G., Speegle, M., & VanGulick, A. E. Experience moderates overlap between object and face recognition, suggesting a common ability. Journal of Vision, 14, 7, 2014] recently showed that these abilities become more correlated as experience with nonface categories increases. They argued that there is a single underlying visual ability, v, that is expressed in performance with both face and nonface categories as experience grows. Using the Cambridge Face Memory Test and the Vanderbilt Expertise Test, they showed that the shared variance between Cambridge Face Memory Test and Vanderbilt Expertise Test performance increases monotonically as experience increases. Here, we address why a shared resource across different visual domains does not lead to competition and to an inverse correlation in abilities? We explain this conundrum using our neurocomputational model of face and object processing ["The Model", TM, Cottrell, G. W., & Hsiao, J. H. Neurocomputational models of face processing. In A. J. Calder, G. Rhodes, M. Johnson, & J. Haxby (Eds.), The Oxford handbook of face perception. Oxford, UK: Oxford University Press, 2011]. We model the domain general ability v as the available computational resources (number of hidden units) in the mapping from input to label and experience as the frequency of individual exemplars in an object category appearing during network training. Our results show that, as in the behavioral data, the correlation between subordinate level face and object recognition accuracy increases as experience grows. We suggest that different domains do not compete for resources because the relevant features are shared between faces and objects. The essential power of experience is to generate a "spreading transform" for faces (separating them in representational space) that generalizes to objects that must be individuated. Interestingly, when the task of the network is basic level categorization, no increase in the correlation between domains is observed. Hence, our model predicts that it is the type of experience that matters and that the source of the correlation is in the fusiform face area, rather than in cortical areas that subserve basic level categorization. This result is consistent with our previous modeling elucidating why the FFA is recruited for novel domains of expertise [Tong, M. H., Joyce, C. A., & Cottrell, G. W. Why is the fusiform face area recruited for novel categories of expertise? A neurocomputational investigation. Brain Research, 1202, 14-24, 2008]. PMID- 26741803 TI - Decoding fMRI Signatures of Real-world Autobiographical Memory Retrieval. AB - Extant neuroimaging data implicate frontoparietal and medial-temporal lobe regions in episodic retrieval, and the specific pattern of activity within and across these regions is diagnostic of an individual's subjective mnemonic experience. For example, in laboratory-based paradigms, memories for recently encoded faces can be accurately decoded from single-trial fMRI patterns [Uncapher, M. R., Boyd-Meredith, J. T., Chow, T. E., Rissman, J., & Wagner, A. D. Goal-directed modulation of neural memory patterns: Implications for fMRI-based memory detection. Journal of Neuroscience, 35, 8531-8545, 2015; Rissman, J., Greely, H. T., & Wagner, A. D. Detecting individual memories through the neural decoding of memory states and past experience. Proceedings of the National Academy of Sciences, U.S.A., 107, 9849-9854, 2010]. Here, we investigated the neural patterns underlying memory for real-world autobiographical events, probed at 1- to 3-week retention intervals as well as whether distinct patterns are associated with different subjective memory states. For 3 weeks, participants (n = 16) wore digital cameras that captured photographs of their daily activities. One week later, they were scanned while making memory judgments about sequences of photos depicting events from their own lives or events captured by the cameras of others. Whole-brain multivoxel pattern analysis achieved near-perfect accuracy at distinguishing correctly recognized events from correctly rejected novel events, and decoding performance did not significantly vary with retention interval. Multivoxel pattern classifiers also differentiated recollection from familiarity and reliably decoded the subjective strength of recollection, of familiarity, or of novelty. Classification-based brain maps revealed dissociable neural signatures of these mnemonic states, with activity patterns in hippocampus, medial PFC, and ventral parietal cortex being particularly diagnostic of recollection. Finally, a classifier trained on previously acquired laboratory-based memory data achieved reliable decoding of autobiographical memory states. We discuss the implications for neuroscientific accounts of episodic retrieval and comment on the potential forensic use of fMRI for probing experiential knowledge. PMID- 26741804 TI - Sexuality and Reproduction in HIV-Positive Women: A Meta-Synthesis. AB - The increased access to effective antiretroviral treatment (ART) has made HIV comparable to a chronic disease in terms of life expectancy. Needs related to sexuality and reproduction are central to overall health and well-being. An interpretative meta-synthesis was performed to synthesize and assess how HIV positive women's experiences of sexuality and reproduction have been described in qualitative studies. A total of 18 peer-reviewed qualitative studies were included, which comprised a total of 588 HIV-positive interviewed women. The studies originated from resource-rich countries outside the Asian and African continents. The analysis, resulting in a lines-of-argument synthesis, shows that HIV infection was a burden in relation to sexuality and reproduction. The weight of the burden could be heavier or lighter. Conditions making the HIV burden heavier were: HIV as a barrier, feelings of fear and loss, whereas motherhood, spiritual beliefs, and supportive relationships made the HIV burden lighter. The findings are important in developing optimal health care by addressing conditions making the burden of HIV infection lighter to bear. In future research there is a need to focus not only on examining how HIV-positive women's sexual and relationships manifest themselves, but also on how health care professionals should provide adequate support to the women in relation to sexuality and reproduction. PMID- 26741805 TI - Integration of Attributes from Non-Linear Characterization of Cardiovascular Time Series for Prediction of Defibrillation Outcomes. AB - OBJECTIVE: The timing of defibrillation is mostly at arbitrary intervals during cardio-pulmonary resuscitation (CPR), rather than during intervals when the out of-hospital cardiac arrest (OOH-CA) patient is physiologically primed for successful countershock. Interruptions to CPR may negatively impact defibrillation success. Multiple defibrillations can be associated with decreased post-resuscitation myocardial function. We hypothesize that a more complete picture of the cardiovascular system can be gained through non-linear dynamics and integration of multiple physiologic measures from biomedical signals. MATERIALS AND METHODS: Retrospective analysis of 153 anonymized OOH-CA patients who received at least one defibrillation for ventricular fibrillation (VF) was undertaken. A machine learning model, termed Multiple Domain Integrative (MDI) model, was developed to predict defibrillation success. We explore the rationale for non-linear dynamics and statistically validate heuristics involved in feature extraction for model development. Performance of MDI is then compared to the amplitude spectrum area (AMSA) technique. RESULTS: 358 defibrillations were evaluated (218 unsuccessful and 140 successful). Non-linear properties (Lyapunov exponent > 0) of the ECG signals indicate a chaotic nature and validate the use of novel non-linear dynamic methods for feature extraction. Classification using MDI yielded ROC-AUC of 83.2% and accuracy of 78.8%, for the model built with ECG data only. Utilizing 10-fold cross-validation, at 80% specificity level, MDI (74% sensitivity) outperformed AMSA (53.6% sensitivity). At 90% specificity level, MDI had 68.4% sensitivity while AMSA had 43.3% sensitivity. Integrating available end tidal carbon dioxide features into MDI, for the available 48 defibrillations, boosted ROC-AUC to 93.8% and accuracy to 83.3% at 80% sensitivity. CONCLUSION: At clinically relevant sensitivity thresholds, the MDI provides improved performance as compared to AMSA, yielding fewer unsuccessful defibrillations. Addition of partial end-tidal carbon dioxide (PetCO2) signal improves accuracy and sensitivity of the MDI prediction model. PMID- 26741809 TI - Sublingual Buprenorphine-Induced Psychomimetic Effects. PMID- 26741807 TI - Impact of Different Screw Designs on Durability of Fracture Fixation: In Vitro Study with Cyclic Loading of Scaphoid Bones. AB - PURPOSE: The use of new headless compression screws (HCSs) for scaphoid fixation is growing, but the nonunion rate has remained constant. The aim of this study was to compare the stability of fixation resulting from four modern HCSs using a simulated fracture model to determine the optimal screw design(s). METHODS: We tested 40 fresh-frozen cadaver scaphoids treated with the Acumed Acutrak 2 mini (AA), the KLS Martin HBS2 midi (MH), the Stryker TwinFix (ST) and the Synthes HCS 3.0 with a long thread (SH). The bones with simulated fractures and implanted screws were loaded uniaxially into flexion for 2000 cycles with a constant bending moment of 800 Nmm. The angulation of the fracture fragments was measured continuously. Data were assessed statistically using the univariate ANOVA test and linear regression analysis, and the significance level was set at p < 0.05. RESULTS: The median angulation of bone fragments phi allowed by each screw was 0.89 degrees for AA, 1.12 degrees for ST, 1.44 degrees for SH and 2.36 degrees for MH. With regards to linear regression, the most reliable curve was achieved by MH, with a coefficient of determination of R2 = 0.827. This was followed by AA (R2 = 0.354), SH (R2 = 0.247) and ST (R2 = 0.019). Data assessed using an adapted ANOVA model showed no statistically significant difference (p = 0.291) between the screws. CONCLUSIONS: The continuous development of HCSs has resulted in very comparable implants, and thus, at this time, other factors, such as surgeons' experience, ease of handling and price, should be taken into consideration. PMID- 26741806 TI - Topical Formulation Containing Naringenin: Efficacy against Ultraviolet B Irradiation-Induced Skin Inflammation and Oxidative Stress in Mice. AB - Naringenin (NGN) exhibits anti-inflammatory and antioxidant activities, but it remains undetermined its topical actions against ultraviolet B (UVB)-induced inflammation and oxidative stress in vivo. The purpose of this study was to evaluate the physicochemical and functional antioxidant stability of NGN containing formulations, and the effects of selected NGN containing formulation on UVB irradiation-induced skin inflammation and oxidative damage in hairless mice. NGN presented ferric reducing power, ability to scavenge 2,2'-azinobis (3 ethylbenzothiazoline- 6-sulfonic acid) (ABTS) and hydroxyl radical, and inhibited iron-independent and dependent lipid peroxidation. Among the three formulations containing NGN, only the F3 kept its physicochemical and functional stability over 180 days. Topical application of F3 in mice protected from UVB-induced skin damage by inhibiting edema and cytokine production (TNF-alpha, IL-1beta, IL-6, and IL-10). Furthermore, F3 inhibited superoxide anion and lipid hydroperoxides production and maintained ferric reducing and ABTS scavenging abilities, catalase activity, and reduced glutathione levels. In addition, F3 maintained mRNA expression of cellular antioxidants glutathione peroxidase 1, glutathione reductase and transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), and induced mRNA expression of heme oxygenase-1. In conclusion, a formulation containing NGN may be a promising approach to protecting the skin from the deleterious effects of UVB irradiation. PMID- 26741811 TI - Correction: Structural Diversity of Bacterial Communities Associated with Bloom Forming Freshwater Cyanobacteria Differs According to the Cyanobacterial Genus. PMID- 26741810 TI - Peroxisome proliferator-activated receptor-gamma coactivator-1alpha mediates neuroprotection against excitotoxic brain injury in transgenic mice: role of mitochondria and X-linked inhibitor of apoptosis protein. AB - Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator involved in the regulation of mitochondrial biogenesis and cell defense. The functions of PGC-1alpha in physiology of brain mitochondria are, however, not fully understood. To address this we have studied wild-type and transgenic mice with a two-fold overexpression of PGC-1alpha in brain neurons. Data showed that the relative number and basal respiration of brain mitochondria were increased in PGC-1alpha transgenic mice compared with wild-type mitochondria. These changes occurred concomitantly with altered levels of proteins involved in oxidative phosphorylation (OXPHOS) as studied by proteomic analyses and immunoblottings. Cultured hippocampal neurons from PGC 1alpha transgenic mice were more resistant to cell degeneration induced by the glutamate receptor agonist kainic acid. In vivo kainic acid induced excitotoxic cell death in the hippocampus at 48 h in wild-type mice but significantly less so in PGC-1alpha transgenic mice. However, at later time points cell degeneration was also evident in the transgenic mouse hippocampus, indicating that PGC-1alpha overexpression can induce a delay in cell death. Immunoblotting showed that X linked inhibitor of apoptosis protein (XIAP) was increased in PGC-1alpha transgenic hippocampus with no significant changes in Bcl-2 or Bcl-X. Collectively, these results show that PGC-1alpha overexpression contributes to enhanced neuronal viability by stimulating mitochondria number and respiration and increasing levels of OXPHOS proteins and the anti-apoptotic protein XIAP. PMID- 26741812 TI - Analysis of the Relationship Between ADIPOR1 Variants and the Susceptibility of Chronic Metabolic Diseases in a Northeast Han Chinese Population. AB - OBJECTIVE: Shared genetic variants in ADIPOR1 have been identified as closely related to coronary artery disease (CAD), type 2 diabetes (T2D), and T2D with CAD susceptibility, suggesting that these variants are strong candidates for the common soil hypothesis. Therefore, it is essential to analyze the relationship between ADIPOR1 variants and the susceptibility to CAD, T2D, and T2D with CAD in other populations. MATERIALS AND METHODS: A case-control study was conducted which included three case cohorts [CAD (n = 316), T2D (n = 295), T2D with CAD (n = 302)], and a control cohort (n = 268) from a population in northeast China. Six ADIPOR1 single-nucleotide polymorphisms were genotyped by high-resolution melting and polymerase chain reaction-restriction fragment length polymorphism. RESULTS: We confirmed that the shared variant, rs3737884*G, in ADIPOR1 is associated with CAD, T2D, and T2D with CAD (p-value range: 6.54E-6-1.82E-5, odds ratio [OR] range: 1.770-1.844) and that rs16850797*C is associated with T2D and T2D with CAD (p-value range: 0.001-0.001, OR range: 1.529-1.571). We also found that a novel shared variant, rs7514221*C, is associated with an increased susceptibility to CAD, T2D, and T2D with CAD (p-value range: 0.002-0.004, OR range: 1.194-2.382) in this population. CONCLUSIONS: ADPOR1 variants, rs3737884*G and rs7514221*C, may be shared risk factors associated with CAD, T2D, and T2D with CAD in a population of northeast China. PMID- 26741813 TI - The Sensitive Detection of Telomerase Reverse Transcriptase Promoter Mutation by Amplification Refractory Mutation System-PCR. AB - AIM: In gliomas, mutations in the core promoter region of the telomerase reverse transcriptase (TERT) gene have been associated with specific subtypes and are inversely correlated with IDH1 mutation status, predicting poor prognosis. Thus, TERT promoter mutation status might be a candidate for development as a prognostic biomarker. However, current IDH1 mutation detection methods using conventional polymerase chain reaction (PCR), followed by Sanger sequencing, have low sensitivity and are time-consuming. To improve test efficacy, we developed a more efficient detection protocol based on an amplification refractory mutation system-PCR (ARMS-PCR), which is based on the principle that DNA extension only happens when the 3'-terminal nucleotide of a primer matches its target sequence. MATERIALS AND METHODS: We generated plasmids containing TERT promoter sequences and optimized this new protocol for the identification of the two most common TERT promoter mutations, C250T and C228T. RESULTS: The enhanced sensitivity and efficiency of this protocol were validated using 124 human glioma samples. CONCLUSION: We have described an ARMS-PCR methodology with improved sensitivities that could replace current commonly used methods for the detection of TERT promoter mutations in gliomas. PMID- 26741814 TI - New Roles for Corticosteroid Binding Globulin and Opposite Expression Profiles in Lung and Liver. AB - Corticosteroid-binding globulin (CBG) is the specific plasma transport glycoprotein for glucocorticoids. Circulating CBG is mainly synthesized in liver but, its synthesis has been located also in other organs as placenta, kidney and adipose tissue with unknown role. Using an experimental model of acute pancreatitis in cbg-/- mice we investigated whether changes in CBG affect the progression of the disease as well as the metabolism of glucocorticoids in the lung. Lack of CBG does not modify the progression of inflammation associated to pancreatitis but resulted in the loss of gender differences in corticosterone serum levels. In the lung, CBG expression and protein level were detected, and it is noteworthy that these showed a sexual dimorphism opposite to the liver, i.e. with higher levels in males. Reduced expression of 11beta-HSD2, the enzyme involved in the deactivation of corticosterone, was also observed. Our results indicate that, in addition to glucocorticoids transporter, CBG is involved in the gender differences observed in corticosteroids circulating levels and plays a role in the local regulation of corticosteroids availability in organs like lung. PMID- 26741816 TI - Cerebral and Cutaneous Involvements of Xanthoma Disseminatum Successfully Treated with an Interleukin-1 Receptor Antagonist: A Case Report and Minireview. AB - A young male presented with panhypopituitarism (including diabetes insipidus) and temporal lobe epilepsy. A histology specimen of cutaneous papules was diagnostic of non-Langerhans histiocytosis. The diagnosis of xanthoma granulomata was considered based on the clinical and brain MRI findings. Brain lesions significantly worsened over time despite radiotherapy until anakinra induced a complete clinical and radiological remission of all active lesions. Although a single case, the outcome of this patient with xanthoma disseminatum treated with an interleukin-1 receptor antagonist opens and strengthens new and recent physiopathogenic and treatment perspectives for the otherwise difficult-to-treat non-Langerhans cell histiocytosis. Similar results with anakinra have been observed in patients with Erdheim-Chester disease and in multicentric reticulohistiocytosis. PMID- 26741817 TI - Use of Noninvasive Parameters to Evaluate Swiss Webster Mice During Trypanosoma cruzi Experimental Acute Infection. AB - Until now, there has been neither an agreed-upon experimental model nor descriptors of the clinical symptoms that occur over the course of acute murine infection. The aim of this work is to use noninvasive methods to evaluate clinical signs in Swiss Webster mice that were experimentally infected with the Y strain of Trypanosoma cruzi during acute phase (Inf group). Infected mice showed evident clinical changes beginning in the second week of infection (wpi) when compared to the noninfected group (NI): (1) animals in hunched postures, closed eyes, lowered ears, peeling skin, increased piloerection, prostration, and social isolation; (2) significant decrease in body weight (Inf: 26.2 +/- 2.6 g vs. NI: 34.2 +/- 2.5 g) and in chow (1.5 +/- 0.3 vs. 6.3 +/- 0.5 mg) and water (2.4 +/- 0.5 vs. 5.8 +/- 0.7 ml) intake; (3) significant decrease of spontaneous activity as locomotor parameters: distance (0.64 +/- 0.06 vs. 1.8 +/- 0.13 m), velocity (1.9 +/- 0.3 vs. 6.7 +/- 1.5 cm/sec), and exploratory behavior by frequency (1.0 +/- 0.5 vs. 5.7 +/- 1.0 events) and duration (1.4 +/- 0.3 vs. 5.1 +/- 0.5 sec in central arena region); (4) significant increase in the PR (41.7 +/- 8.7 vs. 27.6 +/- 1.9 msec) and QT intervals (39.7 +/- 2.0 vs. 27.5 +/- 4.0 msec), and a decreased cardiac frequency (505 +/- 52.8 vs. 774 +/- 17.8 msec), showing a marked sinus bradycardia and an atrioventricular block. At 3 and 4 wpi, the surviving animals showed a tendency of recovery in body weight, food intake, locomotor activity, and exploratory interest. Through the use of noninvasive parameters, we were able to monitor the severity of the infection in individuals prior to death. Our perspective is the application of noninvasive methods to describe clinical signs over the course of acute infection complementing the preclinical evaluation of new agents, alone or in combination with benznidazole. PMID- 26741820 TI - Exploring a New Frontier of Small. PMID- 26741815 TI - Visual Task Demands and the Auditory Mismatch Negativity: An Empirical Study and a Meta-Analysis. AB - Because the auditory system is particularly useful in monitoring the environment, previous research has examined whether task-irrelevant, auditory distracters are processed even if subjects focus their attention on visual stimuli. This research suggests that attentionally demanding visual tasks decrease the auditory mismatch negativity (MMN) to simultaneously presented auditory distractors. Because a recent behavioral study found that high visual perceptual load decreased detection sensitivity of simultaneous tones, we used a similar task (n = 28) to determine if high visual perceptual load would reduce the auditory MMN. Results suggested that perceptual load did not decrease the MMN. At face value, these nonsignificant findings may suggest that effects of perceptual load on the MMN are smaller than those of other demanding visual tasks. If so, effect sizes should differ systematically between the present and previous studies. We conducted a selective meta-analysis of published studies in which the MMN was derived from the EEG, the visual task demands were continuous and varied between high and low within the same task, and the task-irrelevant tones were presented in a typical oddball paradigm simultaneously with the visual stimuli. Because the meta-analysis suggested that the present (null) findings did not differ systematically from previous findings, the available evidence was combined. Results of this meta-analysis confirmed that demanding visual tasks reduce the MMN to auditory distracters. However, because the meta-analysis was based on small studies and because of the risk for publication biases, future studies should be preregistered with large samples (n > 150) to provide confirmatory evidence for the results of the present meta-analysis. These future studies should also use control conditions that reduce confounding effects of neural adaptation, and use load manipulations that are defined independently from their effects on the MMN. PMID- 26741821 TI - Tuning the Energy Gap by Supramolecular Approaches: Towards Near-Infrared Organic Assemblies and Materials. AB - Near-infrared (NIR) organic materials are of great importance for both fundamental research and practical applications. While much effort has been taken to covalently design and synthesize NIR organic materials with a low energy gap, there are supramolecular approaches for tuning the energy gap to noncovalently fabricate NIR organic assemblies and materials. In this concept article, we summarize and discuss several supramolecular approaches, including the fabrication of charge transfer supramolecular complexes, the fabrication of supramolecular J-aggregates, and the fabrication of supramolecularly stabilized organic radicals. The nature of noncovalent interactions in supramolecular approaches can provide NIR organic assemblies and materials with unique properties such as reversibility, stimuli-responsiveness, recyclability, and adaptive abilities. PMID- 26741823 TI - Glycemic Index of a Novel High-Fiber White Rice Variety Developed in India--A Randomized Control Trial Study. AB - BACKGROUND: White rice, a common Indian staple, has a high glycemic response and is associated with high risk of type 2 diabetes. The aim of this study was to compare the Glycemic Index (GI) of a newly developed high-fiber white rice (HFWR) with that of commercial white rice (WR). MATERIALS AND METHODS: HFWR was developed using biochemical screening approaches and classical plant breeding techniques. The GI of HFWR was determined using a validated protocol in 30 healthy participants in the year 2013 and repeated in a subsample of 15 participants in the year 2014; the results were compared with the value for WR. The incremental area under the curve was calculated geometrically by applying the trapezoid rule for both reference food (glucose) and the test foods (HFWR and WR). Proximate principles along with dietary fiber, resistant starch, and amylose content were analyzed using standardized methods. RESULTS: The dietary fiber content of HFWR was fivefold higher (8.0 +/- 0.1 vs. 1.58 +/- 0.17 g%), resistant starch content was 6.5-fold higher (3.9 +/- 0.2 vs. 0.6 +/- 0.03 g%) (P < 0.001), and amylose content was significantly higher (32.8 +/- 1.1 vs. 26.0 +/- 0.2 g%) (P < 0.001), compared with WR. HFWR was found to be of medium GI (61.3 +/- 2.8), whereas WR was of high GI (79.2 +/- 4.8). Overall, HFWR had 23% lower GI compared with WR (P = 0.002). CONCLUSIONS: The new HFWR variety can be considered as a potentially healthier alternative to commercial WR in rice-eating populations, on account of its lower GI and high fiber content. PMID- 26741825 TI - Human kidney damage in fatal dengue hemorrhagic fever results of glomeruli injury mainly induced by IL17. AB - Acute kidney injury is an unusual complication during dengue infection. The objective of this study was to better identify the characteristics of glomerular changes focusing on in situ immune cells and cytokines. An immunohistochemical assay was performed on 20 kidney specimens from fatal human cases of dengue hemorrhagic fever (DHF). It was observed a lymphomononuclear infiltrate, neutrophils and nuclear fragmentation in the glomeruli, hydropic degeneration, nuclear retraction, eosinophilic tubules and intense acute congestion. Sickle erythrocytes were frequent in glomeruli and inflammatory infiltrate. The glomeruli presented endothelial swelling and mesangial proliferation. Lymphocytes CD4+ predominated over CD8+ T cells, B cells and natural killer cells. There were also an expressive number of macrophagic CD68+ cells. S100, Foxp3 and CD123 cells were not identified. Cells expressing IL17 and IL18+ cytokines predominated in the renal tissues, while IL4, IL6, IL10, IL13, TNF-alpha and IFN-gamma were rarely visualized. The high number of cells expressing IL17 and IL18+ could reflect the acute inflammatory response and possibly contribute to the local lesion. CD8+ T cells could play a role in the cytotoxic response. DHF is a multifactorial disease of capillary leakage associated with a "Tsunami of cytokines expression". The large numbers of cells expressing IL17 seems to play a role favoring the increased permeability. PMID- 26741824 TI - Chemo-Enzymatic Synthesis of Optically Active gamma- and delta-Decalactones and Their Effect on Aphid Probing, Feeding and Settling Behavior. AB - The enantiomerically enriched gamma- and delta-decalactones (4a and 4b) were prepared from corresponding racemic primary-secondary 1,4- and 1,5-diols (1a and 1b), as products of enzymatic oxidation catalyzed by different alcohol dehydrogenases. The results of biotransformations indicated that the oxidation processes catalyzed by alcohol dehydrogenase (HLADH), both isolated from horse liver and recombinant in Escherichia coli, were characterized by the highest degree of conversion with moderate enantioselectivity of the reaction. Useful, environmentally friendly extraction procedure of decalactones (4a and 4b) based on hydrodistillation using a Deryng apparatus was developed. Both racemic lactones (4a and 4b), as well as their enantiomerically enriched isomers, were tested for feeding deterrent activity against Myzus persicae. The effect of these compounds on probing, feeding and settling behavior of M. persicae was studied in vivo. The deterrent activity of decalactones (4a and 4b) against aphids depended on the size of the lactone ring and the enantiomeric purity of the compounds. delta-Decalactone (4b) appeared inactive against M. persicae while gamma decalactone (4a) restrained aphid probing at ingestional phase. Only (-)-(S) gamma-decalactone (4a) had strong and durable (i.e. lasting for at least 24 hours) limiting effect, expressed at phloem level. PMID- 26741828 TI - Isolation and Localization of Mesenchymal Stem Cells in Human Palatine Tonsil by W5C5 (SUSD2). AB - BACKGROUND/AIMS: Although tonsil-mesenchymal stem cells (T-MSCs) have been studied as a new autologous or homologous source of MSCs, research on specific markers of MSCs and localization for purified T-MSC isolation has not yet been reported. This study investigates the expression of W5C5 (SUSD2) in tonsil stromal cells and the colony-forming ability and differentiation potential of W5C5+ cells to determine the usefulness of W5C5+ MSCs as a marker that can be used for the purification of T-MSCs. In addition, the location of W5C5+ cells expressed in the tonsil tissues is examined. METHODS: T-MSCs were isolated from the tonsillar tissues of 12 patients undergoing tonsillectomy. The colony-forming ability, surface markers, proliferation potential, and differentiation capacities of purified W5C5+ MSCs, W5C5- MSCs, and unselected T-MSCs were evaluated. The location of the W5C5+ cells in the tonsillar tissues was also investigated by immunohistochemistry. RESULTS: W5C5 was expressed in 2.5+/-0.4% of fresh human tonsil stromal cells. W5C5+ cells formed many colonies, but W5C5- cells did not form any colonies. The colony-forming number of W5C5+ cells (74.4 +/- 9.8) was significantly higher than that of unselected tonsil stromal cells (23.6 +/- 3.7). However, the differences in proliferation potential, surface marker expression, and differentiation potential between W5C5+ T-MSCs and unselected T-MSCs were not significant. W5C5+ cells were identified in the perivascular area around the blood vessels. CONCLUSION: W5C5+ T-MSCs possessed typical MSC properties with high colony-forming efficiency, and niches of W5C5+ T-MSCs were located in the perivascular area of tonsil tissues. These findings suggest that W5C5 is a useful single marker for the isolation of purified T-MSCs. PMID- 26741829 TI - Ethanol-Induced ADH Activity in Zebrafish: Differential Concentration-Dependent Effects on High- Versus Low-Affinity ADH Enzymes. AB - Zebrafish express enzymes that metabolize ethanol in a manner comparable to that of mammals, including humans. We previously demonstrated that acute ethanol exposure increases alcohol dehydrogenase (ADH) activity in an inverted U-shaped dose-dependent manner. It was hypothesized that the biphasic dose-response was due to the increased activity of a high-affinity ADH isoform following exposure to low concentrations of ethanol and increased activity of a low-affinity ADH isoform following exposure to higher concentrations of ethanol. To test this hypothesis, we exposed zebrafish to different concentrations of ethanol (0%, 0.25%, 0.5%, and 1.0% v/v) for 30 min and measured the total ADH activity in the zebrafish liver. However, we also repeated this enzyme activity assay using a low concentration of the substrate (ethanol) to determine the activity of high affinity ADH isoforms. We found that total ADH activity in response to ethanol induces an inverted U-shaped dose-response similar to our previous study. Using a lower substrate level in our enzyme assay targeting high-affinity isozymes, we found a similar dose-response. However, the difference in activity between the high and low substrate assays (high substrate activity - low substrate activity), which provide an index of activity for low-affinity ADH isoforms, revealed no significant effect of ethanol exposure. Our results suggest that the inverted U shaped dose-response for total ADH activity in response to ethanol is driven primarily by high-affinity isoforms of ADH. PMID- 26741826 TI - The role of influenza, RSV and other common respiratory viruses in severe acute respiratory infections and influenza-like illness in a population with a high HIV sero-prevalence, South Africa 2012-2015. AB - BACKGROUND: Viruses detected in patients with acute respiratory infections may be the cause of illness or asymptomatic shedding. OBJECTIVE: To estimate the attributable fraction (AF) and the detection rate attributable to illness for each of the different respiratory viruses STUDY DESIGN: We compared the prevalence of 10 common respiratory viruses (influenza A and B viruses, parainfluenza virus 1-3; respiratory syncytial virus (RSV); adenovirus, rhinovirus, human metapneumovirus (hMPV) and enterovirus) in both HIV positive and negative patients hospitalized with severe acute respiratory illness (SARI), outpatients with influenza-like illness (ILI), and control subjects who did not report any febrile, respiratory or gastrointestinal illness during 2012-2015 in South Africa. RESULTS: We enrolled 1959 SARI, 3784 ILI and 1793 controls with a HIV sero-prevalence of 26%, 30% and 43%, respectively. Influenza virus (AF: 86.3%; 95%CI: 77.7-91.6%), hMPV (AF: 85.6%; 95%CI: 72.0-92.6%), and RSV (AF: 83.7%; 95%CI: 77.5-88.2%) infections were associated with severe disease., while rhinovirus (AF: 46.9%; 95%CI: 37.6-56.5%) and adenovirus (AF: 36.4%; 95%CI: 20.6 49.0%) were only moderately associated. CONCLUSIONS: Influenza, RSV and hMPV can be considered pathogens if detected in ILI and SARI while rhinovirus and adenovirus were commonly identified in controls suggesting that they may cause only a proportion of clinical disease observed in positive patients. Nonetheless, they may be important contributors to disease. PMID- 26741827 TI - Predominance of Single Prophage Carrying a CRISPR/cas System in "Candidatus Liberibacter asiaticus" Strains in Southern China. AB - "Candidatus Liberibacter asiaticus" (CLas) is an uncultureable alpha proteobacterium associated with citrus Huanglongbing (HLB, yellow shoot disease), a highly destructive disease affecting citrus production worldwide. HLB was observed in Guangdong Province of China over a hundred years ago and remains endemic there. Little is known about CLas biology due to its uncultureable nature. This study began with the genome sequence analysis of CLas Strain A4 from Guangdong in the prophage region. Within the two currently known prophage types, Type 1 (SC1-like) and Type 2 (SC2-like), A4 genome contained only a Type 2 prophage, CGdP2, namely. An analysis on CLas strains collected in Guangdong showed that Type 2 prophage dominated the bacterial population (82.6%, 71/86). An extended survey covering five provinces in southern China also revealed the predominance of single prophage (Type 1 or Type 2) in the CLas population (90.4%, 169/187). CLas strains with two and no prophage types accounted for 7.2% and 2.8%, respectively. In silico analyses on CGdP2 identified a CRISPR (clustered regularly interspaced short palindromic repeats)/cas (CRISPR-associated protein genes) system, consisting of four 22 bp repeats, three 23 bp spacers and 9 predicted cas. Similar CRISPR/cas systems were detected in all 10 published CLas prophages as well as 13 CLas field strains in southern China. Both Type 1 and Type 2 prophages shared almost identical sequences in spacer 1 and 3 but not spacer 2. Considering that the function of a CRISPR/cas system was to destroy invading DNA, it was hypothesized that a pre-established CLas prophage could use its CRISPR/cas system guided by spacer 1 and/or 3 to defeat the invasion of the other phage/prophage. This hypothesis explained the predominance of single prophage type in the CLas population in southern China. This is the first report of CRISPR/cas system in the "Ca. Liberibacter" genera. PMID- 26741846 TI - A Comparison of the Cross-Sectional and Sequential Designs when Assessing Longitudinal Mediation. AB - Mediational studies are often of interest in psychology because they explore the underlying relationship between 2 constructs. Previous research has shown that cross-sectional designs are prone to biased estimates of longitudinal mediation parameters. The sequential design has become a popular alternative to the cross sectional design for assessing mediation. This design is a compromise between the cross-sectional and longitudinal designs because it incorporates time in the model but has only 1 measurement each of X, M, and Y. As such, this design follows the recommendation of the MacArthur group approach, which stresses the importance of multiple waves of data for studying mediation. These 2 designs were compared to see whether the sequential design assesses longitudinal mediation more accurately than the cross-sectional design. Specifically, analytic expressions are derived for the bias of estimated direct and indirect effects as calculated from the sequential design when the actual mediational process follows a longitudinal autoregressive model. It was found that, in general, the sequential design does not assess longitudinal mediation more accurately than the cross-sectional design. As a result, neither design can be depended on to assess longitudinal mediation accurately. PMID- 26741847 TI - Modeling Growth in Latent Variables Using a Piecewise Function. AB - Latent growth curve models with piecewise functions for continuous repeated measures data have become increasingly popular and versatile tools for investigating individual behavior that exhibits distinct phases of development in observed variables. As an extension of this framework, this research study considers a piecewise function for describing segmented change of a latent construct over time where the latent construct is itself measured by multiple indicators gathered at each measurement occasion. The time of transition from one phase to another is not known a priori and thus is a parameter to be estimated. Utility of the model is highlighted in 2 ways. First, a small Monte Carlo simulation is executed to show the ability of the model to recover true (known) growth parameters, including the location of the point of transition (or knot), under different manipulated conditions. Second, an empirical example using longitudinal reading data is fitted via maximum likelihood and results discussed. Mplus (Version 6.1) code is provided in Appendix C to aid in making this class of models accessible to practitioners. PMID- 26741830 TI - Effect of proteoglycans at interfaces as related to location, architecture, and mechanical cues. AB - INTRODUCTION: Covalently bound functional GAGs orchestrate tissue mechanics through time-dependent characteristics. OBJECTIVE: The role of specific glycosaminoglycans (GAGs) at the ligament-cementum and cementum-dentin interfaces within a human periodontal complex were examined. Matrix swelling and resistance to compression under health and modeled diseased states was investigated. MATERIALS AND METHODS: The presence of keratin sulfate (KS) and chondroitin sulfate (CS) GAGs at the ligament-cementum and cementum-dentin interfaces in human molars (N=5) was illustrated by using enzymes, atomic force microscopy (AFM), and AFM-based nanoindentation. The change in physical characteristics of modeled diseased states through sequential digestion of keratin sulfate (KS) and chondroitin sulfate (CS) GAGs was investigated. One-way ANOVA tests with P<0.05 were performed to determine significant differences between groups. Additionally, the presence of mineral within the seemingly hygroscopic interfaces was investigated using transmission electron microscopy. RESULTS: Immunohistochemistry (N=3) indicated presence of biglycan and fibromodulin small leucine rich proteoglycans at the interfaces. Digestion of matrices with enzymes confirmed the presence of KS and CS GAGs at the interfaces by illustrating a change in tissue architecture and mechanics. A significant increase in height (nm), decrease in elastic modulus (GPa), and tissue deformation rate (nm/s) of the PDL-C attachment site (215+/-63-424+/-94nm; 1.5+/-0.7-0.4+/-0.2GPa; 21+/-7 48+/-22nm/s), and cementum-dentin interface (122+/-69-360+/-159nm; 2.9+/-1.3 0.7+/-0.3GPa; 18+/-4-30+/-6nm/s) was observed. CONCLUSIONS: The sequential removal of GAGs indicated loss in intricate structural hierarchy of hygroscopic interfaces. From a mechanics perspective, GAGs provide tissue recovery/resilience. The results of this study provide insights into the role of GAGs toward conserved tooth movement in the socket in response to mechanical loads, and modulation of potentially deleterious strain at tissue interfaces. PMID- 26741848 TI - A Multidimensional and Multilevel Extension of a Random-Effect Approach to Subjective Judgment in Rating Scales. AB - In responding to rating scale items, respondents may hold different perspectives on the given categories. The random-effect rating scale model (RERSM), developed to account for variations in the category thresholds across respondents, is unidimensional and unilevel. It becomes statistically inefficient when multiple unidimensional tests have to be analyzed and inapplicable when data have a multilevel structure (e.g., respondents nested within organizations, students nested within schools). To resolve these problems, this study develops a multidimensional and multilevel version of the RERSM. The parameters can be estimated with existing computer software. Thus, there is no need to develop estimation procedures or corresponding computer programs. Simulation studies were conducted to evaluate the parameter recovery of the multidimensional RERSM, the multilevel RERSM, and the multidimensional and multilevel RERSM using WinBUGS. The results showed that the parameter recovery was generally satisfactory. An empirical example of the application of the multidimensional and multilevel RERSM to 2006 Program for International Student Assessment inventories about attitudes toward learning sciences is provided. PMID- 26741849 TI - Synergistic Effects of Expectancy and Value on Homework Engagement: The Case for a Within-Person Perspective. AB - Historically, expectancy-value models of motivation assumed a synergistic relation between expectancy and value: motivation is high only when both expectancy and value are high. Motivational processes were studied from a within person perspective, with expectancies and values being assessed or experimentally manipulated across multiple domains and the focus being placed on intraindividual differences. In contrast, contemporary expectancy-value models in educational psychology concentrate almost exclusively on linear effects of expectancy and value on motivational outcomes, with a focus on between-person differences. Recent advances in latent variable methodology allow both issues to be addressed in observational studies. Using the expectancy-value model of homework motivation as a theoretical framework, this study estimated multilevel structural equation models with latent interactions in a sample of 511 secondary school students and found synergistic effects between domain-specific homework expectancy and homework value in predicting homework engagement in 6 subjects. This approach not only brings the "*" back into expectancy-value theory but also reestablishes the within-person perspective as the appropriate level of analysis for latent expectancy-value models. PMID- 26741850 TI - Corrigendum. PMID- 26741851 TI - Growth performance and carcass quality of crossbreds pigs from two Pietrain sire lines fed isoproteic diets varying in energy concentration. AB - The effects of net energy (NE) content of isoproteic diets on growth performance and carcass and meat quality traits were studied in crossbreds from Landrace*Large White females and two Pietrain sire lines (PIC L62 vs. German Pietrain). Feed intake (FI) decreased (Lineal, P<0.001) and feed efficiency improved (Lineal, P<0.001) as the NE content of the diet increased. Crossbreds from PIC L62 had greater (P<0.001) FI and average daily gain (ADG) but were less efficient (P<0.01) than crossbreds from German Pietrain. German Pietrain crossbreds were leaner (P<0.001) and had higher shoulder yield (P<0.01) and less fat at m. Gluteus medius (P<0.001) than carcasses from PIC L62 crossbreds. In summary, an increase in the NE concentration of the diet improved feed efficiency but did not affect ADG. Crossbreeds from PIC L62 sires grew faster and had fatter carcasses than crossbreds from German Pietrain. PMID- 26741852 TI - Does the addition of proteases affect the biogas yield from organic material in anaerobic digestion? AB - The aim of this study was to investigate the biochemical disintegration effect of hydrolytic enzymes in lab scale experiments. Influences of enzyme addition on the biogas yield as well as effects on the process stability were examined. The addition of proteases occurred with low and high dosages in batch and semi continuous biogas tests. The feed mixture consisted of maize silage, chicken dung and cow manure. Only very high concentrated enzymes caused an increase in biogas production in batch experiments. In semi-continuous biogas tests no positive long term effects (100 days) were observed. Higher enzyme-dosage led to a reduced biogas-yield (13% and 36% lower than the reference). Phenylacetate and propionate increased (up to 372 mgl(-1)) before the other volatile fatty acids did. Volatile organic acids rose up to 6.8 gl(-1). The anaerobic digestion process was inhibited. PMID- 26741853 TI - Synthesis, biological evaluation and molecular modeling of a novel series of 7 azaindole based tri-heterocyclic compounds as potent CDK2/Cyclin E inhibitors. AB - From four molecules, inspired by the structural features of fascaplysin, with an interesting potential to inhibit cyclin-dependent kinases (CDKs), we designed a new series of tri-heterocyclic derivatives based on 1H-pyrrolo[2,3-b]pyridine (7 azaindole) and triazole heterocycles. Using a Huisgen type [3 + 2] cycloaddition as the convergent key step, 24 derivatives were synthesized and their biological activities were evaluated. Comparative molecular field analysis (CoMFA), based on three-dimensional quantitative structure-activity relationship (3D-QSAR) studies, was conducted on a series of 30 compounds from the literature with high to low known inhibitory activity towards CDK2/cyclin E and was validated by a test set of 5 compounds giving satisfactory predictive r(2) value of 0.92. Remarkably, it also gave a good prediction of pIC50 for our tri-heterocyclic series which reinforce the validation of this model for the pIC50 prediction of external set compounds. The most promising compound, 43, showed a micro-molar range inhibitory activity against CDK2/cyclin E and also an antiproliferative and proapoptotic activity against a panel of cancer cell lines. PMID- 26741854 TI - Combating P-glycoprotein-mediated multidrug resistance with 10-O-phenyl dihydroartemisinin ethers in MCF-7 cells. AB - A series of 10-beta-phenyl ethers of dihydroartemisinin (DHA) with piperazine substitutions were synthesized with the goal of overcoming multidrug resistance in cancer therapy. These novel compounds exerted significant antiproliferative activities in breast cancer MCF-7 and MCF-7/Adr cell lines at the submicromolar level and were shown to be approximately 100- to 300-times more potent than the lead compound DHA. Remarkably, the P-gp-overexpressed MCF-7/Adr cell line showed collateral sensitivity towards these derivatives. Furthermore, compounds 3d and 5c, with the highest selectivity for MCF-7/Adr towards MCF-7 cells, were free from P-gp efflux in a MDCK-MDR1 assay. Flow cytometry and western blot assays suggested that the antiproliferative effects of 5c were associated with cell cycle arrest at G1 phase through the downregulation of Cyclin D1 and Cyclin B1. PMID- 26741855 TI - Flexible analogues of WAY-267,464: Synthesis and pharmacology at the human oxytocin and vasopressin 1a receptors. AB - A previously identified, non-peptidic oxytocin (OT) receptor agonist WAY-267,464 (1) and nine novel derivatives (3, 4a-7a, 4b-7b) were synthesised and evaluated in vitro with the aim of systematically exploring hydrogen bonding interactions and ligand flexibility. All analogues were subjected to competition radioligand binding assays at human oxytocin (OT) and arginine vasopressin 1a (V1a) receptors. Physiological activity was determined using whole cell IP1 accumulation assays. Under these conditions, WAY-267,464 had higher affinity for the V1a receptor compared to the OT receptor (8.5x more selective) with poor functional selectivity (2x selective for OT receptor agonism over V1a receptor antagonism). Methylation of the resorcinol moiety (3) reversed the OT receptor pharmacological profile, removing agonist activity and inducing antagonist activity, without altering V1a receptor pharmacology. All flexible tethered derivatives removed OT receptor affinity and activity resulting in the generation of highly selective V1a receptor ligands. PMID- 26741857 TI - Mental body representations retain homuncular shape distortions: Evidence from Weber's illusion. AB - Mental body representations underlying tactile perception do not accurately reflect the body's true morphology. For example, perceived tactile distance is dependent on both the body part being touched and the stimulus orientation, a phenomenon called Weber's illusion. These findings suggest the presence of size and shape distortions, respectively. However, whereas each morphological feature is typically measured in isolation, a complete morphological characterization requires the concurrent measurement of both size and shape. We did so in three experiments, manipulating both the stimulated body parts (hand; forearm) and stimulus orientation while requiring participants to make tactile distance judgments. We found that the forearm was significantly more distorted than the hand lengthwise but not widthwise. Effects of stimulus orientation are thought to reflect receptive field anisotropies in primary somatosensory cortex. The results of the present study therefore suggest that mental body representations retain homuncular shape distortions that characterize early stages of somatosensory processing. PMID- 26741856 TI - Yfiler((r)) Plus amplification kit validation and calculation of forensic parameters for two Austrian populations. AB - With the new 6-dye AmpFISTR((r)) Yfiler((r)) Plus amplification kit (Thermo Fisher Scientific, Waltham, MA, USA) a set of 25 Y-chromosomal short tandem repeat loci (Y-STRs), including seven rapidly mutating Y-STRs (RM Y-STRs), is now available for forensic DNA typing. In this study we present our validation data for the AmpFISTR((r)) Yfiler((r)) Plus amplification kit and show the results of Y-chromosomal typing of 425 unrelated male individuals from two Austrian populations (Salzburg and Upper Austria) with the AmpFISTR((r)) Yfiler((r)) Plus amplification kit. Forensic parameters were calculated and compared for four Y STR marker sets. We also typed five brother pairs to evaluate the power of discrimination for related individuals. The AmpFISTR((r)) Yfiler((r)) Plus (Yfiler Plus) kit appeared to be unimpaired by typical inhibitors such as hematin and humic acid or by large amounts of female components. An upgrade of analyzed markers resulted in increased discrimination capacity that is crucial for forensic trace analysis. PMID- 26741858 TI - Temporal perception in joint action: This is MY action. AB - Here we investigated the temporal perception of self- and other-generated actions during sequential joint actions. Participants judged the perceived time of two events, the first triggered by the participant and the second by another agent, during a cooperative or competitive interaction, or by an unspecified mechanical cause. Results showed that participants perceived self-generated events as shifted earlier in time (anticipation temporal judgment bias) and non-self generated events as shifted later in time (repulsion temporal judgment bias). This latter effect was observed independently from the kind of cause (i.e., agentive or mechanical) or interaction (i.e., cooperative or competitive). We suggest that this might represent a mental process which allows discriminating events that cannot plausibly be linked to one's own action. When an event immediately follows a self-generated one, temporal judgment biases operate as self-serving biases in order to separate self-generated events from events of another physical causality. PMID- 26741859 TI - Naming of short words is (almost) the same as naming of alphanumeric symbols: Evidence from two orthographies. AB - Throughout reading development, a gradual shift is seen in the processes underlying word identification from serial decoding toward parallel processing or sight word reading. It has been argued that this shift can be detected in the correlations between serial and discrete naming of alphanumeric symbols (digits and letters) and words. In the current study, we examined the relations between alphanumeric symbol naming and reading of monosyllabic and multisyllabic words and nonwords in two languages that differ in orthographic consistency: English and Dutch. A sample of 92 English-speaking Canadian children and 101 Dutch children, all in Grade 5, were assessed on discrete and serial naming of digits and letters and on serial and discrete naming of monosyllabic and multisyllabic words and nonwords. Results showed that discrete naming of alphanumeric symbols closely resembled discrete reading of monosyllabic words, suggesting that these words are processed in parallel in both languages. Both serial and parallel reading processes were found to underlie identification of multisyllabic words as well as monosyllabic nonwords. However, differences between the two languages emerged when processing multisyllabic nonwords. Whereas English-speaking children relied more on parallel reading processes to read multisyllabic nonwords, Dutch speaking children processed these items serially. Theoretical implications of these findings are discussed. PMID- 26741860 TI - Quantitative Scale for the Trifluoromethylthio Cation-Donating Ability of Electrophilic Trifluoromethylthiolating Reagents. AB - A new parameter, trifluoromethylthio cation-donating ability (Tt(+)DA), is introduced as a quantitative descriptor for the propensity of electrophilic trifluoromethylthiolating reagents to transfer a CF3S moiety in organic synthesis. The first Tt(+)DA scale of popular reagents has been established through DFT calculations. Excellent correlation has been identified between the Tt(+)DAs of N-SCF3-type reagents and the pKa of the corresponding acids, offering a powerful avenue for the rational design of novel reagents. PMID- 26741861 TI - Gold Nanocluster and Quantum Dot Complex in Protein for Biofriendly White-Light Emitting Material. AB - We report the synthesis of a biofriendly highly luminescent white-light-emitting nanocomposite. The composite consisted of Au nanoclusters and ZnQ2 complex (on the surface of ZnS quantum dots) embedded in protein. The combination of red, green, and blue luminescence from clusters, complex, and protein, respectively, led to white light generation. PMID- 26741862 TI - High Rates of STIs in HIV-Infected Patients Attending an STI Clinic. AB - OBJECTIVES: To evaluate the rates and types of sexually transmitted infections (STIs) in patients infected with the human immunodeficiency virus (HIV) attending a public STI clinic in Miami, Florida as compared with HIV-uninfected patients attending the same clinic. METHODS: This was a retrospective review of medical records of individuals attending the Miami-Dade County Health Department STI clinic from March 2012 to May 2012. Demographic and clinical information was abstracted and transferred to an electronic database. Consecutive age-matched HIV infected and HIV-uninfected patients were identified during the study period. Demographics, risk factors, and history and rates of STIs for HIV-infected and HIV-uninfected patients and for those with newly diagnosed and previously diagnosed HIV infection were compared. RESULTS: A total of 175 medical records were reviewed (89 HIV-infected patients and 86 HIV-uninfected patients). The median age was 37 years. A history of STIs, including syphilis, was more common in HIV-infected than in HIV-uninfected patients. Individuals with a prior diagnosis of HIV were more likely to be older (older than 37 years of age, chi(2) = 15.3, P < 0.01), male (chi(2) = 4.74, P = 0.05), to have a new STI (chi(2) = 5.83, P = 0.01), to have a new diagnosis of syphilis (chi(2) = 5.15, P = 0.01), and to be under medical care (chi(2) = 31.19, P < 0.001) than those newly diagnosed as having HIV. CONCLUSIONS: HIV-infected individuals who attended this urban STI clinic had high rates of new and past STIs, suggesting the persistence of high-risk sexual behaviors. STI clinics could be a premier site to identify individuals with HIV and high-risk sexual behaviors who could benefit from additional targeted interventions. PMID- 26741864 TI - Depression in Heart Failure: Is It Well Recognized? PMID- 26741863 TI - House Officer-Driven Reduction in Laboratory Utilization. AB - OBJECTIVES: To determine whether sharing laboratory charge and personal utilization information with physicians can reduce laboratory test orders and expenditures, thereby decreasing the overutilization of laboratory testing. METHODS: This was a prospective study. By querying our electronic medical records, we calculated the median laboratory charges per patient/per day (PP/PD) and median laboratory tests ordered PP/PD for the resident general internal medicine and hospitalist services. For 10 weeks, we shared this team-based information with physicians with weekly updates. We calculated total laboratory charges for the 10 most common discharge diagnoses to capture laboratory charges for entire episodes of care. RESULTS: During the intervention, the mean number of laboratory tests ordered PP/PD by resident service decreased from 5.56 to 5.17 ( 0.389, P <0.001); the mean charge PP/PD decreased from $488 to $461 (-$27, P < 0.001). The hospitalist service decreased the number of laboratory tests ordered PP/PD from 3.54 to 3.36 (-0.18, P = 0.77) and the mean charge PP/PD decreased from $331 to $301 (-$30, P = 0.96). The statistically significant decline in laboratory charges persisted after controlling for the 10 most common discharge diagnoses. Compared with the 3-month period before the study began, physicians in the 10-week intervention period ordered 1464 fewer laboratory tests, resulting in a $188,000 reduction in charges and a 3% to 4% reduction in utilization. CONCLUSIONS: Informing physicians of the charges for laboratory tests and their personal utilization patterns can reduce the number of laboratory tests ordered and laboratory expenditures, especially for physicians in training. PMID- 26741865 TI - Primary Care of Adults with Intellectual and Developmental Disabilities. AB - Most adults with intellectual and developmental disabilities receive care through primary care providers in their communities. An interdisciplinary approach that incorporates home- and community-based services is effective and can be facilitated by care managers in a medical home model. Preventive services should follow established guidelines as in the general population with some modifications, including regular monitoring of weight and height. Swallowing difficulties and gastroesophageal reflux disease are not uncommon and increase the risk for respiratory disorders. A medication review should be conducted at regular intervals to check for polypharmacy, and antipsychotic drugs should no longer be used routinely to treat problem behaviors. Pain and other physical symptoms often are unrecognized and can present atypically in acute situations. PMID- 26741866 TI - Coenzyme Q-10 in Human Health: Supporting Evidence? AB - Coenzyme Q-10 (CoQ10) is a widely used alternative medication or dietary supplement and one of its roles is as an antioxidant. It naturally functions as a coenzyme and component of oxidative phosphorylation in mitochondria. Decreased levels have been demonstrated in diseased myocardium and in Parkinson disease. Farnesyl pyrophosphate is a critical intermediate for CoQ10 synthesis and blockage of this step may be important in statin myopathy. Deficiency of CoQ10 also has been associated with encephalomyopathy, severe infantile multisystemic disease, cerebellar ataxia, nephrotic syndrome, and isolated myopathy. Although supplementation with CoQ10 has been reported to be beneficial in treating hypertension, congestive heart failure, statin myopathy, and problems associated with chemotherapy for cancer treatement, this use of CoQ10 as a supplement has not been confirmed in randomized controlled clinical trials. Nevertheless, it appears to be a safe supplementary medication where usage in selected clinical situations may not be inappropriate. This review is an attempt to actualize the available information on CoQ10 and define its potential benefit and appropriate usage. PMID- 26741867 TI - The View from Outside. PMID- 26741868 TI - Commentary on "The View from Outside". PMID- 26741869 TI - Disparities in Breast Cancer Incidence, Mortality, and Quality of Care among African American and European American Women in South Carolina. AB - OBJECTIVES: Breast cancer is the most frequently diagnosed cancer among women and the second-leading cause of female cancer deaths in the United States. African Americans and other minorities in the United States experience lower survival rates and have a worse prognosis than European Americans despite European Americans having a much higher incidence of the disease. Adherence to breast cancer treatment-quality measures is limited, particularly when the data are stratified by race/ethnicity. METHODS: We aimed to examine breast cancer incidence and mortality trends in South Carolina by race and explore possible racial disparities in the quality of breast cancer treatment received in South Carolina. RESULTS: African Americans have high rates of mammography and clinical breast examination screenings yet suffer lower survival compared with European Americans. For most treatment-quality metrics, South Carolina fairs well in comparison to the United States as a whole; however, South Carolina hospitals overall lag behind South Carolina Commission on Cancer-accredited hospitals for all measured quality indicators, including needle biopsy utilization, breast conserving surgeries, and timely use of radiation therapy. Accreditation may a play a major role in increasing the standard of care related to breast cancer diagnosis and treatment. CONCLUSIONS: These descriptive findings may provide significant insight for future interventions and policies aimed at eliminating racial/ethnic disparities in health outcomes. Further risk-reduction approaches are necessary to reduce minority group mortality rates, especially among African American women. PMID- 26741870 TI - Low 25-Hydroxyvitamin D Levels in Children with Spina Bifida. AB - OBJECTIVE: To determine vitamin D status in children with spina bifida (SB). METHODS: Charts of all patients with SB at the Shriners Hospital for Children in Houston, Texas, seen between July 2011 and June 2013 were retrospectively reviewed. Daily intake of milk, vitamins, amount of screen time, and time spent outdoors were recorded along with height, weight, body mass index, and serum vitamin D levels. RESULTS: A total of 38 patients were identified. The mean level of vitamin D was 58.8 nmol/L (23.5 ng/dL); 30 (81%) had insufficient levels, 50 to 75 nmol/L (20 to 30 ng/mL), or deficient levels, <50 nmol/L (<20 ng/mL). African American and Hispanic descent correlated with decreased levels (P = 0.017). Daily vitamin D supplementation correlated with increased levels (P = 0.046). CONCLUSIONS: Most children with SB have suboptimal vitamin D levels. Despite living in a sunny climate and spending at least 15 minutes per day outdoors, children with SB have suboptimal vitamin D levels. Healthcare providers should consider the routine measurement of vitamin D levels and advise supplementation accordingly in this patient population. PMID- 26741871 TI - Commentary on "Low 25-Hydroxyvitamin D Levels in Children With Spina Bifida". PMID- 26741872 TI - Common Misconceptions, Advancements, and Updates in Pediatric Vaccination Administration. AB - Vaccines are among the greatest achievements in biomedicine and public health. Yet for a variety of reasons, some vaccine-preventable illnesses have experienced resurgences during the last decade. As such, there is a particular need for pediatric providers to be aware of the newest guidelines for vaccination administration to provide consistent and evidence-based recommendations and thoughtful reassurance to families. We aimed to enhance providers' understanding of pediatric vaccinations by highlighting recent changes in vaccination guidelines and addressing common knowledge gaps. This is not a comprehensive list or systematic review of vaccination recommendations. Rather, we present a collection of new developments and misconceptions we have found particularly relevant in our own experience in providing vaccination education at a training institution. PMID- 26741873 TI - "Las Dos Cosas," or Why Mexican American Mothers Breast-Feed, But Not for Long. AB - OBJECTIVES: To determine why mothers in El Paso, Texas, choose to breast-feed but not exclusively and why breast-feeding duration is short. METHODS: This was a cross-sectional observational study of 300, mostly Mexican American, low-income mothers delivering at a county hospital who answered questions about breast feeding and formula feeding, sociodemographics, and health habits. RESULTS: Most mothers (92.6%) in our study initiated breast-feeding, but only 20.3% breast-fed exclusively at the time of hospital discharge. Most mothers (73%) self-identified as Mexicans or Mexican Americans living on the border of the United States and Mexico. Mothers in our study chose to breast-feed if they decided to breast-feed during pregnancy, had breast-fed a previous child, had support from a female relative, and had attended college. Distinctively, most mothers in our study chose "las dos cosas" or to breast-feed and formula feed together early after birth. Acculturation failed to explain the breast-feeding decisions. CONCLUSIONS: Mexican American mothers who decided to breast-feed during pregnancy, breast-fed another child, attended college, and enlist a female relative's breast-feeding help were more likely to choose breast-feeding exclusively. Most Mexican American low-income mothers in our study chose "las dos cosas." PMID- 26741874 TI - Obesity: Changing the Landscape of Pediatric Practice. PMID- 26741875 TI - Editor's Response. PMID- 26741876 TI - Risk Factors for Complications during Outpatient Parenteral Antimicrobial Therapy for Adult Orthopedic and Neurosurgical Infections. AB - OBJECTIVES: Outpatient parenteral antimicrobial therapy (OPAT) is an effective way of treating infections, but complications are common. We identified patient characteristics and OPAT treatment factors associated with increased risk of OPAT related complications. METHODS: We used a retrospective cohort design that assessed 337 adult patients treated with OPAT for orthopedic and neurosurgical infections between August 1, 2008 and May 30, 2010. Independent variables included demographics, infection characteristics, lead time factors, OPAT treatment factors, and comorbid conditions. Multivariable log-binomial regression was used to estimate the risk of OPAT complications. RESULTS: The mean patient age was 55 years (range 19-87), 86% had an orthopedic infection, and 44% were treated with intravenous vancomycin. OPAT complications were seen in 45% (152/337) of the cohort. Risk ratios for OPAT complications were 1.9 (95% confidence interval 1.4-2.5) in patients having no primary care provider, 1.7 (95% confidence interval 1.3-2.1) for those treated with vancomycin. CONCLUSIONS: Identifying specific patient characteristics and OPAT treatment factors could facilitate OPAT process improvements to reduce the risk of OPAT complications for vulnerable patients. PMID- 26741877 TI - Systematic Review and Meta-Analysis of Major Cardiovascular Outcomes for Radial Versus Femoral Access in Patients With Acute Coronary Syndrome. AB - OBJECTIVES: Radial artery access (RA) for left heart catheterization and percutaneous coronary interventions (PCIs) has been demonstrated to be safe and effective. Despite consistent data showing less bleeding complications compared with femoral artery access (FA), it continues to be underused in the United States, particularly in patients with acute coronary syndrome (ACS) in whom aggressive anticoagulation and platelet inhibition regimens are needed. This systematic review and meta-analysis aims to compare major cardiovascular outcomes and safety endpoints in patients with ACS managed with PCI using radial versus femoral access. METHODS: Randomized controlled trials and cohort studies comparing RA versus FA in patients with ACS were analyzed. Our primary outcomes were mortality, major adverse cardiac event, major bleeding, and access-related complications. A fixed-effects model was used for the primary analyses. RESULTS: Fifteen randomized controlled trials and 17 cohort studies involving 44,854 patients with ACS were identified. Compared with FA, RA was associated with a reduction in major bleeding (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.33-0.61, P < 0.001), access-related complications (OR 0.27, 95% CI 0.18-0.39, P < 0.001), mortality (OR 0.64, 95% CI 0.54-0.75, P < 0.001), and major adverse cardiac event (OR 0.70, 95% CI 0.57-0.85, P < 0.001). These significant reductions were consistent across different study designs and clinical presentations. CONCLUSIONS: Based on this large meta-analysis, RA for primary PCI in the setting of ACS is associated with reduction in cardiac and safety endpoints when compared with FA in both urgent and elective procedures. This should encourage a wider adoption of this technique among centers and interventional cardiologists. PMID- 26741878 TI - Takotsubo cardiomyopathy in aneurysmal subarachnoid hemorrhage: Institutional experience and literature review. AB - OBJECTIVES: To review the current practice in the diagnosis, monitoring and management of TCM in SAH patients at our tertiary referral institution and the relevant literature, and to evaluate the effect of certain treatment modalities on the outcome of those patients. PATIENTS AND METHODS: A retrospective institutional chart review of 800 patients with aneurysmal SAH from 2007 to 2014. Eighteen patients were identified to have both aneurysmal SAH and TCM based on echocardiogram. Demographic data, clinical parameters, radiographic findings, treatment modalities, and laboratory results were analyzed. RESULTS: The incidence of typical TCM in our patients was 2.2%. Mortality rate of TCM in SAH was 22% compared to the total mortality rate of all non-traumatic SAH patients of 15% in our institution over the same time period. Use of beta blockers prior to or after the diagnosis of TCM did not seem to affect their outcome. Majority of patients (61%) were on vasopressors prior to the diagnosis of TCM. Of those, 73% had good outcomes. Even after the diagnosis of TCM, good outcomes were observed in 6 of 7 patients who remained on vasopressors. CONCLUSION: Despite the general agreement on the importance of the avoidance of vasopressors in TCM, our experience showed that the use of vasopressors is safe in these patients. The use of beta blockers in our patients was not associated with significantly better outcomes despite multiple previous reports on beta blocker usage in TCM. PMID- 26741879 TI - Ecotoxicological assessment of the potential impact on soil porewater, surface and groundwater from the use of organic wastes as soil amendments. AB - This study aimed to assess the potential impact on soil porewater, surface and groundwater from the beneficial application of organic wastes to soil, using their eluates and acute bioassays with aquatic organisms and plants: luminescence inhibition of Vibrio fischeri (15 and 30 min), Daphnia magna immobilization (48 h), Thamnocephalus platyurus survival (24 h), and seed germination of Lolium perenne (7 d) and Lactuca sativa (5 d). Some organic wastes' eluates promoted high toxic responses, but that toxicity could not be predicted by their chemical characterization, which is compulsory by regulatory documents. In fact, when organisms were exposed to the water-extractable chemical compounds of the organic wastes, the toxic responses were more connected to the degree of stabilization of the organic wastes, or to the treatment used to achieve that stabilization, than to their contaminant load. That is why the environmental risk assessment of the use of organic wastes as soil amendments should integrate bioassays with eluates, in order to correctly evaluate the effects of the most bioavailable fraction of all the chemical compounds, which can be difficult to predict from the characterization required in regulatory documents. According to our results, some rapid and standardized acute bioassays can be suggested to integrate a Tier 1 ecotoxicological evaluation of organic wastes with potential to be land applied, namely luminescence inhibition of V. fischeri, D. magna immobilization, and the germination of L. perenne and L. sativa. PMID- 26741880 TI - Challenges and opportunities in the phytoremediation of heavy metals contaminated soils: A review. AB - Mining operations, industrial production and domestic and agricultural use of metal and metal containing compound have resulted in the release of toxic metals into the environment. Metal pollution has serious implications for the human health and the environment. Few heavy metals are toxic and lethal in trace concentrations and can be teratogenic, mutagenic, endocrine disruptors while others can cause behavioral and neurological disorders among infants and children. Therefore, remediation of heavy metals contaminated soil could be the only effective option to reduce the negative effects on ecosystem health. Thus, keeping in view the above facts, an attempt has been made in this article to review the current status, challenges and opportunities in the phytoremediation for remediating heavy metals from contaminated soils. The prime focus is given to phytoextraction and phytostabilization as the most promising and alternative methods for soil reclamation. PMID- 26741881 TI - Orexin and sleep quality in anorexia nervosa: Clinical relevance and influence on treatment outcome. AB - BACKGROUND AND AIMS: Orexins/hypocretins are orexigenic peptides implicated in the regulation of feeding behavior and the sleep/wake cycle. Little is known about the functioning of these peptides in anorexia nervosa (AN). The aims of the current study were to evaluate the extent to which orexin-A might be linked to sleep and treatment outcome in AN. METHOD: Fasting plasma orexin-A concentrations were measured in 48 females with AN at the start of a day hospital treatment and in 98 normal-eater/healthy-weight controls. The Pittsburgh Sleep Quality Index was administered at the beginning of the treatment as a measure of sleep quality. Other psychopathological variables were evaluated with the Symptom Checklist Revised (SCL90R) and the Eating Disorder Inventory-2 (EDI). Patients were assessed at the start and end of treatment by means of commonly used diagnostic criteria and clinical questionnaires. RESULTS: The AN patients presented more sleep disturbances and poorer overall sleep quality than did the healthy controls (p=.026) but there were no global differences between groups in plasma orexin-A concentrations (p=.071). In the AN sample, orexin-A concentrations were associated with greater sleep disturbances (|r|=.30), sleep inefficiency (|r|=.22) and poorer overall sleep (|r|=.22). Structural Equation Modeling (SEM) showed that both elevated orexin-A concentrations and inadequate sleep predicted poorer treatment outcome. CONCLUSION: Plasma orexin-A concentrations contribute to poor sleep quality in AN, and both of these variables are associated with therapy response. PMID- 26741882 TI - Effect of perfluorotributylamine-enriched alginate on nucleus pulposus cell: Implications for intervertebral disc regeneration. AB - Various scaffolds have been attempted for intervertebral disc regeneration, but their effectiveness was limited by loss of nutrients within the scaffolds. It has been suggested that the disc is not severely hypoxic and limited availability of oxygen results in disc degeneration. Therefore, a certain oxygen level might be beneficial for disc regeneration, which has not been given enough attention in previous studies. Here, we used perfluorotributylamine (PFTBA) for the first time as an oxygen regulator in alginate scaffold for disc regeneration in vitro and in vivo. We found that the characteristics of alginate were not affected by PFTBA and the oxygen level of the scaffold was regulated. Then, human nucleus pulposus (NP) cells were cultured in the PFTBA-enriched alginates. It was found that PFTBA could promote NP cell survival and proliferation. In addition, 2.5% PFTBA was capable of regulating extracellular matrix (ECM) to a disc-like tissue graft with little effect on the expression of NP cell markers. Finally, 2.5% PFTBA-enriched alginate was found to restore the disc height and the ECM in a mouse disc degeneration model, indicating its beneficial effect on alleviating disc degeneration. These findings highlight the promising application of PFTBA in further intervertebral disc regeneration. PMID- 26741883 TI - Porous Silicon's Photoactivity in Water: Insights into Environmental Fate. AB - Interest in porous silicon (pSi) (and, more broadly, silicon nanoparticles (NPs)) has increased along with their concomitant use in various commercial and consumer products, yet little is known about their behavior in the natural environment. In this study, we have investigated the photosensitization, optical, and surface properties of pSi as a function of time in aqueous systems. Samples were prepared via an anodic electrochemical etching procedure, resulting in pSi particles with diameters of ca. 500 nm, composed of a porous network of Si nanocrystallites of 2 4 nm. Initially, pSi particles generated significant amounts of (1)O2, yet they rapidly lost much of this ability due to the formation of an oxide layer on the surface, as determined by X-ray photoelectron spectroscopy, which likely prevented further photosensitization events. Addition of natural organic matter (NOM) did not significantly impact pSi's photosensitization abilities. The pSi lacked any intrinsic bactericidal properties on Escherichia coli and did not produce enough (1)O2 to considerably affect populations of a model virus, PR772, highlighting its relatively benign nature toward microbial communities. Results from this study suggest that the photoactivity of pSi is unlikely to persist in aqueous systems and that it may instead behave more similarly to silica particles from an environmental perspective. PMID- 26741884 TI - Exosomes Mediate LTB4 Release during Neutrophil Chemotaxis. AB - Leukotriene B4 (LTB4) is secreted by chemotactic neutrophils, forming a secondary gradient that amplifies the reach of primary chemoattractants. This strategy increases the recruitment range for neutrophils and is important during inflammation. Here, we show that LTB4 and its synthesizing enzymes localize to intracellular multivesicular bodies that, upon stimulation, release their content as exosomes. Purified exosomes can activate resting neutrophils and elicit chemotactic activity in a LTB4 receptor-dependent manner. Inhibition of exosome release leads to loss of directional motility with concomitant loss of LTB4 release. Our findings establish that the exosomal pool of LTB4 acts in an autocrine fashion to sensitize neutrophils towards the primary chemoattractant, and in a paracrine fashion to mediate the recruitment of neighboring neutrophils in trans. We envision that this mechanism is used by other signals to foster communication between cells in harsh extracellular environments. PMID- 26741886 TI - Effect of SiO2 Spacer-Layer Thickness on Localized Surface Plasmon-Enhanced ZnO Nanorod Array LEDs. AB - Localized surface plasmon (LSP)-enhanced ultraviolet LEDs have been constructed via spin-coating Ag nanoparticles onto ZnO/SiO2 core/shell nanorod array/p-GaN heterostructures. Different from the previous reports where the dielectric spacer layer thickness was determined only through photoluminescence (PL) characterization, the SiO2 shell thickness in this work is also optimized by actual electroluminescence (EL) measurements to maximize the enhancement. It is interesting to find that the enhancement ratios derived from PL and EL measurements demonstrate different thickness dependences on SiO2 shell: an optimal 3.5-fold PL enhancement was obtained at the SiO2 thickness of 16 nm, while an "abnormal" 7-fold EL enhancement was achieved at the thickness of 12 nm. Time-resolved spectroscopy studies, as well as theoretical estimations and numerical simulations, reveal that the higher-ratio EL enhancement stems from joint contributions, both internal-quantum-efficiency improvement induced by exciton-LSP coupling and light-extraction-efficiency improvement aroused by photon-LSP coupling. PMID- 26741885 TI - Renal artery stenosis: if and when to intervene. AB - PURPOSE OF REVIEW: Atherosclerotic renovascular disease remains highly prevalent and presents an array of clinical syndromes. Recent prospective trials have dampened enthusiasm for revascularization generally, but clinicians recognize the need to identify patients likely to benefit from vascular intervention. RECENT FINDINGS: This article highlights the inflammatory nature of vascular occlusive disease and the limits of the kidney to adapt to reduced blood flow. Although moderate reductions can be tolerated, severe impairment of renal perfusion leads to tissue hypoxia and activates inflammatory injury within the kidney. Hence, assessment of kidney viability and potential tools to modify mitochondrial and inflammatory damage may be important to identify patients for whom clinical intervention should be undertaken. SUMMARY: Clinicians must recognize clinical syndromes that identify 'high-risk' groups and apply revascularization in those likely to benefit. Future efforts to protect the kidney (e.g., mitochondrial protection) or cell-based therapy may amplify clinical recovery when combined with restoring renal blood flow. PMID- 26741887 TI - In Vitro Validation of a Closed Device Enabling the Purification of the Fluid Portion of Liposuction Aspirates. AB - BACKGROUND: Adipose tissue harvested through lipoaspiration is widely exploited in plastic and cosmetic surgery, because of its remarkable trophic properties, especially relying on the presence of adipose-derived stem cells. The common procedures for adipose-derived stem cell isolation are mainly based on tissue fractionation and enzymatic digestion, requiring multiple hours of uninterrupted work, unsuitable for direct surgical applications. Recent studies demonstrated the feasibility of isolating adipose stromal cells without the need for enzymatic digestion. These studies reported the processing of the fluid portion of liposuctioned adipose tissue (lipoaspirate fluid), which contains a significant amount of progenitor cells endowed with plastic and trophic features. In this article, the authors introduce a brand new closed device--the MyStem EVO kit- which allows nonenzymatic tissue separation and rapid isolation of lipoaspirate fluid from human liposuctioned adipose tissue. METHODS: Adipose tissue was liposuctioned from 14 donors, split into aliquots, and alternatively processed using either centrifugation or the MyStem EVO kit, to separate fatty and lipoaspirate fluid portions. The samples were analyzed comparatively by flow cytometry, histology, and differentiation assays. Osteoinductive and angioinductive features were analyzed through in vitro co-culture assays. RESULTS: The alternative procedures enabled comparable yields; the kit rapidly isolated lipoaspirate fluid comprising a homogenous cell population with adipose stem cell immunophenotype, bilineage potential, and efficient osteoinductive and angioinductive features. CONCLUSION: MyStem EVO allows the rapid isolation of lipoaspirate fluid with trophic properties within a closed system, and is potentially useful for regenerative medicine applications. PMID- 26741888 TI - Salvage Palmar Fasciectomy after Initial Treatment with Collagenase Clostridium Histolyticum. PMID- 26741889 TI - Permissive Intraabdominal Hypertension following Complex Abdominal Wall Reconstruction. PMID- 26741890 TI - Reply: Salvage Palmar Fasciectomy following Initial Treatment with Collagenase Clostridium Histolyticum. PMID- 26741892 TI - A Novel Pairwise Comparison-Based Method to Determine Radiation Dose Reduction Potentials of Iterative Reconstruction Algorithms, Exemplified Through Circle of Willis Computed Tomography Angiography. AB - OBJECTIVES: The aim of this study was to determine the dose reduction potential of iterative reconstruction (IR) algorithms in computed tomography angiography (CTA) of the circle of Willis using a novel method of evaluating the quality of radiation dose-reduced images. MATERIALS AND METHODS: This study relied on ReconCT, a proprietary reconstruction software that allows simulating CT scans acquired with reduced radiation dose based on the raw data of true scans. To evaluate the performance of ReconCT in this regard, a phantom study was performed to compare the image noise of true and simulated scans within simulated vessels of a head phantom. That followed, 10 patients scheduled for CTA of the circle of Willis were scanned according to our institute's standard protocol (100 kV, 145 reference mAs). Subsequently, CTA images of these patients were reconstructed as either a full-dose weighted filtered back projection or with radiation dose reductions down to 10% of the full-dose level and Sinogram-Affirmed Iterative Reconstruction (SAFIRE) with either strength 3 or 5. Images were marked with arrows pointing on vessels of different sizes, and image pairs were presented to observers. Five readers assessed image quality with 2-alternative forced choice comparisons. RESULTS: In the phantom study, no significant differences were observed between the noise levels of simulated and true scans in filtered back projection, SAFIRE 3, and SAFIRE 5 reconstructions.The dose reduction potential for patient scans showed a strong dependence on IR strength as well as on the size of the vessel of interest. Thus, the potential radiation dose reductions ranged from 84.4% for the evaluation of great vessels reconstructed with SAFIRE 5 to 40.9% for the evaluation of small vessels reconstructed with SAFIRE 3. CONCLUSIONS: This study provides a novel image quality evaluation method based on 2-alternative forced choice comparisons. In CTA of the circle of Willis, higher IR strengths and greater vessel sizes allowed higher degrees of radiation dose reduction. PMID- 26741891 TI - Characterization of Cystic Lesions by Spectral Mammography: Results of a Clinical Pilot Study. AB - OBJECTIVES: Round lesions are a common mammographic finding, which can contribute more than 20% of overall recalls at screening. Discrimination of cystic fluid from solid tissue by spectral x-ray imaging has been demonstrated in specimen experiments. This work translates these results into a clinical pilot study to investigate the feasibility of discriminating cystic from solid lesions using spectral mammography. MATERIALS AND METHODS: Women undergoing mammography as part of their routine diagnostic workup were consented for analysis of spectral information obtained from a photon-counting mammography system. Images were analyzed retrospectively after diagnosis was confirmed with ultrasound and pathology. Well-defined solitary lesions were delineated independently by 3 expert radiologists. A breast lesion model is generated from the spectral mammography data using the energy-dependent x-ray attenuation of cyst fluid, carcinoma, and adipose and glandular tissue. From the breast lesion model, 2 spectral features are computed and combined in a 2-feature discrimination algorithm, which is evaluated in an analysis of the receiver operating characteristic curve for the task of identifying solid lesions ("positive result"). Expected outcomes on a screening population are extrapolated from this pilot study by cross-validation with bootstrapping using a 95% confidence interval (CI). RESULTS: The 2-feature discrimination algorithm was evaluated on the set of 119 eligible lesions (62 solids, 57 cysts) of diameter greater than 10 mm. The area under the receiver operating characteristic curve (AUC) was 0.88 with a specificity of 61% at the 99% sensitivity level on average over all expert radiologists. Cross-validation with bootstrapping of the clinical data revealed an AUC of 0.89 (95% CI, 0.79-0.96) and a specificity of 56% (95% CI, 33%-78%) when operating the algorithm at the 99% sensitivity level. CONCLUSIONS: Discriminating cystic from solid lesions with spectral mammography demonstrates promising results with the potential to reduce mammographic recalls. It is estimated that for each missed cancer at least 625 cystic lesions would have been correctly identified and hence would not have been needed to be recalled. Our results justify undertaking a larger reader study to refine the algorithm and determine clinically relevant thresholds to allow safe classification of cystic lesions by spectral mammography. PMID- 26741893 TI - Dynamic Contrast-Enhanced Computed Tomography: A New Diagnostic Tool to Assess Renal Perfusion After Ischemia-Reperfusion Injury in Mice: Correlation of Perfusion Deficit to Histopathologic Damage. AB - OBJECTIVE: The aim of this study was to investigate the value of dynamic contrast enhanced computed tomography (CT) in the assessment of renal perfusion parameters after ischemia-reperfusion (I/R) injury in an experimental murine model. MATERIALS AND METHODS: Balb/cJ wildtype mice were subjected to 45 minutes (AKI45) or 60 minutes (AKI60) of unilateral warm I/R injury by clamping the pedicle of the right kidney. Two, 7, and 18 days after right I/R injury, renal blood flow (RBF), renal volume of distribution (RVD), and mean transit time were quantitatively assessed in the cortex of both kidneys by dynamic contrast enhanced CT. Acute tubular injury (ATI) was assessed by histologic analysis using a semiquantitative sum score (score, 0-18) and correlated with RBF, RVD, and mean transit time. RESULTS: Histologic signs of ATI could be detected in the clamped kidneys in both groups already at day 2. Pathologic features of ATI worsened in AKI60 until day 18 (score, 7 +/- 0), whereas mice in AKI45 group showed amelioration over time (score, 4 +/- 2). Renal blood flow was significantly reduced in ischemic kidneys in AKI45 (287 +/- 32 mL/100 mL per minute; P < 0.01) and AKI60 group (249 +/- 73 mL/100 mL per minute; P < 0.01) as compared with that in healthy kidneys (402 +/- 49 mL/100 mL per minute) on day 2. It decreased further at day 7 in both groups (AKI45: 165 +/- 44 mL/100 mL per minute, P < 0.01; AKI60: 151 +/- 72 mL/100 mL per minute, P < 0.05) and improved at day 18 in AKI45 (261 +/- 11 mL/100 mL per minute, P < 0.05) and to a lesser degree in AKI60 (197 +/- 52 mL/100 mL per minute, P > 0.05). Values of RVD paralleled RBF at all time points. Renal blood flow (r = -0.79; P < 0.01) and RVD (r = -0.8; P < 0.01) significantly correlated with the histological damage score (Spearman rank correlation). CONCLUSIONS: Dynamic contrast-enhanced CT is a noninvasive method to determine renal perfusion changes in acute kidney injury. It might be a valuable diagnostic tool to predict outcome or monitor treatment effects of renal I/R injury. PMID- 26741894 TI - Why a "Women in Combat Symposium"? PMID- 26741895 TI - Leading Gender Integration. AB - We have a tremendous opportunity not only to integrate women completely into the military but, more importantly, raise the standard of performance for all our service members. A standards-based approach appropriately defines gender neutral standards of physical performance based upon current demands of combat-arms specialties. The key is getting the standards right and sticking to those standards when challenged. PMID- 26741896 TI - Women in Combat: Framing the Issues of Health and Health Research for America's Servicewomen. AB - BACKGROUND: Although women have served in the U.S. military officially since 1901, the medical needs of women in combat have historically been poorly understood. Recent expansion of the opportunities females may now play in combat roles has created an urgent need for a review of how Department of Defense supports females as they transition into these new roles, as well as current science related to key aspects of the health of female warriors. There is currently no systematic institutional structure in place to regularly and methodically examine gaps in policy, research, and treatment for issues related to women in combat. METHOD: This article serves as a brief overview and introduction to some of the critical topics related to the health of women in combat roles, to include women's health issues research and treatment efforts, physiological differences between sexes, and leadership and unit factors. CONCLUSION: The Department of Defense should continue to explore and address policy, research, and practice related to the complex ongoing needs of military females in combat roles, and ensures sufficient staffing, resources and support from senior military leaders. PMID- 26741897 TI - Conceptual Model of Military Women's Life Events and Well-Being. AB - This article presents a life course conceptual model and applies it to the study of military women's experiences and the effect of those life events on their well being. Of special concern are the effects on women serving in direct combat jobs, as well as in any specialties operating in a hostile environment. Drawing on previous research, the model considers and gives examples of how a woman's well being is affected by events in her military career, her family life, and other areas of life. The article emphasizes the effects of intersections of multiple events, as well as how the effects on well-being are mediated or moderated by other factors, including individual characteristics, military contextual variables, and resources. The analysis also includes the impacts of preventative and treatment interventions, as well as of policies, programs, and practices. Based on the model and on previous research, questions for future research are posed. PMID- 26741898 TI - Sexual Harassment and Assault in the U.S. Military: A Review of Policy and Research Trends. AB - Recently, there has been increasing concern regarding the problem of sexual violence in the military. Because sexual harassment and assault are more closely intertwined in the military than in most civilian contexts, the military context affords a unique opportunity to study the interrelationships between these two types of sexual violence. In this review, we briefly summarize existing research on military sexual trauma prevalence rates, effects on victims, and risk factors, as well as prevention and response programs in the military context. In each of these topic areas, we emphasize issues unique to the complex interplay between sexual harassment and assault in the military and make recommendations for future research. PMID- 26741899 TI - The Role of Leadership and Peer Behaviors in the Performance and Well-Being of Women in Combat: Historical Perspectives, Unit Integration, and Family Issues. AB - This article analyzes how the behaviors of leaders and peers affect the performance and well-being of military women. Locating our analysis within the conceptual model in this issue, we summarize the empirical literature and make practice and policy recommendations. We synthesize results about unit integration, such as research on the conditions for successful integration of previously excluded groups and on the relationship between cohesion and performance. We apply lessons learned from the history of diversity integration in military and civilian organizations, analyzing the treatment of military personnel by race, gender, and sexual orientation. The opening of ground combat specialties and units to women is the latest step in personnel policy changes broadening the recruitment base. We analyze research on gender integration in contemporary armed forces, focusing on positive and negative effects on women of leader and peer behaviors. We discuss conditions for successfully integrating women and those that tend to lead to failure. We analyze military women's family issues, including the effects of deployments and how leaders and peers can help ameliorate problems-or exacerbate them with inappropriate or unsupportive behavior. PMID- 26741900 TI - Communicating Difficult and Taboo Information: A How-To Guide for Commanders. AB - Military commanders frequently mention that communicating difficult or taboo information is especially challenging. In the context of gender-integrated ground combat service there may be additional communication challenges for military commanders who may be unaccustomed to leading both men and women. Often, military commanders must communicate and deliver difficult information, or information that causes a negative emotional response from the communicator or the intended audience. This article is intended to identify some of these challenges and present practical examples and tips for military commanders to effectively communicate difficult or taboo topics and information. In addition, this article is a call for communication experts to reach out to military leaders and offer appropriate assistance in facilitating and delivering difficult communication. PMID- 26741901 TI - Designing Military Systems for Women in Combat. PMID- 26741902 TI - Operational Physical Performance and Fitness in Military Women: Physiological, Musculoskeletal Injury, and Optimized Physical Training Considerations for Successfully Integrating Women Into Combat-Centric Military Occupations. AB - This article summarizes presentations from a 2014 United States Department of Defense (DoD) Health Affairs Women in Combat symposium addressing physiological, musculoskeletal injury, and optimized physical training considerations from the operational physical performance section. The symposium was held to provide a state-of-the-science meeting on the U.S. DoD's rescinding of the ground combat exclusion policy opening up combat-centric occupations to women. Physiological, metabolic, body composition, bone density, cardiorespiratory fitness, and thermoregulation differences between men and women were briefly reviewed. Injury epidemiological data are presented within military training and operational environments demonstrating women to be at a higher risk for musculoskeletal injuries than men. Physical training considerations for improved muscle strength and power, occupational task performance, load carriage were also reviewed. Particular focus of this article was given to translating physiological and epidemiological findings from the literature on these topics toward actionable guidance and policy recommendations for military leaders responsible for military physical training doctrine: (1) inclusion of resistance training with special emphasis on strength and power development (i.e., activation of high-threshold motor units and recruitment of type II high-force muscle fibers), upper-body strength development, and heavy load carriage, (2) moving away from "field expediency" as the major criteria for determining military physical training policy and training implementation, (3) improvement of load carriage ability with emphasis placed on specific load carriage task performance, combined with both resistance and endurance training, and (4) providing greater equipment resources, coaching assets, and increased training time dedicated to physical readiness training. PMID- 26741903 TI - Reproductive Health of Active Duty Women in Medically Austere Environments. AB - One in seven of the approximately 2.2 million Department of Defense active duty military personnel are women. Among active duty servicewomen, about 40% are under 26 years old, and almost half are young, lower ranking enlisted personnel. This article will include a review of the literature on military women's health topics such including contraception access, pregnancy, and pregnancy outcomes after environmental exposures. In these early adult years, contraception use may not be consistent, leading to higher rates of unintended pregnancy that is similar to their civilian counterparts, but it may affect troop readiness. Women who become pregnant after deployment must be evacuated from theater. Complications in pregnancy that require immediate intervention, such as ectopic pregnancy, may be more difficult to diagnose and manage if far away from comprehensive medical services. Environmental exposures may affect the pregnancy outcome, or may produce delayed responses for future childbearing. Women face other gynecologic choices including menstrual suppression while deployed. Many of these issues have not been fully studied, sample sizes are small or methodological flaws exist in the analysis limiting conclusions that can be drawn. Further research with greater rigor, larger sample sizes, and careful design are needed to address many of these questions. PMID- 26741904 TI - The Many Faces of Military Families: Unique Features of the Lives of Female Service Members. AB - Female service members' family structures differ from the traditional male service member-female spouse composition of military families. Consequently, this mixed-methods study reviewed demographic data, empirical evidence, and presented findings from secondary analyses of the 2010 wave of the Military Family Life Project regarding structural differences in male and female service members' families and perceptions and experiences of military spouses. In addition, to gain an understanding of the influence of women's service on their family functioning, we conducted in-depth telephone interviews with 20 civilian husbands residing in 11 states around the United States. Empirical evidence suggests service women had higher rates or remarriage and divorce than service men. Women were also more likely than men to be part of nontraditional family forms. Civilian husbands of female service members, however, reported lower marital satisfaction, less support from the community, and less satisfaction with the military lifestyle than military wives. Husbands' accounts indicated that their families experienced both benefits and challenges from wives' service. Integration in the military community and separation presented major challenges for women's families. Implications of benefits and challenges of women's service for their families are discussed. PMID- 26741905 TI - Gender Differences Among Military Combatants: Does Social Support, Ostracism, and Pain Perception Influence Psychological Health? AB - The literature on gender differences related to psychological health among in theater service members who are deployed in a combatant role is limited. Much focuses on retrospective reports of service members who have returned from deployment. Potential key factors that contribute to gender differences in psychological health among combatants are found in literature across several topic areas, but integration of findings across disciplines is lacking. A growing body of literature on gender differences related to psychological health of postdeployment military populations suggests males and females respond differently to perceived levels of social support pre-and postdeployment. One study on service members who were deployed suggested no significant gender differences related to reported psychological health symptoms, but did appear to find significant gender differences related to reported perception of unit morale. In another related area, research explores how ostracism impacts physical and psychological health of individuals and organizations, and can result in perceptions of physical pain, although research on gender differences related to the impact of ostracism is scarce. Research has also begun to focus on sex differences in pain responses, and has identified multiple biopsychosocial, genetic, and hormonal factors that may contribute as potential underlying mechanisms. In this brief review, we focus on and begin to integrate relevant findings related to the psychological health of females in combat roles, gender differences in the impact of perception of social support on psychological health, the psychological and physical impact of ostracism on individuals and organizations, and the current literature on sex differences in pain perception. We conclude with a synthesis and discussion of research gaps identified through this review, implications for clinical practice, and potential future research directions. In conclusion, there appear to be gender differences related to the presence or absence of social support, the impact of ostracism, and the perception of pain. These differences may play a critical role in the psychological health of female combatants. More research on this topic is needed. PMID- 26741906 TI - Optimizing Performance, Health, and Well-being: Nutritional Factors. AB - Nutrition is essential for maintaining peak health and performance of Warfighters. This review will focus on a series of nutrients of concern for female Warfighters. Biological function, dietary sources, and requirements will be reviewed, and recommendations for women in combat roles will be provided. Iron, essential for physical and cognitive performance, is critical for female Warfighters because of elevated dietary requirements as compared to male Warfighters, as well as declines in iron status that may occur in response to physical activities, such as military training. Calcium and vitamin D are essential for bone health, and should be considered in efforts to prevent stress fractures, which occur with greater frequency in female Warfighters as compared to their male counterparts. Folate, essential for the prevention of neural tube defects during pregnancy and gestation, is critical for female Warfighters because of elevated dietary requirements before pregnancy. Providing optimal levels of these nutrients will facilitate readiness as women prepare to serve in combat roles. PMID- 26741907 TI - Characterization and Comparison of Combat-Related Injuries in Women During OIF and OEF. AB - Although historically restricted from combat roles, women suffer from combat related injuries, especially in recent conflicts where asymmetrical warfare erases distinctions between forward and rear operating areas. U.S. servicewomen who sustained combat-related injury in Operation Iraqi Freedom (OIF) or Operation Enduring Freedom (OEF) between January 2003 and May 2014 were identified from the Expeditionary Medical Encounter Database. Injuries were characterized using Abbreviated Injury Scale and International Classification of Diseases, 9th Revision codes. Of the 844 combat-related injury episodes in women, 51% (n = 433) were OIF injuries and 49% (n = 411) were OEF injuries. Blast events were responsible for 90% of injuries. The average Injury Severity Score was 3, with no statistical difference in means between OIF and OEF. Of significance were increased head injuries in OEF compared with OIF (80% vs. 48%; p < 0.001). Although the majority of combat-related injuries suffered by women were mild, some women suffered life-threatening injuries, and nearly 65% of the injury episodes resulted in more than one injury. More research is needed as the roles of women in the military continue to expand. Future studies will investigate quality of life outcomes and gender differences in combat-related injuries. PMID- 26741908 TI - Alcohol Use Among Active Duty Women: Analysis AUDIT Scores From the 2011 Health Related Behavior Survey of Active Duty Military Personnel. AB - BACKGROUND: Numerous studies document higher substance use among military men after deployment; similar studies focused on military women are limited. OBJECTIVES: This study examines alcohol use of active duty women and deployment factors, social/environmental/attitudinal factors, and psychological/intrapersonal factors. METHODS: Secondary data analysis of the 2011 Survey of Health-Related Behavior of active duty military personnel was conducted using bivariate statistics and multiple regression analyses with Alcohol Use Disorders Identification Test scores as the dependent variable. RESULTS: Nearly 94% had low risk for alcohol use disorders. Length of combat experience and extent of combat exposure were unrelated to Alcohol Use Disorders Identification Test scores; noncombat deployment was unrelated after controlling for marital status, age of first drink, pay grade, and branch of service. Significant motivators (p < 0.001) for drinking were "like/enjoy drinking," "drink to cheer up," "drink to forget problems," and significant deterrents were "cost of alcohol" and "fear of upsetting family/friends if used alcohol." Anger propensity, risk propensity, lifetime prevalence of suicidal ideation, and depressed mood were significant predictors in the regression model after controlling for covariates. CONCLUSION: Findings suggest that some active duty women use alcohol to cope with adverse emotional states, whereas others use alcohol consistent with propensity for high-risk behaviors. PMID- 26741909 TI - Women in Combat: Summary of Findings and a Way Ahead. AB - The Women in Combat Symposium was held at the Defense Health Headquarters April 29 to May 1, 2014, cohosted by the Office of the Assistant Secretary of Defense for Health Affairs and the Consortium for Health and Military Performance. The conference was a call to renew and extend research investment and policy commitment to recognize operational scenarios, requirements, health priorities, and combat-related injury exposures uniquely relevant to the performance and well being of female Service members. Symposium participants worked in groups to identify knowledge and capability gaps critical to the successful integration, health, and performance of female Service members in combat roles and to develop recommendations for researchers and policy makers to address gaps in three specific areas of concern: Leadership and Peer Behavior, Operational Performance, and Health and Well-Being. Consensus findings are summarized as 20 research gaps and accompanying recommendations. Each represents an opportunity to advance health and performance outcomes and to leverage female Service members' strengths and capacities to the general benefit of all Service members and their families. PMID- 26741911 TI - Oxygen therapy in palliative care. AB - Breathlessness in advanced disease is a common problem, with the majority of people experiencing breathlessness in the weeks before death. The thrust of the new British Thoracic Society guidelines for home oxygen in adults is that oxygen therapy for home use is most useful in chronic hypoxaemia. However, clinicians make individual clinical decisions, cognisant of the guidelines but ultimately determined by what relieves the symptoms of the individual most effectively. PMID- 26741912 TI - Protein Configuration Landscape Fluctuations Revealed by Exciton Transition Polarizations in Single Light Harvesting Complexes. AB - Protein is a flexible material with broad distribution of conformations forming an energy landscape of quasi-stationary states. Disentangling the system dynamics along this landscape is the key for understanding the functioning of the protein. Here we studied a photosynthetic antenna pigment-protein complex LH2 with single molecule two-dimensional polarization imaging. Modeling based on the Redfield relaxation theory well describes the observed polarization properties of LH2 fluorescence and fluorescence excitation, strongly suggesting that at 77 K the conformational subspace of the LH2 is limited to about three configurations with relatively frequent switching among each other. At room temperature the next level of fluctuations determines the conformational dynamics. The results support the multitier model of the energy landscape of proteins and demonstrate the potential of the method for the studies of structural dynamics in proteins. PMID- 26741910 TI - Regulation of CFTR Expression and Arginine Vasopressin Activity Are Dependent on Polycystin-1 in Kidney-Derived Cells. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of multiple, progressive, fluid-filled renal cysts that distort the renal parenchyma, leading to end-stage renal failure, mainly after the fifth decade of life. ADPKD is caused by a mutation in the PKD1 or PKD2 genes that encode polycystin-1 (PC-1) and polycystin-2 (PC-2), respectively. PC-1 is an important regulator of several signaling pathways and PC-2 is a nonselective calcium channel. The CFTR chloride channel is responsible for driving net fluid secretion into the cysts, promoting cyst growth. Arginine vasopressin hormone (AVP), in turn, is capable of increasing cystic intracellular cAMP, contributing to cell proliferation, transepithelial fluid secretion, and therefore to disease progression. The aim of this study was to assess if AVP can modulate CFTR and whether PC-1 plays a role in this potential modulation. METHODS: M1 cells, derived from mouse cortical collecting duct, were used in the current work. The cells were treated with 10-7 M AVP hormone and divided into two main groups: transfected cells superexpressing PC-1 (Transf) and cells not transfected (Ctrl). CFTR expression was assessed by immunodetection, CFTR mRNA levels were quantified by quantitative reverse transcription-polymerase chain reaction, and CFTR net ion transport was measured using the Ussing chamber technique. RESULTS: AVP treatment increased the levels of CFTR protein and mRNA. CFTR short-circuit currents were also increased. However, when PC-1 was overexpressed in M1 cells, no increase in any of these parameters was detected. CONCLUSIONS: CFTR chloride channel expression is increased by AVP in M1 cells and PC-1 is capable of regulating this modulation. PMID- 26741913 TI - A Chemical Perspective on Allostery. AB - Much work has been done in the past decade to quantify the phenomenon of allosteric communication in proteins. Every new study unveils an extra piece of the puzzle in our search for an understanding of allostery that allows us to make predictions on the response of a protein to medically relevant stimuli such as pathological mutations or drug binding. This review summarizes recent advances in the analysis of mechanisms of allosteric communication in proteins, and combines this new knowledge to offer a perspective of allostery which is consistent with chemical views of molecular processes. First, we review recent work, particularly computational, on the characterization of signal propagation and conformational changes in allosteric proteins. We then compare different models of allostery, and discuss the significance of the concept of an allosteric pathway. We argue that allostery can be rationalized in terms of pathways of residues that efficiently transmit energy between different binding sites. We then provide examples that show how this picture could account for most of the observed data, since energy flow may be manifested as changes in both structure and dynamics. We conclude by acknowledging that the proposed view is still a simplification and should not be taken as a rigorous model of allosteric communication in proteins. Nevertheless, simple pictures like this can go a long way in improving our understanding of many complex phenomena observed in nature. PMID- 26741945 TI - Sequential Au(i)/chiral tertiary amine catalysis: a tandem C-H functionalization of anisoles or a thiophene/asymmetric Michael addition sequence to quaternary oxindoles. AB - We report an unprecedented sequential Au(i)/bifunctional tertiary amine catalysis, which enables a tandem C-H functionalization of weak nucleophiles (anisoles or thiophenes) and asymmetric Michael addition for the highly enantioselective synthesis of quaternary oxindoles from diazooxindoles and nitroenynes. PMID- 26741914 TI - Structural Properties, Order-Disorder Phenomena, and Phase Stability of Orotic Acid Crystal Forms. AB - Orotic acid (OTA) is reported to exist in the anhydrous (AH), monohydrate (Hy1), and dimethyl sulfoxide monosolvate (SDMSO) forms. In this study we investigate the (de)hydration/desolvation behavior, aiming at an understanding of the elusive structural features of anhydrous OTA by a combination of experimental and computational techniques, namely, thermal analytical methods, gravimetric moisture (de)sorption studies, water activity measurements, X-ray powder diffraction, spectroscopy (vibrational, solid-state NMR), crystal energy landscape, and chemical shift calculations. The Hy1 is a highly stable hydrate, which dissociates above 135 degrees C and loses only a small part of the water when stored over desiccants (25 degrees C) for more than one year. In Hy1, orotic acid and water molecules are linked by strong hydrogen bonds in nearly perfectly planar arranged stacked layers. The layers are spaced by 3.1 A and not linked via hydrogen bonds. Upon dehydration the X-ray powder diffraction and solid-state NMR peaks become broader, indicating some disorder in the anhydrous form. The Hy1 stacking reflection (122) is maintained, suggesting that the OTA molecules are still arranged in stacked layers in the dehydration product. Desolvation of SDMSO, a nonlayer structure, results in the same AH phase as observed upon dehydrating Hy1. Depending on the desolvation conditions, different levels of order-disorder of layers present in anhydrous OTA are observed, which is also suggested by the computed low energy crystal structures. These structures provide models for stacking faults as intergrowth of different layers is possible. The variability in anhydrate crystals is of practical concern as it affects the moisture dependent stability of AH with respect to hydration. PMID- 26741946 TI - Graphene and Graphene-like Molecules: Prospects in Solar Cells. AB - Graphene is constantly hyped as a game-changer for flexible transparent displays. However, to date, no solar cell fabricated on graphene electrodes has out performed indium tin oxide in power conversion efficiency (PCE). This Perspective covers the enabling roles that graphene can play in solar cells because of its unique properties. Compared to transparent and conducting metal oxides, graphene may not have competitive advantages in terms of its electrical conductivity. The unique strength of graphene lies in its ability to perform various enabling roles in solar cell architectures, leading to overall improvement in PCE. Graphene can serve as an ultrathin and transparent diffusion barrier in solar cell contacts, as an intermediate layer in tandem solar cells, as an electron acceptor, etc. Inspired by the properties of graphene, chemists are also designing graphene-like molecules in which the topology of pi-electron array, donor-acceptor structures, and conformation can be tuned to offer a new class of light-harvesting materials. PMID- 26741948 TI - Regioselective Electrophilic Fluorination of Rationally Designed Imidazole Derivatives. AB - We report the regioselective and direct functionalization of rationally designed imidazole derivatives through electrophilic fluorination with N fluorobenzenesulfonimide enabled via in situ deprotonation with lithium 2,2,6,6 tetramethylpiperidine. Aided by a controlled protecting group switch, we were able to effectively target both the reactive 5- as well as the difficult to target 4-position of these molecules, leading to a series of fluorinated polysubstituted imidazoles in gram scale. PMID- 26741947 TI - The Rational Design of Selective Benzoxazepin Inhibitors of the alpha-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1 Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9 yl)oxy)propanamide (GDC-0326). AB - Inhibitors of the class I phosphoinositide 3-kinase (PI3K) isoform PI3Kalpha have received substantial attention for their potential use in cancer therapy. Despite the particular attraction of targeting PI3Kalpha, achieving selectivity for the inhibition of this isoform has proved challenging. Herein we report the discovery of inhibitors of PI3Kalpha that have selectivity over the other class I isoforms and all other kinases tested. In GDC-0032 (3, taselisib), we previously minimized inhibition of PI3Kbeta relative to the other class I insoforms. Subsequently, we extended our efforts to identify PI3Kalpha-specific inhibitors using PI3Kalpha crystal structures to inform the design of benzoxazepin inhibitors with selectivity for PI3Kalpha through interactions with a nonconserved residue. Several molecules selective for PI3Kalpha relative to the other class I isoforms, as well as other kinases, were identified. Optimization of properties related to drug metabolism then culminated in the identification of the clinical candidate GDC-0326 (4). PMID- 26741949 TI - Early Gut Colonization of Preterm Infants: Effect of Enteral Feeding Tubes. AB - OBJECTIVE: The aim of the study was to evaluate the potential colonization of nosocomial bacteria in enteral feeding systems and its effect on early gut colonization of preterm neonates. METHODS: Mother's own milk, donor milk, and preterm formula samples obtained after passing through the external part of the enteral feeding tubes were cultured. In addition, meconium and fecal samples from 26 preterm infants collected at different time points until discharge were cultured. Random amplification polymorphism DNA and pulse field gel electrophoresis were performed to confirm the presence of specific bacterial strains in milk and infant fecal samples. RESULTS: Approximately 4000 bacterial isolates were identified at the species level. The dominant species in both feces from preterm infants and milk samples were Staphylococcus epidermidis, S aureus, Enterococcus faecalis, E faecium, Serratia marcescens, Klebsiella pneumoniae, and Escherichia coli. All of them were present at high concentrations independently of the feeding mode. Random amplification polymorphism DNA and pulse field gel electrophoresis techniques showed that several bacteria strains were found in both type of samples. Furthermore, scanning electron microscopy revealed the presence of a dense bacterial biofilm in several parts of the feeding tubes and the tube connectors. CONCLUSIONS: There is a sharing of bacterial strains between the neonates' gastrointestinal microbiota and the feeding tubes used to feed them. PMID- 26741950 TI - Linear and Nonlinear Optical Properties of Monolayer-Protected Gold Nanocluster Films. AB - Gold nanoclusters have been extensively studied in solution for their unique optical properties. However, many applications of nanoclusters involve the use of the material in the solid state such as films. Au25(SR)18 in polymeric hosts was used as the model for studying the optical properties of nanocluster films. Different film-processing conditions as well as types of polymers were explored to produce a good-quality film that is suitable for optical measurements. The best optical film was made using Au25(C6S)18 and polystyrene. The formation of nanocluster films drastically reduces the intercluster distances to a few nanometers, which were estimated and characterized by optical absorption. The steady-state absorption and emission properties of the nanocluster film maintained their molecular characteristics. The emissions from the nanocluster films are found to be strongly enhanced at 730 nm with a smaller enhancement at 820 nm when the intercluster distance is below 8 nm. The emission enhancement can be attributed to the energy transfer between clusters due to the small intercluster distance. Two-photon Z scan revealed that the two-photon absorption cross sections are in the order of 10(6) GM, which is an order of magnitude higher than it is in solution. The two-photon absorption enhancement is correlated with strong dipole coupling. These results show that metal nanoclusters can be made into optical quality films, which increase the interaction between clusters and enhances their linear and nonlinear optical responses. PMID- 26741951 TI - Whole body radioprotective effect of phenolic extracts from the fruits of Malus baccata (Linn.) Borkh. AB - This study was designed to evaluate the radioprotective effect of phenolics extracted from the fruits of Malus baccata (Linn.) Borkh. (MBP-3b) against damage induced by (60)Co gamma-irradiation in vivo. MBP-3b could significantly improve the activity of endogenous antioxidant enzymes and the T-AOC, as well as reduce the MDA level in the liver and kidneys of irradiated mice. In addition, pretreatment with MBP-3b at a dose of 150 mg per kg bw could significantly enhance immunomodulation activity by promoting the proliferation of spenocytes and monocyte phagocytosis. The administration of MBP-3b prevented the decline induced by radiation of haematological parameters (WBC, RBC, PLT and HGB). Furthermore, MBP-3b could protect spenocytes from radiation-induced damage by inhibiting cell apoptosis. The results indicated that MBP-3b possesses strong whole body radioprotective and immunomodulatory activities. The main constituents of MBP-3b were tentatively identified as delphinidin-3,5-diglucoside, cyanidin-3 glucoside, chlorogenic acid, proanthocyanidin C1, quercetin-3-galactoside, quercetin-3-glucoside, quercetin-3-xyloside/arabinoside, phloretin-2 xyloseglucoside, quercetin-3-rhamnoside and phlorizin. MBP-3b could be used as a probable radioprotector against gamma radiation induced oxidative damage. PMID- 26741952 TI - 3-Imidoallenylphosphonates: In Situ Formation and beta-Alkoxylation. AB - 3-Imidoallenylphosphonates, allenes bearing both an electron-withdrawing and donating group, were isolated for the first time. An alkoxy substituent was introduced into these unprecedented intermediates in a one-pot approach, yielding beta-functionalized aminophosphonates in excellent yields and short reaction times. The mechanistic insights gained are important additions to the domain of allene chemistry. Addition of biologically important molecules, including monoglycerides, amino acids, and nucleosides, proves the general applicability of the developed method. PMID- 26741953 TI - The synergistic effect of a well-defined Au@Pt core-shell nanostructure toward photocatalytic hydrogen generation: interface engineering to improve the Schottky barrier and hydrogen-evolved kinetics. AB - A well-defined co-catalyst system TiO2 nanotube-Au (core)-Pt (shell) was demonstrated to be the combination of the localized surface plasmon effect of gold and excellent proton reduction nature of platinum. Furthermore, surface engineering by the descending Fermi energies of gold and platinum was beneficial to electron transfer. PMID- 26741954 TI - Efficient Separation of Europium Over Americium Using Cucurbit-[5]-uril Supramolecule: A Relativistic DFT Based Investigation. AB - Achieving an efficient separation of chemically similar Am(3+)/Eu(3+) pair in high level liquid waste treatment is crucial for managing the long-term nuclear waste disposal issues. The use of sophisticated supramolecules in a rigid framework could be the next step toward solving the long-standing problem. Here, we have investigated the possibility of separating Am(3+)/Eu(3+) pair with cucurbit-[5]-uril (CB[5]), a macrocycle from the cucurbit-[n]-uril family, using relativistic density functional theory (DFT) based calculations. We have explored the structures, binding, and energetics of metal-CB[5] complexation processes with and without the presence of counterions. Our study reveals an excellent selectivity of Eu(3+) over Am(3+) with CB[5] (ion exchange free energy, DeltaDeltaGAm/Eu > 10 kcal mol(-1)). Both metals bind with the carbonyl portals via MU(5) coordination arrangement with the further involvement of three external water molecules. The presence of counterions, particularly nitrate, inside the hydrophobic cavity of CB[5], induces a cooperative cation-anion binding, resulting in enhancement of metal binding at the host. The overall binding process is found to be entropy driven resembling the recent experimental observations (Rawat et al. Dalton Trans. 2015, 44, 4246-4258). The optimized structural parameters for Eu(3+)-CB[5] complexes are found to be in excellent agreement with the available experimental information. To rationalize the computed selectivity trend, electronic structures are further scrutinized using energy decomposition analysis (EDA), quantum theory of atom in molecules (QTAIM), Mulliken population analysis (MPA), Nalewajski-Mrojek (NM) bond order, and molecular orbital analyses. Strong electrostatic ion-dipole interaction along with efficient charge transfer between CB[5] and Eu(3+) outweighs the better degree of covalency between CB[5] and Am(3+) leading to superior selectivity of Eu(3+) over Am(3+). PMID- 26741955 TI - An Uncommon Complication With Use of Topical Local Anesthetic Agents: Methemoglobinemia. AB - Although the use of topical local anesthetics is generally safe, several potentially fatal complications have been reported. Methemoglobinemia is a rare but potentially fatal complication. Methemoglobin is a naturally occurring oxidized metabolite of hemoglobin, and physiologic levels (<1%) are normal. Methemoglobinemia can be congenital or acquired. Several drugs including topical anesthetic agents like benzocaine can induce this condition. Sudden appearance of cyanosis, with a disproportionately better oxygen saturation of 85% after use of local anesthetics can be a helpful for diagnosis. PMID- 26741956 TI - Linezolid Induced Reversible Peripheral Neuropathy. AB - Linezolid has been increasingly used for several severe infections including multidrug-resistant tuberculosis. Peripheral neuropathy is a rare side effect of linezolid and is conventionally considered as irreversible. Here, we report a case of reversible neuropathy induced by linezolid. PMID- 26741957 TI - Antipsychotic Therapy-Induced New Onset Diabetic Ketoacidosis. AB - Atypical antipsychotics are very widely used for various psychiatric ailments because of their less extrapyramidal side effects. Various reports of disturbances in glucose metabolism in the form of new onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, diabetic ketoacidosis, hyperosmolar nonketotic coma, acute pancreatitis, and increased adiposity have been reported. We present a case of new onset diabetic ketoacidosis in a patient without a history of glucose intolerance who was being treated with olanzapine for bipolar disorder. He presented in hyperglycemic, hyperosmolar, hyperketotic state with hyperkalemia, and peaked T waves on electrocardiogram. He was treated with vigorous intravenous hydration, insulin, and kaexylate which stabilized his metabolic profile. He was discontinued off of his olanzapine and started on resperidol for his bipolar disorder. Over the course of 6 months, the patient was discontinued off of his insulin and has been doing well on his follow-up appointments. This case highlights the necessity of close blood glucose monitoring of patient on atypical antipsychotic medications irrespective of their diabetic status. PMID- 26741958 TI - Fatty Liver Index Associates with Relative Sarcopenia and GH/ IGF- 1 Status in Obese Subjects. AB - INTRODUCTION: Recently the association between hepatic steatosis and sarcopenia has been described. GH/IGF-1 axis has been postulated to play a role in linking fatty liver and low muscle mass. The aim of our study was to explore the association between fatty liver index, sarcopenic obesity, insulin sensitivity, and GH/IGF-1 status. METHODS: 427 subjects [age: 45.65+/-13.94 years, BMI: 36.92+/-6.43 kg/m2] were enrolled. Participants were divided into three groups: fatty liver index (FLI) <20, 20>=FLI<60, and FLI>=60. Body composition was assessed by DXA. The truncal fat mass (TrFM) to appendicular skeletal muscle (ASM) ratio was used as an indicator of sarcopenic obesity. ISI-Matsuda index was used. RESULTS: BMI, fat mass, and the TrFM/ASM ratio were higher in subjects with FLI>=60. GH, IGF-1 and ISI-Matsuda were lower in the high FLI group (all p<0.05). A significantly positive correlation between FLI and TrFM/ ASM ratio (r = 0.221, p<0.001) was found, whereas FLI levels were negatively correlated with ISI- Matsuda (r = -0.335, p<0.001), GH (r = -0.200, p = 0.006), and IGF- 1 levels (r = -0.157, p = 0.028). Stepwise linear regression analysis showed that GH levels were significantly negatively correlated with FLI, while the TrFM/ ASM ratio was positively associated with FLI, after adjustment for age, BMI, total fat mass, truncal fat mass, fat- free mass, and ISI- Matsuda. CONCLUSIONS: Impairment of GH/IGF-1 axis seems to be associated to the risk of the development of sarcopenic obesity and ectopic fat deposition in the liver. Metabolic and hormonal derangements as determinants of ectopic fat deposition and body composition deserve to be evaluated in obese subjects. PMID- 26741959 TI - Recovery Trends of Commercial Fish: The Case of an Underperforming Mediterranean Marine Protected Area. AB - Temporal trends in the recovery of exploited species in marine protected areas (MPAs) are useful for a proper assessment of the efficacy of protection measures. The effects of protection on the fish assemblages of the sublittoral rocky reefs in the "Penisola del Sinis-Isola di Mal di Ventre" MPA (W. Sardinia, Italy) were evaluated using a multi-year series of data. Four surveys, conducted 7, 10, 13 and 15 years after the area was designated as an MPA and carried out in the period spanning June and July, were used to estimate the abundance and biomass of commercial species. The surveys were carried out in zones with decreasing levels of fishing restrictions within the MPA (zones A, B, C) and in unprotected zones (OUT1 and OUT2), and underwater video visual census techniques were used. Protected zones only occasionally showed higher levels of abundance or biomass, and the trajectories of those metrics were not consistent across the years. In addition, the zone with the highest level of protection (zone A) never presented levels of abundance and biomass higher than those in zones B and C. This study shows that even 15 years after designation, protection has had no appreciable effect in the MPA studied. It is argued that this is emblematic of several shortcomings in the planning, regulation and enforcement frameworks of the MPA. PMID- 26741960 TI - Orexin gene transfer into the amygdala suppresses both spontaneous and emotion induced cataplexy in orexin-knockout mice. AB - Narcolepsy is a chronic sleep disorder linked to the loss of orexin-producing neurons in the hypothalamus. Cataplexy, a sudden loss of muscle tone during waking, is an important distinguishing symptom of narcolepsy and it is often triggered by strong emotions. The neural circuit underlying cataplexy attacks is not known, but is likely to involve the amygdala, a region implicated in regulating emotions. In mice models of narcolepsy, transfer of the orexin gene into surrogate neurons has been successful in ameliorating narcoleptic symptoms. However, it is not known whether this method also blocks cataplexy triggered by strong emotions. To examine this possibility, the gene encoding mouse prepro orexin was transferred into amygdala neurons of orexin-knockout (KO) mice (rAAV orexin; n = 8). Orexin-KO mice that did not receive gene transfer (no-rAAV; n = 7) or received only the reporter gene (rAAV-GFP; n = 7) served as controls. Three weeks later, the animal's sleep and behaviour were recorded at night (no-odour control night), followed by another recording at night in the presence of predator odour (odour night). Orexin-KO mice given the orexin gene transfer into surrogate amygdala neurons had significantly less spontaneous bouts of cataplexy, and predator odour did not induce cataplexy compared with control mice. Moreover, the mice with orexin gene transfer were awake more during the odour night. These results demonstrate that orexin gene transfer into amygdala neurons can suppress both spontaneous and emotion-induced cataplexy attacks in narcoleptic mice. It suggests that manipulating amygdala pathways is a potential strategy for treating cataplexy in narcolepsy. PMID- 26741961 TI - Differentiating Radiation-Induced Necrosis from Recurrent Brain Tumor Using MR Perfusion and Spectroscopy: A Meta-Analysis. AB - PURPOSE: This meta-analysis examined roles of several metabolites in differentiating recurrent tumor from necrosis in patients with brain tumors using MR perfusion and spectroscopy. METHODS: Medline, Cochrane, EMBASE, and Google Scholar were searched for studies using perfusion MRI and/or MR spectroscopy published up to March 4, 2015 which differentiated between recurrent tumor vs. necrosis in patients with primary brain tumors or brain metastasis. Only two armed, prospective or retrospective studies were included. A meta-analysis was performed on the difference in relative cerebral blood volume (rCBV), ratios of choline/creatine (Cho/Cr) and/or choline/N-acetyl aspartate (Cho/NAA) between participants undergoing MRI evaluation. A chi2-based test of homogeneity was performed using Cochran's Q statistic and I2. RESULTS: Of 397 patients in 13 studies who were analyzed, the majority had tumor recurrence. As there was evidence of heterogeneity among 10 of the studies which used rCBV for evaluation (Q statistic = 31.634, I2 = 97.11%, P < 0.0001) a random-effects analysis was applied. The pooled difference in means (2.18, 95%CI = 0.85 to 3.50) indicated that the average rCBV in a contrast-enhancing lesion was significantly higher in tumor recurrence compared with radiation injury (P = 0.001). Based on a fixed effect model of analysis encompassing the six studies which used Cho/Cr ratios for evaluation (Q statistic = 8.388, I2 = 40.39%, P = 0.137), the pooled difference in means (0.77, 95%CI = 0.57 to 0.98) of the average Cho/Cr ratio was significantly higher in tumor recurrence than in tumor necrosis (P = 0.001). There was significant difference in ratios of Cho to NAA between recurrent tumor and necrosis (1.02, 95%CI = 0.03 to 2.00, P = 0.044). CONCLUSIONS: MR spectroscopy and MR perfusion using Cho/NAA and Cho/Cr ratios and rCBV may increase the accuracy of differentiating necrosis from recurrent tumor in patients with primary brain tumors or metastases. PMID- 26741962 TI - Antimicrobial Activities of Methanol, Ethanol and Supercritical CO2 Extracts of Philippine Piper betle L. on Clinical Isolates of Gram Positive and Gram Negative Bacteria with Transferable Multiple Drug Resistance. AB - Piper betle L. has traditionally been used in alternative medicine in different countries for various therapeutic purposes, including as an anti-infective agent. However, studies reported in the literature are mainly on its activities on drug susceptible bacterial strains. This study determined the antimicrobial activities of its ethanol, methanol, and supercritical CO2 extracts on clinical isolates of multiple drug resistant bacteria which have been identified by the Infectious Disease Society of America as among the currently more challenging strains in clinical management. Assay methods included the standard disc diffusion method and the broth microdilution method for the determination of the minimum inhibitory concentration (MIC) and the minimum bactericidal concentrations (MBC) of the extracts for the test microorganisms. This study revealed the bactericidal activities of all the P. betle leaf crude extracts on methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), extended spectrum beta-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and metallo-beta-lactamase-producing Pseudomonas aeruginosa and Acinetobacter baumannii, with minimum bactericidal concentrations that ranged from 19MUg/ml to 1250 MUg/ml. The extracts proved to be more potent against the Gram positive MRSA and VRE than for the Gram negative test bacteria. VRE isolates were more susceptible to all the extracts than the MRSA isolates. Generally, the ethanol extracts proved to be more potent than the methanol extracts and supercritical CO2 extracts as shown by their lower MICs for both the Gram positive and Gram negative MDRs. MTT cytotoxicity assay showed that the highest concentration (100 MUg/ml) of P. betle ethanol extract tested was not toxic to normal human dermal fibroblasts (HDFn). Data from the study firmly established P. betle as an alternative source of anti-infectives against multiple drug resistant bacteria. PMID- 26741964 TI - Component Analysis versus Common Factor Analysis: Some issues in Selecting an Appropriate Procedure. AB - Should one do a component analysis or a factor analysis? The choice is not obvious, because the two broad classes of procedures serve a similar purpose, and share many important mathematical characteristics. Despite many textbooks describing common factor analysis as the preferred procedure, principal component analysis has been the most widely applied. Here we summarize relevant information for the prospective factor/component analyst. First, we discuss the key algebraic similarities and differences. Next, we analyze a number of theoretical and practical issues. The more practical aspects include: the degree of numeric similarity between solutions from the two methods, some common rules for the number of factors to be retained, effects resulting from overextraction, problems with improper solutions, and comparisons in computational efficiency. Finally, we review some broader theoretical issues: the factor indeterminacy issue, the differences between exploratory and confirmatory procedures, and the issue of latent versus manifest variables. PMID- 26741963 TI - A Cell Internalizing Antibody Targeting Capsid Protein (p24) Inhibits the Replication of HIV-1 in T Cells Lines and PBMCs: A Proof of Concept Study. AB - There remains a need for newer therapeutic approaches to combat HIV/AIDS. Viral capsid protein p24 plays important roles in HIV pathogenesis. Peptides and small molecule inhibitors targeting p24 have shown to inhibit virus replication in treated cell. High specificity and biological stability of monoclonal antibodies (mAbs) make them an attractive contender for in vivo treatments. However, mAbs do not enter into cells, thus are restricted to target surface molecules. This also makes targeting intracellular HIV-1 p24 a challenge. A mAb specific to p24 that can internalize into the HIV-infected cells is hypothesized to inhibit the virus replication. We selected a mAb that has previously shown to inhibit p24 polymerization in an in vitro assay and chemically conjugated it with cell penetrating peptides (CPP) to generate cell internalizing anti-p24 mAbs. Out of 8 CPPs tested, kappaFGF-MTS -conjugated mAbs internalized T cells most efficiently. At nontoxic concentration, the kappaFGF-MTS-anti-p24-mAbs reduced the HIV-1 replication up to 73 and 49% in T-lymphocyte and PBMCs respectively. Marked inhibition of HIV-1 replication in relevant cells by kappaFGF-MTS-anti-p24-mAbs represents a viable strategy to target HIV proteins present inside the cells. PMID- 26741965 TI - Component Analysis versus Common Factor Analysis: A Case of Disputed Authorship. PMID- 26741966 TI - Common Factor Analysis versus Component Analysis: Some Well and Little Known Facts. PMID- 26741968 TI - Facts, Fictions, and Common Sense About Factors and Components. PMID- 26741967 TI - Some Additional Thoughts on Components, Factors, and Factor Indeterminancy. PMID- 26741969 TI - Blurring the Distinctions Between Component Analysis and Common Factor Analysis. PMID- 26741970 TI - Whatever Happened to Broad Perspective? PMID- 26741972 TI - Least Squares and Latent Variables. PMID- 26741971 TI - On the Equivalence of Factors and Components. PMID- 26741973 TI - Principles versus Principals of Structural Factor Analyses. PMID- 26741975 TI - Component Analysis versus Common Factor Analysis: Some Further Observations. PMID- 26741974 TI - Bias in Pattern Loadings Represented by Common Factor Analysis and Component Analysis. PMID- 26741976 TI - Model Modification in Covariance Structure Modeling: A Comparison among Likelihood Ratio, Lagrange Multiplier, and Wald Tests. AB - Model comparisons in covariance structure modeling have traditionally been carried out by the likelihood ratio difference (D) test. Two more convenient approaches are reviewed and evaluated. The Lagrange Multiplier (LM) test evaluates the impact of model modification from a more limited model whereas the Wald (W) test makes the evaluation from a more general model. The empirical performance of the D, LM, and W tests under null and alternative hypotheses are compared in this study. The results indicate that both new tests performed as well as the D test for reasonable sample sizes. The nonmonotonicity of power function for the W test was discovered; however, it is not severe in this study. The LM test behaved as a central or noncentral X[SUP2] variate under null or alternative hypotheses, as expected. However, when a correct null hypothesis was embedded in a composite hypothesis which was false, an incremental LM test tended to suggest more parameters than needed to be freed, especially at larger sample sizes. This incorrect behavior of the LM test was correctable by following up the LM test by a W test, that is, a combination of both LM and W tests seemed to provide a fairly satisfactory outcome in the process of model modification. PMID- 26741977 TI - Cytauxzoon Infections in Wild Felids from Carpathian-Danubian-Pontic Space: Further Evidence for a Different Cytauxzoon Species in European Felids. AB - Parasitic protists of the genus Cytauxzoon are detected in a wide range of wild and domestic felids. Bobcats are a confirmed reservoir of Cytauxzoon felis in North America while domestic cats are susceptible hosts suffering from severe or fatal illness. Cytauxzoon infections are mainly reported from American felids and, recently, several sub-clinical and clinical findings were reported from European, Asian, and African felids. In 2014, the collection of organs of 4 Eurasian lynx and 12 wild cats from 11 Romanian localities was carried out to determine the prevalence and genetic diversity of Cytauxzoon spp. We detected an overall high prevalence of 62.5% in both species of wild felids; 50% in wild cats and 100% in Eurasian lynx. The phylogenetic analysis indicates 2 distinct clades of Cytauxzoon in felids, with all of our sequences clustering with sequences of Cytauxzoon sp./Cytauxzoon manul from Palaearctic felids. Further studies, development of new genetic markers, and experimental transmission studies are required for clarifying the taxonomy and life cycle of feline Cytauxzoon in the Old World. PMID- 26741978 TI - Morphometric Analysis of the Hard Parts of Pseudodactylogyrus anguillae and Pseudodactylogyrus bini (Monogenea: Dactylogyridae) on the Gill Apparatus of the European Eels ( Anguilla anguilla ) from the Freshwaters of Latvia. AB - We investigated the spatial distribution and measured the hard parts of the attachment apparatuses and reproductive organs of the 2 eel-specific monogenean species Pseudodactylogyrus anguillae and Pseudodactylogyrus bini. Comparative analysis focused on parasite microhabitats within the gill apparatus. Additionally, we compared the morphometric characteristics of the monogeneans based on geographical locality and seasonality. The attachment apparatus and reproductive organ characteristics of the monogeneans were similar in all gill apparatus microhabitats. However, measurements differed significantly between localities and between seasons, with the results suggesting that abiotic factors play a larger role in determining parasite morphology than do the gill microhabitats. PMID- 26741979 TI - Phages Fight Back: Inactivation of the CRISPR-Cas Bacterial Immune System by Anti CRISPR Proteins. PMID- 26741980 TI - CXCR7 Is Involved in Human Oligodendroglial Precursor Cell Maturation. AB - Differentiation of oligodendroglial precursor cells (OPCs), a crucial prerequisite for central nervous system (CNS) remyelination in diseases such as Multiple Sclerosis (MS), is modulated by a multitude of extrinsic and intrinsic factors. In a previous study we revealed that the chemokine CXCL12 stimulates rodent OPC differentiation via activation of its receptor CXCR7. We could now demonstrate that CXCR7 is also expressed on NogoA- and Nkx2.2-positive oligodendroglial cells in human MS brains and that stimulation of cultured primary fetal human OPCs with CXCL12 promotes their differentiation as measured by surface marker expression and morphologic complexity. Pharmacological inhibition of CXCR7 effectively blocks these CXCL12-dependent effects. Our findings therefore suggest that a specific activation of CXCR7 could provide a means to promote oligodendroglial differentiation facilitating endogenous remyelination activities. PMID- 26741982 TI - Editorial: obesity in chronic liver diseases - increased infections. PMID- 26741983 TI - Editorial: obesity in chronic liver diseases - increased infections; authors' reply. PMID- 26741981 TI - GSK-3 Beta Does Not Stabilize Cryptochrome in the Circadian Clock of Drosophila. AB - Cryptochrome (CRY) is the primary photoreceptor of Drosophila's circadian clock. It resets the circadian clock by promoting light-induced degradation of the clock protein Timeless (TIM) in the proteasome. Under constant light, the clock stops because TIM is absent, and the flies become arrhythmic. In addition to TIM degradation, light also induces CRY degradation. This depends on the interaction of CRY with several proteins such as the E3 ubiquitin ligases Jetlag (JET) and Ramshackle (BRWD3). However, CRY can seemingly also be stabilized by interaction with the kinase Shaggy (SGG), the GSK-3 beta fly orthologue. Consequently, flies with SGG overexpression in certain dorsal clock neurons are reported to remain rhythmic under constant light. We were interested in the interaction between CRY, Ramshackle and SGG and started to perform protein interaction studies in S2 cells. To our surprise, we were not able to replicate the results, that SGG overexpression does stabilize CRY, neither in S2 cells nor in the relevant clock neurons. SGG rather does the contrary. Furthermore, flies with SGG overexpression in the dorsal clock neurons became arrhythmic as did wild-type flies. Nevertheless, we could reproduce the published interaction of SGG with TIM, since flies with SGG overexpression in the lateral clock neurons shortened their free running period. We conclude that SGG does not directly interact with CRY but rather with TIM. Furthermore we could demonstrate, that an unspecific antibody explains the observed stabilization effects on CRY. PMID- 26741984 TI - Letter: early use of immunomodulators and surgery in Crohn's disease. PMID- 26741985 TI - Erratum. Editorial: preventing disease progression in Crohn's - can we shut the stable door before the horse bolts? PMID- 26741986 TI - Corrigendum. The binding selectivity of vonoprazan (TAK-438) to the gastric H+,K+ ATPase. PMID- 26741987 TI - Three-Dimensional Cultures of Human Subcutaneous Adipose Tissue-Derived Progenitor Cells Based on RAD16-I Self-Assembling Peptide. AB - The prolonged ischemia after myocardial infarction leads to a high degree of cardiomyocyte death, which leads to a reduction of normal heart function. Valuable lessons can be learnt from human myocardium and stem cell biology that would help scientists to develop new, effective, safe, and affordable regenerative therapies. In vivo models are of high interest, but their high complexity limits the possibility to analyze specific factors. In vitro models permit analyzing specific factors of tissue physiology or pathophysiology providing accurate approaches that may guide the creation of three-dimensional (3D) engineered cell aggregates. These systems provide a simplistic way to examine individual factors as compared to animal models, and better mimic the reality than 2D models. In this sense, the objective of this work is to better understand the behavior of a human mesenchymal stem cell-like cell line (subcutaneous adipose tissue-derived progenitor cells [subATDPCs], susceptible to be used in cell therapies) when they are embedded in the 3D environment provided by RAD16-I self-assembling peptide (SAP). Specifically, we study the effect in subATDPCs viability, morphology, proliferation, and protein and gene expression of matrix composition (i.e., RGD motif and heparin polysaccharide modifications) in RAD16-I matrix under different media conditions. Results demonstrated that the 3D environment provided by RAD16-I SAP is able to maintain subATDPCs in this new milieu and at the same time its cardiac commitment. Additionally, it has been observed that chemical induction can induce upregulation of cardiac markers, such as TBX5, MEF2C, ACTN1, and GJA1. Therefore, we propose this 3D model as a promising platform to analyze the effect of specific cues that can help improve cell performance for future cell therapy. PMID- 26741989 TI - Biotransformation and metabolic profile of catalpol with human intestinal microflora by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. AB - Traditional Chinese medicine (TCM) has been used in clinical practice for thousands of years. Catalpol, an iridoid glucoside, abundantly found in the root of the common used herb medicine Rehmannia glutinosa Libosch, has been reported to show various biological effects and pharmacological activities. After oral administration, the active ingredient might have interactions with the intestinal bacteria, which could help unravel how the medicine was processed in vivo. In this work, different pure bacteria from healthy human feces were isolated and used to bioconvert catalpol. Ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) technique combined with Metabolynx(TM) software was applied to analyze catalpol metabolites. Compared with blank samples, parent compound (M0) and four metabolites (M1-M4) were detected and tentatively identified based on the characteristics of their protonated ions. The metabolites were likely to be: catalpol aglycone (M1), acetylated catalpol (M2), dimethylated and hydroxylated catalpol aglycone (M3), nitrogen-containing catalpol aglycone (M4). M1 and M4 were generated in the majority of the samples like Bacteroides sp. 45. M3 was obtained in several bacterial samples like Enterococcus sp. 8-2 and M2 was detected only in the sample of Enterococcus sp. 43-1. To our knowledge, the metabolic routes and metabolites of catalpol produced by human intestinal bacteria were all firstly reported. PMID- 26741990 TI - Ultra-performance liquid chromatography tandem mass spectrometry for simultaneous determination of natural steroid hormones in sea lamprey (Petromyzon marinus) plasma and tissues. AB - This study aims to provide a rapid, sensitive and precise UPLC-MS/MS method for target steroid quantitation in biological matrices. We developed and validated an UPLC-MS/MS method to simultaneously determine 16 steroids in plasma and tissue samples. Ionization sources of Electrospray Ionization (ESI) and Atmospheric Pressure Chemical Ionization (APCI) were compared in this study by testing their spectrometry performances at the same chromatographic conditions, and the ESI source was found up to five times more sensitive than the APCI. Different sample preparation techniques were investigated for an optimal extraction of steroids from the biological matrices. The developed method exhibited excellent linearity for all analytes with regression coefficients higher than 0.99 in broad concentration ranges. The limit of detection (LOD) was from 0.003 to 0.1ng/mL. The method was validated according to FDA guidance and applied to determine steroids in sea lamprey plasma and tissues (fat and testes) by the developed method. PMID- 26741992 TI - Association of Urinary Cadmium with Mortality in Patients at a Coronary Care Unit. AB - BACKGROUND: Determine the effect of the day 1 urinary excretion of cadmium (D1-UE Cd) on mortality of patients admitted to a coronary care unit (CCU). METHODS: A total of 323 patients were enrolled in this 6-month study. Urine and blood samples were taken within 24 h after CCU admission. Demographic data, clinical diagnoses, and hospital mortality were recorded. The scores of established systems for prediction of mortality in critically ill patients were calculated. RESULTS: Compared with survivors (n = 289), non-survivors (n = 34) had higher levels of D1-UE-Cd. Stepwise multiple linear regression analysis indicated that D1-UE-Cd was positively associated with pulse rate and level of aspartate aminotransferase, but negatively associated with serum albumin level. Multivariate Cox analysis, with adjustment for other significant variables and measurements from mortality scoring systems, indicated that respiratory rate and D1-UE-Cd were independent and significant predictors of mortality. For each 1 MUg/day increase of D1-UE-Cd, the hazard ratio for CCU mortality was 3.160 (95% confidence interval: 1.944-5.136, p < 0.001). The chi-square value of Hosmer Lemeshow goodness-of-fit test for D1-UE-Cd was 10.869 (p = 0.213). The area under the receiver operating characteristic curve for D1-UE-Cd was 0.87 (95% confidence interval: 0.81-0.93). CONCLUSIONS: The D1-UE-Cd, an objective variable with no inter-observer variability, accurately predicted hospital mortality of CCU patients and outperformed other established scoring systems. Further studies are needed to determine the physiological mechanism of the effect of cadmium on mortality in CCU patients. PMID- 26741994 TI - The Role of RhoA, RhoB and RhoC GTPases in Cell Morphology, Proliferation and Migration in Human Cytomegalovirus (HCMV) Infected Glioblastoma Cells. AB - BACKGROUND/AIMS: Rho GTPases are crucial regulators of the actin cytoskeleton, membrane trafficking and cell signaling and their importance in cell migration and invasion is well- established. The human cytomegalovirus (HCMV) is a widespread pathogen responsible for generally asymptomatic and persistent infections in healthy people. Recent evidence indicates that HCMV gene products are expressed in over 90% of malignant type glioblastomas (GBM). In addition, the HCMV Immediate Early-1 protein (IE1) is expressed in >90% of tumors analyzed. METHODS: RhoA, RhoB and RhoC were individually depleted in U373MG glioblastoma cells as well as U373MG cells stably expressing the HCMV IE1 protein (named U373MG-IE1 cells) shRNA lentivirus vectors. Cell proliferation assays, migration as well as wound-healing assays were performed in uninfected and HCMV-infected cells. RESULTS: The depletion of RhoA, RhoB and RhoC protein resulted in significant alterations in the morphology of the uninfected cells, which were further enhanced by the cytopathic effect caused by HCMV. Furthermore, in the absence or presence of HCMV, the knockdown of RhoB and RhoC proteins decreased the proliferation rate of the parental and the IE1-expressing glioblastoma cells, whereas the knockdown of RhoA protein in the HCMV infected cell lines restored their proliferation rate. In addition, wound healing assays in U373MG cells revealed that depletion of RhoA, RhoB and RhoC differentially reduced their migration rate, even in the presence or the absence of HCMV. CONCLUSION: Collectively, these data show for the first time a differential implication of Rho GTPases in morphology, proliferation rate and motility of human glioblastoma cells during HCMV infection, further supporting an oncomodulatory role of HCMV depending on the Rho isoforms' state. PMID- 26741995 TI - Blood Pressure Measurement Biases in Clinical Settings, Alabama, 2010-2011. AB - INTRODUCTION: Blood pressure measurement in clinical care settings seldom follows the protocol recommended by national guidelines, potentially leading to overestimates or underestimates of blood pressure control. We evaluated blood pressure measurement methods as a source of bias in determining blood pressure control among community-dwelling adults with diabetes. METHODS: In a community based trial of patients with diabetes, we measured both "clinical blood pressure" (clinical BP) (taken by a community nurse or medical assistant instructed to "take the participant's blood pressure like you do in your own clinic") and "research blood pressure" (research BP) (research staff followed a guideline concordant protocol). Each participant had both types of blood pressure assessment on the same day over the course of 2 hours. RESULTS: The 227 participants had a mean age of 59 years; 86% were black and 74% were women. The mean clinical BP was 5 mm Hg higher than the mean research BP for systolic blood pressure (P < .001) and 2 mm Hg higher for diastolic blood pressure (P < .001). The proportion of participants whose clinical BP was 130/80 mm Hg or higher was 8 percentage points higher than the proportion whose research BP was 130/80 mm Hg or higher (P < .001), and the proportion whose clinical BP was 140/90 mm Hg or higher was 10 percentage points higher than the proportion whose research BP was 140/90 mm Hg or higher (P < .001). Among those aged 65 years or older, the proportion whose clinical BP was 130/80 mm Hg or higher was 10 percentage points higher than proportion whose research BP was 130/80 mm Hg or higher, and the proportion whose clinical BP was 140/90 mm Hg or higher was 14 percentage points higher than the proportion whose research BP was 140/90 mm Hg or higher. Whites and smokers had the greatest risk for having a clinical BP 5 mm Hg or more higher than their research BP. CONCLUSION: Measurement biases in clinical settings may be a component of observed poor blood pressure control rates in real-world settings. PMID- 26741993 TI - Acute Free-Iron Exposure Does Not Explain the Impaired Haemorheology Associated with Haemochromatosis. AB - INTRODUCTION: Given the severity of the current imbalance between blood donor supply and recipient demand, discarded blood drawn from the routine venesections of haemochromatosis (HFE-HH) patients may serve as a valuable alternative source for blood banks and transfusion. We investigated whether functional or biochemical differences existed between HFE-HH and control blood samples, with particular focus upon the haemorheological properties, to investigate the viability of venesected blood being subsequently harvested for blood products. METHODS: Blood samples were collected from HFE-HH patients undergoing venesection treatment (n = 19) and healthy volunteers (n = 8). Moreover, a second experiment investigated the effects of a dose-response of iron (0, 40, 80, 320 mM FeCl3) on haemorheology in healthy blood samples (n = 7). Dependent variables included basic haematology, iron status, haematocrit, red blood cell (RBC) aggregation (native and standardised haematocrit) and "aggregability" (RBC tendency to aggregate in a standard aggregating medium; 0.4 L/L haematocrit in a Dx70), and RBC deformability. RESULTS: Indices of RBC deformability were significantly decreased for HFE-HH when compared with healthy controls: RBC deformability was significantly decreased at 1-7 Pa (p < 0.05), and the shear stress required for half maximal deformability was significantly increased (p < 0.05) for HFE-HH. RBC aggregation in plasma was significantly increased (p < 0.001) for HFE-HH, although when RBC were suspended in plasma-free Dx70 no differences were detected. No differences in RBC deformability or RBC aggregation/aggregability were detected when healthy RBC were incubated with varying dose of FeCl3. CONCLUSION: HFE-HH impairs the haemorheological properties of blood; however, RBC aggregability was similar between HFE-HH and controls when cells were suspended in a plasma-free medium, indicating that plasma factor(s) may explain the altered haemorheology in HFE-HH patients. Acute exposure to elevated iron levels does not appear (in isolation) to account for these differences. Further consideration is required prior to utilising routine venesection blood for harvesting RBC concentrates due to the potential risk of microvascular disorders arising from impaired haemorheology. PMID- 26741996 TI - Association of Chronic Obstructive Pulmonary Disease With Increased Confusion or Memory Loss and Functional Limitations Among Adults in 21 States, 2011 Behavioral Risk Factor Surveillance System. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is associated with cognitive impairment, but consequences of this association on a person's functional limitations are unclear. We examined the association between COPD and increased confusion and memory loss (ICML) and functional limitations among adults with COPD. METHODS: We studied adults aged 45 years or older in 21 states who participated in the 2011 Behavioral Risk Factor Surveillance System (n = 102,739). Presence of COPD was based on self-reported physician diagnosis. ICML was based on self-report that confusion or memory loss occurred more often or worsened during the prior year. ICML-associated difficulties were defined as giving up household chores and former activities, decreased ability to work or engage in social activities, or needing help from family or friends during the prior year due to ICML. General limitations were defined as needing special equipment as a result of a health condition, having had activity limitations for 2 weeks or more in the prior month, or being unable to work. Multivariable models were adjusted for demographics, health behaviors or conditions, and frequent mental distress. RESULTS: COPD was reported by 9.3% of adults. ICML was greater among those with COPD than among those without COPD (25.8% vs 11%; adjusted prevalence ratio [aPR], 1.48; 95% confidence interval [CI], 1.32%-1.66%). People with COPD, either with or without ICML, were more likely than those without COPD to report general functional limitations. Among people reporting ICML, those with COPD were more likely to report interference with work or social activities than those without COPD (aPR, 1.17; 95% CI, 1.01%-1.36%). CONCLUSION: Functional limitations were greater among those with COPD than among those without, and ICML may further affect these limitations. Results from our study can inform future studies of self- management and functional limitations for people with COPD. PMID- 26741998 TI - Designing an Agent-Based Model for Childhood Obesity Interventions: A Case Study of ChildObesity180. AB - Complex systems modeling can provide useful insights when designing and anticipating the impact of public health interventions. We developed an agent based, or individual-based, computation model (ABM) to aid in evaluating and refining implementation of behavior change interventions designed to increase physical activity and healthy eating and reduce unnecessary weight gain among school-aged children. The potential benefits of applying an ABM approach include estimating outcomes despite data gaps, anticipating impact among different populations or scenarios, and exploring how to expand or modify an intervention. The practical challenges inherent in implementing such an approach include data resources, data availability, and the skills and knowledge of ABM among the public health obesity intervention community. The aim of this article was to provide a step-by-step guide on how to develop an ABM to evaluate multifaceted interventions on childhood obesity prevention in multiple settings. We used data from 2 obesity prevention initiatives and public-use resources. The details and goals of the interventions, overview of the model design process, and generalizability of this approach for future interventions is discussed. PMID- 26741997 TI - Physical Activity-Related Policy and Environmental Strategies to Prevent Obesity in Rural Communities: A Systematic Review of the Literature, 2002-2013. AB - INTRODUCTION: Health disparities exist between rural and urban residents; in particular, rural residents have higher rates of chronic diseases and obesity. Evidence supports the effectiveness of policy and environmental strategies to prevent obesity and promote health equity. In 2009, the Centers for Disease Control and Prevention recommended 24 policy and environmental strategies for use by local communities: the Common Community Measures for Obesity Prevention (COCOMO); 12 strategies focus on physical activity. This review was conducted to synthesize evidence on the implementation, relevance, and effectiveness of physical activity-related policy and environmental strategies for obesity prevention in rural communities. METHODS: A literature search was conducted in PubMed, PsycINFO, Web of Science, CINHAL, and PAIS databases for articles published from 2002 through May 2013 that reported findings from physical activity-related policy or environmental interventions conducted in the United States or Canada. Each article was extracted independently by 2 researchers. RESULTS: Of 2,002 articles, 30 articles representing 26 distinct studies met inclusion criteria. Schools were the most common setting (n = 18 studies). COCOMO strategies were applied in rural communities in 22 studies; the 2 most common COCOMO strategies were "enhance infrastructure supporting walking" (n = 11) and "increase opportunities for extracurricular physical activity" (n = 9). Most studies (n = 21) applied at least one of 8 non-COCOMO strategies; the most common was increasing physical activity opportunities at school outside of physical education (n = 8). Only 14 studies measured or reported physical activity outcomes (10 studies solely used self-report); 10 reported positive changes. CONCLUSION: Seven of the 12 COCOMO physical activity-related strategies were successfully implemented in 2 or more studies, suggesting that these 7 strategies are relevant in rural communities and the other 5 might be less applicable in rural communities. Further research using robust study designs and measurement is needed to better ascertain implementation success and effectiveness of COCOMO and non-COCOMO strategies in rural communities. PMID- 26741999 TI - Kinematic analysis of a Duchenne smile. AB - OBJECTIVE: Facial expressions are communicative motor outputs, whose kinematics likely are due to musculoskeletal anatomy, neuromotor activity and the well-being and internal states of the individual. However, little has been published on the kinematics of facial expression. This study quantified lip, eye and cheek movements during the production of a Duchenne smile involving movement of lips and tissues surrounding the eyes. DESIGN: The three-dimensional positions of 20 markers placed around the eyes, cheeks, lips and chins of 24 young adult female subjects were digitized while they performed smiles after practicing to feedback from an investigator trained in the facial action coding system (FACS). Displacement, velocity and acceleration variables were extracted and analyzed from the markers. RESULTS: Results demonstrated several consistencies across subjects including: (1) relatively high peak velocities, accelerations and displacements for lip and cheek markers in the vertical and anteroposterior dimensions, (2) relatively large movements of the lower lateral eye region compared with other eye regions. CONCLUSION: The results indicate that there is significant movement in the anteroposterior dimension that is not observable in frontal views of the face alone. PMID- 26742000 TI - Association of the XPD and XRCC3 gene polymorphisms with oral squamous cell carcinoma in a Northeastern Brazilian population: A pilot study. AB - OBJECTIVE: to evaluate the association between XPD and XRCC3 polymorphisms and oral squamous cell carcinoma (OSCC). DESIGN: the sample consisted of 54 cases of OSCC and 40 cases of inflammatory fibrous hyperplasia (IFH). Genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: XPD-Lys/Gln was more common in IFH (n=28; 70%) than in OSCC (n=24; 44.4%) (OR: 0.3; p<0.05). XPD-Gln was more frequent in high-grade lesions (0.48) than in low-grade lesions (0.21) (OR: 3.4; p<0.05). The Gln/Gln genotype was associated with III and IV clinical stages (OR: 0.07; p<0.05). XRCC3-Met was more frequent in OSCC (0.49) than in IFH (0.35) (OR: 2.6; p<0.05). The Met/Met genotype was associated with the presence of metastases (OR: 8.1; p<0.05) and with III and IV clinical stages (OR: 0.07; p<0.05). CONCLUSIONS: in this sample, the frequency of XPD-Gln in IFH suggests that this variant may protect against OSCC. The presence of the XRCC3-Met allele seems to contribute to the development of OSCC, metastases and more advanced stages in these lesions. PMID- 26742002 TI - Regime-Switching Bivariate Dual Change Score Model. AB - Mixture structural equation model with regime switching (MSEM-RS) provides one possible way of representing over-time heterogeneities in dynamic processes by allowing a system to manifest qualitatively or quantitatively distinct change processes conditional on the latent "regime" the system is in at a particular time point. Unlike standard mixture structural equation models such as growth mixture models, MSEM-RS allows individuals to transition between latent classes over time. This class of models, often referred to as regime-switching models in the time series and econometric applications, can be specified as regime switching mixture structural equation models when the number of repeated measures involved is not large. We illustrate the empirical utility of such models using one special case-a regime-switching bivariate dual change score model in which two growth processes are allowed to manifest regime-dependent coupling relations with one another. The proposed model is illustrated using a set of longitudinal reading and arithmetic performance data from the Early Childhood Longitudinal Study, Kindergarten Class of 1998-99 study (ECLS-K; U.S. Department of Education, National Center for Education Statistics, 2010). PMID- 26742001 TI - The Effects of Live Attenuated Influenza Vaccine on Nasopharyngeal Bacteria in Healthy 2 to 4 Year Olds. A Randomized Controlled Trial. AB - RATIONALE: Viral infections of the upper respiratory tract may influence the commensal nasopharyngeal bacteria. Changes in the bacterial niche could affect transmission dynamics. Attenuated vaccine viruses can be used to investigate this empirically in humans. OBJECTIVES: To study the effects of mild viral upper respiratory infections on nasopharyngeal bacterial colonization using live attenuated influenza vaccine (LAIV) as a surrogate. METHODS: We used trivalent LAIV to evaluate the effects of viral infection on bacterial carriage and density of Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenzae, and Staphylococcus aureus. A total of 151 healthy children were randomized 1:1 to receive the vaccine starting either at recruitment (n = 74) or 28 days later (n = 77) in a stepped wedge fashion, allowing comparisons between recipients and nonrecipients as well as whole-group comparisons pre- and postvaccination. Bacterial carriage and density were determined using quantitative polymerase chain reaction assays. MEASUREMENTS AND MAIN RESULTS: A total of 151 children were recruited, 77 in the LAIV group and 74 in the control group. LAIV recipients (n = 63 analyzed) showed an apparent transient increase in H. influenzae carriage but no further significant differences in carriage prevalence of the four bacterial species compared with controls (n = 72 analyzed). S. pneumoniae density was substantially higher in vaccine recipients (16,687 vs. 1935 gene copies per milliliter) 28 days after the first dose (P < 0.001). Whole-group multivariable analysis (prevaccine, after one dose, and after two doses) also showed increases in density of other species and H. influenzae carriage prevalence. CONCLUSIONS: In the absence of any safety signals despite widespread use of the vaccine, these findings suggest that bacterial density, and thus transmission rates among children and to people in other age groups, may rise following attenuated influenza infections without associated clinical disease. LAIV could therefore be used as an experimental tool to elucidate the dynamics of transmission of nasopharyngeal bacteria. PMID- 26742003 TI - Response Time Modeling Based on the Proportional Hazards Model. AB - Response time data are regularly analyzed in psychology. When several response times are assessed per participant, it is common practice to use latent trait models in order to account for the dependency of the response times from the same participant. One such model is the proportional hazards model with random effects. Despite its popularity in survival analysis, this model is rarely used in psychology because of the difficulty of model estimation when latent variables are present. In this article, a new estimation method is proposed. This method is based on the rank correlation matrix containing Kendall's Tau coefficients and unweighted least squares estimation ( Kendall, 1938 ). Compared with marginal maximum likelihood estimation, the new estimation approach is simple, not computationally intensive, and almost as efficient. Additionally, the approach allows the implementation of a test for model fit. Feasibility of the estimation method and validity of the fit test is demonstrated with a simulation study. An application of the model to a real data set is provided. PMID- 26742004 TI - Functionally Unidimensional Item Response Models for Multivariate Binary Data. AB - The problem of fitting unidimensional item response models to potentially multidimensional data has been extensively studied. The focus of this article is on response data that have a strong dimension but also contain minor nuisance dimensions. Fitting a unidimensional model to such multidimensional data is believed to result in ability estimates that represent a combination of the major and minor dimensions. We conjecture that the underlying dimension for the fitted unidimensional model, which we call the functional dimension, represents a nonlinear projection. In this article we investigate 2 issues: (a) can a proposed nonlinear projection track the functional dimension well, and (b) what are the biases in the ability estimate and the associated standard error when estimating the functional dimension? To investigate the second issue, the nonlinear projection is used as an evaluative tool. An example regarding a construct of desire for physical competency is used to illustrate the functional unidimensional approach. PMID- 26742005 TI - Accuracy and Precision of an Effect Size and Its Variance From a Multilevel Model for Cluster Randomized Trials: A Simulation Study. AB - This article investigates an effect size (MLM ES) and its variance for cluster randomized trials based on parameter estimates from multilevel modeling analysis. Accuracy and precision of MLM ES were evaluated using Monte Carlo simulation methods and compared with the performance of an effect size, computed from summary statistics, proposed by Hedges (2007; Hedges' dB ). Simulation results indicated that MLM ES had acceptable accuracy in all conditions, also demonstrating efficiency and consistency. With small sample sizes, MLM ES did not suffer from the same negative bias as Hedges' dB due to overestimation of between cluster variance. With large sample sizes, MLM ES and Hedges' dB were comparable for accuracy and efficiency. Both MLM ES and Hedges' dB showed considerable bias in some conditions when cluster sizes were unequal. An illustrative example using real data was provided. PMID- 26742006 TI - Androgen receptor expression predicts beneficial tamoxifen response in oestrogen receptor-alpha-negative breast cancer. AB - BACKGROUND: Although the androgen receptor (AR) is frequently expressed in breast cancer, its relevance in the disease is not fully understood. In addition, the relevance of AR in determining tamoxifen treatment efficiency requires evaluation. PURPOSE: To investigate the tamoxifen predictive relevance of the AR protein expression in breast cancer. METHODS: Patients were randomised to tamoxifen 40 mg daily for 2 or 5 years or to no endocrine treatment. Mean follow up was 15 years. Hazard ratios were calculated with recurrence-free survival as end point. RESULTS: In patients with oestrogen receptor (ER)-negative tumours, expression of AR predicted decreased recurrence rate with tamoxifen (hazard ratio (HR)=0.34; 95% confidence interval (CI)=0.14-0.81; P=0.015), whereas the opposite was seen in the AR- group (HR=2.92; 95% CI=1.16-7.31; P=0.022). Interaction test was significant P<0.001. Patients with triple-negative and AR+ tumours benefitted from tamoxifen treatment (HR=0.12; 95% CI=0.014-0.95 P=0.044), whereas patients with AR- tumours had worse outcome when treated with tamoxifen (HR=3.98; 95% CI=1.32-12.03; P=0.014). Interaction test was significant P=0.003. Patients with ER+ tumours showed benefit from tamoxifen treatment regardless of AR expression. CONCLUSIONS: AR can predict tamoxifen treatment benefit in patients with ER- tumours and triple-negative breast cancer. PMID- 26742008 TI - Antibody-drug conjugates--an emerging class of cancer treatment. AB - Antibody-drug conjugates (ADCs) are an emerging novel class of anticancer treatment agents that combines the selectivity of targeted treatment with the cytotoxic potency of chemotherapy drugs. New linker technology associated with novel highly potent cytotoxic payloads has permitted the development of more effective and safe ADCs. In recent years, two ADCs have been licensed, T-DM1 and brentuximab vedotin, and are already establishing their place in cancer treatment. A plethora of ADCs are being investigated in phases I and II trials, emerging data of which appears promising. As we deepen our understanding of what makes a successful ADC, an increasing number of ADCs will likely become viable treatment options as single agents or in combination with chemotherapy. This review will present the philosophy underlying ADCs, their main characteristics and current research developments with a focus on ADCs in solid tumours. PMID- 26742007 TI - Loss of CDH1 (E-cadherin) expression is associated with infiltrative tumour growth and lymph node metastasis. AB - BACKGROUND: Loss of CDH1 (E-cadherin) expression in cancer cells may promote cell migration and invasion. Therefore, we hypothesised that loss of CDH1 expression in colorectal carcinoma might be associated with aggressive features and clinical outcome. METHODS: Utilising molecular pathological epidemiology database of 689 rectal and colon cancer cases in the Nurses' Health Study and the Health Professionals Follow-up Study, we assessed tumour CDH1 expression by immunohistochemistry. Multivariate logistic regression analysis was conducted to assess association of CDH1 loss with tumour growth pattern (expansile intermediate vs infiltrative) and lymph node metastasis and distant metastasis, controlling for potential confounders including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, and PIK3CA, BRAF and KRAS mutations. Mortality according to CDH1 status was assessed using Cox proportional hazards model. RESULTS: Loss of tumour CDH1 expression was observed in 356 cases (52%), and associated with infiltrative tumour growth pattern (odds ratio (OR), 2.02; 95% confidence interval (CI), 1.23-3.34; P=0.006) and higher pN stage (OR, 1.73; 95% CI, 1.23-2.43; P=0.001). Tumour CDH1 expression was not significantly associated with distant metastasis or prognosis. CONCLUSIONS: Loss of CDH1 expression in colorectal cancer is associated with infiltrative tumour growth pattern and lymph node metastasis. PMID- 26742012 TI - Synthesis and spectral characterization of bis(4-amino-5-mercapto-1,2,4-triazol-3 yl)propane. AB - Bis(4-amino-5-mercapto-1,2,4-triazol-3-yl)propane (BAMTP) was synthesized and characterized by FT-IR and FT-Raman spectra. Gas phase structure of BAMTP was examined under density functional theory B3LYP/6-311++G(d, p) level of basis set, wherein the molecule was subjected to conformational analysis. Thus the identified stable structure utilized for the calculations such as geometry optimization, vibrational behavior, hyperpolarizability analysis, natural bond orbital analysis, band gap, chemical hard/softness and stability. Geometry of BAMTP has been discussed elaborately with related crystal data. The results found from experimental and theoretical methods were reported herewith. PMID- 26742010 TI - Regulator of cullins-1 expression knockdown suppresses the malignant progression of muscle-invasive transitional cell carcinoma by regulating mTOR/DEPTOR pathway. AB - BACKGROUND: Regulator of cullins-1 (ROC1) is a key subunit in the cullin-RING ligase (CRL) protein complex. Our previous study indicated that ROC1 was essential for bladder cancer cell survival and that ROC1 knockdown inhibited CRL activity, triggering G2 phase arrest and senescence. However, the role of ROC1 in the malignant progression of bladder cancer remained unknown. METHODS: ROC1 expression in cancer cells was knocked down by siRNA silencing. The effects of ROC1 silencing were evaluated by in vitro assays for cell migration and by an in vivo mouse metastasis model. Epithelial-mesenchymal transition (EMT) induction was evaluated by immunofluorescence staining and western blotting of EMT associated proteins. ROC1 expression in human tumours was further evaluated by immunohistochemical analysis. RESULTS: ROC1 knockdown suppresses bladder cancer cell migration by inhibiting EMT. ROC1 knockdown inhibited EMT by inhibiting mammalian target of rapamycin (mTOR) activity via the accumulation of the mTOR inhibitory protein DEPTOR, a CRL substrate. DEPTOR knockdown partially rescued ROC1 knockdown-inhibited EMT and the ROC1-induced inhibition of cancer cell migration. Furthermore, in vivo studies using a nude mouse metastasis model confirmed the in vitro data. Finally, tissue microarray analysis of clinical bladder cancer specimens indicated a positive correlation between ROC1 expression and EMT. CONCLUSIONS: ROC1 has an important role in the malignant progression of bladder cancer via the mTOR/DEPTOR pathway. ROC1 may serve as a novel therapeutic target for the treatment of muscle-invasive transitional cell carcinoma. PMID- 26742011 TI - Impact of general practice endorsement on the social gradient in uptake in bowel cancer screening. AB - BACKGROUND: There is a socioeconomic gradient in the uptake of screening in the English NHS Bowel Cancer Screening Programme (BCSP), potentially leading to inequalities in outcomes. We tested whether endorsement of bowel cancer screening by an individual's general practice (GP endorsement; GPE) reduced this gradient. METHODS: A cluster-randomised controlled trial. Over 20 days, individuals eligible for screening in England from 6480 participating general practices were randomly allocated to receive a GP-endorsed or the standard invitation letter. The primary outcome was the proportion of people adequately screened and its variation by quintile of Index of Multiple Deprivation. RESULTS: We enrolled 265,434 individuals. Uptake was 58.2% in the intervention arm and 57.5% in the control arm. After adjusting for age, sex, hub and screening episode, GPE increased the overall odds of uptake (OR=1.07, 95% CI 1.04-1.10), but did not affect its socioeconomic gradient. We estimated that implementing GPE could result in up to 165 more people with high or intermediate risk colorectal adenomas and 61 cancers detected, and a small one-off cost to modify the standard invitation (L78,000). CONCLUSIONS: Although GPE did not improve its socioeconomic gradient, it offers a low-cost approach to enhancing overall screening uptake within the NHS BCSP. PMID- 26742009 TI - Relation of statin use with non-melanoma skin cancer: prospective results from the Women's Health Initiative. AB - BACKGROUND: The relationship between statin use and non-melanoma skin cancer (NMSC) is unclear with conflicting findings in literature. Data from the Women's Health Initiative (WHI) Observational Study and WHI Clinical Trial were used to investigate the prospective relationship between statin use and NMSC in non Hispanic white (NHW) postmenopausal women. METHODS: The WHI study enrolled women aged 50-79 years at 40 US centres. Among 133,541 NHW participants, 118,357 with no cancer history at baseline and complete medication/covariate data comprised the analytic cohort. The association of statin use (baseline, overall as a time varying variable, duration, type, potency, lipophilicity) and NMSC incidence was determined using random-effects logistic regression models. RESULTS: Over a mean of 10.5 years of follow-up, we identified 11,555 NMSC cases. Compared with participants with no statin use, use of any statin at baseline was associated with significantly increased NMSC incidence (adjusted odds ratio (ORadj) 1.21; 95% confidence interval (CI): 1.07-1.35)). In particular, lovastatin (OR 1.52; 95% CI: 1.08-2.16), simvastatin (OR 1.38; 95% CI: 1.12-1.69), and lipophilic statins (OR 1.39; 95% CI: 1.18-1.64) were associated with higher NMSC risk. Low and high, but not medium, potency statins were associated with higher NMSC risk. No significant effect modification of the statin-NMSC relationship was found for age, BMI, smoking, solar irradiation, vitamin D use, and skin cancer history. CONCLUSIONS: Use of statins, particularly lipophilic statins, was associated with increased NMSC risk in postmenopausal white women in the WHI cohort. The lack of duration-effect relationship points to possible residual confounding. Additional prospective research should further investigate this relationship. PMID- 26742013 TI - A fluorescent sensor based on methyldopa drug modified gamma-Fe2O3 nanoparticles for ultrasensitive detection of calf thymus DNA. AB - We reported the study of calf thymus DNA (ct-DNA) adsorption by the polymer of methyldopa (2-amino-3-(3,4-dihydroxyphenyl)-2-methyl acid, propanoic) (PMDP), magnetofluorescent PMDP-gamma-Fe2O3 nanocrystal. The method is based on the extraordinarily high quenching efficiency of ct-DNA and the specific interaction between ct-DNA and PMDP-gamma-Fe2O3 via guanine base and metal coordination, probably. It was found that the designed magnetic nanoparticles can adsorb ct-DNA in nM levels in the presence of NaCl and KCl. In acetate and phosphate buffers DNA were adsorbed completely. Also, we found that pH plays an important role in DNA adsorption onto PMDP-gamma-Fe2O3 nanocrystal. PMDP-gamma-Fe2O3 nanocrystal is highly hydrophilic and DNA desorption wasn't observed. We believe this study will further stimulate the application of PMDP-gamma-Fe2O3 nanocrystal in bioanalytical chemistry and nanotechnology. PMDP-gamma-Fe2O3 nanocrystal possesses the ability to interact with ct-DNA via a partial intercalative binding mechanism, as demonstrated by fluorescence displacement experiments and a significant red shift (ca, 10nm) in UV-vis spectra. PMID- 26742014 TI - Metabolic Power and Oxygen Consumption in Team Sports: A Brief Response to Buchheit et al. PMID- 26742015 TI - Solutions Advertised as Erythropoiesis-stimulating Products were Found to Contain Undeclared Cobalt and Nickel Species. PMID- 26742016 TI - Are some "safer alternatives" hazardous as PBTs? The case study of new flame retardants. AB - Some brominated flame retardants (BFRs), as PBDEs, are persistent, bioaccumulative, toxic (PBT) and are restricted/prohibited under various legislations. They are replaced by "safer" flame retardants (FRs), such as new BFRs or organophosphorous compounds. However, informations on the PBT behaviour of these substitutes are often lacking. The PBT assessment is required by the REACH regulation and the PBT chemicals should be subjected to authorization. Several new FRs, proposed and already used as safer alternatives to PBDEs, are here screened by the cumulative PBT Index model, implemented in QSARINS (QSAR Insubria), new software for the development/validation of QSAR models. The results, obtained directly from the chemical structure for the three studied characteristics altogether, were compared with those from the US-EPA PBT Profiler: the two different approaches are in good agreement, supporting the utility of a consensus approach in these screenings. A priority list of the most harmful FRs, predicted in agreement by the two modelling tools, has been proposed, highlighting that some supposed "safer alternatives" are detected as intrinsically hazardous for their PBT properties. This study also shows that the PBT Index could be a valid tool to evaluate appropriate and safer substitutes, a priori from the chemical design, in a benign by design approach, avoiding unnecessary synthesis and tests. PMID- 26742017 TI - Transdermal toxicity of topically applied anticoagulant rodenticide warfarin in rats. AB - Occupational/accidental exposure data have showed hemorrhage as a result of transdermal exposure to warfarin, however, other effects are not known. In the present study, the impact of epicutaneous application of 10 MUg or 100 MUg of warfarin (three times, once a day) on peripheral blood polymorphonuclear (PMN) and mononuclear cells (PBMC) was examined in rats. Both doses resulted in prolongation of prothrombin time and changes in hematologic parameters. Increases in PMN intracellular myeloperoxidase (MPO) activity were seen at higher warfarin dose and both doses resulted in higher percentages of granular CD11b(+) cells. In contrast, a decrease in PMN TNF and IL-6 production (ELISA) and gene expression (RT-PCR) was observed. Epicutaneous application of warfarin resulted in decreased numbers of PBMC, higher numbers of mononuclear CD11b(+) cells, but without effect on PMBC cytokine production. The data obtained showed differential effects of transdermal exposure to warfarin depending on leukocyte type and activity. PMID- 26742018 TI - Novel cytotoxic drugs in advanced nonsmall cell lung cancer. AB - PURPOSE OF REVIEW: This article focuses on novel cytotoxic drugs for the treatment of patients with advanced nonsmall cell lung cancer (NSCLC) and describes their impact on disease outcome. RECENT FINDINGS: Nab-paclitaxel and carboplatin as first-line treatment should be considered a therapeutic option, particularly in patients with squamous histology. Nedaplatin and docetaxel improves survival in Asiatic patients with squamous histology as compared with cisplatin and docetaxel. SUMMARY: NSCLC is a heterogeneous disease with limited available treatment options in the absence of specific molecular alterations. Defining the histological subgroup has an impact on the selection of molecular screening and therapy options. Chemotherapy has reached a plateau of effectiveness showing an overall survival of about 10 months. Therefore, some cytotoxic and antiangiogenic agents display improved efficacy in defined patient subgroups and may lead to prolonged survival. Despite this, the overall outlook of lung cancer survival for most patients remains dismal. PMID- 26742019 TI - Proteomics approaches to understanding mitogen-activated protein kinase inhibitor resistance in melanoma. AB - PURPOSE OF REVIEW: BRAF inhibitors achieve outstanding clinical response rates in BRAF-mutated melanoma patients but therapeutic resistance is common. Although combinatorial targeted therapy has recently improved patient survival, resistance still occurs, which might be because of the plasticity and heterogeneity of melanoma. Proteomics complements the mostly genomics-based approaches used so far to gain additional insights into the pathophysiological mechanisms driving melanoma progression under treatment. RECENT FINDINGS: Few proteomics studies have investigated mitogen-activated protein kinase inhibitor (MAPKi) resistance. Three technologies have been described: shotgun analysis, pressure cycling technology-sequential window acquisition of all theoretical masses (which offers an optimized protein extraction by the pressure cycling technology), and selected reaction monitoring for selected candidate evaluation. Preliminary data demonstrate that BRAFi resistance might be associated with enhanced expression of the lysosomal compartment, cell adhesion, and epithelial-mesenchymal transformation. Melanoma cells change their phenotypes in response to targeted therapy with MAPKi from a proliferative to an invasive state gaining epithelial mesenchymal transformation features, which are associated with drug resistance. SUMMARY: Performing proteomics may lead to an enhanced understanding of the underlying mechanisms of MAPKi resistance and might offer new insights for rational therapies. Selected reaction monitoring can be used to evaluate predictive or pharmacodynamic biomarkers for tracking therapeutic responses and identifying early features of resistance. PMID- 26742020 TI - Hematopoietic growth factors in lung cancer. AB - PURPOSE OF REVIEW: Most patients affected by lung cancer are treated with chemotherapy, and hence are at risk of myelosuppression. Hematopoietic growth factors have a relevant role in this setting, as they can improve quality of life, reduce the rate of chemotherapy-induced complications and allow the administration of full-dose chemotherapy. RECENT FINDINGS: Most data of hematologic growth factors in lung cancer come from dated publications or large trials involving different malignancies, thus limiting specific information for lung neoplasms. Nonetheless, most studies consistently identified myeloid growth factors as effective on specific end-points such as the duration and severity of neutropenia, or complications such as hospitalizations and febrile neutropenia; on the other hand, erythropoiesis-stimulating agents (ESAs) consistently improved anemia-specific end-points including hemoglobin values, transfusions rate and fatigue, although some specific safety issues characterized this drug class. The most recent international guidelines address these characteristics and include the main indications for hematologic growth factors in solid neoplasms, including lung cancer. SUMMARY: Myeloid growth factors and ESAs have a relevant role in selected patients undergoing chemotherapy for nonsmall cell lung cancer and small cell lung cancer. Notably, a comprehensive risk-benefit assessment is required in the specific case of ESAs. PMID- 26742021 TI - To Attract Others, Immune Cells Release a Packet Which Releases a Signal. PMID- 26742022 TI - Effects of a mindfulness-based intervention on fertility quality of life and pregnancy rates among women subjected to first in vitro fertilization treatment. AB - Generally, undergoing an in vitro fertilization (IVF) treatment is an emotional and physical burden for the infertile woman, which may negatively influence the treatment outcome. We conducted a study to investigate the effectiveness of a mindfulness-based intervention (MBI) among women subjected to first IVF treatment at a fertility medical center in China. Among infertile women registered for their first IVF treatment, 58 completed the intervention, and 50 were assigned to a control group using a non-randomized controlled study. Standardized measures of mindfulness, self-compassion, emotion regulation difficulties, infertility related coping strategies and fertility quality of life (FertiQoL) were endorsed pre- and post-MBI, and measure of pregnancy rates at the sixth months after the intervention. Both groups were shown to be equivalent at baseline. By the end of the intervention, women who attended the intervention revealed a significant increase in mindfulness, self-compassion, meaning-based coping strategies and all FertiQoL domains. Inversely, they presented a significant decrease in emotion regulation difficulties, active- and passive-avoidance coping strategies. Women in the control group did not present significant changes in any of the psychological measures. Moreover, there were statistically significant differences between participants in the pregnancy rates, the experiment group higher than the control group. Being fully aware of the present moment without the lens of judgment, seems to help women relate to their infertility and IVF treatment in new ways. This is beneficial for promoting their self-compassion, adaptive emotion regulation and infertility-related coping strategies, which, in turn, may influence the FertiQoL and pregnancy rates. The brief and nonpharmaceutical nature of this intervention makes it a promising candidate for women' use during first IVF treatment. PMID- 26742023 TI - Probing the Serotonin Transporter Availability Among Male Cigarette Smokers: A SPECT Study With [123I] ADAM. AB - OBJECTIVE: Genetic studies have suggested that the serotonin transporter (SERT) could be associated with cigarette smoking. However, evidence from neuroimaging is scarce. The aim of the present study was to examine the SERT availability among cigarette smokers by using single-photon emission computed tomography (SPECT). METHODS: Sixteen male smokers and 32 controls were enrolled. The SERT availability was measured by SPECT with a radiotracer, [I] ADAM, which is highly sensitive and specific to SERT. RESULTS: No significant difference in SERT availability was found between 2 groups in the midbrain (smokers: 2.12 +/- 0.70, nonsmokers: 2.13 +/- 0.63; P = 0.86), basal ganglia (smokers: 0.83 +/- 0.30, nonsmokers:0.90 +/- 0.39; P = 0.95), or thalamus (smokers: 1.14 +/- 0.41, nonsmokers: 1.20 +/- 0.38; P = 0.88). No significant association was found between the SERT availability, and either the breath carbon monoxide level or the score of the Fagerstrom Test for Nicotine Dependence. CONCLUSIONS: Whether the SERT availability in the brain is altered in smokers remains unclear. PMID- 26742024 TI - Removal of Indoor Volatile Organic Compounds via Photocatalytic Oxidation: A Short Review and Prospect. AB - Volatile organic compounds (VOCs) are ubiquitous in indoor environments. Inhalation of VOCs can cause irritation, difficulty breathing, and nausea, and damage the central nervous system as well as other organs. Formaldehyde is a particularly important VOC as it is even a carcinogen. Removal of VOCs is thus critical to control indoor air quality (IAQ). Photocatalytic oxidation has demonstrated feasibility to remove toxic VOCs and formaldehyde from indoor environments. The technique is highly-chemical stable, inexpensive, non-toxic, and capable of removing a wide variety of organics under light irradiation. In this paper, we review and summarize the traditional air cleaning methods and current photocatalytic oxidation approaches in both of VOCs and formaldehyde degradation in indoor environments. Influencing factors such as temperature, relative humidity, deactivation and reactivations of the photocatalyst are discussed. Aspects of the application of the photocatalytic technique to improve the IAQ are suggested. PMID- 26742025 TI - Evaluation of the Nano-TiO2 as a Novel Deswelling Material. AB - Nano-TiO2 is widely applied in the automobile exhaust hose reels as a catalyst to reduce oxynitride emissions, including nitric oxide (NO). In the biomedicine field, NO plays an important role in vasodilation and edema formation in human bodies. However, the deswelling activity of nano-TiO2 has not been reported. Here, we demonstrated that nano-TiO2 can significantly degrade the production of NO in LPS-induced RAW264.7 mouse macrophages. Further study indicated that nano TiO2 exhibited an effect on vascular permeability inhibition, and prevented carrageenan-induced footpad edema. Therefore, we prepared a nano-TiO2 ointment and observed similar deswelling effects. In conclusion, nano-TiO2 might act as a novel deswelling agent related with its degradation of NO, which will aid in our ability to design effective interventions for edema involved diseases. PMID- 26742026 TI - Chemical Analysis of the Herbal Medicine Salviae miltiorrhizae Radix et Rhizoma (Danshen). AB - Radix Salviae miltiorrhizae et Rhizoma, known as Danshen in China, is one of the most popular traditional Chinese medicines. Recently, there has been increasing scientific attention on Danshen for its remarkable bioactivities, such as promoting blood circulation, removing blood stasis, and clearing away heat. This review summarized the advances in chemical analysis of Danshen and its preparations since 2009. Representative established methods were reviewed, including spectroscopy, thin layer chromatography, gas chromatography, liquid chromatography (LC), liquid chromatography-mass spectrometry (LC-MS), capillary electrophoresis, electrochemistry, and bioanalysis. Especially the analysis of polysaccharides in Danshen was discussed for the first time. Some proposals were also put forward to benefit quality control of Danshen. PMID- 26742027 TI - Isolation of Terpenoids from the Stem of Ficus aurantiaca Griff and their Effects on Reactive Oxygen Species Production and Chemotactic Activity of Neutrophils. AB - Three new triterpenoids; namely 28,28,30-trihydroxylupeol (1); 3,21,21,26 tetrahydroxy-lanostanoic acid (2) and dehydroxybetulinic acid (3) and seven known compounds; i.e., taraxerone (4); taraxerol (5); ethyl palmitate (6); herniarin (7); stigmasterol (8); ursolic acid (9) and acetyl ursolic acid (10) were isolated from the stem of Ficus aurantiaca Griff. The structures of the compounds were established by spectroscopic techniques. The compounds were evaluated for their inhibitory effects on polymorphonuclear leukocyte (PMN) chemotaxis by using the Boyden chamber technique and on human whole blood and neutrophil reactive oxygen species (ROS) production by using a luminol-based chemiluminescence assay. Among the compounds tested, compounds 1-4, 6 and 9 exhibited strong inhibition of PMN migration towards the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (fMLP) with IC50 values of 6.8; 2.8; 2.5; 4.1; 3.7 and 3.6 MUM, respectively, comparable to that of the positive control ibuprofen (6.7 MUM). Compounds 2-4, 6, 7 and 9 exhibited strong inhibition of ROS production of PMNs with IC50 values of 0.9; 0.9; 1.3; 1.1; 0.5 and 0.8 MUM, respectively, which were lower than that of aspirin (9.4 MUM). The bioactive compounds might be potential lead molecules for the development of new immunomodulatory agents to modulate the innate immune response of phagocytes. PMID- 26742028 TI - Synthesis of Chlorinated Tetracyclic Compounds and Testing for Their Potential Antidepressant Effect in Mice. AB - The synthesis of the tetracyclic compounds 1-(4,5-dichloro-9,10-dihydro-9,10 ethanoanthracen-11-yl)-N-methylmethanamine (5) and 1-(1,8-dichloro-9,10-dihydro 9,10-ethanoanthracen-11-yl)-N-methylmethanamine (6) as a homologue of the anxiolytic and antidepressant drugs benzoctamine and maprotiline were described. The key intermediate aldehydes (3) and (4) were successfully synthesized via a [4 + 2] cycloaddition between acrolein and 1,8-dichloroanthracene. The synthesized compounds were investigated for antidepressant activity using the forced swimming test. Compounds (5), (6) and (3) showed significant reduction in the mice immobility indicating significant antidepressant effects. These compounds significantly reduced the immobility times at a dose 80 mg/kg by 84.0%, 86.7% and 71.1% respectively. PMID- 26742029 TI - New Phragmalin-Type Limonoids from Chukrasia tabularis and Their alpha Glucosidase Inhibitory Activity. AB - Phytochemical investigation on the stems of C. tabularis led to the isolation of five new phragmalin-type limonoids and six known ones. The structures of the new compounds 1-5, named chukbularisins A-E, were elucidated by spectroscopic techniques (IR, HRESIMS, 1D and 2D NMR) and comparisons with published data. All the compounds were evaluated for in vitro alpha-glucosidase inhibitory activity. Compounds 2, 3, 4, 5, and 8 exhibited inhibitory activity against alpha glucosidase with IC50 values of 0.06 +/- 0.008, 0.04 +/- 0.002, 0.52 +/- 0.039, 1.09 +/- 0.040, and 0.20 +/- 0.057 mM, respectively (using acarbose as positive control, IC50 0.95 +/- 0.092 mM). PMID- 26742030 TI - Ruthenium(III) Complexes of Heterocyclic Tridentate (ONN) Schiff Base: Synthesis, Characterization and its Biological Properties as an Antiradical and Antiproliferative Agent. AB - The current work reports the synthesis, spectroscopic studies, antiradical and antiproliferative properties of four ruthenium(III) complexes of heterocyclic tridentate Schiff base bearing a simple 2',4'-dihydroxyacetophenone functionality and ethylenediamine as the bridging ligand with RCHO moiety. The reaction of the tridentate ligands with RuCl3.3H2O lead to the formation of neutral complexes of the type [Ru(L)Cl2(H2O)] (where L = tridentate NNO ligands). The compounds were characterized by elemental analysis, UV-vis, conductivity measurements, FTIR spectroscopy and confirmed the proposed octahedral geometry around the Ru ion. The Ru(III) compounds showed antiradical potentials against 2,2-Diphenyl-1 Picrylhydrazyl (DPPH) and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals, with DPPH scavenging capability in the order: [(PAEBOD)RuCl2] > [(BZEBOD)RuCl2] > [(MOABOD)RuCl2] > [Vit. C] > [rutin] > [(METBOD)RuCl2], and ABTS radical in the order: [(PAEBOD)RuCl2] < [(MOABOD)RuCl2] < [(BZEBOD)RuCl2] < [(METBOD)RuCl2]. Furthermore, in vitro anti-proliferative activity was investigated against three human cancer cell lines: renal cancer cell (TK-10), melanoma cancer cell (UACC-62) and breast cancer cell (MCF-7) by SRB assay. PMID- 26742031 TI - Binding of Sulpiride to Seric Albumins. AB - The aim of this work was to study the interaction of sulpiride with human serum albumin (HSA) and bovine serum albumin (BSA) through the fluorescence quenching technique. As sulpiride molecules emit fluorescence, we have developed a simple mathematical model to discriminate the quencher fluorescence from the albumin fluorescence in the solution where they interact. Sulpiride is an antipsychotic used in the treatment of several psychiatric disorders. We selectively excited the fluorescence of tryptophan residues with 290 nm wavelength and observed the quenching by titrating HSA and BSA solutions with sulpiride. Stern-Volmer graphs were plotted and quenching constants were estimated. Results showed that sulpiride form complexes with both albumins. Estimated association constants for the interaction sulpiride-HSA were 2.20 (+/-0.08) * 104 M(-1), at 37 degrees C, and 5.46 (+/-0.20) * 104 M(-1), at 25 degrees C. Those for the interaction sulpiride-BSA are 0.44 (+/-0.01) * 104 M(-1), at 37 degrees C and 2.17 (+/-0.04) * 104 M(-1), at 25 degrees C. The quenching intensity of BSA, which contains two tryptophan residues in the peptide chain, was found to be higher than that of HSA, what suggests that the primary binding site for sulpiride in albumin should be located next to the sub domain IB of the protein structure. PMID- 26742032 TI - In Vivo Anti-Tumor Activity and Toxicological Evaluations of Perillaldehyde 8,9 Epoxide, a Derivative of Perillyl Alcohol. AB - Recent studies have revealed the high cytotoxicity of p-menthane derivatives against human tumor cells. In this study, the substance perillaldehyde 8,9 epoxide, a p-menthane class derivative obtained from (S)-(-)-perillyl alcohol, was selected in order to assess antitumor activity against experimental sarcoma 180 tumors. Toxicological effects related to the liver, spleen, kidneys and hematology were evaluated in mice submitted to treatment. The tumor growth inhibition rate was 38.4%, 58.7%, 35.3%, 45.4% and 68.1% at doses of 100 and 200 mg/kg/day for perillaldehyde 8,9-epoxide, perillyl alcohol and 25 mg/kg/day for 5 FU intraperitoneal treatments, respectively. No toxicologically significant effect was found in liver and kidney parameters analyzed in Sarcoma 180 inoculated mice treated with perillaldehyde 8,9-epoxide. Histopathological analyses of the liver, spleen, and kidneys were free from any morphological changes in the organs of the animals treated with perillaldehyde 8,9-epoxide. In conclusion, the data suggest that perillaldehyde 8,9-epoxide possesses significant antitumor activity without systemic toxicity for the tested parameters. By comparison, there was no statistical difference for the antitumor activity between perillaldehyde 8,9-epoxide and perillyl alcohol. PMID- 26742033 TI - Effect of Acetyl Group on Mechanical Properties of Chitin/Chitosan Nanocrystal: A Molecular Dynamics Study. AB - Chitin fiber is the load-bearing component in natural chitin-based materials. In these materials, chitin is always partially deacetylated to different levels, leading to diverse material properties. In order to understand how the acetyl group enhances the fracture resistance capability of chitin fiber, we constructed atomistic models of chitin with varied acetylation degree and analyzed the hydrogen bonding pattern, fracture, and stress-strain behavior of these models. We notice that the acetyl group can contribute to the formation of hydrogen bonds that can stabilize the crystalline structure. In addition, it is found that the specimen with a higher acetylation degree presents a greater resistance against fracture. This study describes the role of the functional group, acetyl groups, in crystalline chitin. Such information could provide preliminary understanding of nanomaterials when similar functional groups are encountered. PMID- 26742034 TI - Porcine Adipose-Derived Mesenchymal Stem Cells Retain Their Stem Cell Characteristics and Cell Activities While Enhancing the Expression of Liver Specific Genes after Acute Liver Failure. AB - Acute liver failure (ALF) is a kind of complicated syndrome. Furthermore, adipose derived mesenchymal stem cells (ADMSCs) can serve as a useful cell resource for autotransplantation due to their abundance and micro-invasive accessability. However, it is unknown how ALF will influence the characteristics of ADMSCs and whether ADMSCs from patients suffering from end-stage liver diseases are potential candidates for autotransplantation. This study was designed to compare various properties of ALF-derived ADMSCs with normal ADMSCs in pig models, with regard to their cellular morphology, cell proliferative ability, cell apoptosis, expression of surface antigens, mitochondrial and lysosomal activities, multilineage potency, and expression of liver-specific genes. Our results showed that ALF does not influence the stem cell characteristics and cell activities of ADMSCs. Intriguingly, the expression levels of several liver-specific genes in ALF-derived ADMSCs are higher than in normal ADMSCs. In conclusion, our findings indicate that the stem cell characteristics and cell activities of ADMSCs were not altered by ALF and these cells can serve as a new source for regenerative medicine. PMID- 26742035 TI - The Metals in the Biological Periodic System of the Elements: Concepts and Conjectures. AB - A significant number of chemical elements are either essential for life with known functions, or present in organisms with poorly defined functional outcomes. We do not know all the essential elements with certainty and we know even less about the functions of apparently non-essential elements. In this article, I discuss a basis for a biological periodic system of the elements and that biochemistry should include the elements that are traditionally part of inorganic chemistry and not only those that are in the purview of organic chemistry. A biological periodic system of the elements needs to specify what "essential" means and to which biological species it refers. It represents a snapshot of our present knowledge and is expected to undergo further modifications in the future. An integrated approach of biometal sciences called metallomics is required to understand the interactions of metal ions, the biological functions that their chemical structures acquire in the biological system, and how their usage is fine tuned in biological species and in populations of species with genetic variations (the variome). PMID- 26742036 TI - Anion Channel Inhibitor NPPB-Inhibited Fluoride Accumulation in Tea Plant (Camellia sinensis) Is Related to the Regulation of Ca2+, CaM and Depolarization of Plasma Membrane Potential. AB - Tea plant is known to be a hyper-accumulator of fluoride (F). Over-intake of F has been shown to have adverse effects on human health, e.g., dental fluorosis. Thus, understanding the mechanisms fluoride accumulation and developing potential approaches to decrease F uptake in tea plants might be beneficial for human health. In the present study, we found that pretreatment with the anion channel inhibitor NPPB reduced F accumulation in tea plants. Simultaneously, we observed that NPPB triggered Ca(2+) efflux from mature zone of tea root and significantly increased relative CaM in tea roots. Besides, pretreatment with the Ca(2+) chelator (EGTA) and CaM antagonists (CPZ and TFP) suppressed NPPB-elevated cytosolic Ca(2+) fluorescence intensity and CaM concentration in tea roots, respectively. Interestingly, NPPB-inhibited F accumulation was found to be significantly alleviated in tea plants pretreated with either Ca(2+) chelator (EGTA) or CaM antagonists (CPZ and TFP). In addition, NPPB significantly depolarized membrane potential transiently and we argue that the net Ca(2+) and H+ efflux across the plasma membrane contributed to the restoration of membrane potential. Overall, our results suggest that regulation of Ca(2+)-CaM and plasma membrane potential depolarization are involved in NPPB-inhibited F accumulation in tea plants. PMID- 26742037 TI - Ischemia, Immunosuppression and Infection--Tackling the Predicaments of Post Stroke Complications. AB - The incidence of stroke has risen over the past decade and will continue to be one of the leading causes of death and disability worldwide. While a large portion of immediate death following stroke is due to cerebral infarction and neurological complications, the most common medical complication in stroke patients is infection. In fact, infections, such as pneumonia and urinary tract infections, greatly worsen the clinical outcome of stroke patients. Recent evidence suggests that the disrupted interplay between the central nervous system and immune system contributes to the development of infection after stroke. The suppression of systemic immunity by the nervous system is thought to protect the brain from further inflammatory insult, yet this comes at the cost of increased susceptibility to infection after stroke. To improve patient outcome, there have been attempts to lessen the stroke-associated bacterial burden through the prophylactic use of broad-spectrum antibiotics. However, preventative antibiotic treatments have been unsuccessful, and therefore have been discouraged. Additionally, with the ever-rising obstacle of antibiotic-resistance, future therapeutic options to reverse immune impairment after stroke by augmentation of host immunity may be a viable alternative option. However, cautionary steps are required to ensure that collateral ischemic damage caused by cerebral inflammation remains minimal. PMID- 26742039 TI - Aberrant DNA Methylation of rDNA and PRIMA1 in Borderline Personality Disorder. AB - Borderline personality disorder (BPD) is a serious psychic disease with a high risk for suicide. DNA methylation is a hallmark for aberrant epigenetic regulation and could be involved in the etiology of BPD. Previously, it has been reported that increased DNA methylation of neuropsychiatric genes is found in the blood of patients with BPD compared to healthy controls. Here, we analyzed DNA methylation patterns of the ribosomal RNA gene (rDNA promoter region and 5' external transcribed spacer/5'ETS) and the promoter of the proline rich membrane anchor 1 gene (PRIMA1) in peripheral blood samples of 24 female patients (mean age (33 +/- 11) years) diagnosed with DSM-IV BPD and in 11 female controls (mean age (32 +/- 7) years). A significant aberrant methylation of rDNA and PRIMA1 was revealed for BPD patients using pyrosequencing. For the promoter of PRIMA1, the average methylation of six CpG sites was 1.6-fold higher in BPD patients compared to controls. In contrast, the methylation levels of the rDNA promoter region and the 5'ETS were significantly lower (0.9-fold) in patients with BPD compared to controls. Thus, for nine CpGs located in the rDNA promoter region and for four CpGs at the 5'ETS decreased methylation was found in peripheral blood of patients compared to controls. Our results suggest that aberrant methylation of rDNA and PRIMA1 is associated with the pathogenesis of BPD. PMID- 26742041 TI - Real-Time Hand Posture Recognition for Human-Robot Interaction Tasks. AB - In this work, we present a multiclass hand posture classifier useful for human robot interaction tasks. The proposed system is based exclusively on visual sensors, and it achieves a real-time performance, whilst detecting and recognizing an alphabet of four hand postures. The proposed approach is based on the real-time deformable detector, a boosting trained classifier. We describe a methodology to design the ensemble of real-time deformable detectors (one for each hand posture that can be classified). Given the lack of standard procedures for performance evaluation, we also propose the use of full image evaluation for this purpose. Such an evaluation methodology provides us with a more realistic estimation of the performance of the method. We have measured the performance of the proposed system and compared it to the one obtained by using only the sampled window approach. We present detailed results of such tests using a benchmark dataset. Our results show that the system can operate in real time at about a 10 fps frame rate. PMID- 26742042 TI - Energy-Efficient Control with Harvesting Predictions for Solar-Powered Wireless Sensor Networks. AB - Wireless sensor networks equipped with rechargeable batteries are useful for outdoor environmental monitoring. However, the severe energy constraints of the sensor nodes present major challenges for long-term applications. To achieve sustainability, solar cells can be used to acquire energy from the environment. Unfortunately, the energy supplied by the harvesting system is generally intermittent and considerably influenced by the weather. To improve the energy efficiency and extend the lifetime of the networks, we propose algorithms for harvested energy prediction using environmental shadow detection. Thus, the sensor nodes can adjust their scheduling plans accordingly to best suit their energy production and residual battery levels. Furthermore, we introduce clustering and routing selection methods to optimize the data transmission, and a Bayesian network is used for warning notifications of bottlenecks along the path. The entire system is implemented on a real-time Texas Instruments CC2530 embedded platform, and the experimental results indicate that these mechanisms sustain the networks' activities in an uninterrupted and efficient manner. PMID- 26742040 TI - Earthworm Lumbricus rubellus MT-2: Metal Binding and Protein Folding of a True Cadmium-MT. AB - Earthworms express, as most animals, metallothioneins (MTs)-small, cysteine-rich proteins that bind d(10) metal ions (Zn(II), Cd(II), or Cu(I)) in clusters. Three MT homologues are known for Lumbricus rubellus, the common red earthworm, one of which, wMT-2, is strongly induced by exposure of worms to cadmium. This study concerns composition, metal binding affinity and metal-dependent protein folding of wMT-2 expressed recombinantly and purified in the presence of Cd(II) and Zn(II). Crucially, whilst a single Cd7wMT-2 species was isolated from wMT-2 expressing E. coli cultures supplemented with Cd(II), expressions in the presence of Zn(II) yielded mixtures. The average affinities of wMT-2 determined for either Cd(II) or Zn(II) are both within normal ranges for MTs; hence, differential behaviour cannot be explained on the basis of overall affinity. Therefore, the protein folding properties of Cd- and Zn-wMT-2 were compared by 1H NMR spectroscopy. This comparison revealed that the protein fold is better defined in the presence of cadmium than in the presence of zinc. These differences in folding and dynamics may be at the root of the differential behaviour of the cadmium- and zinc-bound protein in vitro, and may ultimately also help in distinguishing zinc and cadmium in the earthworm in vivo. PMID- 26742043 TI - Detection of Organic Compounds in Water by an Optical Absorbance Method. AB - This paper proposes an optical method which allows determination of the organic compound concentration in water by measurement of the UV (ultraviolet) absorption at a wavelength of 250 nm~300 nm. The UV absorbance was analyzed by means of a multiple linear regression model for estimation of the total organic carbon contents in water, which showed a close correlation with the UV absorbance, demonstrating a high adjusted coefficient of determination, 0.997. The comparison of the TOC (total organic carbon) concentrations for real samples (tab water, sea, and river) calculated from the UV absorbance spectra, and those measured by a conventional TOC analyzer indicates that the higher the TOC value the better the agreement. This UV absorbance method can be easily configured for real-time monitoring water pollution, and built into a compact system applicable to industry areas. PMID- 26742038 TI - Cardiac Extracellular Vesicles in Normal and Infarcted Heart. AB - Heart is a complex assembly of many cell types constituting myocardium, endocardium and epicardium that intensively communicate to each other in order to maintain the proper cardiac function. There are many types of intercellular intracardiac signals, with a prominent role of extracellular vesicles (EVs), such as exosomes and microvesicles, for long-distant delivering of complex messages. Cardiomyocytes release EVs, whose content could significantly vary depending on the stimulus. In stress, such as hypoxia, inflammation or injury, cardiomyocytes increase secretion of EVs. In hypoxic conditions, cardiac EVs are enriched with angiogenic and prosurvival factors. In acute myocardial infarction (AMI), damaged cardiac muscle cells produce EVs with increased content of angiogenic, anti apoptotic, mitogenic and growth factors in order to induce repair and healing of the infarcted myocardium. Exosomal microRNAs play a central role in cardiac regeneration. In AMI, circulating cardiac EVs abundantly contain cardiac-specific miRNAs that serve as indicators of cardiac damage and have a big diagnostic potential as AMI biomarkers. Cardioprotective and regenerative properties of exosomes derived from cardiac and non-cardiac stem/progenitor cells are very helpful to be used in cell-free cardiotherapy and regeneration of post-infarct myocardium. PMID- 26742044 TI - Characterizations and Electrical Modelling of Sensory Samples Formed from Synthesized Vanadium (V) Oxide and Copper Oxide Graphene Quantum Tunneling Composites (GQTC) Applied in Electrotribology. AB - CuO and V2O5 graphene quantum tunneling composites (GQTC) presented in this article were produced and their sensory properties were analyzed. The composites were synthesised using two stage high-power milling process, which resulted in materials that have good temeprature and pressure sensory properties. Described production process defines internal structure of materials such that when used as sensor in the desired range, it exhibits a strong percolation effect. The experiment, with controlled changing physical conditions during electrotribological measurement, enabled analyzing of the composites' conductivity as a function of the sensory properties: applied temperature, pressure, tangential force and wear. The sensory characteristic was successfully modelled by invertible generalized equations, and used to create sensor capable of estimating temperature or pressure in the real time. The developed materials have the potential to be applied in the areas where miniaturization is essential, due to the materials exhibiting good sensory properties in mini and micro scale. PMID- 26742045 TI - Estimation of Gaze Detection Accuracy Using the Calibration Information-Based Fuzzy System. AB - Gaze tracking is a camera-vision based technology for identifying the location where a user is looking. In general, a calibration process is applied at the initial stage of most gaze tracking systems. This process is necessary to calibrate for the differences in the eyeballs and cornea size of the user, as well as the angle kappa, and to find the relationship between the user's eye and screen coordinates. It is applied on the basis of the information of the user's pupil and corneal specular reflection obtained while the user is looking at several predetermined positions on a screen. In previous studies, user calibration was performed using various types of markers and marker display methods. However, studies on estimating the accuracy of gaze detection through the results obtained during the calibration process have yet to be carried out. Therefore, we propose the method for estimating the accuracy of a final gaze tracking system with a near-infrared (NIR) camera by using a fuzzy system based on the user calibration information. Here, the accuracy of the final gaze tracking system ensures the gaze detection accuracy during the testing stage of the gaze tracking system. Experiments were performed using a total of four types of markers and three types of marker display methods. From them, it was found that the proposed method correctly estimated the accuracy of the gaze tracking regardless of the various marker and marker display types applied. PMID- 26742046 TI - A Deadline-Aware Scheduling and Forwarding Scheme in Wireless Sensor Networks. AB - Many applications in wireless sensor networks (WSNs) require energy consumption to be minimized and the data delivered to the sink within a specific delay. A usual solution for reducing energy consumption is duty cycling, in which nodes periodically switch between sleep and active states. By increasing the duty cycle interval, consumed energy can be reduced more. However, a large duty cycle interval causes a long end-to-end (E2E) packet delay. As a result, the requirement of a specific delay bound for packet delivery may not be satisfied. In this paper, we aim at maximizing the duty cycle while still guaranteeing that the packets arrive at the sink with the required probability, i.e., the required delay-constrained success ratio (DCSR) is achieved. In order to meet this objective, we propose a novel scheduling and forwarding scheme, namely the deadline-aware scheduling and forwarding (DASF) algorithm. In DASF, the E2E delay distribution with the given network model and parameters is estimated in order to determine the maximum duty cycle interval, with which the required DCSR is satisfied. Each node independently selects a wake-up time using the selected interval, and packets are forwarded to a node in the potential forwarding set, which is determined based on the distance between nodes and the sink. DASF does not require time synchronization between nodes, and a node does not need to maintain neighboring node information in advance. Simulation results show that the proposed scheme can satisfy a required delay-constrained success ratio and outperforms existing algorithms in terms of E2E delay and DCSR. PMID- 26742047 TI - Pedestrian Counting with Occlusion Handling Using Stereo Thermal Cameras. AB - The number of pedestrians walking the streets or gathered in public spaces is a valuable piece of information for shop owners, city governments, event organizers and many others. However, automatic counting that takes place day and night is challenging due to changing lighting conditions and the complexity of scenes with many people occluding one another. To address these challenges, this paper introduces the use of a stereo thermal camera setup for pedestrian counting. We investigate the reconstruction of 3D points in a pedestrian street with two thermal cameras and propose an algorithm for pedestrian counting based on clustering and tracking of the 3D point clouds. The method is tested on two five minute video sequences captured at a public event with a moderate density of pedestrians and heavy occlusions. The counting performance is compared to the manually annotated ground truth and shows success rates of 95.4% and 99.1% for the two sequences. PMID- 26742048 TI - Recombinant Expression and Characterization of alpha-Conotoxin LvIA in Escherichia coli. AB - alpha-Conotoxin LvIA is derived from Conus lividus, native to Hainan, and is the most selective inhibitor of alpha3beta2 nicotinic acetylcholine receptors (nAChRs) known to date. In this study, an efficient approach for the production of recombinant alpha-Conotoxin LvIA is described. Tandem repeats of a LvIA gene fragment were constructed and fused with a KSI gene and a His6 tag in a Escherichia coli (E. coli) expression vector pET-31b(+). The recombinant plasmids were transformed into E. coli and were found to express well. The KSI-(LvIA)n His6 fusion protein was purified by metal affinity chromatography and then cleaved with CNBr to release recombinant LvIA (rLvIA). High yields of fusion protein ranging from 100 to 500 mg/L culture were obtained. The pharmacological profile of rLvIA was determined by two-electrode voltage-clamp electrophysiology in Xenopus laevis oocytes expressing rat nAChR subtypes. The rLvIA antagonized the alpha3beta2 nAChR subtype selectively with a nano-molar IC50. The rLvIA was analgesic in a mouse hot-plate test model of pain. Overall, this study provides an effective method to synthesize alpha-conotoxin LvIA in an E. coli recombinant expression system, and this approach could be useful to obtain active conopeptides in large quantity and at low cost. PMID- 26742049 TI - Evaluation of the Survivability of Microorganisms Deposited on Filtering Respiratory Protective Devices under Varying Conditions of Humidity. AB - Bioaerosols are common biological factors in work environments, which require routine use of filtering respiratory protective devices (FRPDs). Currently, no studies link humidity changes in the filter materials of such devices, during use, with microorganism survivability. Our aim was to determine the microclimate inside FRPDs, by simulating breathing, and to evaluate microorganism survivability under varying humidity conditions. Breathing was simulated using commercial filtering facepiece respirators in a model system. Polypropylene melt blown nonwoven fabrics with moisture contents of 40%, 80%, and 200%, were used for assessment of microorganisms survivability. A modified AATCC 100-2004 method was used to measure the survivability of ATCC and NCAIM microorganisms: Escherichia coli, Staphylococcus aureus, Bacillus subtilis, Candida albicans and Aspergillus niger. During simulation relative humidity under the facepiece increased after 7 min of usage to 84%-92% and temperature increased to 29-30 degrees C. S. aureus survived the best on filter materials with 40%-200% moisture content. A decrease in survivability was observed for E. coli and C. albicans when mass humidity decreased. We found that B. subtilis and A. niger proliferated for 48-72 h of incubation and then died regardless of the moisture content. In conclusion, our tests showed that the survivability of microorganisms on filter materials depends on the amount of accumulated moisture and microorganism type. PMID- 26742050 TI - Synthesis of High Valence Silver-Loaded Mesoporous Silica with Strong Antibacterial Properties. AB - A simple chemical method was developed for preparing high valence silver (Ag) loaded mesoporous silica (Ag-ethylenediaminetetraacetic acid (EDTA)-SBA-15), which showed strong antibacterial activity. Ag-EDTA-SBA-15 exhibited stronger and more effective antibacterial activity than commercial Ag nanoparticles did, and it offered high stability of high valence silver in the porous matrix and long lasting antibacterial activity. The synthesized materials were characterized using Fourier transform infrared spectroscopy, powder X-ray diffraction (XRD), X ray photoelectron spectroscopy (XPS) analysis, and transmission electron microscopy (TEM). Ag existed in both surface complexation and Ag particles. EDTA anchored within a porous structure chelated Ag ions in higher oxidation states and prevented their agglomeration and oxidation reduction. The XRD results showed that most Ag in the Ag-EDTA-SBA-15 existed in higher oxidation states such as Ag(II) and Ag(III). However, the XPS and TEM results showed that Ag easily reduced in lower oxidation states and agglomerated as Ag particles on the exterior layer of the SBA-15. PMID- 26742051 TI - A Walk in the Park: The Influence of Urban Parks and Community Violence on Physical Activity in Chelsea, MA. AB - Proximity to a park does not necessarily imply access or use, and the social environment may positively or negatively influence the positive intentions of the built environment. To investigate parks, park use and physical activity, and their associations with exposure to community violence, we interviewed residents (n = 354) of a densely populated urban community. Our findings indicate that proximity to any park is not associated with physical activity. However, proximity to the preferred park reported by residents to be conducive for physical activity (with walking paths, large fields, playgrounds for children and tennis courts) was associated with physical activity. Conversely, knowledge of sexual assault or rape in the neighborhood is inversely associated with every type of physical activity (park-based, outdoor, and indoor). Our findings suggest that improvements to the built environment (parks, green spaces) may be hindered by adverse social environments and both are necessary for consideration in the design of public health interventions. PMID- 26742053 TI - Advanced Wastewater Treatment Engineering-Investigating Membrane Fouling in both Rotational and Static Membrane Bioreactor Systems Using Empirical Modelling. AB - Advanced wastewater treatment using membranes are popular environmental system processes since they allow reuse and recycling. However, fouling is a key limiting factor and so proprietary systems such as Avanti's RPU-185 Flexidisks membrane bioreactor (MBR) use novel rotating membranes to assist in ameliorating it. In earlier research, this rotating process was studied by creating a simulation model based on first principles and traditional fouling mechanisms. In order to directly compare the potential benefits of this rotational system, this follow-up study was carried out using Avanti's newly developed static (non rotating) Flexidisks MBR system. The results from operating the static pilot unit were simulated and modelled using the rotational fouling model developed earlier however with rotational switching functions turned off and rotational parameters set to a static mode. The study concluded that a rotating MBR system could increase flux throughput when compared against a similar static system. It is thought that although the slowly rotating spindle induces a weak crossflow shear, it is still able to even out cake build up across the membrane surface, thus reducing the likelihood of localised critical flux being exceeded at the micro level and lessening the potential of rapid trans-membrane pressure increases at the macro level. PMID- 26742054 TI - Structural Model for the Effects of Environmental Elements on the Psychological Characteristics and Performance of the Employees of Manufacturing Systems. AB - This paper analyzes the effects of environmental elements on the psychological characteristics and performance of employees in manufacturing systems using structural equation modeling. Increasing the comprehension of these effects may help optimize manufacturing systems regarding their employees' psychological characteristics and performance from a macroergonomic perspective. As the method, a new macroergonomic compatibility questionnaire (MCQ) was developed and statistically validated, and 158 respondents at four manufacture companies were considered. Noise, lighting and temperature, humidity and air quality (THAQ) were used as independent variables and psychological characteristics and employees' performance as dependent variables. To propose and test the hypothetical causal model of significant relationships among the variables, a data analysis was deployed. Results found that the macroergonomic compatibility of environmental elements presents significant direct effects on employees' psychological characteristics and either direct or indirect effects on the employees' performance. THAQ had the highest direct and total effects on psychological characteristics. Regarding the direct and total effects on employees' performance, the psychological characteristics presented the highest effects, followed by THAQ conditions. These results may help measure and optimize manufacturing systems' performance by enhancing their macroergonomic compatibility and quality of life at work of the employees. PMID- 26742052 TI - Ethnic Kawasaki Disease Risk Associated with Blood Mercury and Cadmium in U.S. Children. AB - Kawasaki disease (KD) primarily affects children <5 years of age (75%-80%) and is currently the leading cause of acquired heart disease in developed nations. Even when residing in the West, East Asian children are 10 to 20 times more likely to develop KD. We hypothesized cultural variations influencing pediatric mercury (Hg) exposure from seafood consumption may mediate ethnic KD risk among children in the United States. Hospitalization rates of KD in US children aged 0-4 years (n = 10,880) and blood Hg levels in US children aged 1-5 years (n = 713) were determined using separate US federal datasets. Our cohort primarily presented with blood Hg levels <0.1 micrograms (ug) per kg bodyweight (96.5%) that are considered normal and subtoxic. Increased ethnic KD risk was significantly associated with both increasing levels and detection rates of blood Hg or cadmium (Cd) in a linear dose-responsive manner between ethnic African, Asian, Caucasian, and Hispanic children in the US (p <= 0.05). Increasing low-dose exposure to Hg or Cd may induce KD or contribute to its later development in susceptible children. However, our preliminary results require further replication in other ethnic populations, in addition to more in-depth examination of metal exposure and toxicokinetics. PMID- 26742055 TI - Experimental Study on Ultrafine Particle Removal Performance of Portable Air Cleaners with Different Filters in an Office Room. AB - Size- and time-dependent aerodynamic behaviors of indoor particles, including PM1.0, were evaluated in a school office in order to test the performance of air cleaning devices using different filters. In-situ real-time measurements were taken using an optical particle counter. The filtration characteristics of filter media, including single-pass efficiency, volume and effectiveness, were evaluated and analyzed. The electret filter (EE) medium shows better initial removal efficiency than the high efficiency (HE) medium in the 0.3-3.5 MUm particle size range, while under the same face velocity, the filtration resistance of the HE medium is several times higher than that of the EE medium. During service life testing, the efficiency of the EE medium decreased to 60% with a total purifying air flow of 25 * 104 m3/m2. The resistance curve rose slightly before the efficiency reached the bottom, and then increased almost exponentially. The single-pass efficiency of portable air cleaner (PAC) with the pre-filter (PR) or the active carbon granule filter (CF) was relatively poor. While PAC with the pre filter and the high efficiency filter (PR&HE) showed maximum single-pass efficiency for PM1.0 (88.6%), PAC with the HE was the most effective at removing PM1.0. The enhancement of PR with HE and electret filters augmented the single pass efficiency, but lessened the airflow rate and effectiveness. Combined with PR, the decay constant of large-sized particles could be greater than for PACs without PR. Without regard to the lifetime, the electret filters performed better with respect to resource saving and purification improvement. A most penetrating particle size range (MPPS: 0.4-0.65 MUm) exists in both HE and electret filters; the MPPS tends to become larger after HE and electret filters are combined with PR. These results serve to provide a better understanding of the indoor particle removal performance of PACs when combined with different kinds of filters in school office buildings. PMID- 26742056 TI - Individuals with Metabolically Healthy Overweight/Obesity Have Higher Fat Utilization than Metabolically Unhealthy Individuals. AB - The mechanisms underlying the change in phenotype from metabolically healthy to metabolically unhealthy obesity are still unclear. The aim of this study is to investigate whether a difference in fasting fat utilization exists between overweight/obese individuals with a favorable cardiovascular risk profile and those with Metabolic Syndrome and Type 2 diabetes. Furthermore, we sought to explore whether there is an association between fasting fat utilization and insulin resistance. In this cross-sectional study, 172 overweight/obese individuals underwent a nutritional assessment. Those with fasting glucose >= 126 mg/dL or antidiabetic treatment were considered to be diabetics. If at least three of the NCEP criteria were present, they had Metabolic Syndrome, while those with less criteria were considered to be healthy overweight/obese. An indirect calorimetry was performed to estimate Respiratory Quotient, an index of nutrient utilization. A lower Respiratory Quotient (i.e., higher fat utilization) was found in healthy overweight/obese individuals than in those with Metabolic Syndrome and Type 2 diabetes (0.85 +/- 0.05; 0.87 +/- 0.06; 0.88 +/- 0.05 respectively, p = 0.04). The univariate and multivariable analysis showed a positive association between the Respiratory Quotient and HOMA-IR (slope in statistic (B) = 0.004; beta = 0.42; p = 0.005; 95% Confidence interval = 0.001 0.006). In this study, we find, for the first time, that the fasting Respiratory Quotient is significantly lower (fat utilization is higher) in individuals who are metabolically healthy overweight/obese than in those with metabolically unhealthy obesity. In addition, we demonstrated the association between fat utilization and HOMA-IR, an insulin resistance index. PMID- 26742057 TI - Greater Total Antioxidant Capacity from Diet and Supplements Is Associated with a Less Atherogenic Blood Profile in U.S. Adults. AB - Evidence from epidemiologic studies has shown that total antioxidant capacity (TAC) in the diet might be inversely associated with stroke, heart failure, and inflammatory biomarkers. However, studies on the association of TAC from both diet and supplements with cardiovascular disease (CVD) risk factors in the U.S. population are lacking. This cross-sectional population-based study aimed to investigate the association of TAC with both diet and supplements with CVD risk factors among 4039 U.S. adults in National Health and Nutrition Examination Survey (NHANES) 2007-2012. TAC from both food sources and dietary supplements was estimated from two 24-h dietary recalls using the NHANES supplement ingredient database, United States Department of Agriculture (USDA) proanthocyanidin, flavonoid, and isoflavone databases. Top contributors to TAC were tea, antioxidant supplements, vegetable mixture, orange juice, berries, and wine. Antioxidant supplement users had 1.6 times higher TAC than non-users. Greater TAC was associated with reduced triglycerides (TG) (-1.39% change; 95% CI = -2.56 to 0.21), TG to high-density lipoprotein cholesterol (HDL-C) ratio (-2.03% change; 95% CI = -3.45 to -0.60), HDL-C (0.65% change; 95% CI = 0.07 to 1.23), insulin ( 1.37% change; 95% CI = -2.64 to -0.09), homeostasis model assessment of insulin resistance (HOMA-IR) (-1.57% change; 95% CI = -3.02 to -0.09) and C-reactive protein (CRP) (-0.83% change; 95% CI = -1.29 to -0.38) after adjusting for potential confounders. There was no significant association between TAC and waist circumference, BMI, blood pressure, low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and fasting glucose. The findings of this study support the hypothesis that an antioxidant-rich diet and intake of supplements are beneficial to reduce CVD risk. PMID- 26742058 TI - Effect of Glycemic Index of Breakfast on Energy Intake at Subsequent Meal among Healthy People: A Meta-Analysis. AB - Meals with low glycemic index (GI) may suppress short-term appetite and reduce subsequent food intake compared with high-GI meals. However, no meta-analysis has been conducted to synthesize the evidence. This meta-analytic study was conducted to assess the effect of high- and low-GI breakfast on subsequent short-term food intake. Trials were identified through MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled trials, and manual searches of bibliographies until May 2015. Randomized controlled and cross-over trials comparing the effect of low- with high-GI breakfast on subsequent energy intake among healthy people were included. Nine studies consisting of 11 trials met the inclusion criteria. Only one trial was classified with high methodological quality. A total of 183 participants were involved in the trials. The meta analytic results revealed no difference in breakfast GI (high-GI vs. low-GI) on subsequent short-term energy intake. In conclusion, it seems that breakfast GI has no effect on short-term energy intake among healthy people. However, high quality studies are still warranted to provide more concrete evidence. PMID- 26742059 TI - Significant Beneficial Association of High Dietary Selenium Intake with Reduced Body Fat in the CODING Study. AB - Selenium (Se) is a trace element which plays an important role in adipocyte hypertrophy and adipogenesis. Some studies suggest that variations in serum Se may be associated with obesity. However, there are few studies examining the relationship between dietary Se and obesity, and findings are inconsistent. We aimed to investigate the association between dietary Se intake and a panel of obesity measurements with systematic control of major confounding factors. A total of 3214 subjects participated in the study. Dietary Se intake was determined from the Willett food frequency questionnaire. Body composition was measured using dual-energy X-ray absorptiometry. Obese men and women had the lowest dietary Se intake, being 24% to 31% lower than corresponding normal weight men and women, classified by both BMI and body fat percentage. Moreover, subjects with the highest dietary Se intake had the lowest BMI, waist circumference, and trunk, android, gynoid and total body fat percentages, with a clear dose dependent inverse relationship observed in both gender groups. Furthermore, significant negative associations discovered between dietary Se intake and obesity measurements were independent of age, total dietary calorie intake, physical activity, smoking, alcohol, medication, and menopausal status. Dietary Se intake alone may account for 9%-27% of the observed variations in body fat percentage. The findings from this study strongly suggest that high dietary Se intake is associated with a beneficial body composition profile. PMID- 26742062 TI - Plasma Free Amino Acid Responses to Intraduodenal Whey Protein, and Relationships with Insulin, Glucagon-Like Peptide-1 and Energy Intake in Lean Healthy Men. AB - This study determined the effects of increasing loads of intraduodenal (ID) dairy protein on plasma amino acid (AA) concentrations, and their relationships with serum insulin, plasma glucagon-like peptide-1 (GLP-1) and energy intake. Sixteen healthy men had concentrations of AAs, GLP-1 and insulin measured in response to 60-min ID infusions of hydrolysed whey protein administered, in double-blinded and randomised order, at 2.1 (P2.1), 6.3 (P6.3) or 12.5 (P12.5) kJ/min (encompassing the range of nutrient emptying from the stomach), or saline control (C). Energy intake was quantified immediately afterwards. Compared with C, the concentrations of 19/20 AAs, the exception being cysteine, were increased, and this was dependent on the protein load. The relationship between AA concentrations in the infusions and the area under the curve from 0 to 60 min (AUC0-60 min) of each AA profile was strong for essential AAs (R2 range, 0.61 0.67), but more variable for non-essential (0.02-0.54) and conditional (0.006 0.64) AAs. The AUC0-60 min for each AA was correlated directly with the AUC0-60 min of insulin (R2 range 0.3-0.6), GLP-1 (0.2-0.6) and energy intake (0.09-0.3) (p < 0.05, for all), with the strongest correlations being for branched-chain AAs, lysine, methionine and tyrosine. These findings indicate that ID whey protein infused at loads encompassing the normal range of gastric emptying increases plasma concentrations of 19/20 AAs in a load-dependent manner, and provide novel information on the close relationships between the essential AAs, leucine, valine, isoleucine, lysine, methionine, and the conditionally-essential AA, tyrosine, with energy intake, insulin and GLP-1. PMID- 26742061 TI - Fatty Acid Desaturases, Polyunsaturated Fatty Acid Regulation, and Biotechnological Advances. AB - Polyunsaturated fatty acids (PUFAs) are considered to be critical nutrients to regulate human health and development, and numerous fatty acid desaturases play key roles in synthesizing PUFAs. Given the lack of delta-12 and -15 desaturases and the low levels of conversion to PUFAs, humans must consume some omega-3 and omega-6 fatty acids in their diet. Many studies on fatty acid desaturases as well as PUFAs have shown that fatty acid desaturase genes are closely related to different human physiological conditions. Since the first front-end desaturases from cyanobacteria were cloned, numerous desaturase genes have been identified and animals and plants have been genetically engineered to produce PUFAs such as eicosapentaenoic acid and docosahexaenoic acid. Recently, a biotechnological approach has been used to develop clinical treatments for human physiological conditions, including cancers and neurogenetic disorders. Thus, understanding the functions and regulation of PUFAs associated with human health and development by using biotechnology may facilitate the engineering of more advanced PUFA production and provide new insights into the complexity of fatty acid metabolism. PMID- 26742060 TI - DHA Effects in Brain Development and Function. AB - Docosahexaenoic acid (DHA) is a structural constituent of membranes specifically in the central nervous system. Its accumulation in the fetal brain takes place mainly during the last trimester of pregnancy and continues at very high rates up to the end of the second year of life. Since the endogenous formation of DHA seems to be relatively low, DHA intake may contribute to optimal conditions for brain development. We performed a narrative review on research on the associations between DHA levels and brain development and function throughout the lifespan. Data from cell and animal studies justify the indication of DHA in relation to brain function for neuronal cell growth and differentiation as well as in relation to neuronal signaling. Most data from human studies concern the contribution of DHA to optimal visual acuity development. Accumulating data indicate that DHA may have effects on the brain in infancy, and recent studies indicate that the effect of DHA may depend on gender and genotype of genes involved in the endogenous synthesis of DHA. While DHA levels may affect early development, potential effects are also increasingly recognized during childhood and adult life, suggesting a role of DHA in cognitive decline and in relation to major psychiatric disorders. PMID- 26742063 TI - Effects of a Theory-Based Education Program to Prevent Overweightness in Primary School Children. AB - The effectiveness of the "Extra Fit!" (EF!) education program in promoting healthy diet and physical activity to prevent and reduce overweightness among primary school children aged 9 to 11 was evaluated. A randomized controlled design was carried out in 45 primary schools (n = 1112) in the Netherlands, 23 intervention and 22 control schools. The intervention schools received the education program for two successive school years in grades (U.S. system) 4, 5, and 6 (mean 7.6 h during 16 weeks per school per year). The control schools followed their usual curriculum. No positive effects of EF! were found with regard to behavior and anthropometric measures when follow-up measurements were compared to the baseline. However, from baseline to follow-up after one and two school years, the intervention group improved their knowledge score significantly compared to the control group. Moreover, an effect was observed for mean time spent inactively that increased more in the control group than in the intervention group. In conclusion, limited intervention effects were found for the intervention on knowledge and inactivity. To improve the effectiveness of education programs, we advise focusing on parental involvement, attractive lessons to enlarge the acceptability of the program, and multi-component environmental strategies. PMID- 26742064 TI - Rise in DPA Following SDA-Rich Dietary Echium Oil Less Effective in Affording Anti-Arrhythmic Actions Compared to High DHA Levels Achieved with Fish Oil in Sprague-Dawley Rats. AB - Stearidonic acid (SDA; C18:4n-3) has been suggested as an alternative to fish oil (FO) for delivering health benefits of C >= 20 long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA). Echium oil (EO) represents a non-genetically-modified source of SDA available commercially. This study compared EO and FO in relation to alterations in plasma and tissue fatty acids, and for their ability to afford protection against ischemia-induced cardiac arrhythmia and ventricular fibrillation (VF). Rats were fed (12 weeks) diets supplemented with either EO or FO at three dose levels (1, 3 and 5% w/w; n = 18 per group). EO failed to influence C22:6n-3 (DHA) but increased C22:5n-3 (DPA) in tissues dose dependently, especially in heart tissue. Conversely, DHA in hearts of FO rats showed dose-related elevation; 14.8%-24.1% of total fatty acids. Kidney showed resistance for incorporation of LC n-3 PUFA. Overall, FO provided greater cardioprotection than EO. At the highest dose level, FO rats displayed lower (p < 0.05) episodes of VF% (29% vs. 73%) and duration (22.7 +/- 12.0 vs. 75.8 +/- 17.1 s) than the EO group but at 3% EO was comparable to FO. We conclude that there is no endogenous conversion of SDA to DHA, and that DPA may be associated with limited cardiac benefit. PMID- 26742065 TI - Altered Preconception Fatty Acid Intake Is Associated with Improved Pregnancy Rates in Overweight and Obese Women Undertaking in Vitro Fertilisation. AB - Maternal preconception diet is proposed to affect fertility. Prior research assessing the effect of altering the fatty acid profile on female fertility is conflicting. The aim of this study was to assess the effect of preconception maternal diet, specifically fatty acid profile, on pregnancies and live births following in vitro fertilisation (IVF). Forty-six overweight and obese women undergoing IVF were randomised to a diet and physical activity intervention (intervention) or standard care (control). Outcome measures included pregnancy, live birth and pre-study dietary intake from food frequency questionnaire. Twenty pregnancies (n = 12/18 vs. n = 8/20, p = 0.12) and 12 live births (n = 7/18 vs. n = 5/20, p = 0.48) occurred following the intervention with no differences between the treatment groups. On analysis adjusted for BMI and smoking status, women who became pregnant had higher levels of polyunsaturated fatty acid (PUFA) intake (p = 0.03), specifically omega-6 PUFA and linoleic acid (LA) (p = 0.045) with a trend for an elevated intake of omega-3 PUFA (p = 0.06). There were no dietary differences for women who did or did not have a live birth. Maternal preconception PUFA, and specifically omega-6 and LA intake, are associated with improved pregnancy rates in overweight and obese women undergoing IVF. This has implications for optimising fertility through preconception nutrition. PMID- 26742067 TI - High Fat Diet Administration during Specific Periods of Pregnancy Alters Maternal Fatty Acid Profiles in the Near-Term Rat. AB - Excessive fat intake is a global health concern as women of childbearing age increasingly ingest high fat diets (HFDs). We therefore determined the maternal fatty acid (FA) profiles in metabolic organs after HFD administration during specific periods of gestation. Rats were fed a HFD for the first (HF1), second (HF2), or third (HF3) week, or for all three weeks (HFG) of gestation. Total maternal plasma non-esterified fatty acid (NEFA) concentrations were monitored throughout pregnancy. At day 20 of gestation, maternal plasma, liver, adipose tissue, and placenta FA profiles were determined. In HF3 mothers, plasma myristic and stearic acid concentrations were elevated, whereas docosahexaenoic acid (DHA) was reduced in both HF3 and HFG mothers. In HF3 and HFG mothers, hepatic stearic and oleic acid proportions were elevated; conversely, DHA and linoleic acid (LA) proportions were reduced. In adipose tissue, myristic acid was elevated, whereas DHA and LA proportions were reduced in all mothers. Further, adipose tissue stearic acid proportions were elevated in HF2, HF3, and HFG mothers; with oleic acid increased in HF1 and HFG mothers. In HF3 and HFG mothers, placental neutral myristic acid proportions were elevated, whereas DHA was reduced. Further, placental phospholipid DHA proportions were reduced in HF3 and HFG mothers. Maintenance on a diet, high in saturated fat, but low in DHA and LA proportions, during late or throughout gestation, perpetuated reduced DHA across metabolic organs that adapt during pregnancy. Therefore a diet, with normal DHA proportions during gestation, may be important for balancing maternal FA status. PMID- 26742066 TI - Maternal Nutrition and Glycaemic Index during Pregnancy Impacts on Offspring Adiposity at 6 Months of Age--Analysis from the ROLO Randomised Controlled Trial. AB - Childhood obesity is associated with increased risk of adult obesity and metabolic disease. Diet and lifestyle in pregnancy influence fetal programming; however the influence of specific dietary components, including low glycaemic index (GI), remains complex. We examined the effect of a maternal low GI dietary intervention on offspring adiposity at 6 months and explored the association between diet and lifestyle factors in pregnancy and infant body composition at 6 months. 280 6-month old infant and mother pairs from the control (n = 142) and intervention group (n = 138), who received low GI dietary advice in pregnancy, in the ROLO study were analysed. Questionnaires (food diaries and lifestyle) were completed during pregnancy, followed by maternal lifestyle and infant feeding questionnaires at 6 months postpartum. Maternal anthropometry was measured throughout pregnancy and at 6 months post-delivery, along with infant anthropometry. No difference was found in 6 months infant adiposity between control and intervention groups. Maternal trimester three GI, trimester two saturated fats and trimester one and three sodium intake were positively associated with offspring adiposity, while trimester two and three vitamin C intake was negatively associated. In conclusion associations were observed between maternal dietary intake and GI during pregnancy and offspring adiposity at 6 months of age. PMID- 26742068 TI - Effects of Dietary Protein and Fiber at Breakfast on Appetite, ad Libitum Energy Intake at Lunch, and Neural Responses to Visual Food Stimuli in Overweight Adults. AB - Increasing either protein or fiber at mealtimes has relatively modest effects on ingestive behavior. Whether protein and fiber have additive or interactive effects on ingestive behavior is not known. Fifteen overweight adults (5 female, 10 male; BMI: 27.1 +/- 0.2 kg/m2; aged 26 +/- 1 year) consumed four breakfast meals in a randomized crossover manner (normal protein (12 g) + normal fiber (2 g), normal protein (12 g) + high fiber (8 g), high protein (25 g) + normal fiber (2 g), high protein (25 g) + high fiber (8 g)). The amount of protein and fiber consumed at breakfast did not influence postprandial appetite or ad libitum energy intake at lunch. In the fasting-state, visual food stimuli elicited significant responses in the bilateral insula and amygdala and left orbitofrontal cortex. Contrary to our hypotheses, postprandial right insula responses were lower after consuming normal protein vs. high protein breakfasts. Postprandial responses in other a priori brain regions were not significantly influenced by protein or fiber intake at breakfast. In conclusion, these data do not support increasing dietary protein and fiber at breakfast as effective strategies for modulating neural reward processing and acute ingestive behavior in overweight adults. PMID- 26742070 TI - Vitamin D Dietary Intake Questionnaire Validation Conducted among Young Polish Women. AB - Due to inadequate intake of Vitamin D, identification of individuals characterised by the highest risk of deficiencies is one of the more crucial tasks for public health. The aim of the presented study was to assess the validity and reproducibility of the designed Vitamin D dietary intake questionnaire based on food frequency assessment--VIDEO-FFQ (VItamin D Estimation Only--Food Frequency Questionnaire) in a group of Polish women aged 20-30 years. Seventy-five participants kept a three-day dietary record and filled out the VIDEO-FFQ twice (immediately after the three-day dietary record and after six weeks). The assessment of validity and reproducibility was conducted by verifying standard errors of estimation, median differences, and percentages of individuals classified into tertiles, correlations and Bland-Altman plots. The Vitamin D intake for the majority of the surveyed women was inadequate as over 85% of them were characterised by values of intake lower than 5.0 MUg per day. The results allowed concluding that a high accuracy of the VIDEO-FFQ was achieved. The required Bland-Altman index values lower than 5.0% were obtained, confirming satisfactory validity and reproducibility. The VIDEO-FFQ may be deemed a convenient practical tool for the estimation of Vitamin D intake in young women. PMID- 26742069 TI - Peroxisome Proliferator-Activated Receptor Activation is Associated with Altered Plasma One-Carbon Metabolites and B-Vitamin Status in Rats. AB - Plasma concentrations of metabolites along the choline oxidation pathway have been linked to increased risk of major lifestyle diseases, and peroxisome proliferator-activated receptors (PPARs) have been suggested to be involved in the regulation of key enzymes along this pathway. In this study, we investigated the effect of PPAR activation on circulating and urinary one-carbon metabolites as well as markers of B-vitamin status. Male Wistar rats (n = 20) received for 50 weeks either a high-fat control diet or a high-fat diet with tetradecylthioacetic acid (TTA), a modified fatty acid and pan-PPAR agonist with high affinity towards PPARalpha. Hepatic gene expression of PPARalpha, PPARbeta/delta and the enzymes involved in the choline oxidation pathway were analyzed and concentrations of metabolites were analyzed in plasma and urine. TTA treatment altered most biomarkers, and the largest effect sizes were observed for plasma concentrations of dimethylglycine, nicotinamide, methylnicotinamide, methylmalonic acid and pyridoxal, which were all higher in the TTA group (all p < 0.01). Hepatic Pparalpha mRNA was increased after TTA treatment, but genes of the choline oxidation pathway were not affected. Long-term TTA treatment was associated with pronounced alterations on the plasma and urinary concentrations of metabolites related to one-carbon metabolism and B-vitamin status in rats. PMID- 26742073 TI - Rapid Microfluidic Assay for the Detection of Botulinum Neurotoxin in Animal Sera. AB - Potent Botulinum neurotoxins (BoNTs) represent a threat to public health and safety. Botulism is a disease caused by BoNT intoxication that results in muscle paralysis that can be fatal. Sensitive assays capable of detecting BoNTs from different substrates and settings are essential to limit foodborne contamination and morbidity. In this report, we describe a rapid 96-well microfluidic double sandwich immunoassay for the sensitive detection of BoNT-A from animal sera. This BoNT microfluidic assay requires only 5 MUL of serum, provides results in 75 min using a standard fluorescence microplate reader and generates minimal hazardous waste. The assay has a <30 pg.mL(-1) limit of detection (LOD) of BoNT-A from spiked human serum. This sensitive microfluidic BoNT-A assay offers a fast and simplified workflow suitable for the detection of BoNT-A from serum samples of limited volume in most laboratory settings. PMID- 26742072 TI - Quercetin Attenuates Chronic Ethanol-Induced Hepatic Mitochondrial Damage through Enhanced Mitophagy. AB - Emerging evidence suggested mitophagy activation mitigates ethanol-induced liver injury. However, the effect of ethanol on mitophagy is inconsistent. Importantly, the understanding of mitophagy status after chronic ethanol consumption is limited. This study evaluated the effect of quercetin, a naturally-occurring flavonoid, on chronic ethanol-induced mitochondrial damage focused on mitophagy. An ethanol regime to mice for 15 weeks (accounting for 30% of total calories) led to significant mitochondrial damage as evidenced by changes of the mitochondrial ultrastructure, loss of mitochondrial membrane potential and remodeling of membrane lipid composition, which was greatly attenuated by quercetin (100 mg/kg.bw). Moreover, quercetin blocked chronic ethanol-induced mitophagy suppression as denoted by mitophagosomes-lysosome fusion and mitophagy-related regulator elements, including LC3II, Parkin, p62 and voltage-dependent anion channel 1 (VDAC1), paralleling with increased FoxO3a nuclear translocation. AMP activated protein kinase (AMPK) and extracellular signal regulated kinase 2 (ERK2), instead of AKT and Sirtuin 1, were involved in quercetin-mediated mitophagy activation. Quercetin alleviated ethanol-elicited mitochondrial damage through enhancing mitophagy, highlighting a promising preventive strategy for alcoholic liver disease. PMID- 26742074 TI - Identification and Quantification of a Toxigenic and Non-Toxigenic Aspergillus flavus Strain in Contaminated Maize Using Quantitative Real-Time PCR. AB - Aflatoxins, which are produced by Aspergillus flavus, are toxic to humans, livestock, and pets. The value of maize (Zea mays) grain is markedly reduced when contaminated with aflatoxin. Plant resistance and biological control using non toxin producing strains are considered effective strategies for reducing aflatoxin accumulation in maize grain. Distinguishing between the toxin and non toxin producing strains is important in determining the effectiveness of bio control strategies and understanding inter-strain interactions. Using polymorphisms found in the fungal rRNA intergenic spacer region (IGS) between a toxigenic strain of A. flavus (NRRL 3357) and the non-toxigenic strain used in the biological control agent Afla-Guard((r)) (NRRL 21882), we developed a set of primers that allows for the identification and quantification of the two strains using quantitative PCR. This primer set has been used to screen maize grain that was inoculated with the two strains individually and co-inoculated with both strains, and it has been shown to be effective in both the identification and quantification of both strains. Screening of co-inoculated ears from multiple resistant and susceptible genotypic crosses revealed no significant differences in fungal biomass accumulation of either strain in the field tests from 2010 and 2011 when compared across the means of all genotypes. Only one genotype/year combination showed significant differences in strain accumulation. Aflatoxin accumulation analysis showed that, as expected, genotypes inoculated with the toxigenic strain accumulated more aflatoxin than when co-inoculated with both strains or inoculated with only the non-toxigenic strain. Furthermore, accumulation of toxigenic fungal mass was significantly correlated with aflatoxin accumulation while non-toxigenic fungal accumulation was not. This primer set will allow researchers to better determine how the two fungal strains compete on the maize ear and investigate the interaction between different maize lines and these A. flavus strains. PMID- 26742071 TI - Polyphenols and Glycemic Control. AB - Growing evidence from animal studies supports the anti-diabetic properties of some dietary polyphenols, suggesting that dietary polyphenols could be one dietary therapy for the prevention and management of Type 2 diabetes. This review aims to address the potential mechanisms of action of dietary polyphenols in the regulation of glucose homeostasis and insulin sensitivity based on in vitro and in vivo studies, and to provide a comprehensive overview of the anti-diabetic effects of commonly consumed dietary polyphenols including polyphenol-rich mixed diets, tea and coffee, chocolate and cocoa, cinnamon, grape, pomegranate, red wine, berries and olive oil, with a focus on human clinical trials. Dietary polyphenols may inhibit alpha-amylase and alpha-glucosidase, inhibit glucose absorption in the intestine by sodium-dependent glucose transporter 1 (SGLT1), stimulate insulin secretion and reduce hepatic glucose output. Polyphenols may also enhance insulin-dependent glucose uptake, activate 5' adenosine monophosphate-activated protein kinase (AMPK), modify the microbiome and have anti-inflammatory effects. However, human epidemiological and intervention studies have shown inconsistent results. Further intervention studies are essential to clarify the conflicting findings and confirm or refute the anti diabetic effects of dietary polyphenols. PMID- 26742075 TI - Vitamin B12 Uptake by the Gut Commensal Bacteria Bacteroides thetaiotaomicron Limits the Production of Shiga Toxin by Enterohemorrhagic Escherichia coli. AB - Enterohemorrhagic Escherichia coli (EHEC) are foodborne pathogens responsible for the development of bloody diarrhea and renal failure in humans. Many environmental factors have been shown to regulate the production of Shiga toxin 2 (Stx2), the main virulence factor of EHEC. Among them, soluble factors produced by human gut microbiota and in particular, by the predominant species Bacteroides thetaiotaomicron (B. thetaiotaomicron), inhibit Stx2 gene expression. In this study, we investigated the molecular mechanisms underlying the B. thetaiotaomicron-dependent inhibition of Stx2 production by EHEC. We determined that Stx2-regulating molecules are resistant to heat treatment but do not correspond to propionate and acetate, two short-chain fatty acids produced by B. thetaiotaomicron. Moreover, screening of a B. thetaiotaomicron mutant library identified seven mutants that do not inhibit Stx2 synthesis by EHEC. One mutant has impaired production of BtuB, an outer membrane receptor for vitamin B12. Together with restoration of Stx2 level after vitamin B12 supplementation, these data highlight vitamin B12 as a molecule produced by gut microbiota that modulates production of a key virulence factor of EHEC and consequently may affect the outcome of an infection. PMID- 26742076 TI - Profiling the Behavior of Distinct Populations of Head and Neck Cancer Stem Cells. AB - Cancer stem cells (CSCs) are a subpopulation of tumor cells endowed with self renewal properties and the capacity to dynamically adapt to physiological changes that occur in the tumor microenvironment. CSCs play a central role in resistance to therapy and long-term disease recurrence. Better characterization and understanding of the available in vitro tools to study the biology of CSCs will improve our knowledge of the processes underlying tumor response to therapy, and will help in the screening and development of novel strategies targeting CSCs. We investigated the behavior of different populations of head and neck CSCs grown under ultra-low adhesion conditions. We found that invasion and adhesion differ among tumorsphere subtypes (holospheres, merospheres and paraspheres), and their tumor cell progeny also harbor distinct self-renewal and clonogenic potentials. Furthermore, holospheres contained higher numbers of head and neck CSCs, as detected by the CD44 cancer stem cell marker and aldehyde dehydrogenase (ALDH) enzymatic activity. In addition, holospheres showed reduced proliferation (Ki67), hypoacetylation of histones, and increased expression of the BMI-1 epithelial stem cell marker, suggesting activation of stem cell programs. Collectively, our results suggest that holospheres enrich a specific population of CSCs with enhanced "stemness" and invasive potential. PMID- 26742079 TI - Brighter Fluorescent Derivatives of UTI89 Utilizing a Monomeric vGFP. AB - Fluorescent proteins, especially green fluorescent protein (GFP), have been instrumental in understanding urinary tract infection pathogenesis by uropathogenic Escherichia coli (UPEC). We have used a recently developed GFP variant, vsfGFP-9, to create new plasmid- and chromosome-based GFP derivatives of the UPEC strain UTI89. The vsfGFP-9 strains are nearly 10* brighter with no in vitro growth or in vivo virulence defects compared to previously reported GFP expressing UTI89 strains. The chromosomal vsfGFP-9 strain is equivalent to the wild type UTI89 during in vivo UTI, while both plasmid GFP constructs have an equivalent virulence defect compared to non-plasmid carrying UTI89. These new vsfGFP-9 expressing strains should be useful for further studies of the pathogenesis of UTI89, and similar strategies can be used to create improved fluorescent derivatives of other UPEC strains. PMID- 26742077 TI - Cancer Stem Cell Plasticity Drives Therapeutic Resistance. AB - The connection between epithelial-mesenchymal (E-M) plasticity and cancer stem cell (CSC) properties has been paradigm-shifting, linking tumor cell invasion and metastasis with therapeutic recurrence. However, despite their importance, the molecular pathways involved in generating invasive, metastatic, and therapy resistant CSCs remain poorly understood. The enrichment of cells with a mesenchymal/CSC phenotype following therapy has been interpreted in two different ways. The original interpretation posited that therapy kills non-CSCs while sparing pre-existing CSCs. However, evidence is emerging that suggests non-CSCs can be induced into a transient, drug-tolerant, CSC-like state by chemotherapy. The ability to transition between distinct cell states may be as critical for the survival of tumor cells following therapy as it is for metastatic progression. Therefore, inhibition of the pathways that promote E-M and CSC plasticity may suppress tumor recurrence following chemotherapy. Here, we review the emerging appreciation for how plasticity confers therapeutic resistance and tumor recurrence. PMID- 26742078 TI - Subversion of Host Innate Immunity by Uropathogenic Escherichia coli. AB - Uropathogenic Escherichia coli (UPEC) cause the majority of community-onset urinary tract infections (UTI) and represent a major etiologic agent of healthcare-associated UTI. Introduction of UPEC into the mammalian urinary tract evokes a well-described inflammatory response, comprising pro-inflammatory cytokines and chemokines as well as cellular elements (neutrophils and macrophages). In human UTI, this inflammatory response contributes to symptomatology and provides means for diagnosis by standard clinical testing. Early in acute cystitis, as demonstrated in murine models, UPEC gains access to an intracellular niche that protects a population of replicating bacteria from arriving phagocytes. To ensure the establishment of this protected niche, UPEC employ multiple strategies to attenuate and delay the initiation of host inflammatory components, including epithelial secretion of chemoattractants. Recent work has also revealed novel mechanisms by which UPEC blunts neutrophil migration across infected uroepithelium. Taken together, these attributes distinguish UPEC from commensal and nonpathogenic E. coli strains. This review highlights the unique immune evasion and suppression strategies of this bacterial pathogen and offers directions for further study; molecular understanding of these mechanisms will inform the development of adjunctive, anti-virulence therapeutics for UTI. PMID- 26742080 TI - Asymptomatic Bacteriuria in Clinical Urological Practice: Preoperative Control of Bacteriuria and Management of Recurrent UTI. AB - Asymptomatic bacteriuria (ABU) is a common clinical condition that often leads to unnecessary antimicrobial use. The reduction of antibiotic overuse for ABU is consequently an important issue for antimicrobial stewardship and to reduce the emergence of multidrug resistant strains. There are two issues in everyday urological practice that require special attention: the role of ABU in pre operative prophylaxis and in women affected by recurrent urinary tract infections (rUTIs). Nowadays, this is the time to think over our practice and change our way of thinking. Here, we aimed to summarize the current literature knowledge in terms of ABU management in patients undergoing urological surgery and in patients with rUTIs. In the last years, the approach to patient with ABU has changed totally. Prior to all surgical procedures that do not enter the urinary tract, ABU is generally not considered as a risk factor, and screening and treatment are not considered necessary. On the other hand, in the case of all procedures entering the urinary tract, ABU should be treated in line with the results of a urine culture obtained before the procedure. In patients affected by rUTIs, ABU can even have a protective role in preventing symptomatic recurrence, particularly when Enterococcus faecalis (E. faecalis) has been isolated. PMID- 26742081 TI - Influences of Maternal Care on Chicken Welfare. AB - In domestic chickens, the provision of maternal care strongly influences the behavioural development of chicks. Mother hens play an important role in directing their chicks' behaviour and are able to buffer their chicks' response to stressors. Chicks imprint upon their mother, who is key in directing the chicks' behaviour and in allowing them to develop food preferences. Chicks reared by a mother hen are less fearful and show higher levels of behavioural synchronisation than chicks reared artificially. In a commercial setting, more fearful chicks with unsynchronised behaviour are more likely to develop behavioural problems, such as feather pecking. As well as being an inherent welfare problem, fear can also lead to panic responses, smothering, and fractured bones. Despite the beneficial effects of brooding, it is not commercially viable to allow natural brooding on farms and so chicks are hatched in large incubators and reared artificially, without a mother hen. In this review we cover the literature demonstrating the important features of maternal care in domestic chickens, the behavioural consequences of deprivation and the welfare implications on commercial farms. We finish by suggesting ways to use research in natural maternal care to improve commercial chick rearing practice. PMID- 26742082 TI - An Overview of Insulin Pumps and Glucose Sensors for the Generalist. AB - Continuous subcutaneous insulin, or the insulin pump, has gained popularity and sophistication as a near-physiologic programmable method of insulin delivery that is flexible and lifestyle-friendly. The introduction of continuous monitoring with glucose sensors provides unprecedented access to, and prediction of, a patient's blood glucose levels. Efforts are underway to integrate the two technologies, from "sensor-augmented" and "sensor-driven" pumps to a fully automated and independent sensing-and-delivery system. Implantable pumps and an early-phase "bionic pancreas" are also in active development. Fine-tuned "pancreas replacement" promises to be one of the many avenues that offers hope for individuals suffering from diabetes. Although endocrinologists and diabetes specialists will continue to maintain expertise in this field, it behooves the primary care physician to have a working knowledge of insulin pumps and sensors to ensure optimal clinical care and decision-making for their patients. PMID- 26742083 TI - Disease Transmission by Misfolded Prion-Protein Isoforms, Prion-Like Amyloids, Functional Amyloids and the Central Dogma. AB - In 1982, the term "prions" (proteinaceous infectious particles) was coined to specify a new principle of infection. A misfolded isoform of a cellular protein has been described as the causative agent of a fatal neurodegenerative disease. At the beginning of prion research scientists assumed that the infectious agent causing transmissible spongiform encephalopathy (TSE) was a virus, but some unconventional properties of these pathogens were difficult to bring in line with the prevailing viral model. The discovery that prions (obviously devoid of any coding nucleic acid) can store and transmit information similarly to DNA was initially even denoted as being "heretical" but is nowadays mainly accepted by the scientific community. This review describes, from a historical point of view, how the "protein-only hypothesis" expands the Central Dogma. Definition of both, the prion principle and the Central Dogma, have been essential steps to understand information storage and transfer within and among cells and organisms. Furthermore, the current understanding of the infectivity of prion-proteins after misfolding is summarized succinctly. Finally, prion-like amyloids and functional amyloids, as found in yeast and bacteria, will be discussed. PMID- 26742085 TI - Conserved aromatic residues as determinants in the folding and assembly of immunoglobulin variable domains. AB - Detailed analysis of amino acid distribution, focusing on the "framework" regions of both heavy- and light-chain variable immunoglobulin (Ig) domains, distinguished those conserved sequence elements shared by both heavy-chain (VH) and light-chain (VL) domains from those conserved determinants unique to either VH or VL domains alone. Mapping of conserved chemical functionality onto characterized PDB structures showed the analogous placement and utilization of shared determinants in VH and VL structures that are generally similar. Identical Arginine-Aspartic acid ion-pairs located symmetrically on the lateral surfaces of VH and VL domains, respectively, as well as paired glutamine residues that constitute a central contact site between VH and VL domains represent clearly shared molecular features. Three sites of shared aromaticity were found localized to symmetrical sites lining the inaccessible interface of the VH-VL duplex, suggesting an expanded role for strategically conserved aromatic residues from a postulated determinant of individual Ig domain folding to now implicate conserved aromatic sites in the subsequent multi-subunit assembly of native antibody superstructure. Differential domain-specific conservation, representing evolutionary diversification and molecular asymmetry between heavy- and light chain variable domains was limited, but included amino acids from each functional class and must be evaluated with regard to their possible involvement in heterologous aspects of IgV protein structure-function. PMID- 26742084 TI - Metabolic Flux Distribution during Defatting of Steatotic Human Hepatoma (HepG2) Cells. AB - Methods that rapidly decrease fat in steatotic hepatocytes may be helpful to recover severely fatty livers for transplantation. Defatting kinetics are highly dependent upon the extracellular medium composition; however, the pathways involved are poorly understood. Steatosis was induced in human hepatoma cells (HepG2) by exposure to high levels of free fatty acids, followed by defatting using plain medium containing no fatty acids, or medium supplemented with a cocktail of defatting agents previously described before. We measured the levels of 28 extracellular metabolites and intracellular triglyceride, and fed the data into a steady-state mass balance model to estimate strictly intracellular fluxes. We found that during defatting, triglyceride content decreased, while beta oxidation, the tricarboxylic acid cycle, and the urea cycle increased. These fluxes were augmented by defatting agents, and even more so by hyperoxic conditions. In all defatting conditions, the rate of extracellular glucose uptake/release was very small compared to the internal supply from glycogenolysis, and glycolysis remained highly active. Thus, in steatotic HepG2 cells, glycolysis and fatty acid oxidation may co-exist. Together, these pathways generate reducing equivalents that are supplied to mitochondrial oxidative phosphorylation. PMID- 26742088 TI - When should I be considering home oxygen for my patients? AB - The ability to provide oxygen in a patient's home can offer enormous benefits, including improvements in life expectancy when given in the appropriate setting. Confusingly, however, home oxygen is available in many forms, including long-term oxygen therapy (LTOT), ambulatory oxygen therapy (AOT), palliative oxygen therapy (POT) and short-burst oxygen therapy (SBOT)-each with varying degrees of supporting evidence. The British Thoracic Society (BTS) has recently published new guidance on home oxygen therapy, after collating the available evidence. This article aims to summarise those guidelines, focusing on who should and should not be considered for oxygen therapy. Although the BTS guidelines target a UK audience, many of the principles covered below are applicable internationally, even if the availability of certain oxygen modalities and supporting service arrangements may vary between different healthcare systems. PMID- 26742089 TI - Strain tuning of the charge density wave in monolayer and bilayer 1T-TaS2. AB - Using first-principles calculations, we investigate the strain effects on the charge density wave states of monolayer and bilayer 1T-TaS2. The modified stability of the charge density wave in the monolayer is understood in terms of the strain dependent electron localization, which determines the distortion amplitude. On the other hand, in the bilayer, the effect of strain on the interlayer interaction is also crucial. The rich phase diagram under strain opens new venues for applications of 1T-TaS2. We interpret the experimentally observed insulating state of bulk 1T-TaS2 as inherited from the monolayer by effective interlayer decoupling. PMID- 26742086 TI - Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity. AB - The mammalian target of rapamycin complex 1 (mTORC1) is the key signaling hub that regulates cellular protein homeostasis, growth, and proliferation in health and disease. As a prerequisite for activation of mTORC1 by hormones and mitogens, there first has to be an available pool of intracellular amino acids. Arginine, an amino acid essential during mammalian embryogenesis and early development is one of the key activators of mTORC1. Herein, we demonstrate that arginine acts independently of its metabolism to allow maximal activation of mTORC1 by growth factors via a mechanism that does not involve regulation of mTORC1 localization to lysosomes. Instead, arginine specifically suppresses lysosomal localization of the TSC complex and interaction with its target small GTPase protein, Rheb. By interfering with TSC-Rheb complex, arginine relieves allosteric inhibition of Rheb by TSC. Arginine cooperates with growth factor signaling which further promotes dissociation of TSC2 from lysosomes and activation of mTORC1. Arginine is the main amino acid sensed by the mTORC1 pathway in several cell types including human embryonic stem cells (hESCs). Dependence on arginine is maintained once hESCs are differentiated to fibroblasts, neurons, and hepatocytes, highlighting the fundamental importance of arginine-sensing to mTORC1 signaling. Together, our data provide evidence that different growth promoting cues cooperate to a greater extent than previously recognized to achieve tight spatial and temporal regulation of mTORC1 signaling. PMID- 26742087 TI - Dendritic mitochondria reach stable positions during circuit development. AB - Mitochondria move throughout neuronal dendrites and localize to sites of energy demand. The prevailing view of dendritic mitochondria as highly motile organelles whose distribution is continually adjusted by neuronal activity via Ca(2+) dependent arrests is based on observations in cultured neurons exposed to artificial stimuli. Here, we analyze the movements of mitochondria in ganglion cell dendrites in the intact retina. We find that whereas during development 30% of mitochondria are motile at any time, as dendrites mature, mitochondria all but stop moving and localize stably to synapses and branch points. Neither spontaneous nor sensory-evoked activity and Ca(2+) transients alter motility of dendritic mitochondria; and pathological hyperactivity in a mouse model of retinal degeneration elevates rather than reduces motility. Thus, our findings indicate that dendritic mitochondria reach stable positions during a critical developmental period of high motility, and challenge current views about the role of activity in regulating mitochondrial transport in dendrites. PMID- 26742090 TI - Lead accumulation reduces photosynthesis in the lead hyper-accumulator Salvinia minima Baker by affecting the cell membrane and inducing stomatal closure. AB - Salvinia minima Baker accumulates a fair amount of lead in its tissues; however, no studies have investigated the effect of lead on the physiological processes that affect photosynthesis in this species. The objective of the present study was to assess whether the high amounts of lead accumulated by S. minima can affect its photosynthetic apparatus. The physiological changes in the roots and leaves in response to lead accumulation were analyzed. An exposure to 40 MUM Pb(NO3)2 for 24 h (first stage) was sufficient to reduce the photosynthetic rate (Pn) by 44%. This reduction in Pn was apparently the result of processes at various levels, including damage to the cell membranes (mainly in roots). Interestingly, although the plants were transferred to fresh medium without lead for an additional 24 h (second stage), Pn not only remained low, but was reduced even further, which was apparently related to stomatal closure, and may have led to reduced CO2 availability. Therefore, it can be concluded that lead exposure first decreases the photosynthetic rate by damaging the root membrane and then induces stomatal closure, resulting in decreased CO2 availability. PMID- 26742093 TI - School experiences may be important determinants of mental health problems in middle childhood - a Swedish longitudinal population-based study. AB - AIM: Little is known about the association between school experiences and mental health in young schoolchildren. This study explored the cross-sectional and prospective associations between children's school experiences and mental health in middle childhood. METHODS: We gathered comprehensive population-based data on the school experiences and mental health of 592 schoolchildren attending grades three and six in Sweden (ages approximately nine and 12 years). The KIDSCREEN questionnaire was used to measure school experiences in both age groups while the Child Behavior Checklist and the Strengths and Difficulties Questionnaire measured mental health in grades three and six, respectively. RESULTS: Children with problematic school experiences in grade three had an approximately two times higher odds for concurrent total, internalised, externalised, attention hyperactivity and social problems. They also had a 1.5-2.5 higher odds for these mental health problems three years later. Likewise, there was an association between problematic school experiences in grade three and lower levels of prosocial behaviour three years later. These associations were shown in both boys and girls, but were particularly pronounced in girls. CONCLUSION: This study indicated that school experiences in young schoolchildren may be important determinants of concurrent and later mental health problems. PMID- 26742094 TI - On-chip discrimination of orbital angular momentum of light with plasmonic nanoslits. AB - The orbital angular momentum (OAM) of light can be taken as an independent and orthogonal degree of freedom for multiplexing in an optical communication system, potentially improving the system capacity to hundreds of Tbits per second. The high compactness and miniaturization of devices required for optical communications impose strict requirements on discriminating OAM modes of light at a small (micro- or even nano-meter) scale for demultiplexing; these requirements represent a challenge for traditional OAM sorting strategies. Here, we propose a semi-ring plasmonic nanoslit to directly and spatially sort various OAM modes of light into ~120 nm-spaced mode intervals on the metallic surface. Making use of the constructive interference of a helical-phase modulated surface wave excited by a vortex beam, this on-chip interval can be stably demonstrated both theoretically and experimentally with a quasi-linear dependence on the plasmonic wavelength. Furthermore, its immunity to semi-ring geometry (i.e., the radius and number of rings) is verified by simulations. As a result, OAM discriminating is guaranteed by this stable sorting function. This technique shows a viable solution to discriminate the OAM of light at the nano-scale and might lead to broad benefits across the fields of optical communications, plasmonic physics and singular optics. PMID- 26742095 TI - Target-protected dumbbell molecular probe mediated cascade rolling circle amplification strategy for the sensitive assay of DNA methyltransferase activity. AB - A novel fluorescence detection system was developed for DNA methyltransferase (MTase) activity assay based on a target-protected dumbbell molecular probe mediated cascade rolling circle amplification. It showed excellent specificity and sensitivity with a detection limit of 0.0024 U mL(-1), and potential application in quantitatively monitoring MTase activity and screening of anticancer drugs. PMID- 26742096 TI - Wolff-Parkinson-White Syndrome in a Term Infant Presenting With Cardiopulmonary Arrest. AB - BACKGROUND: Wolff-Parkinson-White syndrome is a congenital abnormality of the cardiac conduction system caused by the presence of an abnormal accessory electrical pathway between the atria and the ventricles. This can result in intermittent tachyarrhythmias such as supraventricular tachycardia. In rare occasions, sudden death may occur from atrial fibrillation with rapid ventricular conduction. Supraventricular tachycardia typically has a sudden onset and offset, classified as a paroxysmal arrhythmia. Because of the variable occurrence, Wolff Parkinson-White syndrome may go undiagnosed in the immediate newborn period. PURPOSE: To highlight arrhythmia as a possible cause of sudden decompensation in infants. CASE FINDINGS/RESULTS: The clinical presentation of this infant is complex and a number of potential diagnoses were considered. Preexcitation on electrocardiogram resulted in the diagnosis of Wolff-Parkinson-White syndrome. IMPLICATIONS FOR PRACTICE: Nurses caring for infants should be alert to tachycardia and irregularities of the heart rate, including those in the prenatal history, and should report them for evaluation. While all parents should be taught to watch for signs of illness, parents of infants with Wolff-Parkinson White have additional learning needs, including recognizing early signs and symptoms of heart failure. PMID- 26742097 TI - The Future of Neonatal Advanced Practice Registered Nurse Practice: White Paper. AB - In recent years, the National Association of Neonatal Nurses and the National Association of Neonatal Nurse Practitioners have been monitoring aspects of neonatal advanced practice nursing and providing leadership and advocacy to address concerns related to workforce, education, competency, fatigue, safety, and scope of practice. This white paper discusses current barriers within neonatal advanced practice registered nurse practice as well as strategies to promote the longevity of the neonatal advanced practice registered nurse roles. PMID- 26742098 TI - Prefrontal glutamate correlates of methamphetamine sensitization and preference. AB - Methamphetamine (MA) is a widely misused, highly addictive psychostimulant that elicits pronounced deficits in neurocognitive function related to hypo functioning of the prefrontal cortex (PFC). Our understanding of how repeated MA impacts excitatory glutamatergic transmission within the PFC is limited, as is information about the relationship between PFC glutamate and addiction vulnerability/resiliency. In vivo microdialysis and immunoblotting studies characterized the effects of MA (ten injections of 2 mg/kg, i.p.) upon extracellular glutamate in C57BL/6J mice and upon glutamate receptor and transporter expression, within the medial PFC. Glutamatergic correlates of both genetic and idiopathic variance in MA preference/intake were determined through studies of high vs. low MA-drinking selectively bred mouse lines (MAHDR vs. MALDR, respectively) and inbred C57BL/6J mice exhibiting spontaneously divergent place-conditioning phenotypes. Repeated MA sensitized drug-induced glutamate release and lowered indices of N-methyl-d-aspartate receptor expression in C57BL/6J mice, but did not alter basal extracellular glutamate content or total protein expression of Homer proteins, or metabotropic or alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid glutamate receptors. Elevated basal glutamate, blunted MA-induced glutamate release and ERK activation, as well as reduced protein expression of mGlu2/3 and Homer2a/b were all correlated biochemical traits of selection for high vs. low MA drinking, and Homer2a/b levels were inversely correlated with the motivational valence of MA in C57BL/6J mice. These data provide novel evidence that repeated, low-dose MA is sufficient to perturb pre- and post-synaptic aspects of glutamate transmission within the medial PFC and that glutamate anomalies within this region may contribute to both genetic and idiopathic variance in MA addiction vulnerability/resiliency. PMID- 26742099 TI - Development of a Larvicidal Nanoemulsion with Pterodon emarginatus Vogel Oil. AB - Pterodon emarginatus Vogel is a Brazilian species that belongs to the family Fabaceae, popularly known as sucupira. Its oil has several biological activities, including potent larvicidal property against Aedes aegypti. This insect is the vector of dengue, a tropical disease that has been considered a critical health problem in developing countries, such as Brazil. Most of dengue control methods involve larvicidal agents suspended or diluted in water and making active lipophilic natural products available is therefore considered a technological challenge. In this context, nanoemulsions appear as viable alternatives to solve this major problem. The present study describes the development of a novel nanoemulsion with larvicidal activity against A. aegypti along with the required Hydrophile Lipophile Balance determination of this oil. It was suggested that the mechanism of action might involve reversible inhibition of acetylcholinesterase and our results also suggest that the P. emarginatus nanoemulsion is not toxic for mammals. Thus, it contributes significantly to alternative integrative practices of dengue control, as well as to develop sucupira based nanoproducts for application in aqueous media. PMID- 26742100 TI - Tumor Necrosis Factor, but Not Neutrophils, Alters the Metabolic Profile in Acute Experimental Arthritis. AB - Metabolic alterations are associated with arthritis apart from obesity. However, it is still unclear which is the underlying process behind these metabolic changes. Here, we investigate the role of tumor necrosis factor (TNF) in this process in an acute model of antigen-induced arthritis (AIA). Immunized male BALB/c mice received an intra-articular injection of PBS (control) or methylated bovine serum albumin (mBSA) into their knees, and were also pre-treated with different drugs: Etanercept, an anti-TNF drug, DF2156A, a CXCR1/2 receptor antagonist, or a monoclonal antibody RB6-8C5 to deplete neutrophils. Local challenge with mBSA evoked an acute neutrophil influx into the knee joint, and enhanced the joint nociception, along with a transient systemic metabolic alteration (higher levels of glucose and lipids, and altered adipocytokines). Pre treatment with the conventional biological Etanercept, an inhibitor of TNF action, ameliorated the nociception and the acute joint inflammation dominated by neutrophils, and markedly improved many of the altered systemic metabolites (glucose and lipids), adipocytokines and PTX3. However, the lessening of metabolic changes was not due to diminished accumulation of neutrophils in the joint by Etanercept. Reduction of neutrophil recruitment by pre-treating AIA mice with DF2156A, or even the depletion of these cells by using RB6-8C5 reduced all of the inflammatory parameters and hypernociception developed after AIA challenge, but could not prevent the metabolic changes. Therefore, the induction of joint inflammation provoked acute metabolic alterations which were involved with TNF. We suggest that the role of TNF in arthritis-associated metabolic changes is not due to local neutrophils, which are the major cells present in this model, but rather due to cytokines. PMID- 26742102 TI - Rice Seed Priming with Picomolar Rutin Enhances Rhizospheric Bacillus subtilis CIM Colonization and Plant Growth. AB - The effect of rutin, a bioflavonoid on the growth and biofilm formation of Bacillus subtilis strain CIM was investigated. In addition to swimming, swarming, and twitching potentials of B. subtilis CIM (BS), one picomolar (1 pM) of rutin was also observed to boost the biofilm forming ability of the bacterium. Bio priming of rice seeds with BS and rutin not only augmented root and shoot lengths but also the photosynthetic pigments like chlorophyll and carotenoid. Similarly, high accumulation of phenolic and flavonoid contents was observed in the leaves. Fluorescent microscopic images revealed that BS plus rutin enhanced callose deposition in the leaves. It was also established that the least formation of reactive oxygen species in BS plus rutin treated rice plants was due to higher free radicals scavenging activity and total antioxidant potential. The results highlight chemo attractant nature of BS towards rutin, which by enhancing biofilm formation and root colonization indirectly strengthened the plants' defensive state. PMID- 26742101 TI - Phosphorylation Regulates the Bound Structure of an Intrinsically Disordered Protein: The p53-TAZ2 Case. AB - Disordered regions and Intrinsically Disordered Proteins (IDPs) are involved in critical cellular processes and may acquire a stable three-dimensional structure only upon binding to their partners. IDPs may follow a folding-after-binding process, known as induced folding, or a folding-before-binding process, known as conformational selection. The transcription factor p53 is involved in the regulation of cellular events that arise upon stress or DNA damage. The p53 domain structure is composed of an N-terminal transactivation domain (p53TAD), a DNA Binding Domain and a tetramerization domain. The activity of TAD is tightly regulated by interactions with cofactors, inhibitors and phosphorylation. To initiate transcription, p53TAD binds to the TAZ2 domain of CBP, a co transcription factor, and undergoes a folding and binding process, as revealed by the recent NMR structure of the complex. The activity of p53 is regulated by phosphorylation at multiple sites on the TAD domain and recent studies have shown that modifications at three residues affect the binding towards TAZ2. However, we still do not know how these phosphorylations affect the structure of the bound state and, therefore, how they regulate the p53 function. In this work, we have used computational simulations to understand how phosphorylation affects the structure of the p53TAD:TAZ2 complex and regulates the recognition mechanism. Phosphorylation has been proposed to enhance binding by direct interaction with the folded protein or by changing the unbound conformation of IDPs, for example by pre-folding the protein favoring the recognition mechanism. Here, we show an interesting turn in the p53 case: phosphorylation mainly affects the bound structure of p53TAD, highlighting the complexity of IDP protein-protein interactions. Our results are in agreement with previous experimental studies, allowing a clear picture of how p53 is regulated by phosphorylation and giving new insights into how post-translational modifications can regulate the function of IDPs. PMID- 26742103 TI - Influences of State and Trait Affect on Behavior, Feedback-Related Negativity, and P3b in the Ultimatum Game. AB - The present study investigates how different emotions can alter social bargaining behavior. An important paradigm to study social bargaining is the Ultimatum Game. There, a proposer gets a pot of money and has to offer part of it to a responder. If the responder accepts, both players get the money as proposed by the proposer. If he rejects, none of the players gets anything. Rational choice models would predict that responders accept all offers above 0. However, evidence shows that responders typically reject a large proportion of all unfair offers. We analyzed participants' behavior when they played the Ultimatum Game as responders and simultaneously collected electroencephalogram data in order to quantify the feedback-related negativity and P3b components. We induced state affect (momentarily emotions unrelated to the task) via short movie clips and measured trait affect (longer-lasting emotional dispositions) via questionnaires. State happiness led to increased acceptance rates of very unfair offers. Regarding neurophysiology, we found that unfair offers elicited larger feedback-related negativity amplitudes than fair offers. Additionally, an interaction of state and trait affect occurred: high trait negative affect (subsuming a variety of aversive mood states) led to increased feedback-related negativity amplitudes when participants were in an angry mood, but not if they currently experienced fear or happiness. We discuss that increased rumination might be responsible for this result, which might not occur, however, when people experience happiness or fear. Apart from that, we found that fair offers elicited larger P3b components than unfair offers, which might reflect increased pleasure in response to fair offers. Moreover, high trait negative affect was associated with decreased P3b amplitudes, potentially reflecting decreased motivation to engage in activities. We discuss implications of our results in the light of theories and research on depression and anxiety. PMID- 26742104 TI - Single-Trial Extraction of Pure Somatosensory Evoked Potential Based on Expectation Maximization Approach. AB - It is of great importance for intraoperative monitoring to accurately extract somatosensory evoked potentials (SEPs) and track its changes fast. Currently, multi-trial averaging is widely adopted for SEP signal extraction. However, because of the loss of variations related to SEP features across different trials, the estimated SEPs in such a way are not suitable for the purpose of real time monitoring of every single trial of SEP. In order to handle this issue, a number of single-trial SEP extraction approaches have been developed in the literature, such as ARX and SOBI, but most of them have their performance limited due to not sufficient utilization of multi-trial and multi-condition structures of the signals. In this paper, a novel Bayesian model of SEP signals is proposed to make systemic use of multi-trial and multi-condition priors and other structural information in the signal by integrating both a cortical source propagation model and a SEP basis components model, and an Expectation Maximization (EM) algorithm is developed for single-trial SEP estimation under this model. Numerical simulations demonstrate that the developed method can provide reasonably good single-trial estimations of SEP as long as signal-to noise ratio (SNR) of the measurements is no worse than -25 dB. The effectiveness of the proposed method is further verified by its application to real SEP measurements of a number of different subjects during spinal surgeries. It is observed that using the proposed approach the main SEP features (i.e., latencies) can be reliably estimated at single-trial basis, and thus the variation of latencies in different trials can be traced, which provides a solid support for surgical intraoperative monitoring. PMID- 26742105 TI - SOD Enzymes and Microbial Pathogens: Surviving the Oxidative Storm of Infection. PMID- 26742106 TI - A Rapid Protocol of Crude RNA/DNA Extraction for RT-qPCR Detection and Quantification of 'Candidatus Phytoplasma prunorum'. AB - Many efforts have been made to develop a rapid and sensitive method for phytoplasma and virus detection. Taking our cue from previous works, different rapid sample preparation methods have been tested and applied to Candidatus Phytoplasma prunorum ('Ca. P. prunorum') detection by RT-qPCR. A duplex RT-qPCR has been optimized using the crude sap as a template to simultaneously amplify a fragment of 16S rRNA of the pathogen and 18S rRNA of the host plant. The specific plant 18S rRNA internal control allows comparison and relative quantification of samples. A comparison between DNA and RNA contribution to qPCR detection is provided, showing higher contribution of the latter. The method presented here has been validated on more than a hundred samples of apricot, plum and peach trees. Since 2013, this method has been successfully applied to monitor 'Ca. P. prunorum' infections in field and nursery. A triplex RT-qPCR assay has also been optimized to simultaneously detect 'Ca. P. prunorum' and Plum pox virus (PPV) in Prunus. PMID- 26742107 TI - A Novel Fixation Method for Variable-Sized Endoscopic Submucosal Dissection Specimens: An In Vitro Animal Experiment. AB - BACKGROUND: Endoscopic submucosal dissection is considered a curative and minimally invasive treatment for early gastric cancer; however, precise pathologic assessment of resected specimens is required to develop further treatment plans. Human error during specimen handling can affect objective assessment of resected specimens. In this study, we investigated whether a novel tissue fixation device offered more objective and standardized pathologic evaluation than conventional manual tissue fixation. METHODS: We developed a novel tissue fixation device for endoscopic submucosal dissection specimens. Two circular tissue samples 2, 3, and 4 cm in diameter were obtained from the body of 45 porcine stomachs. One specimen sample was placed in a fixation device; the other was manually fixed on corkboard. We used a pressure indicator to ensure constant pressure in the resected specimens in the fixation device. We measured submucosal diameter and thickness after 24 hr. RESULTS: The diameters for 2, 3, and 4 cm resected tissue samples were 23.85, 32.30, and 45.0 mm and 21.0, 32.0, and 44.50 mm for the fixation device and manual pinning groups, respectively. The submucosal thicknesses in the fixation device group were 397.09, 381.43, and 415.51 MUm and 393.76, 529.69, and 603.82 MUm by manual pinning for 2, 3, and 4 cm tissue samples, respectively. Analysis of standard deviation revealed that the submucosal thickness in the manual fixation group was much more variable than in the fixation device group (p = 0.012, 0.042, and 0.001 for 2, 3, and 4 cm tissue specimens, respectively; Fligner-Killeen test of homogeneity of variances). CONCLUSIONS: Among variously sized resected tissue specimens, submucosal thicknesses were more variable in the conventional fixation group, while the thicknesses were comparatively consistent in the fixation device group. After endoscopic submucosal dissection, pathologic preparation using this fixation device could offer more objective assessment of specimens. PMID- 26742108 TI - Diagnostic Delay of Endometriosis in the Netherlands. AB - BACKGROUND/AIMS: Endometriosis has a long diagnostic delay that is influenced by varying socio-economic and healthcare factors. In the Dutch situation, these factors are not yet identified. The aim of this study is to determine the length of the diagnostic delay of endometriosis in the Netherlands and to identify which variables affect this delay. METHODS: A retrospective study among 139 patients diagnosed with endometriosis in a secondary care hospital with a specialized multidisciplinary endometriosis team. The diagnostic process was evaluated using a questionnaire-guided telephonic interview. RESULTS: The median time interval from the onset of symptoms to diagnosis was 89 months or 7.4 years, divided in 7 months patient delay, 35 months general practitioner (GP) delay and 5 months gynecologist delay. Determinants for a longer diagnostic delay were young age at onset of symptoms, use of oral contraceptives or analgesics prescribed by GP, alternative diagnoses considered by the GP, and cyclic symptoms. Subfertility as presenting symptom resulted in faster diagnosis. CONCLUSION: This study shows that the time interval to the diagnosis of endometriosis is long and mainly consists of the period of time the woman consults her first line medical professional. PMID- 26742111 TI - Beyond Pilots: Scaling and Spreading Innovation in Healthcare. PMID- 26742112 TI - Migrants, Manpower and Math in the Coming Europe. AB - "A dead child" said stalin "is a tragedy. Two million are a statistic." A single photograph of a beach riveted world attention, converting syrian refugees from statistics to tragedy. But the statistics remain. Three Canadian columnists have offered contrasting interpretations. Eric Reguly argues that a static and aging Europe needs more manpower to sustain its economy. Margaret Wente, however, observes the failure of integration of migrants in Sweden. Migrants are drawn by open borders and a generous welfare state, but do not fit an advanced, high-skill economy. Gwynne Dyer notes that current inflows, IF evenly distributed, are a tiny proportion of the overall European Union. But economic migrants from Africa are a much larger issue. Their numbers are effectively inexhaustible. PMID- 26742110 TI - Stochastic Measurement Models for Quantifying Lymphocyte Responses Using Flow Cytometry. AB - Adaptive immune responses are complex dynamic processes whereby B and T cells undergo division and differentiation triggered by pathogenic stimuli. Deregulation of the response can lead to severe consequences for the host organism ranging from immune deficiencies to autoimmunity. Tracking cell division and differentiation by flow cytometry using fluorescent probes is a major method for measuring progression of lymphocyte responses, both in vitro and in vivo. In turn, mathematical modeling of cell numbers derived from such measurements has led to significant biological discoveries, and plays an increasingly important role in lymphocyte research. Fitting an appropriate parameterized model to such data is the goal of these studies but significant challenges are presented by the variability in measurements. This variation results from the sum of experimental noise and intrinsic probabilistic differences in cells and is difficult to characterize analytically. Current model fitting methods adopt different simplifying assumptions to describe the distribution of such measurements and these assumptions have not been tested directly. To help inform the choice and application of appropriate methods of model fitting to such data we studied the errors associated with flow cytometry measurements from a wide variety of experiments. We found that the mean and variance of the noise were related by a power law with an exponent between 1.3 and 1.8 for different datasets. This violated the assumptions inherent to commonly used least squares, linear variance scaling and log-transformation based methods. As a result of these findings we propose a new measurement model that we justify both theoretically, from the maximum entropy standpoint, and empirically using collected data. Our evaluation suggests that the new model can be reliably used for model fitting across a variety of conditions. Our work provides a foundation for modeling measurements in flow cytometry experiments thus facilitating progress in quantitative studies of lymphocyte responses. PMID- 26742113 TI - The Personal Support Worker Program Standard in Ontario: An Alternative to Self Regulation? AB - Personal support workers (PSWS) provide hands-on assistance in a variety of long term care and community settings. The question of whether psws should become regulated similar to other self-regulating health professions is a perennial concern in policy circles, especially because of the intimate nature of their work and the potential for abuse of clients and workers. This article explores a chain of policy decisions around psws in ontario culminating in the creation of a common educational standard for psw programs, titled the psw program standard. We argue that these policy developments may represent an alternative pathway to self regulation of an essential workforce. PMID- 26742114 TI - Incorporating Group Medical Visits into Primary Healthcare: Are There Benefits? AB - OBJECTIVE: Group medical visits (GMVs) have been touted as an innovation to effectively and efficiently provide primary healthcare (PHC) services. The purpose of this paper is to report whether GMVs have tangible benefits for providers and patients. METHODS: This descriptive study included in-depth interviews with patients attending and providers facilitating GMVs and direct observation. Five primary care practices in rural towns and four First Nations communities participated. This paper reports on an analysis of interviews and observations. RESULTS: Thirty-four providers and 29 patients were interviewed. Patient participants were an average of 62 years old, mostly female and married. The three most common chronic conditions reported by patients were diabetes (n = 9), high blood pressure (n = 8) and arthritis (n = 7). Three themes illustrated how GMVs: (1) can foster access to needed health services; (2) expand opportunities for collaboration and team-based care; and (3) improve patient and provider experiences. A fourth theme captured structural challenges in delivering GMVs. DISCUSSION: There are tangible benefits in delivering GMVs in PHC. While whole patient panels can benefit from the integration of GMVs into practice, those who could gain the most are patients with complex medical and social needs. GMVs provide an opportunity to enhance PHC, strengthening the system particularly for patients with chronic conditions. PMID- 26742115 TI - Barriers and Facilitators for Primary Care Reform in Canada: Results from a Deliberative Synthesis across Five Provinces. AB - INTRODUCTION: Since 2000, primary care (PC) reforms have been implemented in various Canadian provinces. Emerging organizational models and policies are at various levels of implementation across jurisdictions. Few cross-provincial analyses of these reforms have been realized. The aim of this study is to identify the factors that have facilitated or hindered implementation of reforms in Canadian provinces between 2000 and 2010. METHODS: A literature and policy scan identified evaluation studies across Canadian jurisdictions. Experts from British Columbia, Manitoba, Nova Scotia, Ontario and Quebec were asked to review the scope of published evaluations and draft provincial case descriptions. A one day deliberative forum was held, bringing together researchers (n = 40) and decision-makers (n = 20) from all the participating provinces. RESULTS: Despite a relative lack of published evaluations, our results suggest that PC reform has varied with regard to the scope and the policy levers used to implement change. Some provinces implemented specific PC models, while other provinces designed overarching policies aiming at changing professional behaviour and practice. The main perceived barriers to reform were the lack of financial investment, resistance from professional associations, too overtly prescriptive approaches lacking adaptability and an overly centralized governance model. The main perceived facilitators were a strong financial commitment using various allocation and payment approaches, the cooperation of professional associations and an incremental emergent change philosophy based on a strong decentralization of decisions allowing adaptation to local circumstances. So far the most beneficial results of the reforms seem to be an increase in patients' affiliation with a usual source of care, improved experience of care by patients and a higher workforce satisfaction. CONCLUSION: PC reforms currently under consideration in other jurisdictions could learn from the factors identified as promoting or hindering change in the provinces that have been most proactive. PMID- 26742109 TI - ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. PMID- 26742117 TI - An Evaluation of In-Person and Online Engagement in Central Newfoundland. AB - BACKGROUND: This study evaluates the use of in-person focus groups and online engagement within the context of a large public engagement initiative conducted in rural Newfoundland. METHODS: Participants were surveyed about their engagement experience and demographic information. Pre and post key informant interviews were also conducted with organizers of the initiative. RESULTS: Of the 111 participants in the focus groups, 97 (87%) completed evaluation surveys; as did 23 (88%) out of 26 online engagement participants. Overall, focus group participants were positive about their involvement, with 87.4% reporting that they would participate in a similar initiative. Online participation was below expectations and these participants viewed their experience less positively than in-person participants. Organizers viewed the engagement initiative and the combined use of online and in-person engagement positively. CONCLUSIONS: This study presents a real-world example of the use of two methods of engagement. It also highlights the importance of the successful execution of whatever engagement mechanism is selected. PMID- 26742116 TI - Inter-Provincial Migration Intentions of Family Physicians in Canada: The Roles of Income and Community Characteristics. AB - The inter-provincial migration patterns of family physicians in canada show that some provinces like newfoundland and saskatchewan experience persistent net out migration, while others, including ontario and british columbia, are destinations more often than origins of migrants. Governments in provinces exhibiting net out migration have responded with a number of incentive and recruitment programs. In this study, we investigate the determinants of the stated interprovincial migration intentions of 3,995 rural and urban family physicians in the 2010 wave of the national physician survey. We consider a range of physician characteristics, community attributes and working conditions. We find that in the intention to move, higher compensation has a modest effect, while the community characteristics have a consistently important influence. Our results suggest that policy and program designers should acknowledge the critical role of community level living and working conditions in their family physician recruitment and retention efforts. PMID- 26742118 TI - From Policy to Practice: Implementation of Treatment for Substance Misuse in Quebec Primary Healthcare Clinics. AB - BACKGROUND AND OBJECTIVES: In 2007, the Quebec Ministry of Health issued a policy document that specifically mandated the development of addiction treatment services including screening, brief interventions and referral (SBIR) to be delivered by primary healthcare clinics throughout Quebec. The current study examined the level of implementation of SBIR one year following the end of the mandate (2007-2012). APPROACH: Semi-structured interviews were conducted with 45 participants from 21 primary health and social service centres throughout the province. Qualitative analysis was used to evaluate the level of success each centre had in implementing SBIR and to identify organizational measures that contributed to successful implementation. RESULTS: The results show that Quebec primary health and social service centres had limited success in their efforts to integrate SBIR into their services. A comparative analysis of the centres, categorized according to their level of implementation, revealed the presence of significant organizational- and staff-level factors, including the creation of formal action plans that were conducive to the successful implementation of SBIR in primary care. CONCLUSION: The findings highlight the importance of offering support and guidance, as well as a menu of specific practices that are likely to assist primary health and social services centres to implement SBIR. At the organizational level, the adoption of local action plans and formal service trajectories offers a framework that allows for horizontal and vertical integration of new practices. PMID- 26742120 TI - Development of Biomarkers Based on DNA Methylation in the NCAPH2/LMF2 Promoter Region for Diagnosis of Alzheimer's Disease and Amnesic Mild Cognitive Impairment. AB - From the standpoint of early interventions for dementia, a convenient method of diagnosis using biomarkers is required for Alzheimer's disease (AD) in the early stage as well as amnesic mild cognitive impairment (aMCI). Focusing on differences in DNA methylation due to AD and aMCI, in the present study, we first conducted genome-wide screening, measuring blood DNA methylation levels by the Illumina Infinium HD Methylation Assay in 3 small age-and gender-matched groups consisting of 4 subjects each: normal controls (NC), aMCI and AD. The genome-wide analysis produced 11 DNA methylation loci that distinguished the 3 groups. For confirmation, we increased group sizes and examined samples by pyrosequencing which revealed that DNA methylation in the NCAPH2/LMF2 promoter region was significantly decreased in the AD (n = 30) and aMCI (n = 28) groups as compared to the NC group (n = 30) (P < 0.0001, ANCOVA). No association was found between methylation levels and APOE genotype. NCAPH2/LMF2 methylation levels were considered to potentially be a convenient and useful biomarker for diagnosis of AD and aMCI. PMID- 26742121 TI - Comparative Profiling of Triple-Negative Breast Carcinomas Tissue Glycoproteome by Sequential Purification of Glycoproteins and Stable Isotope Labeling. AB - BACKGROUND: Women with triple negative breast cancers (TNBCs) have a poor prognosis due to lack of suitable targeted therapies. Changes in the protein glycosylation are increasingly being recognized as an important modification associated with cancer etiology. METHODS: In an attempt to identify TNBC biomarkers with greater diagnostic and prognostic capabilities, hydrazide- based chemistry method combined with LC-MS/MS were used to purify and identify N-linked glycopeptides or glycoproteins of tissues from TNBC patients. RESULTS: A total of 550 unique N-linked glycoproteins were identified, among these proteins, 72 unique N-linked glycoproteins were significantly regulated in tumor tissues, of which 56 proteins were upregulated and 16 proteins were downregulated. To assess the validity of the results, three selected proteins including Vascular endothelial growth factor receptor 1, Insulin receptor, Tissue factor pathway inhibitor were selected for western blot analysis, and these proteins were found as potential biomarkers of TNBC. The top three pathways of differentially expressed glycoproteins participated in were caveolar-mediated endocytosis signaling, agrin interactions at neuromuscular junction and LXR/RXR activation. CONCLUSION: This work provides potential glycoprotein markers to function as a novel tissue-based biomarker for TNBC. PMID- 26742119 TI - Health System-Level Factors Influence the Implementation of Complex Innovations in Cancer Care. AB - BACKGROUND: The movement of new knowledge and tools into healthcare settings continues to be a slow, complex and poorly understood process. In this paper, we present the system-level factors important to the implementation of synoptic reporting tools in two initiatives (or cases) in Nova Scotia, Canada. METHODS: This study used case study methodology. Data were collected through interviews with key informants, document analysis, non-participant observation and tool use/examination. Analysis involved production of case histories, analysis of each case and a cross-case analysis. RESULTS: The healthcare system's delivery and support structure, information technology infrastructure, policy environment and history of collaboration and inter-organizational relationships influenced tool implementation in the two cases. CONCLUSIONS: The findings provide an in-depth, nuanced understanding of how healthcare system components can influence the implementation of a new tool in clinical practice. PMID- 26742122 TI - Physical Models for Simulation and Reconstruction of Human Tissue Deformation Fields in Dynamic MRI. AB - OBJECTIVE: Medical image registration can be formulated as a tissue deformation problem, where parameter estimation methods are used to obtain the inverse deformation. However, there is limited knowledge about the ability to recover an unknown deformation. The main objective of this study is to estimate the quality of a restored deformation field obtained from image registration of dynamic MR sequences. METHODS: We investigate the behavior of forward deformation models of various complexities. Further, we study the accuracy of restored inverse deformations generated by image registration. RESULTS: We found that the choice of 1) heterogeneous tissue parameters and 2) a poroelastic (instead of elastic) model had significant impact on the forward deformation. In the image registration problem, both 1) and 2) were found not to be significant. Here, the presence of image features were dominating the performance. We also found that existing algorithms will align images with high precision while at the same time obtain a deformation field with a relative error of 40%. CONCLUSION: Image registration can only moderately well restore the true deformation field. Still, estimation of volume changes instead of deformation fields can be fairly accurate and may represent a proxy for variations in tissue characteristics. Volume changes remain essentially unchanged under choice of discretization and the prevalence of pronounced image features. SIGNIFICANCE: We suggest that image registration of high-contrast MR images has potential to be used as a tool to produce imaging biomarkers sensitive to pathology affecting tissue stiffness. PMID- 26742123 TI - Insomnia Characterization: From Hypnogram to Graph Spectral Theory. AB - OBJECTIVE: To quantify and differentiate control and insomnia sleep onset patterns through biomedical signal processing of overnight polysomnograms. METHODS: The approach consisted of three tandem modules: 1) biosignal processing module, which used state-space time-varying autoregressive moving average (TVARMA) processes with recursive particle filter, 2) hypnogram generation module that implemented a fuzzy inference system (FIS), and 3) insomnia characterization module that discriminated between control and subjects with insomnia using a logistic regression model trained with a set of similarity measures ( d1, d2 , d3, d4). The study employed sleep onset periods from 16 control and 16 subjects with insomnia. RESULTS: State-spaced TVARMA processes with recursive particle filtering provided resilience to nonlinear, nonstationary, and non-Gaussian conditions of biosignals. FIS managed automated sleep scoring robust to intersubjects' and interraters' variability. The similarity distances quantified in a scalar measure the transitions amongst sleep onset stages, computed from expert and automated hypnograms. A statistical set of unpaired two-tailed t tests suggested that distances d1 , d2, and d3 had larger statistical significance ( ) to characterize sleeping patterns. The logistic regression model classified control and subjects with insomnia with sensitivity 87 % , specificity 75 %, and accuracy 81 %. CONCLUSION: Our approach can perform a supportive role in either biosignal processing, sleep staging, insomnia characterization, or all the previous, coping with time-consuming procedures and massive data volumes of standard protocols. SIGNIFICANCE: The introduction of graph spectral theory and logistic regression for the diagnosis of insomnia represents a novel concept, attempting to describe complex sleep dynamics throughout transitions networks and scalar measures. PMID- 26742124 TI - 3D Fast Automatic Segmentation of Kidney Based on Modified AAM and Random Forest. AB - In this paper, a fully automatic method is proposed to segment the kidney into multiple components: renal cortex, renal column, renal medulla and renal pelvis, in clinical 3D CT abdominal images. The proposed fast automatic segmentation method of kidney consists of two main parts: localization of renal cortex and segmentation of kidney components. In the localization of renal cortex phase, a method which fully combines 3D Generalized Hough Transform (GHT) and 3D Active Appearance Models (AAM) is applied to localize the renal cortex. In the segmentation of kidney components phase, a modified Random Forests (RF) method is proposed to segment the kidney into four components based on the result from localization phase. During the implementation, a multithreading technology is applied to speed up the segmentation process. The proposed method was evaluated on a clinical abdomen CT data set, including 37 contrast-enhanced volume data using leave-one-out strategy. The overall true-positive volume fraction and false positive volume fraction were 93.15%, 0.37% for renal cortex segmentation; 83.09%, 0.97% for renal column segmentation; 81.92%, 0.55% for renal medulla segmentation; and 80.28%, 0.30% for renal pelvis segmentation, respectively. The average computational time of segmenting kidney into four components took 20 seconds. PMID- 26742125 TI - Computer-Assisted Screw Size and Insertion Trajectory Planning for Pedicle Screw Placement Surgery. AB - Pathological conditions that cause instability of the spine are commonly treated by vertebral fixation involving pedicle screw placement surgery. However, existing methods for preoperative planning are based only on geometrical properties of vertebral structures (i.e., shape) without taking into account their structural properties (i.e., appearance). We propose a novel automated method for computer-assisted preoperative planning of the thoracic pedicle screw size and insertion trajectory. The proposed method extracts geometrical properties of vertebral structures by parametric modeling of vertebral bodies and pedicles in three dimensions (3D), and combines them with structural properties, evaluated through underlying image intensities in computed tomography (CT) images while considering the guidelines for pedicle screw design. The method was evaluated on 81 pedicles, obtained from 3D CT images of 11 patients that were appointed for pedicle screw placement surgery. In terms of mean absolute difference (MAD) and corresponding standard deviation (SD), the resulting high modeling accuracy of 0.39+/-0.31 mm for 3D vertebral body models and 0.31+/-0.25 mm for 3D pedicle models created an adequate anatomical frame for 3D pedicle screw models. When comparing the automatically obtained and manually defined plans for pedicle screw placement, a relatively high agreement was observed, with MAD +/-SD of 0.4+/-0.4 mm for the screw diameter, 5.8+/-4.2 mm for the screw length, 2.0+/-1.4 mm for the pedicle crossing point and 7.6+/-5.8( degrees ) for screw insertion angles. However, a statistically significant increase of 48+/-26% in the screw fastening strength in favor of the proposed automated method was observed in 99% of the cases. PMID- 26742126 TI - Continuous Magnetic Field Monitoring Using Rapid Re-Excitation of NMR Probe Sets. AB - MRI relies on static and spatially varying dynamic magnetic fields of high accuracy. NMR field probes permit the direct observation of spatiotemporal field dynamics for diverse purposes such as data correction, field control, sequence validation, and hardware characterization. However, due to probe signal decay and dephasing existing field cameras are limited in terms of readout duration and the extent of k -space that can be covered. The present work aims to overcome these limitations by the transition to short-lived NMR probes and rapid re-excitation. The proposed approach uses probes with T 2 so short that thermal relaxation dominates signal decay even in the presence of strongest gradients. They are integrated with transmit, receive and sequencing electronics that permit high rate re-excitation with optional probe alternation as well as complementary RF pulse recording. The system is demonstrated by monitoring of sample MRI sequences with long readouts and large gradient moments. It is compared with the conventional long-lived probe concept and characterized in terms of net sensitivity and sources of systematic error. Continuous k -space trajectory mapping is demonstrated and validated by trajectory-based image reconstruction. PMID- 26742129 TI - Neurite Tracing With Object Process. AB - In this paper we present a pipeline for automatic analysis of neuronal morphology: from detection, modeling to digital reconstruction. First, we present an automatic, unsupervised object detection framework using stochastic marked point process. It extracts connected neuronal networks by fitting special configuration of marked objects to the centreline of the neurite branches in the image volume giving us position, local width and orientation information. Semantic modeling of neuronal morphology in terms of critical nodes like bifurcations and terminals, generates various geometric and morphology descriptors such as branching index, branching angles, total neurite length, internodal lengths for statistical inference on characteristic neuronal features. From the detected branches we reconstruct neuronal tree morphology using robust and efficient numerical fast marching methods. We capture a mathematical model abstracting out the relevant position, shape and connectivity information about neuronal branches from the microscopy data into connected minimum spanning trees. Such digital reconstruction is represented in standard SWC format, prevalent for archiving, sharing, and further analysis in the neuroimaging community. Our proposed pipeline outperforms state of the art methods in tracing accuracy and minimizes the subjective variability in reconstruction, inherent to semi automatic methods. PMID- 26742128 TI - Comparison of Channel Methods and Observer Models for the Task-Based Assessment of Multi-Projection Imaging in the Presence of Structured Anatomical Noise. AB - Although Laguerre-Gauss (LG) channels are often used for the task-based assessment of multi-projection imaging, LG channels may not be the most reliable in providing performance trends as a function of system or object parameters for all situations. Partial least squares (PLS) channels are more flexible in adapting to background and signal data statistics and were shown to be more efficient for detection tasks involving 2D non-Gaussian random backgrounds (Witten , 2010). In this work, we investigate ways of incorporating spatial correlations in the multi-projection data space using 2D LG channels and two implementations of PLS in the channelized version of the 3D projection Hotelling observer (Park , 2010) (3Dp CHO). Our task is to detect spherical and elliptical 3D signals in the angular projections of a structured breast phantom ensemble. The single PLS (sPLS) incorporates the spatial correlation within each projection, whereas the combined PLS (cPLS) incorporates the spatial correlations both within each of and across the projections. The 3Dp CHO-R indirectly incorporates the spatial correlation from the response space (R), whereas the 3Dp CHO-C from the channel space (C). The 3Dp CHO-R-sPLS has potential to be a good surrogate observer when either sample size is small or one training set is used for training both PLS channels and observer. So does the 3Dp CHO-C-cPLS when the sample size is large enough to have a good sized independent set for training PLS channels. Lastly a stack of 2D LG channels used as 3D channels in the CHO-C model showed the capability of incorporating the spatial correlation between the multiple angular projections. PMID- 26742127 TI - Relationship Induced Multi-Template Learning for Diagnosis of Alzheimer's Disease and Mild Cognitive Impairment. AB - As shown in the literature, methods based on multiple templates usually achieve better performance, compared with those using only a single template for processing medical images. However, most existing multi-template based methods simply average or concatenate multiple sets of features extracted from different templates, which potentially ignores important structural information contained in the multi-template data. Accordingly, in this paper, we propose a novel relationship induced multi-template learning method for automatic diagnosis of Alzheimer's disease (AD) and its prodromal stage, i.e., mild cognitive impairment (MCI), by explicitly modeling structural information in the multi-template data. Specifically, we first nonlinearly register each brain's magnetic resonance (MR) image separately onto multiple pre-selected templates, and then extract multiple sets of features for this MR image. Next, we develop a novel feature selection algorithm by introducing two regularization terms to model the relationships among templates and among individual subjects. Using these selected features corresponding to multiple templates, we then construct multiple support vector machine (SVM) classifiers. Finally, an ensemble classification is used to combine outputs of all SVM classifiers, for achieving the final result. We evaluate our proposed method on 459 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 97 AD patients, 128 normal controls (NC), 117 progressive MCI (pMCI) patients, and 117 stable MCI (sMCI) patients. The experimental results demonstrate promising classification performance, compared with several state-of-the-art methods for multi-template based AD/MCI classification. PMID- 26742130 TI - Computationally Efficient Adaptive Beamformer for Ultrasound Imaging Based on QR Decomposition. AB - Adaptive beamforming methods for ultrasound imaging have been studied to improve image resolution and contrast. The most common approach is the minimum variance (MV) beamformer which minimizes the power of the beamformed output while maintaining the response from the direction of interest constant. The method achieves higher resolution and better contrast than the delay-and-sum (DAS) beamformer, but it suffers from high computational cost. This cost is mainly due to the computation of the spatial covariance matrix and its inverse, which requires O(L(3)) computations, where L denotes the subarray size. In this study, we propose a computationally efficient MV beamformer based on QR decomposition. The idea behind our approach is to transform the spatial covariance matrix to be a scalar matrix sigmaI and we subsequently obtain the apodization weights and the beamformed output without computing the matrix inverse. To do that, QR decomposition algorithm is used and also can be executed at low cost, and therefore, the computational complexity is reduced to O(L(2)). In addition, our approach is mathematically equivalent to the conventional MV beamformer, thereby showing the equivalent performances. The simulation and experimental results support the validity of our approach. PMID- 26742131 TI - Phase Aberration and Attenuation Effects on Acoustic Radiation Force-Based Shear Wave Generation. AB - Elasticity is measured by shear wave elasticity imaging (SWEI) methods using acoustic radiation force to create the shear waves. Phase aberration and tissue attenuation can hamper the generation of shear waves for in vivo applications. In this study, the effects of phase aberration and attenuation in ultrasound focusing for creating shear waves were explored. This includes the effects of phase shifts and amplitude attenuation on shear wave characteristics such as shear wave amplitude, shear wave speed, shear wave center frequency, and bandwidth. Two samples of swine belly tissue were used to create phase aberration and attenuation experimentally. To explore the phase aberration and attenuation effects individually, tissue experiments were complemented with ultrasound beam simulations using fast object-oriented C++ ultrasound simulator (FOCUS) and shear wave simulations using finite-element-model (FEM) analysis. The ultrasound frequency used to generate shear waves was varied from 3.0 to 4.5 MHz. Results: The measured acoustic pressure and resulting shear wave amplitude decreased approximately 40%-90% with the introduction of the tissue samples. Acoustic intensity and shear wave displacement were correlated for both tissue samples, and the resulting Pearson's correlation coefficients were 0.99 and 0.97. Analysis of shear wave generation with tissue samples (phase aberration and attenuation case), measured phase screen, (only phase aberration case), and FOCUS/FEM model (only attenuation case) showed that tissue attenuation affected the shear wave generation more than tissue aberration. Decreasing the ultrasound frequency helped maintain a focused beam for creation of shear waves in the presence of both phase aberration and attenuation. PMID- 26742133 TI - Sparse Contextual Activation for Efficient Visual Re-Ranking. AB - In this paper, we propose an extremely efficient algorithm for visual re-ranking. By considering the original pairwise distance in the contextual space, we develop a feature vector called sparse contextual activation (SCA) that encodes the local distribution of an image. Hence, re-ranking task can be simply accomplished by vector comparison under the generalized Jaccard metric, which has its theoretical meaning in the fuzzy set theory. In order to improve the time efficiency of re ranking procedure, inverted index is successfully introduced to speed up the computation of generalized Jaccard metric. As a result, the average time cost of re-ranking for a certain query can be controlled within 1 ms. Furthermore, inspired by query expansion, we also develop an additional method called local consistency enhancement on the proposed SCA to improve the retrieval performance in an unsupervised manner. On the other hand, the retrieval performance using a single feature may not be satisfactory enough, which inspires us to fuse multiple complementary features for accurate retrieval. Based on SCA, a robust feature fusion algorithm is exploited that also preserves the characteristic of high time efficiency. We assess our proposed method in various visual re-ranking tasks. Experimental results on Princeton shape benchmark (3D object), WM-SRHEC07 (3D competition), YAEL data set B (face), MPEG-7 data set (shape), and Ukbench data set (image) manifest the effectiveness and efficiency of SCA. PMID- 26742132 TI - Motion Estimation Based on Mutual Information and Adaptive Multi-Scale Thresholding. AB - This paper proposes a new method of calculating a matching metric for motion estimation. The proposed method splits the information in the source images into multiple scale and orientation subbands, reduces the subband values to a binary representation via an adaptive thresholding algorithm, and uses mutual information to model the similarity of corresponding square windows in each image. A moving window strategy is applied to recover a dense estimated motion field whose properties are explored. The proposed matching metric is a sum of mutual information scores across space, scale, and orientation. This facilitates the exploitation of information diversity in the source images. Experimental comparisons are performed amongst several related approaches, revealing that the proposed matching metric is better able to exploit information diversity, generating more accurate motion fields. PMID- 26742134 TI - Unified Photo Enhancement by Discovering Aesthetic Communities From Flickr. AB - Photo enhancement refers to the process of increasing the aesthetic appeal of a photo, such as changing the photo aspect ratio and spatial recomposition. It is a widely used technique in the printing industry, graphic design, and cinematography. In this paper, we propose a unified and socially aware photo enhancement framework which can leverage the experience of photographers with various aesthetic topics (e.g., portrait and landscape). We focus on photos from the image hosting site Flickr, which has 87 million users and to which more than 3.5 million photos are uploaded daily. First, a tagwise regularized topic model is proposed to describe the aesthetic topic of each Flickr user, and coherent and interpretable topics are discovered by leveraging both the visual features and tags of photos. Next, a graph is constructed to describe the similarities in aesthetic topics between the users. Noticeably, densely connected users have similar aesthetic topics, which are categorized into different communities by a dense subgraph mining algorithm. Finally, a probabilistic model is exploited to enhance the aesthetic attractiveness of a test photo by leveraging the photographic experiences of Flickr users from the corresponding communities of that photo. Paired-comparison-based user studies show that our method performs competitively on photo retargeting and recomposition. Moreover, our approach accurately detects aesthetic communities in a photo set crawled from nearly 100000 Flickr users. PMID- 26742135 TI - Feature and Region Selection for Visual Learning. AB - Visual learning problems, such as object classification and action recognition, are typically approached using extensions of the popular bag-of-words (BoWs) model. Despite its great success, it is unclear what visual features the BoW model is learning. Which regions in the image or video are used to discriminate among classes? Which are the most discriminative visual words? Answering these questions is fundamental for understanding existing BoW models and inspiring better models for visual recognition. To answer these questions, this paper presents a method for feature selection and region selection in the visual BoW model. This allows for an intermediate visualization of the features and regions that are important for visual learning. The main idea is to assign latent weights to the features or regions, and jointly optimize these latent variables with the parameters of a classifier (e.g., support vector machine). There are four main benefits of our approach: 1) our approach accommodates non-linear additive kernels, such as the popular chi(2) and intersection kernel; 2) our approach is able to handle both regions in images and spatio-temporal regions in videos in a unified way; 3) the feature selection problem is convex, and both problems can be solved using a scalable reduced gradient method; and 4) we point out strong connections with multiple kernel learning and multiple instance learning approaches. Experimental results in the PASCAL VOC 2007, MSR Action Dataset II and YouTube illustrate the benefits of our approach. PMID- 26742136 TI - Shapes From Pixels. AB - Continuous-domain visual signals are usually captured as discrete (digital) images. This operation is not invertible in general, in the sense that the continuous-domain signal cannot be exactly reconstructed based on the discrete image, unless it satisfies certain constraints (e.g., bandlimitedness). In this paper, we study the problem of recovering shape images with smooth boundaries from a set of samples. Thus, the reconstructed image is constrained to regenerate the same samples (consistency), as well as forming a shape (bilevel) image. We initially formulate the reconstruction technique by minimizing the shape perimeter over the set of consistent binary shapes. Next, we relax the non-convex shape constraint to transform the problem into minimizing the total variation over consistent non-negative-valued images. We also introduce a requirement (called reducibility) that guarantees equivalence between the two problems. We illustrate that the reducibility property effectively sets a requirement on the minimum sampling density. We also evaluate the performance of the relaxed alternative in various numerical experiments. PMID- 26742138 TI - An Integrated Circuit for Chip-Based Analysis of Enzyme Kinetics and Metabolite Quantification. AB - We have created a novel chip-based diagnostic tools based upon quantification of metabolites using enzymes specific for their chemical conversion. Using this device we show for the first time that a solid-state circuit can be used to measure enzyme kinetics and calculate the Michaelis-Menten constant. Substrate concentration dependency of enzyme reaction rates is central to this aim. Ion sensitive field effect transistors (ISFET) are excellent transducers for biosensing applications that are reliant upon enzyme assays, especially since they can be fabricated using mainstream microelectronics technology to ensure low unit cost, mass-manufacture, scaling to make many sensors and straightforward miniaturisation for use in point-of-care devices. Here, we describe an integrated ISFET array comprising 2(16) sensors. The device was fabricated with a complementary metal oxide semiconductor (CMOS) process. Unlike traditional CMOS ISFET sensors that use the Si3N4 passivation of the foundry for ion detection, the device reported here was processed with a layer of Ta2O5 that increased the detection sensitivity to 45 mV/pH unit at the sensor readout. The drift was reduced to 0.8 mV/hour with a linear pH response between pH 2-12. A high-speed instrumentation system capable of acquiring nearly 500 fps was developed to stream out the data. The device was then used to measure glucose concentration through the activity of hexokinase in the range of 0.05 mM-231 mM, encompassing glucose's physiological range in blood. Localised and temporal enzyme kinetics of hexokinase was studied in detail. These results present a roadmap towards a viable personal metabolome machine. PMID- 26742139 TI - A PWM Buck Converter With Load-Adaptive Power Transistor Scaling Scheme Using Analog-Digital Hybrid Control for High Energy Efficiency in Implantable Biomedical Systems. AB - We report a pulse width modulation (PWM) buck converter that is able to achieve a power conversion efficiency (PCE) of > 80% in light loads 100 MUA) for implantable biomedical systems. In order to achieve a high PCE for the given light loads, the buck converter adaptively reconfigures the size of power PMOS and NMOS transistors and their gate drivers in accordance with load currents, while operating at a fixed frequency of 1 MHz. The buck converter employs the analog-digital hybrid control scheme for coarse/fine adjustment of power transistors. The coarse digital control generates an approximate duty cycle necessary for driving a given load and selects an appropriate width of power transistors to minimize redundant power dissipation. The fine analog control provides the final tuning of the duty cycle to compensate for the error from the coarse digital control. The mode switching between the analog and digital controls is accomplished by a mode arbiter which estimates the average of duty cycles for the given load condition from limit cycle oscillations (LCO) induced by coarse adjustment. The fabricated buck converter achieved a peak efficiency of 86.3% at 1.4 mA and > 80% efficiency for a wide range of load conditions from 45 MUA to 4.1 mA, while generating 1 V output from 2.5-3.3 V supply. The converter occupies 0.375 mm(2) in 0.18 MUm CMOS processes and requires two external components: 1.2 MUF capacitor and 6.8 MUH inductor. PMID- 26742140 TI - Interference Resilient Sigma Delta-Based Pulse Oximeter. AB - Ambient light and optical interference can severely affect the performance of pulse oximeters. The deployment of a robust modulation technique to drive the pulse oximeter LEDs can reduce these unwanted effects and increases the resilient of the pulse oximeter against artificial ambient light. The time division modulation technique used in conventional pulse oximeters can not remove the effect of modulated light coming from surrounding environment and this may cause huge measurement error in pulse oximeter readings. This paper presents a novel cross-coupled sigma delta modulator which ensures that measurement accuracy will be more robust in comparison with conventional fixed-frequency oximeter modulation technique especially in the presence of pulsed artificial ambient light. Moreover, this novel modulator gives an extra control over the pulse oximeter power consumption leading to improved power management. PMID- 26742141 TI - Reconfigurable Resonant Regulating Rectifier With Primary Equalization for Extended Coupling- and Loading-Range in Bio-Implant Wireless Power Transfer. AB - Wireless power transfer using reconfigurable resonant regulating (R(3)) rectification suffers from limited range in accommodating varying coupling and loading conditions. A primary-assisted regulation principle is proposed to mitigate these limitations, of which the amplitude of the rectifier input voltage on the secondary side is regulated by accordingly adjusting the voltage amplitude Veq on the primary side. A novel current-sensing method and calibration scheme track Veq on the primary side. A ramp generator simultaneously provides three clock signals for different modules. Both the primary equalizer and the R(3) rectifier are implemented as custom integrated circuits fabricated in a 0.35 MUm CMOS process, with the global control implemented in FPGA. Measurements show that with the primary equalizer, the workable coupling and loading ranges are extended by 250% at 120 mW load and 300% at 1.2 cm coil distance compared to the same system without the primary equalizer. A maximum rectifier efficiency of 92.5% and a total system efficiency of 62.4% are demonstrated. PMID- 26742142 TI - A Wearable EEG-HEG-HRV Multimodal System With Simultaneous Monitoring of tES for Mental Health Management. AB - A multimodal mental management system in the shape of the wearable headband and earplugs is proposed to monitor electroencephalography (EEG), hemoencephalography (HEG) and heart rate variability (HRV) for accurate mental health monitoring. It enables simultaneous transcranial electrical stimulation (tES) together with real time monitoring. The total weight of the proposed system is less than 200 g. The multi-loop low-noise amplifier (MLLNA) achieves over 130 dB CMRR for EEG sensing and the capacitive correlated-double sampling transimpedance amplifier (CCTIA) has low-noise characteristics for HEG and HRV sensing. Measured three-physiology domains such as neural, vascular and autonomic domain signals are combined with canonical correlation analysis (CCA) and temporal kernel canonical correlation analysis (tkCCA) algorithm to find the neural-vascular-autonomic coupling. It supports highly accurate classification with the 19% maximum improvement with multimodal monitoring. For the multi-channel stimulation functionality, after effects maximization monitoring and sympathetic nerve disorder monitoring, the stimulator is designed as reconfigurable. The 3.37 * 2.25 mm(2) chip has 2 channel EEG sensor front-end, 2-channel NIRS sensor front-end, NIRS current driver to drive dual-wavelength VCSEL and 6-b DAC current source for tES mode. It dissipates 24 mW with 2 mA stimulation current and 5 mA NIRS driver current. PMID- 26742146 TI - Impulsive Effects and Stability Analysis on Memristive Neural Networks With Variable Delays. AB - In this brief, hybrid impulsive and adaptive feedback controllers are simultaneously exerted on a general delayed memristive neural network (MNN) model to formulate a novel impulsive controlled MNN (IMNN) model with variable delays. By means of Lyapunov-Razumikhin technique and other analytical ways, several new stability criteria of the proposed IMNN model are obtained. In addition, by choosing appropriate impulses and external inputs, the convergence speed of IMNN can be increased, which implies that its dynamic behaviors will be optimized. Finally, the effectiveness of the obtained results is illustrated by one numerical example. PMID- 26742145 TI - Artificial Epigenetic Networks: Automatic Decomposition of Dynamical Control Tasks Using Topological Self-Modification. AB - This paper describes the artificial epigenetic network, a recurrent connectionist architecture that is able to dynamically modify its topology in order to automatically decompose and solve dynamical problems. The approach is motivated by the behavior of gene regulatory networks, particularly the epigenetic process of chromatin remodeling that leads to topological change and which underlies the differentiation of cells within complex biological organisms. We expected this approach to be useful in situations where there is a need to switch between different dynamical behaviors, and do so in a sensitive and robust manner in the absence of a priori information about problem structure. This hypothesis was tested using a series of dynamical control tasks, each requiring solutions that could express different dynamical behaviors at different stages within the task. In each case, the addition of topological self-modification was shown to improve the performance and robustness of controllers. We believe this is due to the ability of topological changes to stabilize attractors, promoting stability within a dynamical regime while allowing rapid switching between different regimes. Post hoc analysis of the controllers also demonstrated how the partitioning of the networks could provide new insights into problem structure. PMID- 26742147 TI - DISC: Deep Image Saliency Computing via Progressive Representation Learning. AB - Salient object detection increasingly receives attention as an important component or step in several pattern recognition and image processing tasks. Although a variety of powerful saliency models have been intensively proposed, they usually involve heavy feature (or model) engineering based on priors (or assumptions) about the properties of objects and backgrounds. Inspired by the effectiveness of recently developed feature learning, we provide a novel deep image saliency computing (DISC) framework for fine-grained image saliency computing. In particular, we model the image saliency from both the coarse-and fine-level observations, and utilize the deep convolutional neural network (CNN) to learn the saliency representation in a progressive manner. In particular, our saliency model is built upon two stacked CNNs. The first CNN generates a coarse level saliency map by taking the overall image as the input, roughly identifying saliency regions in the global context. Furthermore, we integrate superpixel based local context information in the first CNN to refine the coarse-level saliency map. Guided by the coarse saliency map, the second CNN focuses on the local context to produce fine-grained and accurate saliency map while preserving object details. For a testing image, the two CNNs collaboratively conduct the saliency computing in one shot. Our DISC framework is capable of uniformly highlighting the objects of interest from complex background while preserving well object details. Extensive experiments on several standard benchmarks suggest that DISC outperforms other state-of-the-art methods and it also generalizes well across data sets without additional training. The executable version of DISC is available online: http://vision.sysu.edu.cn/projects/DISC. PMID- 26742148 TI - Identification and Control for Singularly Perturbed Systems Using Multitime-Scale Neural Networks. AB - Many well-established singular perturbation theories for singularly perturbed systems require the full knowledge of system model parameters. In order to obtain an accurate and faithful model, a new identification scheme for singularly perturbed nonlinear system using multitime-scale recurrent high-order neural networks (NNs) is proposed in this paper. Inspired by the optimal bounded ellipsoid algorithm, which is originally designed for discrete-time systems, a novel weight updating law is developed for continuous-time NNs identification process. Compared with other widely used gradient-descent updating algorithms, this new method can achieve faster convergence, due to its adaptively adjusted learning rate. Based on the identification results, a control scheme using singular perturbation theories is developed. By using singular perturbation methods, the system order is reduced, and the controller structure is simplified. The closed-loop stability is analyzed and the convergence of system states is guaranteed. The effectiveness of the identification and the control scheme is demonstrated by simulation results. PMID- 26742149 TI - A Graph-Embedding Approach to Hierarchical Visual Word Mergence. AB - Appropriately merging visual words are an effective dimension reduction method for the bag-of-visual-words model in image classification. The approach of hierarchically merging visual words has been extensively employed, because it gives a fully determined merging hierarchy. Existing supervised hierarchical merging methods take different approaches and realize the merging process with various formulations. In this paper, we propose a unified hierarchical merging approach built upon the graph-embedding framework. Our approach is able to merge visual words for any scenario, where a preferred structure and an undesired structure are defined, and, therefore, can effectively attend to all kinds of requirements for the word-merging process. In terms of computational efficiency, we show that our algorithm can seamlessly integrate a fast search strategy developed in our previous work and, thus, well maintain the state-of-the-art merging speed. To the best of our survey, the proposed approach is the first one that addresses the hierarchical visual word mergence in such a flexible and unified manner. As demonstrated, it can maintain excellent image classification performance even after a significant dimension reduction, and outperform all the existing comparable visual word-merging methods. In a broad sense, our work provides an open platform for applying, evaluating, and developing new criteria for hierarchical word-merging tasks. PMID- 26742150 TI - Out-of-Sample Extensions for Non-Parametric Kernel Methods. AB - Choosing suitable kernels plays an important role in the performance of kernel methods. Recently, a number of studies were devoted to developing nonparametric kernels. Without assuming any parametric form of the target kernel, nonparametric kernel learning offers a flexible scheme to utilize the information of the data, which may potentially characterize the data similarity better. The kernel methods using nonparametric kernels are referred to as nonparametric kernel methods. However, many nonparametric kernel methods are restricted to transductive learning, where the prediction function is defined only over the data points given beforehand. They have no straightforward extension for the out-of-sample data points, and thus cannot be applied to inductive learning. In this paper, we show how to make the nonparametric kernel methods applicable to inductive learning. The key problem of out-of-sample extension is how to extend the nonparametric kernel matrix to the corresponding kernel function. A regression approach in the hyper reproducing kernel Hilbert space is proposed to solve this problem. Empirical results indicate that the out-of-sample performance is comparable to the in-sample performance in most cases. Experiments on face recognition demonstrate the superiority of our nonparametric kernel method over the state-of-the-art parametric kernel methods. PMID- 26742143 TI - Robust Nucleus/Cell Detection and Segmentation in Digital Pathology and Microscopy Images: A Comprehensive Review. AB - Digital pathology and microscopy image analysis is widely used for comprehensive studies of cell morphology or tissue structure. Manual assessment is labor intensive and prone to interobserver variations. Computer-aided methods, which can significantly improve the objectivity and reproducibility, have attracted a great deal of interest in recent literature. Among the pipeline of building a computer-aided diagnosis system, nucleus or cell detection and segmentation play a very important role to describe the molecular morphological information. In the past few decades, many efforts have been devoted to automated nucleus/cell detection and segmentation. In this review, we provide a comprehensive summary of the recent state-of-the-art nucleus/cell segmentation approaches on different types of microscopy images including bright-field, phase-contrast, differential interference contrast, fluorescence, and electron microscopies. In addition, we discuss the challenges for the current methods and the potential future work of nucleus/cell detection and segmentation. PMID- 26742151 TI - Exponential Stability of Complex-Valued Memristive Recurrent Neural Networks. AB - In this brief, we establish a novel complex-valued memristive recurrent neural network (CVMRNN) to study its stability. As a generalization of real-valued memristive neural networks, CVMRNN can be separated into real and imaginary parts. By means of M -matrix and Lyapunov function, the existence, uniqueness, and exponential stability of the equilibrium point for CVMRNNs are investigated, and sufficient conditions are presented. Finally, the effectiveness of obtained results is illustrated by two numerical examples. PMID- 26742153 TI - Event-Triggered Fault Detection Filter Design for a Continuous-Time Networked Control System. AB - This paper studies the problem of event-triggered fault detection filter (FDF) and controller coordinated design for a continuous-time networked control system (NCS) with biased sensor faults. By considering sensor-to-FDF network-induced delays and packet dropouts, which do not impose a constraint on the event triggering mechanism, and proposing the simultaneous network bandwidth utilization ratio and fault occurrence probability-based event-triggering mechanism, a new closed-loop model for the considered NCS is established. Based on the established model, the event-triggered H infinity performance analysis, and FDF and controller coordinated design are presented. The combined mutually exclusive distribution and Wirtinger-based integral inequality approach is proposed for the first time to deal with integral inequalities for products of vectors. This approach is proved to be less conservative than the existing Wirtinger-based integral inequality approach. The designed FDF and controller can guarantee the sensitivity of the residual signal to faults and the robustness of the NCS to external disturbances. The simulation results verify the effectiveness of the proposed event-triggering mechanism, and the FDF and controller coordinated design. PMID- 26742154 TI - Learning Sampling Distributions for Efficient Object Detection. AB - Object detection is an important task in computer vision and machine intelligence systems. Multistage particle windows (MPW), proposed by Gualdi et al., is an algorithm of fast and accurate object detection. By sampling particle windows (PWs) from a proposal distribution (PD), MPW avoids exhaustively scanning the image. Despite its success, it is unknown how to determine the number of stages and the number of PWs in each stage. Moreover, it has to generate too many PWs in the initialization step and it unnecessarily regenerates too many PWs around object-like regions. In this paper, we attempt to solve the problems of MPW. An important fact we used is that there is a large probability for a randomly generated PW not to contain the object because the object is a sparse event relative to the huge number of candidate windows. Therefore, we design a PD so as to efficiently reject the huge number of nonobject windows. Specifically, we propose the concepts of rejection, acceptance, and ambiguity windows and regions. Then, the concepts are used to form and update a dented uniform distribution and a dented Gaussian distribution. This contrasts to MPW which utilizes only on region of support. The PD of MPW is acceptance-oriented whereas the PD of our method (called iPW) is rejection-oriented. Experimental results on human and face detection demonstrate the efficiency and the effectiveness of the iPW algorithm. The source code is publicly accessible. PMID- 26742152 TI - Patient Stratification Using Electronic Health Records from a Chronic Disease Management Program. AB - OBJECTIVE: The goal of this study is to devise a machine learning framework to assist care coordination programs in prognostic stratification to design and deliver personalized care plans and to allocate financial and medical resources effectively. MATERIALS AND METHODS: This study is based on a de-identified cohort of 2,521 hypertension patients from a chronic care coordination program at the Vanderbilt University Medical Center. Patients were modeled as vectors of features derived from electronic health records (EHRs) over a six-year period. We applied a stepwise regression to identify risk factors associated with a decrease in mean arterial pressure of at least 2 mmHg after program enrollment. The resulting features were subsequently validated via a logistic regression classifier. Finally, risk factors were applied to group the patients through model-based clustering. RESULTS: We identified a set of predictive features that consisted of a mix of demographic, medication, and diagnostic concepts. Logistic regression over these features yielded an area under the ROC curve (AUC) of 0.71 (95% CI: [0.67, 0.76]). Based on these features, four clinically meaningful groups are identified through clustering - two of which represented patients with more severe disease profiles, while the remaining represented patients with mild disease profiles. DISCUSSION: Patients with hypertension can exhibit significant variation in their blood pressure control status and responsiveness to therapy. Yet this work shows that a clustering analysis can generate more homogeneous patient groups, which may aid clinicians in designing and implementing customized care programs. CONCLUSION: The study shows that predictive modeling and clustering using EHR data can be beneficial for providing a systematic, generalized approach for care providers to tailor their management approach based upon patient-level factors. PMID- 26742155 TI - A Q-Learning Approach to Flocking With UAVs in a Stochastic Environment. AB - In the past two decades, unmanned aerial vehicles (UAVs) have demonstrated their efficacy in supporting both military and civilian applications, where tasks can be dull, dirty, dangerous, or simply too costly with conventional methods. Many of the applications contain tasks that can be executed in parallel, hence the natural progression is to deploy multiple UAVs working together as a force multiplier. However, to do so requires autonomous coordination among the UAVs, similar to swarming behaviors seen in animals and insects. This paper looks at flocking with small fixed-wing UAVs in the context of a model-free reinforcement learning problem. In particular, Peng's Q(lambda) with a variable learning rate is employed by the followers to learn a control policy that facilitates flocking in a leader-follower topology. The problem is structured as a Markov decision process, where the agents are modeled as small fixed-wing UAVs that experience stochasticity due to disturbances such as winds and control noises, as well as weight and balance issues. Learned policies are compared to ones solved using stochastic optimal control (i.e., dynamic programming) by evaluating the average cost incurred during flight according to a cost function. Simulation results demonstrate the feasibility of the proposed learning approach at enabling agents to learn how to flock in a leader-follower topology, while operating in a nonstationary stochastic environment. PMID- 26742156 TI - Unsupervised Feature Learning Classification With Radial Basis Function Extreme Learning Machine Using Graphic Processors. AB - Ever-increasing size and complexity of data sets create challenges and potential tradeoffs of accuracy and speed in learning algorithms. This paper offers progress on both fronts. It presents a mechanism to train the unsupervised learning features learned from only one layer to improve performance in both speed and accuracy. The features are learned by an unsupervised feature learning (UFL) algorithm. Then, those features are trained by a fast radial basis function (RBF) extreme learning machine (ELM). By exploiting the massive parallel computing attribute of modern graphics processing unit, a customized compute unified device architecture (CUDA) kernel is developed to further speed up the computing of the RBF kernel in the ELM. Results tested on Canadian Institute for Advanced Research and Mixed National Institute of Standards and Technology data sets confirm the UFL RBF ELM achieves high accuracy, and the CUDA implementation is up to 20 times faster than CPU and the naive parallel approach. PMID- 26742157 TI - Special Issue on Granular/Symbolic Data Processing. PMID- 26742158 TI - Words. PMID- 26742159 TI - Whitening products provide efficacious whitening. PMID- 26742160 TI - Smile Design 2.0: Evolving from our past to be successful in treating the modern cosmetic patient. PMID- 26742161 TI - Clinical practice guidelines for recall and maintenance of patients with tooth borne and implant-borne dental restorations. AB - The purpose of this article is to provide guidelines for patient recall regimen, professional maintenance regimen, and at-home maintenance regimen for patients with tooth-borne and implant-borne removable and fixed restorations. The American College of Prosthodontists (ACP) convened a scientific panel of experts appointed by the ACP, American Dental Association, Academy of General Dentistry, and American Dental Hygienists Association, who critically evaluated and debated recently published findings from 2 systematic reviews on this topic. The major outcomes and consequences considered during formulation of the clinical practice guidelines (CPGs) were risk for failure of tooth- and implant-borne restorations. The panel conducted a roundtable discussion of the proposed guidelines, which were debated in detail. Feedback was used to supplement and refine the proposed guidelines, and consensus was attained. A set of CPGs was developed for tooth borne restorations and implant-borne restorations. Each CPG comprised (1) patient recall, (2) professional maintenance, and (3) at-home maintenance. For tooth borne restorations, the professional maintenance and at-home maintenance CPGs were subdivided for removable and fixed restorations. For implant-borne restorations, the professional maintenance CPGs were subdivided for removable and fixed restorations and further divided into biological maintenance and mechanical maintenance for each type of restoration. The at-home maintenance CPGs were subdivided for removable and fixed restorations. The clinical practice guidelines presented in this document were initially developed using the 2 systematic reviews. Additional guidelines were developed using expert opinion and consensus, which included discussion of the best clinical practices, clinical feasibility, and risk-benefit ratio to the patient. To the authors' knowledge, these are the first CPGs addressing patient recall regimen, professional maintenance regimen, and at-home maintenance regimen for patients with tooth-borne and implant-borne restorations. This document serves as a baseline with the expectation of future modifications when additional evidence becomes available. PMID- 26742162 TI - Giant keratoacanthoma of the lower lip: case report and review of the published literature. AB - Keratoacanthoma (KA) is an epithelial tumor mainly located on the sun-exposed skin of the face and hands of elderly patients. The giant form of KA affecting the lower lip is relatively rare, and only 2 of 9 recently reported cases were in women. This report describes a case of giant KA of the lower lip in a 62-year-old white woman and discusses clinical and histologic diagnosis and the therapeutic approach to this lesion. The patient reported a 2-month evolution of a nodule characterized by a brownish central plug of keratin and measuring approximately 2.0 cm in its greatest diameter. Keratoacanthoma may present some histopathologic features similar to those of squamous cell carcinoma, and careful attention is required to avoid an incorrect diagnosis. Following histopathologic confirmation of giant KA, complete excision of the lesion was performed. A 17-month follow-up examination revealed complete healing of the area and no signs of recurrence. Because giant KA of the lower lip may impair normal function and esthetics, surgical excision is the best choice for treating this lesion. PMID- 26742163 TI - The impact of endodontic irrigating solutions on the push-out shear bond strength of glass fiber posts luted with resin cements. AB - Resin-based restorative materials, widely used to cement posts, may be influenced by irrigants used during endodontic chemical-mechanical preparation. This study evaluated the impact of endodontic irrigating solutions and adhesive cement systems on the push-out shear bond strength of glass fiber posts to root dentin. Ninety-six bovine incisors were divided into 12 groups (4 irrigants * 3 resin cements; n = 8). Prepared canals were irrigated with saline solution, 2.5% sodium hypochlorite (NaOCl), 5.25% NaOCl, or 2% chlorhexidine gel, and posts were cemented with RelyX ARC, Panavia F, or RelyX U100. The bond strength was evaluated by means of the push-out test, and results were subjected to analysis of variance. The mean bond strength observed for the combination of 5.25% NaOCl irrigant and RelyX U100 cement was significantly lower (8.82 MPa) than the values found for the other groups (P < 0.05). The other combinations of irrigating solution and resin cement had no adverse effect on the bond strength of the glass fiber posts to dentin. PMID- 26742165 TI - Keratocystic odontogenic tumor: role of cone beam computed tomography and magnetic resonance imaging. AB - Keratocystic odontogenic tumors (KCOTs) are known for unique and varied behavior, high recurrence rates, and distinctive histopathologic findings. Differential diagnosis and management of KCOTs may be challenging because other jaw lesions may present similar characteristics. Careful interpretation of cone beam computed tomograms and magnetic resonance images has great significance for precise assessment of KCOTs and their relationships to adjacent anatomic structures as well as for treatment planning. This case report describes a KCOT that developed in the left angle and mandibular ramus in association with a semierupted third molar. PMID- 26742164 TI - Asymptomatic, nonexpansile radiopacity of the jaw associated with external root resorption: a diagnostic dilemma. AB - Incidental radiopacities of the jaws are commonly identified on routine intraoral and extraoral radiographs. Dentists should be able to develop a differential diagnosis of these lesions. This article presents 2 cases in which mandibular radiopacities associated with external root resorption were identified incidentally and discusses the differential diagnosis of these lesions. Both patients were referred by their general practitioners to dental specialists for further evaluation of homogenous osteosclerotic foci surrounding and resorbing the roots of the permanent mandibular right first molar. The lesions were asymptomatic, caused no cortical expansion, and were static over time. The clinical and radiographic features were consistent with a diagnosis of idiopathic osteosclerosis (IO). External root resorption is present in 10%-12% of cases of IO and often involves the permanent mandibular first molars. PMID- 26742166 TI - What every dentist needs to know about cannabis. AB - As the prevalence of marijuana use rises along with its legalization, it has become increasingly important for dentists to understand the potential benefits and risks of marijuana use. This article reviews potential effects of cannabis on oral and systemic health. PMID- 26742167 TI - Mechanical properties of new dental pulp-capping materials. AB - The mechanical properties of pulp-capping materials may affect their resistance to fracture during placement of a final restorative material or while supporting an overlying restoration over time. The purpose of this study was to compare the compressive strength, flexural strength, and flexural modulus of 2 new pulp capping materials (TheraCal LC and Biodentine), mineral trioxide aggregate (MTA), and calcium hydroxide over time. Specimens were created in molds and tested to failure in a universal testing machine after 15 minutes, 3 hours, and 24 hours. The MTA specimens did not set at 15 minutes. At all time periods, TheraCal LC had the greatest compressive and flexural strengths. After 3 and 24 hours, Biodentine had the greatest flexural modulus. TheraCal LC had greater early strength to potentially resist fracture during immediate placement of a final restorative material. Biodentine had greater stiffness after 3 hours to potentially provide better support of an overlying restoration under function over time. PMID- 26742168 TI - Effect of toothbrushes and denture brushes on heat-polymerized acrylic resins. AB - It is important to choose an appropriate brush for denture cleaning to prevent damage to the surface properties of prosthetic devices. The purpose of this study was to evaluate the abrasiveness of toothbrushes and denture brushes on boiled and microwave-processed acrylic resins. Specimens of 4 resin brands were prepared (n = 30). Five brands of brushes (n = 6) were used in a toothbrushing machine, first for 17,800 strokes and then for an additional 35,600 strokes (total of 53,400), at a load of 200 g. An analytical balance and a profilometer were used to assess the weight and surface roughness, respectively, before and after 17,800 and 53,400 strokes. Analysis of variance and Tukey tests were used for data analysis (alpha = 0.05). Weight loss increased with time, while surface roughness remained the same. There were no statistically significant differences among toothbrushes and denture brushes in the resulting weight loss (17,800 strokes, 1.83 mg; 53,400 strokes, 3.78 mg) or surface roughness (17,800 or 53,400 strokes, 0.14 um). The weight loss values after 53,400 brush strokes indicated that Classico (2.28 mg) and VIPI Wave (2.75 mg) presented significantly greater abrasion resistance than Lucitone 550 (3.36 mg) and Onda-Cryl (2.85 mg) (P < 0.05). The type of brush and the polymerization method did not influence resin wear after brushing. PMID- 26742169 TI - Evaluation of periodontitis treatment effects on carotid intima-media thickness and expression of laboratory markers related to atherosclerosis. AB - The objective of this research was to evaluate the treatment of periodontal disease and its effects on carotid intima-media thickness (CIMT) and expression of laboratory markers related to atherosclerosis. Twenty-three healthy patients (group 1) and 21 patients with moderate to severe periodontitis (group 2) underwent evaluation of clinical periodontal parameters. The patients were submitted to CIMT measurements and laboratory evaluations at the start of the study (0 months), 6 months, and 12 months. All patients received oral hygiene instruction; patients in group 2 also underwent supragingival and subgingival scaling and root planing. A statistically significant improvement in clinical periodontal parameters occurred in both groups (P < 0.05). Improvements were more evident between the first and second evaluations and were greater in group 2. Both groups experienced a statistically significant decrease in CIMT in the first 6 months (P < 0.05). Treatments--oral hygiene instruction in group 1 and instruction plus mechanical periodontal instrumentation in group 2--were effective in improving clinical periodontal parameters of both groups and promoting reduction in CIMT at 6 months. PMID- 26742170 TI - Nasopalatine duct cyst mimicking an endodontic periapical lesion: a case report. AB - Lesions of nonendodontic origin, such as nasopalatine or globulomaxillary cysts, may mimic periapical radiolucencies associated with pulpal pathosis, and incorrect diagnosis may lead to unnecessary endodontic treatment. Horizontal root fractures most commonly affect the maxillary central and lateral incisors. Prognosis depends largely on the level of fracture; fractures in the apical third have the best prognosis, and those in the cervical third have the worst. This case report discusses surgical and restorative management of a patient who had a nasopalatine cyst that had been misdiagnosed and treated as an endodontic lesion of the maxillary right central incisor as well as a midroot horizontal fracture of the adjacent lateral incisor. PMID- 26742171 TI - Influence of an arginine-containing toothpaste on bond strength of different adhesive systems to eroded dentin. AB - The aim of this study was to evaluate the bond strength of different adhesive systems to eroded dentin following toothbrushing with an arginine-containing toothpaste. Sixty standardized 3 * 3 * 2-mm fragments of root dentin (n = 10) were prepared. After all surfaces except the buccal surfaces were impermeabilized, specimens were subjected to an erosive wear protocol and stored for 24 hours at 37 degrees C. The specimens underwent 1000 toothbrushing cycles with an arginine-containing toothpaste, an arginine-free toothpaste (positive control group), or artificial saliva (negative control group). Following application of a self-etching or an etch-and-rinse adhesive to the buccal surfaces of the specimens, 6-mm-high composite resin blocks were built up in 2-mm increments. After 24 hours' storage in 100% relative humidity, microtensile test specimens with an approximate area of 1 mm2 were prepared. The test was performed at a speed of 0.5 mm/min until specimen fracture, and the failure patterns were evaluated using a stereoscopic loupe. Two-way analysis of variance revealed no significant difference between the toothpastes, the adhesive systems, or the interactions between toothpaste and adhesive system in terms of the bond strength to eroded dentin (P > 0.05). The predominant failure pattern was adhesive in all groups. It was concluded that a toothpaste containing arginine did not interfere with the bond between either the self-etching or the etch-and-rinse adhesive system and eroded dentin. PMID- 26742172 TI - Silver nitrate burn of the lower lip: a case report. AB - Silver nitrate is used in medicine to treat a number of conditions because of its cauterizing properties. This case report describes management of a silver nitrate burn of the oral mucosa that resulted in a large mass of necrotic tissue and accompanying pain in a 41-year-old man. The patient bit his lip and received silver nitrate treatment from a physician. Significant swelling and pain occurred over a period of 3 weeks after application. Analysis of a biopsy specimen revealed necrotic tissue with chronically inflamed granulation tissue. The lesion persisted, and it was determined that debridement was necessary to enhance wound healing and prevent significant scar formation. The patient was reexamined 10 days and 1 month after debridement. The lesion had significantly decreased in size, and the patient reported notable reduction of pain. The final follow-up at 3 months showed a desirable result with minimal scar formation. Use of concentrated silver nitrate for cautery can result in significant damage to mucous membranes, including oral mucosa. PMID- 26742173 TI - Rough patch of palatal mucosa. Hyperplastic and discolored palatal gingival. PMID- 26742175 TI - Correction: Effects of various mouthpieces on respiratory physiology during steady-state exercise in college-aged subjects. PMID- 26742174 TI - Correction: Space loss following premature loss of primary second molars. PMID- 26742176 TI - The effect of temporary restorative materials on fracture resistance of endodontically treated teeth. AB - This study was designed to investigate the fracture strength of endodontically treated teeth temporarily restored with some commonly used interim materials. Of 90 extracted maxillary premolars used in this study, 15 were left intact as the positive control. Endodontic treatment was performed on the remaining 75 teeth. The endodontically treated teeth were then randomly assigned to 5 groups (n = 15). One group was not restored and served as the negative control. In the remaining 4 experimental groups, the teeth were restored with a temporary cement: Zonalin, IRM, Coltosol, or Fuji II LC resin-modified glass ionomer (RMGI). The fracture strengths of all teeth were measured with a universal testing machine. The fracture strength of teeth restored with RMGI was significantly greater than that of other groups (P < 0.001), including intact teeth (P = 0.025). The fracture strength of teeth restored with other temporary materials was significantly lower than that of intact teeth (P < 0.05) but not significantly different from that of the negative control. From a structural resistance standpoint, RMGI may be the best choice for short-term temporary restoration of endodontically treated teeth. Other types of temporary restorative material had no reinforcing effect on tooth structure. PMID- 26742177 TI - Potential use of snake venom derivatives as hemostatic agents in dentistry. AB - This article reviews the hemostatic properties of snake venoms and their potential clinical application. PMID- 26742178 TI - Rare dental manifestation in Simpson-Golabi-Behmel syndrome. AB - Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked recessive overgrowth disorder with prominent craniofacial manifestations. Macrodontia is also an uncommon dental anomaly that can be an isolated finding and has been associated with numerous systemic conditions and syndromes. This case report describes this previously unreported dental anomaly, macrodontia, in a patient with SGBS, which may broaden the phenotype of this syndrome. A brief review of the literature on orofacial findings associated with SGBS is also presented. PMID- 26742179 TI - Planning extensive esthetic restorations for anterior teeth: use of waxed-up study casts and composite resin mock-ups. AB - The aim of this case report is to highlight the importance of appropriate planning protocols when direct composite resin restorations are used to solve extensive esthetic problems. A 30-year-old patient complained about her small maxillary anterior teeth and short upper lip. All teeth were healthy and light colored, and the patient exhibited good oral hygiene. The anterior teeth were relatively short, resulting in a compromised esthetic relationship between height and width. The maxillary and mandibular right central incisors were in an edge-to edge relationship. After diagnostic casts and waxed-up study casts were obtained, occlusal adjustment and recontouring of the incisal and labial surfaces of the mandibular right central incisor were performed to increase overjet. To increase the volume of the upper lip, composite resin restorations were planned for the maxillary anterior teeth. To confirm that the contours and color of the new smile were acceptable to the patient, composite resin esthetic mock-ups were made directly in the mouth before the definitive procedure. After definitive restoration of the anterior teeth, additional occlusal adjustments were performed. At the 36-month follow-up, no fracturing or severe wear of the restorations was observed. The restored anterior guidance provided excellent function after 3 years of clinical service. PMID- 26742180 TI - [Study of 4 patients implemented to Advance Care Planning]. AB - This is a study of 4 patients implemented to Advance Care Planning (ACP) reflecting on the health care professionals' role and the outcomes. ACP has been defined as a process of formal decision making that aims to help patients establish their decision about future care that take effect when they lose capacity. For about two years, we tried to engage all patients who were referred to our palliative care team and their families to ACP since their first consultation. We informed their conditions at that time, how their health might change and how treatment might impact on their life goals. We also attempted to help patients' decision making and then fulfill their wishes in cooperation with patients' families and healthcare professionals. We learned three important elements: understanding patients' values and wishes, explaining prediction of the clinical course of the patients and establishing a collaborative healthcare team in order to fulfill the patients' hopes. ACP improved quality of life (QOL) not only for the patients involved, but also for the family members. ACP can play a crucial role in ensuring that patients receive the care they want throughout various stages of their lives. PMID- 26742181 TI - Hearing Aid-Compatible Mobile Handsets. Final rule. AB - In this document, the Federal Communications Commission (Commission) modernizes its wireless hearing aid compatibility rules. The Commission adopts these rules to ensure that people with hearing loss have full access to innovative handsets and technologies. PMID- 26742182 TI - Obstetrical and Gynecological Devices; Reclassification of Surgical Mesh for Transvaginal Pelvic Organ Prolapse Repair; Final order. AB - The Food and Drug Administration (FDA or the Agency) is issuing a final order to reclassify surgical mesh for transvaginal pelvic organ prolapse (POP) repair from class II to class III. FDA is reclassifying these devices based on the determination that general controls and special controls together are not sufficient to provide reasonable assurance of safety and effectiveness for this device, and these devices present a potential unreasonable risk of illness or injury. The Agency is reclassifying surgical mesh for transvaginal POP repair on its own initiative based on new information. PMID- 26742183 TI - Effective Date of Requirement for Premarket Approval for Surgical Mesh for Transvaginal Pelvic Organ Prolapse Repair. Final order. AB - The Food and Drug Administration (FDA or the Agency) is issuing a final order to require the filing of a premarket approval application (PMA) or notice of completion of a product development protocol (PDP) for surgical mesh for transvaginal pelvic organ prolapse (POP) repair. PMID- 26742184 TI - Medical Devices; Obstetrical and Gynecological Devices; Classification of the Intravaginal Culture System. Final order. AB - The Food and Drug Administration (FDA) is classifying the intravaginal culture system into class II (special controls). The special controls that will apply to the device are identified in this order and will be part of the codified language for the intravaginal culture system's classification. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 26742185 TI - Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule and the National Instant Criminal Background Check System (NICS). Final rule. AB - The Department of Health and Human Services (HHS or "the Department'') is issuing this final rule to modify the Health Insurance Portability and Accountability Act of 1996 (HIPAA) Privacy Rule to expressly permit certain HIPAA covered entities to disclose to the National Instant Criminal Background Check System (NICS) the identities of individuals who are subject to a Federal "mental health prohibitor'' that disqualifies them from shipping, transporting, possessing, or receiving a firearm. The NICS is a national system maintained by the Federal Bureau of Investigation (FBI) to conduct background checks on persons who may be disqualified from receiving firearms based on Federally prohibited categories or State law. Among the persons subject to the Federal mental health prohibitor established under the Gun Control Act of 1968 and implementing regulations issued by the Department of Justice (DOJ) are individuals who have been involuntarily committed to a mental institution; found incompetent to stand trial or not guilty by reason of insanity; or otherwise have been determined by a court, board, commission, or other lawful authority to be a danger to themselves or others or to lack the mental capacity to contract or manage their own affairs, as a result of marked subnormal intelligence or mental illness, incompetency, condition, or disease. Under this final rule, only covered entities with lawful authority to make the adjudications or commitment decisions that make individuals subject to the Federal mental health prohibitor, or that serve as repositories of information for NICS reporting purposes, are permitted to disclose the information needed for these purposes. The disclosure is restricted to limited demographic and certain other information needed for NICS purposes. The rule specifically prohibits the disclosure of diagnostic or clinical information, from medical records or other sources, and any mental health information beyond the indication that the individual is subject to the Federal mental health prohibitor. PMID- 26742187 TI - Oral hygiene: here we go. PMID- 26742186 TI - Authors' response. PMID- 26742188 TI - Prevalence of Diabetes Mellitus in Human Immunodeficency Virus positive Patients in Puerto Rico--San Juan City Hospital Experience. AB - INTRODUCTION: The total number of patients with Human Immunodeficiency Virus (HIV) is 33 million, with 2.7 million new infections in 2007(1). Puerto Rico has an increasing prevalence trend of Diabetes Mellitus of 12.8% in 2010(3). As treatment of HIV continues to develop, and access to therapy improves, the incidence of HIV associated diabetes is bound to grow. We investigate the prevalence of Diabetes Mellitus and its associated risk factors in a determinate HIV positive population. MATERIALS AND METHODS: A retrospective study, reviewing the medical records of 146 HIV positive patients. The prevalence of DM was statistically measured and a Logistic Regression with Pearson Chi2 Square and Fisher's exact test was used to assess the association between DM and its risks factors. RESULTS: The prevalence of DM in the studied population was 13.7% (n=20). There were 59% (n = 86) males, 43% (n = 63) of patients treated with HAART 46% (n = 67) IVDA, the mean age was 47; with 29% older than 50 years old, and 68% of the patients had a BMI of less than 25. Gender, IVDA, HAART, BMI, and age were not associated as risk factors for the prevalence of DM in the studied population. DISCUSSION: Our data revealed a higher prevalence of DM in HIV infected patients. We observed no significant association between DM and its risks factors. This raises concern for yet unrecognized risk factors contributing to a higher prevalence of the disease in this population. Results of our study alert physicians on the importance of DM screening in the HIV positive patient population. PMID- 26742189 TI - A Hispanic female patient with heartburn: A rare presentation of Paroxysmal Nocturnal Hemoglobinuria. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant, acquired clonal hematopoietic stem cell disease that can present with bone marrow failure, hemolytic anemia, smooth muscle dystonias, and thrombosis. We present a case of a 32 year-old-female, G2P2A0 with no past medical history of any systemic illnesses who refers approximately 2 months of progressively worsening constant heartburn with associated abdominal discomfort. CBC showed leukopenia (WBC 2.9 x 103 /uL) with neutropenia (segmented neutrophils 48%), macrocytic anemia (Hgb 6.1 g/dL, hematocrit 20%, MCV,113 fL) and thrombocytopenia (platelet count 59 x 109/L). Abdomino-pelvic CT scan revealed a superior mesenterc vein thrombosis, which was treated initially with low-molecular-weight heparih for full anticoagulation. Peripheral blood flow cytometry assays revealed diminished expression of CD55 and CD59 on the erythrocytes, granulocytes and monocytes.' Paroxysmal nocturnal hemoglobinuria is a rare, clonal, hematopoietic stem-cell disorder whose manifestations are almost entirely explained by complement-mediated intravascular hemolysis. The natural history of PNH is highly variable, ranging from indolent to life-threatening. The median survival is 10 to 15 years, but with a wide range. Thrombosis is the leading cause of death, but others may die of complications of bone marrow failure, renal failure, myelodysplastic syndrome, and leukemia. Anticoagulation is only partially effective in preventing thrombosis in PNH; thus, thrombosis is an absolute indication for initiating treatment with Eculizumab. Nevertheless, bone marrow transplantation (BMT) is still the only curative therapy for PNH but is associated with significant morbidity and mortality. PMID- 26742190 TI - Pleural Effusion In A Patient With Primary Sjogren's Syndrome Successfully Treated With Corticosteroids. AB - Sjogren's syndrome is a systemic autoimmune disorder characterized by salivary insufficiency and lymphocytic infiltration of the exocrine glands. Bronchiolitis and bronchiectasis are common airway manifestations but interstitial pneumonitis, and lymphocytic interstitial pneumonitis may also occur. It rarely presents with pleuritis. We report a woman with primary Sjogren's syndrome who developed pleuritis with moderately large effusions and antibody levels for SS-A and SS-B in the serum without evidence of infection, malignancy or other collagen diseases. After the initial treatment, daily administration of 20 mg of oral prednisone has effectively controlled the serious manifestations of the disease with minimal side effects. PMID- 26742191 TI - The Racial, Cultural and Social Makeup of Hispanics as a potential Profile Risk for Intensifying the Need for Including this Ethnic Group in Clinical Trials. AB - Hypertension not only is the most frequently listed cause of death worldwide; but also a well-recognized major risk factor for cardiovascular disease and stroke. Based on the latest published statistics published by the American Heart Association, hypertension is very prevalent and found in one of every 3 US adults. Furthermore, data from NHANES 2007 to 2010 claims that almost 6% of US adults have undiagnosed hypertension. Despite this staggering statistic, previous US guidelines for the prevention, detection, and treatment of hypertension (The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure 7 [JNC 7]), released in 2003, stated that; "unfortunately, sufficient numbers of Mexican Americans and other Hispanic Americans... have not been included in most of the major clinical trials to allow reaching strong conclusions about their responses to individual antihypertensive therapies." However, the recently published JNC 8 offers no comment regarding recommendations or guideline treatment suggestions on Hispanics. The purpose of this article not only is to raise awareness of the lack of epidemiological data and treatment options regarding high blood pressure in the US Hispanic population; but also to make a case of the racial, cultural and social makeup of this ethnic group that places them at risk of cardiovascular complications related to hypertension. PMID- 26742192 TI - Usefulness Of Glucocorticoids In The Management Of Foreign Body Aspiration. AB - Foreign body aspiration can be a life-threatening emergency. An aspirated solid or semi-solid object may lodge in the larynx, trachea or other breathing airways. If the object is large enough to cause nearly complete obstruction of the airway, asphyxia may rapidly cause death. We report a 19-year old man admitted with right lower lobe pneumonia who spontaneously expelled a foreign body, one day after admission and glucocorticoids administration. Glucocorticoids should be considered in foreign body aspiration management because improvement of the inflammatory reaction may facilitate expontaneous expulsion or foreign body extraction PMID- 26742193 TI - Previous Exposure to Anesthesia and Autism Spectrum Disorder (ASD): A Puerto Rican Population-Based Sibling Cohort Study. AB - BACKGROUND: Autism Spectrum Disorder (ASD) is characterized by impaired social interaction and communication, and by restricted and repetitive behavior, that begins usually before a child is three years old.1 Researchers have shown that prevalence rates in the U.S. may be as high as 1 in 68.52 A number of studies have examined the effects of early exposure to anesthesia on brain development and subsequent impairment in neurocognitive function; yet, little is known about the possible effects of anesthetic agents on social-behavioral functioning. The association between exposure to anesthesia either in uterus, during the first years of life, or later and development of Autistic Spectrum Disorder (ASD) or its severity was determined in a retrospective population based cohort study. OBJECTIVES: Identify if children who had previous exposure to anesthesia either in uterus, first years of life during their developing brain years, or later, are at risk of developing ASD and its severe form of the disease. METHODS: Data was obtained from structured interviews administered to a sample of 515 parents/guardians distributed in two groups: ASD = 262 children diagnosed with this condition and Non-ASD: 253 children (siblings of ASD group) without diagnosis (p = 0.8069) when comparing exposure to anesthesia in uterus to subsequent severe form of ASD. Of the 262 ASD patients, 99 had exposure to anesthetics before their diagnosis, while in Non-ASD population, 110 had exposure to anesthesia, demonstrating no statistically significant association between both groups (p = 0.2091). Out of 99 ASD patients exposed to anesthesia prior to their diagnosis, 72 were exposed before age 2. When compared to the 110 Non-ASD patients exposed to anesthesia, 86 had exposure during this developing brain period, which indicates no statistically significant association (p = 0.4207). In addition, most of the ASD children exposed to anesthesia during developing brain were diagnosed with mild degree of the disorder when compared to ASD children without any previous exposure to anesthesia (p = 0.9700) during the same period. When the exposure occurred after age 2, ASD children developed mild form of the disorder as compared with ASD children without any previous exposure to anesthesia (p = 0.1699) in that period. CONCLUSIONS: Children under early exposure to anesthesia in uterus, first 2 years of life, or later are not more likely to develop neither ASD nor severe form of the disorder. INDEX WORDS: Anesthesia, Autism Spectrum Disorder, Puerto Rico. (95% confidence interval) that freely decided to participate and agreed to a consent form. Variables studied, include: demographics, diagnosis and severity of ASD, exposure to anesthesia, method of childbirth, and age of exposure. Children less than 2 years of age were considered into have developing brain period. Data was analyzed using Chi-square or Fisher exact test. RESULTS: In contrast to non-ASD group, most of the children within ASD group were male, 76% (p = 0.0001). With regards to methods of childbirth, 64% of the ASD population were vaginal delivery (VD; Non-anesthesia exposure group) and 36% cesarean delivery (CD) compared to non-autistic population with 71% VD and 29% CD, which demonstrates no statistical difference between both groups (p = 0.1113). Out of the 36% of ASD population that underwent CD, 7% were performed using general anesthesia and 93% regional anesthesia, while the 29% of the CD of non-ASD, 5% were performed using general anesthesia and 95% regional anesthesia. This reveals no statistical significance (p = 0.7569) with the development of ASD and the type of anesthesia used when comparing ASD with non-ASD patients. In view of severity of autism, in VD, 56% of ASD population had mild form of the disorder, 34% moderate, and 10% severe; while CD had a 54% mild form of the disorder, 33% moderate, and 13% severe. This shows no statistical association. PMID- 26742195 TI - Diagnostic Studies for the Evaluation of Peripheral Artery Disease. AB - Atherosclerosis is a systemic disease that may affect multiple vascular territories including the coronary, cerebral and peripheral circulation. Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis and has an important impact on quality of life as well as morbidity in affected individuals. The diagnosis of PAD can be challenging and the clinician must know the different methods available and the limitations of each of them. In this article we review noninvasive methods used in the diagnosis of PAD in detail as well as the indications for conventional invasive angiography. PMID- 26742194 TI - Metastatic Ovarian Tumor Masquerading as Atypical Pneumonia. AB - Krukenberg tumor is a malignancy in the ovary from a primary lesion in the gastrointestinal tract and a metastatic signet ring cell adenocarcinoma to the ovary. Stomach is the most common primary site, but other organs can serve as a primary site. The lymphatic system is the most likely route for metastasis. CA 125 levels can be used for screening for early detection of ovarian metastasis as well as for monitoring the course of disease. The prognosis of Krukenberg tumor is poor and no curative treatment is currently available. PMID- 26742196 TI - Endovascular Intervention in the Treatment of Peripheral Artery Disease. AB - Endovascular therapy has emerged as an essential part of the management we can offer patients suffering from peripheral arterial disease. The AHA/ACCF guidelines deemed ballon angioplasty as a reasonable alternative for patients with limb threatening lower extremity ischemia who are not candidates for an autologus venous graft. Endovascular treatment is most useful for the treatment of critical limb ischemia and should ensure adequate proximal flow before engaging in interventions of distal disease.To increase procedure success rate, a thorough diagnostic evaluation is fundamental. This evaluation must take into account amount of calcium, no flow occlusion, length of occlusion, and presence of collaterals. There are different tools and procedure techniques available. Among these are the medicated ballon angioplasty and atherectomy by laser or high speed drill, among others. Further studies may consolidate endovascular intervention as a safe and effective management for patients with lower extremity arterial disease and possibly cause a change in the actual practice guidelines. PMID- 26742197 TI - Non-Invasive Therapy of Peripheral Arterial Disease. AB - Peripheral arterial disease (PAD) is a significant cause of morbidity and mortality worldwide. Lifestyle changes, like the cessation of the use of tobacco as well as a modification of dietary and exercise habits, can be the most cost effective interventions in patients with PAD. Smocking cessation is the most important intervention, since it increases survival in these patients. Antiplatelet therapy is an essential component in the treatment of peripheral arterial disease (PAD) of the lower extremities. In addition to delaying arterial obstructive progression, these agents are most usefull in reducing adverse cardiovascular events such as non-fatal myocardial infarction (MI), stroke and vascular death. Mainstay of treatment continues to be aspirin monotherapy (75 325mg daily). Current treatment for lower extremity PAD is directed towards the relief of symptoms and improvement in QoL. The two agents which have consistently been found to be most efficient in achieving these goals are cilostazol and naftidrofuryl oxalate. Naftidrofuryl oxalate may emerge as the most efficient and cost-effective treatment for symptom relief. PMID- 26742198 TI - [Achondroplasia: a pilot study on the psychosocial and medical features of a sample in Puerto Rico]. AB - This study explores the psychological wellbeing of twenty-two (n = 22) adults with achondroplasia. The sample was composed of seven (n = 7) males and fifteen (n = 15) females between the ages of 21 and 75 (mean age = 39.6). Each individual completed four self-administered questionnaires: the Beck Depression Inventory (BDI-l), the Beck Anxiety Inventory (BAI), the Beck Hopelessness Scale (BHS), and Derogatis Symptom Check-list-90-Revisited (SCL-90-R). They also filled out a socio-demographic questionnaire. We found that 31.8% of the sample reported at least one comorbid condition such as, hypertension, diabetes, rheumatoid arthritis, asthma, scoliosis, thyroid problems, neuropathy, psoriasis, gastritis and/or sleep apnea; 32% reported mild to severe depressive symp- toms; 55% reported mild to severe symptoms associated to anxiety and 18% reported mild to severe symptoms associated with hopelessness; 22.7% reported mild to severe symptoms in at least one of the sub-scales in Derogatis Symptom Checklist-90 Revisited (SCL-90-R) particularly the obsessive-compulsive, paranoid and depressive subscales. Chi Square correlations (X2) were made to observe if there was interdependence between the socio-demographic variables and the administered tests. In general, no significant correlations were found between BDI-Il, BAI, BHS, SCL-90-R and civil status, gender, income and age. However, a significant correlation was found between age and the somatization sub-scale of the SCL-90-R (rs = 0.510, p < 0.05). Our findings suggest that this particular sample is at risk for developing psycho-medical conditions. There is a marked lack of research in Puerto Rico associated to achondroplasia. The development of preventive and cultural sensitive interventions is suggested in order to protect and treat individuals with the condition. PMID- 26742199 TI - Metabolic Changes After Roux-N-Y Bariatric Surgery In Hispanics. AB - The objective was to describe the metabolic outcomes 12 months after bariatric surgery (Roux-N-Y) in morbidly obese Hispanic patients, and evaluate the correlation between weight loss and the observed changes. Medical records from a hundred-and-two Hispanic obese patients who underwent bariatric surgery were identified at the University of Puerto Rico (UPR) Hospital. The following variables were obtained before and 12 months after surgery: Body Mass Index (BMI), body weight, total cholesterol (TC), triglycerides, high density lipoprotein (HDL), low density lipoprotein (LDL), and fasting blood sugar (FBS). Ninety-seven percent of patients underwent Roux-N-Y surgery; 79.4% were females and 44% were diabetics. We observed statistically significant reductions (p < 0.05) 12 months after surgery in: BMI -14.3 (+/- 6.2) kg/m2, weight -86.1 (+/- 34.4) Ibs, TC -17.9 (+/- 32.4) mg/dL, triglycerides -28.7(+/- 40.6) mg/dL, LDL 15.4 (+/- 30.6) mg/dL, and FBS -11.3 (+/- 23.5) mg/dL. HDL, instead increased +5.22 (+/- 12.9) mg/dL (p < 0.0006). Gastric bypass surgery of the Roux-N-Y significantly improves the lipid profile and FBS levels in obese Hispanic patients. The poor correlation factor between weight loss and these variables suggests that other mechanisms, independent from weight loss, are responsible for these changes. PMID- 26742200 TI - Obesity and premature coronary artery disease with myocardial infarction in Puerto Rican young adults. AB - A cross-sectional study examined adults aged 21 to 35 years who underwent left cardiac catheterization in the Cardiovascular Center for Puerto Rico and the Caribbean during 2008-2012 due to myocardial infarction. Demographic characteristics, clinical risk factors, and the extent of CAD were documented. Chi-square statistic or Fisher's exact test was used to compare the distribution of demographic, clinical, and lifestyle characteristics across CAD extent. Polytomous logistic regression models were fitted to estimate the prevalence odds ratios (POR) with 95% confidence intervals (Cl) for non-obstructive and obstructive coronary disease (OCD) compared with normal coronary anatomy. Statistical analyses were performed using Stata 11.0. Sixty-three (n = 63) adults were evaluated (81% were men). The mean age was 31 +/- 4 years. The most frequent clinical risk factors were history of tobacco use, hyper tension, and dyslipidemia. Obesity was present in 45.9% of subjects and OCD was present in 52.38% of subjects. Obesity and family history of CAD were significantly associated with OCD when adjusted by age. Obese patients had 5.94 times the possibility of having OCD than normal weight patients. Obesity was the most important treatable predictor of premature obstructive CAD in our young adult population. PMID- 26742201 TI - Peripheral Arterial Disease: Surgical Treatment. AB - Peripheral arterial disease is a frequent under-diagnosed and poorly recognized clinical entity that can affect a great number of patients. Recognition of risk factors is crucial and a through evaluation of symptoms and use of diagnostic tools to better decide when an intervention is warranted. Lower extremity bypass surgery is one alternative method for treatment of PAD. It is indicated for type D and C lesions with low cardiac risk according to the TASC classification system. Preoperative assessment is imperative for every vascular procedure since it has been associated with major postoperative cardiovascular events; myocardial infarction being the most common. After excluding active disease, functional capacity and clinical risk predictors must be determined via METs and the Revised Cardiac Risk Index (RCRI), respectively. If a patient is considered to have a high cardiac risk, then noninvasive studies should be performed. Aspirin and a statin should be administrated preoperatively and postoperatively. Clopidogrel can be utilized as an alternative if a contraindication to aspirin exists. Periodic follow up consisting of clinical evaluations assessing and return or progression of symptoms of claudication, presence of pulses, ankle-brachial index (ABI) measurement, and smoking cessation counseling should be performed in every patient after vascular surgery. PMID- 26742202 TI - Epidemiology of Traumatic Peripheral Nerve Injuries Evaluated by Electrodiagnostic Studies in a Tertiary Care Hospital Clinic. AB - OBJECTIVES: Describe the etiology and frequency of traumatic peripheral nerve injuries (TPNI) in the electrodiagnostic laboratory of a tertiary care hospital. METHODS: The charts of patients who underwent an electrodiagnostic study for a TPNI were revised. The main outcome measure was the frequency of each injury by anatomic location, involved nerve, mechanism, and severity. RESULTS: 146 charts were included for a total of 163 injured nerves; 109 (74.7%) males and 37 (25.3%) females. The mean age was 33.6 years. The facial nerve and the brachial plexus followed by the ulnar nerve were more frequently involved. The ulnar, sciatic, median, radial nerve, and the lumbosacral plexus were more commonly injured by gunshot wounds, the brachial plexus by motor vehicle accidents, and the facial nerve by iatrogenic causes. The majority of the injuries were incomplete or partial (84.2% were incomplete and 15.8% complete injuries). CONCLUSIONS: TPNIs can lead to significant disability, but further investigation is needed to better understand their socio-economic impact. PMID- 26742203 TI - POEMS Syndrome: A Rare Disease With A Challenging Diagnosis. AB - A complex conglomerate of symptoms, signs, and abnormalities are present with POEMS syndrome, making the diagnosis, management and follow-up a challenge. Recognizing the disease early on may be difficult. Many patients are initially misdiagnosed as having others disorders, for example: multiple myeloma. There is no standard treatment for patients diagnosed with POEMS syndrome. PMID- 26742205 TI - Screening for Peripheral Arterial Disease. AB - Lower extremity peripheral artery disease is a manifestation of systemic atherosclerotic disease, which affects over 8 million Americans and conveys a significant health burden globally. Although PAD can be asymptomatic and subclinical, it is associated with a reduction in functional capacity and quality of life when symptomatic, and, in its most severe form, is a major cause of limb amputation. Peripheral arterial disease (PAD) commonly results from progressive narrowing of arteries in the lower extremities. Previous studies have shown that PAD is associated with a significantly elevated risk of cardiovascular disease morbidity and mortality. This is the reason screening is crucial for diagnosis and prevention of future adverse cardiovascular events. The most common etiology is atherosclerosis, although other disease process like inflammatory, immune, and hypercoagulable disorders can cause signs and symptoms of arterial insufficiency. When recognized early and appropriately managed, complications that lead to limb loss can be minimized. All patients should have a comprehensive history taken and be examined for PAD, but patients with risk factors should be specifically examined which is currently suboptimal in our daily practice. PMID- 26742204 TI - The Prevalence Of Sexually Transmitted Infections On Teen Pregnancies And Their Association To Adverse Pregnancy Outcomes. AB - INTRODUCTION: Based on our population data, the teen pregnancy rate and the prevalence of sexually transmitted infections (STIs) reported during pregnancy are worrisome. STIs appear to pose a threat to pregnancy outcomes including preterm birth (PTB), neonatal low birth weight (NLBW) and premature rupture of membranes (PROM). The objective of this study is to determine the prevalence of STIs in pregnant teens and the association of this variable to adverse pregnancy outcomes. METHODS: We performed a cross sectional study to assess the prevalence of STIs among pregnant teens during a 4-year period at our institution. Birth outcomes such as gestational age at delivery, PROM and NLBW were analyzed and compared with adults. RESULTS: In the four years of our study, teen pregnancy rate fluctuated from 21.7% in 2010 to 16.8% in 2013. The rate of STIs for adult and teen pregnancies was similar, 21% and 23%, respectively. Chlamydia was the most common STI (67.3%) for both groups. PTB was more prevalent among adults affected with STIs than teens, 13.8% and 11.5%, respectively. NLBW was similar among teens and adults with STIs. PROM complicated 9.1% of teen pregnancies with STIs, compared to 6.7% in adults. CONCLUSION: There was no significant correlation between the STIs and adverse pregnancy outcomes on teen pregnancies for our population, except for PROM. This age group is associated with a high risk sexual behavior and poor adherence to treatment. They would benefit from efforts to prevent unintended pregnancies and infectious diseases. PMID- 26742207 TI - [For good teamwork]. PMID- 26742208 TI - [Epidemiology, pathophysiology, and symptoms of headaches]. AB - According to representative analyses about 71% of people in Germany suffer from headaches at least occasionally during their life. There are about 9 million people suffering from migraine and about 29 million people who have tension-type headache. These data underline the great socio-economic importance of these types of headaches. In principle the primary headache disorders migraine (with and without aura) as well as the episodic tension-type headache are indications for self-medication. In order to professionally guide these patients, the pharmacist requires a profound knowledge about the different types of headaches and their origin. PMID- 26742209 TI - [Clinical diagnostics and imaging in headache disorders]. AB - Headache diagnosis is based on the criteria of the International Headache Society. Migraine and tension type headache are the most frequent primary headache disorders. Diagnosis can be made based on clinical criteria and further diagnostics are not mandatory. Imaging is primarily needed in suspected case of secondary headache disorders. Distinct imaging methods are used for research purposes especially for research about underlying pathophysiology of headache disorders. PMID- 26742206 TI - Difficult Diagnosis between B Cell Lymphoma and Classical Hodgkin's Lymphoma. AB - Although primary mediastinal large B-cell lymphoma and classic Hodgkin lymphoma of nodular sclerosis type are distinct disease, they share several clinical characteristics and biologic features. However, there are mediastinal lymphomas that not fit in either category. These types of lymphomas are recognized as mediastinal gray zone lymphomas. Gray zone lymphomas are lymphatic tumors that cannot be assigned to a defined lymphoma entity due to morphological, clinical, or genetic reasons. In this report, we present a case of a 22 year-old-Hispanic female diagnosed with B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Hodgkin lymphoma. PMID- 26742210 TI - [Self-medication of headaches]. AB - Of the relevant people suffering from headaches only about 20% consult a physician until the age of 35. Accordingly, the pharmacy poses the most commonly used contact point for the consultation of patients with headaches. Besides the therapy of headaches with non-opioid analgesics, including non-steroidal anti inflammatory drugs (NSAIDs) such as aspirin or ibuprofen and analgesics without anti-inflammatory action such as paracetamol, two triptans are available for self medication of prior diagnosed migraine. The professional guidance of patients in using these drugs requires a subtle knowledge of contraindications, unwanted side effects and interactions. PMID- 26742211 TI - [Pharmacotherapy of headache apart from self-medication]. AB - The pharmacotherapy of headache differentiates between self-medication and prescribed medication. Furthermore, pharmacotherapy has to consider the different headache disorders. In this article, the evidence-based treatment recommendations of the German Migraine and Headache Society for the different idiopathic headache disorders including trigeminal neuralgia are described. In addition, for most headache disorders acute and preventive medication has to be differentiated. It has to be noted that acute mediation against headache should not be taken too frequently and that in chronic headache disorders most often only a multimodal treatment results in a sufficient pain reduction. PMID- 26742212 TI - [Multimodal pain management in a patient with atypical cervicogenic headache]. AB - A 45-year-old patient presented with an eight-year history of persistent unilateral headache associated with recurrent episodes of ipsilateral conjunctival injections, eyelid edema and ptosis. Prior ineffective pharmacological treatment strategies included tramadol, non-steroidal anti inflammatory drugs and triptans. Palpation of right suboccipital trigger points revealed tenderness in the area of the greater occipital nerve and reinforced the symptoms. The diagnosis of cervicogenic headache was confirmed by symptom resolution following right greater occipital nerve blockade. A multimodal treatment strategy (physical therapy, nerve blockade, pharmacological treatment) was chosen and an emphasis was put on optimizing pharmacological pain relief using the opioid analgesic tapentadol and the tricyclic antidepressant amitriptyline as an adjuvant analgesic. Importantly, the patient reported a substantial and consistent pain reduction and considerable quality of life improvement during implementation of the treatment regimen. PMID- 26742213 TI - [Fat intake and prevention of selected diseases]. PMID- 26742214 TI - [Diagnostic tests in the pharmacy]. AB - Recently a number of diagnostic tests have been developed which are marketed in pharmacies. How reliable are the results and are the tests a sensible option for patients? The pharmacist has to answer these questions after searching for relevant clinical trials and critically appraising the evidence. This article presents key concepts which the pharmacist should consider. PMID- 26742215 TI - [Risk from combination treatment antithrombotics and NSAIDs]. PMID- 26742216 TI - [Vaccination from age 50 makes sense]. PMID- 26742217 TI - [Biological Effects of Physical Stress and Therapeutic Applications-Roles of Reactive Oxygen Species]. PMID- 26742218 TI - Long-Term Results of a Hybrid Revascularization Procedure for Peripheral Arterial Disease. AB - OBJECTIVE: To evaluate the efficacy of hybrid procedure for peripheral arterial disease (PAD), we compared the cases treated using the hybrid procedure with those treated using open revascularization (bypass alone) in our facilities. MATERIALS AND METHODS: We retrospectively reviewed 204 patients who underwent revascularization for PAD between 2007 and 2013. We divided the patients into two groups based on the type of procedure. Group 1 included patients who underwent the hybrid procedure, that is, doing endovascular therapy (EVT) either femoral or iliac resion and added the bypass procedure (infragenicular vein bypass) to the below knee artery, and group 2 included patients who underwent only bypass procedure (used autovein), that is, central anastomotic region was femoral artery region and peripheral anastomotic region was below knee artery. We evaluated various factors between the two groups, including the primary patency rate, secondary patency rate, amputation-free survival rate, and determined the efficacy of the hybrid procedure for PAD. RESULTS: In the patient's characteristics, there was significant difference between the two groups in the cases with cerebrovascular disease, only (p = 0.03). There were no significant differences in the primary or secondary patency rates, and the amputation-free survival rate. CONCLUSIONS: Primary patency rate, secondary patency rate, and amputation-free survival rate of the hybrid procedure were comparable to those of bypass (alone) procedure. The hybrid procedure is therefore an acceptable strategy for patients with PAD. PMID- 26742219 TI - [Laparoscopic-Assisted Percutaneous Endoscopic Gastrostomy--Report of Three Cases]. AB - Laparoscopic-assisted percutaneous endoscopic gastrostomy (LAPEG) was performed in consecutive three patients for whom it was unable to place a percutaneous endoscopic gastrostomy (PEG). The mean operation time was 40.3 min, and mean blood loss was 1.3 g. Three trocars were placed, two for working and another for endoscopy, and a PEG was established by an usual Introducer method. There were no complications both intra- and post-operatively. LAPEG might be a safe alternative when the application of PEG is difficult. PMID- 26742220 TI - [Ha'Emek Medical Center]. PMID- 26742221 TI - [ASYMPTOMATIC ADULT RETROGASTRIC BRONCHOGENIC CYST: DIAGNOSIS AND TREATMENT CONSIDERATION BY ENDOSCOPIC ULTRASOUND FINE NEEDLE ASPIRATION (EUS-FNA)]. AB - BACKGROUND: Adult bronchogenic cysts are rare. Retrogastric bronchogenic cysts are even rarer with only over 30 cases being reported in the English literature. These foregut cysts can be confused with cystic tumors. CASE PRESENTATION: We describe the case of a large gastric bronchogenic cyst in an asymptomatic 61-year old woman who underwent an abdominal computerized tomography as part of a routine follow-up after lumpectomy due to breast cancer. Final diagnosis was made by endoscopic ultrasound fine needle aspiration (EUS-FNA) which led to conservative management of the patient who has remained asymptomatic over the last 8 years. CONCLUSIONS: Preoperative diagnosis of adult gastric bronchogenic cyst has been difficult to achieve. Our case highlights the importance of EUS in establishing the definitive diagnosis, enabling just follow-up with repeated imaging studies. The relevant literature is discussed. PMID- 26742222 TI - [IS THE PREVALENCE OF CHILDHOOD OBESITY IN ISRAEL SLOWING DOWN?]. AB - BACKGROUND: Childhood and adolescent obesity is an ongoing problem in the Western World and has increased dramatically over the last four decades. Similar trends have been observed in Israel, but only limited data has been available on the prevalence of obesity. The rise in the prevalence of childhood obesity is mainly attributed to the change in lifestyle including increased intake of fast food and lowered extent of physical activities. OBJECTIVE: To determine the current prevalence of childhood and adolescent obesity in Northern Israel and to compare results to former years. METHODS/DESIGN: We conducted an analysis of weight, height and body mass index (BMI, in two separate periods: between the years 2010 2012 and 2005-2007, using the electronic medical records of the Clalit Health Services. A total of 94,239 subjects were enrolled between the ages of 2-18 years. RESULTS: Twenty four percent of the children had a BMI above the 85th centile and 10.5% were found to be obese. The prevalence of obesity was higher in males as compared to females [11.5% vs. 9.5%, respectively, p<0.0001). Obesity peaked in girls at age 9 and in boys at age 11 (33%, 30.5%, respectively). The prevalence of overweight and obesity was significantly higher in urban regions when compared with rural regions in all age groups. Among the age groups of 2-5 and 6-11 years, the Jewish population showed a higher rate of overweight and obesity as compared to the Arab population (age group 2-5 years: obesity 9.6% vs. 8.3%, respectively, p=0.15; above 85th centile: 22.2% vs. 19.6%, respectively, p<0.0001; age group 6-11 years: obesity 12.9% vs. 10.5%, respectively, p<0.0001; above 85th centile: 26.5% vs. 23.4%, respectively, p<0.0001). No increase in the prevalence of obesity was observed between the years 2005-2007 and 2010- 2012 and above the age of 6 years a trend towards a decrease in the prevalence of obesity and overweight has been shown. CONCLUSIONS: A high prevalence of overweight and obesity has been shown in northern Israel. The prevalence was high for all age groups. The finding that there was no increase in the prevalence of obesity during the last 5 years may suggest that obesity has reached its peak. PMID- 26742223 TI - [THE CLINICAL AND DEMOGRAPHIC CHARACTERISTICS OF PATIENTS WHO FREQUENT THE PSYCHIATRIC EMERGENCY ROOM IN A GENERAL HOSPITAL]. AB - INTRODUCTION: The recent policy implemented in Israel of reducing psychiatric admissions and the concomitant shifting of treatment to outpatient clinics, together with briefer stays in hospital and a growing number of repeat emergency room (ER) visits have created a "revolving door" phenomenon, whereby a small number of frequent attenders are responsible for a disproportionate fraction of ER visits. OBJECTIVES: To characterize psychiatric ER frequent attenders and understand their special needs by analyzing the "revolving door" phenomenon and defining the at-risk group. METHODS: Psychiatric attenders at the Ha'Emek Medical Center in Afula during a single year were divided retrospectively into three groups according to the number of their visits to the ER. One group had a single ER visit, an intermediate group had two to three ER visits, and a third group had four or more ER visits (frequent attenders). The groups were weighted by the respective number of attenders and analyzed using the optimal allocation technique. RESULTS AND CONCLUSIONS: The findings showed that people prone to frequently repeat visits to a psychiatric emergency room are familiar with the psychiatric system, unemployed, with an unstable income (or recipients of an allowance from the National Insurance), single or divorced, of Sephardic origin, have been hospitalized in the past, and are urban, native-born with social and family problems. From a clinical perspective the findings also showed thatthis subgroup comes to the ER without a referral, suffers from depression and psychotic states, personality disorders or mental retardation, has past suicide attempts, and the patients are under medication treatment. DISCUSSION AND SUMMARY: Frequent attenders make up a particularly difficult group of patients with major psychiatric disorders. The ER is not a fit setting for the treatment of such patients. The construction of a proper therapist-patient relationship is cardinal to attaining a meaningful remission. Prompt recognition of frequent attenders and their respective visiting pattern is required, allowing for a structured therapeutic approach which will include patient and family guidance and an algorithmic handling of emergency situations. PMID- 26742224 TI - [HIGH INCIDENCE AND BROAD GENETIC VARIABILITY OF MECKEL-GRUBER SYNDROME IN THE ARAB POPULATION RESIDING IN NORTH-EAST ISRAEL]. AB - BACKGROUND: Meckel-Gruber syndrome (MKS) is a lethal rare inherited autosomal recessive disease. The syndrome is characterized by multiple congenital anomalies including polycystic kidneys, occipital encephalocele and polydactyly. The presence of two out of these anomalies is sufficient for a definitive diagnosis. At least 11 genes have been reported to-date to underlie MKS. METHODS: In the current study we have retrospectively analyzed all the families at the Ha'Emek Medical Center in which the diagnosis of MKS was determined. RESULTS: In total, 17 affected individuals are reported, originating from 12 sibships. The diagnoses were conducted or suspected by prenatal sonography, and some of the newborns were examined. Polycystic kidneys were present in 94% of cases, occipital encephalocele in 82% and polydactyly in about half of all cases. The underlying genetic cause was identified in 11 of our families, comprising mutations in 7 different genes, revealing high genetic heterogeneity. CONCLUSION: The identification of the genetic basis of MKS in our region allows focused and data based genetic counseling and serves as an important tool for reproductive decisions, including the prevention of recurrence of pregnancies affected with this lethal syndrome. In the near future we plan to study the prevalence of the different MKS mutations found in each community in order to consider the expansion of national genetic screening in high risk populations. PMID- 26742225 TI - [SEAFOOD ALLERGY IN ISRAEL]. AB - Allergy to seafood such as shrimps, crab, lobster and fish eggs is relatively infrequent in Israel compared to fish allergies and allergies to other foods. This is mainly due to the fact that most of the population and restaurants preserve and maintain Kosher food. Changes in the population eating habits, partly due to immigration, were followed by increased frequency of such sensitivities in recent years. We describe three typical cases that illustrate the characteristics of allergy to sea foods. Allergy to seafood can present as a single sensitivity or be part of an allergic tendency, atopy, with other allergic manifestations. Diagnosis by allergy skin test or laboratory evaluation by specific IgE is available for most sea foods but not for fish eggs. The current therapeutic approach is strict avoidance and all patients should be provided with and carry with them an epinephrine auto-injector. PMID- 26742226 TI - [THE PREVALENCE OF SUBCLINICAL MYOCARDITIS AMONG YOUNG CHILDREN WITH ACUTE VIRAL INFECTION]. AB - BACKGROUND: Viruses are the most prevalent ausative agents of myocarditis in young children. Studies have shown acute myocarditis in post mortem examinations during viral disease outbreaks. The aims of this study are to assess the prevalence of and risk factors for subclinical acute myocarditis in young children hospitalized with an acute viral disease. OBJECTIVES: Evaluation of the prevalence of asymptomatic myocarditis or decrease in heart functions during viral infection. METHODS: A prospective study was conducted between 1st January and 30th September, 2009. The study included 45 children 3-60 months old hospitalized with febrile illness with no clinical or microbiological evidence of acute bacterial infection. Serum levels of troponin were obtained, and ECG and echocardiography were performed in all the children. Parameters that determined myocarditis included: (1) ECG ST-T changes suggestive of myocarditis; (2) Increased serum troponin level; (3) Echocardiography findings including: shortening fraction less than 28%, left ventricle end diastolic diameter > than 2 standard deviations for age, abnormal mitral valve incompetence, or abnormal diastolic function. Clinical and epidemiological data were analyzed in order to determine parameters related to findings suggestive of silent acute myocarditis. RESULTS: In 16 (35%) children at least one parameter, and in 7 (16%) at least 2 parameters of acute myocarditis were found. Impaired diastolic function was found in 11 cases (69%), ECG changes in 5 children (35%, left ventricle dilatation in 4 (25%), and decreased shortening fraction in 3 cases (18%]. Other symptoms and signs of myocarditis were not found in any of the 16 children, and no clinical or epidemiological parameter was significantly associated with silent myocarditis. CONCLUSIONS: In a third of the patients, some evidence of myocardial dysfunction was documented. In seven of them (16% of all cases), there were two different categories of myocardial dysfunction. Those cases are suspected to be silent acute myocarditis. No clinical and epidemiological parameters associated with the disease were found. The clinical importance of this phenomenon should be determined by a long-term follow-up study. SUMMARY: In this preliminary study, we found a high prevalence of cardiac involvement in hospitalised children with viral infections. It seems that this cardiac involvement is due to acute sub clinical myocarditis. The importance of these findings should be evaluated. PMID- 26742227 TI - [ABANDONED EMBRYOS OR SURPLUS FERTILIZED OOCYTES--SEEKING THE SOLUTION FOR A FROZEN BURNING PROBLEM]. AB - Israel is a world leader in the utilization rate of in vitro fertilization (IVF). During many IVF cycles, spare fertilized oocytes are cryopreserved. Today, thousands of fertilized oocytes, cryopreserved long ago, are stored in Israeli IVF units. The effort to contact the individuals who own the fertilized oocytes, so that they will approve thawing or finance continued storage, have mostly fAed. In this article we discuss the moral status of the fertilized oocyte and the ethical principles which should govern the way in which we deal with abandoned embryos. We present the different accounts for moral status and the diverse opinions regarding the status of the fertilized oocyte. At the end of the discussion we state our position regarding the ethical way to deal with the abandoned fertilized oocytes. PMID- 26742229 TI - [TURNING THE PYRAMID IN PRENATAL CARE]. AB - Most complications of pregnancy manifest towards the latter part of pregnancy. Nevertheless, present day diagnostic techniques, such as sonography, Doppler, biochemical screening tests, and the newly developed ability to study free fetal DNA in maternal blood, enables early identification of high risk groups for maternal and fetal morbidity, as well as fetal genetic and anatomical pathology. Dr. Nicolaides has coined this changing trend with the term "Turning the Pyramid". Early screening enables earlier and more directed follow-up with the application of relevant diagnostic tests. Obvious advantages include the potential to reduce maternal-fetal morbidity before it becomes apparent clinically. Additionally, the earlier diagnosis of fetal pathology, allows more time for parents and medical staff to assess the situation, and reach a decision regarding the continuation of the pregnancy. A possible drawback of such an approach, of early identification of high risk groups, is the uncertainty it arouses, sometimes for a long duration, with the accompanying apprehension and stress parents have to endure. A multidisciplinary team, consisting of specialists in fetal-maternal medicine, genetics, ultrasound, and perinatology, will be needed in order to best deal with the often complex information, which is becoming increasingly available at a very early stage of pregnancy. PMID- 26742228 TI - [THE COMBINED LAPAROSCOPIC AND ENDOSCOPIC TREATMENT FOR CONCOMITANT GALLSTONES AND COMMON BILE DUCT STONES: TWO STAGE OR SINGLE STAGE MANAGEMENT?]. AB - Common bile duct stones occur in 3%-33% of patients suffering from gallbladder stones. Concurrent gallbladder and common bile duct stones should be treated due to the risk of life-threatening complications such as pancreatitis and cholangitis. There is no consensus regarding the optimal management of common bite duct stones associated with cho[elithiasis. Currently there are variable treatment protocols for concomitant gallstones and common bile duct stones which involve laparoscopic cholecystectomy and laparoscopic bile duct exploration alone, or in combination with preoperative, postoperative, or same session endoscopic retrograde cholangiopancreatography (ERCP). Treatment options depend on local expertise and resources. The aim of this review is to discuss the different treatment options and to assess their utility based on the most recent reports and reviews. PMID- 26742230 TI - [MEDICAL THERAPY FOR THE MANAGEMENT OF PRETERM LABOR: IS THERE A FIRST LINE AGENT?]. AB - Preterm birth is defined as delivery before 37 weeks. It is the leading cause of perinatal morbidity and mortality. Spontaneous preterm birth accounts for approximately 70% of all preterm births. Postponing delivery for 48 hours in order to allow administration of corticosteroids, magnesium for neuroprotection and in order to transfer women to a center with neonatal intensive care unit are the goals of tocolytic therapy. The benefits of tocolytic therapy between 24.0 and 34.0 weeks of gestation outweigh the risk of maternal and fetal complications and it should be initiated provided no contraindications exist. Tocolytic agents that have been used are: prostaglandin synthetase inhibitors, calcium channel antagonists, B-adrenergic agonists, magnesium and oxytocin receptor antagonists. All drugs have demonstrated limited benefit that consists mainly of prolonging the gestational age for 48 hours, without a reduction in the incidence of perinatal mortality and morbidity. Additionally, most available tocolytic agents carry inherent risks of adverse effects. According to the American College of Obstetricians and Gynecologists recommendations, there is no clear first line tocolytic drug to manage preterm labor. Other subjects of debate related to the use of tocolytic therapy include: The effectiveness of combination therapy, the use of tocolytic therapy in multiple pregnancies and the use of progesterone as an adjuvant therapy. We will address the efficacy and tolerability of the tocolytic agents available, the issue of maintenance therapy and debates mentioned above, and try to suggest a first line tocolytic agent based on a study performed at our institution. PMID- 26742231 TI - [THIAMINE--"THE ROAD EXPERIENCE" OF THE VITAMIN AS A MANIFESTATION OF DEFICIENCY IN A WORLD OF ABUNDANCE]. AB - Thiamine or vitamin B1 is a water soluble vitamin of the vitamin B complex. It is synthetized by bacteria, fungi and plants and is an essential component of multicellular living organisms. Humans are not able to synthetize this vitamin and have to obtain it from different foods. Thiamin has a vital role in the normal function of the human body. It functions as a coenzyme in the catabolism of carbohydrates and amino acids and has an antioxidant role. It has an essential function in a series of metabolic processes related to energy production and conversion of sugar to ATP, as a catalyst in the Krebs cycle. It takes part in the synthesis of neurotransmitters and has a main role in the central nervous system and immune system. Deficiency results in Wernicke-Korsakoff syndrome, optic neuropathy, Beri-Beri and other disorders. Vitamin B deficiency in not rare and may occur in conditions related to malnutrition, alcoholism, diabetes, congestive heart failure and others. In this review an effort has been made to demonstrate the presence of thiamine deficiency in various clinical situations frequent in modern medicine, attributed in the past to populations with "classical" inadequate feeding and starvation, or severe malnutrition. Identification of potential causes of vitamin B1 deficiency, knowledge of its metabolic properties and the clinical manifestations of its deficiency are important for the implementation of early therapeutic response required for the reduction and prevention of symptoms related to this disorder. PMID- 26742233 TI - [The Ying and Yang of pulmonary microbiota]. PMID- 26742232 TI - [THE VALLEY IS A DREAM"--ON THE HISTORY OF THE NEONATAL INTENSIVE CARE UNIT IN THE HA'EMEK MEDICAL CENTER]. AB - The establishment of the Cooperative Merhavia in 1910 marked the beginning of the settlement in the Jezreel Valley. The medical services started to develop almost simultaneously, with a small number of physicians and nurses who came in the wake of the first settlers and set up infirmaries in the region's communities mainly to treat malaria and other infectious diseases. The Ha'Emek Medical Center, which celebrates 90 years since its foundation, was the first hospital of Kupat Holim. It started out in a few temporary buildings in Kibbutz Ein Harod and was then transferred to its present location in Afula. Records of treatment of preterm babies go as far back as the 1950s. The Neonatal Intensive Care Unit in Afula was one of the first in Israel and, for many years, served as a referral center for hospitals in the North and Sharon regions, until similar departments were gradually founded. The history of the Neonatal Department of the Ha'Emek Medical Center is described, on the background of the development of the medical services, since the earliest settlement in the Jezreel Valley and the foundation of the hospital in Afula. PMID- 26742234 TI - [The asthma-COPD overlap syndrome]. AB - Asthma and COPD are often considered mutually exclusive diseases, mainly because of the inclusion of only typical cases of asthma or COPD in therapeutic clinical trials. However, clinicians are unable to distinguish between both conditions in a substantial number of patients, a situation that may be called the "asthma-COPD overlap syndrome". It is important to recognize this entity, as patients suffering from an asthma-COPD overlap syndrome are more symptomatic, have a poorer quality of life and suffer more exacerbations than patients with asthma or COPD alone. In the absence of studies specifically designed to assess the treatment modalities for these patients, it appears wise to prescribe inhaled corticosteroids early in the course of the disease, considering their established efficacy in asthma. PMID- 26742235 TI - [Chronic obstructive pulmonary disease and its links with cardiovascular risk factors]. AB - Patients with chronic obstructive pulmonary disease (COPD) often also present with one or more cardiovascular risk factors, resulting not only in an increased mortality rate but also in a major impact on the health care system. Aside from common predisposing and environmental factors, the hypothesis of a chronic systemic inflammation linking COPD and cardiovascular co-morbidities is supported by an increasing body of evidence in recent literature. This could in turn pave the way for new developments, both diagnostic and therapeutic, in the future. In this context, the studies CoLaus and PneumoLaus aim to further investigate characteristics of the Lausanne general population, in particular those relating to cardiovascular and respiratory disease. PMID- 26742236 TI - [Management of massive hemoptysis]. AB - Less than 5% of all cases of haemoptysis are considered to be massive, representing a life-threatening condition that warrants urgent investigations and treatment. Efforts should be concentrated on determining the origin of the haemoptysis and the presence of an underlying respiratory pathology, in order to ensure supportive measures and a rapid control of the bleeding. Bronchial artery embolization is considered to be the treatment of choice and thoracic surgery should only be considered in cases of localized lesions with a high risk of re bleeding, pulmonary artery hemorrhage and failure or contraindications to embolization. PMID- 26742237 TI - [Non-infectious lung diseases after hematopoietic stem cell transplantation]. AB - Non-infectious pulmonary complications following hematopoietic stem cell transplantation are entities occuring early or late, depending on whether they occur before or after 100 days post-transplantation. They have firstly to be differentiated from infectious complications, which is not always easy, as their clinical and radiological aspects can mimic a viral or bacterial pneumonia. Corticosteroids are the most given treatment but a significant subset of patients have a fatal outcome. This article will review the clinical, radiological, functionnal features and the therapeutic options of six entities (engraftment syndrome, diffuse alveolar hemorrage, idiopathic pneumonia syndrome, organizing pneumonia, bronchiolitis obliterans, post-transplantation lympho-proliferative disease). PMID- 26742238 TI - [Interstitial lung disease in connective tissue diseases]. AB - Interstitial lung disease represents a major clinical aspect of the four major connective tissue diseases: rheumatoid arthritis, scleroderma, polymyositis/dermatomyositis and systemic lupus erythematosus (SLE). Early recognition in the course of the disease is essential, as interstitial lung disease will often determine the vital prognosis of these patients. Treatment is most frequently based on experts' opinion, because there are only few randomized controlled trials in this field. PMID- 26742239 TI - [Lung abscess: changes in treatment?]. AB - Lung abscess occurs in very pleomorphic according to germs initially involved. The mechanism commonly found is an aspiration of the oropharyngeal flora in patients with disorders of consciousness or swallowing. The infection is polymicrobial, with presence of anaerobic germs in 2/3 of the cases. The support consists of a prolonged antibiotic treatment, as well as anaerobic until resolution or stability of the radiological image. In case of prolonged toxic state, drainage of the abscess is to be discussed especially if there is no airways drainage. Surgical sanctions is rarely needed regardless of the size of the abscess, unless underlying carcinoma is present. PMID- 26742240 TI - [Minimally invasive spine surgery: past and present]. AB - In the early twentieth century, the understanding of spine biomechanics and the advent of surgical techniques of the lumbar spine, led to the currently emerging concept of minimal invasive spine surgery, By reducing surgical access, blood loss, infection rate and general morbidity, functional prognosis of patients is improved. This is a real challenge for the spine surgeon, who has to maintain a good operative result by significantly reducing surgical collateral damages due to the relatively traumatic conventional access. PMID- 26742241 TI - [Reporting of adult patients in dangerous situations. Article 455 CC, an unrecognized exception of professional confidentiality]. PMID- 26742243 TI - [The first uterine transplants are about to be authorized in France]. PMID- 26742244 TI - [Knowledge of suffering]. PMID- 26742242 TI - [Account of a first healthcare educational experience in Geneva]. PMID- 26742245 TI - [Is the topic of climate change confronted with scepticism?]. PMID- 26742246 TI - [Psychotherapeutic treatments in major depression: the literature shows a very optimistic picture]. PMID- 26742247 TI - [Of women and health]. PMID- 26742248 TI - [Response]. PMID- 26742249 TI - [Miscellaneous - profound coma, smoking and AIDS]. PMID- 26742250 TI - [The increase to 2016 insurance premiums will be more than the 4% already announced]. PMID- 26742251 TI - [Tobacco laws: the economy before health]. PMID- 26742252 TI - [Medical officers: the fatal weapons of insurers]. PMID- 26742253 TI - Research Report: Intermittent hypobaric hypoxia and hyperbaric oxygen on GAP-43 in the rat carotid body. AB - Adaptive changes in the carotid body (CB) including the expression of the growth associated protein-43 (GAP-43) have been studied in response to low, but not high, oxygen exposure. Expression of GAP-43 in the CB of rats under different atmospheric pressures and oxygen partial pressure (PO2) conditions was investigated. Mature male Sprague-Dawley rats were exposed to intermittent hypobaric hypoxia (IHH, 0, 1, 2 and 3 weeks), intermittent hyperbaric oxygen (IHBO2, 0, 1, 5 and 10 days, sacrificed six hours or 24 hours after the last HBO2 exposure), and intermittent hyperbaric normoxia (IHN, same treatment pattern as IHBO2). GAP-43 was highly expressed (mainly in type I cells) in the CB of normal rats. IHH u-regulated GAP-43 expression in the CB with significant differences (immunohistochemical staining [IHC]: F(3,15)=40.64, P < 0.01; western blot [WB]: F(3,16) = 53.52, P < 0.01) across the subgroups. GAP-43 expression in the CB was inhibited by IHBO2 (controls vs. IHBO2 groups, IHC: F(6,30) = 15.85, P < 0.01; WB: F(6,29) = 15.95, P < 0.01). No detectable changes in GAP-43 expression were found for IHN. These findings indicated that different PO2 conditions, but not air pressures, played an important role in the plasticity of the CB, and that GAP 43 might be a viable factor for the plasticity of the CB. PMID- 26742254 TI - Efficiency of hyperbaric oxygen and steroid therapy in treatment of hearing loss following acoustic trauma. AB - INTRODUCTION: Most commonly used treatment modalities for acute acoustic trauma (AAT) include steroid and hyperbaric oxygen (HBO2) therapy. The aim of this study is to investigate the effectiveness of combined steroid and HBO2 therapy in patients who develop AAT during firearms training and the effect of delay to treatment on treatment success. MATERIALS AND METHODS: Patients admitted with the complaint of hearing loss after firearms training between January 2011 and April 2013 were evaluated retrospectively. Patients were grouped according to date of admission; patients admitted within the first 10 days were included in Group A and those admitted between Days 11 and 30 in Group B. RESULTS: A total of 48 patients (73 ears) with AAT were included. There were 37 ears in Group A and 36 ears in Group B. The number of ears with complete treatment response, partial treatment response and treatment failure (unchanged) were one (2.7%), 7 (18.9%) and 29 (78.4%) in Group A and 0 (0%), 3 (8.3%) and 33 (91.7%) in Group B, respectively. There was no statistically significant difference between the groups (p = 0.095). Late-term results (at Week 6) demonstrated Group A showed higher hearing gain on high frequencies than Group B (p < 0.05), but this result was not consistent with clinical outcome results. CONCLUSION: The success rate of combined HBO2 and steroid therapy was very low in our study. However, early initiation of treatment results in better outcomes. Protective measures have great importance in preventing AAT. PMID- 26742255 TI - Residual oxygen time model for oxygen partial pressure near 130 kPa (1.3 atm). AB - A two-part residual oxygen time model predicts the probability of detectible pulmonary oxygen toxicity P(P[O2tox]) after dives with oxygen partial pressure (PO2) approximately 130 kPa, and provides a tool to plan dive series with selected risk of P[O2tox]. Data suggest that pulmonary oxygen injury at this PO2 is additive between dives. Recovery begins after a delay and continues during any following dive. A logistic relation expresses P(P[O2tox]) as a function of dive duration (T(dur)) [hours]: P(P[O2tox]) = 100/[1+exp (3.586-0.49 x T(dur))] This expression maps T(dur) to P(P[O2tox]) or, in the linear mid-portion of the curve, P(P[O2tox]) usefully to T(dur). For multiple dives or during recovery, it maps to an equivalent dive duration, T(eq). T(eq) was found after second dives of duration T(dur 2). Residual time from the first dive t(r) = T(eq) - T(dur2). With known t(r), t and T(dur) a recovery model was fitted. t(r) = T(dur) x exp [-k x((t-5)/T(dur)2], where t = t - 5 hours, k = 0.149 for resting, and 0.047 for exercising divers, and t represents time after surfacing. The fits were assessed for 1,352 man-dives. Standard deviations of the residuals were 8.5% and 18.3% probability for resting or exercise dives, respectively. PMID- 26742256 TI - Risk factors increasing health hazards after air dives. AB - The aim of the present study was to determine the effect of postprandial hypertriglyceridemia on the risk of decompression stress following hyperbaric air exposures. The study involved 55 male individuals aged 20-48 years (31.47 +/- 5.49 years), body mass index 20.3-33.2 kg/m2 (25.5 +/- 2.58 kg/m2). Blood was sampled two hours after a meal each participant had in accordance with individual dietary preferences to determine the following parameters: blood cell counts, activity of aspartate aminotransferase (AST) and alanine ammotransterase (ALT), concentrations of total cholesterol and triglycerides. After each hyperbaric exposure, the presence and intensity of decompression stress were assessed using the Doppler method. Decompression stress was found in 30 individuals. Postprandial hypertriglyceridemia and hypercholesterolemia increased the risk of decompression stress after hyperbaric air exposures. PMID- 26742257 TI - Measurement and modeling of oxygen content in a demand constant mass ratio injection rebreather. AB - Mechanical semi-closed rebreathers do not need oxygen sensors for their functions, thereby reducing the complexity of the system. However, testing and modeling are necessary in order to determine operational limits as well as the decompression obligation and to avoid hyperoxia and hypoxia. Two models for predicting the oxygen fraction in a demand constant mass ratio injection (DCMRI) rebreather for underwater use were compiled and compared. The model validity was tested with an IS-MIX, Interspiro AB rebreather using a metabolic simulator connected to a breathing machine inside a water-filled pressure chamber. The testing schedule ranged from 0.5-liter (L) to 3-liter tidal volumes, breathing frequencies from five to 25 breaths/minute and oxygen consumptions from 0.5 L/minute to 4 L/minute. Tests were carried out at surface and pressure profiles ranging to 920 kPa(a) (81 meters of sea water, 266 feet of sea water). The root mean squared error (RMSE) of the single-compartment model was 2.4 percent-units of oxygen for the surface test with the 30% dosage setting but was otherwise below 1% unit. For the multicompartment model the RMSE was below 1% unit of oxygen for all tests. It is believed that these models will aid divers in operational settings and may constitute a helpful tool when developing semi closed rebreathing apparatuses. PMID- 26742258 TI - Is there a difference between active opening of the Eustachian tube in a hypobaric surrounding compared to a hyperbaric surrounding? AB - INTRODUCTION: The Eustachian tube (ET) is the key to pressure equalization between the middle ear and ambient pressure. To date, little is known about differences of the opening mechanisms under hyper- or hypobaric conditions. Aim of this study was to compare standard ET opening parameters during standardized hypo- and hyperbaric exposures. METHODS: Thirty healthy participants were exposed to a standardized profile of decompression and compression (SPDC) in a hypo /hyperbaric pressure chamber. Impedance, expressed as tympanic membrane compliance, was recorded at intervals during the excursions from 1 atmosphere absolute (atm abs) to 0.8 and 1.2 atm abs respectively. Parameters for tubal opening were obtained during SPDC: ET opening pressure (ETOP), ET opening duration (ETOD) and ET opening frequency (ETOF), hypobaric (Phase 1) and hyperbaric (Phase 2) data were compared. RESULTS: Mean value for Valsalva maneuver ETOP was 40.10 +/- 19.02 mbar in Phase 2 vs. 42.82 +/- 21.75 mbar in Phase 1. For ETOD it was 2.80 +/- 2.09 seconds in Phase 2 vs. 2.51 +/- 1.90 seconds in Phase 1. For swallowing, mean value for ETOP was 33.47 +/- 14.50 mbar in Phase 2 vs. 28.44 +/- 14.04 in Phase 1. ETOD was 0.82 +/- 0.60 seconds in Phase 2 vs. 0.76 +/- 0.55 seconds in Phase 1. There was no statistical significance for ETOP, ETOD and ETOF between the two phases. CONCLUSION: No statistical significant difference was evident for active pressure equalization (Valsalva and swallowing) between a hyperbaric setting (dive) and a hypobaric setting (flight) in healthy subjects. PMID- 26742259 TI - Sudden hearing loss and vertigo after tooth extraction successfully treated with combined therapy including HBO2: a case report. AB - Sudden sensorineural hearing loss (SSNHL) is a decrease in hearing of at least 30 dB that occurs within three days and which affects at least three consecutive frequencies in either ear or both ears. This case report describes a woman who had sudden hearing loss and vertigo in the right ear after tooth extraction. As the first-line therapy, systemic and intratympanic steroid injections were used this led to a slight improvement; however, the majority of improvement in hearing was not observed until hyperbaric oxygen (HBO2) therapy was instituted on the 20th day of hearing loss. Sudden hearing loss and vertigo after tooth extraction is an otologic emergency and early evaluation and treatment are effective. HBO2, although employed beyond the Undersea and Hyperbaric Medical Society's recommended initial 14 days of symptom onset, very was effective for this particular case. PMID- 26742260 TI - Hyperbaric oxygen therapy in treating post-ischemic pain caused by polycythemia vera complications: a case report. AB - One of the complications of polycythemia vera (PV) can be acute thrombotic occlusion. The severity and prolonged duration of this condition can lead to nerve damage. In this case a 34-year-old male had thrombotic occlusions of the popliteal artery, resulting in chronic limb ischemia, which was treated with thrombectomy and amputation of one digit. The administered therapy consisted of hydroxyurea, analgesics, antidepressants and acetylsalicylic acid. When the patient was admitted he suffered from ischemic pain, he had developed an ulcer on his big toe and he was emotionally unstable, with suicidal thoughts. The patient was treated with 14 hyperbaric oxygen (HBO2) treatments in total. There was evident paint relief after four treatments and healing of the ulcerous tissue after three weeks. During the patient's medical examination eight months after the treatment, his condition was still satisfactory, with no presence of pain, ulcer or signs of depression, and with no changes in hemodynamics. This case provides additional evidence to the data for HBO2 use in ischemic pain management. PMID- 26742261 TI - Coronary gas embolism during a dive: a case report. AB - INTRODUCTION: A healthy scuba diver presented with a NSTEMI (non-ST segment elevation myocardial infarction), pneumothorax and pneumomediastinum after diving. CASE REPORT: A 34-year-old woman with no significant medical history presented to the emergency department after an episode of loss of consciousness and seizure-like activity after an uncontrolled ascent during a dive in a freshwater lake at 5,700 feet of altitude. A chest radiograph showed pneumothorax, pneumomediastinum and pneumopericardium. She had septal infarction as indicated by ECG, and elevated troponin. Echocardiogram revealed a mildly depressed left ventricular ejection fraction (LVEF) with apical akinesis. Coronary angiogram showed normal coronary arteries. Hyperbaric oxygen was not given since evaluation occurred 28 hours after the event: The patient had a pneumothorax, and was neurologically normal. She was discharged on angiotensin converting enzyme inhibitors (ACE-I) and opioids for chest pain. Cardiac function normalized on transthoracic echocardiogram (TTE) two weeks later, but she continued to complain of chest pain that was treated with dihydropyridine calcium channel blockers. She then developed pericarditis confirmed by CMRI, requiring treatment with non-steroidal anti-inflammatory drugs (NSAIDS), colchicine and steroids. Five months after the accident, she was asymptomatic, with excellent exercise function and normal exercise stress echocardiogram. CONCLUSIONS: Reports of myocardial injury caused by arterial gas embolism from diving are rare. This case shows coronary air embolism complicating pulmonary barotrauma and may be the first report of pericarditis complicating myocardial injury after an AGE. PMID- 26742262 TI - Pneumothorax in the hyperbaric chamber: easier and earlier diagnosis with ultrasound. PMID- 26742263 TI - Mycoplasma genitalium: the need for testing and emerging diagnostic options. PMID- 26742264 TI - The push to reconcile the gap in LDT regulations. PMID- 26742265 TI - Adding quality to your qualitative IHC. PMID- 26742267 TI - Achieving value: Community outreach and other strategies for labs. PMID- 26742266 TI - Quantifying IHC data from whole slide images is paving the way toward personalized medicine. PMID- 26742268 TI - A LAMP to see in the molecular darkness. PMID- 26742269 TI - Is your POCT program inspection-ready? PMID- 26742270 TI - Meaningful Use stage two--and stage three: Labs take the lead. PMID- 26742271 TI - Co-creating critical limits for enhanced acute care: proven need and web knowledge base. Part 1: A call to action! PMID- 26742273 TI - Increasing Safeguards for Crude Oil Trains. PMID- 26742274 TI - Atmospheric Testing and the New OSHA Construction Confined Spaces Standard. PMID- 26742275 TI - Welding Safety and Health Considerations. PMID- 26742276 TI - Vertical Manufacturing of Flame-Resistant Cotton and Cotton-Rich Fabrics. PMID- 26742277 TI - How to Stay Safe and Stay Warm This Winter. PMID- 26742278 TI - #1 Priority When Disaster Occurs: Everyone Goes Home. PMID- 26742279 TI - Review Floor Maintenance Procedures to Reduce Slip and Fall Incidents. PMID- 26742280 TI - Understand the Dangers of Electrical Shock. PMID- 26742281 TI - Health Care Hazmats: There's More On Site Than Just Bloodborne Pathogens. PMID- 26742282 TI - Behavior-Based Safety: A Visual Workflow Model. PMID- 26742283 TI - Mindfulness: Moving Beyond Trends Toward Performance. PMID- 26742284 TI - [Results of a post-marketing surveillance of meropenem administered over 2 g/day for serious infectious diseases]. AB - The post-marketing surveillance of meropenem (Meropen(r)) administered over 2g/day for serious infectious diseases was conducted between August 2011 and June 2013 to evaluate safety and efficacy under actual clinical use. There were 382 and 322 evaluable cases for safety and efficacy respectively, of 399 case cards collected from 87 institutions. In safety analysis, the incidence of adverse drug reactions (ADRs) associated with use of meropenem (including abnormal laboratory findings) was 19.1% (73/382 cases), and the main ADRs were hepatic function abnormal, aspartate aminotransferase increased, alanine aminotransferase increased, liver disorder, and diarrhoea, which were similar to these observed in the post-marketing surveillances of meropenem conducted before. In efficacy analysis, the efficacy was 73.6% (237/322 cases), which is as same as 71.4% (3214/4504 cases) of post-marketing surveillance of meropenem conducted after first approval under 2 g/day for infectious diseases. These results confirmed meropenem (Meropen(r)) is one of the useful antimicrobial agents for serious infectious diseases. PMID- 26742285 TI - [A multicenter study of the antimicrobial susceptibility of Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis from community acquired infections in Saitama, Japan]. AB - We examined regional surveillance of antimicrobial susceptibility of community acquired bacterial pathogens from patients in Saitama, Japan. The fourth-year survey was conducted in three of the period 2007-2010 (period I, 2007-2008; period II, 2008-2009; period III, 2009-2010). Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Japanese Society of Chemotherapy using maximum 13 antibacterial agents. Susceptibility testing was evaluable with 789 strains (227 Streptococcus pneumoniae, 148 Streptococcus pyogenes, 220 Haemophilus influenzae, and 194 Moraxella catarrhalis). Ratio of penicillin-susceptible S. pneumoniae (PSSP, MIC of benzylpenicillin <= 0.06 MUg/mL) was 43.5% (period I), 43.5% (period II) and 55.8% (period III), and those of erythromycin-sensitive and azithromycin sensitive S. pyogenes were 100% and 65.5% (period I), 47.9% and 47.9% (period II), 29.4%, and 29.4% (period III) , respectively. Among H. influenzae, beta lactamase-nonproducing ampicillin-resistant isolates were 34.9% (period I), 25.8% (period II), and 17.1% (period III); however, beta-lactamase-nonproducing ampicillin-intermediately resistant isolates were 19.8% (period I), 26.9% (period II), and 29.3% (period III). Regarding M. catarrhalis, macrolides showed potent activities, with MIC90s of <= 0.25-0.5 MUg/mL, and fluoroquinolones showed strong activities, with MIC90s <=0.03-0.125 MUg/mL. The result of this survey indicated that the trends observed were similar to the results of previous nationwide surveillance. PMID- 26742286 TI - Inflammatory Bowel Disease in Central and South America--an opportunity to identify the aetiology of these conditions. PMID- 26742287 TI - [Rudolf Carl Virchow]. PMID- 26742288 TI - An unusual cause of persistent gastrointestinal bleeding. PMID- 26742289 TI - [Discovery in upper gastrointestinal video endoscopy]. PMID- 26742290 TI - [Influence of proton pump inhibitors on intestinal fermentative profile: a case control study]. AB - INTRODUCTION: Proton pump inhibitors could have an impact on the results of breath tests performed in patients with irritable bowel syndrome. This impact could be due to the development of small intestine bacterial overgrowth. OBJECTIVE: To compare the prevalence of fermentative profile alterations of irritable bowel syndrome patients exposed and not-exposed to proton pump inhibitor therapy. MATERIAL AND METHODS: Subjects with irritable bowel syndrome were enrolled. A validated questionnaire assessing symptom severity as well as proton pump inhibitor treatment was delivered. A lactulose breath test was undertaken by each enrolled subject. Fermentative profile (area under the curve of hydrogen excretion/time) was compared between proton pump inhibitors consumers and non-consumers. Furthermore, small intestine bacterial overgrowth prevalence was compared. RESULTS: Two hundred and twenty five patients were enrolled. No significant differences were found on the fermentative profile between groups [AUC mediana 3,776 (rango 2,124-5,571) vs 4,347 (rango 2,038-5,481), P = 0.3]. Small intestine bacterial overgrowth prevalence was similar as well [33% vs 27.5%]. These differences remained non-significant after adjusting for proton pump inhibitor dose and treatment time. Surprisingly, symptom score was significantly higher in those patients under proton pump inhibitor therapy [28.5 (23-26) vs 23 (15-29), P = 0.01]. CONCLUSION: Proton pump inhibitors have no significant influence on lactulose breath tests, regardless of the dosage and time of administration. PMID- 26742291 TI - [Prevalence of specific antibodies for celiac disease in children attended in the Nutritional Recovery Program in San Miguel de Tucuman, Argentina]. AB - Celiac disease is a systemic autoimmune disease that affects 1.26% of the Argentine pediatric population. Our purpose was to study the prevalence of specific antibodies of celiac disease in a risk group and to find the association with specific factors. This was a cross-sectional study conducted in children ofa Nutritional Recovery Program from 1 year and 9 months to 6 years and 9 months old, from one Health Area of Tucuman Province, during 2010 and 2011, in a random cluster sample. It was studied a population of 175 children. We identified 3 cases with positive serology, equivalent to 1.7% of the study population. The association between cases with positive serology for celiac disease and other variables referred could not be established. PMID- 26742292 TI - [Endoscopic polypectomy of colorectal adenomas: Monitoring patients in order to review the colonoscopic surveillance interval]. AB - OBJECTIVE: To determine the risk of advanced adenomas at surveillance colonoscopy after polipectomy. To review the colonoscopic surveillance interval and to compare the prevalence of adenomas in patients with low-risk and high-risk adenomas at screening colonoscopies. METHODS: A cohort retrospective study. It was used a database of colonoscopies performed between 1999 and 2012. Seven hundred and sixty patients who had adenomas at first colonoscopy were included (465 males and 295 females, mean age 62 years old). They were divided into two groups: group A, low-risk adenomas, and group B, high-risk adenomas. In each group, it was compared the presence of adenomas in videocolonoscopies performed at 3 and 5 years. RESULTS: At the first colonoscopy 409 patients (53.8%) belonged to group A and 351 (46.2%) than group B. In both groups the risk of new advanced adenomas in endoscopic surveillance at 5years was similar to the control at 3 years. Comparing both groups, the risk of new advanced adenomas in endoscopic surveillance at 3 years in group B was 1.96 times greater than in group A (P = 0.012). CONCLUSIONS: At present, surveillance endoscopy is performed before the suggested interval. In both groups there were no statistically significant differences between surveillance control at 3 or 5 years. However, 62% of patients in group B have developed new advanced adenomas in endoscopic surveillance at 3 years. Therefore, it is recommended the endoscopic control with this interval. PMID- 26742294 TI - [Percutaneous ultrasound-guided pancreas allograft biopsy: a secure procedure]. AB - OBJECTIVE: To describe the complications rate related to percutaneous ultrasound guided pancreas allograft biopsy using an N16 Gauge needle. MATERIAL AND METHODS: In this retrospective study, the results of transplanted pancreas biopsies were analyzed in the Hospital Italiano de Buenos Aires between 1997 and 2012. In all patients, the indication for the procedure was a suspected rejection. After verifying the lack ofcontraindications, a percutaneous biopsy ofthe transplanted pancreas guided by ultrasound using an N16 Gauge needle was performed. A pathologist immediately evaluated the samples in order to establish that the material obtained was adequate. The complications were documented. RESULTS: . A total of92 pancreas percutaneous biopsies were performed in 47 patients in the Interventionism service of the Hospital Italiano de Buenos Aires. In 86% ofthe biopsies two samples were taken and in the 14% remaining only one. It was possible to reach a diagnosis in 100% of the biopsies. Only two patients presented complications: a post-puncture pancreatic fistula that healed with conservative treatment and an intense post-puncture pain with vasovagal reaction that reverted with the increase of venous return. CONCLUSION: Our results with the 16G needle are similar to those reported by other authors that used needles with lower gauge (18G or 20G). Thus, we can interpret that the percutaneous biopsy of transplanted pancreas under ultrasound guide with N16 Gauge needle is a safe (2.2% of complications) and efficient technique for the histopathological diagnosis of rejection (100%). PMID- 26742293 TI - [Detection of polyps, adenomas, advanced adenomas and adenocarcinomas in patients between 45 and 49 years]. AB - BACKGROUND. Colorectal cancer (CRC) can be prevented. Colonoscopy is the first line procedure for screening in average risk population. In 2002, Imperiale evaluated people between 40 to 49 years and reported that adenomas and advanced adenomas presented in 8.5% and 3.5% of cases, respectively. Currently, no recommendations for CRC screening in this population have been made. OBJECTIVE: To estimate the prevalence ofpolyps, adenomas, advanced lesions and adenocarcinomas in the 45- to 49-year-old population. METHODS: We included consecutive adults between 45 and 49 years old who performed colonoscopy because of gastrointestinal signs or symptoms. Exclusion criteria were high risk for CRC, incomplete VCC and/or previous evidence of colonic lesions. The study was conducted in a gastroenterology center from Buenos Aires, between September 2010 and October 2011. The design was prospective and cross-sectional. Polyethylene glycol (PEG) lavage solution or phosphates were usedfor cleansing. Colonoscopies were performed under sedation with Olympus equipment. The protocol was approved by the local IRB. 95% confidence intervals (95% CI) were estimated. RESULTS: 814 patients were evaluated and 764 were included, 440 (57%) were women and the average age was 47 years. The global prevalence of polyps was 20% (160 cases, 95% CI 18%-24%). The global prevalence of adenomas was 14% (107 cases, 95% CI 11% 16%). The prevalence of advanced adenomas was 5% (39 cases, 95% CI 4%-7%) and the prevalence of adenocarcinoma was 0.1% (1 case, 95% CI 0%-0.7%). CONCLUSIONS: The prevalence of lesions in this population is lower than that in the average risk population. At the moment we do understand that there is no evidence to recommend CRC screening in 45- to 49-year-old individuals. PMID- 26742296 TI - An unreported case of pancreatic panniculitis in a liver transplant patient. AB - Pancreatic panniculitis is an uncommon condition that can occur in association with pancreatic disease. Most of the cases reported to date were associated with acute or chronic pancreatitis and pancreas cancer. Recently, development has been described in kidney transplant patients and secondarily to allograft pancreatitis in a pancreas-kidney transplant recipient. Both findings suggest that immunological processes may be involved in the pathogenesis of this entity. We report for the first time a case of acute pancreatitis associated with pancreatic panniculitis in a patient who underwent a liver transplant 10 months before. A 69 year-old man with a history of epigastric pain of a few days of evolution was presented with painful subcutaneous nodules on both legs. Blood chemistry showed raised serum amylase and lipase levels. Ultrasonography and multislice CT scan were suggestive of an acute pancreatitis. A skin biopsy showed typical features of pancreatic panniculitis which included lobular panniculitis with lipocyte degeneration with ghost cells. The administration of octreotide resulted in both a rapid improvement of symptoms and a disappearance of skin lesions. Liver transplant specialists should be aware that the pancreatic panniculitis could be a manifestation ofpancreas disease in patients who have undergone l ver transplantation. PMID- 26742295 TI - [Building a private high-volume center for pancreatic resection]. AB - INTRODUCTION: There is considerable evidence on the direct relationship between higher volume and lower mortality in the pancreatoduodenectomy (DPC). However, there is little evidence of morbidity and mortality in the process of building a high-volume pancreatic surgery center. Objective. To evaluate the morbidity and mortality of the DPC in the process of building a high-volume center for pancreatic resection. METHODS: All consecutive patients undergoing DPC from July 2007 through July 2009 at a single center were included. High volume center was defined as that doing more than 19 DPC per year and high volume surgeon as that doing 16 or more DPC per year. The analysis of data was carried out in two periods according to the number of DPC per year: the first (1998 to 2005) as low volume center and the second (2006 to 2012) as high volume center. RESULTS: Three hundred and thirty five DPC were conducted consecutively. All surgeries were performed by a high volume surgeon. One hundred and seven patients were operated in the first period and 228 in the second period. There were no significant differences in morbidity and mortality between the both periods. In the second period there were significantly less operative time and minor length ofstay. CONCLUSIONS: High volume surgeons in pancreatic surgery can transfer their experience to the creation of a high volume pancreatic surgery center without sacrificing the morbidity and mortality. PMID- 26742297 TI - [Malignant peritoneal mesothelioma in patients without occupational exposure. Case report]. AB - Peritoneal mesothelioma is a rare malignancy that affects more women than men, with an average of 53 years old. The most important risk factor for developing the disease is chronic exposure to asbestos, becoming a disease of occupational origin. This type of cancer is difficult to diagnose, even for pathologists, with few cases reported in the literature as the most common presentation is the pleural type. We report the case of a male patient, without asbestos exposure, who presented malignantperitoneal mesothelioma. PMID- 26742298 TI - [Portomesenteric and intestinal pneumatosis: It is not always what it seems]. AB - Pneumatosis portomesenteric is an unusual radiological finding that traditionally has been associated with mesenteric acute ischemia, although there are many causes that may produce. It is associated with penumatosis intestinalis in 82% of cases, indicating severe abdominal pathology. Clinical diagnosis is difficult and the radiological study of choice is CT scan. The treatment depends on the underlying condition. Emergency laparotomy is indicated when data of mesenteric ischemia without massive intestinal necrosis, in- testinal obstruction with signs of strangulation, abdominal trauma with vascular injury or complicated inflammatory disease are present. Prognostic is poor in those cases associated with mesenteric ischemia, improving very much when the cause is not ischemic. PMID- 26742299 TI - [High-grade dysplasia as a result of gastric metaplasia]. AB - Barrett's esophagus (BE) is an acquired condition in which the normal esophageal squamous epithelium is replaced by columnar epithelium. It has been long pointed out that columnar metaplasia should be of intestinal goblet cells in order to define the BE, because intestinal metaplasia (IM) has been considered as the only conferring oncogenic risk, therefore having pre-neoplastic potential However, the definition ofBE restricted to the presence of IM has been widely discussed and currently constitutes a debated topic. We describe the case ofa patient with gastroesophageal reflux disease and high-grade dysplasia in the distal esophagus. Endoscopic mucosal resection ofthe lesion was performed using the Duette technique in one piece. The pathological study reported high-grade dysplasia with morphological features consistent with gastric metaplasia, without IM. The patient was treated with a proton pump inhibitor (PPI) and developed a disseminated dermatosis. He was evaluated by a dermatologist who diagnosed lichenoid dermatitis probably due to the PPI. The PPI was replaced by a H2 inhibitor and the skin lesions improved. The endoscopic control showed no residual tissue in the site of resection and the biopsies of the scar were negative for dysplasia and gastric metaplasia. PMID- 26742300 TI - Squamous cell carcinoma in Barrett's esophagus. AB - Barrett's esophagus (BE), consequence of chronic gastroesophageal reflux disease (GERD), is a premalignant condition, capable of turning into adenocarcinoma (ACa). However, the presence ofsquamous cell carcinoma (SCa) coexisting with Barrett's metaplasia is reported in some papers. The aim of this paper is to present 17 patients involving synchronous BE and SCa. PMID- 26742301 TI - [Brunner's gland adenoma: a rare tumor as cause of pyloric syndrome in an AIDS patient]. AB - Brunner's gland adenoma is a rare neoplasm that accounts for only the 0.008% of all benign duodenal tumors. Here we describe the case ofan HIV-seropositive man who developed a severe pyloric stenosis due to a Brunner's adenoma of the bulb and the first duodenal portion. Gastroduodenoscopy showed a large polypoid tumor that obstructed the pyloric region. The lesion was resected by surgery and a gastroduodenal anastomosis was made. The histopathologic examination of the surgical specimen showed a large proliferation of Brunner's glands into a large pedunculated polyp that confirmed the diagnosis of this hamartoma. PMID- 26742302 TI - [Intestinal microbiota]. AB - There is accumulative evidence on the multiple functions of the intestinal microflora in relation to the homeostasis of the host. At first considered as a simple mutualism, today this relationship proves to be essential to the health and to pathologic processes, particularly metabolic (eg, obesity) and gastrointestinal (eg, inflammatory bowel disease and functional disorders). The first studies were conducted on the microbiota from fecal material cultured anaerobically. With the advent of molecular biology, it has become possible to determine qualitative and quantitatively the dominant, subdominant and transients species. In recent years, there were advances in the understanding of the relationship betwen the microbiota and the host, as well as among the microorganisms in their respective niches. These advances result from translational integration of microbiology with specialities such as molecular biology, cell phisiology, immunology and ecology. There are few studies on the spatial distribution of the microflora in the gut. Unravelling the topography of the microflora in mammals is a way to validate new animal models for the study of microflora. PMID- 26742303 TI - Effect of miniscalpel-needle on relieving the pain of myofascial pain syndrome: a systematic review. AB - OBJECTIVE: To evaluate the effect and safety of miniscalpel-needle (MSN) on reducing the pain of myofascial pain syndrome (MPS). METHODS: We reviewed the available literatures inception up to February 2014 using Pubmed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure Database, Chinese Biomedical Database and Wanfang Database. RESULTS: Eight randomized controlled trials were finally identified. The main controls involved acupuncture, medications, injection, massage and cupping. We found that all of the studies agreed on the potential benefit of MSN as a strategy for MPS and the superiority compared to the controls, however, randomized methods applied in most of the trials could be criticized for their high or unclear risk of bias. Further research is also needed to clarify questions around the appropriate frequency and number of treatment sessions of MSN. CONCLUSION: This review shows that MSN might have the effect on MPS, even though there were some limitations in the studies included in the review. Studies with robust methodology are warranted to further test its pain-relieving effect on MPS. PMID- 26742304 TI - Effect of direct current pulse stimulating acupoints of JiaJi (T10-13) and Ciliao (BL 32) with Han's Acupoint Nerve Stimulator on labour pain in women: a randomized controlled clinical study. AB - OBJECTIVE: To assess the clinical effect and safety of direct current (DC) pulse produced by Han's Acupoint Nerve Stimulator in reduction (HANS) of labor pain. METHODS: Totally 120 participants were enrolled in this clinical trial, and were randomly divided into 4 groups including: HANS group, patient controlled intravenous analgesia (PCIA) group, patient-controlled epidural analgesia (PCEA) group and control group. The HANS group was treated by stimulating the acupoints of JiaJi (T10-L3) and Ciliao (BL 32) with DC pulse of 100 Hz and 15-30 mA produced by a portable battery-powered Han's Acupoint Nerve Stimulator for 30 min. The PCIA group was intravenously infused Ondansetron (8 mg) for 5 min, then tramadol injection (1.5 mg/kg) was slowly dripped by using BaxterAP II electronic pump with 50 mL tramadol (0.70%) + ondansetron (8 mg), background infusion 2 mL/h, PCA dose of 2 mL, lockout interval of 10 min. In PCEA group, women received intrathecal injection ropivacaine (3 mg) in L2-3, and epidural catheter was connected to BaxterAP II electronic pump, with 100 mL Ropivacaine (0.1%) and Sufentanil (50 ug), background infusion 5 mL, Patient controlled analgesia (PCA) dose of 5 mL, lockout interval of 10 min. The control group was not received analgesia. The visual analogue scale (VAS), stage and manner of labor, Apgar score of newborn, neonatal weights, oxytocin dosage, postpartum hemorrhage and side effects were monitored in all groups. RESULTS: The vital signs were all stable in the four analgesic groups. After analgesia, there was statistical difference in VAS score between HANS group and control group, between PCEA group and the control group, between PCIA group and control group. The analgesic effect in the PCEA group was significantly better than that of other two groups. The second stage of labor in the PCEA group was longer than the other three groups, showing significant difference between them. The Apgar score of newborn 1 min after birth in the PCIA group was slightly lower than that of the other two groups, showing significant difference between them. The neonatal weights between four groups were not significantly different. The rate of cesarean section in the control group was significantly higher than that of the labor analgesia group, there was statistically difference in four groups. The number of PCIA group that used oxytocin was lower than that of other three groups. There was no significant difference in postpartum hemorrhage between four groups. The side effects of the PCEA group were itching, uroschesis and neonatal asphyxia and PCIA group were nausea and vomiting and neonatal asphyxia. However, fewer side-effects were observed in the HANS group. CONCLUSION: The DC pulse produced by HANS may be a non-pharmacological alternative to labor pain with fewer side effects. PMID- 26742305 TI - Effect of Xinfeng capsule in the treatment of active rheumatoid arthritis: a randomized controlled trial. AB - OBJECTIVE: To explore the use of Xinfeng capsule (XFC) in the treatment of active rheumatoid arthritis (RA) and its effect on immunoglobulin titer, B cell activating factor (BAFF) and its receptor (BAFF-R). METHODS: A multi-center randomized, double-blind, parallel-controlled study was conducted. 45 RA patients were assigned to two groups: one was treated with XFC plus the placebo for leflunomide (LEF) and the second group was treated with LEF plus XFC placebo, for 12 weeks. The clinical and laboratory parameters were collected at baseline and at 12 weeks. RESULTS: After 12 weeks of treatment, patients in the two groups all showed an therapeutic effect when ACR20, ACR50 and ACR70 were compared, but the differences between two groups were not significant (P < 0.05). The serum levels of IgG1, BAFF and BAFF-R in the XFC group were lower than those in the LEF group (P < 0.05). The level IgG subtypes correlated with clinical parameters; IgG2 levels positively correlated with C-reactive protein (CRP) (P < 0.01); IgG3 levels positively correlated with white blood cell count and CRP (P < 0.01); IgG4 levels positively correlated with Complement 4 ( C4) (P < 0.01); the level of BAFF negatively correlated with Lymphocyte (LYMPH#) (P < 0.01); however, BAFF-R positively correlated with Platelet (PLT) and a1-acid glycoprotein (AGP) (P < 0.01). CONCLUSION: XFC can regulate the level of BAFF/BAFF-R in active rheumatoid arthritis and improve the levels of immunoglobulins in RA patients. PMID- 26742306 TI - Efficacy and safety of Aloe vera syrup for the treatment of gastroesophageal reflux disease: a pilot randomized positive-controlled trial. AB - OBJECTIVE: To investigate the use of Aloe vera (A. vera) for the treatment of gastroesophageal reflux disease (GERD) symptoms and compare its effects with those of omeprazole and ranitidine. METHODS: In this pilot, randomized controlled trial, 79 subjects were allocated to A. vera syrup (standardized to 5.0 mg polysaccharide per mL of syrup) at a dose of 10 mL/d, omeprazole capsule (20 g/d) or ranitidine tablet (150 mg in a fasted state in the morning and 150 mg 30 min before sleep at night) for a period of 4 weeks. The frequencies of eight main symptoms of GERD (heartburn, food regurgitation, flatulence, belching, dysphagia, nausea, vomiting and acid regurgitation) were assessed at weeks 2 and 4 of the trial. RESULTS: A. vera was safe and well tolerated and reduced the frequencies of all the assessed GERD symptoms, with no adverse events requiring withdrawal. CONCLUSION: A. vera may provide a safe and effective treatment for reducing the symptoms of GERD. PMID- 26742307 TI - Effect of Lixujieyu recipe in combination with Five Elements music therapy on chronic fatigue syndrome. AB - OBJECTIVE: To observe the clinical effects of the Lixujieyu recipe combined with Five Elements music therapy on chronic fatigue syndrome (CFS) identified as the symptom patterns of liver stagnation and spleen deficiency in terms of Traditional Chinese Medicine. METHODS: Patients with CFS were randomly divided into treatment group 1 (Lixujieyu recipe combined with Gong-Tune, n = 15); treatment group 2 (Lixujieyu recipe combined with Jiao-Tune, n = 15); treatment group 3 (Lixujieyu recipe combined with Yu-Tune, n = 15); treatment group 4 (Lixujieyu recipe combined with Shang-Tune, n = 15); treatment group 5 (Lixuiievu recipe combined with Zhi-Tune, n = 15); and the control group (Lixujieyu recipe alone, n = 15). Chinese medicine was given twice daily, and music was listened to for 45 minutes daily, 5 days a week. All patients were treated for 4 weeks. Patients were assessed via the Fatigue Scale, the Hamilton Depression Rating Scale, and the Hamilton Anxiety Rating Scale before and after treatment. RESULTS: Treatment groups 1 and 2 had better effects on relieving the symptoms of physical fatigue related to anxiety and depression than the control group (P < 0.05). CONCLUSION: Lixujieyu recipe combined with Gong-Tune or Jiao-Tune significantly relieved the symptoms of CFS. PMID- 26742308 TI - Evaluation of peripheral perfusion in term newborns before and after Yintang (EX HN 3) massage. AB - OBJECTIVE: To identify how acupressure on the acupoint Yintang (EX-HN 3) impacts oxygen saturation, pulse rate, and peripheral perfusion in term-born infants without underlying disease. METHODS: Infants born between weeks 37 and 42 of gestation were included in this study. The polyclinic's neonatology room was noise-controlled and made half-dark to prevent the perfusion index from being confounded. A pulse oximeter was linked to the baby's left lower extremity. Acupressure was applied on Yintang (EX-HN 3) for 30 s clockwise, held for 30 s, and then acupressure was applied for another 30 s counterclockwise. The baby's SaO2, pulse rate, and perfusion index were recorded for each minute before and after acupressure. RESULTS: When pre- and post-acupressure pulse rate values were compared, a significant decrease in pulse rate values after acupressure application was observed. When pre- and post-acupressure oxygen saturation values were compared, a significant increase in post-acupressure oxygen saturation was observed. In addition, peripheral perfusion increased significantly after acupressure. CONCLUSION: Acupressure application has been used in traditional medicine for many years. However, it is not yet widely used in modern medicine. This study shows the impact of acupressure on neonatal skin perfusion, oxygen saturation, and pulse rate. PMID- 26742309 TI - Differential expression of immune-related genes between healthy volunteers and type 2 diabetic patients with spleen-deficiency pattern. AB - OBJECTIVE: To investigate the clinical differentia tion of spleen-deficiency pattern (SDP), a group of symptoms and signs defined in terms of Traditional Chinese Medicine for its clinical practice. METHODS: Peripheral venous blood (> 3 mL) was collected from each of six type 2 diabetes mellitus (T2DM)-SDP patients and six healthy volunteers. After the isolation of peripheral white blood cells (PWBCs), total RNA was extracted, and quality control was performed on all RNA samples. Microarray experiments were conducted using the Agilent human whole genome gene chip, and genes demonstrating differential expression were screened. Bioinformatics analysis was conducted on these genes using several online databases. RESULTS: We screened a total of 175 differentially expressed genes (DEGs), of which 111 (63%) were down-regulated and 64 (37%) were up-regulated in T2DM-SDP patients compared with healthy controls. Among the 175 genes, 158 had biological function annotations: 46 (29%) were directly related to an individual's immune regulation or response, 25 (16%) were associated with substance and energy metabolism of PWBCs which could also indirectly influence immunity, and the remaining 87 (55%) were involved in a variety of PWBC biological processes that might eventually influence the immune function. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that the DEGs were predominantly enriched in seven immune-related pathways. Hierarchical cluster analysis identified gene expression patterns that were distinguishable between the two study groups. CONCLUSION: Our results suggest that T2DM-SDP patients experience significant hypoimmunity and/or immune dysfunctions, and possess a specific gene expression profile. These findings offer new insights into SDP and the clinical pattern differentiation of T2DM-SDP. PMID- 26742310 TI - Effect of acupuncture at Neiguan (PC 6) on cardiac function using echocardiography in myocardial ischemia rats induced by isoproterenol. AB - OBJECTIVE: To investigate the effect of acupuncture at Neiguan (PC 6) on cardiac function using echocardiography in rat models of myocardial ischemia (MI) induced by isoproterenol (ISO). METHODS: Twenty-seven Sprague-Dawley rats were randomly assigned to normal, model, and acupuncture groups. The model and acupuncture groups were given injections of ISO (85 mg/kg) to establish the MI model. After model establishment, the acupuncture group was treated with acupuncture at Neiguan (PC 6) for 30 min. Echocardiography was used to monitor diastolic and systolic function for 30 min starting from the time after the acupuncture needles were removed. Changes in the length of left ventricular internal diameter at end diastole (LVIDd), length of left ventricular internal diameter at end-systole (LVIDs), the ratio of mitral peak velocity at early diastole and atrial contraction (E/A), ejection fraction (EF), fractional shortening (FS), and stroke volume (SV) were measured. RESULTS: Compared with the model group at 0 and 15 min after needles were removed, the means of LVIDd and LVIDs were significantly lower (P < 0.01) and E/A, EF, FS, and SV significantly higher (P < 0.01) in the acupuncture group. In the acupuncture group, the means of LVIDd and LVIDs 15 min after the needles were removed were significantly higher (P < 0.01) than those at 0 min. The means of E/A, EF, FS, and SV significantly decreased (P < 0.01) from 0 to 15 min in the acupuncture group. CONCLUSION: These findings indicate that acupuncture at Neiguan (PC 6) can affect cardiac function by increasing left ventricular diastolic and systolic function in MI rat models, but the effect only lasts for 15 min. PMID- 26742311 TI - Chaihushugan decoction exerts antiepileptic effects by increasing hippocampal glutamate metabolism in pentylenetetrazole-kindled rats. AB - OBJECTIVE: To investigate the antiepileptic effects of Chaihushugan decoction (CHSGD) in rats with pentylenetetrazole (PTZ)-induced seizures and to discuss the impact of CHSGD on glutamate metabolism, a hypothesized underlying mechanism of seizure reduction. METHODS: Fifty Wistar rats were divided randomly into either control (n = 10) or experimental (n = 40) groups. Rats in the control group were administered physiological saline intraperitoneally. A subconvulsive dose of PTZ (35 mg/kg) was administered intraperitoneally to rats in the experimental group to induce seizures. The fully PTZ-kindled rats were then randomly divided into five subgroups (n = 8 each) based on the following treatment categories: physiological saline, VPA (200 mg/kg), CHSGD (2.5 g/kg), CHSGD (5 g/kg), or CHSGD (10 g/kg), administered orally once per day, respectively. On day 28 following initiation of drug treatment, seizures were monitored. The rats were then sacrificed, and hippocampal dissections were performed for subsequent studies. RESULTS: CHSGD significantly prolonged the latency of myoclonic, clonic, and tonic seizures, while decreasing overall seizure rates in the kindled rats. The measured concentrations of 2-[N-(7-nitrobenz-2-oxa-1,3-diazo-4-yl) amino]-2-deoxy d-glucose (2-NBDG) and glutamate were significantly lower in the hippocampi of kindled rats in groups treated with CHSGD compared with those treated with PTZ alone. In addition, CHSGD was found to up-regulate both the expression of glutamate transporter-1 (GLT-1) protein and the activity of glutamine synthetase (GS) in the hippocampi of kindled rats. CONCLUSION: These results suggest that CHSGD has antiepileptic effects on PTZ-induced seizures. The results further suggest an increase in glutamate metabolism at the synaptic cleft is a putative underlying mechanism of seizure reduction. PMID- 26742312 TI - Gastroprotective effect of aqueous stem bark extract of Ziziphus jujuba L. against HCl/Ethanol-induced gastric mucosal injury in rats. AB - OBJECTIVE: To evaluated the gastroprotective effects of standardized aqueous extract of Ziziphus jujuba (Z. jujuba) stem bark against acidified ethanol induced gastric ulcers as well as anti helicobacter pylori activity of the plant extract in rats. METHODS: Five groups of rats were orally pre-treated with normal saline (0.9%) as ulcer group, 150 mg/kg of ranitidine as positive control group, 100, 200 and 400 mg of standardized extract solution as the experimental groups. Two hours later, acidified ethanol solution was given by gavages in order to induce of gastric ulcer. The antibacterial effect of extract against clinical strains of Helicobacter pylori (H. pylori) was evaluated through disc diffusion test. RESULTS: The ulcer group exhibited significantly severe mucosal injury as compared with ranitidine or extract group which shows significant protective action against gastric mucosal injury. The extract showed no effect on H. pylori. CONCLUSION: The present study indicates that Z. jujuba stem bark extract had a potential antiulcer activity which might be due to its protective activity, providing a direct, protective effect on the gastric mucosa. Our study showed that anti-H. pylori activity was not among gastroprotective mechanism of Z. jujuba. Further pre-clinical and clinical investigations for evaluating natural active agents and efficacy of this plant are recommended. PMID- 26742313 TI - Neuroprotective effect of ethyl acetate extract from gastrodia elata against transient focal cerebral ischemia in rats induced by middle cerebral artery occlusion. AB - OBJECTIVE: To investigate the protective effect of neuroprotection against transient focal cerebral ischemia of the extract from Tianma (Rhizoma Gastrodiae) and the possible mechanisms underlying the action. METHODS: Cerebral ischemia reperfusion injury was induced through middle cerebral artery occlusion (MCAO). Adult male Sprague-Dawley rats were randomly divided into four groups: sham operated, ischemia-reperfusion model, 102.6 mg/kg extract treated and 11.4 mg/kg extract treated groups. The extract was prepared from gastrodia elata with ethyl acetate. The effect of the extract tested on rat neurological deficits and Cerebral index, cerebral infarct volume, brain injury, terminal dexynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and B-cell lymphoma-2 (Bcl-2) positive cells. RESULTS: The extract was able to reduce neurological scores, cerebral index and cerebral infarction rate. The brain injury was also relieved by the extract. The results of immunofluorescence staining analysis indicated that the extract increased the expression of Bcl-2 and reduced TUNEL-positive cells significantly in the extract treated groups. CONCLUSION: These results suggested that the extract relieved ischemic injury induced by transient focal cerebral ischemia in rats, and this neuroprotective effect might be partially due to the attenuated apoptosis pathway. PMID- 26742314 TI - Effect of emodin on Aquaporin 5 expression in rats with sepsis-induced acute lung injury. AB - OBJECTIVE: To investigate the effects of emodin on aquaporin 5 (AQP5) expression in rats with sepsis-induced acute lung injury. METHODS: We divided 60 adult male Sprague-Dawley rats, weighing 200-230 g, into four groups: control, sham surgery, model and emodin groups (n = 15 for each). We created a sepsis model with cecal ligation and puncture; the sham surgery group had their cecums replaced after exposure outside the abdominal cavity. Each group was further divided into three subgroups (n = 5 for each) and expressions of AQP5 mRNA and proteins in lung tissue were measured by real-time fluorescence polymerase chain reaction and western blot at 6,12 and 24 h after surgery. RESULTS: AQP5 expression did not change over time in the control group and sham surgery group, but decreased over time in the model group. The lowest expression was found in 12-h subgroup, which significantly differed from the 6-h subgroup (P < 0.01). Compared with the model group, AQP5 expression in the emodin group was significantly higher in all the subgroups (all P < 0.01). Expressions in the 12-h subgroup were the highest, and significantly differed from the other subgroups. We found that lung tissue damage, such as pulmonary edema, alveolar damage and the exudation of red blood cells in pulmonary interstitium and alveolar, was significantly milder in the emodin group under light microscope than the model group. CONCLUSION: AQP5 expression was significantly down-regulated in rats with sepsis-induced acute lung injury induced by cecal ligation and puncture. Early prophylactic use of emodin can significantly enhance the AQP5 expression, thus effectively reducing the degree of pulmonary edema in septic rats. PMID- 26742315 TI - Anti-proliferative effect of the extract of Guangzao (Fructus Choerospondiatis) on cultured rat cardiac fibroblasts. AB - OBJECTIVE: To ascertain if total flavonoids of Guangzao (Fructus Choerospondiatis) (TFFC) extracted from Guangzao (Fructus Choerospondiatis) can inhibit angiotensin II-induced proliferation of cardiac fibroblasts (CFs). METHODS: CFs were cultured by the differential attachment method. A model of cell proliferation was established by stimulation with Ang II. Cardiac fibroblasts growth was determined using a hemocytometer. Cell proliferation was detected by methyl thiazole tetrazolium. Lactate dehydrogenase activity was measured by chemical colorimetric method. RESULTS: Proliferation of TFFC-treated (25, 50, 100 mg/L) fibroblasts was significantly less than that of cells in the angiotensin II group (P < 0.01), and TFFC inhibited proliferation in a dose-dependent manner. These inhibitory effects were partly blocked by pretreatment with NG-nitro-L arginine methyl ester (L-NAME) and 1H-[1,2,4]-oxadiazole-[4,3-a]-quinoxalin-1-one (ODQ). CONCLUSION: TFFC inhibited angiotensin II-induced proliferation of cardiac fibroblasts via a mechanism that probably involves activation of the NO-cyclic guanosine monophosphate signaling pathway. PMID- 26742316 TI - Enhancement of radiosensitivity of lung adenocarcinoma using a decoction from the Fuzhengzengxiao formula. AB - OBJECTIVE: To study the effects of a decoction of Fuzhengzengxiao formula on lung adenocarcinoma regarding the inflammatory protein S100A9 known to enhance cancer cell sensitivity. METHODS: A nude mouse model of human lung adenocarcinoma was established. The mice were randomly divided into four groups using the random number table method: Group I, control; Group II, treatment with a decoction of the Fuzhengzengxiao formula alone; Group III, treatment with radiotherapy alone; and Group IV, treatment with radiotherapy plus a decoction of Fuzhengzengxiao formula. When the tumor body was 1 cm3 in diameter, the tumor bearing mice in Groups III and IV were irradiated at a single dose of 10 Gy and the tumor inhibition rate was evaluated. The expression of S100A9 was determined using Western blotting and q-PCR (Real-time Quantitative PCR Detecting System). The sensitivity of cells containing RNAi S100A9 to radiotherapy was evaluated using the Click multiple target model,and the cell cycle was analyzed using flow cytometry. RESULTS: Relative to the control group, the expression of S100A9 in the tumors in each treatment group was decreased, especially in Group IV. The sensitizing enhancement ratio (SER) Dq was > 1 after RNAi S100A9; it decreased the surviving fraction after a 2 Gy dose exposure,and also the D0 and Dq of the tumor cells; in addition, the radiosensitivity of G2/M cells was significantly increased. CONCLUSION: The decoction of the Fuzhengzengxiao formula downregulated the expression of S100A9 in lung adenocarcinoma cells. PMID- 26742317 TI - Zhiqiaochuanxiong decoction for major depressive disorder complicated by functional dyspepsia: a case report with fast-acting efficacy. AB - OBJECTIVE: To introduce a clinical case from Professor Huang Xi from Xiangya Hospital in traditional Chinese medical (TCM) treatment for a major depressive disorder (MDD) complicated by functional dyspepsia (FD). METHODS: A 26-year old unemployed male migrant worker (Han nationality) presented himself at the TCM outpatient department of our hospital on May 13th 2013, with the chief complaint of persistent low mood and negative emotions lasting 2.5 years. He was diagnosed as having MDD complicated by FD. The TCM differentiation made was "Ganqi-Yujie" (Liver-Qi stagnation). Zhiqiaochuanxiong (ZQCX) decoction, composed of Zhiqiao (Fructus Aurantii Submaturus) 40 g and Chuanxiong (Rhizoma Chuanxiong) 40 g, was given to be taken twice daily. The patient's condition was evaluated with a 128 channel electroencephalogram (EEG) and high-resolution manometry (HRM). During follow-up the patient was monitored with the Patient Health Questionnaire and Leeds Dyspepsia Questionnaire. RESULTS: After treatment, the symptoms of depression and the FD comorbidity disappeared. Furthermore, the main EEG and HRM were significantly improved after 1-7 weeks of ZQCX decoction administration. CONCLUSION: ZQCX decoction showed rapid prokinetic and anti-depressive effects in a MDD patient complicated by FD. Most commonly used antidepressants target only the brain, whereas ZQCX decoction targets the brain-gut axis according to TCM theory. PMID- 26742318 TI - Physical and mental health conditions of young college students with different Traditional Chinese Medicine constitutions in Zhejiang Province of China. AB - OBJECTIVE: To investigate Traditional Chinese Medicine (TCM) constitutions of youths in colleges, and their physical and mental health conditions of different TCM constitutions, so as to provide a theoretical basis for the TCM way to improve young people's physical and mental health. METHODS: The Standard TCM Constitutions' Classification and Determination Questionnaire was used to measure the body health condition, and the Symptom Checklist 90 Questionnaire and the Questionnaire of the National Student Physical Health Standards were used to determine mental and physical health conditions respectively in 1421 young participants validly answering the questionnaires in Zhejiang Province. RESULTS: The participants had a mean age of 19.96 years (SD = 0.95 years) with the majority of females (55.10%). One fourth of the 1421 participants were the Ping he constitution and others were the tendency constitutions. Participants with Pinghe module (which has characteristics of moderate posture, rosy, energetic and is a healthy condition in TCM) were healthier than those with tendency constitutions in physical and mental health, with 65.81 +/- 7.83 (men) and 77.99 +/- 7.24 (women) scores in the physical test and around 1.25 scores in the mental health test. College students with combined biased constitutions were more likely suffer force, sensitive, depression and anxiety. CONCLUSION: Most of college students have a tendency or biased constitution which could be more likely to suffer suboptimal health status and diseases. Youths in college themselves and health providers should pay more attention to their potential health issues and make proper healthcare plan according to their own TCM constitution. PMID- 26742319 TI - Acupuncture for Parkinson's Disease: a review of clinical, animal, and functional Magnetic Resonance Imaging studies. AB - Acupuncture has been commonly used as an adjuvant therapy or monotherapy in the treatment of Parkinson's disease in China and in other countries. Animal studies have consistently show that this treatment is both neuroprotective, protecting dopaminergic neurons from degeneration and also restorative, restoring tyrosine hydroxylase positive dopaminergic terminals in striatum, resulting in improvements in motor performance in animal models of Parkinsonism. Studies show that this protection is mediated through the same common mechanisms as other neuroprotective agents, including anti-oxidative stress, anti-inflammatory and anti-apoptotic pathways at molecular and cellular levels. Restoration of function seems to involve activation of certain compensatory brain regions as a mechanism at the network level to correct the imbalances to the nervous system resulting from loss of dopaminergic neurons in substantia nigra. Clinical studies in China and Korea, in particular, have shown a positive benefit of acupuncture in treating Parkinson's disease, especially in reducing the doses of dopaminergic medications and the associated side effects. However, large and well-controlled clinical trials are still needed to further demonstrate the efficacy and effectiveness of acupuncture in the treatment of Parkinson's disease. PMID- 26742320 TI - Differences in acquired immune deficiency syndrome treatment and evaluation strategies between Chinese and Western Medicine. AB - Complementary and alternative medicine, including Chinese medicine (CM), has been used to treat acquired immune deficiency syndrome (AIDS) foralmost 30 years. We aimed to compare the main differences between AIDS treatment and evaluation strategies between CM and Western Medicine (WM), and analyze advantages and disadvantages. The characteristics of integrative medicine (IM), based on CM and WM, include a patient-centered mode of medicine based on evidence. IM focuses on complex intervention and management with systemic and individual treatment. The evaluation indexes of IM might consist of objective indicators and subjective indexes. IM might be a more valuable method for treating AIDS in the future instead of WM or CM alone. PMID- 26742321 TI - Identification of pheromone-carrying protein in the preorbital gland post in the endangered Indian male Blackbuck Antelope cervicapra L. AB - In mammals, a low molecular mass protein (17-20 KDa) reported from the pheromone sources such as urine, saliva, glandular secretion, etc., as ligand-carrier (pheromone carrier) has been associated with chemo-communication. Since the preorbital gland post is one of the major pheromone sources in Indian Blackbuck, an endangered species, we assumed that it possibly contains low molecular mass protein for chemical communication. Hence, we investigated the preorbital gland post in territorial and non-territorial male blackbucks for such low molecular mass proteins adopting SDS-PAGE and LC-MS/MS analysis. The total content of protein was higher in the post of territorial males than non-territorial males of adult and sub-adult. In fact, the protein profiles such as 17, 21, 25, 42 and 61 kDa were noted in the gland secretion of territorial and non-territorial males. The intensity of the 17 kDa protein band was higher in territorial males than non territorial males. In-gel trypsin digestion of the 17 kDa band was processed and subjected to LC-MS/MS and SEQUEST analyses. The results of LC-MS/MS and SEQUEST search showed the presence of alpha(2u)-globulin in the 17 kDa band. In addition, the identified alpha(2u)-globulin sequence possessed GDW residues, which are the characteristic signature for lipocalin family. Since the alpha(2u)-globulin has been reported from the pheromone-carrying proteins in some mammals, this protein may carry the volatiles (pheromone compounds) in male Blackbucks preorbital gland to evoke the scent marking for maintaining territoriality (home range) and attraction towards female, through the secretion of glandular protein. PMID- 26742322 TI - Comparison of Immunoprotection of Leptospira Recombinant Proteins with conventional vaccine in experimental animals. AB - Leptospirosis is a bacterial disease caused by bacteria of the genus Leptospira affecting humans and animals. Untreated leptospirosis may result in severe kidney damage, meningitis, liver failure, respiratory distress, and even death. Virulent leptospirosis can rapidly enter kidney fibroblasts and induce a programmed cell death. Thus, it is a challenge for immunologists to develop an effective and safe leptospirosis vaccine. Here, we compared the commercial canine leptospira vaccine and recombinant proteins (OmpL1 and LipL41) with and without adjuvant in terms of immune response and challenge studies in hamsters and immune response studies alone in experimental dogs. The outer membrane proteins viz., lipL41 and OmpL1 of leptospira interrogans serovars icterohaemorrhagiae were amplified. The primers were designed in such a way that amplified products of OmpL1 and lipL41 were ligated and cloned simultaneously into a single vector. The cloned products were expressed in E. coli BL21 cells. The immunoprotection studies were conducted for both recombinant proteins and commercial vaccine. The challenge experiment studies revealed that combination of both rLip41 and rOmpL1 and commercial vaccine gave 83% and 87% protection, respectively. Histopathological investigation revealed mild sub lethal changes were noticed in liver and kidney in commercially vaccinated group alone. The immune responses against recombinant leptospiral proteins were also demonstrated in dogs. PMID- 26742323 TI - Isolation and identification of actinomycetes for production of novel extracellular glutaminase free L-asparaginase. AB - Over the recent years glutaminase free L-asparaginase has gained more importance due to better therapeutic properties for treatment of acute lymphoblastic leukemia. Actinomycetes are known for L-asparaginase activity. In the current study, 80 actinomycetes were isolated from various soil habitats by serial dilution technique. Presence of L-asparaginase was investigated in a total of 240 actinomycetes by tubed agar method using modified M-9 medium. A total of 165 actinomycetes were found positive for L-asparaginase activity. Among these, 57 actinomycetes producing larger zones of L-asparagine hydrolysis were further screened for their capacity to produce glutaminase-free L-asparaginase. Four L glutaminase-free actinomycetes were found to be potential L-asparaginase producers. These actinomycetes were identified as Streptomyces cyaneus (SAP 1287, CFS 1560), S. exfoliates (CFS 1557) and S. phaeochromogenes (GS 1573) on the basis of morphological and biochemical identification studies. Maximum L asparaginase activity (19.2 Uml(-1)) was observed in culture filtrate of S. phaeochromogenes under submerged fermentation. Results indicate that S. phaeochromogenes could be a potential source of glutaminase free L-asparaginase for commercial purpose. To the best of our knowledge, this is the first report on production of glutaminase free L-asparaginase from S. cyaneus, S. exfoliatus and S. phaeochromogenes. PMID- 26742324 TI - Moringa oleifera Lam. seed extract prevents fat diet induced oxidative stress in mice and protects liver cell-nuclei from hydroxyl radical mediated damage. AB - High fat diet (HFD) prompts metabolic pattern inducing reactive oxygen species (ROS) production in mitochondria thereby triggering multitude of chronic disorders in human. Antioxidants from plant sources may be an imperative remedy against this disorder. However, it requires scientific validation. In this study, we explored if (i) Moringa oleifera seed extract (MoSE) can neutralize ROS generated in HFD fed mice; (ii) protect cell-nuclei damage developed by Fenton reaction in vitro. Swiss mice were fed with HFD to develop oxidative stress model (HFD group). Other groups were control, seed extract alone treated, and MoSE simultaneously (HS) treated. Treatment period was of 15 days. Antioxidant enzymes with tissue nitrite content (TNC) and lipid peroxidation (LPO) were estimated from liver homogenate. HS group showed significantly higher (P < 0.05) superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH) activity, and ferric reducing antioxidant power (FRAP) compared to only HFD fed group. Further, TNC and LPO decreased significantly (P < 0.05) in HS group compared to HFD fed group. MoSE also protected hepatocytes nuclei from the hydroxyl radicals generated by Fenton reaction. MoSE was found to be polyphenol rich with potent reducing power, free radicals and hydroxyl radicals scavenging activity. Thus, MoSE exhibited robust antioxidant prospective to neutralize ROS developed in HFD fed mice and also protected the nuclei damage from hydroxyl radicals. Hence, it can be used as herbal medication against HFD induced ROS mediated disorders. PMID- 26742325 TI - Hepatoprotective effect of trimethylgallic acid esters against carbon tetrachloride-induced liver injury in rats. AB - Gallic acid and its derivatives are potential therapeutic agents for treating various oxidative stress mediated disorders. In the present study, we investigated the hepatoprotective effects of newly synthesized conjugated trimethylgallic acid (TMGA) esters against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. Animals were pre-treated with TMGA esters at their respective doses for 7 days against CCl4-induced hepatotoxicity. The histopathological changes were evaluated to find out degenerative fatty changes including vacuole formation, inflammation and tissue necrosis. Various biomarkers of oxidative stress (lipid peroxidation, glutathione levels, and endogenous antioxidant enzyme activities), liver enzymes (AST and ALT), triacylglycerol and cholesterol were evaluated. Pre-treatment with TMGA esters (MRG, MGG, MSG, and MUG at the dose of 28.71, 30.03, 31.35, 33.62 mg/kg/day), respectively reversed the CCl4-induced liver injury scores (reduced vacuole formation, inflammation and necrosis), biochemical parameters of plasma (increased AST, ALT, TG, and cholesterol), antioxidant enzymes (increased lipid peroxidation and nitrite levels; decreased glutathione levels, superoxide dismutase and catalase activities) in liver tissues and inflammatory surge (serum TNF-alpha) significantly. The study revealed that TMGA esters exerted hepatoprotective effects in CCl4-induced rats, specifically by modulating oxidative-nitrosative stress and inflammation. PMID- 26742326 TI - Terminalia arjuna (Roxb.) Wight & Arn. augments cardioprotection via antioxidant and antiapoptotic cascade in isoproterenol induced cardiotoxicity in rats. AB - Worldwide, Ischemic heart disease (IHD) affects a large population. Implication of myocardial infarction (MI) and its multiple pathophysiology in cardiac function is well known. Further, isoproterenol (ISP) is known to induce MI. Today, there is an urgent need for effective drug that could limit the myocardial injury. Therapeutic intervention with antioxidants has been shown useful in preventing the deleterious changes produced by ISP. Here, we investigated the protective effects of oral pre-treatment of hydroalcoholic extract of bark of Terminalia arjuna (HETA) on biochemical and apoptotic changes during cardiotoxicity induced by isoproterenol (ISP) in rats. HETA was orally administered at a dose of 100, 200 and 400 mg/kg body wt., for 30 days with concurrent administration of ISP (85 mg/kg body wt.) on days 28th and 29th at an interval of 24 h. ISP caused deleterious changes in the myocardium and significantly increased (P < 0.05) malondialdehyde, serum glutamate oxaloacitate transaminase, creatine kinase-MB, lactate dehydrogenase and troponin-I. However, it significantly decreased (P < 0.05) glutathione and superoxide dismutase compared to healthy control. Oral pre-treatment of HETA for 30 days significantly decreased (P < 0.05) the biochemical parameters of oxidative stress and cardiac markers as compared to ISP control. Histopathological findings also revealed that architecture of the myocardium was restored towards normal in HETA pre-treated group. Overall, the present study has shown that the hydroalcoholic extract of bark of T. arjuna (HETA) attenuates oxidative stress, apoptosis and improves antioxidant status in ISP-induced cardiotoxicity in rats. PMID- 26742327 TI - Biovalorization potential of peels of Ananas cosmosus (L.) Merr. for ethanol production by Pichia stipitis NCIM 3498 & Pachysolen tannophilus MTCC 1077. AB - Bioethanol, is a potential alternate source of energy, renewable and safe. Ethanol production from value added food and feedstock has also not shown growth as estimated. Of late, the second generation processes of production of ethanol, such as from lignocellulosic biomass out of agricultural/domestic waste has been gaining considerable momentum. Here, we explored a new approach for optimizing the conditions of physiochemical pretreatment as well as fermentation process using peels of Ananas cosmosus as substrate and immobilized yeast Pachysolen tannophilus MTCC.1077 and Pichia stipitis NCIM 3498. We have also studied the influence of process variables such as incubation temperature, inoculum concentration and different nutrients on ethanol production. Pulverized peels of A. cosmosus recorded 25 +/- 0.31% cellulose, 28 +/- 0.18% hemicellulose and 8 +/- 0.07% of lignin on dry solid (DS) basis. Peels of A. cosmosus delignified with 1% H2SO4 yielded 18.89% glucose, 38.81% xylose and 29.31% fructose under thermochemical pretreatment using autoclave (121 degrees C, 20 min.), with a hydrolytic efficiency of 75.52 +/- 0.45%. FTIR spectroscopy results not only indicated the penetration of H2SO4 in the amorphous region of the biomass and degradation of hemicelluloses but also showed the structural differences before and after pretreatment. The enzymes required for hydrolysis were prepared from culture supernatants of Trichoderma reesei NCIM 1052 using wheat bran as carbon source under submerged fermentation conditions on rotatory shaker incubator (at 28 degrees C for 10 days). Enzyme activity (U/ml) of crude cellulase produced by T. reesei NCIM 1052 was 311.1 MUmole/ml/min. Delignified A. cosmosus peel yielded 51.71 +/- 0.44 g/l glucose when enzymatically hydrolysed by crude cellulase at the substrate enzyme ratio of 1:5. Simultaneous saccharification and fermentation (SSF) of peels of A. cosmosus by crude cellulase and separately entrapped Pichia stipitis NCIM 3498 (now known as Scheffersomyces stipitis) and Pachysolen tannophilus MTCC 1077 cells in calcium alginate beads were also investigated in the present study. The fermentation experiments were carried out at flask level. The processing parameters setup for reaching a maximum response for ethanol production was obtained when applying the optimum values for temperature (32 degrees C), inoculum level (6%) and fermentation medium (ammonium sulphate, KH2PO4, peptone and yeast extract) for P. tannophilus MTCC 1077 and temperature (30 degrees C), inoculum level (2%) and fermentation medium (ammonium sulphate, KH2PO4, peptone and yeast extract) for S. stipitis NCIM 3498. Maximum ethanol concentration 10.5 g/l and 10.9 g/l was obtained from P. tannophilus MTCC 1077 and S. stipitis NCIM 3498, respectively at the optimized process conditions in anaerobic batch fermentation. PMID- 26742328 TI - Template based synthesis of gold nanotubes using biologically synthesized gold nanoparticles. AB - Reliable experimental protocols using green technologies to synthesize metallic nanostructures widen their applications, both biological as well as biomedical. Here, we describe a method for synthesizing gold nanotubes using biologically synthesized gold nanoparticles in a template based approach. E. coli DH5alpha was used as bionanofactory to synthesize gold nanoparticles. These nanoparticles were then deposited on sodium sulfate (Na2SO4) nanowires which were employed as sacrificial template for gold nanotube (Au-NT) formation. The gold nanoparticles, sodium sulphate nanowires and gold nanotubes were appropriately characterized using transmission electron microscopy. The TEM results showed that the average diameter of gold nanotubes was 72 nm and length up to 4-7 MUm. The method discussed herein is better than other reported conventional chemical synthesis approaches as it uses biologically synthesized gold nanoparticles, and does not employ any harsh conditions/solvents for template removal which makes it a clean and ecofriendly method. PMID- 26742329 TI - To the editor. PMID- 26742330 TI - Response. PMID- 26742331 TI - Goldie Brangman Remembers the Operation to Save Dr King. AB - In September 1958 the Rev Dr Martin Luther King Jr was stabbed and nearly assassinated. Surgeons at Harlem Hospital in New York City removed a 17.8-cm (7 in)-long letter opener from Dr King's chest. Certified Registered Nurse Anesthetist Goldie Brangman remembers this event because she participated in Dr King's anesthetic. This article correlates Brangman's memories with published accounts of the event. It also places the event within the context of the modern civil rights movement that Dr King led. PMID- 26742332 TI - Methods to Improve Success With the GlideScope Video Laryngoscope. AB - Occasionally intubation of patients is difficult using a video laryngoscope (GlideScope, Verathon Medical) because of an inability to guide the endotracheal tube to the glottis or pass the tube into the trachea despite an adequate view of the glottis. We examined methods to improve success when this difficulty occurs. A literature search revealed 253 potential sources, with 25 meeting search criteria: 7 randomized controlled trials, 4 descriptive studies, 8 case series, and 6 case reports. Findings from the randomized controlled trials suggested that using a flexible-tipped endotracheal tube with a rigid stylet (GlideRite, Verathon Medical) improved intubation success, whereas other methods did not, such as using a forceps-guided endotracheal tube exchanger. If a malleable stylet was used, a 90 degrees bend above the endotracheal tube cuff was preferable to a 60 degrees bend. Evidence from lower-level sources suggested that several interventions were helpful, including using a controllable stylet, a fiberoptic bronchoscope in conjunction with the GlideScope, or an intubation guide, and twisting the endotracheal tube to facilitate passage into the trachea. Providers must consider the risks and benefits of any technique, particularly if the device manufacturer does not recommend the technique. Further rigorous investigations should be conducted examining methods to increase success. PMID- 26742333 TI - Malfunction of the Expiratory Valve During Spontaneous Ventilation. AB - The integrity of inspiratory and expiratory unidirectional valves is very important in the normal functioning of an anesthetic circle breathing system. We describe our experience of an emergency manipulation of a ceramic valve disk of a circle breathing system (Drager Fabius GS, Drager Medical Inc) that altered its characteristics and led to rebreathing only during spontaneous ventilation. PMID- 26742334 TI - Comparison of Successful Intubation Between Video Laryngoscopy View Before Attempted Intubation and Direct Laryngoscopic Intubation by Student Registered Nurse Anesthetists: A Pilot Study. AB - Airway management is a primary focus when student registered nurse anesthetists (SRNAs) begin clinical rotations in their nurse anesthesia program. Successful endotracheal intubation requires both knowledge of and experience with the airway and its structures. Lack of clinical maturity and unfamiliarity with the patient airway intensifies student anxiety in the clinical arena. The purpose of this pilot study was to examine the success rate of direct laryngoscopy by 9 SRNAs who were just entering clinical practice rotations. This study required group 1 to perform direct laryngoscopy in their first clinical opportunity in the operating room; group 2 was required to observe a minimum of 3 video laryngoscopic (GlideScope, Verathon Inc) intubations performed by the clinical preceptor before the students' first attempt using direct laryngoscopy. Other modalities used to secure the airway in this study included the GlideScope and a laryngeal mask airway. Results of the data analysis revealed there was no significant difference between groups for success of direct laryngoscopy (group 1, 54%; group 2, 58%; P = .45). PMID- 26742335 TI - Discovery of Modern Anesthesia: A Counterfactual Narrative about Crawford W. Long, Horace Wells, Charles T. Jackson, and William T. G. Morton. AB - The discovery of anesthesia occurred during a narrow time span in the mid-19th century, but there is no agreement about who deserves credit for this important American contribution to medicine. Based mostly on an examination of primary sources, we explore how formal and informal interactions between the principals affected their careers, lives, and attribution of credit for the discovery of anesthesia. There should be no controversy as to which individual deserves credit for the discovery of anesthesia if credit is ascribed for specific contributions. We suggest that credit for the discovery of anesthesia be divided among 4 individuals who played specific roles. Crawford W. Long first used ether as an anesthetic during surgery, Horace Wells introduced nitrous oxide for pain relief during dental surgery, and William T. G. Morton gave the first public demonstration of ether anesthesia and spread the word about its efficacy. Charles T. Jackson suggested the use of ether as an anesthetic agent to Morton. We also assert that had these individuals not known one another, the discovery of anesthesia would have proceeded in approximately the same timeframe, but Wells, Morton, and Jackson would have enjoyed more productive careers as well as longer, more peaceful lives. PMID- 26742336 TI - Influence of Patients' "Sense of Coherence" on Main Postoperative Variables in the Postanesthesia Care Unit: A Cross-Sectional Study. AB - The objective of this study was to investigate whether patients' sense of coherence (SOC)--ability to comprehend their whole situation and their capacity to use available resources--influences acute postoperative complications in the postanesthesia care unit (PACU). We hypothesized that patients' SOC would be negatively related to their experience of pain and nausea, consumption of opioids, and length of stay in the PACU--the higher the SOC, the lower the experience of pain and nausea, less consumption of opioids, and shorter PACU stay. Data were collected from the anesthesia and electronic medical records, and combined with a questionnaire. A total of 115 adults undergoing general anesthesia for orthopedic surgery were included in the analysis. Results showed a statistically significant negative relationship between SOC and postoperative pain and consumption of opioids in the PACU. Patients with a stronger SOC experienced significantly less pain (P < .01) and consumed significantly less opioids (P < .01) than those with a lower SOC. Patients' SOC influences their experience of pain and opioid consumption in the PACU. Therefore, patients' SOC could be one of many factors that nurse anesthetists consider in their efforts to predict, prevent, and decrease patients' experience of pain in the PACU. PMID- 26742337 TI - A Review of Nonsteroidal Anti-inflammatory Drugs. AB - It is essential that nurse anesthetists are aware of the potential side effects and interaction of drugs that patients are taking before administering an anesthetic. Among the most commonly taken medications are nonsteroidal anti inflammatory drugs (NSAIDs). Because these drugs have become almost ubiquitous, there is a risk underestimating potential effects, which may be harmful for the patient undergoing anesthesia and surgery. These effects can range from mild to severe and can be exacerbated by drug interactions with many commonly administered medications. This review of NSAID pharmacology a d interactions is intended to serve as an update and refresher for nurse anesthetists to increase their awareness of the potential untoward effects of postoperative bleeding, gastrointestinal bleeding, asthma, hepatic and renal toxicity and cardiovascular events. PMID- 26742338 TI - Delivering Value in Healthcare. PMID- 26742339 TI - Shifting Gears: The Move Toward Value-Based Payment. PMID- 26742340 TI - Patient Finance Strategies for a High-Deductible World. PMID- 26742341 TI - ETHICAL LEADERSHIP IN UNCERTAIN TIMES. PMID- 26742342 TI - The ethics of resource allocation in disasters. Anticipate ethical issues before a crisis occurs. PMID- 26742343 TI - Creating a culture of customer service. Making employees' jobs easier is the key to success. PMID- 26742344 TI - Going green in healthcare. With its energy-saving initiatives, Gundersen Health System has become energy independent. PMID- 26742345 TI - Employers re-engage with the healthcare system. Innovative new health benefits are being created and implemented. PMID- 26742346 TI - The value of lifelong mentorship. Mentors are crucial to success throughout the entirety of a career. PMID- 26742347 TI - Leadership for value-based care. Four areas of knowledge and skills must be mastered to make the move from fee for service. PMID- 26742348 TI - Governing for improved health. Hospital trustees play an important role in community health. PMID- 26742349 TI - Innovative strategies for physician partnerships. One health system shares the steps it took to strengthen physician engagement. PMID- 26742350 TI - [Shared decision making in the colorectal cancer screening program in the canton of Vaud]. AB - The colorectal cancer screening program of the canton of Vaud aims to facilitate screening for this cancer for the population aged 50 to 69 years old. The two screening modalities offered are fecal immunochemical testing (FIT) and colonoscopy. The decision to undergo screening and the screening modality is based on an individual medical encounter with a primary care physician. Both screening modalities are reimbursed through basic health coverage in Switzerland. The participation to the screening program allows the exemption of the deductible for the medical encounter and the chosen screening modality. A copay of 10% is maintained for all costs. Communication tools were developed on the basis of recommendations in the literature to facilitate shared decision-making in a medical encounter. PMID- 26742351 TI - [Sharing uncertainties of prostate cancer screening]. AB - The decision of whether our patients should undergo prostate cancer screening with the prostate specifc antigen (PSA) test remains daunting. The role of the primary care doctor is to help men decide between a potential decrease in mortality from a slow evolving but sometimes lethal cancer, and the risk of diagnosing and treating cancers that would have otherwise been indolent and asymptomatic. We can structure our discussions with three steps: choice, option, and decision making. A decision aid, such as the one that we have adapted and simplifed from the College des medecins du Quebec, can help with this complex decision. PMID- 26742352 TI - [Statins in primary prevention: how to share the decision?]. AB - Long-term treatment of hypercholesterolemia with statins diminishes the risk of cardiovascular events. Statins are recommended in secondary prevention of cardiovascular disease. In the absence of preexisting cardiovascular disease, the decision to start a statin or not is most often made by the general practitioner and his patient. An interactive decision aid, developed by the Mayo Clinic, has just been translated in French and adapted to the Swiss epidemiology of cardiovascular risk factors, with the aim of promoting shared decision-making. This paper reviews the conditions and potential benefits of shared decision making about statin therapy in primary prevention. PMID- 26742353 TI - [Management of cardiovascular diseases in adults from 1999 to 2014: what has really changed?]. AB - Every year, a considerable number of clinical guidelines for the management of cardiovascular risk factors are issued. It may give the idea that this area is constantly evolving with regular changes for ambulatory clinical practice, including family medicine. Sometimes important differences between the various recommendations are observed. This led us to wonder about the evolution of recommendations for the management of diabetes, dyslipidemia and high blood pressure over time. This article presents a historical review of US and European recommendations between 1999 and 2014 to highlight what has actually changed. PMID- 26742354 TI - [Chronic fatigue syndrome]. AB - Chronic fatigue syndrome (CFS) is a debilitating disorder, characterized by a severe, persistant and unexplained fatigue, which can be associated with diffuse pain, sleep difficulties, neurocognitive and neurovegetative troubles. Its prevalence has been estimated between 0.3 and 0.9%. Though its physiopathology remains controversial, evidence is growing that dysimmunity, oxidative stress and mitochondrial dysfunction are involved in its pathogeny. No medication has demonstrated specifc efficacy in the CFS. The management of CFS involves limiting unnecessary investigations, promoting graded exercice therapy, and providing empathic counselling in order to prevent negative thoughts. PMID- 26742355 TI - [Skin problems associated with poor living conditions]. AB - People living in poor conditions are at high risk of developing different medical diseases of which dermatological diseases are very common. We present 4 clinical cases of skin diseases, which are the most prevalent amongst the majority of socially and economically vulnerable patients. Early diagnosis and appropriate treatment are of paramount importance, in order to avoid their spread in close- knit communities where these patients often live. PMID- 26742356 TI - [Organ donation and the role of patients' associations in Western Switzerland]. AB - In the context of lay mobilization in health-related areas, this article addresses the role and activities of patients' associations in connection with organ donation, on the basis of interviews carried out with thirty members of transplant patients' associations in the French-speaking part of Switzerland. First, we describe the three main categories of activities conducted by these associations. While self-help and public awareness activities are predominant, policy-oriented actions are marginal. Then, we examine the factors likely to explain why these associations have a limited capacity to be active, especially in the public sphere. Such a lack of social visibility is all the more important in the current political context, characterized by the implementation of a national action plan designed to improve organ donation. PMID- 26742357 TI - [Bad news about the anti-measles fight]. PMID- 26742358 TI - [Libido noscendi]. PMID- 26742359 TI - [Physicians are not the only guilty ones for antibiotic resistance]. PMID- 26742361 TI - [Dignity deluged with German demands]. PMID- 26742360 TI - [Role of ezetimibe in secondary cardiovascular prevention finally determined?]. PMID- 26742362 TI - [The Paris attacks: questions on the French emergency medical/psychological assistance teams]. PMID- 26742363 TI - Three Decades of History and Perspectives of Khon Kaen University's Plastic Surgery. AB - Plastic surgery consists of two major fields: reconstructive surgery and cosmetic surgery with its roots lie in the reconstruction aspect. In Thailand, the plastic surgery procedures, performed during the initial period, included cleft lip and cleft palate repairs and skin graftings: In 1987, the Plastic Surgery Unit was established in the Department of Surgery, Srinagarind Hospital in Khon Kaen, which is the city in the Center of the northeast Thailand. In 1991, the partnership training of resident in plastic surgery with Siriraj Hospital was established and continued until the present time. All fields of plastic surgery were managed and educated in the Plastic Surgery Unit. Since the first batch of plastic surgery training program in 2009, the unit has many advanced in interdisciplinary management, the management of cleft center burn center postgraduate training program, research, community services, and national, regional and international coloration. The future perspectives involve educationfor 21st century skills, integration of teaching, research and community services, and a focus on evidence-based medicine and benchmarked outcomes are the future perspectives. PMID- 26742364 TI - Global Birth Prevalence of Orofacial Clefts: A Systematic Review. AB - BACKGROUND: A birth prevalence of orofacial clefts (OFCs) worldwide has been documented to vary. However a systematic assessment is lacking. OBJECTIVE: To assess the evidence in the literature for the birth prevalence of OFCs. MATERIAL AND METHOD: A systematic literature search was conducted using electronic databases through PubMed between 1950 and June 2015 using key words and search terms of cleft lip palate OR orofacial cleft AND prevalence. RESULTS: There were 45,193 patients with OFCs found in a study population of 30,665,615 live births. According to continents, the OFC birth prevalence (95% confidence interval)from Asia, North America, Europe, Oceania, South America, and Africa were 1.57 (1.54 1.60), 1.56 (1.53-1.59), 1.55 (1.52-1.58), 1.33 (1.30-1.36), 0.99 (0.96-1.02), and 0.57 (0.54-0.60) per 1,000 live births, respectively. The American Indians had the highest prevalence rates of 2.62 per 1,000 live births, followed by the Japanese, the Chinese, and the Whites of 1.73, 1.56, and 1.55 per 1,000 live births, respectively. The Blacks had the lowest rate of 0.58 per 1,000 live births. CONCLUSION: Observed differences may also be of ethnic origin, genetic, environmental factors, and methods of ascertainment. Further investigations are needed to manage this global health problem. PMID- 26742366 TI - Roles of Medical Record and Statistic Staff on Research at the Tawanchai Center. AB - The medical record and statistic staffs play a crucial role behind the achievements of treatment and research of physicians, nurses and other health care professionals. The medical record and statistic staff are in charge of keeping patient medical records; creating databases; presenting information; sorting patient's information; providing patient medical records and related information for various medical teams and researchers; Besides, the medical record and statistic staff have collaboration with the Center of Cleft Lip Palate, Khon Kaen University in association with the Tawanchai Project. The Tawanchai Center is an organization, involving multidisciplinary team which aims to continuing provide care for patients with cleft lip and palate and craniofacial deformities who need a long term of treatment since newborns until the age of 19 years. With support and encouragement from the Tawanchai team, the medical record and statistic staff have involved in research under the Tawanchai Centre since then and produced a number of publications locally and internationally. PMID- 26742365 TI - Prevalence of Congenital Heart Diseases in Patients with Orofacial Clefts: A Systematic Review. AB - BACKGROUND: The reports on prevalence rates of congenital heart diseases (CHDs) in patients with orofacial clefts (OFCs) have varied widely. OBJECTIVE: To systematically review the prevalence rates of CHDs in patients with OFCs. MATERIAL AND METHOD: A computer search was conducted through the PubMed from 1950 to June 2015 using key words or search terms of congenital heart diseases, orofacial clefts, cleft lip/palate and prevalence. RESULTS: The search resulted in nine studies with 598 CHDs cases identified in 5,707 patients with OFCs. The prevalence of CHDs in patients with OFCs ranged from 3.9% to 23.9%. The five prospective studies had prevalence rates of 12.0% (95% confidence interval [CI]: 10.9 to 13.2) whilst the four retrospective studies had prevalence rates of 8.6% (95% CI: 7.5 to 9.8). Concerning the prospective studies, the newborn study had a higher prevalence than those of other childhood studies [23.9% vs. 11.5% (95% CI: 10.4 to 12.7)]. The newborn study with the use of echocardiography had a higher prevalence than those without using echocardiography (23.9% vs. 12.8%). Atrial septal defect was the most frequent CHD found. CONCLUSION: CHD is commonly found in a patient with OFC. Echocardiography should be used to assess CHD in patients with OFCs. PMID- 26742367 TI - Cleft Lip Cleft Palate and Craniofacial Deformities Care: An Anesthesiologist's Perspective at the Tawanchai Center. AB - BACKGROUND: The increasing number of pediatric patients with cleft lip-palate and craniofacial anomalies is a nuisance problem in the Northeast of Thailand. These patients have complicated problems including physical health, psychosocial, and poor quality of life; therefore, a multidisciplinary care team was established, named Tawanchai center. This study encouraged the improvement of the quality of holistic healthcare service system to improve the quality of life the patients and their families. Anesthesiologists are important personnel in the facilitation of the surgical team, and to help improve other activities including academic, service and research. OBJECTIVE: To relate the perspective of anesthesiologist according to the role they play in the multidisciplinary team. MATERIAL AND METHOD: The database of Anesthesiology department and annual report from the period between June 2005 to July 2015 were collected and reviewed. CONCLUSION: Highly-skilled and experienced anesthesiologist in the multidisciplinary patient care team play a vital role through the provision of advanced and specific knowledge to anesthesia management. The role of anesthesiologists should be researched to enhance the quality of anesthesia management, thereby contributing to national and international patient care team development. PMID- 26742368 TI - Challenges and Long-Term Management of Patients with Craniofacial Clefts in Thailand. AB - OBJECTIVE: To report challenges and long-term management of patients with craniofacial clefts, treated at Srinagarind Hospital, Khon Kaen, Thailand. MATERIAL AND METHOD: Patients who were treated at Srinagarind Hospital, between 1993 and 2001. A review of data was performed including general information, classifications, photographs, radiographic findings, dental records, reconstructive surgeries, and long-term management. RESULTS: A total of 20 patients were recruited; six males and 14 females, grouped into six median, two paramedian and 12 oblique clefts. Age of the first treatment ranged from one to 39 years, age of the last follow-up ranged from 11 to 48 years and the range of follow-ups was 11 to 24 years. The reconstructive procedures included a variety of techniques of plastic surgery for soft tissue repairs and bone grafting for facial reconstructions. Four patients with median clefts and paramedian clefts died. One patient lost to follow-up. Fifteen patients were followed-up and the results were satisfying. CONCLUSION: Diagnosis, evaluation, and treatment of clefts and craniofacial deformities are complex. The proper management is challenging because of socioeconomic, cause difficulties in follow-ups according to the planned protocol. Other associated anomalies are important. Protocols with well-co-ordination of an interdisciplinary team in Craniofacial Center and continuing evaluation at appropriate schedule and age group until completion of facial growth are critical factors. Establishment of a foundation and comprehensive care model with families, local health professionals and school will benefit the most to this group of patients. PMID- 26742369 TI - Empowering Volunteers at Tawanchai Centre for Patients with Cleft Lip and Palate. AB - BACKGROUND: Cleft lip and palate (CLP) congenital anomalies have a high prevalence in the Northeast of Thailand. A care team's understand of treatment plan would help to guide the family of patients with CLP to achieve the treatment. OBJECTIVE: To examine the impact of the empowering volunteer project, established in the northeast Thailand. MATERIAL AND METHOD: The Empowering Volunteer project was conducted in 2008 under the Tawanchai Royal Granted project. The patients and family's general information, treatment, the group brainstorming, and satisfaction with the project were analysed. RESULTS: Participants were 12 children with CLP their families and five volunteers with CLP; the participating patients were predominantly females and the mean age was 12.2 years. The treatment comprised of speech training, dental hygiene care, bone graft and orthodontic treatment. Four issues were addressed including: problems in taking care of breast feeding, instructions' needs for care at birth, difficulty in access information and society impact, and needs in having a network of volunteers. CONCLUSIONS: Empowering volunteer is important for holistic care of patients with CLP which provides easy access and multiple channels for patients and their families. It should be developed as part of the self-help and family support group, the development of community based team and comprehensive CLP care program. PMID- 26742370 TI - Development and Monitoring the Key Performent Index of The Quality of Care for Patients with Cleft/Palate in Tawanchai Center and Out-Patient Surgical Room Srinagarind Hospital Thailand. AB - BACKGROUND: Cleft lips and cleft palates have the most incidences in the Northeast of Thailand (2.49/1,000 newborns). Cleft lips and cleft palates (CLP) can affect patients and families both physically and mentally. It takes critical long-term medical treatment starting when prenatal, newborn, and fully grown until 19 years old by a multidisciplinary team; therefore, it was effective to have collaboration with patients, families, and a multidisciplinary team in order to build up the same objective and create key performance index to monitor the treatment outcome also to develop the quality of care. OBJECTIVE: 1) to create the key performance index and 2) to develop the index system by using information technology. MATERIAL AND METHOD: After the research received ethics approval from Khon Kaen University, qualitative and quantitative data were collected. There were two periods in this study. The 1st period as following list below: 1) Field research was performed by conference meetings and problem-learning process, which participants participated in each step. There were two example groups: (1) Patients and families cooperated 2 times and (2) Nursing care cooperated 4 times in October-December 2013 (3) Combining the conclusions to set the key performance index and develop the index system in January-February 2014 (4) Recording the system in March-June 2014. Content analysis and percentage were used in this study. RESULTS: Nine organizations were engaged in this study; eight key performance indexes were established and the research recorded continuously for 4 months. There were three key performance indexes, which performed successfully: 1) Patients/caregivers received follow-up treatment continuously, 92.06%, 2) Patients/caregivers reported 89.69% satisfaction after asking the information, 3) Patients/families reported overall satisfaction of 92.11%. CONCLUSION: It is shown that recording the key performance index for the 1st period covered every quality of care. The Tawanchai Center and Out-patient Surgical Room under Srinagarind Hospital applied eight key performance indexes and found that three key performance indexes were feasibly implemented. For the 2nd period, the 1st outcome of key performance indices will be analyzed and developed including improving the software in order to record data and analyze the percentages automatically. PMID- 26742371 TI - Development and Monitoring the Key Performance Indicators of the Quality of Care for Patients with Cleft Lips/Palates at Srinagarind Hospital. AB - BACKGROUND: Congenital deformities, such as cleft lips and/or cleft palates (CLP), have high incidences in the Northeast of Thailand. These birth defects can affect patient's quality of life. CLP patients need crucial and long-term treatments by a multidisciplinary team starting from prenatal stage to late adulthood. Patients and their families should involve in their own care, and their care objectives should correspond with healthcare providers. Besides the clinical outcome of interdisciplinary team, key performance indicators (KPIs) need to be developed in the hospital service unit in order to improve quality of care and treatment outcomes. OBJECTIVE: 1) to establish KPIs in hospital service units, and 2) to develop the information system to collect, analysis and improve the quality of CLP care. MATERIAL AND METHOD: A nurse coordinator was appointed in the Tawanchai Center to coordinate care. The three periods were conducted for the nurse coordinator to work with nine service units in Srinagarind Hospital for consensus on both qualitative and quantitative data to be used as service unit quality measurement. RESULTS: Thirty one KPIs from nine service units were established, collected and analyzed during a four-month period in 2014. The 20 KPIs achieved the unit targets. Two PKIs of the rates of complication with anesthesia during/after surgery in the first 24 hours and the rates of patient/caregiver's satisfaction in acquiring information from the officer were improving. There were 11 KPIs that did not achieve the targets. The coordinator nurse of the Tawanchai Center discussed with the service unit for the cause and how to improve the outcome. CONCLUSION: The monitoring KPIs will lead to improvement of outcome for better patient quality as well as benchmarking with other hospitals of Cleft Center. The KPIs from hospital service units with the monitoring and analysis of information by the nurse coordinator will enhance and lead to improvement of the quality of the patients and family centered care process. PMID- 26742372 TI - Evaluation of Facial Appearance among Patients With Repaired Unilateral Cleft Lip and Palate: Comparison of Patient- and Clinician-Ratings of Satisfaction. AB - The objective of this study was to determine the levels of patient-satisfaction on facial and dental appearance compared with clinician ratings. Participants included 61 patients with repaired unilateral cleft lip and palate (UCLP), aged 14-25 years. Raters comprised three cleft team clinicians. A Likert scale was used to assess the levels of satisfaction of the patients themselves and the clinicians. The results revealed that the patients were moderately satisfied with their appearance. Nose was the least satisfactory feature, followed by lip appearance. When compared to the clinician ratings, the patients were less satisfied with their own nose and lip, but more satisfied with teeth. Concerning age, self-assessment did not differ between adolescents and young adults. Females were less likely to be satisfied compared to males, but the difference was not statistically significant. In conclusion, patients with repaired UCLP were moderately satisfied with their facial and dental appearance. Clinician- and patient-opinions were different in some aspects. This study highlights the importance of patient satisfaction as a meaningful treatment outcome assessment, which could lead to an improvement in cleft care to meet the patient expectations. PMID- 26742373 TI - Agreement of Tracing and Direct Viewing Techniques for Cervical Vertebral Maturation Assessment. AB - OBJECTIVE: This study aimed to evaluate agreement among three methods for cervical vertebral maturation (CVM) assessment, comprising direct viewing, tracing only, and tracing with digitized points. MATERIAL AND METHOD: Two examiners received training and tests of reliability with each CVM method before evaluation of agreement among methods. The subjects were 96 female-cleft lateral cephalometric radiographs (films of eight subjects for each age ranged from seven to 18 years). The examiners interpreted CVM stages of the subjects with four-week interval between uses of each method. RESULTS: The range of weighted kappa values for paired comparisons among the three methods were: 0.96-0.98 for direct viewing and tracing only comparison; 0.93-0.94 for direct viewing and tracing with digitized points comparison; and 0.96-0.97 for tracing only and tracing with digitized points comparison. The intraclass correlation coefficient (ICC) value among the three methods was 0.95. These results indicated very good agreement among methods. CONCLUSION: Use of direct viewing is suitable for CVM assessment without spending more time for tracing. However, the three methods might be used interchangeably. PMID- 26742374 TI - Oral Health-Related Quality of Life in Children and Young Adolescent Orthodontic Cleft Patients. AB - OBJECTIVE: To evaluate and compare the oral health-related quality of life (OHRQoL) in Thai patients with cleft lip and palate and to evaluate parents' and their children perceptions. MATERIAL AND METHOD: Child Oral Health Impact Profile (COHIP) questionnaire was used to evaluate OHRQoL of the patients and parents' perceptions of patients' OHRQoL. The subjects consisted of 140 cleft patients (aged 8-15 years) and their parents who visited the Department of Orthodontics, Khon Kaen University. RESULTS: COHIP scores in cleft patients were relatively high. No statistically significant differences were found for overall and subscales COHIP scores between gender and age groups (aged 8-11 and 12-15 years) of patients. Comparison among cleft types, overall COHIP and functional well being subscales scores showed statistically significant differences (p = 0.01 and p = 0.002, respectively). Cleft lip with or without alveolus (CL/A) had higher overall and functional well-being subscale scores than unilateral and bilateral cleft lip and palate patients (CLP). Only self-image subscale scores were statistically significant differences between patients and parents at p<0.001. CONCLUSION: Young and adolescent patients with cleft lip and palate had generally positive oral health-related quality of life. Impacts of gender and age of patients on OHRQoL were similar CL/A patients had more positive in overall oral health-related quality of life and functional well-being domains than CLP patients did. Parents had higher perceptions of self-image shown by their children than the children themselves. PMID- 26742375 TI - Correlations between Cervical Vertebral Maturation (CVM) and Dental Development in Thai Cleft Patients. AB - OBJECTIVE: To examine correlations between cervical vertebral maturation stages (CVMs) and dental development stages, and cervical vertebral maturation (CVM) stage 6 and completion of root formation of mandibular third molar in Thai cleft patients. MATERIAL AND METHOD: Lateral cephalograms of 366 cleft subjects aged 7 9 years were assessed for CVMs using Baccetti method. Calcication stages of all left mandibular teeth within each CVMs were assessed from panoramic films using Demirjian method. RESULTS: Spearman rank correlation coefficients comparing CVMs and teeth were 0.51-0.79 (p<0.001). Second molar had the highest and central incisor had the lowest correlations. In CVMs 6, 2.9% of third molars had completed root formation. However, only CVMs 6 could be predicted from third molar stage G that had a high likelihood ratio (30.94). CONCLUSION: Dental development was highly correlated with CVM in clefts. Third molar stage G could predict completed growth of mandible in individual patients, but it should be combined with other maturation indicators. PMID- 26742376 TI - Vascular Anomalies: The Epidemiological Profile at Srinagarind Hospital. AB - BACKGROUND: Vascular anomalies or vascular birthmarks can be divided in to 2 major groups: (i) vascular tumors and (ii) vascular malformations. Currently, there are many treatment modalities for these diseases and the treatment plans are varied among sub-specialty physicians. OBJECTIVE: To explore the epidemiology of vascular anomalies at Srinagrind Hospital during 2009-2011. MATERIAL AND METHOD: Retrospective chart was reviewed from the out patient clinic's database at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Thailand. RESULTS: There were total of 126 vascular anomalies cases. 89 cases were diagnosed with vascular tumors and 37 cases were vascular malformations. Among 89 cases of vascular tumors, infantile hemangiomas are the most common type (95.5%). The treatment methods for vascular tumors were medical treatments, which were used in majority of the cases (60%), followed by surgical excision, laser treatment, intralesional corticosteroids injection, and the combination of medical, laser and surgical treatment. There were total of 37 cases of vascular malformations. Most of the cases were venous and lymphatic malformations. Treatment methods for these patients were surgical excision, bleomycin injection, and radiation. CONCLUSION: Vascular anomalies have various presentations. Treatment is challenging and multidisciplinary teams are involved in taking care the patients with this entity of disease. Setting up vascular anomalies clinic is essential and suggested for the patients with vascular anomalies' problems. PMID- 26742377 TI - Citation Characteristics of Research Articles under the Center of Cleft Lip-Cleft Palate and Craniofacial Deformities, Khon Kaen University. AB - Center of Cleft Lip-Cleft Palate and Craniofacial Deformities, Khon Kaen University, has cooperated with the Medical Association of Thailand in publishing the special five issues of JMT (Journal of the Medical Association of Thailand) during the years 2010-2014 in order to promote research activities and working network of related fields in cleft lip-cleft palate and craniofacial deformities. This study aimed to examine the features of 106 research articles in terms of authors and disciplines, and analyze the citations considering sources, country and years after publication. The scope of study also included citations in the form of journal, which was presented as journal ranking compared with impact factors and Bradford's Law on journal citation. The results of study will be useful in developing multidisciplinary research activities of the center and especially assist in the acquisition of academic journals for essential sources of reference. PMID- 26742378 TI - Cardiac Surgery in Cleft Lip and Cleft Palate Children: Srinagarind Hospital Experience. AB - BACKGROUND: Congenital heart disease is one of the common incidents associated with craniofacial anomalies. OBJECTIVE: To date, there are no published studies from Thailand on review experience regarding operation of congenital heart disease in cleft lip/cleft palate patients. This study aims to report the patterns of our practices in those patients. MATERIAL AND METHOD: A hospital based, descriptive study during 1996-2013 in congenital heart disease associated with cleft lip/cleft palate in Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Khon Kaen Province, Thailand. RESULTS: During the period of study there were 2,600 cases of cleft lip/cleft palate. Congenital heart disease was found in 60 patients (2.3%). Only 11 patients had heart surgery performed, 7 patients were operated on by open heart surgery, 2 PDA (Patent Ductus Arteriosus) ligation and 2 Blalock-Tausig shunts. The most common perioperative complication was aspirated pneumonia. No 30-day mortality occurred. CONCLUSION: Congenital heart disease in cleft lip and cleft palate patients is not uncommon. A multidisciplinary team approach is the key to success in management. Heart operation can be performed at anytime if clinically indicated. PMID- 26742379 TI - A Networking of Community-Based Speech Therapy: Borabue District, Maha Sarakham. AB - BACKGROUND: Most children with cleft lip and palate have articulation problems because of compensatory articulation disorders from velopharyngeal insufficiency. Theoretically, children should receive speech therapy from a speech and language pathologist (SLP) 1-2 sessions per week. For developing countries, particularly Thailand, most of them cannot reach standard speech services because of limitation of speech services and SLP Networking of a Community-Based Speech Model might be an appropriate way to solve this problem. OBJECTIVE: To study the effectiveness of a networking of Khon Kaen University (KKU) Community-Based Speech Model, Non Thong Tambon Health Promotion Hospital, Borabue, Maha Sarakham, in decreasing the number of articulation errors for children with CLP. MATERIAL AND METHOD: Six children with cleft lip and palate (CLP) who lived in Borabue and the surrounding district, Maha Sarakham, and had medical records in Srinagarind Hospital. They were assessed for pre- and post-articulation errors and provided speech therapy by SLP via teaching on service for speech assistant (SA). Then, children with CLP received speech correction (SC) by SA based on assignment and caregivers practiced home program for a year. RESULTS: Networking of Non Thong Tambon Health Promotion Hospital, Borabue, Maha Sarakham significantly reduce the number of post-articulation errors for 3 children with CLP. There were factors affecting the results in treatment of other children as follows: delayed speech and language development, hypernaslaity, and consistency of SC at local hospital and home. CONCLUSION: A networking of KKU Community-Based Speech Model, Non Thong Tambon Health Promotion Hospital, Borabue, and Maha Sarakham was a good way to enhance speech therapy in Thailand or other developing countries, where have limitation of speech services or lack of professionals. PMID- 26742380 TI - Baby Shampoo versus Commercial Anti-fogging Solution to Prevent Fogging during Nasal Endoscopy: A Randomized Double-Blinded, Matched-Pair, Equivalent Trial. AB - OBJECTIVE: To compare the minimization of the fog condensation during nasal endoscopy between a commercial anti-fogging agent and baby shampoo. MATERIAL AND METHOD: This randomized double-blinded matched pair study was conducted at the Department of Otorhinolaryngology, Faculty of Medicine, Khon Kaen University during February 4, 2013 to March 14, 2013. The commercial anti-fogging solution (Ultrastop(r)) and baby shampoo solution (Johnson's(r) no more tear(r)) were compared. A computer generated randomization was performed to select the solution applying on the lens for nasal endoscopy of the right nasal cavity. The other solution was then used for the left one. Three passes of endoscopy were performed to examine the floor of the nose, the sphenoethmoidal recess and the middle meatus area which spent about 30 seconds for each time of endoscopy. The time to become foggy on the lens and the preferred solution assessed by the endoscopists were recorded. RESULTS: There were 71 eligible patients recruited in the study, 37 males (52.1%) and 34 females (47.9%). There was no fogging during a 30-second nasal endoscopy either by baby shampoo or commercial anti-fogging solution. However, 9.86% (95% C12.75-16.97) of endoscopists preferred commercial anti fogging agent, 7.04% (95% CI 0.94-13.14) preferred baby shampoo and 83.10% (95% CI 74.16-92.03) had equal satisfaction. Both agents had no statistically significant difference for preventing foggy on the lens. CONCLUSION: Baby shampoo is an effective agent to prevent fogging during nasal endoscopy and comparable with the commercial anti-fogging agent. PMID- 26742381 TI - Speech Correction for Children with Cleft Lip and Palate by Networking of Community-Based Care. AB - BACKGROUND: Prevalence of cleft lip and palate (CLP) is high in Northeast Thailand. Most children with CLP face many problems, particularly compensatory articulation disorders (CAD) beyond surgery while speech services and the number of speech and language pathologists (SLPs) are limited. OBJECTIVE: To determine the effectiveness of networking of Khon Kaen University (KKU) Community-Based Speech Therapy Model: Kosumphisai Hospital, Kosumphisai District and Maha Sarakham Hospital, Mueang District, Maha Sarakham Province for reduction of the number of articulations errors for children with CLP. MATERIAL AND METHOD: Eleven children with CLP were recruited in 3 1-year projects of KKU Community-Based Speech Therapy Model. Articulation tests were formally assessed by qualified language pathologists (SLPs) for baseline and post treatment outcomes. Teachings on services for speech assistants (SAs) were conducted by SLPs. Assigned speech correction (SC) was performed by SAs at home and at local hospitals. Caregivers also gave SC at home 3-4 days a week. RESULTS: Networking of Community-Based Speech Therapy Model signficantly reduced the number of articulation errors for children with CLP in both word and sentence levels (mean difference = 6.91, 95% confidence interval = 4.15-9.67; mean difference = 5.36, 95% confidence interval = 2.99-7.73, respectively). CONCLUSION: Networking by Kosumphisai and Maha Sarakham of KKU Community-Based Speech Therapy Model was a valid and efficient method for providing speech services for children with cleft palate and could be extended to any area in Thailand and other developing countries, where have similar contexts. PMID- 26742382 TI - Speech Therapy for Children with Cleft Lip and Palate Using a Community-Based Speech Therapy Model with Speech Assistants. AB - OBJECTIVE: Evaluate the speech services using a Community-Based Speech Therapy model by trained speech assistants (SAs) on the improvement of articulation in cleft palate children. MATERIAL AND METHOD: Seventeen children with repaired cleft palates who lived in Chiang Rai and Phayao provinces were registered to the camp. They received speech therapy with a 4-day intensive camp and five follow-up camps at Chiang Rai's The Young Men's Christian Association (YMCA). Eight speech assistants (SAs) were trained to correct articulation errors with specific modeling by the speech-language pathologists (SLPs). SAs encouraged family members to stimulate their children every day with speech exercise at home. Each camp was covered with a main speech therapy and others supported by the multidisciplinary team, as well as, discussion among SLPs, SAs and the care givers for feedback or difficulties. RESULTS: Results showed a sufficient method for treating persistent speech disorders associated with cleft palate. Perceptual analyses presented significant improvement of misarticulation sounds both word and sentence levels after speech camp (mean difference = 1.5, 95% confidence interval = 0.5-2.5, p-value <0.01; mean difference = 2.5, 95% confidence interval = 1-3, p-value <0.001, respectively). CONCLUSION: The Community-Based Speech Therapy model is a valid and efficient method for providing speech therapy in cleft palate children. PMID- 26742383 TI - Development of Information System for Patients with Cleft Lip and Palate undergoing Operation. AB - BACKGROUND: Srinagarind Hospital has 150-200 patients with cleft lip and palate each year. When patients are admitted to hospital for surgery patients and family feel they are in a crisis of life, they feel fear anxiety and need to know about how to take care of wound, they worry if patient will feel pain, how to feed patients and many things about patients. Information is very important for patients/family to prevent complications and help their decision process, decrease parents stress and encourage better co-operation. OBJECTIVE: To develop information system for patients with cleft lip-palate undergoing operation. MATERIAL AND METHOD: This is an action research divided into 3 phases. Phase 1 Situation review: in this phase we interview, nursing care observation, and review nursing documents about the information giving. Phase 2 Develop information system: focus groups, for discussion about what nurses can do to develop the system to give information to patients/parents. Phase 3 evaluation: by interviewing 61 parents using the structure questionnaire. RESULTS: 100 percent of patients/parents received information but some items were not received. Patients/parents satisfaction was 94.9 percent, no complications. CONCLUSION: The information system development provides optimal care for patients and family with cleft lip and palate, but needs to improve some techniques or tools to give more information and evaluate further the nursing outcome after. PMID- 26742384 TI - Anesthetic Techniques and Perioperative Complications of Cleft Lip and Cleft Palate Surgery at Srinagarind Hospital. AB - BACKGROUND: Cleft lip (CL) and cleft palate (CP) are common craniofacial abnormalities with an incidence of around 1:800. Surgical are corrections often performed during the first year of life. These patients have risks for difficult intubation and various perioperative complications due to their young age and craniofacial abnormalities. OBJECTIVE: The purpose of the retrospective descriptive study is to report the data of anesthetic techniques and complications of repairing CLCP in Srinagarind Hospital. These results could improve the caring and services for these groups of patients. MATERIAL AND METHOD: Data was retrieved from anesthetic records of patients undergoing correction of CLCP from the period January 2005 to January 2009. Demographic data, clinical diagnosis, type operation, anesthetic technique, total opiod were analyzed using direct laryngoscopic view, grading intubation, method of intubation, and as well perioperative complications were also analyzed. RESULTS: A total of 469 anesthetic records were obtained. The most common type of CLCP was unilateral side (45.48%). The highest incidence of difficult intubation was found in the CP and unilateral CLCP subgroup (4.48% and 4.48%, respectively). All patients were successfully intubated with a stylet except one patient, in whom retrograde intubation was used. Perioperative complications included desaturation, reintubation, postoperative bleeding, and post-operative nausea and vomiting (PONV). And the highest incidence of PONV was found in the CP (8.95%). Correlation between fentanyl using and postoperative desaturation was statistically significant when multivariate analysis was used (OR = 1.2; p = 0.01). CONCLUSION: Patients with unilateral CLCP or CP had a higher risk for difficult intubation. Fortunately, all of the patients were successfully intubated with advanced anesthetists' skill. Long operative periods and a large dose of opioid could contribute to the postoperative desaturation and PONV. PMID- 26742385 TI - Custodial-HTK Solution for Myocardial Protection in CABG Patients. AB - BACKGROUND: Many steps of myocardial preservation during open heart surgery are practical after the development of the heart-lung machine. A cardioplegia solution, infused after aortic cross clamping, is an important aspect. Two-thirds of cardioplegia solutions are an intracellular solution (such as HTK or Bretschneider solution) or extracellular solution (such as blood cardioplegia). Intracellular cardioplegia solution can provide protection for 3-4 hours after one-time infusion, which differs from extracellular cardioplegia solution requiring intermittent use every 20-30 minutes. MATERIAL AND METHOD: Retrospective case-control study in CABG patients were reviewed in Cardiovascular and Thoracic Unit, Department of Surgery, Khon Kaen University during April 2011 and September 2012. The study group was divided into groups A and B, for myocardial protection by blood cardioplegia and Custodiol-HTK (Histidine Tryptophan-Ketoglutarate) solutions. Baseline data such as age, sex, NYHA, risk factors, associated disease, operation, CPB time, aortic cross clamp time, complication, defibrillation after surgery, ICU stay, length of stay and mortality rate were analyzed. RESULTS: The study patients in groups A and B were 60 and 65 cases. Defibrillation after finishing CABG in groups A, B was 8.3% and 33.8%. Mortality rate in groups A, B were 1.7% and 4.6%. Other post operative complications were similar in both groups. CONCLUSION: There was significantly more spontaneous ventricular fibrillation after release of cross clamping in HTK group. Clinical outcome of single doses of antegrade, cold Custodiol-HTK cardioplegia solution in CABG surgery protected the myocardium equally well as repetitive antegrade, cold blood cardioplegia. PMID- 26742386 TI - Community-Based Hearing Screening of Disabled Elders Using the Thai-FMHT: Clinical Implications and Cost-Effectiveness. AB - OBJECTIVE: The aim of this study was to evaluate the feasibility of using the two stage hearing test to detect hearing disabilities in the community elders. MATERIAL AND METHOD: A prospective cohort study was conducted in the Phuwieng District, Khon Kaen, Thailand from December 1, 2012 to January 31, 2013. All of the elders more than 60 years of age were invited. First, screening using the Thai version of five-minute hearing test (Thai-FMHT) with a score equal to or greater than 12 was included in the group and then given the next audiometric examination. RESULTS: Two hundred fifty-eight elders were interested in this program, but only 192 subjects consented to participate in the entire study. Six participants withdrew before completing the protocol; therefore, 107 males and 79 females were included. The age ranged 60-92 years old. Only 152 participants (81.7%; 95% CI: 75.5-86.6%) had a hearing disability that could be rehabilitated using a hearing aid. The cost of hearing screening using this program was reduced from $114.15 to $28.60 per positive case with the need for hearing rehabilitation. CONCLUSION: The two-stage hearing screening using the Thai-FMHT followed by an audiometric examination was found to be a suitable test for community-based mass screening of hearing loss, particularly in an area with limited resources. PMID- 26742387 TI - Laparoscopic Adrenalectomy: 6 Years Experience in Srinagarind Hospital. AB - BACKGROUND AND OBJECTIVE: Laparoscopic adrenalectomy has become the procedure of choice to treat benign functioning and non-functioning adrenal tumors. This study aims to present our single unit experience of laparoscopic adrenalectomy. MATERIAL AND METHOD: Review of all recorded clinical data was performed in patients who underwent laparoscopic adrenalectomy for adrenal neoplasm, between January 2008 and December 2013 in Srinagarind Hospital. Patients' demographic data, lesion size, operation time, blood loss, conversion rate, length of postoperative stay, morbidity and mortality were collected and analyzed. RESULTS: Forty-six adrenalectomy were done. 11 men and 35 women, with a mean age of 44 years (range 20-69) were enrolled. A right adrenal gland tumor in 14 cases (30.43%) and left adrenal gland tumor in 32 cases (69.57%). Overall mean operative time was 97 minutes and mean blood loss was 61.73 ml. Conversion to open surgery was necessary in 6 of 46 patients (13.04%). Mean length of post operative hospital stay of conversion to open surgery group (9.83 days) was longer than laparoscopic group (4.67 days) significantly p<0.05 (95% CI: -7.28 to -3.03). Tumor mean size was of 2.6 cm and most was cortical adenoma. Morbidity rate was 2.17% and no mortality. CONCLUSION: Laparoscopic adrenalectomy is the procedure of choice for benign adrenal gland tumor. Current review confirms that it has been a safe and feasible procedure associated with minimal morbidity. Surgical skill and laparoscopic experience are important factors to achieve consistently good outcomes. PMID- 26742388 TI - Whether Post-Tonsillectomy Medication Should be Liquid Based or Can be Solid? A Randomised, Single-Blinded, Controlled Trial. AB - BACKGROUND: Tonsillectomy is a common operation for the otolaryngologist. There has been a discrepancy in recommending prescribing a liquid based or solid medication for post-tonsillectomy patients. OBJECTIVE: To compare the pain scores, adverse effects and complications between the post-tonsillectomy patients who were given liquid medication in comparison with patients who were given non restricted medication. MATERIAL AND METHOD: Patients with chronic hypertrophic tonsillitis who underwent tonsillectomy were recruited. In the control group, patients were given liquid medication. The experimental group was given a non restricted form of medication. Pain scores, adverse effects and complications and patient satisfaction data were collected. RESULTS: Twenty-six patients were enrolled. The pain score difference between the 2 groups at 4 hours was -0.23 (95% CI -1.57 to 1.11, p = 0.73) and 0.15 (95% CI -0.77 to 1.08, p = 0.73) at 72 hours. There was no statistically significant difference between the early and late complications between the control group and the experimental group (p > 0.05). CONCLUSION: There was no statistical difference in the pain scores, adverse effects and complications between groups. There is no necessity to restrict patients to liquid medication. PMID- 26742389 TI - Oral Health Status in Pediatric Patients with Renal Disease at Srinagarind Hospital, Khon Kaen University, Thailand. AB - BACKGROUND: Renal diseases involve multiple organs including the soft and hard tissues of the oral cavity. OBJECTIVE: The objective of this study was to explore oral health status in pediatric patients with renal diseases at Srinagarind Hospital, Khon Kaen University, Thailand. MATERIAL AND METHOD: This cross sectional study was conducted between January and August 2013, at Srinagarind Hospital, Khon Kaen University. Ninety-seven pediatric patients with renal diseases were allowed by their parents to participate in this study. Data were collected from medical records, questionnaires and oral examination records. The oral health status was recorded using the Decay, missing and filling teeth index, Plaque index, Calculus index, Modifies gingival index, Developmental defects of enamel index and Gingival enlargement index. An oral examination was conducted using a mouth mirror explorer and periodontal probe. RESULTS: The average age of the pediatric patients with renal diseases was 11.53+/-3.7 years (ranged 4-17 years). The majority of subjects were able to (a) brush their teeth twice a day (77.3%), (b) visit dentists only when they had any symptoms (79.4%) and (c) never visit dentists for previous six months (73.2%). The prevalence rate of dental caries was 78.4%. Decay, missing and filling of deciduous teeth (dmft) were 1.6+/ 3.1 teeth/person. Decay, missing and filling of permanent teeth (DMFT) were 1.7+/ 2.5 teeth/person. The average value of plaque index was 1.4+/-0.6. The average value of calculus index was 0.3+/-0.4. The average value of modified gingival index was 1.3+/-0.4. The prevalence rate of enamel defect and gingival enlargement were 27.8% and 16.5%, respectively. CONCLUSION: The most common oral health problem of these pediatric patients was dental caries. The majority of subjects had visited dentists only when they had symptoms and never visited dentists for the past six months. PMID- 26742390 TI - Comparisons of Amplitude Reduction of Pattern Visual Evoked Potential (VEP) and Flash VEP between Using Srinagarind Eye Patch and Commercial Eye Patch in Normal Subjects. AB - OBJECTIVE: To compare the difference of amplitude reduction of pattern VEP and flash VEP between occluding eye with Srinagarind eye patches and commercial eye patches in normal subjects. MATERIAL AND METHOD: Fifteen subjects (7 males and 8 females) who had normal eye examinations were enrolled. Amplitude of pattern VEP was recorded for each individual subject as baseline data. Right eyes were occluded with Srinagarind eye patches and fellow eyes with commercial eye patches (3M) and then the VEP were retested (pattern and flash VEP). The reduction of amplitude in pattern and flash VEP was recorded. RESULTS: The commercial eye patch significantly reduced the amplitude of retinal stimulation by pattern reversal stimuli on pattern VEP better than the Srinagarind eye patch 1.68 MUV (95% CI 0.48-2.87). The commercial eye patch group had amplitude of retinal stimulation by light stimulation on flash VEP greater than the Srinagarind eye patch 3.92 MUV (95% CI -9.25-1.41), but not statistically significant. There was also no report of any serious side effects in either group. CONCLUSION: This is the first study aiming to demonstrate the ability of the Srinagarind eye patch to reduce the retinal stimulation compared with the commercial eye patch by using the VEP test. Further study is needed to test the effectiveness of the Srinagarind eye patch. PMID- 26742391 TI - Accuracy of Intraocular Lens Calculation by SRK/T Formula in Pediatric Cataracts. AB - OBJECTIVE: To examine the accuracy of the intraocular lens calculation by SRK/T formula in pediatric cataract patients, by means of the prediction error after the cataract surgery. MATERIAL AND METHOD: A retrospective review of pediatric patients requiring cataract extraction with intraocular lens implantation, between January 2006 and December 2013 was performed. Post-operative spherical equivalent was compared with the predicted calculation value from pre-operative SRK/T measurement, defined as prediction error (PE). RESULTS: 139 eyes from 106 patients were studied. The median age of patients at surgery was 4.56 years (IQR, 14). The two most common causes of cataract were idiopathic and traumatic; 85 eyes (61.2%) and 36 eyes (25.9%), respectively. Primary intraocular lens (IOL) implantation was performed in 87 (62.6%) eyes. The mean PE was -1.32+/-1.89 D ( 7.78, 2.24). At one to three months after surgery, the mean PE of IOL in bag and sulcus were -0.87 D and -2.02 D, respectively. In non-traumatic group, the mean PE of IOL in bag and sulcus were -1.1 D and 2.28 D, respectively, whilst the traumatic group was -0.33 D and -1.16 D, respectively. Post-operative PE within +/-1 diopter was found in 30 eyes (37.97%) at one to three months of follow-ups. CONCLUSION: The majority of post-operative refraction was more myopic than the taigeted refractive error, which was calculated by SRK/T formula. Aiming for a more hyperopic target and IOL implantation in the bag would decrease the post operative prediction error in the use of the SRK/T formnula in pediatric cataract patients. PMID- 26742392 TI - A Surveillance Bacteriological Study of Acute Bacterial Rhinosinusitis in Thailand and the Clinical Responses to the Culture-directed Antibiotics. AB - OBJECTIVE: To examine: 1) types of bacteria and antimicrobial sensitivity of commonly used antibiotics for acute bacterial rhinosinusitis (ABRS) in Thailand, 2) the effectiveness of using antibiotics according to antimicrobial sensitivity, and 3) the effectiveness of using antibiotics according to the Thai clinical practice guidelines (CPG) of ABRS. MATERIAL AND METHOD: Descriptive & experimental studies were conducted in seven tertiary hospitals in Thailand. The specimens from maxillary sinuses were taken for bacterial cultures either by maxillary sinus tap or endoscopically directed middle meatus swabs in patients with clinically diagnosed ABRS. Antimicrobial sensitivity was performed and antibiotics were prescribed according to the results of antimicrobial sensitivity or the Thai CPG of ABRS. RESULTS: A total of 113 patients were enrolled between August 2006 and April 2007, 104 cases of which were performed for bacteriological study. The incidence of bacterial growth was 60.6% (95% CI 51.0-69.4%). The most common bacteria was H. influenzae (25.0%, 95% CI 16.9-35.3%), followed by S. pneumoniae (14.3%, 95% CI 8.2-23.5%) and S. aureus (9.5%, 95% CI 4.7-17.9%), respectively, whilst M. catarrhalis was found only in 2.4% (95% CI 0.5-7.3%). Eight in 12 S. pneumoniae isolates were tested for the minimal inhibitory concentration of penicillin and found to be penicillin resistant strain in five specimens. Beta-lactamase producing H. influenzae was found in eight out of 20 isolates. H. influenzae had a tendency to be sensitive to amoxicillin/clavulanate, cefuroxime, cefpodoxime, azithromycin, clarithromycin, ofloxacin, levofloxacin and gatifloxacin, whilst S. pneumoniae had a tendency to be sensitive to amoxicillin/clavulanate, cefaclor ampicillin/sulbactam, cefuroxime, ofloxacin, levofloxacin, gatifloxacin, cefpodoxime, cefixime and cefdinir. The effectiveness of antibiotics prescription according to the Thai CPG of ABRS and antimicrobial sensitivity were comparable, 88.5% (95% CI 69.8-97.6%) and 82.2% (95% CI 67.9-92%), respectively. CONCLUSION: H. influenzae is found to be the most common bacteria in Thai ABRS, followed by S. pneumoniae and S. aureus. There is a high incidence of beta-lactamase producing H. influenzae and penicillin non-susceptible S. pneumoniae. PMID- 26742393 TI - Congenital Malformations of the Inner Ear: Case Series and Review of the Literature. AB - Patients with craniofacial anomalies often present to doctors due to their noticeable disfigurement and are routinely assessed by otolaryngologists for hearing evaluation. However, small percentage of craniofacial anomaly patients may present with delayed speech though they may not have initial obvious external deformation. The objective of case series is to identify the congenital inner ear malformation. The series of clinical presentation, physical examination, investigations, treatments and follow-up results were demonstrated followed by the discussion. PMID- 26742394 TI - Orthodontic Treatment Combined with Orthognathic Surgery and Simultaneous Alveolar Bone Graft of a Unilateral Complete Cleft Lip and Palate Patient: A Case Report. AB - This article aimed to present a case of 22 year-old Thai female with cleft lip and palate who had malocclusion developed from dental problems, skeletal disharmony and unrepaired alveolar cleft. The treatment was orthodontic combined with one-stage surgical correction which corrected skeletal discrepancy and alveolar cleft in single operation. After treatment, the patient had improved in facial esthetics, attaining good occlusal function and continuous maxillary dental arch. This procedure can reduce morbidity, preclude a second hospitalization and the cost of two-stage surgical correction. However this is only an alternative treatment for adult cleft patients who need late alveolar bone graft and orthognathic surgery. PMID- 26742395 TI - Presurgical Nasoalveolar Molding Techniques for a Complete Unilateral Cleft Lip and Palate Infant: A Case Report. AB - The purpose of this article was to present a modified protocol and devices of presurgical nasoalveolar molding techniques to improve deformity of lip, nose and alveolus at Department of Orthodontic, Khon Kaen University (KKU). This new protocol was developed in order to address nasal problems as early as possible with a new extra-oral type of nasal molding device, "forehead type of nasoalveolar molding device". Extra-oral strapping was applied to approximate lip segments and also help to reduce alveolar cleft rapidly. The remaining alveolar cleft was reduced till completely, using alveolar molding plate with traction screw. The forehead type of nasal molding device could be used continuously after cheiloplasty to maintain nasal configuration until the secondary palate repaired. A case of complete unilateral cleft lip and palate girl was presented to clearly demonstrate treatment steps and results of lips, nose and alveolus after being treated with this new presurgical nasoalveolar molding protocol and devices for a period of four months. PMID- 26742396 TI - Carbamazepine-Induced Incomplete Stevens-Johnson Syndrome: Report of a Case in Children without Mycoplasma pneumoniae Infection. AB - Incomplete Stevens-Johnson syndrome (SJS) is a rare reactive skin condition. Most cases are occurred in children and all are associated with Mycoplasma pneumoniae (M. pneumoniae) infection. We reported an unusual case of a 6-year-old boy who developed the presentation of isolated mucosal erosion with a lack of skin findings, which indicated incomplete SJS after two weeks of carbamazepine (CBZ) administration. Findings of positive HLA-B*1502 allele supported a possible causative influence of carbamazepine inducing SJS. Interestingly, this patient was tested negatively for M. pneumoniae. This is a significant finding since there is no previous report of incomplete SJS without M. pneumoniae infection. Discontinuation of CBZ and administration of systemic corticosteroids were accomplished to treat SJS, which resulted in complete recovery. Our interesting findings highlighted the manifestation of incomplete SJS, which can present with other causes rather than M. pneumoniae infection. Early manifestation of mucosal change without typical skin lesions should not be neglected in the diagnosis of incomplete SJS. PMID- 26742397 TI - Migration of Foreign Bodies from the Upper Digestive Tract: A Case Series. AB - Fish bones are considered to be sharp foreign bodies and can penetrate the digestive tract. These penetrations are rarely observed but can pose serious complications when they happen. We present two-case studies where ingested fish bones were found to have migrated from the upper digestive tract to the retropharyngeal area. Initial examinations and endoscopies of the neck returned negative results. The subsequent computed tomography scans documented the locations of the fish bones. Surgical neck explorations were performed via a lateral neck incision and the fish bones were successfully removed from the patients. PMID- 26742398 TI - [Is Extubation Art or Science?]. PMID- 26742399 TI - [Efficacy of Ultrasound-guided Thoracic Paravertebral Block Compared with the Epidural Analgesia in Patients Undergoing Video-assisted Thoracoscopic Surgery]. AB - BACKGROUND: Thoracic paravertebral block (TPVB) has proven to be safer by using ultrasound imaging. This prospective randomized study was designed to investigate postoperative pain relief and intraoperative hemodynamics in patients undergoing ultrasound-guided TPVB or epidural analgesia. METHODS: Twelve patients scheduled for thoracoscopic surgery for lung cancer were randomly divided into two groups and received ultrasound guided TPVB (N=6) or epidural analgesia (N=6). Both groups received postoperative analgesia with continuous infusion of 0.2% ropivacaine 6 ml . hr(-1) via paravertebral or epidural block. Postoperative numeric rating score (NRS) and the data of intraoperative hemodynamics were collected. RESULTS: In comparison with the epidural group, the level of NRS was higher in the TPVB group at 12 hr (4.5+/-1.05 vs 2.7+/-0.82, P<0.01), and 24 hr (4.5+/-1.05 vs 2.7+/-0.82, P<0.01) after surgery. In the TPVB group, the intraoperative amount of transfusion was smaller (1,331+/-147 ml vs 1,693+/-162 ml, P<0.01) and the lowest systolic pressure was higher (87+/-4.56 mmHg vs 73+/ 4.34 mmHg, P<0.01) than that of the epidural group. CONCLUSIONS: Ultrasound guided TPVB was performed affecting hemodynamics less than the epidural anesthetic. There was less postoperative analgesic effect on TPBV than on epidural analgesia after thora- coscopic surgery when continuously infusing 0.2% ropivacaine 6 ml . hr(-1). PMID- 26742400 TI - [Comparison of Analgesic Efficacy between Posterior and Lateral Transversus Abdominis Plane Block Techniques for Laparoscopic Gynecological Surgery]. AB - BACKGROUND: Posterior transversus abdominis plane (TAP) block has been considered as a useful technique for lower abdominal postoperative analgesia, but in ultrasound-guided block, its efficacy and usability are still unknown. We prospectively compared the analgesic efficacy among posterior and lateral TAP block and with control group in laparoscopic gynecological surgery. METHODS: 29 patients were randomly assigned to a study group. Ultrasound-guided TAP block was performed before the operation. In the posterior group (n =10), a needle was inserted from posterior to the middle axillary line, and its tip was centrally positioned at the origin of the transversus abdominis muscle. In the lateral group (n=10), a needle was inserted from the middle axillary line, and the tip was peripherally positioned at the surface of the transversus abdominis muscle. Visual analog scale (VAS), the use frequency of fentanyl rescue dose, and the period of time until initial rescue use after the operation were measured. RESULTS: In posterior group, pain scores both at rest and on movement were significantly lower than other groups at early phase (P<0.05). The number of uses of the fentanyl rescue dose was smaller in posterior group than in control group in the first 6 postoperative hours (1+/-1.2 vs 3+/-1.5, P<0.05). CONCLUSIONS: Ultrasound-guided posterior TAP block could become a more useful tool for postoperative analgesia. We presumed that its additional effect is caused from reduction of visceral pain related to sympathetic nerve block. PMID- 26742401 TI - [Analysis of the Factors in Successful Helmet Non-invasive Positive Pressure Ventilation]. AB - BACKGROUND: Non-invasive positive pressure ventilation (NPPV) reduces the incidences of ventilator-associated pneumonia, the duration of ICU stay and the mortality rate compared with conventional respiratory management of the patients with acute respiratory failure (ARF). Recently, helmet NPPV equipment became available. Because of the high tolerability, the helmet seems to be the best NPPV interface when prolonged and continuous assistance is needed. In this study, we analyzed several factors related to failure of helmet NPPV in ARF patients in intensive care unit (ICU), retrospectively. METHODS: Institutional Research Committee of Nagasaki Rosai Hospital approved this study. We studied consecutive patients with ARF who needed ventilator support in ICU from February 2012 to February 2013. We excluded the patients whose trachea had been intubated before admission to ICU and comatose patients. After admission to ICU, all ARF-patients received helmet NPPV and conventional intensive care therapy including sedation with dexmedetomidine and vasoactive agents. General clinical data including blood gas analysis were recorded at admission to ICU and during ICU stay. Patient's tracheas were intubated if they met at least one of the following criteria, as judged after they had received helmet NPPV: lack of improvement in arterial blood pH or PaCO2; changes in mental status, in patients unable to tolerate noninvasive ventilation; a decrease in SaO2 to less than 85% despite the use of a high FIO2. The final decision of endotracheal intubation was made by a staff intensivist. We defined the failure of helmet NPPV as the execution of endotracheal intubation. The data were presented as median (IQR), and statistical analysis was performed using Mann-Whitney U-test and Fisher's exact probability test at the P<0.05 level of significance. RESULTS: The subjects were 36 patients (25 males and 11 females) aged 27 to 94 years, including 6 patients with acute heart failure (AHF), 8 with pneumonia, 6 with aspiration pneumonia, 2 with hemothorax, 10 with acute respiratory distress syndrome (ARDS), 1 with asthma, and 3 with acute exacerbation of chronic obstructive pulmonary disease (COPD). NPPV was successful in 29 (19 males and 10 females), but unsuccessful in 7 patients (6 males and 1 female). There were no significant differences in demographic data and the variables before induction of NPPV between the successful and unsuccessful groups. The P/F ratio was improved from 133 (99,167) to 209 (143,274) in the successful group, and from 93 (81,157) to 188 (129,271) in the unsuccessful group after the induction of NPPV, but there was no significant difference between the two groups. In the patients with unsuccessful NPPV, expiratory positive airway pressure, inspiratory positive airway pressure, respiratory rate, body temperature and FIO2 before removing NPPV were significantly higher, and ICU stay was longer compared with the patients with successful NPPV. Furthermore, marked excretion of sputum was observed in 4 of the 7 patients with unsuccessful NPPV. CONCLUSIONS: Helmet NPPV improved oxygenation in ARF patients immediately after induction of NPPV. Although there were no significant predictable parameters of unsuccessful NPPV before induction of NPPV, a lot of excretion of sputum might be suggested as a risk factor. PMID- 26742402 TI - [Perioperative Effect of Intraoperative Fluid Restriction with the Same Fixed Volume of 5 ml . kg(-1) . h(-1) in Patients Undergoing Major Abdominal Versus Thoracic Surgery]. AB - BACKGROUND: Major abdominal surgery accompanies the higher magnitude of physiological stress response and may require an additional replacement fluid for the redistributed volume. Intraoperative volume restriction strategy is recommended to avoid fluid overload leading to increased mortality. We conducted a comparative study of the perioperative effects of intraoperative fluid restriction in abdominal versus thoracic surgery. METHODS: Each 15 patients having major abdominal or thoracic surgery were studied prospectively. All participants were identically given intraoperative iv crystalloid of 5 ml . kg( 1) . hr(-1) under combined epidural/general anesthesia. Plasma level of AVP, aldosterone, angiotensin II and IL-6 as well as body water composition by bioelectrical impedance analysis was examined at preoperative period, at the end of surgery and on the first postoperative day. RESULTS: In abdominal surgery group there was significantly less intraoperative urine output compared with thoracic surgery group. No significant differences were found between two groups in extracellular water volume chnages, AVP, aldosterone angiotensin II, IL-6 level and postoperative renal function. CONCLUSIONS: Restrictive fluid therapy with intraoperative crystalloid of 5 ml . kg(-1) . hr(-1) can be safely used with no serious adverse events in abdominal surgery. In conclusion we had better not make any traditional difference in intraoperative fluid management between abdominal and thoracic surgery even if their stress response differs in magnitude. PMID- 26742403 TI - [The Influence of Flurbiprofen on the Frequency of Postoperative Shivering]. AB - BACKGROUND: Many methods to prevent postoperative shivering (POS) has been reported. However, there are few reports demonstrating the effect of flurbiprofen on POS which affects the set point in the thermocenter of the hypothalamus. METHODS: One hundred and forty six patients undergoing lung lobectomy or segmentectomy under video-assisted thoracic surgery were divided into a flurbiprofen-treated group (Group F) and a non-treated group (Group N). We retrospectively investigated the incidence of POS associated with total intravenous anesthesia with epidural anesthesia compared with or without flurbiprofen. We weighed the incidence of POS against age, body mass index, the effective site concentration of fentanyl on extubation, the mean dose of remifentanil, the minimum rectal temperature, the surgical duration and total hemorrhage volume based on the anesthetic chart Chi-square and Student t-test were used for statistical analysis. RESULTS: Although the surgical duration in Group F was shorter than that in Group N (223+/-83 vs. 165+/-80 (min), P<0.01), the incidence of POS in Group F was higher than that in Group N (1/32 vs. 28/114, P<0.01). There were no significant differences in another items between the two groups. CONCLUSIONS: The results of the study indicates that flurbiprofen has a possible beneficial effect in preventing POS. PMID- 26742404 TI - [Perioperative Management of Elderly Patients Over 90 Years of Age with Femoral Neck/Trochanteric Fracture]. AB - BACKGROUND: The use of anesthesia in patients older than 90 years has been increasing. We examined the perioperative management of these patients. METHODS: The perioperative complications, waiting period for surgery, method of anesthesia, and prognosis in patients older than 90 years undergoing operations for femoral neck/trochanteric fractures were retrospectively examined in our anesthesia database. RESULTS: The average age of patients was 94.0+/-2.8 years. All patients had preoperative complications, including hypertensive disease (91.7%), renal dysfunction, anemia, or dementia. The average waiting period for surgery was 3.7+/-2.1 days; 92.6% of the patients underwent surgery within 7 days and 40.7% within 2 days. The main reason for waiting was withdrawal of antiplatelet and anticoagulant drugs. Local anesthesia, including spinal and epidural anesthesia, was used in 77.8% of patients. General anesthesia was selected for those patients on hemodialysis and continuous antiplatelets/anticoagulants. Hypotension was observed in 63.0% of the patients. The postoperative course was satisfactory, with the exception of 2 patients who died within 3 months from pneumonia and heart failure, respectively. CONCLUSIONS: Anesthetic management of the patients was without major complications. Anesthesia, either general or local, was performed safely. Further study of the relative advantages of anesthetic methods is required. PMID- 26742405 TI - [Combined Use of a Videolaryngoscope and a Transilluminating Device for Intubation with Two Difficult Airways]. AB - Videolaryngoscope is useful in patients with difficult airways, but it may not be in some patients. We report the use of a lighted stylet to facilitate tracheal intubation in 2 patients in whom laryngoscopy with a videolaryngoscope was difficult. Case 1: A 52-year-old female with loose teeth and lockjaw presented for a scoliosis surgery under general anesthesia. Laryngoscopy using a blade 3 of a Glide-Scope(r) (Laerdal Medical Corporation, New York, NY, USA) videolaryngoscope (GVL) showed a Cormack-Lehanne grade 3 view. Bag mask ventilation was easily achieved. By using the TrachilightTM (Saturn Biomedical System Burnaby, BC, Canada) with the GVL, we could intubate the trachea succesfully. Case 2: A 16-year-old male with a history of difficult tracheal intubation due to a limited cervical spine movement presented for an external fixation of a femur under general anesthesia. After induction of anaesthesia, bag mask ventilation was easily achieved but the GVL laryngoscopy did not provide a good view of the glottis (Cormack-Lehanne grade 3). Combined use of the TrachilightTM with the GVL, facilitated tracheal intubation. The TrachilightTM is a recognized aid to facilitate trachal intubation but the device is now commercially not available. Neverthless, we believe that a lighted stylet is potentially useful for tracheal intubation when the view of the glottis with a videolaryngoscopy is not ideal. PMID- 26742406 TI - [Use of a New Video-laryngoscope (McGRATH(r) X-bladeTM) in Patients with Difficult Airways]. AB - We describe the use of a new video-laryngoscope (McGRATH(r) X-bladeTM, X-blade) in patients with difficult airways. We report four cases of difficult and failed tracheal intubation using a conventional Machintosh laryngoscope and McGRATH(r) MAC in which tracheal intubation was accomplished swiftly and easily using a newly designed videolaryngoscope, the X-blade. The whole glottis was easily visible (Cormack-Lehane grade 1) with the X-blade. X-blade also provided a good view of glottic opening in a patient with obesity. We believe that X-blade is useful in patients with difficult airways. PMID- 26742407 TI - [A Case of Penetrating Injury of the Neck in Which It Was Difficult to Secure the Airway]. AB - A 76-year-old man sustained a penetrating neck injury caused by a metal rake following an accidental fall. On admission, he showed clear consciousness and no dyspnea. CT revealed that the tips of three prongs of the rake were located close to the vertebral artery and trachea. Cerebral angiography identified an injury to the vertebral artery, but no injury to the trachea or oropharynx. He was scheduled for vertebral artery embolization under general anesthesia. Since the neck must be stabilized, we chose to perform rapid sequence induction of general anesthesia with endotracheal intubation using a fiberoptic bronchoscope. Fiber optic intubation was more difficult than had been expected, and the SpO2 decreased; therefore, mask ventilation was performed using only the jaw-thrust maneuver without neck extension. Although we attempted fiberoptic intubation 5 times, we were unable to obtain a view of the airway for tracheal intubation. We considered tracheostomy, but, finally, 35 min after anesthesia induction, we succeeded in endotracheal intubation using Airwayscope(r) without neck movement. The glottis was noted to have deviated from the midline. No severe hypoxemia occurred during the clinical course. Various airway management devices have been developed, and we should consider switching quickly to alternative methods. PMID- 26742408 TI - [Successful Intubation in a Patient with Limited Oral Opening by Using a Combination of the Parker Flex-ITTM Stylet and McGRATH(r) MAC Laryngoscopy]. AB - A 74-year-old female patient underwent a coil embolization for an unruptured cerebral aneurysm. A routine anesthetic protocol was devised as there was no risk of a difficult airway. We attempted to intubate by using direct laryngoscopy but were unable to because the mouth only opened approximately one finger-breadth. We then attempted to intubate using Mc-GRATH(r) MAC laryngoscopy; the McGRATH(r) MAC laryngoscope could be inserted orally by force, but a tracheal tube and stylet could not been guided into the glottis. We changed the stylet to a Parker Flex ITTM Stylet (Parker Medical, CO, USA), which can be freely curved by pushing the sum button on the top of the stylet. As a result, easy intubation was possible, and the DLT was maneuvered at a proper angle while examining the vocal cords by using the Parker Flex-ITTM Stylet In conclusion, when a McGRATH(r) MAC laryngoscope cannot be operated freely in the oral cavity owing to a limited oral opening, we can instead intubate easily and effectively by using a combination of a Parker Flex-ITTM Stylet and the McGRATH(r) MAC video laryngoscope. PMID- 26742409 TI - [The First Successful Application of a Mask with a Left Side Slit for Passing the Trunk of an Endoscope In Situ and Enabling Respiratory Support during Sedation for Upper Gastrointestinal Endoscopy]. AB - Sedation in patients during gastrointestinal (GI) endoscopy involves the risk of respiratory depression. Ventilation support with a conventional face mask without removing an endoscope is impossible. We devised a ventilation mask with a slit and membranous valve on the left side wall and the circular upper end enabling to pass the trunk of an endoscope in situ, based on an idea published in the Japanese Journal of Anesthesia "Masui" 2013; 62: 105-8. An 82-year-old woman was scheduled for GI endoscopy for severe abdominal pain. An endoscope was inserted into her GI tract through the mouth after midazolam 1.5 mg i.v. Soon after the examination began, she developed respiratory depression, and her SpO2 gradually decreased to 84%, despite oxygen insufflated around the nose and mouth. The new slit mask was applied without removing the endoscope, and respiratory support was started by bag-valve method. Her SpO2 recovered and remained above 95% thereafter as the endoscopic examination continued. The side slit mask offers important advantages allowing its application in situ after an endoscope being inserted and by enabling positive pressure ventilation without interrupting the endoscopic procedure. PMID- 26742410 TI - [Epidural Anesthesia with Non-invasive Positive Pressure Ventilation for Laparotomy in a Patient with Amyotrophic Lateral Sclerosis]. AB - In patients with amyotrophic lateral sclerosis (ALS), general anesthesia carries a significant risk of respiratory complications and may result in prolonged intubation. Epidural anesthesia may be a feasible alternative in selected cases but may impair respiratory function by producing intercostal muscle weakness. Here, we present a case of ALS who underwent emergency laparotomy that was successfully managed with epidural anesthesia and non-invasive positive pressure ventilation. PMID- 26742411 TI - [A Case of Epidural Hematoma after Removal of Epidural Catheter in a Patient with Coagulation Disorder]. AB - A 75-year-old man with abdominal aortic aneurysm underwent Y-graft replacement under combination of general anesthesia and epidural anesthesia. Although we inserted an epidural catheter at first attempt from T11-12, nurse cut the epidural catheter accidently. We re-inserted from the same place. Postoperatively, we found hemopneumothorax in the chest Xp. The patient was transferred to ICU and mechanical ventilation was continued. The next day, he showed motor disturbance of both legs after waking up from sedation. The surgeon pulled out the epidural catheter. At that time, APTT was 41.5 sec, PT-INR was 1.32, PLT was 80,000. After one hour, he could move leg but had numbness of the left leg. MRI revealed epidural hematoma from T8 to T10. Although the cause of epidural hematoma remains unclear, we should have proposed to check anticoagulant data when catheter was pulled out from epidural space. PMID- 26742413 TI - [The Effectiveness of Combining Remifentanil with Propofol to Achieve Seizure Adequacy in a Patient Undergoing Modified Electroconvulsive Therapy]. AB - A patient with medication resistant schizophrenia underwent modified electroconvulsive therapy (12 sessions). Propofol was chosen as a hypnotic agent and the adjustment of its dose and stimulus intensity was attempted. However, despite using propofol of a dose minimally required for hypnosis, adequate seizures could not be induced even with the maximum stimulation. Assuming that propofol was preventing the induction of seizures, it was decided to reduce its dose and at the same time to combine it with remifentanil 100 MUg starting from the fifth session. This allowed to reach the seizure adequacy during the next and the four subsequent sessions. Although from the tenth session on, adequate seizures could no longer be induced (possibly due to the development of resistance to propofol), the patient's symptoms showed improvement after completion of all 12 sessions. PMID- 26742412 TI - [A Case of Epidural Hematoma Associated with Epidural Anesthesia]. AB - We report a case of epidural hematoma in an elderly patient with normal coagulability and without difficulty in epidural catheterization. A 76-year-old man with a history of cervical myelopathy was scheduled for gastrojejunostomy under combined epidural and general anesthesia. He had normal bleeding time, coagulation test results, and platelet count. He underwent an epidural catheterization without difficulty. On the first postoperative day, he noticed that could not move his legs with analgesia. After stopping continuous epidural perfusion, he could move legs slightly, but paraplegia remained. On the second postoperative day, MRI of the spine demonstrated a hematoma-like lesion, and severe thoracic and lumbar spinal canal stenosis. Severe vertebral deformation, especially in cases of the elderly, is a potential risk for epidural hematoma after epidural catheterization, because a small hematoma may compress the spinal cord. A careful preoperative evaluation whether to perform epidural catheterization and postoperative observation are required for elderly patients with severe vertebral deformation. PMID- 26742414 TI - [Metoclopramide Induced Acute Dystonia during Intravenous Patient-controlled Analgesia with Droperidol]. AB - A patient developed acute dystonia following intravenous administration of metocroplamide 20 mg. A 34-year-old woman underwent right hepatectomy, under general anesthesia managed with desflurane, remifentanil, and rocuronium. At the start of surgery, droperidol 1.5 mg was given intravenously for anti-emetic prophylaxis. Operation was completed uneventfully. Intravenous patient-controlled analgesia (i.v.-PCA) with fentanyl, containing droperidol, was selected for postoperative pain management The patient showed a reasonable postoperative course; however, around 15 hours post-operatively, she complained of nausea, although droperidol 2.625 mg had been administrated (maximum dose). Nausea subsequently disappeared following intravenous metocroplamide 20 mg, and i.v.-PCA was terminated. The patient gradually complained of excessive sleepiness. Finally, she showed akinesis and bilateral oculomotor disturbance 140 minutes after metocroplamide administration. However, her vital signs remained stable. Examinations including magnetic resonance imaging, electroencephalogram, and blood test did not show abnormalities. She was diagnosed with acute dystonia. She recovered without medications 300 minutes after the onset of akinesis. She could communicate with her eyes, opening/closing, throughout this episode. The effects of antiemetics acting on different receptors are additive. However, we should remember that coadministration of metocroplamide and butyrophenone induces extrapyramidal signs like acute dystonia. Intraoperative management extending beyond postoperative antiemetic therapy is necessary. PMID- 26742415 TI - [Retrograde Ascending Aortic Dissection during Thoracic Endovascular Stent Graft Repair: A Case Report]. AB - A 66-year-old man (166 cm and 64 kg) with a history of hypertension was diagnosed with a.chronic aortic dissection (DeBakey IIIa type). He underwent thoracic endovascular aortic repair (TEVAR) under general anesthesia (sevoflurane and remifentanil) in an angiography room. After deploying a stent graft (Zenith TX2, Cook Japan, Tokyo) in the descending aorta via the right femoral artery, we checked the condition of the stent by angiography. No remarkable change of vital signs was observed. However, the angiography revealed a decrease in blood flow of both brachiocephalic and left common carotid arteries. The decision was made to operate immediately. The patient was transferred to the operating room under sedation with propofol. Cardiopulmonary bypass commenced 1 hour and 25 minutes after the decision to operate. Exploration of the aortic arch confirmed a retrograde ascending aortic dissection (rAAD). Ascending-arch vascular prosthesis was performed during circulatory arrest. The patient was extubated successfully the day after surgery. The present case demonstrates an intraoperative rAAD following stent placement TEVAR is believed to be less invasive compared to surgical treatment. However, it should be noted that TEVAR could provoke life threatening complications such as rAAD. PMID- 26742416 TI - [Two Cases of Retained Guide Wires after Placement of a Central Venous Catheter via the Internal Jugular Vein]. AB - We report two cases of a retained guide wire after perioperative placement of a central venous catheter during a six-month period. Case 1: A 73-year-old male was scheduled for an open cholecystectomy and hepatectomy. After induction of anesthesia, a central venous (CV) catheter was inserted via the right internal jugular vein using an ultrasound guide. Chest radiographs showed a retained guide wire in the inferior vena cava immediately after surgery, which was removed by interventional radiologist before the patient emerged from anesthesia. Case 2: A 77-year-old male was scheduled for colostomy closure. The surgeon inserted a CV catheter in the right internal jugular vein 4 days before the colostomy. Chest radiographs revealed a retained guide wire in the inferior vena cava, which was removed by interventional radiologists before the patient emerged from anesthesia. Although a retained guide wire is a rare complication, awareness of this mishap is necessary to prevent it from happening. PMID- 26742417 TI - [Acute Tongue Swelling Immediately after Extubation of the Trachea in a Patient Undergoing Bipolar Hip Arthroplasty under General Anesthesia]. AB - An 81-year-old woman underwent bipolar hip arthroplasty in the left lateral position under general anesthesia. Her trachea was intubated with a standard tube and a rolled gauze pad was placed between the left lingual margin and buccal wall. Surgery lasting for 49 minutes and anesthesia were uneventful until extubation in the supine position. After the extubation she gradually developed tongue swelling and finally required a temporary supraglottic airway to avoid airway obstruction. The swelling was localized to the tongue and disappeared completely in a day. There were no specific factors for tongue swelling except for the tracheal tube and gauze pad in this case. Airway management with a tracheal tube may potentially cause acute life-threatening tongue swelling after surgery of a relatively short duration. PMID- 26742418 TI - [McGRATH(r) MAC Is Useful to Learn Tracheal Intubation Using a Macintosh Laryngoscope]. AB - BACKGROUND: Learning tracheal intubation using a Macintosh laryngoscope (McL) is important although video laryngoscope is becoming popular. The purpose of this study was to compare the usefulness as a training device for intubation technique using McL with three devices; McGRATH(r) MAC (MAC), Airwayscope(r) (AWS) and McL. METHODS: In this prospective study, 60 nurses not experienced in tracheal intubation were randomly assigned to MAC, AWS, and McL groups (each group: n=20), and 10 times of practice using each device were carried out. We compared the intubation time using McL and the nurse's anatomical understanding of the larynx before and after the practice. RESULTS: The intubation time before the practice was comparable among the three groups, but the time after the practice was significantly shorter in the McL and MAC groups compared to the AWS group (P=0.001). The practice significantly improved anatomical understanding of the larynx in all groups (P<0.05), and in particular it was improved in the MAC and AWS groups compared with the McL group (P<0.001). CONCLUSIONS: The McGRATH(r) MAC may possess advantages compared to Airwayscope(r) and Macintosh laryngoscope as a training device for learning intubation technique using Macintosh laryngoscope and understanding anatomy of the larynx. PMID- 26742419 TI - [Usefulness of the McGRATH(r) Videolaryngoscope in 100 Children]. AB - BACKGROUND: The McGRATH(r) MAC videolaryngoscope (McG) is a new device for tracheal intubation. Its utility has been reported in both tracheal intubation in children and difficult tracheal intubation for adults. Initially, the blade introduced was for adult use only, but the one for children was also in the market. We examined the usefulness of the McG for tracheal intubation in 100 children. METHODS: Tracheal intubation with the McG (blade # 2) was performed in 100 children who required tracheal intubation. The view of glottic opening was evaluated according to Cormack-Lehane classification. The time required for intubation was recorded. RESULTS: It was possible to perform tracheal intubation in all 100 cases including 10 children with predicted difficult intubation. There was no specific complication. The view of the glottis was good in all cases. Tracheal intubation was easily performed in 91 cases, and relatively easy in 9 cases. CONCLUSIONS: McG is useful in both routine and difficult airway management for children. PMID- 26742420 TI - [Seishu Hanaoka Did Not Describe His Anesthetic as Tsusensan--A Misunderstanding of the Terms Mafutsusan and Tsusensan]. AB - It is widespread even among medical professionals as well as medical historians that the formal term of the general anesthetic that Hanaoka developed is Tsusensan and its alias name is Mafutsusan. Hanaoka himself, however, described it as Mafutsusan in his Nyugan Chikenroku, the case report of the first breast cancer excision under general anesthesia with the anesthetic, and a large number of his disciples all used the term Mafutsusan to denote the anesthetic in their manuscripts. The description of Tsusensan has not been found in the documents written in the Edo period, and this name is detected only in the epitaph of Hanaoka. Consequently, we should refer to Hanaoka's anesththetic as "Mafutsusan, another name Tsusensan" instead of "Tsusensan, another name Mafutsusan." PMID- 26742421 TI - Neuronavigation as a diagnostic tool: An innovative application. AB - The role of neuronavigation in tumour surgery is well established. We present an innovative use for this software, as a tool to compare ventricular size between serial sets of cranial imaging. We conclude that neuronavigation software is potentially a powerful diagnostic tool that should not be overlooked when making comparative assessments between scans. PMID- 26742422 TI - Child Abuse in American Storytelling: Masterful storytellers can make it possible to speak not only of child abuse, but of the abuse of 'our children'. PMID- 26742423 TI - Nuclear EGFRvIII resists hypoxic microenvironment induced apoptosis via recruiting ERK1/2 nuclear translocation. AB - Glioblastoma (GBM) is the most aggressive type of primary brain tumor. Its interaction with the tumor microenvironment promotes tumor progression. Furthermore, GBM bearing expression of EGFRvIII displays more adaptation to tumor microenvironment related stress. But the mechanisms were poorly understood. Here, we presented evidence that in the human U87MG glioblastoma tumor model, EGFRvIII overexpression led aberrant kinase activation and nuclear translocation of EGFRvIII/ERK1/2 under hypoxia, which induced growth advantage by resisting apoptosis. Additionally, EGFRvIII defective in nuclear entry impaired this capacity in hypoxia adaptation, and partially interrupted ERK1/2 nuclear translocation. Pharmacology or genetic interference ERK1/2 decreased hypoxia resistance triggered by EGFRvIII expression, but not EGFRvIII nuclear translocation. In summary, this study identified a novel role for EGFRvIII in hypoxia tolerance, supporting an important link between hypoxia and subcellular localization alterations of the receptor. PMID- 26742424 TI - Phosphatidylinositol 3-kinase p110alpha mediates phosphorylation of AMP-activated protein kinase in myoblasts. AB - AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a sensor of intracellular energy. Activation of AMPK is associated with increased phosphorylation of the alpha-subunit at threonine 172 (T172) and decreased phosphorylation at serine 485 in AMPKalpha1 and serine 491 in AMPKalpha2 (S485/491). One potential mediator of AMPK phosphorylation is phosphatidylinositol 3-kinase (PI3K); however, the mechanism and the identities of the specific PI3K isoforms that regulate AMPK activation are not known. To determine whether PI3K p110alpha regulated AMPK activation in muscle cells, C2C12 myoblasts were subjected to pharmacological inhibition of p110alpha, siRNA directed against p110alpha, or overexpression of constitutively-active or dominant negative p110alpha. Chemical inhibition, siRNA, and expression of dominant-negative p110alpha were all associated with increased AMPK T172 phosphorylation, whereas expression of constitutively-active p110alpha reduced T172 phosphorylation. Conversely, pharmacological inhibition of p110alpha reduced AMPK S485/491 phosphorylation, while constitutively-active p110alpha increased AMPK S485/491 phosphorylation. This p110alpha-mediated increase in AMPK S485/491 phosphorylation was eliminated in the presence of the Akt inhibitor MK2206, suggesting that p110alpha-mediated phosphorylation of AMPKalpha at S485/491 is Akt-dependent. In response to oligomycin or serum-starvation, AMPK T172 phosphorylation was elevated in p110alpha-deficient myoblasts compared to control myoblasts. Overall, our findings identify PI3K p110alpha as a mediator of AMPK phosphorylation in myoblasts. PMID- 26742425 TI - IL-17A up-regulates expression of endothelial tissue factor in liver cirrhosis via the ROS/p38 signal pathway. AB - Interleukin-17A (IL-17A), an inflammatory cytokine, is elevated in liver cirrhosis. Inflammation and coagulation dysfunction are closely related. Tissue factor (TF) is a bridge between endothelial activation, blood coagulation and inflammation. The aims of the present study were to evaluate endothelial TF expression in liver cirrhosis and identify the possible underlying role of IL-17A in TF expression. In the present study, we found that TF expression was increased on endothelium of splenic vein from cirrhotic patients and significantly correlated with intima/media ratios of splenic vein and coagulation parameters. Serum levels of IL-17A were significantly higher in cirrhotic patients as compared with normal controls. Cirrhotic serum and IL-17A stimulated TF expression in HUVECs, which was reduced by blockade of IL-17A, p38, and reactive oxygen species (ROS). Taken together, our data show that enhanced expression of endothelial TF, which plays an important role in coagulopathy and splenic vein remodeling in liver cirrhosis, is induced by IL-17A in a ROS dependent manner. PMID- 26742426 TI - Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling. AB - SHP2, encoded by the PTPN11 gene, is a protein tyrosine phosphatase that plays a key role in the proliferation of cells via RAS-ERK activation. SHP2 also promotes Wnt signaling by dephosphorylating parafibromin. Germline missense mutations of PTPN11 are found in more than half of patients with Noonan syndrome (NS) and LEOPARD syndrome (LS), both of which are congenital developmental disorders with multiple common symptoms. However, whereas NS-associated PTPN11 mutations give rise to gain-of-function SHP2 mutants, LS-associated SHP2 mutants are reportedly loss-of-function mutants. To determine the phosphatase activity of LS-associated SHP2 more appropriately, we performed an in vitro phosphatase assay using tyrosine-phosphorylated parafibromin, a biologically relevant substrate of SHP2 and the positive regulator of Wnt signaling that is activated through SHP2 mediated dephosphorylation. We found that LS-associated SHP2 mutants (Y279C, T468M, Q506P, and Q510E) exhibited a substantially reduced phosphatase activity toward parafibromin when compared with wild-type SHP2. Furthermore, each of the LS-associated mutants displayed a differential degree of decrease in phosphatase activity. Deviation of the SHP2 catalytic activity from a certain range, either too strong or too weak, may therefore lead to similar clinical outcomes in NS and LS, possibly through an imbalanced Wnt signal caused by inadequate dephosphorylation of parafibromin. PMID- 26742427 TI - The suppression of torulene and torularhodin treatment on the growth of PC-3 xenograft prostate tumors. AB - Torulene and torularhodin are two of the principal carotenoids in Sporidiobolus pararoseus and have a similar structure to that of lycopene. The present study was to elucidate the anti-cancer activity of torulene and torularhodin in vivo with lycopene as a control. Nude mice were orally supplemented every day with a low or high dose [9 or 18 mg/kg body weight (BW)] of lycopene, torularhodin or torulene. Two weeks after the supplementation, mice were injected once with hormone-independent prostatic carcinoma PC-3 cells. When the tumor of the control group load exceeded 200 mm(3), mice were killed and the study was terminated. Compared with the controls, high-carotenoid supplementation lowered the mean number of tumors from 248.13 +/- 28.74 to 50.83 +/- 7.63, 70.34 +/- 6.77, and 60.53 +/- 6.78 mm(3) (P < 0.05, n = 8) by, respectively. Histological examination showed tumor degeneration, apoptosis and necrosis presented at the end of the experiment. Quantitative polymerase chain reaction and immunohistochemistry results showed Bcl-2 expression of the control group was higher than that of the carotenoid-treated group while the expression of Bax was lower than the carotenoid-treated group. High-carotenoid supplementation also increased the mRNA expressions of caspase-3, 8 and 9 in tumor tissues. These results show that both torulene and torularhodin supplementation inhibit the growth of prostate cancer in nude mice and suggest that such an action is associated the apoptosis of tumor cells. PMID- 26742428 TI - Activation of IRE1alpha-XBP1 pathway induces cell proliferation and invasion in colorectal carcinoma. AB - Cell proliferation and tumor metastasis are considered as the main reasons for death in colorectal carcinoma (CRC). IRE1alpha-XBP1 pathway is the most conserved UPR pathways, which are activated during ER stress caused by the accumulation of unfolded or misfolded protein in the lumen of ER. Here, we demonstrated the critical role of IRE1alpha-XBP1 pathway and underlying molecular mechanism in cell proliferation and tumor metastasis in CRC. By the use of tissue microarray analysis of samples from 119 patients with CRC, IRE1alpha was determined to be an independent predictor of overall survival as higher expression of IRE1alpha in CRC patients showed lower survival rates (p = 0.0041). RNA interference and ectopic expression of IRE1alpha were applied to determine the molecular effects of IRE1alpha in CRC cells. The silencing of IRE1alpha inhibited the proliferation and blocked the invasion of CRC cells in vitro, while ectopic expression of IRE1alpha in turn promoted cell proliferation and invasion. IRE1alpha-XBP1 pathway regulated the mitosis of CRC cells through the directly binding of XBP1s to Cyclin D1 promoter to activate Cyclin D1 expression. Our results reveal that IRE1alpha-XBP1 pathway plays an important role in tumor progression and epithelial-to-mesenchymal transition (EMT), and IRE1alpha could be employed as a novel prognostic marker and a promising therapeutic target for CRC. PMID- 26742429 TI - miR-935 suppresses gastric signet ring cell carcinoma tumorigenesis by targeting Notch1 expression. AB - Gastric signet ring cell carcinoma (GSRCC) is a unique pathological type of gastric carcinoma that is extremely invasive and has a poor prognosis. Expression of microRNAs (miRNAs) has been closely linked to the carcinogenesis of gastric cancer and has been considered as a powerful prognostic marker. The function of miR-935 has never been reported in cancer before. We found, using microRNA array, that expression of miR-935 in GSRCC cell lines is lower than in non-GSRCC cell lines, and enhanced expression of miR-935 in GSRCC cell-lines inhibit cell proliferation, migration and invasion. We also identified Notch1 as a direct target of miR-935. Knockdown of Notch1 reduced proliferation, migration/invasion of GSRCC cells, and overexpression Notch1's activated form (Notch intracellular domain) could rescue miR-935's tumor suppressive effect on GSRCC. Expression of miR-935 was lower in gastric carcinoma tissue than in paired normal tissue samples, and lower in GSRCC than in non-GSRCC. Our results demonstrate the inverse correlation between the expression of miR-935 and Notch1 in gastric tissues. We conclude that miR-935 inhibits gastric carcinoma cell proliferation, migration and invasion by targeting Notch1, suggesting potential applications of the miR-935-Notch1 pathway in gastric cancer clinical diagnosis and therapeutics, especially in gastric signet ring cell carcinoma. PMID- 26742430 TI - Nanonized itraconazole powders for extemporary oral suspensions: Role of formulation components studied by a mixture design. AB - Itraconazole (ITZ) nanocrystal-containing powders were prepared through the combined use of high pressure homogenization (HPH) and spray drying (SD). These powders were intended as base materials for the preparation of extemporary oral suspensions of the drug. The role and the effect of stabilizers on the size of re dispersed particles were studied using a mixture design and a Scheffe model relating the dried nanosuspension composition to the mean particle diameters. The homogenization process required a surface active agent (Tween 20) to obtain the efficient comminution of itraconazole micronized powder. SD was carried out on ITZ nanosuspensions after addition of a cellulose derivative (Methocel((r)) E5) that allowed the prompt re-dispersion of nanoparticles under "in use" conditions. The powders obtained by drying of homogenized systems showed in vitro dissolution profile faster than that of the micronized drug, suggesting a potential ameliorated GI absorption of itraconazole released from the nanosuspensions. PMID- 26742433 TI - Free-Standing Monolayered Metallic Nanoparticle Networks as Building Blocks for Plasmonic Nanoelectronic Junctions. AB - The effective coupling of optical surface plasmons (SPs) and electron transport in a plasmonic-electronic device is one of the fundamental issues in nanoelectronics and the emerging field of plasmonics, and offer promise in providing a solution to next generation nanocircuits in which all coupling is in the near field. Attempts toward this end, however, are limited because of the integration challenge to compatible nanodevices. To date, direct electrical detection of SP-electron coupling from metallic nanostructures alone are not reported, and thus it remains a great experimental challenge. In this paper, we succeed in preparing a new suspended-film-type nanoelectronic junction, in which free-standing 2D fractal nanoparticle networks act as plasmonically active nanocomponents. Direct electrical detection of optical collective SPs was evidenced by photocurrent response of the junction upon illumination. Room temperature I-V characteristics, differing from nonlinear to Ohmic behaviors, are found to be sensitive to the nanometer-scale morphology changes of the nanomembranes. The finding and approach may enable the development of advanced plasmonic nanocircuits and new nanoelectronics, nanophotonics, and (solar) energy applications. PMID- 26742432 TI - PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia. AB - Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis with resultant cytopenias. Increased apoptosis and aberrantly functioning progenitors are thought to contribute to this phenotype. As is the case for other malignancies, overcoming apoptosis is believed to be important in progression toward acute myeloid leukemia (AML). Using the NUP98-HOXD13 (NHD13) transgenic mouse model of MDS, we previously reported that overexpression of the anti apoptotic protein BCL2, blocked apoptosis and improved cytopenias, paradoxically, delaying leukemic progression. To further understand this surprising result, we examined the role of p53 and its pro-apoptotic effectors, PUMA and NOXA in NHD13 mice. The absence of p53 or PUMA but not NOXA reduced apoptosis and expanded the numbers of MDS-repopulating cells. Despite a similar effect on apoptosis and cell numbers, the absence of p53 and PUMA had diametrically opposed effects on progression to AML: absence of p53 accelerated leukemic progression, while absence of PUMA significantly delayed progression. This may be explained in part by differences in cellular responses to DNA damage. The absence of p53 led to higher levels of gamma-H2AX (indicative of persistent DNA lesions) while PUMA deficient NHD13 progenitors resolved DNA lesions in a manner comparable to wild type cells. These results suggest that targeting PUMA may improve the cytopenias of MDS without a detrimental effect on leukemic progression thus warranting further investigation. PMID- 26742434 TI - Advances in Understanding the Pathogenesis of Epstein-Barr Virus-Associated Lymphoproliferative Disorders. AB - Epstein-Barr virus (EBV) was discovered 50 years ago from an african Burkitt lymphoma cell line. EBV-associated lymphoproliferative disorders (LPDs) are life- threatening diseases, especially in children. In this article, we review EBV associated LPDs, especially in the area of primary immunodeficiency disease (PID). We searched PubMed for publications with key words including EBV infection, lymphoma, LPDs and PID, and selected the manuscripts written in English that we judged to be relevant to the topic of this review.On the basis of the data in the literature, we grouped the EBV-associated LPDs into four categories: nonmalignant disease, malignant disease, acquired immunodeficiency disease and PID. Each category has its own risk factor for LPD development. EBV associated LPD is a complex disease, creating new challenges for diagnosis and treatment. PMID- 26742431 TI - NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy. AB - Mitophagy is critical for cell homeostasis. Externalization of the inner mitochondrial membrane phospholipid, cardiolipin (CL), to the surface of the outer mitochondrial membrane (OMM) was identified as a mitophageal signal recognized by the microtubule-associated protein 1 light chain 3. However, the CL translocating machinery remains unknown. Here we demonstrate that a hexameric intermembrane space protein, NDPK-D (or NM23-H4), binds CL and facilitates its redistribution to the OMM. We found that mitophagy induced by a protonophoric uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP), caused externalization of CL to the surface of mitochondria in murine lung epithelial MLE-12 cells and human cervical adenocarcinoma HeLa cells. RNAi knockdown of endogenous NDPK-D decreased CCCP-induced CL externalization and mitochondrial degradation. A R90D NDPK-D mutant that does not bind CL was inactive in promoting mitophagy. Similarly, rotenone and 6-hydroxydopamine triggered mitophagy in SH SY5Y cells was also suppressed by knocking down of NDPK-D. In situ proximity ligation assay (PLA) showed that mitophagy-inducing CL-transfer activity of NDPK D is closely associated with the dynamin-like GTPase OPA1, implicating fission fusion dynamics in mitophagy regulation. PMID- 26742435 TI - Are There Any Epigenetic Similarities Between Treatment Unresponsive Sarcoidosis, COPD and Severe Asthma? PMID- 26742436 TI - Changes of Airway Reactivity after Mycoplasma Pneumoniae Infection in Children: A Study for Early Precautions against Pediatric Asthma. AB - The relationship between Mycoplasma pneumoniae (MP) infection and asthma has rarely been explored through examination of airway reactivity. The aim of this study was to determine airway reactivity changes after MP infection in children. First, 106 children were divided into four groups according to the existence of MP infection and/or asthma. Then children with only MP belonged to the MP group; children who had both MP infection and asthma belonged to the MP+A group; children with asthma but not MP infection belonged to the non-MP+A group; normal children were classified as normal control (NC) group. Each subject underwent a bronchial provocation test (BPT) after effectively controlling the symptoms. Airway hyperresponsiveness (AHR) parameters were compared among the groups. BPT positive rates were also calculated and compared. All AHR parameters decreased following MP infection, with a more significant decrease of small airway reactivity related indexes. The BPT-positive rate in the MP+A group was significantly higher than that in the MP group. Large airway reactivity showed no significant differences between the MP+A and non-MP+A groups, while the small airway reactivity augmented more significantly in the MP+A group. MP infection caused increased reactivity of both large and small airways in lungs, and BPT positive identification in some patients. PMID- 26742437 TI - Occupational Allergy to Peach (Prunus persica) Tree Pollen and Potential Cross Reactivity between Rosaceae Family Pollens. AB - Orchard workers in north China are highly exposed to orchard pollens, especially peach and other Rosaceae family pollens during pollination season. The aim of this study was to investigate whether occupational allergy to peach tree pollen as a member of Rosaceae family is IgE-mediated and to evaluate the cross reactivity among Rosaceae family pollens. Allergen skin test and conjunctival challenge test were performed; enzyme linked immune-sorbent assay (ELISA), inhibiting ELISA, western immunoblotting and inhibiting western immunoblotting were done with Rosaceae family orchard pollens, including peach, apricot, cherry, apple and pear tree pollens. Mass spectrometry was also performed to probe the main allergen component and cross-reactive protein. Sensitizations to peach pollen were found in both skin test and conjunctival challenge in the patients. Serum specific IgE to three pollens (peach, apricot and cherry) were detected through ELISA. When peach pollen used as solid phase, ELISA inhibition revealed other four kinds of pollens capable of inducing partial to strong inhibitions (45% to 87%), with the strongest inhibition belonging to apricot pollen (87%). Western blotting showed predominant IgE binding to a 20 KD protein among these pollens, which appeared to be a cross-reactive allergen component through western blotting inhibition. It was recognized as a protein homologous to glutathione s transferase 16 from Arabidopsis thaliana. Peach and other Rosaceae family tree pollen may serve as a potential cause of IgE mediated occupational respiratory disease in orchard workers in north China. PMID- 26742438 TI - Frequency of gammadelta T Cells and Invariant Natural Killer T Cells in Helicobacter Pylori-infected Patients with Peptic Ulcer and Gastric Cancer. AB - To clarify the effect of gammadelta T cells and invariant Natural Killer T (iNKT) cells in pathophysiology of dyspeptic disorders, number of these two cells in patients with non-ulcer dyspepsia (NUD), peptic ulcer disease (PUD), and gastric cancer (GC) were compared.Patients with dyspepsia were divided into three groups of NUD, PUD, and GC according to their endoscopic and histopathological examinations. Helicobacter pylori infection was diagnosed by rapid urease test and histopathology. The number of peripheral blood CD3+TCRgammadelta(+) T cells and CD3+Va24Ja18+ iNKT cells were determined by flow cytometry. Immunohistochemistry (IHC) was also used for identifying the TCRgammadelta+ cells.Forty two patients with NUD (31.6%), 44 with PUD (33.1%), and 47 with GC (35.3%) were included in the study. The frequency of CD3+TCRgammadelta(+) T cells in peripheral blood of patients with GC (2.71+/-0.25) was significantly lower than that in NUD (3.97+/-0.32, p<0.05) and PUD groups (3.87+/-0.32, p<0.05). However, there was no significant difference in CD3+TCRgammadelta(+) T cell percentage between the NUD and PUD groups. The frequency of TCRgammadelta(+) lymphocytes was significantly lower in tissue samples from patients with GC (4.81+/-0.53) than in NUD (11.09+/-1.09, p<0.0001) and PUD groups (11.11+/-1.01, p<0.0001). Also, we could not find any significant difference in the percentage of mucosal TCRgammadelta+ cells between the NUD and PUD groups. The results showed no significant difference in iNKT cells percentage among the three groups of patients.The results suggest that decreasing number of gammadelta T cells may be related to development and progression of gastric cancer. PMID- 26742439 TI - Production and Characterization of New Anti-Human CD20 Monoclonal Antibody. AB - The B-cell CD20 antigen is one of the most reliable surface targets in immunotherapy of B lymphoma. In this project, we studied the production and characterization of a new monoclonal antibody against chimeric human CD20 extra loops (hCD20 exl). The results showed that clone C12H, IgG2/k isotype reacted with the antigen in ELISA and immunoblot. The Kd value was found to be 2*10(-9)M and flow cytometry results showed that 99.9% and 99.7% of the Daudi and Raji cells respectively were stained with C12H monoclonal antibody (mab) but not with Jurkat cell lines. It also effectively competed with Rituximab, thus, the staining of the Daudi and Raji cell lines was reduced to 55.9% and 40.5% of cells respectively. Based on the high affinity reaction of C12H mab and appropriate reactivity of C12H mab with the native antigen on the surface of Raji and Daudi cells in flow cytometry, it was concluded that development and evaluation of C12H mab could be a beneficial candidate for further application in genetically engineered monoclonal antibody. PMID- 26742440 TI - Interleukin-21 Is Associated with the Pathogenesis of Lumbar Disc Herniation. AB - Inflammation is an important reaction underlying lumbar disc herniation (LDH). Th17 cells play a critical role in immune activation. Interleukin (IL)-21 controls the functional activity of effector T-helper cells and the differentiation of Th17 cells, and promotes B-cell differentiation. It plays important roles in chronic inflammation and autoimmune diseases. However, little is known about relationship between IL-21 and LDH. This study was aimed to determine the association between IL-21 levels and pain scores in LDH patients compared to healthy controls.We enrolled 34 LDH patients and 20 healthy controls in this study. The LDH patients underwent surgery. Pain intensity was recorded using visual analogue scale (VAS) scores preoperatively. Serum IL-21 and IL-17 levels in the peripheral blood were determined using enzyme-linked immunosorbent assay. Disc tissue was examined using western blot and quantitative reverse transcription polymerase chain reaction to determine IL-21, IL-17, and cyclooxygenase (COX)-2 expression, and using immunohistochemistry to assess IL-21 expression.LDH patients exhibited significantly higher levels of serum IL-21 and IL-17 than healthy controls. Moreover, higher expression of IL-21, IL-17, and COX 2 was found in the protein and mRNA levels in disc tissues from LDH patients than in normal disc tissues. Different parameters like VAS pain scores, IL-17, and COX 2 were positively correlated with the IL-21 levels. Enhanced production of IL-21 in disc tissues of LDH patients was also confirmed using immunohistochemical analyses.We concluded that inflammation was responsible for the pain associated with LDH, and that increased IL-21 expression may be associated with the pathogenesis of LDH. PMID- 26742441 TI - Response of Human T Cells to Tetanus Neurotoxin HCC Sub-Domain: T Cell Cytokine Production and Activation Marker Induced by HCC. AB - Tetanus is caused by the tetanus neurotoxin (TeNT), a 150 kDa single polypeptide molecule which is cleaved into active two-chain molecules composed of a 50 kDa N terminal light (L) and a 100 kDa C-terminal heavy (H) chains. Fragment C is further subdivided into two subdomains: the proximal HCN subdomain and the extreme carboxy subdomain, HCC. HCC is considered as an immunodominant part of TeNT and is responsible for TeNT binding activity to neurons.In the present study, we investigated the ability of recombinant HCC(r HCC) to induce T cell activation. Our results showed that recombinant HCC has a stimulatory effect on IFN-gamma secretion by T cells after 48h co-incubation in the presence of anti TLR-2 Ab. Also, Hcc can induce the expression of CD69 on T cells.Our finding indicated that stimulatory effects of HCC on T cells are TLR-2 independent and anti-TLR-2 inhibitory antibody fails to neutralize HCC stimulatory effects on T cells.Furthermore, HCC is critical for immunogenic activity of TeNT and is able to induce T cells through TLR-2 independent pathway. PMID- 26742442 TI - Hepatitis C Virus Subtype 3a Envelope Protein 1 Binding with Human Leukocyte Antigen Class I Types of Pakistani Population: Candidate Epitopes for Synthetic Peptide Vaccine. AB - The object of this cross sectional study was to determine the HCV subtype 3a envelope protein binding affinity with Human Leukocyte Antigen. Envelope 1 (E1) protein is one of the structural proteins responsible for entering the cells through the receptors. The binding affinity of E1 protein epitopes to the selected Human Leukocyte Antigen (HLA) class I alleles was investigated using the computer-based tools. These prediction tools were also used to design the synthetic vaccine's candidate epitopes and to identify the individuals/populations who are likely to be responder to those vaccines.The mean frequency of HLA I antigens in Pakistani population was calculated. Three alleles each from HLA A and B were selected. E1 protein sequence extracted from HCV 3a isolates was retrieved and twenty-four sequences of it were selected. NetMHCcons 1.0 server was used to determine the binding affinities of HLA alleles to the epitope sequences of 10 amino acids in length.A02, A03, A11, A24, A33, B08, B13, B15, B35 and B40 were the first five antigens more prevalent in Pakistan each from HLA A and HLA B.. We did not find any binding affinity between HLA A*201, B*1501 and B*4001 and epitopes from E1 sequences in a threshold of 50 nM. Totally five various epitopes derived from different isolates were characterized.The prediction of HLA-E1 epitope specific bindings and the forthcoming response can be a useful bioinformatics tool to uncover the right synthetic peptides for vaccine design purposes. PMID- 26742443 TI - The Relationship between HLA-G Gene Polymorphisms and Repeated Implantation Failure in Infertile Couples Undergoing Assisted Reproductive Technique. AB - HLA-G is a tolerogenic molecule that expresses in cytotrophoblast cells and plays an important role in immune response suppression in maternal decidua. Interactions between the extracellular domains of the HLA-G protein with cell receptors of the immune system are well-known.This study investigated the association between HLA-G gene polymorphism with repeated implantation failure (RIF). We used PCR followed by the sequencing technique for exons 2, 3, and 4, as well as intron 2 of the HLA-G gene in 100 couples with histories of two or more failed assisted reproductive technique (ART) attempts. The data were compared with the results of our previous study.The results indicated that some alleles of the HLA-G gene such as: 0106, 010106, 01010106 and 0105N (null) alleles were significantly higher in the patient group compared to the control group (p<0.05). There were higher SNPs at the +482 T/C and +506 -/C positions in failed ART couples compared to controls (p=0.03; p=0.01, respectively).HLA-G gene polymorphisms do not clearly affect the risk for implantation failure in most couples who undergo ART. However allelic variations, particularly in exons 3 and 4, and intron 2 of the HLA-G gene can lead to ART failure in human embryos. PMID- 26742444 TI - Prevalence of Specific IgE to Wheat Flour Allergens in Romanian Pediatric Population. PMID- 26742445 TI - Associated Markers for Adult-onset Allergic Asthma. AB - The clinical behavior of asthma varies with age at onset. This study was undertaken to identify associated markers of adult-onset allergic asthma (age >=20 years).This cross-sectional study compared two groups: 58 patients with asthma onset at >=20 years and 66 with onset at >=20 years. They were compared depending on results of clinical history, and body mass index (BMI), aeroallergen sensitization, total serum IgE, eosinophil count, asthma control test, and asthma severity level.Ages at first asthma episode were 10.0 +/- 6.6 and 33.4 +/- 10.5 (p<0.001) in the <20 and >=20 group, respectively. BMI was higher in adult asthmatic subjects (29.8 versus 27.1, P=0.017), but BMI >=30 kg/m(2) was not associated with asthma onset in >=20 years (odds ratio [OR] = 1.56, 95% confidence interval [CI] 0.759 to 3.211; p= 0.227). After multivariate analysis, allergic rhinitis and IgE >=150 IU/mL were negatively correlated with asthma onset in >=20 years old (OR adjusted [ORa] = 0.255, 95% CI 0.078 to 0.837, P= 0.024, and ORa =0.385, 95% CI 0.175 to 0.849, p= 0.018, respectively).Adult-onset allergic asthma was not different from early-onset asthma. PMID- 26742453 TI - Chromosome engineering in zygotes with CRISPR/Cas9. AB - Deletions, duplications, and inversions of large genomic regions covering several genes are an important class of disease causing variants in humans. Modeling these structural variants in mice requires multistep processes in ES cells, which has limited their availability. Mutant mice containing small insertions, deletions, and single nucleotide polymorphisms can be reliably generated using CRISPR/Cas9 directly in mouse zygotes. Large structural variants can be generated using CRISPR/Cas9 in ES cells, but it has not been possible to generate these directly in zygotes. We now demonstrate the direct generation of deletions, duplications and inversions of up to one million base pairs by zygote injection. PMID- 26742454 TI - Third-generation autologous chondrocyte implantation versus mosaicplasty for knee cartilage injury: 2-year randomized trial. AB - Numerous surgical techniques have been developed to treat osteochondral defects of the knee. A study reported encouraging outcomes of third-generation autologous chondrocyte implantation achieved using the solid agarose-alginate scaffold Cartipatch(r). Whether this scaffold is better than conventional techniques remains unclear. This multicenter randomized controlled trial compared 2-year functional outcomes (IKDC score) after Cartipatch(r) versus mosaicplasty in patients with isolated symptomatic femoral chondral defects (ICRS III and IV) measuring 2.5-7.5 cm(2) . In addition, a histological evaluation based on the O'Driscoll score was performed after 2 years. We needed 76 patients to demonstrate an at least 10-point subjective IKDC score difference with alpha = 5% and 90% power. During the enrolment period, we were able to include 55 patients, 30 of them were allocated at random to Cartipatch(r) and 25 to mosaicplasty. After 2 years, eight patients had been lost to follow-up, six in the Cartipatch(r) group, and two in the mosaicplasty group. The baseline characteristics of the two groups were not significantly different. The mean IKDC score and score improvement after 2 years were respectively 73.7 +/- 20.1 and 31.8 +/- 20.8 with Cartipatch(r) and 81.5 +/- 16.4 and 44.4 +/- 15.2 with mosaicplasty. The 12.6-point absolute difference in favor of mosaicplasty is statistically significant. Twelve adverse events were recorded in the Cartipatch(r) group against six in the mosaicplasty group. After 2 years, functional outcomes were significantly worse after Cartipatch(r) treatment compared to mosaicplasty for isolated focal osteochondral defects of the femur. PMID- 26742456 TI - Hypercalcemia-induced pancreatitis presenting with acute ST-elevations mimicking a myocardial infarction. PMID- 26742455 TI - Magnetic Properties Controlled by Interstitial or Interlayer Cations in Iron Chalcogenides. AB - By applying density functional theory calculations to iron chalcogenides, we find that magnetic order in Fe1+yTe and magnetic instability at (pi, pi) in KyFe2Se2 are controlled by interstitial and interlayer cations, respectively. While in Fe1+yTe, magnetic phase transitions occur among collinear, exotic bicollinear and plaquette-ordered antiferronmagnetic states when the height of interstitial irons measured from iron plane or the concentration of interstitial irons is varied, the magnetic instability at (pi, pi) which is believed to be responsible for the Cooper pairing in iron pnictides is significantly enhanced when y is much smaller than 1 in KyFe2Se2. Our results indicate that, similar to iron pnictides, itinerant electrons play important roles in iron chalcogenides, even though the fluctuating local moments become larger. PMID- 26742457 TI - The effects of air pollution and weather conditions on the incidence of acute myocardial infarction. AB - OBJECTIVE: In this retrospective study, we investigated the association between air pollution and weather conditions with the incidence of acute myocardial infarction (AMI) in the city of Kutahya. METHODS: A total of 402 patients who were admitted with acute ST segment elevation MI and non-ST segment elevation MI were included in the study in 1 year. Daily maximum, minimum, and mean ambient temperature and mean barometric pressure data were obtained from the Kutahya Meteorology Department. Daily air pollution data were obtained from the Web site of National Air Quality Observation Network (http://www.havaizleme.gov.tr). RESULTS: Increase in ambient air temperature in the day of MI and 2 days before the day of MI according to their control days was correlated with increase in number of MI cases. When we grouped the patients according to ages as 30-54, 55 65, and >65 years, we found that there was a relation between sulfur dioxide (SO2) and the occurrence of AMI for the age group of 30-54 for the same day (D0) (P<.017). The number of AMIs was the lowest in fall season, whereas the number of AMIs was the highest in winter season. CONCLUSION: There was no statistically significant association between the particulates with diameter b=10 MUm, SO2 concentrations, air pressure, and the risk of AMI, but there was statistically significant relation between occurrence of MI and SO2 for the patients under age of 55 years. The number of AMIs was the lowest in fall season, whereas the number of AMIs was the highest in winter season. PMID- 26742458 TI - The electrocardiogram in the ACS patient: high-risk electrocardiographic presentations lacking anatomically oriented ST-segment elevation. AB - ST-segment elevation myocardial infarction (STEMI) is defined as pathologic ST segment elevation occurring in at least 2 anatomically contiguous leads in a patient with a clinical presentation consistent with acute myocardial infarction (AMI); these findings can suggest the need for urgent revascularization. Unfortunately, the electrocardiogram (ECG) may be nondiagnostic in a large portion of patients who initially present with AMI; furthermore, it is now recognized that ECG patterns that do not meet the traditional diagnostic criteria for STEMI may represent significant AMI--these patterns are generally referred to as the STEMI equivalent patterns in that they are caused by occlusion of an epicardial coronary artery, place significant portions of the left ventricle in jeopardy, and can result in a poor outcome if not recognized and treated appropriately. PMID- 26742459 TI - Mesoamerican nephropathy: a novel case of kidney failure in a US ED. PMID- 26742460 TI - A synthetic chalcone, 2'-hydroxy-2,3,5'-trimethoxychalcone triggers unfolded protein response-mediated apoptosis in breast cancer cells. AB - The primary aim of this study was to find novel chemopreventive agents effective against breast cancer. Endoplasmic reticulum (ER) stress can induce apoptosis through the unfolded protein response (UPR). 2'-Hydroxy-2,3,5'-trimethoxychalcone (DK143) is a synthetic flavonoid derivative. The present study provides evidence supporting the role of the UPR in mediating the apoptotic effect of DK143. Treatment with DK143 triggered apoptosis through the activation of the caspase pathway in MDA-MB-231 breast cancer cells without affecting viability of MCF10A non-transformed breast epithelial cells. Further analysis revealed that DK143 produced reactive oxygen species (ROS) in MDA-MB-231 cells, but not in MCF10A cells, and upregulated the expression of ER stress sensors, including GRP78/BiP, IRE1alpha, CHOP, and Bim in MDA-MB-231 cells. In addition, UPR-related transcription factors, XBP-1 and CHOP, were activated by DK143. Moreover, silencing of IRE1alpha or CHOP by corresponding siRNA molecules attenuated DK143 induced apoptosis. Furthermore, DK143 suppressed mouse tumor growth in vivo. These results demonstrate that promoting ER stress in breast cancer cells via UPR induction might be a promising strategy for developing new chemotherapeutic or chemopreventive agents for breast cancer. PMID- 26742461 TI - Cancer in adolescents: Incidences and trends during 1995-2009 in Taiwan. AB - This study aimed to describe cancer incidence rates and trends specifically for adolescents aged 15-19 years during 1995-2009 in Taiwan. The incidence counts and census data were obtained from the population-based Taiwan Cancer Registry. During the 15-year study period, 4122 adolescents were diagnosed with cancer. The overall incidence rate was 155.2 per million person-years. Other epithelial tumors were the most frequently diagnosed cancer group (23.7%), followed by leukemias (18.0%) and lymphomas (13.9%). When compared to rates in Western countries, a significantly low rate of lymphomas was found. Moreover, rates of the subtypes of melanomas and nasopharyngeal carcinomas being 1/10- and 4-times rates in Western countries were the most striking variations. During 1995-2009, the overall rate of adolescent cancer did not significantly change. However, the most significant upward and declining trends in incidence rates were found for male germ cell neoplasms (annual percent change, APC, 6.4%) and hepatic tumors (APC, -11.1%), respectively. Further investigation and enhancement of the public discourse of possible lifestyle and environmental risk factors associated with increasing trends of certain adolescent cancers should be carried out in Taiwan. PMID- 26742463 TI - Imaging the microenvironment of pancreatic cancer patient-derived orthotopic xenografts (PDOX) growing in transgenic nude mice expressing GFP, RFP, or CFP. AB - We have developed a multi-color, imageable, orthotopic mouse model for individual patients with pancreatic cancer. The tumors are labeled by first passaging them orthotopically through transgenic nude mice expressing green fluorescent protein (GFP), red fluorescent protein (RFP), or cyan fluorescent protein (CFP). Passage of the tumors in these colored transgenic mice labels the stromal cells of the tumor. The cancer cells in the PDOX are labeled in situ with GFP by telomerase dependent adenovirus OBP-401. The models are termed imageable patient-derived orthotopic xenografts (iPDOX). The tumors acquired brightly-fluorescent stromal cells from the transgenic host mice, which were stably associated with the tumors through multiple passages. The colored fluorescent protein-expressing stromal cells included cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). This model enables powerful color-coded imaging of the interaction of cancer and stromal cells during tumor progression and treatment. PMID- 26742465 TI - Nb K-edge x-ray absorption investigation of the pressure induced amorphization in A-site deficient double perovskite La1/3NbO3. AB - Nb K-edge x-ray absorption spectroscopy is utilized to investigate the changes in the local structure of the A-site deficient double perovskite La1/3NbO3 which undergoes a pressure induced irreversible amorphization. EXAFS results show that with increasing pressure up to 7.5 GPa, the average Nb-O bond distance decreases in agreement with the expected compression and tilting of the NbO6 octahedra. On the contrary, above 7.5 GPa, the average Nb-O bond distance show a tendency to increase. Significant changes in the Nb K-edge XANES spectrum with evident low energy shift of the pre-peak and the absorption edge is found to happen in La1/3NbO3 above 6.3 GPa. These changes evidence a gradual reduction of the Nb cations from Nb(5+) towards Nb(4+) above 6.3 GPa. Such a valence change accompanied by the elongation of the average Nb-O bond distances in the octahedra, introduces repulsion forces between non-bonding adjacent oxygen anions in the unoccupied A-sites. Above a critical pressure, the Nb reduction mechanism can no longer be sustained by the changing local structure and amorphization occurs, apparently due to the build-up of local strain. EXAFS and XANES results indicate two distinct pressure regimes having different local and electronic response in the La1/3NbO3 system before the occurence of the pressure induced amorphization at ~14.5 GPa. PMID- 26742466 TI - C2 in a Box: Determining Its Intrinsic Bond Strength for the X(1)Sigmag(+) Ground State. AB - The intrinsic bond strength of C2 in its (1)Sigmag(+) ground state is determined from its stretching force constant utilizing MR-CISD+Q(8,8), MR-AQCC(8,8), and single-determinant coupled cluster calculations with triple and quadruple excitations. By referencing the CC stretching force constant to its local counterparts of ethane, ethylene, and acetylene, an intrinsic bond strength half way between that of a double bond and a triple bond is obtained. Diabatic MR CISD+Q results do not change this. Confinement of C2 and suitable reference molecules in a noble gas cage leads to compression, polarization, and charge transfer effects, which are quantified by the local CC stretching force constants and differences of correlated electron densities. These results are in line with two pi bonds and a partial sigma bond. Bond orders and bond dissociation energies of small hydrocarbons do not support quadruple bonding in C2. PMID- 26742464 TI - Matrix control of pancreatic cancer: New insights into fibronectin signaling. AB - Pancreatic ductal adenocarcinoma (PDA) is a highly metastatic disease that resists most current therapies. A defining characteristic of PDA is an intense fibrotic response that promotes tumor cell invasion and chemoresistance. Efforts to understand the complex relationship between the tumor and its extracellular network and to therapeutically perturb tumor-stroma interactions are ongoing. Fibronectin (FN), a provisional matrix protein abundant in PDA stroma but not normal tissues, supports metastatic spread and chemoresistance of this deadly disease. FN also supports angiogenesis, which is required for even hypovascular tumors such as PDA to develop and progress. Targeting components of the tumor stroma, such as FN, can effectively reduce tumor growth and spread while also enhancing delivery of chemotherapy. Here, we review the molecular mechanisms by which FN drives angiogenesis, metastasis and chemoresistance in PDA. In light of these new findings, we also discuss therapeutic strategies to inhibit FN signaling. PMID- 26742468 TI - A US Claims-Based Analysis of Real-World Lipid-Lowering Treatment Patterns in Patients With High Cardiovascular Disease Risk or a Previous Coronary Event. AB - The objective was to examine real-world treatment patterns of lipid-lowering therapies and their possible associated intolerance and/or ineffectiveness in patients with high cardiovascular disease (CVD) risk initiating statins and/or ezetimibe. Patients aged >=18 years who initiated statins and/or ezetimibe from January 01, 2007, to June 30, 2011, were retrospectively identified from the IMS LifeLink PharMetrics Plus commercial claims database. Patients were further classified into 2 cohorts: (1) history of cardiovascular event (CVE) and (2) history of coronary heart disease risk equivalent (CHD RE). Patients had continuous health plan enrollment >=1 year pre- and post-index date (statin and/or ezetimibe initiation date). Primary outcomes were index statin intensity, treatment modifications, possible associated statin/nonstatin intolerance and/or ineffectiveness issues (based on treatment modification), and time-to-treatment modifications. Analyses for each cohort were stratified by age group (<65 and >=65 years). A total of 41,934 (history of CVE) and 170,344 patients (history of CHD RE) were included. On the index date, 8.8% to 25.1% of patients were initiated on high-intensity statin. Among patients aged <65, 79.2% and 48.8% of those with history of CVE and 78.6% and 47.3% of those with a history of CHD RE had >=1 and 2 treatment modifications, respectively. Among all patients, 24.6% to 25.6% had possible statin intolerance and/or ineffectiveness issues after accounting for second treatment modification (if any). In conclusion, in patients with high CVD risk, index statin treatment modifications that imply possible statin intolerance and/or ineffectiveness were frequent; low use of high intensity statins indicates unmet need in the management of hyperlipidemia and possible remaining unaccounted CVD residual risk. PMID- 26742467 TI - Identification of novel genes and pathways in carotid atheroma using integrated bioinformatic methods. AB - Atherosclerosis is the primary cause of cardiovascular events and its molecular mechanism urgently needs to be clarified. In our study, atheromatous plaques (ATH) and macroscopically intact tissue (MIT) sampled from 32 patients were compared and an integrated series of bioinformatic microarray analyses were used to identify altered genes and pathways. Our work showed 816 genes were differentially expressed between ATH and MIT, including 443 that were up regulated and 373 that were down-regulated in ATH tissues. GO functional enrichment analysis for differentially expressed genes (DEGs) indicated that genes related to the "immune response" and "muscle contraction" were altered in ATHs. KEGG pathway-enrichment analysis showed that up-regulated DEGs were significantly enriched in the "FcepsilonRI-mediated signaling pathway", while down-regulated genes were significantly enriched in the "transforming growth factor-beta signaling pathway". Protein-protein interaction network and module analysis demonstrated that VAV1, SYK, LYN and PTPN6 may play critical roles in the network. Additionally, similar observations were seen in a validation study where SYK, LYN and PTPN6 were markedly elevated in ATH. All in all, identification of these genes and pathways not only provides new insights into the pathogenesis of atherosclerosis, but may also aid in the development of prognostic and therapeutic biomarkers for advanced atheroma. PMID- 26742469 TI - Midterm Mortality After Transcatheter Aortic Valve Implantation Versus Sutureless Aortic Valve Replacement. PMID- 26742470 TI - New-Onset Left Bundle Branch Block Induced by Transcutaneous Aortic Valve Implantation. AB - New-onset left bundle branch block (LBBB) is a specific concern of transcutaneous aortic valve implantation (TAVI) given its estimated incidence ranging from 5% to 65%. This high rate of occurrence is dependent on the type of device used (size and shape), implantation methods, and patient co-morbidities. The appearance of an LBBB after TAVI reflects a very proximal lesion of the left bundle branch as it exits the bundle of His. At times transient, its persistence can lead to permanent pacemaker implantation in 15% to 20% of cases, most often for high degree atrioventricular block. The management of LBBB after TAVI is currently not defined by international societies resulting in individual centers developing their own management strategy. The potential consequences of LBBB are dysrhythmias (atrioventricular block, syncope, and sudden death) and functional (heart failure) complications. Prompt postprocedural recognition and management (permanent pacemaker implantation) of patients prevents the occurrence of potential complications and may constitute the preferred approach in this frail and elderly population despite additional costs and complications of cardiac pacing. Moreover, the expansion of future indications for TAVI necessitates better identification of the predictive factors for the development of LBBB. Indeed, long-term right ventricular pacing may potentially increase the risk of developing heart failure in this population. In conclusion, it is thus imperative to not only develop new aortic prostheses with a less-deleterious impact on the conduction system but also to prescribe appropriate pacing modes in this frail population. PMID- 26742471 TI - Effect of Mitral Annular Calcium on Left Ventricular Diastolic Parameters. AB - Assessment of left ventricular (LV) diastolic function by Doppler flow imaging and tissue Doppler is an integral part of the echocardiographic examination. Mitral annular calcium (MAC) is frequently encountered on echocardiography. The aim of this study was to assess the impact of MAC, quantitatively measured by computed tomography scan, on echocardiographic LV diastolic parameters. We included 155 patients aged >=65 years. Computed tomography reconstructions of the mitral annulus were created, and calcium identified and quantified by Agatston technique. Calcium locations were assigned using an overlaid template depicting the annular segments in relation to surrounding anatomic structures. Echocardiographic assessment of diastolic function was performed in standard fashion. Mean age was 77 years; 49% were men; and 43% were black. Patients with MAC had lower septal e' (p = 0.003), lateral e' (p = 0.04), and average e' (p = 0.01) compared with those without MAC. They also had a higher E-wave velocity (p = 0.01) and E/e' ratio (p <0.001). When evaluated by severity of MAC, and after adjustment for multiple clinical factors, there was a graded (inverse) relation between MAC severity and septal e' (p = 0.01), lateral e' (p = 0.01), and average e' (p = 0.01). In conclusion, LV diastolic parameters, as measured by Doppler echocardiography, are altered in the presence of MAC. This could be due to direct effects of MAC on annular function or might reflect truly reduced diastolic function. Interpretation of diastolic parameters in patients with MAC should be performed with caution. PMID- 26742472 TI - Reducing Patient Radiation Dose With Image Noise Reduction Technology in Transcatheter Aortic Valve Procedures. AB - X-ray radiation exposure is of great concern for patients undergoing structural heart interventions. In addition, a larger group of medical staff is required and exposed to radiation compared with percutaneous coronary interventions. This study aimed at quantifying radiation dose reduction with implementation of specific image noise reduction technology (NRT) in transcatheter aortic valve implantation (TAVI) procedures. We retrospectively analyzed 104 consecutive patients with TAVI procedures, 52 patients before and 52 after optimization of x ray radiation chain, and implementation of NRT. Patients with 1-step TAVI and complex coronary intervention, or complex TAVI procedures, were excluded. Before the procedure, all patients received a multislice computed tomography scan, which was used to size aortic annulus, select the optimal implantation plane, valve type and size, and guide valve implantation using a software tool. Air kerma and kerma-area product were compared in both groups to determine patient radiation dose reduction. Baseline parameters, co-morbidity, or procedural data were comparable between groups. Mean kerma-area product was significantly lower (p <0.001) in the NRT group compared with the standard group (60 +/- 39 vs 203 +/- 106 Gy * cm(2), p <0.001), which corresponds to a reduction of 70%. Mean air kerma was reduced by 64% (494 +/- 360 vs 1,355 +/- 657 mGy, p <0.001). In conclusion, using optimized x-ray chain combined with specific image noise reduction technology has the potential to significantly reduce by 2/3 radiation dose in standard TAVI procedures without worsening image quality or prolonging procedure time. PMID- 26742473 TI - Statin Use and the Risk of Kidney Disease With Long-Term Follow-Up (8.4-Year Study). AB - Few studies have examined long-term effects of statin therapy on kidney diseases. The objective of this study was to determine the association of statin use with incidence of acute and chronic kidney diseases after prolonged follow-up. In this retrospective cohort study, we analyzed data from the San Antonio area military health care system from October 2003 through March 2012. Statin users were propensity score matched to nonusers using 82 baseline characteristics including demographics, co-morbidities, medications, and health care utilization. Study outcomes were acute kidney injury, chronic kidney disease (CKD), and nephritis/nephrosis/renal sclerosis. Of the 43,438 subjects included, we propensity score matched 6,342 statin users with 6,342 nonusers. Statin users had greater odds of acute kidney injury (odds ratio [OR] 1.30, 95% confidence interval [CI] 1.14 to 1.48), CKD (OR 1.36, 95% CI 1.22 to 1.52), and nephritis/nephrosis/renal sclerosis (OR 1.35, 95% CI 1.05 to 1.73). In a subset of patients without co-morbidities, the association of statin use with CKD remained significant (OR 1.53, 95% CI 1.27 to 1.85). In a secondary analysis, adjusting for diseases/conditions that developed during follow-up weakened this association. In conclusion, statin use is associated with increased incidence of acute and chronic kidney disease. These findings are cautionary and suggest that long-term effects of statins in real-life patients may differ from shorter term effects in selected clinical trial populations. PMID- 26742462 TI - The lymphatic system and pancreatic cancer. AB - This review summarizes current knowledge of the biology, pathology and clinical understanding of lymphatic invasion and metastasis in pancreatic cancer. We discuss the clinical and biological consequences of lymphatic invasion and metastasis, including paraneoplastic effects on immune responses and consider the possible benefit of therapies to treat tumors that are localized to lymphatics. A review of current techniques and methods to study interactions between tumors and lymphatics is presented. PMID- 26742474 TI - Temporal Changes in Postdischarge Mortality Risk After Hospitalization for Heart Failure (from the EVEREST Trial). AB - In observational studies of patients hospitalized for heart failure (HHF), risk of death is highest immediately after discharge and decreases over time. It is unclear whether this population risk trajectory reflects (1) lowering of individual patient mortality risk with increasing time from index hospitalization or (2) temporal changes in population case-mix with earlier postdischarge death for "sicker" patients. Survival rate and longitudinal models were used to estimate temporal changes in postdischarge all-cause mortality risk in 3,993 HHF patients discharged alive in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial. After median follow-up of 9.9 months, 971 patients died (24.2%). Predicted mortality rate decreased from 15.9 per 100 patient-years immediately after discharge to 13.4 at 30 days and 12.8 at 90 days; mortality rate increased steadily thereafter. Risk variation between quintiles of risk was considerably larger than the temporal variation within risk strata. In a longitudinal model serially reassessing predicted patient mortality risk after each follow-up visit using data collected at these visits, predicted mortality risk increased during the 90 days preceding subsequent heart failure readmission and then followed a postdischarge trajectory similar to the index admission. In conclusion, although there is transiently elevated individual patient risk in the 90 days before and after discharge, the patient's individual risk profile, rather than temporal change in risk relative to hospitalization, remains the main determinant of mortality. For purposes of reducing all-cause mortality in HF patients, preventative and therapeutic measures may be best implemented as long-term interventions for high mortality risk patients based on serial risk assessments, irrespective of recent hospitalization. PMID- 26742475 TI - Decade-Long Trends in the Frequency of 90-Day Rehospitalizations After Hospital Discharge for Acute Myocardial Infarction. AB - There are limited data available describing relatively contemporary trends in 90 day rehospitalizations in patients who survive hospitalization after an acute myocardial infarction (AMI) in a community setting. We examined decade-long (2001 to 2011) trends in, and factors associated with, 90-day rehospitalizations in patients discharged from 3 central Massachusetts (MA) hospitals after AMI. Residents of the Worcester, MA, metropolitan area discharged after AMI from 3 central MA hospitals on a biennial basis from 2001 to 2011 comprised the study population (n = 4,810). The average age of this population was 69 years, 42% were women, and 92% were white. From 2001 to 2011, 30.0% of patients were rehospitalized within 90 days after hospital discharge, and 38% of 90-day rehospitalizations occurred after the first month after hospital discharge. Crude 90-day rehospitalization rates decreased from 31.5% in 2001/2003 to 27.3% in 2009/2011. After adjusting for several sociodemographic characteristics, co morbidities, and in-hospital factors, there was a reduced risk of being rehospitalized within 90 days after hospital discharge in 2009/2011 compared with 2001/2003 (risk ratio = 0.87, 95% CI = 0.77 to 0.98); this trend was slightly attenuated (risk ratio = 0.90, 95% CI = 0.79 to 1.02) after further adjustment for hospital treatment practices. Female sex, having several previously diagnosed co-morbidities, an increased hospital stay, and the in-hospital development of atrial fibrillation, cardiogenic shock, and heart failure were significantly associated with an increased risk of being rehospitalized. In conclusion, the likelihood of subsequent 90-day rehospitalizations remained frequent, and we did not observe a significant decrease in these rates during the years under study. PMID- 26742476 TI - Usefulness of Novel Immunotherapeutic Strategies for Idiopathic Recurrent Pericarditis. AB - Idiopathic recurrent pericarditis (IRP) is a debilitating illness which leads to great suffering and multiple hospitalizations. Management of acute pericarditis and subsequent recurrences has evolved significantly as the use of colchicine based strategies become more prevalent, yet there still remains a subset of patients who remain refractory to colchicine therapy, and these patients require prolonged corticosteroid (CS) therapy for the control of symptoms. Since the 1960s, there have been reports of successful management of these cases with immunosuppressive therapy. Current guidelines support the use of anakinra, intravenous immunoglobulins, and azathioprine for management of IRP, with the goals of both control of symptoms and withdrawal of CS. Recent reports supply evidence for both auto-inflammatory and autoimmune activity in these patients. We herein review the current available reports regarding the evidence regarding the pathophysiology and reported cases and case series of IRP cases managed with immunomodulation therapy. PMID- 26742478 TI - High-pressure stabilization of argon fluorides. AB - On account of the rapid development of noble gas chemistry in the past half century both xenon and krypton compounds can now be isolated in macroscopic quantities. The same does not hold true for the next lighter group 18 element, argon, which forms only isolated molecules stable solely in low temperature matrices or supersonic jet streams. Here we present theoretical investigations into a new high-pressure reaction pathway, which enables synthesis of argon fluorides in bulk and at room temperature. Our hybrid DFT calculations (employing the HSE06 functional) indicate that above 60 GPa ArF2-containing molecular crystals can be obtained by a reaction between argon and molecular fluorine. PMID- 26742477 TI - Long-Term Outcomes After Transcatheter Aortic Valve Implantation from a Single High-Volume Center (The Milan Experience). AB - Transcatheter aortic valve implantation (TAVI) is now the treatment of choice for patients with symptomatic aortic stenosis who are inoperable or with high surgical risk. Data with regards to contemporary clinical practice and long-term outcomes are sparse. To evaluate temporal changes in TAVI practice and explore procedural and long-term clinical outcomes of patients in a contemporary "real world" population, outcomes of 829 patients treated from November 2007 to May 2015, at the San Raffaele Scientific Institute, Milan, Italy, were retrospectively analyzed. Median follow-up was 568 days, with the longest follow up of 2,677 days. Overall inhospital mortality was 3.5%. During the study period, there was a trend toward treating younger, lower risk patients. Overall mortality rates were 3.5% (30 days), 14% (1 year), 22% (2 years), 29% (3 years), 37% (4 years), 47% (5 years), 53% (6 years), and 72% (7 years). The survival probability at 5 years was significantly higher in patients treated through the transfemoral (TF) route compared to other vascular access sites (log rank p <0.001). Non-TF vascular access and residual paravalvular leak >=2 (after TAVI) were identified as independent predictors for both all-cause and cardiovascular mortality. No patient required further aortic valve intervention for TAVI prosthesis degeneration. In conclusion, there is a trend toward treating younger, lower-risk patients. Non-TF vascular access approach and >=2 PVL after TAVI were identified as independent predictors for both overall and cardiovascular mortality with no cases of prosthesis degeneration suggesting acceptable durability. PMID- 26742479 TI - Early transcriptomic response to Fe supply in Fe-deficient tomato plants is strongly influenced by the nature of the chelating agent. AB - BACKGROUND: It is well known that in the rhizosphere soluble Fe sources available for plants are mainly represented by a mixture of complexes between the micronutrient and organic ligands such as carboxylates and phytosiderophores (PS) released by roots, as well as fractions of humified organic matter. The use by roots of these three natural Fe sources (Fe-citrate, Fe-PS and Fe complexed to water-extractable humic substances, Fe-WEHS) have been already studied at physiological level but the knowledge about the transcriptomic aspects is still lacking. RESULTS: The (59)Fe concentration recorded after 24 h in tissues of tomato Fe-deficient plants supplied with (59)Fe complexed to WEHS reached values about 2 times higher than those measured in response to the supply with Fe citrate and Fe-PS. However, after 1 h no differences among the three Fe-chelates were observed considering the (59)Fe concentration and the root Fe(III) reduction activity. A large-scale transcriptional analysis of root tissue after 1 h of Fe supply showed that Fe-WEHS modulated only two transcripts leaving the transcriptome substantially identical to Fe-deficient plants. On the other hand, Fe-citrate and Fe-PS affected 728 and 408 transcripts, respectively, having 289 a similar transcriptional behaviour in response to both Fe sources. CONCLUSIONS: The root transcriptional response to the Fe supply depends on the nature of chelating agents (WEHS, citrate and PS). The supply of Fe-citrate and Fe-PS showed not only a fast back regulation of molecular mechanisms modulated by Fe deficiency but also specific responses due to the uptake of the chelating molecule. Plants fed with Fe-WEHS did not show relevant changes in the root transcriptome with respect to the Fe-deficient plants, indicating that roots did not sense the restored cellular Fe accumulation. PMID- 26742480 TI - In vitro and in vivo evaluation of cord blood hematopoietic stem and progenitor cells amplified with glycosaminoglycan mimetic. AB - BACKGROUND: Expansion protocols aim at both increasing the number of umbilical cord blood (UCB) hematopoietic stem cells and progenitor cells (HSPCs) and reducing the period of neutropenia in UCB HSPC graft. Because glycosaminoglycans (GAGs) are known to be important components of the hematopoietic niche and to modulate growth factor effects, we explored the use of GAG mimetic OTR4131 to potentiate HSPC's in vitro expansion and in vivo engraftment. METHODS: UCB CD34+ cells were expanded with serum-free medium, SCF, TPO, FLT3-lig and G-CSF during 12 days in the absence or the presence of increasing OTR4131 concentrations (0 100 MUg/mL). Proliferation ratio, cell viability and phenotype, functional assays, migration capacity and NOD-scid/gammac(-/-) mice engraftment were assessed after expansion. RESULTS: At Day 12, ratios of cell expansion were not significantly increased by OTR4131 treatment. Better total nucleated cell viability was observed with the use of 1 MUg/mL GAG mimetic compared to control (89.6 % +/- 3.7 % and 79.9 % +/- 3.3 %, respectively). Phenotype analysis showed a decrease of monocyte lineage in the presence of OTR4131 and HSPC migration capacity was diminished when GAG mimetic was used at 10 MUg/mL (10.9 % +/- 4.1 % vs. 52.9 % +/- 17.9 % for control). HSPC clonogenic capacities were similar whatever the culture conditions. Finally, in vivo experiments revealed that mice successfully engrafted in all conditions, even if some differences were observed during the first month. Three months after graft, bone marrow chimerism and blood subpopulations were similar in both groups. CONCLUSIONS: UCB HSPCs ex-vivo expansion in the presence of OTR4131 is a safe approach that did not modify cell function and engraftment capacities. In our experimental conditions, the use of a GAG mimetic did not, however, allow increasing cell expansion or optimizing their in vivo engraftment. PMID- 26742481 TI - Ovarian Tissue Cryopreservation for Benign Gynecologic Disease: A Case of Ovarian Torsion and Review of the Literature. AB - Ovarian tissue cryopreservation (OTC) is an emerging method for fertility preservation. Although OTC has been previously proposed for benign indications, to our knowledge this is the first report highlighting the use of OTC for the indication of ovarian torsion. A 36-year-old nulligravid woman with a history of recurrent ovarian torsion presented with an acute episode of ovarian torsion confirmed by ultrasound. She requested a laparoscopic oophorectomy because her previous oophoropexy had failed, and in light of this was counseled to undergo concurrent OTC. On laparoscopy, 10 strips of ovarian cortex were obtained. A portion of this tissue was sent for pathological analysis, which revealed a primordial follicle density of 167 follicles/mm(3), a primary follicle density of 38 follicles/mm(3), and minimal ischemic damage. Although the clinical application of OTC continues to evolve and requires further investigation, the possibility of expanding the indications for benign gynecologic conditions is promising. PMID- 26742482 TI - Needleless Robotic-Assisted Abdominal Cerclage in Pregnant and Nonpregnant Patients. AB - STUDY OBJECTIVE: To demonstrate the step-by-step surgical technique of "needle free" robotic-assisted transabdominal cerclage placement. DESIGN: Through surgical video footage, presentation of a step-by-step demonstration of robotic assisted laparoscopic placement of abdominal cerclage (Canadian Task Force classification III). SETTING: The procedure was undertaken at Banner University Medical Center in Phoenix, Arizona. The local Institutional Review Board does not consider case reports research, and thus its approval was not required. PATIENTS: The patients had a history of cervical insufficiency. The first patient (case 1) was a nongravid 32-year-old woman with 2 late second trimester pregnancies delivered by cesarean section owing to cervical insufficiency. The second patient (case 2) was a 26-year-old woman in her sixth pregnancy with 4 previous second trimester losses due to cervical insufficiency, including a failed McDonald cerclage. INTERVENTIONS: Robotic-assisted abdominal cerclage placement was performed in both patients. The procedure used an 8-mm, 0 degrees scope; an 8 mm, 30 degrees scope; monopolar scissors; and Maryland bipolar graspers. Following a complete survey of the pelvis and abdomen, the cervicouterine isthmus was identified bilaterally. The anterior leaflet of the right broad ligament was entered sharply, and the dissection was carried out in small increments to ensure safety and hemostasis. The right uterine artery was identified and skeletonized. The left broad ligament was entered in a similar fashion. Once a bladder flap was developed, a gentle wiping technique allowed for mobilization of the bladder from the vesicouterine junction with excellent hemostasis. In case 1, a uterine manipulator was used to flex the uterus. In case 2, a laparoscopic paddle device was introduced gently to allow for mobilization of the gravid uterus. An avascular tunnel was created on both sides of the cervicouterine isthmus, thereby eliminating the need for the Mersilene tape needle. Thus, a needleless Mersilene tape was introduced into the tunnel formed previously. In our opinion, the ideal knot placement is in the posterior cul-de-sac, as shown in the nongravid uterus. However, in the gravid uterus, owing to the difficulty of access, the knot was placed anteriorly, and reperitonization was performed. Four square knots were sufficient, with the snug (but not too tight) Mersilene tape at the cervicouterine isthmus. In both cases, there was minimal blood loss with no complications. In addition to these 2 operations, robotic-assisted transabdominal cerclage was successfully performed in another 21 patients. CONCLUSION: A needle less robotic-assisted laparoscopic technique can be performed safely and effectively in both gravid and nongravid patients. PMID- 26742483 TI - Microscopic origins of anisotropic active stress in motor-driven nematic liquid crystals. AB - The cytoskeleton, despite comprising relatively few building blocks, drives an impressive variety of cellular phenomena ranging from cell division to motility. These building blocks include filaments, motor proteins, and static crosslinkers. Outside of cells, these same components can form novel materials exhibiting active flows and nonequilibrium contraction or extension. While dipolar extensile or contractile active stresses are common in nematic motor-filament systems, their microscopic origin remains unclear. Here we study a minimal physical model of filaments, crosslinking motors, and static crosslinkers to dissect the microscopic mechanisms of stress generation in a two-dimensional system of orientationally aligned rods. We demonstrate the essential role of filament steric interactions which have not previously been considered to significantly contribute to active stresses. With this insight, we are able to tune contractile or extensile behavior through the control of motor-driven filament sliding and crosslinking. This work provides a roadmap for engineering stresses in active liquid crystals. The mechanisms we study may help explain why flowing nematic motor-filament mixtures are extensile while gelled systems are contractile. PMID- 26742484 TI - The efficacy and safety of nine South African medicinal plants in controlling Bacillus anthracis Sterne vaccine strain. AB - BACKGROUND: Anthrax is a zoonotic disease caused by Bacillus anthracis, a Gram positive spore-forming bacterium. The presence of the bacteria and the toxins in the blood of infected hosts trigger a cascade of pathological events leading to death. Nine medicinal plants with good activities against other bacteria were selected to determine their in vitro antibacterial activity against Bacillus anthracis Sterne strain. The cytotoxicity of the extracts on Vero kidney cells was also determined. RESULTS: The minimum inhibitory concentration (MIC) values of the extracts against Bacillus anthracis Sterne strain ranged from 0.02 to 0.31 mg/ml. Excellent MIC values were observed for the following plant species: Maesa lanceolata (0.02 mg/ml), Bolusanthus speciosus, Hypericum roeperianum, Morus mesozygia (0.04 mg/ml) and Pittosporum viridiflorum (0.08 mg/ml). The total antibacterial activity of the extracts ranged from 92 to 5562 ml/g. Total activity presents the volume to which the extract from 1 g of plant material can be diluted and still inhibit microbial growth. Maesa lanceolata and Hypericum roeperianum had the highest total activity with values of 5562 and 2999 ml/g respectively. The extracts of Calpurnia aurea had the lowest total activity (92 ml/g). The cytotoxicity determined on Vero cells indicated that most of the extracts were relatively non-toxic compared to doxorubicin (LC50 8.3 +/- 1.76 MUg/ml), except for the extracts of Maesa lanceolata, Elaeodendron croceum and Calpurnia aurea with LC50 values at 2.38 +/- 0.25, 5.20 +/- 0.24 and 13 +/- 2.26 MUg/ml respectively. The selectivity index (SI) ranged from 0.02 to 1.66. Hypericum roeperianum had the best selectivity index, (SI = 1.66) and Elaeodendron croceum had lowest value (SI = 0.02). CONCLUSIONS: The crude acetone extracts of the selected plant species had promising antibacterial activity against Bacillus anthracis. Maesa lanceolata extracts could be useful as a disinfectant and Hypericum roeperianum could be useful to protect animals based on its high total activity and selectivity index. Further investigation of these plant extracts may lead to the development of new therapeutic agents to protect humans or animals against anthrax. PMID- 26742485 TI - Genotoxic effect of tocolytic drug ritodrine in combination with smoking during pregnancy. AB - OBJECTIVE: Tocolytic drugs are used widely in order to prevent preterm birth. Ritodrine, is the only food and drug administration (FDA) approved drug for tocolytic use. We estimated the cytogenetic effect of ritodrine administered as maternal therapy, alone or in combination with smoking, in women and their neonates. METHODS: Lymphocyte and fibroblasts cultures were evaluated and three indices were analyzed; sister chromatid exchanges (SCEs), proliferation rate index (PRI) and mitotic index (MI) as well as average generation time (AGT) and population doubling time (PDT). Campothacin (CPT-11) was used as a positive control. RESULTS: Administration of ritodrine up to a month revealed significant reduction of SCEs/cell in neonates in the presence or absence of the mutagenic agent. A statistical significant increase on SCEs, for mothers and neonates, was noticed in neonate's lymphocytes when tocolytic therapy was over a month. Ritodrine revealed a cytoprotective action against smoking when the two factors were combined, but the synergistic action of ritodrine with smoking increased genotoxicity, cytostaticity and cytotoxicity of neonates after long administration (1-3 months). CONCLUSIONS: The time-depended genotoxic, cytostatic and cytotoxic action of ritodrine alone or in combination with smoking suggests that its administration should not exceed the time period of a month. PMID- 26742486 TI - Mapping the use of research to support strategies tackling maternal and child health inequities: evidence from six countries in Africa and Latin America. AB - BACKGROUND: Striving to foster collaboration among countries suffering from maternal and child health (MCH) inequities, the MASCOT project mapped and analyzed the use of research in strategies tackling them in 11 low- and middle income countries. This article aims to present the way in which research influenced MCH policies and programs in six of these countries - three in Africa and three in Latin America. METHODS: Qualitative research using a thematic synthesis narrative process was used to identify and describe who is producing what kind of research, how research is funded, how inequities are approached by research and policies, the countries' research capacities, and the type of evidence base that MCH policies and programs use. Four tools were designed for these purposes: an online survey for researchers, a semi-structured interview with decision makers, and two content analysis guides: one for policy and programs documents and one for scientific articles. RESULTS: Three modalities of research utilization were observed in the strategies tackling MCH inequities in the six included countries - instrumental, conceptual and symbolic. Instrumental utilization directly relates the formulation and contents of the strategies with research results, and is the least used within the analyzed policies and programs. Even though research is considered as an important input to support decision making and most of the analyzed countries count five or six relevant MCH research initiatives, in most cases, the actual impact of research is not clearly identifiable. CONCLUSIONS: While MCH research is increasing in low- and middle income countries, the impact of its outcomes on policy formulation is low. We did not identify a direct relationship between the nature of the financial support organizations and the kind of evidence utilization within the policy process. There is still a visible gap between researchers and policymakers regarding their different intentions to link evidence and decision making processes. PMID- 26742487 TI - Intragraft transcriptional profiling of renal transplant patients with tubular dysfunction reveals mechanisms underlying graft injury and recovery. AB - BACKGROUND: Proximal tubular dysfunction (PTD) is associated with a decreased long-term graft survival in renal transplant patients and can be detected by the elevation of urinary tubular proteins. This study investigated transcriptional changes in biopsies from renal transplant patients with PTD to disclose molecular mechanisms underlying graft injury and functional recovery. METHODS: Thirty-three renal transplant patients with high urinary levels of retinol-binding protein, a biomarker of PTD, were enrolled in the study. The initial immunosuppressive scheme included azathioprine, cyclosporine, and steroids. After randomization, 18 patients (group 2) had their treatment modified by reducing cyclosporine dosage and substituting azathioprine for mycophenolate mofetil, while the other 15 patients (group 1) remained under the initial scheme. Patients were biopsied at enrollment and after 12 months of follow-up, and paired comparisons were performed between their intragraft gene expression profiles. The differential transcriptome profiles were analyzed by constructing gene co-expression networks and identifying enriched functions and central nodes in each network. RESULTS: Only the alternative immunosuppressive scheme used in group 2 ameliorated renal function and tubular proteinuria after 12 months of follow-up. Intragraft molecular changes observed in group 2 were linked to autophagy, extracellular matrix, and adaptive immunity. Conversely, gene expression changes in group 1 were related to fibrosis, endocytosis, ubiquitination, and endoplasmic reticulum stress. CONCLUSION: These results suggest that molecular networks associated with the control of endocytosis, autophagy, protein overload, fibrosis, and adaptive immunity may be involved in improvement of graft function. PMID- 26742489 TI - Immunologic and Pharmacologic Aspects in an Elderly Recipient of Liver Transplant With Pulmonary Aspergillosis and Multiple Comorbidities. AB - The net state of immunosuppression, the occurrence of infections, drug-drug interactions, and toxicity can compromise the outcome of liver transplant recipients with multiple comorbidities. We present a 67-year-old man who developed early posttransplant severe chronic obstructive pulmonary disease exacerbation, pulmonary aspergillosis, and cytomegalovirus reactivation. Drug drug interactions between azoles and cyclosporine, along with renal and liver toxicity, required adjustments in dosage. Interferon-gamma production from antigen-stimulated T cells was recorded. Early diagnosis and treatment, along with therapeutic drug monitoring and recovery of T-cell immunity, were key factors for a positive outcome. PMID- 26742488 TI - Implementation of meiosis prophase I programme requires a conserved retinoid independent stabilizer of meiotic transcripts. AB - Sexual reproduction is crucially dependent on meiosis, a conserved, specialized cell division programme that is essential for the production of haploid gametes. Here we demonstrate that fertility and the implementation of the meiotic programme require a previously uncharacterized meiosis-specific protein, MEIOC. Meioc invalidation in mice induces early and pleiotropic meiotic defects in males and females. MEIOC prevents meiotic transcript degradation and interacts with an RNA helicase that binds numerous meiotic mRNAs. Our results indicate that proper engagement into meiosis necessitates the specific stabilization of meiotic transcripts, a previously little-appreciated feature in mammals. Remarkably, the upregulation of MEIOC at the onset of meiosis does not require retinoic acid and STRA8 signalling. Thus, we propose that the complete induction of the meiotic programme requires both retinoic acid-dependent and -independent mechanisms. The latter process involving post-transcriptional regulation likely represents an ancestral mechanism, given that MEIOC homologues are conserved throughout multicellular animals. PMID- 26742490 TI - Characterization of hepatitis B virus surface antigen variability and impact on HBs antigen clearance under nucleos(t)ide analogue therapy. AB - For hepatitis B virus (HBV)-related chronic infection under treatment by nucleos(t)ide analogues (NUCs), HBsAg clearance is the ultimate therapeutic goal but very infrequent. We investigated how HBV envelope protein variability could lead to differential HBsAg clearance on NUCs. For 12 HBV genotype D patients receiving NUCs, six resolvers (HBsAg clearance) were compared to six matched nonresolvers (HBsAg persistence). PreS/S amino acid (aa) sequences were analysed with bioinformatics to predict HBV envelope antigenicity and aa covariance. To enrich our analyses on very rare resolvers, these were compared with other HBV genotype D strains in three characterized clinical cohorts including common chronically infected patients. The sT125M+sP127T combination was observed in four nonresolvers of six, corroborated by aa covariance analysis, associated with a lower predicted antigenicity than sT125T+sP127P. Concordant features within this HBV key functional domain, at positions 125 and 127, were reported from two of the three comparative cohorts. In our hands, a lower ELISA reactivity of HBV vaccinated mice sera was observed against the sT125M mutant. In the S gene, 56 aa changes in minor variants were detected in non-resolvers, mainly in the major hydrophilic region, vs 28 aa changes in resolvers. Molecular features in patients showing HBsAg persistence on NUCs argue in favour of a different aa pattern in the HBV S gene compared to those showing HBsAg clearance. In nonresolvers, a decrease in HBs 'a' determinant antigenicity and more frequent mutations in the S gene suggest a role for the HBV envelope characteristics in HBsAg persistence. PMID- 26742491 TI - An automated confirmatory system for analysis of mammograms. AB - This paper presents an integrated system for the automatic analysis of mammograms to assist radiologists in confirming their diagnosis in mammography screening. The proposed automated confirmatory system (ACS) can process a digitalized mammogram online, and generates a high quality filtered segmentation of an image for biological interpretation and a texture-feature based diagnosis. We use a serial of image pre-processing and segmentation techniques, including 2D median filtering, seeded region growing (SRG) algorithm, image contrast enhancement, to remove noise, delete radiopaque artifacts and eliminate the projection of the pectoral muscle from a digitalized mammogram. We also develop an entire-image texture-feature based classification method, by combining a Rough-set approach to extract five fundamental texture features from images, and then an Artificial Neural Network technique to classify a mammogram as: normal; indicating the presence of a benign lump; or representing a malignant tumor. Here, 222 random images from the Mammographic Image Analysis Society (MIAS) database are used for the offline ACS training. Once the system is tuned and trained, it is ready for the automated use for the analysis and diagnosis of new mammograms. To test the trained system, a separate set of 100 random images from the MIAS and another set of 100 random images from the independent BancoWeb database are selected. The proposed ACS is shown to be successful in confirming diagnosis of mammograms from the two independent databases. PMID- 26742494 TI - Varus and valgus stress tests after total knee arthroplasty with and without anesthesia. AB - INTRODUCTION: Retrospective studies demonstrated inadequate soft tissue balance is associated with the long-term outcome of total knee arthroplasty (TKA). However, most of these studies have evaluated the joint laxity only postoperatively without anesthesia. Therefore information about the effect of anesthesia on knee laxity is important for soft tissue balancing at the time of surgery. This study was conducted to determine how anesthesia affects the varus and valgus stress tests after TKA. MATERIALS AND METHODS: A consecutive series of 26 patients undergoing staged bilateral TKA was evaluated. Varus and valgus laxity of the knee with the TKA implant was measured a few days before the contralateral TKA without anesthesia and again immediately after the contralateral TKA under spinal anesthesia. RESULTS: The laxity was significantly increased from 3.0 degrees to 3.6 degrees (p = 0.005) and from 4.7 degrees to 5.7 degrees (p = 0.007) in medial and lateral side, respectively, when the stress tests were performed under anesthesia in comparison to the laxity measured without anesthesia. The major change in laxity (>=3 degrees ) was measured in 6 (23%) patients tested without anesthesia. CONCLUSIONS: Anesthesia significantly influenced knee joint laxity after TKA. The findings of this study suggest that muscular forces impart a stabilizing force across the joint. PMID- 26742493 TI - Tooth loss is associated with increased risk of esophageal cancer: evidence from a meta-analysis with dose-response analysis. AB - Epidemiological studies have revealed the association between tooth loss and the risk of esophageal cancer (EC); however, consistent results were not obtained from different single studies. Therefore, we conducted the present meta-analysis to evaluate the association between tooth loss and EC. We conducted electronic searches of PubMed until to February 10, 2015 to identify relevant observational studies that examined the association between tooth loss and the risk of EC. Study selection and data extraction from eligible studies were independently performed by two authors. The meta-analysis was conducted using Stata 12.0 software. Finally eight eligible publications with ten studies involving 3 cohort studies, 5 case-control studies, and 1 cross-sectional study were yielded. Meta analysis identified tooth loss increased risk of EC 1.30 times (Relative risk = 1.30, 95% confidence interval = 1.06-1.60, I(2) = 13.5%). Dose-response analysis showed linear relationship between tooth loss and risk of EC (RR = 1.01, 95%CI = 1.00-1.03; P for non-linearity test was 0.45). Subgroup analysis proved similar results and publication bias was not detected. In conclusion, tooth loss could be considered to be a significant and dependent risk factor for EC based on the current evidence. PMID- 26742492 TI - RYR2, PTDSS1 and AREG genes are implicated in a Lebanese population-based study of copy number variation in autism. AB - Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders characterized by ritualistic-repetitive behaviors and impaired verbal and non verbal communication. Objectives were to determine the contribution of genetic variation to ASDs in the Lebanese. Affymetrix Cytogenetics Whole-Genome 2.7 M and CytoScan(TM) HD Arrays were used to detect CNVs in 41 Lebanese autistic children and 35 non-autistic, developmentally delayed and intellectually disabled patients. 33 normal participants were used as controls. 16 de novo CNVs and 57 inherited CNVs, including recognized pathogenic 16p11.2 duplications and 2p16.3 deletions were identified. A duplication at 1q43 classified as likely pathogenic encompasses RYR2 as a potential ASD candidate gene. This previously identified CNV has been classified as both pathogenic, and, of uncertain significance. A duplication of unknown significance at 10q11.22, proposed as a modulator for phenotypic disease expression in Rett syndrome, was also identified. The novel potential autism susceptibility genes PTDSS1 and AREG were uncovered and warrant further genetic and functional analyses. Previously described and novel genetic targets in ASD were identified in Lebanese families with autism. These findings may lead to improved diagnosis of ASDs and informed genetic counseling, and may also lead to untapped therapeutic targets applicable to Lebanese and non-Lebanese patients. PMID- 26742495 TI - Early clinical and radiological results of total knee arthroplasty using patient specific guides in obese patients. AB - PURPOSE: Total knee arthroplasty (TKA) is a challenging procedure in patients with a high body mass index (BMI). The aim of our study was to assess the outcome and accuracy of restoration of mechanical alignment in TKA using patient-specific guides (PSG) involving patients with high BMI. MATERIALS AND METHODS: Patients with BMI of 30 or above were enrolled in the study. The mean age of the patients was 65.15 years. The study comprised of 46 males and 54 females. Total knee arthroplasty was planned after a pre-operative MRI and long leg x-ray films using customized PSG. RESULTS: Of the 105 knees (100 patients) in the study, average BMI was 35.42 kg/m(2) (30-56). Twenty patients (20 %) had class III obesity (>=40 kg/m(2)). The average blood loss and operative time were 236.1 ml (range 50-700 ml) and 92.2 min (65-130 min), respectively. The average post-operative mechanical axis was noted to be 1.85 degrees varus (range 4 degrees valgus to 6 degrees varus). Eighty-eight patients (86.27 %) had mechanical alignment within 3 degrees of neutral. There were no adverse intraoperative events. One patient had deep infection that required a two-stage revision. The average post-operative range of motion at 1-year follow-up was 105.8 degrees (range 80 degrees -130 degrees ). CONCLUSION: Patient-specific guides technology restores the coronal mechanical axis reliably in obese patients without adversely affecting outcomes. Our short-term follow-up has shown favorable outcomes. Surgeons should use these customized jigs as a guide and adjust the size of components, alignment and rotation according to normal surgical principles. PMID- 26742497 TI - The contribution of color to attention capture effects during search for onset targets. AB - The literature on top-down contingent capture is concerned with the question of what constitutes a search set. Is it restricted to single stimulus properties such as color or onsets, or can such sets be more complex? In nine experiments (N = 140), we tested whether cueing effects during search for onset targets were affected by cue color. According to the classic theory of contingent capture (Folk, Remington, & Johnston, Journal of Experimental Psychology: Human Perception and Performance, 18, 1030-1044, 1992), during search for onset targets, cues capture attention on the basis of a match between the cue's onset and top-down control settings directed to the target onsets. However, such cueing effects were based on cues of a color similar to the target color. Therefore, matches of the cue color to the target color could have contributed to the effects. Indeed, here we found cueing effects when the cues and targets were of the same color, but not when they were of different colors (Exps. 1a, 1b, 4a, and 4b). In addition, same-color cueing effects were stronger than different-color cueing effects (Exps. 2a, 2b, 3a, 3b, and the white-target conditions of Exp. 5). In Experiment 5, we also identified efficient search for only one target color as a critical prerequisite for the differences between cueing by color-similar and dissimilar onset cues. We conclude with a discussion of the contributions of cue to-set color matches, deallocation of attention, and intertrial priming to what appear to be top-down contingent-capture effects based on abrupt onsets. PMID- 26742498 TI - Previously seen and expected stimuli elicit surprise in the context of visual search. AB - In the context of visual search, surprise is the phenomenon by which a previously unseen and unexpected stimulus exogenously attracts spatial attention. Capture by such a stimulus occurs, by definition, independent of task goals and is thought to be dependent on the extent to which the stimulus deviates from expectations. However, the relative contributions of prior-exposure and explicit knowledge of an unexpected event to the surprise response have not yet been systematically investigated. Here observers searched for a specific color while ignoring irrelevant cues of different colors presented prior to the target display. After a brief familiarization period, we presented an irrelevant motion cue to elicit surprise. Across conditions we varied prior exposure to the motion stimulus - seen versus unseen - and top-down expectations of occurrence - expected versus unexpected - to assess the extent to which each of these factors contributes to surprise. We found no attenuation of the surprise response when observers were pre-exposed to the motion cue and or had explicit knowledge of its occurrence. Our results show that it is neither sufficient nor necessary that a stimulus be new and unannounced to elicit surprise and suggest that the expectations that determine the surprise response are highly context specific. PMID- 26742499 TI - Central nervous system multiple myeloma. PMID- 26742496 TI - Diagnosis and management of acromegaly: the patient's perspective. AB - PURPOSE: Early diagnosis is a success factor for the prevention of long-term comorbidity and premature death in patients with acromegaly, but large-scale data on the diagnostic process and disease management are scarce. Therefore, we aimed to evaluate the diagnostic process, implementation of treatment and changes in life situation in patients with acromegaly, focusing on sex-specific differences. METHODS: Non-interventional patient-reported outcome study. 165 patients with clinically and biochemically proven acromegaly were questioned about the diagnostic process and utilization of health care by means of a self-developed standardized postal survey including questions on acromegaly symptoms experienced before diagnosis, number and specialty of consulted doctors, time to diagnosis and aftercare. RESULTS: The diagnostic process took 2.9 (SD 4.53) years, during which 3.4 (SD 2.99) physicians were consulted. Women waited longer [4.1 (SD 5.53) years] than men [1.6 (SD 2.69) years; p = 0.001] for the correct diagnosis, and consulted more doctors in the process [4.0 (SD 2.99) vs. 2.7 (SD 2.84) doctors, p < 0.001, respectively]. In 48.5 % of patients, acromegaly was diagnosed by an endocrinologist (men: 45.1 %; women: 52.4 %). Overall disease duration from symptom onset until last surgery was 5.5 (SD 6.85) years, with no sex differences. A change in employment status was the most commonly reported event after diagnosis and a quarter of the patients stated that the illness had changed their lives. CONCLUSIONS: Our findings confirm the urgent need to increase awareness of the clinical manifestation of acromegaly to facilitate an earlier diagnosis of the disease and to provide diagnostic equality across the sexes. PMID- 26742500 TI - Personal Transition to the Profession: A Novel Longitudinal Professional Development and Wellness Medical Student Curriculum. PMID- 26742501 TI - GOLGA2, encoding a master regulator of golgi apparatus, is mutated in a patient with a neuromuscular disorder. AB - Golgi apparatus (GA) is a membrane-bound organelle that serves a multitude of critical cellular functions including protein secretion and sorting, and cellular polarity. Many Mendelian diseases are caused by mutations in genes encoding various components of GA. GOLGA2 encodes GM130, a necessary component for the assembly of GA as a single complex, and its deficiency has been found to result in severe cellular phenotypes. We describe the first human patient with a homozygous apparently loss of function mutation in GOLGA2. The phenotype is a neuromuscular disorder characterized by developmental delay, seizures, progressive microcephaly, and muscular dystrophy. Knockdown of golga2 in zebrafish resulted in severe skeletal muscle disorganization and microcephaly recapitulating loss of function human phenotype. Our data suggest an important developmental role of GM130 in humans and zebrafish. PMID- 26742503 TI - Clinical sequencing: is WGS the better WES? AB - Current clinical next-generation sequencing is done by using gene panels and exome analysis, both of which involve selective capturing of target regions. However, capturing has limitations in sufficiently covering coding exons, especially GC-rich regions. We compared whole exome sequencing (WES) with the most recent PCR-free whole genome sequencing (WGS), showing that only the latter is able to provide hitherto unprecedented complete coverage of the coding region of the genome. Thus, from a clinical/technical point of view, WGS is the better WES so that capturing is no longer necessary for the most comprehensive genomic testing of Mendelian disorders. PMID- 26742504 TI - Stochastic multi-objective auto-optimization for resource allocation decision making in fixed-input health systems. AB - The management of hospitals within fixed-input health systems such as the U.S. Military Health System (MHS) can be challenging due to the large number of hospitals, as well as the uncertainty in input resources and achievable outputs. This paper introduces a stochastic multi-objective auto-optimization model (SMAOM) for resource allocation decision-making in fixed-input health systems. The model can automatically identify where to re-allocate system input resources at the hospital level in order to optimize overall system performance, while considering uncertainty in the model parameters. The model is applied to 128 hospitals in the three services (Air Force, Army, and Navy) in the MHS using hospital-level data from 2009 - 2013. The results are compared to the traditional input-oriented variable returns-to-scale Data Envelopment Analysis (DEA) model. The application of SMAOM to the MHS increases the expected system-wide technical efficiency by 18 % over the DEA model while also accounting for uncertainty of health system inputs and outputs. The developed method is useful for decision makers in the Defense Health Agency (DHA), who have a strategic level objective of integrating clinical and business processes through better sharing of resources across the MHS and through system-wide standardization across the services. It is also less sensitive to data outliers or sampling errors than traditional DEA methods. PMID- 26742502 TI - Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome. AB - The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS; MIM #192430; 188400) is the most common microdeletion syndrome. The phenotypic presentation of 22q11DS is highly variable; approximately 60-75 % of 22q11DS patients have been reported to have a congenital heart defect (CHD), mostly of the conotruncal type, and/or aortic arch defect. The etiology of the cardiac phenotypic variability is not currently known for the majority of patients. We hypothesized that rare copy number variants (CNVs) outside the 22q11.2 deleted region may modify the risk of being born with a CHD in this sensitized population. Rare CNV analysis was performed using Affymetrix SNP Array 6.0 data from 946 22q11DS subjects with CHDs (n = 607) or with normal cardiac anatomy (n = 339). Although there was no significant difference in the overall burden of rare CNVs, an overabundance of CNVs affecting cardiac-related genes was detected in 22q11DS individuals with CHDs. When the rare CNVs were examined with regard to gene interactions, specific cardiac networks, such as Wnt signaling, appear to be overrepresented in 22q11DS CHD cases but not 22q11DS controls with a normal heart. Collectively, these data suggest that CNVs outside the 22q11.2 region may contain genes that modify risk for CHDs in some 22q11DS patients. PMID- 26742505 TI - Caregiving in multiple sclerosis and quality of life: A meta-synthesis of qualitative research. AB - OBJECTIVE: The lack of adequate conceptualisation and operationalisation of quality of life (QoL) limits the ability to have a consistent body of evidence to improve QoL research and practice in informal caregiving for people with multiple sclerosis (MS). Thus, we conducted a meta-synthesis of qualitative research to improve the conceptual understanding of the experiences of MS carers and to identify factors that affect carers' QoL. DESIGN: Systematic searches of five electronic databases yielded 17 qualitative studies which were synthesised using the principles of meta-ethnography. RESULTS: The synthesis resulted in nine inter linking themes: Changes and losses; challenges revolving around MS; caregiving demands; burden of care; future concerns; external stressors; experiences of support; strategies used in managing the caregiving role; and motivating factors. Our findings suggest that MS carers can have both positive and negative experiences which may bring challenges and rewards to the carers. CONCLUSION: We present a proposed QoL model for MS caregiving which can be used to inform the development of interventions for MS carers to improve their QoL. However, further empirical research is needed to examine the utility of this model and to explore the concept of QoL in MS carers in more detail. PMID- 26742507 TI - Taking Control of the Time Bomb in Abdominal Aortic Aneurysm. PMID- 26742506 TI - Going longitudinal in biological psychiatric research: All things considered. PMID- 26742508 TI - Intravaginal Practices in Female Sex Workers in Cambodia: A Qualitative Study. AB - Intravaginal practices (IVPs) are associated with several adverse health outcomes, including HIV infection. However, few studies have examined this topic in Asian cultures, particularly in female sex workers (FSWs). This theory-based qualitative study aimed to describe the IVPs and to identify salient determinants of these practices in FSWs in Phnom Penh, Cambodia. We conducted in-depth interviews using open-ended questions with 30 FSWs in July-August 2014. We analyzed data using thematic content analysis, with thematic codes based on the constructs of the theory of planned behavior. The results showed that the most common IVP was a combination of intravaginal washing and wiping, to which we refer as intravaginal cleansing. There was a clear and close connection between IVP and sex work. Perceived benefits of intravaginal cleansing were numerous, while the perceived risks were few. As a result, the attitude toward intravaginal cleansing was favorable. A common misperception of benefit was that intravaginal cleansing could prevent sexually transmitted infections. Local physicians considerably influenced the subjective norm related to IVP. Intention to quit IVPs was suboptimal. In conclusion, the psychological factors associated with IVPs in FSWs were somewhat different from those in the general population of Cambodian women and women in other countries. Behavioral beliefs, attitude, and subjective norms appeared salient and important factors in IVPs. Interventions aimed at reducing IVPs should target these constructs as well as the sex-work associated economic motives. Local physicians may be an agent to change IVP and an effective channel to deliver interventions. PMID- 26742509 TI - A pragmatic analysis comparing once-monthly paliperidone palmitate versus daily oral antipsychotic treatment in patients with schizophrenia. AB - BACKGROUND: Persons with schizophrenia often come in contact with the criminal justice system (CJS). This analysis of subjects with schizophrenia and a history of contact with the CJS estimated and compared mean cumulative function (MCF) of treatment failure events when treated with paliperidone palmitate (PP) or oral antipsychotics (OAs). All events identified during the full study period of the Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) trial were evaluated. METHODS: Subjects were randomly assigned to flexibly dosed, monthly, injectable PP (78-234 mg) or daily OA in a 15-month prospective, open-label, multicenter US study (May 5, 2010-December 9, 2013). Subjects could continue participation after a treatment failure event. Multiple treatment failures in individual subjects were analyzed as recurrent events. Analyses estimated MCF of treatment failure events and MCF of institutionalizations (arrests, incarcerations, or psychiatric hospitalizations) during the 15-month study period. RESULTS: The ITT population included 226 (PP) and 218 (OA) subjects, of whom 41.2% and 40.4%, respectively, completed 15 months of follow-up. The MCF of treatment failures and institutionalizations differed significantly in favor of PP compared with OA (P=0.007 and P=0.005, respectively). Overall, TEAEs were reported by 86.3% of subjects in the PP group and 81.7% in the OA group. CONCLUSIONS: This pragmatic analysis suggests that, compared with OA, PP is not only more effective in delaying median time to treatment failure, but it also reduces the number of treatment failures and institutionalizations per person year follow-up. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov identifier: NCT01157351. PMID- 26742510 TI - Negative symptoms in bipolar disorder and schizophrenia: A psychometric evaluation of the brief negative symptom scale across diagnostic categories. AB - Past studies have demonstrated that the Brief Negative Symptom Scale (BNSS) has excellent psychometric properties in patients with schizophrenia. In the current study, we extended this literature by examining psychometric properties of the BNSS in outpatients diagnosed with bipolar disorder (n=46), outpatients with schizophrenia (n=50), and healthy controls (n=27). Participants completed neuropsychological testing and a clinical interview designed to assess negative, positive, disorganized, mood, and general psychiatric symptoms. Results indicated differences among the 3 groups in the severity of all BNSS items, with SZ and BD scoring higher than CN; however, SZ and BD only differed on blunted affect and alogia items, not anhedonia, avolition, or asociality. BD patients with a history of psychosis did not differ from those without a history of psychosis on negative symptom severity. The BNSS had excellent internal consistency in SZ, BD, and CN groups. Good convergent and discriminant validity was apparent in SZ and BD groups, as indicated by relationships between the BNSS and other clinical rating scales. These findings support the validity of the BNSS in broadly defined serious mental illness populations. PMID- 26742511 TI - Asthma COPD Overlap Syndrome on CT Densitometry: A Distinct Phenotype from COPD. AB - Patients with asthma COPD overlap syndrome (ACOS) are an important but poorly characterized group. This study sought to explore the distinct characteristics of ACOS on CT densitometry. The study population was randomly selected from communities via questionnaires. All participants underwent low-dose volumetric chest CT both before and after bronchodilator administration. Each CT scan was performed at full-inspiration and full-expiration for CT densitometry. Emphysema index (EI), air trapping (AT), mean lung density (MLD) and total lung volume (TLV) were measured and compared between the ACOS and COPD groups. The distributions of both EI and AT were compared between patients with ACOS and COPD. The variations between the pre- and post-BD measurements observed in patients with ACOS were compared with those in patients with COPD. A total of 71 patients completed the study, including 32 patients with COPD and 39 patients with ACOS. The patients with ACOS exhibited lower EI and more upper-zone predominant EI distributions, compared with the patients with COPD. No significant differences were exhibited in AT and its distribution. Following bronchodilator administration, the variations in AT and expiratory MLD were greater in patients with ACOS than in patients with COPD. No differences were observed in the variations of EI and inspiratory MLD. Our results indicate that patients with ACOS have lower extent of emphysema and different emphysema distribution, as well as greater post-BD variations in air trapping, compared with patients with COPD. These findings suggest that CT densitometry characterizes ACOS as a distinct phenotype from COPD. PMID- 26742512 TI - Endogenous Apolipoprotein E (ApoE) Fragmentation Is Linked to Amyloid Pathology in Transgenic Mouse Models of Alzheimer's Disease. AB - The epsilon 4 allele of the apolipoprotein E (ApoE4) gene is the most important risk factor implicated in Alzheimer's disease (AD) etiology. ApoE4 is more susceptible to proteolysis, and ApoE fragments have been shown to promote tau hyperphosphorylation and exert neurotoxic properties. While a plethora of studies deals with the effect of ApoE and its fragments on amyloid-beta peptide (Abeta) deposition and clearance, it is largely unknown whether Abeta in turn influences human or murine ApoE expression and its proteolysis. The present study is the first to show that endogenous murine ApoE becomes proteolytically processed in a way reminiscent of human ApoE fragmentation in different AD mouse models, including APP/PS1KI or 5XFAD. Murine ApoE fragments were demonstrated to accumulate mainly in synaptic fractions in AD mouse models. In vitro experiments, as well as analysis of mouse models at different time points, suggest that the amount of total ApoE is associated with extracellular Abeta while the amount of its fragments is linked to intracellular Abeta levels. Murine ApoE fragmentation is a common feature in different AD transgenic mouse models and could be directly associated with intraneuronal Abeta accumulation. Extracellular amyloid induces an elevation in full-length ApoE expression, which might present a protective mechanism toward Abeta clearance. The demonstrated fragments of murine ApoE in vitro and in vivo might therefore play a crucial role in the progression of AD pathology in murine AD models. PMID- 26742513 TI - Association Between Plasminogen Activator Inhibitor-1 Genetic Polymorphisms and Stroke Susceptibility. AB - The plasminogen activator inhibitor-1 (PAI-1) is a candidate gene for stroke based on PAI-1's crucial role in fibrinolytic system. However, association studies have yielded conflicting results regarding the association between PAI-1 polymorphisms and stroke susceptibility. To further elucidate the putative association, we performed a systematic review and meta-analysis to provide a complete picture of the loci investigated for association of PAI-1 polymorphism with stroke risk and to derive a precise estimation. PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases were searched until June 2015 to identify eligible studies. Forty data sets from 39 studies with a total of 8336 cases and 14,403 controls were included. The most commonly investigated polymorphism was -675 4G/5G, followed by -844 G/A, 11053 T>G, HindIII C/G, and (CA)n. Overall, our meta-analysis provided evidence for the significant association of PAI-1 4G/5G polymorphism with an increased risk of adult but not pediatric ischemic stroke (adult: 4G/4G vs. 4G/5G + 5G/5G, OR = 1.21, 95 % CI = 1.04-1.42). In the subgroup analysis, significant association was detected in Asians (4G/4G vs. 4G/5G + 5G/5G, OR = 1.45, 95 % CI = 1.14-1.85) but not Caucasians. Moreover, we found that -844 G/A but not 11053 T>G polymorphism was associated with an increased risk of ischemic stroke (-844G/A: A/A vs. G/G: OR = 1.32, 95 % CI = 1.01-1.73). A tendency of PAI-1 4G/5G polymorphism towards a decreased risk of hemorrhagic stroke was observed (4G/4G + 4G/5G vs. 5G/5G, OR = 0.77, 95 % CI = 0.59-1.02, P = 0.066). Future well-designed studies in large well characterized sample size and presenting results stratified by gender, age, and stroke subtype are warranted. PMID- 26742514 TI - Huntington's Disease: Relationship Between Phenotype and Genotype. AB - Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease with the typical manifestations of involuntary movements, psychiatric and behavior disorders, and cognitive impairment. It is caused by the dynamic mutation in CAG triplet repeat number in exon 1 of huntingtin (HTT) gene. The symptoms of HD especially the age at onset are related to the genetic characteristics, both the CAG triplet repeat and the modified factors. Here, we reviewed the recent advancement on the genotype-phenotype relationship of HD, mainly focus on the characteristics of different expanded CAG repeat number, genetic modifiers, and CCG repeat number in the 3' end of CAG triplet repeat and their effects on the phenotype. We also reviewed the special forms of HD (juvenile HD, atypical onset HD, and homozygous HD) and their phenotype-genotype correlations. The review will aid clinicians to predict the onset age and disease course of HD, give the genetic counseling, and accelerate research into the HD mechanism. PMID- 26742515 TI - FLZ Attenuates alpha-Synuclein-Induced Neurotoxicity by Activating Heat Shock Protein 70. AB - Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. The pathology of PD is caused by progressive degeneration of dopaminergic neurons and is characterized by the presence of intracellular inclusions known as Lewy bodies, composed mainly of alpha-synuclein. Heat shock proteins (HSPs) are crucial in protein quality control in cells. HSP70 in particular prevents the aggregation of protein aggregation, such as alpha-synuclein, providing a degree of protection against PD. The compound FLZ has been shown to protect several PD models in previous studies and was reported as an HSP inducer to protect against MPP+-induced neurotoxicity, but the mechanism remains unclear. In this study, we investigated the effects of FLZ-mediated HSP70 induction in alpha-synuclein transgenic mice and cells. FLZ treatment alleviated motor dysfunction and improved dopaminergic neuronal function in alpha-synuclein transgenic mice. HSP70 protein expression and transcriptional activity were increased by FLZ treatment, eliciting a reduction of alpha-synuclein aggregation and associated toxicity. The inhibition of HSP70 by quercetin or HSP70 siRNA markedly attenuated the neuroprotective effects of FLZ, confirming that FLZ exerted a neuroprotective effect through HSP70. We revealed that FLZ directly bound to and increased the expression of Hip, a cochaperone of HSP70, which in turn enhanced HSP70 activity. In conclusion, we defined a critical role for HSP70 and its cochaperones activated by FLZ in preventing neurodegeneration and proposed that targeting the HSP70 system may represent a potential therapy for alpha-synuclein-related diseases, such as PD. PMID- 26742517 TI - Sulforaphane Prevents Methylmercury-Induced Oxidative Damage and Excitotoxicity Through Activation of the Nrf2-ARE Pathway. AB - Methylmercury (MeHg) is a prominent environmental neurotoxicant, which induces oxidative damage and an indirect excitotoxicity caused by altered glutamate (Glu) metabolism. However, the interaction between oxidative damage and excitotoxicity in MeHg-exposed rats has not been fully recognized. Here, we explored the interaction between oxidative damage and excitotoxicity and evaluated the preventive effects of sulforaphane (SFN) on MeHg-induced neurotoxicity in rat cerebral cortex. Seventy-two rats were randomly assigned to four groups: control group, MeHg-treated groups (4 and 12 MUmol/kg), and SFN pretreatment group. After treatment (28 days), the rats were killed and the cerebral cortex was analyzed. Then, Hg, glutathione (GSH), malondialdehyde (MDA), protein sulfhydryl, protein carbonyl, 8-hydroxy-2-deoxyguanosine (8-OHdG), and the levels of reactive oxygen species (ROS) and apoptosis were examined. Glu and glutamine (Gln) levels, glutamine synthetase (GS), phosphate-activated glutaminase (PAG), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), Na+-K+-ATPase and Ca2+-ATPase activities, intracellular Ca2+ levels, and the mRNA and protein expressions of Nrf2, Nrf2-regulated gene products, and N-methyl-D-aspartate receptors (NMDARs) were investigated in rat cerebral cortex. In our study, MeHg exposure not only induced Hg accumulation, apoptosis, ROS formation, GSH depletion, inhibition of antioxidant enzyme activities, and activation of Nrf2-ARE pathway signaling but also caused lipid, protein, and DNA peroxidative damage in a dose-dependent manner in rat cerebral cortex. Moreover, MeHg treatment significantly altered Gln/Glu cycling and NMDAR expression and resulted in calcium overloading. Furthermore, the present study also indicated that SFN pretreatment significantly reinforced the activation of the Nrf2-ARE pathway, which could prevent the toxic effects of MeHg exposure. Collectively, MeHg initiates multiple additive or synergistic disruptive mechanisms that lead to oxidative damage and excitotoxicity in rat cerebral cortex; pretreatment with SFN might prevent the MeHg-induced neurotoxicity by reinforcing the activation of the Nrf2-ARE pathway and then downregulating the interaction between oxidative damage and excitotoxicity pathways. PMID- 26742518 TI - Reduction in Autophagy by (-)-Epigallocatechin-3-Gallate (EGCG): a Potential Mechanism of Prevention of Mitochondrial Dysfunction After Subarachnoid Hemorrhage. AB - Mitochondrial dysfunction and subsequent autophagy, which are common features in central nervous system (CNS) disorders, were found to contribute to neuronal cell injury after subarachnoid hemorrhage (SAH). (-)-Epigallocatechin-3-gallate (EGCG), the main biological active of tea catechin, is well known for its beneficial effects in the treatment of CNS diseases. Here, the ability of EGCG to rescue cellular injury and mitochondrial function following the improvement of autophagic flux after SAH was investigated. As expected, EGCG-protected mitochondrial function depended on the inhibition of cytosolic Ca2+ concentration ([Ca2+]i) influx via voltage-gated calcium channels (VGCCs) and, consequently, mitochondrial Ca2+ concentration ([Ca2+]m) overload via mitochondrial Ca2+ uniporter (MCU). The attenuated [Ca2+]i and [Ca2+]m levels observed in the EGCG treated group likely lessened oxyhemoglobin (OxyHb)-induced mitochondrial dysfunction, including mitochondrial membrane potential depolarization, mitochondrial membrane permeability transition pore (mPTP) opening, reactive oxygen species (ROS), and cytochrosome c (cyt c) releasing. Subsequently, EGCG can restore the disrupted autophagy flux after SAH both at the initiation and formation stages by regulating Atg5, LC3B, and Becn-1 (Beclin-1) mRNA expressions. Thus, precondition EGCG resulted in autophagosomes and more autolysosomes compared with SAH group. As a result, EGCG pre-treatment increased the neurological score and decreased cell death. This study suggested that the mitochondrial dysfunction and abnormal autophagy flux synergistically contribute to SAH pathogenesis. Thus, EGCG can be regarded as a new pharmacological agent that targets both mitochondria and altered autophagy in SAH therapy. PMID- 26742516 TI - Impaired Neurovisceral Integration of Cardiovascular Modulation Contributes to Multiple Sclerosis Morbidities. AB - Multiple sclerosis (MS) is an inflammatory demyelinating central nervous system (CNS) disease with an uncertain etiology. MS is heterogeneous, involving multiple clinical pathologies, including neurodegeneration, depression, fatigue and sleep disorders, migraine, osteoporosis and cerebral hemodynamic impairments. The underlying causes of these pathologies remain mostly unknown. Based on the accumulating evidence derived from our studies and those of other investigators, we propose that the dysregulation in the neurovisceral integration of cardiovascular modulation can lead to many MS-related clinical symptoms. We show that MS inflammatory and neurodegenerative processes are intertwined with the aforementioned clinical morbidities and are collectively the manifestations of cardiovascular autonomic nervous system (ANS) dysfunction. The strategies for improving sympathovagal balance would likely prevent and minimize many MS-related clinical symptoms, improving patients' quality of life. Similar strategies could be applied to other autoimmune and neurodegenerative diseases where autonomic imbalance plays a role. PMID- 26742519 TI - Zinc Improves Cognitive and Neuronal Dysfunction During Aluminium-Induced Neurodegeneration. AB - Metals are considered as important components of a physiologically active cell, and imbalance in their levels can lead to various diseased conditions. Aluminium (Al) is an environmental neurotoxicant, which is etiologically related to several neurodegenerative disorders like Alzheimer's, whereas zinc (Zn) is an essential trace element that regulates a large number of metabolic processes in the brain. The objective of the present study was to understand whether Zn provides any physiological protection during Al-induced neurodegeneration. Male Sprague Dawley rats weighing 140-160 g received either aluminium chloride (AlCl3) orally (100 mg/kg b.wt./day), zinc sulphate (ZnSO4) in drinking water (227 mg/L) or combined treatment of aluminium and zinc for 8 weeks. Al treatment resulted in a significant decline in the cognitive behaviour of rats, whereas zinc supplementation caused an improvement in various neurobehavior parameters. Further, Al exposure decreased (p <= 0.001) the levels of neurotransmitters, acetylcholinesterase activity, but increased (p <= 0.001) the levels of L citrulline as well as activities of nitric oxide and monoamine oxidase in the brain. However, zinc administration to Al-treated animals increased the levels of neurotransmitters and regulated the altered activities of brain markers. Western blot of tau, amyloid precursor protein (APP), glial fibrillary acidic protein (GFAP), ubiquitin, alpha-synuclein and Hsp 70 were also found to be elevated after Al exposure, which however were reversed following Zn treatment. Al treatment also revealed alterations in neurohistoarchitecture in the form of loss of pyramidal and Purkinje cells, which were improved upon zinc co-administration. Therefore, the present study demonstrates that zinc improves cognitive functions by regulating alpha-synuclein and APP-mediated molecular pathways during aluminium-induced neurodegeneration. PMID- 26742520 TI - Guanosine Anxiolytic-Like Effect Involves Adenosinergic and Glutamatergic Neurotransmitter Systems. AB - Accumulating evidences indicate that endogenous modulators of excitatory synapses in the mammalian brain are potential targets for treating neuropsychiatric disorders. Indeed, glutamatergic and adenosinergic neurotransmissions were recently highlighted as potential targets for developing innovative anxiolytic drugs. Accordingly, it has been shown that guanine-based purines are able to modulate both adenosinergic and glutamatergic systems in mammalian central nervous system. Here, we aimed to investigate the potential anxiolytic-like effects of guanosine and its effects on the adenosinergic and glutamatergic systems. Acute/systemic guanosine administration (7.5 mg/kg) induced robust anxiolytic-like effects in three classical anxiety-related paradigms (elevated plus maze, light/dark box, and round open field tasks). These guanosine effects were correlated with an enhancement of adenosine and a decrement of glutamate levels in the cerebrospinal fluid. Additionally, pre-administration of caffeine (10 mg/kg), an unspecific adenosine receptors' antagonist, completely abolished the behavioral and partially prevented the neuromodulatory effects exerted by guanosine. Although the hippocampal glutamate uptake was not modulated by guanosine (both ex vivo and in vitro protocols), the synaptosomal K+-stimulated glutamate release in vitro was decreased by guanosine (100 MUM) and by the specific adenosine A1 receptor agonist, 2-chloro-N 6-cyclopentyladenosine (CCPA, 100 nM). Moreover, the specific adenosine A1 receptor antagonist 8-cyclopentyl 1,3-dipropylxanthine (DPCPX, 100 nM) fully reversed the inhibitory guanosine effect in the glutamate release. The pharmacological modulation of A2a receptors has shown no effect in any of the evaluated parameters. In summary, the guanosine anxiolytic-like effects seem closely related to the modulation of adenosinergic (A1 receptors) and glutamatergic systems. PMID- 26742521 TI - Marginal Iodine Deficiency Affects Dendritic Spine Development by Disturbing the Function of Rac1 Signaling Pathway on Cytoskeleton. AB - Iodine deficiency (ID)-induced thyroid hormone (TH) insufficient during development leads to impairments of brain function, such as learning and memory. Marginal ID has been defined as subtle insufficiency of TH, characterized as low thyroxine (T4) levels, whether marginal ID potentially had adverse effects on the development of hippocampus and the underlying mechanisms remain unclear. Thus, in the present study, we established Wistar rat models with ID diet during pregnancy and lactation. The effects of marginal ID on long-term potentiation (LTP) were investigated in the hippocampal CA1 region. To study the development of dendritic spines in pyramidal cells, Golgi-Cox staining was conducted on postnatal day (PN) 7, PN14, PN21, and PN28. The activation of Rac1 signaling pathway, which is essential for dendritic spine development by regulating actin cytoskeleton, was also investigated. Our results showed that marginal ID slightly reduced the field excitatory postsynaptic potential (f-EPSP) slope and the population spike (PS) amplitude. Besides, the density of dendritic spines during the critical period of rat postnatal development was mildly decreased, and we found no significant change of spine morphology in marginal ID group. We also observed decreased activation of the Rac1 signaling pathway in pups subjected to maternal marginal ID. Our study may support the hypothesis that decreased T4 induced by marginal ID results in slight impairments of LTP and leads to mild damage of dendritic spine development, which may be due to abnormal regulation of Rac1 signaling pathway on cytoskeleton. PMID- 26742522 TI - Clozapine Improves Memory Impairment and Reduces Abeta Level in the Tg APPswe/PS1dE9 Mouse Model of Alzheimer's Disease. AB - Alzheimer's disease (AD) is a progressive degenerative condition. In order to treat AD, the use of a "drug repositioning" or "repurposing" approach with potential disease-modifying compounds has been increased. The new generation antipsychotics are commonly used in AD and other dementias for the treatment of psychosis and behavioral symptoms, and several animal models have shown the effects of these potential disease-modifying compounds. In this study, we examined whether long-term clozapine treatment could reduce amyloid beta (Abeta) deposition and cognitive impairment in transgenic mice of AD, Tg-APPswe/PS1dE9. AD mice were fed clozapine at 20 mg/kg/day for 3 months from 4.5 months of age. Intake of clozapine improved the Abeta-induced memory impairment and suppressed Abeta levels and plaque deposition in the brain of AD mice. Clozapine upregulated Trk, brain-derived neurotrophic factor, cyclin-dependent kinase-5, and p35 in the cortex and hippocampus of AD mice and activated AMP-activated protein kinase (AMPK). As a downstream effector of AMPK, beta-secretase expression was decreased by clozapine administration. Moreover, clozapine-phosphorylated synapsin I at Ser9 and Ser549 sites in the hippocampus and cortex of AD mice, which may be involved in synaptic strength. This study suggests that as one of candidate for multi-target approach of AD treatment, clozapine is proposed as a therapeutic drug for treatment of AD patients. PMID- 26742523 TI - Inhibitory Effect of Endomorphin-2 Binding to the MU-Opioid Receptor in the Rat Pre-Botzinger Complex on the Breathing Activity. AB - Opiates are commonly used analgesics that often cause clinical respiratory depression. However, their underlying mechanisms remain unclear. Endomorphin-2 (EM2) is a novel, endogenous tetrapeptide opioid with very high affinity and selectivity for the MU-opioid receptor (MOR). The pre-Botzinger complex (pre BotC) is considered the center of respiratory rhythm generation, and the synaptic connections in this region are essential for respiratory rhythm. The present study identified EM2-like immunoreactive (LI) axonal terminals in the pre-BotC of adult rats. Some EM2-LI axonal terminals made principally symmetric synapses with neurokinin 1 receptor (NK1R)-LI or MOR-LI neuronal dendritic processes in the pre BotC. Unilateral microinjection of EM2 into the pre-BotC decreased breathing frequency and amplitude. A prior microinjection of the selective MOR antagonist beta-funaltrexamine (beta-FNA) into the pre-BotC prevented the effects of EM2. The present results suggest that EM2-LI axonal terminals modulate NK1R-expressing neurons in the pre-BotC and that EM2 plays a role in respiratory depression through MORs in the pre-BotC. PMID- 26742524 TI - High-Glucose-Derived Oxidative Stress-Dependent Heme Oxygenase-1 Expression from Astrocytes Contributes to the Neuronal Apoptosis. AB - An elevated level of glucose has been found in the blood of hyperglycemia and diabetes patients associated with several central nervous system (CNS) complications. These disorders may be due to the up-regulation of many neurotoxic mediators by host cells triggered by high glucose (HG). Moreover, heme oxygenase 1 (HO-1) plays a crucial role in tissue pathological changes such as brain injuries. However, the molecular mechanisms underlying HG-induced HO-1 expression in brain cells remain poorly defined. Thus, we use the rat brain astrocytes (RBA 1) as a model to investigate the signaling mechanisms of HO-1 induction by HG and its effects on neuronal cells. We demonstrated that HG induced HO-1 expression via a reactive oxygen species (ROS)-dependent signaling pathway. NADPH oxidase (Nox)- and mitochondrion-dependent ROS generation led to activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun-N-terminal kinase (JNK) and then activated the downstream transcriptional factors nuclear factor kappaB (NF-kappaB) and c-Fos/activator protein 1 (AP-1), respectively. Subsequently, the activated NF-kappaB and AP-1 turned on transcription of HO-1 gene. These results indicated that in brain astrocytes, activation of MAPK mediated NF-kappaB and c-Fos/AP-1 cascades by Nox/ROS and mitoROS-dependent events is essential for HO-1 up-regulation induced by HG. Moreover, we found that HG-induced extracellular ROS increase and HO-1 expression from astrocytes resulted in neuronal apoptosis. These results offers new insights into the mechanisms and effects of the action of HG, supporting that HG may cause brain disorders in the development of diabetes- and hyperglycemia-induced CNS complications such as neurodegenerative diseases. PMID- 26742525 TI - Synapsins Are Downstream Players of the BDNF-Mediated Axonal Growth. AB - Synapsins (Syns) are synaptic vesicle-associated phosphoproteins involved in neuronal development and neurotransmitter release. While Syns are implicated in the regulation of brain-derived neurotrophic factor (BDNF)-induced neurotransmitter release, their role in the BDNF developmental effects has not been fully elucidated. By using primary cortical neurons from Syn I knockout (KO) and Syn I/II/III KO mice, we studied the effects of BDNF and nerve growth factor (NGF) on axonal growth. While NGF had similar effects in all genotypes, BDNF induced significant differences in Syn KO axonal outgrowth compared to wild type (WT), an effect that was rescued by the re-expression of Syn I. Moreover, the significant increase of axonal branching induced by BDNF in WT neurons was not detectable in Syn KO neurons. The expression analysis of BDNF receptors in Syn KO neurons revealed a significant decrease of the full length TrkB receptor and an increase in the levels of the truncated TrkB.t1 isoform and p75NTR associated with a marked reduction of the BDNF-induced MAPK/Erk activation. By using the Trk inhibitor K252a, we demonstrated that these differences in BDNF effects were dependent on a TrkB/p75NTR imbalance. The data indicate that Syn I plays a pivotal role in the BDNF signal transduction during axonal growth. PMID- 26742526 TI - Acute Morphine, Chronic Morphine, and Morphine Withdrawal Differently Affect Pleiotrophin, Midkine, and Receptor Protein Tyrosine Phosphatase beta/zeta Regulation in the Ventral Tegmental Area. AB - Pleiotrophin (PTN) and midkine (MK) are secreted growth factors and cytokines, proposed to be significant neuromodulators with multiple neuronal functions. PTN and MK are generally related with cell proliferation, growth, and differentiation by acting through different receptors. PTN or MK, signaling through receptor protein tyrosine phosphatase beta/zeta (RPTPbeta/zeta), lead to the activation of extracellular signal-regulated kinases (ERKs) and thymoma viral proto-oncogene (Akt), which induce morphological changes and modulate addictive behaviors. Besides, there is increasing evidence that during the development of drug addiction, astrocytes contribute to the synaptic plasticity by synthesizing and releasing substances such as cytokines. In the present work, we studied the effect of acute morphine, chronic morphine, and morphine withdrawal on PTN, MK, and RPTPbeta/zeta expression and on their signaling pathways in the ventral tegmental area (VTA). Present results indicated that PTN, MK, and RPTPbeta/zeta levels increased after acute morphine injection, returned to basal levels during chronic opioid treatment, and were upregulated again during morphine withdrawal. We also observed an activation of astrocytes after acute morphine injection and during opiate dependence and withdrawal. In addition, immunofluorescence analysis revealed that PTN, but not MK, was overexpressed in astrocytes and that dopaminergic neurons expressed RPTPbeta/zeta. Interestingly, p-ERK 1/2 levels during chronic morphine and morphine withdrawal correlated RPTPbeta/zeta expression. All these observations suggest that the neuroprotective and behavioral adaptations that occur during opiate addiction could be, at least partly, mediated by these cytokines. PMID- 26742527 TI - lncRNA NONRATT021972 siRNA Decreases Diabetic Neuropathic Pain Mediated by the P2X3 Receptor in Dorsal Root Ganglia. AB - Long noncoding RNAs (lncRNAs) participate in physiological and pathophysiological processes. Type 2 diabetes mellitus (T2DM) accounts for more than 90 % of all cases of diabetes mellitus (DM). Diabetic neuropathic pain (DNP) is a common complication of T2DM. The aim of this study was to investigate the effects of lncRNA NONRATT021972 small interference RNA (siRNA) on DNP mediated by the P2X3 receptor in dorsal root ganglia (DRG). These experiments showed that the expression levels of NONRATT021972 in DRG were increased in the T2DM rat model (intraperitoneal injection of STZ with 30 mg/kg). The concentration of NONRATT021972 in T2DM patient serum was higher compared to control healthy subjects. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) in T2DM rats were lower compared to control rats. MWT and TWL in T2DM rats treated with NONRATT021972 siRNA were higher compared with those in T2DM rats. The expression levels of the P2X3 protein and messenger RNA (mRNA) of T2DM rat DRG were higher compared to the control, while those in T2DM rats treated with NONRATT021972 siRNA were significantly lower compared to T2DM rats. The level of tumor necrosis factor-alpha (TNF-alpha) in the serum of T2DM rats treated with NONRATT021972 siRNA was significantly decreased compared with T2DM rats. NONRATT021972 siRNA inhibited the phosphorylation and activation of ERK1/2 in T2DM DRG. Thus, NONRATT021972 siRNA treatment may suppress the upregulated expression and activation of the P2X3 receptor and reduce the hyperalgesia potentiated by the pro-inflammatory cytokine TNF-alpha in T2DM rats. PMID- 26742528 TI - Upregulating the Expression of Survivin-HBXIP Complex Contributes to the Protective Role of IMM-H004 in Transient Global Cerebral Ischemia/Reperfusion. AB - IMM-H004, a 3-piperazinylcoumarin compound derived from coumarin, has been proved effective against CA1 cell loss and spatial learning impairments resulting from transient global ischemia/reperfusion (TGCI/R), while the mechanism is still largely unknown. Here, we confirmed that treatment of rats with IMM-H004 immediately after TGCI/R ameliorated delayed neuronal death (DND) in the CA1 of hippocampus and cortex. Further study suggested that IMM-H004 contributed to the expression of antiapoptotic protein survivin through the activation of PI3K dependent protein kinase B (PKB/Akt), which led to the phosphorylation of forkhead box O1 (FoxO1), then relieved the inhibiting effect on survivin promoter. Additionally, IMM-H004 also enhanced the expression of hepatitis B X interacting protein (HBXIP), which formed a complex with survivin to prevent the activation of caspase death cascade, thereby halting apoptotic cell death. Finally, we injected a HBXIP siRNA into hippocampus and performed microelectroporation before ischemia/reperfusion, which abolished the protective effect of IMM-H004. Further study revealed that HBXIP maintained the high expression of Akt and survivin. Collectively, our findings demonstrated that DND after TGCI/R was alleviated by IMM-H004 through promoting the formation of survivin-HBXIP complex, which further emphasized the importance of endogenous protein involved in self-repair after stroke. PMID- 26742529 TI - Brain REST/NRSF Is Not Only a Silent Repressor but Also an Active Protector. AB - During neurogenesis, specific transcription factors are needed to repress neuronal genes in nonneuronal cells to ensure precise development. Repressor element-1 binding transcription factor (REST), or neuron-restrictive silencer factor (NRSF), has been shown to be an important regulator for the establishment of neuronal specificity. It restricts the expression of neuronal genes by binding to the neuron-restrictive silencer element (NRSE/RE1) domain in neuron-specific genes. REST/NRSF regulates many target genes in stem cells, nonneural cells, and neurons, which are involved in neuronal differentiation, axonal growth, vesicular transport, and release as well as ionic conductance. However, it is also regulated by some cytokines/regulators such as epigenetic factors (microRNAs) and even its truncated isoform. REST/NRSF is widely detected in brain regions and has been shown to be highly expressed in nonneuronal cells, but current findings also reveal that, at least in the human brain, it is also highly expressed in neurons and increases with ageing. However, its loss in expression and cytoplasmic translocation seems to play a pivotal role in several human dementias. Additionally, REST/NRSF knockdown leads to malformations in nerve and nonneural tissues and embryonic lethality. Altered REST/NRSF expression has been not only related to deficient brain functions such as neurodegenerative diseases, mental disorders, brain tumors, and neurobehavioral disorders but also highly correlated to brain injuries such as alcoholism and stroke. Encouragingly, several compounds such as valproic acid and X5050 that target REST/NRSF have been shown to be clinically effective at rescuing seizures or Niemann-Pick type C disease. Surprisingly, studies have also shown that REST/NRSF can function as an activator to induce neuronal differentiation. These findings strongly indicate that REST/NRSF is not only a classical repressor to maintain normal neurogenesis, but it is also a fine fundamental protector against neurodegeneration and other disorders and may be a novel potent therapeutic target for neural disturbances. PMID- 26742531 TI - Effects of Aluminium on Rat Brain Mitochondria Bioenergetics: an In vitro and In vivo Study. AB - Numerous studies have highlighted the potential of aluminium as an aetiological factor for some neurodegenerative disorders, particularly Alzheimer's disease and Parkinson's disease. Our previous studies have shown that aluminium can cause oxidative stress, reduce the activity of some antioxidant enzymes, and enhance the dopaminergic neurodegeneration induced by 6-hydroxydopamine in an experimental model of Parkinson's disease in rats. We now report a study on the effects caused by aluminium on mitochondrial bioenergetics following aluminium addition and after its chronic administration to rats. To develop our study, we used a high-resolution respirometry to test the mitochondrial respiratory capacities under the conditions of coupling, uncoupling, and non-coupling. Our study showed alterations in leakiness, a reduction in the maximum capacity of complex II-linked respiratory pathway, a decline in the respiration efficiency, and a decrease in the activities of complexes III and V in both models studied. The observed effects also included both an alteration in mitochondrial transmembrane potential and a decrease in oxidative phosphorylation capacity when relatively high concentrations of aluminium were added to the isolated mitochondria. These findings contribute to explain both the ability of aluminium to generate oxidative stress and its suggested potential to act as an etiological factor by promoting the progression of neurodegenerative disorders such as Parkinson's disease. PMID- 26742532 TI - Effect of body posture on involuntary swallow in healthy volunteers. AB - Clinically, reclining posture has been reported to reduce risk of aspiration. However, during involuntary swallow in reclining posture, changes in orofacial and pharyngeal movement before and during pharyngeal swallow should be considered. Further, the mechanisms underlying the effect of body posture on involuntary swallow remain unclear. The aim of the present study was to determine the effect of body posture on activity patterns of the suprahyoid muscles and on patterns of bolus transport during a natural involuntary swallow. Thirteen healthy male adults participated in a water infusion test and a chewing test. In the water infusion test, thickened water was delivered into the pharynx at a very slow rate until the first involuntary swallow was evoked. In the chewing test, subjects were asked to eat 10 g of gruel rice. In both tests, the recording was performed at four body postures between upright and supine positions. Results showed that reclining changed the location of the bolus head at the start of swallow and prolonged onset latency of the swallowing initiation. Muscle burst duration and whiteout time measured by videoendoscopy significantly increased with body reclining and prolongation of the falling time. In the chewing test, reclining changed the location of the bolus head at the start of swallow, and the frequency of bolus residue after the first swallow increased. Duration and area of EMG burst and whiteout time significantly increased with body reclining. These data suggest that body reclining may result in prolongation of pharyngeal swallow during involuntary swallow. PMID- 26742530 TI - Effect of CR1 Genetic Variants on Cerebrospinal Fluid and Neuroimaging Biomarkers in Healthy, Mild Cognitive Impairment and Alzheimer's Disease Cohorts. AB - The complement component (3b/4b) receptor 1 gene (CR1) is considered as one of the most important genetic susceptibility loci in Alzheimer's disease (AD). However, to date, few studies were performed to discover the possible effect of CR1 genetic variants on AD pathology in the brain. Here, we evaluated the potential role of CR1 common variants in AD-related pathology by assessing neuroimaging biomarkers and cerebrospinal fluid (CSF) proteins. Finally, a total of 812 subjects from the Alzheimer's disease Neuroimaging Initiative database and eight single nucleotide polymorphisms (SNPs) after quality control procedures are enrolled in our analysis. After applied to multiple linear regression models, significant associations were proved to exist between rs4844609 and amyloid deposition in cingulated, frontal, parietal, and temporal on florbetapir 18F amyloid positron emission tomography. In the analysis of the impacts of CR1 genetic variants on brain structures, three SNPs (rs12034383, rs3737002, and rs6691117) were significantly linked to the changes in volume of middle temporal. In addition, rs10779339 showed a negative connection with the cerebral metabolism rate of glucose in the right temporal on 18F-fluorodeoxyglucose PET imaging. However, no significant statistical findings were detected between CR1 genetic variants and CSF proteins (amyloid beta, total-tau, and p-tau) at baseline diagnose or in the follow-up study of 2 years. The results of our study indicated that CR1 plays a vital role in AD pathology mainly by influencing Abeta deposition, brain structure, and glucose metabolism during AD progression. PMID- 26742533 TI - Motor control exercise for chronic non-specific low-back pain. AB - BACKGROUND: Non-specific low back pain (LBP) is a common condition. It is reported to be a major health and socioeconomic problem associated with work absenteeism, disability and high costs for patients and society. Exercise is a modestly effective treatment for chronic LBP. However, current evidence suggests that no single form of exercise is superior to another. Among the most commonly used exercise interventions is motor control exercise (MCE). MCE intervention focuses on the activation of the deep trunk muscles and targets the restoration of control and co-ordination of these muscles, progressing to more complex and functional tasks integrating the activation of deep and global trunk muscles. While there are previous systematic reviews of the effectiveness of MCE, recently published trials justify an updated systematic review. OBJECTIVES: To evaluate the effectiveness of MCE in patients with chronic non-specific LBP. SEARCH METHODS: We conducted electronic searches in CENTRAL, MEDLINE, EMBASE, five other databases and two trials registers from their inception up to April 2015. We also performed citation tracking and searched the reference lists of reviews and eligible trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that examined the effectiveness of MCE in patients with chronic non specific LBP. We included trials comparing MCE with no treatment, another treatment or that added MCE as a supplement to other interventions. Primary outcomes were pain intensity and disability. We considered function, quality of life, return to work or recurrence as secondary outcomes. All outcomes must have been measured with a valid and reliable instrument. DATA COLLECTION AND ANALYSIS: Two independent review authors screened the search results, assessed risk of bias and extracted the data. A third independent review author resolved any disagreement. We assessed risk of bias using the Cochrane Back and Neck (CBN) Review Group expanded 12-item criteria (Furlan 2009). We extracted mean scores, standard deviations and sample sizes from the included trials, and if this information was not provided we calculated or estimated them using methods recommended in the Cochrane Handbook. We also contacted the authors of the trials for any missing or unclear information. We considered the following time points: short-term (less than three months after randomisation); intermediate (at least three months but less than 12 months after randomisation); and long-term (12 months or more after randomisation) follow-up. We assessed heterogeneity by visual inspection of the forest plots, and by calculating the Chi(2) test and the I(2) statistic. We combined results in a meta-analysis expressed as mean difference (MD) and 95% confidence interval (CI). We assessed the overall quality of the evidence using the GRADE approach. MAIN RESULTS: We included 29 trials (n = 2431) in this review. The study sample sizes ranged from 20 to 323 participants. We considered a total of 76.6% of the included trials to have a low risk of bias, representing 86% of all participants. There is low to high quality evidence that MCE is not clinically more effective than other exercises for all follow-up periods and outcomes tested. When compared with minimal intervention, there is low to moderate quality evidence that MCE is effective for improving pain at short, intermediate and long-term follow-up with medium effect sizes (long-term, MD -12.97; 95% CI -18.51 to -7.42). There was also a clinically important difference for the outcomes function and global impression of recovery compared with minimal intervention. There is moderate to high quality evidence that there is no clinically important difference between MCE and manual therapy for all follow-up periods and outcomes tested. Finally, there is very low to low quality evidence that MCE is clinically more effective than exercise and electrophysical agents (EPA) for pain, disability, global impression of recovery and quality of life with medium to large effect sizes (pain at short term, MD 30.18; 95% CI -35.32 to -25.05). Minor or no adverse events were reported in the included trials. AUTHORS' CONCLUSIONS: There is very low to moderate quality evidence that MCE has a clinically important effect compared with a minimal intervention for chronic low back pain. There is very low to low quality evidence that MCE has a clinically important effect compared with exercise plus EPA. There is moderate to high quality evidence that MCE provides similar outcomes to manual therapies and low to moderate quality evidence that it provides similar outcomes to other forms of exercises. Given the evidence that MCE is not superior to other forms of exercise, the choice of exercise for chronic LBP should probably depend on patient or therapist preferences, therapist training, costs and safety. PMID- 26742536 TI - Letter to the Editor: Robustness is the kind of coherence that matters: a comment on Kendler (2015). PMID- 26742534 TI - Preoperative curves of greater magnitude (>70 degrees ) in adolescent idiopathic scoliosis are associated with increased surgical complexity, higher cost of surgical treatment and a delayed return to function. AB - BACKGROUND: Surgical procedures to correct larger curve magnitudes >70 degrees in patients with adolescent idiopathic scoliosis (AIS) are still common; despite their increased complexity, limited research has assessed the effect of preoperative curve severity on outcomes. AIM: This study aimed to examine the impact of preoperative curves >70 degrees vs. those <=70 degrees on perioperative, functional and financial outcomes in patients with AIS undergoing posterior spinal fusion (PSF). METHODS: Seventy seven eligible AIS patients who underwent PSF were prospectively followed-up, until return to preoperative function was reported. Preoperative curves >70 degrees vs. <=70 degrees were analysed in relation to surgical duration, estimated blood loss, perioperative complications, length of hospitalisation, return to function and cost of surgical treatment per patient. RESULTS: Severe preoperative curves >70 degrees , identified in 21 patients (27.3 %), were associated with significantly longer surgical duration (median 6.5 vs. 5 h, p = 0.001) and increased blood loss (median 1250 vs. 1000 ml, p = 0.005)-these patients were 2.1 times more likely to receive a perioperative blood product transfusion (Relative Risk 2.1, CI 1.4-2.7, p = 0.004). Curves >70 degrees were also associated with a significantly delayed return to school/college, and an increased cost of surgical treatment (?33,730 vs. ?28,620, p < 0.0001). CONCLUSION: Surgeons can expect a longer surgical duration, greater intraoperative blood loss and double the blood product transfusion risk when performing PSF procedures on AIS patients with curves greater than 70 degrees vs. those <=70 degrees . Surgical correction for curves >70 degrees , often as a result of lengthy surgical waiting lists, also incurs added expense and results in a partial delay in early functional recovery. PMID- 26742535 TI - Construction of 3 animal experimental models in the development of honeycomb microporous covered stents for the treatment of large wide-necked cerebral aneurysms. AB - The treatment of large or wide-necked cerebral aneurysms is extremely difficult, and carries a high risk of rupture, even when surgical or endovascular methods are available. We are developing novel honeycomb microporous covered stents for treating such aneurysms. In this study, 3 experimental animal models were designed and evaluated quantitatively before preclinical study. The stents were prepared using specially designed balloon-expandable stents (diameter 3.5-5.0 mm, length 16-28 mm) by dip-coating to completely cover their struts with polyurethane film (thickness 20 um) and microprocessing to form the honeycomb pattern after expansion. (1) In an internal carotid artery canine model (n = 4), all stents mounted on the delivery catheter passed smoothly through the tortuous vessel with minimal arterial damage. (2) In an the large, wide-necked, outer sidewall aneurysm canine model, almost all parts of the aneurysms had embolized immediately after stenting (n = 4), and histological examination at 2 months revealed neointimal formation with complete endothelialization at all stented segments and entirely organized aneurysms. (3) In a perforating artery rabbit model, all lumbar arteries remained patent (n = 3), with minimal change in the vascular flow pattern for over 1 year, even after placement of a second, overlapping stent (n = 3). At 2 months after stenting, the luminal surface was covered with complete thin neointimal formation. Excellent embolization performance of the honeycomb microporous covered stents without disturbing branching flow was confirmed at the aneurysms in this proof-of-concept study. PMID- 26742539 TI - Bismuth-Based, Disposable Sensor for the Detection of Hydrogen Sulfide Gas. AB - A new sensor for the detection of hydrogen sulfide (H2S) gas has been developed to replace commercial lead(II) acetate-based test papers. The new sensor is a wet, porous, paper-like substrate coated with Bi(OH)3 or its alkaline derivatives at pH 11. In contrast to the neurotoxic lead(II) acetate, bismuth is used due to its nontoxic properties, as Bi(III) has been a reagent in medications such as Pepto-Bismol. The reaction between H2S gas and the current sensor produces a visible color change from white to yellow/brown, and the sensor responds to >= 30 ppb H2S in a total volume of 1.35 L of gas, a typical volume of human breath. The alkaline, wet coating helps the trapping of acidic H2S gas and its reaction with Bi(III) species, forming colored Bi2S3. The sensor is suitable for testing human bad breath and is at least 2 orders of magnitude more sensitive than a commercial H2S test paper based on Pb(II)(acetate)2. The small volume of 1.35-L H2S is important, as the commercial Pb(II)(acetate)2-based paper requires large volumes of 5 ppm H2S gas. The new sensor reported here is inexpensive, disposable, safe, and user-friendly. A simple, laboratory setup for generating small volumes of ppb ppm of H2S gas is also reported. PMID- 26742538 TI - Predicting Self-Management Behaviors in Familial Hypercholesterolemia Using an Integrated Theoretical Model: the Impact of Beliefs About Illnesses and Beliefs About Behaviors. AB - PURPOSE: Patients with familial hypercholesterolemia (FH) are at markedly increased risk of coronary artery disease. Regular participation in three self management behaviors, physical activity, healthy eating, and adherence to medication, can significantly reduce this risk in FH patients. We aimed to predict intentions to engage in these self-management behaviors in FH patients using a multi-theory, integrated model that makes the distinction between beliefs about illness and beliefs about self-management behaviors. METHODS: Using a cross sectional, correlational design, patients (N = 110) diagnosed with FH from a clinic in Perth, Western Australia, self-completed a questionnaire that measured constructs from three health behavior theories: the common sense model of illness representations (serious consequences, timeline, personal control, treatment control, illness coherence, emotional representations); theory of planned behavior (attitudes, subjective norms, perceived behavioral control); and social cognitive theory (self-efficacy). RESULTS: Structural equation models for each self-management behavior revealed consistent and statistically significant effects of attitudes on intentions across the three behaviors. Subjective norms predicted intentions for health eating only and self-efficacy predicted intentions for physical activity only. There were no effects for the perceived behavioral control and common sense model constructs in any model. CONCLUSIONS: Attitudes feature prominently in determining intentions to engage in self management behaviors in FH patients. The prominence of these attitudinal beliefs about self-management behaviors, as opposed to illness beliefs, suggest that addressing these beliefs may be a priority in the management of FH. PMID- 26742540 TI - Cardiovascular disease-induced thermal responses during passive heat stress: an integrated computational study. AB - The cardiovascular system plays a crucial role in human thermoregulation; cardiovascular diseases may lead to significantly degrading the thermoregulation ability for patients during exposure to heat stress. To evaluate the thermal responses of patients with common chronic cardiovascular diseases, we here propose an integrated computational model by coupling a two-node thermoregulation model with a closed-loop, multi-compartment, lumped-parameter cardiovascular model. This bioheat transfer model is validated, capable to predict cardiovascular functions and thermal responses under varying environmental conditions. Our results demonstrate that the cardiovascular disease-induced reduction in cardiac output and skin blood flow causes extra elevation in core temperature during hyperthermic challenges. In addition, a combination of aging, obesity, and cardiovascular diseases shows a pronounced increase in core temperature during heat exposure, which implies that such combined effect may increase the risk of heat-related morbidity and mortality. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26742541 TI - Electromechanical control of nitrogen-vacancy defect emission using graphene NEMS. AB - Despite recent progress in nano-optomechanics, active control of optical fields at the nanoscale has not been achieved with an on-chip nano-electromechanical system (NEMS) thus far. Here we present a new type of hybrid system, consisting of an on-chip graphene NEMS suspended a few tens of nanometres above nitrogen vacancy centres (NVCs), which are stable single-photon emitters embedded in nanodiamonds. Electromechanical control of the photons emitted by the NVC is provided by electrostatic tuning of the graphene NEMS position, which is transduced to a modulation of NVC emission intensity. The optomechanical coupling between the graphene displacement and the NVC emission is based on near-field dipole-dipole interaction. This class of optomechanical coupling increases strongly for smaller distances, making it suitable for nanoscale devices. These achievements hold promise for selective control of emitter arrays on-chip, optical spectroscopy of individual nano-objects, integrated optomechanical information processing and open new avenues towards quantum optomechanics. PMID- 26742542 TI - Newer antiplatelet agents in acute coronary syndrome. PMID- 26742543 TI - Too many faces for TOO MANY MOUTHS? PMID- 26742544 TI - A comparison of Geriatric Depression Scale scores in older Australian and Japanese women. AB - AIMS: The aim of this study was to compare the prevalence of depressive symptoms in Australian and Japanese populations of community-dwelling older women using the Geriatric Depression Scale (GDS-15). In addition, the relationship between lifestyle and health factors and higher ratings of depressive symptoms was also examined to determine if there were culturally consistent risk factors associated with higher depressive symptom scores. METHODS: A total of 444 community based women aged between 65 and 77 years completed a depressive symptom measure (GDS 15) and provided information on common lifestyle factors. The Australian sample (n = 222) were drawn from the Women's Healthy Ageing Project and the age-matched, Japanese sample from the Kumamoto Ageing Study of Mental Health (n = 222). The GDS was chosen to; (1) reduce the impact of physical symptoms associated with old age and, (2) reduce the inflation in scores that may result from the Japanese tendency to endorse somatic items more often than Western adults. RESULTS: Mean GDS total scores were significantly higher for the Japanese population 3.97 +/- 3.69 compared with 1.73 +/- 2.7 for Australian women. The percentages of women scoring in the normal; mild and moderate ranges for depression were 91, 7 and 2% for Australia and 67, 24 and 9% for Japan. Scores remained significantly higher for the Japanese cohort when controlling for lifestyle and health factors associated with depression. The analysis of lifestyle and health characteristics showed that the greatest difference between cohorts was in the area of living status, with more Australian women living with their partner and more than three times as many Japanese women living with their children. When the data for the countries was considered independently employment status affected the likelihood of higher depression scores in the Australian sample while heart disease and poor sleep impacted the risk for the Japanese population. CONCLUSIONS: Significantly more Japanese women scored within the mild and moderate ranges on the GDS compared with their Australian peers, even when controlling for possible confounding factors. Of the lifestyle and health factors assessed in this analysis no single variable was a common risk factor for higher depressive scores for both countries. The presence of cultural influences that may impact the risk of experiencing depressive symptoms, and culture specific patterns of item endorsement on depressive symptom measures, needs to be explored in more detail. PMID- 26742546 TI - Beyond Sex: Likelihood and Predictors of Effective and Ineffective Intervention in Intimate Partner Violence in Bystanders Perceiving an Emergency. AB - Within the framework of the bystander model of intervention, we examined specific correlates and the likelihood of effective and ineffective intervention strategies of bystanders to an instance of intimate partner violence (IPV) identified as an emergency. We measured psychological variables associated with general prosocial behavior (including sex, instrumentality, expressiveness, empathy, personal distress, dispositional anger, and perceived barriers) as influential predictors in four IPV intervention behaviors (i.e., calling 911, talking to the victim, talking to the perpetrator, and physically interacting with the perpetrator). One hundred seventeen college community members completed preintervention measures, watched a film clip of IPV which they identified as an emergency, reported their likelihood of becoming involved and utilizing intervention behaviors, and identified perceived barriers to intervention. Participants were more likely to indicate using effective over ineffective intervention tactics. Lower perceived barriers to intervention predicted greater intervention likelihood. Hierarchical regression indicated that men and individuals higher in anger and instrumental traits were more likely to report that they would engage in riskier ineffective forms of intervention. Implications regarding bystander training and associations to intervention in related forms of violence including sexual assault are discussed. PMID- 26742545 TI - Charcoal Suspension Tattoo: A New Technique for Intraoperative Detection of Small Tumors of the Parotid Gland. AB - OBJECTIVE: The current surgical trend in the treatment of pleomorphic adenomas of the parotid gland is to limit the extent of resection. This raises the need to correctly identify the mass within the normal parenchyma so as to avoid dissecting the entire superficial lobe of the gland. We describe ultrasound guided tattooing as a technique to facilitate identification and excision of parotid pleomorphic adenomas. METHODS: We reviewed 23 consecutive patients with pleomorphic adenoma of the parotid gland. All patients underwent ultrasound guided tattooing of the lesions with a charcoal suspension. Baseline tumor and patients' characteristics, major and minor complications, and subjective tolerance to the procedure were recorded. We assessed the number of intralesionally marked masses and the percentage of intraoperatively detected marked lesions. RESULTS: The injection was well tolerated. No major complications were recorded. In 2 cases (9%), a transient increase in lesion size was observed. No other minor complications were encountered. Charcoal was found inside the tumor in 19 cases (83%). In 4 cases (17%), it was found in the tissues above the lesion. Twenty-three lesions were intraoperatively detected (100%) and dissected. CONCLUSION: Charcoal suspension tattooing is safe and well tolerated for the detection of small pleomorphic adenomas during parotid surgery. PMID- 26742547 TI - Can remote STI/HIV testing and eClinical Care be compatible with robust public health surveillance? AB - In this paper we outline the current data capture systems for human immunodeficiency virus (HIV) and sexually transmitted infection (STI) surveillance used by Public Health England (PHE), and how these will be affected by the introduction of novel testing platforms and changing patient pathways. We outline the Chlamydia Online Clinical Care Pathway (COCCP), developed as part of the Electronic Self-Testing for Sexually Transmitted Infections (eSTI2) Consortium, which ensures that surveillance data continue to be routinely collected and transmitted to PHE. We conclude that both novel diagnostic testing platforms and established data capture systems must be adaptable to ensure continued robust public health surveillance. PMID- 26742548 TI - Photodynamic treatment with hexyl-aminolevulinate mediates reversible thiol oxidation in core oxidative stress signaling proteins. AB - Photodynamic therapy (PDT) is a highly selective two-step cancer treatment involving a photosensitizer and illumination with visible light in the presence of molecular oxygen. PDT is clinically approved worldwide for treating several premalignant conditions and cancer forms, especially endoscopically accessible tumors and dermatological malignancies. PDT-mediated cytotoxicity takes place via autophagy, apoptosis and necrosis, but the exact trigger mechanisms for various death-pathways are still unknown. PDT induces reactive oxygen species (ROS) through photochemical reactions. ROS can react with different macromolecules resulting in cellular damage, including oxidation of proteins. One of the known protein modifications is reversible oxidation of cysteine thiols (-SH), which in many cases constitute a redox switch to modulate protein activity and cellular signaling. Here we have examined the role of reversible oxidation of protein thiols as a potential mediator of cytotoxicity after hexylaminolevulinate mediated photodynamic treatment (HAL-PDT) in the human epidermoid carcinoma cell line A431. Nearly 2300 proteins were found to be reversibly oxidized after HAL PDT, of which 374 high-confidence proteins were further allocated to cellular compartments and functional networks. 115 of the high confidence proteins were associated with apoptosis and 257 have previously not been reported to be reversibly oxidized on cysteines. We find an enrichment of DNA damage checkpoint and oxidative stress response proteins. Many of these constitute potential signaling hubs in apoptosis, including ATM, p63, RSK1 p38, APE1/Ref-1 and three 14-3-3 family members. Our study represents the first comprehensive mapping of reversibly oxidized proteins subsequent to HAL-PDT. Several of the proteins constitute potentially novel redox-regulated apoptotic triggers as well as potential targets for adjuvants that may improve the efficacy of HAL-PDT and PDT using other photosensitizers. PMID- 26742550 TI - [Fight against neglected parasitic tropical diseases gets the Nobel prize]. PMID- 26742549 TI - Substituted indoles as HIV-1 non-nucleoside reverse transcriptase inhibitors: a patent evaluation (WO2015044928). AB - The invention described in this patent (WO2015044928) is related to compounds based on the substituted indole scaffold, their synthetic process and application to inhibit HIV-1 replication as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Some of the newly claimed compounds presented improved potency against wild-type (WT) HIV-1 strain in comparison to previously disclosed indole-based NNRTIs and were also shown to be effective against common resistant HIV-1 strains. In light of their novel structural characteristics, simple synthetic route and improved anti-HIV activity, these compounds deserve further study as promising NNRTIs. PMID- 26742551 TI - [Blood transfusion in the Democratic Republic of Congo: efforts and challenges]. AB - The authors trace the history of blood transfusion in the Democratic Republic of Congo, as inherited through the colonial organization of the health system. The current configuration of transfusion system begins with the drafting of the national blood transfusion policy and the establishment of a national technical office within the Ministry of Health to coordinate transfusion activities and of its agents in each province. Despite countless difficulties, several positive points were noted. These involve essentially the drafting of all the necessary documents and standards and the integration of the blood safety system into the country's health system. Initially, the blood transfusion system applied a vertical approach, but with the reform of the country's health system, the performance of blood safety became transversal. In the 12 years from 2001 to 2012, it mobilized 112,882 volunteer blood donors; more than 80% of blood products were checked for safety and covered all blood needs; and 81,806 HIV infections were avoided by routine testing of blood products. During the same period, 7560 people were trained in blood transfusion. The prevalence of viral markers among donors has diminished sharply. Thus, HIV prevalence decreased from 4.7% to 2.1% between 2001 and 2012 that of hepatitis B dropped from 7.1% to 3.5% during the same period, and hepatitis C from 11.8% to 2.3% from 2004 to 2012. Despite this performance, enormous efforts are still required, for the organization of blood safety monitoring, the establishment of a safe supply of reagents and supplies, for sustaining the dynamics of voluntary associations of blood donors, and finally for providing stable funding for these blood safety activities. PMID- 26742552 TI - [A French soldier returns from the Central Africa Republic with hepatitis A: Vaccination failure is possible!]. AB - In stays in tropical countries, the French military, and travelers in general, are exposed to diseases transmitted by the fecal-oral route, some of which are vaccine-preventable. Here we report a 42-yer-old soldier with hepatitis A, which first appeared on his return from a military operation in the Central African Republic. Despite its excellent immunogenicity and a duration of seroprotection extending beyond 20 years in the vast majority of cases, the hepatitis A vaccine can fail. This reminds us of the importance of combining vaccine and non-vaccine prevention in tropical countries, especially in precarious living conditions. PMID- 26742553 TI - [Assessment of treatment adherence among black Africans with heart failure]. AB - STUDY AIM: to analyze patient-related factors that may influence adherence in patients with heart failure in an African cardiology department. METHODOLOGY: This prospective observational study took place in the in-patient department of the Abidjan cardiology institute and enrolled consecutive patients hospitalized for decompensated heart failure from January to November 2014. The inclusion criteria were chronic heart failure in patients older than 18 years, developing for at least 6 months and treated by medication. The revised heart failure compliance questionnaire was used. RESULTS: The study included 121 patients. Overall adherence was poor in 88.4% of patients. Multiple linear regression analyses showed that use of traditional medicine was associated with poor adherence for the following 3 components: keeping follow-up appointments, medication intake, and sodium limitations. Overall adherence increased with the number of hospitalizations (OR = 1.69, 95% CI 1.13-2.53; p = 0.01). This increase persisted after adjustment for age, sex, educational level, marital status, medical insurance coverage and the use of alternative medicines (traditional and Chinese) (OR = 1.70; CI 1.12-2.28; p = 0.01). CONCLUSION: Adherence among black Africans with heart failure remains poor, influenced too much by traditional medicine. Therapeutic education is essential to improve patients' knowledge about their disease and its treatment. PMID- 26742554 TI - [Cost of hospitalization by the Activity Based Costing method in the neonatal department of Principal Hospital of Dakar]. AB - OBJECTIVES: To determine the cost of hospitalization per day in the neonatal department of Principal Hospital of Dakar. METHODOLOGY: This prospective study took place during the month of July 2011 in the newborn unit. The activity-based costing method was used to analyze costs. RESULTS: During the study period, 52 newborns were hospitalized for a total of 590 days. The cost of the human resources during that month was 9,907,832 FCFA (US $ 19,815.66), the cost of depreciation of fixed assets was estimated at 571,952 FCFA (US $ 1143.90), and supplies at 112,084 FCFA (US $ 224.17). External services cost 386,753 FCFA (US $ 773.51) and support services 6,917,380.65 FCFA (US $ 13,834.7613). The monthly expenses incurred for the hospitalization of newborns totaled 17,896,002 FCFA (US $ 35,792), for a cost per patient per day of 30,332.20 FCFA (US $ 60.66) and an average cost of hospitalization 334,153.88 FCFA (US $ 668,31). CONCLUSION: This study is the first of its kind in Senegal and neighboring countries. By applying the ABC approach, we can obtain a more detailed and precise estimate of the cost of activities and services. Process improvements and corrective actions should make it possible to identify cost drivers, such as time. PMID- 26742555 TI - [Vaginal cesarean delivery in modern obstetric practice]. AB - OBJECTIVE: To report the experience of our unit with vaginal cesarean deliveries. PATIENTS AND METHODS: This is a retrospective, descriptive study of seven vaginal cesarean deliveries performed in the maternity unit of the Centre Hospitalier Regional Universitaire de Saint-Louis in Senegal during the third quarter of 2012. The women's clinical characteristics were studied and indications for cesarean sections discussed. RESULTS: The seven vaginal cesareans accounted for 3.2% of the cesarean deliveries performed during the study period (219) and 0.6% of all births (1428). The women's average age was 31 years. Gestational age ranged from 17 to 34 weeks of gestation. The principal indication for surgery was placental abruption, in 5 (72%) cases). The fetus was dead in 4 of the 7 cases. The mean 5-min Apgar score at birth for the liveborn infants was 5 (of an optimum score of 10). Mean fetal weight at birth was 1700 g. The mean operative time was 20.7 minutes. In one case, the incision extended to the uterine corpus. The postoperative course was uneventful in all cases. CONCLUSION: Vaginal cesarean is safe, fast, but not without complications. It requires perfect mastery of vaginal surgery. PMID- 26742556 TI - [Neonatal prognosis for pulsating umbilical cord prolapse at the Befelatanana hospital of Madagascar]. AB - Umbilical cord prolapse is an obstetrical emergency that is life-threatening for the fetus. This retrospective cross-sectional study examined cases of pulsating umbilical cord prolapses at our level-3 maternity unit over the past three years and sought to assess their prognosis. Cord prolapse occurred in 0.27% of deliveries. The women's mean age was 28 years, and 51% of the women were multiparous. Cesarean deliveries were performed in 96% of cases. Factors affecting neonatal outcome were the degree of cord prolapse (p = 0.0002981) and the appearance of amniotic fluid (p = 0.004078). The neonatal complications included admission to neonatal intensive care (33%), perinatal asphyxia (31%), prematurity (29%), neonatal infection (4%), and neonatal mortality (10%). CONCLUSION: The fetus must be delivered rapidly, especially when the umbilical cord drops outside the mother's body and the amniotic fluid is meconial. PMID- 26742557 TI - [Acute cholangitis secondary to ascariasis and complicated by liver abscesses]. AB - Acute cholangitis secondary to ascariasis is rare and occurs mainly in areas of high endemicity. The clinical presentation is non-specific, sometimes complicated by liver abscess. Abdominal ultrasound plays an important role in diagnosis and therapeutic surveillance. We report the case of a 35-year-old Malagasy woman with an acute cholangitis secondary to ascariasis and complicated by liver abscesses and its course to full recovery under medical treatment. PMID- 26742558 TI - [Kikuchi-Fujimoto disease: a rare cause of adenopathy mimicking lymphoma or tuberculosis]. AB - Kikuchi-Fujimoto disease or histiocytic necrotizing lymphadenitis is a rare and unfamiliar clinicopathological entity characterized by cervical lymphadenopathy, often associated with systemic signs such fever and night sweats. We report the first three Malagasy cases of Kikuchi-Fujimoto disease, diagnosed at the Pathology Lab of Joseph Ravoahangy Andrianavalona Hospital, occurring in three female patients of 11, 19 and 35 years old. The clinical course mimicked lymphoma in one case and tuberculosis in two cases. In all cases, lymph node biopsy allowed the diagnosis and showed necrotizing lymphadenitis with acidophil necrosis, histiocyte infiltrate, presence of plasmacytoid monocytes and multiple apoptotic cells. The three patients received a low-dose corticosteroid treatment. Clinical remission was achieved within a few weeks. This disorder must be included in the differential diagnosis of "lymph node enlargement" because its course and treatment differ dramatically from those of lymphoma and tuberculosis. PMID- 26742559 TI - [HIV infection and mortality in the dermatology department in Lome, Togo]. AB - OBJECTIVE: The aim of this study was to document the causes of death in the dermatology department in Lome' and the role of HIV infection in those deaths. PATIENTS AND METHOD: This retrospective study examined the records of all patients admitted to this department from 1992 through 2012. RESULTS: During the study period, 52 (13.5%) of the 386 patients hospitalized in the Sylvanus Olympio University Hospital dermatology department died in the hospital. Their mean age was 37.7 +/- 12.8 years (range: 18 to 68 years) and half (26 patients/52) were female. Kaposi's sarcoma (54.1%) was the most lethal skin disease, followed by cutaneous drug reactions (12.5%) and herpes zoster virus infection (11.1%). Of the 52 patients who died, HIV serology was positive in 28 of the 33 (84.8%) patients tested. The most lethal diseases, including Kaposi's sarcoma, Stevens Johnson syndrome (toxic epidermic necrolysis), and chicken pox/shingles skin diseases were those in which HIV seroprevalence was highest. CONCLUSION: This study shows that HIV infection plays an important role in mortality in the dermatology department at Lome', probably through the immunosuppression it induces. PMID- 26742560 TI - Pseudomonas aeruginosa biofilm disruption using microbial surfactants. AB - AIMS: To establish the ability of the rhamnolipids biosurfactants from Pseudomonas aeruginosa, in the presence and absence of caprylic acid and ascorbic acid, to disrupt bacterial biofilms, compared with the anionic alkyl sulphate surfactant Sodium dodecyl sulphate (SDS). METHODS AND RESULTS: Pseudomonas aeruginosa ATCC 15442 biofilms were disrupted by rhamnolipids at concentrations between 0.5 and 0.4 g l(-1) and with SDS at 0.8 g l(-1) . The combination of rhamnolipids 0.4 g l(-1) and caprylic acid at 0.1 g l(-1) showed a remarkable effect on biofilm disruption and cell killing. After 30 min of treatment most of the biofilm was disrupted and cell viability was significantly reduced. Neither caprylic acid nor ascorbic acid has any effect on biofilm disruption at 0.1 g l( 1) . SDS is an effective antimicrobial agent; however, in the presence of caprylic acid its effect was neutralized. CONCLUSIONS: The results show that rhamnolipids at low concentration in the presence of caprylic acid are promising molecules for inhibition/disruption of biofilms formed by Ps. aeruginosa ATCC 15442. SIGNIFICANCE AND IMPACT OF THE STUDY: The disruption of biofilms has major significance in many industrial and domestic cleaning applications and in medical situations. PMID- 26742561 TI - The role of hydrogen during Pt-Ga nanocatalyst formation. AB - Hydrogen plays an essential role during the in situ assembly of tailored catalytic materials, and serves as key ingredient in multifarious chemical reactions promoted by these catalysts. Despite intensive debate for several decades, the existence and nature of hydrogen-involved mechanisms - such as hydrogen-spillover, surface migration - have not been unambiguously proven and elucidated up to date. Here, Pt-Ga alloy formation is used as a probe reaction to study the behavior and atomic transport of H and Ga, starting from Pt nanoparticles on hydrotalcite-derived Mg(Ga)(Al)Ox supports. In situ XANES spectroscopy, time-resolved TAP kinetic experiments, HAADF-STEM imaging and EDX mapping are combined to probe Pt, Ga and H in a series of H2 reduction experiments up to 650 degrees C. Mg(Ga)(Al)Ox by itself dissociates hydrogen, but these dissociated hydrogen species do not induce significant reduction of Ga(3+) cations in the support. Only in the presence of Pt, partial reduction of Ga(3+) into Ga(delta+) is observed, suggesting that different reaction mechanisms dominate for Pt- and Mg(Ga)(Al)Ox-dissociated hydrogen species. This partial reduction of Ga(3+) is made possible by Pt-dissociated H species which spillover onto non-reducible Mg(Al)Ox or partially reducible Mg(Ga)(Al)Ox and undergo long range transport over the support surface. Moderately mobile Ga(delta+)Ox migrates towards Pt clusters, where Ga(delta+) is only fully reduced to Ga(0) on condition of immediate stabilization inside Pt-Ga alloyed nanoparticles. PMID- 26742563 TI - Homocysteine serum levels are increased and correlate with disease severity in patients with lupus erythematosus. AB - OBJECTIVES: To determine homocysteine (Hcy) serum levels in patients with cutaneous lupus erythematosus (CLE) and a possible correlation with the disease activity. METHODS: Ninety-three patients with LE and 30 healthy controls were included in the study. For each patient, disease activity was calculated and plasma levels of Hcy was measured by enzymatic colorimetric assay. RESULTS: Forty six patients had chronic cutaneous LE (CCLE), 14 had LE tumidus (LET), 17 had subacute CLE (SCLE) and 16 had SLE. Median values [25 degrees -75 degrees percentile] were 7[4-9] for CCLE, 3.5[2.3-4.8] for LET, and 8[7-10] for SCLE; for SLE the RCLASI score was 7.5[4.8-13] and the SELENA/SLEDAI score was 10.5[9 13.3]. HHcy was present in 73.9% of patients with CCLE, 35.7% with LET, 82.4% with SCLE, 81.2% with SLE, 20% of healthy controls. Overall, patients with LE showed a higher median serum Hcy level than the control group (15[13-18.2] vs. 11[8.8-12.2], p<0.001). There was a significant correlation between Hcy serum levels and disease activity, both in patients with CLE and SLE. CONCLUSIONS: We demonstrated that Hcy levels were higher in patients with different forms of CLE and correlated with disease activity calculated by CLASI. Therefore, HHcy could be related to LE pathogenesis and might be a triggering factor in predisposed individuals. PMID- 26742562 TI - PKN3 is the major regulator of angiogenesis and tumor metastasis in mice. AB - PKN, a conserved family member related to PKC, was the first protein kinase identified as a target of the small GTPase Rho. PKN is involved in various functions including cytoskeletal arrangement and cell adhesion. Furthermore, the enrichment of PKN3 mRNA in some cancer cell lines as well as its requirement in malignant prostate cell growth suggested its involvement in oncogenesis. Despite intensive research efforts, physiological as well as pathological roles of PKN3 in vivo remain elusive. Here, we generated mice with a targeted deletion of PKN3. The PKN3 knockout (KO) mice are viable and develop normally. However, the absence of PKN3 had an impact on angiogenesis as evidenced by marked suppressions of micro-vessel sprouting in ex vivo aortic ring assay and in vivo corneal pocket assay. Furthermore, the PKN3 KO mice exhibited an impaired lung metastasis of melanoma cells when administered from the tail vein. Importantly, PKN3 knock-down by small interfering RNA (siRNA) induced a glycosylation defect of cell-surface glycoproteins, including ICAM-1, integrin beta1 and integrin alpha5 in HUVECs. Our data provide the first in vivo genetic demonstration that PKN3 plays critical roles in angiogenesis and tumor metastasis, and that defective maturation of cell surface glycoproteins might underlie these phenotypes. PMID- 26742565 TI - Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty. AB - AIM: We previously reported that biallelic mutations in dual oxidase 2 (DUOX2) cause transient hypothyroidism. Since then, many cases with DUOX2 mutations have been reported. However, the clinical features and prognosis of individuals with DUOX2 defects have not been clarified. OBJECTIVE: We investigated the prognosis of patients with congenital hypothyroidism (CH) due to DUOX2 mutations. PATIENTS: Twenty-five patients were identified by a neonatal screening program and included seven familial cases. Their serum TSH values ranged from 18.9 to 734.6 mU/l. Twenty-two of the patients had low serum free thyroxine (fT4) levels (0.17-1.1 ng/dl). Twenty-four of the patients were treated with L-thyroxine. METHODS: We analyzed the DUOX2, thyroid peroxidase, Na(+)/I(-) symporter, and dual oxidase maturation factor 2 genes of these 25 patients by PCR-amplified direct sequencing. An additional 11 genes were analyzed in 11 of the 25 patients using next-generation sequencing. RESULTS: All patients had biallelic DUOX2 mutations, and seven novel alleles were detected. Fourteen of the patients were able to discontinue replacement therapy, and seven were receiving reduced L-thyroxine doses. Normalization of thyroglobulin lagged several years behind the completion of treatment. Two patients showed permanent hypothyroidism. Except for one case of a learning disability, growth and psychomotor development were normal. CONCLUSION: The prognosis of Japanese patients with DUOX2 defects was usually transient CH. Delayed improvement of thyroglobulin indicates that these patients have subclinical hypothyroidism. Hypothyroidism did not recur in patients during the study period (up to 18 years old). PMID- 26742564 TI - Thrombin stimulates insulin secretion via protease-activated receptor-3. AB - The disease mechanisms underlying type 2 diabetes (T2D) remain poorly defined. Here we aimed to explore the pathophysiology of T2D by analyzing gene co expression networks in human islets. Using partial correlation networks we identified a group of co-expressed genes ('module') including F2RL2 that was associated with glycated hemoglobin. F2Rl2 is a G-protein-coupled receptor (GPCR) that encodes protease-activated receptor-3 (PAR3). PAR3 is cleaved by thrombin, which exposes a 6-amino acid sequence that acts as a 'tethered ligand' to regulate cellular signaling. We have characterized the effect of PAR3 activation on insulin secretion by static insulin secretion measurements, capacitance measurements, studies of diabetic animal models and patient samples. We demonstrate that thrombin stimulates insulin secretion, an effect that was prevented by an antibody that blocks the thrombin cleavage site of PAR3. Treatment with a peptide corresponding to the PAR3 tethered ligand stimulated islet insulin secretion and single beta-cell exocytosis by a mechanism that involves activation of phospholipase C and Ca(2+) release from intracellular stores. Moreover, we observed that the expression of tissue factor, which regulates thrombin generation, was increased in human islets from T2D donors and associated with enhanced beta-cell exocytosis. Finally, we demonstrate that thrombin generation potential in patients with T2D was associated with increased fasting insulin and insulinogenic index. The findings provide a previously unrecognized link between hypercoagulability and hyperinsulinemia and suggest that reducing thrombin activity or blocking PAR3 cleavage could potentially counteract the exaggerated insulin secretion that drives insulin resistance and beta-cell exhaustion in T2D. PMID- 26742567 TI - Resveratrol can prevent CCl4-induced liver injury by inhibiting Notch signaling pathway. AB - We investigated whether Notch signaling was increased in an experimental liver fibrosis model and examined the effects of resveratrol on Notch expression. Rats were divided into four groups: the control group, injected with physiological saline; the CCl4 group; the CCl4 plus resveratrol group; and the resveratrol group. After treatment, immunostaining was performed to detect Notch1, Notch3, Notch4, transforming growth factor (TGF)-beta, alpha-smooth muscle actin (SMA), glial fibrillary acidic protein (GFAP), and proliferating cell nuclear antigen (PCNA), and TUNEL assays were performed to evaluate apoptosis. Sirius red staining was used to detect fibrosis. Samples were also biochemically evaluated for glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT), lipid peroxidation, and protein oxidation. GSH, GPx, and catalase activities were significantly decreased (p?0.001) in the CCl4 group. Distinct collagen accumulation was detected around the central vein and portal areas, and numbers of Notch1-, Notch3-, and Notch4-positive cells were significantly increased (p?0.001) in fibrotic areas in the CCl4 group. Increased expression of Notch proteins in fibrotic areas may support the role of Notch in mediating signaling associated with liver fibrosis through activation of hepatic stellate and progenitor cells. In contrast, resveratrol prevented liver fibrosis by decreasing lipid peroxidation and may be effective for inhibiting Notch signaling. PMID- 26742568 TI - Pulmonary air embolism. PMID- 26742569 TI - Sister Mary Joseph nodule. PMID- 26742566 TI - Reinforcement of the Brain's Rich-Club Architecture Following Early Neurodevelopmental Disruption Caused by Very Preterm Birth. AB - The second half of pregnancy is a crucial period for the development of structural brain connectivity, and an abrupt interruption of the typical processes of development during this phase caused by the very preterm birth (<33 weeks of gestation) is likely to result in long-lasting consequences. We used structural and diffusion imaging data to reconstruct the brain structural connectome in very preterm-born adults. We assessed its rich-club organization and modularity as 2 characteristics reflecting the capacity to support global and local information exchange, respectively. Our results suggest that the establishment of global connectivity patterns is prioritized over peripheral connectivity following early neurodevelopmental disruption. The very preterm brain exhibited a stronger rich-club architecture than the control brain, despite possessing a relative paucity of white matter resources. Using a simulated lesion approach, we also investigated whether putative structural reorganization takes place in the very preterm brain in order to compensate for its anatomical constraints. We found that connections between the basal ganglia and (pre-) motor regions, as well as connections between subcortical regions, assumed an altered role in the structural connectivity of the very preterm brain, and that such alterations had functional implications for information flow, rule learning, and verbal IQ. PMID- 26742570 TI - Self-energy behavior away from the Fermi surface in doped Mott insulators. AB - We analyze self-energies of electrons away from the Fermi surface in doped Mott insulators using the dynamical cluster approximation to the Hubbard model. For large onsite repulsion, U, and hole doping, the magnitude of the self-energy for imaginary frequencies at the top of the band ([Formula: see text]) is enhanced with respect to the self-energy magnitude at the bottom of the band ([Formula: see text]). The self-energy behavior at these two [Formula: see text]-points is switched for electron doping. Although the hybridization is much larger for (0, 0) than for [Formula: see text], we demonstrate that this is not the origin of this difference. Isolated clusters under a downward shift of the chemical potential, [Formula: see text], at half-filling reproduce the overall self-energy behavior at (0, 0) and [Formula: see text] found in low hole doped embedded clusters. This happens although there is no change in the electronic structure of the isolated clusters. Our analysis shows that a downward shift of the chemical potential which weakly hole dopes the Mott insulator can lead to a large enhancement of the [Formula: see text] self-energy for imaginary frequencies which is not associated with electronic correlation effects, even in embedded clusters. Interpretations of the strength of electronic correlations based on self-energies for imaginary frequencies are, in general, misleading for states away from the Fermi surface. PMID- 26742571 TI - Expression of cytomegalovirus in glioblastoma multiforme: Myth or reality? AB - A role for human cytomegalovirus (HCMV) in the pathogenesis of glioblastoma multiforme (GBM) was proposed more than a decade ago and has since generated a considerable debate as a possible therapeutic target. We investigate the presence of HCMV in the specimens of patients with GBM treated in our centre. This is a retrospective cohort study to investigate the presence of HCMV by routine immunohistochemical stains and polymerase chain reaction (PCR)-based molecular analysis on formalin-fixed-paraffin-embedded tissue of all patients with GBM treated in our hospital in 2009-2013 (5 years). The evaluation of positivity by immunohistochemistry (IHC) was semi-quantitative. The molecular analysis was performed by extracting the tumour DNA from representative paraffin-embedded tissue blocks and amplified for detection by a sensitive real time PCR (RT-PCR) CMV assay. During the study period, we treated 45 patients with GBM; however, adequate pathology tissue materials were available only for 32 patients. All the pathology material was reviewed and the diagnosis was confirmed. All the cases were found to be negative for CMV expression by our IHC and RT-PCR CMV assay. Our study has shown no expression of CMV in GBM. Our results were similar to other recent reports that concluded insufficient evidence to recommend routine testing for CMV in GBM or treatment as an add-on therapy. PMID- 26742572 TI - Rituximab Therapy and Infection Risk in Pediatric Renal Transplant Patients. AB - OBJECTIVES: Rituximab is a monoclonal antibody directed against the CD20 molecule on pre-B and mature B cells and is used in transplant recipients for the prevention and treatment of alloantibody-mediated rejection or for the treatment of disease recurrence after transplant. In most patients, rituximab has been safe and well-tolerated, but the long-term adverse effects of rituximab are currently unknown. MATERIALS AND METHODS: We retrospectively evaluated 78 pediatric renal transplant recipients for the occurrence of infectious disease. Patients who received rituximab therapy were divided into 2 groups: those who developed an infection and those who did not. The 2 groups were compared for serious infections, hospitalization, graft loss, and death rates. RESULTS: Eighteen transplant patients received rituximab therapy for various causes. The number of rituximab courses given varied according to the cause and ranged from 1 to 8 courses. The dose at each course was 375 mg/m(2). Median age of all recipients was 16.00 years (min-max:, 5.00-22.00 y), and median follow-up time was 2.00 years (min-max:, 1.00-3.00 y). Serious infections (bacterial sepsis, tuberculosis, Cytomegalovirus infection, varicella-zoster virus infection, Polyomavirus-associated nephropathy, and acute pyelonephritis) were observed in 8 patients who received rituximab therapy. We observed that patients with antibody mediated rejection had significantly increased infection rate. Patients who had used rituximab combined with antithymocyte globulin and higher rituximab course number and higher pretreatment CD19 and CD20 levels had higher risk of infection (P < .05). CONCLUSIONS: The combined use of rituximab with additional treatments such as antithymocyte globulin, intravenous immunoglobulin, and repeated plasma exchange may be associated with high risk of infectious disease. Especially for those patients who required intensive and repetitive treatment, such as antibody mediated rejection, rituximab treatment should be used with caution. Infection risk should be closely monitored, although mainly in patients who receive T-cell depleting agents. PMID- 26742573 TI - Predicting success of labor induction in singleton term pregnancies by combining maternal and ultrasound variables. AB - OBJECTIVE: To assess pre-induction maternal and ultrasonographic factors in the prediction of the onset of labor within 12 h, and vaginal delivery (VD) irrespective of the induction-to-delivery interval in term pregnancies. METHODS: We performed a prospective cohort study with 204 singleton pregnant women between 37 and 42 weeks of gestation. The following maternal and ultrasonographic variables were assessed: parity, marital status, height, body mass index (BMI), previous cesarean section (Cs), Bishop score, variety of fetal position, single deepest pocket (SDP), fetal middle cerebral and umbilical artery resistance indices, cervical length (CL) measurement, posterior cervical angle (PCA), head circumference (HC) and estimated fetal weight (EFW). chi(2) test and logistic regression analysis were applied to compare the groups. Receiver operating characteristics (ROC) curves were determined. RESULTS: VD occurred in 116 (56.9%) women. Prediction of the onset of labor within 12 h was provided by the BMI and resistance index of the fetal middle cerebral artery. Prediction of the VD irrespective of the induction-to-delivery interval was provided by height, BMI, parity, number of prenatal visits, consistency, effacement and dilation of uterine cervix, PCA, oligohydramnios, HC and EFW. Area under ROC curve for PCA and EFW were 63.5 (sensibility: 66.4%, specificity: 59.1%) and 60.2 (sensibility: 54.3%, specificity: 70.4%), respectively. CONCLUSIONS: Several pre-induction maternal and ultrasonographic factors can increase the chance of achieving a successful VD. PCA and EFW were the best ultrasonographic predictors for the success of induction of labor; however, with limited potential to be used in the clinical practice. PMID- 26742574 TI - Corrigendum: Artemisinin-resistant Plasmodium falciparum clinical isolates can infect diverse mosquito vectors of Southeast Asia and Africa. PMID- 26742576 TI - Sulfur Nanogranular Film-Coated Three-Dimensional Graphene Sponge-Based High Power Lithium Sulfur Battery. AB - To meet the requirements of both high energy and power density with cycle durability of modern EVs, we prepared a novel nanosulfur granular assembled film coated on the three-dimensional graphene sponge (3D-GS) composite as a high performance active material for rechargeable lithium sulfur batteries. Instead of conventional graphene powder, three-dimensional rGO sponge (3D-rGO) is employed for the composite synthesis, resulting in a sulfur film directly in contact with the underlying graphene layer. This significantly improves the overall electrical conductivity, strategically addressing challenges of conventional composites of low sulfur utilization and dissolution of polysulfides. Additionally, the synthesis mechanism of 3D-GS is elucidated by XPS and DFT analyses, where replacement of hydroxyl group of 3D-rGO sponge by sulfur (S8) is found to be thermodynamically favorable. As expected, 3D-GS demonstrates outstanding discharge capacity of 1080 mAh g(-1) at a 0.1C rate, and 86.2% capacity retention even after 500 cycles at a 1.0C rate. PMID- 26742575 TI - Macroevolution of hyperdiverse flightless beetles reflects the complex geological history of the Sunda Arc. AB - The Sunda Arc forms an almost continuous chain of islands and thus a potential dispersal corridor between mainland Southeast Asia and Melanesia. However, the Sunda Islands have rather different geological histories, which might have had an important impact on actual dispersal routes and community assembly. Here, we reveal the biogeographical history of hyperdiverse and flightless Trigonopterus weevils. Different approaches to ancestral area reconstruction suggest a complex east to west range expansion. Out of New Guinea, Trigonopterus repeatedly reached the Moluccas and Sulawesi transgressing Lydekker's Line. Sulawesi repeatedly acted as colonization hub for different segments of the Sunda Arc. West Java, East Java and Bali are recognized as distinct biogeographic areas. The timing and diversification of species largely coincides with the geological chronology of island emergence. Colonization was not inhibited by traditional biogeographical boundaries such as Wallace's Line. Rather, colonization patterns support distance dependent dispersal and island age limiting dispersal. PMID- 26742577 TI - Efficacy and safety of dulaglutide in patients with type 2 diabetes: a meta analysis and systematic review. AB - A meta-analysis was conducted to assess the clinical efficacy and safety of dulaglutide in patients with type 2 diabetes mellitus (T2DM). Medline, Embase, Cochrane Library and www. clinicaltrials. gov (up to February 15(th), 2015) were searched. Randomized controlled trials comparing dulaglutide to other drugs for T2DM were collected. Twelve RCTs were included, and the overall bias was low. As the monotherapy, compared with control (placebo, metformin and liraglutide), dulaglutide resulted in a significant reduction in HbA1c (WMD, -0.68%; 95% CI, 0.95 to -0.40), FPG (WMD, -0.90 mmol/L; 95% CI, -1.28 to -0.52), a similar risk of hypoglycemia (7.8% vs. 10.6%), less body weight loss (WMD, 0.51 kg; 95% CI, 0.27 to 0.75). As an add-on intervention with oral antihyperglycemic medication (OAM) and insulin, compared with control (placebo, sitagliptin, exenatide, liraglutide and glargine), dulaglutide lowered HbA1c (WMD, -0.51%; 95% CI, -0.68 to -0.35) and body weight significantly (WMD, -1.30 kg, 95% CI, -1.85 to -1.02) notably, and elicited a similar reduction in FPG (WMD, -0.19 mmol/L; 95% CI, 1.20 to 0.82), an similar incidence of hypoglycemia (24.5% vs. 24.5%). This meta analysis revealed the use of dulaglutide as a monotherapy or an add-on to OAM and lispro appeared to be effective and safe for adults with T2DM. PMID- 26742579 TI - Inhibition of human telomerase reverse transcriptase in vivo and in vitro for retroviral vector-based antisense oligonucleotide therapy in ovarian cancer. AB - Human telomerase is absent in most normal tissues, but is abnormally activated in all major cancer cells. Telomerase enables tumor cells to maintain telomere length, allowing indefinite replicative capacity. Albeit not sufficient in itself to induce neoplasia, telomerase is believed to be necessary for cancer cells to grow without limit. Studies using an antisense oligonucleotide (ASODN) to the RNA component of telomerase or human telomerase reverse transcriptase (hTERT) demonstrate that telomerase in human tumor lines can be blocked in vivo. Inhibition of hTERT led to telomere shortening and cancer cell death, validating telomerase as a target for anticancer genetic therapy. Varieties of approaches for hTERT inhibition have been investigated. The aim of this study was to analyze the biological activity of ASODN to the hTERT mediated by retrovirus vector, which was used as therapy for ovarian tumor. We constructed and characterized a recombinant retrovirus vector with full-length hTERT antisense complementary DNA. The vector was introduced into ES-2 by lipofectamine-mediated gene transfection. The cellular proliferation and telomerase activity of the transformant cells were retarded. The hTERT gene expression and the telomerase activity of the transformant cells were both decreased. The transformant cells show partial reversion of the malignant phenotype. PT67 cells were also transfected with the recombinant vector and virus-producer cells were generated. The retrovirus containing supernatant effectively inhibited the growth of human ovarian tumor xenografts in mouse models (subcutaneous tumor model), and enhanced the mouse survival time. PMID- 26742578 TI - IL-15/sIL-15Ralpha gene transfer suppresses Lewis lung cancer growth in the lungs, liver and kidneys. AB - Nearly 40% of people with lung cancer have tumor growth in other organs at the time of diagnosis. Current treatment strategies for patients with late-stage lung cancer are primarily palliative and only showed modest efficacy. The current study takes advantage of the hydrodynamic gene delivery technique to evaluate the antitumor activity of interleukin (IL)-15/sIL-15Ralpha on lung tumors growing in the lungs, liver and kidneys. We demonstrate that hydrodynamic tail vein injection of 2 MUg of AG209 DP muIL-15sRalpha+IL-15 plasmid resulted in serum IL 15/sIL-15Ralpha reaching a peak level of ~10 MUg ml(-1) 1 day after the injection and gradually declined to ~5 ng ml(-1) within 3 days. Quantitative PCR analysis revealed that overexpression of IL-15/sIL-15Ralpha induced the activation of natural killer and T cells, evidenced by increased mRNA levels of marker genes including granzyme B, perforin, Ifn-gamma, T-bet and Cd8 in the lungs, liver and kidneys. Importantly, transfer of the Il-15/sIl-15Ralpha gene alone, or in combination with gemcitabine chemotherapy, significantly inhibited the tumor growth in these three organs and prolonged median survival time of treated mice by 1.7- and 3.3-fold, respectively. The therapeutic benefits are principally blockade and elimination of tumor growth in the liver and kidneys. Taken together, these results suggest that IL-15/sIL-15Ralpha-based gene therapy could be an effective approach to treat late-stage lung cancer with metastases in other organs. PMID- 26742580 TI - PiggyBac as a novel vector in cancer gene therapy: current perspective. AB - Selection of suitable delivery system is one of the crucial aspects in gene therapy that determines the efficiency of gene therapy. The past two decades have witnessed extensive efforts for finding safe and efficient vectors to overcome the limitations of viral vectors. The utilization of DNA transposon-based vectors for gene therapy has emerged as a promising non-viral alternative. DNA 'cut-and paste' is one of the main mechanisms of genome engineering by transposon elements. However, the lack of an efficient transposition system has limited the utilization of transposon vectors in mice and mammalian systems. PiggyBac (PB) is known as a highly efficient DNA transposon originally isolated from Trichoplusia ni as an alternative to Sleeping Beauty (SB). It has been shown that PB can be functional in various species including mammalian systems. This vector could overcome some limitations of other vectors in cancer gene therapy. Some advantages of PB include the capacity for integration into the genome and providing a stable expression, capacity to harbor 10 and 9.1 kb of foreign DNA into the host genome, without a significant reduction in their transposition activity and display non-overlapping targeting preferences. However, to advance PB to clinical applications, some obstacles still require to be overcome to improve its safety and efficiency. Hence, it seems that this vector could open new horizons in gene and cancer therapy. PMID- 26742581 TI - Biochemical Characterization of Nonamer Binding Domain of RAG1 Reveals its Thymine Preference with Respect to Length and Position. AB - RAG complex consisting of RAG1 and RAG2 is a site-specific endonuclease responsible for the generation of antigen receptor diversity. It cleaves recombination signal sequence (RSS), comprising of conserved heptamer and nonamer. Nonamer binding domain (NBD) of RAG1 plays a central role in the recognition of RSS. To investigate the DNA binding properties of the domain, NBD of murine RAG1 was cloned, expressed and purified. Electrophoretic mobility shift assays showed that NBD binds with high affinity to nonamer in the context of 12/23 RSS or heteroduplex DNA. NBD binding was specific to thymines when single stranded DNA containing poly A, C, G or T were used. Biolayer interferometry studies showed that poly T binding to NBD was robust and comparable to that of 12RSS. More than 23 nt was essential for NBD binding at homothymidine stretches. On a double-stranded DNA, NBD could bind to A:T stretches, but not G:C or random sequences. Although NBD is indispensable for sequence specific activity of RAGs, external supplementation of purified nonamer binding domain to NBD deleted cRAG1/cRAG2 did not restore its activity, suggesting that the overall domain architecture of RAG1 is important. Therefore, we define the sequence requirements of NBD binding to DNA. PMID- 26742582 TI - Molecular analysis of Chinese truffles resembling Tuber californicum in morphology reveals a rich pattern of species diversity with emphasis on four new species. AB - In China the species name Tuber californicum is assigned to pale truffles in the genus Tuber that have more or less regularly globose ascospores; however, we recently discovered that the name was misapplied to some specimens collected in China. In the present study we re-examined all available Chinese collections purported to be T. californicum, including herbarium specimens and newly collected materials, with morphological and molecular methods. The accessions separated into seven clusters in a phylogenetic analysis based on sequences of the internal transcribed spacers sequences of these materials. An ML tree generated with ITS, nuc 28S rDNA and translation elongation factor-1alpha sequences from Chinese and worldwide Tuber species with globose ascospores showed only two clades, the Puberulum clade and Latisporum clade. The Latisporum clade as recognized in this study includes the species known from eastern Asia only and probably represents a new lineage that arose in parallel with the Puberulum, Maculatum and Gibbosum lineages. We concluded that no evidence supports the existence of T. californicum in China and that the specimens misidentified as T. californicum belong to four species newly described herein, T. xuanhuaense, T. jinshajiangense, T. caoi and T. parvomurphium. PMID- 26742584 TI - The diversity of microfungi in peatlands originated from the White Sea. AB - The diversity of culturable filamentous microfungi in peat and sediments of four peatlands at the coastal zone of Kandalaksha Bay of the White Sea (Murmansk region, Russia) was studied by culture methods on standard and selective media. Annually 100 samples were collected from the bogs 2007-2010. Based on morphological, molecular markers and cultural features, 211 taxa were identified. Fungal communities observed at the peatlands were influenced mostly by their sea origin. We discovered a large difference between fungal communities from the peat and the sediments of the peatlands. In contrast to the sediments, the fungal community of the peat was found to be consistent throughout sampling sites. Fungi with specific ecophysiology, such as Sphagnum-decomposing species (Oidiodendron griseum, O. tenuissimum. Penicillium spinulosum, P. thomii, Talaromyces funiculosus), psychrotolerant and associated with insects species (Pseudogymnoascus pannorum, Tolypocladium spp.), typical marine species (Acremonium spp.) were found. In addition, different types of sterile mycelia were characteristic for the researched peatlands. PMID- 26742583 TI - Psathyloma, a new genus in Hymenogastraceae described from New Zealand. AB - A new genus Psathyloma is described based on collections of agarics from New Zealand. We describe two new species in the genus, Ps. leucocarpum and Ps. catervatim, both of which have been known and tentatively named for a long time awaiting a formal description. Morphological traits and phylogenetic analyses reveal that Psathyloma forms a strongly supported sister clade to Hebeloma, Naucoria and Hymenogaster Morphologically Psathyloma resembles Hebeloma from which it differs mainly by producing smooth basidiospores with a germ pore. The geographical range of the genus has been demonstrated to include several regions in the southern hemisphere. A survey of published environmental sequences reveals that Psathyloma spp. were isolated from ectomycorrhizal root tips from Tasmania and Argentina, indicating an ectomycorrhizal association with southern beech. PMID- 26742585 TI - Show Horse Welfare: The Viewpoints of Judges, Stewards, and Show Managers. AB - The purpose of this study was to gain a better understanding of the current state of stock-type show horse welfare based on the perceptions of show officials and to identify potential means of preventing and intervening in compromises to show horse welfare. Thirteen horse show officials, including judges, stewards, and show managers, were interviewed. Findings revealed the officials had an incomplete understanding of nonhuman animal welfare and a high level of concern regarding the public's perception of show horse welfare. The officials attributed most of the frequently observed compromises to show horse welfare to (a) novices', amateurs', and young trainers' lack of experience or expertise, and (b) trainers' and owners' unrealistic expectations and prioritization of winning over horse welfare. The officials emphasized a need for distribution of responsibility among associations, officials, and individuals within the industry. Although the officials noted recent observable positive changes in the industry, they emphasized the need for continued improvements in equine welfare and greater educational opportunities for stakeholders. PMID- 26742587 TI - Prognostic Significance of ST-Segment Elevation in Leads V1-2 in Patients With Severe Aortic Stenosis. AB - BACKGROUND: ST-segment elevation (STE) in leads V1-2 is often observed in patients with severe aortic stenosis (AS), but its significance remains unknown. METHODS AND RESULTS: We retrospectively evaluated baseline ECGs and 5-year clinical outcomes in 211 consecutive patients with severe AS, defined as peak aortic jet velocity (Aortic Vmax) >4.0 m/s, or mean aortic pressure gradient >40 mmHg, or aortic valve area (AVA) <1.0 cm(2). The primary outcome measure was a composite of death or surgical aortic valve replacement (AVR). Patients with STE in leads V1-2(>=0.15 mV) had greater Aortic Vmax and smaller AVA than patients without. With a median follow-up of 4.9 years, the cumulative 5-year incidence of death or AVR was significantly higher in patients with STE in leads V1-2 than in patients without (91.4% vs. 77.1%; P=0.003). After adjusting for confounders, STE in leads V1-2 was independently associated with higher risk for death or AVR (hazard ratio, 1.53; 95% confidence interval, 1.06-2.22; P=0.02). In 64 asymptomatic patients without any indication for AVR at initial diagnosis of severe AS, the cumulative incidence of AVR was significantly higher in patients with STE in leads V1-2 than in patients without (57.6% vs. 30.5%; P<0.001). CONCLUSIONS: STE in leads V1-2 independently predicted poorer prognosis and more frequent need for AVR in patients with severe AS. PMID- 26742586 TI - Western diet induces a shift in microbiota composition enhancing susceptibility to Adherent-Invasive E. coli infection and intestinal inflammation. AB - Recent advances have shown that the abnormal inflammatory response observed in CD involves an interplay among intestinal microbiota, host genetics and environmental factors. The escalating consumption of fat and sugar in Western countries parallels an increased incidence of CD during the latter 20(th) century. The impact of a HF/HS diet in mice was evaluated for the gut micro inflammation, intestinal microbiota composition, function and selection of an E. coli population. The HF/HS diet created a specific inflammatory environment in the gut, correlated with intestinal mucosa dysbiosis characterized by an overgrowth of pro-inflammatory Proteobacteria such as E. coli, a decrease in protective bacteria, and a significantly decreased of SCFA concentrations. The expression of GPR43, a SCFA receptor was reduced in mice treated with a HF/HS diet and reduced in CD patients compared with controls. Interestingly, mice treated with an agonist of GPR43 were protected against DSS-induced colitis. Finally, the transplantation of feces from HF/HS treated mice to GF mice increased susceptibility to AIEC infection. Together, our results demonstrate that a Western diet could aggravate the inflammatory process and that the activation of the GPR43 receptor pathway could be used as a new strategy to treat CD patients. PMID- 26742588 TI - Statin Adherence After Ischemic Stroke or Transient Ischemic Attack Is Associated With Clinical Outcome. AB - BACKGROUND: Statin therapy is beneficial for ischemic stroke patients, but little is known about whether statin adherence affects clinical outcome. We therefore evaluated the effect of statin adherence in patients with ischemic stroke or transient ischemic attack (TIA). METHODS AND RESULTS: From Taiwan Bureau of National Health Insurance database, we enrolled patients with no prior statin therapy admitted for ischemic stroke or TIA between January 2002 and December 2005. Patients were grouped based on statin adherence according to medication possession ratio (MPR): good adherence (MPR >80%; n=2,274), intermittent adherence (MPR=40-80%; n=3,710), and poor adherence (MPR <40%; n=9,424). The study endpoint was the composite outcome of recurrent ischemic stroke, hemorrhagic stroke, and acute coronary event 1 year after statin initiation. Follow-up data were obtained through December 2010. During follow-up, composite endpoints occurred in 5,354 patients (34.7%): good adherence, 798 patients (35.1%); intermittent adherence, 1,338 patients (36.1%); and poor adherence, 3,218 patients (34.1%). Compared with the good adherence group, patients in the poor adherence group and intermittent adherence group had higher risk of worse clinical outcome (adjusted HR, 1.26 and 1.16, respectively; 95% CI: 1.17-1.37 and 1.07-1.27, respectively). CONCLUSIONS: Good statin adherence was associated with better clinical outcome in patients with acute ischemic stroke or TIA. (Circ J 2016; 80: 731-737). PMID- 26742589 TI - Effects of testosterone replacement therapy withdrawal and re-treatment in hypogonadal elderly men upon obesity, voiding function and prostate safety parameters. AB - Whether testosterone replacement therapy (TRT) is a lifelong treatment for men with hypogonadism remains unknown. We investigated long-term TRT and TRT withdrawal on obesity and prostate-related parameters. Two hundred and sixty-two hypogonadal patients (mean age 59.5) received testosterone undecanoate in 12-week intervals for a maximum of 11 years. One hundred and forty-seven men had TRT interrupted for a mean of 16.9 months and resumed thereafter (Group A). The remaining 115 patients were treated continuously (Group B). Prostate volume, prostate-specific antigen (PSA), residual voiding volume, bladder wall thickness, C-reactive protein (CRP), aging male symptoms (AMS), International Index of erectile function - erectile function (IIEF-EF) and International Prostate Symptoms Scores (IPSS) were measured over the study period with anthropometric parameters of obesity, including weight, body mass index (BMI) and waist circumference. Prior to interruption, TRT resulted in improvements in residual voiding volume, bladder wall thickness, CRP, AMS, IIEF-EF, IPSS and obesity parameters while PSA and prostate volume increased. TRT interruption reduced total testosterone to hypogonadal levels in Group A and resulted in worsening of obesity parameters, AMS, IPSS, residual voiding volume and bladder wall thickness, IIEF-EF and PSA while CRP and prostate volume were unchanged until treatment resumed whereby these effects were reversed. TRT interruption results in worsening of symptoms. Hypogonadism may require lifelong TRT. PMID- 26742590 TI - Magnetism-Enhanced Monolith-Based In-Tube Solid Phase Microextraction. AB - Monolith-based in-tube solid phase microextraction (MB/IT-SPME) has received wide attention because of miniaturization, automation, expected loading capacity, and environmental friendliness. However, the unsatisfactory extraction efficiency becomes the main disadvantage of MB/IT-SPME. To overcome this circumstance, magnetism-enhanced MB/IT-SPME (ME-MB/IT-SPME) was developed in the present work, taking advantage of magnetic microfluidic principles. First, modified Fe3O4 nanoparticles were mixed with polymerization solution and in situ polymerized in the capillary to obtain a magnetic monolith extraction phase. After that, the monolithic capillary column was placed inside a magnetic coil that allowed the exertion of a variable magnetic field. The effects of intensity of magnetic field, adsorption and desorption flow rate, volume of sample, and desorption solvent on the performance of ME-MB/IT-SPME were investigated in detail. The analysis of six steroid hormones in water samples by the combination of ME-MB/IT SPME with high-performance liquid chromatography with diode array detection was selected as a paradigm for the practical evaluation of ME-MB/IT-SPME. The application of a controlled magnetic field resulted in an obvious increase of extraction efficiencies of the target analytes between 70% and 100%. The present work demonstrated that application of different magnetic forces in adsorption and desorption steps can effectively enhance extraction efficiency of MB/IT-SPME systems. PMID- 26742591 TI - Introduction Revisiting the Affordable Care Act. PMID- 26742593 TI - Partisan Politics or Public-Health Need? An empirical analysis of state choice during initial implementation of the Affordable Care Act. AB - States' policy decisions regarding the Affordable Care Act (ACA) of 2010 have often been explained as predominantly, if not solely, partisan. Might rival explanations also apply? Using a cross-sectional 50-state regression model, we studied standard political variables coupled with public-health indicators. This work differs from existing research by employing a dependent variable of five additive measures of ACA support, examining the impact of both political and socioeconomic indicators on state policy decisions. Expanding on recent empirical studies with our more nuanced additive index of support measures, we found that same-party control of a state's executive and legislative branches was indeed by far the single best predictor of policy decisions. Public-health indicators, overwhelmed by partisan effect, did not sufficiently explain state policy choice. This result does not allay the concerns that health policy has become synonymous with health politics and that health politics now has little to do with health itself. PMID- 26742592 TI - Are Press Depictions of Affordable Care Act Beneficiaries Favorable to Policy Durability? AB - BACKGROUND: If successfully implemented and enduring, the Affordable Care Act (ACA) stands to expand health insurance access in absolute terms, reduce inter group disparities in that access, and reduce exposure to the financial vulnerabilities illness entails. Its durability--meaning both avoidance of outright retrenchment and fidelity to its policy aims--is thus of scholarly interest. Past literature suggests that social constructions of a policy's beneficiaries may impact durability. QUESTIONS: This paper first describes media portrayals of ACA beneficiaries with an eye toward answering three descriptive questions: (1) Do portrayals depict beneficiaries as economically heterogeneous? (2) Do portrayals focus attention on groups that have acquired new political relevance due to the ACA, such as young adults? (3) What themes that have served as messages about beneficiary "deservingness" in past social policy are most frequent in ACA beneficiary portrayals? The paper then assesses how the portrayal patterns that these questions uncover may work both for and against the ACA's durability, finding reasons for confidence as well as caution. METHODS: Using manual and automated methods, this paper analyzes newspaper text from August 2013 through January 2014 to trace portrayals of two ACA "target populations" before and during the new law's first open-enrollment period: those newly eligible for Medicaid, and those eligible for subsidies to assist in the purchase of private health insurance under the ACA. This paper also studies newspaper text portrayals of two groups informally crafted by the ACA in this timeframe: those gaining health insurance and those losing it. RESULTS: The text data uncover the following answers to the three descriptive questions for the timeframe studied: (1) Portrayals may underplay beneficiaries' economic heterogeneity. (2) Portrayals pay little attention to young adults. (3) Portrayals emphasize themes of workforce participation, economic self-sufficiency, and insider status. Health status, age, gender, and race/ethnicity appear to receive little attention. IMPLICATIONS AND CONCLUSIONS: Existing literature suggests that these portrayal patterns may both support and limit ACA durability. In favor of durability is that ACA beneficiaries are depicted in terms that have been associated with deservingness in past American social policy--particularly being cast as workers and insiders. Yet, the results also give three reasons for caution. First, ACA insurance-losers are also portrayed as deserving. Second, it is unclear how the portrayal patterns found may impact the durability of the ACA's efforts to cut insurance disparities by age, health status, and especially race/ethnicity. Third, portrayals' strong casting of beneficiaries as workers, and limited attention to beneficiaries' economic heterogeneity and to young adults, may do little to help cultivate beneficiary political engagement around the ACA. PMID- 26742594 TI - The Affordable Care Act and Abortion Comparing the U.S. and Western Europe. AB - The 2010 Affordable Health Care Act (ACA) treats abortion differently than any other health service, precluding public funding for abortion and imposing other restrictions on American states. To determine whether the ACA's abortion restrictions are uniquely American or have counterparts in other national health systems, this study employs a cross-sectional design comparing abortion restrictions in the ACA with those in 17 Western European countries. Using a six item scale, the intensity of abortion restrictions is compared across Western European nations. A similar scale is employed for a five-state sample of state level abortion restrictions. Although the United States is not alone in having abortion restrictions, how abortion is proscribed in the ACA has no counterpart in Western Europe. Unlike many Western European countries, the ACA's restrictions focus on abortion funding, not the length of gestation or the health of the pregnant woman. PMID- 26742595 TI - The Affordable Care Act and Assisted Reproductive Technology Use. AB - The Affordable Care Act (ACA) has prompted numerous gender and sexuality controversies. We describe and analyze those involving assisted reproductive technologies (ART). ART in the United States has been regulated in piecemeal fashion, with oversight primarily by individual states. While leaving state authority largely intact, the ACA federalized key practices by establishing essential health benefits (EHBs) that regulate insurance markets and prohibit insurance-coverage denials based on pre-existing conditions. Whatever their intentions, the ACA's drafters thus put infertility in a subtly provocative new light clinically, financially, normatively, politically, and culturally. With particular attention to normative and political dynamics embedded in plausible regulatory trajectories, we review--and attempt to preview--the ACA's effects on infertility-related delivery of health services, on ART utilization, and on reproductive medicine as a factor in American society. PMID- 26742596 TI - The Voyage of a Navigator An aspiring scholar's inside observations on the Affordable Care Act's rocky roll-out in North Carolina. AB - North Carolina, a federally facilitated marketplace under the Affordable Care Act (ACA), stumbled in 2013 when opening its health-insurance exchange. Trouble was easy to foresee, as North Carolina had instituted a law barring any state agency from assisting enrollment in health-insurance plans made available through the ACA. Trained workers were needed to help citizens and legal immigrants "navigate" to these plans. Some of these "navigators" could be paid with federal funds, but many others had to work as volunteers. I was one of these volunteer navigators. Much went wrong in training, staffing, and operations, but much still was accomplished. Here I report observations, share assessments, and offer suggestions for similarly complex situations. PMID- 26742598 TI - Venous thromboembolism bundle: Risk assessment and prophylaxis for obstetric patients. AB - While venous thromboembolism (VTE) is a leading cause of severe maternal morbidity and mortality, maternal death from VTE is amenable to prevention. Thromboprophylaxis is the most readily implementable means of systematically reducing the maternal death rate, and protocols that identify at-risk women have led to a significant reduction in maternal deaths from VTE. Strategies to prevent VTE require minimal resources. A multidisciplinary working group convened as part of American Congress of Obstetricians and Gynecologists' District II Safe Motherhood Initiative reviewed research evidence and major society thromboprophylaxis guidelines and identified clinical strategies to reduce maternal VTE risk. This review provides recommendations for VTE prophylaxis and describes suggested clinical strategies for office and hospital-based implementation. PMID- 26742599 TI - Obstetric hemorrhage: A global review. AB - Postpartum hemorrhage remains the number one cause of maternal death globally despite the fact that it is largely a preventable and most often a treatable condition. While the global problem is appreciated, some may not realize that in the United States postpartum hemorrhage is a leading cause of mortality and unfortunately, the incidence is on the rise. In New York, obstetric hemorrhage is the second leading cause of maternal mortality in the state. National data suggests that hemorrhage is disproportionally overrepresented as a contributor to severe maternal morbidity and we suspect as we explore further this will be true in New York State as well. Given the persistent and significant contribution to maternal mortality, it may be useful to analyze the persistence of this largely preventable cause of death within the framework of the historic "Three Delays" model of maternal mortality. The ongoing national and statewide problem with postpartum hemorrhage will be reviewed in this context of delays in an effort to inform potential solutions. PMID- 26742600 TI - Obstetrical venous thromboembolism: Epidemiology and strategies for prophylaxis. AB - Venous thromboembolism (VTE) is a leading cause of severe maternal morbidity and mortality. While pregnancy alone is a risk factor for VTE, additional population based risk factors such as obesity are becoming increasingly common, particularly in the developed world. Maternal death from VTE is amenable to prevention and VTE thromboprophylaxis is the most readily implementable means of systematically reducing the maternal death rate. In the United States, prophylaxis is recommended primarily for patients at extremely high risk for thromboembolism and women undergoing cesarean delivery, whereas in the United Kingdom a larger proportion of the population is targeted. Given the maternal burden of obstetric VTE and varying strategies for prevention, this article will provide a review of the following topics: (1) global epidemiology of obstetric VTE, (2) prophylaxis guidelines in the United States and the United Kingdom, and (3) maternal mortality from VTE in the United States and the United Kingdom in the setting of differing prophylaxis strategies. PMID- 26742602 TI - NAP-1, Nucleosome assembly protein 1, a histone chaperone involved in Drosophila telomeres. AB - Telomere elongation is a function that all eukaryote cells must accomplish in order to guarantee, first, the stability of the end of the chromosomes and second, to protect the genetic information from the inevitable terminal erosion. The targeted transposition of the telomere transposons HeT-A, TART and TAHRE perform this function in Drosophila, while the telomerase mechanism elongates the telomeres in most eukaryotes. In order to integrate telomere maintenance together with cell cycle and metabolism, different components of the cell interact, regulate, and control the proteins involved in telomere elongation. Different partners of the telomerase mechanism have already been described, but in contrast, very few proteins have been related with assisting the telomere transposons of Drosophila. Here, we describe for the first time, the implication of NAP-1 (Nucleosome assembly protein 1), a histone chaperone that has been involved in nuclear transport, transcription regulation, and chromatin remodeling, in telomere biology. We find that Nap-1 and HeT-A Gag, one of the major components of the Drosophila telomeres, are part of the same protein complex. We also demonstrate that their close interaction is necessary to guarantee telomere stability in dividing cells. We further show that NAP-1 regulates the transcription of the HeT-A retrotransposon, pointing to a positive regulatory role of NAP-1 in telomere expression. All these results facilitate the understanding of the transposon telomere maintenance mechanism, as well as the integration of telomere biology with the rest of the cell metabolism. PMID- 26742601 TI - Haematopoietic ESL-1 enables stem cell proliferation in the bone marrow by limiting TGFbeta availability. AB - The life-long maintenance of haematopoietic stem and progenitor cells (HSPCs) critically relies on environmental signals produced by cells that constitute the haematopoietic niche. Here we report a cell-intrinsic mechanism whereby haematopoietic cells limit proliferation within the bone marrow, and show that this pathway is repressed by E-selectin ligand 1 (ESL-1). Mice deficient in ESL-1 display aberrant HSPC quiescence, expansion of the immature pool and reduction in niche size. Remarkably, the traits were transplantable and dominant when mutant and wild-type precursors coexisted in the same environment, but were independent of E-selectin, the vascular receptor for ESL-1. Instead, quiescence is generated by unrestrained production of the cytokine TGFbeta by mutant HSPC, and in vivo or in vitro blockade of the cytokine completely restores the homeostatic properties of the haematopoietic niche. These findings reveal that haematopoietic cells, including the more primitive compartment, can actively shape their own environment. PMID- 26742603 TI - Identification of the first insulin-like peptide in the disease vector Rhodnius prolixus: Involvement in metabolic homeostasis of lipids and carbohydrates. AB - Insulin-like peptides (ILPs) are functional analogs of insulin and have been identified in many insect species. The insulin cell signaling pathway is a conserved regulator of metabolism, and in insects, as well as in other animals, can modulate physiological functions associated with the metabolism of lipids and carbohydrates. In the present study, we have identified the first ILP from the Rhodnius prolixus genome (termed Rhopr-ILP) and investigated its involvement in energy metabolism of unfed and recently fed fifth instars. We have cloned the cDNA sequence and analyzed the expression profile of the transcript, which is predominantly present in neurosecretory cells in the brain, similar to other insect ILPs. Using RNAi, we have reduced the expression of this peptide transcript by 90% and subsequently measured the carbohydrate and lipid levels in the hemolymph, fat body and leg muscles. Reduced levels of Rhopr-ILP transcript induced increased carbohydrate and lipid levels in the hemolymph and increased lipid content in the fat body, in unfed insects and recently fed insects. Also their fat bodies displayed enlarged lipid droplets within the cells. On the other hand, the carbohydrate content in the fat body and in the leg muscles of unfed insects were decreased when compared to control insects. Our results indicate that Rhopr-ILP is a modulator of lipid and carbohydrate metabolism, probably through signaling the presence of available energy and nutrients in the hemolymph. PMID- 26742604 TI - ICARE improves antinuclear antibody detection by overcoming the barriers preventing accreditation. AB - BACKGROUND: Antinuclear antibodies (ANA) are useful biomarkers for the diagnosis and the monitoring of rheumatic diseases. The American College of Rheumatology has stated that indirect immunofluorescence (IIF) analysis remains the gold standard for ANA screening. However, IIF is time consuming, subjective, not fully standardized and presents several issues for accreditation which is the process leading to ISO 15189 certification for medical laboratories. We propose an innovative tool for accreditation by using the quantitative evaluation of the automated image capture and analysis "ICARE" (Immunofluorescence for Computed Antinuclear antibody Rational Evaluation). METHODS: We established the optimal screening dilution (1:160) and a fluorescence index (FI) cutoff for ICARE on a cohort of 91 healthy blood donors. Then, we evaluated performance of ICARE on a routine cohort of 236 patients. Precision parameters of ANA detection by IIF were evaluated according to ISO 15189. RESULTS: ICARE showed an excellent concordance with visual evaluation (88%, Kappa=0.76) and significantly discriminated between weak to moderate (1:160-1:320 titers) and high (>1:320 titers) ANA levels. A significant correlation was found between FI and ANA titers (Spearman's rho=0.67; P<0.0001). Using ICARE, we reported precision parameters such as repeatability (CV<13.8%) and reproducibility (CV<13.1%) as well as absence of inter-sample contamination for ANA detection by IIF according to ISO 15189 standards. CONCLUSIONS: ICARE offers a precious help for the accreditation of IIF qualitative methods. This innovative quantitative approach is in adequacy with the process of continuous improvement of the quality of clinical laboratories. PMID- 26742605 TI - Measuring the expressed emotion in Chinese family caregivers of persons with dementia: Validation of a Chinese version of the Family Attitude Scale. AB - BACKGROUND: Expressed emotion (EE) captures the affective quality of the relationship between family caregivers and their care recipients and is known to increase the risk of poor health outcomes for caregiving dyads. Little is known about expressed emotion in the context of caregiving for persons with dementia, especially in non-Western cultures. The Family Attitude Scale (FAS) is a psychometrically sound self-reporting measure for EE. Its use in the examination of caregiving for patients with dementia has not yet been explored. OBJECTIVES: This study was performed to examine the psychometric properties of the Chinese version of the FAS (FAS-C) in Chinese caregivers of relatives with dementia, and its validity in predicting severe depressive symptoms among the caregivers. METHODS: The FAS was translated into Chinese using Brislin's model. Two expert panels evaluated the semantic equivalence and content validity of this Chinese version (FAS-C), respectively. A total of 123 Chinese primary caregivers of relatives with dementia were recruited from three elderly community care centers in Hong Kong. The FAS-C was administered with the Chinese versions of the 5-item Mental Health Inventory (MHI-5), the Zarit Burden Interview (ZBI) and the Revised Memory and Behavioral Problem Checklist (RMBPC). RESULTS: The FAS-C had excellent semantic equivalence with the original version and a content validity index of 0.92. Exploratory factor analysis identified a three-factor structure for the FAS C (hostile acts, criticism and distancing). Cronbach's alpha of the FAS-C was 0.92. Pearson's correlation indicated that there were significant associations between a higher score on the FAS-C and greater caregiver burden (r=0.66, p<0.001), poorer mental health of the caregivers (r=-0.65, p<0.001) and a higher level of dementia-related symptoms (frequency of symptoms: r=0.45, p<0.001; symptom disturbance: r=0.51, p<0.001), which serves to suggest its construct validity. For detecting severe depressive symptoms of the family caregivers, the receiving operating characteristics (ROC) curve had an area under curve of 0.78 (95% confidence interval (CI)=0.69-0.87, p<0.0001). The optimal cut-off score was >47 with a sensitivity of 0.720 (95% CI=0.506-0.879) and specificity of 0.742 (95% CI=0.643-0.826). CONCLUSIONS: The FAS-C is a reliable and valid measure to assess the affective quality of the relationship between Chinese caregivers and their relatives with dementia. It also has acceptable predictability in identifying family caregivers with severe depressive symptoms. PMID- 26742606 TI - Enhanced interdisciplinary care improves self-care ability and decreases emergency department visits for older Taiwanese patients over 2 years after hip fracture surgery: A randomised controlled trial. AB - BACKGROUND: Little evidence is available on the longer-term effects (beyond 12 months) of intervention models consisting of hip fracture-specific care in conjunction with management of malnutrition, depression, and falls. OBJECTIVE: To compare the relative effects of an interdisciplinary care, and a comprehensive care programme with those of usual care for elderly patients with a hip fracture on self-care ability, health care use, and mortality. DESIGN: Randomised experimental trial. SETTING: A 3000-bed medical centre in northern Taiwan. PARTICIPANTS: Patients with hip fracture aged 60 years or older (N=299). METHOD: Patients were randomly assigned to three groups: comprehensive care (n=99), interdisciplinary care (n=101), and usual care (control) (n=99). Usual care entailed only one or two in-hospital rehabilitation sessions. Interdisciplinary care included not only hospital rehabilitation, but also geriatric consultation, discharge planning, and 4-month in-home rehabilitation. Building upon interdisciplinary care, comprehensive care extended in-home rehabilitation to 12 months and added management of malnutrition and depressive symptoms, and fall prevention. Patients' self-care ability was measured by activities of daily living and instrumental activities of daily living using the Chinese Barthel Index and Chinese version Instrumental Activities of Daily Living scale, respectively. Outcomes were assessed before discharge, and 1, 3, 6, 12, 18, 24 months following hip fracture. Hierarchical linear models were used to analyse health outcomes and health care utilisation, including emergency department visit and hospital re-admission. RESULTS: The comprehensive care group had better performance trajectories for both measures of activities of daily living and fewer emergency department visits than the usual care group, but no difference in hospital readmissions. The interdisciplinary care and usual care groups did not differ in trajectories of self-care ability and service utilisation. The three groups did not differ in mortality during the 2-year follow-up. CONCLUSION: Comprehensive care, with enhanced rehabilitation, management of malnutrition and depressive symptoms, and fall prevention, improved self-care ability and decreased emergency department visits for elders up to 2 years after hip-fracture surgery, above and beyond the effects of usual care and interdisciplinary care. PMID- 26742607 TI - An evaluation of a nurse-led rehabilitation programme (the ProBalance Programme) to improve balance and reduce fall risk of community-dwelling older people: A randomised controlled trial. AB - OBJECTIVE: This study aims to assess the effect of a nurse-led rehabilitation programme (the ProBalance Programme) on balance and fall risk of community dwelling older people from Madeira Island, Portugal. DESIGN: Single-blind, randomised controlled trial. SETTING: University laboratory. PARTICIPANTS: Community-dwelling older people, aged 65-85, with balance impairments. Participants were randomly allocated to an intervention group (IG; n=27) or a wait-list control group (CG; n=25). INTERVENTION: A rehabilitation nursing programme included gait, balance, functional training, strengthening, flexibility, and 3D training. One trained rehabilitation nurse administered the group-based intervention over a period of 12 weeks (90min sessions, 2 days per week). A wait-list control group was instructed to maintain their usual activities during the same time period. OUTCOME: Balance was assessed using the Fullerton Advanced Balance (FAB) scale. The time points for assessment were at zero (pre-test), 12 (post-test), and 24 weeks (follow up). RESULTS: Changes in the mean (SD) FAB scale scores immediately following the 12-week intervention were 5.15 (2.81) for the IG and -1.45 (2.80) for the CG. At follow-up, the mean (SD) change scores were -1.88 (1.84) and 0.75 (2.99) for the IG and CG, respectively. The results of a mixed between-within subjects analysis of variance, controlling for physical activity levels at baseline, revealed a significant interaction between group and time (F (2, 42)=27.89, p<0.001, Partial Eta Squared=0.57) and a main effect for time (F (2, 43)=3.76, p=0.03, Partial Eta Squared=0.15), with both groups showing changes in the mean FAB scale scores across the three time periods. A significant main effect comparing the two groups (F (1, 43)=21.90, p<0.001, Partial Eta Squared=0.34) confirmed a clear positive effect of the intervention when compared to the control. CONCLUSION: This study demonstrated that the rehabilitation nursing programme was effective in improving balance and reducing fall risk in a group of older people with balance impairment, immediately after the intervention. A decline in balance was observed for the IG after a period of no intervention. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12612000301864. PMID- 26742608 TI - Health literacy and fear of cancer progression in elderly women newly diagnosed with breast cancer--A longitudinal analysis. AB - OBJECTIVE: This study aims to investigate the distribution of health literacy levels and the association of health literacy with fear of cancer progression (FoP) over the course of cancer treatment in a sample of elderly women newly diagnosed with breast cancer. METHODS: The analyses are part of a prospective, multicenter cohort-study (PIAT) that took place in Germany between 2013 and 2014. Elderly women (aged 65 years and older) newly diagnosed with breast cancer completed validated measures of health literacy and FoP directly after the breast cancer surgery and 40 weeks later. Multivariate random-effects regression analysis for longitudinal data was applied to estimate the association of health literacy with FoP considering socio-demographic, clinical and psychosocial characteristics of the patients. RESULTS: About half of the elderly breast cancer patients in our sample were classified as having limited health literacy (inadequate and problematic levels). Inadequate and problematic health literacy were significantly associated with higher levels of FoP in the elderly breast cancer patients. CONCLUSION: Limited health literacy is an independent risk factor for increased FoP. PRACTICE IMPLICATIONS: Enhancing health literacy could contribute to reducing patients' cancer-related fears. PMID- 26742609 TI - Tools and resources for preventing childhood obesity in primary care: A method of evaluation and preliminary assessment. AB - OBJECTIVES: To pilot-test a mixed methods approach to evaluate tools and resources (TRs) that healthcare providers (HCPs) use for preventing childhood obesity in primary care, and report a preliminary descriptive assessment of commonly-used TRs. METHODS: This mixed methods study included individual, semi structured interviews with purposefully-sampled HCPs in Alberta, Canada; interviews were digitally recorded and analyzed thematically (phase I). Two independent reviewers used three assessment checklists to evaluate commonly-used TRs (phase II). HCPs provided feedback on our coding scheme and checklist data (phase III). RESULTS: Three themes described how HCPs (n=19) used TRs: purpose of use (e.g., clinical support), logistical factors (e.g., accessibility), and decision to use (e.g., suitability). The latter theme overlapped with constructs of suitability on the checklists. Overall, participants used 15 TRs, most of which scored 'average' on the checklists. CONCLUSION: Phases I and II provided unique insights on the evaluation of TRs used for preventing childhood obesity. Criteria on the checklists overlapped with HCPs' perceptions of TR suitability, but did not reflect logistical factors that influenced their use of TRs. PRACTICE IMPLICATIONS: Developers of TRs should collaborate with HCPs to ensure that subjective and objective criteria are used to optimize TR suitability in the primary care setting. PMID- 26742610 TI - Survival of Penicillium spp. conidia during deep-frying and baking steps of frozen chicken nuggets processing. AB - This study aimed at determining whether Penicillium spp. strains could survive through the heat treatment applied during the processing of frozen chicken nuggets. Firstly, it was found that the conidia of Penicillium were not able to survive the heat shock in phosphate buffer at pH 7.2 in thermal death tubes (TDT) at 80 degrees C/30 min. Subsequently, each Penicillium strain was inoculated in frozen chicken nuggets, which were subjected to the following treatments: i) only deep frying (frying oil at 195-200 degrees C), ii) only baking (120-130 degrees C until the internal temperature reached 70 degrees C) and iii) deep frying followed by baking (frying oil temperature of 195-200 degrees C and baking temperature of 120-130 degrees C, until the internal temperature reached 70 degrees C). The results indicated that Penicillium polonicum NGT 23/12, Penicillium commune NGT 16/12, Penicillium solitum NGT 30/12 and Penicillium crustosum NGT 51/12 were able to survive after the combined treatment (deep frying followed by baking) when inoculated in chicken nuggets. P. polonicum NGT 23/12 was the most resistant strain to the combined treatment (deep frying and baking), as its population was reduced by 3 log cycles CFU/g, when the internal temperature reached 78 degrees C after 10 min and 30 s of baking. The present data show that if Penicillium spp. is present in high numbers in raw materials, such as breading flours, it will survive the thermal processing applied during chicken nuggets production. PMID- 26742611 TI - Expression of Listeria monocytogenes key virulence genes during growth in liquid medium, on rocket and melon at 4, 10 and 30 degrees C. AB - The aim of the present study was to assess the expression of key virulence genes, during growth of a Listeria monocytogenes isolate in liquid medium, on melon and rocket at different temperatures and time. For that purpose, BHI broth, rocket and melon were inoculated at 7.0-7.5 log CFU mL(-1) or g(-1)and stored at 4, 10 and 30 degrees C. Sampling took place upon inoculation and after 0.5, 6 and 24 h of incubation. The RNA was stabilized and the expression of hly, plcA, plcB, sigB, inlA, inlB, inlC, inlJ, lmo2672 and lmo2470 was assessed by RT-qPCR. The results obtained were summarized into two observations; the first one referring to the interactive effect of incubation temperature and type of substrate and the second one to the effect of time on gene expression. Regarding the latter, nearly all genes were regulated upon inoculation and exhibited differential expression in the subsequent sampling times indicating the existence of additional regulatory mechanisms yet to be explored. PMID- 26742612 TI - Application and validation of autochthonous Lactobacillus plantarum starter cultures for controlled malolactic fermentation and its influence on the aromatic profile of cherry wines. AB - Lactic acid bacteria (LAB) used for malolactic fermentation (MLF) has a great effect on the production and quality of cherry wines. The present study used an autochthonous Lb. plantarum strain of SGJ-24 which was isolated from spontaneous MLF cherry wines and selected by its best MLF performance and tolerance, to investigate its effect on the kinetic of vinification and on chemical and volatile characteristics of Rainer and May Duck cherry wines, in comparison with a commercial Oenococcus oeni strain of 31 MBR. Monitoring of MLF was carried out by measuring cell viability and malic acid metabolism, and results showed that for both cherry varieties, SGJ-24 can significantly minimize MLF duration. After fermentation, wine samples were chemically characterized and analyzed for volatile profiles. Results demonstrated that no negative impact on the analytical parameters has been found, and a general increase of volatile esters and terpenes was observed when SGJ-24 was involved. Sensory analysis revealed that the global aromatic intensity was enhanced by the introduction of SGJ-24. All these data suggested that the application of Lb. plantarum strain of SGJ-24 as a worthwhile alternative LAB species for Rainer and May Duck cherry winemaking. PMID- 26742613 TI - Development of a predictive model for the growth kinetics of aerobic microbial population on pomegranate marinated chicken breast fillets under isothermal and dynamic temperature conditions. AB - The aim of this study was the development of a model to describe the growth kinetics of aerobic microbial population of chicken breast fillets marinated in pomegranate juice under isothermal and dynamic temperature conditions. Moreover, the effect of pomegranate juice on the extension of the shelf life of the product was investigated. Samples (10 g) of chicken breast fillets were immersed in marinades containing pomegranate juice for 3 h at 4 degrees C following storage under aerobic conditions at 4, 10, and 15 degrees C for 10 days. Total Viable Counts (TVC), Pseudomonas spp and lactic acid bacteria (LAB) were enumerated, in parallel with sensory assessment (odor and overall appearance) of marinated and non-marinated samples. The Baranyi model was fitted to the growth data of TVC to calculate the maximum specific growth rate (MUmax) that was further modeled as a function of temperature using a square root-type model. The validation of the model was conducted under dynamic temperature conditions based on two fluctuating temperature scenarios with periodic changes from 6 to 13 degrees C. The shelf life was determined both mathematically and with sensory assessment and its temperature dependence was modeled by an Arrhenius type equation. Results showed that the MUmax of TVC of marinated samples was significantly lower compared to control samples regardless temperature, while under dynamic temperature conditions the model satisfactorily predicted the growth of TVC in both control and marinated samples. The shelf-life of marinated samples was significantly extended compared to the control (5 days extension at 4 degrees C). The calculated activation energies (Ea), 82 and 52 kJ/mol for control and marinated samples, respectively, indicated higher temperature dependence of the shelf life of control samples compared to marinated ones. The present results indicated that pomegranate juice could be used as an alternative ingredient in marinades to prolong the shelf life of chicken. PMID- 26742614 TI - Exploring the phenotypic space of non-Saccharomyces wine yeast biodiversity. AB - Tremendous microbial diversity exists in vineyards, and the potential to harness this diversity for novel mixed or pure starter cultures for wine fermentation has received significant attention in recent years. However, most studies are limited to a small subset of strains and species. Here we present data from a systematic screen of 91 yeast isolates from South African grape must and vineyard samples for oenologically relevant traits. One focus area was finding non-Saccharomyces isolates showing both reduced ethanol yields, as well as improved aromatic characteristics. Of the 91 isolates evaluated initially, 21 showed lower ethanol yields when compared to commercial wine yeast strain controls. Collectively, the metabolic data (primary fermentation and secondary aroma compounds) highlight the enormity of the 'phenotypic space' of yeast communities in South African vineyards. The data also emphasise intraspecies variability, challenging our concept of species typicity. Of particular oenological interest was the ability of several isolates to produce high levels of terpenoid compounds. A few strains were ultimately found which showed a substantial reduction (>1.5%) in the final ethanol content of sequential fermentations, as well as unique aroma compound production profiles. Four of these strains were selected for comprehensive wine trials in both red and white grape musts, complete with microbial, chemical and sensory analyses of the red wines. This presents, for the first time, a full bench-to-bottle characterisation of non-Saccharomyces strains showing the most potential for commercial application. The findings of this study enlarge the potential range of oenological applications for non-Saccharomyces yeast, while also suggesting the potential usefulness of several yeast species that have previously not been considered for winemaking applications. PMID- 26742616 TI - Abundance, diversity and community composition of free-living protozoa on vegetable sprouts. AB - Interactions with free-living protozoa (FLP) have been implicated in the persistence of pathogenic bacteria on food products. In order to assess the potential involvement of FLP in this contamination, detailed knowledge on their occurrence, abundance and diversity on food products is required. In the present study, enrichment and cultivation methods were used to inventory and quantify FLP on eight types of commercial vegetable sprouts (alfalfa, beetroot, cress, green pea, leek, mung bean, red cabbage and rosabi). In parallel, total aerobic bacteria and Escherichia coli counts were performed. The vegetable sprouts harbored diverse communities of FLP, with Tetrahymena (ciliate), Bodo saltans and cercomonads (flagellates), and Acanthamoeba and Vannella (amoebae) as the dominant taxa. Protozoan community composition and abundance significantly differed between the sprout types. Beetroot harbored the most abundant and diverse FLP communities, with many unique species such as Korotnevella sp., Vannella sp., Chilodonella sp., Podophrya sp. and Sphaerophrya sp. In contrast, mung bean sprouts were species-poor and had low FLP numbers. Sampling month and company had no significant influence, suggesting that seasonal and local factors are of minor importance. Likewise, no significant relationship between protozoan community composition and bacterial load was observed. PMID- 26742615 TI - Effect of sanitizer combined with steam heating on the inactivation of foodborne pathogens in a biofilm on stainless steel. AB - The combined effect of chemical sanitizers including sodium hypochlorite, hydrogen peroxide, iodophor, and benzalkonium chloride with steam heating on the inactivation of biofilms formed by Escherichia coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes on stainless steel was investigated. Six day old biofilms, comprised of a mixture of three strains each of three foodborne pathogens, were produced on stainless steel coupons at 25 degrees C and treated with each sanitizer alone (for 5, 15, and 30 s), steam alone (for 5, 10, and 20 s), and the combination. There was a synergistic effect of sanitizer and steam on the viability of biofilm cells of the three pathogens as evidenced by plating counts and imaging. The combination treatment achieved an additional 0.01 to 2.78 log reduction compared to the sum of each individual treatment. The most effective combination for reducing levels of biofilm cells was the combination of steam and iodophor; steam for 20 s and merely 20 ppm iodophor for 30 s reduced cell numbers to below the detection limit (<1.48 log CFU/coupon). These results suggest that the combination treatment of sanitizer with steam can be applied to control foodborne pathogens biofilm cells in food processing facilities as a potential intervention. PMID- 26742617 TI - Effect of pH on Thermoanaerobacterium thermosaccharolyticum DSM 571 growth, spore heat resistance and recovery. AB - Thermophilic spore-forming bacteria are potential contaminants in several industrial sectors involving high temperatures (40-65 degrees C) in the manufacturing process. Among those thermophilic spore-forming bacteria, Thermoanaerobacterium thermosaccharolyticum, called "the swelling canned food spoiler", has generated interest over the last decade in the food sector. The aim of this study was to investigate and to model pH effect on growth, heat resistance and recovery abilities after a heat-treatment of T. thermosaccharolyticum DSM 571. Growth and sporulation were conducted on reinforced clostridium media and liver broth respectively. The highest spore heat resistances and the greatest recovery ability after a heat-treatment were obtained at pH condition allowing maximal growth rate. Growth and sporulation boundaries were estimated, then models using growth limits as main parameters were extended to describe and quantify the effect of pH on recovery of injured spores after a heat-treatment. So, cardinal values were used as a single set of parameters to describe growth, sporulation and recovery abilities. Besides, this work suggests that T. thermosaccharolyticum preserve its ability for germination and outgrowth after a heat-treatment at a low pH where other high resistant spore forming bacteria like Geobacillus stearothermophilus are unable to grow. PMID- 26742618 TI - Transcriptome analysis of Bacillus thuringiensis spore life, germination and cell outgrowth in a vegetable-based food model. AB - Toxigenic species belonging to Bacillus cereus sensu lato, including Bacillus thuringiensis, cause foodborne outbreaks thanks to their capacity to survive as spores and to grow in food matrixes. The goal of this work was to assess by means of a genome-wide transcriptional assay, in the food isolate B. thuringiensis UC10070, the gene expression behind the process of spore germination and consequent outgrowth in a vegetable-based food model. Scanning electron microscopy and Energy Dispersive X-ray microanalysis were applied to select the key steps of B. thuringiensis UC10070 cell cycle to be analyzed with DNA microarrays. At only 40 min from heat activation, germination started rapidly and in less than two hours spores transformed in active growing cells. A total of 1646 genes were found to be differentially expressed and modulated during the entire B. cereus life cycle in the food model, with most of the significant genes belonging to transport, transcriptional regulation and protein synthesis, cell wall and motility and DNA repair groups. Gene expression studies revealed that toxin-coding genes nheC, cytK and hblC were found to be expressed in vegetative cells growing in the food model. PMID- 26742620 TI - Survival mechanism of Escherichia coli O157:H7 against combined treatment with acetic acid and sodium chloride. AB - The combination of salt and acid is commonly used in the production of many foods, including pickles and fermented foods. However, in our previous studies, the addition of salt significantly reduced the inhibitory effect of acetic acid on Escherichia coli O157:H7 in laboratory media and pickled cucumbers. Therefore, this study was conducted to determine the mechanism by which salt confers resistance against acetic acid in E. coli O157:H7. The addition of high concentrations (up to 9% or 15% [w/v]) of salt increased the resistance of E. coli O157:H7 to acetic acid treatment. Combined treatment with acetic acid and salt showed varying results among different bacterial strains (an antagonistic effect for E. coli O157:H7 and Shigella and a synergistic effect for Listeria monocytogenes and Staphylococcus aureus). The addition of salt increased the cytoplasmic pH of E. coli O157:H7, but decreased the cytoplasmic pH of L. monocytogenes and S. aureus on treatment with acetic acid. Therefore, the addition of salt increases the acid resistance of E. coli O157:H7 possibly by increasing its acid resistance response and consequently preventing the acidification of its cytoplasm by organic acids. PMID- 26742619 TI - Novel method based on chromogenic media for discrimination and selective enumeration of lactic acid bacteria in fermented milk products. AB - Microbial analyses of fermented milk products require selective methods to discriminate between close species simultaneously present in high amounts. A culture-based method combining novel chromogenic agar media and appropriate incubation conditions was developed to enumerate lactic acid bacteria (LAB) strains in fermented milk. M1 agar, containing two chromogenic substrates, allowed selective enumeration of Lactobacillus rhamnosus, two strains of Lactobacillus paracasei subsp. paracasei and Streptococcus salivarius subsp. thermophilus based on differential beta-galactosidase and beta-glucosidase activities. Depending on the presence of some or all of the above strains, M1 agar was supplemented with L-rhamnose or vancomycin and incubations were carried out at 37 degrees C or 44 degrees C to increase selectivity. A second agar medium, M2, containing one chromogenic substrates was used to selectively enumerate beta-galactosidase producing Lactobacillus delbrueckii subsp. bulgaricus at 47 degrees C. By contrast with the usual culture media, the chromogenic method allowed unambiguous enumeration of each species, including discrimination between the two L. paracasei, up to 10(9) CFU/g of fermented milk. In addition, the relevance of the method was approved by enumerating reference ATCC strains in pure cultures and fermented milk product. The method could also be used for enumerations on non-Danone commercial fermented milk products containing strains different from those used in this study, showing versatility of the method. To our knowledge, this is the first description of a chromogenic culture method applied to selective enumeration of LAB. PMID- 26742621 TI - Use of a novel medium, the Polymyxin Ceftazidime Oxford Medium, for isolation of Listeria monocytogenes from raw or non-pasteurized foods. AB - Polymyxin Ceftazidime Oxford Medium (PCOM), a novel selective and differential plating medium for Listeria monocytogenes was compared with Modified Oxford Agar (MOX) for efficacy to isolate L. monocytogenes and other Listeria spp. naturally present in non-pasteurized Mexican-style cheese (n = 50), non-pasteurized fresh squeezed orange juice (n = 50), raw beef chunks (n = 36), and fresh cabbage (n = 125). Samples were collected from retail markets and farms in Mexico and tested following the US Department of Agriculture enrichment technique. Listeria spp. were isolated from 23.4% of analyzed samples, and from those, 75.0% corresponded to raw beef chunks, 38.0% to non-pasteurized Mexican-style cheese, and 30.0% to fresh squeezed orange juice. No Listeria spp. were isolated from fresh cabbage samples. L. monocytogenes was recovered from 15.3% of food samples analyzed. Non pasteurized Mexican-style cheese showed the highest proportion of L. monocytogenes positive samples (36.0%), followed by orange juice (26.0%) and raw beef (25.0%). The frequency of isolation of Listeria spp. and L. monocytogenes was not different (P > 0.05) between PCOM and MOX. The advantages of using PCOM when comparing to MOX, include the easier way to identify Listeria species, the lower cost per plate and the availability of its ingredients for Latin-American countries. PMID- 26742623 TI - Enrichment of Acinetobacter spp. from food samples. AB - Relatively little is known about the role of foods in the chain of transmission of acinetobacters and the occurrence of different Acinetobacter spp. in foods. Currently, there is no standard procedure to recover acinetobacters from food in order to gain insight into the food-related ecology and epidemiology of acinetobacters. This study aimed to assess whether enrichment in Dijkshoorn enrichment medium followed by plating in CHROMagarTM Acinetobacter medium is a useful method for the isolation of Acinetobacter spp. from foods. Recovery of six Acinetobacter species from food spiked with these organisms was compared for two selective enrichment media (Baumann's enrichment and Dijkshoorn's enrichment). Significantly (p < 0.01) higher cell counts were obtained in Dijkshoorn's enrichment. Next, the Dijkshoorn's enrichment followed by direct plating on CHROMagarTM Acinetobacter was applied to detect Acinetobacter spp. in different foods. Fourteen different presumptive acinetobacters were recovered and assumed to represent nine different strains on the basis of REP-PCR typing. Eight of these strains were identified by rpoB gene analysis as belonging to the species Acinetobacter johnsonii, Acinetobacter calcoaceticus, Acinetobacter guillouiae and Acinetobacter gandensis. It was not possible to identify the species level of one strain which may suggests that it represents a distinct species. PMID- 26742622 TI - Metaproteomics and ultrastructure characterization of Komagataeibacter spp. involved in high-acid spirit vinegar production. AB - Acetic acid bacteria (AAB) are widespread microorganisms in nature, extensively used in food industry to transform alcohols and sugar alcohols into their corresponding organic acids. Specialized strains are used in the production of vinegar through the oxidative transformation of ethanol into acetic acid. The main AAB involved in the production of high-acid vinegars using the submerged fermentation method belong to the genus Komagataeibacter, characterized by their higher ADH stability and activity, and higher acetic acid resistance (15-20%), compared to other AAB. In this work, the bacteria involved in the production of high-acid spirit vinegar through a spontaneous acetic acid fermentation process was studied. The analysis using a culture-independent approach revealed a homogeneous bacterial population involved in the process, identified as Komagataeibacter spp. Differentially expressed proteins during acetic acid fermentation were investigated by using 2D-DIGE and mass spectrometry. Most of these proteins were functionally related to stress response, the TCA cycle and different metabolic processes. In addition, scanning and transmission electron microscopy and specific staining of polysaccharide SDS-PAGE gels confirmed that Komagataeibacter spp. lacked the characteristic polysaccharide layer surrounding the outer membrane that has been previously reported to have an important role in acetic acid resistance in the genus Acetobacter. PMID- 26742624 TI - Inhibition of epidermal growth factor receptor induces tumor necrosis factor alpha via activation of peroxisome proliferator-activated receptor-gamma and nuclear factor-kappaB in sebocytes: A possible pathogenesis of papulopustular rash. PMID- 26742625 TI - Complete genome sequence of Pandoraea oxalativorans DSM 23570(T), an oxalate metabolizing soil bacterium. AB - Pandoraea oxalativorans DSM 23570(T) is an oxalate-degrading bacterium that was originally isolated from soil litter near to oxalate-producing plant of the genus Oxalis. Here, we report the first complete genome of P. oxalativorans DSM 23570(T) which would allow its potential biotechnological applications to be unravelled. PMID- 26742627 TI - Design, synthesis and cytotoxic activity of a novel series of steroidal phenylpyrazoles. AB - Thirty novel steroidal pyrazole derivatives were designed and synthesized via a highly efficient route from pregnenolone (1) as starting material. The key intermediates 3a-c were obtained under Vilsmeier conditions, and the subsequent hydrolysis, acetylation or Borch reduction afforded thirty target compounds. These compounds were mainly characterized by (1)H NMR, (13)C NMR, DEPT135 degrees . The structure of compound 3a was also confirmed by X-ray single crystal diffraction. The cytotoxicity of these compounds was evaluated by the SRB method against four cancer cell lines, including A549, Hela, MCF-7 and HepG2, and the results indicated that compounds 5a, 6a, 7a and 8a exhibited significant cytotoxicity with IC50 values ranging from 0.91 to 5.44 MUM. Most importantly, compound 5a exhibited excellent cytotoxicity against A549 with an IC50 value of 0.91 MUM. On the basis of our research the structure-activity relationships (SAR) of these compounds were discussed. This work provides some important hints for further structural modification of steroids towards developing novel and highly effective anticancer drugs. PMID- 26742626 TI - Influence of respiratory dead space on lung clearance index in preterm infants. AB - Lung clearance index (LCI), a marker of ventilation inhomogeneity derived from multiple breath washout (MBW), is used for clinical monitoring and as a key outcome of clinical trials in infants and children with cystic fibrosis. Utility of LCI is controversial in preterm infants with bronchopulmonary dysplasia (BPD) who tend to have high dead space to tidal volume ratio (VD/VT). We investigated the effect of VD/VT on LCI in a cohort of preterm infants with and without BPD and term healthy controls. We analyzed MBW data from 455 infants at a mean (SD) of 43.4 (3.5) w postmenstrual age. VD was estimated from the molar mass signal of an ultrasonic flowmeter (VD,MM). LCI was associated with VD,MM/VT (r(2)=0.13, p<0.001) but was not associated with BPD. Adjusting for VD,MM/VT did not reveal an association between LCI and BPD. We conclude that VD,MM/VT is a relevant factor when interpreting LCI in this population but the effect size of this association is moderate. PMID- 26742628 TI - Expression and regulation of the estrogen receptors in PC-3 human prostate cancer cells. AB - The aim of this study was to identify the expression, cellular localization and regulation of classic estrogen receptors ERalpha and ERbeta, ER-alpha36 isoform and GPER in the androgen-independent prostate cancer cell line PC-3. In addition, we evaluated the relative contribution of these receptors to the activation of the ERK1/2 (extracellular signal-regulated protein kinases) signaling pathway. These four estrogen receptors were detected by Western blot assays and were shown by immunofluorescence assays to localize preferentially in extranuclear regions of PC-3 cells. In addition, treatment with 17beta-estradiol (E2) (1 MUM) for 24 h led to down-regulation of the classic estrogen receptors, whereas E2 at physiological concentration (0.1 nM) for 24h tended to increase the levels of ERalpha and ERbeta. Furthermore, the ERalpha-selective agonist PPT selectively increased the expression of ERbeta and the ERbeta-selective agonist DPN increased ERalpha levels. None of these treatments affected expression of the ER-alpha36 isoform. The unusual cytoplasmic localization of the classic estrogen receptors in these cells differs from the nuclear localization in the majority of estrogen target cells and suggests that rapid signaling pathways may be preferentially activated. In fact, treatment with selective agonists of ERalpha, ERbeta and GPER induced ERK1/2 phosphorylation that was blocked by the respective antagonists. On the other hand, activation of ERK1/2 induced by E2 may involve additional mechanisms because it was not blocked by the three antagonists. Taken together, the results indicate that there is a crosstalk between ERalpha and ERbeta to regulate the expression of each other, and suggest the involvement of other receptors, such as ER-alpha36, in the rapid ERK1/2 activation by E2. The identification of new isoforms of ERs, regulation of the receptors and signaling pathways is important to develop new therapeutic strategies for the castration resistant prostate cancer. PMID- 26742629 TI - Oxysterols: Synthesis and anti-leishmanial activities. AB - Oxygenated sterols (2-16) were synthesized by skeletal rearrangement of steroidal allylic alcohols. All the derivatives were screened for their anti-leishmanial activities. Compounds 3, 11 and 12 showed potent activities. Compound 12 was found least toxic and induced highest nitric oxide (NO) at 48 h. Least toxicity of compound 12 on splenocytes validated its best anti-amastigote effect and induction of NO. PMID- 26742630 TI - Solid-phase synthesis of libraries of ethynylated aminosteroid derivatives as potential antileukemic agents. AB - Steroids possessing an ethynyl group at position 17alpha (tertiary alcohols) are well known to be more stable than their non-ethynyl analogs (secondary alcohols). To facilitate the development of new drugs with better metabolic stability, we developed a new diethylsilyl acetylenic linker allowing us to rapidly synthesize libraries of ethynylated steroid derivatives using a solid-phase strategy. To illustrate its usefulness, this linker was used to expand the molecular diversity of a lead compound having a hydroxy acetylenic pattern and to potentially find new compounds with interesting cytotoxic activity against leukemia cell lines. Herein, we report the chemical synthesis and the characterization of three libraries of ethynylated aminosteroid derivatives using the diethylacetylenic linker. We discuss their antiproliferative activities obtained in 2 leukemia cell lines (HL-60 and Jurkat), which results provided new structure-activity relationships. We also identified a new promising aminosteroid derivative with an azetidine moiety (compound B1) inhibiting 60% and 75% of HL-60 and Jurkat cell proliferation, respectively, at 1 MUM. More generally, these results validate the use of a diethylsilyl acetylenic linker for researchers interested in generating libraries of alcohol derivatives with better stability and drug profile. PMID- 26742631 TI - Identification of the fragmentation of brittle particles during compaction process by the acoustic emission technique. AB - Some nuclear fuels are currently manufactured by a powder metallurgy process that consists of three main steps, namely preparation of the powders, powder compaction, and sintering of the compact. An optimum between size, shape and cohesion of the particles of the nuclear fuels must be sought in order to obtain a compact with a sufficient mechanical strength, and to facilitate the release of helium and fission gases during irradiation through pores connected to the outside of the pellet after sintering. Being simple to adapt to nuclear-oriented purposes, the Acoustic Emission (AE) technique is used to control the microstructure of the compact by monitoring the compaction of brittle Uranium Dioxide (UO2) particles of a few hundred micrometers. The objective is to identify in situ the mechanisms that occur during the UO2 compaction, and more specifically the particle fragmentation that is linked to the open porosity of the nuclear matter. Three zones of acoustic activity, strongly related to the applied stress, can be clearly defined from analysis of the continuous signals recorded during the compaction process. They correspond to particle rearrangement and/or fragmentation. The end of the noteworthy fragmentation process is clearly defined as the end of the significant process that increases the compactness of the material. Despite the fact that the wave propagation strongly evolves during the compaction process, the acoustic signature of the fragmentation of a single UO2 particle and a bed of UO2 particles under compaction is well identified. The waveform, with a short rise time and an exponential-like decay of the signal envelope, is the most reliable descriptor. The impact of the particle size and cohesion on the AE activity, and then on the fragmentation domain, is analyzed through the discrete AE signals. The maximum amplitude of the burst signals, as well as the mean stress corresponding to the end of the recorded AE, increase with increasing mean diameter of the particles. Moreover, the maximum burst amplitude increases with increasing particle cohesion. PMID- 26742632 TI - Age-related macular degeneration: Complement in action. AB - The complement system plays a key role in host-defense against common pathogens but must be tightly controlled to avoid inflammation and tissue damage. Polymorphisms in genes encoding two important negative regulators of the alternative complement pathway, complement factor H (CFH) and complement factor I (CFI), are associated with the risk for Age-Related Macular Degeneration (AMD), a leading cause of vision impairment in the ageing population. In this review, we will discuss the genetic basis of AMD and the potential impact of complement de regulation on disease pathogenesis. Finally, we will highlight recent therapeutic approaches aimed at controlling complement activation in patients with AMD. PMID- 26742633 TI - Nanoproteomic analysis of ischemia-dependent changes in signaling protein phosphorylation in colorectal normal and cancer tissue. AB - BACKGROUND: Clinical diagnostic research relies upon the collection of tissue samples, and for those samples to be representative of the in vivo situation. Tissue collection procedures, including post-operative ischemia, can impact the molecular profile of the tissue at the genetic and proteomic level. Understanding the influence of factors such as ischemia on tissue samples is imperative in order to develop both markers of tissue quality and ultimately accurate diagnostic tests. METHODS: Using NanoPro1000 technology, a rapid and highly sensitive immunoassay platform, the phosphorylation status of clinically relevant cancer-related biomarkers in response to ischemia was quantified in tissue samples from 20 patients with primary colorectal cancer. Tumor tissue and adjacent normal tissue samples were collected and subjected to cold ischemia prior to nanoproteomic analysis of AKT, ERK1/2, MEK1/2, and c-MET. Ischemia induced relative changes in overall phosphorylation and phosphorylation of individual isoforms were calculated and statistical significance determined. Any differences in baseline levels of phosphorylation between tumor tissue and normal tissue were also analyzed. RESULTS: Changes in overall phosphorylation of the selected proteins in response to ischemia revealed minor variations in both normal and tumor tissue; however, significant changes were identified in the phosphorylation of individual isoforms. In normal tissue post-operative ischemia, phosphorylation was increased in two AKT isoforms, two ERK1/2 isoforms, and one MEK1/2 isoform and decreased in one MEK1/2 isoform and one c-MET isoform. Following ischemia in tumor tissue, one AKT isoform showed decreased phosphorylation and there was an overall increase in unphosphorylated ERK1/2, whereas an increase in the phosphorylation of two MEK1/2 isoforms was observed. There were no changes in c-MET phosphorylation in tumor tissue. CONCLUSION: This study provides insight into the influence of post-operative ischemia on tissue sample biology, which may inform the future development of markers of tissue quality and assist in the development of diagnostic tests. PMID- 26742634 TI - An integrated global chemomics and system biology approach to analyze the mechanisms of the traditional Chinese medicinal preparation Eriobotrya japonica - Fritillaria usuriensis dropping pills for pulmonary diseases. AB - BACKGROUND: Traditional Chinese medicine (TCM) herbal formulae provide valuable therapeutic strategies. However, the active ingredients and mechanisms of action remain unclear for most of these formulae. Therefore, the identification of complex mechanisms is a major challenge in TCM research. METHODS: This study used a network pharmacology approach to clarify the anti-inflammatory and cough suppressing mechanisms of the Chinese medicinal preparation Eriobotrya japonica - Fritillaria usuriensis dropping pills (ChuanbeiPipa dropping pills, CBPP). The chemical constituents of CBPP were identified by high-quality ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS), and anti-inflammatory ingredients were selected and analyzed using the PharmMapper and Kyoto Encyclopedia of Genes and Genomes (KEGG) bioinformatics websites to predict the target proteins and related pathways, respectively. Then, an RNA-sequencing (RNA-Seq) analysis was carried out to investigate the different expression of genes in the lung tissue of rats with chronic bronchitis. RESULTS: Six main constituents affected 19 predicted pathways, including ursolic acid and oleanolic acid from Eriobotrya japonica (Thunb.) Lindl. (Eri), peiminine from Fritillaria usuriensis Maxim. (Fri), platycodigenin and polygalacic acid from Platycodon grandiflorum (Jacq.) A. DC. (Pla) and guanosine from Pinellia ternata (Thunb.) Makino. (Pin). Expression of 34 genes was significantly decreased after CBPP treatment, affecting four therapeutic functions: immunoregulation, anti inflammation, collagen formation and muscle contraction. CONCLUSION: The active components acted on the mitogen activated protein kinase (MAPK) pathway, transforming growth factor (TGF)-beta pathway, focal adhesion, tight junctions and the action cytoskeleton to exert anti-inflammatory effects, resolve phlegm, and relieve cough. This novel approach of global chemomics-integrated systems biology represents an effective and accurate strategy for the study of TCM with multiple components and multiple target mechanisms. PMID- 26742635 TI - Genome-wide analysis of tomato NF-Y factors and their role in fruit ripening. AB - BACKGROUND: Fruit ripening is a complex developmental process that depends on a coordinated regulation of numerous genes, including ripening-related transcription factors (TFs), fruit-related microRNAs, DNA methylation and chromatin remodeling. It is known that various TFs, such as MADS-domain, MYB, AP2/ERF and SBP/SPL family proteins play key roles in modulating ripening. However, little attention has been given to members of the large NF-Y TF family in this regard, although genes in this family are known to have important functions in regulating plant growth, development, and abiotic or biotic stress responses. RESULTS: In this study, the evolutionary relationship between Arabidopsis thaliana and tomato (Solanum lycopersicum) NF-Y genes was examined to predict similarities in function. Furthermore, through gene expression analysis, 13 tomato NF-Y genes were identified as candidate regulators of fruit ripening. Functional studies involving suppression of NF-Y gene expression using virus induced gene silencing (VIGS) indicated that five NF-Y genes, including two members of the NF-YB subgroup (Solyc06g069310, Solyc07g065500) and three members of the NF-YA subgroup (Solyc01g087240, Solyc08g062210, Solyc11g065700), influence ripening. In addition, subcellular localization analyses using NF-Y proteins fused to a green fluorescent protein (GFP) reporter showed that the three NF-YA proteins accumulated in the nucleus, while the two NF-YB proteins were observed in both the nucleus and cytoplasm. CONCLUSIONS: In this study, we identified tomato NF-Y genes by analyzing the tomato genome sequence using bioinformatics approaches, and characterized their chromosomal distribution, gene structures, phylogenetic relationship and expression patterns. We also examined their biological functions in regulating tomato fruit via VIGS and subcellular localization analyses. The results indicated that five NF-Y transcription factors play roles in tomato fruit ripening. This information provides a platform for further investigation of their biological functions. PMID- 26742636 TI - Immunity raised by recent European subtype 1 PRRSV strains allows better replication of East European subtype 3 PRRSV strain Lena than that raised by an older strain. AB - Stable spatial distribution of porcine reproductive and respiratory syndrome (PRRSV)-1 subtypes in Europe is accompanied by a strong population immunity induced by local PRRSV strains. In the present study, it was examined if the immunity induced by three West European subtype 1 PRRSV strains (2007 isolate 07V063 and 2013 isolates 13V091 and 13V117) offers protection against the highly virulent East European subtype 3 PRRSV strain Lena. The number of fever days was greater (p < 0.05) in the control group (7.6 +/- 1.7 days) compared to the immune groups (07V063-immune: 4.0 +/- 1.2 days, 13V091-immune: 4.6 +/- 1.1 days, 13V117 immune: 4.0 +/- 2.9 days). In all groups, protection was characterized by reduction (p < 0.05) of AUC values of nasal shedding (control: 14.6, 07V063 immune: 3.4, 13V091-immune: 8.9, 13V117-immune: 8.0) and viremia (control: 28.1, 07V063-immune: 5.4, 13V091-immune: 9.0, 13V117-immune: 8.3). Reduction of respiratory disease, nasal shedding (mean AUC and mean peak values) and viremia (mean AUC and mean peak values) was more pronounced in 07V063-immune (p < 0.05) than in 13V091-immune and 13V117-immune animals. Inoculation with subtype 1 PRRSV strains caused priming of the Lena-specific virus neutralization antibody response. Upon challenge with Lena, we observed a very strong serological booster effect for neutralizing antibodies against strains used for the first inoculation. Our results indicate that inoculation with subtype 1 PRRSV strains can partially protect against antigenically divergent subtype 3 strains. The lower protection level elicited by recently isolated subtype 1 PRRSV strains may impair the outcome of the spatial expansion of subtype 3 strains from East Europe to West Europe. PMID- 26742638 TI - The effects of selective and divided attention on sensory precision and integration. AB - In our daily lives, our capacity to selectively attend to stimuli within or across sensory modalities enables enhanced perception of the surrounding world. While previous research on selective attention has studied this phenomenon extensively, two important questions still remain unanswered: (1) how selective attention to a single modality impacts sensory integration processes, and (2) the mechanism by which selective attention improves perception. We explored how selective attention impacts performance in both a spatial task and a temporal numerosity judgment task, and employed a Bayesian Causal Inference model to investigate the computational mechanism(s) impacted by selective attention. We report three findings: (1) in the spatial domain, selective attention improves precision of the visual sensory representations (which were relatively precise), but not the auditory sensory representations (which were fairly noisy); (2) in the temporal domain, selective attention improves the sensory precision in both modalities (both of which were fairly reliable to begin with); (3) in both tasks, selective attention did not exert a significant influence over the tendency to integrate sensory stimuli. Therefore, it may be postulated that a sensory modality must possess a certain inherent degree of encoding precision in order to benefit from selective attention. It also appears that in certain basic perceptual tasks, the tendency to integrate crossmodal signals does not depend significantly on selective attention. We conclude with a discussion of how these results relate to recent theoretical considerations of selective attention. PMID- 26742637 TI - Associated degeneration of ventral tegmental area dopaminergic neurons in the rat nigrostriatal lactacystin model of parkinsonism and their neuroprotection by valproate. AB - Parkinson's disease (PD) manifests clinically as bradykinesia, rigidity, and development of a resting tremor, primarily due to degeneration of dopaminergic nigrostriatal pathways in the brain. Intranigral administration of the irreversible ubiquitin proteasome system inhibitor, lactacystin, has been used extensively to model nigrostriatal degeneration in rats, and study the effects of candidate neuroprotective agents on the integrity of the dopaminergic nigrostriatal system. Recently however, adjacent extra-nigral brain regions such as the ventral tegmental area (VTA) have been noted to also become affected in this model, yet their integrity in studies of candidate neuroprotective agents in the model have largely been overlooked. Here we quantify the extent and distribution of dopaminergic degeneration in the VTA of rats intranigrally lesioned with lactacystin, and quantify the extent of VTA dopaminergic neuroprotection after systemic treatment with an epigenetic therapeutic agent, valproate, shown previously to protect dopaminergic SNpc neurons in this model. We found that unilateral intranigral administration of lactacystin resulted in a 53.81% and 31.72% interhemispheric loss of dopaminergic SNpc and VTA neurons, respectively. Daily systemic treatment of lactacystin lesioned rats with valproate however resulted in dose-dependant neuroprotection of VTA neurons. Our findings demonstrate that not only is the VTA also affected in the intranigral lactacystin rat model of PD, but that this extra-nigral brain region is substrate for neuroprotection by valproate, an agent shown previously to induce neuroprotection and neurorestoration of SNpc dopaminergic neurons in this model. Our results therefore suggest that valproate is a candidate for extra-nigral as well as intra-nigral neuroprotection. PMID- 26742639 TI - Higher level of NT-proCNP in cerebrospinal fluid of patients with meningitis. AB - Aminoterminal pro-C type natriuretic peptide (NT-proCNP) as an active form of CNP, has been recently proven to be a potential marker of sepsis and to be linked to inflammatory diseases. So far, there are no studies describing the level of NT proCNP in meningitis. The purpose of this study was to evaluate the diagnostic value of NT-proCNP in cerebrospinal fluid (CSF) in patients with meningitis and to compare it with the serum level of CRP and procalcitonin (PCT) in this group of patients. The results were compared to serum levels of CRP, PCT and CSF levels of cytosis, protein and lactate. NT-proCNP levels were statistically significant between the control group and the meningitis groups (p=0.02; R=0.3). We also noted a correlation between the level of NT-proCNP in the CSF of all of the study groups (controls and meningitis patients) and the CSF levels of cytosis (p<0.5; R=0.43), protein (p<0.05; R=0.39) and lactate (p<0.05; R=0.34), and also the serum level of CRP (p<0.05; R=0.30), but not serum PCT (p>0.05; R=0.11). These results suggest that NT-proCNP could be a potential marker of meningitis, but it cannot be used to distinguish between the types of meningitis. PMID- 26742640 TI - Phosphorylation of Fe65 amyloid precursor protein-binding protein in response to neuronal differentiation. AB - Fe65 is a brain enriched multi domain adaptor protein involved in diverse cellular functions. One of its binding partners is the amyloid-beta (Abeta) precursor protein (APP), which after sequential proteolytic processing by secretases gives rise to the Alzheimer's Abeta peptide. Fe65 binds to the APP intracellular domain (AICD). Several studies have indicated that Fe65 binding promotes the amyloidogenic processing of APP. It has previously been shown that expression of APP increases concomitantly with a shift of its processing to the non-amyloidogenic pathway during neuronal differentiation. In this study we wanted to investigate the effects of neuronal differentiation on Fe65 expression. We observed that differentiation of SH-SY5Y human neuroblastoma cells induced by retinoic acid (RA), the phorbol ester PMA, or the gamma-secretase inhibitor DAPT resulted in an electrophoretic mobility shift of Fe65. Similar effects were observed in rat PC6.3 cells treated with nerve growth factor. The electrophoretic mobility shift was shown to be due to phosphorylation. Previous studies have shown that Fe65 phosphorylation can prevent the APP-Fe65 interaction. We propose that phosphorylation is a way to modify the functions of Fe65 and to promote the non-amyloidogenic processing of APP during neuronal differentiation. PMID- 26742641 TI - Functional lateralization in cingulate cortex predicts motor recovery after basal ganglia stroke. AB - The basal ganglia (BG) is involved in higher order motor control such as movement planning and execution of complex motor synergies. Neuroimaging study on stroke patients specifically with BG lesions would help to clarify the consequence of BG damage on motor control. In this paper, we performed a longitudinal study in the stroke patients with lesions in BG regions across three motor recovery stages, i.e., less than 2week (Session 1), 1-3m (Session 2) and more than 3m (Session 3). The patients showed an activation shift from bilateral hemispheres during early sessions (<3m) to the ipsilesional cortex in late session (>3m), suggesting a compensation effect from the contralesional hemisphere during motor recovery. We found that the lateralization of cerebellum(CB) for affected hand task correlated with patients' concurrent Fugl-Meyer index (FMI) in Session 2. Moreover, the cingulate cortex lateralization index in Session 2 was shown to significantly correlate with subsequent FMI change between Session 3 and Session 2, which serves as a prognostic marker for motor recovery. Our findings consolidated the close interactions between BG and CB during the motor recovery after stroke. The dominance of activation in contralateral cingulate cortex was associated with a better motor recovery, suggesting the important role of ipsilesional attention modulation in the early stage after BG stroke. PMID- 26742642 TI - Gray matter atrophy associated with mild cognitive impairment in Parkinson's disease. AB - OBJECTIVE: The underlying pathology of brain leading to cognitive impairment in Parkinson's disease (PD) remains poorly understood. The aim of our study was to test the hypothesis that mild cognitive impairment (MCI) in PD may be related to atrophy of special gray matter regions. METHODS: High-resolution T1-weighted magnetic resonance images of the brains and comprehensive cognitive function tests were acquired in 37 PD patients and 21 healthy controls (HC) from September 2013 to October 2014. Patients were divided into two groups: PD with MCI (PD-MCI, n=18) and PD with normal cognition (PDNC, n=19). Gray matter density differences were analyzed using voxel-based morphometry (VBM). VBM and cognitive results, UPDRS scores and Hoehn-Yahr stages were compared between PD-MCI, PDCN and HC group, and correlation analyses were performed between those brain areas and cognition scores, UPDRS scores and disease duration, which showed significant group differences. RESULTS: The demographic data and motor severity among three groups were similar. However, comprehensive cognitive function results were more severe in PD-MCI than the other two groups. Compared to the HC group, the PDNC group showed reductions in gray matter density in frontal, temporal, parietal, bilateral insula lobes and many other regions of brain. Besides above changes, the PD-MCI group also revealed gray matter concentration decrease in left hippocampus and thalamus, and these changes still remained when compared with the PDNC group. The HC group did not show any more areas of atrophy in gray matter than others. Gray matter loss in PD represented significant correlations with global cognitive scores, motor severity or disease duration in some of these atrophic regions. CONCLUSION: The initial stages of cognitive function decline in patients with PD is closely associated with gray matter atrophy in left hippocampus and thalamus. These two regions may serve as potential imaging biomarkers for PD-MCI. PMID- 26742643 TI - Sensorimotor activation related to speaker vs. listener role during natural conversation. AB - Although the main function of speech is communication, the brain bases of speaking and listening are typically studied in single subjects, leaving unsettled how brain function supports interactive vocal exchange. Here we used whole-scalp magnetoencephalography (MEG) to monitor modulation of sensorimotor brain rhythms related to the speaker vs. listener roles during natural conversation. Nine dyads of healthy adults were recruited. The partners of a dyad were engaged in live conversations via an audio link while their brain activity was measured simultaneously in two separate MEG laboratories. The levels of ~10 Hz and ~20-Hz rolandic oscillations depended on the speaker vs. listener role. In the left rolandic cortex, these oscillations were consistently (by ~20%) weaker during speaking than listening. At the turn changes in conversation, the level of the ~10Hz oscillations enhanced transiently around 1.0 or 2.3s before the end of the partner's turn. Our findings indicate left-hemisphere-dominant involvement of the sensorimotor cortex during own speech in natural conversation. The ~10-Hz modulations could be related to preparation for starting one's own turn, already before the partner's turn has finished. PMID- 26742644 TI - Identification of novel gene and pathway targets for human epilepsy treatment. AB - BACKGROUND: The aim of this study was to explore epilepsy-related mechanism so as to figure out the possible targets for epilepsy treatment. METHODS: The gene expression profile dataset GES32534 was downloaded from Gene Expression Omnibus database. We identified the differentially expressed genes (DEGs) by Affy package. Then the DEGs were used to perform gene ontology (GO) and pathway enrichment analyses. Furthermore, a protein-protein interaction (PPI) network was constructed with the DEGs followed by co-expression modules construction and analysis. RESULTS: Total 420 DEGs were screened out, including 214 up-regulated and 206 down-regulated genes. Functional enrichment analysis revealed that down regulated genes were mainly involved in the process of immunity regulation and biological repairing process while up-regulated genes were closely related to transporter activity. PPI network analysis showed the top ten genes with high degrees were all down-regulated, among which FN1 had the highest degree. The up regulated and down-regulated DEGs in the PPI network generated two obvious sub-co expression modules, respectively. In up-co-expression module, SCN3B (sodium channel, voltage gated, type III beta subunit) was enriched in GO:0006814 ~ sodium ion transport. In down-co-expression module, C1QB (complement C1s), C1S (complement component 1, S subcomponent) and CFI (complement factor I) were enriched in GO:0006955 ~ immune response. CONCLUSION: The immune response and complement system play a major role in the pathogenesis of epilepsy. Additionally, C1QB, C1S, CFI, SCN3B and FN1 may be potential therapeutic targets for epilepsy. PMID- 26742645 TI - Analysis of anti-asthmatic drug patents published in China between 2004 and 2013. AB - INTRODUCTION: We previously reported that 789 anti-allergic patents were granted in China between 1988 and 2008, but the number of patents seems to have grown much faster in China in recent years. Therefore, it is necessary to analyse the patents for anti-asthmatic products between 2004 and 2013 to give pharmaceutical companies and individuals a better understanding of potential candidates for anti asthmatic drug development from patents published in China. AREAS COVERED: The current report analyses the scientific progress that supports anti-asthmatic drug patent applications and reviews the published patent literature in China from 2004 to 2013. EXPERT OPINION: The rapid increase in the number of anti-asthmatic patents in China indicates that more specific discoveries have been made and that more people are aware of the importance of intellectual property protection in China. Holding patents may guarantee protection for an innovative new product. PMID- 26742646 TI - Abnormal spontaneous brain activity in minimal hepatic encephalopathy: resting state fMRI study. AB - PURPOSE: We aimed to assess the abnormality of baseline spontaneous brain activity in minimal hepatic encephalopathy (MHE) by amplitude of low frequency fluctuation (ALFF) and fraction ALFF (fALFF). METHODS: A total of 14 MHE patients and 14 healthy controls were included in our study. Both ALFF and fALFF of functional magnetic resonance imaging were calculated for statistical analysis. RESULTS: Compared with healthy controls, patients with MHE had significantly decreased ALFF in the bilateral medial prefrontal cortex (MPFC), left superior frontal gyrus, right precentral gyrus, left opercular part of inferior frontal gyrus, left gyrus rectus, bilateral precuneus, and the posterior lobe of right cerebellum; and they had significantly decreased fALFF in the bilateral MPFC, right middle frontal gyrus, right superior temporal gyrus, and the posterior lobe of left cerebellum. CONCLUSION: ALFF and fALFF changes in many brain regions demonstrate abnormality of the spontaneous neuronal activity in MHE. Especially the impairment of right precuneus and left MPFC may play a critical role in manifestation of MHE. Changes of ALFF and fALFF in the precuneus and the MPFC can be used as a potential marker for MHE. PMID- 26742648 TI - Panniculitis: an unusual presenting manifestation of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a systemic inflammatory disease affecting primarily the joints but also other organs including skin. Panniculitis is an extremely rare manifestation of the disease manifesting mainly as reddish, ulcerative painful nodules and papules, usually in the legs. Histopathologically, it is characterised by liponecrobiosis, granulocytic and histiocytic infiltrates and vasculopathy. Herein, we describe a middle-aged woman with past medical history of hypertension and diabetes mellitus, and unremarkable family history, who presented with symmetrical polyarthritis, low grade fever and painful subcutaneous nodules in the abdomen. Her laboratory tests showed high acute phase reactants, positive rheumatoid factor and anti-Ro autoantibodies and negative anti-CCP. Surgical resection and histological examination of the nodules revealed neutrophilic lobular panniculitis associated with RA. She was treated with low doses of glucocorticosteroids and methotrexate. The latter was substituted with leflunomide due to toxicity. The patient had significant clinical and laboratory improvement. PMID- 26742647 TI - 17beta-estradiol counteracts neuropathic pain: a behavioural, immunohistochemical, and proteomic investigation on sex-related differences in mice. AB - Sex differences play a role in pain sensitivity, efficacy of analgesic drugs and prevalence of neuropathic pain, even if the underlying mechanisms are far from being understood. We demonstrate that male and female mice react differently to structural and functional changes induced by sciatic nerve ligature, used as model of neuropathic pain. Male mice show a gradual decrease of allodynia and a complete recovery while, in females, allodynia and gliosis are still present four months after neuropathy induction. Administration of 17beta-estradiol is able to significantly attenuate this difference, reducing allodynia and inducing a complete recovery also in female mice. Parallel to pain attenuation, 17beta estradiol treated-mice show a functional improvement of the injured limb, a faster regenerative process of the peripheral nerve and a decreased neuropathy induced gliosis. These results indicate beneficial effects of 17beta-estradiol on neuropathic pain and neuronal regeneration and focuses on the importance of considering gonadal hormones also in clinical studies. PMID- 26742649 TI - Effects of lidocaine on torn rotator cuff tendons. AB - We determined lidocaine's action on torn rotator cuff tendons in vitro and in vivo. For in vitro experiments, cell proliferation and viability assays were performed using tenocytes derived from human torn rotator cuff tendons. For in vivo experiments, acute rotator cuff tears were made on the supraspinatus tendons in the rats' bilateral shoulders; before closure, lidocaine was injected into the shoulder and saline into the contralateral shoulder (control). After sacrifice, the specimens underwent biomechanical testing or histological analysis at 24 h and at 2, 4, and 8 weeks after surgery. The extent of collagen organization and apoptosis were semi-quantitatively evaluated using collagen picrosirius red staining. Apoptosis was examined using TUNEL staining and electron microscopy. Cell proliferation decreased dose-dependently. After exposure to 0.1% lidocaine for 24 h, cell viability decreased. Two and 4 weeks after surgery, the ultimate load to failure decreased more in the lidocaine group than in the control group, with significantly reduced stiffness in the lidocaine group 2 weeks after surgery. Collagen organization significantly decreased in the lidocaine group by 4 weeks after surgery but returned to baseline at 8 weeks. TUNEL staining detected numerous apoptotic tenocytes at the torn tendon edge exposed to lidocaine 24 h after surgery; electron microscopy confirmed the condensed cell nuclei. These changes were not observed in controls. Lidocaine caused cytotoxicity to tenocytes under both conditions, decreased biomechanical properties, and induced apoptosis and delay of collagen organization in this model. Subacromial lidocaine injections in patients with rotator cuff tears should be performed carefully. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1620-1627, 2016. PMID- 26742651 TI - Observing climate change trends in ocean biogeochemistry: when and where. AB - Understanding the influence of anthropogenic forcing on the marine biosphere is a high priority. Climate change-driven trends need to be accurately assessed and detected in a timely manner. As part of the effort towards detection of long-term trends, a network of ocean observatories and time series stations provide high quality data for a number of key parameters, such as pH, oxygen concentration or primary production (PP). Here, we use an ensemble of global coupled climate models to assess the temporal and spatial scales over which observations of eight biogeochemically relevant variables must be made to robustly detect a long-term trend. We find that, as a global average, continuous time series are required for between 14 (pH) and 32 (PP) years to distinguish a climate change trend from natural variability. Regional differences are extensive, with low latitudes and the Arctic generally needing shorter time series (<~30 years) to detect trends than other areas. In addition, we quantify the 'footprint' of existing and planned time series stations, that is the area over which a station is representative of a broader region. Footprints are generally largest for pH and sea surface temperature, but nevertheless the existing network of observatories only represents 9-15% of the global ocean surface. Our results present a quantitative framework for assessing the adequacy of current and future ocean observing networks for detection and monitoring of climate change-driven responses in the marine ecosystem. PMID- 26742650 TI - Notch signal reception is required in vascular smooth muscle cells for ductus arteriosus closure. AB - The ductus arteriosus is an arterial vessel that shunts blood flow away from the lungs during fetal life, but normally occludes after birth to establish the adult circulation pattern. Failure of the ductus arteriosus to close after birth is termed patent ductus arteriosus, and is one of the most common congenital heart defects. Our previous work demonstrated that vascular smooth muscle cell expression of the Jag1 gene, which encodes a ligand for Notch family receptors, is essential for postnatal closure of the ductus arteriosus in mice. However, it was not known what cell population was responsible for receiving the Jag1 mediated signal. Here we show, using smooth muscle cell-specific deletion of the Rbpj gene, which encodes a transcription factor that mediates all canonical Notch signaling, that Notch signal reception in the vascular smooth muscle cell compartment is required for ductus arteriosus closure. These data indicate that homotypic vascular smooth muscle cell interactions are required for proper contractile smooth muscle cell differentiation and postnatal closure of the ductus arteriosus in mice. PMID- 26742653 TI - Visual quantification of embolism reveals leaf vulnerability to hydraulic failure. AB - Vascular plant mortality during drought has been strongly linked to a failure of the internal water transport system caused by the rapid invasion of air and subsequent blockage of xylem conduits. Quantification of this critical process is greatly complicated by the existence of high water tension in xylem cells making them prone to embolism during experimental manipulation. Here we describe a simple new optical method that can be used to record spatial and temporal patterns of embolism formation in the veins of water-stressed leaves for the first time. Applying this technique in four diverse angiosperm species we found very strong agreement between the dynamics of embolism formation during desiccation and decline of leaf hydraulic conductance. These data connect the failure of the leaf water transport network under drought stress to embolism formation in the leaf xylem, and suggest embolism occurs after stomatal closure under extreme water stress. PMID- 26742652 TI - Retinal vessel oxygen saturation in a healthy young Chinese population. AB - PURPOSE: To measure retinal vessel oxygen saturation in a healthy young Chinese population and to determine the effects of multiple factors (gender, age, dioptre, vessel diameter and ocular perfusion pressure - OPP) on retinal oxygen saturation. METHODS: A total of 126 healthy Chinese individuals aged from 19 to 30 were included in this study. A retinal oximeter (Oxymap T1) was used to measure retinal vessel oxygen saturation by retinal imaging at two different wavelengths. The mean retinal vessel oxygen saturation (Sat_O2 ) of arterioles, venules and arteriovenous (AV) difference overall and in four separate quadrants were measured. Intra-ocular pressure, blood pressure, finger pulse oximetry value, vessel diameter and dioptre were also measured. The correlations between OPP and dioptre, OPP and vessel diameter, and dioptre and vessel diameter were analysed. And the effects of multiple factors on the retinal oxygen saturation were analysed. RESULTS: The mean oxygen saturation was 93.2 +/- 6.3% in the retinal arterioles, 60.4 +/- 5.3% in venules and 32.9 +/- 6.4% in AV difference. The temporal quadrants had lower measurements of arteriolar and venular oxygen saturation and AV difference compared with nasal quadrants (p < 0.001). The oxygen saturation of the arterioles, venules and AV difference were unaffected by any unique factor. Arteriolar and venular retinal oxygen saturation correlated negatively with the product of dioptre and OPP. Arteriolar retinal oxygen saturation correlated positively with the product of dioptre and vessel diameter. CONCLUSIONS: This study provided a normal reference of Sat_O2 in healthy young Chinese individuals. It was a reflection of the normal state of retinal oxygen metabolism affected by several factors. PMID- 26742654 TI - Quantitative Flow Cytometry Measurements in Antibodies Bound per Cell Based on a CD4 Reference. AB - Multicolor flow cytometer assays with fluorescently labeled antibodies are routinely used in clinical laboratories to measure the cell number of specific immunophenotypes and to estimate expression levels of specific receptors/antigens either on the cell surface or intracellularly. The cell number and specific receptors/antigens serve as biomarkers for pathological conditions at various stages of a disease. Existing methods and cell reference materials for quantitative expression measurements have not yet produced results that are of wide clinical interest or are instrument-independent across all fluorescence channels. This unit details a procedure for quantifying surface and intracellular biomarkers by calibrating the output of a multicolor flow cytometer in units of antibody bound per cell (ABC). The procedure includes (1) quality control of the flow cytometer, (2) fluorescence intensity calibration using hard dyed microspheres assigned with fluorescence intensity values, (3) compensation for fluorescence spillover between adjacent fluorescence channels, and (4) application of a biological reference calibrator to establish an ABC scale. The unit also points out current efforts for quantifying biomarkers in a manner that is independent of instrument platforms and reagent differences. PMID- 26742655 TI - Optimized MOL-PCR for Characterization of Microbial Pathogens. AB - Characterization of microbial pathogens is necessary for surveillance, outbreak detection, and tracing of outbreak sources. This unit describes a multiplex oligonucleotide ligation-PCR (MOL-PCR) optimized for characterization of microbial pathogens. With MOL-PCR, different types of markers, like unique sequences, single-nucleotide polymorphisms (SNPs) and indels, can be simultaneously analyzed in one assay. This assay consists of a multiplex ligation for detection of the markers, a singleplex PCR for signal amplification, and hybridization to MagPlex-TAG beads for readout on a Luminex platform after fluorescent staining. The current protocol describes the MOL-PCR, as well as methods for DNA isolation, probe design, and data interpretation and it is based on an optimized MOL-PCR assay for subtyping of Salmonella Typhimurium. PMID- 26742657 TI - S-Trifluoromethylation of Thiols by Hypervalent Iodine Reagents: A Joint Experimental and Computational Study. AB - The radical trifluoromethylation of thiophenol in condensed phase applying reagent 1 (3,3-dimethyl-1-(trifluoromethyl)-1lambda(3),2-benziodoxol) has been examined by both theoretical and experimental methodologies. On the basis of ab initio molecular dynamics and metadynamics we show that radical reaction mechanisms favourably compete with polar ones involving the S-centred nucleophile thiophenol, their free energies of activation, DeltaF(?), lying between 9 and 15 kcal mol(-1). We further show that the origin of the proton activating the reagent is important. Hammett plot analysis reveals intramolecular protonation of 1, thus generating negative charge on the sulfur atom in the rate-determining step. The formation of a CF3 radical can be thermally induced by internal dissociative electron transfer, its activation energy, DeltaF(?), amounting to as little as 10.8 and 2.8 kcal mol(-1) for reagent 1 and its protonated form 2, respectively. The reduction of the iodine atom by thiophenol occurs either subsequently or in a concerted fashion. PMID- 26742656 TI - Simultaneous, Single-Cell Measurement of Messenger RNA, Cell Surface Proteins, and Intracellular Proteins. AB - Nucleic acid content can be quantified by flow cytometry through the use of intercalating compounds; however, measuring the presence of specific sequences has hitherto been difficult to achieve by this methodology. The primary obstacle to detecting discrete nucleic acid sequences by flow cytometry is their low quantity and the presence of high background signals, rendering the detection of hybridized fluorescent probes challenging. Amplification of nucleic acid sequences by molecular techniques such as in situ PCR have been applied to single cell suspensions, but these approaches have not been easily adapted to conventional flow cytometry. An alternative strategy implements a Branched DNA technique, comprising target-specific probes and sequentially hybridized amplification reagents, resulting in a theoretical 8,000- to 16,000-fold increase in fluorescence signal amplification. The Branched DNA technique allows for the quantification of native and unmanipulated mRNA content with increased signal detection and reduced background. This procedure utilizes gentle fixation steps with low hybridization temperatures, leaving the assayed cells intact to permit their concomitant immunophenotyping. This technology has the potential to advance scientific discovery by correlating potentially small quantities of mRNA with many biological measurements at the single-cell level. PMID- 26742658 TI - Bacterial endophytes from wild and ancient maize are able to suppress the fungal pathogen Sclerotinia homoeocarpa. AB - AIMS: The aim of this study was to determine if endophytes from wild and ancient Zea plants (corn family) have anti-fungal activities, specifically against the most important fungal pathogen (Sclerotinia homoeocarpa) of creeping bentgrass, a relative of Zea, used here as a model grass. METHODS AND RESULTS: A library of 190 bacterial endophytes from wild, ancient and modern Zea plants were tested for their ability to suppress S. homoeocarpa in vitro, followed by in planta testing of candidates using greenhouse trials. Three endophytes could suppress S. homoeocarpa, originating from wild maize and an ancient Mexican landrace, consistent with our hypothesis. 16S phylogenetic analysis and BOX-PCR DNA fingerprinting suggest that the anti-fungal endophytes are distinct strains of Burkholderia gladioli. One strain (3A12) was confirmed to colonize creeping bentgrass using green fluorescent protein (GFP) tagging. Evans blue vitality staining demonstrated that the bacterial endophytes exhibited fungicidal activities against the pathogen. The endophytes inhibited a wide spectrum of plant-associated fungi including diverse crop pathogens. CONCLUSIONS: The results support the hypothesis that wild and ancient Zea genotypes host bacterial endophytes that can control fungal pathogen(s). SIGNIFICANCE AND IMPACT OF THE STUDY: These results suggest that wild and ancient crops may be an unexplored reservoir of anti-fungal bacterial endophytes. PMID- 26742659 TI - Comparison of posaconazole serum concentrations from haematological cancer patients on posaconazole tablet and oral suspension for treatment and prevention of invasive fungal infections. AB - Posaconazole tablet formulation (PTF) was developed to optimise bioavailability. This study compared posaconazole levels between patients on the PTF and oral suspension formulation (OSF). We also examined factors that may impact posaconazole levels. The primary and secondary objectives were analysed by comparing trough levels and attainment of target level between the formulation groups. For the 86 patients on PTF and 176 on OSF, the mean first levels was 1.32 MUg ml-1 (SD = 0.69) and 0.81 MUg ml-1 (SD = 0.59), P < 0.0001 respectively. PTF group was more likely to achieve levels >=0.7 MUg ml-1 than OSF group (OR 7.97 [95 CI; 3.75-16.93], P < 0.0001). Levels from patients on PTF and with presence of acid suppression, GI GVHD, mucositis or diarrhoea were not statistically different from those without these factors. For PTF, no correlation was found between patient's weight (kg) and levels (R2 = 0.0536, P = 0.035). The incidences of elevation in ALT/AST or Tbili were similar between the formulation groups. In conclusion, PTF should be considered the preferred formulation because it demonstrated better absorption than the OSF. Patients on PTF for prophylaxis are more likely to attain target level and may not routinely require therapeutic drug monitoring during prophylaxis. PMID- 26742660 TI - Recent developments in automatic scoring of rodent sleep. AB - Sleep research carried out on rat and mouse model led to the publication of more than 5000 papers in the last 15 years, of which more than 500 in 2014. Wake-sleep scoring represents a crucial step of the work performed in pre- clinical sleep laboratories; it is a time consuming task and a potential source of errors affecting research outcomes. Several algorithms have been developed to perform automatic sleep scoring. Automatic scoring can accelerate the work of researchers substantially. Moreover, the use of sleep scoring algorithms facilitates the direct comparison of the results produced in different laboratories, with clear advantages from the viewpoint of the advancement of science and reduction of the number of animals used for research. The intent of this review is to provide the readers with the last developments in scoring in rodent sleep and to stress about the need of a cross-lab and cross-species validated algorithm. PMID- 26742661 TI - Wake-sleep, thermoregulatory, and autonomic effects of cholinergic activation of the lateral hypothalamus in the rat: a pilot study. AB - A major role in the wake-promoting effects of the activation of the lateral hypothalamus (LH) has been ascribed to a population of orexin (ORX)-containing neurons that send projections to central areas which regulate Wake-Sleep and autonomic function. Since, in the rat, a substantial amount of ORX neurons receive cholinergic projections from cells involved in Wake-Sleep regulation, the aim of this study was to assess the role played by LH cholinoceptive cells in Wake-Sleep and autonomic regulations. To this end, the effects of a microinjection of the cholinergic agonist Carbachol (CBL) into the LH were compared to those obtained through the activation of a wider cell population by the microinjection of the GABAA antagonist GABAzine (GBZ). The results of this pilot study showed that both drugs elicited the same behavioral and autonomic effects, those caused by GBZ being larger and longer-lasting than those following administration of CBL. Briefly, wakefulness was enhanced and sleep was depressed, and brain temperature and heart rate consistently increased, while mean arterial pressure showed only a mild increment. Surprisingly, the administration of the drug vehicle (SAL) elicited a similar pattern of Wake-Sleep effects which, although much smaller, were sufficient to mask any statistical significance between treatment and control data. In conclusion, the results of this work show that the arousal elicited by LH disinhibition by GABAzine is concomitant with autonomic responses set by the intervention of cold-defense mechanisms. Since the same response is elicited at a lower level by CBL administration, the hypothesis of an involvement of cholinoceptive ORX neurons in its generation is discussed. PMID- 26742662 TI - High amplitude theta wave bursts: a novel electroencephalographic feature of rem sleep and cataplexy. AB - High amplitude theta wave bursts (HATs) were originally described during REMS and cataplexy in ORX-deficient mice as a novel neurophysiological correlate of narcolepsy (Bastianini et al., 2012). This finding was replicated the following year by Vassalli et al. in both ORX-deficient narcoleptic mice and narcoleptic children during cataplexy episodes (Vassalli et al., 2013). The relationship between HATs and narcolepsy-cataplexy in mice and patients indicates that the lack of ORX peptides is responsible for this abnormal EEG activity, the physiological meaning of which is still unknown. This review aimed to explore different phasic EEG events previously described in the published literature in order to find analogies and differences with HATs observed in narcoleptic mice and patients. We found similarities in terms of morphology, frequency and duration between HATs and several physiological (mu and wicket rhythms, sleep spindles, saw-tooth waves) or pathological (SWDs, HVSs, bursts of polyphasic complexes EEG complexes reported in a mouse model of CJD, and BSEs) EEG events. However, each of these events also shows significant differences from HATs, and thus cannot be equaled to them. The available evidence thus suggests that HATs are a novel neurophysiological phenomenon. Further investigations on HATs are required in order to investigate their physiological meaning, to individuate their brain structure(s) of origin, and to clarify the neural circuits involved in their manifestation. PMID- 26742663 TI - Slow cortical rhythms: from single-neuron electrophysiology to whole-brain imaging in vivo. AB - The slow cortical oscillation is the major brain rhythm occurring during sleep, and has been the object of thorough investigation for over thirty years. Despite all these efforts, the function and the neuronal mechanisms behind slow cortical rhythms remain only partially understood. In this review we will provide an overview of the techniques available for the in vivo study of slow cortical oscillations in animal models. Our goal is to provide an up to date resource for the selection of the best experimental strategies to study specific aspects of slow oscillations. We will cover both traditional, population-level electrophysiological approaches (electroencephalography - EEG, local field potentials) as well as more recent techniques, such as two photon calcium imaging and optogenetics. Overall, we believe that new breakthroughs in our understanding of slow cortical rhythms will require the integration of different techniques, to bridge the gap between different spatio-temporal scales and go from a correlative to a causal level of analysis. PMID- 26742664 TI - Sleep to grow smart? AB - Sleep is undisputable an essential part of our life, if we do not sleep enough we feel the consequences the next day. The importance of sleep for healthy brain functioning has been well studied in adults, but less is known for the role of sleep in the paediatric age. Childhood and adolescence is a critical phase for brain development. The increased need for sleep during this developmental phase fosters the growing recognition for a central role of sleep during development. In this review we summarize the findings that demonstrate a close relationship between sleep and brain maturation, discuss the consequences of insufficient sleep during childhood and adolescence and outline initial attempts that have been made in order to improve sleep in this age range. PMID- 26742665 TI - The assessment of somatosensory cortex plasticity during sleep deprivation by paired associative stimulation. AB - Many animal studies suggest that during sleep deprivation (SD) synaptic strength should progressively increase, leading to the saturation of the ability to induce long-term potentiation (LTP). Nevertheless, direct evidences about the effects of sustained wakefulness on cortical plasticity in humans are still lacking. The aim of the present study was to assess changes in the ability to induce LTP-like mechanism in humans during a period of SD by means of a paired associative stimulation (PAS) protocol, which combines median nerve stimulation with transcranial magnetic stimulation (TMS) applied over the contralateral somatosensory cortex. During a 41-h SD protocol, 16 healthy subjects, defined as responders to the PAS protocol after a pre-selection session, were involved in 4 experimental sessions (11.00 a.m. and 11.00 p.m. of first and second day) with: a) pre-PAS somatosensory evoked potentials (SEPs) recordings; b) PAS protocol; c) post-PAS SEPs recordings. The effect of PAS on SEPs early components (N20-P25 complex) was assessed. During the first experimental session (without SD) no significant PAS effects on SEPs components amplitude have been found, and large intra- and inter-individual variability have been observed. A lack of significant changes has been observed also in the subsequent sessions. Our results index a low intra- and inter-individual reliability of the PAS protocol, suggesting particular caution when longitudinally evaluating the effect of this technique on cortical plasticity. PMID- 26742666 TI - Frequency-dependent effects of oscillatory-tDCS on EEG oscillations: a study with Better OSCillation detection method (BOSC). AB - Oscillating transcranial direct current stimulation (osc-tDCS) modulates the spontaneous brain activity in a frequency-specific manner. Most studies evaluated cortical effects of osc-tDCS through spectral measures, without differentiating components associated with rhythmic and non-rhythmic activity. Since osc-tDCS mainly affects brain oscillatory activity, our aim was to investigate on the specific changes of EEG oscillations following a frontal osc-tDCS at 0.8 and at 5 Hz. 20 healthy subjects (26.8 +/- 2.5 years) participated in one of two experiments (Exp.1= 0.8-Hz tDCS, n= 10; Exp.2= 5-Hz tDCS, n= 10), consisting of 3 within-subject sessions: two active conditions with different stimulation polarity (anodal osctDCS, cathodal osc-tDCS), and a control condition (sham). EEG oscillatory components (28 cortical derivations) at the stimulation frequency were measured by the Better OSCillation detection method (BOSC). Variations between before and after the osc-tDCS were compared between conditions as a function of polarity (anodal vs. cathodal vs. sham) and frequency (0.8 vs. 5 Hz) of stimulation. The main finding is a significant local increase of 0.81-Hz slow oscillations (F(1,18)=19.97; p=0.0004) and 5.3-Hz theta oscillations (F(1,18)=26.93; p= 0.0001) after 5 Hz compared to 0.8-Hz tDCS. Our study shows larger frequency-specific and cross-frequency effects of 5-Hz compared to 0.8-Hz stimulation, not revealed by conventional FFT analyses. This finding is consistent with a more effective induction of EEG synchronization during wakefulness by means of a stimulation in the theta range, and it suggests to combine measurement of EEG power and EEG oscillations in future studies involving transcranial stimulations. PMID- 26742667 TI - Linking Sleep Slow Oscillations with consciousness theories: new vistas on Slow Wave Sleep unconsciousness. AB - We review current models of consciousness in the context of wakefulness and sleep. We show that recent results on Slow Wave Sleep, including our own works, naturally fit within consciousness models. In particular, Sleep Slow Oscillations, namely low-frequency (<1Hz) oscillations, contain electrophysiological properties (up and down states) able to elicit and quench neural integration during Slow Wave Sleep. The physiological unconsciousness related to the Sleep Slow Oscillation derives from the interplay between spontaneous or evoked wake-like activities (up states) and half-a-second's electrical silences (down states). Sleep Slow Oscillation induces unconsciousness via the formation of parallel and segregated neural activities. PMID- 26742668 TI - Pediatric insomnia: new insights in clinical assessment and treatment options. AB - Sleep disorders in children can compromise quality of life of both children and families and chronic sleep deprivations is associated with poorer developmental outcome, overweight and behavioral disturbances. Clinicians should incorporate questions about sleep into their routine health assessment, and the assessment of insomnia should follow a medical approach primary and secondary contributing factors should be assessed, as well as maladaptive behaviors related to sleep. A careful examination of sleep/wake schedule, abnormal movements or behavior during sleep, and daytime consequences of sleep disruption or deprivation is mandatory. Sleeping environment, and bedtime routines should be examined to identify behavioral issues related to sleep. Polysomnography is not routinely indicated for children with insomnia, but actigraphy can give an objective estimation of sleep parameters. The Authors propose a new classification of pediatric insomnia, based on both genetic and clinical aspects, and suggest specific treatment options, including sleep hygiene, behavioral strategies and pharmacological treatment. PMID- 26742669 TI - Respiratory sleep disorders in Jeune syndrome: a case description. AB - PURPOSE: Jeune syndrome (JS, also described as asphyxiating thoracic dystrophy, ATD) is a rare autosomal recessive skeletal dysplasia characterized by a small, narrow chest and variable limb shortness with a considerable neonatal mortality as a result of respiratory distress. Significant life-threatening cervical spine abnormalities can be typical. METHOD: Here we describe the case of a male infant of Sardinian origin, who developed respiratory distress and feeding difficulties from the first months, correlated with muscle?skeletal dysmorphism prevalent on chest. Nocturnal respiratory sleep alterations were reported from parents. RESULTS: After clinical, genetics, radiographic and cervical MRI investigations, ATD diagnosis with C1 stenosis. A full-night video-polysomnographic study was performed in order to evaluate the sleep apnea condition. The study showed a condition of tachipnea?tachicardia, with several short respiratory events during sleep, both obstructive and central type with apneahypopnea index (AHI) 17/ h, mean duration 3.7 sec with longest 20 sec. CONCLUSION: It can be hypothesized that the combination of altered respiratory and cardiac frequency is related to central type of sleep respiratory disorders consequent to C1 compression, while the obstructive minor component is related to thoracic restrictive disorders. Full night lab-polygraphy is recommended in dysmorphic skeletal disorders like JS. PMID- 26742670 TI - Effect of ethylic alcohol on attentive functions involved in driving abilities. AB - The burden of injuries due to drunk drivers has been estimated only indirectly. Indeed, alcohol is considered one of the most important contributing cause of car crash injuries and its effect on cognitive functions needs to be better elucidated. Aims of the study were i) to examine the effect of alcohol on attentive abilities involved while driving, and ii) to investigate whether Italian law limits for safe driving are sufficiently accurate to prevent risky behaviours and car crash risk while driving. We conducted a cross-over study at IRCCS Fondazione Santa Lucia Rehabilitation Hospital in Rome. Thirty-two healthy subjects were enrolled in this experiment. Participants were submitted to an attentive test battery assessing attention before taking Ethylic Alcohol (EA-) and after taking EA (EA+). In the EA+ condition subjects drank enough wine until the blood alcohol concentration, measured by means of Breath Analyzer, was equal to or higher than 0.5 g/l. Data analysis revealed that after alcohol assumption, tonic and phasic alertness, selective, divided attention and vigilance were significantly impaired when BAC level was at least 0.5 g/l. These data reveal that alcohol has a negative effect on attentive functions which are primarily involved in driving skills and that Italian law limits are adequate to prevent risky driving behaviour. PMID- 26742671 TI - The association between restless legs syndrome, cardiovascular and metabolic diseases: hypotheses and evidence from the literature. AB - The association between RLS and both CVRFs, such as hypertension and diabetes, and CVDs still remains elusive. Although several shared physiopathological causes could explain these possible relationships, the emerging body of literature focusing on these disorders remains controversial. The reasons for these inconsistent findings are mainly due to the different methodologies applied. First, considering that RLS, CVRFs and CVDs are influenced by age and sex, many clinical and population-based studies performed a selection bias by restricting the sample collection to these covariates. Second, assessments of covariates are often incomparable and the methods applied for diseases assessment are often affected by low sensitivity and specificity. Only few population-based studies collected data by means of face-to-face interview or physical examination in order to limit the false positive rate compared to questionnaires administered by mail or telephone. The assessment of RLS was not always performed according to IRLSSG criteria and anyway the four diagnostic criteria did not allow the exclusion of other disorders that may act as mimics (Hening et al., 2009; Allen et al., 2014). Disease assessment ranged from a self-reported diagnosis, information on the use of specific medications, or a direct measurement of BP and blood glucose levels. Moreover, some antihypertensive medications, such as beta blockers and certain calcium channel blockers, could both ameliorate and aggravate RLS symptoms (Innes et al., 2012) and therefore it would be important to consider medications as confounding factors. In addition, the co-occurrence of several CVRFs is frequent and they may influence each other. Therefore, the cross sectional nature of most studies cannot assess the causal relationship between them and the variables of interest (i.e., RLS and/ or CVDs). Finally, only few studies adjusted their analyses for other cardiovascular risk factors, such as diabetes mellitus, history of myocardial infarction, BMI, dyslipidemia, and smoking status, that might act as confounders or mediators. In summary, longitudinal population-based studies and meta-analyses will be necessary in order to build a sufficiently robust body of evidence on this topic. PMID- 26742672 TI - Restless legs syndrome/Willis Ekbom disease: new diagnostic criteria according to different nosology. AB - Restless Legs Syndrome/Willis Ekbom Disease (RLS/WED) is a common neurological disorder characterized by uncomfortable and unpleasant sensations in the legs, with an urge to move. The symptoms typically begin or worsen during periods of rest, in particular during the evening and at night, while the activity may typically relieve them. The majority of patients complains of poor sleep. Recent studies reported the prevalence is ranging from 5 to 10%. RLS/WED can be divided into primary (patients without associated conditions that may explain the symptoms) and secondary forms (mostly iron deficiency). RLS/WED is typically a chronic condition. The clinical course varies according to the age of onset. A great load of accumulating research and clinical data have led to an extended consensus for a need to enhance the diagnostic criteria. The aim of this paper is to provide a critical comparison among different diagnostic criteria, taking into account respectively the International Classification of Sleep Disorders (ICSD), the International RLS Study Group (IRLSSG) and the Diagnostic and Statistical Manual of Mental Disorders (DSM). There are several remarkable distinctions between the IRLSSG revised criteria, ICSD-3 and DSM-V. Contrary to the DSM-V criteria, ICSD-3 diagnostic criteria are more aligned to the IRLSSG ones. In fact, the five essential criteria of the IRLSSG are also required for the diagnosis of RLS/WED according to ICSD-3. The new IRLSSG criteria provide a more rigorous approach to case ascertainment and a better characterization of patients by specifying clinical significance and course. Future ascertainment of correct diagnosis should include documentation that all five diagnostic criteria are considered. PMID- 26742673 TI - Can sleep microstructure improve diagnosis of OSAS? Integrative information from CAP parameters. AB - PURPOSE: The scoring of American Academy of Sleep Medicine (AASM) arousal is mandatory for the definition of respiratory event-related arousal (RERA). However there are other EEG activation phenomena, such as A phases of cyclic alternating pattern (CAP) which are associated with respiratory events in non rapid eye movements (NREM) sleep. This study aims at quantifying the additional value of CAP for the definition of respiratory events and sleep alterations in OSAS. METHODS: Analysis of polysomnographic recordings from nineteen OSAS patients was carried out. Scoring was focused on investigation of the cerebral response to flow limitation (FL) events. For this purpose we used both CAP rules and AASM arousal criteria. MAIN RESULTS: While no difference was demonstrated in the arousal index between mild and moderate-severe OSAS patients, CAP time showed a progressive enhancement from normal subjects (152.5+/-20.76) to mild (180.64+/ 34.76) and moderate-severe (282.27+/-58.02) OSAS patients. In NREM sleep, only 41.1% of FL events met the criteria for the definition of RERA, while, 75.5% of FL events ended with a CAP A phase and most FL CAP (69.1%) terminated with a CAP phase A3 subtype. CONCLUSIONS: Our data indicate that the RERA scoring has a limited accuracy in the detection of FL events. In NREM sleep, CAP rules provided more information than AASM arousal for the definition of respiratory events and sleep alterations in OSAS. PMID- 26742674 TI - Sleep disorders in menopause: results from an Italian Multicentric Study. AB - Menopause in the female life cycle is a special period due to important hormonal, physical and psychological changes. Sleep disruption represents a common complaint for midlife and menopausal women, related to primary sleep disorders, including insomnia, sleep disordered breathing, restless legs syndrome (RLS), mood and anxiety disorder, other medical illness, hormonal-related vasomotor symptoms, and aging per se. Aims of our study were to evaluate the prevalence of sleep disorders in a sample of pre and post menopausal women, and to investigate the relationship between sleep and other medical disorders, and life habits. Among workers in the six participant centers, we enrolled 334 women, aged between 40 and 60 years, that completed a questionnaire that included screening on menarche, menstrual cycle, fertility, parity, menopause, life habits, personal medical and sleep history and related treatment, and self-administered scales for sleep quality (PSQI), excessive daytime sleepiness [Epworth Sleepiness Scale (ESS)], mood disorder [Beck Depression Inventory (BDI)], Berlin Questionnaire for sleep disordered breathing (SDB), IRLS diagnostic interview and Rating Scale. Menopausal and perimenopausal women showed an increased prevalence of poor sleep, high risk of SDB, and mood disorder; menopausal women also reported increased RLS severity. Mood disorder had a significant impact on night sleep measures and excessive daytime sleepiness, as well as on RLS severity, and had a greater prevalence in hypertensive women. Sleep disturbances are frequent in menopausal women. Their aetiology is unclear, but probably multifactorial, and many factors contribute to the sleep disruption. Our data suggest the importance of correctly investigate and address sleep problems associated with menopause, through sleep history, and a sleep study could be obtained if clinically warranted. Pharmacological and behavioural treatment strategies should then be aimed at improving sleep and life quality in perimenopausal and menopausal women. PMID- 26742675 TI - NREM sleep transient events in fronto-temporal dementia: beyond sleep stage architecture. AB - Frontotemporal dementia (FTD) is increasingly becoming recognized as a major cause of early onset (<65 years) neurodegenerative dementia. Although sleep disorders significantly impair patients' and caregivers' quality of life in neurodegenerative diseases, polysomnographic data in FTD patients are scarce in literature. Aim of our study was to investigate sleep microstructure in FTD, by means of Cyclic Alternating Pattern (CAP), in a group of ten behavioral variant FTD patients (6 M, 4 F; mean age 61.2+/-7.3 years; disease duration: 1.4+/-0.7 years) and to compare them with cognitively intact healthy elderly. Sleep in FTD patients was altered at different levels, involving not only the conventional sleep stage architecture parameters (total sleep time, single stage percentage, NREM/REM cycle organization), but also microstructure. FTD subjects showed CAP disruption with decreased slow wave activity related phases (A1 index, n/h:14.5+/ 6.8 vs 38.8+/-6.6; p<.001) and increased arousal-related fast CAP components (A2 index 22.9+/-8.2 vs 11.6+/-3.7; p=.006; A3 index 41.9+/-20.7 vs 13.0+/-6.5; p=.002). Several correlations between sleep variables and neuropsychological tests were found. Sleep impairment in FTD may be specifically related to the specific frontal lobe involvement in the neurodegenerative process. The pattern of alterations seems somewhat peculiar, probably due to the anatomical distribution of the neurodegenerative process with a major impact on frontal lobe generated sleep transients, and a substantial sparing of phenomena related to the posterior cortex. PMID- 26742676 TI - Sleep disturbances and cognitive decline: recommendations on clinical assessment and the management. AB - In 2004, in Genoa (Italy), the Italian Dementia Research Association (SINDem) was born. The first congress of this new scientific society took place in Rome in 2006. SINDem soon recognized the importance to investigate sleep problems in cognitive decline and created a national "sleep study group "composed by neurologists and sleep specialists. In 2012, The SINDem study group, in close relationship with the Italian Association of sleep medicine (AIMS), published the study "Prevalence of sleep disturbances in mild cognitive impairment and dementing disorders: a multicenter Italian clinical cross-sectional study on 431 patients ", confirming the high prevalence of sleep disturbances in a wide Italian population of persons with cognitive decline. The study was supported by a grant from the Italian Minister of Health and was conducted with the fundamental contribution of the Italian National Research Center (CNR). In 2014, the same group published the paper "Recommendations of the Sleep Study Group of the Italian Dementia Research Association (SINDem) on clinical assessment and management of sleep disorders in individuals with mild cognitive impairment and dementia: a clinical review". The recommendations are wide and directed to professionals (neurologists but not exclusively) to try to establish uniform levels of care, promote collaborative studies into areas of uncertainty, and define the qualitative characteristics of Dementia Reference Centers about sleep disturbances. PMID- 26742677 TI - Subjective hypnotic efficacy of Trazodone and Mirtazapine in patients with chronic insomnia: a retrospective, comparative study. AB - OBJECTIVE: To compare the efficacy of two sedating antidepressants, trazodone and mirtazapine, for the treatment of chronic insomnia. DESIGN: Retrospective cross sectional study. Patients received trazodone or mirtazapine for at least three months at the dosage that was effective in the titration period. MATERIAL AND METHODS: 150 patients with chronic insomnia, referred to the Sleep Disorder Center of Bari, diagnosed as chronic insomniacs according to ICSD-3 diagnostic criteria, with or without dysthymic disorder according to DSM V diagnostic criteria, and treated with trazodone or mirtazapine were retrospectively chart reviewed. 79 patients satisfying inclusion criteria were enrolled: 33 had been treated with trazodone (12 males and 21 females aged 36 to 77 years, mean age 63.57+10.38 years; 18 with psychophysiological insomnia and 15 with insomnia associated with dysthymic disorder) and 46 with mirtazapine (26 males and 20 females aged 25 to 86 years, mean age 60.04+16.67 years; 25 with psychophysiological insomnia and 21 with insomnia comorbid with dysthymic disorder). The patients were considered responsive to the treatment when they no longer met the criteria for insomnia at the end of the maintenance period. RESULTS: Both drugs were efficacious in more than 60% without any difference in the proportion of responders between the two medication groups (87.87% in the trazodone group versus 86.95% in the mirtazapine group; p=0.26 and regardless of sex, age and possible association of insomnia with depression). The minimum dosages used for both drugs (25 mg for trazodone and 7.5 mg for mirtazapine) corresponded to the highest percentage of responders in the groups treated successfully with either trazodone (37.93%) or mirtazapine (52.5%). For each medication group, subgroup analysis revealed higher statistically significant rates of responders in patients with lower final dosage (25 to 75 mg for trazodone and 7.5 to 15 mg for mirtazapine) than in those with higher final dosage (100 to 150 mg for trazodone and 15 to 30 mg for mirtazapine) (100% versus 42.85%; p<0.001 in the trazodone group and 100% versus 53.84%; p<0.001 in mirtazapine group) Conclusion. On a long term basis trazodone administration appeared as effective and well tolerated as mirtazapine in the treatment of chronic insomnia regardless of its association with dysthymia. Both medications resulted efficacious at very low doses and had a sustained efficacy, likely without problems of tolerance. PMID- 26742678 TI - Daytime rumination as a feature of Insomnia Disorder: sleep related cognition is not merely a problem of the night. AB - Night-time sleep related cognitions have been shown to play a perpetuating role in insomnia. According to the cognitive model of insomnia day time cognitions (i.e. worry, rumination, etc.) may also contribute to it. The aim of this study was to investigate the possible role of daytime sleep-related rumination in Insomnia Disorder (n= 55, mean age 49.7+/-16.7 years), Obstructive Sleep Apnea Syndrome (OSAS) (n=33, mean age 58.1+/-10.2 years) and healthy subjects (n=33, mean age 49.8+/-13.9), using a set of sleep related variables which included the Daytime Insomnia Symptom Response Scale (DISRS), the Dysfunctional Beliefs about Sleep Scale (DBAS), the Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index (ISI). Daytime sleep related rumination was higher in insomnia when compared to both OSAS (p<.001) and good sleepers (p<.001). In insomnia, elevated sleep related daytime rumination was best determined by unhelpful sleep related beliefs (coeff=0.3 p=.004), while in OSAS by insomnia symptoms (coeff=0.9, p=.02). These findings suggest that the association between insomnia specific daytimerumination and unhelpful beliefs may be considered a cognitive feature of insomnia. In insomnia, sleep related cognition may dominate the 24 hour period. This finding might be of use for further investigations studying therapeutic strategies acting on cognitive processes to prevent and treat insomnia disorder and its comorbid conditions. PMID- 26742679 TI - Frustrated magnetism in the spin-chain metal Yb2Fe12P7. AB - Magnetization measurements for magnetic fields [Formula: see text] up to 60 T are reported for the noncentrosymmetric spin-chain metal Yb2Fe12P7. These measurements reveal behavior that is consistent with Ising-like spin chain magnetism that produces pronounced spin degeneracy. In particular, we find that although a Brillouin field dependence is observed in M(H) for [Formula: see text] with a saturation moment that is close to the expected value for free ions of Yb(3+) , non-Brillouin-like behavior is seen for [Formula: see text] with an initial saturation moment that is nearly half the free ion value. In addition, hysteretic behavior that extends above the ordering temperature [Formula: see text] is seen for [Formula: see text] but not for [Formula: see text], suggesting out-of-equilibrium physics. This point of view is strengthened by the observation of a spin reconfiguration in the ordered state for [Formula: see text] which is only seen for [Formula: see text] and after polarizing the spins. Together with the heat capacity data, these results suggest that the anomalous low temperature phenomena that were previously reported (Baumbach 2010 et al Phys. Rev. Lett. 105 106403) are driven by spin degeneracy that is related to the Ising-like one dimensional chain-like configuration of the Yb ions. PMID- 26742680 TI - Is there a role for telemedicine in adult allergy services? AB - Telemedicine refers to the application of telecommunication and information technology (IT) in the delivery of health and clinical care at a distance or remotely and can be broadly considered in two modalities: store-and-forward and real-time interactive services. Preliminary studies have shown promising results in radiology, dermatology, intensive care, diabetes, rheumatology and primary care. However, the evidence is limited and hampered by small sample sizes, paucity of randomized control studies and lack of data relating to cost effectiveness, health-related quality of life and patient and clinician satisfaction. This review appraises the evidence from studies that have employed telemedicine tools in other disciplines and makes suggestions for its potential applications in specific clinical scenarios in adult allergy services. Possible examples include: triaging patients to determine the need for allergy tests; pre assessment for specialized treatments such as allergen immunotherapy, follow-up to assess treatment response and side effects; and education in self-management plan including training updates for self-injectable adrenaline and nasal spray use. This approach might improve access for those with limited mobility or living far away from regional centres, as well as bringing convenience and cost savings for the patient and service provider. These potential benefits need to be carefully weighed against evidence of service safety and quality. Keys to success include delineation of appropriate clinical scenarios, patient selection, training, IT support and robust information governance framework. Well-designed prospective studies are needed to evaluate its role. PMID- 26742681 TI - The anaesthetist's SonoSite Probe - Successful adjunct to complex intradural spinal surgery or poor man's intraoperative ultrasound? AB - The use of expensive, sophisticated, intraoperative ultrasound systems is established in cranial neurosurgery and less so in the realms of intradural spine. For units yet to acquire such costly devices, we demonstrate our experience of the readily available, anaesthetist's SonoSiteTM probe in intradural spinal surgery. PMID- 26742682 TI - Nonequilibrium phase transitions, fluctuations and correlations in an active contractile polar fluid. AB - We study the patterning, fluctuations and correlations of an active polar fluid consisting of contractile polar filaments on a two-dimensional substrate, using a hydrodynamic description. The steady states generically consist of arrays of inward pointing asters and show a continuous transition from a moving lamellar phase, a moving aster street, to a stationary aster lattice with no net polar order. We next study the effect of spatio-temporal athermal noise, parametrized by an active temperature TA, on the stability of the ordered phases. In contrast to its equilibrium counterpart, we find that the active crystal shows true long range order at low TA. On increasing TA, the asters dynamically remodel, concomitantly we find novel phase transitions characterized by bond-orientational and polar order upon "heating". PMID- 26742683 TI - Public Perceptions of Regulatory Costs, Their Uncertainty and Interindividual Distribution. AB - Public perceptions of both risks and regulatory costs shape rational regulatory choices. Despite decades of risk perception studies, this article is the first on regulatory cost perceptions. A survey of 744 U.S. residents probed: (1) How knowledgeable are laypeople about regulatory costs incurred to reduce risks? (2) Do laypeople see official estimates of cost and benefit (lives saved) as accurate? (3) (How) do preferences for hypothetical regulations change when mean preserving spreads of uncertainty replace certain cost or benefit? and (4) (How) do preferences change when unequal interindividual distributions of hypothetical regulatory costs replace equal distributions? Respondents overestimated costs of regulatory compliance, while assuming agencies underestimate costs. Most assumed agency estimates of benefits are accurate; a third believed both cost and benefit estimates are accurate. Cost and benefit estimates presented without uncertainty were slightly preferred to those surrounded by "narrow uncertainty" (a range of costs or lives entirely within a personally-calibrated zone without clear acceptance or rejection of tradeoffs). Certain estimates were more preferred than "wide uncertainty" (a range of agency estimates extending beyond these personal bounds, thus posing a gamble between favored and unacceptable tradeoffs), particularly for costs as opposed to benefits (but even for costs a quarter of respondents preferred wide uncertainty to certainty). Agency-acknowledged uncertainty in general elicited mixed judgments of honesty and trustworthiness. People preferred egalitarian distributions of regulatory costs, despite skewed actual cost distributions, and preferred progressive cost distributions (the rich pay a greater than proportional share) to regressive ones. Efficient and socially responsive regulations require disclosure of much more information about regulatory costs and risks. PMID- 26742685 TI - A very rapid electronic relaxation process in a highly conjugated Zn(II)porphyrin [26]hexaphyrin-Zn(II)porphyrin hybrid tape. AB - The excited-state energy relaxation processes of a Zn(II)porphyrin-[26]hexaphyrin Zn(II)porphyrin triply linked hybrid tape, FZn, have been investigated by femtosecond transient absorption spectroscopy (TA), using a directly meso-meso linked hybrid trimer, HZn, as a reference compound. FZn has a very small S1-S0 energy gap through the expansion of pi-conjugation and the absorption band at 1897 nm corresponds to its lowest singlet excited-state as a consequence of enhanced transition dipole moment that lies parallel to the long molecular axis. In TA measurements, we observe an energy transfer process (0.4 ps) from the Zn(II)porphyrin moiety to the [26]hexaphyrin core in HZn. In contrast to HZn, a biexponential decay with the time constants of 0.25 and 6.5 ps was observed in the decay profile of FZn. The detailed analysis of excitation wavelength, temperature and solvent dependent TA in FZn revealed that the electronic relaxation process (0.25 ps) from S1 to S0 is faster than the vibrational relaxation processes (5.9 ps) in the excited and ground states due to a very small S1-S0 energy gap through the expansion of pi-conjugation. Accordingly, we demonstrate that electronic deactivation overtakes vibrational relaxation processes in a highly conjugated FZn. PMID- 26742686 TI - Paramagnetic spherical nanoparticles by the self-assembly of persistent trityl radicals. AB - Spherical nanoparticles and fibres observable by cryo-electron microscopy are spontaneously formed by the Finland trityl radical at concentrations above 15 mM. These species represent a new class of paramagnetic, metal-free, nanoscale supramolecular materials. Self-association was observed under a variety of experimental conditions, including aqueous solution at room temperature, low temperature frozen glasses and the gas phase. Oligomers formed by at least 5 Finland radicals were detected by ion-mobility mass spectrometry. Magnetic susceptibility data as well as low temperature EPR spectra show coupling between electronic spins in the self-assembled species. Quantum chemical calculations show stacking along the C3 symmetry axis. Nanoparticle formation requires additional lateral packing that can be provided by hydrogen bonding involving the triangular array of carboxylic acid groups leading to the assembly of geodesic spheres. PMID- 26742687 TI - Coupling calcium dynamics and mitochondrial bioenergetic: an in silico study to simulate cardiomyocyte dysfunction. AB - The coupling of intracellular Ca(2+) dynamics with mitochondrial bioenergetic is crucial for the functioning of cardiomyocytes both in healthy and disease conditions. The pathophysiological signature of the Cardiomyocyte Dysfunction (CD) is commonly related to decreased ATP production due to mitochondrial functional impairment and to an increased mitochondrial calcium content ([Ca(2+)]m). These features advanced the therapeutic approaches which aim to reduce [Ca(2+)]m. But whether [Ca(2+)]m overload is the pathological trigger for CD or a physiological consequence, remained controversial. We addressed this issue in silico and showed that [Ca(2+)]m might not directly cause CD. Through model parameter recalibration, we demonstrated how mitochondria cope up with functionally impaired processes and consequently accumulate calcium. A strong coupling of the [Ca(2+)]m oscillations with the ATP synthesis rate ensures robust calcium cycling and avoids CD. We suggested a cardioprotective role of the mitochondrial calcium uniporter and predicted that a mitochondrial sodium calcium exchanger could be a potential therapeutic target to restore the normal functioning of the cardiomyocyte. PMID- 26742688 TI - Factors that influence excessive gestational weight gain: moving beyond assessment and counselling. AB - One in four Canadian adults is obese, and more women are entering pregnancy with a higher body mass index (BMI) than in the past. Pregnant women who are overweight or obese have a higher risk of pregnancy-related complications than women of normal weight. Gestational weight gain (GWG) is also associated with childhood obesity. Although the factors influencing weight gain during pregnancy are multifaceted, little is known about the social inequality of GWG. This review will address some of the socioeconomic factors and maternal characteristics influencing weight gain and the impact that excessive GWG has on health outcomes such as post-partum weight retention. The effects of an overweight or obese pre pregnancy BMI on GWG and neonatal outcomes will also be addressed. The timing of weight gain is also important, as recommendations now include trimester-specific guidelines. While not conclusive, preliminary evidence suggests that excessive weight gain during the first trimester is most detrimental. PMID- 26742689 TI - Increased nuclear stiffness via FAK-ERK1/2 signaling is necessary for synthetic mechano-growth factor E peptide-induced tenocyte migration. AB - We have previously reported that a synthetic mechano-growth factor (MGF) C terminal E-domain with 25 amino acids (MGF-C25E) promotes rat tenocyte migration through the FAK-ERK1/2 signaling pathway. However, the role of the nucleus in MGF C25E-promoted tenocyte migration and the molecular mechanisms involved remain unclear. In this study, we demonstrate that MGF-C25E increases the Young's modulus of tenocytes through the FAK-ERK1/2 signaling pathway. This increase is not accompanied by an obvious change in the expression of Lamin A/C but is accompanied by significant chromatin condensation, indicating that MGF-C25E induced chromatin condensation may contribute to the increased nuclear stiffness. Moreover, DNA methylation is observed in MGF-C25E-treated tenocytes. Inhibition of DNA methylation suppresses the elevation in chromatin condensation, in nuclear stiffness, and in tenocyte migration induced by MGF-C25E. The inhibition of the focal adhesion kinase (FAK) or extracellular signal regulated kinase 1/2 (ERK1/2) signals represses MGF-C25E-promoted DNA methylation. It also abolishes chromatin condensation, nuclear stiffness, and cell migration. Taken together, our results suggest that MGF-C25E promotes tenocyte migration by increasing nuclear stiffness via the FAK-ERK1/2 signaling pathway. This provides strong evidence for the role of nuclear mechanics in tenocyte migration and new insight into the molecular mechanisms of MGF-promoted tenocyte migration. PMID- 26742690 TI - Molecular switches of the kappa opioid receptor triggered by 6'-GNTI and 5'-GNTI. AB - The kappa opioid receptor (kappaOR) is a member of G-protein-coupled receptors, and is considered as a promising drug target for treating neurological diseases. kappaOR selective 6'-GNTI was proved to be a G-protein biased agonist, whereas 5' GNTI acts as an antagonist. To investigate the molecular mechanism of how these two ligands induce different behaviors of the receptor, we built two systems containing the 5'-GNTI-kappaOR complex and the 6'-GNTI-kappaOR complex, respectively, and performed molecular dynamics simulations of the two systems. We observe that transmembrane (TM) helix 6 of the kappaOR rotates about 4.6(o) on average in the kappaOR-6'-GNTI complex. Detailed analyses of the simulation results indicate that E297(6.58) and I294(6.55) play crucial roles in the rotation of TM6. In the simulation of the kappaOR-5'-GNTI system, it is revealed that 5'-GNTI can stabilize TM6 in the inactive state form. In addition, the kink of TM7 is stabilized by a hydrogen bond between S324(7.47) and the residue V69(1.42) on TM1. PMID- 26742692 TI - Nickel Cobalt Hydroxide @Reduced Graphene Oxide Hybrid Nanolayers for High Performance Asymmetric Supercapacitors with Remarkable Cycling Stability. AB - Nanolayered structures present significantly enhanced electrochemical performance by facilitating the surface-dependent electrochemical reaction processes for supercapacitors, which, however, causes capacitance fade upon cycling due to their poor chemical stability. In this work, we report a simple and effective approach to develop a stable, high performance electrode material by integrating 2D transition metal hydroxide and reduced graphene oxide sheets at nanometer scale. Specifically, a hybrid nanolayer of Ni-Co hydroxide @reduced graphene oxide (Ni,Co-OH/rGO) with an average thickness of 1.37 nm is synthesized through an easy one-pot hydrothermal method. Benefiting from the face to face contact model between Ni-Co hydroxide and rGO sheets, such unique structure presents superior specific capacitance and cycling performance as compared to the pure Ni Co hydroxide nanolayers. An asymmetric supercapacitor based on Ni,Co-OH/rGO and three-dimensional (3D) hierarchical porous carbon is developed, exhibiting a high energy density of 56.1 Wh kg(-1) along with remarkable cycling stability (80% retention after 17 000 cycles), which holds great promise for practical applications in energy storage devices. PMID- 26742691 TI - Pre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination. AB - Aging is associated with hyporesponse to vaccination, whose mechanisms remain unclear. In this study hepatitis B virus (HBV)-naive older adults received three vaccines, including one against HBV. Here we show, using transcriptional and cytometric profiling of whole blood collected before vaccination, that heightened expression of genes that augment B-cell responses and higher memory B-cell frequencies correlate with stronger responses to HBV vaccine. In contrast, higher levels of inflammatory response transcripts and increased frequencies of pro inflammatory innate cells correlate with weaker responses to this vaccine. Increased numbers of erythrocytes and the haem-induced response also correlate with poor response to the HBV vaccine. A transcriptomics-based pre-vaccination predictor of response to HBV vaccine is built and validated in distinct sets of older adults. This moderately accurate (area under the curve~65%) but robust signature is supported by flow cytometry and cytokine profiling. This study is the first that identifies baseline predictors and mechanisms of response to the HBV vaccine. PMID- 26742693 TI - Effects of Ideal Versus Total Body Weight Dosage of Rabbit Antithymocyte Globulin on Outcomes of Kidney Transplant Patients With High Immunologic Risk. AB - OBJECTIVES: The optimal dose of rabbit antithymocyte globulin induction therapy in kidney transplant recipients with high immunologic risk lacks consensus. The purpose of this study was to evaluate the effect of using ideal body weight rather than total body weight for the weight-based dose calculations in this patient population. MATERIALS AND METHODS: Data were retrospectively collected on 89 adult patients who received rabbit antithymocyte globulin induction therapy for high immunologic risk kidney transplant. Hospital protocol changed from the use of cumulative rabbit antithymocyte globulin doses of 7.5 mg/kg total body weight to 7.5 mg/kg ideal body weight in 2009. Patients were separated into 2 cohorts based on the amount of rabbit antithymocyte globulin (in mg/kg total body weight) received. Rate of biopsy-proven acute rejection, patient survival, and allograft function were evaluated at 90 days and 1 year after transplant. Cost of induction therapy was also evaluated. RESULTS: Baseline demographics were predominantly similar between the 2 cohorts. No significant difference in maintenance immunosuppression was identified. Rates of biopsy-proven acute rejection at 90 days and 1 year were similar between ideal and total body weight cohorts (4.2% vs 0% at 90 days, P = .5; 8.7% vs 0% at 1 year, P = .13). Patient survival and allograft function were also similar. Median cost of rabbit antithymocyte globulin induction therapy per patient was lower in the ideal body weight cohort, but this difference was not statistically significant ($17 542 vs $19 934; P = .3). CONCLUSIONS: Our results suggest that use of ideal body weight for dose calculations of rabbit antithymocyte globulin induction therapy in high immunologic risk kidney transplant recipients at 7.5 mg/kg results in low rates of acute rejection with a safety profile similar to that shown with a total body weight dosage. Use of ideal body weight for lower cumulative doses may still need further evaluation in this patient population. PMID- 26742694 TI - Pluripotency-associated miR-290/302 family of microRNAs promote the dismantling of naive pluripotency. AB - The molecular mechanism controlling the dismantling of naive pluripotency is poorly understood. Here we show that microRNAs (miRNAs) have important roles during naive to primed pluripotency transition. Dgcr8(-/-) embryonic stem cells (ESCs) failed to completely silence the naive pluripotency program, as well as to establish the primed pluripotency program during differentiation. miRNA profiling revealed that expression levels of a large number of miRNAs changed dynamically and rapidly during naive to primed pluripotency transition. Furthermore, a miRNA screen identified numerous miRNAs promoting naive to primed pluripotency transition. Unexpectedly, multiple miRNAs from miR-290 and miR-302 clusters, previously shown as pluripotency-promoting miRNAs, demonstrated the strongest effects in silencing naive pluripotency. Knockout of both miR-290 and miR-302 clusters but not either alone blocked the silencing of naive pluripotency program. Mechanistically, the miR-290/302 family of miRNAs may facilitate the exit of naive pluripotency in part by promoting the activity of MEK pathway and through directly repressing Akt1. Our study reveals miRNAs as an important class of regulators potentiating ESCs to transition from naive to primed pluripotency, and uncovers context-dependent functions of the miR-290/302 family of miRNAs at different developmental stages. PMID- 26742695 TI - Maternal immune activation produces neonatal excitability defects in offspring hippocampal neurons from pregnant rats treated with poly I:C. AB - Maternal immune activation (MIA) resulting from prenatal exposure to infectious pathogens or inflammatory stimuli is increasingly recognized to play an important etiological role in neuropsychiatric disorders with neurodevelopmental features. MIA in pregnant rodents induced by injection of the synthetic double-stranded RNA, Poly I:C, a mimic of viral infection, leads to a wide spectrum of behavioral abnormalities as well as structural and functional defects in the brain. Previous MIA studies using poly I:C prenatal treatment suggested that neurophysiological alterations occur in the hippocampus. However, these investigations used only juvenile or adult animals. We postulated that MIA-induced alterations could occur earlier at neonatal/early postnatal stages. Here we examined the neurophysiological properties of cultured pyramidal-like hippocampal neurons prepared from neonatal (P0-P2) offspring of pregnant rats injected with poly I:C. Offspring neurons from poly I:C-treated mothers exhibited significantly lower intrinsic excitability and stronger spike frequency adaptation, compared to saline. A similar lower intrinsic excitability was observed in CA1 pyramidal neurons from hippocampal slices of two weeks-old poly I:C offspring. Cultured hippocampal neurons also displayed lower frequency of spontaneous firing, higher charge transfer of IPSCs and larger amplitude of miniature IPSCs. Thus, maternal immune activation leads to strikingly early neurophysiological abnormalities in hippocampal neurons. PMID- 26742696 TI - Characterization of Rv0888, a Novel Extracellular Nuclease from Mycobacterium tuberculosis. AB - Bacterial extracellular nucleases play important roles in virulence, biofilm formation, utilization of extracellular DNA as a nutrient, and degradation of neutrophil DNA extracellular traps. However, there is no current data available for extracellular nucleases derived from M. tuberculosis. Herein, we have identified and characterized Rv0888, an extracellular nuclease in M. tuberculosis. The protein was overexpressed in E. coli, and the purified Rv0888 protein was found to require divalent cations for activity, with an optimal temperature and pH of 41 degrees C and 6.5, respectively. Further results demonstrated that Rv0888 nuclease activity could be inhibited by four Chinese medicine monomers. Based on sequence analysis, Rv0888 nuclease exhibited no homology with any known extracellular nucleases, indicating that Rv0888 is a novel nuclease. Site-directed mutagenesis studies revealed that the H353, D387, and D438 residues play catalytic roles in Rv0888. In vivo infection studies confirmed that Rv0888 is required for infection and is related to pathogenicity, as the persistent ability of recombinant Mycobacterium smegmatis (rMS) Rv0888NS/MS and Rv0888S/MS is significantly higher than pMV262/MS in the lung tissue, and the Rv0888NS/MS and Rv0888S/MS could produce pathological changes in the mice lung. These results show that Rv0888 is relevant to pathogenicity of M. tuberculosis. PMID- 26742698 TI - An update on multipurpose prevention technologies for the prevention of HIV transmission and pregnancy. AB - INTRODUCTION: Multipurpose Prevention Technologies (MPTs) are designed to address two or more indications from a single product. The overall goal is to prevent unintended pregnancy and transmission of one or more STIs including HIV-1. AREAS COVERED: The topics covered herein are advances in over the past three years. Advances include development of novel intravaginal rings capable of releasing microbicides to prevent transmission of HIV-1 and unintended pregnancy. These rings include the potential to prevent transmission of more than one STI and unintended pregnancy. There are also gels that can potentially accomplish the same thing. Finally, combination of a drug and barrier device are also covered. EXPERT OPINION: There has been considerable advance in this field over the past three years. There is one ring currently in a Phase I clinical trial and others are soon to follow. Some of these drug delivery systems are by necessity rather complicated and hence could be prohibitively expensive in the developing world. Conducting multiple clinical trials to support regulatory approval of two or more indications represents a significant barrier. It remains unclear that women will be more motivated to use MPT products than has been observed in recent microbicide-only clinical trials. Despite these challenges, the need for MPTs remain acute hopefully ensuring they will continue to be developed over the coming years. PMID- 26742699 TI - Comparison of Inflammatory Biomarkers in Outpatients With Prior Myocardial Infarction. AB - Inflammatory biomarkers have been proposed for use in the risk stratification of patients with acute myocardial infarction (AMI). We examined the value of inflammatory biomarkers over clinical features for predicting cardiovascular (CV) events in stable outpatients with MI. We enrolled 430 post-MI patients and measured their levels of high-sensitivity C reactive protein (hs-CRP), growth differentiation factor-15 (GDF-15), and the interleukin-1 receptor family member called ST2 (ST2), one month after AMI. Patients were prospectively followed for 3 years. In our study cohort (mean age, 66 +/- 12 years; left ventricular ejection fraction, 55 +/- 13%), CV events were observed in 39 patients (9.1%). Kaplan- Meier analysis revealed that patients with high levels of GDF-15 (>= 1221.0 ng/L) showed poorer prognoses than those with low levels of GDF-15 (< 1221.0 ng/L) (20.4% versus 3.6%, P < 0.001); hs-CRP and ST2 did not show a similar correlation with prognoses. GDF-15 remained associated with CV events after adjusting for age, chronic kidney disease, and B-type natriuretic peptide (hazard ratio, 1.001; 95% confidence interval, 1.000 - 1.001; P = 0.046). GDF-15 provided an incremental predictive value for CV events over clinical features (incremental value in global chi(2) = 43.81, P < 0.001). In outpatients with prior MI, GDF-15 was an independent indicator of CV events, unlike hs-CRP and ST2. GDF15 provided an incremental prognostic value over clinical features. PMID- 26742700 TI - Improvements in Augmentation Index and Urinary Albumin Excretion With Benidipine in Hypertensive Patients With Chronic Kidney Disease. AB - Although calcium channel blockers (CCB) are expected to improve the augmentation index (AI) in CKD patients, the potential effect of benidipine on AI has been poorly studied.The present study aimed to compare the effect of benidipine and amlodipine in the treatment of CKD patients as measured through AI and urinary albumin excretion (UAE). Eligible patients with CKD were randomized to either the benidipine group or amlodipine group. Changes in UAE and AI were compared with target blood pressure level set at < 130/80 mmHg. A total of 108 patients were enrolled; 88 patients who were followed up were included in the analysis. Although no significant change in renal function was noted in either group, there was a significant improvement in AI only in the benidipine group (85.7 +/- 13.3% to 81.4 +/- 15.2%; P = 0.021) A subgroup analysis of 64 patients who achieved SBP < 140 mmHg at the end of follow-up (31 on amlodipine and 33 on benidipine) was carried out. Significant improvement in AI was noted only in the benidipine group (84.5 +/- 13.6% to 79.5 +/- 15.2%; P = 0.0138). In another subgroup of patients with UAE >= 300 mg/g Cr, a significant improvement in UAE in the benidipine group was found compared with the amlodipine group (-25 +/- 46, 51 +/- 60%, P = 0.031, respectively).These results suggest that benidipine might reduce significantly AI and might have potentially greater improvements in UAE than amlodipine in advanced CKD patients receiving RAS inhibitors. PMID- 26742701 TI - A Case of Useful Short-Spaced Bipolar Pacing of a Left Ventricular Lead to Avoid Phrenic Nerve Stimulation. AB - A 48-year-old woman underwent cardiac resynchronization therapy defibrillator implantation. Coronary sinus (CS) venography showed only one adequate anterior branch for a left ventricular lead. We were able to introduce a quadripolar left ventricular lead (Medtronic 4398-88 cm) to the distal portion of the anterior branch. Although phrenic nerve stimulation (PNS) occurred due to distal bipolar pacing (distal 1-mid 2, with 21-mm distance) and proximal pacing (mid 3-proximal 4, distance 21mm), short-spaced bipolar pacing (mid 2-3, distance 1.3 mm) did not induce PNS until 9V pacing. Shared bipolar pacing from each left ventricular electrode (distal 1 to proximal 4) as cathode and a right ventricular (RV) coil as anode resulted in PNS by 3.0V at 0.4 ms. Although quadripolar pacing could avoid PNS by switching the pacing site (ie, from distal bipolar to proximal bipolar), it might not avoid PNS in cases where the phrenic nerve and CS branch are parallel and in close proximity. We found that even though the phrenic nerve and CS branch were parallel and close, short-spaced bipolar pacing could avoid PNS. In conclusion, short-spaced bipolar pacing selected by quadripolar pacing might be beneficial to avoid PNS when the implantable branch is limited. PMID- 26742702 TI - Preoperative Prediction of Aortic Insufficiency During Ventricular Assist Device Treatment. AB - Survival rate in patients with stage D heart failure has improved significantly owing to the development of continuous flow left ventricular assist devices (LVAD), but aortic insufficiency (AI) still remains one of the major unsolved complications that impairs patient quality of life. There are no established treatments for AI, and preoperative prediction and prevention of AI is needed. The opening of a native aortic valve (AV) is a sufficient condition for prevention of AI, and improvement of LV ejection fraction due to LV reverse remodeling (LVRR) is essential to open a native AV. Preoperative insufficient beta-blocker treatment and pulsatile flow LVAD usage are keys for LVRR, opening of an AV, and prevention of AI. The second mechanism that leads to AI is remodeling of the aortic root and degeneration of a native AV, which results from reduced pulse pressure during LVAD support. Centrifugal or pulsatile flow LVAD usage has an advantage in terms of preserving pulsatility, and may prevent AI compared with an axial pump. There is less probability of avoiding AI with sufficient beta-blocker treatment, and these patients may be good candidates for concomitant surgical intervention to a native AV at the time of LVAD implantation. PMID- 26742703 TI - A Case of Multiple Coronary Artery-Left Ventricular Micro Fistulae Complicated With Hepatic Arteriovenous Fistulae. AB - We present the first case of multiple coronary artery-left ventricular micro fistulae complicated with hepatic arteriovenous fistulae (AVF) in an adult patient. Multiple coronary artery fistulae originated from the left anterior descending coronary artery with aneurysmal change. Multiple coronary artery-left ventricular micro fistulae presented on the left ventricular wall and showed significant localized hypertrophic change. Stress and enhanced cardiac magnetic resonance imaging (CMR) revealed myocardial ischemia that could not be detected by stress Tl-201 cardiac scintigraphy, and late patchy gadolinium enhancement (LGE) in the mid-ventricular wall apex. This LGE pattern did not match the typical pattern observed in patients with apical hypertrophic cardiomyopathy. These observations may help distinguish multiple coronary artery-associated myocardial ischemia and hypertrophy from apical cardiomyopathy. PMID- 26742704 TI - Centrifugal Pump EVAHEART Prevents Development of Aortic Insufficiency Preserving Pulse Pressure. PMID- 26742705 TI - Growth Differentiation Factor 15 (GDF15) as a Reliable Biomarker for Cardiovascular Risk Assessment. PMID- 26742706 TI - What is the psychological impact of self-weighing? A meta-analysis. AB - Many people self-weigh and many interventions addressing weight-related problems such as obesity promote self-weighing. However, while self-weighing has been associated with weight loss, there is mixed evidence regarding the psychological impact of this behaviour. The present review aimed to quantify the relationship between self-weighing and: (i) affect (e.g., anxiety, depression); (ii) psychological functioning (e.g., self-esteem); (iii) body-related attitudes and (iv) disordered eating. A computerized search of scientific databases in September 2014 and subsequent ancestry and citation searches identified 29 independent tests of the relationship between self-weighing on psychological outcomes. Meta-analysis was used to quantify the size of the association across the tests. Results indicated that there was no association between self-weighing and affect, body-related attitudes or disordered eating. There was, however, a small-sized negative association between self-weighing and psychological functioning. The age of participants, obesity status, the extent of weight loss, duration of self-weighing and study design (RCT versus correlational) were found to influence at least some of the psychological outcomes of self-weighing. The findings suggest that, for the most part, self-weighing is not associated with adverse psychological outcomes. However, in some cases the association between self-weighing and psychological outcomes may be more negative than in others. PMID- 26742707 TI - Patients' decision making process and expectations of a left ventricular assist device pre and post implantation. AB - OBJECTIVES: To examine patients' pre-implantation decision-making and pre and post-implantation expectations of left ventricular assist devices (LVADs). BACKGROUND: LVADs have been shown to improve both quantity and quality of life of patients living with Stage D heart failure (HF). However, they also pose significant risks. METHODS: 15 LVAD participants followed in a longitudinal study of Stage D HF patients were included in this thematic analysis. RESULTS: Three themes were identified: no choice; I thought I would be doing better; I feel good, but now what. Evidence from pre-implantation to post-implantation suggested that patients' perceived expectations of quality of life improvement were not met. CONCLUSIONS: In light of their declining health, most patients felt their only alternative to implantation was death. In the post-implantation period, patients expected greater improvements in their quality of life. Evidence based guidelines for discussions of goals of care, post-implant expectations, and palliative care are necessary. PMID- 26742708 TI - Arsenic Trioxide as a Radiation Sensitizer for 131I-Metaiodobenzylguanidine Therapy: Results of a Phase II Study. AB - Arsenic trioxide has in vitro and in vivo radiosensitizing properties. We hypothesized that arsenic trioxide would enhance the efficacy of the targeted radiotherapeutic agent (131)I-metaiodobenzylguanidine ((131)I-MIBG) and tested the combination in a phase II clinical trial. METHODS: Patients with recurrent or refractory stage 4 neuroblastoma or metastatic paraganglioma/pheochromocytoma (MP) were treated using an institutional review board-approved protocol (Clinicaltrials.gov identifier NCT00107289). The planned treatment was (131)I MIBG (444 or 666 MBq/kg) intravenously on day 1 plus arsenic trioxide (0.15 or 0.25 mg/m(2)) intravenously on days 6-10 and 13-17. Toxicity was evaluated using National Cancer Institute Common Toxicity Criteria, version 3.0. Response was assessed by International Neuroblastoma Response Criteria or (for MP) by changes in (123)I-MIBG or PET scans. RESULTS: Twenty-one patients were treated: 19 with neuroblastoma and 2 with MP. Fourteen patients received (131)I-MIBG and arsenic trioxide, both at maximal dosages; 2 patients received a 444 MBq/kg dose of (131)I-MIBG plus a 0.15 mg/kg dose of arsenic trioxide; and 3 patients received a 666 MBq/kg dose of (131)I-MIBG plus a 0.15 mg/kg dose of arsenic trioxide. One did not receive arsenic trioxide because of transient central line-induced cardiac arrhythmia, and another received only 6 of 10 planned doses of arsenic trioxide because of grade 3 diarrhea and vomiting with concurrent grade 3 hypokalemia and hyponatremia. Nineteen patients experienced myelosuppression higher than grade 2, most frequently thrombocytopenia (n = 18), though none required autologous stem cell rescue. Twelve of 13 evaluable patients experienced hyperamylasemia higher than grade 2 from transient sialoadenitis. By International Neuroblastoma Response Criteria, 12 neuroblastoma patients had no response and 7 had progressive disease, including 6 of 8 entering the study with progressive disease. Objective improvements in semiquantitative (131)I-MIBG scores were observed in 6 patients. No response was seen in MP. Seventeen of 19 neuroblastoma patients continued on further chemotherapy or immunotherapy. Mean 5 year overall survival (+/-SD) for neuroblastoma was 37% +/- 11%. Mean absorbed dose of (131)I-MIBG to blood was 0.134 cGy/MBq, well below myeloablative levels in all patients. CONCLUSION: (131)I-MIBG plus arsenic trioxide was well tolerated, with an adverse event profile similar to that of (131)I-MIBG therapy alone. The addition of arsenic trioxide to (131)I-MIBG did not significantly improve response rates when compared with historical data with (131)I-MIBG alone. PMID- 26742710 TI - Safety, Efficacy, and Prognostic Factors After Radioembolization of Hepatic Metastases from Breast Cancer: A Large Single-Center Experience in 81 Patients. AB - The present study evaluated safety, efficacy, and prognostic factors for (90)Y yttrium microsphere radioembolization of unresectable liver metastases from breast cancer. METHODS: Eighty-one patients were treated with radioembolization. Acute toxicity was monitored through daily physical examination and serum tests until 3 d after radioembolization; late toxicity was evaluated until 12 wk after radioembolization. Overall survival and response according to (18)F-FDG PET (>30% decrease of tracer uptake) and CA15-3 serum level (any decline) were recorded. Pretherapeutic characteristics, including pretreatment history, liver function tests, and PET/CT parameters, were assessed by univariate and subsequent multivariate Cox regression for predicting patient survival. RESULTS: A toxicity grade of 3 or more based on clinical symptoms, bilirubin, ulcer, pancreatitis, ascites, or radioembolization-induced liver disease occurred in 10% or less of patients. Two patients eventually died from radioembolization-induced liver disease. Sequential lobar treatment and absence of prior angiosuppressive therapy were both associated with a lower rate of serious adverse events. On the basis of PET/CA15-3 criteria, 52/61% of patients responded to treatment. Median overall survival after radioembolization was 35 wk (interquartile range, 41 wk). Pretherapeutic tumor burden of the liver greater than 50% or more (P< 0.001; hazard ratio, 5.67; 95% confidence interval, 2.41-13.34) and a transaminase toxicity grade of 2 or more (P= 0.009; hazard ratio, 2.15; 95% confidence interval, 1.21-3.80) independently predicted short survival. CONCLUSION: Radioembolization for breast cancer liver metastases shows encouraging local response rates with low incidence of serious adverse events, especially in those patients with sequential lobar treatment or without prior angiosuppressive therapy. High hepatic tumor burden and liver transaminase levels at baseline indicate poor outcome. PMID- 26742709 TI - 18F-FDG PET/CT and PET/MRI Perform Equally Well in Cancer: Evidence from Studies on More Than 2,300 Patients. AB - (18)F-FDG PET/CT has become the reference standard in oncologic imaging against which the performance of other imaging modalities is measured. The promise of PET/MRI includes multiparametric imaging to further improve diagnosis and phenotyping of cancer. Rather than focusing on these capabilities, many investigators have examined whether (18)F-FDG PET combined with mostly anatomic MRI improves cancer staging and restaging. After a description of PET/MRI scanner designs and a discussion of technical and operational issues, we review the available literature to determine whether cancer assessments are improved with PET/MRI. The available data show that PET/MRI is feasible and performs as well as PET/CT in most types of cancer. Diagnostic advantages may be achievable in prostate cancer and in bone metastases, whereas disadvantages exist in lung nodule assessments. We conclude that (18)F-FDG PET/MRI and PET/CT provide comparable diagnostic information when MRI is used simply to provide the anatomic framework. Thus, PET/MRI could be used in lieu of PET/CT if this approach becomes economically viable and if reasonable workflows can be established. Future studies should explore the multiparametric potential of MRI. PMID- 26742711 TI - Prognostic Significance of 18F-FDG Uptake in Hepatocellular Carcinoma Treated with Transarterial Chemoembolization or Concurrent Chemoradiotherapy: A Multicenter Retrospective Cohort Study. AB - This study aimed to assess the prognostic value of (18)F-FDG uptake in hepatocellular carcinoma (HCC) patients who had transarterial chemoembolization (TACE) or concurrent intraarterial chemotherapy with external-beam radiotherapy (CCRT) and to compare the prognosis between patients treated with TACE and those with CCRT according to (18)F-FDG uptake. METHODS: Two hundred fourteen intermediate-to-advanced-stage HCC patients without extrahepatic metastasis who underwent staging (18)F-FDG PET/CT before TACE (153 patients) or CCRT (61 patients) were recruited from 7 hospitals. Progression-free survival (PFS) and overall survival (OS) were compared using an optimal cutoff value for tumor-to normal liver uptake ratio (TLR). Further, PFS and OS were compared according to treatment modalities (TACE vs. CCRT) using the same TLR cutoff value. RESULTS: On multivariate analysis, age and TLR were independent prognostic factors for PFS (P< 0.050). For OS, Child-Pugh classification and TLR were independent prognostic factors (P< 0.050). When the TLR was greater than 2.0, patients treated with CCRT showed significantly better PFS and OS than those treated with TACE after adjusting for tumor size and number (P= 0.014, for all). In contrast, there was no significant difference in PFS and OS between patients treated with TACE or CCRT when the TLR was 2.0 or less. CONCLUSION: (18)F-FDG uptake was an independent prognostic factor for PFS and OS in HCC patients treated with TACE or CCRT. Especially, in HCCs with high (18)F-FDG uptake, patients treated with CCRT showed better survival than those treated with TACE. (18)F-FDG PET/CT may help determine the treatment modality for intermediate-to-advanced-stage HCCs. PMID- 26742712 TI - Synthesis and Characterization of 18F-Interleukin-8 Using a Cell-Free Translation System and 4-18F-Fluoro-L-Proline. AB - Macromolecules such as proteins are attracting increasing interest for molecular imaging. We previously proposed a novel strategy for preparing macromolecules labeled with a PET radionuclide, (11)C, using a cell-free translation system with (11)C-methionine. However, macromolecules tend to exhibit slower kinetics, thus requiring a longer scanning time. Here, we expand our strategy using (18)F, which has a longer half-life, with the cell-free translation system with 4-(18)F-fluoro L-proline ((18)F-FPro). We evaluated (18)F-interleukin-8 ((18)F-IL-8) produced by this method in vitro and in vivo to provide a proof of concept of our strategy. METHODS: We tested some fluorinated amino acids to be incorporated into a protein. Trans-(18)F-FPro was radiolabeled from the corresponding precursor. (18)F-IL-8 was produced using the cell-free translation system with trans-(18)F FPro instead of natural L-proline with incubation at 37 degrees C for 120 min. An in vitro binding assay of (18)F-IL-8 was performed using IL-8 receptor-expressing cells. After intravenous administration of (18)F-IL-8, in vivo PET imaging of IL 8 receptor-expressing xenograft-bearing mice was performed using a small-animal PET system. RESULTS: FPro was identified as an amino acid incorporated into the protein. (18)F-IL-8 was successfully prepared using the cell-free translation system and trans-(18)F-FPro with the radiochemical yield of 1.5% (decay corrected) based on trans-(18)F-FPro. In vitro binding assays of (18)F-IL-8 demonstrated its binding to IL-8 receptor. In vivo PET imaging demonstrated that (18)F-IL-8 clearly accumulated in IL-8 receptor-expressing xenografts in mice, unlike trans-(18)F-FPro. CONCLUSION: (18)F-IL-8 produced by this method binds to IL-8 receptors in vitro, and (18)F-IL-8 PET clearly visualizes its target receptor-expressing xenograft in vivo. Therefore, this technique might be useful for labeling macromolecules and performing preclinical evaluations of proteins of interest in vitro and in vivo. PMID- 26742715 TI - Comparative Performance of 18F-FDG PET/MRI and 18F-FDG PET/CT in Detection and Characterization of Pulmonary Lesions in 121 Oncologic Patients. AB - Our objective was to compare (18)F-FDG PET/MRI (performed using a contrast enhanced T1-weighted fat-suppressed volume-interpolated breath-hold examination [VIBE]) with (18)F-FDG PET/CT for detecting and characterizing lung lesions in oncologic patients. METHODS: In 121 oncologic patients with 241 lung lesions, PET/MRI was performed after PET/CT in a single-injection protocol (260 +/- 58 MBq of (18)F-FDG). The detection rates were computed for MRI, the PET component of PET/CT, and the PET component of PET/MRI in relation to the CT component of PET/CT. Wilcoxon testing was used to assess differences in lesion contrast (4 point scale) and size between morphologic datasets and differences in image quality (4-point scale), SUVmean, SUVmax, and characterization (benign/malignant) between PET/MRI and PET/CT. Correlation was determined using the Pearson coefficient (r) for SUV and size and the Spearman rank coefficient (rho) for contrast. RESULTS: The detection rates for MRI, the PET component of PET/CT, and the PET component of PET/MRI were 66.8%, 42.7%, and 42.3%, respectively. There was a strong correlation in size (r= 0.98) and SUV (r= 0.91) and a moderate correlation in contrast (rho = 0.48). Image quality was better for PET/CT than for PET/MRI (P< 0.001). Lesion measurements were smaller for MRI than for CT (P< 0.001). SUVmax and SUVmean were significantly higher for PET/MRI than for PET/CT (P< 0.001 each). There was no significant difference in lesion contrast (P= 0.11) or characterization (P= 0.076). CONCLUSION: In the detection and characterization of lung lesions 10 mm or larger, (18)F-FDG PET/MRI and (18)F-FDG PET/CT perform comparably. Lesion size, SUV and characterization correlate strongly between the two modalities. However, the overall detection rate of PET/MRI remains inferior to that of PET/CT because of the limited ability of MRI to detect lesions smaller than 10 mm. Thus, thoracic staging with PET/MRI bears a risk of missing small lung metastases. PMID- 26742713 TI - Ex Vivo and In Vivo Evaluation of Overexpressed VLA-4 in Multiple Myeloma Using LLP2A Imaging Agents. AB - Very-late-antigen-4 (VLA-4, alpha4beta1 integrin, CD49d/CD29) is a transmembrane adhesion receptor that plays an important role in cancer and immune responses. Enhanced VLA-4 expression has been observed in multiple myeloma (MM) cells and surrounding stroma. VLA-4 conformational activation has been associated with MM pathogenesis. VLA-4 is a promising MM imaging and therapeutic biomarker. METHODS: Specificity of (64)Cu-LLP2A ((64)Cu-CB-TE1A1P-PEG4-LLP2A), a high-affinity VLA-4 peptidomimetic-based radiopharmaceutical, was evaluated in alpha4 knock-out mice and by competitive blocking in wild-type tumor-bearing mice. (64)Cu-LLP2A PET/CT (static and dynamic) imaging was conducted in C57BL6/KaLwRij mice bearing murine 5TGM1-GFP syngeneic tumors generated after intravenous injection via the tail. Blood samples were collected for serum protein electrophoresis. Bone marrow and splenic cells extracted from tumor-bearing and control mice (n= 3/group) were coincubated with the optical analog LLP2A-Cy5 and mouse B220, CD4, Gr1, and Mac1 antibodies and analyzed by fluorescence-activated cell sorting. Human radiation dose estimates for (64)Cu-LLP2A were extrapolated from mouse biodistribution data (6 time points, 0.78 MBq/animal, n= 4/group). Ten formalin-fixed paraffin embedded bone marrow samples from deceased MM patients were stained with LLP2A Cy5. RESULTS: (64)Cu-LLP2A and LLP2A-Cy5 demonstrated high specificity for VLA-4 positive mouse 5TGM1-GFP myeloma and nonmalignant inflammatory host cells such as T cells and myeloid/monocytic cells. Ex vivo flow cytometric analysis supported a direct effect of myeloma on increased VLA-4 expression in host hematopoietic microenvironmental elements. SUVs and the number of medullar lesions detected by (64)Cu-LLP2A PET corresponded with increased monoclonal (M) protein (g/dL) in tumor-bearing mice over time (3.29 +/- 0.58 at week 0 and 9.97 +/- 1.52 at week 3). Dynamic PET with (64)Cu-LLP2A and (18)F-FDG demonstrated comparable SUV in the prominent lesions in the femur. Human radiation dose estimates indicated urinary bladder wall as the dose-limiting organ (0.200 mGy/MBq), whereas the dose to the red marrow was 0.006 mGy/MBq. The effective dose was estimated to be 0.017 mSv/MBq. Seven of the ten human samples displayed a high proportion of cells intensely labeled with LLP2A-Cy5 probe. CONCLUSION: (64)Cu-LLP2A and LLP2A-Cy5 demonstrated binding specificity for VLA-4 in an immune-competent murine MM model. (64)Cu-LLP2A displayed favorable dosimetry for human studies and is a potential imaging candidate for overexpressed VLA-4. PMID- 26742716 TI - Making hybrid [n]-rotaxanes as supramolecular arrays of molecular electron spin qubits. AB - Quantum information processing (QIP) would require that the individual units involved--qubits--communicate to other qubits while retaining their identity. In many ways this resembles the way supramolecular chemistry brings together individual molecules into interlocked structures, where the assembly has one identity but where the individual components are still recognizable. Here a fully modular supramolecular strategy has been to link hybrid organic-inorganic [2]- and [3]-rotaxanes into still larger [4]-, [5]- and [7]-rotaxanes. The ring components are heterometallic octanuclear [Cr7NiF8(O2C(t)Bu)16](-) coordination cages and the thread components template the formation of the ring about the organic axle, and are further functionalized to act as a ligand, which leads to large supramolecular arrays of these heterometallic rings. As the rings have been proposed as qubits for QIP, the strategy provides a possible route towards scalable molecular electron spin devices for QIP. Double electron-electron resonance experiments demonstrate inter-qubit interactions suitable for mediating two-qubit quantum logic gates. PMID- 26742717 TI - Agarose/gelatin immobilisation of tissues or embryo segments for orientated paraffin embedding and sectioning. AB - The technique described in this protocol allows the user to position small tissues in the optimal orientation for paraffin embedding and sectioning by first immobilising the tissue in an agarose/gelatin cube. This method is an adaptation of methods used for early embryos and can be used for any small tissues or embryo segments. Processing of larger tissue sections using molds to create agarose/gelatin blocks has been described previously; this detailed protocol provides a method for dealing with much smaller tissues or embryos (<=5mm). The tissue is briefly fixed then an agarose/gelatin drop is created to surround the tissue. The tissue can be orientated as per the user's preference in the drop before it sets as is carved into a cube with a domed top. The cube is then dehydrated and goes through the embedding and sectioning process. The domed cube is easy to orientate when embedding the tissue in a wax block giving the user assured orientation of the small tissue for sectioning. Additionally, the agarose/gelatin cube is easy to see in the unmolded wax once embedded, making the region of interest easy to identify. PMID- 26742718 TI - A Synthesis of Peer-Reviewed Literature on Team-Coordinated and Delivered Early Supported Discharge After Stroke. AB - This review aimed to summarize data from peer-reviewed studies of team coordinated and delivered early supported discharge (ESD) for postacute, poststroke rehabilitation. A systematic review was performed in Medline, Embase, and CINAHL for appropriate studies. Information on program details and patient cohorts was synthesized. All programs sought patients with mild-to-moderate functional impairment and minimal cognitive impairment (often based on Barthel Index and Mini-Mental State Examination scores, respectively). All also included at least one subjective admission criterion related to rehabilitation suitability or the suitability of the home environment. Based on the identified studies, ESD programs can assume that 15% of patients screened for ESD will be eligible and care should be provided for 4 to 5 weeks postdischarge. Although the benefits of team-coordinated and delivered ESD poststroke have been well-documented, this review may be helpful for clinicians, administrators, and policy makers looking to establish or refine an ESD program for stroke. PMID- 26742719 TI - Chronic mild stress-induced alterations of clock gene expression in rat prefrontal cortex: modulatory effects of prolonged lurasidone treatment. AB - Disruptions of biological rhythms are known to be associated with depressive disorders, suggesting that abnormalities in the molecular clock may contribute to the development of these disorders. These mechanisms have been extensively characterized in the suprachiasmatic nucleus, but little is know about the role exerted by individual clock genes in brain structures that are important for depressive disorders. Using the chronic mild stress model we found a significant reduction of BMAL1 and CLOCK protein levels in the nuclear compartment of the prefrontal cortex of CMS rats, which was paralleled by a down-regulation of the expression of several target genes, including Pers and Crys but also Reverbbeta and Pparalpha. Interestingly, chronic treatment with the multi receptor modulator lurasidone (3mg/kg for 5 weeks) was able to normalize the molecular changes induced by CMS exposure in prefrontal cortex, but it was also able to regulate some of these genes within the hippocampus. We believe that changes in clock genes expression after CMS exposure may contribute to the disturbances associated with depressive disorders and that the ability of chronic lurasidone to normalize such alterations may be relevant for its therapeutic properties in ameliorating functions that are deteriorated in patients with major depression and other stress-related disorders. PMID- 26742721 TI - Quantification of darunavir and etravirine in human peripheral blood mononuclear cells using high performance liquid chromatography tandem mass spectrometry (LC MS/MS), clinical application in a cohort of 110 HIV-1 infected patients and evidence of a potential drug-drug interaction. AB - OBJECTIVES: To describe the validation of a sensitive high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method allowing the simultaneous quantification of darunavir (DRV) and etravirine (ETR) in peripheral blood mononuclear cells (PBMCs) and its application in a cohort of HIV-1 infected patients. METHODS: Blood samples were obtained from 110 patients. PMBCs were isolated using density gradient centrifugation. Drug extraction from PBMCs was performed with a 60:40 methanol-water (MeOH-H2O) solution containing deuterated IS (DRV-d9 and ETR-d8). The chromatographic separation was performed on a RP18 XBridgeTM column. RESULTS: The geometric mean (GM) of cell associated concentration ([DRV]CC) and plasmatic concentration ([DRV]plasma) were 360.5ng/mL (CI95%:294.5-441.2) and 1733ng/mL (CI95%:1486-2021), respectively. A geometric mean intracellular (IC)/plasma ratio (GMR) of 0.21 (CI95%:0.18-0.24) was calculated. Adjusted for dose/body surface area and post-intake time, a statistically significant correlation was observed between [DRV]Plasma and the eGFR (p=0.002) and between [DRV]Plasma and the concomitant use of ETR (p=0.038). For the 10 patients receiving ETR in addition to DRV, the GM of [ETR]Plasma (available for 8 out of 10 patients) and [ETR]CC were 492.3ng/mL and 2951ng/mL respectively. The GMR of ETR was 7.6 (CI95%: 3.61-13.83). CONCLUSIONS: A handy and sensitive high performance LC-MS/MS method allowing the simultaneous quantification of DRV and ETR in PBMCs has been described and successfully applied in the largest cohort of DRV-treated patients reported to date. ETR accumulates more efficiently in PBMCs compared to DRV. We have also highlighted a possible impact of ETR on DRV plasma concentrations requiring further investigations. PMID- 26742720 TI - Validation of predicted patellofemoral mechanics in a finite element model of the healthy and cruciate-deficient knee. AB - Healthy patellofemoral (PF) joint mechanics are critical to optimal function of the knee joint. Patellar maltracking may lead to large joint reaction loads and high stresses on the articular cartilage, increasing the risk of cartilage wear and the onset of osteoarthritis. While the mechanical sources of PF joint dysfunction are not well understood, links have been established between PF tracking and abnormal kinematics of the tibiofemoral (TF) joint, specifically following cruciate ligament injury and repair. The objective of this study was to create a validated finite element (FE) representation of the PF joint in order to predict PF kinematics and quadriceps force across healthy and pathological specimens. Measurements from a series of dynamic in-vitro cadaveric experiments were used to develop finite element models of the knee for three specimens. Specimens were loaded under intact, ACL-resected and both ACL and PCL-resected conditions. Finite element models of each specimen were constructed and calibrated to the outputs of the intact knee condition, and subsequently used to predict PF kinematics, contact mechanics, quadriceps force, patellar tendon moment arm and patellar tendon angle of the cruciate resected conditions. Model results for the intact and cruciate resected trials successfully matched experimental kinematics (avg. RMSE 4.0 degrees , 3.1mm) and peak quadriceps forces (avg. difference 5.6%). Cruciate resections demonstrated either increased patellar tendon loads or increased joint reaction forces. The current study advances the standard for evaluation of PF mechanics through direct validation of cruciate-resected conditions including specimen-specific representations of PF anatomy. PMID- 26742722 TI - Mariniluteicoccus endophyticus sp. nov., an endophytic actinobacterium isolated from root of Ocimum basilicum. AB - Two strains of Gram-stain-positive, aerobic, non-motile, irregular coccus-shaped bacteria, designated YIM 2617T and YIM 2617-2, were isolated from the root of Ocimum basilicum. Phylogenetic analysis on the basis of 16S rRNA gene sequence comparison revealed that the two strains were closely related to Mariniluteicoccus flavus YIM M13146T (98.1 and 98.0 % similarities, respectively) and formed a robust clade with M. flavus in the neighbour-joining tree. Optimum growth of the strains was observed at 28-32 degrees C, at pH 7.0-8.0 and in the presence of 0-2 % (w/v) NaCl. The chemotaxonomic profiles of the strains comprised anteiso-C15 : 0 as the major cellular fatty acid, MK-9(H4) as the predominant menaquinone, alanine, glycine, glutamic acid and ll-diaminopimelic acid as peptidoglycan components, and phosphatidylcholine and diphosphatidylglycerol as the major polar lipids. The G+C contents of the genomic DNA of strains YIM 2617T and YIM 2617-2 were 66.4 and 66.6 mol%, respectively. DNA-DNA hybridizations of the two strains with M. flavus YIM M13146T gave mean relatedness values of 47.6 +/- 2.0 and 43.2 +/- 1.5 %, respectively, while the relatedness value between them was 92.1 +/- 2.2 %. On the basis of the data recorded from the present study, strains YIM 2617T and YIM 2617-2 represent a novel species of the genus Mariniluteicoccus, for which the name Mariniluteicoccus endophyticus sp. nov. is proposed. The type strain is YIM 2617T ( = KCTC 29482T = DSM 28728T = JCM 30097T). PMID- 26742723 TI - SBIRT-A: Adapting SBIRT to Maximize Developmental Fit for Adolescents in Primary Care. AB - The Screening, Brief Intervention and Referral to Treatment (SBIRT) model is widely recommended as part of routine visits in pediatric primary care despite a dearth of evidence on its effectiveness, feasibility, and developmental appropriateness for adolescents in this setting. The purpose of this article is to explicate ways that SBIRT may be tailored to better serve adolescents in primary care under a set of recommended adaptations that we refer to collectively as SBIRT-A or Screening, Brief Intervention, and Referral to Treatment for Adolescents. Each component of the SBIRT-A framework incorporates recommendations to optimize developmental fit with adolescents based on extant empirical research, developmental theory, and well-documented barriers to service delivery in primary care. Commonalities across proposed adaptations include reliance upon proactive methods to identify and engage youth; innovation in service delivery aimed at improving the consistency and reach of interventions; and a family focused approach to engagement, assessment, and intervention. Specific recommendations include taking advantage of every clinical encounter with the family to screen, involving caregivers in assessments and brief interventions, leveraging technology to administer brief interventions and booster sessions, and patient- and family-centered procedures for treatment referral and engagement. The adaptations proposed in this article have the potential to enhance the detection of adolescents with SU problems in primary care, the consistency of intervention provision, and engagement of this typically recalcitrant population into appropriate treatment. PMID- 26742724 TI - The Effectiveness of the Treatment Readiness and Induction Program (TRIP) for Improving During-Treatment Outcomes. AB - Treatment engagement is a primary pathway to change. Because motivation consistently predicts engagement and sustained recovery following treatment, targeted efforts at improving problem recognition (i.e., a significant ingredient in motivation) during early weeks of treatment are critical. The purpose of this study is to compare the effectiveness of Standard Operating Practice (SOP) versus SOP plus an 8-session Treatment Readiness and Induction Program (TRIP; delivered in the first weeks of treatment) on cognitive indicators and treatment engagement among youth in 5 residential substance use treatment settings. Structural Equation Modeling (SEM) documented higher problem recognition, decision making, and treatment engagement (participation, satisfaction, counselor rapport) among youth receiving TRIP (compared to SOP only), even when controlling for background characteristics such as age, race-ethnicity, gender, baseline drug use severity, etc. Findings suggest that TRIP is an effective induction tool that directly impacts targeted constructs (i.e., problem recognition, decision making), and also directly affects indicators of engagement. PMID- 26742725 TI - Behavioral Couples Treatment for Substance Use Disorder: Secondary Effects on the Reduction of Risk for Child Abuse. AB - Risk for child abuse was examined prior to and after behavioral couples treatment (BCT) among 61 couples in which one or both parents were diagnosed with substance use disorder (SUD). All couples were residing with one or more school-age children. Mothers and fathers completed pretreatment, post-intervention, and 6 month post-intervention follow-up assessments. Results of piecewise latent growth models tested whether the number of BCT sessions attended and number of days abstinent from drugs and alcohol influenced relationship satisfaction and its growth over time, and in turn if relationship satisfaction and change in relationship satisfaction influenced risk for child abuse. For both mothers and fathers, attending more BCT sessions lead to a direct increase in relationship satisfaction, which in turn led to stronger reductions in risk for child abuse. This effect was maintained from the post-intervention through the 6-month post intervention follow-up. For fathers, number of days abstinent significantly influenced reduction in child abuse potential at post-intervention via relationship satisfaction. This indirect effect was not present for mothers. The overall benefits of BCT on mothers' and fathers' risk for child abuse suggest that BCT may have promise in reducing risk for child abuse among couples in which one or both parents have SUD. PMID- 26742726 TI - Tigecycline treatment experience against multidrug-resistant Acinetobacter baumannii infections: a systematic review and meta-analysis. AB - The role of tigecycline in treating multidrug-resistant Acinetobacter baumannii (MDR-AB) infections remains controversial. A systematic review and meta-analysis was performed to assess the efficacy and safety of tigecycline in treating MDR-AB infections. PubMed, Embase and Cochrane Library databases were searched up to 20 September 2015. Studies evaluating the efficacy and/or safety of tigecycline in treating MDR-AB infections were included. PRISMA guidelines were followed and the I(2) method was used for heterogeneity. Seven controlled and seventeen single-arm studies were included. No significant difference was noted when tigecycline was compared with control groups in terms of all-cause mortality (OR=0.87, 95% CI 0.50-1.52; P=0.63) and clinical response (OR=1.58, 95% CI 0.61-4.05; P=0.34). Subgroup analysis indicated that treatment with tigecycline was associated with higher in-hospital mortality (OR=1.57, 95% CI 1.04-2.35; P=0.03). Compared with controls, tigecycline had a significantly lower microbial eradication rate (OR=0.20, 95% CI 0.07-0.59; P=0.003) and trend for longer hospital stay (mean difference, 4.69 days, 95% CI -0.17 to 9.55 days; P=0.06). In comparison with monotherapy, tigecycline combination therapy did not affect mortality, clinical response or microbiological response. Tigecycline was well tolerated in the patient populations studied. The pooled rates of resistance emergence and superinfection during treatment were 12.47% and 19.11%, respectively. These findings disfavour the use of a tigecycline-based regimen for the treatment of MDR-AB infections. Well-designed RCTs are needed to clarify the role of tigecycline for MDR-AB infections. PMID- 26742727 TI - Clinical features and mortality of patients on renal replacement therapy receiving polymyxin B. AB - There are no clinical data for polymyxin B (PMB) in patients on renal replacement therapy (RRT). The aim of this study was to evaluate the characteristics of patients on RRT receiving PMB and to identify predictors of 30-day mortality, with special focus on dosage. A multicentre prospective cohort study including patients aged >=18 years treated with PMB for >=48h while on any type of RRT was performed. In total, 88 patients were evaluated, including 34 (38.6%) on continuous venovenous haemodialysis (CVVH) and 54 (61.4%) on intermittent haemodialysis. Most patients (81.8%) received recommended doses between 1.5mg/kg/day and 3.0mg/kg/day. The 30-day mortality was 51.1% (45/88 patients). There was no significant association of dose (in mg/kg) with mortality. A PMB average daily dose >=200mg was predictive of decreased 30-day mortality in the multivariate model (hazard ratio=0.35, 95% confidence interval 0.14-0.90; P=0.03), whilst CVVH (P=0.04), higher Charlson co-morbidity index (P=0.02) and Acute Physiology and Chronic Health Evaluation (APACHE) II score (P=0.04), and Pseudomonas aeruginosa infection (P=0.001) were independent risk factors for mortality. The results were not changed by the inclusion of patient weight or dose (in mg/kg) in the model, although the latter was significantly correlated with total daily dose. This is the first clinical study to show that higher doses of PMB are associated with lower mortality in patients on RRT. PMID- 26742728 TI - Emergence of ST119 Acinetobacter pittii co-harbouring NDM-1 and OXA-58 in Malaysia. PMID- 26742729 TI - Introduction of basic obstetrical ultrasound screening in undergraduate medical education. AB - PURPOSE: Teaching ultrasound procedures to undergraduates has recently been proposed to improve the quality of medical education. We address the impact of applying standardized ultrasound teaching to our undergraduates. METHODS: Medical students received an additional theoretical and practical course involving hands on ultrasound screening during their mandatory practical training week in obstetrics and gynecology. The students' theoretical knowledge and fetal image recognition skills were tested before and after the course. After the course, the students were asked to answer a course evaluation questionnaire. To standardize the teaching procedure, we used Peyton's 4-Step Approach to teach the skills needed for a German Society of Ultrasound in Medicine Level 1 ultrasound examiner. RESULTS: The multiple-choice question scores after the course showed statistically significant improvement (50 vs. 80 %; P < 0.001). The questionnaire revealed that students were satisfied with the course, felt that it increased their ultrasound knowledge, and indicated that they wanted more sonographic hands on training in both obstetrics and gynecology and other medical fields. CONCLUSION: Using practical, hands-on medical teaching is an emerging method for undergraduate education that should be further evaluated, standardized, and developed. PMID- 26742730 TI - Accuracy of sonographic fetal weight estimation: influence of the scan-to delivery interval in combination with the applied weight estimation formula. AB - INTRODUCTION: To evaluate the influence of the time interval between examination and delivery on the accuracy of sonographic fetal weight estimation (WE). MATERIALS AND METHODS: 8723 singleton pregnancies were included in this retrospective cohort study. Fetuses were divided into eight groups with regard to the time interval between estimation and delivery (group 1: 0 days; group 2: 1-3 days; group 3: 4-7 days; group 4: 8-14 days; group 5: 15-21 days; group 6: 22-28 days; group 7: 29-35 days; group 8: 36-42 days). The accuracy of WE was compared between the different time interval groups and five commonly used formulas using means of percentage errors (MPE), medians of absolute percentage errors, and proportions of estimates within 10 % of actual birth weight. RESULTS: In group one, the Hadlock I and Warsof formula showed a systematic underestimation of fetal weight (negative MPEs). No systematic error was found with the Hadlock II formula and the equations of Merz and Shepard showed a systematic overestimation (positive MPEs). MPE values of the Hadlock I, II and Warsof formulas were closest to zero in WEs of group two. From group three to six, MPE values decreased continuously. With the Merz and Shepard equations MPEs were closest to zero in group four. DISCUSSION: The best accuracy of sonographic WE with most of the commonly used equations is achieved within a scan-to-delivery interval of 1 week. PMID- 26742731 TI - Epidural anesthesia for cesarean section for pregnant women with rheumatic heart disease and mitral stenosis. AB - PURPOSE: Pregnancy increases stress on the circulation of parturient with mitral stenosis secondary to rheumatic heart disease and increases the risk of peripartum heart failure, especially during delivery. This study investigated the epidural anesthesia management for cesarean section in pregnant women with rheumatic heart disease and mitral stenosis. METHODS: 48 parturients with rheumatic heart disease and mitral stenosis that had cesarean section deliveries with epidural anesthesia in the Union Hospital, Fujian Medical University (Fuzhou, China) from Jan 2002 to Dec 2012 were retrospectively analyzed. Heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), central venous pressure (CVP), fluid intake volume and fluid output volume (blood loss + urine volume) were analyzed. RESULTS: Medication included digitalis drugs for heart failure or potential heart failure, digoxin and furosemide for chronic congestive heart failure and beta blockers for arrhythmia. Frequent premature ventricular contractions were treated with lidocaine and propafenone. Dexamethasone was administered when heart failure occurred during less than 37 weeks gestation. HR, SAP, DAP, MAP and CVP were significantly increased at the time of delivery. The fluid intake volume was more elevated in the NYHA III-IV group of parturients than the NYHA I-II group, while fluid output volume was less. All parturients survived. CONCLUSIONS: Epidural anesthesia was applied successfully for cesarean sections for parturients with rheumatic heart disease and mitral stenosis. PMID- 26742732 TI - Prostate cancer treated with image-guided helical TomoTherapy(r) and image-guided LINAC-IMRT : Correlation between high-dose bladder volume, margin reduction, and genitourinary toxicity. AB - BACKGROUND: We compared different image-guidance (IG) strategies for prostate cancer with high-precision IG intensity-modulated radiation therapy (IMRT) using TomoTherapy(r) (Accuray Inc., Madison, WI, USA) and linear accelerator (LINAC) IMRT and their impact on planning target volume (PTV) margin reduction. Follow-up data showed reduced bladder toxicity in TomoTherapy patients compared to LINAC IMRT. The purpose of this study was to quantify whether the treatment delivery technique and decreased margins affect reductions in bladder toxicity. PATIENTS AND METHODS: Setup corrections from 30 patients treated with helical TomoTherapy and 30 treated with a LINAC were analyzed. These data were used to simulate three IG protocols based on setup error correction and a limited number of imaging sessions. For all patients, gastrointestinal (GI) and genitourinary (GU) toxicity was documented and correlated with the treatment delivery technique. RESULTS: For fiducial marker (FM)-based RT, a margin reduction of up to 3.1, 3.0, and 4.8 mm in the left-right (LR), superior-inferior (SI), and anterior-posterior (AP) directions, respectively, could be achieved with calculation of a setup correction from the first three fractions and IG every second day. Although the bladder volume was treated with mean doses of 35 Gy in the TomoTherapy group vs. 22 Gy in the LINAC group, we observed less GU toxicity after TomoTherapy. CONCLUSION: Intraprostate FMs allow for small safety margins, help decrease imaging frequency after setup correction, and minimize the dose to bladder and rectum, resulting in lower GU toxicity. In addition, IMRT delivered with TomoTherapy helps to avoid hotspots in the bladder neck, a critical anatomic structure associated with post-RT urinary toxicity. PMID- 26742733 TI - Trichoderma L-Lysine-alpha-Oxidase Producer Strain Culture Fluid Inhibits Impatiens Necrotic Spot Virus. AB - A method for PCR diagnosis of impatiens necrotic spot virus is developed. Concentrated culture fluid with active L-lysine-alpha-oxidase (0.54 U/ml) from Trichoderma harzianum Rifai fungus producer strain F-180 inhibits vitally hazardous impatiens necrotic spot phytovirus. PMID- 26742734 TI - Nephroprotective Effect Exogenous Antioxidant Enzymes during Ischemia/Reperfusion Induced Damage of Renal Tissue. AB - Nephroprotective effect of exogenous chimeric antioxidant enzyme with combined superoxide dismutase and peroxide activities (PSH protein) was studied on the model of ischemia/reperfusion damage of the renal tissue. It was shown that post ischemic (25- and 45-min ischemia) intravenous administration of PSH protein significantly normalized the levels of creatinine and urea. Histological studies showed that as distinct from ischemic kidney, the structure of renal corpuscles and tubules remained unchanged, the number of atrophied glomeruli and glomeruli with exudates and protein inclusions decreased in the capsular teeth after postischemic intravenous administration of PSH protein. Immunohistochemical investigations showed that post-ischemic intravenous injection of PSH protein significantly reduced the intensity of apoptosis in ischemic renal tissues. PMID- 26742735 TI - Cardiomyocyte Autophagia and Morphological Alterations in the Left Ventricular Myocardium during Acute Focal Ischemia. AB - In experiments on rabbits we evaluated the intensity of cardiomyocyte autophagia by the level beclin-1 protein and morphology of the left ventricular myocardium on days 1, 3, and 5 after the onset of focal ischemia caused by ligation of the descending branch of the left coronary artery. The morphological alterations in the left ventricular myocardium were accompanied by intensification of cardiomyocyte autophagia, which attained maximum on postligation day 1. PMID- 26742736 TI - Recombination of Correlations between Bioelements in the Liver and Lungs during Modeling of Diet-Induced Obesity. AB - In rats with obesity induced by high fat ration, the concentrations of K, Ca, Mn, Fe, Cu, Zn, Se, Br, Rb, and Sr were measured in the liver and lungs using synchrotron X-ray fluorescence analysis. Recombinations of inter-element correlations in the liver and lungs of rats receiving or not receiving additional Zn were observed under fasting conditions and after eating lard. Sr and Ca made the most pronounced contribution in the redistribution of correlations in the liver of obese rats. In contrast to other bioelements, Sr had negative correlations with all study elements in the liver of obese rats during physiological starvation. Long-term administration of Zn to rats was followed by recombination of both fasting and postprandial inert-element correlations in the liver and lungs, but Zn concentration did not change under these conditions. Redistribution of correlations in the liver and lungs of obese rats under fasting conditions reflects fundamental changes in metabolic processes, while redistribution observed after fat meal indicates temporary (postprandial) changes. PMID- 26742737 TI - Effects of S-Nitrosoglutathione on the Expression of MMP-1 mRNA in HT1080 Cells during Hypoxic Hypoxia. AB - Synthetic antioxidant S-nitrosoglutathione suppressed the expression of MMP-1 mRNA in HT1080 cells exposed to hypoxic hypoxia; hyperexpression of superoxide dismutase 2 increased and hyperexpression of catalase inhibited the expression of MMP-1 mRNA in HT1080 cells. PMID- 26742738 TI - Protection of Neurovascular Unit Cells with Lithium Chloride and Sodium Valproate Prevents Brain Damage in Neonatal Ischemia/Hypoxia. AB - Here we studied the cytoprotective effect of lithium chloride and sodium valproate in the in vivo model of neonatal cerebral ischemia/hypoxia and analyzed the influence of these substances on the death of the major neurovascular unit components in experimental ischemia in vitro. Lithium chloride and sodium valproate effectively prevented death of neurons, astrocytes, and endothelial cells in the oxygen-glucose deprivation. This treatment protected the brain of newborn rats from ischemia/hypoxia injury. The results suggest that lithium and sodium valproate can be used for the treatment of neurodegenerative pathologies associated with hypoxia and ischemia in newborns. PMID- 26742739 TI - Morphology of Synovial Membrane and Articular Cartilage in the Knee Joint in Experimental Chronic Heart Failure. AB - Structural-and-functional reorganization of the synovial membrane and articular cartilage in the knee joint was studied in rats with experimental chronic heart failure. Separation of fibers, decrease in the relative volume density of microcirculatory vessels, and increase in the expression of MMP-9 and caspase 3 were found in the synovial membrane. A decrease in the thickness of the surface layer (tendency to erosion), vacuolization and necrosis of chondrocytes, and increase in their readiness to programmed cell death were observed in the articular cartilage. Changes in the content of type II collagen and metachromasia were revealed in the cartilage matrix. These changes illustrate the development of degenerative arthropathy in cartilage components. PMID- 26742740 TI - Dominant and Non-Dominant Structure of Ventricular Fibrillation in Canine Heart. AB - Organized activity of the myocardium manifested in dominant frequency structure of ESG was typical of the first 10 min of ventricular fibrillation in canine heart. The first minute of fibrillation was characterized by the most pronounced changes in the structure of oscillation frequency and transition from domination of high frequency oscillations (13-17 Hz) to domination of medium (8-12 Hz) and then low frequency (4-7 Hz) oscillations. The second minute was characterized by transition from domination of low frequency oscillations to domination of low and medium frequency oscillations; minutes 3-10 were characterized by domination of low and medium frequency oscillations; after 10 min, non-dominant ventricular oscillations were recorded. PMID- 26742741 TI - Influence of High Blood Pressure on Microcirculation in Cerebral Cortex of Young Rats. AB - We studied the density and structure of the microvascular network of the pia mater, the blood flow rate and oxygen saturation in the sensorimotor cortex of young spontaneously hypertensive rats (SHR). The density of the microvascular network in hypertensive animals was by ~1.4 times lower than in normotensive Wistar-Kyoto rats (control) and arteriolar bed density was lower by ~1.9 times. The blood flow rate in tissue and oxygen saturation in the sensorimotor cortex in SHR rats were significantly lower than in control animals. PMID- 26742742 TI - Effect of Liver Damage and Hyperbaric Oxygenation on Glutamine Synthetase of Hepatocytes. AB - Activity of glutamine synthetase in the hepatocytes of healthy animals and animals with chronic CCl4-induced hepatitis was studied on white mature female rats after liver resection (15-20% of organ weight) and hyperbaric oxygenation (3 atm, 50 min, 3 times). Surgically operated left and non-operated middle lobes of the liver were analyzed on day 3 after liver resection and exposure to hyperbaric oxygenation. On day 65 of CCl4 poisoning, activity of glutamine synthetase decreased in both lobes and did not recover on day 3 after toxin cessation. Liver resection under conditions of CCl4-induced hepatitis restored reduced activity of glutamine synthetase in both liver lobes to the normal level. In healthy rats, the increase in glutamine synthetase activity after liver resection was found only in the middle lobe of the liver. Hyperbaric oxygenation enhanced the stimulatory effect of liver resection on glutamine synthetase activity in hepatocytes during chronic CCl4-induced hepatitis. In healthy animals with liver resection, activity of glutamine synthetase did not change after hyperbaric oxygenation, while normally oxygenation inhibited glutamine synthetase activity. PMID- 26742743 TI - Antiepileptic Activity of a New Derivative of Benzimidazole RU-1205. AB - Antiepileptic activity of a new derivative of benzimidazole RU-1205 was studied on the model of pentylenetetrazole-induced generalized seizures in mice. Sodium valproate was used as the reference substance. RU-1205 was superior to sodium valproate by anticonvulsant activity (by 12 times) and therapeutic index (by 8.5 times). In contrast to sodium valproate, RU-1205 exhibited significant anticonvulsant activity on the model of pentylenetetrazole-induced kindling without tendency to resistance development. PMID- 26742744 TI - N,N'-Substituted Selenoureas as Polyfunctional Antioxidants. AB - Analysis of antioxidant activity of synthesized selenourea derivatives showed that N,N'-substituted selenoureas inhibited Fe(III)-induced LPO in rat brain homogenate. On the other hand, oxygen- and sulfur-containing analogs exhibited no antioxidant activity or even slight prooxidant activity. Intramolecular alkylation of selenium atom also led to loss of antioxidant activity. Thus, antioxidant activity of the compounds was due to the presence of a nonalkylated selenium atom in N,N'-substituted selenourea analogs. PMID- 26742745 TI - Role of Nitric Oxide Produced by Lactobacilli in Relaxation of Intestinal Smooth Muscles. AB - Application of NO-producing lactobacilli to a rat jejunum segment induced muscle relaxation that was potentiated after activation of bacterial NO production with NO synthase substrate L-arginine. Similar changes in the intestinal contractile activity were observed in response to exogenous NO formed by sodium nitroprusside. These results indicated the involvement of NO synthesized by probiotic lactobacilli in the regulation of the intestinal motor function. PMID- 26742746 TI - Antitumor Properties of Modified Detonation Nanodiamonds and Sorbed Doxorubicin on the Model of Ehrlich Ascites Carcinoma. AB - We studied antitumor properties of modified detonation nanodiamonds loaded with doxorubicin on in vivo model of Ehrlich ascites carcinoma. The type of tumor development and morphological characteristics of the liver, kidneys, and spleen were evaluated in experimental animals. Modified nanodiamonds injected intraperitoneally produced no antitumor effect on Ehrlich carcinoma. However, doxorubicin did not lose antitumor activity after sorption on modified nanodiamonds. PMID- 26742747 TI - Formation of Hyaline Membranes in the Lungs of Albino Rat as a Result of Exposure to Bleomycin During the Neonatal Period. AB - We studied the effect of bleomycin (1 mg/kg) in 1-day-old rat pups (single intraperitoneal injection) and 4-day-old pups (3 injections on postnatal days 1, 2, and 3). The formation of hyaline membranes against the background of oxidative stress was documented in all bleomycin-treated rats. Repeated injection of bleomycin (4-day-old pups) led to more pronounced destructive alterations in the lungs characterized by the formation of microcysts and atelectases as well as hypertrophy of the interstitial connective tissue. These alterations persisted in 14-day-old rats. Administration of bleomycin during the neonatal period can be a promising approach to simulation of hyaline membrane disease (respiratory distress syndrome). PMID- 26742748 TI - Short Peptides and Telomere Length Regulator Hormone Irisin. AB - Irisin produced by muscles during exercise and promoting fat burning also exhibits geroprotective effect and induces telomere elongation in normal somatic cells. Special attention is paid to studies of the role of peptides Lys-Glu, Glu Asp-Arg, and Ala-Glu-Asp-Gly in epigenetic regulation of irisin content. The data suggest that the immunomodulatory peptide Lys-Glu and neuroprotective peptide Glu Asp-Arg modulate the life span by modulating irisin gene expression. PMID- 26742749 TI - Effects of Water-Soluble Polysaccharides with Different Chemical Structure, Isolated from Acorus calamus L. and Trifolium pratense L., on Nitric Oxide Production: A Screening Study. AB - Screening study of the effects of sweet flag (Acorus calamus L.) rhizome and clover (Trifolium pratense L.) aerial part on the production of NO by mouse macrophages was carried out. The polysaccharides were separated by ion exchange chromatography into fractions differing by monomeric composition and ramification type and were used in concentrations of 20, 40, and 100 MUg/ml. Four fractions of Acorus calamus L. (PSF-101, PSF-102, PSF-103, and PSF-105), used in different concentrations, moderately stimulated nitrite production by macrophages. Three of five Trifolium pratense L. polysaccharides (PS62-3, PS62-4, and PS62-5) exhibited a significant specific effect on NO production. Rhamnogalactouronans from clover PS63-3 in all concentrations and from PS62-5 in a concentration of 100 MUg/ml exhibited the highest activity, comparable to the NO-stimulatory activity of the reference LPS, while polysaccharide PS62-3 in a concentration of 40 MUg/ml exhibited even higher activity. PMID- 26742750 TI - Effect of Annexin V on Development of Apoptosis in Placental Syncytiotrophoblast Nuclei during Exacerbation of Cytomegalovirus Infection in the Third Trimester. AB - During exacerbation of cytomegalovirus infection during pregnancy, cytomegalovirus proteins penetrate across the external membrane of placental villous syncytiotrophoblast and suppress activities of ATPase and Bcl-2 protein. Simultaneous increase in the content of annexin V and caspase 3 leads to structural disturbances in DNA in syncytiotrophoblast nuclei and stimulates their apoptosis. Structural abnormalities in the syncytiotrophoblast during exacerbation of cytomegalovirus infection are dangerous for fetal development. PMID- 26742751 TI - Lubinska Phenomenon: Simultaneous Bidirectional Axoplasmic Flow in Nerve Fibers. AB - Experiments on live mollusk neurons isolated with a neurite fragmentsat its various levels demonstrated that axoplasm is characterized by mechanical strain realized in the form of retraction up to complete invagination of the axoplasm into the soma. Changes in axon geometry were attributed to neuroplasm movement. It was found that the direction of axoplasm movement depends on the location of adhesion points. It was always simultaneous and oppositely directed, as is the case with contractile myofibrils. The formation of distant paired adhesion sites can promote moving away of the axoplasm mass and organelles carried by it. The velocity and activity of axoplasm movement depend on the quantity and intensity of adhesion points along the axon. PMID- 26742752 TI - A Method of Ground Simulation of Physiological Effects of Hypogravity on Humans. AB - A novel method of ground simulation in humans of physiological effects induced by the stay on the surface of celestial bodies with hypogravity was developed and successfully tested. This method is based on the change of gravity force angle, which decreases the gravitational component of the blood hydrostatic pressure characteristic of human vertical posture on the Earth and the load-weight onto the locomotor apparatus to the lower values expected at celestial bodies with hypogravity. The methodological requirements for ground simulation of the physiological effects of lunar gravity on human body are specified and substantiated by theoretical calculations. The experimental study revealed redistribution of liquid media in the human organism, functional changes in the cardiorespiratory system, and a decrease in the load-weight applied to the locomotor apparatus. PMID- 26742753 TI - The time course of visual influences in letter recognition. AB - This study builds on a specific characteristic of letters of the Roman alphabet namely, that each letter name is associated with two visual formats, corresponding to their uppercase and lowercase versions. Participants had to read aloud the names of single letters, and event-related potentials (ERPs) for six pairs of visually dissimilar upper- and lowercase letters were recorded. Assuming that the end product of processing is the same for upper- and lowercase letters sharing the same vocal response, ERPs were compared backward, starting from the onset of articulatory responses, and the first significant divergence was observed 120 ms before response onset. Given that naming responses were produced at around 414 ms, on average, these results suggest that letter processing is influenced by visual information until 294 ms after stimulus onset. This therefore provides new empirical evidence regarding the time course and interactive nature of visual letter perception processes. PMID- 26742754 TI - Investigation of the S1/ICT equilibrium in fucoxanthin by ultrafast pump-dump probe and femtosecond stimulated Raman scattering spectroscopy. AB - Time-resolved multi-pulse spectroscopic methods-pump-dump-probe (PDP) and femtosecond stimulated Raman spectroscopy-were used to investigate the excited state photodynamics of the carbonyl group containing carotenoid fucoxanthin (FX). PDP experiments show that S1 and ICT states in FX are strongly coupled and that the interstate equilibrium is rapidly (<5 ps) reestablished after one of the interacting states is deliberately depopulated. Femtosecond stimulated Raman scattering experiments indicate that S1 and ICT are vibrationally distinct species. Identification of the FSRS modes on the S1 and ICT potential energy surfaces allows us to predict a possible coupling channel for the state interaction. PMID- 26742755 TI - Microscopic colitis in patients with Takayasu's arteritis: a potential association between the two disease entities. AB - The association of Takayasu's arteritis (TAK) and inflammatory bowel disease (IBD) has previously been reported in case series. Microscopic colitis (MC) has IBD-like symptoms with regard to clinical and histopathological feature. We aim to assess the presence of MC in TAK patients in this study. We cross-sectionally assessed TAK patients, between the ages of 18-65 years, who were diagnosed according to the American College of Rheumatology (ACR) criteria. Disease activity was evaluated by Kerr's criteria. Age- and sex-matched irritable bowel syndrome (IBS) patients were selected as control group. All patients and controls have been interviewed for IBD and IBS symptoms using the questionnaires of WHO guideline and Rome III criteria, respectively. Lower endoscopic procedure was performed with at least five random biopsies taken from different colonic segments and the terminal ileum. A blinded expert pathologist evaluated the specimens for the features of MC. Thirty TAK patients (29 females and 1 male) with the mean age of 35 +/- 11 years (range, 20-59 years) and 15 IBS controls with the mean age of 38 +/- 13 years were included in the study. TAK patients all fulfilled the MC criteria (three "complete" and six "incomplete" cases). MC was found to be significantly higher in active TAK patients in comparison to inactive group (67 vs 14 %, p = 0.03, OR = 7.9). Our results show that there is an increased frequency of MC in TAK patients, and this is the first report on the association of TAK and MC. PMID- 26742756 TI - Arterial stiffness is associated with left ventricular dysfunction in patients with rheumatoid arthritis. AB - Arterial stiffness (AS) has a detrimental effect on cardiovascular system particularly on left ventricle (LV). The aim of the study was to evaluate the impact of AS on LV functions in patients with rheumatoid arthritis (RA). Forty patients with RA and 25 age-sex matched control subjects (mean age 48.5 +/- 6.3 vs. 45.1 +/- 6.9 years, respectively, p = 0.06) were enrolled in study. AS was assessed by carotid-femoral pulse wave velocity (CF-PWV) and heart rate corrected augmentation index (AIx@75) measured by applanation tonometry (SphygmoCor). LV function was evaluated using tissue Doppler-derived myocardial performance index (MPI) from lateral mitral annulus. CF-PWV (28.3 +/- 10.3 vs. 21.8 +/- 9.3 m/s, p = 0.03), AIx@75 (10.2 +/- 2.3 vs. 9.2 +/- 1, %, p = 0.01) and MPI (0.46 +/- 0.12 vs. 0.36 +/- 0.1, p < 0.001) were significantly higher in patients with RA than in controls. LV MPI was found to be significantly positive correlated with CF PWV, AIx@75, and ESR (r = 0.360, p = 0.005; r = 0.334, p = 0.009; r = 0.293, p = 0.023, respectively). Arterial stiffness parameters including CF-PWV and AIx@75 are associated with subclinical left ventricular dysfunction in patients with RA. PMID- 26742757 TI - Effect of xanthine oxidase inhibitors on the renal clearance of uric acid and creatinine. PMID- 26742758 TI - Poor renal outcomes in patients with anti-neutrophil cytoplasmic antibody associated crescentic glomerulonephritis and normal renal function at diagnosis. AB - The aim of this study is to investigate the renal outcomes of anti-neutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis in patients with normal estimated glomerular filtration rate (eGFR) at diagnosis. Twenty seven patients with biopsy-proven ANCA-associated crescentic glomerulonephritis were retrospectively recruited and were divided into 12 with normal eGFR (>=60 ml/min/1.73 m(2)) and 15 with low eGFR (<60 ml/min/1.73 m(2)) at baseline. Clinical and renal pathological findings at diagnosis and renal outcomes for up to 3 years were compared between the two groups. Two patients in the low eGFR group died of severe bacterial pneumonia. In the normal eGFR group, the following characteristics were observed: younger age at diagnosis (p = 0.04), diagnosis of granulomatosis polyangiitis (GPA) (p < 0.01), and lower frequency of cyclophosphamide treatment (p = 0.03). On renal pathological analysis, the normal eGFR group had a significantly lower proportion of cellular crescent formation (p = 0.01), fibrinoid necrosis (p = 0.01), interstitial fibrosis (p = 0.02), and tubular atrophy (p = 0.02). As a result, the two groups did not significantly differ in remission rates, relapse rates, Birmingham vasculitis score, vasculitis damage index, or eGFR on 3-year follow-up. Patients with biopsy-proven ANCA associated glomerulonephritis and normal eGFR at diagnosis have poor renal outcomes and may require standard intensive immunosuppressive treatment to prevent accrual of damage. PMID- 26742760 TI - IgG4 Characteristics and Functions in Cancer Immunity. AB - IgG4 is the least abundant subclass of IgG in normal human serum, but elevated IgG4 levels are triggered in response to a chronic antigenic stimulus and inflammation. Since the immune system is exposed to tumor-associated antigens over a relatively long period of time, and tumors notoriously promote inflammation, it is unsurprising that IgG4 has been implicated in certain tumor types. Despite differing from other IgG subclasses by only a few amino acids, IgG4 possesses unique structural characteristics that may be responsible for its poor effector function potency and immunomodulatory properties. We describe the unique attributes of IgG4 that may be responsible for these regulatory functions, particularly in the cancer context. We discuss the inflammatory conditions in tumors that support IgG4, the emerging and proposed mechanisms by which IgG4 may contribute to tumor-associated escape from immune surveillance and implications for cancer immunotherapy. PMID- 26742761 TI - Microwave ablation of hepatocellular carcinoma with portal vein tumor thrombosis after transarterial chemoembolization: a prospective study. AB - AIMS: To prospectively assess the use of microwave ablation (MWA) to treat hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) after transarterial chemoembolization (TACE), and to evaluate factors that significantly affect treatment outcomes. METHODS: Sixty patients with HCC [55 male, 5 female; mean age, 54.1 +/- 10.2 (range 36-77) years] + PVTT were enrolled. Patients were treated with MWA after TACE. Results were compared with those of 54 patients treated by TACE alone in another retrospective study. Data analyzed included patient demographics, Eastern Cooperative Oncology Group performance status, liver cirrhosis, liver volume, Child-Pugh class, Cancer of the Liver Italian Program (CLIP) score, and imaging findings. Survival time (from occurrence of PVTT to last follow-up) and predictive factors and their correlation with survival were statistically evaluated. RESULTS: The median 3 year overall survival (OS) duration was 13.5 months, and the 1- and 3-year OS rates were 48 and 23 %, respectively. Cox hazards regression analysis revealed that change in the neutrophil-to-lymphocyte ratio, CLIP score, and treatment efficacy were the only independent predictive factors for outcome (p = 0.035, 0.024, and 0.000, respectively). CONCLUSIONS: Combination therapy with MWA after TACE may provide a substantial benefit for patients with HCC + PVTT type I, II, or partial III and Child-Pugh class A or B by reducing the tumor burden. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Register (ChiCTR): ChiCTR-ONC 12002689. PMID- 26742764 TI - Paracoccus gahaiensis sp. nov. isolated from sediment of Gahai Lake, Qinghai Tibetan Plateau, China. AB - An aerobic, orange-pigmented, Gram-negative, coccoid bacterium, named CUG 00006(T), was isolated from the sediment of Gahai Lake, Qinghai Province, China. This organism was alkaline and grew optimally at pH 9 and 20 degrees C in the presence of 4 % (w/v) NaCl. Strain CUG 00006(T) contained Q-10 as the major isoprenoid quinone and C18:1omega7c as the main fatty acids. The DNA G + C content was 67.8 mol%. The analysis of 16S rRNA gene sequences indicated that strain CUG 00006(T) was phylogenetically related to members of the genus Paracoccus, with the similarities ranging from 93.5 to 97.9 %. In particular, strain CUG 00006(T) was closely related to P. marcusii DSM 11574(T) (97.7 %), P. haeundaensis KCCM 10460(T) (97.8 %), and P. carotinifaciens IFO 16121(T) (97.7 %). On the basis of phylogenetic, physiological, and biochemical characterization, strain CUG 00006(T) is described as a new species of the genus Paracoccus, for which the name Paracoccus gahaiensis sp. nov. is proposed. The type strain is strain CUG 00006(T) (=CCTCC M 2014217(T) = KCTC 42687(T)). PMID- 26742763 TI - Liver progenitor cells-mediated liver regeneration in liver cirrhosis. AB - Cirrhosis is defined as the histological development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury. In cirrhotic liver where hepatocytes proliferation is compromised, liver progenitor cells (LPCs) are activated and then differentiated into hepatocytes and cholangiocytes, leading to the generation of regenerative nodules and functional restoration. Here, we summarize and discuss recent findings on the mechanisms underlying LPCs mediated regeneration in liver cirrhosis. Firstly, we provide recent research on the mechanism underlying LPCs activation in severe or chronic liver injury. Secondly, we present new and exciting data on exploring the origin of LPCs, which reveal that the hepatocytes give rise to duct-like progenitors that then differentiate back into hepatocytes in chronic liver injury or liver cirrhosis. Finally, we highlight recent findings from the literature exploring the role of LPCs niche in directing the behavior and fate of LPCs. This remarkable insight into the cellular and molecular mechanisms of LPCs-mediated regeneration in liver cirrhosis will provide a basis for translating this knowledge into clinical application. PMID- 26742762 TI - Fibrosis assessment: impact on current management of chronic liver disease and application of quantitative invasive tools. AB - Fibrosis, a common pathogenic pathway of chronic liver disease (CLD), has long been indicated to be significantly and most importantly associated with severe prognosis. Nowadays, with remarkable advances in understanding and/or treatment of major CLDs such as hepatitis C, B, and nonalcoholic fatty liver disease, there is an unprecedented requirement for the diagnosis and assessment of liver fibrosis or cirrhosis in various clinical settings. Among the available approaches, liver biopsy remains the one which possibly provides the most direct and reliable information regarding fibrosis patterns and changes in the parenchyma at different clinical stages and with different etiologies. Thus, many endeavors have been undertaken for developing methodologies based on the strategy of quantitation for the invasive assessment. Here, we analyze the impact of fibrosis assessment on the CLD patient care based on the data of recent clinical studies. We discuss and update the current invasive tools regarding their technological features and potentials for the particular clinical applications. Furthermore, we propose the potential resolutions with application of quantitative invasive tools for some major issues in fibrosis assessment, which appear to be obstacles against the nowadays rapid progress in CLD medicine. PMID- 26742765 TI - Canonical and non-canonical Wnt signaling control the regeneration of amputated rodent vibrissae follicles. AB - Although mammals are notoriously poor at regeneration compared with many lower order species, the hair follicle, particular to mammals, is capable of regeneration following partial amputation. The detailed internal mechanism of this phenomenon is still unclear. Development and regrowth of the hair follicle depends on dermal-epidermal interaction within the hair follicle. Previous studies have shown that Wnt/beta-catenin, Shh, Bmp, PDGF, TGF and Notch signals all take part in the development and growth of the hair follicle, and the Wnt/beta-catenin signaling additionally plays an indispensable role in hair follicle morphogenesis and regrowth. In this study, we investigated the localization, as well as, protein levels of Wnt/beta-catenin signaling molecules during amputated whisker follicle regeneration. PMID- 26742766 TI - Propidium Monoazide Coupled with PCR Predicts Infectivity of Enteric Viruses in Swine Manure and Biofertilized Soil. AB - The use of propidium monoazide (PMA) coupled with real-time PCR (RT-qPCR or qPCR for RNA or DNA viruses, respectively) was assessed to discriminate infectious enteric viruses in swine raw manure, swine effluent from anaerobic biodigester (AB) and biofertilized soils. Those samples were spiked either with infectious and heat-inactivated human adenovirus-2 (HAdV-2) or mengovirus (vMC0), and PMA qPCR/RT-qPCR allowed discriminating inactivated viruses from the infective particles, with significant reductions (>99.9%). Then, the procedure was further assayed to evaluate the presence and stability of two non-cultivable viruses (porcine adenovirus and rotavirus A) in natural samples (swine raw manure, swine effluent from AB and biofertilized soils); it demonstrated viral inactivation during the storage period at 23 degrees C. As a result, the combination of PMA coupled to real-time PCR can be a promising alternative for prediction of viral infectivity in comparison to more labour-intensive and costly techniques such as animal or tissue-culture infectivity methods, and for those viruses that do not have currently available cell culture techniques. PMID- 26742767 TI - Connective tissue cells expressing fibro/adipogenic progenitor markers increase under chronic damage: relevance in fibroblast-myofibroblast differentiation and skeletal muscle fibrosis. AB - Fibrosis occurs in skeletal muscle under various pathophysiological conditions such as Duchenne muscular dystrophy (DMD), a devastating disease characterized by fiber degeneration that results in progressive loss of muscle mass, weakness and increased extracellular matrix (ECM) accumulation. Fibrosis is also observed after skeletal muscle denervation and repeated cycles of damage followed by regeneration. The ECM is synthesized largely by fibroblasts in the muscle connective tissue under normal conditions. Myofibroblasts, cells that express alpha-smooth muscle actin (alpha-SMA), play a role in many tissues affected by fibrosis. In skeletal muscle, fibro/adipogenic progenitors (FAPs) that express cell-surface platelet-derived growth factor receptor-alpha (PDGFR-alpha) and the transcription factor Tcf4 seem to be responsible for connective tissue synthesis and are good candidates for the origin of myofibroblasts. We show that cells positive for Tcf4 and PDGFR-alpha are expressed in skeletal muscle under normal conditions and are increased in various skeletal muscles of mdx mice, a murine model for DMD, wild type muscle after sciatic denervation and muscle subjected to chronic damage. These cells co-label with the myofibroblast marker alpha-SMA in dystrophic muscle but not in normal tissue. The Tcf4-positive cells lie near macrophages mainly concentrated in dystrophic necrotic-regenerating foci. The close proximity of Tcf4-positive cells to inflammatory cells and their previously described role in muscle regeneration might reflect an active interaction between these cell types and growth factors, possibly resulting in a muscular regenerative or fibrotic condition. PMID- 26742768 TI - Parkin modulates expression of HIF-1alpha and HIF-3alpha during hypoxia in gliobastoma-derived cell lines in vitro. AB - Mutation of the Parkin gene causes an autosomal recessive juvenile-onset form of Parkinson's disease. However, recently, it has been also linked to a wide variety of malignancies, including glioblastoma multiforme (GBM). In this pathology, Parkin exhibits a tumor suppressor role by mitigating the proliferation rate in both in vitro and in vivo models. However, Parkin involvement in the hypoxic process has not as yet been investigated. GBM is the most common and aggressive primary brain tumor in adults and is characterized by hypoxic areas. The low oxygen supply causes the expression of hypoxia-inducible factors (HIFs) leading to an accumulation of pro-angiogenic factors and tumoral invasiveness. We assess the relationship between Parkin and two HIFs expressed during hypoxic conditions, namely HIF-1alpha and HIF-3alpha. Our data show that Parkin is downregulated under hypoxia and that it interferes with HIF expression based on cellular oxygen tension. These results suggest a role for the involvement of Parkin in GBM, although further studies will be needed to understand the mechanism by which it modulates HIF-1alpha and HIF-3alpha expression. PMID- 26742769 TI - RpoE is a Putative Antibiotic Resistance Regulator of Salmonella enteric Serovar Typhi. AB - Bacterial antimicrobial resistance has been associated with the up regulation of genes encoding efflux pumps and the down regulation of genes encoding outer membrane proteins (OMPs). Gene expression in bacteria is primarily initiated by sigma factors (sigma factors) such as RpoE, which plays an important role in responding to many environmental stresses. Here, we report the first observation that RpoE serves as an antibiotic resistance regulator in Salmonella enteric serovar Typhi (S. Typhi). In this study, we found that the rpoE mutant (DeltarpoE) of S. Typhi GIFU10007 has elevated resistance to several antimicrobial agents, including beta-lactams, quinolones, and aminoglycosides. Genomic DNA microarray analysis was used to investigate the differential gene expression profiles between a wild type and rpoE mutant in response to ampicillin. The results showed that a total of 57 genes displayed differential expression (two-fold increase or decrease) in DeltarpoE versus the wild-type strain. The expressions of two outer membrane protein genes, ompF and ompC, were significantly down-regulated in DeltarpoE (six and seven-fold lower in comparison to wild-type strain) and RamA, a member of the efflux pump AraC/XylS family, was up-regulated about four-fold in the DeltarpoE. Our results suggest RpoE is a potential antimicrobial regulator in S. Typhi, controlling both the down regulation of the OMP genes and up-regulating the efflux system. PMID- 26742770 TI - Efficient Construction of Large Genomic Deletion in Agrobacterium tumefaciens by Combination of Cre/loxP System and Triple Recombineering. AB - In order to develop an efficient system for deleting genomic segment in Agrobacterium tumefaciens to analyze gene functions and construct marker gene free recombinant strains, a Cre recombinase expression plasmid was constructed by placing its encoding gene under the control of Ptet promoter and cloning into the plasmid replicable in both A. tumefaciens and E. coli. Triple recombineering was applied to efficiently construct integrative vectors which were used to introduce loxP sites and selection markers into the chromosome of A. tumefaciens. Cre recombinase could be properly induced by anhydrotetracycline in A. tumefaciens, which was revealed by the fact that kanamycin resistance gene flanked by two parallel loxP sites was excised from the genome of A. tumefaciens with virtually 100% efficiency. And what is more, an A. tumefaciens mutant carrying large deletion (~85 kb) in genome was successfully constructed by Cre/loxP system. Here, we described the application of combination of Cre/loxP system and triple recombineering to efficiently excise genomic segment in A. tumefaciens, which also would facilitate efficient construction of multiple gene disruptions in A. tumefaciens. PMID- 26742772 TI - Pseudomonas putida Stimulates Primordia on Agaricus bitorquis. AB - Casing layer is one step of Agaricus bisporus cultivation where there is a competitive environment with a high number of microorganisms and diversity interacting with mycelia. It is suggested that a minimal community of these microorganisms would be necessary to stimulate fructification. However, A. bisporus is not able to produce primordia in sterile casing layers or Petri dishes. Thus, the objective of this study was to characterize bacterial microbiota of casing layers from A. bisporus cultivation, isolate, identify and characterize the bacteria responsible for the stimulation of primordium and their action mechanism using Agaricus bitorquis as a primordium stimulation model. Bacterial and Pseudomonas spp. communities of different casing layers of A. bisporus cultivation were collected and quantified. It was concluded that Pseudomonas spp. corresponds to 75-85% of bacterial population of the casing layers in A. bisporus cultivation and among those 12% are Pseudomonas putida. Four biochemical assays were used to identify P. putida. In vitro primordium stimulation of living P. putida and non-living bacterial suspensions, after chemical or physical treatments, was tested using A. bitorquis as a primordium stimulation model. Primordium stimulation assay was registered by photographs, and micrographs of vertical cut of primordium were registered by scanning electron microscope. Interaction of living P. putida with A. bitorquis mycelia is capable of stimulating primordial instead of non-living bacterial suspensions. Stimulation of A. bitorquis primordia does not imply or is related to mycelial growth inhibition, but a hierarchical relation of primordium succession and development is suggested. PMID- 26742771 TI - Production and Biomedical Applications of Probiotic Biosurfactants. AB - Biosurfactants have been widely used for environmental and industrial applications. However, their use in medical field is still limited. Probiotic biosurfactants possess an immense antimicrobial, anti-adhesive, antitumor, and antibiofilm potential. Moreover, they have an additional advantage over conventional microbial surfactants because probiotics are an integral part of normal human microflora and their biosurfactants are innocuous to human. So, they can be effectively exploited for medicinal use. Present review is aimed to discourse the production and biomedical applications of probiotic biosurfactants. PMID- 26742773 TI - Different Photoresponses of Microorganisms: From Bioinhibition to Biostimulation. AB - The effective treatment of antimicrobial modalities continues to be a serious challenge, mainly due to the increasing number of multidrug resistance pathogenic microorganisms. Microbial bioinhibition is an alternative method that has shown to be effective. This study investigated and described the effect of the visible light on five different microorganisms. The studied groups were composed by the species Acanthamoeba polyphaga, Candida albicans, Mycobacterium massiliense, Pseudomonas aeruginosa, and Staphylococcus aureus. These microorganisms were analyzed after six light doses exposition with three different wavelengths: 450, 520, and 630 nm. The present study indicates two different behaviors: bioinhibition and/or biostimulation. The bioinhibition effect was calculated using different percentages of the microorganism population, compared to the control group, in which the maximum value corresponds to 94% growth inhibition. The biostimulation effect was evaluated by the microorganism population increment for specific light doses. Our results showed a 132% population growth as the maximum value. These results were assessed by variance analysis. The Tukey's test was used for differentiating or comparing, depending on the circumstances. The obtained results suggested a visible light phototherapeutic effect that could be used as a microorganism inactivation method for the studied microorganisms. In some approaches, the biostimulation effect might also be a very interesting effect to be considered. This study supports the relevance of understanding the important role that phototherapy plays as a useful method for microbiological control studies and applications. PMID- 26742774 TI - Propagation of field highly pathogenic porcine reproductive and respiratory syndrome virus in MARC-145 cells is promoted by cell apoptosis. AB - Infection of porcine reproductive and respiratory syndrome virus (PRRSV) induces cell apoptosis both in vivo and in vitro. However, the correlation between host cell apoptosis and PRRSV replication is unclear. Here, the promotion of PRRSV propagation by cell apoptosis in MARC-145 cells was reported. The observation on propagation of field highly pathogenic PRRSV (HP-PRRSV) in MARC-145 cells showed that infection of overgrown MARC-145 cells obviously elevated virus production and cell apoptosis was triggered in these cells before virus inoculation. The investigation on propagation of field HP-PRRSV in apoptosis induced MARC-145 cells displayed that induction of apoptosis further increased the virus production and a vigorous viral RNA replication accompanied by fast virus release in these cells was detected in the initial 24h post infection. In addition, when field HP-PRRSV was serially passed in drug-treated MARC-145 cells, the progeny viruses kept a stable viral titer and infectivity to its native target cells in the tested generations. In summary, these findings demonstrated that apoptotic MARC-145 cells were more susceptible to field HP-PRRSV and propagation of the virus was promoted by effective replication and cell-to-cell transmission of the virus in these cells. PMID- 26742775 TI - Photodecomposition of bromophenols. AB - Photodecomposition of bromophenols (BPs) represents a potent channel of debromination and elimination of these species in the environment. From this perspective, the present contribution reports geometrical parameters, electronic absorption spectra and excited states of the complete series of BPs in their ground state (S0), as well as their first singlet exited state (S1). We calculate excitation energies for S0 -> S1 transition within the framework of the time dependent density functional theory (TDDFT). We estimate and discuss charges on bromine atoms and HOMO-LUMO energy gaps (E(H-L)) as molecular descriptors for the photoreactivity of BPs and photo-induced debromination mechanism of BPs. Spectral patterns reveal that, as the degree of bromination increases, peaks of absorption spectra red-shift toward wavelengths near 300 nm, for the pentabrominated phenol. Based on the analysis of optimised geometries and Hirshfeld's atomic charges, photodebromination of BPs commences via the loss of an ortho Br atom. The excitation energies decrease linearly with increasing number of bromine atoms. This indicates that, higher brominated congeners of BPs photodecompose more readily than lower brominated congeners. PMID- 26742776 TI - Neuroimaging in the modern era. PMID- 26742777 TI - Lesinurad in combination with allopurinol: results of a phase 2, randomised, double-blind study in patients with gout with an inadequate response to allopurinol. AB - OBJECTIVES: To assess the efficacy and tolerability of lesinurad, an oral selective uric acid reabsorption inhibitor, in combination with allopurinol versus allopurinol alone in patients with gout and an inadequate response to allopurinol. METHODS: Patients (N=227) with an inadequate response to allopurinol, defined as serum urate (sUA) >=6 mg/dL on >=2 occasions >=2 weeks apart despite >=6 weeks of allopurinol, were randomised 2:1 to 4 weeks of double blind treatment with lesinurad (200, 400 or 600 mg/day) or matching placebo in combination with their prestudy allopurinol dose (200-600 mg/day). Colchicine prophylaxis for gout flares was required. The primary end point was percent reduction from baseline sUA levels at 4 weeks. A pharmacokinetic substudy was also conducted. Safety was assessed throughout. RESULTS: Patients (n=208) received >=1 dose of blinded medication. Lesinurad 200, 400 and 600 mg in combination with allopurinol produced significant mean percent reductions from baseline sUA of 16%, 22% and 30%, respectively, versus a mean 3% increase with placebo (p<0.0001, all doses vs placebo). Similar results were observed in patients with mild or moderate renal insufficiency (estimated creatinine clearance 30 to <90 mL/min). The incidence of >=1 treatment-emergent adverse event was 46%, 48% and 54% with lesinurad 200, 400 and 600 mg, respectively, and 46% with placebo (most frequent, gout flares, arthralgia, headache and nasopharyngitis), with no deaths or serious adverse events. CONCLUSIONS: Lesinurad achieves clinically relevant and statistically significant reductions in sUA in combination with allopurinol in patients who warrant additional therapy on allopurinol alone. TRIAL REGISTRATION NUMBER: NCT01001338. PMID- 26742778 TI - How medical teachers use narratives in lectures: a qualitative study. AB - BACKGROUND: There are strong theoretical arguments for using narratives in teaching and learning within medicine, but little is known about how they are used in medical lectures. This study explores the types of narratives lecturers use, the attitudes of lecturers and students to the use of narratives in teaching, and the aspects of learning that narratives may facilitate. METHODS: Observation of three medical lectures was followed by one-to-one interviews with the respective lecturers, and separate focus group interviews with medical students who attended each of the three lectures. RESULTS: Lecturers used a variety of narratives on a range of themes, from clinical cases to patient experience narratives or narratives about their professional careers. Students and lecturers highlighted key aspects of narrative learning: for example providing a relevant context, as a "hook" to engage the audience, and as a memory aid. CONCLUSION: The findings support existing literature which suggests that narratives may be a useful tool for learning in medicine. This study suggests that narratives tap into several key learning processes including providing a relevant context for understanding, engaging learners, and promoting memory. For medical students in lectures, narratives may be particularly relevant in promoting humanistic aspects of medicine, including professional identity and empathy. PMID- 26742779 TI - Ecological momentary assessment of the relationship between headache pain intensity and pain interference in women with migraine and obesity. AB - Background While pain intensity during migraine headache attacks is known to be a determinant of interference with daily activities, no study has evaluated: (a) the pain intensity-interference association in real-time on a per-headache basis, (b) multiple interference domains, and (c) factors that modify the association. Methods Participants were 116 women with overweight/obesity and migraine seeking behavioral treatment to lose weight and decrease headaches in the Women's Health and Migraine trial. Ecological momentary assessment, via smartphone-based 28-day headache diary, and linear mixed-effects models were used to study associations between pain intensity and total- and domain-specific interference scores using the Brief Pain Inventory. Multiple factors (e.g. pain catastrophizing (PC) and headache management self-efficacy (HMSE)) were evaluated either as independent predictors or moderators of the pain intensity-interference relationship. Results Pain intensity predicted degree of pain interference across all domains either as a main effect (coeff = 0.61-0.78, p < 0.001) or interaction with PC, allodynia, and HMSE ( p < 0.05). Older age and greater allodynia consistently predicted higher interference, regardless of pain intensity (coeff = 0.04-0.19, p < 0.05). Conclusions Pain intensity is a consistent predictor of pain interference on migraine headache days. Allodynia, PC, and HMSE moderated the pain intensity interference relationship, and may be promising targets for interventions to reduce pain interference. PMID- 26742782 TI - Relocating people with intellectual disability to new accommodation and support settings: Contrasts between personalized arrangements and group home placements. AB - Internationally the relocation of people with intellectual disability from institutions has brought significant gains to their quality of life. This study contrasted three groups of persons in Ireland who moved either to personalized arrangements (n = 29) or to community group homes (n = 31) with those who remained in congregated settings awaiting relocation (n = 29). Persons moving to rented accommodation with personalized support tended to be younger and had fewer support needs than those in group homes. They had greater control and choice in their lives, more community engagement and increased personal relationships compared to residents in group homes but those remaining in congregated settings fared worse of all. However, average staff costs were significantly higher in the latter settings. The implications for the future provision of group living arrangements are discussed along with the need for further longitudinal research to assess the sustained impact of personalized arrangements and their funding. PMID- 26742781 TI - Sinoporphyrin sodium mediated photodynamic therapy inhibits the migration associated with collapse of F-actin filaments cytoskeleton in MDA-MB-231 cells. AB - OBJECTIVE: We previously demonstrated that the photosensitizer sinoporphyrin sodium (DVDMS) mediated photodynamic therapy (PDT) had potential advantages in inhibiting tumor growth and metastasis. However, details regarding the mechanism of cell migration inhibition remain unclear. Therefore, in this study, we aimed to investigate the effects of DVDMS-PDT on F-actin filaments, cell migration, apoptotic response and the possible interactions between them in human breast cancer MDA-MB-231 cells. MATERIALS AND METHODS: The cell viability was evaluated by MTT and Guava ViaCount assays. The subcellular localization of DVDMS and reactive oxygen species (ROS) generation were analyzed by fluorescence microscope and flow cytometry. FITC-phalloidin was used to evaluate the changes of F-actin filaments. Cell migration was analyzed by scratch assay and Transwell assay. Cell apoptosis was determined by nuclear TUNEL staining and Annexin V-PE/7-AAD assay. Jasplakinolide, an F-actin stabilizer, was applied to dissect the influences of F actin filaments disruption on cell migration and apoptosis. RESULTS: DVDMS-PDT significantly suppressed cell proliferation, promoted early apoptotic response, triggered collapse of F-actin filaments and inhibited cell migration in MDA-MB 231 cells. Cell migration significantly increased when cells were pretreated with F-actin stabilizer jasplakinolide after PDT, while cell apoptosis was not obviously affected. Moreover, ROS was a key factor in causing collapse of F-actin filaments. CONCLUSION: We demonstrated that DVDMS-PDT triggered cell apoptosis and collapse of F-actin filaments through the induction of ROS in MDA-MB-231 cells. F-actin filaments contributed to cell migration but produced no obvious effect on cell apoptosis. PMID- 26742780 TI - Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2alpha mediated stress signaling. AB - Phosphorylation of translation initiation factor 2alpha (eIF2alpha) attenuates global protein synthesis but enhances translation of activating transcription factor 4 (ATF4) and is a crucial evolutionarily conserved adaptive pathway during cellular stresses. The serine-threonine protein phosphatase 1 (PP1) deactivates this pathway whereas prolonging eIF2alpha phosphorylation enhances cell survival. Here, we show that the reactive oxygen species-generating NADPH oxidase-4 (Nox4) is induced downstream of ATF4, binds to a PP1-targeting subunit GADD34 at the endoplasmic reticulum, and inhibits PP1 activity to increase eIF2alpha phosphorylation and ATF4 levels. Other PP1 targets distant from the endoplasmic reticulum are unaffected, indicating a spatially confined inhibition of the phosphatase. PP1 inhibition involves metal center oxidation rather than the thiol oxidation that underlies redox inhibition of protein tyrosine phosphatases. We show that this Nox4-regulated pathway robustly enhances cell survival and has a physiologic role in heart ischemia-reperfusion and acute kidney injury. This work uncovers a novel redox signaling pathway, involving Nox4-GADD34 interaction and a targeted oxidative inactivation of the PP1 metal center, that sustains eIF2alpha phosphorylation to protect tissues under stress. PMID- 26742783 TI - Clinical expertise and its accuracy in differentiating arthralgia patients at risk for rheumatoid arthritis from other patients presenting with joint symptoms. PMID- 26742784 TI - Of grave concern. AB - A 73-year-old woman presented with vision loss and recurrent proptosis with conjunctival chemosis 4 weeks after an uncomplicated fat-only orbital decompression for thyroid eye disease. Her Graves disease was biochemically "burnt out," and she had diabetes mellitus. Initial neuro-imaging showed a straightened optic nerve and orbital apex fat streaking so a bilateral bony decompression of the orbital apex was performed for presumed compressive optic neuropathy. Vision failed to improve, and she experienced cognitive decline. She described metamorphopsia and insomnia. Examination showed a hemifield loss of red sensitivity, difficulties with higher visual processing, and memory problems. Occipital cortical ribboning was seen on diffusion weighted magnetic resonance imaging, cerebrospinal fluid was positive for 14-3-3, and her electroencephalogram showed periodic complexes. A diagnosis of the Heidenhain variant of Creutzfeldt-Jakob disease was made. She became akinetic and mute, dying a few months later. PMID- 26742785 TI - Famous. AB - A 62-year-old woman with multiple sclerosis experienced painless loss of vision in both eyes after starting fingolimod. Fundus examination revealed bilateral macular edema confirmed by optical coherence tomography. Fingolimod was discontinued, and a topical nonsteroidal inflammatory drug and corticosteroid were initiated. Within 2 months, vision returned to baseline with complete resolution of the macular edema. PMID- 26742786 TI - Teens' e-cigarette use rises as spending on advertising soars, says CDC. PMID- 26742787 TI - X. couchianus and X. hellerii genome models provide genomic variation insight among Xiphophorus species. AB - BACKGROUND: Xiphophorus fishes are represented by 26 live-bearing species of tropical fish that express many attributes (e.g., viviparity, genetic and phenotypic variation, ecological adaptation, varied sexual developmental mechanisms, ability to produce fertile interspecies hybrids) that have made attractive research models for over 85 years. Use of various interspecies hybrids to investigate the genetics underlying spontaneous and induced tumorigenesis has resulted in the development and maintenance of pedigreed Xiphophorus lines specifically bred for research. The recent availability of the X. maculatus reference genome assembly now provides unprecedented opportunities for novel and exciting comparative research studies among Xiphophorus species. RESULTS: We present sequencing, assembly and annotation of two new genomes representing Xiphophorus couchianus and Xiphophorus hellerii. The final X. couchianus and X. hellerii assemblies have total sizes of 708 Mb and 734 Mb and correspond to 98 % and 102 % of the X. maculatus Jp 163 A genome size, respectively. The rates of single nucleotide change range from 1 per 52 bp to 1 per 69 bp among the three genomes and the impact of putatively damaging variants are presented. In addition, a survey of transposable elements allowed us to deduce an ancestral TE landscape, uncovered potential active TEs and document a recent burst of TEs during evolution of this genus. CONCLUSIONS: Two new Xiphophorus genomes and their corresponding transcriptomes were efficiently assembled, the former using a novel guided assembly approach. Three assembled genome sequences within this single vertebrate order of new world live-bearing fishes will accelerate our understanding of relationship between environmental adaptation and genome evolution. In addition, these genome resources provide capability to determine allele specific gene regulation among interspecies hybrids produced by crossing any of the three species that are known to produce progeny predisposed to tumor development. PMID- 26742789 TI - Keratinocytes derived from chicken embryonic stem cells support Marek's disease virus infection: a highly differentiated cell model to study viral replication and morphogenesis. AB - BACKGROUND: Marek's disease is a virus disease with worldwide distribution that causes major losses to poultry production. Vaccines against Marek's disease virus, an oncogenic alphaherpesvirus, reduce tumour formation but have no effect on virus shedding. Successful horizontal virus transmission is linked to the active viral replication in feather follicle epithelial cells of infected chickens, from which infectious viral particles are shed into the environment. The feather follicle epithelium is the sole tissue in which those infectious particles are produced and no in vitro cell-systems can support this highly efficient morphogenesis. We previously characterized embryonic stem-cell-derived keratinocytes, showing they display a marker-gene profile similar to skin keratinocytes, and therefore we tested their susceptibility to Marek's disease virus infection. FINDINGS: We show herein that keratinocytes derived from chicken embryonic stem-cells are fully permissive to the replication of either non pathogenic or pathogenic Marek's disease viruses. All viruses replicated on all three keratinocyte lines and kinetics of viral production as well as viral loads were similar to those obtained on primary cells. Morphogenesis studies were conducted on infected keratinocytes and on corneocytes, showing that all types of capsids/virions were present inside the cells, but extracellular viruses were absent. CONCLUSIONS: The keratinocyte lines are the first epithelial cell-line showing ectodermal specific markers supporting Marek's disease virus replication. In this in vitro model the replication lead to the production of cell-associated viral progeny. Further work will be devoted to the study of relationship between 3D differentiation of keratinocytes and Marek's disease virus replication. PMID- 26742788 TI - Transmission of sheep-bovine spongiform encephalopathy to pigs. AB - Experimental transmission of the bovine spongiform encephalopathy (BSE) agent has been successfully reported in pigs inoculated via three simultaneous distinct routes (intracerebral, intraperitoneal and intravenous). Sheep derived BSE (Sh BSE) is transmitted more efficiently than the original cattle-BSE isolate in a transgenic mouse model expressing porcine prion protein. However, the neuropathology and distribution of Sh-BSE in pigs as natural hosts, and susceptibility to this agent, is unknown. In the present study, seven pigs were intracerebrally inoculated with Sh-BSE prions. One pig was euthanized for analysis in the preclinical disease stage. The remaining six pigs developed neurological signs and histopathology revealed severe spongiform changes accompanied by astrogliosis and microgliosis throughout the central nervous system. Intracellular and neuropil-associated pathological prion protein (PrP(Sc)) deposition was consistently observed in different brain sections and corroborated by Western blot. PrP(Sc) was detected by immunohistochemistry and enzyme immunoassay in the following tissues in at least one animal: lymphoid tissues, peripheral nerves, gastrointestinal tract, skeletal muscle, adrenal gland and pancreas. PrP(Sc) deposition was revealed by immunohistochemistry alone in the retina, optic nerve and kidney. These results demonstrate the efficient transmission of Sh-BSE in pigs and show for the first time that in this species propagation of bovine PrP(Sc) in a wide range of peripheral tissues is possible. These results provide important insight into the distribution and detection of prions in non-ruminant animals. PMID- 26742790 TI - Effects of isoflurane and ethanol administration on c-Fos immunoreactivity in mice. AB - Noninvasive functional imaging holds great promise for the future of translational research, due to the ability to directly compare between preclinical and clinical models of psychiatric disorders. Despite this potential, concerns have been raised regarding the necessity to anesthetize rodent and monkey subjects during these procedures, because anesthetics may alter neuronal activity. For example, in studies on drugs of abuse and alcohol, it is not clear to what extent anesthesia can interfere with drug-induced neural activity. Therefore, the current study investigated whole-brain c-Fos activation following isoflurane anesthesia as well as ethanol-induced activation of c-Fos in anesthetized mice. In the first experiment, we examined effects of one or three sessions of gaseous isoflurane on c-Fos activation across the brain in male C57BL/6J mice. Isoflurane administration led to c-Fos activation in several areas, including the piriform cortex and lateral septum. Lower or similar levels of activation in these areas were detected after three sessions of isoflurane, suggesting that multiple exposures may eliminate some of the enhanced neuronal activation caused by acute isoflurane. In the second experiment, we investigated the ability of ethanol injection (1.5 or 2.5g/kgi.p.) to induce c-Fos activation under anesthesia. Following three sessions of isoflurane, 1.5g/kg of ethanol induced c-Fos in the central nucleus of amygdala and the centrally-projecting Edinger-Westphal nucleus (EWcp). This induction was lower after 2.5g/kg of ethanol. These results demonstrate that ethanol-induced neural activation can be detected in the presence of isoflurane anesthesia. They also suggest, that while habituation to isoflurane helps reduce neuronal activation, interaction between effects of anesthesia and alcohol can occur. Studies using fMRI imaging could benefit from using habituated animals and dose-response analyses. PMID- 26742792 TI - Subtle alterations in memory systems and normal visual attention in the GAERS model of absence epilepsy. AB - OBJECTIVE: Even if considered benign, absence epilepsy may alter memory and attention, sometimes subtly. Very little is known on behavior and cognitive functions in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model of absence epilepsy. We focused on different memory systems and sustained visual attention, using Non Epileptic Controls (NECs) and Wistars as controls. METHODS: A battery of cognitive/behavioral tests was used. The functionality of reference, working, and procedural memory was assessed in the Morris water maze (MWM), 8-arm radial maze, T-maze and/or double-H maze. Sustained visual attention was evaluated in the 5-choice serial reaction time task. RESULTS: In the MWM, GAERS showed delayed learning and less efficient working memory. In the 8-arm radial maze and T-maze tests, working memory performance was normal in GAERS, although most GAERS preferred an egocentric strategy (based on proprioceptive/kinesthetic information) to solve the task, but could efficiently shift to an allocentric strategy (based on spatial cues) after protocol alteration. Procedural memory and visual attention were mostly unimpaired. SIGNIFICANCE: Absence epilepsy has been associated with some learning problems in children. In GAERS, the differences in water maze performance (slower learning of the reference memory task and weak impairment of working memory) and in radial arm maze strategies suggest that cognitive alterations may be subtle, task-specific, and that normal performance can be a matter of strategy adaptation. Altogether, these results strengthen the "face validity" of the GAERS model: in humans with absence epilepsy, cognitive alterations are not easily detectable, which is compatible with subtle deficits. PMID- 26742791 TI - Density of GFAP-immunoreactive astrocytes is decreased in left hippocampi in major depressive disorder. AB - Neuroimaging and postmortem studies of subjects with major depressive disorder (MDD) reveal smaller hippocampal volume with lengthening duration of illness. Pathology in astrocytes may contribute significantly to this reduced volume and to the involvement of the hippocampus in MDD. Postmortem hippocampal tissues were collected from 17 subjects with MDD and 17 psychiatrically-normal control subjects. Sections from the body of the hippocampus were immunostained for glial fibrillary acidic protein (GFAP), a marker of intermediate filament protein expressed in astrocytes. The density of GFAP-immunoreactive astrocytes was measured in the hippocampus using 3-dimensional cell counting. Hippocampal subfields were also assessed for GFAP-immunoreactive area fraction. In CA1, there was a significant positive correlation between age and either density or area fraction in MDD. The density of astrocytes in the hilus, but not CA1 or CA2/3, was significantly decreased only in depressed subjects not taking an antidepressant drug, but not for depressed subjects taking an antidepressant drug. The area fraction of GFAP-immunoreactivity was significantly decreased in the dentate gyrus in women but not men with depression. In CA2/3, the area fraction of GFAP-immunoreactivity was inversely correlated with the duration of depression in suicide victims. Astrocyte contributions to neuronal function in the hilus may be compromised in depressed subjects not taking antidepressant medication. Due to the cross-sectional nature of the present study of postmortem brain tissue, it remains to be determined whether antidepressant drug treatment prevented a decrease in GFAP-immunoreactive astrocyte density or restored cell density to normal levels. PMID- 26742793 TI - Effects of rapamycin on cerebral oxygen supply and consumption during reperfusion after cerebral ischemia. AB - Activation of the mammalian target of rapamycin (mTOR) leads to cell growth and survival. We tested the hypothesis that inhibition of mTOR would increase infarct size and decrease microregional O2 supply/consumption balance after cerebral ischemia-reperfusion. This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1h and reperfusion for 2h with and without rapamycin (20mg/kg once daily for two days prior to ischemia). Regional cerebral blood flow was determined using a C(14)-iodoantipyrine autoradiographic technique. Regional small-vessel arterial and venous oxygen saturations were determined microspectrophotometrically. The control ischemic-reperfused cortex had a similar blood flow and O2 consumption to the contralateral cortex. However, microregional O2 supply/consumption balance was significantly reduced in the ischemic reperfused cortex. Rapamycin significantly increased cerebral O2 consumption and further reduced O2 supply/consumption balance in the reperfused area. This was associated with an increased cortical infarct size (13.5+/-0.8% control vs. 21.5+/-0.9% rapamycin). We also found that ischemia-reperfusion increased AKT and S6K1 phosphorylation, while rapamycin decreased this phosphorylation in both the control and ischemic-reperfused cortex. This suggests that mTOR is important for not only cell survival, but also for the control of oxygen balance after cerebral ischemia-reperfusion. PMID- 26742794 TI - Coenzyme Q10 defects may be associated with a deficiency of Q10-independent mitochondrial respiratory chain complexes. AB - BACKGROUND: Coenzyme Q10 (CoQ10 or ubiquinone) deficiency can be due either to mutations in genes involved in CoQ10 biosynthesis pathway, or to mutations in genes unrelated to CoQ10 biosynthesis. CoQ10 defect is the only oxidative phosphorylation disorder that can be clinically improved after oral CoQ10 supplementation. Thus, early diagnosis, first evoked by mitochondrial respiratory chain (MRC) spectrophotometric analysis, then confirmed by direct measurement of CoQ10 levels, is of critical importance to prevent irreversible damage in organs such as the kidney and the central nervous system. It is widely reported that CoQ10 deficient patients present decreased quinone-dependent activities (segments I + III or G3P + III and II + III) while MRC activities of complexes I, II, III, IV and V are normal. We previously suggested that CoQ10 defect may be associated with a deficiency of CoQ10-independent MRC complexes. The aim of this study was to verify this hypothesis in order to improve the diagnosis of this disease. RESULTS: To determine whether CoQ10 defect could be associated with MRC deficiency, we quantified CoQ10 by LC-MSMS in a cohort of 18 patients presenting CoQ10-dependent deficiency associated with MRC defect. We found decreased levels of CoQ10 in eight patients out of 18 (45 %), thus confirming CoQ10 disease. CONCLUSIONS: Our study shows that CoQ10 defect can be associated with MRC deficiency. This could be of major importance in clinical practice for the diagnosis of a disease that can be improved by CoQ10 supplementation. PMID- 26742795 TI - Patterns and Implications of Intracranial Arterial Remodeling in Stroke Patients. AB - BACKGROUND AND PURPOSE: Preliminary studies suggest that intracranial arteries are capable of accommodating plaque formation by remodeling. We sought to study the ability and extent of intracranial arteries to remodel using 3-dimensional high-resolution black blood magnetic resonance imaging and investigate its relation to ischemic events. METHODS: Forty-two patients with cerebrovascular ischemic events underwent 3-dimensional time-of-flight magnetic resonance angiography and contrast-enhanced black blood magnetic resonance imaging examinations at 3 T for intracranial atherosclerotic disease. Each plaque was classified by location (eg, posterior versus anterior circulation) and its likelihood to have caused a stroke identified on magnetic resonance imaging (culprit, indeterminate, or nonculprit). Lumen area, outer wall area, and wall area were measured at the lesion and reference sites. Plaque burden was calculated as wall area divided by outer wall area. The arterial remodeling ratio (RR) was calculated as outer wall area at the lesion site divided by outer wall area at the reference site after adjusting for vessel tapering. Arterial remodeling was categorized as positive if RR>1.05, intermediate if 0.95<=RR<=1.05, and negative if RR<0.95. RESULTS: One hundred and thirty-seven plaques were identified in 42 patients (37% [50] posterior and 63% [87] anterior). Compared with anterior circulation plaques, posterior circulation plaques had a larger plaque burden (77.7+/-15.7 versus 69.0+/-14.0; P=0.008), higher RR (1.14+/-0.38 versus 0.95+/-0.32; P=0.002), and more often exhibited positive remodeling (54.0% versus29.9%; P=0.011). Positive remodeling was marginally associated with downstream stroke presence when adjusted for plaque burden (odds ratio 1.34, 95% confidence interval: 0.99-1.81). CONCLUSIONS: Intracranial arteries remodel in response to plaque formation, and posterior circulation arteries have a greater capacity for positive remodeling and, consequently, may more likely elude angiographic detection. Arterial remodeling may provide insight into stroke risk. PMID- 26742796 TI - Endovascular Therapy in Acute Ischemic Stroke: Challenges and Transition From Trials to Bedside. PMID- 26742797 TI - Modeling Ischemic Stroke In Vitro: Status Quo and Future Perspectives. PMID- 26742798 TI - Online Tool to Improve Stratification of Adverse Events in Stroke Clinical Trials. AB - BACKGROUND AND PURPOSE: Knowing characteristic adverse events (AEs) and their incidence among patients participating in acute stroke trials may assist interpretation of future studies. We aimed to develop an online tool to inform stroke trial safety. METHODS: We identified relevant AEs from patients within the Virtual International Stroke Trials Archive (VISTA), using receiver operating characteristic principles. We modeled their incidence on patient age, baseline National Institutes of Health Stroke Scale, and comorbidities using binary logistic regression. Models with an R(2) >5% were deemed powerful enough to predict expected AE incidences and were included. The calculator was developed using programs R and Visual Studios. RESULTS: Forty-eight of the most common AEs were identified and incorporated into the IschAEmic Stroke Calculator. The calculator, publicly available at http://www.vistacollaboration.org calculates the expected incidence of AEs or groups of AEs in a trial cohort and where possible compares them with the observed incidence. CONCLUSIONS: The IschAEmic Stroke Calculator is an open access resource to support safety interpretation within acute stroke trials. Prediction of AEs with higher likelihood of occurrence may direct preventive clinical measures. PMID- 26742799 TI - Emerging Evidence for Pathogenesis of Sporadic Cerebral Small Vessel Disease. PMID- 26742800 TI - Preexisting Heart Disease Underlies Newly Diagnosed Atrial Fibrillation After Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Whether newly diagnosed atrial fibrillation (nAF) after stroke reflects underlying heart disease and represents an increased risk of cardioembolic stroke, or whether it is triggered by neurogenic mechanisms remains uncertain. We investigated, whether cardiovascular risk factors and echocardiographic parameters in patients with nAF are similar to patients with known AF (kAF) and differ from patients without AF. METHODS: Consecutive acute ischemic stroke patients were enrolled into a prospective stroke database. All patients with echocardiography were included and univariable and multivariable testing was applied to compare clinical characteristics and echocardiographic findings among patients with nAF, kAF, and no AF. RESULTS: A total of 1397 patients were included (male, 62.3%; median age, 71 years). AF was present in 320 (22.9%) patients. Of those, nAF was present in 36.2% (116/320) and kAF in 63.8% (204/320). No clinical or echocardiographic factor was independently associated with detection of nAF compared with kAF but a trend toward larger left atrial diameters in patients with kAF was observed (P=0.070). In contrast, patients with nAF were more often female (P<0.001), older (P<0.001) and had a larger left atrial diameters (P<0.001) compared with patients without AF. While stroke severity in patients with nAF and kAF was similar, patients without AF had less severe strokes. CONCLUSIONS: Stroke patients with nAF and with kAF share common cardiovascular risk factors, have similar echocardiographic findings and suffer equally severe strokes. We conclude that preexisting heart disease is the major cause of AF that is first diagnosed after stroke. PMID- 26742801 TI - Retinal Artery Occlusion and the Risk of Stroke Development: Twelve-Year Nationwide Cohort Study. AB - BACKGROUND AND PURPOSE: Our aim was to evaluate the risk of subsequent stroke development after retinal artery occlusion (RAO). METHODS: National registry data were collected from the Korean National Health Insurance Service, comprised 1 025 340 random subjects. Patients diagnosed with RAO in 2002 and 2003 were excluded. The RAO group was composed of patients with an initial diagnosis of either central or other RAO between January 2004 and December 2013 (n=401). The comparison group was composed of randomly selected patients (5 per RAO patient; n=2003) who were matched to the RAO group according to sociodemographic factors and year of RAO diagnosis. Each sampled patient was tracked until 2013. Cox proportional hazard regression was used. RESULTS: Stroke occurred in 15.0% of the RAO group and in 8.0% of the comparison group (P < 0.001). RAO was associated with an increased risk of stroke occurrence (hazard ratio, 1.78; 95% confidence interval, 1.32-2.41). The magnitude of the RAO effect for stroke was larger among younger adults aged <65 years (hazard ratio, 3.11) than older adults aged >=65 years (hazard ratio, 1.26). However, the risk of subsequent stroke was significantly increased in older adults aged >=65 years at the 4-year follow-up (hazard ratio, 1.58; 95% confidence interval, 1.01-2.48). CONCLUSIONS: RAO was significantly associated with subsequent stroke after adjusting for comorbidities and sociodemographic factors. These findings are limited by uncontrolled confounding factors and need to be replicated by other observational studies. PMID- 26742802 TI - Enhanced Effective Connectivity Between Primary Motor Cortex and Intraparietal Sulcus in Well-Recovered Stroke Patients. AB - BACKGROUND AND PURPOSE: Ischemic strokes with motor deficits lead to widespread changes in neural activity and interregional coupling between primary and secondary motor areas. Compared with frontal circuits, the knowledge is still limited to what extent parietal cortices and their interactions with frontal motor areas undergo plastic changes and might contribute to residual motor functioning after stroke. METHODS: Fifteen well-recovered patients were evaluated 3 months after stroke by means of functional magnetic resonance imaging while performing visually guided hand grips with their paretic hand. Dynamic causal modeling was used to investigate task-related effective connectivity between ipsilesional posterior parietal regions along the intraparietal sulcus and frontal key motor areas, such as the primary motor cortex, the ventral premotor cortex, and the supplementary motor area. RESULTS: Compared with healthy controls of similar age and sex, we observed significantly enhanced reciprocal facilitatory connectivity between the primary motor cortex and the anterior intraparietal sulcus of the ipsilesional hemisphere. Beyond that and as a fingerprint of excellent recovery, the coupling pattern of the parietofrontal network was near-normal. An association between coupling parameters and clinical scores was not detected. CONCLUSIONS: The present analysis further adds to the understanding of the parietofrontal network of the ipsilesional hemisphere as a prominent circuit involved in plastic changes after stroke. PMID- 26742803 TI - Risk Analysis of Unruptured Intracranial Aneurysms: Prospective 10-Year Cohort Study. AB - BACKGROUND AND PURPOSE: The natural history of unruptured intracranial aneurysms remains unclear, and management strategy is not well defined. METHODS: From January 2003 to December 2012, we enrolled patients with aneurysm in our institution. In total, 2252 patients with 2897 aneurysms were eligible for analysis, and 1960 eligible aneurysms were conservatively managed. Precise 3 dimensional evaluation was conducted using computed tomography angiography, digital subtraction angiography, or magnetic resonance angiography. We then assessed the risk of aneurysm rupture, mortality, and morbidity associated with aneurysm characteristics, demographics, and known health/lifestyle risk factors. RESULTS: The mean follow-up duration was 7388 aneurysm-years. During observation, 56 aneurysms ruptured, resulting in an overall rupture rate per year of 0.76% (95% confidence interval, 0.58-0.98). The mean initial visit to rupture interval was 547 days. Aneurysm size, location, daughter sac, and history of subarachnoid hemorrhage were significant independent predictors for aneurysm rupture. Aneurysms that were >=5 mm were associated with a significantly increased risk of rupture when compared with 2- to 4-mm aneurysms (unadjusted hazard ratio, 12.24; 95% confidence interval, 7.15-20.93). Of 56 patients who experienced hemorrhage, 29 (52 %) died or were rendered severely disabled. Of the patients who had large or giant aneurysms, none recovered without deficits, and the mortality rate after rupture was 69%. For aneurysms sized <5 mm, the mortality rate was 18%. CONCLUSIONS: Larger aneurysms are at greater risk for rupture and poor outcome. Ethnic factors may play a role in the risk of rupture. PMID- 26742805 TI - An evaluation of homocysteine, C-reactive protein, lipid levels, neutrophils to lymphocyte ratio in postmenopausal osteopenic women. AB - OBJECTIVE: In the present study, the risk coefficients of serum homocysteine (hcy), lipid levels, C-reactive protein (CRP), neutrophils to lymphocyte ratio (NLR) in postmenopausal osteopenic women were determined. METHODS: We enrolled 269 patients with postmenopausal women from Hangzhou No.1 Hospital gynecological clinic, who aged 45 to 60 years old and never received menopause hormone therapy. According to the bone mineral density determination results, subjects were divided into normal group (n = 128), osteopenia group (n = 141). Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA). Serum hcy, CRP and lipid indexes were determined by enzyme chemiluminescence immunoassay. RESULTS: The odds ratios (OR) and 95% confidence intervals (CI) of those variables (menopausal age, duration of menopause, LDL, CRP, hcy and NLR) were found significant (p < 0.05). Menopausal age, duration of menopause, LDL, CRP, hcy and NLR variables were found statistically significant in the analysis of receiver operating characteristic (ROCs). CONCLUSION: The present study shows that menopause age, duration of menopause, serum LDL, CRP, hcy and NLR levels are risk factors for postmenopausal osteopenic women, which may be used as the indicators of bone loss in postmenopausal women. PMID- 26742804 TI - Risk of Stroke After the International Classification of Diseases-Ninth Revision Discharge Code Diagnosis of Hypertensive Encephalopathy. AB - BACKGROUND AND PURPOSE: Although chronic hypertension is a well-established risk factor for stroke, little is known about stroke risk after hypertensive encephalopathy (HE), when neurologic sequelae of hypertension become evident. Therefore, we evaluated the risk of stroke after a diagnosis of HE. METHODS: We identified all patients discharged from California, New York, and Florida emergency departments and acute care hospitals between 2005 and 2012 with a primary International Classification of Diseases, Ninth Edition, Clinical Modification discharge diagnosis of HE (437.2). Patients discharged with a primary diagnosis of seizure (345.x) served as negative controls, whereas patients with a primary diagnosis of transient ischemic attack (435.x) were positive controls. Our primary outcome was the composite of subsequent ischemic stroke or intracerebral hemorrhage. Kaplan-Meier survival statistics were used to calculate cumulative outcome rates, and Cox proportional hazard analysis was used to examine the association between index disease types and outcomes while adjusting for vascular risk factors. RESULTS: We identified 8233 patients with HE, 191 091 with seizure, and 308 680 with transient ischemic attack. The 1-year cumulative rate of ischemic stroke or intracerebral hemorrhage after HE was 4.90% (95% confidence interval [CI], 4.45-5.40) when compared with 0.92% (95% CI, 0.88 0.97) after seizure and 4.49% (95% CI, 4.42-4.57) after transient ischemic attack. The risk of intracerebral hemorrhage was significantly elevated in those with HE (hazard ratio, 2.0; 95% CI, 1.7-2.5) but not in those with transient ischemic attack (hazard ratio, 1.0; 95% CI, 0.9-1.1), when compared with seizure patients. CONCLUSIONS: Patients discharged with a diagnosis of HE face a high risk of future cerebrovascular events, particularly intracerebral hemorrhage. PMID- 26742806 TI - Partitioning of fungal assemblages across different marine habitats. AB - Fungi are a highly diverse group of microbes that fundamentally influence the biogeochemistry of the biosphere, but we currently know little about the diversity and distribution of fungi in aquatic habitats. Here we describe shifts in marine fungal community composition across different marine habitats, using targeted pyrosequencing of the fungal Internal Transcribed Spacer (ITS) region. Our results demonstrate strong partitioning of fungal community composition between estuarine, coastal and oceanic samples, with each habitat hosting discrete communities that are controlled by patterns in salinity, temperature, oxygen and nutrients. Whereas estuarine habitats comprised a significant proportion of fungal groups often found in terrestrial habitats, the open ocean sites were dominated by previously unidentified groups. The patterns observed here indicate that fungi are potentially a significant, although largely overlooked, feature of the ocean's microbiota, but greater efforts to characterize marine species are required before the full ecological and biogeochemical importance of marine fungi can be ascertained. PMID- 26742807 TI - Browsing the Real World using Organic Electronics, Si-Chips, and a Human Touch. AB - Organic electronics have been developed according to an orthodox doctrine advocating "all-printed'', "all-organic'' and "ultra-low-cost'' primarily targeting various e-paper applications. In order to harvest from the great opportunities afforded with organic electronics potentially operating as communication and sensor outposts within existing and future complex communication infrastructures, high-quality computing and communication protocols must be integrated with the organic electronics. Here, we debate and scrutinize the twinning of the signal-processing capability of traditional integrated silicon chips with organic electronics and sensors, and to use our body as a natural local network with our bare hand as the browser of the physical world. The resulting platform provides a body network, i.e., a personalized web, composed of e-label sensors, bioelectronics, and mobile devices that together make it possible to monitor and record both our ambience and health-status parameters, supported by the ubiquitous mobile network and the resources of the "cloud". PMID- 26742809 TI - Elderly Learners and Massive Open Online Courses: A Review. AB - BACKGROUND: Massive open online courses (MOOCs) have become commonplace in the e learning landscape. Thousands of elderly learners are participating in courses offered by various institutions on a multitude of platforms in many different languages. However, there is very little research into understanding elderly learners in MOOCs. OBJECTIVE: We aim to show that a considerable proportion of elderly learners are participating in MOOCs and that there is a lack of research in this area. We hope this assertion of the wide gap in research on elderly learners in MOOCs will pave the way for more research in this area. METHODS: Pre course survey data for 10 University of Reading courses on the FutureLearn platform were analyzed to show the level of participation of elderly learners in MOOCs. Two MOOC aggregator sites (Class Central and MOOC List) were consulted to gather data on MOOC offerings that include topics relating to aging. In parallel, a selected set of MOOC platform catalogues, along with a recently published review on health and medicine-related MOOCs, were searched to find courses relating to aging. A systematic literature search was then employed to identify research articles on elderly learners in MOOCs. RESULTS: The 10 courses reviewed had a considerable proportion of elderly learners participating in them. For the over-66 age group, this varied from 0.5% (on the course "Managing people") to 16.3% (on the course "Our changing climate"), while for the over-56 age group it ranged from 3.0% (on "A beginners guide to writing in English") to 39.5% (on "Heart health"). Only six MOOCs were found to include topics related to aging: three were on the Coursera platform, two on the FutureLearn platform, and one on the Open2Study platform. Just three scholarly articles relating to MOOCs and elderly learners were retrieved from the literature search. CONCLUSIONS: This review presents evidence to suggest that elderly learners are already participating in MOOCs. Despite this, there has been very little research into their engagement with MOOCs. Similarly, there has been little research into exploiting the scope of MOOCs for delivering topics that would be of interest to elderly learners. We believe there is potential to use MOOCs as a way of tackling the issue of loneliness among older adults by engaging them as either resource personnel or learners. PMID- 26742816 TI - Productivity benchmarks for operative service units. AB - BACKGROUND: Easily accessible reliable information is crucial for strategic and tactical decision-making on operative processes. We report development of an analysis tool and resulting metrics for benchmarking purposes at a Finnish university hospital. METHODS: The analysis tool is based on data collected in a resource management system and an in-house cost-reporting database. RESULTS: The exercise reports key metrics for four operative service units and six surgical units from 2014 and the change from year 2013. Productivity, measured as total costs per total hours, ranged from 658 to 957 ?/h and utilization of the total available resource hours at the service unit level ranged from 66% to 74%. The lowest costs were in a unit running only regular working hour shifts, whereas the highest costs were in a unit operating on 24/7 basis. The tool includes additional metrics on operating room (OR) scheduling and monthly data to support more detailed analysis. CONCLUSION: This report provides the hospital management with an improved and detailed overview of its operative service units and the surgical process and related costs. The operating costs are associated with on call duties, size of operative service units, and the requirements of the surgeries. This information aids in making mid- to long range decisions on managing OR capacity. PMID- 26742808 TI - Potentiation of amygdala AMPA receptor activity selectively promotes escalated alcohol self-administration in a CaMKII-dependent manner. AB - Growing evidence indicates that drugs of abuse gain control over the individual by usurping glutamate-linked mechanisms of neuroplasticity in reward-related brain regions. Accordingly, we have shown that glutamate alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid receptor (AMPAR) activity in the amygdala is required for the positive reinforcing effects of alcohol, which underlie the initial stages of addiction. It is unknown, however, if enhanced AMPAR activity in the amygdala facilitates alcohol self-administration, which is a kernel premise of glutamate hypotheses of addiction. Here, we show that low-dose alcohol (0.6 g/kg/30 minutes) self-administration increases phosphorylation (activation) of AMPAR subtype GluA1 S831 (pGluA1 S831) in the central amygdala (CeA), basolateral amygdala and nucleus accumbens core (AcbC) of selectively bred alcohol-preferring P-rats as compared with behavior-matched (non-drug) sucrose controls. The functional role of enhanced AMPAR activity was assessed via site specific infusion of the AMPAR positive modulator, aniracetam, in the CeA and AcbC prior to alcohol self-administration. Intra-CeA aniracetam increased alcohol reinforced but not sucrose-reinforced responding and was ineffective following intra-AcbC infusion. Because GluA1 S831 is a Ca2+/calmodulin-dependent protein kinase II (CaMKII) substrate, we sought to determine if AMPAR regulation of enhanced alcohol self-administration is dependent on CaMKII activity. Intra-CeA infusion of the cell-permeable CaMKII peptide inhibitor myristolated autocamtide 2-related inhibitory peptide (m-AIP) dose-dependently reduced alcohol self administration. A subthreshold dose of m-AIP also blocked the aniracetam-induced escalation of alcohol self-administration, demonstrating that AMPAR-mediated potentiation of alcohol reinforcement requires CaMKII activity in the amygdala. Enhanced activity of plasticity-linked AMPAR-CaMKII signaling in the amygdala may promote escalated alcohol use via increased positive reinforcement during the initial stages of addiction. PMID- 26742818 TI - Stereodivergent Synthesis and Stereochemical Reassignment of the C79-C104 Fragment of Symbiodinolide. AB - We have synthesized eight possible diastereoisomers 3 a-h of the C79-C97 fragment of symbiodinolide (1) in a stereodivergent manner by utilizing a dithiane addition to the aldehyde as a key step. Comparison of the 13 C NMR chemical shifts of the natural product 1 and the synthetic products 3 a-h indicated that the relative stereostructure of this fragment in symbiodinolide (1) is that represented in 3 a or f. We have stereodivergently synthesized eight possible diastereoisomers of the C94-C104 fragment 4 a-h, and we have compared their 13 C NMR chemical shifts with those of the natural product, which established the relative stereochemistry of this fragment to be that described in diastereoisomers 4 a or e. By combining the stereostructural outcomes of the C79 C97 and C94-C104 fragments, we have proposed four candidate compounds of the C79 C104 fragment 2 a-d. We also synthesized diastereoisomers 2 a and b (2 a in the preceding article; Chem. Eur. J. 2015, DOI: 10.1002/chem.201503880) by a Julia Kocienski olefination and diastereoisomers 2 c and d by a Wittig reaction. By comparing the 13 C NMR chemical shifts of natural symbiodinolide (1) with those of the synthetic products 2 a-d, we have reassigned the stereostructure of the C79-C104 fragment of natural product 1 to be that depicted in diastereoisomer 2 b. PMID- 26742817 TI - Inner membrane fusion mediates spatial distribution of axonal mitochondria. AB - In eukaryotic cells, mitochondria form a dynamic interconnected network to respond to changing needs at different subcellular locations. A fundamental yet unanswered question regarding this network is whether, and if so how, local fusion and fission of individual mitochondria affect their global distribution. To address this question, we developed high-resolution computational image analysis techniques to examine the relations between mitochondrial fusion/fission and spatial distribution within the axon of Drosophila larval neurons. We found that stationary and moving mitochondria underwent fusion and fission regularly but followed different spatial distribution patterns and exhibited different morphology. Disruption of inner membrane fusion by knockdown of dOpa1, Drosophila Optic Atrophy 1, not only increased the spatial density of stationary and moving mitochondria but also changed their spatial distributions and morphology differentially. Knockdown of dOpa1 also impaired axonal transport of mitochondria. But the changed spatial distributions of mitochondria resulted primarily from disruption of inner membrane fusion because knockdown of Milton, a mitochondrial kinesin-1 adapter, caused similar transport velocity impairment but different spatial distributions. Together, our data reveals that stationary mitochondria within the axon interconnect with moving mitochondria through fusion and fission and that local inner membrane fusion between individual mitochondria mediates their global distribution. PMID- 26742820 TI - The first crystal structures of six- and seven-membered tellurium- and nitrogen containing (Te-N) heterocycles: 2H-1,4-benzotellurazin-3(4H)-one and 2,3-dihydro 1,5-benzotellurazepin-4(5H)-one. AB - There is a paucity of data concerning the structures of six- and seven-membered tellurium- and nitrogen-containing (Te-N) heterocycles. The title compounds, C8H7NOTe, (I), and C9H9NOTe, (II), represent the first structurally characterized members of their respective classes. Both crystallize with two independent molecules in the asymmetric unit. When compared to their sulfur analogs, they exhibit slightly greater deviations from planarity to accommodate the larger chalcogenide atom, with (II) adopting a pronounced twist-boat conformation. The C Te-C angles of 85.49 (15) and 85.89 (15) degrees for the two independent molecules of (I) were found to be somewhat smaller than those of 97.4 (2) and 97.77 (19) degrees for the two independent molecules of (II). The C-Te bond lengths [2.109 (4)-2.158 (5) A] are in good agreement with those predicted by the covalent radii. Intermolecular N-H...O hydrogen bonding in (I) forms centrosymmetric R2(2)(8) dimers, while that in (II) forms chains. In addition, intermolecular Te...O contacts [3.159 (3)-3.200 (3) A] exist in (I). PMID- 26742819 TI - Chronic hepatitis B infection is not associated with increased risk of vascular mortality while having an association with metabolic syndrome. AB - This study aimed to assess the association of chronic hepatitis B (CHB) with vascular mortality and metabolic syndrome (MS) using data from a large population based cohort study in Iran. A total of 12,781 participants (2249 treatment-naive CHB and 10,532 without CHB) were studied. Logistic regression model was used to assess the association between MS and CHB with adjustment for age, ALT, PLT, alcohol intake, smoking, exercise, and socioeconomic status. MS was defined according to the ATPIII guidelines. Cox proportional hazards model was used to assess the hazard ratios for overall and vascular related mortality. There was a significant association between CHB infection and overall mortality (hazard ratio (95%CI) of 1.44 (1.16-1.79), P < 0.001) after adjusting for other confounders. However, we found no association between CHB infection and mortality from vascular events (hazard ratio (95%CI) of 1.31 (0.93-1.84), P = 0.124) even after subgroup analysis by ALT. Furthermore, increased risk of overall mortality in CHB infected individuals was not related to MS and vice versa (P for interaction = 0.06). We noted a significant direct association between CHB infection and MS in women (OR (95%CI); 1.23 (1.07-1.42), P < 0.004). However, CHB was inversely associated with MS in men (OR (95%CI), 0.85 (0.79-0.99). This gender dependent association was related to high BP levels in women. In this study no association between CHB infection and mortality from vascular events was found. Further longitudinal studies should be done to investigate the exact impact of HBV infection on metabolic parameters and vascular pathology. PMID- 26742821 TI - Four supramolecular isomers of dichloridobis(1,10-phenanthroline)cobalt(II): synthesis, structure characterization and isomerization. AB - Crystal engineering can be described as the understanding of intermolecular interactions in the context of crystal packing and the utilization of such understanding to design new solids with desired physical and chemical properties. Free-energy differences between supramolecular isomers are generally small and minor changes in the crystallization conditions may result in the occurrence of new isomers. The study of supramolecular isomerism will help us to understand the mechanism of crystallization, a very central concept of crystal engineering. Two supramolecular isomers of dichloridobis(1,10-phenanthroline kappa(2)N,N')cobalt(II), [CoCl2(C12H8N2)2], i.e. (IA) (orthorhombic) and (IB) (monoclinic), and two supramolecular isomers of dichloridobis(1,10-phenanthroline kappa(2)N,N')cobalt(II) N,N-dimethylformamide monosolvate, [CoCl2(C12H8N2)2].C3H7NO, i.e. (IIA) (orthorhombic) and (IIB) (monoclinic), were synthesized in dimethylformamide (DMF) and structurally characterized. Of these, (IA) and (IIA) have been prepared and structurally characterized previously [Li et al. (2007). Acta Cryst. E63, m1880-m1880; Cai et al. (2008). Acta Cryst. E64, m1328-m1329]. We found that the heating rate is a key factor for the crystallization of (IA) or (IB), while the temperature difference is responsible for the crystallization of (IIA) or (IIB). Based on the crystallization conditions, isomerization behaviour, the KPI (Kitajgorodskij packing index) values and the density data, (IB) and (IIA) are assigned as the thermodynamic and stable kinetic isomers, respectively, while (IA) and (IIB) are assigned as the metastable kinetic products. The 1,10-phenanthroline (phen) ligands interact with each other through offset face-to-face (OFF) pi-pi stacking in (IB) and (IIB), but by edge-to-face (EF) C-H...pi interactions in (IA) and (IIA). Meanwhile, the DMF molecules in (IIB) connect to neighbouring [CoCl2(phen)2] units through two C H...Cl hydrogen bonds, whereas there are no obvious interactions between DMF molecules and [CoCl2(phen)2] units in (IIA). Since OFF pi-pi stacking is generally stronger than EF C-H...pi interactions for transition-metal complexes with nitrogen-containing aromatic ligands, (IIA) is among the uncommon examples that are stable and densely packed but that do not following Etter's intermolecular interaction hierarchy. PMID- 26742822 TI - Structural corroboration of two important building blocks of the anticancer drug eribulin mesylate through two-dimensional NMR and single-crystal X-ray diffraction studies. AB - Eribulin mesylate, one of the most synthetically challenging drugs to date, possesses 19 stereocentres in its structure and ascertaining the absolute stereochemistry at every stage of the 64-stage synthesis is crucial. In our quest to synthesize eribulin, we identified two critical building blocks of this molecule, namely 3,4:6,7-di-O-cyclohexylidene-D-glycero-alpha-L-talo heptopyranose methanol monosolvate, C19H30O7.CH3OH, and (2R,3R,4R,5S)-5-allyl-2 [(S)-2,3-dihydroxypropyl]-4-[(phenylsulfonyl)methyl]tetrahydrofuran-3-ol, C17H24O6S, for which two-dimensional NMR (2D-NMR) data were not sufficient to prove the absolute configuration. To ensure structural integrity, single-crystal X-ray diffraction data were obtained to confirm the structures. This information provides useful insights into the structural framework of the large eribulin mesylate molecule. PMID- 26742823 TI - Synthesis, crystal structure and magnetic properties of a two-dimensional cyanide based heterometallic coordination polymer with cationic piperazinium ligands: poly[aquatetra-MU2-cyanido-kappa(8)C:N-dicyanido-kappa(2)C-(piperazinium kappaN(4))cobalt(III)copper(II)]. AB - Cyanide as a bridge can be used to construct homo- and heterometallic complexes with intriguing structures and interesting magnetic properties. These ligands can generate diverse structures, including clusters, one-dimensional chains, two dimensional layers and three-dimensional frameworks. The title cyanide-bridged Cu(II)-Co(III) heterometallic compound, [Cu(II)Co(III)(CN)6(C4H11N2)(H2O)]n, has been synthesized and characterized by single-crystal X-ray diffraction analysis, magnetic measurement, thermal study, vibrational spectroscopy (FT-IR) and scanning electron microscopy/energy-dispersive X-ray spectroscopy (SEM-EDS). The crystal structure analysis revealed that it has a two-dimensional grid-like structure built up of [Cu(Hpip)(H2O)](3+) cations (Hpip is piperazinium) and [Co(CN)6](3-) anions that are linked through bridging cyanide ligands. The overall three-dimensional supramolecular network is expanded by a combination of interlayer O-H...N and N-H...O hydrogen bonds involving the coordinated water molecules and the N atoms of the nonbridging cyanide groups and monodentate cationic piperazinium ligands. A magnetic investigation shows that antiferromagnetic interactions exist in the title compound. PMID- 26742824 TI - Hydrogen-bonding patterns in bis[2,4,6-triazaniumylcyclohexane-1,3,5-tris(olate) kappa(3)O,O',O'']germanium(IV) tetrachloride hexahydrate. AB - A first preliminary report on the crystal structure of a hydrated salt formulated as [Ge(taci)2]Cl4.13H2O (taci is 1,3,5-triamino-1,3,5-trideoxy-cis-inositol) appeared more than 20 years ago [Ghisletta (1994). PhD thesis, ETH Zurich. Switzerland]. At that time it was not possible to discriminate unambiguously between the positions of some of the chloride ions and water O atoms, and disorder was thus postulated. In a new determination, a conclusive scheme of hydrogen bonding proves to be a particularly appealing aspect of the structure. Single crystals of the title compound, C12H30GeN6O6(4+).4Cl(-).6H2O or [Ge(taci)2]2Cl8.12H2O, were grown from an aqueous solution by slow evaporation of the solvent. The two [Ge(taci)2](4+) cations exhibit a double-adamantane-type structure with exclusive O-atom coordination and approximate D3d symmetry. The taci ligands adopt a zwitterionic form with deprotonated hydroxy groups and protonated amino groups. Both cations are hydrogen bonded to six water molecules. The structure of the hydration shell of the two cations is, however, slightly different. The {[Ge(taci)2].6H2O}(4+) aggregates are interlinked in all three dimensions by further hydrogen bonds of the types N-H...Cl...H-N, N-H...O(H)2...H N, (Ge)O...H-O(H)...H-N, N-H...O(H)-H...Cl...H-N, (Ge)O...H-O-H...Cl...H-N, N H...O(H)-H...Cl...H-(H)O...H-N, (Ge)O...H-O-H...Cl...H-(H)O...H-N and Ge(O)...H-O H...Cl...H-O-H...O(Ge). PMID- 26742825 TI - 3':5'-Cyclic nucleotides: two sodium salts of cdTMP. AB - 3':5'-Cyclic nucleotides play an outstanding role in signal transduction at the cellular level but, in spite of comprehensive knowledge of the biological role of cyclic nucleotides, their structures are not established fully. Two hydrated sodium salts of thymidine 3':5'-cyclic phosphate (cdTMP, C10H12N2O7P), namely sodium thymidine 3':5'-cyclic phosphate heptahydrate, Na(+).C10H12N2O7P(-).7H2O or Na(cdTMP).7H2O, (I), and sodium thymidine 3':5'-cyclic phosphate 3.7-hydrate, Na(+).C10H12N2O7P(-).3.7H2O or Na(cdTMP).3.7H2O, (II), have been obtained in crystalline form and structurally characterized, revealing one nucleotide in the asymmetric unit of (I) and eight different nucleotides in (II). All the cyclic nucleotide anions adopt a similar conformation with regard to nucleobase orientation, sugar conformation and 1,3,2-dioxaphosphorinane ring puckering. In (I), no direct inter-nucleotide hydrogen bonds are present, and adjacent nucleotide anions interact via water-mediated and Na(+)-mediated contacts. In contrast, in (II), direct thymine-phosphate N-H...O inter-nucleotide hydrogen bonds occur and these are assisted by numerous inter-nucleotide C-H...O contacts, giving rise to the self-assembly of cdTMP(-) anions into three different ribbons. Two of these three ribbons run in the same direction, while the third is antiparallel. PMID- 26742826 TI - The dangerous new synthetic drug alpha-PVP as the hydrated chloride salt alpha pyrrolidinopentiophenone hydrochloride 0.786-hydrate. AB - alpha-Pyrrolidinovalerophenone (alpha-PVP), a dangerous designer drug, is now being marketed around the world as a harmless 'bath salt', when in reality it is a powerful beta-ketone phenethylamine stimulant. A sample of the free base from a recent law-enforcement seizure was crystallized as the HCl salt [systematic name: 1-(1-oxo-1-phenylpentan-2-yl)pyrrolidin-1-ium chloride 0.786-hydrate], C15H22NO(+).Cl(-).0.786H2O. In the crystal structure, the propyl chain is nearly perpendicular to both the phenyl ring and the carbonyl group. The hydrogen bonding scheme involves the quaternary N atom, the Cl(-) anion and the partially occupied (0.786) water molecule, forming centrosymmetric dimers. PMID- 26742827 TI - Similar molecular constitutions but different conformations and different supramolecular assemblies in two related fused tetracyclic benzo[b]pyrimido[5,4 f]azepine derivatives. AB - A simple and effective two-step approach to tricyclic pyrimidine-fused benzazepines has been adapted to give the tetracyclic analogues. In (RS)-8-chloro 6-methyl-1,2,6,7-tetrahydropyrimido[5',4':6,7]azepino[3,2,1-hi]indole, C15H14ClN3, (I), the five-membered ring adopts an envelope conformation, as does the reduced pyridine ring in (RS)-9-chloro-7-methyl-2,3,7,8-tetrahydro-1H pyrimido[5',4':6,7]azepino[3,2,1-ij]quinoline, C16H16ClN3, (II). However, the seven-membered rings in (I) and (II) adopt very different conformations, with the result that the methyl substituent occupies a quasi-axial site in (I) but a quasi equatorial site in (II). The molecules of (I) are linked by C-H...N hydrogen bonds to form C(5) chains and inversion-related pairs of chains are linked by a pi-pi stacking interaction. A combination of a C-H...pi hydrogen bond and two C Cl...pi interactions links the molecules of (II) into complex sheets. Comparisons are made with some similar fused heterocyclic compounds. PMID- 26742828 TI - Triclinic and monoclinic polymorphs of meso-(E,E)-1,1'-[1,2-bis(4 chlorophenyl)ethane-1,2-diyl]bis(phenyldiazene): the high-yield synthesis of an unexpected product, concomitant polymorphism and configurational disorder. AB - Pyrazolidine-3,5-diones and their derivatives exhibit a wide range of biological activities. Seeking to explore the effect of combining a hydrocarbyl ring substituent, as present in sulfinpyrazone (used to treat gout), with a chlorinated aryl ring, as present in muzolimine (a diuretic), we explored the reaction between 1-phenylpyrazolidine-3,5-dione and 4-chlorobenzaldehyde under mildly basic conditions in the expectation of producing the simple condensation product 4-(4-chlorobenzylidene)-1-phenylpyrazolidine-3,5-dione. However, the reaction product proved to be meso-(E,E)-1,1'-[1,2-bis(4-chlorophenyl)ethane-1,2 diyl]bis(phenyldiazene), C26H20Cl2N4, and a tentative mechanism is proposed. Crystallization from ethanol produces two concomitant polymorphs, i.e. a triclinic form, (I), in the space group P-1, and a monoclinic form, (II), in the space group C2/c. In both polymorphs, the molecules lie across centres of inversion, but in (II), the molecules are subject to whole-molecule disorder equivalent to configurational disorder with occupancies of 0.6021 (19) and 0.3979 (19). There are no hydrogen bonds in the crystal structure of polymorph (I), but the molecules of polymorph (II) are linked by C-H...pi(arene) hydrogen bonds into complex chains, which are further linked into sheets by C-H...N interactions. PMID- 26742830 TI - A coordinatively flexible hexadentate ligand gives structurally isomeric complexes M2(L)X3 (M = Cu, Zn; X = Br, Cl). AB - Polypyridyl multidentate ligands based on ethylenediamine backbones are important metal-binding agents with applications in biomimetics and homogeneous catalysis. The seemingly hexadentate tpena ligand [systematic name: N,N,N'-tris(pyridin-2 ylmethyl)ethylenediamine-N'-acetate] reacts with zinc chloride and zinc bromide to form trichlorido[MU-N,N,N'-tris(pyridin-2-ylmethyl)ethylenediamine-N' acetato]dizinc(II), [Zn2(C22H24N5O2)Cl3], and tribromido[MU-N,N,N'-tris(pyridin-2 ylmethyl)ethylenediamine-N'-acetato]dizinc(II), [Zn2Br3(C22H24N5O2)]. One Zn(II) ion shows the anticipated N5O coordination in an irregular six-coordinate site and is linked by an anti carboxylate bridge to a tetrahedral ZnX3 (X = Cl or Br) unit. In contrast, the Cu(II) ions in aquatribromido[MU-N,N,N'-tris(pyridin-2 ylmethyl)ethylenediamine-N'-acetato]dicopper(II)-tribromido[MU-N,N,N' tris(pyridin-2-ylmethyl)ethylenediamine-N'-acetato]dicopper(II)-water (1/1/6.5) [Cu2Br3(C22H24N5O2)][Cu2Br3(C22H24N5O2)(H2O)].6.5H2O, occupy two tpena-chelated sites, one a trigonal bipyramidal N3Cl2 site and the other a square-planar N2OCl site. In all three cases, electrospray ionization mass spectra were dominated by a misleading ion assignable to [M(tpena)](+) (M = Zn(2+) and Cu(2+)). PMID- 26742829 TI - An unusual coordination polymer containing Cu(+) ions and featuring possible Cu...Cu 'cuprophilic' interactions: poly[di-MU-chlorido-(MU4-3,5-diaminobenzoato kappa(4)O:O':N:N')tricopper(I)(3 Cu-Cu)]. AB - Compounds containing copper(I) are of interest for their role in biological processes. The nature of short (< ~ 3.2 A) Cu...Cu contacts within these compounds has been debated, being either described as weakly attractive (bonding) 'cuprophilic' interactions, or simply as short metal-metal distances constrained by ligand geometry or largely ionic in nature. The title three-dimensional Cu(+) containing coordination polymer, [Cu3(C7H7N2O2)Cl2]n, was formed from the in situ reduction of CuCl2 in the presence of 3,5-diaminobenzoic acid and KOH under hydrothermal conditions. Its complex crystal structure contains ten distinct Cu(I) atoms, two of which lie on crystallographic inversion centres. The copper coordination geometries include near-linear CuOCl and CuN2, T-shaped CuOCl2 and distorted tetrahedral CuOCl3 groups. Each Cu(I) atom is also associated with two adjacent metal atoms, with Cu...Cu distances varying from 2.7350 (14) to 3.2142 (13) A; if all these are regarded as 'cuprophilic' interactions, then infinite [ 101] zigzag chains of Cu(I) atoms occur in the crystal. The structure is consolidated by N-H...Cl hydrogen bonds. PMID- 26742831 TI - Planarity of benzoyldithiocarbazate tuberculostatics. II. Diesters of benzoyldithiocarbazic acid. AB - The emergence of drug-resistant strains of Mycobacterium tuberculosis has intensified efforts to identify new lead tuberculostatics. Our earlier studies concluded that the planarity of a molecule correlates well with its tuberculostatic activity. According to our hypothesis, only derivatives whose molecules are capable of adopting a planar conformation may show tuberculostatic activity. The structures of three new potentially tuberculostatic compounds, namely N'-[bis(methylsulfanyl)methylidene]-N-methyl-4-nitrobenzohydrazide (denoted G1), C11H13N3O3S2, N'-[bis(benzylsulfanyl)methylidene]-N-methyl-4 nitrobenzohydrazide (denoted G2), C23H21N3O3S2, and N' [(benzylsulfanyl)(methylsulfanyl)methylidene]-4-nitrobenzohydrazide (denoted G3), C16H15N3O3S2, were determined by X-ray diffraction. The significant distortion from planarity caused by the methyl substituent at the N atom of the hydrazide group or the NO2 substituent in the aromatic ring leads to the loss of tuberculostatic activity for G1, G2 and G4 {systematic name: N' [bis(methylsulfanyl)methylidene]-2-nitrobenzohydrazide}. A similar effect is observed when there are large substituents at the S atoms (G2 and G3). PMID- 26742832 TI - V2O2F4(H2O)2.H2O: a new V(4+) layer structure related to VOF3. AB - V(IV) oxyfluorides are of interest as frustrated magnets. The successful synthesis of two-dimensionally connected vanadium(IV) oxyfluoride structures generally requires the use of ionic liquids as solvents. During solvothermal synthesis experiments aimed at producing two- and three-dimensional vanadium(IV) selenites with triangular lattices, the title compound, diaquatetra-MU-fluorido dioxidodivanadium(IV) monohydrate, V2O2F4(H2O)2.H2O, was discovered and features a new infinite V(4+)-containing two-dimensional layer comprised of fluorine bridged corner- and edge-sharing VOF4(H2O) octahedral building units. The synthesis was carried out under solvothermal conditions. The V(4+) centre exhibits a typical off-centring, with a short V=O bond and an elongated trans-V-F bond. Hydrogen-bonded water molecules occur between the layers. The structure is related to previously reported vanadium oxyfluoride structures, in particular, the same layer topology is seen in VOF3. PMID- 26742833 TI - 6-Chloroisocytosine and 5-bromo-6-methylisocytosine: again, one or two tautomers present in the same crystal? AB - It is well known that pyrimidin-4-one derivatives are able to adopt either the 1H or the 3H-tautomeric form in (co)crystals, depending on the coformer. As part of ongoing research to investigate the preferred hydrogen-bonding patterns of active pharmaceutical ingredients and their model systems, 2-amino-6-chloropyrimidin-4 one and 2-amino-5-bromo-6-methylpyrimidin-4-one have been cocrystallized with several coformers and with each other. Since Cl and Br atoms both have versatile possibilities to interact with the coformers, such as via hydrogen or halogen bonds, their behaviour within the crystal packing was also of interest. The experiments yielded five crystal structures, namely 2-aminopyridin-1-ium 2-amino 6-chloro-4-oxo-4H-pyrimidin-3-ide-2-amino-6-chloropyrimidin-4(3H)-one (1/3), C5H7N2(+).C4H3ClN3O(-).3C4H4ClN3O, (Ia), 2-aminopyridin-1-ium 2-amino-6-chloro-4 oxo-4H-pyrimidin-3-ide-2-amino-6-chloropyrimidin-4(3H)-one-2-aminopyridine (2/10/1), 2C5H7N2(+).2C4H3ClN3O(-).10C4H4ClN3O.C5H6N2, (Ib), the solvent-free cocrystal 2-amino-5-bromo-6-methylpyrimidin-4(3H)-one-2-amino-5-bromo-6 methylpyrimidin-4(1H)-one (1/1), C5H6BrN3O.C5H6BrN3O, (II), the solvate 2-amino-5 bromo-6-methylpyrimidin-4(3H)-one-2-amino-5-bromo-6-methylpyrimidin-4(1H)-one-N methylpyrrolidin-2-one (1/1/1), C5H6BrN3O.C5H6BrN3O.C5H9NO, (III), and the partial cocrystal 2-amino-5-bromo-6-methylpyrimidin-4(3H)-one-2-amino-5-bromo-6 methylpyrimidin-4(1H)-one-2-amino-6-chloropyrimidin-4(3H)-one (0.635/1/0.365), C5H6BrN3O.C5H6BrN3O.C4H4ClN3O, (IV). All five structures show R2(2)(8) hydrogen bond-based patterns, either by synthon 2 or by synthon 3, which are related to the Watson-Crick base pairs. PMID- 26742834 TI - Effects and mechanisms of potent caspase-1 inhibitor VX765 treatment on collagen induced arthritis in mice. AB - OBJECTIVES: VX765, a potent and selective caspase-1 inhibitor, inhibits the release of IL-1, IL-18 and IL-33. In this study we investigated the effect of VX765 treatment on collagen-induced arthritis (CIA). METHODS: Twenty-four mice were randomly divided into three groups of 8: Normal (wild-type), CIA and VX765 (CIA with VX765 treatment) groups. Mice in the VX765 group received intraperitoneal injection of VX765 (100 mg/kg, twice daily) starting at the day of the booster immunisation (week 3) for a duration of 4 weeks. At the end of experiments (week 7), joints clinical scores, radiographic scores and histologic scores were evaluated. Serum IL-1beta, IL-18 and IL-33 levels were assessed by ELISA. RESULTS: VX765 prophylactic treatment significantly reduced joints clinical scores, suppressed bone marrow oedema and synovitis at the early stage of CIA, prevented bone erosion in progressive CIA, and decreased histologic scores and serum cytokine levels. CONCLUSIONS: VX765 prophylactic treatment ameliorated the severity and progression of CIA. These findings suggest that caspase-1 is a potential therapeutic target for RA treatment. PMID- 26742835 TI - Evidence of melatonin synthesis in the ram reproductive tract. AB - Melatonin is a ubiquitous molecule found in a wide range of fluids, one of them being ram seminal plasma, in which it can reach higher concentrations than those found in blood, suggesting an extrapineal secretion by the reproductive tract. In order to identify the source of the melatonin found in ram seminal plasma, we first tried to determine whether the melatonin levels were maintained during the day. For this purpose, melatonin concentrations were measured in seminal plasma obtained from first ejaculates of six rams at 6:00 a.m. in total darkness, at 10:00 a.m. and at 14:00 p.m. The melatonin concentration was higher (p < 0.05) in ejaculates collected at 6:00 a.m. than at 10:00 and 14:00. There was no statistical difference between the latter. To further corroborate an extrapineal secretion of melatonin, the presence of the two key enzymes involved in melatonin synthesis, arylalkylamine-N-acetyltransferase (AANAT) and N-acetylserotonin-O methyltransferase (ASMT) was analyzed by RT-PCR, q-PCR and Western-blot in ram testes, epididymis, and accessory glands. The RT-PCR showed the presence of the m RNA codifying both AANAT and ASTM in all the tissues under study, but the q-PCR and Western-blot revealed that gene expression of these enzymes was significantly higher in the testis (p < 0.05). Immunohistochemistry confirmed the presence of AANAT and ASMT in the testis and revealed that they were found in the Leydig cells, spermatocytes, and spermatids. Also, measurable levels of melatonin were found in testicular tissue and the tail of the epididymis. In conclusion, our study indicates that the testes are one of the likely sources of the high levels of melatonin found in ram seminal plasma, at least during the day. PMID- 26742836 TI - Traumatic acute extradural haematoma - Indications for surgery revisited. AB - Extradural haematomas (EDH) occur in approximately 2% of all head injuries but account for a significant proportion of fatal head injuries with mortality rates ranging from 1.2 to 33%. The expeditious surgical evacuation of EDH is associated with an excellent prognosis and is considered the most cost-effective operation performed by neurosurgeons. The Brain Trauma Foundation (BTF) has produced informative guidance on the management of EDH. The criteria laid out for conservative management comprises non-comatose patients with EDH less than 30 cm in volume, less than 15 mm thick and causing less than 5 mm midline shift. The BTF recommends that all patients with an EDH volume of greater than 30 cm(3) should undergo surgical evacuation regardless of Glasgow Coma Scale. This recommendation was based upon early case series and cohort studies from two decades. Within an ageing population, we now see many older patients who may accommodate greater extra-axial blood volumes. With this in mind, we believe the indications for surgical evacuation of EDH merit renewed consideration. PMID- 26742837 TI - Liquid plasticine: controlled deformation and recovery of droplets with interfacial nanoparticle jamming. AB - Air-exposed droplet systems are widely applied in material preparation and experimental design. Recently, a droplet system with unusual properties featured by a liquid-like appearance and solid-like deformability was produced. However, it was then just an interesting and perplexing phenomenon in the absence of basic understandings and clear perspectives for applications. Here we reveal that stable droplet deformation is attributed to monolayer nanoparticle jamming at the water/vapor interface, and that the normal shape can be recovered by jamming relieving. The degree of jamming affects the droplet shape and transparency and can be tuned by the squeezing force and droplet volume. Using these properties and control methods, we develop the deformed droplet into "liquid plasticine" with predesigned shapes, super-high transparency, and arbitrarily large volume. We demonstrate that liquid plasticine could be used as liquid lenses, channel like containers, and miniature reactors. PMID- 26742838 TI - Electric-field and strain-tunable electronic properties of MoS2/h-BN/graphene vertical heterostructures. AB - Vertical heterostructures of MoS2/h-BN/graphene have been successfully fabricated in recent experiments. Using first-principles analysis, we show that the structural and electronic properties of such vertical heterostructures are sensitive to applied vertical electric fields and strain. The applied electric field not only enhances the interlayer coupling but also linearly controls the charge transfer between graphene and MoS2 layers, leading to a tunable doping in graphene and controllable Schottky barrier height. Applied biaxial strain could weaken the interlayer coupling and results in a slight shift of graphene's Dirac point with respect to the Fermi level. It is of practical importance that the tunable electronic properties by strain and electric fields are immune to the presence of sulfur vacancies, the most common defect in MoS2. PMID- 26742839 TI - Filamin A Is Involved in HIV-1 Vpu-mediated Evasion of Host Restriction by Modulating Tetherin Expression. AB - Tetherin, also known as bone marrow stromal antigen 2 (BST-2), inhibits the release of a wide range of enveloped viruses, including human immunodeficiency virus, type 1 (HIV-1) by directly tethering nascent virions to the surface of infected cells. The HIV-1 accessary protein Vpu counteracts tetherin restriction via sequestration, down-regulation, and/or displacement mechanisms to remove tetherin from sites of virus budding. However, the exact mechanism of Vpu mediated antagonism of tetherin restriction remains to be fully understood. Here we report a novel role for the actin cross-linking regulator filamin A (FLNa) in Vpu anti-tetherin activities. We demonstrate that FLNa associates with tetherin and that FLNa modulates tetherin turnover. FLNa deficiency was found to enhance cell surface and steady-state levels of tetherin expression. In contrast, we observed that overexpression of FLNa reduced tetherin expression levels both on the plasma membrane and in intracellular compartments. Although FLNb shows high amino acid sequence similarity with FLNa, we reveal that only FLNa, but not FLNb, plays an essential role in tetherin turnover. We further showed that FLNa deficiency inhibited Vpu-mediated enhancement of virus release through interfering with the activity of Vpu to down-regulate cellular tetherin. Taken together, our studies suggest that Vpu hijacks the FLNa function in the modulation of tetherin to neutralize the antiviral factor tetherin. These findings may provide novel strategies for the treatment of HIV-1 infection. PMID- 26742840 TI - 7-Rhamnosylated Flavonols Modulate Homeostasis of the Plant Hormone Auxin and Affect Plant Development. AB - Flavonols are a group of secondary metabolites that affect diverse cellular processes. They are considered putative negative regulators of the transport of the phytohormone auxin, by which they influence auxin distribution and concomitantly take part in the control of plant organ development. Flavonols are accumulating in a large number of glycosidic forms. Whether these have distinct functions and diverse cellular targets is not well understood. The rol1-2 mutant of Arabidopsis thaliana is characterized by a modified flavonol glycosylation profile that is inducing changes in auxin transport and growth defects in shoot tissues. To determine whether specific flavonol glycosides are responsible for these phenotypes, a suppressor screen was performed on the rol1-2 mutant, resulting in the identification of an allelic series of UGT89C1, a gene encoding a flavonol 7-O-rhamnosyltransferase. A detailed analysis revealed that interfering with flavonol rhamnosylation increases the concentration of auxin precursors and auxin metabolites, whereas auxin transport is not affected. This finding provides an additional level of complexity to the possible ways by which flavonols influence auxin distribution and suggests that flavonol glycosides play an important role in regulating plant development. PMID- 26742841 TI - Cell Adhesion on Amyloid Fibrils Lacking Integrin Recognition Motif. AB - Amyloids are highly ordered, cross-beta-sheet-rich protein/peptide aggregates associated with both human diseases and native functions. Given the well established ability of amyloids in interacting with cell membranes, we hypothesize that amyloids can serve as universal cell-adhesive substrates. Here, we show that, similar to the extracellular matrix protein collagen, amyloids of various proteins/peptides support attachment and spreading of cells via robust stimulation of integrin expression and formation of integrin-based focal adhesions. Additionally, amyloid fibrils are also capable of immobilizing non adherent red blood cells through charge-based interactions. Together, our results indicate that both active and passive mechanisms contribute to adhesion on amyloid fibrils. The present data may delineate the functional aspect of cell adhesion on amyloids by various organisms and its involvement in human diseases. Our results also raise the exciting possibility that cell adhesivity might be a generic property of amyloids. PMID- 26742842 TI - Reductions in the Cardiac Transient Outward K+ Current Ito Caused by Chronic beta Adrenergic Receptor Stimulation Are Partly Rescued by Inhibition of Nuclear Factor kappaB. AB - The fast transient outward potassium current (Ito,f) plays a critical role in the electrical and contractile properties of the myocardium. Ito,f channels are formed by the co-assembly of the pore-forming alpha-subunits, Kv4.2 and Kv4.3, together with the accessory beta-subunit KChIP2. Reductions of Ito,f are common in the diseased heart, which is also associated with enhanced stimulation of beta adrenergic receptors (beta-ARs). We used cultured neonatal rat ventricular myocytes to examine how chronic beta-AR stimulation decreases Ito,f. To determine which downstream pathways mediate these Ito,f changes, adenoviral infections were used to inhibit CaMKIIdeltac, CaMKIIdeltab, calcineurin, or nuclear factor kappaB (NF-kappaB). We observed that chronic beta-AR stimulation with isoproterenol (ISO) for 48 h reduced Ito,f along with mRNA expression of all three of its subunits (Kv4.2, Kv4.3, and KChIP2). Inhibiting either CaMKIIdeltac nor CaMKIIdeltab did not prevent the ISO-mediated Ito,f reductions, even though CaMKIIdeltac and CaMKIIdeltab clearly regulated Ito,f and the mRNA expression of its subunits. Likewise, calcineurin inhibition did not prevent the Ito,f reductions induced by beta-AR stimulation despite strongly modulating Ito,f and subunit mRNA expression. In contrast, NF-kappaB inhibition partly rescued the ISO mediated Ito,f reductions in association with restoration of KChIP2 mRNA expression. Consistent with these observations, KChIP2 promoter activity was reduced by p65 as well as beta-AR stimulation. In conclusion, NF-kappaB, and not CaMKIIdelta or calcineurin, partly mediates the Ito,f reductions induced by chronic beta-AR stimulation. Both mRNA and KChIP2 promoter data suggest that the ISO-induced Ito,f reductions are, in part, mediated through reduced KChIP2 transcription caused by NF-kappaB activation. PMID- 26742843 TI - Critical Molecular Determinants of alpha7 Nicotinic Acetylcholine Receptor Allosteric Activation: SEPARATION OF DIRECT ALLOSTERIC ACTIVATION AND POSITIVE ALLOSTERIC MODULATION. AB - The alpha7 nicotinic acetylcholine receptors (nAChRs) are uniquely sensitive to selective positive allosteric modulators (PAMs), which increase the efficiency of channel activation to a level greater than that of other nAChRs. Although PAMs must work in concert with "orthosteric" agonists, compounds such as GAT107 ((3aR,4S,9bS)-4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8 sulfonamide) have the combined properties of agonists and PAMs (ago-PAM) and produce very effective channel activation (direct allosteric activation (DAA)) by operating at two distinct sites in the absence of added agonist. One site is likely to be the same transmembrane site where PAMs like PNU-120596 function. We show that the other site, required for direct activation, is likely to be solvent accessible at the extracellular domain vestibule. We identify key attributes of molecules in this family that are able to act at the DAA site through variation at the aryl ring substituent of the tetrahydroquinoline ring system and with two different classes of competitive antagonists of DAA. Analyses of molecular features of effective allosteric agonists allow us to propose a binding model for the DAA site, featuring a largely non-polar pocket accessed from the extracellular vestibule with an important role for Asp-101. This hypothesis is supported with data from site-directed mutants. Future refinement of the model and the characterization of specific GAT107 analogs will allow us to define critical structural elements that can be mapped onto the receptor surface for an improved understanding of this novel way to target alpha7 nAChR therapeutically. PMID- 26742844 TI - Uncovering the Catalytic Direction of Chondroitin AC Exolyase: FROM THE REDUCING END TOWARDS THE NON-REDUCING END. AB - Glycosaminoglycans (GAGs) are polysaccharides that play vital functional roles in numerous biological processes, and compounds belonging to this class have been implicated in a wide variety of diseases. Chondroitin AC lyase (ChnAC) (EC 4.2.2.5) catalyzes the degradation of various GAGs, including chondroitin sulfate and hyaluronic acid, to give the corresponding disaccharides containing an Delta(4)-unsaturated uronic acid at their non-reducing terminus. ChnAC has been isolated from various bacteria and utilized as an enzymatic tool for study and evaluating the sequencing of GAGs. Despite its substrate specificity and the fact that its crystal structure has been determined to a high resolution, the direction in which ChnAC catalyzes the cleavage of oligosaccharides remain unclear. Herein, we have determined the structural cues of substrate depolymerization and the cleavage direction of ChnAC using model substrates and recombinant ChnAC protein. Several structurally defined oligosaccharides were synthesized using a chemoenzymatic approach and subsequently cleaved using ChnAC. The degradation products resulting from this process were determined by mass spectrometry. The results revealed that ChnAC cleaved the beta1,4-glycosidic linkages between glucuronic acid and glucosamine units when these bonds were located on the reducing end of the oligosaccharide. In contrast, the presence of a GlcNAc-alpha-1,4-GlcA unit at the reducing end of the oligosaccharide prevented ChnAC from cleaving the GalNAc-beta1,4-GlcA moiety located in the middle or at the non-reducing end of the chain. These interesting results therefore provide direct proof that ChnAC cleaves oligosaccharide substrates from their reducing end toward their non-reducing end. This conclusion will therefore enhance our collective understanding of the mode of action of ChnAC. PMID- 26742845 TI - Heterogeneity of Collagen VI Microfibrils: STRUCTURAL ANALYSIS OF NON-COLLAGENOUS REGIONS. AB - Collagen VI, a collagen with uncharacteristically large N- and C-terminal non collagenous regions, forms a distinct microfibrillar network in most connective tissues. It was long considered to consist of three genetically distinct alpha chains (alpha1, alpha2, and alpha3). Intracellularly, heterotrimeric molecules associate to form dimers and tetramers, which are then secreted and assembled to microfibrils. The identification of three novel long collagen VI alpha chains, alpha4, alpha5, and alpha6, led to the question if and how these may substitute for the long alpha3 chain in collagen VI assembly. Here, we studied structural features of the novel long chains and analyzed the assembly of these into tetramers and microfibrils. N- and C-terminal globular regions of collagen VI were recombinantly expressed and studied by small angle x-ray scattering (SAXS). Ab initio models of the N-terminal globular regions of the alpha4, alpha5, and alpha6 chains showed a C-shaped structure similar to that found for the alpha3 chain. Single particle EM nanostructure of the N-terminal globular region of the alpha4 chain confirmed the C-shaped structure revealed by SAXS. Immuno-EM of collagen VI extracted from tissue revealed that like the alpha3 chain the novel long chains assemble to homotetramers that are incorporated into mixed microfibrils. Moreover, SAXS models of the C-terminal globular regions of the alpha1, alpha2, alpha4, and alpha6 chains were generated. Interestingly, the alpha1, alpha2, and alpha4 C-terminal globular regions dimerize. These self interactions may play a role in tetramer formation. PMID- 26742846 TI - NusG Is a Sequence-specific RNA Polymerase Pause Factor That Binds to the Non template DNA within the Paused Transcription Bubble. AB - NusG, referred to as Spt5 in archaeal and eukaryotic organisms, is the only transcription factor conserved in all three domains of life. This general transcription elongation factor binds to RNA polymerase (RNAP) soon after transcription initiation and dissociation of the RNA polymerase sigma factor. Escherichia coli NusG increases transcription processivity by suppressing RNAP pausing, whereas Bacillus subtilis NusG dramatically stimulates pausing at two sites in the untranslated leader of the trpEDCFBA operon. These two regulatory pause sites participate in transcription attenuation and translational control mechanisms, respectively. Here we report that B. subtilis NusG makes sequence specific contacts with a T-rich sequence in the non-template DNA (ntDNA) strand within the paused transcription bubble. NusG protects T residues of the recognition sequence from permanganate oxidation, and these T residues increase the affinity of NusG to the elongation complex. Binding of NusG to RNAP does not require interaction with RNA. These results indicate that bound NusG prevents forward movement of RNA polymerase by simultaneously contacting RNAP and the ntDNA strand. Mutational studies indicate that amino acid residues of two short regions within the NusG N-terminal domain are primarily responsible for recognition of the trp operon pause signals. Structural modeling indicates that these two regions are adjacent to each another in the protein. We propose that recognition of specific sequences in the ntDNA and stimulation of RNAP pausing is a conserved function of NusG-like transcription factors. PMID- 26742847 TI - Identification of Glycosylation Sites Essential for Surface Expression of the CaValpha2delta1 Subunit and Modulation of the Cardiac CaV1.2 Channel Activity. AB - Alteration in the L-type current density is one aspect of the electrical remodeling observed in patients suffering from cardiac arrhythmias. Changes in channel function could result from variations in the protein biogenesis, stability, post-translational modification, and/or trafficking in any of the regulatory subunits forming cardiac L-type Ca(2+) channel complexes. CaValpha2delta1 is potentially the most heavily N-glycosylated subunit in the cardiac L-type CaV1.2 channel complex. Here, we show that enzymatic removal of N glycans produced a 50-kDa shift in the mobility of cardiac and recombinant CaValpha2delta1 proteins. This change was also observed upon simultaneous mutation of the 16 Asn sites. Nonetheless, the mutation of only 6/16 sites was sufficient to significantly 1) reduce the steady-state cell surface fluorescence of CaValpha2delta1 as characterized by two-color flow cytometry assays and confocal imaging; 2) decrease protein stability estimated from cycloheximide chase assays; and 3) prevent the CaValpha2delta1-mediated increase in the peak current density and voltage-dependent gating of CaV1.2. Reversing the N348Q and N812Q mutations in the non-operational sextuplet Asn mutant protein partially restored CaValpha2delta1 function. Single mutation N663Q and double mutations N348Q/N468Q, N348Q/N812Q, and N468Q/N812Q decreased protein stability/synthesis and nearly abolished steady-state cell surface density of CaValpha2delta1 as well as the CaValpha2delta1-induced up-regulation of L-type currents. These results demonstrate that Asn-663 and to a lesser extent Asn-348, Asn-468, and Asn-812 contribute to protein stability/synthesis of CaValpha2delta1, and furthermore that N-glycosylation of CaValpha2delta1 is essential to produce functional L-type Ca(2+) channels. PMID- 26742849 TI - Evolutionary Ancestry of Eukaryotic Protein Kinases and Choline Kinases. AB - The reversible phosphorylation of proteins catalyzed by protein kinases in eukaryotes supports an important role for eukaryotic protein kinases (ePKs) in the emergence of nucleated cells in the third superkingdom of life. Choline kinases (ChKs) could also be critical in the early evolution of eukaryotes, because of their function in the biosynthesis of phosphatidylcholine, which is unique to eukaryotic membranes. However, the genomic origins of ePKs and ChKs are unclear. The high degeneracy of protein sequences and broad expansion of ePK families have made this fundamental question difficult to answer. In this study, we identified two class-I aminoacyl-tRNA synthetases with high similarities to consensus amino acid sequences of human protein-serine/threonine kinases. Comparisons of primary and tertiary structures supported that ePKs and ChKs evolved from a common ancestor related to glutaminyl aminoacyl-tRNA synthetases, which may have been one of the key factors in the successful of emergence of ancient eukaryotic cells from bacterial colonies. PMID- 26742850 TI - Rhizobiales-like Phosphatase 2 from Arabidopsis thaliana Is a Novel Phospho tyrosine-specific Phospho-protein Phosphatase (PPP) Family Protein Phosphatase. AB - Cellular signaling through protein tyrosine phosphorylation is well established in mammalian cells. Although lacking the classic tyrosine kinases present in humans, plants have a tyrosine phospho-proteome that rivals human cells. Here we report a novel plant tyrosine phosphatase from Arabidopsis thaliana (AtRLPH2) that, surprisingly, has the sequence hallmarks of a phospho-serine/threonine phosphatase belonging to the PPP family. Rhizobiales/Rhodobacterales/Rhodospirillaceae-like phosphatases (RLPHs) are conserved in plants and several other eukaryotes, but not in animals. We demonstrate that AtRLPH2 is localized to the plant cell cytosol, is resistant to the classic serine/threonine phosphatase inhibitors okadaic acid and microcystin, but is inhibited by the tyrosine phosphatase inhibitor orthovanadate and is particularly sensitive to inhibition by the adenylates, ATP and ADP. AtRLPH2 displays remarkable selectivity toward tyrosine-phosphorylated peptides versus serine/threonine phospho-peptides and readily dephosphorylates a classic tyrosine phosphatase protein substrate, suggesting that in vivo it is a tyrosine phosphatase. To date, only one other tyrosine phosphatase is known in plants; thus AtRLPH2 represents one of the missing pieces in the plant tyrosine phosphatase repertoire and supports the concept of protein tyrosine phosphorylation as a key regulatory event in plants. PMID- 26742851 TI - Simulations of iron K pre-edge X-ray absorption spectra using the restricted active space method. AB - The intensities and relative energies of metal K pre-edge features are sensitive to both geometric and electronic structures. With the possibility to collect high resolution spectral data it is important to find theoretical methods that include all important spectral effects: ligand-field splitting, multiplet structures, 3d 4p orbital hybridization, and charge-transfer excitations. Here the restricted active space (RAS) method is used for the first time to calculate metal K pre edge spectra of open-shell systems, and its performance is tested against on six iron complexes: [FeCl6](n-), [FeCl4](n-), and [Fe(CN)6](n-) in ferrous and ferric oxidation states. The method gives good descriptions of the spectral shapes for all six systems. The mean absolute deviation for the relative energies of different peaks is only 0.1 eV. For the two systems that lack centrosymmetry [FeCl4](2-/1-), the ratios between dipole and quadrupole intensity contributions are reproduced with an error of 10%, which leads to good descriptions of the integrated pre-edge intensities. To gain further chemical insight, the origins of the pre-edge features have been analyzed with a chemically intuitive molecular orbital picture that serves as a bridge between the spectra and the electronic structures. The pre-edges contain information about both ligand-field strengths and orbital covalencies, which can be understood by analyzing the RAS wavefunction. The RAS method can thus be used to predict and rationalize the effects of changes in both the oxidation state and ligand environment in a number of hard X-ray studies of small and medium-sized molecular systems. PMID- 26742848 TI - Conserved Amphipathic Helices Mediate Lipid Droplet Targeting of Perilipins 1-3. AB - Perilipins (PLINs) play a key role in energy storage by orchestrating the activity of lipases on the surface of lipid droplets. Failure of this activity results in severe metabolic disease in humans. Unlike all other lipid droplet associated proteins, PLINs localize almost exclusively to the phospholipid monolayer surrounding the droplet. To understand how they sense and associate with the unique topology of the droplet surface, we studied the localization of human PLINs inSaccharomyces cerevisiae,demonstrating that the targeting mechanism is highly conserved and that 11-mer repeat regions are sufficient for droplet targeting. Mutations designed to disrupt folding of this region into amphipathic helices (AHs) significantly decreased lipid droplet targetingin vivoandin vitro Finally, we demonstrated a substantial increase in the helicity of this region in the presence of detergent micelles, which was prevented by an AH-disrupting missense mutation. We conclude that highly conserved 11-mer repeat regions of PLINs target lipid droplets by folding into AHs on the droplet surface, thus enabling PLINs to regulate the interface between the hydrophobic lipid core and its surrounding hydrophilic environment. PMID- 26742852 TI - Survey of Ambient Air Pollution Health Risk Assessment Tools. AB - Designing air quality policies that improve public health can benefit from information about air pollution health risks and impacts, which include respiratory and cardiovascular diseases and premature death. Several computer based tools help automate air pollution health impact assessments and are being used for a variety of contexts. Expanding information gathered for a May 2014 World Health Organization expert meeting, we survey 12 multinational air pollution health impact assessment tools, categorize them according to key technical and operational characteristics, and identify limitations and challenges. Key characteristics include spatial resolution, pollutants and health effect outcomes evaluated, and method for characterizing population exposure, as well as tool format, accessibility, complexity, and degree of peer review and application in policy contexts. While many of the tools use common data sources for concentration-response associations, population, and baseline mortality rates, they vary in the exposure information source, format, and degree of technical complexity. We find that there is an important tradeoff between technical refinement and accessibility for a broad range of applications. Analysts should apply tools that provide the appropriate geographic scope, resolution, and maximum degree of technical rigor for the intended assessment, within resources constraints. A systematic intercomparison of the tools' inputs, assumptions, calculations, and results would be helpful to determine the appropriateness of each for different types of assessment. Future work would benefit from accounting for multiple uncertainty sources and integrating ambient air pollution health impact assessment tools with those addressing other related health risks (e.g., smoking, indoor pollution, climate change, vehicle accidents, physical activity). PMID- 26742853 TI - The impact of gestational diabetes and hypothyroidism on the third-trimester ultrasound parameters and in adverse perinatal outcomes: a retrospective cohort study. AB - OBJECTIVE: To assess the impact of gestational diabetes and hypothyroidism on the third-trimester ultrasound parameters and in adverse perinatal outcomes. METHODS: We performed a retrospective cohort study with 817 singleton pregnant women between 26w0d and 37w6d of gestation which were divided in four groups: 56 gestational diabetes mellitus (GDM), 63 hypothyroidism, 14 GDM + hypothyroidism, and 684 controls. The following ultrasound parameters were assessed: mean uterine artery pulsatility index (PI), umbilical artery PI, middle cerebral artery PI, single deepest pocket (SDP) and cerebroplacental ratio (CPR). Adverse perinatal outcomes were the following: low birth weight, macrosomia, and Agar score at 1st min <7. These four groups were compared using the Kruskall-Wallis and chi(2) tests. RESULTS: Pregnant women from GDM showed higher weight (p < 0.001), BMI (p < 0.001), SDP (p < 0.001) and newborns with higher birth weight (p = 0.008) and macrosomia (p = 0.02) than other groups. Comparing with control, hypothyroidism showed higher SDP (p < 0.05). CONCLUSION: Pregnant women with GDM showed higher risk of macrosomic newborns than other three groups. Both pregnant women with GDM and hypothyroidism showed higher SDP than normal pregnancies. PMID- 26742854 TI - "Click on the bidirectional switch": the aptasensor for simultaneous detection of lysozyme and ATP with high sensitivity and high selectivity. AB - A bifunctional and simple aptasensor was designed to one-spot simultaneously detect two analytes, lysozyme and ATP. The aptasensor was obtained by the electronic interaction between methyl violet (MV) and dsDNA. The dsDNA was obtained by hybridization of ATP aptamer and lysozyme aptamer. And we used the resonance light scattering (RLS) technique to detect the concentration of lysozyme and ATP. During the procedure of detection, the aptasensor works like a bidirectional switch, the corresponding side of the dsDNA will open when the target (lysozyme or ATP) "click" the aptamer, which results in corresponding RLS signal change. By the combination of the RLS technique, it is found that the changed RLS intensity was proportional to the concentration of lysozyme and ATP. The mixtures of ATP and lysozyme also met two binary function relations. The results indicated that the aptasensor could achieve simultaneous detection of ATP and lysozyme, the detection limits of ATP and lysozyme could reach 10(-11) M and 10(-12) M, respectively. The aptasensor shows potential application for small molecule and protein detection by RLS, it could extend the application of RLS technique. PMID- 26742855 TI - Experiences of and attitudes towards receiving information about non-steroidal anti-inflammatory drugs: a cross-sectional survey of patients in Thailand. AB - OBJECTIVE: To determine sources of information about NSAIDs used by out-patients, factors related to receipt of information and patient attitudes towards receiving safety information. RESEARCH DESIGN AND METHODS: Cross-sectional survey, using self-completed questionnaires distributed directly to 500 outpatients prescribed any NSAIDs from an orthopaedic clinic in Thailand, over a 4-month period. RESULTS: There were 548 patients approached and 474 completed questionnaires returned (94.8%). The most frequent aspects of medicines information that were provided related to administration (97.2%), mostly provided by pharmacists, and indication (85.8%), mostly provided by physicians. Information on identifying, monitoring and managing adverse effects was received by fewer than 50% of patients. Safety information was received significantly more frequently by younger patients (P<0.01), those using non-selective COX-2 inhibitors (P<0.001), intermittent NSAIDs (P<0.05) and fewer concomitant medicines (P<0.05). Only 14.1% patients used additional information sources. Attitudes towards receiving medicines safety information were positive. Most patients agreed they should know about ADRs (98.1%) and receive information leaflets with first prescription (96.8%). CONCLUSIONS: Patients received medicines information mostly from healthcare professionals, but safety information was limited. Type of NSAIDs, regularity of NSAID use and age affected receipt of safety information about NSAIDs. Provision of more medicine information is needed, particularly written documents. PMID- 26742856 TI - Tau Protein Quantification in Human Cerebrospinal Fluid by Targeted Mass Spectrometry at High Sequence Coverage Provides Insights into Its Primary Structure Heterogeneity. AB - Tau protein plays a major role in neurodegenerative disorders, appears to be a central biomarker of neuronal injury in cerebrospinal fluid (CSF), and is a promising target for Alzheimer's disease immunotherapies. To quantify tau at high sensitivity and gain insights into its naturally occurring structural variations in human CSF, we coupled absolute quantification using protein standard with the multiplex detection capability of targeted high-resolution mass spectrometry (MS) on a Quadrupole-Orbitrap instrument. Using recombinant tau we developed a step-by step workflow optimization including an extraction protocol that avoided affinity reagents and achieved the monitoring of 22 tau peptides uniformly distributed along the tau sequence. The lower limits of quantification ranged (LLOQ) from 150 to 1500 pg/mL depending on the peptide. Applied to endogenous CSF tau, up to 19 peptides were detected. Interestingly, there were significant differences in the abundance of peptides depending on their position in the sequence, with peptides from the tau mid-domain appearing significantly more abundant than peptides from the N- and C-terminus domains. This MS-based strategy provided results complementary to those of previous ELISA or Western Blot studies of CSF tau and could be applied to tau monitoring in human CSF cohorts. PMID- 26742857 TI - A new physical mapping approach refines the sex-determining gene positions on the Silene latifolia Y-chromosome. AB - Sex chromosomes are particularly interesting regions of the genome for both molecular genetics and evolutionary studies; yet, for most species, we lack basic information, such as the gene order along the chromosome. Because they lack recombination, Y-linked genes cannot be mapped genetically, leaving physical mapping as the only option for establishing the extent of synteny and homology with the X chromosome. Here, we developed a novel and general method for deletion mapping of non-recombining regions by solving "the travelling salesman problem", and evaluate its accuracy using simulated datasets. Unlike the existing radiation hybrid approach, this method allows us to combine deletion mutants from different experiments and sources. We applied our method to a set of newly generated deletion mutants in the dioecious plant Silene latifolia and refined the locations of the sex-determining loci on its Y chromosome map. PMID- 26742858 TI - Retransplant as Rescue Treatment for ABO-Compatible Living-Donor Liver Transplant Related Antibody-Mediated Rejection: A Case Report. AB - Antibody-mediated rejection after liver transplant, especially when the donor is not a direct relative; it is associated with additional inconvenience for patients. We encountered a case in which antibody-mediated rejection because of de novo donor specific antibodies against donor human leukocyte antigen developed 6 months after ABO-compatible living-donor liver transplant and was treated with retransplant. A 38-year-old man with hepatitis B virus-related hepatocellular carcinoma underwent living-donor liver transplant with a graft from his wife. Six months later, he experienced fatigue and jaundice. Liver biopsy revealed C4d deposits, and histologic examination showed an antibody-mediated rejection pattern. We re-evaluated recipient-donor human leukocyte antigen matching and tested the patient's blood for antihuman leukocyte antigen donor-specific antibodies against donor human leukocyte antigen. De novo auto-antibodies against human leukocyte antigen-DQ6 were identified by Luminex single antigen beads.Because exhausting all treatment options, a rescue second living-donor liver transplant was planned with the patient's stepdaughter as the donor. Pretransplant human leukocyte antigen matching was performed, and the patient was discharged without event. Two months later, hyperbilirubinemia was noted, and a residual common bile duct from the first donor with chronic fibrosis and stricture was strongly suspected. Redo hepaticojejunostomy was successfully performed, with no problems during 1-years' follow-up. Thus, liver retransplant could be a rescue treatment for antibody-mediated rejection complicated with hepatic failure. PMID- 26742859 TI - Three-Tone Chemical Patterns for Block Copolymer Directed Self-Assembly. AB - Chemical patterns for directed self-assembly (DSA) of lamellae-forming block copolymers (BCP) with density multiplication can be fabricated by patterning resist on a cross-linked polystyrene layer, etching to create guide stripes, and depositing end-grafted brushes in between the stripes as background. To date, two tone chemical patterns have been targeted with the guide stripes preferentially wet by one block of the copolymer and the background chemistry weakly preferentially wet by the other block. In the course of fabricating chemical patterns in an all-track process using 300 mm wafers, it was discovered that the etching process followed by brush grafting could produce a three-tone pattern. We characterized the three regions of the chemical patterns with a combination of SEM, grazing-incidence small-angle X-ray scattering (GISAXS), and assessment of BCP-wetting behavior, and evaluated the DSA behavior on patterns over a range of guide stripe widths. In its best form, the three-tone pattern consists of guide stripes preferentially wet by one block of the copolymer, each flanked by two additional stripes that wet the other block of the copolymer, with a third chemistry as the background. Three-tone patterns guide three times as many BCP domains as two-tone patterns and thus have the potential to provide a larger driving force for the system to assemble into the desired architecture with fewer defects in shorter time and over a larger process window. PMID- 26742860 TI - Does Acamprosate Really Produce its Anti-Relapse Effects via Calcium? No Support from the PREDICT Study in Human Alcoholics. PMID- 26742861 TI - Reply to: Does acamprosate really produce its anti-relapse effects via calcium? No support from the PREDICT study in human alcoholics. PMID- 26742862 TI - Comparative study of 27-gauge vs 25-gauge vitrectomy for epiretinal membrane. AB - PURPOSE: The purpose of this study was to compare 27-gauge (27G) with 25-gauge (25G) microincision vitrectomy in patients with epiretinal membrane (ERM).ParticipantsSeventy-four eyes of 66 patients undergoing 3-port pars plana vitrectomy using 27G or 25G instrumentation. METHODS: Seventy-four eyes of 66 patients with ERM, who underwent 27G or 25G microincision vitrectomy were prospectively evaluated. RESULTS: The mean operation time for vitrectomy was significantly longer in the 27G group than in the 25G group (9.9+/-3.5 vs 6.2+/ 2.7 min, respectively, P<0.0001). No statistically significant difference was found between the two groups in terms of the mean operation time for ERM-inner limiting membrane peeling (27G vs 25G: 20.2+/-9.9 vs 16.1+/-9.3 min, P=0.14), although the time for vitreous cutting was longer in the 27G group (9.9+/-3.5 vs 6.2+/-2.7 min, respectively, P<0.0001). The flare value, intraocular pressure (IOP), and rate of hypotony 1 day after surgery did not differ between the 27G and 25G groups (flare value: 18.7 vs 17.2; IOP: 8.8 vs 9.7 mm Hg; rate of hypotony: 30 vs 35%, respectively). There was no significant difference in the surgically induced astigmatism between the two groups in the follow-up period. The mean time required for wound closure did not show a significant difference between the 27G and 25G groups (7.7 vs 8.6 weeks, respectively). CONCLUSION: The 27G system is as safe and useful for ERM vitrectomy as the 25G system. Based on its potential, further improvement of 27G instruments could result in greater efficiency. PMID- 26742864 TI - Light in man's environment. AB - Light in the form of solar radiation influenced early civilisations and resulted in the independent development of a number of sun-worshipping dieties. These were of particular importance as hunter gatherers transformed into settled agricultural societies. All artificial light sources were synonymous with fire, and early civilisations began to expand their visual day by burning brands, oil, and candles. Fire-based light sources extended for thousands of years and were still present in the era of gas lighting. Light meant fire risk. The advent of incandescent bulbs and the era of electric lighting really only expanded in the early part of the twentieth century. Fluorescent lighting became available in the 1940s, and today the drive for low energy has resulted in a plethora of novel light sources-in particular, light-emitting diodes (LEDs). Evolution governed the development of the eye in relation to roughly 12 h of light gradually changing to 12 h of darkness. Today almost daylight levels can be achieved abruptly at the flick of a switch. Many studies have demonstrated the spectral dependence of eye health, with the retinal hazard zone associated with wavelengths in the blue, peaking at 441 nm- many of today's low-energy sources peak in this region. Given the increased longevity and artificial light sources emitting at biologically unfriendly wavelengths, attention has to be directed towards light in man's environment as a risk factor in age-related ocular diseases. PMID- 26742863 TI - Orbital granular cell tumours: clinical and pathologic characteristics of six cases and literature review. AB - OBJECTIVE: To retrospectively assess the clinicopathological characteristics of orbital granular cell tumours (GCTs). METHODS: A non-comparative review of the clinical characteristics, imaging, histopathological features, management, and prognosis of five cases of benign GCT and one case of malignant GCT (MGCT) was conducted, along with a review of the English language literature. RESULTS: Among the six cases, four tumours were adherent to the extraocular muscle (EOM), and three tumours to the optic nerve (ON). Morphologic examinations revealed polygonal cells containing periodic-acid-Schiff-positive eosinophilic granules. All tumours (100%) were positive for VIM and NSE, five (83.3%) tumours were positive for S-100, and three (50%) tumours were positive for CD68. The follow-up examination of the MGCT witnessed recurrence and brain metastasis despite several thorough resections, but the patient remained alive; the follow-up examination of the four benign GCTs that had received incomplete excision revealed recurrence in one patient and dramatic shrinkage of the residual tumour in another; there was no recurrence in the other two patients. CONCLUSIONS: GCT should be considered in the differential diagnosis of orbital tumours, which may affect EOMs and ON. The natural course of GCT can include tumour progression, stability, or spontaneous regression. To avoid recurrence, complete resection is recommended for orbital GCT. To the best of our knowledge, primary orbital MGCT is reported for the first time. PMID- 26742865 TI - Visual outcomes and ocular morbidity of patients with uveitis referred to a tertiary center during first year of follow-up. AB - PURPOSE: To describe the visual outcomes and morbidity of newly referred uveitis patients. METHODS: Retrospective cohort study of 133 newly referred uveitis patients with active uveitis who required care in a tertiary center for at least 1 year. Main outcomes were best-corrected visual acuity (BCVA) at referral and 1 year after referral, duration of visual impairment, systemic medications used, as well as all complications and surgeries during the first year of follow-up. Generalized estimating equation models was used to assess prognosticators for poor BCVA. RESULTS: The mean age at onset of uveitis was 43 years. The proportion of patients with at least one eye with BCVA <=0.3 decreased from 35% at referral to 26% (P=0.45) at 1-year follow-up. The mean duration of visual impairment in the first year after referral was 4 months per affected eye. At 1-year follow-up, bilateral visual impairment was observed in 4% but at least one ocular complication developed in 66% and 30% of patients required at least one intraocular surgery. Systemic immunosuppressive treatment was required in 35% of patients and the mean number of visits to ophthalmologist was 11 per year, while 8% of patients required hospital admission. Prognosticators for poor visual outcome included surgery undergone before referral (odds ratio (OR), 3; 95% CI, 1 11; P=0.047), visual impairment at referral (OR, 21; 95% CI, 8-54; P<0.001), and glaucoma before referral (OR, 7; 95% CI, 2-28; P=0.007). CONCLUSIONS: Patients with severe uveitis had a favorable BCVA 1 year after referral with only 4% of patients having bilateral visual impairment. This, in contrast to the prolonged duration of visual impairment during the first year of follow-up and the demanding care. PMID- 26742866 TI - Ultraviolet or blue-filtering intraocular lenses: what is the evidence? AB - Cataract surgery was revolutionised by the introduction of modern intraocular lenses in the late 1940's. By the late 1960's to 1970's evidence had emerged that short-wavelength light caused phototoxicity at the retina and retinal pigment epithelium. By the early 1980's ultraviolet filters had been incorporated into intraocular lenses. This caused intense controversy, as there was concern that the UV-filtering chromophore might leach out into the eye causing toxicity. With the arrival of blue-filtering intraocular lenses (BFIOLs) in 1990's, a further debate was ignited as to their safety and potential disadvantages. Selecting the optimal performing intraocular lens to obtain the best visual performance with the fewest potential drawbacks has become complex and challenging for cataract surgeons and their patients with the wide choice of lenses available. Choosing a personalised lens to address astigmatism, presbyopia, spherical aberration, chromatic aberration, and potentially to shield the retina from short-wavelength light is now possible. The potential benefits and possible side effects of these different innovations emphasise the importance of assessing the evidence for their clinical utility, allowing the surgeon and the patient to weigh-up the risk benefit ratio and make an informed decision. The BFIOLs were developed to reduce cyanopsia, address chromatic aberration, and improve contrast sensitivity in different lighting conditions, as well as to prevent short-wavelength light reaching the retina thus potentially reducing the risk of developing age-related macular degeneration. Further design development of the BFIOLs was to mimic the natural crystalline lens absorption and transmittance properties in adulthood. Multiple publications have reported on the potential benefits and pitfalls of implanting a blue-filtering lens. The potential disadvantages raised in the literature over the last 25 years since their introduction, regarding compromise of visual function and disruption of the circadian system, have been largely dispelled. The clear benefits of protecting the retina from short-wavelength light make a BFIOLs a sensible choice. The purpose of this article presented at the Cambridge symposium 2015 is to review the literature on this subject. PMID- 26742868 TI - Anterior transposition vs anterior and nasal transposition of inferior oblique muscle in treatment of dissociated vertical deviation associated with inferior oblique overaction. AB - PURPOSE: To compare results of two surgical techniques; anteriorization (ATIO) vs anterior nasalization (ANT) of IO muscle in management of DVD associated with IOOA. METHODS: Twenty-one patients with DVD associated with IOOA were included in this study. Group A consists of 11 patients who underwent ATIO and group B with 10 patients who underwent anterior transposition of IO to the nasal border of inferior rectus ANT. All patients were followed for at least 6 months postoperatively. The primary outcome variables were changes in DVD in primary position and side gazes, IO action and V pattern. RESULTS: The average of correction of DVD in primary position, in adduction and in abduction was 10.63 PD, 24.6 PD (P<0.001) and 0.45 PD5 (P>0.05) in ATIO group and 14.6 PD, 25.2 PD and 1.7 PD (P<0.001) in ANT group respectively. Mean IOOA decreased from +2.0+/ 0.7 to +0.18+/-0.4 in group A (P<0.001) and from +2.5+/-0.7 to +0.1+/-0.5 (P<0.001) in group B. Mean V pattern was corrected from 19.18+/-7.1 PD to 11.18+/ 4.9 PD (P<0.01) in group A and from 17.8+/-7.9 PD to 6.0+/-2.49 PD (P<0.001) in group B. In group B, two patients developed hypotropia of 2 and 4 PD and one patient developed consecutive exotropia. CONCLUSIONS: In DVD associated with IOOA, both surgical techniques are almost similar in alleviating true hypertropia in side gaze, IOOA, and V pattern. ANT gives more statistically significant DVD correction in primary position and in abduction while in adduction; there is no significant difference between both groups. However, ANT may induce hypotropia and consecutive horizontal strabismus. PMID- 26742867 TI - Photodynamic therapy: current role in the treatment of chorioretinal conditions. AB - Verteporfin photodynamic therapy (vPDT) is a selective vaso-occlusive treatment that targets choroidal vascular abnormalities. It was initially developed to treat neovascular age-related macular degeneration using the 'standard' vPDT protocol (verteporfin 6 mg/m(2), vPDT laser fluence 50 J/cm(2)). vPDT therapy has subsequently evolved as an important treatment modality for a range of other chorioretinal conditions including choroidal haemangioma, central serous chorioretinopathy, polypoidal choroidal vasculopathy, and peripapillary choroidal neovascularisation. Various 'safety-enhanced' vPDT protocols have been devised to optimise treatment outcomes, typically using reduced dose verteporfin (verteporfin 3 mg/m(2)) or reduced fluence vPDT (vPDT laser fluence 25 J/cm(2)). This paper reviews the current role of vPDT therapy in the treatment of chorioretinal conditions. PMID- 26742869 TI - Four cases of Raoultella planticola conjunctivitis. AB - AIMS: This brief report of four cases of conjunctivitis caused by Raoultella planticola provides a description of possibly the first documented cases of this eye infection. METHODS: The laboratory database and medical records were used to trace all the R. planticola-positive conjunctival swabs obtained in our institution. Four cases were identified and available relevant information was obtained. RESULTS: This organism causes a non-specific purulent conjunctivitis that seems to have a benign course and tends to be responsive to a topical fluoroquinolone. CONCLUSIONS: The possibility of atypical organisms must be considered when managing infective conjunctivitis. Conjunctival swabs should be obtained and topical treatment switched when initial empirical therapy fails. PMID- 26742871 TI - Retinal nerve fiber layer and macular thickness measurement in patients with schizophrenia. AB - PURPOSE: To investigate the retina and macular thickness in patients with schizophrenia and to compare the results with those of healthy controls. METHODS: Sixty-eight eyes of 34 patients with schizophrenia and 60 eyes of 30 randomly selected healthy volunteers were involved in the study. Measurements of peripapillary retinal nerve fiber layer (RNFL) thickness, macula thickness, and macula volume were taken in both eyes using spectral-domain optical coherence tomography (OCT). Statistical analysis was performed using Statistical Package for the Social Sciences version 20.0. RESULTS: Average and nasal RNFL thicknesses were found to be significantly lower in the patient group than the control group (p = 0.030, p = 0.04, respectively). Macular thicknesses of nasal outer and inferior outer quadrants in the patient group were significantly lower than in the control group (p = 0.009, p = 0.027, respectively). Average macular thickness and macular thicknesses in the superior outer, superior inner, temporal outer, temporal inner, nasal inner, and inferior inner areas were lower in the patient group compared to the control group, but not significantly (p = 1.000, p = 1.000, p = 0.837, p = 1.000, p = 0.279, p = 1.000, p = 0.180, respectively). CONCLUSIONS: We detected RNFL and macular thinning in patients with schizophrenia. Based on these findings and results of other studies evaluating retina using OCT and brain magnetic resonance imaging studies in patients with schizophrenia, a neurodegenerative process may be an underlying pathologic mechanism in this disease. PMID- 26742870 TI - Persistent subfoveolar fluid following retinal detachment surgery: an SD-OCT guided study on the incidence, aetiological associations, and natural history. AB - PURPOSE: To investigate the incidence and natural history of persistent subfoveolar fluid (PSF) following surgery for macular off rhegmatogenous retinal detachment and the effect of PSF on photoreceptor structure and final visual acuity. METHODS: Retrospective study of 61 cases with post-operative optical coherence tomography (OCT) performed within 12 weeks of surgery. Based on aetiology, cases were categorized into tractional retinal tears (TRT) group or atrophic round holes and dialyses (RHD) group to investigate the incidence and duration of PSF. A Kaplan-Meier graph was plotted to compare survival time of subfoveolar fluid for both groups. Following secondary reclassification of cases into those with and without PSF, the effect of PSF on final visual acuity and photoreceptor structure was investigated with Mann-Whitney U-test used for comparison. Spearman's correlation testing was used to probe associations between time to recorded resolution of PSF with final visual acuity and photoreceptor structure. RESULTS: Incidence of PSF was greater in the RHD group and persisted for longer compared with TRT group. No detectable adverse effect of PSF on final visual acuity was seen however an individual case of severe photoreceptor atrophy was observed. No significant correlation was found between the time to recorded resolution of PSF and the final visual acuity or to photoreceptor grading scores. CONCLUSIONS: A difference in incidence of PSF was detected between the aetiological groups. PSF was ubiquitous and slow to resolve in the RHD group. Most cases of PSF resolve without adverse sequelae; however, progressive photoreceptor atrophy and sub-optimal visual outcome may result in a minority. PMID- 26742872 TI - Comparison of 3 different releasable suture techniques in trabeculectomy. AB - PURPOSE: The use of releasable sutures provides an effective and simple way of titrating intraocular pressure (IOP) postoperatively. The purpose of this study was to compare the surgical outcome of 3 releasable suture techniques for closing scleral flaps in patients undergoing primary trabeculectomy. METHODS: The Wills Eye Glaucoma Research Center retrospectively reviewed the charts of patients who underwent primary trabeculectomy by 3 surgeons using 3 different releasable suture techniques. Ninety eyes of 90 glaucoma patients were divided into 3 groups by releasable suture technique (n = 30 eyes for each group). Main outcome measures included best-corrected visual acuity (BCVA), intraocular pressure (IOP), rate of surgical success, use of supplemental medical therapy, need for additional glaucoma surgery, and complications during suture removal. RESULTS: The BCVA and IOP were similar among the groups for all follow-up visits. As a determinant of success rate of trabeculectomy, mean decrease of IOP after surgery was over 30% in all groups (p = 0.43). The number of postoperative antiglaucomatous medications, number of complications, and need for an additional glaucoma surgery were similar in all groups (p = 0.40, p = 0.87, and p = 0.47, respectively). The differences in suture-related complications, defined as suture break or need for laser suture lysis, were not significant among the groups (p = 0.09). CONCLUSIONS: We found that the 3 most common surgical techniques had similar mechanisms of action. All techniques were safe and effective, yielding similar outcomes. All 3 techniques can be used for closing scleral flaps in patients undergoing primary trabeculectomy. PMID- 26742873 TI - Short-term results of platelet-rich plasma as adjuvant to 23-G vitrectomy in the treatment of high myopic macular holes. AB - PURPOSE: To investigate the short-term safety and efficacy of autologous platelet rich plasma (a-PRP) as adjuvant to pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling in the treatment of highly myopic macular holes (MH). METHODS: This was a prospective, nonrandomized interventional case series. Patients with MH associated with high myopia, with or without previous PPV, were included. All patients underwent 23-G PPV with the use of a-PRP. Anatomical and functional results of surgery were recorded. RESULTS: We included 7 eyes of 6 patients with highly myopic MH. Primary anatomical success was achieved in 7 out of 7 eyes. Mean best-corrected visual acuity improved by more than 1 line from baseline (0.66 +/- 0.36 LogMAR) to final visit (0.52 +/- 0.25 logMAR), but with no statistically significant difference (p = 0.246, Wilcoxon test). No surgical related complications were noticed. CONCLUSIONS: The use of a-PRP as adjuvant to PPV with ILM peeling is effective in the treatment of highly myopic MH. This approach may represent a valid alternative to the inverted ILM flap technique, with comparable visual and anatomical results and the advantage of a simpler procedure. Further studies are necessary to confirm its usefulness in the management of high myopic MH. PMID- 26742874 TI - Prevalence and risk factors of vision impairment among children of employees of Telecom, Italy. AB - PURPOSE: To define the prevalence, causes, and risk factors of vision impairment (VI) in children. METHODS: In this study, relatives of Association for Supplemental Health Insurance to the Employees of Telecom members aged 5-16 years were examined in all Italian regions. A standardized record card was used to collect data on medical history; keratometry; objective refraction; uncorrected, presenting, and best-corrected visual acuity (VA); examination of the pupils, adnexa, and anterior segment; direct ophthalmoscopy; posterior segment and fundus examination; and assessment for ocular pathology. Binocular and monocular VI were defined by a VA <5/10 (or <20/40). RESULTS: The campaign included 17,508 children, 12,798 of whom (73.1%) were examined (and 12,740 on whom all VA data were gathered). The prevalence of uncorrected, presenting, and best-corrected VI in the better eye was 9.0%, 2.51%, and 0.10%, respectively. The following variables were associated with presenting VI: age 10-16 years, family history of myopia, female sex, family history of keratoconus, and hypertension. Myopia is the main cause of VI (82.6%). A total of 96% of children with presenting VI had correctable VI. CONCLUSIONS: Correctable VI because of myopia is an important public health problem in school-age children in Italy. PMID- 26742875 TI - Resolution of vitreomacular traction and pigment epithelium detachment. AB - PURPOSE: To report a case of spontaneous combined resolution of vitreomacular traction (VMT) and pigment epithelial detachment (PED). METHODS: A 70-year-old woman presented with a 10-day history of metamorphopsia in her right eye. Medical history was unremarkable. The patient underwent a complete ophthalmic examination. Best-corrected visual acuity (BCVA) was 20/50 in the right eye. Fundus examination, fluorescein angiography, indocyanine green angiography, and optical coherence tomography (OCT) revealed a shallow elevated area with irregular edges suggestive of drusenoid avascular PED associated with VMT. RESULTS: During the follow-up, OCT showed combined resolution of VMT and PED with almost complete normalization of the outer retinal layers; BCVA increased to 20/40. CONCLUSIONS: The temporal sequence of events in our case strongly suggests that the spontaneous resolution of PED could be the consequence of or could be favorably influenced by the VMT resolution. PMID- 26742876 TI - Tirofiban as treatment for acute retinal artery occlusion following internal carotid artery flow diverter implantation. AB - PURPOSE: To report a favorable outcome of branch retinal artery occlusion (BRAO) treated by means of early administration of tirofiban, a glycoprotein IIb-IIIa platelet receptor inhibitor. METHODS: Case report. RESULTS: A 65-year-old woman developed dramatic visual impairment in her left eye secondary to BRAO after left internal carotid artery endovascular reconstruction with flow diverter stent implant; visual acuity was hand motion. A dose of intravenous tirofiban was injected 10 minutes after symptoms onset. Fourteen hours after drug infusion, retinal fluorescein angiography revealed a well-perfused macula with a partial reperfusion of the inferior temporal branch of the central retinal artery; visual acuity was 20/20 in both eyes. CONCLUSIONS: This case supports the effectiveness of tirofiban in secondary BRAO in neurosurgery and may open its usage to further research. PMID- 26742877 TI - Comparison of refractive error in phacovitrectomy for epiretinal membrane using ultrasound and partial coherence interferometry. AB - PURPOSE: To compare the postoperative refractive error (RE) using A-scan ultrasound (US) and partial coherence interferometry (PCI) after phacovitrectomy for idiopathic epiretinal membrane (iERM) and cataract. METHODS: Eighty-eight participants (88 eyes) with iERM and cataracts underwent phacovitrectomies with internal limiting membrane removal. Postoperative RE was the main outcome measured, calculated by subtracting intended spherical equivalent (SE) from 6 month postoperative SE. Secondary outcomes included axial length (AL) measured by 2 methods, change in best-corrected visual acuity (BCVA), and change in central subfield thickness (CSFT). RESULTS: Mean postoperative RE using US showed greater myopic shift compared with that using PCI (-0.569 +/- 0.571 D vs -0.169 +/- 0.415 D, respectively, p<0.001). The 6-month postoperative RE was within +/-0.50 D in 43.2% (38/88) using US vs 84.1% (74/88) using PCI and within +/-1.00 D in 84.1% (74/88) using US vs 96.6% (85/88) using PCI. Mean AL measured by US was shorter than that measured by PCI (23.50 +/- 1.27 mm vs 23.58 +/- 1.30 mm, respectively, p<0.001). Postsurgery, BCVA improved from 0.374 +/- 0.264 logMAR to 0.144 +/- 0.124 logMAR (p<0.001), and CSFT decreased from 449.2 +/- 78.5 um to 378.2 +/- 47.0 um (p<0.001). The BCVA improvement significantly correlated with decreased CSFT (R = 0.268, p = 0.011). CONCLUSIONS: Estimation of intraocular lens power for phacovitrectomies for iERM and cataracts is more accurate when assessed by PCI than by US. PMID- 26742878 TI - Frustration of Negative Capacitance in Al2O3/BaTiO3 Bilayer Structure. AB - Enhancement of capacitance by negative capacitance (NC) effect in a dielectric/ferroelectric (DE/FE) stacked film is gaining a greater interest. While the previous theory on NC effect was based on the Landau-Ginzburg Devonshire theory, this work adopted a modified formalism to incorporate the depolarization effect to describe the energy of the general DE/FE system. The model predicted that the SrTiO3/BaTiO3 system will show a capacitance boost effect. It was also predicted that the 5 nm-thick Al2O3/150 nm-thick BaTiO3 system shows the capacitance boost effect with no FE-like hysteresis behavior, which was inconsistent with the experimental results; the amorphous Al2O3/epitaxial-BaTiO3 system showed a typical FE-like hysteresis loop in the polarization - voltage test. This was due to the involvement of the trapped charges at the DE/FE interface, originating from the very high field across the thin Al2O3 layer when the BaTiO3 layer played a role as the NC layer. Therefore, the NC effect in the Al2O3/BaTiO3 system was frustrated by the involvement of reversible interface charge; the highly stored charge by the NC effect of the BaTiO3 during the charging period could not be retrieved during the discharging process because integral part of the polarization charge was retained within the system as a remanent polarization. PMID- 26742879 TI - Safety and Effectiveness of Endovenous Laser Ablation Combined With Ligation for Severe Saphenous Varicose Veins in Japanese Patients. AB - Endovenous laser ablation (EVLA), which is a relatively new therapeutic option for saphenous varicose veins of the legs, is less invasive than conventional stripping surgery with ligation. In this study, we evaluated the safety and effectiveness of EVLA combined with ligation for severe saphenous varicose veins that were graded as >= C4 by the CEAP classification. We treated 119 Japanese patients (141 limbs) between July 2005 and December 2007 utilizing a 1320-nm Nd:YAG laser. The obliteration rate of the treated veins was found to be 100% over the entire follow-up period (2.5 years). Consistent with this finding, all of the patients exhibited improved skin lesions (ie, skin pigmentation and ulceration). No major complications, including deep vein thrombosis (DVT) and nerve injury, were observed. A questionnaire survey with a reasonable response rate (66.4%) demonstrated that subjective symptoms and minor complications that were initially observed after EVLA, such as mild pain, numbness, indurations, and localized hot flashes, were remarkably improved by the end of the follow-up period. Furthermore, high levels of patient satisfaction were noted. Thus, EVLA combined with ligation constituted a safe and effective strategy for treating severe saphenous varicose veins in Japanese patients. PMID- 26742880 TI - Elevation of Derivatives of Reactive Oxygen Metabolites Elevated in Young "Disaster Responders" in Hypertension due to Great East Japan Earthquake. AB - There have been very few studies on serum biomarkers associated with hypertension in disaster situations. We assessed biomarkers associated with disaster-related hypertension (DRH) due to the Great East Japan Earthquake of March 2011.We collected blood samples from members of the Japan Self Defense Forces (JSDF) (n = 77) after completing disaster relief operations. We divided them into two groups based on systolic blood pressure. We defined DRH as either systolic blood pressure greater than 140 mmHg or diastolic blood pressure greater than 90 mmHg at the time of completing missions.In subjects with DRH, the mean blood pressure was 143.5 +/- 5.0/99.5 +/- 2.4 mmHg. Height and body weight measurements were slightly greater in the DRH group but the differences were not significant, and age was significantly higher in the DRH group. There were no differences in serum biochemical tests including metabolic markers, sulfur-containing amino acids, and cytokines. Among nitric oxide-related amino acids, asymmetric dimethylarginine (ADMA) was lower in the DRH group than in the normotension group (0.40 +/- 0.02 versus 0.31 +/- 0.02 MUmol/L P = 0.04). The serum oxidative stress metabolite levels (d-ROMs; indicators of active oxygen metabolite products) were significantly higher in the DRH group (273.6 +/- 6.08 versus 313.5 +/- 13.7 U.CARR P = 0.016). Using multivariable regression analysis, d-ROMs levels were particularly predictive for DRH.Oxidative stress is associated with DRH in responders to the disaster of the Great East Japan Earthquake. PMID- 26742881 TI - Tolvaptan Prolongs Blockage of the Vasopressin Type II Receptor Over 24 Hours in Responders With Stage D Heart Failure. AB - The urine aquaporin-2 (U-AQP2) level relative to the plasma arginine vasopressin (P-AVP) level is a novel predictor of the responsiveness to the vasopressin type 2 receptor (V2R) antagonist tolvaptan (TLV). However, little has been reported about the concentration-time profile of U-AQP2 after TLV treatment. We evaluated 24 patients with decompensated stage D heart failure (HF) who had received 3.75 mg/day of TLV on a de novo basis for > 7 days to treat congestion refractory to conventional diuretics. Seventeen patients were TLV-responders, whose 24-hour urine volume (UV) increased after TLV initiation; the other 7 patients were TLV non-responders. The U-AQP2 of the TLV-responders, corrected for the urine creatinine concentration, decreased significantly at 4 hours after TLV administration without returning to the day-1 morning level on the morning of day 7. The TLV-non-responder U-AQP2 levels remained low even before the TLV treatment. On the morning of day-7, the TLV-responder U-AQP2/P-AVP ratio was comparable to that of the TLV-non-responders. Among 18 patients (11 responders and 7 non-responders), the day-7 TLV trough concentration was 64 +/- 62 ng/mL and was negatively correlated with the estimated glomerular filtration rate (eGFR). TLV has antagonistic effects on the V2R over 24 hours in TLV-responders with advanced heart failure and chronic kidney disease, probably due to persistently elevated blood TLV concentration. The unresponsiveness to TLV in the TLV-non responders is not attributable to malabsorption. PMID- 26742882 TI - The Relationships Between the Arterial Stiffness Index Measured at the Radial Artery and Left Ventricular Diastolic Dysfunction in Asymptomatic High Risk Patients Without Atherosclerotic Cardiovascular Disease. AB - Arterial stiffness is associated with atherosclerosis and left ventricular (LV) diastolic function in general or hypertensive patients. However, the relationships between the arterial stiffness index measured at the radial artery and LV diastolic dysfunction in asymptomatic high-risk patients without atherosclerotic cardiovascular disease (ASCVD) have not been fully established.A total 532 statin-naive patients (male:female ratio, 230:302, mean age, 56.0 +/- 9.2 years) without ASCVD were enrolled from among subjects who simultaneously underwent transthoracic echocardiography and noninvasive semiautomated radial artery applanation tonometry from July 2011 to May 2014. Of these patients, 213 were categorized as the statin benefit group (Benefit) according to guidelines for blood cholesterol treatment, and the rest were placed in the nonbenefit control group (NoBenefit). Each group was subdivided into two groups (Y or N) according to antihypertensive medication administration. Thus, there were 4 groups: BenefitN (n = 80), BenefitY (n = 133), NoBenefitN (n = 251), and NoBenefitY (n = 68). There were significant differences in echocardiographic parameters of LV function and indices of arterial stiffness between the Benefit and NoBenefit groups. After adjusting for several risk factors, independent significant associations between echocardiographic parameters of LV diastolic function and arterial indices were identified with multivariate linear regression analysis in the Benefit patients.Parameters of arterial stiffness measured at the radial artery are associated with echocardiographic indices of LV diastolic function in asymptomatic high-risk patients without ASCVD. Therapies that prevent progression of arterial stiffness and reduce late-systolic pressure overload may help to reduce the prevalence of LV diastolic dysfunction in this population. PMID- 26742883 TI - Long-Term Adaptive Servo-Ventilator Treatment Prevents Cardiac Death and Improves Clinical Outcome. AB - Adaptive servo-ventilation (ASV) is a recently developed, noninvasive therapeutic tool for the treatment of heart failure (HF). However, the efficacy of ASV therapy in patients with advanced HF remains uncertain, especially as regards its contribution to freedom from cardiac replacement therapy. A total of 85 patients with advanced HF (New York Heart Association [NYHA] class IV 71%, inotrope infusion-dependent 34%) refractory to guideline-directed medical therapy, received ASV therapy, irrespective of sleep-disordered breathing, at our institute between 2008 and 2014. Among these 85 patients, 46 continued ASV therapy for > 1 month (continued group), whereas 39 discontinued the therapy after < 1 month because of intolerance (discontinued group). There were no significant differences in baseline variables between the two groups. Heart rate indicating sympathetic activity, left ventricular (LV) reverse remodeling assessed by LV diastolic diameter, LV ejection fraction, and the grades of mitral and tricuspid regurgitations, HF severity assessed by NYHA class and plasma level of B-type natriuretic peptide, and end-organ dysfunction, improved significantly at 6 months following the initiation of ASV therapy (P < 0.05 for all). All-cause mortality and cardiac death rate were significantly lower during 2-year follow up in the continued group (P < 0.05 for both). In conclusion, ASV is a novel therapeutic tool prior to cardiac replacement therapy in patients with advanced HF and may prolong the period until cardiac replacement therapy becomes necessary. PMID- 26742884 TI - Aberrant Glycosylation of Lumican in Aortic Valve Stenosis Revealed by Proteomic Analysis. AB - To identify proteins related to the pathophysiology of aortic valve stenosis (AS), we investigated the protein profiles of AS aortic valves. Specifically, proteins were extracted from a thickened and calcified area (AS-C) and an apparently non-thickened and non-calcified area (AS-N) in an identical aortic valve leaflet in each of 6 AS patients. The proteins were then separated by 2 dimensional gel electrophoresis (2DE). Protein spots detected by 2DE were compared between the AS-C and AS-N samples. Protein spots of interest were subjected to protein identification by mass spectrometry.In total, 670 protein spots were detected by 2DE, 28 of which showed more than 1.5-fold different intensity (P < 0.05) between the AS-C and AS-N samples. Proteins were identified in 17 out of the 28 spots. Fibrinogen and lumican were identified in 9 and 3 spots, respectively. Intensity of these 12 spots was lower in the AS-C samples than in the AS-N samples. In the 1D-Western blot analysis, 4 lumican bands (80 kDa, 75 kDa, 65 kDa, and 53 kDa) were detected, of which 2 bands with 80 kDa and 75 kDa showed lower intensity in the AS-C samples than in the AS-N samples. When de-glycosylated protein samples were used in the 1D-Western blot, only a single lumican band with ~40 kDa was detected, indicating that lumican was variously glycosylated and that highly glycosylated lumican molecules were decreased in AS C.Collectively, insufficient glycosylation of lumican in the thickened and calcified areas of AS aortic valves may be involved in the pathophysiology of AS. PMID- 26742885 TI - Obesity Is Associated With the Development of Interstitial Pneumonia Under Long Term Administration of Amiodarone in Refractory Atrial Fibrillation Patients. AB - Although oral amiodarone (AMD) has been used for the management of atrial fibrillation (AF), serious complications such as interstitial pneumonia (IP) occur very occasionally. We evaluated which factors were associated with the development of IP under the long-term administration of AMD in patients with refractory AF.This study included 122 consecutive patients (65.8 +/- 11.4 years, mean body mass index [BMI] of 23.2 +/- 4.3 kg/m(2)) who orally received AMD to inhibit AF between January 2004 and December 2013. Administration of AMD was begun at 400 mg daily as a loading dose, and was continued at a dosage of 50-400 mg daily after the initial loading phase, determined by the control of the arrhythmias and occurrence of side-effects. The clinical factors were compared between the patients with and without adverse effects, especially IP.During an average follow-up period of 49.2 +/- 28.2 months, 53 patients (43.4%) were determined to have converted and maintained sinus rhythm. In contrast, adverse effects were detected in 46 patients (37.7%) with AMD. IP occurred in 8 patients (6.6%), thyrotoxicosis in 35 (28.7%), and others in 5 (4.1%). Four (50.0%) out of 8 patients complicated with IP had obesity (BMI > 27 kg/m(2)). Among the clinical factors, only obesity was significantly associated with the development of IP (P = 0.026).In patients with refractory AF, AMD had an antiarrhythmic effect with long-term administration, but greater adverse effects were also observed. Obesity was the most significant factor associated with the development of IP. PMID- 26742887 TI - Cross-Sectional Study of Characteristics of Owners and Nonowners Surrendering Cats to Four Australian Animal Shelters. AB - Unwanted cats surrendered to nonhuman animal shelters are generally categorized as either "owned" or "stray." This classification is misleading because "stray" cats may include many "semiowned" cats, for which people provide care but who are not perceived as being owned. This differentiation is important because effective strategies designed to reduce cat admissions to, and euthanasia rates in, shelters rely on accurate information about cat populations contributing to shelter intake; cat semiowners will likely respond to different strategies than people with no relationship with the cats they surrender. People surrendering cats to four Australian animal shelters were surveyed to identify factors associated with perception of ownership. Many self-classified nonowners had fed the cats they surrendered, often for a considerable period of time. The factor most strongly associated with ownership perception was an increasing association time with the cat. These findings confirm that enduring relationships between surrenderers and cats, consistent with cat semiownership, are common for cats surrendered to Australian animal shelters. This finding should be taken into account when planning education messages and cat population management strategies aimed at reducing cat admissions. PMID- 26742886 TI - Thermodynamics and kinetics of amphotericin B self-association in aqueous solution characterized in molecular detail. AB - Amphotericin B (AmB) is a potent but toxic drug commonly used to treat systemic mycoses. Its efficiency as a therapeutic agent depends on its ability to discriminate between mammalian and fungal cell membranes. The association of AmB monomers in an aqueous environment plays an important role in drug selectivity, as oligomers formed prior to membrane insertion - presumably dimers - are believed to act differently on fungal (ergosterol-rich) and mammalian (cholesterol-rich) membranes. In this work, we investigate the initial steps of AmB self-association by studying the structural, thermodynamic and spectral properties of AmB dimers in aqueous medium using molecular dynamics simulations. Our results show that in water, the hydrophobic aggregation of AmB monomers yields almost equiprobable populations of parallel and antiparallel dimers that rapidly interconvert into each other, and the dipole-dipole interaction between zwitterionic head groups plays a minor role in determining the drug's tendency for self-aggregation. A simulation of circular dichroism (CD) spectra indicates that in experimental measurements, the signature CD spectrum of AmB aggregates should be attributed to higher-order oligomers rather than dimers. Finally, we suggest that oligomerization can impair the selectivity of AmB molecules for fungal membranes by increasing their hydrophobic drive for non-specific membrane insertion. PMID- 26742888 TI - Increases in Anthropogenic Gadolinium Anomalies and Rare Earth Element Concentrations in San Francisco Bay over a 20 Year Record. AB - We evaluated both the spatial distribution of gadolinium (Gd) and other rare earth elements (REE) in surface waters collected in a transect of San Francisco Bay (SFB) and their temporal variations within the Bay over two decades. The REE were preconcentrated using the NOBIAS PA-1 resin prior to analysis by high resolution inductively coupled plasma mass spectrometry. Measurements revealed a temporal increase in the Gd anomaly in SFB from the early 1990s to the present. The highest Gd anomalies were observed in the southern reach of SFB, which is surrounded by several hospitals and research centers that use Gd-based contrast agents for magnetic resonance imaging. Recent increases in that usage presumably contributed to the order of magnitude increase in anthropogenic Gd concentrations in SFB, from 8.27 to 112 pmol kg(-1) over the past two decades, and reach the northeast Pacific coastal waters. These measurements (i) show that "exotic" trace elements used in new high-tech applications, such as Gd, are emerging contaminants in San Francisco Bay and that anthropogenic Gd concentrations increased substantially over a 20 year period; (ii) substantiate proposals that REE may be used as tracers of wastewater discharges and hydrological processes; and (iii) suggest that new public policies and the development of more effective treatment technologies may be necessary to control sources and minimize future contamination by REE that are critical for the development of new technologies, which now overwhelm natural REE anomalies. PMID- 26742889 TI - Profiling the Secretome of Human Stem Cells from Dental Apical Papilla. AB - Recent studies have shown that secretion of bioactive factors from mesenchymal stem cells (MSCs) plays a primary role in MSC-mediated therapy; especially for bone marrow-derived MSCs (BMSCs). MSCs from dental apical papilla (SCAPs) are involved in root development and may play a critical role in the formation of dentin and pulp. Bioactive factors secreted from SCAPs actively contribute to their environment; however, the SCAPs secretome remains unclear. To address this and gain a deeper understanding of the relevance of SCAPs secretions in a clinical setting, we used isobaric chemical tags and high-performance liquid chromatography with tandem mass spectrometry to profile the secretome of human SCAPs and then compared it to that of BMSCs. A total of 2,046 proteins were detected from the conditioned medium of SCAPs, with a false discovery rate of less than 1.0%. Included were chemokines along with angiogenic, immunomodulatory, antiapoptotic, and neuroprotective factors and extracellular matrix (ECM) proteins. The secreted levels of 151 proteins were found to differ by at least twofold when BMSCs and SCAPs were compared. Relative to BMSCs, SCAPs exhibited increased secretion of proteins that are involved in metabolic processes and transcription and lower levels of those associated with biological adhesion, developmental processes, and immune function. In addition, SCAPs secreted significantly larger amounts of chemokines and neurotrophins than BMSCs, whereas BMSCs secreted more ECM proteins and proangiogenic factors. These results may provide important clues regarding the molecular mechanisms associated with tissue regeneration and how they differ between cell sources. PMID- 26742890 TI - Protein-targeted corona phase molecular recognition. AB - Corona phase molecular recognition (CoPhMoRe) uses a heteropolymer adsorbed onto and templated by a nanoparticle surface to recognize a specific target analyte. This method has not yet been extended to macromolecular analytes, including proteins. Herein we develop a variant of a CoPhMoRe screening procedure of single walled carbon nanotubes (SWCNT) and use it against a panel of human blood proteins, revealing a specific corona phase that recognizes fibrinogen with high selectivity. In response to fibrinogen binding, SWCNT fluorescence decreases by >80% at saturation. Sequential binding of the three fibrinogen nodules is suggested by selective fluorescence quenching by isolated sub-domains and validated by the quenching kinetics. The fibrinogen recognition also occurs in serum environment, at the clinically relevant fibrinogen concentrations in the human blood. These results open new avenues for synthetic, non-biological antibody analogues that recognize biological macromolecules, and hold great promise for medical and clinical applications. PMID- 26742891 TI - Automatic Cataract Hardness Classification Ex Vivo by Ultrasound Techniques. AB - To demonstrate the feasibility of a new methodology for cataract hardness characterization and automatic classification using ultrasound techniques, different cataract degrees were induced in 210 porcine lenses. A 25-MHz ultrasound transducer was used to obtain acoustical parameters (velocity and attenuation) and backscattering signals. B-Scan and parametric Nakagami images were constructed. Ninety-seven parameters were extracted and subjected to a Principal Component Analysis. Bayes, K-Nearest-Neighbours, Fisher Linear Discriminant and Support Vector Machine (SVM) classifiers were used to automatically classify the different cataract severities. Statistically significant increases with cataract formation were found for velocity, attenuation, mean brightness intensity of the B-Scan images and mean Nakagami m parameter (p < 0.01). The four classifiers showed a good performance for healthy versus cataractous lenses (F-measure >= 92.68%), while for initial versus severe cataracts the SVM classifier showed the higher performance (90.62%). The results showed that ultrasound techniques can be used for non-invasive cataract hardness characterization and automatic classification. PMID- 26742892 TI - Ultrasonographic Assessment of Fifth Metatarsophalangeal Joint Erosion in Rheumatoid Arthritis: Which Aspect Is Better? AB - In this study, the best ultrasound (US) aspect for detection of fifth metatarsophalangeal (MTP) joint erosions, the most frequently eroded joint, in rheumatoid arthritis (RA) patients is investigated. Forty-eight RA patients (F/M = 35/13, mean age and disease durations 50.3 +/- 11.8 and 7.9 +/- 6.9 y, respectively) were evaluated by B-mode US for erosion. Images were obtained from the dorsal, lateral and plantar aspect of the fifth MTP joint, in longitudinal and transverse scans. The fifth MTP erosions were detected in 36 of 48 patients (75%) and 67 of 96 feet (69.8%). Of the erosions, 15 (22.4%), 53 (79.1%) and 59 (88.0%) were observed at dorsal, lateral and plantar aspects, respectively. Despite not being statistically different, the detection rate of fifth MTP erosions was numerically higher in the plantar aspect than both the lateral and dorsal aspects. In conclusion, the fifth MTP erosions in RA patients are more commonly detected in the plantar aspect US than in dorsal and lateral assessments. PMID- 26742893 TI - Effects of Low-Intensity Pulsed Ultrasound on Orthodontic Tooth Movement and Orthodontically Induced Inflammatory Root Resorption in Ovariectomized Osteoporotic Rats. AB - This study investigated the effects of low-intensity pulsed ultrasound (LIPUS) on orthodontic tooth movement (OTM) and orthodontically induced inflammatory root resorption (OIRR) in ovariectomized osteoporotic rats. Forty-eight 28-d-old female Wistar rats were divided into ovariectomized and intact groups. In both groups, animals were left untreated; treated with 50 g mesially directed orthodontic force on the maxillary first molars using nickel-titanium closed-coil springs for 28 d; or treated with the same orthodontic protocol along with a 20 min LIPUS application on alternate days for 28 d. Extent of OTM and amount of OIRR of mesial roots were measured on three-dimensionally reconstructed micro computed tomography images. Ovariectomy increased OIRR (p < 0.05). LIPUS reduced root volumetric loss regardless of ovariectomy status (p < 0.05); only ovariectomized animals had decreased OTM (p < 0.05). LIPUS normalizes OTM and attenuates OIRR in ovariectomized osteoporotic rats. It may therefore be beneficial in women with postmenopausal osteoporosis. PMID- 26742894 TI - Investigation of Ultrasound-Measured Flow Rate and Wall Shear Rate in Wrist Arteries Using Flow Phantoms. AB - The aim of this study was to evaluate the errors in measurement of volumetric flow rate and wall shear rate measured in radial and ulnar arteries using a commercial ultrasound scanning system. The Womersley equations were used to estimate the flow rate and wall shear rate waveforms, based on the measured vessel diameter and centerline velocity waveform. In the experiments, each variable (vessel depth, diameter, flow rate, beam-vessel angle and different waveform) in the phantom was investigated in turn, and its value was varied within a normal range while others were fixed at their typical values. The outcomes revealed that flow rate and wall shear rate were overestimated in all cases, from around 13% to nearly 50%. It is concluded that measurements of flow rate and wall shear rate in radial and ulnar arteries with a clinical ultrasound scanner are vulnerable to overestimation. PMID- 26742895 TI - Automated Breast Volume Scanning: Identifying 3-D Coronal Plane Imaging Features May Help Categorize Complex Cysts. AB - The study described here sought to identify specific ultrasound (US) automated breast volume scanning (ABVS) features that distinguish benign from malignant lesions. Medical records of 750 patients with 792 breast lesions were retrospectively reviewed. Of the 750 patients, 101 with 122 cystic lesions were included in this study, and the results ABVS results were compared with biopsy pathology results. These lesions were classified into six categories based on ABVS sonographic features: type I = simple cyst; type II = clustered cyst; type III = cystic masses with thin septa; type IV = complex cyst; type V = predominantly cystic masses; and type VI = predominantly solid masses. Comparisons were conducted between the ABVS coronal plane features of the lesions and histopathology results, and the positive predictive value (PPV) was calculated for each feature. Of the 122 lesions, 90 (73.8%) were classified as benign, and 32 (26.2%) were classified as malignant. The sensitivity, specificity and accuracy associated with ABVS features for cystic lesions were 78.1%, 74.4% and 75.4%, respectively. The 11 cases (8.9%) of type I-IV cysts were all benign. Of the 22 (18.0%) type V cysts, 16 (13.1%) were benign and 6 (4.9%) were malignant. Of the 89 (72.9%) type VI cysts, 63 (51.7%) were benign and 26 (21.3%) were malignant. The typical symptoms of malignancy on ABVS include retraction (PPV = 100%, p < 0.05), hyper-echoic halos (PPV = 85.7%, p < 0.05), microcalcification (PPV = 66.7%, p < 0.05), thick walls or thick septa (PPV = 62.5%, p < 0.05), irregular shape (PPV: 51.2%, p < 0.05), indistinct margin (PPV: 48.6%, p < 0.05) and predominantly solid masses with eccentric cystic foci (PPV = 46.8%, p < 0.05). ABVS can reveal sonographic features of the lesions along the coronal plane, which may be of benefit in the detection of malignant, predominantly cystic masses and provide high clinical values. PMID- 26742896 TI - In-vivo Axial-strain Sonoelastography Helps Distinguish Acutely-inflamed from Fibrotic Terminal Ileum Strictures in Patients with Crohn's Disease: Preliminary Results. AB - We tested real-time sonoelastography (RTS) in-vivo to differentiate fibrotic from inflammatory terminal ileum strictures in patients with Crohn's disease (CD), using magnetic resonance enterography (MRE) as a reference standard. Sixteen patients (13 male, 3 female; median [interquartile interval] age = 41 [31-48.5] y; median C-reactive protein (CRP) = 0.95 [0-2.23] mg/dL; median disease duration = 108.5 [35-213.75] mo; median Harvey-Bradshaw Index (HBI) = 3 [3-5.25]) with terminal ileum CD were prospectively included. Short-axis scans were performed; each cross-section was ideally sub-divided into eight circular sectors. Color map provided by RTS was translated into semi-quantitative scale (1 = red; 2 = green; 3 = blue). At MRE, inflammation was seen in nine patients and fibrosis in seven. Total median RTS score was significantly lower in patients with inflammatory stricture (16 [16-18]) than in patients with fibrosis (20 [17.5-22]; p = 0.003). The same happened when the four most superficial quadrants of the loop were considered (8 [7-9] vs. 10 [9-11.5]; p = 0.003). No significant correlation was seen between RTS and HBI (r = 0.467; p = 0.686), RTS and CRP (r = -0.750; p = 0.567) or RTS and disease duration (r = 0.238; p = 0.483). RTS of the terminal ileum in patients with CD is feasible in-vivo, potentially differentiating between fibrotic and inflammatory strictures. PMID- 26742897 TI - An integrated strategy to quantitatively differentiate chemome between Cistanche deserticola and C. tubulosa using high performance liquid chromatography-hybrid triple quadrupole-linear ion trap mass spectrometry. AB - It is important to conduct large-scale detection, identification, and quantitation of metabolites in a given sample. Herein, a practical strategy was proposed to quantitatively compare the chemome between Cistanche deserticola (CD) and C. tubulosa (CT), which have been widely believed as the ideal edible and medicinal plants for conquering the deserts. The entire workflow was implemented on high performance liquid chromatography-hybrid triple quadrupole-linear ion trap mass spectrometer and consisted of three primary steps: (1) component detection and identification, various mass spectrometric approaches were applied to globally screen the chemical constituents, and structural elucidation was achieved by comparing with authentic compounds, analyzing MS(2) spectra, and referring to the literature along with accessible databases; (2) comprehensive relative quantitation, scheduled multiple reaction monitoring algorithm was introduced for relative quantitation of all detected ingredients; and (3) chemome comparison, the quantitative dataset was subjected for multivariate statistical analysis to carry out comparative study. A total of 513 metabolites were detected and relatively quantitated, and 379 ones were annotated. Betaine, Krebs cycle intermediates, phenylethanoid glycosides, and iridoids were picked out as the chemical markers being responsible for the discrimination of the chemical profiles between CD and CT. Above all, the quantitative chemome of CD and CT were exhaustively characterized and compared, which could advance their values concerning drug development, economics, and desertification control. The proposed strategy is expected as a reliable choice for widely targeted metabolomics of plants. PMID- 26742898 TI - Extraction and purification methods in downstream processing of plant-based recombinant proteins. AB - During the last two decades, the production of recombinant proteins in plant systems has been receiving increased attention. Currently, proteins are considered as the most important biopharmaceuticals. However, high costs and problems with scaling up the purification and isolation processes make the production of plant-based recombinant proteins a challenging task. This paper presents a summary of the information regarding the downstream processing in plant systems and provides a comprehensible overview of its key steps, such as extraction and purification. To highlight the recent progress, mainly new developments in the downstream technology have been chosen. Furthermore, besides most popular techniques, alternative methods have been described. PMID- 26742899 TI - No Place Like Home? Surveillance and What Home Means in Old Age. AB - New surveillance technologies like those included in ambient assisted living - such as body-worn and passive environmental sensors, smart interfaces, and communications networks - are being developed to improve the security and safety of "at risk" older people, but ethical questions have been raised about the extent to which they compromise the rights and privacy of the people being monitored. The qualitative study we conducted was designed to help us understand the ways these novel surveillance technologies would influence individuals' everyday experiences of home. Participants felt new forms of surveillance would influence their sense of security, autonomy, and self-confidence, and would alter perceptions of home. The findings emphasize the need to improve our understanding of how ambient assisted living will affect the lives of those being monitored. PMID- 26742900 TI - RP105 protects against myocardial ischemia-reperfusion injury via suppressing TLR4 signaling pathways in rat model. AB - Myocardial ischemia-reperfusion (I/R) injury severely impacts the postoperative survival rate of coronary atherosclerotic heart disease. Radioprotective 105 kDa protein (RP105) is a regulator of Toll-like receptor 4 (TLR4), an inflammatory factor whose functions have been reported in myocardial I/R injury. To investigate the roles of RP105 in mediating myocardial I/R injury, we overexpressed RP105 by injecting its adenovirus vectors, and induced myocardial I/R injury rat model in this study. Myocardial structure injuries of rat hearts were examined by hematoxylin eosin staining, and myocardial infarct area was calculated after Evans blue and triphenyltetrazolium chloride dual staining. Expression changes of TLR4, myeloid differentiation factor 88 (MyD88), and nuclear factor kappaB (NF-kappaB) in myocardia were detected by quantitative real time PCR and Western blot. Amount changes of tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) were detected by enzyme-linked immunosorbent assay. Results showed that RP105 attenuated myocardial injuries and effectively reduced myocardial infarct area after I/R (P<0.05). RP105 was also proved to significantly inhibit TLR4 and downstream inflammatory factors MyD88, NF-kappaB, TNF-alpha and IL-6 (P<0.05), whose expression levels were up-regulated by I/R induction. These results indicated that RP105 could protect against myocardial I/R injury via suppressing inflammatory responses mediated by TLR4 signaling pathways. This study revealed the anti-inflammatory roles of RP105 and its potential in preventing and treating myocardial I/R injury. PMID- 26742901 TI - Effects of omega-3 polyunsaturated fatty acids on human brain morphology and function: What is the evidence? AB - Public opinion and media coverage suggest that there are benefits of long-chain omega-3 polyunsaturated fatty acid (LC-PUFA) intake on brain functioning. However, it is an open question whether this is indeed the case. Therefore, we reviewed the evidence for effects of omega-3 LC-PUFA on human brain morphology and function. We included studies on (1) naturalistic long-term omega-3 LC-PUFA intake during life (2) the effects of short-term omega-3 LC-PUFA supplementation in healthy subjects and (3) the effects of omega-3 LC-PUFA supplementation as alternative or add-on treatment for psychiatric or neurological disorders. To date, 24 studies have been published on the effect of omega-3 LC-PUFA on brain function and structure. Findings from naturalistic studies and clinical trials in healthy individuals indicate that omega-3 LC-PUFA intake may be associated with increased functional activation of the prefrontal cortex in children, and greater gray matter volume and white matter integrity during aging. However, most naturalistic studies were cross-sectional or did not find any effect on cognition. As such, it is hard to estimate the magnitude of any beneficial effects. Furthermore, there is only limited evidence to support that omega-3 LC PUFA supplementation is beneficial in brain disorders, such as Alzheimer's Disease, Attention Deficit/Hyperactivity Disorder, Major Depressive Disorder and schizophrenia. Overall, the literature suggests that sensitivity to supplementation may vary over development, and as a consequence of brain disorders. The biological mechanisms underlying any (beneficial) effects omega-3 LC-PUFAs on the brain are currently unknown and need to be investigated. PMID- 26742902 TI - The Cemented Unipolar Prosthesis for the Management of Displaced Femoral Neck Fractures in the Dependent Osteopenic Elderly. AB - BACKGROUND: Significant variability exists across orthopedic surgeons in the management of the displaced femoral neck fracture in the elderly patient (>75 years old). These patients tend to be less healthy, have inferior bone quality, and gait instability leading to increased risk of periprosthetic fracture, compromised implant fixation, dislocation, and need for revision. The surgeon's goals should be to restore mobility while eliminating pain and need for reoperation. METHODS: In this review article, we examine the best available evidence in the literature to determine which strategy achieves optimal outcomes. We examine outcome studies comparing use of hemiarthroplasty and total hip arthroplasty, unipolar and bipolar hemiarthroplasty, and cemented vs cementless fixation of femoral stems. RESULTS AND CONCLUSIONS: For the active, healthy, and lucid patient, or one who has preexisting groin pain, who sustains a displaced femoral neck fracture, the literature supports a total hip arthroplasty. Patients sustaining a displaced femoral neck fracture and who are less active, have decreased bone mass, and are at increased risk of falls would benefit most from a device that optimally balances the need for revision surgery, restores ambulation, and eliminates pain. Thus, the current evidence favors cemented, unipolar hemiarthroplasty for the dependent osteopenic elderly patient with a displaced femoral neck fracture. PMID- 26742903 TI - Outcomes of Custom Flange Acetabular Components in Revision Total Hip Arthroplasty and Predictors of Failure. AB - BACKGROUND: Custom triflange acetabular components (CTAC) have become more popular in the treatment of Paprosky type IIIB defects with an average survivorship of 80% at 4 years. Many studies report survivorship of CTAC, but radiographic parameters of CTAC success or failure have not been previously reported. The purpose of the study was to assess radiographic and patient factors predictive of failure in CTAC. METHODS: A retrospective review of 63 patients with >24 months of follow-up was completed. Continuous and categorical variables were compared between failed vs successful CTAC using Wilcoxon rank-sum test and Fisher exact test, respectively. RESULTS: The failure rate of the CTAC was 13.5% over an average follow-up of 4.32 years (+/-2.94). Patients had a mean of 2 revisions (range, 0-11) before CTAC implantation. Compared with the contralateral hip center of rotation, the failed CTAC group tended to lateralize the hip center by a mean of 18.29 mm (+/-11.90 mm) compared to a mean of 9.86 mm (+/-11.89) in the intact group, although this did not reach statistical significance (P = .1029). The Western Ontario and McMaster Universities Osteoarthritis Index function score improved from 38.94 (+/-14.23) to 71.35 (+/-21.96) at most recent follow-up (P = .0002). The Western Ontario and MacMaster Universities Osteoarthritis Index scores were not significantly different between intact and failed CTAC groups. CONCLUSIONS: CTAC tends to lateralize the hip center by approximately 1 cm, and there is a trend toward nearly 2 cm of lateralization in the small subset of failed CTAC. Future efforts should focus on medializing the hip center in CTAC to improve ingrowth and survivorship. PMID- 26742904 TI - Vestibular evoked myogenic potentials in patients with ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is a chronic systemic inflammatory disease with unknown etiology. Although sacroiliac joint involvement is the classic sign along with the formed immune mediators, it may result in immune-mediated inner ear disease and may cause damage to the audiovestibular system. Vestibular evoked myogenic potentials (VEMP) is a clinical reflex test used in the diagnosis of vestibular diseases and is performed by recording and evaluating the muscle potentials resulting from the stimulation of the vestibular system with different stimuli. The aim of this study is to evaluate the cervical VEMP test results in AS patients without vestibular symptoms. Thirty-three patients with AS and a control group of 30 healthy volunteers with similar demographic characteristics were evaluated in the study. VEMP wave latency, P13-N23 wave amplitude, and VEMP asymmetry ratio (VAR) values were compared between the groups. The relationship between clinical and laboratory findings of the AS patients and VEMP data were also investigated. Compared with healthy people, this study shows the response rate of patients with ankylosing spondylitis was reduced in the VEMP test, and P13-N23 wave amplitude showed a decrease in AS patients who had VEMP response (p < 0.001). There was no correlation between the clinical and laboratory findings and VEMP findings in patients with ankylosing spondylitis. The data obtained from this study suggest that AS may lead to decreased sensitivity of the vestibular system. PMID- 26742905 TI - Is endoscopic ear surgery an alternative to the modified Bondy technique for limited epitympanic cholesteatoma? AB - The objective of this study is to evaluate the outcomes of the modified Bondy's technique performed at our center and for limited epitympanic cholesteatomas and to debate the purported benefits of endoscopic surgery for the same indication. This is a retrospective study. 269 ears of 258 patients with a minimum of 5-year follow-up that were operated for limited epitympanic cholesteatoma using the modified Bondy's technique were included in the study. All patients had primary acquired cholesteatoma with good preoperative hearing in the affected ear and an intact ossicular chain. The outcomes of were analyzed and the results were compared with a literature review of outcomes of endoscopic ear surgery for the same indication. The mean follow-up was 81.63 months. The mean preoperative air bone gap was 13.6 +/- 7 dB. Intraoperatively, the ossicular chain was preserved in all patients. Postoperatively, there was no significant change from preoperative levels in mean air conduction, mean bone conduction and the air-bone gap. There were no recurrent cholesteatomas in our series. A residual pearl-like cholesteatoma was found lateral to the tympanic membrane in 8.1 % of ears, which was removed in the outpatient clinic. Three patients (1.2 %) developed stenosis of the meatoplasty. Eight (3.1 %) ears exhibited retraction pockets involving the attic. Postoperative ear discharge was observed in 1.5 % cases. The modified Bondy technique, which provides excellent postoperative outcomes, is the surgery of choice for limited epitympanic cholesteatomas. The endoscope, despite its better visualization of hidden areas does not provide a distinct overall technical advantage or better results over the microscope. PMID- 26742906 TI - The effective stimulating pulse for restoration of blink function in unilateral facial nerve paralysis rabbits, verified by a simple FES system. AB - The trains of 200 ms biphasic square pulses with the width of 9 ms delivered at 50 Hz were found to be the most suitable and effective mean as stimulation in FES system of restoring the blink function in unilateral facial nerve paralysis rabbit model. FES system is a reliable tool for these patients. Facial paralysis affects thousands of people every year. Many will have long term facial difficulties and the loss of the ability to blink the eye, which can lead to potential loss of the eye. Although many treatments exist, no one approach corrects all the deficits associated with the loss of orbicularis oculi function. FES is a means of providing movement in paralysed muscles to assist with practical activities and one possible way of restoring blink and other functions in these patients. Although some previous researches had investigated the effect of simple FES system on restoration of paralyzed facial muscles, there is still controversy about the appropriate details of the most effective stimulating pulses, such as the frequency, wave pattern and pulse width. Our aim is to find out the parameters of the most appropriate and effective stimulatin verify it by a simple FES system. 24 healthy adult male New Zealand white rabbits were accepted the surgery of right side facial nerve main trunk transaction under general anesthesia as the unilateral facial nerve paralysis models. The platinum tungsten alloy electrodes were implanted in orbicularis oculi muscle. The parameters of stimulus pulses were set to a 200 ms biphasic pulse with different waveforms (square, sine and triangle), different frequencies (25, 50, 100 Hz) and different widths from 1 to 9 ms. Next, we set up a simple FES system to verify the previous results as the stimulus signal. We observed the movement of the both sides of eyelid when eye blink induced by different kinds of pulses. In all animals, the three kinds of waveforms pulse with frequency of 25 Hz could not evoke the smooth blink movement. But the pulses with frequency of 50 and 100 Hz can achieve this effect. The voltage threshold of the square pulse was lower than that of the sine pulse and triangle pulse. With the increase of pulse width from 1 to 9 ms, the voltage threshold decreased gradually. The voltage threshold of the pulse with frequency of 100 Hz was obviously lower than that of 50 Hz. But the amount of total charge of the stimulation pulse of 100 Hz was significantly more than that of 50 Hz. In addition, when the FES system was turned on, the eye blink on the affected side with the stimulation pulses that were set by the previous step results was successfully aroused by the blink movement as a trigger on the contralateral. PMID- 26742908 TI - Photocoagulation therapy for laryngeal dysplasia using angiolytic lasers. AB - In the management of laryngeal pre-cancerous lesions such as dysplasia or carcinoma in situ (CIS), it is important that lesion regression occur without any complications. As a minimally invasive treatment option, photocoagulation therapy using angiolytic lasers has been attracting attention. Therapeutic effects have been reported for this type of treatment, however, vocal function after treatment has not been well discussed. In this retrospective case series, we examined the therapeutic effects of photocoagulation therapy on laryngeal dysplasia and the impact on vocal function. Twenty-four patients with laryngeal dysplasia or CIS were treated with photocoagulation therapy using angiolytic lasers. Two patients were treated under general anesthesia, the remaining 22 patients were treated with topical anesthesia. Before and after treatment the extent of the lesion and vocal function was evaluated by endoscopic examination and acoustic and aerodynamic analyses, respectively. More than 50 % disease regression was observed in 20 of 24 patients. Acoustic and aerodynamic analyses revealed improvement in pitch perturbation quotient with no impairment in other parameters. Photocoagulation therapy using angiolytic lasers has proven to be feasible and safe for the treatment of laryngeal dysplasia. PMID- 26742907 TI - Short-term effect of caffeine on olfactory function in hyposmic patients. AB - The purpose of this study was to investigate the potential effects of caffeine in patients with olfactory loss. The suggested mechanisms of action consist in the non-selective blocking of adenosine receptors as well as inhibition of the phospodiesterase. Olfactory function was tested twice in 76 hyposmic patients either because of URTI or because of sinunasal causes. For definition of hyposmia and for later assessment of phenyl ethyl alcohol odor threshold, and odor discrimination the Sniffin Sticks data test was used. Using a double-blinded design, the participants were divided into two groups: one received a cup of espresso with caffeine (65 mg/cup), the other a cup of espresso without caffeine (placebo). Before and approximately 45 min after espresso consumption olfactory function was assessed. Across all participants, in comparison to placebo there was no significant effect of caffeine on olfactory function, regardless whether it was caused by an acute infection of the upper respiratory tract or sinunasal disease. These results indicate that-under the current conditions-the phosphodiesterase-inhibitor/adenosine-receptor agonist caffeine has little or no short-term effect on olfactory function in patients with olfactory loss. PMID- 26742909 TI - A survey on chronic rhinosinusitis: opinions from experts of 50 countries. AB - Chronic rhinosinusitis (CRS) is a very prevalent inflammatory disease. Treatments vary in different countries. In the present study, we explored the approaches of physicians in 50 countries. In this cross-sectional study, a rhinosinusitis survey (RSS) was completed by Honorary and Corresponding Members (otorhinolaryngologists) of the Italian Society of Rhinology. In 79.1 % of the 50 countries, the proportion of patients suffering from CRS was 15 %. Nasal symptoms were more intense in winter (46 % of countries), and spring and autumn (22 %). The most common symptoms were nasal obstruction (86 %), postnasal drip (82 %) and headache (52 %). The most common investigative modalities in the assessment of CRS are paranasal sinus CT, fiberoptic endoscopy, and anterior rhinoscopy. CRS patients were principally treated by otorhinolaryngologists (70 %). Medical treatments included nasal corticosteroids (90 %), nasal washes (68 %), and nasal decongestants (32 %). In 88 % of countries, more than 50 %, or "about 50 %", of all patients reported subjective symptom improvement after treatment. In most of the countries, surgery was required by 20-35 % of all CRS patients. During post surgery follow-up, nasal washes (90 %), nasal corticosteroids (76 %), and systemic antibiotics (32 %) were prescribed. In 20-40 % of all patients, CRS was associated with nasal polyps. In such patients, the medical treatment options were nasal corticosteroids (90 %), systemic corticosteroids (50 %), nasal washes (46 %), and systemic antibiotics (34 %). Treatment of CRS patients varies in different countries. Paranasal sinus CT is the most common investigative modality in the assessment of CRS, and nasal corticosteroids are the first-line treatment, in the absence or presence of nasal polyps. PMID- 26742910 TI - Endolymphatic duct blockage: quality of life assessment of a novel surgical technique for Meniere disease. AB - The aim of this study is to evaluate the quality of life (QOL) of patients treated by endolymphatic duct blockage (EDB) for Meniere's disease with a dedicated questionnaire. This is a retrospective cross-sectional study which included 54 patients diagnosed with severe, refractory Meniere's disease according to the AAO-HNS criteria and treated with EDB between 2010 and 2013. Answers to the first 38 questions have assigned scores from 0 to 4 (0 corresponding to the poorest QOL). A preoperative score called S1 was calculated as follows: S1 = sum of preoperative question scores/maximum possible preoperative score *100. The same formula was used to calculate the postoperative score S2. The change in QOL score, S3, was then calculated (S3 = S2-S1). All answers were analyzed anonymously. Statistical analysis was done using Student t test and Chi square test. A response rate of 89 % was obtained with the Meniere's disease outcome questionnaire. The preoperative (S1) score was 21.4 (+/-12.6) and the postoperative score (S2) was 64.6 (+/-21.6) with a change in QOL (S3) of 43.3 (p < 0.001). Postoperatively, 89.9 % reported no Meniere's attacks (p < 0.001). Seventy-nine percent (15/19) of the questions showed a significant improvement after surgery. These results show that EDB is associated with a significant improvement of the QOL of patients suffering from severe Meniere's disease. PMID- 26742911 TI - Study of Mast Cells and Granules from Primo Nodes Using Scanning Ionic Conductance Microscopy. AB - Acupuncture points have a notable characteristic in that they have a higher density of mast cells (MCs) compared with nonacupoints in the skin, which is consistent with the augmentation of the immune function by acupuncture treatment. The primo vascular system, which was proposed as the anatomical structure of the acupuncture points and meridians, also has a high density of MCs. We isolated the primo nodes from the surfaces of internal abdominal organs, and the harvested primo nodes were stained with toluidine blue. The MCs were easily recognized by their stained color and their characteristic granules. The MCs were classified into four stages according to the degranulation of histamine granules in the MCs. Using conventional optical microscopes details of the degranulation state of MCs in each stage were not observable. However, we were able to investigate the distribution of the granules on the surfaces of the MCs in each stage, and to demonstrate the height profiles and three-dimensional structures of the MCs without disturbance of the cell membrane by using the scanning ion conductance microscopy. PMID- 26742912 TI - Number Density of Mast Cells in the Primo Nodes of Rats. AB - Mast cells (MCs) play a major role in allergic reactions. Surprisingly, the acupuncture points have a higher density of MCs compared with nonacupoints in the skin, which is consistent with the augmentation of the immune function by acupuncture treatment. We hypothesized that the primo vascular system (PVS), which was proposed as the anatomical structure of the acupuncture points and meridians, should have a high density of MCs. In order to test that hypothesis, we investigated the primo nodes isolated from the surfaces of internal organs, such as the liver, the small and the large intestines, and the bladder. The harvested primo nodes were stained with toluidine blue, and the MCs were easily recognized by their red-purple stains and their characteristic granules. The results showed a high density of MCs in the primo nodes and confirmed the hypothesis. The MCs were uniformly distributed in the nodes. The relative concentration of the MCs with respect to other cells was ~15%. We divided the sizes of the primo nodes into three classes: large, medium, and small. The number density and the relative concentration of MCs did not show a size-dependence. The current work suggests that the PVS may participate in the immune response to allergic inflammation, which closely involves MCs. PMID- 26742913 TI - A Novel Technique for Visualizing the Intralymphatic Primo Vascular System by Using Hollow Gold Nanospheres. AB - Until recently, the primo vascular system (PVS) has been unnoticed by most anatomists due to the small diameter and translucent features of the threadlike network. These properties make primo vessels (PVs) difficult to visualize for harvest and for further characterization. One particular PVS subtype that is located within the lymphatic vessels (LVs) is of strong interest because with a proper contrast, these long PVs can be visualized through the transparent LV wall and can be harvested to provide sufficient sample material for analysis. The most common method to visualize this PVS subtype utilizes Alcian blue as the contrast agent. This technique is effective, but tedious, and has relatively low repeatability. The purpose of this study was to develop a new technique that allows reliable visualization of the intralymphatic PVS (IL-PVS) in a user friendly manner. The method was designed to provide optical contrast to the PVS by taking advantage of the porous nature of the PV's external wall and interstitial matrix. Turquoise-green-colored hollow gold nanospheres (HGNs) in the size range of 50-125 nm were found to provide excellent optical contrast for the IL-PVS in rats. The PVS was visualized within 10 minutes after HGN administration at a 95% success rate. PMID- 26742914 TI - Primo Vessel Stressed by Lipopolysaccharide in Rabbits. AB - For tracking the primo vascular system, we observed the primo vessels in vivo in situ using the lipopolysaccharide (LPS) response in the lymphatic vessels of a rabbit. Injection of LPS (200 MUg/kg) into the lymph nodes resulted in greatly stained primo vessels, which were swollen in some cases. We were able to obtain comparative images through alcian blue and diaminobenzidine staining, which clearly showed different morphologies of the primo vessels. The mechanism causing the response of the primo vessels to the injected LPS is still unclear; however, these results might be a first attempt at giving an explanation of the function of the primo vascular system and identifying the changes in the structure and function of the primo vascular system in response to an external stimulus such as an injection of LPS. PMID- 26742915 TI - Finding Blue Tracks in Gephyrocharax melanocheir Fish Similar to the Locations of Acupuncture Meridians after Injecting Alcian Blue. AB - This study investigated whether a meridian-like distribution of Alcian blue (AB) existed after it was injected into a fish's body and suggested a new animal model for meridian study. Twenty Gephyrocharax melanocheir fish with translucent bodies were injected with AB at a point near the spinal column or the dorsal fin. Distribution of AB was observed using a digital camera and a stereomicroscope. Three or more obvious blue tracks were found: one along the spinal column, another along the posterior margin of the abdomen extending to the superior margin of the anal fin, and a third along both sides of the dorsal fin. They were similar to the locations of the governor, conceptual vessel, and urinary bladder meridians, respectively, on the human body according to the classic theory of traditional Chinese medicine. A few other blue tracks were also found, which apparently did not correspond to any known meridians. The results show that the tracks of AB share important similarities with the locations of classically described meridians and that they are mainly distributed in the interstitial space around bones and blood vessels and inside muscular interstices. This study may provide a new experimental animal model for exploring acupuncture meridians. PMID- 26742916 TI - Tracing Mercox Injected at Acupuncture Points Under the Protocol of Partial Body Macerations in Mice. AB - We used for the first time a vascular casting material to take advantage of a simple tracing procedure and to isolate the peculiar features of acupuncture point injections. The polymer Mercox was injected into the skin of a dead mouse at acupuncture points along the bladder meridian lines. After a partial maceration of the whole body with a potassium-hydroperoxide solution, we anatomized it under a stereomicroscope to trace the injected Mercox. Many organs were checked to determine whether or not they contained some Mercox tracing. Connections between the injection sites along the acupuncture points were observed. Two to three layers of Mercox in a plate shape were found under the skin at the acupuncture points, and Mercox travelled throughout the adipose tissue, the fascia, and the parietal and visceral serous membranes inside the organ's parenchyma. The casting material Mercox used with a modified partial maceration procedure is a promising method for visualizing the routes of the meridian system and the primo vascular system. The routes for Mercox are different from those of the blood and lymphatic vessels. PMID- 26742918 TI - Neurovascular Primo Bundles at the Kidney Meridian Revealed Using Hemacolor Staining. PMID- 26742917 TI - Protocol for Detecting the Primo Vascular System in the Lymph Ducts of Mice. AB - The primo vascular system (PVS), which is the proposed conduit for the acupuncture Qi, is a complex network distributed throughout an animal's body. However, even with a microscope, it is not easily detectable because of its transparency. Thus, its existence is largely unknown in current anatomy. A convincing demonstration of its existence is needed. The lymph-primo vessel (PV), which is a subsystem of the PVS, is a very effective visual demonstration of the PVS. The lymph-PVS is a mobile threadlike structure floating in lymph ducts that has been observed in rabbits, rats, and mice by several independent teams. The involved techniques are novel and rather complicated; therefore, we have already provided detailed protocols for the surgery; for the injection of the staining dye; and for the detection, extraction, and identification of the PVS in rabbits and rats. However, the mouse is one of the most important laboratory animals used for various biomedical research purposes. For the convenience of researchers who wish to initiate the PVS experiments in mice, we provide a shortened version of the protocol, despite many similarities with previously published protocols. Thus, researcher can easily obtain the samples of the lymph-PVS of mice. PMID- 26742919 TI - Admission after the gold interval in acute calculous cholecystitis: Should we really cool it off? AB - PURPOSE: The aim of this study was to compare early and delayed cholecystectomy for the treatment of acute calculous cholecystitis (ACC). MATERIALS AND METHODS: The medical records of patients who were diagnosed to have ACC by combined clinical and radiological examination were evaluated retrospectively. The patients were divided into two non-randomized groups according to the duration between the onset of symptoms and cholecystectomy. Group 1 included the patients who underwent cholecystectomy within the first 72 h after the onset of symptoms and Group 2 those who underwent beyond the 72nd hour after the onset of symptoms. RESULTS: We reviewed records for 203 patients. There were 109 patients in Group 1 and 74 patients in Group 2. Access-related complications occurred in four patients. One patient in Group 1 and two patients in Group 2 had trocar site bleeding. In one patient in Group 1, liver trauma occurred. Two patients had bile duct injury in Group 1 as Type D injury according to the Strasberg classification in one patient and E2 injury in other. CONCLUSION: Early cholecystectomy in acute cholecystitis with biliary stones could be performed regardless of time with similar complication, mortality and conversion rates. PMID- 26742920 TI - What is the diagnostic value of computed tomography tractography in patients with abdominal stab wounds? AB - INTRODUCTION: Computed tomography (CT) tractography is a promising technique; it is a CT performed after an entire stab wound tract with a water-soluble contrast agent in patients with abdominal stab wounds. The aim of the current study was to investigate the diagnostic value of CT tractography and to compare with other radiodiagnostic tools in patients with abdominal stab wounds. MATERIALS AND METHODS: All of the patients with anterior abdominal stab wounds were retrospectively reviewed between January 2012 and December 2014. Included in this study for statistical analyses were patients who had contrast-enhanced (oral and intravenous, not rectal) abdominal CTs alone or had contrast-enhanced abdominal CTs combined the CT tractographies and laparotomies in the first 24 h. These patients were divided two groups: the CT scan group (patients who had abdominal CTs alone) and the CT tractography group (patients who had CT tractographies). Both groups underwent laparotomies. The endpoint of this study was to determine whether CT tractography predicted peritoneal violation, not requiring therapeutic laparotomy. The gold standard of diagnosis peritoneal violation was considered laparotomy (therapeutic or not therapeutic). RESULTS: A total of 102 patients with anterior abdomen stab wounds who had laparotomies were enrolled and 29 (27 %) of the patients were excluded for several causes in the study period. Finally, 73 of the patients were enrolled in this study for statistical analyses. The diagnostic performance of a CT tractography in detecting peritoneal violation resulted in 100 % sensitivity, 100 % specificity, 100 % positive predictive values (PPV), 100 % negative predictive values (NPV), and 100 % accuracy. CONCLUSION: A CT tractography combined with an abdominal CT scan seems successful in detecting peritoneal violation in hemodynamically stable patients with abdominal stab wounds. Certainly, randomized controlled trials are required on this topic to recommend this as a routine diagnostic procedure. PMID- 26742921 TI - Observation period for asymptomatic penetrating chest trauma: 1 or 3 h? AB - BACKGROUND: Current recommendations for evaluation and safe discharge of penetrating chest trauma patients regarding pneumothorax (PTX) include a Chest X Ray (CXR) at the Emergency Department (ED) upon arrival and second CXR after 3 h if the first one is negative. PURPOSE: To compare CXRs taken at the first and third hours of ED arrival and evaluate a 1 h period of observation instead of 3 h for safe discharge of patients with penetrating chest trauma. METHODS: In this cross-sectional study, all asymptomatic patients with penetrating chest trauma referred to a level 1 trauma center with negative initial Postero-Anterior (PA) CXRs (hour 0) were enrolled. Those with intoxication, tube thoracostomy, chest computed tomography, evidence of abdominal penetration, an overall elapsed timed of more than 1 h for admission to the ED, and refusal to take part in the study were excluded. Patients underwent subsequent PA CXRs at hours 1 and 3. A phone call follow up after 24 h was organized for each patient. RESULTS: A total of 68 patients were enrolled. There was 100 % concordance among CXRs performed at hours 1 and 3 in the study population. None of the patients showed clinical deterioration or PTX in CXR at hour 1 if remained asymptomatic during the first hour of observation. CONCLUSION: Asymptomatic patients with penetrating chest trauma, negative initial PA CXR, no signs of intoxication, and no deterioration during the first hour of observation may be considered for discharge. Further evidence is required to make recommendations based on these findings. PMID- 26742922 TI - Association Between Vitamin D Receptor Polymorphism and Familial Mediterranean Fever Disease in Turkish Children. AB - Familial Mediterranean fever (FMF) is an autosomal recessive, inherited autoinflammatory disease characterized by recurrent, self-limited attacks of fever, and inflammation of serosal surfaces. The aim of our study was to determine a possible relationship between Vitamin D receptor (VDR) gene polymorphisms and the risk of children with FMF. We investigated VDR FokI (rs10735810), TaqI (rs731236), BsmI (rs1544410), and ApaI (rs7975232) polymorphisms in 50 children with FMF and 150 age-matched healthy control subjects. This study was performed by polymerase chain reaction-based restriction fragment length polymorphism. There was no significant difference between patients and controls for VDR FokI, TaqI, BsmI, and ApaI genotypes and alleles (p > 0.05). Results need to be supported by further investigations that define haplotype patterns for VDR gene polymorphisms in a larger group and different ethnic groups of FMF patients. PMID- 26742924 TI - The Importance of Keeping in Mind the Diagnosis of N-Methyl-D-Aspartate Receptor Encephalitis. PMID- 26742923 TI - Reply to: The Importance of Keeping in Mind the Diagnosis of N-Methyl-D-Aspartate Receptor Encephalitis. PMID- 26742925 TI - Leptin Dysregulation Is Specifically Associated With Major Depression With Atypical Features: Evidence for a Mechanism Connecting Obesity and Depression. AB - BACKGROUND: Obesity-related dysregulation of leptin signaling (e.g., hyperleptinemia due to central functional resistance) may affect mood. However, evidence for leptin dysregulation in major depressive disorder (MDD) is conflicting. Inconclusive findings may be attributable to heterogeneity of MDD, aggregating biologically different subtypes. We examined the relationship of leptin with MDD, its common subtypes (typical and atypical), and clinical features. METHODS: The sample consisted of participants (aged 18 to 65 years) from the Netherlands Study of Depression and Anxiety with current (n = 1062) or remitted (n = 711) MDD and healthy control subjects (n = 497). Diagnoses of MDD and subtypes were based on DSM-IV symptoms. Additional symptoms were measured with the Inventory of Depressive Symptomatology. Blood levels of leptin and adiposity indexes (body mass index and waist circumference) were assessed. RESULTS: As compared to control subjects, higher leptin was associated with the atypical MDD subtype both for remitted (n = 144, odds ratio = 1.53, 95% confidence interval = 1.16-2.03, p = .003) and current (n = 270, odds ratio = 1.90, 95% confidence interval = 1.51-2.93, p = 5.3e-8) cases. This association was stronger for increasing adiposity levels (leptin by body mass index interaction, p < .02), strengthening the hypothesis of the involvement of leptin resistance. No association with leptin was found for overall MDD or the typical subtype. Among currently depressed patients, higher leptin was associated with key symptoms identifying the atypical subtype, such as hyperphagia, increased weight, and leaden paralysis. CONCLUSIONS: Leptin dysregulation (resistance) may represent an underlying mechanism connecting obesity and MDD with atypical features. Development of treatment effectively targeting leptin resistance may benefit patients with atypical depression characterized by obesity-related metabolic alterations. PMID- 26742927 TI - Transcription inhibitors prevent amnesia induced by NMDA antagonist-mediated impairment of memory reconsolidation. AB - Recent studies report that long-term memory retrieval can induce memory reconsolidation, and impairment of this reconsolidation might lead to amnesia. Previously, we found that reconsolidation of a conditioned food aversion memory could be disrupted by translation inhibitors for up to 3 h following a reconsolidation event, thus inducing amnesia. We examined the role of transcription processes in the induction of amnesia in the land snail, Helix lucorum. It received N-methyl-D-aspartate (NMDA) glutamate receptor antagonist and transcription inhibitor 2 days after learning in a neutral context environment; it was then transferred to the learning context followed by reminder with conditioned food stimulus. NMDA receptor blockade, followed by a reminder session, impaired reconsolidation of an aversive memory. Simultaneous administration of an NMDA receptor antagonist and a transcription inhibitor prior to reminder of an aversive event prevented amnesia induction. In contrast, when a transcription inhibitor alone was injected prior to a reminder session, the blockade had no effect on memory. We found that transcription inhibition 0-6 h after amnesia induction suppressed memory loss, but this suppression was lost when inhibitors were administered 9 h after amnesia. Thus, amnesia is likely dependent on transcription processes within a 9-h time window. We can hypothesize that amnesia induction initiates synthesis of specific mRNAs and proteins; furthermore, these events occur within specific time-dependent windows. Our findings could prove useful for the analysis of amnesia formation and for the development of possible ways to prevent memory loss associated with various diseases and injuries in animals and humans. PMID- 26742926 TI - The Number of Genomic Copies at the 16p11.2 Locus Modulates Language, Verbal Memory, and Inhibition. AB - BACKGROUND: Deletions and duplications of the 16p11.2 BP4-BP5 locus are prevalent copy number variations (CNVs), highly associated with autism spectrum disorder and schizophrenia. Beyond language and global cognition, neuropsychological assessments of these two CNVs have not yet been reported. METHODS: This study investigates the relationship between the number of genomic copies at the 16p11.2 locus and cognitive domains assessed in 62 deletion carriers, 44 duplication carriers, and 71 intrafamilial control subjects. RESULTS: IQ is decreased in deletion and duplication carriers, but we demonstrate contrasting cognitive profiles in these reciprocal CNVs. Deletion carriers present with severe impairments of phonology and of inhibition skills beyond what is expected for their IQ level. In contrast, for verbal memory and phonology, the data may suggest that duplication carriers outperform intrafamilial control subjects with the same IQ level. This finding is reminiscent of special isolated skills as well as contrasting language performance observed in autism spectrum disorder. Some domains, such as visuospatial and working memory, are unaffected by the 16p11.2 locus beyond the effect of decreased IQ. Neuroimaging analyses reveal that measures of inhibition covary with neuroanatomic structures previously identified as sensitive to 16p11.2 CNVs. CONCLUSIONS: The simultaneous study of reciprocal CNVs suggests that the 16p11.2 genomic locus modulates specific cognitive skills according to the number of genomic copies. Further research is warranted to replicate these findings and elucidate the molecular mechanisms modulating these cognitive performances. PMID- 26742928 TI - Factors influencing psychosocial adjustment and quality of life in Parkinson patients and informal caregivers. AB - OBJECTIVE: The influence that social conditions and personal attitudes may have on the quality of life (QoL) of Parkinson's disease (PD) patients and informal caregivers does not receive enough attention in health care, as a result of it not being clearly identified, especially in informal caregivers. The aim of this study was to provide a comprehensive analysis of psychosocial adjustment and QoL determinants in PD patients and informal caregivers. METHODS: Ninety-one PD patients and 83 caregivers participated in the study. Multiple regression analyses were performed including benefit finding, coping, disease severity and socio-demographic factors, in order to determine how these aspects influence the psychosocial adjustment and QoL in PD patients and caregivers. RESULTS: Regression models showed that severity of PD was the main predictor of psychosocial adjustment and QoL in patients. Nevertheless, multiple regression analyses also revealed that coping was a significant predictor of psychosocial adjustment in patients and caregivers. Furthermore, psychosocial adjustment was significantly related to QoL in patients and caregivers. Also, coping and benefit finding were predictors of QoL in caregivers but not in patients. CONCLUSIONS: Multidisciplinary interventions aimed at improving PD patients' QoL may have more effective outcomes if education about coping skills, and how these can help towards a positive psychosocial adjustment to illness, were included, and targeted not only at patients, but also at informal caregivers. PMID- 26742930 TI - The effect of oxytocin on biological motion perception in dogs (Canis familiaris). AB - Recent studies have shown that the neuropeptide oxytocin is involved in the regulation of several complex human social behaviours. There is, however, little research on the effect of oxytocin on basic mechanisms underlying human sociality, such as the perception of biological motion. In the present study, we investigated the effect of oxytocin on biological motion perception in dogs (Canis familiaris), a species adapted to the human social environment and thus widely used to model many aspects of human social behaviour. In a within-subjects design, dogs (N = 39), after having received either oxytocin or placebo treatment, were presented with 2D projection of a moving point-light human figure and the inverted and scrambled version of the same movie. Heart rate (HR) and heart rate variability (HRV) were measured as physiological responses, and behavioural response was evaluated by observing dogs' looking time. Subjects were also rated on the personality traits of Neuroticism and Agreeableness by their owners. As expected, placebo-pretreated (control) dogs showed a spontaneous preference for the biological motion pattern; however, there was no such preference after oxytocin pretreatment. Furthermore, following the oxytocin pretreatment female subjects looked more at the moving point-light figure than males. The individual variations along the dimensions of Agreeableness and Neuroticism also modulated dogs' behaviour. Furthermore, HR and HRV measures were affected by oxytocin treatment and in turn played a role in subjects' looking behaviour. We discuss how these findings contribute to our understanding of the neurohormonal regulatory mechanisms of human (and non-human) social skills. PMID- 26742929 TI - A reappraisal of successive negative contrast in two populations of domestic dogs. AB - When an anticipated food reward is unexpectedly reduced in quality or quantity, many mammals show a successive negative contrast (SNC) effect, i.e. a reduction in instrumental or consummatory responses below the level shown by control animals that have only ever received the lower-value reward. SNC effects are believed to reflect an aversive emotional state, caused by the discrepancy between the expected and the actual reward. Furthermore, how animals respond to such discrepancy has been suggested to be a sign of animals' background mood state. However, the occurrence and interpretation of SNC effects are not unequivocal, and there is a relative lack of studies conducted outside of laboratory conditions. Here, we tested two populations of domestic dogs (24 owned pet dogs and 21 dogs from rescue kennels) in a SNC paradigm following the methodology by Bentosela et al. (J Comp Psychol 123:125-130, 2009), using a design that allowed a within-, as well as a between-, subjects analysis. We found no evidence of a SNC effect in either population using a within- or between subjects design. Indeed, the within-subjects analysis revealed a reverse SNC effect, with subjects in the shifted condition showing a significantly higher level of response, even after they received an unexpected reduction in reward quality. Using a within-, rather than a between-, subjects design may be beneficial in studies of SNC due to higher sensitivity and statistical power; however, order effects on subject performance need to be considered. These results suggest that this particular SNC paradigm may not be sufficiently robust to replicate easily in a range of environmental contexts and populations. PMID- 26742931 TI - Wolfram Syndrome: Diagnosis, Management, and Treatment. AB - Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, diabetes insipidus, optic nerve atrophy, hearing loss, and neurodegeneration. Although there are currently no effective treatments that can delay or reverse the progression of Wolfram syndrome, the use of careful clinical monitoring and supportive care can help relieve the suffering of patients and improve their quality of life. The prognosis of this syndrome is currently poor, and many patients die prematurely with severe neurological disabilities, raising the urgency for developing novel treatments for Wolfram syndrome. In this article, we describe natural history and etiology, provide recommendations for diagnosis and clinical management, and introduce new treatments for Wolfram syndrome. PMID- 26742932 TI - Prevalence of Gestational Diabetes and Risk of Progression to Type 2 Diabetes: a Global Perspective. AB - Despite the increasing epidemic of diabetes mellitus affecting populations at different life stages, the global burden of gestational diabetes mellitus (GDM) is not well assessed. Systematically synthesized data on global prevalence estimates of GDM are lacking, particularly among developing countries. The hyperglycemic intrauterine environment as exemplified in pregnancies complicated by GDM might not only reflect but also fuel the epidemic of type 2 diabetes mellitus (T2DM). We comprehensively reviewed available data in the past decade in an attempt to estimate the contemporary global prevalence of GDM by country and region. We reviewed the risk of progression from GDM to T2DM as well. Synthesized data demonstrate wide variations in both prevalence estimates of GDM and the risk of progression from GDM to T2DM. Direct comparisons of GDM burden across countries or regions are challenging given the great heterogeneity in screening approaches, diagnostic criteria, and underlying population characteristics. In this regard, collaborative efforts to estimate global GDM prevalence would be a large but important leap forward. Such efforts may have substantial public health implications in terms of informing health policy makers and healthcare providers for disease burden and for developing more targeted and effective diabetes prevention and management strategies globally. PMID- 26742933 TI - Pioglitazone alleviates cardiac and vascular remodelling and improves survival in monocrotaline induced pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a fatal disease with limited therapeutic options. Pathophysiological changes comprise obliterative vascular remodelling of small pulmonary arteries, elevated mean pulmonary arterial systolic pressure (PASP) due to elevated resistance of pulmonary vasculature, adverse right ventricular remodelling, and heart failure. Recent findings also indicate a role of increased inflammation and insulin resistance underlying the development of PAH. We hypothesized that treatment of this condition with the peroxisome proliferator-activated receptor-gamma (PPARgamma) activator pioglitazone, known to regulate the expression of different genes addressing insulin resistance, inflammatory changes, and vascular remodelling, could be a beneficial approach. PAH was induced in adult rats by a single subcutaneous injection of monocrotaline (MCT). Pioglitazone was administered for 2 weeks starting 3 weeks after MCT injection. At day 35, hemodynamics, organ weights, and -indices were measured. We performed morphological and molecular characterization of the pulmonary vasculature, including analysis of the degree of muscularization, proliferation rates, and medial wall thickness of the small pulmonary arteries. Furthermore, markers of cardiac injury, collagen content, and cardiomyocyte size were analyzed. Survival rates were monitored throughout the experimental period. Pioglitazone treatment improved survival, reduced PASP, muscularization of small pulmonary arteries, and medial wall thickness. Further, MCT-induced right ventricular hypertrophy and fibrosis were attenuated. This was accompanied with reduced cardiac expression of brain natriuretic peptide, as well as decreased cardiomyocyte size. Finally, pulmonary macrophage content and osteopontin gene expression were attenuated. Based on the beneficial impact of pioglitazone, activation of PPARgamma might be a promising treatment option in PAH. PMID- 26742934 TI - Clinical Validity of the ADI-R in a US-Based Latino Population. AB - The Autism Diagnostic Interview-Revised (ADI-R) has been validated as a tool to aid in the diagnosis of Autism; however, given the growing diversity in the United States, the ADI-R must be validated for different languages and cultures. This study evaluates the validity of the ADI-R in a US-based Latino, Spanish speaking population of 50 children and adolescents with ASD and developmental disability. Sensitivity and specificity of the ADI-R as a diagnostic tool were moderate, but lower than previously reported values. Validity of the social reciprocity and restrictive and repetitive behaviors domains was high, but low in the communication domain. Findings suggest that language discordance between caregiver and child may influence reporting of communication symptoms and contribute to lower sensitivity and specificity. PMID- 26742935 TI - Clinical presentation and management of patients with primary hyperparathyroidism of the Swiss Primary Hyperparathyroidism Cohort: a focus on neuro-behavioral and cognitive symptoms. AB - PURPOSE: To describe the clinical and biochemical profile of patients with primary hyperparathyroidism (PHPT) of the Swiss Hyperparathyroidism Cohort, with a focus on neurobehavioral and cognitive symptoms and on their changes in response to parathyroidectomy. METHODS: From June 2007 to September 2012, 332 patients were enrolled in the Swiss PHPT Cohort Study, a nationwide prospective and non-interventional project collecting clinical, biochemical, and outcome data in newly diagnosed patients. Neuro-behavioral and cognitive status were evaluated annually using the Mini-Mental State Examination, the Hospital Anxiety and Depression Scale, and the Clock Drawing tests. Follow-up data were recorded every 6 months. Patients with parathyroidectomy had one follow-up visit 3-6 months' postoperatively. RESULTS: Symptomatic PHPT was present in 43 % of patients. Among asymptomatic patients, 69 % (131/189) had at least one of the US National Institutes for Health criteria for surgery, leaving thus a small number of patients with cognitive dysfunction or neuropsychological symptoms, but without any other indication for surgery. At baseline, a large proportion showed elevated depression and anxiety scores and cognitive dysfunction, but with no association between biochemical manifestations of the disease and test scores. In the 153 (46 %) patients who underwent parathyroidectomy, we observed an improvement in the Mini-Mental State Examination (P = 0.01), anxiety (P = 0.05) and depression (P = 0.05) scores. CONCLUSION: PHPT patients often present elevated depression and anxiety scores and cognitive dysfunction, but rarely as isolated manifestations. These alterations may be relieved upon treatment by parathyroidectomy. PMID- 26742936 TI - Prognosticating metastatic osteosarcoma treated with uniform chemotherapy protocol without high dose methotrexate and delayed metastasectomy: a single center experience of 102 patients. AB - PURPOSE: Data on prognostic factors in patients with metastatic osteosarcoma treated with uniform chemotherapy protocol are lacking. The objective of this study was to analyze demographic data, treatment outcome and prognostic factors for patients with metastatic osteosarcoma at our center treated with a uniform chemotherapy protocol without high dose methotrexate. METHODS: This is a single institutional data review of patients treated between June 2003 and December 2012 with neoadjuvant chemotherapy, local site surgery followed by adjuvant chemotherapy and metastasectomy at completion of adjuvant chemotherapy. RESULTS: 102 patients of metastatic osteosarcoma were treated with a median age of 18 years (range 8-48 years), male to female ratio of 3.3:1 and median symptom duration of 4 months. EFS and OS at 5 years were 12.7 +/- 0.1 and 28.1 +/- 0.1 %, respectively. On multivariate analysis, elevated serum alkaline phosphatase (p < 0.001) and number of metastasis >3 (p = 0.04) were predictive of lower EFS, whereas elevated serum alkaline phosphatase (p = 0.01), number of metastasis >3 (p = 0.05), and margin positivity (p < 0.001) were predictive of lower OS. CONCLUSIONS: This is the largest data on metastatic osteosarcoma treated with a uniform chemotherapy protocol without high dose methotrexate. The data showed prognostic factors similar to what have been observed previously such as elevated serum alkaline phosphatase and >3 metastatic lesions in lung predicting inferior outcome. Notably our survival was comparable to data from other studies despite our practice of delaying metastasectomy to completion of chemotherapy rather than performing the same along with local site surgery. PMID- 26742937 TI - Ki-67 is a prognostic marker for hormone receptor positive tumors. AB - PURPOSE: To evaluate the utility of Ki67 as a prognostic marker in Luminal B node negative breast cancer patients. METHODS: We identified 888 patients with invasive breast carcinomas who underwent surgery between 1997 and 2004. Several classical factors were collected: age, tumor size, node involvement, tumor grade, estrogen and progesterone receptors, HER2 and Ki-67 expression. We analyzed if these parameters could be considered as a prognostic factor. In early Luminal B group, we investigated which of the following biological features provide information about bad prognosis: lack of progesterone receptor expression, HER2 overexpression/amplification or high Ki-67 value. RESULTS: The majority of patients were alive and without relapse of tumor at the moment of the analysis (70 %). The prognostic factors founded in multivariate analysis were: tumor size, node involvement, grade 3 and Ki-67 expression. When we stratified the sample by immunohistochemistry (IHC) in tumor subtypes, we assessed 680 patients and we observed 191 Luminal B tumors. The biological parameter related to the worst survival in absence of nodal involvement was Ki-67 value. CONCLUSIONS: Ki-67 represents an additional predictor of survival in Luminal B node negative breast cancer. Conversely, neither Progesterone-receptor nor HER2 status proved prognostic significance in this group in our study. PMID- 26742938 TI - Germline BRCA testing is moving from cancer risk assessment to a predictive biomarker for targeting cancer therapeutics. AB - PURPOSE: Originally, BRCA testing was used for risk assessment and prevention strategies for breast and ovarian cancer. Nowadays, BRCA status may influence therapeutic decision making at cancer diagnosis. Our objective was to analyze whether the medical advances have changed the burden and pattern of referral, and the pathogenic mutation detection rate. METHODS: We included 969 probands from our hereditary cancer registry who undertook a full BRCA analysis between 2006 and 2014. Chi-square tests were used to compare categorical variables. RESULTS: The number of genetic tests have raised from 28 to 170, representing a sixfold increase. In 2006, we tested 1.6 relatives/proband while this proportion was four in 2014. Overall, 20 % harbored a deleterious mutation and 11 % had a variant of unknown significance (VUS). There has been a downward trend in the detection rate of VUS. Testing patients with breast cancer during neoadjuvancy has raised from 4 to 25 % (p = 0.002), while testing them during remission has decreased from 79 to 29 % (p < 0.001). The proportion of patients assessed during the first 6 months after their cancer diagnosis has increased from 3 to 34 % (p = 0.001). Risk reducing mastectomy and salpingoophorectomy have raised from 0 to 24 %, and from 36 to 65 %, respectively. CONCLUSIONS: BRCA testing has experienced a sixfold increase, the number of relatives being tested has doubled, and the test is being performed at earlier phases of the disease. It is necessary to adequate the health resources to preserve the BRCA genetic counseling quality while incorporating BRCA testing for therapeutic decision making. PMID- 26742941 TI - Human health and environmental risks of unconventional shale gas hydrofracking. PMID- 26742939 TI - Signaling and molecular basis of bone marrow niche angiogenesis in leukemia. AB - Angiogenesis, the process of blood vessel formation, is necessary for tissue survival in normal and pathologic conditions. Increased angiogenesis in BM niche is correlated with leukemia progression and resistance to treatment. Angiogenesis can interfere with disease progression and several angiogenic (such as vascular growth factors) as well as anti-angiogenic factors (i.e. angiostatin) can affect angiogenesis. Furthermore, miRs can affect the angiogenic process by inhibiting angiogenesis or increasing the expression of growth factors. Given the importance of angiogenesis in BM for maintenance of leukemic clones, recognition of angiogenic and anti-angiogenic factors and miRs as well as drug resistance mechanisms of leukemic blasts can improve the therapeutic strategies. We highlight the changes in angiogenic balance within the BM niche in different leukemia types. Moreover, we explored the pathways leading to drug resistance in relation to angiogenesis and attempted to assign interesting candidates for future research. PMID- 26742940 TI - Gemcitabine versus FOLFIRINOX in patients with advanced pancreatic adenocarcinoma hENT1-positive: everything was not too bad back when everything seemed worse. AB - PURPOSE: hENT1 is a transmembrane protein which acts as a nucleoside transporter and is the main mediator of Gemcitabine (GEM) uptake into human cells. In this retrospective study we compared GEM versus FOLFIRINOX in patients with metastatic pancreatic cancer in which hENT1 evaluation was available. METHODS: 149 patients affected by unresectable metastatic pancreatic cancer, treated in our institution from 2009 to 2013, have been screened for inclusion in this retrospective study. Seventy patients, treated with GEM or FOLFIRINOX in first-line therapy, fulfilled clinical inclusion criteria for survival analysis. Thirty-one patients were available and contained sufficient quality/quantity RNA for evaluation of hENT1 expression by RT-PCR. The primary endpoint was OS and the secondary endpoint was PFS. RESULTS: The survival analysis, carried out on 70 patients regardless of hENT1 expression, showed a statistically longer OS and PFS in the group treated with FOLFIRINOX compared to GEM. Within the exploratory analysis, which included 31 patients, no differences were found in hENT1 positive patients treated with FOLFIRINOX compared to GEM in terms of OS (8.5 vs 7 months, HR: 0.89; 95 % CI 0.3 2.5; p = 0.8) and PFS (5.5 vs 5 months, HR: 0.8, 95 % CI 0.2-2.2; p = 0.61). GEM treated hENT1 positive patients showed a statistically significant improvement both of OS (8 vs 2 months; p = 0.0012) and PFS (5 vs 1 months; p = 0.0004) in comparison to GEM-treated hENT1 negative patients. CONCLUSIONS: In our exploratory analysis GEM seems as effective as FOLFIRINOX in terms of survival with a better safety profile in hENT1 positive metastatic pancreatic cancer. PMID- 26742942 TI - A novel liposomal Clodronate depletes tumor-associated macrophages in primary and metastatic melanoma: Anti-angiogenic and anti-tumor effects. PMID- 26742943 TI - Targeting CXCR4/SDF-1 axis by lipopolymer complexes of siRNA in acute myeloid leukemia. AB - In spite of high complete remission rates in Acute Myeloid Leukemia (AML), little progress has been made in the long-term survival of relapsing AML patients, urging for the development of novel therapies. The CXCR4/SDF-1 axis is a potential therapeutic target in AML to reduce the enhanced survival and proliferation of leukemic cells, with current drug development efforts focusing on antagonists and blocking antibodies. The RNAi technology mediated by siRNA is a promising alternative; however, further development of clinically relevant siRNA carriers is needed since siRNA on its own is an incompetent silencing agent. Here, we report on lipid-substituted polymeric carriers for siRNA delivery to AML cells, specifically targeting CXCR4. Our results demonstrate an effective suppression of CXCR4 protein with the polymeric siRNA delivery in AML THP-1 cells. The suppression of CXCR4 as well as its ligand, SDF-1 (CXCL12), decreased THP-1 cell numbers due to reduced cell proliferation. The reduced proliferation was also observed in the presence of human bone marrow stromal cells (hBMSC), suggesting that our approach would be effective in the protective bone marrow microenvironment. The combination of CXCR4 silencing and cytarabine treatment resulted in more effective cytotoxicity when the cells were co-incubated with hBMSC. We observed a decrease in the toxicity of the lipopolymer/siRNA complexes when THP-1 cells were treated in the presence of hBMSC but this effect did not negatively affect CXCR4 silencing. In addition, siRNA delivery to mononuclear cells derived from AML patients led to significant CXCR4 silencing in 2 out of 5 samples, providing a proof-of-concept for clinical translation. We conclude that decreasing CXCR4 expression via lipopolymer/siRNA complexes is a promising option for AML therapy and could provide an effective alternative to current CXCR4 inhibition strategies. PMID- 26742944 TI - Kinetics of functionalised carbon nanotube distribution in mouse brain after systemic injection: Spatial to ultra-structural analyses. AB - Earlier studies proved the success of using chemically functionalised multi walled carbon nanotubes (f-MWNTs) as nanocarriers to the brain. Little insight into the kinetics of brain distribution of f-MWNTs in vivo has been reported. This study employed a wide range of qualitative and quantitative techniques with the aim of shedding the light on f-MWNT's brain distribution following intravenous injection. gamma-Scintigraphy quantified the uptake of studied radiolabelled f-MWNT in the whole brain parenchyma and capillaries while 3D single photon emission computed tomography/computed tomography imaging and autoradiography illustrated spatial distribution within various brain regions. Raman and multiphoton luminescence together with transmission electron microscopy confirmed the presence of intact f-MWNT in mouse brain, in a label-free manner. The results evidenced the presence of f-MWNT in mice brain parenchyma, in addition to brain endothelium. Such information on the rate and extent of regional and cellular brain distribution is needed before further implementation into neurological therapeutics can be made. PMID- 26742947 TI - The short-term impact of each primary dose of pneumococcal conjugate vaccine on nasopharyngeal carriage: Systematic review and meta-analyses of randomised controlled trials. AB - BACKGROUND: Early onset of persistent otitis media is a priority issue for Australian Indigenous populations. The objective is to determine the direct and short-term impact of one, two and three doses of any pneumococcal conjugate vaccine (PCV) formulation on nasopharyngeal (NP) carriage of Streptococcus pneumoniae (Spn) and non-typeable Haemophilus influenzae (NTHi), the otopathogens targeted by current PCVs. METHODS: We searched MEDLINE (PubMed) and CENTRAL (Cochrane Library) to 29 September 2015. We also scanned reference lists of recent reviews and contacted authors. We included randomised controlled trials (RCTs) with a PCV schedule commencing <=3 months of age that reported controlled non-cumulative group-specific prevalence data for carriage of Spn or NTHi at age<12 months. We performed a standard risk of bias assessment. We estimated the pooled relative risk (RR) and 95% confidence interval (95%CI) for each vaccine dose on NP carriage by meta-analysis. RESULTS: We included 16 RCTs involving 14,776 participants. The PCVs were conjugated to diphtheria toxin CRM197, diphtheria toxoid, tetanus toxoid or NTHi protein D and varied in valency (4-13). Controls were non-PCVs, placebo or no vaccine. The earliest carriage outcome was from 2 to 9 months of age. Compared to controls, there were no significant differences between one or two doses of PCV on vaccine-type (VT) pneumococcal carriage at ~4 and ~6 months respectively. However, VT carriage was significantly lower at ~7 months RR 0.67 95%CI 0.56-0.81 from 9 studies and 7613 infants and non-vaccine type (NVT) carriage was higher RR 1.23 95%CI 1.09-1.40 from 8 studies and 5861 infants. No impact on overall pneumococcal or NTHi carriage was found. CONCLUSIONS: The primary PCV schedule had no significant short-term impact on overall pneumococcal or NTHi NP carriage and a limited impact on VT pneumococcal carriage before the third dose. PMID- 26742945 TI - The transfer and decay of maternal antibody against Shigella sonnei in a longitudinal cohort of Vietnamese infants. AB - BACKGROUND: Shigella sonnei is an emergent and major diarrheal pathogen for which there is currently no vaccine. We aimed to quantify duration of maternal antibody against S. sonnei and investigate transplacental IgG transfer in a birth cohort in southern Vietnam. METHODS AND RESULTS: Over 500-paired maternal/infant plasma samples were evaluated for presence of anti-S. sonnei-O IgG and IgM. Longitudinal plasma samples allowed for the estimation of the median half-life of maternal anti-S. sonnei-O IgG, which was 43 days (95% confidence interval: 41-45 days). Additionally, half of infants lacked a detectable titer by 19 weeks of age. Lower cord titers were associated with greater increases in S. sonnei IgG over the first year of life, and the incidence of S. sonnei seroconversion was estimated to be 4/100 infant years. Maternal IgG titer, the ratio of antibody transfer, the season of birth and gestational age were significantly associated with cord titer. CONCLUSIONS: Maternal anti-S. sonnei-O IgG is efficiently transferred across the placenta and anti-S. sonnei-O maternal IgG declines rapidly after birth and is undetectable after 5 months in the majority of children. Preterm neonates and children born to mothers with low IgG titers have lower cord titers and therefore may be at greater risk of seroconversion in infancy. PMID- 26742948 TI - Standardizing endpoints in perioperative research. AB - Measuring patient-relevant, clinically important, and valid outcomes is fundamental to the delivery of high-quality clinical care and to the innovation and development of such care through research. As surgical innovations become more complex and the burden of age and comorbidities in the surgical patient population continues to increase, understanding the benefits and harms of surgical interventions becomes ever more important. Nevertheless, we can understand only what we can adequately describe. Truly collaborative decision making, delivery of safe effective care, and on-going quality improvement are also critically dependent on reliable valid measurement of patient-relevant and clinically important data. Attempts to describe the full spectrum of outcomes following surgery necessarily entail moving beyond the traditional endpoints of mortality and resource use towards more complex measures of morbidity, patient reported outcomes, and functional status. Without standardization and consensus to guide the use of increasingly complex and nuanced endpoints, there is a real risk that perioperative research will become embroiled in a mire of inconsistent heterogeneous outcome measures that cannot be meaningfully compared and contrasted between trials or combined within meta-analyses. This would result in limiting the value of the research effort and depriving patients and clinicians of definitive answers. Collaboration in perioperative medicine-whether between institutions or across continents-has enormous potential to improve the value of research output. Standardizing endpoints for outcome measurement is fundamental to maximizing the quality of such collaboration and ensuring the impact of future perioperative research. PMID- 26742949 TI - Management of acute epiglottitis in an infant with a family history of malignant hyperthermia. PMID- 26742946 TI - Nasopharyngeal carriage of Streptococcus pneumoniae among children in an urban setting in Brazil prior to PCV10 introduction. AB - Information on pneumococcal carriage in the pre-vaccine period is essential to predict and assess the impact of PCV in settings where disease surveillance is particularly difficult. Therefore, we present data on pneumococcal carriage before the introduction of the 10-valent-pneumococcal conjugate vaccine (PCV10) in Brazil. We conducted a prospective study on a cohort of 203 children aged <5 years old, randomly selected in an urban community located in the periphery of the city of Salvador, Brazil and followed them from January/2008 to January/2009. Nasopharyngeal swabs were collected from each child at four times. In total, 721 swabs were collected, yielding a pneumococcal carriage prevalence of 55% (n=398). In multivariate analyses, the variables associated with carriage were having contact with three or more children <2 years old (OR, 2.00; 95% CI 1.33-2.89) and living in a house with an average of 3 residents per room (OR, 1.77; 95% CI 1.05 3.10). Also, white participants were more likely to be protected from colonization (OR, 0.52; 95% CI 0.29-0.93), and prevalence of carriage varied over time, with lower prevalence occurring from February to June (OR, 0.53; 95% CI 0.37-0.78) compared to July to January. Contact with children under 2 years of age and living in crowded housing also were associated with colonization by highly invasive serotypes, although this relationship was not significant. The most prevalent vaccine serotypes were 6A/B (25.4%), 19F (10.1%) and 14 (9.0%), while the most prevalent non-vaccine serotypes were 16F (4.8%), 15B/C (4.5%) and 6C/D (3.5%). Overall, 38.4% (153/398) of the isolates were non-susceptible to penicillin, and of those, 73.8% (113/153) were non-susceptible to trimethoprim/sulfamethoxazole. Colonization rate by PCV10 serotypes was 52.2%. Routine PCV10 vaccination can lead to significant changes in pneumococcal serotypes found in NP colonization, indicating a need for continued monitoring, especially in crowded settings, as occurs in Brazil's slums. PMID- 26742950 TI - [Meeting of the working group on gynecological and breast pathology of the German Society of Pathology 2015]. PMID- 26742952 TI - Bioconversion of Iminodiacetonitrile to Iminodiacetic acid with whole cells of Lysinibacillus boronitolerans MTCC 107614 (IICT-akl252). AB - Biotechnological potential of nitrilases are prompting significant interest in finding the novel microbes capable of hydrolyzing nitriles. In this view, we have screened about 450 bacterial strains for nitrilase production using bioconversion of iminodiacetonitrile (IDAN) to iminodiacetic acid (IDA) through hydrolysis and obtained six nitrilase-producing isolates. Among these six isolates, IICT-akl252 was promising which was identified as Lysinibacillus boronitolerans. This is the first report on L. boronitolerans for nitrilase activity. Optimization of various medium and reaction parameters for maximizing the nitrilase production using whole cells in shake flask was carried out for L. boronitolerans IICT-akl252. Sucrose (2 %) as a carbon source attained better nitrilase yield while IDAN appeared to be the preferable inducer (0.2 %). The maximum IDA formation was achieved with 100 mM IDAN and 150 mg/ml cells at 30 degrees C and pH 6.5. After optimization of the culture and reaction conditions, the activity of nitrilase was increased by 2.3-fold from 27.2 to 64.5 U. The enzyme was stable up to 1 h at 50 degrees C. The enzyme was able to hydrolyze aliphatic, aromatic and heterocyclic nitrile substrates. PMID- 26742953 TI - A TOMM40 poly-T variant modulates gene expression and is associated with vocabulary ability and decline in nonpathologic aging. AB - The Translocase of Outer Mitochondrial Membrane 40 Homolog and Apolipoprotein E (TOMM40-APOE) locus has been associated with a number of age-related phenotypes in humans including nonpathologic cognitive aging, late-onset Alzheimer's disease, and longevity. Here, we investigate the influence of the TOMM40 intron 6 poly-T variant (rs10524523) on TOMM40 gene expression and cognitive abilities and decline in a cohort of 1613 community-dwelling elderly volunteers who had been followed for changes in cognitive functioning over a period of 14 years (range = 12-18 years). We showed that the shorter length poly-T variants were found to act as a repressor of luciferase gene expression in reporter gene constructs. Expression was reduced to approximately half of that observed for the very long variant. We further observed that the shorter poly-T variant was significantly associated with reduced vocabulary ability and a slower rate of vocabulary decline with age compared to the very long poly-T variants. No significant associations were observed for memory, fluid intelligence or processing speed, although the direction of effect, where the short variant was correlated with reduced ability and slower rate of decline was observed for all tests. Our results indicate that the poly-T variant has the ability to interact with transcription machinery and differentially modulate reporter gene expression and influence vocabulary ability and decline with age. PMID- 26742955 TI - Transcriptome Survey of the Contribution of Alternative Splicing to Proteome Diversity in Arabidopsis thaliana. PMID- 26742956 TI - Butterflies visit more frequently, but bees are better pollinators: the importance of mouthpart dimensions in effective pollen removal and deposition. AB - Pollination studies often use visitation frequency of potential pollinators as an indicator of their importance, but this is only one component and may not reflect actual pollen transfer rates. In this study, we determine the most effective pollinator group of Angadenia berteroi, a tropical perennial subshrub with large yellow flowers that set few fruits. We determined visitation frequency and pollen transfer effectiveness of the four most common groups of visitors (long- and short-tongued bees, and skipper and non-skipper butterflies). Using potted plants, we exposed flowers to single visits from different types of pollinators to measure fruit set. We demonstrate that A. berteroi is most effectively pollinated by long-tongued bees, though many other species visit the flowers; the most frequent visitor group is not the most important pollinator, because they neither carry nor deposit much pollen, as the width of their proboscis is small compared with long-tongued bees. In this system, the width of the proboscis of the pollinators correlates with pollen transfer efficiency. Our results demonstrate the importance of pollen removal, pollen deposition, and fruit set, in determining the most effective pollinators, rather than visitor frequency. The distinctive morphology of these flowers, with a large bell and a narrow, short tube, suggests that other flowers of this shape may similarly benefit more from visitors with mouthparts shorter than previously considered optimal. PMID- 26742954 TI - Next-generation sequencing of 28 ALS-related genes in a Japanese ALS cohort. AB - We investigated the frequency and contribution of variants of the 28 known amyotrophic lateral sclerosis (ALS)-related genes in Japanese ALS patients. We designed a multiplex, polymerase chain reaction-based primer panel to amplify the coding regions of the 28 ALS-related genes and sequenced DNA samples from 257 Japanese ALS patients using an Ion Torrent PGM sequencer. We also performed exome sequencing and identified variants of the 28 genes in an additional 251 ALS patients using an Illumina HiSeq 2000 platform. We identified the known ALS pathogenic variants and predicted the functional properties of novel nonsynonymous variants in silico. These variants were confirmed by Sanger sequencing. Known pathogenic variants were identified in 19 (48.7%) of the 39 familial ALS patients and 14 (3.0%) of the 469 sporadic ALS patients. Thirty-two sporadic ALS patients (6.8%) harbored 1 or 2 novel nonsynonymous variants of ALS related genes that might be deleterious. This study reports the first extensive genetic screening of Japanese ALS patients. These findings are useful for developing genetic screening and counseling strategies for such patients. PMID- 26742957 TI - Tazarotene 0.1% Cream as Monotherapy for Early-Stage Cutaneous T-Cell Lymphoma. AB - BACKGROUND: Numerous treatments are available for cutaneous T-cell lymphoma (CTCL), including systemic retinoids. Very few data are available on topical retinoids. OBJECTIVES: The aim of this study was to evaluate the safety and efficiency of tazarotene as monotherapy for early-stage CTCL. METHODS: An open label, prospective study of tazarotene as monotherapy for stages IA to IIA CTCL was conducted. Index lesions on 10 patients were followed for 6 months on treatment, plus at least 6 months off treatment. RESULTS: Six patients (60%) showed complete response (CR). Erythema, scaling, thickness, and lesion area decreased progressively throughout treatment. The mean time to CR was 3.8 months; CR was durable for at least 6 months in 83%. Of the 4 patients (40%) without CR, 2 (20%) had stable disease and 2 (20%) stopped the medication because of local side effects; none showed progression. CONCLUSIONS: This is the first Canadian trial providing evidence that topical tazarotene has excellent potential as a monotherapy agent for stages I to IIA CTCL. PMID- 26742959 TI - Aggregation dynamics explain vegetation patch-size distributions. AB - Vegetation patch-size distributions have been an intense area of study for theoreticians and applied ecologists alike in recent years. Of particular interest is the seemingly ubiquitous nature of power-law patch-size distributions emerging in a number of diverse ecosystems. The leading explanation of the emergence of these power-laws is due to local facilitative mechanisms. There is also a common transition from power law to exponential distribution when a system is under global pressure, such as grazing or lack of rainfall. These phenomena require a simple mechanistic explanation. Here, we study vegetation patches from a spatially implicit, patch dynamic viewpoint. We show that under minimal assumptions a power-law patch-size distribution appears as a natural consequence of aggregation. A linear death term also leads to an exponential term in the distribution for any non-zero death rate. This work shows the origin of the breakdown of the power-law under increasing pressure and shows that in general, we expect to observe a power law with an exponential cutoff (rather than pure power laws). The estimated parameters of this distribution also provide insight into the underlying ecological mechanisms of aggregation and death. PMID- 26742958 TI - Genome-wide copy number variant analysis for congenital ventricular septal defects in Chinese Han population. AB - BACKGROUND: Ventricular septal defects (VSDs) constitute the most prevalent congenital heart disease (CHD), occurs either in isolation (isolated VSD) or in combination with other cardiac defects (complex VSD). Copy number variation (CNV) has been highlighted as a possible contributing factor to the etiology of many congenital diseases. However, little is known concerning the involvement of CNVs in either isolated or complex VSDs. METHODS: We analyzed 154 unrelated Chinese individuals with VSD by chromosomal microarray analysis. The subjects were recruited from four hospitals across China. Each case underwent clinical assessment to define the type of VSD, either isolated or complex VSD. CNVs detected were categorized into syndrom related CNVs, recurrent CNVs and rare CNVs. Genes encompassed by the CNVs were analyzed using enrichment and pathway analysis. RESULTS: Among 154 probands, we identified 29 rare CNVs in 26 VSD patients (16.9 %, 26/154) and 8 syndrome-related CNVs in 8 VSD patients (5.2 %, 8/154). 12 of the detected 29 rare CNVs (41.3 %) were recurrently reported in DECIPHER or ISCA database as associated with either VSD or general heart disease. Fifteen genes (5 %, 15/285) within CNVs were associated with a broad spectrum of complicated CHD. Among these15 genes, 7 genes were in "abnormal interventricular septum morphology" derived from the MGI (mouse genome informatics) database, and nine genes were associated with cardiovascular system development (GO:0072538).We also found that these VSD-related candidate genes are enriched in chromatin binding and transcription regulation, which are the biological processes underlying heart development. CONCLUSIONS: Our study demonstrates the potential clinical diagnostic utility of genomic imbalance profiling in VSD patients. Additionally, gene enrichment and pathway analysis helped us to implicate VSD related candidate genes. PMID- 26742960 TI - Liver and blood cytokine microenvironment in HCV patients is associated to liver fibrosis score: a proinflammatory cytokine ensemble orchestrated by TNF and tuned by IL-10. AB - BACKGROUND: In this study, we have evaluated the immunological status of hepatitis C virus (HCV)-infected patients aiming at identifying putative biomarkers associated with distinct degrees of liver fibrosis. Peripheral blood and tissue T-cells as well as cytokine levels were quantified by flow cytometry. RESULTS: Data analysis demonstrated higher frequency of circulating CD8(+) T cells and Tregs along with a mixed proinflammatory/IL-10-modulated cytokine pattern in HCV patients. Patients with severe liver fibrosis presented lower frequency of circulating CD8(+) T-cells, higher levels of proinflammatory cytokines, but lower levels of IL-10, in addition to the higher viral load. Despite the lower frequency of intrahepatic T-cells and scarce frequency of Tregs, patients with severe liver fibrosis showed higher levels of proinflammatory cytokines (TNF and IFN-gamma). The tissue proinflammatory cytokine pattern supported further studies of serum cytokines as relevant biomarkers associated with different liver fibrosis scores. Serum cytokine signature showed that mild liver fibrosis is associated with higher IL-10 serum levels as compared to severe liver disease. There was a clear positive connection of IL-10 with the TNF node in patients with mild liver fibrosis, whereas there is an evident inverse correlation between IL-10 with all other cytokine nodes. CONCLUSIONS: These results suggest the absence of modulatory events in patients with severe liver damage as opposed to mild fibrosis. Machine-learning data mining pointed out TNF and IL-10 as major attributes to differentiate HCV patients from non-infected individuals with highest performance. In conclusion, our findings demonstrated that HCV infection triggers a local and systemic cytokine ensemble orchestrated by TNF and tuned by IL-10 in such a manner that mirrors the liver fibrosis score, which highly suggests the relevance of these set of biomarkers for clinical investigations. PMID- 26742962 TI - Factors associated with the Journal Impact Factor (JIF) for Urology and Nephrology Journals. AB - PURPOSE: The Journal Impact Factor (JIF) is an index used to compare a journal's quality among academic journals and it is commonly used as a proxy for journal quality. We sought to examine the JIF in order to elucidate the main predictors of the index while generating awareness among scientific community regarding need to modify the index calculation in the attempt to turn it more accurate. MATERIALS AND METHODS: Under the Urology and Nephrology category in the Journal Citations Report Website, the top 17 Journals by JIF in 2011 were chosen for the study. All manuscripts' abstracts published from 2009-2010 were reviewed; each article was categorized based on its research design (Retrospective, Review, etc). T and correlation tests were performed for categorical and continuous variables respectively. The JIF was the dependent variable. All variables were then included in a multivariate model. RESULTS: 23,012 articles from seventeen journals were evaluated with a median of 1,048 (range=78-6,342) articles per journal. Journals with a society affiliation were associated with a higher JIF (p=0.05). Self-citations (rho=0.57, p=0.02), citations for citable articles (rho=0.73,p=0.001), citations to non-citable articles (rho=0.65,p=0.0046), and retrospective studies (rho=-0.51,p=0.03) showed a strong correlation. Slight modifications to include the non-citable articles in the denominator yield drastic changes in the JIF and the ranking of the journals. CONCLUSION: The JIF appears to be closely associated with the number of citable articles published. A change in the formula for calculating JIF to include all types of published articles in the denominator would result in a more accurate representation. PMID- 26742961 TI - Dynamic assembly of the exomer secretory vesicle cargo adaptor subunits. AB - The trans-Golgi network (TGN) is the main secretory pathway sorting station, where cargoes are packed into appropriate transport vesicles targeted to specific destinations. Exomer is a cargo adaptor necessary for direct transport of a subset of cargoes from the TGN to the plasma membrane in yeast. Here, we show that unlike classical adaptor complexes, exomer is not recruited en bloc to the TGN, but rather assembles through a stepwise pathway, in which first the scaffold protein Chs5 and then the cargo-binding units, the ChAPs, are recruited. Although all ChAPs are able to assemble functional exomer complexes, they do so with different efficiencies. The mutual relationship between ChAPs varies from cooperation to competition depending on their expression levels and affinities to Chs5 allowing an optimized and efficient cargo transport. The multifactorial assembly pathway results in an exquisitely fine-tuned adaptor complex, enabling the cell to quickly respond and adapt to changes such as stress. PMID- 26742963 TI - Adjuvant chemotherapy for locally advanced upper tract urothelial carcinoma: updated results of the Seoul National University Hospital experience. AB - OBJECTIVES: The objective of this study was to update the long-term outcome in the treatment of locally advanced upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU) regarding the role of adjuvant chemotherapy. MATERIALS AND METHODS: Clinical data from 138 patients who underwent RNU for locally advanced UTUC (pT3/4 or pN+) were analyzed. RESULTS: The adjuvant chemotherapy group comprised 66 patients, and other 72 patients did not receive adjuvant chemotherapy. Cisplatin-based chemotherapy was the most common regimen, depending on the patient's eligibility and renal function. The median follow-up period was 48.7 months (interquartile range: 29.2-96.9 months). The 3-and 5-year disease-specific survival (DSS) rates were 76.0% and 69.9% for the non- -adjuvant chemotherapy group versus 74.6% and 54.5% for the adjuvant chemotherapy group (p=0.301, log-rank test). Overall survival (OS) rates for the same time period were 70.1% and 62.9% for the non-adjuvant chemotherapy group versus 73.8% and 53.2% for the adjuvant chemotherapy group (p=0.931, log-rank test). On multivariate analysis, adjuvant chemotherapy could not predict DSS and OS after surgery. When patients who received cisplatin-based adjuvant chemotherapy (n=59) were compared to those who did not receive adjuvant chemotherapy, similar results were found. CONCLUSIONS: There does not appear to be a significant DSS or OS benefit associated with adjuvant chemotherapy. Prospective randomized clinical trials are necessary to verify the effect of adjuvant chemotherapy on locally advanced UTUC. PMID- 26742966 TI - Safety of 12 core transrectal ultrasound guided prostate biopsy in patients on aspirin. AB - OBJECTIVE: To prospectively assess safety outcome of TRUS guided prostate biopsy in patients taking low dose aspirin. MATERIALS AND METHODS: Consecutive patients, who were planned for 12 core TRUS guided prostate biopsy and satisfied eligibility criteria, were included in the study and divided into two Groups: Group A: patients on aspirin during biopsy, Group B: patients not on aspirin during biopsy, including patients in whom aspirin was stopped prior to the biopsy. Parameters included for statistical analysis were: age, serum prostate specific antigen (PSA), prostate volume, hemoglobin (Hb %), number of hematuria episodes, number of patient reporting hematuria, hematuria requiring intervention, number of patient reporting hematospermia and number of patient reporting rectal bleeding. RESULTS: Of 681 eligible patients, Group A and B had 191 and 490 patients respectively. The mean age, prostate volume, serum PSA and pre-biopsy hemoglobin were similar in both Groups with no significant differences noted between them. None of the post-biopsy complications, including number of hematuria episodes (p=0.83), number of patients reporting hematuria (p=0.55), number of patients reporting hematospermia (p=0.36) and number of patients reporting rectal bleeding (p=0.65), were significantly different between Groups A and B respectively. None of the hemorrhagic complication in either group required intervention and were self limiting. CONCLUSION: Continuing low dose aspirin during TRUS guided prostate biopsy neither alters the minor bleeding episodes nor causes major bleeding complication. So, discontinuation of low dose aspirin prior to TRUS guided prostate biopsy is not required. PMID- 26742964 TI - Clinical significance of serum and urinary HER2/neu protein levels in primary non muscle invasive bladder cancer. AB - OBJECTIVE: We aimed to compare serum and urinary HER2/neu levels between healthy control group and patients with non-muscle invasive bladder cancer. Additionally, we evaluated relationship of HER2/neu levels with tumor stage, grade, recurrence and progression. MATERIALS AND METHODS: Fourty-four patients with primary non muscle invasive bladder tumors (Group 2) and 40 healthy control group (Group 1) were included the study. Blood and urinary samples were collected from all patients and HER2/neu levels were measured by ELISA method. Blood and urinary HER2/neu levels and additionally, ratio of urinary HER2/neu levels to urinary creatinine levels were recorded. Demographic data and tumor characteristics were recorded. RESULTS: Mean serum HER2/neu levels were similar between two groups and statistically significant difference wasn't observed. Urinary HER2/neu levels were significantly higher in group 2 than group 1. Ratio of urinary HER2/neu to urinary creatinine was significantly higher in group 2 than group 1, (p=0,021). Serum and urinary HER2/ neu levels were not associated with tumor stage, grade, recurrence and progression while ratio of urinary HER2/neu to urinary creatinin levels were significantly higher in high-grade tumors. HER2/neu, the sensitivity of the test was found to be 20.5%, and the specificity was 97.5%, also for the urinary HER2/neu/urinary creatinine ratio, the sensitivity and specificity of the test were found to be 31.8% and 87.5%, respectively. CONCLUSIONS: Urinary HER2/neu and ratio of urinary creatinine urine were significantly higher in patients with bladder cancer compared to healthy subjects. Large series and controlled studies are needed for use as a tumor marker. PMID- 26742967 TI - Serum Levels of Trace Elements in Patients with Testicular Cancers. AB - INTRODUCTION: Trace elements are primary components of biological structures; however, they can be toxic when their concentrations are higher than those needed for biological functions. MATERIALS AND METHODS: In the present study serum levels of trace elements were measured in 30 patients (mean age was 26.9+/-11.2 years) newly diagnosed with germ cell testicular cancer and 32 healthy volunteers (mean age: 27.4+/-10.8) by using furnace atomic absorption spectrophotometer. Serum samples were stored at-20oC until assays. RESULTS: In patients with germ cell testicular cancer, the diagnosis was seminoma in 15, mix germ cell tumor in 7, embryonal carcinoma in 4, yolk sac tumor in 2 and teratoma in 2 patients. There was stage I testicular tumor in 19 patients (63.3%) while stage II in 6 patients (20.0%), stage IIIA in 4 patients (13.3%) and stage IIIC in one patient (3.4%). It was found that serum Co, Cu, Mg and Pb levels were increased (p<0.05), whereas Fe, Mn, and Zn levels were decreased in patients with testicular cancer (p<0.05). CONCLUSIONS: These alterations may be important in the pathogenesis of testicular cancers; however, further prospective studies are needed to identify the relationship between testicular cancer and trace elements. PMID- 26742968 TI - Beyond biology: the impact of marital status on survival of patients with adrenocortical carcinoma. AB - PURPOSE: To analyze the association of marital status and survival of patients with ACC using a population-based database. MATERIAL AND METHODS: Patients with ACC were abstracted from the Surveillance Epidemiology and End Results (SEER) database from 1988-2010 (n=1271). Variables included marital status (married vs single/divorced/widowed (SDW)), gender, age, race, tumor (T) and node (N) classification, receipt of surgery, and SEER stage. Statistical analysis was performed using Cox proportional hazard models to generate hazard ratios and 95% confidence intervals. RESULTS: There were 728 (57.3%) females and median age was 56 years (IQR 44-66). Patients who were alive were more frequently married (65.6% vs 61.6%, p=0.008), female (61.1% vs 58.0%, p=0.001), younger (median 51 vs 57 years, p=0.0001), submitted to adrenalectomy (88.6% vs 63.8%, p<0.0001), and more favorable SEER stage (localized- 64.9% vs 29.9%; regional-25.1% vs 30.1%; distant 4.8% vs 31.5%, p<0.0001) compared to patients dead of disease (DOD). On multivariable analysis, factors significantly associated with all-cause mortality were SDW status (HR 1.28, 95% CI 1.09-1.51), age, non-operative management, and N+ disease. Risk factors for disease-specific mortality included SDW status (HR 1.30, 95% CI 1.07-1.56), age, non-operative management, T-classification, and N+ disease. CONCLUSIONS: Marital status is significantly associated with survival in patients with ACC. Our results suggest that the decreased survival seen among SDW individuals highlights an area for further research and needed intervention to reduce disparity. PMID- 26742965 TI - Loss of TIMP-1 immune expression and tumor recurrence in localized prostate cancer. AB - INTRODUCTION AND OBJECTIVE: Overexpression of MMPs has been related to biochemical recurrence after radical prostatectomy. TIMP1 and TIMP2 are controllers of MMPs and the aim of this study is to evaluate the expression levels of MMPs and their regulators using immunohistochemistry in tissue microarray of localized prostate cancer (PC). MATERIALS AND METHODS: Immune expression of MMP-9, MMP-2, TIMP1, TIMP-2, MMP-14 and IL8, were analyzed by immunohistochemistry in radical prostatectomy specimens of 40 patients with localized PC who underwent surgery between September 1997 and February 2000. Protein expression was considered as categorical variables, negative or positive. The results of the immune-expression were correlated to Gleason score (GS), pathological stage (TNM), pre-operatory PSA serum levels and biochemical recurrence in a mean follow up period of 92.5 months. RESULTS: The loss of TIMP1 immune-expression was related to biochemical recurrence. When TIMP1 was negative, 56.3% patients recurred versus 22.2% of those whose TIMP1 was positive (p=0.042). MMP-9, MMP-2, IL8 and MMP-14 were positive in the majority of PC. TIMP-2 was negative in all cases. CONCLUSION: Negative immune-expression of TIMP1 is correlated with biochemical recurrence in patients with PC possibly by failing to control MMP-9, an important MMP related to cancer progression. PMID- 26742969 TI - Effect of mitochondrial potassium channel on the renal protection mediated by sodium thiosulfate against ethylene glycol induced nephrolithiasis in rat model. AB - PURPOSE: Sodium thiosulfate (STS) is clinically reported to be a promising drug in preventing nephrolithiasis. However, its mechanism of action remains unclear. In the present study, we investigated the role of mitochondrial KATP channel in the renal protection mediated by STS. MATERIALS AND METHODS: Nephrolithiasis was induced in Wistar rats by administrating 0.4% ethylene glycol (EG) along with 1% ammonium chloride for one week in drinking water followed by only 0.75% EG for two weeks. Treatment groups received STS, mitochondrial KATP channel opener and closer exclusively or in combination with STS for two weeks. RESULTS: Animals treated with STS showed normal renal tissue architecture, supported by near normal serum creatinine, urea and ALP activity. Diazoxide (mitochondria KATP channel opening) treatment to the animal also showed normal renal tissue histology and improved serum chemistry. However, an opposite result was shown by glibenclamide (mitochondria KATP channel closer) treated rats. STS administered along with diazoxide negated the renal protection rendered by diazoxide alone, while it imparted protection to the glibenclamide treated rats, formulating a mitochondria modulated STS action. CONCLUSION: The present study confirmed that STS render renal protection not only through chelation and antioxidant effect but also by modulating the mitochondrial KATP channel for preventing urolithiasis. PMID- 26742970 TI - Hemorrhagic Cystitis Requiring Bladder Irrigation is Associated with Poor Mortality in Hospitalized Stem Cell Transplant Patients. AB - PURPOSE: To evaluate the overall prognosis of post-stem cell transplant inpatients who required continuous bladder irrigation (CBI) for hematuria. MATERIALS AND METHODS: We performed a retrospective analysis of adult stem cell transplant recipients who received CBI for de novo hemorrhagic cystitis as inpatients on the bone marrow transplant service at Washington University from 2011-2013. Patients who had a history of genitourinary malignancy and/or recent surgical urologic intervention were excluded. Multiple variables were examined for association with death. RESULTS: Thirty-three patients met our inclusion criteria, with a mean age of 48 years (23-65). Common malignancies included acute myelogenous leukemia (17/33, 57%), acute lymphocytic leukemia (3/33, 10%), and peripheral T cell lymphoma (3/33, 10%). Median time from stem cell transplant to need for CBI was 2.5 months (0 days-6.6 years). All patients had previously undergone chemotherapy (33/33, 100%) and 14 had undergone prior radiation therapy (14/33, 42%). Twenty-eight patients had an infectious disease (28/33, 85%), most commonly BK viremia (19/33, 58%), cytomegalovirus viremia (17/33, 51%), and bacterial urinary tract infection (8/33, 24%). Twenty-two patients expired during the same admission as CBI treatment (22/33 or 67% of total patients, 22/28 or 79% of deaths), with a 30-day mortality of 52% and a 90-day mortality of 73% from the start of CBI. CONCLUSIONS: Hemorrhagic cystitis requiring CBI is a symptom of severe systemic disease in stem cell transplant patients. The need for CBI administration may be a marker for mortality risk from a variety of systemic insults, rather than directly attributable to the hematuria. PMID- 26742971 TI - Efficacy of botulinum toxin type A 100 Units versus 200 units for treatment of refractory idiopathic overactive bladder. AB - OBJECTIVE: To evaluate the efficacy and safety of a single intra detrusor injection of BoNTA comparing two different doses (100 U or 200 U) in patients with idiopathic overactive bladder. MATERIALS AND METHODS: A randomized prospective study evaluated the efficacy of BoNTA in management of refractory idiopathic overactive bladder and included 80 patients. All patients were assessed initially by taking a history, a physical examination, overactive bladder symptom score, urine analysis, routine laboratory investigations, KUB and pelviabdominal. OABSS was adjusted on all patients postoperative at 1,3,6,9 months also Urodynamic was done for all patients preoperative and postoperative at 3, 6, 9 months. RESULTS: The mean age was 30.22+/-8.37 and 31.35+/-7.61 in group I and II respectively. There was no statistically difference between both groups in all parameters all over the study except at 9 months after treatment. Hematuria was observed 6 and 9 patients in group I and II respectively. Dysuria was observed in 6 and 15 patients in group I and II respectively. UTI was detected in 3 and 7 patients in group I and II respectively. CONCLUSION: A single injection procedure of 100 U or 200 U BoNTA is an effective and safe treatment for patients with IOAB who failed anticholinergic regimens. OABSS and QoL were improved for 6 months; 100 U injections seemed to have comparable results with 200 U. There was a significant difference at month 9 towards 200 U with more incidences of adverse events. PMID- 26742972 TI - Sphingosine Kinase 1 urothelial expression is increased in patients with neurogenic detrusor overactivity. AB - To evaluate the expression of sphingosine kinase 1 (SPK1) in the bladder wall in patients with neurogenic lower urinary tract dysfunction and its association with clinical, urodynamic and pathological features. MATERIALS AND METHODS: The expression of SPK1 was studied in bladder wall specimens obtained from cystectomy using immunohistochemistry in ten patients with spinal cord injury (n=8) or multiple sclerosis (n=2) with urodynamically proven neuropathic bladder dysfunction, and in controls (n=5). Inflammation and fibrosis were analysed with histological criteria and SPK1 expression was determined by individual immunohistochemical staining. RESULTS: Significant increased SPK1 urothelial immunoreactivity was shown in patients compared to control group (p=0.03). By contrast, SPK1 immunoreactivity in patients was significantly decreased in the sub-urothelium, muscles and nerves, p=0.02; 0.01 and 0.003, respectively. Patients with neurogenic detrusor overactivity (NDO) had higher SPK1 urothelium expression than those without any DO (p=0.04). CONCLUSIONS: SPK1 is expressed in the human bladder wall, specifically the urothelium, in bladder specimens from patients with NDO. The role of SPK1 in the pathophysiology of NDO needs further elucidation. PMID- 26742973 TI - Experimental use of a cellulosic biopolymer as a new material for suburethral sling in the treatment of stress urinary incontinence. AB - PURPOSE: To analyze the interaction between the cellulose exopolysaccharide (CEC) and urethral tissue when used as a pubovaginal sling. MATERIALS AND METHODS: Forty Wistar rats were divided into four groups. In groups A and B the cellulose exopolysaccharide (CEC) was implanted around the urethral tissue (bladder neck below the upper margin) and the rats were sacrificed at 30 and 90 days. Similar procedure was used in groups C and D using a polypropylene mesh. After sacrifice bladder and urethra were sent for histological analysis. The histological parameters (inflammatory reaction) by evaluated by quantitative analysis. For collagen deposition analysis it was used stereological method. RESULTS: The cellulose exopolysaccharide (CEC) was inert and well preserved at the implanted region at the time of examination. Morphologic alterations were not found at the CEC implant but some reactions of foreign body type were observed at the adjacent structures. In some areas a process of neovascular formation was observed. Stereological analysis at the suburethral area showed a significant difference in collagen presence in favor of CEC. CONCLUSIONS: The CEC implant showed adequate results when used as a suburethral sling with good integration to the host tissue, preserving its architecture. PMID- 26742974 TI - Contemporary Series of Robotic-Assisted Distal Ureteral Reconstruction Utilizing Side Docking Position. AB - PURPOSE: The robot-assisted approach to distal ureteral reconstruction is increasingly utilized. Traditionally, the robot is docked between the legs in lithotomy position resulting in limited bladder access for stent placement. We examined the use of side docking of the daVinci robot(r) to perform distal ureteral reconstruction. MATERIALS AND METHODS: A retrospective review of distal ureteral reconstruction (ureteral reimplantation and uretero-ureterostomy) executed robotically was performed at a single institution by a single surgeon. The daVinci robotic(r) Si surgical platform was positioned at the right side of the patient facing towards the head of the patient, i.e. side docking. RESULTS: A total of 14 cases were identified from 2011-2013. Nine patients underwent ureteral reimplantation for ureteral injury, two for vesicoureteral reflux, one for ureteral stricture, and one for megaureter. One patient had an uretero ureterostomy for a distal stricture. Three patients required a Boari flap due to extensive ureteral injury. Mean operative time was 286 minutes (189-364), mean estimated blood loss was 40cc (10-200), and mean length of stay was 2.3 days (1 4). Follow-up renal ultrasound was available for review in 10/14 patients and revealed no long-term complications in any patient. Mean follow-up was 20.7 months (0.1-59.3). CONCLUSION: Robot-assisted laparoscopic distal ureteral reconstruction is safe and effective. Side docking of the robot allows ready access to the perineum and acceptable placement of the robot to successfully complete ureteral repair. PMID- 26742975 TI - Serum interleukin -8 is not a reliable marker for prediction of vesicoureteral reflux in children with febrile urinary tract infection. AB - OBJECTIVE: In view of the side effects of voiding cystourethrography (VCUG), identification of noninvasive markers predicting the presence of vesicoureteral reflux (VUR) is important. This study was conducted to determine the predictive value of serum interleukin-8 (IL-8) in diagnosis of VUR in children with first febrile urinary tract infection (UTI). MATERIALS AND METHODS: Eighty children with first febrile UTI were divided into two groups, with and without VUR, based on the results of VCUG .The sensitivity, specificity, positive and negative predictive value positive and negative likelihood ratio, and accuracy of IL-8 for prediction of VUR were investigated. RESULTS: Of the 80 children with febrile UTI, 30 (37.5%) had VUR. There was no significant difference between the children with and without VUR and also between low and high-grade VUR groups in terms of serum concentration of IL-8 (P>0.05). Based on ROC curve, the sensitivity, specificity, likelihood ratio positive, and accuracy of serum IL-8 was lower than those of erythrocyte sedimentation rate and C-reactive protein. Multivariate logistic regression analysis showed significant positive correlation only between erythrocyte sedimentation rate and VUR. CONCLUSIONS: This study showed no significant difference between the children with and without VUR in terms of the serum concentration of IL-8. Therefore, it seems that serum IL-8 is not a reliable marker for prediction of VUR. PMID- 26742976 TI - Outcomes of Prostate Biopsy in Men with Hypogonadism Prior or During Testosterone Replacement Therapy. AB - INTRODUCTION: The relationship between Testosterone Replacement Therapy (TRT) and prostate cancer remains controversial. Most TRT studies show no change in prostate specific antigen (PSA) but some men do have PSA rise or develop an abnormal digital rectal exam (aDRE). Our objective was to examine the biopsy results of men with symptomatic hypogonadism before or during therapy. MATERIALS AND METHODS: Data was extracted from our medical record on men with hypogonadism who had a prostate biopsy within the past 4 years done by 3 Urologists with guideline driven practice patterns. RESULTS: 96 men were identified. Mean age at biopsy was 63 (range 40-85) and median PSA was 3.78ng/dL (0.5-662). Of the 61 men not on TRT, median PSA was 4.34 (0.5 to 662) and mean total testosterone 254 (191 341). There were 29 (47.5%) prostate cancers found (6 Gleason score 6, 13 Gleason score 7, 10 Gleason score 8 or 9). Of the 35 men on TRT, median PSA was 3.27 (0.5 to 13.7). The %PSA increase ranged from 2 to 251% (mean 93.5%). Mean total testosterone was 383 (146-792). Of the 14 men treated < 2 years, none had cancer. Of the 21 men treated 2 or more years 5 had cancer (2 Gleason score 6, 3 Gleason score 7). CONCLUSIONS: Men with hypogonadism and a clinical indication for biopsy often have prostate cancer, many high grade. No men with an initial PSA rise on TRT had cancer. Men on long term TRT should be monitored with PSA and DRE per guidelines. PMID- 26742978 TI - Comparison of Cajal-like cells in pelvis and proximal ureter of kidney with and without hydronephrosis. AB - OBJECTIVES: To evaluate effects of Cajal-like cells on human renal pelvis and proximal ureter on peristalsis. MATERIALS AND METHODS: 63 patients submitted to nephrectomy due to atrophic non-functional kidney associated with hydroureteronephrosis were included as study group and 30 cases with nephrectomy due to other reasons were included as control group. Samples from renal pelvis and proximal ureters were obtained and sections of 5u form paraffin blocks of these samples were prepared; layers of lamina propria and muscularis mucosa were examined by immune-histochemistry using CD117 in order to determine count and distribution of Cajal-like cells. RESULTS: During immune-histochemical examinations of sections, obtained from renal pelvis and proximal ureter of hydronephrotic kidneys by CD117, Cajal-like cells number determined in lamina propria and muscularis propria was statistically significantly lower compared to control group (p<0.001). Distribution of Cajal-like cells in renal pelvis and proximal tubulus was similar under examination by light microscope, and also both groups were not different from each other regarding staining intensity of Cajal like cells by c-kit. CONCLUSION: Significantly reduced number of Cajal-like cells in study group compared to control group, shows that these cells may have a key role in regulation of peristalsis at level of renal pelvis and proximal ureter in urinary system. PMID- 26742977 TI - Prospective comparison of ligation and bipolar cautery technique in non-scalpel vasectomy. AB - OBJECTIVES: There is no trial comparing bipolar cautery and ligation for occlusion of vas in non-scalpel vasectomy. This study aimed to compare the effectiveness of these vasectomy occlusion techniques. MATERIALS AND METHODS: Between January 2002-June 2009, patients were allocated in alternate order. We recruited 100 cases in cautery group and 100 cases in ligation group. Non-scalpel approach was performed during vasectomy and fascial interposition was performed in all cases. First semen analysis was done 3 months after vasectomy. Vasectomy success was defined as azoospermia or non-motile sperm lower than 100.000/mL. RESULTS: Four patients from the cautery group were switched to the ligation group due to technical problem of cautery device. Thus, data of 96 patients as cautery group and 104 patients as ligation group were evaluated. After vasectomy, semen analyses were obtained from 59 of 96 (61.5%) patients in cautery group and to 66 of 104 (63.5%) patients in ligation group. There was no statistical significant difference between the two groups in terms of the success of vasectomy (p=0.863). CONCLUSION: Although bipolar cautery technique is safe, effective and feasible in non-scalpel vasectomy, it has no superiority to ligation. There was no statistically significant difference in terms of the success and complications between the two groups. PMID- 26742980 TI - Bladder response to acute sacral neuromodulation while treating rats in different phases of complete spinal cord injury: a preliminary study. AB - BACKGROUND: Compared to conventional therapies, sacral neuromodulation (SNM) may offer an alternative, non-destructive treatment for SCI patients with bladder dysfunction. Understanding bladder response to SNM treatment for SCI in different phases may yield new insights for innovative use of this promising technique. MATERIALS AND METHODS: Female Sprague-Dawley rats were used in this study to examine the effects of acute SNM on bladder reflex in complete SCI rats. All rats were anesthetized and set up for continuous saline infusion. Acute SNM treatment was implemented for about 6 hours for each rat. Cystometric parameters, including time between contractions, contraction duration, bladder peak pressure, and number of uninhibited contractions, were analyzed and compared within rats before and after SNM treatment. RESULTS: For the spinally transected rats during early phase (less than two weeks post spinalization), the time between contractions and contraction duration both increased after SNM treatments, yet the increased amplitude was about or less than 20%. For the spinally transected rats with a longer days survival (about two to four weeks post spinalization), the time between contractions and contraction duration substantially increased after SNM treatment and the changes for their average values were more than 90%. For the spinally transected rats with a much longer days survival (more than five weeks post spinalization), the time between contractions and contraction duration increased after SNM treatments, yet the magnitude of changes were less than 30%. CONCLUSION: The present study suggested that the significant effectiveness of SNM for complete SCI played its role after the spinal shock phase and prior to the development of detrusor overactivity. It indicated that the time point of SNM treatment is necessary to be paid attention. PMID- 26742979 TI - Protective effect of hydrogen sulfide on renal injury in the experimental unilateral ureteral obstruction. AB - INTRODUCTION/OBJECTIVE: Ureteral obstruction is a common pathology and causes kidney fibrosis and dysfunction at late period. In this present study, we investigated the antifibrotic and antiinflammatory effects of hydrogen sulfide on kidney damage after unilateral ureteral obstruction (UUO) in rats. MATERIALS AND METHODS: 24 rats were divided into four groups. Group 1 was control, group 2 was sham, group 3 included rats with UUO and group 4 rats with UUO which were given sodium hydrogen sulfide (NaHS)-exogenous donor of hydrogen sulfide (intraperitoneally 56 umoL/kg/day). After 14 days, rats were killed and their kidneys were taken and blood analysis was performed. Tubular necrosis, mononuclear cell infiltration and interstitial fibrosis were determined histopathologically in a part of the kidneys; nitric oxide (NO), malondialdehyde (MDA) and reduced glutathione (GSH) levels were determined in the other part of the kidneys. Urea-creatinine levels were investigated by blood analysis. Statistical analyses were made by the Chi-square test and one-way analysis of variance (ANOVA). RESULTS: There was no significantly difference for urea creatinine levels among groups. Pathologically, there was serious tubular necrosis and fibrosis in group 3 and there was significantly decreasing of tubular necrosis and fibrosis in group 4 (p<0.005). Also, there was significantly increase of NO and MDA levels and decrease of GSH levels in group 3 compared to other groups (p<0.005). CONCLUSIONS: hydrogen sulfide prevents kidney damage with antioxidant and antiinflammatory effect. PMID- 26742981 TI - The evaluation of pulmonary function and blood gas analysis in patients submitted to laparoscopic versus open nephrectomy. AB - BACKGROUND: The aim of this study was to assess the early postoperative pulmonary function and arterial blood gases in patients who have undergone open versus laparoscopic nephrectomy. MATERIALS AND METHODS: Forty patients were randomly assigned to undergo laparoscopic (LN, n=20) or open nephrectomy (ON, n=20). Pulmonary function tests including forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), forced expiratory volume at 25% (FEF25), forced expiratory volume at 50% (FEF50), forced expiratory volume at 25% to 75% (FEF25 75), forced expiratory volume in 1 second (FIV1) and peak expiratory flow (PEF) were performed one day before the operation and on the postoperative day 1. The arterial blood gas analysis (pH, pCO2, pO2, SaO2) was made at breathing room preoperatively, in the recovery phase and on postoperative day 1. RESULTS: All spirometric variables decreased after both open and laparoscopic nephrectomy on postoperative day 1. FEV1, FVC, FEF25 and FEF25-75 values decreased on postoperative day 1 (39.7%, 37.4%, 27.7%, 51.8% respectively) in the open surgery group and they were significantly lower in laparoscopic group (29.9%, 32.5%, 23.2%, 44.5% respectively). There were no significant differences in FEF50, PEF and FIV1 between the groups. The SaO2 and pO2 values also decreased in both groups. During early recovery, pH decreased while pCO2 increased significantly but they returned to preoperative values on postoperative day 1 in both groups. CONCLUSION: Laparoscopic nephrectomy is better than open nephrectomy considering pulmonary functions. PMID- 26742983 TI - Pregnancy and birth after intracytoplasmic sperm injection with normal testicular spermatozoa in a patient with azoospermia and tail stump epididymal sperm. AB - MAIN FINDINGS: An intriguing yet perplexing case report of a successful pregnancy and live birth with intracytoplasmic sperm injection using normal testicular sperm, after the finding of azoospermia in the semen analysis and discovering only tail stump abnormal sperm in the epididymis. Case hypothesis: A tail stump sperm defect of genetic origin was suspected. However, after obtaining normal testicular sperm we concluded that obstructive azoospermia, either idiopathic or secondary to multiple minor genital trauma was the plausible scenario. This has rendered the search of previous reports on a similar condition, but none was found. However, it has raised scientific thoughts for future research. Promising future implications: The importance of reporting this case is to alert urologists performing sperm retrieval that healthy and morphologically normal sperm may be found in the testis of azoospermic men with 100% tail stump epididymal sperm. Retrieval of normal testicular sperm obviates the need of a more complex investigation, including sperm electron microscopy. It also offers the possibility of utilizing such gametes for sperm injections rather than abnormal tail stump sperm that may be associated with a poor reproductive outcome. PMID- 26742984 TI - Adult granulosa cell tumor of the testis masquerading as hydrocele. AB - Adult testicular granulosa cell tumor is a rare, potentially malignant sex cord stromal tumor, of which 30 cases have been described to date. We report the case of a 43-year-old male who complained of a left testicular swelling. Scrotal ultrasound showed a cystic lesion, suggestive of hydrocele. However, due to a clinical suspicion of a solid-cystic neoplasm, a high inguinal orchidectomy was performed, which, on pathological examination, was diagnosed as adult granulosa cell tumor. Adult testicular granulosa cell tumors have aggressive behaviour as compared to their ovarian counterparts. They may rarely be predominantly cystic and present as hydrocele. Lymph node and distant metastases have been reported in few cases. Role of MIB-1 labelling index in prognostication is not well defined. Therefore, their recognition and documentation of their behaviour is important from a diagnostic, prognostic and therapeutic point of view. PMID- 26742985 TI - Pancake kidney with bladder herniation. PMID- 26742982 TI - Robot-Assisted Extended Pelvic Lymph Nodes Dissection for Prostate Cancer: Personal Surgical Technique and Outcomes. AB - OBJECTIVE: Extended pelvic lymph nodes dissection (EPLND) allows the removal of a higher number of lymph nodes than limited PLND. The aims of this study were to describe our robot-assisted EPLND (RAEPLND) technique with related complications, and to report the number of lymph nodes removed and the rate of lymph nodal metastasis. MATERIALS AND METHODS: 153 patients underwent RAEPLND prior to robot assisted radical prostatectomy (RARP). Indications were defined according to Briganti nomogram, to predict risk of lymph-nodal metastasis. Lymphatic packages covering the distal tract of the common iliac artery, the medial portion of the external iliac artery, the external iliac vein and the internal iliac vessels, together with the obturator and the presacral lymphatic packages were removed on both sides. RESULTS: Median preoperative PSA was 7.5 ng/mL (IQR 5.5-11.5). Median operative time was 150 min (135-170). Median RAEPLND alone operative time was 38 min (32.75-41.25); for right and left side, 18 (15-29) and 20 min (15.75-30) (p=0.567). Median number of lymph nodes retrieved per patient was 25 (19.25-30); 13 (11-16) and 11 (8-15) for right and left side. In 19 patients (12.41%) metastasis was found at the level of pelvic lymph nodes. Median number of positive lymph nodes was 1 (1-4.6) per patient. Complications occurred in 11 patients (7.3%). CONCLUSIONS: the number of lymph nodes removed was comparable to published data about open series, allowing the increase of detection rate of lymph nodal metastasis for minimally invasive approach without compromising complications' rate if performing the procedure following reported technique. PMID- 26742986 TI - Resection of the Urethral Plate and Augmented Ventral Buccal Graft in Patients with Long Obliterative Urethral Strictures. AB - Video available at: http://www.brazjurol.com.br/videos/november_december_2015/Ignjatovic_1234_1235vid o.htm PMID- 26742987 TI - Re: Mini incision open pyeloplasty--improvement in patient outcome. PMID- 26742988 TI - Effects of Perceived Discrimination on Depressive Symptoms Among Black Men Residing in the United States: A Meta-Analysis. AB - Research reports that perceived discrimination is positively associated with depressive symptoms. The literature is limited when examining this relationship among Black men. This meta-analysis systematically examines the current literature and investigates the relationship of perceived discrimination on depressive symptoms among Black men residing in the United States. Using a random effects model, study findings indicate a positive association between perceived discrimination and depressive symptoms among Black men ( r = .29). Several potential moderators were also examined in this study; however, there were no significant moderation effects detected. Recommendations and implications for future research and practice are discussed. PMID- 26742990 TI - The detection of magnetotactic bacteria in deep sea sediments from the east Pacific Manganese Nodule Province. AB - Magnetotactic bacteria (MTB) are distributed ubiquitously in sediments from coastal environments to the deep sea. The Pacific Manganese Nodule Province contains numerous polymetallic nodules mainly composed of manganese, iron, cobalt, copper and nickel. In the present study we used Illumina MiSeq sequencing technology to assess the communities of putative MTB in deep sea surface sediments at nine stations in the east Pacific Manganese Nodule Province. A total of 402 sequence reads from MTB were classified into six operational taxonomic units (OTUs). Among these, OTU113 and OTU759 were affiliated with the genus Magnetospira, OTU2224 and OTU2794 were affiliated with the genus Magnetococcus and Magnetovibrio, respectively, OTU3017 had no known genus affiliation, and OTU2556 was most similar to Candidatus Magnetananas. Interestingly, OTU759 was widely distributed, occurring at all study sites. Magnetism measurements revealed that all sediments were dominated by low coercivity, non-interacting single domain magnetic minerals. Transmission electron microscopy confirmed that the magnetic minerals were magnetosomes. Our data suggest that diverse putative MTB are widely distributed in deep sea surface sediments from the east Pacific Manganese Nodule Province. PMID- 26742989 TI - Expression of immunogenic structural proteins of cyprinid herpesvirus 3 in vitro assessed using immunofluorescence. AB - Cyprinid herpesvirus 3 (CyHV-3), also called koi herpesvirus (KHV), is the aetiological agent of a fatal disease in carp and koi (Cyprinus carpio L.), referred to as koi herpesvirus disease. The virus contains at least 40 structural proteins, of which few have been characterised with respect to their immunogenicity. Indirect immunofluorescence assays (IFAs) using two epitope specific monoclonal antibodies (MAbs) were used to examine the expression kinetics of two potentially immunogenic and diagnostically relevant viral antigens, an envelope glycoprotein and a capsid-associated protein. The rate of expression of these antigens was determined following a time-course of infection in two CyHV-3 susceptible cell lines. The results were quantified using an IFA, performed in microtitre plates, and image analysis was used to analyse confocal micrographs, enabling measurement of differential virus-associated fluorescence and nucleus-associated fluorescence from stacks of captured scans. An 8-tenfold increase in capsid-associated protein expression was observed during the first 5 days post-infection compared to a <= 2-fold increase in glycoprotein expression. A dominant protein of ~100 kDa reacted with the capsid-associated MAb (20F10) in western blot analysis. This band was also recognised by sera obtained from carp infected with CyHV-3, indicating that this capsid-associated protein is produced in abundance during infection in vitro and is immunogenic to carp. Mass spectrometry carried out on this protein identified it as a previously uncharacterised product of open reading frame 84. This abundantly expressed and immunogenic capsid-associated antigen may be a useful candidate for KHV serological diagnostics. PMID- 26742991 TI - Burnout among anaesthetists in Chinese hospitals: a multicentre, cross-sectional survey in 6 provinces. AB - OBJECTIVES: Anesthesiology has reached a new stage which anaesthesia safety is significantly affected by human factors. The number of Chinese anaesthetists has increased to nearly twice as many as that in 2005. Attributed to traditional concepts, many problems in anesthesiology persist in Chinese hospitals. This study aims to determine the current status of anaesthesia job burnout, including problems related to burnout, as well as the conditions of anaesthesia human resources in Chinese hospitals. METHODS: A multi-center, cross-sectional survey of 395 anaesthetists from 60 hospitals in 6 provinces was conducted to collect data on the work conditions of anesthesiologists by using questionnaires. The Maslach Burnout Inventory (MBI) was used to measure burnout. Different statistical models were also used to evaluate the data. RESULTS: The number of Chinese anaesthetists has increased to nearly twice as many as that in 2005. According to our field survey of burnout among anaesthetists, only 17 (4.30%) respondents exhibited high levels of burnout. The average scores corresponding to the dimensions of burnout are 14.64 +/- 11.40 (emotional exhaustion, EE), 4.22 +/ 5.74 (depersonalization, DP), and 33.41 +/- 10.05 (personal accomplishment, PA), as determined by MBI. These results indicate the differences in the spatial distribution of anaesthetists. Moreover, 15.3% of the anaesthetists showed high EE, 8.1% exhibited high DP, and 33.6% had low PA. CONCLUSION: Anxiety and undesirable conditions experienced by professional groups in anaesthesiology need to be addressed. Educational level, an important factor in anaesthesia care, influences not only psychological health of practitioners but patient safety as well. Thus, personnel structure must be optimized to relieve tension in the practice of the profession and reduce burnout among anaesthetists in hospitals in China. Meanwhile, the management must increase its effort toward improving the mental health of practitioners and patient safety in anaesthesia care. PMID- 26742992 TI - Forming a joint dialogue among faith healers, traditional healers and formal health workers in mental health in a Kenyan setting: towards common grounds. AB - BACKGROUND: Qualitative evidence on dialogue formation and collaboration is very scanty in Kenya. This study thus aimed at the formation of dialogue and establishment of collaboration among the informal (faith and traditional healers) and formal health workers (clinicians) in enhancing community-based mental health in rural Kenya. METHODS: Qualitative approach was used to identify barriers and solutions for dialogue formation by conducting nine Focus Group Discussions each consisting of 8-10 participants. Information on age, gender and role in health care setting as well as practitioners' (henceforth used to mean informal (faith and traditional healers) and formal health workers) perceptions on dialogue was collected to evaluate dialogue formation. Qualitative and quantitative data analysis was performed using thematic content analysis and Statistical Package Social Sciences (SPSS) software respectively. RESULTS: We identified four dominant themes such as; (i) basic understanding about mental illnesses, (ii) interaction and treatment skills of the respondents to mentally ill persons, (iii) referral gaps and mistrust among the practitioners and (iv) dialogue formation among the practitioners. Although participants were conversant with the definition of mental illness and had interacted with a mentally ill person in their routine practice, they had basic information on the causes and types of mental illness. Traditional and faith healers felt demeaned by the clinicians who disregarded their mode of treatment stereotyping them as "dirty". After various discussions, majority of practitioners showed interest in collaborating with each other and stated that they had joined the dialogue in order interact with people committed to improving the lives of patients. CONCLUSION: Dialogue formation between the formal and the informal health workers is crucial in establishing trust and respect between both practitioners and in improving mental health care in Kenya. This approach could be scaled up among all the registered traditional and faith healers in Kenya. PMID- 26742994 TI - Bruno Danieli (1939-2014). PMID- 26742993 TI - Interchangeable SF3B1 inhibitors interfere with pre-mRNA splicing at multiple stages. AB - The protein SF3B1 is a core component of the spliceosome, the large ribonucleoprotein complex responsible for pre-mRNA splicing. Interest in SF3B1 intensified when tumor exome sequencing revealed frequent specific SF3B1 mutations in a variety of neoplasia and when SF3B1 was identified as the target of three different cancer cell growth inhibitors. A better mechanistic understanding of SF3B1's role in splicing is required to capitalize on these discoveries. Using the inhibitor compounds, we probed SF3B1 function in the spliceosome in an in vitro splicing system. Formerly, the inhibitors were shown to block early steps of spliceosome assembly, consistent with a previously determined role of SF3B1 in intron recognition. We now report that SF3B1 inhibitors also interfere with later events in the spliceosome cycle, including exon ligation. These observations are consistent with a requirement for SF3B1 throughout the splicing process. Additional experiments aimed at understanding how three structurally distinct molecules produce nearly identical effects on splicing revealed that inactive analogs of each compound interchangeably compete with the active inhibitors to restore splicing. The competition indicates that all three types of compounds interact with the same site on SF3B1 and likely interfere with its function by the same mechanism, supporting a shared pharmacophore model. It also suggests that SF3B1 inhibition does not result from binding alone, but is consistent with a model in which the compounds affect a conformational change in the protein. Together, our studies reveal new mechanistic insight into SF3B1 as a principal player in the spliceosome and as a target of inhibitor compounds. PMID- 26742995 TI - Two new peroxy fatty acids with antibacterial activity from Ophioglossum thermale Kom. AB - Two new peroxy fatty acids, thermalic acids A (1) and B (2), together with eight known compounds, (3beta)-methyl-3-hydroxy-urs-11-en-28 oate (3), luteolin (4), quercetin (5), 3-methoxyquercetin (6), ophioglonol (7), ophioglonol 4'-O-alpha-D glucopyranoside (8), pedunculosumoside B (9), syringol (10), were isolated from the herba of Ophioglossum thermale Kom. The structures of 1 and 2 were identified by HRESIMS, EIMS, 1D and 2D NMR, and electronic circular dichroism (ECD) spectra. Both two acids exhibited potential antibacterial activities against Staphylococcus aureus, Bacillus subtilis, and Escherichia coli. This is the first report of peroxy fatty acids isolated from herbaceous plants of Ophioglossaceae. PMID- 26742996 TI - Young Sexual Minority Males in the United States: Sociodemographic Characteristics And Sexual Attraction, Identity and Behavior. AB - CONTEXT: HIV incidence is increasing among 13-24-year-old U.S. men who have sex with men, yet limited research is available to guide HIV prevention efforts for this population. METHODS: National Survey of Family Growth data collected in 2002, in 2006-2010 and in 2011-2013 from 8,068 males aged 15-24 were analyzed to describe the population of U.S. young sexual minority males (i.e., males reporting same-sex attraction, identity or behavior). Correlates of sexual minority classification were assessed in logistic regression models. RESULTS: An estimated 10% of young males, representing a population of 2.1 million, were sexual minorities. Males had an elevated likelihood of being sexual minorities if they were aged 18-19 or 20-24, rather than 15-17 (prevalence ratio, 1.7 for each); belonged to nonblack, non-Hispanic racial or ethnic minority groups (1.6); had no religious affiliation, rather than considering religion very important (1.9); or lived below the federal poverty level (1.3). They had a reduced likelihood of being sexual minorities if they lived in metropolitan areas outside of central cities (0.7). Among young sexual minority males, 44% were 15-19 years old, 29% were poor and 59% resided outside central cities. Forty-seven percent had engaged in same-sex behavior. Of those with data on all measured dimensions of sexuality, 24% reported same-sex attraction, identity and behavior; 22% considered themselves heterosexual, yet had had a male sex partner. CONCLUSION: Future investigations can further explore subpopulations of young sexual minority males and assess sexual trajectories, resilience and HIV risk. PMID- 26742997 TI - Helicenes--A New Class of Organic Spin Filter. AB - Chiral helicene, a fully conjugated system without stereogenic carbon, can filter spins effectively at room temperature, a consequence of the chiral-induced spin selectivity effect. The chirality dictates the spin of the electrons transferred through helicene, and magnetoresistance devices based on these molecules show antisymmetric magnetoresistance versus H plots. PMID- 26742998 TI - Cancer statistics, 2016. AB - Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program), the Centers for Disease Control and Prevention (National Program of Cancer Registries), and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2016, 1,685,210 new cancer cases and 595,690 cancer deaths are projected to occur in the United States. Overall cancer incidence trends (13 oldest SEER registries) are stable in women, but declining by 3.1% per year in men (from 2009-2012), much of which is because of recent rapid declines in prostate cancer diagnoses. The cancer death rate has dropped by 23% since 1991, translating to more than 1.7 million deaths averted through 2012. Despite this progress, death rates are increasing for cancers of the liver, pancreas, and uterine corpus, and cancer is now the leading cause of death in 21 states, primarily due to exceptionally large reductions in death from heart disease. Among children and adolescents (aged birth-19 years), brain cancer has surpassed leukemia as the leading cause of cancer death because of the dramatic therapeutic advances against leukemia. Accelerating progress against cancer requires both increased national investment in cancer research and the application of existing cancer control knowledge across all segments of the population. PMID- 26743000 TI - Former ministers call for commission to review NHS and social care funding. PMID- 26742999 TI - Text Messaging for Exercise Promotion in Older Adults From an Upper-Middle-Income Country: Randomized Controlled Trial. AB - BACKGROUND: Mobile technology to promote exercise is effective; however, most evidence is from studies of younger groups in high-income countries. Investigating if short message service (SMS) texting can affect exercise participation in older adults from an upper-middle-income country is important considering the proliferation of mobile phones in developing regions and the increased interest of older adults in using mobile phones. OBJECTIVE: The main objective was to examine the short- and long-term effects of SMS text messaging on exercise frequency in older adults. Secondary objectives were to investigate how SMS text messages impact study participants' exercise frequency and the effects of the intervention on secondary outcomes. METHODS: The Malaysian Physical Activity for Health Study (myPAtHS) was a 24-week, 2-arm, parallel randomized controlled trial conducted in urban Malaysia. Participants were recruited via health talks in resident associations and religious facilities. Older Malaysians (aged 55-70 years) who used mobile phones and did not exercise regularly were eligible to participate in the study. Participants randomly allocated to the SMS texting arm received an exercise booklet and 5 weekly SMS text messages over 12 weeks. The content of the SMS text messages was derived from effective behavior change techniques. The non-SMS texting arm participants received only the exercise booklet. Home visits were conducted to collect outcome data: (1) exercise frequency at 12 and 24 weeks, (2) secondary outcome data (exercise self-efficacy, physical activity-related energy expenditure, sitting time, body mass index, grip and leg strength) at baseline and at 12 and 24 weeks. Intention-to-treat procedures were applied for data analysis. Semistructured interviews focusing primarily on the SMS text messages and their impact on exercise frequency were conducted at weeks 12 and 24. RESULTS: In total, 43 participants were randomized into the SMS texting arm (n=22) and the non-SMS texting arm (n=21). Study-unrelated injuries forced 4 participants to discontinue after a few weeks (they were not included in any analyses). Overall retention was 86% (37/43). After 12 weeks, SMS texting arm participants exercised significantly more than non-SMS texting arm participants (mean difference 1.21 times, bias corrected and accelerated bootstrap [BCa] 95% CI 0.18-2.24). Interview analysis revealed that the SMS text messages positively influenced SMS texting arm participants who experienced exercise barriers. They described the SMS text messages as being encouraging, a push, and a reminder. After 24 weeks, there was no significant difference between the research arms (mean difference 0.74, BCa 95% CI -0.30 to 1.76). There were no significant effects for secondary outcomes. CONCLUSIONS: This study provides evidence that SMS text messaging is effective in promoting exercise in older adults from an upper-middle-income country. Although the effects were not maintained when SMS text messaging ceased, the results are promising and warrant more research on behavioral mobile health interventions in other regions. TRIAL REGISTRATION: Clinicaltrials.gov NCT02123342; http://clinicaltrials.gov/ct2/show/NCT02123342 (Archived by WebCite at http://www.webcitation.org/6eGSsu2EI). PMID- 26743001 TI - The structure and DNA-binding properties of Mgm101 from a yeast with a linear mitochondrial genome. AB - To study the mechanisms involved in the maintenance of a linear mitochondrial genome we investigated the biochemical properties of the recombination protein Mgm101 from Candida parapsilosis. We show that CpMgm101 complements defects associated with the Saccharomyces cerevisiae mgm101-1(ts) mutation and that it is present in both the nucleus and mitochondrial nucleoids of C. parapsilosis. Unlike its S. cerevisiae counterpart, CpMgm101 is associated with the entire nucleoid population and is able to bind to a broad range of DNA substrates in a non-sequence specific manner. CpMgm101 is also able to catalyze strand annealing and D-loop formation. CpMgm101 forms a roughly C-shaped trimer in solution according to SAXS. Electron microscopy of a complex of CpMgm101 with a model mitochondrial telomere revealed homogeneous, ring-shaped structures at the telomeric single-stranded overhangs. The DNA-binding properties of CpMgm101, together with its DNA recombination properties, suggest that it can play a number of possible roles in the replication of the mitochondrial genome and the maintenance of its telomeres. PMID- 26743003 TI - Structural characterization of a dimer of RNA duplexes composed of 8 bromoguanosine modified CGG trinucleotide repeats: a novel architecture of RNA quadruplexes. AB - Fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS) are neurodegenerative disorders caused by the pathogenic expansion of CGG triplet repeats in the FMR1 gene. FXTAS is likely to be caused by a 'toxic' gain-of function of the FMR1 mRNA. We provide evidence for the existence of a novel quadruplex architecture comprising CGG repeats. The 8-bromoguanosine ((Br)G) modified molecule GC(Br)GGCGGC forms a duplex in solution and self-associates via the major groove to form a four-stranded, antiparallel (GC(Br)GGCGGC)4 RNA quadruplex with (Br)G3:G6:(Br)G3:G6 tetrads sandwiched between mixed G:C:G:C tetrads. Self-association of Watson-Crick duplexes to form a four-stranded structure has previously been predicted; however, no experimental evidence was provided. This novel four-stranded RNA structure was characterized using a variety of experimental methods, such as native gel electrophoresis, NMR spectroscopy, small-angle X-ray scattering and electrospray ionization mass spectrometry. PMID- 26743002 TI - S. cerevisiae Mre11 recruits conjugated SUMO moieties to facilitate the assembly and function of the Mre11-Rad50-Xrs2 complex. AB - Double-strand breaks (DSBs) in chromosomes are the most challenging type of DNA damage. The yeast and mammalian Mre11-Rad50-Xrs2/Nbs1 (MRX/N)-Sae2/Ctp1 complex catalyzes the resection of DSBs induced by secondary structures, chemical adducts or covalently-attached proteins. MRX/N also initiates two parallel DNA damage responses-checkpoint phosphorylation and global SUMOylation-to boost a cell's ability to repair DSBs. However, the molecular mechanism of this SUMO-mediated response is not completely known. In this study, we report that Saccharomyces cerevisiae Mre11 can non-covalently recruit the conjugated SUMO moieties, particularly the poly-SUMO chain. Mre11 has two evolutionarily-conserved SUMO interacting motifs, Mre11(SIM1) and Mre11(SIM2), which reside on the outermost surface of Mre11. Mre11(SIM1) is indispensable for MRX assembly. Mre11(SIM2) non covalently links MRX with the SUMO enzymes (E2/Ubc9 and E3/Siz2) to promote global SUMOylation of DNA repair proteins. Mre11(SIM2) acts independently of checkpoint phosphorylation. During meiosis, the mre11(SIM2) mutant, as for mre11S, rad50S and sae2Delta, allows initiation but not processing of Spo11 induced DSBs. Using MRX and DSB repair as a model, our work reveals a general principle in which the conjugated SUMO moieties non-covalently facilitate the assembly and functions of multi-subunit protein complexes. PMID- 26743004 TI - Non-canonical uracil processing in DNA gives rise to double-strand breaks and deletions: relevance to class switch recombination. AB - During class switch recombination (CSR), antigen-stimulated B-cells rearrange their immunoglobulin constant heavy chain (CH) loci to generate antibodies with different effector functions. CSR is initiated by activation-induced deaminase (AID), which converts cytosines in switch (S) regions, repetitive sequences flanking the CH loci, to uracils. Although U/G mispairs arising in this way are generally efficiently repaired to C/Gs by uracil DNA glycosylase (UNG)-initiated base excision repair (BER), uracil processing in S-regions of activated B-cells occasionally gives rise to double strand breaks (DSBs), which trigger CSR. Surprisingly, genetic experiments revealed that CSR is dependent not only on AID and UNG, but also on mismatch repair (MMR). To elucidate the role of MMR in CSR, we studied the processing of uracil-containing DNA substrates in extracts of MMR proficient and -deficient human cells, as well as in a system reconstituted from recombinant BER and MMR proteins. Here, we show that the interplay of these repair systems gives rise to DSBs in vitro and to genomic deletions and mutations in vivo, particularly in an S-region sequence. Our findings further suggest that MMR affects pathway choice in DSB repair. Given its amenability to manipulation, our system represents a powerful tool for the molecular dissection of CSR. PMID- 26743005 TI - Effects on the transcriptome upon deletion of a distal element cannot be predicted by the size of the H3K27Ac peak in human cells. AB - Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with increased risk for colorectal cancer (CRC). A molecular understanding of the functional consequences of this genetic variation is complicated because most GWAS SNPs are located in non-coding regions. We used epigenomic information to identify H3K27Ac peaks in HCT116 colon cancer cells that harbor SNPs associated with an increased risk for CRC. Employing CRISPR/Cas9 nucleases, we deleted a CRC risk-associated H3K27Ac peak from HCT116 cells and observed large-scale changes in gene expression, resulting in decreased expression of many nearby genes. As a comparison, we showed that deletion of a robust H3K27Ac peak not associated with CRC had minimal effects on the transcriptome. Interestingly, although there is no H3K27Ac peak in HEK293 cells in the E7 region, deletion of this region in HEK293 cells decreased expression of several of the same genes that were downregulated in HCT116 cells, including the MYC oncogene. Accordingly, deletion of E7 causes changes in cell culture assays in HCT116 and HEK293 cells. In summary, we show that effects on the transcriptome upon deletion of a distal regulatory element cannot be predicted by the size or presence of an H3K27Ac peak. PMID- 26743007 TI - Anaerobic decomposition of humic substances by Clostridium from the deep subsurface. AB - Decomposition of humic substances (HSs) is a slow and cryptic but non-negligible component of carbon cycling in sediments. Aerobic decomposition of HSs by microorganisms in the surface environment has been well documented; however, the mechanism of anaerobic microbial decomposition of HSs is not completely understood. Moreover, no microorganisms capable of anaerobic decomposition of HSs have been isolated. Here, we report the anaerobic decomposition of humic acids (HAs) by the anaerobic bacterium Clostridium sp. HSAI-1 isolated from the deep terrestrial subsurface. The use of (14)C-labelled polycatechol as an HA analogue demonstrated that the bacterium decomposed this substance up to 7.4% over 14 days. The decomposition of commercial and natural HAs by the bacterium yielded lower molecular mass fractions, as determined using high-performance size exclusion chromatography. Fourier transform infrared spectroscopy revealed the removal of carboxyl groups and polysaccharide-related substances, as well as the generation of aliphatic components, amide and aromatic groups. Therefore, our results suggest that Clostridium sp. HSAI-1 anaerobically decomposes and transforms HSs. This study improves our understanding of the anaerobic decomposition of HSs in the hidden carbon cycling in the Earth's subsurface. PMID- 26743008 TI - The effect of melatonin on oxidative stress and apoptosis in experimental diabetes mellitus-related ovarian injury. AB - We aimed to evaluate the effect of melatonin on oxidative stress and ovarian injury in rats. Twenty-four Sprague-Dawley albino rats were divided into three groups: Group 1 as nondiabetic healthy controls (n = 8), group 2 as nontreated diabetic rats (n = 8) and group 3 as melatonin-treated diabetic rats (n = 8). After overt diabetes was produced by intraperitoneal injection of streptozosin, 20 mg/kg/day of melatonin was given intraperitoneally to group 3 for a week. NF kB and caspase-3 immunoexpressions, lipid peroxidation, the activities of antioxidative enzymes, total oxidant capacity and total antioxidant capacity were assessed. Immunoexpressions of NF-kB and caspase-3 were significantly lower in group 3 than group 2. There was a significant decrease in superoxide dismutase activity in group 2 than group 1 and a significant increase in group 3 compared with group 2. We observed a nonsignificant decrease in catalase activity between group 1 and group 2 and a nonsignificant increase between group 2 and group 3. There was a nonsignificant increase in the plasma level of total oxidant status in group 2 than group 1, but a significant decrease was observed in group 3 compared to group 2. Total antioxidant status was significantly lower in group 2 compared with group 1 and group 3. In conclusion, melatonin ameliorates the negative effects of oxidative stress on DM-related ovarian injury. PMID- 26743009 TI - Squalyl Crown Ether Self-Assembled Conjugates: An Example of Highly Selective Artificial K+ Channels. AB - The natural KcsA K+ channel, one of the best-characterized biological pore structures, conducts K+ cations at high rates while excluding Na+ cations. The KcsA K+ channel is of primordial inspiration for the design of artificial channels. Important progress in improving conduction activity and K+ /Na+ selectivity has been achieved with artificial ion-channel systems. However, simple artificial systems exhibiting K+ /Na+ selectivity and mimicking the biofunctions of the KcsA K+ channel are unknown. Herein, an artificial ion channel formed by H-bonded stacks of squalyl crown ethers, in which K+ conduction is highly preferred to Na+ conduction, is reported. The K+ -channel behavior is interpreted as arising from discreet stacks of dimers resulting in the formation of oligomeric channels, in which transport of cations occurs through macrocycles mixed with dimeric carriers undergoing dynamic exchange within the bilayer membrane. The present highly K+ -selective macrocyclic channel can be regarded as a biomimetic alternative to the KcsA channel. PMID- 26743006 TI - Integrative analysis identifies targetable CREB1/FoxA1 transcriptional co regulation as a predictor of prostate cancer recurrence. AB - Identifying prostate cancer-driving transcription factors (TFs) in addition to the androgen receptor promises to improve our ability to effectively diagnose and treat this disease. We employed an integrative genomics analysis of master TFs CREB1 and FoxA1 in androgen-dependent prostate cancer (ADPC) and castration resistant prostate cancer (CRPC) cell lines, primary prostate cancer tissues and circulating tumor cells (CTCs) to investigate their role in defining prostate cancer gene expression profiles. Combining genome-wide binding site and gene expression profiles we define CREB1 as a critical driver of pro-survival, cell cycle and metabolic transcription programs. We show that CREB1 and FoxA1 co localize and mutually influence each other's binding to define disease-driving transcription profiles associated with advanced prostate cancer. Gene expression analysis in human prostate cancer samples found that CREB1/FoxA1 target gene panels predict prostate cancer recurrence. Finally, we showed that this signaling pathway is sensitive to compounds that inhibit the transcription co-regulatory factor MED1. These findings not only reveal a novel, global transcriptional co regulatory function of CREB1 and FoxA1, but also suggest CREB1/FoxA1 signaling is a targetable driver of prostate cancer progression and serves as a biomarker of poor clinical outcomes. PMID- 26743010 TI - Complete genome sequence and cell structure of Limnochorda pilosa, a Gram negative spore-former within the phylum Firmicutes. AB - Limnochorda pilosa is a pleomorphic facultative anaerobe and the sole species in the class Limnochordia, which has tentatively been placed in the phylum Firmicutes. In the present study, the complete genome sequence of L. pilosa HC45T was obtained and analysed. The genome size was 3.82 Mbp and the DNA G+C content was 69.73 %. Phylogenetic analyses based on the 30S-50S ribosomal proteins and 23S rRNA gene consistently indicated that L. pilosa is phylogenetically isolated from the other members of the phylum Firmicutes. Ultrastructural observation revealed that L. pilosa possesses a Gram-negative-type cell wall and the capacity to form endospores. Accordingly, the L. pilosa genome has characteristics that are specific to Gram-negative bacteria and contains many genes that are involved in sporulation. On the other hand, several sporulation genes were absent from the L. pilosa genome although they have been regarded as essential for the endospore forming system of members of the phylum Firmicutes. The gyrB gene of L. pilosa possesses an intein sequence. The genome has a high percentage of GTG start codons and lacks several conserved genes related to cell division. PMID- 26743011 TI - Would a cigarette by any other name taste as good in China? PMID- 26743013 TI - Treating achalasia; more than just flipping a coin. PMID- 26743012 TI - Low progression of intraductal papillary mucinous neoplasms with worrisome features and high-risk stigmata undergoing non-operative management: a mid-term follow-up analysis. AB - OBJECTIVE: To evaluate mid-term outcomes and predictors of survival in non operated patients with pancreatic intraductal papillary mucinous neoplasms (IPMNs) with worrisome features or high-risk stigmata as defined by International Consensus Guidelines for IPMN. Reasons for non-surgical options were physicians' recommendation, patient personal choice or comorbidities precluding surgery. METHODS: In this retrospective, multicentre analysis, IPMNs were classified as branch duct (BD) and main duct (MD), the latter including mixed IPMNs. Univariate and multivariate analysis for overall survival (OS) and disease-specific survival (DSS) were obtained. RESULTS: Of 281 patients identified, 159 (57%) had BD-IPMNs and 122 (43%) had MD-IPMNs; 50 (18%) had high-risk stigmata and 231 (82%) had worrisome features. Median follow-up was 51 months. The 5-year OS and DSS for the entire cohort were 81% and 89.9%. An invasive pancreatic malignancy developed in 34 patients (12%); 31 had invasive IPMNs (11%) and 3 had IPMN-distinct pancreatic ductal adenocarcinoma (1%). Independent predictors of poor DSS in the entire cohort were age >70 years, atypical/malignant cyst fluid cytology, jaundice and MD >15 mm. Compared with MD-IPMNs, BD-IPMNs had significantly better 5-year OS (86% vs 74.1%, p=0.002) and DSS (97% vs 81.2%, p<0.0001). Patients with worrisome features had better 5-year DSS compared with those with high-risk stigmata (96.2% vs 60.2%, p<0.0001). CONCLUSIONS: In elderly patients with IPMNs that have worrisome features, the 5-year DSS is 96%, suggesting that conservative management is appropriate. By contrast, presence of high-risk stigmata is associated with a 40% risk of IPMN-related death, reinforcing that surgical resection should be offered to fit patients. PMID- 26743014 TI - Occult hepatitis C virus infection among Egyptian hemodialysis patients. AB - Occult hepatitis C virus (HCV) infection (OCI) was reported in an apparently disease-free state in the absence of liver disease, anti-HCV and HCV-RNA in the serum. The existing data examining the clinical significance of OCI and its potential as a source of HCV infection among hemodialysis patients are very limited. We examined the presence of OCI among patients on maintenance hemodialysis at Minia Governorate, Egypt; an HCV endemic country. A total of 81 subjects with negative markers for HCV were enrolled. HCV-RNA was tested in PBMCs by real-time PCR. For the 81 subjects, the average dialysis duration was 32.7 +/- 21.7 months and the average ALT level (+/-SD) was 26 +/- 12 U/L while that of AST was 29 +/- 16 U/L. Out of the 81 subjects, three (3.7%) were HCV-RNA positive in PBMCs in the absence of serum anti-HCV and HCV-RNA indicating OCI. The viral load of the OCI subjects ranged from 172 to 4150 IU/ml. History of liver disease was positive in one of the three positive patients. These results highlight the potential risk of HCV transmission from patients within hemodialysis units in Egypt. J. Med. Virol. 88:1388-1393, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26743015 TI - Subclinical atherosclerosis is not increased in patients with non-radiographic axial spondyloarthritis. PMID- 26743017 TI - Mini-incision microdissection testicular sperm extraction: a useful technique for men with cryptozoospermia. AB - Microdissection testicular sperm extraction (micro-TESE) was developed to minimize the testicular injury associated with multiple open TESEs. We sought to evaluate a mini-incision micro-TESE in men with cryptozoospermia and non obstructive azoospermia (NOA). We conducted a retrospective study of 26 consecutive men with NOA and cryptozoospermia who underwent a primary (first) micro-TESE between March 2015 and August 2015. Final assessment of sperm recovery (reported on the day of intra-cytoplasmic sperm injection (ICSI)) was recorded as (i) successful (available spermatozoa for ICSI) or (ii) unsuccessful (no spermatozoa for ICSI). The decision to perform a mini-incision micro-TESE (with limited unilateral micro-dissection) or standard/extensive (with unilateral or bilateral micro-dissection) was guided by the intra-operative identification of sperm recovery (>=5 spermatozoa) from the first testicle. Overall, sperm recovery was successful in 77% (20/26) of the men. In 37% of the men (8/26), the mini incision micro-TESE was successful (positive sperm recovery). The remaining 18 men required a standard (extensive) microdissection: 61% (11/18) underwent a unilateral and 39% (7/18) a bilateral micro-TESE. We found that 90% (9/10) of the men with cryptozoospermia and 63% (10/16) of the men with NOA underwent a unilateral (mini or standard micro-TESE). The mini-incision micro-TESE allowed for successful sperm recovery in 60% (6/10) of the men with cryptozoospermia and 13% (2/16) of the men with NOA. The data demonstrate that a mini-incision micro TESE together with rapid intra-operative assessment and identification of spermatozoa recovery can be useful in men undergoing microTESE, particularly, men with cryptozoospermia. PMID- 26743016 TI - Combination of 5-ALA and iMRI in re-resection of recurrent glioblastoma. AB - Background Tumour resection plays a role in the initial treatment but also in the setting of recurrent glioblastoma (rGBM). To achieve maximum resection, 5 aminolevulinic acid (5-ALA) and intraoperative MRI (iMRI) are used as surgical tools. Aiming at complete tumour re-resection, we started combining iMRI with 5 ALA to find out if this leads to better surgical results. Methods We performed tumour resections in seven patients with rGBM, combining 5-ALA (20 mg/kg bodyweight) with iMRI (0.15 T). Radiologically complete resections were intended in all seven patients. We assessed intraoperative fluorescence findings and compared these with intraoperative imaging. All patients had early postoperative MRI (3 T) to verify final iMRI scans and received adjuvant treatment according to interdisciplinary tumour board decision. Results Median patient age was 63 years. Median KPS score was 90, and median tumour volume was 8.2 cm(3). In six of seven patients (85%), 5-ALA induced fluorescence of tumour-tissue was detected intraoperatively. All tumours were good to visualise with iMRI and contrast media. One patient received additional resection of residual contrast enhancing tissue on intraoperative imaging, which did not show fluorescence. Radiologically complete resections according to early postoperative MRI were achieved in all patients. Median survival since second surgery was 7.6 months and overall survival since diagnosis was 27.8 months. Conclusions 5-ALA and iMRI are important surgical tools to maximise tumour resection also in rGBM. However, not all rGBMs exhibit fluorescence after 5-ALA administration. We propose the combined use of 5-ALA and iMRI in the surgery of rGBM. PMID- 26743018 TI - Flicker-defined form stimuli are minimally affected by centre-surround lateral contrast interactions. AB - PURPOSE: Flicker-defined form (FDF) stimuli have recently been adopted for visual field testing. A key difference between FDF and traditional perimetric stimuli is that the entire display background contains flickering dots. The purpose of this study was to determine whether the perception of FDF stimuli is influenced by lateral interactions involving regions beyond the stimulus border in young healthy observers. METHODS: Experiment 1 measured the effect of surround size and retinal eccentricity on the detection of the FDF contour. Psychometric functions were collected for surround diameters of 20 degrees , 30 degrees and 40 degrees , and with stimuli centred at eccentricities of 0 degrees , 10 degrees and 20 degrees . Experiment 2 measured the effect of target-surround temporal phase difference on apparent temporal contrast (flicker strength) of the target for both the FDF stimulus and a solid-field stimulus. Psychometric functions were collected for target-surround phase differences of 0 degrees , 45 degrees , 90 degrees , 135 degrees and 180 degrees . RESULTS: Our results show a mild surround-suppression effect for FDF stimuli that is independent of surround size. Magnitudes of FDF surround suppression were consistent with the reduced temporal contrast energy of the stimulus compared to solid-field stimuli. CONCLUSION: FDF stimuli necessarily have both flickering target and background. Our results suggest that visual field defects outside the target are unlikely to markedly influence the detection and perception of the FDF stimulus. Nevertheless, mild surround suppression of contrast arises for FDF stimuli, hence interactions between the background and the target area may influence FDF results in conditions that alter centre-surround perceptual effects. PMID- 26743019 TI - Photodissociation dynamics of ICH2Cl -> CH2Cl + I*/I: photofragment translational spectroscopy at 304 and 277 nm. AB - The photodissociation dynamics of ICH2Cl -> CH2Cl + I*/I at 304 and 277 nm has been investigated with our mini-TOF photofragment translational spectrometer with a weak acceleration field of <1 V cm(-1). Many peaks are resolved or partially resolved in the TOF spectra and the photofragment translational spectra (PTS) of both the I*((2)P1/2) channel and the I((2)P3/2) channel. These resolved peaks are assigned to the C-Cl stretch vibrational states of the CH2Cl fragment. The rotational energy ER of the CH2Cl fragment is highly excited due to its asymmetric structure. The value of ER/ET is measured to be about 0.71. In the I* channel, the partitioning of the available energy Eavl into the translational energy ET, the rotational energy ER, and the vibrational energy EV for each resolved vibrational state has been calculated. PMID- 26743020 TI - Screening for trisomies by cell-free DNA testing of maternal blood: consequences of a failed result. AB - OBJECTIVES: First, to report the distribution of the fetal fraction of cell-free (cf) DNA and the rate of a failed cfDNA test result in trisomies 21, 18 and 13, by comparison with pregnancies unaffected by these trisomies, second, to examine the possible effects of maternal and fetal characteristics on the fetal fraction, and third, to consider the options for further management of pregnancies with a failed result. METHODS: This was a cohort study of 10 698 singleton pregnancies undergoing screening for fetal trisomies 21, 18 and 13 by cfDNA testing at 10-14 weeks' gestation. There were 160 cases of trisomy 21, 50 of trisomy 18, 16 of trisomy 13 and 10 472 were unaffected by these trisomies. Multivariate regression analysis was used to determine significant predictors of fetal fraction and a failed cfDNA test result amongst maternal and fetal characteristics. RESULTS: Fetal fraction decreased with increasing body mass index and maternal age, was lower in women of South Asian racial origin than in Caucasians and in assisted compared to natural conceptions. It increased with fetal crown-rump length and higher levels of serum pregnancy-associated plasma protein-A and free beta-human chorionic gonadotropin. The median fetal fraction was 11.0% (interquartile range (IQR), 8.3-14.4%) in the unaffected group, 10.7% (IQR, 7.8-14.3%) in trisomy 21, 8.6% (IQR, 5.0-10.2%) in trisomy 18 and 7.0% (IQR, 6.0-9.4%) in trisomy 13. There was a failed result from cfDNA testing after first sampling in 2.9% of the unaffected group, 1.9% of trisomy 21, 8.0% of trisomy 18 and 6.3% of trisomy 13. In the cases with a failed result, 7% of women had invasive testing, mainly because of high risk from the combined test and/or presence of sonographic features suggestive of trisomies 18 and 13. All cases of trisomies were detected prenatally. CONCLUSIONS: In cases of a failed cfDNA test, the rate of trisomies 18 and 13, but not trisomy 21, is higher than in those with a successful test. In the management of such cases, the decision in favor of invasive testing should depend on the risk of prior screening and the results of detailed ultrasound examination. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26743021 TI - Near-post meniscus-induced migration and assembly of bubbles. AB - Although the effect of interfacial tension of liquids is often negligible at the macroscale, it plays an essential role in areas such as superhydrophobicity on rough surfaces, water walking of aquatic creatures and self-assembly of small particles or droplets. In this study, we investigate the migration and assembly of bubbles near the meniscus produced by a slender post with various cross sections. The results show that the bubble always migrates to the solid wall of the post, although the cross-section shape, material and tilt angle of the post are different. In particular, the final position of the bubble is not located at the singular point of the cross-section, which is beyond what we have imagined. We simulate the morphology of the triple contact line via Surface Evolver, and then address the mechanism of bubble's migration from the viewpoint of force analysis and energy calculation. The factors governing the final position of the bubble are analyzed according to the scaling law. These obtained results cast new light on modulating the assembly of bubbles and small droplets by varying the material, geometric shape and posture of the post in water. These findings also have important implications for oil collection and oil displacement in petroleum engineering, drug delivery, design of microfluidic devices and chemical sensors. PMID- 26743022 TI - Nucleophilic ring-opening of iron(III)-hydroxy-isoporphyrin. AB - The reactions of iron(III) hydroxyisoporphyrin, chloro[5-(hydroxy)-5,10,15,20 tetrakis(4-methyl)-5,21H-porphinato]iron(III) [Fe(4-Me-HTPI)(Cl)](-), 1 and chloro[5-(hydroxy)-5,10,15,20-tetrakis(4-methoxy-5,21H-porphinato]iron(III) [Fe(4 OMe-HTPI)(Cl)](-), 2 with different O(-), N(-) and S(-) nucleophiles have been performed to understand the reactivity of iron isoporphyrins with nucleophiles. The treatment of iron(III) hydroxy isoporphyrin with alcohols is found to form ring opened 19-benzoyl-1-alkoxy-bilin iron complexes. When alkyl amines were used the formation of ring opened 19-benzoyl-1-alkylamine-bilin iron complexes was observed, but heterocyclic N-nucleophiles such as pyridine and imidazole form benzoyl bilinone iron complexes. No role of oxygen was found in these nucleophilic ring opening reactions. The treatment of a S-nucleophile such as PhSH is found to reduce iron(III)-hydroxyisoporphyrin in the parent iron(III) porphyrin compound. The ring opening products were characterized using electronic and ESI-mass spectroscopy. The mechanism for the formation of ring opening products is based on the formation of a tetrahedral intermediate at the carbon atom near the saturated meso carbon atom similar to the hydrolytic pathway of verdoheme conversion to biliverdin. PMID- 26743023 TI - The Effectiveness of Group Family Training About the Principles of Harm Reduction Approach on Marital Satisfaction of Spouses of Patients Under Methadone Maintenance Treatment. AB - One of the most important problems in treatment of drug dependence is the cooperation of the patient's family. Many families do not look at drug dependence as a chronic and relapsing disorder and expect a quick and definite recovery of the disease. These families, including wives, are unfamiliar with the concept of harm reduction as a realistic approach. The aim of this study was to educate the spouses of patients undergoing methadone maintenance treatment (MMT) on the different aspects of harm reduction approach and assess the impact of this training on marital satisfaction and relapse rate. This study was a pretest posttest study with control group. The sample consisted of 50 MMT patients and their wives in private methadone maintenance treatment clinics in the city of Bojnurd, located in the northeastern region of Iran. The experimental group received eight group training sessions run by a psychiatrist. The content of the training sessions was based on harm reduction programs for families of patients with high-risk behaviors. Two groups are compared in terms of marital satisfaction and relapse rate. A paired t test was used to compare changes before and after the training. The results of this study showed that harm reduction education and efforts for changing wives' views toward MMT are effective in increasing their marital satisfaction. However, the conducted training showed no effect on relapse rate in the six-month follow-up. Regarding the fact that this type of training has not been paid enough attention in the national protocol, the proposed training program of this research can be considered in MMT clinics. PMID- 26743024 TI - Non-invasive prenatal testing: impact on invasive prenatal diagnosis at a mainland Chinese tertiary medical center. AB - OBJECTIVE: We describe the changes over a 4-year period in the number of diagnostic testing after the introduction of non-invasive prenatal testing (NIPT). METHODS: The rate of NIPT as an indication in women who received amniocentesis, and the number of amniocentesis required for detection of one case with major aneuploidy were compared between a 1-year baseline period before the introduction of NIPT, and the 3 years following NIPT introduction. RESULTS: A total of 7536 amniocentesis procedures were performed over the 4-year study period. During the baseline period of the year 2011, the number of invasive testing required for detection of one common trisomy was 57. During the first 2 years that NIPT was offered, NIPT averaged 1.7 percent of the total indications for amniocentesis, and the required number of invasive testing decreased to 30. With the increase of the percentage of NIPT during the 3rd year, the required number of invasive testing further decreased to 26. CONCLUSION: After the clinical introduction of NIPT, invasive prenatal diagnostic testing had not decreased at a Chinese prenatal diagnostic unit, but a remarkably improved detection rate of major aneuploidies in diagnostic procedures was observed. PMID- 26743025 TI - New insights into functional regulation in MS-based drug profiling. AB - We present a novel data analysis strategy which combined with subcellular fractionation and liquid chromatography-mass spectrometry (LC-MS) based proteomics provides a simple and effective workflow for global drug profiling. Five subcellular fractions were obtained by differential centrifugation followed by high resolution LC-MS and complete functional regulation analysis. The methodology combines functional regulation and enrichment analysis into a single visual summary. The workflow enables improved insight into perturbations caused by drugs. We provide a statistical argument to demonstrate that even crude subcellular fractions leads to improved functional characterization. We demonstrate this data analysis strategy on data obtained in a MS-based global drug profiling study. However, this strategy can also be performed on other types of large scale biological data. PMID- 26743026 TI - Application of de Novo Sequencing to Large-Scale Complex Proteomics Data Sets. AB - Dependent on concise, predefined protein sequence databases, traditional search algorithms perform poorly when analyzing mass spectra derived from wholly uncharacterized protein products. Conversely, de novo peptide sequencing algorithms can interpret mass spectra without relying on reference databases. However, such algorithms have been difficult to apply to complex protein mixtures, in part due to a lack of methods for automatically validating de novo sequencing results. Here, we present novel metrics for benchmarking de novo sequencing algorithm performance on large-scale proteomics data sets and present a method for accurately calibrating false discovery rates on de novo results. We also present a novel algorithm (LADS) that leverages experimentally disambiguated fragmentation spectra to boost sequencing accuracy and sensitivity. LADS improves sequencing accuracy on longer peptides relative to that of other algorithms and improves discriminability of correct and incorrect sequences. Using these advancements, we demonstrate accurate de novo identification of peptide sequences not identifiable using database search-based approaches. PMID- 26743027 TI - Prognostic significance of histomolecular subgroups of adult anaplastic (WHO Grade III) gliomas: applying the 'integrated' diagnosis approach. AB - AIMS: Anaplastic gliomas (AGs; WHO Grade III) include anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) and are known to have variable prognosis. Since biomarkers have a major impact on prognosis of gliomas, we compared the prognostic significance of the established biomarkers of AGs and the 'histomolecular' subgroups based on the proposed International Society of Neuropathology-Haarlem ('ISN-Haarlem') guidelines, with the current WHO 2007 classification. METHODS: The study was carried out on formalin-fixed paraffin-embedded (FFPE) tissues from 91 adult patients with AG. Clinical, histological and molecular parameters, including 1p/19q codeletion, isocitrate dehydrogenase gene (IDH1)-R132H positivity, alpha thalassemia/mental retardation syndrome X-linked gene (ATRX) expression and O(6)-methylguanine-DNA methyltransferase gene (MGMT) promoter methylation (mMGMT), were correlated with overall survival (OS) and recurrence-free survival (RFS). Subsequently, following sequencing for rare IDH mutations, we derived three 'histomolecular' subgroups based on the 'integrated' diagnosis approach proposed by 'ISN-Haarlem' guidelines and correlated this with clinical outcome. RESULTS: Gross tumour resection, administration of radiochemotherapy, 1p/19q codeletion, IDH1-R132H positivity and mMGMT were associated with favourable OS and RFS (p<=0.001), while the WHO histological subgroups were prognostically not significant. The ISN 'histomolecular' subgroups prognosticated best with AOs (IDHmut, 1p/19q codeleted, ATRX predominantly retained) having the best survival, followed by the AAs (IDHmut, ATRX loss or retained, 1p19q non-codeleted) and AA IDH wild type group having the worst OS and RFS (p=<0.001 for OS). CONCLUSIONS: Our study reiterates the prognostic significance of biomarkers, 1p/19q codeletion, IDH1 R132H positivity and mMGMT in AGs. Importantly, we show that the 'histomolecular' subgroups of AGs based on the 'integrated' diagnosis has a prognostic value, superior to the WHO histological classification. PMID- 26743028 TI - Extraction, purification and anti-fatigue activity of gamma-aminobutyric acid from mulberry (Morus alba L.) leaves. AB - Mulberry (Morus alba L.) is a tree species of Moraceae widely distributed in Southern China. In the present study, the white crystal of gamma-aminobutyric acid (GABA) was purified from mulberry leaves, and its bioactivity was also investigated. The main results were as follows: first, the crude GABA was extracted from mulberry leaves by using biochemical methods. Then, the crude was purified by chromatography over an S-8 macroporous resin, Sephadex G-10, and 732 cation exchange resin to yield a white crystal. Lavage administration and exposure of GABA to male NIH mice showed no adverse effects on their growth and development. In an endurance capacity test, the average loaded-swimming time of medium dose was 111.60% longer than the control (P < 0.01). Further investigations showed that relative to that of model control, the respective blood lactate (BL) concentrations of low- and medium-dose were 28.52% and 28.81% lower (P < 0.05), whereas the levels of blood urea nitrogen (BUN) were 36.83% and 40.54% lower (P < 0.05), and that of liver glycogen (LG) levels were 12.81% and 17.22% lower (P < 0.05). The results indicated that GABA has an advantage over taurine of anti-fatigue effect. These findings were indicative of the anti fatigue activity of GABA. PMID- 26743030 TI - Tumorigenesis: Tracking early tumour cells. PMID- 26743029 TI - High photosensitivity and broad spectral response of multi-layered germanium sulfide transistors. AB - In this paper, we report the optoelectronic properties of multi-layered GeS nanosheet (~28 nm thick)-based field-effect transistors (called GeS-FETs). The multi-layered GeS-FETs exhibit remarkably high photoresponsivity of Rlambda ~ 206 A W(-1) under 1.5 MUW cm(-2) illumination at lambda = 633 nm, Vg = 0 V, and Vds = 10 V. The obtained Rlambda ~ 206 A W(-1) is excellent as compared with a GeS nanoribbon-based and the other family members of group IV-VI-based photodetectors in the layered-materials realm, such as GeSe and SnS2. The gate-dependent photoresponsivity of GeS-FETs was further measured to be able to reach Rlambda ~ 655 A W(-1) operated at Vg = -80 V. Moreover, the multi-layered GeS photodetector holds high external quantum efficiency (EQE ~ 4.0 * 10(4)%) and specific detectivity (D* ~ 2.35 * 10(13) Jones). The measured D* is comparable to those of the advanced commercial Si- and InGaAs-based photodiodes. The GeS photodetector also shows an excellent long-term photoswitching stability over a long period of operation (>1 h). These extraordinary properties of high photocurrent generation, broad spectral range, and long-term stability make the GeS-FET photodetector a highly qualified candidate for future optoelectronic applications. PMID- 26743031 TI - Metabolism: Totally addicted to NAD(.). PMID- 26743032 TI - Dissimilar Crystal Dependence of Vanadium Oxide Cathodes in Organic Carbonate and Safe Ionic Liquid Electrolytes. AB - Advances in Li metal anode stabilization, solid-state electrolytes, and capabilities to insert a variety of active ions (Li(+), Na(+), Mg(2+), and Al(3+)) have renewed the interest in layered vanadium oxides. Here we show that crystal characteristics such as size and crystallinity are fundamental variables that control the dissimilar electrochemical capabilities of 1D vanadium oxides immersed in different electrolytes (organic carbonates and safe electrolytes containing 80% of ionic liquid). We show that this opposite behavior can be understood in terms of a subtle interplay between crystal characteristics (size and crystallinity), electrolyte degradability, and the ionic conductivity of the electrolyte. Thus, through this control we are able to obtain pure 1D vanadium oxides that show reversibility in carbonate electrolytes at a cutoff voltage of 1.5 V (voltage region where insertion of more than two lithium ions is possible). Furthermore, these materials are able to uptake ca. 1.0 mol of Li at a rate of 20C (1C = 295 mAh/g) and retain excellent capabilities (Coulombic efficiency of 98% after 200 cycles at a rate of 5C). Finally, what, to our knowledge, is really remarkable is that this optimization allows building vanadium oxide electrodes with an excellent electrochemical response in a safe electrolyte composition (80% of ionic liquid). Specifically, we reach uptakes also at a cutoff voltage of 1.5 V of ca. 1.0 mol of Li after 200 cycles at 5C (charge/discharge) with Coulombic efficiencies higher than 99.5%. PMID- 26743033 TI - Fully human MAP-fusion protein selectively targets and eliminates proliferating CD64(+) M1 macrophages. AB - Classical immunotoxins compromise a binding component (for example, a ligand, antibody or fragment thereof) and a cytotoxic component, usually derived from bacteria or plants (for example, Pseudomonas exotoxin A or ricin). Despite successful testing in vitro, the clinical development of immunotoxins has been hampered by immunogenicity and unsatisfactory safety profiles. Therefore, research has focused on fully human pro-apoptotic components suitable for the development of cytolytic fusion proteins (CFP). We recently reported that human microtubule-associated protein tau (MAP) can induce apoptosis when delivered to rapidly proliferating cancer cells. Here, we describe a new fully human CFP called H22(scFv)-MAP, which specifically targets CD64(+) cells. We show that H22(scFv)-MAP can efficiently kill proliferating HL-60 pro-monocytic cells in vitro. In addition, the human CFP specifically eliminates polarized M1 macrophages in a transgenic mouse model of cutaneous chronic inflammation. Because M1 macrophages promote the pathogenesis of many chronic inflammatory diseases, targeting this cell population with H22(scFv)-MAP could help to treat diseases such as atopic dermatitis, rheumatoid arthritis and inflammatory bowel disease. PMID- 26743036 TI - Clear aligners generations and orthodontic tooth movement. AB - Clear aligner technology has evolved over the last 15 years, with these appliances continually being modified to increase the range of tooth movements that they can achieve. However, there is very little clinical research available to show how these appliances achieve their results. This article describes the different generations of clear aligners that are available and highlights their use. However, until more clinical research becomes available, aligners cannot be routinely prescribed as an effective alternative to fixed labial appliances. PMID- 26743034 TI - Unearthing the Antibacterial Mechanism of Medicinal Clay: A Geochemical Approach to Combating Antibiotic Resistance. AB - Natural antibacterial clays, when hydrated and applied topically, kill human pathogens including antibiotic resistant strains proliferating worldwide. Only certain clays are bactericidal; those containing soluble reduced metals and expandable clay minerals that absorb cations, providing a capacity for extended metal release and production of toxic hydroxyl radicals. Here we show the critical antibacterial components are soluble Fe(2+) and Al(3+) that synergistically attack multiple cellular systems in pathogens normally growth limited by Fe supply. This geochemical process is more effective than metal solutions alone and provides an alternative antibacterial strategy to traditional antibiotics. Advanced bioimaging methods and genetic show that Al(3+) misfolds cell membrane proteins, while Fe(2+) evokes membrane oxidation and enters the cytoplasm inflicting hydroxyl radical attack on intracellular proteins and DNA. The lethal reaction precipitates Fe(3+)-oxides as biomolecular damage proceeds. Discovery of this bactericidal mechanism demonstrated by natural clays should guide designs of new mineral-based antibacterial agents. PMID- 26743035 TI - Enhanced engraftment, proliferation, and therapeutic potential in heart using optimized human iPSC-derived cardiomyocytes. AB - Human pluripotent stem cell-derived cardiomyocytes (CMs) are a promising tool for cardiac cell therapy. Although transplantation of induced pluripotent stem cell (iPSC)-derived CMs have been reported in several animal models, the treatment effect was limited, probably due to poor optimization of the injected cells. To optimize graft cells for cardiac reconstruction, we compared the engraftment efficiency of intramyocardially-injected undifferentiated-iPSCs, day 4 mesodermal cells, and day 8, day 20, and day 30 purified iPSC-CMs after initial differentiation by tracing the engraftment ratio (ER) using in vivo bioluminescence imaging. This analysis revealed the ER of day 20 CMs was significantly higher compared to other cells. Transplantation of day 20 CMs into the infarcted hearts of immunodeficient mice showed good engraftment, and echocardiography showed significant functional improvement by cell therapy. Moreover, the imaging signal and ratio of Ki67-positive CMs at 3 months post injection indicated engrafted CMs proliferated in the host heart. Although this graft growth reached a plateau at 3 months, histological analysis confirmed progressive maturation from 3 to 6 months. These results suggested that day 20 CMs had very high engraftment, proliferation, and therapeutic potential in host mouse hearts. They also demonstrate this model can be used to track the fate of transplanted cells over a long time. PMID- 26743037 TI - A cemented cup with acetabular impaction bone grafting is more cost-effective than an uncemented cup in patients under 50 years. AB - PURPOSE: Acetabular deficiencies in young patients can be restored in several ways during total hip arthroplasty. Currently, cementless cups are most frequently used. Impaction bone grafting of acetabular defects is a more biological approach, but is it cost-effective in young patients on the long term? METHODS: We designed a decision model for a cost-utility analysis of a cemented cup with acetabular impaction bone grafting versus an uncemented cup, in terms of cost per quality-adjusted life year (QALY) for the young adult with acetabular bone deficiency, in need for a primary total hip arthroplasty. Outcome probabilities and effectiveness were derived from the Radboud University Nijmegen Medical Centre and the Norwegian Hip Register. Multiple sensitivity analyses were used to assess the contribution of the included variables in the model's outcome. RESULTS: Cemented cups with impaction bone grafting were more cost-effective compared to the uncemented option in terms of costs per QALY. A scenario suggesting equal primary survival rates of both cemented and uncemented cups still showed an effect gain of the cemented cup with impaction bone grafting, but at higher costs. CONCLUSIONS: Based on this model, the first choice of treatment of the acetabular bone deficient osteoarthritic hip in a young patient is reconstruction with impaction bone grafting and a cemented cup. PMID- 26743038 TI - Executive Function in Adolescence: A Commentary on Regulatory Control and Depression in Adolescents: Findings From Neuroimaging and Neuropsychological Research. AB - This commentary addresses the manner in which executive control processes and their development is impacted by major depressive episodes during adolescence. Strengths of the articles within this special issue include the breadth of executive functions that were examined, incorporation of biological probes to understand neural mechanisms involved in observed impairments, the use of longitudinal paradigms to assess developmental timing, consideration and modeling of comorbid conditions, and the identification of individual difference factors that may serve as both liabilities and resilience factors. This work is timely; a close examination of negative emotions and how they change during adolescence is needed if we are to fully understand motivation-cognition interactions and how they are impaired by psychopathology. PMID- 26743039 TI - Observation of Resonant Quantum Magnetoelectric Effect in a Multiferroic Metal Organic Framework. AB - A resonant quantum magnetoelectric coupling effect has been demonstrated in the multiferroic metal-organic framework of [(CH3)2NH2]Fe(HCOO)3. This material shows a coexistence of a spin-canted antiferromagnetic order and ferroelectricity as well as clear magnetoelectric coupling below TN ~ 19 K. In addition, a component of single-ion quantum magnets develops below ~ 8 K because of an intrinsic magnetic phase separation. The stair-shaped magnetic hysteresis loop at 2 K signals resonant quantum tunneling of magnetization. Meanwhile, the magnetic field dependence of dielectric permittivity exhibits sharp peaks just at the critical tunneling fields, evidencing the occurrence of resonant quantum magnetoelectric coupling effect. This resonant effect enables a simple electrical detection of quantum tunneling of magnetization. PMID- 26743040 TI - Phosphodiesterase Type 5 Inhibitor Use and Disease Recurrence After Prostate Cancer Treatment. AB - BACKGROUND: Phosphodiesterase type 5 inhibitor (PDE5i) use is common for management of erectile dysfunction. Single-institution studies have reported conflicting data on the relationship between PDE5i use and biochemical recurrence of prostate cancer (BCR) after radical prostatectomy. OBJECTIVE: To evaluate the association between PDE5i use and BCR after radical prostatectomy and radiation therapy in a nationwide population-based cohort. DESIGN, SETTING, AND PARTICIPANTS: This was a nested case-control study using the National Prostate Cancer Register of Sweden linked to the Prescribed Drug Register. Among men with localized prostate cancer who underwent primary radical prostatectomy or radiation therapy during 2006-2007 with 5 yr of follow-up, 293 had BCR after treatment (cases). For each case we identified 20 BCR-free controls (n=5767) using incidence density sampling. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable conditional logistic regression was used to examine the association between PDE5i use and BCR risk. Separate multivariable models including clinical variables for men undergoing prostatectomy or radiotherapy and including surgical pathology after prostatectomy were also analyzed. RESULTS AND LIMITATIONS: PDE5i use was not associated with BCR after radical prostatectomy (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.59-1.03) or radiation therapy (OR 0.98, 95% CI 0.49-1.97) after adjusting for marital status, education, income, prostate specific antigen, clinical stage, Gleason score, and proportion of positive biopsies. Results were similar after additional adjustment for surgical pathology (OR 0.86, 95% CI 0.64-1.16). Men whose cumulative number of PDE5i pills was above the median had a slightly lower BCR risk after prostatectomy in the clinical model, and no difference in BCR risk after adjustment for pathologic tumor features. CONCLUSIONS: Our results from a population-based cohort suggest that BCR risk is not higher among men using PDE5i after prostate cancer treatment. PATIENT SUMMARY: Erectile dysfunction medications are not associated with a higher risk of disease recurrence after prostate cancer treatment. PMID- 26743042 TI - Delayed extinction and stronger drug-primed reinstatement of methamphetamine seeking in rats prenatally exposed to morphine. AB - Prenatal morphine (PM) affects the development of brain reward system and cognitive function. The present study aimed to determine whether PM exposure increases the vulnerability to MA addiction. Pregnant Sprague-Dawley rats were administered saline or morphine during embryonic days 3-20. The acquisition, extinction and reinstatement of methamphetamine (MA) conditioned place preference (CPP) and intravenous self-administration (SA) paradigms were assessed in the male adult offspring. There was no difference in the acquisition and expression of MA CPP between saline- and PM-exposed rats, whereas PM-exposed rats exhibited slower extinction and greater MA priming-induced reinstatement of drug-seeking behavior than controls. Similarly, MA SA under progressive ratio and fixed ratio schedules was not affected by PM exposure, but PM-exposed rats required more extinction sessions to reach the extinction criteria and displayed more severe MA priming-, but not cue-induced, reinstatement. Such alterations in extinction and reinstatement were not present when PM-exposed rats were tested in an equivalent paradigm assessing operant responding for food pellets. Our results demonstrate that PM exposure did not affect the association memory formation during acquisition of MA CPP or SA, but impaired extinction learning and increased MA primed reinstatement in both tasks. These findings suggest that the offspring of women using morphine or heroin during pregnancy might predict persistent MA seeking during extinction and enhanced propensity to MA relapse although they might not be more susceptible to the reinforcing effect of MA during initiation of drug use. PMID- 26743041 TI - Elevated glucose and oligomeric beta-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation. AB - Metabolic syndrome (MetS) and Type 2 diabetes mellitus (T2DM) increase risk for Alzheimer's disease (AD). The molecular mechanism for this association remains poorly defined. Here we report in human and rodent tissues that elevated glucose, as found in MetS/T2DM, and oligomeric beta-amyloid (Abeta) peptide, thought to be a key mediator of AD, coordinately increase neuronal Ca(2+) and nitric oxide (NO) in an NMDA receptor-dependent manner. The increase in NO results in S nitrosylation of insulin-degrading enzyme (IDE) and dynamin-related protein 1 (Drp1), thus inhibiting insulin and Abeta catabolism as well as hyperactivating mitochondrial fission machinery. Consequent elevation in Abeta levels and compromise in mitochondrial bioenergetics result in dysfunctional synaptic plasticity and synapse loss in cortical and hippocampal neurons. The NMDA receptor antagonist memantine attenuates these effects. Our studies show that redox-mediated posttranslational modification of brain proteins link Abeta and hyperglycaemia to cognitive dysfunction in MetS/T2DM and AD. PMID- 26743045 TI - Salmonella burden in Lebanon. AB - Salmonellosis is a disease that represents a major public health concern in both developing and developed countries. The aim of this article is to evaluate the public health burden of Salmonella illness in Lebanon. The current scope of the Salmonella infection problem was assessed in relation to disease incidence and distribution with respect to age, gender and district. Factors that provide a better understanding of the magnitude of the problem were explored and highlighted. Data reported to the Epidemiologic Surveillance Department at the Lebanese Ministry of Public Health between 2001 and 2013 was reviewed. Information obtained was compared to information reported regionally and globally. The estimated true incidence was derived using multipliers from the CDC and Jordan. A literature review of all published data from Lebanon about Salmonella susceptibility/resistance patterns and its serious clinical complications was conducted. The estimated incidence was 13.34 cases/100 000 individuals, most cases occurred in the 20-39 years age group with no significant gender variation. Poor and less developed districts of Lebanon had the highest number of cases and the peak incidence was in summer. Reflecting on the projected incidence derived from the use of multipliers indicates a major discrepancy between what is reported and what is estimated. We conclude that data about Salmonella infection in Lebanon and many Middle Eastern and developing countries lack crucial information and are not necessarily representative of the true incidence, prevalence and burden of illness. PMID- 26743044 TI - Rho GTPase signaling promotes constitutive expression and release of TGF-beta2 by human trabecular meshwork cells. AB - Elevated intraocular pressure (IOP) is causally implicated in the pathophysiology of primary open-angle glaucoma (POAG). The molecular mechanisms responsible for elevated IOP remain elusive, but may involve aberrant expression and signaling of transforming growth factor (TGF)-beta2 within the trabecular meshwork (TM). Consistent with previously published studies, we show here that exogenous addition of TGF-beta2 to cultured porcine anterior segments significantly attenuates outflow facility in a time-dependent manner. By comparison, perfusing segments with a TGFbetaRI/ALK-5 antagonist (SB-431542) unexpectedly elicited a significant and sustained increase in outflow facility, implicating a role for TM localized constitutive expression and release of TGF-beta2. Consistent with this thesis, cultured primary or transformed (GTM3) quiescent human TM cells were found to constitutively express and secrete measurable amounts of biologically active TGF-beta2. Disrupting monomeric GTPase post-translational prenylation and activation with lovastatin or GGTI-298 markedly reduced constitutive TGF-beta2 expression and release. Specifically, inhibiting the Rho subfamily of GTPases with C3 exoenzyme similarly reduced constitutive expression and secretion of TGF beta2. These findings suggest that Rho GTPase signaling, in part, regulates constitutive expression and release of biologically-active TGF-beta2 from human TM cells. Localized constitutive expression and release of TGF-beta2 by TM cells may promote or exacerbate elevation of IOP in POAG. PMID- 26743046 TI - Removing Contamination-Induced Reconstruction Artifacts from Cryo-electron Tomograms. AB - Imaging of fully hydrated, vitrified biological samples by electron tomography yields structural information about cellular protein complexes in situ. Here we present a computational procedure that removes artifacts of three-dimensional reconstruction caused by contamination present in samples during imaging by electron microscopy. Applying the procedure to phantom data and electron tomograms of cellular samples significantly improved the resolution and the interpretability of tomograms. Artifacts caused by surface contamination associated with thinning by focused ion beam, as well as those arising from gold fiducial markers and from common, lower contrast contamination, could be removed. Our procedure is widely applicable and is especially suited for applications that strive to reach a higher resolution and involve the use of recently developed, state-of-the-art instrumentation. PMID- 26743043 TI - Getting directions from the hippocampus: The neural connection between looking and memory. AB - Investigations into the neural basis of memory in human and non-human primates have focused on the hippocampus and associated medial temporal lobe (MTL) structures. However, how memory signals from the hippocampus affect motor actions is unknown. We propose that approaching this question through eye movement, especially by assessing the changes in looking behavior that occur with experience, is a promising method for exposing neural computations within the hippocampus. Here, we review how looking behavior is guided by memory in several ways, some of which have been shown to depend on the hippocampus, and how hippocampal neural signals are modulated by eye movements. Taken together, these findings highlight the need for future research on how MTL structures interact with the oculomotor system. Probing how the hippocampus reflects and impacts motor output during looking behavior renders a practical path to advance our understanding of the hippocampal memory system. PMID- 26743047 TI - Direct Measurement of the Structure of Reconstituted High-Density Lipoproteins by Cryo-EM. AB - Early forms of high-density lipoproteins (HDL), nascent HDL, are formed by the interaction of apolipoprotein AI with macrophage and hepatic ATP-binding cassette transporter member 1. Various plasma activities convert nascent to mature HDL, comprising phosphatidylcholine (PC) and cholesterol, which are selectively removed by hepatic receptors. This process is important in reducing the cholesterol burden of arterial wall macrophages, an important cell type in all stages of atherosclerosis. Interaction of apolipoprotein AI with dimyristoyl (DM)PC forms reconstituted (r)HDL, which is a good model of nascent HDL. rHDL have been used as an antiathersclerosis therapy that enhances reverse cholesterol transport in humans and animal models. Thus, identification of the structure of rHDL would inform about that of nascent HDL and how rHDL improves reverse cholesterol transport in an atheroprotective way. Early studies of rHDL suggested a discoidal structure, which included pairs of antiparallel helices of apolipoprotein AI circumscribing a phospholipid bilayer. Another rHDL model based on small angle neutron scattering supported a double superhelical structure. Herein, we report a cryo-electron microscopy-based model of a large rHDL formed spontaneously from apolipoprotein AI, cholesterol, and excess DMPC and isolated to near homogeneity. After reconstruction we obtained an rHDL structure comprising DMPC, cholesterol, and apolipoprotein AI (423:74:1 mol/mol) forming a discoidal particle 360 A in diameter and 45 A thick; these dimensions are consistent with the stoichiometry of the particles. Given that cryo-electron microscopy directly observes projections of individual rHDL particles in different orientations, we can unambiguously state that rHDL particles are protein bounded discoidal bilayers. PMID- 26743048 TI - Universal Poisson Statistics of mRNAs with Complex Decay Pathways. AB - Messenger RNA (mRNA) dynamics in single cells are often modeled as a memoryless birth-death process with a constant probability per unit time that an mRNA molecule is synthesized or degraded. This predicts a Poisson steady-state distribution of mRNA number, in close agreement with experiments. This is surprising, since mRNA decay is known to be a complex process. The paradox is resolved by realizing that the Poisson steady state generalizes to arbitrary mRNA lifetime distributions. A mapping between mRNA dynamics and queueing theory highlights an identifiability problem: a measured Poisson steady state is consistent with a large variety of microscopic models. Here, I provide a rigorous and intuitive explanation for the universality of the Poisson steady state. I show that the mRNA birth-death process and its complex decay variants all take the form of the familiar Poisson law of rare events, under a nonlinear rescaling of time. As a corollary, not only steady-states but also transients are Poisson distributed. Deviations from the Poisson form occur only under two conditions, promoter fluctuations leading to transcriptional bursts or nonindependent degradation of mRNA molecules. These results place severe limits on the power of single-cell experiments to probe microscopic mechanisms, and they highlight the need for single-molecule measurements. PMID- 26743049 TI - Resolution and Probabilistic Models of Components in CryoEM Maps of Mature P22 Bacteriophage. AB - CryoEM continues to produce density maps of larger and more complex assemblies with multiple protein components of mixed symmetries. Resolution is not always uniform throughout a cryoEM map, and it can be useful to estimate the resolution in specific molecular components of a large assembly. In this study, we present procedures to 1) estimate the resolution in subcomponents by gold-standard Fourier shell correlation (FSC); 2) validate modeling procedures, particularly at medium resolutions, which can include loop modeling and flexible fitting; and 3) build probabilistic models that combine high-accuracy priors (such as crystallographic structures) with medium-resolution cryoEM densities. As an example, we apply these methods to new cryoEM maps of the mature bacteriophage P22, reconstructed without imposing icosahedral symmetry. Resolution estimates based on gold-standard FSC show the highest resolution in the coat region (7.6 A), whereas other components are at slightly lower resolutions: portal (9.2 A), hub (8.5 A), tailspike (10.9 A), and needle (10.5 A). These differences are indicative of inherent structural heterogeneity and/or reconstruction accuracy in different subcomponents of the map. Probabilistic models for these subcomponents provide new insights, to our knowledge, and structural information when taking into account uncertainty given the limitations of the observed density. PMID- 26743050 TI - [Intrinsic factors, genes, and skin aging]. AB - Skin aging is determined by a combination of endogenous and environmental influences, including epigenetic, posttranslational, microbial, and lifestyle factors. In particular genetic changes, programmed or not, play a pivotal role and understanding of these complex mechanisms may contribute to the prevention of age-related diseases and extension of healthy lifespan. In this article, new knowledge about genes and biological processes that can significantly affect skin homeostasis in old age and can lead to the typical morphological and physiological characteristics of aging skin are summarized. PMID- 26743052 TI - [Diagnosis of the porphyrias : From A (as in aminolevulinic acid) to Z (as in zinc protoporphyrin)]. AB - The porphyrias comprise a clinically, biochemically, and genetically heterogeneous group of predominantly hereditary metabolic disorders resulting from a dysfunction along the heme biosynthetic pathway. Whereas most variants can manifest with different cutaneous symptoms, some types only reveal life threatening acute neurovisceral attacks. Therefore, interdisciplinary care of these patients is advisable. In this article, we provide an overview of characteristic clinical and laboratory findings in the various forms of porphyria and a diagnostic algorithm. PMID- 26743051 TI - [Experimental models of human skin aging]. AB - The skin is a representative model for the study of human aging. Despite the high regenerative capacity of the skin, skin physiology changes over the course of life. Medical and cosmetic research is trying to prevent aging, to slow, to stop, or to reverse it. Effects of age-related DNA damage and of changing skin structure on pharmacological parameters are largely unknown. This review article summarizes the state of scientific knowledge in the field of experimental models of human skin aging and shows approaches to improve organotypic skin models, to develop predictive models of aging, and improve aging research. PMID- 26743053 TI - [Neurocutaneous porphyrias]. AB - Porphyrias comprise a heterogeneous group of predominantly genetically determined metabolic diseases which are due to a dysfunction in heme biosynthesis. Variegate porphyria and hereditary coproporphyria are referred to as neurocutaneous porphyrias because affected patients can develop both cutaneous symptoms on light exposed body sites and potentially life-threatening acute neurovisceral symptoms, thereby mimicking several other diseases. In this overview, we provide an update on pathogenesis, clinical manifestation, diagnosis, and therapy of these two types of porphyria. PMID- 26743054 TI - [Porphyria cutanea tara]. AB - Porphyria cutanea tara (PCT) has a prevelance of about 40 new diagnoses per 1 million people per year and is the most frequently occurring type of porphyria worldwide. Inhibition of the uroporphyrinogen decarboxylase (UROD) is the main cause of the disease, which can be the result of a heterozygous or homozygous mutation of the UROD gene; however, xenobiotics or other diseases may play an important role for the precipitation of the disease. Risk factors include alcohol, estrogen, iron overload, and hemochromatosis, hepatitis C or poisoning, e.g., with polyhalogenated aromatic compounds such as hexachlorobenzene. Signs and symptoms are blisters, skin fragility, erosions hyperpigmentation, sclerodermoid plaques. Therapy includes sun protection, prevention of risk factors, phlebotomy, and chloroquine. PMID- 26743056 TI - [Porphyrias : Metabolic disorders of heme biosynthesis]. PMID- 26743055 TI - [Dermatosurgery in the elderly]. AB - In recent decades, the portion of elderly has increased substantially due to demographic changes in developed countries. Dermatological surgery is particularly affected by this development, because a large proportion of the elderly suffer from skin tumors, which are primarily treated surgically. Physiological changes of age and multimorbidity, often associated with polypharmacy, present the treating physician with enormous challenges. What aspects of care are important? What must be considered? What are possible complications and how can they be prevented? These important questions are answered. Finally, selected surgical approaches for the care of very old patients are also described. PMID- 26743057 TI - Pride and protein. AB - OBJECTIVE: In Jane Austen's Pride and Prejudice, members of the Bennet family are either sensible or silly, and males are under-represented. This study searches for an underlying medical diagnosis that explains these features. DESIGN: Very retrospective literature review. PARTICIPANTS: Mrs Bennet, her five daughters (Jane, Elizabeth, Mary, Kitty and Lydia), her brother (Mr Gardiner) and her sister (Mrs Phillips). MAIN OUTCOME MEASURES: Family tree and associated phenotypes METHODS: The author read Pride and Prejudice. A Bennet family tree was constructed. The number of male and female descendants was analysed using a binomial model. For each character, evidence of behaviour was collected, and members of the Bennet family were categorised as either sensible or silly. RESULTS: Males are under-represented in Mrs Bennet's family. Assuming an equal probability of male or female offspring, this reaches statistical significance (binomial model, P = 0.03). Approximately 50% of females in the family are silly. Silly behaviour is more prevalent during social gatherings. CONCLUSIONS: The family tree suggests an X-linked genetic disorder, fatal in utero or in early life to affected males, explaining the paucity of male offspring. Female carriers survive, but with cognitive difficulties, explaining the approximate 50-50 distribution of sensible and silly females in the family. The exacerbation of silliness during social gatherings may suggest an effect of protein intake, raising suspicions of a disorder of protein metabolism. Ornithine transcarbamylase deficiency is one such condition. Unfortunately, there remain significant challenges in performing genetic testing on fictional characters, so definitive evidence remains elusive. Jane and Elizabeth Bennet do not show signs of the disorder. However, carriers may be asymptomatic; they should be offered genetic counselling before Bingley or Darcy offspring are considered. PMID- 26743058 TI - The natural history of elevated tetradecenoyl-L-carnitine detected by newborn screening in New Zealand: implications for very long chain acyl-CoA dehydrogenase deficiency screening and treatment. AB - Very long chain acyl-CoA dehydrogenase deficiency (VLCADD, OMIM #201475) has been increasingly diagnosed since the advent of expanded newborn screening (NBS). Elevated levels of tetradecenoyl-L-carnitine (C14:1) in newborn screening blood spot samples are particularly common in New Zealand, however this has not translated into increased VLCADD clinical presentations. A high proportion of screen-positive cases in NZ are of Maori or Pacific ethnicity and positive for the c.1226C > T (p.Thr409Met) ACADVL gene variant. We performed a retrospective, blinded, case-control study of 255 cases, born between 2006 and 2013, with elevated NBS C14:1 levels between 0.9 and 2.4 MUmol/L, below the NZ C14:1 notification cut-off of 2.5 MUmol/L. Coded healthcare records were audited for cases and age- and ethnicity- matched controls. The clinical records of those with possible VLCADD-related symptoms were reviewed. The follow-up period was 6 months to 7 years. Two of 247 cases (0.8 %) had possible VLCADD-like symptoms while four of 247 controls (2 %) had VLCADD-like symptoms (p = 0.81). Maori were overrepresented (68 % of the cohort vs 15 % of population). Targeted analysis of the c.1226 locus revealed the local increase in screening C14:1 levels is associated with the c.1226C > T variant (97/152 alleles tested), found predominantly in Maori and Pacific people. There was no increase in clinically significant childhood disease, irrespective of ethnicity. The study suggests that children with elevated C14:1, between 0.9-2.4 MUmol/L, on NBS are at very low risk of clinically significant childhood disease. A minimally interventional approach to managing these patients is indicated, at least in the New Zealand population. PMID- 26743060 TI - Splitting the variance of statistical learning performance: A parametric investigation of exposure duration and transitional probabilities. AB - What determines individuals' efficacy in detecting regularities in visual statistical learning? Our theoretical starting point assumes that the variance in performance of statistical learning (SL) can be split into the variance related to efficiency in encoding representations within a modality and the variance related to the relative computational efficiency of detecting the distributional properties of the encoded representations. Using a novel methodology, we dissociated encoding from higher-order learning factors, by independently manipulating exposure duration and transitional probabilities in a stream of visual shapes. Our results show that the encoding of shapes and the retrieving of their transitional probabilities are not independent and additive processes, but interact to jointly determine SL performance. The theoretical implications of these findings for a mechanistic explanation of SL are discussed. PMID- 26743059 TI - Inductive generalization relies on category representations. AB - The ability to take information learned about one object (e.g., a cat) and extend it to other objects (e.g., a tiger, a lion) makes human learning efficient and powerful. How are these inductive generalizations performed? Fisher, Godwin, and Matlen (2015) proposed a developmental mechanism that operates exclusively over the perceptual and semantic features of the objects involved (e.g., furry, carnivorous); this proposed mechanism does not use information concerning these objects' category memberships. In the present commentary, we argue that Fisher and colleagues' experiments cannot differentiate between their feature-based mechanism and its category-based competitors. More broadly, we suggest that any proposal that does not take into account the central role of category representations in children's mental lives is likely to mischaracterize the development of inductive generalization. The key question is not whether, but how, categories are involved in children's generalizations. PMID- 26743061 TI - Thromboinflammatory response and predictors of outcomes in patients undergoing transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement (TAVR) has been increasingly used to treat patients with symptomatic aortic stenosis. Despite improvements in valve deployment, patients that have undergone TAVR are at high risk for major adverse events following the procedure. Blood cell numbers, platelet function, and biomarkers of systemic inflammation were analyzed in 58 patients undergoing TAVR with the Edward's SAPIEN valve. Following valve deployment, platelet count and agonist-induced platelet activity declined and plasma markers of systemic inflammation (interleukin-6 and S100A8/A9) increased. Baseline platelet activity prior to TAVR correlated with perioperative changes plasma interleukin-6 levels. Moreover, perioperative changes in plasma inflammatory markers predicted the decline in platelet count in the days following the TAVR procedure. Additionally, a significant effect of gender on platelet count following TAVR and was observed. Finally, post-procedural mortality was associated with sustained thrombocytopenia after TAVR. Our findings suggest that TAVR elicits a thromboinflammatory state that may contribute to post-procedural thrombocytopenia. Importantly, our results add to the growing body of literature that suggests the thromboinflammatory changes that occur early after TAVR may predict long-term outcomes. PMID- 26743062 TI - Thrombomodulin gene c.1418C>T polymorphism and risk of recurrent venous thromboembolism. AB - Thrombomodulin gene (THBD) is a critical cofactor in protein C anticoagulant system. THBD c.1418C>T polymorphism is reported to be associated with higher risk of primary venous thromboembolism (VTE) but its role in VTE recurrence is unknown. The aim of this study was to investigate the role of THBD polymorphism in VTE recurrence. THBD c.1418C>T polymorphism was genotyped by using Taqman polymerase chain reaction in a prospective population based study of 1465 consecutive objectively verified VTE patients. Uni- and multivariate Cox regression were performed for the risk assessment of VTE recurrence. Patients who had VTE before inclusion or had recurrence or died during anticoagulant treatment were excluded. Among the remaining (N = 1046) patients, 126 (12.05 %) had VTE recurrence during the follow up period (from 1998 to 2008). THBD polymorphism was not significantly associated with risk of VTE recurrence in the univariate [Hazard ratio (HR) 1.11, 95 % confidence interval (CI) 0.78-1.59, p = 0.55] as well as the multivariate analysis adjusted for age, sex and thrombophilia (HR 1.11, 95 % CI 0.78-1.59, p = 0.54). Similarly, in unprovoked first VTE (n = 614), no association was observed between THBD polymorphism and risk of VTE recurrence (HR 1.22 and 95 % CI 0.78-1.89, p = 0.38). In this prospective study, our results do not suggest a predictive role for THBD c.1418C>T polymorphism in VTE recurrence. PMID- 26743063 TI - Lactodifucotetraose, a human milk oligosaccharide, attenuates platelet function and inflammatory cytokine release. AB - Human milk strongly quenches inflammatory processes in vitro, and breastfed infants have lower incidence of inflammatory diseases than those fed artificially. Platelets from neonates, in contrast to those from adults, are less responsive to platelet agonists such as collagen, thrombin, ADP, and epinephrine. Breastfed infants absorb oligosaccharides intact from the human milk in their gut to the circulation. This study was to determine whether these oligosaccharides can attenuate platelet function and platelet secretion of pro-inflammatory proteins, and to identify the active component. The natural mixture of oligosaccharides from human milk and pure individual human milk oligosaccharides were tested for their ability to modulate responses of platelets isolated from human blood following exposure to thrombin, ADP, and collagen. Human milk and the natural mixture of human milk oligosaccharides inhibited platelet release of inflammatory proteins. Of the purified human milk oligosaccharides tested, only lactodifucotetraose (LDFT) significantly inhibited thrombin induced release of the pro-inflammatory proteins RANTES and sCD40L. LDFT also inhibited platelet adhesion to a collagen-coated surface, as well as platelet aggregation induced by ADP or collagen. These data indicate that LDFT may help modulate hemostasis by suppressing platelet-induced inflammatory processes in breastfed infants. This activity suggests further study of LDFT for its potential as a therapeutic agent in infants and adults. PMID- 26743064 TI - Association of reversible splenial lesion syndrome (RESLES) with Anti-VGKC autoantibody syndrome: a case report. AB - A 50-year-old male presented with complaints of fatigue, confusion, and memory problems. Neurological evaluation revealed altered cognition, unsteady gait, ataxia, dysmetria, and weakness. MRI of the brain was initially unremarkable. Over several days, the patient experienced improvement of symptoms and a follow up MRI revealed a small lesion in the splenium of the corpus callosum seen on diffusion weighted and T2 sequences. The patient was discovered to have elevated anti-voltage gated potassium channel serum autoantibodies. Follow-up MRI revealed resolution of the splenial lesion. The patient was treated with intravenous immune globulin, and improved back to his pre-treatment baseline. We believe this to be the first case of a reversible splenial lesion syndrome as a manifestation of the anti-voltage gated potassium channel autoantibody syndrome, and propose a pathophysiologic mechanism. PMID- 26743065 TI - Unusual presentations and intrafamilial phenotypic variability in infantile onset Alexander disease. AB - Alexander disease is an hereditary leukodystrophy related to mutations of GFAP. Classically AxD was divided in infantile, juvenile, and adult subgroups. Recent data suggested considering only two subtypes: type I (infantile onset with lesions extending to the cerebral hemispheres); type II (adult onset with primary involvement of subtentorial structures). We report two related and one unrelated patients presenting with a peculiar association of clinical and neuroradiological features. GFAP analysis disclosed the presence of one novel and two previously reported mutations. Our patients underline the importance of considering AxD in patients with bulbar symptoms and autonomic dysfunction even if MRI shows only posterior fossa abnormalities, supporting the hypothesis of a third type of AxD sharing features of both type I and type II. The evidence of an intrafamilial phenotypic variability suggests the possible role of still unknown factors influencing the effect of GFAP mutation and determining the phenotype. PMID- 26743066 TI - A case report of eight and a half syndrome. PMID- 26743067 TI - Anterior cutaneous nerve entrapment syndrome following an appendectomy: case report. PMID- 26743068 TI - Neuropsychological and psychiatric aspects of multiple sclerosis: preliminary investigation of discrete profiles across neurological subtypes. AB - Cognitive deficits affecting memory, attention, speed of information processing and executive functions are common in multiple sclerosis (MS). In this study we examine the possibility of discrete pattern of neuropsychological deficits of MS subtypes. 28 patients (13 RRMS, 6 CIS, and 9 SPMS) were assessed with a comprehensive neuropsycholgical battery. Results indicate that only the SPMS group demonstrates memory and executive impairment. This finding indicates possible differentiation of the three subtypes in terms of neuropsychological profiles. Psychiatric aspects of MS are also briefly discussed. PMID- 26743069 TI - Blood Pressure: Return of the Sympathetics? AB - This brief review highlights new ideas about the role of the sympathetic nervous system in human blood pressure regulation. We emphasize how this role varies with age and sex and use our findings to raise questions about the sympathetic nervous system and hypertension in humans. We also focus on three additional areas, including (1) novel ideas about the carotid body and sympathoexcitation as it relates to hypertension, (2) clinical trials of renal denervation that attempted to treat hypertension by reducing ongoing sympathoexcitation, and (3) new ideas about resistant hypertension and cerebral blood flow. We further highlight that success of device-based therapy to modulate the sympathetic nervous system relies heavily on patient selection. Furthermore, data suggest that the majority of patients respond to anti-hypertensive therapy and the major cause of "resistant" hypertension is poor patient adherence. While the enthusiasm for device therapy or perhaps even "precision medicine" is high, it is likely that by far the most benefit to the most patients will occur via better screening, more aggressive therapy, and the development of strategies that improve patient adherence to medication regimens and lifestyle changes. PMID- 26743070 TI - Contact force monitoring during catheter ablation of intraatrial reentrant tachycardia in patients with congenital heart disease. AB - BACKGROUND: Monitoring of catheter contact force during catheter ablation of atrial fibrillation has been shown to increase efficacy and safety. However, almost no data exists on the use of this technology in catheter ablation of intraatrial reentrant tachycardia in patients with congenital heart disease. The aim of the present study was to evaluate the impact of contact force monitoring during catheter ablation of intraatrial reentrant tachycardia in those patients. METHODS: Catheter ablation of intraatrial reentrant tachycardia using monitoring of catheter contact force was performed in 28 patients with congenital heart disease (CHD). Thirty-two patients matched according to gender, age, and body weight with congenital heart disease undergoing catheter ablation without contact force monitoring served as control group. Parameters reflecting acute procedural success, long-term efficacy, and safety were compared. RESULTS: Acute procedural success was statistically not different in both groups (contact force 93 % vs. control 84 %, p = 0.3). Likewise the recurrence rate 1 year after ablation as shown by Kaplan-Meier analysis did not differ (contact force 28 % vs. control 37 %, p = 0.63). Major complications were restricted to groin vessel injuries and occurred in 3 out of 60 patients (contact force n = 1; control n = 2). Complications related to excessive catheter contact force were not observed. CONCLUSION: The present study did not show superiority of catheter contact force monitoring during ablation of intraatrial reentrant tachycardia in patients with CHD in terms of efficacy and safety. Higher contact force compared to pulmonary vein isolation might therefore be required to increase the efficacy of catheter ablation of intraatrial reentrant tachycardia in patients with congenital heart disease. PMID- 26743071 TI - The success of shock wave lithotripsy (SWL) in treating moderate-sized (10-20 mm) renal stones. AB - Many centres favour endourological management over shock wave lithotripsy (SWL) in the management of moderate-sized (10-20 mm) renal stones. International guidelines support all available modalities for the treatment of these stones. The aim of this study was to evaluate the efficacy of SWL in the treatment of 10- to 20-mm renal stones. From January 2013 to October 2014, all patients with a renal stone measuring between 10 and 20 mm in maximum diameter on CT scan that were eligible for lithotripsy were included. 130 consecutive patients were evaluated. Demographics, location of stone within the kidney, number of SWL sessions and treatment outcomes were analysed. Treatment success was classified into complete stone clearance and the presence of clinically insignificant residual fragments <4 mm (CIRF). 119 patients (92 %) completed treatment and radiological follow-up. Eleven patients were excluded due to incomplete follow-up data. The mean age was 56.8 (23-88). Male to female ratio was 1.9:1 (78:41) and the mean BMI was 28.4 (17.9-58). The mean stone size was 12.8 mm (10-14 mm: n = 87; 15-20 mm: n = 32). The mean number of treatments was 2.14 and 2.82 for stones 10-14 and 15-20 mm, respectively. Overall treatment success was 66.4 % (combined complete stone clearance and CIRFs). Subdivided by stone size <15 mm and >=15 mm, the success rate was 70.4 and 53.1 %, respectively. The treatment success by stone location was 65, 64 and 70 % for upper, middle and lower pole stones, respectively and 67 % for PUJ stones. For those who failed SWL treatment, the majority 50 % (n = 20) were managed expectantly, 42.5 % (n = 17) required URS, and 7.5 % (n = 3) required PNL. This study suggests that SWL has an efficacy for treating larger renal stones (10-20 mm) that is equivalent to success rates for smaller stones in other series. As a low-risk and non-invasive procedure SWL should be considered a first-line treatment for these stones. PMID- 26743072 TI - Prevalence of monosodium urate deposits in a population of rheumatoid arthritis patients with hyperuricemia. AB - OBJECTIVES: To investigate the prevalence of monosodium urate (MSU) crystal deposits, indicative for gout, in a population of rheumatoid arthritis (RA) patients with concomitant hyperuricemia and to analyze the clinical and disease specific characteristics of RA patients who exhibit MSU crystal deposits. METHODS: Overall, 100 consecutive patients with the diagnosis of RA and a serum urate level above 6mg/dl underwent dual energy computed tomography (DECT) of both feet and hands to search for MSU crystals in a prospective study between October 2011 and July 2013. Presence and extent of MSU crystal deposits on DECT was assessed by automated volume measurement. Demographic and disease-specific characteristics were recorded and included into two logistic regression models to test for the factors associated with MSU crystal deposits in RA. RESULTS: Hyperuricemic RA patients were mostly male (55%), over 60 years of age (63 +/- 11 years), had established disease (8.7 +/- 10.5 years) and a mean disease activity score 28 (DAS 28) of 3.2. In total, 20 out of 100 patients displayed MSU crystal deposits in DECT. Interestingly, the majority (70%) of the RA patients positive for MSU crystal deposits were seronegative RA patients. Hence, every third seronegative RA patient had MSU crystal deposits. According to logistic regression model analysis, seronegative status correlated positively with presence of urate deposits (p = 0.019). CONCLUSIONS: These data show that a considerable number of RA patients display periarticular MSU crystal deposits. Seronegative patients were shown to be predominantly affected with every third patient being positive for urate deposits. PMID- 26743073 TI - Tocilizumab in severe and refractory Behcet's disease: Four cases and literature review. AB - INTRODUCTION: In Behcet's disease (BD), interleukin (IL)-6 drive the immune mediated inflammatory process. The IL-6 receptor can be targeted using tocilizumab. As an off-label treatment, we tested its efficacy in patients with BD. METHODS: Overall, 4 patients with refractory BD were treated with tocilizumab, 8mg/kg/4 weeks. Patients were clinically and biologically assessed before administering each dose and the literature was reviewed. RESULTS: Tocilizumab was found to be safe and well tolerated. BD activity decreased significantly in all patients, and prednisone dose was reduced in all cases (up to 50% of the baseline dose). Treatment appeared effective in alleviating skin/mucosal effects, neurological involvement, and uveitis, but less effective for arthralgia and abdominal pain. A very short time lag between the onset of treatment with tocilizumab and the clinical response was observed. The literature review revealed 11 previous cases reporting improvement to BD with this treatment, and 3 previous cases without efficacy. CONCLUSIONS: We reported the most important study treating refractory BD with tocilizumab; this treatment could be safe and efficient, but will require further evaluation by randomized clinical trials. PMID- 26743074 TI - Direct and indirect costs for systemic lupus erythematosus in Sweden. A nationwide health economic study based on five defined cohorts. AB - OBJECTIVES: The main objectives of this study were to calculate total costs of illness and cost-driving disease features among patients with systemic lupus erythematosus (SLE) in Sweden. METHODS: Five cohorts of well-defined SLE patients, located in different parts of the country were merged. Incident and prevalent cases from 2003 through 2010 were included. The American College of Rheumatology (ACR) classification criteria was used. From the local cohorts, data on demographics, disease activity (SLEDAI 2K), and organ damage (SDI) were collected. Costs for inpatient care, specialist outpatient care and drugs were retrieved from national registries at the National Board of Health and Welfare. Indirect costs were calculated based on sickness leave and disability pensions from the Swedish Social Insurance Agency. RESULTS: In total, 1029 SLE patients, 88% females, were included, and approximately 75% were below 65 years at the end of follow-up, and thus in working age. The mean number of annual specialist physician visits varied from six to seven; mean annual inpatient days were 3.1 3.6, and mean annual sick leave was 123-148 days, all per patient. The total annual cost was 208,555 SEK ($33,369 = 22,941?), of which direct cost was 63,672kr ($10,188 = 7004?) and the indirect cost was 144,883 SEK ($23,181 = 15,937?), all per patient. The costs for patients with short disease duration were higher. Higher disease activity as measured by a SLEDAI 2K score > 3 was associated with approximately 50% increase in both indirect and direct costs. Damage in the neuropsychiatric and musculoskeletal domains were also linked to higher direct and indirect costs, while organ damage in the renal and ocular systems increased direct costs. CONCLUSION: Based on this study and an estimate of slightly more than 6000 SLE patients in Sweden, the total annual cost for SLE in the country is estimated at $188 million (=129.5 million ?). Both direct (30%) and indirect costs (70%) are substantial. Medication accounts for less than 10% of the total cost. The tax paid national systems for health care and social security in Sweden ensure equal access to health care, sick leave reimbursements, and disability pensions nationwide. Our extrapolated annual costs for SLE in Sweden are therefore the best supported estimations thus far, and they clearly underline the importance of improved management, especially to reduce the indirect costs. PMID- 26743075 TI - Biological implications and therapeutic significance of DNA methylation regulated genes in cervical cancer. AB - Cervical cancer is the second most common cancer among women worldwide. About 528,000 women are diagnosed with cervical cancer contributing to around 266,000 deaths, across the globe every year. Out of these, the burden of 226,000 (85%) deaths occurs in the developing countries, who are less resource intensive to manage the disease. This is despite the fact that cervical cancer is amenable for early detection due to its long and relatively well-known natural history prior to its culmination as invasive disease. Infection with high risk human papillomavirus (hrHPVs) is essential but not sufficient to cause cervical cancer. Although it was thought that genetic mutations alone was sufficient to cause cervical cancer, the current epidemiological and molecular studies have shown that HPV infection along with genetic and epigenetic changes are frequently associated and essential for initiation, development and progression of the disease. Moreover, aberrant DNA methylation in host and HPV genome can be utilized not only as biomarkers for early detection, disease progression, diagnosis and prognosis of cervical cancer but also to design effective therapeutic strategies. In this review, we focus on recent studies on DNA methylation changes in cervical cancer and their potential role as biomarkers for early diagnosis, prognosis and targeted therapy. PMID- 26743077 TI - Advances in the Understanding of the Genetic Causes of Hearing Loss in Children Inform a Rational Approach to Evaluation. AB - Hearing loss represents the most common sensory disability of children. Remarkable advances in the identification of genes underlying nonsyndromic and syndromic hearing loss in just the last 2 decades have led to the ability to determine the specific genetic cause of hearing loss in many children. Surprisingly one gene, GJB2, encoding the protein connexin-26, accounts for about 20 % of sensorineural hearing loss (including in India) and is considered the first tier test in evaluating an infant with unexplained congenital hearing loss. Using the knowledge of the etiology of hearing loss, the authors propose a diagnostic reasoning process for the assessment of a child in the pediatric setting. Second tier testing consists of the multiple gene panels using whole exome sequencing strategies, and is becoming available in some regions of the world including the US. Referral to medical genetics is always a consideration in a child with no explanation for the hearing loss and in families with questions about recurrence risk. PMID- 26743076 TI - Biliary epithelium and liver B cells exposed to bacteria activate intrahepatic MAIT cells through MR1. AB - BACKGROUND & AIMS: Mucosal-Associated Invariant T (MAIT) cells are innate-like T cells characterised by the invariant TCR-chain, Valpha7.2-Jalpha33, and are restricted by MR1, which presents bacterial vitamin B metabolites. They are important for antibacterial immunity at mucosal sites; however, detailed characteristics of liver-infiltrating MAIT (LI-MAIT) and their role in biliary immune surveillance remain unexplored. METHODS: The phenotype and intrahepatic localisation of human LI-MAIT cells was examined in diseased and normal livers. MAIT cell activation in response to E. coli-exposed macrophages, biliary epithelial cells (BEC) and liver B cells was assessed with/without anti-MR1. RESULTS: Intrahepatic MAIT cells predominantly localised to bile ducts in the portal tracts. Consistent with this distribution, they expressed biliary tropic chemokine receptors CCR6, CXCR6, and integrin alphaEbeta7. LI-MAIT cells were also present in the hepatic sinusoids and possessed tissue-homing chemokine receptor CXCR3 and integrins LFA-1 and VLA-4, suggesting their recruitment via hepatic sinusoids. LI-MAIT cells were enriched in the parenchyma of acute liver failure livers compared to chronic diseased livers. LI-MAIT cells had an activated, effector memory phenotype, expressed alpha4beta7 and receptors for IL 12, IL-18, and IL-23. Importantly, in response to E. coli-exposed macrophages, liver B cells and BEC, MAIT cells upregulated IFN-gamma and CD40 Ligand and degranulated in an MR1-dependent, cytokine-independent manner. In addition, diseased liver MAIT cells expressed T-bet and RORgammat and the cytokines IFN gamma, TNF-alpha, and IL-17. CONCLUSIONS: Our findings provide the first evidence of an immune surveillance effector response for MAIT cells towards BEC in human liver; thus they could be manipulated for treatment of biliary disease in the future. PMID- 26743078 TI - Treatment of IgA nephropathy with renal insufficiency. AB - IgA Nephropathy leads young people to dialysis more often than other glomerular diseases, because often diagnosis and therapy are made late. Nephrologists waive to treat IgAN pts with chronic renal insufficiency, believing that treatment may not be effective and safe. Moreover, studies in IgAN pts with reduced renal function are lacking. Small studies seem to indicate a possible utility of RAS blockers and corticosteroids in these patients. Recently, VALIGA study showed that corticosteroids and immunosuppressants were more frequently used in pts with eGFR <30 ml/min than in those with eGFR >30 ml/min (60 vs. 44 %, respectively; p = 0.004). The goal of treating IgAN pts is to obtain a time-average proteinuria <1 g/day, regardless of the degree of renal function and histological damage. RASB and corticosteroids seem to be able to obtain this result. However, it's important to pay attention to the appearance of adverse events of CS. In the literature, major side effects occurred in 29 of 463 (6.2 %) patients enrolled in RCTs. However, scarce informations are obtained about the safety of CS in patients with reduced renal function. To better evaluate this aspect, we considered three studies, that used similar schemes of therapy and included patients with different degrees of renal function (1: GFR 90 ml/min/1.73 m(2), 2: 81 ml/min/1.73 m(2), 3: 34 ml/min/1.73 m(2)). The occurrence of adverse events increased with the worsening of renal function (2.3, 5.7 and 15.4 % in studies 1, 2 and 3 respectively). The aim of the treatment for a patient with an eGFR <30 is to slow the progression and to delay the need for dialysis. Therefore, in stage CKD 2, 3 and 4 with a proteinuria >1 g/day a 6-month course of corticosteroids could be useful and safe. PMID- 26743079 TI - Acute renal infarction: a single center experience. AB - BACKGROUND: Acute renal infarction is a rare condition whose diagnosis is often delayed. Major risk factors include atrial fibrillation, valvular or ischemic heart disease, renal artery thrombosis/dissection and coagulopathy. METHODS: We reviewed the medical records of 18 patients admitted to our Nephrology Department between 1999 and 2015 for acute renal infarction diagnosed by computed tomography. Tc-99m dimercaptosuccinic acid (DMSA) scintigraphy was performed in some patients during follow-up to assess parenchymal lesions and estimate differential kidney function. RESULTS: Mean age was 59.8 years. Major associated risk factors included hypertension (44 %), obesity (33 %), atrial fibrillation (28 %), peripheral vascular disease (17 %), smoking (17 %), prior thromboembolic event (11 %), diabetes (11 %), estroprogestinic therapy (11 %). Seventy-two percent of patients presented with flank pain. Mean serum creatinine was 1.2 +/- 0.6 mg/dl. Acute kidney injury occurred as the initial manifestation in two patients. Patients were managed conservatively, with low molecular weight heparin (83 %) or aspirin (11 %). At the end of follow-up serum creatinine was 1.1 +/- 0.3 mg/dl; one patient remained on chronic hemodialysis. 58 % of patients who underwent renal scintigraphy after a median of 8 months had a reduced contribution of the previously affected kidney to total renal function. CONCLUSION: Risk factors associated with the development of chronic kidney disease following renal infarction are unknown. In our subjects, renal function remained stable in all but one patient who developed end stage renal disease. Further studies should focus on etiology and evolution of kidney function in patients with acute renal infarction. PMID- 26743081 TI - RASGRF2 controls nuclear migration in postnatal retinal cone photoreceptors. AB - Detailed immunocytochemical analyses comparing wild-type (WT), GRF1-knockout (KO), GRF2-KO and GRF1/2 double-knockout (DKO) mouse retinas uncovered the specific accumulation of misplaced, 'ectopic' cone photoreceptor nuclei in the photoreceptor segment (PS) area of retinas from GRF2-KO and GRF1/2-DKO, but not of WT or GRF1-KO mice. Localization of ectopic nuclei in the PS area of GRF2 depleted retinas occurred postnatally and peaked between postnatal day (P)11 and P15. Mechanistically, the generation of this phenotype involved disruption of the outer limiting membrane and intrusion into the PS layer by cone nuclei displaying significant perinuclear accumulation of signaling molecules known to participate in nuclear migration and cytoskeletal reorganization, such as PAR3, PAR6 and activated, phosphorylated forms of PAK, MLC2 and VASP. Electroretinographic recordings showed specific impairment of cone-mediated retinal function in GRF2 KO and GRF1/2-DKO retinas compared with WT controls. These data identify defective cone nuclear migration as a novel phenotype in mouse retinas lacking GRF2 and support a crucial role of GRF2 in control of the nuclear migration processes required for proper postnatal development and function of retinal cone photoreceptors. PMID- 26743082 TI - Third harmonic generation microscopy of cells and tissue organization. AB - The interaction of cells within their microenvironmental niche is fundamental to cell migration, positioning, growth and differentiation in order to form and maintain complex tissue organization and function. Third harmonic generation (THG) microscopy is a label-free scatter process that is elicited by water-lipid and water-protein interfaces, including intra- and extracellular membranes, and extracellular matrix structures. In applied life sciences, THG delivers a versatile contrast modality to complement multi-parameter fluorescence, second harmonic generation and fluorescence lifetime microscopy, which allows detection of cellular and molecular cell functions in three-dimensional tissue culture and small animals. In this Commentary, we review the physical and technical basis of THG, and provide considerations for optimal excitation, detection and interpretation of THG signals. We further provide an overview on how THG has versatile applications in cell and tissue research, with a particular focus on analyzing tissue morphogenesis and homeostasis, immune cell function and cancer research, as well as the emerging applicability of THG in clinical practice. PMID- 26743083 TI - Computational 'microscopy' of cellular membranes. AB - Computational 'microscopy' refers to the use of computational resources to simulate the dynamics of a molecular system. Tuned to cell membranes, this computational 'microscopy' technique is able to capture the interplay between lipids and proteins at a spatio-temporal resolution that is unmatched by other methods. Recent advances allow us to zoom out from individual atoms and molecules to supramolecular complexes and subcellular compartments that contain tens of millions of particles, and to capture the complexity of the crowded environment of real cell membranes. This Commentary gives an overview of the main concepts of computational 'microscopy' and describes the state-of-the-art methods used to model cell membrane processes. We illustrate the power of computational modelling approaches by providing a few in-depth examples of large-scale simulations that move up from molecular descriptions into the subcellular arena. We end with an outlook towards modelling a complete cell in silico. PMID- 26743080 TI - Loss of PPARgamma in endothelial cells leads to impaired angiogenesis. AB - Tie2-promoter-mediated loss of peroxisome proliferator-activated receptor gamma (PPARgamma, also known as PPARG) in mice leads to osteopetrosis and pulmonary arterial hypertension. Vascular disease is associated with loss of PPARgamma in pulmonary microvascular endothelial cells (PMVEC); we evaluated the role of PPARgamma in PMVEC functions, such as angiogenesis and migration. The role of PPARgamma in angiogenesis was evaluated in Tie2CrePPARgamma(flox/flox) and wild type mice, and in mouse and human PMVECs. RNA sequencing and bioinformatic approaches were utilized to reveal angiogenesis-associated targets for PPARgamma. Tie2CrePPARgamma(flox/flox) mice showed an impaired angiogenic capacity. Analysis of endothelial progenitor-like cells using bone marrow transplantation combined with evaluation of isolated PMVECs revealed that loss of PPARgamma attenuates the migration and angiogenic capacity of mature PMVECs. PPARgamma-deficient human PMVECs showed a similar migration defect in culture. Bioinformatic and experimental analyses newly revealed E2F1 as a target of PPARgamma in the regulation of PMVEC migration. Disruption of the PPARgamma-E2F1 axis was associated with a dysregulated Wnt pathway related to the GSK3B interacting protein (GSKIP). In conclusion, PPARgamma plays an important role in sustaining angiogenic potential in mature PMVECs through E2F1-mediated gene regulation. PMID- 26743084 TI - Reverse overshot water-wheel retroendocytosis of apotransferrin extrudes cellular iron. AB - Iron (Fe), a vital micronutrient for all organisms, must be managed judiciously because both deficiency or excess can trigger severe pathology. Although cellular Fe import is well understood, its export is thought to be limited to transmembrane extrusion through ferroportin (also known as Slc40a1), the only known mammalian Fe exporter. Utilizing primary cells and cell lines (including those with no discernible expression of ferroportin on their surface), we demonstrate that upon Fe loading, the multifunctional enzyme glyceraldehyde-3 phosphate dehydrogenase (GAPDH), which is recruited to the cell surface, 'treadmills' apotransferrin in and out of the cell. Kinetic analysis utilizing labeled ligand, GAPDH-knockdown cells, (55)Fe-labeled cells and pharmacological inhibitors of endocytosis confirmed GAPDH-dependent apotransferrin internalization as a prerequisite for cellular Fe export. These studies define an unusual rapid recycling process of retroendocytosis for cellular Fe extrusion, a process mirroring receptor mediated internalization that has never before been considered for maintenance of cellular cationic homeostasis. Modulation of this unusual pathway could provide insights for management of Fe overload disorders. PMID- 26743085 TI - A dual phosphorylation switch controls 14-3-3-dependent cell surface expression of TASK-1. AB - The transport of the K(+) channels TASK-1 and TASK-3 (also known as KCNK3 and KCNK9, respectively) to the cell surface is controlled by the binding of 14-3-3 proteins to a trafficking control region at the extreme C-terminus of the channels. The current model proposes that phosphorylation-dependent binding of 14 3-3 sterically masks a COPI-binding motif. However, the direct effects of phosphorylation on COPI binding and on the binding parameters of 14-3-3 isoforms are still unknown. We find that phosphorylation of the trafficking control region prevents COPI binding even in the absence of 14-3-3, and we present a quantitative analysis of the binding of all human 14-3-3 isoforms to the trafficking control regions of TASK-1 and TASK-3. Surprisingly, the affinities of 14-3-3 proteins for TASK-1 are two orders of magnitude lower than for TASK-3. Furthermore, we find that phosphorylation of a second serine residue in the C terminus of TASK-1 inhibits 14-3-3 binding. Thus, phosphorylation of the trafficking control region can stimulate or inhibit transport of TASK-1 to the cell surface depending on the target serine residue. Our findings indicate that control of TASK-1 trafficking by COPI, kinases, phosphatases and 14-3-3 proteins is highly dynamic. PMID- 26743086 TI - Ubiquitin-mediated regulation of the E3 ligase GP78 by MGRN1 in trans affects mitochondrial homeostasis. AB - Cellular quality control provides an efficient surveillance system to regulate mitochondrial turnover. This study elucidates a new interaction between the cytosolic E3 ligase mahogunin RING finger 1 (MGRN1) and the endoplasmic reticulum (ER) ubiquitin E3 ligase GP78 (also known as AMFR). Loss of Mgrn1 function has been implicated in late-onset spongiform neurodegeneration and congenital heart defects, among several developmental defects. Here, we show that MGRN1 ubiquitylates GP78 in trans through non-canonical K11 linkages. This helps maintain constitutively low levels of GP78 in healthy cells, in turn downregulating mitophagy. GP78, however, does not regulate MGRN1. When mitochondria are stressed, cytosolic Ca(2+) increases. This leads to a reduced interaction between MGRN1 and GP78 and its compromised ubiquitylation. Chelating Ca(2+) restores association between the two ligases and the in trans ubiquitylation. Catalytic inactivation of MGRN1 results in elevated levels of GP78 and a consequential increase in the initiation of mitophagy. This is important because functional depletion of MGRN1 by the membrane-associated disease-causing prion protein (Ctm)PrP affects polyubiquitylation and degradation of GP78, also leading to an increase in mitophagy events. This suggests that MGRN1 participates in mitochondrial quality control and could contribute to neurodegeneration in a subset of (Ctm)PrP-mediated prion diseases. PMID- 26743087 TI - SMN affects membrane remodelling and anchoring of the protein synthesis machinery. AB - Disconnection between membrane signalling and actin networks can have catastrophic effects depending on cell size and polarity. The survival motor neuron (SMN) protein is ubiquitously involved in assembly of spliceosomal small nuclear ribonucleoprotein particles. Other SMN functions could, however, affect cellular activities driving asymmetrical cell surface expansions. Genes able to mitigate SMN deficiency operate within pathways in which SMN can act, such as mRNA translation, actin network and endocytosis. Here, we found that SMN accumulates at membrane protrusions during the dynamic rearrangement of the actin filaments. In addition to localization data, we show that SMN interacts with caveolin-1, which mediates anchoring of translation machinery components. Importantly, SMN deficiency depletes the plasma membrane of ribosomes, and this correlates with the failure of fibroblasts to extend membrane protrusions. These findings strongly support a relationship between SMN and membrane dynamics. We propose that SMN could assembly translational platforms associated with and governed by the plasma membrane. This activity could be crucial in cells that have an exacerbated interdependence of membrane remodelling and local protein synthesis. PMID- 26743089 TI - Etiology of Cellulitis and the Validity of New and Old Methods. PMID- 26743088 TI - Regulation of glucose metabolism by p62/SQSTM1 through HIF1alpha. AB - The signaling adaptor sequestosome 1 (SQSTM1)/p62 is frequently overexpressed in tumors and plays an important role in the regulation of tumorigenesis. Although great progress has been made, biological roles of p62 and relevant molecular mechanisms responsible for its pro-tumor activity remain largely unknown. Here, we show that p62 knockdown reduces cell growth and the expression of glycolytic genes in a manner that depends on HIF1alpha activity in renal cancer cells. Knockdown of p62 decreases HIF1alpha levels and transcriptional activity by regulating mTORC1 activity and NF-kappaB nuclear translocation. Furthermore, p62 interacts directly with the von Hippel-Lindau (VHL) E3 ligase complex to modulate the stability of HIF1alpha. Mechanistically, p62 binds to the VHL complex and competes with HIF1alpha. Expression of p62 inhibits the interaction of DCNL1 (also known as DCUN1D1) with CUL2 and attenuates the neddylation of CUL2, and thus downregulates the VHL E3 ligase complex activity. Functionally, HIF1alpha expression is required for p62-induced glucose uptake, lactate production and soft agar colony growth. Taken together, our findings demonstrate that p62 is a crucial positive regulator of HIF1alpha, which is a facilitating factor in p62 enhanced tumorigenesis. PMID- 26743091 TI - Addressing the Needs of Youth With HIV Infection in the Era of Combination Antiretroviral Therapy. PMID- 26743090 TI - Progressive Multifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of Function and Review of the Literature. AB - BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare, severe, otherwise fatal viral infection of the white matter of the brain caused by the polyomavirus JC virus, which typically occurs only in immunocompromised patients. One patient with dominant gain-of-function (GOF) mutation in signal transducer and activator of transcription 1 (STAT1) with chronic mucocutaneous candidiasis and PML was reported previously. We aim to identify the molecular defect in 3 patients with PML and to review the literature on PML in primary immune defects (PIDs). METHODS: STAT1 was sequenced in 3 patients with PML. U3C cell lines were transfected with STAT1 and assays to search for STAT1 phosphorylation, transcriptional response, and target gene expression were performed. RESULTS: We identified 3 new unrelated cases of PML in patients with GOF STAT1 mutations, including the novel STAT1 mutation, L400Q. These STAT1 mutations caused delayed STAT1 dephosphorylation and enhanced interferon-gamma-driven responses. In our review of the literature regarding PML in primary immune deficiencies we found 26 cases, only 54% of which were molecularly characterized, the remainder being syndromically diagnosed only. CONCLUSIONS: The occurrence of PML in 4 cases of STAT1 GOF suggests that STAT1 plays a critical role in the control of JC virus in the central nervous system. PMID- 26743092 TI - Editorial Commentary: Interferon-free Hepatitis C Treatment Efficacy From Clinical Trials Will Translate to "Real World" Outcomes. PMID- 26743094 TI - Scale-up of Routine Viral Load Testing in Resource-Poor Settings: Current and Future Implementation Challenges. AB - Despite immense progress in antiretroviral therapy (ART) scale-up, many people still lack access to basic standards of care, with our ability to meet the Joint United Nations Programme on HIV/AIDS 90-90-90 treatment targets for HIV/AIDS dependent on dramatic improvements in diagnostics. The World Health Organization recommends routine monitoring of ART effectiveness using viral load (VL) testing at 6 months and every 12 months, to monitor treatment adherence and minimize failure, and will publish its VL toolkit later this year. However, the cost and complexity of VL is preventing scale-up beyond developed countries and there is a lack of awareness among clinicians as to the long-term patient benefits and its role in prolonging the longevity of treatment programs. With developments in this diagnostic field rapidly evolving-including the recent improvements for accurately using dried blood spots and the imminent appearance to the market of point-of-care technologies offering decentralized diagnosis-we describe current barriers to VL testing in resource-limited settings. Effective scale-up can be achieved through health system and laboratory system strengthening and test price reductions, as well as tackling multiple programmatic and funding challenges. PMID- 26743095 TI - Reply to Bruun et al. PMID- 26743093 TI - How Generalizable Are the Results From Trials of Direct Antiviral Agents to People Coinfected With HIV/HCV in the Real World? AB - BACKGROUND: Direct-acting antivirals (DAAs) against hepatitis C virus (HCV) have been described as revolutionary. However, it remains uncertain how effective these drugs will be for individuals coinfected with human immunodeficiency virus (HIV)-HCV. Bridging this gap between efficacy and effectiveness requires a focus on the generalizability of clinical trials. METHODS: Generalizability of DAA trials was assessed by applying the eligibility criteria from 5 efficacy trials: NCT01479868, PHOTON-1 (NCT01667731), TURQUOISE-I (NCT01939197), ION-4 (NCT02073656), and ALLY-2 (NCT02032888) that evaluated simeprevir; sofosbuvir; ombitasvir, paritaprevir/ritonavir/dasabuvir; sofosbuvir/ledipasvir; and daclatasvir/sofosbuvir, respectively, to the Canadian Coinfection Cohort, representing approximately 23% of the total coinfected population in care in Canada. RESULTS: Of 874 active participants, 70% had chronic HCV, of whom 410, 26, 94, and 11 had genotypes 1, 2, 3, and 4, respectively. After applying trial eligibility criteria, only 5.9% (24/410) would have been eligible for enrollment in the simeprevir trial, 9.8% (52/530) in PHOTON-1, 6.3% (26/410) in TURQUOISE-I, and 8.1% (34/421) in ION-4. The ALLY-2 study was more inclusive; 43% (233/541) of the cohort would have been eligible. The most exclusive eligibility criteria across all trials with the exception of ALLY-2 were restriction to specific antiretroviral therapies (63%-79%) and active illicit drug use (53%-55%). CONCLUSIONS: DAA trial results may have limited generalizability, since the majority of coinfected individuals were not eligible to participate. Exclusions appeared to be related to improving treatment outcomes by not including those at higher risk of poor adherence and reinfection--individuals for whom real-world data are urgently needed. PMID- 26743096 TI - Vertebral Osteomyelitis Guidelines. PMID- 26743097 TI - Reply to Dr Fierer. PMID- 26743098 TI - Growth of the Journal from Age 8 to 23: An Exciting and Joyous Journey for a Proud Guardian. PMID- 26743099 TI - Intervention Research in Late-Life Depression: Challenges and Opportunities. PMID- 26743100 TI - Problem-Solving Therapy Reduces Suicidal Ideation In Depressed Older Adults with Executive Dysfunction. AB - OBJECTIVE: To test the hypothesis that Problem Solving Therapy (PST) is more effective than Supportive Therapy (ST) in reducing suicidal ideation in older adults with major depression and executive dysfunction. We further explored whether patient characteristics, such as age, sex, and additional cognitive impairment load (e.g., memory impairments) were related to changes in suicidal ideation over time. DESIGN: Secondary data analysis using data from a randomized clinical trial allocating participants to PST or ST at 1:1 ratio. Raters were blind to patients' assignments. SETTING: University medical centers. PARTICIPANTS: 221 people aged 65 years old and older with major depression determined by Structured Clinical Interview for DSM-III-R diagnosis and executive dysfunction as defined by a score of 33 or less on the Initiation-Perseveration Score of the Mattis Dementia Rating Scale or a Stroop Interference Task score of 25 or less. INTERVENTIONS: 12 weekly sessions of PST or ST. MAIN OUTCOME MEASURES: The suicide item of the Hamilton Depression Rating Scale. RESULTS: Of the 221 participants, 61% reported suicidal ideation (SI). The ST group had a lower rate of improvement in SI after 12 weeks (44.6%) than did the PST group (60.4%, Fisher's exact test p = 0.031). Logistic regression showed significantly greater reductions in SI in elders who received PST at both 12 weeks (OR: .50, Z = -2.16, p = 0.031) and 36 weeks (OR: 0.5, Z = -1.96, p = 0.05) after treatment. CONCLUSIONS: PST is a promising intervention for older adults who are at risk for suicide. ClinicalTrials.gov Identifier: NCT00052091. PMID- 26743101 TI - Comparative evaluation of magnetic resonance cholangiopancreatography/magnetic resonance splenoportovenography and endoscopic ultrasound in the diagnosis of portal cavernoma cholangiopathy. AB - BACKGROUND: Magnetic resonance cholangiopancreatography/magnetic resonance splenoportovenography (MRCP/MRSPV) is now the investigation of choice for the diagnosis of portal cavernoma cholangiopathy (PCC). Endoscopic ultrasound (EUS) is an emerging diagnostic modality for the diagnosis of PCC and may be better than MRCP/MRSPV to see the layer-wise localization of varices and to differentiate between varices, stone, and malignancy. METHODS: Retrospective data of 50 patients of extrahepatic portal vein obstruction (EHPVO) were collected, and comparison between MRCP/MRSPV and EUS was done for the diagnosis of PCC. RESULTS: Out of 50 patients, 56 % (28) were males, 44 % (22) females, and 24 % (12) symptomatic. Biliary changes were seen in 40 patients (80 %). Epicholedochal collateral (EPEC) was detected in 48 % and 20 % in MRCP/MRSPV and EUS, respectively. Perforators (PER) and intracholedochal collateral (ICC) were better seen with EUS (72 % and 48 %) as compared to MRCP/MRSPV (0 % and 8 %), and p values were significant (<0.05). EUS has a sensitivity of 33.33 % and a specificity of 92.31 % for EPEC. Portal cavernoma (PC) and collateral at porta (CP), paracholedochal collateral (PAC), perisplenic (PS) and peripancreatic collateral (PPC), pericholedochal collateral (PEC), intrahepatic biliary radical dilatation (IHBRD), perigallbladder collateral (PG), common bile duct dilatation (CBDD) and common hepatic duct dilatation (CHDD), common bile duct stricture (CBDS), and retropancreatic collateral (RPC) were comparable between the two modalities. CONCLUSIONS: EUS detected PER and ICC better than MRCP/MRSPV, while MRCP/MRSPV was more sensitive for detecting EPEC. PMID- 26743102 TI - The martyrdom of St. Zoilus, a urological issue. History and development of the tradition. AB - OBJECTIVES: To highlight, for its urological importance, the martyrdom of St. Zoilus. To elaborate on the tradition of invocation and worship of the saint and to establish their historical bases. MATERIAL AND METHODS: We conducted a study of the images of the martyrdom of St. Zoilus, with a detailed review of the history and tradition of the saint and performed a comparative study of the various saints known as patrons of kidney pain and disease. RESULT: We found three paintings in different churches and locations depicting the kidney extraction of St. Zoilus. In addition to the three pieces, a preserved chest at the National Archaeological Museum and 2 tapestries in the sacristy of the church of the monastery of St. Zoilus in the Palencian town of Carrion de los Condes provided abundant information on the circumstances in which they were made. By analysing the style, we can deduce its affiliation to a specific artistic milieu and thereby propose a timeframe. CONCLUSION: Without meaning to dethrone St. Liborius as the patron saint of urologists, an office claimed earlier by colleagues from various European countries, the martyrdom of St. Zoilus is, in light of the tradition and images provided, an unquestionable urological issue. The tradition is vindicated from a new viewpoint 1,712 years later. PMID- 26743103 TI - Phenotypic plasticity within yeast colonies: differential partitioning of cell fates. AB - Across many phyla, a common aspect of multicellularity is the organization of different cell types into spatial patterns. In the budding yeast Saccharomyces cerevisiae, after diploid colonies have completed growth, they differentiate to form alternating layers of sporulating cells and feeder cells. In the current study, we found that as yeast colonies developed, the feeder cell layer was initially separated from the sporulating cell layer. Furthermore, the spatial pattern of sporulation in colonies depended on the colony's nutrient environment; in two environments in which overall colony sporulation efficiency was very similar, the pattern of feeder and sporulating cells within the colony was very different. As noted previously, under moderately suboptimal conditions for sporulation-low acetate concentration or high temperature-the number of feeder cells increases as does the dependence of sporulation on the feeder-cell transcription factor, Rlm1. Here we report that even under a condition that is completely blocked sporulation, the number of feeder cells still increased. These results suggest broader implications to our recently proposed "Differential Partitioning provides Environmental Buffering" or DPEB hypothesis. PMID- 26743104 TI - Acute lymphoblastic leukemia and lymphoma in the context of constitutional mismatch repair deficiency syndrome. AB - Constitutional mismatch repair deficiency (CMMRD) syndrome is one of the rare diseases associated with a high risk of cancer. Causative mutations are found in DNA mismatch repair genes PMS2, MSH6, MSH2 or MLH1 that are well known in the context of Lynch syndrome. CMMRD follows an autosomal recessive inheritance trait and is characterized by childhood brain tumors and hematological malignancies as well as gastrointestinal cancer in the second and third decades of life. There is a high risk of multiple cancers, occurring synchronously and metachronously. In general, the prognosis is poor. About one third of CMMRD patients develop hematological malignancies as primary (sometimes the only) malignancy or as secondary neoplasm. T-cell non-Hodgkin lymphomas, mainly of mediastinal origin, are the most frequent hematological malignancies. Besides malignant diseases, non neoplastic features are frequently observed, e.g. cafe-au-lait spots sometimes resembling neurofibromatosis type I, hypopigmented skin lesions, numerous adenomatous polyps, multiple pilomatricomas, or impaired immunoglobulin class switch recombination. Within the present review, we summarize previously published CMMRD patients with at least one hematological malignancy, provide an overview of steps necessary to substantiate the diagnosis of CMMRD, and refer to the recent most relevant literature. PMID- 26743105 TI - Subcutaneous dissection area contributes less to endoscopic thyroidectomy-related invasiveness. AB - OBJECTIVE: To clarify the contribution of the subcutaneous area during breast approach endoscopic thyroidectomy (BAET), with regard to invasiveness-related outcomes. METHODS: Seventy-two patients were randomly assigned to two groups: standard dissection and limited dissection. Postoperative pain and inflammatory response were compared between groups. RESULTS: The groups were well matched except for subcutaneous dissection area (137.11 +/- 21.10 vs. 83.69 +/- 12.10 cm(2), p < 0.0001). No significant difference was found with regard to VAS score and postoperative inflammatory response. CONCLUSION: Our RCT indicated that the subcutaneous area plays a less important role with regard to BAET-related postoperative pain. PMID- 26743107 TI - A single-center experience with the laparoscopic Warshaw technique in 122 consecutive patients. AB - BACKGROUND: Preservation of the spleen in distal pancreatectomy has recently attracted considerable attention. Our current study aimed in the first instance to define the safety of lap-WT in relation to the capacity of this technique to achieve preservation of the spleen and secondly to investigate the effectiveness of a planned lap-WT procedure or early conversion to lap-WT in selected patients with a large tumor attached to the splenic vessels. METHODS: Among 1056 patients who underwent a laparoscopic distal pancreatectomy between January 2005 and December 2014 at our hospital, 122 (24.6 %) underwent lap-WT which were analyzed. The 122 patients were categorized into two groups chronologically (early group: 2005-2012, late group: 2013-2014). RESULTS: The median follow-up was 35 months, and the median operation time was 181 min. The median postoperative hospital stay was 7 days, and the median estimated blood loss was 316 ml. Postoperative complications occurred in 9 patients (7.3 %), including 4 patients (3.2 %) with major pancreatic fistula (ISGPF grade B, C). A reoperation to address postoperative bleeding was needed in one patient. During a median follow-up of 35 months, there were no clinical significant splenic infarctions or gastric varices in any case. All patients were observed conservatively. In patients in the late group who underwent the lap-WT, the mean operating time (171 vs. 205 min, p = 0.001) and mean estimated blood loss (232.1 vs. 370.0 ml, p = 0.017) were significantly less than the early group cases who received lap-WT. CONCLUSIONS: A lap-WT is a safe treatment strategy in select cases when used as a way of preserving the spleen. When splenic vessel preservation is technically challenging, for example when the tumor is enlarged or is attached to the splenic vessels, planned lap-WT or early conversion to lap-WT may be a feasible option. PMID- 26743106 TI - Endosonographer's macroscopic evaluation of EUS-FNAB specimens after interactive cytopathologic training: a single-center prospective validation cohort study. AB - BACKGROUND: In many centers, rapid on-site evaluation (ROSE) for the specimens obtained from endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS FNAB) is not available. The aim of this study was to compare the diagnostic yields of EUS-FNAB in the presence or absence of ROSE. METHODS: Seventy-five patients who underwent EUS-FNAB for the pancreatic, gastric subepithelial, and mesenteric mass lesions at our institution from November 2013 to August 2014 were included. For 20 patients in the pilot cohort, EUS-FNAB was performed with ROSE, and simultaneously, training of the staff endosonographer for tissue adequacy by an on-site cytopathologist was also performed. RESULTS: The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of EUS-FNAB in the pilot cohort were 91.7, 100.0, 100.0, 88.9, and 95.0 %, respectively. The 3.2 +/- 0.8 [mean +/- standard deviation (SD)] needle passes were needed in this cohort. Fifty-five patients were enrolled as a validation cohort from April 2014 to August 2014, and tissue adequacies were assessed by an experienced endosonographer without ROSE in this cohort. The sensitivity, specificity, PPV, NPV, and accuracy of EUS-FNAB in this validation cohort were 92.1, 100.0, 100.0, 85.0, and 94.6 %, respectively. The 4.5 +/- 0.6 (mean +/- SD) needle passes were needed in this cohort (p < 0.01 compared to pilot cohort). CONCLUSIONS: Diagnostic accuracy of EUS-FNAB in which the adequacy of sample was assessed by an attending endosonographer was acceptable. This study suggests that on-site evaluation by a trained endosonographer may be an alternative tool to ROSE where ROSE is not available. PMID- 26743109 TI - Re-sleeve gastrectomy as revisional bariatric procedure after biliopancreatic diversion with duodenal switch. AB - BACKGROUND: Re-sleeve gastrectomy (re-SG) is a possible option to increase weight loss after biliopancreatic diversion with duodenal switch (BPD-DS). We report the feasibility, efficacy and safety of re-SG in patients presenting with long-term weight regain after BPD-DS. METHODS: From October 2010 to December 2013, a total of 17 patients (12 female, 5 male) with a mean age of 42.1 +/- 19.4 years underwent re-SG, mainly because of weight regain after BPD-DS. Re-SG was performed laparoscopically over a 32 French stomach tube. RESULTS: At the time of BPD-DS, the mean weight and BMI of all patients were 130.1 +/- 17.9 kg and 46.1 +/- 6.5 kg/m(2), respectively. The mean time interval between BPD-DS and re-SG was 63.1 +/- 20.3 months. At the time of re-SG, the mean weight and BMI were 115.4 +/- 14.2 kg and 39.8 +/- 5.3 kg/m(2), and the %EWL after BPD-DS was 22.9 +/ 17.4 %. Three conversions (17.6 %) to open surgery were required. No mortality occurred. One patient (5.9 %) developed a leak within the first week after re-SG that was treated conservatively with an endoluminal stent. The mean follow-up was 37.2 +/- 7.1 months after re-SG. One- and three-year follow-up showed a mean weight, BMI, and cumulative %EWL of 96.0 +/- 17.1 kg, 33.8 +/- 7.3 kg/m(2), and 53.1 +/- 18.3 % (17/17 patients; 100 %), and 100.3 +/- 21.1 kg, 35.1 +/- 8.3 kg/m(2), and 47.2 +/- 19.7 % (13/17 patients; 76 %) after re-SG, respectively. CONCLUSIONS: This study shows that re-SG in patients with weight regain after BPD DS is a feasible, effective and safe option as a revisional bariatric procedure. However, patients have to be carefully considered for revisional surgery since re SG is associated with the potential risk of surgical complications. PMID- 26743108 TI - The relationship between intracranial pressure and obesity: an ultrasonographic evaluation of the optic nerve. AB - BACKGROUND: Measurements of optic nerve sheath diameter (ONSD) with noninvasive ocular ultrasonography have been shown to be accurate in determining increased intracranial pressure. Obesity is associated with chronic increases in intraabdominal pressure that could consequently result in intracranial hypertension. By utilizing ONSD ultrasonographic measurements, we compare the difference that may exist between obese and non-obese patients. STUDY DESIGN: We prospectively collected data from patients who underwent laparoscopic procedures in the supine position between July 2013 and March 2014. Ophthalmic pathology was not present in any patient. Ultrasonographic measurement of the ONSD was obtained sagittally with a 12-MHz transducer 3 mm from its origin. The measurements were taken at 0, 15, and 30 min, and at the end of surgery. RESULTS: There were 62 subjects, 28 females (45.2 %) and 34 males (54.8 %), with a mean age of 44.22 +/- 10.44 years (range 23-66). Forty-eight percent of patients were non-obese, and 52 % of patients were obese. The mean body mass index was 30.70 +/- 7.61 kg/m(2) (range 20.0-59.5). The mean ONSD of non-obese and obese patients was 4.7 and 5.5 mm at baseline (p = 0.01), 5.4 and 6.2 mm at 15 min (p = 0.01), 5.8 and 6.6 mm at 30 min (p = 0.01), and 5.1 and 5.7 mm after deflation of pneumoperitoneum (p = 0.03), respectively. CONCLUSIONS: Utilizing a noninvasive method to measure the ONSD, a chronic increase in intracranial pressure in obese patients was demonstrated. The increase in the ONSD during laparoscopic procedures reflects a temporary increase in the intracranial pressure from baseline. PMID- 26743110 TI - Systematic review and meta-analysis of robotic versus laparoscopic distal pancreatectomy for benign and malignant pancreatic lesions. AB - BACKGROUND AND OBJECTIVE: The number of published series on minimally invasive distal pancreatectomy has significantly increased. Robotic systems can overcome some limitations of laparoscopy. This study aimed to compare two techniques in distal pancreatectomy. METHODS: Multiple electronic databases were systematically searched to identify studies (up to July 2015) that compared perioperative outcomes between robotic distal pancreatectomy (RDP) and laparoscopic distal pancreatectomy (LDP). Relative risks with 95 % confidence intervals (CIs) were estimated. RESULTS: Nine studies were enrolled in this review. Four studies reported on operative time, indicating no difference between the RDP and LDP groups (WMD = 21.55, 95 % CI -65.28-108.37, P = 0.63). No significant difference between the two groups was indicated with respect to the number of patients who converted to open (OR 0.35, 95 % CI 0.11-1.13, P = 0.08), spleen preservation rate (OR 2.37, 95 % CI 0.50-11.30, P = 0.28), and transfusion rate (OR 1.30, 95 % CI 0.54-3.13, P = 0.56). In addition, no difference was indicated in the incidence of pancreatic fistulas (OR 1.05, 95 % CI 0.67-1.65, P = 0.83) and length of hospital stay between the two groups (WMD = -0.61, 95 % CI -1.40-0.19, P = 0.13). CONCLUSIONS: RDP seems to be a safe and effective alternative to LDP. Large randomized controlled trials are needed to verify the results of this meta analysis. PMID- 26743111 TI - Factors influencing difficulty of the thoracic procedure in minimally invasive esophagectomy. AB - BACKGROUND: Minimally invasive esophagectomy (MIE) is being increasingly performed worldwide. When performing MIE, we sometimes experienced difficulties due to a narrow upper mediastinum or a middle to lower thoracic esophagus hidden by the projection of the vertebral body. However, there were no reports regarding the influence of anatomical factors on the difficulty of performing MIE. The aim of this study was to evaluate whether anatomical factors could be related to the difficulty of the thoracic procedure in MIE. METHODS: We investigated 87 consecutive patients undergoing MIE for primary esophageal cancer between 2013 and 2015 and created novel indices to assess the upper mediastinal narrowness and vertebral body projection at middle thoracic part on preoperative computed tomography images. We assessed clinicopathological and anatomical factors and determined the factors influencing the thoracic procedural difficulty in MIE. The thoracic procedure duration was selected as the variable representing technical difficulty. RESULTS: The mean thoracic procedure duration was 280.2 +/- 52.5 min. There were no significant correlations between the indices and patient factors such as age, sex, and body mass index. Meanwhile, there was a significant correlation between the upper mediastinal narrowness and the vertebral body projection (p < 0.01). Of the clinicopathological and anatomical factors, blood loss during the thoracic procedure, thoracic duct resection, and vertebral body projection independently were related to the prolonged thoracic procedure duration in multiple linear regression analysis (p = 0.01, 0.03, and <0.01, respectively). The other factors including upper mediastinal narrowness were not statistically significant. CONCLUSIONS: This is the first study to reveal the influence of anatomical factors on the difficulty of the thoracic procedure in MIE. The vertebral body projection at middle thoracic part appears to be a useful tool for predicting the thoracic procedural difficulty in MIE preoperatively. PMID- 26743113 TI - Local envenomation from the bite of a juvenile false water cobra (Hydrodynastes gigas; Dipsadidae). AB - The false water cobra (Hydrodynastes gigas) is a non-front-fanged colubroid snake frequently exhibited in zoos, and maintained by amateur collectors. Little detailed documentation regarding the time-course of symptoms development and the consequences of their bites to humans has been published. Reported here is a case of envenoming in a 25 yo male that occurred after the bite of a juvenile H. gigas. The victim was bitten on the fourth digit of the left hand while processing the snake for sex determination, and the snake remained attached to the digit for approximately 30 s; there was no jaw advancement. Within 5 min, intense local pain developed, and at 4hr post bite the entire dorsal aspect of the hand was significantly edematous, The local effects progressed and involved the entire forearm, and the local pain referred to the axillary region. Mild paresthesia and local blanching ("pallor") were noted in the affected digit, but resolved within 7 days. The clinical course in the patient showed that moderate localized symptoms may result from the bite of a juvenile H.gigas. PMID- 26743112 TI - Multitask training promotes automaticity of a fundamental laparoscopic skill without compromising the rate of skill learning. AB - BACKGROUND: A defining characteristic of expertise is automated performance of skills, which frees attentional capacity to better cope with some common intraoperative stressors. There is a paucity of research on how best to foster automated performance by surgical trainees. This study examined the use of a multitask training approach to promote automated, robust laparoscopic skills. METHODS: Eighty-one medical students completed training of a fundamental laparoscopic task in either a traditional single-task training condition or a novel multitask training condition. Following training, participants' laparoscopic performance was tested in a retention test, two stress transfer tests (distraction and time pressure) and a secondary task test, which was included to evaluate automaticity of performance. The laparoscopic task was also performed as part of a formal clinical examination (OSCE). RESULTS: The training groups did not differ in the number of trials required to reach task proficiency (p = .72), retention of skill (ps > .45), or performance in the clinical examination (p = .14); however, the groups did differ with respect to the secondary task (p = .016). The movement efficiency (number of hand movements) of single-task trainees, but not multitask trainees, was negatively affected during the secondary task test. The two stress transfer tests had no discernable impact on the performance of either training group. CONCLUSION: Multitask training was not detrimental to the rate of learning of a fundamental laparoscopic skill and added value by providing resilience in the face of a secondary task load, indicative of skill automaticity. Further work is needed to determine the extent of the clinical utility afforded by multitask training. PMID- 26743114 TI - Interactions between the intestinal cestode Polyonchobothrium clarias (Pseudophyllidea: Ptychobothriidae) from the African sharptooth catfish Clarias gariepinus and heavy metal pollutants in an aquatic environment in Egypt. AB - In an aquatic environment, there is a profound and inverse relationship between environmental quality and disease status of fish. Parasites are one of the most serious limiting factors in aquaculture. Therefore, the present investigation was carried out during the period of February-December 2014 to determine the parasitic infections in the African sharptooth catfish Clarias gariepinus, relative to the capability of internal parasites to accumulate heavy metals. Up to 100 catfish were examined for gastrointestinal helminths and 38% of fish were found to be infected with the cestode Polyonchobothrium clarias. The morphology of this parasite species, based on light and scanning electron microscopy, revealed that the adult worm was characterized by a rectangular scolex measuring 0.43-0.58 (0.49 +/- 0.1) mm long and 0.15-0.21 (0.19 +/- 0.1) mm wide, with a flat to slightly raised rostellum armed with a crown with two semicircles each bearing 13-15 hooks, followed by immature, mature and gravid proglottids which were about 29-55 (45), 16-30 (24) and 15-39 (28) in number, respectively. The mature proglottid contained a single set of genitalia in which medullary testes measured 0.09-0.13 (0.11 +/- 0.01) mm long and 0.05-0.08 (0.06 +/- 0.01) mm wide; a bi-lobed ovary was situated near the posterior margin of the proglottid, extending laterally up to the longitudinal excretory canals; the tubular uterus arose from the ootype up to the anterior margin of the proglottid; and vitelline follicles were cortical. The greater portion of the gravid proglottid was occupied by a uterus filled with unoperculate and embryonated eggs. Chemical analysis confirmed that the concentrations of heavy metals (Zn, Cu, Mn, Cd, Ni and Pb) accumulated in P. clarias were higher than in fish tissues and values recommended by FAO/WHO, with the exception of Zn, which was found to be higher in fish kidneys than in the cestode. This supports the hypothesis that cestodes of fish can be regarded as useful bioindicators when evaluating the environmental pollution of aquatic ecosystems by heavy metals. PMID- 26743115 TI - Low viral predation pressure in cold hypersaline Arctic sediments and limits on lytic replication. AB - Viruses are ubiquitous drivers of microbial ecology and evolution and contribute to biogeochemical cycling. Attention to these attributes has been more substantial for marine viruses than viruses of other environments. Microscopy based investigation of the viral communities from two cold, hypersaline Arctic springs was undertaken to explore the effects of these conditions on microbe viral ecology. Sediments and water samples were collected along transects from each spring, from anoxic spring outlets through oxygenated downstream channels. Viral abundance, virus-microbe ratios and modelled virus-microbe contact rates were lower than comparable aqueous and sedimentary environments and most similar to deep subsurface sediments. No individual cell from either spring was visibly infected. Viruses in these springs appear to play a smaller role in controlling microbial populations through lytic activity than in marine water column or surface sedimentary environments. Relief from viral predation indicates the microbial communities are primarily controlled by nutrient limitation. The similarity of these springs to deep subsurface sediments suggests a biogeographic divide in viral replication strategy in marine sediments. PMID- 26743116 TI - Lower-extremity amputation as a marker for renal and cardiovascular events and mortality in patients with long standing type 1 diabetes. AB - BACKGROUND: We evaluated the risks of renal and cardiovascular complications, and mortality associated with lower extremity amputation (LEA) in patients with type 1 diabetes. METHODS: We studied two cohorts of people with long standing type 1 diabetes: GENEDIAB (n = 456) and GENESIS (n = 611). Subsets of the cohorts (n = 260, n = 544) were followed for 9 and 5 years, respectively. Outcomes were the incidence of end stage renal disease (ESRD), myocardial infarction, stroke and mortality during follow-up. Analyses were performed in pooled cohorts. RESULTS: The prevalence of LEA at baseline was 9.3 % (n = 99). A positive history of LEA was associated with the baseline prevalence of established (OR 4.50, 95 % CI 2.33 8.91, p < 0.0001) and advanced diabetic nephropathy (OR 5.50, 95 % CI 2.89-10.78, p < 0.0001), ESRD (OR 2.86, 95 % CI 1.43-5.50, p = 0.004), myocardial infarction (OR 3.25, 95 % CI 1.68-6.15, p = 0.0006) and stroke (OR 3.88, 95 % CI 1.67-8.72, p = 0.002, adjusted for sex, age, and cohort membership). A positive history of LEA at baseline was associated with the incidence during follow-up of ESRD (HR 2.69, 95 % CI 1.17-6.20, p = 0.02), and myocardial infarction (HR 3.53, 95 % CI 1.79-6.97, p = 0.0001). History of LEA was also associated with increased risk for all-cause (HR 3.55, 95 % CI 2.05-6.16, p < 0.0001), cardiovascular (HR 3.30, 95 % CI 1.36-8.02, p = 0.008), infectious disease (HR 5.18, 95 % CI 1.13-23.84, p = 0.03) and other-cause mortality (HR 2.81, 95 % CI 1.09-7.26, p = 0.03). History of LEA at baseline was associated with a 40 % reduction in the duration of survival in the subset of patients who died during follow-up. Population attributable risk of the history of LEA at baseline for total mortality during follow-up was 0.31. CONCLUSIONS: Patients with LEA have a higher risk of ESRD, myocardial infarction and cardiovascular and non-cardiovascular mortality. Our results highlight the importance of LEA as a key-predictor for major vascular events and premature death in type 1 diabetic patients. PMID- 26743117 TI - Ultra-deep sequencing of VHSV isolates contributes to understanding the role of viral quasispecies. AB - The high mutation rate of RNA viruses enables the generation of a genetically diverse viral population, termed a quasispecies, within a single infected host. This high in-host genetic diversity enables an RNA virus to adapt to a diverse array of selective pressures such as host immune response and switching between host species. The negative-sense, single-stranded RNA virus, viral haemorrhagic septicaemia virus (VHSV), was originally considered an epidemic virus of cultured rainbow trout in Europe, but was later proved to be endemic among a range of marine fish species in the Northern hemisphere. To better understand the nature of a virus quasispecies related to the evolutionary potential of VHSV, a deep sequencing protocol specific to VHSV was established and applied to 4 VHSV isolates, 2 originating from rainbow trout and 2 from Atlantic herring. Each isolate was subjected to Illumina paired end shotgun sequencing after PCR amplification and the 11.1 kb genome was successfully sequenced with an average coverage of 0.5-1.9 * 10(6) sequenced copies. Differences in single nucleotide polymorphism (SNP) frequency were detected both within and between isolates, possibly related to their stage of adaptation to host species and host immune reactions. The N, M, P and Nv genes appeared nearly fixed, while genetic variation in the G and L genes demonstrated presence of diverse genetic populations particularly in two isolates. The results demonstrate that deep sequencing and analysis methodologies can be useful for future in vivo host adaption studies of VHSV. PMID- 26743118 TI - Bilingualism alters children's frontal lobe functioning for attentional control. AB - Bilingualism is a typical linguistic experience, yet relatively little is known about its impact on children's cognitive and brain development. Theories of bilingualism suggest that early dual-language acquisition can improve children's cognitive abilities, specifically those relying on frontal lobe functioning. While behavioral findings present much conflicting evidence, little is known about its effects on children's frontal lobe development. Using functional near infrared spectroscopy (fNIRS), the findings suggest that Spanish-English bilingual children (n = 13, ages 7-13) had greater activation in left prefrontal cortex during a non-verbal attentional control task relative to age-matched English monolinguals. In contrast, monolinguals (n = 14) showed greater right prefrontal activation than bilinguals. The present findings suggest that early bilingualism yields significant changes to the functional organization of children's prefrontal cortex for attentional control and carry implications for understanding how early life experiences impact cognition and brain development. PMID- 26743121 TI - Coping Strategies of Jordanian Adolescents With Cancer: An Interpretive Phenomenological Analysis Study. AB - Interpretive phenomenological analysis methodology was used to explore coping strategies used by hospitalized Jordanian adolescents with cancer. In-depth face to-face interviews were conducted with 10 Jordanian adolescents, aged 13 to18 years, who were receiving chemotherapy for cancer. During treatment, participants were confronted with physical, psychosocial, and emotional distresses resulting from the disease process, the treatment, and its associated side-effects. To cope with the impact of their illness, participants utilized 4 coping strategies: "Strengthening spiritual convictions," "Being optimistic and rebuilding hope," "Enhancing appearance," and "Finding self again." The findings of this study can assist health team members to promote positive psychological care to Arab Muslim adolescents with cancer in a supportive and therapeutic treatment environment. PMID- 26743119 TI - Effectiveness of Motivational Interviewing in Decreasing Hospital Readmission in Adults With Heart Failure and Multimorbidity. AB - Hospitalizations are common in heart failure (HF). Multimorbidity, defined as >=2 comorbid conditions, drives many readmissions. The purpose of this pilot study was to test the effectiveness of motivational interviewing (MI) in decreasing these hospital readmissions. We enrolled 100 hospitalized HF patients into a randomized controlled trial, randomizing in a 2:1 ratio: intervention (n = 70) and control (n = 30). The intervention group received MI tailored to reports of self-care during one home visit and three to four follow-up phone calls. After 3 months, 34 participants had at least one hospital readmission. The proportion of patients readmitted for a condition unrelated to HF was lower in the intervention (7.1%) compared with the control group (30%, p = .003). Significant predictors of a non-HF readmission were intervention group, age, diabetes, and hemoglobin. Together, these variables explained 35% of the variance in multimorbidity readmissions. These preliminary results are promising in suggesting that MI may be an effective method of decreasing multimorbidity hospital readmissions in HF patients. PMID- 26743122 TI - HYbriD Resonant Acoustics (HYDRA). AB - The existence of what is termed here as a surface-reflected bulk wave is unraveled and elucidated, and it is shown, quite counterintuitively, that it is possible to obtain an order-of-magnitude improvement in microfluidic manipulation efficiency, and, in particular, nebulization, through a unique combination of surface and bulk waves without increasing complexity or cost. PMID- 26743123 TI - miR-193a-3p regulation of chemoradiation resistance in oesophageal cancer cells via the PSEN1 gene. AB - Chemoradiation therapy is an important component of the curative treatment for oesophageal carcinomas. These therapeutic effects are prevented in patients according to radioresistance and multi-drug resistance, and the cause of such resistance remains unclear. In this study, we identified the role of miR-193a-3p in modulating the radioresistance and chemoresistance of oesophageal cancer cells. We found that KYSE150 and KYSE410 cells could be characterized as relatively radiation-sensitive and radiation-resistant cells, respectively. Similarly, KYSE150 and KYSE410 cells were found to be chemosensitive and chemoresistant, respectively. Over-expression of miR-193a-3p increased the radioresistance and chemoresistance of oesophageal squamous cell carcinoma (ESCC) cells. In contrast, the down-regulation of miR-193a-3p decreased the radioresistance and chemoresistance of ESCC cells. In addition, miR-193a-3p inducing DNA damage has also been demonstrated through measuring the level of gamma-H2AX associated with miR-193a-3p. Moreover, a small interfering RNA(siRNA) induced repression of the PSEN1 gene had an effect similar to that of miR-193a-3p up-regulation. The above processes also inhibited oesophageal cancer cells apoptosis. These findings suggest that miR-193a-3p contributes to the radiation and chemotherapy resistance of oesophageal carcinoma by down-regulating PSEN1. Thus, miR-193a-3p and PSEN1 might be potential biomarkers for chemoradiation resistant cancers. PMID- 26743120 TI - Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study. AB - In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki 67 <= 10%) non-functioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n = 101) or placebo (n = 103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n = 41; placebo, n = 47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection bias by assuming that patients with SD on lanreotide in the core study and not entering the OLE (n=13) had PD 24 weeks after last core assessment, found median PFS remaining consistent: 30.8 months (95% CI: 30.0, 31.3). Median time to further PD after placebo-to-lanreotide switch (n=32) was 14.0 months (10.1; not reached). This OLE study suggests long-term treatment with lanreotide Autogel 120 mg maintained favourable safety/tolerability. CLARINET OLE data also provide new evidence of lanreotide anti-tumour benefits in indolent and progressive pancreatic/intestinal NETs. PMID- 26743124 TI - Molecular characterization and expression patterns of emerin (EMD) gene in skeletal muscle between Meishan and Large White pigs. AB - The emerin protein is a nuclear membrane protein and has important functions in muscle development, regeneration, and cell signal transduction. However, knowledge regarding emerin in the domestic animal is limited. In this study, we cloned and characterized the pig emerin (EMD) gene. Semi-quantitative RT-PCR analysis revealed that the EMD gene was expressed at the highest level in the heart and fat at 120d. However, the fetal skeletal muscles displayed a greater abundance of EMD mRNA than that in skeletal muscles at postnatal development stages. In addition, the expression level of EMD at 60 day was significantly higher (p<0.05) in Meishan than Large White pigs. Pig EMD protein displayed the sarcolemma and perinuclear distribution in skeletal muscle sections, and there was no distribution change of EMD in skeletal muscle sections between Large White and Meishan pigs. These studies provide useful information for further research on the functions of pig EMD gene in skeletal muscle. PMID- 26743125 TI - Genome-wide identification, characterization of sugar transporter genes in the silkworm Bombyx mori and role in Bombyx mori nucleopolyhedrovirus (BmNPV) infection. AB - Sugar transporters play an essential role in controlling carbohydrate transport and are responsible for mediating the movement of sugars into cells. These genes exist as large multigene families within the insect genome. In insects, sugar transporters not only have a role in sugar transport, but may also act as receptors for virus entry. Genome-wide annotation of silkworm Bombyx mori (B. mori) revealed 100 putative sugar transporter (BmST) genes exists as a large multigene family and were classified into 11 sub families, through phylogenetic analysis. Chromosomes 27, 26 and 20 were found to possess the highest number of BmST paralogous genes, harboring 22, 7 and 6 genes, respectively. These genes occurred in clusters exhibiting the phenomenon of tandem gene duplication. The ovary, silk gland, hemocytes, midgut and malphigian tubules were the different tissues/cells enriched with BmST gene expression. The BmST gene BGIBMGA001498 had maximum EST transcripts of 134 and expressed exclusively in the malphigian tubule. The expression of EST transcripts of the BmST clustered genes on chromosome 27 was distributed in various tissues like testis, ovary, silk gland, malphigian tubule, maxillary galea, prothoracic gland, epidermis, fat body and midgut. Three sugar transporter genes (BmST) were constitutively expressed in the susceptible race and were down regulated upon BmNPV infection at 12h post infection (hpi). The expression pattern of these three genes was validated through real-time PCR in the midgut tissues at different time intervals from 0 to 30hpi. In the susceptible B. mori race, expression of sugar transporter genes was constitutively expressed making the host succumb to viral infection. PMID- 26743126 TI - tRFs: miRNAs in disguise. AB - tRFs and tiRNAs are two new classes of regulatory non-coding small RNAs that are derived from the cleavage of pre-existing tRNAs. tRFs are 18-22 nt long and are classified into the tRF-5, tRF-3, and tRF-1 series. Here, we discuss in detail the regulatory roles of tRFs in translation, viral infections, and carcinogenesis. Moreover, we have reviewed the association of tRFs with Argonaute proteins, including their potential to function as miRNAs. Interestingly, few miRNAs are generated from pre-existing tRNAs. Hence, tRNAs generate similar-sized tRFs and miRNAs, leading to misannotations due to cross mapping of tRFs and tRNA derived miRNAs during deep sequencing data analysis. Therefore, it is important to catalogue the overlapping sequences between tRNA-derived miRNAs and tRFs. We have catalogued the miRNAs that overlap with tRFs sequences in humans using miRBase. We identified 20 tRNA-derived miRNAs that share sequences with tRFs. Of the 20 miRNAs, 5 miRNAs (miR-3182, miR-4521, miR-1260a, miR-1260b, and miR-7977) showed significant prediction scores. Furthermore, we have identified a lysine degradation pathway as a common regulatory pathway for miR-1260a, miR-1260b, and miR-3182 by using DIANA-mirPath. PMID- 26743127 TI - A FASTQ compressor based on integer-mapped k-mer indexing for biologist. AB - Next generation sequencing (NGS) technologies have gained considerable popularity among biologists. For example, RNA-seq, which provides both genomic and functional information, has been widely used by recent functional and evolutionary studies, especially in non-model organisms. However, storing and transmitting these large data sets (primarily in FASTQ format) have become genuine challenges, especially for biologists with little informatics experience. Data compression is thus a necessity. KIC, a FASTQ compressor based on a new integer-mapped k-mer indexing method, was developed (available at http://www.ysunlab.org/kic.jsp). It offers high compression ratio on sequence data, outstanding user-friendliness with graphic user interfaces, and proven reliability. Evaluated on multiple large RNA-seq data sets from both human and plants, it was found that the compression ratio of KIC had exceeded all major generic compressors, and was comparable to those of the latest dedicated compressors. KIC enables researchers with minimal informatics training to take advantage of the latest sequence compression technologies, easily manage large FASTQ data sets, and reduce storage and transmission cost. PMID- 26743128 TI - Genetic variation in Whitmania pigra, Hirudo nipponica and Poecilobdella manillensis, three endemic and endangered species in China using SSR and TRAP markers. AB - Leeches are not only important medicinal animals worldwide but also are endangered. We aimed to (i) explore the level of genetic diversity within/among populations of three leeches, (ii) assess genetic differentiation among these three leeches, and (iii) discuss an appropriate strategy for conserving leech germplasm. A total of 315 individuals of Whitmania pigra, Hirudo nipponica and Poecilobdella manillensis from 21 populations were collected in China and Vietnam. The genetic structure and genetic diversity among and within the 21 populations were evaluated using target region amplified polymorphism (TRAP) and simple sequence repeat (SSR) markers. Sixteen pairs of TRAP primers generated a total of 398 fragments, of which 396 (99.50%) were polymorphic; fourteen pairs of SSR primers generated a total of 60 fragments, of which 59 (98.33%) were polymorphic. Shannon's index (I) and Nei's gene diversity index (H) for the three leeches were high at the species level (I=0.4980 and H=0.3323 for TRAPs, I=0.4487 and H=0.2969 for SSRs in W. pigra; I=0.4147/0.3769, H=0.2788/0.2566 for H. nipponica; and I=0.4616/0.4717, H=0.3099/0.3203 for P. manillensis). However, low genetic diversity was determined at the population level; the average genetic diversity measures within populations were H=0.1767/0.1376, I=0.2589/0.2043 for W. pigra, H=0.2149/0.2021, I=0.3184/0.3000 for H. nipponica and H=0.2850/0.2724, I=0.4152/0.3967 for P. manillensis. We conclude that there was limited gene exchange within/among populations and species, as the gene flow number (Nm) was 0.5493/0.5807. However, for all three species, the genetic diversity was different at the population level. Gene differentiation (Gst) and Nm were 0.4682 /0.5364 and 0.5678/0.4321 for W. pigra, 0.2294/0.2127 and 1.6797/1.8512 for H. nipponica and 0.1214/0.1496 and 3.6202/2.8412 for P. manillensis. STRUCTURE analysis, Unweighted Pair-Group Method with Arithmetic means (UPGMA) cluster analysis and Principal Coordinates Analysis (PCOA) all yielded similar results. The isolation-by-distance pattern was not significant for any of the three species by the Mantel test. These data emphasize the need for management, conservation, and rehabilitation of this animal species. Finally, an appropriate strategy for conserving leech is proposed. PMID- 26743129 TI - A novel homolog of protein tyrosine kinase Fyn identified in Lampetra japonica with roles in the immune response. AB - The non-receptor protein tyrosine kinase (nrPTK) Fyn, a member of the avian sarcoma virus transforming gene (Src) kinase family, plays a very significant role in cell growth, survival, apoptosis, tumor formation and immune response. In this study, a homolog of nrPTK Fyn was identified for the first time in the lamprey, Lampetra japonica and was named "Lja-Fyn". The cDNA fragment of lamprey lja-fyn contains a 1611-bp open reading frame, which encodes a protein of 537 amino acids. Multiple sequence alignment analysis showed that it shares four conserved domains (Src homology (SH) 4, SH3, SH2 and protein kinases catalytic domains) and a variable unique domain with vertebrates Fyn molecules. Though Lja Fyn has high sequence similarity with typical Fyn and Yes molecules of jawed vertebrates, the identities among Lja-Fyn and typical Fyn molecules in unique domain are relatively higher than that among Lja-Fyn and typical Yes molecules. The result indicates that Lja-Fyn is a homolog of Fyn rather than Yes. The phylogenetic analysis showed that Fyn, Yes and Src molecules are grouped into three distinct phylogenetic clusters, and Lja-Fyn is grouped as a single branch in Fyn cluster. The real-time quantitative PCR assay revealed the wide distribution of the lja-fyn mRNA in lamprey immune related tissues. After stimulation with mixed antigens, the levels of lja-fyn mRNA were obviously up regulated in the gill and lymphocyte-like cells, and the similar results were got by western blot analysis of Lja-Fyn protein expression. These results indicated that nrPTK Lja-Fyn was likely to be involved in immune response. Furthermore, our present findings also provide the necessary information for understanding the distinction between lamprey Lja-Fyn and other members of jawed vertebrates in Src family. PMID- 26743130 TI - High orientation of long chain branched poly (lactic acid) with enhanced blood compatibility and bionic structure. AB - Highly oriented poly (lactic acid) (PLA) with bionic microgrooves was fabricated through solid hot drawing technology for further improving the mechanical properties and blood biocompatibility of PLA. In order to enhance the melt strength and thus obtain high orientation degree, long chain branched PLA was prepared at first through a two-step ring-opening reaction during processing. Linear viscoelasticity combined with branch-on-branch model was used to predict probable compositions and chain topologies of the products, and it was found that the molecular weight of PLA increased and topological structures with star like chain with three arms and tree-like chain with two generations formed during reactive processing, and consequently draw ratio as high as1200% can be achieved during the subsequent hot stretching. With the increase of draw ratio, the tensile strength and orientation degree of PLA increased dramatically. Long chain branching and orientation could significantly enhance the blood compatibility of PLA by prolonging clotting time and decreasing platelet activation. Microgrooves can be observed on the surface of the oriented PLA which were similar to the intimal layer of blood vessel, and such bionic structure resulted from the formation of the oriented shish kebab-like crystals along the draw direction. PMID- 26743131 TI - Optimal number of atlases and label fusion for automatic multi-atlas-based brachial plexus contouring in radiotherapy treatment planning. AB - BACKGROUND: The present study aimed to define the optimal number of atlases for automatic multi-atlas-based brachial plexus (BP) segmentation and to compare Simultaneous Truth and Performance Level Estimation (STAPLE) label fusion with Patch label fusion using the ADMIRE(r) software. The accuracy of the autosegmentations was measured by comparing all of the generated autosegmentations with the anatomically validated gold standard segmentations that were developed using cadavers. MATERIALS AND METHODS: Twelve cadaver computed tomography (CT) atlases were used for automatic multi-atlas-based segmentation. To determine the optimal number of atlases, one atlas was selected as a patient and the 11 remaining atlases were registered onto this patient using a deformable image registration algorithm. Next, label fusion was performed by using every possible combination of 2 to 11 atlases, once using STAPLE and once using Patch. This procedure was repeated for every atlas as a patient. The similarity of the generated automatic BP segmentations and the gold standard segmentation was measured by calculating the average Dice similarity (DSC), Jaccard (JI) and True positive rate (TPR) for each number of atlases. These similarity indices were compared for the different number of atlases using an equivalence trial and for the two label fusion groups using an independent sample t test. RESULTS: DSC's and JI's were highest when using nine atlases with both STAPLE (average DSC = 0,532; JI = 0,369) and Patch (average DSC = 0,530; JI = 0,370). When comparing both label fusion algorithms using 9 atlases for both, DSC and JI values were not significantly different. However, significantly higher TPR values were achieved in favour of STAPLE (p < 0,001). When fewer than four atlases were used, STAPLE produced significantly lower DSC, JI and TPR values than did Patch (p = 0,0048). CONCLUSIONS: Using 9 atlases with STAPLE label fusion resulted in the most accurate BP autosegmentations (average DSC = 0,532; JI = 0,369 and TPR = 0,760). Only when using fewer than four atlases did the Patch label fusion results in a significantly more accurate autosegmentation than STAPLE. PMID- 26743132 TI - Developing an Internet- and Mobile-Based System to Measure Cigarette Use Among Pacific Islanders: An Ecological Momentary Assessment Study. AB - BACKGROUND: Recent prevalence data indicates that Pacific Islanders living in the United States have disproportionately high smoking rates when compared to the general populace. However, little is known about the factors contributing to tobacco use in this at-risk population. Moreover, few studies have attempted to determine these factors utilizing technology-based assessment techniques. OBJECTIVE: The objective was to develop a customized Internet-based Ecological Momentary Assessment (EMA) system capable of measuring cigarette use among Pacific Islanders in Southern California. This system integrated the ubiquity of text messaging, the ease of use associated with mobile phone apps, the enhanced functionality offered by Internet-based Cell phone-optimized Assessment Techniques (ICAT), and the high survey completion rates exhibited by EMA studies that used electronic diaries. These features were tested in a feasibility study designed to assess whether Pacific Islanders would respond to this method of measurement and whether the data gathered would lead to novel insights regarding the intrapersonal, social, and ecological factors associated with cigarette use. METHODS: 20 young adult smokers in Southern California who self-identified as Pacific Islanders were recruited by 5 community-based organizations to take part in a 7-day EMA study. Participants selected six consecutive two-hour time blocks per day during which they would be willing to receive a text message linking them to an online survey formatted for Web-enabled mobile phones. Both automated reminders and community coaches were used to facilitate survey completion. RESULTS: 720 surveys were completed from 840 survey time blocks, representing a completion rate of 86%. After adjusting for gender, age, and nicotine dependence, feeling happy (P=<.001) or wanting a cigarette while drinking alcohol (P=<.001) were positively associated with cigarette use. Being at home (P=.02) or being around people who are not smoking (P=.01) were negatively associated with cigarette use. CONCLUSIONS: The results of the feasibility study indicate that customized systems can be used to conduct technology-based assessments of tobacco use among Pacific Islanders. Such systems can foster high levels of survey completion and may lead to novel insights for future research and interventions. PMID- 26743133 TI - Young Children's Knowledge of the Symbolic Nature of Writing. AB - Two experiments with one hundred and fourteen 3- to 5-year-old children examined whether children understand that a printed word represents a specific spoken word and that it differs in this way from a drawing. When an experimenter read a word to children and then a puppet used a different but related label for it, such as "dog" for the word , children often stated the puppet's label was incorrect. In an analogous task with drawings, children were more likely to state that the puppet was correct in using an alternative label. The results suggest that even young children who cannot yet read have some understanding that a written word stands for a specific linguistic unit in a way that a drawing does not. PMID- 26743135 TI - Climate determines vascular traits in the ecologically diverse genus Eucalyptus. AB - Current theory presumes that natural selection on vascular traits is controlled by a trade-off between efficiency and safety of hydraulic architecture. Hence, traits linked to efficiency, such as vessel diameter, should show biogeographic patterns; but critical tests of these predictions are rare, largely owing to confounding effects of environment, tree size and phylogeny. Using wood sampled from a phylogenetically constrained set of 28 Eucalyptus species, collected from a wide gradient of aridity across Australia, we show that hydraulic architecture reflects adaptive radiation of this genus in response to variation in climate. With increasing aridity, vessel diameters narrow, their frequency increases with a distribution that becomes gradually positively skewed and sapwood density increases while the theoretical hydraulic conductivity declines. Differences in these hydraulic traits appear largely genotypic in origin rather than environmentally plastic. Data reported here reflect long-term adaptation of hydraulic architecture to water availability. Rapidly changing climates, on the other hand, present significant challenges to the ability of eucalypts to adapt their vasculature. PMID- 26743134 TI - High glucose enhances progression of cholangiocarcinoma cells via STAT3 activation. AB - Epidemiological studies have indicated diabetes mellitus (DM) as a risk of cholangiocarcinoma (CCA), however, the effects and mechanisms of high glucose on progression of CCA remain unclear. This study reports for the first time of the enhancing effects of high glucose on aggressive phenotypes of CCA cells via STAT3 activation. CCA cells cultured in high glucose media exerted significantly higher rates of cell proliferation, adhesion, migration and invasion than those cultured in normal glucose. The phosphokinase array revealed STAT3 as the dominant signal activated in response to high glucose. Increased nuclear STAT3, p-STAT3 and its downstream target proteins, cyclin D1, vimentin and MMP2, were shown to be underling mechanisms of high glucose stimulation. The link of high glucose and STAT3 activation was confirmed in tumor tissues from CCA patients with DM that exhibited higher STAT3 activation than those without DM. Moreover, the levels of STAT3 activation were correlated with the levels of blood glucose. Finally, decreasing the level of glucose or using a STAT3 inhibitor could reduce the effects of high glucose. These findings suggest that controlling blood glucose or using a STAT3 inhibitor as an alternative approach may improve the therapeutic outcome of CCA patients with DM. PMID- 26743137 TI - Self-navigation under non-steady-state conditions: Cardiac and respiratory self gating of inversion recovery snapshot FLASH acquisitions in mice. AB - PURPOSE: An algorithm is presented to enable cardiac and respiratory self-gating in combination with Inversion Recovery Look-Locker read-outs. METHODS: A radial inversion recovery snapshot FLASH sequence was adapted for retrospective cardiac T1 measurements in mice. Cardiac and respiratory data were extracted from the k space center of radial projections and an adapted method for retrospective cardiac synchronization is introduced. Electrocardiogram (ECG) data was acquired concurrently for validation of the proposed self-gating technique. T1 maps generated by the proposed technique were compared with maps reconstructed with the ECG reference. RESULTS: Respiratory gating and cardiac trigger points could be obtained for the whole time course of the relaxation dynamic and correlate very well to the ECG signal. T1 maps reconstructed with the self-gating technique are in very good agreement with maps reconstructed with the external reference. CONCLUSION: The proposed method extends "wireless" cardiac MRI to non-steady state inversion recovery measurements. T1 maps were generated with a quality comparable to ECG based reconstructions. As the method does not rely on an ECG trigger signal it provides easier animal handling. Magn Reson Med 76:1887-1894, 2016. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26743138 TI - Chiral Triazoles in Anion-Binding Catalysis: New Entry to Enantioselective Reissert-Type Reactions. AB - Easily accessible and tunable chiral triazoles have been introduced as a novel class of C-H bond-based H-donors for anion-binding organocatalysis. They have proven to be effective catalysts for the dearomatization reaction of different N heteroarenes. Although this dearomatization approach represents a powerful strategy to build chiral heterocycles, to date only a few catalytic methods to this end exist. In this work, the organocatalyzed enantioselective Reissert-type dearomatization of isoquinoline derivatives employing a number of structurally diverse chiral triazoles as anion-binding catalysts was realized. The here presented method was employed to synthesize a number of chiral 1,2 dihydroisoquinoline substrates with an enantioselectivity up to 86:14 e.r. Moreover, a thorough study of the determining parameters affecting the activity of this type of anion- binding catalysts was carried out. PMID- 26743136 TI - Dienogest as preoperative treatment of submucous myomas for hysteroscopic surgery: a prospective, randomized study. AB - The aim of this single-center, prospective, randomized, parallel-group study was to compare Dienogest and Danazol as endometrial preparation in patients who have to undergo hysteroscopic surgery for submucous myomas. We enrolled 80 consecutive eligible patients, in reproductive age, affected by submucous myomas. Pre- and posttreatment characterization of endometrium was performed by hysteroscopic visual observation and histologic confirmation. The enrolled patients were randomly assigned to two groups: 40 were treated with 2 mg of Dienogest/die, 40 with 100 mg of Danazol/die, both orally for 5 weeks, starting on day 1 of menstruation. Posttreatment comparison of endometrial patterns showed a significant more marked effect of Dienogest, respect to Danazol, in atrophying endometrium ("normotrophic non-responders" versus "hypotrophic"-"atrophic", p = 0.028). Intraoperative data showed no significant difference between the two groups for cervical dilatation time (p = 0.326), while in the Dienogest group, we found a significant reduction of operative time (p = 0.001), infusion volume (p = 0.001), and severity of bleeding (p = 0.042). Moreover, Dienogest caused less side effects (p = 0.008). According to our data analysis, Dienogest, respect to Danazol, is more effective for the preparation of the endometrium in patients who have to undergo hysteroscopic surgery for submucous myomas, and causes less side effects. PMID- 26743139 TI - Diagnostic Value of Common Inflammatory Markers on Fever of Unknown Origin. AB - This study was designed to evaluate the diagnostic value of common inflammatory markers with regard to fever of unknown origin (FUO). We investigated 383 patients who were hospitalized with FUO at the Henan Province People's hospital between January 2009 and June 2015. Of all the cases, infectious diseases accounted for 33.9%, neoplasms for 21.1%, collagen vascular diseases for 25.1%, miscellaneous diseases for 4.7%, and no diagnosis for 15.1%. Patients in the neoplasm group were older than those in the infectious disease, collagen vascular disease, and miscellaneous disease groups (p = 0.006, p < 0.0001, and p = 0.001, respectively). The duration of fever before admission of patients in the neoplasm and collagen vascular disease group was longer than that of patients in the infectious disease group (p = 0.002 and p = 0.007, respectively). The diagnostic time after admission of patients from the neoplasm and collagen vascular disease groups was longer than that for patients from the infectious disease group (both p < 0.0001). Serum ferritin levels of patients in the infectious disease group were lower than those of patients in the neoplasm and collagen vascular disease groups (p = 0.029 and p = 0.032, respectively), while serum procalcitonin (PCT) levels in the infectious disease group was higher than that in the neoplasm and collagen vascular disease groups (p = 0.016 and p = 0.007, respectively). Therefore, FUO remains a clinical problem in China and serum ferritin and PCT may be useful in discriminating infectious from non-infectious causes (neoplasms and collagen vascular diseases) in patients with FUO. PMID- 26743140 TI - The Rapid Induction of Carbapenem-Resistance in an Aeromonas dhakensis Blood Isolate. AB - Meropenem-susceptible and -resistant Aeromonas dhakensis isolates from blood cultures of a fatal case of septicemia were analyzed. The two isolates were homologous and gene expression of metallo-beta-lactamase in the resistant strain was upregulated. Physicians should be aware of the possibility of the induction of carbapenem-resistance, following the use of carbapenems in the treatment of Aeromonas infection. PMID- 26743141 TI - Molecular Characterization of Mosquitoes (Diptera: Culicidae) in Northwestern Iran by Using rDNA-ITS2. AB - Several mosquito species are vectors of disease; however, to understand their role in disease transmission, accurate species identification is of particular importance. Morphological identification is the main method used, but molecular techniques have emerged as a tool for the identification of closely related species. In this study, mosquitoes from the West Azerbaijan Province in northwestern Iran were characterized on the basis of their rDNA-ITS2 sequences. Nine populations of 6 species of mosquitoes belonging to the genera Anopheles, Culex, Culiseta, and Ochlerotatus were studied. To the best of our knowledge, ITS2 sequences of Culiseta longiareolata and Culex hortensis have been reported for the first time. In addition, ITS2 sequences of Culex theileri and Ochlerotatus caspius have been reported for the first time in Iran. Phylogenetic analysis based on ITS2 showed that subfamilies Anophelinae and Culicinae of the family Culicidae could be differentiated successfully and subgenera Anopheles and Cellia of the genus Anopheles were separated. The analysis showed that the genera Culex, Culiseta, and Ochlerotatus have diverged separately. PMID- 26743142 TI - Catheter-Related Bloodstream Infection Due to Lodderomyces elongisporus. AB - Lodderomyces elongisporus infrequently causes bloodstream infections and has been isolated from Asia and Mexico. We encountered a catheter-related bloodstream infection, which involved some risk factors, due to L. elongisporus masquerading as Candida parapsilosis. A 39-year-old man who received a total arch and thoracoabdominal aortic replacement was admitted with a diagnosis of aorto esophageal fistula. After thoracic drainage for the aorto-esophageal fistula, a catheter-related bloodstream infection was diagnosed. Micafungin (100 mg/day) was successfully administered to treat the catheter-related bloodstream infection for 42 days in total. The bloodstream and catheter tip yeast was grown on Candida agar medium and produced dark green colonies indicating Candida albicans. We performed sequencing analysis using a GenBank BLAST search. The sequence of the internal transcribed spacer region was 99.9% identical with that of the type strain L. elongisporus. This yeast organism has frequently been technically mistaken for non-albicans Candida spp. Furthermore, the prognosis and risk factors of L. elongisporus infection remain unclear owing to the scarcity of reported cases. Catheter-related bloodstream infection caused by this organism has not been described to date. PMID- 26743143 TI - Qualitative Real-Time PCR Assay for HIV-1 and HIV-2 RNA. AB - Because western blotting occasionally causes cross-reactions between human immunodeficiency virus (HIV)-1 and HIV-2, it is difficult to distinguish a coinfection status from a false-positive result. Therefore, we developed a qualitative real-time PCR assay to detect HIV-1 and HIV-2 RNA that can be performed in parallel. Viral RNA extracted from 500 MUl of plasma was examined using real-time PCR with minor groove binder probes. Bovine leukemia virus was used as an internal standard. The sensitivity was determined by probit regression analysis using the World Health Organization international standards for HIV-1 and HIV-2. The lower detection limits at a 95% hit rate were 54 IU/ml for HIV-1 and 5.0 IU/ml for HIV-2, which were lower than any HIV-2 assays reported previously. HIV-1 RNA was detected in 51 of 52 HIV-1 seropositive plasma samples. HIV-2 RNA was detected in 7 of 10 HIV-2 seropositive plasma samples. Non-specific signals and cross reactivity between HIV-1 and HIV-2 were not observed in 100 HIV seronegative samples. The assay developed in this study is highly sensitive and specific for the detection of HIV-1 and HIV-2 RNA. The test is expected to be useful for the differential diagnosis of HIV-1 and HIV-2 infections. PMID- 26743144 TI - Crimean-Congo Hemorrhagic Fever Due to Consumption of Raw Meat: Case Reports From East-North of Iran. PMID- 26743146 TI - Multilocus Sequence Types and Virulence Determinants of Hypermucoviscosity Positive Klebsiella pneumoniae Isolated from Community-Acquired Infection Cases in Harbin, North China. AB - We investigated the molecular epidemiologic characteristics and virulence of hypermucoviscosity-positive Klebsiella pneumoniae in mainland China. We detected 16 hypermucoviscosity-positive strains in 65 total clinical isolates (24.62%). We found that 68.75% (11/16) of the positive strains had K2 genotype and carried the rmpA and iucA genes. Multilocus sequence typing revealed 5 sequence types (STs): ST65 [7], ST23 [4], ST86 [3], ST412 [1], ST375 [1], whereas the remaining 4 isolates were defined as other STs. The order of the median lethal dose values for the ST types was ST23 (2.19 * 10(3) CFU/mouse) < ST86 (1.70 * 10(4) CFU/mouse) < ST65 (5.05 * 10(7) CFU/mouse) < the other STs (1.90 * 10(8) CFU/mouse). In conclusion, the K2 with ST65 carrying rmpA and iucA was the most predominant among the hypermucoviscosity-positive K. pneumoniae strains obtained from community-acquired infection cases in Harbin, North China. Sequence types are a valuable tool to predict the risk of K. pneumoniae infection. PMID- 26743145 TI - Epidemiological Analysis of Nosocomial MRSA Outbreaks Using Phage Open-Reading Frame Typing in a Tertiary-Care Hospital. AB - Pulsed-field gel electrophoresis (PFGE) is a reliable method for analyzing outbreaks of methicillin-resistant Staphylococcus aureus (MRSA); however, it is time-consuming and technically demanding. A new strain-differentiation method for MRSA, namely phage open reading frame (ORF) typing (POT), is a rapid PCR-based technique, in which the ORFs of lysogenized phage genomes in MRSA are amplified. The aim of this study was to evaluate the utility of the POT method for epidemiological analysis of nosocomial MRSA outbreaks. Forty-four strains from 12 episodes of 3 or more nosocomial MRSA infections in 1 ward within a 4-week period were characterized using PFGE and POT methods. The strains were classified into 16 distinct types using POT and 19 subtypes using PFGE. We defined an outbreak as 3 or more new MRSA infections caused by strains with indistinguishable genetic patterns. The identification of 11 (91.7%) episodes by PFGE, including 4 outbreaks and 7 sporadic events, was consistent with the results of POT analysis. These results suggest that POT is a useful epidemiological tool for evaluating nosocomial MRSA outbreaks. PMID- 26743147 TI - PCR-RFLP Provides Discrimination for Total flaA Sequence Analysis in Clinical Campylobacter jejuni Isolates. AB - The aims of this study were to determine the genetic relatedness among 20 clinical Campylobacter jejuni samples isolated from children with diarrhea in Iran and to introduce the best method of discrimination based on flagellin gene (flaA) sequence divergence. A total of 400 stool specimens were obtained from children under 5 years of age from July 2012 to June 2013. Primers were designed based on conserved sequences flanking the flaA gene that encompassed and amplified the entire flaA gene and followed by sequencing and data analysis with MEGA version 6.0.6 software. Ninety amino acids and 560 nucleotide polymorphic sequences were detected within 1,681 bp of the flaA sequence of which 43 (2.5%) and 12 (0.7%) were singletons, respectively. New repeat boxes within the flaA sequences were found in this study. Unweighted Pair Group Method with Arithmetic Mean dendrogram based on nucleotides of the full length flaA gene, the flaA short variable region gene and the in silico flaA phylogenic tree of DdeI restriction fragment length polymorphism (RFLP) profiles produced very similar clustering with a diversity index of 0.86 for each of the 3 methods. We conclude that flaA typing based on DdeI RFLP of the PCR products is a cheap, rapid, and reliable method for the epidemiological study of C. jejuni isolates of clinical origin in resource-limited regions or in large-scale population surveillance. PMID- 26743148 TI - Infectious Spondylitis in a Patient with Chronic Kidney Disease: Identification of Campylobacter fetus Subsp. testudinum by 16S Ribosomal RNA Sequencing. AB - We report the first case of spondylitis with bacteremia caused by Campylobacter fetus subsp. testudinum identified by 16S ribosomal ribonucleic acid (rRNA) gene sequencing. An 81-year-old man presented with fever and general weakness. His medical history included end-stage renal disease, hypertension, and type 2 diabetes. Despite empirical antibiotic treatment, his fever and back pain persisted. Magnetic resonance imaging with gadolinium enhancement showed a low signal-intensity lesion in T1-weighted imaging and a high-signal-intensity lesion in T2-weighted imaging at the L3 vertebral body. C. fetus grew on 1 pair of blood cultures. C. fetus subsp. testudinum was identified via 16S rRNA sequencing of the cultivated organisms. The patient recovered uneventfully after 6 weeks of optimal antibiotic treatment, selected using susceptibility tests. C. fetus spondylitis is a very rare disease. In this unique case involving end-stage renal disease, the underlying pathogen was identified by 16S rRNA sequencing. PMID- 26743149 TI - Ulcerative Lesions with Hemorrhage in a Patient with Severe Fever with Thrombocytopenia Syndrome Observed via Upper Gastrointestinal Endoscopy. AB - Severe fever with thrombocytopenia syndrome (SFTS) is a novel bunyavirus infection caused by the SFTS virus (SFTSV, family Bunyaviridae, genus Phlebovirus) with a high case fatality rate. A previously healthy 72-year-old man showed symptoms of fever, general fatigue, and altered consciousness. He was hospitalized for treatment. On day 3, considering the day on which fever appeared first during the disease course as day 0, he had bloody emesis. An emergency upper gastrointestinal endoscopic examination revealed multiple ulcerative lesions with continuously oozing hemorrhage in the stomach. He died on day 7. He was retrospectively diagnosed as having SFTS, Although it was less likely that the gastric ulcerative lesions were directly induced by SFTSV replication, it was evident that hemorrhagic emesis might occur in the patient in association with the pathophysiology of SFTS. The real-time imaging of gastric ulcerative lesions in a patient with SFTS is reported. PMID- 26743150 TI - A Strong Correlation between the Annual Incidence of Amebiasis and Homosexual Human Immunodeficiency Virus Type Infection in Men. PMID- 26743151 TI - Clinical Implications of 5 Cases of Middle East Respiratory Syndrome Coronavirus Infection in a South Korean Outbreak. AB - The Korea Middle East respiratory syndrome coronavirus (MERS-CoV) was first confirmed on May 20, 2015, with a subsequent outbreak in South Korea. Five patients with suspected MERS-CoA infection were admitted to our hospital during this outbreak. One patient had no major symptoms upon admission, but pneumonia was identified upon chest radiography. Two patients progressed rapidly to acute respiratory failure and required ventilator-assisted respiration. One patient required extracorporeal membrane oxygenation to treat refractory hypoxemia, and one patient died of shock with multiorgan failure. All the patients had fever, myalgia, leucopenia, normal procalcitonin level, and pneumonia. Importantly, clinicians should test for pneumonia in all suspected patients with MERS-CoV infection, even in the absence of respiratory symptoms. The pneumonia usually affected the lower lobes. A shorter incubation period was associated with more severe disease and greater risk of mortality, and the severity of fever predicted the prognosis of MERS-CoV infection-related pneumonia. Therefore, in cases of lower-lobe pneumonia that occur during an MERS-CoV outbreak and are unesponsive to antibiotics, clinicians should consider the possibility of MERS-CoV infection. PMID- 26743152 TI - Distribution of Chlamydia trachomatis Infection Determined by Nucleic Acid Amplification Tests in Pregnant Women in Japan. PMID- 26743153 TI - Molecular Epidemiology of Monophasic Salmonella enterica serovar O7: -: 1, 5 Isolates in Akita Prefecture, Japan. PMID- 26743154 TI - Parkinson's disease: fetal cell or stem cell derived treatments. PMID- 26743155 TI - Seroprevalence of hepatitis E virus infection among dogs in several developed cities in the Guangdong province of China. AB - Hepatitis E virus (HEV), as a zoonotic disease virus, was seldom studied in dogs especially in stray dogs. As previously reported, dog might be an accidental host of HEV for human beings and some risk factors might play an important role in HEV transmission. Thus, we designed this study to evaluate the seroprevalence of HEV infection among dogs in several cities in Guangdong province of China. This surveillance may help us understand risk factors including location, gender, live type, and diet habit for HEV transmission. The overall seroprevalence of anti-HEV antibodies in dogs was 19.00%. Positive rate of anti-HEV antibodies in other food groups (21.13%) was higher than that in dog food groups (9.77%) (P < 0.05), which suggested that diet habit might be a vital element of infecting HEV for dogs and play an important role in living environment. However, the analysis indicated that no strong relationship was observed among different cities, gender groups, and live type. Our study demonstrated that HEV is prevalent in dogs in the Guangdong province of China. As diet habit might become a vital element of infecting HEV for dogs and play an important role in living environment, similar studies of dogs should be conducted in the future. J. Med. Virol. 88:1404-1407, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26743156 TI - Quantifying the influence of child abuse history on the cardinal symptoms of fibromyalgia. AB - OBJECTIVES: To quantify the influence of abuse, particularly in childhood, with pain sensitivity and other adverse symptoms experienced by women with fibromyalgia (FM). METHODS: Subjects with FM completed a detailed abuse interview, dolorimetry, and questionnaire-based assessments of fatigue, cognitive self-appraisal, and depression. Student's t- and chi-square tests were used to analyse differences in FM symptoms between those with and without a history of childhood abuse. Linear regression was used to evaluate the relationship between abuse and symptom severity, adjusting for possible confounders. RESULTS: In 111 women with FM, physical abuse during childhood demonstrated a clinically modest, yet statistically significant, association with increased tenderness as measured by pain pressure thresholds (beta=-0.25, p=0.011) and tender points (beta=0.23, p=.022). Physical child abuse was also associated with cognitive language impairment after adjusting for depression (beta=0.27, p=0.001). While emotional child abuse was associated with fatigue, the association did not persist after adjustment for depressive symptoms. CONCLUSIONS: Group differences are of small magnitude and might not directly impact clinical practice, however, the experience of child abuse is associated with FM symptom severity and may shape the biological development of interoception in ways that predispose to pain and polysymptomatic distress. PMID- 26743157 TI - The SPRINT study: Outcome may be driven by difference in diuretic treatment demasking heart failure and study design may support systolic blood pressure target below 140 mmHg rather than below 120 mmHg. PMID- 26743158 TI - Apibacter adventoris gen. nov., sp. nov., a member of the phylum Bacteroidetes isolated from honey bees. AB - Honey bees and bumble bees harbour a small, defined set of gut bacterial associates. Strains matching sequences from 16S rRNA gene surveys of bee gut microbiotas were isolated from two honey bee species from East Asia. These isolates were mesophlic, non-pigmented, catalase-positive and oxidase-negative. The major fatty acids were iso-C15 : 0, iso-C17 : 0 3-OH, C16 : 0 and C16 : 0 3 OH. The DNA G+C content was 29-31 mol%. They had ~87 % 16S rRNA gene sequence identity to the closest relatives described. Phylogenetic reconstruction using 20 protein-coding genes showed that these bee-derived strains formed a highly supported monophyletic clade, sister to the clade containing species of the genera Chryseobacterium and Elizabethkingia within the family Flavobacteriaceae of the phylum Bacteroidetes. On the basis of phenotypic and genotypic characteristics, we propose placing these strains in a novel genus and species: Apibacter adventoris gen. nov., sp. nov. The type strain of Apibacter adventoris is wkB301T ( = NRRL B-65307T = NCIMB 14986T). PMID- 26743159 TI - "Doping" pentacene with sp(2)-phosphorus atoms: towards high performance ambipolar semiconductors. AB - Recent research progress in black phosphorus sheets strongly encourages us to employ pentacene as a parent system to systematically investigate how the "doping" of sp(2)-phosphorus atoms onto the backbone of pentacene influences its optical and charge transport properties. Our theoretical investigations proved that increasing the contribution of the pz atomic orbital of the sp(2)-phosphorus to the frontier molecular orbital of phosphapentacenes could significantly decrease both hole and electron reorganization energies and dramatically red shift the absorption of pentacene. The record smallest hole and electron reorganization energies of 69.80 and 95.74 meV for heteropentacene derivatives were obtained. These results suggest that phosphapentacenes (or phosphaacenes) could be potential promising candidates to achieve both higher and balanced mobilities in organic field effect transistors and realize a better power conversion efficiency in organic photovoltaics. PMID- 26743160 TI - In-situ monitoring of Saccharomyces cerevisiae ITV01 bioethanol process using near-infrared spectroscopy NIRS and chemometrics. AB - The application feasibility of in-situ or in-line monitoring of S. cerevisiae ITV01 alcoholic fermentation process, employing Near-Infrared Spectroscopy (NIRS) and Chemometrics, was investigated. During the process in a bioreactor, in the complex analytical matrix, biomass, glucose, ethanol and glycerol determinations were performed by a transflection fiber optic probe immersed in the culture broth and connected to a Near-Infrared (NIR) process analyzer. The NIR spectra recorded between 800 and 2,200 nm were pretreated using Savitzky-Golay smoothing and second derivative in order to perform a partial least squares regression (PLSR) and generate the calibration models. These calibration models were tested by external validation and then used to predict concentrations in batch alcoholic fermentations. The standard errors of calibration (SEC) for biomass, ethanol, glucose and glycerol were 0.212, 0.287, 0.532, and 0.296 g/L and standard errors of prediction (SEP) were 0.323, 0.369, 0.794, and 0.507 g/L, respectively. Calibration and validation criteria were defined and evaluated in order to generate robust and reliable models for an alcoholic fermentation process matrix. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:510-517, 2016. PMID- 26743162 TI - Influence of side chains on the self-alignment capability of electroluminescent polyfluorenes. AB - We report a significant role of side chains in the propagation of molecular orientation upon annealing the liquid crystal phase of polyfluorenes. Direct rubbing of poly(9,9-di(octyl)fluorene) led to the orientation of polymer segments in the top-most region of the film and enhanced propagation of this orientation along the rubbing direction was observed upon annealing. In contrast, the rubbing induced molecular orientation of poly(9,9-di(ethylhexyl)fluorene) segments completely disappeared upon annealing in the nematic melt state. The higher order of the side chain structures in poly(9,9-di(octyl)fluorene) were found to allow the propagation of the three-dimensional molecular alignment. From integrated experimental and density functional theory studies, we propose that side chain interdigitation generates a unique alignment behavior of poly(9,9 di(octyl)fluorene). PMID- 26743161 TI - Effect of contact lens use on Computer Vision Syndrome. AB - PURPOSE: To analyse the relationship between Computer Vision Syndrome (CVS) in computer workers and contact lens use, according to lens materials. METHODS: Cross-sectional study. The study included 426 civil-service office workers, of whom 22% were contact lens wearers. Workers completed the Computer Vision Syndrome Questionnaire (CVS-Q) and provided information on their contact lenses and exposure to video display terminals (VDT) at work. CVS was defined as a CVS-Q score of 6 or more. The covariates were age and sex. Logistic regression was used to calculate the association (crude and adjusted for age and sex) between CVS and individual and work-related factors, and between CVS and contact lens type. RESULTS: Contact lens wearers are more likely to suffer CVS than non-lens wearers, with a prevalence of 65% vs 50%. Workers who wear contact lenses and are exposed to the computer for more than 6 h day(-1) are more likely to suffer CVS than non-lens wearers working at the computer for the same amount of time (aOR = 4.85; 95% CI, 1.25-18.80; p = 0.02). CONCLUSIONS: Regular contact lens use increases CVS after 6 h of computer work. PMID- 26743163 TI - Novel core-shell structure microspheres based on lanthanide complexes for white light emission and fluorescence sensing. AB - A series of new core-shell structure materials based on lanthanide complexes [H2NMe2]3[Ln(dpa)3] (Ln = Eu, Tb, Sm, Dy, Nd, and Yb; [H2NMe2](+) = dimethylamino cation; dpa = 2-dipicolinate) and silica microspheres has been prepared under solvothermal conditions. Electron microscopy reveals that the nanosized materials SiO2@Ln-dpa are spherical with a narrow size distribution and a [H2NMe2]3[Ln(L)3] coating was generated on the surface of silica microspheres successfully. The core-shell structure materials exhibit excellent optical performance. The white light-emitting material SiO2@(Dy:Eu)-dpa has a potential application in the development of a white-light device, as a result of the fact that its CIE chromaticity coordinate is very close to that of pure white. Then, we selected SiO2@Eu-dpa as a representative sample for sensing experiments. Eventually, we found that the core-shell structure sensors are highly selective and sensitive for acetone and Cu(2+) cations. The detection of Cu(2+) in the human body is an important issue. Interestingly, the core-shell structure materials display better selectivity and higher sensitivity than the pure lanthanide complexes in sensing Cu(2+) and the value of the quenching effect coefficient has increased by more than 20%. PMID- 26743164 TI - What do we know about care home managers? Findings of a scoping review. AB - This article reports selected findings from a scoping review of the literature about care home managers in England. The review was undertaken between December 2013 and April 2014, with searches conducted in December 2013, and completed in July 2014. Its aim was to identify the characteristics of care home managers, descriptions of their leadership and managerial roles, their experience, skills and support, and the managers' perceptions of their work and status and to identify knowledge gaps. The databases searched included Web of Knowledge, EBSCO, ASSIA, Embase, AgeInfo, NHS Evidence, Social Care Online and the publication platforms IngentaConnect, Wiley Online and JSTOR together with specialist sites and national information providers. Sixteen relevant studies directly about care home managers, reported in 24 articles, were identified. A further body of literature pertinent to the questions was located (n = 84), including sector reports, professional press, expert opinion, enquiries and reviews, and other material, which also informed the review. A consultation exercise with stakeholders informed the findings of the review. The review found that, despite frequent allusions to their impact on organisational culture, few studies have focused on care home managers, and, such as there are, mainly relate to managers of care homes for older people. This is despite managers' major responsibilities for the care of many frail and disabled people. PMID- 26743165 TI - Epigenetic dysregulation of Insulin-like growth factor (IGF)-related genes and adverse pregnancy outcomes: a systematic review. AB - OBJECTIVES: Preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA) are leading causes of neonatal mortality and morbidity around the world. Epigenetic alterations of the human genome may be involved in the causal chain of adverse pregnancy outcomes. In this systematic review we investigated whether PTB, LBW and SGA are associated with epigenetic dysregulation of insulin like growth factor-related genes (IGF). METHODS: We searched MEDLINE and EMBASE for peer-reviewed articles about IGF and PTB, LBW and SGA published up to February 2015. Two independent reviewers selected original, controlled, human studies published in any language and graded them using the Newcastle-Ottawa Quality Assessment Scale. Disagreements were resolved by consensus with a third reviewer. RESULTS: Eighteen observational studies of low-to-moderate quality met the eligibility criteria out of 210 unique studies. There was substantial heterogeneity across studies. Most studies reported no, limited or borderline association between epigenetic changes (methylation or imprinting) of IGF-related genes and LBW or SGA. There were no IGF-related epigenetic studies of PTB. CONCLUSIONS: Overall, evidence of an association between epigenetic abnormalities of IGF-related genes and LBW or SGA was weak and inconsistent. Methodological concerns limited results validity. PMID- 26743167 TI - Directional Movement of Droplets in Grooves: Suspended or Immersed? AB - The behavior of droplets trapped in geometric structures is essential to droplet manipulation applications such as for droplet transport. Here we show that directional droplet movement can be realized by a V-shaped groove with the movement direction controlled by adjusting the surface wettability of the groove inner wall and the cross sectional angle of the groove. Experiments and analyses show that a droplet in a superhydrophobic groove translates from the immersed state to the suspended state as the cross sectional angle of the groove decreases and the suspended droplet departs from the groove bottom as the droplet volume increases. We also demonstrate that this simple grooved structure can be used to separate a water-oil mixture and generate droplets with the desired sizes. The structural effect actuated droplet movements provide a controllable droplet transport method which can be used in a wide range of droplet manipulation applications. PMID- 26743166 TI - Towards defining restlessness in individuals with dementia. AB - OBJECTIVES: Most individuals with dementia develop significant behavioral problems. Restlessness is a behavioral symptom frequently endorsed by caregivers as distressing, yet is variably defined and measured. Lack of conceptual and operational clarity hinders an understanding of this common behavioral type, its prevalence, and development of effective interventions. We advance a systematic definition and understanding of restlessness from which to enhance reporting and intervention development. METHOD: We reviewed the literature for existing definitions and measures of restlessness, identified common elements across existing definitions, assessed fit with relevant theoretical frameworks, and explored the relationship between restlessness and other behavioral symptoms in a data set of 272 community-dwelling persons with dementia. RESULTS: Twenty-five scales assessing restlessness were identified. Shared components included motor/neurological, psychiatric, and needs-based features. Exploratory analyses suggest that restlessness may co-occur primarily with argumentation, anxiety, waking the caregiver, delusions/hallucinations, and wandering. We propose that restlessness consists of three key attributes: diffuse motor activity or motion subject to limited control, non-productive or disorganized behavior, and subjective distress. Restlessness should be differentiated from and not confused with wandering or elopement, pharmacological side effects, a (non-dementia) mental or movement disorder, or behaviors occurring in the context of a delirium or at end-of-life. CONCLUSION: Restlessness appears to denote a distinct set of behaviors that have overlapping but non-equivalent features with other behavioral symptoms. We propose that it reflects a complex behavior involving three key characteristics. Understanding its specific manifestations and which components are present can enhance tailoring interventions to specific contexts of this multicomponent behavioral type. PMID- 26743168 TI - Factor XIII A-Subunit V34L Variant Affects Thrombus Cross-Linking in a Murine Model of Thrombosis. AB - OBJECTIVE: Factor XIII (FXIII) cross-links fibrin upon activation by thrombin. Activation involves cleavage at residue 37 by thrombin, releasing an activation peptide. A common polymorphism (valine to leucine variant at residue 34, V34L), located in the activation peptide, has been associated with increased activation rates and paradoxically a protective effect in cardiovascular disease. There is, currently, no data available on the effects of V34L from in vivo models of thrombosis. We examined the effect of FXIII V34L on clot formation and cross linking in vivo. APPROACH AND RESULTS: We generated a panel of full-length recombinant human FXIII-A2 variants with amino acid substitutions in the activation peptide to investigate the effect of these variants on activation rate, and we used wild-type, V34L, and alanine to glycine variant at residue 33 variants to study the effects of varying FXIII activation rate on thrombus formation in a murine model of FeCl3 injury. FXIII activation assay showed that residues 29, 30, 33, and 34 play a critical role in thrombin interaction. Full length recombinant human FXIII-A2 V34L has significant effects on clot formation, structure, and lysis in vitro, using turbidity assay. This variant influenced fibrin cross-linking but not size of the thrombus in vivo. CONCLUSIONS: Mutations in the activation peptide of full-length recombinant FXIII regulate activation rates by thrombin, and V34L influences in vivo thrombus formation by increased cross-linking of the clot. PMID- 26743171 TI - Chitosan-Based Conventional and Pickering Emulsions with Long-Term Stability. AB - Chitosan-based conventional and Pickering oil-in-water (O/W) emulsions with very fine droplet size (volume average diameter, dv, as low as 1.7 MUm) and long-term stability (up to 5 months) were ultrasonically generated at different pH values without the addition of any surfactant or cross-linking agent. The ultrasonication treatment was found to break and disperse chitosan agglomerates effectively (particularly at pH >= 4.5) and also reduce the chitosan molecular weight, benefiting its emulsification properties. The emulsion stability and emulsion type could be controlled by chitosan solution pH. Increasing pH from 3.5 to 5.5 led to the formation of conventional emulsions with decreasing droplet size (dv from 14 to 2.1 MUm) and increasing emulsion stability (from a few days to 2 months). These results can be explained by the increase of dynamic interfacial pressure, which results from the conformation transition of chitosan molecules from an extended state to a more flexible structure as pH increases. At pH = 6.5 (the acid dissociation constant (pKa) of chitosan), the chitosan molecules self-assembled into well-dispersed nanoparticles (dv = 82.1 nm) with the assistance of ultrasonication, which resulted in a Pickering emulsion with the smallest droplet size (dv = 1.7 MUm) and highest long-term stability (up to 5 months) because of the presence of chitosan solid nanoparticles at the oil/water interface. The key originality of this study is the elucidation of the role of pH in the formation of conventional and Pickering chitosan-based O/W emulsions with the assistance of ultrasonication. Our results suggest that chitosan possesses great potential to be used as an effective pH-controlled emulsifier and stabilizer without the need of other additives. PMID- 26743169 TI - Synergistic Inhibition of Both P2Y1 and P2Y12 Adenosine Diphosphate Receptors As Novel Approach to Rapidly Attenuate Platelet-Mediated Thrombosis. AB - OBJECTIVE: Unlike currently approved adenosine diphosphate receptor antagonists, the new diadenosine tetraphosphate derivative GLS-409 targets not only P2Y12 but also the second human platelet adenosine diphosphate receptor P2Y1 and may, therefore, be a promising antiplatelet drug candidate. The current study is the first to investigate the in vivo antithrombotic effects of GLS-409. APPROACH AND RESULTS: We studied (1) the in vivo effects of GLS-409 on agonist-stimulated platelet aggregation in anesthetized rats, (2) the antithrombotic activity of GLS 409 and the associated effect on the bleeding time in a canine model of platelet mediated coronary artery thrombosis, and (3) the inhibition of agonist-stimulated platelet aggregation by GLS-409 versus selective P2Y1 and P2Y12 inhibition in vitro in samples from healthy human subjects before and 2 hours after aspirin intake. In vivo treatment with GLS-409 significantly inhibited adenosine diphosphate- and collagen-stimulated platelet aggregation in rats. Further, GLS 409 attenuated cyclic flow variation, that is, platelet-mediated thrombosis, in vivo in our canine model of unstable angina. The improvement in coronary patency was accompanied by a nonsignificant 30% increase in bleeding time. Of note, GLS 409 exerted its effects without affecting rat and canine hemodynamics. Finally, in vitro treatment with GLS-409 showed effects similar to that of cangrelor and the combination of cangrelor with the selective P2Y1 inhibitor MRS 2179 on agonist-stimulated platelet aggregation in human platelet-rich plasma and whole blood before and 2 hours after aspirin intake. CONCLUSIONS: Synergistic inhibition of both P2Y1 and P2Y12 adenosine diphosphate receptors by GLS-409 immediately attenuates platelet-mediated thrombosis and effectively blocks agonist-stimulated platelet aggregation irrespective of concomitant aspirin therapy. PMID- 26743170 TI - MicroRNA-150 Suppression of Angiopoetin-2 Generation and Signaling Is Crucial for Resolving Vascular Injury. AB - OBJECTIVE: Increased vascular permeability is a hallmark of sepsis and acute respiratory distress syndrome. Angiopoietin (Ang2) induces vascular leak, and excess Ang2 generation is associated with patient mortality from these diseases. However, mechanisms dampening Ang2 generation during injury remain unclear. Interestingly, microRNA (miR)-150 levels were decreased in septic patients. miR regulate signaling networks by silencing mRNAs containing complementary sequences. Thus, we hypothesized that miR-150 suppresses Ang2 generation and thereby resolves vascular injury. APPROACH AND RESULTS: Wild-type or miR-150(-/-) mice or endothelial cells were exposed to lipopolysaccharide or sepsis, and Ang2 levels, adherens junction reannealing, endothelial barrier function, and mortality were determined. Although Ang2 transiently increased during lipopolysaccharide-induced injury in wild-type endothelial cells and lungs, miR 150 expression was elevated only during recovery from injury. Deletion of miR-150 caused a persistent increase in Ang2 levels and impaired adherens junctions reannealing after injury, resulting thereby in an irreversible increase in vascular permeability. Also, miR-150(-/-) mice died rapidly after sepsis. Rescuing miR-150 expression in endothelial cells prevented Ang2 generation, thereby restoring vascular barrier function in miR-150(-/-) mice. miR-150 terminated Ang2 generation by targeting the transcription factor, early growth response 2. Thus, early growth response 2 or Ang2 depletion in miR-150(-/-) endothelial cells restored junctional reannealing and reinstated barrier function. Importantly, upregulating miR-150 expression by injecting a chemically synthesized miR-150 mimic into wild-type mice vasculature decreased early growth response 2 and Ang2 levels and hence mortality from sepsis. CONCLUSIONS: miR-150 is a novel suppressor of Ang2 generation with a key role in resolving vascular injury and reducing mortality resulting from sepsis. PMID- 26743173 TI - Field-effect transistors based on wafer-scale, highly uniform few-layer p-type WSe2. AB - The synthesis of few-layer tungsten diselenide (WSe2) via chemical vapor deposition typically results in highly non-uniform thickness due to nucleation initiated growth of triangular domains. In this work, few-layer p-type WSe2 with wafer-scale thickness and electrical uniformity is synthesized through direct selenization of thin films of e-beam evaporated W on SiO2 substrates. Raman maps over a large area of the substrate show small variations in the main peak position, indicating excellent thickness uniformity across several square centimeters. Additionally, field-effect transistors fabricated from the wafer scale WSe2 films demonstrate uniform electrical performance across the substrate. The intrinsic field-effect mobility of the films at a carrier concentration of 3 * 10(12) cm(-2) is 10 cm(2) V(-1) s(-1). The unprecedented uniformity of the WSe2 on wafer-scale substrates provides a substantial step towards producing manufacturable materials that are compatible with conventional semiconductor fabrication processes. PMID- 26743172 TI - A Generic Platform for Cellular Screening Against Ubiquitin Ligases. AB - Ubiquitin signalling regulates most aspects of cellular life, thus deregulation of ubiquitylation has been linked with a number of diseases. E3 ubiquitin ligases provide substrate selectivity in ubiquitylation cascades and are therefore considered to be attractive targets for developing therapeutic molecules. In contrast to established drug target classes, such as protein kinases, GPCRs, hormone receptors and ion channels, ubiquitin drug discovery is in its early stages. This is, in part, due to the complexity of the ubiquitylation pathways and the lack of robust quantitative technologies that allow high-throughput screening of inhibitors. Here we report the development of a Ubiquitin Ligase Profiling system, which is a novel and generic cellular technology designed to facilitate identification of selective inhibitors against RING type E3 ubiquitin ligases. Utilization of this system requires a single co-transfection of cells with assay vectors, thereby enabling readout of E3 ubiquitin ligase catalytic activity within the cellular environment. Therefore, our robust high-throughput screening platform offers novel opportunities for the development of inhibitors against this difficult-to-target E3 ligase enzyme class. PMID- 26743174 TI - Stroke in 2015: Acute endovascular recanalization therapy comes of age. PMID- 26743175 TI - Toward the Ultimate Limit of Connectivity in Quantum Dots with High Mobility and Clean Gaps. AB - Colloidal quantum dots (CQDs) are highly versatile nanoscale optoelectronic building blocks, but despite their materials engineering flexibility, there is a considerable lack of fundamental understanding of their electronic structure as they couple within thin films. By employing a joint experimental-theoretical study, we reveal the impact of connectivity in CQD assemblies, going beyond the single CQD picture. High-resolution transmission electron microscopy (HR-TEM) demonstrates connectivity motifs across different CQD sizes and length scales and provides the necessary perspective to build robust computational models to systematically study the achievable degree of connectivity in these materials. We focused on state-of-the-art surface ligand treatments, taking into account both the degree of connectivity and nanocrystal orientation, and performed ab initio simulations within the phonon-assisted hopping regime. Importantly, both the TEM studies and our simulation results revealed morphological and electronic defects that could dramatically reduce optoelectronic performance, and yet would not have been captured within a single CQD model that neglects connectivity. We calculate carrier mobility in the presence of such defect states and conclude that the best achievable CQD assemblies for optoelectronics will require a modest degree of fusing via the {001} facet, followed by atomic ligand passivation to generate a clean band gap and unprecedentedly high charge transport. PMID- 26743176 TI - Development and initial validation of prescribing quality indicators for patients with chronic kidney disease. AB - BACKGROUND: Quality assessment is a key element for improving the quality of care. Currently, a comprehensive indicator set for measuring the quality of medication treatment in patients with chronic kidney disease (CKD) is lacking. Our aim was to develop and validate a set of prescribing quality indicators (PQIs) for CKD care, and to test the feasibility of applying this set in practice. METHODS: Potential indicators were based on clinical practice guidelines and evaluated using the RAND/UCLA Appropriateness Method. This is a structured process in which an expert panel assesses the validity of the indicators. Feasibility was tested in a Dutch primary care database including >4500 diabetes patients with CKD. RESULTS: An initial list of 22 PQIs was assessed by 12 experts. After changing 10 PQIs, adding 2 and rejecting 8, a final list of 16 indicators was accepted by the expert panel as valid. These PQIs focused on the treatment of hypertension, albuminuria, mineral and bone disorder, statin prescribing and possible unsafe medication. The indicators were successfully applied to measure treatment quality in the primary care database, but for some indicators the number of eligible patients was too small for reliable calculation. Results showed that there was room for improvement in the treatment quality of this population. CONCLUSIONS: We developed a set of 16 PQIs for measuring the quality of treatment in CKD patients, which had sufficient content and face validity as well as operational feasibility. These PQIs can be used to point out priority areas for improvement. PMID- 26743177 TI - Why minorities live longer on dialysis: an in-depth examination of the Danish nephrology registry. PMID- 26743179 TI - Surfactants for Bubble Removal against Buoyancy. AB - The common phenomenon of buoyancy-induced vapor bubble lift-off from a heated surface is of importance to many areas of science and technology. In the absence of buoyancy in zero gravity of space, non-departing bubbles coalesce to form a big dry patch on the heated surface and heat transfer deteriorates despite the high latent heat of vaporization of water. The situation is worse on an inverted heater in earth gravity where both buoyancy and surface tension act upwards to oppose bubble removal. Here we report a robust passive technique which uses surfactants found in common soaps and detergents to avoid coalescence and remove bubbles downwards, away from an inverted heater. A force balance model is developed to demonstrate that the force of repulsion resulting from the interaction of surfactants adsorbed at the neighboring liquid-vapor interfaces of the thin liquid film contained between bubbles is strong enough to overcome buoyancy and surface tension. Bubble removal frequencies in excess of ten Hz resulted in more than twofold enhancement in heat transfer in comparison to pure water. We believe that this novel bubble removal mechanism opens up opportunities for designing boiling-based systems for space applications. PMID- 26743178 TI - Acute Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCIPP) Causes Hepatic Inflammation and Leads to Hepatotoxicity in Zebrafish. AB - Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) has been frequently detected in environmental media and has adverse health effect on wildlife and humans. It has been implicated to have hepatotoxicity, but its molecular mechanisms remain unclear. In the present study, adult male zebrafish were exposed to TDCIPP and global hepatic gene expression was examined by RNA-Seq and RT-qPCR in order to understand the molecular mechanisms of TDCIPP-induced hepatotoxicity. Our results indicated that TDCIPP exposure significantly up-regulated the expression of genes involved in endoplasmic reticulum stress and Toll-like receptor (TLR) pathway, implying an inflammatory response, which was supported by up-regulation of inflammation-related biomaker genes. Hepatic inflammation was further confirmed by histological observation of increase of infiltrated neutrophils and direct observation of liver recruitment of neutrophils labeled with Ds-Red fluorescent protein of Tg(lysC:DsRed) zebrafish upon TDCIPP exposure. To further characterize the hepatotoxicity of TDCIPP, the expression of hepatotoxicity biomarker genes, liver histopathology and morphology were examined. The exposure to TDCIPP significantly up-regulated the expression of several biomarker genes for hepatotoxicity (gck, gsr and nqo1) and caused hepatic vacuolization and apoptosis as well as increase of the liver size. Collectively, our results suggest that exposure to TDCIPP induces hepatic inflammation and leads to hepatotoxicity in zebrafish. PMID- 26743181 TI - Theoretical basis for and improvement of Daugirdas' second generation formula for single-pool Kt/V. AB - PURPOSE: An empirically-derived equation to estimate hemodialysis treatment variable-volume single-pool Kt/V, where Kt/V = -In(R-GFAC * t) + (4-3.5 * R) * UFV/W, was published in 1993 (1) and quickly became a standard tool for the estimation of dialysis dose. We aim to find a theoretical basis for this equation. METHODS: A mathematical derivation is used to find the connection between Kt/V and modeled urea concentrations. RESULTS: There is a theoretical basis for the empirical structure of the estimating equation, but the estimation of the effect of ultrafiltration on Kt/V can be improved. Finally, we show that the accuracy of the formula may be suboptimal for some extreme dialysis schedules and propose a new equation that is more robust across atypical dialysis prescriptions. CONCLUSIONS: The currently used Kt/V estimating equation has a sound theoretical basis and an improved version is proposed that can maintain accuracy with a broader range of fluid removal. PMID- 26743182 TI - The Role of Interference and Inhibition Processes in Dysphoric Early Adolescents. AB - Cognitive theories emphasize the importance of attentional biases in the development and maintenance of depression. Noteworthy, recent studies indicate that depression-related biases only occur in later stages of attentional processing. This is consistent with the idea that attention is a multicomponent process, consisting of at least two mechanisms: selection and inhibition. Therefore, this study aims to investigate interference and inhibition toward angry and happy stimuli in dysphoric adolescents compared to nondysphoric adolescents. To examine interference and inhibition of emotional information in 21 dysphoric (17 girls) and 28 nondysphoric adolescents (17 girls), 10-16 years of age, a Negative Affective Priming task was used. In this task, a target has to be evaluated as positive or negative while ignoring a distractor. As expected, dysphoric adolescents showed both higher interference from and higher inhibition of angry stimuli relative to nondysphoric adolescents. In contrast, happy stimuli did not lead to interference and consequently did not have to be inhibited in either group. Finally, a positive relation was found between interference and the subsequent inhibition of emotional stimuli. These observations confirm the existence of a bias toward angry faces in dysphoric adolescents and indicate a higher inhibition of angry faces in dysphoric adolescents compared to nondysphoric adolescents. The obtained results are different from those of similar previous studies in depressed or dysphoric adults using sad faces or negatively valenced words and might reveal important emotion-specific or age specific inhibitory biases. PMID- 26743183 TI - Nanostructured Ternary FeCrAl Oxide Photocathodes for Water Photoelectrolysis. AB - A sol-gel method for the synthesis of semiconducting FeCrAl oxide photocathodes for solar-driven hydrogen production was developed and applied for the production of meso- and macroporous layers with the overall stoichiometry Fe0.84Cr1.0Al0.16O3. Using transmission electron microscopy and energy-dispersive X-ray spectroscopy, phase separation into Fe- and Cr-rich phases was observed for both morphologies. Compared to prior work and to the mesoporous layer, the macroporous FeCrAl oxide photocathode had a significantly enhanced photoelectrolysis performance, even at a very early onset potential of 1.1 V vs RHE. By optimizing the macroporous electrodes, the device reached current densities of up to 0.68 mA cm(-2) at 0.5 V vs RHE under AM 1.5 with an incident photon-to-current efficiency (IPCE) of 28% at 400 nm without the use of catalysts. Based on transient measurements, this performance increase could be attributed to an improved collection efficiency. At a potential of 0.75 V vs RHE, an electron transfer efficiency of 48.5% was determined. PMID- 26743180 TI - The tumor microenvironment: An irreplaceable element of tumor budding and epithelial-mesenchymal transition-mediated cancer metastasis. AB - Tumor budding occurs at the invasive front of cancer; the tumor cells involved have metastatic and stemness features, indicating a poor prognosis. Tumor budding is partly responsible for cancer metastasis, and its initiation is based on the epithelial-mesenchymal transition (EMT) process. The EMT process involves the conversion of epithelial cells into migratory and invasive cells, and is a profound event in tumorigenesis. The EMT, associated with the formation of cancer stem cells (CSCs) and resistance to therapy, results from a combination of gene mutation, epigenetic regulation, and microenvironmental control. Tumor budding can be taken to represent the EMT in vivo. The EMT process is under the influence of the tumor microenvironment as well as tumor cells themselves. Here, we demonstrate that the tumor microenvironment dominates EMT development and impacts cancer metastasis, as well as promotes CSC formation and mediates drug resistance. In this review, we mainly discuss components of the microenvironment, such as the extracellular matrix (ECM), inflammatory cytokines, metabolic products, and hypoxia, that are involved in and impact on the acquisition of tumor-cell motility and dissemination, the EMT, metastatic tumor-cell formation, tumor budding and CSCs, and cancer metastasis, including subsequent chemo resistance. From our point of view, the tumor microenvironment now constitutes a promising target for cancer therapy. PMID- 26743184 TI - Three-dimensional controlled growth of monodisperse sub-50 nm heterogeneous nanocrystals. AB - The ultimate frontier in nanomaterials engineering is to realize their composition control with atomic scale precision to enable fabrication of nanoparticles with desirable size, shape and surface properties. Such control becomes even more useful when growing hybrid nanocrystals designed to integrate multiple functionalities. Here we report achieving such degree of control in a family of rare-earth-doped nanomaterials. We experimentally verify the co existence and different roles of oleate anions (OA(-)) and molecules (OAH) in the crystal formation. We identify that the control over the ratio of OA(-) to OAH can be used to directionally inhibit, promote or etch the crystallographic facets of the nanoparticles. This control enables selective grafting of shells with complex morphologies grown over nanocrystal cores, thus allowing the fabrication of a diverse library of monodisperse sub-50 nm nanoparticles. With such programmable additive and subtractive engineering a variety of three-dimensional shapes can be implemented using a bottom-up scalable approach. PMID- 26743185 TI - Complicated uveitis in late onset juvenile idiopathic psoriatic arthritis. AB - CASE REPORT: A 6 year-old girl with juvenile psoriatic arthritis (JPsA) and bilateral complicated anterior uveitis developed several ocular complications that required 5 surgical procedures. Despite the aggressive course of ocular inflammation, her visual acuity remained good. Arthritis (main criterion for the diagnosis of JPsA) appeared years after ocular involvement. She showed a good anti-tumour necrosis factor initial response. DISCUSSION: The definitive diagnosis of JPsA was established years after the onset of symptoms. In addition, the patient maintained a good visual acuity, despite its complicated disease course. Finally, she showed a good clinical response to adalimumab. PMID- 26743186 TI - Contact topical anesthesia versus general anaesthesia in strabismus surgery. AB - OBJECTIVE: To evaluate the anesthetic block provided by contact topical anesthesia (CTA) in strabismus surgery in adult patients. To analyze postoperative pain and surgical outcome obtained by CTA compared with general anesthesia (GA). METHODOLOGY: Prospective longitudinal cohort study of adult patients undergoing strabismus surgery by CTA or GA. The intensity of pain perceived by patients during the course of surgery and in the postoperative period was measured using Numerical Pain Scale. The success of the surgical outcome, considered as a residual ocular deviation<10 prism diopters, was evaluated. RESULTS: Twenty-three patients were operated using CTA and 26 using AG. During the course of surgery, pain intensity experienced by patients in ATC group was 3.17+/-2.44. There were no differences between CTA group and AG group in the intensity of pain in the immediate postoperative period (2.13+/-2.39 vs. 2.77+/-2.18, respectively; P=.510) and during the first postoperative day (3.22+/ 2.84 vs. 3.17+/-2.73; P=.923). Surgical success was significantly higher in the CTA group than in the GA group (78.3 vs. 73.1%; P=.019). CONCLUSIONS: CTA provides adequate sensory block to perform strabismus surgery. The control of postoperative pain is similar to that obtained with AG. Conservation of ocular motility providing CTA enables better surgical outcome. PMID- 26743187 TI - Clostridium difficile associated reactive arthritis: Case report and literature review. AB - INTRODUCTION: Extra-gastro-intestinal tract manifestations associated with Clostridium difficile infection (CDI), including reactive arthritis (ReA), are uncommon. METHOD: We report a case of ReA associated with a relapse of CDI in a 46-year-old woman. A toxigenic C. difficile strain was isolated from stools and characterized as PCR-ribotype 014/020/077. We conducted a comprehensive literature review of ReA associated with CDI (ReA-CDI). Diagnostic criteria for ReA-CDI were: (i) evidence of aseptic synovitis (confirmed by culture) developing during or immediately after colitis, (ii) presence of a toxigenic C. difficile strain in stool samples, and (iii) absence of other causes of colitis and arthritis. RESULTS: Forty-nine cases of ReA-CDI (excluding the present report) have already been described since 1976. Of these reports, Mean age of patients was 38 years (SD: 18.5), 46% were male, and 68% had HLA B27 genotype. Sixty-nine percent of patients received a beta-lactamin treatment before CDI. ReA-CDI occurred a median 10 days (range 0-55 days) after CDI. Outcome was favorable in 90% of patients and oral non anti-inflammatory drugs were required for 55%. CONCLUSION: ReA-CDI remains uncommon. Compared to the general population, it is more likely observed in younger patients with HLA B27-positive genotype. PMID- 26743190 TI - Editorial: A Look Back at 2015: Hope, Hype and Hypocrisy. PMID- 26743189 TI - Introduction and prolonged circulation of G12 rotaviruses in Sicily. AB - Genotype G12 strains are now considered to be the sixth most prevalent human rotaviruses worldwide. In two Sicilian cities, Palermo and Messina, surveillance of rotavirus circulation performed since 1985 and 2009, respectively, did not detect G12 strains until 2012. From 2012 to 2014 rotavirus infection was detected in 29.7% of 1647 stool samples collected from children admitted for acute gastroenteritis to three Sicilian hospitals in Palermo, Messina and Ragusa. In 2012, G12P[8] was first detected in Palermo and then in Messina where it represented the second most frequent genotype (20% prevalence) after G1P[8]. Thereafter, G12 strains continued to circulate in Sicily, showing a marked prevalence in Ragusa (27.8%) in 2013 and in Palermo (21%) and Messina (16.6%) in 2014. All but one of the Sicilian G12 strains carried a P[8] VP4 genotype, whereas the single non-P[8] rotavirus strain was genotyped as G12P[9]. Phylogenetic analysis of the VP7 and VP4 sequences allowed distinction of several genetic lineages and separation of the G12P[8] strains into three cluster combinations. These findings indicate independent introductions of G12 rotavirus strains in Sicily in recent years. PMID- 26743188 TI - Identification and immunogenicity of microneme protein 2 (EbMIC2) of Eimeria brunetti. AB - There have been only a few antigen genes of Eimeria brunetti reported up to now. In this study, the gene encoding the microneme protein 2 (EbMIC2) was isolated from oocysts of E. brunetti by RT-PCR and the immunogenicity of recombinant EbMIC2 was observed. The EbMIC2 was cloned into vector pMD19-T for sequencing. The sequence was compared with the published EbMIC2 gene from GenBank revealed homology of the nucleotide sequence and amino acids sequence were 99.43 and 98.63%, respectively. The correct recombinant pMD-EbMIC2 plasmid was inserted into the pET-28a (+) expressing vector and transformed into competent Escherichia coli BL21 cells for expression. The expressed product was analyzed using SDS-PAGE and Western-blot. The results indicated that the recombinant EbMIC2 protein was recognized strongly by serum from naturally infected chicken with E. brunetti. Rat rcEbMIC2 antisera bound to bands of about 36 kDa in the somatic extract of E. brunetti sporozoites. The recombinant plasmid pVAX1-EbMIC2 was constructed and then the efficacies of recombinant plasmid and recombinant protein were evaluated. The results of IgG antibody level and cytokines concentration suggested that recombinant EbMIC2 could increase the IgG antibody level and induce the expressions of cytokines. Animal challenge experiments demonstrated that the recombinant EbMIC2 protein and recombinant plasmid pVAX1-EbMIC2 could significantly increase the average body weight gains, decrease the mean lesion scores and the oocyst outputs of the immunized chickens and presented high anti coccidial index. All results suggested that EbMIC2 could become an effective candidate for the development of new vaccine against E. brunetti infection. PMID- 26743193 TI - The extracellular matrix in breast cancer. AB - The extracellular matrix (ECM) is increasingly recognized as an important regulator in breast cancer. ECM in breast cancer development features numerous changes in composition and organization when compared to the mammary gland under homeostasis. Matrix proteins that are induced in breast cancer include fibrillar collagens, fibronectin, specific laminins and proteoglycans as well as matricellular proteins. Growing evidence suggests that many of these induced ECM proteins play a major functional role in breast cancer progression and metastasis. A number of the induced ECM proteins have moreover been shown to be essential components of metastatic niches, promoting stem/progenitor signaling pathways and metastatic growth. ECM remodeling enzymes are also markedly increased, leading to major changes in the matrix structure and biomechanical properties. Importantly, several ECM components and ECM remodeling enzymes are specifically induced in breast cancer or during tissue regeneration while healthy tissues under homeostasis express exceedingly low levels. This may indicate that ECM and ECM-associated functions may represent promising drug targets against breast cancer, providing important specificity that could be utilized when developing therapies. PMID- 26743192 TI - Evaluation of a von Willebrand factor three test panel and chemiluminescent-based assay system for identification of, and therapy monitoring in, von Willebrand disease. AB - von Willebrand disease (VWD) is reportedly the most common bleeding disorder and arises from deficiency and/or defects of von Willebrand factor (VWF). Laboratory diagnosis and typing of VWD has important management implications and requires a wide range of tests, including VWF antigen (VWF:Ag) and various activities, involving differential identification of qualitative vs quantitative VWF defects. We have assessed a new hemostasis instrument, the chemiluminescent assay based ACL AcuStarTM, and an associated HemosIL AcuStar three test panel comprising VWF:Ag, VWF ristocetin cofactor (VWF:RCo) and VWF collagen binding (VWF:CB) (Instrumentation Laboratory, Bedford, Ma. USA) for ability to identify VWD, to help provisionally type VWD, and for potential use in therapy monitoring. This test system was compared to previously evaluated and validated test systems including VWF:RCo on CS-5100 and BCS analyzers, the new Siemens INNOVANCE assay (VWF Ac) on CS-5100, and VWF:Ag and VWF:CB assays performed by automated ELISA. We employed a large total sample test set (n=535) comprising plasma and platelet lysate samples from individuals with and without VWD, some on treatment, normal plasmas, and normal and pathological controls. We also evaluated desmopressin (DDAVP) responsiveness, plus differential sensitivity to reduction in high molecular weight (HMW) VWF. The chemiluminescent test panel (VWF:Ag, VWF:RCo, VWF:CB) showed good comparability to similar assays performed by alternate methods, and broadly similar data for identification of VWD, provisional VWD type identification, DDAVP and VWD therapy, and HMW VWF sensitivity, although some notable differences were evident. The chemiluminescent system showed best low level VWF sensitivity, and lowest inter-assay variability, compared to all other systems. In conclusion, we have validated theACL AcuStar and the chemiluminescent HemosIL AcuStar VWF test panel for use in VWD diagnostics, and have identified some favorable characteristics that may improve the future diagnosis of VWD. PMID- 26743191 TI - Muscular Dysfunction in COPD: Systemic Effect or Deconditioning? AB - BACKGROUND: Muscular dysfunction has been described as one of the systemic manifestations of chronic obstructive pulmonary disease (COPD). OBJECTIVE: The aim of this study was to evaluate muscular strength of the different anatomical compartments in patients with severe COPD compared with healthy controls. METHOD: We performed a cross-sectional study in patients with severe COPD. We evaluated the muscular strength of the respiratory muscles, flexors and extensors of the cervical spine and knee, as well as handgrip force. The 6-min walking test (6MWT) and serum inflammatory markers were also analysed. RESULTS: Twenty-eight male patients with COPD (mean age 67.8 years, mean FEV1 (%) 39 %) and 24 male healthy controls (mean age 70.2 years) were studied. The strength of the flexors and extensors of the knee was significantly reduced in patients with COPD (p < 0.001 and p = 0.003). No differences were observed in the flexors and extensors of the cervical spine and handgrip force between groups. No correlation was observed between the muscular strength in the different anatomic compartments and the concentrations of blood inflammatory biomarkers or the metres walked in the 6MWT in COPD patients. However, a significant negative linear correlation was observed between the 6MWT and IL-6 and IL-8 levels (rho = -0.67, p = 0.001; rho = -0.57, p = 0.008). In addition, we found a negative correlation between the 6MWT and inspiratory capacity (rho = -0.755, p = 0.031). CONCLUSIONS: Our results suggest that muscular dysfunction in patients with COPD differs in different muscular compartments. The main factor for a reduced exercise capacity was a reduction in inspiratory capacity. PMID- 26743194 TI - Taxonomy, affinities, and paleobiology of the tiny metatherian mammal Minusculodelphis, from the early Eocene of South America. AB - With less than 3 g of estimated body mass, the early Eocene Minusculodelphis minimus Paula Couto (Mammalia, Metatheria, Jaskhadelphyidae) is one of the smallest mammals, living or extinct. It has alternatively been regarded as a didelphid or a derorhynchid "ameridelphian," or even as an eometatherian marsupial. Here, we describe a new species of Minusculodelphis coming from the same locality (Itaborai Quarry, Brazil) and age (Itaboraian age) of the type species of the genus. It differs from M. minimus in its larger size and several dental characters. The new species offers data on the upper dentition and femur, which are unknown in the type species. Compared to other Paleogene metatherians, Minusculodelphis shows closer relationships with Jaskhadelphys, from the early Paleocene of Tiupampa, Bolivia, as well as with Kiruwamaq, from the late Eocene early Oligocene of Peru. A cladistic analysis places all three genera within the family Jaskhadelphyidae (Metatheria, Order indet.), which includes small to tiny, insectivorous-like metatherians. We argue that insectivory (soft insects) is the best-supported diet for both species of Minusculodelphis, and that the most probable microhabitat for them was the understorey or leaf litter of tropical, rain forested environments. PMID- 26743196 TI - Erratum to: Manipulability agreement as a predictor of action initiation latency. PMID- 26743195 TI - CATOS (Computer Aided Training/Observing System): Automating animal observation and training. AB - In animal behavioral biology, an automated observing/training system may be useful for several reasons: (a) continuous observation of animals for documentation of specific, irregular events, (b) long-term intensive training of animals in preparation for behavioral experiments, (c) elimination of potential cues and biases induced by humans during training and testing. Here, we describe an open-source-based system named CATOS (Computer Aided Training/Observing System) developed for such situations. There are several notable features in this system. CATOS is flexible and low cost because it is based on free open-source software libraries, common hardware parts, and open-system electronics based on Arduino. Automated video condensation is applied, leading to significantly reduced video data storage compared to the total active hours of the system. A data-viewing utility program helps a user browse recorded data quickly and more efficiently. With these features, CATOS has the potential to be applied to many different animal species in various environments such as laboratories, zoos, or even private homes. Also, an animal's free access to the device without constraint, and a gamified learning process, enhance the animal's welfare and enriches their environment. As a proof of concept, the system was built and tested with two different species. Initially, the system was tested for approximately 10 months with a domesticated cat. The cat was successfully and fully automatically trained to discriminate three different spoken words. Then, in order to test the system's adaptability to other species and hardware components, we used it to train a laboratory rat for 3 weeks. PMID- 26743197 TI - Database of synesthetic color associations for Japanese kanji. AB - Synesthesia is a neurological phenomenon in which certain types of stimuli elicit involuntary perceptions in an unrelated pathway. A common type of synesthesia is grapheme-color synesthesia, in which the visual perception of letters and numbers stimulates the perception of a specific color. Previous studies have often collected relatively small numbers of grapheme-color associations per synesthete, but the accumulation of a large quantity of data has greater promise for uncovering the mechanisms underlying synesthetic association. In this study, we therefore collected large samples of data from a total of eight synesthetes. All told, we obtained over 1000 synesthetic colors associated with Japanese kanji characters from each of two synesthetes, over 100 synesthetic colors form each of three synesthetes, and about 80 synesthetic colors associated with Japanese hiragana, Latin letters, and Arabic numerals from each of three synesthetes. We then compiled the data into a database, called the KANJI-Synesthetic Colors Database (K-SCD), which has a total of 5122 colors for 483, 46, and 46 Japanese kanji, hiragana, and katakana characters, respectively, as well as for 26 Latin letters and ten Arabic numerals. In addition to introducing the K-SCD, this article demonstrates the database's merits by using two examples, in which two new rules for synesthetic association, "shape similarity" and "synesthetic color clustering," were found. The K-SCD is publicly accessible ( www.cv.jinkan.kyoto u.ac.jp/site/uploads/K-SCD.xlsm ) and will be a valuable resource for those who wish to conduct statistical analyses using a rich dataset in order to uncover the rules governing synesthetic association and to understand its mechanisms. PMID- 26743198 TI - Urinary Phthalate Metabolites in American Alligators (Alligator mississippiensis) from Selected Florida Wetlands. AB - Phthalates have been shown to cause endocrine disruption in laboratory animals and are associated with altered development of the reproductive system in humans. Further, human have significant exposure to phthalates. However, little is known concerning the exposure of wildlife to phthalates. We report urinary phthalate metabolite concentrations from fifty juvenile alligators from three Florida lakes and a site in the Everglades. Urinary phthalate monoester concentrations varied widely among alligators from the different sites but also among alligators from the same site. Mono-2-ethylhexy phthalate and monobutyl phthalate were found in most samples of alligator urine with maximums of 35,700 ng/mL and 193 ng/mL, respectively. Monobenzyl phthalate was found in 5 alligators with a maximum of 66.7 ng/mL. Other monoesters were found in only one or two alligator urine samples. The wide variation within and among sites, in addition to the high levels of mEHP, mBP and mBzP, is consistent with exposure arising from the intermittent spraying of herbicide formulations to control invasive aquatic plants in Florida freshwater sites. Phthalate diesters are used as adjuvants in many of these formulations. PMID- 26743199 TI - Strong Acid Mixture and Sequential Geochemical Arsenic Extractions in Surface Sediments from the Santa Maria La Reforma Coastal Lagoon, Mexico: A Bioavailability Assessment. AB - Thirty-three sediment samples were collected from the Santa Maria La Reforma coastal lagoon and digested by way of a strong acid mixture and sequential arsenic (As)-extraction method to determine the arsenic (As) content and bioavailability. The As content was determined by atomic fluorescence spectrometry. In addition, grain-size analyses were performed, and organic carbon, carbonate, and iron (Fe) and manganese (Mn) concentrations were determined. Fe and Mn determination was performed by atomic absorption spectroscopy. A Pearson correlation matrix and As enrichment factors were calculated. Sediment concentrations from Santa Maria La Reforma ranged from 3.6 to 25 ug As g(-1) with an average of 13.4 +/- 7.6 ug As g(-1). The highest values were observed in the northern (Playa Colorada), north-central (Mocorito River discharge zone), and southern zones ("El Tule" agricultural drain). Most samples were classified as exhibiting no or minor As enrichment and were lower than the threshold effect level (TEL; 7.24 ug g(-1)) for biota (MacDonald et al. in Ecotoxicology 5:253-278, 1996). Low bioavailable As values (<3 %) were measured in the majority of the sediment. The highest As percentages were associated with the oxyhydroxide fraction (F5). The results indicate that As bioavailability is negligible. PMID- 26743200 TI - Infectious Considerations in the Pre-Transplant Evaluation of Cirrhotic Patients Awaiting Orthotopic Liver Transplantation. AB - The incidence of end-stage liver disease (ESLD) is increasing and many of these patients may be considered for orthotopic liver transplantation. As patients with ESLD are at risk of a number of infections, infectious disease physicians should be aware of the management of these infections in order to provide optimal patient care and ensure transplantation success. We present a review of the literature pertaining to infectious disease considerations in the liver transplant candidate. It highlights several topics with recent developments including the management of hepatitis C virus infection prior to transplantation, treatment of hepatitis B virus infection, colonization and infection with multidrug resistant organisms, and management of spontaneous bacterial peritonitis. PMID- 26743201 TI - Cytomegalovirus Infection in Pediatric Solid Organ Transplant Recipients: a Focus on Prevention. AB - Solid organ transplantation is a life-saving procedure that has changed the prognosis for infants and children with end-stage organ disease. Cytomegalovirus (CMV) is one of the most common infections that occur after organ transplantation in pediatric patients, yet the standard of care for CMV prevention remains unclear. We review the literature regarding CMV disease effects, risk factors, diagnostics, prevention strategies, and antiviral treatment in pediatric solid organ transplantation. This discussion focuses on the current prevention strategies: prophylaxis, preemptive, and hybrid therapy, as well as novel strategies that may help better prevent the CMV disease in the pediatric solid organ transplant population. PMID- 26743203 TI - Chemical shift assignments of calmodulin constructs with EF hand mutations. AB - Calmodulin (CaM) is a ubiquitous cytosolic Ca(2+)-binding protein able to bind and regulate hundreds of different proteins. It consists of two globular domains joined by a flexible central linker region. Each one of these domains contains two EF hand pairs capable of binding to Ca(2+). Upon Ca(2+) binding CaM undergoes a conformational change exposing hydrophobic patches that interact with its intracellular target proteins. CaM is able to bind to target proteins in the Ca(2+)-replete and Ca(2+)-deplete forms. To study the Ca(2+) dependent/independent properties of binding and activation of target proteins by CaM, CaM constructs with Ca(2+) binding disrupting mutations of Asp to Ala at position one of each EF hand have been used. One target protein of CaM is nitric oxide synthase, which catalyzes the production of nitric oxide. At elevated Ca(2+) concentrations, CaM binds to neuronal NOS and endothelial NOS, making them the Ca(2+)-dependent NOS enzymes. In contrast, inducible NOS is transcriptionally regulated in vivo and binds to CaM at basal levels of Ca(2+). Here we report the NMR backbone and sidechain resonance assignments of C-lobe Ca(2+)-replete and deplete CaM12, N-lobe Ca(2+)-replete and deplete CaM34, CaM1234 in the absence of Ca(2+) and N-lobe Ca(2+)-replete CaM34 with the iNOS CaM-binding domain peptide. PMID- 26743202 TI - Identifying when choice helps: clarifying the relationships between choice making, self-construal, and pain. AB - Prior research indicates that making choices before a painful task can sometimes reduce pain. We examined the possibility that independent and interdependent self construals moderate the effect of choice on pain. Further, we tested between two types of choice: instrumental and non-instrumental. Healthy normotensive undergraduates were randomly assigned to one of three conditions prior to the cold pressor task. Participants in an instrumental choice condition selected which hand to immerse in the water and were told this choice might help reduce their pain. Non-instrumental choice participants selected which hand to immerse but were given no information about potential pain reduction. Control participants were given no choice or additional instructions. Low interdependence individuals reported less pain than high interdependence individuals-but only when given an instrumental choice. These data indicate that not all forms of choice reduce pain and not all individuals benefit from choice. Instead, individuals low in interdependence exhibit pain relief from instrumental choices. PMID- 26743206 TI - Hexose-derived glycation sites in processed bovine milk. AB - Milk products are consumed by many people on a daily basis, which demands sophisticated technical processes to guarantee the microbiological safety and to retain the nutritional value. The heating during pasteurization and ultra high temperature (UHT) treatment triggers diverse chemical reactions, such as the reaction of sugars and amino groups of proteins typically termed protein glycation. The glycation by lactose as dominant sugar in milk has been recently investigated, whereas the contribution of hexoses remains open. We identified first hexose-derived glycation sites in raw milk, colostrum, three brands of pasteurized milk, three brands of UHT milk, five brands of infant formula, and one brand of lactose-free pasteurized and UHT milk using tandem mass spectrometry and electron transfer dissociation. In total, we could identify 124 hexosylated tryptic peptides in a bottom-up proteomics approach after enriching glycated peptides by boronate affinity chromatography, which corresponded to 86 glycation sites in 17 bovine milk proteins. In quantitative terms glycation increased from raw milk to pasteurized milk to UHT milk and infant formula. Lactose-free milk contained significantly higher hexosylation degrees than the corresponding regular milk product. Interestingly, the glycation degrees varied considerably among different brands with lactose-free UHT milk and infant formula showing the highest levels. BIOLOGICAL SIGNIFICANCE: The established proteomics strategy enables the identification and relative quantification of different protein glycation types in diverse milk products ranging from raw milk to milk powders. This will allow detailed in vitro studies to judge positive or negative aspects when consuming differently processed milk products including lactose-free milk that is obligatory for people with lactose intolerance but is increasingly consumed by the general population assuming health benefits. The established analytics will also permit studying the influence of each technical processing step on the glycation degrees and thus offers the possibility to reduce glycation early during production, as obvious from the variation among different brands. Special attention should be given to the high hexose- and lactose-derived glycation levels found in infant formula, although it is still controversially discussed if protein glycation has a negative biological impact. PMID- 26743205 TI - [Activity involvement and extraversion as predictors of psychological wellbeing in older people]. AB - INTRODUCTION: The relationship between extraversion and wellbeing has been discussed in the literature, however, the impact that this trait has on the wellbeing of older people has been studied to a lesser extent. The relationship between extraversion, participation in activities and psychological wellbeing in older people is analysed in this study. MATERIAL AND METHODS: The sample comprised 139 individuals over 55 years from rural and urban areas of the province of Granada who completed the extraversion subscale of the NEO-FFI and the Ryff Scales of the Psychological Wellbeing, as well as responding to questions that evaluated their social participation. RESULTS: A greater social participation was found in rural areas and among women. The activities more frequently performed by the participants were educational and religious activities, walking, everyday chores, crafts, and home improvements. A low positive correlation between extraversion and wellbeing was observed. The multiple regression analysis revealed that extraversion explained 19.9% of the variance in psychological wellbeing, which increased to 25.3% when social participation, gender, and the origin of the sample were considered. CONCLUSIONS: Psychological wellbeing appears to be associated with personality traits, such as extraversion. In addition this personality trait is linked to the number and type of activities the elderly perform which also contributes to wellbeing in old age. PMID- 26743207 TI - Human sinoatrial node structure: 3D microanatomy of sinoatrial conduction pathways. AB - INTRODUCTION: Despite a century of extensive study on the human sinoatrial node (SAN), the structure-to-function features of specialized SAN conduction pathways (SACP) are still unknown and debated. We report a new method for direct analysis of the SAN microstructure in optically-mapped human hearts with and without clinical history of SAN dysfunction. METHODS: Two explanted donor human hearts were coronary-perfused and optically-mapped. Structural analyses of histological sections parallel to epicardium (~13-21 MUm intervals) were integrated with optical maps to create 3D computational reconstructions of the SAN complex. High resolution fiber fields were obtained using 3D Eigen-analysis of the structure tensor, and used to analyze SACP microstructure with a fiber-tracking approach. RESULTS: Optical mapping revealed normal SAN activation of the atria through a lateral SACP proximal to the crista terminalis in Heart #1 but persistent SAN exit block in diseased Heart #2. 3D structural analysis displayed a functionally observed SAN border composed of fibrosis, fat, and/or discontinuous fibers between SAN and atria, which was only crossed by several branching myofiber tracts in SACP regions. Computational 3D fiber-tracking revealed that myofiber tracts of SACPs created continuous connections between SAN #1 and atria, but in SAN #2, SACP region myofiber tracts were discontinuous due to fibrosis and fat. CONCLUSIONS: We developed a new integrative functional, structural and computational approach that allowed for the resolution of the specialized 3D microstructure of human SACPs for the first time. Application of this integrated approach will shed new light on the role of the specialized SAN microanatomy in maintaining sinus rhythm. PMID- 26743208 TI - Conformational changes of an ion-channel during gating and emerging electrophysiologic properties: Application of a computational approach to cardiac Kv7.1. AB - Ion channels are the "building blocks" of the excitation process in excitable tissues. Despite advances in determining their molecular structure, understanding the relationship between channel protein structure and electrical excitation remains a challenge. The Kv7.1 potassium channel is an important determinant of the cardiac action potential and its adaptation to rate changes. It is subject to beta adrenergic regulation, and many mutations in the channel protein are associated with the arrhythmic long QT syndrome. In this theoretical study, we use a novel computational approach to simulate the conformational changes that Kv7.1 undergoes during activation gating and compute the resulting electrophysiologic function in terms of single-channel and macroscopic currents. We generated all possible conformations of the S4-S5 linker that couples the S3 S4 complex (voltage sensor domain, VSD) to the pore, and all associated conformations of VSD and the pore (S6). Analysis of these conformations revealed that VSD-to-pore mechanical coupling during activation gating involves outward translation of the voltage sensor, accompanied by a translation away from the pore and clockwise twist. These motions cause pore opening by moving the S4-S5 linker upward and away from the pore, providing space for the S6 tails to move away from each other. Single channel records, computed from the simulated motion trajectories during gating, have stochastic properties similar to experimentally recorded traces. Macroscopic current through an ensemble of channels displays two key properties of Kv7.1: an initial delay of activation and fast inactivation. The simulations suggest a molecular mechanism for fast inactivation; a large twist of the VSD following its outward translation results in movement of the base of the S4-S5 linker toward the pore, eliminating open pore conformations to cause inactivation. PMID- 26743210 TI - Sarcopenia and cachexia in the era of obesity: clinical and nutritional impact. AB - Our understanding of body composition (BC) variability in contemporary populations has significantly increased with the use of imaging techniques. Abnormal BC such as sarcopenia (low muscle mass) and obesity (excess adipose tissue) are predictors of poorer prognosis in a variety of conditions or clinical situations. As a catabolic illness, a defining feature of cancer is muscle loss. Although the conceptual model of wasting in cancer is typically conceived as involuntary weight loss leading to low body weight, recent studies have shown that both sarcopenia and cachexia can be present with obesity. The combination of low muscle and high adipose tissue (sarcopenic obesity) is an emerging abnormal BC phenotype prevalent across the body weight, and hence BMI spectra. Sarcopenia and sarcopenic obesity in cancer are in most instances occult conditions, which have been independently associated with higher incidence of chemotherapy toxicity, shorter time to tumour progression, poorer outcomes of surgery, physical impairment and shorter survival. Although the mechanisms are yet to be fully understood, the associations with poorer clinical outcomes emphasise the value of nutritional assessment as well as the need to develop appropriate interventions to countermeasure abnormal BC. Sarcopenia and sarcopenic obesity create diverse nutritional requirements, highlighting the compelling need for a more comprehensive and differentiated understanding of energy and protein requirements in this heterogeneous population. PMID- 26743209 TI - Current understanding of metformin effect on the control of hyperglycemia in diabetes. AB - Metformin is a first-line oral anti-diabetic agent that has been used clinically to treat patients with type 2 diabetes for over 60 years. Due to its efficacy in therapy and affordable price, metformin is taken by more than 150 million people each year. Metformin improves hyperglycemia mainly through the suppression of hepatic gluconeogenesis along with the improvement of insulin signaling. However, its mechanism of action remains partially understood and controversial, especially in regard to the role of AMPK in metformin's action and the mechanism of AMPK activation. In this review, we discuss recent advances in the understanding of metformin's suppression of hepatic glucose production and the mechanism related to the improvement of insulin signaling. PMID- 26743211 TI - Effects of carbazole-degradative plasmid pCAR1 on biofilm morphology in Pseudomonas putida KT2440. AB - Bacteria typically form biofilms under natural conditions. To elucidate the effect of the carriage of carbazole-degradative plasmid pCAR1 on biofilm formation by host bacteria, we compared the biofilm morphology, using confocal laser scanning microscopy, of three pCAR1-free and pCAR1-carrying Pseudomonas hosts: P. putida KT2440, P. aeruginosa PAO1 and P. fluorescens Pf0-1. Although pCAR1 did not significantly affect biofilm formation by PAO1 or Pf0-1, pCAR1 carrying KT2440 became filamentous and formed flat biofilms, whereas pCAR1-free KT2440 formed mushroom-like biofilms. pCAR1 contains three genes encoding nucleoid-associated proteins (NAPs), namely, Pmr, Pnd and Phu. The enhanced filamentous morphology was observed in two double mutants [KT2440(pCAR1DeltapmrDeltapnd) and KT2440(pCAR1DeltapmrDeltaphu)], suggesting that these NAPs are involved in modulating the filamentous phenotype. Transcriptome analyses of the double mutants identified 32 candidate genes that may be involved in filamentation of KT2440. Overexpression of PP_2193 in KT2440 induced filamentation and overexpression of PP_0308 or PP_0309 in KT2440(pCAR1) enhanced filamentation of cells over time. This suggests that pCAR1 induces development of an abnormal filamentous morphology by KT2440 via a process involving overexpression of several genes, such as PP_2193. In addition, pCAR1 encoded NAPs partly suppress too much filamentation of KT2440(pCAR1) by repressing transcription of some genes, such as PP_0308 and PP_0309. PMID- 26743215 TI - Survival and Reproductive Strategies in Two-Spotted Spider Mites: Demographic Analysis of Arrhenotokous Parthenogenesis of Tetranychus urticae (Acari: Tetranychidae). AB - Tetranychus urticae Koch is a cosmopolitan pest whose rapid developmental rate enables it to produce colonies of thousands of individuals within a short time period. When a solitary virgin female colonizes a new host plant, it is capable of producing male offspring through the arrhenotokous parthenogenesis; once her sons mature, oedipal mating occurs and the female will produce bisexual offspring. To analyze the effect of arrhenotokous reproduction on population growth, we devised and compared separate life tables for arrhenotokous and bisexual populations of T. urticae using the age-stage, two-sex life table theory. For the cohort with bisexual reproduction, the intrinsic rate of increase (r), finite rate (lambda), net reproductive rate (R0), and mean generation time (T) were 0.2736 d(-1), 1.3146 d(-1), 44.66 offspring, and 13.89 d, respectively. Because only male eggs were produced during the first 8 d of the oviposition period and the cohort would soon begin bisexual reproduction, it would be theoretically wrong to calculate the population parameters using the survival rate and fecundity of an arrhenotokous cohort. We demonstrated that the effect of arrhenotokous reproduction could be accurately described and evaluated using the age-stage, two-sex life table. We also used population projection based on life table data, quantitatively showing the effect that arrhenotokous reproduction has on the growth potential and management of T. urticae. PMID- 26743216 TI - Postecdysis Sclerotization of Mouthparts of the Formosan Subterranean Termites (Isoptera: Rhinotermitidae). AB - In termites, it is challenging to recognize the incidence of molting in workers because of their successive stationary molt, asynchronous molting among individuals, cryptic behavior, a soft and poorly sclerotized cuticle, and they immediately consume the shed exuvia of nestmates. This study describes a method in which the degree of sclerotization of the mouthparts in newly molted workers of the Formosan subterranean termite can be quantified and used to determine if an individual has recently molted, within a 36-h time frame. Changes in the tanning of mouthparts over time were used as a measure of the index of sclerotization in workers postmolting. Upon ecdysis, the primary point of articulation of the mandible already initiated sclerotization, which may allow the movement of the mandibles during the shedding of the exuvium. The sclerotization of the secondary point of articulation and the mandibular teeth, and the width of sclerotization of the mandibles, progressively increased until reaching a plateau around 36-h postecdysis, which imply that workers can regain some level of activity as early as 2 d after ecdysis. Our observations allowed for the determination of variables for the sclerotization of the mouthparts to easily identify workers that recently molted, and this method will be useful in future studies that focus on the molting activity of workers over time and space within a termite colony, in the scope of improving current control strategies for termite pests. PMID- 26743212 TI - After Intracerebral Hemorrhage, Oligodendrocyte Precursors Proliferate and Differentiate Inside White-Matter Tracts in the Rat Striatum. AB - Damage to myelinated axons contributes to neurological deficits after acute CNS injury, including ischemic and hemorrhagic stroke. Potential treatments to promote re-myelination will require fully differentiated oligodendrocytes, but almost nothing is known about their fate following intracerebral hemorrhage (ICH). Using a rat model of ICH in the striatum, we quantified survival, proliferation, and differentiation of oligodendrocyte precursor cells (OPCs) (at 1, 3, 7, 14, and 28 days) in the peri-hematoma region, surrounding striatum, and contralateral striatum. In the peri-hematoma, the density of Olig2(+) cells increased dramatically over the first 7 days, and this coincided with disorganization and fragmentation of myelinated axon bundles. Very little proliferation (Ki67(+)) of Olig2(+) cells was seen in the anterior subventricular zone from 1 to 28 days. However, by 3 days, many were proliferating in the peri hematoma region, suggesting that local proliferation expands their population. By 14 days, the density of Olig2(+) cells declined in the peri-hematoma region, and, by 28 days, it reached the low level seen in the contralateral striatum. At these later times, many surviving axons were aligned into white-matter bundles, which appeared less swollen or fragmented. Oligodendrocyte cell maturation was prevalent over the 28-day period. Densities of immature OPCs (NG2(+)Olig2(+)) and mature (CC-1(+)Olig2(+)) oligodendrocytes in the peri-hematoma increased dramatically over the first week. Regardless of the maturation state, they increased preferentially inside the white-matter bundles. These results provide evidence that endogenous oligodendrocyte precursors proliferate and differentiate in the peri-hematoma region and have the potential to re-myelinate axon tracts after hemorrhagic stroke. PMID- 26743217 TI - Wood Preference of Reticulitermes virginicus (Blattodea: Rhinotermitidae) Using No-, Two-, and Four-Choice Designs and Seven Different Measures of Wood Consumption. AB - Three hundred Reticulitermes virginicus (Banks) workers were exposed to three 1 cm3 wood blocks of either Quercus sp. (Red Oak), Populus sp. (Poplar), Pinus sp. (Pine), or Sequoia sp. (Redwood) placed into one of the three bioassay designs (no-, two-, and four-choice) for 21 d. Termite wood consumption was measured by wood weight loss, resistance class, and visual rating. Wood consumption rates were determined using four formulas in addition to two standardized visual rating scales (American Society for Testing and Materials [ASTM] and American Wood Protection Association [AWPA]) and a preference ranking obtained for each measure. The wood consumption formula, rating scale, and preference rankings were compared by bioassay design. The overall preference ranking of the four wood types as determined by the combination of all three designs was-1) Pine, 2) Red Oak, 3) Redwood, and 4) Poplar. Results indicate that bioassay design influenced both wood consumption and preference rankings. A no-choice design can determine aversion; a four-choice design the most preferred wood; and a two-choice design can illuminate the fine details of comparative preference. The different formulas employed for calculation of consumption rate influenced preference ranking in the no- and four-choice designs but not the two-choice design. PMID- 26743213 TI - The IL-33 gene is related to increased susceptibility to systemic sclerosis. AB - Systemic sclerosis (SSc) is a chronic inflammatory disease characterized by widespread fibrosis of the skin and several visceral organs. The pro-fibrotic potential of interleukin (IL)-33 has been demonstrated by in both in vitro and in vivo settings; moreover, increased level of IL-33 has also been reported in patients with SSc. Therefore, the aim of the present study was to detect the potential association of IL-33 gene polymorphisms on the susceptibility of SSc. A total of 300 SSc patients and 280 healthy controls (HC) were enrolled in this multicentric preliminary candidate gene study. DNA samples were harvested using an appropriate commercial DNA isolation kit. Four single nucleotide polymorphisms (SNPs) of IL-33 gene (rs7044343, rs1157505, rs11792633 and rs1929992) were genotyped using the appropriate commercial primer/probe sets on real-time PCR. There was no significant difference in terms of the allelic distributions and minor allele frequencies of evaluated four IL-33 polymorphisms between the SSc and HC groups (P > 0.05 for all). Moreover, the genotypic distributions of rs1157505, rs11792633 and rs1929992 polymorphisms were not significantly different (P > 0.05 for all). However, CC genotype of rs7044343 SNP was significantly higher in the SSc group compared to the HC group (P = 0.013, OR 1.75, 95 % CI 1.12-2.72). This preliminary candidate gene study demonstrates that rs7044343 polymorphism of IL-33 gene is associated with the susceptibility to the SSc in Turkish population. It may be suggested that IL-33 gene may be a candidate gene to research in SSc. PMID- 26743218 TI - Acoustic Detection of Rhynchophorus ferrugineus (Coleoptera: Dryophthoridae) and Oryctes elegans (Coleoptera: Scarabaeidae) in Phoenix dactylifera (Arecales: Arecacae) Trees and Offshoots in Saudi Arabian Orchards. AB - Rhynchophorus ferrugineus (Olivier) (Coleoptera: Dryophthoridae) larvae are cryptic, internal tissue-feeding pests of palm trees that are difficult to detect; consequently, infestations may remain hidden until they are widespread in an orchard. Infested trees and propagable offshoots that develop from axillary buds on the trunk frequently are transported inadvertently to previously uninfested areas. Acoustic methods can be used for scouting and early detection of R. ferrugineus, but until now have not been tested on multiple trees and offshoots in commercial date palm orchard environments. For this report, the acoustic detectability of R. ferrugineus was assessed in Saudi Arabian date palm orchards in the presence of commonly occurring wind, bird noise, machinery noise, and nontarget insects. Signal analyses were developed to detect R. ferrugineus and another insect pest, Oryctes elegans Prell (Coleoptera: Scarabaeidae), frequently co-occurring in the orchards, and discriminate both from background noise. In addition, it was possible to distinguish R. ferrugineus from O. elegans in offshoots by differences in the temporal patterns of their sound impulses. As has been observed often with other insect pests, populations of the two species appeared clumped rather than uniform or random. The results are discussed in relation to development of automated methods that could assist orchard managers in quickly identifying infested trees and offshoots so that R. ferrugineus infestations can be targeted and the likelihood of transferring infested offshoots to uninfested areas can be reduced. PMID- 26743214 TI - The associations of serum uric acid level and hyperuricemia with knee osteoarthritis. AB - To examine the cross-sectional associations of the serum uric acid level and hyperuricemia (HU) with the radiographic features of osteoarthritis (OA), including osteophytes (OST) and joint space narrowing (JSN), a total of 4685 subjects were included in this study. Blood samples were drawn from all subjects. Serum uric acid and some other indexes were detected. OST and JSN were assessed for each subject according to the Osteoarthritis Research Society International (OARSI) atlas. A multivariable logistic analysis model was applied to test the target associations after adjusting a number of potential confounding factors. The prevalence of OST was increased in the highest tertile of uric acid compared to the lowest in female subjects (OR 1.46, 95 % CI 1.07-1.99, P for trend = 0.02). Meanwhile, a positive association between OST and HU was observed in female subjects (OR 1.43, 95 % CI 1.01-2.03, P = 0.05). However, serum uric acid and HU were not significantly associated with JSN in male subjects. The findings of this study indicated that the serum uric acid concentration and prevalence of HU are positively associated with OST of the knee in the female population. Level of evidence Cross-sectional study, Level III. PMID- 26743219 TI - Effectiveness of Sulfuryl Fluoride Fumigation for the Control of Phosphine Resistant Grain Insects Infesting Stored Wheat. AB - A field experiment was conducted in eight 13.6-MT steel bins containing 6.8 MT each of wheat to assess efficacy of sulfuryl fluoride or SF fumigant to control phosphine-resistant and susceptible Rhyzopertha dominica (F.) and Tribolium castaneum (Herbst). Approximately 400 adults of each type of beetle were added to each bin. Additionally, muslin bags containing immature stages and adults, with their respective diets, were also placed in bins. Four bins were fumigated with SF and others were untreated control bins. The SF dosages in treated bins ranged from 1,196-1,467 mg-h/liter. Mortality of adults in each bag was assessed 5 d postfumigation; diet minus adults was incubated in a jar, and number of adults counted after 8 wk. No significant change occurred in number of insect-damaged kernels in SF-treated bins. In trier samples from SF-treated bins, R. dominica numbers declined from 24 prefumigation to 0 at 3- and 6-wk postfumigation; T. castaneum numbers were unchanged. In WBII traps from SF-treated bins, numbers R. dominica and T. castaneum declined from 25 and 33, respectively, prefumigation to 0 or near 0 at 3- and 6-wk postfumigation. Mortalities of resistant and susceptible adult R. dominica, and adult and large larvae of T. castaneum in SF treated bags was 100%. For all four types of beetles, adult numbers in jars associated with SF-treated bins were 0 or near 0. Results show SF is effective against all life stages of phosphine-resistant R. dominica and T. castaneum, and can be used for phosphine resistance management. PMID- 26743220 TI - Developmental changes of MPA exposure in children. AB - BACKGROUND: Developmental changes (ontogeny) of drug disposition of Mycophenolate mofetil (MMF) have been understudied. METHODS: The charts of 37 pediatric renal transplant recipients (median age 7.3 years, median follow-up 7.8 (IQR 6.6, 14.3 years) who had regular mycophenolic acid (MPA) trough level monitoring in combination with tacrolimus (n = 31) or sirolimus (n = 6) therapy were analyzed retrospectively for their dose-normalized MPA exposure, steroid dose, albumin, hematocrit, and cystatin C estimated glomerular filtration rate (eGFR). Using appropriate univariate and multivariate methods, we determined whether MPA exposure was age dependent when controlling for the confounders. RESULTS: Dose normalized MPA trough levels could be calculated in 2,128 (median 45/patient) instances. Spearman rank correlation analysis revealed that age correlated with dose-normalized MPA trough level for both body weight and body surface area, as well as serum albumin, hematocrit, steroid dose, and eGFR. In the multivariate analysis, serum albumin and steroid dose were not significant, and hematocrit only being significant when the youngest group of patients < 6 years of age was compared. eGFR was the most important confounder, but age dependency remained significant when controlling for all confounders. CONCLUSIONS: Small children are at a significantly greater risk for low MPA trough levels than adolescents, highlighting the need for pharmacokinetic monitoring of MPA. PMID- 26743221 TI - The role of early visual input in the development of contour interpolation: the case of subjective contours. AB - We tested the effect of early monocular and binocular deprivation of normal visual input on the development of contour interpolation. Patients deprived from birth by dense central cataracts in one or both eyes, and age-matched controls, discriminated between fat and thin shapes formed by either illusory or luminance defined contours. Thresholds indicated the minimum amount of curvature (the fatness or thinness) required for discrimination of the illusory shape, providing a measure of the precision of interpolation. The results show that individuals deprived of visual input in one eye, but not those deprived in both eyes, later show deficits in perceptual interpolation. The deficits were shown mostly for weakly supported contours in which interpolation of contours between the inducers was over a large distance relative to the size of the inducers. Deficits shown for the unilateral but not for the bilateral patients point to the detrimental effect of unequal competition between the eyes for cortical connections on the later development of the mechanisms underlying contour interpolation. PMID- 26743222 TI - From cyanochemicals to cyanofactories: a review and perspective. AB - Engineering cyanobacteria for production of chemicals from solar energy, CO2 and water is a potential approach to address global energy and environment issues such as greenhouse effect. To date, more than 20 chemicals have been synthesized by engineered cyanobacteria using CO2 as raw materials, and these studies have been well reviewed. However, unlike heterotrophic microorganisms, the low CO2 fixation rate makes it a long way to go from cyanochemicals to cyanofactories. Here we review recent progresses on improvement of carbon fixation and redistribution of intercellular carbon flux, and discuss the challenges for developing cyanofactories in the future. PMID- 26743223 TI - Effects of continuous infusion of etomidate at various dose rates on adrenal function in dogs. AB - BACKGROUND: Etomidate is a commonly used sedative in intravenous anesthesia. The aim of this study was to compare the effects of various etomidate doses administered by continuous infusion on adrenal function in dogs under general anesthesia. METHODS: Thirty-six healthy adult male dogs were randomly divided into six groups. Sodium pentobarbital alone was administered to the control group (group C); five experimental groups (E1, E2, E3, E4, and E5) were also given etomidate at doses of 10, 15, 20, 25, and 30 MUg . kg(-1) . min(-1), respectively, to maintain anesthesia. Heart rate (HR), mean arterial pressure (MAP), and bispectral index (BIS) were monitored. Serum cortisol, aldosterone, adrenaline, and noradrenaline levels were measured, and HR, MAP, and BIS values recorded, before intubation (T0), and at 1 h, 2 h, and 3 h after intubation (T1 3). RESULTS: Cortisol and aldosterone levels in groups E1-5 decreased as the doses and times of continuous infusion of etomidate increased. The cortisol level was significantly decreased compared with baseline at T3 in group E1 and at T1-3 in groups E2-5 (P < 0.05). Compared with the corresponding levels in group C, cortisol levels were significantly lower than T0 values at T3 in group E1 and at T1-3 in groups E2-5 (P < 0.05). The aldosterone level was significantly lower at T3 in group E2 and at T1-3 in groups E3-5 (P < 0.05). Significant reductions in cortisol levels at T2-3 in group E2 and at T1-3 in groups E3-5 compared with group C were also observed (P < 0.05). The plasma adrenaline and noradrenaline levels, HR, MAP, and BIS in groups E1-5 were within the normal range at the different times and with the different doses (P > 0.05). CONCLUSIONS: Cortisol and aldosterone levels decreased with time and continuous infusion of etomidate; there were no significant changes in adrenaline and noradrenaline levels, HR, MAP, and BIS in any group. PMID- 26743224 TI - TLR-4 may mediate signaling pathways of Astragalus polysaccharide RAP induced cytokine expression of RAW264.7 cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Polysaccharides of Radix Astragali (Astragalus membranaceus (Fisch) Bge.; Huangqi) are able to induce cytokine production of macrophages and are considered the main active ingredient for the immune enhancing effect of this commonly used medicinal herb. AIM OF STUDY: To investigate the molecular mechanism of immunomodulating activities of a reported Astragalus polysaccharide, RAP, which is a hyperbranched heteroglycan with average molecular weight of 1334kDa. MATERIALS AND METHODS: The cytokine production of RAW264.7 cells were analyzed by using ELISA assays while cell viability was assessed by MTT method. Western blot analysis was used for determining protein contents of mitogen-activated protein kinases (MAPKs). In addition, the level of IL-6, iNOS, and TNF-alpha mRNA was determined by RT-PCR. RESULTS: It has been found that RAP itself did not have any cytotoxic effect on mouse mammary carcinoma 4T1 cells, but it significantly enhanced cytotoxicity of the supernatant of RAW264.7cells on 4T1 cells. Furthermore, RAP enhanced the production of NO and cytokines in RAW264.7 cells, and significantly up-regulated gene expressions of TNF-alpha, IL-6, iNOS. All these bioactivities were blocked by the inhibitor of TLR4 (Toll-like receptor 4), suggesting that TLR4 is a receptor of RAP and mediates its immunomodulating activity. Further analyses demonstrated that RAP rapidly activated TLR4-related MAPKs, including phosphorylated ERK, phosphorylated JNK, and phosphorylated p38, and induced translocation of NF-kappaB as well as degradation of IkappaB-alpha. These results are helpful to better understand the immunomodulating effects of Radix Astragali. CONCLUSIONS: RAP may induce cytokine production of RAW264.7 cells through TLR4 mediated activation of MAPKs and NF-kappaB. PMID- 26743225 TI - Potent anti-inflammatory and analgesic steroidal alkaloids from Veratrum taliense. AB - ETHNOPHARMACOLOGICAL RELEVANCE: "Pimacao" (the roots and rhizomes of Veratrum taliense Loes.) has been used as traditional folk medicine in Yunnan province (PR China) for the treatment of pain, swelling, and inflammation. It is the main component of the renowned traditional Chinese medicine, "Yunnan Baiyao". Previous investigations and clinical research have shown significant analgesic activity of Pimacao. AIM OF THE STUDY: The aim of the present study was to find out the compounds responsible for anti-inflammatory and analgesic activity present in V. taliense. MATERIALS AND METHODS: The total alkaloids were the subject of phytochemical investigation and the compounds were isolated by multiple step chromatography. Their structures were elucidated on the basis of comprehensive spectroscopic data. Anti-inflammatory activity was evaluated using carrageenan induced paw oedema and analgesic activity was assessed using acetic acid-induced writhing in mice. RESULTS: Three new steroidal alkaloids, veratralines A-C (1-3), together with five known analogs, were isolated from the roots and rhizomes of V. taliense. All the compounds had the analgesic activity and significantly decreased the number of writhes caused by acetic acid much better than Dolantin. All the alkaloids except 8, possessed anti-inflammatory activity, in which 3, 5, and 7 significantly inhibited the paw oedema caused by carrageenan compared with Indomethacin. CONCLUSION: This is the first report of jervine-type alkaloids responsible for the anti-inflammatory and analgesic properties of Pimacao. We provide scientific evidence to support that the roots and rhizomes of V. taliense are useful in traditional Chinese medicine for the treatment of pain and inflammation. PMID- 26743226 TI - The effect of Flos Lonicerae Japonicae extract on gastro-intestinal motility function. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Flos Lonicerae Japonicae is a well-known herb of traditional Chinese medicine that has been used for heat-clearing, detoxification, anti-inflammation, throat pain and gastro-intestinal (GI) disorder. In order to verify the effect of Flos Lonicerae Japonicae on GI disorder, we investigated the prokinetic effect of GC-7101 on GI motility function. MATERIALS AND METHODS: GC-7101 is the standardized extract of Flos Lonicerae Japonicae. The contractile action of GC-7101 on feline esophageal smooth muscle cell (ESMC) was evaluated by measuring dispersed cell length. The isometric tension study was performed to investigate the effect of GC-7101 on feline lower esophageal sphincther (LES). The prokinetic effect of GC-7101 was investigated by gastric emptying (GE) and gastro-intestinal transit (GIT) in rats. RESULTS: GC-7101 produced concentration-dependent contractions in ESMCs. Pretreatment with 5-HT3 and 5-HT4 receptor blocker (ondansetron and GR113808) inhibited the contractile responses of the GC-7101-induced ESMCs. In isometric tension study, GC-7101 recovered the HCl-induced decreased tone of LES muscle strips. The treatment of GC-7101 enhanced the carbachol-induced contractile responses and the electric field stimulation (EFS)-induced on-contraction. The oral administration of GC-7101 not only significantly accelerated GE and GIT in normal rats but also recovered the delayed GE and GIT, and its effect was more potent than that of conventional prokinetics (e.g., domperidone, a dopamine receptor antagonist, and mosapride, a 5-HT4-receptor agonist). CONCLUSION: GC 7101 revealed a prokinetic effect through enhancing the contractile responses of ESMCs, tone increases, enhancing the carbarchol- or EFS-induced contractile responses of LES muscle strips, and the acceleration of GE and GIT. We have identified the significant potential of GC-7101 for the development of new prokinetic drugs through this study. PMID- 26743227 TI - Antidiabetic effect of total saponins from Polygonatum kingianum in streptozotocin-induced daibetic rats. AB - BACKGROUND: Polygonatum kingianum has been used in the prevention and treatment of diabetes, hyperlipidemia and related metabolic syndrome in Asian counties for centuries. In this study, the blood glucose regulation activity and mechanism of total saponins from P. kingianum (TSPK) were investigated in streptozotocin (STZ) induced diabetic rats in this research. METHODS: TSPK (0.025g/kg and 0.1mg/kg) was administrated by gavage to STZ-induced diabetic rats for 8 weeks. Changes of body weight, food intakes, blood glucose, serum insulin and lipid indexes were observed. Genome-wide expression profiling was applied to explore the gene expression alternation after treated with TSPK. Expressions of adenosine monophosphate activated protein kinase (AMPK), phosphoenolpyruvate carboxykinase (PEPCK), the relative transcript level of glucose kinase and glucose-6 phosphatase (GK/G6P) in the liver were investigated. Meanwhile, contents of AMPK, and glucose transporter subtype-4 (GLUT4) in skeletal muscle, and peroxysome proliferator-activated receptor (PPAR-gamma) in adipose tissue were investigated. RESULTS: TSPK could effectively alleviate hyperglycemia and hyperlipidemia in diabetic rats. Genome-wide expression profiling showed that TSPK up-regulated the expression of GLUT4 while down-regulated the expression of G6P in insulin signal pathway. In the liver, the expression of AMPK and GK are increased. Further more, TSPK promoted the expressions of GLUT4 in skeletal muscle, and PPAR-gamma in adipose tissue, respectively. CONCLUSION: These results provide possible mechanisms for the antidiabetic effects of TSPK. TSPK could promote not only glycogenesis but also glucose utilization in peripheral tissue. Our results suggested that TSPK may be used as adjuvant therapy to control blood glucose and insulin resistance in type 2 diabetic individuals. PMID- 26743228 TI - Large Pore-Sized Hollow Mesoporous Organosilica for Redox-Responsive Gene Delivery and Synergistic Cancer Chemotherapy. AB - A stability-difference-selective bond-breakage strategy for the fabrication of largepore-sized hollow mesoporous organosilica nanoparticles (HMONs) is successfully developed. Moreover, surfacefunctionalized HMONs are successfully constructed to simultaneously deliver P-gp modulator siRNA and anticancer drug doxorubicin to reverse the multidrug resistance of cancer cells. PMID- 26743229 TI - Role of the IFN I system against the VHSV infection in juvenile Senegalese sole (Solea senegalensis). AB - Senegalese sole is susceptible to marine VHSV isolates but is not affected by freshwater isolates, which may indicate differences regarding virus-host immune system interaction. IFN I induces an antiviral state in fish, stimulating the expression of genes encoding antiviral proteins (ISG). In this study, the stimulation of the Senegalese sole IFN I by VHSV infections has been evaluated by the relative quantification of the transcription of several ISG (Mx, Isg15 and Pkr) after inoculation with marine (pathogenic) and freshwater (non-pathogenic) VHSV isolates. Compared to marine VHSV, lower levels of RNA of the freshwater VHSV induced transcription of ISG to similar levels, with the Isg15 showing the highest fold induction. The protective role of the IFN I system was evaluated in poly I:C-inoculated animals subsequently challenged with VHSV isolates. The cumulative mortality caused by the marine isolate in the control group was 68%, whereas in the poly I:C-stimulated group was 5%. The freshwater VHSV isolate did not cause any mortality. Furthermore, viral RNA fold change and viral titers were lower in animals from the poly I:C + VHSV groups than in the controls. The implication of the IFN I system in the protection observed was confirmed by the transcription of the ISG in animals from the poly I:C + VHSV groups. However, the marine VHSV isolate exerts a negative effect on the ISG transcription at 3 and 6 h post-inoculation (hpi), which is not observed for the freshwater isolate. This difference might be partly responsible for the virulence shown by the marine isolate. PMID- 26743230 TI - Long-term evaluation of the degradation behavior of three apatite-forming calcium phosphate cements. AB - Calcium phosphate cements (CPCs) are injectable bone substitutes with a long clinical history because of their biocompatibility and osteoconductivity. Nevertheless, their cohesion upon injection into perfused bone defects as well as their long-term degradation behavior remain major clinical challenges. Therefore, the long-term degradation behavior of two types of alpha-tricalcium phosphate based, apatite-forming CPCs was compared to a commercially available apatite forming cement, that is HydroSetTM . Carboxyl methylcellulose (CMC) was used as cohesion promotor to improve handling properties of the two experimental cements, whereas poly (d, l-lactic-co-glycolic) acid (PLGA) microparticles were added to introduce macroporosity and stimulate CPC degradation. All three CPCs were injected into defects drilled into rabbit femoral condyles and explanted after 4, 12, or 26 weeks, after which the bone response was assessed both qualitatively and quantitatively. CPCs without PLGA microparticles degraded only at the periphery of the implants, while the residual CPC volume was close to 90%. On the contrary, bone ingrowth was observed not only at the periphery of the CPC, but also throughout the center of the implants after 26 weeks of implantation for the PLGA-containing CPCs with a residual CPC volume of approximately 55%. In conclusion, it was shown that CPC containing CMC and PLGA was able to induce partial degradation of apatite-forming CPCs and concomitant replacement by bone tissue. PMID- 26743232 TI - Assessing Risks of Shallow Riparian Groundwater Quality Near an Oil Sands Tailings Pond. AB - The potential discharge of groundwater contaminated by oil sands process-affected water (OSPW) is a concern for aquatic ecosystems near tailings ponds. Groundwater in the area, but unaffected by OSPW, may contain similar compounds, complicating the assessment of potential ecological impacts. In this study, 177 shallow groundwater samples were collected from riparian areas along the Athabasca River and tributaries proximate to oil sands developments. For "pond-site" samples (71; adjacent to study tailings pond), Canadian aquatic life guidelines were exceeded for 11 of 20 assessed compounds. However, "non-pond" samples (54; not near any tailings pond) provided similar exceedances. Statistical analyses indicate that pond-site and non-pond samples were indistinguishable for all but seven parameters assessed, including salts, many trace metals, and fluorescence profiles of aromatic naphthenic acids (ANA). This suggests that, regarding the tested parameters, groundwater adjacent to the study tailings pond generally poses no greater ecological risk than other nearby groundwaters at this time. Multivariate analyses applied to the groundwater data set separated into 11 smaller zones support this conclusion, but show some variation between zones. Geological and potential OSPW influences could not be distinguished based on major ions and metals concentrations. However, similarities in indicator parameters, namely ANA, F, Mo, Se, and Na-Cl ratio, were noted between a small subset of samples from two pond-site zones and two OSPW samples and two shallow groundwater samples documented as likely OSPW affected. This indicator-based screening suggests that OSPW-affected groundwater may be reaching Athabasca River sediments at a few locations. PMID- 26743231 TI - Molecular genetic and physical analysis of gas vesicles in buoyant enterobacteria. AB - Different modes of bacterial taxis play important roles in environmental adaptation, survival, colonization and dissemination of disease. One mode of taxis is flotation due to the production of gas vesicles. Gas vesicles are proteinaceous intracellular organelles, permeable only to gas, that enable flotation in aquatic niches. Gene clusters for gas vesicle biosynthesis are partially conserved in various archaea, cyanobacteria, and some proteobacteria, such as the enterobacterium, Serratia sp. ATCC 39006 (S39006). Here we present the first systematic analysis of the genes required to produce gas vesicles in S39006, identifying how this differs from the archaeon Halobacterium salinarum. We define 11 proteins essential for gas vesicle production. Mutation of gvpN or gvpV produced small bicone gas vesicles, suggesting that the cognate proteins are involved in the morphogenetic assembly pathway from bicones to mature cylindrical forms. Using volumetric compression, gas vesicles were shown to comprise 17% of S39006 cells, whereas in Escherichia coli heterologously expressing the gas vesicle cluster in a deregulated environment, gas vesicles can occupy around half of cellular volume. Gas vesicle production in S39006 and E. coli was exploited to calculate the instantaneous turgor pressure within cultured bacterial cells; the first time this has been performed in either strain. PMID- 26743234 TI - A maximum-likelihood method to estimate a single ADC value of lesions using diffusion MRI. AB - PURPOSE: Design a statistically rigorous procedure to estimate a single apparent diffusion coefficient (ADC) of lesion from the mean lesion signal intensity in diffusion MRI. THEORY AND METHODS: A rigorous maximum-likelihood technique that incorporated the statistics of the mean lesion intensity and accounted for lesion heterogeneity was derived to estimate the ADC value. Performance evaluation included comparison with the conventionally used linear-regression and a statistically rigorous state-of-the-art ADC-map technique using realistic and clinically relevant simulation studies conducted with assistance of patient data for homogeneous and heterogeneous lesion models. RESULTS: The proposed technique outperformed the linear-regression and ADC-map approaches over a large spectrum of signal-to-noise ratio, ADC, lesion size, image-misalignment parameters, including at no image misalignment, and different amounts of lesion heterogeneity. The method was also superior at different sets of b values and in studies from specific patient-image-derived data. The technique took less than a second to execute. CONCLUSIONS: A rigorous, computationally fast, easy-to implement, and convenient-to-use maximum-likelihood technique was proposed to estimate a single ADC value of the lesion. Results provide strong evidence in support of the method. Magn Reson Med 76:1919-1931, 2016. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26743233 TI - CPUY201112, a novel synthetic small-molecule compound and inhibitor of heat shock protein Hsp90, induces p53-mediated apoptosis in MCF-7 cells. AB - Heat-shock protein 90 (Hsp90) is highly expressed in many tumor cells and is associated with the maintenance of malignant phenotypes. Targeting Hsp90 has had therapeutic success in both solid and hematological malignancies, which has inspired more studies to identify new Hsp90 inhibitors with improved clinical efficacy. Using a fragment-based approach and subsequent structural optimization guided by medicinal chemistry principles, we identified the novel compound CPUY201112 as a potent Hsp90 inhibitor. It binds to the ATP-binding pocket of Hsp90 with a kinetic dissociation (Kd) constant of 27 +/- 2.3 nM. It also exhibits potent in vitro antiproliferative effects in a range of solid tumor cells. In MCF-7 cells with high Hsp90 expression, CPUY201112 induces the degradation of Hsp90 client proteins including HER-2, Akt, and c-RAF. We prove that treating MCF-7 cells with CPUY201112 results in cell cycle arrest and apoptosis through the wild-type (wt) p53 pathway. CPUY201112 also synergizes with Nutlin-3a to induce cancer cell apoptosis. CPUY201112 significantly inhibited the growth of MCF-7 xenografts in nude mice without apparent body weight loss. These results demonstrate that CPUY201112 is a novel Hsp90 inhibitor with potential use in treating wild-type p53 related cancers. PMID- 26743235 TI - The effect of endometrial thickness on the day of hCG administration on pregnancy outcome in the first fresh IVF/ICSI cycle. AB - The aim of this study was to investigate the effect of endometrial thickness (EMT) on human chorionic gonadotropin (hCG) day on in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcome. A retrospective study was conducted on the clinical data of 756 patients in their first fresh IVF/ICSI cycle at the Wuxi Maternity and Child Health Hospital. Compared with the pregnancy failure group, the clinical pregnancy group had more transferable embryos and good-quality embryos and had a thicker endometrium (p < 0.05). The endometrial pattern was not significantly different between the two groups. EMT was found to be an independent prognostic factor for clinical pregnancy (adjusted OR = 1.25, 95% CI: 1.15-1.36, p < 0.01). Seven hundred and fifty-six cycles were categorized into three groups upon EMT on the hCG day: group 1 (EMT < 8 mm), 2 (EMT 8-14 mm) and 3 (EMT > 14 mm). Group1 had significantly lower clinical pregnancy, embryo implantation and live birth rates compared with group 2 and 3 (p < 0.01), while there was no significant difference in either spontaneous abortion or multiple-birth rate among these three groups. It was concluded that EMT on the hCG day was associated with pregnancy outcome in the first fresh IVF/ICSI cycle. A higher clinical pregnancy rate could be achieved when EMT >= 8 mm, and no adverse pregnancy outcome was observed when EMT > 14 mm. PMID- 26743237 TI - Novel ICD Programming and Inappropriate ICD Therapy in CRT-D Versus ICD Patients: A MADIT-RIT Sub-Study. AB - BACKGROUND: The Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate therapy (MADIT-RIT) trial showed a significant reduction in inappropriate implantable cardioverter defibrillator (ICD) therapy in patients programmed to high-rate cut-off (Arm B) or delayed ventricular tachycardia therapy (Arm C), compared with conventional programming (Arm A). There is limited data on the effect of cardiac resynchronization therapy with a cardioverter defibrillator (CRT-D) on the effect of ICD programming. We aimed to elucidate the effect of CRT-D on ICD programming to reduce inappropriate ICD therapy in patients implanted with CRT-D or an ICD, enrolled in MADIT-RIT. METHODS AND RESULTS: The primary end point of this study was the first inappropriate ICD therapy. Secondary end points were inappropriate anti-tachycardia pacing and inappropriate ICD shock. The study enrolled 742 (49%) patients with an ICD and 757 (51%) patients with a CRT-D. Patients implanted with a CRT-D had 62% lower risk of inappropriate ICD therapy than those with an ICD only (hazard ratio [HR] =0.38, 95% confidence interval: 0.25-0.57; P<0.001). High-rate cut-off or delayed ventricular tachycardia therapy programming significantly reduced the risk of inappropriate ICD therapy compared with conventional ICD programming in ICD (HR=0.14 [B versus A]; HR=0.21 [C versus A]) and CRT-D patients (HR=0.15 [B versus A]; HR=0.23 [C versus A]; P<0.001 for all). There was a significant reduction in inappropriate anti-tachycardia pacings in both group and a significant reduction in inappropriate ICD shock in CRT-D patients. CONCLUSIONS: Patients implanted with a CRT-D have lower risk of inappropriate ICD therapy than those with an ICD. Innovative ICD programming significantly reduces the risk of inappropriate ICD therapy in both ICD and CRT-D patients. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov; Unique identifier: NCT00947310. PMID- 26743238 TI - Patient Outcomes From a Specialized Inherited Arrhythmia Clinic. AB - BACKGROUND: Patients with inherited arrhythmia syndromes are at an increased risk of sudden cardiac death (SCD). Specialized inherited arrhythmia clinics were founded to optimize management and prevention of SCD in this population. However, the clinical effectiveness of these clinics has never been evaluated. METHODS AND RESULTS: Clinical outcome data of patients referred to a specialized inherited arrhythmia clinic between 2005 and 2014 for a possible primary electric syndrome or arrhythmogenic right ventricular cardiomyopathy were analyzed. Of 720 patients evaluated, 278 received a definite or probable diagnosis and received long-term management in the inherited arrhythmia clinic. All patients diagnosed with long QT syndrome and catecholaminergic polymorphic ventricular tachycardia received routine beta-blocker therapy and demonstrated >90% long-term compliance. In patients with arrhythmogenic right ventricular cardiomyopathy, those demonstrating an arrhythmia burden on Holter or treadmill testing received beta blocker therapy (17%). In diagnosed channelopathy or arrhythmogenic right ventricular cardiomyopathy index cases, 44 patients received secondary prevention implantable cardioverter-defibrillators (long QT syndrome, 9; Brugada syndrome, 8; catecholaminergic polymorphic ventricular tachycardia, 3; short QT syndrome, 1; and arrhythmogenic right ventricular cardiomyopathy, 23). Median follow-up was 4.1 years with 43% having a follow-up period of >5 years. SCD occurred in a single patient (annualized risk of SCD, 0.1% per year). In individuals determined to have clinical or genetic disease by cascade screening, no SCD has occurred over a median follow-up of 5.6 years (55%, >5 years). Low event rates occurred despite a low rate (4.0%) of primary prevention implantable cardioverter defibrillator utilization. CONCLUSIONS: Longitudinal care in a specialized inherited arrhythmia clinic is associated with a low incidence of SCD and a low rate of primary implantable cardioverter-defibrillator utilization in patients with inherited arrhythmia syndromes. PMID- 26743239 TI - K2 Au(IO3)5 and beta-KAu(IO3)4: Polar Materials with Strong SHG Responses Originating from Synergistic Effect of AuO4 and IO3 Units. AB - Two new polar potassium gold iodates, namely, K2 Au(IO3)5 (Cmc21) and beta KAu(IO3)4 (C2), have been synthesized and structurally characterized. Both compounds feature zero-dimensional polar [Au(IO3)4](-) units composed of an AuO4 square-planar unit coordinated by four IO3(-) ions in a monodentate fashion. In beta-KAu(IO3)4, isolated [Au(IO3)4](-) ions are separated by K(+) ions, whereas in K2 Au(IO3)5, isolated [Au(IO3)4](-) ions and non-coordinated IO3(-) units are separated by K(+) ions. Both compounds are thermally stable up to 400 degrees C and exhibit high transmittance in the NIR region (lambda=800-2500 nm) with measured optical band gaps of 2.65 eV for K2 Au(IO3 )5 and 2.75 eV for beta KAu(IO3)4. Powder second-harmonic generation measurements by using lambda=2.05 MUm laser radiation indicate that K2 Au(IO3)5 and beta-KAu(IO3)4 are both phase matchable materials with strong SHG responses of approximately 1.0 and 1.3 times that of KTiOPO4, respectively. Theoretical calculations based on DFT methods confirm that such strong SHG responses originate from a synergistic effect of the AuO4 and IO3 units. PMID- 26743236 TI - Synthetic Bax-Anti Bcl2 combination module actuated by super artificial hTERT promoter selectively inhibits malignant phenotypes of bladder cancer. AB - BACKGROUND: The synthetic biology technology which enhances the specificity and efficacy of treatment is a novel try in biomedical therapy during recent years. A high frequency of somatic mutations was shown in the human telomerase reverse transcriptase (hTERT) promoter in bladder cancer, indicating that a mutational hTERT promoter might be a tumor-specific element for bladder cancer therapy. In our study, we aimed to construct a synthetic combination module driven by a super artificial hTERT promoter and to investigate its influence on the malignant phenotypes of bladder cancer. METHODS: The dual luciferase assay system was used to verify the driven efficiency and tumor-specificity of the artificial hTERT promoter and to confirm the relationship between ETS-1 and the driven efficiency of the artificial hTERT promoter. CCK-8 assay and MTT assay were used to test the effects of the Bax-Anti Bcl2 combination module driven by the artificial hTERT promoter on cell proliferation. Simultaneously, the cell apoptosis was detected by the caspase 3ELISA assay and the flow cytometry analysis after transfection. The results of CCK-8 assay and MTT assay were analyzed by ANOVA. The independent samples t-test was used to analyze other data. RESULTS: We demonstrated that the artificial hTERT promoter had a higher driven efficiency which might be regulated by transcription factor ETS-1 in bladder cancer cells, compared with wild-type hTERT promoter. Meanwhile, the artificial hTERT promoter showed a strong tumor specific effect. The cell proliferation inhibition and apoptosis induction were observed in artificial hTERT promoter- Bax-Anti Bcl2 combination module transfected bladder cancer 5637 and T24 cells, but not in the module -transfected normal human fibroblasts. CONCLUSION: This module offers us a useful synthetic biology platform to inhibit the malignant phenotypes of bladder cancer in a more specific and effective way. PMID- 26743240 TI - Effects of exenatide and liraglutide on 24-hour glucose fluctuations in type 2 diabetes. AB - We evaluated the influence of short-term treatment with exenatide twice daily or liraglutide once daily on daily blood glucose fluctuations in 40 patients with type 2 diabetes inadequately controlled by sulfonylureas. The patients in a multicenter, open-label trial were randomly assigned to receive add-on exenatide (10 MUg/day, n = 21) or add-on liraglutide (0.3-0.9 mg/day, n = 19), and underwent 24-hour continuous subcutaneous glucose monitoring. There was no significant between-group difference in glucose fluctuations during the day, as assessed by calculating mean amplitude of glycemic excursion (MAGE) and standard deviation (SD). However, the mean blood glucose levels at 3 hours after breakfast and dinner were significantly lower in the exenatide group than the liraglutide group (breakfast: 127.3 +/- 24.1 vs. 153.4 +/- 28.7 mg/dL; p = 0.006, dinner: 108.7 +/- 17.3 vs. 141.9 +/- 24.2 mg/dL; p < 0.001). In contrast, mean blood glucose levels and their SD were significantly lower between 0000 h and 0600 h in the liraglutide group than the exenatide group (average glucose: 126.9 +/- 27.1 vs. 107.1 +/- 24.0 mg/dL; p = 0.029, SD: 15.2 +/- 10.5 vs. 8.7 +/- 3.8; p = 0.020). Both groups had similar glucose fluctuations despite differences in 24 hour blood glucose profiles. Therefore, each of these agents may have advantages or disadvantages and should be selected according to the blood glucose profile of the patient. PMID- 26743241 TI - [Efficacy of combination antiviral therapy following childbirth in pregnant HBV carriers receiving telbivudine for prevention of mother-to-child transmission]. AB - OBJECTIVE: To observe the clinical efficacy of combination therapy with peg IFNalpha and adefovir (CPIA) in women who were hepatfis B virus (HBV) carriers and had just given birth and received telbivudine (LdT) during pregnancy for prevention of mother-to-child transmission. METHODS: One-hundred-and-fifty third trimester-pregnant women who were HBV carriers with highly-viremic were treated with LdT until time of birth. After delivery, those women with alanine aminotransferase (ALT) level exceeding two times the upper limit of normal and HBV DNA level that had decreased more than 31 gIU/mL or hepatitis B e antigen (HBeAg) titer that had decreased more than 50% were switched to CPIA for 96 weeks. RESULTS: Following delivery, 45 of the women were switched to the CPIA treatment, of which 91.1% (41/45) achieved virological response, 55.6% (25/45) achieved HBeAg clearance or seroconversion, and 26.7% (12/45) achieved hepatitis B surface antigen (HBsAg) clearance or seroconversion.The immediate post-delivery (and pre-CPIA) levels of HBeAg and HBV DNA were negatively associated with HBeAg clearance. Ninety-eight of the total study participants stopped the LdT treatment and there were no cases of significant deterioration of liver function. CONCLUSION: Pregnant women who are HBV carriers and receive LdT for protection against mother-to-child transmission, and who show significant ALT elevation and decreased HBeAg titer and/or reduced HBV DNA after delivery, may be good candidates for the CPIA therapy following delivery. PMID- 26743242 TI - [Efficacy of pegylated-interferon alpha-2a treatment in patients with HBeAg positive chronic hepatitis B and partial viral response to nucleoside analogue therapy]. AB - OBJECTIVE: To investigate the efficacy and related factors of pegylated interferon alpha-2a (PEG-IFN-2a) treatment in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) who achieved partial viral response with nucleoside analogue (NA) therapy. METHODS: Patients with HBeAg-positive CHB and partial viral response to NA treatment were administered a PEG-IFN-2a therapy regimen of 180 g subcutaneous injection once weekly for a personlized duration of time. The existing NA therapy was continued in combination with the new PEG-IFN 2a treatment for 12 weeks. Measurements of serum HBV DNA load, hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), HBeAg and hepatitis B e antibody (anti-HBe) were taken at baseline (prior to addition of the PEG-IFN-2a therapy) and every 3 months afterwards.For determining response to treatment, primary efficacy was defined as undetectable HBsAg and seroconversion, and secondary efficacy was defined as HBsAg less than 10 IU/mL and HBeAg seroconversion.Statistical analysis was carried out using SPSS statistical software. RESULTS: A total of 81 consecutive patients with an average of 12.0 months (range: 6.0-24.0 months) of NA therapy were included in the study and received an average of 19.6 months (range: 15.5-33.3 months) of PEG-IFN-2a treatment. At the end of PEG-IFN-2a therapy, 7 (8.6%) of the patients achieved undetectable HBsAg and seroconversion, and 14 (17.3%) showed HBsAg less than 10IU/mL. In addition, 40.7% achieved undetectable HBeAg and seroconversion, a rate that was slightly higher than that (38.3%) seen in treatment-naive patients who received PEG-IFN-2a. Statistical analyses suggest that baseline level of HBsAg at less than 1500 IU/mL may predict end of PEG-IFN-2a treatment response for HBsAg less than 10 IU/mL, as evidenced by the area under the curve measure of 0.747, sensitivity measure of 87.3%, specificity measure of 33.3%, positive predictive value of 82.1% and negative predictive value of 42.8%. CONCLUSION: Patients with HBeAg-positive CHB and partial viral response to NA therapy can achieve undetectable HBsAg and HBeAg seroconversion after switching to PEG-IFN-2a treatment. Baseline HBsAg level may be predictive of response to this therapeutic strategy. PMID- 26743243 TI - [Effects of autologous peripheral stem cell transplantation on acoustic radiation force impulse in patients with HBV-related decompensated cirrhosis]. AB - OBJECTIVE: To perform a prospective study the effects of autologous peripheral blood stem cell (APBSC) transplantation on acoustic radiation force impulse (ARFI) in patients with hepatitis B virus (HBV)-related decompensated cirrhosis. METHODS: A total of 68 hospitalized patients with HBV-related decompensated cirrhosis undergoing conventional treatment were included in the study. Thirty three of these patients also received APBSC transplantation therapy (treatment group) and 35 did not (control group). The treatment group was observed for postoperative adverse reaction, and changes (pre-vs.post-treatment) in total bilirubin, prothrombin time (PT), albumin (Alb), spleen size and ARFI imaging findings. Statistical analyses were carried out using the t-test, non-parametric test, and chi-square test. RESULTS: The patients who received APBSC transplantation showed improving levels of Alb and PT, but not of total bilirubin, at postoperative weeks 24, 36 and 48, and reduced spleen length and ARFI findings at postoperative weeks 36 and 48.Compared to the baseline data (week 0) for the treatment group and to the data for the control groups, these differences were statistically significant (P less than 0.05). CONCLUSIONS: APBSC transplantation can reduce ARFI imaging findings and improve the pathology of liver fibrosis in patients with HBV-related decompensated cirrhosis. PMID- 26743245 TI - [Down-regulated clusterin expression enhances sensitivity of hepatoma cells to anti-cancer drugs]. AB - OBJECTIVE: To investigate the relationship between and underlying mechanistic pathway of clusterin (CLU) and chemo-resistance ofhepatocellular carcinoma (HCC) cells. METHODS: CLU protein expression in HCC cell lines (Hep3B, SMMC7721, PLC, and HepG2) and HepG2/ADM cells was quantified by western blotting. Four short hairpin (sh)RNAs designed to block CLU-mRNA were generated, screened by RT-PCR, and transfected into the cells to determine effects of CLU on cell viability and apoptosis. Effects of CLU blockade on drug efflux pump activity were measured by flow cytometry. RESULTS: CLU was found to be over-expressed in HCC cell lines and HepG2/ADM cells. The four shRNAs inhibited CLU-mRNA as follows (vs. levels in untransfected cells): shRNA-1: 73.68% (q =23.011, P < 0.01), shRNA-2: 39.26% (q =11.991, P < 0.01), shRNA-3: 62.36% (q =19.392, P < 0.01), and shRNA-4: 55.35% (q =17.149, P < 0.01). shRNA-mediated depletion of CLU led to increased sensitivity to anti-cancer drugs and increased doxorubicin-induced apoptosis in HepG2/ADM cells, as evidenced by the apoptosis ratio of the shRNA-1 group of 39.28% vs. the apoptosis ratio of the untransfected control group of 4.92%. Silencing of CLU also decreased drug etflux pump activity, and the level of MDR1/P-gp expression was significantly reduced (shRNA-1 group vs.untransfected control group: q =14.604, P < 0.01). CONCLUSION: CLU repression may enhance sensitivity of HCC cells to anti-cancers drugs and represents a potential molecular-target for reversal of multidrug-resistant HCC. PMID- 26743244 TI - [Inhibitory effect of lentivirus-mediated hTERTp-TK combined with hTERTp tumstatin on human hepatocarcinoma HepG2 cells]. AB - OBJECTIVE: To observe targeted expression of recombinant lentivirus-mediated (Lv) hTERTp-TK and Lv-hTERTp-tumstatin in HepG2 cells, and explore the inhibitory effect of their combination on HepG2 cells both in vitro and in vivo. METHODS: Lv hTERTp-TK and Lv-hTERTptumstatin were used to infect HepG2 and L02 cells at different MOIs. Transfection efficiency was observed by fluorescence microscopy. Expression of TK and tumstatin mRNA was detected by reverse-transcriptase PCR. Proliferation and apoptosis were detected by MTT and flow cytometry, respectively. The HepG2 cells were examined by real time-PCR and western blotting to determine expression level of bcl-2 and VEGF mRNA and protein.A murine hepatocellular carcinoma model was established by injecting 1 * 10(7) HepG2 cells into 30 BALB/c nude mice. The modeled mice were randomly divided into a control group, mock group, Lv-hTERTp-tumstatin group, Lv-hTERTp-TK group, and combination group for four weeks of injections at regular intervals of PBS, Lv-hTERTp-null, Lv-hTERTp-tumstatin, Lv-hTERTp-TK, and Lv-hTERTp-tumstatin plus Lv-hTERTp-TK, respectively.Changes in tumor volume and weight, and cell morphology of tumor and major organs, were assessed by hematoxylin-eosin staining.Microvascular density of tumor tissue and cell apoptosis were assessed by immunohistochemical and TUNEL staining, respectively. RESULTS: The Lv-infected HepG2 cells, and not the Lv infected L02 cells, expressed TK and tumstatin. Lv-hTERTp-TK and Lv-hTERTp tumstatin, alone or in combination, inhibited proliferation and increased apoptosis of the HepG2 cells, but the combination was more effective than either alone (P less than 0.05). None of the treatments affected proliferation or apoptosis of the L02 cells (P more than 0.05). The combination also led to a greater reduction of bcl-2 and VEGF than either alone (all, P less than 0.05). Tumor growth was significantly inhibited by the combination (P less than 0.05). In vivo, the combination treatment induced the greatest amount of apoptosis of the HepG2 cells. Cell morphology of major organs such as liver, spleen and kidney were similar to the control group. The combination also produced the most significant effect on tumor microvascular density (P less than 0.05) and the highest apoptosis index (P less than 0.05). CONCLUSION: The HTERT promoter can induce targeted expression of TK and tumstatin in HepG2 cells. Lv-hTERTp-TK combined with Lv-hTERTp-tumstatin can significantly inhibit proliferation and induce apoptosis of human HepG2 cells in vitro and in vivo, which may be related to down-regulation ofbcl-2 and VEGF. PMID- 26743246 TI - [Gene expression and functional profiles related to differentiation of human hepatic progenitor cells]. AB - OBJECTIVE: To identify the genes playing a functional role in differentiation of human hepatic progenitor cells to hepatocytes by comparing the gene expression and functional profiles of the two cell types. METHODS: mRNA was isolated from human fetal hepatic progenitor cells (hFHPCs) and functional hepatocyte-like cells (HLCs) that had differentiated from hFHPCs. Global gene expression profiling was performed on triplicate samples of each cell type. The differential gene expression was analyzed using volcano plot filtering and functional annotation was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). RESULTS: Compared to the hFHPCs, the HLCs had a total of 1878 significantly up-regulated genes and 1441 significantly down regulated genes. The up-regulated genes included functional groups related to the hexose metabolic process, positive regulation of apoptosis, angiogenesis, regulation of cell motion, and protein amino acid phosphorylation. The down regulated genes included functional groups related to cell cycle, DNA metabolic process, cytoskeleton organization, regulation cell cycle, and chromosome segregation. CONCLUSION: Differentiation of HLCs from hFHPCs may involve increased expression of genes related to hepatocyte function and decreased expression of genes related to cell cycle regulation. PMID- 26743247 TI - [EPCAM-positive normal hepatic progenitor cells transformation into liver stem cells and HBx-mediated effects on stability in adult mouse]. AB - OBJECTIVE: To investigate the transformative potential of hepatic progenitor cells to differentiate into liver stem cells using a normal adult mouse system and to determine the effects of HBx protein in these liver stem cells' differentiation into hepatic cells. METHODS: Hepatic progenitor cells were obtained from mice by means of an optimized two-step digestion and perfusion method followed by joint differential centrifugation and density gradient centrifugation. Transformation of the hepatic progenitor cells into liver stem cells was observed by immunofluorescent detection of CD 133, EPCAM, CD49f and CK19. Differentiation of the resultant liver stem cells into hepatic cells and bile duct epithelial cells was observed after DMSO addition by Periodic Acid Schiff (PAS) staining followed by cell immunofluorescence and flow cytometry. To determine the effects of HBx on these liver stem cells' ability to differentiate into hepatic cells, cell transfection was used followed by observation of morphology and proliferation capacity. RESULTS: Cell viability of the isolated hepatic progenitor cells was 78.67+/-4.04%. Stimulation with EGF and collagen led to growth of some of the paving-stone shaped cells attached to the hepatic progenitor cells which had gathered into spherical clumps, as is the nature of stem cells. The liver stem cells showed high expression of CD133, CD49f and CK19, and low expression of EPCAM. Under the effect of DMSO, the liver stem cells differentiated into hepatocytes and bile duct epithelial cells. After HBx transfecfion, the liver stem cells maintained the characteristic shape of stem cells and showed enhanced proliferation. CONCLUSION: EPCAM-positive adult hepatic progenitor cells can transform into liver stem cells.The HBx protein may play an important role in maintaining the stability of liver stem cells in the adult mouse. PMID- 26743248 TI - [Clinical analysis of liver transplantation for autoimmune hepatitis]. AB - OBJECTIVE: To describe the outcomes and recurrence of autoimmune hepatitis (AIH) after liver transplantation. METHODS: Clinical data of 16 patients with AIH who underwent liver transplantation were analyzed retrospectively. The postoperative cumulative survival rate of the patients was calculated. The postoperative rejections and AIH recurrence were analyzed. The Kaplan-Meier method was used for statistical analysis of survival. RESULTS: All patients were female, with an average age of 52.6 years (range: 41-66 years), and an average MELD score of 21.4. According serological analysis, 15 patients were AIH type 1 and 1 patient was AIH type 2. Three patients died, including 2 of pulmonary infection and 1 of graft dysfunction.The 1-, 2-and 5-year cumulative survival rates were 93.8%, 87.1% and 79.1%, respectively. Five cases (31.3%) of recurrent AIH were diagnosed based on histological evidence. Acute rejection occurred in 6 (37.5%) patients, and de novo HBV infection occurred in 1 (6.3%) patient. CONCLUSION: Liver transplantation is an effective treatment for end-stage AIH. Recurrence and rejection were commonly associated with AIH, but did not negatively impact patient survival. PMID- 26743249 TI - [Clinical analysis of 370 patients with terminal primary hepatic cancer using the model for end-stage liver disease scoring system]. PMID- 26743250 TI - [Warfarin-induced autoimmune hepatitis: a case report]. PMID- 26743251 TI - [Pathology-based differential diagnosis of high-grade dysplastic nodule from well differentiated small hepatocellular carcinoma]. PMID- 26743252 TI - [Recent advances in serum biomarkers for liver fibrosis]. PMID- 26743253 TI - [Role of vitamin D deficiency in nonalcoholic fatty liver disease]. PMID- 26743254 TI - CRUCIAL PARAMETERS FOR PROPER SIMULATION OF THE DETECTOR USED IN IN VIVO MEASUREMENTS. AB - Mathematical calibration is an increasingly popular technique among laboratories with a whole- or partial-body counters. A mathematical calibration employing a voxel phantom and Monte Carlo radiation transport code simulations has many benefits and can overcome many limitations of detector efficiency calibration using physical anthropomorphic phantoms. This publication tries to identify key factors for detector modelling. The influence of such parameters depends on energy and thus is studied in the gamma energy range of detectable radionuclides, i.e. from 15 keV to 1.5 MeV. PMID- 26743255 TI - BASIC RADIATION PROTECTION EDUCATION AND TRAINING FOR MEDICAL PROFESSIONALS; GEORGIAN EXPERIENCE AND FUTURE PERSPECTIVE. AB - The level of knowledge provided by the Tbilisi State Medical University (TSMU) standard curriculum modules in 'Medical physics' and 'Radiation risk estimates' was assessed as was the learning outcome of modern standards elective course in 'Radiation protection'. Two groups of medical students were examined: Group 1: 5 y students, participants in elective course 'Radiobiology and radiogenic health risk' and Group 2: 1-2 y students, participants in winter and summer schools. Students were tested before and after training courses with the same tests questionnaire. The results of the tests showed the necessity for improvement of the educational curriculum. The changes needed are the inclusion of a basic radiobiological course in the curricula of the faculty of medicine and expansion of the medical physics course through a more detailed presentation of medical imaging methods. PMID- 26743256 TI - IMPLICATIONS OF PATIENT CENTRING ON ORGAN DOSE IN COMPUTED TOMOGRAPHY. AB - Automatic exposure control (AEC) in computed tomography (CT) facilitates optimisation of dose absorbed by the patient. The use of AEC requires appropriate 'patient centring' within the gantry, since positioning the patient off-centre may affect both image quality and absorbed dose. The aim of this experimental study was to measure the variation in organ and abdominal surface dose during CT examinations of the head, neck/thorax and abdomen. The dose was compared at the isocenter with two off-centre positions-ventral and dorsal to the isocenter. Measurements were made with an anthropomorphic adult phantom and thermoluminescent dosemeters. Organs and surfaces for ventral regions received lesser dose (5.6-39.0 %) than the isocenter when the phantom was positioned +3 cm off-centre. Similarly, organ and surface doses for dorsal regions were reduced by 5.0-21.0 % at -5 cm off-centre. Therefore, correct vertical positioning of the patient at the gantry isocenter is important to maintain optimal imaging conditions. PMID- 26743257 TI - DEVELOPMENT OF A RAPID PROCEDURE TO ANALYSE Pu, Am AND 90Sr IN EMERGENCY URINE BIOASSAY IN CIEMAT BIOELIMINATION LABORATORY: METHOD VALIDATION BY EMERGENCY BIOASSAY INTERCOMPARISON EXERCISES. AB - After a radiological or nuclear incident, it is necessary to give a prompt response and to know the number of persons exposed to internal contamination, to evaluate the contamination levels in each person and even and to identify the radionuclides involved. In vitro laboratories routine monitoring measurements employed to quantify (90)Sr and actinides in urine require radiochemical separation and long counting time, which implies a minimum of 1 or 2 weeks to obtain the results, respectively. In this work, rapid radiochemical separation method applied directly to urine samples is presented. It is based on minimal sample preparation, without co-precipitation phase, using extraction resin columns and vacuum box technology. Pu isotopes and (241)Am are isolated, electrodeposited and measured by alpha spectrometry, whereas (90)Sr is measured by liquid scintillation counting. Finally, results of the participation in European Radiation Dosimetry Group intercomparison on Emergency Bioassay exercise and Bundesamt fur Strahlenschutz exercise validate the accuracy of this procedure. PMID- 26743258 TI - PATIENT DOSES IN COMPUTED TOMOGRAPHY EXAMINATIONS IN TWO REGIONS OF THE RUSSIAN FEDERATION. AB - Computed tomography (CT) is often a justified diagnostic tool, but is also associated with high exposure of the patients. Due to the rapid increase in the number of CT units and thus the availability of CT examinations in Russia, there is a growing need for optimisation within this field. In order to develop proper optimisation procedures for CT, the two regions St. Petersburg and Belgorod of Russia were chosen, representing an urban and a rural region, respectively. In 2014, a survey was conducted of the parameters applied in CT examinations in these regions, and the results show that the highest effective doses were observed for investigations of abdomen, reaching up to 137 mSv, and pelvic CT examinations, reaching up to 58 mSv, both with contrast agents. The dose distributions were approximately log-normal, and for the majority of the examinations, the 75th percentiles of the CT dose distributions in the Belgorod region were higher than observed in St. Petersburg. The aim of the current project is primarily to define and implement diagnostic reference levels as a part of the process of optimisation of CT examinations in Russia. PMID- 26743259 TI - SCALING PARAMETERS FOR HOT-PARTICLE BETA DOSIMETRY. AB - Scaling of dose-point kernel (DPK) values for beta particles transmitted by high Z sources will overestimate dose at shallow depths while underestimating dose at greater depths due to spectral hardening. A new model has been developed based on a determination of the amount of monoenergetic electron absorption that occurs in a given source thickness through the use of EGSnrc (Electron Gamma Shower) Monte Carlo simulations. Integration over a particular beta spectrum provides the beta particle DPK following self-absorption as a function of source thickness and radial depth in water, thereby accounting for spectral hardening that may occur in higher-Z materials. Beta spectra of varying spectral shapes and endpoint energies were used to test the model for select source materials with 7.42 <= Z <= 94. The results demonstrate that significant improvements can be made to DPK based dosimetry models when dealing with high-Z volumetric sources. This new scaling model is currently being used to improve the accuracy of the beta dosimetry calculations in VARSKIN 5. PMID- 26743260 TI - PATIENT DOSE ASSESSMENT AFTER INTERVENTIONAL CARDIOLOGY PROCEDURES: A MULTI CENTRIC APPROACH TO TRIGGER OPTIMISATION. AB - As the number and complexity of fluoroscopically guided interventions increase, a serious effort has to be put on the optimisation of the X-ray dose delivered to the patient. In order to set up this optimisation process, the clinical practice for a given cardiology centre has to be analysed with relevant statistical power and compared with the data at local or national level. Data from 8 Swiss cardiology centres for 10 different vascular and heart rhythm procedures have been collected. The collected dose indicators were, when available, cumulated air kerma, cumulated dose-area product, fluoroscopy time and the number of images per procedure. Data analysis was performed using an in-house software solution in terms of the first, second and third quartiles. This kind of large-scale analysis could yield some onsets towards local practice optimisation based on anonymous dose indicator cross-comparison. Further effort should nevertheless be made in order to proceed towards an operator-based data analysis, thus allowing for an individual practice optimisation. PMID- 26743261 TI - ACCURATE KAP METER CALIBRATION AS A PREREQUISITE FOR OPTIMISATION IN PROJECTION RADIOGRAPHY. AB - Modern X-ray units register the air kerma-area product, PKA, with a built-in KAP meter. Some KAP meters show an energy-dependent bias comparable with the maximum uncertainty articulated by the IEC (25 %), adversely affecting dose-optimisation processes. To correct for the bias, a reference KAP meter calibrated at a standards laboratory and two calibration methods described here can be used to achieve an uncertainty of <7 % as recommended by IAEA. A computational model of the reference KAP meter is used to calculate beam quality correction factors for transfer of the calibration coefficient at the standards laboratory, Q0, to any beam quality, Q, in the clinic. Alternatively, beam quality corrections are measured with an energy-independent dosemeter via a reference beam quality in the clinic, Q1, to beam quality, Q Biases up to 35 % of built-in KAP meter readings were noted. Energy-dependent calibration factors are needed for unbiased PKA Accurate KAP meter calibration as a prerequisite for optimisation in projection radiography. PMID- 26743262 TI - SKIN DOSE, EFFECTIVE DOSE AND RELATED RISK IN TRANSCATHETER AORTIC VALVE IMPLANTATION (TAVI) PROCEDURES: IS THE CANCER RISK ACCEPTABLE FOR YOUNGER PATIENTS? AB - The aim of this study was to estimate conversion coefficients for maximum entrance skin dose (MESD) and effective dose (E) for patients undergoing transcatheter aortic valve implantation (TAVI) and to evaluate the risk of exposure-induced cancer death (REID) for prospectively younger patients. Effective doses and risks were estimated for 22 patients using PCXMC whereas MESDs were estimated for a sub-group of 15 patients using Gafchromic film. The estimated conversion coefficients for skin dose [CCS = MESD/dose-area product (DAP)] and E (CCE = E/DAP) were 9.7+/-1.5 and 0.24+/-0.02 mSv/Gy cm(2), respectively. The REID ranged from 1:9900 to 1:1400 and by decreasing the age of examination to 40-50 y of age, the REID increased with a factor of 2 for females and 1.5 for males. The organ at risk was the lung. Currently, the patient population is elderly with radiation-induced skin injuries as the main risk. The risk of cancer induction should additionally be considered if younger patient populations are to be treated. PMID- 26743263 TI - The influence of illness acceptance on the adherence to pharmacological and non pharmacological therapy in patients with hypertension. AB - BACKGROUND: The available publications show that 50% of patients with hypertension discontinue their medications within the first 12 months after the beginning of treatment. AIM: The aim of the study was to analyse the relationship between the acceptance of illness and the adherence to pharmacological and non pharmacological therapy in patients with hypertension. METHODS: The study included 102 patients with hypertension examined with validated instruments: Acceptance of Illness Scale (AIS), Health Behavior Inventory (HBI) and Morisky Medication Adherence Scale (MMAS-8). RESULTS: High (>30 points) and moderate (19 29 points) levels of AIS were presented respectively by 59 and 43 patients. In a univariate analysis, the level of AIS had a statistically significant, independent, positive influence on all domains of the HBI questionnaire: HBI (Spearman's coefficient of rank correlation (rS) =+0.3997), healthy eating habits (rS=+ 0.376), preventive behaviours (rS=+0.242), positive mental attitude (rS=+0.504), health practices (rS=+0.264). In univariate analysis the level of MMAS-8 was influenced by female gender (rS=+0.325; p=0.001), higher education level (rS=+0.241; p=0.015), employment (rS=+0.217; p=0.029) and short duration of illness (rS=+0.229; p=0.022). Multiple regression analysis showed that female gender was an independent predictor of pharmacological adherence (beta=+0.325; p=0.001). Illness acceptance was an independent predictor in two domains of the HBI: positive mental attitude HBI domain (beta=+0.468; p<0.001) and healthy eating habits (beta=+0.321; p=0.001). CONCLUSIONS: (1) Correlation analysis shows that illness acceptance is an important factor contributing to a higher level of adherence to non-pharmacological therapy of hypertension (total index of health behaviours: healthy eating habits, preventive behaviours, positive mental attitude, health practice) but has no influence on adherence to pharmacological treatment. (2) Female gender, higher levels of education, and the short duration of the disease significantly improve patients' adherence to the prescribed pharmacological and non-pharmacological therapy of hypertension. PMID- 26743264 TI - New non-invasive method for early detection of metabolic syndrome in the working population. AB - BACKGROUND: We propose a new method for the early detection of metabolic syndrome in the working population, which was free of biomarkers (non-invasive) and based on anthropometric variables, and to validate it in a new working population. METHODS: Prevalence studies and diagnostic test accuracy to determine the anthropometric variables associated with metabolic syndrome, as well as the screening validity of the new method proposed, were carried out between 2013 and 2015 on 636 and 550 workers, respectively. The anthropometric variables analysed were: blood pressure, body mass index, waist circumference, waist-height ratio, body fat percentage and waist-hip ratio. We performed a multivariate logistic regression analysis and obtained receiver operating curves to determine the predictive ability of the variables. The new method for the early detection of metabolic syndrome we present is based on a decision tree using chi-squared automatic interaction detection methodology. RESULTS: The overall prevalence of metabolic syndrome was 14.9%. The area under the curve for waist-height ratio and waist circumference was 0.91 and 0.90, respectively. The anthropometric variables associated with metabolic syndrome in the adjusted model were waist-height ratio, body mass index, blood pressure and body fat percentage. The decision tree was configured from the waist-height ratio (?0.55) and hypertension (blood pressure ?128/85 mmHg), with a sensitivity of 91.6% and a specificity of 95.7% obtained. CONCLUSIONS: The early detection of metabolic syndrome in a healthy population is possible through non-invasive methods, based on anthropometric indicators such as waist-height ratio and blood pressure. This method has a high degree of predictive validity and its use can be recommended in any healthcare context. PMID- 26743265 TI - Intrinsic coordination for revealing local structural changes in protein folding unfolding. AB - With a deformed object of a rigid rod inside, the local dislocations may be tracked relatively easily with respect to the internal rigid rod. We apply this concept on protein folding-unfolding to track the internal structural changes of an unfolded protein in solution. Proposed here is a protein internal coordination based on the major axis X of an ellipsoidal protein and the stable intrinsic transition dipole moment MU of the protein during unfolding. In this methodology, small-angle X-ray scattering (SAXS) is used to provide the protein global morphologies in the native and unfolded states. Furthermore, time-resolved fluorescence anisotropy (TRFA) provides the relative orientation between X and MU of Trp59 of the model protein cytochrome c. Hence observed in the protein unfolding with denaturants, acid, urea, or GuHCl, is the elongation of the native protein conformation along a reoriented protein major axis; accompanied are the different extents of relocations of the terminal alpha helices and loop structures of the protein in the corresponding unfolding. PMID- 26743266 TI - Downsizing: policy options to reduce portion sizes to help tackle obesity. PMID- 26743267 TI - Mineralized periodontia in extinct relatives of mammals shed light on the evolutionary history of mineral homeostasis in periodontal tissue maintenance. AB - AIM: Dental ankylosis is a rare pathological condition in mammals, however, it is prevalent in their extinct relatives, the stem mammals. This study seeks to compare the mineralized state of the periodontal attachment apparatus between stem and crown mammals and discuss its implications for the evolution of non mineralized periodontal attachment in crown mammals, including humans. MATERIALS AND METHODS: Thin sections of a fossil mammal and three stem mammals were compared to reconstruct periodontal tissue development across distantly related lineages. RESULTS: Comparisons revealed that the extinct relatives of mammals possessed the same periodontal tissues as those in mammals, albeit in different arrangements. The ankylotic condition in stem mammals was achieved through extensive alveolar bone deposition, which eventually contacted the root cementum, thus forming a calcified periodontal ligament. CONCLUSIONS: Dental ankylosis was part of the normal development of the stem mammal periodontium for millions of years prior to the evolution of a permanent gomphosis in mammals. Mammals may have evolved a permanent gomphosis by delaying the processes that produced dental ankylosis in stem mammals. Pathological ankylosis may represent a reversion to the ancestral condition, which now only forms via advanced ageing and pathology. PMID- 26743268 TI - Biology of ageing: principles, challenges and perspectives. AB - Living systems owe their survival and health to a series of complex biochemical pathways of maintenance and repair. These defense systems create the homeodynamic space of an individual, which is characterized by stress tolerance, molecular damage control and continuous remodeling. Ageing, age-related diseases and eventual death are the consequences of a progressive shrinkage of the homeodynamic space, due to the failure of maintenance and repair. Whereas longevity assurance genes do affect the essential lifespan of a species, there are no ageing-specific gerontogenes to cause ageing and to limit the lifespan of an individual. The challenge of preventing, managing or treating age-related chronic diseases and other health problems requires abandoning the traditional "one-target, one-shot" biomedical approach. Wholistic methods incorporating lifestyle-based hormetic interventions, including food, physical activity and mental engagement, appear to be potentially more successful in maintaining health and in extending healthspan and longevity. PMID- 26743270 TI - Needle-based confocal laser endomicroscopy in pancreatic cystic tumors assessment. AB - Pancreatic cystic tumors (PCT) are relatively common findings in general population due to the widespread use of cross-sectional imaging. PCT can be benign, with premalignant potential or malignant, a different management being applied for each type: benign cysts are usually referred for follow-up (based on imaging), while premalignant or malignant lesions should be surgically resected. The aim of this review is to describe the latest imaging technique that could be used for PCT diagnosis and to establish its clinical impact. Endoscopic ultrasound (EUS) is generally used to evaluate a pancreatic mass and to identify its characteristics. It offers a good visualization of the lesion. When combined with fine needle aspiration and cystic fluid analysis, the diagnosis potential is increased, although its accuracy for differentiating benign and malign tumors remains modest. EUS-guided needle-based confocal laser endomicroscopy (nCLE) is a new imaging technique that uses a miniprobe thin enough to be passed through a 19G needle. It provides in vivo images of the pancreas at a cellular level, offering the possibility to assess any changes that might have occurred. Several studies have shown that nCLE is feasible to use for PCT evaluation, imaging criteria being established with 100% specificity for intraductal papillary mucinous neoplasms (IPMN) and serous cystadenoma (SCA). Regarding the safety, more studies are needed. EUS-guided nCLE appears to be a new imaging technique that provides encouraging results for differential diagnosis between mucinous/non mucinous cysts. PMID- 26743269 TI - Molecular signatures of cardiac stem cells. AB - The discovery of cardiac stem cells (CSCs) able to renew the pool of cardiomyocyte raised the question of how these cells can be recognized and directed towards cardiac reconstruction after severe ischemic injury. The functional studies demonstrated that the differentiation of adult cardiac stem cells reproduce the stages observed in the embryonic development. Each stage is characterized by a complex molecular signature, which can be used for identification and molecular targeting. Three major markers have been used to isolate CSCs: c-kit, Sca-1, and Isl1 and different progenitor populations have been described: side-population (SP), cardiosphere-derived, epicardial-derived. Combinations between the main three markers and other transcription factors, cell surface proteins and regulatory RNAs may delimit even further the cardiac precursors. Accumulation of data leads to the idea that a single, yet unidentified unique cardiac stem cell is at the origin of those observed variants. In this review, we intended to summarize the actual knowledge about the main molecular markers of cardiac stem cells. PMID- 26743271 TI - The prognostic role of EBER in pediatric cancer. AB - The Epstein-Barr virus (EBV) infection is an endemic disease, over 90% of the population being exposed to it by adulthood. EBV is implicated in the etiology of a significant number of neoplasms, which acquire particular features in terms of course and prognosis. Incidence rates are much higher in children. To establish the link between EBV and neoplasms, EBER (Epstein-Barr virus non-encoded RNAs) needs to be highlighted in tumor tissue. The role of EBV in patient response to oncological treatment remains controversial. PMID- 26743272 TI - Overexpression of CSF-1R in nasopharyngeal carcinoma. AB - BACKGROUND: Tumor-associated macrophages play a significant role in tumor progression. CSF-1/CSF-1R is one of the most primary regulators of macrophage physiology in immune system. The expression of CSF-1/CSF-1R in nasopharyngeal carcinoma is unclear. OBJECTIVES: The aim of this study was to compare the expression of CSF-1R in nasopharyngeal carcinoma to nasopharyngitis for assessing the role CSF-1/CSF-1R in nasopharyngeal carcinoma. MATERIALS AND METHODS: Diagnostic tissues from 56 nasopharyngeal carcinoma patients and 32 nasopharyngitis patients were evaluated retrospectively by immunohistochemical analysis for the expression of CSF-1R. RESULTS: Significant differences of CSF-1R expression exists between nasopharyngeal carcinoma patients and nasopharyngitis patients (p<0.001). However, there is no relevance between CSF-1R and worse survival. PMID- 26743273 TI - The impact of two-socket preservation approaches on the soft and hard tissue healing: a short-term study in dogs. AB - The present study was designed in the context of the uncertain circumstances related to the best therapeutic option for ridge preservation. The research aimed to investigate the quality of early healing processes developed in the former sockets preserved with a collagen matrix alone or associated with a bone substitute in comparison with naturally-healed sockets, using an animal model previously validated. In both quadrants of the mandible of two dogs, the distal sockets of the second and fourth premolars served as experimental sites. Two sockets healed naturally, three sockets were preserved with the collagen matrix and three sockets were preserved with the collagen matrix plus a bone substitute. After one month of healing, the samples were harvested and histologically processed. The soft tissue covering the preserved ridges displayed an obviously thicker epithelial layer containing mostly areas of parakeratinized epithelium alternating with keratinized ones in comparison with naturally-healed sockets. In the apical third of the sockets, a mature bone structure was recorded for all three types of post-extraction approaches. While in naturally-healed and collagen matrix-preserved specimens the central third of the sockets contained bone with a mature aspect, in collagen matrix plus bone substitute-preserved sockets an immature appearance was observed. In the external third of the sockets, only in matrix-preserved alveoli a well-developed cancellous bone was present. The bovine bone substitute seemed to delay hard tissue development. The use of the collagen matrix could be a clinical option to preserve post-extraction ridges especially when an improvement in soft tissue quality is desired. PMID- 26743274 TI - Ischemic preconditioning and inflammatory response syndrome after reperfusion injury: an experimental model in diabetic rats. AB - Quantification of local ischemia and inflammatory response syndrome correlated with histological changes associated with ischemia-reperfusion injury (IRI) after revascularization techniques. We included 12 adult male Wistar rats, aged eight weeks that were randomly divided into two groups. The first group acted as the control and at the second group, we induced diabetes by intraperitoneal streptozotocin administration (60 mg/kg). After eight weeks, the rats were subject to ischemic preconditioning for 10 minutes at three regular intervals. Twenty-four hours post-preconditioning, both groups were subject to ischemia for 20 minutes, followed by 30 minutes of reperfusion. Oxygen extraction was higher in Group 1, the arterio-venous CO2 gradient was higher in the control group, but not significant. The lactate production was higher in Group 1. The second group had a higher Na+ and also a significant difference in K+ values. Receptor for Advanced Glycation End (RAGE) values were higher in the second group but with no significant difference (RAGE1=0.32 ng/mL versus RAGE2=0.40 ng/mL). The muscle samples from the control group displayed significant rhabdomyolysis, damage to the nucleus, while the preconditioned group showed almost normal morphological characteristics. The lungs and kidneys were most damaged in the control group, with damage expressed as thickened alveolar septa, neutrophil infiltrates, eosinophilic precipitates in the proximal convolute tubule. Ischemic preconditioning significantly attenuates the ischemic reperfusion injury. PMID- 26743275 TI - The assessment of immunohistochemical profile of endometriosis implants, a practical method to appreciate the aggressiveness and recurrence risk of endometriosis. AB - Endometriosis represents a chronic female genital tract disease characterized by implants outside the endometrial cavity, leading to alteration of pelvic anatomy and having as result chronic pelvic pain and infertility. AIM: From the molecular perspective, the aim of studying endometriosis is identifying a cause and a consequence, that lead to the appearance and perpetual arising of new implants. The description of the immunohistochemical (IHC) profile of ectopic endometrium could represent a new element in the pathogenesis of endometriosis and also a practical method to appreciate the aggressiveness and possibility of recurrence of the disease. The study consisting of histopathological and immunohistochemical (IHC) analysis of the tissues excised included 14 patients, operated from June to December 2014, to which was confirmed the presumptive diagnosis of endometriosis, based on anamnesis, clinical examination and ultrasound appearance. We identified the expression of estrogen and progesterone receptors, whose presence in the ectopic endometrium guides the medical hormone postoperative treatment. We also identified the expression of a cellular proliferation marker - Ki-67, and inhibition marker of cellular apoptosis - Bcl-2, in order to characterize the aggressiveness of endometriosis implantations and a stromal marker CD10. Although there are plenty of medical and surgical therapeutic methods available, the treatment of endometriosis must be individualized for every patient taking into consideration the IHC analysis. Consolidation of surgical treatment by prescription of a medical long-term treatment is indispensable, because endometriosis is a chronic relapsing disease. PMID- 26743276 TI - Morphological changes in membranoproliferative glomerulonephritis - a quantitative approach. AB - Our study aimed to investigate the quantitative profile of the renal corpuscle components in membranoproliferative glomerulinephritis (MPGN). We have analyzed digital color images corresponding to relevant microscopic fields from renal biopsies (10 cases type I MPGN and 10 cases type II MPGN). A computerized morphometric algorithm was designed and applied in both red-green-blue (RGB) and hue-lightness-saturation (HLS) color spaces, allowing the automated measurement of areas for the following morphological characteristics of the renal corpuscles (RCs): glomerulus, Bowman space, cells, mesangial matrix and glomerular basement membranes, and capillaries. Student's t-test comparatively applied between the numerical data obtained for the measured morphological characteristics, for each individual color space, showed significant differences between type I MPGN and type II MPGN for Bowman space area (p=0.006) and for mesangial matrix and glomerular basement membranes area - exclusively in RGB color space (p=0.013). We have also demonstrated larger RCs and glomerular size in type II MPGN, comparative to those in type I MPGN. Consequently, we assume that the morphometrical characterization of RCs histological components could be used as an additional criterion not only in the diagnosis of MPGNs, but also in the stratification of evolution and prognosis of patients diagnosed with type I and II MNGN, respectively. PMID- 26743277 TI - Correlations between intratumoral interstitial fibrillary network and vascular network in Srigley patterns of prostate adenocarcinoma. AB - OBJECTIVE: The study aims to assess the both individual behavior and correlations of stromal fibrillary component (SFC) and vascular density (VD) in relation with Srigley architectural patterns of prostate carcinoma. MATERIALS AND METHODS: Digital images of prostate adenocarcinoma labeled following both Gleason and Srigley systems were acquired with *20 objective from two serial sections, 340 from the section stained using Gomori technique for SFC assessment and another corresponding 340 from the section immunomarked with anti-CD34 antibody for assessment of VD. The SFC amount and VD were determined and compared. Srigley patterns were divided in two redefined behavioral groups: "solid" group (Srigley I, Srigley III, Srigley IV) and "necrotizing" group (Srigley II with subdivisions: Gleason 3A, 3C and 5A). RESULTS: SFC mean values had an ascending trend in both "solid" and "necrotizing" groups. VD mean values had an ascending trend in "solid" group but a descending trend in "necrotizing" group towards Gleason 5A pattern. SFC and VD values had a direct, ascending correlation for all determinations (p=0.0006), but also for "solid" (p=0.005) and "necrotizing" (p=0.026) groups. The two stromal elements had different behaviors both individually and in their correlation that seem to be related with their interaction with different tumor cellular populations. CONCLUSIONS: Our results could plead for the hypothesis that the different subtypes of tumor architecture represent steps of a continuous process from well-differentiated status to poorly or undifferentiated status but who is accomplished by two different tumor cells populations with different distinct behavior in their relationship with the stromal microenvironment. PMID- 26743279 TI - Orthodontic tooth movement following analgesic treatment with Aspirin and Algocalmin. An experimental study. AB - The objective of this study was the tracing of the effect of Aspirin and Algocalmin, two of the most frequently used analgesics after the application of orthodontic appliances, on the dental displacements, starting from the hypothesis according to whom any substance that inhibits prostaglandins' production will have as result the inhibition of the osteoclasts' activity and of the orthodontic tooth movements implicit. Twenty-four male Wistar rats, separated into three groups were used. Group I (control) included eight rats in which the orthodontic device was applied, without a subsequent administration of any analgesic; Group II - eight rats in which after the device application Aspirin was administrated; and Group III - eight animals in which Algocalmin was administrated. A histological study was completed in order to establish the size of bone areola. Average mesial displacement of the first left inferior maxillary molar 28 days after applying the orthodontic device was of 3.61+/-0.29 mm for the control group. The average displacement in the group in which Aspirin was administrated was 0.03 mm. In the group treated with Algocalmin, the dental displacement was of 0.19+/-0.08 mm. Histological examination revealed the presence of large sizes bone areola in control group (244 MUm), more reduced in the group treated with Aspirin (74 MUm), and intermediate in that treated with Algocalmin (127 MUm). Treatments with Aspirin and Algocalmin in experimental groups, immediately after the orthodontic device application, induced a decreased dental displacement rate. PMID- 26743278 TI - Time- and dose-dependent severity of lung injury in a rat model of sepsis. AB - Different animal models of experimental lung injury have been used to investigate mechanisms of lung injury. Lipopolysaccharide (LPS) administration is the most often used approach to model the consequences of bacterial sepsis. We created an endotoxemia rat model, simulating sepsis-related lung injury, in order to quantify the time and dose dependent severity lesions induced by the administration of lipopolysaccharide. Our study included 42 male Wistar rats, randomly divided into four groups: one control group (n=6) and three experimental groups (n=12/group) in whom we induced sepsis by intraperitoneal injection of progressively increasing doses of LPS (3, 5, 10 mg/kg). At six hours, the animals included in the groups with higher doses of LPS developed thrombocytopenia, elevated lactate levels, and liver and renal injury in a dose and time dependent manner. The severity of hypoxemia at six hours correlated with the increasing doses of LPS, with a slight improvement at 24 hours. Lung injury scores became more severe with increased dose and time of exposure to LPS without reaching the level of hyaline membranes formation. We also demonstrated translocation of a protein from the airspaces into plasma (RAGE - receptor for advanced glycation end products). Induction of sepsis using LPS is a known experimental model, but LPS treatment in rats does not cause the severe endothelial and epithelial injury that occurs in humans with acute respiratory distress syndrome (ARDS). In our study, the clinical, laboratory and histopathological findings confirmed sepsis and the damage of the alveolar-capillary membrane in a dose-dependent manner. PMID- 26743280 TI - Comparative study of clinical-morphological profiles of different types of gastric carcinoma. AB - AIM: Gastric carcinoma shows considerable variation in the histological pattern and degree of differentiation. The aim of the study was to assess especially the morphological differences between gastric carcinomas revealing one morphological feature and those including two morphological features. MATERIALS AND METHODS: Two groups of patients were selected: Group 1, including 43 patients with tumors revealing only one architectural pattern, and Group 2, including 16 patients with two architectural patterns within the tumor. In addition to gender and age, the main morphological parameters were: lesion location and macroscopic appearance on the surgical excision sample and microscopic appearance of the surgical excision sample, assessed for architectural pattern, secretory properties and prognosis based on histological features, degree of tumor extension and the degree of tumor aggressiveness, using a wide range of histological and immunohistochemical stainings. All data were compared between the two groups using statistical tests. RESULTS AND DISCUSSION: Significant differences were observed between the values and distributions of morphological parameters in the two groups and were discussed comparatively. CONCLUSIONS: Tumors with two dominant histological aspects present simultaneously are a reality that cannot be argued but whose morphological and biological profile needs to be completed and validated. PMID- 26743281 TI - Different patterns of heterogeneity in ovarian carcinoma. AB - Ovarian cancer is still the leading cause of death from malignant genital tract lesions. Ovarian carcinomas represent about 90% of cancers that arise in the ovaries and are commonly diagnosed around menopausal age. This study examines different aspects of the heterogeneity of ovarian carcinomas and included 50 cases, 10 cases for each subtype. Our data showed that tumor types have distinct morphological and phenotypic patterns: high- and low-grade serous carcinoma, endometrioid, clear cell and mucinous carcinoma. The different subtypes of ovarian carcinomas have different molecular, pathological and clinical characteristics, the histological diversity of epithelial ovarian carcinoma mirroring thus distinct entities not just one disease. PMID- 26743282 TI - Comparison of hepatic nuclear factor-4 expression in two- and three-dimensional culture of Wharton's jelly-derived cells exposed to hepatogenic medium. AB - The research on Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) from the umbilical cord suggests promising therapeutic use for hepatocyte replacement therapy. One of the highly conserved members of the nuclear receptor superfamily in the liver is hepatocyte nuclear factor-4alpha (HNF4alpha), involved in hepatocyte differentiation. The objectives of this study were to determine the effects of two- and three-dimensional (2D and 3D) cultures of WJ-MSCs on hepatocyte differentiation. MSCs were isolated from human Wharton's jelly, characterized by flow cytometry, and differentiated toward osteogenic and adipogenic lineage. WJ-MSCs were cultured in 2D collagen films and 3D collagen scaffolds in the presence of hepatogenic media with or without pre-treatment with fibroblast growth factor-4 (FGF4) for 21 days. The expression of HNF4alpha was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). According to flow cytometry data, the cells isolated from Wharton's jelly were shown to express MSC markers. HNF4alpha expression analysis revealed that pre exposing the cells with FGF4 was more effective in hepatocyte differentiation. 3D cultures also improve the expression of HNF4alpha compared with 2D culture system. In conclusion, the combination of FGF4 and 3D culture improved hepatocyte differentiation. It seems 3D interaction of the cells improved the hepatogenesis. PMID- 26743283 TI - Particular molecular and ultrastructural aspects in invasive mammary carcinoma. AB - Electron microscopic investigations of invasive mammary carcinoma tumors revealed that intercellular junctions, namely desmosomes are severely altered; some desmosomes became internalized. Tumor cells, especially by their invadopodia, generate and disseminate membrane vesicles, including exosomes, inside of peritumoral stroma. Telocytes, a new described interstitial/stromal cell phenotype, considered to play important roles in cell signaling, exhibited a reduced number of hetero-cellular contacts, which suggests a possible perturbation of tissular homeostasis modulation. Signaling PIK3/Akt pathway plays an important role both in carcinogenesis and in proliferation, differentiation, and cell survival. Alteration of this pathway has been observed in many human cancers, often involving an increase in the activity of PIK3CA, p110alpha catalytic subunit of PI3K. Our study confirms the high prevalence of PIK3CA mutations in breast cancer. In accordance with the results of the largest previous studies, 87.5% of mutations detected by DNA direct sequencing were hot spot mutations, most of them located in the kinase domain. High percentage of mutations detected by high-resolution melting makes the assay an attractive choice for mutation scanning, especially, in samples with low percentage of tumor cell. PMID- 26743284 TI - A study on the type of lesions achieved by three electrosurgical methods and their way of healing. AB - The technical progress in the medical sector in the past decades has continuously driven the development of electrosurgical techniques. The controversies surrounding the superiority of a certain technique relative to another - electrocautery, laser and radiofrequency - have determined us to carry out a histopathological design with the aim of comparing the healing sort of the shallow wounds generated by the three types of electrosurgical devices. The experimental study has investigated the healing process inflicted by the electrosurgical devices mentioned beforehand on 12 Wistar albino rats. The wounds were inflicted under intravenous general anesthesia with Xylazine and Ketamine and were performed lateral to the spine region, using laser, radiofrequency and electric cautery. The histological samples harvested at one, three, five, and seven days were sent to pathological examination. We followed by comparison the evolution of the first two phases of the wound healing produced by the three electrosurgical methods analyzed. We described the histopathological changes occurred in the epidermis, dermis and hypodermis and also the subcutaneous soft tissues in all of the three types of lesions. Electrocautery remains the most frequently used electrosurgical device, even if it has unquestionable disadvantages as compared to other modern instruments. Laser-assisted surgery and radiofrequency are refine energy-based instrumentation, being utilized at a multidisciplinary surgical level. PMID- 26743285 TI - Changes in immunoexpression of p53, Ki-67, Ets-1, APAF-1 and PTEN in serrated and conventional colon adenomas. AB - The balance between apoptosis and proliferation is tipped towards a decrease of apoptosis as the colonocyte progresses in the adenoma to carcinoma sequence of colon carcinogenesis. According to literature data, proteins like p53, Ki-67, APAF-1, Ets-1, PTEN contribute to inhibition of apoptosis and stimulation of proliferation. AIM: Considering the complex interference among colorectal carcinogenetic mechanisms, our aim was to study the markers Ets-1 and APAF-1 relative to p53, Ki-67 and PTEN expression in colon adenomas/polyps (A/P). MATERIALS AND METHODS: We performed immunohistochemistry on 99 colon A/P cases from the material of the Department of Pathology, Emergency County Hospital of Tirgu Mures, Romania. Secondary EnVision Flex/HRP (Horseradish peroxidase) (20 minutes) was used for signal amplification. RESULTS: The majority of A/P show increased Ki-67, p53, Ets-1 expression, decreased APAF-1 expression and preserved PTEN expression. p53, Ki-67, Ets-1 and APAF-1 demonstrated statistically significant correlations with histological type and grade of dysplasia. We also observed that expression of these proteins in the intestinal crypts has a typical distribution according to histological type and grade of dysplasia. CONCLUSIONS: In case of hyperplastic polyps APAF-1 expression decreases as p53 and Ki-67 expression increases, followed by a decrease in PTEN expression in serrated adenomas, and an increase of Ets-1 expression in conventional adenomas. PMID- 26743286 TI - Phyllodes tumor: diagnostic imaging and histopathology findings. AB - Phyllodes tumors are rare breast tumors, accounting for less than 1% of all primary tumors of the breast. Histologically, phyllodes tumors can be divided into benign (60%), borderline (20%) and malignant (20%). The mammography examination was performed by means of a digital mammography system Giotto 3D Images; the ultrasound examination was performed through a GE Logiq P6 device and histological confirmation was possible after surgery or following the histological biopsy. We grouped the nine patients who presented clinically palpable nodules into two groups, namely: the six patients presenting histological benign results into Group I, and Group II where we included those with borderline and malignant histological results. Mammography performed in 77.7% revealed a well-circumscribed round or oval opacity or with contour lobules. Ultrasound examination was performed in all patients. Mammography and ultrasound have limitation in differentiating between benign lesion and phyllodes tumor. In the nine analyzed cases, mammographic and ultrasound examinations did not allow the differentiation into the three groups of phyllodes tumor. Histopathological examination is considered the golden standard for their diagnosis. Correlations between mammographic and microscopic aspects were inconclusive for determining the degree of differentiation, ultrasound changes could be correlated with the histopathological aspects. PMID- 26743287 TI - Morphological variability of arterial sources of the renal polar parenchyma and its clinical importance. AB - A sample of 250 kidneys (200 corrosion casts and 50 dissection pieces) provided the basis for the analysis of the number, source, origin point and parenchymal penetration of the arterial branches supplying the two renal poles. Of the studied pieces, 76.80% had a single renal artery, while 23.20% had multiple renal arteries. The superior pole had only one arterial source in 95.20% of cases, and the inferior pole had only one arterial source in 97.20% of cases. The arteries supplying the superior pole originated from one of the renal artery's branches in 59.60% of cases and from its' main trunk in 17.20% of cases. They were also found to originate from branches of the multiple renal arteries in 18% of cases and from the abdominal aorta (5.20% of cases - inferior polar arteries). The arteries supplying the inferior pole arose in similar fashion - from the single renal artery's trunk in 9.20% of cases; from its division branches in 66.40% of cases; from the abdominal aorta in 9.60% of cases and from branches of multiple renal arteries in 14.80% of cases. Familiarity with the renal arteries' morphological variability is becoming increasingly important, as new urologic surgical and radiological techniques develop. PMID- 26743288 TI - Histological evaluation of oral maintenance programs upon gingival condition in orthodontic patients. AB - The aim of the study was to conduct a histological evaluation of gingival condition in patients under orthodontic treatment with fixed appliances, according to different oral hygiene maintenance programs. We performed a randomized prospective study on 36 patients with fixed orthodontic appliances (17 25 years of age) divided in three study groups. The investigations were represented by measurements of plaque index and sulcular bleeding index, followed by pathological examination of specimens from gingival tissue. Treatment of orthodontic patients must follow an interdisciplinary approach. All modalities of oral hygiene procedures and their effect on the periodontal tissues must be explained to the patient prior to fixed orthodontic treatment. Fixed orthodontics do not induce periodontal disease if basic principles of oral hygiene are followed in compliant patients, which are correctly instructed to deal with real challenge, represented by complete elimination of debris and bacterial accumulation. PMID- 26743289 TI - Efficiency of gentamicin loaded in bacterial polysaccharides microcapsules against intracellular Gram-positive and Gram-negative invasive pathogens. AB - Gentamicin is an aminoglycoside antibiotic with a wide spectrum of anti-bacterial activity, but however, due to its high solubility in water, it poorly penetrates inside the cells. This major inconvenient constitutes an important challenge for the treatment of intracellular bacterial infections, which might be solved using appropriate delivery systems for the targeted release of the bioactive agents at the intracellular sites of infection. Thus, in the case of antibiotics, the use drug delivery systems may contribute to increase their therapeutic activity against intracellular pathogens. This paper presents an efficient polymeric delivery system for the intracellular release of gentamicin based on bacterial polysaccharides. PMID- 26743290 TI - Tissue prints for the rapid diagnosis of malignancy in lung cancer. AB - Rapid diagnosis of malignancy during oncological surgery is crucial for making decisions related to the extension of the resection. The tissue prints, used initially for plant biology but also for prostate or breast cancer diagnosis, might be useful as a rapid cytological diagnosis. MATERIALS AND METHODS: Tissue prints were done from freshly sectioned excised tissue fragments in patients operated between March 2010 and February 2012 in the Department of Surgery for cancer or benign lesions. Tissue prints were examined by a cytologist and considered as malignant or benign. Same fragments were then processed in the pathology laboratory using the typical paraffin-embedding method. All slides were examined by the same pathologist and considered the golden standard for malignancy and histological type. RESULTS: Three hundred and eleven fragments were examined, obtained from lung masses, lymph nodes, pleura and mediastinal masses, pathology showed 208 malignant and 103 benign. Tissue prints identified 227 malignant and 84 benign. For identifying malignancy, tissue prints had a sensibility of 0.91, specificity 0.64. Positive predictive value was 0.86 and negative predictive value 0.78. For lymph nodes, the specificity was better. In lymphomas and adenocarcinomas, tissue prints identified also the histology type in most cases. CONCLUSIONS: Tissue prints are rapid, easy to perform, cheap, with high sensibility but specificity lower than literature data on frozen sections. This might be improved by a better selection of cases where tissue prints are used for rapid diagnosis. PMID- 26743291 TI - Ki-67 and p53 immunostaining assessment of proliferative activity in salivary tumors. AB - Salivary gland tumors are rare neoplasias with approximately 34 different histological types. Because they have a considerably histological and biological behavior variability, salivary gland tumors represent a challenge both for the pathologist and the surgeon regarding their diagnosis, prognosis and treatment. Evaluation of mitotic index in case of Ki-67 and p53 expression has proved to be useful in predicting the biological aggressiveness in many tumors. In this study, we have analyzed the p53 and Ki-67 immunohistochemical expressions in 40 cases of salivary gland tumors, their correlations with clinicopathological factors and the prognostic relevance and diagnostic value of the results obtained. We analyzed eight pleomorphic adenomas (PA), seven Warthin tumors (WT), five basal cell adenomas (BA), four carcinomas ex pleomorphic adenoma (CEPA), four mucoepidermoid carcinomas (MEC), four acinic cell carcinomas (AC), four adenoid cystic carcinomas (ACC) and four adenocarcinomas not otherwise specified (ADK NOS). p53 positive staining was detected in 18 of the 40 cases studied, with higher expression in the malignant salivary tumors investigated. Ki-67 was expressed in 29 cases. High p53 and Ki-67 expression was noted in 3/4 CEPA, 3/4 ADK NOS and 2/4 MEC. Also, 2/8 PA, 3/7 WT and 2/5 BA were p53 positive and 2/7 WT and 2/5 BA had high Ki-67 mitotic index. The investigation of p53 and Ki-67 expression is useful in identifying highly proliferative forms of salivary tumors, with aggressive potential of evolution. The evaluation of these proliferative markers seems to have a prognostic value for CEPA, ADK NOS and MEC types of salivary tumors. PMID- 26743292 TI - Cyclooxygenase-2 and matrix metalloproteinase-9 expressions correlate with tissue inflammation degree in periodontal disease. AB - INTRODUCTION: Cyclooxygenase-2 (Cox-2) and matrix metalloproteinase-9 (MMP-9) have synergistic effects in the degradation of the extra-cellular matrix. OBJECTIVE: The aim of our study was to correlate the intensity of inflammation with MMP-9 and Cox-2 expression in the periodontal tissue of patients with chronic inflammatory disease (gingivitis and chronic periodontitis) in order to determine the role of these two biomarkers in the progression of periodontal disease. MATERIALS AND METHODS: To conduct this study we analyzed the gingival biopsies taken from patients clinically divided into three study groups: Group I (control): Patients free of periodontal disease (seven biopsies); Group II: Patients with gingivitis (10 biopsies); Group III: Patients with chronic periodontitis (10 biopsies). In these three groups, we graded the intensity of inflammation in the lamina propria and the immunohistochemical expression of MMP 9 and Cox-2. RESULTS: The presence of a large number of inflammatory cells in the lamina propria in patients with gingivitis or chronic periodontitis (Groups II and III) correlated with the clinically diagnosed inflammation of the gingival tissue. The expression of MMP-9 was higher in patients with chronic periodontitis than in those with gingivitis, showing a trend towards statistical significance (p=0.07, Mann-Whitney U-test). The expression of Cox-2 in periodontitis was also higher compared to gingivitis (p=0.05, Mann-Whitney U-test) and to controls (p=0.001, Mann-Whitney U-test).The inflammation score could be positively correlated to the MMP-9 and Cox-2 expression scores at the overall study group, but not separately on gingivitis and periodontitis patients. CONCLUSIONS: The presence of an intensive inflammatory infiltrate is characteristic both for periodontitis and gingivitis. MMP-9 and Cox-2 show higher expression in periodontitis, than in gingivitis and healthy controls, but MMP-9 and Cox-2 expression scores cannot be directly correlated to the grade of inflammatory infiltrate in the two different disease entities. As biomarkers of chronic inflammation activity, angiogenesis, and degradation of the extracellular matrix, MMP-9 and Cox-2 can be used in clinical practice for the detection of patients with chronic periodontitis risk, at whom treatment with Cox-2 and MMP-9 inhibitors may be considered. PMID- 26743293 TI - Imaging and histopathological aspects in aseptic osteonecrosis of the femoral head. AB - Aseptic osteonecrosis causes various clinical manifestations, depending on its location, but has in common a histopathological and radiological substrate. Aseptic osteonecrosis of the femoral head is a condition whose pathogenesis remains unclear despite many theories developed so far, and the discovery of numerous risk factors. The objective of this study is to emphasize the role of imaging techniques and correlating histology and immunohistochemistry methods in order to more accurately stage the disease. This retrospective study was performed on a total of 103 patients with clinical and radiological suspicion of unilateral or bilateral osteonecrosis. For the diagnosis criteria, we used clinical information, pelvic X-ray images, magnetic resonance imaging (MRI) or computed tomography (CT). For the inclusion of patients in a disease stage, we used the Association Research Circulation Osseous (ARCO) classification system. For patients diagnosed at an advanced stage, who underwent hip arthroplasty, we harvested biological material necessary for the histopathological study. There were differences in the appearance and extent of the lesion on the histological samples compared to macroscopic examination and even those obtained through imaging means, particularly for patients in evolutionary stage III. Aspects such as the extension of the area of fibrosis, bone tissue remodeling, the density of the newly formed vascular network and degree of impairment of the cartilage, are determined more accurately using histology and immunohistochemistry techniques. Before classifying patients in a certain stage, after correlating clinical and imaging data, histopathological aspects have to be considered, particularly in patients in stages III and IV, in which total hip arthroplasty could be delayed. PMID- 26743294 TI - Histological evidence of novel ceramic implant: evaluation of tolerability in rabbit femur. AB - The investigation of desired optimal interface between bone and dental or orthopedic implants, and whether a newly developed material conforms to the requirements of biocompatibility and mechanical stability, are important and rigorous procedures as an essential step prior to clinical trials. The present study proposes the investigation of a novel ceramic implant in terms of biocompatibility, osseointegration and bone response, by an experimental study using a small animal model (rabbit). Radiological examination after six weeks post-surgery highlighted the stability and well integration of the implant, without fibrous tissue or other undesirable complications. The histological analyses highlighted the morphological details of the new tissue, which was well vascularized throughout its thickness. The new bone formation ensured not only the coverage of the implant hole, but also the continuity with the adjacent bone. The chemical stability is suggested by the XRD (X-rays diffraction) pattern, as the implant did not showed erosion marks at the surface, not even discrete ones. Moreover, the XRD pattern recorded on the surface of femoral bone showed the fingerprints of hydroxyapatite indicating that the new bone covered the surface of the implanted area. The qualitative and quantitative aspects of the new bone were highlighted through light microscopy and SEM/EDX (scanning electron microscopy/energy dispersive X-rays), especially the lamellar architecture of the new bone at the contact area with the implant, six weeks after insertion. The CA/P ratio was evaluated, which is a valuable indicator in qualitative assessment of the osseous tissue. PMID- 26743295 TI - Hepatocellular carcinoma and metabolic diseases - histological perspectives from a series of 14 cases. AB - Hepatocellular carcinoma (HCC) represents a major health burden, as curative methods only apply to a select small portion of the affected population. Screening programs are ineffective in the absence of established underlying conditions such as viral hepatitis or alcohol abuse resulting in liver cirrhosis. Thus, overweight or obese, diabetic patients as well as non-alcoholic fatty liver disease (NAFLD) cases are often overlooked as potential candidates for HCC development. Current diagnostic methods for HCC are restricted to non-invasive imaging tests; however, the need for accurate predictive or therapeutic markers make histological studies a necessity; the latest guidelines and recommendations demand an increased effort in obtaining pertinent data from immunohistochemical investigations. Our aim was to retrospectively evaluate a series of patients with common symptoms and manifestations of metabolic syndrome who underwent liver biopsy after imaging revealed suspicious liver masses. We describe the major findings of both common histological evaluation and microvessel density evaluated by positive CD34 immunostaining. PMID- 26743296 TI - Digital dermoscopic follow-up of 1544 melanocytic nevi. AB - The use of dermatoscopy increases melanocytic nevi diagnostic accuracy, and is important for dermoscopic monitoring of atypical lesions, allowing to find significant changes in the earliest stage. Dermoscopic diagnosis of melanocytic nevi type in a group of patients and their follow-up with the assessment of changes occurred during dermoscopic monitoring. Dermoscopically, we followed the nevic size and pattern, the color and pigment distribution. Follow-up visits were scheduled depending on the type of the melanocytic lesions and the patient's compliance. The nevi that have shown significant dermoscopic changes were excised and histopathologically examined. The study was performed on a group of 92 patients, mostly females (56.5%), mean age of 29.1 years. Of the total of 1544 melanocytic nevi examined, 27.4% were atypical and 72.6% common nevi. The average dermoscopic examination interval was 14.1 months. During monitoring, 35.5% atypical nevi and 22.5% common nevi have modified, especially changes in pigmentation and color (31% atypical nevi and 9.9% common nevi) and the appearance of new dermoscopic structures (12.7% atypical nevi and common nevi 8.5%). Of the total nevi monitored, 3% showed significant changes and were excised and examined pathologically, without diagnose of any malignant transformation. In our study, dermoscopic changes appeared in atypical as well as in common nevi. The dermoscopic monitoring of melanocytic-pigmented lesions remains an accessible method of assessment the evolution of nevi and can reduce the risk of appearance of malignant melanoma in the general population. PMID- 26743297 TI - Myocardial interstitial fibrosis - histological and immunohistochemical aspects. AB - BACKGROUND AND AIM: The process of myocardial fibrosis is based on the remodeling of the extracellular matrix (ECM), which leads to increased myocardium stiffness and, in turn, severe alterations of the cardiac function. This phenomenon is consecutive to various types of cardiac disease, primarily infarction, due to inflammatory reactions involving various types of cellular mechanisms. We aimed in this paper to assess both microscopically and immunohistochemically the main aspects of ischemic myocardium found in areas of fibrosis and compare the findings with normal images from unaffected cardiac tissue of the same type. MATERIALS AND METHODS: Our study included infarction fragments of 2/2/2 cm harvested after autopsy from 26 patients who died during 2014 at the Emergency County Hospital of Craiova, Romania, following the diagnostic of ischemic cardiomyopathy. After usual histological preparations, we performed both classical staining with Hematoxylin-Eosin and trichromic Goldner-Szekely, as well as immunohistochemical assessment using anti-alpha-SMA, anti-desmin, anti-CD34 and anti-CD68 antibodies. RESULTS: We have evaluated myocardial fibrosis in all areas of the myocardium and noted that it primarily develops around the arterioles and metarterioles. The area of myocardial fibrosis was more extensive, myocardiocytes being surrounded by collagen fibers. Collagen interstitial fibrosis, gave a "brindle" look to the myocardium. Myocardial fibrosis areas did not reveal myofibroblasts. We found lower numbers of blood vessels with an uneven distribution in areas of myocardial fibrosis. In the areas of normal myocardium, the macrophage numbers were two to three times lower than in areas of fibrosis, also displaying larger volume, with intense reaction to CD68. CONCLUSIONS: Myocardial interstitial fibrosis occurs in outbreaks, mainly perivascular, but it affects larger areas of the myocardium interstitial space. We believe that interstitial fibrosis is a progressive process that can become permanent, thus constituting a promising therapeutic target for a large variety of cardiac conditions. PMID- 26743298 TI - In vivo biodistribution of CNTs using a BALB/c mouse experimental model. AB - BACKGROUND: Due to their unique behaviors, carbon nanotubes (CNTs)-based systems meet essential requirements for modern applications, such as electronics, optics, photovoltaics, fuel cells, aerospace engineering, military and biomedical applications. CNTs biocompatibility and toxic effects were assessed both in vitro and in vivo, in terms of hemocompatibility, cytocompatibility, immunoreactions and genetic behavior. AIM: The aim of this paper is to evaluate the in vivo biodistribution and biocompatibility of carbon nanopowder synthesized by plasma processing, using a BALB/c mouse experimental model. MATERIALS AND METHODS: Three months old BALB/c mice were aseptically injected with 100 MUL of 1 mg/mL dispersions. The obtained carbon-based nano-systems were dispersed in saline solution and subsequently sterilized by using a 30 minutes treatment with UV irradiation. The reference mice were injected with 100 MUL of saline. The mice were kept under standard conditions of light, temperature, humidity, food and water (ad libitum) before the vital organ harvest. The animal welfare was daily monitored. At two and 10 days after the inoculation, the animals were euthanized under general anesthesia, for the sampling of internal organs (brain, myocardium, pancreas, liver, lung, kidney and spleen). RESULTS: No animal died during the experiment. Brain, myocardium and pancreas were histologically normal, with no tissue damage, inflammatory infiltrate or inorganic deposits. CNTs were evidenced only in hepatic, renal, pulmonary and spleen tissue samples. Increased amounts of inorganic granular structures were reported after 10 days of treatment, when compared to the short-term (two days) inoculation. CONCLUSIONS: Our BALB/c mouse experimental model was found to be useful for the in vivo assessment of biodistribution and biocompatibility of CNTs. PMID- 26743299 TI - Pitfalls in diagnosing a pancreatic neuroendocrine tumor: a case report. AB - Pancreatic neuroendocrine tumors are a rare subset of pancreatic neoplasms. We report the case of a 33-year-old female patient who was admitted to the Diabetes Clinic of Craiova, Romania, due to a two-year history of episodic neuroglycopenic hyperinsulinemic hypoglycemic symptoms, suggestive for insulinoma associated with facial and upper trunk flushing characteristic to carcinoid syndrome. During these episodes, the laboratory investigations showed hypoglycemia (38 mg/dL), hyperinsulinemia (54.72 MUU/mL) and normal values of beta-hydroxybutyrate, chromogranin A, serotonin, anti-insulin antibodies and urinary levels of 5 hydroxyindoleacetic acid. Endoscopic ultrasound with SonoVue and 3T MRI revealed an 18.3/16.3 mm hypervascular tissular mass situated in the uncinate process of the pancreatic head in close contact with the superior mesenteric vein without invasion and no other detectable secondary lesions in the pancreas or any other abdominal viscera. Patient underwent enucleation of pancreatic tumor. The histological and immunohistochemical findings indicated a functional well differentiated pancreatic neuroendocrine tumor, G1 category according to the World Health Organization (WHO) criteria, with uncertain behavior (Ki67 index was 3%), confined to the pancreas, but with tumoral invasion of the delimiting conjunctive capsule. No evidence of tumoral CK19 staining, mitoses and necrosis, angioinvasion or extra-pancreatic invasion was observed. A post-operative nine month follow-up showed resolution of hypoglycemic symptoms, normalized blood glucose and insulin levels and no evidence of recurrence. Our case report highlights the pitfalls in diagnosing a functional pancreatic neuroendocrine tumor due to atypical symptoms, the difficulty of identification and precise location of the small-size tumor and uncertain histopathological and immunohistochemical behavior. PMID- 26743300 TI - Giant gastrointestinal stromal tumor of the stomach: a challenging diagnostic and therapeutically approach. AB - Gastrointestinal stromal tumors (GISTs) are rare but challenging tumors regarding the diagnosis and therapy. The symptomatology depends on the tumor size and location, and can be totally non-specific, as in the present case. We present the case of a 76-year-old female that was hospitalized with postprandial nausea and vomiting. Bulging of the posterior wall of the stomach was seen at endoscopically examination and confirmed by the computed tomography. Surgical resection of the 120*100 mm-sized tumor that involved the posterior gastric wall and gastrocolic ligament, was performed; the posterior wall of the stomach was also partially excised. Histological examination revealed a 120*95*70 mm nodular tumor with solid aspect and large necrotic and hemorrhagic area on cut section. The tumor cells were marked by c-KIT, DOG-1, smooth muscle actin and MSH-2 and were negative for Ki67, maspin, E-cadherin, S-100, and keratin AE1/AE3. The resection margins were free of tumor cells. No recurrences were reported three years after surgical intervention; no postoperative chemotherapy was performed. This case highlights that a well-conducted trans-disciplinary approach can have real benefits, even in borderline-operable giant potentially-malignant GISTs. New criteria to establish the malignant potential of GIST should be explored. PMID- 26743301 TI - Bilateral triple renal arteries. AB - We report an atypical case of a 53-year-old male with the presence of six renal arteries (RAs) (bilateral triple) found incidentally on multi-detector computed tomography (MDCT) angiography, which was used to investigate peripheral vascular disease of the lower limbs. The distance between the extreme points of RAs origin from abdominal aorta (AA) was in right 4.42 cm, and in left 2.40 cm. The distance between the extreme points of penetration into the renal parenchyma was in right 2.01 cm, and in left 2.56 cm. On each side, the endoluminal diameter at the origin of the main RA (in right 0.54 cm, and in left 0.42 cm) was significantly larger in comparison with the other additional renal arteries (AdRAs) (in right 0.21-0.29 cm, in left 0.24-0.35 cm); however, the AdRAs were much longer (in right 7.42-10.82 cm, in left 5.90-6.85 cm) than the main RA (in right 6.21 cm, in left 5.73 cm). All the four AdRAs were hilar RAs. Knowledge of this anatomical variation should not be ignoring when planning the adequate interventional radiological and surgical procedure. PMID- 26743302 TI - Laryngeal primary malignant melanoma: a case report. AB - Malignant melanoma of the larynx is a rare cancer that can appear as a primary tumor or as a metastasis from a cutaneous head and neck primary lesion. We present a new case of primary laryngeal malignant melanoma diagnosed by histological examination of an excisional biopsy specimen. The patient was a 53 year-old man with a history of smoking and hoarseness but without any clinical evidence of other cutaneous malignant melanocytic lesions. Microscopically, the tumor consisted of polygonal-epithelioid cells admixed with more elongated, spindle-shaped cells. Some of the tumoral cells demonstrated dark brown cytoplasmic and nuclear melanin. Despite significant ulceration and disruption of the epithelium, in situ malignant melanocytes were recognized within the remaining epithelium. Immunohistochemical stains were strongly positive for S-100 protein, HMB-45 and Melan-A. On the other hand, cytokeratin stains were negative. Based on the clinical and histological findings, a diagnosis of primary malignant melanoma of the larynx was established. PMID- 26743304 TI - Intramuscular high-grade myxofibrosarcoma of left buttock of 66-year-old male patient - approach to systematic histopathological reporting. AB - Here we present a systematic approach to histopathological reporting of high grade myxofibrosarcoma of 66-year-old male patient. The tumor was biopsied with fine-needle aspiration (FNA) and core-needle biopsy (CNB) and then the whole myxoid tumor was excised with left musculus gluteus maximus. The lesion was stained with Hematoxylin-Eosin (HE), Periodic acid-Schiff (PAS), Alcian blue, Masson's trichrome, Ki67, alpha-smooth muscle actin (alpha-SMA), S100, CD34 and vimentin. FNA material grounded the diagnosis of non-epithelial neoplasia, while CNB was enough to produce diagnosis of myxoid sarcoma. The tumor lied under superficial fascia with no extension beyond deep fascia or any invasion of skin, vessels or nerves, either. The tumor was intramuscular, mainly myxoid with hypercellular areas of highly atypical cells with bizarre giant multinucleated cells that clearly belonged to category of high-grade sarcoma. According to Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC), the case was assessed for 5 points. Ki67 index reached more than 80% malignant cells. Alcian blue was strongly positive in myxoid background. Masson's trichrome emphasized fibrillary structure of tumor. Negativity for S100, alpha-SMA with strong co expression of CD34 and vimentin supported the diagnosis of myxofibrosarcoma. The lesion was diagnosed as high-grade myxo-fibrosarcoma (formerly myxoid malignant fibrous histiocytoma) G2 pT2b [7th edition pTNM (pathological tumor-node metastasis), code ICD-O 8811/3 in World Health Organization (WHO) Classification 2013]. In approach to diagnosis of soft tissue malignancies, a strict sequence of procedures should be applied as only meticulous and ordered diagnostic pathway would succeed in and correct identification of a peculiar type of sarcoma. PMID- 26743303 TI - Retroperitoneal ancient schwannoma - case presentation. AB - Retroperitoneal ancient schwannomas are rare tumors, more usually found in the head, neck and flexor surfaces of the extremities. Ancient schwannomas are a subtype of classic schwannomas with a predominance of degenerative changes, calcifications, hemosiderin deposition, interstitial fibrosis and vascular hyaline degeneration. A 33-year-old male was referred on our hospital with a painful mass in left iliac fossa. The patient underwent surgery and intra operatively the cystic encapsulated mass was found to be retroperitoneal, between the left psoas major muscle and left iliac muscle. On microscopic examination, we found the presence of Schwann cells in regions with high and low cellularity (Antoni A and B areas) and S100 protein immunohistochemical examination was intensely positive, being consistent with the diagnosis of schwannoma. Complete excision is the only method of the surgical treatment; schwannomas are not sensitive to radiotherapy and chemotherapy. Some authors consider that a complete excision of the tumor, while others believe that enucleated or partial excision of the tumor is sufficient. The prognosis is good, and the most common complication is recurrence, possibly by incomplete excision of it being reported in 5-10% of cases. In conclusion, retroperitoneal schwannomas is usually identified incidentally on tomographic images. Diagnosis is based on histopathological examination after surgery and immunohistochemical examination. PMID- 26743305 TI - Borderline ovarian cyst treated by laparoscopic surgery: clinical case report and literature review. AB - Borderline ovarian serous tumors are a rare distinct category of epithelial ovarian tumors, distinguished from both benign and invasive ovarian tumors. As borderline ovarian cysts are only a small part of the gynecological conditions of children, the therapeutic approach to this special type of tumor has not been standardized yet. Despite the technological breakthroughs that we have witnessed lately, the positive diagnosis of ovarian tumors is possible only by surgery and histopathological examination, and laparoscopic surgery has become the golden standard in the management of this condition. The aim of this case report is to demonstrate a very good long-term evolution after minimal invasive treatment and minimal damage to the reproductive apparatus in children with borderline ovarian tumors. The case reported in this paper is that of a 17-year-old adolescent with borderline serous papilliferous cystadenoma diagnosed by ultrasound and computed tomography (CT) scanning, whose CA-125 biomarker had normal values. As the purpose was to preserve the patient's reproductive function, we chose to remove and excise the cyst by laparoscopic surgery, without removing the ovaries. The patient's subsequent evolution was positive and at 19-year-old, she gave natural birth to a healthy baby girl. Nevertheless, as relapses are possible after many years, the patient's long-term monitoring is necessary. PMID- 26743306 TI - A rare complication of CMV infection in Crohn's disease - hemophagocytic syndrome: a case report. AB - We report a case of CMV (cytomegalovirus) infection in a Crohn's disease patient, resulting in severe hemophagocytic syndrome and death. A 63-year-old man with a 10-year history of ileal and colonic Crohn's disease presented with general malaise, loss of appetite and weight loss over the last month. He was in clinical remission for two years, with maintenance therapy 5-Aminosalicylic acid (5-ASA) derived Mesalamine. The patient had no prior immunomodulators or suppressive treatment. A colonoscopy was performed and we found appearance suggestive of active Crohn's disease, confirmed by histopathological examination. A diagnosis of an exacerbation of Crohn's disease was established. Although the specific treatment was initiated, patient's general condition degraded progressively and diarrheal stools appeared, followed by an episode of massive gastrointestinal bleeding - hematochezia. We performed a new colonoscopy and the pathological examination revealed Crohn's ileocolitis with superimposed CMV infection. Despite the initiation of Ganciclovir alongside with other intensive care measures, he increasingly deteriorated and chest X-ray confirmed multilobar pneumonia. The occurrence of rapidly progressing pancytopenia and evidence for disseminated intravascular coagulopathy as well as hyperferritinemia, raised the suspicion of hemophagocytic syndrome confirmed by bone marrow aspiration. Hence, CMV associated hemophagocytic syndrome in the context of recent corticotherapy for Crohn's disease was established. There is enough evidence that supports the gravity of the CMV infection in the case of inflammatory bowel disease (IBD) patients, especially the ones on immunomodulator treatment. The hemophagocytic syndrome reactively occurs in patients with infections in cases of immunodeficiency, displaying a hematological aspect of multiple organ dysfunction syndrome. PMID- 26743307 TI - Unusual finding of a mediastinal T-cell lymphoma in a 13-year-old patient - a case report. AB - T-cell lymphoblastic lymphoma is an aggressive malignancy that represents 85% of all lymphoblastic lymphomas. It usually occurs in late childhood, adolescence and young adulthood with a 2:1 male preponderance and it presents with pleural effusion and respiratory symptoms and in rare cases vena cava syndrome can be encountered. We present the case of a 13-year-old patient who was referred to our clinic from a local hospital where he was diagnosed with a mediastinal tumor. The patient presented with thoracic pain, fever, coughing and fatigability for a month prior to admission, after having underwent surgery for abdominal pain (appendectomy). On admission to our hospital, a thoracic computed tomography (CT) scan was performed and showed the presence of an anterior mediastinal mass measuring 109/76/140 mm, well defined, which came in close contact with the superior vena cava, the ascending aorta and the pulmonary artery, right pleural effusion and a collapsed lung on the right side. The decision was taken to perform a tumor biopsy and a right pleural drain was placed. The patient's post operative evolution was favorable with the remission of the respiratory symptoms. The histopathological result showed the presence of T-cell lymphoblastic lymphoma and the patient was then transferred to the oncology ward where he underwent chemotherapeutic treatment, with a favorable outcome. T-cell lymphoblastic lymphoma is an aggressive type of lymphoma and it is usually hard to diagnose considering the fact that the symptoms are often vague. It is essential to establish the diagnosis without delay and start appropriate chemotherapeutic treatment. PMID- 26743308 TI - Teofil Simchowicz (1879-1957): the scientist who coined senile plaques in neuropathology. AB - Teofil Simchowicz (1879-1957) was a Polish-Jewish neurologist who studied medicine at the Warsaw University, and worked under the founder of modern Polish school of neurology, Edward Flatau (1868-1932). It was Flatau who encouraged him to join Alois Alzheimer (1864-1915) in Munich. Simchowicz focused his research on the neuropathological changes in dementia. He emigrated with his wife to Palestine, where he continued to work as a consulting neurologist. Simchowicz coined the terms senile plaques, senile index, and granulovacuolar degeneration - discovered in the hippocampus in patients with Alzheimer's disease, and described the nasomental reflex. Simchowicz was a prolific researcher in the field of neuropathology, especially neurodegeneration but also in clinical neurology. PMID- 26743309 TI - Analysis of Professor Ioan Dragoiu's Opening Lecture at the Chair of Histology from the Cluj Faculty of Medicine, Romania. AB - One of the personalities who marked in a positive way the evolution of Romanian histology was Ioan Dragoiu (1873-1941). Unfortunately, after nearly three quarters of a century after his death his name is not sufficiently known, both in Cluj (where he had the most significant part of his career), as well as in whole Romania. He was the first full professor of histology who devoted himself to the Romanian Faculty of Medicine from Cluj, where he worked from 1924 until 1941. During this period, he created a school of histology, among his disciples being Cornel Crisan (1895-1958) and Iosif Mihalca (1906-1981). The most important achievement of Dragoiu was his complete histology textbook, which was a premiere in the Romanian scientific literature. The title is "Histological Elements and Microscopic Techniques" (1931-1933). Our paper presents the opening lecture of histology, held by Dragoiu on January 19, 1925 at the Faculty of Medicine from Cluj. Although this lecture is neglected, it represents a very significant document in which Dragoiu gave arguments concerning the role of histology in the curricula of medical faculties. It also reveals his conception about the usefulness of correlating the notions of histology with those of physiology. A special part of this lecture was focused on the presentation of the majority of the most important masters of histology from the past. PMID- 26743310 TI - Letter to the Editor: Concerns about Marjolin's ulcer. PMID- 26743311 TI - Design and synthesis of BODIPY-clickate based Hg(2+) sensors: the effect of triazole binding mode with Hg(2+) on signal transduction. AB - BODIPY-clickates, F1 and F2, for the detection of Hg(2+) have been designed, synthesized and characterized. Both F1 and F2 showed hyperchromic shifts in the UV-visible spectra in response to increasing Hg(2+) concentrations. Hg(2+) ion binding caused perturbation of the emission quenching process and chelation induced enhanced bathochromic emission of F1 and F2 to 620 nm and 660 nm, respectively. Job's plot clearly indicated that the binding ratio of F1 and F2 with Hg(2+) was 1 : 1. The NMR titration of BODIPY-clickates with Hg(2+) confirmed that aromatic amines and triazoles were involved in the binding event. Furthermore, HRMS data of F1-Hg(2+) and F2-Hg(2+) supported the formation of mercury complexes of BODIPY-clickates. The dissociation constant for the interaction between fluorescent probes F1 and F2 with Hg(2+) was found to be 24.4 +/- 5.1 MUM and 22.0 +/- 3.9 MUM, respectively. The Hg(2+) ion induced fluorescence enhancement was almost stable in a pH range of 5 to 8. Having less toxicity to live cells, both the probes were successfully used to map the Hg(2+) ions in live A549 cells. PMID- 26743312 TI - Mental health literacy in religious leaders: a qualitative study of Korean American Clergy. AB - Although religious leaders in ethnic minority communities are often the first point of contact for mental health needs, little is known about their mental health literacy. The aim of the current study was to explore the knowledge and beliefs about depression held by Korean American clergy, using a qualitative approach. The Gateway Provider Model (GPM) and Jorm's conceptualisation of mental health literacy served as a framework for the enquiry. Seventeen clergy members serving in Korean communities in two U.S. metropolitan cities participated in an individual in-depth interview during the spring of 2013. Using the constant comparison method, the research team coded the data independently, compared and modified codes, and derived major categories and themes in consensus approach. Eight themes emerged from the interviews, and they were grouped into five categories: (i) the ability to identify the problem; (ii) knowledge about causes and risk factors; (iii) knowledge and beliefs about treatment; (iv) knowledge about resources and services; and (v) contextual factors. Despite some variations, a majority of the participants acknowledged that depression is an important issue in the Korean American community and felt a sense of responsibility for the well-being of their community members. The findings highlight the need for mental health education and training for religious leaders in ethnic minority communities to help them properly respond to community mental health needs. PMID- 26743313 TI - Determinants of exercise intention and behaviour among individuals diagnosed with schizophrenia. AB - OBJECTIVE: The Theory of Planned Behaviour (TPB) has been applied to understand exercise behaviour in the general population with little consideration to individuals diagnosed with a psychiatric disability, despite physical inactivity among them presenting a significant risk of cardiovascular disease and other physical and mental health problems. This study tested the applicability of the TPB in the prediction of exercise intention and behaviour among people with schizophrenia. METHOD: Using a cross-sectional research design, 214 participants (105 diagnosed with schizophrenia and 109 community controls) completed a questionnaire measuring TPB components, self-efficacy, health professional support and exercise behaviour. RESULTS: Those with schizophrenia walked significantly more than the general population, but did significantly less moderate to strenuous exercise. Among those with schizophrenia, self-efficacy, perceived behavioural control and health professional support predicted 33.4% of the variance in intention to exercise. Exercise behaviour was predicted by self efficacy and fruit and vegetable intake. CONCLUSION: It is hoped that these findings will prompt health practitioners to respond to these low levels of exercise among individuals diagnosed with schizophrenia by providing support and exercise programmes that enhance self-efficacy. PMID- 26743314 TI - The PB1 segment of an influenza A virus H1N1 2009pdm isolate enhances the replication efficiency of specific influenza vaccine strains in cell culture and embryonated eggs. AB - Influenza vaccine strains (IVSs) contain the haemagglutinin (HA) and neuraminidase (NA) genome segments of relevant circulating strains in the genetic background of influenza A/PR/8/1934 virus (PR8). Previous work has shown that the nature of the PB1 segment may be a limiting factor for the efficient production of IVSs. Here, we showed that the PB1 segment (PB1Gi) from the 2009 pandemic influenza A virus (IAV) A/Giessen/06/2009 (Gi wt, H1N1pdm) may help to resolve (some of) these limitations. We produced a set of recombinant PR8-derived viruses that contained (i) the HA and NA segments from representative IAV strains (H3N2, H5N1, H7N9, H9N2); (ii) the PB1 segment from PR8 or Gi wt, respectively; and (iii) the remaining five genome segments from PR8. Viruses containing the PB1Gi segment, together with the heterologous HA/NA segments and five PR8 segments (5+2+1), replicated to higher titres compared with their 6+2 counterparts containing six PR8 segments and the equivalent heterologous HA/NA segments. Compared with PB1PR8-containing IVSs, viruses with the PB1Gi segment replicated to higher or similar titres in both cell culture and embryonated eggs, most profoundly IVSs of the H5N1 and H7N9 subtype, which are known to grow poorly in these systems. IVSs containing either the PB1Gi or the cognate PB1 segment of the respective specific HA/NA donor strain showed enhanced or similar virus replication levels. This study suggests that substitution of PB1PR8 with the PB1Gi segment may greatly improve the large-scale production of PR8-derived IVSs, especially of those known to replicate poorly in vitro. PMID- 26743315 TI - Heterologous live infectious bronchitis virus vaccination in day-old commercial broiler chicks: clinical signs, ciliary health, immune responses and protection against variant infectious bronchitis viruses. AB - Groups of one-day-old broiler chicks were vaccinated via the oculo-nasal route with different live infectious bronchitis virus (IBV) vaccines: Massachusetts (Mass), 793B, D274 or Arkansas (Ark). Clinical signs and gross lesions were evaluated. Five chicks from each group were humanely killed at intervals and their tracheas collected for ciliary activity assessment and for the detection of CD4+, CD8+ and IgA-bearing B cells by immunohistochemistry (IHC). Blood samples were collected at intervals for the detection of anti-IBV antibodies. At 21 days post-vaccination (dpv), protection conferred by different vaccination regimes against virulent M41, QX and 793B was assessed. All vaccination programmes were able to induce high levels of CD4+, CD8+ and IgA-bearing B cells in the trachea. Significantly higher levels of CD4+ and CD8+ expression were observed in the Mass2 + 793B2-vaccinated group compared to the other groups (subscripts indicate different manufacturers). Protection studies showed that the group of chicks vaccinated with Mass2 + 793B2 produced 92% ciliary protection against QX challenge; compared to 53%, 68% and 73% ciliary protection against the same challenge virus by Mass1 + D274, Mass1 + 793B1 and Mass3 + Ark, respectively. All vaccination programmes produced more than 85% ciliary protection against M41 and 793B challenges. It appears that the variable levels of protection provided by different heterologous live IBV vaccinations are dependent on the levels of local tracheal immunity induced by the respective vaccine combination. The Mass2 + 793B2 group showed the worst clinical signs, higher mortality and severe lesions following vaccination, but had the highest tracheal immune responses and demonstrated the best protection against all three challenge viruses. PMID- 26743317 TI - Modeling the Maximum Spreading of Liquid Droplets Impacting Wetting and Nonwetting Surfaces. AB - Droplet impact has been imaged on different rigid, smooth, and rough substrates for three liquids with different viscosity and surface tension, with special attention to the lower impact velocity range. Of all studied parameters, only surface tension and viscosity, thus the liquid properties, clearly play a role in terms of the attained maximum spreading ratio of the impacting droplet. Surface roughness and type of surface (steel, aluminum, and parafilm) slightly affect the dynamic wettability and maximum spreading at low impact velocity. The dynamic contact angle at maximum spreading has been identified to properly characterize this dynamic spreading process, especially at low impact velocity where dynamic wetting plays an important role. The dynamic contact angle is found to be generally higher than the equilibrium contact angle, showing that statically wetting surfaces can become less wetting or even nonwetting under dynamic droplet impact. An improved energy balance model for maximum spreading ratio is proposed based on a correct analytical modeling of the time at maximum spreading, which determines the viscous dissipation. Experiments show that the time at maximum spreading decreases with impact velocity depending on the surface tension of the liquid, and a scaling with maximum spreading diameter and surface tension is proposed. A second improvement is based on the use of the dynamic contact angle at maximum spreading, instead of quasi-static contact angles, to describe the dynamic wetting process at low impact velocity. This improved model showed good agreement compared to experiments for the maximum spreading ratio versus impact velocity for different liquids, and a better prediction compared to other models in literature. In particular, scaling according to We(1/2) is found invalid for low velocities, since the curves bend over to higher maximum spreading ratios due to the dynamic wetting process. PMID- 26743316 TI - Enhancing immunogenicity and transmission-blocking activity of malaria vaccines by fusing Pfs25 to IMX313 multimerization technology. AB - Transmission-blocking vaccines (TBV) target the sexual-stages of the malaria parasite in the mosquito midgut and are widely considered to be an essential tool for malaria elimination. High-titer functional antibodies are required against target antigens to achieve effective transmission-blocking activity. We have fused Pfs25, the leading malaria TBV candidate antigen to IMX313, a molecular adjuvant and expressed it both in ChAd63 and MVA viral vectors and as a secreted protein-nanoparticle. Pfs25-IMX313 expressed from viral vectors or as a protein nanoparticle is significantly more immunogenic and gives significantly better transmission-reducing activity than monomeric Pfs25. In addition, we demonstrate that the Pfs25-IMX313 protein-nanoparticle leads to a qualitatively improved antibody response in comparison to soluble Pfs25, as well as to significantly higher germinal centre (GC) responses. These results demonstrate that antigen multimerization using IMX313 is a very promising strategy to enhance antibody responses against Pfs25, and that Pfs25-IMX313 is a highly promising TBV candidate vaccine. PMID- 26743319 TI - Improving the photocatalytic hydrogen production of Ag/g-C3N4 nanocomposites by dye-sensitization under visible light irradiation. AB - Ag nanoparticles were deposited on the surface of g-C3N4 by a chemical reduction method to increase visible-light absorption via the localized surface plasmon resonance effect, resulting in the reduced recombination of photo-generated electron-holes and enhanced photocatalytic activity. The Ag/g-C3N4 composite with a Ag loading of 3 wt% has the optimum photoactivity that is almost 3.6 and 3.4 times higher than pure g-C3N4 and the same photocatalysis system which has been reported, respectively. Fluorescein was introduced as a photosensitizer and H2 evolution soared to 2014.20 MUmol g(-1) h(-1) and the rate is even about 4.8 times higher than that of the 3 wt% Ag/g-C3N4 composite. The chemical structure, composites, morphologies and optical properties of the obtained products are well characterized by XRD, FTIR, TEM, EDS, XPS and UV-Vis DRS. Meanwhile, the photocatalyst exhibits high stability and reusability. PMID- 26743318 TI - High level of depressive symptoms as a barrier to reach an ideal cardiovascular health. The Paris Prospective Study III. AB - We hypothesized that depression might represent a barrier to reach an ideal cardiovascular health (CVH) as estimated by the 7-item tool proposed by the American Heart Association. Between 2008 and 2012, 9,417 subjects 50-75 years of age were examined in a large health center and enrolled in the Paris Prospective Study III (PPS3). Participants with 0-2, 3-4 and 5-7 health metrics at the ideal level were categorized as having poor, intermediate and ideal CVH, respectively. Participants with a score >= 7 on the 13-item Questionnaire of Depression 2nd version, Abridged or who were on antidepressants were referred as having high level of depressive symptoms (HLDS). The mean age of the 9417 study participants was 59.57 (SD 6.28) years and 61.16% were males. A total of 9.55% had HLDS. Poor, intermediate and ideal CVH was present in 40.38%, 49.52% and 10.10% of the participants. In multivariate polytomous logistic regression analysis, HLDS was inversely associated with ideal CVH (odds ratio = 0.70; 95% CI: 0.55;0.90). This was driven by an association with the behavioural component of the CVH. Participants with HLDS had a substantial reduced chance of reaching an ideal CVH. PMID- 26743320 TI - Elucidation of the potential disease-promoting influence of IgM apoptotic cell reactive antibodies in lupus. AB - The undigested remnants of apoptosis are believed to stimulate the generation of autoantibodies in lupus. The biological properties of initiator, disease-specific IgM antibodies that specifically recognize apoptotic cells, readily detected in the sera of lupus patients, remain unclear. Apoptotic cell-reactive IgM monoclonal antibodies (generated from lupus-prone mice), as opposed to control IgM, preferentially stimulated maturation of bone marrow-derived dendritic cells (BMDCs) derived from such mice, relative to BMDCs derived from healthy mice. An influence of both antibody specificity and cell genotype was also apparent in the secretion of signature inflammatory cytokines. Immunization of such antibodies in lupus-prone animals induced increases in total serum IgG levels, with the elicited antibodies also preferentially recognizing moieties on dying cells. An expanded specificity was apparent both upon Western blot on cellular lysate and from the enhanced recognition of dsDNA, Ro60, RNP68 and Sm; the antibody most efficient in mediating autoreactive diversity, while being germline encoded, also induced the highest degree of phenotypic changes on BMDCs. Apoptotic cell reactive IgM antibodies may therefore be potentially capable of influencing the course of systemic autoimmune disease by affecting both innate and adaptive immunity. PMID- 26743321 TI - Direct oral anticoagulants in antiphospholipid syndrome: a real life case series. AB - AIM: The aim of this study was to describe a case series of patients with primary or secondary antiphospholipid syndrome (APS) treated with direct oral anticoagulants (DOACs). PATIENTS AND METHODS: Clinical charts of eight patients with thrombotic primary or secondary APS treated with direct oral anticoagulants (DOACs) between January 2012 and May 2015 were reviewed. RESULTS: The mean age was 45 +/- 14.36 (range 27-69 years). Four patients had secondary APS (50%). All patients were initially treated with warfarin by a mean time of 70.87 +/- 57.32 months (range 17-153 months). Changes in anticoagulation were defined by recurring thrombosis in five patients (62.5%) and life-threatening bleeding in the other three cases. Seven patients (87.5%) received rivaroxaban treatment and one patient (12.5%) apixaban. The mean follow-up period with DOACs was 19 +/- 10.06 months (range 2-36 months). There was no recurrence of thrombosis by the time of data collection. CONCLUSIONS: Despite not being the standard treatment in APS, we propose DOACs as a rational alternative for the management of patients with this diagnosis. Further interventional clinical studies are necessary for possible standardization of this therapy in APS patients. PMID- 26743322 TI - Progressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus: a systematic literature review. AB - OBJECTIVE: To determine risk factors for progressive multifocal leukoencephalopathy (PML) in systemic lupus erythematosus (SLE) patients, and understand how underlying disease or treatment for SLE may be associated with PML in this population. METHODS: Studies published in English between January 1, 1984 and October 31, 2014 that reported PML in adult SLE patients were included. Immunosuppression was defined as exposure to >=1 immunosuppressant drug of interest at PML diagnosis: belimumab, rituximab, mycophenolate mofetil, azathioprine, cyclophosphamide, methotrexate and high-dose corticosteroids (>15 mg/day). Minimal immunosuppression was defined as low-dose corticosteroids (<=15 mg/day) and/or anti-malarials. RESULTS: Thirty-five publications met our inclusion criteria: four observational studies, two large case series, and 29 case reports that described 35 cases. Reported PML incidence rates among SLE patients based on observational studies ranged from 1.0 to 2.4 cases/100,000 person-years. Of the 35 case reports, three cases were exposed to no immunosuppressant drugs at PML diagnosis, five cases had minimal immunosuppression, 23 cases had immunosuppression, and four cases were indeterminate. CONCLUSIONS: The evidence from this literature review suggests that, while PML is a very rare disease in SLE patients, there does appear to be an increased risk of PML associated with SLE compared to the general population, potentially due to immunosuppression, other contributing factors in their underlying disease, treatments prescribed to manage disease, or some combination of these factors. Additional large observational studies, designed to assess exposure to drugs of interest and complicated treatment histories, are needed to provide further evidence about potential mechanisms contributing to the onset of PML in SLE patients. PMID- 26743323 TI - Take care to avoid pitfalls in research. PMID- 26743324 TI - Nanoparticle Shape Evolution and Proximity Effects During Tip-Induced Electrochemical Processes. AB - Voltage spectroscopies in scanning probe microscopy (SPM) techniques are widely used to investigate the electrochemical processes in nanoscale volumes, which are important for current key applications, such as batteries, fuel cells, catalysts, and memristors. The spectroscopic measurements are commonly performed on a grid of multiple points to yield spatially resolved maps of reversible and irreversible electrochemical functionalities. Hence, the spacing between measurement points is an important parameter to be considered, especially for irreversible electrochemical processes. Here, we report nonlocal electrochemical dynamics in chains of Ag particles fabricated by the SPM tip on a silver ion solid electrolyte. When the grid spacing is small compared with the size of the formed Ag particles, anomalous chains of unequally sized particles with double periodicity evolve. This behavior is ascribed to a proximity effect during the tip-induced electrochemical process, specifically, size-dependent silver particle growth following the contact between the particles. In addition, fractal shape evolution of the formed Ag structures indicates that the growth-limiting process changes from Ag(+)/Ag redox reaction to Ag(+)-ion diffusion with the increase in the applied voltage and pulse duration. This study shows that characteristic shapes of the electrochemical products are good indicators for determining the underlying growth-limiting process, and emergence of complex phenomena during spectroscopic mapping of electrochemical functionalities. PMID- 26743325 TI - The Cognitive Effects of Obstructive Sleep Apnea: An Updated Meta-analysis. AB - This meta-analysis set out to ascertain the cognitive function of obstructive sleep apnea (OSA) patients as measured through objective neuropsychological tests. The meta-analysis investigated the cognitive functioning of these patients prior to them receiving any treatment such as continuous positive airway pressure (CPAP). A total of 19 studies met the study inclusion criteria. Results revealed statistically significant negative effect sizes in the cognitive domains of non verbal memory, concept formation, psychomotor speed, construction, executive functioning, perception, motor control and performance, attention, speed of processing, working and verbal memory, verbal functioning and verbal reasoning. The clinical implication of these results, the possible causal mechanisms of the cognitive impairments and the implication of these for future research were each discussed. Despite a number of important limitations, the analysis highlights the need for clinicians to comprehensively explore complaints about sleep disturbance, particularly OSA, in all clinical assessments to ensure control for this important confounder in order to ensure appropriate attribution of the source of any observed cognitive compromise. PMID- 26743326 TI - Examination of Variables That May Affect the Relationship Between Cognition and Functional Status in Individuals with Mild Cognitive Impairment: A Meta-Analysis. AB - The objective of this meta-analysis was to improve understanding of the heterogeneity in the relationship between cognition and functional status in individuals with mild cognitive impairment (MCI). Demographic, clinical, and methodological moderators were examined. Cognition explained an average of 23% of the variance in functional outcomes. Executive function measures explained the largest amount of variance (37%), whereas global cognitive status and processing speed measures explained the least (20%). Short- and long-delayed memory measures accounted for more variance (35% and 31%) than immediate memory measures (18%), and the relationship between cognition and functional outcomes was stronger when assessed with informant-report (28%) compared with self-report (21%). Demographics, sample characteristics, and type of everyday functioning measures (i.e., questionnaire, performance-based) explained relatively little variance compared with cognition. Executive functioning, particularly measured by Trails B, was a strong predictor of everyday functioning in individuals with MCI. A large proportion of variance remained unexplained by cognition. PMID- 26743327 TI - Health-Related Everyday Functioning in the Internet Age: HIV-Associated Neurocognitive Disorders Disrupt Online Pharmacy and Health Chart Navigation Skills. AB - This study evaluated the effects of HIV-associated Neurocognitive Disorders (HAND) on 2 Internet-based tests of healthcare management. Study participants included 46 individuals with HIV infection, 19 of whom were diagnosed with HAND, and 21 seronegatives. Participants were administered Internet-based tests of online pharmacy and health records navigation skills in which they used mock credentials to log in to an experimenter-controlled website and independently perform a series of typical online health-related behaviors (e.g., refill a prescription, read and interpret an electronic chart note). HAND was associated with significantly lower accuracy on both the online pharmacy and health records navigation tasks. Among the HIV+ participants, poorer performance on the online healthcare navigation tasks was associated with fewer years of education, higher plasma viral load, less frequent Internet use, and lower health literacy. Findings indicate that individuals with HAND may have marked difficulties navigating the Internet to complete important health-related behaviors. PMID- 26743328 TI - Ti nanorod arrays with a medium density significantly promote osteogenesis and osteointegration. AB - Ti implants are good candidates in bone repair. However, how to promote bone formation on their surface and their consequent perfect integration with the surrounding tissue is still a challenge. To overcome such challenge, we propose to form Ti nanorods on their surface to promote the new bone formation around the implants. Here Ti nanorod arrays (TNrs) with different densities were produced on pure Ti surfaces using an anodizing method. The influence of TNr density on the protein adsorption as well as on the adhesion, proliferation, and osteogenic differentiation of MC3T3-E1 pre-osteoblastic cells were assessed. The TNrs were also implanted into the bone defects in rabbits to test their application in promoting bone formation and osteointegration at the implant-bone interface. TNrs with the medium density were found to show the best capability in promoting the protein adsorption from surrounding medium, which in turn efficiently enhanced osteogenic differentiation in vitro and osteointegration in vivo. Our work suggests that growing TNrs with a medium density on the surface of traditional Ti implants is an efficient and facile method for promoting bone formation and osteointegration in bone repair. PMID- 26743329 TI - Development of a self-administered web-based test for longitudinal cognitive assessment. AB - Sequential testing with brief cognitive tools has been recommended to improve cognitive screening and monitoring, however the few available tools still depend on an external evaluator and periodic visits. We developed a self-administered computerized test intended for longitudinal cognitive testing (Brain on Track). The test can be performed from a home computer and is composed of several subtests, expected to evaluate different cognitive domains, all including random elements to minimize learning effects. An initial (A) and a refined version of the test (B) were applied to patients with mild cognitive impairment or early dementia (n = 88) and age and education-matched controls. A subsample of a population-based cohort (n = 113) performed the test at home every three months to evaluate test-retest reliability. The test's final version Cronbach's alpha was 0.90, test scores were significantly different between patients and controls (p = 0.001), the area under the receiver operating characteristic curve was 0.75 and the smallest real difference (43.04) was lower than the clinical relevant difference (56.82). In the test-retest reliability analysis 9/10 subtests showed two-way mixed single intraclass consistency correlation coefficient >0.70. These results imply good internal consistency, discriminative ability and reliability when performed at home, encouraging further longitudinal clinical and population based studies. PMID- 26743331 TI - Regulatory Control and Depression in Adolescents: Findings from Neuroimaging and Neuropsychological Research. PMID- 26743332 TI - Effect of Increasing Doses of Linoleic and alpha-Linolenic Acids on High-Fructose and High-Fat Diet Induced Metabolic Syndrome in Rats. AB - Doses and ratio of linoleic acid (LA) and alpha-linolenic acid (ALA) preventing metabolic syndrome (MS) were investigated. SD rats were fed (i) basal diet, (ii) high-fructose and high-fat diet (HFFD), (iii) HFFD with increasing-dose LA (0.75 energy-% ALA + 3, 6, 9, 12, 15, and 30 energy-% LA), and (iv) HFFD with increasing-dose ALA (6 energy-% LA + 0.3, 0.5, 0.75, 1.5, 2.25, and 3.75 energy-% ALA) for 18 weeks. Results showed 6, 12, 15, and 30 energy-% LA significantly ameliorated central obesity, hyperlipidemia, glucose homeostasis, and leptin status; 0.5 and 0.75 energy-% ALA significantly improved insulin sensitivity, adiponectin, and anti-inflammatory status. Moreover, high intakes of ALA (1.5, 2.25, and 3.75 energy-%) presented a pro-oxidant activity. In conclusion, dose instead of ratio determines the prevention of MS. The optimal doses are 6 energy % LA and 0.75 energy-% ALA; high intakes of ALA may have side effects. PMID- 26743333 TI - Diagnostic accuracy of epithelial membrane antigen for malignant effusions: a meta-analysis. AB - BACKGROUND AND OBJECTIVES: Body cavity fluid examination sometimes presents a diagnostic challenge in cytology practice. This meta-analysis was undertaken to comprehensively assess the diagnostic potential of epithelial membrane antigen (EMA) in malignant effusions. MATERIALS AND METHODS: All relevant original articles about EMA in the diagnosis of malignant effusions published up to July 1, 2014 were retrieved. The overall sensitivity, specificity, positive and negative likelihood ratio, diagnostic odds ratio, and summary receiver operating characteristic (SROC) curve were pooled to evaluate the diagnostic value of EMA for malignant effusions using the Meta-Disc 1.4 and STATA 12.0 statistical software. RESULTS: Eleven studies met the inclusion criteria for the meta analysis and the summary estimates for EMA in the diagnosis of malignant effusions were as follows: sensitivity 0.9 (95% CI 0.83-0.87), specificity 0.87 (95% CI 0.96-0.99), positive likelihood ratio 5.8 (95% CI 15.59-36.37), negative likelihood ratio 0.15 (95% CI 0.07-0.20) and diagnostic odds ratio 52.63 (95% CI 20.91-132.49). The SROC curve indicated that the maximum joint sensitivity and specificity (Q-value) was 0.88; the area under the curve was 0.94. CONCLUSION: The present meta-analysis indicated that EMA may be a useful diagnostic tool with good sensitivity and specificity for differentiating malignant effusions from benign effusions. PMID- 26743330 TI - Intrauterine trophoblast migration: A comparative view of humans and rodents. AB - Trophoblast migration and invasion through the decidua and maternal uterine spiral arteries are crucial events in placentation. During this process, invasive trophoblast replace vascular endothelial cells as the uterine arteries are remodeled to form more permissive vessels that facilitate adequate blood flow to the growing fetus. Placentation failures resulting from either extensive or shallow trophoblastic invasion can cause pregnancy complications such as preeclampsia, intrauterine growth restriction, placenta creta, gestational trophoblastic disease and even maternal or fetal death. Consequently, the use of experimental animal models such as rats and mice has led to great progress in recent years with regards to the identification of mechanisms and factors that control trophoblast migration kinetics. This review aims to perform a comparative analysis of placentation and the mechanisms and factors that coordinate intrauterine trophoblast migration in humans, rats and mice under physiological and pathological conditions. PMID- 26743334 TI - A comparison of an opioid abuse screening tool and prescription drug monitoring data in the emergency department. AB - OBJECTIVES: This study aimed to: (a) determine the percentage of ED patients receiving prescriptions for opioid pain medications that meet the criteria for "high-risk for abuse potential" on the Screener and Opioid Assessment for Patients with Pain (SOAPP((r))-R), (b) determine the percentage of patients with high-risk behavior on the state prescription drug monitoring program (PDMP) database, (c) compare the SOAPP-R with data from the PDMP, and (d) determine psychometric properties of SOAPP-R for ED patients METHODS: Convenience sample of ED patients who were being considered for discharge with a prescription for an opioid pain medication. Subjects completed SOAPP-R on an electronic tablet and PDMP data was obtained. Scores on SOAPP-R >= 18 were defined as "at-risk", and PDMP data showing both >= 4 opioid prescriptions and >= 4 providers in 12 months was considered the criterion standard for high-risk behavior. RESULTS: 82 patients (88.2%) provided consent. 32.9% (n=27) were determined to be "at-risk" (score >= 18) by SOAPP-R. 15.9% (n=13) subjects met PDMP criteria and 53.9% (n=7) of those had SOAPP-R scores >= 18 (sensitivity 54%, specificity 71%, positive predictive value 26%, negative predictive value 89%). The association of an at risk SOAPP-R score and PDMP high-risk criteria was an adjusted odds ratio of 1.39 (95% confidence interval 0.73-3.68). CONCLUSIONS: In our population, about one third of patients being considered for discharge with an opioid prescription scored "at-risk" on SOAPP-R and 15.9% met the PDMP high-risk criteria. The high negative predictive value of SOAPP-R indicates it may be a useful screening tool for the ED patient population. PMID- 26743336 TI - Intubation-Surfactant-Extubation Strategy in a Medical Resource-limited Department: A Prospective Study. PMID- 26743335 TI - mTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2. AB - Mechanistic target of rapamycin complex 1 (mTORC1), defined by the presence of Raptor, is an evolutionarily conserved and nutrient-sensitive regulator of cellular growth and other metabolic processes. To date, all known functions of Raptor involve its scaffolding mTOR kinase with substrate. Here we report that mTORC1-independent ('free') Raptor negatively regulates hepatic Akt activity and lipogenesis. Free Raptor levels in liver decline with age and in obesity; restoration of free Raptor levels reduces liver triglyceride content, through reduced beta-TrCP-mediated degradation of the Akt phosphatase, PHLPP2. Commensurately, forced PHLPP2 expression ameliorates hepatic steatosis in diet induced obese mice. These data suggest that the balance of free and mTORC1 associated Raptor governs hepatic lipid accumulation, and uncover the potentially therapeutic role of PHLPP2 activators in non-alcoholic fatty liver disease. PMID- 26743337 TI - Genetic Diversity among Group A Streptococcus Isolated from Throats of Healthy and Symptomatic Children. AB - BACKGROUND: Group A streptococcus (GAS) is the commonest bacterial cause of pharyngitis. Children in the age group of 5-15 years are most commonly affected. It can also colonize throats of healthy children in this age group. Both cases and carriers can transmit it in the community. METHODS: Throat swab samples were collected from 1849 asymptomatic and 371 symptomatic children. RESULTS: The rate of isolation of GAS was 1.41% among the asymptomatic group and 7.55% among the symptomatic group. Nine different emm types were encountered in the asymptomatic children and 14 among the symptomatic children. CONCLUSION: Throat swab cultures must be used in all cases of pharyngitis. Early and appropriate antibiotic therapy will prevent complications. Asymptomatic throat carriage of GAS in children was low in our study. However, they can still act as reservoirs. Emm typing helps in understanding epidemiology and finding new types. PMID- 26743338 TI - Factors associated with discontinuation of aripiprazole treatment after switching from other antipsychotics in patients with chronic schizophrenia: A prospective observational study. AB - The purpose of the study was to identify factors associated with discontinuation of aripiprazole after switching from other antipsychotics in patients with schizophrenia in real world clinical settings. From January 2011 to December 2012, a prospective, 48-week open-label study was undertaken. Thirty-eight subjects on antipsychotic monotherapy were switched to aripiprazole. Patients who discontinued aripiprazole were compared to those who continued with regards to demographic characteristics as well as treatment factors. Multiple regression analysis was conducted to identify predictors for aripiprazole discontinuation. Thirteen out of 38 patients (34.2%) discontinued aripiprazole during the follow up period. Nine patients (23.7%) discontinued aripiprazole due to worsening of psychotic symptoms. Multiple logistic regression analysis revealed that only the duration of previous antipsychotic treatment was associated with aripiprazole discontinuation after switching to aripiprazole. The receiver operating curve (ROC) analysis identified that the cut-off length for duration of illness to predict aripiprazole discontinuation was 10.5 years. Longer duration of illness was associated with aripiprazole discontinuation. Greater caution may be required when treating such patients with aripiprazole. PMID- 26743339 TI - Are UHR patients who present with hallucinations alone at lower risk of transition to psychosis? AB - The aim of this study was to investigate whether Ultra High Risk for psychosis (UHR) patients who present with hallucinations alone at identification as UHR are at lower risk of transition to psychosis than UHR patients who present with symptoms other than hallucinations or hallucinations plus other symptoms. Our primary dataset was a retrospective "case-control" study of UHR patients (N=118). The second, independent dataset was a long-term longitudinal follow up study of UHR patients (N=416). We performed a survival analysis using Log-rank test and Cox regression to investigate the relationship between symptom variables and transition to a psychotic disorder. Hallucinations alone at baseline were not significantly associated with a reduced risk of transition to psychosis. In the case control study the presence of hallucinations when found in the absence of any thought disorder and visual hallucinations in the absence of substance misuse was associated with a reduced risk of transition to psychosis. In the longitudinal follow-up dataset perceptual disturbance found in the absence of a disorder of affect or emotion was associated with an increased risk of transition to psychosis. PMID- 26743340 TI - Granulocyte Colony-Stimulating Factor-Mobilized Allografts Contain Activated Immune Cell Subsets Associated with Risk of Acute and Chronic Graft-versus-Host Disease. AB - We defined associations among immune cell subsets in granulocyte colony stimulating factor (G-CSF)-mobilized allografts and clinical outcomes after allogeneic hematopoietic cell transplantation (alloHCT). Fresh peripheral blood stem cell (PBSC) aliquots from 238 G-CSF-mobilized allografts were extensively characterized by immunophenotype. Subset-specific transplanted cells were correlated with acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), malignant disease relapse, nonrelapse mortality, and overall survival. Of 238 assessable alloHCT recipients, 185 patients (78%) received reduced-intensity conditioning and 152 (64%) antithymocyte globulin-based serotherapy. Incidences of aGVHD and cGVHD were 58% and 48%, respectively. Median follow-up was 21 months (range, 1.4 to 41.1). In multivariable analyses adjusted for relevant clinical factors, allograft activated natural killer (NK) cells (CD56(+)CD16(+)CD69(+)CD158b(+)) were associated with a significantly lower risk of aGVHD (P = .0016; HR, .51; 95% confidence interval, .33 to .78), whereas late activated HLA-DR(+) CD3(+) cells were associated with significantly higher aGVHD (P < .0005; HR, 2.31; 95% confidence interval, 1.55 to 3.43). In a subgroup of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), receipt of an allograft from an older donor (>=40 years) was associated with a higher incidence of relapse (P = .0042; HR, 2.99); allograft content of early activated CD3(+) cells (CD3(+)CD69(+); P = .0024; HR, .4) and NKT cells (CD3(+)CD56(+); P = .0006; HR, .54) were associated with a lower incidence of relapse. Presence of HLA-Bw4-80Ile(+) genotype was associated with lower relapse incidence. In conclusion, activated NK cells within PBSC allografts associate with lower aGVHD risk, whereas HLA-DR(+) T cells associate with higher aGVHD and cGVHD risk. NKT cells and early activated T cells are associated with lower relapse risk in AML and MDS patients. These findings may have implications in therapeutic targeting of select populations in the allograft to minimize incidence of GVHD. PMID- 26743341 TI - Impact of Polymorphic Variations of Gemcitabine Metabolism, DNA Damage Repair, and Drug-Resistance Genes on the Effect of High-Dose Chemotherapy for Relapsed or Refractory Lymphoid Malignancies. AB - The goal of this study was to determine whether single nucleotide polymorphisms (SNPs) in genes involved in gemcitabine metabolism, DNA damage repair, multidrug resistance, and alkylator detoxification influence the clinical outcome of patients with refractory/relapsed lymphoid malignancies receiving high-dose gemcitabine/busulfan/melphalan (Gem/Bu/Mel) with autologous stem cell support. We evaluated 21 germline SNPs of the gemcitabine metabolism genes CDA, deoxycytidine kinase, and hCNT3; DNA damage repair genes RECQL, X-ray repair complementing 1, RAD54L, ATM, ATR, MLH1, MSH2, MSH3, TREX1, EXO1, and TP73; and multidrug resistance genes MRP2 and MRP5; as well as glutathione-S-transferase GSTP1 in 153 patients with relapsed or refractory lymphoma or myeloma receiving Gem/Bu/Mel. We studied the association of genotypes with overall survival (OS), progression-free survival (PFS), and nonhematological grade 3 or 4 toxicity. CDA C111T and TREX1 Ex14-460C>T genotypes had a significant effect on OS (P = .007 and P = .005, respectively), and CDA C111T, ATR C340T, and EXO1 P757L genotypes were significant predictors for severe toxicity (P = .037, P = .024, and P = .025, respectively) in multivariable models that adjusted for clinical variables. The multi-SNP risk score analysis identified the combined genotypes of TREX1 Ex14-460 TT and hCNT3 Ex5 +25A>G AA as significant predictors for OS and the combination of MRP2 Ex10 + 40GG/GA and MLH1 IVS12-169 TT as significant predictor for PFS. Polymorphic variants of certain genes involved in gemcitabine metabolism and DNA damage repair pathways may be potential biomarkers for clinical outcome in patients with refractory/relapsed lymphoid tumors receiving Gem/Bu/Mel. PMID- 26743342 TI - Late Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation. AB - There are little data regarding the incidence, clinical manifestations, risk factors, and outcomes of late acute graft-versus-host disease (aGVHD). We evaluated patients with late aGVHD after allogeneic hematopoietic cell transplantation (HCT) between 2007 and 2012 and compared their outcomes to patients with early-onset aGVHD. Of the 511 allogeneic HCT recipients, 75 developed late aGVHD (cumulative incidence: 14.7% (95% confidence interval [CI], 11.6% to 17.8%) versus 248 with early-onset aGVHD (cumulative incidence: 49% [95% CI, 45% to 53%]). Among those with late aGVHD, 52% had persistent, 39% had recurrent, and 9% had de novo late aGVHD. Advanced (grades III and IV) early onset aGVHD was associated with a higher risk of developing late aGVHD (hazard ratio [HR], 1.9; 95% CI, 1.2 to 3.1; P = .01). Forty-eight percent (95% CI, 36% to 60%) of late aGVHD versus only 31% (95% CI, 26% to 37%) of early-onset aGVHD progressed to chronic GVHD by 2 years. Higher proportion of persistent (53%) as compared to recurrent (39%) and de novo (46%) late aGVHD progressed to cGVHD at 2 years. The overall survival was 59% (95% CI, 49% to 72%) in late aGVHD and 50% (95% CI, 44% to 57%) in early-onset aGVHD. Persistent late aGVHD had worse overall survival and nonrelapse mortality (45% and 39%, respectively) than recurrent (74% and 18%, respectively) and de novo (83% and 0%, respectively) late aGVHD. Compared with HLA-identical sibling HCT, unrelated donor transplantations were associated with a higher risk of mortality in patients developing late aGVHD (HR, 6.1; 95% CI, 2.3 to 16.2; P < .01). In a landmark analysis (evaluating 100 day survivors among early-onset aGVHD), no difference was seen in late mortality (after 100 days) between early-onset and late aGVHD (HR, .96; 95% CI, .59 to 1.55; P = .85); however, the risk of cGVHD was nearly doubled (HR, 1.81; 95% CI, 1.16 to 2.82; P = .01) in patients with late aGVHD. Late aGVHD is a relatively common complication after allogeneic HCT. Poorer outcomes in those with persistent late aGVHD imply need for more effective therapy in this group to improve transplantation outcomes. A higher risk of subsequent chronic GVHD needs further evaluation and close monitoring. PMID- 26743343 TI - New Light Chain Amyloid Response Criteria Help Risk Stratification of Patients by Day 100 after Autologous Hematopoietic Cell Transplantation. AB - Hematologic response criteria in light chain (AL) amyloidosis were updated in 2012 to incorporate free light chain responses. These criteria have been validated in autologous hematopoietic cell transplantation in AL at 6 and 12 months after transplantation. Using a transplantation registry, we assessed day 100 responses in AL amyloidosis. We validate the prognostic significance of the new criteria at this time point. Further, we show that patients who do not achieve at least a very good partial response by this time point have equally worse outcomes, regardless of depth of response (partial versus no response). Thus, we conclude that the new criteria help identify the poor responders by day 100 after transplantation and that this subset of patients should be studied for early evaluation in consolidation trials. PMID- 26743344 TI - The extramucosal interrupted end-to-end intestinal anastomosis in infants and children; a single surgeon 21year experience. AB - BACKGROUND/PURPOSE: To report outcomes of a standardised technique for intestinal anastomosis in infants and children. METHODS: Data were prospectively collected on all paediatric intestinal anastomosis by a single surgeon over a 21year period. Anastomoses were constructed using an end-to-end extramucosal technique with interrupted polypropylene sutures. Demographic and clinical data were recorded. RESULTS: Six-hundred and thirteen anastomoses were constructed in 550 patients. Median age at time of anastomosis was 6months (range 1day-226months). The most common reason for anastomosis was stoma closure (n=271, 49%). For those patients that required multiple anastomoses the most common pathology was acute NEC (n=22/41, 54%). One-hundred and one (18.4%) patients passed stool within 24hours of surgery, 175 (31.8%) between 24-48 hours and 95 (17.3%) between 48-72 hours. Anastomotic complications occurred in 7 patients (1.3%) including anastomotic leakage (n=5, 0.9%) and anastomotic stricture (n=2, 0.4%). The majority of anastomotic leakages (80%) followed resection of acute NEC. CONCLUSIONS: The interrupted extramucosal anastomosis is safe and effective. The return of bowel function is rapid and the complication rate acceptable. We recommend this technique be used for all intestinal anastomoses in children and infants. PMID- 26743345 TI - Postsurgical diaphragmatic herniation: A rare delayed complication of pediatric intraabdominal surgery. AB - Spontaneous diaphragmatic herniation as a delayed complication of intraabdominal surgery is an exceedingly rare event in children with few cases reported in the literature. Almost all reported cases are on the right side and followed liver transplantation surgery. We present two pediatric cases of spontaneous diaphragmatic herniation as complications of two different abdominal surgeries: pancreatic pseudocyst resection with splenectomy and liver transplantation. PMID- 26743346 TI - Development of a widely applicable immunoassay for insulin in marine teleosts that regulates cross-reactivity using biotinylation and inhibits interference by plasma components. AB - Amino acids are important insulinotropins in fish, and their effects vary between amino acids and fish species. Insulin levels are indicative of growth efficiency and stress levels in fish; however, interspecies comparisons of insulin levels are hampered by the difficulty of measuring insulin concentration in each fish. We developed a widely applicable competitive immunoassay using biotinylated yellowtail (Seriola quinqueradiata) insulin for measuring insulin in marine teleosts, including yellowtail and red seabream (Pagrus major), which are the most common species raised by aquaculture in Japan. Amino acid sequence substitution was limited at the ninth residue of the A-chain (A9) between these two species, and analysis of the primary structures of insulins from six phylogenetically far teleosts suggested that the sequences of yellowtail and red seabream insulins are identical to those of many teleosts, except the A9 residue. However, A9 is known to be an epitope that confers cross-reactive differences on insulin. We solved this problem through immunoreactive invalidation of this residue by biotinylation. The binding-inhibition curves of yellowtail and red seabream insulins were identical following the use of this technique. However, yellowtail and red seabream plasma was found to contain components that interfere with immunoassays. This problem was solved by the extraction of plasma using equal volume of acid-ethanol in yellowtail and by cooling at 0 degrees C during the cross-reaction between the ligand and antibody in red seabream. Serially diluted plasma samples from both species exhibited linearity after these treatments. In a recovery test using plasma with added yellowtail insulin, the average recovery varied from 96.2% to 109.4%. A post-feeding rise in insulin was confirmed by this immunoassay in yellowtail, and peak of the rise was 39.8+/ 7ng/ml at 1h postfeeding from 3.9+/-1.1ng/ml at 0h. This indicates that this assay is sufficient for measuring the baseline concentration of plasma insulin after starvation and is a useful indicator of nutritional status in yellowtail, as in other teleosts. This immunoassay demonstrated high performance and resisted interference from plasma components; consequently, it constitutes a useful tool for the interspecies evaluation of insulinotropins and represents a widely applicable insulin immunoassay for many teleosts. PMID- 26743347 TI - Phenotypic and genotypic characterization of two Toxoplasma gondii isolates in free-range chickens from Uberlandia, Brazil. AB - The aim of this study was to determine the seroprevalence of Toxoplasma gondii infection in free-range chickens from Uberlandia, Minas Gerais state, Brazil, and characterize the genotypic and phenotypic features of two isolates of this parasite, considering the importance of these hosts in the epidemiology of toxoplasmosis. Serum samples from 108 free-range chickens were obtained from ten different districts, and submitted to the modified agglutination test (MAT) for the presence of anti-T. gondii antibodies, and brain and heart tissue samples from infected chickens were processed for mouse bioassay. An overall seroprevalence of 71.3% was found and antibody titres ranged from 16 to 4096. After confirmation of seropositivity by mouse bioassay, the determination of the T. gondii genotypes of two isolates was performed by PCR-RFLP, using primers for the following markers: SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, new SAG2, Apico and CS3. These T. gondii isolates, designated TgChBrUD1and TgChBrUD2, were obtained from heart samples of free-range chickens. The TgChBrUD1 isolate belonged to ToxoDB PCR-RFLP genotype 11 and the TgChBrUD2 isolate belonged to ToxoDB PCR-RFLP genotype 6. Both isolates demonstrated high virulence in a rodent model, with the TgChBrUD1 isolate able to induce brain cysts, in accord with its pattern of multiplication rates in human fibroblast culture. Taken together, these results reveal high prevalence of T. gondii infection in free-range chickens throughout Uberlandia, indicating an important degree of oocyst environmental contamination and the existence of considerable risk for T. gondii transmission to humans by consumption of free-range chicken as a food source. PMID- 26743348 TI - Effect of High-Dose Atorvastatin Reload on the Release of Endothelial Progenitor Cells in Patients on Long-Term Statin Treatment Who Underwent Percutaneous Coronary Intervention (from the ARMYDA-EPC Study). AB - Endothelial progenitor cells (EPCs) may concur to endogenous vascular repair. Previous studies have reported that statin treatment increases EPC levels. We investigated whether this occurs in patients on long-term statin treatment who underwent percutaneous coronary interventions (PCIs). In a phase A study, 53 patients (atorvastatin reload [AR] 80 mg 12 hours before + 40 mg 2 hours before PCI, n = 27; placebo [P], n = 26) were evaluated for EPC mobilization as CD45dim/CD34+/CD133+/KDR+ cell number by flow cytometry. Assays were run at randomization (12 hours before PCI, R), immediately before PCI (T0) at 8 (T8) and 24 hours (T24). In phase B study, 50 patients (AR, n = 25; P, n = 25) were evaluated for early colony formation by Hill colony forming unit (CFU) assay, with sampling at randomization and 24 hours later. In phase A, EPCs levels were similar at randomization between 2 arms (0.23% [0.14 to 0.54] of total events in AR vs 0.22% [0.04 to 0.37] in P group; p = 0.33). At PCI, EPC levels were higher in AR arm (0.42% [0.06 to 0.30] vs 0.19% [0.06 to 030]; p = 0.009). Higher EPC levels in AR group were also found at 8 and 24 hours. In phase B, EPC CFUs/well numbers at randomization were similar in the 2 arms (8 [6 to 12] in AR vs 12 [6 to 20] in P group, p = 0.109). EPC CFU/well at 24 hours became significantly higher in AR arm (17 [10 to 23] vs 5 [2 to 13], p = 0.002). In conclusion, high dose AR before PCI in patients on long-term statin therapy promptly increases EPCs mobilization, which are capable of early colony formation and may contribute to cardioprotection. PMID- 26743349 TI - Autonomic Findings in Takotsubo Cardiomyopathy. AB - Takotsubo cardiomyopathy (TC) often occurs after emotional or physical stress. Norepinephrine levels are unusually high in the acute phase, suggesting a hyperadrenergic mechanism. Comparatively little is known about parasympathetic function in patients with TC. We sought to characterize autonomic function at rest and in response to physical and emotional stimuli in 10 women with a confirmed history of TC and 10 age-matched healthy women. Sympathetic and parasympathetic activity was assessed at rest and during baroreflex stimulation (Valsalva maneuver and tilt testing), cognitive stimulation (Stroop test), and emotional stimulation (event recall, patients). Ambulatory blood pressure monitoring and measurement of brachial artery flow-mediated vasodilation were also performed. TC women (tested an average of 37 months after the event) had excessive pressor responses to cognitive stress (Stroop test: p <0.001 vs baseline and p = 0.03 vs controls) and emotional arousal (recall of TC event: p = 0.03 vs baseline). Pressor responses to hemodynamic stimuli were also amplified (Valsalva overshoot: p <0.05) and prolonged (duration: p <0.01) in the TC women compared with controls. Plasma catecholamine levels did not differ between TC women and controls. Indexes of parasympathetic (vagal) modulation of heart rate induced by respiration and cardiovagal baroreflex gain were significantly decreased in the TC women versus controls. In conclusion, even long after the initial episode, women with previous episode of TC have excessive sympathetic responsiveness and reduced parasympathetic modulation of heart rate. Impaired baroreflex control may therefore play a role in TC. PMID- 26743350 TI - The distribution of mucous secreting cells in the gastrointestinal tracts of three small rodents from Saudi Arabia: Acomys dimidiatus, Meriones rex and Meriones libycus. AB - The proportion of mucin phenotypes (which form the protective biofilm of the gastrointestinal tract) differs between intestinal regions. This study examines the distribution of mucin secreting cells in the gastrointestinal tracts of the Eastern spiny mouse (Acomys dimidiatus), King jird (Meriones rex) and Libyan jird (Meriones libycus), which inhabit the dry and hot deserts of Saudi Arabia. Intestinal tract samples were processed to wax and tissue sections stained with Alcian Blue-Periodic Acid Schiff (AB-PAS) and High Iron Diamine-Alcian Blue (HID AB) in order to determine different mucin phenotypes by quantitative analysis. Mixed mucin secreting cells (combined neutral and acid) was the predominant mucin secreting cell type observed throughout the gastrointestinal tract in all species. Acid mucin secreting goblet cells were mainly located in the colon. A. dimidiatus presented with significantly more total sialo than sulfomucin secreting cells while the opposite was true for both Meriones species. The distribution of mucin secreting cells is therefore similar to previously reported results for small mammals not living under arid conditions. PMID- 26743351 TI - Present and Future of Cardiac Troponin in Clinical Practice: A Paradigm Shift to High-Sensitivity Assays. AB - Despite its wide utilization and central role in the evaluation of patients with potential ischemic symptoms, misconceptions and confusion about cardiac troponin (cTn) prevail. The implementation of high-sensitivity (hs) cTn assays in clinical practice has multiple potential advantages provided there is an education process tied to the introduction of these assays that emphasizes the appropriate utilization of the test. Several diagnostic strategies have been explored with hs cTn assays, including the use of undetectable values, accelerated serial hs-cTn sampling, hs-cTn measurements in combination with a clinical-risk score, and the use of a single hs-cTn measurement with a concentration threshold tailored to meet a clinical need. In this document we discuss basic concepts that should facilitate the integration of hs-cTn assays into clinical care in years to come. PMID- 26743352 TI - My child at mealtime: A visually enhanced self-assessment of feeding styles for low-income parents of preschoolers. AB - The importance of caregiver feeding styles on children's dietary outcomes is well documented. However, the instruments used to assess feeding style are limited by high literacy demands, making selfassessment with low-income audiences challenging. The purpose of the current study is to report on the development of My Child at Mealtime (MCMT), a self-assessment tool with reduced literacy demands, designed to measure feeding styles with parents of preschool-aged children. Cognitive interviews were conducted with 44 Head Start parents of 2-5 year old children to develop question wording and identify appropriate visuals. The resulting tool was administered to 119 ethnically diverse, low-income parents of 2-5 year old children. Factor analysis resulted in a two-factor structure that reflects responsiveness and demandingness in a manner consistent with existing assessment tools. Results indicate the final visually enhanced MCMT self assessment tool provides a measure of parenting style consistent with existing measures, while reducing the literacy demand. PMID- 26743353 TI - Chitosan Functionalized CuS Nanoparticles Boots Gene Transfection via Photothermal Effect. AB - BACKGROUND: The lack of smart and controllable gene vectors with high safety and efficiency is still a main obstruction for clinical applications of gene therapy. Recently, the external physical stimuli, such as near infrared light induced temperature elevation, have been applied to enhance the gene transfection efficiency and specificity. The aim of this paper is to fabricate chitosan functionalized CuS nanoparticles (CuS@CS NPs) with small size and higher biocompatibility for enhanced gene delivery by photothermal effect. METHODS: CuS@CS NPs were successfully prepared by simple hydrothermal method. The biocompatibility was detected by MTT method and hymolytic analysis. pEGFP-C1was used as gene model, and its expression efficiency was detected by fluorescence microscopy and flow cytometry to investigate the effect of photothermal effect on the transfection efficiency. RESULTS: The CuS@CS NPs around 15 nm were successfully engineered. The modification of CuS nanoparticles with chitosan conduced to higher physiological stability and biocompatibility. The utilization of CuS@CS NPs in combination with external near infrared (NIR) laser irradiation could enhance gene transfection efficiency due to photothermal effect. The gene transfection efficiency of CuS@CS NPs found to increase from 5.05+/-0.54% (0 min) to 23.47+/-1.27% (10 min), significantly higher than the free polyethylenimine (18.15+/-1.03%). CONCLUSION: CuS@CS NPs showed great capability to control gene delivery by an external NIR laser irradiation and enhance the gene transfection efficiency and specificity because of convenient preparation, stabilized optical properties, excellent photothermal effect and good biocompatibility. It encourages further exploration of the CuS@CS NPs as a photocontrollable nanovector for combined photothermal and gene therapy, as well as image guided therapy. PMID- 26743354 TI - Tumor Thermal Ablation Enhancement by Micromaterials. AB - Thermal ablation is a minimally invasive therapeutic technique that has shown remarkable potential in treating unresectable tumors. However, clinical applications have stalled, due to safety ambiguities, slow heat induction, lengthy ablation times, and post-therapeutic monitoring issues. To further improve treatment efficacy, an assortment of micromaterials (e.g., nanoparticulates of gold, silica, or iron oxide and single-walled carbon nanotubes) are under study as thermal ablative adjuncts. In recent years, the micromaterial domain has become especially interesting. In vivo and in vitro animal studies have validated the use of microspheres as embolic agents in liver tumors, in advance of radiofrequency ablation. Microcapsules and microbubbles serving as ultrasound contrast and ablation sensibilizers are strong prospects for clinical applications. This review was conducted to explore benefits of the three aforementioned microscale technologies, in conjunction with tumor thermal ablation. PMID- 26743355 TI - Micro-Nanomaterials for Tumor Microwave Hyperthermia: Design, Preparation, and Application. AB - BACKGROUND: Cancer hyperthermia is attracting much attention in basic science and clinics. Among the hyperthermia techniques, microwave (MW) heating is most commonly used for cancer treatment. It offers highly competitive advantages: faster heat generation from microwave radiation, less susceptibility to heat up local tissues, maneuverability, and depth of penetration in tissues and capability of killing tumor cells. Although the encouraging clinical results are being collected, MW hyperthermia has its own challenges, such as inaccurate targeting and low selectivity, which lead to damage to the surrounding vital organs and tissues. To address these issues, this review aims to introduce micronanomaterials as promising agents for receiving the electromagnetic wave, which should be beneficial for improving the efficacy of MW hyperthermia. METHODS: We have searched many peer-reviewed papers in medical and chemical material databases about micro-nanomaterials for tumor microwave hyperthermia. Distinguishing features and important progresses are introduced in this review. RESULTS: One hundred and forty papers were chosen and included in this review. Four parts were described, including hyperthermia techniques and the application of micro-nanomaterials, microwave thermal therapy and treatment principle, microwave absorbing micro-nanomaterials, the preparation and application of micro nanomaterials in microwave thermal therapy. CONCLUSION: We review the most recent literatures on micro-nanomaterials-based MW heating strategies for cancer treatment, with the aim to give the reader an overview of the state-of-the-art of MW hyperthermia therapy. The future of MW responsive materials will also be discussed, including combination of imaging probes and targeting moieties. PMID- 26743356 TI - Pregnant Women's Experiences and Views on an "Opt-Out" Referral Pathway to Specialist Smoking Cessation Support: A Qualitative Evaluation. AB - INTRODUCTION: Smoking in pregnancy remains an important and costly public health concern with policy makers worldwide researching methods to aid cessation. UK government guidelines recommend implementation of an "opt-out" (ie, whether requested or not) referral pathway for pregnant smokers to specialist smoking cessation support using carbon monoxide (CO) screening. This study explores the views of pregnant smokers who experienced this new pathway in one UK hospital trust. METHODS: Eighteen semi-structured telephone interviews with women who experienced the opt-out pathway were undertaken. Data were analyzed thematically. RESULTS: Three themes were identified relating to expectations, acceptability and impact of the pathway. Women were generally very accepting of the CO testing especially when it met their prior expectations and was perceived as being a routine component of antenatal care. They considered the visual feedback from the CO monitoring improved their motivation to quit. Views on the automatic referral for cessation support were divided with questions raised as to the removal of choice, with many women also expressing dissatisfaction about perceived lack of contact by Stop Smoking Services (SSS) following referral. CONCLUSION: The opt out pathway is potentially an acceptable addition to current practice. The women considered CO monitoring to be the most valuable element of the pathway. Women keen to engage with SSS desired a more efficient system of contact. IMPLICATIONS: This study presents a unique insight into pregnant women's views on the implementation of opt-out referrals for smoking cessation. Introducing CO testing and opt-out referrals at the time of antenatal ultrasound examination can potentially increase motivation to stop smoking in pregnancy. The findings demonstrate that facilitating access to SSS was not always achieved, and further refinement is needed to ensure more effective contact procedures. Ensuring all women are fully informed prior to the CO testing may further improve both the impact of the opt-out referral pathway and the chance of successfully engaging with SSS. PMID- 26743357 TI - Letter to the Editor "Radiation and environmental biophysics" Authors' response to comments by Scherb et al. (REBS-D-15-00121) on "Sex ratio at birth: scenario from normal- and high-level natural radiation areas of Kerala coast in Southwest India" REBS 54:453-463 (2015). PMID- 26743358 TI - Detection of Growth-Related Quantitative Trait Loci and High-Resolution Genetic Linkage Maps Using Simple Sequence Repeat Markers in the Kelp Grouper (Epinephelus bruneus). AB - To initiate breeding programs for kelp grouper (Epinephelus bruneus), the establishment of genetic linkage maps becomes essential accompanied by the search for quantitative trait loci (QTLs) that may be utilized in selection programs. We constructed a high-resolution genetic linkage map using 1055 simple sequence repeat (SSR) markers in an F1 family. Genome-wide and chromosome-wide significances of growth-related QTLs (body weight: BW and total length: TL) were detected using non-parametric mapping, Kruskal-Wallis analysis, simple interval mapping (IM), and a permutation test (PT). Two stages and two families of fish were used to confirm the QTL regions. Ultimately, 714 SSR markers were matched that evenly covered the 24 linkage groups. In total, 509 and 512 markers were localized to the female and male maps, respectively. The genome lengths were approximately 1475.95 and 1370.39 cM and covered 84.68 and 83.21 % of the genome, with an average interval of 4.1 and 4.0 cM, in females and males, respectively. One major QTL affecting BW and TL was found on linkage group EBR 17 F that identified for 1 % of the genome-wide significance and accounted for 14.6-18.9 % and 14.7-18.5 % of the phenotypic variance, and several putative QTL with 5 % chromosome-wide significance were detected on eight linkage groups. Furthermore, the confirmed results of the regions harboring the major and putative QTLs showed consistent significant experiment-wide values of 1 and 5 % as well as a chromosome-wide value of 5 %. We identified growth-related QTLs that could be applied to find candidate genes for growth traits in further studies and potentially useful in marker assisted selection (MAS) breeding. PMID- 26743359 TI - [Not Available]. PMID- 26743360 TI - Extracorporeal shock wave lithotripsy as rescue for a balloon dilator trapped in the pancreatic duct. PMID- 26743361 TI - First experience of obtaining pancreatic tissue with a puncture biopsy forceps versus fine needle aspiration. PMID- 26743362 TI - [Reinforcing access to care for the most vulnerable]. PMID- 26743363 TI - [Intestinal obstruction, a management emergency]. PMID- 26743364 TI - [Intestinal obstruction, an overview]. AB - Intestinal obstruction is a pathology commonly encountered in emergency and surgical departments. Its origin is usually mechanical, caused by obstruction of the digestive tract. It is a therapeutic emergency. Surgical treatment is required for the most severe cases. PMID- 26743365 TI - [Diagnosis and treatment of an intestinal obstruction]. AB - Intestinal obstruction, revealed by obstruction syndrome, is defined by the cessation of the bowel function whatever the cause. Bowel obstructions are one of the most frequent reasons for hospitalisation in digestive system surgery. They represent a surgical emergency. Diagnosis must enable the obstruction to be confirmed and its mechanisms and location to be specified. The treatment must always include restoring water-electrolyte balance, particularly in elderly people. PMID- 26743366 TI - [Nursing procedures carried out with an intestinal obstruction]. AB - In addition to the evacuation of the liquid which has accumulated above the intestinal obstruction, the nurse performs various tasks such as the monitoring of the patient's hydration status. She also follows up the patient in the event of complications and if the doctor decides to perform a coelioscopy or laparotomy. PMID- 26743367 TI - [Management of patients with stomas]. AB - With the occurrence of an intestinal obstruction, many patients may need an intestinal stoma. This decision is often taken in an emergency context but may also be planned. The treatment will be multi-disciplinary involving the surgeon, anaesthetist, nurse, health care assistant, physiotherapist, dietician and stoma therapist. PMID- 26743368 TI - [Can diet prevent the reoccurrence of an intestinal obstruction?]. AB - Mechanical obstructions are mainly linked to old age which can favour constipation and faecal impaction, to abdominal surgery, to chronic inflammatory diseases of the intestine or to digestive tract malignant tumours. In addition to monitoring the patient and ensuring their compliance with prescribed treatments, educating the patient with the aim of restoring a good nutritional status is essential. PMID- 26743369 TI - [From the hospital in white to the pre-hospital in red]. AB - Having started out in the hospital sector, Christian Marchal has had a rewarding and original career. His credo: emergency assistance and the interest of the victims. As part of the fire and rescue service nursing corps, he has acquired skills and trained as a supervisor. PMID- 26743370 TI - [Pain management and music therapy]. AB - The benefit of music in the treatment of pain is now recognised. The U sequence is a music therapy technique specifically developed for this purpose. It improves the overall management of pain and facilitates patient support. Its standardised use by caregivers has been made possible thanks to the development of a digital application. PMID- 26743371 TI - [Nepal earthquake: nursing missions in Paris and Kathmandu]. AB - A violent earthquake hit Nepal on 25th April 2015, injuring and killing thousands. A nurse manager and a nurse, both working in anaesthesia and reservists in the French Health Emergency Preparedness and Response Organisation, describe their mission: one working in the crisis centre in Paris, the other on the ground, providing assistance to French victims. PMID- 26743372 TI - [Combining clinical pathway and patient education approaches]. AB - The integration of the therapeutic education of the patient into a clinical pathway approach helps to optimise nursing practice. Despite some limits, this method allows the position of the caregiver to evolve, going beyond the required methodological framework. It results in the emergence of several new educational facets which are essential for the patient and enable them to become a player in their own care. PMID- 26743373 TI - [Nursing expertise in post-stroke rehabilitation]. AB - The pathway of a patient after a stroke involves a continuation of care, from their admission to the emergency department to their discharge from the rehabilitation unit. Here, a Genevan hospital team shares its experience in the creation of a video of information for the patients and their family about the process of rehabilitation. PMID- 26743374 TI - [Defining and spotting violent situations]. PMID- 26743375 TI - Psychological care. AB - Pierre works now in a health and social centre for autistic children. He takes care of Gilles, a three year old, who has just been diagnosed with autism. This evening, his mother, Mrs Wilson, is picking him up. PMID- 26743376 TI - [Increasing rights of patients]. PMID- 26743377 TI - [Teaching patient education]. PMID- 26743378 TI - [Diagnosis of meningitis]. PMID- 26743379 TI - Circulating PCSK9 in patients with type 2 diabetes and related metabolic disorders. AB - BACKGROUND: PCSK9 is a pivotal molecule in the regulation of lipid metabolism. Previous studies have suggested that PCSK9 expression and its function in LDL receptor regulation could be altered in the context of diabetes. The aim was to assess PCSK9 plasma levels in patients with type 2 diabetes (T2DM) and other related metabolic disorders as well as its relation to the metabolomic profile generated by nuclear magnetic resonance (NMR) and glucose homeostasis. METHODS: There were recruited a total of 457 patients suffering from T2DM and other metabolic disorders (metabolic syndrome (MetS), obesity and atherogenic dyslipidaemia (AD) and other disorders). Anamnesis, anthropometry and physical examinations were conducted, and vascular and abdominal adiposity imaging were carried out. Biochemical studies were performed to determine PCSK9 plasma levels 6 weeks after lipid lowering drug wash-out in treated patients. A complete metabolomic lipid profile was also generated by NMR. The rs505151 and rs11591147 genetic variants of PCSK9 gene were identified in patients. RESULTS: The results showed that PCSK9 levels are increased in patients with T2DM and MetS (14% and 13%; p<0.005, respectively). Circulating PCSK9 levels were correlated with an atherogenic lipid profile and with insulin resistance parameters. PCSK9 levels were also positively associated with AD, as defined by lipoprotein particle number and size. The rs11591147 genetic variant resulted in lower levels of circulating PCSK9 and LDL cholesterol (LDL-C). CONCLUSIONS: PCSK9 plasma levels are increased in T2DM and MetS patients and are associated with LDL-C and other parameters of AD and glucose metabolism. PMID- 26743381 TI - The Difficulties and Risks of Y-Stent-Assisted Coiling: A Comparison of First and Second Stenting Procedures. AB - OBJECTIVE: Y-stent-assisted coiling (YSAC) requires multiple device accesses for double stenting. The purpose of this study was to test the hypothesis that second stenting procedures are riskier than first stenting procedures. METHODS: We retrospectively reviewed the medical records of 19 patients with 20 aneurysms undergoing YSAC. Difficulty was determined for each device when the difficulty number was >1. Procedure-based and device-based difficulties were compared between 2 stenting procedures. For second stenting procedures, stent-delivery catheter difficulties (SDs) in passing through the struts of the first stent were assessed for 3 catheter types, 2 delivery methods, and 3 first-stent types. RESULTS: All YSACs were successful. Difficulties occurred more frequently with second stenting procedures than with first stenting procedures (procedure-based difficulties, 4 [20%] vs. 7 [35%], P = 0.29; device-based difficulties, 4 [9%] vs. 8 [18%], P = 0.19). In second stenting procedures, SDs occurred in 4 (20%) procedures and caused the midportion of the first stent to be bent into aneurysms in 2 of the procedures. Failures following difficulties were observed in only 2 (10%) second stenting procedures, necessitating other methods to complete procedures: 1 of the procedures had SD-related thrombosis leading to morbidity at discharge (modified Rankin Scale score 2). SDs were found only with 1 catheter type (4 of 15; PROWLER SELECT Plus) and 1 delivery method (4 of 15; direct over the-wire) and not with the other catheter types (Rebar-18 or Excelsior 1018) and the other method (catheter-exchange). SDs were found most frequently with the use of the CODMAN ENTERPRISE stent in first stenting procedures (50%). CONCLUSIONS: In YSAC, second stenting procedures seem riskier than first stenting procedures, particularly when SDs occur. A proper device or delivery method may reduce the risks. PMID- 26743380 TI - Gene-based analysis of the fibroblast growth factor receptor signaling pathway in relation to breast cancer in African American women: the AMBER consortium. AB - We conducted gene-based analysis in 26 genes in the FGFR signaling pathway to identify genes carrying genetic variation affecting risk of breast cancer and the specific estrogen receptor (ER) subtypes. Tagging single-nucleotide polymorphisms (SNPs) for each gene were selected and genotyped on a customized Illumina Exome Array. Imputation was carried out using 1000 Genomes haplotypes. The analysis included 3237 SNPs in 3663 breast cancer cases (including 1983 ER-positive, and 1098 ER-negative) and 4687 controls from the African American Breast Cancer Epidemiology and Risk consortium, a collaborative project of four large studies of breast cancer in African American women (Carolina Breast Cancer Study, Black Women's Health Study, Women's Circle of Health Study, and Multiethnic Cohort). We used a multi-locus adaptive joint (AdaJoint) test to determine the association of each gene in the FGFR signaling pathway with overall breast cancer and ER subtypes. The FGF1 gene was significantly associated with risk of ER-negative breast cancer (P = 0.001). The FGFR2 gene was associated with risk of overall breast cancer (P = 0.002) and ER-positive breast cancer (P = 0.002). The FGF1 gene affects risk of ER-negative breast cancer in African American women. We confirmed the association of the FGFR2 gene with risk of overall and ER-positive breast cancer. These results highlight the importance of the FGFR signaling pathway in the pathogenesis of breast cancer, and suggest that different genes in the same pathway may be associated with different ER breast cancer subtypes. PMID- 26743382 TI - Implant Site Infection and Bone Flap Osteomyelitis Associated with the NeuroPace Responsive Neurostimulation System. AB - BACKGROUND: The NeuroPace RNS System is a method recently approved by the U.S. Food and Drug Administration for closed-loop direct brain stimulation in selected patients with drug-resistant partial seizures. The long-term risks of implant site infection and accompanying bone flap osteomyelitis associated with responsive neurostimulation (RNS) devices have not been fully appreciated. CASE DESCRIPTION: We report 3 cases of refractory partial epilepsy that were treated with RNS therapy in conjunction with antiepileptic drugs. Patients underwent invasive epilepsy monitoring and resection of seizure foci. All patients continued to have debilitating partial seizures and underwent implantation of the RNS device, which resulted in various degrees of symptomatic relief. On average, the battery of the implantable pulse generator was replaced every 2 years. All 3 patients developed implant site infection and bone flap osteomyelitis with multiple implantable pulse generator replacements, and the RNS devices were removed. Bone flaps were removed in 2 patients because of significant osteomyelitis and were reconstructed in a delayed fashion with customized cranial implants. No patient had evidence of meningitis or cerebritis. The patients were treated via a multidisciplinary approach, and all patients recovered well with satisfactory wound healing and seizure control. CONCLUSIONS: Implant site infection and bone flap osteomyelitis are significant adverse events associated with the RNS device. The incidence of infection in this series (10%) is comparable to the incidence reported in the long-term trial. The infection risk is mainly associated with reoperations and increases with multiple implantable pulse generator replacements. The RNS device may benefit from reducing technical risk factors that are associated with postoperative bone and soft tissue infections. PMID- 26743383 TI - Epilepsy in Historical Figures. PMID- 26743386 TI - Closer to the Edge-The Value of Intraoperative Brain Mapping. PMID- 26743384 TI - Predictors of Surgical Site Infection Following Craniotomy for Intracranial Neoplasms: An Analysis of Prospectively Collected Data in the American College of Surgeons National Surgical Quality Improvement Program Database. AB - OBJECTIVE: To determine the rate of surgical site infection (SSI) after resection of an intracranial neoplasm using the American College of Surgeons National Surgical Quality Improvement Program data set and to identify potential risk factors associated with SSI. METHODS: The National Surgical Quality Improvement Program Participant Use Data File was queried during the period 2006-2013 for patients who underwent a resection for an intracranial neoplasm. Multivariable logistic regression analysis was used to identify risk factors associated with SSI. RESULTS: Inclusion criteria were met by 12,021 patients. SSI occurred at a rate of 2.04%. SSI was significantly associated with increased rates of return to the operating room (56.1% vs. 4.0%, P < 0.001) and postoperative lengths of stay >30 days (5.3% vs. 1.3%, P < 0.001) on unadjusted bivariate analysis. On multivariable analysis, age (odds ratio [OR] = 0.991, 95% confidence interval [CI] = 0.982-0.999) and female sex (OR = 0.697, 95% CI = 0.538-0.902) were associated with a reduction in the odds of SSI. Preoperative wound infections (OR = 3.833, 95% CI = 1.834-8.0011) and operative times >4 hours (OR = 1.891, 95% CI = 1.298-2.756) were associated with an increased odds of SSI. Among cases with available chemotherapy data (n = 3504), recent chemotherapy (OR = 3.007, 95% CI = 1.460-6.196) was associated with an increased odds of SSI. CONCLUSIONS: This study identified patient risk factors that may assist clinical decision making regarding patient risk stratification, timing of surgery, and preoperative antibiotic prophylaxis for patients with an intracranial neoplasm undergoing craniotomy. PMID- 26743385 TI - Posterior Fossa Intra-Axial Tumors in Adults. AB - BACKGROUND: The posterior fossa is the site of many types of tumors, and brain metastases are the most common malignancies in that location among adults. Other brain tumors, such as ependymomas, medulloblastomas, and juvenile pilocytic astrocytomas, mostly occur during childhood and are relatively rare in adults. Most primary malignant brain tumors, such as gliomas and lymphomas, tend to be located in the supratentorial compartment. METHODS: This review summarizes prognostic factors, therapeutic management, and molecular data of intra-axial posterior fossa tumors in adults, including ependymomas, medulloblastomas, and pilocytic astrocytomas. RESULTS: The literature on intra-axial posterior fossa tumors in adults relies mainly on limited retrospective clinical studies, and such studies employ a wide range of treatment approaches that are usually based on therapies developed specifically for children or for supratentorial brain tumors. CONCLUSIONS: The clinical course and surgical outcome of adult patients with intra-axial brain tumors in the posterior fossa are summarized in this review. The prognostic factors and therapeutic management of patients with these tumors are controversial because of their rarity, their heterogeneity, and the lack of sufficient data in the literature. PMID- 26743387 TI - A Rare Urachal Cyst in a Case of Ketamine-induced Cystitis Provides Mechanistic Insights. AB - OBJECTIVE: To establish whether the urothelial ulceration observed in ketamine induced cystitis is triggered by urinary or systemic factors. This was achieved with a rare case where an urachal cyst was found near the bladder dome in a patient undergoing cystectomy for unremitting pain following ketamine abuse. METHODS: Clinical investigations included cystoscopy, video urodynamic investigation, and computed tomography of the kidneys, ureters, and bladder. Histological staining was combined with immunoperoxidase labeling for markers of transitional epithelial differentiation. RESULTS: The urachus found near the dome of the bladder was observed to be a separate cyst, with no evidence of patency found during surgery or video urodynamic investigation. The urachus was lined by a mildly reactive metaplastic epithelium of mixed transitional and columnar morphologies. Evidence of widespread cytokeratin 13, basal p75(NTR), and sparse superficial uroplakin 3a immunoreactivity suggested the urachal epithelium was fundamentally transitional in nature. Near total loss of bladder urothelium was observed from regions in contact with urine, whereas the urachal epithelium (not exposed to urine) remained healthy. CONCLUSION: This study supports the hypothesis that urinary (and not systemic) factors are the main driver of urothelial ulceration in ketamine-induced cystitis. The most likely excreted factors responsible are ketamine and potentially its metabolites. This study reinforces the importance of complete cessation of ketamine use in patients with ketamine-induced cystitis. PMID- 26743388 TI - Partial Nephrectomy in Clinical T1b Renal Tumors: Multicenter Comparative Study of Open, Laparoscopic and Robot-assisted Approach (the RECORd Project). AB - OBJECTIVE: To evaluate perioperative results of open (OPN), laparoscopic (LPN), and robot-assisted partial nephrectomies (RAPN) and to identify predictive factors of Trifecta achievement for clinical T1b renal tumors in a multicenter prospective dataset. METHODS: Data of 285 patients who had OPN (133), LPN (57), or RAPN (95) for cT1b renal tumors were extracted from the RECORd Project. High volume centers were defined as >=50 overall cases of partial nephrectomy per year. Trifecta was defined as simultaneous absence of perioperative complications, negative surgical margins, and ischemia time <25 minutes. RESULTS: The 3 groups had comparable body mass index, preoperative hemoglobin, creatinine and estimated glomerular filtration rate, tumor clinical diameter, and growth pattern. LPN and RAPN were more frequently exclusive of high-volume centers. RAPN showed significantly lower median estimated blood loss compared with OPN and LPN. Trifecta was achieved in 62.4%, 63.2%, and 69.5% of OPN, LPN, and RAPN (P = NS) cases. Median warm ischemia time (WIT) was significantly shorter during OPN than during LPN and RAPN. RAPN had significantly shorter WIT compared with LPN. RAPN was significantly less morbid than OPN regarding intraoperative and postoperative complications. LPN (1.9%) and RAPN (2.5%) showed a lower rate of positive margins compared with OPN (6.8%) (P = NS). At multivariable analysis, exophytic tumor growth pattern, estimated blood loss, and high-volume centers were significant predictive factors for Trifecta achievement. CONCLUSION: Clinically, T1b renal tumors suitable for NSS can be safely treated by LPN or RAPN in high-volume centers. RAPN allows for significantly lower WIT and estimated blood loss with higher rate of Trifecta achievement compared with LPN. PMID- 26743389 TI - Age, Body Mass Index, and Frequency of Sexual Activity are Independent Predictors of Testosterone Deficiency in Men With Erectile Dysfunction. AB - OBJECTIVES: To identify clinical predictors of testosterone deficiency (TD) in men with erectile dysfunction (ED), thereby identifying subgroups that are most likely to benefit from targeted testosterone screening. METHODS: Retrospective review was conducted on 498 men evaluated for ED between January 2013 and July 2014. Testing for TD by early morning serum measurement was offered to all eligible men. Patients with history of prostate cancer or testosterone replacement were excluded. Univariable linear regression was conducted to analyze 19 clinical variables for associations with serum total testosterone (TT), calculated free testosterone (cFT), and TD (T <300 ng/dL or cFT <6.5 ng/dL). Variables significant on univariable analysis were included in multiple regression models. RESULTS: A total of 225 men met inclusion criteria. Lower TT levels were associated with greater body mass index (BMI), less frequent sexual activity, and absence of clinical depression on multiple regression analysis. TT decreased by 49.5 ng/dL for each 5-point increase in BMI. BMI and age were the only independent predictors of cFT levels on multivariable analysis. Overall, 62 subjects (27.6%) met criteria for TD. Older age, greater BMI, and less frequent sexual activity were the only independent predictors of TD on multiple regression. We observed a 2.2-fold increase in the odds of TD for every 5-point increase in BMI, and a 1.8-fold increase for every 10 year increase in age. CONCLUSIONS: Men with ED and elevated BMI, advanced age, or infrequent sexual activity appear to be at high risk of TD, and such patients represent excellent potential candidates for targeted testosterone screening. PMID- 26743390 TI - Foley or Fix: A Comparative Analysis of Reparative Procedures at the Time of Explantation of Artificial Urinary Sphincter for Cuff Erosion. AB - OBJECTIVE: To examine artificial urinary sphincter (AUS) cuff erosion intraoperative management methods: Foley catheter placement, abbreviated urethroplasty (AU), or mobilization with primary urethral anastomosis (PA). We reviewed these options to compare postoperative complications and probability of AUS reimplantation. MATERIALS AND METHODS: Medical records of patients treated for AUS cuff erosion from 2005 to 2015 were retrospectively reviewed. We divided patients into 3 groups based on intraoperative management of the urethra: Foley only, AU, or PA. Patient characteristics, operative times, outcomes, complications, and reimplantation factors were recorded and analyzed. RESULTS: Seventy-five patients with a median age of 77 years (72-83) were treated for AUS cuff erosion. Fifty-two underwent Foley placement, 8 AU, and 15 PA. Mean follow up was 13 months (0-106). Severe erosions were more common in the PA group than Foley or AU (100% vs 37%, 100% vs 38%, P <.001, P <.001, respectively). Severe erosions treated with Foley were more likely to develop strictures than mild erosions (38% vs 5%, P = .009). Tandem cuff patients treated with Foley were more likely to develop diverticuli than single cuff patients (33% vs 4%, P = .016). There was no difference in probability of reimplantation between PA and Foley or AU (63% vs 69%, 63% vs 33%, P = .748, P = .438, respectively). CONCLUSIONS: Foley catheter placement alone may represent suboptimal management for severe or tandem cuff erosions due to increased risk of urethral complications. Urethral defect management should be determined at the time of explantation by individual patient characteristics and surgeon experience. PMID- 26743391 TI - Conservative Treatment of Serous Borderline Paratesticular Tumor in a Pediatric Patient. AB - Serous borderline tumors are rare neoplasms. Herein we report our conservative approach, whose rationale is neoplasm low-malignant potential. Tumor was removed under general anesthesia, and frozen section ruled out a germinal malignancy or a stromal tumor such as rhabdomyosarcoma. Ultrasound evaluation was initially performed every 3 months during the first 2 years, every 6 months during the next 3 years, and annually thereafter. After 8 years, the patient has not experienced any relapse, either clinical or ultrasonographical. In our opinion, conservative approach, whose final decision relies on intraoperative frozen section, represents the best option and does not jeopardize long-term oncological outcome. PMID- 26743392 TI - Current Status of Focal Cryoablation for Small Renal Masses. AB - Focal cryoablation is an established minimally invasive technique for the treatment of small renal masses. Because of the lack of robust evidence, it is indicated in selected patients who have relative contraindications to extirpative approaches. With appropriate selection of patients, cryoablation is safe and effective. Main advantages are low risk for complication, minimal invasiveness, and good functional outcomes; oncological outcomes require further studies. The role of the percutaneous approach has been expanding because of its ability to reduce pain and hospitalization, the possibility of performing the procedure under sedation, and the fact that it is potentially more cost effective. PMID- 26743393 TI - Robotic Anterior Pelvic Exenteration for Bladder Cancer in Patient With Previous Kidney-Pancreas Transplantation. AB - INTRODUCTION: To demonstrate the feasibility of robotic anterior pelvic exenteration with intracoporeal ileal conduit for bladder cancer in a patient with previous kidney-pancreas transplantation. TECHNICAL CONSIDERATIONS: Technical considerations included avoiding injury to transplant graft, minimizing devascularization of transplant ureter, intracorporeal mobilization of bowel with pancreas graft, and positioning of ileal conduit. Surgical approach required multidisciplinary approach for surgical planning and medical management. CONCLUSION: The patient's preoperative serum creatinine was 1.22 ng/mL and was unchanged at 1.21 ng/mL 1 month following surgery. Total robotic console time was 4 hours and 21 minutes and estimated blood loss is 30 cc. There were no intraoperative complications. Final pathology demonstrated pT1N0 high-grade multifocal micropappilary urothelial cell carcinoma with carcinoma in situ, and all surgical margins were negative. Robotic anterior pelvic exenteration with intracorporeal urinary diversion for bladder cancer in patient with previous kidney-pancreas transplantation is a challenging but a feasible surgical technique that requires a multidisciplinary team and a low threshold to convert to open surgery. PMID- 26743394 TI - Urethroplasty for Stricture Disease: Contemporary Techniques and Outcomes. AB - Urethral reconstruction is now considered optimal therapy for most men presenting with symptomatic urethral strictures. The rapid development of innovative tissue transfer techniques over the past decade provides today's reconstructive urologist with a high probability of achieving excellent long-term outcomes after urethroplasty, even in the reoperative setting. Fundamental principles such as accurate initial stricture staging by urethrography, along with critical assessment of both stricture severity and tissue quality during urethroplasty are critical for success. This review illustrates the way in which stricture length, location, severity, and etiology influences the application of reconstructive techniques during contemporary urethroplasty. PMID- 26743395 TI - Kulkarni Dorsolateral Graft Urethroplasty Using Penile Skin. AB - OBJECTIVES: To investigate the safety, efficacy, and versatility of dorsolateral graft urethroplasty using penile skin. MATERIALS AND METHODS: Between 2010 and 2013, 37 men with anterior urethral strictures underwent dorsolateral graft urethroplasty using penile skin by a single surgeon (EP). Inclusion criterion was patients with anterior urethral strictures. Exclusion criteria were lichen sclerosus-related strictures, absence of available penile skin because of previous surgery, and obliterative urethral strictures. Clinical outcome was considered a failure when any postoperative instrumentation was needed, including dilatation. RESULTS: Mean (+/- standard deviation) patients age was 51 (+/-15.4) years. Stricture etiology was iatrogenic in 25 cases (67%), unknown in 10 (27%), trauma in 2 (6%). Stricture site was penile in 21 (57%) and peno-bulbar in 16 (43%). Median (range) stricture length was 5 cm (1-15). Of 37 patients, 30 (81%) had received previous treatments. Median (range) follow-up was 21 months (12-47). Of 37 patients, 34 (92%) had successful treatment and 3 (8%) had failed treatment. The 3 patients with failed treatment were treated with urethrostomy and are awaiting further reconstruction. Study limitations include the small sample size and the limited follow-up. CONCLUSION: With a mid-term follow-up time, the dorsolateral graft urethroplasty using penile skin is shown to be a safe, efficient, and versatile technique for the repair of short-mid-long anterior urethral strictures. PMID- 26743396 TI - Adverse Event Rates, Timing of Complications, and the Impact of Specialty on Outcomes Following Adrenal Surgery: An Analysis of 30-Day Outcome Data From the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP). AB - OBJECTIVE: To report on 30-day adverse event rates and timing of complications following adrenal surgery; further, to investigate the impact of specialty (general surgery vs urology) on these outcomes using a large prospective multi institutional data registry. MATERIALS AND METHODS: Within the American College of Surgeons National Surgical Quality Improvement Program (2005-2012), patients undergoing adrenalectomy were identified (CPT-codes: 60540, 60545, 60650). Outcomes evaluated included complications, blood transfusion, length of stay, reintervention, readmission, and mortality. Complications were further evaluated in relation to discharge status (pre-/postdischarge). Multivariable regression models assessed association between specialty and 30-day morbidity/mortality. RESULTS: During the study period, 4844 patients underwent adrenalectomy (95.7% general surgery). The overall complication rate was 7.5% (n = 363); 43.2% of the complications occurred postdischarge with a substantial proportion of major complications, including cardiac, pulmonary, renal, neurologic, septic, and deep venous thrombosis/pulmonary embolism also occurring postdischarge (29.9%). The overall blood transfusion, reintervention, readmission, and mortality rates were 3.9%, 2.0%, 6.4%, and 0.6%, respectively. In adjusted analyses, specialty did not have an effect on any of the outcomes (P > .05 all). CONCLUSION: One in 13 patients suffers a complication postadrenalectomy. Approximately 40% of these complications occur postdischarge, primarily within the first 2 weeks of surgery. Accurate knowledge regarding 30-day adverse event rates and timing of complications that this study provides may facilitate improved patient-physician communication and encourage early patient follow-up in this critical window. Lastly, specialty does not seem to affect outcomes in American College of Surgeons National Surgical Quality Improvement Program participant hospitals. PMID- 26743398 TI - Examining cellular immune responses to inform development of a blood-stage malaria vaccine. AB - Naturally acquired immunity to the blood-stage of the malaria parasite develops slowly in areas of high endemicity, but is not sterilizing. It manifests as a reduction in parasite density and clinical symptoms. Immunity as a result of blood-stage vaccination has not yet been achieved in humans, although there are many animal models where vaccination has been successful. The development of a blood-stage vaccine has been complicated by a number of factors including limited knowledge of human-parasite interactions and which antigens and immune responses are critical for protection. Opinion is divided as to whether this vaccine should aim to accelerate the acquisition of responses acquired following natural exposure, or whether it should induce a different response. Animal and experimental human models suggest that cell-mediated immune responses can control parasite growth, but these responses can also contribute to significant immunopathology if unregulated. They are largely ignored in most blood-stage malaria vaccine development strategies. Here, we discuss key observations relating to cell-mediated immune responses in the context of experimental human systems and field studies involving naturally exposed individuals and how this may inform the development of a blood-stage malaria vaccine. PMID- 26743399 TI - Virus and calcium: an unexpected tandem to optimize insecticide efficacy. AB - The effective control of insect pests is based on the rational use of the most efficient and safe insecticide treatments. To increase the effects of classical insecticides and to avoid the ability of certain pest insects to develop resistance, it is essential to propose novel strategies. Previous studies have shown that calcium-dependent phosphorylation/dephosphorylation is now considered as a new cellular mechanism for increasing the target sensitivity to insecticides. Because it is known that virus entry is correlated with intracellular calcium concentration rise, this report attempts to present the most important data relevant to the feasibility of combining an insect virus such as baculovirus or densovirus with an insecticide. In this case, the insect virus is not used as a bioinsecticide but acts as a synergistic agent able to trigger calcium rise and to activate calcium-dependent intracellular signalling pathways involved in the increase of the membrane receptors and/or ion channels sensitivity to insecticides. This virus-insecticide mixture represents a promising alternative to optimize the efficacy of insecticides against insect pests while reducing the doses. PMID- 26743401 TI - Arthroscopy Journal Prizes Are Major Decisions. AB - According to the Harvard Business Review, the optimal number of people in a decision-making group is no more than 8. Thus, it is no surprise that 18 Arthroscopy journal associate editors had difficulty making a major decision. In the end, 18 editors did successfully select the 2015 winner of the Best Comparative Study Prize. All studies have limitations, but from a statistical standpoint, the editors believe that the conclusions of the winning study are likely correct. PMID- 26743397 TI - Clinical evaluation of an antiinflammatory and antioxidant diet effect in 30 dogs affected by chronic otitis externa: preliminary results. AB - The aim of this evaluation study was to assess the possible role of a specific nutraceutical diet in relieving main clinical symptoms of chronic bilateral otitis externa (occlusion of ear canal, erythema, discharge quantity, and odor) in 30 adult dogs. Thirty dogs of different breeds (mean age +/- SEM; 6.03 +/- 0.15 years and mean weight +/- SEM; 32.01 +/- 1.17 Kg; 53.3% males, 46.6% females) with evident chronic clinical otitis symptoms were equally divided and randomly assigned to receive either the nutraceutical diet (ND group) or a standard diet (SD group) over a period of 90 days. In all cases a topical pharmacological treatment was given. The nutraceutical diet, also endowed with anti-inflammatory and antioxidant activities, significantly decreased the mean score intensity of all symptoms after 90 days of intervention (P < 0.0001) with the exception of Malassezia pachydermatis infection which was only slightly reduced. Our investigation is one of the few evidence-based results where a commercial nutraceutical diet has been proven effective, in combination with drugs, in relieving otitis externa-related symptoms. This study opens new insights into otitis externa clinical management providing evidence of efficacy of a combined therapy with drugs and a specific nutraceutical diet. PMID- 26743400 TI - Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D): Review of 16 Pediatric Cases and a Proposal of Modified Pediatric Criteria. AB - Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heritable cardiomyopathy characterized by fibro-fatty replacement of right ventricular myocardium. Diagnostic criteria, established in 1994 and modified in 2010, are based on predominately adult manifestations of ARVC/D. The goal of this paper is to review a single-center experience with pediatric ARVC/D and propose modifications of current diagnostic criteria to appropriately include pediatric ARVC/D. We identified 16 pediatric cases of ARVC/D from our tertiary care center. Patient demographics, presentation, course, genetic testing, and family history were reviewed. Sixteen patients were diagnosed with ARVC/D through the modified diagnostic criteria, genetic testing, and pathology. Five patients had positive family histories. Five patients presented with cardiac arrest, and six were found to have ventricular tachycardia. Two patients presented with heart failure. Six autopsies, six explanted hearts, and three biopsies found massive fibro-fatty infiltration of the right ventricular wall. Six patients underwent heart transplantation, and two have received automatic implantable cardioverter defibrillator. Two patients had identifiable genetic mutations previously noted in the literature. One patient had a novel mutation of a known ARVC/D gene. Many pediatric patients do not meet the current ARVC/D diagnostic criteria, resulting in delays in diagnosis and treatment. The current criteria need further revision to encompass pediatric manifestations of ARVC/D. In our opinion, pathological and clinical findings alone are sufficient for accurate diagnosis of pediatric ARVC/D. Creating modified pediatric criteria would facilitate prompt diagnosis and management of ARVC/D and facilitate structured research with the goal of improving outcomes. PMID- 26743404 TI - In Memoriam: David A. McGuire, M.D. PMID- 26743405 TI - Editorial Commentary: Another Drop of Knowledge on Ischiofemoral Impingement. AB - In patients with symptomatic hip ischiofemoral impingement, mean femoral neck anteversion and the angle between the femoral neck and lesser trochanter is higher, whereas mean lesser trochanter version is not increased. PMID- 26743406 TI - Editorial Commentary: The Demise of Randomized Controlled Trials in Hip Arthroscopy? AB - Hip arthroscopists asked to participate in randomized controlled trials are reluctant to offer treatment without correction of osseous deformities but may be more willing to enroll patients in studies on management of capsulolabral structures. PMID- 26743407 TI - Editorial Commentary: Iliotibial Band Allograft Shows Promise for Arthroscopic Hip Labral Reconstruction. AB - Arthroscopic hip labral reconstruction using iliotibial band allograft in a modified front-to-back technique results in improved outcomes after 2-year follow up. The authors' reasoning for reconstruction are reminiscent of similar arguments for restoring hoop stresses in knee meniscal surgery. Results are comparable to reported outcomes of labral repair, and allograft is particularly indicated for severe labral damage when repair is not possible. Don't miss the related technical note with video in Arthroscopy Techniques. PMID- 26743408 TI - Editorial Commentary: Single-Bundle Versus Double-Bundle Anterior Cruciate Ligament Reconstruction. AB - There are no significant differences in the clinical outcomes between single bundle and double-bundle procedures in hamstring anterior cruciate ligament reconstruction. Although most previous studies have shown better stability achieved by the double-bundle procedure, its clinical significance still needs to be determined. PMID- 26743409 TI - Editorial Commentary: Should We Repair Posterior Cruciate Ligament Tibial Avulsion Fractures by Opening the Hood or Through the Tailpipe? AB - While the controversy of open versus arthroscopic methods has been settled for many procedures in favor of arthroscopic treatment, the article by Sabat et al. all shows that posterior cruciate ligament tibial avulsion fractures can be equally well treated with either open or arthroscopic techniques. PMID- 26743410 TI - Editorial Commentary: Elevated Tibial Tubercle-Trochlear Groove Distance and Patellar Instability. AB - In patients with unilateral patellar instability, tibial tuberosity-trochlear groove, lateral patellar tilt, and subluxation are greater on the side of instability. Dynamic computed tomography scan may represent a more physiologic assessment of patellofemoral tracking. A laterally positioned tuberosity may be a predisposing factor for patellar instability, a role perhaps further defined by future dynamic studies of the extensor mechanism. PMID- 26743411 TI - Editorial Commentary: Tibial Tubercle-Trochlear Groove Distance as an Independent Risk Factor for Noncontact Anterior Cruciate Ligament Injury Is Possible but Remains Uncertain. AB - The MRI tibial tubercle-trochlear groove distance is statistically significantly higher in adolescent and young adults with noncontact anterior cruciate ligament (ACL) tears compared with those without tears. The authors use lateral thinking to assess this marker for extensor mechanism alignment as a potential risk factor for ACL tear. Yet the approximate 2 mm increase seen in those with ACL tears portends unproven clinical significance. PMID- 26743412 TI - Editorial Commentary: Quadriceps Tendon Autograft Use for Anterior Cruciate Ligament Reconstruction Predicted to Increase. AB - Quadriceps tendon autograft is the least utilized choice for anterior cruciate ligament reconstruction, but use is expected to increase. Harvest of the full thickness of the distal quadriceps tendon is of concern, but morbidity seems low. PMID- 26743413 TI - Editorial Commentary: Intra-articular Corticosteroid Injection at the Time of Knee Arthroscopy Is Not Recommended. AB - In a population of Medicare patients undergoing knee arthroscopy, a significant increase in the incidence of postoperative infection at 3 and 6 months was found in patients who received an intra-articular corticosteroid injection at the time of knee arthroscopy compared with a matched control group that did not receive an injection. Intra-articular corticosteroid injection at the time of knee arthroscopy is not recommended. PMID- 26743414 TI - Editorial Commentary: Doc, Can You Inject Stem Cells in My Knee? AB - Stem cell therapy is one of the most promising treatments to restore and repair damaged articulate cartilage. Koh et al. present in this issue their study on the treatment of articulate cartilage defects with adipose derived stem cell. We believe that it is a matter of time to when stem cells will become cost effective and commercially available for the treatment of articulate cartilage injuries. PMID- 26743415 TI - Editorial Commentary: Anterolateral Ligament: How Do We Find It? AB - There is considerable current interest in the role of the anterolateral ligament in persistent instability after anterior cruciate ligament reconstruction. The normal ligament may be identified using magnetic resonance imaging or ultrasound techniques. However, imaging evaluation of the ligament in vivo after injury requires further study to determine indications for repair or reconstruction. PMID- 26743416 TI - Editorial Commentary: Single-Image Slice Magnetic Resonance Imaging Assessments Do Not Predict 3-Dimensional Muscle Volume. AB - No single-image magnetic resonance imaging (MRI) assessment-Goutallier classification, Fuchs classification, or cross-sectional area-is predictive of whole-muscle volume or fatty atrophy of the supraspinatus or infraspinatus. Rather, 3-dimensional MRI measurement of whole-muscle volume and fat-free muscle volume is required and is associated with shoulder strength, which is clinically relevant. Three-dimensional MRI may represent a new gold standard for assessment of the rotator cuff musculature using imaging and may help to predict the feasibility of repair of a rotator cuff tear as well as the postoperative outcome. Unfortunately, 3-dimensional MRI assessment of muscle volume is labor intensive and is not widely available for clinical use. PMID- 26743417 TI - Editorial Commentary: Anatomic Femoral Tunnel Drilling: Does It Really Matter? AB - An anatomic anteromedial portal and outside-in technique for creating the anterior cruciate ligament femoral tunnel may improve rotational stability but shows no published differences in clinical outcomes. PMID- 26743418 TI - Editorial Commentary: Anterior Cruciate Ligament Reconstruction: Auto or Allo? AB - Considerable controversy exists regarding appropriate graft choice for patients undergoing anterior cruciate ligament reconstruction. Allografts pretreated with high-dose irradiation should be avoided. Otherwise, multiple factors should be considered to individualize patient decision making, including patient age and activity level, graft type, and fixation type. PMID- 26743419 TI - Editorial Commentary: Options Abound for Calcific Tendonitis of the Shoulder Without a Rotator Cuff Tear. AB - For patients with calcific tendonitis of the shoulder without a rotator cuff tear, nonsurgical options exist. When nonsurgical options fail, or when patients have a concomitant rotator cuff tear, arthroscopy is a safe and effective treatment. PMID- 26743420 TI - Arthroscopy Up to Date: Hip Femoroacetabular Impingement. AB - PURPOSE: To provide a comprehensive review and summary of the research published in Arthroscopy: The Journal of Arthroscopic and Related Surgery and The American Journal of Sports Medicine (AJSM) related to hip arthroscopy for femoroacetabular impingement (FAI). METHODS: A comprehensive review was conducted in duplicate of Arthroscopy and AJSM from February 2012 to February 2015 for all articles related to FAI, and a quality assessment was completed for all included studies. Clinical outcomes were dichotomized into short-term (<6 months) and midterm (<24 months) outcomes, and values were pooled when possible. RESULTS: We identified 60 studies in Arthroscopy and 44 studies in AJSM, primarily from North America (78.8%), that predominantly assessed clinical outcomes after arthroscopic hip surgery (46.1%). Seventy-one percent of Arthroscopy studies and 20.5% of AJSM studies were Level IV evidence. The modified Harris Hip Score (mHHS) was used by 81.5% of included studies. Pooled weighted mean mHHS values after arthroscopic surgery for FAI showed improvements at the midterm from 60.5 points (range, 56.6 to 83.6 points) to 80.5 points (range, 72.1 to 98.0 points) out of a possible 100 points. Pooled weighted outcomes for labral repair showed mean mHHS improvements from 63.8 points (range, 62.5 to 69.0 points) preoperatively to 86.9 points (range, 85.5 to 89.9 points) up to 24 months postoperatively. CONCLUSIONS: This comprehensive review of research published in Arthroscopy and AJSM over the past 3 years identified a number of key findings. Arthroscopic intervention results in improvements in functional outcomes at both the short-term and midterm for patients with symptomatic FAI in the absence of significant existing degenerative changes. Labral repair may result in improvements over labral debridement. The most commonly used outcome score was the mHHS for objective assessment of surgical success. There is a need for continued focus on improvement of methodologic quality and reporting of research pertaining to FAI. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies. PMID- 26743421 TI - Editorial Commentary: Microfracture for Focal Cartilage Defects: Is the Hip Like the Knee? AB - Reading about microfracture for focal cartilage defects of the hip, we ponder whether the hip resembles the knee with regard to focal cartilage defects. Minimally invasive microfracture has been a first-line therapy for focal cartilage defects. Microfracture results in fibrous cartilage and unpredictable repair volume, which could be better than absent cartilage, particularly if knee symptoms abate. However, of late, microfracture is not recommended because destruction of subchondral anatomy may result in subchondral cyst formation. PMID- 26743422 TI - Arthroscopy Up to Date: Anterior Cruciate Ligament Anatomy. AB - PURPOSE: To categorize and summarize up-to-date anterior cruciate ligament (ACL) research published in Arthroscopy and The American Journal of Sports Medicine and systematically review each subcategory, beginning with ACL anatomy. METHODS: After searching for "anterior cruciate ligament" OR "ACL" in Arthroscopy and The American Journal of Sports Medicine from January 2012 through December 2014, we excluded articles more pertinent to ACL augmentation; open growth plates; and meniscal, chondral, or multiligamentous pathology. Studies were subcategorized for data extraction. RESULTS: We included 212 studies that were classified into 8 categories: anatomy; basic science and biomechanics; tunnel position; graft selection; graft fixation; injury risk and rehabilitation; practice patterns and outcomes; and complications. Anatomic risk factors for ACL injury and post reconstruction graft failure include a narrow intercondylar notch, low native ACL volume, and increased posterior slope. Regarding anatomic footprints, the femoral attachment is 43% of the proximal-to-distal lateral femoral condylar length whereas the posterior border of the tendon is 2.5 mm from the articular margin. The tibial attachment of the ACL is two-fifths of the medial-to-lateral interspinous distance and 15 mm anterior to the posterior cruciate ligament. Anatomic research using radiology and computed tomography to evaluate ACL graft placement shows poor interobserver and intraobserver reliability. CONCLUSIONS: With a mind to improving outcomes, surgeons should be aware of anatomic risk factors (stenotic femoral notch, low ligament volume, and increased posterior slope) for ACL graft failure, have a precise understanding of arthroscopic landmarks identifying femoral and tibial footprint locations, and understand that imaging to evaluate graft placement is unreliable. LEVEL OF EVIDENCE: Level III, systematic review of Level III evidence. PMID- 26743423 TI - Editorial Commentary: Anatomy of the Anterior Cruciate Ligament - Are We Up to Date? AB - This systematic review demonstrates that knee anterior cruciate ligament (ACL) anatomic landmarks continue to be better defined, but debate as to the precise location of the ACL femoral and tibial footprints persists. The ACL anatomy of an individual patient may ultimately be impossible to determine using generalized research data, but current research probably gets us pretty close. PMID- 26743424 TI - Editorial Commentary: Cartilage Clinical Research Challenges Show No Signs of Abatement. AB - Medical research methods are generally poor, including methods found in recent research, research from academic institutions, and research supported by commercial funding. A solution is for systematic review authors to avoid additional review of prior publications with poor methods, and focus instead on returning to original scientific research (with improved methods) to address gaps in our clinical knowledge. PMID- 26743425 TI - LcGST4 is an anthocyanin-related glutathione S-transferase gene in Litchi chinensis Sonn. AB - KEY MESSAGE: A novel LcGST4 was identified and characterized from Litchi chinensis . Expression and functional analysis demonstrated that it might function in anthocyanin accumulation in litchi. Glutathione S-transferases (GSTs) have been defined as detoxification enzymes for their ability to recognize reactive electrophilic xenobiotic molecules as well as endogenous secondary metabolites. Anthocyanins are among the few endogenous substrates of GSTs for vacuolar accumulation. The gene encoding a GST protein that is involved in anthocyanin sequestration from Litchi chinensis Sonn. has not been reported. Here, LcGST4, an anthocyanin-related GST, was identified and characterized. Phylogenetic analysis showed that LcGST4 was clustered with other known anthocyanin-related GSTs in the same clade. Expression analysis revealed that the expression pattern of LcGST4 was strongly correlated with anthocyanin accumulation in litchi. ABA- and light-responsive elements were found in the LcGST4 promoter, which is in agreement with the result that the expression of LcGST4 was induced by both ABA and debagging treatment. A GST activity assay in vitro verified that the LcGST4 protein shared universal activity with the GST family. Functional complementation of an Arabidopsis mutant tt19 demonstrated that LcGST4 might function in anthocyanin accumulation in litchi. Dual luciferase assay revealed that the expression of LcGST4 was activated by LcMYB1, a key R2R3 MYB transcription factor that regulates anthocyanin biosynthesis in litchi. PMID- 26743426 TI - Functional investigation of two 1-aminocyclopropane-1-carboxylate (ACC) synthase like genes in the moss Physcomitrella patens. AB - KEY MESSAGE: Two ACC synthase-like (ACL) proteins in the moss Physcomitrella patens have no ACS activity, and PpACL1 functions as an L -cystine/ L -cysteine C S lyase. The ethylene biosynthetic pathway has been well characterized in higher plants, and homologs of a key enzyme in this pathway, ACS, have been reported in several algae and mosses, including Physcomitrella patens. However, the function of the ACS homologs in P. patens has not been investigated. In this research, we cloned two putative ACS genes from the P. patens genome, namely PpACS-Like 1 and 2, and investigated whether their encoded proteins had in vitro and in vivo ACS activity. In vitro biochemical assays using purified PpACL1 and PpACL2 showed that neither protein had ACS activity. Subsequently, we generated transgenic Arabidopsis lines expressing 35S:PpACL1 and 35S:PpACL2, and found that the transgenic etiolated seedlings that overexpressed either of these proteins lacked the constitutive triple response phenotype and did not emit excess levels of ethylene, indicating that neither of the PpACS-Like proteins had in vivo ACS activity. Furthermore, we found that PpACL1 functions as a C-S lyase that uses L cystine and L-cysteine as substrates, rather than as an aminotransferase. Together, these results indicated that PpACL1 and PpACL2 are not true ACS genes as those found in higher plants. PMID- 26743427 TI - Characterizing root-associated fungal communities and soils of Douglas-fir (Pseudotsuga menziesii) stands that naturally produce Oregon white truffles (Tuber oregonense and Tuber gibbosum). AB - Many truffle species in the genus Tuber are endemic to North America. Some of these have commercial value such as Tuber oregonense and Tuber gibbosum, commonly known as Oregon white truffles. Most of what is known about the ecology of these truffles comes from observational data. These truffle species form ectomycorrhizas with Douglas-fir (Pseudotsuga menziesii) and sometimes fruit abundantly in early successional forest regrowth. The goal of this study was to characterize fungal communities and soils associated with truffle-producing Douglas-fir sites. We extracted DNA from roots of five trees at four different truffle-producing Douglas-fir sites (n = 20). We amplified the internal transcribed spacer (ITS) region of the nuclear ribosomal DNA (nrDNA) and sequenced amplicons with 454 pyrosequencing. After quality filtering, we assembled 15,713 sequences into 150 fungal operational taxonomic units (OTUs). Pezizomycetes (Tuber and Pyronemataceae) were the most abundant taxa detected followed by Helotiales. Agaricomycetes represented most by Thelephoraceae, Russulaceae, and Inocybaceae were also abundant. A total of five Tuber species were detected. T. oregonense was the most abundant OTU, followed by T. gibbosum and Wilcoxina mikolae. Fungal root endophytes were also detected and well represented by Chalara and Phialocephala spp. Fungal community structure and soil chemistry differed between sites. This study represents the first characterization of the fungal communities in Douglas-fir stands producing Oregon white truffles. We found that Tuber species can be dominant ectomycorrhizal symbionts of Douglas-fir. Truffle fungi are also important in forest health, food webs, and as a non-timber forest resource that can contribute to rural economies. PMID- 26743428 TI - Quantitative microstructural deficits in chronic phase of stroke with small volume infarcts: A diffusion tensor 3-D tractographic analysis. AB - BACKGROUND: Non-infarct zone white matter wallerian degeneration is well documented in large volume territorial infarctions. However to what extent these abnormalities exist in small volume infarction is not known, particularly since routine T2/FLAIR MR images show minimal changes in such cases. We therefore utilized DTI based quantitative 3D tractography for quantitative assessment of white matter integrity in chronic phase of small volume anterior circulation infarcts. METHODS: Eleven chronic stroke subjects with small anterior circulation large vessel infarcts (<=10cm(3) volume of primary infarct) were compared with 8 age matched controls. These infarcts had negligible to mild gliosis and encephalomalacia in the primary infarct territory without obvious wallerian degeneration on conventional MRI. Quantitative Diffusion Tensor 3-D tractography was performed for CST, genu and splenium of corpus callosum. Tract based Trace and fractional anisotropy (FA) were compared with age matched controls. RESULTS: On univariate analysis, Chronic stroke subjects had significant elevation in Trace measurement in genu of corpus callosum (GCC), ipsilesional and contralesional CST, (p<0.05), compared to controls. After adjusting for smoking, hypertension (HTN) and non-specific white matter hyperintensities, (WMHs), there was significant elevation in trace within the ipsilesional CST (p=0.05). Contralesional CST FA correlated significantly with walking speed, r=0.67, p=0.03. CONCLUSIONS: Stroke subjects with small volume infarcts demonstrate significant quantitative microstructural white matter abnormalities in chronic phase, which are otherwise subthreshold for detection on routine imaging. Ability to quantify these changes provides an important marker for assessing non-infarct zone neuroaxonal integrity in the chronic phase even in the setting of small infarction. PMID- 26743429 TI - Feasibility of MR elastography of the intervertebral disc. AB - Low back pain (LBP) is a costly and widely prevalent health disorder in the U.S. One of the most common causes of LBP is degenerative disc disease (DDD). There are many imaging techniques to characterize disc degeneration; however, there is no way to directly assess the material properties of the intervertebral disc (IVD) within the intact spine. Magnetic resonance elastography (MRE) is an MRI based technique for non-invasively mapping the mechanical properties of tissues in vivo. The purpose of this study was to investigate the feasibility of using MRE to detect shear wave propagation in and determine the shear stiffness of an axial cross-section of an ex vivo baboon IVD, and compare with shear displacements from a finite element model of an IVD motion segment in response to harmonic shear vibration. MRE was performed on two baboon lumbar spine motion segments (L3-L4) with the posterior elements removed at a range of frequencies (1000-1500Hz) using a standard clinical 1.5T MR scanner. Propagating waves were visualized in an axial cross-section of the baboon IVDs in all three motion encoding directions, which resembled wave patterns predicted using finite element modeling. The baboon nucleus pulposus showed an average shear stiffness of 79+/ 15kPa at 1000Hz. These results suggest that MRE is capable of visualizing shear wave propagation in the IVD, assessing the stiffness of the nucleus of the IVD, and can differentiate the nucleus and annulus regions. PMID- 26743430 TI - Intramuscular adipose tissue determined by T1-weighted MRI at 3T primarily reflects extramyocellular lipids. AB - PURPOSE: The purpose of this study was to assess relationships between intramuscular adipose tissue (IntraMAT) content determined by MRI and intramyocellular lipids (IMCL) and extramyocellular lipids (EMCL) determined by (1)H magnetic resonance spectroscopy ((1)H MRS) or echo intensity determined by B mode ultrasonography of human skeletal muscles. METHODS: Thirty young and elderly men and women were included. T1-weighted MRI was taken from the right mid-thigh to measure IntraMAT content of the vastus lateralis (VL) and biceps femoris (BF) using a histogram shape-based thresholding technique. IMCL and EMCL were measured from the VL and BF at the right mid-thigh using (1)H MRS. Ultrasonographic images were taken from the VL and BF of the right mid-thigh to measure echo intensity based on gray-scale level for quantitative analysis. RESULTS: There was a significant correlation between IntraMAT content by MRI and EMCL of the VL and BF (VL, r=0.506, P<0.01; BF, r=0.591, P<0.001) and between echo intensity and EMCL of the VL and BF (VL, r=0.485, P<0.05; BF, r=0.648, P<0.01). IntraMAT content was also significantly correlated with echo intensity of the VL and BF (VL, r=0.404, P<0.05; BF, r=0.493, P<0.01). CONCLUSION: Our study suggests that IntraMAT content determined by T1-weighted MRI at 3T primarily reflects extramyocellular lipids, not intramyocellular lipids, in human skeletal muscles. PMID- 26743431 TI - Malaria burden and anti-malarial drug efficacy in Owando, northern Congo. AB - BACKGROUND: In the Republic of Congo, previous epidemiological studies have only been conducted in the south of the country where it is most accessible. Nationally representative data on the efficacy of new anti-malarial tools are lacking in the country. As an initial step to close the gap, clinical efficacy of two artemisinin-based combinations, artesunate-amodiaquine (ASAQ) and artemether lumefantrine (AL), was assessed in Owando, a city in equatorial flooded forest in northern Republic of Congo. METHODS: Under 12 years old febrile children attending public health facilities were screened for malaria parasites using lactate dehydrogenase (LDH)-based rapid diagnostic test (RDT) for malaria and microscopic examination of thick blood films. Patients with at least 1,000 asexual Plasmodium falciparum parasites/ul of blood were clinically examined, included after informed consent, and followed up for 28 days, according to the 2009 World Health Organization protocol. Patients were randomly assigned to co formulated ASAQ (Coarsucam((r))) or AL (Coartem((r))) treatment groups. Plasmodium falciparum recrudescent isolates were compared to pre-treatment isolates by polymerase chain reaction (PCR) using msp1, msp2, and glurp genes to distinguish between re-infection and recrudescence. RESULTS: Between November 2012 and February 2013, 857 under 12 years old febrile children were screened, of whom 198 (23.1%) had positive RDT and 167 (19.5%) positive thick films. ASAQ and AL efficacies were 92.7 and 94.2% before PCR correction, respectively. After genotyping, the overall efficacy was 100% for ASAQ and 98.0% for AL. CONCLUSION: The data reported here represent partially the burden of malaria in 0-11 years old febrile children examined in public health centres of Owando city and serve as reference for further studies. Both artemisinin-based combinations were highly efficacious in patients under 12 years old with acute uncomplicated malaria. ASAQ was associated with more adverse events, which may reduce compliance in unsupervised treatment. TRIAL REGISTRATION: ACTRN12612000940875. PMID- 26743434 TI - Highly Energetic, Low Sensitivity Aromatic Peroxy Acids. AB - The synthesis, structure, and energetic materials properties of a series of aromatic peroxy acid compounds are described. Benzene-1,3,5-tris(carboperoxoic) acid is a highly sensitive primary energetic material, with impact and friction sensitivities similar to those of triacetone triperoxide. By contrast, benzene 1,4-bis(carboperoxoic) acid, 4-nitrobenzoperoxoic acid, and 3,5 dinitrobenzoperoxoic acid are much less sensitive, with impact and friction sensitivities close to those of the secondary energetic material 2,4,6 trinitrotoluene. Additionally, the calculated detonation velocities of 3,5 dinitrobenzoperoxoic acid and 2,4,6-trinitrobenzoperoxoic acid exceed that of 2,4,6-trinitrotoluene. The solid-state structure of 3,5-dinitrobenzoperoxoic acid contains intermolecular O-H???O hydrogen bonds and numerous N???O, C???O, and O???O close contacts. These attractive lattice interactions may account for the less sensitive nature of 3,5-dinitrobenzoperoxoic acid. PMID- 26743433 TI - Addressing challenges of validity and internal consistency of mental health measures in a 27- year longitudinal cohort study - the Northern Swedish Cohort study. AB - BACKGROUND: There are inherent methodological challenges in the measurement of mental health problems in longitudinal research. There is constant development in definitions, taxonomies and demands concerning the properties of mental health measurements. The aim of this paper was to construct composite measures of mental health problems (according to today's standard) from single questionnaire items devised in the early 1980s, and to evaluate their internal consistency and factorial invariance across the life course using the Northern Swedish Cohort. METHODS: All pupils in the last year of compulsory school in Lulea in 1981 (n = 1083) form a prospective cohort study where the participants have been followed with questionnaires from the age of 16 (in 1981) until the age of 43 (in 2008). We created and tested the following composite measures from self-reports at each follow-up: depressive symptoms, anxiety symptoms, functional somatic symptoms, modified GHQ and positive health. Validity and internal consistency were tested by confirmatory factor analysis, including tests of factorial invariance over time. RESULTS: As an overall assessment, the results showed that the composite measures (based on more than 30-year-old single item questions) are likely to have acceptable factorial invariance as well as internal consistency over time. CONCLUSIONS: Testing the properties of the mental health measures used in older studies according to the standards of today is of great importance in longitudinal research. Our study demonstrates that composite measures of mental health problems can be constructed from single items which are more than 30 years old and that these measures seem to have the same factorial structure and internal consistency across a significant part of the life course. Thus, it can be possible to overcome some specific inherent methodological challenges in using historical data in longitudinal research. PMID- 26743432 TI - Increased abscisic acid levels in transgenic maize overexpressing AtLOS5 mediated root ion fluxes and leaf water status under salt stress. AB - Abscisic acid (ABA) is a vital cellular signal in plants, and effective ABA signalling is pivotal for stress tolerance. AtLOS5 encoding molybdenum cofactor sulphurase is a key regulator of ABA biosynthesis. Here, transgenic AtLOS5 plants were generated to explore the role of AtLOS5 in salt tolerance in maize. AtLOS5 overexpression significantly up-regulated the expression of ZmVp14-2, ZmAO, and ZmMOCO, and increased aldehyde oxidase activities, which enhanced ABA accumulation in transgenic plants under salt stress. Concurrently, AtLOS5 overexpression induced the expression of ZmNHX1, ZmCBL4, and ZmCIPK16, and enhanced the root net Na(+) efflux and H(+) influx, but decreased net K(+) efflux, which maintained a high cytosolic K(+)/Na(+) ratio in transgenic plants under salt stress. However, amiloride or sodium orthovanadate could significantly elevate K(+) effluxes and decrease Na(+) efflux and H(+) influx in salt-treated transgenic roots, but the K(+) effluxes were inhibited by TEA, suggesting that ion fluxes regulated by AtLOS5 overexpression were possibly due to activation of Na(+)/H(+) antiport and K(+) channels across the plasma membrane. Moreover, AtLOS5 overexpression could up-regulate the transcripts of ZmPIP1:1, ZmPIP1:5, and ZmPIP2:4, and enhance root hydraulic conductivity. Thus transgenic plants had higher leaf water potential and turgor, which was correlated with greater biomass accumulation under salt stress. Thus AtLOS5 overexpression induced the expression of ABA biosynthetic genes to promote ABA accumulation, which activated ion transporter and PIP aquaporin gene expression to regulate root ion fluxes and water uptake, thus maintaining high cytosolic K(+) and Na(+) homeostasis and better water status in maize exposed to salt stress. PMID- 26743435 TI - 5-Aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside reduces intimal hyperplasia of tissue engineering blood vessel by inhibiting phenotype switch of vascular smooth muscle cell. AB - Intimal hyperplasia (IH) is the cause of clinical failure in patients with vascular transplants and intravascular stents. The proliferation and phenotype switching of vascular smooth muscle cells (VSMCs) play important roles in IH. Inhibiting the proliferation of VSMCs and maintaining the differentiated phenotype of VSMCs is one way to reduce IH. In this article, 5-aminoimidazole-4 carboxamide 1-beta-D-ribofuranoside (AICAR) was used in experiments after drug screening. We found that the metabolism, autophagy, and differentiation of VSMCs were enhanced which were important to the normal function of VSMCs, but the secretion of VSMCs was reduced after AICAR treatment. AICAR induces G1 phase arrest and inhibits the proliferation of VSMCs using the MTT and EdU assays and cell cycle analysis. Then, the rat carotid artery vessel transplantation model was used to evaluate the function of AICAR in vivo. AICAR-modified tissue engineered blood vessels (TEBVs) had a higher patency rate and less IH than the control TEBVs. In conclusion, AICAR can improve the normal function of VSMCs by increasing the metabolism and autophagy of VSMCs but inhibit the proliferation, paracrine, and phenotypes switching of VSMCs, further contribute the reducing of IH in TEBVs. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 744-752, 2017. PMID- 26743437 TI - Selective attention to a talker's mouth in infancy: role of audiovisual temporal synchrony and linguistic experience. AB - Previous studies have found that infants shift their attention from the eyes to the mouth of a talker when they enter the canonical babbling phase after 6 months of age. Here, we investigated whether this increased attentional focus on the mouth is mediated by audio-visual synchrony and linguistic experience. To do so, we tracked eye gaze in 4-, 6-, 8-, 10-, and 12-month-old infants while they were exposed either to desynchronized native or desynchronized non-native audiovisual fluent speech. Results indicated that, regardless of language, desynchronization disrupted the usual pattern of relative attention to the eyes and mouth found in response to synchronized speech at 10 months but not at any other age. These findings show that audio-visual synchrony mediates selective attention to a talker's mouth just prior to the emergence of initial language expertise and that it declines in importance once infants become native-language experts. PMID- 26743436 TI - Comparative transcriptomic analysis uncovers the complex genetic network for resistance to Sclerotinia sclerotiorum in Brassica napus. AB - Sclerotinia stem rot caused by Sclerotinia sclerotiorum is one of the most devastating diseases in many important crops including Brassica napus worldwide. Quantitative resistance is the only source for genetic improvement of Sclerotinia resistance in B. napus, but the molecular basis for such a resistance is largely unknown. Here, we performed dynamic transcriptomic analyses to understand the differential defense response to S. sclerotiorum in a resistant line (R-line) and a susceptible line (S-line) of B. napus at 24, 48 and 96 h post-inoculation. Both the numbers of and fold changes in differentially expressed genes in the R-line were larger than those in the S-line. We identified 9001 relative differentially expressed genes in the R-line compared with the S-line. The differences between susceptibility and resistance were associated with the magnitude of expression changes in a set of genes involved in pathogen recognition, MAPK signaling cascade, WRKY transcription regulation, jasmonic acid/ethylene signaling pathways, and biosynthesis of defense-related protein and indolic glucosinolate. The results were supported by quantitation of defense-related enzyme activity and glucosinolate contents. Our results provide insights into the complex molecular mechanism of the defense response to S. sclerotiorum in B. napus and for development of effective strategies in Sclerotinia-resistance breeding. PMID- 26743438 TI - Dehalococcoides has a dehalogenation complex. PMID- 26743439 TI - A Fractured Rock Geophysical Toolbox Method Selection Tool. PMID- 26743441 TI - Transcranial direct current stimulation for the treatment of post-stroke depression in aphasic patients: a case series. AB - Aphasia is a common consequence of stroke; it is estimated that about two-thirds of aphasic patients will develop depression in the first year after the stroke. Treatment of post-stroke depression (PSD) is challenging due to the adverse effects of pharmacotherapy and difficulties in evaluating clinical outcomes, including aphasia. Transcranial direct current stimulation (tDCS) is a novel treatment that may improve clinical outcomes in the traditionally pharmacotherapy refractory PSD. Our aim was to evaluate the safety and efficacy of tDCS for patients with PSD and with aphasia. The Stroke Aphasic Depression Questionnaire (SADQ) and the Aphasic Depression Rating Scale (ADRS) were used to evaluate the severity of PSD. The diagnoses of PSD and aphasia were confirmed by a psychiatrist and a speech-language pathologist, respectively. In this open case series, patients (n = 4) received 10 sessions (once a day) of bilateral tDCS to the dorsolateral prefrontal cortex (DLPFC) and two additional sessions after two and four weeks, for a total of 12 sessions. All patients exhibited improvement in depression after tDCS, as indicated by a decrease in SADQ (47.5%) and in ADRS (65.7%). This improvement was maintained four weeks after the treatment. In this preliminary, open-label study conducted in four PSD patients with aphasia, bilateral tDCS over the DLPFC was shown to induce a substantial mood improvement; tDCS was safe and well tolerated by every patient. Stroke patients with aphasia can be safely treated for PSD with tDCS. Sham-controlled studies are necessary to evaluate this technique further. PMID- 26743440 TI - Simultaneous assessment of cardiac metabolism and perfusion using copolarized [1 13 C]pyruvate and 13 C-urea. AB - PURPOSE: To demonstrate the feasibility of imaging a bolus of co-polarized [1-13 C]pyruvate and 13 C-urea to simultaneously assess both metabolism and perfusion in the rodent heart. METHODS: Copolarized [1-13 C]pyruvate and 13 C-urea was imaged using a multi-echo, flow-sensitized spiral pulse sequence. Healthy rats were scanned in a two-factor factorial design (n = 12 total; metabolism: overnight fasting versus fed with dichloroacetate injection; perfusion: rest versus adenosine stress-induced hyperemia). RESULTS: Alterations in metabolism were detected by changes in pyruvate metabolism into 13 C-bicarbonate. Statistically independent alterations in perfusion were detected by changes in myocardial pyruvate and urea signals. CONCLUSION: The new pulse sequence was used to obtain maps of metabolism and perfusion in the rodent heart in a single acquisition. This hyperpolarized 13 C imaging test is expected to enable new studies in which the cardiac metabolism/perfusion mismatch can be studied in the acute environment. Magn Reson Med 77:151-158, 2017. (c) 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. PMID- 26743442 TI - Pathogenesis of experimental salmonid alphavirus infection in vivo: an ultrastructural insight. AB - Salmonid alphavirus (SAV) is an enveloped, single-stranded, positive sense RNA virus belonging to the family Togaviridae. It causes economically devastating disease in cultured salmonids. The characteristic features of SAV infection include severe histopathological changes in the heart, pancreas and skeletal muscles of diseased fish. Although the presence of virus has been reported in a wider range of tissues, the mechanisms responsible for viral tissue tropism and for lesion development during the disease are not clearly described or understood. Previously, we have described membrane-dependent morphogenesis of SAV and associated apoptosis-mediated cell death in vitro. The aims of the present study were to explore ultrastructural changes associated with SAV infection in vivo. Cytolytic changes were observed in heart, but not in gill and head-kidney of virus-infected fish, although they still exhibited signs of SAV morphogenesis. Ultrastructural changes associated with virus replication were also noted in leukocytes in the head kidney of virus-infected fish. These results further describe the presence of degenerative lesions in the heart as expected, but not in the gills and in the kidney. PMID- 26743443 TI - GNAS mutations in adrenal aldosterone-producing adenomas. AB - Mutations in GNAS, which encodes Gsalpha, have been documented in detail, particularly in human pituitary GH-secreting adenomas. Mutations have also recently been reported in adrenal cortisol-producing adenomas (CPAs), in addition to those in the PRKACA gene. However, mutations have not yet been examined in aldosterone-producing adenomas (APAs). Therefore, we herein investigated mutations in the GNAS gene in APAs. Two of the 15 (13%) CPAs with overt Cushing's syndrome and one of the 9 (11%) CPAs with subclinical Cushing's syndrome examined had the somatic mutations, p.R201S and p.R201C in the GNAS gene. We identified mutations in the GNAS gene (p.R201C) in 2 out of the 33 (6%) APAs tested, both of which showed autonomous cortisol secretion, while 24 APAs had mutations in the KCNJ5 gene (18 with p.G151R and 6 with p.L168R). These GNAS and KCNJ5 mutations were mutually exclusive in these adenomas. We herein demonstrated for the first time the presence of GNAS mutations in APAs, as well as in some cortisol secreting adenomas. Our results suggest that these mutations, in addition to mutations in the KCNJ5 gene and other genes such as ATP1A1, ATP2B3 and CACNA1D, may be responsible for the tumorigenesis of APAs and CPAs with subclinical Cushing's syndrome. PMID- 26743444 TI - Production of genome-edited pluripotent stem cells and mice by CRISPR/Cas. AB - Clustered regularly at interspaced short palindromic repeats (CRISPR) and CRISPR associated (Cas) nucleases, so-called CRISPR/Cas, was recently developed as an epoch-making genome engineering technology. This system only requires Cas9 nuclease and single-guide RNA complementary to a target locus. CRISPR/Cas enables the generation of knockout cells and animals in a single step. This system can also be used to generate multiple mutations and knockin in a single step, which is not possible using other methods. In this review, we provide an overview of genome editing by CRISPR/Cas in pluripotent stem cells and mice. PMID- 26743445 TI - Charge-Transfer-Induced Fluorescence Quenching of Anthracene Derivatives and Selective Detection of Picric Acid. AB - 2,6-Divinylpyridine-appended anthracene derivatives flanked by two alkyl chains at the 9,10-position of the core have been designed, synthesized, and characterized by NMR, MALDI-TOF, FTIR, and single-crystal XRD. These anthracene derivatives are able to recognize picric acid (2,4,6-trinitrophenol, PA) selectively down to parts per billion (ppb) level in aqueous as well as nonaqueous medium. Fluorescence emission of these derivatives in solution is significantly quenched by adding trace amounts of PA, even in the presence of other competing analogues, such as 2,4-dinitrophenol (2,4-DNP), 4-nitrophenol (NP), nitrobenzene (NB), benzoic acid (BA), and phenol (PH). The high sensitivity of these derivatives toward PA is considered as a combined effect of the proton induced intramolecular charge transfer (ICT) as well as electron transfer from the electron-rich anthracene to the electron-deficient PA. Moreover, visual detection of PA has been successfully demonstrated in the solid state by using different substrates. PMID- 26743446 TI - Influence of cyclic loading on the adhesive effectiveness of resin-zirconia interface after femtosecond laser irradiation and conventional surface treatments. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the influence of cyclic loading on the shear bond strength (SBS) of a self-adhesive resin cement to zirconia surfaces after femtosecond laser irradiation at different steps and several conventional surface treatments. MATERIALS AND METHODS: One hundred fifty square-shaped zirconia samples were divided into five groups according their surface treatment: NT Group-no surface treatment; APA25 Group-airborne abrasion with 25 MUm alumina particles; TSC Group-tribochemical silica coating; FS20 Group femtosecond laser irradiation (800 nm, 4 mJ, 40 fs/pulse, 1 kHz, step 20); and FS40 Group-femtosecond laser irradiation (same parameters except step 40). Self adhesive resin cement cylinders were bonded at the centre of the zirconia surface. For each experimental group, half of the specimens were subject to cyclic loading under 90 N (50.000 cycles, 3 cycles/sec) and the rest of the specimens were stored in distilled water at 37 degrees C. All subgroups were tested for SBS with a universal testing machine at a crosshead speed of 0.5 mm/min, until fracture. The results were analyzed statistically. RESULTS: When cyclic loading was applied, all surface treatments had lower SBS values, except APA25. The four surface treatments had the same SBS values when cyclic loading was employed. CONCLUSIONS: Use of femtosecond laser irradiation could be an alternative to conventional surface treatments to achieve suitable adhesion zirconia and resin cements. Femtosecond laser irradiation at step 40 is preferable because it is more efficient and faster. PMID- 26743447 TI - Neonatal lupus erythematosus: a cutaneous cases based update. AB - BACKGROUND: Neonatal Lupus Erythematosus (NLE) is an uncommon autoimmune disease characterized by cutaneous, hepatic, hematological, neurological and cardiac involvement. CASE PRESENTATION: Here we report four cases of cutaneous NLE which were referred to our department in the last 10 years and update literature. The newborns presented with different skin, clinical and laboratory features. This underlines the phenotypic variability of NLE. We investigated the passage of maternal antinuclear antibodies (ANA) and extractable nuclear antigen antibodies (ENA) - particularly anti-Ro/SSA, anti-La/SSB and anti-U1 ribonucleoprotein RNP - through the placenta. Despite the positive family background, cutaneous NLE and serological data improved in infants within 4 months without treatment. CONCLUSION: The evolution of cutaneous NLE may be the spontaneous regression of lesions within six months without progression to Systemic Lupus Erytehmatosus. PMID- 26743448 TI - An indirect comparison and cost per responder analysis of adalimumab, methotrexate and apremilast in the treatment of methotrexate-naive patients with psoriatic arthritis. AB - OBJECTIVE: Apremilast was recently approved for the treatment of active psoriatic arthritis (PsA). However, no studies compare apremilast with methotrexate or biologic therapies, so its relative comparative efficacy remains unknown. This study compared the response rates and incremental costs per responder associated with methotrexate, apremilast, and biologics for the treatment of active PsA. METHODS: A systematic literature review was performed to identify phase 3 randomized controlled clinical trials of approved biologics, methotrexate, and apremilast in the methotrexate-naive PsA population. Using Bayesian methods, a network meta-analysis was conducted to indirectly compare rates of achieving a >=20% improvement in American College of Rheumatology component scores (ACR20). The number needed to treat (NNT) and the incremental costs per ACR20 responder (2014 US$) relative to placebo were estimated for each of the therapies. RESULTS: Three trials (MIPA for methotrexate, PALACE-4 for apremilast, and ADEPT for adalimumab) met all inclusion criteria. The NNTs relative to placebo were 2.63 for adalimumab, 6.69 for apremilast, and 8.31 for methotrexate. Among methotrexate-naive PsA patients, the 16 week incremental costs per ACR20 responder were $3622 for methotrexate, $26,316 for adalimumab, and $45,808 for apremilast. The incremental costs per ACR20 responder were $222,488 for apremilast vs. methotrexate. CONCLUSION: Among methotrexate-naive PsA patients, adalimumab was found to have the lowest NNT for one additional ACR20 response and methotrexate was found to have the lowest incremental costs per ACR20 responder. There was no statistical evidence of greater efficacy for apremilast vs. methotrexate. A head-to-head trial between apremilast and methotrexate is recommended to confirm this finding. PMID- 26743449 TI - Switchable self-assembly of Prussian blue analogs nano-tiles triggered by salt stimulus. AB - Prussian blue analogs (PBAs) are materials well known for their bulk physical and (electro)-chemical properties, with an outstanding selectivity for caesium in ion exchange processes. Crystalline nano-tiles, made of copper based PBA, are produced and dispersed in water by tuning their electrostatic interactions. The shape and size of the nano-crystals are determined by combining scattering, microscopic and spectral techniques. We show here that Cu-PBA nano-tiles form planar superstructures by an edge to edge self-assembly process controlled by specific cation effect and ionic strength. Sedimentation and (re-)dispersion of the nano-tiles are found to be fully reversible. This switchable anisotropic self assembly triggered by salt stimulus makes PBA nanocrystals potentially interesting for applications. PMID- 26743450 TI - Empirical evidence of the effect of school gathering on the dynamics of dengue epidemics. AB - INTRODUCTION: Dengue fever is an important vector-transmitted disease that affects more than 100 countries worldwide. Locations where individuals tend to gather may play an important role in disease transmission in the presence of the vector. By controlling mosquitoes' breeding places, this study aims to analyze the effect of reducing transmission in elementary schools (grades 1-9) on the dynamics of the epidemic at a regional level. MATERIALS AND METHODS: In 2007, we implemented a massive campaign in a region of Mexico (Colima state, 5,191 km(2), population 568,000) focused on training janitors to locate and avoid mosquitoes' breeding places, the objective being to maintain elementary schools free of mosquitoes. RESULTS: We observed 45% reduction in dengue incidence compared to the previous year. In contrast, the rest of Mexico observed an 81% increase in incidence on average. DISCUSSION: Costs associated with campaigns focusing on cleaning schools are very low and results seem to be promising. Nevertheless, more controlled studies are needed. PMID- 26743451 TI - Association between depression and periodontitis: a systematic review and meta analysis. AB - AIM: The aim of this systematic review and meta-analysis was to assess the scientific evidence on the association between depression and periodontitis. METHODS: An electronic search was conducted in three databases until October 2015 (PROSPERO-CRD42014006451). Hand searches and grey literature were also included. Search retrieved 423 potentially studies. Two independent reviewers selected the studies, extracted data and assessed risk bias through a modified version of Newcastle-Ottawa scale. Meta-analysis was performed for the presence/absence of periodontitis (dichotomic). Summary effect measures and odds ratio (OR) 95% CI were calculated. RESULTS: After selecting the studies, 15 were included in the systematic review (eight cross-sectional, six case-control and one cohort study). Six studies reported that depression was associated with periodontitis, whereas nine studies did not. The majority of studies had low risk of bias by methodological quality assessment. Meta-analysis of seven cross-sectional studies showed no significant association between depression and periodontitis (OR = 1.03, 95% CI = 0.75-1.41). CONCLUSION: Findings from the present systematic review showed a great heterogeneity among the studies and the summary effect measure of the meta-analysis cannot affirm an association between depression and periodontitis. Future studies with different designs in distinct populations should be conducted to investigate this association. PMID- 26743452 TI - Microvesicles and exosomes: new players in metabolic and cardiovascular disease. AB - The past decade has witnessed an exponential increase in the number of publications referring to extracellular vesicles (EVs). For many years considered to be extracellular debris, EVs are now seen as novel mediators of endocrine signalling via cell-to-cell communication. With the capability of transferring proteins and nucleic acids from one cell to another, they have become an attractive focus of research for different pathological settings and are now regarded as both mediators and biomarkers of disease including cardio-metabolic disease. They also offer therapeutic potential as signalling agents capable of targeting tissues or cells with specific peptides or miRNAs. In this review, we focus on the role that microvesicles (MVs) and exosomes, the two most studied classes of EV, have in diabetes, cardiovascular disease, endothelial dysfunction, coagulopathies, and polycystic ovary syndrome. We also provide an overview of current developments in MV/exosome isolation techniques from plasma and other fluids, comparing different available commercial and non-commercial methods. We describe different techniques for their optical/biochemical characterization and quantitation. We also review the signalling pathways that exosomes and MVs activate in target cells and provide some insight into their use as biomarkers or potential therapeutic agents. In summary, we give an updated focus on the role that these exciting novel nanoparticles offer for the endocrine community. PMID- 26743453 TI - The importance of safety, agency and control during involuntary mental health admissions. AB - BACKGROUND: Constructs such as personal recovery, patient engagement and consumer involvement are central in mental health care delivery. These approaches emphasise the importance of empowerment and choice. AIMS: Under some circumstances Involuntary Treatment Orders (ITO) allow a person to be treated for a mental illness without their consent. This study explores the tensions between the principles of empowerment and control and involuntary treatment. METHODS: Twenty-five involuntary inpatients of a major teaching hospital were interviewed about their experiences of being placed under an ITO. The interviews were analysed thematically. RESULTS: Being able to have some sense of agency and re asserting personal control are critical components of an involuntary mental health admission. Participants wanted information about their treatment, the ITO process and their environment. They also spoke about the importance of a space where they felt safe from themselves and others to make sense of the experience. CONCLUSIONS: This study suggests that for coercive treatment to aid, rather than disrupt recovery, treatment services need to focus on: the provision of rights; the creation of a sense of safety; establishing supportive relationships; carrying hope and finding ways to foster a strong sense of agency and empowerment. PMID- 26743454 TI - Abnormal hippocampal structure and function in clinical anxiety and comorbid depression. AB - Given the high prevalence rates of comorbidity of anxiety and depressive disorders, identifying a common neural pathway to both disorders is important not only for better diagnosis and treatment, but also for a more complete conceptualization of each disease. Hippocampal abnormalities have been implicated in anxiety and depression, separately; however, it remains unknown whether these abnormalities are also implicated in their comorbidity. Here we address this question by testing 32 adults with generalized anxiety disorder (15 GAD only and 17 comorbid MDD) and 25 healthy controls (HC) using multimodal MRI (structure, diffusion and functional) and automated hippocampal segmentation. We demonstrate that (i) abnormal microstructure of the CA1 and CA2-3 is associated with GAD/MDD comorbidity and (ii) decreased anterior hippocampal reactivity in response to repetition of the threat cue is associated with GAD (with or without MDD comorbidity). In addition, mediation-structural equation modeling (SEM) reveals that our hippocampal and dimensional symptom data are best explained by a model describing a significant influence of abnormal hippocampal microstructure on both anxiety and depression-mediated through its impact on abnormal hippocampal threat processing. Collectively, our findings show a strong association between changes in hippocampal microstructure and threat processing, which together may present a common neural pathway to comorbidity of anxiety and depression. PMID- 26743455 TI - Context Matters: Practitioner Perspectives on Immunization Delivery Quality Improvement Efforts. AB - Uneven adherence to immunization guidelines might leave some communities vulnerable to outbreaks of vaccine-preventable diseases. To examine factors related to implementation of immunization delivery best practices, we analyzed responses to monthly surveys and debriefing interviews from 16 diverse pediatric practices engaged in a year-long virtual learning collaborative. The collaborative provided a toolkit, online learning sessions, performance feedback, and conference calls with a quality improvement coach. Participants used iterative plan-do-study-act cycles to implement self-selected changes in immunization practices. Descriptive statistics were applied to quantitative data; qualitative data were analyzed using a framework approach. Impediments to implementing guidelines included difficulties with electronic record systems, rigid management structures, competing priorities, and parental resistance. Facilitators included linkage with regional immunization registries, positive social interactions, and performance feedback. Findings suggest that improving immunization delivery requires not only awareness of recommendations and training in improvement methods but also efforts to ameliorate contextual factors that impede immunization delivery. PMID- 26743456 TI - A novel fractional crystallization route to porous TiO2-Fe2O3 composites: large scale preparation and high performances as a photocatalyst and Li-ion battery anode. AB - Meso/macroporous TiO2-Fe2O3 composite particles are prepared using naturally abundant ilmenite via a novel heat treatment induced fractional crystallization strategy in a fluidized bed. Fluid-bed roasting in oxidizing and reducing environments is carried out in order to realize the fractional crystallization of ilmenite. Subsequently, acid leaching is employed to remove most of the ferrous phase and form porous TiO2-Fe2O3 composites. The influences of the reaction parameters on the composition, structure and properties of the products are studied. It is found that the pore structure and composition of the porous TiO2 Fe2O3 composite particles can be controlled simply by controlling some parameters, such as the roasting time, temperature, precursor particle size, and post-roasting treatment. Photocatalytic and electrochemical cycling measurements show that the synergism of porous structures and the controlled doping of alpha Fe2O3 endow the as-obtained products with excellent visible light photocatalytic activity and provide enhanced performance in lithium ion batteries. The composite porous particles thus obtained may have some promising applications in the fields of photocatalysts, electrode materials, absorbers, pigments etc. This work opens a new avenue for reasonable combination of cost-effective raw materials, a large scale fabricating process and fine control over the structure and composition in the design and preparation of functional materials. PMID- 26743457 TI - Variable protection against experimental broiler necrotic enteritis after immunization with the C-terminal fragment of Clostridium perfringens alpha-toxin and a non-toxic NetB variant. AB - Necrotic enteritis toxin B (NetB) is a pore-forming toxin produced by Clostridium perfringens and has been shown to play a key role in avian necrotic enteritis, a disease causing significant costs to the poultry production industry worldwide. The aim of this work was to determine whether immunization with a non-toxic variant of NetB (NetB W262A) and the C-terminal fragment of C. perfringens alpha toxin (CPA247-370) would provide protection against experimental necrotic enteritis. Immunized birds with either antigen or a combination of antigens developed serum antibody levels against NetB and CPA. When CPA247-370 and NetB W262A were used in combination as immunogens, an increased protection was observed after oral challenge by individual dosing, but not after in-feed challenge. PMID- 26743459 TI - Synthesis of Substituted Tetralins and Benzosuberans via BF3.OEt2-Mediated Formal (4 + 2) and (5 + 2) Stereocontrolled Cycloaddition of 4-Alkenols with Veratrol. AB - BF3.OEt2-mediated one-pot formal (4 + 2) and (5 + 2) stereocontrolled cycloaddition of 4-alkenols 3 and 4 with veratrol affords the respective substituted tetralins 5 and benzosuberans 6 in good yields. The cascade protocol combines a facile double Friedel-Crafts benzannulation of 4-alkenols 3 and 4 (having two electrophilic sites) and veratrol (7a) (having two nucleophilic sites). A plausible mechanism was studied and proposed. PMID- 26743458 TI - Revealing Potential Biomarkers of Functional Dyspepsia by Combining 1H NMR Metabonomics Techniques and an Integrative Multi-objective Optimization Method. AB - Metabonomics methods have gradually become important auxiliary tools for screening disease biomarkers. However, recognition of metabolites or potential biomarkers closely related to either particular clinical symptoms or prognosis has been difficult. The current study aims to identify potential biomarkers of functional dyspepsia (FD) by a new strategy that combined hydrogen nuclear magnetic resonance ((1)H NMR)-based metabonomics techniques and an integrative multi-objective optimization (LPIMO) method. First, clinical symptoms of FD were evaluated using the Nepean Dyspepsia Index (NDI), and plasma metabolic profiles were measured by (1)H NMR. Correlations between the key metabolites and the NDI scores were calculated. Then, LPIMO was developed to identify a multi-biomarker panel by maximizing diagnostic ability and correlation with the NDI score. Finally, a KEGG database search elicited the metabolic pathways in which the potential biomarkers are involved. The results showed that glutamine, alanine, proline, HDL, beta-glucose, alpha-glucose and LDL/VLDL levels were significantly altered in FD patients. Among them, phosphatidycholine (PtdCho) and leucine/isoleucine (Leu/Ile) were positively and negatively correlated with the NDI Symptom Index (NDSI) respectively. Our procedure not only significantly improved the credibility of the biomarkers, but also demonstrated the potential of further explorations and applications to diagnosis and treatment of complex disease. PMID- 26743460 TI - Genomic characterization of coxsackievirus type B3 strains associated with acute flaccid paralysis in south-western India. AB - Acute flaccid paralysis (AFP) associated with coxsackievirus type B3 (CV-B3) of the species Enterovirus B is an emerging concern worldwide. Although CV-B3 associated AFP in India has been demonstrated previously, the genomic characterization of these strains is unreported. Here, CV-B3 strains detected on the basis of the partial VP1 gene in 10 AFP cases and five asymptomatic contacts identified from different regions of south-western India during 2009-2010 through the Polio Surveillance Project were considered for complete genome sequencing and characterization. Phylogenetic analysis of complete VP1 gene sequences of global CV-B3 strains classified Indian CV-B3 strains into genogroup GVI, along with strains from Uzbekistan and Bangladesh, and into a new genogroup, GVII. Genomic divergence between genogroups of the study strains was 14.4 % with significantly lower divergence (1.8 %) within GVI (n = 12) than that within GVII (8.5 %) (n = 3). The strains from both AFP cases and asymptomatic contacts, identified mainly in coastal Karnataka and Kerala, belonged to the dominant genogroup GVI, while the GVII strains were recovered from AFP cases in north interior Karnataka. All study strains carried inter-genotypic recombination with the structural region similar to reference CV-B3 strains, and 5' non-coding regions and non-structural regions closer to other enterovirus B types. Domain II structures of 5' non coding regions, described to modulate virus replication, were predicted to have varied structural folds in the two genogroups and were attributed to differing recombination patterns. The results indicate two distinct genomic compositions of CV-B3 strains circulating in India and suggest the need for concurrent analysis of viral and host factors to further understand the varied manifestations of their infections. PMID- 26743461 TI - Facile synthesis of hybrid nanorods with the Sb2Se3/AgSbSe2 heterojunction structure for high performance photodetectors. AB - An effective colloidal process involving the hot-injection method is developed to synthesize uniform single-crystalline Sb2Se3 nanorods in high yields. The photoconductive characteristics of the as-synthesized Sb2Se3 nanorods are investigated by developing a film-based photodetector and this device displays a remarkable response to visible light with an "ON/OFF" ratio as high as 50 (with an incident light density of 12.05 mW cm(-2)), short response/recovery times and long-term durability. To overcome the challenge of the intrinsic low electrical conductivity of Sb2Se3, hybrid nanorods with the Sb2Se3/AgSbSe2 heterojunction structure having a type-II band alignment are firstly prepared. The electric current of the photodetector based on the Sb2Se3/AgSbSe2 hybrid nanorod film has been significantly increased both in the dark and under light illumination. The responsivity of the photodetector based on the Sb2Se3/AgSbSe2 hybrid nanorod film is about 4.2 times as much as that of the photodetector based on the Sb2Se3 nanorod film. This improvement can be considered as an important step to promote Sb2Se3 based semiconductors for applications in high performance photodetectors. PMID- 26743462 TI - Gene targets of mouse miR-709: regulation of distinct pools. AB - MicroRNA (miRNA) are short non-coding RNA molecules that regulate multiple cellular processes, including development, cell differentiation, proliferation and death. Nevertheless, little is known on whether miRNA control the same gene networks in different tissues. miR-709 is an abundant miRNA expressed ubiquitously. Through transcriptome analysis, we have identified targets of miR 709 in hepatocytes. miR-709 represses genes implicated in cytoskeleton organization, extracellular matrix attachment, and fatty acid metabolism. Remarkably, none of the previously identified targets in non-hepatic tissues are silenced by miR-709 in hepatocytes, even though several of these genes are abundantly expressed in liver. In addition, miR-709 is upregulated in hepatocellular carcinoma, suggesting it participates in the genetic reprogramming that takes place during cell division, when cytoskeleton remodeling requires substantial changes in gene expression. In summary, the present study shows that miR-709 does not repress the same pool of genes in separate cell types. These results underscore the need for validating gene targets in every tissue a miRNA is expressed. PMID- 26743463 TI - Coronary Calcification and Plaque Vulnerability: An Optical Coherence Tomographic Study. AB - BACKGROUND: Spotty superficial calcium deposits have been implicated in plaque vulnerability based on previous intravascular imaging studies. Biomechanical models suggest that microcalcifications between 5 and 65 um in diameter can intensify fibrous cap stress, promoting plaque rupture. However, the 100- to 200 um resolution of intravascular ultrasound limits its ability to discriminate single calcium deposits from clusters of smaller deposits, and a previous optical coherence tomographic investigation evaluated calcifications within a long segment of artery, which may not truly reflect the mechanics involved in potentiating focal plaque rupture. METHODS AND RESULTS: Detailed optical coherence tomographic assessment of coronary calcification at the culprit plaque (10-mm length) was performed in 53 patients with acute ST-segment-elevation myocardial infarction mediated by plaque rupture and 55 patients with stable angina pectoris. The number and longitudinal length of individual calcium deposits were recorded. Cross-sectional images were analyzed every 1 mm for calcium arc and depth, and these quantitative parameters were used to define individual deposits as spotty, large, and superficial. There was no significant difference between ST-segment-elevation myocardial infarction mediated by plaque rupture and stable angina pectoris groups in the number of total (P=0.58), spotty (P=0.87), or large calcium deposits (P=0.27). Minimum calcium depth was similar between groups (P=0.27), as was the number of superficial deposits (P=0.35 using a 65-um depth threshold and P=0.84 using a 100-um depth threshold). CONCLUSIONS: The number and pattern of culprit plaque calcifications did not differ between patients presenting with ST-segment-elevation myocardial infarction mediated by plaque rupture versus stable angina pectoris. The optical coherence tomographic assessment of coronary calcification may not be a useful marker of local plaque vulnerability as previously suspected. REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01110538. PMID- 26743464 TI - The Mystery of Spotty Calcification: Can We Solve It by Optical Coherence Tomography? PMID- 26743465 TI - Diversity and interactions of microbial functional genes under differing environmental conditions: insights from a membrane bioreactor and an oxidation ditch. AB - The effect of environmental conditions on the diversity and interactions of microbial communities has caused tremendous interest in microbial ecology. Here, we found that with identical influents but differing operational parameters (mainly mixed liquor suspended solid (MLSS) concentrations, solid retention time (SRT) and dissolved oxygen (DO) concentrations), two full-scale municipal wastewater treatment systems applying oxidation ditch (OD) and membrane bioreactor (MBR) processes harbored a majority of shared genes (87.2%) but had different overall functional gene structures as revealed by two datasets of 12 day time-series generated by a functional gene array-GeoChip 4.2. Association networks of core carbon, nitrogen and phosphorus cycling genes in each system based on random matrix theory (RMT) showed different topological properties and the MBR nodes showed an indication of higher connectivity. MLSS and DO were shown to be effective in shaping functional gene structures of the systems by statistical analyses. Higher MLSS concentrations resulting in decreased resource availability of the MBR system were thought to promote positive interactions of important functional genes. Together, these findings show the differences of functional potentials of some bioprocesses caused by differing environmental conditions and suggest that higher stress of resource limitation increased positive gene interactions in the MBR system. PMID- 26743467 TI - Chiral Graphene Quantum Dots. AB - Chiral nanostructures from metals and semiconductors attract wide interest as components for polarization-enabled optoelectronic devices. Similarly to other fields of nanotechnology, graphene-based materials can greatly enrich physical and chemical phenomena associated with optical and electronic properties of chiral nanostructures and facilitate their applications in biology as well as other areas. Here, we report that covalent attachment of l/d-cysteine moieties to the edges of graphene quantum dots (GQDs) leads to their helical buckling due to chiral interactions at the "crowded" edges. Circular dichroism (CD) spectra of the GQDs revealed bands at ca. 210-220 and 250-265 nm that changed their signs for different chirality of the cysteine edge ligands. The high-energy chiroptical peaks at 210-220 nm correspond to the hybridized molecular orbitals involving the chiral center of amino acids and atoms of graphene edges. Diverse experimental and modeling data, including density functional theory calculations of CD spectra with probabilistic distribution of GQD isomers, indicate that the band at 250-265 nm originates from the three-dimensional twisting of the graphene sheet and can be attributed to the chiral excitonic transitions. The positive and negative low energy CD bands correspond to the left and right helicity of GQDs, respectively. Exposure of liver HepG2 cells to L/D-GQDs reveals their general biocompatibility and a noticeable difference in the toxicity of the stereoisomers. Molecular dynamics simulations demonstrated that d-GQDs have a stronger tendency to accumulate within the cellular membrane than L-GQDs. Emergence of nanoscale chirality in GQDs decorated with biomolecules is expected to be a general stereochemical phenomenon for flexible sheets of nanomaterials. PMID- 26743466 TI - Positive coping styles and perigenual ACC volume: two related mechanisms for conferring resilience? AB - Stress exposure has been linked to increased rates of depression and anxiety in adults, particularly in females, and has been associated with maladaptive changes in the anterior cingulate cortex (ACC), which is an important brain structure involved in internalizing disorders. Coping styles are important mediators of the stress reaction by establishing homeostasis, and may thus confer resilience to stress-related psychopathology. Anatomical scans were acquired in 181 healthy participants at age 25 years. Positive coping styles were determined using a self report questionnaire (German Stress Coping Questionnaire, SVF78) at age 22 years. Adult anxiety and depression symptoms were assessed at ages 22, 23 and 25 years with the Young Adult Self-Report. Information on previous internalizing diagnoses was obtained by diagnostic interview (2-19 years). Positive coping styles were associated with increased ACC volume. ACC volume and positive coping styles predicted anxiety and depression in a sex-dependent manner with increased positive coping and ACC volume being related to lower levels of psychopathology in females, but not in males. These results remained significant when controlled for previous internalizing diagnoses. These findings indicate that positive coping styles and ACC volume are two linked mechanisms, which may serve as protective factors against internalizing disorders. PMID- 26743469 TI - Benign and low-grade fibroepithelial neoplasms of the breast have low recurrence rate after positive surgical margins. AB - Breast phyllodes tumors are uncommon fibroepithelial neoplasms with a range of histologic features. Surgical excision is the primary management, but the need for excision to negative margins in benign and borderline phyllodes tumors is unclear. Here, we review the surgical management patterns and outcomes of 90 patients with benign and low-grade fibroepithelial lesions of the breast treated at our institution, including 19 borderline phyllodes tumors, 52 benign phyllodes tumors, and 19 representative neoplasms with overlapping features of fibroadenoma and benign phyllodes tumors, which were classified as 'fibroadenomas with phyllodal features'. In total, 52 (58%) had positive surgical margins on first excision, and of these 17 (33%) underwent re-excision to achieve negative margins. Residual tumor was identified in three (18%) re-excisions. Patients with fibroadenoma with phyllodal features were more likely to have a positive surgical margin than with benign phyllodes tumors or borderline phyllodes tumors (89 vs 49%, P=0.0015), and were less likely to undergo re-excision for positive margins (12 vs 43%, P=0.031). In total, there were three recurrences (3%), with one per fibroadenoma with phyllodal features, benign phyllodes tumor, and borderline phyllodes tumor. There was no statistically significant difference in recurrence rates between patients with positive or negative margins, or between patients with positive margin with or without re-excision. The extent of the positive margin did not predict recurrence. In conclusion, the recurrence rate of benign and low-grade fibroepithelial lesions is low and not associated with the original margin status. Patients with fibroadenomas with phyllodal features, benign phyllodes tumors, or selected borderline phyllodes tumors and positive margins on initial excision may be managed conservatively, with close follow-up and timely re-excision of any potential recurrence. PMID- 26743468 TI - Clonal evaluation of prostate cancer foci in biopsies with discontinuous tumor involvement by dual ERG/SPINK1 immunohistochemistry. AB - The presence of two or more prostate cancer foci separated by intervening benign tissue in a single core is a well-recognized finding on prostate biopsy. Cancer involvement can be measured by including intervening benign tissue or only including the actual cancer involved area. Importantly, this parameter is a common enrollment criterion for active surveillance protocols. We hypothesized that spatially distinct prostate cancer foci in biopsies may arise from separate clones, impacting cancer involvement assessment. Hence, we used dual ERG/SPINK1 immunohistochemistry to determine the frequency of separate clones-when separate tumor foci showed discordant ERG and/or SPINK1 status-in discontinuously involved prostate biopsy cores from two academic institutions. In our cohort of 97 prostate biopsy cores with spatially discrete tumor foci (from 80 patients), discontinuous cancer involvement including intervening tissue ranged from 20 to 100% and Gleason scores ranged from 6 to 9. Twenty-four (25%) of 97 discontinuously involved cores harbored clonally distinct cancer foci by discordant ERG and/or SPINK1 expression status: 58% (14/24) had one ERG(+) focus, and one ERG(-)/SPINK1(-) focus; 29% (7/24) had one SPINK1(+) focus and one ERG( )/SPINK1(-) focus; and 13% (3/24) had one ERG(+) focus and one SPINK1(+) focus. ERG and SPINK1 overexpression were mutually exclusive in all tumor foci. In summary, our results show that ~25% of discontinuously involved prostate biopsy cores showed tumor foci with discordant ERG/SPINK1 status, consistent with multiclonal disease. The relatively frequent presence of multiclonality in discontinuously involved prostate biopsy cores warrants studies on the potential clinical impact of clonality assessment, particularly in cases where tumor volume in a discontinuous core may impact active surveillance eligibility. PMID- 26743470 TI - The presence of intraductal carcinoma of the prostate in needle biopsy is a significant prognostic factor for prostate cancer patients with distant metastasis at initial presentation. AB - Intraductal carcinoma of the prostate is an adverse prognostic factor in localized prostate cancer patients. However, whether it influences outcome of those patients with distant metastases discovered at initial diagnosis is unclear. Here, we evaluated whether the presence of intraductal carcinoma of the prostate in prostate needle biopsies is an adverse prognostic factor for cancer specific survival and overall survival in such prostate cancer patients. We retrospectively enrolled 150 eligible patients. All patients received androgen deprivation therapy and/or chemotherapy. Their age, performance status, pain, metastatic sites, clinical T stage, serum prostate-specific antigen, alkaline phosphatase, hemoglobin, Gleason score, and the presence of Gleason pattern 5 were analyzed. Primary end point was cancer-specific survival; secondary end points included prostate-specific antigen progression-free survival and overall survival. Fine and Gray's model and the Cox proportional hazards model were used as statistical tests. Intraductal carcinoma of the prostate was detected in 100 (67%) patients. At a median follow-up of 38 months, 79 patients (53%) had died of the disease and nine (6%) had died of other causes. The average time interval to cancer-related death was 28 months. On multivariate analysis, only intraductal carcinoma of the prostate was significantly associated with cancer-specific survival (P=0.018) and overall survival (P=0.001), and only the presence of Gleason pattern 5 was significantly associated with prostate-specific antigen progression-free survival (P=0.026). The presence of intraductal carcinoma of the prostate was the only significant prognostic parameter for cancer-specific survival and overall survival in prostate cancer patients with distant metastasis at presentation. These results may prove useful in planning future treatments. PMID- 26743471 TI - Next generation sequencing of Cytokeratin 20-negative Merkel cell carcinoma reveals ultraviolet-signature mutations and recurrent TP53 and RB1 inactivation. AB - Merkel cell carcinoma is a rare but highly aggressive cutaneous neuroendocrine carcinoma. Cytokeratin 20 (CK20) is expressed in ~95% of Merkel cell carcinomas and is useful for distinction from morphologically similar entities including metastatic small-cell lung carcinoma. Lack of CK20 expression may make diagnosis of Merkel cell carcinoma more challenging, and has unknown biological significance. Approximately 80% of CK20-positive Merkel cell carcinomas are associated with the oncogenic Merkel cell polyomavirus. Merkel cell carcinomas lacking Merkel cell polyomavirus display distinct genetic changes from Merkel cell polyomavirus-positive Merkel cell carcinoma, including RB1 inactivating mutations. Unlike CK20-positive Merkel cell carcinoma, the majority of CK20 negative Merkel cell carcinomas are Merkel cell polyomavirus-negative, suggesting CK20-negative Merkel cell carcinomas predominantly arise through virus independent pathway(s) and may harbor additional genetic differences from conventional Merkel cell carcinoma. Hence, we analyzed 15 CK20-negative Merkel cell carcinoma tumors (10 Merkel cell polyomavirus-negative, four Merkel cell polyomavirus-positive, and one undetermined) using the Ion Ampliseq Comprehensive Cancer Panel, which assesses copy number alterations and mutations in 409 cancer relevant genes. Twelve tumors displayed prioritized high-level chromosomal gains or losses (average 1.9 per tumor). Non-synonymous high-confidence somatic mutations were detected in 14 tumors (average 11.9 per tumor). Assessing all somatic coding mutations, an ultraviolet-signature mutational profile was present, and more prevalent in Merkel cell polyomavirus-negative tumors. Recurrent deleterious tumor suppressor mutations affected TP53 (9/15, 60%), RB1 (3/15, 20%), and BAP1 (2/15, 13%). Oncogenic activating mutations included PIK3CA (3/15, 20%), AKT1 (1/15, 7%) and EZH2 (1/15, 7%). In conclusion, CK20-negative Merkel cell carcinoma display overlapping genetic changes with CK20-positive Merkel cell carcinoma, including RB1 mutations restricted to Merkel cell polyomavirus-negative tumors. However, some CK20-negative Merkel cell carcinomas harbor mutations not previously described in Merkel cell carcinoma. Hence, CK20 negative Merkel cell carcinomas harbor diverse oncogenic drivers which may represent therapeutic targets in individual tumors. PMID- 26743472 TI - Prognostic significance of L1CAM expression and its association with mutant p53 expression in high-risk endometrial cancer. AB - Studies in early-stage, predominantly low- and intermediate-risk endometrial cancer have demonstrated that L1 cell adhesion molecule (L1CAM) overexpression identifies patients at increased risk of recurrence, yet its prognostic significance in high-risk endometrial cancer is unclear. To evaluate this, its frequency, and the relationship of L1CAM with the established endometrial cancer biomarker p53, we analyzed the expression of both markers by immunohistochemistry in a pilot series of 116 endometrial cancers (86 endometrioid, 30 non endometrioid subtype) with high-risk features (such as high tumor grade and deep myometrial invasion) and correlated results with clinical outcome. We used The Cancer Genome Atlas (TCGA) endometrial cancer series to validate our findings. Using the previously reported cutoff of 10% positive staining, 51/116 (44%) tumors were classified as L1CAM-positive, with no significant association between L1CAM positivity and the rate of distant metastasis (P=0.195). However, increasing the threshold for L1CAM positivity to 50% resulted in a reduction of the frequency of L1CAM-positive tumors to 24% (28/116), and a significant association with the rate of distant metastasis (P=0.018). L1CAM expression was strongly associated with mutant p53 in the high-risk and TCGA series (P<0.001), although a substantial fraction (36% of endometrioid, 10% of non-endometrioid morphology) of p53-mutant endometrial cancers displayed <10% L1CAM positivity. Moreover, 30% of p53-wild-type non-endometrioid endometrial cancers demonstrated diffuse L1CAM staining, suggesting p53-independent mechanisms of L1CAM overexpression. In conclusion, the previously proposed threshold for L1CAM positivity of >10% does not predict prognosis in high-risk endometrial cancer, whereas an alternative threshold (>50%) does. L1CAM expression is strongly, but not universally, associated with mutant p53, and may be strong enough for clinical implementation as prognostic marker in combination with p53. The high frequency of L1CAM expression in high-risk endometrial cancers suggests that it may also be a promising therapeutic target in this tumor subset. PMID- 26743473 TI - Silent subtype 3 pituitary adenomas are not always silent and represent poorly differentiated monomorphous plurihormonal Pit-1 lineage adenomas. AB - Originally classified as a variant of silent corticotroph adenoma, silent subtype 3 adenomas are a distinct histologic variant of pituitary adenoma of unknown cytogenesis. We reviewed the clinical, biochemical, radiological, immunohistochemical and ultrastructural features of 31 silent subtype 3 adenomas to clarify their cellular origin. Among 25 with clinical and/or radiological data, all were macroadenomas; there was cavernous sinus invasion in 30% of cases and involvement of the clivus in 17% of cases. Almost 90% of patients were symptomatic; 67% had mass effect symptoms, 37% were hypogonadal and 8% had secondary adrenal insufficiency. Significant hormonal excess in 29% of cases included hyperthyroidism in 17%, acromegaly in 8% and hyperprolactinemia above 150 MUg/l in 4%. Two individuals with hyperprolactinemia who were younger than 30 years had multiple endocrine neoplasia type 1. Immunohistochemically, all 31 tumors were diffusely positive for the pituitary lineage-specific transcription factor Pit-1. Although three only expressed Pit-1, others revealed variable positivity for one or more hormones of Pit-1 cell lineage (growth hormone, prolactin, thyroid-stimulating hormone), as well as alpha-subunit and estrogen receptor. Most tumors exhibited perinuclear reactivity for keratins with the CAM5.2 antibody; scattered fibrous bodies were noted in five (16%) tumors. The mean MIB-1 labeling index was 4% (range, 1-9%). Fourteen cases examined by electron microscopy were composed of a monomorphous population of large polygonal or elongated cells with nuclear spheridia. Sixty-five percent of patients had residual disease after surgery; after a mean follow-up of 48.4 months (median 41.5; range=2-171) disease progression was documented in 53% of those cases. These data identify silent subtype 3 adenomas as aggressive monomorphous plurihormonal adenomas of Pit-1 lineage that may be associated with hyperthyroidism, acromegaly or galactorrhea and amenorrhea. Our findings argue against the use of the nomenclature 'silent' for these tumors. To better reflect the characteristics of these tumors, we propose that they be classified as 'poorly differentiated Pit-1 lineage adenomas'. PMID- 26743475 TI - microRNA-10b is a prognostic biomarker for melanoma. AB - Malignant melanoma is an aggressive form of skin cancer. Recently, drug therapy of advanced disease has been revolutionized by new agents. More therapeutic options, coupled with the desire to extend treatment to the adjuvant setting mean that prognostic biomarkers that can be assayed from formalin-fixed paraffin embedded clinical would be valuable. microRNAs have potential to fill this need. We analyzed 377 microRNAs in 79 primary melanomas and 32 metastases using a split sample discovery strategy. From a discovery analysis using 40 thick primary melanomas (20 cases with metastasis and 20 controls without metastasis at 5 years), microRNA expression was measured by quantitative RT-PCR (QRT-PCR). MiR 10b emerged as a candidate prognostic microRNA. This was confirmed in an independent validation set of thick primary melanomas (20 cases with metastasis and 19 controls without metastasis at 5 years). In the combined discovery and validation cohorts (n=79), miR-10b expression showed a 3.7-fold increase in expression between cases and controls (P=0.005) and showed a trend of increasing expression between primary melanomas and their matched metastases (P<0.001). In situ hybridization showed expression was in melanoma cells and correlated with expression measured by QRT-PCR (P=0.0005). We used the combined discovery and validation samples to verify the prognostic value of additional candidate microRNAs identified from other studies, and proceeded to analyze miR-200b. We demonstrated that miR-10b and miR-200b showed independent prognostic value (P=0.002 and 0.047, respectively) in multivariable analysis alongside known clinico-pathological prognostic features (eg, Breslow thickness) using a Cox proportional hazards regression model. Furthermore, the addition of these microRNAs to the clinico-pathological features led to an improved regression model with better identification of aggressive thick melanomas. Taken together, these data suggest that miR-10b is a new prognostic microRNA for melanoma and that there could be a place for microRNA analysis in stratifying melanoma for therapy. PMID- 26743474 TI - Loss of switch/sucrose non-fermenting complex protein expression is associated with dedifferentiation in endometrial carcinomas. AB - Dedifferentiated endometrial carcinoma is an aggressive type of endometrial cancer that contains a mix of low-grade endometrioid and undifferentiated carcinoma components. We performed targeted sequencing of eight dedifferentiated carcinomas and identified somatic frameshift/nonsense mutations in SMARCA4, a core ATPase of the switch/sucrose non-fermenting (SWI/SNF) complex, in the undifferentiated components of four tumors. Immunohistochemical analysis confirmed the loss of SMARCA4 in the undifferentiated component of these four SMARCA4-mutated cases, whereas the corresponding low-grade endometrioid component showed retained SMARCA4 expression. An expanded survey of other members of the SWI/SNF complex showed SMARCB1 loss in the undifferentiated component of two SMARCA4-intact tumors, and all SMARCA4- or SMARCB1-deficient tumors showed concomitant loss of expression of SMARCA2. We subsequently examined the expression of SMARCA2, SMARCA4, and SMARCB1 in an additional set of 22 centrally reviewed dedifferentiated carcinomas and 31 grade 3 endometrioid carcinomas. Combining the results from the index and the expansion set, 15 of 30 (50%) of the dedifferentiated carcinomas examined showed either concurrent SMARCA4 and SMARCA2 loss (37%) or concurrent SMARCB1 and SMARCA2 loss (13%) in the undifferentiated component. The loss of SMARCA4 or SMARCB1 was mutually exclusive. All 31 grade 3 endometrioid carcinomas showed intact expression of these core SWI/SNF proteins. The majority (73%) of the SMARCA4/SMARCA2-deficient and half of SMARCB1/SMARCA2 deficient undifferentiated component developed in a mismatch repair-deficient molecular context. The observed spatial association between SWI/SNF protein loss and histologic dedifferentiation suggests that inactivation of these core SWI/SNF proteins may contribute to the development of dedifferentiated endometrial carcinoma. PMID- 26743476 TI - Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation. AB - Intestinal metaplasia in gastric mucosa is considered a preneoplastic lesion that progresses to gastric cancer. However, the molecular networks underlying this lesion formation are largely unknown. NKX6.3 is known to be an important regulator in gastric mucosal epithelial differentiation. In this study, we characterized the effects of NKX6.3 that may contribute to gastric intestinal metaplasia. NKX6.3 expression was significantly reduced in gastric mucosae with intestinal metaplasia. The mRNA expression levels of both NKX6.3 and CDX2 predicted the intestinal metaplasia risk, with an area under the receiver operating characteristic curve value of 0.9414 and 0.9971, respectively. Notably, the NKX6.3 expression level was positively and inversely correlated with SOX2 and CDX2, respectively. In stable AGS(NKX6.3) and MKN1(NKX6.3) cells, NKX6.3 regulated the expression of CDX2 and SOX2 by directly binding to the promoter regions of both genes. Nuclear NKX6.3 expression was detected only in gastric epithelial cells without intestinal metaplasia. Furthermore, NKX6.3-induced TWSG1 bound to BMP4 and inhibited BMP4-binding activity to BMPR-II. These data suggest that NKX6.3 might function as a master regulator of gastric differentiation by affecting SOX2 and CDX2 expression and the NKX6.3 inactivation may result in intestinal metaplasia in gastric epithelial cells. PMID- 26743478 TI - Genomic copy number analysis of a spectrum of blue nevi identifies recurrent aberrations of entire chromosomal arms in melanoma ex blue nevus. AB - Blue nevi may display significant atypia or undergo malignant transformation. Morphologic diagnosis of this spectrum of lesions is notoriously difficult, and molecular tools are increasingly used to improve diagnostic accuracy. We studied copy number aberrations in a cohort of cellular blue nevi, atypical cellular blue nevi, and melanomas ex blue nevi using Affymetrix's OncoScan platform. Cases with sufficient DNA were analyzed for GNAQ, GNA11, and HRAS mutations. Copy number aberrations were detected in 0 of 5 (0%) cellular blue nevi, 3 of 12 (25%) atypical cellular blue nevi, and 6 of 9 (67%) melanomas ex blue nevi. None of the atypical cellular blue nevi displayed more than one aberration, whereas complex aberrations involving four or more regions were seen exclusively in melanomas ex blue nevi. Gains and losses of entire chromosomal arms were identified in four of five melanomas ex blue nevi with copy number aberrations. In particular, gains of 1q, 4p, 6p, and 8q, and losses of 1p and 4q were each found in at least two melanomas. Whole chromosome aberrations were also common, and represented the sole finding in one atypical cellular blue nevus. When seen in melanomas, however, whole chromosome aberrations were invariably accompanied by partial aberrations of other chromosomes. Three melanomas ex blue nevi harbored aberrations, which were absent or negligible in their precursor components, suggesting progression in tumor biology. Gene mutations involving GNAQ and GNA11 were each detected in two of eight melanomas ex blue nevi. In conclusion, copy number aberrations are more common and often complex in melanomas ex blue nevi compared with cellular and atypical cellular blue nevi. Identification of recurrent gains and losses of entire chromosomal arms in melanomas ex blue nevi suggests that development of new probes targeting these regions may improve detection and risk stratification of these lesions. PMID- 26743477 TI - Neoplasms derived from plasmacytoid dendritic cells. AB - Plasmacytoid dendritic cell neoplasms manifest in two clinically and pathologically distinct forms. The first variant is represented by nodular aggregates of clonally expanded plasmacytoid dendritic cells found in lymph nodes, skin, and bone marrow ('Mature plasmacytoid dendritic cells proliferation associated with myeloid neoplasms'). This entity is rare, although likely underestimated in incidence, and affects predominantly males. Almost invariably, it is associated with a myeloid neoplasm such as chronic myelomonocytic leukemia or other myeloid proliferations with monocytic differentiation. The concurrent myeloid neoplasm dominates the clinical pictures and guides treatment. The prognosis is usually dismal, but reflects the evolution of the associated myeloid leukemia rather than progressive expansion of plasmacytoid dendritic cells. A second form of plasmacytoid dendritic cells tumor has been recently reported and described as 'blastic plasmacytoid dendritic cell neoplasm'. In this tumor, which is characterized by a distinctive cutaneous and bone marrow tropism, proliferating cells derive from immediate CD4(+)CD56(+) precursors of plasmacytoid dendritic cells. The diagnosis of this form can be easily accomplished by immunohistochemistry, using a panel of plasmacytoid dendritic cells markers. The clinical course of blastic plasmacytoid dendritic cell neoplasm is characterized by a rapid progression to systemic disease via hematogenous dissemination. The genomic landscape of this entity is currently under intense investigation. Recurrent somatic mutations have been uncovered in different genes, a finding that may open important perspectives for precision medicine also for this rare, but highly aggressive leukemia. PMID- 26743479 TI - Comparison of risk assessment strategies for not-high-risk pulmonary embolism. AB - We compared the prognostic performance of the 2014 European Society of Cardiology (ESC) risk stratification algorithm with the previous 2008 ESC algorithm, the Bova score and the modified FAST score (based on a positive heart-type fatty acid binding protein (H-FABP) test, syncope and tachycardia, modified using high sensitivity troponin T instead of H-FABP) in 388 normotensive pulmonary embolism patients included in a single-centre cohort study.Overall, 25 patients (6.4%) had an adverse 30-day outcome. Regardless of the score or algorithm used, the rate of an adverse outcome was highest in the intermediate-high-risk classes, while all patients classified as low-risk had a favourable outcome (no pulmonary embolism related deaths, 0-1.4% adverse outcome). The area under the curve for predicting an adverse outcome was higher for the 2014 ESC algorithm (0.76, 95% CI 0.68-0.84) compared with the 2008 ESC algorithm (0.65, 95% CI 0.56-0.73) and highest for the modified FAST score (0.82, 95% CI 0.75-0.89). Patients classified as intermediate high-risk by the 2014 ESC algorithm had a 8.9-fold increased risk for an adverse outcome (3.2-24.2, p<0.001 compared with intermediate-low- and low-risk patients), while the highest OR was observed for a modified FAST score >=3 points (OR 15.9, 95% CI 5.3-47.6, p<0.001).The 2014 ESC algorithm improves risk stratification of not-high-risk pulmonary embolism compared with the 2008 ESC algorithm. All scores and algorithms accurately identified low-risk patients, while the modified FAST score appears more suitable to identify intermediate-high risk patients. PMID- 26743480 TI - Influenza virus damages the alveolar barrier by disrupting epithelial cell tight junctions. AB - A major cause of respiratory failure during influenza A virus (IAV) infection is damage to the epithelial-endothelial barrier of the pulmonary alveolus. Damage to this barrier results in flooding of the alveolar lumen with proteinaceous oedema fluid, erythrocytes and inflammatory cells. To date, the exact roles of pulmonary epithelial and endothelial cells in this process remain unclear.Here, we used an in vitro co-culture model to understand how IAV damages the pulmonary epithelial endothelial barrier. Human epithelial cells were seeded on the upper half of a transwell membrane while human endothelial cells were seeded on the lower half. These cells were then grown in co-culture and IAV was added to the upper chamber.We showed that the addition of IAV (H1N1 and H5N1 subtypes) resulted in significant barrier damage. Interestingly, we found that, while endothelial cells mounted a pro-inflammatory/pro-coagulant response to a viral infection in the adjacent epithelial cells, damage to the alveolar epithelial-endothelial barrier occurred independently of endothelial cells. Rather, barrier damage was associated with disruption of tight junctions amongst epithelial cells, and specifically with loss of tight junction protein claudin-4.Taken together, these data suggest that maintaining epithelial cell integrity is key in reducing pulmonary oedema during IAV infection. PMID- 26743481 TI - Pulmonary hypertension associated with ponatinib therapy. PMID- 26743482 TI - Endoscopy evaluation to predict oral appliance outcomes in obstructive sleep apnoea. AB - The objective of this study was to determine the utility of nasoendoscopy of the upper airway as a predictor of the efficacy of oral appliance treatment in obstructive sleep apnoea (OSA).A total of 61 consecutive patients with moderate to-severe polysomnographically diagnosed OSA were recruited for this study. Using nasoendoscopy, we prospectively assessed the velopharynx and oro/hypopharynx in each patient while awake and in the supine position. We measured cross-sectional area (CSA), and anteroposterior and lateral diameters of the airway before and after mandibular advancement, and expressed the changes in dimensions as expansion ratios (after/before). We then compared the measurements of responders and nonresponders with oral appliance treatment.The expansion ratio (median (interquartile range)) for the CSA was greater in responders compared with nonresponders in the velopharynx (2.9 (2.3-5.0) versus 1.7 (1.5-1.9), p<0.001) and in the oro/hypopharynx (3.4 (2.5-5.6) versus 2.4 (1.8-3.7), p<0.05). Baseline apnoea-hypopnoea index and the CSA expansion ratio of the velopharynx were independent predictors of oral appliance treatment outcome based on a multivariate logistic regression analysis. The estimated area under the receiver operator characteristic curve was 0.87 and the cut-off value of the expansion ratio was 2.00.These results indicate that nasoendoscopy may have significant clinical utility in predicting the success of oral appliance treatment. PMID- 26743483 TI - Deficient interleukin-17 production in response to Mycobacterium abscessus in cystic fibrosis. PMID- 26743484 TI - Pharmacokinetics of ertapenem in patients with multidrug-resistant tuberculosis. AB - Treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) is becoming more challenging because of increased levels of drug resistance against second-line TB drugs. One promising group of antimicrobial drugs is carbapenems. Ertapenem is an attractive carbapenem for the treatment of MDR- and XDR-TB because its relatively long half-life enables once daily dosing.A retrospective study was performed for all patients with suspected MDR-TB at the Tuberculosis Center Beatrixoord of the University Medical Center Groningen (Haren, the Netherlands) who received ertapenem as part of their treatment regimen between December 1, 2010 and March 1, 2013. Safety and pharmacokinetics were evaluated.18 patients were treated with 1000 mg ertapenem for a mean (range) of 77 (5-210) days. Sputum smear and culture were converted in all patients. Drug exposure was evaluated in 12 patients. The mean (range) area under the concentration-time curve up to 24 h was 544.9 (309-1130) h.mg.L(-1) The mean (range) maximum observed plasma concentration was 127.5 (73.9-277.9) mg.L( 1)In general, ertapenem treatment was well tolerated during MDR-TB treatment and showed a favourable pharmacokinetic/pharmacodynamic profile in MDR-TB patients. We conclude that ertapenem is a highly promising drug for the treatment of MDR-TB that warrants further investigation. PMID- 26743485 TI - NLRP3 inflammasome expression in idiopathic pulmonary fibrosis and rheumatoid lung. AB - In this study we investigated the implication of NLRP3 inflammasomes in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis usual interstitial pneumonia (RA-UIP).NLRP3 inflammasome activation at baseline and following stimulation with lipopolysaccharide/ATP was evaluated by measuring interleukin (IL)-1beta and IL-18 levels released in the bronchoalveolar lavage fluid (BALF) fluid and by cultures of BALF cells. IL-1beta and IL-18 levels were significantly elevated in the BALF and BALF macrophage cultures from RA-UIP patients, consistent with pre-existing inflammasome activation in these patients. In contrast, in IPF, BALF levels of IL-1beta were significantly less elevated relative to RA-UIP and IL-18 was lower than controls. Furthermore, upon inflammasome stimulation, IPF BALF macrophage cultures failed to upregulate IL 1beta and partly IL-18 secretion, in contrast to controls, which showed robust IL 1beta and IL-18 upregulation. Interestingly, RA-UIP BALF cell cultures treated with lipopolysaccharide/ATP showed a potent stimulation of IL-18 secretion but not IL-1beta, the latter being already elevated in the unstimulated cultures, while examination of the intracellular IL-1beta levels in RA-UIP BALF cells upon NLRP3 inflammasome stimulation showed a significant upregulation of IL-1beta suggesting the NLRP3 pathway could be further activated.Taken together, our results suggest distinct inflammasome activation profiles between autoimmune and idiopathic lung fibrosis. PMID- 26743486 TI - Proposed new definition of exercise pulmonary hypertension decreases false positive cases. PMID- 26743487 TI - Obstructive sleep apnoea as a risk factor for osteopenia and osteoporosis in the male population. PMID- 26743488 TI - Empiric antimicrobial therapy for ventilator-associated pneumonia after brain injury. AB - Issues regarding recommendations on empiric antimicrobial therapy for ventilator associated pneumonia (VAP) have emerged in specific populations.To develop and validate a score to guide empiric therapy in brain-injured patients with VAP, we prospectively followed a cohort of 379 brain-injured patients in five intensive care units. The score was externally validated in an independent cohort of 252 brain-injured patients and its extrapolation was tested in 221 burn patients.The multivariate analysis for predicting resistance (incidence 16.4%) showed two independent factors: preceding antimicrobial therapy >=48 h (p<0.001) and VAP onset >=10 days (p<0.001); the area under the receiver operating characteristic curve (AUC) was 0.822 (95% CI 0.770-0.883) in the learning cohort and 0.805 (95% CI 0.732-0.877) in the validation cohort. The score built from the factors selected in multivariate analysis predicted resistance with a sensitivity of 83%, a specificity of 71%, a positive predictive value of 37% and a negative predictive value of 96% in the validation cohort. The AUC of the multivariate analysis was poor in burn patients (0.671, 95% CI 0.596-0.751).Limited-spectrum empirical antimicrobial therapy has low risk of failure in brain-injured patients presenting with VAP before day 10 and when prior antimicrobial therapy lasts <48 h. PMID- 26743490 TI - Carbon: nitrogen stoichiometry following afforestation: a global synthesis. AB - Though carbon (C): nitrogen (N) stoichiometry has been widely studied in terrestrial ecosystems, little is known about its variation following afforestation. By synthesizing the results of 53 studies, we examined temporal and spatial variation in C: N ratios and in N-C scaling relationships of both the organic and the mineral soil horizons. Results showed that C: N ratios remained constant in the mineral horizon but significantly decreased in the organic horizon over the age sequence following afforestation. Among different climate zones, C: N ratios of the organic and the mineral horizons increased and decreased, respectively, with increasing mean annual temperature (MAT) (decreasing latitude). Pasture exhibited higher C: N ratios than cropland in the organic horizon while C: N of the mineral horizon did not change much among different land use types. For both the organic and the mineral horizons, hardwoods exhibited lower C: N ratios than pine and softwoods. Additionally, N and C in general scaled isometrically in both the organic and the mineral horizons over the age sequence and among different climate zones, land use types, and plantation species following afforestation. Our results suggest that C and N may remain coupled following afforestation. PMID- 26743489 TI - The ATM- and ATR-related SCD domain is over-represented in proteins involved in nervous system development. AB - ATM and ATR are cellular kinases with a well-characterized role in the DNA-damage response. Although the complete set of ATM/ATR targets is unknown, they often contain clusters of S/TQ motifs that constitute an SCD domain. In this study, we identified putative ATM/ATR targets that have a conserved SCD domain across vertebrates. Using this approach, we have identified novel putative ATM/ATR targets in pathways known to be under direct control of these kinases. Our analysis has also unveiled significant enrichment of SCD-containing proteins in cellular pathways, such as vesicle trafficking and actin cytoskeleton, where a regulating role for ATM/ATR is either unknown or poorly understood, hinting at a much broader and overarching role for these kinases in the cell. Of particular note is the overrepresentation of conserved SCD-containing proteins involved in pathways related to neural development. This finding suggests that ATM/ATR could be directly involved in controlling this process, which may be linked to the adverse neurological effects observed in patients with mutations in ATM. PMID- 26743491 TI - Osteoprotegerin disrupts peripheral adhesive structures of osteoclasts by modulating Pyk2 and Src activities. AB - Osteoprotegerin has previously been shown to modulate bone mass by blocking osteoclast maturation and function. The detailed mechanisms of osteoprotegerin induced disassembly of podosomes, disruption of adhesive structures and modulation of adhesion-related proteins in osteoclasts, however, are not well characterized. In this study, tartrate-resistant acidic phosphatase staining demonstrated that osteoprotegerin inhibited differentiation of osteoclasts. The use of scanning electron microscopy, real-time cell monitoring and confocal microscopy indicated that osteoclasts responded in a time and dose-dependent manner to osteoprotegerin treatments with retraction of peripheral adhesive structures and detachment from the extracellular substrate. Combined imaging and Western blot studies showed that osteoprotegerin induced dephosphorylation of Tyr 402 in Pyk2 and decreased its labeling in peripheral adhesion regions. osteoprotegerin induced increased intracellular labeling of Tyr 402 in Pyk2, Tyr 416 in Src, increased dephosphorylation of Tyr 527 in Src, and increased Pyk2/Src association in the central region of osteoclasts. This evidence suggests that Src may function as an adaptor protein that competes for Pyk2 and relocates it from the peripheral adhesive zone to the central region of osteoclasts in response to osteoprotegerin treatment. Osteoprotegerin may induce podosome reassembly and peripheral adhesive structure detachment by modulating phosphorylation of Pyk2 and Src and their intracellular distribution in osteoclasts. PMID- 26743493 TI - Maternal N-acetylcysteine therapy regulates hydrogen sulfide-generating pathway and prevents programmed hypertension in male offspring exposed to prenatal dexamethasone and postnatal high-fat diet. AB - Nitric oxide (NO) and hydrogen sulfide (H2S) pathways are involved in the development of hypertension, a condition that can originate from early life. We examined whether asymmetric dimethylarginine (ADMA, a nitric oxide synthase inhibitor)/NO and H2S generating pathway contributed to programmed hypertension in offspring exposed to prenatal dexamethasone (DEX) and postnatal high-fat (HF) and whether N-acetylcysteine (NAC) therapy prevented this process. We examined 16 week-old male rat offspring from five groups: control, DEX (0.1 mg/kg i.p. from gestational day 16-22), HF (58% high-fat diet from weaning to 4 months of age), DEX+HF, and NAC (1% in drinking water during lactation). Prenatal DEX and postnatal HF diet synergistically induced programmed hypertension in adult offspring, which was prevented by maternal NAC therapy. We attributed the protective effects of NAC on two-hit induced programmed hypertension to the reduction of plasma ADMA, restoration of plasma l-arginine-to-ADMA ratio, upregulation of gene expression of H2S-generating enzymes, restoration of renal 3 mercaptopyruvate sulphurtransferase (3MST) protein levels and activity, induction of plasma glutathione level, and reduction of oxidative stress. Manipulation of the ADMA-NO and H2S-generating pathways by maternal NAC therapy may be a potential approach to prevent programmed hypertension induced by two-hit insults. PMID- 26743492 TI - Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake. AB - Agouti-related peptide (AgRP) neurons of the hypothalamus play a key role in regulating food intake and body weight, by releasing three different orexigenic molecules: AgRP; GABA; and neuropeptide Y. AgRP neurons express various G protein coupled receptors (GPCRs) with different coupling properties, including Gs-linked GPCRs. At present, the potential role of Gs-coupled GPCRs in regulating the activity of AgRP neurons remains unknown. Here we show that the activation of Gs coupled receptors expressed by AgRP neurons leads to a robust and sustained increase in food intake. We also provide detailed mechanistic data linking the stimulation of this class of receptors to the observed feeding phenotype. Moreover, we show that this pathway is clearly distinct from other GPCR signalling cascades that are operative in AgRP neurons. Our data suggest that drugs able to inhibit this signalling pathway may become useful for the treatment of obesity. PMID- 26743494 TI - Disseminated Congenital Cytomegalovirus Infection Presenting as Severe Sepsis in a Preterm Neonate. PMID- 26743495 TI - A Validated Method for Identifying Unplanned Pediatric Readmission. AB - OBJECTIVE: To validate the accuracy of pre-encounter hospital designation as a novel way to identify unplanned pediatric readmissions and describe the most common diagnoses for unplanned readmissions among children. STUDY DESIGN: We examined all hospital discharges from 2 tertiary care children's hospitals excluding deaths, normal newborn discharges, transfers to other institutions, and discharges to hospice. We performed blinded medical record review on 641 randomly selected readmissions to validate the pre-encounter planned/unplanned hospital designation. We identified the most common discharge diagnoses associated with subsequent 30-day unplanned readmissions. RESULTS: Among 166,994 discharges (hospital A: n = 55,383; hospital B: n = 111,611), the 30-day unplanned readmission rate was 10.3% (hospital A) and 8.7% (hospital B). The hospital designation of "unplanned" was correct in 98% (hospital A) and 96% (hospital B) of readmissions; the designation of "planned" was correct in 86% (hospital A) and 85% (hospital B) of readmissions. The most common discharge diagnoses for which unplanned 30-day readmissions occurred were oncologic conditions (up to 38%) and nonhypertensive congestive heart failure (about 25%), across both institutions. CONCLUSIONS: Unplanned readmission rates for pediatrics, using a validated, accurate, pre-encounter designation of "unplanned," are higher than previously estimated. For some pediatric conditions, unplanned readmission rates are as high as readmission rates reported for adult conditions. Anticipating unplanned readmissions for high-frequency diagnostic groups may help focus efforts to reduce the burden of readmission for families and facilities. Using timing of hospital registration in administrative records is an accurate, widely available, real-time way to distinguish unplanned vs planned pediatric readmissions. PMID- 26743496 TI - Technology at the Service of Pediatric Mental Health: Review and Assessment. PMID- 26743497 TI - CD4+ and CD8+ T Cell Activation in Children with Hepatitis C. AB - OBJECTIVES: To assess if peripheral T cell populations in children with chronic hepatitis C virus (HCV) infection would show evidence of activation/exhaustion and an attenuated functional response. STUDY DESIGN: Compared with adults, children with HCV infection have a higher rate of spontaneous viral clearance. In adults, chronic HCV has been linked to T cell exhaustion. Little is known of the immune status of children with HCV. Peripheral blood mononuclear cells were isolated from 16 children with HCV (6 males, 10 females; mean age 8.6 years, range 2-17), 16 age- and sex-matched control children without HCV infection, and 20 adults with chronic HCV. Multiparameter flow cytometry was performed to characterize T cell differences across the 3 groups. RESULTS: Controls and children with HCV had similar levels of CD4(+), CD8(+), and gammadelta(+) T cells. Children with HCV demonstrated a decrease in naive T cells compared with control children and increased activation/exhaustion marker expression on both CD8(+) and CD4(+) T cells. Transcription factor analysis suggested functional activation of T cells in children with HCV; however, only the CD4(+) subset had enhanced cytokine production (interferon gamma and interleukin-2) compared with control children. CONCLUSIONS: The HCV response in children is characterized by several changes in T cell phenotype. Many of these changes, such as increased T cell expression of programmed cell death-1, are similar to responses in adults. Of note, cytokine production by CD4(+) helper T cells is increased in children with HCV compared with age- and sex-matched control children, which may influence long-term prognosis in children with HCV. PMID- 26743498 TI - Cerebral Oxygen Saturation to Guide Oxygen Delivery in Preterm Neonates for the Immediate Transition after Birth: A 2-Center Randomized Controlled Pilot Feasibility Trial. AB - OBJECTIVE: To assess if monitoring of cerebral regional tissue oxygen saturation (crSO2) using near-infrared spectroscopy (NIRS) to guide respiratory and supplemental oxygen support reduces burden of cerebral hypoxia and hyperoxia in preterm neonates during resuscitation after birth. STUDY DESIGN: Preterm neonates <34(+0) weeks of gestation were included in a prospective randomized controlled pilot feasibility study at 2 tertiary level neonatal intensive care units. In a NIRS-visible group, crSO2 monitoring in addition to pulse oximetry was used to guide respiratory and supplemental oxygen support during the first 15 minutes after birth. In a NIRS-not-visible group, only pulse oximetry was used. The primary outcomes were burden of cerebral hypoxia (<10th percentile) or hyperoxia (>90th percentile) measured in %minutes crSO2 during the first 15 minutes after birth. Secondary outcomes were all cause of mortality and/or cerebral injury and neurologic outcome at term age. Allocation sequence was 1:1 with block randomization of 30 preterm neonates at each site. RESULTS: In the NIRS-visible group burden of cerebral hypoxia in %minutes, crSO2 was halved, and the relative reduction was 55.4% (95% CI 37.6-73.2%; P = .028). Cerebral hyperoxia was observed in NIRS-visible group in 3 neonates with supplemental oxygen and in NIRS not-visible group in 2. Cerebral injury rate and neurologic outcome at term age was similar in both groups. Two neonates died in the NIRS-not-visible group and none in the NIRS-visible group. No severe adverse reactions were observed. CONCLUSIONS: Reduction of burden of cerebral hypoxia during immediate transition and resuscitation after birth is feasible by crSO2 monitoring to guide respiratory and supplemental oxygen support. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02017691. PMID- 26743499 TI - A Subcortical Pathway for Rapid, Goal-Driven, Attentional Filtering. AB - Prefrontal cortex can exercise goal-driven attentional control over sensory information via cortical pathways. However, recent work demonstrates that prefrontal cortex can also influence thalamic relay nuclei via the thalamic reticular nucleus. This suggests the prefrontal-thalamic pathway mediates rapid and goal-driven attentional filtering at the earliest stages of sensory processing. PMID- 26743500 TI - Budded baculovirus particle structure revisited. AB - Baculoviruses are a group of enveloped, double-stranded DNA insect viruses with budded (BV) and occlusion-derived (ODV) virions produced during their infection cycle. BVs are commonly described as rod shaped particles with a high apical density of protein extensions (spikes) on the lipid envelope surface. However, due to the fragility of BVs the conventional purification and electron microscopy (EM) staining methods considerably distort the native viral structure. Here, we use cryo-EM analysis to reveal the near-native morphology of two intensively studied baculoviruses, Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) and Spodoptera exigua MNPV (SeMNPV), as models for BVs carrying GP64 and F as envelope fusion protein on the surface. The now well-preserved AcMNPV and SeMNPV BV particles have a remarkable elongated, ovoid shape leaving a large, lateral space between nucleocapsid (NC) and envelope. Consistent with previous findings the NC has a distinctive cap and base structure interacting tightly with the envelope. This tight interaction may explain the partial retaining of the envelope on both ends of the NC and the disappearance of the remainder of the BV envelope in the negative-staining EM images. Cryo-EM also reveals that the viral envelope contains two layers with a total thickness of ~ 6-7 nm, which is significantly thicker than a usual biological membrane (<4 nm) as measured by X ray scanning. Most spikes are densely clustered at the two apical ends of the virion although some envelope proteins are also found more sparsely on the lateral regions. The spikes on the surface of AcMNPV BVs appear distinctly different from those of SeMNPV. Based on our observations we propose a new near native structural model of baculovirus BVs. PMID- 26743501 TI - Ethiopian pre-school children consuming a predominantly unrefined plant-based diet have low prevalence of iron-deficiency anaemia. AB - OBJECTIVE: Children from low-income countries consuming predominantly plant-based diets but little animal products are considered to be at risk of Fe deficiency. The present study determined the Fe status of children from resource-limited rural households. DESIGN: A cross-sectional study. SETTING: Twenty six kebeles (the smallest administrative unit) from six zones of the Amhara region, Ethiopia. SUBJECTS: Children aged 54-60 months (n 628). RESULTS: Grain, roots or tubers were the main dietary components consumed by 100 % of the study participants, followed by pulses, legumes or nuts (66.6 %). Consumption of fruit and vegetables (19.3 %) and meat, poultry and fish (2.2 %) was low. Children had a mean dietary diversity score of 2.1 (sd 0.8). Most children (74.8 %, n 470) were in the lowest dietary diversity group (1-2 food groups). Rate of any morbidity in the preceding 14 d was 22.9 % (n 114). Infection or inflammation (alpha1-acid glycoprotein >1.2 g/l) was present in 30.2 % (n 184) of children. Children had a high rate of stunting (43.2 %). Of the total sample, 13.6 % (n 82) of children were anaemic, 9.1 % (n 57) were Fe deficient and 5.3 % (n 32) had Fe-deficiency anaemia. Fe deficiency erythropoiesis was present in 14.2 % (n 60) of children. CONCLUSIONS: Despite consuming a predominantly plant-based diet and little animal-source foods, there was a low prevalence of Fe-deficiency anaemia. This illustrates that dietary patterns can be inharmonious with Fe biochemical status; thus, Fe-related interventions require biochemical screening. PMID- 26743503 TI - Bovine ischaemic teat necrosis: a further potential role for digital dermatitis treponemes. AB - A recent outbreak of ischaemic teat necrosis (ITN) on mainland UK has resulted in large economic losses for dairy farmers. Typical cases start as an area of dry, thickened and encrusted skin on the medial aspect of the base of the teat, where the teat joins the udder, often with a fetid odour. The erosion spreads down the teat, often causing intense irritation, which in turn leads to more severely affected animals removing the entire teat. Due to the severity of ITN and the substantial economic costs to the industry, analyses were undertaken to ascertain if an infectious agent might be involved in the pathology. The study has considered a role for digital dermatitis (DD) treponemes in the aetiopathogenesis of ITN because, as well as being the prime bacteria associated with infectious lameness, they have been associated with a number of emerging skin diseases of cattle, including udder lesions. A high association between presence of DD associated treponemes and incidence of ITN (19/22), compared with absence in the control population is reported. Furthermore, sequencing of the 16S rRNA gene of treponeme isolates supports the hypothesis that the identified treponemes are similar or identical to those isolated from classical foot DD lesions in cattle (and sheep). Further studies are required to allow effective targeted prevention measures and/or treatments to be developed. PMID- 26743502 TI - Pay-for-Performance: Disappointing Results or Masked Heterogeneity? AB - Research on the effects of pay-for-performance (P4P) in health care indicates largely disappointing results. This central finding, however, may mask important heterogeneity in the effects of P4P. We conducted a literature review to assess whether hospital and physician performance in P4P vary by patient and catchment area factors, organizational and structural capabilities, and P4P program characteristics. Several findings emerged: organizational size, practice type, teaching status, and physician age and gender modify performance in P4P. For physician practices and hospitals, a higher proportion of poor and minority patients is consistently associated with worse performance. Other theoretically influential characteristics-including information technology and staffing levels yield mixed results. Inconsistent and contradictory effects of bonus likelihood, bonus size, and marginal costs on performance in P4P suggest organizations have not responded strategically to financial incentives. We conclude that extant heterogeneity in the effects of P4P does not fundamentally alter current assessments about its effectiveness. PMID- 26743504 TI - Endothelium-derived intermedin/adrenomedullin-2 protects human ventricular cardiomyocytes from ischaemia-reoxygenation injury predominantly via the AM1 receptor. AB - Application of intermedin/adrenomedullin-2 (IMD/AM-2) protects cultured human cardiac vascular cells and fibroblasts from oxidative stress and simulated ischaemia-reoxygenation injury (I-R), predominantly via adrenomedullin AM1 receptor involvement; similar protection had not been investigated previously in human cardiomyocytes (HCM). Expression of IMD, AM and their receptor components was studied in HCM. Receptor subtype involvement in protection by exogenous IMD against injury by simulated I-R was investigated using receptor component specific siRNAs. Direct protection by endogenous IMD against HCM injury, both as an autocrine factor produced in HCM themselves and as a paracrine factor released from HCMEC co-cultured with HCM, was investigated using peptide-specific siRNA for IMD. IMD, AM and their receptor components (CLR, RAMPs1-3) were expressed in HCM. IMD 1nmol L(-1), applied either throughout ischaemia (3h) and re-oxygenation (1h) or during re-oxygenation (1h) alone, attenuated HCM injury (P<0.05); cell viabilities were 59% and 61% respectively vs. 39% in absence of IMD. Cytoskeletal disruption, protein carbonyl formation and caspase activity followed similar patterns. Pre-treatment (4 days) of HCM with CLR and RAMP2 siRNAs attenuated (P<0.05) protection by exogenous IMD. Pre-treatment of HCMEC with IMD (and AM) siRNA augmented (P<0.05) I-R injury: cell viabilities were 22% (and 32%) vs. 39% untreated HCMEC. Pre-treatment of HCM with IMD (and AM) siRNA did not augment HCM injury: cell viabilities were 37% (and 39%) vs. 39% untreated HCM. Co-culture with HCMEC conferred protection from injury on HCM; such protection was attenuated when HCMEC were pre-treated with IMD (but not AM) siRNA before co culture. Although IMD is present in HCM, IMD derived from HCMEC and acting in a paracrine manner, predominantly via AM1 receptors, makes a marked contribution to cardiomyocyte protection by the endogenous peptide against acute I-R injury. PMID- 26743506 TI - Prior uterine evacuation of pregnancy as independent risk factor for preterm birth: a systematic review and metaanalysis. AB - BACKGROUND: Preterm birth (PTB) is the number one cause of perinatal mortality. Prior surgery on the cervix is associated with an increased risk of PTB. History of uterine evacuation, by either induced termination of pregnancy (I-TOP) or spontaneous abortion (SAB), which involve mechanical and/or osmotic dilatation of the cervix, has been associated with an increased risk of PTB in some studies but not in others. OBJECTIVE: The objective of the study was to evaluate the risk of PTB among women with a history of uterine evacuation for I-TOP or SAB. DATA SOURCES: Electronic databases (MEDLINE, Scopus, ClinicalTrials.gov, EMBASE, and Sciencedirect) were searched from their inception until January 2015 with no limit for language. STUDY ELIGIBILITY CRITERIA: We included all studies of women with prior uterine evacuation for either I-TOP or SAB, compared with a control group without a history of uterine evacuation, which reported data about the subsequent pregnancy. STUDY APPRAISAL AND SYNTHESIS METHODS: The primary outcome was the incidence of PTB < 37 weeks. Secondary outcomes were incidence of low birthweight (LBW) and small for gestational age (SGA). We planned to assess the primary and the secondary outcomes in the overall population as well as in studies on I-TOP and SAB separately. The pooled results were reported as odds ratio (OR) with 95% confidence interval (CI). RESULTS: We included 36 studies in this metaanalysis (1,047,683 women). Thirty-one studies reported data about prior uterine evacuation for I-TOP, whereas 5 studies reported data for SAB. In the overall population, women with a history of uterine evacuation for either I-TOP or SAB had a significantly higher risk of PTB (5.7% vs 5.0%; OR, 1.44, 95% CI, 1.09-1.90), LBW (7.3% vs 5.9%; OR, 1.41, 95% CI, 1.22-1.62), and SGA (10.2% vs 9.0%; OR, 1.19, 95% CI, 1.01-1.42) compared with controls. Of the 31 studies on I TOP, 28 included 913,297 women with a history of surgical I-TOP, whereas 3 included 10,253 women with a prior medical I-TOP. Women with a prior surgical I TOP had a significantly higher risk of PTB (5.4% vs 4.4%; OR, 1.52, 95% CI, 1.08 2.16), LBW (7.3% vs 5.9%; OR, 1.41, 95% CI, 1.22-1.62), and SGA (10.2% vs 9.0%; OR, 1.19, 95% CI, 1.01-1.42) compared with controls. Women with a prior medical I TOP had a similar risk of PTB compared with those who did not have a history of I TOP (28.2% vs 29.5%; OR, 1.50, 95% CI, 1.00-2.25). Five studies, including 124,133 women, reported data about a subsequent pregnancy in women with a prior SAB. In all of the included studies, the SAB was surgically managed. Women with a prior surgical SAB had a higher risk of PTB compared with those who did not have a history of SAB (9.4% vs 8.6%; OR, 1.19, 95% CI, 1.03-1.37). CONCLUSION: Prior surgical uterine evacuation for either I-TOP or SAB is an independent risk factor for PTB. These data warrant caution in the use of surgical uterine evacuation and should encourage safer surgical techniques as well as medical methods. PMID- 26743505 TI - A prospective investigation of fluorescence imaging to detect sentinel lymph nodes at robotic-assisted endometrial cancer staging. AB - BACKGROUND: The accuracy of sentinel lymph node mapping has been shown in endometrial cancer, but studies to date have primarily focused on cohorts at low risk for nodal involvement. In our practice, we acknowledge the lack of benefit of lymphadenectomy in the low-risk subgroup and omit lymph node removal in these patients. Thus, our aim was to evaluate the feasibility and accuracy of sentinel node mapping in women at sufficient risk for nodal metastasis warranting lymphadenectomy and in whom the potential benefit of avoiding nodal procurement could be realized. OBJECTIVE: To evaluate the detection rate and accuracy of fluorescence-guided sentinel lymph node mapping in endometrial cancer patients undergoing robotic-assisted staging. STUDY DESIGN: One hundred twenty-three endometrial cancer patients undergoing sentinel lymph node sentinel node mapping using indocyanine green were prospectively evaluated. Two mL (1.0 mg/mL) of dye were injected into the cervical stroma divided between the 2-3 and 9-10 o'clock positions at the time of uterine manipulator placement. Before hysterectomy, the retroperitoneal spaces were developed and fluorescence imaging was used for sentinel node detection. Identified sentinel nodes were removed and submitted for touch prep intraoperatively, followed by permanent assessment with routine hematoxylin and eosin levels. Patients then underwent hysterectomy, bilateral salpingo-oophorectomy, and completion bilateral pelvic and periaortic lymphadenectomy based on intrauterine risk factors determined intraoperatively (tumor size >2 cm, >50% myometrial invasion, and grade 3 histology). RESULTS: Of 123 patients enrolled, at least 1 sentinel node was detected in 119 (96.7%). Ninety-nine patients (80%) had bilateral pelvic or periaortic sentinel nodes detected. A total of 85 patients met criteria warranting completion lymphadenectomy. In 14 patients (16%) periaortic lymphadenectomy was not feasible, and the mean number of pelvic nodes procured was 13 (6-22). Of the 71 patients undergoing pelvic and periaortic lymphadenectomy, the mean nodal count was 23.2 (8-51). Of patients undergoing lymphadenectomy, 10.6% had lymph node metastasis on final hematoxylin and eosin evaluation. Notably, the sentinel node was the only positive node in 44% of cases. There were no cases in which final pathology of the sentinel node was negative and metastatic disease was detected upon completion lymphadenectomy in the non-sentinel nodes (no false negatives), yielding a sensitivity of 100%. Of the 14 sentinel nodes ultimately found to harbor metastases, 3 were negative on touch prep, yielding a sensitivity of 78.6% for intraoperative detection of sentinel node involvement. In all 3 of the false negative touch preps, final pathology detected a single micrometastasis (0.24 mm, 1.4 mm, 1.5 mm). As expected, there were no false-positive results, yielding a specificity of 100%. No complications related to sentinel node mapping or allergic reactions to the dye were encountered. CONCLUSION: Intraoperative sentinel node mapping using fluorescence imaging with indocyanine green in endometrial cancer patients is feasible and yields high detection rates. In our pilot study, sentinel node mapping identified all women with Stage IIIC disease. Low false-negative rates are encouraging, and if confirmed in multi-institutional trials, this approach would be anticipated to reduce the morbidity, operative times, and costs associated with complete pelvic and periaortic lymphadenectomy. PMID- 26743507 TI - OEFinder: a user interface to identify and visualize ordering effects in single cell RNA-seq data. AB - A recent article identified an artifact in multiple single-cell RNA-seq (scRNA seq) datasets generated by the Fluidigm C1 platform. Specifically, Leng et al. showed significantly increased gene expression in cells captured from sites with small or large plate output IDs. We refer to this artifact as an ordering effect (OE). Including OE genes in downstream analyses could lead to biased results. To address this problem, we developed a statistical method and software called OEFinder to identify a sorted list of OE genes. OEFinder is available as an R package along with user-friendly graphical interface implementations which allows users to check for potential artifacts in scRNA-seq data generated by the Fluidigm C1 platform. AVAILABILITY AND IMPLEMENTATION: OEFinder is freely available at https://github.com/lengning/OEFinder CONTACT: rstewart@morgridge.org or lengning1@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26743508 TI - MAESTROweb: a web server for structure-based protein stability prediction. AB - The prediction of change in stability upon point mutations in proteins has many applications in protein analysis and engineering. We recently adjoined a new structure-based method called MAESTRO, which is distributed as command line program. We now provide access to the most important features of MAESTRO by an easy to use web service. MAESTROweb allows the prediction of change in stability for user-defined mutations, provides a scan functionality for the most (de)stabilizing n-point mutations for a maximum of n = 5, creates mutation sensitivity profiles and evaluates potential disulfide bonds. MAESTROweb operates on monomers, multimers and biological assemblies as defined by PDB. AVAILABILITY AND IMPLEMENTATION: MAESTROweb is freely available for non-commercial use at https://biwww.che.sbg.ac.at/maestro/web CONTACT: peter.lackner@sbg.ac.at. PMID- 26743509 TI - MMseqs software suite for fast and deep clustering and searching of large protein sequence sets. AB - MOTIVATION: Sequence databases are growing fast, challenging existing analysis pipelines. Reducing the redundancy of sequence databases by similarity clustering improves speed and sensitivity of iterative searches. But existing tools cannot efficiently cluster databases of the size of UniProt to 50% maximum pairwise sequence identity or below. Furthermore, in metagenomics experiments typically large fractions of reads cannot be matched to any known sequence anymore because searching with sensitive but relatively slow tools (e.g. BLAST or HMMER3) through comprehensive databases such as UniProt is becoming too costly. RESULTS: MMseqs (Many-against-Many sequence searching) is a software suite for fast and deep clustering and searching of large datasets, such as UniProt, or 6-frame translated metagenomics sequencing reads. MMseqs contains three core modules: a fast and sensitive prefiltering module that sums up the scores of similar k-mers between query and target sequences, an SSE2- and multi-core-parallelized local alignment module, and a clustering module.In our homology detection benchmarks, MMseqs is much more sensitive and 4-30 times faster than UBLAST and RAPsearch, respectively, although it does not reach BLAST sensitivity yet. Using its cascaded clustering workflow, MMseqs can cluster large databases down to ~30% sequence identity at hundreds of times the speed of BLASTclust and much deeper than CD-HIT and USEARCH. MMseqs can also update a database clustering in linear instead of quadratic time. Its much improved sensitivity-speed trade-off should make MMseqs attractive for a wide range of large-scale sequence analysis tasks. AVAILABILITY AND IMPLEMENTATION: MMseqs is open-source software available under GPL at https://github.com/soedinglab/MMseqs CONTACT: martin.steinegger@mpibpc.mpg.de, soeding@mpibpc.mpg.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26743510 TI - Improving microRNA target prediction by modeling with unambiguously identified microRNA-target pairs from CLIP-ligation studies. AB - MOTIVATION: MicroRNAs (miRNAs) are small non-coding RNAs that are extensively involved in many physiological and disease processes. One major challenge in miRNA studies is the identification of genes targeted by miRNAs. Currently, most researchers rely on computational programs to initially identify target candidates for subsequent validation. Although considerable progress has been made in recent years for computational target prediction, there is still significant room for algorithmic improvement. RESULTS: Here, we present an improved target prediction algorithm, which was developed by modeling high throughput profiling data from recent CLIPL (crosslinking and immunoprecipitation followed by RNA ligation) sequencing studies. In these CLIPL-seq studies, the RNA sequences in each miRNA-target pair were covalently linked and unambiguously determined experimentally. By analyzing the CLIPL data, many known and novel features relevant to target recognition were identified and then used to build a computational model for target prediction. Comparative analysis showed that the new algorithm had improved performance over existing algorithms when applied to independent experimental data. AVAILABILITY AND IMPLEMENTATION: All the target prediction data as well as the prediction tool can be accessed at miRDB (http://mirdb.org). CONTACT: xwang@radonc.wustl.edu. PMID- 26743511 TI - Homology-driven assembly of NOn-redundant protEin sequence sets (NOmESS) for mass spectrometry. AB - To enable mass spectrometry (MS)-based proteomic studies with poorly characterized organisms, we developed a computational workflow for the homology driven assembly of a non-redundant reference sequence dataset. In the automated pipeline, translated DNA sequences (e.g. ESTs, RNA deep-sequencing data) are aligned to those of a closely related and fully sequenced organism. Representative sequences are derived from each cluster and joined, resulting in a non-redundant reference set representing the maximal available amino acid sequence information for each protein. We here applied NOmESS to assemble a reference database for the widely used model organism Xenopus laevis and demonstrate its use in proteomic applications. AVAILABILITY AND IMPLEMENTATION: NOmESS is written in C#. The source code as well as the executables can be downloaded from http://www.biochem.mpg.de/cox Execution of NOmESS requires BLASTp and cd-hit in addition. CONTACT: cox@biochem.mpg.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26743512 TI - Estimating the number and assignment of clock models in analyses of multigene datasets. AB - MOTIVATION: Molecular-clock methods can be used to estimate evolutionary rates and timescales from DNA sequence data. However, different genes can display different patterns of rate variation across lineages, calling for the employment of multiple clock models. Selecting the optimal clock-partitioning scheme for a multigene dataset can be computationally demanding, but clustering methods provide a feasible alternative. We investigated the performance of different clustering methods using data from chloroplast genomes and data generated by simulation. RESULTS: Our results show that mixture models provide a useful alternative to traditional partitioning algorithms. We found only a small number of distinct patterns of among-lineage rate variation among chloroplast genes, which were consistent across taxonomic scales. This suggests that the evolution of chloroplast genes has been governed by a small number of genomic pacemakers. Our study also demonstrates that clustering methods provide an efficient means of identifying clock-partitioning schemes for genome-scale datasets. AVAILABILITY AND IMPLEMENTATION: The code and data sets used in this study are available online at https://github.com/sebastianduchene/pacemaker_clustering_methods CONTACT: sebastian.duchene@sydney.edu.au SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26743513 TI - Molecular Targeted Therapy Approaches for BRAF Wild-Type Melanoma. AB - Patients with metastatic melanoma have historically had dismal outcomes. The last several years has seen the emergence of effective immune and targeted therapies for metastatic melanoma. Targeted therapies have primarily impacted the 40-50% of patients with BRAF(V600) mutated melanoma. The remainder of patients with advanced melanoma harbor a wide spectrum of mutations other than BRAF(V600) that are associated with unique pathophysiological, prognostic, and therapeutic implications. The treatment of this subset of patients is a challenging problem. In recent years, preclinical and early clinical studies have suggested that inhibitors of mitogen activated protein kinase (MAPK) pathway and parallel signaling networks may have activity in treatment of BRAF(V600) wild-type (WT) melanoma. In this review, we will discuss available and developing therapies for BRAF WT patients with metastatic melanoma, particularly focusing on molecular targeted options for various genetically defined melanoma subsets. PMID- 26743514 TI - Octreotide and Lanreotide in Gastroenteropancreatic Neuroendocrine Tumors. AB - Neuroendocrine tumors are heterogeneous, rare malignancies that arise most commonly in the gastrointestinal tract and pancreas. They often secrete vasoactive substances resulting in carcinoid syndrome and the tumor cells exclusively express somatostatin receptors. Octreotide and lanreotide are the two synthetic somatostatin analogs used for the control of carcinoid symptoms and tumor progression in advanced inoperable disease. Recent pivotal trials (PROMID and CLARINET studies) established their antitumor activity. We discuss the available data to support their use as symptom controlling and antiproliferative agents. This article also reviews the guidelines (National Comprehensive Cancer Network and North American Neuro Endocrine Tumor Society), cost-analysis (suggesting the cost-effectiveness of lanreotide autogel compared to higher doses of octreotide long acting release formulation in refractory patients), and future directions of somatostatin analogs in the management of patients refractory to conventional doses of octreotide and lanreotide. PMID- 26743515 TI - Autosomal Dominant Hyper IgE Syndrome--Treatment Strategies and Clinical Outcomes. PMID- 26743518 TI - Role of microRNA in regulating cell signaling pathways, cell cycle, and apoptosis in non-small cell lung cancer. AB - Dysregulation in expression of miRNAs has been observed in various human cancers, including lung cancer. Recent studies have identified the role of a number of miRNAs in regulating key cellular processes and signaling pathways involved in lung tumourigenesis, including cell proliferation, differentiation, angiogenesis, apoptosis, invasion and metastasis. Due to their variable behavior and regulatory role in various nodal junctions in cellular pathways, miRNAs have also been used as potential therapeutic targets and clinical biomarkers in lung cancer. In this non-systematic review, we briefly focus on biogenesis and function of cytoplasmic miRNA and the role of methylation in the regulation of miRNA biogenesis in non small cell lung cancer (NSCLC). Further, we elaborate on the role of differentially expressed miRNAs and their regulatory role on various signaling pathways, cell cycle, and apoptosis in NSCLC. PMID- 26743517 TI - Evaluation of Antimicrobial and Antiviral Activities of Different Venoms. AB - BACKGROUND: Animals' venomous secretions or peptides obtained from those secretions are used in the development of new therapeutic agents. The aims of this study were to investigate antimicrobial and antiviral activity of four different venoms obtained from the frog named Bufo arenarum and the snakes Crotalus atrox, Causus rhombeatus and Naja melanoleuca. METHODS: Antimicrobial activities of the venoms tested against 9 bacteria, 1 yeast, 1 fungal species and 2 viral species based on micro-well dilution assay and antiviral assay. RESULTS: Four different venoms were examined to evaluate the antimicrobial and antiviral activity against 9 bacteria, 1 yeast and 1 fungal and 2 viral species. None of the venoms exhibited anticandidal or antifungal activity. However, all of the four venoms tested were found to have both antibacterial and antiviral activities. CONCLUSION: This is the first study demonstrating that venoms of Crotalus atrox and Bufo arenarum have antibacterial activities against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, Bacillus subtilis, Aeromonas hydrophila, Aeromonas spp. Antiviral activities of 4 venoms against Poliovirus and Adenovirus were also investigated for the first time. PMID- 26743519 TI - Ebola Virus Altered Innate and Adaptive Immune Response Signalling Pathways: Implications for Novel Therapeutic Approaches. AB - Ebola virus (EBOV) arise attention for their impressive lethality by the poor immune response and high inflammatory reaction in the patients. It causes a severe hemorrhagic fever with case fatality rates of up to 90%. The mechanism underlying this lethal outcome is poorly understood. In 2014, a major outbreak of Ebola virus spread amongst several African countries, including Leone, Sierra, and Guinea. Although infections only occur frequently in Central Africa, but the virus has the potential to spread globally. Presently, there is no vaccine or treatment is available to counteract Ebola virus infections due to poor understanding of its interaction with the immune system. Accumulating evidence indicates that the virus actively alters both innate and adaptive immune responses and triggers harmful inflammatory responses. In the literature, some reports have shown that alteration of immune signaling pathways could be due to the ability of EBOV to interfere with dendritic cells (DCs), which link innate and adaptive immune responses. On the other hand, some reports have demonstrated that EBOV, VP35 proteins act as interferon antagonists. So, how the Ebola virus altered the innate and adaptive immune response signaling pathways is still an open question for the researcher to be explored. Thus, in this review, I try to summarize the mechanisms of the alteration of innate and adaptive immune response signaling pathways by Ebola virus which will be helpful for designing effective drugs or vaccines against this lethal infection. Further, potential targets, current treatment and novel therapeutic approaches have also been discussed. PMID- 26743516 TI - The cryptic Y-autosome translocation in the small Indian mongoose, Herpestes auropunctatus, revealed by molecular cytogenetic approaches. AB - In initial studies of the eutherian small Indian mongoose (Herpestes auropunctatus), the Y chromosome could not be identified in somatic cells. The male chromosome number is uniquely odd, 2n = 35, whereas that of females is 2n = 36. Previous reports indicated that this unique karyotype resulted from a translocation of the ancestral Y chromosome to an autosome. However, it has been difficult to identify the chromosomes that harbor the translocated Y chromosomal segment because it is an extremely small euchromatic region. Using a Southern blot analysis, we detected four conserved Y-linked genes, SRY, EIF2S3Y, KDM5D, and ZFY, in the male genome. We cloned homologues of these genes and determined their sequences, which showed high homology to genes in two carnivore species, cat and dog. To unambiguously identify the Y-bearing autosome, we performed immunostaining of pachytene spermatocytes using antibodies against SYCP3, gammaH2AX, and the centromere. We observed trivalent chromosomes, and the associations between the distal ends of the chromosomes were consistent with those of Y and X1 chromosomes. The centromere of the Y chromosome was located on the ancestral Y chromosomal segment. We mapped the complementary DNA (cDNA) clones of these genes to the male chromosomes using fluorescence in situ hybridization (FISH), and the linear localization of all genes was confirmed by two-colored FISH. These Y-linked genes were localized to the proximal region of the long arm of a single telomeric chromosome, and we successfully identified the chromosome harboring the ancestral Y chromosomal segment. PMID- 26743520 TI - Identification and characterization of microRNAs in the plant parasitic root-knot nematode Meloidogyne incognita using deep sequencing. AB - The root-knot nematode Meloidogyne incognita is among the most damaging plant parasitic pests of several crops including cotton (Gossypium hirsutum) and tomato (Lycopersicon escultentum). Recently, a genome has become available for M. incognita, which greatly facilitates investigation of the interactions between M. incognita and its plant hosts at the molecular level and enables formation of hypotheses concerning development at the cellular level. MicroRNAs (miRNAs) are a class of small RNA molecules that serve as endogenous gene regulators. They regulate many biological processes including reproduction, the sequencing of morphological development, and potentially of parasitism as well. Certain miRNAs regulate fundamental metabolism pathways and stress responses in M. incognita. Since a list of miRNAs has not been generated for M. incognita, we employed a bioinformatics tool called mirDeepFinder to identify miRNAs from the small RNA database of M. incognita (GSM611102) that was generated from deep sequencing. A total of 254 conserved miRNAs belonging to 161 miRNA families were identified, as were 35 novel miRNAs belonging to 31 families. The 16 most commonly found miRNAs in order of abundance were min-miR-100a, min-miR-124, min-miR-71a, min-miR-1, min miR-228, min-miR-92, min-miR-72, min-miR-49b, min-miR-58, min-miR-252, min-miR lin-4, min-miR-87, min-miR-2a, min-miR-34a, min-miR-50a, and min-miR-279a. The length of the pre-miRNAs varied greatly from 50 to 197 nt, with an average of 88 +/- 39 nt. The average minimal folding free energy (MFE) and MFE index (MFEI) of the identified miRNAs were -30.3 Kcal/mol and 0.92, respectively, indicating that these miRNAs can readily fold into a typical hairpin secondary structure. PMID- 26743523 TI - The yellow-fruited tomato 1 (yft1) mutant has altered fruit carotenoid accumulation and reduced ethylene production as a result of a genetic lesion in ETHYLENE INSENSITIVE2. AB - KEY MESSAGE: The isolated yft1 allele controls the formation of fruit color in n3122 via the regulation of response to ethylene, carotenoid accumulation and chromoplast development. Fruit color is one of the most important quality traits of tomato (Solanum lycopersicum) and is closely associated with both nutritional and market value. In this study, we characterized a tomato fruit color mutant n3122, named as yellow-fruited tomato 1 (yft1), which produces yellow colored mature fruit. Fruit color segregation of the progeny from an intra-specific cross (M82 * n3122) and an inter-specific cross (n3122 * LA1585) revealed that a single recessive nuclear gene determined the yellow fruit phenotype. Through map-based cloning, the yft1 locus was assigned to an 88.2 kb region at the top of chromosome 9 that was annotated as containing 12 genes. Sequencing revealed that one gene, Solyc09g007870, which encodes ETHYLENE INSENSITIVE2 (EIN2), contained two mutations in yft1: a 13 bp deletion and a 573 bp insertion at position -318 bp upstream of the translation initiation site. We detected that EIN2 expression was substantially lower in yft1 than in the red-fruited M82 wild type and that, in addition, carotenoid accumulation was decreased, ethylene synthesis and perception were impaired and chromoplast development was delayed. The results implied that the reduced expression of EIN2 in yft1 leads to suppressed ethylene signaling which results in abnormal carotenoid production. PMID- 26743524 TI - The triploid East African Highland Banana (EAHB) genepool is genetically uniform arising from a single ancestral clone that underwent population expansion by vegetative propagation. AB - KEY MESSAGE: All East African Highland Banana varieties are genetically uniform having arisen from a single clone introduced to Africa. East African Highland bananas (EAHBs) are a subgroup of triploid (AAA genome) bananas of importance to food security in the Great Lakes region of Africa. Little is known about their genetic variation, population structure and evolutionary history. Ninety phenotypically diverse EAHB cultivars were genotyped at 100 SSR microsatellite markers to investigate population genetic diversity, the correlation of genetic variability with morphological classes, and evolutionary origins since introduction to Africa. Population-level statistics were compared to those for plantain (AAB) and dessert (AAA) cultivars representing other M. acuminata subgroups. EAHBs displayed minimal genetic variation and are largely genetically uniform, irrespective of whether they were derived from the distinct Ugandan or Kenyan germplasm collections. No association was observed between EAHB genetic diversity and currently employed morphological taxonomic systems for EAHB germplasm. Population size dynamics indicated that triploid EAHBs arose as a single hybridization event, which generated a genetic bottleneck during foundation of the EAHB genepool. As EAHB triploids are sterile, subsequent asexual vegetative propagation of EAHBs allowed a recent rapid expansion in population size. This provided a basis for emergence of genetically near-isogenic somatic mutants selected across farmers and environments in East Africa over the past 2000 years since EAHBs were first introduced to the African continent. PMID- 26743525 TI - The development and validation of the Clinical Teaching Behavior Inventory (CTBI 23): Nurse preceptors' and new graduate nurses' perceptions of precepting. AB - BACKGROUND: Few studies have examined the perceptions of clinical teaching behaviors among both nurse preceptors and preceptees. PURPOSES: To develop a Clinical Teaching Behavior Inventory (CTBI) for nurse preceptors' self evaluation, and for new graduate nurse preceptee evaluation of preceptor clinical teaching behaviors and to test the validity and reliability of the CTBI. METHODS: This study used mixed research techniques in five phases. Phase I: based on a literature review, the researchers developed an instrument to measure clinical teaching behaviors. Phase II: 17 focus group interviews were conducted with 63 preceptors and 24 new graduate nurses from five hospitals across Taiwan. Clinical teaching behavior themes were extracted from the focus group data and integrated into the domains and items of the CTBI. Phase III: two rounds of an expert Delphi study were conducted to determine the content validity of the instrument. Phase IV: a total of 290 nurse preceptors and 260 new graduate nurses were recruited voluntarily in the same five hospitals in Taiwan. Of these, 521 completed questionnaires to test the construct validity of CTBI by using confirmatory factory analysis. Phase V: the internal consistency and reliability of the instrument were tested. RESULTS: CTBI consists of 23 items in six domains: (1) 'Committing to Teaching'; (2) 'Building a Learning Atmosphere'; (3) 'Using Appropriate Teaching Strategies'; (4) 'Guiding Inter-professional Communication'; (5) 'Providing Feedback and Evaluation'; and (6) 'Showing Concern and Support'. The confirmatory factor analysis yielded a good fit and reliable scores for the CTBI-23 model. CONCLUSIONS: The CTBI-23 is a valid and reliable instrument for identifying the clinical teaching behaviors of a preceptor as perceived by preceptors and new graduate preceptees. The CTBI-23 depicts clinical teaching behaviors of nurse preceptors in Taiwan. PMID- 26743526 TI - Selenium Supplementation Affects Insulin Resistance and Serum hs-CRP in Patients with Type 2 Diabetes and Coronary Heart Disease. AB - To our knowledge, this study is the first indicating the effects of selenium supplementation on metabolic status of patients with type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD). This study was conducted to evaluate the effects of selenium supplementation on metabolic profiles, biomarkers of inflammation, and oxidative stress of patients with T2DM and CHD. This randomized, double-blind, placebo-controlled trial was performed among 60 patients with T2DM and CHD aged 40-85 years. Participants were randomly divided into 2 groups. Group A received 200 MUg selenium supplements (n=30) and group B received placebo per day (n=30) for 8 weeks. Fasting blood samples were taken at the beginning of the study and after 8-week intervention to quantify metabolic profiles. After 8 weeks, compared with the placebo, selenium supplementation resulted in a significant decrease in serum insulin levels (- 2.2+/-4.6 vs. + 3.6+/-8.4 MUIU/ml, p=0.001), homeostasis model of assessment-insulin resistance (HOMA-IR) (- 0.7+/-1.3 vs. + 0.9+/-2.4, p=0.004), homeostatic model assessment beta cell function (HOMA-B) (- 7.5+/-17.2 vs. + 15.1+/-34.5, p=0.002) and a significant increase in quantitative insulin sensitivity check index (QUICKI) (+0.01+/-0.03 vs. - 0.01+/-0.03, p=0.02). In addition, patients who received selenium supplements had a significant reduction in serum high-sensitivity C reactive protein (hs-CRP) (- 1 372.3+/-2 318.8 vs. - 99.8+/-1 453.6 ng/ml, p=0.01) and a significant rise in plasma total antioxidant capacity (TAC) concentrations (+ 301.3+/-400.6 vs. - 127.2+/-428.0 mmol/l, p<0.001) compared with the placebo. A 200 MUg/day selenium supplementation among patients with T2DM and CHD resulted in a significant decrease in insulin, HOMA-IR, HOMA-B, serum hs CRP, and a significant increase in QUICKI score and TAC concentrations. PMID- 26743527 TI - Serum Levels of Osteocalcin and Insulin Resistance in Patients with Impaired Glucose Tolerance or New-Onset Diabetes Mellitus After Liver Transplantation. AB - Liver transplantation (LT) patients are at high risk of developing new-onset diabetes after transplantation (NODAT). Osteocalcin has been proposed as a mediator between bone tissue and glucose metabolism, but its role in the pathogenesis of diabetes is not defined yet. Our objective was to assess the relationship between serum osteocalcin and glucose metabolism parameters in liver transplantation recipients. A total of 187 liver transplantation patients were cross-sectionally studied, 54 of them developed NODAT. None had been diagnosed of diabetes mellitus prior to transplant. In 133 nondiabetic patients, a 75 g oral glucose tolerance test (OGTT) was performed to assess blood glucose, insulin, and C-peptide levels at baseline and 120 min. Serum total osteocalcin was measured at baseline in all patients.After OGTT, 10.5% of LT patients had NODAT criteria, 51.9% showed impaired glucose tolerance, and 37.6% had normal glucose tolerance. Overall, NODAT prevalence was 36.3%. HOMA-IR was significantly higher in NODAT compared with impaired glucose tolerance and normal glucose tolerance groups (p<0.001). Osteocalcin was inversely correlated to HOMA-IR (r=- 0.16, p=0.05), BMI (r=- 0.27, p=0.000) and waist circumference (r=- 0.21, p=0.005). Patients in the lowest osteocalcin tertile (< 16.5 ng/ml) had significantly higher fasting plasma glucose and HOMA-IR index (p=0.029 and 0.037, respectively) than those in medium or highest tertiles. In multiple linear regression analysis, osteocalcin was negatively associated with fasting plasma glucose (standardized beta coefficient-0.16; p=0.041) and 2-h insulin (standardized beta coefficient-0.21; p=0.028). Prevalence of NODAT/impaired glucose tolerance is high in liver transplantation patients and is associated with insulin resistance. In these patients total osteocalcin is inversely associated with plasma glucose level and insulin resistance indexes. PMID- 26743528 TI - Insulin-like Growth Factor 1 Regulates the Expression of ATP-Binding Cassette Transporter A1 in Pancreatic Beta Cells. AB - ATP-binding cassette transporter A1 (ABCA1) in pancreatic beta cells influences insulin secretion and cholesterol homeostasis. The present study investigates whether insulin-like growth factor 1 (IGF-1), which mediates stimulation of ABCA1 gene expression, could also interfere with the phosphatidylinositol 3-kinase (PI3 K) cascade.ABCA1 expression was examined by real-time polymerase chain reaction (PCR), Western blot analysis, and a reporter gene assay in rat insulin-secreting INS-1 cells incubated with IGF-1. The binding of forkhead box O1 (FoxO1) protein to the ABCA1 promoter was assessed by a chromatin immunoprecipitation (ChIP) assay. ABCA1 protein levels increased in response to rising concentrations of IGF 1. Real-time PCR analysis showed a significant increase in ABCA1 mRNA expression. However, both effects were suppressed after silencing the IGF-1 receptor. In parallel with its effect on endogenous ABCA1 mRNA levels, IGF-1 induced the activity of a reporter construct containing the ABCA1 promoter, while it was abrogated by LY294002, a specific inhibitor of PI3-K. Constitutively active Akt stimulated activity of the ABCA1 promoter, and a dominant-negative mutant of Akt or mutagenesis of the FoxO1 response element in the ABCA1 promoter abolished the ability of IGF-1 to stimulate promoter activity. A ChIP assay showed that FoxO1 mediated its transcriptional activity by directly binding to the ABCA1 promoter region. The knockdown of FoxO1 disrupted the effect of IGF-1 on ABCA1 expression. Furthermore, IGF-1 promoted cholesterol efflux and reduced the pancreatic lipotoxicity. These results demonstrate that the PI3-K/Akt/FoxO1 pathway contributes to the regulation of ABCA1 expression in response to IGF-1 stimulation. PMID- 26743529 TI - Naturally acquired immunity to sexual stage P. falciparum parasites. AB - Gametocytes are the specialized form of Plasmodium parasites that are responsible for human-to-mosquito transmission of malaria. Transmission of gametocytes is highly effective, but represents a biomass bottleneck for the parasite that has stimulated interest in strategies targeting the transmission stages separately from those responsible for clinical disease. Studying targets of naturally acquired immunity against transmission-stage parasites may reveal opportunities for novel transmission reducing interventions, particularly the development of a transmission blocking vaccine (TBV). In this review, we summarize the current knowledge on immunity against the transmission stages of Plasmodium. This includes immune responses against epitopes on the gametocyte-infected erythrocyte surface during gametocyte development, as well as epitopes present upon gametocyte activation in the mosquito midgut. We present an analysis of historical data on transmission reducing immunity (TRI), as analysed in mosquito feeding assays, and its correlation with natural recognition of sexual stage specific proteins Pfs48/45 and Pfs230. Although high antibody titres towards either one of these proteins is associated with TRI, the presence of additional, novel targets is anticipated. In conclusion, the identification of novel gametocyte-specific targets of naturally acquired immunity against different gametocyte stages could aid in the development of potential TBV targets and ultimately an effective transmission blocking approach. PMID- 26743530 TI - Low-Molecular-Weight Fucoidan Attenuates Mitochondrial Dysfunction and Improves Neurological Outcome After Traumatic Brain Injury in Aged Mice: Involvement of Sirt3. AB - Traumatic brain injury (TBI) is a leading cause of death and long-term disability. Fucoidan, a sulfated polysaccharide extracted from brown algae, possesses potent anti-oxidative and anti-inflammatory effects. Considering TBI happens frequently in adults, especially in aged individuals, we herein sought to define the protective effects of low-molecular-weight fucoidan (LMWF) in the aged mice. 16- to 18-month-old mice administered with LMWF (1-50 mg/kg) or vehicle were subjected to TBI using a controlled cortical impact (CCI) model. LMWF at the doses of 10 and 50 mg/kg significantly reduced both cortical and hippocampal lesion volume. This protection was associated with reduced neuronal apoptosis, as evidenced by TUNEL staining. Importantly, LMWF was effective even when administered up to 4 h after TBI. Treatment with LMWF improved long-term neurobehavioral outcomes, including sensorimotor function, and hippocampus associated spatial learning and memory. In addition, LMWF significantly suppressed protein carbonyl, lipid peroxidation, reactive oxygen species (ROS) generation, as well as mitochondrial dysfunction, which was evidenced by mitochondrial cytochrome c release and collapse of mitochondrial membrane potential (MMP). To evaluate the underlying molecular mechanisms, the expression of sirtuin 3 (Sirt3) was detected by RT-PCR and Western blot. The results showed that TBI significantly increased the expression of Sirt3, which was further elevated by LMWF treatment. Knockdown of Sirt3 using intracerebroventricular injection of small interfering RNA (siRNA) partially prevented the therapeutic effects of LMWF. Collectively, these findings demonstrated that LMWF exerts neuroprotection against TBI in the aged brain, which may be associated with the attenuation of mitochondrial dysfunction through Sirt3 activation. PMID- 26743532 TI - Variable but persistent coexistence of Prochlorococcus ecotypes along temperature gradients in the ocean's surface mixed layer. AB - The vast majority of the phytoplankton communities in surface mixed layer of the oligotrophic ocean are numerically dominated by one of two ecotypes of Prochlorococcus, eMIT9312 or eMED4. In this study, we surveyed large latitudinal transects in the Atlantic and Pacific Ocean to determine if these ecotypes discretely partition the surface mixed layer niche, or if populations exist as a continuum along key environmental gradients, particularly temperature. Transitions of dominance occurred at approximately 19-21 degrees C, with the eMED4 ecotype dominating the colder, and eMIT9312 ecotype dominating the warmer regions. Within these zones of regional dominance, however, the minority ecotype was not competed to extinction. Rather, a robust log-linear relationship between ecotype ratio and temperature characterized this stabilized coexistence: for every 2.5 degrees C increase in temperature, the eMIT9312:eMED4 ratio increased by an order of magnitude. This relationship was observed in both quantitative polymerase chain reaction and in pyrosequencing assays. Water column stratification also contributed to the ecotype ratio along the basin-scale transects, but to a lesser extent. Finally, instances where the ratio of the eMED4 and eMIT9312 abundances did not correlate well with temperature were identified. Such occurrences are likely due to changes in water temperatures outpacing changes in community structure. PMID- 26743531 TI - Ovarian cancer outcomes: Predictors of early death. AB - OBJECTIVE: To describe the outcomes and mortality in advanced ovarian cancer patients in a population-based cohort in the 90 days after diagnosis. METHODS: Using the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database, we identified a cohort of women with stage III/IV epithelial ovarian cancer diagnosed between 1995 and 2007. A chi(2) test was used to assess demographic and clinical factors. Kaplan-Meier curves and Cox proportional hazards models were used to assess factors associated with variation in survival. RESULTS: Of the 9491 patients with stage III/IV ovarian cancer identified from the SEER/Medicare system, 4131 (43.6%) patients died in the first year after diagnosis. Of these, 2472 (26.0%) patients died in the first 90 days after diagnosis. Over the study period, the number of patients who died in the first 90 days after diagnosis slightly increased (p=0.053). Older age (>75 years of age), increased comorbidity, stage IV disease, lack of a visit with a gynecologic oncologist, and surgery were associated with an increase in 90-day mortality. Chemotherapy was associated with a reduction in 90-day mortality. CONCLUSIONS: Approximately 25% of patients with advanced ovarian cancer in our study period died within 90 days of diagnosis, and more than 40% died within the first year of diagnosis. In addition, a substantial proportion of patients did not receive any treatment. Further research into the characteristics of these patients should be performed to elucidate clinical areas for intervention to either prevent these poor outcomes or allocate appropriate resources to patients with extremely poor prognoses. PMID- 26743534 TI - Genome sequencing and analysis of a novel recombinant porcine epidemic diarrhea virus strain from Henan, China. AB - Porcine epidemic diarrhea virus (PEDV) has caused devastating impact on pig rearing industry in China and current vaccine is not effective against the circulating PEDV variants. In the present study, the full-length genome sequence from a PEDV isolate (CH/HNQX-3/14) was determined. The complete genome sequence analysis showed that the CH/HNQX-3/14 possessed unique deletion regions in the S and ORF3 genes. It was identified as a recombinant strain using phylogenetic analysis and recombination detection program. Further analyses of the full-length sequence suggest that CH/HNQX-3/14 is a natural recombinant between the attenuated vaccine strains (CV777 and DR13) and circulating wild-type strain (CH/ZMDZY/11). The recombination occurred not only in structural protein-coding region (S1 and N genes) but also in non-structural protein-coding region (replicases 1a and ORF3 genes). These results provided new evidence that PEDV strains circulating in China underwent recombination between vaccine and field strains, suggesting that recombination contributes to the genetic diversity of PEDV. Our findings provide valuable information on PEDV evolution and underscore the need for ongoing surveillance of this economically important swine disease. PMID- 26743535 TI - Current recommendations on managing tuberculosis patients with diabetes & its epidemiology. AB - BACKGROUND & OBJECTIVE: Tuberculosis (TB) & Diabetes Mellitus (DM) are common diseases globally & both are mutually on rising trend, and co-existing together. To analyze the effect of TB on diabetes by causing hyperglycemia and causing impaired glucose tolerance. Impaired glucose tolerance that is one of the major risk factor for developing diabetes. STUDY DESIGN: Literature study regarding co association of TB & DM with its complications and management through published articles. The drugs used to treat tuberculosis especially rifampicin and isoniazid interacts with oral anti-diabetic drugs and can lead to suboptimal glycemic control. Therefore the interaction of diabetes and tuberculosis is at multiple levels exacerbating each other. DM is also well recognized as an independent risk factor for lower respiratory tract infection. Infection with, staphylococcus aureus, gram negative bacteria, and fungi occur more frequently in diabetics. RESULT & CONCLUSION: The prevalence of diabetes globally is projected to rise from the current estimate of 150 million to 200 million in 2010 and to 300 million (5.4%) in 2025. The potential for increase in the number of cases of diabetes is greatest in Asia. It is an emerging public health problem leading in an associated significant proportion. This article reviews the association between diabetes and tuberculosis and suggests appropriate management for these conditions. PMID- 26743533 TI - Dispositional Mindfulness Predicts Enhanced Smoking Cessation and Smoking Lapse Recovery. AB - BACKGROUND: Although mindfulness has been hypothesized to promote health behaviors, no research has examined how dispositional mindfulness might influence the process of smoking cessation. PURPOSE: The current study investigated dispositional mindfulness, smoking abstinence, and recovery from a lapse among African American smokers. METHODS: Participants were 399 African Americans seeking smoking cessation treatment (treatments did not include any components related to mindfulness). Dispositional mindfulness and other psychosocial measures were obtained pre-quit; smoking abstinence was assessed 3, 31 days, and 26 weeks post-quit. RESULTS: Individuals higher in dispositional mindfulness were more likely to quit smoking both initially and over time. Moreover, among individuals who had lapsed at day 3, those higher in mindfulness were more likely to recover abstinence by the later time points. The mindfulness-early abstinence association was mediated by lower negative affect, lower expectancies to regulate affect via smoking, and higher perceived social support. CONCLUSIONS: Results suggest that mindfulness might enhance smoking cessation among African American smokers by operating on mechanisms posited by prominent models of addiction. PMID- 26743537 TI - Abstracts for GEER-Congress in Malaga, Spain, June 2015. PMID- 26743538 TI - Microstructured Nickel-Titanium Thin Film Leaflets for Hybrid Tissue Engineered Heart Valves Fabricated by Magnetron Sputter Deposition. AB - Heart valves are constantly exposed to high dynamic loading and are prone to degeneration. Therefore, it is a challenge to develop a durable heart valve substitute. A promising approach in heart valve engineering is the development of hybrid scaffolds which are composed of a mechanically strong inorganic mesh enclosed by valvular tissue. In order to engineer an efficient, durable and very thin heart valve for transcatheter implantations, we developed a fabrication process for microstructured heart valve leaflets made from a nickel-titanium (NiTi) thin film shape memory alloy. To examine the capability of microstructured NiTi thin film as a matrix scaffold for tissue engineered hybrid heart valves, leaflets were successfully seeded with smooth muscle cells (SMCs). In vitro pulsatile hydrodynamic testing of the NiTi thin film valve leaflets demonstrated that the SMC layer significantly improved the diastolic sufficiency of the microstructured leaflets, without affecting the systolic efficiency. Compared to an established porcine reference valve model, magnetron sputtered NiTi thin film material demonstrated its suitability for hybrid tissue engineered heart valves. PMID- 26743536 TI - Use of the VH6-1 gene segment to code for anti-interleukin-18 autoantibodies in multiple sclerosis. AB - We investigated whether levels and repertoires of anti-interleukin-18 (IL-18) autoantibodies (auto-Abs) differ in multiple sclerosis (MS) patients and healthy donors (HDs). IL-18 concentration in MS patients' sera was higher than in HD, but the level of anti-IL-18 auto-Abs was lower in MS patients. Correlation patterns of IL-18/anti-IL-18 auto-Abs system differed in HD and MS patients, so we have compared segment composition of the anti-IL-18 single-chain variable fragments (scFvs) selected from MS and naive phage display libraries. Considerable differences between anti-IL-18 auto-Abs of these libraries were found. MS panel contained auto-Abs displaying both signs of "fetal" and somatically hypermutated repertoires. Naive panel mainly contained the naive antibodies. These variations from the norm are possible results of abnormal regulation of the repertoire perhaps determined by remodeling of the molecular mechanisms involved in the V(D)J recombination and/or abnormal selection by antigen in MS pathogenesis. PMID- 26743539 TI - Alterations of blood coagulation in controlled human malaria infection. AB - BACKGROUND: Alterations of blood coagulation are thought to be involved in malaria pathogenesis. This study had the aim to investigate changes of blood coagulation under the standardized conditions of controlled human malaria infection. METHODS: In a clinical trial aseptic, purified, cryopreserved Plasmodium falciparum sporozoites were intravenously (n = 24) or intradermally (n = 6) injected into 30 healthy volunteers. Twenty-two participants developed parasitaemia. Serial blood samples before and during prepatent period and at parasitaemia, diagnosed by microscopic assessment of thick blood smear, were obtained. Biomarkers of blood coagulation (thrombin generation potential, D dimer, prothrombin fragment 1 + 2, von Willebrand factor, ADAMTS13 activity and soluble P-selectin) were determined. RESULTS: At first detection of P. falciparum parasitaemia, 72.7% of volunteers had peak thrombin generation 10% above their baseline. Overall, peak thrombin generation was 17.7% higher at parasitaemia compared to baseline [median (25th-75th percentile): 225.4 nM (168.1-295.6) vs. 191.5 nM (138.2-231.9); p = 0.026]. There were no significant changes of other coagulation parameters. CONCLUSIONS: The thrombin generation potential, an in vitro blood coagulation test, which reflects an individual's global coagulation status, was increased by 17.7% at very early stages of P. falciparum malaria, suggesting a hypercoagulable state may be induced, even when parasite density is low. PMID- 26743540 TI - Highly Enantioselective Bromocyclization of Allylic Amides with a P/P=O Double Site Lewis Base Catalyst. AB - The enantioselective bromocyclization of allylic amides catalyzed by phosphorus containing Lewis bases was examined in detail. A series of control experiments and NMR studies showed that a partially oxidized bis-phosphine generated in situ serves as the actual enantioselective catalyst. The reaction mechanism involves distinct roles of two Lewis basic sites, P and P=O, with P+ Br serving as a fine tuning element for substrate fixation in the chiral environment, and P+ OBr as the Br+ transfer agent to the olefin. Catalyst loading could be reduced to as little as 1 mol %, and the reaction affords enantioenriched oxazolines with up to >99.5 % ee. PMID- 26743541 TI - Rapid diagnosis of Propionibacterium acnes infection in patient with hyperpyrexia after hematopoietic stem cell transplantation by next-generation sequencing: a case report. AB - BACKGROUND: The rapid determination of pathogenic agent is very important to clinician for guiding their clinical medication. However, current diagnostic methods are of limitation in many aspects, such as detecting range, time consuming, specificity and sensitivity. In this report, we apply our new developing pathogen detection method to clarify that Propionibacterium acnes is the causative agent of a two-year-old boy with juvenile myelomonocytic leukemia presenting clinical symptoms including serious rash and hyperpyrexia while traditional clinical methods of diagnosis fail to detect the pathogenic agent and multiple antimicrobial drugs are almost ineffective Propionibacterium acnes is confirmed to be the infectious agent by quantitative real-time polymerase chain reaction. CASE PRESENTATION: After haploidentical hematopoietic stem cell transplantation, a two-year-old boy with juvenile myelomonocytic leukemia presented to a pediatrist in a medical facility with hyperpyrexia and red skin rash which later changed to black skin rash all over his body. Traditional diagnostic assays were unrevealing, and several routine antimicrobial treatments were ineffective, including the vancomycin, meropenem, tobramycin, cefepime and rifampin. In this case, pediatrist resorted to the next-generation sequencing technology for uncovering potential pathogens so as to direct their use of specific drugs against pathogenic bacteria. Therefore, based on the BGISEQ100 (Ion Proton System) which performed sequencing-by-synthesis, with electrochemical detection of synthesis, and each such reaction coupled to its own sensor, which are in turn organized into a massively parallel sensor array on a complementary metal-oxidesemiconductor chip, we detect and identify the potential pathogens. As a result, we detected a significantly higher abundance of skin bacteria Propionibacterium acnes in patient's blood than controls. It had been reported that patients infected by Propionibacterium acnes almost always had history of immunodeficiency, trauma or surgery. Considering this possible cause, antimicrobial treatment was adjusted to target this rare opportunistic pathogen. Fever and black skin rashes were rapidly reduced after administrating specific drugs against Propionibacterium acnes. CONCLUSION: This case showed our new developing pathogen detection method was a powerful tool in assisting clinical diagnosis and treatment. And it should be paid more attention to Propionibacterium acnes infection in clinical cases. PMID- 26743542 TI - Fingerprinting Electronic Molecular Complexes in Liquid. AB - Predicting the electronic framework of an organic molecule under practical conditions is essential if the molecules are to be wired in a realistic circuit. This demands a clear description of the molecular energy levels and dynamics as it adapts to the feedback from its evolving chemical environment and the surface topology. Here, we address this issue by monitoring in real-time the structural stability and intrinsic molecular resonance states of fullerene (C60)-based hybrid molecules in the presence of the solvent. Energetic levels of C60 hybrids are resolved by in situ scanning tunnelling spectroscopy with an energy resolution in the order of 0.1 eV at room-temperature. An ultra-thin organic spacer layer serves to limit contact metal-molecule energy overlap. The measured molecular conductance gap spread is statistically benchmarked against first principles electronic structure calculations and used to quantify the diversity in electronic species within a standard population of molecules. These findings provide important progress towards understanding conduction mechanisms at a single-molecular level and in serving as useful guidelines for rational design of robust nanoscale devices based on functional organic molecules. PMID- 26743544 TI - Ethanol adaptation induces direct protection and cross-protection against freezing stress in Salmonella enterica serovar Enteritidis. AB - AIMS: Salmonella enterica serovar Enteritidis (Salm. Enteritidis) encounters mild ethanol stress during its life cycle. However, adaptation to a stressful condition may affect bacterial resistance to subsequent stresses. Hence, this work was undertaken to investigate the influences of ethanol adaptation on stress tolerance of Salm. Enteritidis. METHODS AND RESULTS: Salmonella Enteritidis was subjected to different ethanol adaptation treatments (2.5-10% ethanol for 1 h). Cellular morphology and tolerance to subsequent environmental stresses (15% ethanol, -20 degrees C, 4 degrees C, 50 degrees C and 10% NaCl) were evaluated. It was found that 10% was the maximum ethanol concentration that allowed growth of the target bacteria. Ethanol adaptation did not cause cell-surface damage in Salm. Enteritidis as revealed by membrane permeability measurements and electron micrograph analysis. Salmonella Enteritidis adapted with 2.5-10% ethanol displayed an enhanced resistance to a 15%-ethanol challenge compared with an unchallenged control. The maximum ethanol resistance was observed when ethanol concentration used for ethanol adaptation was increased to 5.0%. Additionally, pre-adaptation to 5.0% ethanol cross-protected Salm. Enteritidis against -20 degrees C, but not against 4 degrees C, 50 degrees C or 10% NaCl. CONCLUSIONS: Ethanol adaptation provided Salm. Enteritidis direct protection from a high level ethanol challenge and cross-protection from freezing, but not other stresses tested (low temperature, high salinity or high temperature). SIGNIFICANCE AND IMPACT OF THE STUDY: The results are valuable in developing adequate and efficient control measures for Salm. Enteritidis in foods. PMID- 26743543 TI - Highly controlled coating of strontium-doped hydroxyapatite on electrospun poly(E caprolactone) fibers. AB - Electrospun fibers show great potential as scaffolds for bone tissue engineering due to their architectural biomimicry to the extracellular matrix (ECM). Cation substitution of strontium for calcium in hydroxyapatite (HAp) positively influences the mechanism of bone remodeling including enhancing bone regeneration and reducing bone resorption. The objective of this study was to attach strontium doped HAp (SrHAp) to electrospun poly(E-caprolactone) (PCL) fibers for creation of novel composite scaffolds that can not only mimic the architecture and composition of ECM but also affect bone remodeling favorably. We demonstrated for the first time the highly controlled SrHAp coatings on electrospun PCL fibers. We showed the reproducible manufacturing of composite fiber scaffolds with controllable thickness, composition, and morphology of SrHAp coatings. We further showed that the released strontium and calcium cations from coatings could reach effective concentrations within 1 day and endure more than 28 days. Additionally, the Young's modulus of the SrHAp-coated PCL fibers was up to around six times higher than that of raw fibers dependent on the coating thickness and composition. Together, this novel class of composite fiber scaffolds may hold great promise for bone regeneration. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 753-763, 2017. PMID- 26743545 TI - Green House Adoption and Nursing Home Quality. AB - OBJECTIVE: To evaluate the impact of the Green House (GH) model on nursing home resident-level quality of care measures. DATA SOURCES/STUDY SETTING: Resident level minimum data set (MDS) assessments merged with Medicare inpatient claims for the period 2005 through 2010. STUDY DESIGN: Using a difference-in-differences framework, we compared changes in care quality and outcomes in 15 nursing homes that adopted the GH model relative to changes over the same time period in 223 matched nursing homes that had not adopted the GH model. PRINCIPAL FINDINGS: For individuals residing in GH homes, adoption of the model lowered readmissions and several MDS measures of poor quality, including bedfast residents, catheter use, and pressure ulcers, but these results were not present across the entire GH organization, suggesting possible offsetting effects for residents of non-GH "legacy" units within the GH organization. CONCLUSIONS: GH adoption led to improvement in rehospitalizations and certain nursing home quality measures for individuals residing in a GH home. The absence of evidence of a decline in other clinical quality measures in GH nursing homes should reassure anyone concerned that GH might have sacrificed clinical quality for improved quality of life. PMID- 26743547 TI - To establish the "Early Chronic Pancreatitis". PMID- 26743548 TI - A new era of the HCV treatment with oral agents. PMID- 26743546 TI - Oxygen-dependent regulation of c-di-GMP synthesis by SadC controls alginate production in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa produces increased levels of alginate in response to oxygen-deprived conditions. The regulatory pathway(s) that links oxygen limitation to increased synthesis of alginate has remained elusive. In the present study, using immunofluorescence microscopy, we show that anaerobiosis induced alginate production by planktonic PAO1 requires the diguanylate cyclase (DGC) SadC, previously identified as a regulator of surface-associated lifestyles. Furthermore, we found that the gene products of PA4330 and PA4331, located in a predicted operon with sadC, have a major impact on alginate production: deletion of PA4330 (odaA, for oxygen-dependent alginate synthesis activator) caused an alginate production defect under anaerobic conditions, whereas a PA4331 (odaI, for oxygen-dependent alginate synthesis inhibitor) deletion mutant produced alginate also in the presence of oxygen, which would normally inhibit alginate synthesis. Based on their sequence, OdaA and OdaI have predicted hydratase and dioxygenase reductase activities, respectively. Enzymatic assays using purified protein showed that unlike OdaA, which did not significantly affect DGC activity of SadC, OdaI inhibited c-di-GMP production by SadC. Our data indicate that SadC, OdaA and OdaI are components of a novel response pathway of P. aeruginosa that regulates alginate synthesis in an oxygen dependent manner. PMID- 26743549 TI - Standard antiviral therapies against HCV infection. PMID- 26743550 TI - Future perspectives of treatment of chronic hepatitis C. PMID- 26743551 TI - Issues in need for a solution among patients with successful eradication of hepatitis C virus. PMID- 26743552 TI - Changing nomenclature for PBC : from 'cirrhosis' to 'cholangitis'. PMID- 26743553 TI - [Not available]. PMID- 26743554 TI - Severe refractory Clostridium difficile infection with good response to fecal microbiota transplantation: a case report. AB - A 49-year-old woman diagnosed with pseudomembranous enterocolitis was transferred to our hospital for medical treatment. She responded poorly to treatment with vancomycin hydrochloride and metronidazole, so she underwent fecal microbiota transplantation. Treatment effects were observed the next day, and the diarrhea disappeared within 3 days. Colonoscopy 4 days later revealed the resolution of pseudomembranes, and no recurrences were reported within the first year after discharge. PMID- 26743555 TI - A case of esophageal mucosa-associated lymphoid tissue lymphoma diagnosed using endoscopic ultrasound-guided fine-needle aspiration. AB - A 65-year-old man presenting with an esophageal lesion underwent esophagogastroduodenoscopy and computed tomography and an upper esophageal submucosal mass was found. Endoscopic ultrasound-guided fine-needle aspiration led to the diagnosis of mucosa-associated lymphoid tissue lymphoma of the esophagus. Positron emission tomography showed abnormal uptake in the internal iliac lymph nodes, and laparoscopic biopsy findings confirmed the diagnosis of esophageal cancer. The patient declined treatment of any kind and has been followed up for 39 months with no progression of the lymphoma. PMID- 26743556 TI - Endoscopic ultrasound-guided cystogastrostomy for successful drainage of pancreatic pseudocyst: a pediatric case report. AB - A 15-year-old boy was admitted to our hospital with a recent increase in the size of a preexisting pancreatic pseudocyst. At 11 years of age, he was diagnosed with acute lymphoid leukemia (ALL) and received chemotherapy with L-asparaginase (L Asp); he developed the pancreatic pseudocyst following L-Asp-induced acute pancreatitis. The pancreatic pseudocyst had increased to 120mm in diameter. He developed epigastralgia and portal hypertension. Endoscopic ultrasound (EUS) guided cystogastrostomy with the placement of a 7-cm 7-Fr plastic stent and a 5 Fr NB pigtail catheter led to the near-complete resolution of the pseudocyst. There were no signs of recurrence within the first year after intervention. EUS guided drainage, increasingly used for pseudocysts, should be considered as an effective treatment approach for pediatric pancreatic pseudocysts. PMID- 26743557 TI - Angiosarcoma of the gallbladder with hemobilia: a case report. AB - A 61-year-old woman presented to our hospital with epigastric pain. She underwent abdominal contrast-enhanced computed tomography, which showed signal enhancement in the gallbladder fundus. As biliary obstruction was suspected, endoscopic nasobiliary drainage was performed, which revealed hemobilia. Based on this finding, gallbladder tumor was suspected, and open cholecystectomy was performed. Immunohistological staining of the resected tissue was positive for factor VIII that led to the diagnosis of gallbladder angiosarcoma. Hepatectomy and biliary reconstruction were performed for disease control; however, the patient died due to multiple liver metastases 4 months after the surgery. PMID- 26743558 TI - (68)Ga-DOTATOC-PET/CT for effective diagnosis and treatment of pancreatic tail gastrinoma with multiple liver metastases: a case report. AB - A 40-year-old man admitted to our hospital with diarrhea underwent abdominal computed tomography (CT) which showed multiple masses in the liver and pancreatic tail. Although there were no abnormal accumulations with fluorodeoxyglucose ((18)F) positron emission tomography (FDG-PET), (68)Ga-DOTATOC-PET/CT detected obvious abnormal accumulations for the both lobes of liver and pancreatic tail tumors. The serum gastrin was markedly high, and liver tumor biopsy demonstrated the presence of malignant cells with round nuclei that were positive for gastrin and somatostatin receptor. The patient was diagnosed with pancreatic tail gastrinoma with multiple liver metastases and treated with octreotide, everolimus, and a proton pump inhibitor which functionally controlled tumor growth. This case demonstrates (68)Ga-DOTATOC-PET/CT as a useful modality for the localization, qualitative diagnosis, and treatment of gastrinoma. PMID- 26743559 TI - Bleeding due to acquired hemophilia A in acute pancreatitis: a case report. AB - Acquired hemophilia A leads to severe bleeding and is known to be related to many underlying diseases; however, it has not been reported to occur as a complication of pancreatitis. We present a case of acquired hemophilia A secondary to severe acute pancreatitis. A 76-year-old female developed a hematoma in the lower leg muscle while being treated for severe acute pancreatitis. Blood tests revealed prolonged activated partial thromboplastin time (APTT) and the presence of an autoantibody to factor VIII. The bleeding diathesis was successfully controlled by immunosuppressive therapy. This case highlights the need for careful differential diagnosis for successful management of bleeding disorders as complications of pancreatitis. PMID- 26743560 TI - The First Enantioselective Organocatalytic Synthesis of 3-Spiro-alpha-Alkylidene gamma-Butyrolactone Oxindoles. AB - A new and flexible methodology catalyzed by bifunctional chiral thioureas has been developed to react beta-nitro oxindoles 1 with aldehydes. This approach allowed us to achieve the first enantioselective organocatalytic synthesis of 3 spiro-alpha-alkylidene-gamma-butyrolactone oxindoles 3. We examined the scope of the two starting materials and, varying the structure of the beta-nitro oxindole 1, intriguing new products, derived from unexpected transformations, have been stereoselectively obtained. The aim of this study was to merge two potentially bioactive structural motifs: the spirooxindole substructure and the alpha alkylidene-gamma-butyrolactone moiety. A preliminary NMR study on the ability to reversibly trap 2-aminoethanethiol gave us promising results. PMID- 26743562 TI - Temperature dependent radiative and non-radiative recombination dynamics in CdSe CdTe and CdTe-CdSe type II hetero nanoplatelets. AB - We investigate the temperature-dependent decay kinetics of type II CdSe-CdTe and CdTe-CdSe core-lateral shell nanoplatelets. From a kinetic analysis of the photoluminescence (PL) decay and a measurement of the temperature dependent quantum yield we deduce the temperature dependence of the non-radiative and radiative lifetimes of hetero nanoplates. In line with the predictions of the giant oscillator strength effect in 2D we observe a strong increase of the radiative lifetime with temperature. This is attributed to an increase of the homogeneous transition linewidth with temperature. Comparing core only and hetero platelets we observe a significant prolongation of the radiative lifetime in type II platelets by two orders in magnitude while the quantum yield is barely affected. In a careful analysis of the PL decay transients we compare different recombination models, including electron hole pairs and exciton decay, being relevant for the applicability of those structures in photonic applications like solar cells or lasers. We conclude that the observed biexponential PL decay behavior in hetero platelets is predominately due to spatially indirect excitons being present at the hetero junction and not ionized e-h pair recombination. PMID- 26743563 TI - Treatment patterns, overall survival, healthcare resource use and costs in elderly Medicare beneficiaries with chronic myeloid leukemia using second generation tyrosine kinase inhibitors as second-line therapy. AB - Objective Though the median age at diagnosis is 64 years, few studies focus on elderly (>=65 years) patients with chronic myeloid leukemia (CML). This study examines healthcare outcomes among elderly Medicare beneficiaries with CML who started nilotinib or dasatinib after imatinib. Research design and methods Patients were identified in the Medicare Research Identifiable Files (2006-2012) and had continuous Medicare Parts A, B, and D coverage. Main outcome measures Treatment patterns, overall survival (OS), monthly healthcare resource utilization and medical costs were measured from the second-line tyrosine kinase inhibitor (TKI) initiation (index date) to end of Medicare coverage. Results Despite similar adherence, dasatinib patients (N = 379) were more likely to start on the recommended dose (74% vs. 53%; p < 0.001), and to have dose reductions (21% vs. 11%, adjusted hazard ratio [HR] = 1.94; p = 0.002) or dose increases (9% vs. 7%; adjusted HR = 1.81; p = 0.048) than nilotinib patients (N = 280). Fewer nilotinib patients discontinued (59% vs. 67%; adjusted HR = 0.80; p = 0.026) or switched to another TKI (21% vs. 29%; adjusted HR = 0.72; p = 0.044) than dasatinib patients. Nilotinib patients had longer median OS (>4.9 years vs. 4.0 years; p = 0.032) and 37% lower mortality risk than dasatinib patients (adjusted HR = 0.63; p = 0.008). Nilotinib patients had 23% fewer inpatient admissions, 30% fewer emergency room visits, 13% fewer outpatient visits (all p < 0.05), and lower monthly medical costs (by $513, p = 0.024) than dasatinib patients. Limitations Lack of clinical assessment (disease phase and response to first-line therapy) and retrospective nature of study (unobservable potential confounding factors, non-randomized treatment choice). Conclusions In the current study of elderly CML patients, initiation of second-line TKIs frequently occurs at doses lower than the recommended starting doses and, despite this, many patients require dose adjustments. Here, nilotinib patients required fewer dose adjustments than dasatinib patients. Further research focusing on elderly CML patients is warranted in order to help define future best clinical practices. PMID- 26743561 TI - What results to disclose, when, and who decides? Healthcare professionals' views on prenatal chromosomal microarray analysis. AB - OBJECTIVES: This study explored the views of healthcare professionals (HCPs) in the UK about what information should be disclosed, when; and whether women/parents should be given a choice as to what they wish to know. METHODS: Q methodology was used to assess the views of 40 HCPs (genetic HCPs, fetal medicine experts, lab-scientists). RESULTS: Most participants agreed that variants of unknown clinical significance should not be disclosed. Participants were divided between those who considered variants of uncertain clinical significance helpful for parents and clinicians, and those who considered them harmful. Although recognising the potential disadvantages of disclosing risks for adult-onset conditions, participants thought it would be difficult to withhold such information once identified. Participants largely supported some parental involvement in determining which results should be returned. Most participants believed that information obtained via CMA testing in pregnancy should either be disclosed during pregnancy, or not at all. CONCLUSION: HCPs taking part in the study largely believed that variants that will inform the management of the pregnancy, or are relevant to other family members, should be reported. Recent UK guidelines, published after this research was completed, reflect these opinions. PMID- 26743564 TI - The use of endothelial progenitor cells combined with barrier membrane for the reconstruction of peri-implant osseous defects: an animal experimental study. AB - BACKGROUND: The aim of this research was to study the efficacy of endothelial progenitor cells (EPC) with beta tri-calcium phosphate (beta-TCP) and barrier in the treatment of experimental peri-implantitis. METHODS: Thirty implants were placed in five American foxhounds. Following osseointegration, ligature-induced peri-implantitis was initiated. EPC were isolated from peripheral blood. Two months later, open flap debridement was performed and implants' surface was decontaminated with 24% EDTA. The sites were grafted with beta-TCP and collagen membrane (beta-TCP group) or beta-TCP loaded with EPC and covered with membrane (EPC group) or left un-grafted (OFD group). At 3 months, animals were killed and specimens sent for histomorphometric and micro-CT analysis. Bone height and %BIC served as primary and secondary outcomes. RESULTS: EPC group showed shorter distance to first BIC (3.29 +/- 0.69 mm) compared to 4.2 +/- 0.92 mm (beta-TCP) and 3.82 +/- 0.73 mm (OFD). Mean histological BIC was 2-3 folds higher in the EPC group (17.65 +/- 3.3%) compared with OFD (7.55 +/- 2.24%, p = 0.01) and beta-TCP (5.68 +/- 2.91%, p = 0.05). BIC greater than 25% was found only in the EPC group. The distance between the implant shoulder to 1st BIC was 2.51 +/- 0.7 mm (lingual sites) compared to 3.64 +/- 0.8 mm for buccal sites (p < 0.0001). CONCLUSION: beta-TCP loaded with EPC and covered with a membrane-enhanced bone formation around previously contaminated dental implants in an experimental peri implantitis canine model. PMID- 26743565 TI - Rainbow trout (Oncorhynchus mykiss) muscle satellite cells are targets of salmonid alphavirus infection. AB - Sleeping disease in rainbow trout is characterized by an abnormal swimming behaviour of the fish which stay on their side at the bottom of the tanks. This sign is due to extensive necrosis and atrophy of red skeletal muscle induced by the sleeping disease virus (SDV), also called salmonid alphavirus 2. Infections of humans with arthritogenic alphaviruses, such as Chikungunya virus (CHIKV), are global causes of debilitating musculoskeletal diseases. The mechanisms by which the virus causes these pathologies are poorly understood due to the restrictive availability of animal models capable of reproducing the full spectrum of the disease. Nevertheless, it has been shown that CHIKV exhibits a particular tropism for muscle stem cells also known as satellite cells. Thus, SDV and its host constitute a relevant model to study in details the virus-induced muscle atrophy, the pathophysiological consequences of the infection of a particular cell-type in the skeletal muscle, and the regeneration of the muscle tissue in survivors together with the possible virus persistence. To study a putative SDV tropism for that particular cell type, we established an in vivo and ex vivo rainbow trout model of SDV-induced atrophy of the skeletal muscle. This experimental model allows reproducing the full panel of clinical signs observed during a natural infection since the transmission of the virus is arthropod-borne independent. The virus tropism in the muscle tissue was studied by immunohistochemistry together with the kinetics of the muscle atrophy, and the muscle regeneration post infection was observed. In parallel, an ex vivo model of SDV infection of rainbow trout satellite cells was developed and virus replication and persistence in that particular cell type was followed up to 73 days post-infection. These results constitute the first observation of a specific SDV tropism for the muscle satellite cells. PMID- 26743566 TI - Zebrafish scarb2a insertional mutant reveals a novel function for the Scarb2/Limp2 receptor in notochord development. AB - BACKGROUND: Scarb2 or Limp2 belong to a subfamily of Scavenger receptors described as lysosomal transmembrane glycosylated receptors, that are mutated in the human syndrome AMRF (action myoclonus-renal failure). The zebrafish insertional mutant scarb2a(hi1463Tg) has notochord defects, the notochord is a defining feature of chordates running along the center of the longitudinal axis and it is essential for forming the spinal column in all vertebrates. RESULTS: There are three paralogous scarb2 genes in zebrafish; scarb2a, scarb2b, and scarb2c. Both Scarb2a and Scarb2b proteins lack the classical di-leucine motif. We found that scarb2a(hi1463Tg) homozygous zebrafish embryos have a null mutation impairing vacuole formation in the notochord and simultaneously disrupting proper formation of the basement membrane resulting in its thickening at the ventral side of the notochord, which may be the cause for the anomalous upward bending observed in the trunk. Through whole-mount in situ hybridization, we detected scarb2a mRNA expression in the notochord and in the brain early in development. However, it is puzzling that scarb2a notochord mRNA expression is short-lived in the presumptive notochord and precedes the complete differentiation of the notochord. CONCLUSIONS: This work describes a novel function for the Scarb2 receptor as an essential glycoprotein for notochord development. PMID- 26743567 TI - The downregulation of SnoN expression in human renal proximal tubule epithelial cells under high-glucose conditions is mediated by an increase in Smurf2 expression through TGF-beta1 signaling. AB - Transforming growth factor (TGF)-beta1 is a profibrotic cytokine that plays a critical role in the progression of diabetic nephropathy (DN). Previous studies have demonstrated that the Smad transcriptional co-repressor, Ski-related novel protein N (SnoN), an antagonizer of TGF-beta1/Smad signaling, is downregulated in the kidneys of diabetic rats; however, the underlying molecular mechanisms remain elusive. In the present study, we demonstrated that the upregulation of Smad ubiquitination regulatory factor-2 (Smurf2), through TGF-beta1/Smad signaling, contributes to the downregulation of SnoN under high-glucose conditions in primary human renal proximal tubule epithelial cells (hRPTECs). The hRPTECs were cultured in high-glucose (30 mmol/l D-glucose) medium in the presence or absence of either the proteasome inhibitor, MG132, or the TGF-beta type I receptor kinase inhibitor, SB-431542. Small interfering RNA (siRNA) was used to silence Smurf2. The expression levels of SnoN, Smurf2, Smad2 and phosphorylated (p-)Smad2 were measured by western blot analysis and RT-qPCR. The protein levels of SnoN were markedly downregulated, while its mRNA levels were increased in the hRPTECs cultured under high-glucose conditions. The protein and mRNA levels of Smurf2 were significantly increased under high-glucose conditions. The knockdown of Smurf2 increased SnoN expression in the hRPTECs cultured in high-glucose medium. Moreover, MG132 partially inhibited SnoN degradation in the hRPTECs under high glucose conditions and SB-431542 decreased the phosphorylation of Smad2 and the expression of Smurf2 induced under high-glucose conditions. Taken together, the findings of this study demonstrate that the downregulation of SnoN expression in hRPTECs under high-glucose conditions is mediated by the increased expression of Smurf2 through the TGF-beta1/Smad signaling pathway. PMID- 26743568 TI - Clinical relevance of autophagic therapy in cancer: Investigating the current trends, challenges, and future prospects. AB - Oncophagy (cancer-related autophagy) has a complex dual character at different stages of tumor progression. It remains an important clinical problem to unravel the reasons that propel the shift in the role of oncophagy from tumor inhibition to a protective mechanism that shields full-blown malignancy. Most treatment strategies emphasize curbing protective oncophagy while triggering the oncophagy that is lethal to tumor cells. In this review, we focus on the trends in current therapeutics as well as various challenges in clinical trials to address the oncophagic dilemma and evaluate the potential of these developing therapies. A detailed analysis of the clinical and pre-clinical scenario of the anticancer medicines highlights the various inducers and inhibitors of autophagy. The ways in which tumor stage, the microenvironment and combination drug treatment continue to play an important tactical role are discussed. Moreover, autophagy targets also play a crucial role in developing the best possible solution to this oncophagy paradox. In this review, we provide a comprehensive update on the current clinical impact of autophagy-based cancer therapeutic drugs and try to lessen the gap between translational medicine and clinical science. PMID- 26743569 TI - Lanthanide doped Bi2O3 upconversion luminescence nanospheres for temperature sensing and optical imaging. AB - Water-soluble lanthanide (Ln(3+)) doped Bi2O3 nanospheres have been successfully prepared through a solid-state-chemistry thermal decomposition process. The nanospheres exhibit intense upconversion luminescence (UCL) by doping the Ln(3+) (Ln = Yb, Er/Ho/Tm) ions into the Bi2O3 host matrix under 980 nm excitation. The ratio of red/green emission of Bi2O3:Yb(3+)/Er(3+) nanospheres exhibits a significant change as the calcination temperature increases and the value could reach 105.6. Moreover, the UCL of Bi2O3:Yb(3+)/Tm(3+) nanospheres are temperature sensitive, where the intensity ratios of 799 and 808 nm emissions increase monotonously with temperature. The MTT assay reveals that Bi2O3:Yb(3+)/Tm(3+) nanospheres exhibit good biocompatibility by grafting citric acid molecules on the surface. The application possibility of Bi2O3:Yb(3+)/Tm(3+) nanospheres as bioprobes for optical imaging in vivo is also confirmed by the high-contrast photoluminescence images between the background and the UCL imaging area. PMID- 26743570 TI - Influence of different electrode belt positions on electrical impedance tomography imaging of regional ventilation: a prospective observational study. AB - BACKGROUND: Electrical impedance tomography (EIT) is a non-invasive bedside tool which allows an individualized ventilator strategy by monitoring tidal ventilation and lung aeration. EIT can be performed at different cranio-caudal thoracic levels, but data are missing about the optimal belt position. The main goal of this prospective observational study was to evaluate the impact of different electrode layers on tidal impedance variation in relation to global volume changes in order to propose a proper belt position for EIT measurements. METHODS: EIT measurements were performed in 15 mechanically ventilated intensive care patients with the electrode belt at different thoracic layers (L1-L7). All respiratory and hemodynamic parameters were recorded. Blood gas analyses were obtained once at the beginning of EIT examination. Off-line tidal impedance variation/tidal volume (TV/VT) ratio was calculated, and specific patterns of impedance distribution due to automatic and user-defined adjustment of the colour scale for EIT images were identified. RESULTS: TV/VT ratio is the highest at L1. It decreases in caudal direction. At L5, the decrease of TV/VT ratio is significant. We could identify patterns of diaphragmatic interference with ventilation-related impedance changes, which owing to the automatically adjusted colour scales are not obvious in the regularly displayed EIT images. CONCLUSIONS: The clinical usability and plausibility of EIT measurements depend on proper belt position, proper impedance visualisation, correct analysis and data interpretation. When EIT is used to estimate global parameters like VT or changes in end-expiratory lung volume, the best electrode plane is between the 4th and 5th intercostal space. The specific colour coding occasionally suppresses user relevant information, and manual rescaling of images is necessary to visualise this information. PMID- 26743571 TI - Live Eimeria vaccination success in the face of artificial non-uniform vaccine administration in conventionally reared pullets. AB - Live Eimeria vaccines against coccidiosis in poultry initiate immunity using a vaccine dose containing few oocysts; protection is enhanced through subsequent faecal-oral transmission ("cycling") of parasites in the poultry house. Spray administered Eimeria vaccines can permit wide variations in doses ingested by individual chicks; some chicks may receive no primary vaccination at all. Consequently, protective immunity for the entire flock depends on successful environmental cycling of vaccine progeny. Pullets missing primary vaccination at day of age can become protected from coccidial challenge through cycling of vaccine progeny oocysts from vaccinated (V) cage mates. This study tested whether 40% cage floor coverage (CFC) with a durable material could improve protection against challenge in these "contact-vaccinated" (CV) or successfully V pullets. The six treatment groups tested were CV, V or sham-vaccinated pullets cage-reared on either 0% or 40% CFC. Oocyst output was measured separately for each group for 30 days following vaccine administration. Lesion scores, body weights and total oocyst outputs were measured to quantify protection at 30 days of age against single or mixed Eimeria species challenge infections. Use of 40% CFC to promote low-level oocyst cycling impacted the flock in two ways: (1) more uniform flock immunity was achieved in the 40% CFC (CV similar to V pullets) compared with 0% CFC and (2) protection was enhanced in the 40% CFC compared with the 0% CFC. The use of CFC is an easily adopted means of improving live Eimeria vaccination of caged pullets. PMID- 26743573 TI - Making the Business Case for Coverage of Family-Based Behavioral Group Interventions for Pediatric Obesity. AB - BACKGROUND: Pediatric obesity presents a significant burden. However, family based behavioral group (FBBG) obesity interventions are largely uncovered by our health care system. The present study uses Return on Investment (ROI) and Internal Rate of Return (IRR) analyses to analyze the business side of FBBG interventions. METHODS: ROI and IRR were calculated to determine longitudinal cost-effectiveness of a FBBG intervention. Multiple simulations of cost savings are projected using three estimated trajectories of weight change and variations in assumptions. RESULTS: The baseline model of child savings gives an average IRR of 0.2% +/- 0.08% and an average ROI of 20.8% +/- 0.4%, which represents a break even IRR and a positive ROI. More pessimistic simulations result in negative IRR values. CONCLUSIONS: Under certain assumptions, FBBGs offer a break-even proposition. Results are limited by lack of data regarding several assumptions, and future research should evaluate changes in cost savings following changes in child and adult weight. PMID- 26743574 TI - A case report with Fitz-Hugh-Curtis syndrome, what does it mean? AB - Fitz-Hugh-Curtis (FHC) syndrome, also known as acute perihepatitis, was discovered in 1930 and is a rare disorder characterised by inflammation of the peritoneum and the tissues surrounding the liver. This syndrome can arise as a potential complication from a pelvic inflammatory disease caused by Neisseria gonorrhoeae or Chlamydia trachomatis. This syndrome is not well known in the medical community and is often underdiagnosed. In this case report, we revisit FHC syndrome, particularly its noninvasive diagnosis and complications. PMID- 26743572 TI - In situ genetic correction of F8 intron 22 inversion in hemophilia A patient specific iPSCs. AB - Nearly half of severe Hemophilia A (HA) cases are caused by F8 intron 22 inversion (Inv22). This 0.6-Mb inversion splits the 186-kb F8 into two parts with opposite transcription directions. The inverted 5' part (141 kb) preserves the first 22 exons that are driven by the intrinsic F8 promoter, leading to a truncated F8 transcript due to the lack of the last 627 bp coding sequence of exons 23-26. Here we describe an in situ genetic correction of Inv22 in patient specific induced pluripotent stem cells (iPSCs). By using TALENs, the 627 bp sequence plus a polyA signal was precisely targeted at the junction of exon 22 and intron 22 via homologous recombination (HR) with high targeting efficiencies of 62.5% and 52.9%. The gene-corrected iPSCs retained a normal karyotype following removal of drug selection cassette using a Cre-LoxP system. Importantly, both F8 transcription and FVIII secretion were rescued in the candidate cell types for HA gene therapy including endothelial cells (ECs) and mesenchymal stem cells (MSCs) derived from the gene-corrected iPSCs. This is the first report of an efficient in situ genetic correction of the large inversion mutation using a strategy of targeted gene addition. PMID- 26743575 TI - Cerebral vasculitis as a major manifestation of rheumatoid arthritis. AB - OBJECTIVE AND IMPORTANCE: Cerebral vasculitis (CV) is a rare described complication of rheumatoid arthritis (RA). Although the most frequent neurological manifestations of RA are peripheral neuropathy and cervical spinal cord compression due to subluxation of the cervical vertebrae, CV can be seen especially in patients with seropositive and long-standing RA. CLINICAL PRESENTATION: We report two cases of CV associated with RA. Both patients had no extraarticular manifestations and RA clinics were under control. Our first case is a 30-years-old woman with seropositive RA for 15 years who had suddenly onset left facial and upper extremity weakness. In magnetic resonance imaging (MRI) DWI, hyperintensity in frontotemporal region due to acute ischaemia was detected. The new lacuner acute ischaemic lesions in right precentral gyrus, bilateral frontoparietal and corpus callosal region were detected in the control MRI. The cerebral MR angiography and transcranial doppler findings were consistent with CV. The patient responded favourably to pulse methylprednisolone and oral azathiopurine treatments. The second patient is a 52-year-old man who had been RA for 29 years. He admitted to our neurology clinic with speech difficulty and right upper extremity minimal weakness. Magnetic resonance imaging DWI showed left parietooccipital acute ischaemia which was progressed within a week and a new right parietooccipital ischaemia was added. His cerebral MR angiography and cerebral angiography were concordant with CV. The cyclophosphamide therapy was started since the cerebral ischaemia was progressed during pulse methylprednisolone and he responded well to this therapy. CONCLUSION: CV due to RA is an uncommon serious complication which can be life-threatening. Therefore clinicians should be aware of the possibility of CV especially in progressive strokes in RA. PMID- 26743577 TI - Thermal exfoliation of stoichiometric single-layer silica from the stishovite phase: insight from first-principles calculations. AB - Mechanical cleavage, chemical intercalation and chemical vapor deposition are the main methods that are currently used to synthesize nanosheets or monolayers. Here, we propose a new strategy, thermal exfoliation for the fabrication of silica monolayers. Using a variety of state-of-the-art theoretical calculations we show that a stoichiometric single-layer silica with a tetragonal lattice, T silica, can be thermally exfoliated from the stishovite phase in a clean environment at room temperature. The resulting single-layer silica is dynamically, thermally, and mechanically stable with exceptional properties, including a large band gap of 7.2 eV, an unusual negative Poisson's ratio, a giant Stark effect, and a high breakdown voltage. Moreover, other analogous structures like single-layer GeO2 can also be obtained by thermal exfoliation of its bulk phase. Our findings are expected to motivate experimental efforts on developing new techniques for the synthesis of monolayer materials. PMID- 26743576 TI - Proximal ileitis secondary to anisakiasis. AB - Intestinal anisakiasis is a disease caused by human infection by Anisakis larva that can be found in undercooked fish that is increasing worldwide. The symptoms, typically abdominal pain, develop within 5-7 days after the fish intake. The diagnosis may be suspected based on common anamnesis (unfrozen fish intake) with abdominal pain or bowel obstruction and confirmed by blood serology. Resective surgery is only used in severe cases. PMID- 26743579 TI - Adapting to Adaptations: Behavioural Strategies that are Robust to Mutations and Other Organisational-Transformations. AB - Genetic mutations, infection by parasites or symbionts, and other events can transform the way that an organism's internal state changes in response to a given environment. We use a minimalistic computational model to support an argument that by behaving "interoceptively," i.e. responding to internal state rather than to the environment, organisms can be robust to these organisational transformations. We suggest that the robustness of interoceptive behaviour is due, in part, to the asymmetrical relationship between an organism and its environment, where the latter more substantially influences the former than vice versa. This relationship means that interoceptive behaviour can respond to the environment, the internal state and the interaction between the two, while exteroceptive behaviour can only respond to the environment. We discuss the possibilities that (i) interoceptive behaviour may play an important role of facilitating adaptive evolution (especially in the early evolution of primitive life) and (ii) interoceptive mechanisms could prove useful in efforts to create more robust synthetic life-forms. PMID- 26743578 TI - Hippocampal Transcriptome Profile of Persistent Memory Rescue in a Mouse Model of THRA1 Mutation-Mediated Resistance to Thyroid Hormone. AB - Hypothyroidism due to THRA1 (gene coding for thyroid hormone receptor alpha1) mutation-mediated Resistance to Thyroid Hormone (RTH) has been recently reported in human and is associated with memory deficits similar to those found in a mouse model for Thra1 mutation mediated RTH (Thra1(+/m) mice). Here, we show that a short-term treatment of Thra1(+/m) mice with GABAA receptor antagonist pentylenetetrazol (PTZ) completely and durably rescues their memory performance. In the CA1 region of the hippocampus, improvement of memory is associated with increased in long-term potentiation (LTP) and an augmentation of density of dendritic spines (DDS) onto the apical dendrites of pyramidal cells reflecting an increase in the local excitatory drive. Unbiased gene profiling analysis of hippocampi of treated Thra1(+/+) and Thra1(+/m) mice were performed two weeks and three months post treatment and identified co-expression modules that include differentially expressed genes related with and predicting higher memory, LTP and DDS in the hippocampi of PTZ-treated animals. We observed that PTZ treatment changed similar sets of genes in both Thra1(+/+) and Thra1(+/m) mice, which are known to be involved in memory consolidation and neurotransmission dynamics and could participate in the persistent effects of PTZ on memory recovery. PMID- 26743581 TI - Short- and Long-Term Tracking of Anionic Ultrasmall Nanoparticles in Kidney. AB - While biodistribution of nanoparticles (NPs) has been widely studied at the organ level, relatively little is known about their disposition in organs at the cellular level, especially after long-term exposure. The kidney is regarded as the key organ for the clearance of ultrasmall NPs (<5.5 nm). However, recent studies indicate that NPs in this size range could accumulate in the kidney for extended times without urinary excretion. Using negatively charged quantum dots (QDs) (~3.7 nm) as a model system, we examined the suborgan disposition of anionic ultrasmall NPs in the kidney at the cellular level after intravenous injection by multiphoton microscopy coupled with fluorescence lifetime imaging. Most of the NPs were initially distributed in the peritubular capillaries or glomerular arterioles after injection, whereas they passed through the fenestrated glomerular endothelium and were gradually taken up by mesangial cells up to 30 days after injection. Only trace amounts of anionic QDs could be detected in the urine, which could be attributed to the barrier of the anionic glomerular basement membrane preventing filtration of anionic QDs. In contrast, cationic QDs of similar size (~5.67 nm) were found to be readily excreted into urine. This study thus highlights the importance of surface charge in determining renal clearance of ultrasmall NPs. It provides a framework for characterizing and predicting the subcellular disposition in organs and long-term targeting of other NPs, with a physiologically based kinetic model being subsequently developed to describe the suborgan kinetics of anionic ultrasmall NPs. PMID- 26743580 TI - E6 proteins from low-risk human papillomavirus types 6 and 11 are able to protect keratinocytes from apoptosis via Bak degradation. AB - Infection of epithelial surfaces with low-risk human papillomavirus (HPV) types 6 and 11 causes troublesome clinical diseases, such as recurrent respiratory papillomatosis, that carry a significant cost burden to the healthcare system. Despite this, less has been studied at the molecular level for the low-risk HPV types when compared with their high-risk counterparts. Recent studies have shown the ability of the HPV E6 protein to degrade the pro-apoptotic family member Bak in high-risk and betapapillomavirus HPV types, which confers a cytoprotective advantage on E6-expressing cells. It is unknown whether low-risk E6 expression disrupts the apoptosis pathway and confers a cytoprotective advantage as a result of Bak degradation. We tested the abilities of 6E6 and 11E6 to degrade Bak and protect keratinocytes from UV-initiated apoptosis. Both low-risk 6E6 and 11E6 proteins were able to degrade activated Bak following UV treatment of keratinocytes. The degradation of Bak in 6E6- and 11E6-expressing cells occurred through the proteasomal pathway, and protected them from apoptosis, specifically through the intrinsic pathway to the same extent as their high-risk HPV16 E6 counterpart. In conclusion, we have found a new, critical and conserved function of low-risk HPV E6 proteins, i.e. the ability to degrade Bak, which gives them a cytoprotective advantage over normal, uninfected cells by specifically disrupting the intrinsic pathway of apoptosis. PMID- 26743582 TI - Novel Conserved-region T-cell Mosaic Vaccine With High Global HIV-1 Coverage Is Recognized by Protective Responses in Untreated Infection. AB - An effective human immunodeficiency virus type 1 (HIV-1) vaccine is the best solution for halting the acquired immune deficiency syndrome epidemic. Here, we describe the design and preclinical immunogenicity of T-cell vaccine expressing novel immunogens tHIVconsvX, vectored by DNA, simian (chimpanzee) adenovirus, and poxvirus modified vaccinia virus Ankara (MVA), a combination highly immunogenic in humans. The tHIVconsvX immunogens combine the three leading strategies for elicitation of effective CD8(+) T cells: use of regions of HIV-1 proteins functionally conserved across all M group viruses (to make HIV-1 escape costly on viral fitness), inclusion of bivalent complementary mosaic immunogens (to maximize global epitope matching and breadth of responses, and block common escape paths), and inclusion of epitopes known to be associated with low viral load in infected untreated people (to induce field-proven protective responses). tHIVconsvX was highly immunogenic in two strains of mice. Furthermore, the magnitude and breadth of CD8(+) T-cell responses to tHIVconsvX-derived peptides in treatment-naive HIV-1(+) patients significantly correlated with high CD4(+) T cell count and low viral load. Overall, the tHIVconsvX design, combining the mosaic and conserved-region approaches, provides an indisputably better coverage of global HIV-1 variants than previous T-cell vaccines. These immunogens delivered in a highly immunogenic framework of adenovirus prime and MVA boost are ready for clinical development. PMID- 26743583 TI - Runx2-Modified Adipose-Derived Stem Cells Promote Tendon Graft Integration in Anterior Cruciate Ligament Reconstruction. AB - Runx2 is a powerful osteo-inductive factor and adipose-derived stem cells (ADSCs) are multipotent. However, it is unknown whether Runx2-overexpressing ADSCs (Runx2 ADSCs) could promote anterior cruciate ligament (ACL) reconstruction. We evaluated the effect of Runx2-ADSCs on ACL reconstruction in vitro and in vivo. mRNA expressions of osteocalcin (OCN), bone sialoprotein (BSP) and collagen I (COLI) increased over time in Runx2-ADSCs. Runx2 overexpression inhibited LPL and PPARgamma mRNA expressions. Runx2 induced alkaline phosphatase activity markedly. In nude mice injected with Runx2-ADSCs, promoted bone formation was detected by X rays 8 weeks after injection. The healing of tendon-to-bone in a rabbit model of ACL reconstruction treated with Runx2-ADSCs, fibrin glue only and an RNAi targeting Runx2, was evaluated with CT 3D reconstruction, histological analysis and biomechanical methods. CT showed a greater degree of new bone formation around the bone tunnel in the group treated with Runx2-ADSCs compared with the fibrin glue group and RNAi Runx2 group. Histology showed that treatment with Runx2-ADSCs led to a rapid and significant increase at the tendon-to-bone compared with the control groups. Biomechanical tests demonstrated higher tendon pullout strength in the Runx2-ADSCs group at early time points. The healing of the attachment in ACL reconstruction was enhanced by Runx2-ADSCs. PMID- 26743584 TI - LIN28B: an orchestrator of oncogenic signaling in neuroblastoma. PMID- 26743585 TI - Elevated CO2 impacts bell pepper growth with consequences to Myzus persicae life history, feeding behaviour and virus transmission ability. AB - Increasing atmospheric carbon dioxide (CO2) impacts plant growth and metabolism. Indirectly, the performance and feeding of insects is affected by plant nutritional quality and resistance traits. Life history and feeding behaviour of Myzus persicae were studied on pepper plants under ambient (aCO2, 400 ppm) or elevated CO2 (eCO2, 650 ppm), as well as the direct impact on plant growth and leaf chemistry. Plant parameters were significantly altered by eCO2 with a negative impact on aphid's life history. Their pre-reproductive period was 11% longer and fecundity decreased by 37%. Peppers fixed significantly less nitrogen, which explains the poor aphid performance. Plants were taller and had higher biomass and canopy temperature. There was decreased aphid salivation into sieve elements, but no differences in phloem ingestion, indicating that the diminished fitness could be due to poorer tissue quality and unfavourable C:N balance, and that eCO2 was not a factor impeding feeding. Aphid ability to transmit Cucumber mosaic virus (CMV) was studied by exposing source and receptor plants to ambient (427 ppm) or elevated (612 ppm) CO2 before or after virus inoculation. A two-fold decrease on transmission was observed when receptor plants were exposed to eCO2 before aphid inoculation when compared to aCO2. PMID- 26743586 TI - Decision-making processes as predictors of relapse and subsequent use in stimulant-dependent patients. AB - BACKGROUND: Decision-making processes have been posited to affect treatment outcome in addicted patients. OBJECTIVE: The present multi-site study assessed whether two measures of decision-making predicted relapse and subsequent use in stimulant-dependent patients. METHODS: A total of 160 methamphetamine- or cocaine dependent patients participating in a multi-site clinical trial evaluating a modified 12-step facilitation intervention for stimulant-dependent patients (STAGE-12) were assessed. Decision-making processes of risk and delay (Iowa Gambling Task [IGT]) and response reversal (Wisconsin Card Sorting Task [WCST]) were obtained shortly after treatment admission followed by assessment of stimulant use over the next six months. The relationships of the IGT and WCST (Perseverative Errors) with relapse (yes/no) and days of stimulant use during the 6-month period following post-randomization were evaluated. RESULTS: Performance on the IGT and WCST did not significantly predict relapse status or time to relapse. Unexpectedly, worse performance on the IGT was associated with a fewer number of stimulant use days (p = 0.001). In contrast, worse performance on the WCST (more perseverative errors) was associated with a greater number of stimulant use days (p = 0.0003). The predictive effects of perseverative errors on subsequent use were confined to methamphetamine-dependent and Minority participants. CONCLUSIONS: Decision-making processes, as measured in the current study, do not uniformly predict relapse or subsequent use. A decrease in the salience attribution of non-drug reinforcers may explain the positive relationship between IGT performance and post-relapse use. More comprehensive and global measures of impulsiveness may better assess relapse risk and use. PMID- 26743587 TI - Estimated cardiovascular relative risk reduction from fixed-dose combination pill (polypill) treatment in a wide range of patients with a moderate risk of cardiovascular disease. AB - AIMS: Recent data indicate that fixed-dose combination (FDC) pills, polypills, can produce sizeable risk factor reductions. There are very few published data on the consistency of the effects of a polypill in different patient populations. It is unclear for example whether the effects of the polypill are mainly driven by the individuals with high individual risk factor levels. The aim of the present study is to examine whether baseline risk factor levels modify the effect of polypill treatment on low-density lipoprotein (LDL)-cholesterol, blood pressure (BP), calculated cardiovascular relative risk reduction and adverse events. METHODS: This paper describes a post-hoc analysis of a randomised, placebo controlled trial of a polypill (containing aspirin 75 mg, simvastatin 20 mg, lisinopril 10 mg and hydrochlorothiazide 12.5 mg) in 378 individuals without an indication for any component of the polypill, but who had an estimated five-year risk for cardiovascular disease >=7.5%. The outcomes considered were effect modification by baseline risk factor levels on change in LDL-cholesterol, systolic BP, calculated cardiovascular relative risk reduction and adverse events. RESULTS: The mean LDL-cholesterol in the polypill group was 0.9 mmol/l (95% confidence interval (CI): 0.8-1.0) lower compared with the placebo group during follow-up. Those with a baseline LDL-cholesterol >3.6 mmol/l achieved a greater absolute LDL-cholesterol reduction with the polypill compared with placebo, than patients with an LDL-cholesterol <=3.6 mmol/l (-1.1 versus -0.6 mmol/l, respectively). The mean systolic BP was 10 mm Hg (95% CI: 8-12) lower in the polypill group. In participants with a baseline systolic BP >135 mm Hg the polypill resulted in a greater absolute systolic BP reduction with the polypill compared with placebo, than participants with a systolic BP <= 135 mm Hg (-12 versus -7 mm Hg, respectively). Calculated from individual risk factor reductions, the mean cardiovascular relative risk reduction was 48% (95% CI: 43 52) in the polypill group. Both baseline LDL-cholesterol and estimated cardiovascular risk were significant modifiers of the estimated cardiovascular relative risk reduction caused by the polypill. Adverse events did not appear to be related to baseline risk factor levels or the estimated cardiovascular risk. CONCLUSION: This study demonstrated that the effect of a cardiovascular polypill on risk factor levels is modified by the level of these risk factors. Groups defined by baseline LDL-cholesterol or systolic BP had large differences in risk factor reductions but only moderate differences in estimated cardiovascular relative risk reduction, suggesting also that patients with mildly increased risk factor levels but an overall raised cardiovascular risk benefit from being treated with a polypill. PMID- 26743588 TI - Could the two-minute step test be an alternative to the six-minute walk test for patients with systolic heart failure? AB - BACKGROUND: The consequence of exercise intolerance for patients with heart failure is the difficulty climbing stairs. The two-minute step test is a test that reflects the activity of climbing stairs. DESIGN: The aim of the study design is to evaluate the applicability of the two-minute step test in an assessment of exercise tolerance in patients with heart failure and the association between the six-minute walk test and the two-minute step test. METHODS: Participants in this study were 168 men with systolic heart failure (New York Heart Association (NYHA) class I-IV). In the study we used the two-minute step test, the six-minute walk test, the cardiopulmonary exercise test and isometric dynamometer armchair. RESULTS: Patients who performed more steps during the two-minute step test covered a longer distance during the six-minute walk test (r = 0.45). The quadriceps strength was correlated with the two-minute step test and the six-minute walk test (r = 0.61 and r = 0.48). The greater number of steps performed during the two-minute step test was associated with higher values of peak oxygen consumption (r = 0.33), ventilatory response to exercise slope (r = -0.17) and longer time of exercise during the cardiopulmonary exercise test (r = 0.34). Fatigue and leg fatigue were greater after the two-minute step test than the six-minute walk test whereas dyspnoea and blood pressure responses were similar. CONCLUSION: The two-minute step test is well tolerated by patients with heart failure and may thus be considered as an alternative for the six-minute walk test. PMID- 26743589 TI - Time-dependent depletion of nitrite in pork/beef and chicken meat products and its effect on nitrite intake estimation. AB - The food additive nitrite (E249, E250) is commonly used in meat curing as a food preservation method. Because of potential negative health effects of nitrite, its use is strictly regulated. In an earlier study we have shown that the calculated intake of nitrite in children can exceed the acceptable daily intake (ADI) when conversion from dietary nitrate to nitrite is included. This study examined time dependent changes in nitrite levels in four Swedish meat products frequently eaten by children: pork/beef sausage, liver pate and two types of chicken sausage, and how the production process, storage and also boiling (e.g., simmering in salted water) and frying affect the initial added nitrite level. The results showed a steep decrease in nitrite level between the point of addition to the product and the first sampling of the product 24 h later. After this time, residual nitrite levels continued to decrease, but much more slowly, until the recommended use-by date. Interestingly, this continuing decrease in nitrite was much smaller in the chicken products than in the pork/beef products. In a pilot study on pork/beef sausage, we found no effects of boiling on residual nitrite levels, but frying decreased nitrite levels by 50%. In scenarios of time dependent depletion of nitrite using the data obtained for sausages to represent all cured meat products and including conversion from dietary nitrate, calculated nitrite intake in 4-year-old children generally exceeded the ADI. Moreover, the actual intake of nitrite from cured meat is dependent on the type of meat source, with a higher residual nitrite levels in chicken products compared with pork/beef products. This may result in increased nitrite exposure among consumers shifting their consumption pattern of processed meats from red to white meat products. PMID- 26743591 TI - Base-Promoted Formal [4 + 3] Annulation between 2-Fluorophenylacetylenes and Ketones: A Route to Benzoxepines. AB - The first base-promoted formal [4 + 3] annulation between 2 fluorophenylacetylenes and ketones has been disclosed. The reaction proceeds through a tandem alpha-vinylation of ketones followed by an intramolecular nucleophilic aromatic substitution (SNAr) reaction of the in situ generated beta,gamma-unsaturated ketone intermediates, providing a straightforward access to a wide range of functionalized benzoxepines in moderate to high yields. The transition-metal-free methodology featured a wide substrate scope, the use of easily available starting materials, and a high functional group tolerance. PMID- 26743590 TI - Violence victimisation-a watershed for young women's mental and physical health. AB - PURPOSE: The association between victimisation and adverse health in children is well established but few studies have addressed the effect of victimisation, especially multiple victimisations, in older adolescents and young adults. The aim of this study was to assess self-reported health in young women (15-22 years) victimised to one or more types of violence, compared with non-victimised. METHODS: Young women visiting youth health centres in Sweden answered a questionnaire constructed from standardised instruments addressing violence victimisation (emotional, physical, sexual and family violence), socio demographics, substance use and physical and mental health. Adjusted odds ratio (AOR) with 95% confidence interval (CI) and attributable risk (AR) were assessed. RESULTS: Of 1051 women (73% of eligible women), 25% were lifetime victims of one type of violence and 31% of two or more types of violence. Sexual-minority young women were more victimised than heterosexual women. Violence victimisation increased the risk for adverse health outcomes, especially evident for those multiply victimised. Victims of two or more types of violence had AOR 11.8 (CI 6.9-20.1) for post-traumatic stress symptoms, 6.3 (CI 3.9-10.2) for anxiety symptoms and 10.8 (CI 5.2-22.5) for suicide ideation. The AR of victimisation accounted for 41% of post-traumatic stress symptoms, 30% of anxiety symptoms and 27% of suicide ideation. Stratified analyses showed that lower economic resources did not influence health negatively for non-victimised, whereas it multiplicatively reinforced ill-health when combined with violence victimisation. CONCLUSION: Violence victimisation, and particularly multiple victimisations, was strongly associated with mental ill-health in young women, especially evident in those with low economic resources. PMID- 26743593 TI - Predictors of prostate cancer in ultrasound-guided transperineal saturation biopsy in Turkish men with multiple prior negative biopsies. AB - BACKGROUND: Transperineal prostate biopsy (STPB) is associated with an improved cancer detection rate and an increase in anterior and apical prostate cancers compared to standard transrectal biopsy. PATIENTS AND METHODS: A total of 48 men with at least two sets of prior prostate biopsies underwent transrectal ultrasound-guided STPB. Prostate rebiopsy indications were serum prostate specific antigen (PSA) levels greater than 2.5 ng/mL and/or abnormal digital rectal examination and/or presence of high-grade prostatic intraepithelial neoplasia (HGPIN; >=2 cores) or atypical small acinar proliferation (ASAP) at previous biopsies. The procedure was performed at dorsal lithotomy position under general anesthesia using a perineal 0.5 cm brachytherapy template attached to the transrectal ultrasound probe. Specimens from each zone were sent separately for pathological examination. RESULTS: Mean PSA level at STPB was 15.9 ng/mL (range 4.03 to 59.57). An average of 54.5 cores was obtained. Prostate adenocarcinoma was detected in 15 of 48 (31%) patients. Mean percentage of malignant cores was 11.9%. Multivariate logistic regression analysis revealed that age and presence of ASAP or HGPIN at previous biopsies were independent predictors of prostate cancer (p<0.05). No major complications, including sepsis and severe urinary or rectal bleeding, were observed in any of the patients. Five patients (10%) developed acute urinary retention after the procedure requiring urethral catheterization. CONCLUSIONS: Considerable number of patients with negative multiple biopsies were diagnosed with prostate cancer. STPB is a well-tolerated procedure with minimal morbidity, which can be considered for the diagnosis of prostate cancer in patients with previous negative biopsies. PMID- 26743594 TI - Changes in Synapsin Levels in the Millipede Gymnostreptus olivaceus Schubart, 1944 Exposed to Different Concentrations of Deltamethrin. AB - Millipedes are ecologically important soil organisms and may also be an economically threatening species in rural and urban areas when population outbreaks occur. In order to control infestations commercial formulations of deltamethrin have been commonly applied, even though there are few studies about the effects of such insecticide on millipedes. This paper describes the effects of this insecticide on millipedes showing neurotoxic effects assessed by synapsin labeling and confocal microscopy. Deltamethrin concentrations related to the DL50 of the active ingredient and a field concentration were applied topically in the diplopod Gymnostreptus olivaceus to evaluate the behavior, mortality rate, and synapsin levels in the brain 12, 24, and 48h after contact with deltamethin. The insecticide caused mortality at the higher concentrations employed, in which no change was observed in neurotransmission in the survivors. In contrast, at field concentrations, deltamethrin did not cause any deaths, but triggered significant changes in synapsin levels. The results obtained form the synapsin labeling provide several interpretations suggesting that the isolated application of this tool must be associated with additional tools in order to evaluate biologically induced effects of deltamethrin in an accurate way. In addition, the feasibility of chemical control of millipedes with deltamethrin is questioned. PMID- 26743595 TI - A cross-sectional study of the impact of regular use of insecticides in dogs on Canine Leishmaniosis seroprevalence in southeast Spain. AB - The relationship between Canine Leishmaniosis (CanL) seroprevalence and regular use of topical insecticides was investigated in 800 pet dogs with no visible signs of CanL in Murcia, southeast Spain in 2011. Dogs were clients to 17 veterinary practices and were analyzed for Leishmania infantum antibodies in blood plasma using two commercial ELISAs (Ingezim, Ingenasa(r), Spain; Leishcan, Hipra(r), Spain). Owners were interviewed to gather data on dog related variables. They included date of birth, home address and frequency, duration and timing of insecticide treatments used to prevent ectoparasite infestations. The dog's residence was georeferenced and environmental data potentially associated with the dog's risk of L. infantum infection was obtained. A mixed logistic regression model was then developed to analyze the relationship between the dog's serological status and insecticidal treatment adjusted for demographic and environmental variables. Overall, CanL seroprevalence (95% confidence limits) was 18% (16-21%) including 11% in dogs not using insecticide treatments (n=60) and 19% in those using them (n=740) (p>0.05). At least 16 different insecticide products were used and 73%, 26% and 1% of dogs received 1, 2 and 3 products a year. The most frequent commercial brands used and the only ones in the market claiming anti-sandfly activity, were Scalibor collars (deltametrin 40mg/g; MSD(r)), Advantix pipettes (permethrin 500mg/ml and imidacloprid 100mg/ml; Bayer(r)) and Exspot spot-on pipettes (permethrin 715mg/ml; MSD(r)). Seroprevalence was 9%, 16%, 20%, 22% and 25% for dogs with Scalibor collars plus Advantix pipettes, Scalibor collars plus ExSpot pipettes, Advantix pipettes alone, Scalibor collars alone and Exspot pipettes alone, respectively. The multivariable model confirmed a significant reduction in the risk of Leishmania spp. seropositivity in dogs using the Scalibor and Advantix combination compared to those using either product alone and provided evidence of greatly increased risk of CanL in rural areas situated at 300-500m altitude and average March-July temperatures of 18.6-19 degrees C. The study highlights the difficulty in controlling CanL infection by means of insecticide use alone and that it could be improved by using the Scalibor and Advantix combination and identifying and targeting specific geographical areas. PMID- 26743596 TI - In silico methods to address polypharmacology: current status, applications and future perspectives. AB - Polypharmacology, a new paradigm in drug discovery that focuses on multi-target drugs (MTDs), has potential application for drug repurposing, the process of finding new uses for existing approved drugs, prediction of off-target toxicities and rational design of MTDs. In this scenario, computational strategies have demonstrated great potential in predicting polypharmacology and in facilitating drug repurposing. Here, we provide a comprehensive overview of various computational approaches that enable the prediction and analysis of in vitro and in vivo drug-response phenotypes and outline their potential for drug discovery. We give an outlook on the latest advances in rational design of MTDs and discuss possible future directions of algorithm development in this field. PMID- 26743597 TI - Open innovation in early drug discovery: roadmaps and roadblocks. AB - Open innovation in pharmaceutical R&D evolved from a triple helix of convergent paradigm shifts in academic, industrial and government research sectors. The birth of the biotechnology sector catalyzed shifts in location dynamics that led to the first wave of open innovation in pharmaceutical R&D between big pharma and startup companies. The National Institutes of Health (NIH) Roadmap was a crucial inflection point that set the stage for a new wave of open innovation models between pharmaceutical companies and universities that have the potential to transform the pharmaceutical R&D landscape. We highlight the attributes of leading protected open innovation models that foster the sharing of proprietary small molecule collections by lowering the risk of premature escape of intellectual property, particularly structure-activity data. PMID- 26743592 TI - IL-7 signalling represses Bcl-6 and the TFH gene program. AB - The transcriptional repressor Bcl-6 is linked to the development of both CD4(+) T follicular helper (TFH) and central memory T (TCM) cells. Here, we demonstrate that in response to decreased IL-2 signalling, T helper 1 (TH1) cells upregulate Bcl-6 and co-initiate TFH- and TCM-like gene programs, including expression of the cytokine receptors IL-6Ralpha and IL-7R. Exposure of this potentially bi potent cell population to IL-6 favours the TFH gene program, whereas IL-7 signalling represses TFH-associated genes including Bcl6 and Cxcr5, but not the TCM-related genes Klf2 and Sell. Mechanistically, IL-7-dependent activation of STAT5 contributes to Bcl-6 repression. Importantly, antigen-specific IL 6Ralpha(+)IL-7R(+) CD4(+) T cells emerge from the effector population at late time points post influenza infection. These data support a novel role for IL-7 in the repression of the TFH gene program and evoke a divergent regulatory mechanism by which post-effector TH1 cells may contribute to long-term cell-mediated and humoral immunity. PMID- 26743599 TI - A Distinct Genotype of XP Complementation Group A: Surprisingly Mild Phenotype Highly Prevalent in Northern India/Pakistan/Afghanistan. PMID- 26743598 TI - Pro-Proliferative Function of Mitochondrial Sirtuin Deacetylase SIRT3 in Human Melanoma. AB - Melanoma, the most aggressive form of skin cancer, is often fatal if not treated early. Therefore, novel target-based strategies are required to combat this neoplasm. The objective of this study was to determine the role and functional significance of the mitochondrial sirtuin 3 (SIRT3) in melanoma. We found that compared with normal primary and immortalized human melanocytes, SIRT3 is significantly overexpressed in multiple human melanoma cells at mRNA and protein levels. Further, employing human tissue microarray, we found that SIRT3 is significantly upregulated in clinical melanoma tissues, compared with melanocytic nevi tissues. Furthermore, a short hairpin RNA-mediated knockdown of SIRT3 in human melanoma cells resulted in (i) a decrease in cellular proliferation, colony formation, and cellular migration; (ii) induction of senescence as shown by an increase in senescence-associated beta-galactosidase activity and formation of senescence-associated heterochromatin foci as well as an increase in mRNA and protein levels of p16(INK4a) and p21(Waf1); (iii) G1-phase arrest of the cell cycle; and (iv) decreases in mRNA and protein levels of cyclins (D1, E1) and cyclin-dependent kinases (2, 4, and 6). Conversely, forced exogenous overexpression of SIRT3 promoted an increase in proliferative potential of Hs294T melanoma cells and normal immortalized Mel-ST melanocytes. Finally, we found that SIRT3 knockdown significantly inhibited tumorigenesis in a xenograft model in vivo. To our knowledge, this is the first study supporting the pro-proliferative function of SIRT3 in melanoma. PMID- 26743600 TI - The Antifibrotic Effect of alpha2AP Neutralization in Systemic Sclerosis Dermal Fibroblasts and Mouse Models of Systemic Sclerosis. AB - Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by the fibrosis of skin and visceral organs, and peripheral circulatory disturbance. We recently demonstrated that alpha2-antiplasmin (alpha2AP), which is the physiological inhibitor of plasmin, is associated with the development of fibrosis. The aim of this study was to clarify the role of alpha2AP in the pathogenesis of SSc. The administration of alpha2AP in mice induced profibrotic changes, such as increased dermal thickness, collagen production, and myofibroblast differentiation. Conversely, the alpha2AP neutralization prevented not only profibrotic changes, but also the production of autoantibodies in bleomycin-induced mouse models of SSc. The expression of alpha2AP was elevated in dermal fibroblasts obtained from patients with SSc. Furthermore, alpha2AP treatment promoted profibrotic changes in human normal dermal fibroblasts, and alpha2AP neutralization reversed a profibrotic phenotype of SSc dermal fibroblasts, in the absence of plasmin. Our findings demonstrated that alpha2AP has a profibrotic effect probably not by the action as a plasmin inhibitor, and that the blocking of alpha2AP exerts an antifibrotic effect in humans and mice with SSc. PMID- 26743601 TI - Bacterial Sepsis Increases Survival in Metastatic Melanoma: Chlamydophila Pneumoniae Induces Macrophage Polarization and Tumor Regression. PMID- 26743602 TI - The p.Glu477Lys Mutation in Keratin 5 Is Strongly Associated with Mortality in Generalized Severe Epidermolysis Bullosa Simplex. PMID- 26743603 TI - Structural and Functional Analysis of Intact Hair Follicles and Pilosebaceous Units by Volumetric Multispectral Optoacoustic Tomography. AB - Visualizing anatomical and functional features of hair follicle development in their unperturbed environment is key in understanding complex mechanisms of hair pathophysiology and in discovery of novel therapies. Of particular interest is in vivo visualization of the intact pilosebaceous unit, vascularization of the hair bulb, and evaluation of the hair cycle, particularly in humans. Furthermore, noninvasive visualization of the sebaceous glands could offer crucial insight into the pathophysiology of follicle-related diseases and dry or seborrheic skin, in particular by combining in vivo imaging with other phenotyping, genotyping, and microbial analyses. The available imaging techniques are limited in their ability for deep tissue in vivo imaging of hair follicles and lipid-rich sebaceous glands in their entirety without biopsy. We developed a noninvasive, painless, and risk-free volumetric multispectral optoacoustic tomography method for deep tissue three-dimensional visualization of whole hair follicles and surrounding structures with high spatial resolution below 80 MUm. Herein we demonstrate on-the-fly assessment of key morphometric parameters of follicles and lipid content as well as functional oxygenation parameters of the associated capillary bed. The ease of handheld operation and versatility of the newly developed approach poise it as an indispensable tool for early diagnosis of disorders of the pilosebaceous unit and surrounding structures, and for monitoring the efficacy of cosmetic and therapeutic interventions. PMID- 26743604 TI - Epigenome-Wide Association Analysis Identified Nine Skin DNA Methylation Loci for Psoriasis. AB - Psoriasis is a chronic hyperproliferative and inflammatory skin disease caused by the interplay of genetic and environmental factors. DNA methylation has been linked to psoriasis, but the manner in which this process contributes to the disease is not fully understood. In this study, we carried out a three-stage epigenome-wide association study to identify disease-associated differentially methylated sites using a combination of 262 skin and 48 peripheral blood mononuclear cell samples. We not only revealed genome-wide methylation patterns for psoriasis but also identified strong associations between the skin-specific DNA methylation of nine disease-associated differentially methylated sites and psoriasis (Wilcoxon ranked PBonferroni < 0.01; methylation level difference > 0.10). Further analysis revealed that these nine disease-associated differentially methylated sites were not significantly affected by genetic variations, supporting their remarkable contributions to disease status. The expression of CYP2S1, ECE1, EIF2C2, MAN1C1, and DLGAP4 was negatively correlated with DNA methylation. These findings will help us to better understand the molecular mechanism of psoriasis. PMID- 26743605 TI - Genome-Wide Pathway Analysis Identifies Genetic Pathways Associated with Psoriasis. AB - Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the psoriasis heritability is only partially explained. However, there is increasing evidence that the missing heritability in psoriasis could be explained by multiple genetic variants of low effect size from common genetic pathways. The objective of this study was to identify new genetic variation associated with psoriasis risk at the pathway level. We genotyped 598,258 single nucleotide polymorphisms in a discovery cohort of 2,281 case-control individuals from Spain. We performed a genome-wide pathway analysis using 1,053 reference biological pathways. A total of 14 genetic pathways (PFDR <= 2.55 * 10(-2)) were found to be significantly associated with psoriasis risk. Using an independent validation cohort of 7,353 individuals from the UK, a total of 6 genetic pathways were significantly replicated (PFDR <= 3.46 * 10(-2)). We found genetic pathways that had not been previously associated with psoriasis risk such as retinol metabolism (Pcombined = 1.84 * 10(-4)), the transport of inorganic ions and amino acids (Pcombined = 1.57 * 10(-7)), and post-translational protein modification (Pcombined = 1.57 * 10(-7)). In the latter pathway, MGAT5 showed a strong network centrality, and its association with psoriasis risk was further validated in an additional case-control cohort of 3,429 individuals (P < 0.05). These findings provide insights into the biological mechanisms associated with psoriasis susceptibility. PMID- 26743606 TI - Persistent Vocal Fold Granuloma Following Superficial PAAG Injection Laryngoplasty: A Case Report. AB - The injection material polyacrylamide hydrogel (PAAG; Ferrosan, Soborg, Denmark) is often used as space filler for soft-tissue defects. PAAG is a suitable alternative to the materials used for injection laryngoplasty. Over the past decade, 427 patients have undergone injection laryngoplasty in our clinic using PAAG, and no major complications, such as material migration or foreign body granuloma, were identified. Here, we report the case of the first woman to undergo laryngomicrosurgery to remove a vocal fold granuloma that developed after a superficial injection laryngoplasty performed 4 years previously. PMID- 26743607 TI - Metastatic Cancer to the Larynx: A Case Report and Update. AB - OBJECTIVE: The aim of this study was to describe a case of colorectal carcinoma metastatic to the larynx and provide a review of the current literature. METHODS: A case report with chart review was performed. A review of the current literature was performed by systematically searching PubMed, OVID, CINAHL Plus, and EMBASE. RESULTS: In 1988, a comprehensive literature review identified melanoma as the most common neoplasm to exhibit laryngeal involvement. Since that study, 41 subsequent cases have been reported, and among these, colorectal adenocarcinoma was the most frequent distant primary (24%). In 25 (58%) cases, curative surgery was attempted, but only 4 patients remained disease-free at last follow up. We report the history of a 52-year-old man who presented with rectal adenocarcinoma metastatic to his larynx 4 years after definitive treatment of the primary site. CONCLUSIONS: In patients with a laryngeal mass and a history of colorectal cancer, or those at high risk of having an occult colorectal primary, metastatic spread to the larynx must always be considered. Although secondary laryngeal metastasis portends a poor prognosis, for the select patient, surgical intervention can provide long-term disease control. PMID- 26743608 TI - Effects of an Open Jaw Posture on Vowel Perception in the Aging Voice. AB - PURPOSE: This study aimed to verify through an auditory-perceptual approach, whether an "open jaw" posture would result in improved speech quality for older adults. METHODS: Forty normal-hearing listeners (20 males; 20 females) aged between 18 and 47 listened to vowel segments and performed two separate tasks: identifying vowels and comparing vowel clarity. Stimuli included vowels segmented from a sentence ("We saw two cars.") produced using a normal and an open jaw posture by 40 individuals aged between 30s and 80s. Three types of stimuli were presented: variable length and intensity, fixed length and variable intensity, and fixed length and normalized intensity. Mixed model analyses of variance were used to determine whether there was a jaw posture effect on the percentage of correct vowel identification. Chi-square tests were used to determine whether vowels produced with an open jaw posture were more likely to be identified as being "clearer." RESULTS: Open jaw posture resulted in higher rates of correct vowel identification, and vowels from contrast pairs were consistently judged as being "clearer" than vowels produced in normal jaw posture. Investigations on the effect of stimulus type revealed that the jaw-related improvement in speech quality was not solely due to an increase in intensity or length induced by an open jaw posture. CONCLUSIONS: Listeners assessing vowel identification and clarity in the aging voice were able to better differentiate among vowels spoken using an open jaw posture, and a greater number of vowels produced in an open jaw posture were perceived as sounding clearer. PMID- 26743610 TI - Analysing breast tissue composition with MRI using currently available short, simple sequences. AB - AIM: To determine the most robust commonly available magnetic resonance imaging (MRI) sequence to quantify breast tissue composition at 1.5 T. MATERIALS AND METHODS: Two-dimensional (2D) T1-weighted, Dixon fat, Dixon water and SPAIR images were obtained from five participants and a breast phantom using a 1.5 T Siemens Aera MRI system. Manual segmentation of the breasts was performed, and an in-house computer program was used to generate signal intensity histograms. Relative trough depth and relative peak separation were used to determine the robustness of the images for quantifying the two breast tissues. Total breast volumes and percentage breast densities calculated using the four sequences were compared. RESULTS: Dixon fat histograms had consistently low relative trough depth and relative peak separation compared to those obtained using other sequences. There was no significant difference in total breast volumes and percentage breast densities of the participants or breast phantom using Dixon fat and 2D T1-weighted histograms. Dixon water and SPAIR histograms were not suitable for quantifying breast tissue composition. CONCLUSION: Dixon fat images are the most robust for the quantification of breast tissue composition using a signal intensity histogram. PMID- 26743609 TI - Behavior of suspended particles in the Changjiang Estuary: Size distribution and trace metal contamination. AB - Suspended particulate matter (SPM) samples were collected along a salinity gradient in the Changjiang Estuary in June 2011. A custom-built water elutriation apparatus was used to separate the suspended sediments into five size fractions. The results indicated that Cr and Pb originated from natural weathering processes, whereas Cu, Zn, and Cd originated from other sources. The distribution of most trace metals in different particle sizes increased with decreasing particle size. The contents of Fe/Mn and organic matter were confirmed to play an important role in increasing the level of heavy metal contents. The Cu, Pb, Zn, and Cd contents varied significantly with increasing salinity in the medium-low salinity region, thus indicating the release of Cu, Pb, Zn, and Cd particles. Thus, the transfer of polluted fine particles into the open sea is probably accompanied by release of pollutants into the dissolved compartment, thereby amplifying the potential harmful effects to marine organisms. PMID- 26743617 TI - Advances in GBA-associated Parkinson's disease--Pathology, presentation and therapies. AB - GBA mutations are to date the most common genetic risk factor for Parkinson's disease. The GBA gene encodes the lysomal hydrolase glucocerebrosidase. Whilst bi allelic GBA mutations cause Gaucher disease, both mono- and bi-allelic mutations confer risk for Parkinson's disease. Clinically, Parkinson's disease patients with GBA mutations resemble idiopathic Parkinson's disease patients. However, these patients have a modest reduction in age-of-onset of disease and a greater incidence of cognitive decline. In some cases, GBA mutations are also responsible for familial Parkinson's disease. The accumulation of alpha-synuclein into Lewy bodies is the central neuropathological hallmark of Parkinson's disease. Pathologic GBA mutations reduce enzymatic function. A reduction in glucocerebrosidase function increases alpha-synuclein levels and propagation, which in turn inhibits glucocerebrosidase in a feed-forward cascade. This cascade is central to the neuropathology of GBA-associated Parkinson's disease. The lysosomal integral membrane protein type-2 is necessary for normal glucocerebrosidase function. Glucocerebrosidase dysfunction also increases in the accumulation of beta-amyloid and amyloid-precursor protein, oxidative stress, neuronal susceptibility to metal ions, microglial and immune activation. These factors contribute to neuronal death. The Mendelian Parkinson's disease genes, Parkin and ATP13A2, intersect with glucocerebrosidase. These factors sketch a complex circuit of GBA-associated neuropathology. To clinically interfere with this circuit, central glucocerebrosidase function must be improved. Strategies based on reducing breakdown of mutant glucocerebrosidase and increasing the fraction that reaches the lysosome has shown promise. Breakdown can be reduced by interfering with the ability of heat-shock proteins to recognize mutant glucocerebrosidase. This underlies the therapeutic efficacy of certain pharmacological chaperones and histone deacetylase inhibitors. These therapies are promising for Parkinson's disease, regardless of mutation status. Recently, there has been a boom in studies investigating the role of glucocerebrosidase in the pathology of Parkinson's disease. This merits a comprehensive review of the current cell biological processes and pathological pictures involving Parkinson's disease associated with GBA mutations. PMID- 26743618 TI - Discriminant Value of Custom Ocular Response Analyzer Waveform Derivatives in Forme Fruste Keratoconus. AB - PURPOSE: To evaluate the performance of corneal hysteresis (CH), corneal resistance factor (CRF), 37 Ocular Response Analyzer (ORA) waveform parameters, and 15 investigator-derived ORA variables in differentiating forme fruste keratoconus (KC) from normal corneas. DESIGN: Case-control study. METHODS: Seventy-eight eyes of 78 unaffected patients and 21 topographically normal eyes of 21 forme fruste KC patients with topographically manifest KC in the contralateral eye were matched for age, the thinnest point of the cornea, central corneal thickness, and maximum keratometry. Fifteen candidate variables were derived from exported ORA signals to characterize putative indicators of biomechanical behavior, and 37 waveform parameters were tested. Differences between groups were assessed by the Mann-Whitney test. The area under the receiver operating characteristic curve (AUROC) was used to compare the diagnostic performance. RESULTS: Ten of 54 parameters reached significant differences between the groups (Mann-Whitney test, P < .05). Neither CRF nor CH differed significantly between the groups. Among the ORA waveform measurements, the best parameters were those related to the area under the first peak, p1area, and p1area1 (AUROC, 0.714 +/- 0.064 and 0.721 +/- 0.065, respectively). Among the investigator ORA variables, a measure incorporating the pressure-deformation relationship of the entire response cycle performed best (hysteresis loop area, AUROC, 0.694 +/- 0.067). CONCLUSION: Waveform-derived ORA parameters, including a custom measure incorporating the pressure-deformation relationship of the entire response cycle, performed better than traditional CH and CRF parameters in differentiating forme fruste KC from normal corneas. PMID- 26743621 TI - Erratum to: What Are the Long-term Results of MUTARS(r) Modular Endoprostheses for Reconstruction of Tumor Resection of the Distal Femur and Proximal Tibia? PMID- 26743622 TI - Corticosteroids as a therapy for bacterial keratitis: an evidence-based review of 'who, when and why'. AB - Corticosteroids have been proposed as an adjunct to antibiotics for the treatment of bacterial keratitis, with significant controversy regarding the appropriate use of this therapy. Recent prospective randomised controlled trials have provided additional evidence to guide clinical decision-making. A review of the epidemiology and mechanisms of pathogenesis, preliminary animal studies, retrospective human studies and prospective randomised clinical trials that address the potential risks and benefits of corticosteroids in patients with bacterial keratitis was performed. Four prospective randomised controlled trials were identified. Three small studies found no benefit of topical corticosteroids, but were underpowered to evaluate adverse events. The Steroids for Corneal Ulcers Trial (SCUT) study and subgroup analyses provide evidence for a relative gain of one line of best spectacle-corrected visual acuity in patients with non-Nocardia bacterial keratitis, especially when corticosteroids were initiated within 3 days of presentation; no increase in adverse events was noted. No evidence was found to support the concern for corneal thinning attributable to corticosteroids in the absence of an inadequately treated infectious process. In patients with culture-proven non-Nocardia bacterial keratitis, corticosteroids provide one line of vision improvement over antimicrobials alone, with no increase in adverse events. This benefit should not be extrapolated to patients with other aetiologies of keratitis, such as fungus, herpes viruses, acanthamoeba or atypical mycobacteria, and these entities should be excluded before considering adjunctive steroid therapy. PMID- 26743619 TI - Choroidal Thickness Changes in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy: A 12-Month Prospective Study. AB - PURPOSE: To describe 12-month changes in choroidal thickness after anti-vascular endothelial growth factor (anti-VEGF) therapy for typical age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). DESIGN: Prospective, consecutive, noninterventional, longitudinal case series. METHODS: This study included patients with typical AMD and PCV who received anti-VEGF therapy over a 12-month period. We used spectral-domain optical coherence tomography with enhanced depth imaging mode to measure choroidal thickness. RESULTS: Of the 163 patients, 77 had typical AMD and 86 had PCV. Patients with PCV were younger (67.6 vs 72.5 years, P < .01) and received fewer anti-VEGF injections (3.9 vs 5.6, P = .02) than patients with typical AMD. Baseline subfoveal choroidal thickness was not significantly different between PCV and typical AMD eyes, and was thicker in the study eye compared to fellow eye in the typical AMD group (223.1 vs 208.8 MUm, P < .01). Subfoveal choroidal thickness decreased significantly in both typical AMD (213.7 MUm to 190.3 MUm, P < .001) and PCV (240.8 MUm to 213.4 MUm, P < .01) eyes, but no significant change was noted in fellow unaffected eyes. Reduction in choroidal thickness was associated with elevated C-reactive protein (odds ratio [OR]: 1.4, P = .04) and smoking (OR: 7.6, P = .03) at baseline, but not with age, refractive error, diagnosis of typical AMD or PCV, number or type of anti-VEGF injections, PDT therapy, or baseline choroidal thickness. CONCLUSIONS: A significant reduction in subfoveal choroidal thickness was noted after anti-VEGF therapy in typical AMD and PCV. Choroidal thickness changes were similar despite differences in number of anti VEGF treatment. PMID- 26743623 TI - The 3.8 A structure of the U4/U6.U5 tri-snRNP: Insights into spliceosome assembly and catalysis. AB - Splicing of precursor messenger RNA is accomplished by a dynamic megacomplex known as the spliceosome. Assembly of a functional spliceosome requires a preassembled U4/U6.U5 tri-snRNP complex, which comprises the U5 small nuclear ribonucleoprotein (snRNP), the U4 and U6 small nuclear RNA (snRNA) duplex, and a number of protein factors. Here we report the three-dimensional structure of a Saccharomyces cerevisiae U4/U6.U5 tri-snRNP at an overall resolution of 3.8 angstroms by single-particle electron cryomicroscopy. The local resolution for the core regions of the tri-snRNP reaches 3.0 to 3.5 angstroms, allowing construction of a refined atomic model. Our structure contains U5 snRNA, the extensively base-paired U4/U6 snRNA, and 30 proteins including Prp8 and Snu114, which amount to 8495 amino acids and 263 nucleotides with a combined molecular mass of ~1 megadalton. The catalytic nucleotide U80 from U6 snRNA exists in an inactive conformation, stabilized by its base-pairing interactions with U4 snRNA and protected by Prp3. Pre-messenger RNA is bound in the tri-snRNP through base pairing interactions with U6 snRNA and loop I of U5 snRNA. This structure, together with that of the spliceosome, reveals the molecular choreography of the snRNAs in the activation process of the spliceosomal ribozyme. PMID- 26743625 TI - Phytoplankton. The fate of photons absorbed by phytoplankton in the global ocean. AB - Solar radiation absorbed by marine phytoplankton can follow three possible paths. By simultaneously measuring the quantum yields of photochemistry and chlorophyll fluorescence in situ, we calculate that, on average, ~60% of absorbed photons are converted to heat, only 35% are directed toward photochemical water splitting, and the rest are reemitted as fluorescence. The spatial pattern of fluorescence yields and lifetimes strongly suggests that photochemical energy conversion is physiologically limited by nutrients. Comparison of in situ fluorescence lifetimes with satellite retrievals of solar-induced fluorescence yields suggests that the mean values of the latter are generally representative of the photophysiological state of phytoplankton; however, the signal-to-noise ratio is unacceptably low in extremely oligotrophic regions, which constitute 30% of the open ocean. PMID- 26743624 TI - Pulmonary neuroendocrine cells function as airway sensors to control lung immune response. AB - The lung is constantly exposed to environmental atmospheric cues. How it senses and responds to these cues is poorly defined. Here, we show that Roundabout receptor (Robo) genes are expressed in pulmonary neuroendocrine cells (PNECs), a rare, innervated epithelial population. Robo inactivation in mouse lung results in an inability of PNECs to cluster into sensory organoids and triggers increased neuropeptide production upon exposure to air. Excess neuropeptides lead to an increase in immune infiltrates, which in turn remodel the matrix and irreversibly simplify the alveoli. We demonstrate in vivo that PNECs act as precise airway sensors that elicit immune responses via neuropeptides. These findings suggest that the PNEC and neuropeptide abnormalities documented in a wide array of pulmonary diseases may profoundly affect symptoms and progression. PMID- 26743628 TI - An Improvement of Robust and Efficient Biometrics Based Password Authentication Scheme for Telecare Medicine Information Systems Using Extended Chaotic Maps. AB - Recently, numerous extended chaotic map-based password authentication schemes that employ smart card technology were proposed for Telecare Medical Information Systems (TMISs). In 2015, Lu et al. used Li et al.'s scheme as a basis to propose a password authentication scheme for TMISs that is based on biometrics and smart card technology and employs extended chaotic maps. Lu et al. demonstrated that Li et al.'s scheme comprises some weaknesses such as those regarding a violation of the session-key security, a vulnerability to the user impersonation attack, and a lack of local verification. In this paper, however, we show that Lu et al.'s scheme is still insecure with respect to issues such as a violation of the session-key security, and that it is vulnerable to both the outsider attack and the impersonation attack. To overcome these drawbacks, we retain the useful properties of Lu et al.'s scheme to propose a new password authentication scheme that is based on smart card technology and requires the use of chaotic maps. Then, we show that our proposed scheme is more secure and efficient and supports security properties. PMID- 26743629 TI - Investigations of Sulfur Chemical Status with Synchrotron Micro Focused X-ray fluorescence and X-ray Absorption Spectroscopy. AB - Sulfur (S) is an essential macronutrient for all living organisms. A variety of organic and inorganic S species with oxidation states ranging from -2 to +6 exist. Today few spectroscopic and biochemical methods are used to investigate sulfur oxidation state and reactivity in biological samples. X-ray absorption near edge spectroscopy (XANES) is a very well suited spectroscopic technique to probe the oxidation state and the surrounding chemical environment of sulfur. Microspectroscopy beamlines, operating at almost all synchrotron facilities, allow the combination of XANES with X-ray fluorescence mapping (uXRF). Using this approach distribution maps of S in complex biological samples (intact parts of tissue, or individual cells) can be obtained using uXRF and its oxidation state can be probed in-situ (uXANES). Moreover, uXRF mapping at specific energies enables for chemical contrast of S at different oxidation states without the need of staining chemicals. This review introduces the basic concepts of synchrotron uXRF and uXANES and discusses the most recent applications in life science. Important methodological and technical issues will be discussed and results obtained in different complex biological samples will be presented. PMID- 26743627 TI - Disrupted effective connectivity of the sensorimotor network in amyotrophic lateral sclerosis. AB - Although dysfunctional sensorimotor network (SMN) has been frequently involved in the pathogenesis of amyotrophic lateral sclerosis (ALS), the causal relationship within this network remains unexplored. In this study, spectral dynamic causal modeling was applied to resting-state functional magnetic resonance imaging data to estimate the causal relationship of SMN in a cohort of 20 ALS patients and 21 healthy controls. The SMN components were first extracted using an independent component analysis, and then compared between the two groups to identify the abnormalities in SMN. In ALS patients, we found significant regional activity alterations in the left primary motor cortex (M1), the left primary somatosensory cortex (S1), and the right supplementary motor cortex (SMA). Among these regions, spectral DCM revealed missing closed-loop circuit between the left M1 and the right SMA, and lost projection from the right SMA to the left S1 in ALS. These findings may reflect the influences of the loss of motor neurons on motor function in ALS, and provide compelling evidence for a breakdown of the sensorimotor neural circuits in ALS. In conclusion, this study elucidates a neurobiological model that may explain the functional impairments of the SMN in ALS, and provides much deeper insights into the pathophysiology of this disease. PMID- 26743630 TI - The-N-End Rule: The Beginning Determines the End. AB - In eukaryotic cells, regulated protein degradation of intracellular proteins is mediated largely by the ubiquitin proteasome system (UPS). UPS-mediated protein degradation regulates virtually all crucial aspects of cellular physiology, such as cell proliferation, cell division, cell differentiation, and cell death. Concomitantly, the deregulation by the UPS contributes to human disorders including cancer. Cellular regulation by UPS- mediated protein degradation is a highly specific and selective process that depends on time (e.g. cell cycle) and location (nucleus, mitochondria or endoplasmic reticulum). An ongoing challenge in the protein degradation field is identification of degradation signals for specific proteins that trigger their degradation by the proteasome. More than 25 years ago, the first degradation signal was discovered and defined as destabilizing N-terminal amino-acid residue (or N-degron) of protein substrates. The discovery and subsequent detailed analysis of N-degrons gave rise to the so called N-end rule, which states that the half-life time of a protein is determined by the identity of its N-terminal amino-acid residue. The N-end rule pathway recognizes proteins containing N-terminal destabilizing residues and mediates their polyubiquitination and subsequent degradation in the proteasome. Recent investigations have revealed a role for N-terminal acetylation on the recognition of N-degrons by the N-end rule pathway. Here we summarize these recent findings and highlight the impact on our understanding of the N-end rule pathway with respect to cellular physiology. PMID- 26743626 TI - Plasmodium malaria and antimalarial antibodies in the first year of life. AB - Malaria is one of the most serious infectious diseases with most of the severe disease caused by Plasmodium falciparum (Pf). Naturally acquired immunity develops over time after repeated infections and the development of antimalarial antibodies is thought to play a crucial role. Neonates and young infants are relatively protected from symptomatic malaria through mechanisms that are poorly understood. The prevailing paradigm is that maternal antimalarial antibodies transferred to the fetus in the last trimester of pregnancy protect the infant from early infections. These antimalarial antibodies wane by approximately 6 months of age leaving the infant vulnerable to malaria, however direct evidence supporting this epidemiologically based paradigm is lacking. As infants are the target population for future malaria vaccines, understanding how they begin to develop immunity to malaria and the gaps in their responses is key. This review summarizes the antimalarial antibody responses detected in infants and how they change over time. We focus primarily on Pf antibody responses and will briefly mention Plasmodium vivax responses in infants. PMID- 26743631 TI - Interventions for prevention and treatment of tobacco smoking in school-aged children and adolescents: A systematic review and meta-analysis. AB - OBJECTIVES: To determine the effectiveness of primary health care relevant interventions to prevent and treat tobacco smoking in school-aged children and adolescents. METHODS: This systematic review considered studies included in a prior review. We adapted and updated the search to April 2015. Titles, abstracts and full-text articles were reviewed in duplicate; data extraction and quality assessments were performed by one reviewer and verified by another. Meta-analyses and pre-specified sub-group analyses were performed when possible. PROSPERO #CRD42015019051. RESULTS: After screening 2118 records, we included nine randomized controlled trials. The mostly moderate quality evidence suggested targeted behavioral interventions can prevent smoking and assist with cessation. Meta-analysis showed intervention participants were 18% less likely to report having initiated smoking at the end of intervention relative to controls (Risk Ratio 0.82; 95% confidence interval 0.72, 0.94); the absolute effect is 1.92% for smoking initiation, Number Needed to Treat is 52 (95% confidence interval 33, 161). For cessation, meta-analysis showed intervention participants were 34% more likely to report having quit smoking at the end of intervention relative to controls (Risk Ratio 1.34; 95% confidence interval 1.05, 1.69); the absolute effect is 7.98% for cessation, Number Needed to Treat is 13 (95% confidence interval 6, 77). Treatment harms were not mentioned in the literature and no data were available to assess long-term effectiveness. CONCLUSION: Primary care relevant behavioral interventions improve smoking outcomes for children and youth. The evidence on key components is limited by heterogeneity in methodology and intervention strategy. Future trials should target tailored prevention or treatment approaches, establish uniform definition and measurement of smoking, isolate optimal intervention components, and include long-term follow-up. PMID- 26743632 TI - Cigarette smoking and cigarette marketing exposure among students in selected African countries: Findings from the Global Youth Tobacco Survey. AB - OBJECTIVE: To investigate cigarette smoking prevalence and exposure to various forms of cigarette marketing among students in 10 African countries. METHODS: We used data collected during 2009-2011 from the Global Youth Tobacco Survey (GYTS), a school-based cross-sectional survey of students aged 13-15years, to measure the prevalence of cigarette smoking and exposure to cigarette marketing; comparisons to estimates from 2005 to 2006 were conducted for five countries where data were available. RESULTS: Current cigarette smoking ranged from 3.4% to 13.6% among students aged 13-15 in the 10 countries studied, although use of tobacco products other than cigarettes was more prevalent in all countries except in Cote D'Ivoire. Cigarette smoking was higher among boys than girls in seven out of the 10 countries. Among the five countries with two rounds of surveys, a significant decrease in cigarette smoking prevalence was observed in Mauritania and Niger; these two countries also experienced a decline in three measures of cigarette marketing exposure. It is also possible that smoking prevalence might have risen faster among girls than boys. CONCLUSION: Cigarette smoking among youth was noticeable in 10 African countries evaluated, with the prevalence over 10% in Cote D'Ivoire, Mauritania, and South Africa. Cigarette marketing exposure varied by the types of marketing; traditional venues such as TV, outdoor billboards, newspapers, and magazines were still prominent. PMID- 26743633 TI - [Direct to consumer genetic testing: is it the moment?]. AB - Since the development of new human genome sequencing technologies at the beginning of the 2000, commercial companies have developped direct to consumer genomic services, which means without medical prescription. From 2007 to 2013, many companies have offered services assesing associated risk with human public health in the world especially in the United States. This kind of company is forbidden in France. From 2009 to 2013, in United States, under the pressure of national or state health administrations, these companies have been progressively forbidden. However, in certain parts of the world, companies are still offering such services. The latter raise many different questions such as ethical, juridical, medical, scientific, educative, professional one. Many studies and debates have demonstrated their limit and the lack of usefulness and advantage in the field of human health for the time being. The commercialization of this type of services has arrived all too soon et is not yet ripe. In our time of globalization, with the lack of international rules controlling direct access to genetic services in the field of human health, there is an urgent need to regulate. International administrations and politicians must act fast. Inevitably, under the pressure of lobbies and citizens, companies (multinational or not) will develop especially as 1) new sequencing technologies evolve rapidly, 2) are cheaper from year to year, 3) scientific and medical knowledges are progressing quickly, 4) services are spreading faster through the web and other networks. PMID- 26743634 TI - Retraction Note: Abstracts of 51st EASD Annual Meeting. PMID- 26743635 TI - Erratum to: 'Costs of treating cardiovascular events in Germany: a systematic literature review'. PMID- 26743638 TI - Deep microbial life in high-quality granitic groundwater from geochemically and geographically distinct underground boreholes. AB - Deep granitic aquifer is one of the largest, but least understood, microbial habitats. To avoid contamination from the surface biosphere, underground drilling was conducted for 300 m deep granitic rocks at the Mizunami underground research laboratory (URL), Japan. Slightly alkaline groundwater was characterized by low concentrations of dissolved organic matter and sulfate and the presence of > 100 nM H2 . The initial biomass was the highest (~10(5) cells ml(-1) ) with the dominance of Hydrogenophaga spp., whereas the phylum Nitrospirae became predominant after 3 years with decreasing biomass (~10(4) cells ml(-1) ). One week incubation of groundwater microbes after 3 years with (13) C-labelled bicarbonate and 1% H2 and subsequent single-cell imaging with nanometer-scale secondary ion mass spectrometry demonstrated that microbial cells were metabolically active. Pyrosequencing of microbial communities in groundwater retrieved at 3-4 years after drilling at the Mizunami URL and at 14 and 25 years after the drilling at the Grimsel Test Site, Switzerland, revealed the occurrence of common Nitrospirae lineages at the geographically distinct sites. As the close relatives of the Nitrospirae lineages were exclusively detected from deep groundwaters and terrestrial hot springs, it suggests that these bacteria are indigenous and potentially adapted to the deep terrestrial subsurface. PMID- 26743636 TI - Experimental measurement of preferences in health and healthcare using best-worst scaling: an overview. AB - Best-worst scaling (BWS), also known as maximum-difference scaling, is a multiattribute approach to measuring preferences. BWS aims at the analysis of preferences regarding a set of attributes, their levels or alternatives. It is a stated-preference method based on the assumption that respondents are capable of making judgments regarding the best and the worst (or the most and least important, respectively) out of three or more elements of a choice-set. As is true of discrete choice experiments (DCE) generally, BWS avoids the known weaknesses of rating and ranking scales while holding the promise of generating additional information by making respondents choose twice, namely the best as well as the worst criteria. A systematic literature review found 53 BWS applications in health and healthcare. This article expounds possibilities of application, the underlying theoretical concepts and the implementation of BWS in its three variants: 'object case', 'profile case', 'multiprofile case'. This paper contains a survey of BWS methods and revolves around study design, experimental design, and data analysis. Moreover the article discusses the strengths and weaknesses of the three types of BWS distinguished and offered an outlook. A companion paper focuses on special issues of theory and statistical inference confronting BWS in preference measurement. PMID- 26743637 TI - Wanting it Too Much: An Inverse Relation Between Social Motivation and Facial Emotion Recognition in Autism Spectrum Disorder. AB - This study examined social motivation and early-stage face perception as frameworks for understanding impairments in facial emotion recognition (FER) in a well-characterized sample of youth with autism spectrum disorders (ASD). Early stage face perception (N170 event-related potential latency) was recorded while participants completed a standardized FER task, while social motivation was obtained via parent report. Participants with greater social motivation exhibited poorer FER, while those with shorter N170 latencies exhibited better FER for child angry faces stimuli. Social motivation partially mediated the relationship between a faster N170 and better FER. These effects were all robust to variations in IQ, age, and ASD severity. These findings augur against theories implicating social motivation as uniformly valuable for individuals with ASD, and augment models suggesting a close link between early-stage face perception, social motivation, and FER in this population. Broader implications for models and development of FER in ASD are discussed. PMID- 26743639 TI - Tocilizumab and multiple sclerosis: a causal relationship? Clinical Commentary on the case report entitled--MS arising during Tocilizumab therapy for rheumatoid arthritis. AB - This clinical commentary discusses on the potential relationship between multiple sclerosis (MS) and tocilizumab in a patient with rheumatoid arthritis who developed MS while on treatment with this anti-interleukin-6 agent. PMID- 26743640 TI - MS arising during Tocilizumab therapy for rheumatoid arthritis. AB - BACKGROUND: Interleukin-6 (IL6) blockage is a treatment strategy used in many inflammatory conditions. Trials in Neuromyelitis Optica Spectrum Disorder (NMOSD) are ongoing. Secondary auto-immunity affecting the central nervous system (CNS) is well described with some biologic agents, mainly tumor necrosis factor (TNF) alpha inhibitors. These treatments can also aggravate patients with known multiple sclerosis (MS). OBJECTIVES: To describe a case of a patient who developed MS using another biologic, IL6 receptor antibody Tocilizumab. RESULTS: A 48-year-old woman developed MS while on treatment with Tocilizumab for Rheumatoid Arthritis (RA). This is the first published report of this association. It has obvious implications for NMOSD patients receiving anti-IL6 therapy. Development of new white matter lesions suggestive of MS in a patient treated with anti-IL6 therapy might represent an important complication of therapy. CONCLUSION: This case illustrates that Tocilizumab might cause secondary auto-immunity in CNS. It is important to be aware of this potential complication as anti-IL6 therapy might become an option for the treatment NMOSD. PMID- 26743642 TI - Investigation into the Effect of Ethylcellulose Viscosity Variation on the Drug Release of Metoprolol Tartrate and Acetaminophen Extended Release Multiparticulates-Part I. AB - Ethylcellulose is one of the most commonly used polymers to develop reservoir type extended release multiparticulate dosage forms. For multiparticulate extended release dosage forms, the drug release is typically governed by the properties of the barrier membrane coating. The ICH Pharmaceutical Development Guideline (ICH Q8) requires an understanding of the influence of critical material attributes and critical process parameters on the drug release of a pharmaceutical product. Using this understanding, it is possible to develop robust formulations with consistent drug release characteristics. Critical material attributes for ethylcellulose were evaluated, and polymer molecular weight variation (viscosity) was considered to be the most critical attribute that can impact drug release. To investigate the effect of viscosity variation within the manufacturer's specifications of ethylcellulose, extended release multiparticulate formulations of two model drugs, metoprolol tartrate and acetaminophen, were developed using ETHOCELTM as the rate controlling polymer. Quality by Design (QbD) samples of ETHOCEL Std. 10, 20, and 100 Premium grades representing the low, medium, and high molecular weight (viscosity) material were organically coated onto drug layered multiparticulates to a 15% weight gain (WG). The drug release was found to be similar (f 2 > 50) for both metoprolol tartrate and acetaminophen multiparticulates at different coating weight gains of ethylcellulose, highlighting consistent and robust drug release performance. The use of ETHOCEL QbD samples also serves as a means to develop multiparticulate dosage formulations according to regulatory guidelines. PMID- 26743641 TI - Cancer Care Professionals' Attitudes Toward Systematic Standardized Symptom Assessment and the Edmonton Symptom Assessment System After Large-Scale Population-Based Implementation in Ontario, Canada. AB - CONTEXT: Cancer patients experience a high symptom burden throughout their illness. Despite this, patients' symptoms and needs are often not adequately screened for, assessed, and managed. OBJECTIVES: This study investigated the attitudes of cancer care professionals toward standardized systematic symptom assessment and the Edmonton Symptom Assessment System (ESAS) and their self reported use of the instrument in daily practice in a large healthcare jurisdiction where this is routine. METHODS: A 21-item electronic survey, eliciting both closed and open-ended anonymous responses, was distributed to all 2806 cancer care professionals from four major provider groups: physicians, nurses, radiotherapists, and psychosocial oncology (PSO) staff at the 14 Regional Cancer Centres across Ontario, Canada. RESULTS: A total of 1065 questionnaires were returned (response rate: 38%); 960 were eligible for analysis. Most respondents (88%) considered symptom management to be within their scope of practice. Sixty-six percent of physicians considered the use of standardized tools to screen for symptoms as "best practice," compared to 81% and 93% of nurses and PSO staff, respectively. Sixty-seven percent of physicians and 85% of nurses found the ESAS to be a useful starting point to assess patients' symptoms. Seventy-nine percent of physicians looked at their patient's ESAS scores at visits either "always" or "often," compared to 29%, 66%, and 89% of radiotherapists, PSO staff, and nurses, respectively. Several areas for improvement of ESAS use and symptom screening were identified. CONCLUSION: Findings show significant albeit variable uptake across disciplines in the use of the ESAS since program initiation. Several barriers to using the ESAS in daily practice were identified. These need to be addressed. PMID- 26743643 TI - Development, Optimization, and Evaluation of Carvedilol-Loaded Solid Lipid Nanoparticles for Intranasal Drug Delivery. AB - Carvedilol, a beta-adrenergic blocker, suffers from poor systemic availability (25%) due to first-pass metabolism. The aim of this work was to improve carvedilol bioavailability through developing carvedilol-loaded solid lipid nanoparticles (SLNs) for nasal administration. SLNs were prepared by emulsion/solvent evaporation method. A 23 factorial design was employed with lipid type (Compritol or Precirol), surfactant (1 or 2% w/v poloxamer 188), and co-surfactant (0.25 or 0.5% w/v lecithin) concentrations as independent variables, while entrapment efficiency (EE%), particle size, and amount of carvedilol permeated/unit area in 24 h (Q 24) were the dependent variables. Regression analysis was performed to identify the optimum formulation conditions. The in vivo behavior was evaluated in rabbits comparing the bioavailability of carvedilol after intravenous, nasal, and oral administration. The results revealed high drug EE% ranging from 68 to 87.62%. Carvedilol-loaded SLNs showed a spherical shape with an enriched core drug loading pattern having a particle size in the range of 66 to 352 nm. The developed SLNs exhibited significant high amounts of carvedilol permeated through the nasal mucosa as confirmed by confocal laser scanning microscopy. The in vivo pharmacokinetic study revealed that the absolute bioavailability of the optimized intranasal SLNs (50.63%) was significantly higher than oral carvedilol formulation (24.11%). Hence, we conclude that our developed SLNs represent a promising carrier for the nasal delivery of carvedilol. PMID- 26743644 TI - Application of Faecalibacterium 16S rDNA genetic marker for accurate identification of duck faeces. AB - The aim of this study was to judge the legal duty of pollution liabilities by assessing a duck faeces-specific marker, which can exclude distractions of residual bacteria from earlier contamination accidents. With the gene sequencing technology and bioinformatics method, we completed the comparative analysis of Faecalibacterium sequences, which were associated with ducks and other animal species, and found the sequences unique to duck faeces. Polymerase chain reaction (PCR) and agarose gel electrophoresis techniques were used to verify the reliability of both human and duck faeces-specific primers. The duck faeces specific primers generated an amplicon of 141 bp from 43.3 % of duck faecal samples, 0 % of control samples and 100 % of sewage wastewater samples that contained duck faeces. We present here the initial evidence of Faecalibacterium based applicability as human faeces-specificity in China. Meanwhile, this study represents the initial report of a Faecalibacterium marker for duck faeces and suggests an independent or supplementary environmental biotechnology of microbial source tracking (MST). PMID- 26743645 TI - Toxicity profile of choline chloride-based deep eutectic solvents for fungi and Cyprinus carpio fish. AB - An investigation on the toxicological assessment of 10 choline chloride (ChCl) based deep eutectic solvents (DESs) towards four fungi strains and Cyprinus carpio fish was conducted. ChCl was combined with materials from different chemical groups such as alcohols, sugars, acids and others to form DESs. The study was carried out on the individual DES components, their aqueous mixture before DES formation and their formed DESs. The agar disc diffusion method was followed to investigate their toxicity on four fungi strains selected as a model of eukaryotic microorganisms (Phanerochaete chrysosporium, Aspergillus niger, Lentinus tigrinus and Candida cylindracea). Among these DESs, ChCl:ZnCl2 exhibited the highest inhibition zone diameter towards the tested fungi growth in vitro, followed by the acidic group (malonic acid and p-toluenesulfonic acid). Another study was conducted to test the acute toxicity and determine the lethal concentration at 50 % (LC50) of the same DESs on C. carpio fish. The inhibition range and LC50 of DESs were found to be different from their individual components. DESs were found to be less toxic than their mixture or individual components. The LC50 of ChCl:MADES is much higher than that of ChCl:MAMix. Moreover, the DESs acidic group showed a lower inhibition zone on fungi growth. Thus, DESs should be considered as new components with different physicochemical properties and toxicological profiles, and not merely compositions of compounds. PMID- 26743646 TI - Determination and human exposure assessment of polybrominated diphenyl ethers and tetrabromobisphenol A in indoor dust in South Africa. AB - The concentration of TBBPA in dust samples from automobiles (n = 14), computer laboratories (n = 8), homes (n = 7), and offices (n = 7), and, also, PBDE concentrations in the indoor dust of 19 personal and previously owned automobiles in Durban, South Africa, were determined. Gas chromatography coupled with mass spectrometry was applied for the separation, identification, and quantitation of TBBPA and PBDEs. The median concentrations of TBBPA were 1156, 269, 120, and 492 ng g(-1) in automobiles, computer laboratories, homes, and offices, respectively. The ? n = 8 PBDE in 19 automobile samples ranged from 573 to 11,833 ng g(-1). BDE 209 accounted for approximately 42% of ? n = 8 PBDE in the samples. Household characteristics influenced the distribution of TBBPA in the various microenvironments. By assuming an average dust ingestion rate, and a median TBBPA concentration, the ?DED (in ng kg(-1) bw day(-1)) of TBBPA is 0.08, 0.08, and 0.60, for an adult, teenager, and toddler, respectively. These doses are similar to dust ingestion intakes reported for Asian countries where there is a high demand for TBBPA as a flame retardant. Similarly, automobiles provide ample opportunity for human exposure to PBDEs via dust ingestion, particularly for toddlers and occupationally exposed adults. PMID- 26743647 TI - Profile of particulate-bound organic compounds in ambient environment of Srinagar: a high-altitude urban location in the North-Western Himalayas. AB - Twenty-four hourly samples of total suspended particulate matter (TSPM) were collected once a week over 17 months in the ambient environment of Srinagar (altitude 1524 m), an urban montane location in the North-Western Himalayas. The samples were analyzed to identify and quantify the presence of diverse organic compounds (OCs) using thermal desorption gas chromatography mass spectroscopy (TD GCMS). Non-polar organic compounds-n-alkanes, polycyclic aromatic hydrocarbons (PAHs), and molecular tracers (retene and nicotine), were detected in the TSPM samples. Molecular diagnostic ratios, derived from the quantified n-alkanes and PAHs in TSPM, assisted in characterization of the contributing sources. Significant variation in the planetary boundary layer height (meters) with change in season (summer to winter) in this region, also, affected the observed variation in the temporal profile of TSPM-bound OCs. TSPM-bound OCs were predominantly contributed from petroleum and biomass combustion; to a lesser extent from biogenic sources. High concentrations of retene and nicotine, known molecular tracers for coniferous wood combustion and tobacco smoke, respectively, were detected in the winter samples. Seasonal variation in TSPM-bound retene corresponded with the periodicity of biomass burning activity in the region. The benzo(a)pyrene equivalent (BAPE) concentrations, a measure for the carcinogenicity of TSPM-bound PAHs was calculated and the value exceeded the prescribed international standards in winter. This finding poses a major health concern for the inhabitants of this region. High BAPE concentration of PAHs during winter was linked to fossil fuel and biomass combustion, where the prevalent meteorology and topography played a synergistic role. PMID- 26743648 TI - Revisiting the emissions-energy-trade nexus: evidence from the newly industrializing countries. AB - This paper applies Pedroni's panel cointegration approach to explore the causal relationship between trade openness, carbon dioxide emissions, energy consumption, and economic growth for the panel of newly industrialized economies (i.e., Brazil, India, China, and South Africa) over the period of 1970-2013. Our panel cointegration estimation results found majority of the variables cointegrated and confirm the long-run association among the variables. The Granger causality test indicates bidirectional causality between carbon dioxide emissions and energy consumption. A unidirectional causality is found running from trade openness to carbon dioxide emission and energy consumption and economic growth to carbon dioxide emissions. The results of causality analysis suggest that the trade liberalization in newly industrialized economies induces higher energy consumption and carbon dioxide emissions. Furthermore, the causality results are checked using an innovative accounting approach which includes forecast-error variance decomposition test and impulse response function. The long-run coefficients are estimated using fully modified ordinary least square (FMOLS) method, and results conclude that the trade openness and economic growth reduce carbon dioxide emissions in the long run. The results of FMOLS test sound the existence of environmental Kuznets curve hypothesis. It means that trade liberalization induces carbon dioxide emission with increased national output, but it offsets that impact in the long run with reduced level of carbon dioxide emissions. PMID- 26743650 TI - Influences of artificial root exudate components on the behaviors of BDE-28 and BDE-47 in soils: desorption, availability, and biodegradation. AB - Behaviors of BDE-28 and BDE-47 in two distinct soils (Phaeozem and Acrisol) as affected by the separate addition of root exudate components (i.e., oxalic acid, glycine, and fructose) were investigated by a soil microcosm incubation experiment. The results showed that root exudate components promoted the desorption of BDE-28 (57.6-235.0 %) and BDE-47 (56.9-223.7 %) from the soils due to the enhancement of their water solubilities. The addition of root exudate components increased the n-butanol extractability of BDE-28 and BDE-47 by 20.3 72.5 and 48.6-169.2 %, respectively, which had a positive correlation with the concentrations of dissolved organic carbon (DOC) in the soils (p < 0.01), suggesting that the increase of DOC in the soils by root exudate components was the major factor to enhance the extractability. Fructose and oxalic acid promoted the desorption and increased the availability of BDE-28 and BDE-47 in the soils more efficiently than glycine. The addition of different root exudate components resulted in distinct shifts in soil microbial community structure (p < 0.05). Oxalic acid caused the greatest impacts on the soil bacterial communities and increased the degradation rates of BDE-28 and BDE-47 most obviously. The findings of this study clarified the roles of root exudate components in affecting the behaviors of polybrominated diphenyl ethers (PBDEs) in soils. PMID- 26743649 TI - Development of a magnetic coagulant based on Moringa oleifera seed extract for water treatment. AB - In this work, to evaluate the effectiveness of the coagulation/flocculation using a natural coagulant, using Moringa oleifera Lam functionalized with magnetic iron oxide nanoparticles, producing flakes that are attracted by an external magnetic field, thereby allowing a fast settling and separation of the clarified liquid, is proposed. The removal efficiency of the parameters, apparent color, turbidity, and compounds with UV254nm absorption, was evaluated. The magnetic functionalized M. oleifera Lam coagulant could effectively remove 90 % of turbidity, 85 % of apparent color, and 50 % for the compounds with absorption at UV254nm, in surface waters under the influence of an external magnetic field within 30 min. It was found that the coagulation/flocculation treatment using magnetic functionalized M. oleifera Lam coagulant was able to reduce the values of the physico-chemical parameters evaluated with reduced settling time. PMID- 26743651 TI - Evidence for genetic regulation of mRNA expression of the dosage-sensitive gene retinoic acid induced-1 (RAI1) in human brain. AB - RAI1 (retinoic acid induced-1) is a dosage-sensitive gene that causes Smith Magenis syndrome (SMS) when mutated or deleted and Potocki-Lupski Syndrome (PTLS) when duplicated, with psychiatric features commonly observed in both syndromes. How common genetic variants regulate this gene, however, is unknown. In this study, we found that RAI1 mRNA expression in Chinese prefrontal and temporal cortex correlate with genotypes of common single nucleotide polymorphisms (SNPs) located in the RAI1 5'-upstream region. Using genotype imputation, "R(2) Delta(2)" analysis, and data from the RegulomeDB database, we identified SNPs rs4925102 and rs9907986 as possible regulatory variants, accounting for approximately 30-40% of the variance in RAI1 mRNA expression in both brain regions. Specifically, rs4925102 and rs9907986 are predicted to disrupt the binding of retinoic acid RXR-RAR receptors and the transcription factor DEAF1 (Deformed epidermal autoregulatory factor-1), respectively. Consistent with these predictions, we observed binding of RXRalpha and RARalpha to the predicted RAI1 target in chromatin immunoprecipitation assays. Retinoic acid is crucial for early development of the central neural system, and DEAF1 is associated with intellectual disability. The observation that a significant portion of RAI1 mRNA expression is genetically controlled raises the possibility that common RAI1 5' region regulatory variants contribute more generally to psychiatric disorders. PMID- 26743653 TI - Properties, structure, and applications of microbial sterol esterases. AB - According to their substrate preferences, carboxylic ester hydrolases are organized in smaller clusters. Among them, sterol esterases (EC 3.1.1.13), also known as cholesterol esterases, act on fatty acid esters of cholesterol and other sterols in aqueous media, and are also able to catalyze synthesis by esterification or transesterification in the presence of organic solvents. Mammalian cholesterol esterases are intracellular enzymes that have been extensively studied since they are essential in lipid metabolism and cholesterol absorption, and the natural role of some microbial sterol esterases is supposed to be similar. However, besides these intracellular enzymes, a number of microbes produce extracellular sterol esterases, which show broad stability, selectivity, or wide substrate specificity, making them interesting for the industry. In spite of this, there is little information about microbial sterol esterases, and only a small amount of them have been characterized. Some of the most commercially exploited cholesterol esterases are produced by Pseudomonas species and by Candida rugosa, although in the last case they are usually described and named as "high substrate versatility lipases." From a structural point of view, most of them belong to the alpha/beta-hydrolase superfamily and have a conserved "catalytic triad" formed by His, an acidic amino acid and a Ser residue that is located in a highly conserved GXSXG sequence. In this review, the information available on microbial sterol esterases has been gathered, taking into account their origin, production and purification, heterologous expression, structure, stability, or substrate specificity, which are the main properties that make them attractive for different applications. Moreover, a comprehensive phylogenetic analysis on available sequences of cholesterol esterases has been done, including putative sequences deduced from public genomes. PMID- 26743652 TI - Characterization and application of monoclonal antibodies against Mycoplasma hyorhinis pyruvate dehydrogenase E1 complex subunit alpha. AB - Mycoplasma hyorhinis is commonly found in the respiratory tract of pigs and is the etiological agent of polyserositis. The metabolic enzymes of M. hyorhinis may play important roles in host-pathogen interactions. We immunized BALB/c mice with sodium deoxycholate-extracted antigens (DOC-Ags) and screened 10 hybridomas that secreted antibodies against various M. hyorhinis proteins. Pyruvate dehydrogenase E1 complex subunit alpha (PDHA) was identified as the protein that reacted with five of the 10 monoclonal antibodies (mAbs). Sequence analysis indicated that PDHA was highly conserved among M. hyorhinis strains, but not among other mycoplasmas. We predicted the three-dimensional structure of PDHA and identified three epitopes ((277)RTEEEEK(283), (299)KDKKYITDE(307), and (350)LKEQKQHAKDY(360)). The mAb 1H12 we generated was used to detect M. hyorhinis PDHA in vitro and in piglets infected with M. hyorhinis. We observed that PDHA was mainly located in the epithelial cells of the lungs. Our results indicate that the mAbs we generated could be used to further investigate the structure and function of M. hyorhinis PDHA. In addition, they could be used in the differential diagnosis of M. hyorhinis and other mycoplasmas. PMID- 26743654 TI - Advanced functionalization of polyhydroxyalkanoate via the UV-initiated thiol-ene click reaction. AB - Polyhydroxyalkanoates (PHAs) incorporating vinyl-bearing 3-hydroxyalkanoates were prepared in 8.5-12.9 g L(-1) yield. The molar ratios (0-16 mol%) of the vinyl bearing 3-hydroxyalkanoate derivatives were controlled by the continuous feeding of undecylenate at various concentrations. Subsequently, the PHAs were functionalized by UV-initiated thiol-ene click reaction and chemical modification. (1)H NMR spectra suggested that 3-mercaptopropionic acid and 2 aminoethanethiol were successfully introduced into the vinyl-bearing PHA. Subsequently, chemical modification using fluorescein or a fibronectin active fragment (GRGDS) was attempted. The former yielded a PHA derivative capable of emitting fluorescence under UV irradiation, which was useful for determining the miscibility of PHA in a composite film comprising poly-L-lactic acid (PLLA) and PHA. In the latter case, PHA bearing GRGDS peptides exhibited cell adhesiveness, suggesting that its biocompatibility was improved upon peptide introduction. Taken together, the UV-initiated thiol-ene click reaction was demonstrated to be useful in PHA modification. PMID- 26743655 TI - Mechanism of antifungal activity of antimicrobial peptide APP, a cell-penetrating peptide derivative, against Candida albicans: intracellular DNA binding and cell cycle arrest. AB - We investigated the antifungal properties and anti-candidal mechanism of antimicrobial peptide APP. The minimum inhibitory concentration of APP was 8 MUM against Candida albicans and Aspeogillus flavus, the concentration against Saccharomyces cerevisiae and Cryptococcus neoformans was 16 MUM, while 32 MUM inhibited Aspergilla niger and Trichopyton rubrum. APP caused slight depolarization (12.32 +/- 0.87%) of the membrane potential of intact C. albicans cells when it exerted its anti-candidal activity and only caused 21.52 +/- 0.48% C. albicans cell membrane damage. APP interacted with cell wall membrane, caused potassium efflux and nucleotide leakage. However, confocal fluorescence microscopy experiment and flow cytometry confirmed that FITC-labeled APP penetrated C. albicans cell membrane with 52.31 +/- 1.88% cell-penetrating efficiency and accumulated in the cytoplasm. Then, APP interact with C. albicans genomic DNA and completely suppressed DNA migration above weight ratio (peptide/DNA) of 2, and significantly arrested cell cycles during the S-phase (S phase cell population was 27.09 +/- 0.73%, p < 0.05) after penetrating the cell membrane. Results indicated that APP kills C. albicans for efficient cell penetrating efficiency, strong DNA-binding affinity and significant physiological changes inducing S-phase arrest in intracellular environment. PMID- 26743656 TI - Comparative characterization of physicochemical properties and bioactivities of polysaccharides from selected medicinal mushrooms. AB - Mushroom polysaccharides have been known to possess various pharmacological activities. However, information on their chemical and biological differences between mushrooms remains limited. In this study, we aimed to examine the differences in physicochemical characteristics of polysaccharides prepared from Antrodia cinnamomea (AC-P), Coriolus versicolor (CV-P), Grifola frondosa (GF-P), Ganoderma lucidum (GL-P), and Phellinus linteus (PL-P), followed by evaluating their inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Results showed that under similar conditions of preparation, the monosaccharide composition of polysaccharides varied between different mushrooms, and glucose was the predominant monosaccharide, followed by galactose and mannose. AC-P and GF-P contained the highest amount of (1,3;1,6)-beta-D-glucans. The degree of branching of (1,3;1,6) beta-D-glucans in all polysaccharides ranged from 0.21 to 0.26, with the exception of GF-P (0.38). The molecular weights of different polysaccharides showed diverse distributions; AC-P, CV-P, and GF-P contained two major macromolecular populations (< 30 and >200 kDa) and possessed triple-helix conformation, whereas GL-P (10.2 kDa) and PL-P (15.5 kDa) only had a low molecular weight population without triple-helix structure. These polysaccharides showed different inhibitory potency on NO production in LPS-stimulated RAW264.7 cells. PMID- 26743657 TI - Bacterial nanocellulose production and application: a 10-year overview. AB - Production of bacterial nanocellulose (BNC) is becoming increasingly popular owing to its environmentally friendly properties. Based on this benefit of BNC production, researchers have also begun to examine the capacity for cellulose production through microbial hosts. Indeed, several research groups have developed processes for BNC production, and many studies have been published to date, with the goal of developing methods for large-scale production. During BNC bioproduction, the culture medium represents approximately 30 % of the total cost. Therefore, one important and challenging aspect of the fermentation process is identification of a new cost-effective culture medium that can facilitate the production of high yields within short periods of time, thereby improving BNC production and permitting application of BNC in the biotechnological, medical, pharmaceutical, and food industries. In this review, we addressed different aspects of BNC production, including types of fermentation processes and culture media, with the aim of demonstrating the importance of these parameters. PMID- 26743659 TI - Response of nitrite accumulation and microbial community to free ammonia and dissolved oxygen treatment of high ammonium wastewater. AB - The effects of free ammonia (FA) and dissolved oxygen (DO) on nitrite accumulation in the treatment of high ammonium wastewater and on the evolution of the microbial community were investigated. Under high DO conditions (3.75 +/- 0.49 mg/L), FA as high as 10.61 +/- 2.89 mg NH3/L maintained stable nitrite accumulation rate (NAR) of 84 % with NH4 (+)-N load of 2.05 kg N/(m(3) day) at sludge retention time (SRT) of 15-18 days. After 56 days of operation, Proteobacteria and Nitrosomonas were the dominant phylum and genus, respectively; Nitrosomonas increased from 21.14 to 54.57 %. By contrast, under relative low DO and low FA, nitrite-oxidizing bacteria (NOB) were nearly eliminated (NOB/AOB of 0; ammonium-oxidizing bacteria (AOB)), and NAR of 94 % was achieved with lower NH4 (+)-N load of 0.48 kg N/(m(3) day). DO correlated with AOB and NOB abundance, and FA decreased NOB activity and the NOB/AOB ratio. In conclusion, high FA and high DO conditions are optimal for efficient nitrite accumulation. PMID- 26743658 TI - Alcohol dehydrogenase gene ADH3 activates glucose alcoholic fermentation in genetically engineered Dekkera bruxellensis yeast. AB - Dekkera bruxellensis is a non-conventional Crabtree-positive yeast with a good ethanol production capability. Compared to Saccharomyces cerevisiae, its tolerance to acidic pH and its utilization of alternative carbon sources make it a promising organism for producing biofuel. In this study, we developed an auxotrophic transformation system and an expression vector, which enabled the manipulation of D. bruxellensis, thereby improving its fermentative performance. Its gene ADH3, coding for alcohol dehydrogenase, was cloned and overexpressed under the control of the strong and constitutive promoter TEF1. Our recombinant D. bruxellensis strain displayed 1.4 and 1.7 times faster specific glucose consumption rate during aerobic and anaerobic glucose fermentations, respectively; it yielded 1.2 times and 1.5 times more ethanol than did the parental strain under aerobic and anaerobic conditions, respectively. The overexpression of ADH3 in D. bruxellensis also reduced the inhibition of fermentation by anaerobiosis, the "Custer effect". Thus, the fermentative capacity of D. bruxellensis could be further improved by metabolic engineering. PMID- 26743660 TI - Tumor homing indocyanine green encapsulated micelles for near infrared and photoacoustic imaging of tumors. AB - Photoacoustic imaging (PAI) is an emerging analytical modality that is under intense preclinical development for the early diagnosis of various medical conditions, including cancer. However, the lack of specific tumor targeting by various contrast agents used in PAI obstructs its clinical applications. In this study, we developed indocyanine green (ICG)-encapsulated micelles specific for the CD 44 receptor and used in near infrared and photoacoustic imaging of tumors. ICG was hydrophobically modified prior to loading into hyaluronic acid (HA)-based micelles utilized for CD 44 based-targeting. We investigated the physicochemical characteristics of prepared HA only and ICG-encapsulated HA micelles (HA-ICG micelles). After intravenous injection of tumor-bearing mice, the bio distribution and in vivo photoacoustic images of ICG-encapsulated HA micelles accumulating in tumors were also investigated. Our study further encourages the application of this HA-ICG-based nano-platform as a tumor-specific contrast agent for PAI. PMID- 26743661 TI - Origin of the Ability of alpha-Fe2 O3 Mesopores to Activate C-H Bonds in Methane. AB - Methane is a most abundant and inexpensive hydrocarbon feedstock for the production of chemicals and fuels. However, it is extremely difficult to directly convert methane to higher hydrocarbons because the C-H bonds in methane are the most stable C-H bonds of all hydrocarbons. The activation of the C-H bonds in methane by using an efficient and mild route remains a daunting challenge. Here, we show that the inner surface structures of the pore walls in mesoporous alpha Fe2 O3 possess excellent catalytic performance for methane activation and convert C-H bonds into the C-O bonds in an O2 atmosphere at 140 degrees C. We found that such unusual structures are mainly comprised of turbostratic ribbons and K crystal faces and have higher catalytic activity than the (110) plane. These results are without precedent in the history of catalysis chemistry and will provide a new pathway for designing and preparing highly efficient catalytic materials. PMID- 26743662 TI - High-throughput multiplex real-time PCR assay for the simultaneous quantification of DNA and RNA viruses infecting cassava plants. AB - AIMS: To develop a multiplex TaqMan-based real-time PCR assay (qPCR) for the simultaneous detection and quantification of both RNA and DNA viruses affecting cassava (Manihot esculenta) in eastern Africa. METHODS AND RESULTS: The diagnostic assay was developed for two RNA viruses; Cassava brown streak virus (CBSV) and Uganda cassava brown streak virus (UCBSV) and two predominant DNA viruses; African cassava mosaic virus (ACMV) and East African cassava mosaic virus (EACMV), which cause the economically important cassava brown streak disease (CBSD) and cassava mosaic disease (CMD) respectively. Our method, developed by analysing PCR products of viruses, was highly sensitive to detect target viruses from very low quantities of 4-10 femtograms. Multiplexing did not diminish sensitivity or accuracy compared to uniplex alternatives. The assay reliably detected and quantified four cassava viruses in field samples where CBSV and UCBSV synergy was observed in majority of mixed-infected varieties. CONCLUSIONS: We have developed a high-throughput qPCR diagnostic assay capable of specific and sensitive quantification of predominant DNA and RNA viruses of cassava in eastern Africa. SIGNIFICANCE AND IMPACT OF THE STUDY: The qPCR methods are a great improvement on the existing methods and can be used for monitoring virus spread as well as for accurate evaluation of the cassava varieties for virus resistance. PMID- 26743663 TI - Temporal stability of digital radiographic detectors. AB - With the current preference for digital radiographic detectors in modern radiology facilities, there has been increasing demand for baseline technical data for equipment comparison and benchmarking. Key system parameters were monitored in 12 individual digital detectors over a 6 months period following installation, to establish baseline performance fluctuations for current generation indirect digital detectors. Performance criteria monitored included exposure index consistency, detector uniformity, system transfer function, artifact presentation, automatic exposure control reproducibility and dose area product consistency. Two indirect digital detector models were included, with the final set of measurements for each detector taken after routine detector calibrations were completed by technical staff. Suggested performance limits are presented based on observed temporal fluctuations, as well as national and international standards, where applicable. PMID- 26743664 TI - Disparities in socioeconomic status and neighborhood characteristics affect all cause mortality in patients with newly diagnosed hypertension in Korea: a nationwide cohort study, 2002-2013. AB - BACKGROUND: Previous studies have shown that contextual factors and individual socioeconomic status (SES) were associated with mortality in Western developed countries. In Korea, there are few empirical studies that have evaluated the association between SES and health outcomes. METHODS: We conducted cohort study to investigate the socioeconomic disparity in all-cause mortality for patients newly diagnosed with hypertension in the setting of universal health care coverage. We used stratified random sample of Korean National Health Insurance enrollees (2002-2013). We included patients newly diagnosed with hypertension (n = 28,306) from 2003-2006, who received oral medication to control their hypertension. We generated a frailty model using Cox's proportional hazard regression to assess risk factors for mortality. RESULTS: A total of 7,825 (27.6%) of the 28,306 eligible subjects died during the study period. Compared to high income patients from advantaged neighborhoods, the adjusted hazard ratio (HR) for high income patients from disadvantaged neighborhoods was 1.10 (95% CI, 1.00-1.20; p-value = 0.05). The adjusted HR for middle income patients who lived in advantaged versus disadvantaged neighborhoods was 1.17 (95% CI, 1.08-1.26) and 1.27 (95% CI, 1.17-1.38), respectively. For low income patients, the adjusted HR for patients who lived in disadvantaged neighborhoods was higher than those who lived in advantaged neighborhoods (HR, 1.35; 95% CI, 1.22-1.49 vs HR, 1.28; 95% CI, 1.16-1.41). CONCLUSIONS: Neighborhood deprivation can exacerbate the influence of individual SES on all-cause mortality among patients with newly diagnosed hypertension. PMID- 26743665 TI - The Impact of Green House Adoption on Medicare Spending and Utilization. AB - OBJECTIVE: To evaluate the impact of the Green House (GH) model of nursing home care on Medicare acute hospital, other hospital, skilled nursing facility, and hospice spending and utilization. DATA SOURCES/STUDY SETTING: Medicare claims and enrollment data from 2005 through 2010 merged with resident-level minimum data set (MDS) assessments. STUDY DESIGN: Using a difference-in-differences framework, we compared Medicare Part A and hospice expenditures and utilization in 15 nursing homes that adopted the GH model relative to changes over the same time period in 223 matched nonadopting nursing homes. We applied the same method for residents of GH homes and for residents of "legacy" homes, the original nursing homes that stay open alongside the GH home(s). PRINCIPAL FINDINGS: The adoption of GH had no detectable impact on Medicare Part A (plus hospice) spending and utilization across all residents living in the nursing home. When we analyzed residents living in GH homes and legacy units separately, however, we found that the adoption of the GH model reduced overall annual Medicare Part A spending by $7,746 per resident, although this appeared to be partially offset by an increase in spending in legacy homes. CONCLUSIONS: To the extent that the GH model reduces Medicare spending, adopting nursing homes do not receive any of the related Medicare savings under traditional payment mechanisms. New approaches that are currently being developed and piloted, which better align financial incentives for providers and payers, could incentivize greater adoption of the GH model. PMID- 26743667 TI - Seed Oil from Ten Algerian Peanut Landraces for Edible Use and Biodiesel Production. AB - As a result of a recent ad hoc prospection of the Algerian territory, a collection of peanut (groundnut; Arachis hypogaea L.) landraces was established, covering a remarkable array of diversity in terms of morphological and physiological features, as well as of adaptation to local bioclimatic conditions. In the present work, the oils extracted from the seeds of these landraces were evaluated in terms of edible properties and suitability for biodiesel production. As for edible use, a low free acidity (ranging from 0.62 to 1.21%) and a high oleic acid content (44.61-50.94%) were common features, although a poor stability to oxidation [high peroxide values, high spectrophotometric indices, and low % of inhibition in the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH). test] was observed in a few cases. As for biodiesel production, low values of acidity [1.23 2.40 mg KOH (g oil)(-1)], low iodine values [90.70-101.54 g I2 (g oil)(-1)], high cetane numbers (56.95-58.88) and high calorific values (higher heating value 37.34-39.27 MJ kg(-1)) were measured. Edible properties and suitability for biodiesel production were discussed with respect to the German standard DIN 51605 for rapeseed oil and to the EN 14214 standard, respectively. One way ANOVA and Hierarchical Cluster Analysis showed significant differences among the oils from the Algerian peanut landraces. PMID- 26743668 TI - Preparation and Thermal Properties of Fatty Alcohol/Surfactant/Oil/Water Nanoemulsions and Their Cosmetic Applications. AB - Physicochemical properties of oil-in-water (O/W) emulsions containing fatty alcohols and surfactants have been investigated with the aim of developing new formulations that are less viscous and more transparent than conventional milky lotions, as well as for providing greater skin-improving effects. O/W-based creams can be converted to low viscosity milky lotions following their emulsification with a homogenizer at temperatures greater than the transition temperatures of their molecular assemblies (alpha-gel). The stability of the O/W emulsions evaluated in the current study increased as the transition temperatures of the molecular assemblies formed from their fatty alcohol and surfactant constituents increased. A decrease in the emulsion droplet size led to the formation of a new formulation, which was transparent in appearance and showed a very low viscosity. The absence of a molecular assembly (alpha-gel) formed by the fatty alcohol and surfactant molecules in the aqueous phase allowed for the formation of a stable transparent and low viscosity nanoemulsion. Furthermore, this decrease in droplet size led to an increase in the interfacial area of the emulsion droplets, with almost all of the fatty alcohol and surfactant molecules being adsorbed on the surfaces of the emulsion droplets. This was found to be important for preparing a stable transparent formulation. Notably, this new formulation exhibited high occlusivity, which was equivalent to that of an ordinary cosmetic milky lotion, and consequently provided high skin hydration. The nanoemulsion was destroyed following its application to the skin, which led to the release of the fatty alcohol and surfactant molecules from the surface of the nanoemulsion into the aqueous phase. These results therefore suggest that the fatty alcohol and surfactant molecules organized the molecular assembly (alpha gel) and allowed for the reconstruction of the network structure. PMID- 26743669 TI - Synthesis and Monolayer Behaviors of Succinic Acid-Type Gemini Surfactants Containing Semifluoroalkyl Groups. AB - In this work, novel succinic acid-type gemini surfactants containing semifluoroalkyl groups, dl- and meso-2,3-bis[Rf-(CH2)n]-succinic acids (Rf = C4F9, C6F13, C8F17; n = 2, 9), were successfully synthesized, and the effects of Rf, methylene chain length (n), and stereochemistry on their monolayer behaviors were studied. Critical micelle concentrations (CMC) of dl- and meso-2,3 bis[C4F9(CH2)9]-succinic acids were one order of magnitude smaller than that of the corresponding 1+1 type surfactant, C4F9(CH2)9COOH. From surface pressure-area (pi-A) measurements, the lift-off areas of the geminis were found to decrease in the order C4F9 >= C6F13 > C8F17, regardless of methylene chain length and stereochemistry. The zero-pressure molecular areas of the geminis were twice those of the corresponding 1+1 type surfactants. Based on Gibbs compression modulus analysis, it was clarified that 2,3-bis[C8F17(CH2)n]-succinic gemini with short methylene chains (n = 2) would form more rigid monolayers than those having long methylene chains (n = 9). Unlike for 2,3-bis(alkyl)-succinic acids, the effects of stereochemistry on the monolayer behavior of semifluoroalkylated geminis were small. PMID- 26743666 TI - Clinical inertia with regard to intensifying therapy in people with type 2 diabetes treated with basal insulin. AB - AIM: To investigate whether clinical inertia, the failure to intensify treatment regimens when required, exists in people with type 2 diabetes treated with basal insulin. METHODS: This was a retrospective cohort study involving patients with type 2 diabetes in the UK Clinical Practice Research Datalink database between January 2004 and December 2011, with follow-up until December 2013. RESULTS: A total of 11 696 patients were included in the analysis. Among all patients, 36.5% had their treatment intensified during the study period; of these, the treatment of 50.0, 42.5 and 7.4% was intensified with bolus or premix insulin or glucagon like peptide-1 receptor agonists, respectively. The median time from initiation of basal insulin to treatment intensification was 4.3 years [95% confidence interval (CI) 4.1, 4.6]. Among patients clinically eligible for treatment intensification [glycated haemoglobin (HbA1c) >=7.5% (58 mmol/mol)], 30.9% had their treatment regimen intensified. The median time to intensification in this group was 3.7 years (95% CI 3.4, 4.0). Increasing age, duration of diabetes, oral antihyperglycaemic agent usage and Charlson comorbidity index score were associated with a significant delay in the time to intensification (p < 0.05). Among patients with HbA1c >=7.5% (58 mmol/mol), 32.1% stopped basal insulin therapy. CONCLUSIONS: Strategies should be developed to increase the number of patients undergoing therapy intensification and to reduce the delay in intensifying therapy for suitable patients on basal insulin. Initiatives to support patients continuing on insulin are also required. PMID- 26743670 TI - Effects of Fatty Acid Quality and Quantity in the Japanese Diet on the Suppression of Lipid Accumulation. AB - Japan has been known as a healthy country since its life expectancy became among the highest in the world in the 1980s. The influence of the Japanese diet is one of the factors explaining Japan's high life expectancy. Our recent study that fed representative freeze-dried and powdered Japanese diets from 1960, 1975, 1990, and 2005 based on National Health and Nutrition Research to mice showed the 1975 Japanese diet exhibited the strongest visceral fat accumulation suppression and overall health benefits. However, it is unclear why. We investigated the effects of the fatty acid composition in Japanese diets on visceral fat accumulation in mice. ICR mice were fed diets replicating the fatty acid composition and macronutrient ratios of Japanese diets from 1960, 1975, 1990, and 2005 for four weeks. The 1975 diet suppressed visceral fat accumulation and adipocyte hypertrophy. DNA microarray analysis showed the 1975 diet suppressed Acyl-CoA synthetase and prostaglandin D2 synthase mRNA expressions in white adipose tissue. As the effects of the 1975 diet are likely due to differences in fatty acid intake and/or composition, we investigated test diets that replicated only the fatty acid composition of Japanese diets. There were no significant differences in visceral fat mass. Therefore, both the quality and quantity of fatty acids are involved in the anti-obesity effects of the 1975 Japanese diet. PMID- 26743671 TI - Evolving concepts in muscle-invasive bladder cancer. PMID- 26743672 TI - Adipose-derived stem cells seeded on polyglycolic acid for the treatment of stress urinary incontinence. AB - PURPOSE: To evaluate the effect and possible mechanism of suburethral tissue engineered sling in an animal model of stress urinary incontinence (SUI). METHODS: Adipose-derived stem cells (ADSCs) were obtained from the adipose tissues of rats. The differentiation potential, proliferation, and viability of rat ADSCs were evaluated after infecting these cells with a lentiviral vector encoding green fluorescent protein (GFP). Next, GFP transfected ADSCs were seeded on polyglycolic acid (PGA) fibers to construct the tissue-engineered sling with the induction of 5-azacytidine (5-Aza). Afterward, the tissue-engineered slings were transplanted into a rat model of SUI that was established by vaginal balloon dilatation method and bilateral ovariectomy. Histology and the leak point pressure measurements were performed at 2 months after tissue-engineered sling implantation. RESULTS: The ADSCs were found to be efficiently transfected with GFP, without any effects on proliferation, cell cycle and multi-differentiation potential. After been seeded on PGA fibers, ADSCs formed tissue-engineered slings in 4 weeks of induction culture. Two months after implantation, the mean leak point pressure (LPP) was significantly increased in sling-treated rats compared with the balloon-injured ovariectomized rats. Immunofluorescence assay showed that some of the GFP expressing cells stained positive for muscle-specific markers. CONCLUSIONS: The newly suburethral tissue-engineered sling restores LPP in the rat model of SUI, which could be an effective treatment in future SUI therapy. PMID- 26743674 TI - Scope of negative solvatochromism and solvatofluorochromism of merocyanines. AB - A vinylogous series of highly dipolar merocyanines were designed to study their solvatochromism in a wide range of solvents including low-polarity alkanes. It has been revealed that the lower vinylogues indeed have negative solvatochromism in the full range of solvent polarities starting from n-hexane, while the hexamethinemerocyanine exhibits reversed solvatochromism. With the extreme ranges of solvatochromism, the studied dyes possess 5-7 times weaker solvatofluorochromism, which can be rationalized via their decreased dipolarity in the fluorescent state. They also demonstrate an inverse dependence of their fluorescence quantum yield on solvent polarity and have near-record Stokes shifts in high-polarity media. The experimental data are supplemented by the results of DFT quantum chemical analysis of dye electronic structures in both the ground and excited states with PCM solvent field simulation. PMID- 26743675 TI - Does the Sign of the Cu-Gd Magnetic Interaction Depend on the Number of Atoms in the Bridge? AB - Several theoretical investigations with CASSCF methods confirm that the magnetic behavior of Cu-Gd complexes can only be reproduced if the 5d Gd orbitals are included in the active space. These orbitals, expected to be unoccupied, do present a low spin density, which is mainly due to a spin polarization effect. This theory is strengthened by the experimental results reported herein. We demonstrate that Cu-Gd complexes characterized by Cu-Gd interactions through single-oxygen and three-atom bridges consisting of oxygen, carbon, and nitrogen atoms, present weak ferromagnetic exchange interactions, whereas complexes with bridges made of two atoms, such as the nitrogen-oxygen oximato bridge, are subject to weak antiferromagnetic exchange interactions. Therefore, a bridge with an odd number of atoms induces a weak ferromagnetic exchange interaction, whereas a bridge with an even number of atoms supports a weak antiferromagnetic exchange interaction, as observed in pure organic compounds and also, as in this case, in metal-organic compounds with an active spin polarization effect. PMID- 26743673 TI - Clinical features of children hospitalized with influenza A and B infections during the 2012-2013 influenza season in Italy. AB - BACKGROUND: Influenza is a major public health issue worldwide. It is characterized by episodes of infection that involve hundreds of millions of people each year. Since that in the seasons 2010-2011 and 2011-2012 the circulation of FLUB was decreasing we evaluated the clinical presentation, demographic characteristics, admitting department, and length of stay in children who contracted influenza admitted to Bambino Gesu Children's Hospital, during the 2012-2013 influenza season, with the aim to establish if the recover of FLUB was associated to a clinical worsening, in comparison with those due to FLUA. METHODS: A total of 133 respiratory specimens, collected from patients with symptoms of respiratory tract infections, positive for the Influenza A and B viruses (FLUA and B) were subtyped. Comparisons between the FLUA and FLUB groups were performed with the one-way ANOVA for continuous parametric variables, the Mann-Whitney test for non-parametric variables, or the Chi-Square test or Fisher's exact test (if cells <5) for categorical variables. RESULTS: 87.09% of the FLUA isolates were the H1N1 subtype and 12.90% were H3N2. Among the FLUB isolates, 91.54% were the B/Yamagata/16/88 lineage and 8.45% were the B/Victoria/02/87 lineage. The largest number of FLUA/H1N1 cases was observed in children less than 1 years old, while the B/Yamagata/16/88 lineage was most prevalent in children 3-6 years old. Fever was a common symptom for both FLUA and B affected patients. However, respiratory symptoms were more prevalent in patients affected by FLUA. The median length of stay in the hospital was 5 days for FLUA and 3 days for FLUB. CONCLUSIONS: The clinical features correlated to different Influenza viruses, and relevant subtypes, were evaluated concluding that the increasing of FLUB in the season 2012-2013 was without any dramatic change in clinical manifestation. Our findings suggest, finally, that a stronger commitment to managing patients affected by FLUA is required, as the disease is more severe than FLUB. PMID- 26743676 TI - Impact of patient attitudes and beliefs to insulin therapy upon initiation, and their attitudinal changes after initiation: the DAWN Japan study. AB - Objective As a part of the Diabetes Attitudes, Wishes and Needs (DAWN) Japan study, a multi-center, questionnaire-based survey conducted between 2004 and 2005, this analysis aimed to (1) explore patients' attitudes and beliefs contributing to their decision to start insulin therapy, and (2) assess the changes in their attitudes and beliefs after actual initiation. Methods Insulin naive patients with type 2 diabetes who were recommended to start insulin therapy (n = 149) were invited to answer a 21-item questionnaire consisting of five clusters assessing their attitudes and beliefs toward insulin therapy. The questionnaire was administered twice: first upon insulin recommendation, and then 1 month after insulin initiation for those who started and 4 months after for those who did not. Results Of 130 patients included in the analysis, 74 patients (56.9%) started insulin therapy. 'Negative image of injections' and 'Positive image toward insulin therapy' were significantly associated with patient decision to start insulin therapy (odds ratios [95% CI]: 0.49 [0.32-0.76] and 2.58 [1.51 4.42], respectively). After insulin initiation, 'Negative image of injections', 'Positive image toward insulin therapy', 'Feelings of guilt regarding diabetes self-management', and 'Negative image toward insulin therapy' decreased significantly (P < 0.001 for all). 'Social/interpersonal effects' did not change after insulin initiation. Conclusions This study demonstrated that patients who started insulin therapy were less likely to have negative images of injections and more likely to have positive images toward insulin therapy. Starting insulin therapy did not deteriorate the patient's overall impression of therapy. The key limitation is the relatively small sample size (n = 130). The results suggest that education about the benefits of insulin therapy may help patients who are not ready to initiate insulin overcome their barrier to early insulin initiation and practical support may help those who have already started therapy to maintain its use. PMID- 26743677 TI - Physicochemical properties of radiographic contrast media, potential nephrotoxicity and prophylaxis. AB - Contrast induced nephropathy (CIN) remains a controversial topic. The clinical relevance of changes in laboratory parameters has been challenged; some authors have even suggested that CIN simply reflects natural fluctuations. Other areas of controversy include the pathophysiology of CIN, effectiveness of prophylactic approaches and differences in nephrotoxicity between individual contrast media (CM). The aim of this review is to summarize the current understanding of laboratory findings and explore its relationship to CM toxicity. PMID- 26743678 TI - Ectopic expression of Hoxb4a in hemangioblasts promotes hematopoietic development in early embryogenesis of zebrafish. AB - Hemangioblast, including primitive hematopoietic progenitor cells, play an important role in hematopoietic development, however, the underlying mechanism for the propagation of hematopoietic progenitor cells remains elusive. A variety of regulatory molecules activated in early embryonic development play a critical role in the maintenance of function of hematopoietic progenitor cells. Homeobox transcription factors are an important class of early embryonic developmental regulators determining hematopoietic development. However, the effect of homeobox protein Hox-B4 (HOXB4) ectopic expression on the development of hemangioblasts has not been fully addressed. This study aimed to investigate the role of Hoxb4a, an ortholog gene of HOXB4 in zebrafish, in the hematopoietic development in zebrafish. A transgenic zebrafish line was established with Cre-loxP system that stably overexpressed enhanced green fluorescent protein (EGFP)-tagged Hoxb4a protein under the control of hemangioblast-specific lmo2 promoter. Overexpression of Hoxb4a in the development of hemangioblasts resulted in a considerable increase in the number of stem cell leukemia (scl) and lmo2-positive primitive hematopoietic progenitor cells occurring in the posterior intermediate cell mass (ICM). Interestingly, Hoxb4a overexpression also disrupted the development of myelomonocytes in the anterior yolk sac and the posterior ICM, without affecting erythropoiesis in the posterior ICM. Taken together, these results indicate that Hoxb4a favours the development of hematopoietic progenitor cells originated from hemangioblasts in vivo. PMID- 26743679 TI - The non-structural protein MUNS of piscine orthoreovirus (PRV) forms viral factory-like structures. AB - Piscine orthoreovirus (PRV) is associated with heart- and skeletal muscle inflammation in farmed Atlantic salmon. The virus is ubiquitous and found in both farmed and wild salmonid fish. It belongs to the family Reoviridae, closely related to the genus Orthoreovirus. The PRV genome comprises ten double-stranded RNA segments encoding at least eight structural and two non-structural proteins. Erythrocytes are the major target cells for PRV. Infected erythrocytes contain globular inclusions resembling viral factories; the putative site of viral replication. For the mammalian reovirus (MRV), the non-structural protein MUNS is the primary organizer in factory formation. The analogous PRV protein was the focus of the present study. The subcellular location of PRV MUNS and its co localization with the PRV sigmaNS, u2 and lambda1 proteins was investigated. We demonstrated that PRV MUNS forms dense globular cytoplasmic inclusions in transfected fish cells, resembling the viral factories of MRV. In co-transfection experiments with MUNS, the sigmaNS, MU2 and lambda1 proteins were recruited to the globular structures. The ability of MUNS to recruit other PRV proteins into globular inclusions indicates that it is the main viral protein involved in viral factory formation and pivotal in early steps of viral assembly. PMID- 26743680 TI - An Analysis of Altmetrics in Emergency Medicine. AB - OBJECTIVES: Alternative-level metrics (Altmetrics) are a new method to assess the sharing and spread of scientific knowledge. The primary objective of this study was to describe the traditional metrics and Altmetric scores of the 50 most frequently cited articles published in emergency medicine (EM) journals. Since many articles related to EM are published in other journals, the secondary aim of this study was to describe the Altmetric scores of the most frequently cited articles relevant to EM in other biomedical journals. METHODS: A structured search of the Institute for Scientific Information Web of Science version of the Science Citation Index Expanded was conducted. The 200 most frequently cited articles in the top 10 EM journals (2011 Journal Citation Report) were identified. The 200 most frequently cited articles from the rest of the medical literature, matching a predefined list of keywords relevant to the specialty of EM, were identified. Two authors reviewed the lists of citations for relevance to EM and a consensus approach was used to arrive at the final lists of the top 50 cited articles. The Altmetric scores for the top 50 cited articles in EM and other journals were determined. Descriptive statistics and Spearman correlation were performed. RESULTS: The highest Altmetric score for EM articles was 25.0; the mean (+/-SD) was 1.9 (+/-5.0). The EM journal with the highest mean article Altmetric score was Resuscitation. The main clinical areas shared for articles from EM articles were trauma (mean +/- SD = 11.0 +/- 15.6, median = 11.0) and cardiac arrest (mean +/- SD = 2.7 +/- 5.8, median = 0). The highest Altmetric score for other journals was 176.0 (mean +/- SD = 23.3 +/- 40.8). The other journal with the highest mean article Altmetric score was the New England Journal of Medicine. The main clinical areas shared for articles were critical care (mean +/- SD score = 36.5 +/- 47.4, median = 36.5), sepsis (mean +/- SD = 24.6 +/- 48.8, median = 12.0), cardiology (mean +/- SD = 19.2 +/- 35.6, median = 7.0), and infectious diseases (mean +/- SD = 17.0 +/- 12.7, median = 17.0). Spearman correlation demonstrated weakly positive correlation between citation counts and Altmetric scores for EM articles and other journals. CONCLUSIONS: This study is the first analysis of Altmetric scores for the top cited articles in EM. We demonstrated that there is a mild correlation between citation counts and Altmetric scores for the top papers in EM and other biomedical journals. We also demonstrated that there is a gap between the sharing of the top articles in EM journals and those related to EM in other biomedical journals. Future research to explore this relationship and its temporal trends will benefit the understanding of the reach and dissemination of EM research within the scientific community and society in general. PMID- 26743681 TI - A commentary on the 2015 Canadian Clinical Practice Guidelines in glutamine supplementation to parenteral nutrition. AB - Glutamine is one of the conditionally essential free amino acids with multiple biological functions. Its supplementation to parenteral nutrition has been widely used for the management of complications in intensive care. However, controversial clinical reports have generated reluctance in the use of this pharmaco-nutrient. In this commentary, we address the impact of four studies that influenced the recommendations on glutamine supplementation by the Canadian Clinical Practice Guide 2015. Because of the importance of this guideline in clinical practice, we strongly believe that a more rigorous and critical evaluation is required to support recommendations in future guidelines. PMID- 26743683 TI - Respiratory tract infection caused by Mycobacterium bovis in a black swan (Cygnus atratus). AB - A 3-year-old male black swan (Cygnus atratus), belonging to a private collection, died suddenly and was subjected to post mortem examination. At necropsy, caseous exudate was observed in the lungs and air sacs; granulomatous lesions characterized by epithelioid macrophages and abundant mycobacteria were observed microscopically. Avian tuberculosis associated with Mycobacterium bovis was confirmed by bacteriologic isolation, biochemical tests and molecular methods. The organism was identified as spoligotype SB0140, which is frequently found in cattle and people in North America. In this case, interspecies transmission could have been the source of infection because the swan cohabited with cattle. PMID- 26743684 TI - Assessing the impact of humidex on HFMD in Guangdong Province and its variability across social-economic status and age groups. AB - Humidex is a meteorological index that combines the impacts of temperature and humidity, and is directly comparable with dry temperature in degrees Celsius. However, to date, no research has focused on the effect of humidex on hand, foot and mouth disease (HFMD). The current study was designed to address this research need. Case-based HFMD surveillance data and daily meteorological data collected between 2010 and 2012 was obtained from the China CDC and the National Meteorological Information Center, respectively. Distributed lag nonlinear models were applied to assess the impact of humidex on HFMD among children under 15 years oldin Guangdong, and its variability across social-economic status and age groups. We found that relative risk (RR) largely increased with humidex. Lag specific and cumulative humidex-RR curves for children from the Pearl-River Delta Region as well as older children were more likely to show two-peak distribution patterns. One RR peak occurred at a humidex of between 15 and 20, and the other occurred between 30 and 35. This study provides a comprehensive picture of the impact of humidex on HFMD incidence in Guangdong Province. Results from the present study should be important in the development of area-and-age-targeted control programs. PMID- 26743686 TI - Neutral nickel(II) phthalocyanine as a stable catalyst for visible-light-driven hydrogen evolution from water. AB - Neutral nickel(ii) phthalocyanine was found to be an efficient and stable catalyst for photocatalytic H2 evolution from water when coupled with an iridium complex as the photosensitizer and triethanolamine as the sacrificial electron donor. The result shows that the Ni-N sigma bond can enhance the stability of the catalyst. PMID- 26743685 TI - Proposed reference sequences for hepatitis E virus subtypes. AB - The nomenclature of hepatitis E virus (HEV) subtypes is inconsistent and makes comparison of different studies problematic. We have provided a table of proposed complete genome reference sequences for each subtype. The criteria for subtype assignment vary between different genotypes and methodologies, and so a conservative pragmatic approach has been favoured. Updates to this table will be posted on the International Committee on Taxonomy of Viruses website (http://talk.ictvonline.org/r.ashx?C). The use of common reference sequences will facilitate communication between researchers and help clarify the epidemiology of this important human pathogen. This subtyping procedure might be adopted for other taxa of the genus Orthohepevirus. PMID- 26743682 TI - A highly selective and sensitive near-infrared fluorescent probe for imaging of hydrogen sulphide in living cells and mice. AB - Hydrogen sulphide (H2S), the third endogenous gaseous signalling molecule, has attracted attention in biochemical research. The selective detection of H2S in living systems is essential for studying its functions. Fluorescence detection methods have become useful tools to explore the physiological roles of H2S because of their real-time and non-destructive characteristics. Herein we report a near-infrared fluorescent probe, NIR-HS, capable of tracking H2S in living organisms. With high sensitivity, good selectivity and low cytotoxicity, NIR-HS was able to recognize both the exogenous and endogenous H2S in living cells. More importantly, it realized the visualization of endogenous H2S generated in cells overexpressing cystathionine beta-synthase (CBS), one of the enzymes responsible for producing endogenous H2S. The probe was also successfully applied to detect both the exogenous and endogenous H2S in living mice. The superior sensing properties of the probe render it a valuable research tool in the H2S-related medical research. PMID- 26743687 TI - Skill complementarity enhances heterophily in collaboration networks. AB - Much empirical evidence shows that individuals usually exhibit significant homophily in social networks. We demonstrate, however, skill complementarity enhances heterophily in the formation of collaboration networks, where people prefer to forge social ties with people who have professions different from their own. We construct a model to quantify the heterophily by assuming that individuals choose collaborators to maximize utility. Using a huge database of online societies, we find evidence of heterophily in collaboration networks. The results of model calibration confirm the presence of heterophily. Both empirical analysis and model calibration show that the heterophilous feature is persistent along the evolution of online societies. Furthermore, the degree of skill complementarity is positively correlated with their production output. Our work sheds new light on the scientific research utility of virtual worlds for studying human behaviors in complex socioeconomic systems. PMID- 26743688 TI - MiR-192 suppresses the tumorigenicity of prostate cancer cells by targeting and inhibiting nin one binding protein. AB - Nin one binding (NOB1) protein has been identified as an oncogene in various human cancers, including prostate cancer. MicroRNAs (miRs) have also been recognized as novel regulatory molecules of gene expression. The present study aimed to discover potential miRs that target NOB1 and regulate NOB1 expression in prostate cancer. miR-192, which is an important regulator of numerous cancers, was found to be significantly downregulated in prostate cancer cells. Moreover, we noted that miR-192 overexpression markedly inhibited the proliferation, colony forming ability, and migratory capacity of the prostate cancer cells. miR-192 overexpression also induced cell cycle arrest in the G1 phase, as shown by flow cytometry. Bioinformatics analysis results revealed that NOB1 was a possible candidate target gene of miR-192. This discovery was further verified through dual-luciferase reporter assay, RT-qPCR, and western blot analysis. We suggest that miR-192 directly regulates the mRNA and protein expression of NOB1. Furthermore, miR-192 inhibited the expression of p38 mitogen-activated protein kinase. The results of our study indicated that miR-192 negatively regulated NOB1 expression and impaired the tumorigenicity of prostate cancer cells. Therefore, we suggest that targeting miR-192 and NOB1 is a novel strategy which will assist in the development of new therapeutics that will be used in the future to prevent and treat prostate cancer. PMID- 26743689 TI - Precise Analysis of Polymer Rotational Dynamics. AB - Through the analysis of individual chain dynamics alongside the corresponding molecular structures under shear via nonequilibrium molecular dynamics simulations of C178H358 linear and short-chain branched polyethylene melts under shear flow, we observed that the conventional method based on the chain end-to end vector (and/or the gyration tensor of chain) is susceptible to quantitatively inaccurate measurements and often misleading information in describing the rotational dynamics of polymers. Identifying the flaw as attributed to strong irregular Brownian fluctuations inherent to the chain ends associated with their large free volume and strong molecular collisions, we propose a simple, robust way based on the chain center-to-center vector connecting the two centers of mass of the bisected chain, which is shown to adequately describe polymer rotational dynamics without such shortcomings. We present further consideration that the proposed method can be useful in accurately measuring the overall chain structure and dynamics of polymeric materials with various molecular architectures, including branched and ring polymers. PMID- 26743690 TI - Dihydroartemisinin prevents breast cancer-induced osteolysis via inhibiting both breast caner cells and osteoclasts. AB - Bone is the most common site of distant relapse in breast cancer, leading to severe complications which dramatically affect the patients' quality of life. It is believed that the crosstalk between metastatic breast cancer cells and osteoclasts is critical for breast cancer-induced osteolysis. In this study, the effects of dihydroartemisinin (DHA) on osteoclast formation, bone resorption, osteoblast differentiation and mineralization were initially assessed in vitro, followed by further investigation in a titanium-particle-induced osteolysis model in vivo. Based on the proved inhibitory effect of DHA on osteolysis, DHA was further applied to MDA-MB-231 breast cancer-induced mouse osteolysis model, with the underlying molecular mechanisms further investigated. Here, we verified for the first time that DHA suppressed osteoclast differentiation, F-actin ring formation and bone resorption through suppressing AKT/SRC pathways, leading to the preventive effect of DHA on titanium-particle-induced osteolysis without affecting osteoblast function. More importantly, we demonstrated that DHA inhibited breast tumor-induced osteolysis through inhibiting the proliferation, migration and invasion of MDA-MB-231 cells via modulating AKT signaling pathway. In conclusion, DHA effectively inhibited osteoclastogenesis and prevented breast cancer-induced osteolysis. PMID- 26743691 TI - Ciliated neurons lining the central canal sense both fluid movement and pH through ASIC3. AB - Cerebrospinal fluid-contacting (CSF-c) cells are found in all vertebrates but their function has remained elusive. We recently identified one type of laterally projecting CSF-c cell in lamprey spinal cord with neuronal properties that expresses GABA and somatostatin. We show here that these CSF-c neurons respond to both mechanical stimulation and to lowered pH. These effects are most likely mediated by ASIC3-channels, since APETx2, a specific antagonist of ASIC3, blocks them both. Furthermore, lowering of pH as well as application of somatostatin will reduce the locomotor burst rate. The somatostatin receptor antagonist counteracts the effects of both a decrease in pH and of somatostatin. Lateral bending movement imposed on the spinal cord, as would occur during natural swimming, activates CSF-c neurons. Taken together, we show that CSF-c neurons act both as mechanoreceptors and as chemoreceptors through ASIC3 channels, and their action may protect against pH-changes resulting from excessive neuronal activity. PMID- 26743693 TI - Atomic-Scale Visualization of Quantum Interference on a Weyl Semimetal Surface by Scanning Tunneling Microscopy. AB - Weyl semimetals may open a new era in condensed matter physics, materials science, and nanotechnology after graphene and topological insulators. We report the first atomic scale view of the surface states of a Weyl semimetal (NbP) using scanning tunneling microscopy/spectroscopy. We observe coherent quantum interference patterns that arise from the scattering of quasiparticles near point defects on the surface. The measurements reveal the surface electronic structure both below and above the chemical potential in both real and reciprocal spaces. Moreover, the interference maps uncover the scattering processes of NbP's exotic surface states. Through comparison between experimental data and theoretical calculations, we further discover that the orbital and/or spin texture of the surface bands may suppress certain scattering channels on NbP. These results provide a comprehensive understanding of electronic properties on Weyl semimetal surfaces. PMID- 26743694 TI - Enantioselective Synthesis of alpha-Methyl-beta-cyclopropyldihydrocinnamates. AB - alpha- and beta-substitution of dihydrocinnamates has been shown to increase the biological activity of various drug candidates. Recently, we identified enantio- and diastereopure alpha-methyl-beta-cyclopropyldihydrocinnamates to be important pharmacophores in one of our drug discovery programs and endeavored to devise an asymmetric hydrogenation strategy to improve access to this valuable framework. We used high throughput experimentation to define stereoconvergent Suzuki-Miyaura cross-coupling conditions affording (Z)-alpha-methyl-beta-cyclopropylcinnamates and subsequent ruthenium-catalyzed asymmetric hydrogenation conditions affording the desired products in excellent enantio- and diastereoselectivities. These conditions were executed on multigram to kilogram scale to provide three key enantiopure alpha-methyl-beta-cyclopropyldihydrocinnamates with high selectivity. PMID- 26743696 TI - Impact of childhood experience and adult well-being on eating preferences and behaviours. AB - OBJECTIVES: To examine the relative contribution of childhood experience, measured by childhood violence and childhood happiness, and adult well-being on adult eating preferences and behaviours, independent of proximal factors such as current deprivation. DESIGN: A cross-sectional, stratified, randomised sample survey using retrospective measures of childhood violence and happiness and self reported measures of current well-being. SETTING: The North West Region of England between September 2012 and March 2013. PARTICIPANTS: Individuals aged 18 95-year-olds from randomly selected households (participation was successful for 90% of eligible households and 78% of the total visited addresses; n=11,243). OUTCOMES: Dichotomised measures for preference of healthy foods or 'feel good' foods and low or high daily fruit and vegetable consumption. RESULTS: After correcting for demographics, combined categories for childhood experience and dichotomised measures of adult well-being were found to be significantly related to adult food preferences and eating behaviours. Participants with unhappy and violent childhoods compared to those with happy and non-violent childhoods had adjusted ORs (95% CI, significance) of 2.67 (2.15 to 3.06, p<0.001) of having low daily fruit and vegetable intake (two or less portions) and 1.53 (1.29 to 1.81, p<0.001) of choosing 'feel good' foods over foods which were good for their long term health. CONCLUSIONS: Daily intake of fruit and vegetables, linked to non communicable diseases, and preference for 'feel good' foods, linked to obesity, are affected by childhood experience and adult well-being independent of demographic factors. Preventative interventions which support parent-child relationships and improve childhood experience are likely to reduce the development of poor dietary and other health-risk behaviours. PMID- 26743692 TI - TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-kbeta inhibition. AB - Multiple myeloma (MM) is a B-cell malignancy characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Introduction of the proteasome inhibitor bortezomib has improved MM prognosis and survival; however hypoxia induced or acquired bortezomib resistance remains a clinical problem. This study highlighted the role of thioredoxin reductase 1 (TrxR1) in the hypoxia-induced and acquired bortezomib resistance in MM. Higher TrxR1 gene expression correlated with high-risk disease, adverse overall survival, and poor prognosis in myeloma patients. We demonstrated that hypoxia induced bortezomib resistance in myeloma cells and increased TrxR1 protein levels. Inhibition of TrxR1 using auranofin overcame hypoxia-induced bortezomib resistance and restored the sensitivity of hypoxic-myeloma cells to bortezomib. Hypoxia increased NF-kbeta subunit p65 nuclear protein levels and TrxR1 inhibition decreased hypoxia-induced NF-kbeta p65 protein levels in the nucleus and reduced the expression of NF-kbeta regulated genes. In addition, higher TrxR1 protein levels were observed in bortezomib-resistant myeloma cells compared to the naive cells, and its inhibition using either auranofin or TrxR1-specific siRNAs reversed bortezomib resistance. TrxR1 inhibition reduced p65 mRNA and protein expression in bortezomib-resistant myeloma cells, and also decreased the expression of NF-kbeta regulated anti-apoptotic and proliferative genes. Thus, TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance by inhibiting the NF-kbeta signaling pathway. Our findings demonstrate that elevated TrxR1 levels correlate with the acquisition of bortezomib resistance in MM. We propose considering TrxR1-inhibiting drugs, such as auranofin, either for single agent or combination therapy to circumvent bortezomib-resistance and improve survival outcomes of MM patients. PMID- 26743697 TI - Intraclass correlation and design effect in BMI, physical activity and diet: a cross-sectional study of 56 countries. AB - OBJECTIVES: Measuring the intraclass correlation coefficient (ICC) and design effect (DE) may help to modify the public health interventions for body mass index (BMI), physical activity and diet according to geographic targeting of interventions in different countries. The purpose of this study was to quantify the level of clustering and DE in BMI, physical activity and diet in 56 low income, middle-income and high-income countries. DESIGN: Cross-sectional study design. SETTING: Multicountry national survey data. METHODS: The World Health Survey (WHS), 2003, data were used to examine clustering in BMI, physical activity in metabolic equivalent of task (MET) and diet in fruits and vegetables intake (FVI) from low-income, middle-income and high-income countries. Multistage sampling in the WHS used geographical clusters as primary sampling units (PSU). These PSUs were used as a clustering or grouping variable in this analysis. Multilevel intercept only regression models were used to calculate the ICC and DE for each country. RESULTS: The median ICC (0.039) and median DE (1.82) for BMI were low; however, FVI had a higher median ICC (0.189) and median DE (4.16). For MET, the median ICC was 0.141 and median DE was 4.59. In some countries, however, the ICC and DE for BMI were large. For instance, South Africa had the highest ICC (0.39) and DE (11.9) for BMI, whereas Uruguay had the highest ICC (0.434) for MET and Ethiopia had the highest ICC (0.471) for FVI. CONCLUSIONS: This study shows that across a wide range of countries, there was low area level clustering for BMI, whereas MET and FVI showed high area level clustering. These results suggested that the country level clustering effect should be considered in developing preventive approaches for BMI, as well as improving physical activity and healthy diets for each country. PMID- 26743699 TI - Systematic review of the literature on viral persistence and sexual transmission from recovered Ebola survivors: evidence and recommendations. AB - OBJECTIVE: The main aim of this article is to present a comprehensive, systematic review on evidence of sexual transmission from Ebola survivors and persistence of Ebola virus in body fluids of relevance to sexual transmission, and additionally to review condom effectiveness against sexual transmission of Ebola. DESIGN: We performed a systematic review of viral persistence in body fluids of relevance to sexual transmission of Ebola survivors and evidence of sexual transmission of Ebola, and carried out a targeted review of condom effectiveness. RESULTS: We identified nine published original articles presenting results on persistence of Ebola virus in relevant body fluids, or reporting suspect sexual transmission from Ebola survivors. We also included unpublished reports from the current 2014/2015 Ebola epidemic in West Africa. We found no articles reporting on condom effectiveness, but have included a targeted review on general condom efficacy and effectiveness. CONCLUSIONS: We conclude that the risk of sexual transmission from people who have recovered from Ebola cannot be ruled out. We found the longest duration of persistent Ebola RNA in a relevant body fluid from a survivor, to be reported from a man in Sierra Leone who had reverse transcriptase PCR (RT-PCR) positive semen 284 days after symptom onset. In line with current WHO recommendations. We recommend that men are offered the possibility to test their semen regularly for presence of Ebola RNA from 3 months post-symptom onset. Safe sex practices including sexual abstinence, or else condom use, are recommended by WHO until semen has tested negative twice, or in absence of testing for at least 6 months post-symptom onset. Based on evidence reviewed, we conclude that male and female latex condoms offer some protection against EBOV compared to no condom use. Survivors should be offered access to care and prevention, in order to provide them with possibilities to mitigate any risks that may occur, and efforts should be linked to destigmatising activities. PMID- 26743698 TI - Progressive resistance training in Parkinson's disease: a systematic review and meta-analysis. AB - OBJECTIVES: To investigate if there is evidence on effectiveness of progressive resistance training in rehabilitation of Parkinson disease. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Central, Medline, Embase, Cinahl, Web of Science, Pedro until May 2014. Randomised controlled or controlled clinical trials. The methodological quality of studies was assessed according to the Cochrane Collaboration's domain-based evaluation framework. DATA SYNTHESIS: random effects meta-analysis with test for heterogeneity using the I2 and pooled estimate as the raw mean difference. PARTICIPANTS: Adults with primary/idiopathic Parkinson's disease of any severity, excluding other concurrent neurological condition. INTERVENTIONS: Progressive resistance training defined as training consisting of a small number of repetitions until fatigue, allowing sufficient rest between exercises for recovery, and increasing the resistance as the ability to generate force improves. COMPARISON: Progressive resistance training versus no treatment, placebo or other treatment in randomised controlled or controlled clinical trials. PRIMARY AND SECONDARY OUTCOME MEASURES: Any outcome. RESULTS: Of 516 records, 12 were considered relevant. Nine of them had low risk of bias. All studies were randomised controlled trials conducted on small samples with none or 1 month follow-up after the end of intervention. Of them, six were included in quantitative analysis. Pooled effect sizes of meta-analyses on fast and comfortable walking speed, the 6 min walking test, Timed Up and Go test and maximal oxygen consumption were below the level of minimal clinical significance. CONCLUSIONS: There is so far no evidence on the superiority of progressive resistance training compared with other physical training to support the use of this technique in rehabilitation of Parkinson's disease. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO 2014:CRD42014009844. PMID- 26743700 TI - Assessment of adult body composition using bioelectrical impedance: comparison of researcher calculated to machine outputted values. AB - OBJECTIVES: To explore the usefulness of Bioelectrical Impedance Analysis (BIA) for general use by identifying best-evidenced formulae to calculate lean and fat mass, comparing these to historical gold standard data and comparing these results with machine-generated output. In addition, we explored how to best to adjust lean and fat estimates for height and how these overlapped with body mass index (BMI). DESIGN: Cross-sectional observational study within population representative cohort study. SETTING: Urban community, North East England PARTICIPANTS: Sample of 506 mothers of children aged 7-8 years, mean age 36.3 years. METHODS: Participants were measured at a home visit using a portable height measure and leg-to-leg BIA machine (Tanita TBF-300MA). MEASURES: Height, weight, bioelectrical impedance (BIA). OUTCOME MEASURES: Lean and fat mass calculated using best-evidenced published formulae as well as machine-calculated lean and fat mass data. RESULTS: Estimates of lean mass were similar to historical results using gold standard methods. When compared with the machine generated values, there were wide limits of agreement for fat mass and a large relative bias for lean that varied with size. Lean and fat residuals adjusted for height differed little from indices of lean (or fat)/height(2). Of 112 women with BMI >30 kg/m(2), 100 (91%) also had high fat, but of the 16 with low BMI (<19 kg/m(2)) only 5 (31%) also had low fat. CONCLUSIONS: Lean and fat mass calculated from BIA using published formulae produces plausible values and demonstrate good concordance between high BMI and high fat, but these differ substantially from the machine-generated values. Bioelectrical impedance can supply a robust and useful field measure of body composition, so long as the machine-generated output is not used. PMID- 26743701 TI - What do pharmaceutical industry professionals in Europe believe about involving patients and the public in research and development of medicines? A qualitative interview study. AB - OBJECTIVES: To explore European-based pharmaceutical industry professionals' beliefs about patient and public involvement (PPI) in medicines research and development (R&D). SETTING: Pharmaceutical companies in the UK, Poland and Spain. PARTICIPANTS: 21 pharmaceutical industry professionals, four based in the UK, five with pan-European roles, four based in Spain and eight based in Poland. METHOD: Qualitative interview study (telephone and face-to-face, semistructured interviews). All interviews were audio taped, translated (where appropriate) and transcribed for analysis using the Framework approach. RESULTS: 21 pharmaceutical industry professionals participated. Key themes were: beliefs about (1) whether patients and the public should be involved in medicines R&D; (2) the barriers and facilitators to PPI in medicines R&D and (3) how the current relationships between the pharmaceutical industry, patient organisations and patients influence PPI in medicines R&D. CONCLUSIONS: Although interviewees appeared positive about PPI, many were uncertain about when, how and which patients to involve. Patients and the public's lack of knowledge and interest in medicines R&D, and the pharmaceutical industry's lack of knowledge, interest and receptivity to PPI were believed to be key challenges to increasing PPI. Interviewees also believed that relationships between the pharmaceutical industry, patient organisations, patients and the public needed to change to facilitate PPI in medicines R&D. Existing pharmaceutical industry codes of practice and negative media reporting of the pharmaceutical industry were also seen as negative influences on these relationships. PMID- 26743704 TI - Relationship between use of general practice and healthcare costs at the end of life: a data linkage study in New South Wales, Australia. AB - OBJECTIVE: This analysis investigated the relationships between healthcare expenditures in the last 6 months of life and use of general practitioner (GP) services in the preceding 12-month period among older residents of New South Wales, Australia. METHODS: Questionnaire data (2006-2009) for more than 260,000 people aged 45 years and over were linked to individual hospital and death records and cost data. For 14,819 participants who died during follow-up, generalised linear mixed models were used to explore the relationships between costs of hospital, emergency department (ED) and Medicare-funded outpatient and pharmaceutical services in the last 6 months of life, and quintile of GP use in the 18-7 months before death. Analyses were adjusted for age at death, sex, educational level, language, private health insurance, household income, self reported health status, functional limitation, psychological distress, number of comorbidities and geographic clustering. RESULTS: Almost 85% of decedents had at least one hospitalisation in the last 6 months, and the mean (median) of total cost for each person in this period was $A20,453 (14,835). There was no significant difference in the hospital cost, including cost for preventable hospitalisations in the last 6 months of life, across quintiles of GP use in the 18-7 months before death. Participants in the lowest quintile of GP use incurred more ED costs, but ED costs were similar across the other quintiles of GP use. Costs for Medicare-funded outpatient services and pharmaceuticals increased steeply according to quintile of GP use. CONCLUSIONS: In the Australian setting, there was no association between use of GP services in the 18-7 months before death and hospital costs in the last 6 months, but there was significant association with higher costs for outpatient services and pharmaceuticals. However, there was some indication that limited GP access might be associated with increased ED use at end of life. PMID- 26743703 TI - A nationwide survey of public healthcare providers' impressions of family medicine specialists in Malaysia: a qualitative analysis of written comments. AB - OBJECTIVE: To examine impressions of public healthcare providers/professionals (PHCPs) who are working closely with family medicine specialists (FMSs) at public health clinics. DESIGN: Cross-sectional study. SETTING: This study is part of a larger national study on the perception of Malaysian public healthcare professionals on FMSs (PERMFAMS). PARTICIPANTS: PHCPs from three categories of health facility: hospitals, health clinics and health offices. MAIN OUTCOME MEASURES: Qualitative analyses of written comments of respondents' general impression of FMSs. RESULTS: The participants' response rate was 58.0% (780/1345), with almost equal proportions from each public healthcare facility. A total of 23 categories for each of the 648 impression comments were identified. The six emerging themes were: (1) importance of FMSs; (2) roles of FMSs; (3) clinical performance of FMSs; (4) attributes of FMSs; (5) FMS practice challenges; (6) misconception of FMS roles. Overall, FMS practice was perceived to be safe and able to provide effective treatments in a challenging medical discipline that was in line with the current standards of medical care and ethical and professional values. The areas of concern were in clinical performance expressed by PHCPs from some hospitals and the lack of personal attributes and professionalism among FMSs mentioned by PHCPs from health clinics and offices. CONCLUSIONS: FMSs were perceived to be capable of providing effective treatment and were considered to be important primary care physicians. There were a few negative impressions in some areas of FMS practice, which demanded attention by the FMSs themselves and the relevant authorities in order to improve efficiency and safeguard the fraternity's reputation. PMID- 26743702 TI - Markers of achievement for assessing and monitoring gender equity in translational research organisations: a rationale and study protocol. AB - INTRODUCTION: Translational research organisations (TROs) are a core component of the UK's expanding research base. Equity of career opportunity is key to ensuring a diverse and internationally competitive workforce. The UK now requires TROs to demonstrate how they are supporting gender equity. Yet, the evidence base for documenting such efforts is sparse. This study is designed to inform the acceleration of women's advancement and leadership in two of the UK's leading TROs--the National Institute for Health Research (NIHR) Biomedical Research Centres (BRCs) in Oxford and London--through the development, application and dissemination of a conceptual framework and measurement tool. METHODS AND ANALYSIS: A cross-sectional retrospective evaluation. A conceptual framework with markers of achievement and corresponding candidate metrics has been specifically designed for this study based on an adapted balanced scorecard approach. It will be refined with an online stakeholder consultation and semistructured interviews to test the face validity and explore practices and mechanisms that influence gender equity in the given settings. Data will be collected via the relevant administrative databases. A comparison of two funding periods (2007-2012 and 2012 2017) will be carried out. ETHICS AND DISSEMINATION: The University of Oxford Clinical Trials and Research Governance Team and the Research and Development Governance Team of Guy's and St Thomas' National Health Service (NHS) Foundation Trust reviewed the study and deemed it exempt from full ethics review. The results of the study will be used to inform prospective planning and monitoring within the participating NIHR BRCs with a view to accelerating women's advancement and leadership. Both the results of the study and its methodology will be further disseminated to academics and practitioners through the networks of collaborating TROs, relevant conferences and articles in peer-reviewed journals. PMID- 26743705 TI - A qualitative study exploring how Somali women exposed to female genital mutilation experience and perceive antenatal and intrapartum care in England. AB - OBJECTIVES: To explore how Somali women exposed to female genital mutilation experience and perceive antenatal and intrapartum care in England. We explored women's perceptions of deinfibulation, caesarean section and vaginal delivery; their experiences of care during pregnancy and labour; and factors that affect ability to access these services, in order to make recommendations about future practice. DESIGN: A descriptive, exploratory qualitative study using face-to-face semistructured interviews. Interviews were audio-recorded, transcribed and data were analysed using a thematic approach. An interpreter was used when required (n=3). SETTING: Participants recruited from 2 community centres in Birmingham, England. PARTICIPANTS: Convenience and snowball sample of 10 Somali women resident in Birmingham, who had accessed antenatal care services in England within the past 5 years. RESULTS: 3 core themes were interpreted: (1) Experiences of female genital mutilation during life, pregnancy and labour: Female genital mutilation had a significant physical and psychological impact, influencing decisions to undergo deinfibulation or caesarean section. Women delayed deinfibulation until labour to avoid undergoing multiple operations if an episiotomy was anticipated. (2) Experience of care from midwives: Awareness of female genital mutilation from midwives led to open communication and stronger relationships with women, resulting in more positive experiences. (3) Adaptation to English life: Good language skills and social support networks enabled women to access these services, while unfavourable social factors (eg, inability to drive) impeded. CONCLUSIONS: Female genital mutilation impacts Somali women's experiences of antenatal and intrapartum care. This study suggests that midwives should routinely ask Somali women about female genital mutilation to encourage open communication and facilitate more positive experiences. As antenatal deinfibulation is unpopular, we should consider developing strategies to promote deinfibulation to non-pregnant women, to align with current guidelines. Women with unfavourable social factors may require additional support to improve access to English antenatal care services. PMID- 26743706 TI - Physical Activity through Sustainable Transport Approaches (PASTA): a study protocol for a multicentre project. AB - INTRODUCTION: Only one-third of the European population meets the minimum recommended levels of physical activity (PA). Physical inactivity is a major risk factor for non-communicable diseases. Walking and cycling for transport (active mobility, AM) are well suited to provide regular PA. The European research project Physical Activity through Sustainable Transport Approaches (PASTA) pursues the following aims: (1) to investigate correlates and interrelations of AM, PA, air pollution and crash risk; (2) to evaluate the effectiveness of selected interventions to promote AM; (3) to improve health impact assessment (HIA) of AM; (4) to foster the exchange between the disciplines of public health and transport planning, and between research and practice. METHODS AND ANALYSIS: PASTA pursues a mixed-method and multilevel approach that is consistently applied in seven case study cities. Determinants of AM and the evaluation of measures to increase AM are investigated through a large scale longitudinal survey, with overall 14,000 respondents participating in Antwerp, Barcelona, London, Orebro, Rome, Vienna and Zurich. Contextual factors are systematically gathered in each city. PASTA generates empirical findings to improve HIA for AM, for example, with estimates of crash risks, factors on AM-PA substitution and carbon emissions savings from mode shifts. Findings from PASTA will inform WHO's online Health Economic Assessment Tool on the health benefits from cycling and/or walking. The study's wide scope, the combination of qualitative and quantitative methods and health and transport methods, the innovative survey design, the general and city specific analyses, and the transdisciplinary composition of the consortium and the wider network of partners promise highly relevant insights for research and practice. ETHICS AND DISSEMINATION: Ethics approval has been obtained by the local ethics committees in the countries where the work is being conducted, and sent to the European Commission before the start of the survey. The PASTA website (http://www.pastaproject.eu) is at the core of all communication and dissemination activities. PMID- 26743708 TI - Complexity in the new NHS: longitudinal case studies of CCGs in England. AB - OBJECTIVE: The reform in the English National Health Services (NHS) under the Health and Social Care Act 2012 is unlike previous NHS reorganisations. The establishment of clinical commissioning groups (CCGs) was intended to be 'bottom up' with no central blueprint. This paper sets out to offer evidence about how this process has played out in practice and examines the implications of the complexity and variation which emerged. DESIGN: Detailed case studies in CCGs across England, using interviews, observation and documentary analysis. Using realist framework, we unpacked the complexity of CCG structures. SETTING/PARTICIPANTS: In phase 1 of the study (January 2011 to September 2012), we conducted 96 interviews, 439 h of observation in a wide variety of meetings, 2 online surveys and 38 follow-up telephone interviews. In phase 2 (April 2013 to March 2015), we conducted 42 interviews with general practitioners (GPs) and managers and observation of 48 different types of meetings. RESULTS: Our study has highlighted the complexity inherent in CCGs, arising out of the relatively permissive environment in which they developed. Not only are they very different from one another in size, but also in structure, functions between different bodies and the roles played by GPs. CONCLUSIONS: The complexity and lack of uniformity of CCGs is important as it makes it difficult for those who must engage with CCGs to know who to approach at what level. This is of increasing importance as CCGs are moving towards greater integration across health and social care. Our study also suggests that there is little consensus as to what being a 'membership' organisation means and how it should operate. The lack of uniformity in CCG structure and lack of clarity over the meaning of 'membership' raises questions over accountability, which becomes of greater importance as CCG is taking over responsibility for primary care co-commissioning. PMID- 26743707 TI - 'Keeping your body and mind active': an ethnographic study of aspirations for healthy ageing. AB - OBJECTIVE: To describe and explore perceptions, practices and motivations for active living in later life. DESIGN: Qualitative study with semistructured interviews and 'semistructured' participant observations of participant-selected activities, such as exercise classes, private or organised walks, shopping and gardening. PARTICIPANTS: 27 participants (65-80 years) from the European Prospective Investigation into Cancer Norfolk study, purposefully selected by gender, age, occupational class, living status and residential location; 19 of the participants agreed to be accompanied for observed activities. SETTING: Participants' homes, neighbourhoods, places of leisure activities and workplaces in Norfolk, England. RESULTS: All participants regarded a positive attitude as important for healthy ageing; this included staying active, both physically and mentally through sedentary activities such as reading and crosswords. 'Getting out of the house', being busy, or following a variety of interests were regarded as both important motivators and descriptions of their 'activeness'. Purposeful activities formed an important part of this, for example, still being engaged in paid or voluntary work, having caring responsibilities, or smaller incidental activities such as helping neighbours or walking for transport. Many also reported adapting previous, often lifelong, activity preferences and habits to their ageing body, or replacing them altogether with lower impact activities such as walking. This included adapting to the physical limitations of partners and friends which dictated the intensity and frequency of shared activities. The social context of activities could thus form a barrier to active living, but could also encourage it through companionship, social responsibilities and social pressures. CONCLUSIONS: Promoting and maintaining physical activity among older people may require more attention to activeness as an attitude and way of life as well as to its social context, and initiatives encouraging broader activity habits rather than discrete activities. PMID- 26743710 TI - Physicochemical Properties, Biomolecular Corona, Bioactivity, and Pharmacology Based Issues of Biopolymers: A Brief Overview: Letter in Response to an Opinion Article Published in Trends in Biotechnology: Wang, C. and Dong, L. (2015) Exploring 'New' Bioactivities of Polymers at the Nano-Bio Interface. Trends Biotechnol. 33, 10-14. PMID- 26743709 TI - Community-based InterVentions to prevent serIous Complications (CIVIC) following spinal cord injury in Bangladesh: protocol of a randomised controlled trial. AB - INTRODUCTION: In low-income and middle-income countries, people with spinal cord injury (SCI) are vulnerable to life-threatening complications after they are discharged from hospital. The aim of this trial is to determine the effectiveness and cost-effectiveness of an inexpensive and sustainable model of community-based care designed to prevent and manage complications in people with SCI in Bangladesh. METHODS AND ANALYSIS: A pragmatic randomised controlled trial will be undertaken. 410 wheelchair-dependent people with recent SCI will be randomised to Intervention and Control groups shortly after discharge from hospital. Participants in the Intervention group will receive regular telephone-based care and three home visits from a health professional over the 2 years after discharge. Participants in the Control group will receive standard care, which does not involve regular contact with health professionals. The primary outcome is all-cause mortality at 2 years. Recruitment started on 12 July 2015 and the trial is expected to take 5 years to complete. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Institutional Ethics Committee at the site in Bangladesh and from the University of Sydney, Australia. The study will be conducted in compliance with all stipulations of its protocol, the conditions of ethics committee approval, the NHMRC National Statement on Ethical Conduct in Human Research (2007), the Note for Guidance on Good Clinical Practice (CPMP/ICH 135/95) and the Bangladesh Guidance on Clinical Trial Inspection (2011). The results of the trial will be disseminated through publications in peer-reviewed scientific journals and presentations at scientific conferences. TRIAL REGISTRATION NUMBERS: ACTRN12615000630516, U1111-1171-1876. PMID- 26743711 TI - Behaviour of spirotetramat residues and its four metabolites in citrus marmalade during home processing. AB - The effect of home processing on the residues of spirotetramat and its four metabolites (B-enol, B-glu, B-mono and B-keto) in citrus marmalade is comprehensively investigated in this paper by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A five-fold recommended dose of spirotetramat was applied to citrus fruit under field conditions and the processing included five steps: washing, peeling, pre-treatment for peel, mixing and boiling. The results showed that spirotetramat was the predominant component detected in unprocessed citrus, accounting for 64%. All the detected residues were primarily deposited on citrus peel, except for B-enol which was also present in the citrus pulp. Washing reduced spirotetramat, B-enol, B-glu and B-keto by 83%, 56%, 41% and 16%, respectively, and pre-treatment of the peel removed between 42% and 68% of the residues. Four compounds were all below the limit of detection after the mixing step. In the final product, only B-keto was detected at the concentration of 0.010 mg kg(-1). After the whole process, the processing factors for spirotetramat, B-enol, B-glu and B-keto were < 0.041, < 0.125, < 0.294 and 0.313, respectively, which indicated that home processing can significantly reduce residues of spirotetramat and its metabolites in citrus marmalade. PMID- 26743712 TI - Geometric morphometric analysis reveals sexual dimorphism in the distal femur. AB - An individual's sex can be determined by the shape of their distal femur. The goal of this study was to show that differences in distal femur shape related to sexual dimorphism could be identified, visualized, and quantified using 3D geometric morphometric analysis. Geometric morphometric analysis was carried out on CT scans of the distal femur of 256 subjects living in the south of France. Ten landmarks were defined on 3D reconstructions of the distal femur. Both traditional metric and geometric morphometric analyses were carried out on these bone reconstructions; these analyses identified trends in bone shape in sex-based subgroups. Sex-related differences in shape were statistically significant. The subject's sex was correctly assigned in 77.3% of cases using geometric morphometric analysis. This study has shown that geometric morphometric analysis of the distal femur is feasible and has revealed sexual dimorphism differences in this bone segment. This reliable, accurate method could be used for virtual autopsy and be used to perform diachronic and interethnic comparisons. Moreover, this study provides updated morphometric data for a modern population in the south of France. PMID- 26743713 TI - Statistical hypothesis testing and common misinterpretations: Should we abandon p value in forensic science applications? AB - Many people regard the concept of hypothesis testing as fundamental to inferential statistics. Various schools of thought, in particular frequentist and Bayesian, have promoted radically different solutions for taking a decision about the plausibility of competing hypotheses. Comprehensive philosophical comparisons about their advantages and drawbacks are widely available and continue to span over large debates in the literature. More recently, controversial discussion was initiated by an editorial decision of a scientific journal [1] to refuse any paper submitted for publication containing null hypothesis testing procedures. Since the large majority of papers published in forensic journals propose the evaluation of statistical evidence based on the so called p-values, it is of interest to expose the discussion of this journal's decision within the forensic science community. This paper aims to provide forensic science researchers with a primer on the main concepts and their implications for making informed methodological choices. PMID- 26743716 TI - Quantification of diabetes consultations by the main primary health care nurse groups in Auckland, New Zealand. AB - BACKGROUND: Diabetes prevalence continues to increase, with most diabetes patients managed in primary care. AIM: This report quantifies the number of diabetes consultations undertaken by primary healthcare nurses in Auckland, New Zealand. METHODS: Of 335 primary healthcare nurses randomly selected, 287 (86%) completed a telephone interview in 2006-2008. FINDINGS: On a randomly sampled day (from the past seven) for each nurse, 42% of the nurses surveyed (n=120) consulted 308 diabetes patients. From the proportion of nurses sampled in the study, it is calculated that the number of diabetes patients consulted by primary healthcare nurses per week in Auckland between September 2006 and February 2008 was 4210, with 61% consulted by practice, 23% by specialist and 16% by district nurses. These findings show that practice nurses carry out the largest number of community diabetes consultations by nurses. Their major contribution needs to be incorporated into future planning of the community management of diabetes. PMID- 26743714 TI - Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells. AB - Human induced pluripotent stem cells (hiPSCs) are capable of unlimited proliferation and can differentiate in vitro to generate derivatives of the three primary germ layers. Genetic and epigenetic abnormalities have been reported by Wissing and colleagues to occur during hiPSC derivation, including mobilization of engineered LINE-1 (L1) retrotransposons. However, incidence and functional impact of endogenous retrotransposition in hiPSCs are yet to be established. Here we apply retrotransposon capture sequencing to eight hiPSC lines and three human embryonic stem cell (hESC) lines, revealing endogenous L1, Alu and SINE-VNTR-Alu (SVA) mobilization during reprogramming and pluripotent stem cell cultivation. Surprisingly, 4/7 de novo L1 insertions are full length and 6/11 retrotransposition events occurred in protein-coding genes expressed in pluripotent stem cells. We further demonstrate that an intronic L1 insertion in the CADPS2 gene is acquired during hiPSC cultivation and disrupts CADPS2 expression. These experiments elucidate endogenous retrotransposition, and its potential consequences, in hiPSCs and hESCs. PMID- 26743717 TI - An improved Bathocuproine assay for accurate valence identification and quantification of copper bound by biomolecules. AB - Copper is an essential metal in all organisms. Reliably quantifying and identifying the copper content and oxidation state is crucial, since the information is essential to understanding protein structure and function. Chromophoric ligands, such as Bathocuproine (BC) and its water-soluble analog, Bathocuproinedisulfonic acid (BCS), preferentially bind Cu(I) over Cu(II), and therefore have been widely used as optical probes to determine the oxidation state of copper bound by biomolecules. However, the BCS assay is commonly misused, leading to erroneous conclusions regarding the role of copper in biological processes. By measuring the redox potential of Cu(II)-BCS2 and conducting UV-vis absorption measurements in the presence of oxidizable amino acids, the thermodynamic origin of the potential artifacts becomes evident. The BCS assay was improved by introducing a strong Cu(II) chelator EDTA prior to the addition of BCS to prevent interference that might arise from Cu(II) present in the sample. The strong Cu(II) chelator rids of all the potential errors inherent in the conventional BCS assay. Applications of the improved assay to peptides and protein containing oxidizable amino acid residues confirm that free Cu(II) no longer leads to artifacts, thereby resolving issues related to this persistently misused colorimetric assay of Cu(I) in biological systems. PMID- 26743715 TI - Phospholamban and sarcolipin: Are they functionally redundant or distinct regulators of the Sarco(Endo)Plasmic Reticulum Calcium ATPase? AB - In muscle, the Sarco(Endo)plasmic Reticulum Calcium ATPase (SERCA) activity is regulated by two distinct proteins, PLB and SLN, which are highly conserved throughout vertebrate evolution. PLB is predominantly expressed in the cardiac muscle, while SLN is abundant in skeletal muscle. SLN is also found in the cardiac atria and to a lesser extent in the ventricle. PLB regulation of SERCA is central to cardiac function, both at rest and during extreme physiological demand. Compared to PLB, the physiological relevance of SLN remained a mystery until recently and some even thought it was redundant in function. Studies on SLN suggest that it is an uncoupler of the SERCA pump activity and can increase ATP hydrolysis resulting in heat production. Using genetically engineered mouse models for SLN and PLB, we showed that SLN, not PLB, is required for muscle-based thermogenesis. However, the mechanism of how SLN binding to SERCA results in uncoupling SERCA Ca(2+) transport from its ATPase activity remains unclear. In this review, we discuss recent advances in understanding how PLB and SLN differ in their interaction with SERCA. We will also explore whether structural differences in the cytosolic domain of PLB and SLN are the basis for their unique function and physiological roles in cardiac and skeletal muscle. PMID- 26743720 TI - Probe-free allele-specific copy number detection and analysis of tumors. AB - Cancer development and progression frequently involve nucleotide mutations as well as amplifications and deletions of genomic segments. Quantification of allele-specific copy number is an important step in characterizing tumor genomes for precision medicine. Despite advances in approaches to high-throughput genomic DNA analysis, inexpensive and simple methods for analyzing complex nucleotide and copy number variants are still needed. Real-time polymerase chain reaction (PCR) methods for discovering and genotyping single nucleotide polymorphisms are becoming increasingly important in genetic analysis. In this study, we describe a simple, single-tube, probe-free method that combines SYBR Green I-based quantitative real-time PCR and quantitative melting curve analysis both to detect specific nucleotide variants and to quantify allele-specific copy number variants of tumors. The approach is based on the quantification of the targets of interest and the relative abundance of two alleles in a single tube. The specificity, sensitivity, and utility of the assay were demonstrated in detecting allele specific copy number changes critical for carcinogenesis and therapeutic intervention. Our approach would be useful for allele-specific copy number analysis or precise genotyping. PMID- 26743718 TI - Building homogeneous time-resolved fluorescence resonance energy transfer assays for characterization of bivalent inhibitors of an inhibitor of apoptosis protein target. AB - XIAP (X-chromosome-linked inhibitor of apoptosis protein) is a central apoptosis regulator that blocks cell death by inhibiting caspase-3, caspase-7, and caspase 9 via binding interactions with the XIAP BIR2 and BIR3 domains (where BIR is baculovirus IAP repeat). Smac protein, in its dimeric form, effectively antagonizes XIAP by concurrently targeting both its BIR2 and BIR3 domains. Here we describe the development of highly sensitive homogeneous time-resolved fluorescence resonance energy transfer (HTRF) assays to measure binding affinities of potent bivalent peptidomimetic inhibitors of XIAP. Our results indicate that these assays can differentiate Smac-mimetic inhibitors with a wide range of binding affinities down to the picomolar range. Furthermore, we demonstrate the utility of these fluorescent tools for characterization of inhibitor off-rates, which as a crucial determinant of target engagement and cellular potency is another important parameter to guide optimization in a structure-based drug discovery effort. Our study also explores how increased inhibitor valency can lead to enhanced potency at multimeric proteins such as IAP. PMID- 26743719 TI - Enrichment and identification of glycoproteins in human saliva using lectin magnetic bead arrays. AB - Aberrant glycosylation of proteins is a hallmark of tumorigenesis and could provide diagnostic value in cancer detection. Human saliva is an ideal source of glycoproteins due to the relatively high proportion of glycosylated proteins in the salivary proteome. Moreover, saliva collection is noninvasive and technically straightforward, and the sample collection and storage is relatively easy. Although differential glycosylation of proteins can be indicative of disease states, identification of differential glycosylation from clinical samples is not trivial. To facilitate salivary glycoprotein biomarker discovery, we optimized a method for differential glycoprotein enrichment from human saliva based on lectin magnetic bead arrays (saLeMBA). Selected lectins from distinct reactivity groups were used in the saLeMBA platform to enrich salivary glycoproteins from healthy volunteer saliva. The technical reproducibility of saLeMBA was analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify the glycosylated proteins enriched by each lectin. Our saLeMBA platform enabled robust glycoprotein enrichment in a glycoprotein- and lectin-specific manner consistent with known protein-specific glycan profiles. We demonstrated that saLeMBA is a reliable method to enrich and detect glycoproteins present in human saliva. PMID- 26743721 TI - Nylon mesh filtration technique for the collection of metacercariae from host tissue by digestion with artificial gastric juice. AB - The traditional method of collecting parasite larvae by digestion with artificial gastric juice requires time-consuming processes of repeated sedimentation and washing that is likely to result in a loss of some of the larvae. The author introduces an improved filtration technique using nylon mesh to wash out the digestive fluid. The technique shortens the processing duration of the process and increases the efficiency of larva collection. PMID- 26743731 TI - Patient and Clinical Characteristics Associated with Primary Healing of Iatrogenic Perforations after Root Canal Treatment: Results of a Long-term Italian Study. AB - INTRODUCTION: There are few data on the long-term efficacy of mineral trioxide aggregate (MTA) in treating root canal perforations. We investigated the extent of primary healing after perforation repair with MTA and non-healing as a result of repair. We also investigated patient/clinical characteristics affecting treatment outcomes and long-term prognosis. METHODS: This was a prospective cohort study that enrolled consecutive patients with a single dental perforation treated with MTA (January 1999-June 2009). Patients were followed up until December 2012 for a maximum of 13 years after treatment, with analyses carried out at 8 years. RESULTS: Of the 110 patients (median age, 36 years; 54.5% male) eligible for inclusion, 101 were judged to have started to heal at the first (n = 98, 89%) or second (n = 3, 3%) annual post-treatment checkup, and 9 (8%, 4 women and 5 men, aged between 18 and 65 years) did not show any sign of healing. Patients >50 years had a higher percentage of non-healing perforations compared with those <= 50 years (12% versus 7%). The percentages of perforations at post treatment analysis that failed to heal were 13% (intermediate/middle), 4% (coronal), and 0% (apical). The percentages of non-healing perforations according to size were 16% for >3 mm, 6% for 2-3 mm, and 0% for smaller perforations. Characteristics associated with probability of progressing after initial healing were gender, positive probing, size, and site of perforation. CONCLUSIONS: Our results show that having obtained primary healing with MTA, the likelihood of progressing is very low. They provide good evidence of the combined effectiveness of experienced operators and use of state-of-the-art materials. PMID- 26743722 TI - Antidepressant medication use and glycaemic control in co-morbid type 2 diabetes and depression. AB - OBJECTIVE: Depression is prevalent in diabetes and is associated with increased risks of hyperglycaemia, morbidity and mortality. The effect of antidepressant medication (ADM) on glycaemic control is uncertain owing to a paucity of relevant data. We sought to determine whether the use of ADM is associated with glycaemic control in depressed patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A retrospective cohort study (n = 1399) was conducted using electronic medical record registry data of ambulatory primary care visits from 2008 to 2013. Depression and type 2 diabetes were identified from ICD-9-CM codes; ADM use was determined from prescription orders; and glycaemic control was determined from measures of glycated haemoglobin (A1c). Good glycaemic control was defined as A1c < 7.0% (53 mmol/mol). Generalized estimating equations were used to determine the effect of depression and ADM use on glycaemic control. RESULTS: Good glycaemic control was achieved by 50.9% of depressed subjects receiving ADM versus 34.6% of depressed subjects without ADM. After adjusting for covariates, depressed patients receiving ADM were twice as likely as those not receiving ADM to achieve good glycaemic control (odds ratio = 1.95; 95% confidence interval: 1.02-3.71). CONCLUSIONS: In this retrospective cohort study of a large sample of primary care patients with type 2 diabetes, ADM use was associated with improved glycaemic control. PMID- 26743732 TI - Right Ventricular Function and Prognosis in Patients with Low-Flow, Low-Gradient Severe Aortic Stenosis. AB - BACKGROUND: Patients with low left ventricular ejection fractions and low-flow, low-gradient aortic stenosis (AS) represent a challenging cohort with high morbidity and mortality. The prevalence and clinical impact of right ventricular dysfunction (RVD) on risk stratification and prognosis in these patients is unknown. METHODS: A retrospective analysis was performed of 65 patients with low flow, low-gradient AS who underwent low-dose dobutamine stress echocardiography to determine AS severity and to ascertain flow reserve status (>=20% stroke volume increase). Clinical, demographic, and imaging data were prospectively collected. Per guidelines, RVD was defined as tricuspid annular plane systolic excursion < 16 mm in the apical four-chamber view and measured at baseline. Cox proportional hazards modeling was used to risk-adjust comparisons for the end point of all-cause mortality. RESULTS: The mean age was 74 +/- 9 years, the mean left ventricular ejection fraction was 29 +/- 10%, the mean indexed aortic valve (AV) area was 0.49 +/- 0.1 cm(2)/m(2), and the mean AV gradient 22 +/- 7 mm Hg. RVD was present in 37 patients (57% of the study cohort). After a median follow up period of 13 months (interquartile range, 5-30 months), there were 29 AV replacements and 30 deaths. The presence of RVD (hazard ratio, 2.86; 95% CI, 1.21 6.75; P = .02) was an independent risk factor associated with all-cause mortality despite many adjustments for potential clinical and echocardiographic confounders such as AV replacement, Society of Thoracic Surgeons Predicted Risk of Mortality score, severity of tricuspid regurgitation, and left ventricular global longitudinal strain. CONCLUSIONS: Baseline RVD is prevalent in patients with low flow, low-gradient AS undergoing dobutamine stress echocardiography. Quantification of right ventricular systolic function in these complex patients provides important prognostic value and risk stratification adjunctive to Society of Thoracic Surgeons Predicted Risk of Mortality score and should be incorporated into the decision-making process. PMID- 26743733 TI - Association of Decreased Right Ventricular Strain with Worse Survival in Non Acute Coronary Syndrome Angina. AB - BACKGROUND: Regional strain by speckle-tracking echocardiography can be used to detect occult right ventricular (RV) myocardial dysfunction. However, in patients with coronary artery disease, the impact of RV strain is unknown. The aim of this study was to validate the prognostic value of RV strain in patients with non acute coronary syndrome angina. METHODS: In total, 208 patients with coronary artery disease proved by coronary angiography were retrospectively identified (mean age, 63.81 +/- 10.12 years; 161 men). In addition to clinical and traditional echocardiographic parameters, RV free wall longitudinal strain (RVLS_FW) was measured using speckle-tracking echocardiography from the apical four-chamber view. Cardiac mortality and major cardiovascular events were recorded. RESULTS: During follow-up (23.1 +/- 6.6 months), 27 patients (12.98%) died of cardiovascular causes. These patients were found to have lower left ventricular ejection fractions and greater reductions in the amplitudes of left ventricular peak systolic global longitudinal strain and RVLS_FW. Using -18% as a cutoff point for RV strain, patients with strain <= -18% had superior outcomes (log-rank chi(2) = 9.04 and 6.94 for cardiovascular mortality and arrhythmia, respectively, P = .003). In Cox multivariate regression analysis, RVLS_FW was an independent prognostic factor for both cardiovascular mortality (hazard ratio, 1.27; 95% CI, 1.03-1.72; P = .01) and hemodynamically unstable ventricular arrhythmia (hazard ratio, 1.72; 95% CI, 1.08-2.41; P = .01). CONCLUSIONS: RVLS_FW is significantly related to cardiovascular outcomes and hemodynamically unstable ventricular arrhythmia in patients with non-acute coronary syndrome angina. PMID- 26743735 TI - Independent Echocardiographic Markers of Cardiovascular Involvement in Chronic Kidney Disease: The Value of Left Atrial Function and Volume. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with increased cardiovascular mortality and morbidity, particularly ischemic heart disease and cardiomyopathy. Newer echocardiographic techniques such as myocardial strain analysis provides the opportunity to detect early myocardial dysfunction. The aim of this study was to examine echocardiographic parameters, in particular left atrial (LA) function and volume, in patients with CKD. A further aim was to determine echocardiographic parameters that are sensitive to detect cardiovascular involvement in early CKD. METHODS: Seventy-six patients with stage 3 CKD (estimated glomerular filtration rate, 30-59 mL/min/1.73 m(2)) with hypertension and/or diabetes mellitus, without any previous cardiac illness, were prospectively recruited. These patients were compared with subjects matched for age, sex, and risk factors (hypertension and/or diabetes mellitus) with normal renal function and 76 healthy age-matched control subjects. Two-dimensional strain analyses of the left atrium and left ventricle were performed. Comprehensive echocardiographic examinations were performed in all participants, and traditional echocardiographic parameters including indexed LA volume (LAVI) and two-dimensional strain analysis of the left ventricle and left atrium were performed in all participants. Differences among the three groups on demographic, clinical, and echocardiographic parameters were examined. RESULTS: LA systolic strain (20.9 +/- 6.3% vs 27.4 +/- 7.9%, P < .0001) and systolic and late diastolic strain rates were altered in the CKD group, while early diastolic strain rate was similar to that in the risk factor-matched group. LAVI was significantly larger in the CKD group compared with the risk factor-matched group and healthy control subjects (38.5 +/- 10 vs 31.2 +/- 9 vs 22.3 +/- 5 mL/m(2), P < .0001). LV strain as well as LV systolic and early diastolic strain rates were similar in the CKD and risk factor-matched groups. LV late diastolic strain rate, a surrogate measure of LA contractile function, was, however, reduced in the CKD group. Forward logistic regression analysis showed LA global strain to be the most sensitive predictor for the presence of CKD, followed by LAVI; though LV late diastolic strain rate was reduced in the CKD group, it was not an independent predictor. Furthermore, the addition of LA strain to traditional echocardiographic parameters significantly increased the predictive power to detect cardiovascular involvement (C statistic = 0.65 vs C statistic = 0.84, P < .0001). Increased LAVI, reduced left ventricular global strain, and the presence of CKD were independent predictors of LA strain, while left ventricular mass index, E/e' ratio, and the presence of CKD were predictors of LAVI. CONCLUSION: LA strain and LAVI are more sensitive parameters than traditional echocardiographic parameters as well as left ventricular strain in patients with early CKD. LA strain and LAVI may be useful to detect myocardial involvement in stage 3 CKD, and LA alterations may be consequent to increased activation of the renin-angiotensin-aldosterone pathway, causing myocardial fibrosis in CKD. PMID- 26743734 TI - Left Ventricular Myocardial and Hemodynamic Response to Exercise in Young Patients after Endovascular Stenting for Aortic Coarctation. AB - BACKGROUND: Endovascular stenting has emerged as a treatment option for children with coarctation of the aortic (CoA), but the impact on left ventricular (LV) function has been poorly documented. The aim of this study was to characterize the LV myocardial and hemodynamic response to exercise in young patients who underwent endovascular stenting for CoA during childhood using semisupine bicycle exercise stress echocardiography. METHODS: This was a single-center prospective cross-sectional study including 30 patients with CoA and 30 age- and gender matched control subjects who underwent semisupine bicycle exercise stress echocardiography. Color Doppler tissue imaging peak systolic (s') and early diastolic (e') velocities in the LV lateral wall and basal septum, LV myocardial acceleration during isovolumic acceleration were measured at rest and with incremental heart rate (HR). The relationship with increasing HR was evaluated for each parameter by plotting the values at each stage of exercise versus HR. RESULTS: At rest, HR was similar between the two groups. LV ejection fraction and fractional shortening were within the normal range in the CoA group. LV lateral wall and basal septal s' and e' velocities did not differ between the two groups, but isovolumic acceleration values were significantly lower in the CoA group. At peak exercise, HR was similar between the groups, but all Doppler tissue imaging parameters were lower in patients than in control subjects. When assessing the increase of each parameter versus HR, the increase in slope was significantly lower in patients than in control subjects for LV lateral wall Doppler tissue imaging s' and e' velocities, and septal e' velocity, but not for septal s'. The relationship of isovolumic acceleration with HR was significantly reduced in the CoA group. CONCLUSION: The results of this study demonstrate reduced systolic and diastolic myocardial reserve in patients with CoA compared with control subjects. An abnormal myocardial contractile response to exercise was also found, as shown by an abnormal LV force-frequency relationship in patients with stented CoA. The prognostic clinical implications require further study. PMID- 26743736 TI - Effects of Transthoracic Echocardiographic Simulator Training on Performance and Satisfaction in Medical Students. PMID- 26743737 TI - Insertion of percutaneous endoscopic gastrostomy by head and neck surgeons: systematic review. AB - Percutaneous endoscopic gastrostomy to maintain nutrition in patients with cancer of the head and neck is increasingly being done by head and neck surgeons. We have reviewed published papers to assess the success rate of insertion and the incidence of complications. PMID- 26743738 TI - The use of TissealTM fibrin glue in the management of chronic oro-cutaneous fistula in the radiotherapy treated neck - a technical note. PMID- 26743739 TI - Image-guided nasal endoscopic drainage of an orbital superior subperiosteal abscess. AB - A 48-year-old woman presented to the emergency department with swelling and erythema of the right upper eyelid for 4 days. Computed tomography showed a superiorly-based subperiosteal orbital abscess together with paranasal sinusitis. She was managed medically, but symptoms did not improve, so we drained the abscess using image-guided intranasal endoscopy. Her symptoms began to improve 2 days after drainage, and her recovery was uneventful. Drainage of an orbital subperiosteal abscess should be considered if there are ophthalmological symptoms such as visual disturbances, raised intraocular pressure, or proptosis of over 5mm. Various approaches are available, but endoscopic intranasal drainage was thought to be the most safe and effective. Image-guided drainage may help to minimise the extent and risk of operative complications. PMID- 26743740 TI - Effect of variable power levels on the yield of total aerosol mass and formation of aldehydes in e-cigarette aerosols. AB - The study objective was to determine the effect of variable power applied to the atomizer of refillable tank based e-cigarette (EC) devices. Five different devices were evaluated, each at four power levels. Aerosol yield results are reported for each set of 25 EC puffs, as mass/puff, and normalized for the power applied to the coil, in mass/watt. The range of aerosol produced on a per puff basis ranged from 1.5 to 28 mg, and, normalized for power applied to the coil, ranged from 0.27 to 1.1 mg/watt. Aerosol samples were also analyzed for the production of formaldehyde, acetaldehyde, and acrolein, as DNPH derivatives, at each power level. When reported on mass basis, three of the devices showed an increase in total aldehyde yield with increasing power applied to the coil, while two of the devices showed the opposite trend. The mass of formaldehyde, acetaldehyde, and acrolein produced per gram of total aerosol produced ranged from 0.01 to 7.3 mg/g, 0.006 to 5.8 mg/g, and <0.003 to 0.78 mg/g, respectively. These results were used to estimate daily exposure to formaldehyde, acetaldehyde, and acrolein from EC aerosols from specific devices, and were compared to estimated exposure from consumption of cigarettes, to occupational and workplace limits, and to previously reported results from other researchers. PMID- 26743741 TI - Systematic comparison of study quality criteria. AB - Approaches for the systematic review and evaluation of chemical toxicity are currently being reconsidered, with a specific focus on the evaluation of individual studies and their integration into the overall body of evidence. This renewed interest has arisen, in part, as a result of several prominent reviews of these approaches by special committees of the National Research Council (NRC), among others. We conducted a critical evaluation of several available frameworks for evaluating study quality. We assessed the criteria separately for human, animal, and in vitro studies as well as for systematic reviews. We then evaluated commonalities across disciplines. We also considered the potential implications of applying criteria frameworks and how they bear on fundamental risk assessment questions. We found that the available frameworks within each discipline differed in terms of their intended purpose and level of guidance for decision making. All the frameworks across disciplines shared common themes, however, including the adequate reporting of specific details of study conditions and design/protocol, selection and randomization of study groups (where applicable), outcome assessment methods and applicability (e.g., validity and reliability), avoidance of selective reporting, and the consideration of potential confounders or bias. We identified the most informative study quality considerations, which will enable researchers to implement more objective and standardized methods for evaluating studies and, ultimately, improve risk assessment methods. PMID- 26743742 TI - HESI/FDA workshop on immunomodulators and cancer risk assessment: Building blocks for a weight-of-evidence approach. AB - Profound immunosuppression (e.g., AIDS, transplant therapy) is epidemiologically associated with an increased cancer risk, and often with oncogenic viruses. It is currently unclear how broadly this association translates to therapeutics that modulate immunity. A workshop co-sponsored by the FDA and HESI examined how perturbing the immune system may contribute to carcinogenesis, and highlighted priorities for improving non-clinical risk assessment of targeted immunomodulatory therapies. Conclusions from the workshop were as follows. 1) While profound altered immunity can promote tumorigenesis, not all components of the immune system are equally important in defense against or promotion of cancer and a similar cancer risk for all immunomodulatory molecules should not be assumed. 2) Rodent carcinogenicity studies have limitations and are generally not reliable predictors of cancer risk associated with immunosuppression. 3) Cancer risk needs to be evaluated based on mechanism-based weight-of-evidence, including data from immune function tests most relevant to tumor immunosurveillance or promotion. 4) Information from nonclinical experiments, clinical epidemiology and immunomodulatory therapeutics show that immunosurveillance involves a complex network of cells and mediators. To support a weight-of-evidence approach, an increased focus on understanding the quantitative relationship between changes in relevant immune function tests and cancer risk is needed. PMID- 26743743 TI - Pitfalls of Multiple Ligation-Dependent Probe Amplifications in Detecting DMD Exon Deletions or Duplications. AB - Multiple ligation-dependent probe amplifications (MLPAs) are a key technology for the molecular diagnosis of Duchenne/Becker muscular dystrophy, which is mainly caused by large gene arrangements. However, little is known about the false positive rates of MLPA for this disease. Here, we review MLPA analysis results from 398 patients suspected to have Duchenne/Becker muscular dystrophy. MLPA assay was used for screening the entire coding region. If these amplifications produced normal results, direct sequencing was performed to search for sequence variations and to determine single-exon deletions, duplications, or indeterminate results. Using MLPA, 290 cases (72.9%) showed exon deletion or duplication results. Among those, 75 cases (25.9%) resulted in a deletion or duplication of a single exon. Direct sequencing revealed that 11 single-exon deletion cases resulted in false-positives due to sequence variations within the patient population interfering with probe binding at the probe-hybridization sites. Abnormal MLPA results were closely related to the type of sequence change and the position within the probe-hybridization locus. The most common type was C-T transition (n = 19, 55.9%). Abnormal MLPA results correlated with CA mismatch and low melting temperature (<=75 degrees C). False-positive events for large gene rearrangements involving a single exon in DMD accounted for approximately 15% (11/75). Therefore, careful design of MLPA probes is required to avoid false positive results. PMID- 26743744 TI - Impaired endogenous nighttime melatonin secretion relates to intrarenal renin angiotensin system activation and renal damage in patients with chronic kidney disease. AB - BACKGROUND: Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. The circadian rhythm of intrarenal RAS activation leads to renal damage and hypertension, which are associated with diurnal blood pressure (BP) variation. The activation of intrarenal RAS following reactive oxygen species (ROS) activation, sympathetic hyperactivity and nitric oxide (NO) inhibition leads to the development of renal damage. Melatonin is a hormone regulating the circadian rhythm, and has multiple functions such as anti-oxidant and anti adrenergic effects and enhancement of NO bioavailability. Nocturnal melatonin concentrations are lower in CKD patients. However, it is not known if impaired endogenous melatonin secretion is related to BP, intrarenal RAS, or renal damage in CKD patients. METHODS: We recruited 53 CKD patients and conducted 24-h ambulatory BP monitoring. urine was collected during the daytime and nighttime. We investigated the relationship among the melatonin metabolite urinary 6 sulphatoxymelatonin (U-aMT6s), BP, renal function, urinary angiotensinogen (U AGT), and urinary albumin (U-Alb). RESULTS: Patients' U-aMT6s levels were significantly and negatively correlated with clinical parameters such as renal function, systolic BP, U-AGT, and U-Alb, during both day and night. Multiple regression analyses for U-aMT6s levels were performed using age, gender, renal function, and each parameter (BPs, U-AGT or U-Alb), at daytime and nighttime. U aMT6s levels were significantly associated with U-AGT (beta = -0.31, p = 0.044) and U-Alb (beta = -0.25, p = 0.025) only at night. CONCLUSION: Impaired nighttime melatonin secretion may be associated with nighttime intrarenal RAS activation and renal damage in CKD patients. PMID- 26743745 TI - Gene expression and molecular characterization of a chaperone protein HtpG from Bacillus licheniformis. AB - Heat shock protein 90 (Hsp90/HtpG) is a highly abundant and ubiquitous ATP dependent molecular chaperone consisting of three flexibly linked regions, an N terminal nucleotide-binding domain, middle domain, and a C-terminal domain. Here the putative htpG gene of Bacillus licheniformis was cloned and heterologously expressed in Escherichia coli M15 cells. Native-gel electrophoresis, size exclusion chromatography, and cross-linking analysis revealed that the recombinant protein probably exists as a mixture of monomer, dimer and other oligomers in solution. The optimal conditions for the ATPase activity of B. licheniformis HtpG (BlHtpG) were 45 degrees C and pH 7.0 in the presence of 0.5mM Mg(2+) ions. The molecular architecture of this protein was stable at higher temperatures with a transition point (Tm) of 45 degrees C at neutral pH, whereas the Tm value was reduced to 40.8 degrees C at pH 10.5. Acrylamide quenching experiment further indicated that the dynamic quenching constant (Ksv) of BlHtpG became larger at higher pH values. BlHtpG also experienced a significant change in the protein conformation upon the addition of ATP and organic solvents. Collectively, our experiment data may provide insights into the molecular properties of BlHtpG and identify the alteration of protein structure to forfeit the ATPase activity at alkaline conditions. PMID- 26743746 TI - Catalytic, kinetic and thermodynamic properties of Bacillus pumilus FH9 keratinase conjugated with activated pectin. AB - Bacillus pumilus FH9 keratinase was covalently coupled to several oxidized polysaccharides. The conjugates were evaluated for the retained activity, kinetic and thermodynamic stability. Among all preparations, the conjugated enzyme with oxidized pectin had the highest recovered activity (71.75%) and the highest thermal stability at 60 degrees C (t1/2=333 min). Compared to the native enzyme, the conjugated preparation exhibited higher optimum temperature, lower activation energy (Ea), lower deactivation constant rate (kd), higher t1/2, and higher decimal reduction time values (D) within the temperature range of 50-80 degrees C. The thermodynamic parameters (DeltaH*, DeltaG*, DeltaS*) of irreversible thermal denaturation for the native and conjugated keratinase were also evaluated. The values of enthalpy of activation (DeltaH*), free energy of activation (DeltaG*), and free energy of transition state binding (DeltaG*E-T) for keratin hydrolysis were lower for the conjugated enzyme. Moreover, there was highly significant impact on improving the values of Vmax/Km, kcat, kcat/Km, and DeltaG*E-S for the modified enzyme. Both native and conjugated enzymes were slightly activated by CaCl2 and MgCl2. However, the inhibitory effects of EDTA, HgCl2 and ZnSO4 were more pronounced with the native enzyme. PMID- 26743747 TI - Immunological processes underlying the slow acquisition of humoral immunity to malaria. AB - Malaria is one of the most serious infectious diseases with ~250 million clinical cases annually. Most cases of severe disease are caused by Plasmodium falciparum. The blood stage of Plasmodium parasite is entirely responsible for malaria associated pathology. Disease syndromes range from fever to more severe complications, including respiratory distress, metabolic acidosis, renal failure, pulmonary oedema and cerebral malaria. The most susceptible population to severe malaria is children under the age of 5, with low levels of immunity. It is only after many years of repeated exposure, that individuals living in endemic areas develop clinical immunity. This form of protection does not result in sterilizing immunity but prevents clinical episodes by substantially reducing parasite burden. Naturally acquired immunity predominantly targets blood-stage parasites and it is known to require antibody responses. A large body of epidemiological evidence suggests that antibodies to Plasmodium antigens are inefficiently generated and rapidly lost in the absence of ongoing exposure, which suggests a defect in the development of B cell immunological memory. This review summarizes the main findings to date contributing to our understanding on cellular processes underlying the slow acquisition of humoral immunity to malaria. Some of the key outstanding questions in the field are discussed. PMID- 26743748 TI - Outcomes of Descemet membrane endothelial keratoplasty, Descemet stripping automated endothelial keratoplasty and penetrating keratoplasty from a single centre study. AB - PURPOSE: According to some pioneer surgeons, lamellar endothelial keratoplasty techniques (EK), including Descemet membrane endothelial keratoplasty (DMEK) and Descemet stripping automated endothelial keratoplasty (DSAEK), yield excellent clinical results. However, there is a lack of studies with high levels of evidence and results of large national keratoplasty registers are contradictory. Therefore, two large cohorts of DMEK and DSAEK procedures are compared to a cohort of penetrating keratoplasty (PK). METHODS: The study reports 868 keratoplasty procedures at a single centre (694 eyes with Fuchs endothelial dystrophy (FED) and 174 with bullous keratopathy (BK)). Patients underwent DMEK (450 eyes), DSAEK (89 eyes), or PK (329 eyes). Postoperative visual acuity, endothelial cell density (ECD), rate of regrafting, and rejections were recorded. RESULTS: Visual acuity recovers faster and to a greater extent in EK compared to PK. DMEK performs better than DSAEK. ECD drops faster initially for EK compared to PK. In EK the rate of regrafting is higher than in PK (7 % in DMEK, 20 % in DSAEK and 2 % in PK in FED). The rejection rate is lowest following DMEK (7 % after DMEK, 21 % after DSAEK and 18 % after PK in FED). CONCLUSIONS: In contrast to recent reports from national keratoplasty registers, the overall clinical outcome of EK in FED and BK is superior to PK. Including ocular comorbidities and learning curves, these data reflect a realistic setting for comparing the different keratoplasty techniques. Corneal surgeons may be encouraged to preferentially use DMEK in FED and BK. PMID- 26743750 TI - The influence of varying the number of characters per row on the accuracy and reproducibility of the ETDRS visual acuity chart. AB - BACKGROUND: As part of an effort to improve upon the Snellen chart, we provide a standardized version of the ETDRS chart utilizing five characters in each row. The choice of five characters contradicts the recommended ten characters per row determined by the NAS-NRC, a committee established to provide guidelines for testing visual acuity. We set out to quantify the influence of varying the number of characters per line on the ETDRS chart with respect to the accuracy and reproducibility of visual acuity measurement. METHODS: Eleven different ETDRS charts were created, each with a different number of characters appearing in each row. A computer simulation was programmed to run 10,000 virtual patients, each with a unique visual acuity, false-positive and false-negative error value. RESULTS: Accuracy and reproducibility were found to roughly correlate with the number of characters present in each row, such that charts with 1, 3, 5, 7, 9, and 11 characters per row provided accuracy of 0.164, 0.094, 0.078, 0.073, 0.071, and 0.070 logMAR, respectively. A non-linear relationship was observed, with little improvement found beyond seven characters per row. In addition, charts with an even number of characters per row provided higher accuracy than their greater-number odd counterparts. In certain instances, accuracy and reproducibility were not well correlated. CONCLUSIONS: Increasing the number of characters per row in the ETDRS chart provides a trade-off between accuracy and test duration. An optimized chart layout would take these findings into account, allowing for the use of different chart layouts for clinical versus research settings. PMID- 26743749 TI - Ischemic regulation of brain-derived neurotrophic factor-mediated cell volume and TrkB expression in glial (Muller) and bipolar cells of the rat retina. AB - BACKGROUND: Osmotic swelling of neurons and glial cells contributes to retinal edema and neurodegeneration. BDNF, a major neuroprotectant in the retina, was shown to inhibit osmotic swelling of glial (Muller) and bipolar cells in the rat retina; the effect of BDNF on the bipolar cell swelling is mediated by inducing a release of neuroprotective cytokines from Muller cells (Berk et al., Neuroscience 295:175-186, 2015). We determined whether BDNF-mediated cell volume regulation was altered after transient retinal ischemia. METHODS: Retinal slices from the eyes of rats that underwent a 1-h pressure-induced retinal ischemia and from control eyes were superfused with a hypoosmotic solution. RESULTS: Exogenous BDNF prevented osmotic swelling of Muller cells in both control and post-ischemic retinal slices. BDNF also prevented osmotic swelling of bipolar cells in the control retina, but not in the ischemic retina. On the other hand, exogenous bFGF prevented the swelling of both Muller and bipolar cells in the ischemic retina. Freshly isolated Muller cells of control retinas displayed immunoreactivity of truncated but not full-length TrkB. In contrast, Muller cells of post-ischemic retinas displayed immunoreactivity of both TrkB isoforms. Bipolar cells isolated from control and post-ischemic retinas were immunolabeled for both TrkB isoforms. CONCLUSIONS: The data may suggest that the ischemic abrogation of the BDNF effect in bipolar cells is related to altered BDNF receptor expression in Muller cells. Glial upregulation of full-length TrkB may support the survival of Muller cells in the ischemic retina, but may impair the BDNF-induced release of neuroprotective cytokines such as bFGF from Muller cells. PMID- 26743752 TI - False reaching movements in localization test and effect of auditory feedback in simulated ultra-low vision subjects and patients with retinitis pigmentosa. AB - PURPOSE: To determine the accuracy of reaching movements with localization tests in subjects with simulated ultra-low vision, and to examine the effectiveness of auditory feedback training in improving the accuracy of the reaching movements. METHODS: Twenty-one subjects with simulated ultra-low vision and three patients with advanced retinitis pigmentosa (RP) were studied with the localization tester. The localization tester had white square targets with a visual angle of 10 degrees that were projected randomly on a computer monitor screen. The subjects or RP patients were instructed to touch the center of the target. Each subject was tested 20 trials. The distance from the center of the target to the point where subjects touched, the deviation, was calculated automatically by the computer. We also examined the effect of auditory feedback on improving the accuracy of reaching movements. RESULTS: The average angle of deviation in the subjects was not significantly correlated with visual acuity. The points touched by subjects with simulated low vision were located downward and horizontally toward the hand they used. They were condensed around the barycenter of the touched points (paired t tests; *p = 0.037). The touched points of the patients also deviated downward and condensed around the barycenter. The deviations decreased significantly with auditory feedback when trained over 100 trials. CONCLUSIONS: The subjects with simulated ultra-low vision and the advanced RP patients had false orientations against the position of localized target systematically. An auditory feedback system may help to correct the false orientations for reaching movements in patients with very low vision. PMID- 26743751 TI - En face OCT in Stargardt disease. AB - PURPOSE: To evaluate the structural features of the macular region by enface OCT imaging in patients with clinical diagnosis of Stargardt disease, confirmed by the detection of ABCA4 mutations. METHODS: Thirty-two STGD patients were included in the study for a total of 64 eyes. All patients received a comprehensive ophthalmological examination, color fundus photography, fundus auto-fluorescence imaging and OCT. Five OCT scans were considered: ILM and RPE scans (both automatically obtained from the instrument), above-RPE slab, photoreceptor slab and sub-RPE slab (these last three manually obtained). RESULTS: ILM scans showed evident radial folds on the retinal surface in 8/64 eyes (12.5 %). In 6 of the 7 patients, these vitreo-retinal interface abnormalities were unilateral. The photoreceptor slab showed some macular alterations ranging from dis-homogeneous, hypo-reflective abnormalities (7/64 eyes, 11 %) to a homogeneous, well-defined, roundish, hypo-reflective area (17/64 eyes, 27 %) in all the eyes. The sub-RPE slab showed a centrally evident, hyper-reflective abnormality in 58/64 eyes (90.6 %). Superimposing the sub-RPE slab over the images corresponding to the photoreceptor slab, the area of the photoreceptor atrophy sharply exceeded that of the RPE atrophy (44/46 eyes, 96 %). CONCLUSION: Enface OCT proved to be a clinically useful tool for the management of STGD patients, illustrating in vivo the structural abnormalities of the different retinal layers. PMID- 26743753 TI - Gas-mediated vitreomacular adhesion release with intravitral ranibizumab injections for exudative age-related macular degeneration. AB - PURPOSE: To evaluate the efficiency of gas-assisted vitreomacular adhesion (VMA) release combined with intravitreal ranibizumab injections for exudative age related macular degeneration (AMD) patients. MATERIALS AND METHODS: This prospective, interventional case series included a total of 23 eyes of 22 patients. The eyes were treated with intravitreal injection of 0.3 mL of perfluoropropane (C3F8) gas and concomitant intravitreal ranibizumab injection to stimulate VMA release. After three initial loading injections, additional intravitreal ranibizumab injections were performed pro re nata. Over a 12-month period, monthly examinations were performed for best-corrected visual acuity (BCVA, logMAR; logarithm of the minimum angle resolution), optical coherence tomography, and dilated fundus examinations. RESULTS: After gas injection, 22 eyes (95.7 %) showed complete VMA release at 1 week. Complete VMA was achieved in all eyes at 2 months after VMA release, without serious ocular adverse events except one patient who developed a retinal tear. Mean BCVA was 0.61 +/- 0.37 logMAR (20/81 Snellen equivalents) at baseline and 0.46 +/- 0.30 logMAR (20/57 Snellen equivalents) at 12 months (P = 0.135). Mean central macular thickness was 357.9 +/- 128.6 MUm at baseline and 245.6 +/- 60.0 MUm at 12 months (P = 0.188). Mean numbers of intravitreal ranibizumab injections were 4.8 +/- 2.4 times during 12 months (4 to 8 injections). CONCLUSION: Gas-assisted VMA release can be used as an efficient alternative for exudative AMD patients with obvious VMA. PMID- 26743755 TI - A cross-linked hyaluronic acid hydrogel (Healaflow((r))) as a novel vitreous substitute. AB - PURPOSE: Vitrectomy requires the substitution of the natural vitreous, as well as tamponading of retinal breaks. Clinically available alternatives such as gas and silicone oil have side effects such as inflammation, secondary glaucoma, cataract, and a need for head posturing. In this study, a hydrogel of cross linked sodium hyaluronic acid (Healaflow((r))) is evaluated for use as a novel vitreous substitute. METHODS: A combined 25-20-gauge pars plana vitrectomy with posterior vitreous detachment was performed in the right eye of twelve pigmented rabbits, with subsequent injection of approximately 1 ml Healaflow((r)). Clinical evaluation, measurement of intraocular pressure (IOP), and full-field ERG were performed postoperatively. The rabbits were sacrificed at different time-points between 42 and 105 days. After enucleation, the eyes were examined macroscopically, photographed, and prepared for histological examination with routine microscopy and immunohistochemistry. RESULTS: Healaflow((r)) was successfully used with standard surgical procedures and remained translucent but did lose most of its viscosity during the postoperative period. One rabbit was lost due to unrelated causes. In two eyes iatrogenic partial retinal detachments were seen, and in two eyes significant cataract developed due to intra-operative complications. ERG-recordings revealed no toxic effect on rod or cone function. Routine microscopy and immunohistochemistry demonstrated normal morphology with some Muller cell activation (up-regulation of glial acidic fibrillary protein, GFAP) compared to unoperated eyes and no significant DNA-fragmentation (TUNEL assay). CONCLUSIONS: Healaflow(r) did not affect retinal morphology or function negatively during long-term use as a vitreous substitute, making it highly interesting in this setting. An estimated retention time of a few weeks suggests potential for use as a short-term tamponade. Future work will include an increased ratio of cross-linking to prolong the structural integrity of the gel. PMID- 26743754 TI - Functional and morphological evaluation of blue light-emitting diode-induced retinal degeneration in mice. AB - PURPOSE: The purpose of this study was to evaluate a retinal degeneration (RD) model induced by exposing mice to a blue light-emitting diode (LED), which led to photoreceptor cell death. METHODS: RD was induced in BALB/c mice by exposure to a blue LED (460 nm) for 2 hours. Retinal function was examined using scotopic electroretinography (ERG). Histopathological changes were assessed by hematoxylin and eosin (H&E) staining and electron microscopy. Apoptotic cell death was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. In addition, retinal inflammation and oxidative stress were evaluated by immunohistochemistry with anti-glial fibrillary acidic protein (GFAP) and anti-8 hydroxy-2'-deoxyguanosine (8-OHdG), respectively. RESULTS: Scotopic ERG showed that blue LED exposure resulted in a decrease in both a-waves and b-waves in mice retinas in an illuminance-dependent manner. H&E, TUNEL assay, and electron microscopy revealed massive photoreceptor cell death by apoptosis in the central region of the retina. Retinal stress and inflammation were detected by increased expression of GFAP and by electron microscopy findings demonstrating microglia infiltration in the outer nuclear layer and subretinal space. In addition, increased labeling of 8-OHdG was observed in the retinas from blue LED exposure. CONCLUSIONS: These results suggest that blue LED-induced RD may be a useful animal model in which to study the pathogenesis of RD, including age-related macular degeneration, and to evaluate the effects of new therapeutic agents prior to clinical trials, where oxidative stress and inflammation are the underlying RD mechanisms. PMID- 26743758 TI - In Silico Characterization of the Binding Affinity of Dendrimers to Penicillin Binding Proteins (PBPs): Can PBPs be Potential Targets for Antibacterial Dendrimers? AB - We have shown that novel silver salts of poly (propyl ether) imine (PETIM) dendron and dendrimers developed in our group exhibit preferential antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus. This led us to examine whether molecular modeling methods could be used to identify the key structural design principles for a bioactive lead molecule, explore the mechanism of binding with biological targets, and explain their preferential antibacterial activity. The current article reports the conformational landscape as well as mechanism of binding of generation 1 PETIM dendron and dendrimers to penicillin-binding proteins (PBPs) in order to understand the antibacterial activity profiles of their silver salts. Molecular dynamics at different simulation protocols and conformational analysis were performed to elaborate on the conformational features of the studied dendrimers, as well as to create the initial structure for further binding studies. The results showed that for all compounds, there were no significant conformational changes due to variation in simulation conditions. Molecular docking calculations were performed to investigate the binding theme between the studied dendrimers and PBPs. Interestingly, in significant accordance with the experimental data, dendron and dendrimer with aliphatic cores were found to show higher activity against S. aureus than the dendrimer with an aromatic core. The latter showed higher activity against MRSA. The findings from this computational and molecular modeling report together with the experimental results serve as a road map toward designing more potent antibacterial dendrimers against resistant bacterial strains. PMID- 26743757 TI - Cell cycle of primitive hematopoietic progenitors decelerated in senescent mice is reactively accelerated after 2-Gy whole-body irradiation. AB - Aging is considered to be a functional retardation of continuous xenobiotic responses over a lifetime after the developmental period; thus, the effects of ionizing radiation over a lifetime may be somewhat accounted for by a modifier of aging effects. This study was conducted to evaluate the possible/synergic effects of radiation during aging by determining cell-cycle parameters of hematopoietic stem cells/hematopoietic progenitor cells (HSCs/HPCs), such as the percent of cells in cycling, the generation doubling time, and the cumulative cycling-cell fraction, by bromodeoxyuridine-ultraviolet assay, which enables the determination of their cycling capacity in vivo. Colony-forming progenitor cells, such as colony-forming unit (CFU)-granulocyte/macrophage (GM), CFU in the spleen on day 9 (CFU-S9), and CFU-S on day 13 (CFU-S13) for mature, less mature, and immature HPCs, respectively, were evaluated in young and old mice (6 weeks and 21 months of age, respectively) with or without 2-Gy whole-body irradiation and a 4-week recovery period. Then, cell-cycle parameters were evaluated and compared. As a result, the generation doubling time of all types of HPC was prolonged by the irradiation in both young and old mouse groups, except that of CFU-S13 in old mice, which showed acceleration of the cell cycle following the irradiation. In addition, only CFU-S13 in irradiated old mice showed a significant increase in the cumulative cycling-cell-fraction ratio. Significant changes due to the effects of aging and irradiation on HPCs were observed only in the immature HPCs, i.e., the cell cycle of immature HPCs was suppressed by aging without irradiation and was, in contrast, accelerated as the cells recovered from radiation-induced damage. This suggests that the mechanisms of peripheral blood recovery after 2-Gy whole-body irradiation are markedly different between young and old mice, although 21-month-old mice showed almost the same level of recovery as the young mice. PMID- 26743756 TI - Preparation and evaluation of reduction-responsive nano-micelles for miriplatin delivery. AB - A reduction-responsive amphiphilic core-shell micelle for miriplatin delivery was prepared and evaluated. A pyrene-terminated poly(2-(dimethylamino) ethyl acrylate) was synthesized through reversible addition-fragmentation chain transfer polymerization with 4-cyano-4-(ethylthiocarbonothioylthio) pentanoic acid as reversible addition-fragmentation chain transfer reagent and further modified by 2,2'-dithiodiethanol and 1-pyrenebutyric acid. Self-assembled blank micelles and drug-loaded micelles were obtained by dialysis method, and the particle size was proved to be about 40 nm with narrow dispersity by dynamic laser light scattering. Morphology results showed that blank micelles and drug loaded micelles were spherical nanoparticles confirmed by transmission electron microscope, and the critical micelle concentration was as low as 6.09 ug/mL via pyrene fluorescence probe method. The reductive sensitivity of disulfide bond in BMs was further verified by changes in particle size, pyrene fluorescence intensity ratio (I338/I333), and morphology after treatment by dithiothreitol. Moreover, drug release rate in vitro of drug-loaded micelles was evaluated and the results suggested that this amphiphilic pyrene-modified poly(2 (dimethylamino) ethyl acrylate) can be used as reduction-triggered controlled release drug delivery carrier for hydrophobic drug. PMID- 26743759 TI - [Viral infections of human central nervous system]. AB - The viruses that can infect the central nervous system of humans are numerous and form a heterogeneous group with respect to their structural, functional and epidemiological properties. The pathophysiological mechanisms leading to associated neurological diseases, mainly meningitis and encephalitis, also are complex and often intertwined. Overall, neurological clinical symptoms correspond either to acute viral diseases associated with primary infections or to acute, subacute or chronic diseases associated with persistent viral infections. The frequent severity of the clinical situation requires in all cases the practice of virological diagnosis for which the PCR techniques applied to cerebrospinal fluid samples occupy a prominent place. The severity of clinical manifestations justifies the use of prophylactic vaccination when available and antiviral treatment as soon as the causative virus is identified or suspected. PMID- 26743760 TI - Dynamics of immature mAb glycoform secretion during CHO cell culture: An integrated modelling framework. AB - Ensuring consistent glycosylation-associated quality of therapeutic monoclonal antibodies (mAbs) has become a priority in pharmaceutical bioprocessing given that the distribution and composition of the carbohydrates (glycans) bound to these molecules determines their therapeutic efficacy and immunogenicity. However, the interaction between bioprocess conditions, cellular metabolism and the intracellular process of glycosylation remains to be fully understood. To gain further insight into these interactions, we present a novel integrated modelling platform that links dynamic variations in mAb glycosylation with cellular secretory capacity. Two alternative mechanistic representations of how mAb specific productivity (qp ) influences glycosylation are compared. In the first, mAb glycosylation is modulated by the linear velocity with which secretory cargo traverses the Golgi apparatus. In the second, glycosylation is influenced by variations in Golgi volume. Within our modelling framework, both mechanisms accurately reproduce experimentally-observed dynamic changes in mAb glycosylation. In addition, an optimisation-based strategy has been developed to estimate the concentration of glycosylation enzymes required to minimise mAb glycoform variability. Our results suggest that the availability of glycosylation machinery relative to cellular secretory capacity may play a crucial role in mAb glycosylation. In the future, the modelling framework presented here may aid in selecting and engineering cell lines that ensure consistent mAb glycosylatio. PMID- 26743761 TI - Involvement of hypoxia-inducible factor-1alpha in the oxidative stress induced by advanced glycation end products in murine Leydig cells. AB - Hyperglycemia increases the formation of advanced glycation end products (AGEs), triggers oxidative impairments and influences inducible factor (HIF)-1alpha protein levels and transactivation function. Compromised HIF-1alpha in testis leads to male infertility. The aim of the study was to investigate the role of HIF-1alpha in oxidative stress induced by AGEs in murine Leydig TM3 cells. TM3 cells were treated with 50 MUg/ml of AGEs, or HIF-1alpha siRNA or 500 MUM of DMOG (dimethyloxalylglycine) respectively. The cells were also pretreated with HIF 1alpha siRNA or 500 MUM of DMOG and then were treated with 50 MUg/ml of AGEs. The formation of reactive oxygen species (ROS) and cell apoptosis was evaluated. The expression of caspase-3, Heme oxygenase (HO)-1, steroidogenic acute regulatory protein (StAR) and cytochrome P450 17alpha polypeptide 1 (CYP17A1) was examined by Western blotting. AGEs increased ROS production, induced apoptosis and activated HIF-1alpha and HO-1 in TM3 cells. HIF-1alpha attenuated the AGE-induced ROS formation and promoted apoptosis via the upregulation of caspase-3. Knockdown of HIF-1alpha inhibited the expression of CYP17A1 and StAR, and enhanced the inhibition of StAR and CYP17A1 by AGEs. These findings indicate that attenuated HIF-1alpha exacerbates the oxidative stress injury by AGEs in murine Leydig cells, and contributes to diabetic male infertility. PMID- 26743762 TI - Autophagic activity in BC3H1 cells exposed to yessotoxin. AB - The marine toxin yessotoxin (YTX) can induce programmed cell death through both caspase-dependent and -independent pathways in various cellular systems. It appears to stimulate different forms of cellular stress causing instability among cell death mechanisms and making them overlap and cross-talk. Autophagy is one of the key pathways that can be stimulated by multiple forms of cellular stress which may determine cell survival or death. The present work evaluates a plausible link between ribotoxic stress and autophagic activity in BC3H1 cells treated with YTX. Such treatment produces massive cytoplasmic compartments as well as double-membrane vesicles termed autophagosomes which are typically observed in cells undergoing autophagy. The observed autophagosomes contain a large amount of ribosomes associated with the endoplasmic reticulum (ER). Western blotting analysis of Atg proteins and detection of the autophagic markers LC3-II and SQSTM1/p62 by flow cytometry and immunofluorescence verified autophagic activity during YTX-treatment. The present work supports the idea that autophagic activity upon YTX exposure may represent a response to ribotoxic stress. PMID- 26743763 TI - Structural Characterizations of the Fas Receptor and the Fas-Associated Protein with Death Domain Interactions. AB - The Fas receptor is a representative death receptor, and the Fas-associated protein with death domain (FADD) is a crucial adapter protein needed to support the Fas receptor's activity. The Fas-FADD interactions constitute an important signaling pathway that ultimately induces apoptosis or programmed cell death in biological systems. The interactions responsible for this cell-death process are governed by the binding process of the Fas ligand to the Fas, followed by the caspase cascade activation. Using a computational approach, the present communication explores certain essential structural aspects of the Fas-FADD death domains and their interfacial interactions. PMID- 26743764 TI - Factors that Influence Health-Related Quality of Life in Patients with Primary Sclerosing Cholangitis. AB - BACKGROUND: Primary sclerosing cholangitis (PSC) is an incurable, cholestatic liver disease often coincident with inflammatory bowel disease (IBD). AIMS: To evaluate the impact of liver disease and IBD on health-related quality of life (HRQoL) in PSC. METHODS: A mixed-methods, cross-sectional study was performed at a tertiary center. Short Form-36 (SF-36) scores were compared between PSC, Canadian normative data, and disease controls. Disease-specific instruments scores [PBC-40, Short IBD questionnaire, Liver Disease Quality of Life Questionnaire (LDQOL)] were compared between PSC and disease controls. Multivariable regression identified factors independently associated with final SF-36 component scores. Qualitative evaluation of patient questionnaires was performed using a content analysis framework. RESULTS: One hundred and sixty-two surveys were completed (99 PSC, 26 primary biliary cirrhosis, 16 non-autoimmune cholestatic liver disease, and 21 IBD). PSC patients had significantly lower SF 36 scores than Canadian controls, but similar scores to disease controls. LDQOL most accurately predicted HRQoL. Factors negatively associated with physical HRQoL included shorter IBD duration, liver disease symptoms, and decompensated cirrhosis. Mental HRQoL was influenced by liver disease and IBD symptoms, pruritus, social isolation, and depression. Nearly 75 % expressed existential anxiety regarding disease progression and diminished life expectancy, with 25 % disclosing social isolation. CONCLUSIONS: Patients with PSC have significantly lower HRQoL than healthy controls. Both symptoms of IBD and chronic liver disease impact HRQoL in patients with PSC, which lead to significant psychologic burden that is expressed by existential anxieties and social isolation. A PSC-specific HRQoL tool is critical to adequately quantify the distinct impact of IBD and cholestatic liver disease. PMID- 26743765 TI - Tomato yellow leaf curl virus (TYLCV-IL): a seed-transmissible geminivirus in tomatoes. AB - Tomato yellow leaf curl virus (TYLCV) is one of the most well-known tomato infecting begomoviruses and transmitted by Bemisia tabaci. Seed transmission has previously been reported for some RNA viruses, but TYLCV has not previously been described as a seed-borne virus. In 2013 and 2014, without whitefly-mediated transmission, TYLCV was detected in young tomato plants germinated from fallen fruits produced from TYLCV-infected tomato plants in the previous cultivation season. In addition, TYLCV-Israel (TYLCV-IL) was also detected in seeds and their seedlings of TYLCV-infected tomato plants that were infected by both viruliferous whitefly-mediated transmission and agro-inoculation. The seed infectivity was 20 100%, respectively, and the average transmission rate to seedlings was also 84.62% and 80.77%, respectively. TYLCV-tolerant tomatoes also produced TYLCV infected seeds, but the amount of viral genome was less than seen in TYLCV susceptible tomato plants. When tomato plants germinated from TYLCV-infected seeds, non-viruliferous whiteflies and healthy tomato plants were placed in an insect cage together, TYLCV was detected from whiteflies as well as receiver tomato plants six weeks later. Taken together, TYLCV-IL can be transmitted via seeds, and tomato plants germinated from TYLCV-infected seeds can be an inoculum source of TYLCV. This is the first report about TYLCV seed transmission in tomato. PMID- 26743766 TI - Identifying Subphenotypes of Antibody-Mediated Rejection in Kidney Transplants. AB - The key lesions in antibody-mediated kidney transplant rejection (ABMR) are microcirculation inflammation (peritubular capillaritis and/or glomerulitis lesions, abbreviated "pg") and glomerular double contours (cg lesions). We used these features to explore subphenotypes in 164 indication biopsies with ABMR related diagnoses: 137 ABMR (109 pure and 28 mixed with T cell-mediated rejection [TCMR]) and 27 transplant glomerulopathy (TG), identified from prospective multicenter studies. The lesions indicated three ABMR subphenotypes: pgABMR, cgABMR, and pgcgABMR. Principal component analysis confirmed these subphenotypes and showed that TG can be reclassified as pgcgABMR (n = 17) or cgABMR (n = 10). ABMR-related biopsies included 45 pgABMR, 90 pgcgABMR, and 25 cgABMR, with four unclassifiable. Dominating all time intervals was the subphenotype pgcgABMR. The pgABMR subphenotype presented earliest (median <2 years), frequently mixed with TCMR, and was most associated with nonadherence. The cgABMR subphenotype presented late (median 9 years). Subphenotypes differed in their molecular changes, with pgABMR having the most histologic-molecular discrepancies (i.e. potential errors). Donor-specific antibody (DSA) was not identified in 29% of pgcgABMR and 46% of cgABMR, but failure rates and molecular findings were similar to cases where DSA was known to be positive. Thus, ABMR presents distinct subphenotypes, early pg-dominant, late cg-dominant, and combined pgcg phenotype, differing in time, molecular features, accompanying TCMR, HLA antibody, and probability of nonadherence. PMID- 26743768 TI - Gold Nanoparticle Assemblies on Surfaces: Reactivity Tuning through Capping-Layer and Cross-Linker Design. AB - The immobilization of metal nanoparticles (NPs) with molecular control over their organization is challenging. Herein, we report the formation of molecularly cross linked AuNP assemblies using a layer-by-layer approach. We observed four types of assemblies: 1) small aggregates of individual AuNPs, 2) large aggregates of individual AuNPs, 3) networks of fused AuNPs, and 4) gold islands. Interestingly, these assemblies with the different cross-linkers and capping layers represent different stages in the complete fusion of AuNPs to afford islands of continuous gold. We demonstrate that the stability toward fusion of the nanoparticles of the on-surface structures can be controlled by the reactivity of the cross-linkers and the hydrophilicity/hydrophobicity of the nanoparticles. PMID- 26743767 TI - A high-density SNP panel reveals extensive diversity, frequent recombination and multiple recombination hotspots within the chicken major histocompatibility complex B region between BG2 and CD1A1. AB - BACKGROUND: The major histocompatibility complex (MHC) is present within the genomes of all jawed vertebrates. MHC genes are especially important in regulating immune responses, but even after over 80 years of research on the MHC, much remains to be learned about how it influences adaptive and innate immune responses. In most species, the MHC is highly polymorphic and polygenic. Strong and highly reproducible associations are established for chicken MHC-B haplotypes in a number of infectious diseases. Here, we report (1) the development of a high density SNP (single nucleotide polymorphism) panel for MHC-B typing that encompasses a 209,296 bp region in which 45 MHC-B genes are located, (2) how this panel was used to define chicken MHC-B haplotypes within a large number of lines/breeds and (3) the detection of recombinants which contributes to the observed diversity. METHODS: A SNP panel was developed for the MHC-B region between the BG2 and CD1A1 genes. To construct this panel, each SNP was tested in end-point read assays on more than 7500 DNA samples obtained from inbred and commercially used egg-layer lines that carry known and novel MHC-B haplotypes. One hundred and one SNPs were selected for the panel. Additional breeds and experimentally-derived lines, including lines that carry MHC-B recombinant haplotypes, were then genotyped. RESULTS: MHC-B haplotypes based on SNP genotyping were consistent with the MHC-B haplotypes that were assigned previously in experimental lines that carry B2, B5, B12, B13, B15, B19, B21, and B24 haplotypes. SNP genotyping resulted in the identification of 122 MHC-B haplotypes including a number of recombinant haplotypes, which indicate that crossing-over events at multiple locations within the region lead to the production of new MHC-B haplotypes. Furthermore, evidence of gene duplication and deletion was found. CONCLUSIONS: The chicken MHC-B region is highly polymorphic across the surveyed 209-kb region that contains 45 genes. Our results expand the number of identified haplotypes and provide insights into the contribution of recombination events to MHC-B diversity including the identification of recombination hotspots and an estimation of recombination frequency. PMID- 26743770 TI - Mental Health Providers' Decision-Making Around the Implementation of Evidence Based Treatment for PTSD. AB - It is estimated that <15% of veterans with posttraumatic stress disorder (PTSD) have engaged in two evidence-based psychotherapies highly recommended by VA cognitive processing therapy (CPT) and prolonged exposure (PE). CPT and PE guidelines specify which patients are appropriate, but research suggests that providers may be more selective than the guidelines. In addition, PTSD clinical guidelines encourage "shared decision-making," but there is little research on what processes providers use to make decisions about CPT/PE. Sixteen licensed psychologists and social workers from two VA medical centers working with >=1 patient with PTSD were interviewed about patient factors considered and decision making processes for CPT/PE use. Qualitative analyses revealed that patient readiness and comorbid conditions influenced decisions to use or refer patients with PTSD for CPT/PE. Providers reported mentally derived and instances of patient-involved decision-making around CPT/PE use. Continued efforts to assist providers in making informed and collaborative decisions about CPT/PE use are discussed. PMID- 26743771 TI - Heterologous biosynthesis of artemisinic acid in Saccharomyces cerevisiae. AB - Artemisinic acid is a precursor of antimalarial compound artemisinin. The titre of biosynthesis of artemisinic acid using Saccharomyces cerevisiae platform has been achieved up to 25 g l(-1) ; however, the performance of platform cells is still industrial unsatisfied. Many strategies have been proposed to improve the titre of artemisinic acid. The traditional strategies mainly focused on partial target sites, simple up-regulation key genes or repression competing pathways in the total synthesis route. However, this may result in unbalance of carbon fluxes and dysfunction of metabolism. In this review, the recent advances on the promising methods in silico and in vivo for biosynthesis of artemisinic acid have been discussed. The bioinformatics and omics techniques have brought a great prospect for improving production of artemisinin and other pharmacal compounds in heterologous platform. PMID- 26743769 TI - Rice Improvement Through Genome-Based Functional Analysis and Molecular Breeding in India. AB - Rice is one of the main pillars of food security in India. Its improvement for higher yield in sustainable agriculture system is also vital to provide energy and nutritional needs of growing world population, expected to reach more than 9 billion by 2050. The high quality genome sequence of rice has provided a rich resource to mine information about diversity of genes and alleles which can contribute to improvement of useful agronomic traits. Defining the function of each gene and regulatory element of rice remains a challenge for the rice community in the coming years. Subsequent to participation in IRGSP, India has continued to contribute in the areas of diversity analysis, transcriptomics, functional genomics, marker development, QTL mapping and molecular breeding, through national and multi-national research programs. These efforts have helped generate resources for rice improvement, some of which have already been deployed to mitigate loss due to environmental stress and pathogens. With renewed efforts, Indian researchers are making new strides, along with the international scientific community, in both basic research and realization of its translational impact. PMID- 26743772 TI - IDO-Expressing Fibroblasts Protect Islet Beta Cells From Immunological Attack and Reverse Hyperglycemia in Non-Obese Diabetic Mice. AB - Indoleamine 2,3-dioxygenase (IDO) induces immunological tolerance in physiological and pathological conditions. Therefore, we used dermal fibroblasts with stable IDO expression as a cell therapy to: (i) Investigate the factors determining the efficacy of this cell therapy for autoimmune diabetes in non obese diabetic (NOD) mice; (ii) Scrutinize the potential immunological mechanisms. Newly diabetic NOD mice were randomly injected with either 10 * 10(6) (10M) or 15 * 10(6) (15M) IDO-expressing dermal fibroblasts. Blood glucose levels (BGLs), body weight, plasma kynurenine levels, insulitis severity, islet beta cell function, autoreactive CD8(+) T cells, Th17 cells and regulatory T cells (Tregs) were then investigated in these mice. IL-1beta and cleaved caspase-3 levels were assessed in islets co-cultured with IDO-expressing fibroblasts. BGLs in 83% mice treated with 15M IDO-expressing fibroblasts recovered to normal up to 120 days. However, only 17% mice treated with 10M IDO-expressing cells were reversed to normoglycemia. A 15M IDO-expressing fibroblasts significantly reduced infiltrated immune cells in islets and recovered the functionality of remaining islet beta cells in NOD mice. Additionally, they successfully inhibited autoreactive CD8(+) T cells and Th17 cells as well as increased Tregs in different organs of NOD mice. Islet beta cells co-cultured with IDO-expressing fibroblasts had reduced IL-1beta levels and cell apoptosis. Both cell number and IDO enzymatic activity contributes to the efficiency of IDO cell therapy. Optimized IDO-expressing fibroblasts successfully reverse the progression of diabetes in NOD mice through induction of Tregs as well as inhibition of beta cell specific autoreactive CD8(+) T cells and Th17 cells. J. Cell. Physiol. 231: 1964-1973, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26743774 TI - Risk of error estimated from Palestine pharmacists' knowledge and certainty on the adverse effects and contraindications of active pharmaceutical ingredients and excipients. AB - PURPOSE: This study aimed to investigate community pharmacists' knowledge and certainty of adverse effects and contraindications of pharmaceutical products to estimate the risk of error. Factors influencing their knowledge and certainty were also investigated. METHODS: The knowledge of community pharmacists was assessed in a cross-sectional design using a multiple-choice questions test on the adverse effects and contraindications of active pharmaceutical ingredients and excipients from May 2014 to March 2015. Self-rated certainty scores were also recorded for each question. Knowledge and certainty scores were combined to estimate the risk of error. RESULTS: Out of 315 subjects, 129 community pharmacists (41.0%) completed the 30 multiple-choice questions test on active ingredients and excipients. Knowledge on active ingredients was associated with the year of graduation and obtaining a licence to practice pharmacy. Knowledge on excipients was associated with the degree obtained. There was higher risk of error in items on excipients than those on ingredients (P<0.01). CONCLUSION: The knowledge of community pharmacists in Palestine was insufficient with high risk of errors. Knowledge of community pharmacists on the safety issues of active ingredients and excipients need to be improved. PMID- 26743773 TI - Catheter-Related Complications in Children With Cancer Receiving Parenteral Nutrition: Change in Risk Is Moderated by Catheter Type. AB - BACKGROUND: Although central venous catheters (CVCs) are essential to pediatric cancer care, complications are common (eg, occlusion, central line-associated bloodstream infection [CLABSI]). Parenteral nutrition (PN) and external CVCs are associated with an increased complication risk, but their interaction is unknown. METHODS: A retrospective matched cohort study of pediatric oncology patients who received PN through subcutaneous ports or external CVCs. Complication rates were compared between CVC types during PN and non-PN periods (log-negative binomial model). RESULTS: Risk of CLABSI was higher during PN for children with ports (relative risk [RR] = 39.6; 95% confidence interval, 5.0-309) or external CVCs (RR = 2.9; 95% confidence interval, 1.1-7.4). This increased risk during PN was greater for ports than for external CVCs (ratio of relative risks = 13.6). Occlusion risk was higher during PN in both groups (RR = 10.0 for ports; RR = 2.0 for external CVCs), and the increase was significantly greater in ports (ratio of relative risks, 4.9). Overall, complication rates for ports were much lower than for external CVCs during the non-PN period but similar during the PN period. CONCLUSION: Children with cancer who receive PN have increased risk of CLABSI and occlusion. The risk increase is greatest in children with ports: a 40- and 10 fold increase in infection risk and occlusion, respectively, resulting in similar complication rates during PN regardless of CVC type and negating the usual benefits of ports. Children with cancer who will require PN should have primary insertion of external CVCs where possible. PMID- 26743775 TI - Effects of subcutaneous, low-dose glucagon on insulin-induced mild hypoglycaemia in patients with insulin pump treated type 1 diabetes. AB - AIM: To investigate the dose-response relationship of subcutaneous (s.c.) glucagon administration on plasma glucose and on counter-regulatory hormone responses during s.c. insulin-induced mild hypoglycaemia in patients with type 1 diabetes treated with insulin pumps. METHODS: Eight insulin pump-treated patients completed a blinded, randomized, placebo-controlled study. Hypoglycaemia was induced in the fasting state by an s.c. insulin bolus and, when plasma glucose reached 3.4 mmol/l [95% confidence interval (CI) 3.2-3.5], an s.c. bolus of either 100, 200, 300 ug glucagon or saline was administered. Plasma glucose, counter-regulatory hormones, haemodynamic variables and side effects were measured throughout each study day. Peak plasma glucose level was the primary endpoint. RESULTS: Plasma glucose level increased significantly by a mean (95% CI) of 2.3 (1.7-3.0), 4.2 (3.5-4.8) and 5.0 (4.3-5.6) mmol/l to 6.1 (4.9-7.4), 7.9 (6.4-9.3) and 8.7 (7.8-9.5) vs 3.6 (3.4-3.9) mmol/l (p < 0.001) after the three different glucagon doses as compared with saline, and the increase was neither correlated with weight nor insulin levels. Area under the plasma glucose curve, peak plasma glucose, time to peak plasma glucose and duration of plasma glucose level above baseline were significantly enhanced with increasing glucagon doses; however, these were not significantly different between 200 and 300 ug glucagon. Free fatty acids and heart rates were significantly lower initially after glucagon than after saline injection. Other haemodynamic variables, counter regulatory hormones and side effects did not differ between interventions. CONCLUSIONS: An s.c. low-dose glucagon bolus effectively restores plasma glucose after insulin overdosing. Further research is needed to investigate whether low dose glucagon may be an alternative treatment to oral carbohydrate intake for mild hypoglycaemia in patients with type 1 diabetes. PMID- 26743776 TI - Multi-parametric MR imaging of quadriceps musculature in the setting of clinical frailty syndrome. AB - OBJECTIVE: Frailty is a common geriatric syndrome associated with loss of skeletal muscle mass (sarcopenia) conferring an increased risk of rapid decline in health and function with increased vulnerability to adverse outcomes. The purpose of this study was to investigate the correlation between diffusion tensor, T2 and intramuscular fat content values of the quadriceps muscle group and clinical frailty status using diffusion tensor MR imaging. MATERIAL AND METHODS: Subjects were recruited from the Arizona Frailty cohort composed of all females with frailty status based on the Fried criteria, including 6 non-frail and 10 pre-frail/frail adults, as well as a community sample of 11 young, healthy controls. Axial images of both thighs were obtained on a 3-T magnet with T1, T2 and diffusion tensor imaging as well as intramuscular fat analysis. Diffusion tensor and T2 values were determined by region-of-interest measurements at the proximal, mid and distal thirds of both thighs. Data were evaluated to determine differences between measured values and frailty status. RESULTS: The mean fractional anisotropy (FA) values in the bilateral quadriceps muscles demonstrated significant differences (F = 7.558, p = 0.0030) between the control and pre-frail/frail and non-frail and pre-frail/frail groups. There was a significant difference in mean T2 (F = 21.675, p < 0.0001) and lipid content (F = 19.266, p < 0.0001) among all three groups in the total quadriceps muscle group. CONCLUSION: The quadriceps musculature of pre-frail/frail adults demonstrated increased FA compared to young controls and non-frail adults with increasing T2 and intramuscular fat among the control, non-frail and pre-frail/frail categories. PMID- 26743778 TI - A preliminary study of apoptosis induction in glioma cells via alteration of the Bax/Bcl-2-p53 axis by transformed and non-transformed root extracts of Leonurus sibiricus L. AB - Leonurus sibiricus L. is a traditional medicinal plant which occurs in southern Siberia, China, Korea, Japan, and Vietnam. The plant shows several pharmacological effects, but the most interesting is its anti-cancer activity. The aim of our study was to examine the induction of apoptosis in malignant glioma cells, the most aggressive primary brain tumors of the central nervous system, following treatment with transformed root (TR) or non-transformed root (NR) L. sibiricus extracts. Both the NR and TR extracts were found to have cytotoxic activity in the glioma primary cells. The human glioblastoma cell lines obtained from patients were confirmed to be tumorogenic by the following three markers: D10S1709, D10S1172, and D22S283. HPLC and MS analysis revealed the presence of polyphenolic compounds (chlorogenic acid, ferulic acid, caffeic acid, p-coumaric acid, ellagic acid, and verbascoside) in both sets of root extracts. In summary, our findings demonstrate that treatment of the glioma cells with NR and TR extracts resulted (a) in significant cell growth inhibition, (b) S- and G2/M-phase cell cycle arrest, and (c) apoptosis in a dose-dependent fashion by changing Bax/Bcl-2 ratio (about 4-fold increase) and p53 (5-fold increase) activation. These findings indicate that NR and TR extracts exhibit anti-cancer activity through the regulation of genes involved in apoptosis. This is the first report to demonstrate the cytotoxic effect of polyphenolic extracts from L. sibiricus roots against glioma cells, but further studies are required to understand the complete mechanism of its apoptosic activity. PMID- 26743777 TI - Cellular uptake and intracellular degradation of poly(alkyl cyanoacrylate) nanoparticles. AB - BACKGROUND: Poly(alkyl cyanoacrylate) (PACA) nanoparticles have shown promise as drug carriers both to solid tumors and across the blood-brain barrier. Efficient drug delivery requires both high cellular uptake of the nanoparticles and release of the drug from the nanoparticles. Release of hydrophobic drugs from PACA nanoparticles is primarily governed by nanoparticle degradation, and this process has been poorly studied at the cellular level. Here we use the hydrophobic model drug Nile Red 668 (NR668) to investigate intracellular degradation of PACA nanoparticles by measuring changes in NR668 fluorescence emission and lifetime, as the spectral properties of NR668 depend on the hydrophobicity of the dye environment. We also assess the potential of poly(butyl cyanoacrylate) (PBCA) and poly(octyl cyanoacrylate) (POCA) nanoparticles for intracellular drug delivery in the prostate cancer cell line PC3 and rat brain endothelial cell line RBE4 and the role of endocytosis pathways in PACA nanoparticle uptake in those cell lines. RESULTS: Fluorescence lifetime imaging, emission spectra analysis and Forster resonance energy transfer indicated that the intracellular degradation was in line with the degradation found by direct methods such as gas chromatography and scanning electron microscopy, showing that PBCA has a faster degradation rate compared to POCA. The combined P(BCA/OCA) nanoparticles had an intermediate degradation rate. The uptake of POCA and PBCA nanoparticles was much higher in RBE4 than in PC3 cells. Endocytosis inhibition studies showed that both clathrin- and caveolin-mediated endocytosis were involved in PACA nanoparticle uptake, and that the former played a predominant role, particularly in PC3 cells. CONCLUSIONS: In the present study, we used three different optical techniques to show that within a 24-hour period PBCA nanoparticles degraded significantly inside cells, releasing their payload into the cytosol, while POCA nanoparticles remained intact. This indicates that it is possible to tune the intracellular drug release rate by choosing appropriate monomers from the PACA family or by using hybrid PACA nanoparticles containing different monomers. In addition, we showed that the uptake of PACA nanoparticles depends not only on the monomer material, but also on the cell type, and that different cell lines can use different internalization pathways. PMID- 26743780 TI - Correlations of fascin-1 and cadherin-17 protein expression with clinicopathologic features and prognosis of patients with gastric cancer. AB - We aim to explore the associations of fascin-1 and cadherin-17 in gastric cancer (GC) to the clinicopathologic features and prognosis of GC. Case group included 204 GC tissues while control group comprised 204 paired adjacent cancer tissues. Expressions of fascin-1 and cadherin-17 were measured with immunohistochemistry and western blot and then analyzed statistically in relation to clinicopathologic features and survival time. Survival curve was drawn by Kaplan-Meier method, and independent prognostic factors were identified with Cox proportional hazards regression model. Fascin-1 was positively expressed in 45.1 % of GC tissues and in 27.5 % of adjacent cancer tissues, respectively (P < 0.05); cadherin-17 was positively expressed in 51.5 % of GC tissues and in 33.8 % of adjacent cancer tissues (P < 0.05). Fascin-1 expression in GC tissues was related to tumor size (P = 0.001) and Lauren classification (P = 0.001). Cadherin-17 expression in GC tissues was related to tumor size (P < 0.001), Lauren classification (P = 0.009), clinical staging (P = 0.001), and distant metastasis (P = 0.002). Fascin-1 expression was positively correlated with cadherin-17 expression in GC tissues (r = 0.828, P < 0.01). Patients with positive expression of both fascin-1 and cadherin-17 had lower survival rates than those with negative expression (all P < 0.01). Cox regression analysis showed that fascin-1 expression, cadherin-17 expression, tumor size, and differentiation were independent risk factors for GC (all P < 0.05). Fascin-1 and cadherin-17 are related to clinicopathologic features of GC and are independent adverse prognostic factors for GC. PMID- 26743779 TI - Inhibition of miR-15b decreases cell migration and metastasis in colorectal cancer. AB - Colorectal cancer (CRC) has a high prevalence and mortality rate. Biomarkers for predicting the recurrence of CRC are not clinically available. This study investigated the role of circulating miR-15b in the prediction of CRC recurrence and the associated mechanism. miR-15b levels in plasma and tissues were measured by real-time PCR. Metastasis suppressor-1 (MTSS1) and Klotho protein expression were detected by Western blot and immunohistochemistry. Invasion and migration of CRC tumor cells were measured by transwell plates. Liver metastasis was established by intraspleen injection of HCT116 cells. Plasma miR-15b levels were significantly higher in CRC patients than in healthy controls, in CRC patients with metastasis than in CRC patients without metastasis, and in CRC patients with recurrence than in CRC patients without recurrence in the 5-year follow-up. miR 15b level in CRC tumors was significantly higher than that in peritumoral tissues. High plasma miR-15b level and negative MTSS1 and Klotho expression in tumor tissues significantly correlated with poor survival. Inhibition of miR-15b activity by adenovirus carrying antimiR-15b sequence significantly increased MTSS1 and Klotho protein expression and subsequently decreased colony formation ability, invasion, and migration of HCT116 cells in vitro and liver metastasis of HCT116 tumors in vivo. In conclusion, high abundance of circulating miR-15b correlated with tumor metastasis, recurrence, and poor patient prognosis through downregulation of MTSS1 and Klotho protein expression. PMID- 26743781 TI - Bilaterality weighs more than unilateral multifocality in predicting prognosis in papillary thyroid cancer. AB - Papillary thyroid cancer (PTC) often presents as multifocal tumor;, however, whether multifocality is associated with poor prognosis remains controversial. The aims of this retrospective study were to identify the characteristics of PTC with multifocal tumors and evaluate the association between the location and prognosis. We reviewed the medical records of 496 patients who underwent total thyroidectomy for PTC. Patients were classified as three groups: N1 (solitary tumor), N2 (2 or more foci within unilateral lobe of thyroid), and N3 (bilateral tumors, at least one tumor focus for each lobe of thyroid). We analyzed the differences of clinicopathologic features and clinical outcomes among the three groups. Cox regression model was used to assess the relation between the different locations of multifocal tumors and prognosis. Although the differences of clinicopathologic features such as the size of tumor, extrathyroidal extension, and cervical lymph node metastasis were not significant among the three groups, the bilateral-multifocality was proved to be an independent risk factor for neck recurrence (hazard ratio (HR) = 4.052, 95 % confidence interval (CI) 2.070-7.933), distant metastasis (HR = 3.860, 95 % CI 1.507-9.884), and cancer death (HR = 7.252, 95 % 2.189-24.025). In addition, extrathyroidal extension (HR = 2.291, 95 % CI 1.185-4.427) and older age >45 years (HR = 6.721, 95 % CI 2.300-19.637) were also significant predictors for neck recurrence and cancer death, respectively. Therefore, bilateral-multifocality as an indicator for more extensive tumor location could be used to assess the risk of recurrence and mortality in PTC. Given the poor prognosis associated with bilateral multifocality and other risk factors, aggressive therapy and intensive follow-up were recommended for PTC patients with them. PMID- 26743783 TI - Pedicle muscle flap transposition for chronic empyema with persistent bronchopleural fistula: experience of a single clinical center in China. AB - PURPOSE: The management of chronic empyema with persistent bronchopleural fistula (BPF) is a major challenge for surgeons. We report our experience of performing pedicle muscle flap transposition for chronic empyema with BPF in a clinical center in China. METHODS: The subjects of this study were 13 patients with postoperative chronic empyema and persistent BPF. The surgical procedure performed was chosen according to the degree of infection in the empyema cavity. Patients with mild contamination underwent one-stage cavity decortication with flap transposition, whereas patients with severe infection underwent two-stage surgery including open-window thoracostomy and pedicle muscle flap transposition. RESULTS: Five patients underwent one-stage surgery, followed by an uneventful postoperative course in all except one. The other eight patients underwent two stage surgery. The fistulas closed spontaneously during the course of dressings and six of these eight patients underwent second-stage surgery uneventfully. A bronchopleurocutaneous sinus developed in the wounds of the other two patients. CONCLUSIONS: Pedicle muscle flap transposition is a viable option for chronic empyema with BPF; however, surgical procedures should be selected according to the degree of contamination. For two-stage surgery, obliteration of the cavity should be considered, preferably after closure of the fistula. PMID- 26743782 TI - A novel variable exonic region and differential expression of LINC00663 non coding RNA in various cancer cell lines and normal human tissue samples. AB - Long non-coding RNAs (lncRNAs) are found to play crucial roles in several biological processes and have been associated with many complex human diseases including cancers. Several lines of evidences indicate that lncRNAs deregulated in many cancer tissues. In this particular study, differential expression of long intergenic non-coding RNA 663 (LINC00663) was demonstrated in various cancer cell lines and healthy human tissues by using RT-PCR and qPCR methods. While expression level of LINC00663 was most prominent in thyroid gland and uterus, it is least expressed in skeletal muscle tissues. Moreover, LINC00663 was found to be differentially expressed in various cancer cells. Particularly, its expression was highly diminished in DU-145, PC3, HGC-27, CRL-1469, A549, MCF7, and BCPAP cancer cells. Also, LINC00663 expression was most prominent in A172 glioblastoma cells. Additionally, a novel splice variant of LINC00663 RNA was also detected. The sequence and Basic Local Alignment Search Tool (BLAST) analysis results revealed the presence of a novel exonic region between exons 2 and 3. Subsequently, five potential splice variants showing high level of variation have been identified. Secondary structures of these variants with minimum free energy were also demonstrated. Furthermore, putative microRNA (miRNA) binding sites to these variants have been shown. In conclusion, LINC00663 was shown to be differentially expressed in various human tissues and cancer cell lines. Also, LINC00663 undergoes alternative splicing and the novel exonic region alters its secondary structure and its interactions with potential targeting miRNAs. The role of LINC00663 in cancer formation further needs to be investigated with a wide range of studies. PMID- 26743785 TI - [OCT angiography for exudative age-related macular degeneration : Initial experiences]. AB - The new technique of optical coherence tomography (OCT) angiography allows a non invasive reconstruction of the three-dimensional structure of the total retinal and choroidal vascularization within seconds. There are still limitations caused by movement artefacts, superimposition of superficial retinal vessels at the retinal pigment epithelium (RPE) level and insufficient three-dimensional imaging modalities. Initial experiences with this new method and especially the correlation with the current standard diagnostic procedure of fluorescein angiography show that new information can be obtained regarding specific vascular and neovascular changes. For three-dimensional neovascular changes, such as those found in exudative age-related macular degeneration (AMD,) a more sophisticated diagnostic analysis strategy must be specifically developed. Initial experiences demonstrate that the differentiation into the various types of choroidal neovascularization (CNV) by fluorescein angiography, specifically for type 1 (occult) and type 2 (classical) can also be visualized by OCT angiography. Furthermore, the new technology provides additional information on the choroidal and outer retinal changes associated with this disease, which may result in a better understanding of the underlying pathology. PMID- 26743784 TI - Clinicopathological characteristics of young patients with sporadic colorectal cancer. AB - PURPOSE: To evaluate the clinicopathological features of and prognosis associated with sporadic colorectal cancer (CRC) in Japanese patients younger than 40 years old. METHODS: The subjects of this study were patients with sporadic stage 0-III CRC, who underwent curative resection between 2004 and 2012 at the Cancer Institute Hospital. Clinicopathological characteristics and survival were compared between the young (<40 years; n = 81) and older groups (>=40 years; n = 2257). RESULTS: The median age was 36 years in the young group and 64 years in the older group. Young patients had a lower incidence of right-sided colon cancer (14 vs 28 %) and a higher incidence of rectal cancer (47 vs 32 %; P < 0.0001). The number of retrieved lymph nodes was significantly higher in the young group than in the older group (P = 0.0049). The young patients had similar overall survival and relapse-free survival to their older counterparts, except for overall survival in stage II patients (P = 0.0229). However, multivariate analysis indicated that age was not an independent prognostic factor for overall survival in patients with stage II CRC. CONCLUSIONS: Young Japanese patients with sporadic CRC have unique characteristics such as a high incidence of rectal cancer and similar pathological features; however, they appear to have comparable survival to older patients. PMID- 26743786 TI - Butterfly community shifts over two centuries. AB - Environmental changes strongly impact the distribution of species and subsequently the composition of species assemblages. Although most community ecology studies represent temporal snap shots, long-term observations are rather rare. However, only such time series allow the identification of species composition shifts over several decades or even centuries. We analyzed changes in the species composition of a southeastern German butterfly and burnet moth community over nearly 2 centuries (1840-2013). We classified all species observed over this period according to their ecological tolerance, thereby assessing their degree of habitat specialisation. This classification was based on traits of the butterfly and burnet moth species and on their larval host plants. We collected data on temperature and precipitation for our study area over the same period. The number of species declined substantially from 1840 (117 species) to 2013 (71 species). The proportion of habitat specialists decreased, and most of these are currently endangered. In contrast, the proportion of habitat generalists increased. Species with restricted dispersal behavior and species in need of areas poor in soil nutrients had severe losses. Furthermore, our data indicated a decrease in species composition similarity between different decades over time. These data on species composition changes and the general trends of modifications may reflect effects from climate change and atmospheric nitrogen loads, as indicated by the ecological characteristics of host plant species and local changes in habitat configuration with increasing fragmentation. Our observation of major declines over time of currently threatened and protected species shows the importance of efficient conservation strategies. PMID- 26743787 TI - Synthesis of Cyclic Carbonates Catalysed by Chromium and Aluminium Salphen Complexes. AB - Chromium and aluminium salphen complexes have been found to display remarkable catalytic activity in the synthesis of cyclic carbonates from a range of epoxides and carbon dioxide. The Al(salphen) complex is more reactive towards terminal epoxides at ambient temperature and pressure, whereas the Cr(salphen) complex exhibits higher catalytic activity towards more challenging internal epoxides at elevated temperature and pressure. PMID- 26743788 TI - Effect of economic recession on psychosocial working conditions by workers' nationality. AB - BACKGROUND: Several publications have documented the effects of economic recessions on health. However, little is known about how economic recessions influence working conditions, especially among vulnerable workers. OBJECTIVE: To explore the effects of 2008 economic crisis on the prevalence of adverse psychosocial working conditions among Spanish and foreign national workers. METHODS: Data come from the 2007 and 2011 Spanish Working Conditions Surveys. Survey year, sociodemographic, and occupational information were independent variables and psychosocial factors exposures were dependent variables. Analyses were stratified by nationality (Spanish versus foreign). Prevalence and adjusted prevalence ratios (aPRs) of psychological job demands, job control, job social support, physical demands and perceived job insecurity were estimated using Poisson regression. RESULTS: The Spanish population had higher risk of psychological and physical job demand (aPR = 1.07, 95% CI = [1.04-1.10] and aPR = 1.05, 95% CI = [1.01-1.09], respectively) in 2011 compared to 2007. Among both Spanish and foreign national workers, greater aPR were found for job loss in 2011 compared to 2007 (aPR = 2.47, 95% CI = [2.34-2.60]; aPR = 2.44, 95% CI = [2.15 2.77], respectively). CONCLUSION: The 2008 economic crisis was associated with a significant increase in physical demands in Spanish workers and increased job insecurity for both Spanish and foreign workers. PMID- 26743789 TI - Asbestos in commercial cosmetic talcum powder as a cause of mesothelioma in women. PMID- 26743791 TI - Asbestos in commercial cosmetic talcum powder as a cause of mesothelioma in women. PMID- 26743790 TI - Response to RE: Gordon R, Fitzgerald S, and Millette J. Asbestos in commercial cosmetic talcum powder as a cause of mesothelioma in women. Int J Occup Environ Health. 2014;20(4):318-332. PMID- 26743792 TI - State of The Journal: JADA offers new features for readers and authors. PMID- 26743793 TI - Clinical practice guidelines for recall and maintenance: Why now? PMID- 26743794 TI - Shared decision making. PMID- 26743795 TI - Economic analysis studies. PMID- 26743796 TI - Authors' response. PMID- 26743798 TI - The changing nature of overhead. PMID- 26743799 TI - Titanate cathodes with enhanced electrical properties achieved via growing surface Ni particles toward efficient carbon dioxide electrolysis. AB - Ionic conduction in perovskite oxide is commonly tailored by element doping in lattices to create charge carriers, while few studies have been focused on ionic conduction enhancement through tailoring microstructures. In this work, remarkable enhancement of ionic conduction in titanate has been achieved via in situ growing active nickel nanoparticles on an oxide surface by controlling the oxide material nonstoichiometry. The combined use of XRD, SEM, XPS and EDS indicates that the exsolution/dissolution of the nickel nanoparticles is completely reversible in redox cycles. With the synergetic effect of enhanced ionic conduction of titanate and the presence of catalytic active Ni nanocatalysts, significant improvement of electrocatalytic performances of the titanate cathode is demonstrated. A current density of 0.3 A cm(-2) with a Faradic efficiency of 90% has been achieved for direct carbon dioxide electrolysis in a 2 mm-thick YSZ-supported solid oxide electrolyzer with the modified titanate cathode at 2 V and 1073 K. PMID- 26743797 TI - Clinical practice guidelines for recall and maintenance of patients with tooth borne and implant-borne dental restorations. AB - PURPOSE: To provide guidelines for patient recall regimen, professional maintenance regimen, and at-home maintenance regimen for patients with tooth borne and implant-borne removable and fixed restorations. MATERIALS AND METHODS: The American College of Prosthodontists (ACP) convened a scientific panel of experts appointed by the ACP, American Dental Association (ADA), Academy of General Dentistry (AGD), and American Dental Hygienists Association (ADHA) who critically evaluated and debated recently published findings from two systematic reviews on this topic. The major outcomes and consequences considered during formulation of the clinical practice guidelines (CPGs) were risk for failure of tooth- and implant-borne restorations. The panel conducted a round table discussion of the proposed guidelines, which were debated in detail. Feedback was used to supplement and refine the proposed guidelines, and consensus was attained. RESULTS: A set of CPGs was developed for tooth-borne restorations and implant-borne restorations. Each CPG comprised (1) patient recall, (2) professional maintenance, and (3) at-home maintenance. For tooth-borne restorations, the professional maintenance and at-home maintenance CPGs were subdivided for removable and fixed restorations. For implant-borne restorations, the professional maintenance CPGs were subdivided for removable and fixed restorations and further divided into biological maintenance and mechanical maintenance for each type of restoration. The at-home maintenance CPGs were subdivided for removable and fixed restorations. CONCLUSIONS: The clinical practice guidelines presented in this document were initially developed using the two systematic reviews. Additional guidelines were developed using expert opinion and consensus, which included discussion of the best clinical practices, clinical feasibility, and risk-benefit ratio to the patient. To the authors' knowledge, these are the first CPGs addressing patient recall regimen, professional maintenance regimen, and at-home maintenance regimen for patients with tooth borne and implant-borne restorations. This document serves as a baseline with the expectation of future modifications when additional evidence becomes available. PMID- 26743800 TI - The value of surrogate endpoints for predicting real-world survival across five cancer types. AB - OBJECTIVE: It is unclear how well different outcome measures in randomized controlled trials (RCTs) perform in predicting real-world cancer survival. We assess the ability of RCT overall survival (OS) and surrogate endpoints - progression-free survival (PFS) and time to progression (TTP) - to predict real world OS across five cancers. METHODS: We identified 20 treatments and 31 indications for breast, colorectal, lung, ovarian, and pancreatic cancer that had a phase III RCT reporting median OS and median PFS or TTP. Median real-world OS was determined using a Kaplan-Meier estimator applied to patients in the Surveillance and Epidemiology End Results (SEER)-Medicare database (1991-2010). Performance of RCT OS and PFS/TTP in predicting real-world OS was measured using t-tests, median absolute prediction error, and R(2) from linear regressions. RESULTS: Among 72,600 SEER-Medicare patients similar to RCT participants, median survival was 5.9 months for trial surrogates, 14.1 months for trial OS, and 13.4 months for real-world OS. For this sample, regression models using clinical trial OS and trial surrogates as independent variables predicted real-world OS significantly better than models using surrogates alone (P = 0.026). Among all real-world patients using sample treatments (N = 309,182), however, adding trial OS did not improve predictive power over predictions based on surrogates alone (P = 0.194). Results were qualitatively similar using median absolute prediction error and R(2) metrics. CONCLUSIONS: Among the five tumor types investigated, trial OS and surrogates were each independently valuable in predicting real-world OS outcomes for patients similar to trial participants. In broader real-world populations, however, trial OS added little incremental value over surrogates alone. PMID- 26743801 TI - Antibacterial and leishmanicidal activity of Bolivian propolis. AB - The antimicrobial activity of Bolivian propolis was assessed for the first time on a panel of bacteria and two endemic parasitic protozoa. Ten samples of Bolivian propolis and their main constituents were tested using the micro-broth dilution method against 11 bacterial pathogenic strains as well as against promastigotes of Leishmania amazonensis and L. braziliensis using the XTT-based colorimetric method. The methanolic extracts showed antibacterial effect ranging from inactive (MICs > 1000 MUg ml(-1) ) to low (MICs 250-1000 MUg ml(-1) ), moderate (62.5-125 MUg ml(-1) ) and high antibacterial activity (MIC 31.2 MUg ml( 1) ), according to the collection place and chemical composition. The most active samples towards Leishmania species were from Cochabamba and Tarija, with IC50 values of 12.1 and 7.8, 8.0 and 10.9 MUg ml(-1) against L. amazonensis and Leishmania brasiliensis respectively. The results show that the best antibacterial and antiprotozoal effect was observed for some phenolic-rich propolis. SIGNIFICANCE AND IMPACT OF THE STUDY: Propolis is used in Bolivia as an antimicrobial agent. Bolivian propolis from the main production areas was assessed for antibacterial and leishmanicidal effect and the results were compared with the propolis chemical composition. The active antibacterial propolis samples were phenolic-rich while those containing mainly triterpenes were devoid of activity or weakly active. A similar picture was obtained for the effect on Leishmania, with better effect for the phenolic-rich samples. As propolis is used for the same purposes regardless of the production area and composition, our findings indicate the need for the standardization of this natural product as antimicrobial. PMID- 26743805 TI - Comparison of infectious bursal disease live vaccines and a HVT-IBD vector vaccine and their effects on the immune system of commercial layer pullets. AB - Infectious bursal disease (IBD) is an economically important disease affecting poultry production worldwide. Previous experimental studies indicated that IBD live vaccination may induce transient immunosuppression, leading to suboptimal vaccine responses and therefore insufficient protection against other pathogens. Layer pullets are commonly not only vaccinated against IBD within their rearing period, but also against a variety of other pathogens. Therefore, it is of interest to investigate the effects of different IBD vaccination regimes on conventionally applied vaccines against other pathogens, and possible protection against widely spread very virulent IBD-virus (vvIBDV). A commercially available Herpesvirus of turkey vector vaccine (vHVT-IBD) expressing viral protein 2 of IBDV, and two IBD live vaccines were compared in commercial pullets for their effects on circulating B cell numbers, the ability of vaccinated birds to mount a humoral immune response against different antigens as well as their ability to induce protection against vvIBDV challenge. The results of this study demonstrate a clear immunosuppressive effect of the intermediate plus IBD live vaccine on the humoral branch of the immune system. On the other hand, no detectable effects of vHVT-IBD vaccination on these parameters were observed. All tested IBD vaccines protected against clinical IBD, although none induced sterile immunity in commercial layer pullets. vHVT-IBD-vaccinated birds showed significantly less lesions after vvIBDV challenge than IBD live-vaccinated or non-vaccinated birds (P < 0.05). Therefore, vHVT-IBD may be a suitable alternative to conventional IBD live vaccines, and may be applied even in the presence of maternally derived IBD antibodies without induction of detectable humoral immunosuppression. PMID- 26743804 TI - Muscle Oxygen Saturation Improves Diagnostic Association Between Initial Vital Signs and Major Hemorrhage: A Prospective Observational Study. AB - OBJECTIVES: During initial assessment of trauma patients, vital signs do not identify all patients with life-threatening hemorrhage. We hypothesized that a novel vital sign, muscle oxygen saturation (SmO2 ), could provide independent diagnostic information beyond routine vital signs for identification of hemorrhaging patients who require packed red blood cell (RBC) transfusion. METHODS: This was an observational study of adult trauma patients treated at a Level I trauma center. Study staff placed the CareGuide 1100 tissue oximeter (Reflectance Medical Inc., Westborough, MA), and we analyzed average values of SmO2 , systolic blood pressure (sBP), pulse pressure (PP), and heart rate (HR) during 10 minutes of early emergency department evaluation. We excluded subjects without a full set of vital signs during the observation interval. The study outcome was hemorrhagic injury and RBC transfusion >= 3 units in 24 hours (24-hr RBC >= 3). To test the hypothesis that SmO2 added independent information beyond routine vital signs, we developed one logistic regression model with HR, sBP, and PP and one with SmO2 in addition to HR, sBP, and PP and compared their areas under receiver operating characteristic curves (ROC AUCs) using DeLong's test. RESULTS: We enrolled 487 subjects; 23 received 24-hr RBC >= 3. Compared to the model without SmO2 , the regression model with SmO2 had a significantly increased ROC AUC for the prediction of >= 3 units of 24-hr RBC volume, 0.85 (95% confidence interval [CI], 0.75-0.91) versus 0.77 (95% CI, 0.66-0.86; p < 0.05 per DeLong's test). Results were similar for ROC AUCs predicting patients (n = 11) receiving 24-hr RBC >= 9. CONCLUSIONS: SmO2 significantly improved the diagnostic association between initial vital signs and hemorrhagic injury with blood transfusion. This parameter may enhance the early identification of patients who require blood products for life-threatening hemorrhage. PMID- 26743806 TI - On the shedding of impaled droplets: The role of transient intervening layers. AB - Maintaining the non-wetting property of textured hydrophobic surfaces is directly related to the preservation of an intervening fluid layer (gaseous or immiscible liquid) between the droplet and substrate; once displaced, it cannot be recovered spontaneously as the fully penetrated Wenzel wetting state is energetically favorable. Here, we identify pathways for the "lifting" of droplets from the surface texture, enabling a complete Wenzel-to-Cassie-Baxter wetting state transition. This is accomplished by the hemiwicking of a transient (limited lifetime due to evaporation) low surface tension (LST) liquid, which is capable of self-assembling as an intervening underlayer, lifting the droplet from its impaled state and facilitating a skating-like behavior. In the skating phase, a critical substrate tilting angle is identified, up to which underlayer and droplet remain coupled exhibiting a pseudo-Cassie-Baxter state. For greater titling angles, the droplet, driven by inertia, detaches itself from the liquid intervening layer and transitions to a traditional Cassie-Baxter wetting state, thereby accelerating and leaving the underlayer behind. A model is also presented that elucidates the mechanism of mobility recovery. Ultimately, this work provides a better understanding of multiphase mass transfer of immiscible LST liquid-water mixtures with respect to establishing facile methods towards retaining intervening layers. PMID- 26743807 TI - Virulence of viral haemorrhagic septicaemia virus (VHSV) genotype III in rainbow trout. AB - In general, viral haemorrhagic septicaemia virus (VHSV) isolates from marine fish species in European waters (genotypes GIb, GII and GIII) are non- to low virulent in rainbow trout. However, a VHSV isolation was made in 2007 from a disease outbreak in sea farmed rainbow trout in Norway. The isolate, named NO-2007-50 385, was demonstrated to belong to GIII. This isolate has attracted attention to assess which of the viral genome/proteins might be associated with the virulence in rainbow trout. In this study, we describe the difference of virulence in rainbow trout between the NO-2007-50-385 and 4p168 isolates as representatives of virulent and non-virulent GIII isolates, respectively. Rainbow trout were bath challenged with VHSV NO-2007-50-385 for 1 and 6 h, resulting in cumulative mortalities of 5 and 35%, respectively. No mortality was observed in the rainbow trout groups immersed with the genotype III VHSV isolate 4p168 for 1 and 6 h. The viral titre in organs from fish challenged with NO-2007-50-385 for 6 h increased more rapidly than those exposed for 1 h. By in vitro studies it was demonstrated that the final titres of VHSV DK-3592B (GI), NO-2007-50-385 and 4p168 inoculated on EPC cells were very similar, whereas when inoculated on the rainbow trout cell line RTG-2 the titre of the non-virulent 4p168 isolate was 3-4 logs below the two other VHSV isolates. Based on a comparative analysis of the entire genome of the genotype III isolates, we suggest that substitutions of amino acids in positions 118-123 of the nucleo-protein are candidates for being related to virulence of VHSV GIII in rainbow trout. PMID- 26743808 TI - An exploratory randomised trial of a simple, brief psychological intervention to reduce subsequent suicidal ideation and behaviour in patients admitted to hospital for self-harm. AB - BACKGROUND: Implementation intentions link triggers for self-harm with coping skills and appear to create an automatic tendency to invoke coping responses when faced with a triggering situation. AIMS: To test the effectiveness of implementation intentions in reducing suicidal ideation and behaviour in a high risk group. METHOD: Two hundred and twenty-six patients who had self-harmed were randomised to: (a) forming implementation intentions with a 'volitional help sheet'; (b) self-generating implementation intentions without help; or (c) thinking about triggers and coping, but not forming implementation intentions. We measured self-reported suicidal ideation and behaviour, threats of suicide and likelihood of future suicide attempt at baseline and then again at the 3-month follow-up. RESULTS: All suicide-related outcome measures were significantly lower at follow-up among patients forming implementation intentions compared with those in the control condition (ds>0.35). The volitional help sheet resulted in fewer suicide threats (d = 0.59) and lowered the likelihood of future suicide attempts (d = 0.29) compared with patients who self-generated implementation intentions. CONCLUSIONS: Implementation intention-based interventions, particularly when supported by a volitional help sheet, show promise in reducing future suicidal ideation and behaviour. PMID- 26743809 TI - Parity of publication for psychiatry. AB - BACKGROUND: There is an established disparity between physical and mental healthcare. Parity of research outputs has not been assessed internationally across influential medical journals. AIMS: To assess parity of publication between physical and mental health, and within psychiatry. METHOD: Four major medical disciplines were identified and their relative burden estimated. All publications from the highest-impact general medical journals in 2001, 2006 and 2011 were categorised accordingly. The frequency of psychiatry, cardiology, oncology and respiratory medicine articles were compared with the expected proportion (given illness burdens). Six subspecialties within psychiatry were also compared. RESULTS: Psychiatry was consistently and substantially underrepresented; other specialties were overrepresented. Dementia and psychosis demonstrated overrepresentation, with addiction and anxiety disorders represented proportionately and other disorders underrepresented. The underrepresentation of mood disorders increased more recently. CONCLUSIONS: There appears to be an important element of disparity of esteem; further action is required to achieve equivalence between mental and physical health research publications. PMID- 26743810 TI - Assisted and unassisted suicide in men and women: longitudinal study of the Swiss population. AB - BACKGROUND: In Switzerland assisted suicide is legal if no self-interest is involved. AIMS: To compare the strength and direction of associations with sociodemographic factors between assisted and unassisted suicides. METHOD: We calculated rates and used Cox and logistic regression models in a longitudinal study of the Swiss population. RESULTS: Analyses were based on 5 004 403 people, 1301 assisted and 5708 unassisted suicides from 2003 to 2008. The rate of unassisted suicides was higher in men than in women, rates of assisted suicides were similar in men and women. Higher education was positively associated with assisted suicide, but negatively with unassisted. Living alone, having no children and no religious affiliation were associated with higher rates of both. CONCLUSIONS: Some situations that indicate greater vulnerability such as living alone were associated with both assisted and unassisted suicide. Among the terminally ill, women were more likely to choose assisted suicide, whereas men died more often by unassisted suicide. PMID- 26743813 TI - Preparation and reactivity of a Ru(0) phosphino-carbene complex. AB - The reaction of the phosphino-carbene MeNC3H2NPtBu2 with RuHCl(CO)(PPh3)3 is shown to give facile access to the Ru(0) species (MeNC3H2NPtBu2)Ru(CO)(PPh3)2 (). This species undergoes oxidative addition of H2 and silanes to give (MeNC3H2NPtBu2)RuH2(CO)(PPh3)2, (MeNC3H2NPtBu2)Ru H(SiRPh2)(CO)(PPh3) (R = Ph 5, H 6) and (MeNC3H2NPtBu2) RuH(PhSi(SCH2CH2)2O)(CO)(PPh3) . PMID- 26743811 TI - Structural brain alterations in primary open angle glaucoma: a 3T MRI study. AB - Glaucoma is not only an eye disease but is also associated with degeneration of brain structures. We now investigated the pattern of visual and non-visual brain structural changes in 25 primary open angle glaucoma (POAG) patients and 25 age gender-matched normal controls using T1-weighted imaging. MRI images were subjected to volume-based analysis (VBA) and surface-based analysis (SBA) in the whole brain as well as ROI-based analysis of the lateral geniculate nucleus (LGN), visual cortex (V1/2), amygdala and hippocampus. While VBA showed no significant differences in the gray matter volumes of patients, SBA revealed significantly reduced cortical thickness in the right frontal pole and ROI-based analysis volume shrinkage in LGN bilaterally, right V1 and left amygdala. Structural abnormalities were correlated with clinical parameters in a subset of the patients revealing that the left LGN volume was negatively correlated with bilateral cup-to-disk ratio (CDR), the right LGN volume was positively correlated with the mean deviation of the right visual hemifield, and the right V1 cortical thickness was negatively correlated with the right CDR in glaucoma. These results demonstrate that POAG affects both vision-related structures and non-visual cortical regions. Moreover, alterations of the brain visual structures reflect the clinical severity of glaucoma. PMID- 26743812 TI - Temperature-controlled laminar airflow in severe asthma for exacerbation reduction (The LASER Trial): study protocol for a randomised controlled trial. AB - BACKGROUND: Asthma affects more than 5 million patients in the United Kingdom. Nearly 500,000 of these patients have severe asthma with severe symptoms and frequent exacerbations that are inadequately controlled with available treatments. The burden of severe asthma on the NHS is enormous, accounting for 80 % of the total asthma cost (L1 billion), with frequent exacerbations and expensive medications generating much of this cost. Of those patients with severe asthma, 70 % are sensitised to indoor aeroallergens, and the level of exposure to allergens determines the symptoms; patients exposed to high levels are therefore most at risk of exacerbations and hospital admissions. The LASER trial aims to assess whether a new treatment, temperature controlled laminar airflow (TLA) delivered by the AirsonettTM device, can reduce the frequency of exacerbations in patients with severe allergic asthma by reducing exposure to aeroallergens overnight. METHODS: This multicentre study is a placebo-controlled, blinded, randomised controlled, parallel group trial. A total of 222 patients with a new or current diagnosis of severe allergic asthma will be assigned with a random element in a 1:1 ratio to receive either an active device for one year or a placebo device. The primary outcome is the frequency of severe asthma exacerbations occurring over a 12-month period, defined in accordance with the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines. Secondary outcomes include changes in asthma control, lung function, asthma specific and global quality of life for participants and their carers, adherence to intervention, healthcare resource use and costs, and cost-effectiveness. Qualitative interviews will be conducted to elicit participant's and their partner's perceptions of the treatment. DISCUSSION: Effective measures of allergen avoidance have, to date, proved elusive. The LASER trial aims to address this. The study will ascertain whether home-based nocturnal TLA usage over a 12 month period can reduce the frequency of exacerbations and improve asthma control and quality of life as compared to placebo, whilst being cost-effective and acceptable to adults with poorly controlled, severe allergic asthma. The results of this study will be widely applicable to the many patients with allergic asthma both in the UK and internationally. TRIAL REGISTRATION: Current controlled trials ISRCTN46346208 (Date assigned 22 January 2014). PMID- 26743814 TI - Hierarchical ZnO Nanowires-loaded Sb-doped SnO2-ZnO Micrograting Pattern via Direct Imprinting-assisted Hydrothermal Growth and Its Selective Detection of Acetone Molecules. AB - We propose a novel synthetic route by combining imprinting transfer of a Sb-doped SnO2 (ATO)-ZnO composite micrograting pattern (MP), i.e., microstrip lines, on a sensor substrate and subsequent hydrothermal growth of ZnO nanowires (NWs) for producing a hierarchical ZnO NW-loaded ATO-ZnO MP as an improved chemo-resistive sensing layer. Here, ATO-ZnO MP structure with 3-MUm line width, 9-MUm pitch, and 6-MUm height was fabricated by direct transfer of mixed ATO and ZnO nanoparticle (NP)-dispersed resists, which are pre-patterned on a polydimethylsiloxane (PDMS) mold. ZnO NWs with an average diameter of less than 50 nm and a height of 250 nm were quasi-vertically grown on the ATO-ZnO MP, leading to markedly enhanced surface area and heterojunction composites between each ATO NP, ZnO NP, and ZnO NW. A ZnO NW-loaded MP sensor with a relative ratio of 1:9 between ATO and ZnO (1:9 ATO-ZnO), exhibited highly sensitive and selective acetone sensing performance with 2.84-fold higher response (R air/R gas = 12.8) compared to that (R air/R gas = 4.5) of pristine 1:9 ATO-ZnO MP sensor at 5 ppm. Our results demonstrate the processing advantages of direct imprinting-assisted hydrothermal growth for large-scale homogeneous coating of hierarchical oxide layers, particularly for applications in highly sensitive and selective chemical sensors. PMID- 26743815 TI - Cu-Au alloy nanostructures coated with aptamers: a simple, stable and highly effective platform for in vivo cancer theranostics. AB - As a star material in cancer theranostics, photoresponsive gold (Au) nanostructures may still have drawbacks, such as low thermal conductivity, irradiation-induced melting effect and high cost. To solve the problem, copper (Cu) with a much higher thermal conductivity and lower cost was introduced to generate a novel Cu-Au alloy nanostructure produced by a simple, gentle and one pot synthetic method. Having the good qualities of both Cu and Au, the irregularly-shaped Cu-Au alloy nanostructures showed several advantages over traditional Au nanorods, including a broad and intense near-infrared (NIR) absorption band from 400 to 1100 nm, an excellent heating performance under laser irradiation at different wavelengths and even a notable photostability against melting. Then, via a simple conjugation of fluorophore-labeled aptamers on the Cu Au alloy nanostructures, active targeting and signal output were simultaneously introduced, thus constructing a theranostic platform based on fluorophore labeled, aptamer-coated Cu-Au alloy nanostructures. By using human leukemia CCRF CEM cancer and Cy5-labeled aptamer Sgc8c (Cy5-Sgc8c) as the model, a selective fluorescence imaging and NIR photothermal therapy was successfully realized for both in vitro cancer cells and in vivo tumor tissues. It was revealed that Cy5 Sgc8c-coated Cu-Au alloy nanostructures were not only capable of robust target recognition and stable signal output for molecular imaging in complex biological systems, but also killed target cancer cells in mice with only five minutes of 980 nm irradiation. The platform was found to be simple, stable, biocompatible and highly effective, and shows great potential as a versatile tool for cancer theranostics. PMID- 26743816 TI - Lysophosphatidic acid upregulates connective tissue growth factor expression in osteoblasts through the GPCR/PKC and PKA pathways. AB - Lysophosphatidic acid (LPA) is an efficient, bioactive phospholipid involved in various biological processes. In this study, LPA-induced connective tissue growth factor (CTGF/CCN2) expression and the underlying mechanisms were investigated using the MC3T3-E1 cell line. The MC3T3-E1 cells were stimulated with an inhibitor of LPA receptors, an activator and inhibitor of protein kinase C (PKC) and protein kinase A (PKA) for indicated periods of time. RT-qPCR and western blot analyses were used to measure the expression levels of CCN2. Immunofluorescence staining was used to observe the translocation of PKC. The mRNA expression level of CCN2 was increased following stimulation of the cells with LPA; LPA transiently induced the mRNA expression of CCN2; maximum expression levels were observed 2 h following stimulation with LPA. This increase was accompanied by CCN2 protein synthesis. LPA receptor1/3 was inhibited by Ki16425, a specific inhibitor of LPA1/3; as a result, the LPA-induced increase in CCN2 expression was abrogated. LPA also induced the membrane translocation of PKC and enhanced PKC activity in the osteoblasts. Pre-treatment of the osteoblasts with staurosporine prevented the increase in CCN2 expression by induced by LPA, and the activation of PKC by phorbol 12-myristate 13-acetate (PMA) enhanced CCN2 expression, indicating that the PKC pathway is involved in the LPA-induced increase in CCN2 expression. The interference of PKA signaling also led to the induction of CCN2 expresion by LPA. These data indicate that LPA increases CCN2 expression through the activation of PKC and PKA. Thus, the regulatory functions of the PKC and PKA pathways are implicated in the LPA-induced increase in CCN2 expression. PMID- 26743817 TI - Hypotension Associated With Intravitreal Bevacizumab Therapy for Retinopathy of Prematurity. AB - Intravitreal bevacizumab therapy in preterm infants for retinopathy of prematurity (ROP) can be associated with hypotension. We report twin preterm infants who developed hypotension within 1 day after intravitreal bevacizumab therapy for ROP. Before receiving the medication, their clinical statuses were stable and similar. The dose, procedure, and premedication were the same; however, twin B presented with hypotension for 3 days. Although bevacizumab related hypotension has been described in product information (incidence rate 7% 15%), this is the first case report of intravitreal bevacizumab for ROP inducing hypotension. Physicians should be aware of intravitreal bevacizumab therapy related hypotension when treating ROP. We suggest conducting a postmarketing active surveillance on the systemic adverse effects of this regimen in preterm infants. PMID- 26743818 TI - Changes in Efficiency and Safety Culture After Integration of an I-PASS-Supported Handoff Process. AB - BACKGROUND AND OBJECTIVES: Recent publications have shown improved outcomes associated with resident-to-resident handoff processes. However, the implementation of similar handoff processes for patients moving between units and teams with expansive responsibilities presents unique challenges. We sought to determine the impact of a multidisciplinary standardized handoff process on efficiency, safety culture, and satisfaction. METHODS: A prospective improvement initiative to standardize handoffs during patient transitions from the cardiovascular ICU to the acute care unit was implemented in a university affiliated children's hospital. RESULTS: Time between verbal handoff and patient transfer decreased from baseline (397 +/- 167 minutes) to the postintervention period (24 +/- 21 minutes) (P < .01). Percentage positive scores for the handoff/transitions domain of a national culture of safety survey improved (39.8% vs 15.2% and 38.8% vs 19.6%; P = .005 and 0.03, respectively). Provider satisfaction improved related to the information conveyed (34% to 41%; P = .03), time to transfer (5% to 34%; P < .01), and overall experience (3% to 24%; P < .01). Family satisfaction improved for several questions, including: "satisfaction with the information conveyed" (42% to 70%; P = .02), "opportunities to ask questions" (46% to 74%; P < .01), and "Acute Care team's knowledgeabout my child's issues" (50% to 73%; P = .04). No differences in rates of readmission, rapid response team calls, or mortality were observed. CONCLUSIONS: Implementation of a multidisciplinary I-PASS-supported handoff process for patients transferring from the cardiovascular ICU to the acute care unit resulted in improved transfer efficiency, safety culture scores, and satisfaction of providers and families. PMID- 26743819 TI - Scar Management in the Pediatric and Adolescent Populations. AB - For most children and adolescents who have developed symptomatic scars, cosmetic concerns are only a portion of the motivation that drives them and their caregivers to obtain treatment. In addition to the potential for cosmetic disfigurement, scars may be associated with a number of physical comorbidities including hypertrichosis, dyshidrosis, tenderness/pain, pruritus, dysesthesias, and functional impairments such as contractures, all of which may be compounded by psychosocial factors. Although a plethora of options for treating scars exists, specific management guidelines for the pediatric and adolescent populations do not, and evidence must be extrapolated from adult studies. New modalities such as the scar team approach, autologous fat transfer, and ablative fractional laser resurfacing suggest a promising future for children who suffer symptomatically from their scars. In this state-of-the-art review, we summarize cutting-edge scar treatment strategies as they relate to the pediatric and adolescent populations. PMID- 26743820 TI - Development and application of two independent real-time PCR assays to detect clinically relevant Mucorales species. AB - PCR-based detection of Mucorales species could improve diagnosis of suspected invasive fungal infection, leading to a better patient outcome. This study describes two independent probe-based real-time PCR tests for detection of clinically relevant Mucorales, targeting specific fragments of the 18S and the 28S rRNA genes. Both assays have a short turnaround time, allow fast, specific and very sensitive detection of clinically relevant Mucorales and have the potential to be used as quantitative tests. They were validated on various clinical samples (fresh and formalin-fixed paraffin-embedded specimens, mainly biopsies, n = 17). The assays should be used as add-on tools to complement standard techniques; a combined approach of both real-time PCR assays has 100 % sensitivity. Genus identification by subsequent sequencing is possible for amplicons of the 18S PCR assay. In conclusion, combination of the two independent Mucorales assays described in this study, 18S and 28S, detected all clinical samples associated with proven Mucorales infection (n = 10). Reliable and specific identification of Mucorales is a prerequisite for successful antifungal therapy as these fungi show intrinsic resistance to voriconazole and caspofungin. PMID- 26743821 TI - Altered functional connectivity in persistent developmental stuttering. AB - Persistent developmental stuttering (PDS) is a speech disorder that impairs communication skills. Despite extensive research, the core causes of PDS are elusive. Converging evidence from task-induced neuroimaging methods has demonstrated the contributions of the basal ganglia and the cerebellum to PDS, but such task-state neuroimaging findings are often confounded by behavioral performance differences between subjects who stutter and normal controls. Here, using resting-state functional magnetic resonance imaging, we investigated functional connectivity within cerebellar-cortical and basal ganglia thalamocortical networks in 16 adults who stutter and 18 age-matched fluent speakers. Seed-to-voxel analysis demonstrated that, compared to controls, adults who stutter showed alternations in functional connectivity of cerebellum to motor cortex as well as connectivity among different locals within cerebellum. Additionally, we found that functional connectivity within cerebellar circuits was significantly correlated with severity of stuttering. The alternations of functional connectivity within basal ganglia-thalamocortical networks were identified as the reduced connectivity of the putamen to the superior temporal gyrus and inferior parietal lobules in adults who stutter. The abnormalities of resting state functional connectivity are assumed to affect language planning and motor execution critical for speaking fluently. Our findings may yield neurobiological cues to the biomarkers of PDS. PMID- 26743823 TI - On-Chip Construction of Liver Lobule-like Microtissue and Its Application for Adverse Drug Reaction Assay. AB - Engineering the liver in vitro is promising to provide functional replacement for patients with liver failure, or tissue models for drug metabolism and toxicity analysis. In this study, we describe a microfluidics-based biomimetic approach for the fabrication of an in vitro 3D liver lobule-like microtissue composed of a radially patterned hepatic cord-like network and an intrinsic hepatic sinusoid like network. The hepatic enzyme assay showed that the 3D biomimetic microtissue maintained high basal CYP-1A1/2 and UGT activities, responded dynamically to enzyme induction/inhibition, and preserved great hepatic capacity of drug metabolism. Using the established biomimetic microtissue, the potential adverse drug reactions that induced liver injury were successfully analyzed via drug-drug interactions of clinical pharmaceuticals. The results showed that predosed pharmaceuticals which agitated CYP-1A1/2 and/or UGT activities would alter the toxic effect of the subsequently administrated drug. All the results validated the utility of the established biomimetic microtissue in toxicological studies in vitro. Also, we anticipate the microfluidics-based bioengineering strategy would benefit liver tissue engineering and liver physiology/pathophysiology studies, as well as in vitro assessment of drug-induced hepatotoxicity. PMID- 26743824 TI - The frequency and severity of intracranial hypotension post-intraoperative lumbar drainage using a Tuohy needle and the traditional needle. AB - Background Intraoperative lumbar cerebrospinal fluid (CSF) drainage is a well recognised technique in cranial and vascular surgery. The goal of the study was to assess the frequency and severity of intracranial hypotension post intraoperative lumbar drainage performed using two different techniques, a 14G Tuohy needle versus an 18G traditional needle. Methods The medical records and imaging studies of 94 patients who had undergone open cranial operation were retrospectively studied: 47 patients had intraoperative lumbar drainage and 47 patients did not. A 14G Tuohy needle was employed in 27 (57.4%) patients and an 18G traditional needle was employed in 20 (42.6%) patients. Results There were signs of intracranial hypotension on MR images in nine (19.1%) patients who had intraoperative lumbar CSF drainage; none of the patients in the control group exhibited the MR signs of intracranial hypotension. A 14G needle was used in 6/9 patients and resulted in severe complications: one patient developed a delayed intracranial epidural hematoma that required emergency evacuation and a blood patch. Another patient developed somnolence that required two epidural blood patches and a third patient had protracted headaches. The 18G needle was used in the remaining 3/9 patients who were asymptomatic or presented with mild headaches. Conclusion The use of the smaller 18G traditional needle was associated with better outcomes with regards to intracranial hypotension, and the frequency of severe complications was higher with the use of the 14G Tuohy needle. PMID- 26743822 TI - Repetitive magnetic stimulation induces plasticity of inhibitory synapses. AB - Repetitive transcranial magnetic stimulation (rTMS) is used as a therapeutic tool in neurology and psychiatry. While repetitive magnetic stimulation (rMS) has been shown to induce plasticity of excitatory synapses, it is unclear whether rMS can also modify structural and functional properties of inhibitory inputs. Here we employed 10-Hz rMS of entorhinohippocampal slice cultures to study plasticity of inhibitory neurotransmission on CA1 pyramidal neurons. Our experiments reveal a rMS-induced reduction in GABAergic synaptic strength (2-4 h after stimulation), which is Ca(2+)-dependent and accompanied by the remodelling of postsynaptic gephyrin scaffolds. Furthermore, we present evidence that 10-Hz rMS predominantly acts on dendritic, but not somatic inhibition. Consistent with this finding, a reduction in clustered gephyrin is detected in CA1 stratum radiatum of rTMS treated anaesthetized mice. These results disclose that rTMS induces coordinated Ca(2+)-dependent structural and functional changes of specific inhibitory postsynapses on principal neurons. PMID- 26743825 TI - Sox2 goes beyond stem cell biology. PMID- 26743826 TI - C6-Selective Direct Alkylation of Pyridones with Diazo Compounds under Rh(III) Catalyzed Mild Conditions. AB - A Rh(III)-catalyzed highly efficient C6-alkylation of 2-pyridones has been achieved successfully with alpha-diazo carbonyl compounds. The developed method is simple, mild, and highly regioselective with a broad range of substrate scope. The regioselectivity is guided by the pyridyl substituent attached to the nitrogen center of the pyridone ring. The directing group can be easily removed, and the only formed byproduct is nitrogen. Furthermore, other similar heterocyclic scaffolds can also be functionalized regioselectively under the developed conditions. PMID- 26743827 TI - Genome-wide association study identifies three key loci for high mesocarp oil content in perennial crop oil palm. AB - GWAS in out-crossing perennial crops is typically limited by insufficient marker density to account for population diversity and effects of population structure resulting in high false positive rates. The perennial crop oil palm is the most productive oil crop. We performed GWAS for oil-to-dry-mesocarp content (O/DM) on 2,045 genotyped tenera palms using 200K SNPs that were selected based on the short-range linkage disequilibrium distance, which is inherent with long breeding cycles and heterogeneous breeding populations. Eighty loci were significantly associated with O/DM (p <= 10(-4)) and three key signals were found. We then evaluated the progeny of a Deli x AVROS breeding trial and a 4% higher O/DM was observed amongst those having the beneficial genotypes at two of the three key loci (p < 0.05). We have initiated MAS and large-scale planting of elite dura and pisifera parents to generate the new commercial tenera palms with higher O/DM potential. PMID- 26743828 TI - Neurobiology of Elderly Suicide. AB - Suicide in the elderly is an underestimated and complex issue that has mainly been explored in sociological, clinical and psychological perspectives. Suicide in non-elderly adults has been associated with diverse neurobiological alterations that may shed light on future predictive markers and more efficient preventative interventions. The aim of this paper was to review studies specifically investigating the neurobiology of elderly suicidal behaviour. We performed a systematic English and French Medline and EMBASE search until 2013. Contrary to literature about the non-elderly, we found a paucity of studies investigating the biomarkers of suicidal risk in elderly adults. Main findings were found in the neurocognitive domain. Studies generally supported the existence of cognitive deficits, notably decision-making impairment and reduced cognitive inhibition, in patients with a history of suicidal act compared to patients without such history. However, replications are needed to confirm findings. Due to several limitations including the small number of available studies, frequent lack of replication and small sample size, no firm conclusions can be drawn. The authors encourage further investigations in this field as insight in the neurobiology of these complex behaviors may limit cliches about end of life and aging, as well as improve future prevention of suicide in the elderly. PMID- 26743829 TI - Impact of fractionation and number of fields on dose homogeneity for intra fractionally moving lung tumors using scanned carbon ion treatment. AB - BACKGROUND AND PURPOSE: Scanned particle beam therapy may result in over and under dosages within the target volume. This study quantifies how CTV dose coverage improves with number of fractions and fields. MATERIALS AND METHODS: Based on 4DCTs of nine lung tumor patients, treatment plans were optimized separately for four different fields using an ITV approach. 4D RBE-weighted dose distributions were calculated for varying motion parameters and fraction numbers. The total RBE-weighted dose was determined for one and four-field application per fraction. DVHs were analyzed for the tumor and interpreted based on statistical modeling. RESULTS: Dose homogeneity within the CTV increased with the fraction number, but depends significantly on the tumor motion amplitude. For single-field schedules and amplitudes >6mm, the dose coverage indices (V95min=90.7% and V107max=0.4%) differed to the stationary case even after 40 fractions. Target coverage for a four-field approach followed a proposed model and homogeneous dose distributions could be achieved 6-times faster than single-field treatments. CONCLUSIONS: Fractionated delivery improves dose homogeneity in scanned ion beam therapy of moving targets. The achievable homogeneity depends mainly on tumor volume and motion amplitude. The outcome of multiple-field irradiations can be predicted based on single-field results and accelerates the achievement of homogeneous dose distributions. PMID- 26743830 TI - Mastication structures definition in head and neck cancer. PMID- 26743831 TI - Vessel based delineation guidelines for the elective lymph node regions in breast cancer radiation therapy - PROCAB guidelines. PMID- 26743833 TI - Individualised 3D printed vaginal template for MRI guided brachytherapy in locally advanced cervical cancer. AB - Intracavitary-interstitial applicators for MRI guided brachytherapy are becoming increasingly important in locally advanced cervical cancer. The 3D printing technology enables a versatile method for obtaining a high degree of individualisation of the implant. Our clinical workflow is presented and exemplified by a stage IVA cervical cancer with superior dose distribution. PMID- 26743832 TI - Relationship between fatigue, sleep quality and inflammatory cytokines during external beam radiation therapy for prostate cancer: A prospective study. AB - BACKGROUND AND PURPOSE: Mechanisms of fatigue reported during radiotherapy are poorly defined but may include inflammatory cytokines and/or sleep disturbances. This prospective, longitudinal, phase II study assessed fatigue, sleep, and serum cytokine levels during radiotherapy for early-stage prostate cancer (PCa). MATERIAL AND METHODS: Twenty-eight men undergoing radiotherapy for early-stage PCa wore an Actiwatch Score to record fatigue level, sleep time, onset latency, efficiency and wake after sleep onset. Serum levels of IL-1alpha, IL-1beta, TNF alpha, IL-6, IL-8, IL-10 and VEGF were measured weekly during radiotherapy. Patient reported quality of life (QOL) metrics were collected before and after treatment. Linear mixed effects models examined trajectories across treatment weeks. RESULTS: Fatigue increased across treatment weeks (P<.01), and fatigue was associated with decreased patient-reported QOL. Sleep efficiency increased across treatment weeks (rate of change over time=.29, P=.03), and sleep onset latency decreased (rate of change over time=.86, P=.06). IL-6 tended to increase during treatment (P=0.09), but none of the cytokine levels or sleep variables were significantly related to fatigue trajectories. CONCLUSIONS: Despite increased sleep efficiency across treatment weeks, fatigue significantly increased. Although IL-6 increased during the course of radiotherapy, cytokines levels were not associated with fatigue scores or sleep disturbance. Further studies are needed to define the mechanisms for fatigue during radiotherapy. PMID- 26743834 TI - Medically inoperable endometrial cancer in patients with a high body mass index (BMI): Patterns of failure after 3-D image-based high dose rate (HDR) brachytherapy. AB - BACKGROUND AND PURPOSE: High BMI is a reason for medical inoperability in patients with endometrial cancer in the United States. Definitive radiation is an alternative therapy for these patients; however, data on patterns of failure after definitive radiotherapy are lacking. We describe the patterns of failure after definitive treatment with 3-D image-based high dose rate (HDR) brachytherapy for medically inoperable endometrial cancer. MATERIALS AND METHODS: Forty-three consecutive patients with endometrial cancer FIGO stages I-III were treated definitively with HDR brachytherapy with or without external beam radiation therapy. Cumulative incidence of failures was estimated and prognostic variables were identified RESULTS: Mean follow up was 29.7 months. Median BMI was 50.2 kg/m(2) (range: 25.1-104 kg/m(2)). The two-year overall survival was 65.2%. The two-year cumulative incidence of pelvic and distant failures was 8.3% and 13.5%, respectively. Grade 3 disease was associated with a higher risk of all failures (Hazard Ratio [HR]: 4.67, 95% CI: 1.04-20.9, p=0.044). The incidence of acute Grade 3 GI/GU toxicities was 4.6%. CONCLUSIONS: Pelvic failure at two years was less than 10%. Patients with grade 3 disease were more likely to experience disease failure and may warrant closer follow up. PMID- 26743835 TI - Validation of automatic segmentation of ribs for NTCP modeling. AB - BACKGROUND AND PURPOSE: Determination of a dose-effect relation for rib fractures in a large patient group has been limited by the time consuming manual delineation of ribs. Automatic segmentation could facilitate such an analysis. We determine the accuracy of automatic rib segmentation in the context of normal tissue complication probability modeling (NTCP). MATERIALS AND METHODS: Forty-one patients with stage I/II non-small cell lung cancer treated with SBRT to 54 Gy in 3 fractions were selected. Using the 4DCT derived mid-ventilation planning CT, all ribs were manually contoured and automatically segmented. Accuracy of segmentation was assessed using volumetric, shape and dosimetric measures. Manual and automatic dosimetric parameters Dx and EUD were tested for equivalence using the Two One-Sided T-test (TOST), and assessed for agreement using Bland-Altman analysis. NTCP models based on manual and automatic segmentation were compared. RESULTS: Automatic segmentation was comparable with the manual delineation in radial direction, but larger near the costal cartilage and vertebrae. Manual and automatic Dx and EUD were significantly equivalent. The Bland-Altman analysis showed good agreement. The two NTCP models were very similar. CONCLUSIONS: Automatic rib segmentation was significantly equivalent to manual delineation and can be used for NTCP modeling in a large patient group. PMID- 26743836 TI - Bioactive TGF-beta1/HA alginate-based scaffolds for osteochondral tissue repair: design, realization and multilevel characterization. AB - BACKGROUND: The design of an appropriate microenvironment for stem cell differentiation constitutes a multitask mission and a critical step toward the clinical application of tissue substitutes. With the aim of producing a bioactive material for orthopedic applications, a transforming growth factor-beta (TGF- beta1)/hydroxyapatite (HA) association within an alginate-based scaffold was investigated. The bioactive scaffold was carefully designed to offer specific biochemical cues for an efficient and selective cell differentiation toward the bony and chondral lineages. METHODS: Highly porous alginate scaffolds were fabricated from a mixture of calcium cross-linked alginates by means of a freeze drying technique. In the chondral layer, the TGF in citric acid was mixed with an alginate/alginate-sulfate solution. In the bony layer, HA granules were added as bioactive signal, to offer an osteoinductive surface to the cells. Optical and scanning electron microscopy analyses were performed to assess the macro-micro architecture of the biphasic scaffold. Different mechanical tests were conducted to evaluate the elastic modulus of the grafts. For the biological validation of the developed prototype, mesenchymal stem cells were loaded onto the samples; cellular adhesion, proliferation and in vivo biocompatibility were evaluated. RESULTS AND CONCLUSIONS: The results successfully demonstrated the efficacy of the designed osteochondral graft, which combined interesting functional properties and biomechanical performances, thus becoming a promising candidate for osteochondral tissue-engineering applications. PMID- 26743837 TI - Temporal bone chondroblastoma totally invisible on MRI. AB - We report a case of temporal bone chondroblastoma that was totally invisible on MRI. The patient was a 64-year-old man who presented with several months history of vertigo. The CT scan with bone window setting showed destruction of the temporomandibular joint, the floor of the middle cranial fossa, and the superior semicircular canal. Calcific foci were seen within the tumor. On MR imaging, the tumor, situating mainly medial to the temporomandibular joint, showed no signal on both T1- and T2-weighted images. The tumor was not enhanced with gadolinium. In summary, the tumor was totally signal negative or "invisible" on pre- and postcontrast T1- and T2-weighted images. The tumor was resected through transpetrosal - transzygomatic approach. PMID- 26743838 TI - Correlation between olfactory acuity and sinonasal radiological findings in adult patients with chronic rhinosinusitis. AB - OBJECTIVE: This study aimed to clarify the correlation between olfactory disorder severity and radiological findings in patients with chronic rhinosinusitis (CRS) in the preoperative stage. METHODS: From 2007 to 2014, 272 adult patients (163 men, 109 women; age range 22-80 years) with olfactory disorder due to bilateral CRS who were scheduled to undergo primary endoscopic sinus surgery (ESS) were enrolled. Two groups were studied: eosinophilic CRS (ECRS, n=193); and non-ECRS (n=79). T&T olfactometer recognition and intravenous olfaction tests were used. Computed tomography (CT) scores for sinuses and olfactory clefts (OC) were applied. Correlations between olfactory acuity and CT score were statistically analysed. RESULTS: In both groups, recognition threshold correlated significantly with CT score. Recognition threshold and CT score were significantly more severe in ECRS than in non-ECRS. CT score at OC showed the strongest correlation with recognition threshold. CT scores for total sinuses and OC in patients showing a positive response to the intravenous olfaction test (239 patients) were significantly milder than those in the negative group (29 patients), but ethmoid CT score was not. CONCLUSION: Olfactory disorder severity correlated significantly with CT opacification. Olfactory disorder and CT findings were more severe in patients with ECRS than in those with non-ECRS. PMID- 26743839 TI - Non-invasive detection and monitoring of experimental hydrocephalus with distortion product otoacoustic emissions. AB - OBJECTIVE: We aimed to find out the effects of short term and long term hydrocephalus and intracranial ventricular volume changes on cochlear functions by using distortion product otoacoustic emission (DPOAE) in experimental hydrocephalus rat models for the first time in literature. METHODS: This study was performed with 48 healthy, adult (8 weeks old), Sprague-Dawley rats which weighed between 200 and 240g. Six groups were formed in this study: short term control, short term sham, short term hydrocephalus, long term control, long term sham and long term hydrocephalus groups. Each group contained eight rats. Short term period was 4 weeks and long term period was 8 weeks after the study started. At the end of these periods, DPOAE measurements were performed and then rats were sacrificed to determine ventricular volumes. RESULTS: DPOAE values at all frequencies were significantly decreased in the short term hydrocephalus group when compared to the short term control and short term sham groups. DPOAE values at all frequencies were significantly decreased in the long term hydrocephalus group when compared to the long term control and long term sham groups. Besides, long term sham group which had higher ventricular volumes than long term control group also had lower DPOAE measurements. Significant associations were present between DPOAE measurements and ventricular volumes in hydrocephalus models. CONCLUSION: The functional disturbances in cochlear functions due to hydrocephalus have been demonstrated with DPOAE measurements in this study. DPOAE measurements may be thought as an easily applicable non-invasive method in detection and follow-up of patients with hydrocephalus. Our findings should be supported with clinical studies in humans. PMID- 26743840 TI - Genome-wide association study identifies variation at 6q25.1 associated with survival in multiple myeloma. AB - Survival following a diagnosis of multiple myeloma (MM) varies between patients and some of these differences may be a consequence of inherited genetic variation. In this study, to identify genetic markers associated with MM overall survival (MM-OS), we conduct a meta-analysis of four patient series of European ancestry, totalling 3,256 patients with 1,200 MM-associated deaths. Each series is genotyped for ~600,000 single nucleotide polymorphisms across the genome; genotypes for six million common variants are imputed using 1000 Genomes Project and UK10K as the reference. The association between genotype and OS is assessed by Cox proportional hazards model adjusting for age, sex, International staging system and treatment. We identify a locus at 6q25.1 marked by rs12374648 associated with MM-OS (hazard ratio=1.34, 95% confidence interval=1.22-1.48, P=4.69 * 10(-9)). Our findings have potential clinical implications since they demonstrate that inherited genotypes can provide prognostic information in addition to conventional tumor acquired prognostic factors. PMID- 26743843 TI - Influenza Vaccine Effectiveness: Mysteries, Enigmas, and a Few Clues. PMID- 26743844 TI - New Insights Into Shiga Toxigenic Escherichia coli Pathogenesis: When Less Is More. PMID- 26743841 TI - Shiga Toxin (Stx) Type 1a Reduces the Oral Toxicity of Stx Type 2a. AB - BACKGROUND: Shiga toxin (Stx) is the primary virulence factor of Stx-producing Escherichia coli (STEC). STEC can produce Stx1a and/or Stx2a, which are antigenically distinct. However, Stx2a-producing STEC are associated with more severe disease than strains producing both Stx1a and Stx2a. METHODS AND RESULTS: To address the hypothesis that the reason for the association of Stx2a with more severe disease is because Stx2a crosses the intestinal barrier with greater efficiency that Stx1a, we covalently labeled Stx1a and Stx2a with Alexa Fluor 750 and determined the ex vivo fluorescent intensity of murine systemic organs after oral intoxication. Surprisingly, both Stxs exhibited similar dissemination patterns and accumulated in the kidneys. We next cointoxicated mice to determine whether Stx1a could impede Stx2a. Cointoxication resulted in increased survival and an extended mean time to death, compared with intoxication with Stx2a only. The survival benefit was dose dependent, with the greatest effect observed when 5 times more Stx1a than Stx2a was delivered, and was amplified when Stx1a was delivered 3 hours prior to Stx2a. Cointoxication with an Stx1a active site toxoid also reduced Stx2a toxicity. CONCLUSIONS: These studies suggest that Stx1a reduces Stx2a-mediated toxicity, a finding that may explain why STEC that produce only Stx2a are associated with more severe disease than strains producing Stx1a and Stx2a. PMID- 26743842 TI - Influenza Vaccine Effectiveness Against 2009 Pandemic Influenza A(H1N1) Virus Differed by Vaccine Type During 2013-2014 in the United States. AB - BACKGROUND: The predominant strain during the 2013-2014 influenza season was 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09). This vaccine-component has remained unchanged from 2009. METHODS: The US Flu Vaccine Effectiveness Network enrolled subjects aged >=6 months with medically attended acute respiratory illness (MAARI), including cough, with illness onset <=7 days before enrollment. Influenza was confirmed by reverse-transcription polymerase chain reaction (RT PCR). We determined the effectiveness of trivalent or quadrivalent inactivated influenza vaccine (IIV) among subjects ages >=6 months and the effectiveness of quadrivalent live attenuated influenza vaccine (LAIV4) among children aged 2-17 years, using a test-negative design. The effect of prior receipt of any A(H1N1)pdm09-containing vaccine since 2009 on the effectiveness of current-season vaccine was assessed. RESULTS: We enrolled 5999 subjects; 5637 (94%) were analyzed; 18% had RT-PCR-confirmed A(H1N1)pdm09-related MAARI. Overall, the effectiveness of vaccine against A(H1N1)pdm09-related MAARI was 54% (95% confidence interval [CI], 46%-61%). Among fully vaccinated children aged 2-17 years, the effectiveness of LAIV4 was 17% (95% CI, -39% to 51%) and the effectiveness of IIV was 60% (95% CI, 36%-74%). Subjects aged >=9 years showed significant residual protection of any prior A(H1N1)pdm09-containing vaccine dose(s) received since 2009, as did children <9 years old considered fully vaccinated by prior season. CONCLUSIONS: During 2013-2014, IIV was significantly effective against A(H1N1)pdm09. Lack of LAIV4 effectiveness in children highlights the importance of continued annual monitoring of effectiveness of influenza vaccines in the United States. PMID- 26743845 TI - Shear-Resistant Binding to von Willebrand Factor Allows Staphylococcus lugdunensis to Adhere to the Cardiac Valves and Initiate Endocarditis. AB - BACKGROUND: Staphylococcus lugdunensis is an emerging cause of endocarditis. To cause endovascular infections, S. lugdunensis requires mechanisms to overcome shear stress. We investigated whether platelets and von Willebrand factor (VWF) mediate bacterial adhesion to the vessel wall and the cardiac valves under flow. METHODS: S. lugdunensis binding to VWF, collagen, and endothelial cells was studied in a parallel flow chamber in the absence and presence of platelets. In vivo adhesion of S. lugdunensis was evaluated in a mouse microvasculature perfusion model and a new mouse model of endocarditis. RESULTS: Contrary to other coagulase-negative staphylococci, S. lugdunensis bound to VWF under flow, thus enabling its adhesion to endothelial cells and to the subendothelial matrix. In inflamed vessels of the mesenteric circulation, VWF recruited S. lugdunensis to the vessel wall. In a novel endocarditis mouse model, local inflammation and the resulting release of VWF enabled S. lugdunensis to bind and colonize the heart valves. CONCLUSIONS: S. lugdunensis binds directly to VWF, which proved to be vital for withstanding shear forces and for its adhesion to the vessel wall and cardiac valves. This mechanism explains why S. lugdunensis causes more-aggressive infections, including endocarditis, compared with other coagulase-negative staphylococci. PMID- 26743847 TI - Where Do We Stand with Super-Resolution Optical Microscopy? AB - Super-resolution fluorescence microscopy has become an invaluable, powerful approach to study biomolecular dynamics and interactions via selective labeling and observation of specific molecules in living cells, tissues and even entire organisms. In this perspective, we present a brief overview of the main techniques and their application to cellular biophysics. We place special emphasis on super-resolution imaging via single-molecule localization microscopy and stimulated emission depletion/reversible saturable optical fluorescence transitions microscopy, and we also briefly address fluorescence fluctuation approaches, notably raster image correlation spectroscopy, as tools to record fast diffusion and transport. PMID- 26743846 TI - Combination Emtricitabine and Tenofovir Disoproxil Fumarate Prevents Vaginal Simian/Human Immunodeficiency Virus Infection in Macaques Harboring Chlamydia trachomatis and Trichomonas vaginalis. AB - Genital inflammation associated with sexually transmitted infections increases susceptibility to human immunodeficiency virus (HIV), but it is unclear whether the increased risk can reduce the efficacy of pre-exposure prophylaxis (PrEP). We investigated whether coinfection of macaques with Chlamydia trachomatis and Trichomonas vaginalis decreases the prophylactic efficacy of oral emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). Macaques were exposed to simian/human immunodeficiency virus (SHIV) vaginally each week for up to 16 weeks and received placebo or FTC/TDF pericoitally. All animals in the placebo group were infected with SHIV, while 4 of 6 PrEP recipients remained uninfected (P= .03). Oral FTC/TDF maintains efficacy in a macaque model of sexually transmitted coinfection, although the infection of 2 macaques signals a modest loss of PrEP activity. PMID- 26743849 TI - Mechanistic implications from structures of yeast alcohol dehydrogenase complexed with coenzyme and an alcohol. AB - Yeast alcohol dehydrogenase I is a homotetramer of subunits with 347 amino acid residues, catalyzing the oxidation of alcohols using NAD(+) as coenzyme. A new X ray structure was determined at 3.0 A where both subunits of an asymmetric dimer bind coenzyme and trifluoroethanol. The tetramer is a pair of back-to-back dimers. Subunit A has a closed conformation and can represent a Michaelis complex with an appropriate geometry for hydride transfer between coenzyme and alcohol, with the oxygen of 2,2,2-trifluoroethanol ligated at 2.1 A to the catalytic zinc in the classical tetrahedral coordination with Cys-43, Cys-153, and His-66. Subunit B has an open conformation, and the coenzyme interacts with amino acid residues from the coenzyme binding domain, but not with residues from the catalytic domain. Coenzyme appears to bind to and dissociate from the open conformation. The catalytic zinc in subunit B has an alternative, inverted coordination with Cys-43, Cys-153, His-66 and the carboxylate of Glu-67, while the oxygen of trifluoroethanol is 3.5 A from the zinc. Subunit B may represent an intermediate in the mechanism after coenzyme and alcohol bind and before the conformation changes to the closed form and the alcohol oxygen binds to the zinc and displaces Glu-67. PMID- 26743848 TI - Risk of Monozygotic Twins After Assisted Reproduction: A Population-Based Approach. AB - BACKGROUND: Recent studies have suggested that ovarian stimulation and assisted reproductive techniques (ART) may increase the frequency of monozygotic twins. In this article, we present the analysis of the estimated frequency of twin deliveries following in vitro fertilization (IVF) in Lombardy during the period 2010-2014 for a total of 450,949 pregnancies. METHOD: This is a population-based study using data from the regional data base of Lombardy, a northern Italian region with a population of about 10 million inhabitants. During the considered period, a total of 461,424 single or multiple births were registered in Lombardy. After exclusion of triplets or more pregnancies, the total number of twin deliveries, in separate strata of like and unlike sex pregnancies twin deliveries, were obtained and the rate of twin deliveries was computed according to spontaneous and non-spontaneous conception and type of ART. Further, estimates of dizygotic or monozygotic twin births were calculated using Weinberg's methods. RESULTS: The frequency of twins deliveries was 1.24/100 deliveries after natural conception and 20.05 after assisted conception. The estimated rates of monozygotic twins was 0.45 and 0.72/100 (95% CI: 0.58-0.91) deliveries after natural and assisted conception, respectively. This difference was statistically significant (p < .05). CONCLUSION: the present population based study suggests that the risk of monozygotic twin is about 60% higher among assisted than after natural conception. PMID- 26743851 TI - [Factors associated with low levels of aerobic fitness among adolescents]. AB - OBJECTIVE: To evaluate the prevalence of low aerobic fitness levels and to analyze the association with sociodemographic factors, lifestyle and excess body fatness among adolescents of southern Brazil. METHODS: The study included 879 adolescents aged 14 to 19 years the city of Sao Jose/SC, Brazil. The aerobic fitness was assessed by Canadian modified test of aerobic fitness. Sociodemographic variables (skin color, age, sex, study turn, economic level), sexual maturation and lifestyle (eating habits, screen time, physical activity, consumption of alcohol and tobacco) were assessed by a self-administered questionnaire. Excess body fatness was evaluated by sum of skinfolds triceps and subscapular. We used logistic regression to estimate odds ratios and 95% confidence intervals. RESULTS: Prevalence of low aerobic fitness level was 87.5%. The girls who spent two hours or more in front screen, consumed less than one glass of milk by day, did not smoke and had an excess of body fatness had a higher chance of having lower levels of aerobic fitness. White boys with low physical activity had had a higher chance of having lower levels of aerobic fitness. CONCLUSIONS: Eight out of ten adolescents were with low fitness levels aerobic. Modifiable lifestyle factors were associated with low levels of aerobic fitness. Interventions that emphasize behavior change are needed. PMID- 26743850 TI - Lipid regulators of Pkh2 in Candida albicans, the protein kinase ortholog of mammalian PDK1. AB - Pkh is the yeast ortholog of the mammalian 3-phosphoinositide-dependent protein kinase 1 (PDK1). Pkh phosphorylates the activation loop of Ypks, Tpks, Sch9 and also phosphorylates the eisosome components Lsp1 and Pil1, which play fundamental roles upstream of diverse signaling pathways, including the cell wall integrity and sphingosine/long-chain base (LCB) signaling pathways. In S. cerevisiae, two isoforms, ScPkh1 and ScPkh2, are required for cell viability, while only one ortholog exists in C. albicans, CaPkh2. In spite of the extensive information gathered on the role of Pkh in the LCB signaling, the yeast Pkh kinases are not known to bind lipids and previous studies did not identify PH domains in Pkh sequences. We now describe that the C-terminal region of CaPkh2 is required for its intrinsic kinase activity. In addition, we found that the C-terminal region of CaPkh2 enables its interaction with structural and signaling lipids. Our results further show that phosphatidylserine, phosphatidic acid, phosphatidylinositol (3,4 and 4,5)-biphosphates, and phosphatidylinositol (3,4,5) trisphosphate inhibit Pkh activity, whereas sulfatide binds with high affinity but does not affect the intrinsic activity of CaPkh2. Interestingly, we identified that its human ortholog PDK1 also binds to sulfatide. We propose a mechanism by which lipids and dihydrosphingosine regulate CaPkh2 kinase activity by modulating the interaction of the C-terminal region with the kinase domain, while sulfatide-like lipids support localization CaPkh2 mediated by a C-terminal PH domain, without affecting kinase intrinsic activity. PMID- 26743852 TI - Absorption, distribution, metabolism, excretion, and kinetics of 2,3,3,3 tetrafluoro-2-(heptafluoropropoxy)propanoic acid ammonium salt following a single dose in rat, mouse, and cynomolgus monkey. AB - Ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate has been developed as a processing aid used in the manufacture of fluoropolymers. The absorption, distribution, elimination, and distribution (ADME) and kinetic behavior of this substance has been evaluated in rats, mice, and cynomolgus monkeys by oral and intravenous routes of exposure and studied in both plasma and urine. The test substance is rapidly and completely absorbed in both rats and mice and both in vivo and in vitro experiments indicate that it is not metabolized. The test substance is rapidly eliminated exclusively in the urine in both rats and mice, with rats eliminating it more quickly than mice (approximately 5h elimination half-life in rats, 20 h half-life in mice). Pharmacokinetic analysis in monkeys, rats, and mice indicate rapid, biphasic elimination characterized by a very fast alpha phase and a slower beta phase. The beta phase does not contribute to potential accumulation after multiple dosing in rats or monkeys. Comparative pharmacokinetics in rats, mice, and monkeys indicates that the rat is more similar to the monkey and is therefore a more appropriate rodent model for pharmacokinetics in primates. PMID- 26743853 TI - Antibacterial and antifungal screening of natural products sourced from Australian fungi and characterisation of pestalactams D-F. AB - Eighteen natural products sourced from Australian micro- or macro-fungi were screened for antibacterial and antifungal activity. This focused library was comprised of caprolactams, polyamines, quinones, and polyketides, with additional large-scale isolation studies undertaken in order to resupply previously identified compounds. Chemical investigations of the re-fermented culture from the endophytic fungus Pestalotiopsis sp. yielded three caprolactam analogues, pestalactams D-F, along with larger quantities of the known metabolite pestalactam A, which was methylated using diazomethane to yield 4-O methylpestalactam A. The chemical structures of the previously undescribed fungal metabolites were determined by analysis of 1D/2D NMR and MS data. The structure of 4-O-methylpestalactam A was confirmed following single crystal X-ray diffraction analysis. The antibacterial and antifungal activity of all compounds was assessed, which identified three compounds, (1S,3R)-austrocortirubin, (1S,3S) austrocortirubin, and 1-deoxyaustrocortirubin with mild activity (100 MUM) against Gram-positive isolates and one compound, 2-hydroxy-6-methyl-8-methoxy-9 oxo-9H-xanthene-1-carboxylic acid, with activity against Cryptococcus neoformans and Cryptococcus gattii at 50 MUM. PMID- 26743854 TI - Activation of corticotropin-releasing factor neurons and microglia in paraventricular nucleus precipitates visceral hypersensitivity induced by colorectal distension in rats. AB - Visceral hypersensitivity is a major contributor to irritable bowel syndrome and other disorders with visceral pain. Substantial evidence has established that glial activation and neuro-glial interaction play a key role in the establishment and maintenance of visceral hypersensitivity. We recently demonstrated that activation of spinal microglial toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor kappaB (NF-kappaB) signaling facilitated the development of visceral hypersensitivity in a rat model developed by neonatal and adult colorectal distensions (CRDs). Hypothalamic paraventricular nucleus (PVN) plays a pivotal role in the pathogenesis of chronic pain. In this study, we examined the mechanism by which microglia and neurons in PVN establish and maintain visceral hypersensitivity and the involvement of TLR4 signaling. Visceral hypersensitivity was precipitated by adult colorectal distension (CRD) only in rats that experienced neonatal CRDs. Visceral hypersensitivity was associated with an increase in the expression of c-fos, corticotropin-releasing factor (CRF) protein and mRNA in PVN, which could be prevented by intra-PVN infusion of lidocaine or small interfering RNA targeting the CRF gene. These results suggest PVN CRF neurons modulate visceral hypersensitivity. Adult CRD induced an increase in the expression of Iba-1 (a microglial marker), TLR4 protein, and its downstream effectors MyD88, NF-kappaB, as well as proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta) only in rats that experienced neonatal CRDs. Intra-PVN infusion of minocycline, a nonselective microglial inhibitor, attenuated the hyperactivity of TLR4 signaling cascade, microglial activation, and visceral hypersensitivity. Taken together, these data suggest that neonatal CRDs induce a glial activation in PVN. Adult CRD potentiates the glial and CRF neuronal activity, and precipitates visceral hypersensitivity and pain. TLR4 signaling and proinflammatory cytokines TNF-alpha and IL-1beta may participate in neuro-glial interaction during the pathogenesis of visceral hypersensitivity. PMID- 26743855 TI - EGFR Mutation Impact on Definitive Concurrent Chemoradiation Therapy for Inoperable Stage III Adenocarcinoma. AB - BACKGROUND: Concurrent chemoradiation therapy (CRT) is the current standard of care for patients with locally advanced lung adenocarcinoma; however, little has been reported about the impact of epidermal growth factor receptor (EGFR) mutation on CRT efficacy. METHODS: From 2006 to 2013, we retrospectively screened 104 unresectable stage III adenocarcinoma patients who were examined for EGFR mutation status and received definitive concurrent CRT consisting of platinum doublet chemotherapy in first-line setting and compared the clinical outcomes and recurrence patterns according to mutation status. RESULTS: Among 104 patients, EGFR mutation was detected in 29 (28%). The overall response rate did not differ between EGFR-mutant and wild-type patients (72.4% versus 72.0%, p = 0.607). The median progression-free survival in concurrent CRT was significantly shorter in EGFR-mutant patients than in wild-type patients (9.8 [95% confidence interval, CI: 7.6-19.0] versus 16.5 [95% CI: 11.8-19.9] months, p = 0.041). The 2-year recurrence-free survival rate was 7.7% and 28.1% in EGFR-mutant and wild-type patients, respectively (p = 0.028). Distant metastases were more frequently identified as the first recurrence site in EGFR-mutant patients than in wild-type patients (76% versus 40%, p = 0.001). The brain was the most often affected site in EGFR-mutant patients (35%). However, locoregional recurrence was less common in EGFR-mutant patients than in the wild-type population (14% versus 35%, p = 0.027). Overall survival was similar between EGFR-mutant and wild-type patients (51.1 [95% CI: 28.2-70.2] versus 42.9 [95% CI: 35.3 to not available] months, p = 0.637). Among the EGFR wild-type population who were examined for Kras mutation, Kras-mutant patients had significantly worse overall survival than Kras wild-type patients (21.6 versus 49.8 months, p = 0.024). CONCLUSION: Concurrent CRT resulted in shorter progression-free survival in EGFR-mutant stage III adenocarcinoma patients than in wild-type patients, mainly because of distant metastasis relapse, regardless of better local control. Because of these distinct biological features, a different strategy, including EGFR-tyrosine kinase inhibitors for EGFR-mutant locally advanced adenocarcinoma patients receiving definitive CRT may be needed. PMID- 26743857 TI - Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology. AB - Sex differences in schizophrenia are apparent in almost all features of the illness, from incidence and mean age of onset to symptomatology, course of illness and response to pharmacological treatments. Understanding how men and women with schizophrenia differ provides significant clues into the pathophysiology of the disorder. Animal models are powerful tools when dissecting the molecular biology which underlies behavioural disturbances, and allow structured comparisons of biological sex differences without the social environmental gender influence that so often confounds human sex comparison studies. This review will provide a summary of sex differences described in developmental, genetic and drug-induced animal models of schizophrenia and will link sex-specific molecular and behavioural phenotypes of these models in an attempt to unravel the role that sex plays in the pathophysiology of schizophrenia. Both sex and stress hormones interact to shape the developing brain and behaviour and animal models of schizophrenia that include both sexes provide significant insight into the complexities of these interactions and can direct toward novel therapeutic strategies. PMID- 26743856 TI - Monotherapy Administration of Sorafenib in Patients With Non-Small Cell Lung Cancer (MISSION) Trial: A Phase III, Multicenter, Placebo-Controlled Trial of Sorafenib in Patients with Relapsed or Refractory Predominantly Nonsquamous Non Small-Cell Lung Cancer after 2 or 3 Previous Treatment Regimens. AB - INTRODUCTION: Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non-small-cell lung cancer (NSCLC). METHODS: The phase III, multinational, double-blind, placebo-controlled Monotherapy admInistration of Sorafenib in patientS wIth nOn-small-cell luNg cancer (MISSION) trial randomized patients with advanced relapsed/refractory NSCLC, following two or three prior treatment regimens, to sorafenib 400 mg twice a day (n = 350) or matching placebo (n = 353) plus best supportive care. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS) and time to progression. Epidermal growth factor receptor and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening. RESULTS: Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 mo; hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.84-1.17; p = 0.47). Median PFS (2.8 versus 1.4 mo; HR, 0.61; 95% CI, 0.51-0.72; p < 0.0001), and time to progression (2.9 versus 1.4 mo; HR, 0.54; 95% CI, 0.45-0.65; p < 0.0001) were significantly greater with sorafenib than with placebo. Among the 89 patients with epidermal growth factor receptor mutations, OS (13.9 versus 6.5 mo; HR, 0.48; 95% CI, 0.30-0.76; p = 0.002) and PFS (2.7 versus 1.4 mo; HR, 0.27; 95% CI, 0.16-0.46; p < 0.001) were significantly higher with sorafenib than placebo. PFS was significantly longer with sorafenib than placebo in patients with either wild type or mutated KRAS, but OS was similar. Common drug-related adverse events were rash/desquamation, diarrhea, and fatigue, consistent with the safety profile of sorafenib. CONCLUSIONS: Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS. PMID- 26743858 TI - Increased risk of psychosis in patients with hearing impairment: Review and meta analyses. AB - Several studies suggest hearing impairment as a risk factor for psychosis. Hearing impairment is highly prevalent and potentially reversible, as it can be easily diagnosed and sometimes improved. Insight in the association between hearing impairment and psychosis can therefore contribute to prevention of psychosis. This paper provides meta-analyses of all epidemiologic evidence on the association between hearing impairment and psychosis and summarizes mechanisms that potentially underlie this relationship. Meta-analyses showed an increased risk of hearing impairment on all psychosis outcomes, such as hallucinations (OR 1.40(95%CI 1.18-1.65; n=227,005)), delusions (OR 1.55(95%CI 1.36-1.78; n=250,470)), psychotic symptoms (OR 2.23(95%CI 1.83-2.72; n=229,647) and delirium (OR 2.67(95%CI 2.05-3.48; n=12,432). Early exposure to hearing impairment elevated the risk of later development of schizophrenia (OR 3.15(95%CI 1.25-7.95; n=50,490)). Potential mechanisms underlying this association include loneliness, diminished theory of mind, disturbances of source monitoring and top-down processing and deafferentiation. Early assessment and treatment of hearing impairment in patients with (high risk of) psychosis may be essential in psychosis treatment and prevention. PMID- 26743859 TI - Sex/gender differences in the brain and cognition in schizophrenia. AB - The early conceptualizations of schizophrenia have noted some sex/gender differences in epidemiology and clinical expression of the disorder. Over the past few decades, the interest in differences between male and female patients has expanded to encompass brain morphology and neurocognitive function. Despite some variability and methodological shortcomings, a few patterns emerge from the available literature. Most studies of gross neuroanatomy show more enlarged ventricles and smaller frontal lobes in men than in women with schizophrenia; finding reflecting normal sexual dimorphism. In comparison, studies of brain asymmetry and specific corticolimbic structures, suggest a disturbance in normal sexual dimorphism. The neurocognitive findings are somewhat consistent with this picture. Studies of cognitive functions mediated by the lateral frontal network tend to show sex differences in patients which are in the same direction as those observed in the general population, whereas studies of processes mediated by the corticolimbic system more frequently reveal reversal of normal sexual dimorphisms. These trends are faint and future research would need to delineate neurocognitive differences between men and women with various subtypes of schizophrenia (e.g., early versus late onset), while taking into consideration hormonal status and gender of tested participants. PMID- 26743860 TI - An artificial self-sufficient cytochrome P450 directly nitrates fluorinated tryptophan analogs with a different regio-selectivity. AB - Aromatic nitration is an immensely important industrial process to produce chemicals for a variety of applications, but it often suffers from multiple unsolved challenges. Enzymes as biocatalysts have been increasingly used for organic chemistry synthesis due to their high selectivity and environmental friendliness, but nitration has benefited minimally from the development of biocatalysis. In this work, we aimed to develop TxtE as practical biocatalysts for aromatic nitration. TxtE is a unique class I cytochrome P450 enzyme that nitrates the indole of l-tryptophan. To develop cost-efficient nitration processes, we fused TxtE with the reductase domains of CYP102A1 (P450BM3) and of P450RhF to create class III self-sufficient biocatalysts. The best engineered fusion protein was comparable with wild type TxtE in terms of nitration performance and other key biochemical properties. To demonstrate the application potential of the fusion enzyme, we nitrated 4-F-dl-tryptophan and 5-F-l tryptophan in large scale enzymatic reactions. Tandem MS/MS and NMR analyses of isolated products revealed altered nitration sites. To our knowledge, these studies represent the first practice in developing biological nitration approaches and lay a solid basis to the use of TxtE-based biocatalysts for the production of valuable nitroaromatics. PMID- 26743861 TI - Critical Thresholds of Antioxidant and Immune Function Parameters for Se deficiency Prediction in Dairy Cows. AB - The aim of this study was to determine the plasma selenium (Se) levels of lactating cows and to evaluate its association with antioxidant ability and immune function. In a descriptive study, 20 healthy Holstein cows with normal Se level (C) and 30 Holstein cows with subclinical Se deficiency (T) were randomly selected between 14 and 21 days postpartum from a dairy farm, according to a cutoff point of 70 mg/L Se in plasma. Analysis of biochemical parameters of antioxidant and immune function were performed on all the cows, and the risk prediction thresholds for subclinical Se deficiency were determined by area under receiver operating characteristic curve. Cows in the T group had significantly lower plasma Se concentrations compared with cows in the C group (52.16 +/- 8.81 vs. 80.37 +/- 8.46 MUg/L, P = 0.02). There was a marked decrease in plasma glutathione peroxidase (GSH-Px) activity in the T group that correlated positively with the plasma Se level (R = 0.65, P = 0.00), and a significant increase of plasma methane dicarboxylic aldehyde (MDA), total nitric oxide synthase, and lipid peroxidation that correlated negatively with plasma Se levels (R = -0.47, P = 0.01; R = -0.33, P = 0.04; R = -0.40, P = 0.03). Furthermore, there were significantly lower plasma tumor necrosis factor-alpha and immunoglobulin G levels in the T group that correlated positively with plasma Se levels (R = 0.41, P = 0.01 and R = 0.45, P = 0.01), and a markedly lower plasma interleukin-6 level that correlated negatively with plasma Se levels (R = -0.38, P = 0.02). In addition, if plasma GSH-Px activity was less than 42.37 U/ml, the risk of Se deficiency was significantly increased in lactating cows. These results suggest that low plasma Se levels may reduce the antioxidant ability and immune function, and the risk of low plasma Se level may be predicted effectively by plasma GSH-Px activity in lactating cows. PMID- 26743862 TI - The Effect of Caffeic Acid Phenethyl Ester (CAPE) Fortification on the Liver Element Distribution that Occurs After Exercise. AB - The purpose of this study is to examine the effect of the caffeic acid phenethyl ester (CAPE) fortification applied to the rats, which were made to exercise, on the liver elements. The study was conducted on 32 Sprague-Dawley male rats. The experimental animals were divided into 4 groups in equal numbers. Group 1 is the group which was applied 10 MUmol/kg/day CAPE as intraperitoneal (IP) for 4 weeks, and they were not made to exercise at the end of the application. Group 2 is the group which was applied 10 MUmol/kg/day CAPE as IP for 4 weeks, and they were made to exercise at the end of the 4th week. Group 3 is the general control group. Group 4 is the swimming control group. A 10 mmol/kg CAPE application dissolved in ethyl alcohol of 10 % was applied to the CAPE group. Sodium (Na), zinc (Zn), calcium (Ca), iron (Fe), chrome (Cr), magnesium (Mg), potassium (K), copper (Cu) and cadmium (Cd) levels were identified in the liver samples at the end of the application. The results of the study suggest that exercise and CAPE fortification in rats cause changes in the Na, Zn, Ca, Fe and Cr parameters in liver tissues, and it does not affect Cd, Cu, Mg and K element distribution. It is thought that CAPE fortification would be helpful for preserving those parameters whose levels are known to be changing with exercise. PMID- 26743863 TI - MeHg Suppressed Neuronal Potency of Hippocampal NSCs Contributing to the Puberal Spatial Memory Deficits. AB - Hippocampal neurogenesis-related structural damage, particularly that leading to defective adult cognitive function, is considered an important risk factor for neurodegenerative and psychiatric diseases. Normal differentiation of neurons and glial cells during development is crucial in neurogenesis, which is particularly sensitive to the environmental toxicant methylmercury (MeHg). However, the exact effects of MeHg on hippocampal neural stem cell (hNSC) differentiation during puberty remain unknown. This study investigates whether MeHg exposure induces changes in hippocampal neurogenesis and whether these changes underlie cognitive defects in puberty. A rat model of methylmercury chloride (MeHgCl) exposure (0.4 mg/kg/day, PND 5-PND 33, 28 days) was established, and the Morris water maze was used to assess cognitive function. Primary hNSCs from hippocampal tissues of E16 day Sprague-Dawley rats were purified, identified, and cloned. hNSC proliferation and differentiation and the growth and morphology of newly generated neurons were observed by MTT and immunofluorescence assays. MeHg exposure induced defects in spatial learning and memory accompanied by a decrease in number of doublecortin (DCX)-positive cells in the dentate gyrus (DG). DCX is a surrogate marker for newly generated neurons. Proliferation and differentiation of hNSCs significantly decreased in the MeHg-treated groups. MeHg attenuated microtubule-associated protein-2 (MAP-2) expression in neurons and enhanced the glial fibrillary acidic protein (GFAP)-positive cell differentiation of hNSCs, thereby inducing degenerative changes in a dose-dependent manner. Moreover, MeHg induced deficits in hippocampus-dependent spatial learning and memory during adolescence as a consequence of decreased generation of DG neurons. Our findings suggested that MeHg exposure could be a potential risk factor for psychiatric and neurodegenerative diseases. PMID- 26743864 TI - Effect of Supplementing Organic Forms of Zinc, Selenium and Chromium on Performance, Anti-Oxidant and Immune Responses in Broiler Chicken Reared in Tropical Summer. AB - Two experiments were conducted to study the effect of supplementing organic forms of zinc (Zn), selenium (Se) and chromium (Cr) on performance, anti-oxidant activities and immune responses in broiler chickens from 1 to 21 days of age, which were reared in cyclic heat-stressed condition under tropical summer in open sided poultry house. A total of 200 (experiment I) and 450-day-old (experiment II) broiler male chicks (Cobb 400) were randomly distributed in stainless steel battery brooders (610 mm * 762 mm * 475 mm) at the rate of five birds per pen. A maize-soybean meal-based control diet (CD) containing recommended (Vencobb 400, Broiler Management Guide) concentrations of inorganic trace minerals and other nutrients was prepared. The CD was supplemented individually with organic form of selenium (Se, 0.30 mg/kg), chromium (Cr, 2 mg/kg) and zinc (Zn, 40 mg/kg) in experiment I. In experiment II, two concentrations of each Zn (20 and 40 mg/kg), Se (0.15 and 0.30 mg/kg) and Cr (1 and 2 mg/kg) were supplemented to the basal diet in 2 * 2 * 2 factorial design. A group without supplementing inorganic trace minerals was maintained as control group in both experiments. Each diet was allotted randomly to ten replicates in both experiments and fed ad libitum from 1 to 21 days of age. At 19th day of age, blood samples were collected for estimation of anti-oxidant and immune responses. Supplementation of Se, Cr and Zn increased (P < 0.05) body mass gain (BMG) and feed intake compared to those fed the CD in experiment I. The feed efficiency (FE) in Cr-fed group was higher (P < 0.05) compared to the CD-fed group. Se or Cr supplementation reduced lipid peroxidation (LP) compared to broilers fed the CD. In experiment II, BMG was not affected (P > 0.05) by the interaction between levels of Zn, Se and Cr in broiler diet. The FE improved (P < 0.05) with supplementation of the trace minerals tested at both concentrations except in group fed 40 mg Zn, 0.5 mg Se and 1 mg Cr/kg. Reduction in lipid peroxidation (LP, P < 0.05) and increased (P < 0.05) activity of superoxide dismutase were observed in broiler fed organic Zn, Se and Cr compared to the CD-fed group. The dietary concentrations of Zn, Se and Cr did not influence (P > 0.05) the immune responses (Newcastle disease titre and cell mediated immune response to phytohaemagglutinin-P) in both the experiments. Based on the results, it is concluded that supplementation of organic form of Se, Cr and Zn (0.30, 2 and 40 mg/kg, respectively) either alone or in combination significantly improved performance and anti-oxidant responses (reduced LP and increased superoxide dismutase) in commercial broiler chicks (21 days of age) reared in cyclic heat stress conditions in open-sided poultry house during summer. PMID- 26743866 TI - Effects of Dietary Selenium Against Lead Toxicity Are Related to the Ion Profile in Chicken Muscle. AB - Complex antagonistic interactions between Selenium (Se) and heavy metals have been reported in previous studies. However, little is known regarding the effects of Se on lead (Pb)-induced toxicity and the ion profile in the muscles of chickens. In this present study, we fed chickens either Se or Pb or both Se and Pb supplement and later analyzed the concentrations of 26 ions in chicken muscle tissues. We determined that a Se- and Pb-containing diets significantly affected microelements in chicken muscle. Treatment with Se increased the content of Se but resulted in a reduced concentration of Cu, As, Cd, Sn, Hg, and Ba. Treatment with Pb increased concentrations of Ni while reducing those of B, V, Cr, Fe, Co, Cu, Zn, and Mo. Moreover, Se also reduced the concentration of Pb, Zn, Co, Fe, V, and Cr, which in contrast were induced by Pb. Additionally, we also found that synergistic and antagonistic interactions existed between Se and Pb supplementation. Our findings suggested that Se can exert a negative effect on Pb in chicken muscle tissues and may be related to changes in ion profiles. PMID- 26743865 TI - Antioxidant and Hepatoprotective Activities of Mycelia Selenium Polysaccharide by Hypsizigus marmoreus SK-02. AB - This work was designed to investigate the characteristic properties (bond types and monosaccharide compositions), and hepatoprotective effects on carbon tetrachloride (CCl4)-induced liver damage of mycelia selenium polysaccharides (MSPS) separated and purified from Hypsizigus marmoreus SK-02. Characteristic analysis of MSPS showed the selenium content (70.15 MUg/g) in mycelia. The antioxidant activities in vitro demonstrated that MSPS had potential effects on scavenging reactive oxygen species and enhancing the reducing power. The treatment of MSPS for CCl4-induced animal experiment demonstrated that the MSPS could reduce the levels of malondiadehyde (MDA), lipid peroxide (LPO), glutamic oxalacetic transaminase (AST), and glutamic-pyruvic transaminase (ALT) activities and improve the levels of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), total cholesterol (TC), and triglyceride (TG) in serum/liver homogenate against CCl4-induced injures. Findings presented in this study clearly demonstrated that MSPS might be suitable for functional foods and natural drugs in preventing the CCl4-induced acute liver damage. PMID- 26743867 TI - Selenium Deficiency Facilitates Inflammation Following S. aureus Infection by Regulating TLR2-Related Pathways in the Mouse Mammary Gland. AB - Selenium (Se) is an essential micronutrient affecting various aspects of health. Se deficiency has been associated with inflammation and immune responses. Mastitis poses a serious problem for humans and animals in the postpartum period. Staphylococcus aureus (S. aureus) is the most common infectious bacterial pathogen associated with mastitis. The present study sought to determine the effects and underlying mechanism of dietary Se on S. aureus-induced inflammation using a model of mouse mastitis. ELISA and Western blotting were performed to detect protein levels. Quantitative PCR (qPCR) was performed to detect messenger RNA (mRNA) levels. The histopathological changes indicated that Se deficiency resulted in increased inflammatory lesions in S. aureus mastitis, whereas Se deficiency did not induce inflammatory lesions in the mammary gland. Myeloperoxidase (MPO) activity was increased in Se-deficient mice with S. aureus mastitis. Analysis of cytokine mRNA and protein showed that Se deficiency leads to increased TNF-alpha, IL-1beta, and IL-6 production in S. aureus mastitis. In addition, Se deficiency enhanced the mRNA and protein expressions of toll-like receptor 2 (TLR2), which were originally upregulated by S. aureus in the mammary gland tissues and human embryonic kidney 293 (HEK293)-mTLR2 cells. When Se deficient mice were infected with S. aureus, the phosphorylation of IkappaB, nuclear factor-kappaB (NF-kappaB), extracellular signal-regulated kinase (ERK), c Jun N-terminal kinase (JNK), and p38 was greatly increased. The results indicate that Se deficiency could intensify the inflammatory reaction in S. aureus mastitis. This work contributes to the exploration of new methods of preventing or treating of S. aureus mastitis and other infectious diseases. PMID- 26743868 TI - Anatomical and biomechanical evaluation of an intramedullary nail for fractures of proximal humerus fractures based on tuberosity fixation. AB - BACKGROUND: For unstable proximal humerus fractures, both plates and nails may be recommended. We introduce an anterograde nail designed for the treatment of 3- and 4-parts proximal humerus fractures. The aim of this study is to compare the biomechanics of this nail versus a plate and then to analyze the relationships of the screws with the axillary nerve. Our working hypotheses are as follows: (1) this nail is biomechanically equal or better to the reference plate and (2) it does not endanger the axillary nerve. METHODS: Biomechanical study: using 40 sawbones, a reproducible 4-part fracture was created and fixed first with an angle-stable plate for proximal humeral fracture, then fixed with the nail using 2 posterior screws. All specimens were mounted in a custom testing apparatus. Two trails were performed needing each time 5 "normal" and 5 "osteoporotic" bones. ANATOMICAL STUDY: On 20 unpaired shoulders, a nail was inserted with all screws through a superior approach (deltoid split approach). Dissection of all shoulders was done to identify the axillary nerve. The distance between each screw and the axillary nerve or its branches was measured. FINDINGS: The proximal humerus nail demonstrated higher values than locking plate for both stiffness and load to failure. The failure mode differs in function of the type of osteosynthesis. The lowest distance between a screw and the axillary nerve was 20.13 mm. INTERPRETATIONS: We introduce a biomechanically efficient nail without increased neurological risks to improve the pullout strength of the screws to provide more secure fixation of proximal humeral fractures. LEVEL OF EVIDENCE: Basic Science Study, Anatomic Cadaver Study. PMID- 26743869 TI - Biomechanical comparison of different external fixator configurations for stabilization of supracondylar humerus fractures in children. AB - BACKGROUND: Currently, closed reduction and percutaneous pinning are considered the treatment of choice for displaced supracondylar humerus fractures. However, indications exist for the use of external fixation with Schanz screws. In this in vitro study, we evaluate the biomechanical properties of a new variation for external fixation and compare them to an established construct. METHODS: Twenty distal cadaver humeri (10 pairs) were allocated to 2 groups. The humeri of the first group were fixed by an external fixator consisting of Schanz screws and an oblique K-wire inserted from the distal radial cortex of the humerus, those of the second group were fixed by a new variation with the oblique K-wire inserted from the distal ulnar cortex of the humerus. Displacement and stiffness in static loading in internal and external rotation, as well as in extension and flexion were evaluated and compared. FINDINGS: The variation of the external fixator of the second group proved to be statistically significantly superior to the variation of the first group in internal rotation loading (p>0.05). In sagittal loading conditions and external rotation loading, the variations were equally stable (p>0.05). There was no significant effect of the samples' bone density on displacement and stiffness values in any direction of loading. INTERPRETATION: In cases of pediatric supracondylar humerus fractures when an external fixator is used for osteosynthesis, the insertion of an additional ulnarly inserted anti rotation K-wire should be preferred to a radially inserted one as it reduces secondary displacement of the distal fragment. PMID- 26743870 TI - [Direct oral anticoagulants: what is the exact assessment of coagulation tests and plasma levels by laboratory tests in clinical practice?]. AB - Direct oral anticoagulants (DAO), anti-IIa or anti-Xa, are intended to be widely used for the treatment and prevention of thrombotic disorders in venous thromboembolic disease and atrial fibrillation as an alternative of vitamin K antagonists (VKA). Despite predictable pharmacological properties, spontaneous or provoked hemorrhagic risks by DAO are major limitations. Thus, after few years of inconsistence concerning biological implication and in particular coagulation tests, it is now established that we need biology to evaluate hemorrhagic risk before surgery or in hemorrhagic cases. PMID- 26743872 TI - Distinct pharmacological and molecular properties of the acid-sensitive outwardly rectifying (ASOR) anion channel from those of the volume-sensitive outwardly rectifying (VSOR) anion channel. AB - Expressed by many cell types, acid-sensitive outwardly rectifying (ASOR) anion channels are known to be activated by extracellular acidification and involved in acidotoxic necrotic cell death. In contrast, ubiquitously expressed volume sensitive outwardly rectifying (VSOR) anion channels are activated by osmotic cell swelling and involved in cell volume regulation and apoptotic cell death. Distinct inhibitors to distinguish ASOR from VSOR anion channels have not been identified. Although leucine-rich repeats containing 8A (LRRC8A) was recently found to be an essential component of VSOR anion channels, the possibility of an LRRC8 family member serving as a component of ASOR anion channels has not been examined. In this study, we explored the effects of 12 known VSOR channel inhibitors and small interfering RNA (siRNA)-mediated knockdown of LRRC8 family members on ASOR and VSOR currents in HeLa cells. Among these inhibitors, eight putative VSOR blockers, including 4-(2-butyl-6,7-dichlor-2-cyclopentylindan-1-on 5-yl) oxobutyric acid (DCPIB) and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), were totally ineffective at blocking ASOR channel activity, whereas suramin, R-(+)-[(2-n-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden 5-yl)oxy] acetic acid (DIOA), arachidonic acid, and niflumic acid were found to be effective ASOR anion channel antagonists. In addition, gene-silencing studies showed that no LRRC8 family members are essentially involved in ASOR anion channel activity, whereas LRRC8A is involved in VSOR anion channel activity in HeLa cells. PMID- 26743873 TI - Rates and predictors of remission, recurrence and conversion to bipolar disorder after the first lifetime episode of depression--a prospective 5-year follow-up study. AB - BACKGROUND: In depression, non-remission, recurrence of depressive episodes after remission and conversion to bipolar disorder are crucial determinants of poor outcome. The present study aimed to determine the cumulative incidences and clinical predictors of these long-term outcomes after the first lifetime episode of depression. METHOD: A total of 301 in- or out-patients aged 18-70 years with a validated diagnosis of a single depressive episode were assessed from 2005 to 2007. At 5 years of follow-up, 262 patients were reassessed by means of the life chart method and diagnostic interviews from 2011 to 2013. Cumulative incidences and the influence of clinical variables on the rates of remission, recurrence and conversion to bipolar disorder, respectively, were estimated by survival analysis techniques. RESULTS: Within 5 years, 83.3% obtained remission, 31.5% experienced recurrence of depression and 8.6% converted to bipolar disorder (6.3% within the first 2 years). Non-remission increased with younger age, co-morbid anxiety and suicidal ideations. Recurrence increased with severity and treatment resistance of the first depression, and conversion to bipolar disorder with treatment resistance, a family history of affective disorder and co-morbid alcohol or drug abuse. CONCLUSIONS: The identified clinical characteristics of the first lifetime episode of depression should guide patients and clinicians for long-term individualized tailored treatment. PMID- 26743874 TI - Repair of Chronic Tibialis Anterior Tendon Rupture With a Major Defect Using Gracilis Allograft. AB - BACKGROUND: Tibialis anterior tendon (TAT) rupture is an uncommon injury, however, it can cause substantial deficit. Diagnosis is often delayed due to lack of initial symptoms; yet loss of function over time typically causes the patient to present for treatment. This delay usually ends up with major defects creating a great technical challenge for the operating surgeon. We present a novel technique and operative algorithm for the management of chronic TAT ruptures with a major gap after a delayed diagnosis not otherwise correctable with currently described techniques in the literature. This technique has been performed in 4 cases without any complications with fairly successful functional outcomes. METHODS: For the reconstruction of chronic TAT rupture with an average delay of nine weeks after initial injury and gap of greater than 10 cm, a thorough operative algorithm was implemented in 4 patients using a double bundle gracilis allograft. Patients were then kept nonweightbearing for 6 weeks followed by weightbearing as tolerated. They began physical therapy with a focus on ankle exercises and gradual return to normal activity at 8 weeks, with resistance training exercises allowed at 12 weeks. RESULTS: At a mean follow-up time of 24.5 months, all patients reported significant pain relief with normal gait pattern. There were no reported intra- or postoperative complications. The average Foot and Ankle Ability Measure score increased to 90 from 27.5 in the postoperative period. All patients were able to return their previous activity levels. CONCLUSIONS: Gracilis allograft reconstruction as used in this study is a viable and reproducible alternative to primary repair with postoperative results being favorable without using complex tendon transfer techniques or autograft use necessitating the functional sacrifice of transferred or excised tendon. To the best of our knowledge, this is the first study demonstrating a successful technique and operative algorithm of gracilis allograft reconstruction of the TAT with a substantial deficit of greater than 10 cm with favorable results. LEVELS OF EVIDENCE: Level IV: Operative algorithm with case series. PMID- 26743871 TI - Kv10.1 K(+) channel: from physiology to cancer. AB - K(+) ions play a major role in many cellular processes. The deregulation of K(+) signaling is associated with a variety of diseases including cancer. Ether-a-go go-1 (Eag1, Kv10.1, KCNH1) is a member of the voltage-activated potassium channel family and was the first K(+) channel to be associated with oncogenesis and tumor development. Interestingly, in healthy tissue, Kv10.1 is only detected in the central nervous system, where it is involved in the regulation of excitability under repeated stimulation. Kv10.1 is in contrast robustly expressed in over 70 % human tumors, where its expression seems to be controlled by key regulators of proliferation and survival such as p53 and E2F1, often altered in cancer. Otherwise, Kv10.1 is involved in cell proliferation, survival, angiogenesis, migration, and invasion. This review aims to provide a comprehensive overview of the current status of research on the role of Kv10.1 channel in physiopathology. Focus is placed on biophysical and pharmacological properties of Kv10.1 channel, as well as its cycling, trafficking, and its role in the neuron and cancer. The possible mechanisms by which Kv10.1 channel affects tumor cell migration and survival in breast cancer and its regulation by extracellular proteins are discussed. PMID- 26743875 TI - Built-in Electric Field Induced Mechanical Property Change at the Lanthanum Nickelate/Nb-doped Strontium Titanate Interfaces. AB - The interactions between electric field and the mechanical properties of materials are important for the applications of microelectromechanical and nanoelectromechanical systems, but relatively unexplored for nanoscale materials. Here, we observe an apparent correlation between the change of the fractured topography of Nb-doped SrTiO3 (Nb:STO) within the presence of a built-in electric field resulting from the Schottky contact at the interface of a metallic LaNiO3 thin film utilizing cross-sectional scanning tunneling microscopy and spectroscopy. The change of the inter-atomic bond length mechanism is argued to be the most plausible origin. This picture is supported by the strong-electric field-dependent permittivity in STO and the existence of the dielectric dead layer at the interfaces of STO with metallic films. These results provided direct evidence and a possible mechanism for the interplay between the electric field and the mechanical properties on the nanoscale for perovskite materials. PMID- 26743876 TI - Research on Intercessory Prayer: Theoretical and Methodological Considerations. AB - Belief in the healing power of prayer is found in various religious traditions. Spiritually grounded clinical interventions, such as intercessory prayer (IP), need to be understood in a broader sense. This essay features the IP trials, observing the controversial relationship between inconsistent results and allegedly inadequate methods and theoretical hypothesis. A survey of the literature was conducted including publications indexed until September 2013, focusing on the trials developed in the field and on the critics about the methodological design. Recent meta-analyses and multicenter studies found inconclusive results in the investigation of IP. Clinical trials on IP present some methodological difficulties: The intervention is not fully controlled; the primary outcome is not properly defined; and the theoretical models seem inconsistent. The "non-local consciousness" model may be appropriate for studies of IP. Directions for future research: greater emphasis on the evaluation of the effectiveness of this intervention in animal models; selection of subjects and healers who have previous connection; considering the hypothesis of non-local consciousness in the study design. PMID- 26743877 TI - Health and Well-Being Among the Non-religious: Atheists, Agnostics, and No Preference Compared with Religious Group Members. AB - Although recent research suggests that the proportion of the US population identifying as non-religious has been rapidly expanding over the course of the last decade, relatively little research has examined the implications of this development for health and well-being. This study uses data from a large representative survey study of religion and health in the adult US population (N = 3010) to examine group differences among religious group members (N = 2401) and three categories of non-religious individuals: atheists (N = 83), agnostics (N = 189), and those stating no religious preference (N = 329). MANCOVA was used to analyze group differences on five outcome dimensions, incorporating 27 outcome variables. Religious non-affiliates did not differ overall from affiliates in terms of physical health outcomes (although atheists and agnostics did have better health on some individual measures including BMI, number of chronic conditions, and physical limitations), but had worse positive psychological functioning characteristics, social support relationships, and health behaviors. On dimensions related to psychological well-being, atheists and agnostics tended to have worse outcomes than either those with religious affiliation or those with no religious preference. If current trends in the religious composition of the population continue, these results have implications for its future healthcare needs. PMID- 26743878 TI - Survey of Lung Transplant Community's Views on Primary Graft Dysfunction. PMID- 26743879 TI - Magnetic and Electrochemical Properties of a TEMPO-Substituted Disulfide Diradical in Solution, in the Crystal, and on a Surface. AB - A study of the magnetic and electrochemical properties of a TEMPO-substituted disulfide diradical in three different environments was carried out: in solution, in the crystal, and as a self-assembled monolayer (SAM) on an Au(111) substrate, and the relationship between them was explored. In solution, this flexible diradical shows a strong spin-exchange interaction between the two nitroxide functions that depends on the temperature and solvent. Structural, dynamic, and thermodynamic information has been extracted from the EPR spectra of this dinitroxide. The magnetic interactions in the crystal include intra- and intermolecular contributions, which have been studied separately and shown to be antiferromagnetic in both cases. Finally, we demonstrate that both the magnetic and electrochemical properties are preserved upon chemisorption of the diradical on a gold surface. The resulting SAM displayed anisotropic magnetic properties, and angle-resolved EPR spectra of the monocrystal allowed a rough determination of the orientation of the molecules in the SAM. PMID- 26743880 TI - Electrically evoked electroretinograms and pupil responses in Argus II retinal implant wearers. AB - PURPOSE: We have recorded the electrically evoked electroretinogram (eERG) and flash ERG in Argus II retinal prosthesis wearers with end-stage retinitis pigmentosa to estimate response properties of the degenerated inner retina to local electrical stimulation. In addition, we have recorded pupil diameters during electrical stimulation. METHODS: Raw corneal eERGs were recorded at multiple stimulus levels in three subjects. eERG signals were heavily contaminated with various artifacts, including switching artifacts generated by the implant electronics, stimulus, blink, and eye-movement artifacts. Pupil responses were recorded in one subject using a pupil tracker. RESULTS: eERGs were decontaminated by a variety of techniques, including wavelet transformation and response averaging. The dominant component was a negative wave peaking at approximately 200 ms. eERG amplitudes correlated significantly with stimulus level, but peak latencies did not correlate with stimulus level. Pupil constriction correlated significantly with stimulus level and pupil responses could be accurately used to estimate subjective threshold. CONCLUSION: eERG recordings hold the potential to be developed further for use as a diagnostic tool for retinal implants. A straightforward approach to increase eERG amplitudes would be the development of intraocular recording methods based on reverse telemetry. The robust pupil response to electrical stimulation in one subject indicates that pupillography can be exploited to assess implant functionality, but reliable pupil recordings could not be obtained in all subjects. PMID- 26743881 TI - Systemic antifungal therapy for proven or suspected invasive candidiasis: the AmarCAND 2 study. AB - BACKGROUND: In the context of recent guidelines on invasive candidiasis (IC), how French intensive care units (ICUs) are managing IC? METHODS: This is a prospective observational multicenter cohort study. During 1 year (2012-2013), 87 French ICUs enrolled consecutive patients with suspected or proven IC (SIC or PIC) and receiving systemic antifungal therapy (SAT). Data were collected up to 28 days after inclusion. RESULTS: We studied 835 patients, 291 with PIC and 544 with SIC. At SAT initiation, patients with SIC were significantly more severe (SAPS II 50.1 +/- 18.7 vs. 46.2 +/- 18.0). Severe sepsis or septic shock prompted to initiate empiric SAT in 70 % of SIC. Within 4 days in median, the initial SAT was modified in 49 % of patients with PIC vs. 33 % patients with SIC. Modifications were most often motivated by mycological results, and de-escalation was the most frequent change. Regarding compliance to IC management guidelines, echinocandin was used for 182 (62.5 %) patients with PIC, and 287 (52.7 %) of those with SIC; central venous catheter was removed in 87 (54.3 %) of patients with candidaemia, and 43 of the remaining patients received echinocandin; and de escalation was undertaken after 5 days of SAT in 142 patients, after 10 days in 13 patients. As 20.6 % of SIC were secondarily documented, 403/835 (48 %) patients had finally a proven IC. Candida albicans was the main pathogen (65.3 %), then Candida glabrata (15.9 %). The 28-day mortality rates were 40.0 % in candidaemia, 25.4 % in cIAI, and 26.7 % in deep-seated candidiasis. In the overall population of patients with proven IC, four independent prognostic factors were identified: immunosuppression (Odds Ratio (OR) = 1.977: 1.03-3.794 95 % confidence interval (CI), p = 0.04), age (OR = 1.035; 1.017-1.053 95 % CI; p < 0.001), SAPS >46 on ICU admission (OR = 2.894; 1.81-4.626 95 % CI; p < 0.001), and surgery just before or during ICU stay (OR = 0.473; 0.29-0.77 95 % CI; p < 0.001). CONCLUSION: When SAT is initiated in French ICUs, the IC is ultimately proven for 48 % of patients. Empiric SAT is initiated in severely ill ICU patients. The initial SAT is often adapted, with de-escalation to fluconazole when possible. Mortality rate remains high. PMID- 26743883 TI - The cocoa bean fermentation process: from ecosystem analysis to starter culture development. AB - Cocoa bean fermentation is still a spontaneous curing process to facilitate drying of nongerminating cocoa beans by pulp removal as well as to stimulate colour and flavour development of fermented dry cocoa beans. As it is carried out on farm, cocoa bean fermentation is subjected to various agricultural and operational practices and hence fermented dry cocoa beans of variable quality are obtained. Spontaneous cocoa bean fermentations carried out with care for approximate four days are characterized by a succession of particular microbial activities of three groups of micro-organisms, namely yeasts, lactic acid bacteria (LAB) and acetic acid bacteria (AAB), which results in well-fermented fully brown cocoa beans. This has been shown through a plethora of studies, often using a multiphasic experimental approach. Selected strains of several of the prevailing microbial species have been tested in appropriate cocoa pulp simulation media to unravel their functional roles and interactions as well as in small plastic vessels containing fresh cocoa pulp-bean mass to evaluate their capacity to dominate the cocoa bean fermentation process. Various starter cultures have been proposed for successful fermentation, encompassing both cocoa derived and cocoa nonspecific strains of (hybrid) yeasts, LAB and AAB, some of which have been implemented on farms successfully. PMID- 26743884 TI - Preface. PMID- 26743882 TI - The association between major depression prevalence and sex becomes weaker with age. AB - BACKGROUND: Women have a higher prevalence of major depressive episodes (MDE) than men, and the annual prevalence of MDE declines with age. Age by sex interactions may occur (a weakening of the sex effect with age), but are easily overlooked since individual studies lack statistical power to detect interactions. The objective of this study was to evaluate age by sex interactions in MDE prevalence. METHODS: In Canada, a series of 10 national surveys conducted between 1996 and 2013 assessed MDE prevalence in respondents over the age of 14. Treating age as a continuous variable, binomial and linear regression was used to model age by sex interactions in each survey. To increase power, the survey specific interaction coefficients were then pooled using meta-analytic methods. RESULTS: The estimated interaction terms were homogeneous. In the binomial regression model I (2) was 31.2 % and was not statistically significant (Q statistic = 13.1, df = 9, p = 0.159). The pooled estimate (-0.004) was significant (z = 3.13, p = 0.002), indicating that the effect of sex became weaker with increasing age. This resulted in near disappearance of the sex difference in the 75+ age group. This finding was also supported by an examination of age- and sex-specific estimates pooled across the surveys. CONCLUSIONS: The association of MDE prevalence with sex becomes weaker with age. The interaction may reflect biological effect modification. Investigators should test for, and consider inclusion of age by sex interactions in epidemiological analyses of MDE prevalence. PMID- 26743885 TI - Racial Disparities in Readmissions for Patients with Inflammatory Bowel Disease (IBD) After Colorectal Surgery. AB - BACKGROUND: The incidence of inflammatory bowel disease (IBD) in minorities is increasing, and health outcome disparities are becoming more apparent. Our aim was to investigate the contribution of race to readmissions in IBD patients undergoing colorectal surgery. DESIGN: The National Surgical Quality Improvement Program database from 2012 to 2013 was queried for all patients with IBD undergoing elective colorectal surgery. After stratifying by race, unadjusted univariate and bivariate comparisons were made. Primary outcome was all-cause 30 day readmission. Predictors of readmission were identified using multivariable logistic regression. RESULTS: Of the 2523 patients with IBD who underwent elective colon surgery, 15.0 % were readmitted within 30 days of index operation. Black patients constituted 7.7 % of the entire cohort. Black patients were significantly different in smoking status (27 vs. 22 %) and Crohn's diagnosis (84 vs. 73 %) (p < 0.05). Black patients had significantly higher readmission rates (20 vs. 15 %) and longer length-of-stays (8 vs. 6 days) after surgery (p < 0.05). On multivariable analysis, black race remained a significant predictor for 30-day readmissions in patients with IBD (odds ratio 1.6, 95 % confidence interval 1.1 2.5). CONCLUSIONS: Black patients with IBD have an increased risk for readmission after colorectal surgery. Efforts to reduce readmissions need to target not only well-studied risk factors such as postoperative complications, but also investigate non-NSQIP-measured elements such as social and behavioral determinants of health. PMID- 26743887 TI - Diabetic nephropathy: where are we on the journey from pathophysiology to treatment? AB - Diabetic nephropathy affects 30-40% of people with diabetes, and is the leading cause of end-stage kidney disease. The current treatment paradigm relies on early detection, glycaemic control and tight blood pressure management with preferential use of renin-angiotensin system blockade. This strategy has transformed outcomes in diabetic kidney disease over the last 20 years. Over the last two decades we have also witnessed significant advances in the understanding of the pathophysiology of diabetic nephropathy; however, despite this new knowledge, we have yet to develop new treatments of proven efficacy. Whilst a continued emphasis on preclinical and clinical research is clearly needed, clinicians treating people with diabetes should not forget that, in the short term, the greatest gains are likely to be realised by more consistent deployment of existing therapies. PMID- 26743893 TI - Serendipitous Observation of AlI Insertion into a C-O Bond in L2 PhB (L=Oxazol-2 ylidene). AB - Oxidative addition of the C-O bond in L2 PhB: (L=oxazol-2-ylidene) to an AlI center induced ring expansion of an oxazol-2-ylidene ring, affording a unique organoboron species formally involving either an Al, N, O mixed heterocyclic carbene or anionic (amino)(boryl)carbene fragment. PMID- 26743886 TI - The Value of Performing Early Non-enhanced CT in Developing Strategies for Treating Acute Gallstone Pancreatitis. AB - BACKGROUND: The purpose of this study is to assess the value of early abdominal non-enhanced computed tomography (NECT) in developing strategies for treating acute gallstone pancreatitis (AGP). METHODS: AGP patients underwent NECT within 48 h after symptom onset to determine the presence of peripancreatic fluid collection, gallstones, and common bile duct stones. Patients with mild AGP who had neither organ failure by clinical data nor peripancreatic fluid collection by NECT (classified as grade A, B, or C based on the Balthazar CT grading system) were randomized to undergo an early laparoscopic cholecystomy (ELC; LC performed within 7 days after a pancreatitis attack, without waiting for symptom resolution) or late laparoscopic cholecystomy (LLC; LC performed >= 7 days following an attack, with the patient being completely free of AGP symptoms). RESULTS: The study enrolled 102 patients with mild AGP defined by clinical data and NECT. NECT was 89.2 % and 87.8 % accurate in detecting gallbladder stones and CBD stones, respectively. Totals of 49 and 53 patients were assigned to an ELC and LLC group, respectively. All patients in both groups were cured, no LC related complications occurred, and no case of AGP increased in severity following LC. The mean lengths of hospital stay and LC operation time were significantly shorter in the ELC group than the LLC group (P < 0.05). CONCLUSIONS: NECT can accurately detect peripancreatic fluid collection and biliary obstructions; thus, early abdominal NECT is valuable when developing strategies for treating AGP. Patients with mild AGP without organ failure or peripancreatic fluid collection can safely undergo ELC without waiting for complete resolution of their pancreatitis. PMID- 26743894 TI - Esthetic assessment of immediately restored implants combined with GBR and free connective tissue graft. AB - AIM: Esthetic assessment of immediately restored implants combined with GBR and free connective tissue (CT) graft METHODS: A case-control, retrospective study involving 34 patients treated with maxillary anterior single implants, immediately placed and restored. Clinical and esthetic results were analyzed using standard clinical examination and a comprehensive index, comprising pink esthetic and white esthetic scores (PES/WES). The height of the implant crown and the corresponding height of the contralateral tooth crown were measured to identify mucosal recessions. The distance from the mucosal margin to the implant shoulder (DIM) was measured on the master model. RESULTS: Thirty of 34 implants fulfilled the strict success criteria set for dental implants with regard to osseointegration. Success was defined as implants with bone loss not exceeding 1.5 mm during the first year and loosing not more than 0.2 for each successive year. The other four implants were stable but did not meet the bone loss criteria mentioned above and defined as survived implants. Mean PES/WES was 14.44 +/- 2.34 (range: 9-20). Mean PES was 7.12 +/- 1.89 (range: 1-10). The highest mean values were achieved for the variable of root convexity/soft tissue color and texture (1.71 +/- 0.46) whereas the mesial papilla (1.09 +/- 0.62) proved to be the least pleasing. The mean WES was 7.32 +/- 1.25 (range: 5-10). The difference between IC and contralateral TC was 0.54 mm. The mean value for the facial DIM was 3.82 +/- 0.87 mm. CONCLUSIONS: An evaluation of soft and hard tissue augmentation in immediately restored immediate implant procedures was employed to obtain stable hard and soft tissues. The combined GBR and CT graft procedure achieved favorable peri-implant soft tissue condition and esthetic results. However, recession and incomplete papillas were frequently observed. PMID- 26743896 TI - Metabolic-structural concordance in paraneoplastic limbic encephalitis. PMID- 26743897 TI - (68)Ga-PSMA PET/CT imaging in primary hepatocellular carcinoma. PMID- 26743895 TI - Metabotropic glutamate receptor 5 - a promising target in drug development and neuroimaging. AB - This review summarizes the contributions by various teams of scientists in assessing the metabotropic glutamate receptor 5 (mGluR5) as a biomarker in neuropsychiatric disorders and diseases. Development of positive and negative allosteric modulators of mGluR5 is reviewed, as is the development of PET radioligands that have the potential to measure mGluR5 receptor density in neurological disorders and during therapeutic interventions. PET imaging provides an effective tool to assess the specificity of new drugs, select dose regimens in clinical trials, and study drug mechanisms of action. We summarize and deliver comparative analyses of mGluR5-specific PET radiotracers and their applications in understanding the pathophysiology of mGluR5-related nervous system disorders and to speed up drug development. PMID- 26743898 TI - Cancer theranostics with 64Cu/177Lu-loaded liposomes. PMID- 26743899 TI - Variation in electrosurgical vessel seal quality along the length of a porcine carotid artery. AB - Electrosurgical vessel sealing has been demonstrated to have benefits for both patients and practitioners, but significant variation in the strength of the seal continues to be a concern. This study aims to examine the variation in electrosurgical seal quality along the length of a porcine common carotid artery and explore the relationships between seal quality, vessel size and morphology. Additionally, the study aimed to investigate the minimum safety threshold for successful seals and the influence of vessel characteristics on meeting this requirement. A total of 35 porcine carotid arteries were sealed using the PlasmaKinetic Open Seal device (Gyrus). Each seal was burst pressure tested and a sample taken for staining with elastin van Gieson's stain, with morphological quantification using image processing software ImageJ. With increasing distance from the bifurcation, there was an increase in seal strength and a reduction in both elastin content and vessel outer diameter. A significant correlation was found between burst pressure with both outer diameter (p < 0.0001) and elastin content (p = 0.001). When considering the safe limits of operation, vessels of less than 5 mm in outer diameter were shown to consistently produce a seal of a sufficient strength (burst pressure > 360 mmHg) irrespective of vessel morphology. PMID- 26743900 TI - miR-101 Inhibiting Cell Proliferation, Migration and Invasion in Hepatocellular Carcinoma through Downregulating Girdin. AB - miR-101 is considered to play an important role in hepato-cellular carcinoma (HCC), but the underlying molecular mechanism remains to be elucidated. Here, we aimed to confirm whether Girdin is a target gene of miR-101 and determine the tumor suppressor of miR-101 through Girdin pathway. In our previous studies, we firstly found Girdin protein was overexpressed in HCC tissues, and it closely correlated to tumor size, T stage, TNM stage and Edmondson-Steiner stage of HCC patients. After specific small interfering RNA of Girdin was transfected into HepG2 and Huh7.5.1 cells, the proliferation and invasion ability of tumor cells were significantly inhibited. In this study, we further explored the detailed molecular mechanism of Girdin in HCC. Interestingly, we found that miR-101 significantly low-expressed in HCC tissues compared with that in matched normal tissues while Girdin had a relative higher expression, and miR-101 was inversely correlated with Girdin expression. In addition, after miR-101 transfection, the proliferation, migration and invasion abilities of HepG2 cells were weakened. Furthermore, we confirmed that Girdin is a direct target gene of miR-101. Finally we confirmed Talen-mediated Girdin knockout markedly suppressed cell proliferation, migration and invasion in HCC while down-regulation of miR-101 significantly restored the inhibitory effect. Our findings suggested that miR 101/Girdin axis could be a potential application of HCC treatment. PMID- 26743902 TI - De Novo Transcriptome Analysis of Cucumis melo L. var. makuwa. AB - Oriental melon (Cucumis melo L. var. makuwa) is one of six subspecies of melon and is cultivated widely in East Asia, including China, Japan, and Korea. Although oriental melon is economically valuable in Asia and is genetically distinct from other subspecies, few reports of genome-scale research on oriental melon have been published. We generated 30.5 and 36.8 Gb of raw RNA sequence data from the female and male flowers, leaves, roots, and fruit of two oriental melon varieties, Korean landrace (KM) and Breeding line of NongWoo Bio Co. (NW), respectively. From the raw reads, 64,998 transcripts from KM and 100,234 transcripts from NW were de novo assembled. The assembled transcripts were used to identify molecular markers (e.g., single-nucleotide polymorphisms and simple sequence repeats), detect tissue-specific expressed genes, and construct a genetic linkage map. In total, 234 single-nucleotide polymorphisms and 25 simple sequence repeats were screened from 7,871 and 8,052 candidates, respectively, between the KM and NW varieties and used for construction of a genetic map with 94 F2 population specimens. The genetic linkage map consisted of 12 linkage groups, and 248 markers were assigned. These transcriptome and molecular marker data provide information useful for molecular breeding of oriental melon and further comparative studies of the Cucurbitaceae family. PMID- 26743903 TI - Caffeine Induces the Stress Response and Up-Regulates Heat Shock Proteins in Caenorhabditis elegans. AB - Caffeine has both positive and negative effects on physiological functions in a dose-dependent manner. C. elegans has been used as an animal model to investigate the effects of caffeine on development. Caffeine treatment at a high dose (30 mM) showed detrimental effects and caused early larval arrest. We performed a comparative proteomic analysis to investigate the mode of action of high-dose caffeine treatment in C. elegans and found that the stress response proteins, heat shock protein (HSP)-4 (endoplasmic reticulum [ER] chaperone), HSP-6 (mitochondrial chaperone), and HSP-16 (cytosolic chaperone), were induced and their expression was regulated at the transcriptional level. These findings suggest that high-dose caffeine intake causes a strong stress response and activates all three stress-response pathways in the worms, including the ER-, mitochondrial-, and cytosolic pathways. RNA interference of each hsp gene or in triple combination retarded growth. In addition, caffeine treatment stimulated a food-avoidance behavior (aversion phenotype), which was enhanced by RNAi depletion of the hsp-4 gene. Therefore, up-regulation of hsp genes after caffeine treatment appeared to be the major responses to alleviate stress and protect against developmental arrest. PMID- 26743901 TI - Salubrinal-Mediated Upregulation of eIF2alpha Phosphorylation Increases Doxorubicin Sensitivity in MCF-7/ADR Cells. AB - Eukaryotic translation initiation factor 2 alpha (eIF2alpha), which is a component of the eukaryotic translation initiation complex, functions in cell death and survival under various stress conditions. In this study, we investigated the roles of eIF2alpha phosphorylation in cell death using the breast cancer cell lines MCF-7 and MCF-7/ADR. MCF-7/ADR cells are MCF-7-driven cells that have acquired resistance to doxorubicin (ADR). Treatment of doxorubicin reduced the viability and induced apoptosis in both cell lines, although susceptibility to the drug was very different. Treatment with doxorubicin induced phosphorylation of eIF2alpha in MCF-7 cells but not in MCF 7/ADR cells. Basal expression levels of Growth Arrest and DNA Damage 34 (GADD34), a regulator of eIF2alpha, were higher in MCF-7/ADR cells compared to MCF-7 cells. Indeed, treatment with salubrinal, an inhibitor of GADD34, resulted in the upregulation of eIF2alpha phosphorylation and enhanced doxorubicin-mediated apoptosis in MCF-7/ADR cells. However, MCF-7 cells did not show such synergic effects. These results suggest that dephosphorylation of eIF2alpha by GADD34 plays an important role in doxorubicin resistance in MCF-7/ADR cells. PMID- 26743904 TI - Copper Ion from Cu2O Crystal Induces AMPK-Mediated Autophagy via Superoxide in Endothelial Cells. AB - Copper is an essential element required for a variety of functions exerted by cuproproteins. An alteration of the copper level is associated with multiple pathological conditions including chronic ischemia, atherosclerosis and cancers. Therefore, copper homeostasis, maintained by a combination of two copper ions (Cu(+) and Cu(2+)), is critical for health. However, less is known about which of the two copper ions is more toxic or functional in endothelial cells. Cubic shaped Cu2O and CuO crystals were prepared to test the role of the two different ions, Cu(+) and Cu(2+), respectively. The Cu2O crystal was found to have an effect on cell death in endothelial cells whereas CuO had no effect. The Cu2O crystals appeared to induce p62 degradation, LC3 processing and an elevation of LC3 puncta, important processes for autophagy, but had no effect on apoptosis and necrosis. Cu2O crystals promote endothelial cell death via autophagy, elevate the level of reactive oxygen species such as superoxide and nitric oxide, and subsequently activate AMP-activated protein kinase (AMPK) through superoxide rather than nitric oxide. Consistently, the AMPK inhibitor Compound C was found to inhibit Cu2O-induced AMPK activation, p62 degradation, and LC3 processing. This study provides insight on the pathophysiologic function of Cu(+) ions in the vascular system, where Cu(+) induces autophagy while Cu(2+) has no detected effect. PMID- 26743905 TI - Substitution of Heavy Complementarity Determining Region 3 (CDR-H3) Residues Can Synergistically Enhance Functional Activity of Antibody and Its Binding Affinity to HER2 Antigen. AB - To generate a biobetter that has improved therapeutic activity, we constructed scFv libraries via random mutagenesis of several residues of CDR-H3 and -L3 of hu4D5. The scFv clones were isolated from the phage display libraries by stringent panning, and their anti-proliferative activity against HER2-positive cancer cells was evaluated as a primary selection criterion. Consequently, we selected AH06 as a biobetter antibody that had a 7.2-fold increase in anti proliferative activity (IC50: 0.81 nM) against the gastric cancer cell line NCI N87 and a 7.4-fold increase in binding affinity (KD: 60 pM) to HER2 compared to hu4D5. The binding energy calculation and molecular modeling suggest that the substitution of residues of CDR-H3 to W98, F100c, A101 and L102 could stabilize binding of the antibody to HER2 and there could be direct hydrophobic interactions between the aromatic ring of W98 and the aliphatic group of I613 within HER2 domain IV as well as the heavy and light chain hydrophobic interactions by residues F100c, A101 and L102 of CDR-H3. Therefore, we speculate that two such interactions were exerted by the residues W98 and F100c. A101 and L102 may have a synergistic effect on the increase in the binding affinity to HER2. AH06 specifically binds to domain IV of HER2, and it decreased the phosphorylation level of HER2 and AKT. Above all, it highly increased the overall level of p27 compared to hu4D5 in the gastric cancer cell line NCI-N82, suggesting that AH06 could potentially be a more efficient therapeutic agent than hu4D5. PMID- 26743908 TI - Profiles of emotion regulation: Understanding regulatory patterns and the implications for posttraumatic stress. AB - Trauma survivors often experience posttraumatic stress (PTS) and report concurrent difficulties with emotion regulation (ER). Although individuals typically use multiple regulatory strategies to manage emotion, no studies yet examine the influence of a constellation of strategies on PTS in a community sample. We assessed six ER strategies and investigated whether specific profiles of ER (i.e. the typical pattern of regulation, determined by how often each strategy is used) were related to PTS. A hierarchical cluster analysis indicated that four distinct profiles were present: Adaptive Regulation, Active Regulation, Detached Regulation, and Maladaptive Regulation. Further analyses revealed that an individual's profile was not related to frequency of past trauma, but had the power to differentiate symptom severity for overall PTS and each symptom cluster of posttraumatic stress disorder. These findings highlight how profiles characterising multiple regulatory strategies offer a more complete understanding of the ways ER can account for PTS. PMID- 26743906 TI - Human Amnion-Derived Mesenchymal Stem Cells Protect Human Bone Marrow Mesenchymal Stem Cells against Oxidative Stress-Mediated Dysfunction via ERK1/2 MAPK Signaling. AB - Epidemiological evidence suggests that bone is especially sensitive to oxidative stress, causing bone loss in the elderly. Previous studies indicated that human amnion-derived mesenchymal stem cells (HAMSCs), obtained from human amniotic membranes, exerted osteoprotective effects in vivo. However, the potential of HAMSCs as seed cells against oxidative stress-mediated dysfunction is unknown. In this study, we systemically investigated their antioxidative and osteogenic effects in vitro. Here, we demonstrated that HAMSCs signicantly promoted the proliferation and osteoblastic differentiation of H2O2-induced human bone marrow mesenchymal stem cells (HBMSCs), and down-regulated the reactive oxygen species (ROS) level. Further, our results suggest that activation of the ERK1/2 MAPK signal transduction pathway is essential for both HAMSCs-mediated osteogenic and protective effects against oxidative stress-induced dysfunction in HBMSCs. U0126, a highly selective inhibitor of extracellular ERK1/2 MAPK signaling, significantly suppressed the antioxidative and osteogenic effects in HAMSCs. In conclusion, by modulating HBMSCs, HAMSCs show a strong potential in treating oxidative stress- mediated bone deficiency. PMID- 26743907 TI - Pharmacoeconomics of ruxolitinib therapy in patients with myelofibrosis. AB - BACKGROUND: Overall survival (OS) and other important clinical trial end-points seem increasingly more elusive in supporting rapid and efficient incorporation of innovative cancer drugs in clinical practice. This study proposes a clinical trial based pharmacoeconomic framework to assess the therapeutic and economic value of ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. METHODS: Individual patient level 144 week follow-up data from the COMFORT-II trial was used to account for the crossover effect on overall survival. Lifetime treatment benefits and costs were estimated considering detailed patterns of both ruxolitinib dose adjustments and blood transfusion needs. RESULTS: The authors estimate a 3.3 years increment in life expectancy (HR = 0.30; 95% CI = 0.17-0.55; p-value <0.001) and an incremental cost-effectiveness ratio of ?40,000 per life year gained with the use of ruxolitinib. CONCLUSION: This study also demonstrates how valuable information from clinical trials can be used to support informed decisions about the early incorporation of innovative drugs. PMID- 26743910 TI - Human perceptions of landscape change: The case of a monodominant forest of Attalea speciosa Mart ex. Spreng (Northeast Brazil). AB - From the perception of human populations, we can assess the changes occurring in certain landscapes and the factors that cause those changes. Such studies have proven helpful in increasing the knowledge of the history of a landscape, recognizing past formations and projecting its future. Our research objective was to determine how a landscape dominated by the palm tree Attalea speciosa, a species of ecological, economic, and cultural importance, has been changing over time by synthesizing and comparing historical documents and local perceptions. This study was conducted in Araripe Environmental Protection Area, Northeast Region, Brazil. To understand local landscape change, we interviewed active harvesters in four communities in which A. speciosa use has been documented. Historical documents were evaluated as a complement to the interview data. According to local informants, areas previously used for cultivation and animal husbandry that were abandoned or decimated by droughts in the region may have fostered the expansion of a monodominant A. speciosa forest. Furthermore, other forms of landscape management resulting from human population growth may also have affected the current and past distribution of this forest. PMID- 26743909 TI - Attitudes towards a maintenance (-agonist) treatment approach in high-dose benzodiazepine-dependent patients: a qualitative study. AB - BACKGROUND: High-dose benzodiazepine dependence constitutes a major clinical concern. Although withdrawal treatment is recommended, it is unsuccessful for a significant proportion of affected patients. More recently, a benzodiazepine maintenance approach has been suggested as an alternative for patients' failing discontinuation treatment. While there is some data supporting its effectiveness, patients' perceptions of such an intervention have not been investigated. METHODS: An exploratory qualitative study was conducted among a sample of 41 high dose benzodiazepine (BZD)-dependent patients, with long-term use defined as doses equivalent to more than 40 mg diazepam per day and/or otherwise problematic use, such as mixing substances, dose escalation, recreational use, or obtainment by illegal means. A qualitative content analysis approach was used to evaluate findings. RESULTS: Participants generally favored a treatment discontinuation approach with abstinence from BZD as its ultimate aim, despite repeated failed attempts at withdrawal. A maintenance treatment approach with continued prescription of a slow-onset, long-acting agonist was viewed ambivalently, with responses ranging from positive and welcoming to rejection. Three overlapping themes of maintenance treatment were identified: "Only if I can try to discontinue...and please don't call it that," "More stability and less criminal activity...and that is why I would try it," and "No cure, no brain and no flash...and thus, just for everybody else!" CONCLUSIONS: Some patients experienced slow-onset, long-acting BZDs as having stabilized their symptoms and viewed these BZDs as having helped avoid uncontrolled withdrawal and abstain from criminal activity. We therefore encourage clinicians to consider treatment alternatives if discontinuation strategies fail. PMID- 26743911 TI - Anti-icing properties of a superhydrophobic surface in a salt environment: an unexpected increase in freezing delay times for weak brine droplets. AB - Superhydrophobic coatings on the aluminum alloy were fabricated by intensive nanosecond pulsed laser treatment and chemical surface hydrophobization, which are chemically stable in contact with 0.5 M NaCl aqueous solutions and mechanically durable against stresses arising in the repetitive freezing/thawing of brine. The statistics of the crystallization of ensembles of sessile supercooled droplets deposited on above superhydrophobic coatings indicate considerable anti-icing properties. The comparative analysis of crystallization statistics of deionized water and of brine at a temperature of -20 degrees C allows detecting a striking increase in freezing delay times for the latter case with freezing delay for brine droplets reaching more than 6 hours. We explain the observed phenomenon based on the structure of the double electric layer in the vicinity of the hydrophobic surface and the solution/air interface and on the concept of structure making/breaking ions. PMID- 26743913 TI - Major recanalization occurs more often in young patients after unruptured aneurysm coil embolization. AB - BACKGROUND: The recanalization rate after coil embolization of unruptured aneurysms was compared between young and old age groups. METHODS: From May 2003 to December 2010, 636 patients with 715 saccular unruptured intracranial aneurysms (UIA) underwent endovascular coiling and were followed for at least 6 months. For comparative analysis, patients were categorized into two groups according to age 40: 42 patients with 46 aneurysms who were 40 years or younger (young age group) and 594 patients with 669 aneurysms who were older than 40 years (old age group). Angiographic and clinical outcomes including recanalization rates were compared. RESULTS: Angiographically, class 1 or 2 occlusion according to the Raymond-Roy Occlusion Classification system was achieved in 89.2 % of the patients (91.3 % in the young age group and 89.1 % in the old age group, p = 0.74). Procedure-related complication rate was 2.2 % and 3.4 % in the young and the old age group (p = 0.16), respectively. The mean follow-up duration was 30.51 +/- 18.59 months. Major recanalization occurred in seven aneurysms (15.2 %) in the young age group and in 44 aneurysms (6.6 %) in the old age group (p = 0.03). Retreatment was performed in seven patients (15.2 %) in the young age group and in 35 patients (5.2 %) in the old age group (p = 0.01). CONCLUSIONS: The present study showed that the technical feasibility and safety of endovascular coiling for UIA did not differ between the two age groups. However, the major recanalization rate was higher in the young age group. PMID- 26743912 TI - Trigeminal and sphenopalatine ganglion stimulation for intractable craniofacial pain--case series and literature review. AB - INTRODUCTION: Facial pain is often debilitating and can be characterized by a sharp, stabbing, burning, aching, and dysesthetic sensation. Specifically, trigeminal neuropathic pain (TNP), anesthesia dolorosa, and persistent idiopathic facial pain (PIFP) are difficult diseases to treat, can be quite debilitating and an effective, enduring treatment remains elusive. METHODS: We retrospectively reviewed our early experience with stimulation involving the trigeminal and sphenopalatine ganglion stimulation for TNP, anesthesia dolorosa, and PIFP between 2010-2014 to assess the feasibility of implanting at these ganglionic sites. Seven patients received either trigeminal and/or sphenopalatine ganglion stimulation with or without peripheral nerve stimulation, having failed multiple alternative modalities of treatment. The treatments were tailored on the physical location of pain to ensure regional coverage with the stimulation. RESULTS: Fluoroscopy or frameless stereotaxy was utilized to place the sphenopalatine and/or trigeminal ganglion stimulator. All patients were initially trialed before implantation. Trial leads implanted in the pterygopalatine fossa near the sphenopalatine ganglion were implanted via transpterygoid (lateral-medial, infrazygomatic) approach. Trial leads were implanted in the trigeminal ganglion via percutaneous Hartel approach, all of which resulted in masseter contraction. Patients who developed clinically significant pain improvement underwent implantation. The trigeminal ganglion stimulation permanent implants involved placing a grid electrode over Meckel's cave via subtemporal craniotomy, which offered a greater ability to stimulate subdivisions of the trigeminal nerve, without muscular (V3) side effects. Two of the seven overall patients did not respond well to the trial and were not implanted. Five patients reported pain relief with up to 24-month follow-up. Several of the sphenopalatine ganglion stimulation patients had pain relief without any paresthesias. There were no electrode migrations or post-surgical complications. CONCLUSIONS: Refractory facial pain may respond positively to ganglionic forms of stimulation. It appears safe and durable to implant electrodes in the pterygopalatine fossa via a lateral transpterygoid approach. Also, implantation of an electrode grid overlying Meckel's cave appears to be a feasible alternative to the Hartel approach. Further investigation is needed to evaluate the usefulness of these approaches for various facial pain conditions. PMID- 26743914 TI - Usefulness of four-dimensional computed tomographic angiography in a vertebral artery dissection case. AB - Discrimination of intramural hematoma from intra-aneurysmal blood flow is a critical issue for determining the necessity of treatment in vertebral artery dissection (VAD) cases. We describe modified four-dimensional computed tomographic angiography (4D-CTA) that is useful for evaluating blood flow in a dissected vertebral artery in a 41-year-old man who was diagnosed as VAD. Magnetic resonance angiography (MRA) showed a growth of intramural hematoma, which was confusingly similar to intra-aneurysmal blood flow. Modified 4D-CTA enabled us to discriminate the intramural hematoma from blood flow because of its fine time and spatial resolution. Modified 4D-CTA may be a substitute for angiography in VAD cases. PMID- 26743915 TI - Developmental venous anomaly, capillary telangiectasia, cavernous malformation, and arteriovenous malformation: spectrum of a common pathological entity? AB - Vascular malformations of the central nervous system are thought to originate from abnormal developmental processes during embryogenesis. Reports have cited the dynamic nature of these lesions and their "maturation" into other types of malformations. Herein we report on three patients with vascular malformations who exhibited dynamic alterations with stepwise progression of their lesions. These cases lend support to the hypothesis that these malformations may constitute the spectrum of a single disease caused by alterations in a common developmental program and that accumulating injury (e.g., by radiation) may allow one malformation type to mature into another. This concept warrants further investigation. PMID- 26743916 TI - Cerebrospinal fluid disturbance in overweight women after occipitocervical decompression in Chiari malformation type I. AB - BACKGROUND: Cerebrospinal fluid disturbance (CSFD) is a well-known complication after occipitocervical decompression (OCD) in patients with Chiari malformation type I (CMI). There is scarce data focusing on preoperative patients' factors predisposing to development of CSF disturbance. The aim of this study is to evaluate a prognostic value of some patients' factors in the prediction of CSFD after OCD in CMI patients. MATERIALS AND METHODS: We undertook a 10-year (2003 2013) retrospective study of all OCD in patients with CMI performed at Sahlgrenska IC, Sahlgrenska University Hospital, Sweden. A total of 52 consecutive patients were obtained from the operation database and we excluded one patient who was previously diagnosed with normal-pressure hydrocephalus. Data regarding preoperative age, body mass index, gender, degree of tonsillar herniation and syrinx were registered. Development of CSFD after OCD was noted. RESULTS: Of the 51 patients reviewed, six had CSFD after OCD and were managed using a form of CSF diversion procedure. All of the patients who developed CSFD were females. They had a mean body mass index of 32.3 compared to a mean of 24.3 in patients without CSFD (p = 0.0011). There was no difference between the two groups with regard to the other examined patient factors. CONCLUSIONS: CSF diversion was needed in six consecutive adult Chiari malformation type I patients who underwent occipitocervical decompression. All patients with postoperative CSFD were female and their mean BMI was significantly higher than patients without this complication. PMID- 26743917 TI - Surgical management of medium and large petroclival meningiomas: a single institution's experience of 199 cases with long-term follow-up. AB - BACKGROUND: Petroclival meningiomas (PCMs) were once regarded as 'inoperable' due to their complex anatomy and limited surgical exposure. This study aimed to evaluate the long-term outcomes of surgically treated PCMs larger than 2 cm. METHODS: A series of 199 consecutive patients (137 females, 68.8 %) with PCMs larger than 2 cm from between 1993 and 2003 were included. The clinical charts, radiographs, and follow-ups were evaluated. RESULTS: Gross total resection (GTR) was achieved in 111 (55.8 %) patients, subtotal resection (STR) in 65, and partial resection (PR) in 23. Cranial nerve dysfunctions were the most common complications and occurred in 133 (66.8 %) cases. The surgical mortality was 2.0 %. The Karnofsky Performance Scale (KPS) scores significantly decreased 1 month after the operations (preoperative KPS = 76.8 and postoperative KPS = 64.8; p = 0.011, Paired-samples t test). Long-term follow-ups were obtained in 142 patients, the follow-up duration was 171.6 months, and the most recent KPS was 83.2. Permanent morbidities remained in 24 patients (18.9 %). Multivariate analysis revealed that brainstem edema and tumors larger than 4 cm in diameter were independent risk factors in terms of outcomes (KPS < 80). The recurrence/progression rates were 14.5, 31.8, and 53.3 % for the GTR, STR, and PR cases, respectively (p = 0.002, Pearson chi (2) test). Gamma Knife radiosurgery for the remnants exhibited good tumor control. CONCLUSIONS: Favorable outcomes and low mortality were achieved with the microsurgical management of medium and large PCMs; however, the rates of cranial nerves dysfunction remained high. Radically aggressive resection might not be judicious in terms of postoperative morbidity. The preoperative evaluations and intraoperative findings were informative regarding the outcomes. The low follow-up rate likely compromised our findings, and additional consecutive studies were required. PMID- 26743918 TI - Sequential imaging of intraneural sciatic nerve endometriosis provides insight into symptoms of cyclical sciatica. AB - Endometriosis of the nerve often remains an elusive diagnosis. We report the first case of intraneural lumbosacral plexus endometriosis with sequential imaging at different phases of the menstrual cycle: during the luteal phase and menstruation. Compared to the first examination, the examination performed during the patient's period revealed the lumbosacral plexus larger and hyperintense on T2-weighted imaging. The intraneural endometriosis cyst was also larger and showed recent hemorrhage. Additionally, this case represents another example of perineural spread of endometriosis from the uterus to the lumbosacral plexus along the autonomic nerves and then distally to the sciatic nerve and proximally to the spinal nerves. PMID- 26743919 TI - Intracranial pressure wave morphological classification: automated analysis and clinical validation. AB - BACKGROUND: Recently, different software has been developed to automatically analyze multiple intracranial pressure (ICP) parameters, but the suggested methods are frequently complex and have no clinical correlation. The objective of this study was to assess the clinical value of a new morphological classification of the cerebrospinal fluid pulse pressure waveform (CSFPPW), comparing it to the elastance index (EI) and CSF-outflow resistance (Rout), and to test the efficacy of an automatic ICP analysis. METHODS: An artificial neural network (ANN) was trained to classify 60 CSFPPWs in four different classes, according to their morphology, and its efficacy was compared to an expert examiner's classification. The morphology of CSFPPW, recorded in 60 patients at baseline, was compared to EI and Rout calculated at the end of an intraventricular infusion test to validate the utility of the proposed classification in patients' clinical evaluation. RESULTS: The overall concordance in CSFPPW classification between the expert examiner and the ANN was 88.3 %. An elevation of EI was statistically related to morphological class' progression. All patients showing pathological baseline CSFPPW (class IV) revealed an alteration of CSF hydrodynamics at the end of their infusion test. CONCLUSIONS: The proposed morphological classification estimates the global ICP wave and its ability to reflect or predict an alteration in CSF hydrodynamics. An ANN can be trained to efficiently recognize four different CSF wave morphologies. This classification seems helpful and accurate for diagnostic use. PMID- 26743920 TI - Walking with Only Non-Invasive Ventilation in Stable Hypercapnic COPD Patients: Sufficient or Not? PMID- 26743921 TI - Computer-assisted shape descriptors for skull morphology in craniosynostosis. AB - PURPOSE: Our aim was to develop a novel method for characterizing common skull deformities with high sensitivity and specificity, based on two-dimensional (2D) shape descriptors in computed tomography (CT) images. METHODS: Between 2003 and 2014, 44 normal subjects and 39 infants with craniosynostosis (sagittal, 29; bicoronal, 10) enrolled for analysis. Mean age overall was 16 months (range, 1 120 months), with a male:female ratio of 56:29. Two reference planes, sagittal (S plane: through top of lateral ventricle) and coronal (C-plane: at maximum dimension of fourth ventricle), were utilized to formulate three 2D shape descriptors (cranial index [CI], cranial radius index [CR], and cranial extreme spot index [CES]), which were then applied to S- and C-plane target images of both groups. RESULTS: In infants with sagittal craniosynostosis, CI in S-plane (S CI) usually was <1.0 (mean, 0.78; range, 0.67-0.95), with CR consistently at 3 and a characteristic CES pattern of two discrete hot spots oriented diagonally. In the bicoronal craniosynostosis subset, CI was >1.0 (mean 1.11; range, 1.04 1.25), with CR at -3 and a CES pattern of four discrete diagonally oriented hot spots. Scatter plots underscored the highly intuitive joint performance of CI and CES in distinguishing normal and deformed states. Altogether, these novel 2D shape descriptors enabled effective discrimination of sagittal and bicoronal skull deformities. CONCLUSIONS: Newly developed 2D shape descriptors for cranial CT imaging enabled recognition of common skull deformities with statistical significance, perhaps providing impetus for automated CT-based diagnosis of craniosynostosis. PMID- 26743923 TI - In vitro profiling of antimethicillin-resistant Staphylococcus aureus activity of thymoquinone against selected type and clinical strains. AB - This study explores antimethicillin-resistant Staphylococcus aureus (MRSA) activity of a bioactive phytochemical constituent, thymoquinone obtained from the medicinal herb, Nigella sativa Linn. Based on initial assessment on crude extract of seeds of Nigella sativa Linn, the pure active constituent was employed in the study. A total of 99 MRSA strains which comprised of 40 types and 59 clinical strains were selected for the study. Minimum inhibitory concentration (MIC), bactericidal activity, postantibiotic effect (PAE) and propensity to select resistant mutants were determined using standard protocols. Results revealed that thymoquinone exhibited MIC in the range of 8-16 MUg ml(-1) and MIC90 of 16 MUg ml(-1) against MRSA strains. It was bactericidal to MRSA by demonstrating >3 log kill. It showed a longer PAE of 3.2 +/- 0.2 h. Upon exposure to high-density inoculum of MRSA, it did not select resistant mutants. Transmission electron microscopy of thymoquinone-treated MRSA showed no lysis but damage to cell wall and cell membrane which corroborated well with the salt tolerance and bacteriolysis assays. In conclusion, MIC90 , bactericidal property, longer PAE, absence of resistant mutant selection and damages in cell membrane and cell wall imply a promising anti-MRSA activity of thymoquinone. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first detailed report on anti-MRSA activity of thymoquinone. The assessment was made with both type and clinical strains. Thymoquinone may be a potential lead compound which can be further optimized to discover novel anti-MRSA agents. PMID- 26743922 TI - Recurrent adult-type fibrosarcoma of the frontal bone in a child. AB - INTRODUCTION: Primary, adult-type bone fibrosarcoma is an uncommon, malignant spindle-cell tumor of fibroblastic origin, rarely affecting children. Most frequently diagnosed among bone malignancies in the past, improved diagnostic techniques and further restrictive classification criteria have currently made the diagnosis of fibrosarcoma very unusual. CASE REPORT: We hereby report the case of a 7-year-old child with a right frontal swelling mass. A computed tomography scan showed an osteolytic lesion of the right frontal bone, involving the diploe and the outer table of the skull. An en bloc surgical excision, followed by a thorough immunohistological evaluation, led to the diagnosis of fibroblastic proliferation, with low cellularity and minimal atypias. The patient had four recurrences during the 4-year follow-up. With an increasing histological grade at recurrences, a diagnosis of adult-type fibrosarcoma was made. CONCLUSION: To the best of the authors' knowledge, this is the first reported case of an adult-type fibrosarcoma arising in the frontal bone of a child. PMID- 26743924 TI - Consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. PMID- 26743925 TI - An 82-year-old woman with a cardiac mass. AB - CLINICAL INTRODUCTION: An 82-year-old woman suspected of a cardiac tumour was referred for evaluation. Patient's medical history included atrial fibrillation, implantation of a VVI (ventricular stimulation) pacemaker 3 years earlier due to advanced atrioventicular (AV) block, arterial hypertension and hypothyroidism. Patient was adequately anticoagulated with warfarin (international normalized ratio (INR) 3.0 at admission). She reported occasional palpitations and a 2 kg weight loss in the last 2 years, but denied shortness of breath, chest pain, malaise, fever, chills or cough. Blood samples were taken for tests and cultures. Red blood cells, haemoglobin, white blood cells, platelets, C- reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were within normal ranges. Blood cultures were negative. Echocardiogram (figure 1A) (see online supplementary videos 1 and 2) and cardiac CT were performed (figure 1B). QUESTION: Which of the following is the most likely diagnosis?Caseous calcification of the mitral annulusCoconut left atriumMitral valve myxomaPeriannular abscess. PMID- 26743926 TI - Update on percutaneous mitral commissurotomy. AB - Percutaneous mitral commissurotomy (PMC) is the first-line therapy for managing rheumatic mitral stenosis. Over the past two decades, the indications of the procedure have expanded to include patients with unfavourable valve anatomy as a consequence of epidemiological changes in patient population. The procedure is increasingly being performed in patients with increased age, more deformed valves and associated comorbidities. Echocardiography plays a crucial role in patient selection and to guide a more efficient procedure. The main echocardiographic predictors of immediate results after PMC are mitral valve area, subvalvular thickening and valve calcification, especially at the commissural level. However, procedural success rate is not only dependent on valve anatomy, but a number of other factors including patient characteristics, interventional management strategies and operator expertise. Severe mitral regurgitation continues to be the most common immediate procedural complication with unchanged incidence rates over time. The long-term outcome after PMC is mainly determined by the immediate procedural results. Postprocedural parameters associated with late adverse events include mitral valve area, mitral regurgitation severity, mean gradient and pulmonary artery pressure. Mitral restenosis is an important predictor of event free survival rates after successful PMC, and repeat procedure can be considered in cases with commissural refusion. PMC can be performed in special situations, which include high-risk patients, during pregnancy and in the presence of left atrial thrombus, especially in centres with specialised expertise. Therefore, procedural decision-making should take into account the several determinant factors of PMC outcomes. This paper provides an overview and update of PMC techniques, complications, immediate and long-term results over time, and assessment of suitability for the procedure. PMID- 26743928 TI - Improving Mental Health Care: What Nurses Can Do. PMID- 26743927 TI - The potential exploitation of research participants in high income countries who lack access to health care. AB - There are millions of individuals living in North America and the European Union who lack access to healthcare services. When these individuals participate in research, they are at increased risk of being exposed to the risks and burdens of clinical trials without realizing the benefits that result from them. The mechanisms that have been proposed to ensure that research participants in low- and middle-income countries are not exploited are unlikely to protect participants in high-income countries. The present manuscript argues that one way to address concerns about exploitation in high-income countries would be to require sponsors to provide targeted benefits such as medical treatment during the trial, or the study drug after the trial. The latter could be achieved through extension studies, expanded access programs, or named-patient programs. Sponsors also might provide non-medical benefits, such as education or social support. Ethical and regulatory guidance should be revised to ensure that research participants in high-income countries who lack access to healthcare services receive sufficient benefits. PMID- 26743929 TI - Comparing Image Perception of Bladder Tumors in Four Different Storz Professional Image Enhancement System Modalities Using the iSPIES App. AB - OBJECTIVES: To evaluate the variation of interpretation of the same bladder urothelium image in different Storz Professional Image Enhancement System (SPIES) modalities. SPIES contains a White light (WL), Spectra A (SA), Spectra B (SB), and Clara and Chroma combined (CC) modality. MATERIALS AND METHODS: An App for the iPAD retina was developed to study evaluation of images. A total of 80 images from 20 bladder areas acquired in four modalities were included. Seventy-three participants completed the study. Images were analyzed on differences in delineated tumor margin variation, perceived quality of the image, and delineation time. RESULTS: A separation between high agreement (n = 14) and low agreement (n = 6) images was found. In high agreement images, no difference in root mean square (RMS) was found between modalities. In low agreement images, WL (26.5 pixels) and SA (33.4 pixels) had a higher RMS than CC (18 pixels) and SB (21.4 pixels). The quality of SPIES modalities images was rated significantly higher. Delineation time was similar. CONCLUSION: In low agreement cases, images in CC and SB have less variation in interpretation than WL and SA. The image quality in SPIES modalities is graded significantly higher than WL. There is no difference in delineation time between modalities. PMID- 26743930 TI - Pathway of FeEDTA transformation and its impact on performance of NOx removal in a chemical absorption-biological reduction integrated process. AB - A novel chemical absorption-biological reduction (CABR) integrated process, employing ferrous ethylenediaminetetraacetate (Fe(II)EDTA) as a solvent, is deemed as a potential option for NOx removal from the flue gas. Previous work showed that the Fe(II)EDTA concentration was critical for the NOx removal in the CABR process. In this work, the pathway of FeEDTA (Fe(III)/Fe(II)-EDTA) transformation was investigated to assess its impact on the NOx removal in a biofilter. Experimental results revealed that the FeEDTA transformation involved iron precipitation and EDTA degradation. X-ray photoelectron spectroscopy analysis confirmed the iron was precipitated in the form of Fe(OH)3. The iron mass balance analysis showed 44.2% of the added iron was precipitated. The EDTA degradation facilitated the iron precipitation. Besides chemical oxidation, EDTA biodegradation occurred in the biofilter. The addition of extra EDTA helped recover the iron from the precipitation. The transformation of FeEDTA did not retard the NO removal. In addition, EDTA rather than the iron concentration determined the NO removal efficiency. PMID- 26743931 TI - Case report: imaging and treatment of ophthalmic manifestations in oculodentodigital dysplasia. AB - BACKGROUND: Diagnostic and surgical management of severe chronic angle- closure glaucoma secondary to ciliary body cysts can be difficult to manage in a patient with oculodentodigital dysplasia. CASE PRESENTATION: A 6-year old girl with oculodentodigital dysplasia, with progressive chronic angle- closure glaucoma secondary to ciliary body cysts presented to our clinic. The initial examination revealed counting fingers vision in the left eye. Intraocular pressure (IOP), as assessed by tonopen, was 31 mm Hg. Ultrasound biomicroscopy revealed ciliary body cysts in the left eye, and gonioscopy confirmed chronic angle closure. A tube shunt was placed to control the elevated IOP. A year after her tube shunt placement in the left eye, ultrasound biomiscropy was performed on her right eye and showed no ciliary body cysts. Gonioscopy in the right eye revealed an open angle to the ciliary body band. Subsequent serial gonioscopy every 3 months showed gradual narrowing of the right eye angle and finally three-and-a-half years after tube placement of the left eye, her right eye IOP became uncontrolled with medications alone and a tube shunt was similarly placed in the right eye. Intraoperative ultrasound biomicroscopy performed at the time of the right eye tube shunt revealed extensive ciliary body cysts in the right eye. Her IOP in both eyes have been well controlled since the placement of tube shunts. CONCLUSIONS: This is one of the first reported cases of severe chronic angle- closure glaucoma secondary to ciliary body cysts in a patient with oculodentodigital dysplasia. We believe that early screening for ciliary body cysts is important in patients with oculodentodigital dysplasia. PMID- 26743932 TI - Resolvin D4 stereoassignment and its novel actions in host protection and bacterial clearance. AB - Resolvins of the D-series are specialized pro-resolving lipid mediators that regulate cellular response by orchestrating resolution networks involved in host responses to injury and infection. Here, endogenous resolvin D4 was identified in human tissues and found to persist late into the resolution phase of acute murine Staphylococcus aureus infections. Completion of the first total synthesis of resolvin D4 established the absolute stereochemical configuration of RvD4 confirmed by matching with endogenous RvD4 from resolving exudates in dorsal pouch S. aureus infections. In vivo, RvD4 (ng/mouse) reduced neutrophilic infiltration (~40%) and enhanced uptake of apoptotic PMN (51%) by human dermal fibroblasts at concentrations as low as 0.1 nM. These results establish the complete stereochemistry of RvD4 as 4S,5R,17S-trihydroxydocosa 6E,8E,10Z,13Z,15E,19Z-hexaenoic acid and its novel pro-resolving actions in S. aureus infections as well as its potent ability to stimulate clearance of apoptotic cells by skin fibroblasts. PMID- 26743933 TI - SJNNV down-regulates RGNNV replication in European sea bass by the induction of the type I interferon system. AB - European sea bass is highly susceptible to the betanodavirus RGNNV genotype, although the SJNNV genotype has also been detected in this fish species. The coexistence of both genotypes may affect the replication of both viruses by viral interaction or by stimulation of the host antiviral defense system in which the IFN I system plays a key role. IFN I triggers the transcription of interferon stimulated genes, including Mx genes, whose expression has been used as a reporter of IFN I activity. The present study evaluated the effect of a primary exposure to an SJNNV isolate on a subsequent RGNNV infection and analyzed the role of the IFN I system in controlling VNNV infections in sea bass using different in vivo approaches. VNNV infection and Mx transcription were comparatively evaluated after single infections, superinfection (SJ+RG) and co infection (poly I:C+RG). The single RGNNV infection resulted in a 24% survival rate, whereas the previous SJNNV or poly I:C inoculation increased the survival rate up to 96 and 100%, respectively. RGNNV replication in superinfection was reduced compared with RGNNV replication after a single inoculation. Mx transcription analysis shows differential induction of the IFN I system by both isolates. SJNNV was a potent Mx inducer, whereas RGNNV induced lower Mx transcription and did not interfere with the IFN I system triggered by SJNNV or poly I:C. This study demonstrates that an antiviral state exists after SJNNV and poly I:C injection, suggesting that the IFN I system plays an important role against VNNV infections in sea bass. PMID- 26743934 TI - The Influence of Doping on the Optoelectronic Properties of PbS Colloidal Quantum Dot Solids. AB - We report on an extensive spectroscopic investigation of the impact of substitutional doping on the optoelectronic properties of PbS colloidal quantum dot (CQD) solids. N-doping is provided by Bi incorporation during CQD synthesis as well as post-synthetically via cation exchange reactions. The spectroscopic data indicate a systematic quenching of the excitonic absorption and luminescence and the appearance of two dopant-induced contributions at lower energies to the CQD free exciton. Temperature-dependent photoluminescence indicates the presence of temperature-activated detrapping and trapping processes of photoexcitations for the films doped during and after synthesis, respectively. The data are consistent with a preferential incorporation of the dopants at the QDs surface in the case of the cation-exchange treated films versus a more uniform doping profile in the case of in-situ Bi incorporation during synthesis. Time-resolved experiments indicate the presence of fast dopant- and excitation-dependent recombination channels attributed to Auger recombination of negatively charged excitons, formed due to excess of dopant electrons. The data indicate that apart from dopant compensation and filling of dopant induced trap states, a fraction of the Bi ionized electrons feeds the QD core states resulting in n-doping of the semiconductor, confirming reported work on devices based on such doped CQD material. PMID- 26743935 TI - Rhodium complexes as therapeutic agents. AB - The landscape of inorganic medicinal chemistry has been dominated by the investigation of platinum, and to a lesser extent ruthenium, complexes over the past few decades. Recently, complexes based on other metal centers such as rhodium have attracted attention due to their tunable chemical and biological properties as well as distinct mechanisms of action. This perspective highlights recent examples of rhodium complexes that show diverse biological activities against various targets, including enzymes and protein-protein interactions. PMID- 26743936 TI - A deficiency in cold-inducible RNA-binding protein accelerates the inflammation phase and improves wound healing. AB - Chronic or non-healing wounds are a major concern in clinical practice and these wounds are mostly associated with diabetes, and venous and pressure ulcers. Wound healing is a complex process involving overlapping phases and the primary phase in this complex cascade is the inflammatory state. While inflammation is necessary for wound healing, a prolonged inflammatory phase leads to impaired healing. Cold-inducible RNA-binding protein (CIRP) belongs to a family of cold shock proteins that are expressed in high levels under stress conditions. Recently, we demonstrated that a deficiency in CIRP led to decreased inflammation and mortality in an experimental model of hemorrhagic shock. Thus, we hypothesized that a deficiency in CIRP would accelerate the inflammatory phase and lead to an improvement in cutaneous wound healing. In this study, to examine this hypothesis, a full-thickness wound was created on the dorsum of wild-type (WT) and CIRP-/- mice. The wound size was measured every other day for 14 days. The wound area was significantly decreased in the CIRP-/- mice by day 9 and continued to decrease until day 14 compared to the WT mice. In a separate cohort, mice were sacrificed on days 3 and 7 after wounding and the skin tissues were harvested for histological analysis and RNA measurements. On day 3, the mRNA expression of tumor necrossis factor (TNF)-alpha in the skin tissues was increased by 16-fold in the WT mice, whereas these levels were increased by 65 fold in the CIRP-/- mice. Of note on day 7, while the levels of TNF-alpha remained high in the WT mice, these levels were significantly decreased in the CIRP-/- mice. The histological analysis of the wounded skin tissue indicated an improvement as early as day 3 in the CIRP-/- mice, whereas in the WT mice, infiltrated immune cells were still present on day 7. On day 7 in the CIRP-/- mice, Gr-1 expression was low and CD31 expression was high, whereas in the WT mice, Gr-1 expression was high and CD31 expression was low, indicating that the CIRP-/- mice have already moved into the angiogenesis and tissue formation phase, whereas the WT mice were still in the inflammatory state. These data collectively suggest that a deficiency in CIRP accelerates the wound healing process. PMID- 26743938 TI - Fast and large-area growth of uniform MoS2 monolayers on molybdenum foils. AB - A controllable synthesis of two-dimensional crystal monolayers in a large area is a prerequisite for potential applications, but the growth of transition metal dichalcogenide monolayers in a large area with spatial homogeneity remains a great challenge. Here we report a novel and efficient method to fabricate large scale MoS2 monolayers by direct sulfurization of pre-annealed molybdenum foil surfaces with large grain boundaries of more than 50 MUm in size at elevated temperatures. Continuous MoS2 monolayers can be formed uniformly by sulfurizing the Mo foils in sulfur vapor at 600 degrees C within 1 min. At a lower temperature even down to 500 degrees C, uniform MoS2 monolayers can still be obtained but in a much longer sulfurizing duration. It is demonstrated that the formed monolayers can be nondestructively transferred onto arbitrary substrates by removing the Mo foil using diluted ferric chloride solution and can be successfully fabricated into photodetectors. The results show a novel avenue to efficiently fabricate two-dimensional crystals in a large area in a highly controllable way and should have great potential for the development of large scale applications of two-dimensional crystals in electrophotonic systems. PMID- 26743939 TI - Discovering and validating between-subject variations in plasma lipids in healthy subjects. AB - Lipid levels are commonly used in clinical settings as disease biomarkers, and the advent of mass spectrometry-based (MS) lipidomics heralds the possibility of identifying additional lipids that can inform disease predispositions. However, the degree of natural variation for many lipids remains poorly understood, thus confounding downstream investigations on whether a specific intervention is driving observed lipid fluctuations. Here, we performed targeted mass spectrometry with multiple reaction monitoring across a comprehensive spectrum of 192 plasma lipids on eight subjects across three time-points separated by six hours and two standardized meals. A validation study to confirm the initial discoveries was performed in a further set of nine subjects, subject to the identical study design. Technical variation of the MS was assessed using duplicate measurements in the validation study, while biological variation was measured for lipid species with coefficients of variation <20%. We observed that eight lipid species from the phosphatidylethanolamine and phosphatidylcholine lipid classes were discovered and validated to vary consistently across the three time-points, where the within-subject variance can be up to 1.3-fold higher than between-subject variance. These findings highlight the importance of understanding the range of biological variation in plasma lipids as a precursor to their use in clinical biochemistry. PMID- 26743941 TI - Dosimetric comparison of brachytherapy sources for high-dose-rate treatment of endometrial cancer: (192)Ir, (60)Co and an electronic brachytherapy source. AB - OBJECTIVE: To compare high-dose-rate (HDR) brachytherapy systems with (192)Ir, (60)Co and electronic brachytherapy source (EBS) for treatment of endometrial cancers. METHODS: Two additional plans were generated per patient fraction using a (60)Co source and Xoft-EBS on 10 selected patients, previously treated with a vaginal cylinder applicator using a (192)Ir source. Dose coverage of "PTV_CYLD", a 5-mm shell surrounding the cylinder, was evaluated. Doses to the following organs at risk (OARs) the rectum, bladder and sigmoid were evaluated in terms of V35% and V50%, the percentage volume receiving 35% and 50% of the prescription dose, respectively, and D2cm(3), the highest dose to a 2-cm(3) volume of an OAR. RESULTS: Xoft-EBS reduces doses to all OARs in the lower dose range, but it does not always provide better sparing of the rectum in higher dose range as does evaluation using D2cm3. V150% and V200% for PTV_CYLD was up to four times greater for Xoft-EBS plans than for plans generated with (192)Ir or (60)Co. Surface mucosal (vaginal cylinder surface) doses were also 23% higher for Xoft-EBS than for (192)Ir or (60)Co plans. CONCLUSION: Xoft-EBS is a suitable HDR source for vaginal applicator treatment with advantages of reducing radiation exposure to OARs in the lower dose range, while simultaneously increasing the vaginal mucosal dose. ADVANCES IN KNOWLEDGE: This work presents newer knowledge in dosimetric comparison between (192)Ir or (60)Co and Xoft-EBS sources for endometrial vaginal cylinder HDR planning. PMID- 26743942 TI - Ribosome dimerization is essential for the efficient regrowth of Bacillus subtilis. AB - Ribosome dimers are a translationally inactive form of ribosomes found in Escherichia coli and many other bacterial cells. In this study, we found that the 70S ribosomes of Bacillus subtilis dimerized during the early stationary phase and these dimers remained in the cytoplasm until regrowth was initiated. Ribosome dimerization during the stationary phase required the hpf gene, which encodes a homologue of the E. coli hibernation-promoting factor (Hpf). The expression of hpf was induced at an early stationary phase and its expression was observed throughout the rest of the experimental period, including the entire 6 h of the stationary phase. Ribosome dimerization followed the induction of hpf in WT cells, but the dimerization was impaired in cells harbouring a deletion in the hpf gene. Although the absence of ribosome dimerization in these Hpf-deficient cells did not affect their viability in the stationary phase, their ability to regrow from the stationary phase decreased. Thus, following the transfer of stationary-phase cells to fresh LB medium, Deltahpf mutant cells grew slower than WT cells. This observed lag in growth of Deltahpf cells was probably due to a delay in restoring their translational activity. During regrowth, the abundance of ribosome dimers in WT cells decreased with a concomitant increase in the abundance of 70S ribosomes and growth rate. These results suggest that the ribosome dimers, by providing 70S ribosomes to the cells, play an important role in facilitating rapid and efficient regrowth of cells under nutrient-rich conditions. PMID- 26743937 TI - Serum levels of the proinflammatory cytokine interleukin-6 vary based on diagnoses in individuals with lumbar intervertebral disc diseases. AB - BACKGROUND: Many intervertebral disc diseases cause low back pain (LBP). Proinflammatory cytokines and matrix metalloproteinases (MMPs) participate in disc pathology. In this study, we examined levels of serum cytokines and MMPs in human subjects with diagnoses of disc herniation (DH), spinal stenosis (SS), or degenerative disc disease (DDD) relative to levels in control subjects. Comparison between subjects with DH and those with other diagnoses (Other Dx, grouped from SS and DDD) was performed to elaborate a pathological mechanism based on circulating cytokine levels. METHODS: Study participants were recruited from a spine neurosurgery practice (n = 80), a back pain management practice (n = 27), or a control cohort (n = 26). Serum samples were collected before treatment and were assayed by multiplex assays for levels of interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-gamma, tumor necrosis factor alpha, MMP-1, MMP-3, and MMP-9. Inflammatory and degradative mediator levels were compared for subjects with LBP and control subjects, by diagnosis and by treatment groups, controlling for effects of sex, age, and reported history of osteoarthritis. Spearman's correlation coefficient was used to examine relationships with age, body mass index (BMI), symptom duration, and smoking history. RESULTS: Serum levels of IL-6 were significantly higher in subjects with LBP compared with control subjects. Participants with LBP due to Other Dx had significantly higher levels of IL-6 than DH and controls. Serum levels of MMP-1 were significantly lower in LBP subjects, specifically those with DH, than in control subjects. Positive correlations were found between IL-6 levels and BMI, symptom duration, and age. MMP-1 levels were positively correlated with age. CONCLUSIONS: The findings of the present clinical study are the results of the first examination of circulating cytokine levels in DDD and SS and provide evidence for a more extensive role of IL-6 in disc diseases, where patients with DDD or SS have higher serum cytokine levels than those with DH or control subjects. These findings suggest that LBP subjects have low-grade systemic inflammation, and biochemical profiling of circulating cytokines may assist in refining personalized diagnoses of disc diseases. PMID- 26743943 TI - Cryoglobulinemic vasculitis with primary Sjogren's syndrome: A case report. AB - A 63-year-old Japanese woman with Sjogren's syndrome and peripheral neuropathy was admitted for evaluation of purpura on her lower extremities. Skin biopsy revealed leukocytoclastic vasculitis with the deposition of IgM, and serum cryoglobulin was positive. Accordingly, cryoglobulinemic vasculitis was diagnosed. There was no response to high-dose steroid therapy and plasmapheresis, but intravenous cyclophosphamide pulse therapy was effective for 4 years. Thereafter, proteinuria and hematuria developed, with cryoglobulinemic glomerulopathy being diagnosed by renal biopsy. Because the total dose of cyclophosphamide had reached 8000 mg, treatment with rituximab was selected. While rituximab was initially effective for her skin lesions and nephropathy, relapse occurred within 2 years and additional administration of this agent was required. The long-term efficacy of treatment for cryoglobulinemic vasculitis remains uncertain in patients with Sjogren's syndrome. PMID- 26743944 TI - Attapulgite Nanoparticles-Modified Monolithic Column for Hydrophilic In-Tube Solid-Phase Microextraction of Cyromazine and Melamine. AB - In current study, a novel monolithic capillary column with embedded attapulgite nanoparticles has been developed and exploited as a stationary phase in hydrophilic in-tube solid phase microextraction (SPME) of cyromazine and melamine. The fibrillar attapulgite nanoparticles were embedded in the poly(1 vinyl-3-(butyl-4-sulfonate) imidazolium-co-acrylamide-co-N,N' methylenebis(acrylamide)) (poly(VBSIm-AM-MBA)) monolith via in situ polymerization. The attapulgite/polymerization ratio of the monolith was finely optimized. Primary factors of in-tube SPME including sample solvent, elution solvent, sample loading volume, elution volume, sample loading flow rate, and elution flow rate were thoroughly evaluated. Under optimal conditions, the limits of detection (LODs) were found to be 21.1 and 0.3 ng mL(-1) for cyromazine and melamine in the milk formula sample, respectively. Also, the recoveries of cyromazine and melamine spiked in the sample ranged from 94.5% to 109.9% with RSDs less than 7.6%. PMID- 26743940 TI - Cep57 is a Mis12-interacting kinetochore protein involved in kinetochore targeting of Mad1-Mad2. AB - The spindle assembly checkpoint (SAC) arrests cells in mitosis by sensing unattached kinetochores, until all chromosomes are bi-oriented by spindle microtubules. Kinetochore accumulation of the SAC component Mad1-Mad2 is crucial for SAC activation. However, the mechanism by which Mad1-Mad2 accumulation at kinetochores is regulated is not clear. Here we find that Cep57 is localized to kinetochores in human cells, and binds to Mis12, a KMN (KNL1/Mis12 complex/Ndc80 complex) network component. Cep57 also interacts with Mad1, and depletion of Cep57 results in decreased kinetochore localization of Mad1-Mad2, reduced SAC signalling and increased chromosome segregation errors. We also show that the microtubule-binding activity of Cep57 is involved in the timely removal of Mad1 from kinetochores. Thus, these findings reveal that the KMN network-binding protein Cep57 is a mitotic kinetochore component, and demonstrate the functional connection between the KMN network and the SAC. PMID- 26743945 TI - Semi-recumbent position versus supine position for the prevention of ventilator associated pneumonia in adults requiring mechanical ventilation. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is associated with increased mortality, prolonged length of hospital stay and increased healthcare costs in critically ill patients. Guidelines recommend a semi-recumbent position (30o to 45o) for preventing VAP among patients requiring mechanical ventilation. However, due to methodological limitations in existing systematic reviews, uncertainty remains regarding the benefits and harms of the semi-recumbent position for preventing VAP. OBJECTIVES: To assess the effectiveness and safety of semi recumbent positioning versus supine positioning to prevent ventilator-associated pneumonia (VAP) in adults requiring mechanical ventilation. SEARCH METHODS: We searched CENTRAL (2015, Issue 10), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1946 to October 2015), EMBASE (2010 to October 2015), CINAHL (1981 to October 2015) and the Chinese Biomedical Literature Database (CBM) (1978 to October 2015). SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing semi-recumbent versus supine positioning (0o to 10o), or RCTs comparing alternative degrees of positioning in mechanically ventilated patients. Our outcomes included clinically suspected VAP, microbiologically confirmed VAP, intensive care unit (ICU) mortality, hospital mortality, length of ICU stay, length of hospital stay, duration of ventilation, antibiotic use and any adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently and in duplicate screened titles, abstracts and full texts, assessed risk of bias and extracted data using standardised forms. We calculated the mean difference (MD) and 95% confidence interval (95% CI) for continuous data and the risk ratio (RR) and 95% CI for binary data. We performed meta-analysis using the random-effects model. We used the grading of recommendations, assessment, development and evaluation (GRADE) approach to grade the quality of evidence. MAIN RESULTS: We included 10 trials involving 878 participants, among which 28 participants in two trials did not provide complete data due to loss to follow-up. We judged all trials to be at high risk of bias. Semi-recumbent position (30o to 60o) versus supine position (0 degrees to 10 degrees ) A semi recumbent position (30o to 60o) significantly reduced the risk of clinically suspected VAP compared to a 0o to 10o supine position (eight trials, 759 participants, 14.3% versus 40.2%, RR 0.36; 95% CI 0.25 to 0.50; risk difference (RD) 25.7%; 95% CI 20.1% to 30.1%; GRADE: moderate quality evidence).There was no significant difference between the two positions in the following outcomes: microbiologically confirmed VAP (three trials, 419 participants, 12.6% versus 31.6%, RR 0.44; 95% CI 0.11 to 1.77; GRADE: very low quality evidence), ICU mortality (two trials, 307 participants, 29.8% versus 34.3%, RR 0.87; 95% CI 0.59 to 1.27; GRADE: low quality evidence), hospital mortality (three trials, 346 participants, 23.8% versus 27.6%, RR 0.84; 95% CI 0.59 to 1.20; GRADE: low quality evidence), length of ICU stay (three trials, 346 participants, MD -1.64 days; 95% CI -4.41 to 1.14 days; GRADE moderate quality evidence), length of hospital stay (two trials, 260 participants, MD -9.47 days; 95% CI -34.21 to 15.27 days; GRADE: very low quality evidence), duration of ventilation (four trials, 458 participants, MD -3.35 days; 95% CI -7.80 to 1.09 days), antibiotic use (three trials, 284 participants, 84.8% versus 84.2%, RR 1.00; 95% CI 0.97 to 1.03) and pressure ulcers (one trial, 221 participants, 28% versus 30%, RR 0.91; 95% CI 0.60 to 1.38; GRADE: low quality evidence). No other adverse events were reported. Semi-recumbent position (45 degrees ) versus 25 degrees to 30 degrees We found no statistically significant differences in the following prespecified outcomes: clinically suspected VAP (two trials, 91 participants, RR 0.74; 95% CI 0.35 to 1.56; GRADE: very low quality evidence), microbiologically confirmed VAP (one trial, 30 participants, RR 0.61; 95% CI 0.20 to 1.84: GRADE: very low quality evidence), ICU mortality (one trial, 30 participants, RR 0.57; 95% CI 0.15 to 2.13; GRADE: very low quality evidence), hospital mortality (two trials, 91 participants, RR 1.00; 95% CI 0.38 to 2.65; GRADE: very low quality evidence), length of ICU stay (one trial, 30 participants, MD 1.6 days; 95% CI -0.88 to 4.08 days; GRADE: very low quality evidence) and antibiotic use (two trials, 91 participants, RR 1.11; 95% CI 0.84 to 1.47). No adverse events were reported. AUTHORS' CONCLUSIONS: A semi-recumbent position (? 30o) may reduce clinically suspected VAP compared to a 0 degrees to 10 degrees supine position. However, the evidence is seriously limited with a high risk of bias. No adequate evidence is available to draw any definitive conclusion on other outcomes and the comparison of alternative semi-recumbent positions. Adverse events, particularly venous thromboembolism, were under-reported. PMID- 26743946 TI - The (elusive) role of the SMC5/6 complex. PMID- 26743948 TI - Physical Properties and Hydrogen-Bonding Network of Water-Ethanol Mixtures from Molecular Dynamics Simulations. AB - While many numerical and experimental works were focused on water-ethanol mixtures at low ethanol concentration, this work reports predictions of a few physical properties (thermodynamical, interfacial, dynamical, and dielectrical properties) of water-ethanol mixture at high alcohol concentrations by means of molecular dynamics simulations. By using a standard force field a good agreement was found between experiment and molecular simulation. This was allowed us to explore the dynamics, structure, and interplay between both hydrogen-bonding networks of water and ethanol. PMID- 26743947 TI - Pituitary apoplexy causing clival and spinal haematoma. PMID- 26743949 TI - Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults. AB - Many studies suggest that trimethylamine-N-oxide (TMAO), a gut-flora-dependent metabolite of choline, contributes to the risk of cardiovascular diseases, but little is known for non-alcoholic fatty liver disease (NAFLD). We examined the association of circulating TMAO, choline and betaine with the presence and severity of NAFLD in Chinese adults. We performed a hospital-based case-control study (CCS) and a cross-sectional study (CSS). In the CCS, we recruited 60 biopsy proven NAFLD cases and 35 controls (18-60 years) and determined serum concentrations of TMAO, choline and betaine by HPLC-MS/MS. For the CSS, 1,628 community-based adults (40-75 years) completed the blood tests and ultrasonographic NAFLD evaluation. In the CCS, analyses of covariance showed adverse associations of ln-transformed serum levels of TMAO, choline and betaine/choline ratio with the scores of steatosis and total NAFLD activity (NAS) (all P-trend <0.05). The CSS revealed that a greater severity of NAFLD was independently correlated with higher TMAO but lower betaine and betaine/choline ratio (all P-trend <0.05). No significant choline-NAFLD association was observed. Our findings showed adverse associations between the circulating TMAO level and the presence and severity of NAFLD in hospital- and community-based Chinese adults, and a favorable betaine-NAFLD relationship in the community-based participants. PMID- 26743951 TI - Light Higgs channel of the resonant decay of magnon condensate in superfluid (3)He-B. AB - In superfluids the order parameter, which describes spontaneous symmetry breaking, is an analogue of the Higgs field in the Standard Model of particle physics. Oscillations of the field amplitude are massive Higgs bosons, while oscillations of the orientation are massless Nambu-Goldstone bosons. The 125 GeV Higgs boson, discovered at Large Hadron Collider, is light compared with electroweak energy scale. Here, we show that such light Higgs exists in superfluid (3)He-B, where one of three Nambu-Goldstone spin-wave modes acquires small mass due to the spin-orbit interaction. Other modes become optical and acoustic magnons. We observe parametric decay of Bose-Einstein condensate of optical magnons to light Higgs modes and decay of optical to acoustic magnons. Formation of a light Higgs from a Nambu-Goldstone mode observed in (3)He-B opens a possibility that such scenario can be realized in other systems, where violation of some hidden symmetry is possible, including the Standard Model. PMID- 26743953 TI - WITHDRAWN: Effects of atorvastatin treatment and withdrawal on blood brain barrier in focal cerebral ischemia-reperfusion injury. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26743950 TI - Familial pachygyria in both genders related to a DCX mutation. AB - Doublecortin (DCX) and tubulin play critical roles in neuronal migration. DCX mutations usually cause anterior dominant lissencephaly in males and subcortical band heterotopia (SBH) in females. We used whole-exome sequencing to investigate causative gene variants in a large family with late-childhood-onset focal epilepsy and anterior dominant pachygyria without SBH in both genders. Two potential variants were found for the genes encoding DCX and beta tubulin isotype 1 (TUBB1). The novel DCX mutation (p.D90G, NP_000546.2) appeared to be a major causative variant, whereas the novel mutation of TUBB1 (p.R62fsX, NP_110400.1) was found only in patients with more-severe intellectual disability after gender matching. We report an unusual DCX-related disorder exhibiting familial pachygyria without SBH in both genders. PMID- 26743952 TI - Size-dependent cytotoxicity of silver nanoparticles in human neutrophils assessed by multiple analytical approaches. AB - AIMS: Silver nanoparticles (AgNPs) have emerged as an important class of nanomaterials with a wide range of industrial and medical applications. The assessment of AgNPs' biological effects in the human organism is therefore essential to evaluate the impact of these nanomaterials in public health and reassure the ratio benefit/risk. In the present study, the effect of polyvinyl pyrrolidone (PVP)-coated AgNPs with distinct sizes (10 and 50nm) on neutrophils' oxidative burst and toxicity were tested. MAIN METHODS: The effect of AgNPs on human neutrophils viability was evaluated by trypan blue, neutral red and propidium iodide methods. The measurement of neutrophils' oxidative burst was performed using the probe dihydrorhodamine 123. The cytomorphological alterations of human neutrophils exposed to AgNPs were evaluated by optical microscopy and transmission electron microscopy. KEY FINDINGS: It was observed that PVP-coated AgNPs are toxic to human neutrophils being the 10nm AgNPs more toxic than the 50nm AgNPs. The smallest AgNPs lead to membrane damage, impaired lysosomal activity and induce neutrophils' oxidative burst. Despite the production of reactive species, the toxicity of AgNPs is not NADPH oxidase-dependent. SIGNIFICANCE: These data indicate that AgNPs are toxic to human neutrophils in concentration-, time- and size-dependent manner, but independent of NADPH oxidase activation. PMID- 26743954 TI - Effort-Reward Imbalance and Post-Traumatic Stress After a Workplace Terror Attack. AB - OBJECTIVE: Following adverse work conditions, health consequences can be explained by an imbalance between the effort made and the reward received. We investigated the association between extra effort, perceived reward, and post traumatic stress disorder (PTSD). The Effort-Reward Imbalance Model was used to examine whether extra effort at work in the aftermath of a workplace-related terrorist attack affected the risk of PTSD and the effects of reward for extra effort from a leader or colleagues. METHODS: Cross-sectional data were collected 10 months after a terrorist attack in Norway in 2011. Out of 3520 Ministry employees invited, 1927 agreed to participate. Employees reported any extra effort performed as a result of the bomb explosion and any reward received from a leader or colleagues. PTSD was assessed with the PTSD Checklist. RESULTS: Employees who reported extra effort displayed increased risk for PTSD (odds ratio [OR]=1.71, 95% confidence interval [CI]: 1.15-2.55, P=0.008). Perceived reward for extra effort from a leader was associated with lower risk for PTSD (OR=0.39, 95% CI: 0.23-0.64, P<0.001) but not perceived reward from colleagues. CONCLUSIONS: Extra effort may increase the risk of PTSD, but reward from a leader may mitigate this effect. The Effort-Reward Imbalance Model appears to be an appropriate approach that may contribute to understanding of the etiology of work related PTSD. PMID- 26743955 TI - Stratification of Treatment in a Community-Based Musculoskeletal Service: A Mixed Methods Study to Assess Predictors of Requiring Complex Care. AB - OBJECTIVE: To explore factors that might be relevant when designing a triage tool. DESIGN: A mixed-methods study using multivariable logistic regression analysis to identify significant factors associated with requiring different levels of care, and qualitative focus groups exploring views of patients and physiotherapy clinicians regarding case complexity. SETTING: A community-based adult musculoskeletal service delivering tier 1 (standard physiotherapy) and tier 2 care (complex care beyond the scope of standard physiotherapy) and providing onward referral to orthopedic clinics (tier 3). PARTICIPANTS: Quantitative data were extracted from a random sample of patients (N=484) who had received treatment for musculoskeletal conditions. Patients and physiotherapists who had received care or who worked in the service participated in focus groups. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Themes that emerged from focus groups were compared against predictors of requiring complex care found to be significant (P<.05) after quantitative data analysis. RESULTS: A total of 184 patients (38.0%; 95% confidence interval, 33.8-42.4) received complex care. Peripheral joint problems, unclear diagnosis, and symptoms affecting sleep were significant independent predictors of requiring complex care. These data supported some of the main themes raised at focus groups. CONCLUSIONS: A substantial proportion of patients receive tier 2 complex care. Further studies are needed to evaluate whether the predictive factors found to be significant in our study might be useful for developing a tool for more effective triage to the most appropriate tier of musculoskeletal care. PMID- 26743956 TI - Cerium oxide nanoparticles exhibit minimal cardiac and cytotoxicity in the freshwater fish Catostomus commersonii. AB - Metal oxide nanomaterials can cause oxidative, cardiorespiratory, and osmoregulatory stress in freshwater fish. In contrast, cerium oxide nanoparticles (nCeO2) can have antioxidant effects but their aquatic toxicity has not been fully characterized. Heart rate and heart rate variability were followed in white sucker (Catostomus commersonii) acutely exposed to 1.0 mg L(-1) nCeO2 for 25 h. Malondialdehyde (MDA) was measured to assess oxidative tissue damage, and plasma cortisol, glucose, lactate, and osmolality were assessed as indicators of physiological and osmoregulatory stress. There was no MDA accumulation in gill or heart of fish exposed to nCeO2 and heart function was unchanged over the 25 h treatment. Plasma cortisol increased 6-fold but there was no change in plasma glucose or lactate. Cellular osmoregulatory toxicity was studied using an isolated red blood cell (RBC) model. In vitro exposure to 1.0 mg L(-1) nCeO2 for 1h had no effect on cell morphological parameters and did not sensitize RBCs to hemolysis under hypotonic stress. Overall, there were no indications of oxidative, cardiorespiratory, or osmoregulatory stress following acute exposure to nCeO2. Elevated plasma cortisol levels suggest that nCeO2 may exert mild toxicity to tissues outside of the cardiorespiratory system. PMID- 26743958 TI - Daily rhythms of the expression of genes from the somatotropic axis: The influence on tilapia (Oreochromis niloticus) of feeding and growth hormone administration at different times. AB - The aim of this research was to investigate the presence of daily rhythms in the somatotropic axis of tilapia fed at two times (mid-light, ML or mid-dark, MD) and the influence of the time of day of growth hormone (GH) administration on the response of this axis. Two different GH injection times were tested: ZT 3 (3h after lights on) and ZT 15 (3h after lights off). In both experiments, the mRNA expression levels of hypothalamic pituitary adenylate cyclase-activating polypeptide (pacap), pituitary growth hormone (gh), liver insulin-like growth factors (igf1 and igf2a), and liver and muscle growth hormone receptors (ghr1 and ghr2) and IGF receptors (igf1ra and igf2r) were evaluated by means of qPCR. Daily rhythms were observed in the liver for ghr1, ghr2 and igf2r but only in fish fed at ML, with the acrophases located in the light phase (ZT 3:30, 3:31 and 7:38 h, respectively). In the muscle, ghr1 displayed a significant rhythm in both groups and ghr2 in ML fed fish (acrophases at ZT 5:29, 7:14 and 9:23h). The time of both GH administration and feeding influenced the response to GH injection: ML fed fish injected with GH at ZT 15 h showed a significant increase in liver igf1, igf2a and ghr2; and muscle ghr2 expression. This is the first report that describes the existence of daily rhythms in the somatotropic axis of tilapia and its time-dependent responses of GH administration. Our results should be considered when investigating the elements of the somatotropic axis in tilapia and GH administration. PMID- 26743957 TI - Peroxisome proliferator-activated receptors and biotransformation responses in relation to condition factor and contaminant burden in tilapia species from Ogun River, Nigeria. AB - A major development in fishery science has been the Fulton's condition factor (CF) as a reliable physiological index of fish growth and health status (Fulton 1902). As a general rule, CF-value greater than 1 (>1) should be regarded as an indicator for good growth and health. Therefore, exposure of fish to contaminants in the environment will be expected to produce a reduction in scope for growth, since energy for growth will be allocated to overcome stressful conditions. In the present study, we hypothesized that tilapia species from Ogun River (Nigeria) are experiencing severe contaminant-induced obesogen effects leading to high CF (>= 2) in fish with pathological alterations. The environmental obesogen hypothesis has related the interaction between environmental pollutants and PPAR isoform activation In this respect, peroxisome proliferator-activated receptors (PPARs) and biotransformation responses in relation to contaminant burden were investigated in a total of 1074 specimens of Tilapias species (Tilapia guineensis, Sarotherodon galileaus and Oreochromis niloticus) collected from three areas with different degrees of anthropogenic contamination and from a putative control site along the Ogun River. Liver mRNA expression of cytochrome cyp1 isoforms (cyp1a, 1b and 1c) and PPAR isoforms (ppar-alpha, beta and gamma) were analyzed using validated real-time PCR. Fish were also analyzed for CF and muscle contaminant burden (aliphatic and polycyclic aromatic hydrocarbons, organochlorine pesticides, and polychlorinated biphenyls). A significant increase in mRNA expression of cyp1- and ppar isoforms was observed in fish from polluted areas, and these results paralleled data on PCBs and PAHs tissue concentrations. Further, cyp1 isoforms showed clear sex-related differences, with higher mRNA expression in male fish than in females. Principal component analysis revealed a relationship between cyp1 isoforms, ppar-alpha, beta, PCBs and PAHs and these interactions may suggest a crosstalk between AhR- and PPARs mediated pathways on metabolic and energetic processes. The PCA biplot also highlighted a positive relationship between ppar-gamma, body weight, total length and PAHs. The CF for fish from all the sites was >= 2 indicating that this parameter may not be a reliable index for evaluating fish growth and health condition, especially in wild fish population exposed to complex cocktails of environmental pollutants. PMID- 26743966 TI - Occlusal loading and cross-linking effects on dentin collagen degradation in physiological conditions. AB - OBJECTIVE: This study evaluated the ability of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) to improve the stability of demineralized dentin collagen matrices when subjected to mechanical cycling by means of Chewing Simulation (CS). METHODS: Demineralized dentin disks were randomly assigned to four groups (N=4): (1) immersion in artificial saliva at 37 degrees C for 30 days; (2) pre-treatment with 0.5 M EDC for 60 s, then stored as in Group 1; (3) CS challenge (50 N occlusal load, 30 s occlusal time plus 30 s with no load, for 30 days); (4) pre-treatment with 0.5 M EDC as in Group 2 and CS challenge as in Group 3. Collagen degradation was evaluated by sampling storage media for ICTP and CTX telopeptides. RESULTS: EDC treated specimens showed no significant telopeptides release, irrespective of the aging method. Cyclic stressing of EDC untreated specimens caused significantly higher ICTP release at day 1, compared to static storage, while by days 3 and 4, the ICTP release in the cyclic group fell significantly below the static group, and then remained undetectable from 5 to 30 days. CTX release in the cyclic groups, on EDC-untreated control specimens was always lower than in the static group in days 1-4, and then fell to undetectable for 30 days. SIGNIFICANCE: This study showed that chewing stresses applied to control untreated demineralized dentin increased degradation of collagen in terms of CTX release, while collagen crosslinking agents may prevent dentin collagen degradation, irrespective of simulated occlusal function. PMID- 26743967 TI - Mechanisms of degradation of the hybrid layer in adhesive dentistry and therapeutic agents to improve bond durability--A literature review. AB - OBJECTIVE: Success in adhesive dentistry means long lasting restorations. However, there is substantial evidence that this ideal objective is not always achieved. Current research in this field aims at increasing the durability of resin-dentin bonds. The objective of this paper is to examine the fundamental processes responsible for the aging mechanisms involved in the degradation of resin-bonded interfaces and the potential approaches to prevent and counteract this degradation. METHODS: PubMed searches on the hybrid layer degradation were carried out. Keywords were chosen to assess hybrid layer degradation for providing up-dated information on the basis of scientific coherence with the research objective. Approaches to prevent and counteract this degradation were also reviewed. RESULTS: 148 peer-review articles in the English language between 1982 and 2015 were reviewed. Literature shows that resin-dentin bond degradation is a complex process, involving the hydrolysis of both the resin and the collagen fibril phases contained within the hybrid layer. Collagen fibers become vulnerable to mechanical and hydraulic fatigue, as well as degradation by host derived proteases with collagenolytic activity (matrix metalloproteinases and cysteine cathepsins). Inhibition of the collagenolytic activity and the use of cross-linking agents are the two main strategies to increase the resistance of the hybrid layer to enzymatic degradation. SIGNIFICANCE: This review analyzes the issues regarding the durability of the adhesive interface, and the techniques to create stable resin-dentin bonds able to resist the collagenolytic hydrolysis that are currently studied. PMID- 26743965 TI - A self-setting iPSMSC-alginate-calcium phosphate paste for bone tissue engineering. AB - OBJECTIVES: Calcium phosphate cements (CPCs) are promising for dental and craniofacial repairs. The objectives of this study were to: (1) develop an injectable cell delivery system based on encapsulation of induced pluripotent stem cell-derived mesenchymal stem cells (iPSMSCs) in microbeads; (2) develop a novel tissue engineered construct by dispersing iPSMSC-microbeads in CPC to investigate bone regeneration in an animal model for the first time. METHODS: iPSMSCs were pre-osteoinduced for 2 weeks (OS-iPSMSCs), or transduced with bone morphogenetic protein-2 (BMP2-iPSMSCs). Cells were encapsulated in fast degradable alginate microbeads. Microbeads were mixed with CPC paste and filled into cranial defects in nude rats. Four groups were tested: (1) CPC-microbeads without cells (CPC control); (2) CPC-microbeads-iPSMSCs (CPC-iPSMSCs); (3) CPC microbeads-OS-iPSMSCs (CPC-OS-iPSMSCs); (4) CPC-microbeads-BMP2-iPSMSCs (CPC-BMP2 iPSMSCs). RESULTS: Cells maintained good viability inside microbeads after injection. The microbeads were able to release the cells which had more than 10 fold increase in live cell density from 1 to 14 days. The cells exhibited up regulation of osteogenic markers and deposition of minerals. In vivo, new bone area fraction (mean+/-SD; n=5) for CPC-iPSMSCs group was (22.5+/-7.6)%. New bone area fractions were (38.9+/-18.4)% and (44.7+/-22.8)% for CPC-OS-iPSMSCs group and CPC-BMP2-iPSMSCs group, respectively, 2-3 times the (15.6+/-11.2)% in CPC control at 12 weeks (p<0.05). Cell-CPC constructs accelerated scaffold resorption, with CPC-BMP2-iPSMSCs having remaining scaffold material that was 7 fold less than CPC control. SIGNIFICANCE: Novel injectable CPC-microbead-cell constructs promoted bone regeneration, with OS-iPSMSCs and BMP2-iPSMSCs having 2 3 fold the new bone of CPC control. Cell delivery accelerated scaffold resorption, with CPC-BMP2-iPSMSC having remaining scaffold material that was 7 fold less than CPC control. Therefore, CPC-microbead-iPSMSC is a promising injectable material for orthopedic, dental and craniofacial bone regenerations. PMID- 26743968 TI - Effect of resin and photoinitiator on color, translucency and color stability of conventional and low-shrinkage model composites. AB - OBJECTIVE: To study the effect of a low-shrinkage methacrylate monomer and monoacylphosphine oxide photoinitiator on color, translucency, and color stability of model resin-based composites (RBCs). METHODS: Four micro-hybrid RBCs were prepared containing barium-glass fillers in bisphenol A-glycidyl methacrylate (BisGMA) and triethyleneglycol-dimethacrylate (TEGDMA) or urethane based low-shrinkage monomer FIT-852 (FIT; Esstech Inc.) and TEGDMA matrix. Camphorquinone (CQ)/amine or Lucirin TPO were used as photoinitiators. Commercial low-shrinkage RBCs (Charisma Diamond, Heraeus Kulzer and N'Durance, Septodont) and conventional RBCs (Tetric EvoCeram, Ivoclar Vivadent and Filtek Z250, 3M ESPE) were used as controls. Color and translucency were measured using Thermo Scientific Evolution (Thermo Fisher Scientific) and SpectroShadeTM Micro (MHT Optic Research) spectrophotometers. Color stability was evaluated after immersion in black tea (pure, with milk or lemon) and distilled water. Data were analyzed using analyses of variance with Tukey's post-test (alpha=0.05). RESULTS: Photoinitiators had no significant effect on baseline color. Initially whiter FIT based RBCs showed greater staining in all staining solutions than BisGMA-based RBCs. TPO-containing RBCs showed better color stability than CQ-containing RBCs irrespective of the base monomer. Tea and tea with lemon induced greatest color changes. Adding milk to tea significantly reduced material staining. SIGNIFICANCE: Urethane-based low-shrinkage monomer FIT and conventional BisGMA affected color, translucency and color stability of their respective RBCs. Despite being used in posterior teeth, low-shrinkage RBCs are expected to have favorable optical and esthetic properties. Manufacturers are urged to provide information on optical properties of monomers and monomer mixtures in their low shrinkage RBCs to allow understanding of interaction with fillers and photoinitiators. PMID- 26743969 TI - Novel self-healing dental resin with microcapsules of polymerizable triethylene glycol dimethacrylate and N,N-dihydroxyethyl-p-toluidine. AB - OBJECTIVE: Bulk fracture is one of the primary reasons for resin-based dental restoration failures. To date, there has been no report on the use of polymerizable dental monomers with acceptable biocompatibility to develop a resin with substantial self-healing capability. The objectives of this study were to: (1) develop a self-healing resin containing microcapsules with triethylene glycol dimethacrylate (TEGDMA)-N,N-dihydroxyethyl-p-toluidine (DHEPT) healing liquid in poly(urea-formaldehyde) (PUF) shells for the first time, and (2) determine the physical and mechanical properties, self-healing efficiency, and fibroblast cytotoxicity. METHODS: Microcapsules of polymerizable TEGDMA-DHEPT in PUF were prepared via an in situ polymerization method. Microcapsules were added into a BisGMA-TEGDMA resin at microcapsule mass fractions of 0%, 5%, 10%, 15% and 20%. A flexural test was used to measure composite strength and elastic modulus. A single edge V-notched beam method was used to measure fracture toughness KIC and self-healing efficiency. RESULTS: Flexural strength and elastic modulus (mean+/ sd; n=6) of resin containing 5-15% microcapsules were similar to control without microcapsules (p>0.1). Adding microcapsules into the resin increased the virgin KIC, which was about 40% higher at 15% microcapsules than that with 0% microcapsules (p<0.05). Specimens were fractured and healed, then fractured again to measure the healed KIC. A self-healing efficiency of about 65% in KIC recovery was obtained with 10-20% microcapsules. All specimens with 0-20% microcapsules had fibroblast viability similar to control without resin eluents (p>0.1). SIGNIFICANCE: Self-healing dental resin containing microcapsules with polymerizable TEGDMA-DHEPT healing liquid in PUF shells were prepared for the first time with excellent self-healing capability. These microcapsules and self healing resins containing them may be promising for dental restorations to heal cracks/damage and increase durability. PMID- 26743971 TI - Cost-of-illness analysis and regression modeling in cystic fibrosis: a retrospective prevalence-based study. AB - BACKGROUND: Economic data pertaining to cystic fibrosis (CF), is limited in Europe generally, and completely lacking in Central and Eastern Europe. We performed an analysis of all direct costs associated with CF relative to key disease features and laboratory examinations. METHODS: A retrospective prevalence based cost-of-illness (COI) study was performed in a representative cohort of 242 CF patients in the Czech Republic, which represents about 65 % of all Czech CF patients. Medical records and invoices to health insurance companies for reference year 2010 were analyzed. RESULTS: The mean total health care costs were ?14,486 per patient, with the majority of the costs going towards medicinal products and devices (?10,321). Medical procedures (?2676) and inpatient care (?1829) represented a much smaller percentage of costs. A generalized linear model showed that the strongest cost drivers, for all cost categories, were associated with patient age and lung disease severity (assessed using the FEV1 spirometric parameter), when compounded by chronic Pseudomonas aeruginosa airway infections. Specifically, maximum total costs are around the age 16 years; a FEV1 increase of 1 % point represented a cost decrease of: 0.9 % (medicinal products), 1.7 % (total costs), 2.8 % (procedures) and 7.0 % (inpatient care). CONCLUSIONS: COI analysis and regression modeling using the most recent data available can provide a better understanding of the overall economic CF burden. A comparison of our results with other methodologically similar studies demonstrates that although overall costs may differ, FEV1 can nonetheless be utilized as a generally transferrable indicator of the relative economic impact of CF. PMID- 26743970 TI - Novel rechargeable calcium phosphate dental nanocomposite. AB - OBJECTIVES: Calcium phosphate (CaP) composites with Ca and P ion release can remineralize tooth lesions and inhibit caries. But the ion release lasts only a few months. The objectives of this study were to develop rechargeable CaP dental composite for the first time, and investigate the Ca and P recharge and re release of composites with nanoparticles of amorphous calcium phosphate (NACP) to achieve long-term inhibition of caries. METHODS: Three NACP nanocomposites were fabricated with resin matrix of: (1) bisphenol A glycidyl dimethacrylate (BisGMA) and triethylene glycol dimethacrylate (TEGDMA) at 1:1 mass ratio (referred to as BT group); (2) pyromellitic glycerol dimethacrylate (PMGDM) and ethoxylated bisphenol A dimethacrylate (EBPADMA) at 1:1 ratio (PE group); (3) BisGMA, TEGDMA, and Bis[2-(methacryloyloxy)ethyl] phosphate (BisMEP) at 2:1:1 ratio (BTM group). Each resin was filled with 20% NACP and 50% glass particles, and the composite was photo-cured. Specimens were tested for flexural strength and elastic modulus, Ca and P ion release, and Ca and P ion recharge and re-release. RESULTS: NACP nanocomposites had strengths 3-fold of, and elastic moduli similar to, commercial resin-modified glass ionomer controls. CaP ion recharge capability was the greatest for PE group, followed by BTM group, with BT group being the lowest (p<0.05). For each recharge cycle, CaP re-release reached similarly high levels, showing that CaP re-release did not decrease with more recharge cycles. After six recharge/re-release cycles, NACP nanocomposites without further recharge had continuous CaP ion release for 42 d. SIGNIFICANCE: Novel rechargeable CaP composites achieved long-term and sustained Ca and P ion release. Rechargeable NACP nanocomposite is promising for caries-inhibiting restorations, and the Ca and P ion recharge and re-release method has wide applicability to dental composites, adhesives, cements and sealants to achieve long-term caries inhibition. PMID- 26743972 TI - An improved approach to align and embed multiple brain samples in a gelatin-based matrix for simultaneous histological processing. AB - BACKGROUND: Preparation and processing of free-floating histological sections involve a series of steps. The amount of labor, particularly sectioning and mounting, quickly multiplies as the number of samples increases. Embedding tissue samples in a flexible matrix allows simultaneous handling of multiple samples and preserves the integrity of the tissue during histological processing. However, aligning multiple asymmetrical samples, for example small-animal brains, in a particular orientation requires skillful arrangement and securing of the samples by pinning onto a solid surface. Consequently, costly technical services offered by contract research organizations are often sought. NEW METHOD: An improved approach to align and embed multiple whole or half rodent brain samples into a gelatin-based matrix is described. Using a template specifically designed to form arrayed mouse brain-shaped cavities, a "receiving matrix" is prepared. Inserting brain samples directly into the cavities allows the samples to be effortlessly positioned into a uniform orientation and embedded in a block of matrix. RESULTS: Multiple mouse brains were arrayed in a uniform orientation in a gelatin matrix block with ease using the receiving matrix. The gelatin-embedded brains were simultaneously sectioned and stained, and effortlessly mounted onto glass slides. COMPARISON WITH EXISTING METHODS: The improved approach allowed multiple whole or half mouse brains to be easily arrayed without pinning the samples onto a solid surface and prevented damages or shifting of the samples during embedding. CONCLUSIONS: The new approach to array multiple brain samples provides a simple way to prepare gelatin-embedded whole or half brain arrays of commercial quality. PMID- 26743974 TI - Machine learning on Parkinson's disease? Let's translate into clinical practice. AB - Machine learning techniques represent the third-generation of clinical neuroimaging studies where the principal interest is not related to describe anatomical changes of a neurological disorder, but to evaluate if a multivariate approach may use these abnormalities to predict the correct classification of previously unseen clinical cohort. In the next few years, Machine learning will revolutionize clinical practice of Parkinson's disease, but enthusiasm should be turned down before removing some important barriers. PMID- 26743973 TI - Improved segmentation of cerebellar structures in children. AB - BACKGROUND: Consistent localization of cerebellar cortex in a standard coordinate system is important for functional studies and detection of anatomical alterations in studies of morphometry. To date, no pediatric cerebellar atlas is available. NEW METHOD: The probabilistic Cape Town Pediatric Cerebellar Atlas (CAPCA18) was constructed in the age-appropriate National Institute of Health Pediatric Database asymmetric template space using manual tracings of 16 cerebellar compartments in 18 healthy children (9-13 years) from Cape Town, South Africa. The individual atlases of the training subjects were also used to implement multi atlas label fusion using multi atlas majority voting (MAMV) and multi atlas generative model (MAGM) approaches. Segmentation accuracy in 14 test subjects was compared for each method to 'gold standard' manual tracings. RESULTS: Spatial overlap between manual tracings and CAPCA18 automated segmentation was 73% or higher for all lobules in both hemispheres, except VIIb and X. Automated segmentation using MAGM yielded the best segmentation accuracy over all lobules (mean Dice Similarity Coefficient 0.76; range 0.55-0.91; mean Hausdorff distance 0.9 mm; range 0.8-2.7 mm). COMPARISON WITH EXISTING METHODS: In all lobules, spatial overlap of CAPCA18 segmentations with manual tracings was similar or higher than those obtained with SUIT (spatially unbiased infra tentorial template), providing additional evidence of the benefits of an age appropriate atlas. MAGM segmentation accuracy was comparable to values reported recently by Park et al. (Neuroimage 2014;95(1):217) in adults (across all lobules mean DSC=0.73, range 0.40-0.89). CONCLUSIONS: CAPCA18 and the associated multi subject atlases of the training subjects yield improved segmentation of cerebellar structures in children. PMID- 26743975 TI - Kaffir lime leaves extract inhibits biofilm formation by Streptococcus mutans. AB - OBJECTIVES: Although kaffir lime has been reported to exhibit antioxidant and antileukemic activity, little is known about the antimicrobial effect of kaffir lime extract. Because Streptococcus mutans has been known to cause biofilm formation, it has been considered the most important causative pathogen of dental caries. Thus, the effective control of its effects on the oral biofilm is the key to the prevention of dental caries. The aims of the present study were to investigate the effect of kaffir lime leaves extract on biofilm formation and its antibacterial activity on S. mutans. METHODS: We examined the effect of kaffir lime leaves extract on growth and biofilm formation of S. mutans. For the investigation we used a kaffir lime extract with high phenolic content. The minimum inhibitory concentration of the extract was determined by broth microdilution assay. The inhibitory effect of the test substances on biofilm formation was also investigated by biofilm formation assay and qRT-PCR of biofilm formation-associated genes. RESULTS: Kaffir lime leaves extract inhibits the growth of S. mutans, corresponding to the activity of an antibiotic, ampicillin. Formation of biofilm by S. mutans was also inhibited by the extract. These results were confirmed by the down-regulation of genes associated with the biofilm formation. CONCLUSIONS: The findings highlight the ability of kaffir lime leaves extract to inhibit S. mutans activity, which may be beneficial in the prevention of biofilm formation on dental surface, reducing dental plaque and decreasing the chance of dental carries. PMID- 26743976 TI - The association of excessive growth with development of general and central obesity at 7 years of age in every period after birth in Chilean children. AB - OBJECTIVE: To determine whether overweight or obesity between 0 and 6 y increases the probability of developing general/central obesity at 7 y. METHODS: Weight, height, and waist circumference were assessed between 0 and 6 y in 628 Chilean children. Body mass index, incidence of overweight (IOW), incidence of obesity (IOB), and prevalence at birth and 0 to 6, 6 to 24, 24 to 48, and 48 to 72 mo and odds ratio (OR) and 95% confidence interval (95% CI) for developing obesity/central obesity at 84 mo were calculated by sex. RESULTS: IOW was highest at 6 to 24 mo (20.3% and 21.1% for girls and boys, respectively); IOB was highest at 6 to 24 and 24 to 48 mo (11% and 10%, respectively). OR for developing obesity at 7 y was significant if overweight was present 24 to 48 mo in girls and 6 to 24 mo in boys OR 2.47 [95% CI, 1.5-4] and OR 2.26 [95% CI, 1.30-3.92], respectively, and much higher for children who were obese, OR 6.1 (95% CI, 3.03-12.21) for girls 6 to 24 mo and OR 6.57 (95% CI, 2.55-16.86) for boys 0 to 6 mo. IOW or IOB was not associated with obesity at 84 mo, except for the previous period. Overweight also increased the risk of central obesity very early on, after 6 mo in girls and after birth in boys OR 3.8 [95% CI, 2.3-6.2] and OR 2.5 [95% CI, 2.04-3] at 6 to 24 and 0 to 6 mo, respectively, whereas obesity in all periods was associated with a significantly higher OR of presenting central obesity at 7 y. CONCLUSION: There is tracking not only of obesity but also of overweight after birth for developing general or central obesity at 7 y. Prevention should begin very early on. PMID- 26743978 TI - [Distribution and Scattering of APHAB Answers Before and After Hearing Aid Fitting]. AB - Objective: Questionnaires are an important diagnostic elements in audiology. In Germany the APHAB is regularly used for hearing aid fitting. This study is investigating whether there are any specific questions which are answered more rarely by the subjects than other and whether inverted questions have any influence to this. Methods: Between April 2013 and August 2015 the number of 23 557 APHAB forms by 10 associations of statutory health insurance registered physicians have been collected and evaluated. For all questions the frequency of answers before and after hearing aid fitting have been determined. Results: For the EC scale there was one group of patients without hearing aid which a lot of problems of hearing and a second without. For the BN and RV subscale the majority of the patients addresses problems of understanding. For the AV scale no specific kind of problems found has been found. After successful hearing aid fitting problems of understanding for EC, BN, and RV subscale were reduced on average, for the AV scale no relevant change could be observed. Except for the numbers 11, 18, and 21 all APHAB questions were answered by 93-94% by all subjects. The questions number 11 and 18 were answered by 92%, question number 21 by 87%. Some questions have a similar tendency in deviation from the average (1, 3, 13, 16, and 17). Conclusions: Inverted questions have no influence to the frequency of answers in APHAB questions. The 3 questions which are answered more rarely are describing hearing situations in cinemas, theatres, and at church. Presumably, this hearing situations are not so common for most patients than the other described by the APHAB. PMID- 26743977 TI - [Voice Self-Concept (FESS) in Medical Students]. AB - Introduction: The questionnaire "Fragebogen zur Erfassung des stimmlichen Selbstkonzepts (FESS)" was published in 2015 by Nusseck et al. It consists of 17 items measuring 3 scales on voice related self-concept. This paper examines the distribution of scale values in young adults by examination of medical students. Material and Methods: 96 FESS questionnaires were filled in by medical students. An additional item was added, stating whether it felt easy to answer the questionnaire. The distribution of the scales as well as percentile ranks are given in the paper. Results: In all 3 scales there were no significant differences between females and males, therefore they were analysed as one group. The distributions of all 3 scales show no relevant ceiling nor floor effects. Probands with lower scores in 2 of the three scales found it less easy to answer the questions. Discussion: The results encourage the use of the questionnaire in patients. There was no indication of relevant floor or ceiling effects and there was enough variance in each scale. If used in patients further investigation is needed on the result that patients with lower scores tend to find it more difficult to fill in the questionnaire. The percentile ranks published herein are valid for medical students at this stage. Until bigger normative data on more diverse populations are conducted we will use these data as an orientation to judge other young adults' scores, too. PMID- 26743979 TI - [Cost Analysis of Cochlear Implantation in Adults]. AB - OBJECTIVE: The number of implantation of cochlear implants has steadily risen in recent years. Reasons for this are an extension of indication criteria, demographic change, increased quality of life needs and greater acceptance. The consequences are rising expenditure for statutory health insurance (SHI) for cochlear implantation. A detailed calculation of lifetime costs from SHI's perspective for postlingually deafened adolescents and adults is essential in estimating future cost developments. METHODS: Calculations are based on accounting data from the Hannover Medical School. With regard to further life expectancy, average costs of preoperative diagnosis, surgery, rehabilitation, follow-ups, processor upgrades and electrical maintenance were discounted to their present value at age of implantation. RESULTS: There is an inverse relation between cost of unilateral cochlear implantation and age of initial implantation. From SHI's perspective, the intervention costs between 36,001 and 68,970 ? ($ 42,504-$ 81,429). The largest cost components are initial implantation and processor upgrades. CONCLUSION: Compared to the UK the cost of cochlear implantation in Germany seems to be significantly lower. In particular the costs of, rehabilitation and maintenance in Germany cause only a small percentage of total costs. Also, the costs during the first year of treatment seem comparatively low. With regard to future spending of SHI due to implant innovations and associated extension of indication, increasing cost may be suspected. PMID- 26743980 TI - Up-regulation of cytosolic tryparedoxin in Amp B resistant isolates of Leishmania donovani and its interaction with cytosolic tryparedoxin peroxidase. AB - Leishmania is a unicellular protozoan parasite which causes leishmaniasis, a neglected tropical disease. It possess a unique thiol metabolism comprising of several proteins among which, tryparedoxin (cTXN) and tryparedoxin peroxidase (cTXNPx), function in concert as oxidoreductases, utilizing trypanothione as a source of electrons to reduce the hydroperoxides produced by macrophages during infection. This detoxification pathway is unique and essential for the survival of Leishmania. Herein, we report the functional characterization of Leishmania donovani cTXN and its interaction with cTXNPx. The full length recombinant cTXN and cTXNPx proteins were purified in the native state and biochemical analysis showed that the cTXN-cTXNPx coupled system efficiently degraded hydrogen peroxide and tert-butyl hydroperoxide by transferring reducing equivalents from trypanothione. In silico investigation of the potential interaction between cTXN and cTXNPx proteins showed strong interaction of model structures with amino acids Ile109, Thr132, Glu107, Trp70, Trp39, Cys40 and His129 of Ld-cTXN and Thr54, Lys93, Arg128 and Asn152 of Ld-cTXNPx predicted to be involved in interaction. Moreover, co-purification, pull down assay and immunoprecipitation studies confirmed the interaction between Ld-cTXN and Ld-cTXNPx proteins. In addition, for the first time, we demonstrated at the translational level that Ld cTXN protein is upregulated in Amp B resistant isolates accompanied by enhanced peroxidase activity, as compared to sensitive strains. Thus, our results show that Ld-cTXN and Ld-cTXNPx proteins acts in concert by physical interaction to form a strong peroxide stress detoxification system in Leishmania and their upregulation in Amp B resistant isolates imparts better stress tolerance, and hence fitter pathogens, as compared to sensitive strains. PMID- 26743981 TI - A Decade of ChemMedChem. AB - Happy birthday! Issue 01/2016 marks the 10th anniversary of ChemMedChem. With a complete set of 10 volumes, the Editorial Team takes a look back at how the journal, and indeed the field of medicinal chemistry, have evolved and changed over the past decade. PMID- 26743983 TI - Presepsin (sCD14-ST) secretion and kinetics by peripheral blood mononuclear cells and monocytic THP-1 cell line. AB - Presepsin could help for early diagnosis of systemic infection. Little is known regarding its kinetics. We studied presepsin concentration after challenge with bacterial agonist lipopolysaccharide (LPS) stimulation in peripheral mononuclear cells (PMNC) collected from 5 healthy volunteers and in a human cell line of monocytic cells (THP1). In PMNC, an exposure to LPS (100 ng/mL) induced an increase of median presepsin levels as early as hour 1 (+31%, p=0.007), concomitantly to IL-6 synthesis. In THP1 cells, presepsin was detected at 1 hour after LPS exposure, and peaked at 3 hours, in THP1 cells. In conclusion, we report here that presepsin, a surrogate marker of the host response to bacteria, increases early in PMNC and in a monocytic cell lineage. Our findings might confirm the potential usefulness of presepsin bedside as an early marker of infectious diseases. PMID- 26743984 TI - The Epigenetic Reprogramming Roadmap in Generation of iPSCs from Somatic Cells. AB - Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) is a comprehensive epigenetic process involving genome-wide modifications of histones and DNA methylation. This process is often incomplete, which subsequently affects iPSC reprogramming, pluripotency, and differentiation capacity. Here, we review the epigenetic changes with a focus on histone modification (methylation and acetylation) and DNA modification (methylation) during iPSC induction. We look at changes in specific epigenetic signatures, aberrations and epigenetic memory during reprogramming and small molecules influencing the epigenetic reprogramming of somatic cells. Finally, we discuss how to improve iPSC generation and pluripotency through epigenetic manipulations. PMID- 26743986 TI - Characterization of a Putative New Semi-Dominant Reduced Height Gene, Rht_NM9, in Wheat (Triticum aestivum L.). AB - Plant height is an important agronomic trait in cereal crops, and can affect both plant architecture and grain yield. New dwarfing genes are required for improving the genetic diversity of wheat. In this study, a novel dwarf mutant, NM9, was created by treating seeds of the wheat variety NAU9918 with ethyl methanesulfonate (EMS). NM9 showed obvious phenotypic changes, which were distinct from those caused by other dwarfing genes, especially the reduced plant height, increased effective tiller number, and elongated spike and grain length. The reduced plant height in NM9 was attributable to a semi-dominant dwarfing gene Rht_NM9, which was flanked by two closely linked SNP markers, SNP34 and SNP41, covering an 8.86-Mb region on the chromosome arm 2AS. The results of gibberellic acid (GA) sensitivity evaluation, comparative genomics analysis and allelism test indicated that Rht_NM9 was neither allelic to Rht7 and Rht21 nor homoeoallelic to Rht8, so Rht_NM9 was proposed to be a new dwarfing locus on the homoeologous group 2 chromosomes of wheat. Rht_NM9 has a negative effect on plant height and positive effects on effective tiller number and grain size, thus, Rht_NM9 could be used for elucidating the mechanisms underlying plant architecture and grain development. PMID- 26743985 TI - Deletion of Mitochondrial Porin Alleviates Stress Sensitivity in the Yeast Model of Shwachman-Diamond Syndrome. AB - Shwachman-Diamond syndrome (SDS) is a multi-system disorder characterized by bone marrow failure, pancreatic insufficiency, skeletal abnormalities, and increased risk of leukemic transformation. Most patients with SDS contain mutations in the Shwachman-Bodian-Diamond syndrome gene (SBDS), encoding a highly conserved protein that has been implicated in ribosome biogenesis. Emerging evidence also suggests a distinct role of SBDS beyond protein translation. Using the yeast model of SDS, we examined the underlying mechanisms that cause cells lacking Sdo1p, the yeast SBDS ortholog, to exhibit reduced tolerance to various stress conditions. Our analysis indicates that the environmental stress response (ESR), heat shock response (HSR), and endoplasmic reticulum unfolded protein response (UPR) of sdo1Delta cells are functional and that defects in these pathways do not produce the phenotypes observed in sdo1Delta yeast. Depletion of mitochondrial DNA (mtDNA) was observed in sdo1Delta cells, and this is a probable cause of the mitochondrial insufficiency in SDS. Prior disruption of POR1, encoding the mitochondrial voltage dependent anion channel (VDAC), abrogated the effects of SDO1 deletion and substantially restored resistance to environmental stressors and protected against damage to mtDNA. Conversely, wild-type cells over expressing POR1 exhibited growth impairment and increased stress sensitivity similar to that seen in sdo1Delta cells. Overall, our results suggest that specific VDAC inhibitors may have therapeutic benefits for SDS patients. PMID- 26743987 TI - Isolation and Identification of a Functional Centromere Element in the Wild Rice Species Oryza granulata with the GG Genome. PMID- 26743988 TI - A Simple CRISPR/Cas9 System for Multiplex Genome Editing in Rice. PMID- 26743989 TI - Genome-Wide Analysis and Expression Patterns of the YUCCA Genes in Maize. PMID- 26743990 TI - Natural rubber latex allergy. PMID- 26743991 TI - Association between internet addiction and high-risk sexual attitudes in Chinese university students from Hong Kong and Macau. PMID- 26743992 TI - Re: Letter to the Editor of Public Health in response to Deurloo and Verkerk To screen or not to screen for adolescent idiopathic scoliosis? A review of the literature. PMID- 26743993 TI - Adaptive and Background-Aware GAL4 Expression Enhancement of Co-registered Confocal Microscopy Images. AB - GAL4 gene expression imaging using confocal microscopy is a common and powerful technique used to study the nervous system of a model organism such as Drosophila melanogaster. Recent research projects focused on high throughput screenings of thousands of different driver lines, resulting in large image databases. The amount of data generated makes manual assessment tedious or even impossible. The first and most important step in any automatic image processing and data extraction pipeline is to enhance areas with relevant signal. However, data acquired via high throughput imaging tends to be less then ideal for this task, often showing high amounts of background signal. Furthermore, neuronal structures and in particular thin and elongated projections with a weak staining signal are easily lost. In this paper we present a method for enhancing the relevant signal by utilizing a Hessian-based filter to augment thin and weak tube-like structures in the image. To get optimal results, we present a novel adaptive background aware enhancement filter parametrized with the local background intensity, which is estimated based on a common background model. We also integrate recent research on adaptive image enhancement into our approach, allowing us to propose an effective solution for known problems present in confocal microscopy images. We provide an evaluation based on annotated image data and compare our results against current state-of-the-art algorithms. The results show that our algorithm clearly outperforms the existing solutions. PMID- 26743994 TI - Maternal exposure to arsenic and cadmium and the risk of congenital heart defects in offspring. AB - Hair arsenic and cadmium from 339 women with congenital heart defect (CHD) affected pregnancies (case women) and 333 women with normal live births (control women) in China were estimated using inductively coupled plasma mass spectrometry. The median levels of hair arsenic and cadmium in the case women were 98.30 (74.30-136.30)ng/g and 14.60 (8.30-32.50)ng/g, respectively, which were significantly higher than the levels in the control group (P<0.05). Arsenic concentrations >=62.03ng/g were associated with increased risk for almost every CHD subtype, with a dose-response relationship. However, only the group with the highest cadmium levels (>=25.85ng/g) displayed an increased risk of CHDs (AOR 1.96; 95% CI 1.24-3.09), with a 2.81-fold increase found for the occurrence of conotruncal defects in their offspring. Furthermore, an interaction between arsenic and cadmium was observed. Our findings suggest that maternal exposure to arsenic and cadmium may be a significant risk factor for CHDs in offspring. Cadmium may have an enhancing effect on the association between arsenic and the risk of CHDs in offspring. PMID- 26743995 TI - Sampling artifacts in active air sampling of semivolatile organic contaminants: Comparing theoretical and measured artifacts and evaluating implications for monitoring networks. AB - The effects of sampling artifacts are often not fully considered in the design of air monitoring with active air samplers. Semivolatile organic contaminants (SVOCs) are particularly vulnerable to a range of sampling artifacts because of their wide range of gas-particle partitioning and degradation rates, and these can lead to erroneous measurements of air concentrations and a lack of comparability between sites with different environmental and sampling conditions. This study used specially adapted filter-sorbent sampling trains in three types of active air samplers to investigate breakthrough of SVOCs, and the possibility of other sampling artifacts. Breakthrough volumes were experimentally determined for a range of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and polybrominated diphenyl ethers (PBDEs) in sampling volumes from 300 to 10,000 m(3), and sampling durations of 1 7 days. In parallel, breakthrough was estimated based on theoretical sorbent vapor pressure relationships. The comparison of measured and theoretical determinations of breakthrough demonstrated good agreement between experimental and estimated breakthrough volumes, and showed that theoretical breakthrough estimates should be used when developing air monitoring protocols. Significant breakthrough in active air samplers occurred for compounds with vapor pressure >0.5 Pa at volumes <700 m(3). Sample volumes between 700 and 10,000 m(3) may lead to breakthrough for compounds with vapor pressures between 0.005 and 0.5 Pa. Breakthrough is largely driven by sample volume and compound volatility (therefore indirectly by temperature) and is independent of sampler type. The presence of significant breakthrough at "typical" sampling conditions is relevant for air monitoring networks, and may lead to under-reporting of more volatile SVOCs. PMID- 26743996 TI - Route towards Localization for Quantum Anomalous Hall Systems with Chern Number 2. AB - The quantum anomalous Hall system with Chern number 2 can be destroyed by sufficiently strong disorder. During its process towards localization, it was found that the electronic states will be directly localized to an Anderson insulator (with Chern number 0), without an intermediate Hall plateau with Chern number 1. Here we investigate the topological origin of this phenomenon, by calculating the band structures and Chern numbers for disordered supercells. We find that on the route towards localization, there exists a hidden state with Chern number 1, but it is too short and too fluctuating to be practically observable. This intermediate state cannot be stabilized even after some "smart design" of the model and this should be a universal phenomena for insulators with high Chern numbers. By performing numerical scaling of conductances, we also plot the renormalization group flows for this transition, with Chern number 1 state as an unstable fixed point. This is distinct from known results, and can be tested by experiments and further theoretical analysis. PMID- 26743997 TI - Failed cooperative, but not competitive, interaction between large-scale brain networks impairs working memory in schizophrenia. AB - BACKGROUND: A large-scale network named the default mode network (DMN) dynamically cooperates and competes with an external attention system (EAS) to facilitate various cognitive functioning that is prominently impaired in schizophrenia. However, it is unclear whether the cognitive deficit in schizophrenia is related to the disrupted competition and/or cooperation between these two networks. METHOD: A total of 35 schizophrenia patients and 30 healthy controls were scanned using gradient-echo echo-planar imaging during n-back working memory (WM) processing. Brain activities of the DMN and EAS were measured using general linear modelling of the functional magnetic resonance imaging data. Dynamic interaction between the DMN and EAS was decomposed into two directions using Granger causality analysis. RESULTS: We observed a significant failure of DMN suppression in patients with schizophrenia, which was significantly related to WM/attentional deficit. Granger causality modelling showed that in healthy controls, while the EAS inhibitorily influenced the DMN, the DMN exerted an 'excitatory' or cooperative influence back on the EAS, especially in those with lower WM accuracy. In schizophrenia, this 'excitatory' DMN->EAS influence within the reciprocal EAS-DMN loop was significantly reduced, especially in patients with WM/attentional deficit. CONCLUSIONS: The dynamic interaction between the DMN and EAS is likely to be comprised of both competitive and cooperative influences. In healthy controls, both the 'inhibitory' EAS->DMN interaction and 'excitatory' DMN->EAS interaction are correlated with WM performance. In schizophrenia, reduced 'cooperative' influence from the DMN to dorsal nodes of the EAS occurs in the context of non-suppression of the DMN and may form a possible pathophysiological substrate of WM deficit and attention disorder. PMID- 26743999 TI - Defra moves to replace statutory animal welfare codes. PMID- 26743998 TI - Liquid-Phase Beam Pen Lithography. AB - Beam pen lithography (BPL) in the liquid phase is evaluated. The effect of tip substrate gap and aperture size on patterning performance is systematically investigated. As a proof-of-concept experiment, nanoarrays of nucleotides are synthesized using BPL in an organic medium, pointing toward the potential of using liquid phase BPL to perform localized photochemical reactions that require a liquid medium. PMID- 26744000 TI - CBE for CVO in New Year honours list. PMID- 26744001 TI - BVA calls for innovation in capturing disease surveillance data. PMID- 26744002 TI - 'Numerous flaws' in antimicrobials report. PMID- 26744003 TI - VMD assesses the implications of colistin resistance in UK pigs. PMID- 26744004 TI - Wales tightens TB testing rules for cattle on common land. PMID- 26744005 TI - Bursary recipients present their research. PMID- 26744006 TI - Opportunities for vets in a society that eats less meat. AB - While global demand for meat is rising, there are signs in the UK that eating meat is becoming a more conscious choice for consumers. A debate at the BVA Congress at the London Vet Show explored the opportunities this might provide for vets, particularly with regard to improving animal welfare. Georgina Mills reports. PMID- 26744007 TI - Refining the process for electing the BVA's officers. PMID- 26744008 TI - Disease surveillance in England and Wales. AB - This issue of Veterinary Record introduces a new look for the monthly disease surveillance report for England and Wales from the APHA. The format and content has been changed to provide a report that brings together data and information from different sources of government-funded and other veterinary scanning surveillance activity. This first report in the new format considers current issues, such as actions to prevent porcine epidemic diarrhea and what to do if it is suspected, and provides an update on international disease threats, such as bluetongue and avian influenza. It also discusses the seasonal impact of porcine reproductive and respiratory syndrome virus in pig herds, and guidance for laboratory investigation of ovine abortion/stillbirths. Highlights from the scanning surveillance network for November/December 2015 are reported and, on p 43, a separate article describes the work of the Veterinary Risk Group. PMID- 26744009 TI - Identifying new and re-emerging animal-related threats to the UK. AB - The Veterinary Risk Group (VRG) plays a key role in the identification, assessment and management of new and re-emerging animal health-related threats in the UK. This article describes the work of VRG and provides an example of one such case. PMID- 26744010 TI - Preventing haemorrhage in equine guttural pouch mycosis. PMID- 26744011 TI - Risk factors and effect of selective removal on retroviral infections prevalence in Belgian stray cats. AB - The aim of this study was to evaluate the effect of several risk/protective factors and predictors on the prevalence of feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV) infections in 302 stray cats captured during a trap-neuter-release programme in a mixed urban-rural area from Belgium, from 2010 to 2012. The impact of selective removal of FIV-positive cats on the apparent prevalence in the remaining population over this three-year period was also assessed. The seroprevalences over three years were 18.8 per cent for FIV and 0.7 per cent for FeLV. For FIV, the seroprevalence decreased significantly from the first year of the programme (2010; 30.5 per cent) to the last (2012; 13.1 per cent). Sex (male) and age (adult and old cats) were risk factors, while the year of sampling (years 2011 and 2012) was a protective factor. Age, sex and location were the most relevant predictors of FIV status. The data presented in this study revealed a very high FIV seroprevalence in Belgian stray cats, while FeLV was almost absent. The selective removal of positive cats had a drastic effect on the FIV seroprevalence in the remaining cat population. PMID- 26744012 TI - Changes to the monthly APHA disease surveillance report in Veterinary Record. PMID- 26744013 TI - Employers' group. PMID- 26744014 TI - Making the most of a veterinary education. AB - Karen Hiestand grew up in New Zealand where the family business was dairy farming. Her desire to be a vet was fixed at the age of seven, but, after qualifying, the reality of practice wasn't quite what she expected. Having made the decision to move out of practice, she found that there are many other ways to use a veterinary education. PMID- 26744015 TI - Probing Supramolecular Interactions between a Crown Ether Appended Zinc Phthalocyanine and an Ammonium Group Appended to a C60 Derivative. AB - Self-assembly driven by crown ether complexation of zinc phthalocyanines equipped with one 18-crown-6 moiety and fullerenes bearing an ammonium head group afforded a novel donor-acceptor hybrid. In reference experiments, fullerenes containing a Boc-protected amine functionality have been probed. The circumvention of zinc phthalocyanine aggregation is important for the self-assembly, which required the addition of pyridine. From absorption and fluorescence titration assays, which provided sound and unambiguous evidence for mutual interactions between the electron donor and the electron acceptor within the hybrids, association constants in the order of 8.0*105 m-1 have been derived. The aforementioned is based on 1:1 stoichiometries, which have been independently confirmed by Job's plot measurements. In the excited state, which has been examined by transient absorption experiments, intermolecular charge separation evolves from the photoexcited zinc phthalocyanine to the fullerene subunit and leads to short lived charge-separated states. Interestingly, photoexcitation of zinc phthalocyanine dimers/aggregates can also be followed by an intermolecular charge separation between vicinal phthalocyanines. These multicomponent supramolecular ensembles have also been shown by in-depth electrospray ionization mass spectrometry (ESI-MS) studies, giving rise to the formation and detection of a variety of non-covalently linked species. PMID- 26744016 TI - Culturable endophytic bacterial communities associated with field-grown soybean. AB - AIMS: Assess the diversity of the culturable endophytic bacterial population associated with transgenic and nontransgenic soybean grown in field trial sites in Brazil and characterize them phenotypically and genotypically focusing on characteristics related to plant growth promotion. METHODS AND RESULTS: Endophytic bacteria were isolated from roots, stems and leaves of soybean cultivars (nontransgenic (C) and glyphosate-resistant (GR) transgenic soybean), including the isogenic BRS133 and BRS245RR. Significant differences were observed in bacterial densities in relation to genotype and tissue from which the isolates were obtained. The highest number of bacteria was observed in roots and in GR soybean. Based on characteristics related to plant growth promotion, 54 strains were identified by partial 16S rRNA sequence analysis, with most of the isolates belonging to the species Enterobacter ludwigii and Variovorax paradoxus. Among the isolates, 44.4% were able to either produce indoleacetic acid (IAA) or solubilize phosphates, and 9.2% (all from GR soybean) presented both plant growth promoting activities. CONCLUSIONS: The results from this study indicate that the abundance of endophytic bacterial communities of soybean differs between cultivars and in general it was higher in the transgenic cultivars than in nontransgenic cultivars. BRS 245 RR exhibited no significant difference in abundance compared to nontransgenic BRS133. This suggests that the impact of the management used in the GR soybean fields was comparable with the impacts of some enviromental factors. However, the bacterial endophytes associated to GR and nontransgenic soybean were different. The soybean-associated bacteria showing characteristics related to plant growth promotion were identified as belonging to the species Pantoea agglomerans and Variovorax paradoxus. SIGNIFICANCE AND IMPACT OF THE STUDY: Our study demonstrated differences concerning compostion of culturable endophytic bacterial population in nontransgenic and transgenic soybean. PMID- 26744017 TI - Identification of a novel hedycaryol synthase gene isolated from Camellia brevistyla flowers and floral scent of Camellia cultivars. AB - MAIN CONCLUSION: A novel terpene synthase (Tps) gene isolated from Camellia brevistyla was identified as hedycaryol synthase, which was shown to be expressed specifically in flowers. Camellia plants are very popular because they bloom in winter when other plants seldom flower. Many ornamental cultivars of Camellia have been bred mainly in Japan, although the fragrance of their flowers has not been studied extensively. We analyzed floral scents of several Camellia cultivars by gas chromatography-mass spectrometry (GC-MS) and found that Camellia brevistyla produced various sesquiterpenes in addition to monoterpenes, whereas Camellia japonica and its cross-lines produced only monoterpenes, including linalool as the main product. From a flower of C. brevistyla, we isolated one cDNA encoding a terpene synthase (TPS) comprised of 554 amino acids, which was phylogenetically positioned to a sole gene clade. The cDNA, designated CbTps1, was expressed in mevalonate-pathway-engineered Escherichia coli, which carried the Streptomyces mevalonate-pathway gene cluster in addition to the acetoacetate CoA ligase gene. A terpene product was purified from recombinant E. coli cultured with lithium acetoacetate, and analyzed by (1)H-nulcear magnetic resonance spectroscopy ((1)H-NMR) and GC-MS. It was shown that a sesquiterpene hedycaryol was produced, because (1)H-NMR signals of the purified product were very broad, and elemol, a thermal rearrangement product from hedycaryol, was identified by GC MS analysis. Spectroscopic data of elemol were also determined. These results indicated that the CbTps1 gene encodes hedycaryol synthase. Expression analysis of CbTps1 showed that it was expressed specifically in flowers, and hedycaryol is likely to be one of the terpenes that attract insects for pollination of C. brevistyla. A linalool synthase gene, which was isolated from a flower of Camellia saluenensis, is also described. PMID- 26744018 TI - Riluzole rescues alterations in rapid glutamate transients in the hippocampus of rTg4510 mice. AB - Those at risk for Alzheimer's disease (AD) often exhibit hippocampal hyperexcitability in the years preceding diagnosis. Our previous work with the rTg(TauP301L)4510 tau mouse model of AD suggests that this increase in hyperexcitability is likely mediated by an increase in depolarization-evoked glutamate release and a decrease in glutamate uptake, alterations of which correlate with learning and memory deficits. Treatment with riluzole restored glutamate regulation and rescued memory deficits in the TauP301L model. Here, we used enzyme-based ceramic microelectrode array technology to measure real-time phasic glutamate release and uptake events in the hippocampal subregions of TauP301L mice. For the first time, we demonstrate that perturbations in glutamate transients (rapid, spontaneous bursts of glutamate) exist in a tau mouse model of AD mouse model and that riluzole mitigates these alterations. These results help to inform our understanding of how glutamate signaling is altered in the disease process and also suggest that riluzole may serve as a clinically applicable therapeutic approach in AD. PMID- 26744019 TI - Relative bioaccessibility of Pb-based paint in soil. AB - The threat posed by lead (Pb) in soil for pediatric populations continues to be a public health issue. In long-established residential areas, a principal source of Pb in soil is likely to be old Pb-based paint originating from building surfaces. The health hazard posed by Pb from paint in soil will likely depend on quantity of paint incorporated, its Pb-mineral composition, whether the Pb is locked in some other material and the paint residence time in the soil (degree of aging). Here the relative bioavailability (RBA) of Pb in different types of Pb-bearing paint has been assessed. Tests were performed with individual paints, with paints mixed with a low-Pb soil, and with paints mixed with soil and the biogenic phosphate apatite II. Thirteen Pb-bearing paint samples were ground and passed through 250- and 100-um screens. Samples nominally <100 um from all the paints were analyzed, and six of the paints for which there was sufficient material in the 100- to 250-um-size range were also tested. RBA extraction of Pb employed a simulated gastric fluid (SGF) of HCl and glycine adjusted to a pH of 1.5 in which samples were agitated (in an end-over-end rotator) for 2 h. Original paints were examined by SEM/EDX, and by XRD, residues collected after RBA extraction were examined by SEM/EDX. The concentration of Pb in the extraction fluid was measured by AAS. The quantity of Pb mobilized in each test batch was approximately an order of magnitude less in the paint-soil mix compared to the corresponding paint only sample. The difference in the amount of Pb extracted from the paint-soil mix compared to the paint-soil-phosphate mix was minimal. However, in the post-RBA residues of the paint-soil mix, a PbCl precipitate was observed, and in the extraction residues of the paint-soil-apatite II mixes PbClP phases were recorded. Precipitation of these secondary phases obviously modified the amount of Pb in the extraction fluid, and this may need to be considered, i.e., under reporting of extractable Pb, when this form of in vitro extraction is used to determine the RBA of Pb in environmental media. PMID- 26744020 TI - Documented cutaneous loxoscelism in the south of France: an unrecognized condition causing delay in diagnosis. AB - BACKGROUND: Loxoscelism is an envenomation due to a bite by spiders of the genus Loxosceles, very well known on the American continent but unrecognized in Europe. CASE REPORT: We report the case of a 36-year-old woman, without any medical history or treatment, who went to a University Hospital in the South of France, for a painful skin lesion on the internal part of her left thigh, which appeared in the morning and developed rapidly during the day. She was directed to the infectious disease department with a diagnosis of skin infection. In spite of the antibiotics, the lesion increased, with a hemorrhagic central blister, an irregular ecchymotic center, a pale perimeter, and an extensive inflammatory and indurate oedema affecting the whole thigh. There was also a low-grade fever, chills, intense pain and a generalized scarlatiniform exanthema. The lesion was finally diagnosed as cutaneous loxoscelism, then confirmed by collection and identification of a Loxosceles rufescens spider killed by the patient the morning of the occurrence of the lesion. Following an initial symptomatic treatment, the development of a necrotic ulcer justified a delayed surgical reconstruction, after stabilization of the lesion. CONCLUSIONS: Loxosceles bites are usually painless and rarely noticed by patients, often leading to a presumptive diagnosis. Therefore, in the case of a dermonecrotic lesion developing unfavourably with antibiotics, cutaneous loxoscelism should be one of the diagnoses to be considered. PMID- 26744022 TI - Use of the Integrated Biomarker Response to Measure the Effect of Short-term Exposure to Dibenz[a,h]anthracene in Common carp (Cyprinus carpio). AB - Dibenz[a,h]anthracene (DbA) is a polycyclic aromatic hydrocarbon that is released into the environment through incomplete combustion of gasoline, cigarettes, and coal tar. The effects of short-term (10 days) exposure of common carp (Cyprinus carpio) to DbA (0-50 ug L(-1)) were evaluated using the following four biomarkers: DNA damage, 7-ethoxyresorufin-O-deethylase (EROD) activity, acetylcholinesterase (AChE) activity, and vitellogenin (VTG) levels. An integrated biomarker response (IBR) was calculated for exposure to DbA, and the results were compared with those in our previous study of two other PAHs, benzo[k]fluoranthene (BkF) and benzo[a]pyrene (BaP). DbA exposure resulted in a significant (p < 0.05) increase in DNA damage, EROD activity, and VTG levels relative to the control. By contrast, DbA did not affect AChE activity. The IBR increased as the concentration of DbA increased. Based on the IBR values, the order of toxicity for the PAHs was BkF > BaP > DbA. Our results suggest that the IBR can be used as a quantitative tool for evaluating the responses of multiple biomarkers to PAH exposure. PMID- 26744021 TI - Fast and accurate branch lengths estimation for phylogenomic trees. AB - BACKGROUND: Branch lengths are an important attribute of phylogenetic trees, providing essential information for many studies in evolutionary biology. Yet, part of the current methodology to reconstruct a phylogeny from genomic information - namely supertree methods - focuses on the topology or structure of the phylogenetic tree, rather than the evolutionary divergences associated to it. Moreover, accurate methods to estimate branch lengths - typically based on probabilistic analysis of a concatenated alignment - are limited by large demands in memory and computing time, and may become impractical when the data sets are too large. RESULTS: Here, we present a novel phylogenomic distance-based method, named ERaBLE (Evolutionary Rates and Branch Length Estimation), to estimate the branch lengths of a given reference topology, and the relative evolutionary rates of the genes employed in the analysis. ERaBLE uses as input data a potentially very large collection of distance matrices, where each matrix is obtained from a different genomic region - either directly from its sequence alignment, or indirectly from a gene tree inferred from the alignment. Our experiments show that ERaBLE is very fast and fairly accurate when compared to other possible approaches for the same tasks. Specifically, it efficiently and accurately deals with large data sets, such as the OrthoMaM v8 database, composed of 6,953 exons from up to 40 mammals. CONCLUSIONS: ERaBLE may be used as a complement to supertree methods - or it may provide an efficient alternative to maximum likelihood analysis of concatenated alignments - to estimate branch lengths from phylogenomic data sets. PMID- 26744023 TI - Agriculturally Induced Heavy Metal Accumulation in Seyfe Lake, Turkey. AB - The aim of the present 1-year study was to investigate the effect of heavy metals in synthetic fertilizers on water and sediment quality in the Seyfe Lake, where agricultural activity was the only anthropogenic source. Metal concentrations of five different types of synthetic fertilizers used in agricultural fields within the Seyfe Lake closed basin were as follows: Zn > Pb > Cu > Cr > Cd > As > Ni > Co. The annual average of heavy metal concentrations in the sediment samples were as follows: Zn > Pb > As > Cr > Ni > Cu > Cd > Co. Seyfe Lake sediment was classified as anthropogenically "highly polluted" in terms of the As and Zn concentrations at each sample station based on the sediment quality guidelines. Furthermore, the sediment could be classified as "moderately to highly polluted" in terms of the As concentration, based on the geo-accumulation index. PMID- 26744024 TI - Noni (Morinda citrifolia L.) fruit extract attenuates the rewarding effect of heroin in conditioned place preference but not withdrawal in rodents. AB - The present study was designed to investigate the effect of a methanolic extract of Morinda citrifolia Linn. fruit (MMC) on the rewarding effect of heroin in the rat conditioned place preference (CPP) paradigm and naloxone-precipitated withdrawal in mice. In the first experiment, following a baseline preference test (preconditioning score), the rats were subjected to conditioning trials with five counterbalanced escalating doses of heroin versus saline followed by a preference test conducted under drug-free conditions (post-conditioning score) using the CPP test. Meanwhile, in the second experiment, withdrawal jumping was precipitated by naloxone administration after heroin dependence was induced by escalating doses for 6 days (3*/ day). The CPP test results revealed that acute administration of MMC (1, 3, and 5 g/kg body weight (bw), p.o.), 1 h prior to the CPP test on the 12th day significantly reversed the heroin-seeking behavior in a dose-dependent manner, which was similar to the results observed with a reference drug, methadone (3 mg/kg bw, p.o.). On the other hand, MMC (0.5, 1, and 3 g/kg bw, p.o.) did not attenuate the heroin withdrawal jumps precipitated by naloxone. These findings suggest that the mechanism by which MMC inhibits the rewarding effect of heroin is distinct from naloxone-precipitated heroin withdrawal. PMID- 26744026 TI - Water Adsorption and Dissociation on Ceria-Supported Single-Atom Catalysts: A First-Principles DFT+U Investigation. AB - Single-atom catalysts have attracted wide attention owing to their extremely high atom efficiency and activities. In this paper, we applied density functional theory with the inclusion of the on-site Coulomb interaction (DFT+U) to investigate water adsorption and dissociation on clean CeO2 (111) surfaces and single transition metal atoms (STMAs) adsorbed on the CeO2 (111) surface. It is found that the most stable water configuration is molecular adsorption on the clean CeO2 (111) surface and dissociative adsorption on STMA/CeO2 (111) surfaces, respectively. In addition, our results indicate that the more the electrons that transfer from STMA to the ceria substrate, the stronger the binding energies between the STMA and ceria surfaces. A linear relationship is identified between the water dissociation barriers and the d band centers of STMA, known as the generalized Bronsted-Evans-Polanyi principle. By combining the oxygen spillovers, single-atom dispersion stabilities, and water dissociation barriers, Zn, Cr, and V are identified as potential candidates for the future design of ceria-supported single-atom catalysts for reactions in which the dissociation of water plays an important role, such as the water-gas shift reaction. PMID- 26744027 TI - The maintenance of inserted titanium implants: in-vitro evaluation of exposed surfaces cleaned with three different instruments. AB - OBJECTIVE: Changes to titanium implants smooth-surfaces after instrumentation were comparatively analyzed using low-vacuum scanning electron microscopy (LV SEM) and white-light confocal (WLC) profilometry, to accurately evaluate curved surfaces. MATERIAL AND METHODS: Sixty titanium implants screwed to their abutments were randomly split into three groups for cleaning treatment with (S) stainless-steel Gracey-curettes, (T) titanium Langer-curettes, and (P) an ultrasonic-device with the probe covered with a plastic-tip. One sector of each implant was left unprocessed (U). The other sectors were cleaned for either 60 s, to simulate a single cleaning session, or 180 s to simulate a series of sessions. Surface morphology was analyzed by LV-SEM, without metal sputtering. Quantitative evaluations of the roughness of surfaces were performed using a WLC-profilometer. The Wilcoxon and the Mann-Whitney tests were used in statistical comparisons. RESULTS: U-surfaces showed that thin transverse ridges and grooves, i.e. a polarized surface roughness was substantially compromised after S instrumentation. Small surface alterations, increasing with time, were also recorded after T-.and.P-instrumentation, although to a lesser degree. The gap of the fixture-abutment connection appeared almost completely clean after T-, clotted with titanium debris after S-, and clotted with plastic debris after P treatment. The mean roughness (Ra) was unchanged after P-, significantly increased after S- and decreased after T-treatment, when compared with U. The Rz roughness-parameter, calculated along the fixture Y-axis, of S, T, and P resulted similar and significantly lower than that of U. Rz (X-axis) resulted unchanged after P-, slightly increased (+40%) after T-, and greatly increased (+260%) after S-treatment, this latter being statistically significant when compared with U. CONCLUSIONS: The careful use of titanium-curettes could produce only minimal smooth surface alteration particularly over prolonged treatments, and avoid debris production that could endanger implant preservation. PMID- 26744025 TI - Efficacy and safety of liraglutide 3.0 mg for weight management are similar across races: subgroup analysis across the SCALE and phase II randomized trials. AB - The efficacy and safety of liraglutide 3.0 mg versus placebo, as adjunct to diet and exercise, was evaluated in racial subgroups. This post hoc analysis of pooled data from five double-blind randomized, placebo-controlled trials was conducted in 5325 adults with either a body mass index (BMI) >=27 kg/m(2) plus >=1 comorbidity or a BMI >=30 kg/m(2). Statistical interaction tests evaluated possible treatment effect differences between racial subgroups: white (4496, 84.4%), black/African-American (550, 10.3%), Asian (168, 3.2%) and other (111, 2.1%). Effects of liraglutide 3.0 mg on weight loss, associated metabolic effects and safety profile were generally consistent across racial subgroups. All achieved statistically significant mean weight loss at end-of-treatment with liraglutide 3.0 mg versus placebo: white 7.7% versus 2.3%, black/African-American 6.3% versus 1.4%, Asian 6.3% versus 2.5%, other 7.3% versus 0.49%. Treatment effects on weight and cardiovascular risk markers generally showed no dependence on race (interaction test p > 0.05). Adverse events were similar across racial subgroups. PMID- 26744028 TI - In vitro capacitation and acrosome reaction in sperm of the phyllostomid bat Artibeus jamaicensis. AB - Sperm capacitation occurs during the passage of sperm through the female reproductive tract. Once the sperm binds to the pellucid zone, the acrosome reaction to enable penetration of the oocyte is completed. In this study, sperm of Artibeus jamaicensis bat was used to evaluate both capacitation status and the acrosome reaction under in vitro conditions, incubating sperm at 32 and 37 degrees C with and without progesterone. Sperm was incubated at different times to assess sperm cells' functionality in terms of capacitation and acrosome reaction, using the chlortetracycline staining, lectin fluoresceinisocyanate conjugate-Pisum sativum agglutinin (FITC-PSA), and transmission electron microscopy. Sperm cells that presented uniform fluorescence throughout the head and mid-piece were classified as non-capacitated. Subsequently, sperm cells, which were observed with fluorescence only in the anterior portion of the head and mid-piece, were classified as capacitated. Sperm cells with no fluorescence in the head, but fluorescence in the mid-piece, were categorized as sperm cells that have carried out the acrosome reaction. During the acrosome reaction, sperm cells showed changes in their morphology, so it was not possible to distinguish the plasma and acrosomal membranes. Around the entire head, it was not possible to distinguish the fusion points between these membranes that made it possible for the acrosomal reaction to take place and thus to release the enzymes necessary to penetrate the pellucid zone. In conclusion, under appropriate in vitro conditions and by supplementing the culture medium with progesterone, A. jamaicensis bat sperm cells are able to be capacitated in a period from 6 to 8 h and to carry out the acrosome reaction. PMID- 26744030 TI - Bovine lactotroph cultures for the study of prolactin synthesis functions. AB - The aim of this study was to establish a bovine anterior pituitary-derived lactotroph (BAPDL) line that expresses prolactin (PRL) in vitro to study the mechanisms of bovine PRL synthesis and secretion. Immunohistochemistry assay of PRL in the newborn calves' anterior pituitary glands showed that most lactotrophs were located within the superior border of the lateral wings of the anterior pituitary. Tissues of the superior border of the lateral wings of the anterior pituitary were dispersed and cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS). The limiting dilution method was used to establish BAPDL from single cell clone. BAPDL cells constantly expressed mRNAs for PRL and pituitary-specific transcription factor 1 (Pit-1) gene and grew steadily and rapidly in the DMEM supplemented with 10% FBS. PRL immunoreactivity was present in BAPDL at passage 20. The concentration of bovine PRL in BAPDL at passage 20 culture supernatant was decreased to below 35% compared with that in BAPDL at passage 1. The effects of human epidermal growth factor (hEGF) and dopamine (DA) on the expression and secretion of PRL in BAPDL at passage 4 were also investigated. The results are consistent with those of previous studies. Thus, it can be used successfully for studying the mechanisms of stimuli regulating PRL synthesis and release. PMID- 26744029 TI - Characterization of swine testicular cell line as immature porcine Sertoli cell line. AB - Swine testicular (ST) cell line is isolated from swine fetal testes and has been widely used in biomedical research fields related to pig virus infection. However, the potential benefit and utilization of ST cells in boar reproductive studies has not been fully explored. As swine fetal testes mainly contain multiple types of cells such as Leydig cells, Sertoli cells, gonocytes, and peritubular myoid cells, it is necessary to clarify the cell type of ST cell line. In this study, we identified ST cell line was a collection of Sertoli cells by analyzing the unique morphological characteristic with satellite karyosomes and determining the protein expression of two markers (androgen-binding protein, ABP; Fas ligand, FASL) of Sertoli cells. Then ST cells were further confirmed to be immature Sertoli cells by examining the expression of three markers (anti Mullerian hormone, AMH; keratin 18, KRT18; follicle-stimulating hormone receptor, FSHR). In conclusion, ST cells are a collection of immature Sertoli cells which can be good experimental materials for the researches involved in Sertoli cell functions and maturation, or even in boar reproductions. PMID- 26744032 TI - Metachronous Bilateral Extremity Soft Tissue Sarcomas. AB - BACKGROUND: Soft tissue sarcomas (STS) account for approximately 1% of adult malignancies, with 50 to 60% occurring in the extremities. Liposarcoma is the most common type of STS and represent about 20% of total adult sarcomas. There are rare syndromes associated with increased risk of developing STS. Further, chemical compounds such as chlorinated phenols and a few chemotherapeutic drugs have been linked to STS, along with ionizing radiation. Nevertheless, the etiology is uncertain for most of these lesions. CASE REPORT: This report details 2 cases of metachronous bilateral STS of the lower extremities. The first of these presented as a local recurrence of a previously resected right thigh liposarcoma and a new liposarcoma in the left thigh. As mentioned above, among the different subtypes of STS, liposarcoma has the highest tendency for multifocality. The second patient had multifocal metachronous leiomyosarcoma with lung metastases occurring simultaneously with the second presentation. Leiomyosarcoma is another subtype reported to present with multifocal disease. CONCLUSIONS: Despite the rarity of bilateral lesions, their occurrence should not be overlooked in the initial diagnosis and follow-up of the initially detected tumor. Early detection can affect patient survival because their presence predicts unfavorable outcomes. PMID- 26744031 TI - Effect of mesenchymal stem cells and mouse embryonic fibroblasts on the development of preimplantation mouse embryos. AB - Despite advances in assisted reproduction techniques, the poor quality and failures in embryo in vitro development remain as drawbacks resulting in low pregnancy rate. Mouse embryonic fibroblasts (MEFs) have been widely used to support embryonic stem cells. Mesenchymal cells (MSCs) have also been shown to release bioactive factors. In the present study, we have evaluated the ability of MSCs and MEFs to support early development of mouse embryos. The embryos were cultivated alone or in coculture with inactivated MSC or MEF for 4 d. After 4 d in culture, the percentage of blastocyst formation in coculture with MSC (91.7 +/ 4.3%) or MEF (95.1 +/- 3.3%) was higher than in the control group (72.2 +/- 9.0%). We did not observe any difference in proliferation or apoptosis. However, the blastocysts cocultured with MSC or MEF presented a significantly higher number of cells within the inner cell mass per embryo when compared to the controls. The MSC and MEF groups presented also a higher cell number and diameter when compared to the control (CTRL). In summary, our data indicate that coculture with MSC or MEF improves early embryonic development and quality in vitro. PMID- 26744038 TI - How Universal Are Universal Symbols? An Estimation of Cross-Cultural Adoption of Universal Healthcare Symbols. AB - OBJECTIVE: To evaluate the effectiveness of universal health symbol usage and to analyze the factors influencing the adoption of those symbols in Taiwan. BACKGROUND: Universal symbols are an important innovative tool for health facility wayfinding systems. Hablamos Juntos, a universal healthcare symbol system developed in the United States, is a thoughtful, well-designed, and thoroughly tested symbol system that facilitates communication across languages and cultures. METHODS: We designed a questionnaire to test how well the selected graphic symbols were understood by Taiwanese participants and determined factors related to successful symbol decoding, including participant-related factors, stimulation factors, and the interaction between stimulation and participants. Additionally, we further established a design principle for future development of localized healthcare symbols. RESULTS: (1) Eleven symbols were identified as highly comprehensible and effective symbols that can be directly adopted in Taiwanese healthcare settings. Sixteen symbols were deemed incomprehensible or confusing and thus had to be redesigned. Finally, 14 were identified as relatively incomprehensible and could thus be redesigned and then have their effectiveness evaluated again. (2) Three factors were found to influence the participants' differing levels of comprehension of the Hablamos Juntos symbols. CONCLUSIONS: In order to prevent the three aforementioned factors from causing difficulty in interpreting symbols, we suggest that the local symbol designers should (1) use more iconic images, (2) carefully evaluate the indexical and symbolic meaning of graphic symbols, and (3) collect the consensus of Taiwanese people with different educational backgrounds. PMID- 26744037 TI - Counterintuitive effects of negative social feedback on attention. AB - Which stimuli we pay attention to is strongly influenced by learning. Stimuli previously associated with reward outcomes, such as money and food, and stimuli previously associated with aversive outcomes, such as monetary loss and electric shock, automatically capture attention. Social reward (happy expressions) can bias attention towards associated stimuli, but the role of negative social feedback in biasing attentional selection remains unexplored. On the one hand, negative social feedback often serves to discourage particular behaviours. If attentional selection can be curbed much like any other behavioural preference, we might expect stimuli associated with negative social feedback to be more readily ignored. On the other hand, if negative social feedback influences attention in the same way that other aversive outcomes do, such feedback might ironically bias attention towards the stimuli it is intended to discourage selection of. In the present study, participants first completed a training phase in which colour targets were associated with negative social feedback. Then, in a subsequent test phase, these same colour stimuli served as task-irrelevant distractors during a visual search task. The results strongly support the latter interpretation in that stimuli previously associated with negative social feedback impaired search performance. PMID- 26744039 TI - The Efficacy of a Brief Nature Sound Intervention on Muscle Tension, Pulse Rate, and Self-Reported Stress: Nature Contact Micro-Break in an Office or Waiting Room. AB - BACKGROUND: There is a growing recognition that environmental design impacts health and well-being. Nature contact is a design feature or exposure that is especially important in public health and healthcare. To date, there are limited findings on the impact of nature sounds. OBJECTIVE: This experimental study was designed to examine the effect of nature sounds on physiological and psychological stress. METHODS: Participants were randomized into one of three groups-silence (n = 9), nature sound (n = 17), and classical music (n = 14)-and listened to the assigned sound for 15 min in an office or waiting room-like environment. Pre- and postdata were collected including muscle tension (electromyogram), pulse rate, and self-reported stress. RESULTS: With the exception of pulse rate, there were no statistical differences in baseline or demographics among groups. A paired t-test by group showed a decrease in muscle tension, pulse rate, and self-reported stress in the nature group and no significant differences in the control or the classical music groups. The significant reduction in muscle tension occurred at least by 7 min of listening to the nature sound. CONCLUSION: This study highlights the potential benefit of even very brief (less than 7 min) exposure to nature sounds. Brief nature sound "booster breaks" are a promising area for future research with important practical implications. PMID- 26744040 TI - Erratum to: psychometric evaluation of the Mental Health Continuum-Short Form (MHC-SF) in Chinese adolescents - a methodological study. PMID- 26744041 TI - Sodium modified molybdenum sulfide via molten salt electrolysis as an anode material for high performance sodium-ion batteries. AB - The paper reports a facile and cost effective method for fabricating sodium molybdenum sulfide nanoparticles through using MoS2 sheets as the precursor by sodium-modification. The electrochemical performances of sodium molybdenum sulfide nanoparticles are studied as anode materials for sodium-ion batteries. The galvanostatic charge-discharge measurements have been performed in a voltage range of 0.01-2.6 V vs. Na(+)/Na under different current densities, using the as prepared sodium molybdenum sulfide nanoparticles as a working electrode. Typically, the initial discharge and charge capacities of sodium molybdenum sulfide nanoparticles are 475 and 380 mA h g(-1), respectively, at a current density of 20 mA g(-1). The sodium molybdenum sulfide nanoparticles exhibit high capacity with a reversible discharge capacity of about 190 mA h g(-1) after 100 cycles. It should be emphasized that the discharge reaction consists of two steps which correspond to voltage plateaus of 0.93 V and 0.85 V vs. Na(+)/Na in the first discharge curve of the Na/MoS2 battery, respectively. But there is only one apparent voltage plateau in the Na/Na-Mo-S battery, and it reduces to below 0.5 V vs. Na(+)/Na, which can enhance the power density. All of the findings demonstrate that sodium molybdenum sulfide nanoparticles have steady cycling performance and environmental and cost friendliness as next generation secondary batteries. PMID- 26744042 TI - Domiciliary Non-invasive Ventilation in COPD: An International Survey of Indications and Practices. AB - Despite the fact that metanalyses and clinical guidelines do not recommend the routine use of domiciliary non-invasive ventilation (NIV) for patients diagnosed with severe stable Chronic Obstructive Pulmonary Disease (COPD) and with chronic respiratory failure, it is common practice in some countries. We conducted an international web-survey of physicians involved in provision of long-term NIV to examine patterns of domiciliary NIV use in patients diagnosed with COPD. The response rate was 41.6%. A reduction of hospital admissions, improvements in quality of life and dyspnea relief were considered as the main expected benefits for patients. Nocturnal oxygen saturation assessment was the principal procedure performed before NIV prescription. Recurrent exacerbations (>3) requiring NIV and failed weaning from in hospital NIV were the most important reasons for starting domiciliary NIV. Pressure support ventilation (PSV) was the most common mode, with "low" intensity settings (PSV-low) the most popular (44.4 +/- 30.1%) compared with "high" intensity (PSV-high) strategies (26.9 +/- 25.9%), with different geographical preferences. COPD is confirmed to be a common indication for domiciliary NIV. Recurrent exacerbations and failed weaning from in-hospital NIV were the main reasons for its prescription. PMID- 26744044 TI - Changing ideas in forestry: A comparison of concepts in Swedish and American forestry journals during the early twentieth and twenty-first centuries. AB - By combining digital humanities text-mining tools and a qualitative approach, we examine changing concepts in forestry journals in Sweden and the United States (US) in the early twentieth and early twenty-first centuries. Our first hypothesis is that foresters at the beginning of the twentieth century were more concerned with production and less concerned with ecology than foresters at the beginning of the twenty-first century. Our second hypothesis is that US foresters in the early twentieth century were less concerned with local site conditions than Swedish foresters. We find that early foresters in both countries had broader-and often ecologically focused-concerns than hypothesized. Ecological concerns in the forestry literature have increased, but in the Nordic countries, production concerns have increased as well. In both regions and both time periods, timber management is closely connected to concerns about governance and state power, but the forms that governance takes have changed. PMID- 26744043 TI - Interdisciplinary science for future governance and management of forests. AB - The sustainable use of forests constitutes one of the great challenges for the future due to forests' large spatial coverage, long-term planning horizons and inclusion of many ecosystem services. The mission of the Future Forests programme is to provide a scientifically robust knowledge base for sustainable governance and management of forests preparing for a future characterized by globalization and climate change. In this introduction to the Special Issue, we describe the interdisciplinary science approach developed in close collaboration with actors in the Future Forests programme, and discuss the potential impacts of this science on society. In addition, we introduce the 13 scientific articles and present results produced by the programme. PMID- 26744045 TI - In the eye of the stakeholder: The challenges of governing social forest values. AB - This study examines which kinds of social benefits derived from forests are emphasised by Swedish stakeholders and what governance modes and management tools they accept. Our study shows that there exists a great variety among stakeholders' perceptions of forests' social values, where tourism and recreation is the most common reference. There are also differences in preferred governance modes and management where biomass and bioenergy sectors advocate business as usual (i.e. framework regulations and voluntarism) and other stakeholders demand rigid tools (i.e. coercion and targeting) and improved landscape planning. This divide will have implications for future policy orientations and require deliberative policy processes and improved dialogue among stakeholders and authorities. We suggest that there is a potential for these improvements, since actors from almost all stakeholder groups support local influence on governance and management, acknowledged and maintained either by the authorities, i.e. targeting, or by the stakeholders themselves, i.e. voluntarism. PMID- 26744046 TI - Understanding consistencies and gaps between desired forest futures: An analysis of visions from stakeholder groups in Sweden. AB - Conflicting perspectives on forests has for a long time challenged forest policy development in Sweden. Disagreements about forest futures create intractable deadlocks when stakeholders talk past each other. The purpose of this study is to move beyond this situation through the application of participatory backcasting. By comparing visions of the future forest among stakeholder groups, we highlight contemporary trajectories and identify changes that were conceived as desirable. We worked with four groups: the Biomass and Bioenergy group, the Conservation group, the Sami Livelihood group and the Recreation and Rural Development group; in total representatives from 40 organizations participated in workshops articulating the groups' visions. Our results show well-known tensions such as intrinsic versus instrumental values but also new ones concerning forests' social values. Identified synergies include prioritization of rural development, new valued-added forest products and diversified forest management. The results may feed directly into forest policy processes facilitating the process and break current deadlocks. PMID- 26744047 TI - Socio-ecological implications of modifying rotation lengths in forestry. AB - The rotation length is a key component of even-aged forest management systems. Using Fennoscandian forestry as a case, we review the socio-ecological implications of modifying rotation lengths relative to current practice by evaluating effects on a range of ecosystem services and on biodiversity conservation. The effects of shortening rotations on provisioning services are expected to be mostly negative to neutral (e.g. production of wood, bilberries, reindeer forage), while those of extending rotations would be more varied. Shortening rotations may help limit damage by some of today's major damaging agents (e.g. root rot, cambium-feeding insects), but may also increase other damage types (e.g. regeneration pests) and impede climate mitigation. Supporting (water, soil nutrients) and cultural (aesthetics, cultural heritage) ecosystem services would generally be affected negatively by shortened rotations and positively by extended rotations, as would most biodiversity indicators. Several effect modifiers, such as changes to thinning regimes, could alter these patterns. PMID- 26744048 TI - Replacing monocultures with mixed-species stands: Ecosystem service implications of two production forest alternatives in Sweden. AB - Whereas there is evidence that mixed-species approaches to production forestry in general can provide positive outcomes relative to monocultures, it is less clear to what extent multiple benefits can be derived from specific mixed-species alternatives. To provide such insights requires evaluations of an encompassing suite of ecosystem services, biodiversity, and forest management considerations provided by specific mixtures and monocultures within a region. Here, we conduct such an assessment in Sweden by contrasting even-aged Norway spruce (Picea abies) dominated stands, with mixed-species stands of spruce and birch (Betula pendula or B. pubescens), or spruce and Scots pine (Pinus sylvestris). By synthesizing the available evidence, we identify positive outcomes from mixtures including increased biodiversity, water quality, esthetic and recreational values, as well as reduced stand vulnerability to pest and pathogen damage. However, some uncertainties and risks were projected to increase, highlighting the importance of conducting comprehensive interdisciplinary evaluations when assessing the pros and cons of mixtures. PMID- 26744050 TI - The role of biogeochemical hotspots, landscape heterogeneity, and hydrological connectivity for minimizing forestry effects on water quality. AB - Protecting water quality in forested regions is increasingly important as pressures from land-use, long-range transport of air pollutants, and climate change intensify. Maintaining forest industry without jeopardizing sustainability of surface water quality therefore requires new tools and approaches. Here, we show how forest management can be optimized by incorporating landscape sensitivity and hydrological connectivity into a framework that promotes the protection of water quality. We discuss how this approach can be operationalized into a hydromapping tool to support forestry operations that minimize water quality impacts. We specifically focus on how hydromapping can be used to support three fundamental aspects of land management planning including how to (i) locate areas where different forestry practices can be conducted with minimal water quality impact; (ii) guide the off-road driving of forestry machines to minimize soil damage; and (iii) optimize the design of riparian buffer zones. While this work has a boreal perspective, these concepts and approaches have broad-scale applicability. PMID- 26744049 TI - Avoiding the pitfalls of adaptive management implementation in Swedish silviculture. AB - There is a growing demand for alternatives to Sweden's current dominant silvicultural system, driven by a desire to raise biomass production, meet environmental goals and mitigate climate change. However, moving towards diversified forest management that deviates from well established silvicultural practices carries many uncertainties and risks. Adaptive management is often suggested as an effective means of managing in the context of such complexities. Yet there has been scepticism over its appropriateness in cases characterised by large spatial extents, extended temporal scales and complex land ownership characteristics typical of Swedish forestry. Drawing on published research, including a new paradigm for adaptive management, we indicate how common pitfalls can be avoided during implementation. We indicate the investment, infrastructure, and considerations necessary to benefit from adaptive management. In doing so, we show how this approach could offer a pragmatic operational model for managing the uncertainties, risks and obstacles associated with new silvicultural systems and the challenges facing Swedish forestry. PMID- 26744051 TI - Managing Swedish forestry's impact on mercury in fish: Defining the impact and mitigation measures. AB - Inputs of anthropogenic mercury (Hg) to the environment have led to accumulation of Hg in terrestrial and aquatic ecosystems, contributing to fish Hg concentrations well above the European Union standards in large parts of Fennoscandia. Forestry operations have been reported to increase the concentrations and loads of Hg to surface waters by mobilizing Hg from the soil. This summary of available forestry effect studies reveals considerable variation in treatment effects on total Hg (THg) and methylmercury (MeHg) at different sites, varying from no effect up to manifold concentration increases, especially for the bioavailable MeHg fraction. Since Hg biomagnification depends on trophic structures, forestry impacts on nutrient flows will also influence the Hg in fish. From this, we conclude that recommendations for best management practices in Swedish forestry operations are appropriate from the perspective of mercury contamination. However, the complexity of defining effective policies needs to be recognized. PMID- 26744052 TI - Nitrogen dynamics in managed boreal forests: Recent advances and future research directions. AB - Nitrogen (N) availability plays multiple roles in the boreal landscape, as a limiting nutrient to forest growth, determinant of terrestrial biodiversity, and agent of eutrophication in aquatic ecosystems. We review existing research on forest N dynamics in northern landscapes and address the effects of management and environmental change on internal cycling and export. Current research foci include resolving the nutritional importance of different N forms to trees and establishing how tree-mycorrhizal relationships influence N limitation. In addition, understanding how forest responses to external N inputs are mediated by above- and belowground ecosystem compartments remains an important challenge. Finally, forestry generates a mosaic of successional patches in managed forest landscapes, with differing levels of N input, biological demand, and hydrological loss. The balance among these processes influences the temporal patterns of stream water chemistry and the long-term viability of forest growth. Ultimately, managing forests to keep pace with increasing demands for biomass production, while minimizing environmental degradation, will require multi-scale and interdisciplinary perspectives on landscape N dynamics. PMID- 26744053 TI - Conceptualizing and communicating management effects on forest water quality. AB - We present a framework for evaluating and communicating effects of human activity on water quality in managed forests. The framework is based on the following processes: atmospheric deposition, weathering, accumulation, recirculation and flux. Impairments to water quality are characterized in terms of their extent, longevity and frequency. Impacts are communicated using a "traffic lights" metaphor for characterizing severity of water quality impairments arising from forestry and other anthropogenic pressures. The most serious impairments to water quality in managed boreal forests include (i) forestry activities causing excessive sediment mobilization and extirpation of aquatic species and (ii) other anthropogenic pressures caused by long-range transport of mercury and acidifying pollutants. The framework and tool presented here can help evaluate, summarize and communicate the most important issues in circumstances where land management and other anthropogenic pressures combine to impair water quality and may also assist in implementing the "polluter pays" principle. PMID- 26744054 TI - Comparison of carbon balances between continuous-cover and clear-cut forestry in Sweden. AB - Continuous-cover forestry (CCF) has been recognized for the production of multiple ecosystem services, and is seen as an alternative to clear-cut forestry (CF). Despite the increasing interest, it is still not well described how CCF would affect the carbon balance and the resulting climate benefit from the forest in relation to CF. This study compares carbon balances of CF and CCF, applied as two alternative land-use strategies for a heterogeneous Norway spruce (Picea abies) stand. We use a set of models to analyze the long-term effects of different forest management and wood use strategies in Sweden on carbon dioxide emissions and carbon stock changes. The results show that biomass growth and yield is more important than the choice of silvicultural system per se. When comparing CF and CCF assuming similar growth, extraction and product use, only minor differences in long-term climate benefit were found between the two principally different silvicultural systems. PMID- 26744055 TI - Possibility to implement invasive species control in Swedish forests. AB - Invasive alien species constitute an increasing risk to forestry, as indeed to natural systems in general. This study reviews the legislative framework governing invasive species in the EU and Sweden, drawing upon both a legal analysis and interviews with main national level agencies responsible for implementing this framework. The study concludes that EU and Sweden are limited in how well they can act on invasive species, in particular because of the weak interpretation of the precautionary principle in the World Trade Organisation and Sanitary and Phytosanitary agreements. In the Swedish case, this interpretation also conflicts with the stronger interpretation of the precautionary principle under the Swedish Environmental Code, which could in itself provide for stronger possibilities to act on invasive species. PMID- 26744056 TI - Reducing the risk of invasive forest pests and pathogens: Combining legislation, targeted management and public awareness. AB - Intensifying global trade will result in increased numbers of plant pest and pathogen species inadvertently being transported along with cargo. This paper examines current mechanisms for prevention and management of potential introductions of forest insect pests and pathogens in the European Union (EU). Current European legislation has not been found sufficient in preventing invasion, establishment and spread of pest and pathogen species within the EU. Costs associated with future invasions are difficult to estimate but past invasions have led to negative economic impacts in the invaded country. The challenge is combining free trade and free movement of products (within the EU) with protection against invasive pests and pathogens. Public awareness may mobilise the public for prevention and detection of potential invasions and, simultaneously, increase support for eradication and control measures. We recommend focus on commodities in addition to pathways, an approach within the EU using a centralised response unit and, critically, to engage the general public in the battle against establishment and spread of these harmful pests and pathogens. PMID- 26744057 TI - Pasteurellaceae bacteria from the oral cavity of Tasmanian devils (Sarcophilus Harrisii) show high minimum inhibitory concentration values towards aminoglycosides and clindamycin. AB - Threatened by Devil Facial Tumor Disease, the Tasmanian devil populations are vulnerable and decreasing. Additionally, the devils' biting behaviour elevates their risk of acquiring bite wound infections caused by members of the bacterial Pasteurellaceae family that are natural inhabitants of the oral microbiota. In medical management of such bite wounds, antimicrobial susceptibility profiles are crucial. Prior to this investigation, no available data on minimal inhibitory concentration (MIC) values existed. A total of 26 isolates obtained from the oral cavity of 26 healthy Tasmanian devils were tested for their antimicrobial susceptibility by broth micro dilution. Most prominently, high MIC values for clindamycin (>=4 MUg ml(-1) ), gentamicin (>=8 MUg ml(-1) ) and amikacin (>=32 MUg ml(-1) ), were observed for 92, 77 and 73% of the strains tested respectively. This study may be used as a guideline for antimicrobial therapy against bite wound infections caused by Pasteurellaceae originating from the oral cavity of Tasmanian devils. SIGNIFICANCE AND IMPACT OF THE STUDY: Tasmanian devils' aggressive behaviour makes bite wounds in fellow devils and human caretakers a common entity. Pasteurellaceae bacteria are common inhabitants of the oral microbiota of Tasmanian devils and a likely cause of bite wound infections. Here, for the first time, we report antimicrobial sensitivity profiles from a broad collection of Pasteurellaceae isolates obtained from the oral cavity of Tasmanian devils. Low MIC values were observed for the majority of the 22 antimicrobial agents included, yet nearly all strains were tolerant to clindamycin and the aminoglycosides. The work can serve as a guide for clinicians involved in treatment of bite wounds inflicted by devils in animals and humans. PMID- 26744058 TI - Blood-brain barrier crossing and breakthroughs in glioblastoma therapy. PMID- 26744059 TI - IMPAIRED FEAR EXTINCTION ASSOCIATED WITH PTSD INCREASES WITH HOURS-SINCE-WAKING. AB - BACKGROUND: Prior research has demonstrated that time-of-day may play an important role in the extinction of conditioned fear, with extinction better learned earlier in the day rather than later. Impaired fear extinction memory is widely considered a key mechanism of posttraumatic stress disorder (PTSD). The relationship between fear extinction and PTSD symptoms may be moderated by hours since-waking. METHOD: In the present experiment, we examined whether hours-since waking would moderate fear extinction learning ability in a clinical PTSD sample (n = 15), compared to trauma-exposed (n = 33) and nonexposed controls (n = 22). Participants completed a standardized differential fear conditioning and extinction paradigm, providing skin conductance response measures to quantify conditioned responding. RESULTS: Mixed-model analysis of variance revealed a PTSD specific impairment in extinction learning ability in the late extinction phase. A moderation analysis showed that hours-since-waking was a significant moderator of the relationship between impaired late extinction and PTSD symptoms. Specifically, we found that participants with higher PTSD symptoms demonstrated poorer fear extinction learning ability as they were awake for longer. CONCLUSIONS: The results of the current study add to a growing literature indicating deficits in fear extinction learning in PTSD samples, compared to trauma-exposed and nonexposed controls. These results support previous findings that fear extinction is impaired later in the day, and extends this to a clinical sample, suggesting that exposure-therapy may be optimized by scheduling sessions in the morning. PMID- 26744060 TI - Alkaloids with antioxidant activities from Aconitum handelianum. AB - A new C20-diterpenoid alkaloid handelidine (1) and twenty-seven known alkaloids (2-28) were isolated from the roots of Aconitum handelianum. Their structures were established on the basis of extensive spectroscopic analyses. The study indicated that denudatine-type C20-diterpenoid alkaloids with vicinal-triol system and benzyltetrahydroisoquinoline alkaloids exhibited significant antioxidant activities measured by three antioxidant test systems. The aconitine type C19-diterpenoid alkaloids could serve as potential secondary antioxidants for their strong binding effects to metal ions. PMID- 26744062 TI - Complete genome sequence of a novel zantedeschia mild mosaic virus isolate: the first report from Australia and from Alocasia sp. AB - The complete genome of an Australian isolate of zantedeschia mild mosaic virus (ZaMMV) causing mosaic symptoms on Alocasia sp. (designated ZaMMV-AU) was cloned and sequenced. The genome comprises 9942 nucleotides (excluding the poly-A tail) and encodes a polyprotein of 3167 amino acids. The sequence is most closely related to a previously reported ZaMMV isolate from Taiwan (ZaMMV-TW), with 82 and 86 % identity at the nucleotide and amino acid level, respectively. Unlike the amino acid sequence of ZaMMV-TW, however, ZaMMV-AU does not contain a polyglutamine stretch at the N-terminus of the coat-protein-coding region upstream of the DAG motif. This is the first report of ZaMMV from Australia and from Alocasia sp. PMID- 26744061 TI - Inhibition of ethylene production by putrescine alleviates aluminium-induced root inhibition in wheat plants. AB - Inhibition of root elongation is one of the most distinct symptoms of aluminium (Al) toxicity. Although putrescine (Put) has been identified as an important signaling molecule involved in Al tolerance, it is yet unknown how Put mitigates Al-induced root inhibition. Here, the possible mechanism was investigated by using two wheat genotypes differing in Al resistance: Al-tolerant Xi Aimai-1 and Al-sensitive Yangmai-5. Aluminium caused more root inhibition in Yangmai-5 and increased ethylene production at the root apices compared to Xi Aimai-1, whereas the effects were significantly reversed by ethylene biosynthesis inhibitors. The simultaneous exposure of wheat seedlings to Al and ethylene donor, ethephon, or ethylene biosynthesis precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), increased ethylene production and aggravated root inhibition, which was more pronounced in Xi Aimai-1. In contrast, Put treatment decreased ethylene production and alleviated Al-induced root inhibition in both genotypes, and the effects were more conspicuous in Yangmai-5. Furthermore, our results indicated that Al-induced ethylene production was mediated by ACC synthase (ACS) and ACC oxidase, and that Put decreased ethylene production by inhibiting ACS. Altogether, these findings indicate that ethylene is involved in Al-induced root inhibition and this process could be alleviated by Put through inhibiting ACS activity. PMID- 26744063 TI - A critical role of LAMP-1 in avian reovirus P10 degradation associated with inhibition of apoptosis and virus release. AB - Avian reovirus (ARV) causes viral arthritis, chronic respiratory diseases, retarded growth and malabsorption syndrome. The ARV p10 protein, a viroporin responsible for the induction of cell syncytium formation and apoptosis, is rapidly degraded in host cells. However, the mechanism of p10 degradation and its relevance are still unclear. We report here the identification of cellular lysosome-associated membrane protein 1 (LAMP-1) as an interaction partner of p10 by yeast two-hybrid screening, immunoprecipitation and confocal microscopy assays. We found that rapid degradation of p10 was associated with ubiquitination. Importantly, ARV p10 degradation in host cells could be completely abolished by knockdown of LAMP-1 by siRNA, indicating that LAMP-1 is required for ARV p10 degradation in host cells. In contrast, overexpression of LAMP-1 facilitated p10 degradation. Furthermore, knockdown of LAMP-1 allowed p10 accumulation, enhancing p10-induced apoptosis and viral release. Thus, LAMP-1 plays a critical role in ARV p10 degradation associated with inhibition of apoptosis and viral release. PMID- 26744064 TI - Study on colorectal cancer presentation, treatment and follow-up. AB - BACKGROUND: Colorectal carcinoma (CRC) is the second most common cancer in women and men affecting 9.7 % population worldwide. Although CRC mortality has been progressively declining since 1990 at a rate of about 3 % per year, it still remains the third most common cause of cancer deaths. OBJECTIVE: The objective of this study is to evaluate the patterns of clinical presentation, treatment options and follow-up of colorectal carcinoma. METHODOLOGY: Medical records of patients with colorectal carcinoma admitted at St. Luke's Hospital Kilkenny from January 2009 to December 2014 were included in the study. RESULTS: Out of 113, 57 were males and 28 were 75 years or older. Sixty-seven percent presented in the outpatient clinic. The main presentation symptom was bleeding per rectum (40 %), followed by abdominal pain, altered bowel habit, bowel obstruction and weight loss. Mean time delay was 4.79, 6.20 and 4.83 weeks for surgical outpatient department (SOPD), colonoscopy and surgery, respectively. Ninety-eight percent of patients underwent preoperative staging with computed tomography of thorax, abdomen and pelvis (CTTAP) and 78 % had preoperative carcinoembryonic antigen (CEA) measurement. Thirty-four percent of cancers had already metastasized to distant organs. Twenty five percent underwent a right hemicolectomy. Seventy eight percent received a primary anastomosis. Ninety-five percent achieved a R0 resection. Sixty-two percent were given adjuvant chemotherapy. Seventy-six percent had surgery follow-up and 57 % had excellent follow-up. Cancer recurred in two patients. Thirty day mortality was 2 %. CONCLUSION: Our study shows that the mean age group at risk for colorectal cancer is 65 years (range 54-75). Still, 33 % of patients present to acute surgical assessment units with advanced disease. Though we did well in terms of operative resections, follow-up still remains a challenge. PMID- 26744065 TI - UbcH10 overexpression is less pronounced in older colorectal cancer patients. PMID- 26744066 TI - Day and night surgery: is there any influence in the patient postoperative period of urgent colorectal intervention? AB - BACKGROUND: Medical activity performed outside regular work hours may increase risk for patients and professionals. There is few data with respect to urgent colorectal surgery. The aim of this work was to evaluate the impact of daytime versus nighttime surgery on postoperative period of patients with acute colorectal disease. METHODS: A retrospective study was conducted in a sample of patients with acute colorectal disease who underwent urgent surgery at the General Surgery Unit of Braga Hospital, between January 2005 and March 2013. Patients were stratified by operative time of day into a daytime group (surgery between 8:00 and 20:59) and the nighttime group (21:00-7:59) and compared for clinical and surgical parameters. A questionnaire was distributed to surgeons, covering aspects related to the practice of urgent colorectal surgery and fatigue. RESULTS: A total of 330 patients were included, with 214 (64.8%) in the daytime group and 116 (35.2%) in the nighttime group. Colorectal cancer was the most frequent pathology. Waiting time (p < 0.001) and total length of hospital stay (p = 0.008) were significantly longer in the daytime group. There were no significant differences with respect to early or late complications. However, 100% of surgeons reported that they are less proficient during nighttime. CONCLUSIONS: Among patients with acute colorectal disease subjected to urgent surgery, there was no significant association between nighttime surgery and the presence of postoperative medical and surgical morbidities. Patients who were subjected to daytime surgery had longer length of stay at the hospital. PMID- 26744067 TI - The musk chemical composition and microbiota of Chinese forest musk deer males. AB - Male musk deer secrete musk from the musk gland located between their naval and genitals. Unmated male forest musk deer generate a greater amount of musk than mated males, potentially allowing them to attract a greater number of females. In this study, we used gas chromatography and mass spectrometry (GC/MS) to explore musk chemical composition of the musk pods of captive mated and unmated sexually mature Chinese forest musk deer and used next-generation sequencing to intensively survey the bacterial communities within them. Analysis of the chemical composition of the musk showed that unmated males have more muscone and cholesterol. Features of the musk16S rRNA gene showed that mated Chinese forest musk deer have both a greater Shannon diversity (p < 0.01) and a greater number of estimated operational taxonomic units than unmated ones; many bacterial genera were overrepresented in unmated Chinese forest musk deer males. Members of these genera might be involved in musk odor fermentation. PICRUSt analysis revealed that metabolic pathways such as aldosterone-regulated sodium reabsorption, metabolism of terpenoids and polyketides, flavone and flavonol biosynthesis, and isoflavonoid biosynthesis were enriched in the musk of unmated Chinese forest musk deer males. PMID- 26744069 TI - Five-Month-Old Infants Have General Knowledge of How Nonsolid Substances Behave and Interact. AB - Experience puts people in touch with nonsolid substances, such as water, blood, and milk, which are crucial to survival. People must be able to understand the behavior of these substances and to differentiate their properties from those of solid objects. We investigated whether infants represent nonsolid substances as a conceptual category distinct from solid objects on the basis of differences in cohesiveness. Experiment 1 established that infants can distinguish water from a perceptually matched solid and can correctly predict whether the item will pass through or be trapped by a grid. Experiments 2 and 3 showed that infants extend this knowledge to less familiar granular substances. These experiments indicate that concepts of cohesive and noncohesive material appear early in development, apply across several types of nonsolid substances, and may serve as the basis of later knowledge of physical phases. PMID- 26744068 TI - Propensity for Risk Taking Across the Life Span and Around the Globe. AB - Past empirical work suggests that aging is associated with decreases in risk taking. But are such effects universal? Life-history theory suggests that the link between age and risk taking is a function of specific reproductive strategies that can be more or less risky depending on the ecology. We assessed variation in the age-risk curve using World Values Survey data from 77 countries (N = 147,118). The results suggest that propensity for risk taking tends to decline across the life span in the vast majority of countries. In addition, there is systematic variation among countries: Countries in which hardship (e.g., high infant mortality) is higher are characterized by higher levels of risk taking and flatter age-risk curves. These findings suggest that hardship may function as a cue to guide life-history strategies. Age-risk relations thus cannot be understood without reference to the demands and affordances of the environment. PMID- 26744070 TI - Sensillar expression and responses of olfactory receptors reveal different peripheral coding in two Helicoverpa species using the same pheromone components. AB - Male moths efficiently recognize conspecific sex pheromones thanks to their highly accurate and specific olfactory system. The Heliothis/Helicoverpa species are regarded as good models for studying the perception of sex pheromones. In this study, we performed a series of experiments to investigate the peripheral mechanisms of pheromone coding in two-closely related species, Helicoverpa armigera and H. assulta. The morphology and distribution patterns of sensilla trichoidea are similar between the two species when observed at the scanning electron microscope, but their performances are different. In H. armigera, three functional types of sensilla trichoidea (A, B and C) were found to respond to different pheromone components, while in H. assulta only two types of such sensilla (A and C) could be detected. The response profiles of all types of sensilla trichoidea in the two species well matched the specificities of the pheromone receptors (PRs) expressed in the same sensilla, as measured in voltage clamp experiments. The expressions of PRs in neighboring olfactory sensory neurons (OSNs) within the same trichoid sensillum were further confirmed by in situ hybridization. Our results show how the same pheromone components can code for different messages at the periphery of two Helicoverpa species. PMID- 26744071 TI - A family of tetranuclear quinolinolate Dy(iii)-based single-molecule magnets: effects of periphery ligand replacement on their magnetic relaxation. AB - Three complexes with formula {Dy(q)2(L)}2(MU3-OH)2{Dy(q)(L)}2(solvents) (where q = 8-quinolinolate; L = acetylacetone (acac) with (CH2Cl2)2 = solvent (1), 1,3 diphenyl-1,3-propanedione (DBM) and (CH2Cl2)2 = solvent (2), and hexafluoroacetylacetone (hfac) and CHCl3 = solvent (3)) were structurally and magnetically characterized. They have similar Dy4 structural cores bridged by N and O atoms from 8-quinolinolate, and only differ in the peripheral beta diketonate ligands. The variable-frequency and temperature alternating-current (ac) magnetic susceptibility measurements reveal that complexes 1 and 2 display significant zero-field single-molecule-magnet (SMM) behavior, while complex 3 exhibits the field-induced SMM behavior, albeit they possess the nearly same primary coordination sphere. The ac susceptibility measurement on the diluted samples verified that their relaxation was of purely molecular origin, and their distinct slow magnetic behaviors were related to the replacement of the peripheral beta-diketonate ligand, which is responsible for their different individual Dy(iii) ions' magnetic anisotropy and intramolecular coupling, as confirmed by ab initio calculation. PMID- 26744072 TI - Mimosine suppresses the PGF2alpha-induced synthesis of osteoprotegerin but not interleukin-6 in osteoblasts. AB - Mimosine, a plant amino acid, is known to act as a normoxic inducer of hypoxia inducible factor (HIF). Previous research has suggested that HIF plays important roles in angiogenesis-osteogenesis coupling and bone metabolism. We previously reported that prostaglandin F2alpha (PGF2alpha) induced osteoprotegerin synthesis through p38 mitogen-activated protein (MAP) kinase, p44/p42 MAP kinase and stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells. We have also demonstrated that PGF2alpha induced the synthesis of interleukin-6 (IL-6) via p38 MAP kinase and p44/p42 MAP kinase but not SAPK/JNK in these cells. In the present study, we investigated the effects of mimosine on the PGF2alpha-induced synthesis of osteoprotegerin or IL-6 in MC3T3-E1 cells. We found that deferoxamine, another inducer of HIF, as well as mimosine, upregulated the protein levels of HIF-1alpha. Both mimosine and deferoxamine significantly suppressed the PGF2alpha-induced release of osteoprotegerin, and the mRNA expression level, without markedly affecting PGF2alpha-induced IL-6 release. Both mimosine and deferoxamine, by themselves, induced the release of vascular endothelial growth factor. The phosphorylation of p38 MAP kinase, p44/p42 MAP kinase or SAPK/JNK induced by PGF2alpha was not markedly affected by either mimosine or deferoxamine. Thus, the results of the present study strongly suggest that mimosine, a normoxic inducer of HIF, inhibits the PGF2alpha-induced osteoprotegerin synthesis without affecting the IL-6 synthesis in osteoblasts. PMID- 26744073 TI - Surgical correction in orbitotemporal neurofibromatosis with dystopia. AB - BACKGROUND: Orbitotemporal neurofibromatosis is a challenging disease for orbital surgeons. Ptosis correction may be needed following correction of orbital dystopia. CASE PRESENTATION: A 34-year-old man, who underwent excision of a neurofibroma on the right eyelid in our clinic, returned to our clinic four years later complaining of dystopia and bulkiness of the protruding mass in the right eyelid and eyebrow. Computed tomographic imaging showed dysplasia and deformity in the sphenoid bone and orbit. A large mass was found in the superior portion of the orbit, protruding towards the temporal lobe, which in turn displaced the orbit downwards. A bicoronary incision and transcranial approach were performed, followed by the excision of the superior orbital space and temporal lobe mass by uncovering certain portions of the frontal, temporal, and zygomatic bones. After the excision of the mass, a calvarial bone graft was used to remodel the longitudinal widened orbit to correct the dystopia. While primary surgery was successful in the correction of dystopia, secondary surgery was performed to correct the exacerbated ptosis by levator muscle resection. CONCLUSIONS: Correction of orbitotemporal neurofibromatosis with dystopia involves three steps: removal of the mass in the orbit to eliminate the effect of downward dislocation of the orbit, placement of a bone graft in the orbit floor after repositioning the orbit for suspension and remodeling of the orbit, and following the correction of dystopia, ptosis may be corrected if needed. PMID- 26744075 TI - Asymmetric AgPd-AuNR heterostructure with enhanced photothermal performance and SERS activity. AB - Most as-reported nanostructures through galvanic replacement reactions are still symmetric hollow structures, until now. Asymmetric structures fabricated through a galvanic replacement reaction have been rarely reported. However, asymmetric heterostructures can generally lead to new intriguing properties through asymmetric synergistic coupling. Here, we report a simple synthesis of an asymmetric one-ended AgPd bimetal on Au nanorods (AuNR) by combining a galvanic replacement reaction with an Ostwald ripening process. The morphological evolution from a nanodumbbell to a dandelion structure is thoroughly investigated. The unique asymmetric AgPd-AuNR heterostructures possess the required plasmonic performance and avoid strong damping caused by the poor plasmonic metal Pd, resulting in a superior photothermal heating performance and enhanced SERS sensitivity for in situ monitoring of a catalytic reaction compared with the symmetric counterparts. PMID- 26744074 TI - Managing diabetes in people with dementia: protocol for a realist review. AB - BACKGROUND: Worldwide, the prevalences of diabetes and dementia are both increasing, particularly in older people. Rates of diabetes in people with dementia are between 13 and 20 %. Diabetes management and diabetic self-care may be adversely affected by the presence of dementia. There is a need to know what interventions work best in the management of diabetes in people living with dementia (PLWD) in different settings and at different stages of the dementia trajectory. The overall aim is to develop an explanatory account or programme theory about 'what works' in the management of diabetes in people in what context and to identify promising interventions that merit further evaluation. METHODS/DESIGN: This study uses a realist approach including studies on the management of diabetes in older people, medication management, diabetes-related self-care, workforce issues and assessment and treatment. We will use an iterative, stakeholder driven, four-stage approach. Phase 1: development of initial programme theory/ies through a first scoping of the literature and consultation with key stakeholder groups (user/patient representatives, dementia care providers, clinicians, diabetes and dementia researchers and diabetes specialists). Phase 2: systematic searches of the evidence to test and develop the theories identified in phase 1. Phase 3: validation of programme theory/ies with a purposive sample of participants from phase 1. Phase 4: actionable recommendations for the management of diabetes in PLWD. DISCUSSION: A realist synthesis of the evidence will provide a theoretical framework (i.e. an explanation of how interventions work, for whom, in what context and why) for practice and future research work that articulates the barriers and facilitators to effective management of diabetes in people with dementia. By providing possible explanations for the way in which interventions are thought to work and how change is achieved, it will demonstrate how to tailor an intervention to the setting and patient group. The propositions arising from the review will also inform the design of future intervention studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42015020625. PMID- 26744076 TI - Ncl Synchronously Regulates Na+, K+, and Cl- in Soybean and Greatly Increases the Grain Yield in Saline Field Conditions. AB - Salt stress inhibits soybean growth and reduces gain yield. Genetic improvement of salt tolerance is essential for sustainable soybean production in saline areas. In this study, we isolated a gene (Ncl) that could synchronously regulate the transport and accumulation of Na(+), K(+), and Cl(-) from a Brazilian soybean cultivar FT-Abyara using map-based cloning strategy. Higher expression of the salt tolerance gene Ncl in the root resulted in lower accumulations of Na(+), K(+), and Cl(-) in the shoot under salt stress. Transfer of Ncl with the Agrobacterium-mediated transformation method into a soybean cultivar Kariyutaka significantly enhanced its salt tolerance. Introgression of the tolerance allele into soybean cultivar Jackson, using DNA marker-assisted selection (MAS), produced an improved salt tolerance line. Ncl could increase soybean grain yield by 3.6-5.5 times in saline field conditions. Using Ncl in soybean breeding through gene transfer or MAS would contribute to sustainable soybean production in saline-prone areas. PMID- 26744077 TI - SEaRCHTM expert panel process: streamlining the link between evidence and practice. AB - BACKGROUND: With rising health care costs and the diversity of scientific and clinical information available to health care providers it is essential to have methodologies that synthesize and distill the quality of information and make it practical to clinicians, patients and policy makers. Too often research synthesis results in the statement that "more and better research is needed" or the conclusions are slanted toward the biases of one type of stakeholder. Such conclusions are discouraging to clinicians and patients who need better guidance on the decisions they make every day. METHOD: Expert panels are one method for offering valuable insight into the scientific evidence and what experts believe about its application to a given clinical situation. However, with improper management their conclusions can end up being biased or even wrong. There are several types of expert panels, but two that have been extensively involved in bringing evidence to bear on clinical practice are consensus panels, and appropriateness panels. These types of panels are utilized by organizations such as the National Institutes of Health, the Institute of Medicine, RAND, and other organizations to provide clinical guidance. However, there is a need for a more cost effective and efficient approach in conducting these panels. In this paper we describe both types of expert panels and ways to adapt those models to form part of Samueli Institute's Scientific Evaluation and Research of Claims in Health Care (SEaRCHTM) program. DISCUSSION: Expert Panels provide evidence-based information to guide research, practice and health care decision making. The panel process used in SEaRCH seeks to customize, synthesize and streamline these methods. By making the process transparent the panel process informs decisions about clinical appropriateness and research agenda decisions. PMID- 26744080 TI - Dual-Emission of Lanthanide Metal-Organic Frameworks Encapsulating Carbon-Based Dots for Ratiometric Detection of Water in Organic Solvents. AB - Nitrogen and sulfur codoped carbon-based dots (N,S-CDs) with strong blue light emission are encapsulated into red light-emitting europium metal-organic frameworks (Eu-MOFs) to form two color light-emitting nanohybrids (Eu-MOFs/N,S CDs). In organic solvents, the encapsulated N,S-CDs are aggregated and confined in the cavities of the Eu-MOFs, exhibiting only a very weak photoluminescence (PL) signal. Therefore, the nanohybrids show red light emission of the Eu-MOFs. Contrarily, when the Eu-MOFs/N,S-CDs are dispersed in water, the encapsulated N,S CDs are released into solution while the red light emission of the Eu-MOFs is quenched due to the effect of O-H oscillators. The nanohybrids are used as the probe for the water content in organic solvents. Take ethanol as an example; as the water content is increased from 0.2 to 30%, the nanoprobe provides distinguishable PL color change. The ratio of light intensity at 420 nm to that at 623 nm (I420/I623) increases linearly with increasing water content in the range from 0.05 to 4% with a low detection limit of 0.03%. PMID- 26744078 TI - A role of stochastic phenotype switching in generating mosaic endothelial cell heterogeneity. AB - Previous studies have shown that biological noise may drive dynamic phenotypic mosaicism in isogenic unicellular organisms. However, there is no evidence for a similar mechanism operating in metazoans. Here we show that the endothelial restricted gene, von Willebrand factor (VWF), is expressed in a mosaic pattern in the capillaries of many vascular beds and in the aorta. In capillaries, the mosaicism is dynamically regulated, with VWF switching between ON and OFF states during the lifetime of the animal. Clonal analysis of cultured endothelial cells reveals that dynamic mosaic heterogeneity is controlled by a low-barrier, noise sensitive bistable switch that involves random transitions in the DNA methylation status of the VWF promoter. Finally, the hearts of VWF-null mice demonstrate an abnormal endothelial phenotype as well as cardiac dysfunction. Together, these findings suggest a novel stochastic phenotype switching strategy for adaptive homoeostasis in the adult vasculature. PMID- 26744081 TI - Effect of chirality in gamma-PNA: PNA interaction, another piece in the picture. AB - Modification of the PNA backbone can be used to broaden their utility by introducing new functional groups. In particular, gamma-modified PNA have been found to be quite effective in a number of applications, and exhibit particularly high DNA binding affinity. The introduction of one side chain imply that the achiral backbone of PNA becomes chiral, and binding properties depend on the stereochemistry. A new paper on gamma-modified PNA by Ly and co-workers complete the existing knowledge by displaying that in binding to complementary PNA stereochemical orthogonality can be demonstrated. This opens the way to the exploitation of stereochemical features in diagnostic assays and in nanofabrication. PMID- 26744079 TI - Evolution of radiation techniques in the treatment of mediastinal lymphoma: from 3D conformal radiotherapy (3DCRT) to intensity-modulated RT (IMRT) using helical tomotherapy (HT): a single-centre experience and review of the literature. AB - OBJECTIVE: To evaluate radiation techniques and their toxicity in the treatment of Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL) with mediastinal disease over a 10-year period. METHODS: Between 2003 and 2015, 173 patients with Stage I-III nodal lymphoma were treated in our institution: some of these patients were irradiated for HL or NHL with mediastinal disease. Some of the patients were treated by three-dimensional conformal radiotherapy (3DCRT), others by intensity-modulated radiotherapy (IMRT). RESULTS: We studied 26 males and 43 females with a median age of 26 years. The median follow-up was 43 months. 49 patients were treated by 3DCRT and 20 patients by IMRT. The median dose received by patients treated for NHL was 40 Gy (range: 36-44 Gy), and the median dose received by patients with HL was 30 Gy (range: 30-36 Gy). Between 2003 and 2006, 16 patients were treated by 3DCRT vs 0 patients by IMRT. Between 2007 and 2009, 16 patients received 3DCRT and one patient received IMRT. Between 2010 and 2015, 19 patients received IMRT, and no patients received 3DCRT. 11 of the 20 (55%) patients treated by IMRT and 35 of the 49 (71.4%) patients treated by 3DCRT experienced acute toxicity. Among the patients treated by 3DCRT, one patient experienced Grade 1 radiation pneumonitis and two patients experienced Grade 1 acute mucositis. No late toxicity was observed in patients treated by IMRT. CONCLUSION: Improvement of radiation techniques for HL and NHL appears to have improved acute and late clinical safety. Longer follow-up is necessary to evaluate very late toxicity. ADVANCES IN KNOWLEDGE: Improvement of radiation techniques for HL and NHL appears to improve the tolerance. PMID- 26744083 TI - GntR family regulator SCO6256 is involved in antibiotic production and conditionally regulates the transcription of myo-inositol catabolic genes in Streptomyces coelicolor A3(2). AB - SCO6256 belongs to the GntR family and shows 74% identity with SCO6974, which is the repressor of myo-inositol catabolism in Streptomyces coelicolor A3(2). Disruption of SCO6256 significantly enhanced the transcription of myo-inositol catabolic genes in R2YE medium. The purified recombinant SCO6256 directly bound to the upstream regions of SCO2727, SCO6978 and SCO6985, as well as its encoding gene. Footprinting assays demonstrated that SCO6256 bound to the same sites in the myo-inositol catabolic gene cluster as SCO6974. The expression of SCO6256 was repressed by SCO6974 in minimal medium with myo-inositol as the carbon source, but not in R2YE medium. Glutathione-S-transferase pull-down assays demonstrated that SCO6974 and SCO6256 interacted with each other; and both of the proteins controlled the transcription of myo-inositol catabolic genes in R2YE medium. These results indicated SCO6256 regulates the transcription of myo-inositol catabolic genes in coordination with SCO6974 in R2YE medium. In addition, SCO6256 negatively regulated the production of actinorhodin and calcium-dependent antibiotic via control of the transcription of actII-ORF4 and cdaR. SCO6256 bound to the upstream region of cdaR and the binding sequence was proved to be TTTCGGCACGCAGACAT, which was further confirmed through base substitution. Four putative targets (SCO2652, SCO4034, SCO4237 and SCO6377) of SCO6256 were found by screening the genome sequence of Strep. coelicolor A3(2) based on the conserved binding motif, and confirmed by transcriptional analysis and electrophoretic mobility shift assays. These results revealed that SCO6256 is involved in the regulation of myo-inositol catabolic gene transcription and antibiotic production in Strep. coelicolor A3(2). PMID- 26744082 TI - Endoscopic approach for quadrigeminal cistern arachnoid cyst. AB - Objectives Quadrigeminal cistern arachnoid cysts (QCACs), which are usually asymptomatic and may be accidental findings during radiological evaluation, are rare, comprising 5-10% of all intracranial arachnoid cysts (ACs). We report a series of eight patients with QCACs treated with neuroendoscopic intervention and try to discuss the different endoscopic approaches according to the different types of QCACs. Materials and methods Between October 2007 and January 2013, eight patients affected by QCACs were endoscopically treated. All the endoscopic procedures were completed uneventfully (infratentorial approaches in four cases and supratentorial approaches in four cases), which included ventriculocystostomy in seven cases (lateral ventriculocystostomy in one case, third ventricle cystostomy in five cases and both in one case), endoscopic third ventriculostomy in three cases and cystocisternostomy in one case. Results Five patients achieved complete cure after the endoscopic procedure alone; nevertheless, in none of the patients did the cyst totally collapse following the endoscopic procedure during follow-up. The number of episodes decreased significantly even after cessation of all medications and headache disappeared in one patient and the two patients who had unsteady gait together with visual complaints showed remarkable improvement. Conclusion QCAC is one kind of pineal region ACs and it is advisable to plan the operative approach before the endoscopic procedure according to the different types of pineal region ACs. Pineal region ACs and the associated hydrocephalus can be successfully treated with simple, minimally invasive endoscopic procedure. PMID- 26744085 TI - Contextualizing older women's body images: Time dimensions, multiple reference groups, and age codings of appearance. AB - The article sheds light on older women's body images and problematizes assumptions that women's aging is more painful and shameful than men's aging since men are not expected to live up to youthful beauty norms, the so-called double standard of aging hypothesis. Based on 12 qualitative interviews with women from the age of 75 from the Swedish capital area, I argue that older women have access to a double perspective of beauty, which means that they can relate to both youthful and age-related beauty norms. The results also illustrate that women's body image is created in a context where previous body images are central and that this time perspective can contribute toward a positive body image. Further, the results show how age codings of appearance-related qualities create a narrow framework for older women's body images and point to the benefits of shifting the analytical focus toward a material-semiotic body where corporeality and discourse are seen as interwoven. PMID- 26744086 TI - Artificial Neural Networks and risk stratification models in Emergency Departments: The policy maker's perspective. AB - The primary goal of Emergency Department (ED) physicians is to discriminate between individuals at low risk, who can be safely discharged, and patients at high risk, who require prompt hospitalization. The problem of correctly classifying patients is an issue involving not only clinical but also managerial aspects, since reducing the rate of admission of patients to EDs could dramatically cut costs. Nevertheless, a trade-off might arise due to the need to find a balance between economic interests and the health conditions of patients. This work considers patients in EDs after a syncope event and presents a comparative analysis between two models: a multivariate logistic regression model, as proposed by the scientific community to stratify the expected risk of severe outcomes in the short and long run, and Artificial Neural Networks (ANNs), an innovative model. The analysis highlights differences in correct classification of severe outcomes at 10 days (98.30% vs. 94.07%) and 1 year (97.67% vs. 96.40%), pointing to the superiority of Neural Networks. According to the results, there is also a significant superiority of ANNs in terms of false negatives both at 10 days (3.70% vs. 5.93%) and at 1 year (2.33% vs. 10.07%). However, considering the false positives, the adoption of ANNs would cause an increase in hospital costs, highlighting the potential trade-off which policy makers might face. PMID- 26744084 TI - Association between the DOCK7, PCSK9 and GALNT2 Gene Polymorphisms and Serum Lipid levels. AB - This study was to determine the association between several single nucleotide polymorphisms (SNPs) in the dedicator of cytokinesis 7 (DOCK7), proprotein convertase subtilisin/kexin type 9 (PCSK9) and polypeptide N acetylgalactosaminyltransferase 2 (GALNT2) and serum lipid levels. Genotyping of 9 SNPs was performed in 881 Jing subjects and 988 Han participants. Allele and genotype frequencies of the detected SNPs were different between the two populations. Several SNPs were associated with triglyceride (TG, rs10889332, rs615563, rs7552841, rs1997947, rs2760537, rs4846913 and rs11122316), high density lipoprotein (HDL) cholesterol (rs1997947), low-density lipoprotein (LDL) cholesterol (rs1168013 and rs7552841), apolipoprotein (Apo) A1 (rs1997947), ApoB (rs10889332 and rs7552841), and ApoA1/ApoB ratio (rs7552841) in Jing minority; and with TG (rs10889332, rs615563, rs7552841, rs11206517, rs1997947, rs4846913 and rs11122316), HDL cholesterol (rs11206517 and rs4846913), LDL cholesterol (rs1168013), ApoA1 (rs11206517 and rs4846913), ApoB (rs7552841), and ApoA1/ApoB ratio (rs4846913) in Han nationality. Strong linkage disequilibria were noted among the SNPs. The commonest haplotype was G-C-G-C-T-G-C-C-G (>10%). The frequencies of C-C-G-C-T-G-T-C-G, G-C-A-C-T-G-C-C-G, G-C-G-C-T-A-C-C-A, G-C-G-C-T G-C-C-A, G-C-G-C-T-G-T-C-A haplotypes were different between the two populations. Haplotypes could explain much more serum lipid variation than any single SNP alone especially for TG. Differences in lipid profiles between the two populations might partially attribute to these SNPs and their haplotypes. PMID- 26744088 TI - Negative magnetoresistance in Dirac semimetal Cd3As2. AB - A large negative magnetoresistance (NMR) is anticipated in topological semimetals in parallel magnetic fields, demonstrating the chiral anomaly, a long-sought high energy-physics effect, in solid-state systems. Recent experiments reveal that the Dirac semimetal Cd3As2 has the record-high mobility and positive linear magnetoresistance in perpendicular magnetic fields. However, the NMR has not yet been unveiled. Here we report the observation of NMR in Cd3As2 microribbons in parallel magnetic fields up to 66% at 50 K and visible at room temperatures. The NMR is sensitive to the angle between magnetic and electrical fields, robust against temperature and dependent on the carrier density. The large NMR results from low carrier densities in our Cd3As2 samples, ranging from 3.0 * 10(17) cm( 3) at 300 K to 2.2 * 10(16) cm(-3) below 50 K. We therefore attribute the observed NMR to the chiral anomaly. In perpendicular magnetic fields, a positive linear magnetoresistance up to 1,670% at 14 T and 2 K is also observed. PMID- 26744087 TI - Comparison of phenotypic tests for detecting BKC-1-producing Enterobacteriaceae isolates. AB - Carbapenemase-producing Enterobacteriaceae may exhibit in vitro susceptibility to carbapenems, especially those producing weak carbapenemases. Routine clinical laboratories have employed phenotypic tests for screening such isolates. BKC-1 is a recently reported carbapenemase that shows weak carbapenemase activity. In this study, we aimed to evaluate the behavior of distinct phenotypic methods against BKC-1-producing Enterobacteriaceae. PMID- 26744089 TI - Inversion of hematocrit partition at microfluidic bifurcations. AB - Partitioning of red blood cells (RBCs) at the level of bifurcations in the microcirculatory system affects many physiological functions yet it remains poorly understood. We address this problem by using T-shaped microfluidic bifurcations as a model. Our computer simulations and in vitro experiments reveal that the hematocrit (phi0) partition depends strongly on RBC deformability, as long as phi0<20% (within the normal range in microcirculation), and can even lead to complete deprivation of RBCs in a child branch. Furthermore, we discover a deviation from the Zweifach-Fung effect which states that the child branch with lower flow rate recruits less RBCs than the higher flow rate child branch. At small enough phi0, we get the inverse scenario, and the hematocrit in the lower flow rate child branch is even higher than in the parent vessel. We explain this result by an intricate up-stream RBC organization and we highlight the extreme dependence of RBC transport on geometrical and cell mechanical properties. These parameters can lead to unexpected behaviors with consequences on the microcirculatory function and oxygen delivery in healthy and pathological conditions. PMID- 26744090 TI - Injury Patterns After the Landslide Disaster in Oshima, Tokyo, Japan on October 16, 2013. AB - INTRODUCTION: Landslides represent a frequent and threatening natural disaster. The aim of this study was to investigate the injury patterns observed after a landslide and to discuss how to minimize the damage caused by a landslide disaster. METHODS: A landslide occurred on Oshima Island, Japan, on October 16, 2013. A total of 49 victims with landslide-related injuries were identified and analyzed. RESULTS: The patients ranged in age from 5 to 89 years with an average age of 61.0+/-19.3 years. Of all patients, 69.4% were triaged as black. Of 15 patients who were treated in the nearest hospital (the only hospital on the island), 8 were triaged as red and yellow with severe chest or pelvic injury and a high Injury Severity Score (average score, 25.6; range, 4-45). Of these, 75% had chest injury and 75% had pelvic injury. The percentage of chest and/or pelvic injury was 100% in patients triaged as red or yellow. Traumatic asphyxia was diagnosed in 62.5% of these patients. CONCLUSIONS: Compression of the trunk was the main injury in patients triaged as red or yellow after this landslide disaster. Evacuation in advance, the rapid launch of emergency medical support, and knowledge of this specific injury pattern are essential to minimize the potential damage resulting from landslide disasters. PMID- 26744091 TI - Efficient light-harvesting using non-carbonyl carotenoids: Energy transfer dynamics in the VCP complex from Nannochloropsis oceanica. AB - Violaxanthin-chlorophyll a protein (VCP) from Nannochloropsis oceanica is a Chl a only member of the LHC family of light-harvesting proteins. VCP binds carotenoids violaxanthin (Vio), vaucheriaxanthin (Vau), and vaucheriaxanthin-ester (Vau ester). Here we report on energy transfer pathways in the VCP complex. The overall carotenoid-to-Chla energy transfer has efficiency over 90%. Based on their energy transfer properties, the carotenoids in VCP can be divided into two groups; blue carotenoids with the lowest energy absorption band around 480nm and red carotenoids with absorption extended up to 530nm. Both carotenoid groups transfer energy efficiently from their S2 states, reaching efficiencies of ~70% (blue) and ~60% (red). The S1 pathway, however, is efficient only for the red carotenoid pool for which two S1 routes characterized by 0.33 and 2.4ps time constants were identified. For the blue carotenoids the S1-mediated pathway is represented only by a minor route likely involving a hot S1 state. The relaxed S1 state of blue carotenoids decays to the ground state within 21ps. Presence of a fraction of non-transferring red carotenoids with the S1 lifetime of 13ps indicates some specific carotenoid-protein interaction that must shorten the intrinsic S1 lifetime of Vio and/or Vau whose S1 lifetimes in methanol are 26 and 29ps, respectively. The VCP complex from N. oceanica is the first example of a light-harvesting complex binding only non-carbonyl carotenoids with carotenoid-to chlorophyll energy transfer efficiency over 90%. PMID- 26744092 TI - Reply to the Editor--Prevalence of interatrial block during lifetime. PMID- 26744094 TI - Reply to the Editor--Treat the patient, not the T wave. PMID- 26744093 TI - Subcutaneous nerve activity and mechanisms of sudden death in a rat model of chronic kidney disease. AB - BACKGROUND: The mechanisms of sudden death in chronic kidney disease (CKD) remain unclear. OBJECTIVE: The purpose of this study was to test the hypotheses that subcutaneous nerve activity (SCNA) can be used to estimate sympathetic tone in ambulatory rats and that abrupt reduction of SCNA precedes the spontaneous arrhythmic death of Cy/+ rats. METHODS: Radiotransmitters were implanted in ambulatory normal (N = 6) and Cy/+ (CKD; N = 6) rats to record electrocardiogram and SCNA. Two additional rats were studied before and after chemical sympathectomy with 6-hydroxydopamine. RESULTS: In normal rats, the baseline heart rate (HR) and SCNA were 351 +/- 29 bpm and 5.12 +/- 2.97 mV.s, respectively. SCNA abruptly increased HR by 4.31% (95% confidence interval 4.15%-4.47%). In comparison, the CKD rats had reduced baseline HR (336 +/- 21 bpm, P < .01) and SCNA (4.27 +/- 3.19 mV.s, P < .01). When SCNA was observed, HR increased by only 2.48% (confidence interval 2.29%-2.67%, P < .01). All Cy/+ rats died suddenly, preceded by sinus bradycardia, advanced (second- and third-degree) AV block (N = 6), and/or ventricular tachycardia or fibrillation (N = 3). Sudden death was preceded by a further reduction of SCNA (3.22 +/- 2.86 mV.s, P < .01) and sinus bradycardia (243 +/- 55 bpm, P < .01). Histologic studies in CKD rats showed myocardial calcification that involved the conduction system. Chemical sympathectomy resulted in progressive reduction of SCNA over 7 days. CONCLUSION: SCNA can be used to estimate sympathetic tone in ambulatory rats. CKD is associated with reduced HR response to SCNA and conduction system diseases. Abrupt reduction of sympathetic tone precedes AV block, ventricular arrhythmia, and sudden death of CKD rats. PMID- 26744095 TI - Letter to the Editor--Prevalence of interatrial block during lifetime. PMID- 26744096 TI - Primary prevention of idiopathic ventricular fibrillation: Not for the faint of heart. PMID- 26744097 TI - Letter to the Editor--Can reducing quantitative T-wave alternans save lives? PMID- 26744098 TI - Aberrant levels of natural IgM antibodies in osteoarthritis and rheumatoid arthritis patients in comparison to healthy controls. AB - Natural IgM antibodies (nIgM) are polyreactive autoantibodies that have diverse roles in regulating autoimmunity, systemic inflammation and removal of oxidized low-density lipoproteins (oxLDL). We hypothesized that aberrant states of nIgM may exist in persons with osteoarthritis (OA) and rheumatoid arthritis (RA). Herein, we characterized and compared the levels of nIgM specific for phosphorylcholine (anti-PC), double-stranded DNA (anti-dsDNA), and galactosyl (anti-Gal) in persons with OA, RA and healthy controls (HC). Levels of anti-PC nIgM in OA patients were significantly lower than both HC and RA patients in an age-adjusted analysis (P<0.05). In contrast, anti-Gal nIgM levels were significantly higher in RA patients than OA patients (P<0.05) and markedly increased in comparison to HC. Anti-PC nIgM significantly correlated with anti dsDNA and anti-Gal nIgM levels in HC and RA (P<0.05) but not in OA patients. Elevated CRP levels were associated with RA conditions and old ages in general. There was no significant correlation between anti-PC nIgM and CRP or oxLDL levels. Our study highlights for the first time the evidence of aberrant state of nIgM in human OA compared to healthy individuals that implicates a deficiency in immune responses to oxLDL which may contribute to the metabolic syndromes in the development of OA. PMID- 26744099 TI - Reconstruction of low hairline microtia of Treacher Collins syndrome with a hinged mastoid fascial flap. AB - Treacher Collins syndrome (TCS) is a rare genetic disorder leading to congenital craniofacial malformations. Although this syndrome presents with various symptoms, corrective surgery for bilateral microtia with low hairline is one of the most challenging operations given the complex contours of the external ear. In this technical note, a novel, simple procedure for dealing with the low hairline by using a hinged mastoid fascial flap simultaneously with costal cartilage grafting is described. Several techniques for the reconstruction of low hairline microtia have been reported previously, such as skin graft, skin flap, and tissue expander, but the high number of repeat operations and residual scars remain problematic. As a simultaneous procedure with framework grafting, the use of a temporoparietal flap with skin grafting is popular; however, its drawbacks include the operative scar, decreased hair growth, and hair thinning. Patients with TCS show anatomical variations of the superficial temporal vessels supplying the temporoparietal flap. In contrast, due to the high vascularity of the mastoid fascia, the mastoid fascial flap can be elevated safely and easily as an anteriorly, posteriorly, superiorly, or inferiorly based flap. PMID- 26744100 TI - Subjective Reasons for Non-Reporting of Adverse Drug Reactions in a Sample of Physicians in Outpatient Care. AB - INTRODUCTION: Drug safety surveillance strongly depends on the spontaneous reporting of adverse drug reactions (ADRs). A major limiting factor of spontaneous reporting systems is underreporting (UR) which describes incorrectly low reporting rates of ADRs. Factors contributing to UR are numerous and feature country-dependent differences. Understanding causes of and factors associated with UR is necessary to facilitate targeted interventions to improve ADR reporting and pharmacovigilance. METHODS: A cross-sectional questionnaire-based telephone survey was performed among physicians in outpatient care in a federal state of Germany. RESULTS: From n=316 eligible physicians n=176 completed the questionnaire (response rate=55.7%). Most of the physicians (n=137/77.8%) stated that they report ADRs which they have observed to the competent authority rarely (n=59/33.5%), very rarely (n=59/33.5%) or never (n=19/10.8%); the majority (n=123/69.9%) had not reported any ADRs in 2014. Frequent subjective reasons for non-reporting of ADR were (specified response options): lack of time (n=52/29.5%), the subjective evaluation that the required process of reporting is complicated (n=47/26.7%) or requires too much time (n=25/14.2%) or the assessment that reporting of an ADR is needless (n=22/12.5%); within open answers the participants frequently stated that they do not report ADRs that are already known (n=72/40.9%) and they only report severe ADRs (n=46/26.1%). DISCUSSION: Our results suggest a need to inform physicians about pharmacovigilance and to modify the required procedure of ADR reporting or to offer other reporting options. PMID- 26744101 TI - Measuring outcome after cardiac arrest: construct validity of Cerebral Performance Category. AB - INTRODUCTION: Approximately half of the survivors of cardiac arrest have cognitive impairments due to hypoxic brain injury. To describe the outcome after a cardiac arrest, the Cerebral Performance Category (CPC) is frequently used. Although widely used, its validity is still debatable. OBJECTIVE: To investigate the construct validity of the Cerebral Performance Category in survivors of a cardiac arrest. Participants were 18 years and older that survived a cardiac arrest more than six months. METHODS: Cross-sectional design. A method to administer the CPC in a structured and reproducible manner was developed. This 'Structured CPC' was administered by a structured interview. Construct variables were Cognitive Failure Questionnaire (CFQ), Barthel Index (BI), Frenchay Activity Index (FAI), Community Integration Questionnaire (CIQ) and Quality of Life after Brain Injury (Qolibri). Associations were tested based on Spearman correlation coefficients. RESULTS: A total of 62 participants responded. In 58 (94%) patients the CPC was determined, resulting in CPC 1 (48%), CPC 2 (23%) and CPC 3 (23%). The CPC-scoring correlated significantly with the CFQ (r=-0.40); BI (r=-0.57); FAI (r=-0.65), CIQ (r=-0.53) and Qolibri (r=-0.67). DISCUSSION AND CONCLUSIONS: In this study we developed the 'Structured CPC' to improve the transparency and reproducibility of the original CPC. A moderate correlation between the 'Structured CPC' and the constructs 'activities', 'participation' and 'quality of life' confirmed the validity of the 'Structured CPC'. CLINICAL MESSAGE: The 'Structured CPC' can be used as an instrument to measure the level of functioning after cardiac arrest. PMID- 26744102 TI - The influences of adrenaline dosing frequency and dosage on outcomes of adult in hospital cardiac arrest: A retrospective cohort study. AB - AIM: To investigate the influence of dosing frequency and dosage of adrenaline on outcomes of cardiopulmonary resuscitation (CPR). METHODS: We conducted a retrospective observational study in a single medical centre and included adult patients who had suffered an in-hospital cardiac arrest between 2006 and 2012. We used multivariable logistic regression analysis to evaluate the associations between independent variables and outcomes. Adrenaline average dosing frequency was calculated as the total dosage of adrenaline administered during CPR divided by the duration of CPR. Body weight (BW) was analysed as an interaction term to investigate the effect of adrenaline dosage on outcomes. Favourable neurological outcome was defined as a score of 1 or 2 on the Cerebral Performance Category scale at hospital discharge. RESULTS: We included 896 patients in the analysis. After adjusting for multiple confounding factors, including CPR duration, the results indicated that higher adrenaline dosing frequency was associated with lower rates of survival (odds ratio (OR): 0.05, 95% confidence interval (CI): 0.01-0.23) and favourable neurological outcome at hospital discharge (OR: 0.02, 95% CI: 0.002-0.16). A significant interaction was noted between total adrenaline dosage and BW, which indicated that, with the same adrenaline dosage, the outcomes for patients with BW>=82.5kg would be worse than those for patients with lower BW. CONCLUSION: Higher adrenaline average dosing frequency may be associated with worse outcomes after CPR. Besides, according to current recommendations, patients with BW above 82.5kg may not receive adequate dose of adrenaline. PMID- 26744103 TI - Diagnosis deserves greater emphasis in resuscitation practice, research and guidance. PMID- 26744104 TI - Parenchyma-preserving hepatectomy based on portal ramification and perfusion of the right anterior section: preserving the ventral or dorsal area. AB - BACKGROUND: Anatomical hepatectomy aims to eliminate the spread of malignant tumor cells via portal vein systemically. An anatomical concept of the right anterior section (RAS) and preservation of the liver parenchyma within the RAS has been proposed. METHODS: We focused on the anatomical concept of the RAS based on portal perfusion and described surgical procedures to preserve the ventral or dorsal RAS using preoperative simulation. RESULTS: In 370 patients undergoing a preoperative simulation, the ramification of the tertiary portal branches of the RAS could be divided into three types including the cranio-caudal type; Couinaud's classification in 50% of patients, ventro-dorsal type in 26% of patients, and multiple type in 24% of patients. Then in 32 patients of the ventro dorsal type, curative parenchyma-sparing hepatectomy of the RAS was performed, preserving the ventral and dorsal RAS in 14 and 18 patients, respectively. There were no differences in the postoperative complications and long-term survival compared with the results obtained after segment 5 or 8 resection (n = 33). CONCLUSION: Three-dimensional simulation revealed three types of portal vein ramification of the RAS. Parenchyma-preserving hepatectomy based on the precise portal ramification may contribute to safe and curative hepatectomy in selected cases with liver neoplasm involving the RAS. PMID- 26744105 TI - [Setting up of 15 POC blood gas analyzers at Montpellier Hosptital (France)]. AB - The purpose of this article is to describe the setting up of 15 blood gas analyzers GEM((r)) PremierTM 4000 (IL) at Montpellier hospital. This experience includes analytical characterization (within and between run coefficient of variation) using GSE and GHE IL controls, correlation of 35 samples with a routinely used laboratory blood gas analyzer (Cobas b221, Roche((r))). We shall also develop the training, the habilitation and its follow-up for the user staff (450 people) of the different hospital's units in the aim of the accreditation. PMID- 26744106 TI - Oncologic Risk Stratification Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Appendiceal Carcinomatosis. AB - INTRODUCTION: Patients with peritoneal carcinomatosis (PC) of appendiceal origin demonstrate variable oncologic outcomes, despite aggressive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). We sought to devise a prognostic risk stratification system for oncologic outcomes following CRS-HIPEC. METHODS: A total of 197 patients undergoing CRS-HIPEC for the treatment of appendiceal PC were reviewed from a prospective database. Kaplan-Meier survival curves and multivariate Cox regression models were used to identify prognostic factors affecting oncologic outcomes. Clinicopathologic variables affecting overall survival (OS) were utilized to develop a prognostic staging system and nomograms. RESULTS: Univariate and multivariate Cox regression analysis indicated that high-grade tumor histology, lymph node metastasis, and incomplete cytoreduction were high-risk features, adversely affecting OS. Patients were stratified on the presence of high-risk features as follows: low-risk patients had no risk factors (n = 102); intermediate-risk patients had one risk factor (n = 49); and high-risk patients had more than one risk factor (n = 46). Median OS for low-risk patients was not reached, and was 43 and 22 months for intermediate risk and high-risk patients, respectively. Five-year OS was 72, 43, and 13 % for low-, intermediate- and high-risk patients, respectively (p < 0.0003 for low vs. intermediate risk, and p = 0.06 for intermediate vs. high risk). CONCLUSIONS: We propose a three-tier staging system for appendiceal PC following CRS-HIPEC, based on histologic grade, lymph node involvement, and completeness of cytoreduction. The presence of any one or more of these high-risk features significantly decreased survival in our single-institution database and provided the basis for a prognostic staging system and corresponding nomograms. PMID- 26744109 TI - From the Interim Editor. PMID- 26744107 TI - Melanoma Patient-Reported Quality of Life Outcomes Following Sentinel Lymph Node Biopsy, Completion Lymphadenectomy, and Adjuvant Interferon: Results from the Sunbelt Melanoma Trial. AB - BACKGROUND: Quality of life (QOL) and physical condition (PC) outcomes after sentinel lymph node biopsy (SLNB), completion lymph node dissection (CLND), and adjuvant therapy with interferon alfa-2b (IFN) were evaluated in this study. METHODS: Self-reported QOL and PC scores were evaluated in patients enrolled in a prospective, multicenter, randomized, clinical trial evaluating adjuvant IFN. After SLN biopsy, patients with a positive SLN underwent CLND then were randomized to adjuvant IFN or observation. QOL and PC scores were compared between patients who underwent SLNB alone, CLND without IFN, and CLND with IFN. Time to return to baseline QOL and PC scores reported at the time of SLNB was recorded and compared. RESULTS: There were statistically significant differences in time to return to baseline QOL (p = 0.0018) and PC (p = 0.0018) scores across the three treatment groups. The time to return to baseline QOL and PC scores was similar for SLND and CLND alone. Differences in time to return to baseline QOL and PC were sustained when stratified by recurrence status but did not differ significantly for different lymph node regions. There was a delay in return to baseline QOL and PC condition scores that was sustained beyond the cessation of IFN therapy. CONCLUSIONS: CLND is well-tolerated with a similar effect on self reported QOL outcomes in both the short- and long-term compared with SLNB alone. IFN therapy is associated with worse QOL outcomes compared with SLNB and CLND, an effect that may be sustained following cessation of adjuvant IFN. PMID- 26744110 TI - Predictors of Weight Loss in African Americans with Prediabetes or Early Diabetes. AB - ACKNOWLEGMENT: This study was supported by Clinical Research Grant (7-08-CR-27) from the American Diabetes Association and by a contract (58-1950-7-707) with the Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University. This article does not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. PURPOSE: This analysis was undertaken to describe healthcare seeking, weight loss efforts and predictors of weight loss among African Americans recently identified with prediabetes or early diabetes METHODS: A secondary analysis was conducted on data collected from 89 participants who completed a previously published 12-week randomized placebo-controlled trial testing the benefit of vitamin D supplementation on blood measures predictive of diabetes risk. Information about care seeking, weight loss strategies and weight loss effort was collected by questionnaire at three data collection visits. Weight was measured by trained staff at each visit. RESULTS: More than half of the participants saw a healthcare provider during the study, but few recalled receiving advice about diet, physical activity or other strategies for weight loss. Thirty-seven % of participants maintained their weight within 1 kg of their baseline weight. Of the remaining participants, half gained >1 kg and half lost >1 kg during the study period. Age adjusted independent predictors of weight loss included a visit to a healthcare provider for preventive care, dietary restrictions, and consistent weight loss effort. Vitamin D supplementation had no effect on weight change. CONCLUSIONS: This study reinforces the importance of preventive healthcare and sustainable changes in diet and physical activity. It also suggests that physicians need better tools for motivating and supporting their patients to adopt behaviors that can reduce diabetes risk. For the millions of Americans who are trying to lose weight to reduce their risk for chronic disease, this study reinforces the importance of sustained effort. PMID- 26744108 TI - Impact of Robotic Platforms on Surgical Approach and Costs in the Management of Morbidly Obese Patients with Newly Diagnosed Uterine Cancer. AB - BACKGROUND: Minimally invasive surgery (MIS) is associated with decreased complication rates, length of hospital stay, and cost compared with laparotomy. Robotic-assisted surgery-a method of laparoscopy-addresses many of the limitations of standard laparoscopic instrumentation, thus leading to increased rates of MIS. We sought to assess the impact of robotics on the rates and costs of surgical approaches in morbidly obese patients with uterine cancer. METHODS: Patients who underwent primary surgery at our institution for uterine cancer from 1993 to 2012 with a BMI >=40 mg/m(2) were identified. Surgical approaches were categorized as laparotomy (planned or converted), laparoscopic, robotic, or vaginal. We identified two time periods based on the evolving use of MIS at our institution: laparoscopic (1993-2007) and robotic (2008-2012). Direct costs were analyzed for cases performed from 2009 to 2012. RESULTS: We identified 426 eligible cases; 299 performed via laparotomy, 125 via MIS, and 2 via a vaginal approach. The rates of MIS for the laparoscopic and robotic time periods were 6 % and 57 %, respectively. The rate of MIS was 78 % in this morbidly obese cohort in 2012; 69 % were completed robotically. The median length of hospital stay was 5 days (range 2-37) for laparotomy cases and 1 day (range 0-7) for MIS cases (P < 0.001). The complication rate was 36 and 15 %, respectively (P < 0.001). The rate of wound-related complications was 27 and 6 %, respectively (P < 0.001). Laparotomy was associated with the highest cost. CONCLUSIONS: The robotic platform provides significant health and cost benefits by increasing MIS rates in this patient population. PMID- 26744112 TI - Use of the Word "Crisis" in Sickle Cell Disease: The Language of Sickle Cell. AB - Language matters. The words used to name and describe disease phenomena are a reflection of society. The authors address the use of the word "crisis" in SCD from sociological, historical, medical, and patient perspectives. The term "crisis" became associated with sickle cell disease in the mid-1920s, more than a decade after the first description of the disease had been published. The term had been used for centuries in conjunction with fever and as a signifier of severe pain in certain diseases during the nineteenth century. The application of the term to this new disease in the 1920s resulted from physicians' observations of their patients' urgent situations. Though commonly used by health care providers and patients today, "crisis" may not be the appropriate term for sickle cell patients suffering severe pain, because people endure differing amounts of pain before stating they are "in crisis." The result can be undertreatment of the pain or mistrust between physicians and patients about use of strong (narcotic) pain-relievers. Some patients believe the term is useful in communicating the severity of their pain and the urgency of their need for relief from it, especially when seeking care at hospital emergency departments, while others believe "crisis" does not accurately reflect the severity or seriousness of their situation. PMID- 26744111 TI - An Examination of Factors Associated with Healthcare Discrimination in Latina Immigrants: The Role of Healthcare Relationships and Language. AB - ACKNOWLEDGEMENT: The authors are grateful to all of the women who took time to participate in the study, Dr. Elmer Huerta and members of the Latin American Cancer Research Coalition. Funding for these activities were supported, in part, by ACS grants MRSGT-06-132-01-CPPB (VBS), Herbert W. Nickens, M.D., Junior Faculty Achievement Award, AAMC (VBS), and MRSGT-05-104-01-CPPB (JW), National Cancer Institute grants UO1 CA86114 (EH, JM), U01-CA114593 (JM), and KO5 CA96940 (JM). BACKGROUND: Understanding factors that are associated with perceived discrimination in Latina immigrants may provide opportunities to improve care for this growing population. OBJECTIVE: To examine the prevalence of discrimination experiences in urban Latina immigrants and identify socio-cultural and healthcare factors that predict discrimination experiences. DESIGN: Cross-sectional survey of 166 Latina immigrants. MEASUREMENTS: Socio-cultural: region of origin, primary language, and education. Healthcare factors: insurance, place of care, patient provider communication, trust in provider, and satisfaction with care. Multivariable logistic regression was used to examine factors that predicted discrimination. RESULTS: 42% had at least one discrimination experience. Communication with providers was the factor most strongly associated with reporting having a discrimination experience while controlling for other variables (p < 01). Women with good communication with their provider were 71% less likely to report discrimination. CONCLUSION: Better communication with providers may reduce Latinas' perceptions of discrimination and thereby improve healthcare access and use of services. PMID- 26744113 TI - Learning About Sickle Cell: The Patient in Early Sickle Cell Disease Case Reports, 1910-1933. AB - Case reports of sickle cell disease (SCD) from its discovery in 1910 to 1933 provide glimpses into the disease's impact on patients and families. Attending physicians, trying to understand the pathophysiology of and treatments for this newly recognized disease, reported also on the effect of SCD on patients' ability to attend school, play, and work, the kinds and severity of the pain patients endured, the late onset of puberty and slowed development of secondary sex characteristics, and the ways families dealt with loved ones who had the disease. These anonymous patients and families helped "teach" physicians about SCD in the early years after its discovery. The current study uses information gleaned from the third published article in 1915 to 1933. PMID- 26744114 TI - Linking Cultural Competence to Functional Life Outcomes in Mental Health Care Settings. AB - Minorities in the United States have well-documented health disparities. Cultural barriers and biases by health care providers may contribute to lower quality of services which may contribute to these disparities. However, evidence linking cultural competency and health outcomes is lacking. This study, part of an ongoing quality improvement effort, tested the mediation hypothesis that patients' perception of provider cultural competency indirectly influences patients' health outcomes through process of care. Data were from patient satisfaction surveys collected in seven mental health clinics (n=94 minority patients). Consistent with our hypothesis, patients' perception of clinicians' cultural competency was indirectly associated with patients' self-reported improvements in social interactions, improvements in performance at work or school, and improvements in managing life problems through the patients' experience of respect, trust, and communication with the clinician. These findings indicate that process of care characteristics during the clinical encounter influence patients' perceptions of clinicians' cultural competency and affect functional outcomes. PMID- 26744115 TI - Perceptions Revisited: Pediatric Chief Resident views on Minority Housestaff Recruitment and Retention in Pediatric Residency Programs. AB - PURPOSE: This study examined institutional strategies among pediatric residency programs for recruitment and retention of underrepresented minorities (URM) housestaff. PROCEDURES: A questionnaire developed by the authors in a 1992 study was modified and then mailed to 185 pediatric chief residents at non-military pediatric training programs in the United States. Descriptive statistics (means and frequency) were calculated for each question. There were three rounds of mailings and a telephone follow-up. MAIN FINDING: The response rate was 39% (n=73). Thirty-eight percent reported that URM housestaff recruitment and retention was a priority for their program directors, 37% reported that it was a priority for themselves, 25% reported it was a priority for the hospital administration, and 36% reported that they were not sure about the priority of URM housestaff recruitment and retention within their organization. Sixty-seven percent stated that their housestaff selection committees do not have defined recruitment goals, 6% indicated that their committees have specifically defined recruitment goals, and 27% were not sure. CONCLUSIONS: Despite numerous initiatives from government agencies, medical institutions, and institutions of higher education, a critical gap remains among institutions in their recruitment efforts for URM at the level of residency training. Our study suggests that pediatric chief residents may not be adequately educated or primed regarding the importance of recruitment and retention of URM. As individuals involved with both medical training and hospital hierarchy, they are uniquely positioned to influence and carry out program goals and objectives. PMID- 26744116 TI - Laparoscopic Repair of Sportman's Hernia - The Trinidad Experience. AB - Sportman's hernia: (Athletic pubalgia) is an uncommon and poorly understood condition afflicting athletic individuals. Sufferers complain of chronic groin pain and often present diagnostic dilemmas to physicians and physiotherapists. We present a series of cases illustrating the varying presentations of sportman's hernia and diagnostic approaches that can be utilized to exclude common differentials. We also describe laparoscopic mesh repair as an effective treatment option for this condition. PMID- 26744117 TI - The Search for the Legacy of the USPHS Syphilis Study at Tuskegee. Lexington 2011. PMID- 26744118 TI - Combination of grafted Schwann cells and lentiviral-mediated prevention of glial scar formation improve recovery of spinal cord injured rats. AB - The present study was intended to combine three therapeutic approaches in a well defined rat model of spinal cord injury, a lateral hemisection at thoracic level. A guidance channel was implanted at the lesion site. This channel was seeded with native Schwann cells or Schwann cells that had been previously transduced with a lentiviral vector carrying the GDNF gene. Thereafter, these experiences were reproduced in animals injected with lentiviral vectors carrying a shRNA for GFAP (Lv-shGFAP), which has recently been shown to block glial scar formation. Functional evaluations showed that Lv-shGFAP induced a significant improvement in recovery in animals grafted with Schwann cells. Histological studies demonstrated the outgrowth of axons in the guidance channel containing Schwann cells transduced or not with GDNF. This axonal growth was enhanced in rats receiving Lv shGFAP vector. Also, a significant increase of serotonergic innervation of the injured hemicord, distal to the lesion, was found only in animals treated with Lv shGFAP vectors. Importantly, this study confirms that glial scar formation is a major impediment for axonal sprouting after spinal cord injury, and emphasizes the importance of serotonergic innervation for locomotor function. Moreover we show a significant additive effect of a combinatorial approach to axonal regeneration in the injured spinal cord. PMID- 26744120 TI - Different neural substrates for executive functions in youths with ADHD: a diffusion spectrum imaging tractography study. AB - BACKGROUND: The relationship between white-matter tracts and executive functions (EF) in attention deficit hyperactivity disorder (ADHD) has not been well studied and previous studies mainly focused on frontostriatal (FS) tracts. The authors explored the microstructural property of several fibre tracts hypothesized to be involved in EF, to correlate their microstructural property with EF, and to explore whether such associations differ between ADHD and typically developing (TD) youths. METHOD: We assessed 45 youths with ADHD and 45 individually matched TD youths with a computerized test battery for multiple dimensions of EF. From magnetic resonance imaging, FS tract, superior longitudinal fasciculus (SLF), arcuate fasciculus (AF) and cingulum bundle (CB) were reconstructed by diffusion spectrum imaging tractography. The generalized fractional anisotropy (GFA) values of white-matter tracts were computed to present microstructural property of each tract. RESULTS: We found lower GFA in the left FS tract, left SLF, left AF and right CB, and poorer performance in set-shifting, sustained attention, cognitive inhibition and visuospatial planning in ADHD than TD. The ADHD and TD groups demonstrated different association patterns between EF and fibre tract microstructural property. Most of the EF were associated with microstructural integrity of the FS tract and CB in TD youths, while with that of the FS tract, SLF and AF in youths with ADHD. CONCLUSIONS: Our findings support that the SLF, AF and CB also involve in a wide range of EF and that the main fibre tracts involved in EF are different in youths with ADHD. PMID- 26744119 TI - Regulatory role of FZP in the determination of panicle branching and spikelet formation in rice. AB - FRIZZLE PANICLE (FZP) and RFL/ABERRANT PANICLE ORGANIZATION 2 (APO2) play important roles in regulating the ABCDE floral organ identity genes. However, the relationships among FZP and these floral identity genes in the regulation of panicle formation remain unclear. Here, we used the novel mutant fzp-11, wild type and FZP-overexpressing plants to compare the expression of these genes during panicle development by real-time PCR and in situ hybridization. The results indicate that FZP is a major negative regulator of RFL/APO2 and determines the transition from panicle branching to spikelet formation. Moreover, overexpression of FZP severely represses axillary meristem formation in both the vegetative and reproductive phases and the outgrowth of secondary branches in panicle. FZP overexpression positively regulates the expression of a subset of the class B genes, AGL6 genes (OsMADS6 and OsMADS17) as well as class E genes (OsMADS1, OsMADS7 and OsMADS8) in floral meristem (FM). Thus, it suggested that FZP could specify floral organ identity by regulating the related OsMADS-box genes. PMID- 26744122 TI - Hysteroscopic intrauterine morcellation of submucosal fibroids: preliminary results in Hong Kong and comparisons with conventional hysteroscopic monopolar loop resection. AB - INTRODUCTION: Hysteroscopic management of submucosal fibroids using the intrauterine morcellation technique is increasingly being adopted worldwide but no literature concerning its safety and efficacy is available within our local population. We aimed to determine the safety, satisfaction, and efficiency of hysteroscopic intrauterine morcellation of submucosal fibroids, and to compare this technique with conventional hysteroscopic monopolar loop resection to identify its potential benefits. METHODS: All cases of hysteroscopic resection of submucosal fibroids performed in a regional hospital in Hong Kong between 1 January 2011 and 31 December 2014, either by hysteroscopic intrauterine morcellation (MyoSure; Hologic, Bedford [MA], US) or conventional hysteroscopic monopolar loop resection, were selected and case notes reviewed. Technical details such as fibroid size, operating time, fluid deficit, operative complications, patient satisfaction, and improvement in haemoglobin level were analysed and compared between the hysteroscopic intrauterine morcellation and the conventional groups. All statistical results were calculated using the Mann Whitney test. RESULTS: During the 3-year period, 29 cases of submucosal fibroids were managed by hysteroscopic surgery. Conventional hysteroscopic monopolar loop resection was performed in 14 patients and another 15 underwent hysteroscopic intrauterine morcellation with the MyoSure device. At 3-month follow-up, there was no significant difference in overall patient satisfaction (84.6% for conventional method vs 93.3% for hysteroscopic intrauterine morcellation method; P=0.841). Both techniques showed improvement in haemoglobin level at 3 months but without significant difference between the two groups: +21.5 g/L (+1 to +44 g/L) for conventional group and +17.0 g/L (-4 to +40 g/L) for hysteroscopic intrauterine morcellation group (P=0.235). Both techniques achieved 100% satisfaction if the submucosal fibroid had over 60% of its contents protruding into the uterine cavity. The operating time was significantly reduced for the hysteroscopic intrauterine morcellation technique (mean, 36.6 mins vs 53.6 mins in conventional hysteroscopic monopolar loop resection; P=0.005), particularly in those whose fibroids were <=3.0 cm (mean, 27.6 mins vs 53.4 mins; P=0.019). CONCLUSIONS: This retrospective review suggests that hysteroscopic intrauterine morcellation of submucosal fibroids is a safe and effective method in the management of menorrhagia in Chinese women. Preliminary data suggest this technique to be less time-consuming, especially when managing fibroids of <=3.0 cm. PMID- 26744121 TI - Targeted Next-Generation Sequencing Analysis of a Pendred Syndrome-Associated Thyroid Carcinoma. AB - Pendred syndrome is an autosomal recessive disorder characterized by hearing loss and goiter and is caused by bi-allelic mutations (homozygous or compound heterozygous) of the PDS (SLC26A4) gene. The incidence of Pendred syndrome is 7.5 10/100,000 in the general population, and it carries a 1 % risk of developing thyroid carcinoma. Herein, we report a case of a patient with Pendred syndrome who developed a follicular variant of papillary thyroid carcinoma (FVPTC)-that is approximately at an odd of 1/1,000,000. Targeted next-generation sequencing with ThyroSeq v2 was performed on the tumor, and only a TP53 mutation (TP53 p.R175H) was identified. The mutation was limited to the tumor nodule of FVPTC as shown by immunohistochemistry. This report represents the first extensive molecular study of a Pendred syndrome-associated thyroid carcinoma. The evidences support that thyroid carcinomas arising from dyshormonogenetic goiter require additional genetic alteration in addition to the purported thyroid-stimulating hormone (TSH) overstimulation. It is intrigue to note that the mutant p53 is involved in the development of a low-grade malignant thyroid tumor as FVPTC in this patient. PMID- 26744123 TI - Simultaneous pancreas and kidney transplantation as the standard surgical treatment for diabetes mellitus patients with end-stage renal disease. AB - OBJECTIVES: To review the outcome following simultaneous pancreas and kidney transplantation in patients with type 1 diabetes mellitus and end-stage renal disease, as well as those with type 2 diabetes mellitus, and to discuss the applicability of this treatment in this locality. METHODS: A systematic literature review was performed by searching the PubMed and Elsevier databases. The search terms used were "simultaneous pancreas and kidney transplantation", "diabetes", "pancreas transplant" and "SPK". Original and major review articles related to simultaneous pancreas and kidney transplantation were reviewed. Papers published in English after 1985 were included. Clinical outcomes following transplantation were extracted for comparison between different treatment methods. Outcomes of simultaneous pancreas and kidney transplant and other transplantation methods were identified and categorised into patient survival, graft survival, diabetic complications, and quality of life. Patient survivals and graft survivals were also compared. RESULTS: Currently available clinical evidence shows good outcomes for type 1 diabetes mellitus in terms of patient survival, graft survival, diabetic complications, and quality of life. For type 2 diabetes mellitus, the efficacy and application of the procedure remain controversial but the outcomes are possibly comparable with those in type 1 diabetes mellitus. CONCLUSIONS: Simultaneous pancreas and kidney transplantation is a technically demanding procedure that is associated with significant complications, and it should be regarded as a 'last resort' treatment in patients whose diabetic complications have become life-threatening or severely burdensome despite best efforts in maintaining good diabetic control through lifestyle modifications and medications. PMID- 26744124 TI - Alternatives to colonoscopy for population-wide colorectal cancer screening. AB - Colorectal cancer is one of the top three cancers in the world in terms of incidence. Colonoscopy, which many regard as the gold standard in diagnosis of colonic polyps and neoplasm, is costly, invasive and labour-intensive, and deemed an unsuitable population-wide index screening tool. Alternative modalities, including guaiac and immunohistochemical faecal occult blood tests, computed tomographic colonography, colon capsule endoscopy, flexible sigmoidoscopy, and double-contrast barium enema are available. The procedures, test characteristics, and their implications are reviewed. Immunohistochemical faecal occult blood testing appears to be the most suitable population-wide screening test for an average-risk population, with flexible sigmoidoscopy as an alternative. More evidence is needed to determine the role of computed tomographic colonography and colon capsule endoscopy in colorectal cancer screening. PMID- 26744125 TI - Asymmetric Rhodamine-Based Fluorescent Probe for Multicolour In Vivo Imaging. AB - To achieve rapid and sensitive detection of cancer, activatable fluorescent probes targeting proteases that are overexpressed in various types of cancer have been developed, based on the hydroxymethyl rhodamine green (HMRG) scaffold. However, to visualize altered activities of multiple enzymes in cancer sites, other scaffolds with distinct fluorescence properties from those of HMRG are needed. A novel asymmetrically modified rhodamine with suitable absorption/emission, brightness and equilibrium constant of intramolecular spirocyclization, working in the yellow/orange region, is introduced. As a proof of concept, a probe targeting gamma-glutamyl transpeptidase (gGlu-HMJCR) was developed on the basis of the new scaffold. Simultaneous visualization and discrimination of tumours expressing gamma-glutamyl transpeptidase (with gGlu HMJCR) and cathepsins (with Z-Phe-Arg-HMRG) by colour were achieved in a mouse model in vivo. PMID- 26744126 TI - Prediabetes and Risk of Glomerular Hyperfiltration and Albuminuria in the General Nondiabetic Population: A Prospective Cohort Study. AB - BACKGROUND: The role of prediabetes as a risk factor for hyperfiltration and albuminuria in persons who do not develop diabetes is unclear. The lack of evidence is mainly due to the difficulty of accurately assessing the glomerular filtration rate (GFR) in the near-normal range of GFR. We investigated whether prediabetes is an independent risk factor for glomerular hyperfiltration and high normal urinary albumin-creatinine ratio (ACR) using measured GFR (mGFR) rather than estimated GFR. STUDY DESIGN: Prospective cohort study based on the Renal Iohexol Clearance Survey in Tromso 6 (RENIS-T6) and the RENIS Follow-Up Study. Median observation time was 5.6 years. SETTING & PARTICIPANTS: A representative sample of 1,261 persons without diabetes mellitus (DM) from the general population aged 50 to 62 years. PREDICTOR: Prediabetes defined by fasting glucose and hemoglobin A1c according to levels suggested by the American Diabetes Association (preDMADA) and the International Expert Committee of 2009 (preDMIEC). OUTCOMES: Change in mGFR; hyperfiltration defined as mGFR>90th percentile adjusted for age, sex, weight, and height; and high-normal ACR (>10mg/g) at follow-up. MEASUREMENTS: GFR was measured with iohexol clearance. RESULTS: Baseline fasting glucose, hemoglobin A1c, and both definitions of prediabetes were predictors of higher mGFR at follow-up and lower annual mGFR decline in multivariable-adjusted regression analyses. Participants with preDMIEC had an OR for hyperfiltration of 1.95 (95% CI, 1.20-3.17) and for high-normal ACR of 1.83 (95% CI, 1.04-3.22) at follow-up. We adjusted for cardiovascular risk factors including ambulatory blood pressure at baseline and change in use of antihypertensive medication between baseline and follow-up. LIMITATIONS: Only middle-aged white patients participated. There is no consensus on how to define glomerular hyperfiltration. CONCLUSIONS: Our findings imply an independent role of prediabetes in the development of glomerular hyperfiltration and albuminuria. Prediabetes might be a target for early treatment to prevent chronic kidney disease in chronic hyperglycemia. PMID- 26744127 TI - Pregnancy in a Patient With Primary Membranous Nephropathy and Circulating Anti PLA2R Antibodies: A Case Report. AB - There is little information about pregnancy outcomes in patients with active membranous nephropathy (MN), especially those with circulating autoantibodies to M-type phospholipase A2receptor (PLA2R), the major autoantigen in primary MN. We present what we believe to be the first known case of successful pregnancy in a 39-year-old woman with PLA2R-associated MN. In the year prior to pregnancy, the patient developed anasarca, hypoalbuminemia (albumin, 1.3-2.2g/dL), and proteinuria (protein excretion, 29.2 g/d). Kidney biopsy revealed MN with staining for PLA2R, and the patient was seropositive for anti-PLA2R autoantibodies. She did not respond to conservative therapy and was treated with intravenous rituximab (2 doses of 1 g each). Several weeks after presentation, she was found to be 6 weeks pregnant and was closely followed up without further immunosuppressive treatment. Proteinuria remained with protein excretion in the 8 to 12-g/d range. Circulating anti-PLA2R levels declined but were still detectable. At 38 weeks, a healthy baby girl was born, without proteinuria at birth or at her subsequent 6-month postnatal visit. At the time of delivery, the mother still had detectable circulating anti-PLA2R of immunoglobulin G1 (IgG1), IgG3, and IgG4 subclasses, although at low titers. Only trace amounts of IgG4 anti-PLA2R were found in cord blood. Potential reasons for the discrepancy between anti-PLA2R levels in the maternal and fetal circulation are discussed. PMID- 26744130 TI - The vegetative compatibility group to which the US biocontrol agent Aspergillus flavus AF36 belongs is also endemic to Mexico. AB - AIMS: To assess frequencies of the Aspergillus flavus atoxigenic vegetative compatibility group (VCG) YV36, to which the biocontrol agent AF36 belongs, in maize-growing regions of Mexico. METHODS AND RESULTS: Over 3500 A. flavus isolates recovered from maize agroecosystems in four states of Mexico during 2005 through 2008 were subjected to vegetative compatibility analyses based on nitrate nonutilizing mutants. Results revealed that 59 (1.6%) isolates belong to VCG YV36. All 59 isolates had the MAT1-2 idiomorph at the mating-type locus and the single nucleotide polymorphism in the polyketide synthase gene that confers atoxigenicity. Additional degradation of the aflatoxin gene cluster was detected in three isolates. Microsatellite loci analyses revealed low levels of genetic diversity and no linkage disequilibrium within VCG YV36. CONCLUSIONS: The VCG to which the biocontrol agent AF36 belongs, YV36, is also native to Mexico. The North American Free Trade Agreement should facilitate adoption of AF36 for use by Mexico in aflatoxin prevention programs. SIGNIFICANCE AND IMPACT OF THE STUDY: An USEPA registered biocontrol agent effective at preventing aflatoxin contamination of crops in the US, is also native to Mexico. This should facilitate the path to registration of AF36 as the first biopesticide for aflatoxin mitigation of maize in Mexico. Economic and health benefits to the population of Mexico should result once aflatoxin mitigation programs based on AF36 applications are implemented. PMID- 26744131 TI - Recurrence and survival analysis of resected soft tissue sarcomas of pelvic retroperitoneal structures. AB - BACKGROUND: The purpose is to determine the clinicopathologic factors related to survival and recurrence of primary resected pelvic soft tissue sarcomas (STS). METHODS: Demographic/clinical variables were recorded. RESULTS: Thirty-five pts were identified. Median follow-up was 24.2 months. There were 23 (65.7%) high/intermediate-grade and 12 (34.3%) low-grade tumors included in the final analysis. Eight patients (22.9%) received neoadjuvant therapy. Margins were grossly negative in 27 (77.1%, 17-R0, 10-R1) and grossly positive (R2) in 8 (22.9%). Adjuvant therapy was used in 13 patients (37.1%). The 2- and 3-year RFS was 56.5% and 51.3%, with 14 patients recurring at a median time of 16 months (6 local, 8-distant). All distant recurrences were in high-grade tumors. There were no differences in RFS for margins (R0 vs. R1), neoadjuvant/adjuvant therapy, size (>=10 vs. <10 cm) or gender. High/intermediate-grade tumors had worse RFS (P < 0.008). The 2- and 3-year OS was 80.9%. OS was improved for R0/R1 resection (P < 0.001). Resection to R0/R1 margin was a significant predictor of improved OS (P = 0.001). CONCLUSIONS: High/intermediate-grade lesions were associated with worse OS and RFS. Resection to gross negative margins was the only independent predictor of OS. Adjuvant therapy may be reserved for high-grade lesions due to increased metastatic potential. J PMID- 26744129 TI - The pseudorabies virus vhs protein cleaves RNA containing an IRES sequence. AB - The virion host shutoff protein (vhs), encoded by the gene UL41, has RNase activity and is the key regulator of the early host shutoff response induced by type 1 herpes simplex virus. Despite low amino acid similarity, the vhs protein of the swine herpesvirus, pseudorabies virus (PrV), also exhibits RNase activity. However, the mechanism underlying the action of vhs remains undefined. Here, we report that the RNA degradation profile of PrV vhs is similar, but not identical, to that of type 1 herpes simplex virus vhs. Notably, the presence of a cap structure enhances both the degradation rate and the preferential targeting of the vhs protein towards the 3'-end of the encephalomyocarditis virus internal ribosome entry site (IRES). Furthermore, type 1 herpes simplex virus vhs produces a simple degradation pattern, but PrV vhs gives rise to multiple intermediates. The results of northern blotting using probes recognizing various regions of the RNA substrate found that PrV vhs also cleaves downstream of the IRES region and this vhs protein overall shows 5' to 3' RNase activity. Moreover, addition of the translation initiation factors eIF4H and eIF4B significantly increased the RNase activity of recombinant PrV vhs against capped RNA. Nonetheless, these proteins did not fully reconstitute the IRES-directed targeting pattern observed for vhs translated in a rabbit reticular lysate system. The interaction between PrV vhs and eIF4H/eIF4B implies that the translation initiation machinery within the cell is able to stimulate the nuclease activity of PrV vhs. However, this process remains inefficient in terms of the IRES-targeting pattern. PMID- 26744132 TI - Neonates and medicines: a roadmap to further improve neonatal pharmaceutical care. PMID- 26744128 TI - The Brain in Kidney Disease (BRINK) Cohort Study: Design and Baseline Cognitive Function. AB - BACKGROUND: The Brain in Kidney Disease (BRINK) Study aims to identify mechanisms that contribute to increased risk for cognitive impairment in patients with chronic kidney disease (CKD). We describe the rationale, design, and methods of the study and report baseline recruitment and cognitive function results. STUDY DESIGN: Longitudinal observational cohort study of the epidemiology of cognitive impairment in CKD. The primary aim is to characterize the association between (1) baseline and incident stroke, white matter disease, estimated glomerular filtration rate (eGFR), inflammation, microalbuminuria, and dialysis initiation and (2) cognitive decline over 3 years in a CKD cohort with a mean eGFR<45 mL/min/1.73 m(2). SETTING & PARTICIPANTS: Community-dwelling participants 45 years or older recruited from 4 health systems into 2 groups: reduced eGFR, defined as eGFR<60 mL/min/1.73 m(2) (non-dialysis dependent), and control, defined as eGFR>=60 mL/min/1.73 m(2). PREDICTOR: eGFR group. OUTCOMES: Performance on cognitive function tests and structural brain magnetic resonance imaging. MEASUREMENTS: Sequential cognitive and physical function testing, serum and urine biomarker measurement, and brain magnetic resonance images over 3 years. RESULTS: Of 554 participants, mean age was 69.3 years; 333, 88, and 133 had eGFRs<45 (non-dialysis dependent, nontransplantation), 45 to <60, and >=60 (controls) mL/min/1.73 m(2), respectively. Mean eGFR in reduced-eGFR participants was 34.3 mL/min/1.73 m(2). Baseline cognitive performance was significantly associated with eGFR in all domains except language. Participants with eGFRs<30 mL/min/1.73 m(2) performed significantly worse than those with eGFRs>=30 mL/min/1.73 m(2) on tests of memory, processing speed, and executive function. Participants with reduced eGFRs overall scored worst on the Immediate Brief Visual-Spatial Memory Test-Revised. LIMITATIONS: Healthy cohort bias, competing risk for death versus cognitive decline. CONCLUSIONS: Cognitive function was significantly worse in participants with eGFRs<30 mL/min/1.73 m(2). Future BRINK analyses will measure risk factors for cognitive decline using the longitudinal data. PMID- 26744133 TI - Outcomes of children with central nervous system germinoma treated with multi agent chemotherapy followed by reduced radiation. AB - CNS germinomas have an excellent prognosis with radiation therapy alone. However, in children, volume and dose of CNS radiation are associated with neurocognitive and neuroendocrine sequelae. Our objective was to determine long-term outcomes of our cohort who received chemotherapy and reduced radiation. This retrospective cohort study analyzed treatment and outcome of intracranial germinoma patients consecutively treated at Sick Kids, Toronto, Canada, from January 2000 to December 2013. 24 children (13 male, 11 female; median age 13.36 years) were identified. Median follow up was 61 months (range 1-144 months). Tumor location was suprasellar (n = 9), bifocal (8), pineal (6), and basal ganglia (1). Three children showed dissemination on imaging. 2/24 had only elevated serum human chorionic gonadotropin, 3/24 only elevated lumbar cerebrospinal fluid (CSF) hCG, and 2/24 had both elevated serum and lumbar CSF hCG. 23/24 children completed treatment and received multi-agent chemotherapy followed by either ventricular radiation (2340-2400 cGy) (n = 9), ventricular radiation + boost (1600 cGy) (n = 8), whole brain (2340 cGy) (n = 3), focal (4000 cGy) (n = 2) or craniospinal radiation (2340 cGy) (n = 1). Five-year progression free and overall survival was 96 and 100 % respectively. 8/24 patients with ventricular radiation +/- boost (2340/4000 cGy) displayed stable full scale intelligence quotient over a mean interval of 3 years following radiation, but showed declined processing speed. In this limited experience, excellent 5-year overall survival rates were achieved with chemotherapy followed by reduced whole ventricular radiation even if ventricular radiation was delivered without boost. PMID- 26744135 TI - Effects of land use and land cover on selected soil quality indicators in the headwater area of the Blue Nile basin of Ethiopia. AB - Understanding changes in soil quality resulting from land use and land management changes is important to design sustainable land management plans or interventions. This study evaluated the influence of land use and land cover (LULC) on key soil quality indicators (SQIs) within a small watershed (Jedeb) in the Blue Nile Basin of Ethiopia. Factor analysis based on principal component analysis (PCA) was used to determine different SQIs. Surface (0-15 cm) soil samples with four replications were collected from five main LULC types in the watershed (i.e., natural woody vegetation, plantation forest, grassland, cultivated land, and barren land) and at two elevation classes (upland and midland), and 13 soil properties were measured for each replicate. A factorial (2 * 5) multivariate analysis of variance (MANOVA) showed that LULC and altitude together significantly affected organic matter (OM) levels. However, LULC alone significantly affected bulk density and altitude alone significantly affected bulk density, soil acidity, and silt content. Afforestation of barren land with eucalypt trees can significantly increase the soil OM in the midland part but not in the upland part. Soils under grassland had a significantly higher bulk density than did soils under natural woody vegetation indicating that de-vegetation and conversion to grassland could lead to soil compaction. Thus, the historical LULC change in the Jedeb watershed has resulted in the loss of soil OM and increased soil compaction. The study shows that a land use and management system can be monitored if it degrades or maintains or improves the soil using key soil quality indicators. PMID- 26744134 TI - Targeted next generation sequencing reveals unique mutation profile of primary melanocytic tumors of the central nervous system. AB - Melanocytic tumors originating in the central nervous system (MT-CNS) are rare tumors that generally have a favorable prognosis, however malignant tumors do occur. Pathogenetically MT-CNS are not well characterized. Similar to uveal melanoma and blue nevi, they frequently harbor activating GNAQ or GNA11 mutations. Rare NRAS mutations have also been reported. Other mutations have not yet been described. We analyzed 19 MT-CNS, 7 uveal melanomas and 19 cutaneous melanomas using a targeted next generation sequencing approach analyzing 29 genes known to be frequently mutated in other melanocytic tumors (in particular uveal and cutaneous melanomas). In concordance with previous studies, cutaneous melanoma samples showed frequent NRAS or BRAF mutations, as well as mutations in other genes (e.g. NF1, RAC1, PIK3CA, ARID1A). Metastasized uveal melanomas exhibited mutations in GNAQ, GNA11 and BAP1. In contrast, MT-CNS almost exclusively demonstrated mutations in GNAQ (71 %) or GNA11 (12 %). Interestingly both GNA11 mutations identified were detected in MT-CNS diagnosed as intermediate grade melanocytomas which also recurred. One of these recurrent cases also harbored an inactivating BAP1 mutation and was found to have lost one copy of chromosome 3. Our findings show that while MT-CNS do have GNAQ or GNA11 mutations, they rarely harbor other recurrent mutations found in uveal or cutaneous melanomas. Considering chromosome 3 and BAP1 loss are robust markers of poor prognosis in uveal melanoma, it will prove interesting to determine whether these genomic alterations are also of prognostic significance in MT-CNS. PMID- 26744136 TI - Direct Interaction between TalinB and Rap1 is necessary for adhesion of Dictyostelium cells. AB - BACKGROUND: The small G-protein Rap1 is an important regulator of cellular adhesion in Dictyostelium, however so far the downstream signalling pathways for cell adhesion are not completely characterized. In mammalian cells talin is crucial for adhesion and Rap1 was shown to be a key regulator of talin signalling. RESULTS: In a proteomic screen we identified TalinB as a potential Rap1 effector in Dictyostelium. In subsequent pull-down experiments we demonstrate that the Ras association (RA) domain of TalinB interacts specifically with active Rap1. Studies with a mutated RA domain revealed that the RA domain is essential for TalinB-Rap1 interaction, and that this interaction contributes to cell-substrate adhesion during single-celled growth and is crucial for cell-cell adhesion during multicellular development. CONCLUSIONS: Dictyostelium Rap1 directly binds to TalinB via the conserved RA domain. This interaction is critical for adhesion, which becomes essential for high adhesive force demanding processes, like morphogenesis during multicellular development of Dictyostelium. In mammalian cells the established Rap1-talin interaction is indirect and acts through the scaffold protein - RIAM. Interestingly, direct binding of mouse Rap1 to the RA domain of Talin1 has recently been demonstrated. PMID- 26744139 TI - Combining the Advantages of Tetrazoles and 1,2,3-Triazoles: 4,5-Bis(tetrazol-5 yl)-1,2,3-triazole, 4,5-Bis(1-hydroxytetrazol-5-yl)-1,2,3-triazole, and their Energetic Derivatives. AB - In the development of new energetic materials, the main challenge is the combination of high energy content with chemical and mechanical stability, two properties that are often contradictory. In this study, the syntheses and comprehensive characterizations of 4,5-bis(tetrazole-5-yl)-1,2,3-triazole and the novel 4,5-bis(1-hydroxytetrazole-5-yl)-1,2,3-triazole, as well as their energetic properties, are presented, combining the advantages of the more energetic tetrazole and the more stable 1,2,3-triazole rings. Nitrogen-rich salts of both compounds were synthesized to investigate their detonation performances and combustion behavior calculated by computer codes for potential application in erosion-reduced gun propellant mixtures due to their high nitrogen content. The structures of several of the compounds were studied by single-crystal X-ray diffraction and, especially in the case of 4,5-bis(tetrazol-5-yl)-1,2,3-triazole, revealed the site of deprotonation. PMID- 26744141 TI - An open, prospective, non-randomized, controlled, multicentre study to evaluate the clinical outcome of implant treatment in women over 60 years of age with osteoporosis/osteopenia: 1-year results. AB - BACKGROUND: Osteoporosis has been called a potential risk factor for bone healing around implants. AIM: The aim of this multicentre study was to verify the clinical performance of fluoridated implants in the maxilla of subjects with diagnosed systemic primary osteoporosis/osteopenia. MATERIAL AND METHODS: Postmenopausal women in need of 2-8 splinted implants in maxilla underwent bone mineral density measurements in the hip and spine, using dual-energy X-ray absorptiometry scans. Based on their T-scores, they were divided into two study groups: Group O (osteoporosis/osteopenia group) subjects had a T-score <=-2, Group C (control group) had a T-score of >=-1, and subjects with a T-score <-1 but >-2 were excluded. Implants were placed with a two-stage procedure and loaded 4-8 weeks after abutment surgery. At 6 months and 1 year after functional loading, clinical parameters (including peri-apical radiographs) were assessed. RESULTS: One hundred and forty-eight implants were placed in 48 subjects (mean age: 67 years (range [59-83]). Sixty-three implants were placed in 20 osteoporosis subjects (Group O, mean age: 69 years; range [59-83]), and 85 were placed in control subjects (Group C, mean age: 65 years; range [60-74]). The cumulative survival rate, on an implant level, was 99.3% (Group O: 98.4%; Group C: 100.0%). The cumulative survival rate, on a subject level, was 97.9% (Group O: 94.7%; Group C: 100.0%). Marginal bone level (MBL) alterations from functional loading to the 1-year follow-up visit were measured on an implant level and a subject level. The overall MBL alteration on an implant level was -0.01 +/- 0.51 mm (Group O: -0.11 +/- 0.49 mm; Group C: 0.05 +/- 0.52 mm). The overall MBL alteration on a subject level was -0.04 +/- 0.27 mm (Group O: -0.17 +/- 0.30 mm; Group C: 0.04 +/- 0.23 mm). CONCLUSION: Within the limitations of this prospective, non-randomized, controlled, multicentre study, it can be concluded that oral implant therapy in patients suffering from osteoporosis/osteopenia is a reliable treatment option with comparable integration rates as in healthy patients. Long-term follow of the study groups is necessary to compare marginal bone alterations and treatment outcomes. PMID- 26744140 TI - Prospective comparison of magnetic resonance imaging to transient elastography and serum markers for liver fibrosis detection. AB - BACKGROUND & AIMS: Establishing accurate non-invasive methods of liver fibrosis quantification remains a major unmet need. Here, we assessed the diagnostic value of a multiparametric magnetic resonance imaging (MRI) protocol including diffusion-weighted imaging (DWI), dynamic contrast-enhanced (DCE)-MRI and magnetic resonance elastography (MRE) in comparison with transient elastography (TE) and blood tests [including ELF (Enhanced Liver Fibrosis) and APRI] for liver fibrosis detection. METHODS: In this single centre cross-sectional study, we prospectively enrolled 60 subjects with liver disease who underwent multiparametric MRI (DWI, DCE-MRI and MRE), TE and blood tests. Correlation was assessed between non-invasive modalities and histopathologic findings including stage, grade and collagen content, while accounting for covariates such as age, sex, BMI, HCV status and MRI-derived fat and iron content. ROC curve analysis evaluated the performance of each technique for detection of moderate-to-advanced liver fibrosis (F2-F4) and advanced fibrosis (F3-F4). RESULTS: Magnetic resonance elastography provided the strongest correlation with fibrosis stage (r = 0.66, P < 0.001), inflammation grade (r = 0.52, P < 0.001) and collagen content (r = 0.53, P = 0.036). For detection of moderate-to-advanced fibrosis (F2-F4), AUCs were 0.78, 0.82, 0.72, 0.79, 0.71 for MRE, TE, DCE-MRI, DWI and APRI, respectively. For detection of advanced fibrosis (F3-F4), AUCs were 0.94, 0.77, 0.79, 0.79 and 0.70, respectively. CONCLUSIONS: Magnetic resonance elastography provides the highest correlation with histopathologic markers and yields high diagnostic performance for detection of advanced liver fibrosis and cirrhosis, compared to DWI, DCE-MRI, TE and serum markers. PMID- 26744143 TI - Time to take health economics seriously-medical education in the United Kingdom. AB - In the UK, the General Medical Council clearly stipulates that upon completion of training, medical students should be able to discuss the principles underlying the development of health and health service policy, including issues relating to health economics. With the National Health Service facing the threat of large gaps in funding, there is pressure on doctors to identify where and how savings can be made. Whilst many may be keen to learn about health economics, the teaching environment and level of student knowledge differs considerably across medical schools in the UK. There is a compelling argument to suggest that key concepts such as economic evaluation, equity and priority-setting should form part of the curriculum in UK medical schools. To address the complex nature of modern health care problems, doctors must have a perspective that combines medical expertise with economic proficiency. PMID- 26744144 TI - The need for logbooks to evolve in the undergraduate medical setting. PMID- 26744142 TI - MicroRNA-21 Contributes to Liver Regeneration by Targeting PTEN. AB - BACKGROUND: Multiple microRNAs (miRNAs, miRs), including miR-21, have been documented to be critical regulators of liver regeneration, but the mechanism underlying their roles in hepatocyte proliferation and cell cycle progression is still far from understood. MATERIAL/METHODS: miR-21 levels were determined using qRT-PCRs in mouse livers at 48 h after 70% partial hepatectomy (PH-48 h). Cell proliferation was determined by use of a cell-counting kit-8 (CCK-8), EdU incorporation staining, and flow cytometry. Phosphatase and tensin homolog (PTEN) expressions were determined using qRT-PCR and Western blot analysis. PTEN siRNA was used to perform the rescue experiment. RESULTS: A marked upregulation of miR 21 was observed in mouse livers at 48 h after 70% partial hepatectomy (PH-48 h) compared to 0 h after PH (PH-0 h). Overexpression of miR-21 was associated with increased proliferation and a rapid G1-to-S phase transition of the cell cycle in BNL CL.2 normal liver cells in vitro. In addition, we showed that PTEN expression was inversely correlated with miR-21 in BNL CL.2 cells and demonstrated that PTEN expression is lower in mouse livers at PH-48 h. Moreover, the presence of PTEN siRNA significantly abolished the suppressive effect of miR-21 inhibitor on hepatocyte proliferation. CONCLUSIONS: miR-21 overexpression contributes to liver regeneration and hepatocyte proliferation by targeting PTEN. Upregulation of miR 21 might be a useful therapeutic strategy to promote liver regeneration. PMID- 26744145 TI - Vancomycin-resistant enterococci colonization in a neonatal intensive care unit: who will be infected? AB - OBJECTIVE: To determine the incidence of vancomycin-resistant enterococcus (VRE) colonization in our neonatal intensive care unit (NICU) over five-year period, rate of progression to VRE infection and associated risk factors. METHODS: A retrospective analysis of a prospective surveillance for VRE colonization and health care-associated infections was made. Contact precautions were taken against colonization, although the application varied over the years due to repairs in the unit. RESULTS: VRE rectal colonization was detected in 200/1671 neonates (12%) admitted to NICU. It showed great interannual variability from 1.9% to 30.3%. Sytemic VRE infection developed in 6/200 VRE-colonized patients (3%) within a median of 9 days (range: 3-58 days). The risk factors for VRE infection development identified in the univariate analysis were long hospital stay (>=30 days), necrotizing enterocolitis, surgical procedure, extraventricular drainage, receipt of amphotericin B and receipt of glycopeptides after detection of VRE colonization. Crude in-hospital mortality was higher in neonates who developed a systemic VRE infection (p < 0.001). CONCLUSION: Maintaining physical conditions in the unit favorable for infection control and rational use of antibiotics are essential in the control of VRE colonization and resultant infections. Special attention should be directed to VRE-colonized babies carrying the risk factors. PMID- 26744146 TI - Highly Efficient Elimination of Carbon Monoxide with Binary Copper-Manganese Oxide Contained Ordered Nanoporous Silicas. AB - Ordered nanoporous silicas containing various binary copper-manganese oxides were prepared as catalytic systems for effective carbon monoxide elimination. The carbon monoxide elimination efficiency was demonstrated as a function of the [Mn]/[Cu] ratio and reaction time. The prepared catalysts were characterized by Brunauer-Emmett-Teller (BET) method, small- and wide-angle X-ray diffraction (XRD), and high-resolution transmission electron microscopy (HR-TEM) for structural analysis. Moreover, quantitative analysis of the binary metal oxides within the nanoporous silica was achieved by inductively coupled plasma (ICP). The binary metal oxide-loaded nanoporous silica showed high room temperature catalytic efficiency with over 98 % elimination of carbon monoxide at higher concentration ratio of [Mn]/[Cu]. PMID- 26744147 TI - Photoluminescence Enhancement of Adsorbed Species on Si Nanoparticles. AB - We have fabricated Si nanoparticles from Si swarf using the beads milling method. The mode diameter of produced Si nanoparticles was between 4.8 and 5.2 nm. Si nanoparticles in hexane show photoluminescence (PL) spectra with peaks at 2.56, 2.73, 2.91, and 3.09 eV. The peaked PL spectra are attributed to the vibronic structure of adsorbed dimethylanthracene (DMA) impurity in hexane. The PL intensity of hexane with DMA increases by ~3000 times by adsorption on Si nanoparticles. The PL enhancement results from an increase in absorption probability of incident light by DMA caused by adsorption on the surface of Si nanoparticles. PMID- 26744148 TI - Spin transport in undoped InGaAs/AlGaAs multiple quantum well studied via spin photocurrent excited by circularly polarized light. AB - The spin diffusion and drift at different excitation wavelengths and different temperatures have been studied in undoped InGaAs/AlGaAs multiple quantum well (MQW). The spin polarization was created by optical spin orientation using circularly polarized light, and the reciprocal spin Hall effect was employed to measure the spin polarization current. We measured the ratio of the spin diffusion coefficient to the mobility of spin-polarized carriers. From the wavelength dependence of the ratio, we found that the spin diffusion and drift of holes became as important as electrons in this undoped MQW, and the ratio for light holes was much smaller than that for heavy holes at room temperature. From the temperature dependence of the ratio, the correction factors for the common Einstein relationship for spin-polarized electrons and heavy holes were firstly obtained to be 93 and 286, respectively. PMID- 26744149 TI - Cerebellum: from Fundamentals to Translational Approaches. The Seventh International Symposium of the Society for Research on the Cerebellum. AB - In terms of cerebellar research and ataxiology, a most fascinating period is currently going on. Numerous academic groups are now focusing their innovative research on the so-called little brain, hidden at the bottom of our brain. Indeed, its unique anatomical features make the cerebellum a wonderful window to address major questions about the central nervous system. The seventh international symposium of the SRC was held in Brussels at the Palace of Academies from May 8 to 10, 2015. The main goal of this dense symposium was to gather in a 2-day meeting senior researchers of exceptional scientific quality and talented junior scientists from all over the world working in the multidisciplinary field of cerebellar research. Fundamental and clinical researchers shared the latest knowledge and developments in this rapidly growing field. New ideas, addressed in a variety of inspiring talks, provoked a vivid debate. Advances in genetics, development, electrophysiology, neuroimaging, neurocognition and affect, as well as in the cerebellar ataxias and the controversies on the roles and functions of the cerebellum were presented. The Ferdinando Rossi lecture and the key-note lecture were delivered by Jan Voogd and Chris De Zeeuw, respectively. Contacts between researchers of different neuroscientific disciplines established a robust basis for novel trends and promising new cooperations between researchers and their centers spread all over the world. PMID- 26744150 TI - Beriberi in Cambodia. AB - Beriberi had plagued humans for centuries. It was responsible for over 50% of infant deaths in the Philippines in the early 1900s. But since the discovery of its cause and treatment it has become a rarity, or has it? PMID- 26744151 TI - Improving survival for children with sickle cell disease: newborn screening is only the first step. AB - Invited commentary on 'Survival of children with sickle cell disease in the comprehensive newborn screening programme in Minas Gerais, Brazil', Sabarense et al. PMID- 26744152 TI - Pakistan and the Millennium Development Goals for Maternal and Child Health: progress and the way forward. AB - The world has made substantial progress in reducing maternal and child mortality, but many countries are projected to fall short of achieving their Millennium Development Goals (MDGs) 4 and 5 targets. The major objective of this paper is to examine progress in Pakistan in reducing maternal and child mortality and malnutrition over the last two decades. Data from recent national and international surveys suggest that Pakistan lags behind on all of its MDGs related to maternal and child health and, for some indicators especially related to nutrition, the situation has worsened from the baseline of 1990. Progress in addressing key social determinants such as poverty, female education and empowerment has also been slow and unregulated population growth has further compromised progress. There is a need to integrate the various different sectors and programmes to achieve the desired results effectively and efficiently as many of the determinants and influencing factors are outside the health sector. PMID- 26744153 TI - Integration of HIV infant testing into immunization programmes: a systematic review. AB - BACKGROUND: Integration of HIV infant testing into immunization sessions is one of the strategies designed to increase coverage of early infant diagnosis. OBJECTIVE: To determine the evidence on the outcomes of such integration. METHODS: A systematic review of peer-reviewed and grey literature was undertaken from electronic sources such as MEDLINE, Google Scholar, websites of international agencies, past conferences and ministries of health reports published between year 2002 and 2013. Randomized controlled trials, observational and qualitative studies were searched and those meeting selection criteria were selected and relevant information extracted using structured tool. Statistical pooling was not possible owing to the heterogeneity of the study designs and outcome measures. RESULTS: Of the nine articles which met the selection criteria, none used a randomized controlled design. Of these, five articles measured mother's acceptability of their infants being tested for HIV during its first pentavalent or DPT vaccination visit, and 89.5-100% accepted. Four articles reported the proportion of mothers who returned for HIV test results, ranging from 56.8% to 86.0%. Increased uptake of HIV testing following integration was confirmed by two articles. Only one study in Tanzania determined the uptake of vaccinations following integration, with urban facilities showing stable or slight increase of monthly vaccine uptake while decreases were observed across the rural sites. In two articles, stigma was perceived by service-providers and mothers as the potential risk following integration, particularly in rural settings. DISCUSSION: Despite the limited number of articles, the findings in this systematic review suggest that HIV testing during immunization clinic visits is acceptable and feasible as a possible model for service delivery. However, the impact on vaccination uptake needs further study. PMID- 26744154 TI - Relationship between leisure time screen activity and aggressive and violent behaviour in Iranian children and adolescents: the CASPIAN-IV Study. AB - BACKGROUND: This study aimed to assess the relationship between leisure time spent watching television (TV) and at a computer and aggressive and violent behaviour in children and adolescents. METHODS: In this nationwide study, 14,880 school students, aged 6-18 years, were selected by cluster and stratified multi stage sampling method from 30 provinces in Iran. The World Health Organization Global School-based Health Survey questionnaire (WHO-GSHS) was used. RESULTS: Overall, 13,486 children and adolescents (50.8% boys, 75.6% urban residents) completed the study (participation rate 90.6%). The risk of physical fighting and quarrels increased by 29% (OR 1.29, 95% CI 1.19-1.40) with watching TV for >2 hr/day, by 38% (OR 1.38, 95% CI 1.21-1.57) with leisure time computer work of >2 hr/day, and by 42% (OR 1.42, 95% CI 1.28-1.58) with the total screen time of >2 hr/day. Watching TV or leisure time spent on a computer or total screen time of >2 hr/day increased the risk of bullying by 30% (OR 1.30, 95% CI 1.18-1.43), 57% (1.57, 95% CI 1.34-1.85) and 62% (OR 1.62, 95% CI 1.43-1.83). Spending >2 hr/day watching TV and total screen time increased the risk of being bullied by 12% (OR 1.12, 95% CI 1.02-1.22) and 15% (OR 1.15, 95% CI 1.02-1.28), respectively. This relationship was not statistically significant for leisure time spent on a computer (OR 1.10, 95% CI 0.9-1.27). CONCLUSIONS: Prolonged leisure time spent on screen activities is associated with violent and aggressive behaviour in children and adolescents. In addition to the duration of screen time, the association is likely to be explained also by the media content. PMID- 26744155 TI - Thiamine deficiency in tachypnoeic Cambodian infants. AB - BACKGROUND: Beriberi is endemic in South-east Asia. Diagnosis is based on clinical findings, but correlation of clinical features with blood thiamine concentrations is uncertain. OBJECTIVES: To investigate in tachypnoeic Cambodian infants the correlation between whole blood thiamine diphosphate (TDP) concentrations, clinical findings and blood TDP levels after therapy. METHODS: Infants hospitalised with tachypnoea were enrolled from October 2011 to January 2012. Initial clinical features, diagnostic test results and final diagnoses were recorded. Blood for TDP determination was collected prior to treatment and at discharge. Matched infants from the general outpatient clinic with minor complaints were enrolled as controls. Thiamine was administered at the discretion of the treating paediatrician. RESULTS: Of the 47 tachypnoeic and 47 control infants, median initial blood TDP concentrations were 83 and 93 nmol/L, respectively (P = 0.69), and were below the estimated limit of normal (<70 nmol/L) in 43% vs 34% (P = 0.40). Median initial TDP levels were 72 and 91 nmol/L in tachypnoeic infants who did or did not receive thiamine, respectively (P = 0.56); at hospital discharge, median TDP concentration had increased by 107 and 3.5 nmol/L in these two subgroups (P<0.001). Classical findings of beriberi such as dysphonia, tachycardia and hepatomegaly did not correlate with low initial TDP concentrations, but infant age, Tiger Balm use, absence of wheezing and low blood CRP levels were associated with low initial TDP levels. Use of infant formula was associated with higher initial TDP levels. CONCLUSIONS: Thiamine deficiency is common in tachypnoeic Cambodian infants, but routine clinical assessments do not accurately identify those with low blood TDP concentrations. Parenteral thiamine administration markedly increases TDP levels. Empirical thiamine treatment should be considered for tachypnoeic infants in regions with endemic thiamine deficiency. PMID- 26744156 TI - Hospitalisation of children aged 0-59 months with rotavirus gastro-enteritis before the introduction of routine vaccination (Sicily 2003-2012). AB - BACKGROUND: Recent evidence demonstrates that rotavirus vaccination is the best strategy for reducing rotavirus gastro-enteritis (RVGE) in young children. AIMS: This study describes the epidemiology of RVGE hospitalisation of Sicilian children before universal rotavirus vaccination was introduced into the regional immunisation programme in January 2013. METHODS: An observational study was undertaken by analyzing data obtained from the Regional Hospital Discharge database, including hospitalisation from 2003 to 2012 of subjects aged 0-59 months who lived in Sicily. Children discharged with the rotavirus-specific ICD-9 CM code of 008.61 on first or any diagnosis stage were considered to be RVGE cases. RESULTS: From 2003 to 2012, 9317 children (median age 19 months, M/F ratio 1.19) were hospitalised with a diagnosis of RVGE. During the study period, annual rates of hospitalisation were between 2.64 and 4.68 cases/1000 children (mean 3.74 cases). Incidence rates were higher in children aged 6-11 months (8.85/1,000 children/year), decreasing significantly with age (P<0.001). RVGE hospitalisation peaked during winter and spring with a statistically significant downward trend throughout summer and autumn. CONCLUSION: During the study period, the cumulative risk of hospitalisation with RVGE was determined to be about one in 54 Sicilian children in the 1st 5 years of life. Although the present study cannot be considered a proper pharmaco-economic evaluation, the findings suggest that in Sicily the health and economic burden of RVGE hospitalisation strongly supports the introduction of rotavirus vaccination into the regional immunisation programme as a probably cost-saving intervention. PMID- 26744157 TI - Retinopathy of prematurity and associated factors in Lagos, Nigeria. AB - BACKGROUND: Screening and early treatment of retinopathy of prematurity (ROP) is important to reduce visual impairment in at risk infants. AIM: To determine the frequency and risk factors associated with ROP in preterm infants in Lagos University Teaching Hospital. METHODS: This was a prospective cohort study of preterm infants with gestational age (GA) less than 32 weeks and birthweight 1500 g or less conducted from November 2011 to May 2014. The infants' eyes were examined using an indirect ophthalmoscope at 4-6 weeks of life or at 34 weeks post-conceptual age. Examinations were repeated weekly until regression or progression to a high risk pre-threshold disease. Staging was according to the revised International Classification for ROP and treatment criteria were as defined by the Early Treatment for ROP study. The GA, birth weight (BW), use of oxygen, presence of respiratory distress syndrome and other risk factors were recorded and tested for significance. RESULTS: Twelve (15%) of the 80 infants examined had any ROP and six (7.5%) had treatable ROP. The mean (SD) GA and BW for infants with ROP were both lower than for those without ROP; 28.2 (1.7) weeks vs 29.1 (1.6) weeks and 1124 (212) g vs 1251 (274) g for GA and BW, respectively. Risk factors such as supplemental oxygen, sepsis, respiratory distress and anaemia were not significantly associated with ROP. CONCLUSION: The frequency of ROP and treatable ROP was high; it is therefore recommended that routine care of preterm infants should include screening for ROP and that affordable treatment facilities should be provided in public hospitals. PMID- 26744158 TI - Survival of children with sickle cell disease in the comprehensive newborn screening programme in Minas Gerais, Brazil. AB - BACKGROUND: Children in developing countries with sickle cell disease SCD have high rates of mortality, especially in some parts of Africa. AIM: To compare the 5-year estimated mortality rate in children born between 1999 and 2001 with that of children born between 2009 and 2011. METHODS: During the period 1998-2012, sickle cell disease was diagnosed in 2591 of 3,617,919 newborns screened in Minas Gerais, Brazil (1 : 1,400). The estimated probability of death [1 - Survival] was calculated by the Kaplan-Meier method. The logrank test was used to compare groups of survival data. RESULTS: Of the 2576 children (15 were excluded), 193 died (7.4%): 153 (79.3%) had SS/Sbeta(0)-thalassaemia, 34 had SC (17.6%), and six (3.1%) had Sbeta(+) thalassaemia. The 5-year estimated mortality was lower for children born between 2009 and 2011 (n=509) than for those born between 1999 and 2001 (n=624), although not significantly [mean (SD) 5.8% (1.1) vs 6.2% (1.0)], respectively). CONCLUSION: Despite an effective ongoing comprehensive screening programme, mortality from SCD in Minas Gerais is still high. To decrease mortality rates, socio-economic development and SCD education programmes for health professionals and families are required. PMID- 26744160 TI - Cow milk protein allergy presenting as feeding intolerance and eosinophilia: case reports of three preterm neonates. AB - Three preterm infants with cow milk protein allergy (CMPA) presented with feeding intolerance, sepsis-like episodes and persistent moderate-to-severe eosinophilia. After eliminating cow milk, the clinical symptoms improved significantly. CMPA can cause common manifestations in sick preterm infants such as feeding intolerance and eosinophilia. PMID- 26744161 TI - Impact on rotavirus gastro-enteritis hospitalisation during the first year of universal vaccination in Sicily. PMID- 26744159 TI - Haemophagocytic lymphohistiocytosis: a cause of unresponsive malaria in a 5-year old girl. AB - A 5-year-old immunocompetent girl presented with fever, jaundice, hepatosplenomegaly and pancytopenia. The peripheral blood smear demonstrated mixed malaria infection (Plasmodium vivax and Plasmodium falciparum). Fever was persistent despite antimalarials in the absence of any coexisting bacterial or viral infection. Laboratory findings included cytopaenia, hyperbilirubinaemia, hyperferritinaemia, hypertriglyceridaemia, hyponatraemia, deranged partial thromboplastin time, decreasing ESR and megaloblastic changes on bone marrow aspiration. A final diagnosis of haemophagocytic lymphohistiocytosis (HLH) with megaloblastic anaemia associated with severe mixed malaria was made. There was a dramatic response to corticosteroid treatment with improvement in her clinical condition. This report endorses the use of corticosteroids in malaria-associated HLH whenever there is no clinical improvement with antimalarials alone. PMID- 26744162 TI - Cortical femoral suspensory fixation using screw post in anatomic single-bundle anterior cruciate ligament reconstruction: a prospective study and mid-term outcome results. AB - PURPOSE: Cortical femoral suspensory fixation using screw post in ACLR has the advantage of allowing complete filling of the femoral tunnel with graft tissue. In addition, the low cost of the implants is an advantage in countries where cost is an issue of concern. The purpose of the current study was to evaluate the clinical functional outcome results of cortical femoral suspensory fixation using screw post at mid-term follow-up. METHODS: Single surgeon single centre prospective case series study. Sixty two patients having complete ACL tears were included in the current study. Average follow-up was 52.6 months (range 38-68). Objective and subjective IKDC scores, Lysholm knee score, SF-36 score, VAS for patients' satisfaction, VAS for pain and Kellgren & Lawrence (K/L) classification of osteoarthritis were used for follow-up evaluation. RESULTS: Objective IKDC score revealed that 59 patients had grade "A" and 3 had grade "B", while no single patient had neither grade "C" nor "D". The average Lysholm score was 90.7, average subjective IKDC was 89.5. Average SF-36 score was 94.8. The average VAS for operation satisfaction was 9.4. Average VAS for pain was 0.2. Forty six patients were classified as normal K/L classification, nine were grade "1", seven were grade "2". Comparing pre-operative and follow-up objective IKDC, subjective IKDC, Lysholm, SF-36, and VAS for pain scores revealed statistically significant differences (P-value <0.05). CONCLUSION: Femoral suspensory fixation using screw post in ACLR showed excellent functional outcome results at mid-term follow-up. PMID- 26744163 TI - Quantitative evaluation of revascularization at bone tunnels and grafts with contrast-enhanced magnetic resonance angiography after anterior cruciate ligament reconstruction. AB - PURPOSE: Quantitative evaluation of vascular ingrowth to the bone tunnel walls and tendon graft after anterior cruciate ligament reconstruction for up to two years post-surgery using magnetic resonance angiography (MRA). METHODS: The study population consists of 100 patients that underwent reconstruction with multi stranded semitendinosus tendons. The patients were retrospectively divided into those that underwent MRA two, three, four to six, and >= seven months after surgery (46, 17, 16, and 21 patients, respectively). Digital imaging and communication in medicine (DICOM) MRA images were imported into image processing software (OsiriX(r)), and the mean signal-to-noise ratio (SNR) of the bone tunnel walls in the femur and tibia and tendon graft parenchyma in the bone tunnels were measured. RESULTS: On MRA, the signal intensities of the bone tunnel walls in the femur and tibia (12.6 +/- 3.41 and 10.7 +/- 3.04) were greater than that in the tendon graft (2.65 +/- 1.94 and 2.50 +/- 2.02, respectively) at two months after surgery. At three months after surgery, the intensities of the tendon grafts (6.25 +/- 2.18 and 5.77 +/- 1.57, respectively) were greater than those of the bone tunnel wall (2.56 +/- 1.29 and 2.50 +/- 1.11, respectively). At four to six months, the intensities in the bone tunnel wall were 1.76 +/- 0.73 and 1.62 +/- 0.72, respectively, and those in the tendon graft were 5.01 +/- 2.11 and 4.01 +/- 2.35, respectively. At >= seven months after surgery, the intensities in the bone tunnel wall were 1.36 +/- 0.63 and 1.21 +/- 0.87, respectively, and those in the tendon graft were 4.25 +/- 1.87 and 3.44 +/- 1.99, respectively. CONCLUSION: Blood flow was seen around the bone tunnel on the femoral and tibial sides two months after ACL reconstruction and in the tendon graft parenchyma three months after surgery. The remodeling process continued after seven months. PMID- 26744164 TI - The use of traction for treating femoral shaft fractures in low- and middle income countries: a systematic review. AB - PURPOSE: The use of traction for treatment of femoral shaft fractures remains common in low- and middle-income countries (LMICs). The objective of this study is to systematically review the literature on outcomes of traction as definitive treatment for adult femoral shaft fractures in LMICs. METHODS: Using the recommended PRISMA methods for systematic reviews, MEDLINE, EMBASE, LILACS, and AJOL were searched for relevant publications. Results were limited to studies occurring in LMICs as defined by the World Bank. Data on time spent in traction (TT), length of stay (LOS), time to partial weight bearing (PWB), complication incidences, and a total complication incidence were recorded. RESULTS: Of the 693 initial results, nine were eligible for analysis giving a total of 455 unique patients with a mean age of 32.9 years (range: 0 to 96). The average time spent in traction was 52.8 days (range: 19.8 to 122.5), the average length of stay was 55.4 days (range: 45 to 140), and the average time to partial weight bearing was 52.2 days (range: 42 to 60 days). There were a total of 91 malunions, 25 un united fractures, 60 infections, 45 other complications, giving a total of 221 complications in 455 patients. CONCLUSIONS: The use of traction in treating femoral shaft fractures is associated with a high incidence of complications and prolonged course of treatment. Although operative stabilization may be a better alternative, comparative studies are needed to assess whether this can be achieved in a safe and cost-effective manner for widespread application in LMICs. PMID- 26744165 TI - Non-operative treatment of four-part fractures of the proximal end of the humerus: results of a prospective and retrospective multicentric study. AB - PURPOSE: The aim of this study was to evaluate the short- and medium-term results of non-operative treatment of four-part fractures of the proximal end of the humerus. The initial hypothesis was that non-operative treatment of fractures with little or no displacement is equivalent or superior to surgical treatment, and that non-operative treatment is probably insufficient for displaced fractures. METHODS: This was a multicentric, prospective and retrospective study, based on 384 four-part proximal humerus fractures, 58 of which involved non operative treatments - 37 in the prospective study (Pro-CT4) and 21 in the retrospective study (Retro-CT4). The average patient age was 64 +/- 14 years (39 90); 66 % were female and 34 % male. In 88 % of these cases, non-operative treatment was chosen for the fracture, as there was little or no displacement. In 10 % of cases, non-operative treatment was chosen "by default", due to the patient's medical conditions, as surgery was contraindicated, and in 2 % of cases due to the patient refusing surgery. All patients were reviewed clinically and radiologically, with SSV evaluation, absolute and weighted Constant scores and the Quick DASH score all assessed. The main evaluation criterion was the weighted Constant score which was considered a failure when below 70 %. RESULTS: In the Pro-CT4 study, the average follow-up period was 11 +/- four months (5-18) with functional scores as follows: average SSV: 72 +/- 26 % (8-100); average Constant score: 65 +/- 21 points (21-95); average weighted Constant score: 86 +/- 26 % (32 130); average Quick DASH: 23 +/- 21 (0-64). 27 % of patients had a weighted Constant score below 70 %. In the Retro-CT4 study, the average follow-up period was 38 +/- 13 months (18-62) with functional scores as follows: average SSV: 73 +/- 17 % (30-100); average Constant score: 68 +/- 18 points (33-95); average weighted Constant score: 88 +/- 27 % (47-133); average Quick DASH: 18 +/- 16 (0 48); 24 % of patients had a weighted Constant score below 70 %. CONCLUSION: This study confirms our initial hypothesis. When non-operative treatment of four-part proximal humerus fractures is carried out by choice, the results are excellent. However, when this treatment is carried out "by default" - especially because surgery is contraindicated - the results are disappointing. LEVEL OF EVIDENCE IV: prospective and retrospective studies. PMID- 26744166 TI - Clinical and radiological analysis of Bryan cervical disc arthroplasty: eight year follow-up results compared with anterior cervical discectomy and fusion. AB - PURPOSE: Bryan cervical disc arthroplasty has been reported with satisfactory short- and medium-term clinical results. However, the long-term clinical and radiographic outcomes are seldom reported. The purpose of this study was to compare the eight-year follow-up results in patients who underwent Bryan disc arthroplasty with patients received ACDF, and assess the incidence of heterotopic ossification (HO) and its effect on clinical outcome and mobility of the device. METHODS: Thirty-one patients underwent Bryan disc arthroplasty, and 35 patients underwent ACDF were included in the study. The Japanese Orthopedic Association (JOA) scores, neck disability index (NDI), visual analogue scale (VAS) of neck and arm pain, and the radiographs were used to evaluate the outcomes. The heterotopic ossification (HO) was determined by CT scan and was classified into three subgroups to compare the related effect. Adjacent segment degeneration (ASD) was also observed. RESULTS: At final follow-up, there were no significant differences in JOA scores between two groups, but the improvement in NDI and neck or arm VAS were significantly greater in the Bryan disc cohort. The range of motion at the index level was 7.0 degrees in Bryan group, while 100 % bone fusion were achieved in ACDF group. HO was observed in 18 (51.4 %) levels. There were more restricted movement of the prosthesis and slight higher rate of axial pain in patients with severe-HO (grade III and IV). Fourteen (28.6 %) levels developed ASD in Bryan group, which was significantly lower than that (58.6 %) in ACDF group. CONCLUSIONS: At eight year follow-up, the clinical and radiographic outcomes of Bryan cervical disc arthroplasty compared favorably to those of ACDF. It avoided accelerated adjacent segment degeneration by preserving motion. However, severe HO restricted the ROM of the index levels and maybe associated with post-operative axial pain. PMID- 26744168 TI - Peri-operative blood-loss after total hip arthroplasty can be significantly reduced with topical application of epsilon-aminocaproic acid. AB - PURPOSE: To evaluate the peri-operative blood loss with the use of epsilon aminocaproic acid (epsilon-ACA) in total hip arthroplasty (THA). METHODS: One hundred sixty patients treated with THA were followed; 5 g epsilon-ACA diluted in 100 ml normal saline was applied intra-operatively. Eighty patients not receiving epsilon-ACA (non epsilon-ACA group) and eighty patients receiving epsilon-ACA (epsilon-ACA group) were compared regarding blood loss, need of transfusion, and thrombo-embolic complications. RESULTS: Blood loss (mean +/- SD) for the non epsilon-ACA group was 1678 +/- 515 ml and for the epsilon-ACA group 1403 +/- 417 ml (p < 0.05). In the non epsilon-ACA group 23 patients needed blood transfusions compared to ten patients in the epsilon-ACA group (p < 0.05). Cost savings were $284.39 per patient. No patient in either group developed a thrombo-embolic complication. CONCLUSIONS: This study demonstrates a significant reduction in peri-operative blood loss after THA with topically applied epsilon-ACA. The application of epsilon-ACA reduced costs by lowering transfusion rates and did not increase thrombo-embolic events. epsilon-ACA is safe and effective in reducing blood loss and cost-efficient in THA. PMID- 26744167 TI - Joint line level in revision total knee replacement: assessment and functional results with an average of seven years follow-up. AB - INTRODUCTION: It has been shown that the distance between the joint line (JL) and the fibular head is constant in both knees in a given individual. We analysed the influence of the JL level difference between the revised knee and the native knee from the functional outcomes after TKR revision. METHODS: This multicentre study assessed retrospectively a consecutive series of 177 revised total knee replacements. Patients with contralateral knees that had undergone previous major surgery or trauma were excluded. The JL level difference between both knees was measured on Knee's AP standing X-rays and compared to the KSS Knee and Function scores at the final follow-up. RESULTS: Eighty-five cases were analysed at a mean of seven years follow-up. There was a significant increase in KSS Knee and Function scores after surgery. The average elevation of the JL was 2.2 mm (s.d. 2.66 mm) compared with the healthy contralateral knee. When the JL was elevated more than 4 mm this correlated with a decreased KSS Function score and decreased post-operative knee flexion. CONCLUSIONS: Poorer functional results are significantly associated with an elevation in the JL compared to the contralateral healthy knee. In those patients with a suitable contralateral knee the JL level to restore can be assessed by the distance between the femoral condyle and the apex of the fibular head of the contralateral knee. PMID- 26744169 TI - Safety of neuromuscular electrical stimulation in patients implanted with cardioverter defibrillators. AB - Neuromuscular electrical stimulation (NMES) is one of the few exercise modes that have been confirmed to be effective for advanced heart failure patients. Previous clinical trials that verified the effects of NMES excluded patients with implantable cardioverter defibrillators (ICDs). We investigated whether NMES to leg muscles could be applied in heart failure patients implanted with ICDs. As a result, we found that NMES could be conducted without any instances of electromagnetic interference. NMES to leg muscles could be applied safely to ICD patients if the aforementioned common stimulation methods were used with sufficient monitoring during NMES. PMID- 26744170 TI - Metabolome Analyses Uncovered a Novel Inhibitory Effect of Acyclic Retinoid on Aberrant Lipogenesis in a Mouse Diethylnitrosamine-Induced Hepatic Tumorigenesis Model. AB - Acyclic retinoid (ACR) is a promising drug under clinical trials for preventing recurrence of hepatocellular carcinoma. The objective of this study was to gain insights into molecular basis of the antitumorigenic action of ACR from a metabolic point of view. To achieve this, comprehensive cationic and lipophilic liver metabolic profiling was performed in mouse diethylnitrosamine (DEN)-induced hepatic tumorigenesis model using both capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography time-of-flight mass spectrometry. ACR significantly counteracted against acceleration of lipogenesis but not glucose metabolism in DEN-treated mice liver, suggesting an important role of lipid metabolic reprogramming in the initiation step of hepatic tumorigenesis. Knowledge-based pathway analysis suggested that inhibition of linoleic acid metabolites such as arachidonic acid, a proinflammatory precursor, played a crucial role in the prevention by ACR of DEN-induced chronic inflammation mediated tumorigenesis of the liver. As a molecular mechanism of the ACR's effect to prevent the aberrant lipogenesis, microarray analysis identified that a key transcription regulator of both embryogenesis and tumorigenesis, COUP transcription factor 2, also known as NR2F2, was associated with the metabolic effect of ACR in human hepatocellular carcinoma cells. Our study provided potential therapeutic targets for the chemoprevention of hepatocellular carcinoma as well as new insights into the mechanisms underlying prevention of hepatic tumorigenesis. PMID- 26744171 TI - Safety and Tolerability of Nebulized Amoxicillin-Clavulanic Acid in Patients with COPD (STONAC 1 and STONAC 2). AB - The safety and tolerability of nebulized amoxicillin clavulanic acid were determined in patients with stable COPD and during severe exacerbations of COPD. Nine stable COPD patients received doses ranging from 50:10 mg up to 300:60 mg amoxicillin clavulanic acid and eight patients hospitalised for a COPD exacerbation received fixed doses 200/40 mg twice daily. Safety was evaluated by spirometry before and after inhalation. Tolerability was evaluated by questionnaire. Plasma and expectorated sputum samples were assayed for amoxicillin content. Seventeen patients underwent in total 100 nebulizations with amoxicillin clavulanic acid. In this safety and tolerability study no clinically relevant deteriorations in FEV1 were observed. Nebulized amoxicillin clavulanic acid produces sputum concentrations well above the Minimal Inhibiting Concentration of 90% for potential pathogenic micro-organisms, with low concentrations in the central compartment (low systemic exposure). Based on spirometry and reported side effects, inhalation of nebulized amoxicillin clavulanic acid seems to be safe and well tolerated, both in stable patients with COPD as in those experiencing a severe exacerbation. Levels of amoxicillin were adequate. PMID- 26744172 TI - Photoelectron diffraction in methane probed via vibrationally resolved inner valence photoionization cross-section ratios. AB - Vibrationally resolved photoionization of the 2a1 orbital in methane has been studied both experimentally and theoretically, over a wide range of photon energies (40-475 eV). A vibrational progression associated with the symmetric stretch mode of the 2a1(-1) single-hole state was observed in the experimental photoelectron spectra. Individual vibrational sub-states of the spectra were found to be best modeled by asymmetric line-shapes with linewidths gradually increasing with the vibrational quantum number. This indicates the occurrence of a pre-dissociation process for the involved ionic state, discussed here in detail. Finally, diffraction patterns were observed in the vibrational branching ratios for the first three vibrational sub-states ("v-ratios") of the experimental photoelectron spectra. They are found to be in excellent qualitative agreement with those obtained from ab initio models. Compared with previous studies of the 1a1(-1) core-shell photoionization of methane, the period of oscillation of the v-ratios is found to be very different and the phases are of opposite signs. This suggests a strong interplay between the electron diffraction and interference effects inside the molecular potential. PMID- 26744174 TI - Temporal genetic stability of Stegomyia aegypti (= Aedes aegypti) populations. AB - The mosquito Stegomyia aegypti (= Aedes aegypti) (Diptera: Culicidae) is the primary vector of viruses that cause yellow fever, dengue and Chikungunya fever. In the absence of effective vaccines, the reduction of these diseases relies on vector control strategies. The success of these strategies is tightly linked to the population dynamics of target populations. In the present study, 14 collections from St. aegypti populations separated by periods of 1-13 years were analysed to determine their temporal genetic stability. Although temporal structure is discernible in most populations, the degree of temporal differentiation is dependent on the population and does not obscure the geographic structure of the various populations. The results suggest that performing detailed studies in the years prior to and after population reduction- or modification-based control interventions at each target field site may be useful in assessing the probability of success. PMID- 26744173 TI - Value of diffusion-weighted imaging combined with conventional magnetic resonance imaging in the diagnosis of thecomas/fibrothecomas and their differential diagnosis with malignant pelvic solid tumors. AB - BACKGROUND: Our study aims to determine the value of diffusion-weighted imaging (DWI) combined with conventional magnetic resonance imaging (MRI) in the diagnosis of thecomas/fibrothecomas and their differential diagnosis with malignant pelvic solid tumors. METHODS: In total, 36 thecomas/fibrothecomas and 40 malignant pelvic solid tumors were included in our study. All patients underwent 1.5 T conventional MRI and DWI examinations except one patient with a fibrothecoma in whom DWI examination was not performed. The clinical features and characteristics of conventional MRI and DWI of these two groups were analyzed. Apparent diffusion coefficient (ADC) values were measured and compared between groups. Univariate analysis, multivariate logistic regression analysis, and the receiver operating characteristic curve were used for statistical analysis. RESULTS: All the thecomas/fibrothecomas showed isointensity on T1 weighted imaging (T1WI) and 77.8% (28/36) lesions showed hypo- to isointensity on T2 weighted imaging (T2WI). After administration of contrast medium, 94.4% (34/36) tumors appeared as minor to mild enhancement. On DWI, they showed a diversity of low to very high signal intensity. All malignant pelvic masses manifested as hyperintensity on T2WI and 87.5% (35/40) tumors showed very high signal (grade 3) on DWI. Higher area under the curve (AUC) and specificity could be achieved by using the lowest ADC value than the mean ADC value. Multivariate logistic regression analysis showed that shape, signal intensity on T2WI, capsule, and the lowest ADC value were the important indicators in discriminating thecomas/fibrothecomas from malignant pelvic solid tumors. CONCLUSIONS: The combination of DWI and conventional MRI is of great value in the diagnosis of thecomas/fibrothecomas and their differential diagnosis with malignant pelvic solid tumors. PMID- 26744176 TI - Building Capacity to Increase Health Promotion Funding to American Indian Communities: Recommendations From Community Members. AB - Foundations and government agencies have historically played a critical role in supporting community-based health promotion programs. Increased access to health promotion funding may help address significant health issues existing within American Indian (AI) communities, such as childhood obesity, type 2 diabetes, and cardiovascular disease. Understanding the capacity of AI communities to successfully apply for and receive funding may serve to increase resources for health promotion efforts within AI communities in Montana. This exploratory qualitative study completed 17 semistructured interviews across three AI reservations in the state of Montana. Dimensions of community capacity within the context of the funding application process and partnership with funding agencies were identified, including resources, leadership, community need, networks, and relationship with the funding agency. Dimensions of AI community capacity were then used to suggest capacity-building strategies for improved partnership between AI communities in Montana and the funding agencies. PMID- 26744175 TI - Stress increases descending inhibition in mouse and human colon. AB - BACKGROUND: A relationship between stress and the symptoms of irritable bowel syndrome (IBS) has been well established but the cellular mechanisms are poorly understood. Therefore, we investigated effects of stress and stress hormones on colonic descending inhibition and transit in mouse models and human tissues. METHODS: Stress was applied using water avoidance stress (WAS) in the animal model or mimicked using stress hormones, adrenaline (5 nM), and corticosterone (1 MUM). Intracellular recordings were obtained from colonic circular smooth muscle cells in isolated smooth muscle/myenteric plexus preparations and the inhibitory junction potential (IJP) was elicited by nerve stimulation or balloon distension oral to the site of recording. KEY RESULTS: Water avoidance stress increased the number of fecal pellets compared to control (p < 0.05). WAS also caused a significant increase in IJP amplitude following balloon distension. Stress hormones also increased the IJP amplitude following nerve stimulation and balloon distension (p < 0.05) in control mice but had no effect in colons from stressed mice. No differences were observed with application of ATP between stress and control tissues, suggesting the actions of stress hormones were presynaptic. Stress hormones had a large effect in the nerve stimulated IJP in human colon (increased >50%). Immunohistochemical studies identified alpha and beta adrenergic receptor immunoreactivity on myenteric neurons in human colon. CONCLUSIONS & INFERENCES: These studies suggest that WAS and stress hormones can signal via myenteric neurons to increase inhibitory neuromuscular transmission. This could lead to greater descending relaxation, decreased transit time, and subsequent diarrhea. PMID- 26744178 TI - Anti-phytopathogen, multi-target acetylcholinesterase inhibitory and antioxidant activities of metabolites from endophytic Chaetomium globosum. AB - Fourteen metabolites with various structure types were isolated from endophytic Chaetomium globosum. Five compounds were separated from genus Chaetomium for the first time. Some compounds exhibited remarkable inhibition against phytopathogenic fungi causing root rot of Panax notoginseng. Compounds 1-5 had significant DPPH-free radical-scavenging activity. Compounds 3 and 5 indicated significant inhibitions against the acetylcholinesterase (AChE). From preliminary structure-activity relationship, it was found that the oxygenic five-membered ring of 3 and 5 was crucial in the anti-AChE activity. These structures provide new templates for the potential treatment and management of plant diseases and Alzheimer disease. PMID- 26744177 TI - Sertoli cells have a functional NALP3 inflammasome that can modulate autophagy and cytokine production. AB - Sertoli cells, can function as non-professional tolerogenic antigen-presenting cells, and sustain the blood-testis barrier formed by their tight junctions. The NOD-like receptor family members and the NALP3 inflammasome play a key role in pro-inflammatory innate immunity signalling pathways. Limited data exist on NOD1 and NOD2 expression in human and mouse Sertoli cells. Currently, there is no data on inflammasome expression or function in Sertoli cells. We found that in primary pre-pubertal Sertoli cells and in adult Sertoli line, TLR4?NOD1 and NOD2 crosstalk converged in NFkappaB activation and elicited a NALP3 activation, leading to de novo synthesis and inflammasome priming. This led to caspase-1 activation and IL-1beta secretion. We demonstrated this process was controlled by mechanisms linked to autophagy. NOD1 promoted pro-IL-1beta restriction and autophagosome maturation arrest, while NOD2 promoted caspase-1 activation, IL 1beta secretion and autophagy maturation. NALP3 modulated NOD1 and pro-IL-1beta expression, while NOD2 inversely promoted IL-1beta. This study is proof of concept that Sertoli cells, upon specific stimulation, could participate in male infertility pathogenesis via inflammatory cytokine induction. PMID- 26744179 TI - A concise review on smart polymers for controlled drug release. AB - Design and synthesis of efficient drug delivery systems are of critical importance in health care management. Innovations in materials chemistry especially in polymer field allows introduction of advanced drug delivery systems since polymers could provide controlled release of drugs in predetermined doses over long periods, cyclic and tunable dosages. To this end, researchers have taken advantages of smart polymers since they can undergo large reversible, chemical, or physical fluctuations as responses to small changes in environmental conditions, for instance, in pH, temperature, light, and phase transition. The present review aims to highlight various kinds of smart polymers, which are used in controlled drug delivery systems as well as mechanisms of action and their applications. PMID- 26744180 TI - Quantitative in vivo biocompatibility of new ultralow-nickel cobalt-chromium molybdenum alloys. AB - Nickel (Ni) eluted from metallic biomaterials is widely accepted as a major cause of allergies and inflammation. To improve the safety of cobalt-chromium molybdenum (Co-Cr-Mo) alloy implants, new ultralow-Ni Co-Cr-Mo alloys with and without zirconium (Zr) have been developed, with Ni contents of less than 0.01%. In the present study, we investigated the biocompatibility of these new alloys in vivo by subcutaneously implanting pure Ni, conventional Co-Cr-Mo, ultralow-Ni Co Cr-Mo, and ultralow-Ni Co-Cr-Mo with Zr wires into the dorsal sides of mice. After 3 and 7 days, tissues around the wire were excised, and inflammation; the expression of IL-1beta, IL-6, and TNF-alpha; and Ni, Co, Cr, and Mo ion release were analyzed using histological analyses, qRT-PCR, and inductively coupled plasma mass spectrometry (ICP-MS), respectively. Significantly larger amounts of Ni eluted from pure Ni wires than from the other wires, and the degree of inflammation depended on the amount of eluted Ni. Although no significant differences in inflammatory reactions were identified among new alloys and conventional Co-Cr-Mo alloys in histological and qRT-PCR analyses, ICP-MS analysis revealed that Ni ion elution from ultralow-Ni Co-Cr-Mo alloys with and without Zr was significantly lower than from conventional Co-Cr-Mo alloys. Our study, suggests that the present ultralow-Ni Co-Cr-Mo alloys with and without Zr have greater safety and utility than conventional Co-Cr-Mo alloys. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1505-1513, 2016. PMID- 26744181 TI - Gene array of PDL cells exposed to Osteogain in combination with a bone grafting material. AB - OBJECTIVES: The aim of the present study was to investigate the effects of Osteogain, a new formulation of enamel matrix derivative (EMD) in combination with a grafting material on a wide variety of genes for cytokines, transcription factors and extracellular matrix proteins involved in osteoblast differentiation. MATERIALS AND METHODS: Primary human periodontal ligament (PDL) cells were seeded on natural bone mineral (NBM) particles coated with Osteogain for 24 h and analyzed for regulated gene expression using a human osteogenesis gene super array kit. Osteoblast-related genes include those transcribed during bone mineralization, ossification, bone metabolism, cell growth and differentiation as well as gene products representing extracellular matrix molecules, transcription factors and cell adhesion molecules. RESULTS: Osteogain significantly upregulated the expression of over 20 of the 100 genes examined including bone morphogenetic protein 2 (BMP2), TGFbeta1, fibroblast growth factor (FGF), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) as well as some of their associated receptors. Osteogain also promoted gene expression of a number of osteoblast differentiation markers including collagen1alpha2 and alkaline phosphatase as well as cell adhesion molecules including fibronectin and a variety of integrin binding proteins. Interestingly, Osteogain promoted calcitonin receptor 55-fold and also promoted annexin A5 gene expression over 12 fold. CONCLUSION: The present study demonstrates that Osteogain is capable of either upregulating or downregulating the expression of a wide variety of genes including those for growth factors and cytokines when combined with a bone grafting material. CLINICAL RELEVANCE: The results from the present study demonstrate the large and potent effect of addition of Osteogain in combination to a bone grafting material over a wide variety of genes supporting osteogenesis. PMID- 26744184 TI - Np(v) complexation with carbonate in aqueous solutions studied by spectrophotometric titration at various temperatures. AB - The complexation of neptunium(v) with carbonate has been studied at temperatures from 10 to 70 degrees C in 0.1 M LiClO4 by spectrophotometry. Three NpO2(+) CO3(2-) complex species, NpO2(CO3)n((2n-1)-) (n = 1, 2, 3), are identified and the stability constants are calculated by using the absorption spectra in the near-IR region collected from titrations at varying temperatures. The enthalpies and entropies are calculated with van't Hoff equations in the temperature range of 10 to 70 degrees C, indicating that the formation of all NpO2(+)-CO3(2-) complexes is mainly entropy driven. The structures of the NpO2(+)-CO3(2-) complex species in aqueous solutions are also reviewed. Based on the molar absorptivity of Np(v) in the near-IR region the structure of NpO2(CO3)2(3-) is re-constructed as NpO2(CO3)2(H2O)(3-)of low symmetry but not as NpO2(CO3)2(H2O)2(3-)of high symmetry as suggested in a previous study. PMID- 26744183 TI - Deciphering the streamlined genome of Streptomyces xiamenensis 318 as the producer of the anti-fibrotic drug candidate xiamenmycin. AB - Streptomyces xiamenensis 318, a moderate halophile isolated from a mangrove sediment, produces the anti-fibrotic compound xiamenmycin. The whole genome sequence of strain 318 was obtained through long-read single-molecule real-time (SMRT) sequencing, high-throughput Illumina HiSeq and 454 pyrosequencing technologies. The assembled genome comprises a linear chromosome as a single contig of 5,961,401-bp, which is considerably smaller than other reported complete genomes of the genus Streptomyces. Based on the antiSMASH pipeline, a total of 21 gene clusters were predicted to be involved in secondary metabolism. The gene cluster responsible for the biosynthesis of xiamenmycin resides in a strain-specific 61,387-bp genomic island belonging to the left-arm region. A core metabolic network consisting of 104 reactions that supports xiamenmycin biosynthesis was constructed to illustrate the necessary precursors derived from the central metabolic pathway. In accordance with the finding of a putative ikarugamycin gene cluster in the genome, the targeted chemical profiling of polycyclic tetramate macrolactams (PTMs) resulted in the identification of ikarugamycin. A successful genome mining for bioactive molecules with different skeletons suggests that the naturally minimized genome of S. xiamenensis 318 could be used as a blueprint for constructing a chassis cell with versatile biosynthetic capabilities for the production of secondary metabolites. PMID- 26744182 TI - Overexpression of ThVHAc1 and its potential upstream regulator, ThWRKY7, improved plant tolerance of Cadmium stress. AB - As one of the most toxic heavy metals in the environment, cadmium (Cd) poses a severe threat to plant growth. We previously reported that overexpression of the Tamarix hispida V-ATPase c subunit (ThVHAc1) improved the Cd tolerance of Saccharomyces cerevisiae. In the current study, we further explored the Cd tolerance conferred by ThVHAc1 in Arabidopsis and T. hispida. ThVHAc1 transgenic Arabidopsis had higher seed germination, biomass, and chlorophyll content under CdCl2 treatment. In Cd-stressed plants, overexpression of ThVHAc1 significantly improved V-ATPase activity and affected the expression of other V-ATPase subunit encoding genes. Intriguingly, the lower level of ROS accumulation in ThVHAc1 overexpressing lines under CdCl2 treatment demonstrated that ThVHAc1 may modulate Cd stress tolerance by regulating ROS homeostasis. Transient expression of ThVHAc1 in T. hispida further confirmed these findings. Furthermore, promoter analysis and yeast one-hybrid assay revealed that the transcription factor ThWRKY7 can specifically bind to the WRKY cis-element in the ThVHAc1 promoter. ThWRKY7 exhibited similar expression patterns as ThVHAc1 under CdCl2 treatment and improved Cd tolerance, suggesting that ThWRKY7 may be an upstream regulatory gene of ThVHAc1. Therefore, our results show that the combination of ThVHAc1 and its upstream regulator could be used to improve Cd stress tolerance in woody plants. PMID- 26744187 TI - [Quality of German medical services: a review]. AB - In the current draft of the law on the reform of the support structures of hospital provision (German Hospital Structure Law) the future quality of provision is highly significant. Quality assurance measures are mandatory for hospitals. The Federal General Committee was legally charged with developing the relevant quality indicators for structural, procedural and outcome quality that are designed to form the criteria and the basis for planning decisions in the federal states. This involves a paradigm shift in quality assurance measures in hospitals. In the future, subject to the verified quality, this should have an influence on hospital planning, and the funding or regulation of hospital departments should also adhere to this prescribed quality. This review reveals the course of quality or quality assurance measures in medical services in Germany. The status of the institutions responsible for the quality of care in hospitals and the significance of quality indicators are explained. PMID- 26744186 TI - [Type I interferonopathies. Systemic inflammatory diseases triggered by type I interferons]. AB - Type I interferons mediate immune defense against viral infections. The induction of type I interferons has stimulating and modulating effects on the innate and adaptive immune systems thereby reducing tolerance against self-antigens. Genetic defects that result in an inadequate activation of the type I interferon system can cause a group of inflammatory disorders, which are collectively referred to as type I interferonopathies. While the clinical spectrum of type I interferonopathies is broad and heterogeneous, neurological and cutaneous symptoms are the most frequent manifestations. Some clinical and genetic features of type I interferonopathies are shared by multifactorial diseases, such as systemic lupus erythematosus and systemic vasculitis. Advances in understanding the disease mechanisms underlying type I interferonopathies have pinpointed novel targets for therapeutic interventions. PMID- 26744185 TI - [EULAR recommendations for patient education of people with inflammatory arthritis. Translation and evaluation in Germany]. AB - In 2015 EULAR published recommendations for patient education of people with inflammatory arthritis. The recommendations included two superior principles and eight recommendations based on the level of evidence and expert knowledge. The German translation of the recommendations was evaluated by 15 German experts. Experts graded the strength of the recommendations (SOR) on an 11 point numerical rating scale (from 0 = no agreement to 10 = total agreement). The mean score was 8,8 +/- 0,49. PMID- 26744188 TI - Bandgap tunable colloidal Cu-based ternary and quaternary chalcogenide nanosheets via partial cation exchange. AB - Copper based ternary and quaternary semiconductor nanostructures are of great interest for the fabrication of low cost photovoltaics. Although well-developed syntheses are available for zero dimensional (0D) nanoparticles, colloidal synthesis of two dimensional (2D) nanosheets remains a big challenge. Here we report, for the first time, a simple and reproducible cation exchange approach for 2D colloidal Cu2GeSe3, Cu2ZnGeSe4 and their alloyed Cu2GeS(x)Se(3-x), Cu2ZnGeS(x)Se(4-x) nanosheets using pre-synthesized Cu(2x)Se nanosheets as a template. A mechanism for the formation of Cu(2-x)Se nanosheets has been studied in detail. In situ oxidation of Cu(+) ions to form a CuSe secondary phase facilitates the formation of Cu(2-x)Se NSs. The obtained ternary and quaternary nanosheets have average lateral size in micrometers and thickness less than 5 nm. This method is general and can be extended to produce other important ternary semiconductor nanosheets such as CuIn(1-x)Ga(x)Se2. The optical band gap of these nanosheets is tuned from 1 to 1.48 eV, depending on their composition. PMID- 26744189 TI - Erratum to: Pharmacological interventions for challenging behaviour in children with intellectual disabilities: a systematic review and meta-analysis. PMID- 26744190 TI - Chinese military medical teams in the Ebola outbreak of Sierra Leone. AB - The 2014-2015 Ebola virus disease (EVD) epidemic in West Africa was the largest in history. The three most affected countries, Guinea, Liberia and Sierra Leone, have faced enormous challenges in controlling transmission and providing clinical care for patients with EVD. The Chinese government, in response to the requests of the WHO and the governments of the affected countries, responded rapidly by deploying Chinese military medical teams (CMMTs) to the areas struck by the deadly epidemic. A total of three CMMTs, comprising 115 military medical professionals, were rotationally deployed to Freetown, Sierra Leone to assist with infection prevention and control, clinical care and health promotion and training. Between 1 October 2014 and 22 March 2015, the CMMTs in Sierra Leone admitted and treated a total of 773 suspected and 285 confirmed EVD cases. Among the 285 confirmed cases, 146 (51.2%) patients survived after treatment. In addition, the CMMTs maintained the record of zero infections among healthcare workers and zero cross-infections between quarantined patients. In this manuscript, we aim to give an overview of the mission, and share our best practices experience on predeployment preparedness, EVD holding and treatment centre building and EVD case management. PMID- 26744191 TI - Health protection during the Ebola crisis: the Defence Medical Services approach. AB - This paper is a narrative of the policies, procedures, mitigations and observations of the application of Force Health Protection measures applied by the Ministry of Defence (MOD) for the deployment of military personnel to West Africa as part of the UK contribution to the international response to the Ebola crisis from July 2014 to July 2015. The MOD divided the threat into three risk categories: risk from disease and non-battle injury, Ebola risk for non-clinical duties and Ebola risk for healthcare workers. Overall risk management was directed and monitored by the OP GRITROCK Force Health Protection Board. There were six cases of malaria, four outbreaks of gastrointestinal disease, two needlestick injuries in Ebola-facing healthcare workers, one MOD Ebola case and five non-needlestick, high-risk exposures. This experience reinforces the requirement for the Defence Medical Services to have a high level of organisational competence to advise on Force Health Protection for the MOD. PMID- 26744192 TI - Superactivation of AMPA receptors by auxiliary proteins. AB - Glutamate receptors form complexes in the brain with auxiliary proteins, which control their activity during fast synaptic transmission through a seemingly bewildering array of effects. Here we devise a way to isolate the activation of complexes using polyamines, which enables us to show that transmembrane AMPA receptor regulatory proteins (TARPs) exert their effects principally on the channel opening reaction. A thermodynamic argument suggests that because TARPs promote channel opening, receptor activation promotes AMPAR-TARP complexes into a superactive state with high open probability. A simple model based on this idea predicts all known effects of TARPs on AMPA receptor function. This model also predicts unexpected phenomena including massive potentiation in the absence of desensitization and supramaximal recovery that we subsequently detected in electrophysiological recordings. This transient positive feedback mechanism has implications for information processing in the brain, because it should allow activity-dependent facilitation of excitatory synaptic transmission through a postsynaptic mechanism. PMID- 26744193 TI - Antibiotic Use, Its Resistance in Nepal and Recommendations for Action: A Situation Analysis. AB - Antibiotics are crucial, life-saving medicines in the fight against infectious disease, but resistance to these drugs is growing all over. This article presents key findings from a detailed situation analysis produced by the Global Antibiotic Resistance Partnership (GARP)-Nepal working group. In the absence of nationally representative surveillance, it is not possible to fully describe antibiotic resistance in the country, but many important bacterial pathogens are highly resistant to most first-line and some second-line antibiotics, according to available reports. In credible studies, more than half of Escherichia coli, Klebsiella pneumoniae and Streptococcus pneumoniae isolates tested, and over 30 percent of some Shigella spp. and Vibrio cholerae isolates were resistant to first-line antibiotics. The findings for Neisseria gonorrheae and hospital acquired Staphylococcus aureus are similar. Antibiotic use in animal food is poorly documented in Nepal, but it is commonly acknowledged to be widespread, contributing to the overall antibiotic resistance burden. The volume of veterinary antibiotic sales in Nepal rose over 50 percent from 2008 to 2012, most through retailers without veterinarian prescription. Antibiotics are necessary to treat infections in animals, but they are also used extensively for preventing disease, a use that can be restricted without jeopardizing animal or human health. They may also be used for promoting animal growth, which can be eliminated with no health consequences. Nepal has made important advances in reducing mortality and morbidity and increasing health coverage, but has not yet taken steps to address antibiotic resistance. The GARP-Nepal working group outlines the components of a national strategy on antibiotic resistance, consistent with the recent call by the World Health Organization for national action plans, to be developed collaboratively with stakeholders and partners from government and all relevant sectors. PMID- 26744194 TI - Health Seeking Behavior among Mothers of Sick Children. AB - BACKGROUND: Infant and under-five mortality rate in Nepal are 46 and 54 deaths per 1,000 live births, respectively. These mortality indicates, one in every 22 Nepalese children dies before reaching age 1, and one in every 19 does not survive to his or her fifth birthday. Delay in seeking appropriate care and not seeking any care contributes to the large number of child deaths. Existing interventions could prevent many deaths among children if they are presented at health facility and timely care. METHODS: A descriptive research was carried out in Lele VDC, ward no.7, Lalitpur. The objective of this study was to find out health seeking behavior among mothers of sick children. Non probability, purposive sampling method was used. Sample size was 102 mothers who had sick children from 0 to 59 months. A set of semi structured questionnaire was used to obtain the data. RESULTS: The mean age of the respondent was 25.8 years and child was 29 months. Respondents' children who suffered with pneumonia, diarrhoea and malnutrition were 64(62.7%),29(28%), 9(8.8%) respectively. Majority 84(81.4%) mothers had sought treatment and among them 58(69%) sought treatment from health facility whereas 26(31%) sought treatment from traditional healer. There was significant relationship between education of the mother(p=0.05), sex of the child (p=0.004), type of sickness of children (p=0.001) of the mother and health seeking behaviour of mothers. However occupation of the mothers for seeking treatment (p=0.66) and treatment seeking at first (p=0.82) were not significant. So there was no relationship between occupation of the mothers and health seeking behaviour. CONCLUSIONS: Majority of the mothers sought treatment from health facility, yet around one fourth went at traditional healers. Education of the mother, sex of the child, sickness of child and mother's awareness are the factors affecting health seeking behavior of the mothers. PMID- 26744195 TI - Computed Tomography in the Evaluation of Pathological Lesions of Paranasal Sinuses. AB - BACKGROUND: Computed tomography is now the modality of choice for imaging paranasal sinuses and along with Functional Endoscopic Sinus Surgery has empowered the modern rhinologist to treat patients more effectively. This study aims to evaluate anatomical variation in paranasal sinuses; compare computed tomography with histopathological and surgical findings and establish its diagnostic value. METHODS: A hospital based observational study including all patients referred from the department of Ear, Nose and Throat for computed tomography scan of paranasal sinus to the department of radiology and imaging of Trubhuvan University Teaching Hospital from August 2011 to July 2012. Both axial and coronal sections were evaluated and findings were correlated with surgical findings and histopathology. RESULTS: A total of 44 patients were included in the study. The most common clinical diagnosis was sinonasal polyposis and chronic rhinosinusitis. Most common anatomical variation was deviated nasal septum (68.2%) followed by choncha bullosa(27%). In most cases more than one sinus was involved. Maxillary sinus was involved in 90.9% followed by ethmoid sinus in 81.8%. Inflammatory pathology was seen in 35 (79.5%) patients with sinonasal polyposis pattern being the most common pattern of involvement. Findings of computed tomography were similar to surgical findings in 84.6% cases. The sensitivity and specificity of computed tomography was fairly good except for fungal rhinosinusitis. CONCLUSIONS: CT scan should be performed preoperatively in order to guide the surgeon for Functional Endoscopic Sinus Surgery or other surgical procedures. PMID- 26744196 TI - Association of Maternal Factors with Low Birth Weight in Selected Hospitals of Nepal. AB - BACKGROUND: The high prevalence of low birth weight remains a major public health problem around the world. Nepal has prevalence of it as high as 21%. Because of poor dietary intake, majorities of Nepalese women have low body mass index and are anaemic that results in poor pregnancy outcome. METHODS: This hospital based case-control study was carried out in four hospitals of Nepal from August 2012 to September 2013. It sought the association of factors to low birth weight like maternal height, weight, and body mass index, food intake, past history of low birth weight, and preterm delivery. Total sample of 1533 were taken, among them 511 were cases and 1022 were controls. RESULTS: Total of 1533 mothers were interviewed across four hospitals. The study revealed mean height, weight and body mass index of mothers were 150cm (SD:6.6), 49kg (SD:6.8), and 21.5kg/m (SD:3) respectively. On crude odds analysis, mothers with height <145cm had 1.5 times (CI:1.1-2.1), weight <45kg had 2.4 times (CI:1.9-3.1), body mass index <18.5kg/m 2 2 had 2.2 times (CI:1.6-2.9), food taken <2 times had 2 times (CI:1.4 2.9) higher chance of delivering low birth weight babies respectively. On adjusted OR analysis, height <145cm (AOR=0.5, CI:0.3-0.9); weight <45kg (AOR=0.5, CI:0.3-1.0) history of low birth weight (AOR=5.1, CI:2.1-12.8) were associated to current low birth weight. CONCLUSIONS: The study concluded that the chances of delivering low birth weight were higher among mothers who are thin, short, low body mass index, less food intake, had history on low birth weight and preterm birth. Among them, a past history on low birth weight was the strongest predictor in this study. PMID- 26744197 TI - Staphylococcus Aureus: Methicillin Resistance and Small Colony Variants from Pyogenic Infections of Skin, Soft Tissue and Bone. AB - BACKGROUND: Staphylococcus aureus (S. aureus) colonizing the nares, is the leading cause of hospital as well as community acquired infections. The aim of this study was to identify the S. aureus from skin, soft tissue and bone related infections and typing them on the basis of antimicrobial susceptibility profile. METHODS: Clinical samples were collected from patients with skin, soft tissue and bone related infections from January to October 2013 at Chitwan Medical College Teaching Hospital, Bharatpur. The S. aureus, small colony variants and methicillin resistant strains were identified by standard microbiological methods recommended by American Society for Microbiology. Antimicrobial susceptibility testing was performed by modified Kirby-Bauer disk diffusion method. RESULTS: Among 333 samples processed, there was positive growth of S. aureus in 66 (19.8%) samples. Among the isolated S. aureus, 10 isolates were small colony variants of S. aureus and all the strains recovered were thymidine independent in this study. Amikacin, vancomycin and teicoplanin were found to be the most effective antibiotics. Methicillin resistance was found in 34.8% isolates of S. aureus. CONCLUSIONS: It can be concluded that, S. aureus is one of the causative agent of pyogenic infections and the trend of antibiotic resistant is alarmingly high and also the rate of methicillin resistant S. aureus is comparably high in this study. PMID- 26744198 TI - Comparative Evaluation of Effect of Chlorhexidine and Sodium Fluoride Mouthwashes on Plaque. AB - BACKGROUND: Dental plaque, deposition of microorganisms embedded in extracellular matrix, initiates dental caries and periodontal diseases Thus, removal of dental plaque by mechanical or chemical means is the key intervention in prevention of dental caries and gingivitis. METHODS: To compare the efficacy of chlorhexidine (0.2%) and sodium fluoride (0.05%) mouthwashes in reduction of plaque deposition, 75 children of age group 8-14 years were divided in three equal groups. Group A and group B were test groups for chlorhexidine and sodium fluoride respectively and group C was control group. The subjects were instructed to rinse the mouth with 10 ml of mouthwash for one minute twice daily for fifteen days. Amount of plaque was analyzed by Silness and Loe index at the beginning and end of the study period. Inter group and intra group comparisons were done to evaluate the efficacy of mouthwashes by using paired t test and Anova test. RESULTS: There was significant reduction in plaque in both test groups (p= 0.000) whereas in control group, there was no significant reduction in amount of plaque (p=0.100) count. Efficacy of the both mouthwashes was statistically equal. CONCLUSIONS: Sodium fluoride is as potent antimicrobial agent as chlorhexidine and would be better mouthwash due to its additional remineralization property for prevention of dental caries and gingivitis in children. PMID- 26744199 TI - Clinical Profile and Early Complications after Single and Dual Chamber Permanent Pacemaker Implantation at Manmohan Cardiothoracic Vascular and Transplant Centre, Kathmandu, Nepal. AB - BACKGROUND: Permanent pacemaker implantation is a minimally invasive surgical procedure in the management of patients with cardiac problems. However, complications during and after implantation are not uncommon. There is lack of evidences in rate of complications with the selection of pacemakers in Nepal. Therefore, this study was performed to compare the frequency of implantation and complication rate between single chamber and dual chamber pacemaker. METHODS: The present study is based on all consecutive pacemaker implantations in a single centre between April 2014 and May 2015. A total of 116 patients were categorized into two cohorts according to the type of pacemaker implanted- single chamber or dual chamber. All patients had regular 2-weeks follow-up intervals with standardized documentation of all relevant patient data till 6-week after implantation. Data were presented as means +/- standard deviation (SD) for continuous variables and as proportions for categorical variables. Comparison of continuous variables between the groups was made with independent Student's t test. For discrete variables distribution between groups were compared with Chi square test. RESULTS: The mean age (+/-SD) of total population at implant was 64.08 (+/- 15.09) years. Dual chamber units were implanted in 44 (37.93%) of patients, single chamber in 72 (62.06%). Only 14 women (31.81%) received dual chamber compared with 42 women (58.33%) who received single chamber (Chi square=18, DF=1, P = 0.0084). Complete atrioventricular block was the commonest (56.03%) indication for permanent pacemaker insertion followed by sick sinus syndrome (33.62%), symptomatic high-grade AV block (11.20%). Hypertension (dual chamber 21.55%, single chamber 40.51%) was the most common comorbidity in both cohorts. Complications occurred in 11 (9.48%) patients. More proportion of complication occurred in single chamber group (9 patients, 12.50%) than in dual chamber (2 patients, 4.54%). Complications occurring in dual chamber group include pocket hematoma 1 patient (2.27%) and arrhythmia in 1 patient (2.27%). Similarly, complications occurring in single chamber include RV perforation in two patients (2.77%) and one each (1.38%) had pocket hematoma, pneumothorax, infection, swelling at pocket site, arrhythmia in the form of NSVT, leads displacement, DVT and mortality. CONCLUSIONS: Women were more likely to receive single chamber systems than men. More proportion of complication occurred in single chamber group than in dual chamber. Future prospective studies on larger number of patients are needed to confirm and support our findings. PMID- 26744200 TI - Post-traumatic Stress Disorder among Medical Personnel after Nepal earthquake, 2015. AB - BACKGROUND: Health professionals involved in a disaster are not immune to the stressors. However, little attention is given on the psychological consequences among these professionals. This study has explored the frequency of posttraumatic stress disorder (PTSD) among them after the Nepal earthquake 2015. METHODS: A descriptive cross sectional study was carried out amongst the medical professionals at Manmohan Memorial Teaching Hospital, Kathmandu to assess the PTSD among them after the Nepal earthquake 2015. Two months after the post disaster the standard PTSD Checklist for DSM-5 (PCL 5) was administered to medical personnel of a hospital(n=64) along with demographic features, disaster related experience and working hours. PTSD was defined by two ways: 1.using DSM V diagnostic criteria (the presence of at least one intrusion, one avoidance, two negative alterations in cognitions/mood and two alterations in arousal and reactivity symptoms); and 2. a cutoff score of 30. RESULTS: The overall prevalence of PTSD was 21.9% and 17.1% using cutoff score and diagnostic criteria respectively. Females scored significantly higher than males. No significant difference was observed according to age, marital status, profession, previous disaster experience, tragic events with relatives. Those who were present in the hospital during the initial influx of victims, witnessed patients suffering, worked extra time were at significantly high risk for development of PTSD. CONCLUSIONS: This study suggest that PTSD is highly prevalent among healthcare professionals after disaster management and therefore it highlights the need for targeted interventions to specific staff who respond to large disasters to reduce the psychological burden. PMID- 26744201 TI - Opportunities and Challenges of a Rural-telemedicine Program in Nepal. AB - BACKGROUND: Telemedicine services are considered essential for improving the accessibility, quality and efficiency of the healthcare services in developing countries. With these expectations, government of Nepal has implemented a rural telemedicine program in thirty peripheral district hospitals to improve the accessibility of specialist health services. Telemedicine can be appropriate to the nation like Nepal with low physician/patient ratio. However the acceptability of telemedicine can be a delayed process, where the healthcare modalities are not well internalized. Similarly, the peoples who are involved in the program play a key role for making it efficient and effective. Hence, assessing the opportunities and challenges is important to address needs and better implement the program. METHODS: This study has used an interpretive case study approach to explore the opportunities and challenges of the program. Fifteen stakeholders were interviewed from central level and program sites namely Darchula, Sindhupalchowk and from Patan hospital. Discussions at peripheral sites with stakeholders were recorded and intensive notes were taken. RESULTS: The findings suggested that the rural-telemedicine programme does offer some benefits, however there are still many challenges associated with the implementation of program. These challenges include infrastructure problems, lack of human resources, competence and financing. CONCLUSIONS: Overall attitude of the stakeholders involved in delivering telemedicine services was favorable however several loopholes were reported in the existing system. Hence it shows sufficient potentialities of rural- telemedicine to improve the health care delivery in rural and inaccessible areas. PMID- 26744202 TI - Magnetic Resonance Imaging Findings in Lumbar Disc Degeneration in Symptomatic Patients. AB - BACKGROUND: The sequel of disc degeneration is one of the leading causes of functional incapacity that leads to chronic disability. The study aims to evaluate the MRI findings of degenerative changes in symptomatic patients. METHODS: The study was a retrospective study for the duration of 3 years. Symptomatic patients undergoing MRI of LS spine were included in the study. Patients undergoing MRI for neurological symptoms alone and acute trauma or suspected infection or tumor were excluded from the study. MRI of patients was evaluated for degenerative changes and their sequel. Data was entered in a predesigned proforma and analysis was done with SPSS version 19.0. RESULTS: A total of 2037 MRIs of LS spine of symptomatic patients were included in the study. Degenerative changes were demonstrated in 1906 (93.8 %) patients, which comprised 1039 (54.5 %) males and 867 (45.4 %) females. Disc bulge along with disc desiccation was the most common degenerative findings noted in 1667 (81.8 %). Disc herniation was seen in 1032(50.6%), neural foraminal stenosis in 1220 (59.8 %), central spinal canal in 1136 (55.8%) and nerve root compression in 650 (31.9%). Disc bulge, neural foraminal stenosis, central spinal canal stenosis was significantly more common in patients older than 40 years. Disc herniation was however significantly more frequent in patients younger than 40 years. CONCLUSIONS: Degenerative changes are common in symptomatic patients and increase in frequency with aging. Disc herniation is however more common in younger patients. PMID- 26744203 TI - Diagnostic Disparity in Solitary Cysticercosis of the Forearm in a Child. AB - Solitary cysticercosis of muscle is a rare disease causing diagnostic dilemma. Cysticercosis commonly affects the central nervous system and other tissues by dissemination imposing a serious health problem. We report this rare presentation of solitary cysticercosis of flexor digitorum superficialis in a five year old otherwise healthy child. The fine needle aspiration cytology and histopathological diagnosis were inconclusive but ultrasonography of the muscle clinched the diagnosis. PMID- 26744204 TI - Spectacles in Stomach: A Case of Successful Endoscopic Removal. AB - Ingestion of foreign bodies is a common reason for emergency visit. The ingested objects include batteries, needles, dentures, coins, sharps etc. Radiolucency and the length of the objects are important factors that affect their management. Long objects over 10 cm are less likely to pass through the duodenal curve. Sharp object that is not retrieved at the earliest may penetrate the wall and cause complications. We present here a challenging case of a middle aged psychiatric patient who swallowed long and sharp arms of her spectacles that were successfully retrieved endoscopically. PMID- 26744205 TI - Bilateral Ovarian Teratoma: One Parasitic Twisted In-situ and Another Parasitic at the Hepato Renal Space. AB - Parasitic ovarian dermoid cysts are very rare. We report a rare case of bilateral ovarian dermoid cysts with parasitic teratoma at the hepato renal space measuring 11x11x6 cm while the other was twisted measuring 10x6x5 cm.Right ovary and tube were absent. The mass found at the hepato renal space was surrounded by and adherent to the omentum with viable tubal fimbria like structure at upper surface. Histopathologically both masses were confirmed as mature ovarian teratoma. The etiology of parasitic teratoma would be due to torsion followed by autoamputation and reimplantation of the right ovarian dermoid cyst. PMID- 26744206 TI - Oral Cancer Care and Oromaxillofacial Surgery. AB - Oral cancers are one of the most common cancers affecting people of Nepal and it the sixth most common cancer in the world. Unlike other cancers the early detection of the disease is possible through a routine examination of the oral cavity which is usually done by a dental practitioner. Through a series of phases like prevention, screening, early intervention, diagnosis and staging, management with tumor ablative surgeries, and rehabilitation to restore the function and esthetic part for better clinical outcome, the role of the specialty of dentistry is immensified. From a patient perspective, having a direct referral line within the dental community between dentists and oral and maxillofacial surgeons will contribute to cost reduction and improvement in outcomes. Trained oral and maxillofacial surgeon especially in the head and neck oncology plays a vital role in exploring functional multidisciplinary efforts to enhance patient care, academic excellence and research initiatives and evaluate for gaps in patient care. This article highlights the role of such professionals in a multidisciplinary team approach for the proper management of head and neck cancers which have significantly and logically additive effect for a better outcome. PMID- 26744207 TI - Birth Defects: Emerging Public Health Issue. PMID- 26744208 TI - Structural color changes in permanent enamel of patients with cleft lip and palate: a case-control study. AB - OBJECTIVES: White spots are more common in patients with cleft lip and palate (CLP) than in the normal population. Whether these are due to the cleft itself or concomitant circumstances (e.g., surgical procedures, orthodontic treatments, systemic fluoridation, increased caries risk) remains unclear. This case-control study evaluated both their prevalence in CLP patients versus control subjects and associated risk factors. PATIENTS AND METHODS: A total of 73 CLP patients (average age 8.7 years, range 6-18 years, 42 % male) and a control group of 73 age- and gender-matched non-CLP patients were included. Enamel color changes, subsuming mineralization defects (DDE index), mild dental fluorosis (Dean's index), and initial caries (ICDAS score 2), were recorded. Caries index (dmf t/DMF-T) scores were also recorded to distinguish between high or low caries risk as defined by the Deutsche Arbeitsgemeinschaft fur Jugendzahnpflege criteria. Histories of systemic fluoridation, trauma to primary teeth, surgery, and orthodontic treatment were obtained using a questionnaire. Statistical analysis included t test, chi (2) test, and multivariable logistic regression. RESULTS: Enamel color changes were observed three times more often in the CLP group than in the control group (39.7 vs. 12.3 %; p < 0.001). Significantly more patients in the CLP group had a history of orthodontic treatment (38.4 vs. 15.1 %; p < 0.05). An increased risk for enamel color changes was associated with CLP itself [OR (odds ratio) 3.6; 95 % confidence interval (CI) 1.3-9.9] and table salt plus tablets combined for systemic fluoridation (OR 2.7, 95 % CI 1.1-6.9). No increased risks were identified for increased caries risk, history of primary tooth trauma, or history of orthodontic treatment. CONCLUSION: The higher prevalence of enamel color changes in the CLP group (more than threefold compared to the control group) was not related to previous orthodontic treatments; however, systemic fluoridation (table salt and tablets) constituted a risk factor for the enamel color changes seen in the CLP patients. PMID- 26744209 TI - Occurrence and impact of domestic violence and abuse in gay and bisexual men: A cross sectional survey. AB - This cross-sectional survey measured adult experience and perpetration of negative and potentially abusive behaviours with partners and its associations with mental and sexual health problems, drug and alcohol abuse in gay and bisexual men attending a UK sexual health service. Of 532 men, 33.9% (95% CI: 29.4-37.9) experienced and 16.3% (95% CI: 13.0-19.8) reported carrying out negative behaviour. Ever being frightened of a partner (aOR 2.5; 95% CI: 2.0-3.1) and having to ask a partner's permission (aOR 2.7; 95% CI: 1.6-4.7) were associated with increased odds of being anxious. There were increased odds of cannabis use in the last 12 months amongst men who reported ever being physically hurt (aOR 2.4; 95% CI: 1.7-3.6). Being frightened (aOR 2.2; 95% CI: 1.5-3.2), being physically hurt (aOR 2.3; 95% CI: 1.4-3.8), being forced to have sex (aOR 2.5; 95% CI: 1.3-4.9) and experiencing negative behaviour in the last 12 months (aOR 1.7; 95% CI: 1.2-2.5) were associated with increased odds of using a Class A drugs in the last 12 months. Sexual health practitioners should be trained with regards to the risk indicators associated with domestic violence and abuse, how to ask about domestic violence and abuse and refer to support. PMID- 26744211 TI - Quench-Shield Ratiometric Upconversion Luminescence Nanoplatform for Biosensing. AB - Upconversion nanoparticles (UCNPs) possess several unique features, but they suffer from surface quenching effects caused by the interaction between the UCNPs and fluorophore. Thus, the use of UCNPs for target-induced emission changes for biosensing and bioimaging has been challenging. In this work, fluorophore and UCNPs are effectively separated by a silica transition layer with a thickness of about 4 nm to diminish the surface quenching effect of the UCNPs, allowing a universal and efficient luminescence resonance energy transfer (LRET) ratiometric upconversion luminescence nanoplatform for biosensing applications. A pH sensitive fluorescein derivative and Hg(2+)-sensitive rhodamine B were chosen as fluoroionphores to construct the LRET nanoprobes. Both showed satisfactory target triggered ratiometric upconversion luminescence responses in both solution and live cells, indicating that this strategy may find wide applications in the design of nanoprobes for various biorelated targets. PMID- 26744210 TI - Hyperoxia increases arterial oxygen pressure during exercise in type 2 diabetes patients: a feasibility study. AB - OBJECTIVE: The study investigated the feasibility and potential outcome measures during acute hyperoxia in type 2 diabetes patients (DM2). METHODS: Eleven DM2 patients (7 men and 4 women) were included in the study. The patients cycled (30 min at 20% Wmax) whilst breathing three different supplemental oxygen flows (SOF, 5, 10, 15 L min(-1)). During hyperoxic exercise, arterial blood gases and intra arterial blood pressure measurements were obtained. RESULTS: Arterial pO2 levels increased significantly (ANOVA, p < 0.05) with SOF: 13.9 +/- 1.2 (0 L min(-1)); 18.5 +/- 1.5 (5 L min(-1)); 21.7 +/- 1.7 (10 L min(-1)); 24.0 +/- 2.3 (15 L min( 1)). Heart rate (HR) and pH increased significantly after terminating administration of hyperoxic air. CONCLUSIONS: An SOF of 15 L min(-1) appears to be more effective than 5 or 10 L min(-1). Moreover, HR, blood pressure, blood lactate and pH are not recommended as primary outcome measures. PMID- 26744212 TI - Comparison of RNA extraction kits and histological stains for laser capture microdissected prostate tissue. AB - BACKGROUND: Laser capture microdissection offers unique possibilities for the isolation of specific cell populations or histological structures. However, isolation of RNA from microdissected tissue is challenging due to degradation and minimal yield of RNA during laser capture microdissection (LCM). Our aim was to optimize the isolation of high-quality RNA from laser capture microdissected fresh frozen prostate tissue on the level of staining and RNA extraction. RESULTS: Cresyl violet and haematoxylin were compared as histological stains for LCM. While RNA quality was similar for cresyl violet (median RIN 7.4) and haematoxylin (median RIN 7.6), tissue morphology was more detailed with cresyl violet as compared to haematoxylin. RNA quality from the following kits was compared: RNeasy((r)) Micro (median RIN 7.2), miRNeasy Mini (median RIN 6.6), Picopure((r)) (median RIN 6.0), mirVanaTM miRNA (median RIN 6.5) and RNAqueous((r))-Micro (median RIN 6.3). RNA quality from microdissected samples with either the RNeasy Micro or miRNeasy Mini kit, was comparable to RNA isolated directly from whole tissue slices (median RIN 7.5, p = 0.09). Isolated RNA from benign and prostate cancer microdissected tissue demonstrated that RNA quality can vary between regions from the same clinical sample. Additionally, RNA quality (r = 0.89), but not quantity (r = 0.69) could be precisely measured with the Agilent Bioanalyzer. CONCLUSIONS: We demonstrate that staining with cresyl violet results in the isolation of high quality RNA from laser capture microdissected tissue with high discriminative morphology. The RNeasy Micro and miRNeasy Mini RNA extraction kits generated the highest quality RNA compared to Picopure, mirVana and RNAqueous with minimal loss of RNA quality during LCM. PMID- 26744213 TI - Identification of a Distinct, Cutin-Related Pathway for Biosynthesis of Triacylglycerol Lipids in Bayberry. PMID- 26744214 TI - The Arabidopsis NRG2 Protein Mediates Nitrate Signaling and Interacts with and Regulates Key Nitrate Regulators. AB - We show that NITRATE REGULATORY GENE2 (NRG2), which we identified using forward genetics, mediates nitrate signaling in Arabidopsis thaliana. A mutation in NRG2 disrupted the induction of nitrate-responsive genes after nitrate treatment by an ammonium-independent mechanism. The nitrate content in roots was lower in the mutants than in the wild type, which may have resulted from reduced expression of NRT1.1 (also called NPF6.3, encoding a nitrate transporter/receptor) and upregulation of NRT1.8 (also called NPF7.2, encoding a xylem nitrate transporter). Genetic and molecular data suggest that NRG2 functions upstream of NRT1.1 in nitrate signaling. Furthermore, NRG2 directly interacts with the nitrate regulator NLP7 in the nucleus, but nuclear retention of NLP7 in response to nitrate is not dependent on NRG2. Transcriptomic analysis revealed that genes involved in four nitrogen-related clusters including nitrate transport and response to nitrate were differentially expressed in the nrg2 mutants. A nitrogen compound transport cluster containing some members of the NRT/PTR family was regulated by both NRG2 and NRT1.1, while no nitrogen-related clusters showed regulation by both NRG2 and NLP7. Thus, NRG2 plays a key role in nitrate regulation in part through modulating NRT1.1 expression and may function with NLP7 via their physical interaction. PMID- 26744215 TI - Gene Duplicability of Core Genes Is Highly Consistent across All Angiosperms. AB - Gene duplication is an important mechanism for adding to genomic novelty. Hence, which genes undergo duplication and are preserved following duplication is an important question. It has been observed that gene duplicability, or the ability of genes to be retained following duplication, is a nonrandom process, with certain genes being more amenable to survive duplication events than others. Primarily, gene essentiality and the type of duplication (small-scale versus large-scale) have been shown in different species to influence the (long-term) survival of novel genes. However, an overarching view of "gene duplicability" is lacking, mainly due to the fact that previous studies usually focused on individual species and did not account for the influence of genomic context and the time of duplication. Here, we present a large-scale study in which we investigated duplicate retention for 9178 gene families shared between 37 flowering plant species, referred to as angiosperm core gene families. For most gene families, we observe a strikingly consistent pattern of gene duplicability across species, with gene families being either primarily single-copy or multicopy in all species. An intermediate class contains gene families that are often retained in duplicate for periods extending to tens of millions of years after whole-genome duplication, but ultimately appear to be largely restored to singleton status, suggesting that these genes may be dosage balance sensitive. The distinction between single-copy and multicopy gene families is reflected in their functional annotation, with single-copy genes being mainly involved in the maintenance of genome stability and organelle function and multicopy genes in signaling, transport, and metabolism. The intermediate class was overrepresented in regulatory genes, further suggesting that these represent putative dosage balance-sensitive genes. PMID- 26744216 TI - Comparative Analysis of the Flax Immune Receptors L6 and L7 Suggests an Equilibrium-Based Switch Activation Model. AB - NOD-like receptors (NLRs) are central components of the plant immune system. L6 is a Toll/interleukin-1 receptor (TIR) domain-containing NLR from flax (Linum usitatissimum) conferring immunity to the flax rust fungus. Comparison of L6 to the weaker allele L7 identified two polymorphic regions in the TIR and the nucleotide binding (NB) domains that regulate both effector ligand-dependent and independent cell death signaling as well as nucleotide binding to the receptor. This suggests that a negative functional interaction between the TIR and NB domains holds L7 in an inactive/ADP-bound state more tightly than L6, hence decreasing its capacity to adopt the active/ATP-bound state and explaining its weaker activity in planta. L6 and L7 variants with a more stable ADP-bound state failed to bind to AvrL567 in yeast two-hybrid assays, while binding was detected to the signaling active variants. This contrasts with current models predicting that effectors bind to inactive receptors to trigger activation. Based on the correlation between nucleotide binding, effector interaction, and immune signaling properties of L6/L7 variants, we propose that NLRs exist in an equilibrium between ON and OFF states and that effector binding to the ON state stabilizes this conformation, thereby shifting the equilibrium toward the active form of the receptor to trigger defense signaling. PMID- 26744217 TI - A Novel Pathway for Triacylglycerol Biosynthesis Is Responsible for the Accumulation of Massive Quantities of Glycerolipids in the Surface Wax of Bayberry (Myrica pensylvanica) Fruit. AB - Bayberry (Myrica pensylvanica) fruits synthesize an extremely thick and unusual layer of crystalline surface wax that accumulates to 32% of fruit dry weight, the highest reported surface lipid accumulation in plants. The composition is also striking, consisting of completely saturated triacylglycerol, diacylglycerol, and monoacylglycerol with palmitate and myristate acyl chains. To gain insight into the unique properties of Bayberry wax synthesis, we examined the chemical and morphological development of the wax layer, monitored wax biosynthesis through [(14)C]-radiolabeling, and sequenced the transcriptome. Radiolabeling identified sn-2 monoacylglycerol as an initial glycerolipid intermediate. The kinetics of [(14)C]-DAG and [(14)C]-TAG accumulation and the regiospecificity of their [(14)C]-acyl chains indicated distinct pools of acyl donors and that final TAG assembly occurs outside of cells. The most highly expressed lipid-related genes were associated with production of cutin, whereas transcripts for conventional TAG synthesis were >50-fold less abundant. The biochemical and expression data together indicate that Bayberry surface glycerolipids are synthesized by a pathway for TAG synthesis that is related to cutin biosynthesis. The combination of a unique surface wax and massive accumulation may aid understanding of how plants produce and secrete non-membrane glycerolipids and also how to engineer alternative pathways for lipid production in non-seeds. PMID- 26744218 TI - MATE Transporter-Dependent Export of Hydroxycinnamic Acid Amides. AB - The ability of Arabidopsis thaliana to successfully prevent colonization by Phytophthora infestans, the causal agent of late blight disease of potato (Solanum tuberosum), depends on multilayered defense responses. To address the role of surface-localized secondary metabolites for entry control, droplets of a P. infestans zoospore suspension, incubated on Arabidopsis leaves, were subjected to untargeted metabolite profiling. The hydroxycinnamic acid amide coumaroylagmatine was among the metabolites secreted into the inoculum. In vitro assays revealed an inhibitory activity of coumaroylagmatine on P. infestans spore germination. Mutant analyses suggested a requirement of the p-coumaroyl CoA:agmatine N4-p-coumaroyl transferase ACT for the biosynthesis and of the MATE transporter DTX18 for the extracellular accumulation of coumaroylagmatine. The host plant potato is not able to efficiently secrete coumaroylagmatine. This inability is overcome in transgenic potato plants expressing the two Arabidopsis genes ACT and DTX18. These plants secrete agmatine and putrescine conjugates to high levels, indicating that DTX18 is a hydroxycinnamic acid amide transporter with a distinct specificity. The export of hydroxycinnamic acid amides correlates with a decreased ability of P. infestans spores to germinate, suggesting a contribution of secreted antimicrobial compounds to pathogen defense at the leaf surface. PMID- 26744221 TI - The ageing population is neglected in research studies of traumatic brain injury. AB - INTRODUCTION: The UK population is ageing with increasing number of elderly patients suffering traumatic brain injury (TBI). The purpose of this study was to identify national TBI admission demographics, analyse the temporal evolution of TBI mortality in a single centre and conduct a systematic review of the literature to identify whether there is an age bias amongst researchers studying TBI. METHODS: National demographics for TBI were obtained from Health Episode Statistics. TBI patients admitted from 2000 to 2011 to Cambridge University Hospitals Neurocritical Care Unit (NCCU) were divided into age groups (<60, 60 74, >=75 years). Temporal evolution of mortality was analysed using a logistic regression method. A systematic literature review was conducted to identify primary TBI research studies. Patient's ages were extracted and an average mean age was calculated and compared over time. RESULTS: From 1998, national TBI admissions have increased with the greatest rise in >60-year age group (p < 0.0001). In a tertiary referral critical care unit (n = 1145), the 60-74 year age group (compared to <60) had a significantly lower improvement in mortality over time (OR: 1.15, 95% CI: 1.02-1.31). A literature review revealed a mean age of 32.73 years (SD +/- 12.85) for patients recruited to primary TBI studies. CONCLUSION: Despite increased admissions of elderly patients following TBI and static mortality (single centre, 60-74 year age group) there is little or no evidence of a corresponding increase in the age of patients recruited for TBI studies. In addition to the difficulties this presents in forming evidence-based decisions for the patient with TBI, it may also represent a wider problem for ICU research in an ever-ageing critical care population. More research needs to be conducted to establish the treatment end points for an ageing population. PMID- 26744220 TI - Chemical modifications of artificial restriction DNA cutter (ARCUT) to promote its in vivo and in vitro applications. AB - Recently, completely chemistry-based tools for site-selective scission of DNA (ARCUT) have been prepared by combining 2 strands of pseudo-complementary PNA (pcPNA: site-selective activator) and a Ce(IV)-EDTA complex (molecular scissors). Its site-specificity is sufficient to cut the whole human genome at one predetermined site. In this first-generation ARCUT, however, there still remain several problems to be solved for wider applications. This review presents recent approaches to solve these problems. They are divided into (i) covalent modification of pcPNA with other functional groups and (ii) new strategies using conventional PNA, in place of pcPNA, as site-selective activator. Among various chemical modifications, conjugation with positively-charged nuclear localization signal peptide is especially effective. Furthermore, unimolecular activators, a single strand of which successfully activates the target site in DNA for site selective scission, have been also developed. As the result of these modifications, the site-selective scission by Ce(IV)-EDTA was achieved promptly even under high salt conditions which are otherwise unfavourable for double duplex invasion. Furthermore, it has been shown that "molecular crowding effect," which characterizes the inside of living cells, enormously promotes the invasion, and thus the invasion seems to proceed effectively and spontaneously in the cells. Strong potential of pcPNA for further applications in vivo and in vitro has been confirmed. PMID- 26744219 TI - It's Time for Some "Site"-Seeing: Novel Tools to Monitor the Ubiquitin Landscape in Arabidopsis thaliana. AB - Ubiquitination, the covalent binding of the small protein modifier ubiquitin to a target protein, is an important and frequently studied posttranslational protein modification. Multiple reports provide useful insights into the plant ubiquitinome, but mostly at the protein level without comprehensive site identification. Here, we implemented ubiquitin combined fractional diagonal chromatography (COFRADIC) for proteome-wide ubiquitination site mapping on Arabidopsis thaliana cell cultures. We identified 3009 sites on 1607 proteins, thereby greatly increasing the number of known ubiquitination sites in this model plant. Finally, The Ubiquitination Site tool (http://bioinformatics.psb.ugent.be/webtools/ubiquitin_viewer/) gives access to the obtained ubiquitination sites, not only to consult the ubiquitination status of a given protein, but also to conduct intricate experiments aiming to study the roles of specific ubiquitination events. Together with the antibodies recognizing the ubiquitin remnant motif, ubiquitin COFRADIC represents a powerful tool to resolve the ubiquitination maps of numerous cellular processes in plants. PMID- 26744224 TI - Loss of sigmaI affects heat-shock response and virulence gene expression in Bacillus anthracis. AB - The pathogenesis of Bacillus anthracis depends on several virulence factors, including the anthrax toxin. Loss of the alternative sigma factor sigmaI results in a coordinate decrease in expression of all three toxin subunits. Our observations suggest that loss of sigmaI alters the activity of the master virulence regulator AtxA, but atxA transcription is unaffected by loss of sigmaI. sigmaI-containing RNA polymerase does not appear to directly transcribe either atxA or the toxin gene pagA. As in Bacillus subtilis, loss of sigmaI in B. anthracis results in increased sensitivity to heat shock and transcription of sigI, encoding sigmaI, is induced by elevated temperature. Encoded immediately downstream of and part of a bicistronic message with sigI is an anti-sigma factor, RsgI, which controls sigmaI activity. Loss of RsgI has no direct effect on virulence gene expression. sigI appears to be expressed from both the sigmaI and sigmaA promoters, and transcription from the sigmaA promoter is likely more significant to virulence regulation. We propose a model in which sigmaI can be induced in response to heat shock, whilst, independently, sigmaI is produced under non-heat-shock, toxin-inducing conditions to indirectly regulate virulence gene expression. PMID- 26744222 TI - The Impact of Dietary Energy Intake Early in Life on the Colonic Microbiota of Adult Mice. AB - The complex and dynamic interactions between diet, gut microbiota (GM) structure and function, and colon carcinogenesis are only beginning to be elucidated. We examined the colonic microbiota and aberrant crypt foci (ACF) in C57BL/6N female mice fed various dietary interventions (control, energy restricted and high-fat) provided during two phases (initiation and progression) of azoxymethane (AOM) induced early colon carcinogenesis. During progression (wks. 22-60), a high-fat diet enhanced ACF formation compared to a control or energy restricted diet. In contrast, energy restriction during initiation phase (wks. 3-21) enhanced ACF burden at 60 weeks, regardless of the diet in progression phase. Alterations in GM structure during the initiation phase diet were partially maintained after changing diets during the progression phase. However, diet during the progression phase had major effects on the mucosal GM. Energy restriction in the progression phase increased Firmicutes and reduced Bacteroidetes compared to a high-fat diet, regardless of initiation phase diet, suggesting that diet may have both transient effects as well as a lasting impact on GM composition. Integration of early life and adult dietary impacts on the colonic microbial structure and function with host molecular processes involved in colon carcinogenesis will be key to defining preventive strategies. PMID- 26744223 TI - The Floating (Pathogenicity) Island: A Genomic Dessert. AB - Among the prokaryotic genomic islands (GIs) involved in horizontal gene transfer (HGT) are the classical pathogenicity islands, including the integrative and conjugative elements (ICEs), the gene-transfer agents (GTAs), and the staphylococcal pathogenicity islands (SaPIs), the primary focus of this review. While the ICEs and GTAs mediate HGT autonomously, the SaPIs are dependent on specific phages. The ICEs transfer primarily their own DNA, the GTAs exclusively transfer unlinked host DNA, and the SaPIs combine the capabilities of both. Thus the SaPIs derive their importance from the genes they carry (their genetic cargo) and the genes they move. They act not only as versatile high-frequency mobilizers but also as mediators of phage interference and consequently are major benefactors of their host bacteria. PMID- 26744225 TI - Anodal-tDCS over the human right occipital cortex enhances the perception and memory of both faces and objects. AB - Accurate face processing skills are pivotal for typical social cognition, and impairments in this ability characterise various clinical conditions (e.g., prosopagnosia). No study to date has investigated whether transcranial direct current stimulation (tDCS) can causally enhance face processing. In addition, the category- and the process-specificity of tDCS effects, as well as the role of the timing of neuromodulation with respect to the execution of cognitive tasks are still unknown. In this single-blind, sham-controlled study, we examined whether the administration of anodal-tDCS (a-tDCS) over the right occipital cortex of healthy volunteers (N=64) enhances performance on perceptual and memory tasks involving both face and object stimuli. Neuromodulation was delivered in two conditions: online (a-tDCS during task execution) and offline (a-tDCS before task execution). The results demonstrate that offline a-tDCS enhances the perception and memory performance of both faces and objects. There was no effect of online a tDCS on behaviour. Furthermore, the offline effect was site-specific since a-tDCS over the sensory-motor cortex did not lead to behavioural changes. Our results add relevant information about the breadth of cognitive processes and visual stimuli that can be modulated by tDCS, and about the design of effective neuromodulation protocols, which have implications for advancing theories in cognitive neuroscience and clinical applications. PMID- 26744227 TI - Rapid and Early Diagnosis of Posttransplant Lymphoproliferative Disease Using Cross-Sectional Nuclear Medicine Imaging and Laparoscopic Lymph Node Biopsy: A Report of 2 Cases. AB - Posttransplant lymphoproliferative disease is a complication of organ transplant with a myriad clinical and anatomic manifestations, thus making diagnosis difficult without histologic confirmation. In cases of lymphadenopathy confined to the abdomen, the diagnosis can be delayed because of late presentation and difficulty obtaining a tissue for histologic analyses. We describe the use of cross-sectional nuclear medicine imaging to locate enlarged abdominal lymph nodes; this facilitated minimally invasive laparoscopic lymph node excision biopsy to rapidly diagnose 2 cases of post-transplant lymphoproliferative disease. Prompt diagnosis has enabled early effective treatment, resulting in good patient outcomes. PMID- 26744226 TI - Interplay of active processes modulates tension and drives phase transition in self-renewing, motor-driven cytoskeletal networks. AB - The actin cytoskeleton--a complex, nonequilibrium network consisting of filaments, actin-crosslinking proteins (ACPs) and motors--confers cell structure and functionality, from migration to morphogenesis. While the core components are recognized, much less is understood about the behaviour of the integrated, disordered and internally active system with interdependent mechano-chemical component properties. Here we use a Brownian dynamics model that incorporates key and realistic features--specifically actin turnover, ACP (un)binding and motor walking--to reveal the nature and underlying regulatory mechanisms of overarching cytoskeletal states. We generate multi-dimensional maps that show the ratio in activity of these microscopic elements determines diverse global stress profiles and the induction of nonequilibrium morphological phase transition from homogeneous to aggregated networks. In particular, actin turnover dynamics plays a prominent role in tuning stress levels and stabilizing homogeneous morphologies in crosslinked, motor-driven networks. The consequence is versatile functionality, from dynamic steady-state prestress to large, pulsed constrictions. PMID- 26744228 TI - Comparing the Accuracy of Three Pediatric Disaster Triage Strategies: A Simulation-Based Investigation. AB - BACKGROUND: It is unclear which pediatric disaster triage (PDT) strategy yields the best accuracy or best patient outcomes. METHODS: We conducted a cross sectional analysis on a sample of emergency medical services providers from a prospective cohort study comparing the accuracy and triage outcomes for 2 PDT strategies (Smart and JumpSTART) and clinical decision-making (CDM) with no algorithm. Participants were divided into cohorts by triage strategy. We presented 10-victim, multi-modal disaster simulations. A Delphi method determined patients' expected triage levels. We compared triage accuracy overall and for each triage level (RED/Immediate, YELLOW/Delayed, GREEN/Ambulatory, BLACK/Deceased). RESULTS: There were 273 participants (71 JumpSTART, 122 Smart, and 81 CDM). There was no significant difference between Smart triage and CDM. When JumpSTART triage was used, there was greater accuracy than with either Smart (P<0.001; OR [odds ratio]: 2.03; interquartile range [IQR]: 1.30, 3.17) or CDM (P=0.02; OR: 1.76; IQR: 1.10, 2.82). JumpSTART outperformed Smart for RED patients (P=0.05; OR: 1.48; IQR: 1.01,2.17), and outperformed both Smart (P<0.001; OR: 3.22; IQR: 1.78,5.88) and CDM (P<0.001; OR: 2.86; IQR: 1.53,5.26) for YELLOW patients. Furthermore, JumpSTART outperformed CDM for BLACK patients (P=0.01; OR: 5.55; IQR: 1.47, 20.0). CONCLUSION: Our simulation-based comparison suggested that JumpSTART triage outperforms both Smart and CDM. JumpSTART outperformed Smart for RED patients and CDM for BLACK patients. For YELLOW patients, JumpSTART yielded more accurate triage results than did Smart triage or CDM. PMID- 26744229 TI - Introducing an artificial photo-switch into a biological pore: A model study of an engineered alpha-hemolysin. AB - In recent years, engineered biological pores responsive to external stimuli have been fruitfully used for various biotechnological applications. Moreover, the strategy of tethering photo-switchable moieties into biomolecules has provided an unprecedented temporal control of purposely designed nanodevices, as demonstrated, for example, by the light-mediated regulation of the activity of enzymes and biochannels. Inspired by these advancements, we propose here a de novo designed nanodevice featuring the alpha-hemolysin (alphaHL) membrane channel purposely functionalized by an artificial "on/off" molecular switch. The switch, which is based on the photo-isomerization of the azobenzene moiety, introduces a smart nano-valve into the natural non-gated pore to confer tunable transport properties. We validated through molecular dynamics simulations and free energy calculations the effective inter-conversion of the engineered alphaHL pore between two configurations corresponding to an "open" and a "closed" form. The reported switchable translocation of a single-stranded DNA fragment under applied voltage supports the promising capabilities of this nanopore prototype in view of molecular sensing, detection and delivery applications at single-molecule level. PMID- 26744230 TI - Re-evaluation of the water exchange lifetime value across red blood cell membrane. AB - The water exchange lifetime (tau(i)) through red blood cell (RBC) membranes can be measured by analyzing the water protons bi-exponential T1 and T2 curves when RBCs are suspended in a medium supplemented with paramagnetic species. Since the seminal papers published in the early '70s of the previous century, paramagnetic Mn(2+) ions were used for doping the extracellular compartment in the RBCs suspension. The obtained tau(i) values fall in the range of 9.8-14 ms. Conversely, other physic-chemical measurements afforded longer tau(i) values. Herein, it is shown that the replacement of Mn(2+) with the highly stable, hydrophilic Gd(III) complexes used as paramagnetic magnetic resonance imaging (MRI) contrast agents led to measure tau(iI) values of 19.1 +/- 0.65 ms at 25 degrees C. The observed difference is ascribed to the occurrence of enhanced permeability of RBC membrane in the presence of Mn(2+) ions. This view finds support from the observation that an analogous behavior was shown in the presence of other divalent cations, such Ca(2+) and Zn(2+) ions. A possible role of scramblase has been hypothesized. Finally, tau(i) has been measured in presence of alcohols to show that the herein proposed method can detect minor changes in RBC membranes' stiffness upon the incorporation of aliphatic alcohols. PMID- 26744231 TI - Comparison of different clinical development plans for confirmatory subpopulation selection. AB - Given ever increasing costs to develop a new drug and intense competition, adaptive enrichment designs are an attractive option for a development program that allows selecting a potential subgroup defined by a binary biomarker. Such designs explicitly factor in the possibility that the new drug might differentially benefit distinct biomarker subgroups. We have compared three clinical development plans for a time-to-event endpoint, such as overall survival, that all lead to a decision in a pivotal trial either in all comers only, in allcomers and biomarker positive, in the biomarker positive only, or to declare the drug futile. The decision about which hypothesis to test at the final analysis is made based on a fast time-to-event endpoint, such as progression-free survival, at an interim analysis. We quantify the time gain when using an adaptive enrichment Phase II/III design versus alternative development approaches and we outline what type of biomarker needs to be available prior to Phase II in each scenario. We conclude with a discussion of further features of each of the considered development plans. PMID- 26744232 TI - Design and baseline characteristics of participants in the Enhancing Physical Activity and Reducing Obesity through Smartcare and Financial Incentives (EPAROSFI): A pilot randomized controlled trial. AB - BACKGROUND: An activity tracker combined with a smartphone application (smartcare) may help people track and receive feedback on their own activities. However, activity trackers themselves generally fail to drive long-term sustained engagement for a majority of users. One potential strategy for increasing the effectiveness of smartcare is through the use of incentives. The purpose of this pilot randomized trial is to test the feasibility of our intervention and to assess the extent to which smartcare with or without financial incentives can increase physical activity levels and reduce weight over a 12-week period. METHODS/DESIGN: This study employs a three-arm, open-label randomized controlled trial design: control (standard basic education), smartcare, and smartcare plus financial incentives. Male university students with body mass index >= 27 are enrolled. Our primary and secondary endpoints are the amount of weight loss and the level of physical activity respectively. The weight loss goal is 3% of baseline at week 4, 5% at week 8, and 7% at week 12. The daily physical activity goal was individualized according to the participants' weight. Process incentives are accumulated when participants met daily physical activity goals, and outcome incentives are provided when they met weight reduction goals. DISCUSSION: Given the global increase in physical inactivity and obesity, there is a growing need for effective, scalable, and affordable health promotion strategies. Our proof-of concept study will provide the evidence for the combination of rising health promotion technology of activity trackers and smartphone applications with the modern concept of behavioral economics using financial incentives. PMID- 26744233 TI - Ca(2+) coding and decoding strategies for the specification of neural and renal precursor cells during development. AB - During embryogenesis, a rise in intracellular Ca(2+) is known to be a widespread trigger for directing stem cells towards a specific tissue fate, but the precise Ca(2+) signalling mechanisms involved in achieving these pleiotropic effects are still poorly understood. In this review, we compare the Ca(2+) signalling events that appear to be one of the first steps in initiating and regulating both neural determination (neural induction) and kidney development (nephrogenesis). We have highlighted the necessary and sufficient role played by Ca(2+) influx and by Ca(2+) transients in the determination and differentiation of pools of neural or renal precursors. We have identified new Ca(2+) target genes involved in neural induction and we showed that the same Ca(2+) early target genes studied are not restricted to neural tissue but are also present in other tissues, principally in the pronephros. In this review, we also described a mechanism whereby the transcriptional control of gene expression during neurogenesis and nephrogenesis might be directly controlled by Ca(2+) signalling. This mechanism involves members of the Kcnip family such that a change in their binding properties to specific DNA sites is a result of Ca(2+) binding to EF-hand motifs. The different functions of Ca(2+) signalling during these two events illustrate the versatility of Ca(2+) as a second messenger. PMID- 26744234 TI - Development of single chain variable fragment (scFv) antibodies against surface proteins of 'Ca. Liberibacter asiaticus'. AB - 'Candidatus Liberibacter asiaticus' is the causal agent of citrus huanglongbing, the most serious disease of citrus worldwide. We have developed and applied immunization and affinity screening methods to develop a primary library of recombinant single chain variable fragment (scFv) antibodies in an M13 vector, pKM19. The antibody population is enriched for antibodies that bind antigens of 'Ca. Liberibacter asiaticus'. The primary library has more than 10(7) unique antibodies and the genes that encode them. We have screened this library for antibodies that bind to specifically-chosen proteins that are present on the surface of 'Ca. Liberibacter asiaticus'. These proteins were used as targets for affinity-based selection of scFvs that bind to the major outer membrane protein, OmpA; the polysaccharide capsule protein KpsF; a protein component of the type IV pilus (CapF); and, two flagellar proteins FlhA and FlgI. These scFvs have been used in ELISA and dot blot assays against purified protein antigens and 'Ca. Liberibacter asiaticus' infected plant extracts. We have also recloned many of these scFvs into a plasmid expression vector designed for the production of scFvs. Screening of these scFvs was more efficient when phage-bound, rather than soluble scFvs, were used. We have demonstrated a technology to produce antibodies at will and against any protein target encoded by 'Ca. Liberibacter asiaticus'. Applications could include advanced diagnostic methods for huanglongbing and the development of immune labeling reagents for in planta applications. PMID- 26744235 TI - Postprandial hyperlipidemia as a potential residual risk factor. AB - Statin therapy targeting reduction of low-density lipoprotein cholesterol (LDL-C) decreases the risk of coronary heart disease (CHD) and all-cause mortality. However, a substantial number of cases of CHD are not prevented and residual risk factors remain unsettled. A high triglyceride (TG) level is considered to be an important and residual risk factor. Postprandial hyperlipidemia is a condition in which TG-rich chylomicron remnants are increased during the postprandial period and hypertriglycedemia is protracted. Postprandial hyperlipidemia evokes atherogenesis during the postprandial period. Several prospective studies have revealed that nonfasting serum TG levels predict the incidence of CHD. Values of TG, remnant lipoprotein cholesterol, and remnant lipoprotein TG after fat loading were significantly higher in diabetes patients with insulin resistance than in diabetes patients without insulin resistance. Endothelial dysfunction is an initial process of atherogenesis and it contributes to the pathogenesis of CHD. Postprandial hyperlipidemia (postprandial hypertriglyceridemia) is involved in the production of proinflammatory cytokines, recruitment of neutrophils, and generation of oxidative stress, resulting in endothelial dysfunction in healthy subjects, hypertriglyceridemic patients, or type 2 diabetic patients. Effective treatment has not been established till date. Ezetimibe or omega-3 fatty acids significantly decrease postprandial TG elevation and postprandial endothelial dysfunction. Ezetimibe or omega-3 fatty acids added to statin therapy reduce serum TG levels and result in good outcomes in patients with CHD. In conclusion, postprandial hyperlipidemia is an important and residual risk factor especially in patients with insulin resistance syndrome (metabolic syndrome) and diabetes mellitus. Further studies are needed to establish effective treatment. PMID- 26744236 TI - Genetic effects on source level evoked and induced oscillatory brain responses in a visual oddball task. AB - Stimuli in simple oddball target detection paradigms cause evoked responses in brain potential. These responses are heritable traits, and potential endophenotypes for clinical phenotypes. These stimuli also cause responses in oscillatory activity, both evoked responses phase-locked to stimulus presentation and phase-independent induced responses. Here, we investigate whether phase locked and phase-independent oscillatory responses are heritable traits. Oscillatory responses were examined in EEG recordings from 213 twin pairs (91 monozygotic and 122 dizygotic twins) performing a visual oddball task. After group Independent Component Analysis (group-ICA) and time-frequency decomposition, individual differences in evoked and induced oscillatory responses were compared between MZ and DZ twin pairs. Induced (phase-independent) oscillatory responses consistently showed the highest heritability (24-55%) compared to evoked (phase-locked) oscillatory responses and spectral energy, which revealed lower heritability at 1-35.6% and 4.5-32.3%, respectively. Since the phase-independent induced response encodes functional aspects of the brain response to target stimuli different from evoked responses, we conclude that the modulation of ongoing oscillatory activity may serve as an additional endophenotype for behavioral phenotypes and psychiatric genetics. PMID- 26744238 TI - [Paroxysmal nocturnal hemoglobinuria and myelodysplastic syndrome: a case report]. AB - Paroxysmal nocturnal hemoglobinuria is a rare clonal non-malignant disease, linked to an acquired PIG-A gene mutation. We report the case of 81 years old patient hospitalized for articular ache, swelling and temporal arteries' induration in which we diagnose PNH associated with refractory cytopenia with multilineage dysplasia. PMID- 26744237 TI - Fetal Tendinous Connection Between the Tensor Tympani and Tensor Veli Palatini Muscles: A Single Digastric Muscle Acting for Morphogenesis of the Cranial Base. AB - Some researchers contend that in adults the tensor tympani muscle (TT) connects with the tensor veli palatini muscle (TVP) by an intermediate tendon, in disagreement with the other researchers. To resolve this controversy, we examined serial sections of 50 human embryos and fetuses at 6-17 weeks of development. At 6 weeks, in the first pharyngeal arch, a mesenchymal connection was found first to divide a single anlage into the TT and TVP. At and after 7 weeks, the TT was connected continuously with the TVP by a definite tendinous tissue mediolaterally crossing the pharyngotympanic tube. At 11 weeks another fascia was visible covering the cranial and lateral sides of the tube. This "gonial fascia" had two thickened borders: the superior one corresponded to a part of the connecting tendon between the TT and TVP; the inferior one was a fibrous band ending at the os goniale near the lateral end of the TVP. In association with the gonial fascia, the fetal TT and TVP seemed to provide a functional complex. The TT-TVP complex might first help elevate the palatal shelves in association with the developing tongue. Next, the tubal passage, maintained by contraction of the muscle complex, seems to facilitate the removal of loose mesenchymal tissues from the tympanic cavity. Third, the muscle complex most likely determined the final morphology of the pterygoid process. Consequently, despite the controversial morphologies in adults, the TT and TVP seemed to make a single digastric muscle acting for the morphogenesis of the cranial base. PMID- 26744239 TI - From physical inactivity to immobilization: Dissecting the role of oxidative stress in skeletal muscle insulin resistance and atrophy. AB - In the literature, the terms physical inactivity and immobilization are largely used as synonyms. The present review emphasizes the need to establish a clear distinction between these two situations. Physical inactivity is a behavior characterized by a lack of physical activity, whereas immobilization is a deprivation of movement for medical purpose. In agreement with these definitions, appropriate models exist to study either physical inactivity or immobilization, leading thereby to distinct conclusions. In this review, we examine the involvement of oxidative stress in skeletal muscle insulin resistance and atrophy induced by, respectively, physical inactivity and immobilization. A large body of evidence demonstrates that immobilization-induced atrophy depends on the chronic overproduction of reactive oxygen and nitrogen species (RONS). On the other hand, the involvement of RONS in physical inactivity-induced insulin resistance has not been investigated. This observation outlines the need to elucidate the mechanism by which physical inactivity promotes insulin resistance. PMID- 26744241 TI - Lobulated Lesions on the Fingers. PMID- 26744240 TI - Remarkably high mobility ultra-thin-film metal-oxide transistor with strongly overlapped orbitals. AB - High mobility channel thin-film-transistor (TFT) is crucial for both display and future generation integrated circuit. We report a new metal-oxide TFT that has an ultra-thin 4.5 nm SnO2 thickness for both active channel and source-drain regions, very high 147 cm(2)/Vs field-effect mobility, high ION/IOFF of 2.3 * 10(7), small 110 mV/dec sub-threshold slope, and a low VD of 2.5 V for low power operation. This mobility is already better than chemical-vapor-deposition grown multi-layers MoS2 TFT. From first principle quantum-mechanical calculation, the high mobility TFT is due to strongly overlapped orbitals. PMID- 26744242 TI - Histochemical Evaluation of the Vessel Wall Destruction and Selectivity After Treatment with Intense Pulsed Light in Capillary Malformations. AB - BACKGROUND: Among the different approaches for improving the effectiveness in the treatment of Capillary Malformations type Port Wine Stain (CM type PWS) are the intense pulsed light sources. There are few clinical studies prove useful in the treatment of CM. Furthermore, no studies have been published yet demonstrating the histological effects of IPL in CM. OBJECTIVES: To assess the histological effects of pulsed light in capillary malformations type port wine stain. We wanted to compare epidermal, dermal and vessel wall damage after treatment with different combinations of IPL parameters. MATERIAL AND METHODS: Fifty-five post treatment biopsies were performed in 15 consenting patients with CM and stained with nitroblue-tetrazolium chloride (NBTC). Patients had not been treated previously. RESULTS: Fifteen patients with CM, with a median age of 39 years-old were enrolled in this study. In this series, the patients with the most severe epidermal damage were those with a darker phototype. Pink CM were especially resistant to treatment, even using high fluences, short pulse durations and stacking pulses. Longer intra- and interpulse delays were effective in purple CM, achieving adequate vessel destruction. CONCLUSIONS: IPL devices provide a vast amount of treatment possibilities and further studies are necessary to optimize therapeutic approaches to CM. In this study we have observed the histological effects of different pulses on the MC type PWS. PMID- 26744244 TI - Reply: Should we operate for an intraabdominal emergency in the setting of disseminated cancer? PMID- 26744245 TI - Regarding: Impact of the preoperative quantity and quality of skeletal muscle on outcomes after resection of extrahepatic biliary malignancies. PMID- 26744246 TI - Clarification of the terms used to describe procedures for acute airway obstruction management. PMID- 26744243 TI - Chondroinductive Hydrogel Pastes Composed of Naturally Derived Devitalized Cartilage. AB - Hydrogel precursors are liquid solutions that are prone to leaking from the defect site once implanted in vivo. Therefore, the objective of the current study was to create a hydrogel precursor that exhibited a yield stress. Additionally, devitalized cartilage extracellular matrix (DVC) was mixed with DVC that had been solubilized and methacrylated (MeSDVC) to create hydrogels that were chondroinductive. Precursors composed of 10% MeSDVC or 10% MeSDVC with 10% DVC were first evaluated rheologically, where non-Newtonian behavior was observed in all hydrogel precursors. Rat bone marrow stem cells (rBMSCs) were mixed in the precursor solutions, and the solutions were then crosslinked and cultured in vitro for 6 weeks with and without exposure to human transforming growth factor beta3 (TGF-beta3). The compressive modulus, gene expression, biochemical content, swelling, and histology of the gels were analyzed. The DVC-containing gels consistently outperformed the MeSDVC-only group in chondrogenic gene expression, especially at 6 weeks, where the relative collagen II expression of the DVC containing groups with and without TGF-beta3 exposure was 40- and 78-fold higher, respectively, than that of MeSDVC alone. Future work will test for chondrogenesis in vivo and overall, these two cartilage-derived components are promising materials for cartilage tissue engineering applications. PMID- 26744247 TI - AcuBlade((r)) laser system: A new tool for interventional bronchoscopist. PMID- 26744248 TI - Interstitial lung disease with statin-associated necrotizing autoimmune myopathy responding to rituximab. PMID- 26744249 TI - Taxometric evidence of a dimensional latent structure for depression in an epidemiological sample of children and adolescents. AB - BACKGROUND: A basic phenomenological question of much theoretical and empirical interest is whether the latent structure of depression is dimensional or categorical in nature. Prior taxometric studies of youth depression have yielded mixed findings. In a step towards resolving these contradictory findings, the current taxometric investigation is the first to utilize a recently developed objective index, the comparison curve fit index, to evaluate the latent structure of major depression in an epidemiological sample of children and adolescents. METHOD: Data were derived from Mental Health of Children and Young People in Great Britain surveys. Participants were administered a structured diagnostic interview to assess for current depression. Parents (n = 683) were interviewed for children aged 5-16 years, and child interviews (n = 605) were conducted for those aged 11-16 years. RESULTS: MAMBAC (mean above minus below a cut), MAXEIG (maximum eigenvalue) and L-Mode (latent mode) analyses provided convergent support for a dimensional latent structure. CONCLUSIONS: The current findings suggest that depression in youth is more accurately conceptualized as a continuous syndrome rather than a discrete diagnostic entity. PMID- 26744251 TI - Accreditation process in European countries - an EFLM survey. AB - BACKGROUND: Accreditation is a valuable resource for medical laboratories. The development of quality systems based on ISO 15189 has taken place in many laboratories in the European countries but data about accreditation remain scarce. The EFLM Working Group "Accreditation and ISO/CEN standards" conducted a survey that reviews the current state of the accreditation process in European countries. METHODS: An on-line questionnaire was addressed to delegates of 39 EFLM scientific societies in March 2014. One answer by country was taken into account. The survey was dealing with mandatory status, number of accredited medical laboratories in each country, possibility of flexible scope and concerned medical fields. The status of point-of-care testing (POCT) in each country was also studied. RESULTS: Twenty-nine responses (74%) were registered. All the assessed countries (100%) have begun an accreditation process in various ways. All the national accreditation bodies (NAB) offer or are working to offer an ISO 15189 accreditation. The accreditation process most often concerns all phases of the examination and various medical fields. Medical laboratories are responsible for POCT in 20 (69%) countries. The accreditation process for POCT, according to ISO 15189 and ISO 22870, is also developing. CONCLUSIONS: While there are several variations in the approaches to accreditation of medical laboratories in the European countries, the ISO 15189 accreditation project has been widely accepted. The use of a unique standard and the cooperation among countries due to scientific societies, EFLM, accreditation bodies and EA enable laboratory professionals to move toward uniform implementation of the accreditation concept. PMID- 26744250 TI - Mechanistic Investigations into the Application of Sulfoxides in Carbohydrate Synthesis. AB - The utility of sulfoxides in a diverse range of transformations in the field of carbohydrate chemistry has seen rapid growth since the first introduction of a sulfoxide as a glycosyl donor in 1989. Sulfoxides have since developed into more than just anomeric leaving groups, and today have multiple roles in glycosylation reactions. These include as activators for thioglycosides, hemiacetals, and glycals, and as precursors to glycosyl triflates, which are essential for stereoselective beta-mannoside synthesis, and bicyclic sulfonium ions that facilitate the stereoselective synthesis of alpha-glycosides. In this review we highlight the mechanistic investigations undertaken in this area, often outlining strategies employed to differentiate between multiple proposed reaction pathways, and how the conclusions of these investigations have and continue to inform upon the development of more efficient transformations in sulfoxide-based carbohydrate synthesis. PMID- 26744254 TI - Structure of AmtR, the global nitrogen regulator of Corynebacterium glutamicum, in free and DNA-bound forms. AB - Corynebacterium glutamicum is a bacterium used for industrial amino acid production, and understanding its metabolic pathway regulation is of high biotechnological interest. Here, we report crystal structures of AmtR, the global nitrogen regulator of C. glutamicum, in apo (2.25-A and 2.65-A resolution) and DNA-bound (3-A resolution) forms. These structures reveal an all-alpha homodimeric TetR family regulator composed of a helix-turn-helix-hosting N terminal DNA-binding domain and a C-terminal dimerization domain. AmtR has several unique structural features that appear to be invariant among AmtR proteins, which may be related to its regulation by the nitrogen-sensing trimeric protein GlnK rather than by small-molecule effectors. As compared with other TetR family members, AmtR has an extra C-terminal helix, a large extended external loop that resembles the flexible tranducer T-loop of GlnK in sequence, and a large open cavity towards the intersubunit region that changes shape upon DNA binding. The marked kinking of helix 4 decreases in the DNA-bound form. The binding of one AmtR dimer to its DNA operator involves not only the insertion of helices 3 and 3' in adjacent turns of the double-helix major groove, but also the anchoring of 19-residue, arginine-rich and proline-rich N-terminal extensions to two external minor grooves. Electrophoretic mobility shift assays with a deletion mutant reveal that the 19-residue extension is crucial for AmtR binding to DNA. N extension anchoring explains the flanking by AT sequences of the recognized target DNA sequence core. The significance of these findings for the entire TetR family of regulators and for GlnK regulation of AmtR is discussed. DATABASE: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org [PDB ID codes 5DXZ (native AmtR), 5DY1 (SeMet-AmtR), and 5DY0 (AmtR.DNA)]. PMID- 26744252 TI - Dietary Dihydromethysticin Increases Glucuronidation of 4-(Methylnitrosamino)-1 (3-Pyridyl)-1-Butanol in A/J Mice, Potentially Enhancing Its Detoxification. AB - Effective chemopreventive agents are needed against lung cancer, the leading cause of cancer death. Results from our previous work showed that dietary dihydromethysticin (DHM) effectively blocked initiation of lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice, and it preferentially reduced 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) derived DNA adducts in lung. This study explored the mechanism(s) responsible for DHM's differential effects on NNK/NNAL-derived DNA damage by quantifying their metabolites in A/J mice. The results showed that dietary DHM had no effect on NNK or NNAL abundance in vivo, indicating that DHM does not affect NNAL formation from NNK. DHM had a minimal effect on cytochrome P450 2A5 (CYP2A5, which catalyzes NNK and NNAL bioactivation in A/J mouse lung), suggesting that it does not inhibit NNAL bioactivation. Dietary DHM significantly increased O glucuronidated NNAL (NNAL-O-gluc) in A/J mice. Lung and liver microsomes from dietary DHM-treated mice showed enhanced activities for NNAL O-glucuronidation. These results overall support the notion that dietary DHM treatment increases NNAL detoxification, potentially accounting for its chemopreventive efficacy against NNK-induced lung tumorigenesis in A/J mice. The ratio of urinary NNAL-O gluc and free NNAL may serve as a biomarker to facilitate the clinical evaluation of DHM-based lung cancer chemopreventive agents. PMID- 26744253 TI - Calorie Restriction Increases P-Glycoprotein and Decreases Intestinal Absorption of Digoxin in Mice. AB - There is wide variation in how patients respond to therapeutics. Factors that contribute to pharmacokinetic variations include disease, genetics, drugs, age, and diet. The purpose of this study was to determine the effect of calorie restriction on the expression of Abcb1a in the intestine and whether calorie restriction can alter the absorption of an Abcb1a substrate (i.e., digoxin) in mice. Ten-week-old C57BL/6 mice were given either an ad libitum diet or a 25% calorie-restricted diet for 3 weeks. To determine digoxin absorption, mice were administered [(3)H]-labeled digoxin by oral gavage. Blood and intestine with contents were collected at 1, 2, 4, and 12 hours after digoxin administration. Concentrations of [(3)H]-digoxin in plasma and tissues were determined by liquid scintillation. Calorie restriction decreased plasma digoxin concentrations (about 60%) at 1, 2, and 4 hours after administration. Additionally, digoxin concentrations in the small intestine of calorie-restricted mice were elevated at 4 and 12 hours after administration. Furthermore, calorie restriction increased Abcb1a transcripts in the duodenum (4.5-fold) and jejunum (12.5-fold). To confirm a role of Abcb1a in the altered digoxin pharmacokinetics induced by calorie restriction, the experiment was repeated in Abcb1a/b-null mice 4 hours after drug administration. No difference in intestine or plasma digoxin concentrations were observed between ad libitum-fed and calorie-restricted Abcb1a/b-null mice. Thus, these findings support the hypothesis that calorie restriction increases intestinal Abcb1a expression, leading to decreased absorption of digoxin in mice. Because Abcb1a transports a wide variety of therapeutics, these results may be of important clinical significance. PMID- 26744255 TI - Antibacterial activity and proposed action mechanism of a new class of synthetic tricyclic flavonoids. AB - AIMS: This study reports on the inhibitory and bactericidal properties of a new synthetized flavonoid. METHODS AND RESULTS: Tricyclic flavonoid 1 has been synthesized through a two-step reaction sequence. The antimicrobial effects were tested using the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays. Also DNA fragmentation assay, fluorescence microscopy and SEM were used to study the mechanism of action. Our tested flavonoid displayed a strong antimicrobial activity with MIC and MBC values as low as 0.24 MUg ml(-1) against Staphylococcus aureus and 3.9 MUg ml(-1) against Escherichia coli. Flavonoid 1 displayed antimicrobial properties, causing not only the inhibition of bacterial growth, but also killing bacterial cells. The mechanism of action is related to the impairment of the cell membrane integrity and to cell agglutination. CONCLUSIONS: Tricyclic flavonoid 1 was found to have a stronger antibacterial effect at lower concentrations than those described in the earlier reports. SIGNIFICANCE AND IMPACT OF THE STUDY: Based on the strong antimicrobial activity observed, this new tricyclic flavonoid has a good potential for the design of new antimicrobial agents. PMID- 26744258 TI - Erratum for Chandran and Mazumder, Pathogenic Potential, Genetic Diversity, and Population Structure of Escherichia coli Strains Isolated from a Forest-Dominated Watershed (Comox Lake) in British Columbia, Canada. PMID- 26744256 TI - Heterogeneous clinical spectrum of anti-SRP myositis and importance of the methods of detection of anti-SRP autoantibodies: a multicentric study. AB - Anti-signal recognition particle (SRP) antibodies are important serological markers for the diagnosis and the prognosis of idiopathic inflammatory myopathy (IIM), especially to distinguish immune-mediated necrotizing myopathy (IMNM). This study was set up to investigate the phenotype associated with anti-SRP antibodies and to evaluate the methods for detecting these antibodies. Clinical and biological data were retrospectively obtained from 60 adult patients with anti-SRP antibodies detected by a dot immunoassay from 12 centers. Thirty-six (60 %) out of these 60 patients suffered from an IIM, and among them, 21 patients were diagnosed as IMNM. Among patients with a definite IIM, proximal weakness and myalgia were prominent symptoms at the time of diagnosis. Only few patients displayed severe extra-muscular symptoms such as cardiac involvement or severe myositis. Mean creatine kinase levels were high for all patients except for two of them. When testing by indirect immunofluorescence (IIF) on HEp2 cells, the fraction of patients displaying the typical anti-SRP fine speckled staining of the cytoplasm was higher in patients with IIM (30/36) (83 %) than in patients with non-IIM (3/24) (12.5 %) (p < 0.0001). Thirty (91 %) out of 33 patients with a positive immunodot and a characteristic IIF cytoplasmic staining suffered from a clinical definite myositis, whereas only 6 (22 %) out of 27 patients with a positive immunodot but a negative cytoplasmic pattern suffered from a myositis (p < 0.00001). This series highlights the strong heterogeneity of anti-SRP positivity that encompassed IMNM and non-IMNM and supports the necessity of considering both IIF and dot immunoassay to confirm the diagnosis of anti-SRP associated myositis. PMID- 26744260 TI - Norstictic Acid Inhibits Breast Cancer Cell Proliferation, Migration, Invasion, and In Vivo Invasive Growth Through Targeting C-Met. AB - Breast cancer is a major health problem affecting the female population worldwide. The triple-negative breast cancers (TNBCs) are characterized by malignant phenotypes, worse patient outcomes, poorest prognosis, and highest mortality rates. The proto-oncogenic receptor tyrosine kinase c-Met is usually dysregulated in TNBCs, contributing to their oncogenesis, tumor progression, and aggressive cellular invasiveness that is strongly linked to tumor metastasis. Therefore, c-Met is proposed as a promising candidate target for the control of TNBCs. Lichens-derived metabolites are characterized by their structural diversity, complexity, and novelty. The chemical space of lichen-derived metabolites has been extensively investigated, albeit their biological space is still not fully explored. The anticancer-guided fractionation of Usnea strigosa (Ach.) lichen extract led to the identification of the depsidone-derived norstictic acid as a novel bioactive hit against breast cancer cell lines. Norstictic acid significantly suppressed the TNBC MDA-MB-231 cell proliferation, migration, and invasion, with minimal toxicity to non-tumorigenic MCF-10A mammary epithelial cells. Molecular modeling, Z'-LYTE biochemical kinase assay and Western blot analysis identified c-Met as a potential macromolecular target. Norstictic acid treatment significantly suppressed MDA-MB-231/GFP tumor growth of a breast cancer xenograft model in athymic nude mice. Lichen-derived natural products are promising resources to discover novel c-Met inhibitors useful to control TNBCs. PMID- 26744262 TI - Peri-implant bone loss clinical and radiographic evaluation around rough neck and microthread implants: a 5-year study. AB - OBJECTIVE: To evaluate marginal bone loss over 5 years around microthreaded implants placed in the maxillary anterior/esthetic zone and immediate restored with non-occlusal loading. MATERIALS AND METHODS: Seventy-one implants (with microthreads up to the platform-rough surface body and neck, internal connection and platform switching) were placed in healed bone in the maxillary arches of 30 men and 23 women (mean age 37.85 +/- 7.09 years, range 27-60). All subjects had at least 3 mm of soft tissue to allow the establishment of adequate biologic width and to reduce bone resorption. Each patient received a provisional restoration immediately after implant placement with slight occlusal contact. Mesial and distal bone height was evaluated using digital radiography on the day following implant placement (baseline) and after 1, 2, 3, 4 and 5 years. Primary stability was measured with resonance frequency analysis. RESULTS: No implants failed, resulting in a cumulative survival rate of 100% after 3 years. Marginal bone loss from implant collar to bone crest measured at baseline (peri-implant bone defect at the fresh extraction socket) and after 5 years was 0.90 mm +/- 0.26 mm. Mesial and distal site crestal bone loss ranged from 3.42 +/- 1.2 mm at baseline to 3.51 +/- 1.5 mm after 5 years and from 3.38 +/- 0.9 mm at baseline to 3.49 +/- 0.9 mm after 5 years, respectively (P = 0.086). CONCLUSIONS: The results of this study showed limited implant crestal bone loss 0.90 mm +/- 0.26 mm and 100% of implant survival rate at 5-year follow-up of immediate restored implants with rough surface neck and microthreads. PMID- 26744261 TI - Utstein-style guidelines on uniform reporting of in-hospital cardiopulmonary resuscitation in dogs and cats. A RECOVER statement. AB - OBJECTIVE: To provide recommendations for reviewing and reporting clinical in hospital cardiopulmonary resuscitation (CPR) events in dogs and cats and to establish nonambiguous operational definitions for CPR terminology. DESIGN: Consensus guidelines. SETTING: International, academia, referral practice, general practice, and human medicine. METHODS: An international veterinary Utstein task force was convened in April 2013 in San Francisco to determine the scope of the project, the variables to be reported, their definitions, and a reporting template. Factors that were essential for meaningful data reporting and were amenable to accurate collection (ie, core variables) and additional variables useful for research projects and hypothesis generation (ie, supplemental variables) were defined. Consensus on each item was either achieved during that meeting or during the subsequent online modified Delphi process and dialogue between task force members. RESULTS: Variables were defined and categorized as hospital, animal, event (arrest), and outcome variables. This report recommends a template for standardized reporting of veterinary in-hospital CPR studies involving dogs or cats. Core elements include the suspected cause(s) and location of arrest, first rhythm identified, the occurrence of return of spontaneous circulation (ROSC) of more than 30 seconds (any ROSC) or more than 20 minutes (sustained ROSC), survival to discharge, and functional capacity at discharge. If CPR is discontinued or the patient is euthanized by owner request, a reason is reported. The task force suggests a case report form to be used for individual resuscitation events. CONCLUSIONS: The availability of these veterinary small animal CPR reporting guidelines will encourage and facilitate high-quality veterinary CPR research, improve data comparison between studies and across study sites, and serve as the foundation for veterinary CPR registries. PMID- 26744263 TI - Defining Multiple Characteristic Raman Bands of alpha-Amino Acids as Biomarkers for Planetary Missions Using a Statistical Method. AB - Biomarker molecules, such as amino acids, are key to discovering whether life exists elsewhere in the Solar System. Raman spectroscopy, a technique capable of detecting biomarkers, will be on board future planetary missions including the ExoMars rover. Generally, the position of the strongest band in the spectra of amino acids is reported as the identifying band. However, for an unknown sample, it is desirable to define multiple characteristic bands for molecules to avoid any ambiguous identification. To date, there has been no definition of multiple characteristic bands for amino acids of interest to astrobiology. This study examined L-alanine, L-aspartic acid, L-cysteine, L-glutamine and glycine and defined several Raman bands per molecule for reference as characteristic identifiers. Per amino acid, 240 spectra were recorded and compared using established statistical tests including ANOVA. The number of characteristic bands defined were 10, 12, 12, 14 and 19 for L-alanine (strongest intensity band: 832 cm(-1)), L-aspartic acid (938 cm(-1)), L-cysteine (679 cm(-1)), L-glutamine (1090 cm(-1)) and glycine (875 cm(-1)), respectively. The intensity of bands differed by up to six times when several points on the crystal sample were rotated through 360 degrees ; to reduce this effect when defining characteristic bands for other molecules, we find that spectra should be recorded at a statistically significant number of points per sample to remove the effect of sample rotation. It is crucial that sets of characteristic Raman bands are defined for biomarkers that are targets for future planetary missions to ensure a positive identification can be made. PMID- 26744264 TI - Impact of AxotrackTM for ultrasound-guided central venous catheter insertion: a randomized controlled study conducted on inanimate manikin. PMID- 26744265 TI - The heart of the art. PMID- 26744267 TI - The quality and lifespan of guidelines. PMID- 26744266 TI - Screening for sleep apnea in the perioperative setting: looking for the right compromise. PMID- 26744268 TI - Differential regulation of pro- and antiapoptotic proteins in fish adipocytes during hypoxic conditions. AB - Worldwide, the frequencies and magnitudes of hypoxic events in estuarine waters have increased considerably over the past two decades. Fish populations are suitable indicators for the assessment of quality of aquatic ecosystems and often comprise a variety of adaptation systems by triggering oxidants, antioxidants and hypoxia-responsive signaling proteins. Signaling pathway may lead to cell survival or cell death which is fine-tuned by both positive and negative factors, which includes hypoxia-inducible factor-1alpha (HIF1alpha), heat-shock protein-70 (HSP70), phospho-c-Jun N-terminal kinase 1/2 (p-JNK1/2) and apoptosis signal regulating kinase-1 (ASK1). In the present study, we attempt to determine stress mediated signaling changes and molecular mechanism behind the cell survival by comparing adipocytes of fish from field hypoxic condition and laboratory-induced hypoxic condition (in vitro hypoxia). Comparison of field and laboratory studies in fish adipocytes showed differential expression of HIF1alpha, HSP70, p-JNK1/2 and ASK1 with altered oxidants and antioxidants. Further, the results also suggest that in vitro hypoxic conditions mimic field hypoxic conditions. Trends of hypoxia response were same in in vitro hypoxia of control adipocytes as in Ennore estuary, and hypoxia response was more pronounced in the test adipocytes under in vitro hypoxic condition. Results of the present work suggest that hypoxia is the major crusade of water pollutants affecting fish by differential regulation of pro- and antiapoptotic proteins probably through HSP70. This may play a vital role by providing cytoprotection in pollutant-induced stressed fish adipocytes substantiated by the in vitro hypoxic studies. PMID- 26744269 TI - Early biochemical biomarkers for zinc in silver catfish (Rhamdia quelen) after acute exposure. AB - Contamination of aquatic ecosystems by metals causes various biochemical changes in aquatic organisms, and fish are recognized as indicators of environmental quality. Silver catfish were exposed to six concentrations of zinc (Zn): 1.0, 2.5, 5.0, 7.5, 10.0 and 12.5 mg/L for 96 h to determine the mean lethal concentration (LC50). The value obtained was 8.07 mg/L. In a second experiment, fish were exposed to concentrations of 1.0 or 5.0 mg/L Zn and a control for 96 h. Afterward, the tissues were collected for biochemical analysis. Lipid peroxidation, as indicated by thiobarbituric acid-reactive substance (TBARS), decreased in the liver and brain for all Zn concentrations tested, while in the gills TBARS levels increased at 1.0 mg/L and declined at 5.0 mg/L. Zn increased protein carbonyls in the muscle of silver catfish and decreased it in the other tissues. The enzyme superoxide dismutase increased in both exposed groups. However, catalase did not change. Glutathione S-transferase decreased in the liver and increased in the gills (1.0 mg/L), muscle (5.0 mg/L) and brain (1.0 and 5.0 mg/L). Nonprotein thiols changed only in brain and muscle tissue. Zn exposure inhibited acetylcholinesterase (AChE) activity in the brain at both concentrations tested, but did not change it in muscle. Exposure to Zn inhibited the activity of Na(+)/K(+)-ATPase in the gills and intestine at both concentrations tested. Our results demonstrate that Zn alters biochemical parameters in silver catfish and that some parameters such as AChE and Na(+)/K(+) ATPase could be considered as early biomarkers of waterborne Zn toxicity. PMID- 26744271 TI - Elevated mRNA expression of PGF2alpha receptor splice variant 2(FP-V2) in human decidua is associated with incomplete mifepristone-misoprostol-induced early medical abortion by regulation of interleukin-8. AB - OBJECTIVE: The combination of mifepristone and misoprostol is an established method for the induction of early abortion, but 15% of women still experience the unpleasant side effect of incomplete medical abortion. The purpose of this study was to determine whether prostaglandin (PG) F2alpha receptor (FP) and its two isoforms (FP-V1 and FP-V2) in human decidua are associated incomplete abortion. METHODS: Forty women who underwent medical abortion were recruited. Among them, there were 20 cases of incomplete abortion. The other 20 cases of complete abortion were used as controls. The expression levels of FP, FPV1 and FP-V2 in the decidua between of the two groups was detected by quantitative real-time polymerase chain reaction (PCR). Additionally, FP-V2 was knocked down using specific small interfering RNAs (siRNAs) in the primary cultures of decidual cells. The expression levels of cytokines in FP-V2 knockdown primary decidual cells and control decidual cells were detected by quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA). RESULTS: The FP and FP-V2 mRNA expression in the incomplete group was significantly higher than that in the complete group (p < 0.05). IL-8 was up-regulated by FP-V2 knockdown in primary cultured decidual cells (p < 0.05). CONCLUSIONS: These results suggested that the elevated expression of FP-V2 in human decidua is significantly associated with incomplete mifepristone-misoprostol-induced early medical abortion and that IL-8 could be lined to this process. PMID- 26744272 TI - Asfotase Alfa: A Review in Paediatric-Onset Hypophosphatasia. AB - Hypophosphatasia (HPP) is a rare inheritable disease that results from loss-of function mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). Therapeutic options for treating the underlying pathophysiology of the disease have been lacking, with the mainstay of treatment being management of symptoms and supportive care. HPP is associated with significant morbidity and mortality in paediatric patients, with mortality rates as high as 100 % in perinatal-onset HPP and 50 % in infantile-onset HPP. Subcutaneous asfotase alfa (Strensiq((r))), a first-in-class bone-targeted human recombinant TNSALP replacement therapy, is approved in the EU for long-term therapy in patients with paediatric-onset HPP to treat bone manifestations of the disease. In noncomparative clinical trials in infants and children with paediatric-onset HPP, asfotase alfa rapidly improved radiographically-assessed rickets severity scores at 24 weeks (primary timepoint) as reflected in improvements in bone mineralization, with these benefits sustained after more than 3 years of treatment. Furthermore, patients typically experienced improvements in respiratory function, gross motor function, fine motor function, cognitive development, muscle strength (normalization) and ability to perform activities of daily living, and catch-up height-gain. In life-threatening perinatal and infantile HPP, asfotase alfa also improved overall survival. Asfotase alfa was generally well tolerated in clinical trials, with relatively few patients discontinuing treatment and most treatment-related adverse events being of mild to moderate intensity. Thus, subcutaneous asfotase alfa is a valuable emerging therapy for the treatment of bone manifestations in patients with paediatric-onset HPP. PMID- 26744270 TI - Subtelomere organization in the genome of the microsporidian Encephalitozoon cuniculi: patterns of repeated sequences and physicochemical signatures. AB - BACKGROUND: The microsporidian Encephalitozoon cuniculi is an obligate intracellular eukaryotic pathogen with a small nuclear genome (2.9 Mbp) consisting of 11 chromosomes. Although each chromosome end is known to contain a single rDNA unit, the incomplete assembly of subtelomeric regions following sequencing of the genome identified only 3 of the 22 expected rDNA units. While chromosome end assembly remains a difficult process in most eukaryotic genomes, it is of significant importance for pathogens because these regions encode factors important for virulence and host evasion. RESULTS: Here we report the first complete assembly of E. cuniculi chromosome ends, and describe a novel mosaic structure of segmental duplications (EXT repeats) in these regions. EXT repeats range in size between 3.5 and 23.8 kbp and contain four multigene families encoding membrane associated proteins. Twenty-one recombination sites were identified in the sub-terminal region of E. cuniculi chromosomes. Our analysis suggests that these sites contribute to the diversity of chromosome ends organization through Double Strand Break repair mechanisms. The region containing EXT repeats at chromosome extremities can be differentiated based on gene composition, GC content, recombination sites density and chromosome landscape. CONCLUSION: Together this study provides the complete structure of the chromosome ends of E. cuniculi GB-M1, and identifies important factors, which could play a major role in parasite diversity and host-parasite interactions. Comparison with other eukaryotic genomes suggests that terminal regions could be distinguished precisely based on gene content, genetic instability and base composition biais. The diversity of processes assciated with chromosome extremities and their biological consequences, as they are presented in the present study, emphasize the fact that great effort will be necessary in the future to characterize more carefully these regions during whole genome sequencing efforts. PMID- 26744280 TI - The biomechanical strength of a hardware-free femoral press-fit method for ACL bone-tendon-bone graft fixation. AB - PURPOSE: The purpose was to investigate graft slippage and ultimate load to failure of a femoral press-fit fixation technique for anterior cruciate ligament (ACL) reconstruction. METHODS: Nine fresh-frozen knees were used. Standardized harvesting of the B-PT-B graft was performed. The femora were cemented into steel rods, and a tunnel was drilled outside-in into the native ACL footprint and expanded using a manual mill bit. The femoral bone block was fixed press-fit. To pull the free end of the graft, it was fixed to a mechanical testing machine using a deep-freezing technique. A motion capture system was used to assess three dimensional micro-motion. After preconditioning of the graft, 1000 cycles of tensile loading were applied. Finally, an ultimate load to failure test was performed. Graft slippage in mm ultimate load to failure as well as type of failure was noted. RESULTS: In six of the nine measured specimens, a typical pattern of graft slippage was observed during cyclic loading. For technical reasons, the results of three knees had to be discarded. 78.6 % of total graft slippage occurred in the first 100 cycles. Once the block had settled, graft slippage converged to zero, highlighting the importance of initial preconditioning of the graft in the clinical setting. Graft slippage after 1000 cycles varied around 3.4 +/- 3.2 mm (R = 1.3-9.8 mm) between the specimens. Ultimate loading (n = 9) revealed two characteristic patterns of failure. In four knees, the tendon ruptured, while in five knees the bone block was pulled out of the femoral tunnel. The median ultimate load to failure was 852 N (R = 448-1349 N). CONCLUSION: The implant-free femoral press-fit fixation provided adequate primary stability with ultimate load to failure pull forces at least equal to published results for interference screws; hence, its clinical application is shown to be safe. PMID- 26744281 TI - Morphology of insertion sites on patellar side of medial patellofemoral ligament. AB - PURPOSE: The purpose of this study was to clarify the insertion sites on the patellar side of the medial patellofemoral ligament (MPFL). METHODS: A total of 35 nonpaired human cadaveric knees were used in this study. After identification of the MPFL, the insertion sites on the patellar side of the MPFL were marked. Three-dimensional images were created, and the location and morphology of these insertion sites were analysed. RESULTS: The morphology of the insertion sites on the patellar side of the MPFL was consistent. The proximal fibres of the MPFL were inserted to the deep fascia of the vastus medialis obliquus (VMO) and medial margin of the vastus intermedius (VI). The distal fibres of the MPFL were inserted to the medial margin of the patella directly. The insertion lengths of the VMO, VI, and patella were 26.7 +/- 5.0, 28.5 +/- 4.4, and 18.5 +/- 4.4 mm, respectively. The rate of the vertical distance from the superior pole of the patella to the superior edge of the MPFL in relation to the total patellar height was 12 +/- 4.4 %. At the distal edge, the rate was 58 +/- 9.6 %. CONCLUSION: The insertion sites on the patellar side of the MPFL were consistent. The MPFL inserted into the VMO and VI was significantly longer than into the patella. The clinical relevance of this study is to improve understanding of the anatomy of the insertion sites on the patellar side of the MPFL and the pathophysiology of patellar dislocation. PMID- 26744282 TI - Evidence-based indications for hindfoot endoscopy. AB - PURPOSE: The 2-portal hindfoot endoscopic technique with the patient in prone position, first introduced by van Dijk et al. (Arthroscopy 16:871-876, 2000), is currently the most used by foot and ankle surgeons to address endoscopically pathologies located in the hindfoot. This article aims to review the literature to provide a comprehensive description of the level of evidence available to support the use of the 2-portal hindfoot endoscopy technique for the current generally accepted indications. METHODS: A comprehensive review was performed by use of the PubMed database to isolate literature that described therapeutic studies investigating the results of different hindfoot endoscopy treatment techniques. All articles were reviewed and assigned a classification (I-V) of level of evidence. An analysis of the literature reviewed was used to assign a grade of recommendation for each current generally accepted indication for hindfoot endoscopy. A subscale was used to further describe the evidence base for indications receiving a grade of recommendation indicating poor-quality evidence. RESULTS: On the basis on the available evidence, posterior ankle impingement syndrome, subtalar arthritis and retrocalcaneal bursitis have the strongest recommendation in favour of treatment (grade Cf). CONCLUSION: Although a low level of evidence of the included studies, the review showed that adequate literature to support the use of the 2-portal endoscopic techniques for most currently accepted indications exists. Future "higher quality" evidence could strengthen current recommendations and further help surgeons in evidence-based practice. LEVEL OF EVIDENCE: Level V, Review of Level III, IV and V studies. PMID- 26744283 TI - Achieving the "Minimal Scarring" Concept in Bariatrics by Port-Site Relocation. AB - BACKGROUND: The aim of single incision laparoscopic surgery (SILS) and other types of trans-umbilical procedures (TU) has been to perform operations with minimal or no visible scars. However, in bariatric surgery, they are in particular demanding and the final esthetic advantage is in question given the long-term abdominal skin alteration, or abdominoplasty. We propose an alternative rationale and approach to achieve the minimal scarring concept in bariatric surgery. METHODS: A retrospective report of a straight forward method using four access ports, where three ports are concealed at either the lower panniculectomy region or the lateral folds of the umbilicus. The technique was performed on a pilot series of 65 female patients who underwent laparoscopic sleeve gastrectomy (LSG). RESULTS: The study sample had a mean age of 40.3 years and a mean BMI of 41.1 +/- 4.2 kg/m(2). All procedures were completed laparoscopically. Field ergometry, working angles, and surgeon's convenience were not impaired. Mean operation time was 46 min and mean hospital stay was 2.3 days. Complications were minimal. Postoperative esthetic outcome and the rationale behind port placement were well appreciated by the patients. CONCLUSIONS: Performing LSG with the described approach is feasible, safe, and consistent with basic principles of ergometry including correct working triangulation. Esthetic outcome is up to the minimal scarring concept and future body contouring is not hampered. PMID- 26744285 TI - Is Bariatric Surgery Effective in Reducing Comorbidities and Drug Costs?: Letter to the editor. PMID- 26744284 TI - Food Intake and Changes in Eating Behavior After Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) results in reduced calorie intake and weight loss. Whether patients consume the same types of food before and after surgery or whether they reduce the volume and calorie density of the foods they consume remains unknown. OBJECTIVES: The aim of this prospective study was to evaluate the changes in daily caloric and macronutrient intake after LSG and the relation between changes of taste and food tolerance over 2 years. METHODS: Thirty morbidly obese patients with median body mass index (BMI) of 43.9 kg/m(2) (39.5-57.3) were prospectively enrolled prior to LSG. Weight, BMI, %EWL, weight loss percentage (%WL), and daily intake were evaluated preoperatively at 1, 3, 6, 12, and 24 months after surgery along with a questionnaire evaluating food choices, quality of eating, tolerance of certain types of food, frequency of vomiting, and changes in taste. RESULTS: The median %EWL and %WL at 12 and 24 months was 65 % (33.9-93.6 %), 27.3 % (14.2-45.5 %) and 71.5 % (39.6-101.1 %), 31 % (19.1-50.3 %) respectively. Six months after surgery, the daily caloric intake reduced by 68 % and the reduction was maintained until 24 months. The median score of the eating questionnaire was 18 (10-27) at 6 months, 22 (16-26) at 12 months, and 23 (10-27) at 24 months, suggesting that the quality of nutrition improved over time. At 6, 12, and 24 months, 75 % of the patients reported changes in taste with reduced interest in sweets, high fat food, and alcoholic drinks. However, at 24 months, 20 % of patients reported a heightened interest in sweets compared to 12 months previously. CONCLUSIONS: LSG reduced calorie intake both through volume of food and the calorie density of the food consumed. The mechanisms for the changes in food preferences may involve both unconditioned and conditioned effects. The influence of dietary counseling on learning which foods are consumed still requires further exploration. PMID- 26744286 TI - Letter: Primary Hyperparathyroidism after Roux-en-Y gastric Bypass. PMID- 26744287 TI - Combined supine and prone imaging acquisition in cardiac SPECT: A turn for the better. PMID- 26744288 TI - Multifunctional biosensors based on peptide-polyelectrolyte conjugates. AB - A novel enzymatic platform for the sensing of H2O2 and glucose that uses L,L diphenylalanine micro/nanostructures (FF-MNSs) as an enzyme support is shown. This platform is obtained by the self-assembly of poly(allylamine hydrochloride) (PAH), FF-MNSs, and microperoxidase-11 (MP11) anchored onto the peptide matrix, in two different crystal structures of FF-MNSs: hexagonal (P61) and orthorhombic (P22121). The electroactive area of the electrodes increases in the presence of FF-MNSs. We also demonstrate via theoretical calculations that the valence band energy of the orthorhombic structure allows it to be doped, similarly to p-type semiconductors, where PAH acts as a doping agent for the orthorhombic peptide structure, decreasing the band-gap by around 1 eV, which results in a smaller charge transfer resistance. These results are consistent with electrochemical impedance spectroscopy measurements, which further elucidate the role of the band structure of the orthorhombic FF-MNSs in the conductivity and electron transfer rates of the hybrid material. An effective communication between the electrode and the active site of a glucose oxidase enzyme through MP11-protein complexes occurs, paving the way for FF-MNSs in the orthorhombic phase for the future development of bioelectronics sensing devices. PMID- 26744289 TI - Extensive Metoidioplasty as a Technique Capable of Creating a Compatible Analogue to a Natural Penis in Female Transsexuals. AB - OBJECTIVE: To introduce the operative technique of "extensive metoidioplasty" (EM) in female transsexual surgery, for achieving an effective reconstruction of a male-appearing, normally functioning, fully sensate and erectile external genitalia. PATIENTS AND METHODS: Ten female transsexuals (46 xx karyotype) between the ages of 20 and 40 years underwent EM as their sex reassignment surgical procedure with the mean operative time of 171 min (45-211, SD 19.55 min) between 2007 and 2014 in a general hospital in Tehran, Iran. Subjects were closely followed for the mean time of 68.4 months. All participants were thoroughly rehearsed about the nature of their surgical procedure and an informed written consent was obtained before surgery. We extensively detached the native clitoris to the point of a nearly complete detachment from its attachments to the pubic arch and approximated the originally divergent corporal bodies to each other. We were also able to increase the penile size by the application of PEP, a procedure which is in practice at our clinic. RESULTS: Postoperatively all ten patients achieved a mean penile length of 8.7 (6-12) cm and 7/10 (70 %) were capable of obtaining erection, rigid enough for intromission. We did not observe any significant postoperative complications. CONCLUSION: EM in association with the application of PEP could result in a natural-looking, erotically fully sensate and functional penis in majority of female transsexuals undergoing this procedure. This operative technique should be given serious considerations in well-informed female transsexual. Larger studies may be needed to validate this technique further. LEVEL OF EVIDENCE V: This journal requires that the authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26744290 TI - Emergence of Culicoides obsoletus group species from farm-associated habitats in Germany. AB - Biting midges of the genus Culicoides (Diptera: Ceratopogonidae) may transmit several arboviruses to ruminant livestock. The species of the Obsoletus group are considered to be among the most important vectors of bluetongue virus (BTV) in northern Europe. As agricultural environments offer suitable habitats for the development of their immature stages, the emergence of adult Culicoides from potential breeding sites was investigated at 20 cattle farms throughout Germany in 2012 and 2013. In analyses of species-specific habitat preferences and relationships between Culicoides abundance in breeding substrates and their physicochemical characteristics, dungheaps emerged as the most important substrate for the development of Culicoides obsoletus sensu stricto (s.s.) (Meigen), whereas Culicoides chiopterus (Meigen) and Culicoides dewulfi Goetghebuer were generally restricted to cowpats. A decreasing pH value was associated with a higher abundance or a higher probability of observing these three species. Furthermore, the abundance of C. obsoletus s.s. was positively related to increasing moisture. Dungheaps were very productive breeding sites for this species and are therefore suggested as a target for potential control measures. PMID- 26744291 TI - Tumour-induced osteomalacia: a literature review and a case report. AB - Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterised by severe hypophosphataemia and osteomalacia, with renal phosphate wasting that occurs in association with tumour. The epidemiology likewise aetiology is not known. The clinical presentation of TIO includes bone fractures, bone and muscular pains, and sometimes height and weight loss. TIO may be associated with mesenchymal tumours which may be benign or malignant in rare cases. Mesenchymal tumour itself may be related to fibroblast growth factor 23 (FGF23), which is responsible for hypophosphataemia and phosphaturia occurring in this paraneoplastic syndrome. Hypophosphataemia, phosphaturia and elevated alkaline phosphatase are the main laboratory readings that may lead to more precise investigations and better diagnosis. Finding the tumour can be a major diagnostic challenge and may involve total body magnetic resonance imaging, computed tomography and scintigraphy using radiolabelled somatostatin analogue. The treatment of choice for TIO is resection of a tumour with a wide margin to insure complete tumour removal, as recurrences of these tumours have been reported. We provide here an overview on the current available TIO case reports and review the best practices that may lead to earlier recognition of TIO and the subsequent treatment thereof, even though biochemical background and the long-term prognosis of the disease are not well understood. This review also includes a 4-year-long history of a patient that featured muscular pains, weakness and multiple stress fractures localised in the hips and vertebra with subsequent recovery after tumour resection. Because the occurrence of such a condition is rare, it may take years to correctly diagnose the disease, as is reported in this case report. PMID- 26744293 TI - Compatibility of Spatially Coded Apertures with a Miniature Mattauch-Herzog Mass Spectrograph. AB - In order to minimize losses in signal intensity often present in mass spectrometry miniaturization efforts, we recently applied the principles of spatially coded apertures to magnetic sector mass spectrometry, thereby achieving increases in signal intensity of greater than 10* with no loss in mass resolution Chen et al. (J. Am. Soc. Mass Spectrom. 26, 1633-1640, 2015), Russell et al. (J. Am. Soc. Mass Spectrom. 26, 248-256, 2015). In this work, we simulate theoretical compatibility and demonstrate preliminary experimental compatibility of the Mattauch-Herzog mass spectrograph geometry with spatial coding. For the simulation-based theoretical assessment, COMSOL Multiphysics finite element solvers were used to simulate electric and magnetic fields, and a custom particle tracing routine was written in C# that allowed for calculations of more than 15 million particle trajectory time steps per second. Preliminary experimental results demonstrating compatibility of spatial coding with the Mattauch-Herzog geometry were obtained using a commercial miniature mass spectrograph from OI Analytical/Xylem. PMID- 26744292 TI - Supragastric belch may be related to globus symptom - a prospective clinical study. AB - BACKGROUND: The etiology of globus is poorly understood. It is controversial, whether gastroesophageal reflux disease (GERD) has a role in globus. To investigate the possible esophageal background of this symptom, we performed transnasal esophagoscopy (TNE), high-resolution manometry (HRM), and 24-h multichannel intraluminal impedance (MII) and pH monitoring on globus patients. METHODS: Thirty consecutive patients were referred to Helsinki University Hospital, Department of Otorhinolaryngology - Head and Neck Surgery for treatment of globus; 24 consecutive patients with difficult reflux symptoms from the Department of Surgery served as controls. We compared the results of the patient groups in endoscopies, HRM, and 24-h MII-pH monitoring. KEY RESULTS: In MII monitoring, globus patients had supragastric belch (6/20, 30% vs 1/24, 4%; p = 0.038) more often than controls. Total reflux time was higher in controls (p = 0.004), and they had more acid reflux events (p = 0.002) in MII, but between groups, the number of non-acid reflux events was similar. In pH monitoring, DeMeester score and total pH <4 time were higher in controls (P < 0.001). In HRM, the upper esophageal sphincter (UES) mean basal and residual pressures did not differ. CONCLUSIONS & INFERENCES: Supragastric belch was more common in globus patients, suggesting the possible role of this condition in globus sensation. However, globus patients in this series had no acid or non-acid GERD or elevated UES pressure. PMID- 26744294 TI - Contact Ion Pairs on a Protonated Azamacrocycle: the Role of the Anion Basicity. AB - A potassium-containing hexaazamacrocyclic dication, [M*H*K](2+), is able to add in the gas phase mono- and dicarboxylate anions as well as inorganic anions by forming the corresponding monocharged adducts, the structure of which markedly depends on the basicity of the anion. With anions, such as acetate or fluoride, the neutral hexaazamacrocycle M acts as an acceptor of monosolvated K(+) ion. With less basic anions, such as trifluoroacetate or chloride, the protonated hexaazamacrocycle [M*H](+) performs the unusual functions of an acceptor of contact K(+)/anion pairs. Graphical Abstract ?. PMID- 26744295 TI - Improvement of photovoltaic performance by substituent effect of donor and acceptor structure of TPA-based dye-sensitized solar cells. AB - We report a computational study of a series of organic dyes built with triphenylamine (TPA) as an electron donor group. We designed a set of six dyes called (TPA-n, where n = 0-5). In order to enhance the electron-injection process, the electron-donor effect of some specific substituent was studied. Thus, we gave insights into the rational design of organic TPA-based chromophores for use in dye-sensitized solar cells (DSSCs). In addition, we report the HOMO, LUMO, the calculated excited state oxidized potential E(dye*)(eV) and the free energy change for electron-injection DeltaGinject(eV), and the UV-visible absorption bands for TPA-n dyes by a time-dependent density functional theory (TDDFT) procedure at the B3LYP and CAM-B3LYP levels with solvent effect. The results demonstrate that the introduction of the electron-acceptor groups produces an intramolecular charge transfer showing a shift of the absorption wavelengths of TPA-n under studies. Graphical Abstract Several organic dyes TPA-n with different donors and acceptors are modeled. A strong conjugation acrros the donor and anchoring groips (TPA-n) bas been studied. Candidate TPA-3 shows a promising results. PMID- 26744297 TI - Trends in childhood obesity and central adiposity between 1998-2001 and 2010-2012 according to household income and urbanity in Korea. AB - BACKGROUND: This study examined trends in body mass index (BMI), waist circumference (WC), and childhood overweight and obesity prevalence between 1998 2001 and 2010-2012 according to household income and urbanity among nationally representative Korean children and adolescents aged 10-19. METHODS: The repeated cross-sectional data from Korean National Health and Nutrition Examination Surveys in 1998-2001 and 2010-2012 were used. Gender specific trends in age adjusted means of WC and BMI by household equivalized income and urbanity were compared between years. The age-standardized prevalence of childhood overweight and obesity was calculated using three international criteria (International Obesity Task Force, World Health Organization, US Centers for Disease Control and Prevention) and a Korean national reference standard. RESULTS: Among boys, overall BMI and overweight prevalence increased between 1998-2001 and 2010-2012, while overall WC decreased. Clear gender differences were found in the relationship of childhood obesity metrics with household income and urbanity and the time trends of those relationships. Positive relationships between these parameters were found for boys while negative relationships appeared for girls. In addition, compared with the childhood obesity prevalence among boys in rural areas, the prevalence among boys in urban areas were slightly lower in 1998-2001 but became greater in 2010-2012. CONCLUSIONS: This study revealed gender difference in the association of childhood obesity with household income and urbanity and its time trends. The long-term gender-specific monitoring of socioeconomic and urban-rural differences in childhood obesity measures is warranted in South Korea. PMID- 26744296 TI - Solvation of the morpholinium cation in acetonitrile. Effect of an anion. AB - Ionic liquids (ILs) constitute a fast growing class of compounds finding multiple applications in science and technology. Morpholinium-based ILs (MBILs) and their mixtures with polar molecular co-solvents are interesting as sustainable electrolyte systems for electrochemistry. We investigate local structures of protic and apropic morpholinium cations in acetonitrile (ACN) using semi empirical molecular dynamics (MD) simulations. An impact of an anion (acetate) on the cation solvation regularities is discussed. Unlike oxygen, nitrogen of the morpholine ring is a strong electrophilic binding center. This site is responsible for the interactions of the cation with the solvent and with the anion. In protic MBILs, the role of nitrogen is delegated to the proton, which is linked to nitrogen. The acetate anion weakens solvation of the cation due to occupation of space near nitrogen or proton. The analysis reveals a favorable solvation of MBILs in ACN, which is a prerequisite for a new high-performance electrolyte system. The reported structural data were validated through point-to point comparison with the MP2 post-Hartree-Fock theory and density functional theory. PMID- 26744298 TI - General scheme to reduce the knee adduction moment by modifying a combination of gait variables. AB - Reducing the knee adduction moment (KAM) is a promising treatment for medial compartment knee osteoarthritis (OA). Although several gait modifications to lower the KAM have been identified, the potential to combine modifications and individual dose-responses remain unknown. This study hypothesized that: (i) there is a general scheme consisting of modifications in trunk sway, step width, walking speed, and foot progression angle that reduces the KAM; (ii) gait modifications can be combined; and (iii) dose-responses differ among individuals. Walking trials with simultaneous modifications in step width, walking speed, progression angle, and trunk sway were analyzed for 10 healthy subjects. Wider step width, slower speed, toeing-in, and increased trunk sway resulted in reduced first KAM peak, whereas wider step width, faster speed, and increased trunk sway reduced the KAM angular impulse. Individual regressions accurately modeled the amplitude of the KAM variables relative to the amplitude of the gait modification variables, while the dose-responses varied strongly among participants. In conclusion, increasing trunk sway, increasing step width, and toeing-in are three gait modifications that could be combined to reduce KAM variables related to knee OA. Results also indicated that some gait modifications reducing the KAM induced changes in the knee flexion moment possibly indicative of an increase in knee loading. Taken together with the different dose-responses among subjects, this study suggested that gait retraining programs should consider this general scheme of modifications with individualization of the modification amplitudes. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1547-1556, 2016. PMID- 26744299 TI - Well-defined and biocompatible hydrogels with toughening and reversible photoresponsive properties. AB - In the present study, novel hydrogels with extremely high strength, reversible photoresponsive and excellent biocompatible properties were prepared. The functional hydrogels were synthesized from a well-defined poly (ethylene glycol) polymer with spiropyran groups at a given position (PEG-SP) via a Cu(i)-catalyst Azide-Alkyne Cycloaddition (CuAAC) reaction. The molecular structures of the sequential intermediates for PEG-SP hydrogel preparation were verified by (1)HNMR and FT-IR. The mechanical property, swelling ratio, compression strength, surface hydrophilicity, and biocompatibility of the resulting hydrogel were characterized. Since spiropyran is pivotal to the switch in hydrophilicity on the hydrogel surface, the swelling ratio of PEG-SP hydrogel under Vis irradiation has a major decrease (155%). Before and after UV light irradiation, the contact angle of the hydrogel has a change of 13.8 degrees . The photoresponsive property of this hydrogel was thus demonstrated, and such a property was also shown to be reversible. The well-defined PEG-SP hydrogel can also sustain a compressive stress of 49.8 MPa without any macro- or micro-damage, indicating its outstanding mechanical performance. Furthermore, it possessed excellent biocompatibility as demonstrated by its performance in an in vivo porcine subcutaneous implantation environment. No inflammation was observed and it got along well with the adjacent tissue. The above features indicate that PEG-SP hydrogels are promising as an implantable matrix for potential applications in biomaterial. PMID- 26744300 TI - Examining techniques for measuring the effects of nutrients on mental performance and mood state. AB - PURPOSE: Intake of specific nutrients has been linked to mental states and various indices of cognitive performance although the effects are often subtle and difficult to interpret. Measurement of so-called objective variables (e.g. reaction times) is often considered to be the gold standard for assessing outcomes in this field of research. It can, however, be argued that data on subjective experience (e.g. mood) are also important and may enrich existing objective data. The aim of this review is to evaluate methods for measuring mental performance and mood, considering the definition of subjective mood and the validity of measures of subjective experience. METHODS: A multi-stakeholder expert group was invited by ILSI Europe to come to a consensus around the utility of objective and subjective measurement in this field, which forms the basis of the paper. Therefore, the present review reflects a succinct overview of the science but is not intended to be a systematic review. RESULTS: The proposed approach extends the traditional methodology using standard 'objective' measurements to also include the consumers' subjective experiences in relation to food. Specific recommendations include 1) using contemporary methods to capture transient mood states; 2) using sufficiently sensitive measures to capture effects of nutritional intervention; 3) considering the possibility that subjective and objective responses will occur over different time frames; and 4) recognition of the importance of expectancy and placebo effects for subjective measures. CONCLUSIONS: The consensus reached was that the most informative approach should involve collection and consideration of both objective and subjective data. PMID- 26744301 TI - Dietary intake of subjects with diabetes is inadequate in Switzerland: the CoLaus study. AB - PURPOSE: To characterize the dietary intake of subjects aged 40-80 years according to self-reported diabetes and presence of an anti-diabetic diet. METHODS: Cross-sectional study conducted between 2009 and 2012 on 4289 participants (2274 women) living in Lausanne. RESULTS: Of the 299 (7 %) participants with self-reported diabetes, only 151 (51 %) reported an anti diabetic diet. Compared to participants not reporting diabetes, participants with self-reported diabetes (with or without a diet) had a higher consumption of artificial sweeteners (0.3 +/- 0.7 vs. 0.4 +/- 0.8 and 0.8 +/- 1.0 times/day) and a lower consumption of honey/jam (mean +/- standard deviation: 0.5 +/- 0.5 vs. 0.4 +/- 0.4 and 0.4 +/- 0.4 times/day) or sugar (0.6 +/- 0.9 vs. 0.4 +/- 0.7 and 0.2 +/- 0.5 times/day) for participants not reporting diabetes, participants with self-reported diabetes not on a diet and on a diet, respectively. Compared to participants not on a diet, participants on a diet had a higher consumption of vegetables (1.8 +/- 1.3 vs. 1.4 +/- 1.0 portions/day), while no differences were found regarding all other food groups and nutrients. Participants with self reported diabetes on a diet had a higher consumption of meat (5.6 +/- 3.6 vs. 4.8 +/- 2.9 portions/week) and a lower consumption of simple carbohydrates (21.0 +/- 7.9 vs. 23.5 +/- 8.4 % total energy intake) than participants not reporting diabetes. CONCLUSION: People with diabetes eat less simple carbohydrates, but do not comply with current advice on fish, nuts, fruits and vegetables. Improvement of the dietary intake in persons with diabetes in Switzerland is needed. PMID- 26744303 TI - Inhibition of alpha-glucosidase by vitamin D3 and the effect of vitamins B1 and B2. AB - alpha-Glucosidase is a vital enzyme in carbohydrate metabolism. Over-expression of this enzyme is correlated with hyperglycemia. The inhibitory effect of vitamin D3 on alpha-glucosidase as well as its mechanism of action was investigated in this work. The results showed that vitamin D3 exhibited stronger inhibition on alpha-glucosidase than acarbose with the IC50 value of 1.28 * 10(-4) mol L(-1), and the inhibition was a mixed-type mechanism through a multiphase kinetic process. The inhibition constant was determined to be (5.66 +/- 0.03) * 10(-5) mol L(-1). Vitamin D3 interacted with alpha-glucosidase by hydrophobic interactions, and molecular docking further verified that the inhibitor inserted into the active site pocket of alpha-glucosidase and interacted with the amino residues, which induced the rearrangement and conformational changes of alpha glucosidase, and might move to cover the active pocket, hindering the binding of the substrate leading to the inhibition of the enzyme activity. Moreover, it was found that vitamin D3 combined with vitamin B1 or vitamin B2 exhibited significant synergistic effects on inhibition of alpha-glucosidase. This study has provided new insights into the role of vitamin D3 in inhibiting alpha glucosidase catalysis and offered useful information on the dietary recommendation of vitamin D3 for the treatment of type 2 diabetes. PMID- 26744302 TI - Dietary patterns in weight loss maintenance: results from the MedWeight study. AB - PURPOSE: The dietary habits contributing to weight loss maintenance are not sufficiently understood. We studied weight loss maintainers in comparison with regainers, to identify the differentiating behaviors. METHODS: The MedWeight study is a Greek registry of weight loss maintainers and regainers. Participants had intentionally lost >=10 % of their weight and either had maintained this loss for over a year, or had regained weight. Questionnaires on demographics and lifestyle habits were completed online. Dietary assessment was carried out by two telephone 24-h recalls. RESULTS: Present analysis focused on 361 participants (32 years old, 39 % men): 264 maintainers and 97 regainers. Energy and macronutrient intake did not differ by maintenance status (1770 +/- 651 kcal in maintainers vs. 1845 +/- 678 kcal in regainers, p = 0.338), although protein intake per kg of body weight was higher in maintainers (1.02 +/- 0.39 vs. 0.83 +/- 0.28 g/kg in regainers, p < 0.001). Physical activity energy expenditure was greater for maintainers in men (by 1380 kcal per week, p = 0.016), but not women. Salty snacks, alcohol and regular soda were more frequently consumed by men regainers. Principal component analysis identified a healthy dietary pattern featuring mainly unprocessed cereal, fruit, vegetables, olive oil and low-fat dairy. Male maintainers were 4.6 times more likely to follow this healthy pattern compared to regainers (OR 4.6, 95 % CI 2.0-11.0). No similar finding was revealed in women. Other characteristics of maintainers but not of regainers were: involvement in meal preparation and eating at home for men, and a higher eating frequency and slower eating rate for women. CONCLUSIONS: Men maintaining weight loss were much more likely to adhere to a healthy eating pattern. Eating at home, involvement in meal preparation, higher eating frequency and slower eating rate were also associated with maintenance. These lifestyle habits of successful maintainers provide target behaviors to improve obesity treatment. PMID- 26744304 TI - Radiological Evaluation of Infratentorial Gangliogliomas in Various Anatomic Locations of the Cerebellum and Brainstem. AB - PURPOSE: To review the imaging features of infratentorial gangliogliomas (GGs) and compare between Infratentorial GGs located within the cerebellum and brainstem. METHODS: The cases of 24 patients with histologically-confirmed infratentorial GGs were reviewed retrospectively. These subjects' cases were divided into a cerebellar group (n = 8) and a brainstem group (n = 16) based upon the anatomic location of the tumor. Imaging features (including tumor volume, margins, cystic/solid ratio, enhancement, peritumoral edema, and ipsilateral cerebellar atrophy) were compared between these two groups. RESULTS: On magnetic resonance imaging, infratentorial GGs showed isointensity or hypointensity on T1WI and heterogeneous hyperintensity on T2WI, with ipsilateral cerebellar atrophy observed in seven cases. Computed tomography images available in the cerebellar group showed heterogeneous isodensity with calcifications. Cerebellar GGs (median = 67.25 cm3, inter-quartile range = 27.78-83.27 cm3) were larger in volume than brainstem GGs (median = 16.89 cm3, interquartile range = 6.08-27.26 cm3) (p = 0.002). Cystic-solid mass (5 of 8) and solid mass (11 of 16) were more commonly represented in the cerebellar and brainstem group, respectively (p = 0.033). Cerebellar GGs showed varying degrees of enhancement, while most of brainstem GGs showed moderate-to-marked enhancement (p = 0.012). Dorsal predominant enhancement (n = 3) and posterior-marginal enhancement (n = 5) were observed in the brainstem group. The degrees of peritumoral edema and rate of ipsilateral cerebellar atrophy were not significantly different between the two study groups. CONCLUSION: Ipsilateral cerebellar atrophy can be found in infratentorial GGs involving the middle and inferior cerebellar peduncles. GGs should therefore be considered in the differential diagnoses when a solid-cystic mass with calcification is encountered in the cerebellum. Brainstem GGs tend to be smaller, solid masses with moderate-to-marked enhancement. Dorsal-predominant and posterior-marginal enhancement may be the specific imaging findings for brainstem GGs. PMID- 26744307 TI - 'Is this knowledge mine and nobody else's? I don't feel that.' Patient views about consent, confidentiality and information-sharing in genetic medicine. AB - In genetic medicine, a patient's diagnosis can mean their family members are also at risk, raising a question about how consent and confidentiality should function in clinical genetics. This question is particularly pressing when it is unclear whether a patient has shared information. Conventionally, healthcare professionals view confidentiality at an individual level and 'disclosure without consent' as the exception, not the rule. The relational joint account model, by contrast, conceptualises genetic information as confidential at the familial level and encourages professionals to take disclosure as the default position. In this study, we interviewed 33 patients about consent and confidentiality and analysed data thematically. Our first theme showed that although participants thought of certain aspects of genetic conditions--for example, the way they affect day-to-day health--as somewhat personal, they perceived genetic information--for example, the mutation in isolation--as familial. Most thought these elements were separable and thought family members had a right to know the latter, identifying a broad range of harms that would justify disclosure. Our second theme illustrated that participants nonetheless had some concerns about what, if any, implications there would be of professionals treating such information as familial and they emphasised the importance of being informed about the way their information would be shared. Based on these results, we recommend that professionals take disclosure as the default position, but make clear that they will treat genetic information as familial during initial consultations and address any concerns therein. PMID- 26744306 TI - Seroconversion of sheep experimentally infected with enzootic nasal tumor virus. AB - BACKGROUND: Enzootic nasal tumor virus (ENTV-1) is an exogenous betaretrovirus of sheep that transforms epithelial cells lining the ethmoid turbinates leading to a disease called enzootic nasal adenocarcinoma (ENA). A unique feature of ENA is the apparent absence of a specific humoral immune response to the virus, despite the highly productive infection in nasal tumors. The sheep genome contains approximately 27 copies of endogenous ovine betaretroviral sequences (enJSRVs) and expression of enJSRVs in the ovine placenta and uterine endometrium throughout gestation is thought to induce immunological tolerance to exogenous ovine betaretroviruses, a factor that may influence the likelihood of exogenous ENTV infection and disease outcome. Nevertheless, we recently demonstrated the presence of neutralizing antibodies directed against the ENTV-1 envelope glycoprotein in sheep naturally exposed to ENTV-1. FINDINGS: Here, we employed an ENTV-1 envelope glycoprotein surface subunit specific ELISA and a virus neutralization assay to monitor serum antibody responses to ENTV-1 in a group of lambs experimentally infected with ENTV-1 virus containing filtered ENA tumor homogenate. Seroconversion and development of neutralizing antibodies was detected in one of six experimentally infected lambs. CONCLUSIONS: Our results demonstrate that sheep can respond immunologically and seroconvert following ENTV 1 infection suggesting that anti-viral immune responses may play a role in the development of ENA. PMID- 26744308 TI - MiR-125b Functions as a Tumor Suppressor and Enhances Chemosensitivity to Cisplatin in Osteosarcoma. AB - MicroRNAs are highly conserved noncoding RNA that negatively modulate protein expression at a posttranscriptional and/or translational level and are deeply involved in the pathogenesis of several types of cancers. To date, the potential microRNAs regulating the growth and progression of osteosarcoma are not fully identified yet. Previous reports have shown differentially expressed miR-125b in osteosarcoma. However, the role of miR-125b in human osteosarcoma has not been totally illuminated. In this study, we have shown that miR-125b was downregulated in human osteosarcoma tissues compared to the adjacent tissues and effects as a tumor suppressor in vitro We found that stable overexpression of miR-125b in osteosarcoma cell lines U2OS and MG-63 inhibited cell proliferation, migration, and invasion. Our data also verified that Bcl-2 is the target of miR-125b. Meanwhile, we showed that Bcl-2 was inversely correlated with miR-125b in osteosarcoma tissues. More importantly, we proved that miR-125b increased the chemosensitivity of osteosarcoma cell lines to cisplatin by targeting Bcl-2. In conclusion, our data demonstrate that miR-125b is a tumor suppressor and support its potential application for the treatment of osteosarcoma in the future. PMID- 26744305 TI - Whole exome sequencing identifies novel candidate genes that modify chronic obstructive pulmonary disease susceptibility. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible airflow limitation in response to inhalation of noxious stimuli, such as cigarette smoke. However, only 15-20 % smokers manifest COPD, suggesting a role for genetic predisposition. Although genome-wide association studies have identified common genetic variants that are associated with susceptibility to COPD, effect sizes of the identified variants are modest, as is the total heritability accounted for by these variants. In this study, an extreme phenotype exome sequencing study was combined with in vitro modeling to identify COPD candidate genes. RESULTS: We performed whole exome sequencing of 62 highly susceptible smokers and 30 exceptionally resistant smokers to identify rare variants that may contribute to disease risk or resistance to COPD. This was a cross-sectional case-control study without therapeutic intervention or longitudinal follow-up information. We identified candidate genes based on rare variant analyses and evaluated exonic variants to pinpoint individual genes whose function was computationally established to be significantly different between susceptible and resistant smokers. Top scoring candidate genes from these analyses were further filtered by requiring that each gene be expressed in human bronchial epithelial cells (HBECs). A total of 81 candidate genes were thus selected for in vitro functional testing in cigarette smoke extract (CSE)-exposed HBECs. Using small interfering RNA (siRNA)-mediated gene silencing experiments, we showed that silencing of several candidate genes augmented CSE-induced cytotoxicity in vitro. CONCLUSIONS: Our integrative analysis through both genetic and functional approaches identified two candidate genes (TACC2 and MYO1E) that augment cigarette smoke (CS)-induced cytotoxicity and, potentially, COPD susceptibility. PMID- 26744310 TI - Salivaricin E and abundant dextranase activity may contribute to the anti cariogenic potential of the probiotic candidate Streptococcus salivarius JH. AB - Dental caries is an infectious disease that is continuing to increase in prevalence, reducing the quality of life for millions worldwide as well as causing considerable expense, with an estimated US$108 billion spent on dental care in the USA each year. Oral probiotics are now being investigated to determine whether they could play a role in the prevention and treatment of this disease. Streptococcus salivarius strain JH is a potential probiotic candidate that produces multiple proteinaceous antimicrobials (bacteriocins), the inhibitory spectrum of which includes Streptococcus mutans, one of the principal causative agents of dental caries. The genome of strain JH has previously been shown to contain the biosynthetic loci for the bacteriocins salivaricin A3, streptin and streptococcin SA-FF22. Here we show that strain JH also produces salivaricin E, a 32 aa lantibiotic with a mass of 3565.9 Da, which is responsible for the inhibition of S. mutans growth. In addition, strain JH was shown to produce dextranase, an enzyme that hydrolyses (1 -> 6)-alpha-D-glucosidic linkages, at levels higher than any other S. salivarius tested. In vitro testing showed that partial hydrolysis of the exopolymeric substances of S. mutans, using strain JH dextranase, improved the anti-S. mutans inhibitory activity of the lytic bacteriocin, zoocin A. The multiple bacteriocin and dextranase activities of strain JH support its candidature for development as an oral probiotic. PMID- 26744309 TI - The future of mental health care: peer-to-peer support and social media. AB - AIMS: People with serious mental illness are increasingly turning to popular social media, including Facebook, Twitter or YouTube, to share their illness experiences or seek advice from others with similar health conditions. This emerging form of unsolicited communication among self-forming online communities of patients and individuals with diverse health concerns is referred to as peer to-peer support. We offer a perspective on how online peer-to-peer connections among people with serious mental illness could advance efforts to promote mental and physical wellbeing in this group. METHODS: In this commentary, we take the perspective that when an individual with serious mental illness decides to connect with similar others online it represents a critical point in their illness experience. We propose a conceptual model to illustrate how online peer to-peer connections may afford opportunities for individuals with serious mental illness to challenge stigma, increase consumer activation and access online interventions for mental and physical wellbeing. RESULTS: People with serious mental illness report benefits from interacting with peers online from greater social connectedness, feelings of group belonging and by sharing personal stories and strategies for coping with day-to-day challenges of living with a mental illness. Within online communities, individuals with serious mental illness could challenge stigma through personal empowerment and providing hope. By learning from peers online, these individuals may gain insight about important health care decisions, which could promote mental health care seeking behaviours. These individuals could also access interventions for mental and physical wellbeing delivered through social media that could incorporate mutual support between peers, help promote treatment engagement and reach a wider demographic. Unforeseen risks may include exposure to misleading information, facing hostile or derogatory comments from others, or feeling more uncertain about one's health condition. However, given the evidence to date, the benefits of online peer-to peer support appear to outweigh the potential risks. CONCLUSION: Future research must explore these opportunities to support and empower people with serious mental illness through online peer networks while carefully considering potential risks that may arise from online peer-to-peer interactions. Efforts will also need to address methodological challenges in the form of evaluating interventions delivered through social media and collecting objective mental and physical health outcome measures online. A key challenge will be to determine whether skills learned from peers in online networks translate into tangible and meaningful improvements in recovery, employment, or mental and physical wellbeing in the offline world. PMID- 26744313 TI - Testing the Similarity Fit/Misfit Hypothesis in Adolescents and Parents With ADHD. AB - OBJECTIVE: Higher rates of conflict are observed between adolescents with ADHD and their parents due to cognitive, academic, social, and behavioral difficulties. Conflict should be even more pronounced when parents have ADHD themselves; however, some research suggests that parents with ADHD may have increased tolerance toward children who share similar challenges (i.e., similarity-fit hypothesis). METHOD: We tested the similarity-fit model and its converse, the similarity-misfit model, in a sample of 93 ADHD adolescents, 63 comparison adolescents, and their parents with varying levels of ADHD. Quantity and intensity of conflict were examined in mothers and fathers separately. RESULTS: We found evidence for the similarity-fit process in fathers, and similarity misfit in mothers, particularly regarding quantity of conflict between parent and adolescent. CONCLUSION: Results indicate the importance of differential parental roles in mothers and fathers, and have implications for involving parents in treatment for ADHD in adolescents. PMID- 26744311 TI - Structural basis of collagen recognition by human osteoclast-associated receptor and design of osteoclastogenesis inhibitors. AB - Human osteoclast-associated receptor (OSCAR) is an immunoglobulin (Ig)-like collagen receptor that is up-regulated on osteoclasts during osteoclastogenesis and is expressed in a range of myeloid cells. As a member of the leukocyte receptor complex family of proteins, OSCAR shares a high degree of sequence and structural homology with other collagen receptors of this family, including glycoprotein VI, leukocyte-associated Ig-like receptor-1, and leukocyte Ig-like receptor B4, but recognizes a unique collagen sequence. Here, we present the crystal structures of OSCAR in its free form and in complex with a triple-helical collagen-like peptide (CLP). These structures reveal that the CLP peptide binds only one of the two Ig-like domains, the membrane-proximal domain (domain 2) of OSCAR, with the middle and trailing chain burying a total of 661 A(2) of solvent accessible collagen surface. This binding mode is facilitated by the unusual topography of the OSCAR protein, which displays an obtuse interdomain angle and a rotation of domain 2 relative to the membrane-distal domain 1. Moreover, the binding of the CLP to OSCAR appears to be mediated largely by tyrosine residues and conformational changes at a shallow Phe pocket. Furthermore, we investigated CLP peptides as inhibitors of osteoclastogenesis and found that a peptide length of 40 amino acids is required to ensure adequate inhibition of osteoclastogenesis in vitro. These findings provide valuable structural insights into the mode of collagen recognition by OSCAR and into the use of synthetic peptide matrikines for osteoclastogenesis inhibition. PMID- 26744314 TI - Deficient Emotional Self-Regulation in Preschoolers With ADHD: Identification, Comorbidity, and Interpersonal Functioning. AB - OBJECTIVE: This study aims to develop an age-adjusted Child Behavior Checklist- (CBCL) and Teacher Report Form (TRF)-based method for the detection of deficient emotional self-regulation (DESR) in preschoolers with ADHD and to assess its incidence, comorbidities, and consequences on interpersonal functioning. METHOD: Eighty-six ADHD preschoolers and 104 controls were assessed using CBCL, TRF/11/2 to 5, Psychiatric Interview With Preschool Age Psychiatric Assessment, Leiter-R, and ADHD rating scales. RESULTS: Greatest sensitivity and specificity were obtained applying slightly lower threshold scores compared with school-age children (CBCL: Anxiety/Depression [A/D] >= 59, Attention Problems [AP] >= 60, Aggression Behaviors [AB] >= 58; TRF: A/D >= 59, AP >= 60, AB >= 60). DESR was detected in 33/86 (38.4%) and in 16/54 (29.6%) ADHD preschoolers versus 2/104 (1.9%) controls using CBCL and TRF, respectively. DESR is associated with significantly greater comorbidity and impairment in interpersonal functioning. CONCLUSION: Among ADHD preschoolers, DESR (a) requires lower CBCL and TRF threshold scores for detection, compared with school-age children, (b) displays similar incidence rates, and (c) is associated with enhanced psychiatric comorbidity and interpersonal difficulties. PMID- 26744312 TI - Hairy and Groucho mediate the action of juvenile hormone receptor Methoprene tolerant in gene repression. AB - The arthropod-specific juvenile hormone (JH) controls numerous essential functions. Its involvement in gene activation is known to be mediated by the transcription factor Methoprene-tolerant (Met), which turns on JH-controlled genes by directly binding to E-box-like motifs in their regulatory regions. However, it remains unclear how JH represses genes. We used the Aedes aegypti female mosquito, in which JH is necessary for reproductive maturation, to show that a repressor, Hairy, is required for the gene-repressive action of JH and Met. The RNA interference (RNAi) screen for Met and Hairy in the Aedes female fat body revealed a large cohort of Met- and Hairy-corepressed genes. Analysis of selected genes from this cohort demonstrated that they are repressed by JH, but RNAi of either Met or Hairy renders JH ineffective in repressing these genes in an in vitro fat-body culture assay. Moreover, this JH action was prevented by the addition of the translational inhibitor cycloheximide (CHX) to the culture, indicating the existence of an indirect regulatory hierarchy. The lack of Hairy protein in the CHX-treated tissue was verified using immunoblot analysis, and the upstream regions of Met/Hairy-corepressed genes were shown to contain common binding motifs that interact with Hairy. Groucho (gro) RNAi silencing phenocopied the effect of Hairy RNAi knockdown, indicating that it is involved in the JH/Met/Hairy hierarchy. Finally, the requirement of Hairy and Gro for gene repression was confirmed in a cell transfection assay. Thus, our study has established that Hairy and its cofactor Gro mediate the repressive function of JH and Met. PMID- 26744315 TI - First-Year GPA and Academic Service Use Among College Students With and Without ADHD. AB - OBJECTIVE: ADHD is a chronic neurodevelopmental disorder that typically results in persistent academic difficulties over time. Although most colleges offer support services, students often do not use the available services or those to which they are entitled. The present study examined predictors of academic performance among college students with and without ADHD. In addition, the rate, predictors, and outcomes of academic service use were explored. METHODS: A series of multivariate analyses of variance (MANOVAs) and regression analyses were conducted using SPSS v. 21 (r) software. RESULTS: First year college students with ADHD earned significantly lower grade point averages (GPAs) relative to students without ADHD. Additionally, ADHD combined with other disorders, but not ADHD alone, predicted higher rates of service use relative to students without ADHD. Finally, the findings suggest that typically available academic services are not independently related to GPA among first-year college students with or without ADHD. CONCLUSION: This study replicates previous work demonstrating significantly lower GPAs among a rigorously defined sample of students with ADHD relative to students without ADHD. Second, this study indicates that traditional predictors of college success may be less meaningful for students with ADHD relative to those without ADHD. Finally, additional research needs to be conducted regarding the use and effectiveness of academic services on college campuses. PMID- 26744316 TI - Feedback from Outcome Measures and Treatment Effectiveness, Treatment Efficiency, and Collaborative Practice: A Systematic Review. AB - Due to recent increases in the use of feedback from outcome measures in mental health settings, we systematically reviewed evidence regarding the impact of feedback from outcome measures on treatment effectiveness, treatment efficiency, and collaborative practice. In over half of 32 studies reviewed, the feedback condition had significantly higher levels of treatment effectiveness on at least one treatment outcome variable. Feedback was particularly effective for not-on track patients or when it was provided to both clinicians and patients. The findings for treatment efficiency and collaborative practice were less consistent. Given the heterogeneity of studies, more research is needed to determine when and for whom feedback is most effective. PMID- 26744317 TI - Down-regulation of the zinc-finger homeobox protein TSHZ2 releases GLI1 from the nuclear repressor complex to restore its transcriptional activity during mammary tumorigenesis. AB - Although breast cancer is one of the most common malignancies, the molecular mechanisms underlying its development and progression are not fully understood. To identify key molecules involved, we screened publicly available microarray datasets for genes differentially expressed between breast cancers and normal mammary glands. We found that three of the genes predicted in this analysis were differentially expressed among human mammary tissues and cell lines. Of these genes, we focused on the role of the zinc-finger homeobox protein TSHZ2, which is down-regulated in breast cancer cells. We found that TSHZ2 is a nuclear protein harboring a bipartite nuclear localization signal, and we confirmed its function as a C-terminal binding protein (CtBP)-dependent transcriptional repressor. Through comprehensive screening, we identified TSHZ2-suppressing genes such as AEBP1 and CXCR4, which are conversely up-regulated by GLI1, the downstream transcription factor of Hedgehog signaling. We found that GLI1 forms a ternary complex with CtBP2 in the presence of TSHZ2 and that the transcriptional activity of GLI1 is suppressed by TSHZ2 in a CtBP-dependent manner. Indeed, knockdown of TSHZ2 increases the expression of AEBP1 and CXCR4 in TSHZ2-expressing immortalized mammary duct epithelium. Concordantly, immunohistochemical staining of mammary glands revealed that normal duct cells expresses GLI1 in the nucleus along with TSHZ2 and CtBP2, whereas invasive ductal carcinoma cells, which does not express TSHZ2, show the increase in the expression of AEBP1 and CXCR4 and in the cytoplasmic localization of GLI1. Thus, we propose that down-regulation of TSHZ2 is crucial for mammary tumorigenesis via the activation of GLI1. PMID- 26744318 TI - MicroRNA 100 sensitizes luminal A breast cancer cells to paclitaxel treatment in part by targeting mTOR. AB - Luminal A breast cancer usually responds to hormonal therapies but does not benefit from chemotherapies, including microtubule-targeted paclitaxel. MicroRNAs could play a role in mediating this differential response. In this study, we examined the role of micro RNA 100 (miR-100) in the sensitivity of breast cancer to paclitaxel treatment. We found that while miR-100 was downregulated in both human breast cancer primary tumors and cell lines, the degree of downregulation was greater in the luminal A subtype than in other subtypes. The IC50 of paclitaxel was much higher in luminal A than in basal-like breast cancer cell lines. Ectopic miR-100 expression in the MCF-7 luminal A cell line enhanced the effect of paclitaxel on cell cycle arrest, multinucleation, and apoptosis, while knockdown of miR-100 in the MDA-MB-231 basal-like line compromised these effects. Similarly, overexpression of miR-100 enhanced the effects of paclitaxel on tumorigenesis in MCF-7 cells. Rapamycin-mediated inhibition of the mammalian target of rapamycin (mTOR), a target of miR-100, also sensitized MCF-7 cells to paclitaxel. Gene set enrichment analysis showed that genes that are part of the known paclitaxel-sensitive signature had a significant expression correlation with miR-100 in breast cancer samples. In addition, patients with lower levels of miR-100 expression had worse overall survival. These results suggest that miR-100 plays a causal role in determining the sensitivity of breast cancers to paclitaxel treatment. PMID- 26744319 TI - HBx regulates fatty acid oxidation to promote hepatocellular carcinoma survival during metabolic stress. AB - Due to a high rate of nutrient consumption and inadequate vascularization, hepatocellular carcinoma (HCC) cells constantly undergo metabolic stress during tumor development. Hepatitis B virus (HBV) X protein (HBx) has been implicated in the pathogenesis of HBV-induced HCC. In this study, we investigated the functional roles of HBx in HCC adaptation to metabolic stress. Up-regulation of HBx increased the intracellular ATP and NADPH generation, and induced the resistance to glucose deprivation, whereas depletion of HBx via siRNA abolished these effects and conferred HCC cells sensitive to glucose restriction. Though HBx did not affect the glycolysis and oxidative phosphorylation capacity of HCC cells under normal culture conditions, it facilitated fatty acid oxidation (FAO) in the absence of glucose, which maintained NADPH and ATP levels. Further investigation showed that HBx expression, under glucose deprivation, stimulated phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) via a calcium/CaMKK-dependent pathway, which was required for the activation of FAO. Conversely, inhibition of FAO by etomoxir (ETO) restored the sensitivity of HBx-expressing cells to glucose deficiency in vitro and retarded xenograft tumor formation in vivo. Finally, HBx-induced activation of the AMPK and FAO pathways were also observed in xenograft tumors and HBV-associated HCC specimens. Our data suggest that HBx plays a key role in the maintenance of redox and energy homeostasis by activating FAO, which is critical for HCC cell survival under conditions of metabolic stress and might be exploited for therapeutic benefit. PMID- 26744320 TI - Oncogenic KRAS activates an embryonic stem cell-like program in human colon cancer initiation. AB - Colorectal cancer is the third most frequently diagnosed cancer worldwide. Prevention of colorectal cancer initiation represents the most effective overall strategy to reduce its associated morbidity and mortality. Activating KRAS mutation (KRASmut) is the most prevalent oncogenic driver in colorectal cancer development, and KRASmut inhibition represents an unmet clinical need. We apply a systems-level approach to study the impact of KRASmut on stem cell signaling during human colon cancer initiation by performing gene set enrichment analysis on gene expression from human colon tissues. We find that KRASmut imposes the embryonic stem cell-like program during human colon cancer initiation from colon adenoma to stage I carcinoma. Expression of miR145, an embryonic SC program inhibitor, promotes cell lineage differentiation marker expression in KRASmut colon cancer cells and significantly suppresses their tumorigenicity. Our data support an in vivo plasticity model of human colon cancer initiation that merges the intrinsic stem cell properties of aberrant colon stem cells with the embryonic stem cell-like program induced by KRASmut to optimize malignant transformation. Inhibition of the embryonic SC-like program in KRASmut colon cancer cells reveals a novel therapeutic strategy to programmatically inhibit KRASmut tumors and prevent colon cancer. PMID- 26744321 TI - Type 2 diabetes-induced neuronal pathology in the piriform cortex of the rat is reversed by the GLP-1 receptor agonist exendin-4. AB - Type 2 diabetes (T2D) patients often present olfactory dysfunction. However, the histopathological basis behind this has not been previously shown. Since the piriform cortex plays a crucial role in olfaction, we hypothesize that pathological changes in this brain area can occur in T2D patients along aging. Thus, we determined potential neuropathology in the piriform cortex of T2D rats, along aging. Furthermore, we determined the potential therapeutic role of the glucagon-like peptide-1 receptor (GLP1-R) agonist exendin-4 to counteract the identified T2D-induced neuropathology. Young-adult and middle-aged T2D Goto Kakizaki rats were compared to age-matched Wistars. Additional Goto-Kakizaki rats were treated for six weeks with exendin-4/vehicle before sacrifice. Potential T2D induced neuropathology was assessed by quantifying NeuN-positive neurons and Calbindin-D28k-positive interneurons by immunohistochemistry and stereology methods. We also quantitatively measured Calbindin-D28k neuronal morphology and JNK phosphorylation-mediated cellular stress. PI3K/AKT signalling was assessed by immunohistochemistry, and potential apoptosis by TUNEL.We show T2D-induced neuronal pathology in the piriform cortex along aging, characterized by atypical nuclear NeuN staining and increased JNK phosphorylation, without apoptosis. We also demonstrate the specific vulnerability of Calbindin-D28k interneurons. Finally, chronic treatment with exendin-4 substantially reversed the identified neuronal pathology in correlation with decreased JNK and increased AKT phosphorylation.Our results reveal the histopathological basis to explain T2D olfactory dysfunction. We also show that the identified T2D-neuropathology can be counteracted by GLP-1R activation supporting recent research promoting the use of GLP-1R agonists against brain diseases. Whether the identified neuropathology could represent an early hallmark of cognitive decline in T2D remains to be determined. PMID- 26744322 TI - Capecitabine-Induced Severe Toxicity Secondary to DPD Deficiency and Successful Treatment with Low Dose 5-Fluorouracil. PMID- 26744323 TI - Effect of polypharmacy and potentially inappropriate medications on treatment and posttreatment courses in elderly patients with head and neck cancer. AB - PURPOSE: The use of excessive and inappropriate medications is a common problem in elderly populations. The use of polypharmacy (PP) and potentially inappropriate medication (PIM) may affect treatment-related morbidities in elderly cancer patients, which has rarely been studied in patients with head and neck cancer (HNC). Here, we evaluate the effects of PP and PIM on treatment and posttreatment courses in elderly HNC patients. METHODS: This study included 229 elderly HNC patients who underwent definitive treatment. Medications were carefully recorded, and the prevalences of PP and PIM are reported. We evaluated the associations between PP, PIM, treatment, and posttreatment course in terms of comorbidities, treatment-related toxicity, prolonged hospitalization, and posttreatment noncancer health events. RESULTS: The prevalences of PP and PIM in our elderly HNC patients were 29.3 and 24.0 %, respectively, and frequently described PIMs include aspirin (12.2 %), calcium channel blockers (4.8 %), benzodiazepines (4.3 %), and nonsteroidal anti-inflammatory drugs (3.9 %). PP and PIM were not significantly associated with treatment-related toxicity, but were associated with modestly increased prolonged hospitalization [odds ratio [OR] 2.30 (95 % confidence interval 0.89-5.95); P = 0.080] and noncancer health events [OR 1.81 (0.99-3.31); P = 0.052], respectively. Among high-risk medications, benzodiazepine [OR 5.09 (1.21-21.5); P = 0.015] and calcium channel blockers [OR 5.69 (1.07-33.25); P = 0.031) were significantly associated with prolonged hospitalization. CONCLUSIONS: Neither PP nor PIM are significantly associated with treatment-related toxicity in elderly HNC patients, but these are associated with modest increases in prolonged hospitalization and noncancer health events. PMID- 26744324 TI - Conserved pharmacological rescue of hereditary spastic paraplegia-related phenotypes across model organisms. AB - Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases causing progressive gait dysfunction. Over 50 genes have now been associated with HSP. Despite the recent explosion in genetic knowledge, HSP remains without pharmacological treatment. Loss-of-function mutation of the SPAST gene, also known as SPG4, is the most common cause of HSP in patients. SPAST is conserved across animal species and regulates microtubule dynamics. Recent studies have shown that it also modulates endoplasmic reticulum (ER) stress. Here, utilizing null SPAST homologues in C. elegans, Drosophila and zebrafish, we tested FDA approved compounds known to modulate ER stress in order to ameliorate locomotor phenotypes associated with HSP. We found that locomotor defects found in all of our spastin models could be partially rescued by phenazine, methylene blue, N acetyl-cysteine, guanabenz and salubrinal. In addition, we show that established biomarkers of ER stress levels correlated with improved locomotor activity upon treatment across model organisms. Our results provide insights into biomarkers and novel therapeutic avenues for HSP. PMID- 26744326 TI - A dominant mutation in MAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium. AB - Inherited retinal dystrophies are clinically and genetically heterogeneous with significant number of cases remaining genetically unresolved. We studied a large family from the West Indies islands with a peculiar retinal disease, the Martinique crinkled retinal pigment epitheliopathy that begins around the age of 30 with retinal pigment epithelium (RPE) and Bruch's membrane changes resembling a dry desert land and ends with a retinitis pigmentosa. Whole-exome sequencing identified a heterozygous c.518T>C (p.Leu173Pro) mutation in MAPKAPK3 that segregates with the disease in 14 affected and 28 unaffected siblings from three generations. This unknown variant is predicted to be damaging by bioinformatic predictive tools and the mutated protein to be non-functional by crystal structure analysis. MAPKAPK3 is a serine/threonine protein kinase of the p38 signaling pathway that is activated by a variety of stress stimuli and is implicated in cellular responses and gene regulation. In contrast to other tissues, MAPKAPK3 is highly expressed in the RPE, suggesting a crucial role for retinal physiology. Expression of the mutated allele in HEK cells revealed a mislocalization of the protein in the cytoplasm, leading to cytoskeleton alteration and cytodieresis inhibition. In Mapkapk3-/- mice, Bruch's membrane is irregular with both abnormal thickened and thinned portions. In conclusion, we identified the first pathogenic mutation in MAPKAPK3 associated with a retinal disease. These findings shed new lights on Bruch's membrane/RPE pathophysiology and will open studies of this signaling pathway in diseases with RPE and Bruch's membrane alterations, such as age-related macular degeneration. PMID- 26744325 TI - Genome-wide meta-analyses identify novel loci associated with n-3 and n-6 polyunsaturated fatty acid levels in Chinese and European-ancestry populations. AB - Epidemiological studies suggest that levels of n-3 and n-6 long-chain polyunsaturated fatty acids are associated with risk of cardio-metabolic outcomes across different ethnic groups. Recent genome-wide association studies in populations of European ancestry have identified several loci associated with plasma and/or erythrocyte polyunsaturated fatty acids. To identify additional novel loci, we carried out a genome-wide association study in two population based cohorts consisting of 3521 Chinese participants, followed by a trans-ethnic meta-analysis with meta-analysis results from 8962 participants of European ancestry. Four novel loci (MYB, AGPAT4, DGAT2 and PPT2) reached genome-wide significance in the trans-ethnic meta-analysis (log10(Bayes Factor) >= 6). Of them, associations of MYB and AGPAT4 with docosatetraenoic acid (log10(Bayes Factor) = 11.5 and 8.69, respectively) also reached genome-wide significance in the Chinese-specific genome-wide association analyses (P = 4.15 * 10(-14) and 4.30 * 10(-12), respectively), while associations of DGAT2 with gamma-linolenic acid (log10(Bayes Factor) = 6.16) and of PPT2 with docosapentaenoic acid (log10(Bayes Factor) = 6.24) were nominally significant in both Chinese- and European-specific genome-wide association analyses (P <= 0.003). We also confirmed previously reported loci including FADS1, NTAN1, NRBF2, ELOVL2 and GCKR. Different effect sizes in FADS1 and independent association signals in ELOVL2 were observed. These results provide novel insight into the genetic background of polyunsaturated fatty acids and their differences between Chinese and European populations. PMID- 26744328 TI - Synphilin-1 attenuates mutant LRRK2-induced neurodegeneration in Parkinson's disease models. AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal-dominant Parkinsonism with pleomorphic pathology including deposits of aggregated protein and neuronal degeneration. The pathogenesis of LRRK2-linked Parkinson's disease (PD) is not fully understood. Here, using co-immunoprecipitation, we found that LRRK2 interacted with synphilin-1 (SP1), a cytoplasmic protein that interacts with alpha-synuclein and has implications in PD pathogenesis. LRRK2 interacted with the N-terminus of SP1 whereas SP1 predominantly interacted with the C terminus of LRRK2, including kinase domain. Co-expression of SP1 with LRRK2 increased LRRK2-induced cytoplasmic aggregation in cultured cells. Moreover, SP1 also attenuated mutant LRRK2-induced toxicity and reduced LRRK2 kinase activity in cultured cells. Knockdown of SP1 by siRNA enhanced LRRK2 neuronal toxicity. In vivo Drosophila studies, co-expression of SP1 and mutant G2019S-LRRK2 in double transgenic Drosophila increased survival and improved locomotor activity. Expression of SP1 protects against G2019S-LRRK2-induced dopamine neuron loss and reduced LRRK2 phosphorylation in double transgenic fly brains. Our findings demonstrate that SP1 attenuates mutant LRRK2-induced PD-like phenotypes and plays a neural protective role. PMID- 26744327 TI - Genetic interaction of hnRNPA2B1 and DNAJB6 in a Drosophila model of multisystem proteinopathy. AB - Adult-onset inherited myopathies with similar pathological features, including hereditary inclusion body myopathy (hIBM) and limb-girdle muscular dystrophy (LGMD), are a genetically heterogeneous group of muscle diseases. It is unclear whether these inherited myopathies initiated by mutations in distinct classes of genes are etiologically related. Here, we exploit a genetic model system to establish a mechanistic link between diseases caused by mutations in two distinct genes, hnRNPA2B1 and DNAJB6. Hrb98DE and mrj are the Drosophila melanogaster homologs of human hnRNPA2B1 and DNAJB6, respectively. We introduced disease homologous mutations to Hrb98DE, thus capturing mutation-dependent phenotypes in a genetically tractable model system. Ectopic expression of the disease associated mutant form of hnRNPA2B1 or Hrb98DE in fly muscle resulted in progressive, age-dependent cytoplasmic inclusion pathology, as observed in humans with hnRNPA2B1-related myopathy. Cytoplasmic inclusions consisted of hnRNPA2B1 or Hrb98DE protein in association with the stress granule marker ROX8 and additional endogenous RNA-binding proteins (RBPs), suggesting that these pathological inclusions are related to stress granules. Notably, TDP-43 was also recruited to these cytoplasmic inclusions. Remarkably, overexpression of MRJ rescued this phenotype and suppressed the formation of cytoplasmic inclusions, whereas reduction of endogenous MRJ by a classical loss of function allele enhanced it. Moreover, wild-type, but not disease-associated, mutant forms of MRJ interacted with RBPs after heat shock and prevented their accumulation in aggregates. These results indicate both genetic and physical interactions between disease-linked RBPs and DNAJB6/mrj, suggesting etiologic overlap between the pathogenesis of hIBM and LGMD initiated by mutations in hnRNPA2B1 and DNAJB6. PMID- 26744330 TI - Deletion of the miR-379/miR-410 gene cluster at the imprinted Dlk1-Dio3 locus enhances anxiety-related behaviour. AB - The brain-specific miR-379/miR-410 gene cluster at the imprinted Dlk1-Dio3 domain is implicated in several aspects of brain development and function, particularly in fine-tuning the dendritic outgrowth and spine remodelling of hippocampal neurons. Whether it might influence behaviour and memory-related processes has not yet been explored at the whole organism level. We previously reported that constitutive deletion of the miR-379/miR-410 gene cluster affects metabolic adaptation in neonatal mice. Here, we examined the role of this cluster in adult brain functions by subjecting mice with the constitutive deletion to a battery of behavioural and cognitive tests. We found that the lack of miR-379/miR-410 expression is associated with abnormal emotional responses, as demonstrated by increased anxiety-related behaviour in unfamiliar environments. In contrast, spontaneous exploration, general locomotion, mood levels and sociability remained unaltered. Surprisingly, miR-379/miR-410-deficient mice also showed normal learning and spatial (or contextual) memory abilities in hippocampus-dependent tasks involving neuronal plasticity. Taken together, the imprinted miR-379/miR 410 gene cluster thus emerges as a novel regulator of the two main post-natal physiological processes previously associated with imprinted, protein-coding genes: behaviour and energy homeostasis. PMID- 26744329 TI - Genetic overexpression of Serpina3n attenuates muscular dystrophy in mice. AB - Muscular dystrophy (MD) is associated with mutations in genes that stabilize the myofiber plasma membrane, such as through the dystrophin-glycoprotein complex (DGC). Instability of this complex or defects in membrane repair/integrity leads to calcium influx and myofiber necrosis leading to progressive dystrophic disease. MD pathogenesis is also associated with increased skeletal muscle protease levels and activity that could augment weakening of the sarcolemma through greater degradation of cellular attachment complexes. Here, we observed a compensatory increase in the serine protease inhibitor Serpina3n in mouse models of MD and after acute muscle tissue injury. Serpina3n muscle-specific transgenic mice were generated to model this increase in expression, which reduced the activity of select proteases in dystrophic skeletal muscle and protected muscle from both acute injury with cardiotoxin and from chronic muscle disease in the mdx or Sgcd(-/-) MD genetic backgrounds. The Serpina3n transgene mitigated muscle degeneration and fibrosis, reduced creatine kinase serum levels, restored running capacity on a treadmill and reduced muscle membrane leakiness in vivo that is characteristic of mdx and Sgcd(-/-) mice. Mechanistically, we show that increased Serpina3n promotes greater sarcolemma membrane integrity and stability in dystrophic mouse models in association with increased membrane residence of the integrins, the DGC/utrophin-glycoprotein complex of proteins and annexin A1. Hence, Serpina3n blocks endogenous increases in the activity of select skeletal muscle resident proteases during injury or dystrophic disease, which stabilizes the sarcolemma leading to less myofiber degeneration and increased regeneration. These results suggest the use of select protease inhibitors as a strategy for treating MD. PMID- 26744331 TI - Gene network and familial analyses uncover a gene network involving Tbx5/Osr1/Pcsk6 interaction in the second heart field for atrial septation. AB - Atrial septal defects (ASDs) are a common human congenital heart disease (CHD) that can be induced by genetic abnormalities. Our previous studies have demonstrated a genetic interaction between Tbx5 and Osr1 in the second heart field (SHF) for atrial septation. We hypothesized that Osr1 and Tbx5 share a common signaling networking and downstream targets for atrial septation. To identify this molecular networks, we acquired the RNA-Seq transcriptome data from the posterior SHF of wild-type, Tbx5(+/) (-), Osr1(+/-), Osr1(-/-) and Tbx5(+/ )/Osr1(+/-) mutant embryos. Gene set analysis was used to identify the Kyoto Encyclopedia of Genes and Genomes pathways that were affected by the doses of Tbx5 and Osr1. A gene network module involving Tbx5 and Osr1 was identified using a non-parametric distance metric, distance correlation. A subset of 10 core genes and gene-gene interactions in the network module were validated by gene expression alterations in posterior second heart field (pSHF) of Tbx5 and Osr1 transgenic mouse embryos, a time-course gene expression change during P19CL6 cell differentiation. Pcsk6 was one of the network module genes that were linked to Tbx5. We validated the direct regulation of Tbx5 on Pcsk6 using immunohistochemical staining of pSHF, ChIP-quantitative polymerase chain reaction and luciferase reporter assay. Importantly, we identified Pcsk6 as a novel gene associated with ASD via a human genotyping study of an ASD family. In summary, our study implicated a gene network involving Tbx5, Osr1 and Pcsk6 interaction in SHF for atrial septation, providing a molecular framework for understanding the role of Tbx5 in CHD ontogeny. PMID- 26744333 TI - Identification of New Cocrystal Systems with Stoichiometric Diversity of Salicylic Acid Using Thermal Methods. AB - PURPOSE: The purpose of this work was to develop thermal methods to identify cocrystal systems with stoichiometric diversity. METHODS: Differential scanning calorimetry (DSC) and hot stage microscopy (HSM) have been applied to study the stoichiometric diversity phenomenon on cocrystal systems of the model compound salicylic acid (SA) with different coformers (CCFs). The DSC method was particularly useful in the identification of cocrystal re-crystallization, especially to improve the temperature resolution using a slower heating rate. HSM was implemented as a complementary protocol to confirm the DSC results. The crystal structures were elucidated by single-crystal X-ray diffraction (SXRD). RESULTS: Two new cocrystal systems consisting of salicylic acid-benzamide (SA BZD, 1:1, 1:2) and salicylic acid-isonicotinamide (SA-ISN, 1:1, 2:1) have been identified in the present work. The chemical structures of the newly discovered cocrystals SA-BZD (1:2) and SA-ISN (2:1) have been elucidated using X-ray single crystal and powder diffraction methods. CONCLUSIONS: The developed thermal methods could rapidly identify cocrystal systems with stoichiometric diversity, with the potential to discover new pharmaceutical cocrystals in the future. PMID- 26744334 TI - Bioethics as a Governance Practice. AB - Bioethics can be considered as a topic, an academic discipline (or combination of disciplines), a field of study, an enterprise in persuasion. The historical specificity of the forms bioethics takes is significant, and raises questions about some of these approaches. Bioethics can also be considered as a governance practice, with distinctive institutions and structures. The forms this practice takes are also to a degree country specific, as the paper illustrates by drawing on the author's UK experience. However, the UNESCO Universal Declaration on Bioethics can provide a starting point for comparisons provided that this does not exclude sensitivity to the socio-political context. Bioethics governance practices are explained by various legitimating narratives. These include response to scandal, the need to restrain irresponsible science, the accommodation of pluralist views, and the resistance to the relativist idea that all opinions count equally in bioethics. Each approach raises interesting questions and shows that bioethics should be studied as a governance practice as a complement to other approaches. PMID- 26744332 TI - LRRK2 BAC transgenic rats develop progressive, L-DOPA-responsive motor impairment, and deficits in dopamine circuit function. AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) lead to late-onset, autosomal dominant Parkinson's disease, characterized by the degeneration of dopamine neurons of the substantia nigra pars compacta, a deficit in dopamine neurotransmission and the development of motor and non-motor symptoms. The most prevalent Parkinson's disease LRRK2 mutations are located in the kinase (G2019S) and GTPase (R1441C) encoding domains of LRRK2. To better understand the sequence of events that lead to progressive neurophysiological deficits in vulnerable neurons and circuits in Parkinson's disease, we have generated LRRK2 bacterial artificial chromosome transgenic rats expressing either G2019S or R1441C mutant, or wild-type LRRK2, from the complete human LRRK2 genomic locus, including endogenous promoter and regulatory regions. Aged (18-21 months) G2019S and R1441C mutant transgenic rats exhibit L-DOPA-responsive motor dysfunction, impaired striatal dopamine release as determined by fast-scan cyclic voltammetry, and cognitive deficits. In addition, in vivo recordings of identified substantia nigra pars compacta dopamine neurons in R1441C LRRK2 transgenic rats reveal an age-dependent reduction in burst firing, which likely results in further reductions to striatal dopamine release. These alterations to dopamine circuit function occur in the absence of neurodegeneration or abnormal protein accumulation within the substantia nigra pars compacta, suggesting that nigrostriatal dopamine dysfunction precedes detectable protein aggregation and cell death in the development of Parkinson's disease. In conclusion, our longitudinal deep-phenotyping provides novel insights into how the genetic burden arising from human mutant LRRK2 manifests as early pathophysiological changes to dopamine circuit function and highlights a potential model for testing Parkinson's therapeutics. PMID- 26744336 TI - Return to Sports and Physical Activity After Total and Unicondylar Knee Arthroplasty: A Systematic Review and Meta-Analysis. AB - BACKGROUND: People today are living longer and want to remain active. While obesity is becoming an epidemic, the number of patients suffering from osteoarthritis (OA) is expected to grow exponentially in the coming decades. Patients with OA of the knee are progressively being restricted in their activities. Since a knee arthroplasty (KA) is a well accepted, cost-effective intervention to relieve pain, restore function and improve health-related quality of life, indications are expanding to younger and more active patients. However, evidence concerning return to sports (RTS) and physical activity (PA) after KA is sparse. OBJECTIVES: Our aim was to systematically summarise the available literature concerning the extent to which patients can RTS and be physically active after total (TKA) and unicondylar knee arthroplasty (UKA), as well as the time it takes. METHODS: PRISMA guidelines were followed and our study protocol was published online at PROSPERO under registration number CRD42014009370. Based on the keywords (and synonyms of) 'arthroplasty', 'sports' and 'recovery of function', the databases MEDLINE, Embase and SPORTDiscus up to January 5, 2015 were searched. Articles concerning TKA or UKA patients who recovered their sporting capacity, or intended to, were included and were rated by outcomes of our interest. Methodological quality was assessed using Quality in Prognosis Studies (QUIPS) and data extraction was performed using a standardised extraction form, both conducted by two independent investigators. RESULTS: Out of 1115 hits, 18 original studies were included. According to QUIPS, three studies had a low risk of bias. Overall RTS varied from 36 to 89% after TKA and from 75 to >100% after UKA. The meta-analysis revealed that participation in sports seems more likely after UKA than after TKA, with mean numbers of sports per patient postoperatively of 1.1-4.6 after UKA and 0.2-1.0 after TKA. PA level was higher after UKA than after TKA, but a trend towards lower-impact sports was shown after both TKA and UKA. Mean time to RTS after TKA and UKA was 13 and 12 weeks, respectively, concerning low-impact types of sports in more than 90 % of cases. CONCLUSIONS: Low- and higher-impact sports after both TKA and UKA are possible, but it is clear that more patients RTS (including higher-impact types of sports) after UKA than after TKA. However, the overall quality of included studies was limited, mainly because confounding factors were inadequately taken into account in most studies. PMID- 26744337 TI - Muscle Weakness Thresholds for Prediction of Diabetes in Adults. AB - BACKGROUND: Despite the known links between weakness and early mortality, what remains to be fully understood is the extent to which strength preservation is associated with protection from cardiometabolic diseases, such as diabetes. PURPOSE: The purposes of this study were to determine the association between muscle strength and diabetes among adults, and to identify age- and sex-specific thresholds of low strength for detection of risk. METHODS: A population representative sample of 4066 individuals, aged 20-85 years, was included from the combined 2011-2012 National Health and Nutrition Examination Survey (NHANES) data sets. Strength was assessed using a handheld dynamometer, and the single highest reading from either hand was normalized to body mass. A logistic regression model was used to assess the association between normalized grip strength and risk of diabetes, as determined by haemoglobin A1c levels >=6.5 % (>=48 mmol/mol), while controlling for sociodemographic characteristics, anthropometric measures and television viewing time. RESULTS: For every 0.05 decrement in normalized strength, there were 1.26 times increased adjusted odds for diabetes in men and women. Women were at lower odds of having diabetes (odds ratio 0.49; 95 % confidence interval 0.29-0.82). Age, waist circumference and lower income were also associated with diabetes. The optimal sex- and age specific weakness thresholds to detect diabetes were 0.56, 0.50 and 0.45 for men at ages of 20-39, 40-59 and 60-80 years, respectively, and 0.42, 0.38 and 0.33 for women at ages of 20-39, 40-59 and 60-80 years, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: We present thresholds of strength that can be incorporated into a clinical setting for identifying adults who are at risk of developing diabetes and might benefit from lifestyle interventions to reduce risk. PMID- 26744338 TI - Trends in the aetiology of urogenital fistula: a case of 'retrogressive evolution'? AB - It has long been held as conventional wisdom that urogenital fistulae in low income and middle-income countries are almost exclusively of obstetric aetiology, related to prolonged neglected obstructed labour, whereas those seen in high income countries are largely iatrogenic in nature. There is, however, a growing perception amongst those working in the field that an increasing proportion of urogenital fistulae in low-income and middle-income countries may be iatrogenic, resulting from caesarean section. Recent studies suggest that adverse patterns of care may also be emerging in high-income countries; an increase in the risk of both vesicovaginal and ureterovaginal fistulae following hysterectomy has been reported, concurrently with the reduction in overall use of the procedure. These apparent secular trends are discussed in the context of evolution of practice, teaching and training in obstetrics and gynaecology. PMID- 26744335 TI - Massage and Performance Recovery: A Meta-Analytical Review. AB - BACKGROUND: Post-exercise massage is one of the most frequently applied interventions to enhance recovery of athletes. However, evidence to support the efficacy of massage for performance recovery is scarce. Moreover, it has not yet been concluded under which conditions massage is effective. OBJECTIVE: The objective of this study was to perform a systematic review and meta-analysis of the available literature on massage for performance recovery. METHODS: We conducted a structured literature search and located 22 randomized controlled trials. These were analysed with respect to performance effects and various characteristics of the study design (type and duration of massage, type of exercise and performance test, duration of recovery period, training status of subjects). RESULTS: Of the 22 studies, 5 used techniques of automated massage (e.g., vibration), while the other 17 used classic manual massage. A tendency was found for shorter massage (5-12 min) to have larger effects (+6.6%, g = 0.34) than massage lasting more than 12 min (+1.0%, g = 0.06). The effects were larger for short-term recovery of up to 10 min (+7.9%, g = 0.45) than for recovery periods of more than 20 min (+2.4%, g = 0.08). Although after high-intensity mixed exercise, massage yielded medium positive effects (+14.4%, g = 0.61), the effects after strength exercise (+3.9%, g = 0.18) and endurance exercise (+1.3%, g = 0.12) were smaller. Moreover, a tendency was found for untrained subjects to benefit more from massage (+6.5%, g = 0.23) than trained athletes (+2.3%, g = 0.17). CONCLUSION: The effects of massage on performance recovery are rather small and partly unclear, but can be relevant under appropriate circumstances (short-term recovery after intensive mixed training). However, it remains questionable if the limited effects justify the widespread use of massage as a recovery intervention in competitive athletes. PMID- 26744342 TI - Rate-dependent left bundle branch block caused by hyperkalaemia. PMID- 26744339 TI - Health information needs and preferences in relation to survivorship care plans of long-term cancer survivors in the American Cancer Society's Study of Cancer Survivors-I. AB - PURPOSE: Survivorship care plans (SCPs) provide cancer patients and health care providers with a treatment summary and outline of recommended medical follow-up. Few studies have investigated the information needs and preferred sources among long-term cancer survivors. METHODS: Cancer survivors of the ten most common cancers enrolled in the longitudinal Study of Cancer Survivors-I (SCS-I) completed a survey 9 years post-diagnosis (n = 3138); at time of diagnosis of the SCS-I cohort, SCPs were not considered usual care. We assessed participants' current desire and preferred sources for information across ten SCP items and evaluated factors associated with information need 9 years after diagnosis. RESULTS: The proportion of long-term cancer survivors endorsing a need for cancer and health information 9 years post-diagnosis ranged from 43 % (cancer screening) to 9 % (consequences of cancer on ability to work). Print media and personalized reading materials were the most preferred information sources. Younger age, higher education, race other than non-Hispanic white, later cancer stage, having breast cancer, having >=2 comorbidities, and self-reporting poor health were associated with greater informational need (p < 0.05). CONCLUSIONS/IMPLICATIONS FOR CANCER SURVIVORS: Long-term cancer survivors continue to report health information needs for most SCP items and would prefer a print format; however, level of need differs by socio-demographic and cancer characteristics. Cancer survivors who did not previously receive a SCP may still benefit from receiving SCP content, and strategies for enabling dissemination to long-term survivors warrant further investigation. PMID- 26744341 TI - Transcutaneous Ultrasonography in Early Postoperative Diagnosis of Vocal Cord Palsy After Total Thyroidectomy. AB - PURPOSE: This study evaluated the efficiency of transcutaneous laryngeal ultrasonography (TLUS) as an alternative to direct flexible laryngoscopy (DFL) in the early postoperative screening of vocal cord palsy (VCP) after total thyroidectomy, performed for benign and non-extensive malignant disease. METHODS: A prospective study was performed on patients who underwent total thyroidectomy between October 2013 and January 2015 at the Nantes University Hospital (France). Patients underwent DFL on postoperative day 1 performed by an otolaryngologist, followed by TLUS performed by a radiologist on postoperative day 1 or 2. RESULTS: One hundred and three (103) patients were included in this study, 17.5% were male and 82.5% were female, with a mean age of 51 +/- 12 years. Nine patients (9.5%) were diagnosed with postoperative VCP using DFL of these cases 2 were not completely resolved at 3 months postoperatively. Three cases of VCP (33%) were diagnosed using TLUS. TLUS had a sensitivity of 33% and a negative predictive value (NPV) of 95% for the diagnosis of postoperative VCP. Vocal cords (VC) were unassessable in 27.2% of patients. Unassessable VC were significantly associated with male gender (p = 0.0001), age (p = 0.0001), weight (p = 0.002), operating time (p = 0.032), postoperative drainage (p = 0.001), and thyroid weight (p = 0.001). Independent risk factors in the multivariate analysis were male gender (p = 0.0001) and age (p = 0.0001). In the group of women under 50-year old, TLUS had a sensitivity of 50% and a NPV of 97.4%. CONCLUSION: TLUS sensitivity is insufficient in early postoperative screening of VCP after thyroid surgery. Ultrasonographic VCP diagnosis should be confirmed with DFL. PMID- 26744340 TI - Clinical Trials of Active Surveillance of Papillary Microcarcinoma of the Thyroid. AB - BACKGROUND: The incidence of thyroid cancer is increasing globally. This is mainly due to the increase in the detection of small papillary carcinomas, including papillary microcarcinomas (PMC) 1 cm or smaller. It was suggested recently that PMCs are overdiagnosed and overtreated. METHODS: In 1993, the author proposed a clinical trial to compare surgery and observation for low-risk PMC at doctors' meeting in Kuma Hospital, which was approved and the trial started in the same year. Patients choose immediate surgery or observation. This paper shares our 22-year experience with the active surveillance of more than 2000 patients with low-risk PMC and compares the outcomes of immediate surgery with that of active observation. RESULTS: The oncological outcomes of these management groups were similarly excellent. In our active surveillance trial on 1235 patients, 8% of patients showed tumor enlargement by 3 mm or more at 10 years of observation, and 3.8% of the patients showed novel appearance of lymph node metastasis at 10 years. Patients 40 years or younger tended to show progression of the disease. Patients with these slight progressions of the disease were successfully treated with a rescue surgery. None of the patients in both study groups died of the disease. However, incidences of unfavorable events, such as temporary vocal cord paralysis (VCP) and temporary and permanent hypoparathyroidism, were significantly higher in the immediate surgery group than in the observation group (4.1 vs. 0.6%, p < 0.0001; 16.7 vs. 2.8%, p < 0.0001; and 1.6 vs. 0.08%, p < 0.0001, respectively). Permanent VCP occurred in two of the surgery group. CONCLUSIONS: As a result, although we still offer two options, immediate surgery or observation, to patients with low-risk PMC at Kuma Hospital, we now strongly recommend observation as the best choice. PMID- 26744343 TI - Novel imaging strategies for the detection of prosthetic heart valve obstruction and endocarditis. AB - Prosthetic heart valve (PHV) dysfunction remains difficult to recognise correctly by two-dimensional (2D) transthoracic and transoesophageal echocardiography (TTE/TEE). ECG-triggered multidetector-row computed tomography (MDCT), 18 fluorine-fluorodesoxyglucose positron emission tomography including low-dose CT (FDG-PET) and three-dimensional transoesophageal echocardiography (3D-TEE) may have additional value. This paper reviews the role of these novel imaging tools in the field of PHV obstruction and endocarditis.For acquired PHV obstruction, MDCT is of additional value in mechanical PHVs to differentiate pannus from thrombus as well as to dynamically study leaflet motion and opening/closing angles. For biological PHV obstruction, additional imaging is not beneficial as it does not change patient management. When performed on top of 2D-TTE/TEE, MDCT has additional value for the detection of both vegetations and pseudoaneurysms/abscesses in PHV endocarditis. FDG-PET has no complementary value for the detection of vegetations; however, it appears more sensitive in the early detection of pseudoaneurysms/abscesses. Furthermore, FDG-PET enables the detection of metastatic and primary extra-cardiac infections. Evidence for the additional value of 3D-TEE is scarce.As clinical implications are major, clinicians should have a low threshold to perform additional MDCT in acquired mechanical PHV obstruction. For suspected PHV endocarditis, both FDG-PET and MDCT have complementary value. PMID- 26744344 TI - An anomalous left coronary artery with a malignant course: coronary angiography and myocardial perfusion imaging with computed tomography. PMID- 26744346 TI - Cardiac Response to Oxidative Stress Induced by Mitochondrial Dysfunction. AB - The heart works without resting, requiring enormous amounts of energy to continuously pump blood throughout the body. Because of its considerable energy requirements, the heart is vulnerable to oxidative stress caused by the generation of endogenous reactive oxygen species (ROS). Therefore, the heart has effective regulatory and adaptive mechanisms to protect against oxidative stress. Inherited or acquired mitochondrial respiratory chain dysfunction disrupts energy metabolism and causes excessive ROS production and oxidative stress. The physiological cardiac response to oxidative stress can strengthen the heart, but pathological cardiac responses or altered regulatory mechanisms can cause heart disease. Therefore, mitochondria-targeted antioxidants have been tested and some are used clinically. In this review, we briefly discuss the role of mitochondrial DNA mutations, mitochondrial dysfunction, and ROS generation in the development of heart disease and recent developments in mitochondria-targeted antioxidants for the treatment of heart disease. PMID- 26744345 TI - MiR-613 induces cell cycle arrest by targeting CDK4 in non-small cell lung cancer. AB - BACKGROUND: Deregulation of microRNAs (miRNAs) has been associated with a variety of cancers, including non-small cell lung cancer (NSCLC). Here, we investigated anomalous miR-613 expression and its possible functional consequences in primary NSCLC samples and NSCLC-derived cell lines. METHODS: The expression of miR-613 was measured by quantitative RT-PCR in 56 primary NSCLC tissues and adjacent non tumor tissues. The effect of miR-613 up- or down-regulation in NSCLC-derived cells was evaluated in vitro by cell viability and colony formation assays and in vivo by growth assays in xenografted nude mice. RESULTS: Using quantitative RT PCR, we found that miR-613 was down-regulated in 76.8 % (43/56) of the primary NSCLC tissues tested when compared to the adjacent non-tumor tissues. We also found that the miR-613 mimic used reduced in vitro cell viability and colony formation by inducing cell cycle arrest in NSCLC-derived cells, and inhibited in vivo tumor cell growth in xenografted nude mice. Inversely, we found that the miR 613 inhibitor used increased the viability and colony forming capacity of NSCLC derived cells and tumor cell growth in xenografted nude mice. In addition, we identified CDK4 as a potential target of miR-613 using in silico Miranda predictions. Subsequent dual-luciferase reporter assays revealed that CDK4 acts as a direct target of miR-613. Concordantly, we found that both miR-613 mimics and inhibitors could decrease and increase CDK4 protein levels in NSCLC-derived cells, respectively. CONCLUSIONS: From our results we conclude that miR-613 may act as a tumor suppressor in NSCLC and may serve as a tool for miRNA-based NSCLC therapy. PMID- 26744347 TI - Erratum to: Gliomatosis cerebri: no evidence for a separate brain tumor entity. AB - Erratum to: Acta Neuropathol DOI 10.1007/s00401-015-1495-z. The original version of this article contained errors in the alignment of several entries in Tables 4 and 5. The corrected Tables 4 and 5 are given below. The original article has been updated accordingly. PMID- 26744348 TI - Mitochondria-associated membranes as hubs for neurodegeneration. AB - There is a growing appreciation that membrane-bound organelles in eukaryotic cells communicate directly with one another through direct membrane contact sites. Mitochondria-associated membranes are specialized subdomains of the endoplasmic reticulum that function as membrane contact sites between the endoplasmic reticulum and mitochondria. These sites have emerged as major players in lipid metabolism and calcium signaling. More recently also autophagy and mitochondrial dynamics have been found to be regulated at ER-mitochondria contact sites. Neurons critically depend on mitochondria-associated membranes as a means to exchange metabolites and signaling molecules between these organelles. This is underscored by the fact that genes affecting mitochondrial and endoplasmic reticulum homeostasis are clearly overrepresented in several hereditary neurodegenerative disorders. Conversely, the processes affected by the contact sites between the endoplasmic reticulum and mitochondria are widely implicated in neurodegeneration. This review will focus on the most recent data addressing the structural composition and function of the mitochondria-associated membranes. In addition, the 3D morphology of the contact sites as observed using volume electron microscopy is discussed. Finally, it will highlight the role of several key proteins associated with these contact sites that are involved not only in dementias, amyotrophic lateral sclerosis and Parkinson's disease, but also in axonopathies such as hereditary spastic paraplegia and Charcot-Marie-Tooth disease. PMID- 26744350 TI - Gliomatosis cerebri in children shares molecular characteristics with other pediatric gliomas. AB - Gliomatosis cerebri (GC), a rare and deadly CNS neoplasm characterized by involvement of at least three cerebral lobes, predominantly affects adults. While a few small series have reported its occurrence in children, little is known about the molecular characteristics of pediatric GC. We reviewed clinical, radiological, and histological features of pediatric patients with primary GC treated at our institution over 15 years. Targeted sequencing of mutational hotspots in H3F3A, IDH1/2, and BRAF, and genome-wide analysis of DNA methylation and copy number abnormalities was performed in available tumors. Thirty-two patients [23 (72 %) with type 1 and 9 (28 %) with type 2 GC] were identified. Median age at diagnosis was 10.2 years (range 1.5-19.1). A median of 4 cerebral lobes (range 3-8) was affected at diagnosis. In addition, symmetrical bithalamic involvement was observed in 9 (28 %) patients. Twenty-two patients (69 %) had an anaplastic astrocytoma. Despite aggressive therapy, only two patients younger than 3 years at diagnosis are long-term survivors. Clustering analysis of methylation array data from 18 cases classified tumors as IDH (n = 3, 17 %), G34 (n = 4, 22 %), mesenchymal (n = 3, 17 %), and RTK I 'PDGFRA' (n = 8, 44 %). No tumors were classified as K27 subgroup. PDGFRA was the most commonly amplified oncogene in 4 of 22 tumors (18 %). H3F3A p.G34 occurred in all cases classified as G34. Two of 3 cases in the IDH subgroup had IDH1 p.R132H. No H3F3A p.K27 M, IDH2 p.R172, or BRAF p.V600E mutations were observed. There was a trend towards improved survival in the IDH subgroup (P = 0.056). Patients with bithalamic involvement had worse outcomes (P = 0.019). Despite some overlap, the molecular features of pediatric GC are distinct from its adult counterpart. Like in adults, the similarity of genetic and epigenetic characteristics with other infiltrative high-grade gliomas suggests that pediatric GC does not represent a distinct molecular entity. PMID- 26744352 TI - Inhibition of signaling between human CXCR4 and zebrafish ligands by the small molecule IT1t impairs the formation of triple-negative breast cancer early metastases in a zebrafish xenograft model. AB - Triple-negative breast cancer (TNBC) is a highly aggressive and recurrent type of breast carcinoma that is associated with poor patient prognosis. Because of the limited efficacy of current treatments, new therapeutic strategies need to be developed. The CXCR4-CXCL12 chemokine signaling axis guides cell migration in physiological and pathological processes, including breast cancer metastasis. Although targeted therapies to inhibit the CXCR4-CXCL12 axis are under clinical experimentation, still no effective therapeutic approaches have been established to block CXCR4 in TNBC. To unravel the role of the CXCR4-CXCL12 axis in the formation of TNBC early metastases, we used the zebrafish xenograft model. Importantly, we demonstrate that cross-communication between the zebrafish and human ligands and receptors takes place and human tumor cells expressing CXCR4 initiate early metastatic events by sensing zebrafish cognate ligands at the metastatic site. Taking advantage of the conserved intercommunication between human tumor cells and the zebrafish host, we blocked TNBC early metastatic events by chemical and genetic inhibition of CXCR4 signaling. We used IT1t, a potent CXCR4 antagonist, and show for the first time its promising anti-tumor effects. In conclusion, we confirm the validity of the zebrafish as a xenotransplantation model and propose a pharmacological approach to target CXCR4 in TNBC. PMID- 26744351 TI - Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis. AB - Microglia are the resident mononuclear phagocytes of the central nervous system and have been implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). During neurodegeneration, microglial activation is accompanied by infiltration of circulating monocytes, leading to production of multiple inflammatory mediators in the spinal cord. Degenerative alterations in mononuclear phagocytes are commonly observed during neurodegenerative diseases, yet little is known concerning the mechanisms leading to their degeneration, or the consequences on disease progression. Here we observed that the serotonin 2B receptor (5-HT2B), a serotonin receptor expressed in microglia, is upregulated in the spinal cord of three different transgenic mouse models of ALS. In mutant SOD1 mice, this upregulation was restricted to cells positive for CD11b, a marker of mononuclear phagocytes. Ablation of 5-HT2B receptor in transgenic ALS mice expressing mutant SOD1 resulted in increased degeneration of mononuclear phagocytes, as evidenced by fragmentation of Iba1 positive cellular processes. This was accompanied by decreased expression of key neuroinflammatory genes but also loss of expression of homeostatic microglial genes. Importantly, the dramatic effect of 5-HT2B receptor ablation on mononuclear phagocytes was associated with acceleration of disease progression. To determine the translational relevance of these results, we studied polymorphisms in the human HTR2B gene, which encodes the 5-HT2B receptor, in a large cohort of ALS patients. In this cohort, the C allele of SNP rs10199752 in HTR2B was associated with longer survival. Moreover, patients carrying one copy of the C allele of SNP rs10199752 showed increased 5-HT2B mRNA in spinal cord and displayed less pronounced degeneration of Iba1 positive cells than patients carrying two copies of the more common A allele. Thus, the 5-HT2B receptor limits degeneration of spinal cord mononuclear phagocytes, most likely microglia, and slows disease progression in ALS. Targeting this receptor might be therapeutically useful. PMID- 26744353 TI - A new gestational diabetes mellitus model: hyperglycemia-induced eye malformation via inhibition of Pax6 in the chick embryo. AB - Gestational diabetes mellitus (GDM) is one of the leading causes of fetal malformations. However, few models have been developed to study the underlying mechanisms of GDM-induced fetal eye malformation. In this study, a high concentration of glucose (0.2 mmol per egg) was injected into the air sac of chick embryos on embryo development day (EDD) 1 to develop a hyperglycemia model. Results showed that 47.3% of embryonic eye malformation happened on EDD 5. In this model, the key genes regulating eye development, Pax6, Six3 and Otx2, were downregulated by hyperglycemia. Among these genes, the expression of Pax6 was the most vulnerable to hyperglycemia, being suppressed by 70%. A reduction in Pax6 gene expression induced eye malformation in chick embryos. However, increased expression of Pax6 in chick embryos could rescue hyperglycemia-induced eye malformation. Hyperglycemia stimulated O-linked N-acetylglucosaminylation, which caused oxidative stress in chick embryos. Pax6 was found to be vulnerable to free radicals, but the antioxidant edaravone could restore Pax6 expression and reverse eye malformation. These results illustrated a successful establishment of a new chick embryo model to study the molecular mechanism of hyperglycemia-induced eye malformation. The suppression of the Pax6 gene is probably mediated by oxidative stress and could be a crucial target for the therapy of GDM-induced embryonic eye malformation. PMID- 26744349 TI - Host-pathogen interactions in bacterial meningitis. AB - Bacterial meningitis is a devastating disease occurring worldwide with up to half of the survivors left with permanent neurological sequelae. Due to intrinsic properties of the meningeal pathogens and the host responses they induce, infection can cause relatively specific lesions and clinical syndromes that result from interference with the function of the affected nervous system tissue. Pathogenesis is based on complex host-pathogen interactions, some of which are specific for certain bacteria, whereas others are shared among different pathogens. In this review, we summarize the recent progress made in understanding the molecular and cellular events involved in these interactions. We focus on selected major pathogens, Streptococcus pneumonia, S. agalactiae (Group B Streptococcus), Neisseria meningitidis, and Escherichia coli K1, and also include a neglected zoonotic pathogen, Streptococcus suis. These neuroinvasive pathogens represent common themes of host-pathogen interactions, such as colonization and invasion of mucosal barriers, survival in the blood stream, entry into the central nervous system by translocation of the blood-brain and blood cerebrospinal fluid barrier, and induction of meningeal inflammation, affecting pia mater, the arachnoid and subarachnoid spaces. PMID- 26744354 TI - Pulmonary transcriptome analysis in the surgically induced rabbit model of diaphragmatic hernia treated with fetal tracheal occlusion. AB - Congenital diaphragmatic hernia (CDH) is a malformation leading to pulmonary hypoplasia, which can be treated in utero by fetal tracheal occlusion (TO). However, the changes of gene expression induced by TO remain largely unknown but could be used to further improve the clinically used prenatal treatment of this devastating malformation. Therefore, we aimed to investigate the pulmonary transcriptome changes caused by surgical induction of diaphragmatic hernia (DH) and additional TO in the fetal rabbit model. Induction of DH was associated with 378 upregulated genes compared to controls when allowing a false-discovery rate (FDR) of 0.1 and a fold change (FC) of 2. Those genes were again downregulated by consecutive TO. But DH+TO was associated with an upregulation of 157 genes compared to DH and controls. When being compared to control lungs, 106 genes were downregulated in the DH group and were not changed by TO. Therefore, the overall pattern of gene expression in DH+TO is more similar to the control group than to the DH group. In this study, we further provide a database of gene expression changes induced by surgical creation of DH and consecutive TO in the rabbit model. Future treatment strategies could be developed using this dataset. We also discuss the most relevant genes that are involved in CDH. PMID- 26744357 TI - Gastrostomy tube replacement by endoscopic cannulation of a narrowed previous tube site. AB - Percutaneous endoscopic gastrostomy is warranted when oral feeding is not feasible. Indications include central nervous system disorders, head trauma and occasionally malignancies of upper gastrointestinal tract. If tube replacement after accidental dislodgement is delayed, the track may become narrowed. This may compromise routine replacement and may require repeated procedures. Occasionally no further external dilation is possible. We describe the endoscopic cannulation of the previously used track after its internal cannulation and subsequent external dilation and the successful replacement of a gastrostomy tube. PMID- 26744355 TI - Early phase clinical and biological markers associated with subclinical atherosclerosis measured at 7 years of evolution in an early inflammatory arthritis cohort. AB - OBJECTIVES: Accelerated atherosclerosis has emerged as a critical issue in rheumatoid arthritis (RA). There is a need to better understand the link between RA and atherosclerosis. Our aim was to identify parameters associated with the development of subclinical atheroma in a very early arthritis (VErA) cohort. METHODS: VErA-cohort patients were prospectively recruited from 1998 to 2002. Arthritis treatment was standardised from onset. The clinical, biological and radiological parameters of all patients were collected from inclusion. Carotid intima-media thickness (cIMT) was measured 7 years after their first symptoms. RESULTS: Among 105 patients included, 82 developed RA (mean age at onset: 51.7+/ 12.8 years). Mean carotid artery IMT at year 7 was 0.67+/-0.12 mm. Larger thickness defined by values above the median (0.66) was associated with inclusion age (p<10-6), swollen joint count (p=0.01), DAS44 (p=0.048) and hypertension (p=0.006). In contrast, anti-CCP positivity (>50 UA/ml) was associated with thinner cIMT (p=0.03). Baseline as well as cumulated values of markers reflecting systemic inflammation, lymphocyte activation, endothelial dysfunction and oxidative stress were not correlated with carotid subclinical atherosclerosis. Major independent atheroma risk factors retained by multivariate analyses were hypertension (OR 4.33 [1.59-11.73]; p=0.004) and swollen joint count at inclusion (OR 3.87 [1.54-9.72]; p=0.004), while methotrexate use was a protective marker (OR 0.27 [0.11-0.71]; p=0.007). CONCLUSIONS: This study conducted from the VErA vascular cohort of community-cases of RA confirm that cIMT is under the influence of classical CV risk (hypertension), disease marker (SJC) and methotrexate intake. PMID- 26744356 TI - Portrait of a process: arts-based research in a head and neck cancer clinic. AB - The role of art in medicine is complex, varied and uncertain. To examine one aspect of the relationship between art and medicine, investigators analysed the interactions between a professional artist and five adult patients with head and neck cancer as they cocreated portraits in a clinical setting. The artist and four members of an interdisciplinary team analysed the portraits as well as journal entries, transcripts of portrait sessions and semistructured interviews. Over the course of 5 months, 24 artworks evolved from sittings that allowed both the patients and the artist to collaborate around stories of illness, suffering and recovery. Using narrative inquiry and qualitative arts-based research techniques five emergent themes were identified: embracing uncertainties; developing trusting relationships; engaging in reflective practices; creating shared stories; and empowerment. Similar themes are found in successful physician patient relationships. This paper will discuss these findings and potential implications for healthcare and medical education. PMID- 26744358 TI - Towards a European Registry and Biorepository for Patients with Spinal and Bulbar Muscular Atrophy. AB - Pathomechanisms of spinal and bulbar muscular atrophy (SBMA) have been extensively investigated and are partially understood, but no effective treatment is currently available for this disabling disorder. Its rarity, the slow disease progression, and lack of sensitive-to-change outcome measures render design and conduction of clinical trials a challenging task. Therefore, it is fundamental to strengthen the network of clinical centers interested in SBMA for clinical trial readiness. We propose to create and maintain an International SBMA Registry where as many well-characterized patients as possible can be included, with the following aims: facilitate planning of clinical trials and recruitment of patients, define natural history of the disease, characterize epidemiology, develop standards of care, and inform the community of patients about research progresses and ongoing trials. We also aim at developing harmonized and coordinated biorepositories. The experience obtained during the last years in the field of other neuromuscular disorders and of Huntington disease offers valuable precedents. PMID- 26744359 TI - Continuous subcutaneous levetiracetam in the management of seizures at the end of life: a case report. AB - We report the case of a man who developed seizures on a background of recurrent metastatic squamous cell carcinoma with intracranial involvement. Initial seizure control with enteral levetiracetam was achieved, and when enteral and intravenous (i.v.) access was no longer available, a continuous subcutaneous infusion (CSCI) of levetiracetam successfully controlled his seizures without the need for sedating anticonvulsants. As a result, end-of-life care was able to be given with the patient retaining the ability to communicate with his family and healthcare staff. This report adds to the sparse but growing evidence base for the use of subcutaneous levetiracetam to manage seizures in palliative and end-of-life care. PMID- 26744360 TI - A randomised trial of the effect of different fluid consistencies used in the management of dysphagia on quality of life: a time trade-off study. AB - BACKGROUND: thickened fluids are commonly advised to minimise the risk of aspiration in people with dysphagia, although many do not comply with this treatment. In health economics, utilities are values that reflect an individual's preferences for different health states. We examined the healthcare utilities, elicited using a time trade-off approach (TTO), from healthcare professionals and non-dysphagic patients, associated with long-term use of thickened fluids. METHODS: the risk of aspiration with thin fluids was explained to consecutive hospital patients without dysphagia (n = 76) and to a convenience sample of healthcare professionals (n = 75) who were then randomly allocated to drink as much as possible of 200 ml of pre-prepared water of Grade 1 (very mildly thick) or Grade 2 (mildly thick) consistency. A standardised script with a ping-pong approach was then used to elicit TTO utilities for use of thickened fluids using a 10-year horizon. RESULTS: median (inter-quartile range) utilities were 0.7 (0.5 0.9) for those receiving Grade 1 and 0.5 (0.3-0.7) for those receiving Grade 2 consistency fluid (Mann-Whitney test, P = 0.001). Thus, for example, on average those allocated to Grade 2 fluid would be willing to sacrifice 5 years of a 10 year lifespan not to be restricted to fluid of that consistency. There were no significant differences between patient and professional values. CONCLUSION: patients and professionals judge that long-term use of thickened fluids would significantly impair quality of life. Utilities associated with more viscous fluids are particularly low. PMID- 26744361 TI - A systematic review and meta-analysis of interventions designed to prevent or stop elder maltreatment. AB - BACKGROUND: elder maltreatment is a major risk for older adults' mental health, quality of life, health, institutionalisation and even mortality. OBJECTIVES: to perform a systematic review and meta-analysis of interventions designed to prevent or stop elder abuse. METHODS: Studies that were posted between January 2000 and December 2014, written in English, specifically designed to prevent or stop elder maltreatment were included. RESULTS: overall, 24 studies (and four records reporting on the same participants) were kept for the systematic review and the meta-analysis. Studies were broadly grouped into three main categories: (i) interventions designed to improve the ability of professionals to detect or stop elder maltreatment (n = 2), (ii) interventions that target older adults who experience elder maltreatment (n = 3) and (iii) interventions that target caregivers who maltreat older adults (n = 19). Of the latter category, one study targeted family caregivers, five targeted psychological abuse among paid carers and the remaining studies targeted restraint use. The pooled effect of randomised controlled trials (RCTs)/cluster-RCTs that targeted restraint use was significant, supporting the effectiveness of these interventions in reducing restraint use: standardised mean difference: -0.24, 95% confidence interval = 0.38 to -0.09. INTERPRETATION: the most effective place to intervene at the present time is by directly targeting physical restraint by long-term care paid carers. Specific areas that are still lacking evidence at the present time are interventions that target (i) elder neglect, (ii) public awareness, (iii) older adults who experience maltreatment, (iv) professionals responsible for preventing maltreatment, (v) family caregivers who abuse and (vi) carers who abuse. PMID- 26744362 TI - Economic and safety benefits of pharmaceutical interventions by community and hospital pharmacists in Japan. AB - BACKGROUND: Pharmaceutical interventions by community and hospital pharmacists can improve medication safety and result in financial savings. Their effect has not been fully explored in Japan. OBJECTIVE: To evaluate the economic and safety contributions of various pharmaceutical interventions by community and hospital pharmacists in Japan. SETTING: Two hospitals and eight community pharmacies in Ehime Prefecture, Japan, in 2014-2015. METHOD: Pharmacists entered data about pharmaceutical interventions via the internet, and the data were divided into 11 types of interventions. The economic impact was estimated based on the rate of avoidance of serious adverse drug reactions and the monetary cost of these reactions in the Japanese compensation system. The cost saving from adjusting prescriptions to take account of unused prescription drugs was calculated using drug prices from the national health insurance scheme. Main OUTCOME MEASURE: The number of pharmaceutical interventions and their economic impact. RESULTS The total cost savings from 500 to 509 pharmaceutical interventions by community and hospital pharmacists were US$207,126.6 and US$592,840, respectively. Community pharmacists mainly intervened to correct prescription errors. They also adjusted 135 prescriptions to take account of unused prescription drugs. This potentially improved patients' adherence and contributed to effective use of medication. Pharmaceutical interventions by hospital pharmacists facilitated avoidance of 10 serious adverse drug reactions, and included 42 transvenous antimicrobial therapy interventions, 88 interventions in cancer chemotherapy, and 47 monitoring recommendations. Hospital pharmacists helped improve patients' quality of life using more aggressive interventions besides correcting prescription errors. Over half of pharmaceutical interventions by community and hospital pharmacists contributed to avoidance of adverse drug reactions. CONCLUSION: These results suggest the importance of pharmaceutical interventions by both community and hospital pharmacists in reducing increasing medical expenses and contributing to safety and effectiveness of medication. They also suggest that community and hospital pharmacists have different roles. PMID- 26744363 TI - Parent and Physician Perceptions Regarding Preventability of Pediatric Readmissions. AB - OBJECTIVE: To assess the causes and preventability of pediatric readmissions from the perspectives of parents and their physicians to guide future interventions. METHODS: Parent interview, physician survey, and medical record review were completed for children who were readmitted to a pediatric hospitalist service within 30 days of an index admission. Questions were asked about Health Belief Model constructs (perceived severity, susceptibility or preventability of admission, and perceived barriers), discharge readiness, and follow-up plans. Parent and physician perceptions about reasons for readmissions were examined, and responses to open-ended questions were coded. RESULTS: 60 parent-physician pairs completed the study. The mean age of the patients was 6.43 (SD 6.42) years; 45% (n=27) had a chronic disease, and 47% (n=28) of patients were readmitted with the same or similar condition as in the previous hospitalization. At readmission, parents were more likely than physicians to think that the condition was serious (parent 98%, physician 76%; P<.001) and that the readmission could have been prevented (parent 59%, physician 36%; P=.04). Most parents (63%) and physicians (65%) thought it was likely that the child may have future hospitalizations. Opportunities to prevent readmission included need for parent education, improving medication access and adherence, and need for coordination of follow-up care. CONCLUSIONS: Many parents and physicians thought the readmission was preventable, and the majority of both thought that the patient was susceptible to another hospitalization. Parents and physicians suggest opportunities to improve care processes during hospitalization and in services provided after discharge to reduce readmissions. PMID- 26744364 TI - A rapid and non-invasive method to determine toxic levels of alcohols and gamma hydroxybutyric acid in saliva samples by gas chromatography-differential mobility spectrometry. AB - A polydimethylsiloxane oral sampler was used to extract methanol, ethanol, ethylene glycol, 1,3-propandiol and gamma-hydroxybutyric acid from samples of human saliva obtained using a passive drool approach. The extracted compounds were recovered by thermal desorption, isolated by gas chromatography and detected with differential mobility spectrometry, operating with a programmed dispersion field. Complex signal behaviours were also observed that were consistent with hitherto unobserved fragmentation behaviours in differential mobility spectrometry. These yielded high-mobility fragments obscured within the envelope of the water-based reactant ion peak. Further, compensation field maxima shifts were also observed which were attributable to transport gas modification phenomena. Nevertheless, the responses obtained indicated that in vivo saliva sampling with thermal desorption gas chromatography may be used to provide a semi quantitative diagnostic screen over the toxicity threshold concentration ranges of 100 mg dm(-3) to 3 g dm(-3). A candidate method suitable for use in low resource settings for the non-invasive screening of patients intoxicated by alcohols and volatile sedatives has been demonstrated. PMID- 26744365 TI - An ultra-high-density bin map facilitates high-throughput QTL mapping of horticultural traits in pepper (Capsicum annuum). AB - Most agricultural traits are controlled by quantitative trait loci (QTLs); however, there are few studies on QTL mapping of horticultural traits in pepper (Capsicum spp.) due to the lack of high-density molecular maps and the sequence information. In this study, an ultra-high-density map and 120 recombinant inbred lines (RILs) derived from a cross between C. annuum'Perennial' and C. annuum'Dempsey' were used for QTL mapping of horticultural traits. Parental lines and RILs were resequenced at 18* and 1* coverage, respectively. Using a sliding window approach, an ultra-high-density bin map containing 2,578 bins was constructed. The total map length of the map was 1,372 cM, and the average interval between bins was 0.53 cM. A total of 86 significant QTLs controlling 17 horticultural traits were detected. Among these, 32 QTLs controlling 13 traits were major QTLs. Our research shows that the construction of bin maps using low coverage sequence is a powerful method for QTL mapping, and that the short intervals between bins are helpful for fine-mapping of QTLs. Furthermore, bin maps can be used to improve the quality of reference genomes by elucidating the genetic order of unordered regions and anchoring unassigned scaffolds to linkage groups. PMID- 26744366 TI - UNEQUAL BRAINS: DISABILITY DISCRIMINATION LAWS AND CHILDREN WITH CHALLENGING BEHAVIOUR. AB - At a time when brain-based explanations of behaviour are proliferating, how will law respond to the badly behaved child? In Australia, children and youth with challenging behaviours such as aggression, swearing, or impulsivity are increasingly understood as having a behavioural disability and so may be afforded the protections of discrimination law. A brain-based approach to challenging behaviour also offers a seemingly neutral framework that de-stigmatises a child's 'bad' behaviour, making it a biological or medical issue rather than a failure of discipline or temperament. Yet this 'brain-based' framework is not as neutral as it appears. How law regulates the brain-based subject in the form of the badly behaved child depends on how law conceptualises the brain. This article examines two competing approaches to the brain in law: a structural, deterministic model and a 'plastic', flexible model. Each of these impacts differently on disabled and abled identity and consequently on discrimination law and equality rights. Using examples from Australian discrimination law, this article argues that as new brain-based models of identity develop, existing inequalities based on race, gender, and disability are imported, and new forms of stigma emerge. In the neurological age, not all brains are created equal. PMID- 26744367 TI - Strain-tuning of vacancy-induced magnetism in graphene nanoribbons. AB - Vacancies in graphene lead to the appearance of localized electronic states with non-vanishing spin moments. Using a mean-field Hubbard model and an effective double-quantum dot description we investigate the influence of strain on localization and magnetic properties of the vacancy-induced states in semiconducting armchair nanoribbons. We find that the exchange splitting of a single vacancy and the singlet-triplet splitting for two vacancies can be widely tuned by applying uniaxial strain, which is crucial for spintronic applications. PMID- 26744369 TI - Complete Genome Sequence of a Novel Clinical Isolate, Mycobacterium abscessus Strain NOV0213. AB - Mycobacterium abscessus is a rapid-growing species of nontuberculous mycobacteria that is frequently associated with opportunistic infections in humans. We determined the complete genome sequence of the M. abscessus strain NOV0213, which was isolated from a patient with tuberculosis-like disease and with various antibiotic resistances. PMID- 26744368 TI - Draft Genomes for Eight Burkholderia mallei Isolates from Turkey. AB - Burkholderia mallei, the etiologic agent of glanders, is a Gram-negative, nonmotile, facultative intracellular pathogen. Although glanders has been eradicated from many parts of the world, the threat of B. mallei being used as a weapon is very real. Here we present draft genome assemblies of 8 Burkholderia mallei strains that were isolated in Turkey. PMID- 26744371 TI - Paenibacillus larvae Phage Tripp Genome Has 378-Base-Pair Terminal Repeats. AB - Paenibacillus larvae bacteriophage Tripp was isolated from an American foulbrood diseased honey bee hive in North Carolina, USA. The 54,439-bp genome is 48.3% G+C, encodes 92 proteins, no tRNAs, and has 378-bp direct terminal repeats. It is currently unique in Genbank. PMID- 26744370 TI - Draft Genome Sequence of Streptococcus sp. X13SY08, Isolated from Murray Cod (Maccullochella peelii peelii). AB - Streptococcus sp. X13SY08, isolated from freshwater Murray cod fish, likely presents a novel species of Streptococcus. Here, we present an annotated draft genome sequence of this species, which will improve our understanding of its physiology and pathogenesis. PMID- 26744372 TI - Complete Genome Sequence of Helicobacter pylori Strain 7C Isolated from a Mexican Patient with Chronic Gastritis. AB - Helicobacter pylori-induced gastritis is a risk factor for developing gastric pathologies. Here, we report the complete genome sequence of a multidrug resistant H. pylori strain isolated from a chronic gastritis patient in Mexico City, Mexico. Nonvirulent VacA and cag-pathogenicity island (PAI) genotypes were found, but the presence of a potential mobilizable plasmid carrying an IS605 element is of outstanding interest. PMID- 26744373 TI - Complete Genome Sequence of a Strain of Azospirillum thiophilum Isolated from a Sulfide Spring. AB - We report the complete, closed genome sequence and complete methylome of Azospirillum thiophilum strain BV-S(T). PMID- 26744374 TI - Draft Genome Sequence of a Virulent Pectobacterium carotovorum subsp. brasiliense Isolate Causing Soft Rot of Cucumber. AB - Pectobacterium carotovorum subsp. brasiliense causes soft rot and blackleg diseases on potatoes, ornamentals, and other crops of economic importance. Here, we report a draft genome sequence of a highly virulent P. carotovorum subsp. brasiliense strain, PcbHPI01, isolated from a cucumber in South Africa. PMID- 26744375 TI - Draft Genome Sequence of Lactobacillus plantarum 2025. AB - A draft genome sequence of Lactobacillus plantarum 2025 was derived using Ion Torrent sequencing technology. The total size of the assembly (3.33 Mb) was in agreement with the genome sizes of other strains of this species. The data will assist in revealing the genes responsible for the specific properties of this strain. PMID- 26744376 TI - Draft Genome Sequences of Six Mycobacterium immunogenum Strains Obtained from a Chloraminated Drinking Water Distribution System Simulator. AB - We report here the draft genome sequences of six Mycobacterium immunogenum strains isolated from a chloraminated drinking water distribution system simulator subjected to changes in operational parameters. M. immunogenum, a rapidly growing mycobacterium previously reported to be the cause of hypersensitivity pneumonitis from contaminated metalworking fluid aerosols, is becoming a public health concern. PMID- 26744377 TI - Preoperative Duplex Scanning is a Helpful Diagnostic Tool in Neurogenic Thoracic Outlet Syndrome. AB - OBJECTIVE: To evaluate the diagnostic role of venous and arterial duplex scanning in neurogenic thoracic outlet syndrome (NTOS). METHODS: Retrospective review of patients who underwent duplex ultrasonography prior to first rib resection and scalenectomy (FRRS) for NTOS from 2005 to 2013. Abnormal scans included ipsilateral compression (IC) with abduction of the symptomatic extremity (>50% change in subclavian vessel flow), contralateral (asymptomatic side) compression (CC) or bilateral compression (BC). RESULTS: A total of 143 patients (76% female, average age 34, range 13-59) underwent bilateral preoperative duplex scanning. Ipsilateral compression was seen in 44 (31%), CC in 12 (8%), and BC in 14 (10%). Seventy-three (51%) patients demonstrated no compression. Patients with IC more often experienced intraoperative pneumothoraces (49% vs. 25%, P < .05) and had positive Adson tests (86% vs. 61%, P < .02). CONCLUSION: Compression of the subclavian vein or artery on duplex ultrasonography can assist in NTOS diagnosis. Ipsilateral compression on abduction often correlates with Adson testing. PMID- 26744378 TI - Crystal orbital studies on the 1D silic-diyne nanoribbons and nanotubes. AB - This work presents crystal orbital studies on novel one-dimensional (1D) nanoscale materials derived from a Si-diyne sheet, based on the density functional theory. The two-dimensional (2D) Si-diyne layer is observed to be carbo-merized silicene, with a similar structure to graphdiyne. The 2D Si-diyne and its 1D ribbons and tubes, of different size and chirality, have been addressed systematically. The low dimensional Si-diyne materials studied exhibit relatively high stability, according to phonon-frequency calculations and molecular dynamics simulations. With comparable diameters, the Si-diyne tubes have lower strain energies than silicene and silicon carbide nanotubes. The Si diyne layer and its 1D derivatives are all semiconductors, regardless of the size and chirality of the strips and tubes. In addition, the band gaps of the 1D Si diyne nanoribbons and nanotubes with different chirality, always monotonically decrease as their sizes increases. A quantitative relationship between the band gap and the size of the ribbons and tubes was obtained. The mobility of charge carriers for the 1D Si-diyne structures was also investigated. It was found that both hole and electron mobility of the ribbons and tubes exhibit linear increase with increasing size. The electrons have greater mobility than the holes for each strip and tube. In addition, the mechanical properties of the Si-diyne nanostructures were also investigated by calculation of the Young's modulus and the Poisson's ratio. PMID- 26744381 TI - Dynamics of charge migration in poly(para-phenylene vinylene) films and nanocomposites with single walled carbon nanotubes. AB - We present in this paper a comprehensive study of the migration dynamics of the charges underlying transient photoluminescence (PL) processes in poly(para phenylene vinylene) (PPV) samples from room temperature to 13 K. In order to interpret experimental data, we have modelled the long-time PL decays (from 100 to 1000 ps) using a time function proportional to [Formula: see text] in which the parameter alpha is evaluated in a Monte Carlo simulation on polymeric chains. The one dimensional chains (2000 sites long) are formed by random sequences of long and short conjugated segments whose bimodal distributions have been elaborated in previous works in order to reproduce the PL band shapes and peak positions. Intra-chain and inter-chain dynamics are taken into account in the migration of the photogenerated charges from short to long conjugated segments. The statistical analysis is performed by averaging over a total of 10(6) trials for each initial conditions. The values of alpha have been determined for pristine PPV films and PPV composite films with single-walled carbon nanotubes. This theoretical analysis is in good agreement with experimental data and provides a coherent description for the migration of the photogenerated charges in such inhomogeneous polymeric systems. PMID- 26744379 TI - Heart Failure Complicating Acute Myocardial Infarction; Burden and Timing of Occurrence: A Nation-wide Analysis Including 86 771 Patients From the Cardiovascular Disease in Norway (CVDNOR) Project. AB - BACKGROUND: Coronary heart disease (CHD) represents often the underlying conditions for the development of heart failure (HF). We aimed at exploring the burden and timing of HF complicating an acute myocardial infarction (AMI), using the total population of AMI patients hospitalized during 2001-2009 in Norway. METHODS AND RESULTS: A total of 86 771 patients with a first AMI during 2001-2009 and without previous HF were identified in the "Cardiovascular Disease in Norway" project and followed until HF development, death, or December 31, 2009. In 16 219 patients (18.7%), HF was present on admission or developed during hospitalization for the incident AMI. HF occurrence varied according to age (8.9%, 15.2%, and 25.6% among men and 10.2%, 16.8%, and 27.1% among women ages 25-54, 55-74, and 75 85 years). Among 63 853 patients discharged alive without HF, 8058 (12.6%) were hospitalized with or died because of HF during a median follow-up time of 3.2 years. HF incidence rates (IRs) per 1000 person-years during follow-up were 31 (95% CI, 30-32) for men and 46 (95% CI, 44-47) for women (P<0.01). IRs of HF were highest during the first 6 months of follow-up, after which they leveled off and remained stable until the end of follow-up. CONCLUSIONS: In this nation-wide cohort study, we observed that HF remains a frequent complication of the first AMI; both during the acute phase and shortly after the discharge from the hospital. PMID- 26744380 TI - Early Access to the Cardiac Catheterization Laboratory for Patients Resuscitated From Cardiac Arrest Due to a Shockable Rhythm: The Minnesota Resuscitation Consortium Twin Cities Unified Protocol. AB - BACKGROUND: In 2013 the Minnesota Resuscitation Consortium developed an organized approach for the management of patients resuscitated from shockable rhythms to gain early access to the cardiac catheterization laboratory (CCL) in the metro area of Minneapolis-St. Paul. METHODS AND RESULTS: Eleven hospitals with 24/7 percutaneous coronary intervention capabilities agreed to provide early (within 6 hours of arrival at the Emergency Department) access to the CCL with the intention to perform coronary revascularization for outpatients who were successfully resuscitated from ventricular fibrillation/ventricular tachycardia arrest. Other inclusion criteria were age >18 and <76 and presumed cardiac etiology. Patients with other rhythms, known do not resuscitate/do not intubate, noncardiac etiology, significant bleeding, and terminal disease were excluded. The primary outcome was survival to hospital discharge with favorable neurological outcome. Patients (315 out of 331) who were resuscitated from VT/VF and transferred alive to the Emergency Department had complete medical records. Of those, 231 (73.3%) were taken to the CCL per the Minnesota Resuscitation Consortium protocol while 84 (26.6%) were not taken to the CCL (protocol deviations). Overall, 197 (63%) patients survived to hospital discharge with good neurological outcome (cerebral performance category of 1 or 2). Of the patients who followed the Minnesota Resuscitation Consortium protocol, 121 (52%) underwent percutaneous coronary intervention, and 15 (7%) underwent coronary artery bypass graft. In this group, 151 (65%) survived with good neurological outcome, whereas in the group that did not follow the Minnesota Resuscitation Consortium protocol, 46 (55%) survived with good neurological outcome (adjusted odds ratio: 1.99; [1.07-3.72], P=0.03). CONCLUSIONS: Early access to the CCL after cardiac arrest due to a shockable rhythm in a selected group of patients is feasible in a large metropolitan area in the United States and is associated with a 65% survival rate to hospital discharge with a good neurological outcome. PMID- 26744384 TI - Biggest opportunity of our age. PMID- 26744382 TI - Sorting nexin 27 interacts with Fzd7 and mediates Wnt signalling. AB - SNX27 is the only sorting nexin (SNX) that contains a PDZ domain, which interacts with PDZ-binding motif of target proteins to regulate the trafficking of these proteins. We here showed that SNX27 interacts with Frizzled (Fzd) receptors via PDZ domain interaction. Immunofluorescence microscopy revealed that Fzd7 can be internalized and associate with SNX27-containing endosomal membrane. In addition, SNX27 enhances the endocytosis of Fzd7 and promotes the degradation of Fzd7. Further examination demonstrated that SNX27 inhibits the Wnt regulated transcription activity of TCF/LEF. Our results suggested that SNX27 interacts with Frizzled receptors to regulate the endocytosis and stability of Fzds, and consequently mediates canonical Wnt signalling. PMID- 26744386 TI - EMERGING DISEASES. A race to explain Brazil's spike in birth defects. PMID- 26744383 TI - rhHMGB1 drives osteoblast migration in a TLR2/TLR4- and NF-kappaB-dependent manner. AB - Osteoblast migration is significant in skeletal development. Recently, high mobility group box 1 protein (HMGB1) has been shown to highly expressed in cartilage to regulate endochondral ossification. Nevertheless, whether HMGB1 can modulate osteoblast proliferation and migration is poorly understood, as well as the intracellular signalling pathways that are involved in this process. Herein, we examined the effects of recombinant human HMGB1 (rhHMGB1) on the proliferation and migration of rat osteoblasts and investigated whether Toll-like receptor 2 (TLR2)- and TLR4-dependent signalling pathways are involved in the regulation of intracellular signalling. A transwell chamber assay was used to evaluate the migration of osteoblasts and the MTT assay was used to assess osteoblast proliferation. rhHMGB1 could significantly promote the migration of osteoblasts without inhibiting their proliferation. Meanwhile, rhHMGB1 can increase the nuclear translocation of nuclear factor-kappa B (NF-kappaB) p65. Specific siRNA constructs that target TLR2 or TLR4 could markedly inhibit HMGB1-induced migration of osteoblasts and HMGB1-enhanced activation of NF-kappaB. Collectively, HMGB1 could significantly enhance the migration of osteoblasts in vitro, and TLR2/TLR4-dependent NF-kappaB pathways are involved in HMGB1-induced osteoblast migration. PMID- 26744387 TI - WATER RESOURCES. Iraq confronts a new enemy--the Persian Gulf. PMID- 26744388 TI - SOLAR ENERGY. Cesium fortifies next-generation solar cells. PMID- 26744389 TI - ENVIRONMENTAL SCIENCE. Conservation researchers get a new roost in Cambridge. PMID- 26744390 TI - BEHIND THE NUMBERS. DATA CHECK: For female scientists, mixed funding results at U.S. agencies. PMID- 26744391 TI - A shot at migraine. PMID- 26744392 TI - ECOLOGY. Ancient grasslands at risk. PMID- 26744393 TI - GEOCHEMISTRY. Lower-mantle materials under pressure. PMID- 26744394 TI - THERMOELECTRICS. Finding merit in dividing neighbors. PMID- 26744395 TI - CELL BIOLOGY. Disrupted nuclear import-export in neurodegeneration. PMID- 26744396 TI - STEM CELLS. Potency finds its niches. PMID- 26744398 TI - Call for conservation: Abandoned pasture. PMID- 26744399 TI - Recognizing thermal plasticity in fish. PMID- 26744397 TI - DEVELOPMENT AND ENVIRONMENT. Balancing hydropower and biodiversity in the Amazon, Congo, and Mekong. PMID- 26744400 TI - HIV/AIDS epidemic: The whole truth. PMID- 26744401 TI - A mixed-cation lead mixed-halide perovskite absorber for tandem solar cells. AB - Metal halide perovskite photovoltaic cells could potentially boost the efficiency of commercial silicon photovoltaic modules from ~20 toward 30% when used in tandem architectures. An optimum perovskite cell optical band gap of ~1.75 electron volts (eV) can be achieved by varying halide composition, but to date, such materials have had poor photostability and thermal stability. Here we present a highly crystalline and compositionally photostable material, [HC(NH2)2](0.83)Cs(0.17)Pb(I(0.6)Br(0.4))3, with an optical band gap of ~1.74 eV, and we fabricated perovskite cells that reached open-circuit voltages of 1.2 volts and power conversion efficiency of over 17% on small areas and 14.7% on 0.715 cm(2) cells. By combining these perovskite cells with a 19%-efficient silicon cell, we demonstrated the feasibility of achieving >25%-efficient four terminal tandem cells. PMID- 26744402 TI - Dominance of the suppressed: Power-law size structure in tropical forests. AB - Tropical tree size distributions are remarkably consistent despite differences in the environments that support them. With data analysis and theory, we found a simple and biologically intuitive hypothesis to explain this property, which is the foundation of forest dynamics modeling and carbon storage estimates. After a disturbance, new individuals in the forest gap grow quickly in full sun until they begin to overtop one another. The two-dimensional space-filling of the growing crowns of the tallest individuals relegates a group of losing, slow growing individuals to the understory. Those left in the understory follow a power-law size distribution, the scaling of which depends on only the crown area to-diameter allometry exponent: a well-conserved value across tropical forests. PMID- 26744404 TI - Reconciliation of the Devils Hole climate record with orbital forcing. AB - The driving force behind Quaternary glacial-interglacial cycles and much associated climate change is widely considered to be orbital forcing. However, previous versions of the iconic Devils Hole (Nevada) subaqueous calcite record exhibit shifts to interglacial values ~10,000 years before orbitally forced ice age terminations, and interglacial durations ~10,000 years longer than other estimates. Our measurements from Devils Hole 2 replicate virtually all aspects of the past 204,000 years of earlier records, except for the timing during terminations, and they lower the age of the record near Termination II by ~8000 years, removing both ~10,000-year anomalies. The shift to interglacial values now broadly coincides with the rise in boreal summer insolation, the marine termination, and the rise in atmospheric CO2, which is consistent with mechanisms ultimately tied to orbital forcing. PMID- 26744406 TI - The structure of the beta-barrel assembly machinery complex. AB - beta-Barrel outer membrane proteins (OMPs) are found in the outer membranes of Gram-negative bacteria and are essential for nutrient import, signaling, and adhesion. A 200-kilodalton five-component complex called the beta-barrel assembly machinery (BAM) complex has been implicated in the biogenesis of OMPs. We report the structure of the BAM complex from Escherichia coli, revealing that binding of BamCDE modulates the conformation of BamA, the central component, which may serve to regulate the BAM complex. The periplasmic domain of BamA was in a closed state that prevents access to the barrel lumen, which indicates substrate OMPs may not be threaded through the barrel during biogenesis. Further, conformational shifts in the barrel domain lead to opening of the exit pore and rearrangement at the lateral gate. PMID- 26744407 TI - Want a letter? You write it for me. PMID- 26744403 TI - The 5300-year-old Helicobacter pylori genome of the Iceman. AB - The stomach bacterium Helicobacter pylori is one of the most prevalent human pathogens. It has dispersed globally with its human host, resulting in a distinct phylogeographic pattern that can be used to reconstruct both recent and ancient human migrations. The extant European population of H. pylori is known to be a hybrid between Asian and African bacteria, but there exist different hypotheses about when and where the hybridization took place, reflecting the complex demographic history of Europeans. Here, we present a 5300-year-old H. pylori genome from a European Copper Age glacier mummy. The "Iceman" H. pylori is a nearly pure representative of the bacterial population of Asian origin that existed in Europe before hybridization, suggesting that the African population arrived in Europe within the past few thousand years. PMID- 26744405 TI - Accurate concentration control of mitochondria and nucleoids. AB - All cellular materials are partitioned between daughters at cell division, but by various mechanisms and with different accuracy. In the yeast Schizosaccharomyces pombe, the mitochondria are pushed to the cell poles by the spindle. We found that mitochondria spatially reequilibrate just before division, and that the mitochondrial volume and DNA-containing nucleoids instead segregate in proportion to the cytoplasm inherited by each daughter. However, nucleoid partitioning errors are suppressed by control at two levels: Mitochondrial volume is actively distributed throughout a cell, and nucleoids are spaced out in semiregular arrays within mitochondria. During the cell cycle, both mitochondria and nucleoids appear to be produced without feedback, creating a net control of fluctuations that is just accurate enough to avoid substantial growth defects. PMID- 26744408 TI - The Anthropocene is functionally and stratigraphically distinct from the Holocene. AB - Human activity is leaving a pervasive and persistent signature on Earth. Vigorous debate continues about whether this warrants recognition as a new geologic time unit known as the Anthropocene. We review anthropogenic markers of functional changes in the Earth system through the stratigraphic record. The appearance of manufactured materials in sediments, including aluminum, plastics, and concrete, coincides with global spikes in fallout radionuclides and particulates from fossil fuel combustion. Carbon, nitrogen, and phosphorus cycles have been substantially modified over the past century. Rates of sea-level rise and the extent of human perturbation of the climate system exceed Late Holocene changes. Biotic changes include species invasions worldwide and accelerating rates of extinction. These combined signals render the Anthropocene stratigraphically distinct from the Holocene and earlier epochs. PMID- 26744409 TI - Gating of hippocampal activity, plasticity, and memory by entorhinal cortex long range inhibition. AB - The cortico-hippocampal circuit is critical for storage of associational memories. Most studies have focused on the role in memory storage of the excitatory projections from entorhinal cortex to hippocampus. However, entorhinal cortex also sends inhibitory projections, whose role in memory storage and cortico-hippocampal activity remains largely unexplored. We found that these long range inhibitory projections enhance the specificity of contextual and object memory encoding. At the circuit level, these gamma-aminobutyric acid (GABA) releasing projections target hippocampal inhibitory neurons and thus act as a disinhibitory gate that transiently promotes the excitation of hippocampal CA1 pyramidal neurons by suppressing feedforward inhibition. This enhances the ability of CA1 pyramidal neurons to fire synaptically evoked dendritic spikes and to generate a temporally precise form of heterosynaptic plasticity. Long-range inhibition from entorhinal cortex may thus increase the precision of hippocampal based long-term memory associations by assessing the salience of mnemonormation to the immediate sensory input. PMID- 26744410 TI - Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4 in pulmonary fibrosis. AB - Fibroblasts derived from the lungs of patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc) produce low levels of prostaglandin (PG) E2, due to a limited capacity to up-regulate cyclooxygenase-2 (COX-2). This deficiency contributes functionally to the fibroproliferative state, however the mechanisms responsible are incompletely understood. In the present study, we examined whether the reduced level of COX-2 mRNA expression observed in fibrotic lung fibroblasts is regulated epigenetically. The DNA methylation inhibitor, 5 aza-2'-deoxycytidine (5AZA) restored COX-2 mRNA expression by fibrotic lung fibroblasts dose dependently. Functionally, this resulted in normalization of fibroblast phenotype in terms of PGE2 production, collagen mRNA expression and sensitivity to apoptosis. COX-2 methylation assessed by bisulfite sequencing and methylation microarrays was not different in fibrotic fibroblasts compared with controls. However, further analysis of the methylation array data identified a transcriptional regulator, chromosome 8 open reading frame 4 (thyroid cancer protein 1, TC-1) (c8orf4), which is hypermethylated and down-regulated in fibrotic fibroblasts compared with controls. siRNA knockdown of c8orf4 in control fibroblasts down-regulated COX-2 and PGE2 production generating a phenotype similar to that observed in fibrotic lung fibroblasts. Chromatin immunoprecipitation demonstrated that c8orf4 regulates COX-2 expression in lung fibroblasts through binding of the proximal promoter. We conclude that the decreased capacity of fibrotic lung fibroblasts to up-regulate COX-2 expression and COX-2-derived PGE2 synthesis is due to an indirect epigenetic mechanism involving hypermethylation of the transcriptional regulator, c8orf4. PMID- 26744411 TI - A Disintegrin and Metalloproteinase Domain 17 Regulates Colorectal Cancer Stem Cells and Chemosensitivity Via Notch1 Signaling. AB - Evidence is accumulating for the role of cancer stem cells (CSCs) in mediating chemoresistance in patients with metastatic colorectal cancer (mCRC). A disintegrin and metalloproteinase domain 17 (ADAM17; also known as tumor necrosis factor-alpha-converting enzyme [TACE]) was shown to be overexpressed and to mediate cell proliferation and chemoresistance in CRC cells. However, its role in mediating the CSC phenotype in CRC has not been well-characterized. The objective of the present study was to determine whether ADAM17 regulates the CSC phenotype in CRC and to elucidate the downstream signaling mechanism that mediates cancer stemness. We treated established CRC cell lines and a newly established human CRC cell line HCP-1 with ADAM17-specific small interfering RNA (siRNA) or the synthetic peptide inhibitor TAPI-2. The effects of ADAM17 inhibition on the CSC phenotype and chemosensitivity to 5-fluorouracil (5-FU) in CRC cells were examined. siRNA knockdown and TAPI-2 decreased the protein levels of cleaved Notch1 (Notch1 intracellular domain) and HES-1 in CRC cells. A decrease in the CSC phenotype was determined by sphere formation and ALDEFLUOR assays. Moreover, TAPI-2 sensitized CRC cells to 5-FU by decreasing cell viability and the median lethal dose of 5-FU and increasing apoptosis. We also showed the cleavage and release of soluble Jagged-1 and -2 by ADAM17 in CRC cells. Our studies have elucidated a role of ADAM17 in regulating the CSC phenotype and chemoresistance in CRC cells. The use of drugs that inhibit ADAM17 activity might increase the therapeutic benefit to patients with mCRC and, potentially, those with other solid malignancies. PMID- 26744413 TI - Mediterranean diet supplemented with extra virgin olive oil reduces the incidence of invasive breast cancer in a randomised controlled trial. PMID- 26744414 TI - Ibuprofen for the treatment of TTH. PMID- 26744412 TI - Human Cortical Neural Stem Cells Expressing Insulin-Like Growth Factor-I: A Novel Cellular Therapy for Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder and a leading cause of dementia. Current treatment fails to modify underlying disease pathologies and very little progress has been made to develop effective drug treatments. Cellular therapies impact disease by multiple mechanisms, providing increased efficacy compared with traditional single-target approaches. In amyotrophic lateral sclerosis, we have shown that transplanted spinal neural stem cells (NSCs) integrate into the spinal cord, form synapses with the host, improve inflammation, and reduce disease-associated pathologies. Our current goal is to develop a similar "best in class" cellular therapy for AD. Here, we characterize a novel human cortex-derived NSC line modified to express insulin-like growth factor-I (IGF-I), HK532-IGF-I. Because IGF-I promotes neurogenesis and synaptogenesis in vivo, this enhanced NSC line offers additional environmental enrichment, enhanced neuroprotection, and a multifaceted approach to treating complex AD pathologies. We show that autocrine IGF-I production does not impact the cell secretome or normal cellular functions, including proliferation, migration, or maintenance of progenitor status. However, HK532-IGF I cells preferentially differentiate into gamma-aminobutyric acid-ergic neurons, a subtype dysregulated in AD; produce increased vascular endothelial growth factor levels; and display an increased neuroprotective capacity in vitro. We also demonstrate that HK532-IGF-I cells survive peri-hippocampal transplantation in a murine AD model and exhibit long-term persistence in targeted brain areas. In conclusion, we believe that harnessing the benefits of cellular and IGF-I therapies together will provide the optimal therapeutic benefit to patients, and our findings support further preclinical development of HK532-IGF-I cells into a disease-modifying intervention for AD. PMID- 26744417 TI - "Reverse Genomics" Predicts Function of Human Conserved Noncoding Elements. AB - Evolutionary changes in cis-regulatory elements are thought to play a key role in morphological and physiological diversity across animals. Many conserved noncoding elements (CNEs) function as cis-regulatory elements, controlling gene expression levels in different biological contexts. However, determining specific associations between CNEs and related phenotypes is a challenging task. Here, we present a computational "reverse genomics" approach that predicts the phenotypic functions of human CNEs. We identify thousands of human CNEs that were lost in at least two independent mammalian lineages (IL-CNEs), and match their evolutionary profiles against a diverse set of phenotypes recently annotated across multiple mammalian species. We identify 2,759 compelling associations between human CNEs and a diverse set of mammalian phenotypes. We discuss multiple CNEs, including a predicted ear element near BMP7, a pelvic CNE in FBN1, a brain morphology element in UBE4B, and an aquatic adaptation forelimb CNE near EGR2, and provide a full list of our predictions. As more genomes are sequenced and more traits are annotated across species, we expect our method to facilitate the interpretation of noncoding mutations in human disease and expedite the discovery of individual CNEs that play key roles in human evolution and development. PMID- 26744416 TI - Environmental Correlation Analysis for Genes Associated with Protection against Malaria. AB - Genome-wide searches for loci involved in human resistance to malaria are currently being conducted on a large scale in Africa using case-control studies. Here, we explore the utility of an alternative approach-"environmental correlation analysis, ECA," which tests for clines in allele frequencies across a gradient of an environmental selection pressure-to identify genes that have historically protected against death from malaria. We collected genotype data from 12,425 newborns on 57 candidate malaria resistance loci and 9,756 single nucleotide polymorphisms (SNPs) selected at random from across the genome, and examined their allele frequencies for geographic correlations with long-term malaria prevalence data based on 84,042 individuals living under different historical selection pressures from malaria in coastal Kenya. None of the 57 candidate SNPs showed significant (P < 0.05) correlations in allele frequency with local malaria transmission intensity after adjusting for population structure and multiple testing. In contrast, two of the random SNPs that had highly significant correlations (P < 0.01) were in genes previously linked to malaria resistance, namely, CDH13, encoding cadherin 13, and HS3ST3B1, encoding heparan sulfate 3-O-sulfotransferase 3B1. Both proteins play a role in glycoprotein-mediated cell-cell adhesion which has been widely implicated in cerebral malaria, the most life-threatening form of this disease. Other top genes, including CTNND2 which encodes delta-catenin, a molecular partner to cadherin, were significantly enriched in cadherin-mediated pathways affecting inflammation of the brain vascular endothelium. These results demonstrate the utility of ECA in the discovery of novel genes and pathways affecting infectious disease. PMID- 26744415 TI - A Genetic Mechanism for Convergent Skin Lightening during Recent Human Evolution. AB - Skin lightening among Eurasians is thought to have been a convergence occurring independently in Europe and East Asia as an adaptation to high latitude environments. Among Europeans, several genes responsible for such lightening have been found, but the information available for East Asians is much more limited. Here, a genome-wide comparison between dark-skinned Africans and Austro-Asiatic speaking aborigines and light-skinned northern Han Chinese identified the pigmentation gene OCA2, showing unusually deep allelic divergence between these groups. An amino acid substitution (His615Arg) of OCA2 prevalent in most East Asian populations-but absent in Africans and Europeans-was significantly associated with skin lightening among northern Han Chinese. Further transgenic and targeted gene modification analyses of zebrafish and mouse both exhibited the phenotypic effect of the OCA2 variant manifesting decreased melanin production. These results indicate that OCA2 plays an important role in the convergent skin lightening of East Asians during recent human evolution. PMID- 26744418 TI - MMP-9 facilitates selective proteolysis of the histone H3 tail at genes necessary for proficient osteoclastogenesis. AB - Although limited proteolysis of the histone H3 N-terminal tail (H3NT) is frequently observed during mammalian differentiation, the specific genomic sites targeted for H3NT proteolysis and the functional significance of H3NT cleavage remain largely unknown. Here we report the first method to identify and examine H3NT-cleaved regions in mammals, called chromatin immunoprecipitation (ChIP) of acetylated chromatin (ChIPac). By applying ChIPac combined with deep sequencing (ChIPac-seq) to an established cell model of osteoclast differentiation, we discovered that H3NT proteolysis is selectively targeted near transcription start sites of a small group of genes and that most H3NT-cleaved genes displayed significant expression changes during osteoclastogenesis. We also discovered that the principal H3NT protease of osteoclastogenesis is matrix metalloproteinase 9 (MMP-9). In contrast to other known H3NT proteases, MMP-9 primarily cleaved H3K18 Q19 in vitro and in cells. Furthermore, our results support CBP/p300-mediated acetylation of H3K18 as a central regulator of MMP-9 H3NT protease activity both in vitro and at H3NT cleavage sites during osteoclastogenesis. Importantly, we found that abrogation of H3NT proteolysis impaired osteoclastogenic gene activation concomitant with defective osteoclast differentiation. Our collective results support the necessity of MMP-9-dependent H3NT proteolysis in regulating gene pathways required for proficient osteoclastogenesis. PMID- 26744419 TI - Control of heterochromatin localization and silencing by the nuclear membrane protein Lem2. AB - Transcriptionally silent chromatin localizes to the nuclear periphery, which provides a special microenvironment for gene repression. A variety of nuclear membrane proteins interact with repressed chromatin, yet the functional role of these interactions remains poorly understood. Here, we show that, in Schizosaccharomyces pombe, the nuclear membrane protein Lem2 associates with chromatin and mediates silencing and heterochromatin localization. Unexpectedly, we found that these functions can be separated and assigned to different structural domains within Lem2, excluding a simple tethering mechanism. Chromatin association and tethering of centromeres to the periphery are mediated by the N terminal LEM (LAP2-Emerin-MAN1) domain of Lem2, whereas telomere anchoring and heterochromatin silencing require exclusively its conserved C-terminal MSC (MAN1 Src1 C-terminal) domain. Particularly, silencing by Lem2 is epistatic with the Snf2/HDAC (histone deacetylase) repressor complex SHREC at telomeres, while its necessity can be bypassed by deleting Epe1, a JmjC protein with anti-silencing activity. Furthermore, we found that loss of Lem2 reduces heterochromatin association of SHREC, which is accompanied by increased binding of Epe1. This reveals a critical function of Lem2 in coordinating these antagonistic factors at heterochromatin. The distinct silencing and localization functions mediated by Lem2 suggest that these conserved LEM-containing proteins go beyond simple tethering to play active roles in perinuclear silencing. PMID- 26744422 TI - Response to: 'Recast the debate about preventable readmissions' by Sutherland et al. PMID- 26744420 TI - A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex. AB - Class switch recombination (CSR) diversifies antibodies for productive immune responses while maintaining stability of the B-cell genome. Transcription at the immunoglobulin heavy chain (Igh) locus targets CSR-associated DNA damage and is promoted by the BRCT domain-containing PTIP (Pax transactivation domain interacting protein). Although PTIP is a unique component of the mixed-lineage leukemia 3 (MLL3)/MLL4 chromatin-modifying complex, the mechanisms for how PTIP promotes transcription remain unclear. Here we dissected the minimal structural requirements of PTIP and its different protein complexes using quantitative proteomics in primary lymphocytes. We found that PTIP functions in transcription and CSR separately from its association with the MLL3/MLL4 complex and from its localization to sites of DNA damage. We identified a tandem BRCT domain of PTIP that is sufficient for CSR and identified PA1 as its main functional protein partner. Collectively, we provide genetic and biochemical evidence that a PTIP PA1 subcomplex functions independently from the MLL3/MLL4 complex to mediate transcription during CSR. These results further our understanding of how multifunctional chromatin-modifying complexes are organized by subcomplexes that harbor unique and distinct activities. PMID- 26744423 TI - Swimming 'upstream' to tackle the social determinants of health. PMID- 26744421 TI - Chromosome-specific NOR inactivation explains selective rRNA gene silencing and dosage control in Arabidopsis. AB - In eukaryotes, scores of excess ribosomal RNA (rRNA) genes are silenced by repressive chromatin modifications. Given the near sequence identity of rRNA genes within a species, it is unclear how specific rRNA genes are reproducibly chosen for silencing. Using Arabidopsis thaliana ecotype (strain) Col-0, a systematic search identified sequence polymorphisms that differ between active and developmentally silenced rRNA gene subtypes. Recombinant inbred mapping populations derived from three different ecotype crosses were then used to map the chromosomal locations of silenced and active RNA gene subtypes. Importantly, silenced and active rRNA gene subtypes are not intermingled. All silenced rRNA gene subtypes mapped to the nucleolus organizer region (NOR) on chromosome 2 (NOR2). All active rRNA gene subtypes mapped to NOR4. Using an engineered A. thaliana line in which a portion of Col-0 chromosome 4 was replaced by sequences of another ecotype, we show that a major rRNA gene subtype silenced at NOR2 is active when introgressed into the genome at NOR4. Collectively, these results reveal that selective rRNA gene silencing is not regulated gene by gene based on mechanisms dependent on subtle gene sequence variation. Instead, we propose that a subchromosomal silencing mechanism operates on a multimegabase scale to inactivate NOR2. PMID- 26744424 TI - Antidepressants are associated with hospital admitted intracranial bleeds in people taking other medication associated with bleeding. PMID- 26744425 TI - Norovirus in 2016-Emesis Aplenty but Clear Signs of Progress. AB - The key theme emerging from the articles in this supplement is that burden of norovirus in the United Kingdom and elsewhere is substantial and that new tools for prevention, diagnosis, and treatment are required. Basic understanding of norovirus biology continues to accelerate, but parallel increases in capacity and research funding are going to be needed to translate this knowledge into clinical trials and translational research that can result in public health gains. PMID- 26744426 TI - Role of the Hospital Environment in Norovirus Containment. AB - Norovirus is an important cause of gastroenteritis in healthcare settings; these infections occur frequently, are highly contagious, and can be difficult to control. Norovirus outbreaks were investigated during a 3-month enhanced surveillance period from 1 February to 30 April 2015 in 6 London, United Kingdom, hospitals (coded A-E). During this surveillance period, 1379 stool samples were tested for the presence of norovirus. Of these, 129 (9.4%) demonstrated the presence of norovirus RNA. Two of these hospitals (A and D) reported 0 outbreaks, 2 (hospitals C and F) reported 1 outbreak, 1 hospital (B) reported 2 outbreaks, and hospital E reported 16 norovirus outbreaks during this period. The hospital with a newer infrastructure (B), which reported 2 norovirus outbreaks, demonstrated that 7 bed-days had been lost over the 3-month period, compared with 512 bed-days lost by the hospital with an older, Nightingale-style infrastructure (E). Control measures included isolation, hand hygiene, environmental cleaning, and rapid diagnostic testing. Our data suggest that outbreak control is more difficult to achieve in a hospital with Nightingale-style wards and limited isolation facilities. PMID- 26744427 TI - Age-Specific Incidence Rates for Norovirus in the Community and Presenting to Primary Healthcare Facilities in the United Kingdom. AB - In a prospective, population-based cohort study and a study of primary-healthcare consultations, we had a rare opportunity to estimate age-specific rates of norovirus-associated infectious intestinal disease in the United Kingdom. Rates in children aged <5 years were significantly higher than those for other age groups in the community (142.6 cases per 1000 person-years [95% confidence interval {CI}, 99.8-203.9] vs 37.6 [95% CI, 31.5-44.7]) and those for individuals presenting to primary healthcare (14.4 cases per 1000 person-years [95% CI, 8.5 24.5] vs 1.4 [95% CI, .9-2.0]). Robust incidence estimates are crucial for vaccination policy makers. This study emphasises the impact of norovirus associated infectious intestinal disease, especially in children aged <5 years. PMID- 26744428 TI - Cost-effectiveness of Ward Closure to Control Outbreaks of Norovirus Infection in United Kingdom National Health Service Hospitals. AB - BACKGROUND: Norovirus is the most common cause of outbreaks of acute gastroenteritis in National Health Service hospitals in the United Kingdom. Wards (units) are often closed to new admissions to stop the spread of the virus, but there is limited evidence describing the cost-effectiveness of ward closure. METHODS: An economic analysis based on the results from a large, prospective, active-surveillance study of gastroenteritis outbreaks in hospitals and from an epidemic simulation study compared alternative ward closure options evaluated at different time points since first infection, assuming different efficacies of ward closure. RESULTS: A total of 232 gastroenteritis outbreaks occurring in 14 hospitals over a 1-year period were analyzed. The risk of a new outbreak in a hospital is significantly associated with the number of admission, general medical, and long-stay wards that are concurrently affected but is less affected by the level of community transmission. Ward closure leads to higher costs but reduces the number of new outbreaks by 6%-56% and the number of clinical cases by 1%-55%, depending on the efficacy of the intervention. The incremental cost per outbreak averted varies from L10 000 ($14 000) to L306 000 ($428 000), and the cost per case averted varies from L500 ($700) to L61 000 ($85 000). The cost effectiveness of ward closure decreases as the efficacy of the intervention increases, and the cost-effectiveness increases with the timing of the intervention. The efficacy of ward closure is critical from a cost-effectiveness perspective. CONCLUSIONS: Ward closure may be cost-effective, particularly if targeted to high-throughput units. PMID- 26744429 TI - Advances Toward a Norovirus Antiviral: From Classical Inhibitors to Lethal Mutagenesis. AB - Human noroviruses are a leading cause of gastroenteritis worldwide, yet there are no licensed antivirals. There is an urgent need for norovirus therapeutics, particularly for chronic infections in immunocompromised individuals, but also a potential need for prophylactic use in epidemics. Continued research has led to the identification of compounds that inhibit norovirus replication in vitro and, at least in some cases, are also effective in vivo against murine norovirus. Progress has included classical approaches targeting viral proteins and harnessing the antiviral action of interferon, strategies targeting essential host cell factors, and novel strategies exploiting the high mutation rate of noroviruses. PMID- 26744430 TI - Mapping Investments and Published Outputs in Norovirus Research: A Systematic Analysis of Research Funded in the United States and United Kingdom During 1997 2013. AB - BACKGROUND: Norovirus accounts for a considerable portion of the global disease burden. Mapping national or international investments relating to norovirus research is limited. METHODS: We analyzed the focus and type of norovirus research funding awarded to institutions in the United States and United Kingdom during 1997-2013. Data were obtained from key public and philanthropic funders across both countries, and norovirus-related research was identified from study titles and abstracts. Included studies were further categorized by the type of scientific investigation, and awards related to vaccine, diagnostic, and therapeutic research were identified. Norovirus publication trends are also described using data from Scopus. RESULTS: In total, US and United Kingdom funding investment for norovirus research was L97.6 million across 349 awards; 326 awards (amount, L84.9 million) were received by US institutions, and 23 awards (L12.6 million) were received by United Kingdom institutions. Combined, L81.2 million of the funding (83.2%) was for preclinical research, and L16.4 million (16.8%) was for translational science. Investments increased from L1.7 million in 1997 to L11.8 million in 2013. Publication trends showed a consistent temporal increase from 48 in 1997 to 182 in 2013. CONCLUSIONS: Despite increases over time, trends in US and United Kingdom funding for norovirus research clearly demonstrate insufficient translational research and limited investment in diagnostics, therapeutics, or vaccine research. PMID- 26744431 TI - Norovirus Surveillance: An Epidemiological Perspective. AB - Surveillance for norovirus is challenging because the nature of illness due to norovirus is such that the majority of people who are infected will not have any contact with medical services and are highly unlikely to have a sample collected for diagnosis. Public health advice urges people to not visit hospitals or their family physicians, to prevent the risk further spread. The recognition of the importance of this pathogen was quickly established following the introduction of surveillance of outbreaks of gastrointestinal infection in England and Wales in 1992. This period saw >1800 outbreaks of norovirus infection reported in hospitals in England, affecting >45 000 patients and staff. A new system for reporting outbreaks of norovirus infection in hospitals, the Hospital Norovirus outbreak Reporting Scheme (HNORS), began in January 2009. Summary information on outbreaks is provided by infection control staff at hospitals and includes questions on the date the first and last person in the outbreak became symptomatic and whether closure of a bay or ward was needed. In the first 3 years (2009-2011) of the HNORS surveillance scheme, 4000 outbreaks were reported, affecting 40 000 patients and 10 000 staff. Over the last 3 years, these outbreaks have been associated with an average of 13 000 patients and 3400 staff becoming ill, with 15 000 lost bed-days annually. With the possible introduction of a vaccine on the horizon, targeted research with a more integrated approach to laboratory testing and outbreak reporting is essential to a greater understanding of the epidemiology of norovirus. PMID- 26744432 TI - Dameshek W, Miller EB. The megakaryocytes in idiopathic thrombocytopenic purpura, a form of hypersplenism. 1946. AB - This paper, by one of the legends of hematology, William Dameshek, and his colleague Edward Miller, is from the inaugural issue of Blood. By studying bone marrow specimens from controls, patients with acute or chronic immune thrombocytopenia, or patients with other thrombocytopenic disorders, the authors concluded that, in idiopathic thrombocytopenic purpura (ITP), production of platelets from megakaryocytes is defective, even while marrow megakaryocytes are greatly increased in number. This defect resolved after splenectomy. The authors appropriately credit E. Frank with having proposed defective platelet production from megakaryocytes in ITP in 1915. The idea that platelet production was defective in ITP was superseded or ignored for decades, but it has now been validated by the therapeutic effectiveness of the thrombopoietin mimetics in ITP. PMID- 26744433 TI - Serendipity in splendid isolation: rapamycin. AB - In this issue of Blood, Bride et al report results of the first prospective multi institutional trial of a long-term single-agent therapy for refractory cytopenias using rapamycin in 30 patients and show remarkable efficacy in children with autoimmune lymphoproliferative syndrome (ALPS). PMID- 26744434 TI - Obinutuzumab: the more the merrier? AB - In this issue of Blood, Byrd et al present data from a randomized phase 2 study in which 78 previously untreated patients with chronic lymphocytic leukemia (CLL) received 8 cycles of either 1000 mg (the current standard dose) or 2000 mg of the anti-CD20 monoclonal antibody (mAb) obinutuzumab. The authors report a higher overall response rate with higher doses of obinutuzumab (67% vs 49%), but there was no significant difference in progression-free survival (PFS) between groups. PMID- 26744435 TI - Rebooting autoimmunity with autologous HSCT. AB - Autologous hematopoietic stem cell transplantation (HSCT) is increasingly used for severe autoimmune and inflammatory diseases, but the mechanisms involved have yet to be elucidated. In this issue of Blood, Delemarre et al report their findings in both animal and human models which provide insights into restoration of functionality and diversity within the regulatory T-cell (Treg) compartment following HSCT. PMID- 26744436 TI - Identifying risk factors for B-cell lymphoma. AB - In this issue of Blood, Melenotte and colleagues provide an interesting and provocative analysis of a potential novel risk factor for B-cell non-Hodgkin lymphoma (NHL). PMID- 26744437 TI - FcgammaRIII in ITP: it ain't over 'til it's over. AB - In this issue of Blood, Yu et al describe a novel anti-Fcgamma receptor III (FcgammaRIII)-albumin fusion protein that inhibits the development of thrombocytopenia in a murine model of immune thrombocytopenia (ITP).1 The unique aspect of this protein is that it blocks FcgammaRIII-mediated uptake of antibody coated platelets without activating FcgammaRIII and the associated inflammatory response. PMID- 26744439 TI - Predicting chronic GVHD outcomes: are we there yet? AB - In this issue of Blood, Palmer et al provide encouragement that important chronic graft-versus-host disease (GVHD) patient outcomes (such as overall survival [OS] and failure-free survival [FFS]) are predicted by clinician-assessed response, patient-reported outcomes, and 2014 National Institutes of Health (NIH)-response criteria. PMID- 26744438 TI - Unconventional cell death in erythroid cells. PMID- 26744440 TI - How to Apply for and Secure EU Funding for Collaborative IBD Research Projects. AB - The European Union offers opportunities for high-level of funding of collaborative European research. Calls are regularly published: after the end of the FP7 funding programme the new round of Horizon 2020 calls started in 2015. Several topics are relevant to inflammatory bowel disease (IBD) challenges, including chronic disease management, biomarker discovery and new treatments developments. The aim of this Viewpoint article is to describe the new Horizon 2020 instrument and the project submission procedures, and to highlight these through the description of tips and tricks, taking advantage of four examples of successful projects in the field of IBD: the SADEL, IBD-BIOM, IBD Character and BIOCYCLE projects. PMID- 26744441 TI - Preventing Collateral Damage in Crohn's Disease: The Lemann Index. AB - Crohn's disease [CD] is a chronic progressive and destructive condition. Half of all CD patients will develop bowel damage at 10 years. As in rheumatic diseases, preventing the organ damage consequent to CD complications [fistula, abscess, and/or stricture] is emerging as a new therapeutic goal for these patients in clinical practice. This might be the only way to alter disease course, as surgery is often required for disease complications. Similar to the joint damage in rheumatoid arthritis, bowel damage has also emerged as a new endpoint in disease modification trials such as the REACT trial. Recently, the Lemann Index [LI] has been developed to measure CD-related bowel damage, and to assess damage progression over time, in order to evaluate the impact of therapeutic strategies in terms of preventing bowel damage. While validation is pending, recent reports suggested that bowel damage is reversible by anti-tumour necrosis factor [TNF] therapy. The Lemann index may play a key role in CD management, and should be implemented in all upcoming disease-modification trials in CD. PMID- 26744442 TI - Computational Identification of Tumor Anatomic Location Associated with Survival in 2 Large Cohorts of Human Primary Glioblastomas. AB - BACKGROUND AND PURPOSE: Tumor location has been shown to be a significant prognostic factor in patients with glioblastoma. The purpose of this study was to characterize glioblastoma lesions by identifying MR imaging voxel-based tumor location features that are associated with tumor molecular profiles, patient characteristics, and clinical outcomes. MATERIALS AND METHODS: Preoperative T1 anatomic MR images of 384 patients with glioblastomas were obtained from 2 independent cohorts (n = 253 from the Stanford University Medical Center for training and n = 131 from The Cancer Genome Atlas for validation). An automated computational image-analysis pipeline was developed to determine the anatomic locations of tumor in each patient. Voxel-based differences in tumor location between good (overall survival of >17 months) and poor (overall survival of <11 months) survival groups identified in the training cohort were used to classify patients in The Cancer Genome Atlas cohort into 2 brain-location groups, for which clinical features, messenger RNA expression, and copy number changes were compared to elucidate the biologic basis of tumors located in different brain regions. RESULTS: Tumors in the right occipitotemporal periventricular white matter were significantly associated with poor survival in both training and test cohorts (both, log-rank P < .05) and had larger tumor volume compared with tumors in other locations. Tumors in the right periatrial location were associated with hypoxia pathway enrichment and PDGFRA amplification, making them potential targets for subgroup-specific therapies. CONCLUSIONS: Voxel-based location in glioblastoma is associated with patient outcome and may have a potential role for guiding personalized treatment. PMID- 26744443 TI - Imaging Features of Juvenile Xanthogranuloma of the Pediatric Head and Neck. AB - BACKGROUND AND PURPOSE: Juvenile xanthogranuloma is a non-Langerhans cell histiocytosis primarily affecting children. The purpose of this study was to characterize the imaging features of histologically confirmed pediatric head and neck juvenile xanthogranuloma. MATERIALS AND METHODS: A retrospective review was performed of medical records and imaging of histologically confirmed head and neck juvenile xanthogranuloma. RESULTS: Ten patients (6 girls, 4 boys) 1 month to 12 years of age were imaged with ultrasound only (n = 1), CT only (n = 2), CT and ultrasound (n = 1), MR imaging only (n = 3), or MR imaging and CT (n = 3). Masses were solitary in 9 patients and multiple in 1. Solitary masses were located in the external auditory canal, infra-auricular region, infratemporal fossa with intracranial extension, frontal scalp, and subperiosteal space eroding the calvaria and along the dura. One patient with disseminated disease had scalp-, calvarial-, and dural-based masses. Clinical presentation included a mass or alteration in function. On sonography, juvenile xanthogranuloma appeared hypoechoic. On contrast-enhanced CT, masses appeared homogeneous and isoattenuating with muscle and sometimes eroded bone. On MR imaging, compared with the cerebral cortex, the masses appeared hyper- or isointense on T1 and hypo or isointense on T2, had decreased diffusivity, and enhanced homogeneously. Juvenile xanthogranuloma was not included in the differential diagnosis in any case. CONCLUSIONS: Head and neck juvenile xanthogranuloma has varied manifestations. Mild hyperintensity on T1, hypointensity on T2 compared with the cerebral cortex, decreased diffusivity, and homogeneous enhancement are characteristic. Awareness of these features should prompt radiologists to include juvenile xanthogranuloma in the differential diagnosis of pediatric head and neck masses. PMID- 26744444 TI - Improved Lesion Detection by Using Axial T2-Weighted MRI with Full Spinal Cord Coverage in Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: Identification of lesions in specific locations gains importance in multiple sclerosis imaging diagnostic criteria. In clinical routine, axial scans are usually exclusively obtained to depict the cervical spinal cord or used to confirm suspected lesions on sagittal scans. We sought to evaluate the detection rate for MS lesions on axial T2WI scans with full spinal cord coverage in comparison with sagittal scans. MATERIALS AND METHODS: One hundred fifteen patients with definite or suspected MS underwent an MR imaging examination including 3-mm sagittal and 3.5-mm axial T2-weighted images with full spinal cord coverage. T2WI lesions were identified on axial and sagittal scans independently by 2 raters. Axial diameter, craniocaudal extension, lesion intensity, and location were analyzed. RESULTS: Four hundred forty-nine of 509 (88.2%) lesions were detected on axial and 337/509 (66.2%) on sagittal scans. Only 277/449 (61.7%) axial lesions were also detected on sagittal images. The number of lesions visible on sagittal and axial images was dependent on the axial lesion diameter (P < .001). CONCLUSIONS: Axial T2WI scans with full spinal cord coverage showed 22% more lesions in patients with MS in comparison with sagittal scans, especially for lesions with small axial diameters. We suggest including biplanar spinal MR imaging with full spinal cord coverage for lesion detection in MS in clinical routine and for clinical studies. PMID- 26744446 TI - Application of Normative Occipital Condyle-C1 Interval Measurements to Detect Atlanto-Occipital Injury in Children. AB - BACKGROUND AND PURPOSE: Prior studies have found that widening or asymmetry of the occipital condyle-C1 interval on CT is a sensitive and specific marker for atlanto-occipital dislocation. Previously reported abnormal occipital condyle-C1 interval values are not age-specific, possibly leading to false-positive findings in younger children, in whom this joint space is normally larger than that in adults. This study assesses the utility of applying age-specific normative occipital condyle-C1 interval ranges to documented cases of atlanto-occipital injury compared with previously reported abnormal cutoff values. MATERIALS AND METHODS: Retrospective review of CT and MR imaging of 14 subjects with atlanto occipital injury was performed, and occipital condyle-C1 interval measurements were made for each subject. Sensitivities and specificities of proposed occipital condyle-C1 interval cutoffs of 2 and 3 SDs above the mean and previously published occipital condyle-C1 interval cutoffs for atlanto-occipital injury were then calculated on the basis of occipital condyle-C1 interval measurements for each subject. RESULTS: An occipital condyle-C1 interval 2 SDs above the age specific mean has a sensitivity of 50% and specificity of 89%-100%, depending on the age group. An occipital condyle-C1 interval 3 SDs above the age-specific mean has a sensitivity of 50% and a specificity of 95%-100%. A 4.0-mm occipital condyle-C1 interval has a sensitivity of 36% and a specificity of 100% in all age groups. A 2.5-mm occipital condyle-C1 interval has a sensitivity of 93% and a specificity of 18%-100%. CONCLUSIONS: Occipital condyle-C1 interval widening cutoffs used to establish atlanto-occipital injury lack both sensitivity and specificity in children and young teenagers. MR imaging is necessary to establish a diagnosis of atlanto-occipital injury in children and young teenagers when the appropriate mechanism of injury is present. PMID- 26744445 TI - Distinguishing Neuroimaging Features in Patients Presenting with Visual Hallucinations. AB - Visual hallucinations are relatively uncommon presentations in medical and psychiatric clinics, where they are generally regarded as a marker of possible underlying "organic" brain disease. Thus, patients with visual hallucinations are often referred for imaging of the brain. This article presents a pragmatic approach for the radiologist reviewing such imaging. Because conditions that can present with visual hallucinations are legion, a familiarity with the features of the hallucinations themselves, which can serve as clues to the underlying cause, can be helpful in interpreting such cases. We consider the nature of visual hallucinations and the mechanisms underlying their formation. We then provide a framework to guide the search for their cause, first in terms of focal lesions along the visual pathway and then global conditions affecting >1 region. PMID- 26744447 TI - Myelography CPT Coding Updates: Effects of 4 New Codes and Unintended Consequences. AB - The Current Procedural Terminology of the American Medical Association has recently introduced coding changes for myelography with the introduction of new bundled codes. The aim of this review was to help neuroradiologists understand these code changes and their unintended consequences and to discuss various scenarios in which permutations of various codes could occur in clinical practice. PMID- 26744448 TI - Catalyzing Cancer Prevention Research CaPR: A New Year/New Opportunities. PMID- 26744450 TI - Correction: Durable Antibody Responses Following One Dose of the Bivalent Human Papillomavirus L1 Virus-Like Particle Vaccine in the Costa Rica Vaccine Trial. PMID- 26744451 TI - CCRL2 regulates M1/M2 polarization during EAE recovery phase. AB - Chemokine (CC motif) receptor-like 2 is a 7-transmembrane protein related to the family of the atypical chemokine receptors, which are proteins devoid of chemotactic activity and involved in the control of inflammation. Experimental autoimmune encephalitis is an autoimmune disorder that replicates the inflammatory aspects of multiple sclerosis. Chemokine (CC motif) receptor-like 2 deficient mice developed exacerbated, nonresolving disease with protracted inflammatory response and increased demyelination. The increased severity of the disease was associated with higher levels of microglia/macrophage activation markers and imbalanced M1/M2 polarization. Thus, chemokine (CC motif) receptor like 2 is involved in the downregulation of central nervous system-associated experimental autoimmune encephalitis inflammation in the recovery phase of the disease. Therefore chemokine (CC motif) receptor-like 2 should be considered to be a molecule involved in the regulation of the inflammatory response associated with multiple sclerosis. PMID- 26744452 TI - CD26/dipeptidylpeptidase IV-chemokine interactions: double-edged regulation of inflammation and tumor biology. AB - Post-translational modification of chemokines is an essential regulatory mechanism to enhance or dampen the inflammatory response. CD26/dipeptidylpeptidase IV, ubiquitously expressed in tissues and blood, removes NH2-terminal dipeptides from proteins with a penultimate Pro or Ala. A large number of human chemokines, including CXCL2, CXCL6, CXCL9, CXCL10, CXCL11, CXCL12, CCL3L1, CCL4, CCL5, CCL11, CCL14, and CCL22, are cleaved by CD26; however, the efficiency is clearly influenced by the amino acids surrounding the cleavage site and although not yet proven, potentially affected by the chemokine concentration and interactions with third molecules. NH2-terminal cleavage of chemokines by CD26 has prominent effects on their receptor binding, signaling, and hence, in vitro and in vivo biologic activities. However, rather than having a similar result, the outcome of NH2-terminal truncation is highly diverse. Either no difference in activity or drastic alterations in receptor recognition/specificity and hence, chemotactic activity are observed. Analogously, chemokine-dependent inhibition of HIV infection is enhanced (for CCL3L1 and CCL5) or decreased (for CXCL12) by CD26 cleavage. The occurrence of CD26-processed chemokine isoforms in plasma underscores the importance of the in vitro-observed CD26 cleavages. Through modulation of chemokine activity, CD26 regulates leukocyte/tumor cell migration and progenitor cell release from the bone marrow, as shown by use of mice treated with CD26 inhibitors or CD26 knockout mice. As chemokine processing by CD26 has a significant impact on physiologic and pathologic processes, application of CD26 inhibitors to affect chemokine function is currently explored, e.g., as add-on therapy in viral infection and cancer. PMID- 26744449 TI - Transforming Cancer Prevention through Precision Medicine and Immune-oncology. AB - We have entered a transformative period in cancer prevention (including early detection). Remarkable progress in precision medicine and immune-oncology, driven by extraordinary recent advances in genome-wide sequencing, big-data analytics, blood-based technologies, and deep understanding of the tumor immune microenvironment (TME), has provided unprecedented possibilities to study the biology of premalignancy. The pace of research and discovery in precision medicine and immunoprevention has been astonishing and includes the following clinical firsts reported in 2015: driver mutations detected in circulating cell free DNA in patients with premalignant lesions (lung); clonal hematopoiesis shown to be a premalignant state; molecular selection in chemoprevention randomized controlled trial (RCT; oral); striking efficacy in RCT of combination chemoprevention targeting signaling pathway alterations mechanistically linked to germline mutation (duodenum); molecular markers for early detection validated for lung cancer and showing promise for pancreatic, liver, and ovarian cancer. Identification of HPV as the essential cause of a major global cancer burden, including HPV16 as the single driver of an epidemic of oropharyngeal cancer in men, provides unique opportunities for the dissemination and implementation of public health interventions. Important to immunoprevention beyond viral vaccines, genetic drivers of premalignant progression were associated with increasing immunosuppressive TME; and Kras vaccine efficacy in pancreas genetically engineered mouse (GEM) model required an inhibitory adjuvant (Treg depletion). In addition to developing new (e.g., epigenetic) TME regulators, recent mechanistic studies of repurposed drugs (aspirin, metformin, and tamoxifen) have identified potent immune activity. Just as precision medicine and immune-oncology are revolutionizing cancer therapy, these approaches are transforming cancer prevention. Here, we set out a brief agenda for the immediate future of cancer prevention research (including a "Pre-Cancer Genome Atlas" or "PCGA"), which will involve the inter-related fields of precision medicine and immunoprevention - pivotal elements of a broader domain of personalized public health. PMID- 26744453 TI - Drought Impacts on Competition in Phoetaliotes nebrascensis (Orthoptera Acrididae) in a Northern Mixed Grassland. AB - Global climate change is predicted to significantly modify patterns of precipitation, making it critical to develop a better understanding of how this will modify biotic interactions. Short-term to decadal-scale weather patterns can impact grasshopper population dynamics, but drought impacts on grasshoppers have rarely been studied in manipulative experiments. A cage experiment was conducted in eastern Montana to examine the impact of intra- and interspecific competition and precipitation manipulation treatments on performance of a common melanopline grasshopper Phoetaliotes nebrascensis (Thomas). High-density and drought treatments had similarly strong negative impacts on food availability. Proportional grasshopper survival did not differ significantly by treatment, but density dependence was evident in both body size and reproductive traits. The impact of precipitation and density treatments on grasshopper body size and reproduction were typically similar in magnitude and much larger than interspecific competition, with the exception of male femur length. Even with high late summer precipitation, drought had strong effects on individual body size and future reproduction. This study provides valuable information on population dynamics of an abundant grasshopper, with moderate precipitation reductions negatively affecting reproduction and body size. No positive impacts of drought as predicted by the plant stress hypothesis were observed. The study reinforces the need to examine drought manipulations to better predict grasshopper population changes due to changing climate conditions. PMID- 26744455 TI - Mischler et al. Epidemiology of Bacteremia in Previously Healthy Febrile Infants: A Follow-up Study. Hospital Pediatrics 2015;5(6):293-300. PMID- 26744454 TI - Cold Tolerance of Halyomorpha halys (Hemiptera: Pentatomidae) Across Geographic and Temporal Scales. AB - The brown marmorated stink bug, Halyomorpha halys (Stal), is native to eastern Asia and is presently invading North America. Little is known about the exposure to and effects of winter temperatures in newly invaded regions on H. halys The overwintering habitats that this species utilizes vary greatly in their thermal buffering capacity. They naturally overwinter in aggregations beneath loose bark on trees and in cliff outcroppings, but will also commonly aggregate in buildings. Effects of cold temperatures such as mortality and freezing have yet to be quantified in the invading population. We report that H. halys is chill intolerant (i.e., dies before reaching its freezing point), and that the degree of cold tolerance of populations in North America differs by season, sex, and acclimation location. The mean winter supercooling point (+/- SEM) of individuals acclimated in Minnesota was -17.06 degrees C +/- 0.13 and in Virginia was -13.90 degrees C +/- 0.09. By using laboratory assays of lower lethal temperatures and ambient air temperature records, we accurately forecasted mortality for field experiments in Minnesota and Virginia. Temperature refugia provided by human built structures are likely crucial for overwintering survival during atypically cold winters and possibly contribute to the northern geographic range expansion of this economically damaging insect in the temperate climates of North America. PMID- 26744456 TI - SIDT2 is involved in the NAADP-mediated release of calcium from insulin secretory granules. AB - The Sidt2 global knockout mouse (Sidt2(-/-)) has impaired insulin secretion. The aim of this study was to assess the role of SIDT2 protein in glucose-induced insulin secretion in primary cultured mouse beta-cells. The major metabolic and electrophysiological steps of glucose-induced insulin secretion of primary cultured beta-cells from Sidt2(-/-) mice were investigated. The beta-cells from Sidt2(-/-) mice had normal NAD(P)H responses and KATP and KV currents. However, they exhibited a lower [Ca(2+)]i peak height when stimulated with 20mM glucose compared with those from WT mice. Furthermore, it took a longer time for the [Ca(2+)]i of beta-cell from Sidt2(-/-) mice to reach the peak. Pretreatment with ryanodine or 2-aminoethoxydiphenyl borate (2-APB) did not change [Ca(2+)]i the response pattern to glucose in Sidt2(-/-) cells. Extraordinarily, pretreatment with bafilomycin A1(Baf-A1) led to a comparable [Ca(2+)]i increase pattern between these two groups, suggesting that calcium traffic from the intracellular acidic compartment is defective in Sidt2(-/-) beta-cells. Bath-mediated application of 50nM nicotinic acid adenine dinucleotide phosphate (NAADP) normalized the [Ca(2+)]i response of Sidt2(-/-) beta-cells. Finally, glucose induced CD38 expression increased to a comparable level between Sidt2(-/-) and WT islets, suggesting that Sidt2(-/-) islets generated NAADP normally. We conclude that Sidt2 is involved in NAADP-mediated release of calcium from insulin secretory granules and thus regulates insulin secretion. PMID- 26744457 TI - Transcatheter treatment of severe tricuspid regurgitation with the MitraClip system. AB - AIM: The aim of this study was to show technical principles and feasibility of transcatheter tricuspid valve repair by use of the MitraClip system. METHODS AND RESULTS: Three consecutive patients were treated successfully for severe symptomatic Tricuspid regurgitation. Three-dimensional transoesophageal echocardiography confirmed reduction of measured effective regurgitant orifice in all patients [effective regurgitant orifice area-baseline/post-procedure (cm(2)): 0.7/0.3; 1.5/0.8; 0.4/0.1], which was accompanied by an increase in left ventricular stroke volumes [baseline/post-procedure (mL): 42.8/45.4; 38/45; 35.2/45], decrease of measured levels of N terminal pro brain natriuretic peptide (pg/mL: baseline/post-procedure: 548/440; 2526/1702; 1754/623), and significant relief of clinical symptoms for chronic right heart failure in all patients. CONCLUSIONS: Transcatheter tricuspid valve repair by use of interventional edge to-edge repair with the MitraClip system was feasible, and safe in three consecutive patients. Reduction of tricuspid insufficiency associates with relief of clinical symptoms for right heart failure. This strategy seems a promising treatment option for patients at prohibitive surgical risk. PMID- 26744458 TI - High-dose dexamethasone corrects impaired myeloid-derived suppressor cell function via Ets1 in immune thrombocytopenia. AB - Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature cells and natural inhibitors of adaptive immunity. In this study, the MDSC population was evaluated in adult patients with primary immune thrombocytopenia (ITP), where cell-mediated immune mechanisms are involved in platelet destruction. Our data demonstrated that both the numbers and suppressive functions of MDSCs were impaired in the peripheral blood and spleens of patients with ITP compared with healthy control patients. High-dose dexamethasone (HD-DXM) treatment rescued MDSC numbers in patients with ITP. And DXM modulation promoted the suppressive function of MDSCs induced in vitro. Moreover, the expression of interleukin 10 and transforming growth factor beta was significantly upregulated in DXM modulated MDSCs compared with the unmodulated cultures. DXM-modulated MDSCs inhibited autologous CD4(+)T-cell proliferation and significantly attenuated cytotoxic T lymphocyte-mediated platelet lysis, further indicating enhanced control over T-cell responses. Elevated expression of the transcription factor Ets1 was identified in DXM-modulated MDSCs. Transfection of Ets-1 small interfering RNA efficiently blocked regulatory effects of MDSCs, which almost offset the augmentation of MDSC function by DXM. Meanwhile, splenocytes from CD61 knockout mice immunized with CD61(+)platelets were transferred into severe combined immunodeficient (SCID) mouse recipients (C57/B6 background) to induce a murine model of severe ITP. We passively transferred the DXM-modulated MDSCs induced from bone marrow of wild-type C57/B6 mice into the SCID mouse recipients, which significantly increased platelet counts in vivo compared with those receiving splenocyte engraftment alone. These findings suggested that impaired MDSCs are involved in the pathogenesis of ITP, and that HD-DXM corrected MDSC functions via a mechanism underlying glucocorticoid action and Ets1. PMID- 26744459 TI - Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. AB - Genetic disorders affecting biogenesis and transport of lysosome-related organelles are heterogeneous diseases frequently associated with albinism. We studied a patient with albinism, neutropenia, immunodeficiency, neurodevelopmental delay, generalized seizures, and impaired hearing but with no mutation in genes so far associated with albinism and immunodeficiency. Whole exome sequencing identified a homozygous mutation in AP3D1 that leads to destabilization of the adaptor protein 3 (AP3) complex. AP3 complex formation and the degranulation defect in patient T cells were restored by retroviral reconstitution. A previously described hypopigmented mouse mutant with an Ap3d1 null mutation (mocha strain) shares the neurologic phenotype with our patient and shows a platelet storage pool deficiency characteristic of Hermansky-Pudlak syndrome (HPS) that was not studied in our patient because of a lack of bleeding. HPS2 caused by mutations in AP3B1A leads to a highly overlapping phenotype without the neurologic symptoms. The AP3 complex exists in a ubiquitous and a neuronal form. AP3D1 codes for the AP3delta subunit of the complex, which is essential for both forms. In contrast, the AP3beta3A subunit, affected in HPS2 patients, is substituted by AP3beta3B in the neuron-specific heterotetramer. AP3delta deficiency thus causes a severe neurologic disorder with immunodeficiency and albinism that we propose to classify as HPS10. PMID- 26744460 TI - The clinical significance of EBV DNA in the plasma and peripheral blood mononuclear cells of patients with or without EBV diseases. AB - Epstein-Barr virus (EBV) is a ubiquitous virus that establishes a latent infection within the host and in some cases can lead to the development of EBV associated lymphomas, lymphoproliferative disorders, hemophagocytic lymphohistiocytosis, solid tumors, and other diseases. We studied the clinical significance of detecting EBV DNA in the plasma and peripheral blood mononuclear cells (PBMCs) of 2146 patients who had blood specimens sent to the Johns Hopkins Hospital clinical laboratory for viral quantitative real-time polymerase chain reaction assay over a 5-year period. Within this largely immunocompromised and hospitalized cohort, 535 patients (25%) had EBV detected in plasma or PBMCs. When EBV was detected in the absence of an EBV(+)disease (n = 402), it was present only in PBMCs in 69% of cases. Immunocompromised patients were less likely to have EBV in plasma than in PBMCs in the absence of EBV(+)disease. In patients with active, systemic EBV(+)diseases (n = 105), EBV was detected in plasma in 99% of cases but detected in PBMCs in only 54%. Across a range of copy number cutoffs, EBV in plasma had higher specificity and sensitivity for EBV(+)disease as compared with EBV in PBMCs. EBV copy number in plasma distinguished untreated, EBV(+)lymphoma from EBV(+)lymphoma in remission and EBV(-)lymphoma, and also distinguished untreated, EBV(+)posttransplantation lymphoproliferative disorder (PTLD) from EBV(+)PTLD in remission and EBV(-)PTLD. EBV copy number quantification is a useful diagnostic marker across the spectrum of EBV(+)diseases, even among immunocompromised patients, with plasma specimens more indicative of EBV(+)disease than PBMCs. PMID- 26744462 TI - Disabled children risk further abuse after unsubstantiated referral for neglect, research finds. PMID- 26744463 TI - National Institute of Justice: investment in career development. PMID- 26744464 TI - Specifying Pathogen Associations of Amblyomma maculatum (Acari: Ixodidae) in Western Tennessee. AB - Amblyomma maculatum Koch (Acari: Ixodidae) is established in western Tennessee, a region with increased risk for Rocky Mountain spotted fever and ehrlichiosis. This tick transmits Rickettsia parkeri to humans, likely contributing to cases of rickettsiosis in the region. The objective was to determine pathogen associations within questing and host-collected A. maculatum, and identify ecological factors associated with pathogen infection that may increase the effectiveness of surveillance methods. Of 265 ticks tested, 60 (22.6%) were infected with R. parkeri, and 15 (5.7%) with Candidatus Rickettsia andeanae, a Rickettsia of unknown pathogenicity. Two deer-collected ticks tested positive for Ehrlichia ewingii. No ticks were positive for Anaplasma or Borrelia species. None of the ecological factors tested (collection month, collection source, sex, and habitat type) were associated with R. parkeri infection. This project developed baseline prevalence and incidence data for monitoring pathogen prevalence in A. maculatum populations, and identified an inexpensive method for distinguishing R. parkeri from Ca. R. andeanae. PMID- 26744461 TI - Synthesis and dephosphorylation of MARCKS in the late stages of megakaryocyte maturation drive proplatelet formation. AB - Platelets are essential for hemostasis, and thrombocytopenia is a major clinical problem. Megakaryocytes (MKs) generate platelets by extending long processes, proplatelets, into sinusoidal blood vessels. However, very little is known about what regulates proplatelet formation. To uncover which proteins were dynamically changing during this process, we compared the proteome and transcriptome of round vs proplatelet-producing MKs by 2D difference gel electrophoresis (DIGE) and polysome profiling, respectively. Our data revealed a significant increase in a poorly-characterized MK protein, myristoylated alanine-rich C-kinase substrate (MARCKS), which was upregulated 3.4- and 5.7-fold in proplatelet-producing MKs in 2D DIGE and polysome profiling analyses, respectively. MARCKS is a protein kinase C (PKC) substrate that binds PIP2. In MKs, it localized to both the plasma and demarcation membranes. MARCKS inhibition by peptide significantly decreased proplatelet formation 53%. To examine the role of MARCKS in the PKC pathway, we treated MKs with polymethacrylate (PMA), which markedly increased MARCKS phosphorylation while significantly inhibiting proplatelet formation 84%, suggesting that MARCKS phosphorylation reduces proplatelet formation. We hypothesized that MARCKS phosphorylation promotes Arp2/3 phosphorylation, which subsequently downregulates proplatelet formation; both MARCKS and Arp2 were dephosphorylated in MKs making proplatelets, and Arp2 inhibition enhanced proplatelet formation. Finally, we used MARCKS knockout (KO) mice to probe the direct role of MARCKS in proplatelet formation; MARCKS KO MKs displayed significantly decreased proplatelet levels. MARCKS expression and signaling in primary MKs is a novel finding. We propose that MARCKS acts as a "molecular switch," binding to and regulating PIP2 signaling to regulate processes like proplatelet extension (microtubule-driven) vs proplatelet branching (Arp2/3 and actin polymerization-driven). PMID- 26744465 TI - Panola Mountain Ehrlichia in Amblyomma maculatum From the United States and Amblyomma variegatum (Acari: Ixodidae) From the Caribbean and Africa. AB - Panola Mountain Ehrlichia (PME) has been suggested as an emerging pathogen of humans and dogs. Domestic goats and white-tailed deer (Odocoileus virginianus) are also susceptible and likely serve as reservoirs. Experimentally, both the lone star tick (Amblyomma americanum (L.)) and the Gulf Coast tick (Amblyomma maculatum Koch) can transmit PME among deer and goats. In the current study, we detected PME in adult wild-caught A. maculatum from the United States and Amblyomma variegatum (F.) from the Caribbean and Africa. This significantly expands the range, potential tick vectors, and risk for exposure to PME. PMID- 26744466 TI - A Revised Checklist of Chigger Mites (Acari: Trombiculidae) From Thailand, with the Description of Three New Species. AB - Chigger mites of Thailand were studied on the basis of larvae collected from 19 small mammal species (17 species of Rodentia, 1 species of Erinaceomorpha, and 1 species of Scandentia) and revision of published data. Samples of 38 trombiculid species were collected from 11 provinces. Three new species were described: Trombiculindus kosapani sp. nov., Helenicula naresuani sp. nov., and Walchia chavali sp. nov. Ten species were recorded in Thailand for the first time: Leptotrombidium sialkotense Vercammen-Grandjean and Langston, 1976; Leptotrombidium subangulare Wen and Xiang, 1984; Leptotrombidium tenompaki Stekolnikov, 2013; Leptotrombidium turdicola Vercammen-Grandjean and Langston, 1976; Leptotrombidium yunlingense Yu, Yang, Zhang and Hu, 1981; Lorillatum hekouensis Yu, Chen and Lin, 1996; Helenicula pilosa (Abonnenc and Taufflieb, 1957); Gahrliepia xiaowoi Wen and Xiang, 1984; Walchia minuscuta Chen, 1978; and Walchia ventralis (Womersley, 1952). In all, 99 chigger mite species were considered; the presence of 93 species was established in Thailand by original data or properly documented records in the scientific literature. Evidence for 64 species records of 147 from a previous checklist of Thai chiggers (Tanskul 1993) remains unknown. Distribution of chigger species by geographical regions of Thailand is discussed. PMID- 26744467 TI - Oral antifungal is associated with increased risk of miscarriage. PMID- 26744468 TI - Mice with hepatocyte-specific FXR deficiency are resistant to spontaneous but susceptible to cholic acid-induced hepatocarcinogenesis. AB - Farnesoid X receptor (FXR) belongs to the nuclear receptor superfamily with its endogenous ligands bile acids. Mice with whole body FXR deficiency develop liver tumors spontaneously, but the underlying mechanism is unclear. Moreover, it is unknown whether FXR deficiency in liver alone serves as a tumor initiator or promoter during liver carcinogenesis. This study aims to evaluate the effects of hepatocyte-specific FXR deficiency (FXR(hep-/-)) in liver tumor formation. The results showed that FXR(hep-/-) mice did not show spontaneous liver tumorigenesis with aging (up to 24 mo of age). Therefore FXR(hep-/-) mice were fed a bile acid (cholic acid)-containing diet alone or along with a liver tumor initiator, diethylnitrosamine (DEN). Thirty weeks later, no tumors were found in wild-type or FXR(hep-/-) mice without any treatment or with DEN only. However, with cholic acid, while only some wild-type mice developed tumors, all FXR(hep-/-) mice presented with severe liver injury and tumors. Interestingly, FXR(hep-/-) mouse livers increased basal expression of tumor suppressor p53 protein, apoptosis, and decreased basal cyclin D1 expression, which may prevent tumor development in FXR(hep-/-) mice. However, cholic acid feeding reversed these effects in FXR(hep /-) mice, which is associated with an increased cyclin D1 and decreased cell cycle inhibitors. More in-depth analysis indicates that the increased in cell growth might result from disturbance of the MAPK and JAK/Stat3 signaling pathways. In conclusion, this study shows that hepatic FXR deficiency may only serve as a tumor initiator, and increased bile acids is required for tumor formation likely by promoting cell proliferation. PMID- 26744470 TI - Involvement of myristoylated alanine-rich C kinase substrate phosphorylation and translocation in cholecystokinin-induced amylase release in rat pancreatic acini. AB - Cholecystokinin (CCK) is a gastrointestinal hormone that induces exocytotic amylase release in pancreatic acinar cells. The activation of protein kinase C (PKC) is involved in the CCK-induced pancreatic amylase release. Myristoylated alanine-rich C kinase substrate (MARCKS) is a ubiquitously expressed substrate of PKC. MARCKS has been implicated in membrane trafficking in several cell types. The phosphorylation of MARCKS by PKC results in the translocation of MARCKS from the membrane to the cytosol. Here, we studied the involvement of MARCKS in the CCK-induced amylase release in rat pancreatic acini. Employing Western blotting, we detected MARCKS protein in the rat pancreatic acini. CCK induced MARCKS phosphorylation. A PKC-delta inhibitor, rottlerin, inhibited the CCK-induced MARCKS phosphorylation and amylase release. In the translocation assay, we also observed CCK-induced PKC-delta activation. An immunohistochemistry study showed that CCK induced MARCKS translocation from the membrane to the cytosol. When acini were lysed by a detergent, Triton X-100, CCK partially induced displacement of the MARCKS from the GM1a-rich detergent-resistant membrane fractions (DRMs) in which Syntaxin2 is distributed. A MARCKS-related peptide inhibited the CCK induced amylase release. These findings suggest that MARCKS phosphorylation by PKC-delta and then MARCKS translocation from the GM1a-rich DRMs to the cytosol are involved in the CCK-induced amylase release in pancreatic acinar cells. PMID- 26744469 TI - Giardia duodenalis induces paracellular bacterial translocation and causes postinfectious visceral hypersensitivity. AB - Irritable bowel syndrome (IBS) is the most frequent functional gastrointestinal disorder. It is characterized by abdominal hypersensitivity, leading to discomfort and pain, as well as altered bowel habits. While it is common for IBS to develop following the resolution of infectious gastroenteritis [then termed postinfectious IBS (PI-IBS)], the mechanisms remain incompletely understood. Giardia duodenalis is a cosmopolitan water-borne enteropathogen that causes intestinal malabsorption, diarrhea, and postinfectious complications. Cause-and effect studies using a human enteropathogen to help investigate the mechanisms of PI-IBS are sorely lacking. In an attempt to establish causality between giardiasis and postinfectious visceral hypersensitivity, this study describes a new model of PI-IBS in neonatal rats infected with G. duodenalis At 50 days postinfection with G. duodenalis (assemblage A or B), long after the parasite was cleared, rats developed visceral hypersensitivity to luminal balloon distension in the jejunum and rectum, activation of the nociceptive signaling pathway (increased c-fos expression), histological modifications (villus atrophy and crypt hyperplasia), and proliferation of mucosal intraepithelial lymphocytes and mast cells in the jejunum, but not in the rectum. G. duodenalis infection also disrupted the intestinal barrier, in vivo and in vitro, which in turn promoted the translocation of commensal bacteria. Giardia-induced bacterial paracellular translocation in vitro correlated with degradation of the tight junction proteins occludin and claudin-4. The extensive observations associated with gut hypersensitivity described here demonstrate that, indeed, in this new model of postgiardiasis IBS, alterations to the gut mucosa and c-fos are consistent with those associated with PI-IBS and, hence, offer avenues for new mechanistic research in the field. PMID- 26744471 TI - MicroRNA-155 deletion promotes tumorigenesis in the azoxymethane-dextran sulfate sodium model of colon cancer. AB - Clinical studies have linked microRNA-155 (miR-155) expression in the tumor microenvironment to poor prognosis. However, whether miR-155 upregulation is predictive of a pro- or antitumorigenic response is unclear, as the limited preclinical data available remain controversial. We examined miR-155 expression in tumor tissue from colon cancer patients. Furthermore, we investigated the role of this microRNA in proliferation and apoptosis, inflammatory processes, immune cell populations, and transforming growth factor-beta/SMAD signaling in a chemically induced (azoxymethane-dextran sulfate sodium) mouse model of colitis associated colon cancer. We found a higher expression of miR-155 in the tumor region than in nontumor colon tissue of patients with colon cancer. Deletion of miR-155 in mice resulted in a greater number of polyps/adenomas, an increased symptom severity score, a higher grade of epithelial dysplasia, and a decrease in survival. Surprisingly, these findings were associated with an increase in apoptosis in the normal mucosa, but there was no change in proliferation. The protumorigenic effects of miR-155 deletion do not appear to be driven solely by dysregulation of inflammation, as both genotypes had relatively similar levels of inflammatory mediators. The enhanced tumorigenic response in miR-155(-/-) mice was associated with alterations in macrophages and neutrophils, as markers for these populations were decreased and increased, respectively. Furthermore, we demonstrated a greater activation of the transforming growth factor-beta/SMAD pathway in miR-155(-/-) mice, which was correlated with the increased tumorigenesis. Given the multiple targets of miR-155, careful evaluation of its role in tumorigenesis is necessary prior to any consideration of its potential as a biomarker and/or therapeutic target in colon cancer. PMID- 26744473 TI - Interferon-gamma is increased in the gut of patients with irritable bowel syndrome and modulates serotonin metabolism. AB - Mucosal immune activation and altered serotonin metabolism participate in the pathophysiology of irritable bowel syndrome (IBS). However, the reciprocal interplay between these two systems remains unknown. We evaluated the expression and release of interferon (IFN)-gamma from the colonic mucosa of patients with IBS and its impact on serotonin reuptake transporter (SERT) gene expression in Caco-2 cells. qPCR was used to evaluate IFN-gamma gene expression in colonic mucosal biopsies, whereas IFN-gamma protein amount was assessed by ELISA. Colonic T box expressed in T cells (T-bet) and phosphorylated signal transducer and activator of transcription 4 protein amount were evaluated by Western blot. The impact of colonic mucosal mediators on SERT gene expression was evaluated in Caco 2 cells using qPCR. IFN-gamma receptor was silenced in Caco-2 cells to determine the effect of IFN-gamma released by mucosal biopsies. Compared with asymptomatic controls (ACs), the expression of IFN-gamma gene and its transcription factor T bet were markedly increased in the colonic mucosa of patients with IBS. Compared with ACs, IFN-gamma protein tissue levels and its release by mucosal biopsies were significantly increased in IBS. The exposure of Caco-2 cells to IBS supernatants induced a significant decrease in SERT gene expression, independently of IBS subtypes, compared with AC mucosal supernatants. In Caco-2 cells, IFN-gamma receptor silencing reversed the reduction of SERT expression evoked by IBS supernatants vs. nonsilenced cell lines. IFN-gamma gene, its transcription factor T-bet, IFN-gamma protein expression, and its release are increased in the colonic mucosa of patients with IBS and downregulate SERT gene expression in vitro. These results suggest that IFN-gamma downregulates SERT expression, hence likely playing a role in altered serotonin metabolism of patients with IBS. PMID- 26744475 TI - Seven days in medicine: 2-8 January. PMID- 26744474 TI - Role of epithelial ion transports in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with a complex pathogenesis. Diarrhea is a highly prevalent and often debilitating symptom of IBD patients that results, at least in part, from an intestinal hydroelectrolytic imbalance. Evidence suggests that reduced electrolyte absorption is more relevant than increased secretion to this disequilibrium. This systematic review analyses and integrates the current evidence on the roles of epithelial Na(+)-K(+)-ATPase (NKA), Na(+)/H(+) exchangers (NHEs), epithelial Na(+) channels (ENaC), and K(+) channels (KC) in IBD-associated diarrhea. NKA is the key driving force of the transepithelial ionic transport and its activity is decreased in IBD. In addition, the downregulation of apical NHE and ENaC and the upregulation of apical large-conductance KC all contribute to the IBD-associated diarrhea by lowering sodium absorption and/or increasing potassium secretion. PMID- 26744476 TI - Junior doctors' contract: the sticking points in negotiations. PMID- 26744472 TI - Urocortins and CRF receptor type 2 variants in the male rat colon: gene expression and regulation by endotoxin and anti-inflammatory effect. AB - Urocortins (Ucns) 1, 2, and 3 and corticotropin-releasing factor receptor 2 (CRF2) mRNA are prominently expressed in various layers of the upper gut. We tested whether Ucns and CRF2 variants are also expressed in the different layers of the rat colon, regulated by LPS (100 MUg/kg ip) and play a modulatory role in the colonic immune response to LPS. Transcripts of Ucns and CRF2b, the most common isoform in the periphery, were detected in all laser microdissected layers, including myenteric neurons. LPS increased the mRNA level of Ucn 1, Ucn 2, and Ucn 3 and decreased that of CRF2b in both the colonic mucosa and submucosa + muscle (S+M) layers at 2, 6, and 9 h after injection with a return to basal at 24 h. In addition, CRF2a, another variant more prominent in the brain, and a novel truncated splice variant CRF2a-3 mRNA were detected in all segments of the large intestine. LPS reciprocally regulated the colonic expression of these CRF2 variants by decreasing both CRF2a and CRF2b, while increasing CRF2a-3 in the mucosa and S+M. The CRF2 antagonist astressin2-B further enhanced LPS-induced increase of mRNA level of interleukin (IL)-1beta, TNF-alpha, and inducible nitric oxide synthase in S+M layers and IL-1beta in the mucosa and evoked TNF-alpha expression in the mucosa. These data indicate that Ucns/CRF2 variants are widely expressed in all colonic layers and reciprocally regulated by LPS. CRF2 signaling dampens the CD14/TLR4-mediated acute inflammatory response to Gram-negative bacteria in the colon. PMID- 26744477 TI - Screening MRI in Women With a Personal History of Breast Cancer. AB - BACKGROUND: Screening MRI is recommended for individuals at high risk for breast cancer, based on genetic risk or family history (GFH); however, there is insufficient evidence to support screening MRI for women with a personal history (PH) of breast cancer. We compared screening MRI performance in women with PH vs GFH of breast cancer. METHODS: We analyzed case-series registry data, collected at time of MRI and at 12-month follow-up, from our regional Clinical Oncology Data Integration project. MRI performance was compared in women with PH with those with GFH. Chi-square testing was used to identify associations between age, prior history of MRI, and clinical indication with MRI performance; logistic regression was used to determine the combined contribution of these variables in predicting risk of a false-positive exam. All statistical tests were two-sided. RESULTS: Of 1521 women who underwent screening MRI from July 2004 to November 2011, 915 had PH and 606 had GFH of breast cancer. Overall, MRI sensitivity was 79.4% for all cancers and 88.5% for invasive cancers. False-positive exams were lower in the PH vs GFH groups (12.3% vs 21.6%, P < .001), specificity was higher (94.0% vs 86.0%, P < .001), and sensitivity and cancer detection rate were not statistically different (P > .99). Age (P < .001), prior MRI (P < .001), and clinical indication (P < .001) were individually associated with initial false positive rate; age and prior MRI remained statistically significant in multivariable modeling (P = .001 and P < .001, respectively). CONCLUSION: MRI performance is superior in women with PH compared with women with GFH. Screening MRI warrants consideration as an adjunct to mammography in women with a PH of breast cancer. PMID- 26744478 TI - RE: Prevalence and Predictors of Inappropriate Delivery of Palliative Thoracic Radiotherapy for Metastatic Lung Cancer. PMID- 26744479 TI - Response. PMID- 26744480 TI - Geographic variation in climate as a proxy for climate change: Forecasting evolutionary trajectories from species differentiation and genetic correlations. AB - PREMISE OF THE STUDY: Climate change models for California predict a warmer, drier future, potentially resulting in shorter growing seasons. If phenotypic differences between closely related species currently distributed across a moisture and temperature gradient represent adaptations to their abiotic environment, then as conditions become warmer and drier, populations presently adapted to cooler and wetter conditions may evolve to become more similar to those adapted to warmer and drier conditions. Two sister species, Clarkia unguiculata and C. exilis, are distributed across a moisture and temperature gradient in the southern Sierra Nevada, providing an opportunity to predict how this process may occur. METHODS: In a greenhouse experiment using wild-collected seeds from 11 populations in the southern Sierra Nevada, we examined relationships among elevation, climatic conditions, and population means for each trait, then evaluated bivariate relationships among maternal family means, using raw values and controlling for population and seed mass effects on phenotype. KEY RESULTS: Clarkia exilis occupied warmer, drier conditions, typically at lower elevations, than C. unguiculata did and flowered earlier and faster, producing smaller flowers with lower herkogamy. In C. unguiculata, petal area, herkogamy, and the rate of flower production were positively correlated with days to first flower. CONCLUSIONS: If selection favors earlier flowering, smaller petals, or faster flower production in C. unguiculata, then the genetic correlations among these traits should reinforce their joint evolution. Moreover, the correlations between these traits and herkogamy may promote the evolution of self fertilization as an indirect response to selection, a previously unrecognized potential outcome of climate change. PMID- 26744481 TI - A cline in seed dormancy helps conserve the environment experienced during reproduction across the range of Arabidopsis thaliana. AB - PREMISE OF THE STUDY: Understanding the factors shaping range limits is critical given current changes in climate as well as human-mediated introduction of species into novel environments. Phenological responses to climate influence range limits by allowing plants to avoid conditions that decrease population growth rates. Studying these processes is a challenge due to the joint contributions of both genetic and environmental variation to phenology. METHODS: Using a previously developed model that predicts phenology of three dormancy "genotypes" in four locations spanning the European range of Arabidopsis thaliana, we examined how variation in seed dormancy influences the environmental conditions experienced by reproductive individuals and how those conditions influence reproductive potential. We calculated two metrics: temperature experienced during reproduction and the length of thermal window available for reproduction. KEY RESULTS: Seed dormancy levels determine whether a spring flowering life cycle is expressed and thus determine the reproductive environment. A genetic cline in seed dormancy across the range reduces differences in reproductive environment and increases the thermal opportunity for reproduction before conditions become unfavorable for survival. Counter intuitively, these putatively local genotypes are predicted to reproduce in slightly cooler conditions in the south than in the north, suggesting that maternal environmental effects on average could induce deeper dormancy in southern seeds reinforcing the observed genetic cline. However, within a location, we found large individual level differences. CONCLUSIONS: Phenological adjustments of early life stages can contribute to the maintenance of consistent reproductive environments experienced by individual plants across ranges despite variable environmental conditions over time and space. PMID- 26744482 TI - Landscape genomic analysis of candidate genes for climate adaptation in a California endemic oak, Quercus lobata. AB - PREMISE OF THE STUDY: The ability of California tree populations to survive anthropogenic climate change will be shaped by the geographic structure of adaptive genetic variation. Our goal is to test whether climate-associated candidate genes show evidence of spatially divergent selection in natural populations of valley oak, Quercus lobata, as preliminary indication of local adaptation. METHODS: Using DNA from 45 individuals from 13 localities across the species' range, we sequenced portions of 40 candidate genes related to budburst/flowering, growth, osmotic stress, and temperature stress. Using 195 single nucleotide polymorphisms (SNPs), we estimated genetic differentiation across populations and correlated allele frequencies with climate gradients using single-locus and multivariate models. RESULTS: The top 5% of FST estimates ranged from 0.25 to 0.68, yielding loci potentially under spatially divergent selection. Environmental analyses of SNP frequencies with climate gradients revealed three significantly correlated SNPs within budburst/flowering genes and two SNPs within temperature stress genes with mean annual precipitation, after controlling for multiple testing. A redundancy model showed a significant association between SNPs and climate variables and revealed a similar set of SNPs with high loadings on the first axis. In the RDA, climate accounted for 67% of the explained variation, when holding climate constant, in contrast to a putatively neutral SSR data set where climate accounted for only 33%. CONCLUSIONS: Population differentiation and geographic gradients of allele frequencies in climate associated functional genes in Q. lobata provide initial evidence of adaptive genetic variation and background for predicting population response to climate change. PMID- 26744484 TI - Ebola in West Africa: lessons we may have learned. PMID- 26744483 TI - Individual Responses to a Barefoot Running Program: Insight Into Risk of Injury. AB - BACKGROUND: Barefoot running is of popular interest because of its alleged benefits for runners, including reduced injury risk and increased economy of running. There is a dearth in understanding whether all runners can gain the proposed benefits of barefoot running and how barefoot running may affect long term injury risk. PURPOSE/HYPOTHESIS: The purpose of this study was to determine whether runners can achieve the proposed favorable kinematic changes and reduction in loading rate after a progressive training program that included barefoot running. It was hypothesized that not all individuals would experience a decrease in initial loading rate facilitated by increased ankle plantar flexion after a progressive barefoot running program; it was further hypothesized that relationships exist between changes in initial loading rate and sagittal ankle angle. STUDY DESIGN: Descriptive laboratory study. METHODS: A total of 26 habitually shod runners completed an 8-week, progressively introduced barefoot running program. Pre- and postintervention barefoot and shod kinematics, electromyography, and ground-reaction force data of the lower limb were collected. Ankle and knee kinematics and kinetics, initial loading rates, spatiotemporal variables, muscle activity during preactivation, and ground contact were assessed in both conditions before and after the intervention. Individual responses were analyzed by separating runners into nonresponders, negative responders, and positive responders based on no change, increase, and decrease in barefoot initial loading rate, respectively. RESULTS: No biomechanical changes were found in the group after the intervention. However, condition differences did persist during both preactivation and ground contact. The positive-responder group had greater plantar flexion, increased biceps femoris and gluteus medius preactivation, and decreased rectus femoris muscle activity between testing periods. The negative responders landed in greater barefoot dorsiflexion after the intervention, and the nonresponders did not change. An overall change in ankle flexion angle was associated with a change in initial loading rate (r(2) = 0.345, P = .002) in the barefoot but not shod condition. CONCLUSION: Eight weeks of progressive barefoot running did not change overall group biomechanics, but subgroups of responders (25% of the entire group) were identified who had specific changes that reduced the initial loading rate. It appears that changes in initial loading rate are explained by changes in ankle flexion angle at initial ground contact. CLINICAL RELEVANCE: Uninstructed barefoot running training does not reduce initial loading rate in all runners transitioning from shod to barefoot conditions. Some factors have been identified that may assist sports medicine professionals in the evaluation and management of runners at risk of injury. Conscious instruction to runners may be required for them to acquire habitual barefoot running characteristics and to reduce risk of injury. PMID- 26744485 TI - Converting between marginal effect measures from binomial models. PMID- 26744486 TI - What should we know about precarious employment and health in 2025? Framing the agenda for the next decade of research. AB - The generalization of flexible labour markets, the declining influence of unions and the degradation of social protection has led to the emergence of new forms of employment at the expense of the Standard Employment Relationship, as well as a considerable amount of research across social and scientific disciplines. Years ago we suggested the urgent need to disentangle the consequences of new types of employment for the health and well-being of workers, contending that the study of precarious employment and health is in its infancy. Today, research challenges include clearer, more precise definitions of the original concepts, a more detailed understanding of the pathways and mechanisms through which precarious employment harms worker health, stronger information systems for monitoring the problem and a complex systems approach to employment conditions and health research. All of these must be guided by the theoretical and policy debates linking precarious employment and health, and be geared towards developing better tools for the design, implementation and evaluation of policies intended to minimize precariousness in the labour market and its effects on public health and health inequalities. Our aim in this paper is to outline an agenda for the next decade of research on precarious employment and health, establishing a compelling programme that expands our understanding of complex causes and links. PMID- 26744487 TI - Mitochondria in Kidney Injury: When the Power Plant Fails. PMID- 26744488 TI - Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI. AB - Inappropriate activation of the renin-angiotensin system (RAS) contributes to many CKDs. However, the role of the RAS in modulating AKI requires elucidation, particularly because stimulating type 1 angiotensin II (AT1) receptors in the kidney or circulating inflammatory cells can have opposing effects on the generation of inflammatory mediators that underpin the pathogenesis of AKI. For example, TNF-alpha is a fundamental driver of cisplatin nephrotoxicity, and generation of TNF-alpha is suppressed or enhanced by AT1 receptor signaling in T lymphocytes or the distal nephron, respectively. In this study, cell tracking experiments with CD4-Cre mT/mG reporter mice revealed robust infiltration of T lymphocytes into the kidney after cisplatin injection. Notably, knockout of AT1 receptors on T lymphocytes exacerbated the severity of cisplatin-induced AKI and enhanced the cisplatin-induced increase in TNF-alpha levels locally within the kidney and in the systemic circulation. In contrast, knockout of AT1 receptors on kidney epithelial cells ameliorated the severity of AKI and suppressed local and systemic TNF-alpha production induced by cisplatin. Finally, disrupting TNF-alpha production specifically within the renal tubular epithelium attenuated the AKI and the increase in circulating TNF-alpha levels induced by cisplatin. These results illustrate discrepant tissue-specific effects of RAS stimulation on cisplatin nephrotoxicity and raise the concern that inflammatory mediators produced by renal parenchymal cells may influence the function of remote organs by altering systemic cytokine levels. Our findings suggest selective inhibition of AT1 receptors within the nephron as a promising intervention for protecting patients from cisplatin-induced nephrotoxicity. PMID- 26744491 TI - Transient presence of lupus anticoagulant associated with mycoplasma pneumonia. AB - We report a case of asymptomatic transient presence of lupus anticoagulant with isolated prolonged activated partial thromboplastin time in a 30-year-old lady with pneumonia caused by Mycoplasma pneumoniae. After treatment of pneumonia, lupus anticoagulant was not detected and the activated partial thromboplastin time normalized. PMID- 26744492 TI - Hidden (end-on) patent ductus arteriosus: recognition and device closure. AB - BACKGROUND: Sometimes, it is difficult to visualize a patent ductus arteriosus and deploy a device in the standard lateral view because of an end-on orientation. The right anterior oblique view may be helpful by separating the ductus arteriosus from the aorta. This study was undertaken to evaluate the incidence of end-on patent ductus arteriosus and the utility of the right anterior oblique view during device closure. METHODS: Aortography was performed in lateral and right anterior oblique views before, during, and after successful device deployment in 117 consecutive patients. When a ductus arteriosus was not clearly visible in the lateral view due to overlapping by the aorta, it was termed "right anterior oblique view useful". RESULTS: The types of patent ductus arteriosus were A, B, C, and E in 86 (73.5%), 20 (17.1%), 4 (3.4%), and 7 (6.0%) patients, respectively. An end-on ductus arteriosus was present in 24 (20.5%) patients (14 type B, 10 type A). The right anterior oblique view was useful during device closure in 15 (12.8%) cases (all end-on type). Among all cases of end-on patent ductus arteriosus, it was useful in 62.5% (most type B and a few type A). In all of these, the device appeared obliquely oriented and foreshortened in the lateral view but fully profiled in the right anterior oblique view. CONCLUSIONS: Recognizing an end-on patent ductus arteriosus and utilizing the right anterior oblique view simplified device closure. For ducts well-profiled in the lateral view, the right anterior oblique view is unnecessary and avoidable. PMID- 26744490 TI - Relationships between root diameter, root length and root branching along lateral roots in adult, field-grown maize. AB - BACKGROUND AND AIMS: Root diameter, especially apical diameter, plays an important role in root development and function. The variation in diameter between roots, and along roots, affects root structure and thus the root system's overall foraging performance. However, the effect of diameter variation on root elongation, branching and topological connections has not been examined systematically in a population of high-order roots, nor along the roots, especially for mature plants grown in the field. METHODS: A method combining both excavation and analysis was applied to extract and quantify root architectural traits of adult, field-grown maize plants. The relationships between root diameter and other root architectural characteristics are analysed for two maize cultivars. KEY RESULTS: The basal diameter of the lateral roots (orders 1-3) was highly variable. Basal diameter was partly determined by the diameter of the bearing segment. Basal diameter defined a potential root length, but the lengths of most roots fell far short of this. This was explained partly by differences in the pattern of diameter change along roots. Diameter tended to decrease along most roots, with the steepness of the gradient of decrease depending on basal diameter. The longest roots were those that maintained (or sometimes increased) their diameters during elongation. The branching density (cm(-1)) of laterals was also determined by the diameter of the bearing segment. However, the location of this bearing segment along the mother root was also involved - intermediate positions were associated with higher densities of laterals. CONCLUSIONS: The method used here allows us to obtain very detailed records of the geometry and topology of a complex root system. Basal diameter and the pattern of diameter change along a root were associated with its final length. These relationships are especially useful in simulations of root elongation and branching in source sink models. PMID- 26744489 TI - Interactive tools for inpatient medication tracking: a multi-phase study with cardiothoracic surgery patients. AB - OBJECTIVE: Prior studies of computing applications that support patients' medication knowledge and self-management offer valuable insights into effective application design, but do not address inpatient settings. This study is the first to explore the design and usefulness of patient-facing tools supporting inpatient medication management and tracking. MATERIALS AND METHODS: We designed myNYP Inpatient, a custom personal health record application, through an iterative, user-centered approach. Medication-tracking tools in myNYP Inpatient include interactive views of home and hospital medication data and features for commenting on these data. In a two-phase pilot study, patients used the tools during cardiothoracic postoperative care at Columbia University Medical Center. In Phase One, we provided 20 patients with the application for 24-48 h and conducted a closing interview after this period. In Phase Two, we conducted semi structured interviews with 12 patients and 5 clinical pharmacists who evaluated refinements to the tools based on the feedback received during Phase One. RESULTS: Patients reported that the medication-tracking tools were useful. During Phase One, 14 of the 20 participants used the tools actively, to review medication lists and log comments and questions about their medications. Patients' interview responses and audit logs revealed that they made frequent use of the hospital medications feature and found electronic reporting of questions and comments useful. We also uncovered important considerations for subsequent design of such tools. In Phase Two, the patients and pharmacists participating in the study confirmed the usability and usefulness of the refined tools. CONCLUSIONS: Inpatient medication-tracking tools, when designed to meet patients' needs, can play an important role in fostering patient participation in their own care and patient-provider communication during a hospital stay. PMID- 26744493 TI - Isolated metastasis of testicular seminoma to extralobar pulmonary sequestration. AB - This case report describes a 46-year-old patient with a very unusual pattern of isolated metastasis to an extralobar pulmonary sequestration following orchidectomy for seminoma. The patient underwent uncomplicated video-assisted thoracoscopic resection of the metastasis, involving the whole of the sequestration mass. PMID- 26744494 TI - Concurrent cystic adenomatoid malformation and sequestration in an elderly woman. PMID- 26744495 TI - Pectus excavatum repair using Prolene polypropylene mesh. AB - OBJECTIVE: We aimed to assess the clinical outcomes of our surgical technique for repair of pectus excavatum using Prolene polypropylene mesh. METHODS: Among 29 patients with pectus excavatum, the major complaint was cosmetic dissatisfaction, and the main symptom was exercise dyspnea in 15 patients. The Haller index used to assess pectus excavatum severity; it was significant in 22 patients. In all patients, a 2-layer sheet of Prolene polypropylene mesh was placed behind the sternum. RESULTS: No serious complication was observed postoperatively, and all patients were satisfied with the cosmetic result. Mitral valve prolapse improved in all cases after 3 months. Spirometry revealed improved pulmonary function after surgery. CONCLUSION: With due attention to the advantages of Prolene polypropylene mesh, such as remaining permanently in place, adapting to various stresses encountered in the body, resisting degradation by tissue enzymes, and trimming without unraveling, we concluded that this mesh is suitable for use as posterior sternal support in pectus excavatum patients. PMID- 26744496 TI - New Beginnings: Changed (Us) for Good. PMID- 26744498 TI - Brazilian Human Milk Banks Network: Numbers in December 2013 and the "Survey of Italian Human Milk Banks". PMID- 26744497 TI - Social Contexts of Infant Feeding and Infant Feeding Decisions. AB - BACKGROUND: Infant feeding takes place within a network of social relationships. However, the social context in which infant feeding advice is received remains underresearched. OBJECTIVE: The objective of this study was to evaluate the social contexts of infant feeding by examining individual and relationship characteristics of mothers and network members associated with advice to exclusively breastfeed, exclusively formula feed, or use a combination of breast milk and formula. METHODS: Information about 287 network members was reported by 80 low-income mothers during a one-time survey. Characteristics of relationships associated with mothers receiving advice (exclusively breastfeed/formula feed, combination feed) from each network member were identified using 2-level logistic regression analyses. RESULTS: Mothers had greater odds of receiving advice to exclusively breastfeed from network members who help make feeding decisions (odds ratio [OR], 2.44; 95% confidence interval [CI], 1.35-4.42), exclusively breastfed their own child or children (OR, 6.99; 95% CI, 2.96-16.51), and were health care providers (OR, 4.82; 95% CI, 1.70-13.67). Mothers had greater odds of receiving advice to breastfeed in combination with formula from network members who provided emotional support (OR, 2.45; 95% CI, 1.31-4.55), combination fed their own child or children (OR, 4.85; 95% CI, 1.80-13.05), and had an opinion that was important to the mother (OR, 2.67; 95% CI, 1.13-6.33). Mothers had greater odds of receiving advice to exclusively formula feed from network members who exclusively formula fed their own child or children (OR, 2.23; 95% CI, 1.07-4.66) than those who did not. CONCLUSION: Social relationship characteristics and network members' infant feeding experiences may have implications for the advice new mothers receive. Future research should investigate social contexts of infant feeding longitudinally to inform interventions. PMID- 26744499 TI - Response to: "Brazilian Human Milk Banks Network: Numbers in December 2013 and the 'Survey of Italian Human Milk Banks'". PMID- 26744500 TI - Degree of Compliance with a Protocol for Performing Safe Skin-to-Skin Care. PMID- 26744502 TI - Transient human anti-mouse antibody generated with immune enhancement in a carbohydrate antigen 19-9 immunoassay after surgical resection of recurrent cancer. AB - We report a case of transient human anti-mouse antibody from a 64-year-old man in a carbohydrate antigen 19-9 immunoassay using an AIA 1800 analyser that generated immune enhancement after surgical resection of recurrent cancer. METHODS: The carbohydrate antigen 19-9 concentration was measured using an AIA 1800 analyser and a UniCel Dxl 800. Size-exclusion high-performance liquid chromatography was carried out on a Superose 12 column to estimate the carbohydrate antigen 19-9 elution profile using an AIA 1800 analyser. To determine whether IgM in the patient contributed to the carbohydrate antigen 19-9 immunoassay, immunoprecipitation was performed. Furthermore, mouse immunoglobulins were added to the patient's serum to verify that the patient's IgM reacted with it. RESULTS: The carbohydrate antigen 19-9 concentration was >400 and 9.5 kU/L using an AIA 1800 analyser and using a UniCel Dxl 800, respectively. In the single carbohydrate antigen 19-9 peak, the molecular weight corresponded to IgM by size exclusion high-performance liquid chromatography on a Superose 12 column. In the immunoprecipitation reaction and addition of mouse immunoglobulins, there was interference for anti-human IgM and mouse immunoglobulins whose recoveries were 3.2 and 14.2%, respectively. These results indicated that IgM in the patient's serum interfered with the carbohydrate antigen 19-9 immunoassay using an AIA 1800 analyser. CONCLUSION: A novel transient human anti-mouse antibody generated with immune activation in a carbohydrate antigen 19-9 immunoassay using an AIA 1800 analyser was identified in a patient with rectal cancer after surgical resection. These findings demonstrate the importance of monitoring tumour markers in patients after treatment with mouse monoclonal antibody. PMID- 26744503 TI - The plasma and peritoneal fluid concentrations of matrix metalloproteinase-9 are elevated in patients with endometriosis. AB - BACKGROUND: Enzyme matrix metalloproteinase-9 is a member of the matrix metalloproteinase family, which is critical to normal tissue remodelling during embryogenesis and wound healing. In patients with endometriosis, increased expression and activity of matrix metalloproteinase-9 have been observed in ectopic endometrium, but the plasma and peritoneal fluid concentrations of matrix metalloproteinase-9 in patients with endometriosis and their relation to disease severity have not been clear. The aim of the study was to investigate the concentrations of matrix metalloproteinase-9 in plasma and peritoneal fluid of patients with endometriosis. METHODS: A prospective case-control study was conducted in Jinan Military General Hospital between January 2010 and December 2013. Fifty patients with proven endometriosis and 26 endometriosis-free controls were enrolled in this study. Patients with endometriosis were evaluated and divided into moderate/severe endometriosis group (stage I-II, n = 26) and minimal/mild endometriosis group (stage III-IV, n = 24) according to the revised criteria of the American Society for Reproductive Medicine. Blood samples and peritoneal fluid were obtained from both patients and controls. Matrix metalloproteinase-9 was measured using enzyme-linked immunosorbent assay in plasma and peritoneal fluid. The concentration of matrix metalloproteinase-9 between different groups was compared and its correlation to disease severity was analysed. RESULTS: Plasma and peritoneal fluid concentrations of matrix metalloproteinase-9 in patients with endometriosis were higher than that in controls. In addition, those patients with moderate/severe endometriosis had significantly higher plasma and peritoneal fluid concentrations of matrix metalloproteinase-9 compared to those with minimal/mild endometriosis. Matrix metalloproteinase-9 concentrations in plasma and peritoneal fluid were both positively correlated with severity of endometriosis and plasma matrix metalloproteinase-9 concentrations had a positive correlation with peritoneal fluid matrix metalloproteinase-9 concentrations in patients with endometriosis. CONCLUSIONS: Increased concentrations of plasma and peritoneal fluid concentrations of matrix metalloproteinase-9 appear to be associated with disease severity of endometriosis and may serve as an alternative biomarker to determine disease severity of endometriosis. PMID- 26744505 TI - Acute exercise mobilizes hematopoietic stem and progenitor cells and alters the mesenchymal stromal cell secretome. AB - Transplantation of hematopoietic stem and progenitor cells (HSPC), collected from peripheral blood, is the primary treatment for many hematological malignancies; however, variable collection efficacy with current protocols merits further examination into factors responsible for HSPC mobilization. HSPCs primarily reside within the bone marrow and are regulated by mesenchymal stromal cells (MSC). Exercise potently and transiently mobilizes HSPCs from the bone marrow into peripheral circulation. Thus the purpose of the present study was to evaluate potential factors in the bone marrow responsible for HSPC mobilization, investigate potential sites of HSPC homing, and assess changes in bone marrow cell populations following exercise. An acute exercise bout increased circulating HSPCs at 15 min (88%, P < 0.001) that returned to baseline at 60 min. Gene expression for HSPC homing factors (CXCL12, vascular endothelial growth factor-a, and angiopoietin-1) were increased at 15 min in skeletal muscle and HSPC content was increased in the spleen 48 h postexercise (45%, P < 0.01). Acute exercise did not alter HSPCs or MSCs quantity in the bone marrow; however, proliferation of HSPCs (40%, P < 0.001), multipotent progenitors (40%, P < 0.001), short-term hematopoietic stem cells (61%, P < 0.001), long-term hematopoietic stem cells (55%, P = 0.002), and MSCs (20%, P = 0.01) increased postexercise. Acute exercise increased the content of the mobilization agent granulocyte-colony stimulating factor, as well as stem cell factor, interleukin-3, and thrombopoeitin in conditioned media collected from bone marrow stromal cells 15 min postexercise. These findings suggest that the MSC secretome is responsible for HSPC mobilization and proliferation; concurrently, HSPCs are homing to extramedullary sites following exercise. PMID- 26744504 TI - 31P magnetization transfer measurements of Pi->ATP flux in exercising human muscle. AB - Fundamental criticisms have been made over the use of (31)P magnetic resonance spectroscopy (MRS) magnetization transfer estimates of inorganic phosphate (Pi) >ATP flux (VPi-ATP) in human resting skeletal muscle for assessing mitochondrial function. Although the discrepancy in the magnitude of VPi-ATP is now acknowledged, little is known about its metabolic determinants. Here we use a novel protocol to measure VPi-ATP in human exercising muscle for the first time. Steady-state VPi-ATP was measured at rest and over a range of exercise intensities and compared with suprabasal oxidative ATP synthesis rates estimated from the initial rates of postexercise phosphocreatine resynthesis (VATP). We define a surplus Pi->ATP flux as the difference between VPi-ATP and VATP. The coupled reactions catalyzed by the glycolytic enzymes GAPDH and phosphoglycerate kinase (PGK) have been shown to catalyze measurable exchange between ATP and Pi in some systems and have been suggested to be responsible for this surplus flux. Surplus VPi-ATP did not change between rest and exercise, even though the concentrations of Pi and ADP, which are substrates for GAPDH and PGK, respectively, increased as expected. However, involvement of these enzymes is suggested by correlations between absolute and surplus Pi->ATP flux, both at rest and during exercise, and the intensity of the phosphomonoester peak in the (31)P NMR spectrum. This peak includes contributions from sugar phosphates in the glycolytic pathway, and changes in its intensity may indicate changes in downstream glycolytic intermediates, including 3-phosphoglycerate, which has been shown to influence the exchange between ATP and Pi catalyzed by GAPDH and PGK. PMID- 26744507 TI - Resident Reactions to Person-Centered Communication by Long-Term Care Staff. AB - Long-term care staff caregivers who are person centered incorporate the life history, preferences, and feelings of residents with dementia during care interactions. Communication is essential for person-centered care. However, little is known about residents' verbal reactions when staff use person-centered communication. Accordingly, this study investigated the impact of person-centered communication and missed opportunities for such communication by staff on resident reactions. Conversations (N = 46) between staff-resident dyads were audio-recorded during routine care tasks over 12 weeks. Staff utterances were coded for person-centered communication and missed opportunities. Resident utterances were coded for positive reactions, such as cooperation, and negative reactions, such as distress. Linear regression analyses revealed that the more staff used person-centered communication, the more likely that residents reacted positively. Additionally, the more missed opportunities in a conversation, the more likely that the residents reacted negatively. Conversation illustrations elaborate on the quantitative findings and implications for staff training are discussed. PMID- 26744506 TI - Resistance training enhances insulin suppression of endogenous glucose production in elderly women. AB - An altered prenatal environment during maternal obesity predisposes offspring to insulin resistance, obesity, and their consequent comorbidities, type 2 diabetes and cardiovascular disease. Telomere shortening and frailty are additional risk factors for these conditions. The aim of this study was to evaluate the effects of resistance training on hepatic metabolism and ectopic fat accumulation. Thirty five frail elderly women, whose mothers' body mass index (BMI) was known, participated in a 4-mo resistance training program. Endogenous glucose production (EGP) and hepatic and visceral fat glucose uptake were measured during euglycemic hyperinsulinemia with [(18)F]fluorodeoxyglucose and positron emission tomography. Ectopic fat was measured using magnetic resonance spectroscopy and imaging. We found that the training intervention reduced EGP during insulin stimulation [from 5.4 (interquartile range 3.0, 7.0) to 3.9 (-0.4, 6.1) MUmol.kg body wt(-1).min( 1), P = 0.042] in the whole study group. Importantly, the reduction was higher among those whose EGP was more insulin resistant at baseline (higher than the median) [-5.6 (7.1) vs. 0.1 (5.4) MUmol.kg body wt(-1).min(-1), P = 0.015]. Furthermore, the decrease in EGP was associated with telomere elongation (r = 0.620, P = 0.001). The resistance training intervention did not change either hepatic or visceral fat glucose uptake or the amounts of ectopic fat. Maternal obesity did not influence the studied measures. In conclusion, resistance training improves suppression of EGP in elderly women. The finding of improved insulin sensitivity of EGP with associated telomere lengthening implies that elderly women can reduce their risk for type 2 diabetes and cardiovascular disease with resistance training. PMID- 26744508 TI - Interpretation of the QuickDASH score after open carpal tunnel decompression: threshold values associated with patient satisfaction. AB - We studied the correlation between change in the QuickDASH score and the absolute post-operative QuickDASH score with patient satisfaction after open carpal tunnel decompression. Threshold values in the QuickDASH score, the point at which the sensitivity and specificity are maximal in predicting patient satisfaction, were identified. During the study period, outcome data were compiled for 937 carpal tunnel decompressions, which included 219 (23%) male and 718 (77%) female patients with a mean age of 58 years (standard deviation (SD) 14). There was a significant improvement (mean difference 32, 95% confidence interval (CI) 30 to 34) in the QuickDASH from a mean of 54 (SD 20) to 22 (SD 23) at 1 year after surgery. There were 808 (86%) patients who defined their outcome as satisfactory at 1 year. The identified threshold values for the post-operative QuickDASH score (?34 points) and the change (?20 points) in the score were highly predictive of patient satisfaction. However, these threshold values varied significantly according to the baseline pre-operative score. The threshold values identified in the QuickDASH can be used to interpret the score. However, the influence of the pre-operative baseline score should be taken into account when comparing different cohorts of patients or using the values to power future studies. LEVEL OF EVIDENCE IV: Prognosis, observational cohort study. PMID- 26744509 TI - Extrinsic versus intrinsic hand muscle dominance in finger flexion. AB - This study aims to identify the patterns of dominance of extrinsic or intrinsic muscles in finger flexion during initiation of finger curl and mid-finger flexion. We recorded 82 hands of healthy individuals (18-74 years) while flexing their fingers and tracked the finger joint angles of the little finger using video motion tracking. A total of 57 hands (69.5%) were classified as extrinsic dominant, where the finger flexion was initiated and maintained at proximal interphalangeal and distal interphalangeal joints. A total of 25 (30.5%) were classified as intrinsic dominant, where the finger flexion was initiated and maintained at the metacarpophalangeal joint. The distribution of age, sex, dominance, handedness and body mass index was similar in the two groups. This knowledge may allow clinicians to develop more efficient rehabilitation regimes, since intrinsic dominant individuals would not initiate extrinsic muscle contraction till later in finger flexion, and might therefore be allowed limited early active motion. For extrinsic dominant individuals, by contrast, initial contraction of extrinsic muscles would place increased stress on the tendon repair site if early motion were permitted. PMID- 26744510 TI - In-vivo three-dimensional measurement of distal radioulnar joint translation in normal and clinically unstable populations. AB - Assessment of distal radioulnar joint instability is clinically difficult and subjective. The distal radioulnar joint is postulated to 'tighten' in ulnar/radial deviation and pronation/supination. Using a rig, we measured mean distal radioulnar joint translation in neutral forearm rotation and neutral wrist radial and ulnar deviation, as well as extremes of wrist radial and ulnar deviation and forearm rotation. We tested the rig on ten cadaver forearms to validate the measurements we made. We tested 50 normal adults and 50 patients with clinical distal radioulnar joint instability. Distal radioulnar joint stability in men and women and on contralateral sides were comparable. Distal radioulnar joint translation decreased significantly with wrist radial and ulnar deviation and forearm pronation and supination, matching clinical practice and further validating the rig. The data in normal patients is comparable with previous computed tomography-based studies. Translation in all positions was statistically increased within the clinical instability group and did not cross over with the normal ranges. Distal radioulnar joint translation is a physically measurable phenomenon. Our device appears to be a valid test of distal radioulnar joint translation, establishing normal data in vivo. LEVEL OF EVIDENCE: III. PMID- 26744511 TI - Copeptin for All. PMID- 26744512 TI - Human Endothelial Cell-Specific Molecule-1 (Endocan) and Coronary Artery Disease and Microvascular Angina. AB - Endothelial cell-specific molecule-1 (endocan) is an immunoinflammatory marker linked to endothelial activation and dysfunction. We investigated the relationship between obstructive coronary artery disease (CAD), microvascular angina (MVA), and plasma levels of endocan. We included 53 healthy individuals as controls, 40 MVA patients, and 120 patients with obstructive CAD. The severity of CAD was assessed by the Gensini and SYNergy between percutaneous coronary intervention with TAXUS and Cardiac Surgery (SYNTAX) scores. Endocan levels were 382.7 (313.8-470.2) pg/mL in patients with obstructive CAD; 324.3 (277.1-460.7) pg/mL in MVA group, and 268.0 (226.4-336.5) pg/mL (P < .001) in controls. Endocan levels in obstructive CAD and MVA groups were similar but both were significantly higher than for the control group (P < .001 and P = .002, respectively). In subgroup analysis, similar to the hypertensive subgroup results, endocan was still an independent predictor of presence of obstructive CAD in normotensives (odds ratio = 1.005, 95% confidence interval = 1.001-1.010, P = .024). There was also an independent positive correlation between endocan levels and SYNTAX score both in the hypertensives (beta = 0.414, t = 3.21, P = .002) and in the normotensives (beta = .301, t = 2.23, P = .031). In conclusion, endocan could be a common predictor of the endothelium-dependent inflammatory processes, rather than related with specific risk factors. PMID- 26744514 TI - CardioPulse Articles. PMID- 26744513 TI - Use, complications, and outcome of novel therapeutic interventions. PMID- 26744515 TI - Building an evidence base for national suicide prevention strategies. PMID- 26744516 TI - The population-level effectiveness of suicide prevention strategies that might be used in a systems-based approach. PMID- 26744517 TI - Improving access to treatment for mental health problems as a major component of suicide prevention strategy. PMID- 26744518 TI - Synergistic effects of multi-level suicide preventive interventions: Important, but difficult to disentangle. PMID- 26744519 TI - Preventing suicide by a systems approach. PMID- 26744520 TI - Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b-Mediated Malignant Progression. AB - Consequences of the obesity epidemic on cancer morbidity and mortality are not fully appreciated. Obesity is a risk factor for many cancers, but the mechanisms by which it contributes to cancer development and patient outcome have yet to be fully elucidated. Here, we examined the effects of coculturing human-derived adipocytes with established and primary breast cancer cells on tumorigenic potential. We found that the interaction between adipocytes and cancer cells increased the secretion of proinflammatory cytokines. Prolonged culture of cancer cells with adipocytes or cytokines increased the proportion of mammosphere forming cells and of cells expressing stem-like markers in vitro. Furthermore, contact with immature adipocytes increased the abundance of cancer cells with tumor-forming and metastatic potential in vivo. Mechanistic investigations demonstrated that cancer cells cultured with immature adipocytes or cytokines activated Src, thus promoting Sox2, c-Myc, and Nanog upregulation. Moreover, Sox2 dependent induction of miR-302b further stimulated cMYC and SOX2 expression and potentiated the cytokine-induced cancer stem cell-like properties. Finally, we found that Src inhibitors decreased cytokine production after coculture, indicating that Src is not only activated by adipocyte or cytokine exposures, but is also required to sustain cytokine induction. These data support a model in which cancer cell invasion into local fat would establish feed-forward loops to activate Src, maintain proinflammatory cytokine production, and increase tumor initiating cell abundance and metastatic progression. Collectively, our findings reveal new insights underlying increased breast cancer mortality in obese individuals and provide a novel preclinical rationale to test the efficacy of Src inhibitors for breast cancer treatment. PMID- 26744521 TI - Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors. AB - Many oncoproteins are considered undruggable because they lack enzymatic activities. In this study, we present a small-molecule-based anticancer agent that acts by inhibiting dimerization of the oncoprotein survivin, thereby promoting its degradation along with spontaneous apoptosis in cancer cells. Through a combination of computational analysis of the dimerization interface and in silico screening, we identified one compound that induced proteasome-dependent survivin degradation. Analysis of a set of structural analogues led us to identify a lead compound (LQZ-7F), which was effective in blocking the survival of multiple cancer cell lines in a low micromolar concentration range. LQZ-7F induced proteasome-dependent survivin degradation, mitotic arrest, and apoptosis, and it blocked the growth of human tumors in mouse xenograft assays. In addition to providing preclinical proof of concept for a survivin-targeting anticancer agent, our work offers novel in silico screening strategies to therapeutically target homodimeric oncogenic proteins considered undruggable. PMID- 26744522 TI - Improved Treatment of Breast Cancer with Anti-HER2 Therapy Requires Interleukin 21 Signaling in CD8+ T Cells. AB - The HER2/ErbB2 monoclonal antibody (mAb) trastuzumab is combined with chemotherapy as a standard-of-care for newly diagnosed HER2(+) breast cancer patients, but some patients treated with this combination therapy experience early relapse. Our analysis of data from a clinical trial evaluating the efficacy of chemotherapy plus/minus trastuzumab suggested that the magnitude of trastuzumab benefit on distant disease-free survival was higher for increasing expression of the IL21 receptor (IL21R). Therefore, we investigated a possible role for IL21 signaling in promoting HER2 mAb therapeutic efficacy. We found that IL21R-deficient mice and wild-type mice treated with a neutralizing anti-IL21 mAb were less susceptible to trastuzumab-like anti-ErbB2 therapy. Furthermore, IL21R expression on CD8(+) T cells, but not on natural killer cells, was required for optimal anti-ErbB2 mAb efficacy, and IL21 expression was enhanced in tumor infiltrating CD4(+) T lymphocytes after anti-ErbB2 therapy. Finally, we found that administering recombinant IL21 in combination with anti-ErbB2 therapy was therapeutic against primary tumors and experimental metastases in mice. Collectively, our findings suggest that elevating IL21 signaling may enhance trastuzumab efficacy, thus constituting a novel candidate strategy to overcome trastuzumab resistance and improve patient survival. Cancer PMID- 26744523 TI - Peritoneal Dissemination Requires an Sp1-Dependent CXCR4/CXCL12 Signaling Axis and Extracellular Matrix-Directed Spheroid Formation. AB - Peritonitis carcinomatosa is an advanced and intractable state of gastrointestinal and ovarian cancer, where mechanistic elucidation might enable the development of more effective therapies. Peritoneal dissemination of this type of malignancy has been generally thought to initiate from "milky spots" of primitive lymphoid tissues in the peritoneal cavity. In this study, we offer evidence challenging this idea, based on the finding that tumor implantation and directional dissemination was not required for the presence of milky spots, but rather SCF/CXCL12-expressing niche-like cells located at the border regions of perivascular adipose tissue. Interestingly, we found that peritoneal cavity lavage fluid, which specifically contains peritoneal collagen type IV and plasma fibronectin, dramatically facilitated spheroid formation of murine and human colon cancer cells. Spheroid formation strongly induced the expression of CXCR4 in an Sp1-dependent manner to promote niche-directed metastasis. Notably, disrupting sphere formation or inhibiting Sp1 activity was sufficient to suppress tumor dissemination and potentiated chemosensitivity to 5-fluorouracil. Our findings illuminate mechanisms of peritoneal cancer dissemination and highlight the Sp1/CXCR4/CXCL12 signaling axis as a rational target for the development of therapeutics to manage this intractable form of malignancy. PMID- 26744525 TI - Skin Cancer Risk Is Modified by KIR/HLA Interactions That Influence the Activation of Natural Killer Immune Cells. AB - Natural killer (NK)-cell phenotype is partially mediated through binding of killer-cell immunoglobulin-like receptors (KIR) with HLA class I ligands. The KIR gene family is highly polymorphic and not well captured by standard genome-wide association study approaches. Here, we tested the hypothesis that variations in KIR gene content combined with HLA class I ligand status is associated with keratinocyte skin cancers using a population-based study of basal cell carcinoma (BCC) and squamous cell carcinomas (SCC). We conducted an interaction analysis of KIR gene content variation and HLA-B (Bw4 vs. Bw6) and HLA-C (C1 vs. C2). KIR centromeric B haplotype was associated with significant risk of multiple BCC tumors (OR, 2.39; 95% confidence interval, 1.10-5.21), and there was a significant interaction between HLA-C and the activating gene KIR2DS3 for BCC (Pinteraction = 0.005). Furthermore, there was significant interaction between HLA-B and telomeric KIR B haplotype (containing the activating genes KIR3DS1 and KIR2DS1) as well as HLA-B and the activating KIR gene KIR2DS5 (Pinteraction 0.001 and 0.012, respectively). Similar but greatly attenuated associations were observed for SCC. Moreover, previous in vitro models demonstrated that p53 is required for upregulation of NK ligands, and accordingly, we observed there was a strong association between the KIR B haplotype and p53 alteration in BCC tumors, with a higher likelihood that KIR B carriers harbor abnormal p53 (P < 0.004). Taken together, our data suggest that functional interactions between KIR and HLA modify risks of BCC and SCC and that KIR encoded by the B genes provides selective pressure for altered p53 in BCC tumors. PMID- 26744524 TI - Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-kappaB-Controlled Oxidative Stress Responses. AB - NF-kappaB plays a variety of roles in oncogenesis and immunity that may be beneficial for therapeutic targeting, but strategies to selectively inhibit NF kappaB to exert antitumor activity have been elusive. Here, we describe IT-901, a bioactive naphthalenethiobarbiturate derivative that potently inhibits the NF kappaB subunit c-Rel. IT-901 suppressed graft-versus-host disease while preserving graft-versus-lymphoma activity during allogeneic transplantation. Further preclinical assessment of IT-901 for the treatment of human B-cell lymphoma revealed antitumor properties in vitro and in vivo without restriction to NF-kappaB-dependent lymphoma. This nondiscriminatory, antilymphoma effect was attributed to modulation of the redox homeostasis in lymphoma cells resulting in oxidative stress. Moreover, NF-kappaB inhibition by IT-901 resulted in reduced stimulation of the oxidative stress response gene heme oxygenase-1, and we demonstrated that NF-kappaB inhibition exacerbated oxidative stress induction to inhibit growth of lymphoma cells. Notably, IT-901 did not elicit increased levels of reactive oxygen species in normal leukocytes, illustrating its cancer selective properties. Taken together, our results provide mechanistic insight and preclinical proof of concept for IT-901 as a novel therapeutic agent to treat human lymphoid tumors and ameliorate graft-versus-host disease. PMID- 26744527 TI - Cancer Cell Dissemination and Homing to the Bone Marrow in a Zebrafish Model. AB - Advancement of many solid tumors and hematologic malignancies is frequently characterized by dissemination and homing of cancer cells to the bone marrow (BM). Methods to quantitatively characterize these key steps of the metastatic cascade in mammalian models are currently limited and do not offer opportunities to perform rapid, large-scale genomic, or drug screening. Because of their optical clarity, we used zebrafish to develop an in vivo model of cancer cell dissemination and homing to the BM. We performed intracardiac injection of multiple myeloma (MM) cells derived from human BM or cell lines and monitored their migration to the caudal hematopoietic tissue (CHT), the region where hematopoiesis occurs in the zebrafish embryo, which recapitulates a BM-like niche. Transcriptomic analyses confirmed that MM cells homing to the CHT displayed gene-expression differences compared with MM cells outside of the CHT, including significant enrichment for genes known to regulate interleukin-6 (IL6) signaling, cell adhesion, and angiogenesis. Collectively, our findings point to the zebrafish as a valuable model in which to study cancer cell homing to the hematopoietic niche and to establish a screening platform for the identification of factors and mechanisms contributing to the early steps of bone metastasis. PMID- 26744528 TI - Redirecting Transport of Nanoparticle Albumin-Bound Paclitaxel to Macrophages Enhances Therapeutic Efficacy against Liver Metastases. AB - Current treatments for liver metastases arising from primary breast and lung cancers are minimally effective. One reason for this unfavorable outcome is that liver metastases are poorly vascularized, limiting the ability to deliver therapeutics from the systemic circulation to lesions. Seeking to enhance transport of agents into the tumor microenvironment, we designed a system in which nanoparticle albumin-bound paclitaxel (nAb-PTX) is loaded into a nanoporous solid multistage nanovector (MSV) to enable the passage of the drug through the tumor vessel wall and enhance its interaction with liver macrophages. MSV enablement increased nAb-PTX efficacy and survival in mouse models of breast and lung liver metastasis. MSV-nAb-PTX also augmented the accumulation of paclitaxel and MSV in the liver, specifically in macrophages, whereas paclitaxel levels in the blood were unchanged after administering MSV-nAb-PTX or nAb-PTX. In vitro studies demonstrated that macrophages treated with MSV-nAb-PTX remained viable and were able to internalize, retain, and release significantly higher quantities of paclitaxel compared with treatment with nAb-PTX. The cytotoxic potency of the released paclitaxel was also confirmed in tumor cells cultured with the supernatants of macrophage treated with MSV-nAB-PTX. Collectively, our findings showed how redirecting nAb-PTX to liver macrophages within the tumor microenvironment can elicit a greater therapeutic response in patients with metastatic liver cancer, without increasing systemic side effects. PMID- 26744529 TI - A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors. AB - Elevated levels of the proinflammatory cytokine IL6 are associated with poor survival outcomes in many cancers. Antibodies targeting IL6 and its receptor have been developed for chronic inflammatory disease, but they have not yet been shown to clearly benefit cancer patients, possibly due to antibody potency or the settings in which they have been tested. In this study, we describe the development of a novel high-affinity anti-IL6 antibody, MEDI5117, which features an extended half-life and potent inhibitory effects on IL6 biologic activity. MEDI5117 inhibited IL6-mediated activation of STAT3, suppressing the growth of several tumor types driven by IL6 autocrine signaling. In the same models, MEDI5117 displayed superior preclinical activity relative to a previously developed anti-IL6 antibody. Consistent with roles for IL6 in promoting tumor angiogenesis, we found that MEDI5117 inhibited the growth of endothelial cells, which can produce IL6 and support tumorigenesis. Notably, in tumor xenograft assays in mice, we documented the ability of MEDI5117 to enhance the antitumor activities of chemotherapy or gefitinib in combination treatment regimens. MEDI5117 also displayed robust activity on its own against trastuzumab-resistant HER2(+) tumor cells by targeting the CD44(+)CD24(-) cancer stem cell population. Collectively, our findings extend the evidence of important pleiotropic roles of IL6 in tumorigenesis and drug resistance, and offer a preclinical proof of concept for the use of IL6 antibodies in combination regimens to heighten therapeutic responses and overcome drug resistance. PMID- 26744530 TI - IL6 Trans-signaling Promotes KRAS-Driven Lung Carcinogenesis. AB - Oncogenic KRAS mutations occur frequently in lung adenocarcinoma. The signaling pathways activated by IL6 promote Kras-driven lung tumorigenesis, but the basis for this cooperation is uncertain. In this study, we used the gp130(F/F) (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRAS-driven lung tumorigenesis. Malignant growths in the gp130(F/F):Kras(G12D) model displayed features of atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma throughout the lung, as compared with parental Kras(G12D) mice, where STAT3 was not hyperactivated. Among IL6 family cytokines, only IL6 was upregulated in the lung. Accordingly, normalization of pulmonary STAT3 activity, by genetic ablation of either Il6 or Stat3, suppressed the extent of lung cancer in the model. Mechanistic investigations revealed elevation in the lung of soluble IL6 receptor (sIL6R), the key driver of IL6 trans-signaling, and blocking this mechanism via interventions with an anti-IL6R antibody or the inhibitor sgp130Fc ameliorated lung cancer pathogenesis. Clinically, expression of IL6 and sIL6R was increased significantly in human specimens of lung adenocarcinoma or patient serum. Our results offer a preclinical rationale to clinically evaluate IL6 trans-signaling as a therapeutic target for the treatment of KRAS-driven lung adenocarcinoma. PMID- 26744526 TI - EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer. AB - Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFR(T790M) mutations in vitro and inhibited tumor growth and progression in an inducible EGFR(L858R+T790M)-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors. PMID- 26744531 TI - HSPB1 Inhibits the Endothelial-to-Mesenchymal Transition to Suppress Pulmonary Fibrosis and Lung Tumorigenesis. AB - The endothelial-to-mesenchymal transition (EndMT) contributes to cancer, fibrosis, and other pathologic processes. However, the underlying mechanisms are poorly understood. Endothelial HSP1 (HSPB1) protects against cellular stress and has been implicated in cancer progression and pulmonary fibrosis. In this study, we investigated the role of HSPB1 in mediating the EndMT during the development of pulmonary fibrosis and lung cancer. HSPB1 silencing in human pulmonary endothelial cells accelerated emergence of the fibrotic phenotype after treatment with TGFbeta or other cytokines linked to pulmonary fibrosis, suggesting that HSPB1 maintains endothelial cell identity. In mice, endothelial-specific overexpression of HSPB1 was sufficient to inhibit pulmonary fibrosis by blocking the EndMT. Conversely, HSPB1 depletion in a mouse model of lung tumorigenesis induced the EndMT. In clinical specimens of non-small cell lung cancer, HSPB1 expression was absent from tumor endothelial cells undergoing the EndMT. Our results showed that HSPB1 regulated the EndMT in lung fibrosis and cancer, suggesting that HSPB1-targeted therapeutic strategies may be applicable for treating an array of fibrotic diseases. PMID- 26744533 TI - Sudden cardiac death in asymptomatic aortic stenosis: is the valve to blame? AB - An active 68-year-old man with asymptomatic severe aortic stenosis and normal functional capacity on a conventional bicycle exercise test underwent a haemodynamic stress test with simultaneous invasive haemodynamic monitoring and echocardiography during supine bicycle testing as part of a research project. With exercise, the patient developed pulmonary venous hypertension and mild regional wall motion abnormalities on echocardiography. The patient terminated the test due to exhaustion. In the recovery period, he developed sustained ventricular tachycardia and became unconscious. No symptoms were present during exercise or prior to cardiac arrest. The following coronary angiogram revealed significant 2-vessel disease, and the patient subsequently underwent successful aortic valve replacement and coronary-artery bypass graft surgery. PMID- 26744532 TI - Infiltrating Macrophages Induce ERalpha Expression through an IL17A-mediated Epigenetic Mechanism to Sensitize Endometrial Cancer Cells to Estrogen. AB - Persistent unopposed estrogen stimulation is a central oncogenic mechanism driving the formation of type I endometrial cancer. Recent epidemiologic and clinical studies of endometrial cancer have also revealed a role for insulin resistance, clinically manifested by chronic inflammation. However, the role of inflammation in estrogen-driven endometrial cancer is not well characterized. In this study, we investigated the association between infiltrating macrophages and estrogen sensitivity in endometrial cancer. Evaluating tissue samples and serum from patients with precancerous lesions or endometrial cancer, we found that tissue macrophage infiltration, but not serum estradiol levels, correlated positively with endometrial cancer development. Furthermore, IL4/IL13-induced CD68(+)CD163(+) macrophages enhanced the proliferative effects of estradiol in endometrial cancer cells by upregulating estrogen receptor alpha (ERalpha), but not ERbeta. Mechanistic investigations revealed that CD68(+)CD163(+) macrophages secreted cytokines, such as IL17A, that upregulated ERalpha expression through TET1-mediated epigenetic modulation of the ERalpha gene. Overall, our findings show how cytokines produced by infiltrating macrophages in the endometrial microenvironment can induce epigenetic upregulation of ERalpha expression, which in turn sensitizes endometrial cells to estrogen stimulation. The concept that inflammation-induced estrogen sensitivity in the endometrium acts as a driver of type I endometrial cancer has implications for infiltrating macrophages as a prognostic biomarker of progression in this disease setting. PMID- 26744534 TI - Charcot's osteoarthropathy mimicking an osteosarcoma of humerus. AB - Charcot's arthropathy or neuropathic osteoarthropathy is a form of destructive arthropathy associated with decreased sensory innervation. We present an unusual case of a patient referred to oncology clinic for further evaluation of a spindle cell neoplasm of the humerus concerning for malignancy. The mass presented as a lytic lesion associated with a right humerus fracture. This was later diagnosed as Charcot's shoulder secondary to cervical syringomyelia. A detailed case report and discussion are presented here. PMID- 26744535 TI - Carpal tunnel syndrome caused by neural fibrolipoma. PMID- 26744536 TI - Polyostotic fibrous dysplasia: a rare cause of pathological fractures in young patients. PMID- 26744537 TI - Spontaneous pulmonary haemorrhage into an existing emphysematous bulla. AB - A patient with chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis presented dyspnoeic with productive cough and large-volume haemoptysis, 1 month after coronary stenting and commencement of clopidogrel. A chest radiograph showed a well-circumscribed opacity in the left lower zone with surrounding consolidation, where previously an emphysematous bulla had been. A CT scan of the thorax confirmed a 14 cm bulla in the left lower lobe, which was 70% filled with blood with associated surrounding consolidation. A diagnosis of pulmonary haemorrhage into an existing emphysematous bulla with co-existing infective exacerbation of COPD was performed. Owing to his significant comorbidities, the patient was managed conservatively, returning to baseline over several days. He had two further admissions due to pulmonary infection over 2 months, where the haematoma was nominally smaller, and died during the second of these. PMID- 26744538 TI - Pathophysiology of tumour-induced microangiopathic haemolytic anaemia. AB - Cancer-associated microangiopathic haemolytic anaemia (CA-MAHA) is a syndrome characterised by Coombs-negative haemolytic anaemia and thrombocytopenia. It is primarily seen in advanced solid tumours and is distinct from thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome. Diagnosis is often delayed and patients have a high mortality. We present the case of CA-MAHA in a patient with metastatic breast cancer treated successfully with early initiation of chemotherapy. In addition, we report longitudinal laboratory evaluation of circulating tumour cells and microparticles and suggest a hypothesis for the mechanism behind CA-MAHA. PMID- 26744539 TI - Post-malaria neurological syndrome or viral encephalitis? AB - We present a case of a 60-year-old Caucasian man recently returned from Angola, where he had been successfully treated for a severe (non-cerebral) falciparum malaria infection. He was presented to the emergency room, with a subacute onset encephalopathy, ataxia and a generalised tonic-clonic seizure. Cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis (123 cells/uL) and hyperproteinorrhachia (188 mg/dL). Brain MRI and EEG were unremarkable. CSF PCR testing for neurotropic viruses was negative as were CSF and blood cultures. The patient was treated with ceftriaxone and acyclovir, with full recovery on the second day of treatment. We believe post-malaria neurological syndrome, a rare self-limited encephalopathy, should be considered in the differential diagnosis. Nevertheless, the presentation, lack of changes on brain MRI and EEG, along with possible false-negative CSF viral PCR, could still represent a viral encephalitis, which brings to question the treatment approach to adopt (conservative vs wide spectrum antiviral plus antibiotics). PMID- 26744540 TI - Shunt malfunction in patients with hydrocephalus: complications revisited. PMID- 26744541 TI - Processing Narratives Concerning Protected Values: A Cross-Cultural Investigation of Neural Correlates. AB - Narratives are an important component of culture and play a central role in transmitting social values. Little is known, however, about how the brain of a listener/reader processes narratives. A receiver's response to narration is influenced by the narrator's framing and appeal to values. Narratives that appeal to "protected values," including core personal, national, or religious values, may be particularly effective at influencing receivers. Protected values resist compromise and are tied with identity, affective value, moral decision-making, and other aspects of social cognition. Here, we investigated the neural mechanisms underlying reactions to protected values in narratives. During fMRI scanning, we presented 78 American, Chinese, and Iranian participants with real life stories distilled from a corpus of over 20 million weblogs. Reading these stories engaged the posterior medial, medial prefrontal, and temporo-parietal cortices. When participants believed that the protagonist was appealing to a protected value, signal in these regions was increased compared with when no protected value was perceived, possibly reflecting the intensive and iterative search required to process this material. The effect strength also varied across groups, potentially reflecting cultural differences in the degree of concern for protected values. PMID- 26744542 TI - The Regulation of Corticofugal Fiber Targeting by Retinal Inputs. AB - Corticothalamic projection systems arise from 2 main cortical layers. Layer V neurons project exclusively to higher-order thalamic nuclei, while layer VIa fibers project to both first-order and higher-order thalamic nuclei. During early postnatal development, layer VIa and VIb fibers accumulate at the borders of the dorsal lateral geniculate nucleus (dLGN) before they innervate it. After neonatal monocular enucleation or silencing of the early retinal activity, there is premature entry of layer VIa and VIb fibers into the dLGN contralateral to the manipulation. Layer V fibers do not innervate the superficial gray layer of the superior colliculus during the first postnatal week, but also demonstrate premature entry to the contralateral superficial gray layer following neonatal enucleation. Normally, layer V driver projections to the thalamus only innervate higher-order nuclei. Our results demonstrate that removal of retinal input from the dLGN induces cortical layer V projections to aberrantly enter, arborize, and synapse within the first-order dLGN. These results suggest that there is cross hierarchical corticothalamic plasticity after monocular enucleation. Cross hierarchical rewiring has been previously demonstrated in the thalamocortical system (Pouchelon et al. 2014), and now we provide evidence for cross hierarchical corticothalamic rewiring after loss of the peripheral sensory input. PMID- 26744545 TI - A 2D 4*4 Channel Readout ASIC for Pixelated CdTe Detectors for Medical Imaging Applications. AB - We present a 16-channel readout integrated circuit (ROIC) with nanosecond resolution time to digital converter (TDC) for pixelated Cadmium Telluride (CdTe) gamma-ray detectors. The 4 * 4 pixel array ROIC is the proof of concept of the 10 * 10 pixel array readout ASIC for positron-emission tomography (PET) scanner, positron-emission mammography (PEM) scanner, and Compton gamma camera. The electronics of each individual pixel integrates an analog front-end with switchable gain, an analog to digital converter (ADC), configuration registers, and a 4-state digital controller. For every detected photon, the pixel electronics provides the energy deposited in the detector with 10-bit resolution, and a fast trigger signal for time stamp. The ASIC contains the 16-pixel matrix electronics, a digital controller, five global voltage references, a TDC, a temperature sensor, and a band-gap based current reference. The ASIC has been fabricated with TSMC 0.25 MUm mixed-signal CMOS technology and occupies an area of 5.3 mm * 6.8 mm. The TDC shows a resolution of 95.5 ps, a precision of 600 ps at full width half maximum (FWHM), and a power consumption of 130 MUW. In acquisition mode, the total power consumption of every pixel is 200 MUW. An equivalent noise charge (ENC) of 160 e-RMS at maximum gain and negative polarity conditions has been measured at room temperature. PMID- 26744543 TI - Spontaneous Fluctuations in Visual Cortical Responses Influence Population Coding Accuracy. AB - Information processing in the cerebral cortex depends not only on the nature of incoming stimuli, but also on the state of neuronal networks at the time of stimulation. That is, the same stimulus will be processed differently depending on the neuronal context in which it is received. A major factor that could influence neuronal context is the background, or ongoing neuronal activity before stimulation. In visual cortex, ongoing activity is known to play a critical role in the development of local circuits, yet whether it influences the coding of visual features in adult cortex is unclear. Here, we investigate whether and how the information encoded by individual neurons and populations in primary visual cortex (V1) depends on the ongoing activity before stimulus presentation. We report that when individual neurons are in a "low" prestimulus state, they have a higher capacity to discriminate stimulus features, such as orientation, despite their reduction in evoked responses. By measuring the distribution of prestimulus activity across a population of neurons, we found that network discrimination accuracy is improved in the low prestimulus state. Thus, the distribution of ongoing activity states across the network creates an "internal context" that dynamically filters incoming stimuli to modulate the accuracy of sensory coding. The modulation of stimulus coding by ongoing activity state is consistent with recurrent network models in which ongoing activity dynamically controls the balanced background excitation and inhibition to individual neurons. PMID- 26744544 TI - Recent Advances in Multinuclear Metal Nitrosyl Complexes. AB - The coordination chemistry of metal nitrosyls has expanded rapidly in the past decades due to major advances of nitric oxide and its metal compounds in biology. This review article highlights advances made in the area of multinuclear metal nitrosyl complexes, including Roussin's salts and their ester derivatives from 2003 to present. The review article focuses on isolated multinuclear metal nitrosyl complexes and is organized into different sections by the number of metal centers and bridging ligands. PMID- 26744547 TI - A Single-Flask Synthesis of alpha-Alkylidene and alpha-Benzylidene Lactones from Ethoxyacetylene, Epoxides/Oxetanes, and Carbonyl Compounds. AB - Low temperature treatment of (ethoxyethynyl)lithium with epoxides or oxetanes in the presence of BF3*OEt2, followed by addition of aldehydes or ketones and warming to room temperature, affords structurally diverse five- and six-membered alpha-alkylidene and alpha-benzylidene lactones (5) in good to excellent yields. This one-pot process, in which three new carbon-carbon bonds and a ring are formed, affords substituted alpha,beta-unsaturated lactones of predominantly Z configuration. The reaction likely occurs via alkyne-carbonyl metathesis of a hydroxy-ynol ether intermediate, acid-promoted alkene E- to Z-isomerization, and lactonization. PMID- 26744546 TI - Fabrication and Characterization of a Glucose-sensitive Antibacterial Chitosan Polyethylene Oxide Hydrogel. AB - A novel glucose-sensitive chitosan-polyethylene oxide (CS/PEO =1:0.5~1:2.5) hydrogel with controlled release of metronidazole (MNZ) was obtained by chemical cross-linking and immobilization of glucose oxidase (GOx). The hydrogel was characterized by Fourier-transformed infrared spectroscopy (FTIR), compressive mechanical test, rheological analysis, cytotoxicity test, and antibacterial test against Porphyromonas gingivalis. The study found that the CS-PEO composite hydrogel possessed significantly better mechanical properties and biocompatibility than a single-component hydrogel. This might result from the physical cross-linking and formation of semi-interpenetrating network (semi-IPN). In addition, this novel hydrogel has self-regulate ability to release MNZ in response to the environmental glucose stimulus. Specifically, it released more drugs at higher glucose concentration, thus can lead to a greater ability to inhibit Porphyromonas gingivalis. This study has demonstrated the glucose sensitive antibacterial hydrogel has a great potential as a new therapeutic material for treatment or prevention of periodontitis in diabetic patients. PMID- 26744549 TI - Interaction Models for Functional Regression. AB - A functional regression model with a scalar response and multiple functional predictors is proposed that accommodates two-way interactions in addition to their main effects. The proposed estimation procedure models the main effects using penalized regression splines, and the interaction effect by a tensor product basis. Extensions to generalized linear models and data observed on sparse grids or with measurement error are presented. A hypothesis testing procedure for the functional interaction effect is described. The proposed method can be easily implemented through existing software. Numerical studies show that fitting an additive model in the presence of interaction leads to both poor estimation performance and lost prediction power, while fitting an interaction model where there is in fact no interaction leads to negligible losses. The methodology is illustrated on the AneuRisk65 study data. PMID- 26744548 TI - Fast single image haze removal via local atmospheric light veil estimation. AB - In this study, a novel single-image based dehazing framework is proposed to remove haze artifacts from images through local atmospheric light estimation. We use a novel strategy based on a physical model where the extreme intensity of each RGB pixel is used to define an initial atmospheric veil (local atmospheric light veil). Across bilateral filter is applied to each veil to achieve both local smoothness and edge preservation. A transmission map and a reflection component of each RGB channel are constructed from the physical atmospheric scattering model. The proposed approach avoids adverse effects caused by the error in estimating the global atmospheric light. Experimental results on outdoor hazy images demonstrate that the proposed method produces image output with satisfactory visual quality and color fidelity. Our comparative study demonstrates a higher performance of our method over several state-of-the-art methods. PMID- 26744550 TI - The effect of Early Head Start on child welfare system involvement: A first look at longitudinal child maltreatment outcomes. AB - The high societal and personal costs of child maltreatment make identification of effective early prevention programs a high research priority. Early Head Start (EHS), a dual generational program serving low-income families with children prenatally through age three years, is one of the largest federally funded programs for infants and toddlers in the United States. A national randomized trial found EHS to be effective in improving parent and child outcomes, but its effectiveness in reducing child maltreatment was not assessed. The current study used administrative data from state child welfare agencies to examine the impact of EHS on documented abuse and neglect among children from seven of the original seventeen programs in the national EHS randomized controlled trial. Results indicated that children in EHS had significantly fewer child welfare encounters between the ages of five and nine years than did children in the control group, and that EHS slowed the rate of subsequent encounters. Additionally, compared to children in the control group, children in EHS were less likely to have a substantiated report of physical or sexual abuse, but more likely to have a substantiated report of neglect. These findings suggest that EHS may be effective in reducing child maltreatment among low-income children, in particular, physical and sexual abuse. PMID- 26744551 TI - It's not as simple as it sounds: Problems and solutions in accessing and using administrative child welfare data for evaluating the impact of early childhood interventions. AB - In recent years, there has been increasing interest in using administrative data collected by state child welfare agencies as a source of information for research and evaluation. The challenges of obtaining access to and using these data, however, have not been well documented. This study describes the processes used to access child welfare records in six different states and the approach to combining and using the information gathered to evaluate the impact of the Early Head Start program on children's involvement with the child welfare system from birth through age eleven. We provide "lessons learned" for researchers who are attempting to use this information, including being prepared for long delays in access to information, the need for deep understanding of how child welfare agencies record and code information, and for considerable data management work for translating agency records into analysis-ready datasets. While accessing and using this information is not easy, and the data have a number of limitations, we suggest that the benefits can outweigh the challenges and that these records can be a useful source of information for policy-relevant child welfare research. PMID- 26744554 TI - Treating asthma flareups at home - an opinion. PMID- 26744555 TI - Letters to the Editor. PMID- 26744553 TI - Effectiveness of a publicly funded clinical paediatric weight management program on obesity outcomes. AB - OBJECTIVE: To determine the effectiveness of a publicly funded, paediatric weight management clinic in decreasing obesity. METHODS: A retrospective chart review of patients four to 16 years of age, from 2006 to 2009, was performed at a medically supervised weight management clinic (n=121). Patients participated in monthly visits and were educated about the cognitive behavioural and nutritional aspects of weight management. RESULTS: The sample included 51 male and 70 female patients with a mean (+/- SD) initial age of 11.7+/-3.0 years. Patients participated in 6.4+/-6.5 visits (range one to 31 visits) over 13.7+/-15.5 months and 7.4% of patients discontinued treatment after their initial visit. Of the patients who attended the clinic >1 time, 66.1% attended for at least four months, 48.2% attended for >8 months and 33.0% attended for >1 year. Over the course of their treatment, patients experienced a weight gain of 3.8+/-9.5 kg, but a reduction in body mass index (BMI) percentile (-1.1+/-3.6%). Post-treatment, the prevalence of obesity decreased from 96.7% to 87.5%. Patients with longer treatment times (>12 months) attained significantly lower final BMI percentiles than patients with shorter treatment times; however, there was no difference in the rate of reduction. Initial treatment age, sex and medical conditions were not related to BMI percentile change. CONCLUSIONS: This paediatric weight management program effectively reduced the prevalence of obesity. Patients who had longer treatment times experienced greater reductions in obesity. Overall, the present study highlights that long-term patient attendance may be needed to better support paediatric weight management patients. PMID- 26744556 TI - CPSP 2014 results: What have we learned? PMID- 26744557 TI - The Committee to Advise on Tropical Medicine and Travel (CATMAT) - a reference for Canadian paediatricians. AB - The Committee to Advise on Tropical Medicine and Travel (CATMAT) is a federal government committee with wide representation in the fields of travel medicine and infectious diseases. They produce evidence-based statements on tropical and travel medicine for Canadian clinicians, including paediatric content ensured by the involvement of paediatric experts and a liaison member from the Canadian Paediatric Society. Links to all of the active statements are provided in the present practice point, with the aim of making Canadian health care providers more aware of this excellent resource. CATMAT statements of special interest to clinicians who deal with children address paediatric travellers, international adoption, personal protective measures to prevent arthropod bites, fever in the returning traveller, malaria, injury risk and travel, and guidelines for the practice of travel medicine. PMID- 26744558 TI - Uncomplicated pneumonia in healthy Canadian children and youth: Practice points for management. AB - Although immunization has decreased the incidence of bacterial pneumonia in vaccinated children, pneumonia remains common in healthy children. Symptoms of bacterial pneumonia frequently overlap those present with viral infections or reactive airway disease. Optimally, the diagnosis of bacterial pneumonia should be supported by a chest radiograph before starting antimicrobials. Factors such as age, vital signs and other measures of illness severity are critical when deciding whether to admit a patient to hospital. Because Streptococcus pneumoniae continues to be the most common cause of bacterial pneumonia in children, prescribing amoxicillin or ampicillin for seven to 10 days remains the mainstay of empirical therapy for nonsevere pneumonia. If improvement does not occur, consideration should be given to searching for complications (empyema or lung abscess). Routine chest radiographs at the end of therapy are not recommended unless clinically indicated. PMID- 26744559 TI - Minimizing blood loss and the need for transfusions in very premature infants. AB - Reducing blood loss and the need for blood transfusions in extremely preterm infants is part of effective care. Delayed cord clamping is well supported by the evidence and is recommended for infants who do not immediately require resuscitation. Cord milking may be an alternative to delayed cord clamping; however, more research is needed to support its use. In view of concerns regarding the increased risk for cognitive delay, clinicians should avoid using hemoglobin transfusion thresholds lower than those tested in clinical trials. Higher transfusion volumes (15 mL/kg to 20 mL/kg) may decrease exposure to multiple donors. Erythropoietin is not recommended for routine use due to concerns about retinopathy of prematurity. Elemental iron supplementation (2 mg/kg/day to 3 mg/kg/day once full oral feeds are achieved) is recommended to prevent later iron deficiency anemia. Noninvasive monitoring (eg, for carbon dioxide, bilirubin) and point-of-care testing reduce the need for blood sampling. Clinicians should strive to order the minimal amount of blood sampling required for safe patient care, and cluster samplings to avoid unnecessary skin breaks. PMID- 26744560 TI - Letters to the Editor. PMID- 26744562 TI - Health and growth status of immigrant and refugee children in Toronto, Ontario: A retrospective chart review. AB - OBJECTIVE: To describe selected anthropometric and health status variables among immigrant and refugee children <=6 years of age within an inner city clinic in Toronto, Ontario. METHODS: A retrospective chart review of patients born between January 1, 1998 and December 31, 2008, was conducted at a Toronto community health centre serving a primarily immigrant and refugee population. Outcome measures included calculated age-specific percentiles for height and weight, and the prevalence of anemia, iron deficiency, enteric parasites, elevated lead levels, HIV and hepatitis B. Postal codes were collected and used to determine the patient's neighbourhood income quintile. RESULTS: A total of 331 patients, born between January 1, 1998 and December 31, 2008, were identified. Of these, a total of 210 charts were manually reviewed. The prevalence of height-for-age and weight-for-age under the third percentile on the Centers for Disease Control and Prevention Growth Charts were 7.2% and 11.6%, respectively, and 8.4% and 5.0%, respectively, on the WHO Growth Standards Chart. Prevalence rates were also calculated for anemia (22.8%), iron deficiency (53.3%), hepatitis B (2.5%), parasitic infections (33.6%), elevated blood lead levels (4.9%) and HIV (0%). Neighbourhood income quintiles revealed that 46.7% of patients were residing in the lowest (ie, poorest) income quintile neighbourhoods. CONCLUSION: These findings reveal a high burden of illness within the population presenting to an immigrant/refugee health clinic, and illustrate the need for further research in this area, as well as increased efforts to ensure appropriate screening within clinics serving a high volume of newcomer patients. PMID- 26744561 TI - Corrigendum. AB - [This corrects the article on p. 293 in vol. 19.][This corrects the article on p. e35 in vol. 19.][This corrects the article on p. 333 in vol. 19, PMID: 25332664.][This corrects the article on p. 355 in vol. 19, PMID: 25332673.][This corrects the article on p. 399 in vol. 19.][This corrects the article on p. 404 in vol. 19, PMID: 25382994.][This corrects the article on p. 405 in vol. 19, PMID: 25382995.][This corrects the article on p. 428 in vol. 19, PMID: 25383000.][This corrects the article on p. 457 in vol. 19, PMID: 25414575.][This corrects the article on p. 473 in vol. 19, PMID: 25414582.][This corrects the article on p. 499 in vol. 19, PMID: 25414586.][This corrects the article on p. 513 in vol. 19, PMID: 25587223.][This corrects the article on p. 529 in vol. 19, PMID: 25587230.][This corrects the article on p. 531 in vol. 19, PMID: 25587231.][This corrects the article on p. 10 in vol. 20, PMID: 25722634.][This corrects the article on p. 19 in vol. 20, PMID: 25722638.][This corrects the article on p. 62 in vol. 20, PMID: 25838774.][This corrects the article on p. 65 in vol. 20, PMID: 25838775.][This corrects the article on p. 121 in vol. 20, PMID: 25914566.][This corrects the article on p. 123 in vol. 20, PMID: 25914567.][This corrects the article on p. 125 in vol. 20, PMID: 25914568.][This corrects the article on p. 129 in vol. 20.][This corrects the article on p. 131 in vol. 20, PMID: 25914570.][This corrects the article on p. 135 in vol. 20, PMID: 25914571.][This corrects the article on p. 139 in vol. 20, PMID: 25914572.][This corrects the article on p. 145 in vol. 20, PMID: 25914573.][This corrects the article on p. 148 in vol. 20, PMID: 25914574.][This corrects the article on p. 149 in vol. 20.][This corrects the article on p. 149 in vol. 20.][This corrects the article on p. 155 in vol. 20, PMID: 25914578.][This corrects the article on p. 157 in vol. 20.][This corrects the article on p. 159 in vol. 20, PMID: 25914579.][This corrects the article on p. 195 in vol. 20, PMID: 26038636.][This corrects the article on p. 233 in vol. 20, PMID: 26175556.][This corrects the article on p. 248 in vol. 20, PMID: 26175562.][This corrects the article on p. 251 in vol. 20.][This corrects the article on p. e30 in vol. 20, PMID: 26435675.][This corrects the article on p. 287 in vol. 20, PMID: 26435663.][This corrects the article on p. 293 in vol. 20, PMID: 26435666.][This corrects the article on p. 307 in vol. 20, PMID: 26435670.][This corrects the article on p. 349 in vol. 20, PMID: 26525858.][This corrects the article on p. 387 in vol. 20, PMID: 26526734.]. PMID- 26744564 TI - Case 1: An 11-year-old girl with bilateral hip and groin pain. PMID- 26744563 TI - Service utilization in a sample of preschool children with autism spectrum disorder: A Canadian snapshot. AB - OBJECTIVE: To describe services received by preschool children diagnosed with autism spectrum disorder (ASD) during the five-year period following their diagnosis. METHOD: An inception cohort of preschoolers diagnosed with ASD from Halifax (Nova Scotia), Montreal (Quebec), Hamilton (Ontario), Edmonton (Alberta) and Vancouver (British Columbia) were invited to participate. Parents/caregivers (n=414) described the services provided to their children at four time points: baseline (T1; within four months of diagnosis; mean age three years); six months later (T2); 12 months later (T3); and at school entry (T4). Data were first coded into 11 service types and subsequently combined into four broader categories (no services, behavioural, developmental and general) for analysis. RESULTS: More than 80% of children at T1, and almost 95% at T4 received some type of service, with a significant number receiving >1 type of service at each assessment point. At T1, the most common service was developmental (eg, speech-language therapy). Subsequently, the most common services were a combination of behavioural and developmental (eg, intensive therapy based on applied behaviour analysis and speech-language therapy). Service provision varied across provinces and over time. DISCUSSION: Although most preschool children with ASD residing in urban centres were able to access specialized services shortly after diagnosis, marked variation in services across provinces remains a concern. PMID- 26744565 TI - Case 2: A toddler with hyperlordosis. PMID- 26744566 TI - Foreword. PMID- 26744567 TI - 1) The Discovery of Robles Disease. PMID- 26744568 TI - 2) Dream of Dr. Horacio Figueroa. PMID- 26744569 TI - 1) Guatemala-Japan Cooperative Project on Onchocerciasis Research and Control: A Review of the Technical Cooperation, Case Study Series No. 6. PMID- 26744570 TI - 2) A Guatemala-Japan Collaboration Project for Onchocerciasis Research Supported by JICA, Japan. PMID- 26744571 TI - 1) International Medical Cooperation. General View. PMID- 26744573 TI - 3) Onchocerciasis. PMID- 26744572 TI - 2) Onchocerciasis. PMID- 26744574 TI - 4) Preliminary Report of Japan-Guatemala Onchocerciasis Control Pilot Project. PMID- 26744576 TI - 6) Epidemiology and Control of Guatemalan Onchocerciasis. AB - Recent studies on the epidemiology and control of Guatemalan onchocerciasis, chiefly made by the Guatemala-Japan Cooperative Project on Onchocerciasis Research and Control, are reviewed. Epidemiological features of Guatemalan onchocerciasis are summarized as to characteristic altitudinal distribution of endemic areas, disease manifestation, vector taxonomy, biology and transmission dynamic of the disease. Extensive insecticide studies in the field and laboratory demonstrate that the characteristic situations of Guatemalan streams where Simulium ochraceum, the main vector of onchocerciasis, breeds require ingenious methods of larviciding. Finally, the feasibility of an area vector control is indicated by the successful control operation in the San Vicente Pacaya Pilot Area, in which a new fixed-dose larviciding method was applied. PMID- 26744575 TI - 5) Review of the Biology and Ecology of Adult Blackflies in Relation to the Transmission of Onchocerciasis in Guatemala. AB - Recent studies on the biology and ecology of adult blackflies in relation to the transmission of human onchocerciasis in Guatemala are reviewed. First, earlier studies on the transmission of the disease since its discovery by Dr. R. Robles in 1915 are outlined. Second, eleven blackfly species caught on humans are evaluated for vector status on the basis of their natural and experimental infections with third-stage larvae of Onchocerca volvulus, and Simulium ochraceum,* S. metallicum* and S. callidum are confirmed as natural vectors of the disease in Guatemala in descending order of importance, whereas S. gonzalezi, S. haematopotum, S. veracruzanum and S. horacioi are potential vectors. Third, the migration and fate of O. volvulus microfilariae ingested by female blackflies are highlighted on the basis of the findings of the cibarial armature of S. ochraceum and physiological incompatibility of S. metallicum as main barriers against microfilariae, both of which greatly decrease the number of ingested O. volvulus microfilariae developing to the third-stage larvae per female. Fourth, among many ecological factors of female blackfly populations, geographical and altitudinal distributions, habits of blood feeding, host preferences for blood feeding, preference for human body parts, parous rates, daily and seasonal fluctuations of biting activities, in particular, of parous females, gonotrophic cycle, longevity, flight range, and annual transmission potential are reviewed, and their influences on the transmission dynamics of the disease agents are considered. Fifth, effects of air temperatures on the O. volvulus-S. ochraceum complex are examined, with a special reference to the characteristic altitudinal distributions of the disease. The importance of reliable identification of both the vector blackfly species and filarial larvae found in female blackflies is emphasized to understand the transmission of the disease. [*It is now known that these two species are actually species complexes.]. PMID- 26744577 TI - 5. List of 105 Original Articles and Reviews Produced in This Project. PMID- 26744579 TI - Modeling the effect of social networks on adoption of multifunctional agriculture. AB - Rotational grazing (RG) has attracted much attention as a cornerstone of multifunctional agriculture (MFA) in animal systems, potentially capable of producing a range of goods and services of value to diverse stakeholders in agricultural landscapes and rural communities, as well as broader societal benefits. Despite these benefits, global adoption of MFA has been uneven, with some places seeing active participation, while others have seen limited growth. Recent conceptual models of MFA emphasize the potential for bottom-up processes and linkages among social and environmental systems to promote multifunctionality. Social networks are critical to these explanations but how and why these networks matter is unclear. We investigated fifty-three farms in three states in the United States (New York, Wisconsin, Pennsylvania) and developed a stylized model of social networks and systemic change in the dairy farming system. We found that social networks are important to RG adoption but their impact is contingent on social and spatial factors. Effects of networks on farmer decision making differ according to whether they comprise weak-tie relationships, which bridge across disparate people and organizations, or strong tie relationships, which are shared by groups in which members are well known to one another. RG adoption is also dependent on features of the social landscape including the number of dairy households, the probability of neighboring farmers sharing strong ties, and the role of space in how networks are formed. The model replicates features of real-world adoption of RG practices in the Eastern US and illustrates pathways toward greater multifunctionality in the dairy landscape. Such models are likely to be of heuristic value in network-focused strategies for agricultural development. PMID- 26744580 TI - An examination of the handheld adapter approach for measuring hand-transmitted vibration exposure. AB - The use of a handheld adapter equipped with a tri-axial accelerometer is the most convenient and efficient approach for measuring vibration exposure at the hand tool interface, especially when the adapter is incorporated into a miniature handheld or wrist-strapped dosimeter. To help optimize the adapter approach, the specific aims of this study are to identify and understand the major sources and mechanisms of measurement errors and uncertainties associated with using these adapters, and to explore their improvements. Five representative adapter models were selected and used in the experiment. Five human subjects served as operators in the experiment on a hand-arm vibration test system. The results of this study confirm that many of the handheld adapters can produce substantial overestimations of vibration exposure, and measurement errors can significantly vary with tool, adapter model, mounting position, mounting orientation, and subject. Major problems with this approach include unavoidable influence of the hand dynamic motion on the adapter, unstable attachment, insufficient attachment contact force, and inappropriate adapter structure. However, the results of this study also suggest that measurement errors can be substantially reduced if the design and use of an adapter can be systematically optimized toward minimizing the combined effects of the identified factors. Some potential methods for improving the design and use of the adapters are also proposed and discussed. PMID- 26744581 TI - Michel G Bergeron "MGB" - a true success. PMID- 26744578 TI - Life in a Diverse Oral Community - Strategies for Oxidative Stress Survival. AB - BACKGROUND: While the oral cavity harbors more than 680 bacterial species, the interaction and association of selected bacterial species play a role in periodontal diseases. Bacterial species including Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia, a consortium previously designated as the "red complex" is now being expanded to include other new emerging pathogens that are significantly associated with periodontal disease. HIGHLIGHT: In addition to novel mechanisms for oxidative resistance of individual species, community dynamics may lead to an overall strategy for survival in the inflammatory environment of the periodontal pocket. Complex systems controlled by response regulators protect against oxidative and nitrosative stress. CONCLUSION: The combination of these multifaceted strategies would provide a comprehensive defense and support system against the repetitive host immune response to promote microbial persistence and disease. PMID- 26744582 TI - Digging for new solutions. PMID- 26744583 TI - Invasive disease due to Haemophilus influenzae type A in children in Canada's north: A priority for prevention. PMID- 26744584 TI - Treatment outcomes with telaprevir-based therapy for HIV/hepatitis C coinfected patients are comparable with hepatitis C monoinfected patients. PMID- 26744585 TI - An unusual case of abdominal pain. PMID- 26744586 TI - Characterization of invasive Neisseria meningitidis from Atlantic Canada, 2009 to 2013: With special reference to the nonpolysaccharide vaccine targets (PorA, factor H binding protein, Neisseria heparin-binding antigen and Neisseria adhesin A). AB - BACKGROUND: Serogroup B Neisseria meningitidis (MenB) has always been a major cause of invasive meningococcal disease (IMD) in Canada. With the successful implementation of a meningitis C conjugate vaccine, the majority of IMD in Canada is now caused by MenB. OBJECTIVE: To investigate IMD case isolates in Atlantic Canada from 2009 to 2013. Data were analyzed to determine the potential coverage of the newly licensed MenB vaccine. METHODS: Serogroup, serotype and serosubtype antigens were determined from IMD case isolates. Clonal analysis was performed using multilocus sequence typing. The protein-based vaccine antigen genes were sequenced and the predicted peptides were investigated. RESULTS: The majority of the IMD isolates were MenB (82.5%, 33 of 40) and, in particular, sequence type (ST)-154 B:4:P1.4 was responsible for 47.5% (19 of 40) of all IMD case isolates in Atlantic Canada. Isolates of this clone expressed the PorA antigen P1.4 and possessed the nhba genes encoding for Neisseria heparin-binding antigen peptide 2, which together matched exactly with two of the four components of the new four component meningococcal B vaccine. Nineteen MenB isolates had two antigenic matches, another five MenB and one meningitis Y isolate had one antigenic match. This provided 75.8% (25 of 33) potential coverage for MenB, or a 62.5% (25 of 40) overall potential coverage for IMD. CONCLUSION: From 2009 to 2013, IMD in Atlantic Canada was mainly caused by MenB and, in particular, the B:4:P1.4 ST-154 clone, which accounted for 47.5% of all IMD case isolates. The new four-component meningococcal B vaccine appeared to offer adequate coverage against MenB in Atlantic Canada. PMID- 26744590 TI - The role of empirical albendazole treatment in idiopathic hypereosinophilia - a case series. AB - Hypereosinophilia is usually defined as a blood eosinophil count >1500/MUL. A broad variety of conditions are associated with hypereosinophilia. The present report describes three cases of hypereosinophilia, in which a thorough history, physical examination, laboratory and imaging investigations were unable to detect any abnormalities. Albendazole was empirically administered in all three cases, with complete normalization of eosinophil counts thereafter. Empirical treatment with albendazole for patients presenting with hypereosinophilia should be strongly considered. PMID- 26744589 TI - Staphylococcus pettenkoferi bacteremia: A case report and review of the literature. AB - Staphylococcus pettenkoferi is a relatively recently described coagulase-negative staphylococci species first described in 2002. Since then, nine additional cases of infection caused by this species have been reported in various countries around the world, including Germany, Belgium, France, South Korea, Italy, Brazil and Mexico. The present report describes a case of S pettenkoferi peripheral line associated bacteremia. To our knowledge, the present report is the first description of human infection caused by S pettenkoferi in Canada. The present report also provides an overview of the laboratory detection of uncommon coagulase-negative staphylococci. PMID- 26744588 TI - Edwardsiella tarda bacteremia. A rare but fatal water- and foodborne infection: Review of the literature and clinical cases from a single centre. AB - BACKGROUND: Edwardsiella tarda bacteremia (ETB) can be a fatal disease in humans. OBJECTIVES: To determine the significant risk factors associated with death caused by ETB, and to examine the geographical, seasonal, environmental and dietary factors of the disease. METHODS: A retrospective, observational, case control study was performed. The PubMed MEDLINE and Japanese Medical Abstract Society (www.jamas.or.jp) databases were searched for ETB case reports and meeting abstracts. In additon, retrospective chart reviews of patients with ETB at the Tokyo Women's Medical University Hospital (Tokyo, Japan) were conducted to evaluate the risk factors associated with death using multivariate analyses. RESULTS: The literature search yielded 46 publications, comprising 72 cases from the English (n=30), French (n=1), Spanish (n=1) and Japanese (n=14) literature. Five cases at the Tokyo Women's Medical University Hospital were also included. Of the included 77 cases, the mean age was 61 years and 39% of patients were female; 77.2% of the cases occurred between June and November, and 45.5% were reported in Japan. Dietary factors (raw fish/meat exposure) were reported for 10.4% of patients and 12.9% reported environmental (ie, brackish water) exposure. The overall mortality rate was 44.6%; however, this rate increased to 61.1% for ETB patients with soft tissue infections. Liver cirrhosis was determined to be an independent risk factor associated with death (OR 12.0 [95% CI 2.46 to 58.6]; P=0.00213) using multivariate analyses. DISCUSSION: To our knowledge, the present analysis was the first and largest multi-language review of ETB. Clinical characteristics of ETB resemble those of Aeromonas, typhoid fever and Vibrio vulnificus infections, in addition to sharing similar risk factors. CONCLUSION: ETB should be categorized as a severe food- and waterborne infection, which results in high mortality for patients with liver cirrhosis. PMID- 26744587 TI - Fidaxomicin: A novel agent for the treatment of Clostridium difficile infection. AB - BACKGROUND: Due to the limitations of existing treatment options for Clostridium difficile infection (CDI), new therapies are needed. OBJECTIVE: To review the available data on fidaxomicin regarding chemistry, mechanisms of action and resistance, in vitro activity, pharmacokinetic and pharmacodynamic properties, efficacy and safety in clinical trials, and place in therapy. METHODS: A search of PubMed using the terms "fidaxomicin", "OPT-80", "PAR-101", "OP-1118", "difimicin", "tiacumicin" and "lipiarmycin" was performed. All English-language articles from January 1983 to November 2014 were reviewed, as well as bibliographies of all articles. RESULTS: Fidaxomicin is the first macrocyclic lactone antibiotic with activity versus C difficile. It inhibits RNA polymerase, therefore, preventing transcription. Fidaxomicin (and its active metabolite OP 1118) is bactericidal against C difficile and exhibits a prolonged postantibiotic effect (approximately 10 h). Other than for C difficile, fidaxomicin demonstrated only moderate inhibitory activity against Gram-positive bacteria and was a poor inhibitor of normal colonic flora, including anaerobes and enteric Gram-negative bacilli. After oral administration (200 mg two times per day for 10 days), fidaxomicin achieved low serum concentration levels but high fecal concentration levels (mean approximately 1400 MUg/g stool). Phase 3 clinical trials involving adults with CDI demonstrated that 200 mg fidaxomicin twice daily for 10 days was noninferior to 125 mg oral vancomycin four times daily for 10 days in regard to clinical response at the end of therapy. Fidaxomicin was, however, reported to be superior to oral vancomycin in reducing recurrent CDI and achieving a sustained clinical response (assessed at day 28) for patients infected with non-BI/NAP1/027 strains. CONCLUSION: Fidaxomicin was noninferior to oral vancomycin with regard to clinical response at the end of CDI therapy. Fidaxomicin has been demonstated to be as safe as oral vancomycin, but superior to vancomycin in achieving a sustained clinical response for CDI in patients infected with non-BI/NAP1/027 strains. Caution should be exercised in using fidaxomicin monotherapy for treatment of severe complicated CDI because limited data are available. Whether fidaxomicin is cost effective (due to its significantly higher acquisition cost versus oral vancomycin) depends on the acceptable willingness to pay threshold per quality-adjusted life year as a measure of assessing cost effectiveness. PMID- 26744592 TI - Exogenous endophthalmitis caused by Enterococcus casseliflavus: A case report and discussion regarding treatment of intraocular infection with vancomycin-resistant enterococci. AB - Endophthalmitis caused by enterococci is rare, and cases involving vancomycin resistant enterococci are even more so. Due to the poor bioavailability of many antibiotics in the vitreous chamber, special considerations are required when choosing antibiotics to treat these infections. The authors report the first case of exogenous endophthalmitis caused by Enterococcus casseliflavus via the unique mechanism of high-velocity water stream trauma from a toy water gun. A previously healthy four-year old boy presented with endophthalmitis of the left eye after injury from a water gun. Empirical treatment for endophthalmitis was started on presentation to the ophthalmologist. After the identification of the pathogen and a review of the literature, the antibiotic regimen was changed to include intravitreal ampicillin and amikacin with systemic linezolid. Endophthalmitis caused by E casseliflavus and other vancomycin-resistant enterococci are challenging to treat. Rapid identification of vancomycin-resistant enterococcal endophthalmitis is important to guide appropriate antibiotic therapy. Systemic linezolid achieves excellent intravitreal concentrations, and should be used in combination with intravitreal and topical antibiotics. PMID- 26744591 TI - Relapse of visceral leishmaniasis in an HIV-infected patient successfully treated with a combination of miltefosine and amphotericin B. AB - The present report documents a 49-year-old HIV-infected man receiving antiretroviral therapy with a suboptimal immune response and a CD4 count of 95 cells/mm(3), despite virological suppression. Investigation of bone marrow was conducted and yielded a diagnosis of visceral leishmaniasis. The clinical course was complicated by gastrointestinal involvment and relapse occurred after amphotericin B therapy. With the addition of miltefosine, the patient no longer presented with bone marrow amastigotes, and displayed an increased CD4 count and negative Leishmania polymerase chain reaction results. The present case highlights atypical presentation of visceral leishmaniasis, including poor immune reconstitution and gastrointestinal involvement. The high likelihood of relapse and response to combination therapy are illustrated. PMID- 26744593 TI - Are physicians obligated to tell parents about the meningococcal serogroup B vaccine? PMID- 26744594 TI - Corrigendum. AB - [This corrects the article on p. 231 in vol. 26, PMID: 26600804.]. PMID- 26744595 TI - MATHEMATICAL MODELING OF VENTILATION DEFECTS IN ASTHMA. AB - Airway narrowing by smooth muscle constriction is a hallmark of asthma attacks that may cause severe difficulties of breathing. However, the causes of asthma and the underlying mechanisms are not fully understood. Bronchoconstriction within a bronchial tree involves complex interactions among the airways that lead to the emergence of regions of poor ventilation (ventilation defects, VDefs) in the lungs. The emphasis of this review is on mathematical modeling of the mechanisms involved in bronchoconstriction and the emergence of the complex airway behavior that leads to VDefs. Additionally, the review discusses characteristic model behaviors and experimental data to demonstrate advances and limitations of different models. PMID- 26744598 TI - A Review of Mathematical Models for Leukemia and Lymphoma. AB - Recently, there has been significant activity in the mathematical community, aimed at developing quantitative tools for studying leukemia and lymphoma. Mathematical models have been applied to evaluate existing therapies and to suggest novel therapies. This article reviews the recent contributions of mathematical modeling to leukemia and lymphoma research. These developments suggest that mathematical modeling has great potential in this field. Collaboration between mathematicians, clinicians, and experimentalists can significantly improve leukemia and lymphoma therapy. PMID- 26744596 TI - Phenotype, endotype and patient-specific computational modelling for optimal treatment design in asthma. AB - Understanding and treatment of asthma is significantly complicated by the heterogeneous spectrum of phenotypes associated with the disease. Recent advances in phenotype classification promise more targeted therapies, but these categories are based on constellations of largely external measurements and are not necessarily indicative of underlying pathophysiology. We propose that computational modelling is a valuable tool that allows the disease spectrum to be decomposed not into phenotypes but rather into groups organized by underlying dysfunction, referred to by some authors as endotypes. By breaking down the asthmatic spectrum in this way, therapies can be targeted more directly to the underlying defects. This would be not only an important improvement in its own right, but also an important step toward the ultimate goal of patient-specific modelling. PMID- 26744597 TI - Volatile Anesthetics and the Treatment of Severe Bronchospasm: A Concept of Targeted Delivery. AB - Status asthmaticus (SA) is a severe, refractory form of asthma that can result in rapid respiratory deterioration and death. Treatment of SA with inhaled anesthetics is a potentially life-saving therapy, but remarkably few data are available about its mechanism of action or optimal administration. In this paper, we will review the clinical use of inhaled anesthetics for treatment of SA, the potential mechanisms by which they dilate constricted airways, and the side effects associated with their administration. We will also introduce the concept of 'targeted' delivery of these agents to the conducting airways, a process which may maximize their therapeutic effects while minimizing associated systemic side effects. Such a delivery regimen has the potential to define a rapidly translatable treatment paradigm for this life-threatening disorder. PMID- 26744599 TI - Factors associated with the first antiretroviral therapy modification in older HIV-1 positive patients. AB - BACKGROUND: Rates of first antiretroviral therapy (cART) modifications are high in most observational studies. The age-related differences in treatment duration and characteristics of first cART modifications remain underinvestigated. With increasing proportion of older patients in HIV population it is important to better understand age-related treatment effects. METHODS: Patients were included into this analysis, if being cART naive at the first visit at the clinic. Follow up time was measured from the first visit date until first cART modification or 28 February 2013. First cART modification was defined as any change in the third drug component i.e. protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), integrase inhibitor or fusion inhibitor. Cox proportional hazard models were used to identify factors related to first cART modification in three age groups: <30, 30-50 and >50. RESULTS: In total 2027 patients with 14,965 person-years of follow-up (PYFU) were included. The oldest group included 136 patients with 1901, middle group 1202 with 8416 PYFU and youngest group consisted of 689 patients with 4648 PYFU. Median follow-up time was 5.8 (IQR 3.4-9.4) years, median time on first cART was 4.4 (IQR 2.1-8.5) years. 72.4 % of patients started PI-based and 26.1 % NNRTI-based regimen. In total 1268 (62.5 %) patients had cART modification (non-adherence 30.8 %, toxicity 29.6 %). Durability of first cART was the best in patients over 50 y.o. (log-rank test, p = 0.001). Factors associated with discontinuation in this group were late presentation (HR 0.45, [95 % CI 0.23-0.90], p = 0.02) and PI use (HR 2.17, [95 % CI 1.18-4.0], p = 0.01). CONCLUSIONS: Rates of first cART modifications or discontinuation were comparable in all groups; however older patients were significantly longer on first cART regimen. PMID- 26744600 TI - From Two to One: Unipolar Sexual Reproduction. AB - While sexual reproduction is universal in eukaryotes, and shares conserved core features, the specific aspects of sexual reproduction can differ dramatically from species to species. This is also true in Fungi. Among fungal species, mating determination can vary from tetrapolar with more than a thousand different mating types, to bipolar with only two opposite mating types, and finally to unipolar without the need of a compatible mating partner for sexual reproduction. Cryptococcus neoformans is a human pathogenic fungus that belongs to the Basidiomycota. While C. neoformans has a well-defined bipolar mating system with two opposite mating types, MATa and MATalpha, it can also undergo homothallic unisexual reproduction from one single cell or between two cells of the same mating type. Recently, it was shown that, as in a-alpha bisexual reproduction, meiosis is also involved in alpha-alpha unisexual reproduction in C. neoformans. Briefly, recombination frequencies, the number of crossovers along chromosomes, as well as frequencies at which aneuploid and diploid progeny are produced, are all comparable between a-alpha bisexual and alpha-alpha unisexual reproduction. The plasticity observed in C. neoformans sexual reproduction highlights the extensive diversity in mating type determination, mating recognition, as well as modes of sexual reproduction across fungal species. PMID- 26744601 TI - Social support and gender differences in coping with depression among emerging adults: a mixed-methods study. AB - BACKGROUND: Depression affects a considerable proportion (12-25 %) of adolescents and so-called emerging adults (ages of 18 and 25). The aims of this study were to explore the relationship between perceived social support and depression in a sample of emerging adults, and subsequently to identify the type of social support young people consider most helpful in dealing with this type of emotional distress. METHODS: A sample of 105 young persons (17-21 years of age) was selected from a previous longitudinal study to create three groups of participants: subjects with a previous diagnosis of depression; subjects with self-perceived but undiagnosed distress compatible with depression; and a group of controls. Qualitative and validated instruments for measuring depressive symptoms (the BDI-II, Beck depression inventory) and social support (the Mannheim interview on social support) were administered. RESULTS: Loss of friendships over time and dissatisfaction with social and psychological support are variables associated with depression in emerging adulthood. Qualitative analysis revealed gender differences both in strategies for managing distress, and in how social support was understood to mitigate depressive symptoms. Male study participants prioritized support that helped them achieve self-control as a first step toward awareness of their emotional distress, while female study participants prioritized support that helped them achieve awareness of the problem as a first step toward self-control. CONCLUSIONS: Treatment for emerging adults with depression should take into account not only the impact of social support, but also gender differences in what they consider to be the most appropriate form of social support for dealing with emotional distress. PMID- 26744603 TI - Comparison of three distinct clean air suits to decrease the bacterial load in the operating room: an observational study. AB - BACKGROUND: Lowering air-borne bacteria counts in the operating room is essential in prevention of surgical site infections in orthopaedic joint replacement surgery. This is mainly achieved by decreasing bacteria counts through dilution, with appropriate ventilation and by limiting the bacteria carrying skin particles, predominantly shed by the personnel. The aim of this study was to investigate if a single use polypropylene clothing system or a reusable polyester clothing system could offer similar air quality in the operating room as a mobile laminar airflow device-assisted reusable cotton/polyester clothing system. METHODS: Prospective observational study design, comparing the performance of three Clean Air Suits by measuring Colony Forming Units (CFU)/m(3) of air during elective hip and knee arthroplasties, performed at a large university-affiliated hospital. The amount of CFU/m(3) of air was measured during 37 operations of which 13 were performed with staff dressed in scrub suits made of a reusable mixed material (69 % cotton, 30 % polyester, 1 % carbon fibre) accompanied by two mobile laminar airflow units. During 24 procedures no mobile laminar airflow units were used, 13 with staff using a reusable olefin fabric clothing (woven polypropylene) and 11 with staff dressed in single-use suits (non-woven spunbonded polypropylene). Air from the operating field was sampled through a filter, by a Sartorius MD8, and bacterial colonies were counted after incubation. There were 6-8 measurements from each procedure, in total 244 measurements. Statistical analysis was performed by Mann-Whitney U-test. RESULTS: The single use polypropylene suit reduced the amount of CFU/m(3) to a significantly lower level than both other clothing systems. CONCLUSION: Single-use polypropylene clothing systems can replace mobile laminar airflow unit-assisted reusable mixed material-clothing systems. Measurements in standardized laboratory settings can only serve as guidelines as environments in real operation settings present a much more difficult challenge. PMID- 26744602 TI - SorGSD: a sorghum genome SNP database. AB - BACKGROUND: Sorghum (Sorghum bicolor) is one of the most important cereal crops globally and a potential energy plant for biofuel production. In order to explore genetic gain for a range of important quantitative traits, such as drought and heat tolerance, grain yield, stem sugar accumulation, and biomass production, via the use of molecular breeding and genomic selection strategies, knowledge of the available genetic variation and the underlying sequence polymorphisms, is required. RESULTS: Based on the assembled and annotated genome sequences of Sorghum bicolor (v2.1) and the recently published sorghum re-sequencing data, ~62.9 M SNPs were identified among 48 sorghum accessions and included in a newly developed sorghum genome SNP database SorGSD (http://sorgsd.big.ac.cn). The diverse panel of 48 sorghum lines can be classified into four groups, improved varieties, landraces, wild and weedy sorghums, and a wild relative Sorghum propinquum. SorGSD has a web-based query interface to search or browse SNPs from individual accessions, or to compare SNPs among several lines. The query results can be visualized as text format in tables, or rendered as graphics in a genome browser. Users may find useful annotation from query results including type of SNPs such as synonymous or non-synonymous SNPs, start, stop of splice variants, chromosome locations, and links to the annotation on Phytozome (www.phytozome.net) sorghum genome database. In addition, general information related to sorghum research such as online sorghum resources and literature references can also be found on the website. All the SNP data and annotations can be freely download from the website. CONCLUSIONS: SorGSD is a comprehensive web portal providing a database of large-scale genome variation across all racial types of cultivated sorghum and wild relatives. It can serve as a bioinformatics platform for a range of genomics and molecular breeding activities for sorghum and for other C4 grasses. PMID- 26744604 TI - Total contact cast wall load in patients with a plantar forefoot ulcer and diabetes. AB - BACKGROUND: The total contact cast (TCC) is an effective intervention to reduce plantar pressure in patients with diabetes and a plantar forefoot ulcer. The walls of the TCC have been indirectly shown to bear approximately 30 % of the plantar load. A new direct method to measure inside the TCC walls with capacitance sensors has shown that the anterodistal and posterolateral-distal regions of the lower leg bear the highest load. The objective of this study was to directly measure these two regions in patients with Diabetes and a plantar forefoot ulcer to further understand the mechanism of pressure reduction in the TCC. METHODS: A TCC was applied to 17 patients with Diabetes and a plantar forefoot ulcer. TCC wall load (contact area, peak pressure and max force) at the anterodistal and posterolateral-distal regions of the lower leg were evaluated with two capacitance sensor strips measuring 90 cm(2) (pliance(r), novel GmbH, Germany). Plantar load (contact area, peak pressure and max force) was measured with a capacitance sensor insole (pedar(r), novel GmbH, Germany) placed inside the TCC. Both pedar(r) and pliance(r) collected data simultaneously at a sampling rate of 50Hz synchronised to heel strike. The magnitude of TCC wall load as a proportion of plantar load was calculated. The TCC walls were then removed to determine the differences in plantar loading between the TCC and the cut down shoe-cast for the whole foot, rearfoot, midfoot and forefoot (region of interest). RESULTS: TCC wall load was substantial. The anterodistal lower leg recorded 48 % and the posterolateral-distal lower leg recorded 34 % of plantar contact area. The anterodistal lower leg recorded 28 % and the posterolateral distal lower leg recorded 12 % of plantar peak pressure. The anterodistal lower leg recorded 12 % and the posterolateral-distal lower leg recorded 4 % of plantar max force. There were significant differences in plantar load between the TCC and the cut down shoe-cast for the whole foot, rearfoot, midfoot and forefoot (region of ulcer). Contact area significantly increased by 5 % beneath the whole foot, 8 % at the midfoot and 6 % at the forefoot in the shoe-cast (p < 0.05). Peak pressure significantly increased by 8 % beneath the midfoot and 13 % at the forefoot in the shoe-cast (p < 0.05). Max force significantly increased 6 % beneath the midfoot in the (shoe-cast p < 0.05). CONCLUSION: In patients with diabetes and a plantar forefoot ulcer, the walls of the TCC bear considerable load. Reduced plantar contact area in the TCC compared to the shoe-cast suggests that the foot is suspended by the considerable load bearing capacity of the walls of the TCC which contributes mechanically to the pressure reduction and redistribution properties of the TCC. PMID- 26744605 TI - In vitro biophysical, microspectroscopic and cytotoxic evaluation of metastatic and non-metastatic cancer cells in responses to anti-cancer drug. AB - The Breast Cancer Metastasis Suppressor 1 (BRMS1) is a nucleo-cytoplasmic protein that suppresses cancer metastasis without affecting the growth of the primary tumor. Previous work has shown that it decreases the expression of protein mediators involved in chemoresistance. This study measured the biomechanical and biochemical changes in BRMS1 expression and the responses of BRMS1 to drug treatments on cancer cells in vitro. The results show that BRMS1 expression affects biomechanical properties by decreasing the Young's modulus and adhesion force of breast cancer cells after doxorubicin (DOX) exposure. Raman spectral bands corresponding to DNA/RNA, lipids and proteins were similar for all cells after DOX treatment. The expression of cytokines were similar for cancer cells after DOX exposure, although BRMS1 expression had different effects on the secretion of cytokines for breast cancer cells. The absence of significant changes on apoptosis, reactive oxygen species (ROS) expression and cell viability after BRMS1 expression shows that BRMS1 has little effect on cellular chemoresistance. Analyzing cancer protein expression is critical in evaluating therapeutics. Our study may provide evidence of the benefit of metastatic suppressor expression before chemotherapy. PMID- 26744607 TI - Coeliac disease, mucosal change and IEL: doing what counts the best. PMID- 26744606 TI - Complete genome sequence of Methanospirillum hungatei type strain JF1. AB - Methanospirillum hungatei strain JF1 (DSM 864) is a methane-producing archaeon and is the type species of the genus Methanospirillum, which belongs to the family Methanospirillaceae within the order Methanomicrobiales. Its genome was selected for sequencing due to its ability to utilize hydrogen and carbon dioxide and/or formate as a sole source of energy. Ecologically, M. hungatei functions as the hydrogen- and/or formate-using partner with many species of syntrophic bacteria. Its morphology is distinct from other methanogens with the ability to form long chains of cells (up to 100 MUm in length), which are enclosed within a sheath-like structure, and terminal cells with polar flagella. The genome of M. hungatei strain JF1 is the first completely sequenced genome of the family Methanospirillaceae, and it has a circular genome of 3,544,738 bp containing 3,239 protein coding and 68 RNA genes. The large genome of M. hungatei JF1 suggests the presence of unrecognized biochemical/physiological properties that likely extend to the other Methanospirillaceae and include the ability to form the unusual sheath-like structure and to successfully interact with syntrophic bacteria. PMID- 26744608 TI - Hemostasis in uncontrolled esophageal variceal bleeding by self-expanding metal stents: a systematic review. AB - AIM: The aim of this systematic review was to evaluate the current reported efficacy and the mortality rate of SEMS treatment in uncontrolled bleeding patients. BACKGROUND: Esophageal variceal bleeding (EVB) represents a life threatening pathology. Despite the adequate pharmacologic and endoscopic treatment, continuous or recurrent bleeding, named as uncontrolled bleeding, occurs in 10-20% of cases. A new removable, covered, and self-expanding metal stent (SEMS) was proposed to control the variceal bleeding. MATERIALS AND METHODS: The study was conducted according to the PRISMA statement. Studies were identified by searching MEDLINE (1989-present) and SCOPUS (1989-present) databases. The last search was run on 01 July 2015. RESULTS: Nine studies (period range=2002-2015) met the inclusion criteria and were included in quantitative analysis. High rate of SEMS efficacy in controling acute bleeding was observed, with a reported percentage ranging from 77.7 to 100%. In 10% to 20% of patients, re-bleeding occurred with SEMS in situ. Stent deployment was successful in 77.8% to 100% of patients while 11 to 36.5% of patients experienced stent migration. CONCLUSION: SEMS could be effective and safe in control EVB and can be proposed as a reliable option to ballon tamponed for patient stabilization and as a bridging to other therapeutic approach. PMID- 26744609 TI - Burden of gastrointestinal cancers and problem of the incomplete information; how to make up the data? AB - Cancer registration is an important source for measuring the burden of cancer in a population. In practice, however, quite frequently incorrect patients are registered or data items can be inaccurately recorded or not recorded at all. Also the process or quality of these registrations varies among countries. In this paper, we briefly discussed some statistical techniques including; Mortality and Incidence Analysis Model (MIAMOD), Prevalence and Incidence Analysis Model (PIAMOD), Bayesian Inference and Capture-recapture methods, which provide tools to re-correct the incomplete or misclassified cancer statistics with regards to gastrointestinal cancers. PMID- 26744610 TI - The likelihood ratio and frequency of DQ2/DQ8 haplotypes in Iranian patients with celiac disease. AB - AIM: The aim of this study was to evaluate the likelihood ratio and frequency of DQ2 and DQ8 in Iranian patients with celiac disease (CD). BACKGROUND: The HLA DQ2 and HLA DQ8 are the important mediators in the development of celiac disease. A few studies evaluated the frequency of HLA DQ2 and HLA DQ8 haplotypes among the Iranian population with low sample size. PATIENTS AND METHODS: In this cross sectional study, to predict HLA-DQ2 and DQ8 haplotypes, 141(73 male, 78 female) confirmed CD patients compared to 151 healthy controls were enrolled into this study during 2013-2014. HLA DQ2/ DQ8 haplotypes was determined in cases and controls using PCR-SSP technique. RESULTS: DQ2 and DQ8 were positive in 80% (n=111) and 49% (n= 69) of CD patients and 36% (n=61) and 13% (n=21) of control group respectively. Moreover, 32% (n=45) of CD patients and 5.3% (n=8) of the control group were carrier of both haplotypes. In the case group about one-third of patients (32.2%) were positive for carrying both DQ2 and DQ8 heterodimers while only 5.3% (n=8) of the control group were carrier. In addition, the positive likelihood ratio of DQ2 and DQ8 were 1.74 (CI: 1.4- 2.1), and 2.6 (CI: 1.8- 2.7), respectively. CONCLUSION: The result of this study showed that the frequency of DQ8 among our population is higher than those reported by European countries, but it is close to those founded in South America and Middle East. This result suggests that the higher prevalence of HLA DQ8 pattern in Iranian CD patients is similar to non-European patients. PMID- 26744611 TI - Gastric atrophy: use of OLGA staging system in practice. AB - AIM: This study used the OLGA system to characterize the histology pattern of gastritis in dyspeptic outpatients with a mean age of 45 years from regions with different gastric cancer risks. BACKGROUND: Several classification systems have been purposed for understanding the status of the gastric mucosa. Currently, the Sydney system is the most widely employed. Nevertheless, the applicability of the Sydney system in therapeutic and prognostic areas is a matter of debate. Given this shortcoming an international group of gastroenterologists and pathologists developed a new system named Operative Link on Gastritis Assessment (OLGA). PATIENTS AND METHODS: In this cross-sectional comparative study the OLGA system was used to characterize the histology pattern of gastritis in 685 dyspeptic patients referring to the department of gastroenterology of a training hospital. RESULTS: No significant correlation was found between active inflammation and total OLGA score (P > 0.05). Also, no statistically significant correlation was found between activity and intestinal metaplasia, dysplasia, atrophy, and cancer (P > 0.05). Even though, there is a positive correlation between mild chronic inflammation and total OLGA score, no correlation has been identified between chronicity and dysplasia or cancer (P > 0.05). Nearly, In all cases with no dysplasia OLGA score was zero but all patients with gastric cancer OLGA score was more than two. CONCLUSION: Generally, the activity is not a useful factor in predicting prognosis and its loss of relation with total OLGA score does not make OLGA score any less predictable. PMID- 26744612 TI - The early efficacy of Heller myotomy in the treatment of Iranian patients with achalasia. AB - AIM: The purpose of this study was to determine the efficacy of Heller myotomy for the treatment of achalasia in a referral center in Tehran, and investigate the clinical characteristics, manometric results and treatment responses among three achalasia subtypes in Iranian patients. BACKGROUND: Esophageal achalasia is an unusual swallowing disorder, characterized by high pressure in the lower esophageal sphincter (LES) on swallowing, failure relaxation of the LES and the absence of peristalsis in esophageal. PATIENTS AND METHODS: In this cross sectional study, clinical symptom and esophageal manometry before and 2 months after treating with Heller myotomy in 20 patients with achalasia who were referred to Taleghani Hospital, Tehran, in 2013 were evaluated. Patients' demographic, clinical features and response to treatment were analyzed using SPSS software (version 20, Chicago, IL, USA). RESULTS: All the diagnostic criteria measured after the treatment were significantly different (P<0.05) before and after the therapy. The average decline in the length of the esophagus was 1.8 cm and dysphasia score was 7.25 units. Also an average decline in LES Resting Pressure, LES Residual Pressure, PIP, and IRP were 23.2 mmHg, 14.3 mmHg, 3.4 mmHg and 17.8 mmHg, respectively. CONCLUSION: Results of this study showed that the Heller myotomy is highly effective in relieving dysphasia in patients with achalasia. Also, type II achalasia is the most common subtype of achalasia with a better response to Heller myotomy compared to the other types. PMID- 26744613 TI - Study of regulatory promoter polymorphism (-248 G>A) of Bax gene in patients with gastric cancer in the northern provinces of Iran. AB - AIM: The aim of this study is to evaluate the polymorphism in Bax gene and its association with some clinical pathology traits in gastric cancer. BACKGROUND: Gastric cancer is considered as the fourth most common cancer in the north and northwest of Iran. Bcl2 family has a key role in regulation of apoptosis, and any changes in the expression of Bcl2 lead to cancer. PATIENTS AND METHODS: Blood samples were collected from 100 cases and 89 controls in the northern provinces of Iran to evaluate promoter polymorphism (-248G 25 it was not significant. Cross section of internal jugular vein had significant association with CVP of patients (P = 0.003). Longitudinal diameter of internal jugular vein had no significant association with CVP of patients (P = 0.052), but transverse diameter of internal jugular generally had significant association with CVP of patients (P = 0.003). Cross section of internal jugular had significant association with CVP (P = 0.001). CONCLUSIONS: Noninvasive assessment of the patient hydration condition using the ultrasound is a simple and practicable measure in emergency. With regard to the considerations, it is possible to estimate CVP via diameter measurement and cross-section of the central veins. PMID- 26744630 TI - Xenotropic Murine Leukemia Virus-Related Virus and RNase L R462Q Variants in Iranian Patients With Sporadic Prostate Cancer. AB - BACKGROUND: Although several studies have confirmed the association of xenotropic murine leukemia virus-related virus (XMRV) and prostate cancer, this association is still controversial, as most studies did not detect XMRV in prostate tissue samples. Furthermore, some genetic and epidemiological studies have highlighted a role for RNase L polymorphisms, particularly R462Q, in the progression of prostate cancer. OBJECTIVES: The focus of this study was on the association of XMRV and RNase L R462Q variants with the risk of prostate cancer in Iranian patients. PATIENTS AND METHODS: In this case-control study, 40 and 80 individuals with sporadic prostate cancer and benign prostatic hyperplasia, respectively, were included. The presence of XMRV was evaluated by real-time polymerase chain reaction (PCR) of integrase and nested-PCR for the gag genes. The RNase L R462Q polymorphism analysis was carried out by PCR and sequencing. RESULTS: In a total of 40 sporadic prostate cancer and 80 benign prostatic hyperplasia cases, no XMRV was detected by real-time PCR and nested-PCR. RNase L R462Q polymorphism analysis reveals that although there was an increase in the risk of prostate cancer correlated with the Q/Q allele of RNase L at position 462, the frequencies of the RNase L R462Q alleles were not statistically significant between the prostate cancer and benign prostatic hyperplasia groups (OR = 2.75 (95% CI = 0.67 - 11.3), P = 0.29). CONCLUSIONS: These results did not support the presence of XMRV in the samples with prostate cancer and showed that RNase L R462Q variants had relatively little or no impact on the risk of prostate cancer in Iranian population. PMID- 26744631 TI - Multifocal Skeletal Tuberculosis Mimicking Langerhans Cell Histiocytosis in a Child: a Case Report With a Long-Term Follow-Up. AB - INTRODUCTION: Multifocal skeletal tuberculosis is a rare condition that may masquerade as Langerhans cell histiocytosis, especially in children. CASE PRESENTATION: We report a case of multifocal osseous tuberculosis in a 5-year-old female patient admitted to our hospital with a complaint of low back pain but no history of respiratory symptoms or malaise. Radiological findings included vertebra plana and multiple lytic lesions in both the frontal and pelvic bones. An initial diagnosis of Langerhans cell histiocytosis was made based on imaging findings; however, the patient underwent further evaluation for Mycobacterium tuberculosis, and histopathologic findings confirmed the diagnosis of tuberculosis. The patient showed a nearly complete response after receiving a course of anti-tuberculosis drugs. CONCLUSIONS: A high index of suspicion is required for the early diagnosis and prompt treatment of patients with osseous tuberculosis. Given the high prevalence of tuberculosis in developing countries, tuberculosis should be considered in the differential diagnosis of multifocal lytic lesions and vertebra plana, especially in children. PMID- 26744633 TI - Preventing falls with Tai Ji Quan: A public health perspective. AB - Falls among people aged 65 and older are a significant public health problem and one that is expected to increase as the population ages. Randomized controlled trials have demonstrated that Tai Ji Quan can reduce falls and associated injuries among older adults. In this paper, we describe how Tai Ji Quan community programs are being utilized by public health and aging services organizations to reduce older adult falls. We conclude that, to have a population-level impact on reducing falls and improving the health of older adults, Tai Ji Quan interventions must be translated into community programs that meet the needs and abilities of older adults. These programs must be adapted to fit into existing community structures, disseminated through multiple delivery channels, adopted and implemented broadly by organizations, and institutionalized to ensure sustainability. PMID- 26744632 TI - Comparing the Efficacy of Bupropion and Amantadine on Sexual Dysfunction Induced by a Selective Serotonin Reuptake Inhibitor. AB - BACKGROUND: Antidepressant-induced sexual dysfunction (SD) is a common problem, associated with a significant risk of non-adherence. Selective Serotonin Reuptake Inhibitors (SSRIs) are associated with a substantial risk of SD. Only 10 % of patients show spontaneous improvement during follow up period. OBJECTIVES: This study aimed to compare two proposed medication (bupropion vs. amantadine) in alleviating SD in patients treated with SSRIs. PATIENTS AND METHODS: In a randomized, single-blinded, clinical trial in Iran, 46 patients were recruited based on DSM-IV-TR criteria and semi-structured interview. Then, they were randomized into two treatment groups using table of random numbers. Eight patients were excluded and finally 38 patients completed the study which lasted for 4 weeks. Twenty patients were given bupropion, 18 patients were randomly assigned to another group, and given amantadine. Patients were assessed with the Arizona sexual experience scale (ASEX) at baseline and 4 weeks after the treatment. RESULTS: A total of 38 patients completed the study (18 patients in amantadine vs. 20 patients in bupropion).The mean ASEX scores gradually declined in both study groups during the trial. The reduction of ASEX score in bupropion group was more than that of amantadine group that was statistically significant. So, the addition of bupropion at higher doses appears to be more effective approach in comparison with amantadine. CONCLUSIONS: These results provide empirical support for conducting a further study on comparing different add-on strategies for treating drug-induced SD. PMID- 26744634 TI - Simultaneous Electroencephalography and Functional Magnetic Resonance Imaging and the Identification of Epileptic Networks in Children. AB - EEG/fMRI takes advantage of the high temporal resolution of EEG in combination with the high spatial resolution of fMRI. These features make it particularly applicable to the study of epilepsy in which the event duration (e.g., interictal epileptiform discharges) is short, typically less than 200 milliseconds. Interictal or ictal discharges can be identified on EEG and be used for source localization in fMRI analyses. The acquisition of simultaneous EEG/fMRI involves the use of specialized EEG hardware that is safe in the MR environment and comfortable to the participant. Advanced data analysis approaches such as independent component analysis conducted alone or sometimes combined with other, e.g., Granger Causality or "sliding window" analyses are currently thought to be most appropriate for EEG/fMRI data. These approaches make it possible to identify networks of brain regions associated with ictal and/or interictal events allowing examination of the mechanisms critical for generation and propagation through these networks. After initial evaluation in adults, EEG/fMRI has been applied to the examination of the pediatric epilepsy syndromes including Childhood Absence Epilepsy, Benign Epilepsy with Centrotemporal Spikes (BECTS), Dravet Syndrome, and Lennox-Gastaut Syndrome. Results of EEG/fMRI studies suggest that the hemodynamic response measured by fMRI may have a different shape in response to epileptic events compared to the response to external stimuli; this may be especially true in the developing brain. Thus, the main goal of this review is to provide an overview of the pediatric applications of EEG/fMRI and its associated findings up until this point. PMID- 26744635 TI - Biocompatibility of a Synthetic Biopolymer for the Treatment of Rhegmatogenous Retinal Detachment. AB - OBJECTIVE: The aim of this study is to evaluate the retinal safety and toxicity of a novel synthetic biopolymer to be used as a patch to treat rhegmatogenous retinal detachment. METHODS: Thirty one adult wild type albino mice were divided in 2 groups. In Group A (n=9) 0.2 MUl balanced salt solution (BSS) and in Group B (n=22), 0.2 MUl biopolymer was injected in the subretinal space. Trans-scleral subretinal injection was performed in one eye and the fellow eye was used as control. In both groups, in vivo color fundus photography, electroretinogram (ERG), spectral domain optical coherence tomography (SD-OCT) were performed before injection and at days 7 and 14 post-intervention. Histological analysis was performed following euthanization at days 1, 7 and 21 post-injection. RESULTS: The biopolymer was visualized in the subretinal space in vivo by SD-OCT and post-life by histology up to 1 week after the injection. There were no significant differences in ERG parameters between the two groups at 1 and 2 weeks post-injection. Minimal inflammatory response and loss of photoreceptor cells was only observed in the immediate proximity of the site of scleral perforation, which was similar in both groups. Overall integrity of the outer, inner retina and retinal pigment epithelial (RPE) layers was unaffected by the presence of the biopolymer in the subretinal space. CONCLUSIONS: Functional and histological evaluation suggests that the synthetic biopolymer is non-inflammatory and non toxic to the eye. It may represent a safe therapeutic agent in the future, for the treatment of rhegmatogenous retinal detachment. PMID- 26744636 TI - "Our commonality is our past:" a qualitative analysis of re-entry community health workers' meaningful experiences. AB - BACKGROUND: Re-entry community health workers (CHWs) are individuals who connect diverse community residents at risk for chronic health issues such as Hepatitis C virus and cardiovascular disease with post-prison healthcare and re-entry services. While the utilization of CHWs has been documented in other marginalized populations, there is little knowledge surrounding the work of re-entry CHWs with individuals released from incarceration. Specifically, CHWs' experiences and perceptions of the uniqueness of their efforts to link individuals to healthcare have not been documented systematically. This study explored what is meaningful to formerly incarcerated CHWs as they work with released individuals. METHODS: The authors conducted a qualitative thematic analysis of twelve meaningful experiences written by re-entry CHWs employed by the Transitions Clinic Network who attended a CHW training program during a conference in San Francisco, CA. Study participants were encouraged to recount meaningful CHW experiences and motivations for working with re-entry populations in a manner consistent with journal-based qualitative analysis techniques. Narratives were coded using an iterative process and subsequently organized according to themes in ATLAS.ti. Study personnel came to consensus with coding and major themes. RESULTS: The narratives highlighted thought processes and meaning related to re-entry CHWs' work helping patients navigate complex social services for successful re integration. Six major themes emerged from the analysis: advocacy and support, empathy relating to a personal history of incarceration, giving back, professional satisfaction and responsibilities, resiliency and educational advancement, and experiences of social inequities related to race. Re-entry CHWs described former incarceration, employment, and social justice as sources of meaning for assisting justice-involved individuals receive effective, efficient, and high-quality healthcare. CONCLUSIONS: Health clinics for individuals released from incarceration provide a unique setting that links high risk patients to needed care and professionalizes career opportunities for formerly incarcerated re-entry CHWs. The commonality of past correctional involvement is a strong indicator of the meaning and perceived effectiveness re-entry CHWs find in working with individuals leaving prison. Expansion of reimbursable visits with re entry CHWs in transitions clinics designed for re-entering individuals is worthy of further consideration. PMID- 26744637 TI - Circumstances and outcomes of falls among high risk community-dwelling older adults. AB - BACKGROUND: For older adults, falls threaten their health, independence, and quality of life. Knowing the circumstances surrounding falls is essential for understanding how behavioral and environmental factors interact in fall events. It is also important for developing and implementing interventions that are effective and acceptable to older adults. This study investigated the circumstances and injury outcomes of falls among community-dwelling older adults at high risk of falling. METHODS: In this secondary analysis, we examined the circumstances and outcomes of falls experienced by 328 participants in the Dane County (Wisconsin) Safety Assessment for Elders (SAFE) Research Study. SAFE was a randomized controlled trial of a community-based multifactorial falls intervention for older adults at high risk for falls, conducted from October 2002 to December 2007. Participants were community-dwelling adults aged >=65 years who reported at least one fall during the year after study enrollment. Falls were collected prospectively using monthly calendars. Everyone who reported a fall was contacted by telephone to determine the circumstances surrounding the event. Injury outcomes were defined as none, mild (injury reported but no treatment sought), moderate (treatment for any injury except head injury or fracture), and severe (treatment for head injury or fracture). RESULTS: Data were available for 1,172 falls. A generalized linear mixed model analysis showed that being age >=85 (OR = 2.1, 95% confidence interval [CI] = 1.2-3.9), female (OR = 2.1, 95% CI = 1.3-3.4), falling backward and landing flat (OR = 5.6, 95% CI = 2.9-10.5), sideways (OR = 4.6, 95% CI = 2.6-8.0) and forward (OR = 3.3, 95% CI = 2.0-5.7) were significantly associated with the likelihood of injury. Of 783 falls inside the home, falls in the bathroom were more than twice as likely to result in an injury compared to falls in the living room (OR = 2.4, 95% CI = 1.2-4.9). CONCLUSIONS: Most falls among these high risk older adults occurred inside the home. The likelihood of injury in the bathroom supports the need for safety modifications such as grab bars, and may indicate a need for assistance with bathing. These findings will help clinicians tailor fall prevention for their patients and have practical implications for retirement and assisted living communities and community-based fall prevention programs. PMID- 26744638 TI - MicroRNAs: an emerging player in autophagy. AB - Autophagy is an evolutionarily conserved self-digestion process for the quality control of intracellular entities in eukaryotes. In the past few years, mounting evidence indicates that microRNAs (miRNAs)-mediated post-transcriptional regulation of gene expression represents an integral part of the autophagy regulatory network and may have a substantial effect on autophagy-related physiological and pathological conditions including cancer. Herein, we examine some of the molecular mechanisms by which miRNAs manipulate the autophagic machinery to maintain cellular homeostasis and their biological outputs during cancer development. A better understanding of interaction between miRNAs and cellular autophagy may ultimately benefit future cancer diagnostic and anticancer therapeutics. PMID- 26744640 TI - A fractured inferior vena cava filter strut migrating to the left pulmonary artery. AB - Inferior vena cava filters are increasingly used in patients with recurrent venous thromboembolism who are contraindicated to anticoagulation. Migration of a broken strut to the pulmonary artery is a very rare complication of these filters. We report the case of an 83-year-old female who experienced this complication with the migratory strut remaining in the same position for years. This case provides evidence that such filters probably have higher rates of complications than what has been thought that remain asymptomatic. The indications and the management of complications of such devices need to be studied further. PMID- 26744641 TI - A case of pulmonary tumour thrombotic microangiopathy. AB - Pulmonary tumour thrombotic microangiopathy (PTTM) is a rapidly progressive pulmonary disease that is a fatal complication of malignancy. It manifests clinically as subacute respiratory failure with pulmonary hypertension, progressive right sided heart failure, and sudden death. We describe here a case of PTTM associated with occult metastatic signet ring cell carcinoma of the stomach. Although rare, PTTM needs to be considered in the differential diagnosis of dyspnoea of unknown origin, particularly in patients with respiratory failure and also pulmonary hypertension, and in patients were there is no improvement in respiratory symptoms with steroid therapy. PMID- 26744639 TI - Gastric rupture after bag-mask-ventilation. AB - A 42 year old woman underwent bronchoscopy with procedural propofol sedation. During the procedure, the patient suffered respiratory arrest, and bag-mask ventilation was initiated. During forced mask ventilation, abdominal distention occurred. Even after correct placement of an endotracheal and a nasogastric tube, high inspiratory pressures persisted. The abdominal CT scan revealed a high amount of intraperitoneal free air. An emergent laparotomy confirmed a stomach rupture. Immediately after opening of the peritoneal cavity, peak ventilatory pressures decreased. In this case forceful bag-mask ventilation led to air insufflation into the stomach, increasing gastric pressure, and consecutive stomach rupture. PMID- 26744642 TI - Cardiopulmonary exercise testing after laryngectomy: A connection conundrum. AB - A patient presents with a new bronchogenic carcinoma 5 years after laryngectomy for recurrent laryngeal tumor and 13 years after chemoradiation for concurrent lung cancer with synchronous base-of-tongue tumor. Due to his complex history and perceived limited respiratory reserve, he was felt high risk for the completion pneumonectomy needed for resection of this new tumor. The attending surgeon requested a full cardiopulmonary exercise test for risk assessment prior to surgery. We found that there was no commercially available connector that would allow our CPET equipment to reliably collect respiratory gases from a patient with tracheostomy stoma or tube. We report here a simple coupling devised "in house" that allowed for the performance of an interpretable test leading to a significant change in medical care. PMID- 26744643 TI - Interstitial lung disease associated with human papillomavirus vaccination. AB - Vaccinations against the human papillomavirus (HPV) have been recommended for the prevention of cervical cancer. HPV-16/18 AS04-adjuvanted vaccines (Cervarix) are said to have favourable safety profiles. Interstitial lung diseases (ILDs) can occur following exposure to a drug or a biological agent. We report a case of ILD associated with a Cervarix vaccination. A woman in her 40's, with a history of conisation, received three inoculations of Cervarix. Three months later, she presented with a cough and shortness of breath. Findings from a computed tomography of the chest and a transbronchial lung biopsy were consistent with non specific interstitial pneumonia. Workup eliminated all other causes of the ILD, except for the vaccination. Over the 11 months of the follow-up period, her symptoms resolved without steroid therapy. The onset and spontaneous resolution of the ILD showed a chronological association with the HPV vaccination. The semi quantitative algorithm revealed that the likelihood of an adverse drug reaction to Cervarix was "Probable". The outcome was relatively good, but more attention should be paid to a potential risk for HPV vaccinations to cause ILDs. Wherever possible, chest radiographic examinations should be performed in order not to overlook any ILDs. PMID- 26744644 TI - Isolated Candida infection of the lung. AB - Candida pneumonia is a rare infection of the lungs, with the majority of cases occurring secondary to hematological dissemination of Candida organisms from a distant site, usually the gastrointestinal tract or skin. We report a case of a 77-year-old male who is life-long smoker with a history of rheumatoid arthritis and polymyalgia rheumatica, but did not take immunosuppressants for those conditions. Here, we present an extremely rare case of isolated pulmonary parenchymal Candida infection in the form pulmonary nodules without evidence of systemic disease which has only been described in a few previous reports. PMID- 26744645 TI - Endobronchial ultrasound and bronchial artery embolization for Dieulafoy's disease of the bronchus in a teenager: A case report. AB - Dieulafoy's disease of the bronchus is a relatively rare cause of hemoptysis. It can be completely asymptomatic and diagnosed as an incidental finding on bronchoscopy. At the other end of the spectrum, it can present with potentially fatal hemorrhage. We present a case of a 13-year old boy who suffered from massive hemoptysis. Endobronchial ultrasound (EBUS) and bronchial artery embolization (BAE) proved useful in the initial management. This case may support the role of EBUS in the diagnosis of Dieulafoy's disease as well as other intrapulmonary vascular lesions. PMID- 26744646 TI - Role of endovascular embolization in improving the quality of life in a patient suffering from complicated intralobar pulmonary sequestration - A case report. AB - Intralobar pulmonary sequestration is a rare congenital malformation characterized by the presence of nonfunctional parenchymal lung tissue, receiving systemic arterial blood supply and lacking normal communication with tracheobronchial tree. Recurrent pneumonia and massive hemoptysis are life threatening complications associated with it. Delay in the diagnosis and management can be fatal. We report here a case of intralobar pulmonary sequestration in a 18 year old female who presented with recurrent severe episodes of pneumonia and hemoptysis forcing her to drop out of school. The diagnosis was confirmed by CECT Thorax and CT Angiography. The patient was managed by minimally invasive endovascular treatment in the form of feeding artery embolization. She made a full recovery with satisfactory outcome. On subsequent follow up, there was no recurrence of symptoms and she is doing well socially and academically. The aim of this case report is to show feasibility and safety of embolization as a less-invasive management option for adult pulmonary sequestration complicated with hemoptysis and LRTIs and emphasize the importance of such minimally invasive technique to enhance the quality of life in such patients. PMID- 26744647 TI - Pulmonary scintigraphy as a method to investigate gastrobronchial communication in tracheostomized patients. AB - Amyotrophic Lateral Sclerosis (ALS) is a degeneration of somatic motor neurons extending from upper motor cortical pyramidal neurons to lower motor neurons of the brainstem and cord. During the course of the disease patients require invasive procedures for nutrition and ventilation. Percutaneous Endoscopic Gastrostomy (PEG), performed in patients with impaired swallowing, is a safe procedure for the administration of Enteral Nutrition (EN). In the advanced stages of the disease patients develop a ventilatory failure due to muscolar weakness in these case they need a permanent tracheal tube with mechanical ventilation. Here we reported a case of a patient with Amyotrophic Lateral Sclerosis (ASL) who developed an increased gastric endocavitary pressure after a Percutaneous Endoscopic Gastrostomy (PEG). PMID- 26744648 TI - Unexpected responses to EGFR inhibition in NSCLC. AB - The presence of activating mutations of the epidermal growth factor receptor (EGFR)-gene identifies a distinct and clinically relevant molecular subset of non small-cell lung cancer. It is now well demonstrated that EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are superior to standard chemotherapy in this subset of tumors. Nevertheless, in many cases, responses are not durable and last for 6-12 months due to the occurrence of secondary or acquired resistance. Here we present three cases of EGFR-mutant lung adenocarcinomas (ADC), that showed an unexpected response to anti-EGFR small molecules. The first patient presented a continued 89 month-long response to erlotinib in a tumor recurred after surgery and conventional chemotherapy. In the other cases, subclinically persistent tumor in the lung tissue was documented histologically in lung resections performed after partial response to TKI treatment. The persistence of interstitial and endolymphatic tumor cells after TKI treatment might explain the common observation of tumor relapse after TKI discontinuation, and sustain the decision to continue treatment in responsive patients as in our first case. PMID- 26744649 TI - Pulmonary tuberculosis masking lung cancer - A case report. AB - Pulmonary Tuberculosis can co-exist with lung malignancy masking the underlying disorder leading to delay in diagnosis and management. Here we present an interesting case of a 60 year old man who on initial presentation was diagnosed with tuberculosis but on nonresponse to therapy and investigation was found to have an underlying lung malignancy. PMID- 26744650 TI - An unusual presentation of pulmonary epitheloid hemangioendothelioma. AB - Pulmonary epitheloid hemangioendothelioma (PEHE) is a rare, often incidentally diagnosed, endothelial tumor of the lung. We present a case of a young adult who presented with acute hypoxemic respiratory failure and severe pulmonary hypertension with subsequent imaging and tissue biopsy confirming a diagnosis of PEHE. We briefly highlight the unique clinical, radiographic and histopathologic aspects of this rare disease. We propose that PEHE should be considered in the differential diagnosis for acute hypoxemic respiratory failure associated with bilateral pulmonary cavitary nodules and bronchoscopy should be considered as an initial diagnostic test. PMID- 26744651 TI - Common variable immunodeficiency diagnosed during the treatment of bronchial asthma: Unusual cause of wheezing. AB - Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency in adults and children. We herein report a case of CVID, who was misdiagnosed with asthma due to wheezing episodes and relatively late onset. A 51 year-old woman had suffered from recurrent upper and lower airway infection for recent 2 years. She repeated wheezing attacks and was treated as asthma exacerbation triggered by infection. She was referred to our hospital for investigation and treatment. Lung function tests showed no reversibility of FEV1 by beta-adrenergic agonist, but the increase of V50/V25. Chest CT showed slight to moderate bronchial wall thickening and bronchiectasis. After that, she suffered from pneumonia with wheezing attacks twice a month, and immunodeficiency was strongly suspected. Her blood tests showed marked decreases of all classes of immunoglobulin and nearly lack of memory B cells, NKT cells and plasmacytoid dendritic cells. She was diagnosed with CVID, and was treated with replacement of gammaglobulin. Thereafter, her wheezing episodes with infection were remarkably improved. Because the delay of diagnosis with CVID likely causes poor mortality and morbidity, a possibility of CVID should be considered in patients with frequent asthma-like symptoms due to recurrent airway infection. PMID- 26744652 TI - Tuberculosis mimicking lung cancer. AB - Tuberculosis (TB) is well known as a diagnostic chameleon and can resemble malignancy. In thorax TB can be manifested as pulmonary infiltrates and/or mediastinal lymphadenopathy. In low incident countries with high incidence of lung cancer and varying clinical presentations, TB often gets misdiagnosed with the result of delayed treatment start and unnecessary diagnostic procedures. Our case report presents two patients, who were referred to the Thorax diagnostic centre at the Department of Respiratory Medicine, Odense University Hospital, with presumptive diagnosis of neoplasm and had proved lung TB with no evidence of malignancy instead. In the first case diagnosis was confirmed after thoracotomy, in the second case after bronchoscopy. PMID- 26744653 TI - Refractile foreign material deposits and alveolar hemorrhage in crack cocaine smoker. AB - Recreational use of alkaloid free-base cocaine, also known as crack cocaine, has reached epidemic proportions in the United States. Inhalation of crack cocaine is known to cause a variety of pulmonary complications. Herein we present a case of diffuse alveolar hemorrhage (DAH) and particulate foreign matter deposition in the setting of crack cocaine inhalation. PMID- 26744654 TI - Delayed diagnosis of hemoptysis in the case of prior aortic coarctation repair: A case report of aortobronchial fistula. AB - We report a case of a 46-year old man who presented with spontaneous bright red blood per mouth for several months. The patient had history of aortic coarctation repair at age 17. Endoscopy and nasopharyngeoscopy revealed no source of bleeding. Computed tomography scan revealed the presence of thoracic aortic pseudoaneurysm with the formation of an aortobronchial fistula (ABF). This case illustrates the high index of suspicion for ABF in the case of hemoptysis or hematemesis with prior history of coarctation repair. Furthermore, we discuss the role of thoracic endovascular aneurysm repair (TEVAR) as the standard of repair over open surgery. PMID- 26744655 TI - Pulmonary melioidosis presenting with pleural effusion: A case report and review of literature. AB - Melioidosis is a serious infection, which can involve multiple systems. We report a case of pulmonary melioidosis with the initial presentation mimicking a partially treated pneumonia complicated by right-sided pleural effusion. The patient is a 49-year old man who did not respond to parenteral ceftriaxone and tazobactam/piperacillin therapy. However, upon culture and sensitivity results from blood and pleural samples isolated Burkholderia pseudomallei; antimicrobial therapy was de-escalated to parenteral ceftazidime. Within 72 h duration, his fever subsided and other respiratory symptoms improved tremendously. This case highlights the importance of early recognition of B. pseudomallei in pulmonary infection in order for prompt institution of appropriate antibiotics treatment; thus reducing morbidity and mortality. PMID- 26744656 TI - Tuberculosis reinfection in a pregnant cystic fibrosis patient. AB - Cystic Fibrosis (CF) is a multisystem disease predominantly affecting the airways and predisposing patients to recurrent infections with various multidrug resistant organisms. Mycobacterium tuberculosis (MTB) infection is rarely seen, but considered a potential pathogen in CF patients. We report a 26 year old pregnant CF patient on Ivacaftor who was admitted with symptoms suggestive of tuberculosis. Three years prior to the current admission, she had completed four drug anti- MTB therapy for pulmonary tuberculosis and was considered cured as her sputum cultures after six months of treatment were negative. Genotype analysis revealed the current MTB strain to be different from the strain causing the previous infection. After receiving first line anti-tuberculous regimen for nine months, the patient's condition markedly improved culminating in an uneventful pregnancy and delivery. To our knowledge, this is the only reported case of reinfection tuberculosis in a CF patient. PMID- 26744657 TI - Update on the spectrum of histoplasmosis among hispanic patients presenting to a New York City municipal hospital: A contemporary case series. AB - Histoplasma capsulatum is the most common endemic mycosis worldwide. Although most of the globe's largest urban hubs fall outside this organism's regions of endemicity, clinicians practicing in a metropolis like New York City or Los Angeles must nevertheless remain vigilant for histoplasmosis because of the large immigrant population that is served by its hospitals. H. capsulatum infection ranges from asymptomatic pulmonary infection to life-threatening diffuse pneumonia with dissemination. The early years of the AIDS epidemic first introduced U.S. clinicians working in areas previously unfamiliar with histoplasmosis to newly immunocompromised patients from endemic regions presenting with disseminated H. capsulatum originally acquired in their home countries. Improvement in HIV prevention and therapeutics has reduced the frequency of such cases. Herein we report three cases of histoplasmosis encountered in our New York City institution over the last three years to emphasize that awareness of this infection remains mandatory for the frontline urban clinician. PMID- 26744658 TI - Successful management of pulmonary hemorrhage and aspergillosis in a patient with acute myeloid leukemia (AML-M3). AB - A 35-year-old man presented with a one month history of gingival bleeding. He was diagnosed with Acute Myeloid Leukemia (AML-M3). During treatment he developed alveolar hemorrhage for which he was treated with a steroid. After the steroid treatment he developed a nodule, a cavitary lesion and atelectasia in the left lung. He was treated with voriconazole. After therapy with voriconazole his lesion significantly decreased. This case illustrates the efficacy and safety of antifungal therapy with voriconazole for aspergillosis complicated by AML. PMID- 26744659 TI - Is percutaneous tracheostomy the best method in the management of patients with prolonged mechanical ventilation? AB - Although percutaneous tracheostomy is a standardized procedure, rare major complications are still being evaluated and discussed. We describe a case of patient, with hemodynamic and respiratory stability, who displayed massive hemorrhage after 16 days of "Ciaglia Blue Rhino" tracheostomy. Unfortunately, neither prompt resuscitation maneuvers nor the surgical approach saved the life of patient. PMID- 26744661 TI - Rasmussen's aneurysm: A forgotten scourge. AB - Rasmussen's aneurysm is an inflammatory pseudo-aneurysmal dilatation of a branch of pulmonary artery adjacent to a tuberculous cavity. Life threatening massive hemoptysis from the rupture of a Rasmussen's aneurysm is an uncommon yet life threatening complication of cavitary tuberculosis (TB). We present a case of a young woman who presented with low-grade fever and hemoptysis. Computed tomographic (CT) angiography showed biapical cavitary lesions and actively bleeding aneurysms involving pulmonary artery, which successfully underwent glue embolization. PMID- 26744660 TI - Mucormycosis causing pulmonary artery aneurysm. AB - Pulmonary artery aneurysm (PAA) is an uncommon entity and is usually congenital in origin or secondary to pulmonary arterial hypertension. Infections causing PAA are few, tuberculosis and bacterial infections being the common causative organisms. There have been few cases reported previously, in which the organism causing PAA was found to be a rare fungus called mucor. Pulmonary mucormycosis causing PAA is an infrequent and almost fatal complication as most of the diagnosis was made post mortem. This report brings out a case of pulmonary mucormycosis causing ruptured PAA in a patient with diabetes. This patient was cured by a timely treatment of a combination of surgery and medical therapy. PMID- 26744662 TI - The sodium-phosphate co-transporter SLC34A2, and pulmonary alveolar microlithiasis: Presentation of an inbred family and a novel truncating mutation in exon 3. AB - Pulmonary alveolar microlithiasis is a disorder in which many tiny fragments (microliths) of calcium phosphate gradually accumulate in alveoli. Loss of function mutations in the gene SLC34A2 coding for the sodium phosphate co transporter (NaPi-IIb) are responsible for genetic forms of alveolar microlithiasis. We now report a consanguineous Italian family from Calabria with two affected members segregating alveolar microlithiasis in a recessive fashion. We describe, for the first time, a novel loss of function mutation in the gene coding for NaPi-IIb. A careful description of the clinical phenotype is provided together with technical details for direct sequencing of the gene. PMID- 26744664 TI - A case of Lemierre's syndrome with septic shock and complicated parapneumonic effusions requiring intrapleural fibrinolysis. AB - Lemierre's syndrome is a septic thrombophlebitis of the internal jugular vein, which can lead to severe systemic illness. We report a case of an otherwise healthy 26-year-old man who suffered from pharyngitis followed by septic shock requiring intubation and vasopressor support from Fusobacterium necrophorum bacteremia. The septic emboli to his lungs caused complicated bilateral parapneumonic effusions, which recurred after initial drainage. He required bilateral chest tubes and intrapleural tPA to successfully drain his effusions. His fever curve and overall condition improved with the resolution of his effusions and after a 33-day hospitalization, he recovered without significant disability. The severity of his illness and difficult to manage complicated parapneumonic effusions were the unique facets of this case. Using an evidence based approach of tPA and DNase for complicated parapneumonic effusions in Lemierre's syndrome can be safe and effective. PMID- 26744663 TI - Concomitant tracheal and subcutaneous glomus tumor: Case report and review of the literature. AB - Glomus tumors are unusual and generally benign neoplasms mainly found in subungeal areas. We describe a case of concomitant subcutaneous and tracheal glomus tumor that underwent successful endoscopic resection. A 48-year old male with a left forearm subcutaneous mass presented with hemoptysis. A chest CT scan demonstrated a polypoid tracheal lesion. He underwent a bronchoscopic resection. A biopsy revealed a glomus tumor, which was the same type of neoplasm that was found on the forearm biopsy. Glomus tumors are rarely found in the respiratory tract. Only 49 cases have been described. The majority of the glomus tumors arise from the lower posterior tracheal wall with no extraluminal extension. Bronchoscopic resection has been successfully used. Glomus tumors should be included in the differential diagnosis of tracheobronchial lesions. Bronchoscopic resection and adjuvant radiotherapy are valid treatment options. This is the first report of concomitant subcutaneous and tracheal glomus tumor, as well as the first reported airway glomus tumor, in Latin America. As part of this study, we also perform a literature review. PMID- 26744665 TI - Lactic acidosis and diastolic hypotension after intermittent albuterol nebulization in a pediatric patient. AB - We describe a case of 13-year-old female with intermittent asthma who developed lactic acidosis and diastolic hypotension after receiving intermittent albuterol nebulizer treatment. She presented to the emergency department (ED) with sudden onset of shortness of breath and chest pain. She received two albuterol nebulizer treatments at home without symptomatic relief. She was treated in the ED with intermittent albuterol nebulization for a total of 22.5 mg over the next 5 hours. A decrease in diastolic blood pressure from 60 mmHg to 40 mmHg was noted after the treatment. Blood lactate level was 5.9 mmol/L. She recovered from it and was discharged to home but she had recurrence of shortness of breath and presented to the ED two days later. She was treated with albuterol nebulization for a total of 17.5 mg over the next two and half hours and developed diastolic hypotension again, as low as 30 mm Hg. After discontinuation of albuterol nebulization, her BP normalized. Cardiopulmonary and metabolic side effects of continuous albuterol therapy have been reported in the recent medical literature. Our patient, however, developed these adverse effects on intermittent albuterol nebulizer treatment. It is important for the pediatrician to recognize the adverse effects of beta2-agonist therapy to avoid carrying out extensive workup for hypotension and hyperlactatemia prolonging hospital stay. PMID- 26744667 TI - Foreign body granuloma mimicking recurrence of malignant pleural mesothelioma. AB - A 72-year-old man visited our hospital due to right pleural effusion. He had worked as a welder at a shipbuilding company and had been exposed to asbestos. Cytological examination and thoracoscopic pleural biopsy yielded a diagnosis of epithelial malignant pleural mesothelioma (MPM); extrapleural pneumonectomy (EPP) was performed. Two years later, he became aware of right-back swelling that became a fist-sized mass over 2 months. Microscopy of a tissue specimen revealed no malignant cells, but did indicate foreign body granuloma. Subcutaneous lesions that develop after EPP do not necessarily result from the recurrence of MPM, but could have benign etiologies. PMID- 26744666 TI - Pneumonia, lung cancer or Medlar's core? AB - Here, we report a case of 57-year-old previously healthy man with six-months medical history of significant chronic cough and recurring episodes of fever. Cytology, bacteria, fungi and acid fast bacilli in the sputum were negative. CT scan, initially interpreted as suspected lung cancer, detected by chest x-ray, revealed pneumonia. Bronchoscopy is frequently necessary for the diagnosis as well as the treatment as a routine practice and in this case was applied. Our patient underwent to fiberoptic rigid bronchoscopy in the right upper lobe in general anaesthesia. Unexpectedly, a vegetal FB, Medlar's core instead a tumor, was removed. After two-months follow-up the patient was found healthy without any old or other symptoms. PMID- 26744668 TI - Subconjunctival haemorrhage from bronchoscopy: A case report. AB - Flexible bronchoscopy has been available for almost five decades. It has evolved as one of the most commonly used invasive diagnostic and therapeutic procedure in pulmonology, and its scope of applications is progressively expanding with the addition of new adjunct technologies such as endobronchial ultrasound, bronchial Thermoplasty, and navigational bronchoscopy. It is a safe procedure with complications ranging from fever, infiltrates, hypoxemia, bleeding, pneumothoraces and death, with most significant complications being bleeding and pneumothorax. We report a case of subconjuctival haemorrhage as an immediate complication of bronchoscopy. To our knowledge this is the first report documenting this rare complication. PMID- 26744669 TI - The role of high-resolution chest CT in the diagnosis of neuroendocrine cell hyperplasia of infancy - A rare form of pediatric interstitial lung disease. AB - Interstitial lung disease (ILD) is rare in infancy or early childhood. Differentiating between the different types of ILD is important for reasons of treatment, monitoring of clinical course and prognosis. We present a case of a 5 month old female with tachypnea and hypoxemia. The clinical suspicion of neuroendocrine cell hyperplasia of infancy (NEHI) was confirmed by high resolution chest CT and subsequent lung biopsy. We conclude that high-resolution chest CT has characteristics findings that can be used as a non-invasive test to support the clinical diagnosis of neuroendocrine cell hyperplasia of infancy. PMID- 26744670 TI - Pulmonary embolus diagnosed by endobronchial ultrasound. AB - Endobronchial ultrasound (EBUS) imaging is commonly used to evaluate and aid in biopsy of mediastinal lymph nodes. Pulmonary arteries are readily viewable with this type of imaging modality. We present a case report of a pulmonary embolism (PE) diagnosed by EBUS. Our patient had no smoking history and presented with respiratory and constitutional symptoms, urinary retention, and leg weakness suspicious for malignancy with metastasis to spine. Chest computed tomography (CT) was suggestive of lung carcinoma and specifically showed no PE. EBUS with TBNA was requested for tissue diagnosis. A mobile filling defect consistent with a PE was observed and reported to primary team. Follow-up chest CT showed an acute PE which confirmed the diagnosis originally made by EBUS. Bronchoscopists should be aware of potential to diagnose a PE while performing EBUS. Additionally, there may be a role in using EBUS specifically to diagnose a PE in the right patient population. PMID- 26744672 TI - Iron deficiency anemia as initial presentation of a non-small cell lung carcinoma: A case report. AB - Duodenal metastases secondary to lung cancer are very rare and most of the time asymptomatic. When symptomatic they usually present with bowel obstruction or perforation. We here describe the case of a 68 year-old man with a solitary metastasis in the duodenum from a non-small cell lung carcinoma (NSCLC). The patient presented with reduced exercise tolerance and iron deficiency anemia without clinical gastrointestinal blood loss. Further investigation showed a tumor in the left upper lung lobe and a duodenal metastasis for which he received chemotherapy. To the best of our knowledge this is the first case report of iron deficiency anemia as initial presentation of a duodenal metastasis from a NSCLC. PMID- 26744671 TI - CO2 measurement for the early differential diagnosis of pulmonary embolism related shock at the emergency department: A case series. AB - OBJECTIVE: An early differential diagnosis is mandatory when facing a patient with clinical shock of unclear aetiology, in order to guide proper treatment. We assessed if the expired CO2 measurement and alveolar-arterial CO2 calculation could improve the differential diagnosis of shock during its initial presentation, particularly in separating pulmonary embolism from other causes of shock. METHODS: We analysed the charts of 12 patients who presented with clinical shock and had end-tidal CO2 (EtCO2) and arterial CO2 partial pressure (PaCO2) measurements. RESULTS: In cases with pulmonary embolism-related shock (n = 3), the gradient between PaCO2 and EtCO2 was increased (37 vs 0.2 mmHg). There was a similar trend for a higher PaCO2 value (60 vs 32.2 mmHg) and a lower EtCO2 value (23 vs 32 mmHg). CONCLUSION: An initial CO2 measurement might be an easily available tool for the early diagnostic work-up of clinical shock. PMID- 26744673 TI - Desmoplastic small round cell tumor of the lung: A case report and literature review. AB - Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive and malignant tumor that is characterized by nests of small tumor cells surrounded by a cellular and vascular collagenous stroma and predominantly affects young adolescent males. This tumor most commonly originates in the abdomen; however, in rare cases, DSRCT can originate in other body regions. The main manifestations of DSRCT are chest pain and respiratory symptoms, and patients' average survival after diagnosis is less than two years. In this report, we describe a case involving DSRCT of the lung that proved to be difficult to diagnose, and we conduct a literature review. PMID- 26744674 TI - A rare clinical case - Solitary fibrous tumor of the pleura. AB - We present a case of a 58 years old man with a large heterogeneous and well circumscribed soft tissue mass arising from the right pleural surface, found at a computer tomography of his chest. This mass after complete resection through a right lateral open thoracotomy, proved to be a Solitary Fibrous Tumor, previously known as 'benign mesothelioma'. This tumor is usually discovered at routine chest X-rays since patients are either asymptomatic or report atypical symptoms. Only 10-20% of the published cases report a malignant solitary fibrous tumor, however, definite diagnosis can only be made after complete resection which is the proposed diagnostic algorithm for these cases. PMID- 26744675 TI - "Lung packing" in breath hold-diving: An impressive case of pulmo-cardiac interaction. AB - There is a complex interaction between the heart and the lungs. We report on a healthy female who performs breath hold diving at a high, international level. In order to optimize pressure equalization during diving and to increase oxygen available, apneists employed a special breathing maneuver, so called "lung packing". Based on cardiac MRI we could demonstrate impressive effects of this maneuver on left ventricular geometry and hemodynamics. Beyond the fact, that our findings support the concept of pulmonary -cardiac interrelationship, it should be emphasized, that the reported, extreme breathing maneuver could have detrimental consequences due to reduction of stroke volume and cardiac output. PMID- 26744676 TI - Benign metastasizing leiomyomatosis (BML): A rare cause of cavitary and cystic pulmonary nodules. AB - Benign metastasizing leiomyomatosis (BML) is a rare cause of pulmonary lesions found in reproductive age women who have undergone a hysterectomy for uterine leiomyoma. Given the relative rarity of the disease, the management of these lesions varies from surgical (oopherectomy) or medical antiestrogen hormonal therapy to clinical observation and survelliance. The disease generally presents asymptomatically with multiple, well-defined pulmonary nodules discovered incidentally on imaging. We report an atypical presentation of a 46-year-old woman with incidentally found bilateral pulmonary cavitating nodules and cysts, concerning for lymphangioleiomyomatosis (LAM), who was ultimately diagnosed with BML. PMID- 26744677 TI - Effect of enterovirus D68 on Lung Clearance Index in patients with cystic fibrosis: A case report. AB - Cystic fibrosis (CF) causes airways obstruction and a decline in percent predicted forced expiratory volume in 1 s (FEV1%). FEV1% is an objective measure of a pulmonary exacerbation of CF; improvement in FEV1% is the endpoint used often to determine success of treatment of these acute declines in pulmonary health. Lung Clearance Index (LCI), derived from multiple breath inert gas washout (MBW) test, measures ventilation inhomogeneity and small airways dysfunction. In the United States in 2014-2015, enterovirus D68 (EV-D68), a novel virus, led to hospitalizations in children because of respiratory distress. This report describes 2 patients with CF admitted for pulmonary exacerbations who were enrolled in an inpatient study to assess patient satisfaction and utility of MBW to measure LCI. Diagnostic testing indicated that these patients were infected with EV-D68. Although their FEV1% improved to their previous baseline following treatment for pulmonary exacerbation, it was discordant with LCI. We discuss LCI as a novel measure of pulmonary function and hypothesize that, based on these cases, it may be a more sensitive indicator of ongoing post-viral airways dysfunction as compared to FEV1%. PMID- 26744678 TI - Mechanical complication of endobronchial tuberculosis. AB - A 19-year-old Vietnamese lady was diagnosed with culture positive, left upper lobe pulmonary tuberculosis for which medical treatment was initiated. Four months into treatment, she developed a 'rubber-band-like' stretching sensation in her left chest with wheezing and shortness of breath. Decreased respiratory excursion over the left lung was present on physical-examination. Chest-Xray revealed left-upper-lobe collapse with leftward deviation of the trachea and mediastinum. CT thorax revealed a long segment of stenosis in the left mainstem bronchus. FEV1 was 1.26 L (45% predicted), FVC 1.53 L (49% predicted), FEV1/FVC 82% (95% predicted) indicating airway limitation. Ventilation-perfusion scan noted 9.8% ventilation to the left lung and 92.8% to the right lung and 7.6% perfusion to the left lung and 92.4% to the right lung. Bronchoscopy was notable for pin point stenosis of the left mainstem bronchus beyond which was inflamed mucosa and abnormal cartilage rings in the left upper and middle lobe bronchi. Nine months of medical therapy for tuberculosis along with oral steroid taper was completed successfully; however the patient has required six serial bronchscopies with dilatations without stent placement at four to six week intervals due to partial restenosis, with the last bronchoscopy at four months after completion of tuberculosis therapy. PMID- 26744679 TI - Chylothorax due to leukemic infiltration in a patient with chronic lymphocytic leukemia. AB - Chylothorax is characterized by accumalation of milky fluid called chyle into the plural space. Most common causes of cyhlothorax are trauma or surgery of thoracic duct and malignancies. Among the malignancies lymphoma is responsible approximately 70% of cyhlothorax but other lymphocytic tumors including chronic lymphocytic leukemia (CLL) is rarely reported. A 71 years old man with known CLL, presented with dispnea and pleural effusion and diagnosed cyhlothorax due to leukemic infiltration that confirmed by immuno flow cytometric analyse. PMID- 26744680 TI - Idiopathic bronchocentric granulomatosis in an asthmatic adolescent. AB - Bronchocentric granulomatosis in asthmatic patients has been generally considered to be associated with allergic bronchopulmonary aspergillosis and represent a histopathologic manifestation of fungal hypersensitivity. Here we report a case of an idiopathic bronchocentric granulomatosis in a 17-year-old man with a history of asthma. He was admitted to the hospital with a fever and cough, and a chest CT scan showed peribronchial consolidation in the pulmonary parenchyma, which was unresponsive to antibiotic therapy. The pathological findings obtained by video-assisted thoracoscopic lung biopsy revealed necrotizing granulomatous inflammation centered on bronchi and bronchioles and there was no evidence of fungal colonization, resulting in a diagnosis of idiopathic bronchocentric granulomatosis. Systemic corticosteroid therapy led to clinical and radiological recovery. Physicians should take into account the possibility of the idiopathic process in bronchocentric granulomatosis of asthmatic patients. PMID- 26744681 TI - Tracheomalatia, to stent or not to stent. AB - Benign thyroid disorders such as goiter, especially retrosternal, can cause tracheostenosis by extrinsic tracheal compression, which is due to the lack of specific symptoms often misdiagnosed. Tracheomalatia develops as a result to long term tracheal compression and refers to weakness of the trachea characterized by softness of the tracheal cartilage arches and by loss of regular tracheal structure. Tracheomalatia is characterized by reduction of the endotracheal lumen and may affect the entire trachea or may be localized to one portion of it. We present the case of a 72-year old patient with distinct tracheostenosis and tracheomalatia, caused by long term pressure by the retrosternal goiter. We have been monitoring the patient for last 20 years after the second endotracheal stent had been placed. The first one was placed 34 years ago, in 1981. On both occasions granulation tissue and colonization of bacteria occurred. In the end the placed stents were rejected and migrated to the main carina. Despite the tracheal diameter narrower than 5 mm the patient has been living normally without the stent for 17 years, with the exception of no hard physical labor. He had a few short term antibiotic therapies and bronchial toilets during symptomatic deteriorations. Diagnosing retrosternal goiter and surgical treatment on time is of crucial importance in cases such as this one. Considering the complications caused by the stent, our opinion is that the majority of patients may require conservative treatment with closely monitoring during respiratory infections. PMID- 26744682 TI - An unusual cause of difficult weaning in a patient with newly diagnosed small cell lung cancer. AB - We describe a patient with acute respiratory insufficiency and difficult ventilator weaning in the ICU ward, leading to diagnosis of small cell lung cancer with superior vena cava superior syndrome. Bilateral vocal cord paralysis caused his respiratory distress and weaning difficulties. Thyroidectomy and neurological problems (such as Parkinson disease and Guillain Barre syndrome) are more common causes of bilateral vocal cord paralysis. Lung cancer patients are also at risk due to mediastinal invasion. The left recurrent laryngeal nerve is more prone to paralysis because of the typical anatomy. In contrary, bilateral vocal cord paralysis is rare and doesn't result in speech problems but rather breathing difficulties. Tracheostomy is the classic therapy, but laser cordectomy and Botulinum toxin injection in the laryngeal muscles are alternatives. PMID- 26744683 TI - Sarcoidosis as unusual cause of massive pleural effusion. AB - Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Pleural involvement is relatively rare. Development of pleural effusion in sarcoidosis needs to be evaluated for other causes, especially tuberculosis in endemic countries. Sarcoid pleural effusion responds to systemic corticosteroids. We are presenting case of 42 year old male patient of sarcoidosis who developed massive pleural effusion while on treatment with steroids, which was attributed to disease per se. Sarcoidosis as a cause of massive pleural effusion has not been mentioned before in published literature. PMID- 26744684 TI - Titanium exposure and yellow nail syndrome. AB - Yellow nail syndrome is a rare disease of unclear etiology. We describe a patient who develops yellow nail syndrome, with primary nail and sinus manifestations, shortly after amalgam dental implants. A study of the patient's nail shedding showed elevated nail titanium levels. The patient had her dental implants removed and had complete resolution of her sinus symptoms with no change in her nail findings. Since the patient's nail findings did not resolve we do not believe titanium exposure is a cause of her yellow nail syndrome but perhaps a possible relationship exists between titanium exposure and yellow nail syndrome that requires further studies. PMID- 26744685 TI - Hyperpharmacotherapy in ageing cystic fibrosis patients: The first report of an atypical hip fracture. AB - Cystic fibrosis (CF) is a common autosomal recessive disorder in Caucasian populations with respiratory, gastrointestinal and endocrine manifestations. Thanks to recent advances in medical therapies and infection control, life expectancy of a patient with CF has significantly increased from less than 5 years in the mid-1900s to almost 50 years nowadays. However, as CF patients are living longer, multimorbidity and Hyperpharmacotherapy are becoming more common. This case illustrates a cascade of problems that ensued from medication side effects, highlighting the increasing challenge of managing an ageing CF population. PMID- 26744686 TI - Endobronchial laser ablation in the management of epithelial-myoepithelial carcinoma of the trachea. AB - A 52 year old, never smoker presented to hospital with progressive shortness of breath and significant stridor over a five month period. He also described the feeling of needing to cough but being unable to expectorate. CT Thorax demonstrated a mass lesion in the trachea just distal to the larynx which was then confirmed on rigid bronchoscopy. Subsequent histology confirmed an epithelial-myoepithelial carcinoma. Only a few case reports document these rare salivary gland tumours occurring in other locations such as the respiratory tract. After staging showed only local disease, the patient was managed with rigid bronchoscopy and laser ablation therapy. We present the first documented case to be treated with endobronchial laser ablation therapy with discussion of the incidence, presentation and characteristics of these tumours including the treatment options, as well as the use of laser ablation in the management of benign and malignant endobronchial lesions. PMID- 26744687 TI - Corynebacterium macginleyi: A cause of ventilator associated pneumonia in an immunocompromised patient. AB - PURPOSE AND IMPORTANCE: Corynebacterium macginleyi, a lipophilic diphtheroid from the genus Corynebacteria, is a known cause of conjunctivitis. It was recently reported as a cause of serious infections in immunocompromised individuals. It has never been reported as a cause of ventilator-associated pneumonia, that which carries a high burden and risk of mortality. Our report intends to increase awareness of a potentially lethal nosocomial bacterial infection. OBSERVATIONS: This case reports on a 73 year old lady with metastatic lung adenocarcinoma on chemotherapy, who was hospitalized for dyspnea and diffuse pulmonary infiltrates in 2011. Trans-bronchial biopsies revealed cryptogenic organizing pneumonia. The patient improved with steroids. Failure to wean ensued with a bronchopleural fistula, increase in secretions, oxygen requirements, and appearance of new infiltrates. Two mini-BAL cultures yielded gram positive pleomorphic rods with palisade arrangement, diagnosed as C. macginleyi. Vancomycin therapy was initiated. She improved and was successfully extubated. CONCLUSION AND RELEVANCE: Non-diphtheria Corynebacteria usually form normal flora. If isolated, they are often dismissed as contaminants. C. macginleyi has emerged as a life-threatening nosocomial infection. Prompt identification and treatment are required. It is resistant to quinolones. Thus far, vancomycin is the preferred treatment. PMID- 26744688 TI - Lung adenocarcinoma presenting with isolated 'chronic cough' of 3 years duration a cautionary tale. AB - Chronic cough that is dry, non-productive and without constitutional symptoms is often thought to have a non-malignant etiology such as asthma, post-nasal drip or gastroesophageal reflux disease (GERD). We present a case of a patient with a 3 year history of 'chronic cough' that was dry, non-productive cough and without any constitutional symptoms. Initial chest x-ray (CXR) done 3 years ago showed some streaky atelectasis in the right middle lobe along with some volume loss on that side. Another CXR performed one and half years later showed progression to a complete right middle lobe collapse. She ultimately presented to our facility a year later with stable CXR findings, but persistent cough. A chest CT scan was suspicious for a right lower lobe mass. A PET scan subsequently confirmed a hypermetabolic right hilar mass causing extrinsic compression of the bronchus intermedius. She ultimately required a complete right pneumonectomy with partial pericardiectomy and had complete resolution of her cough. This case highlights the fact that 'chronic cough' should always be thoroughly investigated and should remain a diagnosis of exclusion until all sinister pathologies have been ruled out. PMID- 26744689 TI - Mycobacterium tuberculosis infection in a HIV-positive patient. AB - Mycobacterium tuberculosis (MTB) and human immunodeficiency virus (HIV) coinfection remains a global public health challenge. We report a 40 year old African American male who is a known HIV-positive patient, non-compliant with his antiretrovirals and developed pulmonary tuberculosis. His chief complaints were chronic cough, fever, night sweats and undocumented weight loss. He had a prior positive T-SPOT-TB test; however, chest radiograph and sputum smear examination revealed normal results. PCR-based GeneXPERT MTB/RIF assay was ordered and confirmed MTB infection. The sputum cultures grew MTB and sensitivities showed susceptibility to all primary anti-tuberculosis medications. A delay in diagnosis and initiation of MTB therapy, in the setting of HIV or AIDS, may result in rapid disease progression and worse clinical outcome. PMID- 26744691 TI - Postobstructive pulmonary edema after biopsy of a nasopharyngeal mass. AB - We describe a case of 17 year-old male with a nasopharyngeal rhabdomyosarcoma who developed postobstructive pulmonary edema (POPE) after removing the endotracheal tube following biopsy. He developed muffled voice, rhinorrhea, dysphagia, odynophagia, and difficulty breathing through nose and weight loss of 20 pounds in the preceding 2 months. A nasopharyngoscopy revealed a fleshy nasopharyngeal mass compressing the soft and hard palate. Head and neck MRI revealed a large mass in the nasopharynx extending into the bilateral choana and oropharynx. Biopsy of the mass was taken under general anesthesia with endotracheal intubation. Immediately after extubation he developed oxygen desaturation, which did not improve with bag mask ventilation with 100% of oxygen, but improved after a dose of succinylcholine. He was re-intubated and pink, frothy fluid was suctioned from the endotracheal tube. Chest radiograph (CXR) was suggestive of an acute pulmonary edema. He improved with mechanical ventilation and intravenous furosemide. His pulmonary edema resolved over the next 24 h. POPE is a rare but serious complication associated with upper airway obstruction. The pathophysiology of POPE involves hemodynamic changes occurring in the lung and the heart during forceful inspiration against a closed airway due to an acute or chronic airway obstruction. This case illustrates the importance of considering the development of POPE with general anesthesia, laryngospasm and removal of endotracheal tube to make prompt diagnosis and to initiate appropriate management. PMID- 26744690 TI - A case of treatment with voriconazole for chronic progressive pulmonary aspergillosis in a patient receiving tacrolimus for dermatomyositis-associated interstitial lung disease. AB - We report a successful treatment with voriconazole (VRCZ) for chronic progressive pulmonary aspergillosis (CPPA) in a patient with dermatomyositis-associated interstitial lung disease (DM-ILD) treated with tacrolimus. A 73-year-old man with DM-ILD, treated with tacrolimus and prednisolone, complained of productive cough and his chest X-ray showed infiltration in the left upper lung field. We diagnosed CPPA and added VRCZ. Although we reduced the dose of tacrolimus for drug interaction, serum VRCZ level increased after the treatment. The patient was found to have cytochrome P450 (CYP) 2C19 *2/*2, a genetic polymorphism in poor metabolizers of VRCZ. We adjusted the doses of both drugs and treated him successfully. We recommend performing individual therapeutic drug monitoring (TDM) in CYP-mediated drug interactions and considering the effect of CYP polymorphisms. PMID- 26744693 TI - Lateralized, nonepileptic convulsions in an adult with cerebral palsy: Case report and review of the literature. AB - The authors report a case of unilateral functional neurological symptoms (nonepileptic convulsions) in a 38-year-old man with mild, motor-predominant cerebral palsy. His convulsions are all lateralized to the same side as his paretic limbs. His episodes significantly decreased after several months of weekly psychodynamic-oriented psychotherapy. Functional neurological disorders have been rarely reported in children or adults with cerebral palsy. Among patients with brain injury, right-hemispheric brain disease may be more helpful than either handedness or the side of symptoms in clinically profiling patients with suspected functional disorders. This case raises biomechanistic questions about brain injury, the development of functional disorders, and the lateralization of functional symptoms. PMID- 26744692 TI - Lymphoproliferative disorder in pleural effusion in a subject with past asbestos exposure. AB - Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin lymphoma that presents as serous effusions without detectable masses or organomegaly. Here we report a case of PEL-like lymphoma in a patient with past asbestos exposure. A 65 year-old man was referred to our hospital due to dyspnea upon exertion. He had been exposed to asbestos for three years in the construction industry. Chest X ray and CT images demonstrated left pleural effusion. Cytological analysis of the pleural effusion revealed large atypical lymphocytes with distinct nuclear bodies and high nucleus-to-cytoplasm ratio. Immunohistochemical analyses showed that the cells were CD20(+), CD3(-), CD5(-), and CD10(-). These findings led to a diagnosis of diffuse large B-cell lymphoma. PEL or PEL-like lymphoma should be considered a potential cause of pleural effusion in subjects with past asbestos exposure. PMID- 26744694 TI - Ictal central apnea and bradycardia in temporal lobe epilepsy complicated by obstructive sleep apnea syndrome. PMID- 26744695 TI - Levetiracetam-induced pancytopenia. AB - Pancytopenia is a rare side effect of levetiracetam (LEV) that is associated with severe morbidity that requires hospitalization. Here, we report a patient with a right temporoparietal tumor who underwent a temporal craniotomy with resection of the mass and was started on LEV for seizure prophylaxis per the neurosurgery local protocol. The patient developed LEV-induced pancytopenia, which was successfully managed by discontinuation of this medication. Our report aims to increase awareness of this rare cause of pancytopenia among clinicians. PMID- 26744697 TI - Bath-induced paroxysmal events - Notes on a case report. PMID- 26744696 TI - Anti-NMDA-receptor antibody encephalitis in infants. AB - PURPOSE: Anti-N-methyl-d-aspartate (NMDA) receptor antibody encephalitis is an autoimmune disorder manifesting subacutely with prominent aberrant movements and psychiatric symptoms. The clinical course is one of progressive clinical deterioration that can be halted and often reversed by early diagnosis and treatment. Patterns of presentation and etiology of anti-NMDA-receptor antibody encephalitis are dependent on age and can be challenging to recognize in very young children. REPORTS: Sequential clinical case observations of anti-NMDA receptor antibody encephalitis presenting in very young children were examined over a year at a single tertiary pediatric institution. Cerebrospinal fluid confirmed anti-NMDA-receptor antibodies in two cases (a 21-month-old boy and a 29 month-old girl) that demonstrated either bizarre behavioral patterns or status epilepticus both associated with progressive deterioration. Once recognized, the clinical course was arrested and reversed by aggressive treatment with plasma exchange, immunoglobulin, and high dose IV steroids. CONCLUSION: Infants with anti-NMDA-receptor antibody encephalitis can present with frank seizures or seizure mimics. Regardless, prompt recognition and aggressive treatment of anti NMDA-receptor antibody encephalitis, while challenging, can quickly arrest deterioration and hasten recovery, thereby, limiting neurological morbidity. PMID- 26744698 TI - Bath-induced paroxysmal events - response to letter from Stephenson. PMID- 26744700 TI - Impact of Lifestyle on Health. PMID- 26744699 TI - Praxis-induced seizures in a patient with juvenile myoclonic epilepsy: MEG-EEG coregistration study. AB - PURPOSE: Juvenile myoclonic epilepsy (JME) is one of the most common generalized idiopathic epilepsies of childhood and adolescence. In some patients with JME, mathematical calculus and praxis may induce myoclonic seizures. METHODS: A reflex myoclonic seizure was recorded by simultaneous magnetoencephalography (MEG) and electroencephalography (EEG) when a generalized spike-wave synchronous pattern at 3 Hz was observed. RESULTS: Source reconstruction localized the epileptogenic area to the right premotor frontal cortex. CONCLUSIONS: The present study demonstrates that the origin of epileptiform activity in JME can be localized in brain areas associated with the premotor frontal cortex. PMID- 26744701 TI - Association of Matrix Metalloproteinase-9 Gene -1562C/T Polymorphism with Essential Hypertension: A Systematic Review and Meta-Analysis Article. AB - BACKGROUND: Matrix metalloproteinase-9 (MMP-9) gene -1562C/T polymorphism could regulate its expression level and thus affected people's predisposition to essential hypertension. However, related studies yielded inconsistent or contradictory results. METHODS: To evaluate the association of MMP-9 -1562C/T polymorphism with essential hypertension, we performed a meta-analysis by combining all available independent case-control studies (n=6).A systematic literature search of PubMed, Web of Science, Scopus and CNKI (Chinese National Knowledge Infrastructure) databases was conducted by two researchers independently for all relevant articles published before March 2015. RESULTS: MMP 9 -1562C/T polymorphism was associated with essential hypertension under the allelic model (T vs.C, OR=1.36, 95% CI=1.17-1.59, P<0.0001). Subsequent sensitivity analysis confirmed the stability of the results. Such association was also observed in the dominant (TT+CT vs. CC, OR=1.30, 95% CI=1.10-1.54, P=0.002) and co-dominant (CT vs. TT+CC, OR=1.27, 95% CI=1.05-1.53, P=0.01) models but not in the recessive model (TT vs. CT+CC, OR=1.30, 95% CI=0.50-3.36, P=0.59). CONCLUSION: MMP-9 -1562C/T polymorphism was associated with the risk of essential hypertension. PMID- 26744704 TI - Characterization of Industrial Wastewater Sludge in Oman from Three Different Regions and Recommendations for Alternate Reuse Applications. AB - BACKGROUND: Domestic and industrial wastewaters are mostly treated by biological process such as activated sludge, aerobic pond, and anaerobic treatment. This study focuses on characterizing the quality of sewage sludge in the Sultanate of Oman chosen from three industrial sewage treatment plants (STPs): Rusayl Industrial Estate (RSL.IE); Sohar Industrial Estate (SIE); and Raysut Industrial Estate (RIE). METHODS: Samples of recycled activated sludge (RAS) and wasted activated sludge (WAS) were collected over a period of 12 months across above mentioned STPs. Parameters analyzed are electrical conductivity (EC), potential of hydrogen (pH), cations, anions and volatile content (VC). RESULTS: The obtained values for pH and EC were low for both RAS and WAS samples, except EC values of RIE that was more than 1000 MUS/cm. The range of VC percentages in RAS and WAS samples were 44 to 86% and 41 to 77%, respectively. The measured values for chloride, sulfate, nitrate and phosphate were higher than the other anions. CONCLUSION: The average values of the cations in RAS and WAS samples were within the Omani Standards, suitable for the re-use of sludge in agriculture except for Cd in RSL.IE. The study recommends that a regular maintenance should be performed at the studied STPs to prevent any accumulation of some harmful substances, which may affect the sludge quality, and the sludge drying beds should be large enough to handle the produced sludge for better management. PMID- 26744703 TI - Prostate-specific Antigen (PSA) Density and Free to Total PSA Ratio in Diagnosing Prostate Cancer with Prostate-Specific Antigen Levels of 4.0 ng/ml or Less. AB - BACKGROUND: We aimed to value the usefulness of free to total prostate-specific antigen and Prostate-specific antigen (PSA) density for prostate cancer in the patients with PSA levels of 4.0 ng/ml or less. METHODS: A total of 343 subjects with PSA levels of 4.0 ng/ml or less were biopsied. All patients were divided into four groups according to the PSA levels: 0 to 1.0 ng/ml, 1.1 to 2.0 ng/ml, 2.1 to 3.0 ng/ml, and 3.1 to 4.0 ng/ml. The reliability of cancer detection in relation to the f/t PSA ratio and PSAD were estimated. RESULTS: Overall, 65 people were diagnosed with prostate cancer. The detection rate was 16.28%,17.17%, 21.82%, 25.00% in subjects with PSA levels of 0 to 1.0 ng/ml, 1.1 to 2.0 ng/ml, 2.1 to 3.0 ng/ml, and 3.1 to 4.0 ng/ml, respectively. The f/t PSA ratio was significantly lower in patients with prostate cancer and PSA levels of 2.1 to 4.0 ng/ml (P<0.05). The PSAD had no statistical significance between the two groups. CONCLUSIONS: Routine prostate biopsy should be undertaken if the f/t PSA ratio less than 15% with /without abnormal DRE/TRUS findings. PMID- 26744702 TI - Communicable Disease Reporting Systems in the World: A Systematic Review Article. AB - BACKGROUND: Communicable disease reporting and surveillance system has poor infrastructure and supporters in most of countries. Its quality improvement is a challenge and requires an accurate and efficient care and reporting systems at all levels to achieve new and simple models. This study evaluates reporting systems of communicable diseases using systematic review. METHODS: This was a systematic review study. For data collection, we used the following database and search engines: Proquest, Science direct, Pub MED, Scopes, Springer, and EBESCO. For Persian databases, we used SID, Iranmedex and Magiran. Our key words were "Communicable Diseases", "Notifiable Disease", "Disease Notification", "Reporting System"," Surveillance Systems" and "evaluation". Two independent researchers reviewed the resources and the results were classified in different domains. RESULTS: From 1889 cases, only 66 resources were studied. The results were classified in several domains, including those who were reporting, reporting methods and procedures, responsibilities and reporting system characteristics, problems and solutions of the report, the reporting process, and receptor level. CONCLUSION: Disease-reporting system has similar problems in all parts of the world. Change, improve, update and continuous monitoring of the reporting system are very important. Although the reporting process can vary in different regions, but being perfect and timely are important principles in system design. Detailed explanations of tasks and providing appropriate instructions are the most important points to integrate an efficient reporting system. PMID- 26744705 TI - Predictors of Glycated Hemoglobin among Jordanian Diabetic Patients. AB - BACKGROUND: We explored the level of Jordanian patients' knowledge, diabetes related distress, self-management activities and these effects on the A1C level. METHODOLOGY: This descriptive cross-sectional correlational design (conducted in 2013) was utilized to recruit 289 diabetic patients from outpatient diabetes clinics, using self-reported questionnaires (Diabetes Knowledge Test, Diabetes Distress Scale, and Diabetes Self-Management Questionnaire) in addition to chart review for selected variables. RESULTS: Participants' had mean glycated hemoglobin of 7.88%. Good glycemic control was significantly associated with higher self-management activities (r= -.147), high income (r= -.171), older age (r= -.252), shorter duration of illness (r= .153), and low levels of distress. Despite these relationships only age, duration of illness and income significantly predicted A1C (F (5, 284) = 11.57, P<.001, R (2) = .17). Further, diabetes knowledge, diabetes-related distress, and self-management could not predict A1C level. CONCLUSION: Only diabetes-related distress and self-management correlated with patients' A1C, with no predictive power. Thus, further research is required to shed the light on the large unexplained components of the A1C variance. PMID- 26744706 TI - Electrolyte Disturbance and the Type of Malarial Infection. AB - BACKGROUND: Electrolytes play an important role in the normal functioning of human body. Electrolyte imbalance and mineral disturbances is the common clinical manifestation in several infectious diseases including malaria. Malaria is a mosquito borne serious infectious disease of the world. Plasmodium vivax and P. falciparum are the main agents responsible for malaria in Pakistan. Electrolyte imbalance in malarial infection may lead towards the severity of disease. METHODS: The present study analyzed the electrolytes levels (Na, K, Ca and Mg) in malarial patients and healthy individuals. Patients were categorized into two groups, P. falciparum and P. vivax, based on causative species of Plasmodium. Study consisted of 173 individuals, out of which 73 were malarial patients and 100 were normal healthy individuals. RESULTS: Concentrations of Na, K, and Ca were low in the blood of malarial patients as compared to healthy individuals (P<0.05). No significant difference for these electrolytes exists between P. falciparum and P. vivax infected groups (P>0.05). The concentration of Mg was changed based on exposure to the type of parasite. In P. falciparum infection, the level of Mg was lower than healthy individuals was (P<0.05). Discordantly, in case of P. vivaxinfection, Mg level was higher than healthy individuals were (P<0.05). No variation was noticed in electrolytes levels due to gender differences (P>0.05). CONCLUSION: Variation in Mg levels occurs due to exposure of Plasmodium depending on its type. The levels of Na, K and Ca are also changed due to Plasmodium, regardless of its type. PMID- 26744707 TI - Multiple Sclerosis Associated Risk Factors: A Case-Control Study. AB - BACKGROUND: Hamadan Province is one of the high-risk regions in Iran for Multiple sclerosis (MS). A majority of the epidemiological studies conducted in Iran addressing MS are descriptive. This study was conducted to assess MS and its associated risk factors in Hamadan Province, the west of Iran. METHODS: This case control study compared 100 patients with MS (case group) and 100 patients with acute infectious diseases (control group) from September 2013 to March 2014. A checklist was used to assess the demographic, medical, and family history of the patients. The Friedman-Rosenman questionnaire was also used to assess personality type. Statistical analysis was performed using logistic regression model with Stata 11 software program. RESULTS: The adjusted odds ratio (OR) estimate of MS was 4.37 (95% CI: 2.33, 8.20) for females compared to males; 0.15 (95% CI: 0.06, 0.43) for people aged above 50 years compared to aged 14 to 29 years; 0.44 (95% CI: 0.21, 0.91) for overweight or obese people compared to normal weights. Crude OR indicated a significant association between the occurrence of MS and exclusive breast feeding, season of birth, and smoking. However, the association was not statistically significant after adjustment for other covariates. CONCLUSION: The risk of MS is significantly lower in male gender, obese/overweight, and old people. Furthermore, non-smoking, non-exclusive breast-feeding, and born in autumn may increase the risk of MS but need further investigation. However, long term large prospective cohort studies are needed to investigate the true effect of the potential risk factors on MS. PMID- 26744708 TI - The Relationship between Disease, Work and Sickness Absence among Psoriasis Patients. AB - BACKGROUND: The aim of this study was to assess the prevalence of absenteeism in patients with psoriasis and determine the factors influencing the incidence of absenteeism in these patients. METHODS: A cross-sectional study from December 2012 to November of 2013 was conducted on 192 psoriasis patients referred to the Dermatology Clinic of Imam Khomeini Hospital, Tehran, Iran. The number day of absence from work due to psoriasis in the last year was asked from the patients; the absence of 7 days has been considered as short-term and more than 7 days as long-term. Logistic regression was used to data analysis. RESULTS: Sickness absence in 21.4% of patients was positive. The average numbers of days of absence were 10.25 and the duration of absence from work in 48.7% were long-term >=7 days. 51.3% had short-term absence (<7 days). Among disease factors: moderate to severe disease (SAPASI score >10), palms and soles involvement, joint problems and radiation therapy and among job factors: hazardous physical and chemical exposures in the workplace, non-office work, disability, exacerbations of disease on work days and problem on employment were associated with high incidence of sickness absence. CONCLUSION: Psoriasis with its chronic and recurrent nature especially in higher severities causes disabilities that deeply affect Work performance and can decrease the efficiency. In better management of psoriasis patients, physicians should pay special attention to occupational factors. PMID- 26744710 TI - Epidemiology of Human Fascioliasis and Intestinal Helminthes in Rural Areas of Boyer-Ahmad Township, Southwest Iran; A Population Based Study. AB - BACKGROUND: Fascioliasis, caused by Fasciola hepatica and F. gigantica, is one of the most important plant and water borne disease in Iran. This study aimed to determine the prevalence of fascioliasis and intestinal helminthes in inhabitants of rural areas of Boyer-Ahmad in Kohgiluyeh and Boyer-Ahmad province in Southwest of Iran. METHODS: Stool samples (1025) were collected from inhabitant of 50 randomly selected villages in Boyer-Ahmad Township. Samples were evaluated with modified Telemann and formalin-ethyl acetate methods. Blood samples of Fasciola positive cases were assessed with ELISA and Western blotting. DNA was extracted from Fasciola eggs from stool of positive individuals and evaluated by molecular (PCR) method and the PCR products were sequenced and analyzed. RESULTS: Of the 1025 participants, 473 (46.1%) were male and 552 (53.9%) were female. The mean age of the subjects was 20.25 (+/-15.86) years. Fasciola eggs were detected in stools of two cases (0.19%). Blood samples were obtained from the Fasciola positive cases and their infection was further confirmed by ELISA and Western blotting. Molecular analysis revealed that both cases are infected with F. hepatica. Furthermore, seven of participants (0.68%) were found to be infected with H. nana, 4 cases (0.39%) with E. vermicularis, and one case (0.09%) with Trichuris trichiura. CONCLUSION: Findings of this study showed that Boyer-Ahmad district is one of the endemic areas of human fascioliasis in Iran. The study also documented that the rate of helminthic infections in rural areas of the district has drastically declined over the past years. PMID- 26744709 TI - Pseudomonas aeruginosa and Heterotrophic Bacteria Count in Bottled Waters in Iran. AB - BACKGROUND: Nowadays, due to increased public awareness about water pollution and water borne diseases as well as water network deficiencies, bottled water consumers have increased dramatically worldwide, including Iran. Pseudomonas aeruginosa is an opportunistic human pathogen capable of causing widespread infections in burn and immune-compromised patients. The aim of this study was to investigate, P. aeruginosa in bottled waters selling in Iranian markets. METHODS: One hundred and twenty samples of five unknown (not famous) domestic bottled water brands were purchased from Tehran retailers during 2013. The samples were evaluated for the presence of P. aeruginosa. In addition, heterotrophic plate counts were determined by incubation at 37 degrees C for 24 h. RESULTS: P. aeruginosa was detected in 36.7% (44 samples) of all samples examined. In addition, heterotrophic bacteria in 32.5% (39 samples) of the samples were higher than 100 CFU/mL, while in 7.5% (9 samples) of the samples HPC relied between 20 and 100 CFU/ml. CONCLUSION: In contrast to public believe, bottled waters are not free of microorganisms, and it is suggested that authorities should provide stricter monitoring and control plan for water resources and plants. Concerning HPC and P. aeruginosa brands B and D were not suitable for drinking. PMID- 26744711 TI - Predicting the Incidence of Smear Positive Tuberculosis Cases in Iran Using Time Series Analysis. AB - BACKGROUND: Determining the temporal variation and forecasting the incidence of smear positive tuberculosis (TB) can play an important role in promoting the TB control program. Its results may be used as a decision-supportive tool for planning and allocating resources. The present study forecasts the incidence of smear positive TB in Iran. METHODS: This a longitudinal study using monthly tuberculosis incidence data recorded in the Iranian National Tuberculosis Control Program. The sum of registered cases in each month created 84 time points. Time series methods were used for analysis. Based on the residual chart of ACF, PACF, Ljung-Box tests and the lowest levels of AIC and BIC, the most suitable model was selected. RESULTS: From April 2005 until March 2012, 34012 smear positive TB cases were recorded. The mean of TB monthly incidence was 404.9 (SD=54.7). The highest number of cases was registered in May and the difference in monthly incidence of smear positive TB was significant (P<0.001). SARIMA (0,1,1)(0,1,1)12 was selected as the most adequate model for prediction. It was predicted that the incidence of smear positive TB for 2015 will be about 9.8 per 100,000 people. CONCLUSION: Based on the seasonal pattern of smear positive TB recorded cases, seasonal ARIMA model was suitable for predicting its incidence. Meanwhile, prediction results show an increasing trend of smear positive TB cases in Iran. PMID- 26744712 TI - Sugar-Sweetened Beverage Consumption and Risk of General and Abdominal Obesity in Iranian Adults: Tehran Lipid and Glucose Study. AB - BACKGROUND: General and abdominal obesity are major global health problems. This cross-sectional study was conducted to evaluate the association between consumption of sugar-sweetened beverages (SSBs) and body mass index and waist circumference status in 5852 Iranian adults within the framework of the Tehran Lipid and Glucose Study (TLGS). METHODS: Intakes of SSBs including carbonated drinks and synthetic fruit juices were measured using a validated food frequency questionnaire. The association between body mass index, waist circumference and body adiposity index in each quartile category of SSB consumption were determined using the multivariable linear regression models. The odds ratio (OR) of general and abdominal obesity in each quartile of SSB consumption was also determined using the multivariable logistic regression models. RESULTS: Mean dietary intake of SSBs was 48.9 g/d or 0.25 servings/d. After adjustment for all potential confounding variables, significant associations were observed between SSB consumption and BMI (beta: 0.49, 95% CI: 0.13-0.86), and waist circumference (beta: 1.28, 95% CI: 0.40-2.16) in the fourth quartile. There was no significant association between SSB consumption and body adiposity index. Participants who consumed > 57.1 g/d of SSBs had 22% higher risk of general obesity (OR: 1.22, 95% CI: 1.00-1.48) and 35% higher risk of abdominal obesity (OR: 1.35, 95% CI: 1.12 1.61), compared with those in the lowest quartile of SSB consumption. CONCLUSION: Higher intakes of SSBs were associated with the higher risk of general and abdominal obesity in adults suggesting that limiting the consumption of SSBs may be a practical approach to prevent and manage obesity. PMID- 26744713 TI - Native Larvivorous Fish in an Endemic Malarious Area of Southern Iran, a Biological Alternative Factor for Chemical Larvicides in Malaria Control Program. AB - BACKGROUND: The widespread use of chemical insecticides, resistance in vectors and environmental problems, all have led to an increased interest in the use of biological agents in malaria control programs. The most important functional elements are the native fish. The aim of this study was to identify the native species of lavivorous fish in Rudan County, southern Iran, to introduce an effective species and to propose its' implementation in the national malaria control program. METHODS: This ecologically descriptive study was conducted during 2011-2012 using random sampling from different fish habitats of Rudan County. The shoals of fish were caught using fishing net. Fish samples were then identified in the Ichthyology lab, Department of Fisheries and the Environment, Hormozgan University. RESULTS: Three species of larvivorous fish were identified as follows: Gambusia holbrooki, Aphaniusdispar dispar and Aphanius sp. The latter species has the most distribution in the study area and needs more morphological and molecular studies for identification at the species level. CONCLUSION: Two species of native fish, i.e., A. dispar and A. sp. with larvivorous potential live in the area. Further studies on their predatory property are recommended in order to apply this local potential against malaria vectors in the area. PMID- 26744714 TI - Multiple Enteroenteric Fistulas- Crohn's Disease- A Case Report. AB - Crohn's disease is a type of chronic inflammatory bowel disease (IBD) of unknown etiology that may affect any part of the gastrointestinal tract from mouth to anus and shows extra-intestinal involvement. It characteristically shows skip lesions. This case report reported in 2014 describes a middle age Pakistani male known to have documented evidence of significant crohn's disease since past 18 years. He was diagnosed with multiple fistulas that are a rare entity of patients with crohn's disease, which is itself a rare disease in Asian countries. PMID- 26744715 TI - The Influence of Health Literacy on Self-Care Agency in an Older Adult Population in Xinjiang, China. PMID- 26744716 TI - Herbal Therapy and Treatment of Worm Infections, Emphasizing Taenia solium. PMID- 26744717 TI - Common Statistical Mistakes in Descriptive Statistics Reports of Normal and Non Normal Variables in Biomedical Sciences Research. PMID- 26744718 TI - Some Facts about Cancer in the World using Registered Cancer in 2012. PMID- 26744719 TI - Aggression: Is that an issue for worrying? PMID- 26744720 TI - Determinants of Supplementary Health Insurance Demand: Case Study of Iran. PMID- 26744721 TI - Social Capital and Its Effects on Health: Implications for Policy Makers. PMID- 26744722 TI - Patient Safety Friendly Hospital Initiative: Does it work in Iran? PMID- 26744724 TI - Factor Analysis of Spiritual Health on the Islam Viewpoint. PMID- 26744723 TI - Retinoic Acid Receptor Beta in Pathophysiology of Age-Related Macular Degeneration. PMID- 26744726 TI - The Opinions of Nursing Students Regarding the Nursing Process and Their Levels of Proficiency in Turkey. AB - INTRODUCTION: Nursing process, as a scientific method of nursing practice, is an important tool for putting nursing knowledge into practice which increases the quality of nursing care. The study was aimed to determine the opinions of nursing students regarding the nursing process and their levels of proficiency. METHODS: A total of 44 nursing students participated in this descriptive study. Data were collected by a three-part questionnaire including the opinion of students on nursing process, Gordon's functional health patterns model and the NANDA diagnoses. Data were analyzed by SPSS software. RESULTS: Most of the students (65.9%) believed that the nursing process was necessary. half of the students explained the diagnosis, 58.3% explained the planning, 41.3% explained the implementation, and 43.6% explained the evaluation sufficiently. CONCLUSION: It is suggested for instructors to use different teaching methods in order to develop critical thinking while teaching the nursing process. PMID- 26744725 TI - Yoga Practice Increases Minimum Muscular Fitness in Children with Visual Impairment. AB - INTRODUCTION: Muscle strength, a component for balance, gait and functional mobility is vital for children with visual impairment. Yoga has frequently been demonstrated to improve physical and mental fitness in children. This study aimed to assess the effect of 16 weeks yoga training on muscular fitness in children with visual impairment. METHODS: This was a wait-listed two-armed-matched case control study. Eighty (41 yoga, 39 control) visual impairment students of both genders aged 9-16 years matched on age, gender and degree of blindness were assessed at pre, mid (after 8 weeks) and post (after 16 weeks) yoga intervention using the Kraus-Weber test. RESULTS: The percentage of students passed in yoga group were 12.2%, 43.9% and 68.3% whereas percentages in the control group were 23.1%, 30.8% and 30.8% in pre, mid, and post tests respectively. McNemar test showed significant differences between pre and mid, mid and post in the yoga group while those parameters were not significantly different in the control group. Yoga therapy seemed to have considerable benefits for the children's muscular fitness. CONCLUSION: The study suggests that yoga have considerable benefits for improvement of fitness level in children with visual impairment and may be recommended as and effective, alternative, inexpensive low risk training activity option for them. PMID- 26744727 TI - Iranian Patients' Experiences of the Internal Cardioverter Defibrillator Device Shocks: a Qualitative Study. AB - INTRODUCTION: Implantable Cardioverter Defibrillator (ICD) is a valuable treatment for the patients at risk of sudden cardiac death. In this method, after diagnosis of pathological cardiac rhythms, shock is automatically applied to normalize the rhythms. Shock is discharged when the patients are conscious, but the patients' experiences of shock have remained unknown. Thus, this study aimed to identify and describe the patients' experiences of shocks received from ICD. METHODS: The present qualitative study was conducted through thematic analysis and semi-structured interviews on 9 patients mean age 41.55 (1.57) with ICD from November 2013 to July 2014. Data analysis was also performed simultaneously using constant comparative analysis. RESULTS: In this study, two main themes, namely "with a parachute for life" and "Faced with nuisance", were obtained representing the patients' experiences regarding ICD shock. With a parachute for life included subthemes, such as "Rebirth", "Comforter and healing", and "Life assurance". In addition, "Faced with nuisance" consisted of 2 subthemes of "Discomfort in moments of shock" and "Displeasure after shock". CONCLUSION: This study provided a basis for evaluation of patients nursing after discharge. By identification of the patients' experiences regarding shock, the present study can help the professional health staff to efficiently play their roles and provide patients with holistic care. It can also be effective in designing behavioral and cognitive interventional programs to change the patients' attitude and promote their adaptation with their conditions. PMID- 26744728 TI - Assessment of the Quality of Delivered Care for Iranian patients with Rheumatoid Arthritis by Using Comprehensive Quality Measurement Model in Health Care (CQMH). AB - Introduction : Quality of care has become increasingly critical in the evaluation of healthcare and healthcare services. The aim of this study was to assess quality of delivered care among patients with rheumatoid arthritis using a model of Comprehensive Quality Measurement in Health Care (CQMH). Methods : This cross sectional study was conducted on 172 patients with rheumatoid arthritis (RA) who were received care from private clinics of Isfahan University of medical sciences in 2013. CQMH questionnaires were used for assessing the quality of care. Data were analyzed using SPSS for Windows. RESULTS: The mean scores of Quality Index, Service Quality (SQ), Technical Quality (TQ), and Costumer Quality (CQ) were 72.70, 79.09, 68.54 and 70.25 out of 100, respectively. For CQ only 19.8% of participations staying the course of action even under stress and financial constraints, there is a significant gap between what RA care they received with what was recommended in the guideline for TQ. Scores of service quality was low in majority of aspects especially in "availability of support group" section. CONCLUSION: Study shows paradoxical findings and expresses that quality scores of service delivery for patients with arthritis rheumatoid from patient's perspective is relatively low. Therefore, for fixing this paradoxical problem, improving the participation of patients and their family and empowering them for self-management and decision should be regarded by health systems. PMID- 26744730 TI - Spiritual wellbeing, Attitude toward Spiritual Care and its Relationship with Spiritual Care Competence among Critical Care Nurses. AB - INTRODUCTION: Nurses' spiritual wellbeing and their attitude toward spirituality and competence of nurses in providing of spiritual care can affect the quality of care in nursing. The aim of this study was to evaluate spiritual wellbeing, attitude toward spiritual care and its relationship with the spiritual care competence among nurses. METHODS: This was a correlational descriptive study conducted on 109 nurses working in the Intensive Care Units of Imam Reza and Madani hospitals in 2015, Tabriz, Iran. Data collection tools were a demographic data form and three standard questionnaires including Spiritual Wellbeing Scale, Spirituality and Spiritual Results: The mean score of the spiritual wellbeing was 94.45 (14.84), the spiritual care perspective was 58.77 (8.67), and the spiritual care competence was 98.51 (15.44). The linear regression model showed 0.42 variance between the spiritual care competence scores which were explained by the two aspects of spiritual wellbeing (religious health, existential health) and three aspects of spiritual care perspective (spirituality, spiritual care, personalized care). The spiritual care competence had a positive relationship with spiritual wellbeing and spiritual care perspective. CONCLUSION: Because of the nature of nursing and importance of close interaction of nurses with patients in ICUs, the higher nurses' SW and the more their positive attitude toward spiritual care, the more they can provide spiritual care to their patients. PMID- 26744731 TI - Reproductive Health of Women in Rural Areas of East Azerbaijan - Iran, before and after Implementation of rural Family Physician Program: an Ecologic Study. AB - INTRODUCTION: Implementation of rural family physician program in Iran in 2005 has been evaluated and shown that this program has been led to some improvements in health indicators. In this study, some reproductive health (RH) indicators were compared before and after implementation of this program in rural areas of East Azerbaijan, Iran. METHODS: In this ecologic- time trend study, the data of 191075 births of rural women of East Azerbaijan from 2001 to 2010 was extracted from vital horoscope (ZIJ) and used for calculation of 20 important RH indicators. The paired t-test and correlation analysis wear used for data analysis. RESULTS: Some indicators such as adolescent marriage rate, adolescent birth and over 35 year olds birth rate were increased after rural family physician program implementation in 2005. Also stillbirth rate and unsafe delivery were decreased during this period. There was a significant correlation between increasing adolescent birth rate and increasing low birth weight deliveries (r= 0.911, P= 0.031) and also between increasing over 35 year olds birth rate and increasing neonatal mortality rate in term of prematurity and congenital malformations (r= 0.912, P= 0.031) after program implementation. CONCLUSION: Perinatal care and safe delivery even for pregnancies outside the typical child-bearing ages are promoting after implementation of rural family physician program in East Azerbaijan. Also decreasing unsafe delivery and stillbirth rate can be considered as achievements of running this program in this province. PMID- 26744729 TI - Comparison of the Effects of Lanolin, Peppermint, and Dexpanthenol Creams on Treatment of Traumatic Nipples in Breastfeeding Mothers. AB - INTRODUCTION: Traumatic nipple is among the most common problems of the breastfeeding period which leads to early cessation of breastfeeding. The study aimed to compare the effects of the lanolin, peppermint, and dexpanthenol creams on the treatment of traumatic nipples. METHODS: This double-blind randomized controlled trial was carried out on 126 breastfeeding mothers. The mothers had visited at the health centers and children's hospitals in Sanandaj City. The selected participants were randomly divided into the following three groups of lanolin, peppermint, and dexpanthenol cream groups. Nipple pain was measured using the Store scale while trauma was measured with the Champion scale. Analyses were carried out through the Kruskal-Wallis test, Chi-square, ANOVA, and repeated measures ANOVA by using SPSS software ver. 13. RESULTS: The result showed that the mean score of nipple pain and nipple trauma at the prior to intervention stage, third, seventh, and fourteenth days of intervention was not significantly different between three groups. But, repeated measures ANOVA showed a significant difference in comparison of the four time periods of intervention in each group. CONCLUSION: RESULTS of this study revealed that the lanolin, peppermint, and dexpanthenol medicines had similar therapeutic effects on traumatic nipple. PMID- 26744732 TI - The Impact of Team-Based Learning on Nervous System Examination Knowledge of Nursing Students. AB - INTRODUCTION: Team-based learning is one of the active learning approaches in which independent learning is combined with small group discussion in the class. This study aimed to determine the impact of team-based learning in nervous system examination knowledge of nursing students. METHODS: This quasi-experimental study was conducted on 3(rd) grade nursing students, including 5th semester (intervention group) and 6(th) semester (control group). The traditional lecture method and the team-based learning method were used for educating the examination of the nervous system for intervention and control groups, respectively. The data were collected by a test covering 40-questions (multiple choice, matching, gap filling and descriptive questions) before and after intervention in both groups. Individual Readiness Assurance Test (RAT) and Group Readiness Assurance Test (GRAT) used to collect data in the intervention group. In the end, the collected data were analyzed by SPSS ver. 13 using descriptive and inferential statistical tests. RESULTS: In team-based learning group, mean and standard deviation was 13.39 (4.52) before the intervention, which had been increased to 31.07 (3.20) after the intervention and this increase was statistically significant. Also, there was a statistically significant difference between the scores of RAT and GRAT in team-based learning group. CONCLUSION: Using team-based learning approach resulted in much better improvement and stability in the nervous system examination knowledge of nursing students compared to traditional lecture method; therefore, this method could be efficiently used as an effective educational approach in nursing education. PMID- 26744733 TI - Nucleus Accumbens AMPA Receptor Trafficking Upregulated by Food Restriction: An Unintended Target for Drugs of Abuse and Forbidden Foods. AB - There is a high rate of comorbidity between eating disorders and substance abuse, and specific evidence that weight-loss dieting can increase risk for binge pathology, rebound excessive weight gain, and initiation and relapse to drug abuse. The present overview discusses basic science findings indicating that chronic food restriction induces dopamine conservation, compensatory upregulation of D-1 dopamine receptor signaling, and synaptic incorporation of calcium permeable glutamatergic AMPA receptors in nucleus accumbens. Evidence is presented which indicates that these neuroadaptations account for increased incentive effects of food, drugs, and associated environments during food restriction. In addition, these same neuroadaptations underlie upregulation of sucrose- and psychostimulant-induced trafficking of AMPA receptors to the nucleus accumbens postsynaptic density, which may be a mechanistic basis of enduring maladaptive behavior. PMID- 26744734 TI - The ratio of phosphatidylcholines to lysophosphatidylcholines in plasma differentiates healthy controls from patients with Alzheimer's disease and mild cognitive impairment. AB - BACKGROUND: Metabolomic processes have been identified as being strongly linked to the development of Alzheimer's disease (AD). Thus, lipid metabolites appear to be highly useful as diagnostic substrates for the diagnosis of AD and mild cognitive impairment (MCI) in plasma. METHODS: We analyzed plasma samples from controls (n = 35), MCI (n = 33), and AD patients (n = 43) using the AbsoluteIDQ p180 Kit (Biocrates Life Sciences), which included quantitative analysis of 40 acylcarnitines, 21 amino acids, 19 biogenic amines, 15 sphingolipids, 90 glycerophospholipids, and sum of hexoses. RESULTS: We found that individual lipid metabolites can differentiate controls from MCI and AD with relevant significance. However, the ratio between PC aa C34:4 and lysoPC a C18:2 differentiates controls from MCI (P = .0000007) and from AD (P = .0000009) with greater significance. CONCLUSIONS: The results provide evidence that the ratio of these two lipid metabolites is useful for diagnosing MCI and AD with an accuracy of 82%-85%. PMID- 26744735 TI - Refining the Structural Model of a Heterohexameric Protein Complex: Surface Induced Dissociation and Ion Mobility Provide Key Connectivity and Topology Information. AB - Toyocamycin nitrile hydratase (TNH) is a protein hexamer that catalyzes the hydration of toyocamycin to produce sangivamycin. The structure of hexameric TNH and the arrangement of subunits within the complex, however, have not been solved by NMR or X-ray crystallography. Native mass spectrometry (MS) clearly shows that TNH is composed of two copies each of the alpha, beta, and gamma subunits. Previous surface induced dissociation (SID) tandem mass spectrometry on a quadrupole time-of-flight (QTOF) platform suggests that the TNH hexamer is a dimer composed of two alphabetagamma trimers; furthermore, the results suggest that alpha-beta interact most strongly (Blackwell et al. Anal. Chem. 2011, 83, 2862-2865). Here, multiple complementary MS based approaches and homology modeling have been applied to refine the structure of TNH. Solution-phase organic solvent disruption coupled with native MS agrees with the previous SID results. By coupling surface induced dissociation with ion mobility mass spectrometry (SID/IM), further information on the intersubunit contacts and relative interfacial strengths are obtained. The results show that TNH is a dimer of alphabetagamma trimers, that within the trimer the alpha, beta subunits bind most strongly, and that the primary contact between the two trimers is through a gamma gamma interface. Collisional cross sections (CCSs) measured from IM experiments are used as constraints for postulating the arrangement of the subunits represented by coarse-grained spheres. Covalent labeling (surface mapping) together with protein complex homology modeling and docking of trimers to form hexamer are utilized with all the above information to propose the likely quaternary structure of TNH, with chemical cross-linking providing cross-links consistent with the proposed structure. The novel feature of this approach is the use of SID-MS with ion mobility to define complete connectivity and relative interfacial areas of a heterohexameric protein complex, providing much more information than is available from solution disruption. That information, when combined with CCS-guided coarse-grained modeling and covalent labeling restraints for homology modeling and trimer-trimer docking, provides atomic models of a previously uncharacterized heterohexameric protein complex. PMID- 26744738 TI - Asunaprevir plus daclatasvir for the treatment of chronic hepatitis C virus infection. AB - Daclatasvir is a nonstructural protein 5A inhibitor of hepatitis C virus (HCV) replication. Asunaprevir is an NS3/4A complex inhibitor of HCV replication. The combination of daclatasvir and asunaprevir has been approved in Japan for the treatment of genotype 1 chronic HCV infection. In vitro studies have documented potent activity of these drugs, individually and in combination, against genotype 1 HCV. Results from completed and ongoing clinical studies have confirmed this potent activity in patients, with better responses noted in genotype 1b patients compared to patients with genotype 1a HCV. Response rates are also better in treatment-naive patients compared to those who are treatment-experienced; in these cases, the addition of interferon and ribavirin appears to enhance the treatment response. The combination of daclatasvir and asunaprevir is, in general, well tolerated. Daclatasvir and asunaprevir are substrates for cytochrome P450 3A4 enzymatic pathway; thus, there is a substantial potential for drug interactions. PMID- 26744737 TI - Toward a Language-General Account of Word Production: The Proximate Units Principle. AB - Theories of language production are monolingual but the world is multilingual. In the domain of word-form encoding, it is clear that languages rely differentially on different phonological units, challenging the generality of the monolingual theories. To address this, we propose the proximate units principle, which holds that the initial selection of sub-lexical phonological units (syllables, morae, phonemic segments, etc) is crucial both to understanding language specific processing, and to identifying what is language general in word production. We define proximate units and the role they play in speech planning and execution. The proximate units principle is consistent with much of what is already known about word form encoding across languages but also makes new predictions and can bring greater clarity to interpretations of experimental and speech error data. PMID- 26744739 TI - Pimavanserin. AB - Pimavanserin (ACP-103) is a selective inverse agonist of the 5-hydroxytryptamine 2A (5-HT2A) receptor intended to treat patients with Parkinson's disease psychosis (PDP). Currently there are no FDA-approved medications in the United States for the treatment of PDP, although on September 2, 2014, the United States Food and Drug Administration granted breakthrough therapy status to pimavanserin, highlighting the unmet need for therapeutics in this class. Most antipsychotic medications worsen motor dysfunction due to dopamine antagonism, and all carry a black box warning for an increased risk of mortality in elderly patients with dementia-related psychosis. Data from phase II and phase III clinical trials suggest that pimavanserin is a safe and effective treatment option for PDP. Trial results indicate a significant reduction in hallucinations and delusions in patients with PDP without worsening motor symptoms. Additional studies are ongoing for the treatment of Alzheimer's psychosis, schizophrenia and insomnia. Such promising outcomes warrant a review of the available literature regarding pimavanserin and its use in the treatment of PDP symptoms. PMID- 26744736 TI - Heart Regeneration with Embryonic Cardiac Progenitor Cells and Cardiac Tissue Engineering. AB - Myocardial infarction (MI) is the leading cause of death worldwide. Recent advances in stem cell research hold great potential for heart tissue regeneration through stem cell-based therapy. While multiple cell types have been transplanted into MI heart in preclinical studies or clinical trials, reduction of scar tissue and restoration of cardiac function have been modest. Several challenges hamper the development and application of stem cell-based therapy for heart regeneration. Application of cardiac progenitor cells (CPCs) and cardiac tissue engineering for cell therapy has shown great promise to repair damaged heart tissue. This review presents an overview of the current applications of embryonic CPCs and the development of cardiac tissue engineering in regeneration of functional cardiac tissue and reduction of side effects for heart regeneration. We aim to highlight the benefits of the cell therapy by application of CPCs and cardiac tissue engineering during heart regeneration. PMID- 26744741 TI - Ulipristal acetate for uterine fibroid-related symptoms. AB - Uterine fibroids are the most common benign uterine tumors in women of reproductive age. Although most women are asymptomatic (80%), fibroids, according to their type and location, can cause several symptoms and impact quality of life. To date, no medical treatment is able to eliminate fibroids. Ulipristal acetate (UPA) is an orally active synthetic selective progesterone receptor modulator (SPRM) characterized by a tissue-specific progesterone antagonist effect that reduces the proliferation of leiomyoma cells and induces apoptosis. It was licensed in Europe for preoperative fibroid treatment in 2012. Its pharmacological and pharmacodynamic characteristics, its efficacy and good tolerance make UPA a new important tool in the management of uterine fibroids. PMID- 26744740 TI - Safinamide for symptoms of Parkinson's disease. AB - Chronic and slow progression of neuronal death in Parkinson's disease is responsible for an altered neurotransmission of various biogenic amines, such as dopamine. Therefore, an individually different pronounced heterogeneity of motor and nonmotor symptoms characterizes each Parkinson's disease patient. Ideal candidates for the balance of these neurotransmitter deficits are compounds like safinamide with broad mechanisms of action such as reversible monoamine oxidase type B inhibition, blockage of voltage-dependent sodium channels, modulation of calcium channels and of glutamate release. Safinamide is administered one time daily with oral doses ranging from 50 to 100 mg. Safinamide was well tolerated and safe, ameliorated motor symptoms when combined with dopamine agonist only or additional levodopa in clinical trials. Safinamide is a novel instrument for the drug therapy of Parkinson's disease with better safety and tolerability particularly concerning diarrhea than inhibitors of catechol-O-methyltransferase, like entacapone, according to an indirect comparison within a meta-analysis with entacapone. PMID- 26744743 TI - A general metal-free route towards the synthesis of 1,2,3-triazoles from readily available primary amines and ketones. AB - An unprecedented approach that enables the direct and selective preparation of 1,5-disubstituted 1,2,3-triazoles from abundantly available building blocks such as primary amines, enolizable ketones and 4-nitrophenyl azide as a renewable source of dinitrogen via an organocascade process has been developed. Furthermore, this efficient methodology also enables the synthesis of fully functionalized and fused N-substituted heterocycles. PMID- 26744742 TI - AACR-NCI-EORTC - 27th International Symposium - Molecular Targets and Cancer Therapeutics (November 5-9, 2015 - Boston, Massachusetts, USA). AB - The 27th joint meeting of the European Organization for Research and Treatment of Cancer, National Cancer Institute and the American Association of Cancer Research (EORTC-NCI-AACR) International Conference on Molecular Targets and Cancer Therapeutics was held this year in Boston. Approximately 3,000 international academics, scientists and pharmaceutical industry representatives discussed new discoveries in the field of molecular biology of cancer and presented the latest information on drug discovery, preclinical research, clinical research and target selection in oncology. This report summarizes data on advances in cancer drug discovery. PMID- 26744744 TI - Synthesis of single-site copper catalysts for methane partial oxidation. AB - Cu-Exchanged zeolites are known as active materials for methane oxidation to methanol. However, understanding of the formation of Cu active species during synthesis, dehydration and activation is fragmented and rudimentary. We show here how a synthesis protocol guided by insight in the ion exchange elementary steps leads to highly uniform Cu species in mordenite (MOR). PMID- 26744745 TI - Contact angle measurements: a preliminary diagnostic tool for evaluating the performance of ZnFe2O4 nano-flake based supercapacitors. AB - Contact angle measurements (surface wettability) of the electrolytes (1 M KOH, NaOH and LiOH) and their combination (1 M 1 : 1 v/v LiOH + KOH, NaOH + KOH and LiOH + NaOH) in contact with ZnFe2O4 nano-flake based electrodes is used as an empirical diagnostic tool to pre-evaluate the performance of a supercapacitor prior to actual fabrication of the device. PMID- 26744746 TI - Ionic liquid@MIL-101 prepared via the ship-in-bottle technique: remarkable adsorbents for the removal of benzothiophene from liquid fuel. AB - Ionic liquids (ILs) were synthesized inside a porous metal-organic framework (MIL 101) via a ship-in-bottle (SIB) technique. Unlike previously reported IL incorporated MIL-101s, IL@MIL-101 prepared by the SIB approach was very stable over several cycles for the liquid phase adsorption of benzothiophene from liquid fuel. PMID- 26744747 TI - Synthesis of 3-alkyl spiro[4,5]trienones by copper-catalyzed oxidative ipso annulation of activated alkynes with unactivated alkanes. AB - A Cu-catalyzed oxidative ipso-annulation of activated alkynes with unactivated alkanes for the synthesis of 3-alkyl spiro[4,5]trienones is described. This method allows the formation of two carbon-carbon bonds and one carbon-oxygen bond in a single reaction through a sequence of C-H oxidative coupling, ipso carbocyclization and dearomatization. PMID- 26744748 TI - Synthesis and evaluations of an acid-cleavable, fluorescently labeled nucleotide as a reversible terminator for DNA sequencing. AB - An acid-cleavable linker based on a dimethylketal moiety was synthesized and used to connect a nucleotide with a fluorophore to produce a 3'-OH unblocked nucleotide analogue as an excellent reversible terminator for DNA sequencing by synthesis. PMID- 26744749 TI - Discovery of a non classic host guest complexation mode in a beta cyclodextrin/propionic acid model. AB - A non-classic complexation mode was discovered upon spectroscopic, thermodynamic, crystallographic and computational studies of a beta-cyclodextrin/propionic acid complex. A "fully immersed" complexation phenomenon, where both the guest's hydrophobic and polar moieties are located inside the host and are stabilized by it, was found and calculated as the most favorable configuration. PMID- 26744750 TI - Surfactant-free nickel-silver core@shell nanoparticles in mesoporous SBA-15 for chemoselective hydrogenation of dimethyl oxalate. AB - Surfactant-free bimetallic Ni@Ag nanoparticles in mesoporous silica, SBA-15 prepared by simple wet co-impregnation catalyse hydrogenation of dimethyl oxalate to methyl glycolate or ethylene glycol in high yield. PMID- 26744751 TI - A triple-function nanotube as a reactant reservoir, reaction platform, and byproduct scavenger for photo-cyclopropanation. AB - Herein, we report the advanced-concept triple-functionality of a metal-organic nanotube (MONT), which acts as a reservoir for unstable reactants, a photoreaction platform, and a scavenger for byproduct iodine. Self-assembly of CdI2 with a new Y-type ligand (L) produces the substantial 1D MOF, [CdI2(L)], thus forming a thick nanotube with a 1.4 nm diameter. PMID- 26744753 TI - [Standard diagnostic and therapeutic approach to chronic infection with hepatitis C virus (HCV)]. PMID- 26744754 TI - [Potential health risks in new asylum seekers coming from non-European countries]. PMID- 26744752 TI - Nitrogenated, phosphorated and arsenicated monolayer holey graphenes. AB - Motivated by a recent experiment that reported the synthesis of a new 2D material nitrogenated holey graphene (C2N) [Mahmood et al., Nat. Commun., 2015, 6, 6486], the electronic, magnetic, and mechanical properties of nitrogenated (C2N), phosphorated (C2P) and arsenicated (C2As) monolayer holey graphene structures are investigated using first-principles calculations. Our total energy calculations indicate that, similar to the C2N monolayer, the formation of the other two holey structures are also energetically feasible. Calculated cohesive energies for each monolayer show a decreasing trend going from the C2N to C2As structure. Remarkably, all the holey monolayers considered are direct band gap semiconductors. Regarding the mechanical properties (in-plane stiffness and Poisson ratio), we find that C2N has the highest in-plane stiffness and the largest Poisson ratio among the three monolayers. In addition, our calculations reveal that for the C2N, C2P and C2As monolayers, creation of N and P defects changes the semiconducting behavior to a metallic ground state while the inclusion of double H impurities in all holey structures results in magnetic ground states. As an alternative to the experimentally synthesized C2N, C2P and C2As are mechanically stable and flexible semiconductors which are important for potential applications in optoelectronics. PMID- 26744755 TI - Data sharing: An open mind on open data. PMID- 26744757 TI - OWNING UP TO THE TRUTH. PMID- 26744758 TI - Standing your ground: the importance of Health Information Managers sharing what they do. AB - Health information management professionals have a broad range of skills that are invaluable to the health sector. The advent of the electronic health record has provided the opportunity to aggregate patient data to answer clinical and policy questions in a systematic, timely and reproducible way. The possibility of linking datasets provides greater opportunities for answering clinical and policy questions, and Health Information Managers (HIMs) have the best skill set to inform about data quality, coding and classification, privacy, security, and medico-legal implications involved in the ethical handling of such datasets. HIMs have access to a wealth of data that could improve patient care and reduce unnecessary service utilisation, and that could be used to answer many research questions. Undertaking and publishing research is an excellent avenue for HIMs to promote and strengthen their profession. PMID- 26744759 TI - Preface. PMID- 26744756 TI - Author Response. PMID- 26744760 TI - HEALTHCARE IN MOTION. LEADERSHIP CENTER STAGE. PMID- 26744761 TI - Tips for Creating an Effective Suggestion System. PMID- 26744762 TI - 5 Change Misconceptions. PMID- 26744763 TI - Decisions Near the End of Life. PMID- 26744764 TI - Adopting a Systematic Approach to Bringing Healthcare Leaders Into a New Position or Organization. PMID- 26744765 TI - Phosphonium Formation by Facile Carbon-Phosphorus Reductive Elimination from Gold(III). AB - A recent trend in homogeneous gold catalysis has been the development of oxidative transformations relying on Au(I)/Au(III) redox cycling. Typically, phosphine-supported Au(I) precatalysts are used in the presence of strong oxidants to presumably generate phosphine Au(III) intermediates. Herein, we disclose that such Au(III) complexes can undergo facile C(aryl)-P reductive elimination to afford phosphonium salts, which have been spectroscopically and crystallographically characterized. Mechanistic studies indicate that this process occurs from cationic species at temperatures as low as -20 degrees C but can be accelerated in the presence of nucleophiles, such as acetonitrile and phosphines, via a five-coordinate intermediate. Importantly, this study highlights that irreversible C(aryl)-P reductive elimination is a feasible decomposition or activation pathway for phosphine-supported Au(III) catalysts and should not be ignored in future reaction development. PMID- 26744766 TI - Membrane-Inspired Acidically Stable Dye-Sensitized Photocathode for Solar Fuel Production. AB - Tandem dye-sensitized photoelectrochemical cells (DSPECs) for water splitting are a promising method for sustainable energy conversion but so far have been limited by their lack of aqueous stability and photocurrent mismatch between the cathode and anode. In nature, membrane-enabled subcellular compartmentation is a general approach to control local chemical environments in the cell. The hydrophobic tails of the lipid make the bilayer impermeable to ions and hydrophilic molecules. Herein we report the use of an organic donor-acceptor dye that prevents both dye desorption and semiconductor degradation by mimicking the hydrophobic/hydrophilic properties of lipid bilayer membranes. The dual functional photosensitizer (denoted as BH4) allows for efficient light harvesting while also protecting the semiconductor surface from protons and water via its hydrophobic pi linker. The protection afforded by this membrane-mimicking dye gives this system excellent stability in extremely acidic (pH 0) conditions. The acidic stability also allows for the use of cubane molybdenum-sulfide cluster as the hydrogen evolution reaction (HER) catalyst. This system produces a proton reducing current of 183 +/- 36 MUA/cm(2) (0 V vs NHE with 300 W Xe lamp) for an unprecedented 16 h with no degradation. These results introduce a method for developing high-current, low-pH DSPECs and are a significant move toward practical dye-sensitized solar fuel production. PMID- 26744768 TI - Mechanism of the Flavoprotein L-Hydroxynicotine Oxidase: Kinetic Mechanism, Substrate Specificity, Reaction Product, and Roles of Active-Site Residues. AB - The flavoprotein L-hydroxynicotine oxidase (LHNO) catalyzes an early step in the bacterial catabolism of nicotine. Although the structure of the enzyme establishes that it is a member of the monoamine oxidase family, LHNO is generally accepted to oxidize a carbon-carbon bond in the pyrrolidine ring of the substrate and has been proposed to catalyze the subsequent tautomerization and hydrolysis of the initial oxidation product to yield 6-hydroxypseudooxynicotine [Kachalova, G., et al. (2011) Proc. Natl. Acad. Sci. U.S.A. 108, 4800-4805]. Analysis of the product of the enzyme from Arthrobacter nicotinovorans by nuclear magnetic resonance and continuous-flow mass spectrometry establishes that the enzyme catalyzes the oxidation of the pyrrolidine carbon-nitrogen bond, the expected reaction for a monoamine oxidase, and that hydrolysis of the amine to form 6-hydroxypseudooxynicotine is nonenzymatic. On the basis of the kcat/Km and kred values for (S)-hydroxynicotine and several analogues, the methyl group contributes only marginally (~ 0.5 kcal/mol) to transition-state stabilization, while the hydroxyl oxygen and pyridyl nitrogen each contribute ~ 4 kcal/mol. The small effects on activity of mutagenesis of His187, Glu300, or Tyr407 rule out catalytic roles for all three of these active-site residues. PMID- 26744769 TI - In vitro antimicrobial studies of new benzimidazolium salts and silver N heterocyclic carbene complexes. AB - A series of new benzimidazolium salts (1a-g) were synthesized from the reaction of 1-(4-vinylbenzyl)benzimidazole with various alkyl halides. These salts were used to synthesize silver N-heterocyclic carbene (Ag-NHC) complexes (2a-f). The thirteen compounds were characterized by FT-IR, NMR ((1)H and (13)C) spectroscopic methods and an elemental analysis technique. These selected candidates were tested for their in vitro antimicrobial activities. Antibacterial and antifungal results indicated that the new salts, and particularly their silver complexes, were found to be strongly effective against seven Gram (-) bacterial strains, three Gram (+) bacterial strains and one yeast (Candida albicans). PMID- 26744767 TI - Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein-Protein Interaction between Menin and Mixed Lineage Leukemia (MLL). AB - Development of potent small molecule inhibitors of protein-protein interactions with optimized druglike properties represents a challenging task in lead optimization process. Here, we report synthesis and structure-based optimization of new thienopyrimidine class of compounds, which block the protein-protein interaction between menin and MLL fusion proteins that plays an important role in acute leukemias with MLL translocations. We performed simultaneous optimization of both activity and druglike properties through systematic exploration of substituents introduced to the indole ring of lead compound 1 (MI-136) to identify compounds suitable for in vivo studies in mice. This work resulted in the identification of compound 27 (MI-538), which showed significantly increased activity, selectivity, polarity, and pharmacokinetic profile over 1 and demonstrated a pronounced effect in a mouse model of MLL leukemia. This study, which reports detailed structure-activity and structure-property relationships for the menin-MLL inhibitors, demonstrates challenges in optimizing inhibitors of protein-protein interactions for potential therapeutic applications. PMID- 26744770 TI - Detecting Character Dependencies in Stochastic Models of Evolution. AB - Stochastic models of biological evolution generally assume that different characters (runs of the stochastic process) are independent and identically distributed. In this article we determine the asymptotic complexity of detecting dependence for some fairly general models of evolution, but simple models of dependence. A key difference from much of the previous work is that our algorithms work without knowledge of the tree topology. Specifically, we consider various stochastic models of evolution ranging from the common ones used by biologists (such as Cavender-Farris-Neyman and Jukes-Cantor models) to very general ones where evolution of different characters can be governed by different transition matrices on each edge of the evolutionary tree (phylogeny). We also consider several models of dependence between two characters. In the most specific model, on each edge of the phylogeny the joint distribution of the dependent characters undergoes a perturbation of a fixed magnitude, in a fixed direction from what it would be if the characters were evolving independently. More general dependence models don't require such a strong "signal." Instead they only require that on each edge, the perturbation of the joint distribution has a significant component in a specific direction. Our main results are nearly tight bounds on the induced or operator norm of the transition matrices that would allow us to detect dependence efficiently for most models of evolution and dependence that we consider. We make essential use of a new concentration result for multistate random variables of a Markov random field on arbitrary trivalent trees: We show that the random variable counting the number of leaves in any particular state has variance that is subquadratic in the number of leaves. PMID- 26744773 TI - Organometallically Anisotropic Growth of Ultralong Sb2Se3 Nanowires with Highly Enhanced Photothermal Response. AB - Ultralong orthorhombic Sb2Se3 nanowires have been successfully fabricated via an alternative facile organometallic synthetic route from the reaction of triphenylantimony(III) with dibenzyldiselenide in oleylamine at 180-240 degrees C without any other additives. The formation and growth mechanism of the Sb2Se3 nanowires is intensively investigated, and it is found that the anisotropic growth of the nanowires with almost constant diameters is resulted from the synergistic effects of the intrinsic property of the orthorhombic crystal structure and the weak binding assistance of oleylamine, and the length of the nanowires can be elongated easily by increasing reaction time in the synthetic route. Moreover, the photothermal response of the Sb2Se3 nanowires is first evaluated under illumination of UV light (320-390 nm), and it is especially noted that the Sb2Se3 nanowires exhibit highly enhanced photothermal responses (more than two times the intensity) as compared to the bulk Sb2Se3. In addition, the Sb2Se3 nanowires show excellent light-to-heat performance, which is superior to that of the nanostructured titanium dioxide and silicon powder under the same conditions. PMID- 26744772 TI - Confirmation of the Factor Structure and Measurement Invariance of the Children's Scale of Hostility and Aggression: Reactive/Proactive in Clinic-Referred Children With and Without Autism Spectrum Disorder. AB - OBJECTIVE: The measurement of aggression in its different forms (e.g., physical and verbal) and functions (e.g., impulsive and instrumental) is given little attention in subjects with developmental disabilities (DD). In this study, we confirm the factor structure of the Children's Scale for Hostility and Aggression: Reactive/Proactive (C-SHARP) and demonstrate measurement invariance (consistent performance across clinical groups) between clinic-referred groups with and without autism spectrum disorder (ASD). We also provide evidence of the construct validity of the C-SHARP. METHODS: Caregivers provided C-SHARP, Child Behavior Checklist (CBCL), and Proactive/Reactive Rating Scale (PRRS) ratings for 644 children, adolescents, and young adults 2-21 years of age. Five types of measurement invariance were evaluated within a confirmatory factor analytic framework. Associations among the C-SHARP, CBCL, and PRRS were explored. RESULTS: The factor structure of the C-SHARP had a good fit to the data from both groups, and strict measurement invariance between ASD and non-ASD groups was demonstrated (i.e., equivalent structure, factor loadings, item intercepts and residuals, and latent variance/covariance between groups). The C-SHARP Problem Scale was more strongly associated with CBCL Externalizing than with CBCL Internalizing, supporting its construct validity. Subjects classified with the PRRS as both Reactive and Proactive had significantly higher C-SHARP Proactive Scores than those classified as Reactive only, who were rated significantly higher than those classified by the PRRS as Neither Reactive nor Proactive. A similar pattern was observed for the C-SHARP Reactive Score. CONCLUSIONS: This study provided evidence of the validity of the C-SHARP through confirmation of its factor structure and its relationship with more established scales. The demonstration of measurement invariance demonstrates that differences in C-SHARP factor scores were the result of differences in the construct rather than to error or unmeasured/nuisance variables. These data suggest that the C-SHARP is useful for quantifying subtypes of aggressive behavior in children, adolescents, and young adults with DD. PMID- 26744771 TI - CCN1 (CYR61) and CCN3 (NOV) signaling drives human trophoblast cells into senescence and stimulates migration properties. AB - During placental development, continuous invasion of trophoblasts into the maternal compartment depends on the support of proliferating extravillous trophoblasts (EVTs). Unlike tumor cells, EVTs escape from the cell cycle before invasion into the decidua and spiral arteries. This study focused on the regulation properties of glycosylated and non-glycosylated matricellular CCN1 and CCN3, primarily for proliferation control in the benign SGHPL-5 trophoblast cell line, which originates from the first-trimester placenta. Treating SGHPL-5 trophoblast cells with the glycosylated forms of recombinant CCN1 and CCN3 decreased cell proliferation by bringing about G0/G1 cell cycle arrest, which was accompanied by the upregulation of activated Notch-1 and its target gene p21. Interestingly, both CCN proteins increased senescence-associated beta galactosidase activity and the expression of the senescence marker p16. The migration capability of SGHPL-5 cells was mostly enhanced in response to CCN1 and CCN3, by the activation of FAK and Akt kinase but not by the activation of ERK1/2. In summary, both CCN proteins play a key role in regulating trophoblast cell differentiation by inducing senescence and enhancing migration properties. Reduced levels of CCN1 and CCN3, as found in early-onset preeclampsia, could contribute to a shift from invasive to proliferative EVTs and may explain their shallow invasion properties in this disease. PMID- 26744775 TI - Placenta-related complications in women carrying a foetus with congenital heart disease. AB - INTRODUCTION: Recent studies pointed to an intrinsically angiogenic imbalance in CHD in the maternal and foetal circulation suggestive of impaired placentation. OBJECTIVES: To assess whether pregnant women with a CHD foetus are at greater risk of placenta-related complications. METHODS: Perinatal results of women with a CDH foetus were compared with those of a non-selected population followed up at our centre. Multiple pregnancies and chromosomal abnormalities were excluded from the analysis. RESULTS: About 279 pregnancies with CHD foetuses were included. Mothers were classified in three groups according to the foetal cardiac defect: 104 (37.3%) atrioventricular defect, 102 (36.5%) conotruncal anomalies and 73 (26.2%) left-ventricular outflow tract obstruction. A significantly higher incidence of pre-eclampsia was observed in the CHD group compared with the normal population (5.7% versus 1.2% p < 0.0001) [OR 5.96 (95% CI - 3.19-10.54)]. About 9.7% of foetuses with CHD had < 3rd birth weight percentile compared with 3% for the normal population [OR 3.32 (95% CI - 2.39-4.56)]. A higher incidence of stillbirth was also observed in the CHD group compared with the normal population (2.5% versus 0.4%) [OR 9.45 (95% CI - 3.35-23.3)]. CONCLUSIONS: Women carrying a foetus with CHD have a high risk of pre-eclampsia and intrauterine growth restriction. The relationship between CHD and placenta-related complications could be an encouraging topic for future research. PMID- 26744774 TI - Antibiotic-treated versus germ-free rodents for microbiota transplantation studies. AB - We recently investigated the applicability of antibiotic-treated recipient mice for transfer of different gut microbiota profiles. With this addendum we elaborate on perspectives and limitations of using antibiotics as an alternative to germ-free (GF) technology in microbial transplantation studies, and we speculate on the housing effect. It is possible to transfer host phenotypes via fecal transplantation to antibiotic-treated animals, but problems with reproducibility, baseline values, and antibiotic resistance genes should be considered. GF animals maintained in isolators still seem to be the best controlled models for long-term microbial transplantation, but antibiotic-treated recipients are also commonly utilized. We identify a need for systematic experiments investigating the stability of microbial transplantations by addressing 1) the recipient status as either GF, antibiotic-treated or specific pathogen free and 2) different levels of protected housing systems. In addition, the developmental effect of microbes on host physiological functions should be evaluated in the different scenarios. PMID- 26744776 TI - Long-Term Changes in Sediment and Nutrient Delivery from Conowingo Dam to Chesapeake Bay: Effects of Reservoir Sedimentation. AB - Reduction of suspended sediment (SS), total phosphorus (TP), and total nitrogen is an important focus for Chesapeake Bay watershed management. The Susquehanna River, the bay's largest tributary, has drawn attention because SS loads from behind Conowingo Dam (near the river's mouth) have been rising dramatically. To better understand these changes, we evaluated histories of concentration and loading (1986-2013) using data from sites above and below Conowingo Reservoir. First, observed concentration-discharge relationships show that SS and TP concentrations at the reservoir inlet have declined under most discharges in recent decades, but without corresponding declines at the outlet, implying recently diminished reservoir trapping. Second, best estimates of mass balance suggest decreasing net deposition of SS and TP in recent decades over a wide range of discharges, with cumulative mass generally dominated by the 75~99.5th percentile of daily Conowingo discharges. Finally, stationary models that better accommodate effects of riverflow variability also support the conclusion of diminished trapping of SS and TP under a range of discharges that includes those well below the literature-reported scour threshold. Overall, these findings suggest that decreased net deposition of SS and TP has occurred at subscour levels of discharge, which has significant implications for the Chesapeake Bay ecosystem. PMID- 26744777 TI - Atomic structure of the 26S proteasome lid reveals the mechanism of deubiquitinase inhibition. AB - The 26S proteasome is responsible for the selective, ATP-dependent degradation of polyubiquitinated cellular proteins. Removal of ubiquitin chains from targeted substrates at the proteasome is a prerequisite for substrate processing and is accomplished by Rpn11, a deubiquitinase within the 'lid' sub-complex. Prior to the lid's incorporation into the proteasome, Rpn11 deubiquitinase activity is inhibited to prevent unwarranted deubiquitination of polyubiquitinated proteins. Here we present the atomic model of the isolated lid sub-complex, as determined by cryo-electron microscopy at 3.5 A resolution, revealing how Rpn11 is inhibited through its interaction with a neighboring lid subunit, Rpn5. Through mutagenesis of specific residues, we describe the network of interactions that are required to stabilize this inhibited state. These results provide significant insight into the intricate mechanisms of proteasome assembly, outlining the substantial conformational rearrangements that occur during incorporation of the lid into the 26S holoenzyme, which ultimately activates the deubiquitinase for substrate degradation. PMID- 26744778 TI - The yin-yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF. AB - Many driver mutations in cancer are specific in that they occur at significantly higher rates than - presumably - functionally alternative mutations. For example, V600E in the BRAF hydrophobic activation segment (AS) pocket accounts for >95% of all kinase mutations. While many hypotheses tried to explain such significant mutation patterns, conclusive explanations are lacking. Here, we use experimental and in silico structure-energy statistical analyses, to elucidate why the V600E mutation, but no other mutation at this, or any other positions in BRAF's hydrophobic pocket, is predominant. We find that BRAF mutation frequencies depend on the equilibrium between the destabilization of the hydrophobic pocket, the overall folding energy, the activation of the kinase and the number of bases required to change the corresponding amino acid. Using a random forest classifier, we quantitatively dissected the parameters contributing to BRAF AS cancer frequencies. These findings can be applied to genome-wide association studies and prediction models. PMID- 26744779 TI - Polypyrimidine tract binding protein 1 protects mRNAs from recognition by the nonsense-mediated mRNA decay pathway. AB - The nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs containing long 3'UTRs to perform dual roles in mRNA quality control and gene expression regulation. However, expansion of vertebrate 3'UTR functions has required a physical expansion of 3'UTR lengths, complicating the process of detecting nonsense mutations. We show that the polypyrimidine tract binding protein 1 (PTBP1) shields specific retroviral and cellular transcripts from NMD. When bound near a stop codon, PTBP1 blocks the NMD protein UPF1 from binding 3'UTRs. PTBP1 can thus mark specific stop codons as genuine, preserving both the ability of NMD to accurately detect aberrant mRNAs and the capacity of long 3'UTRs to regulate gene expression. Illustrating the wide scope of this mechanism, we use RNA-seq and transcriptome-wide analysis of PTBP1 binding sites to show that many human mRNAs are protected by PTBP1 and that PTBP1 enrichment near stop codons correlates with 3'UTR length and resistance to NMD. PMID- 26744780 TI - Structural basis of nucleic-acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha. AB - The neuronal DNA-/RNA-binding protein Pur-alpha is a transcription regulator and core factor for mRNA localization. Pur-alpha-deficient mice die after birth with pleiotropic neuronal defects. Here, we report the crystal structure of the DNA /RNA-binding domain of Pur-alpha in complex with ssDNA. It reveals base-specific recognition and offers a molecular explanation for the effect of point mutations in the 5q31.3 microdeletion syndrome. Consistent with the crystal structure, biochemical and NMR data indicate that Pur-alpha binds DNA and RNA in the same way, suggesting binding modes for tri- and hexanucleotide-repeat RNAs in two neurodegenerative RNAopathies. Additionally, structure-based in vitro experiments resolved the molecular mechanism of Pur-alpha's unwindase activity. Complementing in vivo analyses in Drosophila demonstrated the importance of a highly conserved phenylalanine for Pur-alpha's unwinding and neuroprotective function. By uncovering the molecular mechanisms of nucleic-acid binding, this study contributes to understanding the cellular role of Pur-alpha and its implications in neurodegenerative diseases. PMID- 26744781 TI - Comparative effectiveness of everolimus and axitinib as second targeted therapies for metastatic renal cell carcinoma in the US: a retrospective chart review. AB - Background Second targeted therapies for metastatic renal cell carcinoma (mRCC) include mammalian target of rapamycin inhibitors (mTORis) and tyrosine kinase inhibitors (TKIs). This observational study compares overall survival (OS) and progression-free survival (PFS) of patients treated with everolimus (an mTORi) and axitinib (a TKI) following first TKI, and assesses the impact of type and duration of first TKI on the relative effectiveness of these second targeted therapies. Methods Retrospective reviews of medical records were conducted by medical oncologists or hematologists/oncologists recruited from a nationwide panel. Included patients with mRCC were required to have discontinued a first TKI (sunitinib, sorafenib, or pazopanib) for medical reasons, and to have initiated everolimus or axitinib as second targeted therapy between February 2012 and January 2013. OS and PFS were compared between patients treated with everolimus vs. axitinib using multivariable Cox proportional hazards regression models. Comparative results were also stratified by type and duration of first TKI. Results Included patients (n = 325 for everolimus and n = 127 for axitinib) had a mean age of 61 years and 31% were female. Sunitinib was the most commonly used first TKI (73%). After adjusting for patient characteristics, no statistically significant differences were observed in OS or PFS between everolimus and axitinib. When stratifying by type and duration of first TKI, there was no statistically significant difference in OS between everolimus and axitinib in all subgroups except for patients with <6 months on sunitinib or sorafenib as first TKI. No significant difference in PFS was observed in any subgroup. Limitations Important limitations include potential missing or inaccurate data in medical charts, and confounding due to unobserved factors. Conclusions In this retrospective chart review, no significant differences were detected in OS or PFS between axitinib and everolimus as second targeted therapy. Longer duration of first TKI was not associated with increased effectiveness of subsequent axitinib compared to everolimus. PMID- 26744783 TI - Sleep Duration and Sleep Quality: Associations With Depressive Symptoms Across Adolescence. AB - This study explored whether short sleep duration and sleep quality mediate the relationship between age and depressive symptoms. For comparison, we also explored whether depressive symptoms mediate the relationship between age and short sleep duration and sleep quality. The sample comprised 741 adolescents (63.5% female, mean age 15.78 years, range 11.92-19.67 years) in grades 7-12 from 11 secondary schools in metropolitan Melbourne, Australia. Students completed the Pittsburgh Sleep Quality Index (PSQI) and Center for Epidemiologic Studies Depression Scale (CES-D). Path analyses suggested that short sleep duration significantly mediated the relationship between age and depressive symptoms. Poor sleep quality also significantly mediated this relationship when sleep quality was defined by subjective judgement, but not sleep disturbance, sleep efficiency, or sleep onset latency. Depressive symptoms significantly mediated the relationship between age and short sleep duration and sleep quality (subjective judgement, sleep disturbance, sleep efficiency, and sleep onset latency). These findings suggest that the population-wide increase in depressive symptoms across adolescence is partially mediated by sleep-related developmental changes. They also highlight the importance of examining specific sleep problems when investigating the relationship between sleep and mood in this age group. PMID- 26744782 TI - Excited-State Proton-Transfer-Induced Trapping Enhances the Fluorescence Emission of a Locked GFP Chromophore. AB - The chemical locking of the central single bond in core chromophores of green fluorescent proteins (GFPs) influences their excited-state behavior in a distinct manner. Experimentally, it significantly enhances the fluorescence quantum yield of GFP chromophores with an ortho-hydroxyl group, while it has almost no effect on the photophysics of GFP chromophores with a para-hydroxyl group. To unravel the underlying physical reasons for this different behavior, we report static electronic structure calculations and nonadiabatic dynamics simulations on excited-state intramolecular proton transfer, cis-trans isomerization, and excited-state deactivation in a locked ortho-substituted GFP model chromophore (o LHBI). On the basis of our previous and present results, we find that the S1 keto species is responsible for the fluorescence emission of the unlocked o-HBI and the locked o-LHBI species. Chemical locking does not change the parts of the S1 and S0 potential energy surfaces relevant to enol-keto tautomerization; hence, in both chromophores, there is an ultrafast excited-state intramolecular proton transfer that takes only 35 fs on average. However, the locking effectively hinders the S1 keto species from approaching the keto S1/S0 conical intersections so that most of trajectories are trapped in the S1 keto region for the entire 2 ps simulation time. Therefore, the fluorescence quantum yield of o-LHBI is enhanced compared with that of unlocked o-HBI, in which the S1 excited-state decay is efficient and ultrafast. In the case of the para-substituted GFP model chromophores p-HBI and p-LHBI, chemical locking hardly affects their efficient excited-state deactivation via cis-trans isomerization; thus, the fluorescence quantum yields in these chromophores remain very low. The insights gained from the present work may help to guide the design of new GFP chromophores with improved fluorescence emission and brightness. PMID- 26744784 TI - The association of HLA-DRB1 and HLA-DQB1 alleles with genetic susceptibility to multiple sclerosis in the Slovak population. AB - OBJECTIVE: The aim of the present study was to assess the association between HLA DRB1 and -DQB1 allele groups with the genetic predisposition to multiple sclerosis (MS) in the Caucasian Central European Slovak population. METHODS: A total of 282 unrelated patients with sporadic MS were enrolled in this case control study. HLA-DRB1 and HLA-DQB1 allele groups were genotyped using a polymerase chain reaction with sequence-specific primers. The DRB1 and DQB1 allele carrier frequencies, genotypes and haplotype frequencies were compared between MS cases and healthy controls. RESULTS: Positive association with MS was found for alleles HLA-DRB1*15 (OR = 3.64; Pcor = 6.9x10-11), DRB1*03 (after elimination of carriers of DRB1*15, OR = 2.8; Pcor = 0.0029), DQB1*06 (OR = 1.99; Pcor = 7.0x10-4), genotypes HLA-DRB1*15/*15 (OR = 7.6; Pcor = 0.001) and DQB1*06/*06 (OR = 3.81; Pcor = 4.0x10-4) and for haplotype DRB1*15-DQB1*06 (OR = 3.03; Pcor = 0.001). Carriage of alleles DRB1*07 (OR = 0.53; Pcor = 0.04), DRB1*13 (OR = 0.39; Pcor = 4.0x10-4), DQB1*03 (OR = 0.46; Pcor = 1.0x10-4), genotypes HLA-DRB1*13/*11 (OR = 0.12; Pcor = 0.004), DQB1*05/*03 (OR = 0.39; Pcor = 0.035), DQB1*03/*03 (OR = 0.38; Pcor = 0.029) and haplotypes DRB1*13-DQB1*06 (OR = 0.47; Pcor = 0.0128) and DRB1*11-DQB1*03 (OR = 0.58; Pcor = 0.0352) was found to be protective against MS development. DISCUSSION: This is the first study performed to analyse the association of HLA-DRB1/DQB1 with susceptibility to MS in Slovakia. The results of our study confirm that HLA class II alleles, genotypes and haplotypes are associated with MS risk. PMID- 26744785 TI - Synthesis of Spirocyclic Diarylfluorenes by One-Pot Twofold SNAr Reactions of Diaryl Sulfones with Diarylmethanes. AB - Treatment of dibenzothiophene dioxides with cyclic diarylmethanes in the presence of KN(SiMe3)2 results in the formation of fluorene-based spirocyclic tetraarylmethanes in a single operation. The transformation would proceed via an intermolecular SNAr reaction of the dioxides with cyclic diarylmethylpotassium followed by intramolecular SNAr cyclization. This straightforward strategy provides a wide range of spirocyclic diarylfluorenes including unusual ones that are otherwise difficult to synthesize. PMID- 26744786 TI - The effects of media, self-esteem, and BMI on youth's unhealthy weight control behaviors. AB - PURPOSE: Youth engage in a variety of methods to manage their weight, including unhealthy weight control behaviors (UWCBs). The purpose of this study was to examine factors associated with youth's engagement in UWCBs, including media influence, youth's BMI z-score and self-esteem. METHODS: Participants were 179 youth, aged 10-17, attending a primary care clinic appointment. Youth completed questionnaires assessing frequency of UWCBs, global self-worth, and perception of media influence to lose weight. BMI z-score was calculated based on height and weight measurements obtained from medical charts. The SPSS macro, PROCESS, was used to conduct moderation analyses. RESULTS: Over 40% of youth endorsed using at least one UWCB in the past year. Girls reported using more UWCBs and engaging in UWCBs more frequently than boys. For boys, media influence to lose weight was only related to UWCB frequency for those with a BMI z-score of 1.23 and above. For girls, media influence was only related to UWCB frequency for those with low to average levels of global self-worth. CONCLUSIONS: Girls' and boys' use of UWCBs is impacted by different factors. Prevention efforts should consider targeting factors, such as weight status and self-esteem, which are uniquely associated with gender. PMID- 26744787 TI - A new approach of indirect enzyme-linked immunosorbent assay for determination of D-glutamic acid through in situ conjugation. AB - We propose a new approach of an indirect enzyme-linked immunosorbent assay (ELISA) for determination of D-glutamic acid (D-Glu) using a monoclonal antibody against D-glutamic acid (D-Glu-MAb), which recognizes D-Glu-glutaraldehyde (GA) molecule but not D-Glu molecule. Human serum albumin (HSA) was coated on an immunoplate and reacted with D-Glu via GA to produce D-Glu-GA-HSA conjugates in situ in the well to be recognized by D-Glu-MAb, which enabled the development of an indirect ELISA for the determination of free D-Glu. In this indirect ELISA, D Glu can be specifically detected with limit of detection of 7.81 MU g/mL. Since anti-conjugate antibodies are often produced, even though anti-hapten antibodies are desired, this new approach could be very useful as an application of anti conjugate antibodies to the development of quantitative analysis for detecting hapten. PMID- 26744788 TI - Magnetic molecularly imprinted polymer nanoparticles for selective solid phase extraction and pre-concentration of Tizanidine in human urine. AB - In this work, the magnetic molecularly imprinted polymer nanoparticles (MMIP-NPs) for the selective pre-concentration of Tizanidine have been described. The polymer nanoparticles were synthesized by the polymerization of methacrylic acid as a functional monomer, ethylene glycol dimethacrylate as a cross-linker, 2,2 azobisisobutyronitrile as an initiator and Tizanidine as a template molecule. The MMIP-NPs were characterized by scanning electron microscopy (SEM) and thermogravimeteric analysis (TGA). Imprinted Tizanidine molecules were removed from the polymeric structure using acetic acid in methanol (10:90 V/V%), as the eluent solvent. The limits of detection (L.O.D) for Tizanidine were 1.13*10(-6)M and 1.68*10(-6)M in ultrapure water and urine, respectively. Also, the relative standard deviations (R.S.D) in ultrapure water and urine were 2.21% and 2.58%, respectively. The method was applied to the determination of Tizanidine in the human urine samples. PMID- 26744789 TI - Preparative separation of gallocatechin gallate from Camellia ptilophylla using macroporous resins followed by sephadex LH-20 column chromatography. AB - Gallocatechin gallate (GCG) possesses multiple potential biological activities. However, the content of GCG in traditional green tea is too low which limits its in-depth pharmacological research and application. In the present study, a simple, efficient and environment-friendly chromatographic separation method was developed for preparative enrichment and separation of GCG from cocoa tea (Camellia ptilophylla) which contains high content of GCG. In the first step, the adsorption properties of selected resins were evaluated, and XAD-7HP resin was chosen by its adsorption and desorption properties for GCG. In order to maximize column efficiency for GCG collection, the operating parameters (e.g., flow rate, ethanol concentration, and bed height) were optimized. We found that the best combination was the feed concentration at 20mg/mL, flow rate at 0.75 BV/h and the ratio of diameter to bed heights as 1:12. Under these conditions, the purity of GCG was 45% with a recovery of 89%. In order to obtain pure target, a second step was established using column chromatography with sephadex LH-20 gel and 55% ethanol-water solution as eluent. After this step, the purity of the GCG was 91% with a recovery of 68% finally. PMID- 26744791 TI - GUEST EDITORIAL: TIME AS A FACTOR IN MULTIVARIATE ANALYSIS. PMID- 26744790 TI - Fluorescein: A Photo-CIDNP Sensitizer Enabling Hypersensitive NMR Data Collection in Liquids at Low Micromolar Concentration. AB - Photochemically induced dynamic nuclear polarization (photo-CIDNP) is a powerful approach for sensitivity enhancement in NMR spectroscopy. In liquids, intermolecular photo-CIDNP depends on the transient bimolecular reaction between photoexcited dye and sample of interest. Hence the extent of polarization is sample-concentration dependent. This study introduces fluorescein (FL) as a photo CIDNP dye whose performance is exquisitely tailored to data collection at extremely low sample concentrations. The photo-CIDNP resonance intensities of tryptophan in the presence of either FL or FMN (i.e., the routinely employed flavin mononucleotide photosensitizer) in the liquid state show that FL yields superior sensitivity and enables rapid data collection down to an unprecedented 1 MUM concentration. This result was achieved on a conventional spectrometer operating at 14.1 T and equipped with a room-temperature probe (i.e., noncryogenic). Kinetic simulations show that the excellent behavior of FL arises from its long excited-state triplet lifetime and superior photostability relative to conventional photo-CIDNP sensitizers. PMID- 26744792 TI - ESTIMATING MODULATOR INDICES AND STATE LIABILITIES. AB - An extension of the familiar factor analytic model which deals with traits has been proposed to enable it t o fit the psychological theory of modulation of behavior by ambient situations which change individuals' state levels and role involvements (Cattell, 1963). The present paper gives more substance to this development, defining more precisely the basic assumptions in the new concepts and setting out the procedures for calculating the main new parameters. Most important among the latter are (1) the modulator values for each ambient situation, (2) the characteristic individual state liabilities, and (3) the change in the group state level as related to the individual state changes. This model is also part of a development for integrating the traditional interests of psychometrists, centered on individual differences, with the tradi- tion interests of experimentalists (researchers on processes, such as learning and perception) centered on changes in group means. It is suggested that this model brings to practical experimental work with concepts of mood, role, and the measurement of ambient-situations the precision t o which we have been accustomed in individual difference psychometry in a way not previously pos- sible in this domain. PMID- 26744793 TI - DIMENSIONS OF PERSONALITY: I. CONJOINT FACTOR STRUCTURE OF GUILFORD AND CATTELL TRAIT MARKERS. AB - The Work Component Study was administered to high school students and the stability of the structure of the variables of work motivation examined. The strudure found among college students and college trained employees is well developed at the high school level. The relationship of work motivations to personality variables and to aspirations is also dear: However, there is little relationship found between work motivations and status variables of the students or their parents. This was unanticipated and oreates a question regarding the sources of work motivations. PMID- 26744795 TI - MULTIVARIATE ANALYSIS OF GANG DELINQUENCY: III. AGE AND PHYSIQUE OF GANGS AND CLUBS. AB - A sample of gang members and a Comparison Group of club boys are com- pared with reference to national norms for age, height and weight of juveniles. Possible relationships between these variables and five Behavior Factor Scores are examined. It is found that the gang boys are shorter than club boys at the sub groups as well as the aggregate level. It is also found that gangs differ among themselves on age, height and weight. These differences are related to differences in behaviors. Furthermore, gangs differ sharply among themselves in regard to the within-gang connections between age, height and weight and behavior. Discussion centers upon group process effects. PMID- 26744794 TI - THE RELATIONSHIP BETWEEN PERSONAL DESIRABILITY AND ENDORSEMENT WITH A FORCED CHOICE TECHNIQUE. AB - Reliable differences were found between the personal desirability ratings given by individual Ss to the two statements comprising the EPPS items. PMID- 26744796 TI - ASSESSMENT OF INFORMATION LOSS IN SCORING MONOTONE ITEMS. AB - For monotone, dichotomous items, two interpretations of the usual scoring procedure may be made. One interpretation (A) is that failure of the items to form a perfect Guttman Scale leads to loss of discriminative infor- mation when the usual procedure of scoring is applied. Another interpretation (B) is that nonunidimensionality of the item-set leads to information confusion under usual scoring procedures. Measures of information loss for each interpretation are developed and tested using Monte Carlo methods. It is concluded that interpretation (B) is the most appropriate. PMID- 26744797 TI - STATISTICAL AND PSYCHOMETRIC INFERENCE IN PRINCIPAL COMPONENTS ANALYSIS. AB - Statistical inference applied to principal components analysis deals with estimating the parameters of the correlation matrix, R, found in the population, from the characteristics of the sample matrix, R*. On the other hand, psychometric inference refers to estimating the internal consistency of the components themselves, so that the decisions about retaining a component for further analysis can be based upon psychometric criteria. A slightly modified approach to statistical inference, which focuses upon the variance of the Components in the population, has been suggested. This viewpoint can be extended to estimating the true score variance and the reliabilities of the components in the population of subjects. Psychometric tests of significance can then be made statistical in nature. PMID- 26744798 TI - BRIEF REPORT: HIGHLY CORRELATED PREDICTOR VARIABLES IN MULTIPLE REGRESSION MODELS. AB - The inclusion in a multiple regression model of a predictor variable which is highly correlated with other prediotor variables is usually not recommended. The argument is that the new predictor variable is accouihing for variance which has already been accounted for in the model. The following discussion is a defense for the procedure of including highly correlated predictor variables under certain circumstances. First, highly correlated variables can be used when there is a requirement that the predictor variables account for a certain number of group membership vectors. A second and more important situation occurs when there is theoretical or empirical justification for the inclusion of such a variable. The following discussion is limited to a very specific kind of highly correlated variable-one that contains the squared elements of one of the original variables. PMID- 26744799 TI - BRIEF REPORT: SELECTIVE BREEDING FOR PRINCIPAL COMPONENTS AND FACTORS BASED UPON BEHAVIORAL TRAITS. AB - This is the first of three reports of a taxonomic investigation of person- ality based on a matrix of 600 personality questionnaire items represented equally by marker items derived from the personality trait systems developed by J. P. Guilford and R. B. Cattell. This report outlines the entire prsject (Sells, Demaree, and Will, 1968) and focuses on the factor structure of the total matrix with particular concern for the relative contributions and relations of the two sources. The second report will analyze in detail the separate factor structures found in the Guilford and Cattell trait markers, while the third will summarize the final factor identification, based on analyses of the total matrix and matrices representing the Guilford and Cattell systems. PMID- 26744800 TI - Potential use of the facultative halophyte Chenopodium quinoa Willd. as substrate for biogas production cultivated with different concentrations of sodium chloride under hydroponic conditions. AB - This project analyses the biogas potential of the halophyte Chenopodium quinoa Willd. In a first approach C. quinoa was grown with different concentrations of NaCl (0, 10 and 20 ppt NaCl) and the crop residues were used as substrate for biogas production. In a second approach, C. quinoa was grown with 0, 10, 20 and 30 ppt NaCl under hydroponic conditions and the fresh biomass was used as substrate. The more NaCl is in the culture medium, the higher the sodium, potassium, crude ash and hemicellulose content in the plant tissue whereas the calcium, sulfur, nitrogen and carbon content in the biomass decrease. According to this study, it is possible to produce high yields of methane using biomass of C. quinoa. The highest specific methane yields were obtained using the substrate from the plants cultivated at 10 and 20 ppt NaCl in both experiments. PMID- 26744801 TI - Understanding energy loss in parallelly connected microbial fuel cells: Non Faradaic current. AB - In this work, the mechanisms of energy loss in parallel connection of microbial fuel cells (MFCs) is explored using two MFC units producing different open circuit voltage (OCV) and current. In open circuit mode, non-Faradaic current flows in low OCV unit, implying energy loss caused by different OCVs in parallelly stacked MFCs. In a stacked MFC in parallel under close circuit mode, it is confirmed that energy loss occurs until the working voltage in high OCV unit becomes identical to the other unit having low OCV. This result indicates that different voltage between individual MFC units can cause energy loss due to both non-Faradic and Faradaic current that flow from high voltage unit to low voltage unit even in parallelly stacked MFCs. PMID- 26744802 TI - Aerobic decolorization, degradation and detoxification of azo dyes by a newly isolated salt-tolerant yeast Scheffersomyces spartinae TLHS-SF1. AB - Isolation, identification and characterization of a salt-tolerant yeast capable of degrading and detoxifying azo dyes were investigated in this study. Possible degradation pathway of Acid Scarlet 3R was proposed through analyzing metabolic intermediates using UV-Vis and HPLC-MS methods. Furthermore, the Microtox test was performed to evaluate the acute toxicity of the dye before and after biodegradation. The results showed that a salt-tolerant yeast named TLHS-SF1 was isolated and identified as Scheffersomyces spartinae basing on 26S rDNA analysis. The optimal decolorization and growth parameters were: sucrose 2 g L(-1), (NH4)2SO4 0.6 g L(-1), yeast extract 0.08 g L(-1), NaCl ? 30 g L(-1), 160 rmin( 1), 30 degrees C and pH 5.0-6.0. More than 90% of 80 mg L(-1) 3R could be decolorized within 16 h under the optimal conditions. 3R was possibly degraded successively through azo-reduction, deamination and desulfonation pathways, and its acute toxicity obviously decreased by strain TLHS-SF1. PMID- 26744803 TI - Open fermentative production of fuel ethanol from food waste by an acid-tolerant mutant strain of Zymomonas mobilis. AB - The aim of present study was to develop a process for open ethanol fermentation from food waste using an acid-tolerant mutant of Zymomonas mobilis (ZMA7-2). The mutant showed strong tolerance to acid condition of food waste hydrolysate and high ethanol production performance. By optimizing fermentation parameters, ethanol fermentation with initial glucose concentration of 200 g/L, pH value around 4.0, inoculum size of 10% and without nutrient addition was considered as best conditions. Moreover, the potential of bench scales fermentation and cell reusability was also examined. The fermentation in bench scales (44 h) was faster than flask scale (48 h), and the maximum ethanol concentration and ethanol yield (99.78 g/L, 0.50 g/g) higher than that of flask scale (98.31 g/L, 0.49 g/g). In addition, the stable cell growth and ethanol production profile in five cycles successive fermentation was observed, indicating the mutant was suitable for industrial ethanol production. PMID- 26744804 TI - Phosphoric acid pretreatment of Achyranthes aspera and Sida acuta weed biomass to improve enzymatic hydrolysis. AB - Achyranthes aspera and Sida acuta, two types of weed biomass are abundant and waste in Thailand. We focus on them as novel feedstock for bio-ethanol production because they contain high-cellulose content (45.9% and 46.9%, respectively) and unutilized material. Phosphoric acid (70%, 75%, and 80%) was employed for the pretreatment to improve by enzymatic hydrolysis. The pretreatment process removed most of the xylan and a part of the lignin from the weeds, while most of the glucan remained. The cellulose conversion to glucose was greater for pretreated A. aspera (86.2 +/- 0.3%) than that of the pretreated S. acuta (82.2 +/- 1.1%). Thus, the removal of hemicellulose significantly affected the efficiency of the enzymatic hydrolysis. The scanning electron microscopy images showed the exposed fibrous cellulose on the cell wall surface, and this substantial change of the surface structure contributed to improving the enzyme accessibility. PMID- 26744805 TI - Application of high-content image analysis for quantitatively estimating lipid accumulation in oleaginous yeasts with potential for use in biodiesel production. AB - Biodiesel from oleaginous microorganisms is a viable substitute for a fossil fuel. Current methods for microorganism lipid productivity evaluation do not analyze lipid dynamics in single cells. Here, we described a high-content image analysis (HCA) as a promising strategy for screening oleaginous microorganisms for biodiesel production, while generating single-cell lipid dynamics data in large cell density. Rhodotorula slooffiae yeast were grown in standard (CTL) or lipid trigger medium (LTM), and lipid droplet (LD) accumulation was analyzed in deconvolved confocal microscopy images of cells stained with the lipophilic fluorescent Nile red (NR) dye using automated cell and LD segmentation. The 'vesicle segmentation' method yielded valid morphometric results for limited lipid accumulation in smaller LDs (CTL samples) and for high lipid accumulation in larger LDs (LTM samples), and detected LD localization changes. Thus, HCA can be used to analyze the lipid accumulation patterns likely to be encountered in screens for biodiesel production. PMID- 26744806 TI - Motor system contribution to action prediction: Temporal accuracy depends on motor experience. AB - Predicting others' actions is essential for well-coordinated social interactions. In two experiments including an infant population, this study addresses to what extent motor experience of an observer determines prediction accuracy for others' actions. Results show that infants who were proficient crawlers but inexperienced walkers predicted crawling more accurately than walking, whereas age groups mastering both skills (i.e. toddlers and adults) were equally accurate in predicting walking and crawling. Regardless of experience, human movements were predicted more accurately by all age groups than non-human movement control stimuli. This suggests that for predictions to be accurate, the observed act needs to be established in the motor repertoire of the observer. Through the acquisition of new motor skills, we also become better at predicting others' actions. The findings thus stress the relevance of motor experience for social cognitive development. PMID- 26744807 TI - Effects of statistical learning on the acquisition of grammatical categories through Qur'anic memorization: A natural experiment. AB - Empirical evidence for statistical learning comes from artificial language tasks, but it is unclear how these effects scale up outside of the lab. The current study turns to a real-world test case of statistical learning where native English speakers encounter the syntactic regularities of Arabic through memorization of the Qur'an. This unique input provides extended exposure to the complexity of a natural language, with minimal semantic cues. Memorizers were asked to distinguish unfamiliar nouns and verbs based on their co-occurrence with familiar pronouns in an Arabic language sample. Their performance was compared to that of classroom learners who had explicit knowledge of pronoun meanings and grammatical functions. Grammatical judgments were more accurate in memorizers compared to non-memorizers. No effects of classroom experience were found. These results demonstrate that real-world exposure to the statistical properties of a natural language facilitates the acquisition of grammatical categories. PMID- 26744809 TI - Actovegin, a non-prohibited drug increases oxidative capacity in human skeletal muscle. AB - Actovegin, a deproteinized haemodialysate of calf blood, is suggested to have ergogenic properties, but this potential effect has never been investigated in human skeletal muscle. To investigate this purported ergogenic effect, we measured the mitochondrial respiratory capacity in permeabilized human skeletal muscle fibres acutely exposed to Actovegin in a low and in a high dose. We found that Actovegin, in the presence of complex I-linked substrates increased the oxidative phosphorylation (OXPHOS) capacity significantly in a concentration dependent manner (19 +/- 3, 31 +/- 4 and 45 +/- 4 pmol/mg/s). Maximal OXPHOS capacity with complex I and II-linked substrate was increased when the fibres were exposed to the high dose of Actovegin (62 +/- 6 and 77 +/- 6 pmol/mg/s) (p < .05). The respiratory capacity of the electron transfer system as well as Vmax and Km were also increased in a concentration-dependent manner after Actovegin exposure (70 +/- 6, 79 +/- 6 and 88 +/- 7 pmol/mg/s; 13 +/- 2, 25 +/- 3 and 37 +/ 4 pmol/mg/s; 0.08 +/- 0.02, 0.21 +/- 0.03 and 0.36 +/- 0.03 mM, respectively) (p < .05). In summary, we report for the first time that Actovegin has a marked effect on mitochondrial oxidative function in human skeletal muscle. Mitochondrial adaptations like this are also seen after a training program in human subjects. Whether this improvement translates into an ergogenic effect in athletes and thus reiterates the need to include Actovegin on the World Anti Doping Agency's active list remains to be investigated. PMID- 26744808 TI - Bicyclol promotes toll-like 2 receptor recruiting inosine 5'-monophosphate dehydrogenase II to exert its anti-inflammatory effect. AB - The aim was to investigate potential targets and anti-inflammatory mechanisms of bicyclol, which has been extensively used in clinic for decades in China. Tar-Fis Dock, virtual molecular docking system, showed that inosine 5'-monophosphate dehydrogenase II (IMPDH II) has the highest probability of binding to bicyclol. To investigate the possible role of IMPDH II in mechanisms of bicyclol, recombinant enzyme models, mice splenic lymphocytes, and human lymphocytes were used. Bicyclol (1-5 MUM) significantly inhibited the proliferation of mice splenic lymphocytes stimulated by concanavalin A (conA). However, bicyclol did not show inhibitory effects on proliferation of human peripheral blood mononuclear cells (hPBMC) induced by phytohemagglutinin (PHA). IMPDH II enzyme kinetic model showed that bicyclol only had a slight regulatory effect on IMPDH II enzyme activity. These results revealed that bicyclol may be not a conventional inhibitor of IMPDH II. Further studies showed that bicyclol could promote recruitment of IMPDH II by active toll-like 2 receptor (TLR2) complex. Such effects lead to the reduction of nuclear factor kappaB (NF-kappaB) expression, increase in I-kappaB expression, and decrease in cytokine release, including tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL 1beta). It may be a new mechanism of bicyclol for its anti-inflammatory effect. PMID- 26744810 TI - Skin bacterial diversity of Panamanian frogs is associated with host susceptibility and presence of Batrachochytrium dendrobatidis. AB - Symbiotic bacteria on amphibian skin can inhibit growth of the fungus Batrachochytrium dendrobatidis (Bd) that has caused dramatic population declines and extinctions of amphibians in the Neotropics. It remains unclear how the amphibians' skin microbiota is influenced by environmental bacterial reservoirs, host-associated factors such as susceptibility to pathogens, and pathogen presence in tropical amphibians. We sampled skin bacteria from five co-occurring frog species that differ in Bd susceptibility at one Bd-naive site, and sampled one of the non-susceptible species from Bd-endemic and Bd-naive sites in Panama. We hypothesized that skin bacterial communities (1) would be distinct from the surrounding environment regardless of the host habitat, (2) would differ between Bd susceptible and non-susceptible species and (3) would differ on hosts in Bd naive and Bd-endemic sites. We found that skin bacterial communities were enriched in bacterial taxa that had low relative abundances in the environment. Non-susceptible species had very similar skin bacterial communities that were enriched in particular taxa such as the genera Pseudomonas and Acinetobacter. Bacterial communities of Craugastor fitzingeri in Bd-endemic sites were less diverse than in the naive site, and differences in community structure across sites were explained by changes in relative abundance of specific bacterial taxa. Our results indicate that skin microbial structure was associated with host susceptibility to Bd and might be associated to the history of Bd presence at different sites. PMID- 26744811 TI - Quorum sensing protects bacterial co-operation from exploitation by cheats. AB - Quorum sensing (QS) is a cell-cell communication system found in many bacterial species, commonly controlling secreted co-operative traits, including extracellular digestive enzymes. We show that the canonical QS regulatory architecture allows bacteria to sense the genotypic composition of high-density populations, and limit co-operative investments to social environments enriched for co-operators. Using high-density populations of the opportunistic pathogen Pseudomonas aeruginosa we map per-capita signal and co-operative enzyme investment in the wild type as a function of the frequency of non-responder cheats. We demonstrate mathematically and experimentally that the observed response rule of 'co-operate when surrounded by co-operators' allows bacteria to match their investment in co-operation to the composition of the group, therefore allowing the maintenance of co-operation at lower levels of population structuring (that is, lower relatedness). Similar behavioural responses have been described in vertebrates under the banner of 'generalised reciprocity'. Our results suggest that mechanisms of reciprocity are not confined to taxa with advanced cognition, and can be implemented at the cellular level via positive feedback circuits. PMID- 26744812 TI - Genome-wide selective sweeps and gene-specific sweeps in natural bacterial populations. AB - Multiple models describe the formation and evolution of distinct microbial phylogenetic groups. These evolutionary models make different predictions regarding how adaptive alleles spread through populations and how genetic diversity is maintained. Processes predicted by competing evolutionary models, for example, genome-wide selective sweeps vs gene-specific sweeps, could be captured in natural populations using time-series metagenomics if the approach were applied over a sufficiently long time frame. Direct observations of either process would help resolve how distinct microbial groups evolve. Here, from a 9 year metagenomic study of a freshwater lake (2005-2013), we explore changes in single-nucleotide polymorphism (SNP) frequencies and patterns of gene gain and loss in 30 bacterial populations. SNP analyses revealed substantial genetic heterogeneity within these populations, although the degree of heterogeneity varied by >1000-fold among populations. SNP allele frequencies also changed dramatically over time within some populations. Interestingly, nearly all SNP variants were slowly purged over several years from one population of green sulfur bacteria, while at the same time multiple genes either swept through or were lost from this population. These patterns were consistent with a genome-wide selective sweep in progress, a process predicted by the 'ecotype model' of speciation but not previously observed in nature. In contrast, other populations contained large, SNP-free genomic regions that appear to have swept independently through the populations prior to the study without purging diversity elsewhere in the genome. Evidence for both genome-wide and gene-specific sweeps suggests that different models of bacterial speciation may apply to different populations coexisting in the same environment. PMID- 26744814 TI - When less equal is less human: Intragroup (dis)respect and the experience of being human. AB - Past research has demonstrated that equality-based respect is an important antecedent of positive social interaction and group-serving behavior. In the present research we tested whether intragroup equality-based respect affects perceptions of being treated as a human as well as self-dehumanization. In Experiment 1, we found that high respect received from fellow work group members heightens group members' sense of being treated as a human being, while low respect diminishes it. In Experiment 2, we secured evidence that (dis)respect also affected recipients' self-views in terms of self-dehumanization. More specifically, if respect was withheld by other ingroup members, fewer human nature and human uniqueness traits, as well as secondary positive emotions, were attributed to the self. This increase in self-infrahumanization was further related to higher endorsement of unethical behavior. We discuss the importance of equality-based respect for (de-)humanization processes in social groups. PMID- 26744815 TI - Target and non-target analysis of migrants from PVC-coated cans using UHPLC-Q Orbitrap MS: evaluation of long-term migration testing. AB - A simple, rapid and sensitive method for analyzing multi-target and non-target additives in polyvinyl chloride (PVC) food can coatings using ultra-high performance liquid chromatography coupled to quadrupole-orbital ion-trap mass spectrometry was developed. This procedure was used to study the behaviour of a cross-linking agent, benzoguanamine (BGA), two slip agents, oleamide and erucamide, and 18 other commonly used plasticisers including phthalates, adipates, sebacates, acetyl tributyl citrate and epoxidised soybean or linseed oils. This optimised method was used to detect these analytes in food simulants (water and 3% acetic acid) in a long-term migration test of PVC-coated food cans for a period ranging from 1 day to 1.5 years at 40 degrees C. Although very low detection limits (5 ng ml(-1)) were obtained for the majority of compounds, none of the monitored plasticisers and slip agents was detected in simulants extracted from cans over the period of the test. However, the presence of BGA in both aqueous food simulants was confirmed based on high-resolution mass spectrometry, product ion spectra and analysis of a reference standard. The BGA concentration in both simulants continued to increase with storage time: after 1.5 years storage in aqueous food simulants at 40 degrees C, BGA was detected at concentrations up to 84 ug dm(-2). We believe this is the first study describing the long-term migration capacity of BGA from any vinyl coating material intended for use in PVC-coated food cans. Our results may have implications for migration test protocols for food cans that will be stored for extended time periods. PMID- 26744816 TI - Lifetime Exposure to Intimate Partner Violence and Proinflammatory Cytokine Levels Across the Perinatal Period. AB - BACKGROUND: Intimate partner violence (IPV) is a public health concern, affecting one-third of US women. Prior research suggests an association between exposure to IPV and poor maternal perinatal health, but the underlying biological correlates are not well understood. This study examined the relationship between exposure to IPV and proinflammatory cytokine levels, a candidate mechanism accounting for poor psychiatric and obstetric outcomes, across the perinatal period. MATERIALS AND METHODS: Data were obtained from a prospective, longitudinal cohort study of 171 women receiving obstetrical care from a hospital-based practice serving a predominantly low-income minority population. Participants completed questionnaires on IPV exposure, psychiatric symptoms, and psychosocial and obstetric factors and provided blood samples at 18 and 32 weeks of gestation and 6 weeks and 6 months postpartum. Serum levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) were assayed via enzyme-linked immunosorbent assay. RESULTS: Thirty-five (20.5%) women reported lifetime exposure to IPV and 7 (4.1%) reported being physically hurt in the preceding 12 months (4 while pregnant). Lifetime exposure to IPV was associated with increased likelihood of experiencing perinatal depression and smoking during pregnancy. Women with a history of IPV had significantly higher levels of TNF-alpha at 18 weeks (z = 2.29, p < 0.05), but significantly smaller changes in levels of IL-6 (beta = 0.36, p = 0.04) across time. CONCLUSION: Lifetime exposure to IPV was associated with a range of adverse mental health outcomes and may affect proinflammatory cytokine levels in pregnancy. PMID- 26744829 TI - Multilocus sequence typing of 102 Burkholderia pseudomallei strains isolated from China. AB - The phylogenetic and epidemiological relationships of 102 Burkholderia pseudomallei clinical isolates from different geographical and population sources in China were investigated by multilocus sequence typing (MLST). The MLST data were analysed using the e-BURST algorithm, and an unweighted pair-group method with arithmetic mean dendrogram was constructed based on the pair-wise differences in the allelic profiles of the strains. Forty-one sequence types (STs) were identified, of which eight were novel (ST1341, ST1345, ST1346, ST1347, ST1348, ST1349, ST1350, ST1351). No geographical-specific or host population specific phylogenetic lineages were identified. ST46, ST50, ST55, ST58, ST70 and ST1095 predominated, but ~44% of isolates were assigned to 45 STs illustrating high genetic diversity in the strain collection. Additionally, the phylogenetic relationships of the dominant STs in China showed significant linkeage with B. pseudomallei isolates from Thailand. Analysis of the gmhD allele suggests high genetic variation in B. pseudomallei in China. PMID- 26744830 TI - Oxidation-state sensitive imaging of cerium dioxide by atomic-resolution low angle annular dark field scanning transmission electron microscopy. AB - Low-angle annular dark field (LAADF) scanning transmission electron microscopy (STEM) imaging is presented as a method that is sensitive to the oxidation state of cerium ions in CeO2 nanoparticles. This relationship was validated through electron energy loss spectroscopy (EELS), in situ measurements, as well as multislice image simulations. Static displacements caused by the increased ionic radius of Ce(3+) influence the electron channeling process and increase electron scattering to low angles while reducing scatter to high angles. This process manifests itself by reducing the high-angle annular dark field (HAADF) signal intensity while increasing the LAADF signal intensity in close proximity to Ce(3+) ions. This technique can supplement STEM-EELS and in so doing, relax the experimental challenges associated with acquiring oxidation state information at high spatial resolutions. PMID- 26744813 TI - Epidemiology of Uterine Fibroids: From Menarche to Menopause. AB - Uterine leiomyomata (UL) have a substantial impact on women's health, but relatively few studies have identified opportunities for primary prevention of these neoplasms. Most established risk factors are not modifiable, including premenopausal age, African ancestry, age at menarche, and childbearing history. The main challenge in studying UL is that a large proportion of tumors are asymptomatic. Herein, we review the epidemiology of UL from published studies to date. We highlight the advantages of ultrasound screening studies and the ways in which their innovative methods have helped clarify the etiology of disease. We conclude with a discussion of promising new hypotheses. PMID- 26744832 TI - Biofabrication: reappraising the definition of an evolving field. AB - Biofabrication is an evolving research field that has recently received significant attention. In particular, the adoption of Biofabrication concepts within the field of Tissue Engineering and Regenerative Medicine has grown tremendously, and has been accompanied by a growing inconsistency in terminology. This article aims at clarifying the position of Biofabrication as a research field with a special focus on its relation to and application for Tissue Engineering and Regenerative Medicine. Within this context, we propose a refined working definition of Biofabrication, including Bioprinting and Bioassembly as complementary strategies within Biofabrication. PMID- 26744833 TI - Slow-Wave Oscillations in Awake Healthy Subjects: Methodological and Physiological Considerations. AB - PURPOSE: Detection of pathologic slow-wave oscillations (0.5-7 Hz) in awake subjects has gained increasing interest in clinical diagnostics. Their significance, however, is hampered by the occasional presence of slow waves in healthy subjects, as well as the abundance of artefactual signals at low measurement frequencies. The aim of this study was to assess the occurrence of slow-wave oscillations in healthy subjects and to sharpen the management of possible measurement artifacts, in order to create a normative database for neurological patients. METHODS: The authors analyzed magnetoencephalography recordings of spontaneous brain oscillations in 139 awake healthy adults. Sources of artifacts were first identified and suppressed by temporal extension of signal space separation method, and the remaining artifact components were projected out using signal space projection. Individual amplitude spectra were compared with the channel-level average spectra over all subjects. RESULTS: Slow-wave oscillations deviating +/-2 standard deviations from the average spectrum were detected in 12 subjects (~9%). In 10 subjects, the oscillations were considered as normal physiological phenomena. Only two subjects showed activity that could have been interpreted as pathological: one subject with widespread parietal bilateral polyrhythmic slow-wave activity and one with focal rolandic 2.7-Hz slow wave activity. CONCLUSIONS: The prevalence of slow-wave oscillations in a healthy adult population is low. Knowledge about their occurrence, however, is essential for interpreting their significance in brain diseases. Artifacts and benign oscillatory variants at slow frequencies have to be recognized. PMID- 26744834 TI - Compound Motor Action Potential: Electrophysiological Marker for Muscle Training. AB - PURPOSE: The compound motor action potential (CMAP) represents the summated action potentials of all stimulated motor endplates and potentially reflects muscle hypertrophy and increased muscle contractions. Since electrophysiological biomarkers for high-resistance strength training are lacking, the authors evaluated whether the CMAP of distal and proximal muscles differs between healthy men and women who perform and do not perform high-resistance muscle training. METHODS: Motor neurography was performed with stimulation of the median nerve (recording of abductor pollicis brevis muscle), peroneal nerve (recording of extensor digitorum brevis muscle), femoral nerve (recording of rectus femoris muscle) and musculocutaneous nerve (recording of biceps brachii muscle), and isometric muscle strength, measured with a hand-held dynamometer, were performed on 83 healthy subjects (52 women). RESULTS: Trained women had 25% higher CMAP amplitude in the rectus femoris muscle than untrained women (P < 0.001), whereas CMAP amplitude in the trained male cohort was 25% higher in the biceps (P = 0.005) compared with untrained men. In the trained group, CMAP amplitude in the biceps correlated with isometric muscle strength (R = 0.30; P = 0.046). CONCLUSIONS: The authors' propose the CMAP as an objective neurophysiological parameter for proximal muscle status and training effects in future interventional studies of patients with neuromuscular disorders. PMID- 26744835 TI - The Texting Rhythm: A Novel EEG Waveform Using Smartphones. AB - INTRODUCTION: We report a unique EEG phenomenon in patients with paroxysmal neurological events undergoing video EEG monitoring. METHODS: Two epilepsy centers analyzed the interictal scalp EEG in patients using personal electronic devices during epilepsy monitoring. The texting rhythm (TR) was defined as a reproducible, stimulus-evoked, generalized frontocentral monomorphic burst of 5-6 Hz theta consistently induced by active text messaging. An independent prospective and retrospective cohort was analyzed and compared from two sites in Florida and Illinois. We assessed age, gender, diagnosis, epilepsy classification, MRI, and EEG to compare patients with a TR. Analysis was performed with statistical significance set at P < 0.05. RESULTS: We identified 24 of 98 evaluable patients with a TR in a prospective arm at one center and 7 of 31 patients in a retrospective arm at another totaling 31/129 (24.0%). The waveform prevalence was similar at both centers independent of location. TR was highly specific to active texting. A similar waveform during independent cognitive, speech or language, motor activation and audio cellular telephone use was absent (P < 0.0001). It appeared to be increased in patients with epilepsy in one cohort (P = 0.03) and generalized seizures in the other (P = 0.025). Age, gender, epilepsy type, MRI results, and EEG lateralization in patients with focal epileptic seizures did not bear a relationship to the presence of a TR in either arm of the study (P = NS). CONCLUSIONS: The TR is a novel waveform time-locked to text messaging and associated with active use of smartphones. Electroencephalographers should be aware of the TR to separate it from an abnormality in patients undergoing video EEG monitoring. Larger sample sizes and additional research may help define the significance of this unique cognitive visual-cognitive-motor network that is technology-related and task-specific with implications in communication research and transportation safety. PMID- 26744836 TI - The inhibitory effects of camptothecin (CPT) and its derivatives on the substrate uptakes mediated by human solute carrier transporters (SLCs). AB - 1. Camptothecin (CPT) and its derivatives are potent candidate compounds in treating cancers. However, their clinical applications are largely restricted by severe toxicities. 2. The solute carrier transporters (SLCs), particularly the organic anion transporting polypeptides and organic anion/cation transporters (OATs/OCTs) are widely expressed in human key organs and responsible for the cellular influx of many substances including endogenous substrates and many clinically important drugs. Drug-drug interactions through SLCs often result in unsatisfied therapeutic outcomes and/or unexpected toxicities. 3. This study investigated the inhibitory effects of CPT and its eight derivatives on the cellular uptake of specific substrates mediated by the essential SLCs in over expressing Human embryonic kidney 293 cells. 4. Our data revealed that CPT, 10 hydroxycamptothecin (HCPT), 10-methoxycamptothecin (MCPT) and 9-nitrocamptothecin (9NC) significantly inhibit the uptake activity of OAT3. 9NC also inhibited the substrate transport mediated by OAT1. The substrate uptakes of OAT1, OCTN1 and OCTN2 were significantly decreased in the presence of CZ112, while CPT-11 potently down-regulated the transport activity of OCT1 and OCT3. 5. In summary, our study demonstrated that CPT and its eight derivatives selectively inhibit the substrate uptakes mediated by the essential SLCs. This information contributes to understanding the localized toxicity of CPTs and provides novel molecular targets for the therapeutic optimization of CPTs in the future. PMID- 26744831 TI - Risks and benefits related to alimentary exposure to xenoestrogens. AB - Xenoestrogens are widely diffused in the environment and in food, thus a large portion of human population worldwide is exposed to them. Among alimentary xenoestrogens, phytoestrogens (PhyEs) are increasingly being consumed because of their potential health benefits, although there are also important risks associated to their ingestion. Furthermore, other xenoestrogens that may be present in food are represented by other chemicals possessing estrogenic activities, that are commonly defined as endocrine disrupting chemicals (EDCs). EDCs pose a serious health concern since they may cause a wide range of health problems, starting from pre-birth till adult lifelong exposure. We herein provide an overview of the main classes of xenoestrogens, which are classified on the basis of their origin, their structures and their occurrence in the food chain. Furthermore, their either beneficial or toxic effects on human health are discussed in this review. PMID- 26744839 TI - Using Highlighting to Train Attentional Expertise. AB - Acquiring expertise in complex visual tasks is time consuming. To facilitate the efficient training of novices on where to look in these tasks, we propose an attentional highlighting paradigm. Highlighting involves dynamically modulating the saliency of a visual image to guide attention along the fixation path of a domain expert who had previously viewed the same image. In Experiment 1, we trained naive subjects via attentional highlighting on a fingerprint-matching task. Before and after training, we asked subjects to freely inspect images containing pairs of prints and determine whether the prints matched. Fixation sequences were automatically scored for the degree of expertise exhibited using a Bayesian discriminative model of novice and expert gaze behavior. Highlighted training causes gaze behavior to become more expert-like not only on the trained images but also on transfer images, indicating generalization of learning. In Experiment 2, to control for the possibility that the increase in expertise is due to mere exposure, we trained subjects via highlighting of fixation sequences from novices, not experts, and observed no transition toward expertise. In Experiment 3, to determine the specificity of the training effect, we trained subjects with expert fixation sequences from images other than the one being viewed, which preserves coarse-scale statistics of expert gaze but provides no information about fine-grain features. Observing at least a partial transition toward expertise, we obtain only weak evidence that the highlighting procedure facilitates the learning of critical local features. We discuss possible improvements to the highlighting procedure. PMID- 26744837 TI - Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension. AB - In the pulmonary vasculature, the endothelial and smooth muscle cells are two key cell types that play a major role in the pathobiology of pulmonary vascular disease and pulmonary hypertension. The normal interactions between these two cell types are important for the homeostasis of the pulmonary circulation, and any aberrant interaction between them may lead to various disease states including pulmonary vascular remodeling and pulmonary hypertension. It is well recognized that the endothelial cell can regulate the function of the underlying smooth muscle cell by releasing various bioactive agents such as nitric oxide and endothelin-1. In addition to such paracrine regulation, other mechanisms exist by which there is cross-talk between these two cell types, including communication via the myoendothelial injunctions and information transfer via extracellular vesicles. Emerging evidence suggests that these nonparacrine mechanisms play an important role in the regulation of pulmonary vascular tone and the determination of cell phenotype and that they are critically involved in the pathobiology of pulmonary hypertension. PMID- 26744840 TI - Mortality in Children Aged 0-9 Years: A Nationwide Cohort Study from Three Nordic Countries. AB - BACKGROUND: Mortality in children under five years has been widely studied, whereas mortality at 5-9 years has received little attention. Using unique data from national registers in three Nordic countries, we aimed to characterize mortality directionality in children aged 0 to 9 years. METHODS AND FINDINGS: The cohort study included all children born in Denmark from 1973 to 2008 (n = 2,433,758), Sweden from 1973 to 2006 (n = 3,400,212), and a random sample of 89.3% of children born in Finland from 1987 to 2007 (n = 1,272,083). Children were followed from 0 to 9 years, and cumulative mortality and mortality rates were compared by age, gender, cause of death, and calendar periods. Among the 7,105,962 children, there were 48,299 deaths during study period. From 1981-1985 to 2001-2005, all-cause mortality rates were reduced by between 34% and 62% at different ages. Overall mortality rate ratio between boys and girls decreased from 1.25 to 1.21 with the most prominent reduction in children aged 5-9 years (from 1.59 to 1.19). Neoplasms, diseases of the nervous system and transport accidents were the most frequent cause of death after the first year of life. These three leading causes of death declined by 42% (from 6.2 to 3.6 per 100,000 person years), 43% (from 3.7 to 2.1) and 62% (from 3.9 to 1.5) in boys, and 25% (from 4.1 to 3.1 per 100000 person years), 42% (from 3.4 to 1.9) and 63% (from 3.0 to 1.1) in girls, respectively. Mortality from neoplasms was the highest in each age except infants when comparing cause-specific mortality, and half of deaths from diseases of the nervous system occurred in infancy. Mortality rate due to transport accidents increased with age and was highest in boys aged 5-9 years. CONCLUSIONS: Mortality rate in children aged 0-9 years has been decreasing with diminished difference between genders over the past decades. Our results suggest the importance of further research on mortality by causes of neoplasms, and causes of transport accidents-especially in children aged 5-9 years. PMID- 26744841 TI - Prognostic Significance of Incidental Prostate Cancer at Radical Cystoprostatectomy for Bladder Cancer. AB - OBJECTIVE: The aim of the study was to evaluate the impact of the clinical significance of incidental prostate cancer (PC) on overall survival (OS) after radical cystoprostatectomy (RC) for bladder cancer (BC). METHODS: A total of 822 consecutive men underwent RC in 3 academic centers between 1996 and 2011. The clinical significance of incidental PC was determined according to the Epstein criteria. The Kaplan-Meier analysis with log-rank was used to investigate the impact of PC on OS and univariate and multivariate Cox regression analyses for risk factors of OS. The median follow-up was 36 months (interquartile range 10 49). RESULTS: Of the 822 men, 117 (14.2%) had clinically significant, 243 (29.6%) insignificant and 462 (56.2) no PC at RC. Men with PC were at higher risk for lymphovascular invasion (LVI) of BC compared to men without PC (p < 0.001). The 5 year OS for men with clinically significant, insignificant and no PC was 33.3, 51.3 and 51.5%, respectively (p = 0.050). In the subgroup of pN0 patients (n = 601), clinically significant PC was significantly associated with inferior OS (p = 0.044) but not in multivariable analysis (p = 0.46). CONCLUSIONS: We did not find the clinical significance of incidental PC to be an independent predictor. However, the positive correlation between incidental PC and LVI of BC deserves further investigation. PMID- 26744838 TI - Neonatal Mortality and Long-Term Outcome of Infants Born between 27 and 32 Weeks of Gestational Age in Breech Presentation: The EPIPAGE Cohort Study. AB - OBJECTIVE: To determine whether breech presentation is an independent risk factor for neonatal morbidity, mortality, or long-term neurologic morbidity in very preterm infants. DESIGN: Prospective population-based cohort. POPULATION: Singletons infants without congenital malformations born from 27 to 32 completed weeks of gestation enrolled in France in 1997 in the EPIPAGE cohort. METHODS: The neonatal and long-term follow-up outcomes of preterm infants were compared between those in breech presentation and those in vertex presentation. The relation of fetal presentation with neonatal mortality and neurodevelopmental outcomes was assessed using multiple logistic regression models. RESULTS: Among the 1518 infants alive at onset of labor included in this analysis (351 in breech presentation), 1392 were alive at discharge. Among those eligible to follow up and alive at 8 years, follow-up data were available for 1188 children. Neonatal mortality was significantly higher among breech than vertex infants (10.8% vs. 7.5%, P = 0.05). However the differences were not significant after controlling for potential confounders. Neonatal morbidity did not differ significantly according to fetal presentation. Severe cerebral palsy was less frequent in the group born in breech compared to vertex presentation but there was no difference after adjustment. There was no difference according to fetal presentation in cognitive deficiencies/learning disabilities or overall deficiencies. CONCLUSION: Our data suggest that breech presentation is not an independent risk factor for neonatal mortality or long-term neurologic deficiencies among very preterm infants. PMID- 26744842 TI - PLGA-Curcumin Attenuates Opioid-Induced Hyperalgesia and Inhibits Spinal CaMKIIalpha. AB - Opioid-induced hyperalgesia (OIH) is one of the major problems associated with prolonged use of opioids for the treatment of chronic pain. Effective treatment for OIH is lacking. In this study, we examined the efficacy and preliminary mechanism of curcumin in attenuating OIH. We employed a newly developed PLGA curcumin nanoformulation (PLGA-curcumin) in order to improve the solubility of curcumin, which has been a major obstacle in properly characterizing curcumin's mechanism of action and efficacy. We found that curcumin administered intrathecally or orally significantly attenuated hyperalgesia in mice with morphine-induced OIH. Furthermore, we demonstrated that the effects of curcumin on OIH correlated with the suppression of chronic morphine-induced CaMKIIalpha activation in the superficial laminae of the spinal dorsal horn. These data suggest that PLGA-curcumin may reverse OIH possibly by inhibiting CaMKIIalpha and its downstream signaling. PMID- 26744845 TI - Integrating Microarrays into Routine Prenatal Diagnosis: Determinants of Decision Making. AB - OBJECTIVES: The explosion in genetic technologies, including array comparative genomic hybridization (aCGH), has increased the complexity of genetic counseling. We now offer chorionic villus sampling (CVS) and aCGH to all first-trimester patients, as this allows the prenatal diagnosis of an additional 1% of anomalies not otherwise detectable and can detect genetic copy number variants at a much higher resolution than conventional cytogenetics. Here, we explored some of the determinants of how patients are deciding to use or not use this new technology and evaluate risk-benefit analyses for that decision. METHODS: This is a retrospective case-control study of singleton and multiples pregnancies at our center. Those having aCGH testing along with CVS were defined as 'testers' and those who declined aCGH but had the CVS were 'nontesters'. RESULTS: Demographic data of 181 educated women who chose CVS were compared. Among those carrying singletons (n = 144), older women, defined as over 35 years of age (or 'advanced maternal age'; AMA), were more likely to choose the aCGH than younger women. Further, women who had a prior history of genetic testing and who wanted to know the gender of the fetus were more likely to choose the aCGH test. In women carrying multiples (n = 37), AMA ceases to be a predictor of choice. Having had prior genetic counseling remains a strong predictor for choosing aCGH, as does wanting to know the gender of the fetus. Neither prior abortions nor having prior children were significant for women carrying singletons or multiples. CONCLUSION: Offering pregnant couples an individualized choice regarding aCGH seems an appropriate approach. There are discrete patterns associated with the choice of taking the aCGH that varied depending on whether the patient was carrying a singleton or multiples. PMID- 26744844 TI - Medical Expenditure for Chronic Diseases in Mexico: The Case of Selected Diagnoses Treated by the Largest Care Providers. AB - BACKGROUND: Chronic diseases (CD) are a public health emergency in Mexico. Despite concern regarding the financial burden of CDs in the country, economic studies have focused only on diabetes, hypertension, and cancer. Furthermore, these estimated financial burdens were based on hypothetical epidemiology models or ideal healthcare scenarios. The present study estimates the annual expenditure per patient and the financial burden for the nine most prevalent CDs, excluding cancer, for each of the two largest public health providers in the country: the Ministry of Health (MoH) and the Mexican Institute of Social Security (IMSS). METHODS: Using the Mexican National Health and Nutrition Survey 2012 (ENSANUT) as the main source of data, health services consumption related to CDs was obtained from patient reports. Unit costs for each provided health service (e.g. consultation, drugs, hospitalization) were obtained from official reports. Prevalence data was obtained from the published literature. Annual expenditure due to health services consumption was calculated by multiplying the quantity of services consumed by the unit cost of each health service. RESULTS: The most expensive CD in both health institutions was chronic kidney disease (CKD), with an annual unit cost for MoH per patient of US$ 8,966 while for IMSS the expenditure was US$ 9,091. Four CDs (CKD, arterial hypertension, type 2 diabetes, and chronic ischemic heart disease) accounted for 88% of the total CDs financial burden (US$ 1.42 billion) in MoH and 85% (US$ 3.96 billion) in IMSS. The financial burden of the nine CDs analyzed represents 8% and 25% of the total annual MoH and IMSS health expenditure, respectively. CONCLUSIONS/SIGNIFICANCE: The financial burden from the nine most prevalent CDs, excluding cancer, is already high in Mexico. This finding by itself argues for the need to improve health promotion and disease detection, diagnosis, and treatment to ensure CD primary and secondary prevention. If the status quo remains, the financial burden could be higher. PMID- 26744843 TI - Optimization of Regularization Parameters in Compressed Sensing of Magnetic Resonance Angiography: Can Statistical Image Metrics Mimic Radiologists' Perception? AB - In Compressed Sensing (CS) of MRI, optimization of the regularization parameters is not a trivial task. We aimed to establish a method that could determine the optimal weights for regularization parameters in CS of time-of-flight MR angiography (TOF-MRA) by comparing various image metrics with radiologists' visual evaluation. TOF-MRA of a healthy volunteer was scanned using a 3T-MR system. Images were reconstructed by CS from retrospectively under-sampled data by varying the weights for the L1 norm of wavelet coefficients and that of total variation. The reconstructed images were evaluated both quantitatively by statistical image metrics including structural similarity (SSIM), scale invariant feature transform (SIFT) and contrast-to-noise ratio (CNR), and qualitatively by radiologists' scoring. The results of quantitative metrics and qualitative scorings were compared. SSIM and SIFT in conjunction with brain masks and CNR of artery-to-parenchyma correlated very well with radiologists' visual evaluation. By carefully selecting a region to measure, we have shown that statistical image metrics can reflect radiologists' visual evaluation, thus enabling an appropriate optimization of regularization parameters for CS. PMID- 26744846 TI - Computer modelling of the surface tension of the gas-liquid and liquid-liquid interface. AB - This review presents the state of the art in molecular simulations of interfacial systems and of the calculation of the surface tension from the underlying intermolecular potential. We provide a short account of different methodological factors (size-effects, truncation procedures, long-range corrections and potential models) that can affect the results of the simulations. Accurate calculations are presented for the calculation of the surface tension as a function of the temperature, pressure and composition by considering the planar gas-liquid interface of a range of molecular fluids. In particular, we consider the challenging problems of reproducing the interfacial tension of salt solutions as a function of the salt molality; the simulations of spherical interfaces including the calculation of the sign and size of the Tolman length for a spherical droplet; the use of coarse-grained models in the calculation of the interfacial tension of liquid-liquid surfaces and the mesoscopic simulations of oil-water-surfactant interfacial systems. PMID- 26744847 TI - Electronic and optical properties of graphene nanoribbons in external fields. AB - A review work is done for the electronic and optical properties of graphene nanoribbons in magnetic, electric, composite, and modulated fields. Effects due to the lateral confinement, curvature, stacking, non-uniform subsystems and hybrid structures are taken into account. The special electronic properties, induced by complex competitions between external fields and geometric structures, include many one-dimensional parabolic subbands, standing waves, peculiar edge localized states, width- and field-dependent energy gaps, magnetic-quantized quasi-Landau levels, curvature-induced oscillating Landau subbands, crossings and anti-crossings of quasi-Landau levels, coexistence and combination of energy spectra in layered structures, and various peak structures in the density of states. There exist diverse absorption spectra and different selection rules, covering edge-dependent selection rules, magneto-optical selection rule, splitting of the Landau absorption peaks, intragroup and intergroup Landau transitions, as well as coexistence of monolayer-like and bilayer-like Landau absorption spectra. Detailed comparisons are made between the theoretical calculations and experimental measurements. The predicted results, the parabolic subbands, edge-localized states, gap opening and modulation, and spatial distribution of Landau subbands, have been identified by various experimental measurements. PMID- 26744848 TI - Neural synchronization as a hypothetical explanation of the psychoanalytic unconscious. AB - Cognitive scientists have tried to explain the neural mechanisms of unconscious mental states such as coma, epileptic seizures, and anesthesia-induced unconsciousness. However these types of unconscious states are different from the psychoanalytic unconscious. In this review, we aim to present our hypothesis about the neural correlates underlying psychoanalytic unconscious. To fulfill this aim, we firstly review the previous explanations about the neural correlates of conscious and unconscious mental states, such as brain oscillations, synchronicity of neural networks, and cognitive binding. By doing so, we hope to lay a neuroscientific ground for our hypothesis about neural correlates of psychoanalytic unconscious; parallel but unsynchronized neural networks between different layers of consciousness and unconsciousness. Next, we propose a neuroscientific mechanism about how the repressed mental events reach the conscious awareness; the lock of neural synchronization between two mental layers of conscious and unconscious. At the last section, we will discuss the data about schizophrenia as a clinical example of our proposed hypothesis. PMID- 26744849 TI - Identification of pseudobulbar affect symptoms in Veterans with possible traumatic brain injury. AB - Pseudobulbar affect (PBA), a neurological syndrome characterized primarily by involuntary episodes of laughing and crying, can develop secondary to neurological conditions including traumatic brain injury (TBI). Veterans of the wars in Afghanistan and Iraq have an unprecedented risk for TBI, primarily from blast-related munitions. In this cross-sectional study with linkage to Department of Veterans Affairs (VA) clinical data, Veterans screening positive for TBI on the VA TBI screen (N = 4,282) were mailed packets containing two PBA symptom assessments: a single PBA symptom screen question and the Center for Neurologic Study-Lability Scale (CNS-LS) questionnaire. Seventy percent (n = 513) of the 728 Veteran respondents screened positive for PBA symptoms with a CNS-LS score of 13 or greater. There was strong concordance between PBA symptom prevalence measured with the single screening question and CNS-LS, with high sensitivity (0.87) and positive predictive value (0.93), and moderate specificity (0.79). Posttraumatic stress disorder (54% vs 32%), major depression (35% vs 22%), and anxiety disorder (20% vs 13%) were more common for Veterans with PBA symptoms than for those without. PBA symptoms were common in this Veteran cohort, were detected using simple screening tools, and often co-occurred with other psychiatric disorders common in Veterans. PMID- 26744852 TI - Ratios, Ratios and Ratios of white blood count for evaluation of inflammatory conditions. PMID- 26744851 TI - Selective channel combination of MRI signal phase. AB - PURPOSE: Signal magnitude can robustly be combined using the sum-of-squares approach. Methods have been developed to combine complex images. However, techniques based only on signal phase have not been developed and evaluated. THEORY AND METHODS: We performed simulations to demonstrate the effect of noise on coil combination. 32-channel 7 Tesla human gradient echo MRI brain data were collected. We combined phase images based on phase noise leading to spatially selective and coil selective combination of phase images. We compared our selective combination approach to optimal noise distribution and adaptive combination methods. RESULTS: We found that selective combination of signal phases leads to improved phase signal-to-noise ratio. Furthermore, a phase shift can be present in combined phase images introduced by the method used to combine multiple channel phases. CONCLUSION: Mapping of signal phase from ultra-high field MRI data undoubtedly provides a wealth of information about the ageing brain and the effects of neurodegenerative disorders. Measurement of signal phase is essential in frequency shift mapping and in quantitative susceptibility mapping. The method used to combine signal phase should be informed by an understanding of the noise distribution in signal phase at the individual channel level. Magn Reson Med 76:1469-1477, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26744853 TI - Efficacy of paclitaxel in the treatment of Kaposi sarcoma. PMID- 26744854 TI - Helicobacter pylori and cardiovascular disease: any missing data? PMID- 26744855 TI - Is diffusion-weighted imaging useful for differentiation between Graves' disease and Hashimoto thyroiditis? PMID- 26744856 TI - Quantitative assessment of cardiac electrical heterogeneity in patients with polycystic ovary syndrome by transmural dispersion of repolarization and atrial electromechanical coupling. PMID- 26744857 TI - Important role of shivering suppression during therapeutic hypothermia. PMID- 26744858 TI - Four trace elements in pregnant women and their relationships with adverse pregnancy outcomes. AB - OBJECTIVE: Lack of trace elements during pregnancy is detrimental to maternal and fetal health. Our aim is to study the changes in trace element levels in Chinese pregnant women and their association with adverse pregnancy outcomes. PATIENTS AND METHODS: 1568 cases of Chinese pregnant women in remote areas were collected for a prospective cohort study. Serum copper, zinc, calcium and iron levels were measured at pre-pregnancy, 1st trimester (7w-12w), 2nd trimester (24w-28w) and 3rd trimester (35w-40w). RESULTS: (1) Serum copper levels was significantly higher after pregnancy than before, calcium and iron levels decreased, but zinc levels did not change significantly. (2) Copper and zinc deficiency in pregnant women was not a common finding, but lack of iron and calcium was frequently encountered; iron deficiency was especially common in the 3rd trimester (42.27%). (3) Serum zinc and iron levels in patients who either had a miscarriage or a preterm delivery were significantly lower than in the control group (p < 0.05). In patients with premature rupture of membranes, serum zinc levels were significantly lower (p < 0.05). In patients with intrauterine growth restriction (IUGR), serum copper, zinc, calcium and iron were significantly lower (p < 0.05). CONCLUSIONS: Trace elements is closely associated with fetal growth and development during pregnancy. Deficiency can lead to adverse pregnancy outcomes. Therefore, we should have a reasonable diet, replenish trace elements, therefore reducing the occurrence of adverse pregnancy outcomes. PMID- 26744860 TI - Role of circulating nesfatin-1 in the underweight children with poor appetite. AB - OBJECTIVE: To investigate serum concentration of nesfatin-1 in underweight children who have poor appetite, and its association with anthropometric markers of malnutrition. PATIENTS AND METHODS: We recruited 50 underweight children and adolescents (aged 2-18 years) who presented with loss of appetite. Thirty age- and sex-matched controls were also included in the study. Fasting serum nesfatin 1 concentrations were measured by using Enzyme-Linked Immunosorbent Assay (ELISA) technique. RESULTS: Mean nesfatin-1 level was significantly higher in underweight children when compared to controls (p<0.001). There was no correlation between serum nesfatin-1 levels and anthropometrics markers. CONCLUSIONS: Our results suggest that nesfatin-1 might have an important role in regulation of food intake and pathogenesis of loss of appetite in children. PMID- 26744859 TI - Right arm injection of contrast medium reduces venous artifacts in head and neck multislice spiral computed tomography angiography. AB - OBJECTIVE: We tested whether injection of contrast medium via right or left arm would affect venous artifacts on head and neck multislice spiral computed tomography (CT) angiography. PATIENTS AND METHODS: 326 patients were enrolled. Each patient was injected with 10 ml of contrast medium at 5 ml/sec. Time of peak contrast value plus an additional 1 sec was defined as delay time. Another 40 ml of contrast medium were injected with the same injection speed. The scanning area ranged from the aortic arch to the top of the head. Left and right forearms were used for intravenous injections of contrast medium in, respectively, 151 and 175 patients. Comparative analyses of image quality included determining contrast medium residues remaining in the superior vena cava, brachiocephalic vein, or subclavian vein, and comparisons of quality of three-dimensional CT angiography. RESULTS: In 75% of head and neck angiographies, the delay time of the common carotid artery ranged from 16 to 22 sec. In 60% of the images, the quality was graded as excellent, with the left arm injection resulting in delay time of > 23 sec and the right arm delay time of > 18 sec. The CT imaging quality after contrast injections via left or right arms was statistically significant (p < 0.05). The image quality after right arm injection was better than after left arm injection. CONCLUSIONS: Intravenous injection of contrast medium via right arm reduces artifacts from contrast medium residues and improves the image quality of head and neck CT angiography. PMID- 26744861 TI - Clinical application of anterolateral thigh perforator flap for the reconstruction of severe tibia exposure. AB - OBJECTIVE: Exposure of tibia can result from severe traumatic wounds, such as injuries due to traffic accidents, crush injuries (machine) and amputation wounds. The free anterolateral thigh perforator flap is increasingly being used for trauma reconstruction. Here we report our case load with this surgical intervention. PATIENTS AND METHODS: We reviewed 27 patients who underwent free anterolateral thigh flap reconstruction for tibia exposure in the proximal-middle part. The flap size ranged from 64 cm2 to 270 cm2 (mean, 35 cm2). The recipient artery was the anterior tibial artery (3 cases), the posterior tibial artery (8 cases), the dorsal pedal artery (8 cases) and the contralateral posterior tibial vessels (8 cases). RESULTS: Among the flaps, 20 successfully survived (74%), and the others suffered from partial skin necrosis at flap edge (5 cases, 18.5%) and flap loss was caused by venous or arterial thrombosis (2 cases, 7.4%). The lost flap was reconstructed with a split-thickness skin graft or a cross-leg soleus muscle flap coverage. The follow-up period ranged from 3 to 30 months. Three patients had sinus formation and healed in one year with the repeated debridement and drainage. Among the 27 cases, only one case presented reinfection at the sixth postoperative month, due to the plate fixation and was healed in one month by the removal of steel plate and thorough debridement and drainage. CONCLUSIONS: Our results suggest that free anterolateral thigh flap would be an alternative choice for reconstruction of severe tibia exposure, and careful selection of the location and number of perforators as well as the proper selection of recipient artery are of great importance. PMID- 26744862 TI - Coverage of exposed hardware after lower leg fractures with free flaps or pedicled flaps. AB - OBJECTIVE: The placement of osteosynthetic materials in the leg may be complicated by hardware exposure. Successful soft tissue reconstruction often provides a critical means for limb salvage in patients with hardware exposure in the leg. Free flaps are currently considered the standard surgical procedure for soft tissue coverage of the wounds with internal hardware exposure. However, to date, no conclusive literature shows the superiority of a specific type of flap. MATERIALS AND METHODS: The current review compares data from the literature concerning outcomes and complications of free and pedicled flaps for exposed osteosynthetic material preservation in the leg. RESULTS: A total of 81 cases from twelve different articles presenting internal hardware exposure of the leg were analyzed in our study. Thirty-two patients underwent immediate reconstructive surgery with pedicled flaps, while forty-nine patients underwent free flap reconstruction. The overall survival rate for pedicled flaps was 96.77%, while for free flaps it was 97.77%. The overall implant preservation rate was 78.12% for pedicled flaps and 53.33% for free flaps. With reference to postoperative complications, the overall complication rate was 46.87% for pedicled flaps and 10.20% for free flaps. CONCLUSIONS: No significant difference was found in terms of overall flap survival. However, a significant difference was found regarding successful implant preservation (78.12% in the pedicled flap group vs. 53.33% in the free flap group). In particular, the first observation appears to be in contrast with the current trend of considering the free flaps the first choice procedure for soft tissue coverage of the wounds with internal hardware exposure. Nevertheless, a higher occurrence of postoperative complications was observed in the pedicled flap group (46.87% vs. 10.20%). The choice of the most appropriate reconstructive procedure should take into account several issues including the size of the wounds with internal hardware exposure, the possibility of soft tissue coverage with pedicled flaps, the availability of recipient vessels, general conditions of the patients (such as age, diabetes, smoking history), patients' preference and presence of a microsurgical team. However, according to the results of this review, we believe that pedicled flap reconstruction should be reconsidered as a valid alternative procedure for skin tissue loss with hardware exposure whenever it is possible. PMID- 26744863 TI - The increased risk of globus pharyngeus in patients with chronic thyroiditis: a case control study. AB - OBJECTIVE: A correlation between globus pharyngeus and thyroid gland inflammation has been mentioned in previous studies. However, the potential risk of globus pharyngeus in chronic thyroiditis patients has not been shown so far. The aim of this study is to investigate a possible association between chronic thyroiditis and globus pharyngeus. PATIENTS AND METHODS: The study was performed in an ultrasound (US) center of a tertiary health care institution. Ninety-two patients who were under examination for suspected thyroid pathologies or undergoing follow up for a previously diagnosed thyroid disease were enrolled in the study. The patients were divided into two groups according to the existence of globus symptoms. Subsequently, all patients underwent high-resolution thyroid ultrasounds. The patients whose ultrasound findings were suggestive of chronic thyroiditis constituted the second subgroup. The demographic data of the patients and other ultrasound findings including the volume of the thyroid glands and nodules, if any, were noted as well. RESULTS: Sixty-seven female (73%) and 25 male (27%) patients were enrolled in the study. Thirty-two (35%) of the 92 patients constituted the globus pharyngeus group according to their responses to the questionnaire and the US findings were concordant with chronic thyroiditis in 36 (39%) patients. The correlation between chronic thyroiditis and globus sensation was significant (p = 0.004), and the odds ratio was calculated as 3.7 (95% CI = 1.5-9.11). Other parameters including age, sex, thyroid volume and nodule status were not significantly related to globus pharyngeus in this particular patient series. CONCLUSIONS: In the presented study, the risk of globus pharyngeus occurrence was calculated as 3.7-fold higher in patients with chronic thyroiditis. Being a preliminary report, it is necessary to confirm this finding and understand the pathophysiological mechanism via further investigations with a larger patient series. PMID- 26744865 TI - Prospective clinical study of pre-operative SIB-IMRT in preparing surgical boundary of extremity soft tissue sarcoma. AB - OBJECTIVE: To establish the pre-operative simultaneous integrated boost intensity modulated radiation therapy (SIB-IMRT) technology in preparing the surgical boundary of extremity soft tissue sarcoma (ESTS), aiming to investigate its impacts towards the short-term local control and post-operative wound complications of ESTS. PATIENTS AND METHODS: 16 patients with local advanced ESTS were prospectively collected and performed the SIB-IMRT technology to prepare the surgical boundary. The resection surgery was completed within 3-6 weeks after the radiotherapy. The efficacy was evaluated according to the changes of limb circumference, RECIST criteria and relapse-free survival; and the CTCAE 4.0 standard was used to evaluate the considerations of post-radiotherapy acute radiative skin injury. RESULTS: The radiotherapeutic plan of pre-operative SIB IMRT technology in preparing the surgical boundary of locally advanced ESTS was developed. Before and after SIB-IMRT, the difference of limb circumference was statistically significant (p <0.05); after SIB-IMRT, 13 cases exhibited the decreased lesions, 7 cases exhibited the partial remission (PR), and 9 cases showed the stable lesions (SD); the median time of recurrence-free survival was 6.5 months, the efficiency of pre-operative SIB-IMRT was > 60%, with 13 cases of level 1 acute radiative skin injury, 2 cases of level 2 and 1 case of level 3. CONCLUSIONS: The pre-operative SIB-IMRT was feasible, safe and effective in preparing the surgical boundary of locally advanced ESTS, which could reduce the tumor volume, and improve the short-term relapse-free survival time. PMID- 26744864 TI - MiR-26b suppresses tumor cell proliferation, migration and invasion by directly targeting COX-2 in lung cancer. AB - OBJECTIVE: Lung cancer, including non-small cell lung cancer (NSCLC), is the leading cause of cancer-related mortality worldwide. Despite recent advances in clinical and experimental oncology, the prognosis of patients with NSCLC still remains poor and the average survival time of patients suffer from lung cancer is low. Therefore, the potential mechanism accounting for the tumorigenesis of NSCLC is still needed to be explored. MATERIALS AND METHODS: A lentiviral vector over expressing miR-26b in A549 lung cancer cells was constructed. Cell proliferation, migration and invasion analysis were measured by cell counting kit (MTT), would healing assay and Transwell assay. Direct target of miR-26b in A549 cells was examined using bioinformatics and Luciferase assay. RESULTS: Herein, we found that over-expression of miR-26b significantly inhibited the proliferation, migration and invasion of A549 lung cancer cell in vitro and suppressed the growth of established tumors in vivo. By using bioinformatics, we found that COX 2 (Cyclooxygenase-2) is one of the potential targets of miR-26b. Moreover, miR 26b was found to negatively regulate COX-2 protein level by directly targeting its 3'UTR. In addition, depletion of endogenous COX-2 by the specific siRNA could mimic the function of miR-26b overexpression. CONCLUSIONS: Taken together, our results demonstrate that miR-26b could suppress lung cancer cells proliferation, migration and invasion by directly negative regulation of COX-2. MiR-26b could serve as a novel potential marker for NSCLC therapy. PMID- 26744866 TI - Inhibition of human hepatocellular carcinoma tumor angiogenesis by siRNA silencing of VEGF via hepatic artery perfusion. AB - OBJECTIVE: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. Hepatic arterial chemoembolization transcatheter (TACE) is one of the main treatment methods for liver cancer. However, the long-term therapeutic effect of HCC after TACE is still unsatisfactory, postoperative recurrence and metastasis rate is still very high. Furthermore, TACE operation due to liver cancer tissue ischemia and hypoxia will lead to up-regulation of vascular endothelial growth factor (VEGF) expression. In the current study, we investigated the effects of suppressed VEGF on HCC and its molecular mechanism provided a basis for targeting angiogenesis. MATERIALS AND METHODS: We established rabbits primary HCC model by in situ embedding the VX2 subcutaneous transplantation tumor. Conventional Seldinger femoral artery and hepatic artery catheterization method were used to select the catheter over the tumor-bearing hepatic artery. The different groups were divided into TACE operation, and the experimental group was performed with the VEGF-siRNA molecular preparation in the catheter. 64-slice spiral CT were used to perfusion imaging of liver cancer model before and after TACE operation. We further assessed the efficiency of VEGF silencing and its influence on VX2 cells. The expression of VEGF mRNA and protein were detected by RT-PCR and Western blotting, respectively. Intratumoral microvessel density (MVD), VEGF and CD34 were evaluated by immunohistochemistry. We detected the cell apoptotic by immunofluorescence and flow cytometry. RESULTS: Our findings indicated that VEGF-siRNA-2# could effectively suppress the expression of VEGF expression, inhibited the proliferation capability and promoted apoptosis of VX2 cells in vitro. Silencing of VEGF expression also suppress HCC tumor growth and reduce HCC angiogenesis in rabbits primary HCC model in vivo. Furthermore, We found that phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) activation were considerably reduced while inhibition VEGF expression in VX2 cells. CONCLUSIONS: Our data demonstrated that VEGF silencing could suppress cells proliferation, promote cells apoptosis and reduce HCC angiogenesis through inactivation of VEGF/PI3K/AKT signaling pathway. PMID- 26744867 TI - Low miR-498 expression levels are associated with poor prognosis in ovarian cancer. AB - OBJECTIVE: Decreased expression levels of microRNA (miR)-498 were reported in several human cancers. However, the prognostic value of the miR-498 expression in ovarian cancer has not been assessed. In this study, we addressed this knowledge gap by evaluating an association of miR-498 expression levels with ovarian cancer prognosis. PATIENTS AND METHODS: qPCR was used to detect expression levels of miR 498 in cancer specimens and matched adjacent normal tissue specimens. The log rank test was used to analyze survival rate, whereas the Cox regression model was used fir multivariate analysis of potential prognostic factors. RESULTS: Expression levels of miR-498 were significantly lower in ovarian cancer tissue specimens compared with matched normal adjacent tissue (p < 0.001). Decreased miR 498 expression levels correlated well with FIGO stage, tumour grade and lymph node metastases (respective p = 0.001, 0.015, and 0.017). Furthermore, patients with lower miR-498 expression had shorter overall and progression-free survival (both p < 0.01 vs. those with high miR-498 expression). CONCLUSIONS: Decreased expression levels of miR-498 are associated with worse overall survival and poor prognosis in patients with ovarian cancer, highlighting potential usefulness of this miR for prognosis in patients with ovarian cancer. PMID- 26744869 TI - The PPI network and clusters analysis in glioblastoma. AB - OBJECTIVE: Glioblastoma is the most aggressive tumor of the brain. To further understand its molecular mechanism, we carried out a systemic bioinformatics study of gene chips downloaded from Gene Expression Omnibus database. MATERIALS AND METHODS: LIMMA package in R language was used to identify the differentially expressed genes (DEGs) between glioblastoma samples and normal controls. RESULTS: Further, we constructed protein-protein interaction networks by mapping the DEGs into PPI data and identified network clusters in these networks. The results revealed that expression of 516 genes, which are mainly involved in phosphate metabolic process and signal transduction, were altered in glioblastoma samples. LYN, CD22 and LCP2 form a densely protein complex in the PPI network. CONCLUSIONS: Our results suggest that LYN, CD22 and LCP2 play important roles in the occurrence and progression of glioblastoma. PMID- 26744868 TI - The impact of EUS to predict lymph node metastasis in patients with rectal cancer: a difficult challenge. AB - OBJECTIVE: Current trends in the management of rectal cancer, identify accurate local assessment of positive lymph nodes (LN), as the strongest predictor for stratifying patients who would benefit from preoperative therapy. We a present retrospective analysis of a prospective data collection, to determine the clinical concordance between the suspicious LN at the pre-operative EUS (uN) and a post-operative EUS detection (pN). PATIENTS AND METHODS: From March 2009 to March 2011, 31 patients with suspicious LNs at EUS (uN positive) were enrolled. The surgeon performed pre-operative EUS and directly in the operating room, an ex vivo EUS of the specimen. The immediate mesorectal LN sampling by the surgeon was delivered to the pathologist. Endosonographic staging was compared to postoperative pathological staging. RESULTS: Preoperative EUS identified 67 suspicious LN. The LN medium size was 6.8 mm. We repeated the EUS after surgery. The pathologist found 41 positive LN. The definitive LN medium size was 6.3 mm. Eleven LN presented the same size between ultrasound and pathological examination, 11 LN a smaller size and 41 a bigger size, the remnants 4 were not discovered. EUS LN staging presented 83.9% in overstaging and 3.2% in understaging. Although endo ultrasonography (EUS) is a very effective method for assessing LN metastasis, this is still a difficult challenge. Inaccurate assessment of LNs can conceivably lead to either under-staging or over-staging. The present study indicates that the clinical concordance between the suspected metastatic LN at the pre-operative EUS (uN) and a post-operative (ex-vivo) ultrasound LN detection, is moderate. CONCLUSIONS: We should re-consider all this strategy: we need to switch from morphological information to biological behavior. PMID- 26744870 TI - Should prostate cancer be considered as a differential diagnosis in patients with osteolytic bone lesions? AB - OBJECTIVE: Prostate cancer is the most frequently diagnosed cancer in men, as well as the second leading cause of death among cancers after lung cancer. In the United States, it is more prevalent in African-American men than in Caucasian men. Prostate cancer frequently metastasizes to the bone, with most of the reported lesions appearing to be osteoblastic on radiographs. Here, we describe an unusual presentation of metastatic prostate cancer with diffuse osteolytic bone lesions. CASE PRESENTATION: An 80-year-old previously healthy Hispanic man presented with worsening back pain, difficulty with ambulation, and bladder outlet obstruction. Physical examination was significant for spinal tenderness in the thoracic and lumbar region. Digital rectal examination was remarkable for asymmetric enlargement of the prostate with nodularity and firmness. Imaging studies revealed diffuse osteolytic lesions. His prostate-specific antigen was 562.8 ng/mL (normal 0-4). Prostate biopsy and imaging studies confirmed a diagnosis of metastatic prostate cancer. CONCLUSIONS: This case demonstrates that bone metastases of prostate cancer are not purely osteoblastic although most of the reported bone metastases in prostate cancer have been osteoblastic in nature. Therefore, clinicians are to consider metastatic prostate cancer as a differential diagnosis for patients with osteolytic bone lesions. PMID- 26744871 TI - Effect analysis of early bedside hemo-filtration in treatment of severe pneumonia with acute renal failure of children. AB - OBJECTIVE: To investigate the best opportunity for bedside continuous blood purification (CBP) to treat severe pneumonia with acute renal failure (ARF) of children and look for the sensitive marker to evaluate the clinical effects and prognosis. PATIENTS AND METHODS: 54 children patients that were diagnosed as severe pneumonia with ARF by Pediatric Intensive Care Unit (PICU) were enrolled in our study as experimental group. In the meanwhile, 46 children patients that were diagnosed as severe pneumonia with ARF by PICU were enrolled as a normal control group. Patients in the experimental group started CBP treatment within 24 h after onset while patients in the control group started CBP treatment 24h after onset. The differences of clinical effects between two groups were compared for statistical significance. RESULTS: The survival rates of the observation group in day 7, day 28 and 6 months were significantly higher than those in the control group. After treatment for 7 days, IL-6 and TNF-alpha, YKL-40 and Annexin A1 levels of the experimental group were significantly lower than those of the control group. 7-day infection-related organ failure score (SOFA) of the experimental group was significantly lower than that of the control group. CONCLUSIONS: CBP therapy for treating severe pneumonia with acute renal failure of children within 24 hours could significantly improve the survival rate and reduce the inflammatory reactions. PMID- 26744872 TI - Quantitative PCR detection of t(11;14) bcl-1/JH in mantle cell lymphoma patients: comparison of peripheral blood and bone marrow aspirate samples. AB - OBJECTIVE: Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma (NHL) featured by participation of the lymph nodes, spleen, blood and bone marrow with a short remission period to standard therapies and a median overall survival of 4-5 years. PATIENTS AND METHODS: In this study, we compare the levels of bcl-1/JH fusion products detected by q-PCR in the concurrent peripheral blood (PB) and bone marrow (BM) aspirate samples from 7 patients with MCL. RESULTS: In patients with moderate to high levels of bcl-1/JH copies, the results of q-PCR analysis of PB and BM aspirate samples correlate well. In patients with high levels of bcl 1/JH copies, instead, PB levels are a good indication of tumor burden. Finally, in patients with low levels of bcl-1/JH copies, the t(11;14) may be detected by identification of neoplastic cells. CONCLUSIONS: Our data suggest that PB can be reliably used in place of BM aspirate both for detection of translocation status during minimal residual disease monitoring and for a possible molecular relapse, especially in those patients who have moderate to high levels of bcl-1/JH copies. If these results will be confirmed on a wider number of MCL patients, future study will be required to address the issue. PMID- 26744873 TI - Dysregulated module approach identifies disrupted genes and pathways associated with acute myelocytic leukemia. AB - OBJECTIVE: To identify disrupted genes and pathways involved in acute myelocytic leukemia (AML) by systematically tracking the dysregulated modules across normal and AML conditions. MATERIALS AND METHODS: In this study, we firstly integrated the protein interaction data and expression profiles to infer and reweight the normal and AML networks using Pearson correlation coefficient (PCC). Next, clustering-based on maximal cliques (CMC) approach and a maximum weight bipartite matching method were implemented to infer the condition-specific modules and capture the disturbed modules, respectively, from two conditional networks. Then, the gene compositions and functional enrichment analysis were performed to identify the dysregulated genes and pathways. Finally, reverse transcription polymerase chain reaction (RT-PCR) was implemented to study the expression level of several key genes in AML patients. RESULTS: In two conditional-specific networks, universal changes of gene correlations were revealed, making the differential correlation density among disrupted module pairs. In this work, a total of 84 altered modules were identified by comparing modules in normal and AML networks. Functional enrichment analysis showed that genes in altered modules mainly involved in cell cycle, nucleic acids and cancer signaling process, and differentially expressed genes (DEGs) and changed gene correlations were mainly participated in natural killer cell-mediated cytotoxicity and acute myeloid leukemia pathway. The key genes, such as MYC, EGFR, MAPK1 and CCNA1, were all significantly differentially expressed in AML patients. CONCLUSIONS: This module approach effectively identifies dysregulated pathways and genes associated with AML. The considerable differences of gene correlations yield to these dysfunctional modules, and the coordinated disruption of these very modules contributes to leukemogenesis. PMID- 26744874 TI - Knockdown of PRAME enhances adriamycin-induced apoptosis in chronic myeloid leukemia cells. AB - OBJECTIVE: Leukemia is resistant to currently available chemotherapy, and new strategies have been proposed to improve its efficacy. Such an approach requires know of the mechanisms involved in the resistance and survival of leukemia cells. Previous studied has found that Preferentially Expressed Antigen of Melanoma (PRAME) is overexpressed in the leukemia cells, and knockdown of PRAME promoted apoptosis in leukemia K562 cells. In the present study, we investigated whether inhibition of PRAME could sensitize K562 cells to chemotherapy. MATERIALS AND METHODS: K562 cells were treated with PRAME siRNA, and/or adriamycin (ADR), and cell viability and apoptosis, mRNA and protein expression levels were, then, evaluated. Furthermore, the efficacy of PRAME siRNA combined with ADR was further examined in established xenograft models. RESULTS: PRAME suppression was sufficient to induce spontaneous apoptosis of K562 cells. PRAME knockdown showed antiproliferative effects and induced tumor regression in established K562 xenograft models. ADR showed antitumor activity against K562 cells, co-treatment with PRAME siRNA induced an increased apoptosis rate than the sum of the single treatment rates and promoted tumor regression without enhanced body weight loss in the K562 xenograft models. CONCLUSIONS: PRAME is responsible for the inherent low levels of spontaneous apoptosis in K562 cells. The combination of PRAME siRNA with ADR induced more intense apoptosis compared with each single treatment. PRAME siRNA in combination with ADR is well tolerated and shows greater efficacy than either agent alone in mouse xenograft models. PMID- 26744876 TI - Overexpressed miR-155 is associated with initial presentation and poor outcome in Chinese pediatric acute myeloid leukemia. AB - OBJECTIVE: Acute myeloid leukemia (AML) is the second leading leukemia in children. There is growing evidence that microRNAs (miRNAs) are crucial regulators involved in leukemogenesis. This study aimed to investigate the role of miR-155 in Chinese pediatric AML by evaluating its diagnostic and prognostic significance. PATIENTS AND METHODS: The expression of miR-155 and miR-25 in bone marrow specimens from 83 AML and 29 non-malignancies children were analyzed by TaqMan probe-based real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). RESULTS: The expression level of miR-155 was significantly higher in AML patients than in controls. Besides, a lowest miR-155 level was found in favorable prognosis group and t (15; 17)/M3 subgroup compared to the rest, while a higher level in C-Kit/FLT3-ITD mutation and relatively lower level existed in "Negative" mutation group. Moreover, miR-155 level was positively associated with the white blood cell (WBC) count, serum lactate dehydrogenase (LDH) and C-reaction protein (CRP) value in peripheral blood (PB), as well as miR 25/miR-196b expression levels. Survival analysis showed a statistically negative association with overall survival (OS) in the expression of miR-155 in chemotherapy group. CONCLUSIONS: These finding suggested that miR-155 expression cannot only be promising biomarker for the early detection of pediatric AML but also predict poor outcome. MiR-155 would be a novel biomarker for diagnosis, prognosis and therapy in pediatric AML. PMID- 26744875 TI - Evaluation of serum levels of zinc, copper, and Helicobacter pylori IgG and IgA in iron deficiency anemia cases. AB - OBJECTIVE: Iron deficiency anemia (IDA) is the most common form of anemia. Impaired intake absorption and blood loss are the main factors in the etiology. Impaired absorption can be caused by a decrease in trace elements such as copper and zinc, which are found in the structure of enzymes that coordinate iron metabolism or act as a catalyst for them, and the existence of Helicobacter pylori (H. pylori), which inhibits iron absorption in the stomach. Serum levels of zinc, copper, and H. pylori antibodies were measured in IDA cases, and correlations with IDA were evaluated. PATIENTS AND METHODS: The study group was composed of 115 IDA cases who were followed at hematology outpatient clinics, and the control group was composed of 92 gender- and age-matched healthy individuals. Patients were diagnosed with iron deficiency anemia according to hemoglobin, serum ferritin, and iron levels and total iron-binding capacity. Serum zinc, copper, H. pylori immunoglobulin A (HpIgA) and immunoglobulin G (HpIgG), vitamin B12, and folic acid levels were examined in the blood specimens collected. RESULTS: No statistically significant difference in zinc and copper serum levels between the study and control groups was observed (p > 0.05 for both groups). Although no difference was observed between the HpIgG levels of the two groups, patients with IDA had a statistically significant increase in HpIgA levels (p < 0.05). Pearson's correlation analysis showed that the zinc levels of the IDA group did not have a correlation with any parameters (p < 0.05 for all). Copper levels had a positive correlation with only the HpIgA level in the IDA group (r = 0.222, p = 0.017). CONCLUSIONS: Trace elements and H. pylori infection did not have a correlation with IDA. Elevated levels of HpIgA and positive correlation of HpIgA with copper levels were observed. The literature review clearly suggests that several points require further explanation, and extensive research with larger samples is required. PMID- 26744877 TI - Urinary neutrophil gelatinase associated lipocalin as a biomarker in ifosfamide induced chronic renal failure. AB - OBJECTIVE: Neutrophil gelatinase associated lipocalin (NGAL) have been used with great success in acute renal failure and in some cases in chronic nephrotoxicity. In this work, we aimed to investigate urinary NGAL as an early marker of chronic renal failure (CRF). PATIENTS AND METHODS: We investigated urinary NGAL of 29 children treated with ifosfamide chemotherapy and compared them with those of 12 healthy children. Urinary beta2 microglobulin, serum cystatin C, and creatinine clearance analyses were also studied. RESULTS: The median age was 11 years (4-21) and median remission time was 4.3 years (1.8-14.4). The cumulative dose of ifosfamide was 36 g. Glomerular filtration rate was decreased in 41.4% and urine beta2 microglobulin levels and serum cystatin C levels were elevated in 31% of the patients. As the remission time increased, serum creatinine and cystatin C levels were also increased. The sensitivity for beta2 microglobulin and cystatin C in demonstrating CRF was 35.2% and 23% and specificity was 33.2% and 50% respectively. The 24-hour urine NGAL cut-off level for demonstrating CRF was found to be 1.065 ng/mL/24 hours. The sensitivity and specificity for this cut off value were 83% and 77%, respectively. CONCLUSIONS: NGAL levels were significantly higher in the study group as compared with the control group. Although ifosfamide treatment was suggested to be safe with no complication of renal failure under a dose of 80 g/m2, chronic renal failure and deficits in glomerular and tubular function could be seen when the remission time increased. Elevated NGAL levels may be a good option in determining CRF. PMID- 26744879 TI - Role of mitophagy regulated by Parkin/DJ-1 in remote ischemic postconditioning induced mitigation of focal cerebral ischemia-reperfusion. AB - OBJECTIVE: We evaluated the role of mitophagy controlled by Parkin/DJ-1 in remote ischemic post conditioning-induced mitigation of focal cerebral ischemia reperfusion (I/R) injury in rats. MATERIALS AND METHODS: Ninety adult male rats were randomly assigned into 5 groups including a sham operation group (S) and ischemia-reperfusion group (I/R). Focal cerebral I/R was induced by right middle cerebral artery occlusion (MCAO). I/R+remote ischemic postconditioning (I/R+RIPoC), I/R+RIPoC+ mitophagy inhibitor Mdivi-1 (I/R+RIPoC+M), and I/R+RIPoC+ normal saline (I/R+RIPoC+NS) groups all received 3 cycles of 10 minutes reperfusion followed by 10 minutes ischemia in bilateral femoral arteries at the beginning of cerebral reperfusion. I/R+RIPoC+M received mitochondrial division inhibitor (Mdivi-1) before ischemia and after 24h of reperfusion, neurological deficit scores (NDSs) were measured and rats were then sacrificed. Brain was removed and size of the infarct was determined. Apoptosis index and LC3-II/I ratio, Parkin/DJ-1 proteins expression, SOD activity, MDA and 15-F2t-Isoprostane content in cerebral ischemic penumbra were studied. Linear correlation between Parkin/DJ-1 proteins expression and LC3-II/I ratio and cerebral infarct size were analyzed. RESULTS: In experimental groups the NDSs, percentage of cerebral infarct size, apoptosis index, LC3-II/I ratio, MDA and 15-F2t-Isoprostane content significantly increased and Parkin/DJ-1 proteins were up-regulated (p<0.05). In I/R+RIPoC and I/R+RIPoC+NS groups, NDSs, percentage of cerebral infarct size, apoptosis index, MDA and 15-F2t-Isoprostane content decreased significantly while LC3-II/I ratio and SOD activity increased compared to I/R group. Parkin/DJ-1 proteins were up-regulated in I/R+RIPoC, I/R+RIPoC+NS and I/R+RIPoC+M groups (p<0.05). LC3-II/I ratio and SOD activity significantly decreased (p<0.05). Parkin/DJ-1 proteins expression didn't changed in I/R+RIPoC+M group (p>0.05). The Parkin/DJ-1 proteins expression were positively correlated with LC3-II/I ratio, and negatively correlated with cerebral infarct size (p<0.05). CONCLUSIONS: Remote Ischemic Post Conditioning (RIPoC) promoted the mitophagy via up regulation of Parkin/DJ-1 proteins expression and inhibiting the oxidative stress responses, thus mitigating focal cerebral I/R injury in rats. PMID- 26744878 TI - Propofol suppresses invasion, angiogenesis and survival of EC-1 cells in vitro by regulation of S100A4 expression. AB - OBJECTIVE: Propofol possess anticancer properties in several cancers. In the present study, we investigate the effect of propofol on the human esophageal squamous cell carcinomas (ESCC) EC-1 cells in vitro and its molecular mechanisms of action. MATERIALS AND METHODS: EC-1 cells were explored to 10-100 MUmol/L propofol for 72 h or 100 MUmol/L/mL propofol for 24-72 h. EC-1 cells were explored to 100 MUmol/L propofol for 24 h, then was transiently transfected into PcDNA3.1-S100A4 cDNA or PcDNA3.1 plasmid for 48 hrs. MTT, TUNEL, ELISA, migration, tube formation and immunoblotting were analized. RESULTS: Propofol inhibits invasion, angiogenesis, proliferation and induces apoptosis in a dose and time-dependence manner, followed by deseased S100A4 expression by Western blot assay. Pre-transfection of PcDNA3.1-S100A4 cDNA inhibits propofol-induced apoptosis and promotes invasion and angiogenesis in EC-1 cells in vitro. CONCLUSIONS: Propofol inhibited invasion, angiogenesis and induces apoptosis of human EC-1 cells in vitro through regulation of S100A4 expression. It not only can be an anesthesia agent, but also plays a important role of inhibiting the migration and angiogenesis of ESCC cells in the therapy of ESCC patients. PMID- 26744881 TI - Effect of environmental air pollution on cardiovascular diseases. AB - OBJECTIVE: Environmental air pollution has become a leading health concern especially in the developing countries with more urbanization, industrialization and rapidly growing population. Prolonged exposure to air pollution is a risk factor for cardiovascular diseases. The present study aimed to investigate the effects of environmental air pollution on progression of cardiovascular problems. METHODS: In this study, we identified 6880 published articles through a systematic database including ISI-Web of Science, PubMed and EMBASE. The allied literature was searched by using the key words such as environmental pollution, air pollution, particulate matter pollutants PM 2.5 MUm-PM 10 MUm. Literature in which environmental air pollution and cardiac diseases were discussed was included. Descriptive information was retrieved from the selected literature. Finally, we included 67 publications and remaining studies were excluded. RESULTS: Environmental pollution can cause high blood pressure, arrhythmias, enhanced coagulation, thrombosis, acute arterial vasoconstriction, atherosclerosis, ischemic heart diseases, myocardial infarction and even heart failure. CONCLUSIONS: Environmental air pollution is associated with increased risk of cardiovascular diseases. Environmental pollution exerts its detrimental effects on the heart by developing pulmonary inflammation, systemic inflammation, oxidative stress, endothelial dysfunction and prothrombotic changes. Environmental protection officials must take high priority steps to minimize the air pollution to decrease the prevalence of cardiovascular diseases. PMID- 26744880 TI - Nitric oxide mediated effects of nebivolol in myocardial infarction: the source of nitric oxide. AB - OBJECTIVE: After MI pathological LV remodeling is one of the major causes of death. We previously showed the NO mediated beneficial effects of nebivolol in rat MI model, in this study we aimed to evaluate the NOS related mechanisms in this phenomenon. MATERIALS AND METHODS: Rats were divided into four groups: sham operated (sham-control), MI-induced (MI-control), immediate nebivolol loaded (MI neb1), orally nebivolol treated (MI-neb2). MI was induced by the ligation of the LAD. Loading dose of nebivolol (0.1 mg/kg) was administrated i.v. during reperfusion and continuation dose was administrated orally (2 mg/kg) by gastric gavages once daily. NOS related mechanisms were assessed either in acute (2nd day) and sub-acute (28th day) period of MI by histologic, hemodynamic and biologic studies. RESULTS: Compared to MI-control rats, physiological functions of LV (LVEDP, Delta+/-dp/dt) were prevented in both nebivolol treated groups. Improvements in anatomical parameters (LEV, HW, LVW/HW) were consistent with functional improvement too. Moreover, oxidative (characterized by decreased MDA and increased SOD levels) and nitrosative (characterized by decreased ONOO- levels) damage were limited in these groups. Compared to MI-control rats, most marked change was seen in the nNOS labelling in the nebivolol treated groups. The decrease in iNOS labelling was also prominent in these groups too. CONCLUSIONS: NOS mediated mechanisms of nebivolol can be summarized as: 1) diminishing iNOS expression together with restoration of MI induced eNOS activation both in vascular bed and myocytes at the acute period of MI, and 2) prevention of deterioration in nNOS expression in myocardial cells at the sub-acute period of MI. PMID- 26744882 TI - Opioid risk addiction in the management of chronic pain in primary care: the addition risk questionnaire. AB - OBJECTIVE: Chronic pain is one of the most common complaints for people seeking medical care, with a series of potential detrimental effects on the individual and his social texture. Despite the heavy impact of chronic pain on patients' quality of life, epidemiological data suggest that chronic pain is often untreated or undertreated. An accurate diagnostic flow and appropriate treatment should be considered as key factors for optimal management of patients with chronic pain. Opioids are recommended for treatment of chronic cancer pain (CCP) and chronic non-cancer pain (CNCP) in guidelines and can safely and effectively relieve pain in a number of patients with chronic pain. Conversely, fears of addiction and adverse events could result in ineffective pain management. Recent epidemiological and clinical data demonstrate that only low percentages of patients treated with opioids for chronic pain have a risk to develop addiction, with a prevalence rate similar to that observed in the general population. METHODS: Despite the iatrogenic risk can be considered as low, validated tools for the early identification of patients at higher risk of addiction can help health professionals in the overall management of chronic pain. CONCLUSIONS: Due to the increasing relevance of primary care physicians in chronic pain management, we propose a 28-item questionnaire to validate specifically conceived for GPs' and aimed at the preliminary evaluation of the risk of addiction in patients with chronic pain. PMID- 26744883 TI - Purified Cannabidiol, the main non-psychotropic component of Cannabis sativa, alone, counteracts neuronal apoptosis in experimental multiple sclerosis. AB - OBJECTIVE: Multiple Sclerosis (MS) is a global concern disease leading to a progressive, chronic and demyelinating condition, affecting the central nervous system (CNS). The pathology has an inflammatory/autoimmune origin; nevertheless, neuronal cell death mechanisms are not to be underestimated. The present study was designed to test the effects of intraperitoneal administration of cannabidiol (CBD), the main non-psychotropic cannabinoid of Cannabis sativa (CS), in an experimental model of MS. The aim is to evaluate the capability of CBD administration to thwart the cascade of mediators involved in MS-induced apoptosis. MATERIALS AND METHODS: Experimental Autoimmune Encephalomyelitis (EAE) was induced by immunization with myelin oligodendroglial glycoprotein (MOG)35-55 peptide in mice. After immunization, mice were observed daily for signs of EAE and weight loss. Disease signs were evaluated using a standardized scoring system. RESULTS: Immunohistochemical and Western blot assessments of key apoptotic markers reveal that CBD treatment is able to avoid Fas pathway activation, phospho-ERK p42/44 and cleaved caspase-3 triggering as well as alterations in mitochondrial permeability due to Bax/Bcl-2 unbalance. Moreover, CBD interferes with p53-p21 axis activation. As results, the absence of tissue apobody formation in spinal cord tissues of EAE-mice treated with CBD was established. Most of therapeutic properties of CS are currently ascribed to the psychotropic effects of phenylterpenoid delta-9 tetrahydrocannabinol. CONCLUSIONS: We have demonstrated that, alone, purified CBD possesses an anti apoptotic power against the neurodegenerative processes underlying MS development. This represents an interesting new profile of CBD that could lead to its introduction in the clinical management of MS. PMID- 26744884 TI - Pro-inflammatory responses and oxidative stress induced by ZnO nanoparticles in vivo following intravenous injection. AB - OBJECTIVE: To determine the toxicological effect of ZnO nanoparticles (NPs), inflammatory responses, serum biological parameters and oxidative stress markers of Superoxide dismutase (SOD) were evaluated followed by intravenous treatment of ZnO NPs in mice. MATERIALS AND METHODS: Inflammatory responses induced by a dose of 0.2 mg/kg ZnO NPs, followed by a single intravenous treatment were examined in mice. In addition, the serum biological parameters and oxidative stress markers were evaluated. Blood and spleen were collected following treatment. The mRNA transcript levels of inflammatory-related genes (TNF-alpha and IL1-beta) were elevated in the spleen cells of mice treated with ZnO NPs at 12h. RESULTS: The elevated levels of TNF-alpha and IL1-beta in supernatants of spleen cell cultures of mice treated with ZnO NPs were also observed at 24h. The serum aspartate aminotransferase, glutamate pyruvate alanine aminotransferase, and lactate dehydrogenase levels significantly increased at 6h and 12h in ZnO NPs treated group, indicating liver cell injury and tissue damage. On the other hand, no elevation was observed in BUN and Cre, biochemical markers of kidney damage. SOD activities were significantly elevated at 24 h and 48 h. CONCLUSIONS: This study shows the ZnO induced pro-inflammatory response in vivo, that this response may be related to oxidative stress, and to show hepatic damage at an early stage. PMID- 26744886 TI - Erratum. PMID- 26744885 TI - Blood-brain barrier and neuro-AIDS. AB - Neuro-AIDS is becoming a major health problem among AIDS patients who experience improved survival under combined antiretroviral therapy (cART). Neuronal injury and loss are the critical issues of neuro-AIDS that need the entry of HIV into the central nervous system (CNS) via peripheral infected monocyte/macrophage carriers or viral direct penetration of blood-brain barrier (BBB). The mechanisms of HIV enhancing BBB permeability and entering CNS and the effect of drug abuse in HIV traffic across BBB are discussed. In addition, the current anti-HIV drugs, although they are effective in reducing plasma viral level, cannot eradicate the viruses completely from CNS. The possible mechanism of BBB hindrance and anti-HIV drug efflux by transport proteins, and general methods used to deliver antiretroviral drugs into brain are also discussed. PMID- 26744888 TI - Diagnosis and Treatment of Posterior Sacroiliac Complex Pain: A Systematic Review with Comprehensive Analysis of the Published Data. Pain Med 2015; 16(2): 257-65. PMID- 26744887 TI - High-Frequency Repetitive Transcranial Magnetic Stimulation Reduces Pain in Postherpetic Neuralgia. AB - OBJECTIVES: Postherpetic neuralgia (PHN) is one of the most intractable pain disorders, especially in elderly patients. There is evidence that repetitive transcranial magnetic stimulation (rTMS) reduces neuropathic pain; however, its effectiveness for PHN is unknown. This study investigated the efficacy of high frequency rTMS in patients with PHN. DESIGN: A total of 40 patients were randomly assigned to receive 10 sessions of real or sham rTMS of the primary motor cortex. Each stimulation session consisted of a series of 300 five-second pulses with a frequency of 10 Hz and an interval of 3 seconds between each train, giving a total of 1500 pulses per session. The primary outcome was pain intensity measured before stimulation from first intervention (T0) to the final stimulation (T10), and 1 and 3 months after final stimulation (T11 and T12). Other outcomes measured included scores on the short form McGill pain questionnaire, self-rating depression scale, quality of life (QOL), sleep quality, the patient global impression of change, medication regulation, and reported adverse events. RESULTS: The real rTMS group demonstrated greater reduction of visual analogue scale (VAS) than the sham group at each time point except for T0 (P = 0.399) and T1 (P = 0.091). Mean VAS reduction in the real rTMS group was 16.89% for duration of disease longer than 6 months. These analgesic effects were associated with long-term improvement in rating-scale items related to QOL. CONCLUSION: The results suggest that rTMS is an effective and safe therapy in patients with PHN. PMID- 26744889 TI - Da Ma, Ji-Sheng Han, Quan-Heng Diao, Gui-Fa Deng, Xing-Jie Ping, Wei-Jie Jin, Liu Zhen Wu, Cai-Lian Cui and Xiao-Dong Li. Transcutaneous Electrical Acupoint Stimulation for the Treatment of Withdrawal Syndrome in Heroin Addicts. Pain Med 2015; 16(5): 839-848. PMID- 26744890 TI - Gill JS, Aner M, Jyotsna N, Keel JC, Simopoulos TT. Contralateral oblique view is superior to lateral view for interlaminar cervical and cervicothoracic epidural access. Pain Med 2015;16(1):68-80. PMID- 26744891 TI - Correction: Human beta-D-3 Exacerbates MDA5 but Suppresses TLR3 Responses to the Viral Molecular Pattern Mimic Polyinosinic:Polycytidylic Acid. AB - [This corrects the article DOI: 10.1371/journal.pgen.1005673.]. PMID- 26744894 TI - Correction: Insulin, Central Dopamine D2 Receptors, and Monetary Reward Discounting in Obesity. PMID- 26744893 TI - A Metabolic Study of Huntington's Disease. AB - BACKGROUND: Huntington's disease patients have a number of peripheral manifestations suggestive of metabolic and endocrine abnormalities. We, therefore, investigated a number of metabolic factors in a 24-hour study of Huntington's disease gene carriers (premanifest and moderate stage II/III) and controls. METHODS: Control (n = 15), premanifest (n = 14) and stage II/III (n = 13) participants were studied with blood sampling over a 24-hour period. A battery of clinical tests including neurological rating and function scales were performed. Visceral and subcutaneous adipose distribution was measured using magnetic resonance imaging. We quantified fasting baseline concentrations of glucose, insulin, cholesterol, triglycerides, lipoprotein (a), fatty acids, amino acids, lactate and osteokines. Leptin and ghrelin were quantified in fasting samples and after a standardised meal. We assessed glucose, insulin, growth hormone and cortisol concentrations during a prolonged oral glucose tolerance test. RESULTS: We found no highly significant differences in carbohydrate, protein or lipid metabolism markers between healthy controls, premanifest and stage II/III Huntington's disease subjects. For some markers (osteoprotegerin, tyrosine, lysine, phenylalanine and arginine) there is a suggestion (p values between 0.02 and 0.05) that levels are higher in patients with premanifest HD, but not moderate HD. However, given the large number of statistical tests performed interpretation of these findings must be cautious. CONCLUSIONS: Contrary to previous studies that showed altered levels of metabolic markers in patients with Huntington's disease, our study did not demonstrate convincing evidence of abnormalities in any of the markers examined. Our analyses were restricted to Huntington's disease patients not taking neuroleptics, anti depressants or other medication affecting metabolic pathways. Even with the modest sample sizes studied, the lack of highly significant results, despite many being tested, suggests that the majority of these markers do not differ markedly by disease status. PMID- 26744892 TI - Exploring the Role of Killer Cell Immunoglobulin-Like Receptors and Their HLA Class I Ligands in Autoimmune Hepatitis. AB - BACKGROUND: Natural killer cells are involved in the complex mechanisms underlying autoimmune diseases but few studies have investigated their role in autoimmune hepatitis. Killer immunoglobulin-like receptors are key regulators of natural killer cell-mediated immune responses. METHODS AND FINDINGS: KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 114 patients diagnosed with type 1 autoimmune hepatitis and compared with a group of 221 healthy controls. HLA Class I and Class II antigen frequencies were compared to those of 551 healthy unrelated families representative of the Sardinian population. In our cohort, type 1 autoimmune hepatitis was strongly associated with the HLA-B18, Cw5, DR3 haplotype. The KIR2DS1 activating KIR gene and the high affinity HLA-C2 ligands were significantly higher in patients compared to controls. Patients also had a reduced frequency of HLA-Bw4 ligands for KIR3DL1 and HLA-C1 ligands for KIR2DL3. Age at onset was significantly associated with the KIR2DS1 activating gene but not with HLA-C1 or HLA-C2 ligand groups. CONCLUSIONS: The activating KIR gene KIR2DS1 resulted to have an important predictive potential for early onset of type 1 autoimmune hepatitis. Additionally, the low frequency of the KIR-ligand combinations KIR3DL1/HLA-Bw4 and KIR2DL3/HLA-C1 coupled to the high frequency of the HLA-C2 high affinity ligands for KIR2DS1 could contribute to unwanted NK cell autoreactivity in AIH-1. PMID- 26744896 TI - Patient-reported outcomes of parenteral somatostatin analogue injections in 195 patients with acromegaly. AB - BACKGROUND: Long-acting somatostatin analogues delivered parenterally are the most widely used medical treatment in acromegaly. This patient-reported outcomes survey was designed to assess the impact of chronic injections on subjects with acromegaly. METHODS: The survey was conducted in nine pituitary centres in Germany, UK and The Netherlands. The questionnaire was developed by endocrinologists and covered aspects of acromegaly symptoms, injection-related manifestations, emotional and daily life impact, treatment satisfaction and unmet medical needs. RESULTS: In total, 195 patients participated, of which 112 (57%) were on octreotide (Sandostatin LAR) and 83 (43%) on lanreotide (Somatuline Depot). The majority (>70%) of patients reported acromegaly symptoms despite treatment. A total of 52% of patients reported that their symptoms worsen towards the end of the dosing interval. Administration site pain lasting up to a week following injection was the most frequently reported injection-related symptom (70% of patients). Other injection site reactions included nodules (38%), swelling (28%), bruising (16%), scar tissue (8%) and inflammation (7%). Injection burden was similar between octreotide and lanreotide. Only a minority of patients received injections at home (17%) and 5% were self-injecting. Over a third of patients indicated a feeling of loss of independence due to the injections, and 16% reported repeated work loss days. Despite the physical, emotional and daily life impact of injections, patients were satisfied with their treatment, yet reported that modifications that would offer major improvement over current care would be 'avoiding injections' and 'better symptom control'. CONCLUSION: Lifelong injections of long-acting somatostatin analogues have significant burden on the functioning, well-being and daily lives of patients with acromegaly. PMID- 26744897 TI - Net shape fabrication of calcium phosphate scaffolds with multiple material domains. AB - Calcium phosphate (CaP) materials have been proven to be efficacious as bone scaffold materials, but are difficult to fabricate into complex architectures because of the high processing temperatures required. In contrast, polymeric materials are easily formed into scaffolds with near-net-shape forms of patient specific defects and with domains of different materials; however, they have reduced load-bearing capacity compared to CaPs. To preserve the merits of CaP scaffolds and enable advanced scaffold manufacturing, this manuscript describes an additive manufacturing process that is coupled with a mold support for overhanging features; we demonstrate that this process enables the fabrication of CaP scaffolds that have both complex, near-net-shape contours and distinct domains with different microstructures. First, we use a set of canonical structures to study the manufacture of complex contours and distinct regions of different material domains within a mold. We then apply these capabilities to the fabrication of a scaffold that is designed for a 5 cm orbital socket defect. This scaffold has complex external contours, interconnected porosity on the order of 300 MUm throughout, and two distinct domains of different material microstructures. PMID- 26744898 TI - BWM*: A Novel, Provable, Ensemble-based Dynamic Programming Algorithm for Sparse Approximations of Computational Protein Design. AB - Sparse energy functions that ignore long range interactions between residue pairs are frequently used by protein design algorithms to reduce computational cost. Current dynamic programming algorithms that fully exploit the optimal substructure produced by these energy functions only compute the GMEC. This disproportionately favors the sequence of a single, static conformation and overlooks better binding sequences with multiple low-energy conformations. Provable, ensemble-based algorithms such as A* avoid this problem, but A* cannot guarantee better performance than exhaustive enumeration. We propose a novel, provable, dynamic programming algorithm called Branch-Width Minimization* (BWM*) to enumerate a gap-free ensemble of conformations in order of increasing energy. Given a branch-decomposition of branch-width w for an n-residue protein design with at most q discrete side-chain conformations per residue, BWM* returns the sparse GMEC in O([Formula: see text]) time and enumerates each additional conformation in merely O([Formula: see text]) time. We define a new measure, Total Effective Search Space (TESS), which can be computed efficiently a priori before BWM* or A* is run. We ran BWM* on 67 protein design problems and found that TESS discriminated between BWM*-efficient and A*-efficient cases with 100% accuracy. As predicted by TESS and validated experimentally, BWM* outperforms A* in 73% of the cases and computes the full ensemble or a close approximation faster than A*, enumerating each additional conformation in milliseconds. Unlike A*, the performance of BWM* can be predicted in polynomial time before running the algorithm, which gives protein designers the power to choose the most efficient algorithm for their particular design problem. PMID- 26744899 TI - A Hierarchical Self-Assembly System Built Up from Preorganized Tripodal Helical Metal Complexes. AB - The hierarchical organization strategy has realized elaborate supramolecular structures that are difficult to achieve by a one-pot thermodynamically driven self-assembly. Self-assembly via Schiff base formation of the preorganized tripodal helical unit 2(2+), which is composed of the tris(bipyridyl) ligand 1 and octahedral metal ion (Ru(II) and Fe(II)), lead to two supramolecular structures, i.e., a macrobicyclic dimer and an interlocked helicate. Notably, the interlocked helicate had a unique motif with an elongated shape (~ 58 A) and linearly aligned metal centers with homochiral configurations (all-Delta or all Lambda), which shows potential for allosteric regulation based on the long-range transmittance of the structural information. PMID- 26744900 TI - Synthesis and evaluation of sulfonamide-bearing thiazole as carbonic anhydrase isoforms hCA I and hCA II. AB - Sulfonamide-bearing thiazole compounds were synthesized and their inhibitory effects on the activity of purified human carbonic anhydrase I and II were evaluated. Human carbonic anhydrase isoenzymes (hCA-I and hCA-II) were purified from erythrocyte cells by affinity chromatography. The inhibitory effects of the 12 synthesized sulfonamide (5a-l) on the hydratase and esterase activities of these isoenzymes (hCA-I and hCA-II) were studied in vitro. In relation to these activities, the inhibition equilibrium constants (Ki) were determined. The results showed that all the synthesized compounds inhibited the CA isoenzyme activity. Among them 5b was found to be the most active (IC50 = 0.35 MUM; Ki: 0.33 MUM) for hCA I and hCA II. PMID- 26744895 TI - X-chromosome gene dosage as a determinant of impaired pre and postnatal growth and adult height in Turner syndrome. AB - OBJECTIVE: Short stature is a key aspect of the phenotype of patients with Turner syndrome (TS). SHOX haploinsufficiency is responsible for about two-thirds of the height deficit. The aim was to investigate the effect of X-chromosome gene dosage on anthropometric parameters at birth, spontaneous height, and adult height (AH) after growth hormone (GH) treatment. DESIGN: We conducted a national observational multicenter study. METHODS: Birth parameter SDS for gestational age, height, and AH before and after GH treatment respectively, and height deficit with respect to target height (SDS) were classified by karyotype subgroup in a cohort of 1501 patients with TS: 45,X (36%), isoXq (19%), 45,X/46,XX (15%), XrX (7%), presence of Y (6%), or other karyotypes (17%). RESULTS: Birth weight, length (P<0.0001), and head circumference (P<0.001), height and height deficit with respect to target height (SDS) before GH treatment, at a median age of 8.8 (5.3-11.8) years and after adjustment for age and correction for multiple testing (P<0.0001), and AH deficit with respect to target height at a median age of 19.3 (18.0-21.8) years and with additional adjustment for dose and duration of GH treatment (P=0.006), were significantly associated with karyotype subgroup. Growth retardation tended to be more severe in patients with XrX, isoXq, and, to a lesser extent, 45,X karyotypes than in patients with 45,X/46,XX karyotypes or a Y chromosome. CONCLUSION: These data suggest that haploinsufficiency for an unknown Xp gene increases the risk of fetal and postnatal growth deficit and short AH with respect to target height after GH therapy. PMID- 26744901 TI - Evaluating gaze-driven power wheelchair with navigation support for persons with disabilities. AB - This article describes a novel add-on for powered wheelchairs that is composed of a gaze-driven control system and a navigation support system. The add-on was tested by three users. All of the users were individuals with severe disabilities and no possibility of moving independently. The system is an add-on to a standard power wheelchair and can be customized for different levels of support according to the cognitive level, motor control, perceptual skills, and specific needs of the user. The primary aim of this study was to test the functionality and safety of the system in the user's home environment. The secondary aim was to evaluate whether access to a gaze-driven powered wheelchair with navigation support is perceived as meaningful in terms of independence and participation. The results show that the system has the potential to provide safe, independent indoor mobility and that the users perceive doing so as fun, meaningful, and a way to reduce dependency on others. Independent mobility has numerous benefits in addition to psychological and emotional well-being. By observing users' actions, caregivers and healthcare professionals can assess the individual's capabilities, which was not previously possible. Rehabilitation can be better adapted to the individual's specific needs, and driving a wheelchair independently can be a valuable, motivating training tool. PMID- 26744902 TI - Formation of Hexacoordinate Mn(III) in Bacillus subtilis Oxalate Decarboxylase Requires Catalytic Turnover. AB - Oxalate decarboxylase (OxDC) catalyzes the disproportionation of oxalic acid monoanion into CO2 and formate. The enzyme has long been hypothesized to utilize dioxygen to form mononuclear Mn(III) or Mn(IV) in the catalytic site during turnover. Recombinant OxDC, however, contains only tightly bound Mn(II), and direct spectroscopic detection of the metal in higher oxidation states under optimal catalytic conditions (pH 4.2) has not yet been reported. Using parallel mode electron paramagnetic resonance spectroscopy, we now show that substantial amounts of Mn(III) are indeed formed in OxDC, but only in the presence of oxalate and dioxygen under acidic conditions. These observations provide the first direct support for proposals in which Mn(III) removes an electron from the substrate to yield a radical intermediate in which the barrier to C-C bond cleavage is significantly decreased. Thus, OxDC joins a small list of enzymes capable of stabilizing and controlling the reactivity of the powerful oxidizing species Mn(III). PMID- 26744904 TI - Tuning the Microcavity of Organic Light Emitting Diodes by Solution Processable Polymer-Nanoparticle Composite Layers. AB - In this study, we present a simple method to tune and take advantage of microcavity effects for an increased fraction of outcoupled light in solution processed organic light emitting diodes. This is achieved by incorporating nonscattering polymer-nanoparticle composite layers. These tunable layers allow the optimization of the device architecture even for high film thicknesses on a single substrate by gradually altering the film thickness using a horizontal dipping technique. Moreover, it is shown that the optoelectronic device parameters are in good agreement with transfer matrix simulations of the corresponding layer stack, which offers the possibility to numerically design devices based on such composite layers. Lastly, it could be shown that the introduction of nanoparticles leads to an improved charge injection, which combined with an optimized microcavity resulted in a maximum luminous efficacy increase of 85% compared to a nanoparticle-free reference device. PMID- 26744903 TI - Autophagy deficiency in beta cells blunts incretin-induced suppression of glucagon release from alpha cells. AB - Incretin-based therapy such as GLP-1 receptor agonists and DPP-4 inhibitors for type 2 diabetes mellitus is characterized by glucose-dependent insulin secretion and glucose-inhibited glucagon secretion. Recently, autophagy deficiency in islet beta cells has been shown to contribute to the pathogenesis of type 2 diabetes mellitus however, with the role of incretin has not been established. To evaluate the role of autophagy in incretin effects, 8-week-old male beta cell-specific Atg7 knockout (Atg7(Deltabeta cell)) mice and wild-type mice were administered vildagliptin for 12 weeks. Vildagliptin treatment improved glucose intolerance and hypoinsulinemia; however, it failed to suppress serum glucagon levels after glucose loading in the Atg7(Deltabeta cell) mice. Ex vivo glucose-induced glucagon suppression was also blunted in the islets from vildagliptin-treated Atg7(Deltabeta cell) mice. The alpha cell mass was not affected by beta cell autophagy deficiency or vildagliptin. However, glucagon mRNA expression was significantly increased by vildagliptin in the autophagy-deficient islets, and was significantly reduced by vildagliptin in wild-type islets. Pancreatic glucagon contents were not in agreement with the changes in mRNA expression, suggesting a dysregulation in glucagon translation and secretion. In vitro studies revealed that glucose-stimulated cAMP production was impaired in the autophagy-deficient islets exposed to exendin-4. Taken together, the results suggest that the constitutive autophagy in beta cells could regulate incretin induced glucagon expression and release in alpha cells, and that cAMP may play a role in this process. PMID- 26744905 TI - Review of recent research on biomedical applications of electrospun polymer nanofibers for improved wound healing. AB - Wound dressings play an important role in a patient's recovery from health problems, as unattended wounds could lead to serious complications such as infections or, ultimately, even death. Therefore, wound dressings since ancient times have been continuously developed, starting from simple dressings from natural materials for covering wounds to modern dressings with functionalized materials to aid in the wound healing process and enhance tissue repair. However, understanding the nature of a wound and the subsequent healing process is vital information upon which dressings can be tailored to ensure a patient's recovery. To date, much progress has been made through the use of nanomedicine in wound healing due to the ability of such materials to mimic the natural dimensions of tissue. This review provides an overview of recent studies on the physiology of wound healing and various wound dressing materials made of nanofibers fabricated using the electrospinning technique. PMID- 26744907 TI - 1-[4-Fluoro-2-(2-nitrovinyl)phenyl]pyrrolidine Suppresses Toll-Like Receptor 4 Dimerization Induced by Lipopolysaccharide. AB - Toll-like receptor 4 (TLR4) recognizes LPS and triggers the activation of the myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain containing adapter, inducing interferon-beta (TRIF)-dependent major downstream signaling pathways. Previously, we presented biochemical evidence that 1-[4 Fluoro-2-(2-nitrovinyl)phenyl]pyrrolidine (FPP), which was synthesized in our laboratory, inhibits NF-kappaB activation induced by LPS. Here, we investigated whether FPP modulates the TLR4 downstream signaling pathways and what anti inflammatory target in TLR4 signaling is regulated by FPP. FPP inhibited LPS induced NF-kappaB activation by targeting TLR4 dimerization. These results suggest that FPP can modulate the TLR4 signaling pathway at the receptor level to decrease inflammatory gene expression. PMID- 26744906 TI - Impulsive Aggression as a Comorbidity of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. AB - OBJECTIVE: This article examines the characteristics of impulsive aggression (IA) as a comorbidity in children and adolescents with attention-deficit/hyperactivity disorder (ADHD), focusing on its incidence, impact on ADHD outcomes, need for timely intervention, and limitations of current treatment practices. METHODS: Relevant literature was retrieved with electronic searches in PubMed and PsycINFO using the search strategy of "ADHD OR attention deficit hyperactivity disorder" AND "impulsive aggression OR reactive aggression OR hostile aggression OR overt aggression" AND "pediatric OR childhood OR children OR pre-adolescent OR adolescent" with separate searches using review OR clinical trial as search limits. Key articles published before the 2007 Expert Consensus Report on IA were identified using citation analysis. RESULTS: More than 50% of preadolescents with ADHD combined subtype reportedly display clinically significant aggression, with impulsive aggression being the predominant subtype. Impulsive aggression is strongly predictive of a highly unfavorable developmental trajectory characterized by the potential for persistent ADHD, increasing psychosocial burden, accumulating comorbidities, serious lifelong functional deficits across a broad range of domains, delinquency/criminality, and adult antisocial behavior. Impulsive aggression, which triggers peer rejection and a vicious cycle of escalating dysfunction, may be a key factor in unfavorable psychosocial outcomes attributed to ADHD. Because severe aggressive behavior does not remit in many children when treated with primary ADHD therapy (i.e., stimulants and behavioral therapy), a common practice is to add medication of a different class to specifically target aggressive behavior. CONCLUSIONS: Impulsive aggression in children and adolescents with ADHD is a serious clinical and public health problem. Although adjunctive therapy with an aggression-targeted agent is widely recommended when aggressive behaviors do not remit with primary ADHD therapy, empirical evidence does not currently support the use of any specific agent. Randomized controlled trials are needed to identify aggression-targeted agents with favorable benefit-risk profiles. PMID- 26744908 TI - Two new menthane monoterpenes from Illicium wardii. AB - Two new menthane monoterpenes, wardicines A (1) and B (2), were isolated from the fruits of Illicium wardii A.C. Smith. Their structures were determined on the basis of spectroscopic data analysis. Cytotoxicities of compounds 1 and 2 against three human tumor cell lines A549, HCT-116, and CCRF-CEM were also evaluated, but no significant activities were observed for the two compounds. PMID- 26744910 TI - Influences of teriparatide administration on marrow fat content in postmenopausal osteopenic women using MR spectroscopy. AB - Objective Teriparatide could induce osteoblast differentiation of mesenchymal stem cells while inhibiting adipocyte differentiation. However, there are significant differences between ex vivo and in vivo models. We aimed to evaluate the impact of teriparatide on marrow and abdominal fat accumulation in postmenopausal osteopenic women. Methods Postmenopausal osteopenic women were randomly assigned to receive teriparatide or placebo for 12 months. Subcutaneous (SAT) and visceral adipose tissue (VAT), marrow fat fraction (MFF), bone density (BMD) and bone biomarkers were measured at baseline, 6 and 12 months. Results At 12 months, mean percentage changes in BMD from baseline were 3.51%, 2.21% and 1.80% at lumbar spine, total hip and femoral neck for the teriparatide group, respectively. Relative to baseline conditions, teriparatide reduced MFF (-3.54% at 6 months; -5.87% at 12 months, all p < 0.01). A significant difference in MFF, but not BMD, was first detected at 6 months (p = 0.012) between groups. MFF was negatively associated with SAT (r = -0.479) and positively associated with VAT (r = 0.531) and VAT/SAT (r = 0.415, all p < 0.05). Teriparatide treatment did not alter abdominal fat composition. Conclusion Teriparatide effectively lowers marrow adiposity but not abdominal fat accumulation in postmenopausal osteopenic women. PMID- 26744909 TI - In vitro formation of neuroclusters in microfluidic devices and cell migration as a function of stromal-derived growth factor 1 gradients. AB - Central nervous system (CNS) cells cultured in vitro as neuroclusters are useful models of tissue regeneration and disease progression. However, the role of cluster formation and collective migration of these neuroclusters to external stimuli has been largely unstudied in vitro. Here, 3 distinct CNS cell types, medulloblastoma (MB), medulloblastoma-derived glial progenitor cells (MGPC), and retinal progenitor cells (RPC), were examined with respect to cluster formation and migration in response to Stromal-Derived Growth Factor (SDF-1). A microfluidic platform was used to distinguish collective migration of neuroclusters from that of individual cells in response to controlled concentration profiles of SDF-1. Cell lines were also compared with respect to expression of CXCR4, the receptor for SDF-1, and the gap junction protein Connexin 43 (Cx43). All cell types spontaneously formed clusters and expressed both CXCR4 and Cx43. RPC clusters exhibited collective chemotactic migration (i.e. movement as clusters) along SDF-1 concentration gradients. MGPCs clusters did not exhibit adhesion-based migration, and migration of MB clusters was inconsistent. This study demonstrates how controlled microenvironments can be used to examine the formation and collective migration of CNS-derived neuroclusters in varied cell populations. PMID- 26744913 TI - Experimental Clocking of Nanomagnets with Strain for Ultralow Power Boolean Logic. AB - Nanomagnetic implementations of Boolean logic have attracted attention because of their nonvolatility and the potential for unprecedented overall energy efficiency. Unfortunately, the large dissipative losses that occur when nanomagnets are switched with a magnetic field or spin-transfer-torque severely compromise the energy-efficiency. Recently, there have been experimental reports of utilizing the Spin Hall effect for switching magnets, and theoretical proposals for strain induced switching of single-domain magnetostrictive nanomagnets, that might reduce the dissipative losses significantly. Here, we experimentally demonstrate, for the first time that strain-induced switching of single-domain magnetostrictive nanomagnets of lateral dimensions ~200 nm fabricated on a piezoelectric substrate can implement a nanomagnetic Boolean NOT gate and steer bit information unidirectionally in dipole-coupled nanomagnet chains. On the basis of the experimental results with bulk PMN-PT substrates, we estimate that the energy dissipation for logic operations in a reasonably scaled system using thin films will be a mere ~1 aJ/bit. PMID- 26744912 TI - Determinants of labour migration of elite sport coaches. AB - Previous research examining labour migration in sport focused on athletes in professional team sports. The purpose of this study is to analyse the factors influencing the migration probability of elite sport coaches in Germany (i.e. national coaches, state coaches, and coaches at Olympic training bases). From a theoretical perspective, labour migration of athletes is affected by economic, social, political, competitive, geographic and cultural factors. This study examines whether these factors can be applied to coaches. Primary data were collected using an online survey of elite sport coaches in Germany. Applying a conjoint design, respondents were presented with 10 migration scenarios leading to a sample size of n = 1860 for the empirical analysis. In the scenarios, the coaching position openings abroad differed in terms of income level, contract length, weekly workload, responsibility for personnel, reputation of coaching job, career perspectives, sporting performance of athletes, distance from Germany, and predominant job language. Coaches were asked for their migration probability contingent on the specific scenario. On average, migration probability was 24.2%. The results of regression analysis showed that higher income, contracts of longer duration, responsibility for personnel and speaking the respective language significantly increased the migration probability, while distances of nine flight hours and more, lower reputation and career perspectives reduced it. The findings have implications for policy-makers: they indicate in what areas the situation of coaches needs improvement to increase the likelihood of retaining elite sport coaches in the German sport system. PMID- 26744915 TI - Patterns of Crime in a Birth Cohort. AB - Most attempts at developing typologies of criminal behavior have not involved empirical research. This paper describes an exploratory empirical approach to identifying patterns in criminal behavior. Two data-reduction techniques, factor analysis and cluster analysis, are applied to the official arrest records of a Danish birth cohort of 28,879 men. Four factors emerged from the factor analysis: GENERAL CRIME, TRAFFIC OFFENSES, WHITE-COLLAR CRIME, and SEX OFFENSES. The cluster analysis revealed GENERAL CRIME and TRAFFIC OFFENSES clusters. A substantial number of offenses are shown by both analyses to be independent of any pattern. The results show good split-sample cross-validation and for the most part are robust across the two analytic approaches. PMID- 26744916 TI - Robust Multivariate Analysis for the Comparison of Several Samples. AB - We consider the problem of comparing samples drawn from several subpopulations when the data are multivariate. The method proposed is based on examining distances of all observations from the estimated locations of each sample. The distances examined are extensions of the Mahalanobis distance, where the classical means and covariances are replaced by robust estimates. The analysis of the distances is done by informal graphical methods. The method is illustrated by an example in which three groups of patients are compared with respect to thirteen variables measuring nerve conduction. PMID- 26744917 TI - Assessment of the Multitrait-Multimethod Matrix Validity of Likert Scales Via Confirmatory Factor Analysis. AB - Two samples of adults were administered nine attitude scales: three constructs (attitudes toward discipline of children, mathematics, and the law) each measured by three methods (Likert, Thurstone and Semantic Differential techniques). For one sample a dichotomous Likert response format was used, in the other a nine point Likert continuum. Each of the two resulting 9 x 9 MTMM matrices was assessed for evidence of validity using confirmatory factor analysis, supplemented by an estimation of variance components analysis, and the results compared across matrices. The results showed that the three methods converged across the three constructs but that there was an interaction effect such that it did make a difference which method was chosen to measure any particular construct. There was more shared variance among variables in the matrix where the nine-point Likert scales had been used. The results indicated (a) greater validity of Likert scales with the use of a larger number of scale steps, in the sense that total scores more highly estimated the construct underlying the item set, and (b) the value of conceptualizing "types" of measurement techniques which are nevertheless not interchangeable in any particular context. PMID- 26744914 TI - A unique mosaic Turner syndrome patient with androgen receptor gene derived marker chromosome. AB - Patients with Turner syndrome are generally characterized by having short stature with no secondary sexual characteristics. Some abnormalities, such as webbed neck, renal malformations (>50%) and cardiac defects (10%) are less common. The intelligence of these patients is considered normal. Non-mosaic monosomy X is observed in approximately 45% of postnatal patients with Turner syndrome and the rest of the patients have structural abnormalities or mosaicism involving 46,X,i(Xq), 45,X/46,XX, 45,X and other variants. The phenotype of 45,X/46,X,+mar individuals varies by the genetic continent and degree of the mosaicism. The gene content of the marker chromosome is the most important when correlating the phenotype with the genotype. Here we present an 11-year-old female who was referred for evaluation of her short stature and learning disabilities. Conventional cytogenetic investigation showed a mosaic 45,X/46,X,+mar karyotype. Fluorescence in situ hybridization showed that the marker chromosome originated from the X chromosome within the androgen receptor (AR) and X-inactive specific transcript (XIST) genes. Therefore, it is possible that aberrant activation of the marker chromosome, compromising the AR and XIST genes, may modify the Turner syndrome phenotype. PMID- 26744918 TI - A Comparison of Cluster Analysis Techniques Withing a Sequential Validation Framework. AB - This study involved the comparison of 23 different methods of cluster analysis in a four-stage sequential validation design. These stages included derivation, replication, external validation, and cross-validation. Data were obtained from 750 alcohol abusers on a number of socio-behavioral variables. Results demonstrated that the solution given by Ward's method of cluster analysis was particularly powerful in comparison to solutions yielded by other techniques. PMID- 26744919 TI - A Fast and Simple computational Method of Minimum Residual Factor Analysis. AB - Some new procedures for minimum residual factor analysis are presented. First a successive method developed by Comrey is modified in order to guarantee convergence and to provide a way to handle Heywood cases. Next, this modified Comrey procedure is extended to a simultaneous procedure which is computationally simpler and faster than the Minres method developed by Harman and Jones. This latter method, however, satisfies a stronger necessary condition for the minimum of the sum of squared off-diagonal residuals. Some empirical results are presented. These are in accordance with the theoretical considerations; that is, the Harman and Jones procedure tends to be slower, but attains in general a lower value for the sum of squared off-diagonal residuals. PMID- 26744920 TI - Green Synthesis of Porous Three-Dimensional Nitrogen-Doped Graphene Foam for Electrochemical Applications. AB - A facile and green approach was developed for the production of porous three dimensional (3D) nitrogen-doped graphene with a foam structure. In comparison with conventional methods, this green approach uses environmental precursors in the preparation of graphene products. The resulting crystalline graphene foam product exhibited a uniform structure with large surface area. These appealing features render the prepared graphene foam product a prospective backbone for producing 3D charge-transport networks. The 3D graphene foam products were employed as the skeleton with an interconnected network for lithium-ion batteries. The lithium-ion batteries with the 3D porous foam structure exhibit superior cycling stability and good rate capability. There is no capacity loss after 800 cycles because the capacity stabilized for the first few cycles, and the lithium-ion batteries with 3D graphene foam showed a discharge capacity of 180 mA h g(-1) at a current density of 1000 mA g(-1). This superior cycling stability and good rate capability was ascribed to the 3D structure with an interconnected porous network and the nitrogen-doping strategy for improved conductive properties of graphene foam, which produces an efficient 3D charge transport network. The configuration of this 3D transport network in lithium-ion cells not only can improve the electron-transport efficiency but also can suppress the volume effect during charge/discharge cycling. Besides, nitrogen doping could enhance the formation of chemical bonding between carbon and the nearby nitrogen atoms, which could accelerate the diffusion of lithium ions through the whole graphene network. PMID- 26744921 TI - Stream Nitrogen Inputs Reflect Groundwater Across a Snowmelt-Dominated Montane to Urban Watershed. AB - Snowmelt dominates the hydrograph of many temperate montane streams, yet little work has characterized how streamwater sources and nitrogen (N) dynamics vary across wildland to urban land use gradients in these watersheds. Across a third order catchment in Salt Lake City, Utah, we asked where and when groundwater vs shallow surface water inputs controlled stream discharge and N dynamics. Stream water isotopes (delta(2)H and delta(18)O) reflected a consistent snowmelt water source during baseflow. Near-chemostatic relationships between conservative ions and discharge implied that groundwater dominated discharge year-round across the montane and urban sites, challenging the conceptual emphasis on direct stormwater inputs to urban streams. Stream and groundwater NO3(-) concentrations remained consistently low during snowmelt and baseflow in most montane and urban stream reaches, indicating effective subsurface N retention or denitrification and minimal impact of fertilizer or deposition N sources. Rather, NO3(-) concentrations increased 50-fold following urban groundwater inputs, showing that subsurface flow paths potentially impact nutrient loading more than surficial land use. Isotopic composition of H2O and NO3(-) suggested that snowmelt-derived urban groundwater intercepted NO3(-) from leaking sewers. Sewer maintenance could potentially mitigate hotspots of stream N inputs at mountain/valley transitions, which have been largely overlooked in semiarid urban ecosystems. PMID- 26744922 TI - Vina-Carb: Improving Glycosidic Angles during Carbohydrate Docking. AB - Molecular docking programs are primarily designed to align rigid, drug-like fragments into the binding sites of macromolecules and frequently display poor performance when applied to flexible carbohydrate molecules. A critical source of flexibility within an oligosaccharide is the glycosidic linkages. Recently, Carbohydrate Intrinsic (CHI) energy functions were reported that attempt to quantify the glycosidic torsion angle preferences. In the present work, the CHI energy functions have been incorporated into the AutoDock Vina (ADV) scoring function, subsequently termed Vina-Carb (VC). Two user-adjustable parameters have been introduced, namely, a CHI- energy weight term (chi_coeff) that affects the magnitude of the CHI-energy penalty and a CHI-cutoff term (chi_cutoff) that negates CHI-energy penalties below a specified value. A data set consisting of 101 protein-carbohydrate complexes and 29 apoprotein structures was used in the development and testing of VC, including antibodies, lectins, and carbohydrate binding modules. Accounting for the intramolecular energies of the glycosidic linkages in the oligosaccharides during docking led VC to produce acceptable structures within the top five ranked poses in 74% of the systems tested, compared to a success rate of 55% for ADV. An enzyme system was employed in order to illustrate the potential application of VC to proteins that may distort glycosidic linkages of carbohydrate ligands upon binding. VC represents a significant step toward accurately predicting the structures of protein carbohydrate complexes. Furthermore, the described approach is conceptually applicable to any class of ligands that populate well-defined conformational states. PMID- 26744923 TI - Analysis of saturated and aromatic hydrocarbons migrating from a polyolefin-based hot-melt adhesive into food. AB - Hot-melt adhesives are widely utilised to glue cardboard boxes used as food packaging material. They have to comply with the requirements of Article 3 of the European Framework Regulation for food contact materials (1935/2004). The hot melt raw materials analysed mainly consisted of paraffinic waxes, hydrocarbon resins and polyolefins. The hydrocarbon resins, functioning as tackifiers, were the predominant source of hydrocarbons of sufficient volatility to migrate into dry foods: the 18 hydrocarbon resins analysed contained 8.2-118 g kg(-1) saturated and up to 59 g kg(-1) aromatic hydrocarbons eluted from GC between n C16 and n-C24, substantially more than the paraffinic waxes and the polyolefins. These tackfier resins, especially the oligomers <= C24, have been characterised structurally by GC*GC-MS and (1)H-NMR spectroscopy. Migration into food was estimated using a simulating system with polenta as food simulant, which was verified by the analysis of a commercial risotto rice sample packed in a virgin fibre folding box sealed with a hot melt. About 0.5-1.5% of the potentially migrating substances (between n-C16 and n-C24) of a hot melt were found to be transferred into food under storage conditions, which can result in a food contamination in the order of 1 mg kg(-1) food (depending on the amount of potentially migrating substances from the hot melt, the hot melt surface, amount of food, contact time etc.). Migrates from hot melts are easily mistaken for mineral oil hydrocarbons from recycled cardboard. PMID- 26744924 TI - Access to the Pyrroloindoline Core via [3 + 2] Annulation as well as the Application in the Synthetic Approach to (+/-)-Minfiensine. AB - A [3 + 2] formal cycloaddition reaction using aza-oxyallyl cation as a synthetic synthon was developed to construct the pyrroloindololine core. With this novel method, a variety of C3-substituted indoles were readily converted into the corresponding pyrroloindoline analogues at room temperature in the mixed solvents. To further demonstrate the utility of this method, a synthetic approach to the total synthesis of (+/-)-minfiensine was developed in quite concise fashion. PMID- 26744925 TI - Leukocyte adhesion and polarization: Role of glycosylphosphatidylinositol anchored proteins. AB - Leukocyte traffic out of the blood stream is crucial for an adequate immune response. Leukocyte extravasation is critically dependent on the binding of leukocyte integrins to their endothelial counterreceptors. This interaction enables the firm adhesion of leukocytes to the luminal side of the vascular wall and allows for leukocyte polarization, crawling and diapedesis. Leukocyte adhesion, polarization and migration requires the orchestrated regulation of integrin adhesion/de-adhesion dynamics and actin cytoskeleton rearrangements. Adhesion strength depends on conformational changes of integrin molecules (affinity) as well as the number of integrin molecules engaged at adhesion sites (valency). These two processes can be independently regulated and several molecules modulate either one or both processes. Cholesterol-rich membrane domains (lipid rafts) participate in integrin regulation and play an important role in leukocyte adhesion, polarization and motility. In particular, lipid raft resident glycosyl-phosphatidyl-inositol-anchored proteins (GPI-APs) have been reported to regulate leukocyte adhesion, polarization and motility in both integrin-dependent and independent manners. Here, we present our recent discovery concerning the novel role of the GPI-AP prion protein (PrP) in the regulation of beta1 integrin-mediated monocyte adhesion, migration and shape polarization in the context of existing literature on GPI-AP-dependent regulation of integrins. PMID- 26744926 TI - Renal Blood Oxygenation Level-dependent Imaging in Longitudinal Follow-up of Donated and Remaining Kidneys. AB - Purpose To determine renal oxygenation changes associated with uninephrectomy and transplantation in both native donor kidneys and transplanted kidneys by using blood oxygenation level-dependent (BOLD) MR imaging. Materials and Methods The study protocol was approved by the local ethics committee. Thirteen healthy kidney donors and their corresponding recipients underwent kidney BOLD MR imaging with a 3-T imager. Written informed consent was obtained from each subject. BOLD MR imaging was performed in donors before uninephrectomy and in donors and recipients 8 days, 3 months, and 12 months after transplantation. R2* values, which are inversely related to tissue partial pressure of oxygen, were determined in the cortex and medulla. Longitudinal R2* changes were statistically analyzed by using repeated measures one-way analysis of variance with post hoc pair-wise comparisons. Results R2* values in the remaining kidneys significantly decreased early after uninephrectomy in both the medulla and cortex (P < .003), from 28.9 sec(-1) +/- 2.3 to 26.4 sec(-1) +/- 2.5 in the medulla and from 18.3 sec(-1) +/- 1.5 to 16.3 sec(-1) +/- 1.0 in the cortex, indicating increased oxygen content. In donors, R2* remained significantly decreased in both the medulla and cortex at 3 (P < .01) and 12 (P < .01) months. In transplanted kidneys, R2* remained stable during the first year after transplantation, with no significant change. Among donors, cortical R2* was found to be negatively correlated with estimated glomerular filtration rate (R = -0.47, P < .001). Conclusion The results suggest that BOLD MR imaging may potentially be used to monitor renal functional changes in both remaining and corresponding transplanted kidneys. ((c)) RSNA, 2016. PMID- 26744929 TI - Analysis of nanoporous membrane fouling relying on experimental observation and theoretical model for landfill leachate treatment. AB - This paper is focused on the fouling behaviour of the ultrafiltration membrane for landfill leachate treatment. Natural organic matter fouling is considered a critical factor controlling the membrane performance. In this regard, the polyethersulphone nanoporous membrane was fabricated by phase inversion. In order to investigate the effects of operating conditions on fouling, landfilled leachate treatment was done at different transmembrane pressure and feed concentration. At high concentration of landfill leachate, the effect of operating pressure can be negligible. The maximum amount of RFR was 0.961 for raw landfill leachate. Flux decline data were also obtained for the filtration of landfill leachate. The rates of flux decline drastically dropped to about 46-48% of the initial values in the first 30 minutes of the experiment at all the examined pressures. The data were also analyzed using a model in order to provide explanations for simultaneous pore blockage and cake formation. The model showed very good agreement with the data for all transmembrane pressures and feed concentrations. The initial fouling due to pore blockage is related to the feed concentration at constant pressure, so by diluting the feed concentration, the effect of pore blocking was increased. PMID- 26744928 TI - Pulmonary Imaging Biomarkers of Gas Trapping and Emphysema in COPD: (3)He MR Imaging and CT Parametric Response Maps. AB - PURPOSE: To directly compare magnetic resonance (MR) imaging and computed tomography (CT) parametric response map (PRM) measurements of gas trapping and emphysema in ex-smokers both with and without chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: Participants provided written informed consent to a protocol that was approved by a local research ethics board and Health Canada and was compliant with the HIPAA (Institutional Review Board Reg. #00000940). The prospectively planned study was performed from March 2014 to December 2014 and included 58 ex-smokers (mean age, 73 years +/- 9) with (n = 32; mean age, 74 years +/- 7) and without (n = 26; mean age, 70 years +/- 11) COPD. MR imaging (at functional residual capacity plus 1 L), CT (at full inspiration and expiration), and spirometry or plethysmography were performed during a 2-hour visit to generate ventilation defect percent (VDP), apparent diffusion coefficient (ADC), and PRM gas trapping and emphysema measurements. The relationships between pulmonary function and imaging measurements were determined with analysis of variance (ANOVA), Holm-Bonferroni corrected Pearson correlations, multivariate regression modeling, and the spatial overlap coefficient (SOC). RESULTS: VDP, ADC, and PRM gas trapping and emphysema (ANOVA, P < .001) measurements were significantly different in healthy ex-smokers than they were in ex-smokers with COPD. In all ex-smokers, VDP was correlated with PRM gas trapping (r = 0.58, P < .001) and with PRM emphysema (r = 0.68, P < .001). VDP was also significantly correlated with PRM in ex-smokers with COPD (gas trapping: r = 0.47 and P = .03; emphysema: r = 0.62 and P < .001) but not in healthy ex-smokers. In a multivariate model that predicted PRM gas trapping, the forced expiratory volume in 1 second normalized to the forced vital capacity (standardized coefficients [betaS] = -0.69, P = .001) and airway wall area percent (betaS = -0.22, P = .02) were significant predictors. PRM emphysema was predicted by the diffusing capacity for carbon monoxide (betaS = -0.29, P = .03) and VDP (betaS = 0.41, P = .001). Helium 3 ADC values were significantly elevated in PRM gas-trapping regions (P < .001). The spatial relationship for ventilation defects was significantly greater with PRM gas trapping than with PRM emphysema in patients with mild (for gas trapping, SOC = 36% +/- 28; for emphysema, SOC = 1% +/- 2; P = .001) and moderate (for gas trapping, SOC = 34% +/- 28; for emphysema, SOC = 7% +/- 15; P = .006) COPD. For severe COPD, the spatial relationship for ventilation defects with PRM emphysema (SOC = 64% +/- 30) was significantly greater than that for PRM gas trapping (SOC = 36% +/- 18; P = .01). CONCLUSION: In all ex-smokers, ADC values were significantly elevated in regions of PRM gas trapping, and VDP was quantitatively and spatially related to both PRM gas trapping and PRM emphysema. In patients with mild to moderate COPD, VDP was related to PRM gas trapping, whereas in patients with severe COPD, VDP correlated with both PRM gas trapping and PRM emphysema. PMID- 26744927 TI - TACE Treatment in Patients with Sorafenib-treated Unresectable Hepatocellular Carcinoma in Clinical Practice: Final Analysis of GIDEON. AB - PURPOSE: To evaluate transarterial chemoembolization (TACE) use prior to and concomitantly with sorafenib in patients with unresectable hepatocellular carcinoma (HCC) across different global regions. MATERIALS AND METHODS: GIDEON is an observational registry study of more than 3000 HCC patients. Patients with histologically, cytologically, or radiographically diagnosed HCC, and for whom a decision had been made to treat with sorafenib, were eligible. Patients were enrolled into the registry from 39 countries beginning in January 2009, with the last patient follow-up in April 2012. Detailed data on treatment history, treatment patterns, adverse events, and outcomes were collected. All treatment decisions were at the discretion of the treating physicians. Documented approval from local ethics committees was obtained, and all patients provided signed informed consent. Descriptive statistics, including minimum, median, and maximum, were calculated for metric data, and frequency tables for categorical data. Kaplan-Meier estimates with 95% confidence intervals were calculated for survival end points. RESULTS: A total of 3202 patients were eligible for safety analysis, of whom 2631 (82.2%) were male. Median age was 62 years (range, 15-98 years). A total of 1511 (47.2%) patients underwent TACE prior to sorafenib; 325 (10.1%) underwent TACE concomitantly. TACE prior to sorafenib was more common in Japan and Asia-Pacific compared with all other regions (362 [71.3%] and 560 [60.3%] vs 12-209 [13.3%-37.1%]). Adverse events were reported in 2732 (85.3%) patients overall, with no notable differences in the incidence of adverse events, regardless of TACE treatment history. Overall survival was 12.7 months in prior TACE patients, 9.2 months in non-prior-TACE patients, 21.6 months in concomitant TACE patients, and 9.7 months in non-concomitant-TACE patients. CONCLUSION: Global variation exists in TACE use in sorafenib-treated HCC patients. The combination of TACE with sorafenib appears to be a well-tolerated and viable therapeutic approach. PMID- 26744931 TI - Activated carbons from waste of oil-palm kernel shells, sawdust and tannery leather scraps and application to chromium(VI), phenol, and methylene blue dye adsorption. AB - Phenol, chromium, and dyes are continuously dumped into water bodies; the adsorption of these contaminants on activated carbon is a low-cost alternative for water remediation. We synthesized activated carbons from industrial waste of palm oil seed husks (kernel shells), sawdust, and tannery leather scraps. These materials were heated for 24 h at 600, 700 or 800 degrees C, activated at 900 degrees C with CO2 and characterized by proximate analysis and measurement of specific surface area (Brunauer-Emmett-Teller (BET) and Langmuir), and microporosity (t-plot). Isotherms showed micropores and mesopores in activated carbons. Palm seed activated carbon showed the highest fixed carbon content (96%), and Langmuir specific surface areas up to 1,268 m2/g, higher than those from sawdust (581 m2/g) and leather scraps (400 m2/g). The carbons were applied to adsorption of Cr(VI), phenol, and methylene blue dye from aqueous solutions. Phenol adsorption on activated carbons was 78-82 mg/g; on palm seed activated carbons, Cr(VI) adsorption at pH 7 was 0.35-0.37 mg/g, and methylene blue adsorption was 40-110 mg/g, higher than those from sawdust and leather scraps. Activated carbons from palm seed are promising materials to remove contaminants from the environment and represent an alternative application for vegetal wastes instead of dumping into landfills. PMID- 26744930 TI - Performance of hybrid subsurface constructed wetland system for piggery wastewater treatment. AB - The objective of this study was to evaluate performance of a hybrid constructed wetland (CW) built for high organic content piggery wastewater treatment in a cold region. The system consists of four vertical and one horizontal flow subsurface CWs. The wetland was built in 2009 and water quality was monitored from the outset. Average purification efficiency of this system was 95+/-5, 91+/ 7, 89+/-8, 70+/-10, 84+/-15, 90+/-6, 99+/-2, and 93+/-16% for biochemical oxygen demand (BOD5), chemical oxygen demand (COD), total carbon (TC), total nitrogen (TN), ammonium-N (NH4-N), total phosphorus (TP), total coliform (T. Coliform), and suspended solids (SS), respectively during August 2010-December 2013. Pollutant removal rate was 15+/-18 g m(-2) d(-1), 49+/-52 g m(-2) d(-1), 6+/-4 g m(-2) d(-1), 7+/-5 g m(-2) d(-1), and 1+/-1 g m(-2) d(-1) for BOD5, COD, TN, NH4 N, and TP, respectively. The removal efficiency of BOD5, COD, NH4-N, and SS improved yearly since the start of operation. With respect to removal of TN and TP, efficiency improved in the first three years but slightly declined in the fourth year. The system performed well during both warm and cold periods, but was more efficient in the warm period. The nitrate increase may be attributed to a low C/N ratio, due to limited availability of carbon required for denitrification. PMID- 26744932 TI - Industrial and agroindustrial wastes: an echotechnological approach to the production of supported photocatalysts. AB - Agroindustrial wastes (rice husk, exhausted bark acacia, and tobacco dust) and foundry sands from the iron foundry industry were employed as a support source for photocatalysts. TiCl4 was used as the titanium precursor in the preparation of the supported photocatalysts. The solids were characterized by scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX), diffuse reflectance spectroscopy over the ultraviolet range (DRS-UV), X-ray diffraction (XRD), small-angle X-ray scattering (SAXS), nitrogen adsorption-desorption at 196 degrees C and zeta potential (ZP) measurements. The systems were evaluated for the photodegradation of rhodamine B (RhB). Among the tested systems, the highest percentage of dye degradation was reached by the catalyst prepared with foundry sand supports, with values of 65% under ultraviolet and 39% under visible radiation, whereas under the same conditions, the catalyst prepared with rice husk showed the best photocatalytic performance among the samples prepared with agroindustrial wastes with values of 43% under ultraviolet and 38% under visible radiation. Strong Spearman's correlations among the photocatalytic activity, the zeta potential (zetap>0.900) and the band gap energy (zetap>0.895) were observed. Exploratory tests with tap water samples revealed that the system may be sensitive to other analytes present in these environmental samples. PMID- 26744933 TI - Enzymatic oxidation of phenolic compounds in coffee processing wastewater. AB - Peroxidases can be used in the treatment of wastewater containing phenolic compounds. The effluent from the wet processing of coffee fruits contains high content of these pollutants and although some studies propose treatments for this wastewater, none targets specifically the removal of these recalcitrant compounds. This study evaluates the potential use of different peroxidase sources in the oxidation of caffeic acid and of total phenolic compounds in coffee processing wastewater (CPW). The identification and quantification of phenolic compounds in CPW was performed and caffeic acid was found to be the major phenolic compound. Some factors, such as reaction time, pH, amount of H2O2 and enzyme were evaluated, in order to determine the optimum conditions for the enzyme performance for maximum oxidation of caffeic acid. The turnip peroxidase (TPE) proved efficient in the removal of caffeic acid, reaching an oxidation of 51.05% in just 15 minutes of reaction. However, in the bioremediation of the CPW, the horseradish peroxidase (HRP) was more efficient with 32.70%+/-0.16 of oxidation, followed by TPE with 18.25%+/-0.11. The treatment proposed in this work has potential as a complementary technology, since the efficiency of the existing process is intimately conditioned to the presence of these pollutants. PMID- 26744935 TI - Impacts of variable pH on stability and nutrient removal efficiency of aerobic granular sludge. AB - The impact of pH variation on aerobic granular sludge stability and performance was investigated. A 9-day alkaline (pH=9) and acidic (pH=6) pH shocks were imposed on mature granules with simultaneous chemical oxygen demand (COD), nitrogen and phosphorus removal. The imposed alkaline pH shock (pH 9) reduced nitrogen and phosphorus removal efficiency from 88% and 98% to 66% and 50%, respectively, with no further recovery. However, acidic pH shock (pH 6) did not have a major impact on nutrient removal and the removal efficiencies recovered to their initial values after 3 days of operation under the new pH condition. Operating the reactors under alkaline pH induced granules breakage and resulted in an increased solids concentration in the effluent and a significant decrease in the size of the bio-particles, while acidic pH did not have significant impacts on granules stability. Changes in chemical structure and composition of extracellular polymeric substances (EPS) matrix were suggested as the main factors inducing granules instability under high pH. PMID- 26744936 TI - Preliminary analysis of phosphorus flow in Hue Citadel. AB - Characteristics of waste and wastewater management can affect material flows. Our research investigates the management of waste and wastewater in urban areas of developing countries and its effects on phosphorus flow based on a case study in Hue Citadel, Hue, Vietnam. One hundred households were interviewed to gain insight into domestic waste and wastewater management together with secondary data collection. Next, a phosphorus flow model was developed to quantify the phosphorus input and output in the area. The results showed that almost all wastewater generated in Hue Citadel was eventually discharged into water bodies and to the ground/groundwater. This led to most of the phosphorus output flowing into water bodies (41.2 kg P/(ha year)) and ground/groundwater (25.3 kg P/(ha year)). Sewage from the sewer system was the largest source of phosphorus loading into water bodies, while effluent from on-site sanitation systems was responsible for a major portion of phosphorus into the ground/groundwater. This elevated phosphorus loading is a serious issue in considering surface water and groundwater protection. PMID- 26744934 TI - Sorption and biodegradation characteristics of the selected pharmaceuticals and personal care products onto tropical soil. AB - In the present study, the sorption and biodegradation characteristics of five pharmaceutical and personal care products (PPCPs), including acetaminophen (ACT), carbamazepine (CBZ), crotamiton (CTMT), diethyltoluamide (DEET) and salicylic acid (SA), were studied in laboratory-batch experiments. Sorption kinetics experimental data showed that sorption systems under this study were more appropriately described by the pseudo second-order kinetics with a correlation coefficient (R2)>0.98. Sorption equilibrium data of almost all target compounds onto soil could be better described by the Freundlich sorption isotherm model. The adsorption results showed higher soil affinity for SA, following by ACT. Results also indicated a slight effect of pH on PPCP adsorption with lower pH causing lower adsorption of compounds onto the soil except for SA at pH 12. Moreover, adsorption of PPCPs onto the soil was influenced by natural organic matter (NOM) since the higher amount of NOM caused lower adsorption to the soil. Biodegradation studies of selected PPCPs by indigenous microbial community present in soil appeared that the removal rates of ACT, SA and DEET increased with time while no effect had been observed for the rest. This study suggests that the CBZ and CTMT can be considered as suitable chemical sewage indicators based on their low sorption affinity and high resistance to biodegradation. PMID- 26744937 TI - Can water sensitive urban design systems help to preserve natural channel-forming flow regimes in an urbanised catchment? AB - Increased stormwater runoff and pollutant loads due to catchment urbanisation bring inevitable impacts on the physical and ecological conditions of environmentally sensitive urban streams. Water sensitive urban design (WSUD) has been recognised as a possible means to minimise these negative impacts. This paper reports on a study that investigated the ability of infiltration-based WSUD systems to replicate the predevelopment channel-forming flow (CFF) regime in urban catchments. Catchment models were developed for the 'pre-urban', 'urban' and 'managed' conditions of a case study catchment and the hydrological effect on CFF regime was investigated using a number of flow indices. The results clearly show that changes to flow regime are apparent under urban catchment conditions and are even more severe under highly urbanised conditions. The use of WSUD systems was found to result in the replication of predevelopment flow regimes, particularly at low levels of urbanisation. Under highly urbanised conditions (of managed catchments) overcontrol of the CFF indices was observed as indicated by flow statistics below their pre-urban values. The overall results suggest that WSUD systems are highly effective in replicating the predevelopment CFF regime in urban streams and could be used as a means to protect environmentally sensitive urban streams. PMID- 26744939 TI - Effects of CeO2 nanoparticles on system performance and bacterial community dynamics in a sequencing batch reactor. AB - The effects of CeO2 nanoparticles (NPs) on the system performance and the bacterial community dynamics in a sequencing batch reactor (SBR) were investigated, along with the fate and removal of CeO2 NPs within the SBR. Significant impact was observed on nitrification; NH4+-N removal efficiency decreased from almost 100% to around 70% after 6 days of continuous exposure to 1.0 mg/L of CeO2 NPs, followed by a gradual recovery until a stable value of around 90% after 20 days. Additionally, CeO2 NPs also led to a significant increase in the protein content in the soluble microbial products, showing the disruptive effects of CeO2 NPs on the extracellular polymeric substance matrix and related activated sludge structure. Denaturing gradient gel electrophoresis analysis showed remarkable changes in the bacterial community structure in the activated sludge after exposure to CeO2 NPs. CeO2 NPs were effectively removed in the SBR mainly via sorption onto the sludge. However, the removal efficiency decreased from 95 to 80% over 30 days. Mass balance evaluation showed that up to 50% of the NPs were accumulated within the activated sludge and were removed with the waste sludge. PMID- 26744938 TI - Degradation of Amaranth azo dye in water by heterogeneous photo-Fenton process using FeWO4 catalyst prepared by microwave irradiation. AB - FeWO4 particles were synthesized by a simple, rapid and facile microwave technique and their catalytic properties in heterogeneous photo-Fenton reaction were evaluated. This material was employed in the degradation of Amaranth azo dye. Individual and interactive effects of operational parameters such as pH, dye concentration and H2O2 dosage on the decolorization efficiency of Amaranth dye were evaluated by 2(3) central composite design. According to characterization techniques, a porous material and a well-crystallized phase of FeWO4 oxide were obtained. Regarding the photo-Fenton reaction assays, up to 97% color and 58% organic carbon removal were achieved in the best experimental conditions. In addition, the photo-Fenton process maintained treatment efficiency over five catalyst reuse cycles to indicate the durability of the FeWO4 catalyst. In summary, the results reveal that the synthesized FeWO4 material is a promising catalyst for wastewater treatment by heterogeneous photo-Fenton process. PMID- 26744940 TI - Optimization of leachate treatment using persulfate/H2O2 based advanced oxidation process: case study: Deir El-Balah Landfill Site, Gaza Strip, Palestine. AB - The objective of this study was to investigate the performance of employing H2O2 reagent in persulfate activation to treat stabilized landfill leachate. A central composite design (CCD) with response surface methodology (RSM) was applied to evaluate the relationships between operating variables, such as persulfate and H2O2 dosages, pH, and reaction time, to identify the optimum operating conditions. Quadratic models for the following two responses proved to be significant with very low probabilities (<0.0001): chemical oxygen demand (COD) and NH3-N removal. The obtained optimum conditions included a reaction time of 116 min, 4.97 g S2O8(2-), 7.29 g H2O2 dosage and pH 11. The experimental results were corresponding well with predicted models (COD and NH3-N removal rates of 81% and 83%, respectively). The results obtained in the stabilized leachate treatment were compared with those from other treatment processes, such as persulfate only and H2O2 only, to evaluate its effectiveness. The combined method (i.e., /S2O8(2 )/H2O2) achieved higher removal efficiencies for COD and NH3-N compared with other studied applications. PMID- 26744942 TI - Application of a soft computing technique in predicting the percentage of shear force carried by walls in a rectangular channel with non-homogeneous roughness. AB - Two new soft computing models, namely genetic programming (GP) and genetic artificial algorithm (GAA) neural network (a combination of modified genetic algorithm and artificial neural network methods) were developed in order to predict the percentage of shear force in a rectangular channel with non homogeneous roughness. The ability of these methods to estimate the percentage of shear force was investigated. Moreover, the independent parameters' effectiveness in predicting the percentage of shear force was determined using sensitivity analysis. According to the results, the GP model demonstrated superior performance to the GAA model. A comparison was also made between the GP program determined as the best model and five equations obtained in prior research. The GP model with the lowest error values (root mean square error ((RMSE) of 0.0515) had the best function compared with the other equations presented for rough and smooth channels as well as smooth ducts. The equation proposed for rectangular channels with rough boundaries (RMSE of 0.0642) outperformed the prior equations for smooth boundaries. PMID- 26744941 TI - A pilot-scale study on PVA gel beads based integrated fixed film activated sludge (IFAS) plant for municipal wastewater treatment. AB - In the present study, a pilot-scale reactor incorporating polyvinyl alcohol gel beads as biomass carrier and operating in biological activated sludge mode (a combination of moving bed biofilm reactor (MBBR) and activated sludge) was investigated for the treatment of actual municipal wastewater. The results, during a monitoring period of 4 months, showed effective removal of chemical oxygen demand (COD), biological oxygen demand (BOD) and NH3-N at optimum conditions with 91%, ~92% and ~90% removal efficiencies, respectively. Sludge volume index (SVI) values of activated sludge varied in the range of 25-72 mL/g, indicating appreciable settling characteristics. Furthermore, soluble COD and BOD in the effluent of the pilot plant were reduced to levels well below discharge limits of the Punjab Pollution Control Board, India. A culture dependent method was used to enrich and isolate abundant heterotrophic bacteria in activated sludge. In addition to this, 16S rRNA genes analysis was performed to identify diverse dominant bacterial species in suspended and attached biomass. Results revealed that Escherichia coli, Pseudomonas sp. and Nitrosomonas communis played a significant role in biomass carrier, while Acinetobactor sp. were dominant in activated sludge of the pilot plant. Identification of ciliated protozoa populations rendered six species of ciliates in the plant, among which Vorticella was the most dominant. PMID- 26744944 TI - Determination of greenhouse gas emission reductions from sewage sludge anaerobic digestion in China. AB - Sewage sludge is a considerable source of greenhouse gas (GHG) emission in the field of organic solid waste treatment and disposal. In this case study, total GHG emissions from sludge anaerobic digestion, including direct and indirect emissions as well as replaceable emission reduction due to biogas being reused instead of natural gas, were quantified respectively. The results indicated that no GHG generation needed to be considered during the anaerobic digestion process. Indirect emissions were mainly from electricity and fossil fuel consumption on site and sludge transportation. Overall, the total GHG emission owing to relative subtraction from anaerobic digestion rather than landfill, and replaceable GHG reduction caused by reuse of its product of biogas, were quantified to be 0.7214 (northern China) or 0.7384 (southern China) MgCO2 MgWS(-1) (wet sludge). PMID- 26744943 TI - Co-production of hydrogen and methane from herbal medicine wastewater by a combined UASB system with immobilized sludge (H2 production) and UASB system with suspended sludge (CH4 production). AB - An upflow anaerobic sludge bed (UASB) system with sludge immobilized on granular activated carbon was developed for fermentative hydrogen production continuously from herbal medicine wastewater at various organic loading rates (8-40 g chemical oxygen demand (COD) L(-1) d(-1)). The maximum hydrogen production rate reached 10.0 (+/-0.17) mmol L(-1) hr(-1) at organic loading rate of 24 g COD L(-1) d(-1), which was 19.9% higher than that of suspended sludge system. The effluents of hydrogen fermentation were used for continuous methane production in the subsequent UASB system. At hydraulic retention time of 15 h, the maximum methane production rate of 5.49 (+/-0.03) mmol L(-1) hr(-1) was obtained. The total energy recovery rate by co-production of hydrogen and methane was evaluated to be 7.26 kJ L(-1) hr(-1). PMID- 26744945 TI - Urban domestic wastewater: how to reduce individual injection? AB - The present paper aims to identify ways to reduce pollution injected by residents in the urban wastewater network system. Two approaches are considered. The first one uses flow and pollutant calculation to test whether a polluter can easily be identified in a neighborhood. The second approach uses a survey to examine what incentive would be most effective to influence residents' behavior. Hydrodynamic simulation results show that concentration profiles at the network outlet corresponding to all possible polluters are similar and thus do not point out specific resident source of pollution. Household-level survey results show that most socio-economic and public-good-related characteristics do not play a significant role in explaining choices to discard in the home wastewater network. Apart from the nature of the waste itself, by far the belief that the respondent has about neighbors' and relatives' discarding behavior is the main driver of the choice. PMID- 26744947 TI - Analysis of sludge aggregates produced during electrocoagulation of model wastewater. AB - This paper presents the results of the study of sludge aggregates produced during electrocoagulation of model wastewater of a composition corresponding to the effluents from the cellulose and paper industry. Wastewater was electrocoagulated statically using aluminium electrodes with a current density of 31.25 A m(-2) and 62.50 A m(-2). In subsequent stages of the treatment, sludge flocs were collected, their size was studied and their floc settling velocity (30-520 MUm s( 1)) and fractal dimension (D) were determined. The values of D ranged from 1.53 to 1.95 and were directly proportional to the degree of wastewater treatment. Higher values of D were determined for sludge with lower water content (after 24 hours' settling). Fractal dimension can therefore be used as an additional parameter of wastewater treatment control. PMID- 26744946 TI - Enhanced Fenton-like removal of nitrobenzene via internal microelectrolysis in nano zerovalent iron/activated carbon composite. AB - The efficiency of Fenton-like catalysis using nano zerovalent iron (nZVI) is limited by nZVI aggregation and activity loss due to inactive ferric oxide forming on the nZVI surface, which hinders electron transfer. A novel iron-carbon composite catalyst consisting of nZVI and granular activated carbon (GAC), which can undergo internal iron-carbon microelectrolysis spontaneously, was successfully fabricated by the adsorption-reduction method. The catalyst efficiency was evaluated in nitrobenzene (NB) removal via the Fenton-like process (H2O2-nZVI/GAC). The results showed that nZVI/GAC composite was good for dispersing nZVI on the surface of GAC, which permitted much better removal efficiency (93.0%) than nZVI (31.0%) or GAC (20.0%) alone. Moreover, iron leaching decreased from 1.28 to 0.58 mg/L after reaction of 240 min and the oxidation kinetic of the Fenton-like reaction can be described well by the second order reaction kinetic model (R2=0.988). The composite catalyst showed sustainable catalytic ability and GAC performed as a medium for electron transfer in internal iron-carbon microelectrolysis to promote Fe2+ regeneration and Fe3+/Fe2+ cycles. Therefore, this study represents an important method to design a low cost and high efficiency Fenton-like catalyst in practical application. PMID- 26744948 TI - Adaptation to urbanization impacts on drainage in the city of Hohhot, China. AB - This study presents a quantitative assessment of urbanization effects on hydrological runoff and drainage network in the city of Hohhot, China. The evolution of urban spatial morphology for the historical years (1987-2010) and projected year (2020) is described by changes in geographic information system (GIS)-based land use maps and further represented in hydrological parameters in the Storm Water Management Model (SWMM) simulation. The results show the levels of service of historical drainage were too low to have dominant impacts on flood risks, and hence a significant upward trend in catchment runoff response was observed over time. Comparisons with changes in system overloading indicate that the relative increase in flood risk is greatest at the early stage of urbanization with relatively low levels of development. The proposed adaptation measures based on a cost-effective optimal approach was found feasible to significantly improve the drainage performance and mitigate the increasing flooding impacts. PMID- 26744950 TI - Evaluation of removal efficiency of human antibiotics in wastewater treatment plants in Bangkok, Thailand. AB - This study aimed to investigate the antibiotic concentration at each stage of treatment and to evaluate the removal efficiency of antibiotics in different types of secondary and advanced treatment, as well as the effects of the location of their discharge points on the occurrence of antibiotics in surface water. Eight target antibiotics and four hospital wastewater treatment plants in Bangkok with different conventional and advanced treatment options were investigated. Antibiotics were extracted by solid phase extraction and analysed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The antibiotic with the highest concentration at influent was cefazolin at 13,166 ng/L, while the antibiotic with the highest concentration at effluent was sulfamethoxazole at 1,499 ng/L. The removal efficiency of antibiotics from lowest to highest was sulfamethoxazole, piperacillin, clarithromycin, metronidazole, dicloxacillin, ciprofloxacin, cefazolin, and cefalexin. The adopted conventional treatment systems could not completely remove all antibiotics from wastewater. However, using advanced treatments or disinfection units such as chlorination and UV could increase the antibiotic removal efficiency. Chlorination was more effective than UV, ciprofloxacin and sulfamethoxazole concentration fluctuated during the treatment process, and sulfamethoxazole was the most difficult to remove. Both these antibiotics should be studied further regarding their contamination in sludge and suitable treatment options for their removal. PMID- 26744949 TI - Removal of endocrine disrupting compounds from wastewater using polymer particles. AB - This study evaluated the use of particles of molecularly imprinted and non imprinted polymers (MIP and NIP) as a wastewater treatment method for endocrine disrupting compounds (EDCs). MIP and NIP remove EDCs through adsorption and therefore do not result in the formation of partially degraded products. The results show that both MIP and NIP particles are effective for removal of EDCs, and NIP have the advantage of not being as compound-specific as the MIP and hence can remove a diverse range of compounds including 17-beta-estradiol (E2), atrazine, bisphenol A, and diethylstilbestrol. Removal of E2 from wastewater was also tested to determine the effectiveness of NIP in the presence of interfering substances and natural organic matter. Removal of E2 from wastewater samples was high and increased with increasing NIP. NIP represent an effective way of removing a wide variety of EDCs from wastewater. PMID- 26744951 TI - Optimization of material and energy consumption for removal of Acid Red 14 by simultaneous electrocoagulation and electroflotation. AB - Decolorization of wastewater of industries which consume dye is an environmental priority. Electrocoagulation and electroflotation methods are appropriate for treatment of these wastewaters. This study investigates the effect of four parameters, electrical conductivity, current density, initial dye concentration, and initial pH, on the performance of a simultaneous electrocoagulation/electroflotation system for removal of Acid Red 14. The optimum values of these parameters were determined based on the amount of electrical energy and aluminum consumption and the best performance of coagulation and bubble generation. The optimum condition was revealed to be electrical conductivity=1,600 MUS/cm, current density=60 mA/cm2, initial dye concentration=185 mg/L and initial pH=7. After less than 180 min of electrolysis, 90% dye removal was achieved with a specific energy consumption=102 kWh/kg dyeremoved, anode dissolution=2.09 kg Al/kg dyeremoved and sludge total suspended solids=15,050 mg/L. Liquid chromatography-UV-mass spectroscopy analyses were conducted on samples of raw and treated wastewater. Results showed that intermediate compounds formed from the breaking of the dye molecules. The advantages of this method are a low material and energy consumption. The amount of produced sludge was low; consequently sludge disposal and management costs would be reduced. This method should be used cautiously for treatment of textile wastewater due to the formation of intermediate compounds. PMID- 26744952 TI - Accumulation and risk assessment of heavy metals in sediments and zoobenthos (Bellamya aeruginosa and Corbicula fluminea) from Lake Taihu. AB - Accumulation and risk assessment of metals in sediments and zoobenthos (Bellamya aeruginosa and Corbicula fluminea) from Lake Taihu were studied. Results showed that metal (Cr, Cd, Cu, Zn, Pb and Ni) concentrations in Lake Taihu varied greatly, and Cd in the Zhushan Bay showed higher bioavailability compared to the other metals studied. The spatial distribution of metals in B. aeruginosa and C. fluminea was similar to that in sediments. Zn and Cu exhibited the higher mean concentration in B. aeruginosa and C. fluminea, which was in good accordance with its higher content in surrounding sediment. Labile fractions (i.e., acid-soluble (F1), reducible (F2) and F1+F2) of Cu and Zn in sediments showed a significant positive correlation with them in B. aeruginosa (P<0.01); no correlation relationship was found for metals (Cd, Cr, Cu, Zn, Pb and Ni) between in the tissue of C. fluminea and in sediments. The results of ecological risk assessment showed that Zhushan Bay was seriously contaminated by metal Cd, as it made the main contribution of all the metals. Total target hazard quotients indicated that adults and children both had potential health risk through consuming C. fluminea. Hazard index values suggested that adults and children might experience adverse health effects through consuming B. aeruginosa and C. fluminea. PMID- 26744953 TI - Operating a pilot-scale nitrification/distillation plant for complete nutrient recovery from urine. AB - Source-separated urine contains most of the excreted nutrients, which can be recovered by using nitrification to stabilize the urine before concentrating the nutrient solution with distillation. The aim of this study was to test this process combination at pilot scale. The nitrification process was efficient in a moving bed biofilm reactor with maximal rates of 930 mg N L(-1) d(-1). Rates decreased to 120 mg N L(-1) d(-1) after switching to more concentrated urine. At high nitrification rates (640 mg N L(-1) d(-1)) and low total ammonia concentrations (1,790 mg NH4-N L(-1) in influent) distillation caused the main primary energy demand of 71 W cap(-1) (nitrification: 13 W cap(-1)) assuming a nitrogen production of 8.8 g N cap(-1) d(-1). Possible process failures include the accumulation of the nitrification intermediate nitrite and the selection of acid-tolerant ammonia-oxidizing bacteria. Especially during reactor start-up, the process must therefore be carefully supervised. The concentrate produced by the nitrification/distillation process is low in heavy metals, but high in nutrients, suggesting a good suitability as an integral fertilizer. PMID- 26744955 TI - Xenotransplantation 2.0. PMID- 26744956 TI - Xenotransplantation makes a comeback. PMID- 26744954 TI - Risk factors for dementia diagnosis in German primary care practices. AB - BACKGROUND: Dementia is a psychiatric condition the development of which is associated with numerous aspects of life. Our aim was to estimate dementia risk factors in German primary care patients. METHODS: The case-control study included primary care patients (70-90 years) with first diagnosis of dementia (all-cause) during the index period (01/2010-12/2014) (Disease Analyzer, Germany), and controls without dementia matched (1:1) to cases on the basis of age, sex, type of health insurance, and physician. Practice visit records were used to verify that there had been 10 years of continuous follow-up prior to the index date. Multivariate logistic regression models were fitted with dementia as a dependent variable and the potential predictors. RESULTS: The mean age for the 11,956 cases and the 11,956 controls was 80.4 (SD: 5.3) years. 39.0% of them were male and 1.9% had private health insurance. In the multivariate regression model, the following variables were linked to a significant extent with an increased risk of dementia: diabetes (OR: 1.17; 95% CI: 1.10-1.24), lipid metabolism (1.07; 1.00 1.14), stroke incl. TIA (1.68; 1.57-1.80), Parkinson's disease (PD) (1.89; 1.64 2.19), intracranial injury (1.30; 1.00-1.70), coronary heart disease (1.06; 1.00 1.13), mild cognitive impairment (MCI) (2.12; 1.82-2.48), mental and behavioral disorders due to alcohol use (1.96; 1.50-2.57). The use of statins (OR: 0.94; 0.90-0.99), proton-pump inhibitors (PPI) (0.93; 0.90-0.97), and antihypertensive drugs (0.96, 0.94-0.99) were associated with a decreased risk of developing dementia. CONCLUSIONS: Risk factors for dementia found in this study are consistent with the literature. Nevertheless, the associations between statin, PPI and antihypertensive drug use, and decreased risk of dementia need further investigations. PMID- 26744957 TI - CETP inhibitors boost 'good' cholesterol to no avail. PMID- 26744958 TI - Roche's immuno squeeze. PMID- 26744959 TI - Shire bites deeper into rare disease space. PMID- 26744961 TI - Gates champions CureVac. PMID- 26744960 TI - GM salmon declared fit for dinner plates. PMID- 26744962 TI - Mexico dengue vaccine first. PMID- 26744963 TI - Severe asthma gets first biologic in decades. PMID- 26744964 TI - Go-ahead for human genome editing with caveats. PMID- 26744966 TI - Off-the-shelf CAR-T therapy induces remission in child with ALL. PMID- 26744967 TI - DuPont in CRISPR-Cas patent land grab. PMID- 26744969 TI - Drugs go wireless. PMID- 26744970 TI - Innovative academic startups 2015. PMID- 26744971 TI - Standing up for scientific consensus. PMID- 26744973 TI - Reply to Standing up for transparency. PMID- 26744972 TI - Standing up for transparency. PMID- 26744974 TI - This time may be different. PMID- 26744975 TI - The global pipeline of GM crops out to 2020. PMID- 26744976 TI - The patentability of human embryonic stem cell technology in China. PMID- 26744978 TI - Serotonin neurons in a dish. PMID- 26744980 TI - Optogenetics unleashed. PMID- 26744982 TI - Getting rid of PERVs. PMID- 26744981 TI - A systems approach to HIV-1 vaccines. PMID- 26744983 TI - A reassessment of the PROPATRIA study and its implications for probiotic therapy. AB - The PROPATRIA (Probiotics in Pancreatitis Trial) study was a multicenter, double blind, placebo-controlled clinical trial that aimed to reduce infectious complications in patients with predicted severe acute pancreatitis by the enteral use of a multispecies probiotic preparation. An unprecedented 24 of 152 patients (16%) in the group receiving probiotics died versus 9 of 144 (6%) in the placebo group. This high mortality rate in the probiotic-treated group contrasts strongly with observations from a previous smaller study and from our observations regarding the effects of abundant intestinal lactobacilli in patients with short small bowel (SSB) syndrome. We argue here that a lethal combination of mainly proteolytic pancreas enzymes and probiotic therapy resulted in the high mortality rate of the PROPATRIA trial and that elevated levels of lactic acid produced by bacterial fermentation of carbohydrates were a key contributing factor. We suggest that probiotic therapy may not be counter-indicated for the prevention of secondary infections associated with acute pancreatitis, provided that future clinical studies (i) start probiotic therapy immediately after first onset of disease symptoms, (ii) limit the supply of fermentable carbohydrates, (iii) prevent bacterial (over)growth of patient's own intestinal flora and (iv) massively increase the dose of probiotic bacteria. PMID- 26744984 TI - Preparing future professionals by enhancing workforce readiness. PMID- 26744986 TI - Mixed effects of OATP1B1, BCRP and NTCP polymorphisms on the population pharmacokinetics of pravastatin in healthy volunteers. AB - 1. Pravastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor used for the treatment of hyperlipidaemia. This study aims to investigate the effects of genetic polymorphisms in OATP1B1, BCRP and NTCP on pravastatin population pharmacokinetics in healthy Chinese volunteers using a non linear mixed-effect modelling (NONMEM) approach. A two-compartment model with a first-order absorption and elimination described plasma pravastatin concentrations well. 2. Genetic polymorphisms of rs4149056 (OATP1B1) and rs2306283 (OATP1B1) were found to be associated with a significant (p < 0.01) decrease in the apparent clearance from the central compartment (CL/F), while rs2296651 (NTCP) increased CL/F to a significant degree (p < 0.01). The combination of these three polymorphisms reduced the inter-individual variability of CL/F by 78.8%. 3. There was minimal effect of rs2231137 (BCRP) and rs2231142 (BCRP) on pravastatin pharmacokinetics (0.01 < p < 0.05), whereas rs11045819 (OATP1B1), rs1061018 (BCRP) and rs61745930 (NTCP) genotypes do not appear to be associated with pravastatin pharmacokinetics based on the population model (p > 0.05). 4. The current data suggest that the combination of rs4149056, rs2306283 and rs2296651 polymorphisms is an important determinant of pravastatin pharmacokinetics. PMID- 26744988 TI - Aberrant purine metabolism in allergic asthma revealed by plasma metabolomics. AB - Asthma is a disease characterized by chronic relapsing airways, and its etiology remains incompletely understood. To better understand the metabolic phenotypes of asthma, we investigated a plasma metabolic signature associated with allergic asthma in ovalbumin (OVA)-sensitized mice by using ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q TOF/MS). Sixteen metabolites were characterized as potential pathological biomarkers related to asthma. Among them, 6 (dodecanoic acid (P1), myristic acid (P2), phytosphingosine (P3), sphinganine (P4), inosine (P13) and taurocholic acid (P15)) were first reported to have potential relevance in the pathogenesis of experimental asthma. The identified potential biomarkers were involved in 6 metabolic pathways and achieved the most entire metabolome contributing to the formation of allergic asthma. Purine metabolism was the most prominently influenced in OVA-induced asthma mice according to the metabolic pathway analysis (MetPA), suggesting that significantly changes in inflammatory responses in the pathophysiologic process of asthma. The metabolites of purine metabolism, especially uric acid (P12) and inosine (P13), may denote their potential as targeted biomarkers related to experimental asthma. The decreased plasma uric acid (P12) suggested that inflammation responses of allergic asthma inhibited the activity of xanthine oxidase in purine metabolism, and manifested the severity of asthma exacerbation. The increased level of inosine (P13) suggests that inflammatory cells induce adenosine triphosphate (ATP) breakdown, resulting in excessive expression of adenosine deaminase (ADA) in the formation of allergic asthma. These findings provided a novel perspective on the metabolites signatures related to allergic asthma, which provided us with new insights into the pathogenesis of asthma, and the discovery of targets for clinical diagnosis and treatment. PMID- 26744987 TI - Metabonomic study on the plasma of streptozotocin-induced diabetic rats treated with Ge Gen Qin Lian Decoction by ultra high performance liquid chromatography mass spectrometry. AB - Changes in endogenous metabolites in the plasma of streptozotocin (STZ)-induced diabetic rats treated with Ge Gen Qin Lian Decoction (GGQLD) were studied. The endogenous compounds in plasma were detected using ultra high performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry (UHPLC-Q-TOF-MS). Rats were divided into three groups: control, model, and administration (4.95g crude drug/kg body weight). After the final administration, plasma samples from the three groups were analyzed using metabonomics. The three sample groups could be clearly distinguished. The administration group exhibited a distinct return to the levels of phytosphingosine and dihydrosphingosine of the control group according to the principal component analysis score, and the corresponding biomarkers were defined. Significant changes in endogenous metabolites, such as dihydrosphingosine, phytosphingosine, cholylglycine, and pantothenic acid, were identified in STZ-induced diabetic rats. These biochemical changes are associated with the metabolism of sphingolipids, fats, and acetyl coenzyme-A, which could be useful to further investigate the characteristics of STZ-induced diabetes mellitus and the therapeutic mechanism of action of GGQLD. This metabonomic analysis could provide a useful starting point toelucidate the therapeutic effects and mechanism of action of GGQLD in diabetes mellitus. PMID- 26744989 TI - Determination of major sodium iodide symporter (NIS) inhibitors in drinking waters using ion chromatography with conductivity detector. AB - Goiter is an important health problem all over the world and iodine deficiency is its most common cause. Perchlorate, thiocyanate and nitrate (called as major NIS inhibitors) are known to competitively inhibit iodide uptake by the thyroid gland and thus, human exposure to major NIS inhibitors is a public health concern. In this study, an ion chromatographic method for the determination of most common NIS inhibitor ions in drinking waters was developed and validated. This is the first study where an analytical method is used for the determination of major NIS inhibitors in drinking water by an ion chromatography system in a single run. Chromatographic separations were achieved with an anion-exchange column and separated ions were identified by a conductivity detector. The method was found to be selective, linear, precise accurate and true for all of interested ions. The limits of the detections (LOD) were estimated at 0.003, 0.004 and 0.025mgL( 1) for perchlorate, thiocyanate and nitrate, respectively. Possible interference ions in drinking waters were examined for the best separation of NIS inhibitors. The excellent method validation data and proficiency test result (Z-score for nitrate: -0.1) of the FAPAS((r)) suggested that the developed method could be applied for determination of NIS inhibitor residues in drinking waters. To evaluate the usefulness of the method, 75 drinking water samples from Antalya/Turkey were analyzed for NIS inhibitors. Perchlorate concentrations in the samples ranged from not detected (less than LOD) to 0.07+/-0.02mgL(-1) and the range of nitrate concentrations were found to be 3.60+/-0.01mgL(-1) and 47.42+/-0.40mgL(-1). No thiocyanate residues were detected in tested drinking water samples. PMID- 26744990 TI - Solid phase extraction as sample treatment for the determination of Ochratoxin A in foods: A review. AB - Ochratoxin A (OTA) is a mycotoxin produced by two main types of fungi, Aspergillus and Penicillium species. OTA is a natural contaminant found in a large number of different matrices and is considered as a possible carcinogen for humans. Hence, low maximum permitted levels in foods have been established by competent authorities around the world, making essential the use of very sensitive analytical methods for OTA detection. Sample treatment is a crucial step of analytical methodology to get clean and concentrated extracts, and therefore low limits of quantification. Solid phase extraction (SPE) is a useful technique for rapid and selective sample preparation. This sample treatment enables the concentration and purification of analytes from the sample solution or extract by sorption on a solid sorbent. This review is focused on sample treatment procedures based on SPE prior to the determination of OTA in food matrices, published from 2010. PMID- 26744991 TI - Lower Extremity Handheld Dynamometry Strength Measurement in Children With Cerebral Palsy. AB - PURPOSE: The purpose of this study was to evaluate the evidence on reliability of handheld dynamometry protocols to quantify maximal isometric strength of the muscles of the lower extremities of children with cerebral palsy. METHODS: A systematic search of Cochrane, MEDLINE, CINAHL, and PubMed up to December 2013 and best-evidence synthesis were performed. RESULTS: Seven eligible studies were identified. Best-evidence synthesis revealed "unknown" to "moderate" evidence. Intraclass correlation coefficient values were "positive" for most muscle groups for intrarater reliability and showed mixed results for interrater reliability. CONCLUSIONS: Because of small sample sizes (10-25) in all included studies, the final level of evidence remains "unknown." Reliability data obtained in the included studies of handheld dynamometry in children with cerebral palsy are promising, despite low levels of evidence. When these protocols are applied very carefully, they may prove relevant to different clinical settings. PMID- 26744992 TI - A multicomponent molecular approach to artificial photosynthesis - the role of fullerenes and endohedral metallofullerenes. AB - In this review article, we highlight recent advances in the field of solar energy conversion at a molecular level. We focus mainly on investigations regarding fullerenes as well as endohedral metallofullerenes in energy and/or electron donor-acceptor conjugates, hybrids, and arrays, but will also discuss several more advanced systems. Hereby, the mimicry of the fundamental processes occurring in natural photosynthesis, namely light harvesting (LH), energy transfer (EnT), reductive/oxidative electron transfer (ET), and catalysis (CAT), which serve as a blue print for the rational design of artificial photosynthetic systems, stand at the focalpoint. Importantly, the key processes in photosynthesis, that is, LH, EnT, ET, and CAT, define the structure of this review with the only further differentiation in terms of covalent and non-covalent systems. Fullerenes as well as endohedral metallofullerenes are chosen by virtue of their small reorganization energies in electron transfer processes, on the one hand, and their exceptional redox behaviour, on the other hand. PMID- 26744993 TI - Molecular characterization of a novel mycovirus of the family Tymoviridae isolated from the plant pathogenic fungus Fusarium graminearum. AB - We isolated a novel mycovirus, Fusarium graminearum mycotymovirus 1 (FgMTV1/SX64), which is related to members of the family Tymoviridae, from the plant pathogenic fungus F. graminearum strain SX64. The complete 7863 nucleotide sequence of FgMTV1/SX64, excluding the poly (A) tail, was determined. The genome of FgMTV1/SX64 is predicted to contain four open reading frames (ORFs). The largest ORF1 is 6723 nucleotides (nt) in length and encodes a putative polyprotein of 2242 amino acids (aa), which contains four conserved domains, a methyltransferase (Mtr), tymovirus endopeptidase (Pro), viral RNA helicase (Hel), and RNA-dependent RNA polymerase (RdRp), of the replication-associated proteins (RPs) of the positive-strand RNA viruses. ORFs 2-4 putatively encode three putative small hypothetical proteins, but their functions are still unknown. Sequence alignments and phylogenetic analyses based on the putative RP protein and the three conserved domains (Mtr, Hel and RdRp) showed that FgMTV1/SX64 is most closely related to, but distinctly branched from, the viruses from the family Tymoviridae. Although FgMTV1/SX64 infection caused mild or no effect on conidia production, biomass and virulence of its host F. graminearum strain SX64, its infection had significant effects on the growth rate, colony diameter and deoxynivalenol (DON) production. This is the first molecular characterization of a tymo-like mycovirus isolated from a plant pathogenic fungus. It is proposed that the mycovirus FgMTV1/SX64 is a representative member of new proposed lineage Mycotymovirus in the family Tymoviridae. PMID- 26744994 TI - Treating Hepatitis C in a Ryan White-Funded HIV Clinic: Has the Treatment Uptake Improved in the Interferon-Free Directly Active Antiviral Era? AB - Now that highly efficacious, interferon-free (IFN-free), direct acting antivirals (DAA) for the treatment of hepatitis C (HCV) have closed the gap between treatment and cure, identifying barriers that prevent initiation of treatment is more crucial than ever. This is a retrospective study utilizing Electronic Medical Records and Prior Authorization Records to identify HCV treatment gaps, including predictors for intention-to-treat and treatment initiation in the first 15 months of a Ryan White funded human immunodeficiency virus (HIV)/HCV co infection clinic. This study included 128 adults >= 18 years old with HIV and chronic HCV infection who had visited the treatment center at least once since January 2013. Provider intent-to-treat was used to differentiate patients actively considered for treatment based on documentation kept by a multidisciplinary HCV team. Members of this group who had gone on to initiate treatment were identified. Baseline characteristics were compared. Rates of active treatment consideration and treatment initiation were 30% and 14%, respectively. HCV treatment-naive individuals were less likely to be considered for treatment [risk ratio (RR) 1.58, 95% confidence interval (CI) 1.07-2.32] and initiate therapy (RR 2.33, 95% CI 0.97-5.60). Advanced liver disease had no significant association. Black race (RR 1.96, 95% CI 0.90-4.25) and Medicaid insurance holders (RR 1.90, 95% CI 0.95-3.82) tended to be less likely to initiate therapy. The availability of IFN-free DAA regimens has yet to increase HCV treatment uptake in our HIV/HCV co-infected population. Barriers to HCV treatment initiation have shifted from medical contraindications to socioeconomic variables. PMID- 26744995 TI - Sexually different morphological, physiological and molecular responses of Fraxinus mandshurica flowers to floral development and chilling stress. AB - Fraxinus mandshurica is considered a dioecious hardwood, and the temporal separation of the maturation of the male and female flowers is one reason that F. mandshurica has become an endangered species in China. Rainfall and low temperature influence pollen formation and dispersal and the blooming of female flowers. Therefore, low fertilization efficiency strongly influences the population of F. mandshurica. Nevertheless, few studies have investigated the sex specific morphological, physiological and molecular differentiation of F. mandshurica during flowering and its responses to low temperature. In this study, we investigated the sexual differences in the morphological, physiological, and biochemical parameters of F. mandshurica during flowering and determined the physiological and biochemical parameters and expression levels of related genes in response to low-temperature stress induced by exposure to 4 degrees C (chilling stress) during pollen dispersal and fertilization. Our study supports the hypothesis that male flowers suffer more severe injuries while female flowers are more adaptable to environmental stress during flower development in F. mandshurica. The results showed higher physiological and biochemical levels of malondialdehyde, proline, and soluble sugar, as well as the expression of genes involved in calcium signaling, cold shock and DNA methylation in male flowers compared with female flowers, which suggested that male flowers suffer from more serious peroxidation than female flowers. In contrast, higher antioxidant capacity and FmaCAT expression were detected in female flowers, providing preliminary evidence that male flowers rapidly fade after pollination and further demonstrating that female flowers need a much stronger antioxidant enzyme system to maintain embryonic growth. Most peaks related to physiological and molecular responses were observed at 2-4 h and 8-10 h of exposure to chilling stress in the female and male flowers, respectively. This trend implies that female flowers have higher adaptability to low temperature during fertilization. PMID- 26744996 TI - Pseudomonas putida attunes morphophysiological, biochemical and molecular responses in Cicer arietinum L. during drought stress and recovery. AB - Drought is one of the most important abiotic stresses that adversely affect plant growth and yield potential. However, some drought resistant rhizosphere competent bacteria are known to improve plant health and promote growth during abiotic stresses. Present study showed the role of Pseudomonas putida MTCC5279 (RA) in ameliorating drought stress on cv. BG-362 (desi) and cv. BG-1003 (kabuli) chickpea cultivars under in vitro and green house conditions. Polyethylene glycol induced drought stress severely affected seed germination in both cultivars which was considerably improved on RA-inoculation. Drought stress significantly affected various growth parameters, water status, membrane integrity, osmolyte accumulation, ROS scavenging ability and stress-responsive gene expressions, which were positively modulated upon application of RA in both chickpea cultivars. Quantitative real-time (qRT)-PCR analysis showed differential expression of genes involved in transcription activation (DREB1A and NAC1), stress response (LEA and DHN), ROS scavenging (CAT, APX, GST), ethylene biosynthesis (ACO and ACS), salicylic acid (PR1) and jasmonate (MYC2) signalling in both chickpea cultivars exposed to drought stress and recovery in the presence or absence of RA. The observations imply that RA confers drought tolerance in chickpea by altering various physical, physiological and biochemical parameters, as well as by modulating differential expression of at least 11 stress-responsive genes. To the best of our knowledge, this is the first report on detailed analysis of plant growth promotion and stress alleviation in one month old desi and kabuli chickpea subjected to drought stress for 0, 1, 3 and 7 days and recovery in the presence of a PGPR. PMID- 26744997 TI - Salvaging effect of triacontanol on plant growth, thermotolerance, macro-nutrient content, amino acid concentration and modulation of defense hormonal levels under heat stress. AB - In this study, it was hypothesized that application of triacontanol, a ubiquitous saturated primary alcohol, at different times-before (TBHS), mid (TMHS), and after (TAHS) heat stress-will extend heat stress (HS) protection in mungbean. The effect of triacontanol on the levels of defense hormones abscisic acid (ABA) and jasmonic acid (JA) was investigated along with the plant growth promotion, nutrient and amino acid content with and without heat stress. Heat stress caused a prominent reduction in plant growth attributes, nutrient and amino acid content, which were attributed to the decreased level of ABA and JA. However, application of triacontanol, particularly in the TBHS and TMHS treatments, reversed the deleterious effects of HS by showing increased ABA and JA levels that favored the significant increase in plant growth attributes, enhanced nutrient content, and high amount of amino acid. TAHS, a short-term application of triacontanol, also significantly increased ABA and JA levels and thus revealed important information of its association with hormonal modulation. The growth promoting effect of triacontanol was also confirmed under normal growth conditions. To the best of our knowledge, this study is the first to demonstrate the beneficial effects of triacontanol, with or without heat stress, on mungbean and its interaction with or regulation of the levels of defense hormones. PMID- 26744998 TI - Labour market participation after breast cancer for employees from the private and public sectors: Educational and sector gradients in the effect of cancer. AB - For employees who get cancer and survive, the probability of returning to work may depend on their ability to work, potential earnings losses if they do not return to work, qualifications and job type, but also on characteristics of the pre-cancer workplace. This paper focuses on differences between public and private sector employees in the effect of breast cancer on the probability of being out of the labour force three years after the diagnosis. We use propensity score weighting methods and a large longitudinal Danish administrative dataset which allows us to control for a wide range of important baseline characteristics such as education, sector of employment, labour market status, income, health, and demographics. We find that the educational gradient in the effect of cancer is significant in the public sector, where the estimated effects are 11.5 and 3.8 percentage points, respectively, for the low- and high-educated. The corresponding estimates for the private sector are 6.2 and 3.2 percentage points and here the educational gradient is only marginally significant. We discuss possible mechanisms behind the large sector gradient for the low-educated. PMID- 26744999 TI - Stroke-attributable death among older persons during the great recession. AB - Epidemiological evidence indicates an elevated risk for stroke among stressed persons, in general, and among individuals who have lost their job, in particular. We, therefore, tested the hypothesis that stroke accounted for a larger fraction of deaths during the Great Recession than expected from other deaths and from trends, cycles, and other forms of autocorrelation. Based on vital statistics death data from California spanning 132 months from January 2000 through December 2010, we found support for the hypothesis. These findings appear attributable to non-Hispanic white men, who experienced a 5% increase in their monthly odds of stroke-attributable death. Total mortality in this group, however, did not increase. Findings suggest that 879 deaths among older white men shifted from other causes to stroke during the 36 months following the start of the Great Recession. We infer the Great Recession may have affected social, biologic, and behavioral risk factors that altered the life histories of older white men in ways that shifted mortality risk toward stroke. PMID- 26745000 TI - A structural model of the chiral "Im3m" cubic phase. AB - Assuming the twisted arrangement of rodlike molecules as the origin of the chirality as in the existing model, a new model of the molecular arrangement in the cubic "Im3m" phase is proposed. The adoption of a basic structure different from that assumed in the existing model resolves most difficulties of the model including the random placement of defects concerning the sense of twist. PMID- 26745003 TI - Implication of citrate, malate and histidine in the accumulation and transport of nickel in Mesembryanthemum crystallinum and Brassica juncea. AB - Citrate, malate and histidine have been involved in many processes including metal tolerance and accumulation in plants. These molecules have been frequently reported to be the potential nickel chelators, which most likely facilitate metal transport through xylem. In this context, we assess here, the relationship between organics acids and histidine content and nickel accumulation in Mesembryanthemum crystallinum and Brassica juncea grown in hydroponic media added with 25, 50 and 100 uM NiCl2. Results showed that M. crystallinum is relatively more tolerant to Ni toxicity than B. juncea. For both species, xylem transport rate of Ni increased with increasing Ni supply. A positive correlation was established between nickel and citrate concentrations in the xylem sap. In the shoot of B. juncea, citric and malic acids concentrations were significantly higher than in the shoot of M. crystallinum. Also, the shoots and roots of B. juncea accumulated much more histidine. In contrast, a higher root citrate concentration was observed in M. crystallinum. These findings suggest a specific involvement of malic and citric acid in Ni translocation and accumulation in M. crystallinum and B. juncea. The high citrate and histidine accumulation especially at 100uM NiCl2, in the roots of M. crystallinum might be among the important factors associated with the tolerance of this halophyte to toxic Ni levels. PMID- 26745002 TI - Intratracheal Administration of Prostacyclin Analogue-incorporated Nanoparticles Ameliorates the Development of Monocrotaline and Sugen-Hypoxia-induced Pulmonary Arterial Hypertension. AB - Nanoparticles (NPs) have been used as novel drug delivery systems. Drug incorporated NPs for local delivery might optimize the efficacy and minimize the side effects of drugs. Intravenous prostacyclin improves long-term survival in patients with pulmonary arterial hypertension (PAH), but it causes serious side effects such as catheter-related infections. We investigated the efficacy and safety of intratracheal administration of a prostacyclin analogue, beraprost (BPS), incorporated NPs in Sugen-hypoxia-normoxia and monocrotaline rat models of PAH and in human PAH pulmonary arterial smooth muscle cells (PASMCs). After a single administration, BPS NPs significantly decreased right ventricular pressure, right ventricular hypertrophy, and pulmonary artery muscularization in the 2 rat models. BPS NPs significantly improved the survival rate in the monocrotaline rat model. No infiltration of inflammatory cells, hemorrhage, or fibrosis was found in the liver, kidney, spleen, and heart after the administration of BPS NPs. No liver or kidney dysfunction was found in the blood examinations. BPS and BPS NPs significantly inhibited the proliferation of human PAH PASMCs after 24 hours of treatment. BPS NPs significantly continued to inhibit the proliferation of human PAH PASMCs at 24 hours after the removal of BPS NPs. BPS NPs significantly induced apoptosis in PAH PASMCs compared to that in non-PAH PASMCs. Intratracheal administration of BPS NPs ameliorates pulmonary hypertension in PAH rat models by a sustained antiproliferative effect and a proapoptotic effect on PAH PASMCs. PMID- 26745001 TI - Recombinant Human Elastase Alters the Compliance of Atherosclerotic Tibial Arteries After Ex Vivo Angioplasty. AB - PURPOSE: This study was designed to determine whether vonapanitase (formerly PRT 201), a recombinant human elastase, treatment can fragment the protein elastin in elastic fibers and cause dilation of atherosclerotic human peripheral arteries subjected to ex vivo balloon angioplasty. MATERIALS AND METHODS: Seven patients undergoing lower limb amputation for peripheral artery disease or who died and donated their bodies to science donated 11 tibial arteries (5 anterior, 6 posterior) for this study. All arteries were atherosclerotic by visual inspection. The arteries underwent ex vivo balloon angioplasty and thereafter were cut into rings and studied on wire myographs where the rings were stretched and tension was recorded. After treatment with vonapanitase 2 mg/mL or vehicle control, myography was repeated and the rings were then subject to elastin content measurement using a desmosine radioimmunoassay and elastic fiber visualization by histology. The wire myography data were used to derive compliance, stress-strain, and incremental elastic modulus curves. RESULTS: Vonapanitase treatment reduced elastin (desmosine) content by 60% and decreased elastic fiber histologic staining. Vonapanitase-treated rings experienced less tension at any level of stretch and as a result had shifts in the compliance and stress-strain curves relative to vehicle-treated rings. Vonapanitase treatment did not alter the incremental elastic modulus curve. CONCLUSIONS: Vonapanitase treatment of atherosclerotic human peripheral arteries after ex vivo balloon angioplasty fragmented elastin in elastic fibers, decreased tension in the rings at any level of stretch, and altered the compliance and stress-strain curves in a manner predicting arterial dilation in vivo. Based on this result, local treatment of balloon angioplasty sites may increase blood vessel diameter and thereby improve the success of balloon angioplasty in peripheral artery disease. PMID- 26745004 TI - Effects of fluoride on development and growth of Rana chensinensis embryos and larvae. AB - The present study examined the adverse effects of fluoride exposure on embryos and larvae of Rana chensinensis. Survival, morphological abnormalities, growth and development, time to metamorphosis and size at metamorphic climax of R. chensinensis were examined. Our results showed that embryos malformation occurred in all fluoride treatments. Morphological abnormalities of embryos are characterized by axial flexures, the extrusion of fin axis, edema, and ruffled dorsal and ventral fin. Additionally, 4.1mg F(-)/L and above could significantly inhibit embryos growth and development. On day 15, total length and weight of tadpole were significantly lower in 19.6 and 42.4 mg F(-)/L treatments compared to control. However, significant reductions in total length and weight were observed only at 42.4 mg F(-)/L on day 30. Moreover, significant metamorphic delay and decrease in the size at metamorphic climax were found in larvae exposed to 42.4 mg F(-)/L. Taken together, embryos of R. chensinensis are more vulnerable to fluoride exposure than their tadpoles. Our results suggested that the presence of high concentrations fluoride might increase mortality risk and a reduction in juvenile recruitment in the field by increasing embryos malformation, delaying metamorphosis and decreasing size at metamorphosis. PMID- 26745006 TI - Lead neurotoxicity: exploring the potential impact of lead substitution in zinc finger proteins on mental health. AB - Childhood lead poisoning is a costly and largely preventable public health problem that lowers IQs, decreases attention spans, and leads to the development of other childhood intellectual disabilities. Furthermore, recent evidence links developmental lead poisoning with the etiology of disorders that appear much later in life, such as Alzheimer's disease, Parkinson's disease, and schizophrenia. Little is known about how lead influences the onset of these disorders. This paper reviews the evidence that lead substitution for zinc in zinc-finger proteins contributes to the development of Alzheimer's disease, Parkinson's disease, and schizophrenia. The zinc-finger proteins potentially impacted by lead include DNA methyltransferase 1 (DNMT1) and Presenilin 1 and 2 (PSEN1/2) in Alzheimer's disease, the dopamine receptor in Parkinson's disease, and the NMDA receptor, zinc-finger protein 804A (ZNF804A), and disrupted-in schizophrenia 1 (DISC1)-binding zinc-finger (DBZ) in schizophrenia. PMID- 26745007 TI - Hypoglycemia-Induced Decrease of EEG Coherence in Patients with Type 1 Diabetes. AB - BACKGROUND: Hypoglycemic events in patients with type 1 diabetes (T1D) are associated with measurable electroencephalography (EEG) changes. Previous studies have, however, evaluated these changes on a single EEG channel level, whereas multivariate analysis of several EEG channels has been scarcely investigated. The aim of the present work is to use a coherence approach to quantitatively assess how hypoglycemia affects mutual connectivity of different brain areas. MATERIALS AND METHODS: EEG multichannel data were obtained from 19 patients with T1D (58% males; mean age, 55 +/- 2.4 years; diabetes duration, 28.5 +/- 2.6 years; glycated hemoglobin, 8.0 +/- 0.2%) who underwent a hyperinsulinemic-hypoglycemic clamp study. The information partial directed coherence (iPDC) function was computed through multivariate autoregressive models during eu- and hypoglycemia in the theta and alpha bands. RESULTS: In passing from eu- to hypoglycemia, absolute values of the iPDC function tend to decrease in both bands in all combinations of the considered channels. In particular, the scalar indicator [Formula: see text], which summarizes iPDC information, significantly decreased (P < 0.01) in 17 of 19 subjects: from T5-A1A2 to C3-A1A2 from O1-A1A2 to C4-A1A2 and from O2-A1A2 to Cz-A1A2 in the theta band and from O1-A1A2 to T4-A1A2 and from O1-A1A2 to C4-A1A2 in the alpha band. CONCLUSIONS: The coherence decrease measured by iPDC in passing from eu- to hypoglycemia is likely related to the progressive loss of cognitive function and altered cerebral activity in hypoglycemia. This result encourages further quantitative investigation of EEG changes in hypoglycemia and of how EEG acquisition and real-time processing can support hypoglycemia alert systems. PMID- 26745008 TI - Towards a full understanding of the nature of Ni(II) species and hydroxyl groups over highly siliceous HZSM-5 zeolite supported nickel catalysts prepared by a deposition-precipitation method. AB - Highly siliceous HZSM-5 zeolite supported nickel catalysts prepared by a deposition-precipitation (D-P) method were characterized by Fourier transform infrared (FT-IR), hydrogen temperature programmed reduction (H2-TPR), X-ray diffraction (XRD), N2-absorption/desorption, field emission scanning electron microscopy (FE-SEM), X-ray photoelectron spectroscopy (XPS), and (27)Al magic angle nuclear magnetic resonance (MAS NMR) techniques. The results showed that the D-P of nickel species occurred predominantly on the internal surface of highly siliceous HZSM-5 zeolite, in which the internal silanol groups located on the hydroxylated mesopores or nanocavities played a key role. During the D-P process, nickel hydroxide was first deposited-precipitated via olation/polymerization of neutral hydroxoaqua nickel species over the HZSM-5 zeolite. With the progress of the D-P process, 1 : 1 nickel phyllosilicate was formed over the HZSM-5 via the hetero-condensation/polymerization between charged hydroxoaqua nickel species and monomer silicic species generated due to the partial dissolution of the HZSM-5 framework. The 1 : 1 nickel phyllosilicate could also be generated via the hydrolytic adsorption of hydroxoaqua nickel species and their subsequent olation condensation. After calcination, the deposited-precipitated nickel hydroxide was decomposed into nickel oxide, while the 1 : 1 nickel phyllosilicate was transformed into 2 : 1 nickel phyllosilicate. According to the above mechanism, Ni(ii) species were present both in the form of nickel oxide and 2 : 1 nickel phyllosilicate, which were mutually separated from each other, being highly dispersed over HZSM-5 zeolite. PMID- 26745009 TI - Inhibition of carbonic anhydrase isoforms I, II, IX and XII with secondary sulfonamides incorporating benzothiazole scaffolds. AB - Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of benzothiazole-based sulfonamides were synthesized and tested as possible CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I and hCA II and the transmembrane hCA IX and hCA XII. Several of the investigated derivatives showed interesting inhibition activity and selectivities for inhibiting hCA IX and hCA XII over the off-target ones hCA I and hCA II. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds, within the active site of hCA IX. PMID- 26745010 TI - Lanthanide-Catalyzed Oxyfunctionalization of 1,3-Diketones, Acetoacetic Esters, And Malonates by Oxidative C-O Coupling with Malonyl Peroxides. AB - The lanthanide-catalyzed oxidative C-O coupling of 1,3-dicarbonyl compounds with diacyl peroxides, specifically the cyclic malonyl peroxides, has been developed. An important feature of this new reaction concerns the advantageous role of the peroxide acting both as oxidant and reagent for C-O coupling. It is shown that lanthanide salts may be used in combination with peroxides for selective oxidative transformations. The vast range of lanthanide salts (La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Y) catalyzes oxidative C-O coupling much more efficiently than other used Lewis and Bronsted acids. This oxidative cross coupling protocol furnishes mono and double C-O coupling products chemo selectively in high yields with a broad substrate scope. The double C-O coupling products may be hydrolyzed to vicinal tricarbonyl compounds, which are otherwise cumbersome to prepare. Based on the present experimental results, a nucleophilic substitution mechanism is proposed for the C-O coupling process in which the lanthanide metal ion serves as Lewis acid to activate the enol of the 1,3 dicarbonyl substrate. The side reactions-chlorination and hydroxylation of the 1,3-dicarbonyl partners-may be minimized under proper conditions. PMID- 26745011 TI - Evaluation of wheelchair resistive forces during straight and turning trajectories across different wheelchair configurations using free-wheeling coast down test. AB - The purpose of this study was to develop a simple approach to evaluate resistive frictional forces acting on manual wheelchairs (MWCs) during straight and turning maneuvers. Using a dummy-occupied MWC, decelerations were measured via axle mounted encoders during a coast-down protocol that included straight trajectories and fixed-wheel turns. Eight coast-down trials were conducted to test repeatability and repeated on separate days to evaluate reliability. Without changing the inertia of the MWC system, three tire inflations were chosen to evaluate the sensitivity in discerning deceleration differences using effect sizes. The technique was also deployed to investigate the effect of different MWC masses and weight distributions on resistive forces. Results showed that the proposed coast-down technique had good repeatability and reliability in measuring decelerations and had good sensitivity in discerning differences in tire inflation, especially during turning. The results also indicated that increased loading on drive wheels reduced resistive losses in straight trajectories while increasing resistive losses during turning. During turning trajectories, the presence of tire scrub contributes significantly to the amount of resistive force. Overall, this new coast-down technique demonstrates satisfactory repeatability and sensitivity for detecting deceleration changes during straight and turning trajectories, indicating that it can be used to evaluate resistive loss of different MWC configurations and maneuvers. PMID- 26745013 TI - alpha,beta-Dehydro-Dopa: A Hidden Participant in Mussel Adhesion. AB - Dopa (l-3,4-dihydroxyphenylalanine) is a key chemical signature of mussel adhesive proteins, but its susceptibility to oxidation has limited mechanistic investigations as well as practical translation to wet adhesion technology. To investigate peptidyl-Dopa oxidation, the highly diverse chemical environment of Dopa in mussel adhesive proteins was simplified to a peptidyl-Dopa analogue, N acetyl-Dopa ethyl ester. On the basis of cyclic voltammetry and UV-vis spectroscopy, the Dopa oxidation product at neutral to alkaline pH was shown to be alpha,beta-dehydro-Dopa (DeltaD), a vinylcatecholic tautomer of Dopa-quinone. DeltaD exhibited an adsorption capacity on TiO2 20-fold higher than that of the Dopa homologue in the quartz crystal microbalance. Cyclic voltammetry confirmed the spontaneity of DeltaD formation in mussel foot protein 3F at neutral pH that is coupled to a change in protein secondary structure from random coil to beta sheet. A more complete characterization of DeltaD reactivity adds a significant new perspective to mussel adhesive chemistry and the design of synthetic bioinspired adhesives. PMID- 26745014 TI - Interfacial Shear Strength of Multilayer Graphene Oxide Films. AB - Graphene oxide (GO) is considered as one of the most promising layered materials with tunable physical properties and applicability in many important engineering applications. In this work, the interfacial behavior of multilayer GO films was directly investigated via GO-to-GO friction force microscopy, and the interfacial shear strength (ISS) was measured to be 5.3 +/- 3.2 MPa. Based on high resolution atomic force microscopy images and the available chemical data, targeted molecular dynamics simulations were performed to evaluate the influence of functional structure, topological defects, and interlayer registry on the shear response of the GO films. Theoretical values for shear strength ranging from 17 to 132 MPa were predicted for the different structures studied, providing upper bounds for the ISS. Computational results also revealed the atomic origins of the stochastic nature of friction measurements. Specifically, the wide scatter in experimental measurements was attributed to variations in functional structure and topological defects within the sliding volume. The findings of this study provide important insight for understanding the significant differences in strength between monolayer and bulk graphene oxide materials and can be useful for engineering topological structures with tunable mechanical properties. PMID- 26745015 TI - Prevalence of Cytomegalovirus IgG Antibodies among Pregnant Women Visiting Antenatal Clinic, LAUTECH Teaching Hospital in Osogbo, Osun State, Nigeria. AB - Cytomegalovirus (CMV) is one of the predominant viral infections that lead to congenital diseases and teratogenic risks during the perinatal stage. There is paucity of seroepidemiological data on anti-CMV IgG antibody in pregnant women in Osogbo, Osun State, Nigeria. This study was aimed at determining the seroprevalence of Cytomegalovirus IgG antibody among pregnant women visiting antenatal clinic, LAUTECH Teaching Hospital, Osogbo, Nigeria. One hundred and seventy-four sera from the pregnant women were screened by Enzyme linked Immunosorbent Assay (ELISA) for cytomegalovirus (CMV) IgG antibody. Data analysis was done using SPSS software. In this study, 105 of the 174 pregnant women were seropositive for CMV IgG antibodies giving an antibody prevalence of 60%. There was no association found between CMV IgG seropositivity and the subjects' demographic characteristics, however, the 60.0% prevalence of CMV-IgG antibody observed amongst pregnant women in this study demands for vaccines and regular testing for the presence of CMV and its related risk factors in antenatal clinic. PMID- 26745012 TI - Small-Incision Laparoscopy-Assisted Surgery Under Abdominal Cavity Irrigation in a Porcine Model. AB - BACKGROUND: Laparoscopic and robot-assisted surgeries are performed under carbon dioxide insufflation. Switching from gas to an isotonic irrigant introduces several benefits and avoids some adverse effects of gas insufflation. We developed an irrigating device and apparatus designed for single-incision laparoscopic surgery and tested its advantages and drawbacks during surgery in a porcine model. MATERIALS AND METHODS: Six pigs underwent surgical procedures under general anesthesia. A 30-cm extracorporeal cistern was placed over a 5-6-cm abdominal incision. The abdomen was irrigated with warm saline that was drained via a suction tube placed near the surgical field and continuously recirculated through a closed circuit equipped with a hemodialyzer as a filter. Irrigant samples from two pigs were cultured to check for bacterial and fungal contamination. Body weight was measured before and after surgery in four pigs that had not received treatments affecting hemodynamics or causing diuresis. RESULTS: One-way flow of irrigant ensured laparoscopic vision by rinsing blood from the surgical field. Through a retroperitoneal approach, cystoprostatectomy was successfully performed in three pigs, nephrectomy in two, renal excision in two, and partial nephrectomy in one, under simultaneous ultrasonographic monitoring. Through a transperitoneal approach, liver excision and hemostasis with a bipolar sealing device were performed in three pigs, and bladder pedicle excision was performed in one pig. Bacterial and fungal contamination of the irrigant was observed on the draining side of the circuit, but the filter captured the contaminants. Body weight increased by a median of 2.1% (range, 1.2 4.4%) of initial weight after 3-5 hours of irrigation. CONCLUSIONS: Surgery under irrigation is feasible and practical when performed via a cistern through a small abdominal incision. This method is advantageous, especially in the enabling of continuous and free-angle ultrasound observation of parenchymal organs. Adverse effects of abdominal irrigation need further assessment before use in humans. PMID- 26745016 TI - Retaining Large and Adjustable Elastic Strains of Kilogram-Scale Nb Nanowires. AB - Individual metallic nanowires can sustain ultralarge elastic strains of 4-7%. However, achieving and retaining elastic strains of such magnitude in kilogram scale nanowires are challenging. Here, we find that under active load, ~ 5.6% elastic strain can be achieved in Nb nanowires embedded in a metallic matrix deforming by detwinning. Moreover, large tensile (2.8%) and compressive (-2.4%) elastic strains can be retained in kilogram-scale Nb nanowires when the external load was fully removed, and adjustable in magnitude by processing control. It is then demonstrated that the retained tensile elastic strains of Nb nanowires can increase their superconducting transition temperature and critical magnetic field, in comparison with the unstrained original material. This study opens new avenues for retaining large and tunable elastic strains in great quantities of nanowires and elastic-strain-engineering at industrial scale. PMID- 26745018 TI - Cortical Evolution Conference 2015. PMID- 26745020 TI - Enhancing the Brightness of Cesium Lead Halide Perovskite Nanocrystal Based Green Light-Emitting Devices through the Interface Engineering with Perfluorinated Ionomer. AB - High photoluminescence quantum yield, easily tuned emission colors, and high color purity of perovskite nanocrystals make this class of material attractive for light source or display applications. Here, green light-emitting devices (LEDs) were fabricated using inorganic cesium lead halide perovskite nanocrystals as emitters. By introducing a thin film of perfluorinated ionomer (PFI) sandwiched between the hole transporting layer and perovskite emissive layer, the device hole injection efficiency has been significantly enhanced. At the same time, PFI layer suppressed charging of the perovskite nanocrystal emitters thus preserving their superior emissive properties, which led to the three-fold increase in peak brightness reaching 1377 cd m(-2). The full width at half maximum of the symmetric emission peak with color coordinates of (0.09, 0.76) was 18 nm, the narrowest value among perovskite based green LEDs. PMID- 26745022 TI - beta1,6-branched complex-type N-glycans affect FAK signaling in metastatic melanoma cells. AB - Integrin-dependent binding of the cell to extracellular matrix (ECM) is a key activator of the focal adhesion kinase (FAK) signaling pathway. N-glycosylation of integrins affects their interactions with ECM proteins. Using WM266-4 cells with overexpression of beta1,6-acetylglucosaminyltransferase V, we showed that beta1,6-branched N-glycans increased tyrosine phosphorylation of FAK in metastatic melanoma cells, resulting in enhanced migration on vitronectin (VN). The co-localization of alphavbeta3 integrin and FAK in focal adhesions of melanoma cells growing on VN indicates their interaction in signal transduction. Melanoma cell migration on VN was mediated by alphavbeta3 caring overexpressed beta1,6-branched structures, important for FAK upregulation. PMID- 26745024 TI - Item Overlap Correlations: Definitions, Interpretations, and Implications. AB - Four item overlap coefficient (IOC) formulae have been proposed in the literature to measure the effects of overlapping items on the relation of scales which share these items. 10C derivations of this article lead to (a) six caveats concerning the calculation and interpretation of IOCs, and (b) six possible explanations of why the factor structures of MMPI and MCMI scales appear to be strongly influenced by item overlap. PMID- 26745021 TI - Stromal cell-derived factor-1-directed bone marrow mesenchymal stem cell migration in response to inflammatory and/or hypoxic stimuli. AB - Directing cell trafficking toward a target site of interest is critical for advancing stem cell therapy in clinical theranostic applications. In this study, we investigated the effects of inflammatory and/or hypoxic stimuli on the migration of bone marrow mesenchymal stem cells (BMMSCs) during in vitro culture and after in vivo implantation. Using tablet scratch experiments and observations from a transwell system, we found that both inflammatory and hypoxic stimuli significantly enhanced cell migration. However, the combination of inflammatory and hypoxic stimuli did not result in a synergistic effect. The presence of stromal cell-derived factor-1 (SDF-1) significantly enhanced cell migration irrespective of the incubation conditions, and these positive effects could be blocked by treatment with AMD3100. Based on a time course experiment, we found that preconditioning cells with either inflammatory or hypoxic stimuli for 24 h or with both stimuli for 12 h led to high levels of chemokine receptor type 4 (CXCR4) expression. In vivo studies further demonstrated that pretreatment of BMMSCs with inflammatory and/or hypoxic stimuli resulted in an increased number of systemically injected cells migrating toward skin injuries, and local SDF-1 administration significantly increased cell migration. These findings suggest that in vitro control of either inflammatory or hypoxic stimuli has significant potential to enhance SDF-1-directed BMMSC migration via the upregulation of CXCR4 expression. Although combining the stimuli did not necessarily lead to a synergistic effect, the potential to reduce the dose and time required for cell preconditioning indicates that combinations of various strategies warrant further exploration. PMID- 26745025 TI - A Study of Multivariate Permutation Tests Which May Replace Hotelling's T2 Test in Prescribed Circumstances. AB - Multivariate permutation tests are described and studied which may be profitably substituted for Hotelling's one-sample P test in situations commonly arising in behavioral science research. These tests (a) may be computed even when the number of variables exceeds the number of subjects, (b) are distribution-free, (c) may be tailored for sensitivity to specific treatment alternatives, and (d) provide one-sided as well as two-sided tests of hypotheses. Power comparisons were made between the permutation tests and Hotelling's T(2) test under a variety of treatment effect model, correlation structure and number of variables combinations. Results show that the permutation tests have significant power advantages over the T(2) in a variety of circumstances, but may have considerably less power in others. PMID- 26745026 TI - Crossvalidation of Latent Class Models of Early Substance Use Onset. AB - Cudeck and Browne (1983) were among the first to discuss the advantages of taking a crossvalidation approach to testing of covariance structure models. The purpose of this paper is to expand on Cudeck and Browne's work in two directions. The first direction of expansion is into testing of latent class models. The second direction of expansion involves using crossvalidation to examine differences between groups, where groups may be formed by gender, ethnicity, region, etc. In the present article crossvalidation is used to help select models of early substance use onset in a sample of young adolescents. The results suggest that the nature of the substance use onset process and the rate of movement through the process are the same for males and females at seventh and eighth grade. However, the present study did find evidence for gender differences in substance use experience at the beginning of seventh grade, with males somewhat more advanced in the onset process. The results also suggest that double crossvalidation is greatly to be preferred over single crossvalidation. PMID- 26745023 TI - Sparse Sampling of Water Density Fluctuations in Interfacial Environments. AB - The free energetics of water density fluctuations near a surface, and the rare low-density fluctuations in particular, serve as reliable indicators of surface hydrophobicity; the easier it is to displace the interfacial waters, the more hydrophobic the underlying surface is. However, characterizing the free energetics of such rare fluctuations requires computationally expensive, non Boltzmann sampling methods like umbrella sampling. This inherent computational expense associated with umbrella sampling makes it challenging to investigate the role of polarizability or electronic structure effects in influencing interfacial fluctuations. Importantly, it also limits the size of the volume, which can be used to probe interfacial fluctuations. The latter can be particularly important in characterizing the hydrophobicity of large surfaces with molecular-level heterogeneities, such as those presented by proteins. To overcome these challenges, here we present a method for the sparse sampling of water density fluctuations, which is roughly 2 orders of magnitude more efficient than umbrella sampling. We employ thermodynamic integration to estimate the free energy differences between biased ensembles, thereby circumventing the umbrella sampling requirement of overlap between adjacent biased distributions. Further, a judicious choice of the biasing potential allows such free energy differences to be estimated using short simulations, so that the free energetics of water density fluctuations are obtained using only a few, short simulations. Leveraging the efficiency of the method, we characterize water density fluctuations in the entire hydration shell of the protein, ubiquitin, a large volume containing an average of more than 600 waters. PMID- 26745027 TI - Determination of the Regression Coefficients and Their Associated Standard Errors in Hierarchical Regression Analysis. AB - Hierarchical regression analysis is potentially a very useful statistical technique for establishing the significance of sets of predictor variables. However, when a hierarchical analysis which is based on theory is performed, some estimation procedures for the regression coefficients and their associated standard errors are potentially inappropriate. Specifically, the hierarchical regression equations, the incremental or hierarchical tests, and the parameter estimation of this procedure may not correspond. This problem is investigated by the development of four approaches (simultaneous, stagewise, orthogonal, and hierarchical) of estimation to the analysis. For each method, regression, coefficient estimators and their standard errors are determined. By comparison of these approaches, the use of orthogonalized sets of predictor variates or a modification to a series of simultaneous analyses are recommended as the most sensible technique for a theory driven hierarchical analysis. PMID- 26745029 TI - Production of Molecular Iodine and Tri-iodide in the Frozen Solution of Iodide: Implication for Polar Atmosphere. AB - The chemistry of reactive halogens in the polar atmosphere plays important roles in ozone and mercury depletion events, oxidizing capacity, and dimethylsulfide oxidation to form cloud-condensation nuclei. Among halogen species, the sources and emission mechanisms of inorganic iodine compounds in the polar boundary layer remain unknown. Here, we demonstrate that the production of tri-iodide (I3(-)) via iodide oxidation, which is negligible in aqueous solution, is significantly accelerated in frozen solution, both in the presence and the absence of solar irradiation. Field experiments carried out in the Antarctic region (King George Island, 62 degrees 13'S, 58 degrees 47'W) also showed that the generation of tri iodide via solar photo-oxidation was enhanced when iodide was added to various ice media. The emission of gaseous I2 from the irradiated frozen solution of iodide to the gas phase was detected by using cavity ring-down spectroscopy, which was observed both in the frozen state at 253 K and after thawing the ice at 298 K. The accelerated (photo-)oxidation of iodide and the subsequent formation of tri-iodide and I2 in ice appear to be related with the freeze concentration of iodide and dissolved O2 trapped in the ice crystal grain boundaries. We propose that an accelerated abiotic transformation of iodide to gaseous I2 in ice media provides a previously unrecognized formation pathway of active iodine species in the polar atmosphere. PMID- 26745028 TI - Heterogeneity of maternal characteristics and impact on gestational diabetes (GDM) risk-Implications for universal GDM screening? AB - OBJECTIVE: To study the incidence of gestational diabetes mellitus (GDM) in relation to phenotypic characteristics and gestational weight gain (GWG) among women at high risk for GDM. MATERIALS AND METHODS: This is a secondary analysis of a GDM prevention study (RADIEL), a randomized controlled trial conducted in Finland. 269 women with a history of GDM and/or a pre-pregnancy body mass index (BMI) >= 30 kg/m(2) were enrolled before 20 weeks of gestation and divided into four groups according to parity, BMI and previous history of GDM. The main outcome was incidence of GDM. RESULTS: There was a significant difference in incidence of GDM between the groups (p < 0.001). Women with a history of GDM and BMI <30 kg/m(2) showed the highest incidence (35.9%). At baseline they had fewer metabolic risk factors and by the second trimester they gained more weight. There was no interaction between GWG and GDM outcome and no significant difference in the prevalence of diabetes-associated antibodies. CONCLUSION: Despite a healthier metabolic profile at baseline the non-obese women with a history of GDM displayed a markedly higher cumulative incidence of GDM. GWG and the presence of diabetes associated antibodies were not associated with GDM occurrence among these high risk women. Key message Despite a healthier metabolic profile at baseline the non obese women with previous gestational diabetes mellitus display a markedly higher cumulative incidence of gestational diabetes mellitus. PMID- 26745030 TI - Possible regulation of caveolar endocytosis and flattening by phosphorylation of F-BAR domain protein PACSIN2/Syndapin II. AB - Caveolae are flask-shaped invaginations of the plasma membrane. The BAR domain proteins form crescent-shaped dimers, and their oligomeric filaments are considered to form spirals at the necks of invaginations, such as clathrin-coated pits and caveolae. PACSIN2/Syndapin II is one of the BAR domain-containing proteins, and is localized at the necks of caveolae. PACSIN2 is thought to function in the scission and stabilization of caveolae, through binding to dynamin-2 and EHD2, respectively. These two functions are considered to be switched by PACSIN2 phosphorylation by protein kinase C (PKC) upon hypotonic stress and sheer stress. The phosphorylation decreases the membrane binding affinity of PACSIN2, leading to its removal from caveolae. The removal of the putative oligomeric spiral of PACSIN2 from caveolar membrane invaginations could lead to the deformation of caveolae. Indeed, PACSIN2 removal from caveolae is accompanied by the recruitment of dynamin-2, suggesting that the removal provides space for the function of dynamin-2. Otherwise, the removal of PACSIN2 decreases the stability of caveolae, which could result in the flattening of caveolae. In contrast, an increase in the amount of EHD2 restored caveolar stability. Therefore, PACSIN2 at caveolae stabilizes caveolae, but its removal by phosphorylation could induce both caveolar endocytosis and flattening. PMID- 26745031 TI - Source apportionment of atmospheric polycyclic aromatic hydrocarbons (PAHs) in Palm Beach County, Florida. AB - Due to concerns about adverse health effects associated with inhalation of atmospheric polycyclic aromatic hydrocarbons (PAHs), 30 ambient air samples were obtained at an air quality monitoring station in Palm Beach County, Florida, from March 2013 to March 2014. The ambient PAH concentration measurements and fractional emission rates of known sources were incorporated into a chemical mass balance model, CMB8.2, developed by EPA, to apportion contributions of three major PAH sources including preharvest sugarcane burning, mobile vehicles, and wildland fires. Strong association between the number of benzene rings and source contribution was found, and mobile vehicles were identified to be the prevailing source (contribution>=56%) for the observed PAHs concentration with lower molecular weights (four or fewer benzene rings) throughout the year. Preharvest sugarcane burning was the primary contributing source for PAHs with relatively higher molecular weights (five or more benzene rings) during the sugarcane burning season (from October to May of the next year). Source contribution of wildland fires varied among PAH compounds but was consistently lower than for sugarcane burning during the sugarcane harvest season. Determining the major sources responsible for ground-level PAHs serves as a tool to improving management strategies for PAH emitting sources and a step toward better protection of the health of residents in terms of exposure to PAHs. The results obtain insight into temporal dominance of PAH polluting sources for those residential areas located near sugarcane burning facilities and have implications beyond Palm Beach County, in areas with high concerns of PAHs and their linked sources. IMPLICATIONS: Source apportionment of atmospheric polycyclic hydrocarbons (PAHs) in Palm Beach County, Florida, meant to estimate contributions of major sources in PAH concentrations measured at Belle Glade City of Palm Beach County. Number of benzene rings was found to be the key parameter in determining the source with the prevailing contribution. Mobile vehicle sources showed a higher contribution for species with four or fewer benzene rings, whereas sugarcane burning contributed more for species with five or more benzene rings. Results from this study encourage more control for sugarcane burns and help to better manage authorization of the sugarcane burning incidents and more restrictive transportation plans to limit PAH emissions from mobile vehicles. PMID- 26745032 TI - Developing and sustaining adolescent-friendly health services: A multiple case study from Ecuador and Peru. AB - Adolescent-Friendly Health Services (AFHSs) are those that are accessible, acceptable, equitable, appropriate and effective for different youth sub populations. This study investigated the process through which four clinics in two countries - Peru and Ecuador - introduced, developed and sustained AFHSs. A multiple case study design was chosen, and data from each clinic were collected through document review, observations and informant interviews. National level data were also collected. Data were analysed following thematic analysis. The findings showed that the process of introducing, developing and sustaining AFHSs was long term, and required a creative team effort and collaboration between donors, public institutions and health providers. The motivation and external support was crucial to initiating and sustaining the implementation of AFHSs. Health facilities' transformation into AFHSs was linked to the broader organisation of country health systems, and the evolution of national adolescent health policies. In Peru, the centralised approach to AFHSs introduction facilitated the dissemination of a comprehensive national model to health facilities, but dependency on national directives made it more difficult to systemise them when ideological and organisational changes occurred. In Ecuador, a less centralised approach to introducing AFHSs made for easier integration of the AFHSs model. PMID- 26745034 TI - Phage Particles as Vaccine Delivery Vehicles: Concepts, Applications and Prospects. AB - The development of new strategies for vaccine delivery for generating protective and long-lasting immune responses has become an expanding field of research. In the last years, it has been recognized that bacteriophages have several potential applications in the biotechnology and medical fields because of their intrinsic advantages, such as ease of manipulation and large-scale production. Over the past two decades, bacteriophages have gained special attention as vehicles for protein/peptide or DNA vaccine delivery. In fact, whole phage particles are used as vaccine delivery vehicles to achieve the aim of enhanced immunization. In this strategy, the carried vaccine is protected from environmental damage by phage particles. In this review, phage-based vaccine categories and their development are presented in detail, with discussion of the potential of phage-based vaccines for protection against microbial diseases and cancer treatment. Also reviewed are some recent advances in the field of phage- based vaccines. PMID- 26745035 TI - beta-Adrenergic Receptors : New Target in Breast Cancer. AB - BACKGROUND: Preclinical studies have demonstrated that beta-adrenergic receptor antagonists could improve the prognosis of breast cancer. However, the conclusions of clinical and pharmacoepidemiological studies have been inconsistent. This review was conducted to re-assess the relationship between beta-adrenoceptor blockers and breast cancer prognosis. MATERIALS AND METHODS: The literature was searched from PubMed, EMBASE and Web of Nature (Thompson Reuters) databases through using key terms, such as breast cancer and beta- adrenoceptor blockers. RESULTS: Ten publications met the inclusion criteria. Six suggested that receiving beta- adrenoceptor blockers reduced the risk of breast cancer-specific mortality, and three of them had statistical significance (hazard ratio (HR)=0.42; 95% CI=0.18-0.97; p=0.042). Two studies reported that risk of recurrence and distant metastasis (DM) were both significantly reduced. One study demonstrated that the risk of relapse- free survival (RFS) was raised significantly with beta-blockers (BBS) (HR= 0.30; 95% CI=0.10-0.87; p=0.027). One reported longer disease-free interval (Log Rank (LR)=6.658; p=0.011) in BBS users, but there was no significant association between overall survival (OS) and BBS (HR= 0.35; 95% CI=0.12-1.0; p=0.05) in five studies. CONCLUSIONS: Through careful consideration, it is suggested that beta-adrenoceptor blockers use may be associated with improved prognosis in breast cancer patients. Nevertheless, larger size studies are needed to further explore the relationship between beta blocker drug use and breast cancer prognosis. PMID- 26745033 TI - Preference for brand-name buprenorphine is related to severity of addiction among outpatients in opioid maintenance treatment. AB - As a form of opioid maintenance treatment, high-dose buprenorphine is increasingly being used in the United States. On the French market since 1996, it is the most commonly prescribed and frequently employed opioid maintenance treatment. For unknown reasons, the brand-name form is used far more often than the generic form (76-24%). The objective was to show that the patients' levels of addiction were differentiated according to the form of buprenorphine currently being used and to their previous experience of a different form. An observational study in 9 sites throughout France used self-assessment questionnaires filled out in retail pharmacies by all patients to whom their prescribed buprenorphine treatment was being delivered. The 151 canvassed pharmacies solicited 879 patients, of whom 724 completed the questionnaires. Participants were statistically similar to non-participants. The patients using the brand-name form subsequent to experience with the generic form exhibited a more elevated addiction severity index and a higher dosage than brand-name form users with no experience of a different form. Compared to generic users, their doses were higher, their was addiction more severe, and their alcohol consumption was more excessive; they were also more likely to make daily use of psychotropic substances. However, the level of misuse or illicit consumption was similar between these groups. Preferring the brand-name buprenorphine form to the generic form is associated with a higher level of severe addiction, a more frequent need for daily psychotropics, and excessive drinking; but the study was unable to show a causal link. PMID- 26745036 TI - Identification of HPV Integration and Genomic Patterns Delineating the Clinical Landscape of Cervical Cancer. AB - Cervical cancer is one of the most common cancers in women worldwide. During their life time the vast majority of women become infected with human papillomavirus (HPV), but interestingly only a small portion develop cervical cancer and in the remainder infection regresses to a normal healthy state. Beyond HPV status, associated molecular characterization of disease has to be established. However, initial work suggests the existence of several different molecular classes, based on the biological features of differentially expressed genes in each subtype. This suggests that additional risk factors play an important role in the outcome of infection. Host genomic factors play an important role in the outcome of such complex or multifactor diseases such as cervical cancer and are also known to regulate the rate of disease progression. The aim of this review was to compile advances in the field of host genomics of HPV positive and negative cervical cancer and their association with clinical response. PMID- 26745037 TI - Potential Roles of Protease Inhibitors in Cancer Progression. AB - Proteases are important molecules that are involved in many key physiological processes. Protease signaling pathways are strictly controlled, and disorders in protease activity can result in pathological changes such as cardiovascular and inflammatory diseases, cancer and neurological disorders. Many proteases have been associated with increasing tumor metastasis in various human cancers, suggesting important functional roles in the metastatic process because of their ability to degrade the extracellular matrix barrier. Proteases are also capable of cleaving non-extracellular matrix molecules. Inhibitors of proteases to some extent can reduce invasion and metastasis of cancer cells, and slow down cancer progression. In this review, we focus on the role of a few proteases and their inhibitors in tumors as a basis for cancer prognostication and therapy. PMID- 26745038 TI - Potential Benefit of Metformin as Treatment for Colon Cancer: the Evidence so Far. AB - Metformin is known as a hypoglycaemic agent that regulates glucose homeostasis by inhibiting liver glucose production and increasing muscle glucose uptake. Colorectal cancer (CRC) is one of the most common cancers worldwide, with about a million new cases diagnosed each year. The risk factors for CRC include advanced age, smoking, black race, obesity, low fibre diet, insulin resistance, and the metabolic syndrome. We have searched Medline for the metabolic syndrome and its relation to CRC, and metformin as a potential treatment of colorectal cancer. Administration of metformin alone or in combination with chemotherapy has been shown to suppress CRC. The mechanism that explains how insulin resistance is associated with CRC is complex and not fully understood. In this review we have summarised studies which showed an association with the metabolic syndrome as well as studies which tackled metformin as a potential treatment of CRC. In addition, we have also provided a summary of how metformin at the cellular level can induce changes that suppress the activity of cancer cells. PMID- 26745039 TI - DNA Methylation Biomarkers for Nasopharyngeal Carcinoma: Diagnostic and Prognostic Tools. AB - Nasopharyngeal carcinoma (NPC) is a common tumor in southern China and south eastern Asia. Effective strategies for the prevention or screening of NPC are limited. Exploring effective biomarkers for the early diagnosis and prognosis of NPC continues to be a rigorous challenge. Evidence is accumulating that DNA methylation alterations are involved in the initiation and progression of NPC. Over the past few decades, aberrant DNA methylation in single or multiple tumor suppressor genes (TSGs) in various biologic samples have been described in NPC, which potentially represents useful biomarkers. Recently, large-scale DNA methylation analysis by genome-wide methylation platform provides a new way to identify candidate DNA methylated markers of NPC. This review summarizes the published research on the diagnostic and prognostic potential biomarkers of DNA methylation for NPC and discusses the current knowledge on DNA methylation as a biomarker for the early detection and monitoring of progression of NPC. PMID- 26745040 TI - Long Non-coding RNAs and Drug Resistance. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) are emerging as key players in gene expression that govern cell developmental processes, and thus contributing to diseases, especially cancers. Many studies have suggested that aberrant expression of lncRNAs is responsible for drug resistance, a substantial obstacle for cancer therapy. Drug resistance not only results from individual variations in patients, but also from genetic and epigenetic differences in tumors. It is reported that drug resistance is tightly modulated by lncRNAs which change the stability and translation of mRNAs encoding factors involved in cell survival, proliferation, and drug metabolism. In this review, we summarize recent advances in research on lncRNAs associated with drug resistance and underlying molecular or cellular mechanisms, which may contribute helpful approaches for the development of new therapeutic strategies to overcome treatment failure. PMID- 26745041 TI - Sarcopenia in Cancer Patients. AB - Sarcopenia, characterized by a decline of skeletal muscle plus low muscle strength and/or physical performance, has emerged to be an important prognostic factor for advanced cancer patients. It is associated with poor performance status, toxicity from chemotherapy, and shorter time of tumor control. There is limited data about sarcopenia in cancer patients and associated factors. Moreover, the knowledge about the changes of muscle mass during chemotherapy and its impact to response and toxicity to chemotherapy is still lacking. This review aimed to provide understanding about sarcopenia and to emphasize its importance to cancer treatment. PMID- 26745042 TI - Benefits of Metformin Use for Cholangiocarcinoma. AB - Metformin is an oral anti-hyperglycemic agent, which is the most commonly prescribed medication in the treatment of type-2 diabetes mellitus. It is purportedly associated with a reduced risk for various cancers, mainly exerting anti-proliferation effects on various human cancer cell types, such as pancreas, prostate, breast, stomach and liver. This mini-review highlights the risk and benefit of metformin used for cholangiocarcinoma (CCA) prevention and therapy. The results indicated metformin might be a quite promising strategy CCA prevention and treatment, one mechanism being inhibition of CCA tumor growth by cell cycle arrest in both in vitro and in vivo. The AMPK/mTORC1 pathway in intrahepatic CCA cells is targeted by metformin. Furthermore, metformin inhibited CCA tumor growth via the regulation of Drosha-mediated expression of multiple carcinogenic miRNAs. The use of metformin seems to be safe in patients with cirrhosis, and provides a survival benefit. Once hepatic malignancies are already established, metformin does not offer any therapeutic potential. Clinical trials and epidemiological studies of the benefit of metformin use for CCA should be conducted. To date, whether metformin as a prospective chemotherapeutic for CCA is still questionable and waits further atttention. PMID- 26745043 TI - HPV Infection and Cervical Abnormalities in HIV Positive Women in Different Regions of Brazil, a Middle-Income Country. AB - Human papillomavirus is a virus that is distributed worldwide, and persistent infection with high-risk genotypes (HR-HPV) is considered the most important factor for the development of squamous cell cervical carcinoma (SCC). However, by itself, it is not sufficient, and other factors may contribute to the onset and progression of lesions. For example, infection with other sexually transmitted diseases such as human immunodeficiency virus (HIV) may be a factor. Previous studies have shown the relationship between HPV infection and SCC development among HIV-infected women in many regions of the world, with great emphasis on low and middle- income countries (LMICs). Brazil is considered a LMIC and has great disparities across different regions. The purpose of this review was to highlight the current knowledge about HPV infection and cervical abnormalities in HIV+ women in Brazil because this country is an ideal setting to evaluate HIV impact on SCC development and serves as model of LMICs and low-resource settings. PMID- 26745044 TI - Evaluation of the MTHFR C677T Polymorphism as a Risk Factor for Colorectal Cancer in Asian Populations. AB - BACKGROUND: Genetic and environmental factors play important roles in pathogenesis of digestive tract cancers like those in the esophagus, stomach and colorectum. Folate deficiency and methylenetetrahydrofolate reductase (MTHFR) as an important enzyme of folate and methionine metabolism are considered crucial for DNA synthesis and methylation. MTHFR variants may cause genomic hypomethylation, which may lead to the development of cancer, and MTHFR gene polymorphisms (especially C677T and A1298C) are known to influence predispositions for cancer development. Several case control association studies of MTHFR C677T polymorphisms and colorectal cancer (CRC) have been reported in different populations with contrasting results, possibly reflecting inadequate statistical power. AIM: The present meta-analysis was conducted to investigate the association between the C677T polymorphism and the risk of colorectal cancer. MATERIALS AND METHODS: A literature search of the PubMed, Google Scholar, Springer link and Elsevier databases was carried out for potential relevant articles. Pooled odds ratio (OR) with corresponding 95 % confidence interval (95 % CI) was calculated to assess the association of MTHFR C677T with the susceptibility to CRC. Cochran's Q statistic and the inconsistency index (I2) were used to check study heterogeneity. Egger's test and funnel plots were applied to assess publication bias. All statistical analyses were conducted by with MetaAnalyst and MIX version 1.7. RESULTS: Thirty four case-control studies involving a total of 9,143 cases and 11,357 controls were retrieved according to the inclusion criteria. Overall, no significant association was found between the MTHFR C677T polymorphism and colorectal cancer in Asian populations (for T vs. C: OR=1.03; 95% CI= 0.92-1.5; p= 0.64; for TT vs CC: OR=0.88; 95%CI= 0.74-1.04; p= 0.04; for CT vs. CC: OR = 1.02; 95%CI= 0.93-1.12; p=0.59; for TT+ CT vs. CC: OR=1.07; 95%CI= 0.94-1.22; p=0.87). CONCLUSIONS: Evidence from the current meta analysis indicated that the C677T polymorphism is not associated with CRC risk in Asian populations. Further investigations are needed to offer better insight into any role of this polymorphism in colorectal carcinogenesis. PMID- 26745045 TI - Psychometric Validation of the Bahasa Malaysia Version of the EORTC QLQ-CR29. AB - BACKGROUND: This study examined the psychometric properties of the Bahasa Malaysia (BM) version of the European Organization for Research and Treatment of Cancer (EORTC) Colorectal Cancer-specific Quality Of Life Questionnaire (QLQ CR29). MATERIALS AND METHODS: We studied 93 patients recruited from University Malaya and Universiti Kebangsaan Medical Centers, Kuala Lumpur, Malaysia using a self-administered method. Tools included QLQ-C30, QLQ-CR29 and Karnofsky Performance Scales (KPS). Statistical analyses included Cronbach's alpha, test retest correlations, multi-traits scaling and known-groups comparisons. A p value <= 0.05 was considered significant. RESULTS: The internal consistency coefficients for body image, urinary frequency, blood and mucus and stool frequency scales were acceptable (Cronbach's alpha alpha >= 0.65). However, the coefficients were low for the blood and mucus and stool frequency scales in patients with a stoma bag (alpha = 0.46). Test-retest correlation coefficients were moderate to high (range: r = 0.51 to 1.00) for most of the scales except anxiety, urinary frequency, buttock pain, hair loss, stoma care related problems, and dyspareunia (r <= 0.49). Convergent and discriminant validities were achieved in all scales. Patients with a stoma reported significantly higher symptoms of blood and mucus in the stool, flatulence, faecal incontinence, sore skin, and embarrassment due to the frequent need to change the stoma bag (p < 0.05) compared to patients without stoma. None of the scales distinguished between patients based on the KPS scores. There were no overlaps between scales in the QLQ-C30 and QLQ-CR29 (r < 0.40). CONCLUSIONS: the BM version of the QLQ-CR29 indicated acceptable psychometric properties in most of the scales similar to original validation study. This questionnaire could be used to complement the QLQ C30 in assessing HRQOL among BM speaking population with colorectal cancer. PMID- 26745046 TI - Psychometric Validation of the Malaysian Chinese Version of the EORTC QLQ-C30 in Colorectal Cancer Patients. AB - BACKGROUND AND AIMS: Colorectal cancer is the second most frequent cancer in Malaysia. We aimed to assess the validity and reliability of the Malaysian Chinese version of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire core (QLQ-C30) in patients with colorectal cancer. MATERIALS AND METHODS: Translated versions of the QLQ-C30 were obtained from the EORTC. A cross sectional study design was used to obtain data from patients receiving treatment at two teaching hospitals in Kuala Lumpur, Malaysia. The Malaysian Chinese version of QLQ-C30 was self-administered in 96 patients while the Karnofsky Performance Scales (KPS) was generated by attending surgeons. Statistical analysis included reliability, convergent, discriminate validity, and known-groups comparisons. Statistical significance was based on p value <=0.05. RESULTS: The internal consistencies of the Malaysian Chinese version were acceptable [Cronbach's alpha (alpha>= 0.70)] in the global health status/overall quality of life (GHS/QOL), functioning scales except cognitive scale (alpha<=0.32) in all levels of analysis, and social/family functioning scale (alpha=0.63) in patients without a stoma. All questionnaire items fulfilled the criteria for convergent and discriminant validity except question number 5, with correlation with role (r = 0.62) and social/family (r = 0.41) functioning higher than with physical functioning scales (r = 0.34). The test-retest coefficients in the GHS/QOL, functioning scales and in most of the symptoms scales were moderate to high (r = 0.58 to 1.00). Patients with a stoma reported statistically significant lower physical functioning (p=0.015), social/family functioning (p=0.013), and higher constipation (p=0.010) and financial difficulty (p=0.037) compared to patients without stoma. There was no significant difference between patients with high and low KPS scores. CONCLUSIONS: Malaysian Chinese version of the QLQ-C30 is a valid and reliable measure of HRQOL in patients with colorectal cancer. PMID- 26745047 TI - Glehnia littoralis Root Extract Induces G0/G1 Phase Cell Cycle Arrest in the MCF 7 Human Breast Cancer Cell Line. AB - Glehnia littoralis (GL) is widely used as an oriental medicine for cough, fever, stroke and other disease conditions. However, the anti-cancer properties of GL on MCF-7 human breast cancer cells have not been investigated. In order to elucidate anti-cancer properties and underlying cell death mechanisms, MCF-7cells (5 X 104/well) were treated with Glehnia littoralis root extract at 0-400 ug/ml. A hot water extract of GL root inhibited the proliferation of MCF-7 cells in a dose dependent manner. Analysis of the cell cycle after treatment of MCF-7 cells with increasing concentrations of GL root extract for 24 hours showed significant cell cycle arrest in the G1 phase. RT-PCR and Western blot analysis both revealed that GL root extract significantly increased the expression of p21 and p27 with an accompanyingdecrease in both CDK4 and cyclin D1. Our reuslts indicated that GL root extract arrested the proliferation of MCF-7 cells in G1 phase through inhibition of CDK4 and cyclin D1 via increased induction of p21 and p27. In summary, the current study showed that GL could serve as a potential source of chemotherapeutic or chemopreventative agents against human breast cancer. PMID- 26745048 TI - Anti-tumor and Chemoprotective Effect of Bauhinia tomentosa by Regulating Growth Factors and Inflammatory Mediators. AB - Cancer is a leading cause of death worldwide. Due to the toxic side effects of the commonly used chemotherapeutic drug cyclophosphamide (CTX), the use of herbal medicines with fewer side effects but having potential use as inducing anti cancer outcomes in situ has become increasingly popular. The present study sought to investigate the effects of a methanolic extract of Bauhinia tomentosa against Dalton's ascites lymphoma (DAL) induced ascites as well as solid tumors in BALB/c mice. Specifically, B. tomentosa extract was administered intraperitonealy (IP) at 10 mg/kg. BW body weight starting just after tumor cell implantation and thereafter for 10 consecutive days. In the ascites tumor model hosts, administration of extract resulted in a 52% increase in the life span. In solid tumor models, co-administration of extract and CTX significantly reduced tumor volume (relative to in untreated hosts) by 73% compared to just by 52% when the extract alone was provided. Co-administration of the extract also mitigated CTX induced toxicity, including decreases in WBC count, and in bone marrow cellularity and alpha-esterase activity. Extract treatment also attenuated any increases in serum levels of TNFalpha, iNOS, IL-1beta, IL-6, GM-CSF, and VEGF seen in tumor-bearing hosts. This study confirmed that, the potent antitumor activity of B.tomentosa extract may be associated with immune modulatory effects by regulating anti-oxidants and cytokine levels. PMID- 26745049 TI - Back Massage to Decrease State Anxiety, Cortisol Level, Blood Prsessure, Heart Rate and Increase Sleep Quality in Family Caregivers of Patients with Cancer: A Randomised Controlled Trial. AB - BACKGROUND: The objective of this study was to evaluate the effect of back massage on the anxiety state, cortisol level, systolic/diastolic blood pressure, pulse rate, and sleep quality in family caregivers of patients with cancer. MATERIALS AND METHODS: Forty-four family caregivers were randomly assigned to either the experimental or control group (22 interventions, 22 controls) after they were matched on age and gender. The intervention consisted of back massage for 15 minutes per day for a week. Main research outcomes were measured at baseline (day I) and follow-up (day 7). Unpaired t-test, paired t test and chi square test were used to analyse data. RESULTS: The majority of the caregivers were women, married, secondary school educated and housewife. State anxiety (p<0.001), cortisol level (p<0.05), systolic/diastolic blood pressure (p<0.001, p<0.01 respectively), and pulse rate (p<0.01) were significantly decreased, and sleep quality (p<0.001) increased after back massage intervention. CONCLUSIONS: The study results show that family caregivers for patients with cancer can benefit from back massage to improve state anxiety, cortisol level, blood pressure and heart rate, and sleep quality. Oncology nurses can take advantage of back massage, which is non-pharmacologic and easily implemented method, as an independent nursing action to support caregivers for patients with cancer. PMID- 26745051 TI - Extended Low Anterior Resection with a Circular Stapler in Patients with Rectal Cancer: a Single Center Experience. AB - BACKGROUND: to evaluate the outcome of stapled colo-anal anastomoses after extended low anterior resection for distal rectal carcinoma. MATERIALS AND METHODS: A retrospective study of fifty patients who underwent colo- anal anastomoses after extended low anterior resection was conducted at Imam Hospital from September 2007 up to July 2012. RESULTS: The distance of the tumor from anal verge was 3 to 8 cm. Anastomotic leakage developed in 6% of patients and defecation problems in 16% . One-year local recurrence was 6% while three-year local recurrence was 4%. One-year systemic recurrence was seen in 22% while three year systemic recurrence was seen in 20%. CONCLUSIONS: Colo-anal anastomoses after extended low anterior resection for distal rectal carcinoma can be conducted safely. PMID- 26745050 TI - Cell Cycle Modulation of MCF-7 and MDA-MB-231 by a Sub- Fraction of Strobilanthes crispus and its Combination with Tamoxifen. AB - BACKGROUND: Cell cycle regulatory proteins are suitable targets for cancer therapeutic development since genetic alterations in many cancers also affect the functions of these molecules. Strobilanthes crispus (S. crispus) is traditionally known for its potential benefits in treating various ailments. We recently reported that an active sub-fraction of S. crispus leaves (SCS) caused caspase dependent apoptosis of human breast cancer MCF-7 and MDA-MB-231 cells. MATERIALS AND METHODS: Considering the ability of SCS to also promote the activity of the antiestrogen, tamoxifen, we further examined the effect of SCS in modulating cell cycle progression and related proteins in MCF-7 and MDA-MB-231 cells alone and in combination with tamoxifen. Expression of cell cycle- related transcripts was analysed based on a previous microarray dataset. RESULTS: SCS significantly caused G1 arrest of both types of cells, similar to tamoxifen and this was associated with modulation of cyclin D1, p21 and p53. In combination with tamoxifen, the anticancer effects involved downregulation of ERalpha protein in MCF-7 cells but appeared independent of an ER-mediated mechanism in MDA-MB-231 cells. Microarray data analysis confirmed the clinical relevance of the proteins studied. CONCLUSIONS: The current data suggest that SCS growth inhibitory effects are similar to that of the antiestrogen, tamoxifen, further supporting the previously demonstrated cytotoxic and apoptotic actions of both agents. PMID- 26745052 TI - Clinical Significance of Atypical Squamous Cells of Undetermined Significance among Patients Undergoing Cervical Conization. AB - BACKGROUND: Atypical squamous cells of undetermined significance (ASCUS) feature a wide variety of cervical cells, including benign and malignant examples. The management of ASCUS is complicated. Guidelines for office gynecology in Japan recommend performing a high-risk human papillomavirus (HPV) test as a rule. The guidelines also recommend repeat cervical cytology after 6 and 12 months, or immediate colposcopy. The purpose of this study was to determine the clinical significance of ASCUS. MATERIALS AND METHODS: Between January 2012 and December 2014, a total of 162 patients underwent cervical conization for cervical intraepithelial neoplasia grade 3 (CIN3), carcinoma in situ, squamous cell carcinoma, microinvasive squamous cell carcinoma, and adenocarcinoma in situ at our hospital. The results of cervical cytology prior to conization, the pathology after conization, and high-risk HPV testing were obtained from clinical records and analyzed retrospectively. RESULTS: Based on cervical cytology, 31 (19.1%) of 162 patients were primarily diagnosed with ASCUS. Among these, 25 (80.6%) were positive for high-risk HPV, and the test results of the remaining 6 patients (19.4%) were uncertain. In the final pathological diagnosis after conization, 27 (87.1%) and 4 patients (12.9%) were diagnosed with CIN3 and carcinoma in situ, respectively. CONCLUSIONS: Although ASCUS is known as a low-risk abnormal cervical cytology, approximately 20% of patients who underwent cervical conization had ASCUS. The relationship between the cervical cytology of ASCUS and the final pathological results for CIN3 or invasive carcinoma should be investigated statistically. In cases of ASCUS, we recommend HPV tests or colposcopic examination rather than cytological follow-up, because of the risk of missing CIN3 or more advanced disease. PMID- 26745053 TI - Malignant Neoplasm Prevalence in the Aktobe Region of Kazakhstan. AB - An oncopathological state assessment was conducted among adults, children and teenagers in Aktobe region for 2004-2013. Overall the burden of mortality was in the range of 94.8-100.2 per 100,000 population, without any obvious trend over time. Ranking by pathology, the highest incidences among women were registered for breast cancer (5.8-8.4), cervix uteri (2.9-4.6), ovary (2.4-3.6) and corpus uteri, stomach, esophagus, without any marked change over time except for a slight rise in cervical cancer rates. In males, the first place in rank was trachea, bronchus and lung, followed by stomach and esophagus, which are followed by bladder, lymphoid and hematopoietic tissues pathology. Agian no clear trends were apparent over time. In children, main localizations in cancer incidence blood (acute lymphocytic leukemia, lymphosarcoma, acute myeloid leukemia, Hodgkin's disease), brain and central nervous system, bones and articular cartilages, kidneys, and eye and it's appendages, in both sexes. Similarly, in young adults, the major percentage was in blood and lymphatic tissues (acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin's disease) a significant percentage accruing to lymphosarcoma, lymphoma, other myeloid leukemia and hematological malignancies as well as tumors of brain and central nervous system, bones and articular cartilages. This initial survey provides the basis for more detailed investigation of cancer epidemiology in Aktobe, Kazakhstan. PMID- 26745054 TI - Prognostic Significance of Two Dimensional AgNOR Evaluation in Local Advanced Rectal Cancer Treated with Chemoradiotherapy. AB - The prognostic significance of AgNOR proteins in stage II-III rectal cancers treated with chemoradiotherapy was evaluated. Silver staining was applied to the 3MUm sections of parafin blocked tissues from 30 rectal cancer patients who received 5-FU based chemoradiotherapy from May 2003 to June 2006. The microscopic displays of the cells were transferred into the computer via a video camera. AgNOR area (nucleolus organizer region area) and nucleus area values were determined as a nucleolus organizer regions area/total nucleus area (NORa/ TNa). The mean NORa/TNa value was found to be 9.02+/-3.68. The overall survival and disease free survival in the high NORa/TNa (>9.02) patients were 52.2 months and 39.4 months respectively, as compared to 100.7 months and 98.4 months in the low NORa/TNa (<9.02) cases. (p<0.001 and p<0.001 respectively). In addition, the prognosis in the high NORa/TNa patients was worse than low NORa/TNa patients (p<0.05). In terms of overall survival and disease-free survival, a statistically significant negative correlation was found with the value of NORa/TNa in the correlations tests. Cox regression analyses demostrated that overall survival and disease-free survival were associated with lymph node status (negative or positive) and the NORa/TNa value. We suggest that two-dimensional AgNOR evaluation may be a safe and usable parameter for prognosis and an indicator of cell proliferation instead of AgNOR dots. PMID- 26745056 TI - Evaluation of Nutritional Status of Cancer Patients during Treatment by Patient Generated Subjective Global Assessment: a Hospital-Based Study. AB - Cancer patients frequently experience malnutrition. Cancer and cancer therapy effects nutritional status through alterations in the metabolic system and reduction in food intake. In the present study, fifty seven cancer patients were selected as subjects from the oncology ward of Cachar Cancer Hospital and Research Centre, Silchar, India. Evaluation of nutritional status of cancer patients during treatment was carried out by scored Patient-Generated Subjective Global Assessment (PG-SGA). The findings of PG-SGA showed that 15.8% (9) were well nourished, 31.6% (18) were moderately or suspected of being malnourished and 52.6% (30) were severely malnourished. The prevalence of malnutrition was highest in lip/oral (33.33%) cancer patients. The study showed that the prevalence of malnutrition (84.2%) was high in cancer patients during treatment. PMID- 26745055 TI - Epidemiological Study on Breast Cancer Associated Risk Factors and Screening Practices among Women in the Holy City of Varanasi, Uttar Pradesh, India. AB - BACKGROUND: Breast cancer is the second most cause of death (1.38 million, 10.9% of all cancer) worldwide after lung cancer. In present study, we assess the knowledge, level of awareness of risk factors and screening practices especially breast self examination (BSE) among women, considering the non-feasibility of diagnostic tools such as mammography for breast screening techniques of breast cancer in the holy city Varanasi, Uttar Pradesh, India. MATERIALS AND METHODS: A cross-sectional population based survey was conducted. The investigation tool adopted was self administrated questionnaire format. Data were analysed using SPSS 20 version and Chi square test to determine significant association between various education groups with awareness and knowledge, analysis of variance was applied in order to establish significance. RESULTS: The attitude of participants in this study, among 560 women 500 (89%) responded (age group 18-65 years), 53.8% were married. The knowledge about BSE was very low (16%) and out of them 15.6% were practised BSE only once in life time. study shown that prominent age at which women achieve their parity was 20 yrs, among 500 participants 224 women have achieved their parity from age 18 to 30 yrs. Very well known awareness about risk factors of breast cancer were alcohol (64.6%), smoking (64%) and least known awareness risk factors were early menarche (17.2%) and use of red meat (23%). The recovery factors of breast cancer cases were doctors support (95%) and family support (94.5%) as most familiar responses of the holy city Varanasi. CONCLUSIONS: The study revealed that the awareness about risk factors and practised of BSE among women in Varanasi is extremely low in comparison with other cities and countries as well (Delhi, Mumbai, Himachal Pradesh, Turkey and Nigeria). However, doctors and health workers may promote the early diagnosis of breast cancer. PMID- 26745057 TI - HeLa Cells Containing a Truncated Form of DNA Polymerase Beta are More Sensitized to Alkylating Agents than to Agents Inducing Oxidative Stress. AB - The present study was aimed at determining the effects of alkylating and oxidative stress inducing agents on a newly identified variant of DNA polymerase beta (polbeta Delta208-304) specific for ovarian cancer. Pol beta Delta208-304 has a deletion of exons 11-13 which lie in the catalytic part of enzyme. We compared the effect of these chemicals on HeLa cells and HeLa cells stably transfected with this variant cloned into in pcDNAI/neo vector by MTT, colony forming and apoptosis assays. Polbeta Delta208-304 cells exhibited greater sensitivity to an alkylating agent and less sensitivity towards H2O2 and UV when compared with HeLa cells alone. It has been shown that cell death in Pol beta Delta208-304 transfected HeLa cells is mediated by the caspase 9 cascade. Exon 11 has nucleotidyl selection activity, while exons 12 and 13 have dNTP selection activity. Hence deletion of this part may affect polymerizing activity although single strand binding and double strand binding activity may remain same. The lack of this part may adversely affect catalytic activity of DNA polymerase beta so that the variant may act as a dominant negative mutant. This would represent clinical significance if translated into a clinical setting because resistance to radiation or chemotherapy during the relapse of the disease could be potentially overcome by this approach. PMID- 26745059 TI - Identification and Pharmacological Analysis of High Efficacy Small Molecule Inhibitors of EGF-EGFR Interactions in Clinical Treatment of Non-Small Cell Lung Carcinoma: a Computational Approach. AB - Inhibition of EGFR-EGF interactions forms an important therapeutic rationale in treatment of non-small cell lung carcinoma. Established inhibitors have been successful in reducing proliferative processes observed in NSCLC, however patients suffer serious side effects. Considering the narrow therapeutic window of present EGFR inhibitors, the present study centred on identifying high efficacy EGFR inhibitors through structure based virtual screening strategies. Established inhibitors - Afatinib, Dacomitinib, Erlotinib, Lapatinib, Rociletinib formed parent compounds to retrieve similar compounds by linear fingerprint based tanimoto search with a threshold of 90%. The compounds (parents and respective similars) were docked at the EGF binding cleft of EGFR. Patch dock supervised protein-protein interactions were established between EGF and ligand (query and similar) bound and free states of EGFR. Compounds ADS103317, AKOS024836912, AGN PC-0MXVWT, GNF-Pf-3539, SCHEMBL15205939 were retrieved respectively similar to Afatinib, Dacomitinib, Erlotinib, Lapatinib, Rociletinib. Compound- AGN-PC-0MXVWT akin to Erlotinib showed highest affinity against EGFR amongst all the compounds (parent and similar) assessed in the study. Further, AGN-PC-0MXVWT brought about significant blocking of EGFR-EGF interactions in addition showed appreciable ADMET properties and pharmacophoric features. In the study, we report AGN-PC 0MXVWT to be an efficient and high efficacy inhibitor of EGFR-EGF interactions identified through computational approaches. PMID- 26745058 TI - Detection of High-Risk Human Papillomaviruses in the Prevention of Cervical Cancer in India. AB - Human papillomaviruses (HPVs) are small, non-enveloped, double-stranded DNA viruses that infect epithelial tissues. Specific genotypes of human papillomavirus are the single most common etiological agents of cervical intraepithelial lesions and cervical cancer. Cervical cancer usually arises at squamous metaplastic epithelium of transformation zone (TZ) of the cervix featuring infection with one or more oncogenic or high-risk HPV (HR- HPV) types. A hospital- based study in a rural set up was carried out to understand the association of HR-HPV with squamous intraepithelial lesions (SILs) and cervical cancer. In the present study, HR-HPV was detected in 65.7% of low-grade squamous intraepithelial lesions (LSILs), 84.6% of high-grade squamous intraepithelial lesions (HSILs) and 94% of cervical cancer as compared to 10.7% of controls. The association of HPV infection with SIL and cervical cancer was analyzed with Chi square test (p<0.001). The significant association found confirmed that detection of HR-HPV is a suitable candidate for early identification of cervical precancerous lesions and in the prevention of cervical cancer in India. PMID- 26745060 TI - FHIT Gene Expression in Acute Lymphoblastic Leukemia and its Clinical Significance. AB - BACKGROUND: To investigate the expression of the fragile histidine triad (FHIT) gene in acute lymphoblastic leukemia and its clinical significance. MATERIALS AND METHODS: The level of expressed FHIT mRNA in peripheral blood from 50 patients with acute lymphoblastic leukemia (ALL) and in 50 peripheral blood samples from healthy volunteers was measured via RT-PCR. Correlation analyses between FHIT gene expression and clinical characteristics (gender, age, white blood count, immunophenotype of acute lymphoblastic leukemia and percentage of blast cells) of the patients were performed. RESULTS: The FHIT gene was expressed at 2.49+/-7.37 of ALL patients against 14.4+/-17.9 in the healthy volunteers. The difference in the expression levels between ALL patients and healthy volunteers was statistically significant. The rate of gene expression did not significantly vary with immunophenotype subtypes. Gene expression was also found to be correlated with increase of total leukocyte and decrease in platelets, but not with age, gender, immunophenotyping or percentage of blast cells. CONCLUSIONS: FHIT gene expression is low in acute lymphoblastic leukemia and could be a useful marker to monitor minimal residual disease. This gene is also a candidate target for the immunotherapy of acute lymphoblastic leukemia. PMID- 26745061 TI - Is Immunohistochemical Sex Hormone Binding Globulin Expression Important in the Differential Diagnosis of Adenocarcinomas? AB - Adenocarcinomas (AC) are the most frequently encountered carcinomas. It may be quite challenging to detect the primary origin when those carcinomas metastasize and the first finding is a metastatic tumor. This study evaluated the role of sex hormone binding globulin (SHBG) positivity in tumor cells in the subclassification and detection of the original organ of adenocarcinomas. Between 1994 and 2008, 64 sections of normal tissue belonging to ten organs, and 116 cases diagnosed as adenoid cystic carcinoma and mucoepidermoid carcinoma of the salivary gland, lung adenocarcinoma, invasive ductal carcinoma of the breast, adenocarcinoma of stomach, colon, gallbladder, pancreas and prostate, endometrial adenocarcinoma and serous adenocarcinoma and mucinous adenocarcinoma of the ovary, were sent to the laboratory at the Department of Pathology at the Yuzuncu Yil University School of Medicine, where they were stained immunohistochemically, using antibodies against SHBG. The SHBG immunoreactivity in both the tumor cells and normal cells, together with the type, diffuseness and intensity of the staining were then evaluated. In the differential diagnosis of the adenocarcinomas of the organs, including the glandular structures, impressively valuable results are encountered in the tumor cells, whether the SHBG immunopositivity is evaluated alone or together with other IHC markers. Further extensive research with a larger number of cases, including instances of cholangiocarcinoma and cervix uteri AC [which we could not include in the study for technical reasons] should be performed, in order to appropriately evaluate the role of SHBG in the differential diagnosis of AC. PMID- 26745062 TI - Levels of Conscience and Related Factors among Iranian Oncology Nurses. AB - BACKGROUND: Having a conscience is one of the main pre-requisite of providing nursing care. The knowledge regarding levels of conscience among nurses in eastern countries is limited. So, the purpose of this study was to examine the level of conscience and its related factors among Iranian oncology nurses. MATERIALS AND METHODS: This descriptive-correlational study was conducted in 3 hospitals in Tabriz, Iran. Overall, 68 nurses were selected using a non probability sampling method. The perceptions of conscience questionnaire was used to identify the levels of conscience among nurses. The data were analyzed using SPSS version 13.0. RESULTS: The mean nurses' level of conscience scores was 72.7. In the authority and asset sub-scales nurses acquired higher scores. The mean of nurses' scores in burden and depending on culture sub-scales were the least. Also, there were no statistical relationship between some demographic characteristics of participants and their total score on the perceptions of conscience questionnaire. CONCLUSIONS: According to study findings Iranian nurses had high levels of conscience. However, understanding all the factors that affect nurses' perception of conscience requires further studies. PMID- 26745063 TI - Oral Non Squamous Cell Malignant Tumors in an Iranian Population: a 43 year Evaluation. AB - BACKGROUND: The prevalence of non-squamous cell malignant tumors of the oral cavity has not been evaluated in Iran extensively. The aim of this study was to evaluate epidemiological aspects of the oral malignancies with non-squamous cell origin during a 43-year period in the Faculty of Dentistry, Mashhad University of Medical Sciences, Iran. MATERIALS AND METHODS: In this retrospective study, the records of all patients referred to dental school of Mashhad university of medical sciences in northeast of Iran, during the period 1971-2013 were evaluated. All confirmed samples of oral non squamous cell malignant tumors were included in this study. Demographic information including age, gender and location of the lesions were extracted from patient's records. Data were analyzed using SPSS statistical soft ware, Chi-square and Fisher's exact tests. RESULTS: Among 11,126 patients, 188 (1.68%) non squamous cell malignant tumors were found, with mean age of 39.9 years ranging from 2 to 92 years. The most common tumors were mucoepidermoid carcinoma (33 cases) and lymphoma (32 cases). Non squamous cell malignant tumors occurred almost equally in men (94 cases) and women (93 cases). Most (134 cases) of them were located peripherally with high frequency in salivary glands (89 cases) and 52 cases were centrally with high frequency in the mandible (38 cases). CONCLUSIONS: More findings in this survey were similar to those reported from other studies with differences in some cases; it may be due to variation in the sample size, geographic and racial differences in tumors. PMID- 26745064 TI - Misclassification Adjustment of Family History of Breast Cancer in a Case-Control Study: a Bayesian Approach. AB - BACKGROUND: Misreporting self-reported family history may lead to biased estimations. We used Bayesian methods to adjust for exposure misclassification. MATERIALS AND METHODS: A hospital-based case-control study was used to identify breast cancer risk factors among Iranian women. Three models were jointly considered; an outcome, an exposure and a measurement model. All models were fitted using Bayesian methods, run to achieve convergence. RESULTS: Bayesian analysis in the model without misclassification showed that the odds ratios for the relationship between breast cancer and a family history in different prior distributions were 2.98 (95% CRI: 2.41, 3.71), 2.57 (95% CRI: 1.95, 3.41) and 2.53 (95% CRI: 1.93, 3.31). In the misclassified model, adjusted odds ratios for misclassification in the different situations were 2.64 (95% CRI: 2.02, 3.47), 2.64 (95% CRI: 2.02, 3.46), 1.60 (95% CRI: 1.07, 2.38), 1.61 (95% CRI: 1.07, 2.40), 1.57 (95% CRI: 1.05, 2.35), 1.58 (95% CRI: 1.06, 2.34) and 1.57 (95% CRI: 1.06, 2.33). CONCLUSIONS: It was concluded that self-reported family history may be misclassified in different scenarios. Due to the lack of validation studies in Iran, more attention to this matter in future research is suggested, especially while obtaining results in accordance with sensitivity and specificity values. PMID- 26745065 TI - Polymorphisms in Heat Shock Proteins A1B and A1L (HOM) as Risk Factors for Oesophageal Carcinoma in Northeast India. AB - BACKGROUND: To investigate polymorphisms in heat shock proteins A1B and A1L (HOM) and associated risk of oesophageal carcinoma in Northeast India. MATERIALS AND METHODS: The study includes oesophageal cancer (ECA) patients attending general outpatient department (OPD) and endoscopic unit of Gauhati Medical College. Patients were diagnosed based on endoscopic and histopathological findings. Genomic DNA was typed for HSPA1B1267 and HSPA1L2437 SNPs using the polymerase chain reaction with restriction fragment length polymorphisms. RESULTS: A total of 78 cases and 100 age-sex matched healthy controls were included in the study with a male: female ratio of 5:3 and a mean age of 61.4+/-8.5 years. Clinico pathological evaluation showed 84% had squamous cell carcinoma and 16% were adenocarcinoma. Dysphagia grades 4 (43.5%) and 5 (37.1%) were observed by endoscopic and hispathological evaluation. The frequency of genomic variation of A1B from wild type A/A to heterozygous A/G and mutant G/G showed a positive association [chi sq=19.9, p= <0.05] and the allelic frequency also showed a significant correlation [chi sq=10.3, with cases vs. controls, OR=0.32, p<=0.05]. The genomic variation of A1L from wild T/T to heterozygous T/C and mutant C/C were found positively associated [chi sq= 7.02, p<0.05] with development of ECA. While analyzing the allelic frequency, there was no significant association [chi sq= 3.19, OR=0.49, p=0.07]. Among all the risk factors, betel quid [OR =9.79, Chi square= 35.0, p<0.05], tobacco [OR = 2.95, chi square=10.6, p<0.05], smoking [OR=3.23, chi square=10.1, p<0.05] demonstrated significant differences between consumers vs. non consumers regarding EC development. Alcohol did not show any significant association [OR= 1.34, chi square=0.69, p=0.4] independently. CONCLUSIONS: It can be concluded that the present study provides marked evidence that polymorphisms of HSP70 A1B and HSP70 A1L genes are associated with the development of ECA in a population in Northeast India, A1B having a stronger influence. Betel quid consumption was found to be a highly significant risk factor, followed by smoking and tobacco chewing. Although alcohol was not a potent risk factor independently, alcohol consumption along with tobacco, smoking and betel nut was found to contribute to development of ECA. PMID- 26745066 TI - Clinico-Pathological Profile and Haematological Abnormalities Associated with Lung Cancer in Bangalore, India. AB - BACKGROUND: Lung cancer is one of the most common types of cancer causing high morbidity and mortality worldwide. An increasing incidence of lung cancer has been observed in India. OBJECTIVES: To evaluate the clinic- pathological profile and haematological abnormalities associated with lung cancer in Bangalore, India. MATERIALS AND METHODS: This prospective study was carried out over a period of 2 years. A total of 96 newly diagnosed and histopathologically confirmed cases of lung cancer were included in the study. RESULTS: Our lung cancer cases had a male to female ratio of 3:1. Distribution of age varied from 40 to 90 years, with a major contribution in the age group between 61 and 80 years (55.2%). Smoking was the commonest risk factor found in 69.7% of patients. The most frequent symptom was cough (86.4%) followed by loss of weight and appetite (65.6%) and dyspnea (64.5%). The most common radiological presentation was a mass lesion (55%). The most common histopathological type was squamous cell carcinoma (47.9%), followed by adenocarcinoma (28.1%) and small cell carcinoma (12.5%). Distant metastasis at presentation was seen in 53.1% patients. Among the haematological abnormalities, anaemia was seen in 61.4% of patients, leucocytosis in 36.4%, thrombocytosis in 14.5% and eosinophilia in 19.7% of patients. Haematological abnormalities were more commonly seen in non small cell lung cancer. CONCLUSIONS: Squamous cell carcinoma was found to be the most common histopathological type and smoking still remains the major risk factor for lung cancer. Haematological abnormalities are frequently observed in lung cancer patients, anaemia being the commonest of all. PMID- 26745067 TI - Human Papillomavirus E6 Knockdown Restores Adenovirus Mediated-estrogen Response Element Linked p53 Gene Transfer in HeLa Cells. AB - The p53 gene is inactivated by the human papillomavirus (HPV) E6 protein in the majority of cervical cancers. Treatment of HeLa S3 cells with siRNA for HPV E6 permitted adenovirus-mediated transduction of a p53 gene linked to an upstream estrogen response element (ERE). Our previous study in non-siRNA treated HHUA cells, which are derived from an endometrial cancer and express estrogen receptor beta, showed enhancing effects of an upstream ERE on adenovirus-mediated p53 gene transduction. In HeLa S3 cells treated with siRNA for HPV E6, adenovirus-mediated transduction was enhanced by an upstream ERE linked to a p53 gene carrying a proline variant at codon 72, but not for a p53 gene with arginine variant at codon 72. Expression levels of p53 mRNA and Coxsackie/adenovirus receptor (CAR) mRNA after adenovirus-mediated transfer of an ERE-linked p53 gene (proline variant at codon 72) were higher compared with those after non-ERE-linked p53 gene transfer in siRNA-treated HeLa S3 cells. Western blot analysis showed lower beta-tubulin levels and comparatively higher p53/beta-tubulin or CAR /beta tubulin ratios in siRNA-treated HeLa S3 cells after adenovirus-mediated ERE linked p53 gene (proline variant at codon 72) transfer compared with those in non siRNA-treated cells. Apoptosis, as measured by annexin V binding, was higher after adenovirus-mediated ERE-linked p53 gene (proline variant at codon 72) transfer compared with that after non-ERE-linked p53 gene transfer in siRNA treated cells. PMID- 26745068 TI - Promoter Methylation Status of Two Novel Human Genes, UBE2Q1 and UBE2Q2, in Colorectal Cancer: a New Finding in Iranian Patients. AB - BACKGROUND: The ubiquitin-proteasome system (UPS) degrades a variety of proteins which attach to specific signals. The ubiquitination pathway facilitates degradation of damaged proteins and regulates growth and stress responses. This pathway is altered in various cancers, including acute lymphoblastic leukemia, head and neck squamous cell carcinoma and breast cancer. Recently it has been reported that expression of newly characterized human genes, UBE2Q1 and UBE2Q2, putative members of ubiquitin-conjugating enzyme family (E2), has been also changed in colorectal cancer. Epigenetics is one of the fastest-growing areas of science and nowadays has become a central issue in biological studies of diseases. According to the lack of information about the role of epigenetic changes on gene expression profiling of UBE2Q1 and UBE2Q2, and the presence of CpG islands in the promoter of these two human genes, we decided to evaluate the promoter methylation status of these genes as a first step. MATERIALS AND METHODS: The promoter methylation status of UBE2Q1 and UBE2Q2 was studied by methylation-specific PCR (MSP) in tumor samples of 60 colorectal cancer patients compared to adjacent normal tissues and 20 non-malignant controls. The frequency of the methylation for each gene was analyzed by chi-square method. RESULTS: MSP results revealed that UBE2Q2 gene promoter were more unmethylated, while a higher level of methylated allele was observed for UBE2Q1 in tumor tissues compared to the adjacent normal tissues and the non malignant controls. CONCLUSIONS: UBE2Q1 and UBE2Q2 genes show different methylation profiles in CRC cases. PMID- 26745069 TI - Plasma Soluble CD30 as a Possible Marker of Adult T-cell Leukemia in HTLV-1 Carriers: a Nested Case-Control Study. AB - Elevated levels of soluble CD30 (sCD30) are linked with various T-cell neoplasms. However, the relationship between sCD30 levels and the development of adult T cell leukemia (ATL) in human T-cell leukemia virus type 1 (HTLV-1) carriers remains to be clarified. We here investigated whether plasma sCD30 is associated with risk of ATL in a nested case-control study within a cohort of HTLV-1 carriers. We compared sCD30 levels between 11 cases (i.e., HTLV-1 carriers who later progressed to ATL) and 22 age-, sex- and institution-matched control HTLV-1 carriers (i.e., those with no progression). The sCD30 concentration at baseline was significantly higher in cases than in controls (median 65.8, range 27.2-134.5 U/mL vs. median 22.2, range 8.4-63.1 U/mL, P=0.001). In the univariate logistic regression analysis, a higher sCD30 (>=30.2 U/mL) was significantly associated with ATL development (odds ratio 7.88 and the 95% confidence intervals 1.35-45.8, P = 0.02). Among cases, sCD30 concentration tended to increase at the time of diagnosis of aggressive-type ATL, but the concentration was stable in those developing the smoldering-type. This suggests that sCD30 may serve as a predictive marker for the onset of aggressive-type ATL in HTLV-1 carriers. PMID- 26745071 TI - Cost-Utility of "Doxorubicin and Cyclophosphamide" versus "Gemcitabine and Paclitaxel" for Treatment of Patients with Breast Cancer in Iran. AB - PURPOSE: A cost-utility analysis was performed to assess the cost-utility of neoadjuvant chemotherapy regimens containing doxorubicin and cyclophosphamide (AC) versus paclitaxel and gemcitabine (PG) for locally advanced breast cancer patients in Iran. MATERIALS AND METHODS: This cross-sectional study in Namazi hospital in Shiraz, in the south of Iran covered 64 breast cancer patients. According to the random numbers, the patients were divided into two groups, 32 receiving AC and 32 PG. Costs were identified and measured from a community perspective. These items included medical and non-medical direct and indirect costs. In this study, a data collection form was used. To assess the utility of the two regimens, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core30 (EORTC QLQ-C30) was applied. Using a decision tree, we calculated the expected costs and quality adjusted life years (QALYs) for both methods; also, the incremental cost-effectiveness ratio was assessed. RESULTS: The results of the decision tree showed that in the AC arm, the expected cost was 39,170 US$ and the expected QALY was 3.39 and in the PG arm, the expected cost was 43,336 dollars and the expected QALY was 2.64. Sensitivity analysis showed the cost effectiveness of the AC and ICER=-5535 US$. CONCLUSIONS: Overall, the results showed that AC to be superior to PG in treatment of patients with breast cancer, being less costly and more effective. PMID- 26745070 TI - Upregulation of Mir-34a in AGS Gastric Cancer Cells by a PLGA-PEG-PLGA Chrysin Nano Formulation. AB - BACKGROUND: Nano-therapy has the potential to revolutionize cancer therapy. Chrysin, a natural flavonoid, was recently recognized as having important biological roles in chemical defenses and nitrogen fixation, with anti inflammatory and anti-oxidant effects but the poor water solubility of flavonoids limitstheir bioavailability and biomedical applications. OBJECTIVE: Chrysin loaded PLGA-PEG-PLGA was assessed for improvement of solubility, drug tolerance and adverse effects and accumulation in a gastric cancer cell line (AGS). MATERIALS AND METHODS: Chrysin loaded PLGA-PEG copolymers were prepared using the double emulsion method (W/O/W). The morphology and size distributions of the prepared PLGA-PEG nanospheres were investigated by 1H NMR, FT-IR and SEM. The in vitro cytotoxicity of pure and nano-chrysin was tested by MTT assay and miR-34a was measured by real-time PCR. RESULTS: 1H NMR, FT-IR and SEM confirmed the PLGA PEG structure and chrysin loaded on nanoparticles. The MTT results for different concentrations of chrysin at different times for the treatment of AGS cell line showed IC50 values of 68.2, 56.2 and 42.3 MUM and 58.2, 44.2, 36.8 MUM after 24, 48, and 72 hours of treatment, respectively for chrysin itslef and chrysin-loaded nanoparticles. The results of real time PCR showed that expression of miR-34a was upregulated to a greater extent via nano chrysin rather than free chrysin. CONCLUSIONS: Our study demonstrates chrysin loaded PLGA-PEG promises a natural and efficient system for anticancer drug delivery to fight gastric cancer. PMID- 26745072 TI - Altered Cell to Cell Communication, Autophagy and Mitochondrial Dysfunction in a Model of Hepatocellular Carcinoma: Potential Protective Effects of Curcumin and Stem Cell Therapy. AB - BACKGROUND: Hepato-carcinogenesis is multifaceted in its molecular aspects. Among the interplaying agents are altered gap junctions, the proteasome/autophagy system, and mitochondria. The present experimental study was designed to outline the roles of these players and to investigate the tumor suppressive effects of curcumin with or without mesenchymal stem cells (MSCs) in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Adult female albino rats were divided into normal controls and animals with HCC induced by diethyl-nitrosamine (DENA) and CCl4. Additional groups treated after HCC induction were: Cur/HCC which received curcumin; MSCs/HCC which received MSCs; and Cur+MSCs/ HCC which received both curcumin and MSCs. For all groups there were histopathological examination and assessment of gene expression of connexin43 (Cx43), ubiquitin ligase-E3 (UCP 3), the autophagy marker LC3 and coenzyme-Q10 (Mito.Q10) mRNA by real time, reverse transcription-polymerase chain reaction, along with measurement of LC3II/LC3I ratio for estimation of autophagosome formation in the rat liver tissue. In addition, the serum levels of ALT, AST and alpha fetoprotein (AFP), together with the proinflammatory cytokines TNFalpha and IL-6, were determined in all groups. RESULTS: Histopathological examination of liver tissue from animals which received DENA-CCl4 only revealed the presence of anaplastic carcinoma cells and macro-regenerative nodules. Administration of curcumin, MSCs; each alone or combined into rats after induction of HCC improved the histopathological picture. This was accompanied by significant reduction in alpha-fetoprotein together with proinflammatory cytokines and significant decrease of various liver enzymes, in addition to upregulation of Cx43, UCP-3, LC3 and Mito.Q10 mRNA. CONCLUSIONS: Improvement of Cx43 expression, nonapoptotic cell death and mitochondrial function can repress tumor growth in HCC. Administration of curcumin and/or MSCs have tumor suppressive effects as they can target these mechanisms. However, further research is still needed to verify their effectiveness. PMID- 26745073 TI - High Prevalence of Helicobacter pylori Resistance to Clarithromycin: a Hospital Based Cross-Sectional Study in Nakhon Ratchasima Province, Northeast of Thailand. AB - BACKGROUND: Helicobacter pylori is a cause of chronic gastritis, peptic ulcer disease, and gastric malignancy, infection being a serious health problem in Thailand. Recently, clarithromycin resistant H. pylori strains represent the main cause of treatment failure. Therefore this study aimed to determine the prevalence and pattern of H. pylori resistance to clarithromycin in Suranaree University of Technology Hospital, Suranree University of Technology, Nakhon Ratchasima, Northeastern Thailand, Nakhon Ratchasima province, northeast of Thailand. MATERIALS AND METHODS: This hospital-based cross-sectional study was carried out between June 2014 and February 2015 with 300 infected patients interviewed and from whom gastric mucosa specimens were collected and proven positive by histology. The gastric mucosa specimens were tested for H. pylori and clarithromycin resistance by 23S ribosomal RNA point mutations analysis using real-time polymerase chain reactions. Correlation of eradication rates with patterns of mutation were analyzed by chi-square test. RESULTS: Of 300 infected patients, the majority were aged between 47-61 years (31.6%), female (52.3%), with monthly income between 10,000-15,000 Baht (57%), and had a history of alcohol drinking (59.3%). Patient symptoms were abdominal pain (48.6%), followed by iron deficiency anemia (35.3%). Papaya salad consumption (40.3%) was a possible risk factor for H. pylori infection. The prevalence of H. pylori strains resistant to clarithromycin was 76.2%. Among clarithromycin-resistant strains tested, all were due to the A2144G point mutation in the 23S rRNA gene. Among mutations group, wild type genotype, mutant strain mixed wild type and mutant genotype were 23.8%, 35.7% and 40.5% respectively. With the clarithromycin-based triple therapy regimen, the efficacy decreased by 70% for H. pylori eradication (P<0.01). CONCLUSIONS: Recent results indicate a high rate of H. pylori resistance to clarithromycin. Mixed of wild type and mutant genotype is the most common mutant genotype in Nakhon Ratchasima province, therefore the use of clarithromycin-based triple therapy an not advisable as an empiric first-line regimen for H. pylori eradication in northeast region of Thailand. PMID- 26745074 TI - Thymidylate Synthase Polymorphisms and Risk of Lung Cancer among the Jordanian Population: a Case Control Study. AB - BACKGROUND: Thymidylate synthase (TS) catalyzes the methylation of deoxyuridylate to deoxythymidylate and is involved in DNA methylation, synthesis and repair. Two common polymorphisms have been reported, tandem repeats in the promoter-enhancer region (TSER), and 6bp ins/del in the 5'UTR, that are implicated in a number of human diseases, including cancer. The association between the two polymorphisms in risk for lung cancer (LC) was here investigated in the Jordanian population. MATERIALS AND METHODS: An age, gender, and smoking-matched case-control study involving 84 lung cancer cases and 71 controls was conducted. The polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) technique was used to detect the polymorphism of interest. RESULTS: Individuals bearing the ins/ins genotype were 2.5 times more likely to have lung cancer [(95%CI: 0.98 6.37), p=0.051]. Individuals who were less than or equal to 57 years and carrying ins/ins genotype were 4.6 times more susceptible to lung cancer [OR<57 vs >57years: 4.6 (95%CI: 0.93-22.5), p=0.059)]. Genotypes and alleles of TSER were distributed similarly between cases and controls. Weak linkage disequilibrium existed between the two loci of interest (Lewontin's coefficient [D']) (LC: D' =0.03, r2: 0. 001, p= 0.8; CONTROLS: D' =0.29, r2: 0.08, p=0.02). Carriers of the "3 tandem repeats_insertion" haplotype (3R_ins) were 2 times more likely to have lung cancer [2 (95%CI: 1.13-3.48), p=0.061]. CONCLUSIONS: Genetic polymorphism of TS at 3' UTR and its haplotype analysis may modulate the risk of lung cancer in Jordanians. The 6bp ins/del polymorphism of TS at 3 'UTR is more informative than TSER polymorphism in predicting increased risk. PMID- 26745076 TI - Plasma Circulating Cell-free Nuclear and Mitochondrial DNA as Potential Biomarkers in the Peripheral Blood of Breast Cancer Patients. AB - BACKGROUND: In Egypt, breast cancer is estimated to be the most common cancer among females. It is also a leading cause of cancer-related mortality. Use of circulating cell-free DNA (ccf-DNA) as non-invasive biomarkers is a promising tool for diagnosis and follow-up of breast cancer (BC) patients. OBJECTIVE: To assess the role of circulating cell free DNA (nuclear and mitochondrial) in diagnosing BC. MATERIALS AND METHODS: Multiplex real time PCR was used to detect the level of ccf nuclear and mitochondrial DNA in the peripheral blood of 50 breast cancer patients together with 30 patients with benign lesions and 20 healthy controls. Laboratory investigations, histopathological staging and receptor studies were carried out for the cancer group. Receiver operating characteristic curves were used to evaluate the performance of ccf-nDNA and mtDNA. RESULTS: The levels of both nDNA and mtDNA in the cancer group were significantly higher in comparison to the benign and the healthy control group. There was a statistically significant association between nDNA and mtDNA levels and well established prognostic parameters; namely, histological grade, tumour stage, lymph node status andhormonal receptor status. CONCLUSIONS: Our data suggests that nuclear and mitochondrial ccf-DNA may be used as non-invasive biomarkers in BC. PMID- 26745075 TI - Retrospective Evaluation of Risk Factors and Immunohistochemical Findings for Pre Neoplastic and Neoplastic lesions of Upper Urinary Tract in Patients with Chronic Nephrolithiasis. AB - BACKGROUND: Urinary stones are known predisposing factors for upper urinary tract carcinoma (UUTC) which are commonly detected at advanced stage with poor outcome because of rarity and lack of specific criteria for early detection. AIMS AND OBJECTIVES: The main aim was to evaluate the impact of age, gender andstone characteristics on risk of developing UUTC in patients with chronic nephrolithiasis. We also discuss the role of aberrant angiogenesis (AA) and immunohistochemical expression of p53, p16INK4a, CK20 and Ki-67 in diagnosis of pelvicalyceal neoplastic (NL) and pre-neoplastic lesions (PNL) in these patients. MATERIALS AND METHODS: Retrospective analysis of pelvicalyceal urothelial lesions from 88 nephrectomy specimens were carried out in a tertiary care centre from June 2012 to December 2014. Immunohistochemistry (IHC) was performed on 37 selected cases. Computed image analysis was performed to analyse aberrant angiogenesis. RESULTS: All UUTC (5.7%) and metaplastic lesions were found to be associated with stones. Some 60% were pure squamous cell carcinoma and 40% were transitional cell carcinoma. Odd ratios for developing NL and PNL lesions in presence of renal stone, impacted stones, multiple and large stag horn stones were 9.39 (95% CI 1.15-76.39, p value 0.05), 6.28 (95% CI 1.59-24.85, p value 0.000) and 7.4 (95% CI, 2.29-23.94, p value 0.001) respectively. When patient age was >= 55, the odds ratio for developing NL was 3.43 (95% CI 1.19-9.88, p value 0.019). IHC analysis showed that mean Ki-67 indices were 3.15 +/- 3.63 % for non neoplastic lesions, 10.0+/-9.45 % for PNL and 28.0+/- 18.4% for NL. Sensitivity and specificity of CK20, p53, p16INK4a, AA were 76% and 95.9%; 100% and 27.5%; 100% and 26.5%; 92.3 % and 78.8% respectively. CONCLUSIONS: Age >=55 years, large stag horn stones, multiple stones and impacted stones are found to be associated with increased risk of NL and PNL in UUT. For flat lesions, a panel of markers, Ki 67 index >10 and presence of aberrant angiogenesis were more useful than individual markers. PMID- 26745077 TI - Pharmacophore Development for Anti-Lung Cancer Drugs. AB - Lung cancer is one particular type of cancer that is deadly and relatively common than any other. Treatment is with chemotherapy, radiation therapy and surgery depending on the type and stage of the disease. Focusing on drugs used for chemotherapy and their associated side effects, there is a need to design and develop new anti-lung cancer drugs with minimal side effects and improved efficacy. The pharmacophore model appears to be a very helpful tool serving in the designing and development of new lead compounds. In this paper, pharmacophore analysis of 10 novel anti-lung cancer compounds was validated for the first time. Using LigandScout the pharmacophore features were predicted and 3D pharmacophores were extracted via VMD software. A training set data was collected from literature and the proposed model was applied to the training set whereby validating and verifying similar activity as that of the most active compounds was achieved. Therefore pharmacophore develoipment could be recommended for further studies. PMID- 26745081 TI - Comparative Investigation of Single Voxel Magnetic Resonance Spectroscopy and Dynamic Contrast Enhancement MR Imaging in Differentiation of Benign and Malignant Breast Lesions in a Sample of Iranian Women. AB - PURPOSE: To make a comparison of single voxel magnetic resonance spectroscopy (SV MRS) and dynamic contrast enhancement (DCE) MRI for differentiation of benign and malignant breast lesions in a sample of Iranian women. MATERIALS AND METHODS: A total of 30 women with abnormal breast lesions detected in mammography, ultrasound, or clinical breast exam were examined with DCE and SV-MRS. tCho (total choline) resonance in MRS spectra was qualitatively evaluated and detection of a visible tCho peak at 3.2 ppm was defined as a positive finding for malignancy. Different types of DCE curves were persistent (type 1), plateau (type 2), and washout (type 3). At first, lesions were classified according to choline findings and types of DCE curve, finally being compared to pathological results as the standard reference. RESULTS: this study included 19 patients with malignant lesions and 11 patients with benign ones. While 63.6 % of benign lesions (7 of 11) showed type 1 DCE curves and 36.4% (4 of 11) showed type 2, 57.9% (11of 19) of malignant lesions were type 3 and 42.1% (8 of 19) type 2. Choline peaks were detected in 18 of 19 malignant lesions and in 3 of 11 benign counterparts. 1 malignant and 8 benign cases did not show any visible resonance at 3.2 ppm so SV-MRS featured 94.7% sensitivity, 72.7 % specificity and 86.7% accuracy. CONCLUSIONS: The present findings indicate that a combined approach using MRS and DCE MRI can improve the specificity of MRI for differentiation of benign and malignant breast lesions. PMID- 26745080 TI - Breast Cancer in Lampang, a Province in Northern Thailand: Analysis of 1993-2012 Incidence Data and Future Trends. AB - BACKGROUND: The recent epidemiologic transition in Thailand, with decreasing incidence of infectious diseases along with increasing rates of chronic conditions, including cancer, is a serious problem for the country. Breast cancer has the highest incidence rates among females throughout Thailand. Lampang is a province in the upper part of Northern Thailand. A study was needed to identify the current burden, and the future trends of breast cancer in upper Northern Thai women. MATERIALS AND METHODS: Here we used cancer incidence data from the Lampang Cancer Registry to characterize and analyze the local incidence of breast cancer. Joinpoint analysis, age period cohort model and Nordpred package were used to investigate the incidences of breast cancer in the province from 1993 to 2012 and to project future trends from 2013 to 2030. RESULTS: Age-standardized incidence rates (world) of breast cancer in the upper parts of Northern Thailand increased from 16.7 to 26.3 cases per 100,000 female population which is equivalent to an annual percentage change of 2.0-2.8%, according to the method used. Linear drift effects played a role in shaping the increase of incidence. The three projection method suggested that incidence rates would continue to increase in the future with incidence for women aged 50 and above, increasing at a higher rate than for women below the age of 50. CONCLUSIONS: The current early detection measures increase detection rates of early disease. Preparation of a budget for treatment facilities and human resources, both in surgical and medical oncology, is essential. PMID- 26745079 TI - Epidemiology of Hydatidiform Moles in a Tertiary Hospital in Thailand over Two Decades: Impact of the National Health Policy. AB - BACKGROUND: The incidence of hydatidiform mole (HM) differs among regions but has declined significantly over time. In Thailand, the initiation of universal health coverage in 2002 has resulted in a change of medical services countrywide. However, impacts of these policies on gestational trophoblastic disease (GTD) cases in Thailand have not been reported. This study aimed to find the incidence of hydatidiform mole (HM) in King Chulalongkorn Memorial Hospital (KCMH) from 1994-2013, comparing before and after the implementation of the universal coverage health policy. MATERIALS AND METHODS: All cases of GTD in KCMH from 1994 2013 were reviewed from medical records. The incidence of HM, patient characteristics, treatment and remission rates were compared over two study decades between 1994-2003 and 2004-2013. RESULTS: Hydatidiform mole cases decreased from 204 cases in the first decade to 111 cases in the seond decade. Overall incidence of HM was 1.70 per 1,000 deliveries. The incidence of HM in the first and second decades were 1.70 and 1.71 per 1,000 deliveries, respectively (p=0.65, 95%CI 1.54-1.88). Referred cases of nonmolar gestational trophoblastic neoplasia (GTN) increased from 12 (4.4%) to 23 (14.4%, p<0.01). Vaginal bleeding was the most common presenting symptom which decreased from 89.4% to 79.6% (p=0.02). Asymptomatic HM patients increased from 4.8% to 10.2% (p=0.07). Rate of postmolar GTN was 26%. CONCLUSIONS: The number of HM cases in this study decreased over 2 decades but incidence was unchanged. Referral rates of malignant cases were more common after universal health coverage policy initiation. Classic clinical presentation was decreased significantly in the last decade. PMID- 26745078 TI - In Vitro Anti-Neuroblastoma Activity of Thymoquinone Against Neuro-2a Cells via Cell-cycle Arrest. AB - We have recently shown that thymoquinone (TQ) has a potent cytotoxic effect and induces apoptosis via caspase-3 activation with down-regulation of XIAP in mouse neuroblastoma (Neuro-2a) cells. Interestingly, our results showed that TQ was significantly more cytotoxic towards Neuro-2a cells when compared with primary normal neuronal cells. In this study, the effects of TQ on cell-cycle regulation and the mechanisms that contribute to this effect were investigated using Neuro 2a cells. Cell-cycle analysis performed by flow cytometry revealed cell-cycle arrest at G2/M phase and a significant increase in the accumulation of TQ-treated cells at sub-G1 phase, indicating induction of apoptosis by the compound. Moreover, TQ increased the expression of p53, p21 mRNA and protein levels, whereas it decreased the protein expression of PCNA, cyclin B1 and Cdc2 in a dose dependent manner. Our finding suggests that TQ could suppress cell growth and cell survival via arresting the cell-cycle in the G2/M phase and inducing apoptosis of neuroblastoma cells. PMID- 26745082 TI - Outcome and Cost Effectiveness of Ultrasonographically Guided Surgical Clip Placement for Tumor Localization in Patients undergoing Neo-adjuvant Chemotherapy for Breast Cancer. AB - BACKGROUND: To determine the outcome and cost saving by placing ultrasound guided surgical clips for tumor localization in patients undergoing neo-adjuvant chemotherapy for breast cancer. MATERIALS AND METHODS: This retrospective cross sectional analytical study was conducted at the Department of Diagnostic Radiology, Aga Khan University Hospital, Karachi, Pakistan from January to December 2014. A sample of 25 women fulfilling our selection criteria was taken. All patients came to our department for ultrasound guided core biopsy of suspicious breast lesions and clip placement in the index lesion prior to neo adjuvant chemotherapy. All the selected patients had biopsy proven breast cancer. RESULTS: The mean age was 45 +/- 11.6 years. There were no complications seen after clip placement in terms of clip migration or hemorrhage. The cost of commercially available markers was approximately PKR 9,000 (US$ 90) and that of the surgical clip was PKR 900 (US$ 9). The cost of surgical clips in 25 patients was PKR 22,500 (US$ 225), when compared to the commercially available markers which may have incurred a cost of PKR 225,000 (US$ 2,250). The total cost saving for 25 patients was PKR 202,500 (US$ 2, 025), making it PKR 8100 (US$ 81) per patient. CONCLUSIONS: The results of our study show that ultrasound guided surgical clip placement in index lesions prior to neo-adjuvant therapy is a safe and cost effective method to identify tumor bed and response to treatment for further management. PMID- 26745083 TI - Colorectal Cancer Awareness and Screening Preference: A Survey during the Malaysian World Digestive Day Campaign. AB - BACKGROUND: Although the incidence of colorectal cancer in Malaysia is increasing, awareness of this cancer, including its symptoms, risk factors and screening methods, remains low among Malaysian populations. This survey was conducted with the aim of (i) ascertaining the awareness level regarding colorectal cancer symptoms, risk factors and its screening among the general populations and (ii) assessing the public preference and willingness to pay for colorectal cancer screening. MATERIALS AND METHODS: The questionnaire was distributed in eight major cities in West Malaysia during the World Health Digestive Day (WDHD) campaign. Two thousand four hundred and eight respondents participated in this survey. RESULTS: Generally, awareness of colorectal cancer was found to be relatively good. Symptoms such as change in bowel habit, blood in the stool, weight loss and abdominal pain were well recognized by 86.6%, 86.9%, 83.4% and 85.6% of the respondents, respectively. However, common risk factors such as positive family history, obesity and old age were acknowledged only by less than 70% of the respondents. Almost 80% of the respondents are willing to take the screening test even without any apparent symptoms. Colonoscopy is the preferred screening method, but only 37.5% were willing to pay from their own pocket to get early colonoscopy. CONCLUSIONS: Continous cancer education should be promoted with more involvement from healthcare providers in order to make future colorectal cancer screening programs successful. PMID- 26745084 TI - Automatic Electronic Cleansing in Computed Tomography Colonography Images using Domain Knowledge. AB - Electronic cleansing is an image post processing technique in which the tagged colonic content is subtracted from colon using CTC images. There are post processing artefacts, like: 1) soft tissue degradation; 2) incomplete cleansing; 3) misclassification of polyp due to pseudo enhanced voxels; and 4) pseudo soft tissue structures. The objective of the study was to subtract the tagged colonic content without losing the soft tissue structures. This paper proposes a novel adaptive method to solve the first three problems using a multi-step algorithm. It uses a new edge model-based method which involves colon segmentation, priori information of Hounsfield units (HU) of different colonic contents at specific tube voltages, subtracting the tagging materials, restoring the soft tissue structures based on selective HU, removing boundary between air-contrast, and applying a filter to clean minute particles due to improperly tagged endoluminal fluids which appear as noise. The main finding of the study was submerged soft tissue structures were absolutely preserved and the pseudo enhanced intensities were corrected without any artifact. The method was implemented with multithreading for parallel processing in a high performance computer. The technique was applied on a fecal tagged dataset (30 patients) where the tagging agent was not completely removed from colon. The results were then qualitatively validated by radiologists for any image processing artifacts. PMID- 26745085 TI - Breast Cancer in Lopburi, a Province in Central Thailand: Analysis of 2001-2010 Incidence and Future Trends. AB - BACKGROUND: Thailand has come to an epidemiologic transition with decreasing infectious diseases and increasing burden of chronic conditions, including cancer. Breast cancer has the highest incidence rates among females throughout Thailand. This study aimed to identify the current burden and the future trends of breast cancer of Lopburi, a province in the Central Thailand. MATERIALS AND METHODS: We used cancer incidence data from the Lopburi Cancer Registry to characterize and analyze the incidence of breast cancer in Central Thailand. With joinpoint and age-period-cohort analyses, the incidence of breast cancer in the province from 2001 to 2010 and project future trends from 2011 to 2030 was investigated. RESULTS: Age-adjusted incidence rates of breast cancer in Lopburi increased from 23.4 to 34.3 cases per 100,000 female population during the period, equivalent to an annual percentage change of 4.3% per year. Both period and cohort effects played a role in shaping the increase in incidence. Joinpoint projection suggested that incidence rates would continue to increase in the future with incidence for women ages 50 years and above increasing at a higher rate than for women below the age of 50. CONCLUSIONS: The current situation where early detection measures are being promoted could increase detection rates of the disease. Preparation of sufficient budget for treatment facilities and human resources, both in surgical and medical oncology, is essential for future medical care. PMID- 26745086 TI - Association between Shammah Use and Oral Leukoplakia-like Lesions among Adult Males in Dawan Valley, Yemen. AB - BACKGROUND: Shammah is a traditional form of snuff dipping tobacco (a smokeless tobacco form) that is commonly used in Yemen. Oral mucosal changes due to the use of shammah can usually be observed in the mucosal surfaces that the product touches. The aim of this study was to determine the association between shammah use and oral leukoplakia-like lesions. Other associated factors were also determined. MATERIALS AND METHODS: A cross sectional study was conducted on 346 randomly selected adult males. Multi-stage random sampling was used to select the study location. After completing the structured questionnaire interviews, all the participants underwent clinical exanimation for screening of oral leukoplakia like lesions Clinical features of oral leukoplakia-like lesion were characterized based on the grades of Axell et al (1976). Univariable logistic regression and multivariable logistic regression were used to assess the potential associated factors. RESULTS: Out of 346 male participants aged 18 years and older, 68 (19.7%) reported being current shammah users. The multivariable analysis revealed that age, non-formal or primary level of education, former shammah user, current shammah user, and frequency of shammah use per day were statistically associated with the presence of oral leukoplakia-like lesions [Adjusted odds ratio (AOR) = 1.03; 95% confidence interval (CI) : 1.01, 1.06; P= 0.006], (AOR= 8.65; 95% CI: 2.81, 26.57; P= 0.001), (AOR= 3.65; 95% CI: 1.40, 9.50; P= 0.008), (AOR= 12.99; 95% CI: 6.34, 26.59; P= 0.001), and (AOR= 1.17; 95% CI: 1.02, 1.36; P= 0.026), respectively. CONCLUSIONS: The results revealed oral leukoplakia-like lesions to be significantly associated with shammah use. Therefore, it is important to develop comprehensive shammah prevention programs in Yemen. PMID- 26745087 TI - Factors Associated with Adherence to Colorectal Cancer Screening among Moderate Risk Individuals in Iran. AB - BACKGROUND: Colorectal cancer is one of the most common neoplasms in Iran. Secondary prevention (colorectal cancer screening) is important and a most valuable method of early diagnosis of this cancer. The objectives of this study were to determine the factors associated with colorectal cancer screening adherence among Iranians 50 years and older using the Health Belief Model. MATERIALS AND METHODS: This cross-sectional study was conducted from June 2012 to May 2013. A convenience sample of 200 individuals aged 50 and older was recruited from the population at outpatient clinics in teaching hospitals. Data gathering tools were the Champions health belief model scale (CHBMS) with coverage of socio demographic background and CRC screening information. Multiple logistic regression was performed to identify factors associated with colorectal cancer screening adherence. RESULTS: The mean age of participants was 62.5+/- 10.8 and 75.5% were women. A high percentage of the participants had not heard or read about colorectal cancer (86.5%) and CRC screening (93.5%). Perceived susceptibility to colorectal cancer had the lowest percentage of all of the subscales. Participants who perceived more susceptibility (OR =2.99; CI 95%: 1.23 5.45) and reported higher knowledge (OR =1.29; CI 95%: 1.86-3.40) and those who reported fewer barriers (OR =.37; CI 95%:.21- .89), were more likely to have carried out colorectal cancer screening. CONCLUSIONS: Our findings indicated that CRC knowledge, perceived susceptibility and barriers were significant predictors of colorectal cancer screening adherence. Strategies to increase knowledge and overcome barriers in risk individuals appear necessary. Education programs should be promoted to overcome knowledge deficiency and negative perceptions in elderly Iranians. PMID- 26745088 TI - Association of PNPLA3 Polymorphism with Hepatocellular Carcinoma Development and Prognosis in Viral and Non-Viral Chronic Liver Diseases. AB - BACKGROUND: The aim of this study was to evaluate any association between a single nucleotide polymorphism (SNP) in the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409, C>G) and the development and prognosis in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Two hundred heathy controls and 388 HCC cases were included: 211 with HBV, 98 patients with HCV, 29 with alcoholic steatohepatitis (ASH) and 52 with non-alcoholic steatohepatitis (NASH). The SNP was determined by real-time PCR based on TaqMan assays. RESULTS: The prevalence of rs738409 genotypes CC, CG and GG in controls was 91 (45.5%), 88 (44.0%), and 21 (10.5%), respectively, while the corresponding genotypes in all patients with HCC was 158 (40.7%), 178 (45.9%), and 52 (13.4%). The GG genotype had significantly higher distribution in patients with ASH/NASH related HCC compared with controls (OR=2.34, 95% CI=1.16-4.71, P=0.018), and viral-related HCC cases (OR=2.15, 95% CI=1.13-4.08, P=0.020). However, the frequency of the GG genotype was similar between controls and patients with viral related HCC. At initial diagnosis, HBV-related HCC were larger and at more advanced BCLC stage than the other HCC groups. There were no significant differences between the GG and non-GG groups regarding clinical characteristics, tumor stage and overall survival. CONCLUSIONS: These data suggest an influence of the PNPLA3 polymorphism on the occurrence of HCC in patients with ASH/NASH but not among those with chronic viral hepatitis. However, the polymorphism was not associated with the prognosis of HCC. PMID- 26745089 TI - Treatment of Oral Leukoplakia with Diode Laser: a Pilot Study on Indian Subjects. AB - BACKGROUND: To evaluate the safety, convenience and effectiveness of 940nm diode laser for treatment of homogenous leukoplakia. MATERIALS AND METHODS: Ten patients having homogenous leukoplakia which were diagnosed clinically were selected from an Indian dental educational institution for the study. Toludine blue staining was applied locally over the lesion. The area where there was increased uptake of stain was excised using a 940 nm EZLASE TM diode laser (BIOLASE-USA). RESULTS: Although various treatment modalities have been tried and the search continues for novel treatment modalities for complete removal of homogenous leukoplakia, from results of our preliminary pilot study it is clear that the use of 940 nm diode laser as a treatment modality for homogenous leukoplakia is a good substitute. Healing was perfect without any complication within a duration of 1 month. Pain intensity was also mild and absolutely zero on the VAS scale after 1 month follow up. CONCLUSIONS: 940 nm diode lasers are safe and can be effectively used as a treatment modality of homogenous leukoplakia, without any complication and without compromising health and oral function of patients. Considering recurrence factor, long term follow up for patients is a must. PMID- 26745090 TI - Comparison between Use of PSA Kinetics and Bone Marrow Micrometastasis to Define Local or Systemic Relapse in Men with Biochemical Failure after Radical Prostatectomy for Prostate Cancer. AB - BACKGROUND: Treatment of biochemical failure after radical prostatectomy for prostate cancer is largely empirically based. The use of PSA kinetics has been used as a guide to determine local or systemic treatment of biochemical failure. We here compared PSA kinetics with detection of bone marrow micrometastasis as methods to determine local or systemic relapse. MATERIALS AND METHODS: A transversal study was conducted of men with biochemical failure, defined as a serum PSA >0.2ng/ml after radical prostatectomy. Consecutive patients having undergone radical prostatectomy and with biochemical failure were enrolled and clinical and pathological details were recorded. Bone marrow biopsies were obtained from the iliac crest and touch prints made, micrometastasis (mM) being detected using anti-PSA. The clinical parameters of total serum PSA, PSA velocity, PSA doubling time and time to biochemical failure, age, Gleason score and pathological stage were registered. RESULTS: A total of 147 men, mean age 71.6 +/- 8.2 years, with a median time to biochemical failure of 5.5 years (IQR 1.0-6.3 years) participated in the study. Bone marrow samples were positive for micrometastasis in 98/147 (67%) of patients at the time of biochemical failure. The results of bone marrow micrometastasis detected by immunocytochemistry were not concordant with local relapse as defined by PSA velocity, time to biochemical failure or Gleason score. In men with a PSA doubling time of < six months or a total serum PSA of >2,5ng/ml at the time of biochemical failure the detection of bone marrow micrometastasis was significantly higher. CONCLUSIONS: The detection of bone marrow micrometastasis could be useful in defining systemic relapse, this minimally invasive procedure warranting further studies with a larger group of patients. PMID- 26745092 TI - Association of Histopathological Markers with Clinico- Pathological Factors in Mexican Women with Breast Cancer. AB - BACKGROUND: Breast cancer (BCa) is the most common malignancy in Mexican women. A set of histopathological markers has been established to guide BCa diagnosis, prognosis and treatment. Nevertheless, in only a few Mexican health services, such as that of the Secretariat of National Defense (SEDENA for its acronym in Spanish), are these markers commonly employed for assessing BCa. The aim of this study was to explore the association of Ki67, TP53, HER2/neu, estrogenic receptors (ERs) and progesterone receptors (PRs) with BCa risk factors. MATERIALS AND METHODS: Clinical histories provided background patient information. Immunohistochemical (IHC) analysis was conducted on 48 tissue samples from women diagnosed with BCa and treated with radical mastectomy. The Chi square test or Fisher exact test together with the Pearson and Spearman correlation were applied. RESULTS: On average, patients were 58+/-10.4 years old. It was most common to find invasive ductal carcinoma (95.8%), histological grade 3 (45.8%), with a poor Nottingham Prognostic Index (NPI; 80.4%). ERs and PRs were associated with smoking and alcohol consumption, metastasis at diagnosis and Ki67 expression (p<0.05). PR+ was also related to urea and ER+ (p<0.05). Ki67 was associated with TP53 and elevated triglycerides (p<0.05), and HER2/neu with ER+, the number of pregnancies and tumor size (p<0.05). TP53 was also associated with a poor NPI (p <0.05) and CD34 with smoking (p<0.05). The triple negative status (ER-/PR /HER2/neu-) was related to smoking, alcohol consumption, exposure to biomass, number of pregnancies, metastasis and a poor NPI (p<0.05). Moreover, the luminal B subtype was associated with histological type (p=0.007), tumor size (p=0.03) and high cholesterol (p=0.02). CONCLUSIONS: Ki67, TP53, HER2/neu, ER and PR proved to be related to several clinical and pathological factors. Hence, it is crucial to determine this IHC profile in women at risk for BCa. Certain associations require further study to understand physiological/biochemical/molecular processes. PMID- 26745091 TI - Nutritional Status among Rural Community Elderly in the Risk Area of Liver Fluke, Surin Province, Thailand. AB - Thailand is becoming an aging society, this presenting as a serious problem situation especially regarding health. Chronic diseases found frequently in the elderly may be related to dietary intake and life style. Surin province has been reported as a risk area for liver fluke with a high incidence of cholangiocarcinma especially in the elderly. Therefore, this study aimed to determine the nutritional status and associated factors among elderly in Surin province, northeast of Thailand. A community-based cross-sectional study was conducted among 405 people aged 60 years and above, between September 2012 and July 2014. The participants were selected through a randomized systematic sampling method and completed a pre-designed questionnaire with general information, food recorded, weight, height, waist circumference, and behavior regarding to food consume related to liver fluke infection. The data were analyzed using descriptive statistics and Spearman's rank correlation coefficients. The majority of participants was female (63.5%), age between 60-70 years old (75.6%), with elementary school education (96.6%), living with their (78.9%), and having underlying diseases (38.3%). Carbohydrate (95.3%) was need to improve the consumption. The participants demonstrated under-nutrition (24.4%), over-nutrition (16.4%), and obesity (15.4%). Elderly had a waist circumference as the higher than normal level (34.0%). Gender, female, age 71-80 years old, elementary school and underlying diseases were significantly associated with poor nutritional status. The majority of them had a high knowledge (43.0%), moderate attitude (44.4%), and moderate practice (46.2%) regarding food consumption related to liver fluke infection. In conclusion, these findings data indicated that elderly age group often have an under- or over-nutritional status. Carbohydrate consumption needs to be improved. Some elderly show behavior regarding food consumption that is related to liver fluke infection hat needs to be improved, so that health education pertaining good nutrition is required. PMID- 26745093 TI - Single Nucleotide Polymorphisms in STAT3 and STAT4 and Risk of Hepatocellular Carcinoma in Thai Patients with Chronic Hepatitis B. AB - Hepatitis B virus (HBV) infection is the leading cause of hepatocellular carcinoma (HCC) development. Recent studies demonstrated that single nucleotide polymorphisms (SNPs) rs2293152 in signal transducer and activator of transcription 3 (STAT3) and rs7574865 in signal transducer and activator of transcription 4 (STAT4) are associated with chronic hepatitis B (CHB)-related HCC in the Chinese population. We hypothesized that these polymorphisms might be related to HCC susceptibility in Thai population as well. Study subjects were divided into 3 groups consisting of CHB-related HCC (n=192), CHB without HCC (n=200) and healthy controls (n=190). The studied SNPs were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results showed that the distribution of different genotypes for both polymorphisms were in Hardy-Weinberg equilibrium (P>0.05). Our data demonstrated positive association of rs7574865 with HCC risk when compared to healthy controls under an additive model (GG versus TT: odds ratio (OR) =2.07, 95% confidence interval (CI)=1.06-4.03, P=0.033). This correlation remained significant under allelic and recessive models (OR=1.46, 95% CI=1.09-1.96, P=0.012 and OR=1.71, 95% CI=1.13-2.59, P=0.011, respectively). However, no significant association between rs2293152 and HCC development was observed. These data suggest that SNP rs7574865 in STAT4 might contribute to progression to HCC in the Thai population. PMID- 26745094 TI - Inhibition of NF-kappaB, Bcl-2 and COX-2 Gene Expression by an Extract of Eruca sativa Seeds during Rat Mammary Gland Carcinogenesis. AB - The effect of Eruca sativa seed extract (SE) on nuclear factor kappa B (NF kappaB), cyclooxygenase-2 (COX-2) and B-cell lymphoma-2 (Bcl-2) gene expression levels was investigated in rat mammary gland carcinogenesis induced by 7,12 dimethylbenz(alpha)anthracene (DMBA). DMBA increased NF-kappaB, COX-2 and Bcl-2 gene expression levels and lipid peroxidation (LP), while, decreased glutathione S-transferase (GST) and superoxide dismutase (SOD) activities and total antioxidant concentration (TAC) compared to the control group. After DMBA administration, SE treatment reduced NF-kappaB, COX-2 and Bcl-2 gene expression levels and LP. Hence, SE treatment reduced inflammation and cell proliferation, while increasing apoptosis, GST and SOD activities and TAC. Analysis revealed that SE has high concentrations of total flavonoids, triterpenoids, alkaloids and polyphenolic compounds such as gallic, chlorogenic, caffeic, 3,4-dicaffeoyl quinic, 3,5-dicaffeoyl quinic, tannic, cinnamic acids, catechin and phloridzin. These findings indicate that SE may be considered a promising natural product from cruciferous vegetables against breast cancer, especially given its high antioxidant properties. PMID- 26745096 TI - Safety and Prognostic Impact of Prophylactic Level VII Lymph Node Dissection for Papillary Thyroid Carcinoma. AB - PURPOSE: To study the safety of prophylactic level VII nodal dissection regarding hypoparathyroidism (temporary and permanent) and vocal cord dysfunction (temporary and permanent) and its impact on disease free survival. MATERIALS AND METHODS: This prospective study concerned 63 patients with papillary thyroid carcinoma with N0 neck node involvement (clinically and radiologically) in the period from December 2009 to May 2013. All patients underwent total thyroidectomy and prophylactic central neck dissection including levels VI and VII lymph nodes in group A (31 patients) and level VI only in group B (32 patients). The thyroid gland, level VI and level VII lymph nodes were each examined histopathologically separately for tumor size, multicentricity, bilaterality, extrathyroidal extension, number of dissected LNs and metastatic LNs. Follow-up of both groups, regarding hypoparathyroidism, vocal cord dysfunction and DFS, ranged from 6-61 months. RESULTS: The mean age was 34.8 and 34.3, female predominance in both groups with F: M 24:7 and 27:5 in groups A and B, respectively. Mean tumor size was 12.6 and 14.7mm. No statistical differences were found between both groups regarding age, sex, bilaterality, multicentricity or extrathyroidal extension. The mean no. of dissected level VI LNs was 5.06 and 4.72 and mean no. of metastatic level VI was 1 and 0.84 in groups A and B, respectively. The mean no. of dissected level VII LNs was 2.16 and mean no. of metastatic LNs was 0.48. Postoperatively temporary hypoparathyroidism was detected in 10 and 7 patients and permanent hypoparathyroidism in 2 and 3 patients; temporary vocal cord dysfunction was detected in 4 patients and one patient, and permanent vocal cord dysfunction in one and 2 patients in groups A and B, respectively. No significant statistical differences were noted between the 2 groups regarding hypoparathyroidism (P=0.535) or vocal cord dysfunction (P=0.956). The number of dissected LNs at level VI only significantly affected the occurrence of hypoparathyroidism (<0.001) and vocal cord dysfunction (<0.001).The DFS was significantly affected by bilaterality, multicentricity and extrathyroidal extension. CONCLUSIONS: Level VII nodal dissection is a safe procedure complementary to level VI nodal dissection with prophylactic central neck dissection for papillary thyroid carcinoma. PMID- 26745095 TI - Aqueous Extract of Anticancer Drug CRUEL Herbomineral Formulation Capsules Exerts Anti-proliferative Effects in Renal Cell Carcinoma Cell Lines. AB - PURPOSE: Anti-cancer activity evaluation of aqueous extract of CRUEL (herbomineral formulation) capsules on renal cell carcinoma cell lines, and exploration of mechanisms of cell death. MATERIALS AND METHODS: To detect the cytotoxic dose concentration in renal cell carcinoma (RCC) cells, MTT assays were performed and morphological changes after treatment were observed by inverted microscopy. Drug effects against RCC cell lines were assessed with reference to cell cycle distribution (flow cytometry), anti-metastatic potential (wound healing assay) and autophagy(RT-PCR). RESULTS: CRUEL showed anti-proliferative effects against RCC tumor cell lines with an IC50 value of approximately 4mg/mL in vitro, while inducing cell cycle arrest at S-phase of the cell cycle and inhibiting wound healing. LC3 was found to be up-regulated after drug treatment by RT-PCR resulting in an autophagy mode of cell death. CONCLUSIONS: This study provides experimental validation for antitumor activity of CRUEL. PMID- 26745097 TI - Combined Treatment with 2-Deoxy-D-Glucose and Doxorubicin Enhances the in Vitro Efficiency of Breast Cancer Radiotherapy. AB - Doxorubicin (DOX) was introduced as an effective chemotherapeutic for a wide range of cancers but with some severe side effects especially on myocardia. 2 Deoxy-D-glucose (2DG) enhances the damage caused by chemotherapeutics and ionizing radiation (IR) selectively in cancer cells. We have studied the effects of 1MUM DOX and 500 MUM 2DG on radiation induced cell death, apoptosis and also on the expression levels of p53 and PTEN genes in T47D and SKBR3 breast cancer cells irradiated with 100, 150 and 200 cGy x-rays. DOX and 2DG treatments resulted in altered radiation-induced expression levels of p53 and PTEN genes in T47D as well as SKBR3 cells. In addition, the combination along with IR decreased the viability of both cell lines. The radiobiological parameter (D0) of T47D cells treated with 2DG/DOX and IR was 140 cGy compared to 160 cGy obtained with IR alone. The same parameters for SKBR3 cell lines were calculated as 120 and 140 cGy, respectively. The sensitivity enhancement ratios (SERs) for the combined chemo-radiotherapy on T47D and SKBR3 cell lines were 1.14 and 1.16, respectively. According to the obtained results, the combination treatment may use as an effective targeted treatment of breast cancer either by reducing the single modality treatment side effects. PMID- 26745098 TI - Incidence and Mortality of Breast Cancer and their Relationship with the Human Development Index (HDI) in the World in 2012. AB - BACKGROUND: Breast cancer is the most common malignancy in women worldwide and its incidence is generally increasing. In 2012, it was the second most common cancer in the world. It is necessary to obtain information on incidence and mortality for health planning. This study aimed to investigate the relationship between the human development index (HDI), and the incidence and mortality rates of breast cancer in the world in 2012. MATERIALS AND METHODS: This ecologic study concerns incidence rate and standardized mortality rates of the cancer from GLOBOCAN in 2012, and HDI and its components extracted from the global bank site. Data were analyzed using correlation tests and regression with SPSS software (version 15). RESULTS: Among the six regions of WHO, the highest breast cancer incidence rate (67.6) was observed in the PAHO, and the lowest incidence rate was 27.8 for SEARO. There was a direct, strong, and meaningful correlation between the standardized incidence rate and HDI (r=0.725, p<=0.001). Pearson correlation test showed that there was a significant correlation between age-specific incidence rate (ASIR) and components of the HDI (life expectancy at birth, mean years of schooling, and GNP). On the other, a non-significant relationship was observed between ASIR and HDI overall (r=0.091, p=0.241). In total, a significant relationship was not found between age-specific mortality rate (ASMR) and components of HDI. CONCLUSIONS: Significant positive correlations exist between ASIR and components of the HDI. Socioeconomic status is directly related to the stage of the cancer and patient's survival. With increasing the incidence rate of the cancer, mortality rate from the cancer does not necessariloy increase. This may be due to more early detection and treatment in developed that developing countries. It is necessary to increase awareness of risk factors and early detection in the latter. PMID- 26745099 TI - Effects of Conditioned Medium from Breast Cancer Cells on Tlr2 Expression in Nb4 Cells. AB - BACKGROUND: Breast cancer is the most common neoplasm in women and the most frequent cause of death in those between 35 and 55 years of age. All multicellular organisms have an innate immune system, whereas the adaptive or 'acquired' immune system is restricted to vertebrates. This study focused on the effect of conditioned medium isolated from cultured breast cancer cells on NB4 neutrophil-like cells. MATERIALS AND METHODS: In the current study neutrophil like NB4 cells were incubated with MCF-7 cell-conditioned medium. After 6 h incubation the intracellular receptor TLR2, was analyzed. RESULTS: The results revealed that MCF-7 cell-conditioned medium elicited expression of TLR2 in NB4 cells. CONCLUSIONS: This treatment would result in the production of particular stimulants (i.e. soluble cytokines), eliciting the expression of immune system receptors. Furthermore, the flow cytometry results demonstrated that MCF-7 cell conditioned medium elicited an effect on TLR2 intracellular receptors. PMID- 26745100 TI - Epidemiological Characteristics of Gallbladder Cancer in Jeju Island: A Single Center, Clinically Based, Age-Sex-Matched, Case-Control Study. AB - BACKGROUND: Gallbladder cancer (GBC) is a rare but highly invasive malignancy characterized by poor survival. In a national cancer survey, the age-standardized incidence rate of GBC was highest in Jeju Island among the 15 provinces in South Korea. The aim of this descriptive epidemiological study was to suggest the modifiable risk factors for this rare malignant disease in Jeju Island by performing an age-sex-matched case- control study. MATERIALS AND METHODS: The case group included patients diagnosed with GBC at the Department of Internal Medicine of Cheju Halla General Hospital, Jeju, South Korea, within the 5-year study period. The control group consisted of age-sex-matched subjects selected from among the participants of the health promotion center at the same institute and in the same period. We compared 78 case-control pairs in terms of clinical variables such as histories of hypertension, diabetes, vascular occlusive disorders, alcohol and smoking consumption, obesity, and combined polypoid lesions of the gallbladder (PLG) or gallstone diseases (GSDs). RESULTS: Among the relevant risk factors, alcohol consumption, parity >= 2, PLG, and GSDs were significant risk factors in the univariate analysis. PLG (p < 0.01; OR, 51.1; 95% confidence interval [CI], 2.98-875.3) and GSD (p < 0.01; OR, 54.9; 95% CI, 3.00 1001.8) were associated risk factors of GBC in the multivariate analysis with the conditional logistic regression model. However, we failed to find any correlation between obesity and GBC. We also found a negative correlation between alcohol consumption history and GBC in the multivariate analysis (p < 0.01; OR, 0.06; 95% CI, 0.01-0.31). CONCLUSIONS: These results suggest that combined PLG and GSDs are strongly associated with the GBC in Jeju Island and mild to moderate alcohol consumption may negatively correlate with GBC risk. PMID- 26745101 TI - Improving Participation in Colorectal Cancer Screening: a Randomised Controlled Trial of Sequential Offers of Faecal then Blood Based Non-Invasive Tests. AB - BACKGROUND: Poor participation rates are often observed in colorectal cancer (CRC) screening programs utilising faecal occult blood tests. This may be from dislike of faecal sampling, or having benign bleeding conditions that can interfere with test results. These barriers may be circumvented by offering a blood-based DNA test for screening. The aim was to determine if program participation could be increased by offering a blood test following faecal immunochemical test (FIT) non-participation. MATERIALS AND METHODS: People were invited into a CRC screening study through their General Practice and randomised into control or intervention (n=600/group). Both groups were mailed a FIT (matching conventional screening programs). Participation was defined as FIT completion within 12wk. Intervention group non-participants were offered a screening blood test (methylated BCAT1/IKZF1). Overall participation was compared between the groups. RESULTS: After 12wk, FIT participation was 82% and 81% in the control and intervention groups. In the intervention 96 FIT non- participants were offered the blood test - 22 completed this test and 19 completed the FIT instead. Total screening in the intervention group was greater than the control (88% vs 82%, p<0.01). Of 12 invitees who indicated that FIT was inappropriate for them (mainly due to bleeding conditions), 10 completed the blood test (83%). CONCLUSIONS: Offering a blood test to FIT non-participants increased overall screening participation compared to a conventional FIT program. Blood test participation was particularly high in invitees who considered FIT to be inappropriate for them. A blood test may be a useful adjunct test within a FIT program. PMID- 26745102 TI - DPPA2 Protein Expression is Associated with Gastric Cancer Metastasis. AB - Gastric cancer (GC) as the fourth most common cause of malignancies shows high rate of morbidity appropriating the second leading cause of cancer-related death worldwide. Developmental pluripotency associated-2 (DPPA2), cancer-testis antigen (CT100), is commonly expressed only in the human germ line and pluripotent embryonic cells but it is also present in a significant subset of malignant tumors. To investigate whether or not DPPA2 expression is recalled in GC, our aim in this study was to elucidate DPPA2 protein expression in gastric cancer. Fifty five GC tumor and their related margin normal tissues were recruited to evaluate DPPA2 protein expression and its probable associations with different clinicopathological features of the patients. DPPA2 was overexpressed in GC cases compared with normal tissues (P < .005). While DPPA2 expression was detected in all GC samples, its high expression was found in 23 of 55 tumor tissues (41.8%). Interestingly, 50 of 55 normal samples (90.9%) were negative for DPPA2 protein expression and remained 5 samples showed very low expression of DPPA2. DPPA2 protein expression in GC was significantly correlated with lymph node metastasis (p = 0.012). The clinical relevance of DPPA2 in GC illustrated that high level expression of this protein was associated with lymph node metastasis supporting this hypothesis that alteration in DPPA2 was associated with aggressiveness of gastric cancer and may be an early event in progression of the disease. DPPA2 may be introduced as a new marker for invasive and metastatic GCs. PMID- 26745103 TI - Genetic Variation in the ABCB1 Gene May Lead to mRNA Level Chabge: Application to Gastric Cancer Cases. AB - BACKGROUND: One of the major mechanisms for drug resistance is associated with altered anticancer drug transport, mediated by the human-adenosine triphosphate binding cassette (ABC) transporter superfamily proteins. The overexpression of adenosine triphosphate binding cassette, sub-family B, member 1 (ABCB1) by multidrug-resistant cancer cells is a serious impediment to chemotherapy. In our study we have studied the possibility that structural single-nucleotide polymorphisms (SNP) are the mechanism of ABCB1 overexpression. MATERIALS AND METHODS: A total of 101 gastric cancer multidrug resistant cases and 100 controls were genotyped with sequence-specific primed PCR (SSP-PCR). Gene expression was evaluated for 70 multidrug resistant cases and 54 controls by real time PCR. The correlation between the two groups was based on secondary structures of RNA predicted by bioinformatics tool. RESULTS: The results of genotyping showed that among 3 studied SNPs, rs28381943 and rs2032586 had significant differences between patient and control groups but there were no differences in the two groups for C3435T. The results of real time PCR showed over-expression of ABCB1 when we compared our data with each of the genotypes in average mode. Prediction of secondary structures in the existence of 2 related SNPs (rs28381943 and rs2032586) showed that the amount of DeltaG for original mRNA is higher than the amount of DeltaG for the two mentioned SNPs. CONCLUSIONS: We have observed that 2 of our studied SNPs (rs283821943 and rs2032586) may elevate the expression of ABCB1 gene, through increase in mRNA stability, while this was not the case for C3435T. PMID- 26745104 TI - Knowledge, Attitude and Practices Regarding HPV Vaccination Among Medical and Para Medical in Students, India a Cross Sectional Study. AB - BACKGROUND: High risk human papilloma virus (HPV) types 16 and 18 have been proven as central causes of cervical cancer and safety and immunogenicity of HPV vaccines are sufficiently established. Knowledge and practices of HPV vaccination among medical and paramedical students is vital as these may strongly determine intention to recommend vaccination to others in the future. The present study was therefore undertaken to assess the knowledge, attitude and practices regarding cervical cancer screening and HPV vaccination among medical and paramedical students and to analyze factors influencing them. MATERIALS AND METHODS: The present cross sectional study, conducted in a tertiary care teaching hospital in south India, included undergraduate students aged 18 years and above, belonging to medical, dental and nursing streams, after informed written consent. RESULTS: Out of 957 participants, only 430 (44.9%) displayed good knowledge and only 65 (6.8%) had received HPV vaccination. Among the unvaccinated, 433 (48.54%), were not willing to take the vaccine. Concerns regarding the efficacy (30.5%), safety (26.1%) and cost of the vaccine (21.7%) were responsible for this. Age, gender, family history of malignancy and mother's education had no influence on knowledge. Compared to medical students, nursing students had better knowledge (OR-1.49, 95% CI 0.96 to 2.3, p = 0.072) and students of dentistry had poor knowledge (OR-0.50 95% CI 0.36 to 0.70, p <0.001). CONCLUSIONS: The knowledge and uptake of HPV vaccination among medical and paramedical students in India is poor. Targeted health education interventions may have huge positive impact not only on the acceptance of vaccination among them, but also on their intention to recommend the vaccine in future. PMID- 26745105 TI - Knowledge and Perceptions about Colorectal Cancer in Jordan. AB - BACKGROUND: Colorectal cancer (CRC) is the third most common cancer globally. In Jordan, it is the number one cancer among men and the second most common cancer among women, accounting for 15% and 9.4% respectively of all male and female diagnosed cancers. This study aimed to evaluate the knowledge and perceptions about colorectal cancer risk factors, signs and symptoms in Jordan and to provide useful data about the best modes of disseminating preventive messages about the disease. MATERIALS AND METHODS: A stratified clustered random sampling technique was used to recruit 300 males and 300 females aged 30 to 65 years without a previous history of CRC from four governorates in Jordan. A semi-structured questionnaire and face to face interviews were employed. Descriptive and multivariate analysis was applied to assess knowledge and perceptions about CRC. RESULTS: Both males and females perceived their CRC risk to be low. They had low knowledge scores about CRC with no significant gender association (P= 0.47). From a maximum knowledge score of 18 points, the median scores of males and females were 4 points (SD = 2.346, range 0-13) and 4 points (SD= 2.329, range 0-11) respectively. Better knowledge scores were associated with governorate, higher educational level, older age, higher income, having a chronic disease, having a family history of CRC, previously knowing someone who had CRC and their doctor's knowledge about their family history of CRC. CONCLUSIONS: There is a low level of knowledge about CRC and underestimation of risk among the study participants. This underlines the need for public health interventions to create awareness about the illness. It also calls for further research to assess the knowledge and perceptions about CRC early detection examinations in Jordan. PMID- 26745106 TI - Improved Detection of Helicobacter pylori Infection and Premalignant Gastric Mucosa Using "Site Specific Biopsy": a Randomized Control Clinical Trial. AB - BACKGROUND: Helicobacter pylori infection and premalignant gastric mucosa can be reliably identified using conventional narrow band imaging (C-NBI) gastroscopy. The aim of our study was to compare standard biopsy with site specific biopsy for diagnosis of H. pylori infection and premalignant gastric mucosa in daily clinical practice. MATERIALS AND METHODS: Of a total of 500 patients who underwent gastroscopy for investigation of dyspeptic symptoms, 250 patients underwent site specific biopsy using C-NBI (Group 1) and 250 standard biopsy (Group 2). Sensitivity, specificity, and positive and negative predictive values were assessed. The efficacy of detecting H. pylori associated gastritis and premalignant gastric mucosa according to the updated Sydney classification was also compared. RESULTS: In group 1 the sensitivity, specificity, positive and negative predictive values for predicting H. pylori positivity were 95.4%, 97.3%, 98.8% and 90.0% respectively, compared to 92.9%, 88.6%, 83.2% and 76.1% in group 2. Site specific biopsy was more effective than standard biopsy in terms of both H. pylori infection status and premalignant gastric mucosa detection (P<0.01). CONCLUSIONS: Site specific biopsy using C-NBI can improve detection of H. pylori infection and premalignant gastric mucosa in daily clinical practice. PMID- 26745107 TI - Comparison of Unsatisfactory Rates and Detection of Abnormal Cervical Cytology Between Conventional Papanicolaou Smear and Liquid-Based Cytology (Sure Path(r)). AB - PURPOSE: To compare unsatisfactory rates and detection of abnormal cervical cytology between conventional cytology or Papanicolaou smear (CC) and liquid based cytology (LBC). MATERIALS AND METHODS: A total of 23,030 cases of cervical cytology performed at King Chulalongkorn Memorial Hospital during 2012-2013 were reviewed. The percentage unsatisfactory and detection rates of abnormal cytology were compared between CC and LBC methods. RESULTS: There was no difference in unsatisfactory rates between CC and LBC methods (0.1% vs. 0.1%, p = 0.84). The detection rate for squamous cell abnormalities was significantly higher with the LBC method (7.7% vs. 11.5%, p < 0.001), but those for overall abnormal glandular epithelium were similar (0.4% vs. 0.6%, p = 0.13). Low grade squamous lesion (ASC US and LSIL) were more frequently detected by the LBC method (6.1% vs. 9.5%, p < 0.001). However, there was no difference in high gradd squamous lesions (1.1% vs. 1.1%, p = 0.95). When comparing between types of glandular abnormality, there was no significant difference the groups. CONCLUSIONS: There was no difference in unsatisfactory rates between the conventional smear and LBC. However, LBC could detect low grade squamous cell abnormalities more than CC, while there were similar rates of detection of high grade squamous cell lesions and glandular cell abnormalities. PMID- 26745108 TI - Comparative Assessment of a Self-sampling Device and Gynecologist Sampling for Cytology and HPV DNA Detection in a Rural and Low Resource Setting: Malaysian Experience. AB - PURPOSE: This study was conducted to assess the agreement and differences between cervical self-sampling with a Kato device (KSSD) and gynecologist sampling for Pap cytology and human papillomavirus DNA (HPV DNA) detection. MATERIALS AND METHODS: Women underwent self-sampling followed by gynecologist sampling during screening at two primary health clinics. Pap cytology of cervical specimens was evaluated for specimen adequacy, presence of endocervical cells or transformation zone cells and cytological interpretation for cells abnormalities. Cervical specimens were also extracted and tested for HPV DNA detection. Positive HPV smears underwent gene sequencing and HPV genotyping by referring to the online NCBI gene bank. Results were compared between samplings by Kappa agreement and McNemar test. RESULTS: For Pap specimen adequacy, KSSD showed 100% agreement with gynecologist sampling but had only 32.3% agreement for presence of endocervical cells. Both sampling showed 100% agreement with only 1 case detected HSIL favouring CIN2 for cytology result. HPV DNA detection showed 86.2%agreement (K=0.64, 95% CI 0.524-0.756, p=0.001) between samplings. KSSD and gynaecologist sampling identified high risk HPV in 17.3% and 23.9% respectively (p= 0.014). CONCLUSION: The self-sampling using Kato device can serve as a tool in Pap cytology and HPV DNA detection in low resource settings in Malaysia. Self sampling devices such as KSSD can be used as an alternative technique to gynaecologist sampling for cervical cancer screening among rural populations in Malaysia. PMID- 26745109 TI - Early Activation of Apoptosis and Caspase-independent Cell Death Plays an Important Role in Mediating the Cytotoxic and Genotoxic Effects of WP 631 in Ovarian Cancer Cells. AB - The purpose of this study was to provide a detailed explanation of the mechanism of bisanthracycline,?WP 631 in comparison to doxorubicin (DOX), a first generation anthracycline, currently the most widely used pharmaceutical in clinical oncology. Experiments were performed in SKOV-3 ovarian cancer cells which are otherwise resistant to standard drugs such as cis-platinum and adriamycin. As attention was focused on the ability of WP 631 to induce apoptosis, this was examined using a double staining method with Annexin V and propidium iodide probes, with measurement of the level of intracellular calcium ions and cytosolic cytochrome c. The western blotting technique was performed to confirm PARP cleavage. We also investigated the involvement of caspase activation and DNA degradation (comet assay and immunocytochemical detection of phosphorylated H2AX histones) in the development of apoptotic events. WP 631 demonstrated significantly higher effectiveness as a pro-apoptotic drug than DOX. This was evident in the higher levels of markers of apoptosis, such as the externalization of phosphatidylserine and the elevated level of cytochrome c. An extension of incubation time led to an increase in intracellular calcium levels after treatment with DOX. Lower changes in the calcium content were associated with the influence of WP 631. DOX led to the activation of all tested caspases, 8, 9 and 3, whereas WP 631 only induced an increase in caspase 8 activity after 24h of treatment and consequently led to the cleavage of PARP. The lack of active caspase 3 had no outcome on the single and double-stranded DNA breaks. The obtained results show that WP 631 was considerably more genotoxic towards the investigated cell line than DOX. This effect was especially visible after longer times of incubation. The above detailed studies indicate that WP 631 generates early apoptosis and cell death independent of caspase-3, detected at relatively late time points. The observed differences in the mechanisms of the action of WP631 and DOX suggest that this bisanthracycline can be an effective alternative in ovarian cancer treatment. PMID- 26745110 TI - Breast Cancer Survival at a Leading Cancer Centre in Malaysia. AB - BACKGROUND: GLOBOCAN12 recently reported high cancer mortality in Malaysia suggesting its cancer health services are under-performing. Cancer survival is a key index of the overall effectiveness of health services in the management of patients. This report focuses on Subang Jaya Medical Centre (SJMC) care performance as measured by patient survival outcome for up to 5 years. MATERIALS AND METHODS: All women with breast cancer treated at SJMC between 2008 and 2012 were enrolled for this observational cohort study. Mortality outcome was ascertained through record linkage with national death register, linkage with hospital registration system and finally through direct contact by phone or home visits. RESULTS: A total of 675 patients treated between 2008 and 2012 were included in the present survival analysis, 65% with early breast cancer, 20% with locally advanced breast cancer (LABC) and 4% with metastatic breast cancer (MBC). The overall relative survival (RS) at 5 years was 88%. RS for stage I was 100% and for stage II, III and IV disease was 95%, 69% and 36% respectively. CONCLUSIONS: SJMC is among the first hospitals in Malaysia to embark on routine measurement of the performance of its cancer care services and its results are comparable to any leading centers in developed countries. PMID- 26745111 TI - Religion as an Alleviating Factor in Iranian Cancer Patients: a Qualitative Study. AB - After diagnosis of cancer, many patients show more inclination towards religion and religious activities. This qualitative study using semi-structured interviews explored the perspectives and experiences of 17 Iranian cancer patients and their families regarding the role of religion in their adaptation to cancer in one of the hospitals in Tehran and a charity institute. The content analysis identified two themes: "religious beliefs "(illness as God's will, being cured by God's will, belief in God's supportiveness, having faith in God as a relieving factor, and hope in divine healing) and "relationship with God during the illness." In general, relationship with God and religious beliefs had a positive effect on the patients adapting to their condition, without negative consequences such as stopping their treatment process and just waiting to be cured by God. Thus a strengthening of such beliefs, as a coping factor, could be recommended through religious counseling. PMID- 26745112 TI - Patterns of Cancer in Kurdistan - Results of Eight Years Cancer Registration in Sulaymaniyah Province-Kurdistan-Iraq. AB - BACKGROUND: Cancer has become a major health problem associated with high mortality worldwide, especially in developing countries. The aim of our study was to evaluate the incidence rates of different types of cancer in Sulaymaniyah from January-2006 to January-2014. The data were compared with those reported for other middle east countries. MATERIALS AND METHODS: This retrospective study depended on data collected from Hiwa hospital cancer registry unit, death records and histopathology reports in all Sulaymaniyah teaching hospitals, using international classification of diseases. RESULTS: A total of 8,031 cases were registered during the eight year period, the annual incidence rate in all age groups rose from 38 to 61.7 cases/100,000 population/year, with averages over 50 in males and 50.7 in females. The male to female ratio in all age groups were 0.98, while in the pediatric age group it was 1.33. The hematological malignancies in all age groups accounted for 20% but in the pediatric group around half of all cancer cases. Pediatric cancers were occluding 7% of total cancers with rates of 10.3 in boys and 8.7 in girls. The commonest malignancies by primary site were leukemia, lymphoma, brain, kidney and bone. In males in all age groups they were lung, leukaemia, lymphoma, colorectal, prostate, bladder, brain, stomach, carcinoma of unknown primary (CUP) and skin, while in females they were breast, leukaemia, lymphoma, colorectal, ovary, lung, brain, CUP, and stomach. Most cancers were increased with increasing age except breast cancer where decrease was noted in older ages. High mortality rates were found with leukemia, lung, lymphoma, colorectal, breast and stomach cancers. CONCLUSIONS: We here found an increase in annual cancer incidence rates across the period of study, because of increase of cancer with age and higher rates of hematological malignancies. Our study is valuable for Kurdistan and Iraq because it provides more accurate data about the exact patterns of cancer and mortality in our region. PMID- 26745113 TI - Role of Tumor Necrosis Factor-Producing Mesenchymal Stem Cells on Apoptosis of Chronic B-lymphocytic Tumor Cells Resistant to Fludarabine-based Chemotherapy. AB - BACKGROUND: B-cell chronic lymphocytic leukemia B (B-CLL), the most common type of leukemia, may be caused by apoptosis deficiency in the body. Adipose tissue derived mesenchymal stem cells (AD-MSCs) as providers of pro-apoptotic molecules such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), can be considered as an effective anti-cancer therapy candidate. Therefore, in this study we assessed the role of tumor necrosis factor-producing mesenchymal stem cells oin apoptosis of B-CLL cells resistant to fludarabine- based chemotherapy. MATERIALS AND METHODS: In this study, after isolation and culture of AD-MSCs, a lentiviral LeGO-iG2-TRAIL-GFP vector containing a gene producing the ligand pro apoptotic with plasmid PsPAX2 and PMDG2 virus were transfected into cell-lines to generate T293HEK. Then, T293HEK cell supernatant containing the virus produced after 48 and 72 hours was collected, and these viruses were transduced to reprogram AD-MSCs. Apoptosis rates were separately studied in four groups: group 1, AD-MSCs-TRAIL; group 2, AD-MSCs-GFP; group 3, AD-MSCs; and group 4, CLL. RESULTS: Observed apoptosis rates were: group 1, 42 +/- 1.04%; group 2, 21 +/- 0.57%; group 3, 19+/- 2.6%; and group 4, % 0.01 +/- 0.01. The highest rate of apoptosis thus occurred ingroup 1 (transduced TRAIL encoding vector). In this group, the average medium-soluble TRAIL was 72.7pg/m and flow cytometry analysis showed a pro-apoptosis rate of 63 +/- 1.6%, which was again higher than in other groups. CONCLUSIONS: In this study we have shown that tumor necrosis factor (TNF) secreted by AD-MSCs may play an effective role in inducing B-CLL cell apoptosis. PMID- 26745115 TI - Gene Expression Biodosimetry: Quantitative Assessment of Radiation Dose with Total Body Exposure of Rats. AB - BACKGROUND: Accurate dose assessment and correct identification of irradiated from non-irradiated people are goals of biological dosimetry in radiation accidents. OBJECTIVES: Changes in the FDXR and the RAD51 gene expression (GE) levels were here analyzed in response to total body exposure (TBE) to a 6 MV x ray beam in rats. We determined the accuracy for absolute quantification of GE to predict the dose at 24 hours. MATERIALS AND METHODS: For this in vivo experimental study, using simple randomized sampling, peripheral blood samples were collected from a total of 20 Wistar rats at 24 hours following exposure of total body to 6 MV X-ray beam energy with doses (0.2, 0.5, 2 and 4 Gy) for TBE in Linac Varian 2100C/D (Varian, USA) in Golestan Hospital, in Ahvaz, Iran. Also, 9 rats was irradiated with a 6MV X-ray beam at doses of 1, 2, 3 Gy in 6MV energy as a validation group. A sham group was also included. After RNA extraction and DNA synthesis, GE changes were measured by the QRT-PCR technique and an absolute quantification strategy by taqman methodology in peripheral blood from rats. ROC analysis was used to distinguish irradiated from non-irradiated samples (qualitative dose assessment) at a dose of 2 Gy. RESULTS: The best fits for mean of responses were polynomial equations with a R2 of 0.98 and 0.90 (for FDXR and RAD51 dose response curves, respectively). Dose response of the FDXR gene produced a better mean dose estimation of irradiated "validation" samples compared to the RAD51 gene at doses of 1, 2 and 3 Gy. FDXR gene expression separated the irradiated rats from controls with a sensitivity, specificity and accuracy of 87.5%, 83.5% and 81.3%, respectively, 24 hours after dose of 2 Gy. These values were significantly (p<0.05) higher than the 75%, 75% and 75%, respectively, obtained using gene expression of RAD51 analysis at a dose of 2 Gy. CONCLUSIONS: Collectively, these data suggest that absolute quantification by gel purified quantitative RT-PCR can be used to measure the mRNA copies for GE biodosimetry studies at comparable accuracy to similar methods. In the case of TBE with 6MV energy, FDXR gene expression analysis is more precise than that with RAD51 for quantitative and qualitative dose assessment. PMID- 26745114 TI - Low Coverage and Disparities of Breast and Cervical Cancer Screening in Thai Women: Analysis of National Representative Household Surveys. AB - BACKGROUND: The coverage of breast and cervical cancer screening has only slightly increased in the past decade in Thailand, and these cancers remain leading causes of death among women. This study identified socioeconomic and contextual factors contributing to the variation in screening uptake and coverage. MATERIALS AND METHODS: Secondary data from two nationally representative household surveys, the Health and Welfare Survey (HWS) 2007 and the Reproductive Health Survey (RHS) 2009 conducted by the National Statistical Office were used. The study samples comprised 26,951 women aged 30-59 in the 2009 RHS, and 14,619 women aged 35 years and older in the 2007 HWS were analyzed. Households of women were grouped into wealth quintiles, by asset index derived from Principal components analysis. Descriptive and logistic regression analyses were performed. RESULTS: Screening rates for cervical and breast cancers increased between 2007 and 2009. Education and health insurance coverage including wealth were factors contributing to screening uptake. Lower or non- educated and poor women had lower uptake of screenings, as were young, unmarried, and non-Buddhist women. Coverage of the Civil Servant Medical Benefit Scheme increased the propensity of having both screenings, while the universal coverage scheme increased the probability of cervical screening among the poor. Lack of awareness and knowledge contributed to non-use of both screenings. Women were put off from screening, especially Muslim women on cervical screening, because of embarrassment, fear of pain and other reasons. CONCLUSIONS: Although cervical screening is covered by the benefit package of three main public health insurance schemes, free of charge to all eligible women, the low coverage of cervical screening should be addressed by increasing awareness and strengthening the supply side. As mammography was not cost effective and not covered by any scheme, awareness and practice of breast self examination and effective clinical breast examination are recommended. Removal of cultural barriers is essential. PMID- 26745116 TI - Radiofrequency Ablation in Treating Colorectal Cancer Patients with Liver Metastases. AB - PURPOSE: To evaluate efficacy of radiofrequency ablation (RFA) in treating colorectal cancer patients with liver metastases. METHODS: During January 2010 to April 2012, 56 colorectal cancer patients with liver metastases underwent RFA. CT scans were obtained one month after RFA for all patients to evaluate tumor response. (CR+PR+SD)/n was used to count the disease control rates (DCR). Survival data of 1, 2 and 3 years were obtained from follow up. RESULTS: Patients were followed for 10 to 40 months after RFA (mean time, 25+/-10 months). Median survival time was 27 months. The 1, 2, 3 year survival rate were 80.4%, 71.4%, 41%, 1 % respectively. 3-year survival time for patients with CR or PR after RFA was 68.8% and 4.3% respectively, the difference was statistically significant. The number of CR, PR, SD and PD in our study was 13, 23, 11 and 9 respectively. CONCLUSIONS: RFA could be an effective method for treating colorectal cancer patients with liver metastases, and prolong survival time, especially for metastatic lesions less than or equal to 3 cm. But this result should be confirmed by randomized controlled studies. PMID- 26745117 TI - Effect of Root Extracts of Medicinal Herb Glycyrrhiza glabra on HSP90 Gene Expression and Apoptosis in the HT-29 Colon Cancer Cell Line. AB - Colorectal cancer is one of the most common lethal cancer types worldwide. In recent years, widespread and large-scale studies have been done on medicinal plants for anti-cancer effects, including Glycyrrhiza glabra. The aim of this study was to evaluate the effects of an ethanol extract Glycyrrhiza glabra on the expression of HSP90, growth and apoptosis in the HT-29 colon cancer cell line. HT 29 cells were treated with different concentrations of extract (50,100,150, and 200 MUg/ml). For evaluation of cell proliferation and apoptosis, we used MTT assay and flow cytometry technique, respectively. RT-PCR was also carried out to evaluate the expression levels of HSP90 genes. Results showed that Glycyrrhiza glabra inhibited proliferation of the HT-29 cell line at a concentration of 200 MUg/ml and this was confirmed by the highest rate of cell death as measured by trypan blue and MTT assays. RT-PCR results showed down-regulation of HSP90 gene expression which implied an ability of Glycyrrhiza glabra to induce apoptosis in HT-29 cells and confirmed its anticancer property. Further studies are required to evaluate effects of the extract on other genes and also it is necessary to make an extensive in vivo biological evaluation and subsequently proceed with clinical evaluations. PMID- 26745118 TI - Survival Analysis of Patients with Breast Cancer using Weibull Parametric Model. AB - BACKGROUND: The Cox model is known as one of the most frequently-used methods for analyzing survival data. However, in some situations parametric methods may provide better estimates. In this study, a Weibull parametric model was employed to assess possible prognostic factors that may affect the survival of patients with breast cancer. MATERIALS AND METHODS: We studied 438 patients with breast cancer who visited and were treated at the Cancer Research Center in Shahid Beheshti University of Medical Sciences during 1992 to 2012; the patients were followed up until October 2014. Patients or family members were contacted via telephone calls to confirm whether they were still alive. Clinical, pathological, and biological variables as potential prognostic factors were entered in univariate and multivariate analyses. The log-rank test and the Weibull parametric model with a forward approach, respectively, were used for univariate and multivariate analyses. All analyses were performed using STATA version 11. A P-value lower than 0.05 was defined as significant. RESULTS: On univariate analysis, age at diagnosis, level of education, type of surgery, lymph node status, tumor size, stage, histologic grade, estrogen receptor, progesterone receptor, and lymphovascular invasion had a statistically significant effect on survival time. On multivariate analysis, lymph node status, stage, histologic grade, and lymphovascular invasion were statistically significant. The one-year overall survival rate was 98%. CONCLUSIONS: Based on these data and using Weibull parametric model with a forward approach, we found out that patients with lymphovascular invasion were at 2.13 times greater risk of death due to breast cancer. PMID- 26745119 TI - Development and Evaluation of a Patient-Reported Outcome (PRO) Scale for Breast Cancer. AB - BACKGROUND: This study was guided by principles of the theoretical system of evidence-based medicine. In particular, when searching for evidence of breast cancer, a measuring scale is an instrument for evaluating curative effects in accordance with the laws and characteristics of medicine and exploring the establishment of a system for medically assessing curative effects. At present, there exist few tools for evaluating curative effects. Patient- reported outcomes (PROs) refer to outcomes directly reported by patients (without input or explanations from doctors or other intermediaries) with respect to all aspects of their health. Data obtained from PROs provide evidence of treatment effects. MATERIALS AND METHODS: In accordance with the tenets of theoretical medicine and ancient medical theory regarding breast cancer, principles for developing a PRO scale were established, and a theoretical model was developed and a literature review was performed, items from this pool were combined and split, and an initial scale was constructed. After a pilot survey and additional modifications, a pre-questionnaire scale was formed and used in a field investigation. After the application of statistical methods, the item pool was used to create a formal scale. The reliability, validity and feasibility of this formal scale were then assessed. RESULTS: In a clinical investigation, 479 responses were recovered, with an acceptance rate of 95%. a combination of various methods was employed, and the items that were selected by all methods or more than half of the methods were employed in the questionnaire. In these cases, the screening methods were combined with certain features of the item, A total of four domains and 38 items were reserved. The reliability analysis indicated that the PRO scale was relatively reliable. CONCLUSIONS: Scientific assessment proved that the proposed scale exhibited good reliability and validity. This scale was readily accepted and could be used to assess the curative effects of medical therapy. However, given the limited scope of this investigation, the capacity for adapting this scale to incorporate other theories could not be determined. PMID- 26745120 TI - Significance of Tissue Expression and Serum Levels of Angiopoietin-like Protein 4 in Breast Cancer Progression: Link to NF-kappaB /P65 Activity and Pro Inflammatory Cytokines. AB - BACKGROUND: The molecular mechanisms linking breast cancer progression and inflammation still remain obscure. The aim of the present study was to investigate the possible association of angiopoeitin like protein 4 (ANGPTL4) and its regulatory factor, hypoxia inducible factor-1 alpha (HIF-1alpha), with the inflammatory markers nuclear factor kappa B/p65 (NF-kappaB /P65) and interleukin 1 beta (IL-1beta) in order to evaluate their role in inflammation associated breast cancer progression. MATERIALS AND METHODS: Angiopoietin-like protein 4 (ANGPTL4) mRNA expressions were evaluated using quantitative real time PCR and its protein expression by immunohistochemistry. DNA binding activity of NF-kappaB /P65 was evaluated by transcription factor binding immunoassay. Serum levels of ANGPTL4, HIF-1alpha and IL-1beta were immunoassayed. Tumor clinico-pathological features were investigated. RESULTS: ANGPTL4 mRNA expressions and serum levels were significantly higher in high grade breast carcinoma (1.47+/-0.31 and 184.98+/-18.18, respectively) compared to low grade carcinoma (1.21+/-0.32 and 171.76+/-7.58, respectively) and controls (0.70+/-0.02 and 65.34+/-6.41, respectively), (p<0.05). Also, ANGPTL4 high/moderate protein expression was positively correlated with tumor clinico-pathological features. In addition, serum levels of HIF-1alpha and IL-1beta as well as NF-kappaB /P65 DNA binding activity were significantly higher in high grade breast carcinoma (148.54+/ 14.20, 0.79+/-0.03 and 247.13+/-44.35 respectively) than their values in low grade carcinoma ( 139.14+/-5.83, 0.34+/-0.02 and 184.23+/-37.75, respectively) and controls (33.95+/-3.11, 0.11+/-0.02 and 7.83+/-0.92, respectively), (p<0.001). CONCLUSION: ANGPTL4 high serum levels and tissue expressions in advanced grade breast cancer, in addition to its positive correlation with tumor clinico-pathological features and HIF-1alpha could highlight its role as one of the signaling factors involved in breast cancer progression. Moreover, novel correlations were found between ANGPTL4 and the inflammatory markers, IL-1beta and NF-kappaB/p65, in breast cancer, which may emphasize the utility of these markers as potential tools for understanding interactions for axes of carcinogenesis and inflammation contributed for cancer progression. It is thus hoped that the findings reported here would assist in the development of new breast cancer management strategies that would promote patients' quality of life and ultimately improve clinical outcomes. However, large-scale studies are needed to verify these results. PMID- 26745121 TI - Age-Period-Cohort Analysis of Liver Cancer Mortality in Korea. AB - BACKGROUND: Liver cancer is one of the most common causes of death in the world. In Korea, hepatitis B virus (HBV) is a major risk factor for liver cancer but infection rates have been declining since the implementation of the national vaccination program. In this study, we examined the secular trends in liver cancer mortality to distinguish the effects of age, time period, and birth cohort. MATERIALS AND METHODS: Data for the annual number of liver cancer deaths in Korean adults (30 years and older) were obtained from the Korean Statistical Information Service for the period from 1984-2013. Joinpoint regression analysis was used to study the shapes of and to detect the changes in mortality trends. Also, an age-period-cohort model was designed to study the effect of each age, period, and birth cohort on liver cancer mortality. RESULTS: For both men and women, the age-standardized mortality rate for liver cancer increased from 1984 to 1993 and decreased thereafter. The highest liver cancer mortality rate has shifted to an older age group in recent years. Within the same birth cohort group, the mortality rate of older age groups has been higher than in the younger age groups. Age-period-cohort analysis showed an association with a high mortality rate in the older age group and in recent years, whereas a decreasing mortality rate were observed in the younger birth cohort. CONCLUSIONS: This study confirmed a decreasing trend in liver cancer mortality among Korean men and women after 1993. The trends in mortality rate may be mainly attributed to cohort effects. PMID- 26745122 TI - Electronic Risk Assessment System as an Appropriate Tool for the Prevention of Cancer: a Qualitative Study. AB - BACKGROUND: Decision making modalities for screening for many cancer conditions and different stages have become increasingly complex. Computer-based risk assessment systems facilitate scheduling and decision making and support the delivery of cancer screening services. The aim of this article was to survey electronic risk assessment system as an appropriate tool for the prevention of cancer. MATERIALS AND METHODS: A qualitative design was used involving 21 face-to face interviews. Interviewing involved asking questions and getting answers from exclusive managers of cancer screening. Of the participants 6 were female and 15 were male, and ages ranged from 32 to 78 years. The study was based on a grounded theory approach and the tool was a semi- structured interview. RESULTS: Researchers studied 5 dimensions, comprising electronic guideline standards of colorectal cancer screening, work flow of clinical and genetic activities, pathways of colorectal cancer screening and functionality of computer based guidelines and barriers. Electronic guideline standards of colorectal cancer screening were described in the s3 categories of content standard, telecommunications and technical standards and nomenclature and classification standards. According to the participations' views, workflow and genetic pathways of colorectal cancer screening were identified. CONCLUSIONS: The study demonstrated an effective role of computer-guided consultation for screening management. Electronic based systems facilitate real-time decision making during a clinical interaction. Electronic pathways have been applied for clinical and genetic decision support, workflow management, update recommendation and resource estimates. A suitable technical and clinical infrastructure is an integral part of clinical practice guidline of screening. As a conclusion, it is recommended to consider the necessity of architecture assessment and also integration standards. PMID- 26745123 TI - Methylation Status and Expression of BRCA2 in Epithelial Ovarian Cancers in Indonesia. AB - Ovarian cancer is the main cause of mortality in gynecological malignancy and extensive studies have been conducted to study the underlying molecular mechanisms. The BRCA2 gene is known to be an important tumor suppressor in ovarian cancer, thereby BRCA2 alterations may lead to cancer progression. However, the BRCA2 gene is rarely mutated, and loss of function is suspected to be mediated by epigenetic regulation. In this study we investigated the methylation status and gene expression of BRCA2 in ovarian cancer patients. Ovarian cancer pateints (n=69) were recruited and monitored for 54 months in this prospective cohort study. Clinical specimens were used to study the in situ expression of aberrant BRCA2 proteins and the methylation status of BRCA2. These parameters were then compared with clinical parameters and overall survival rate. We found that BRCA2 methylation was found in the majority of cases (98.7%). However, the methylation status was not associated with protein level expression of BRCA2 (49.3%). Therefore in addition to DNA methylation, other epigenetic mechanisms may regulate BRCA2 expresison. Our findings may become evidence of BRCA2 inactivation mechanism through DNA methylation in the Indonesian population. More importantly, from multivariate analysis, BRCA2 expression was correlated with better overall survival (HR 0.32; p=0.05). High percentage of BRCA2 methylation and correlation of BRCA2 expression with overall survival in epithelial ovarian cancer cases may lead to development of treatment modalities specifically to target methylation of BRCA genes. PMID- 26745124 TI - Assessment of Reliability when Using Diagnostic Binary Ratios of Polycyclic Aromatic Hydrocarbons in Ambient Air PM10. AB - The reliability of using diagnostic binary ratios of particulate carcinogenic polycyclic aromatic hydrocarbons (PAHs) as chemical tracers for source characterisation was assessed by collecting PM10 samples from various air quality observatory sites in Thailand. The major objectives of this research were to evaluate the effects of day and night on the alterations of six different PAH diagnostic binary ratios: An/(An + Phe), Fluo/(Fluo + Pyr), B[a]A/(B[a]A + Chry), B[a]P/(B[a]P + B[e]P), Ind/(Ind + B[g,h,i]P), and B[k]F/Ind, and to investigate the impacts of site-specific conditions on the alterations of PAH diagnostic binary ratios by applying the concept of the coefficient of divergence (COD). No significant differences between day and night were found for any of the diagnostic binary ratios of PAHs, which indicates that the photodecomposition process is of minor importance in terms of PAH reduction. Interestingly, comparatively high values of COD for An/(An + Phe) in PM10 collected from sites with heavy traffic and in residential zones underline the influence of heterogeneous reactions triggered by oxidising gaseous species from vehicular exhausts. Therefore, special attention must be paid when interpreting the data of these diagnostic binary ratios, particularly for cases of low-molecular-weight PAHs. PMID- 26745125 TI - Clinical, Radiologic, and Endoscopic Manifestations of Small Bowel Malignancies: a First Report from Thailand. AB - BACKGROUND: The symptoms of small bowel malignancies are mild and frequently nonspecific, thus patients are often not diagnosed until the disease is at an advanced stage. Moreover, the lack of sufficient studies and available data on small bowel cancer makes diagnosis difficult, further delaying proper treatment for these patients. In fact, only a small number of published studies exist, and there are no studies specific to Thailand. Radiologic and endoscopic studies and findings may allow physicians to better understand the disease, leading to earlier diagnosis and improved patient outcomes. OBJECTIVE: To retrospectively analyze the clinical, radiologic, and endoscopic characteristics of small bowel cancer patients in Thailand's Siriraj Hospital. MATERIALS AND METHODS: This retrospective analysis included 185 adult patients (97 men, 88 women; mean age = 57.6+/-14.9) with pathologically confirmed small bowel cancer diagnosed between January 2006 and December 2013. Clinical, radiologic, and endoscopic findings were collected and compared between each subtype of small bowel cancer. RESULTS: Of the 185 patients analyzed, gastrointestinal stromal tumor (GIST) was the most common diagnosis (39.5%, n=73). Adenocarcinoma was the second most common (25.9%, n = 48), while lymphoma and all other types were identified in 24.3% (n = 45) and 10.3% (n = 19) of cases, respectively. The most common symptoms were weight loss (43.2%), abdominal pain (38.4%), and upper gastrointestinal bleeding (23.8%). CONCLUSIONS: Based on radiology and endoscopy, this study revealed upper gastrointestinal bleeding, an intra-abdominal mass, and a sub-epithelial mass as common symptoms of GIST. Obstruction and ulcerating/circumferential masses were findicative of adenocarcinoma, as revealed by radiology and endoscopy, respectively. Finally, no specific symptoms were related to lymphoma. PMID- 26745126 TI - Assessing the Potential of Thermal Imaging in Recognition of Breast Cancer. AB - BACKGROUND: Breast cancer is a common disorder in women, constituting one of the main causes of death all over the world. The purpose of this study was to determine the diagnostic value of the breast tissue diseases by the help of thermography. MATERIALS AND METHODS: In this paper, we applied non-contact infrared camera, INFREC R500 for evaluating the capabilities of thermography. The study was conducted on 60 patients suspected of breast disease, who were referred to Imam Khomeini Imaging Center. Information obtained from the questionnaires and clinical examinations along with the obtained diagnostic results from ultrasound images, biopsies and thermography, were analyzed. The results indicated that the use of thermography as well as the asymmetry technique is useful in identifying hypoechoic as well as cystic masses. It should be noted that the patient should not suffer from breast discharge. RESULTS: The accuracy of asymmetry technique identification is respectively 91/89% and 92/30%. Also the accuracy of the exact location of identification is on the 61/53% and 75%. The approach also proved effective in identifying heterogeneous lesions, fibroadenomas, and intraductal masses, but not ISO-echoes and calcified masses. CONCLUSIONS: According to the results of the investigation, thermography may be useful in the initial screening and supplementation of diagnostic procedures due to its safety (its non-radiation properties), low cost and the good recognition of breast tissue disease. PMID- 26745127 TI - Could Tumor Size Be A Predictor for Papillary Thyroid Microcarcinoma: a Retrospective Cohort Study. AB - BACKGROUND: Central lymph node metastasis(CLNM) is common in papillary thyroid microcarcinoma (PTMC). The aim of this study was to define the pathohistologic risk grading based on surgical outcomes. MATERIALS AND METHODS: Statistical analysis was performed to figure out the optimal cut-off values of size in preoperative ultrasound images for defining the risk of CLNM in papillary thyroid microcarcinoma. Receiver operating characteristic curves (ROC) studies were carried out to determine the cutoff value(s) for the predictor(s). All the patients were divided into two groups according to the above size and the clinic pathological and immunohistochemical parameters were compared to determine the significance of findings. RESULTS: The optimal cut-off value of tumor size to predict the risk of CLNM in papillary thyroid microcarcinoma was 0.575 cm (area under the curve 0.721) according to the ROC curves. Significant differences were observed on the multifocality, extrathyroidal extension and central lymph node metastasis between two groups which were divided according to the tumor size by the cutoff values. Patients in two groups showed different positive rate and intensity of Ki67. CONCLUSIONS: The size of PTMC in ultrasound images are helpful to predict the aggressiveness of the tumors, it could be an easy predictor for PTMC prognosis and assist us to choose treatment. PMID- 26745129 TI - Expression and Clinical Significance of Sushi Domain- Containing Protein 3 (SUSD3) and Insulin-like Growth Factor-I Receptor (IGF-IR) in Breast Cancer. AB - BACKGROUND: To investigate the expression of insulin-like growth factor-I receptor (IGF-IR) and sushi domaincontaining protein 3 (SUSD3) in breast cancer tissue, and analyze their relationship with clinical parameters and the correlation betweenthe two proteins. MATERIALS AND METHODS: The expression of IGF IR and SUSD3 in 100 cases of breast cancer tissues and adjacent normal breast tissues after surgery was detected by immunohistochemical technique MaxVisionTM, and the relationship with clinical pathological features was further analyzed. RESULTS: The positive rate of IGF-IR protein was 86.0% in breast cancer, higher than 3.0% in adjacent normalbreast tissue (P<0.05) .The positive expression rate of SUSD3 protein was 78.0% in breast cancer, higher than 2.0% in adjacent normal breast tissue (P<0.05). The expression of IGF-IR and SUSD3 was related to estrogen receptor and pathological types (P<0.05),but not with age, stage, the expression of HER-2 and Ki-67 (P>0. 05). The expression of IGF-IR and SUSD3 in breast cancer tissue was positively related (r= 0.553, P<0.01). CONCLUSIONS: The expression of IGF-IR and SUSD3 may be correlated to the occurrence and development of breast cancer. The combined detection of IGF-IR, SUSD3 and ER may play an important role in judging prognosis and guiding adjuvant therapy after surgery of breast cancer. PMID- 26745128 TI - Primary Idiopathic Myelofibrosis: Clinico-Epidemiological Profile and Risk Stratification in Pakistani Patients. AB - BACKGROUND: Primary idiopathic myelofibrosis (PMF) is a clonal Philadelphia chromosome-negative myeloproliferative neoplasm characterized by extramedullary hematopoiesis and marrow fibrosis. It is an uncommon hematopoietic malignancy which primarily affects elderly individuals. The rational of this study was to determine its clinico-epidemiological profile along with risk stratification in Pakistani patients. MATERIALS AND METHODS: In this retrospective cross sectional study, 20 patients with idiopathic myelofibrosis were enrolled from January 2011 to December 2014. Data were analyzed with SPSS version 22. RESULTS: The mean age was 57.9+/-16.5 years with 70% of patients aged above 50. The male to female ratio was 3:1. Overall only 10% of patients were asymptomatic and the remainder presented with constitutional symptoms. In symptomatic patients, major complaints were weakness (80%), weight loss (75%), abdominal discomfort (60%), night sweats (13%), pruritus (5%) and cardiovascular accidents (5%). Physical examination revealed splenomegaly as a predominant finding detected in 17 patients (85%) with the mean splenic span of 22.2+/-2.04cm. The mean hemoglobin was 9.16+/-2.52 g/dl with the mean MCV of 88.2+/-19.7 fl. The total leukocyte count of 17.6+/ 19.2x109/l and platelets count were 346.5+/-321.9x109/l. Serum lactate dehydrogenase, serum creatinine and uric acid were 731.0+/-154.1, 0.82+/-0.22 and 4.76+/-1.33 respectively. According to risk stratification, 35% were in high risk, 40% in intermediate risk and 25% in low risk groups. CONCLUSIONS: The majority of PMF patients were male and presented with constitutional symptoms in our setting. Risk stratification revealed predominance of advanced disease in our series. PMID- 26745130 TI - Intraperitoneal Perfusion Therapy of Endostar Combined with Platinum Chemotherapy for Malignant Serous Effusions: A Meta-analysis. AB - BACKGROUND: Malignant serous effusions (MSE) are one complication in patients with advanced cancer. Endostar is a new anti-tumor drug targeting vessels which exerts potent inhibition of neovascularization. This study aimed to systematically evaluate the efficacy and safety of intraperitoneal perfusion therapy of Endostar combined with platinum chemotherapy for malignant serous effusions (MSE). MATERIALS AND METHODS: Randomized controlled trials (RCTs) on intraperitoneal perfusion therapy of Endostar combined with platinum chemotherapy for malignant serous effusions were searched in the electronic data of PubMed, EMBASE, Web of Science, CNKI, VIP, CBM and WanFang. The quality of RCTs was evaluated by two independent researchers and a meta-analysis was performed using RevMan 5.3 software. RESULTS: The total of 25 RCTs included in the meta-analysis covered 1,253 patients, and all literature quality was evaluated as "B" grade. The meta-analysis showed that Endostar combined with platinum had an advantage over platinum alone in terms of response rate of effusions (76% vs 48%, RR=1.63, 95%CI: 1.50-1.78, P<0.00001) and improvement rate in quality of life (69% vs 44%, RR=1.57, 95%CI: 1.42-1.74, P<0.00001). As for safety, there was no significant difference between the two groups in the incidences of nausea and vomiting (35% vs 34%, RR=1.01, 95%CI: 0.87-1.18, P=0.88), leucopenia (38% vs 38%, RR=1, 95%CI: 0.87-1.15, P=0.99), and renal impairment (18% vs 20%, RR=0.86, 95%CI: 0.43-1.74, P=0.68). CONCLUSIONS: Endostar combined with platinum by intraperitoneal perfusion is effective for malignant serous effusions, and patient quality of life is significantly improved without the incidence of adverse reactions being obviously increased. PMID- 26745131 TI - Turkish Adolescent Perceptions about the Effects of Water Pipe Smoking on their Health. AB - BACKGROUND: Consumption of tobacco in the form of a water pipe has recently increased, especially among young people. This study aimed to develop a scale which would be used in order to detect perceptions about the effects of water pipe smoking on health and to test its validity and reliability. Our scale named "a scale of perception about the effects of water pipe smoking on health" was developed in order to detect factors effecting the perception of adolescents about the effects of water pipe smoking on health. MATERIALS AND METHODS: The sample consisted of 150 voluntary students in scale development and 750 voluntary students in the study group. Data were collected via a questionnaire prepared by researchers themselves and 5-pont Likert scale for "a scale of perception about the effects of water pipe smoking on health" which was prepared through the literature. Data evaluation was carried out on a computer with SPSS. RESULTS: The findings of the study showed that "a scale of perception about the effects of water pipe smoking on health" was valid and reliable. Total score average of the adolescents participated in the study was 58.5+/-1.25. The mean score of the ones who did not smoke water pipe (60.1+/-11.7) was higher than the mean score of the ones who smoked water pipe (51.6+/-13.8), the difference being statistically significant. CONCLUSIONS: It is established that "a scale of perception about the effects of water pipe smoking on health" was a reliable and valid measurement tool. It is also found out that individuals who smoked a water pipe had a lower level of perception of water pipe smoking effects on health than their counterparts who did not smoke a water pipe. PMID- 26745132 TI - Heparanase mRNA and Protein Expression Correlates with Clinicopathologic Features of Gastric Cancer Patients: a Meta- analysis. AB - BACKGROUND: Heparanase is believed to be involved in gastric carcinogenesis. However, the clinicopathologic features of gastric cancer with high heparanase expression remain unclear. AIM: The purpose of this study was to comprehensively and quantitatively summarize available evidence for the use of heparanase mRNA and protein expression to evaluate the clinicopathological associations in gastric cancer in Asian patients by meta-analysis. MATERIALS AND METHODS: Relevant articles listed in MEDLINE, CNKI and the Cochrane Library databases up to MARCH 2015 were searched by use of several keywords in electronic databases. A meta-analysis was performed to clarify the impact of heparanase mRNA and protein on clinicopathological parameters in gastric cancer. Combined ORs with 95%CIs were calculated by Revman 5.0, and publication bias testing was performed by stata12.0. RESULTS: A total of 27 studies which included 3,891 gastric cancer patients were combined in the final analysis. When stratifying the studies by the pathological variables of heparanase mRNA expression, the depth of invasion (633 patients) (OR=4.96; 95% CI=2.38-1.37; P<0.0001), lymph node metastasis (639 patients) (OR=6.22; 95%CI=2.70-14.34, P<0.0001), and lymph node metastasis (383 patients) (OR=6.85; 95% CI=2.04-23.04; P=0.002) were all significant. When stratifying the studies by the pathological variables of heparanase protein expression, this was the case for depth of invasion (1250 patients) (OR=2.76; 95% CI=1.52-5.03; P=0.0009), lymph node metastasis (1178 patients) (OR=4.79 ; 95% CI=3.37-6.80, P<0.00001), tumor size (727 patients) (OR=2.06 ; 95% CI=1.31-3.23; P=0.002) (OR=2.61; 95% CI=2.09-3.27; P=0.000), and TNM stage (1233 patients) (OR=6.85; 95% CI=2.04-23.04; P=0.002). Egger's tests suggested publication bias for depth of invasion, lymph node metastasis, lymph node metastasis and tumor size of heparanase mRNA and protein expression. CONCLUSIONS: This meta- analysis suggests that higher heparanase expression in gastric cancer is associated with clinicopathologic features of depth of invasion, lymph node metastasis and TNM stage at mRNA and protein levels, and of tumor size only at the protein level. Egger's tests suggested publication bias for these clinicopathologic features of heparanase mRNA and protein expression, and which may be caused by shortage of relevant studies. As a result, although abundant reports showed heparanase may be associated with clinicopathologic features in gastric cancer, this meta-analysis indicates that more strict studies were needed to evaluate its clinicopathologic significance. PMID- 26745133 TI - Malignant Neoplasm Burden in Nepal - Data from the Seven Major Cancer Service Hospitals for 2012. AB - In Nepal, while no population based cancer registry program exists to assess the incidence, prevalence, morbidity and mortality of cancer, at the national level a number of hospital based cancer registries are cooperating to provide relevant data. Seven major cancer diagnosis and treatment hospitals are involved, including the BP Koirala Memorial Cancer hospital, supported by WHO-Nepal since 2003. The present retrospective analysis of cancer patients of all age groups was conducted to assess the frequencies of different types of cancer presenting from January 1st to December 31st 2012. A total of 7,212 cancer cases were registered, the mean age of the patients being 51.9 years. The most prevalent age group in males was 60-64 yrs (13.6%), while in females it was 50-54 yrs (12.8%). The commonest forms of cancer in males were bronchus and lung (17.6%) followed by stomach (7.3%), larynx (5.2%) and non Hodgkins lymphoma (4.5%). In females, cervix uteri (19.1%) and breast (16.3%), were the top ranking cancer sites followed by bronchus and lung (10.2%), ovary (6.1%) and stomach (3.8%). The present data provide an update of the cancer burden in Nepal and highlight the relatively young age of breast and cervical cancer patients. PMID- 26745135 TI - Deactivation of Telomerase Enzyme and Telomere Destabilization by Natural Products: a Potential Target for Cancer Green Therapy. PMID- 26745134 TI - Efficacy of Prophylactic Entecavir for Hepatitis B Virus-Related Hepatocellular Carcinoma Receiving Transcatheter Arterial Chemoembolization. AB - BACKGROUND AND AIMS: Hepatitis B virus (HBV) reactivation was reported to be induced by transcatheter arterial chemoembolization (TACE) in HBV-related hepatocellular carcinonma (HCC) patients with a high incidence. The effective strategy to reduce hepatitis flares due to HBV reactivation in this specific group of patients was limited to lamivudine. This retrospective study was aimed to investigate the efficacy of prophylactic entecavir in HCC patients receiving TACE. METHODS: A consecutive series of 191 HBV-related HCC patients receiving TACE were analyzed including 44 patients received prophylactic entecavir. Virologic events, defined as an increase in serum HBV DNA level to more than 1 log10 copies/ml higher than nadir the level, and hepatitis flares due to HBV reactivation were the main endpoints. RESULTS: Patients with or without prophylactic were similar in host factors and the majorities of characteristics regarding to tumor factors, HBV status, liver function and LMR. Notably, cycles of TACE were parallel between the groups. Ten (22.7%) patients receiving prophylactic entecavir reached virologic response. The patients receiving prophylactic entecavir presented significantly reduced virologic events (6.8% vs 54.4%, p=0.000) and hepatitis flares due to HBV reactivation (0.0% vs 11.6%, p=0.039) compared with patients without prophylaxis. Kaplan-Meier analysis illustrated that the patients in the entecavir group presented significantly improved virologic events free survival (p=0.000) and hepatitis flare free survival (p=0.017). Female and Eastern Cooperative Oncology Group (ECOG) performance status 2 was the only significant predictors for virological events in patients without prophylactic antiviral. Rescue antiviral therapy did not reduce the incidence of hepatitis flares due to HBV reactivation. CONCLUSION: Prophylactic entecavir presented promising efficacy in HBV-related cancer patients receiving TACE. Lower performance status and female gender might be the predictors for HBV reactivation in these patients. PMID- 26745136 TI - Clues to Identifying Risk Factors for Nasopharyngeal Carcinoma. PMID- 26745137 TI - Topical aural antibiotic use in the UK - time for a change of policy? PMID- 26745138 TI - Interpreting pre-operative mastoid computed tomography images: comparison between operating surgeon, radiologist and operative findings. AB - OBJECTIVES: This study aimed to compare the interpretations of temporal bone computed tomography scans by an otologist and a radiologist with a special interest in temporal bone imaging. It also aimed to determine the usefulness of this imaging modality. METHODS: A head and neck radiologist and an otologist separately reported pre-operative computed tomography images using a structured proforma. The reports were then compared with operative findings to determine their accuracy and differences in interpretations. RESULTS: Forty-eight patients who underwent pre-operative computed tomography scans in a 30-month period were identified. Six patients were excluded because complete operative findings had not been recorded. Positive and negative predictive values and accuracy of the anatomical and pathological findings were calculated for 42 patients by both reporters. The accuracy was found to be less than 80 per cent, except for identification of the tegmen and lateral semicircular canal erosion. Overall, there was no significant difference in interpretations of computed tomography scans between reporters. There was a slight difference in interpretation for tympanic membrane retraction, facial canal erosion and lateral semicircular canal fistula and/or erosion. CONCLUSION: Pre-operative computed tomography scanning of the temporal bone is useful for predicting anatomy for surgical planning in patients with chronic otitis media, but its reliability remains questionable. PMID- 26745139 TI - External calibration of the spectral coverage for three-dimensional multispectral MRI. AB - PURPOSE: By combining images created at distinct frequency offsets from the Larmor frequency, three-dimensional (3D) multispectral imaging (3D-MSI) sequences help overcome the large spatial frequency dispersion caused by metal implants. This frequency dispersion, however, varies with the implant size, orientation, and composition. Using a MAVRIC 3D-MSI acquisition, we sought to prospectively calibrate the spectral coverage needed for 3D-MSI scans. This calibration should offer a significant improvement to image quality, and reduce the scan time. METHODS: The 24 spectral bins from the calibration scan were used to generate a map of frequency offsets around the implant. The magnitude image was used to remove any outliers in the associated frequency offset map, and this processed map was used to determine the cutoff frequency offset and, hence, number of spectral bins. This approach was tested in 13 subjects, by retrospectively reconstructing MAVRIC-SL images with fewer spectral bins. Subsequently, the spectral coverage for MAVRIC-SL images was prospectively calibrated in six subjects, and based on the cutoff frequency offset, these images were acquired with fewer spectral bins. RESULTS: With fewer spectral bins, both retrospectively and prospectively calibrated MAVRIC-SL images adequately delineated the implant boundary. CONCLUSION: Incorporating this calibration procedure into future 3D-MSI exams will help improve image signal-to-noise ratio, reduce scan time, and significantly improve clinical workflow when imaging near orthopedic implants. Magn Reson Med 76:1494-1503, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26745140 TI - The Relationship between Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms and Mean Platelet Volume: The Role of Metabolic Syndrome. AB - OBJECTIVE: The aim of the present study was to investigate the relationship among serum mean platelet volume (MPV) levels, benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) and metabolic syndrome (MetS), and study the potential role of serum MPV levels in BPH/LUTS progression in an indirect manner. METHODS: Five hundred fifty-one men aged 45 or older with moderate to severe LUTS due to benign prostatic enlargement were recruited into this study by consecutive routine physical examination programs. Urologic evaluation included transrectal ultrasound, International Prostate Symptom Score and maximum urinary flow rate (Qmax). Overnight fasting venous blood specimens were collected and serum levels of prostate-specific antigen, fasting blood glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglyceride and C-reactive protein (CRP) were recorded. In addition, MPV were determined by automated hematology analyzer. We divided subjects into 2 groups according to the presence of MetS. We also took the MPV values as a categorical variable and divided subjects into 2 groups (>=11.8 or <11.8 fl) or 4 groups according to the different levels of MPV (9.3-11.0, 11.1-11.5, 11.6-11.9, 12.0-12.5 and >=12.5 fl). The clinical characteristics and parameters of BPH/LUTS in different groups were measured and compared to identify their relationships. RESULTS: MetS was diagnosed in 37.0% of the subjects. There were significant interactive correlation among the number of positive MetS components, CRP, MPV and parameters of BPH/LUTS. The ratio of PV >=31 ml and Qmax <10.6 ml/s were positively correlated with the increased level of MPV. Additionally, the OR in relation to PV >=31 ml and Qmax <10.6 ml/s significantly rose as the level of MPV increased after adjusting for age, suggesting of a threshold effect at 12.0-12.5 fl for PV >=31 ml (OR 2.678, 95% CI 1.425-5.035) and at >12.5 fl for Qmax <10.6 ml/s (OR 3.190, 95% CI 1.768-5.755). However, only the value of MPV more than 12.5 fl still showed statistically significant effect on Qmax <10.6 ml/s after adjusting for age and the presence of MetS (OR 2.164, 95% CI 1.162-4.032). CONCLUSIONS: Our results add to the evidence that chronic inflammation is a candidate mechanism at the crossroad between MetS and BPH/LUTS, and the presence of elevated MPV may serve as a predictor of MetS-induced inflammation in the progression of BPH/LUTS. PMID- 26745141 TI - Scapular Morphology and Forelimb Use during Foraging in Four Sympatric Cercopithecids. AB - Most investigations of primate scapular morphology use differences in locomotion to explain variation; less is known about how scapular geometry covaries with nonlocomotor behavior. We examined forelimb use during foraging in 4 cercopithecids ranging throughout the Ivory Coast's Tai Forest. During 5-min feeding bouts, we recorded the frequency individuals of Piliocolobus badius, Colobus polykomos, Cercocebus atys and Cercopithecus diana performed 5 forelimb behaviors involved in the acquisition and introduction of food to the oral cavity. Scapulae from these populations were examined to determine whether differences in forelimb use were reflected in features known to correspond with varying degrees of arm flexion, abduction and elevation. Our results reveal that the species differ markedly in forelimb use and that these differences are interpretable via their scapular morphology. For example, P. badius engages in more frequent flexion, abduction and elevation of the arm above the head relative to C. polykomos, and red colobus scapulae are longer craniocaudally and have larger, more cranially directed supraspinous fossae than those of closely related black-and-white colobus. Our attempt to explore how nonlocomotor behavior covaries with skeletal morphology should provide for more informed interpretations of the primate fossil record. PMID- 26745142 TI - Psychosocial Results from a Phase I Trial of a Nonsurgical Circumcision Device for Adult Men in Zimbabwe. AB - Male circumcision (MC), an effective HIV prevention tool, has been added to Zimbabwe's Ministry of Health and Child Care HIV/AIDS Prevention Program. A Phase I safety trial of a nonsurgical male circumcision device was conducted and extensive psychosocial variables were assessed. Fifty-three men (18 and older) were recruited for the device procedure; 13 follow-up clinical visits were completed. Interviews conducted three times (before the procedure, at 2 weeks and 90 days post-procedure) assessed: Satisfaction; expectations; actual experience; activities of daily living; sexual behavior; and HIV risk perception. Using the Integrated Behavioral Model, attitudes towards MC, sex, and condoms, and sources of social influence and support were also assessed. Men (mean age 32.5, range 18 50; mean years of education = 13.6; 55% employed) were satisfied with device circumcision results. Men understand that MC is only partially protective against HIV acquisition. Most (94.7%) agreed that they will continue to use condoms to protect themselves from HIV. Pain ratings were surprisingly negative for a procedure billed as painless. Men talked to many social networks members about their MC experience; post-procedure (mean of 14 individuals). Minimal impact on activities of daily living and absenteeism indicate possible cost savings of device circumcisions. Spontaneous erections occurred frequently post-procedure. The results had important implications for changes in the pre-procedure clinical counseling protocol. Clear-cut counseling to manage pain and erection expectations should result in improved psychosocial outcomes in future roll-out of device circumcisions. Men's expectations must be managed through evidence based counseling, as they share their experiences broadly among their social networks. PMID- 26745143 TI - Do Sexual Networks of Men Who Have Sex with Men in New York City Differ by Race/Ethnicity? AB - The United States HIV epidemic disproportionately affects Black and Hispanic men who have sex with men (MSM). This disparity might be partially explained by differences in social and sexual network structure and composition. A total of 1267 MSM in New York City completed an ACASI survey and egocentric social and sexual network inventory about their sex partners in the past 3 months, and underwent HIV testing. Social and sexual network structure and composition were compared by race/ethnicity of the egos: black, non-Hispanic (N = 365 egos), white, non-Hispanic (N = 466), and Hispanic (N = 436). 21.1% were HIV-positive by HIV testing; 17.2% reported serodiscordant and serostatus unknown unprotected anal/vaginal intercourse (SDUI) in the last 3 months. Black MSM were more likely than white and Hispanic MSM to report exclusively having partners of same race/ethnicity. Black and Hispanic MSM had more HIV-positive and unknown status partners than white MSM. White men were more likely to report overlap of social and sex partners than black and Hispanic men. No significant differences by race/ethnicity were found for network size, density, having concurrent partners, or having partners with >=10 years age difference. Specific network composition characteristics may explain racial/ethnic disparities in HIV infection rates among MSM, including HIV status of sex partners in networks and lack of social support within sexual networks. Network structural characteristics such as size and density do not appear to have such an impact. These data add to our understanding of the complexity of social factors affecting black MSM and Hispanic MSM in the U.S. PMID- 26745146 TI - Inhalation Study of Mycobacteriophage D29 Aerosol for Mice by Endotracheal Route and Nose-Only Exposure. AB - BACKGROUND: Lytic mycobacteriophage D29 has the potential for tuberculosis treatment including multidrug-resistant strains. The aims of this study are to investigate deposition and distribution of aerosolized phage D29 particles in naive Balb/C mice, together with pharmacokinetics and evaluation of acute lung injury. METHODS: Pharmacokinetics and BALF (bronchoalveolar lavage fluids) were analyzed after administration of phage D29 aerosols by endotracheal route using Penn-century aerosolizer; Collison 6-jet and Spinning top aerosol nebulizers (STAG) were used to generate phage aerosols with different particle size distributions in nose-only inhalation experiments. After exposure, deposited amounts of phage D29 particles in respiratory tracts were measured, and deposition efficiencies were calculated. A typical path deposition model for mice was developed, and then comparisons were made between predictions and experimentally measured results. RESULTS: Approximately 10% of aerosolized phages D29 reached lung of mouse for pulmonary delivery, and were completely eliminated until 72 h after administration. In contrast, about 0.1% of intraperitoneal injected phages reached the lung, and were almost eliminated at 12 h time point. The inflammation was hardly observed in lung according to the results of BALF analysis. The CMADs (count median aerodynamic diameters) of generated aerosol by Collison and STAG nebulizer were 0.8 MUm and 1.5 MUm, respectively. After nose only exposure, measured deposition efficiencies in whole respiratory tract for 0.8 and 1.5 MUm phage particles were below 1% and 10%, respectively. Predictions of the computer deposition model compared fairly well with experimentally measured results. CONCLUSIONS: This is the first systematic study of phage D29 aerosol respiratory challenge in laboratory animals. It provides evidence that aerosol delivery of phage D29 is an effective way for treating pulmonary infections caused by Mycobacterium tuberculosis. This research will also provide important data for future inhalation experiments. PMID- 26745144 TI - Head Motion and Inattention/Hyperactivity Share Common Genetic Influences: Implications for fMRI Studies of ADHD. AB - Head motion (HM) is a well known confound in analyses of functional MRI (fMRI) data. Neuroimaging researchers therefore typically treat HM as a nuisance covariate in their analyses. Even so, it is possible that HM shares a common genetic influence with the trait of interest. Here we investigate the extent to which this relationship is due to shared genetic factors, using HM extracted from resting-state fMRI and maternal and self report measures of Inattention and Hyperactivity-Impulsivity from the Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour (SWAN) scales. Our sample consisted of healthy young adult twins (N = 627 (63% females) including 95 MZ and 144 DZ twin pairs, mean age 22, who had mother-reported SWAN; N = 725 (58% females) including 101 MZ and 156 DZ pairs, mean age 25, with self reported SWAN). This design enabled us to distinguish genetic from environmental factors in the association between head movement and ADHD scales. HM was moderately correlated with maternal reports of Inattention (r = 0.17, p-value = 7.4E-5) and Hyperactivity-Impulsivity (r = 0.16, p-value = 2.9E-4), and these associations were mainly due to pleiotropic genetic factors with genetic correlations [95% CIs] of rg = 0.24 [0.02, 0.43] and rg = 0.23 [0.07, 0.39]. Correlations between self-reports and HM were not significant, due largely to increased measurement error. These results indicate that treating HM as a nuisance covariate in neuroimaging studies of ADHD will likely reduce power to detect between-group effects, as the implicit assumption of independence between HM and Inattention or Hyperactivity-Impulsivity is not warranted. The implications of this finding are problematic for fMRI studies of ADHD, as failing to apply HM correction is known to increase the likelihood of false positives. We discuss two ways to circumvent this problem: censoring the motion contaminated frames of the RS-fMRI scan or explicitly modeling the relationship between HM and Inattention or Hyperactivity-Impulsivity. PMID- 26745145 TI - BAD, a Proapoptotic Protein, Escapes ERK/RSK Phosphorylation in Deguelin and siRNA-Treated HeLa Cells. AB - This study has been undertaken to explore the therapeutic effects of deguelin and specific siRNAs in HeLa cells. The data provided clearly show the silencing of ERK 1/2 with siRNAs and inhibition of ERK1/2 with deguelin treatment in HeLa cells. Additionally, we are providing information that deguelin binds directly to anti-apoptotic Bcl-2, Bcl-xl and Mcl-1 in the hydrophobic grooves, thereby releasing BAD and BAX from dimerization with these proteins. This results in increased apoptotic activity through the intrinsic pathway involved in rupture of mitochondrial membrane and release of cytochrome C. Evidence for inhibition of ERK1/2 by deguelin and escape of BAD phosphorylation at serine 112 through ERK/RSK pathway has been further fortified by obtaining similar results by silencing ERK 1/2 each with specific siRNAs. Increase in BAD after treatment with deguelin or siRNAs has been interpreted to mean that deguelin acts through several alternative pathways and therefore can be used as effective therapeutic agent. PMID- 26745148 TI - High Discrepancy in Abdominal Obesity Prevalence According to Different Waist Circumference Cut-Offs and Measurement Methods in Children: Need for Age-Risk Weighted Standardized Cut-Offs? AB - BACKGROUND: Waist circumference (WC) is a good proxy measure of central adiposity. Due to the multiplicity of existing WC cut-offs and different measurement methods, the decision to use one rather than another WC chart may lead to different prevalence estimates of abdominal obesity in the same population. Aim of our study was to assess how much the prevalence of abdominal obesity varies in Italian schoolchildren using the different available WC cut offs. METHODS: We measured WC at just above the uppermost lateral border of the right ilium in 1062 Italian schoolchildren aged 7-14 years, 499 living in Northern Italy and 563 in Southern Italy. Abdominal obesity was defined as WC >=90th percentile for gender and age according to nine WC charts. RESULTS: We found an extremely high variability in the prevalence of abdominal obesity detected in our study-populations according to the different WC charts, ranging in the overall group from 9.1% to 61.4%. In Northern Italy children it varied from 2.4% to 35.7%, and in Southern ones from 15.1% to 84.2%. CONCLUSIONS: On the basis of the chosen WC cut-offs the prevalence of abdominal obesity varies widely, because percentile-charts are strongly influenced by the population status in a particular moment. A further rate of variability may lay on the site of WC measurement and on the statistical method used to calculate WC cut-offs. Risk-weighted WC cut-offs measured in a standardized anatomic site and calculated by the appropriate method are needed to simply identify by WC measurement those children at high risk of cardio-metabolic complications to whom specific and prompt health interventions should be addressed. PMID- 26745149 TI - GENETIC FACTORS ASSOCIATED WITH CHOROIDAL VASCULAR HYPERPERMEABILITY AND SUBFOVEAL CHOROIDAL THICKNESS IN POLYPOIDAL CHOROIDAL VASCULOPATHY. AB - PURPOSE: To investigate genetic factors associated with choroidal vascular hyperpermeability (CVH) and subfoveal choroidal thickness in eyes with treatment naive polypoidal choroidal vasculopathy. METHODS: We studied 149 consecutive patients with polypoidal choroidal vasculopathy. The presence of CVH was evaluated using indocyanine green angiography. Subfoveal choroidal thickness and axial length were measured by spectral domain optical coherence tomography and optical biometry, respectively. Genotyping of three single nubleotide polymorphisms (SNPs), including age-related maculopathy susceptibility 2 (ARMS2) A69S (rs10490924), complement factor H (CFH) I62V (rs800292), and CFH (rs1329428), which are reportedly associated with central serous chorioretinopathy, was conducted using TaqMan technology. RESULTS: Thicker subfoveal choroidal thickness was associated with younger age, shorter axial length, G-allele frequency in ARMS2 A69S (rs10490924), and T-allele frequency in CFH (rs1329428) (P = 0.001, P < 0.001, P = 0.004, and P = 0.002, respectively; multiple regression analysis). Among 149 eyes with polypoidal choroidal vasculopathy, 35 eyes (23.5%) exhibited CVH on indocyanine green angiography. Patients with CVH had a significantly higher frequency of the G allele of ARMS2 A69S (rs10490924) and the T allele of CFH (rs1329428), which are reported to be risk alleles for central serous chorioretinopathy (P = 0.006 and P = 0.032, respectively; multivariate regression analysis). CONCLUSION: Subfoveal choroidal thickness and CVH in eyes with treatment-naive polypoidal choroidal vasculopathy were associated with ARMS2 A69S (rs10490924) and CFH (rs1329428). PMID- 26745151 TI - Can We Improve Access to Quality Pain Care for Patients? PMID- 26745147 TI - Dynamics of Urinary Calprotectin after Renal Ischaemia. AB - BACKGROUND: Urinary calprotectin has been identified as a promising biomarker for acute kidney injury. To date, however, the time-dependent changes of this parameter during acute kidney injury remain elusive. The aim of the present work was to define the time-course of urinary calprotectin secretion after ischaemia/reperfusion-induced kidney injury in comparison to neutrophil gelatinase-associated lipocalin, thereby monitoring the extent of tubular damage in nephron sparing surgery for kidney tumours. METHODS: The study population consisted of 42 patients. Thirty-two patients underwent either open or endoscopic nephron sparing surgery for kidney tumours. During the surgery, the renal arterial pedicle was clamped with a median ischaemic time of 13 minutes (interquartile range, 4.5-20.3 minutes) in 26 patients. Ten retro-peritoneoscopic living donor nephrectomy patients and 6 nephron sparing surgery patients in whom the renal artery was not clamped served as controls. Urinary calprotectin and neutrophil gelatinase-associated lipocalin concentrations were repeatedly measured by enzyme-linked immunosorbent assay and assessed according to renal function parameters. RESULTS: Urinary concentrations of calprotectin and neutrophil gelatinase-associated lipocalin increased significantly after ischaemia/reperfusion injury, whereas concentrations remained unchanged after nephron sparing surgery without ischaemia/reperfusion injury and after kidney donation. Calprotectin and neutrophil gelatinase-associated lipocalin levels were significantly increased 2 and 8 hours, respectively, post-ischaemia. Both proteins reached maximal concentrations after 48 hours, followed by a subsequent persistent decrease. Maximal neutrophil gelatinase-associated lipocalin and calprotectin concentrations were 9-fold and 69-fold higher than their respective baseline values. The glomerular filtration rate was only transiently impaired at the first post-operative day after ischaemia/reperfusion injury (p = 0.049). CONCLUSION: Calprotectin and neutrophil gelatinase-associated lipocalin can be used to monitor clinical and sub-clinical tubular damage after nephron sparing surgery for kidney tumours. Urinary calprotectin concentrations start rising within 2 hours after ischaemia/reperfusion-induced kidney injury. PMID- 26745150 TI - Association between vitamin deficiency and metabolic disorders related to obesity. AB - Inappropriate food behavior contributes to obesity and leads to vitamin deficiency. This review discusses the nutritional status of water- and fat soluble vitamins in obese subjects. We verified that most vitamins are deficient in obese individuals, especially the fat-soluble vitamins, folic acid, vitamin B12 and vitamin C. However, some vitamins have been less evaluated in cases of obesity. The adipose tissue is considered a metabolic and endocrine organ, which in excess leads to changes in body homeostasis, as well as vitamin deficiency which can aggravate the pathological state. Therefore, the evaluation of vitamin status is of fundamental importance in obese individuals. PMID- 26745152 TI - CNS Measures of Pain Responses Pre- and Post-Anesthetic Ketamine in a Patient with Complex Regional Pain Syndrome. AB - BACKGROUND: Previous reports have indicated that ketamine anesthesia may produce significant improvement if not complete recovery of patients with complex regional pain syndrome (CRPS). AIMS: Here we report on a patient who had CRPS affecting mainly the right side of her body who underwent functional magnetic resonance imaging (fMRI) scans prior to and in the months following apparent successful treatment with anesthetic doses of ketamine. MATERIALS AND METHODS: The patient underwent two imaging sessions: one during her pain state (CRPS+) and 1 month after her ketamine treatment in her pain-free state (CRPS-). Both spontaneous and evoked (brush, cold, and heat) pain scores decreased from 7-9/10 on a visual analog scale prior to the treatment to 0-1 immediately following and for months after the treatment. For each imaging session, the identical mechanical (brush) and thermal (cold and heat) stimuli were applied to the same location (the skin of the dorsum of the right hand). RESULTS: Comparison of CRPS+ vs CRPS- for the three stimuli showed significant changes throughout the cerebral cortex (frontal, parietal, temporal, cingulate, and hippocampus), in subcortical regions such as caudate nucleus, and in the cerebellum. In addition, resting state network analysis showed a reversal of brain network state, and the recovered state paralleled specific default networks in healthy volunteers. DISCUSSION: The observed changes in brain response to evoked stimuli provide a readout for the subjective response. CONCLUSION: Future studies of brain function in these patients may provide novel insight into brain plasticity in response to this treatment for chronic pain. PMID- 26745154 TI - Cassie-State Stability of Metallic Superhydrophobic Surfaces with Various Micro/Nanostructures Produced by a Femtosecond Laser. AB - The Cassie-state stability plays a vital role in the applications of metallic superhydrophobic surfaces. Although a large number of papers have reported the superhydrophobic performance of various surface micro/nanostructures, the knowledge of which kind of micro/nanostructure contributes significantly to the Cassie-state stability especially under low temperature and pressure is still very limited. In this article, we fabricated six kinds of typical micro/nanostructures with different topography features on metal surfaces by a femtosecond laser, and these surfaces were modified by fluoroalkylsilane to generate superhydrophobicity. We then systematically studied the Cassie-state stability of these surfaces by means of condensation and evaporation experiments. The results show that some superhydrophobic surfaces, even with high contact angles and low sliding angles under normal conditions, are unstable under low temperature or external pressure. The Cassie state readily transits to a metastable state or even a Wenzel state under these conditions, which deteriorates their superhydrophobicity. Among the six micro/nanostructures, the densely distributed nanoscale structure is important for a stable Cassie state, and the closely packed micrometer-scale structure can further improve the stability. The dependence of the Cassie-state stability on the fabricated micro/nanostructures and the laser-processing parameters is also discussed. This article clarifies optimized micro/nanostructures for stable and thus more practical metallic superhydrophobic surfaces. PMID- 26745155 TI - H2O2-Induced Oxidative Stress Affects SO4= Transport in Human Erythrocytes. AB - The aim of the present investigation was to verify the effect of H2O2-induced oxidative stress on SO4= uptake through Band 3 protein, responsible for Cl-/HCO3- as well as for cell membrane deformability, due to its cross link with cytoskeletal proteins. The role of cytoplasmic proteins binding to Band 3 protein has been also considered by assaying H2O2 effects on hemoglobin-free resealed ghosts of erythrocytes. Oxidative conditions were induced by 30 min exposure of human erythrocytes to different H2O2 concentrations (10 to 300 MUM), with or without GSH (glutathione, 2 mM) or curcumin (10 MUM), compounds with proved antioxidant properties. Since SO4= influx through Band 3 protein is slower and better controllable than Cl- or HCO3- exchange, the rate constant for SO4= uptake was measured to prove anion transport efficiency, while MDA (malondialdehyde) levels and -SH groups were estimated to quantify the effect of oxidative stress. H2O2 induced a significant decrease in rate constant for SO4= uptake at both 100 and 300 MUM H2O2. This reduction, observed in erythrocytes but not in resealed ghosts and associated to increase in neither MDA levels nor in -SH groups, was impaired by both curcumin and GSH, whereas only curcumin effectively restored H2O2-induced changes in erythrocytes shape. Our results show that: i) 30 min exposure to 300 MUM H2O2 reduced SO4= uptake in human erythrocytes; ii) oxidative damage was revealed by the reduction in rate constant for SO4= uptake, but not by MDA or -SH groups levels; iii) the damage was produced via cytoplasmic components which cross link with Band 3 protein; iv) the natural antioxidant curcumin may be useful in protecting erythrocytes from oxidative injury; v) SO4= uptake through Band 3 protein may be reasonably suggested as a tool to monitor erythrocytes function under oxidative conditions possibly deriving from alcohol consumption, use of drugs, radiographic contrast media administration, hyperglicemia or neurodegenerative diseases. PMID- 26745157 TI - ACSM Clinician Profile. PMID- 26745158 TI - News and Views on Russian Doping, Spin Rhabdo, and Renal Stones. PMID- 26745156 TI - Genetically Determined MBL Deficiency Is Associated with Protection against Chronic Cardiomyopathy in Chagas Disease. AB - Chagas disease (CD) is caused by Trypanosoma cruzi, whose sugar moieties are recognized by mannan binding lectin (MBL), a soluble pattern-recognition molecule that activates the lectin pathway of complement. MBL levels and protein activity are affected by polymorphisms in the MBL2 gene. We sequenced the MBL2 promoter and exon 1 in 196 chronic CD patients and 202 controls. The MBL2*C allele, which causes MBL deficiency, was associated with protection against CD (P = 0.007, OR = 0.32). Compared with controls, genotypes with this allele were completely absent in patients with the cardiac form of the disease (P = 0.003). Furthermore, cardiac patients with genotypes causing MBL deficiency presented less heart damage (P = 0.003, OR = 0.23), compared with cardiac patients having the XA haplotype causing low MBL levels, but fully capable of activating complement (P = 0.005, OR = 7.07). Among the patients, those with alleles causing MBL deficiency presented lower levels of cytokines and chemokines possibly implicated in symptom development (IL9, p = 0.013; PDGFB, p = 0.036 and RANTES, p = 0.031). These findings suggest a protective effect of genetically determined MBL deficiency against the development and progression of chronic CD cardiomyopathy. PMID- 26745160 TI - The Female Athlete Triad. PMID- 26745161 TI - Functional Screening for Atraumatic Low Back Pain in Baseball Players. PMID- 26745162 TI - Chiari I Malformation Presenting as Shoulder Pain, Weakness, and Muscle Atrophy in a Collegiate Athlete. PMID- 26745163 TI - Traumatic Superficial Temporal Artery Pseudoaneurysm in a Helmeted Lacrosse Player. PMID- 26745164 TI - The Role of Nutritional Supplements in Sports Concussion Treatment. AB - There has been considerable research conducted in regard to the prevention and treatment of concussions. Numerous supplements and vitamins are being used throughout the country to help patients recover from concussions; however, to date, there are no completed human-based studies specifically examining supplement and vitamin use for the treatment or prevention of concussions. This article examines the most current evidence regarding supplements and vitamins for the treatment and prevention of concussions. The supplements and vitamins reviewed include omega-3 fatty acids, curcumin, resveratrol, melatonin, creatine, and Scutellaria baicalensis. PMID- 26745165 TI - Ultrasound-Guided Nerve Hydrodissection: What is it? A Review of the Literature. AB - Nerve hydrodissection is a technique used when treating peripheral nerve entrapments. It involves using an anesthetic or solution such as saline to separate the nerve from the surrounding tissue, fascia, or adjacent structures. There are no high-level studies to determine the need or effectiveness of hydrodissection or to establish its safety. Low-level studies do demonstrate some effectiveness and safety for the technique, but further research is necessary. PMID- 26745167 TI - Traumatic Optic Neuropathy: A Potentially Unrecognized Diagnosis after Sports Related Concussion. AB - Traumatic optic neuropathy is a rare cause of visual disturbance after head injury that can be difficult to distinguish from coexisting vestibulo-ocular dysfunction because of the overlap in presenting symptoms in patients with these conditions. We present a case report of a 13-year-old girl who sustained a head injury during a ringette game leading to blurred vision and diplopia persisting 5 months after injury. Clinical history and physical examination findings were consistent with a traumatic optic neuropathy, convergence insufficiency, and postconcussion syndrome. Neuroimaging was normal. The patient was managed using a multidisciplinary approach. At 6 months of follow-up, neuro-ophthalmological examination demonstrated evidence of permanent partial optic nerve injury, and formal neuropsychological testing fell primarily within normal limits. The patient was advised to retire from collision sports. The authors discuss the value of a comprehensive multidisciplinary approach to the evaluation and management of concussion patients presenting with persistent visual symptoms. PMID- 26745166 TI - Concussions in Ice Hockey. AB - This literature review will summarize, compare, and evaluate the reviewed studies addressing and investigating the relationship between concussion and the sports of hockey. We will accomplish this by identifying prevalence rates, recognizing common mechanisms of causation, describing and discussing prevention and care, and summarizing the results to provide implications for further studies. We conclude by indicating the important mental health issues as well as potentially severe and long-lasting impact concussions can and do have on those that receive them as well as on the friends and families of those who sustain a concussion. PMID- 26745168 TI - Noniatrogenic Septic Olecranon Bursitis: Report of Two Cases and Review of the Literature. PMID- 26745169 TI - Horseback Riding-Related Vertebral Compression Fracture from Walking in Women with Low Bone Mineral Density: Reports of Two Cases. PMID- 26745170 TI - Syncope in an Athlete: a Case of Infectious Mononucleosis-Induced Postural Tachycardia Syndrome. PMID- 26745171 TI - Medical Care of AQUATIC Athlete--Do Not Overlook the Upper Airway. PMID- 26745172 TI - Author Response. PMID- 26745173 TI - Selected Issues in Injury and Illness Prevention and the Team Physician: A Consensus Statement. AB - This document provides an overview of selected medical issues that are important to team physicians who are responsible for the care and treatment of athletes. It is not intended as a standard of care, and should not be interpreted as such. This document is only a guide, and as such, is of a general nature, consistent with the reasonable, objective practice of the health care profession. Adequate insurance should be in place to help protect the physician, the athlete, and the sponsoring organization. This statement was developed by a collaboration of six major professional associations concerned about clinical sports medicine issues. They have committed to forming an ongoing project-based alliance to bring together sports medicine organizations to best serve active people and athletes. The organizations are the American Academy of Family Physicians, American Academy of Orthopaedic Surgeons, American College of Sports Medicine, American Medical Society for Sports Medicine, American Orthopaedic Society for Sports Medicine, and the American Osteopathic Academy of Sports Medicine. PMID- 26745174 TI - Modeling the improvement of ultrafiltration membrane mass transfer when using biofiltration pretreatment in surface water applications. AB - In surface water treatment, ultrafiltration (UF) membranes are widely used because of their ability to supply safe drinking water. Although UF membranes produce high-quality water, their efficiency is limited by fouling. Improving UF filtrate productivity is economically desirable and has been attempted by incorporating sustainable biofiltration processes as pretreatment to UF with varying success. The availability of models that can be applied to describe the effectiveness of biofiltration on membrane mass transfer are lacking. In this work, UF water productivity was empirically modeled as a function of biofilter feed water quality using either a quadratic or Gaussian relationship. UF membrane mass transfer variability was found to be governed by the dimensionless mass ratio between the alkalinity (ALK) and dissolved organic carbon (DOC). UF membrane productivity was optimized when the biofilter feed water ALK to DOC ratio fell between 10 and 14. PMID- 26745176 TI - Correction: Do Media Use and Physical Activity Compete in Adolescents? Results of the MoMo Study. PMID- 26745175 TI - Occurrence of human-associated Bacteroidetes genetic source tracking markers in raw and treated wastewater of municipal and domestic origin and comparison to standard and alternative indicators of faecal pollution. AB - This was a detailed investigation of the seasonal occurrence, dynamics, removal and resistance of human-associated genetic Bacteroidetes faecal markers (GeBaM) compared with ISO-based standard faecal indicator bacteria (SFIB), human-specific viral faecal markers and one human-associated Bacteroidetes phage in raw and treated wastewater of municipal and domestic origin. Characteristics of the selected activated sludge wastewater treatment plants (WWTPs) from Austria and Germany were studied in detail (WWTPs, n = 13, connected populations from 3 to 49000 individuals), supported by volume-proportional automated 24-h sampling and chemical water quality analysis. GeBaM were consistently detected in high concentrations in raw (median log10 8.6 marker equivalents (ME) 100 ml(-1)) and biologically treated wastewater samples (median log10 6.2-6.5 ME 100 ml(-1)), irrespective of plant size, type and time of the season (n = 53-65). GeBaM, Escherichia coli, and enterococci concentrations revealed the same range of statistical variability for raw (multiplicative standard deviations s* = 2.3-3.0) and treated wastewater (s* = 3.7-4.5), with increased variability after treatment. Clostridium perfringens spores revealed the lowest variability for raw wastewater (s* = 1.5). In raw wastewater correlations among microbiological parameters were only detectable between GeBaM, C. perfringens and JC polyomaviruses. Statistical associations amongst microbial parameters increased during wastewater treatment. Two plants with advanced treatment were also investigated, revealing a minimum log10 5.0 (10th percentile) reduction of GeBaM in the activated sludge membrane bioreactor, but no reduction of the genetic markers during UV irradiation (254 nm). This study highlights the potential of human-associated GeBaM to complement wastewater impact monitoring based on the determination of SFIB. In addition, human-specific JC polyomaviruses and adenoviruses seem to be a valuable support if highly specific markers are needed. PMID- 26745177 TI - High Prevalence of Diabetic Retinopathy in Diabetic Patients Concomitant with Metabolic Syndrome. AB - OBJECTIVE: To evaluate the relationship between metabolic syndrome (MetS) and the prevalence of diabetic retinopathy (DR). RESEARCH DESIGN AND METHODS: We conducted a case-controlled study, with data obtained from 2,551 Chinese participants between 18-79 years of age (representing a population of 1,660,500 in a district of Beijing). 74 cases of DR were found following data assessment by two 45 degrees digital retinal images. Subjects without DR (NDR group) selected from the remaining 2,477 subjects were matched 1:1 to the DR group by HbA1c. MetS was defined by incorporating diagnostic criteria of the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) and the International Diabetes Federation (IDF). RESULTS: There were no statistical differences between the DR group and NDR group in a number of biological or laboratory tests. However, the percentage of patients with DR increased vs. patients without DR with the number of MetS components from 1 to 5 (14.3% vs. 85.7%, 38.9% vs. 61.1%, 49.1% vs. 50.9%, 61.4% vs. 38.6% and 83.3% vs. 16.7%, respectively) (Pearson chi2 = 9.938, P = 0.037). The trend to develop DR with MetS was significantly higher than that without MetS (NMetS) (chi2 = 5.540, P = 0.019). MetS was an independent statistical indicator of the presence of DR after adjusting for age and sex [odds ratio (95% CI): 2.701(1.248-5.849), P = 0.012], which is still the case with an additional adjustment for WC, SBP, TC, HbA1c and duration of diabetes [odds ratio (95% CI): 2.948(1.134-7.664), P = 0.027]. CONCLUSION: DR is one of the diabetic microvascular complications. Apart from poor glycemic control, the concomitance of other metabolic factors can also influence DR. MetS, defined as a cluster of metabolic risk factors, is a strong and independent indicator of DR, even to the same extent as glycemic control. PMID- 26745178 TI - Adsorptive removal of phenol from aqueous solution with zeolitic imidazolate framework-67. AB - ZIF-67(zinc-methylimidazolate framework-67), one of the zeolitic imidazolate frameworks (ZIFs), was used for the removal of phenol from aqueous solutions via adsorption and shows high adsorption capacity for phenol. The thermodynamic and kinetic adsorption behavior of ZIF-67 for phenol in water with concentration ranging from 50 to 300 ppm were investigated in a batch reactor and a ZIF-67 packed column, respectively. The effects of pH, contact time, zeta potential of the adsorbent and temperature on the adsorption behavior were evaluated, and the results demonstrated that the adsorption is primarily brought about by a specific favorable interaction (electrostatic interaction) between phenol and ZIF-67 surface. The suitability of the Langmuir adsorption model to the equilibrium data was investigated for each phenol-adsorbent system, which the results showed that the equilibrium data for all the phenol-sorbent systems fitted the Langmuir model. Thermodynamic parameters such as Gibbs free energy are calculated from the experimental data at different temperatures. The adsorbent could be perfectly regenerated at 120 degrees C with little loss in the adsorption ability. PMID- 26745181 TI - Phase diagrams for clathrate hydrates of methane, ethane, and propane from first principles thermodynamics. AB - Natural gas hydrates are inclusion compounds composed of major light hydrocarbon gaseous molecules (CH4, C2H6, and C3H8) and a water clathrate framework. Understanding the phase stability and formation conditions of natural gas hydrates is crucial for their future exploitation and applications and requires an accurate description of intermolecular interactions. Previous ab initio calculations on gas hydrates were mainly limited by the cluster models, whereas the phase diagram and equilibrium conditions of hydrate formation were usually investigated using the thermodynamic models or empirical molecular simulations. For the first time, we construct the chemical potential phase diagrams of type II clathrate hydrates encapsulated with methane/ethane/propane guest molecules using first-principles thermodynamics. We find that the partially occupied structures (136H2O.1CH4, 136H2O.16CH4, 136H2O.20CH4, 136H2O.1C2H6, and 136H2O.1C3H8) and fully occupied structures (136H2O.24CH4, 136H2O.8C2H6, and 136H2O.8C3H8) are thermodynamically favorable under given pressure-temperature (p-T) conditions. The theoretically predicted equilibrium pressures for pure CH4, C2H6 and C3H8 hydrates at the phase transition point are consistent with the experimental data. These results provide valuable guidance for establishing the relationship between the accurate description of intermolecular noncovalent interactions and the p-T equilibrium conditions of clathrate hydrates and other molecular crystals. PMID- 26745179 TI - Effects of Excess Energy Intake on Glucose and Lipid Metabolism in C57BL/6 Mice. AB - Excess energy intake correlates with the development of metabolic disorders. However, different energy-dense foods have different effects on metabolism. To compare the effects of a high-fat diet, a high-fructose diet and a combination high-fat/high-fructose diet on glucose and lipid metabolism, male C57BL/6 mice were fed with one of four different diets for 3 months: standard chow; standard diet and access to fructose water; a high fat diet; and a high fat diet with fructose water. After 3 months of feeding, the high-fat and the combined high fat/high-fructose groups showed significantly increased body weights, accompanied by hyperglycemia and insulin resistance; however, the high-fructose group was not different from the control group. All three energy-dense groups showed significantly higher visceral fat weights, total cholesterol concentrations, and low-density lipoprotein cholesterol concentrations compared with the control group. Assays of basal metabolism showed that the respiratory quotient of the high-fat, the high-fructose, and the high-fat/high-fructose groups decreased compared with the control group. The present study confirmed the deleterious effect of high energy diets on body weight and metabolism, but suggested that the energy efficiency of the high-fructose diet was much lower than that of the high fat diet. In addition, fructose supplementation did not worsen the detrimental effects of high-fat feeding alone on metabolism in C57BL/6 mice. PMID- 26745180 TI - A Monte Carlo Study of the Early Steps of Functional Amyloid Formation. AB - In addition to their well-known roles in neurodegenerative diseases and amyloidoses, amyloid structures also assume important functional roles in the cell. Although functional amyloid shares many physiochemical properties with its pathogenic counterpart, it is evolutionarily optimized to avoid cytotoxicity. This makes it an interesting study case for aggregation phenomenon in general. One of the most well-known examples of a functional amyloid, E. coli curli, is an essential component in the formation of bacterial biofilm, and is primarily formed by aggregates of the protein CsgA. Previous studies have shown that the minor sequence variations observed in the five different subrepeats (R1-R5), which comprise the CsgA primary sequence, have a substantial influence on their individual aggregation propensities. Using a recently described diffusion optimized enhanced sampling approach for Monte Carlo simulations, we here investigate the equilibrium properties of the monomeric and dimeric states of these subrepeats, to probe whether structural properties observed in these early stage oligomers are decisive for the characteristics of the resulting aggregate. We show that the dimerization propensities of these peptides have strong correlations with their propensity for amyloid formation, and provide structural insights into the inter- and intramolecular contacts that appear to be essential in this process. PMID- 26745182 TI - Clinical phenotype in relation to the distance-to-index-patient in familial hypercholesterolemia. AB - BACKGROUND AND AIM: We evaluated whether the severity of the familial hypercholesterolemia (FH) phenotype, i.e. increased levels of low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD) risk, decreases in more distantly related patients within one family. METHODS: We included heterozygous FH patients identified by genetic cascade screening in the Netherlands from 1994 to 2014. A cascade starts with identification of a genetically proven FH patient ("index patient") followed by testing in first degree relatives. If a mutation carrier is identified, their first degree relatives are tested as well, and so on. The associations between distance-to index (expressed as family relationship) and both LDL-C levels and CVD risk, were evaluated using multivariable linear and Cox regression models. RESULTS: Distance to-index could be determined in 13,374 patients. Mean (+/- standard error) levels of LDL-C did not differ significantly in 1st, 2nd, 3rd, and 4th or more family members: 5.46 (1.42), 5.17 (1.42), 4.89 (1.37), and 4.58 (1.27) mmol/L, respectively (adjusted p-for-trend: 0.104). The adjusted hazard ratio of increasing distance-to-index for CVD was 0.92 (95% CI: 0.82-1.03). CONCLUSION: This study was the first to investigate the association between distance-to-index and the phenotype of a monogenetic disorder. The absence of a decrease of phenotype severity lends support for genetic cascade testing in FH. PMID- 26745184 TI - Distinguishing between donors and their relatives in complex DNA mixtures with binary models. AB - While likelihood ratio calculations were until the recent past limited to the evaluation of mixtures in which all alleles of all donors are present in the DNA mixture profile, more recent methods are able to deal with allelic dropout and drop-in. This opens up the possibility to obtain likelihood ratios for mixtures where this was not previously possible, but it also means that a full match between the alleged contributor and the crime stain is no longer necessary. We investigate in this article what the consequences are for relatives of the actual donors, because they typically share more alleles with the true donor than an unrelated individual. We do this with a semi-continuous binary approach, where the likelihood ratios are based on the observed alleles and the dropout probabilities for each donor, but not on the peak heights themselves. These models are widespread in the forensic community. Since in many cases a simple model is used where a uniform dropout probability is assumed for all (or for all unknown) contributors, we explore the extent to which this alters the false positive probabilities for relatives of donors, compared to what would have been obtained with the correct probabilities of dropout for each donor. PMID- 26745187 TI - A Lifetime of Rejection. PMID- 26745186 TI - Give it a REST! AB - The REST protein helps to prevent the premature activation of genes that are only expressed in mature neurons, and is now found to protect the genome of neural progenitor cells. PMID- 26745188 TI - Treated Versus Untreated Positional Head Deformity. AB - BACKGROUND: Positional head deformity in early childhood is asserted to be a benign and in some cases spontaneously correcting entity encountered in craniofacial surgery. Although many authors have stated that helmet therapy is indicated in moderate and severe cases of deformational plagiocephaly and brachycephaly; others have reported resolution of these conditions within the first 2 to 3 years of life. A recent randomized controlled trial found that helmet therapy does not have beneficial effects for patients with positional head deformity. METHODS: The authors evaluated the clinical course of positional cranial deformation during a period of 5 years and compared the anthropometric parameters of orthotically treated versus untreated children within this timeframe. RESULTS: Although the patients were matched with respect to their cranial deformation at baseline, there were significant differences in the cranial vault asymmetry (CVA), cranial vault asymmetry index (CVAI), and oblique cranial length ratio (OCLR) between Groups 1 and 2 at the initial point (P < 0.05). The mean CVA was 0.95 cm in Group 1 (no helmet) and 1.74 cm in Group 2 (helmet). The mean CVAI at baseline was 7.25 for Group 1 and 13.77 for Group 2. Approximately 5 years after the first examination, the authors found clear improvement in the mean CVA in Group 2 (DeltaCVA 1.35 cm) compared with Group 1 (DeltaCVA 0.01 cm) and the mean CVAI. CONCLUSIONS: In contrast to recently published studies, the authors found clear improvement in nonsynostotic head deformity treated with an individual molding helmet and no clear evidence of improvement of absolute measurements in untreated cranial deformity within a 5 year follow-up period. PMID- 26745189 TI - Routine Screening Ultrasound in Children With Cleft Palate and/or Lip: A Single Center Experience. AB - The aim of this study is to evaluate the incidence of associated congenital anomalies that is picked up by screening ultrasound of the heart, urinary system, and central nervous system (CNS) of children with cleft palate and/or lip deformities in a single regional center. A total of 225 children with cleft deformities were recruited in the study in 2009 to 2013, 91% of them underwent screening echocardiogram and of these, 98% of them were normal findings that do not require further follow-up ultrasound or treatment. Total 85% of the children underwent screening ultrasound of the urinary system and CNS, and of these, 99% were reported to have normal findings. Medium term follow-up of these children did not reveal any significant structural anomalies in the heart, brain, and urinary system that might have missed in the initial ultrasound screening. The authors suggest that in resource-limited settings, routine ultrasound screening of the heart, the CNS, and the urinary system may not be required in asymptomatic and nonsyndromic infants with cleft deformities and in those with "lip-only" cleft deformity. PMID- 26745190 TI - Change of Facial Asymmetry in Patients With Congenital Muscular Torticollis After Surgical Release. AB - BACKGROUND: A number of studies have shown that facial asymmetry improves in congenital muscular torticollis (CMT) patients after surgical release. This study confirmed the improvement in facial asymmetry, and analyzed factors that affect the change of facial asymmetry in CMT patients after surgical release by using objective and quantitative methods. METHODS: Facial asymmetry was analyzed in 60 CMT patients who underwent surgical release before 10 years of age. Horizontal and lower facial asymmetry angles (HFAA and LFAA) in the clinical photograph were used to measure facial asymmetry. Postoperative improvements in HFAA and LFAA were evaluated in each age group, after grouping the patients by age. Patients were divided into 2 groups according to the postoperative head tilt and functional deficit. Postoperative improvements in HFAA and LFAA were compared between 2 groups. The relationships between postoperative improvements in HFAA and LFAA and independent variables (age, follow-up period, preoperative HFAA or LFAA, postoperative head tilt, and postoperative functional deficit) were analyzed. RESULTS: Mean age at operation was 34.8 months (range, 6-120 mo). Horizontal facial asymmetry angle was improved significantly postoperatively in groups <5 years of age. Lower facial asymmetry angle was improved significantly postoperatively in all age groups. No significant difference was found in the postoperative improvements in HFAA and LFAA between 2 groups according to the postoperative head tilt and functional deficit. In the correlation analysis, postoperative improvements in HFAA and LFAA were proportional to the follow-up period (r = 0.256, P = 0.048) and preoperative HFAA or LFAA (r = 0.600, P < 0.001). CONCLUSIONS: Facial asymmetry in CMT patients can be improved in part if surgical release is performed before 10 years of age and the possibility of improvement may be different according to the area of the face. After surgical release, facial asymmetry will improve over a long period of time, and patients with more severe facial asymmetry have a better remodeling potential to achieve facial symmetry. PMID- 26745185 TI - The REST remodeling complex protects genomic integrity during embryonic neurogenesis. AB - The timely transition from neural progenitor to post-mitotic neuron requires down regulation and loss of the neuronal transcriptional repressor, REST. Here, we have used mice containing a gene trap in the Rest gene, eliminating transcription from all coding exons, to remove REST prematurely from neural progenitors. We find that catastrophic DNA damage occurs during S-phase of the cell cycle, with long-term consequences including abnormal chromosome separation, apoptosis, and smaller brains. Persistent effects are evident by latent appearance of proneural glioblastoma in adult mice deleted additionally for the tumor suppressor p53 protein (p53). A previous line of mice deleted for REST in progenitors by conventional gene targeting does not exhibit these phenotypes, likely due to a remaining C-terminal peptide that still binds chromatin and recruits co repressors. Our results suggest that REST-mediated chromatin remodeling is required in neural progenitors for proper S-phase dynamics, as part of its well established role in repressing neuronal genes until terminal differentiation. PMID- 26745191 TI - Cephalometric Measurements With Multislice Computed Tomography in Patients With Obstructive Sleep Apnea Syndrome. AB - INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is characterized by episodes of upper respiratory tract obstruction, decreased oxygen saturation, and sleep fragmentation during sleep, as well as excessive daytime somnolence. Cephalometric analysis offers distance, angle, area, and volume measurements between separate reference points belonging to bony and soft tissues on a film. Cephalometric measurements made with multislice computed tomography (CT) are quite helpful for standardization of measurements and obtaining highly reliable results. The aim of the current study was to make cephalometric measurements with multislice CT in OSAS patients and compare their results with those of a healthy control population. The authors also aimed to determine, which cephalometric parameters might be more valuable for diagnosis of OSAS. MATERIALS AND METHOD: This study included 30 patients who were diagnosed with severe OSAS (apnea hypopnea index >30) by an overnight polysomnography study, performed for suspected OSAS and 10 healthy controls without snoring or apnea who underwent three-dimensional head & neck multislice CT for any indication. All patients underwent a three-dimensional head & neck multislice CT to make cephalometric measurements and compare them across the groups. RESULTS: ANS-PNS (anterior and posterior nasal spine), Go-Gn, and UP-PhW distances, as well as sella-nasion-A and sella-nasion-B angles, were significantly lower in the OSAS group compared with the controls (P < 0.05). Mandibulas plane -H, UD, TT-EA, ANS-B, PNS-TB, TT TB, B-N, and PNS-PhW distances were significantly higher in the patient group compared with the controls (P < 0.05). CONCLUSIONS: Our study reached the conclusion that some cephalometric measurements showed significant differences in patients with obstructive sleep apnea compared with the control group, and hence may lead to a susceptibility to having OSAS. Cephalometric measurements performed with multislice CT have come to the forefront as one of the most important tools for diagnosis of OSAS. An inferiorly located hyoid bone may be most commonly responsible for apnea episodes. It was also concluded that an inferiorly located hyoid bone might have been the result of maxillomandibular underdevelopment. PMID- 26745192 TI - Lateralization of the Pharyngeal Flap for Treatment of Lateral Velopharyngeal Gap. AB - Pharyngeal flap is usually used for treatment of velopharyngeal insufficiency (VPI); it is bridged between the posterior pharyngeal wall and the soft palate traversing the central part of the velopharyngeal port. The aim of this study was to assess the efficacy of lateralization of the pharyngeal flap for treatment of VPI in patients with lateral velopharyngeal gap. Fifteen patients with VPI due to lateral velopharyngeal gap were subjected to closure of the gap by pharyngeal flap that was lateralized to fill the gap. Preoperative and postoperative assessment of velopharyngeal functions including flexible nasopharyngoscopy, auditory perceptual assessment (APA), and nasometric assessment were performed. Postoperatively, flexible nasopharyngoscopy showed complete velopharyngeal closure in all the patients, with significant improvement of speech parameters as measured by APA. Also, nasalance score showed significant improvement for oral and nasal sentences that was measured by nasometry. Lateralization of the pharyngeal flap for treatment of VPI in patients with lateral velopharyngeal gap is an effective method; it improves the velopharyngeal closure and the speech of the patients. PMID- 26745193 TI - Biograft Block Hydroxyapatite: A Ray of Hope in the Reconstruction of Maxillofacial Defects. AB - BACKGROUND: Improving quality of human life has been the rationale for increase in the applications of bone substitute materials for bone regeneration. High prevalence of loss of bone tissue due to disease remains a major challenge for reconstruction. Shortcomings of autografts and allografts have made the clinicians go for artificial implant materials. AIM AND OBJECTIVE: To prospectively study the structural and esthetic reconstruction of resected mandibular site with biograft porous block hydroxyapatite (BBHA). The study evaluated the efficacy of BBHA as a material for reconstruction of large bone defects. METHODS: Patients requiring reconstruction after resection of cyst/tumors and who denied conventional reconstruction were enrolled for BBHA reconstruction during 2008 to 2015. All patients were clinically and radiologically followed and assessed for a range of 4 to 60 months for outcome. RESULTS: During follow-up periods no one had infection, dissolution, migration, or absorption, but new bone formation and bridging observed in proximity with graft and bone interface. CONCLUSION: Structural and esthetic reconstruction using BBHA significantly reduces donor site morbidity. BBHA have satisfactory results in relation to esthetics and are useful material for reconstruction. Clinical application of this technique will minimize an additional surgical procedure required to harvest donor bone. BBHA provides good esthetics and structural balance to face. As this is an ongoing study the outcome is expected to improve. The incorporation of implants in the BBHA block may fulfill the function also in near future. PMID- 26745194 TI - Use of Adipose-Derived Mesenchymal Stem Cells to Accelerate Neovascularization in Interpolation Flaps. AB - OBJECTIVE: Interpolation flaps are commonly used in plastic surgery to cover wide and deep defects. The need to, wait for 2 to 3 weeks until the division of the pedicle still, however, poses a serious challenge, not only extending treatment and hospital stay, but also increasing hospital expenses. To solve this problem, we have aimed to use the angiogenic potential of stem cells to selectively accelerate neovascularization with a view to increasing the viability of interpolation flaps and achieving early pedicle removal. MATERIALS AND METHODS: A total of 32 rats were allocated to 2 groups as control (N = 16) and experiment (N = 16). The cranial flaps 6 * 5 cm in size located on the back of the rats were raised. Then, a total suspension containing 3 * 10(6) adipose-derived mesenchymal stem cells (ADSC) tagged with a green fluorescent protein (GFP) was injected diffusely into the distal part of the flap, receiving bed, and wound edges. In the control group, only a medium solution was injected into the same sites. After covering the 3 * 5 cm region in the proximal part of the area where the flap was removed, the distal part of the flap was adapted to the uncovered distal area. The pedicles of 4 rats in each group were divided on postoperative days 5, 8, 11, and 14. The areas were photographed 7 days after the pedicles were released. The photographs were processed using Adobe Acrobat 9 Pro software (San Jose, CA) to measure the flap survival area in millimeters and to compare groups. Seven days after the flap pedicle was divided, the rats were injected with 250 mCi Tc-99 mm (methoxy-isobutyl-isonitrie) from the penile vein, and scintigraphic images were obtained. The images obtained from each group were subjected to a numerical evaluation, which was then used in the comparison between groups. The flaps were then examined by histology to numerically compare the number of newly formed vessels. Neovascularization was also assessed by microangiography. In addition, radiographic images were obtained by mammography and evaluated quantitatively. RESULTS: An evaluation of statistical results revealed a significant increase in the flap survival area of the group on stem cell treatment in comparison to the control group. In scintigraphic examinations, the rate of radioactive substance retention was significantly higher in the stem cell group, relative to the control group. Histopathologic examination showed that the capillary density in the stem cell group was higher than that in the control group. Green fluorescent protein had been used to label ADSC in the experiment and it was found by immunofluorescence staining that endothelial samples of control animals did not have GFP (+) cells, whereas all the animals in the experiment group had GFP (+) cells. The comparison of microangiographic images of the experiment and control groups demonstrated significantly elevated vascularity in the former, relative to the latter. DISCUSSION: It has been established in the current study that ADSC injection worked well in speeding up the neovascularization of interpolated flaps and reducing the time of pedicle division. It seems possible to minimize the morbidity of interpolated skin flaps with mesenchymal stem cell therapy at an appropriate dose and for an appropriate length of time. PMID- 26745196 TI - Incomplete Reossification After Craniosynostosis Surgery. AB - A patient with unicoronal craniosynostosis was treated by an open cranial vault remodeling procedure at 11 months of age. A calvarial defect persists at the site of the sagittal suture at 7 years follow-up. This unexpected outcome led us to evaluate current literature on incidence and possible causes of incomplete reossification after craniosynostosis surgery.English literature was searched from 1982 to 2013. Variables of interest were incidence, diagnose, type of surgery, age at operation, possible causes for incomplete reossification, and duration and type of follow-up.Incidence in unselected cohorts ranged from 0.5% to 18.2%. Incomplete reossification has been reported in syndromical and nonsyndromical cases, after multiple types of surgery for any type of suture. Follow-up was done by palpation, radiology or both, for a period of 6 to 264 months.Higher age at operation and a dura tear are associated with an increased risk of incomplete reossification.Type and duration of follow-up is inhomogeneous and there is a wide variety in the terminology used for incomplete reossification.To improve international communication on this topic, more long term studies, using a consistent type and length of follow-up and uniform terminology are needed. PMID- 26745197 TI - Correction of Unilateral Congenital Zygomatico-Mandibular Fusion. AB - Sygnathia, or fusion of the jaw, is a rare condition in children, occurring either in isolation or as part of a larger overall syndrome. Consequences of this bony fusion may range from feeding difficulties to a complete inability to protect the airway. Owing to the uncommon nature of this problem and the high recurrence of bony fusion, standardized treatment protocols do not yet exist, making individual reports particularly useful for guiding the first-time management of such patients. In this report, we describe the case of a male infant with complete bony fusion of the right zygomatic maxillary complex to the mandible. Fusion was separated by osteotomy, repair of soft tissue with acellular dermal matrix/grafting, and plate separation. Serial jaw manipulation and operative stretching was necessary to prevent refusion of syngnathia even in the long term. PMID- 26745198 TI - Palatal Osseous Choristoma. AB - Osseous choristoma of soft tissue in the oral cavity is rare. The choristoma is a tumor-like mass of normal cells in an abnormal location. In this report, a case of osseous choristoma of the palate in a 37-year-old male patient was reported. Approximately 6 * 5 mm pedunculated healthy colored and hard mass was observed in the median palate. The mass was surgically removed. Microscopic examination of the hematoxylin and eosin-stained sections of the mass revealed that a dense lamellar bone nodule was surrounded by fibrous connective tissue under the squamous epithelium. Immunohistochemical analysis revealed that the mass was negative for S-100 protein, cytokeratin, and epithelial membrane antigens. According to these findings, the final pathologic diagnosis confirmed that the mass was an osseous choristoma. PMID- 26745199 TI - Concomitant Third Molar Removal During Sagittal Split Osteotomy of the Mandible. AB - It is described in textbook about management of third molar in orthognathic surgery that "ideally, the third molars should be removed 9 to 12 months before sagittal split osteotomy (SSO)." At the Chang Gung Craniofacial Center, the authors always remove mandibular third molars during SSO, because: removal of third molars at the same time of SSO could reduce psychological stress on patients by saving 1 surgical procedure under local anesthesia, better exposure of impacted third molars could be facilitated by sagittal split of buccal cortical plate, rigid fixation could be performed without difficulty by our fixation method using plates and screws crossover anterior oblique line. Strong force during the elevation of third molars, however, may result in the fracture of distal segment of SSO, where the buccal cortical plate is relatively thin because of the presence of third molar. Therefore, more care needs to be taken in the surgical technique, which is different from ordinary tooth extraction. In this paper, the details of surgical procedure of third molar removal during SSO were reported. PMID- 26745200 TI - Novel indole-based melatonin analogues substituted with triazole, thiadiazole and carbothioamides: studies on their antioxidant, chemopreventive and cytotoxic activities. AB - Melatonin (MLT) is a well-known free-radical scavenger, involving in the prevention of cellular damage that can lead to cancer, ageing and a variety of neurodegenerative diseases. Research on MLT-related compounds has been required to optimise the maximum pharmaceutical activity with the lowest side effects. In our ongoing research, we have synthesized new indole-based MLT analogues as potential antioxidant agents by modifying the MLT molecule. In this study, we build on previous findings, through the synthesis, characterization and in vitro antioxidant profiling of a series of new indole-based MLT analogues which possess triazole, thiadiazole and carbothioamides on the third position on the indole ring. In vitro antioxidant activity was investigated by evaluating their reducing effect against oxidation of a redox sensitive fluorescent probe and their radical scavenging activity was assessed via the DPPH assay. In addition, in vitro cytotoxic effects of newly synthesized compounds were investigated in CHO-K1 cells using the MTT assay. PMID- 26745201 TI - Differential Expression of microRNAs in the Ovaries from Letrozole-Induced Rat Model of Polycystic Ovary Syndrome. AB - Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disorder. To understand the pathogenesis of PCOS, we established rat models of PCOS induced by letrozole and employed deep sequencing to screen the differential expression of microRNAs (miRNAs) in PCOS rats and control rats. We observed vaginal smear and detected ovarian pathological alteration and hormone level changes in PCOS rats. Deep sequencing showed that a total of 129 miRNAs were differentially expressed in the ovaries from letrozole-induced rat model compared with the control, including 49 miRNAs upregulated and 80 miRNAs downregulated. Furthermore, the differential expression of miR-201-5p, miR-34b-5p, miR-141-3p, and miR-200a-3p were confirmed by real-time polymerase chain reaction. Bioinformatic analysis revealed that these four miRNAs were predicted to target a large set of genes with different functions. Pathway analysis supported that the miRNAs regulate oocyte meiosis, mitogen-activated protein kinase (MAPK) signaling, phosphoinositide 3-kinase/Akt (PI3K-Akt) signaling, Rap1 signaling, and Notch signaling. These data indicate that miRNAs are differentially expressed in rat PCOS model and the differentially expressed miRNA are involved in the etiology and pathophysiology of PCOS. Our findings will help identify miRNAs as novel diagnostic markers and therapeutic targets for PCOS. PMID- 26745202 TI - Probing the Dipolar Coupling in a Heterospin Endohedral Fullerene-Phthalocyanine Dyad. AB - Paramagnetic endohedral fullerenes and phthalocyanine (Pc) complexes are promising building blocks for molecular quantum information processing, for which tunable dipolar coupling is required. We have linked these two spin qubit candidates together and characterized the resulting electron paramagnetic resonance properties, including the spin dipolar coupling between the fullerene spin and the copper spin. Having interpreted the distance-dependent coupling strength quantitatively and further discussed the antiferromagnetic aggregation effect of the CuPc moieties, we demonstrate two ways of tuning the dipolar coupling in such dyad systems: changing the spacer group and adjusting the solution concentration. PMID- 26745203 TI - Levels of Schistosoma mansoni Circulating Antigen in Chronic Hepatitis C Patients with Different Stages of Liver Fibrosis. AB - The goal of this study was to determine the levels of S. mansoni antigen in different liver fibrosis stages with chronic hepatitis C (CHC) Egyptian patients. A total of 174 CHC patients showing HCV-NS4 antigen and HCV- RNA in their sera were included. S. mansoni antigen was detected in serum using Western blot and ELISA. The levels of interferon-gamma (IFN- gamma) were determined using ELISA. The 50 kDa S. mansoni antigen discriminated patients infected with S. mansoni from healthy individuals with 0.93 area under curve (AUC), 92% sensitivity, and 97% specificity. The level of S. mansoni antigen (MUg/ml) was significantly (P < 0.0001) increased with the progression of liver fibrosis stages (26.9 +/- 17.5 in F1, 42.1 +/- 25.2 in F2, 49.8 +/- 30.3 in F3 and 62.2 +/- 26.3 MUg/mL in F4 liver cirrhosis), 26.9 +/- 17.59 in significant fibrosis (F2-F4); 51.2 +/- 27.9 in advanced fibrosis (F3-F4). A significant correlation (r = 0.506; P < 0.0001) was shown between the levels of the S. mansoni antigen and the HCV-NS4 antigen. In conclusion, the presence of S. mansoni antigen in different liver fibrosis stages of CHC patients confirming that concomitant schistosome infection aggravates liver disease. PMID- 26745204 TI - A Left-Sided, Purely Laparoscopic Approach for Anatomic Caudate Hepatectomy: A Single-Center Experience. AB - BACKGROUND: Laparoscopic caudate hepatectomy, which is a challenging procedure, has been reported sporadically. However, there is no standardized surgical technique, and the safety and feasibility of this procedure remain controversial. MATERIALS AND METHODS: A left-sided, purely laparoscopic approach for anatomic caudate hepatectomy was used for 11 selected patients in our institution. The procedure and technique of laparoscopic caudate hepatectomy were described. Perioperative data of these patients were retrospectively reviewed. RESULTS: The 11 cases included two subgroups: laparoscopic isolated caudate hepatectomy (n = 4) and laparoscopic combined caudate and left hemihepatectomy (n = 7). There were three major steps for anatomic caudate hepatectomy. Two conversions were required (18.2%). Two complications (Clavien Grades I and II) occurred but no deaths. CONCLUSIONS: The left-sided, purely laparoscopic approach for anatomic caudate hepatectomy is safe and feasible in selected patients. This procedure can be performed by hepatobiliary surgeons with abundant experience in laparoscopic liver surgery. PMID- 26745206 TI - The Biochemistry of Chromatin Remodeling. PMID- 26745205 TI - Characteristics of Veterans diagnosed with seizures within Veterans Health Administration. AB - The purpose of this report is to describe the demographics of Veterans diagnosed with seizures and taking antiepileptic drugs (AEDs) within the Veterans Health Administration (VHA) during fiscal year (FY) 2011 (October 1, 2010, to September 30, 2011), particularly with regard to comorbid traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD). Information collected included age; sex; Operation Iraqi Freedom/Operation Enduring Freedom/Operation New Dawn (OIF/OEF/OND) status; and relevant encounter diagnosis codes for seizures, TBI, and PTSD. During FY11, 87,377 Veterans with seizures on AEDs were managed within the VHA. Prevalence was 15.5 per 1,000, and annual incidence was 148.2 per 100,000. The percentages of comorbid TBI and PTSD were 15.8% and 24.1%, respectively. For OIF/OEF/OND Veterans, these percentages increased to 52.6% and 70.4%, respectively. PTSD and TBI are risk factors for both epilepsy and psychogenic nonepileptic seizures. Within the VHA, many Veterans experiencing seizures cannot be successfully treated with AEDs. The VHA Epilepsy Centers of Excellence promotes a multidisciplinary approach to increase and improve access to both epilepsy and mental health specialists for the care of epileptic and nonepileptic seizures. PMID- 26745207 TI - Base Induced Chiral Substituted Furans and Imidazoles from Carbohydrate-Derived 2 Haloenones. AB - Chiral substituted furans and imidazoles are key intermediates to access biologically important molecules. We describe herein a catalyst/ligand free cascade Michael-type addition/intramolecular cyclization/carbohydrate-ring opening of 2-haloenones with 1,3-dicarbonyl compounds or amidines utilizing K2CO3/DMSO at ambient temperature that provides a straightforward approach to a variety of optically active (poly)hydroxy furans and imidazoles containing multiple stereocenters with good yield and excellent regioselectivity. The furan intermediates provide efficient access to synthetically valuable substituted alpha-benzyloxyvinyl ketones. The NMR spectrum of the substituted 2-methylfurans shows an unusual long-range ((5)JH-H) (1)H-(1)H COSY cross-peak between C2-CH3 and C4-H signals. PMID- 26745208 TI - The feeling of the story: Narrating to regulate anger and sadness. AB - Admonitions to tell one's story in order to feel better reflect the belief that narrative is an effective emotion regulation tool. The present studies evaluate the effectiveness of narrative for regulating sadness and anger, and provide quantitative comparisons of narrative with distraction, reappraisal, and reexposure. The results for sadness (n = 93) and anger (n = 89) reveal that narrative is effective at down-regulating negative emotions, particularly when narratives place events in the past tense and include positive emotions. The results suggest that if people tell the "right" kind of story about their experiences, narrative reduces emotional distress linked to those experiences. PMID- 26745209 TI - Piezotronic Effect Enhanced Photocatalysis in Strained Anisotropic ZnO/TiO2 Nanoplatelets via Thermal Stress. AB - Effective piezoelectric semiconductor based hybrid photocatalysts are successfully developed by assembling TiO2 nanoparticles on ZnO monocrystalline nanoplatelets. The piezopotential can be introduced and tuned by thermal stress on the piezoelectric material of ZnO monocrystalline nanoplatelets through cooling hybrid photocatalysts from high temperature to room temperature with different rates based on the mismatched thermal expansion coefficient of the two materials, which can be used to engineer the heterojunction band structure and significantly enhance the photocatalytic performance in a wide range by improving charge separation. It is proposed that the piezotronic effect enhanced photocatalyst will provide a strategy for high-performance photocatalysis applications. PMID- 26745210 TI - Multiferroic BaCoF4 in Thin Film Form: Ferroelectricity, Magnetic Ordering, and Strain. AB - Multiferroic materials have simultaneous magnetic and ferroelectric long-range orders and can be potentially useful for a wide range of applications. Conventional ferroelectricity in oxide perovskites favors nonmagnetic electronic configurations of transition metal ions, thus limiting the number of intrinsic multiferroic materials. On the other hand, this is not necessarily true for multiferroic fluorides. Using molecular beam epitaxy, we demonstrate for the first time that the multiferroic orthorhombic fluoride BaCoF4 can be synthesized in thin film form. Ferroelectric hysteresis measurements and piezoresponse force microscopy show that the films are indeed ferroelectric. From structural information, magnetic measurements, and first-principles calculations, a modified magnetic ground state is identified which can be represented as a combination of bulk collinear antiferromagnetism with two additional canted spin orders oriented along orthogonal axes of the BaCoF4 unit cell. The calculations indicate that an anisotropic epitaxial strain is responsible for this unusual magnetic ground state. PMID- 26745212 TI - Pathobiology of MicroRNAs and Their Emerging Role in Thyroid Fine-Needle Aspiration. AB - OBJECTIVE: MicroRNAs (miRs) are noncoding, single-stranded regulatory RNA molecules involved in the posttranscriptional regulation of gene expression. They control the development and maintenance of the diverse cellular processes including proliferation, differentiation, motility and apoptosis. Expression of miRs is tissue-specific and each alteration of the tissue miR profile is associated with a distinct disease status. STUDY DESIGN: We reviewed the literature on the expression of miRs in thyroid tumors, focusing on methodology and diagnostic and prognostic output. Separately, we analyzed 11 studies on miR profiles in thyroid cytological material. RESULTS: Numerous studies have evaluated the miR profiles of thyroid tumors in an attempt to find a possible diagnostic and prognostic role. Both downregulation and upregulation of numerous miRs was found, but differences between the surgical pathology specimens and corresponding fine-needle aspirates in the expression of the same miRs were also reported. CONCLUSIONS: The results from surgically resected material cannot be extrapolated into preoperative use without validation. For diagnostic use, the strong overlap between follicular adenoma and follicular carcinoma miR profiles is challenging. In summary, miR-221 and miR-222 are consistently upregulated in different types of thyroid carcinomas and might be used as markers of malignancy. PMID- 26745213 TI - A fast inverse dynamics model of walking for use in optimisation studies. AB - Computer simulation of human gait, based on measured motion data, is a well established technique in biomechanics. However, optimisation studies requiring many iterative gait cycle simulations have not yet found widespread application because of their high computational cost. Therefore, a computationally efficient inverse dynamics model of 3D human gait has been designed and compared with an equivalent model, created using a commercial multi-body dynamics package. The fast inverse dynamics model described in this paper led to an eight fold increase in execution speed. Sufficient detail is provided to allow readers to implement the model themselves. PMID- 26745217 TI - Facile Formation of High-Quality InGaN/GaN Quantum-Disks-in-Nanowires on Bulk Metal Substrates for High-Power Light-Emitters. AB - High-quality nitride materials grown on scalable and low-cost metallic substrates are considerably attractive for high-power light-emitters. We demonstrate here, for the first time, the high-power red (705 nm) InGaN/GaN quantum-disks (Qdisks) in-nanowire light-emitting diodes (LEDs) self-assembled directly on metal substrates. The LEDs exhibited a low turn-on voltage of ~2 V without efficiency droop up to injection current of 500 mA (1.6 kA/cm(2)) at ~5 V. This is achieved through the direct growth and optimization of high-quality nanowires on titanium (Ti) coated bulk polycrystalline-molybdenum (Mo) substrates. We performed extensive studies on the growth mechanisms, obtained high-crystal-quality nanowires, and confirmed the epitaxial relationship between the cubic titanium nitride (TiN) transition layer and the hexagonal nanowires. The growth of nanowires on all-metal stack of TiN/Ti/Mo enables simultaneous implementation of n-metal contact, reflector, and heat sink, which greatly simplifies the fabrication process of high-power light-emitters. Our work ushers in a practical platform for high-power nanowires light-emitters, providing versatile solutions for multiple cross-disciplinary applications that are greatly enhanced by leveraging on the chemical stability of nitride materials, large specific surface of nanowires, chemical lift-off ready layer structures, and reusable Mo substrates. PMID- 26745214 TI - Direct Measurement of pH in Individual Particles via Raman Microspectroscopy and Variation in Acidity with Relative Humidity. AB - Atmospheric aerosol acidity is an important characteristic of aqueous particles, which has been linked to the formation of secondary organic aerosol by catalyzing reactions of oxidized organic compounds that have partitioned to the particle phase. However, aerosol acidity is difficult to measure and traditionally estimated using indirect methods or assumptions based on composition. Ongoing disagreements between experiments and thermodynamic models of particle acidity necessitate improved fundamental understanding of pH and ion behavior in high ionic strength atmospheric particles. Herein, Raman microspectroscopy was used to determine the pH of individual particles (H2SO4+MgSO4) based on sulfate and bisulfate concentrations determined from nus(SO4(2-)) and nus(HSO4(-)), the acid dissociation constant, and activity coefficients from extended Debye-Huckel calculations. Shifts in pH and peak positions of nus(SO4(2-)) and nus(HSO4(-)) were observed as a function of relative humidity. These results indicate the potential for direct spectroscopic determination of pH in individual particles and the need to improve fundamental understanding of ion behavior in atmospheric particles. PMID- 26745211 TI - Prevalence and Treatment Outcomes of Persistent Negative Mood Among Children with Attention-Deficit/Hyperactivity Disorder and Aggressive Behavior. AB - OBJECTIVE: Diagnostic criteria for disruptive mood dysregulation disorder (DMDD) require 1) periodic rageful outbursts and 2) disturbed mood (anger or irritability) that persists most of the time in between outbursts. Stimulant monotherapy, methodically titrated, often culminates in remission of severe aggressive behavior, but it is unclear whether those with persistent mood symptoms benefit less.This study examined the association between the presence of persistent mood disturbances and treatment outcomes among children with attention deficit/hyperactivity disorder (ADHD) and periodic aggressive, rageful outbursts. METHODS: Within a cohort of children with ADHD and aggressive behavior (n = 156), the prevalence of persistent mood symptoms was evaluated at baseline and after completion of a treatment protocol that provided stimulant monotherapy and family based behavioral treatment (duration mean [SD] = 70.04 [37.83] days). The relationship of persistent mood symptoms on posttreatment aggressive behavior was assessed, as well as changes in mood symptoms. RESULTS: Aggressive behavior and periodic rageful outbursts remitted among 51% of the participants. Persistent mood symptoms at baseline did not affect the odds that aggressive behavior would remit during treatment. Reductions in symptoms of sustained mood disturbance accompanied reductions in periodic outbursts. Children who at baseline had high irritability but low depression ratings showed elevated aggression scores at baseline and after treatment; however, they still displayed large reductions in aggression. CONCLUSIONS: Among aggressive children with ADHD, aggressive behaviors are just as likely to decrease following stimulant monotherapy and behavioral treatment among those with sustained mood symptoms and those without. Improvements in mood problems are evident as well. Therefore, the abnormalities in persistent mood described by DMDD's criteria do not contraindicate stimulant therapy as initial treatment among those with comorbid ADHD. Rather, substantial improvements may be anticipated, and remission of both behavioral and mood symptoms seems achievable for a proportion of patients. TRIAL REGISTRATION: ClinicalTrials.gov (U.S.); IDs: NCT00228046 and NCT00794625; www.clinicaltrials.gov. PMID- 26745218 TI - Midtarsal Sprain Misdiagnosed as Ankle Sprain: Role of Ultrasonography in Diagnosis. PMID- 26745219 TI - Response to Noninvasive Pco2 Monitoring During Sleep for Patients with Neuromuscular Disease. PMID- 26745220 TI - Ascending Reticular Activating System in a Patient with Persistent Vegetative State. PMID- 26745221 TI - RE: "Sonographic Examination of Knee Ligaments". PMID- 26745222 TI - Eccentric Training Improves Ankle Evertor and Dorsiflexor Strength and Proprioception in Functionally Unstable Ankles. AB - OBJECTIVE: The aim of this study was to investigate the effects of a combined eccentric-concentric exercise program of the ankle evertors and dorsiflexors on proprioception in functionally unstable ankles. DESIGN: Thirteen male recreational athletes with unilateral functional ankle instability were admitted to this study. The unaffected opposite ankles were used as controls. The functionnaly unstable ankle of the subjects performed an isokinetic exercise program of the ankle evertors and dorsiflexors in a combined eccentric-concentric mode for 3 days per week for 6 wks. Before and after the isokinetic exercise program, active and passive joint position sense and kinesthesia and isokinetic strength of the ankle joint were evaluated. RESULTS: Active and passive joint position sense error scores for inversion (P < 0.01-0.001) and plantarflexion (P < 0.05-0.001) direction and kinesthesia scores for inversion (P < 0.001) and plantarlexion (P < 0.01) direction showed significant reductions after 6 wks of intervention in the functionnaly unstable ankle. In addition, eccentric peak torques for the ankle evertor and dorsiflexors represented significant (P < 0.001) increases in the functionnaly unstable ankle compared with the control ankle. CONCLUSIONS: The results of this study suggest that it is possible to improve proprioceptive acuity of the ankle joint after a 6-wk eccentric concentric isokinetic training program in functionally unstable ankles. PMID- 26745223 TI - Response to Letter to the Editor: Sonographic Examination of Knee Ligaments. PMID- 26745224 TI - Reorganization of the Corticobublar Tract in a Patient with Bilateral Middle Cerebral Artery Territory Infarct. PMID- 26745225 TI - Myofascial Release Therapy in the Treatment of Occupational Mechanical Neck Pain: A Randomized Parallel Group Study. AB - OBJECTIVE: As myofascial release therapy is currently under development, the objective of this study was to compare the effectiveness of myofascial release therapy with manual therapy for treating occupational mechanical neck pain. DESIGN: A randomized, single-blind parallel group study was developed. The sample (n = 59) was divided into GI, treated with manual therapy, and GII, treated with myofascial release therapy. Variables studied were intensity of neck pain, cervical disability, quality of life, craniovertebral angle, and ranges of cervical motion. RESULTS: At five sessions, clinical significance was observed in both groups for all the variables studied, except for flexion in GI. At this time point, an intergroup statistical difference was observed, which showed that GII had better craniovertebral angle (P = 0.014), flexion (P = 0.021), extension (P = 0.003), right side bending (P = 0.001), and right rotation (P = 0.031). A comparative analysis between therapies after intervention showed statistical differences indicating that GII had better craniovertebral angle (P = 0.000), right (P = 0.000) and left (P = 0.009) side bending, right (P = 0.024) and left (P = 0.046) rotations, and quality of life. CONCLUSIONS: The treatment of occupational mechanical neck pain by myofascial release therapy seems to be more effective than manual therapy for correcting the advanced position of the head, recovering range of motion in side bending and rotation, and improving quality of life. PMID- 26745226 TI - Analysis of Postural Control During Quiet Standing in a Population with Diabetic Peripheral Neuropathy Undergoing Moderate Intensity Aerobic Exercise Training: A Single Blind, Randomized Controlled Trial. AB - OBJECTIVE: The aim of this study was to investigate the effect of 8 wks of moderate-intensity aerobic exercise on postural control during quiet standing in type 2 diabetic peripheral neuropathy. METHODS: Individuals were included in the study if they had type 2 diabetes with clinical neuropathy, defined by a minimum score of 7 on the Michigan Diabetic Neuropathy Score, following which the patients were randomly assigned to an 8-wk program by computer-generated random number tables to study or control group. Repeated-measures analysis of variance was used for data analysis (P < 0.05 was considered significant). RESULTS: After final randomization, there were 36 patients in the study group and 45 in the control group. On comparison of results for control and study groups using repeated-measures analysis of variance only in the eyes closed on foam condition was there was a significant difference between the two groups for sway velocity along the x-axis (df1, df2 = 1, 18, F = 3.86, P = 0.04) and mediolateral displacement (df1, df2 = 1, 18, F = 4.04, P = 0.03). CONCLUSION: Aerobic exercise training could exert a therapeutic effect on center of pressure movement only along the x-axis in the eyes closed condition on foam surface during quiet standing. PMID- 26745227 TI - Re: Ultrasound-Guided Glenohumeral Joint Injection Using the Posterior Approach. PMID- 26745228 TI - Response to the Letter to the Editor on "Ultrasound-Guided Glenohumeral Joint Injection Using the Posterior Approach". PMID- 26745229 TI - Patterns of Radiation-Associated Lymphopenia in Children with Cancer. AB - Adults with cancer commonly develop severe lymphopenia two months following chemoradiation therapy, which is an independent predictor of survival. In this retrospective study of 53 children with central nervous system tumors and sarcomas, the frequency, severity, and duration of radiation-associated lymphopenia was similar to that seen in adults. Pretreatment lymphocyte counts were 1,000 cells/mm(3) or greater in all patients, with 66% experiencing grade III-IV lymphopenia two months after chemoradiation. Lymphocyte counts remained significantly lower than baseline 12 months later. Further studies are needed to determine if this is also associated with poorer survival, as seen in adults. PMID- 26745231 TI - WHO report on ending childhood obesity echoes earlier recommendations. PMID- 26745230 TI - Telenephrology application in rural and remote areas of Jordan: benefits and impact on quality of life. AB - INTRODUCTION: This study aimed to assess the impact of live interactive telenephrology on diagnosis and disease management, patients' quality of life, and time- and cost savings. METHODS: A pre-test-post-test one-group design was used to evaluate the process and outcomes of the teleconsultations among all consecutive patients who attended or were referred to the teleclinics for suspected kidney diseases. Patients were interviewed for relevant information and their quality of life was assessed during the first visit. The quality-of-life questionnaires (short form (SF) 8) were filled 8 weeks after the last visit to assess the changes in the quality of life. RESULTS: A total of 64 patients were included in this study. The treatment plan changed from that of the referring health provider for 31.2% of patients. The vast majority of patients stated that their visits to teleclinics were associated with less waiting time and lower cost (96.9% and 98.4%, respectively). The total satisfaction score of patients with the services received ranged from 71.2 to 100 with a mean of 96.8 (standard deviation 4.8), indicating a high level of satisfaction. After 2 months of consultations, the mean SF8 score increased significantly from 33.1 to 45.0 (p<0.019), which implies that the telenephrology care was associated with better quality of life, mainly the physical component of quality of life. CONCLUSIONS: Telenephrology care in remote areas of Jordan would improve the access to health care, help to reach proper diagnoses and establish the treatment plan, and is associated with better quality of life. PMID- 26745232 TI - Modeling Incomplete Longitudinal Substance Use Data Using Latent Variable Growth Curve Methodology. AB - Longitudinal data sets typically suffer from attrition and other forms of missing data. When this common problem occurs, several researchers have demonstrated that correct maximum likelihood estimation with missing data can be obtained under mild assumptions concerning the missing data mechanism. With reasonable substantive theory, a mixture of cross-sectional and longitudinal methods developed within multiple-group structural equation modeling can provide a strong basis for inference about developmental change. Using an approach to the analysis of missing data, the present study investigated developmental trends in adolescent (N = 759) alcohol, marijuana, and cigarette use across a 5-year period using multiple-group latent growth modeling. An associative model revealed that common developmental trends existed for all three substances. Age and gender were included in the model as predictors of initial status and developmental change. Findings discuss the utility of latent variable structural equation modeling techniques and missing data approaches in the study of developmental change. PMID- 26745233 TI - Statistical Evidence in Salary Discrimination Studies: Nonparametric Inferential Conditions. AB - Fairness in the allocation of salary is often evaluated using statistical reasoning. A common principle is that among employees of equal merit, there should be no systematic differences in salary distributions between demographic groups. In practice, complete information on merit may be lacking. When observed measures of merit are incomplete or unreliable, statistical analyses that use such measures may be misleading. We present theoretical, nonparametric conditions under which evidence from salary studies using observed merit measures can provide a basis for inferences of fairness. Two types of fairness are defined that contrast fairness with respect to true merit versus observed merit. Latent variable models that have been proposed for use in salary equity studies are reviewed as parametric special cases of the general conditions presented. These models are illustrated using real salary data, demonstrating their specification as structural models with latent means. Implications of the inferential conditions for empirical studies of salary equity are discussed. PMID- 26745234 TI - Some Alternative Approximate Tests for a Split Plot Design. PMID- 26745235 TI - A Simple Method for Procrustean Rotation in Factor Analysis Using Majorization Theory. AB - The essential idea in all analytical rotation schemes for approximating Thurstone's simple structure is to split the factor loadings into two groups, the elements of the one tending toward zero, and of the other, toward unity. In the PROMAX method, the loadings of a preliminary factor pattern are raised to a fixed power to provide a target for Procrustean rotation. In this article, a mathematically better-motivated technique based on vector majorization is proposed for this purpose. The method is illustrated with several standard numerical examples. PMID- 26745236 TI - Structural Factor Analysis Experiments with Incomplete Data. AB - This article presents some benefits and limitations of structural equation models for multivariate experiments with incomplete data. Examples from studies of latent variable path models of cognitive performances illustrate analyses with four different kinds of incomplete data: (a) latent variables, (b) omitted variables, (c) randomly missing data, and (d) non- randomly missing data. Power based cost-benefit analyses for experimental design and planning are also presented. These incomplete data approaches are closely related to models used in classical experimental design, interbattery measurement analysis, longitudinal analyses, and behavioral genetic analyses. These structural equation methods for old experimental design problems indicate some new opportunities for future multivariate research. PMID- 26745239 TI - Simple Molecular Reactive Force Field for Metal-Organic Synthesis. AB - For colloidal quantum dots to transition from research laboratories to deployment as optical and electronic products, there will be a need to scale-up their production to large-scale manufacturing processes. This demand increases the need to understand their formation via a molecular representation of the nucleation of lead sulfide (PbS) quantum dot systems passivated by lead oleate complexes. We demonstrate the effectiveness of a new type of reactive potential, custom-made for this system, that is drawn from simple Morse, Lennard-Jones, and Coulombic components, which can reproduce reactions across a broad range of PbS quantum dot sizes with good accuracy. We validate the capability of this model to capture reactive systems by comparison to ab initio calculations for a reaction between two dots. PMID- 26745240 TI - BTEX exposures in an area impacted by industrial and mobile sources: Source attribution and impact of averaging time. AB - The impacts of emissions plumes from major industrial sources on black carbon (BC) and BTEX (benzene, toluene, ethyl benzene, xylene isomers) exposures in communities located >10 km from the industrial source areas were identified with a combination of stationary measurements, source identification using positive matrix factorization (PMF), and dispersion modeling. The industrial emissions create multihour plume events of BC and BTEX at the measurement sites. PMF source apportionment, along with wind patterns, indicates that the observed pollutant plumes are the result of transport of industrial emissions under conditions of low boundary layer height. PMF indicates that industrial emissions contribute >50% of outdoor exposures of BC and BTEX species at the receptor sites. Dispersion modeling of BTEX emissions from known industrial sources predicts numerous overnight plumes and overall qualitative agreement with PMF analysis, but predicts industrial impacts at the measurement sites a factor of 10 lower than PMF. Nonetheless, exposures associated with pollutant plumes occur mostly at night, when residents are expected to be home but are perhaps unaware of the elevated exposure. Averaging data samples over long times typical of public health interventions (e.g., weekly or biweekly passive sampling) misapportions the exposure, reducing the impact of industrial plumes at the expense of traffic emissions, because the longer samples cannot resolve subdaily plumes. Suggestions are made for ways for future distributed pollutant mapping or intervention studies to incorporate high time resolution tools to better understand the potential impacts of industrial plumes. IMPLICATIONS: Emissions from industrial or other stationary sources can dominate air toxics exposures in communities both near the source and in downwind areas in the form of multihour plume events. Common measurement strategies that use highly aggregated samples, such as weekly or biweekly averages, are insensitive to such plume events and can lead to significant under apportionment of exposures from these sources. PMID- 26745237 TI - DNA damage response during mouse oocyte maturation. AB - Because low levels of DNA double strand breaks (DSBs) appear not to activate the ATM-mediated prophase I checkpoint in full-grown oocytes, there may exist mechanisms to protect chromosome integrity during meiotic maturation. Using live imaging we demonstrate that low levels of DSBs induced by the radiomimetic drug Neocarzinostatin (NCS) increase the incidence of chromosome fragments and lagging chromosomes but do not lead to APC/C activation and anaphase onset delay. The number of DSBs, represented by gammaH2AX foci, significantly decreases between prophase I and metaphase II in both control and NCS-treated oocytes. Transient treatment with NCS increases >2-fold the number of DSBs in prophase I oocytes, but less than 30% of these oocytes enter anaphase with segregation errors. MRE11, but not ATM, is essential to detect DSBs in prophase I and is involved in H2AX phosphorylation during metaphase I. Inhibiting MRE11 by mirin during meiotic maturation results in anaphase bridges and also increases the number of gammaH2AX foci in metaphase II. Compromised DNA integrity in mirin-treated oocytes indicates a role for MRE11 in chromosome integrity during meiotic maturation. PMID- 26745242 TI - Children with alcohol intoxication in Cracow, Poland. AB - Alcoholism among minors is a serious social problem. The aim of the current study was to analyze alcohol intoxication in children based on hospitalizations in the University Children's Hospital in Cracow between the years 2007 and 2015. During these 9 years, 381 patients were hospitalized due to excessive alcohol consumption. Most patients were junior high school or high school students. The highest blood alcohol concentrations in hospitalized patients were found in a 16 year-old boy (BAC .41%) and a 15-year-old girl (BAC .37%). Alcohol consumption and severe intoxication are linked to a wide variety of familial, social, and personal problems. PMID- 26745241 TI - A WEE1 Inhibitor Analog of AZD1775 Maintains Synergy with Cisplatin and Demonstrates Reduced Single-Agent Cytotoxicity in Medulloblastoma Cells. AB - The current treatment for medulloblastoma includes surgical resection, radiation, and cytotoxic chemotherapy. Although this approach has improved survival rates, the high doses of chemotherapy required for clinical efficacy often result in lasting neurocognitive defects and other adverse events. Therefore, the development of chemosensitizing agents that allow dose reductions of cytotoxic agents, limiting their adverse effects but maintaining their clinical efficacy, would be an attractive approach to treat medulloblastoma. We previously identified WEE1 kinase as a new molecular target for medulloblastoma from an integrated genomic analysis of gene expression and a kinome-wide siRNA screen of medulloblastoma cells and tissue. In addition, we demonstrated that WEE1 prevents DNA damage-induced cell death by cisplatin and that the WEE1 inhibitor AZD1775 displays synergistic activity with cisplatin. AZD1775 was developed as a WEE1 inhibitor from an initial hit from a high-throughput screen. However, given the lack of structure-activity data for AZD1775, we developed a small series of analogs to determine the requirements for WEE1 inhibition and further examine the effects of WEE1 inhibition in medulloblastoma. Interestingly, the compounds that inhibited WEE1 in the same nanomolar range as AZD1775 had significantly reduced single-agent cytotoxicity compared with AZD1775 and displayed synergistic activity with cisplatin in medulloblastoma cells. The potent cytotoxicity of AZD1775, unrelated to WEE1 inhibition, may result in dose-limiting toxicities and exacerbate adverse effects; therefore, WEE1 inhibitors that demonstrate low cytotoxicity could be dosed at higher concentrations to chemosensitize the tumor and potentiate the effect of DNA-damaging agents such as cisplatin. PMID- 26745243 TI - Non-conscious processes in changing health-related behaviour: a conceptual analysis and framework. AB - Much of the global burden of non-communicable disease is caused by unhealthy behaviours that individuals enact even when informed of their health-harming consequences. A key insight is that these behaviours are not predominantly driven by deliberative conscious decisions, but occur directly in response to environmental cues and without necessary representation of their consequences. Consequently, interventions that target non-conscious rather than conscious processes to change health behaviour may have significant potential, but this important premise remains largely untested. This is in part due to the lack of a practicable conceptual framework that can be applied to better describe and assess these interventions. We propose a framework for describing or categorising interventions to change health behaviour by the degree to which their effects may be considered non-conscious. Potential practical issues with applying such a framework are discussed, as are the implications for further research to inform the testing and development of interventions. A pragmatic means of conceptualising interventions targeted at non-conscious processes is a necessary prelude to testing the potency of such interventions. This can ultimately inform the development of interventions with the potential to shape healthier behaviours across populations. PMID- 26745244 TI - Effects of Rhamnolipid and Carboxymethylcellulose Coatings on Reactivity of Palladium-Doped Nanoscale Zerovalent Iron Particles. AB - Nanoscale zerovalent iron (NZVI) particles are often coated with polymeric surface modifiers for improved colloidal stability and transport during remediation of contaminated aquifers. Doping the NZVI surface with palladium (Pd NZVI) increases its reactivity to pollutants such as trichloroethylene (TCE). In this study, we investigate the effects of coating Pd-NZVI with two surface modifiers of very different molecular size: rhamnolipid (RL, anionic biosurfactant, M.W. 600 g mol(-1)) and carboxymethylcellulose (CMC, anionic polyelectrolyte, M.W. 700 000 g mol(-1)) on TCE degradation. RL loadings of 13 133 mg TOC/g NZVI inhibited deposition of Pd in a concentration-dependent manner, thus limiting the number of available Pd sites and decreasing the TCE degradation reaction rate constant from 0.191 h(-1) to 0.027 h(-1). Furthermore, the presence of RL in solution had an additional inhibitory effect on the reactivity of Pd NZVI by interacting with the exposed Pd deposits after they were formed. In contrast, CMC had no effect on reactivity at loadings up to 167 mg TOC/g NZVI. There was a lack of correlation between Pd-NZVI aggregate sizes and TCE reaction rates, and is explained by cryo-transmission electron microscopy images that show open, porous aggregate structures where TCE would be able to easily access Pd sites. PMID- 26745245 TI - Current injection and receptor-mediated excitation produce similar maximal firing rates in hypoglossal motoneurons. AB - The maximum firing rates of motoneurons (MNs), activated in response to synaptic drive, appear to be much lower than that elicited by current injection. It could be that the decrease in input resistance associated with increased synaptic activity (but not current injection) might blunt overall changes in membrane depolarization and thereby limit spike-frequency output. To test this idea, we recorded, in the same cells, maximal firing responses to current injection and to synaptic activation. We prepared 300 MUm medullary slices in neonatal rats that contained hypoglossal MNs and used whole-cell patch-clamp electrophysiology to record their maximum firing rates in response to triangular-ramp current injections and to glutamate receptor-mediated excitation. Brief pressure pulses of high-concentration glutamate led to significant depolarization, high firing rates, and temporary cessation of spiking due to spike inactivation. In the same cells, we applied current clamp protocols that approximated the time course of membrane potential change associated with glutamate application and with peak current levels large enough to cause spike inactivation. Means (SD) of maximum firing rates obtained in response to glutamate application were nearly identical to those obtained in response to ramp current injection [glutamate 47.1 +/- 12.0 impulses (imp)/s, current injection 47.5 +/- 11.2 imp/s], even though input resistance was 40% less during glutamate application compared with current injection. Therefore, these data suggest that the reduction in input resistance associated with receptor-mediated excitation does not, by itself, limit the maximal firing rate responses in MNs. PMID- 26745246 TI - Repetition suppression for visual actions in the macaque superior temporal sulcus. AB - In many brain areas, repetition of a stimulus usually weakens the neural response. This "adaptation" or repetition suppression effect has been observed with mass potential measures such as event-related potentials (ERPs), in fMRI BOLD responses, and locally with local field potentials (LFPs) and spiking activity. Recently, it has been reported that macaque F5 mirror neurons do not show repetition suppression of their spiking activity for single repetitions of hand actions, which disagrees with human fMRI adaptation studies. This finding also contrasts with numerous studies showing repetition suppression in macaque inferior temporal cortex, including the rostral superior temporal sulcus (STS). Since the latter studies employed static stimuli, we assessed here whether the use of dynamic action stimuli abolishes repetition suppression in the awake macaque STS. To assess adaptation effects in the STS, we employed the same hand action movies as used when examining adaptation in F5. The upper bank STS neurons showed repetition suppression during the approaching phase of the hand action, which corresponded to the phase of the action for which these neurons responded overall the strongest. The repetition suppression was present for the spiking activity measured in independent single-unit and multiunit recordings as well as for the LFP power at frequencies > 50 Hz. Together with previous data in F5, these findings suggest that adaptation effects differ between F5 mirror neurons and the STS neurons. PMID- 26745247 TI - Trunk stabilization during sagittal pelvic tilt: from trunk-on-pelvis to trunk-in space due to vestibular and visual feedback. AB - The goal of this study was to investigate the human ability to stabilize the trunk in space during pelvic tilt. Upper body sway was evoked in kneeling-seated healthy subjects by angular platform perturbations with a rotation around a virtual low-back pivot point between the L4 and L5 vertebrae. To investigate motor control modulation, variations in task instruction (balance naturally or minimize trunk sway), vision (eyes open or closed), and perturbation bandwidth (from 0.2 up to 1, 3, or 10 Hz) were applied. Cocontraction and proprioceptive muscle spindle feedback were associated with minimizing low-back flexion/extension (trunk-on-pelvis stabilization), while vestibular and visual feedback were supposed to contribute to trunk-in-space stabilization. Trunk-in space stabilization was only observed with the minimize trunk sway task instruction, while the task instruction to balance naturally led to trunk-on pelvis stabilization with trunk rotations even exceeding the perturbations. This indicates that vestibular feedback is used when minimizing trunk sway but has only a minor contribution during natural trunk stabilization in the sagittal plane. The eyes open condition resulted in reduced global trunk rotations and increased global trunk reflexive responses, demonstrating effective visual contributions to trunk-in-space stabilization. On the other hand, increasing perturbation bandwidth caused a decreased feedback contribution leading to deteriorated trunk-in-space stabilization. PMID- 26745248 TI - Endogenous 24S-hydroxycholesterol modulates NMDAR-mediated function in hippocampal slices. AB - N-methyl-D-aspartate receptors (NMDARs), a major subtype of glutamate receptors mediating excitatory transmission throughout the central nervous system (CNS), play critical roles in governing brain function and cognition. Because NMDAR dysfunction contributes to the etiology of neurological and psychiatric disorders including stroke and schizophrenia, NMDAR modulators are potential drug candidates. Our group recently demonstrated that the major brain cholesterol metabolite, 24S-hydroxycholesterol (24S-HC), positively modulates NMDARs when exogenously administered. Here, we studied whether endogenous 24S-HC regulates NMDAR activity in hippocampal slices. In CYP46A1(-/-) (knockout; KO) slices where endogenous 24S-HC is greatly reduced, NMDAR tone, measured as NMDAR-to-alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) excitatory postsynaptic current (EPSC) ratio, was reduced. This difference translated into more NMDAR-driven spiking in wild-type (WT) slices compared with KO slices. Application of SGE-301, a 24S-HC analog, had comparable potentiating effects on NMDAR EPSCs in both WT and KO slices, suggesting that endogenous 24S-HC does not saturate its NMDAR modulatory site in ex vivo slices. KO slices did not differ from WT slices in either spontaneous neurotransmission or in neuronal intrinsic excitability, and exhibited LTP indistinguishable from WT slices. However, KO slices exhibited higher resistance to persistent NMDAR-dependent depression of synaptic transmission induced by oxygen-glucose deprivation (OGD), an effect restored by SGE-301. Together, our results suggest that loss of positive NMDAR tone does not elicit compensatory changes in excitability or transmission, but it protects transmission against NMDAR-mediated dysfunction. We expect that manipulating this endogenous NMDAR modulator may offer new treatment strategies for neuropsychiatric dysfunction. PMID- 26745249 TI - Dissociable saccadic suppression of pupillary and perceptual responses to light. AB - We measured pupillary constrictions in response to full-screen flashes of variable luminance, occurring either at the onset of a saccadic eye movement or well before/after it. A large fraction of perisaccadic flashes were undetectable to the subjects, consistent with saccadic suppression of visual sensitivity. Likewise, pupillary responses to perisaccadic flashes were strongly suppressed. However, the two phenomena appear to be dissociable. Across subjects and luminance levels of the flash stimulus, there were cases in which conscious perception of the flash was completely depleted yet the pupillary response was clearly present, as well as cases in which the opposite occurred. On one hand, the fact that pupillary light responses are subject to saccadic suppression reinforces evidence that this is not a simple reflex but depends on the integration of retinal illumination with complex "extraretinal" cues. On the other hand, the relative independence of pupillary and perceptual responses suggests that suppression acts separately on these systems-consistent with the idea of multiple visual pathways that are differentially affected by saccades. PMID- 26745250 TI - Interneurons contribute to the hemodynamic/metabolic response to epileptiform discharges. AB - Interpretation of hemodynamic responses in epilepsy is hampered by an incomplete understanding of the underlying neurovascular coupling, especially the contributions of excitation and inhibition. We made simultaneous multimodal recordings of local field potentials (LFPs), firing of individual neurons, blood flow, and oxygen level in the somatosensory cortex of anesthetized rats. Epileptiform discharges induced by bicuculline injections were used to trigger large local events. LFP and blood flow were robustly coupled, as were LFP and tissue oxygen. In a parametric linear model, LFP and the baseline activities of cerebral blood flow and tissue partial oxygen tension contributed significantly to blood flow and oxygen responses. In an analysis of recordings from 402 neurons, blood flow/tissue oxygen correlated with the discharge of putative interneurons but not of principal cells. Our results show that interneuron activity is important in the vascular and metabolic responses during epileptiform discharges. PMID- 26745251 TI - Prognostic value of somatosensory evoked potentials, neuron-specific enolase, and S100 for short-term outcome in ischemic stroke. AB - To predict short-term outcome in acute ischemic stroke, we analyzed somatosensory evoked potentials (SEP) and biochemical parameters [neuron-specific enolase (NSE) and S100 protein] in a prospective study with serial measurement. In 31 patients with 1st middle cerebral artery infarction, serum NSE and S100 protein were measured daily between days 1 and 6 poststroke. The N20 and N70 components of the SEP (SEP20 and SEP70) were determined on days 1 and 6. SEP and biochemical markers in stroke patients were compared with a control group. Short-term outcome was assessed by the modified Rankin Scale (mRS) at days 7-10 and was dichotomized between good (mRS 0-2) and poor (mRS >=3) outcome. Specificity and positive predictive value (PPV) were high at day 1 for SEP (SEP20: 100% for both; SEP70: 93 and 88%, respectively) compared with lower values for NSE (67 and 50%) and S100 (23 and 57%). In contrast, S100 showed the highest sensitivity at day 1 with 77% compared with a relatively low sensitivity of NSE (31%) and SEP (SEP20: 35%, SEP70: 47%). The biochemical markers showed an improving sensitivity over time with best values (>90%) between days 3 and 4 at the expense of a lower specificity. Specificity and PPV of SEP on day 6 was still 100% with sensitivity increasing up to 53% (SEP20) and 60% (SEP70). SEP could early differentiate between good and poor outcome and reliably predict poor outcome. Since biochemical markers and SEP complement each other in the prognosis of stroke, a combined application of these markers seems promising. PMID- 26745254 TI - Infancy-Onset T1DM, Short Stature, and Severe Immunodysregulation in Two Siblings With a Homozygous LRBA Mutation. AB - CONTEXT: Type 1 diabetes mellitus (T1DM) is caused by autoimmunity against pancreatic beta-cells. Although a significant number of T1DM patients have or will develop further autoimmune disorders during their lifetime, coexisting severe immunodysregulation is rare. OBJECTIVE: Presuming autosomal-recessive inheritance in a complex immunodysregulation disorder including T1DM and short stature in two siblings, we performed whole-exome sequencing. CASE PRESENTATION: Two Libyan siblings born to consanguineous parents were presented to our diabetology department at ages 12 and 5 years, respectively. Apart from T1DM diagnosed at age 2 years, patient 1 suffered from chronic restrictive lung disease, mild enteropathy, hypogammaglobulinemia, and GH deficiency. Fluorescence activated cell sorting analysis revealed B-cell deficiency. In addition, CD4(+)/CD25(+) and CD25(high)/FoxP3(+) cells were diminished, whereas an unusual CD25(-)/FoxP3(+) population was detectable. The younger brother, patient 2, also developed T1DM during infancy. Although his enteropathy was more severe and electrolyte derangements repeatedly led to hospitalization, he did not have significant pulmonary problems. IgG levels and B-lymphocytes were within normal ranges. RESULTS: By whole-exome sequencing we identified a homozygous truncating mutation (c.2445_2447del(C)3ins(C)2, p.P816Lfs*4) in the lipopolysaccharide responsive beige-like anchor (LRBA) gene in both siblings. The diagnosis of LRBA deficiency was confirmed by a fluorescence-activated cell sorting-based immunoassay showing the absence of LRBA protein in phytohemagglutinin-stimulated peripheral blood mononuclear cells. CONCLUSION: We identified a novel truncating LRBA mutation in two siblings with T1DM, short stature, and severe immunodysregulation. LRBA mutations have previously been reported to cause multiorgan autoimmunity and immunodysfunction. In light of the variable phenotypes reported so far in LRBA-mutant individuals, LRBA deficiency should be considered in all patients presenting with T1DM and signs of severe immunodysregulation. PMID- 26745255 TI - Altered Plasma Levels of Glucagon, GLP-1 and Glicentin During OGTT in Adolescents With Obesity and Type 2 Diabetes. AB - CONTEXT: Proglucagon-derived hormones are important for glucose metabolism, but little is known about them in pediatric obesity and type 2 diabetes mellitus (T2DM). OBJECTIVE: Fasting and postprandial levels of proglucagon-derived peptides glucagon, GLP-1, and glicentin in adolescents with obesity across the glucose tolerance spectrum were investigated. DESIGN: This was a cross-sectional study with plasma hormone levels quantified at fasting and during an oral glucose tolerance test (OGTT). SETTING: This study took place in a pediatric obesity clinic at Uppsala University Hospital, Sweden. PATIENTS AND PARTICIPANTS: Adolescents with obesity, age 10-18 years, with normal glucose tolerance (NGT, n = 23), impaired glucose tolerance (IGT, n = 19), or T2DM (n = 4) and age-matched lean adolescents (n = 19) were included. MAIN OUTCOME MEASURES: Outcome measures were fasting and OGTT plasma levels of insulin, glucagon, active GLP-1, and glicentin. RESULTS: Adolescents with obesity and IGT had lower fasting GLP-1 and glicentin levels than those with NGT (0.25 vs 0.53 pM, P < .05; 18.2 vs 23.6 pM, P < .01) and adolescents with obesity and T2DM had higher fasting glucagon levels (18.1 vs 10.1 pM, P < .01) than those with NGT. During OGTT, glicentin/glucagon ratios were lower in adolescents with obesity and NGT than in lean adolescents (P < .01) and even lower in IGT (P < .05) and T2DM (P < .001). CONCLUSIONS: Obese adolescents with IGT have lowered fasting GLP-1 and glicentin levels. In T2DM, fasting glucagon levels are elevated, whereas GLP-1 and glicentin levels are maintained low. During OGTT, adolescents with obesity have more products of pancreatically than intestinally cleaved proglucagon (ie, more glucagon and less GLP-1) in the plasma. This shift becomes more pronounced when glucose tolerance deteriorates. PMID- 26745256 TI - Effect of Low Vitamin D on Volumetric Bone Mineral Density, Bone Microarchitecture, and Stiffness in Primary Hyperparathyroidism. AB - CONTEXT: Patients with 25-hydroxyvitamin D deficiency (25OHD <20 ng/ml) and primary hyperparathyroidism (PHPT) have more severe disease reflected by higher serum PTH levels compared to those with vitamin D levels in the insufficient (20 29 ng/ml) or replete range (>= 30 ng/ml). OBJECTIVE: To study the effect of low vitamin D in PHPT on volumetric bone mineral density (vBMD), bone microarchitecture, and bone strength. DESIGN, SETTING, AND PARTICIPANTS: This is a cross-sectional analysis of 99 PHPT patients with and without 25OHD insufficiency and deficiency from a university hospital. OUTCOME MEASURES: Bone microarchitecture and strength were assessed with high-resolution peripheral quantitative computed tomography (HRpQCT), microfinite element analysis, and individual trabecula segmentation. RESULTS: In this cohort, 25OHD levels were deficient in 18.1%, insufficient in 35.4% and replete in 46.5%. Those with lower 25OHD levels had higher PTH (P < .0001), were younger (P = .001) and tended to weigh more (P = .053). There were no age-, weight- and sex-adjusted between-group differences (<20 vs 20-29 vs >= 30 ng/ml) in any HRpQCT, microfinite element analysis, or individual trabecula segmentation indices. Because few participants had 25OHD below 20 ng/ml, we also compared those with 25OHD below 30 vs at least 30 ng/ml and found only a trend toward lower adjusted cortical vBMD (3.1%, P = .08) and higher cortical porosity (least squares mean +/- SEM 7.5 +/- 0.3 vs 6.6 +/- 0.3%, P = .07) at the tibia but not the radius. Stiffness did not differ at either site. In multiple regression analysis, 25OHD accounted for only three of the 49.2% known variance in cortical vBMD; 25OHD was not significant in the model for cortical porosity at the tibia. CONCLUSION: Low 25OHD levels are associated with higher PTH levels in PHPT, but contrary to our hypothesis, these differences did not significantly affect vBMD or microarchitecture, nor did they result in lower stiffness. Low vitamin D in PHPT using current 25OHD thresholds for insufficiency and deficiency did not significantly affect skeletal integrity as assessed by HRpQCT. PMID- 26745257 TI - Serum S100A8 and S100A9 Enhance Innate Immune Responses in the Pathogenesis of Baker's Asthma. AB - BACKGROUND: S100A8 and S100A9 can be produced by lipopolysaccharide-stimulated granulocytes and provoke an innate immune-mediated airway inflammation. Involvement of S100A8 and S100A9 has been implicated in asthma. To further understand the role of S100A8 and S100A9 during innate immune responses in baker's asthma, we investigated the associations of serum S100A8 and S100A9 with exposure to bakery allergens and polymorphisms of the Toll-like receptor 4 (TLR4) gene. METHODS: Totally, 381 bakery workers and 100 unexposed healthy controls were recruited. Skin prick tests for bakery allergens were performed. Serum levels of S100A8, S100A9, myeloperoxidase (MPO), tumor necrosis factor (TNF) alpha, and interleukin (IL)-8 were measured using ELISA. Predictive values of serum S100A8 and S100A9 in bakery workers were evaluated by receiver-operating characteristic (ROC) curves. Polymorphisms of TLR4 -2027Ax2192;G and 1608Tx2192;C were genotyped. RESULTS: Higher serum levels of S100A8 and S100A9 were noted in bakery workers compared to the normal controls (p < 0.001); however, no significant differences were noted according to work-related symptoms. The area under the ROC curve of serum S100A8 was 0.886 for occupational exposure (p < 0.001). The TLR4 -1608CC genotype was significantly associated with a higher serum S100A8 level (p = 0.025). Serum S100A8 and S100A9 levels were correlated with serum levels of MPO (r = 0.396 and 0.189, respectively), TNF alpha (r = 0.536 and 0.280, respectively), and IL-8 (r = 0.540 and 0.205, respectively; p < 0.001 for all). CONCLUSION: S100A8 and S100A9 are involved in innate immune responses under the regulation of TLR4 polymorphisms in baker's asthma pathogenesis. Serum S100A8 could be a potential biomarker for predicting occupational exposure to wheat flour in bakery workers. PMID- 26745261 TI - The Nozoe Autograph Books Project: An Assessment. AB - Bonding beyond Borders is a fitting title to the Nozoe Autograph Books project, as the books and their publication involved innumerable contributors from around the globe all in the spirit of personal collaboration. The editors of this project share details of how the project came into being and give their own personal assessment of what it has become and what it means. PMID- 26745259 TI - Impact of functional alterations on quality of life in patients with Alzheimer's disease. AB - AIM: To identify factors associated with health-related quality of life (HRQoL) as assessed by the Dementia Quality of Life (DQoL) in patients with Alzheimer's disease (AD), focusing particularly on functional alterations. METHODS: Cross sectional multicenter study in subjects aged 65 years or older with mild to moderate AD. HRQoL was measured using the DQoL (five domains: self-esteem, positive affect/humor, negative affect, feeling of belonging, and sense of esthetics). Functional alterations were assessed based on activities of daily living (ADLs) and instrumental activities of daily living (IADLs). We also recorded socio-demographic characteristics of the patient and their carer, and comprehensive geriatric assessment including MMSE and psycho-behavioral data (Neuropsychiatric Inventory, Cornell depression score). Factors associated with each domain of the DQol were identified by multivariate linear regression. RESULTS: In total, 123 subjects were included (mean age 82 +/- 6 years, 64% women). Two of the five domains of the DQoL were significantly associated with factors based on functional evaluation. The ability to transfer within the home and the ability to use the telephone were associated with an increase in HRQoL in the 'self-esteem' domain (p = 0.02 and 0.05, respectively). Ability to get dressed without assistance was associated with lower HRQoL in the 'negative affect' domain (p = 0.0007). CONCLUSION: Alterations in functional capacity have a significant effect on HRQoL in several domains of the DQoL. PMID- 26745264 TI - Towards individualized follow-up protocols after endovascular aortic aneurysm repair. AB - Endovascular aneurysm repair (EVAR) has become the primary treatment option for elective abdominal aortic aneurysms. However, a significant number of patients require secondary interventions to maintain adequate aneurysm exclusion and ultimately prevent death from abdominal aortic aneurysm (AAA) rupture. To maintain success and offer timely secondary intervention, intensive image surveillance has been recommended. These rigorous surveillance regimens are costly and may have deleterious effects from radiation and contrast exposure. Improvements in patient selection, operative technique and devices have caused a decline in complications after EVAR. Therefore, there is a need to reduce surveillance after EVAR for patients at lower risk of complications and install individualized follow-up protocols. This review describes the current strategies for surveillance and clarification of risk factors and predictors for late complications and discusses proposed risk-adapted strategies for postoperative surveillance after EVAR. PMID- 26745258 TI - Uncertainty analysis of quantitative imaging features extracted from contrast enhanced CT in lung tumors. AB - PURPOSE: To assess the uncertainty of quantitative imaging features extracted from contrast-enhanced computed tomography (CT) scans of lung cancer patients in terms of the dependency on the time after contrast injection and the feature reproducibility between scans. METHODS: Eight patients underwent contrast enhanced CT scans of lung tumors on two sessions 2-7 days apart. Each session included 6 CT scans of the same anatomy taken every 15s, starting 50s after contrast injection. Image features based on intensity histogram, co-occurrence matrix, neighborhood gray-tone difference matrix, run-length matrix, and geometric shape were extracted from the tumor for each scan. Spearman's correlation was used to examine the dependency of features on the time after contrast injection, with values over 0.50 considered time-dependent. Concordance correlation coefficients were calculated to examine the reproducibility of each feature between times of scans after contrast injection and between scanning sessions, with values greater than 0.90 considered reproducible. RESULTS: The features were found to have little dependency on the time between the contrast injection and the CT scan. Most features were reproducible between times of scans after contrast injection and between scanning sessions. Some features were more reproducible when they were extracted from a CT scan performed at a longer time after contrast injection. CONCLUSION: The quantitative imaging features tested here are mostly reproducible and show little dependency on the time after contrast injection. PMID- 26745263 TI - Diagnostic algorithms and treatment strategies in primary aortic and aortic graft infections. AB - Aortic infections and aortic graft infections are one of the most dreadful clinical entities that a vascular surgeon can face. Clinical presentation of the patient can vary greatly and diagnosis can be difficult to make. In this manuscript, diagnostic modalities are reviewed and a diagnostic algorithm suggested. Further, results of present treatment options are evaluated and treatment strategies for different clinical scenarios suggested. PMID- 26745265 TI - Improved Power System Stability Using Backtracking Search Algorithm for Coordination Design of PSS and TCSC Damping Controller. AB - Power system oscillation is a serious threat to the stability of multimachine power systems. The coordinated control of power system stabilizers (PSS) and thyristor-controlled series compensation (TCSC) damping controllers is a commonly used technique to provide the required damping over different modes of growing oscillations. However, their coordinated design is a complex multimodal optimization problem that is very hard to solve using traditional tuning techniques. In addition, several limitations of traditionally used techniques prevent the optimum design of coordinated controllers. In this paper, an alternate technique for robust damping over oscillation is presented using backtracking search algorithm (BSA). A 5-area 16-machine benchmark power system is considered to evaluate the design efficiency. The complete design process is conducted in a linear time-invariant (LTI) model of a power system. It includes the design formulation into a multi-objective function from the system eigenvalues. Later on, nonlinear time-domain simulations are used to compare the damping performances for different local and inter-area modes of power system oscillations. The performance of the BSA technique is compared against that of the popular particle swarm optimization (PSO) for coordinated design efficiency. Damping performances using different design techniques are compared in term of settling time and overshoot of oscillations. The results obtained verify that the BSA-based design improves the system stability significantly. The stability of the multimachine power system is improved by up to 74.47% and 79.93% for an inter area mode and a local mode of oscillation, respectively. Thus, the proposed technique for coordinated design has great potential to improve power system stability and to maintain its secure operation. PMID- 26745253 TI - Global Consensus Recommendations on Prevention and Management of Nutritional Rickets. AB - BACKGROUND: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. EVIDENCE: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describe the strength of the recommendation and the quality of supporting evidence. PROCESS: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. RESULTS: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. CONCLUSION: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required. PMID- 26745267 TI - Triphenylene-Based Room-Temperature Discotic Liquid Crystals: A New Class of Blue Light-Emitting Materials with Long-Range Columnar Self-Assembly. AB - A straightforward synthesis of multialkynylbenzene-bridged triphenylene-based dyad systems (via flexible alkyl spacers) that self-organize into room temperature columnar structures over a long range is reported. The compounds with spacer lengths (n) of 8 and 10 exhibit a columnar rectangular mesophase whereas a compound with n = 6 shows a columnar rectangular plastic phase. Interestingly, the later compound (n = 6) shows the formation of well-nucleated spherulites of about several hundred micrometers that suggest the existence of a long-range uniform self-assembly of columns. All of these compounds show blue luminescence in solution and in the thin-film state under long-wavelength (365 nm) UV light. These compounds fulfill the described demands such as long-range columnar self assembly at room temperature, a good yield with high purity, and blue-light emitters under the neat condition for possible potential applications in semiconductor devices. They also match the criteria of facile processing from the isotropic state because of their low isotropization temperature. This new class of materials is promising, considering the emissive nature and stabilization of the columnar mesophase at ambient temperature. PMID- 26745266 TI - Reassessing the Potential Activities of Plant CGI-58 Protein. AB - Comparative Gene Identification-58 (CGI-58) is a widespread protein found in animals and plants. This protein has been shown to participate in lipolysis in mice and humans by activating Adipose triglyceride lipase (ATGL), the initial enzyme responsible for the triacylglycerol (TAG) catabolism cascade. Human mutation of CGI-58 is the cause of Chanarin-Dorfman syndrome, an orphan disease characterized by a systemic accumulation of TAG which engenders tissue disorders. The CGI-58 protein has also been shown to participate in neutral lipid metabolism in plants and, in this case, a mutation again provokes TAG accumulation. Although its roles as an ATGL coactivator and in lipid metabolism are quite clear, the catalytic activity of CGI-58 is still in question. The acyltransferase activities of CGI-58 have been speculated about, reported or even dismissed and experimental evidence that CGI-58 expressed in E. coli possesses an unambiguous catalytic activity is still lacking. To address this problem, we developed a new set of plasmids and site-directed mutants to elucidate the in vivo effects of CGI-58 expression on lipid metabolism in E. coli. By analyzing the lipid composition in selected E. coli strains expressing CGI-58 proteins, and by reinvestigating enzymatic tests with adequate controls, we show here that recombinant plant CGI 58 has none of the proposed activities previously described. Recombinant plant and mouse CGI-58 both lack acyltransferase activity towards either lysophosphatidylglycerol or lysophosphatidic acid to form phosphatidylglycerol or phosphatidic acid and recombinant plant CGI-58 does not catalyze TAG or phospholipid hydrolysis. However, expression of recombinant plant CGI-58, but not mouse CGI-58, led to a decrease in phosphatidylglycerol in all strains of E. coli tested, and a mutation of the putative catalytic residues restored a wild-type phenotype. The potential activities of plant CGI-58 are subsequently discussed. PMID- 26745268 TI - A Combination of Mitochondrial Oxidative Stress and Excess Fat/Calorie Intake Accelerates Steatohepatitis by Enhancing Hepatic CC Chemokine Production in Mice. AB - Mitochondrial oxidative stress is considered as a key accelerator of fibrosis in various organs including the liver. However, the production of oxidative stress and progression of liver fibrosis may merely represent the independent consequences of hepatocellular injury caused by the primary disease. Because of a lack of appropriate experimental models to evaluate the sole effects of oxidative stress, it is virtually unknown whether this stress is causatively linked to the progression of liver fibrosis. Here, we examined the direct effects of mitochondrial reactive oxygen species (ROS) on the progression of high fat/calorie diet-induced steatohepatitis using Tet-mev-1 mice, in which a mutated succinate dehydrogenase transgene impairs the mitochondrial electron transport and generates an excess amount of ROS in response to doxycycline administration. Wild type and Tet-mev-1 mice that had been continuously given doxycycline containing water were subsequently fed either normal chow or a cholesterol-free high-fat/high-sucrose diet for 4 months at approximately 1 or 2 years of age. Histopathological examinations indicated that neither the mitochondrial ROS induced in Tet-mev-1 mice nor the feeding of wild type animals with high-fat/high sucrose diet alone caused significant liver fibrosis. Only when the Tet-mev-1 mice were fed a high-fat/high-sucrose diet, it induced lipid peroxidation in hepatocytes and enhanced hepatic CC chemokine expression. These events were accompanied by increased infiltration of CCR5-positive cells and activation of myofibroblasts, resulting in extensive liver fibrosis. Interestingly, this combinatorial effect of mitochondrial ROS and excess fat/calorie intake on liver fibrosis was observed only in 2-year-old Tet-mev-1 mice, not in the 1-year-old animals. Collectively, these results indicate that mitochondrial ROS in combination with excess fat/calorie intake accelerates liver fibrosis by enhancing CC chemokine production in aged animals. We have provided a good experimental model to explore how high fat/calorie intake increases the susceptibility to nonalcoholic steatohepatitis in aged individuals who have impaired mitochondrial adaptation. PMID- 26745271 TI - A field study on the effects of digital billboards on glance behavior during highway driving. AB - Developments in lighting technologies have allowed more dynamic digital billboards in locations visible from the roadway. Decades of laboratory research have shown that rapidly changing or moving stimuli presented in peripheral vision tends to 'capture' covert attention. We report naturalistic glance and driving behavior of a large sample of drivers who were exposed to two digital billboards on a segment of highway largely free from extraneous signage. Results show a significant shift in the number and length of glances toward the billboards and an increased percentage of time glancing off road in their presence. Findings were particularly evident at the time the billboards transitioned between advertisements. Since rapidly changing stimuli are difficult to ignore, the planned increase in episodically changing digital displays near the roadway may be argued to be a potential safety concern. The impact of digital billboards on driver safety and the need for continued research are discussed. PMID- 26745269 TI - Resistant Starch Alters the Microbiota-Gut Brain Axis: Implications for Dietary Modulation of Behavior. AB - The increasing recognition that the gut microbiota plays a central role in behavior and cognition suggests that the manipulation of microbial taxa through diet may provide a means by which behavior may be altered in a reproducible and consistent manner in order to achieve a beneficial outcome for the host. Resistant starch continues to receive attention as a dietary intervention that can benefit the host through mechanisms that include altering the intestinal microbiota. Given the interest in dietary approaches to improve health, the aim of this study was to investigate whether the use of dietary resistant starch in mice to alter the gut microbiota also results in a change in behavior. Forty eight 6 week-old male Swiss-Webster mice were randomly assigned to 3 treatment groups (n = 16 per group) and fed either a normal corn starch diet (NCS) or diets rich in resistant starches HA7 diet (HA7) or octenyl-succinate HA7 diet (OS-HA7) for 6 week and monitored for weight, behavior and fecal microbiota composition. Animals fed an HA7 diet displayed comparable weight gain over the feeding period to that recorded for NCS-fed animals while OS-HA7 displayed a lower weight gain as compared to either NCS or HA7 animals (ANOVA p = 0.0001; NCS:HA7 p = 0.244; HA7:OS-HA7 p<0.0001; NCS:OS-HA7 p<0.0001). Analysis of fecal microbiota using 16s rRNA gene taxonomic profiling revealed that each diet corresponded with a unique gut microbiota. The distribution of taxonomic classes was dynamic over the 6 week feeding period for each of the diets. At the end of the feeding periods, the distribution of taxa included statistically significant increases in members of the phylum Proteobacteria in OS-HA7 fed mice, while the Verrucomicrobia increased in HA7 fed mice over that of mice fed OS-HA7. At the class level, members of the class Bacilli decreased in the OS-HA7 fed group, and Actinobacteria, which includes the genus Bifidobacteria, was enriched in the HA7 fed group compared to the control diet. Behavioral analysis revealed that animals demonstrated profound anxiety-like behavior as observed by performance on the elevated-plus maze with time spent by the mice in the open arm (ANOVA p = 0.000; NCS:HA7 p = 0.004; NCS:OS-HA7 p = 1.000; HA7:OS-HA7 p = 0.0001) as well as entries in the open arm (ANOVA p = 0.039; NCS:HA7 p = 0.041; HA7:OS-HA7 p = 0.221; NCS:OS-HA7 p = 1.000). Open-field behavior, a measure of general locomotion and exploration, revealed statistically significant differences between groups in locomotion as a measure of transitions across quadrant boundaries. Additionally, the open-field assay revealed decreased exploration as well as decreased rearing in HA7 and OS-HA7 fed mice demonstrating a consistent pattern of increased anxiety-like behavior among these groups. Critically, behavior was not correlated with weight. These results indicate that diets based on resistant starch can be utilized to produce quantifiable changes in the gut microbiota and should be useful to "dial-in" a specific microbiome that is unique to a particular starch composition. However, undesirable effects can also be associated with resistant starch, including lack of weight gain and increased anxiety-like behaviors. These observations warrant careful consideration when developing diets rich in resistant starch in humans and animal models. PMID- 26745270 TI - Neuropeptide-Driven Cross-Modal Plasticity following Sensory Loss in Caenorhabditis elegans. AB - Sensory loss induces cross-modal plasticity, often resulting in altered performance in remaining sensory modalities. Whereas much is known about the macroscopic mechanisms underlying cross-modal plasticity, only scant information exists about its cellular and molecular underpinnings. We found that Caenorhabditis elegans nematodes deprived of a sense of body touch exhibit various changes in behavior, associated with other unimpaired senses. We focused on one such behavioral alteration, enhanced odor sensation, and sought to reveal the neuronal and molecular mechanisms that translate mechanosensory loss into improved olfactory acuity. To this end, we analyzed in mechanosensory mutants food-dependent locomotion patterns that are associated with olfactory responses and found changes that are consistent with enhanced olfaction. The altered locomotion could be reversed in adults by optogenetic stimulation of the touch receptor (mechanosensory) neurons. Furthermore, we revealed that the enhanced odor response is related to a strengthening of inhibitory AWC->AIY synaptic transmission in the olfactory circuit. Consistently, inserting in this circuit an engineered electrical synapse that diminishes AWC inhibition of AIY counteracted the locomotion changes in touch-deficient mutants. We found that this cross-modal signaling between the mechanosensory and olfactory circuits is mediated by neuropeptides, one of which we identified as FLP-20. Our results indicate that under normal function, ongoing touch receptor neuron activation evokes FLP-20 release, suppressing synaptic communication and thus dampening odor sensation. In contrast, in the absence of mechanosensory input, FLP-20 signaling is reduced, synaptic suppression is released, and this enables enhanced olfactory acuity; these changes are long lasting and do not represent ongoing modulation, as revealed by optogenetic experiments. Our work adds to a growing literature on the roles of neuropeptides in cross-modal signaling, by showing how activity dependent neuropeptide signaling leads to specific cross-modal plastic changes in neural circuit connectivity, enhancing sensory performance. PMID- 26745272 TI - Drinking and driving among Italian adolescents: Trends over seven years (2007 2013). AB - In recent years, increasing attention has been paid to the issue of driving under the influence of alcohol (DUI), especially among young people. The aims of the present study were (1) to analyse the trends of DUI, riding with a driver under influence of alcohol (RWDUI) and alcohol-related road crashes (A-rC) in a nationally representative sample of students in the period 2007-2013, (2) to assess how different drinking patterns were associated with DUI and RWDUI, (3) to evaluate other influential factors (such as gender, older siblings' and friends' behaviour with alcohol) on DUI and RWDUI. Data were drawn from the cross sectional European School Survey Project on Alcohol and Other Drugs (ESPAD) carried out annually in Italy. The sample size ranged from 25,555 to 40,390 students (15-19 years old). Results were stratified for students <18 years and >=18 years old. Although a significant decreasing trend for alcohol consumption was observed only in the younger group, a significant decrease in DUI [APC (annual percent change) -9.7 in the younger and -6.4 in the older group] and in RWDUI (APC -6.7 in the younger and -4.8 in the older group) was detected. A significant decreasing trend of A-rC was observed only in the older group (APC 3.4). Three specific drinking patterns were identified: "Drinking to Excess" (DE), "Drinking with Intoxication" (DI) and "Drinking but Not to Excess" (DNE). In both age groups, the DE pattern significantly increased the likelihood of DUI, whereas the DI pattern was negatively associated, and the DNE pattern was not associated. Different results were found for RWDUI: the DE and DI patterns where significantly associated with RWDUI, whereas the DNE pattern was negatively associated. Overall, illegal substance use, parental monitoring, peers' and siblings' influence were associated with DUI and RWDUI. The change in behaviour towards DUI and RWDUI suggests a cumulative effectiveness of current alcohol policies, although further actions (greater attention to social context, law enforcement, and promotion of good practice) are needed to substantially reduce alcohol-related crashes. PMID- 26745273 TI - The odds of wrong-way crashes and resulting fatalities: A comprehensive analysis. AB - The United States of America and other nations are grappling with the incidence of wrong-way driving (WWD). The issue is as important today (NTSB, 2012) as it was a half-century ago (Hulbert and Beers, 1966). In the absence of a comprehensive analysis, any effort to implement WWD countermeasures can be counterproductive. Hence, this effort began with the express intent to identify the factors that cause WWD crashes and fatalities. This work is sizeable in that it evaluated one million complete crash records from Florida. The methodology comprised (a) administering a survey on the perceptions about WWD; (b) developing binomial logistic models for computing the odds of WWD crashes, and of fatal crashes within the WWD space; (c) analyzing the contributing variables; and (d) comparing perceptions with crash analysis results. The study parameters included driver's age, gender, licensing state, physical defect, blood alcohol concentration, vehicle use, seatbelt compliance, day and time of crash, roadway lighting, facility type, weather conditions, road geometrics, and traffic volumes. Individual variable analysis of 23 parameters and the model development process included the determination of odds ratios and statistical tests for the predictive power and goodness-of-fit. The results of this work are generally consistent with expectation, yet surprising at times. This work concludes with decision-making inputs to the scientist, policy-maker and practitioner on the need for effectively engineering the roads, actively educating people about wrong way driving, and strictly enforcing traffic laws, rules and regulations. PMID- 26745274 TI - Comparison of methods for auto-coding causation of injury narratives. AB - Manually reading free-text narratives in large databases to identify the cause of an injury can be very time consuming and recently, there has been much work in automating this process. In particular, the variations of the naive Bayes model have been used to successfully auto-code free text narratives describing the event/exposure leading to the injury of a workers' compensation claim. This paper compares the naive Bayes model with an alternative logistic model and found that this new model outperformed the naive Bayesian model. Further modest improvements were found through the addition of sequences of keywords in the models as opposed to consideration of only single keywords. The programs and weights used in this paper are available upon request to researchers without a training set wishing to automatically assign event codes to large data-sets of text narratives. The utility of sharing this program was tested on an outside set of injury narratives provided by the Bureau of Labor Statistics with promising results. PMID- 26745275 TI - A Genetic Screen for Mutations Affecting Cell Division in the Arabidopsis thaliana Embryo Identifies Seven Loci Required for Cytokinesis. AB - Cytokinesis in plants involves the formation of unique cellular structures such as the phragmoplast and the cell plate, both of which are required to divide the cell after nuclear division. In order to isolate genes that are involved in de novo cell wall formation, we performed a large-scale, microscope-based screen for Arabidopsis mutants that severely impair cytokinesis in the embryo. We recovered 35 mutations that form abnormally enlarged cells with multiple, often polyploid nuclei and incomplete cell walls. These mutants represent seven genes, four of which have previously been implicated in phragmoplast or cell plate function. Mutations in two loci show strongly reduced transmission through the haploid gametophytic generation. Molecular cloning of both corresponding genes reveals that one is represented by hypomorphic alleles of the kinesin-5 gene RADIALLY SWOLLEN 7 (homologous to tobacco kinesin-related protein TKRP125), and that the other gene corresponds to the Arabidopsis FUSED ortholog TWO-IN-ONE (originally identified based on its function in pollen development). No mutations that completely abolish the formation of cross walls in diploid cells were found. Our results support the idea that cytokinesis in the diploid and haploid generations involve similar mechanisms. PMID- 26745276 TI - Trypanosoma cruzi Experimental Infection Impacts on the Thymic Regulatory T Cell Compartment. AB - The dynamics of regulatory T cells in the course of Trypanosoma cruzi infection is still debated. We previously demonstrated that acute murine T. cruzi infection results in an impaired peripheral CD4+Foxp3+ T cell differentiation due to the acquisition of an abnormal Th1-like phenotype and altered functional features, negatively impacting on the course of infection. Moreover, T. cruzi infection induces an intense thymic atrophy. As known, the thymus is the primary lymphoid organ in which thymic-derived regulatory T cells, known as tTregs, differentiate. Considering the lack of available data about the effect of T. cruzi infection upon tTregs, we examined tTreg dynamics during the course of disease. We confirmed that T. cruzi infection induces a marked loss of tTreg cell number associated to cell precursor exhaustion, partially avoided by glucocorticoid ablation- and IL-2 survival factor depletion. At the same time, tTregs accumulate within the CD4 single-positive compartment, exhibiting an increased Ki-67/Annexin V ratio compared to controls. Moreover, tTregs enhance after the infection the expression of signature markers (CD25, CD62L and GITR) and they also display alterations in the expression of migration-associated molecules (alpha chains of VLAs and chemokine receptors) such as functional fibronectin-driven migratory disturbance. Taken together, we provide data demonstrating profound alterations in tTreg compartment during acute murine T. cruzi infection, denoting that their homeostasis is significantly affected. The evident loss of tTreg cell number may compromise the composition of tTreg peripheral pool, and such sustained alteration over time may be partially related to the immune dysregulation observed in the chronic phase of the disease. PMID- 26745278 TI - Correction: 1-Methyl-4-Phenylpyridinium Stereotactic Infusion Completely and Specifically Ablated the Nigrostriatal Dopaminergic Pathway in Rhesus Macaque. PMID- 26745277 TI - Social Factors Influencing Child Health in Ghana. AB - OBJECTIVES: Social factors have profound effects on health. Children are especially vulnerable to social influences, particularly in their early years. Adverse social exposures in childhood can lead to chronic disorders later in life. Here, we sought to identify and evaluate the impact of social factors on child health in Ghana. As Ghana is unlikely to achieve the Millennium Development Goals' target of reducing child mortality by two-thirds between 1990 and 2015, we deemed it necessary to identify social determinants that might have contributed to the non-realisation of this goal. METHODS: ScienceDirect, PubMed, MEDLINE via EBSCO and Google Scholar were searched for published articles reporting on the influence of social factors on child health in Ghana. After screening the 98 articles identified, 34 of them that met our inclusion criteria were selected for qualitative review. RESULTS: Major social factors influencing child health in the country include maternal education, rural-urban disparities (place of residence), family income (wealth/poverty) and high dependency (multiparousity). These factors are associated with child mortality, nutritional status of children, completion of immunisation programmes, health-seeking behaviour and hygiene practices. CONCLUSIONS: Several social factors influence child health outcomes in Ghana. Developing more effective responses to these social determinants would require sustainable efforts from all stakeholders including the Government, healthcare providers and families. We recommend the development of interventions that would support families through direct social support initiatives aimed at alleviating poverty and inequality, and indirect approaches targeted at eliminating the dependence of poor health outcomes on social factors. Importantly, the expansion of quality free education interventions to improve would-be-mother's health knowledge is emphasised. PMID- 26745280 TI - Monothermal Caloric Screening to Improve Healthcare Value. AB - OBJECTIVES: To evaluate whether monothermal caloric screening can reduce the number of caloric irrigations required in the vestibular testing battery while maintaining diagnostic accuracy. DESIGN: Prospective controlled cohort study. Three hundred and ninety patients referred for vestibular testing at this tertiary referral health system over a 1-year period were evaluated; 24 patients met exclusion or failure criteria and 366 patients were included in the study. Population was 35.6% male; average age was 50.4 years old. Each patient underwent caloric testing using either warm or cool water irrigation initially and this data was used for monothermal screening data. All patients then completed bithermal binaural caloric testing to obtain the "gold standard" bithermal data for comparison. The sensitivity and specificity of monothermal cool or monothermal warm caloric tests were calculated using a receiver operating characteristic curve analysis. RESULTS: Using a monothermal interear difference threshold of 25%, warm monothermal screening had sensitivity of 98.0%, specificity of 91.3%, false negative rate of 2%, and false positive rate of 8.7%. Cool monothermal screening also had excellent sensitivity (92.3%) and specificity (95.3)%, with a false negative rate of 7.7%, and a false positive rate of 4.7%. The diagnosis associated with the single false negative warm monothermal caloric test was compensated vestibular paresis. In the study population, 71.9% had a negative monothermal screen; if the monothermal data were accepted, 2 fewer irrigations would have been performed resulting in an average saving of $264 (typical Medicare reimbursement for 2 irrigations) billed per patient screened as well as shortening the average testing battery by about 15 min. CONCLUSIONS: Warm monothermal caloric screening can reduce time and cost of vestibular testing while nearly matching the diagnostic accuracy of bithermal testing. PMID- 26745282 TI - Controllable defluorination of fluorinated graphene and weakening of C-F bonding under the action of nucleophilic dipolar solvent. AB - The effect of solvent on the chemical structure and properties of fluorinated graphene (FG) was particularly investigated in this work. It is found that the reduction of FG and the weakening of strong covalent C-F bonding take place under the action of some dipolar solvents even at room temperature. The rate of the C-F bond rupture reaction is positively influenced by the dipole moment of solvent and fluorine coverage of FG sheets. Meanwhile, defluorination of FG is controllable through the time and temperature of solvent treatment. These solvents function as the nucleophilic catalysts, promoting chemical transformation, which leads to a series of changes in the structure and properties of FG, such as a decline of fluorine concentration of about 40% and the reduction of thermal stability and band gap from 3 to 2 eV. After the treatment with dipolar solvent N-methyl-2-pyrrolidinone, FG maintained a capacity of 255 mA h g(-1) and a power density of 2986 W kg(-1) at a high discharge rate, while the pristine FG could not be discharged at all. This is called the "solvent activation" effect on the electrochemical performance of FG. The finding may draw attention to the effect of various external factors on the chemical structure and properties of FG, which is of great importance for the realization of the FG's potential. PMID- 26745279 TI - Coaxial Microincision Cataract Surgery versus Standard Coaxial Small-Incision Cataract Surgery: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: We conducted this meta-analysis to compare the outcomes of coaxial microincision cataract surgery (C-MICS) and standard coaxial small incision cataract surgery (C-SICS). METHODS: The outcomes of randomized controlled trials (RCTs) reporting C-MICS and C-SICS were collected from PubMed, Web of Science, and The Cochrane Library in May 2015. The final meta-analysis was conducted on the following intraoperative and postoperative outcomes: ultrasound time (UST), effective phacoemulsification time (EPT), balanced salt solution use (BSS use), cumulative dissipated energy (CDE), mean surgery time, endothelial cell loss percentage (ECL%), best corrected visual acuity (BCVA), increased central corneal thickness (CCT), laser flare photometry values and surgically induced astigmatism (SIA). RESULTS: A total of 15 RCTs, involving 1136 eyes, were included in the final meta-analysis. No significant between-group differences were detected in EPT, BSS use, CDE, BCVA, laser flare photometry values or increased CCT. However, the C-MICS group showed less SIA (at postoperative day 7: p<0.01; at postoperative day 30 or more: p<0.01) and greater ECL% (at postoperative day 60 or more: p<0.01), whereas the C-SICS group required a shorter UST (p<0.01). CONCLUSIONS: The present meta-analysis suggested that the C-MICS technique was more advantageous than C-SICS in terms of SIA, but C-MICS required a longer UST and induced a higher ECL%. Further studies should be done to confirm our results. PMID- 26745284 TI - 6-Methylpurine derived sugar modified nucleosides: Synthesis and evaluation of their substrate activity with purine nucleoside phosphorylases. AB - 6-Methylpurine (MeP) is cytotoxic adenine analog that does not exhibit selectivity when administered systemically, and could be very useful in a gene therapy approach to cancer treatment involving Escherichia coli PNP. The prototype MeP releasing prodrug, 9-(beta-d-ribofuranosyl)-6-methylpurine, MeP-dR has demonstrated good activity against tumors expressing E. coli PNP, but its antitumor activity is limited due to toxicity resulting from the generation of MeP from gut bacteria. Therefore, we have embarked on a medicinal chemistry program to identify non-toxic MeP prodrugs that could be used in conjunction with E. coli PNP. In this work, we report on the synthesis of 9-(6-deoxy-beta-d allofuranosyl)-6-methylpurine (3) and 9-(6-deoxy-5-C-methyl-beta-d-ribo hexofuranosyl)-6-methylpurine (4), and the evaluation of their substrate activity with several phosphorylases. The glycosyl donors; 1,2-di-O-acetyl-3,5-di-O-benzyl alpha-d-allofuranose (10) and 1-O-acetyl-3-O-benzyl-2,5-di-O-benzoyl-6-deoxy-5-C methyl-beta-d-ribohexofuran-ose (15) were prepared from 1,2:5,6-di-O isopropylidine-alpha-d-glucofuranose in 9 and 11 steps, respectively. Coupling of 10 and 15 with silylated 6-methylpurine under Vorbruggen glycosylation conditions followed conventional deprotection of the hydroxyl groups furnished 5'-C methylated-6-methylpurine nucleosides 3 and 4, respectively. Unlike 9-(6-deoxy alpha-l-talo-furanosyl)-6-methylpurine, which showed good substrate activity with E. coli PNP mutant (M64V), the beta-d-allo-furanosyl derivative 3 and the 5'-di-C methyl derivative 4 were poor substrates for all tested glycosidic bond cleavage enzymes. PMID- 26745281 TI - Quantitative Phosphoproteomics Analysis of ERBB3/ERBB4 Signaling. AB - The four members of the epidermal growth factor receptor (EGFR/ERBB) family form homo- and heterodimers which mediate ligand-specific regulation of many key cellular processes in normal and cancer tissues. While signaling through the EGFR has been extensively studied on the molecular level, signal transduction through ERBB3/ERBB4 heterodimers is less well understood. Here, we generated isogenic mouse Ba/F3 cells that express full-length and functional membrane-integrated ERBB3 and ERBB4 or ERBB4 alone, to serve as a defined cellular model for biological and phosphoproteomics analysis of ERBB3/ERBB4 signaling. ERBB3 co expression significantly enhanced Ba/F3 cell proliferation upon neuregulin-1 (NRG1) treatment. For comprehensive signaling studies we performed quantitative mass spectrometry (MS) experiments to compare the basal ERBB3/ERBB4 cell phosphoproteome to NRG1 treatment of ERBB3/ERBB4 and ERBB4 cells. We employed a workflow comprising differential isotope labeling with mTRAQ reagents followed by chromatographic peptide separation and final phosphopeptide enrichment prior to MS analysis. Overall, we identified 9686 phosphorylation sites which could be confidently localized to specific residues. Statistical analysis of three replicate experiments revealed 492 phosphorylation sites which were significantly changed in NRG1-treated ERBB3/ERBB4 cells. Bioinformatics data analysis recapitulated regulation of mitogen-activated protein kinase and Akt pathways, but also indicated signaling links to cytoskeletal functions and nuclear biology. Comparative assessment of NRG1-stimulated ERBB4 Ba/F3 cells revealed that ERBB3 did not trigger defined signaling pathways but more broadly enhanced phosphoproteome regulation in cells expressing both receptors. In conclusion, our data provide the first global picture of ERBB3/ERBB4 signaling and provide numerous potential starting points for further mechanistic studies. PMID- 26745285 TI - Exploring the thiazole scaffold for the identification of new agents for the treatment of fluconazole resistant Candida. AB - Cyclohexyliden- and 2-methylcyclohexyliden-hydrazo-4-arylthiazoles were synthesized and tested as antifungal agents. All compounds exhibited minimal inhibitory concentration (MIC) values comparable with those of fluconazole (FLC). Moreover, some compounds showed fungicidal activity at low concentration. Worth noting five out of nine compounds were active towards Candida albicans 25 FLC resistant isolated from clinical specimens. The cellular toxicity was evaluated and none of the compounds is toxic at the MIC. On the basis of our data we can conclude that these derivatives are promising agents for the treatment of resistant C. albicans. PMID- 26745286 TI - Enhanced Conductivity in CZTS/Cu(2-x)Se Nanocrystal Thin Films: Growth of a Conductive Shell. AB - Poor charge transport in Cu2ZnSnS4 (CZTS) nanocrystal (NC) thin films presents a great challenge in the fabrication of solar cells without postannealing treatments. We introduce a novel approach to facilitate the charge carrier hopping between CZTS NCs by growing a stoichiometric Cu2Se shell that can be oxidized to form a conductive Cu2-xSe phase when exposed to air. The CZTS/Cu2Se core/shell NCs with varying numbers of shell monolayers were synthesized by the successive ionic layer adsorption and reaction (SILAR) method, and the variation in structural and optical properties of the CZTS NCs with varying shell thicknesses was investigated. Solid-phase sulfide ligand exchange was employed to fabricate NC thin films by layer-by-layer dip coating and a 2 orders of magnitude rise in dark conductivity (~10(-3) S cm(-1) at 0 monolayer and ~10(-1) S cm(-1) at 1.5 monolayers) was observed with an increase in the number of shell monolayers. The approach described herein is the first key step in achieving a significant increase in the photoconductivity of as-deposited CZTS NC thin films. PMID- 26745287 TI - Effect of heterogeneity and anisotropy related to the construction method on transfer processes in waste rock piles. AB - Waste rock piles producing acid mine drainage (AMD) are partially saturated systems involving multiphase (gas and liquid) flow and coupled transfer processes. Their internal structure and heterogeneous properties are inherited from their wide-ranging material grain sizes, their modes of deposition, and the underlying topography. This paper aims at assessing the effect of physical heterogeneity and anisotropy of waste rock piles on the physical processes involved in the generation of AMD. Generic waste rock pile conditions were represented with the numerical simulator TOUGH AMD based on those found at the Doyon mine waste rock pile (Canada). Models included four randomly distributed material types (coarse, intermediate, fine and very fine-grained). The term "randomly" as used in this study means that the vertical profile and spatial distribution of materials in waste rock piles (internal structure) defy stratigraphy principles applicable to natural sediments (superposition and continuity). The materials have different permeability and capillary properties, covering the typical range of materials found in waste rock piles. Anisotropy with a larger horizontal than vertical permeability was used to represent the effect of pile construction by benches, while the construction by end-dumping was presumed to induce a higher vertical than horizontal permeability. Results show that infiltrated precipitation preferentially flows in fine-grained materials, which remain almost saturated, whereas gas flows preferentially through the most permeable coarse materials, which have higher volumetric gas saturation. Anisotropy, which depends on pile construction methods, often controls global gas flow paths. Construction by benches favours lateral air entry close to the pile slope, whereas end-dumping leads to air entry from the surface to the interior of the pile by secondary gas convection cells. These results can be useful to construct and rehabilitate waste rock piles to minimize AMD, while controlling gas flow and oxygen supply. PMID- 26745288 TI - A knowledge-based approach to estimating the magnitude and spatial patterns of potential threats to soil biodiversity. AB - Because of the increasing pressures exerted on soil, below-ground life is under threat. Knowledge-based rankings of potential threats to different components of soil biodiversity were developed in order to assess the spatial distribution of threats on a European scale. A list of 13 potential threats to soil biodiversity was proposed to experts with different backgrounds in order to assess the potential for three major components of soil biodiversity: soil microorganisms, fauna, and biological functions. This approach allowed us to obtain knowledge based rankings of threats. These classifications formed the basis for the development of indices through an additive aggregation model that, along with ad hoc proxies for each pressure, allowed us to preliminarily assess the spatial patterns of potential threats. Intensive exploitation was identified as the highest pressure. In contrast, the use of genetically modified organisms in agriculture was considered as the threat with least potential. The potential impact of climate change showed the highest uncertainty. Fourteen out of the 27 considered countries have more than 40% of their soils with moderate-high to high potential risk for all three components of soil biodiversity. Arable soils are the most exposed to pressures. Soils within the boreal biogeographic region showed the lowest risk potential. The majority of soils at risk are outside the boundaries of protected areas. First maps of risks to three components of soil biodiversity based on the current scientific knowledge were developed. Despite the intrinsic limits of knowledge-based assessments, a remarkable potential risk to soil biodiversity was observed. Guidelines to preliminarily identify and circumscribe soils potentially at risk are provided. This approach may be used in future research to assess threat at both local and global scale and identify areas of possible risk and, subsequently, design appropriate strategies for monitoring and protection of soil biota. PMID- 26745289 TI - Multigenerational effects of the anticancer drug tamoxifen and its metabolite 4 hydroxy-tamoxifen on Daphnia pulex. AB - Tamoxifen and its metabolite 4-hydroxy-tamoxifen (4OHTam) are two potent molecules that have anticancer properties on breast cancers. Their medical use is expected to increase with the increasing global cancer rate. After consumption, patients excrete tamoxifen and the 4OHTam metabolite into wastewaters, and tamoxifen has been already detected in wastewaters and natural waters. The concentrations of 4OHTam in waters have never been reported. A single study reported 4OHTam effects on the microcrustacean Daphnia pulex. The effects of tamoxifen and 4OHTam over more than two generations are unknown in aquatic invertebrates. The main goal of this study was to assess the long-term sensitivity of the microcrustacean D. pulex over four generations, based on size, reproduction, viability and the intrinsic rate of natural increase (r). Additional experiments were carried out to observe whether the effects of tamoxifen and 4OHTam were reversible in the next generation after descendants were withdrawn from chemical stress (i.e., recovery experiment), and whether the lowest test concentration of each chemical induced toxic effects when both concentrations were combined (i.e., mixture experiments). Our results showed that tamoxifen and 4OHTam induced the adverse effects at environmentally relevant concentrations. Tamoxifen and 4OHTam impaired size, viability, reproduction and the r in four generations of treated D. pulex, but these effects were not clearly magnified over generations. Tamoxifen was more potent than 4OHTam on D. pulex. When used in a mixture, the combination of tamoxifen and 4OHTam induced effects in offspring, whereas no effects were observed when these chemicals were tested individually. In the recovery experiment, the reproduction and size were reduced in offspring withdrawn from chemical exposures. Our results suggested that tamoxifen and its metabolite may be a relevant pharmaceutical to consider in risk assessment. PMID- 26745290 TI - Carbon storage potential in size-density fractions from semi-natural grassland ecosystems with different productivities over varying soil depths. AB - Researchers have increasingly recognised a profound need for more information on SOC stocks in the soil and the factors governing their stability and dynamics. Many questions still remain unanswered about the interplay between changes in plant communities and the extent to which changes in aboveground productivity affect the carbon dynamics in soils through changes in its quantity and quality. Therefore, the main aim of this research was to examine the SOC accumulation potential of semi-natural grasslands of different productivities and determine the distribution of SOM fractions over varying soil depth intervals (0-10, 10-20, 20-30 30-50 50-80 and 80+cm). SOM fractionation was considered as a relative measure of stability to separate SOM associated with clay minerals from SOM of specific light densities less than 2 g cm(-3) (size-density fractionation). Two clay-associated fractions (CF1, <1 MUm; and CF2, 1-2 MUm) and two light fractions (LF1, <1.8 g cm(-3); and LF2, 1.8-2.0 g cm(-3)) were separated. The stability of these fractions was characterised by their carbon hot water extractability (CHWE) and stable carbon isotope composition. In the semi-natural grasslands studied, most OC was stored in the top 30 cm, where turnover is rapid. Effects of low productivity grasslands became only significantly apparent when fractional OC contributions of total SOM was considered (CF1 and LF1). In deeper soil depths OC was largely attributed to the CF1 fraction of low productivity grasslands. We suggest that the majority of OM in deeper soil depth intervals is microbially derived, as evidenced by decreasing C/N ratios and decreasing delta(13)C values. The hot water extraction and natural delta(13)C abundance, employed here allowed the characterisation of SOM stabilisation properties, however how climatic changes affect the fate of OM within different soil depth intervals is still unknown. PMID- 26745291 TI - Physico-chemical characteristics of topsoil for contrasted forest, agricultural, urban and industrial land uses in France. AB - Soil quality is related to soil characteristics such as fertility and contamination. The aim of this study is to assess the effect of land use on these soil characteristics and to confirm the following anthropisation gradient: (i) forest, (ii) grassland, (iii) cultivated, (iv) orchard and vineyard, (v) urban vegetable garden, and (vi) SUITMA (urban, industrial, traffic, mining and military areas). A database comprising the characteristics of 2451 soils has been constituted. In order to compare the topsoils from six contrasting land uses, a principal components analysis (PCA) was performed on nine geochemical variables (C, N, pH, POlsen, total Cd, Cu, Ni, Pb, Zn). The first axis of the PCA is interpreted as a global increase of topsoil metallic elements along the anthropisation gradient. Axis 2 reflects the variability of fertility levels. Human activity increases the pressure on soils along the proposed gradient according to six different distribution patterns. This better knowledge of topsoil quality and its dependence on current land use should therefore help to manage and preserve the soil mantle. PMID- 26745292 TI - Adsorption and degradation of five selected antibiotics in agricultural soil. AB - Large quantities of antibiotics are being added to agricultural fields worldwide through the application of wastewater, manures and biosolids, resulting in antibiotic contamination and elevated environmental risks in terrestrial environments. Most studies on the environmental fate of antibiotics focus on aquatic environments or wastewater treatment plants. Little is known about the behavior of antibiotics at environmentally relevant concentrations in agricultural soil. In this study we evaluated the adsorption and degradation of five different antibiotics (tetracycline, sulfamethazine, norfloxacin, erythromycin, and chloramphenicol) in sterilized and non-sterilized agricultural soils under aerobic and anaerobic conditions. Adsorption was highest for tetracycline (Kd, 1093 L/kg), while that for sulfamethazine was negligible (Kd, 1.365 L/kg). All five antibiotics were susceptible to microbial degradation under aerobic conditions, with half-lives ranging from 2.9 to 43.3 d in non-sterilized soil and 40.8 to 86.6 d in sterilized soil. Degradation occurred at a higher rate under aerobic conditions but was relatively persistent under anaerobic conditions. For all the antibiotics, a higher initial concentration was found to slow down degradation and prolong persistence in soil. The degradation behavior of the antibiotics varied in relation to their physicochemical properties as well as the microbial activities and aeration of the recipient soil. The poor adsorption and relative persistence of sulfamethazine under both aerobic and anaerobic conditions suggest that it may pose a higher risk to groundwater quality. An equation was proposed to predict the fate of antibiotics in soil under different field conditions, and assess their risks to the environment. PMID- 26745293 TI - Dissolved inorganic carbon and stable carbon isotopic evolution of neutral mine drainage interacting with atmospheric CO2(g). AB - We investigated the spatial variations in the concentrations of dissolved inorganic carbon (DIC), the stable carbon isotopic composition (delta(13)C) of DIC and the delta(13)C of carbonate precipitated from neutral mine drainage interacting with the atmospheric CO2(g). We assessed the chemical, DIC and delta(13)CDIC evolution of the mine drainage and the delta(13)C evolution of carbonate precipitates for a distance of 562 m from the end of an 8 km tunnel that drains a mine. Our results show that as the mine drainage interacts with atmospheric CO2(g) the outgassing of CO2 due to the high initial partial pressure of CO2 (pCO2) causes the DIC to evolve under kinetic conditions followed by equilibration and then under equilibrium conditions. The carbonate evolution was characterized by spatial increases in pH, decreasing concentrations of Ca(2+) and DIC and by the precipitation of carbonate. The delta(13)CDIC showed a larger enrichment from the tunnel exit to 38 m, moderate continuous enrichment to 318 m and almost no enrichment to 562 m. On the other hand, the delta(13)C of the carbonate precipitates also showed large enrichment from the tunnel exit to 38 m, moderate enrichment to 318 m after which the delta(13)C remained nearly constant. The enrichment in the delta(13)C of the DIC and the carbonate precipitates from 0 to 38 m from kinetic fractionation caused by CO2(g) outgassing was followed by a mix of kinetic fractionation and equilibrium fractionation controlled by carbon exchange between DIC and atmospheric CO2(g) to 318 m and then by equilibrium fractionation from 318 to 562 m. From the carbonate evolution in this neutral mine drainage, we estimated that 20% of the carbon was lost via CO2 outgassing, 12% was sequestered in sediments in the drainage ponds from calcite precipitation and the remainder 68% was exported to the local stream. PMID- 26745294 TI - Probabilistic modeling of the flows and environmental risks of nano-silica. AB - Nano-silica, the engineered nanomaterial with one of the largest production volumes, has a wide range of applications in consumer products and industry. This study aimed to quantify the exposure of nano-silica to the environment and to assess its risk to surface waters. Concentrations were calculated for four environmental (air, soil, surface water, sediments) and two technical compartments (wastewater, solid waste) for the EU and Switzerland using probabilistic material flow modeling. The corresponding median concentration in surface water is predicted to be 0.12 MUg/l in the EU (0.053-3.3 MUg/l, 15/85% quantiles). The concentrations in sediments in the complete sedimentation scenario were found to be the largest among all environmental compartments, with a median annual increase of 0.43 mg/kg . y in the EU (0.19-12 mg/kg . y, 15/85% quantiles). Moreover, probabilistic species sensitivity distributions (PSSD) were computed and the risk of nano-silica in surface waters was quantified by comparing the predicted environmental concentration (PEC) with the predicted no effect concentration (PNEC) distribution, which was derived from the cumulative PSSD. This assessment suggests that nano-silica currently poses no risk to aquatic organisms in surface waters. Further investigations are needed to assess the risk of nano-silica in other environmental compartments, which is currently not possible due to a lack of ecotoxicological data. PMID- 26745295 TI - Direct contact between dust and HBCD-treated fabrics is an important pathway of source-to-dust transfer. AB - Hexabromocyclododecanes (HBCDs) are a class of brominated flame retardant that have found extensive application in consumer products used widely in indoor environments. Although uncertainty remains about the human health impacts of HBCDs, ingestion of HBCD-contaminated indoor dust has been shown to be a particularly significant exposure pathway for young children. Despite this, understanding of the mechanisms via which HBCD transfer from products to indoor dust remains incomplete. In this study, an in-house test chamber was used to investigate transfer of HBCDs from a treated textile sample to indoor dust via direct textile:dust contact. Results were compared with previous data using the same test chamber to examine other pathways via which HBCDs transfer from products to dust, and highlighted HBCD transfer via direct source:dust contact as being particularly important. This novel finding was corroborated by complementary experiments that examined HBCD transfer via direct contact, from other treated textiles to three major components of indoor dust: artificial indoor dust, soil particles, and cotton linters. PMID- 26745296 TI - Regional variation in the biogeochemical and physical characteristics of natural peatland pools. AB - Natural open-water pools are a common feature of northern peatlands and are known to be an important source of atmospheric methane (CH4). Pool environmental variables, particularly water chemistry, vegetation community and physical characteristics, have the potential to exert strong controls on carbon cycling in pools. A total of 66 peatland pools were studied across three regions of the UK (northern Scotland, south-west Scotland, and Northern Ireland). We found that within-region variability of pool water chemistry was low; however, for many pool variables measured there were significant differences between regions. PCA analysis showed that pools in SW Scotland were strongly associated with greater vegetative cover and shallower water depth which is likely to increase dissolved organic carbon (DOC) mineralisation rates, whereas pools in N Scotland were more open and deeper. Pool water DOC, particulate organic carbon and dissolved CH4 concentrations were significantly different between regions. Pools in Northern Ireland had the highest concentrations of DOC (mean=14.5 mg L(-1)) and CH4 (mean=20.6 MUg C L(-1)). Chloride and sulphate concentrations were significantly higher in the pools in N Scotland (mean values 26.3 and 2.40 mg L(-1), respectively) than elsewhere, due to a stronger marine influence. The ratio of UV absorbance at 465 nm to absorbance at 665 nm for pools in Northern Ireland indicated that DOC was sourced from poorly humified peat, potentially increasing the bioavailability and mineralisation of organic carbon in pools compared to the pools elsewhere. This study, which specifically aims to address a lack of basic biogeochemical knowledge about pool water chemistry, clearly shows that peatland pools are highly regionally variable. This is likely to be a reflection of significant regional-scale differences in peatland C cycling. PMID- 26745297 TI - Endotoxin, ergosterol, muramic acid and fungal DNA in dust from schools in Johor Bahru, Malaysia--Associations with rhinitis and sick building syndrome (SBS) in junior high school students. AB - This paper studied associations between ocular symptoms, rhinitis, throat and dermal symptoms, headache and fatigue in students by ethnicity and in relation to exposure to chemical microbial markers and fungal DNA in vacuumed dust in schools in Malaysia. A total of 462 students from 8 randomly selected secondary schools in Johor Bahru, Malaysia, participated (96% response rate). Dust was vacuumed from 32 classrooms and analysed for levels of five types of endotoxin as 3 hydroxy fatty acids (C10, C12, C14, C16 and C18 3-OH), muramic acid, ergosterol and five sequences of fungal DNA. Multiple logistic regression was applied. Totally 11.9% reported weekly ocular symptoms, 18.8% rhinitis, 15.6% throat and 11.1% dermal symptoms, 20.6% headache and 22.1% tiredness. Totally 21.1% reported pollen or furry pet allergy (atopy) and 22.0% parental asthma or allergy. Chinese students had less headache than Malay and Indian had less rhinitis and less tiredness than Malay. Parental asthma/allergy was a risk factor for ocular (odds ratio=3.79) and rhinitis symptoms (OR=3.48). Atopy was a risk factor for throat symptoms (OR=2.66), headache (OR=2.13) and tiredness (OR=2.02). There were positive associations between amount of fine dust in the dust samples and ocular symptoms (p<0.001) and rhinitis (p=0.006). There were positive associations between C14 3-OH and rhinitis (p<0.001) and between C18 3-OH and dermal symptoms (p=0.007). There were negative (protective) associations between levels of total endotoxin (LPS) (p=0.004) and levels of ergosterol (p=0.03) and rhinitis and between C12 3-OH and throat symptoms (p=0.004). In conclusion, the amount of fine dust in the classroom was associated with rhinitis and other SBS symptoms and improved cleaning of the schools is important. Endotoxin in the school dust seems to be mainly protective for rhinitis and throat symptoms but different types of endotoxin could have different effects. The ethnic differences in symptoms among the students deserve further attention. PMID- 26745298 TI - Lead pollution from waterfowl hunting in wetlands and rice fields in Argentina. AB - The pollution of wetlands by lead derived from waterfowl hunting with lead shot was investigated. We determined soil pellet density and Pb concentration in soil, water and vegetation in natural wetlands and rice fields in central-eastern Santa Fe province, Argentina. Pellet density varied greatly among hunting sites (between 5.5-141 pellets/m(2)) and pellets were present in some control sites. Soil Pb concentration in most hunting sites (approximately 10-20 mg kg(-1)) was not much higher than in control sites (~5-10 mg kg(-1)), with the exception of the site with highest pellet density, which also had a high Pb soil concentration. In water, on the other hand, Pb concentration was similar in all sites (~4-7 MUg L(-1)), both control and hunting, and higher than reference values for aquatic media. Lead was also present in vegetation, including grasses and rice crops, in almost all cases. Most soil-collection sites were slightly acidic, and were frequently flooded. These results strongly suggest that metallic Pb from spent shot is oxidized and dissolved due to wetland conditions. Thus, the pollutant is readily mobilized and distributed across all wetland areas, effectively homogenizing its concentration in locations with and without hunting activities. The replacement of lead by nontoxic materials in pellets appears to be the only effective way to prevent Pb pollution in wetlands. PMID- 26745299 TI - Elucidating hydraulic fracturing impacts on groundwater quality using a regional geospatial statistical modeling approach. AB - Hydraulic fracturing operations have been viewed as the cause of certain environmental issues including groundwater contamination. The potential for hydraulic fracturing to induce contaminant pathways in groundwater is not well understood since gas wells are completed while isolating the water table and the gas-bearing reservoirs lay thousands of feet below the water table. Recent studies have attributed ground water contamination to poor well construction and leaks in the wellbore annulus due to ruptured wellbore casings. In this paper, a geospatial model of the Barnett Shale region was created using ArcGIS. The model was used for spatial analysis of groundwater quality data in order to determine if regional variations in groundwater quality, as indicated by various groundwater constituent concentrations, may be associated with the presence of hydraulically fractured gas wells in the region. The Barnett Shale reservoir pressure, completions data, and fracture treatment data were evaluated as predictors of groundwater quality change. Results indicated that elevated concentrations of certain groundwater constituents are likely related to natural gas production in the study area and that beryllium, in this formation, could be used as an indicator variable for evaluating fracturing impacts on regional groundwater quality. Results also indicated that gas well density and formation pressures correlate to change in regional water quality whereas proximity to gas wells, by itself, does not. The results also provided indirect evidence supporting the possibility that micro annular fissures serve as a pathway transporting fluids and chemicals from the fractured wellbore to the overlying groundwater aquifers. PMID- 26745301 TI - Modelling the spatial and seasonal variability of water quality for entire river networks: Relationships with natural and anthropogenic factors. AB - We model the spatial and seasonal variability of three key water quality variables (water temperature and concentration of nitrates and phosphates) for entire river networks in a large area in northern Spain. Models were developed with the Random Forest technique, using 12 (water temperature and nitrate concentration) and 15 (phosphate concentration) predictor variables as descriptors of several environmental attributes (climate, topography, land-uses, hydrology and anthropogenic pressures). The effect of the different predictors on the response variables was assessed with partial dependence plots and partial correlation analysis. Results indicated that land-uses were important predictors in defining the spatial and seasonal patterns of these three variables. Water temperature was positively related with air temperature and the upstream drainage area, whereas increases in forest cover decreased water temperature. Nitrate concentration was mainly related to the area covered by agricultural land-uses, increasing in winter, probably because of catchment run-off processes. On the other hand, phosphate concentration was highly related to the area covered by urban land-uses in the upstream catchment and to the proximity of the closest upstream effluent. Phosphate concentration increased notably during the low flow period (summer), probably due to the reduction of the dilution capacity. These results provide a large-scale continuous picture of water quality, which could help identify the main sources of change in water quality and assist in the prioritization of river reaches for restoration projects. PMID- 26745300 TI - The Lower Danube River-Danube Delta-North West Black Sea: A pivotal area of major interest for the past, present and future of its fish fauna--A short review. AB - The complex Danube-Black Sea geoecosystem, created by a unique combination of integrated biotopes and biocoenoses related forces and counter-forces in time and space, forms a rich "ichthyosystem". The equilibrium among the fish species captured in the Danube Delta reveals its structural and functional roles in the connectivity of the Danube and Black Sea. The key role of the delta is evidenced by the fact that 57.26% of the Lower Danube-Danube Delta-North West Black Sea fish species use two or three of the subsystems in terms of habitats. Therefore, this convergence area can be considered to be a dynamic and rich "ichthyosystem", with three subsystems. All three evolved interdependently, which permits their flexibility and adaptation in an interdependent way. The habitat heterogeneity, native economic and conservation priority fish species of the Lower Danube-Danube Delta-North Western Black Sea have decreased significantly, and there are no indications that this trend will be halted soon. The Danube "sub-ichtyosystem" seems to be more directly affected than the others. The Lower Danube-Danube Delta North Western Black Sea "ichthyosystem" exhibits a significant level of flexibility, resilience and adaptation over geological time, but has become much more sensitive to environmental perturbations due to the last century of human impact. This "ichthyosystem" is affected by non-native fish species. The study area represents an interdependent ecological net, without which the specific "ichthyosystem" formed over geological time will disappear. The studied ecological net fish fauna is an accurate indicator of various human pressures. The Lower Danube-Danube Delta-North West Black Sea geoecosystem, in which the Danube Delta provides the pivotal habitat element, is the matrix for a unique "ichthyosystem." However, human impacts decrease its resilience and can induce its extinction. PMID- 26745302 TI - Toxicity assessment of atmospheric particulate matter in the Mediterranean and Black Seas open waters. AB - Atmospheric deposition of particulate matter (PM) is recognized as a relevant input vector for toxic compounds, such as polycyclic aromatic hydrocarbons (PAHs), into the marine environment. In this work we aimed to analyse the biological activity and potential adverse effects of PM constituents to aquatic organisms. Organic extracts of atmospheric PM samples from different sub-basins of the Mediterranean and Black Seas were screened using different toxicological tests. A yeast-based assay (AhR-RYA) revealed that dioxin-like activity correlated with the concentration of total PAHs in the PM samples, as well as with their predicted toxic equivalent values (TEQs). Although the zebrafish embryotoxicity test (the ZET assay) showed no major phenotypical adverse effects, up-regulation of mRNA expression of cyp1a, fos and development-related genes (previously described as related to PM toxicity) was observed in exposed embryos when compared to controls. Results showed that mRNA patterns of the studied genes followed a similar geographic distribution to both PAH content and dioxin-like activity of the corresponding extracts. The analysis also showed a distinct geographical pattern of activation of pancreatic markers previously related to airborne pollution, probably indicating a different subset of uncharacterized particle-bound toxicants. We propose the combination of the bioassays tested in the present study to be applied to future research with autochthonous species to assess exposure and potential toxic effects of ambient PM. The present study emphasizes the need for more in-depth studies into the toxic burden of atmospheric PM on aquatic ecosystems, in order to improve future regulatory guidelines. PMID- 26745303 TI - Erosion rills offset the efficacy of vegetated buffer strips to mitigate pesticide exposure in surface waters. AB - Regulatory risk assessment considers vegetated buffer strips as effective risk mitigation measures for the reduction of runoff-related pesticide exposure of surface waters. However, apart from buffer strip widths, further characteristics such as vegetation density or the presence of erosion rills are generally neglected in the determination of buffer strip mitigation efficacies. This study conducted a field survey of fruit orchards (average slope 3.1-12.2%) of the Lourens River catchment, South Africa, which specifically focused on the characteristics and attributes of buffer strips separating orchard areas from tributary streams. In addition, in-stream and erosion rill water samples were collected during three runoff events and GIS-based modeling was employed to predict losses of pesticides associated with runoff. The results show that erosion rills are common in buffer strips (on average 13 to 24 m wide) of the tributaries (up to 6.5 erosion rills per km flow length) and that erosion rills represent concentrated entry pathways of pesticide runoff into the tributaries during rainfall events. Exposure modeling shows that measured pesticide surface water concentrations correlated significantly (R(2)=0.626; p<0.001) with runoff losses predicted by the modeling approach in which buffer strip width was set to zero at sites with erosion rills; in contrast, no relationship between predicted runoff losses and in-stream pesticide concentrations were detected in the modeling approach that neglected erosion rills and thus assumed efficient buffer strips. Overall, the results of our study show that erosion rills may substantially reduce buffer strip pesticide retention efficacies during runoff events and suggest that the capability of buffer strips as a risk mitigation tool for runoff is largely overestimated in current regulatory risk assessment procedures conducted for pesticide authorization. PMID- 26745304 TI - Lower-limb amputation and effect of posttraumatic stress disorder on Department of Veterans Affairs outpatient cost trends. AB - Department of Veterans Affairs (VA) outpatient costs were analyzed for combat Veterans injured in Iraq and Afghanistan from 2001 to 2008. Patients had serious lower-limb injuries (n = 170) or unilateral (n = 460) or bilateral (n = 153) lower-limb amputation(s). Total costs over the follow-up period (2003 to 2012) and annual costs were analyzed. Unadjusted mean costs per year in 2012 U.S. dollars were $7,200, $14,700 and $18,700 for limb injuries and unilateral and bilateral lower-limb amputation(s), respectively (p < 0.001). Multivariate modeling indicated that annual cost declined after the first year in the VA for Veterans with limb injuries (p < 0.001, repeated measures). In contrast, annual costs doubled after 3-5 years with unilateral (p < 0.001) and bilateral amputation(s) (p < 0.001). Among amputees, prosthetics comprised more than 50% of outpatient cost; unadjusted mean cost per year for prosthetics was 7-9 times higher in comparison with Veterans with limb injuries. Amputation status was associated with an adjusted 3.12-fold increase in mean prosthetic cost per year (p < 0.001, generalized linear model). In addition, posttraumatic stress disorder (PTSD) was associated with increased prosthetic cost by amputation status (p < 0.001) and increased psychiatric and pharmacy costs (both p < 0.001). Results indicate relatively high and sustained outpatient costs driven by prosthetics following amputation. Finally, PTSD affected cost for multiple domains of health, highlighting the importance of accurate diagnosis, treatment, and support for PTSD. PMID- 26745305 TI - Strategies for incorporation of chia (Salvia hispanica L.) in frankfurters as a health-promoting ingredient. AB - Different strategies were examined for incorporation of chia flour (10%) and olive oil to improve the fat content in frankfurters. Nutritional composition, technological properties, sensory and microbiological analyses were studied as affected by the strategy used and by chilling storage. Chia increased total dietary fibre (98% insoluble dietary fibre) and minerals (K, Mg, Ca, Mn) irrespective of the incorporation strategy. Fat and energy content reduction (>26%) were achieved in all frankfurters reformulated with chia and olive oil. Chia addition increased linolenic acid and reduced processing and purge in all samples. Lightness and redness of frankfurters were affected by the presence of chia, but there was no clear evidence of influence by the mode of addition. Frankfurter texture was influenced by the strategy used to incorporate chia and olive oil and by chilling storage. Samples were judged acceptable and contained low microorganism levels. Frankfurters containing chia were suitable for labelling with certain nutrition and health claims. PMID- 26745306 TI - Selection of a chitosan gelatin-based edible coating for color preservation of beef in retail display. AB - Chitosan gelatin-based coating films were applied to beef steaks, and their effects on color preservation and lipid oxidation during retail display were evaluated. Response surface methodology was used to model and describe the effects of different biopolymer concentrations (0 to 6% gelatin; 0.5 to 1.5% chitosan; and 0 to 12% glycerol based on dry gelatin+chitosan weight) in the coating film for optimizing the best combination for meat application. Film application reduced weight loss and lipid oxidation of the steaks after 5 days of storage, and films with higher gelatin concentrations were more effective. The percentage levels of different myoglobin-redox forms were not affected by coating, but myoglobin oxidation during retail display was reduced and the percentage of deoxymyoglobin increased with the gelatin content of the film. Steak color stability during retail display was promoted by film application; the steaks exhibited a darker, more intensely red color when coated in blends with higher gelatin and chitosan contents. Blends containing between 3% and 6% gelatin, between 0.5% and 1.0% chitosan and 6% glycerol exhibited the best results and provide a promising alternative to the preservation of beef in retail display. PMID- 26745308 TI - Stereoselective Synthesis of Diazabicyclic beta-Lactams through Intramolecular Amination of Unactivated C(sp(3))-H Bonds of Carboxamides by Palladium Catalysis. AB - An efficient C(sp(3))-H bond activation and intramolecular amination reaction via palladium catalysis at the beta-position of carboxyamides to make beta-lactams was described. The investigation of the substrate scope showed that the current reaction conditions favored activation of the beta-methylene group. Short sequences were developed for preparation of various diazabicyclic beta-lactam compounds with this method as the key step from chiral proline and piperidine derivatives. PMID- 26745309 TI - Witchcraft and Biopsychosocial Causes of Mental Illness: Attitudes and Beliefs About Mental Illness Among Health Professionals in Five Countries. AB - This study examines the intercorrelation of measures reflecting beliefs about and attitudes toward people with mental illness in a sample of health professionals (N = 902) from five countries: Brazil, China, Ghana, Nigeria, and the United States, and, more specifically, the association of beliefs in supernatural as contrasted with biopsychosocial causes of mental illness. Factor analysis of a 43 item questionnaire identified four factors favoring a) socializing with people with mental illness; b) normalizing their roles in society; c) belief in supernatural causes of mental illness (e.g., witchcraft, curses); and d) belief in biopsychosocial causes of mental illness. Unexpectedly, a hypothesized negative association between belief in supernatural and biopsychosocial causation of mental illness was not found. Belief in the biopsychosocial causation was weakly associated with less stigmatized attitudes towards socializing and normalized roles. PMID- 26745307 TI - Hippocampus ghrelin signaling mediates appetite through lateral hypothalamic orexin pathways. AB - Feeding behavior rarely occurs in direct response to metabolic deficit, yet the overwhelming majority of research on the biology of food intake control has focused on basic metabolic and homeostatic neurobiological substrates. Most animals, including humans, have habitual feeding patterns in which meals are consumed based on learned and/or environmental factors. Here we illuminate a novel neural system regulating higher-order aspects of feeding through which the gut-derived hormone ghrelin communicates with ventral hippocampus (vHP) neurons to stimulate meal-entrained conditioned appetite. Additional results show that the lateral hypothalamus (LHA) is a critical downstream substrate for vHP ghrelin mediated hyperphagia and that vHP ghrelin activated neurons communicate directly with neurons in the LHA that express the neuropeptide, orexin. Furthermore, activation of downstream orexin-1 receptors is required for vHP ghrelin-mediated hyperphagia. These findings reveal novel neurobiological circuitry regulating appetite through which ghrelin signaling in hippocampal neurons engages LHA orexin signaling. PMID- 26745310 TI - Pathways to Care for Patients With First-Episode Psychosis in Singapore. AB - In this study, we aim to describe the pathways to care for patients with first episode psychosis in Singapore. We analyzed data from 900 individuals accepted by the Singapore Early Psychosis Intervention Programme between 2007 and 2012. The most common first contacts were specialist care (59%), primary care (27%), and the police (12%). Multivariate regression models showed that first contact with services varied according to demographic variables and diagnosis. The duration of untreated psychosis, total number of contacts before referral, and rate of referral to the Early Psychosis Intervention Programme varied according to demographic and clinical variables and first contact. We hope that this information will enable clinicians, managers, and other service providers to target interventions to streamline referrals, reduce distress, and improve the treatment of young people with psychotic illnesses. PMID- 26745311 TI - Cationic Pillararenes Potently Inhibit Biofilm Formation without Affecting Bacterial Growth and Viability. AB - It is estimated that up to 80% of bacterial infections are accompanied by biofilm formation. Since bacteria in biofilms are less susceptible to antibiotics than are bacteria in the planktonic state, biofilm-associated infections pose a major health threat, and there is a pressing need for antibiofilm agents. Here we report that water-soluble cationic pillararenes differing in the quaternary ammonium groups efficiently inhibited the formation of biofilms by clinically important Gram-positive pathogens. Biofilm inhibition did not result from antimicrobial activity; thus, the compounds should not inhibit growth of natural bacterial flora. Moreover, none of the cationic pillararenes caused detectable membrane damage to red blood cells or toxicity to human cells in culture. The results indicate that cationic pillararenes have potential for use in medical applications in which biofilm formation is a problem. PMID- 26745312 TI - Primary pulmonary leiomyosarcoma with invasion of the pulmonary vein-A case report. AB - INTRODUCTION: Primary pulmonary leiomyosacromas are a subset of the rare sarcomatous lung neoplasms, found to be less than 0.5% of the organ's primary malignant tumors (Attanoos et al., 1996). PRESENTATION OF CASE: We describe here a case of a 69-year-old woman who presented with heart palpitations, incidentally found to have a large lung mass abutting the left inferior pulmonary veins. Challenging tissue diagnosis led to invasive alternatives; attempted full neoplastic resection and pneumonectomy. DISCUSSION: The mainstay of treatment for these tumors is complete surgical resection. Chemotherapy and radiation can be helpful adjuncts as well. CONCLUSION: This case presents a unique invasion pattern of a primary leiomyosarcoma of the lung, our diagnostic process, and surgical intervention. PMID- 26745313 TI - Undifferentiated carcinoma of the head of pancreas with osteoclast-like giant cells presenting as a symptomatic cystic mass, following acute pancreatitis: Case report and review of the literature. AB - INTRODUCTION: Undifferentiated head of pancreas carcinoma with osteoclast-like giant cells (UC-OGC) is a rare neoplasm, with less than a hundred cases reported. We present such a case, in which the UC-OGC presented atypically as a cystic lesion following acute pancreatitis and led to late diagnosis. PRESENTATION OF CASE: A 75-year-old female patient, who had suffered acute pancreatitis three years ago, was referred with a diagnosis of osteoclast-like giant cell (OGC) tumor of the head of pancreas. She had suffered acute pancreatitis three years ago. Two years ago she developed abdominal pain, steatorrhea and weight loss. Abdominal computed tomography imaging showed a cystic mass in the head of the pancreas (maximum diameter 4cm). The initial diagnosis was pancreatic pseudocyst; however as the mass gradually increased in size and the patient continued to be symptomatic, a CT-guided biopsy was performed. Histological examination revealed an OGC pancreatic tumor. In laparotomy a large (9cm) encapsulated heterogeneous mass was found with partial involvement of the common hepatic artery. Pancreaticoduodenectomy was performed and the involved part of the common hepatic artery was replaced with a homologous graft from the major saphenous vein. Post operative course was uneventful. Histology revealed an undifferentiated pancreatic adenocarcinoma with OGCs. She survived 10 months after the operation. DISCUSSION: Pancreatic undifferentiated carcinomas with OGCs are very rare neoplasms and can present with an atypical clinical picture. CONCLUSIONS: A symptomatic cystic lesion of the pancreas, which is growing in size, should be investigated promptly in order to exclude the presence of malignancy. PMID- 26745315 TI - Endoscopic evaluation of gastric conduit perfusion in minimally invasive Ivor Lewis esophagectomy. AB - INTRODUCTION: Laser-assisted indocyanine green (ICG) fluorescent dye angiography has been used in esophageal reconstructive surgery where it has been shown to significantly decrease the anastomotic leak rate. Recent advances in technology have made this possible in minimally invasive esophagectomy. PRESENTATION OF CASE: We present a 69-year-old male with a cuT2N0M0 adenocarcinoma of the esophagus at the gastroesophageal junction who presented to our clinic after chemoradiation and underwent a minimally invasive Ivor Lewis esophagectomy. The perfusion of the gastric conduit was assessed intraoperatively using endoscopic ICG fluorescent imaging system. The anastomosis was created at the well-perfused site identified on the fluorescent imaging. The patient tolerated the procedure well, had an uneventful recovery going home on postoperative day 6 and tolerating a regular diet 2 weeks after the surgery. DISCUSSION: Combination of minimally invasive surgery and endoscopic evaluation of perfusion of gastric conduit provide improved outcomes for surgical treatment for patients with esophageal cancer. CONCLUSION: The gastric conduit during minimally invasive Ivor Lewis esophagectomy can be evaluated using endoscopic ICG fluorescent imaging. PMID- 26745314 TI - Giant leiomyosarcoma: A case report. AB - INTRODUCTION: Uterine leiomyosarcoma is a rare uterine malignancy. Most of the patients lack symptoms or present with a rapidly enlarging pelvic mass. PRESENTATION OF CASE: We report on a very large leiomyosarcoma in a woman presenting with a 3 months history of rapidly growing adominal mass and fatigue. Laparotomy was performed and diagnosis was confirmed by pathologic and histologic analysis. Patient refused chemotherapy after surgery and died from recurrence at 4th postoperative month. DISCUSSION: Uterine leiomyosarcomas may follow a rapid clinical course with a doubling time of four weeks. There is no reliable method to distinguish uterine sarcoma from benign leiomyomas preoperatively. CONCLUSION: This case represents the largest leiomyosarcoma reported in the literature. PMID- 26745316 TI - Management of a nail impalement injury to the brain in a non-neurosurgical centre: A case report and review of the literature. AB - A nail impalement injury to the brain usually results from accidents like falls or nail gun miss-fires or suicide attempts or from barbaric punishment for certain crimes which are rarely practiced in some remote areas. We present an unusual, intentional, self-impalement of a 4in. nail into the brain in a mentally challenged young man. This case report describes the challenges encountered in the management of a patient with impaled nail in the brain in a non-neurosurgical centre. PMID- 26745317 TI - Laparoscopic gastric devascularization without splenectomy is effective for the treatment of gastric varices. AB - INTRODUCTION: Laparoscopic gastric devascularization of the upper stomach in patients with gastric varices has rarely been reported. Perioperative clinical data were compared with patients who underwent open surgery. PRESENTATION OF CASES: From 2009 to 2012, we performed laparoscopic gastric devascularization without splenectomy for the treatment of gastric varices in eight patients. The patients included four males and four females. Peri-gastric vessels were divided using electrical coagulating devices or other devices according to the diameter of the vessels. Two patients underwent conversion to open surgery due to intraoperative bleeding. DISCUSSION: Intraoperative blood loss in patients who accomplished laparoscopic devascularization was very small (mean 76ml). However, once bleeding occurs, there is a risk of causing massive bleeding. CONCLUSION: With further improvement of laparoscopic devices, laparoscopic gastric devascularization without splenectomy must be an effective and less-invasive surgical procedure in the treatment of gastric varices. PMID- 26745318 TI - Use of the Memokath Urethral Stent in the management of ileal conduit stomal stenosis. AB - INTODUCTION: Ileal conduit stomal stenosis is a difficult complication to manage. Definitive treatment usually requires refashioning or a reconstruction of the conduit. There remains a need for minimally invasive procedures that can restore function to the stoma while avoiding the risks associated with a significant surgical procedure. This case illustrates a novel approach to the management of this complication. PRESENTATION OF CASE: An 84 year old female with muscle invasive bladder cancer underwent cystectomy with formation of an ileal conduit urinary diversion system. Her recovery was complicated by stomal stenosis leading to recurrent urinary tract infections. The Memokath Stent 045 is a thermo expandable nickel-titanium stent designed for treatment of urethral strictures. The stent was inserted into the stoma under direct vision without the need for general anaesthesia or intraoperative radiography. The conduit remains patent 12 months after insertion and the metal stent showed no evidence of migration, calcification, oxidation or degradation. DISCUSSION: The use of a thermo expandable nickel-titanium stent is able to provide the patency required to treat ileal conduit stomal stenosis. In this case, insertion of the stent was a simple procedure and no adverse events or degradation of the stent was identified at 12 months after insertion. The need for a significant surgical procedure such as a refashioning or reconstruction was avoided and general anaesthesia was not required to perform the procedure. CONCLUSION: This case report highlights the possibility of using the thermo-expandable Memokath Stent 045 as an alternative to the long-term management of ileal conduit stomal stenosis. PMID- 26745319 TI - De Garengeot hernia-Use of a novel surgical approach and literature review. AB - INTRODUCTION: De Garengeot hernia is a rare type of femoral hernia, defined as a sac containing a vermiform appendix. Due to its rare occurrence the information available on diagnosis and management is scarce. We report the use of a recently described technique for femoral hernia repair and appendicectomy. PRESENTATION OF CASE: A 67 year old female presented to the emergency department with features of incarcerated femoral hernia. CT imaging revealed an incarcerated appendix within a femoral hernia. The patient subsequently underwent surgery, where the femoral hernia was repaired and appendicectomy performed concurrently. DISCUSSION: Clinical diagnosis is difficult, and there have only been a few documented cases of pre-operative CT diagnoses in the literature. The usual risk factors for developing a hernia would apply to this pathology, and other anatomical and embryological considerations are explored. The King's College technique for femoral hernia repair involves an incision that allows repair of the hernia and also the ability to enter the peritoneal cavity using the same incision. This approach was used in this case, where the abdominal cavity had to be entered to perform the appendicectomy, before the femoral hernia could be repaired. CONCLUSION: Pre-operative diagnosis of De Garengeot hernia is difficult, as it may mimic an incarcerated femoral hernia containing other contents. The diagnosis becomes apparent intra-operatively. The clinical significance lies in that intra abdominal access may be required to safely perform an appendicectomy before the repair of the hernia defect, and this article includes a description of a suitable technique for this particular pathology. PMID- 26745320 TI - MKK6 from pacific white shrimp Litopenaeus vannamei is responsive to bacterial and WSSV infection. AB - p38 mitogen-actived protein kinases (MAPKs) broadly exist from yeast to mammals and participate in diverse cellular responses to various stimuli, whose activation can be induced by the MAPK kinase 6 (MKK6). In this study, a novel MKK6 homolog from Litopenaeus vannamei (LvMKK6) was cloned and characterized. The transcript of LvMKK6 was 1465bp long with an open reading frame (ORF) of 987bp that encoded a polypeptide of 328 amino acids. LvMKK6 was a both cytoplasmic- and nuclear-localized protein and its expression was up-regulated with the treatment of different stimuli including LPS, Vibrio parahaemolyticus, Staphylococcus aureus, Poly (I:C) and white spot syndrome virus (WSSV). Overexpression of LvMKK6 could lead to activate the promoter activities of several antimicrobial peptides (AMPs) such as PEN4. The further investigation demonstrated that LvMKK6 could interact with and phosphorylate Lvp38, suggesting LvMKK6 was an activator of Lvp38. Knockdown of LvMKK6 caused attenuate expression of several AMPs and resulted in the higher mortality of shrimp under V. parahaemolyticus infection, suggesting LvMKK6 could play vital roles in defense against bacterial infection. Interestingly, silencing of LvMKK6 led to the lower virus loads and suppressed viral gene (VP28) expression during WSSV challenge. In addition, overexpression of LvMKK6 promoted the promoter activities of 19 WSSV immediate-early genes such as wsv069, wsv249, wsv108 and wsv403. These results suggested that LvMKK6 could be used by WSSV. Above all, these data provided experimental evidences that participation of LvMKK6 in regulating AMPs and host defense against bacteria, as well as the immune response to WSSV infection. PMID- 26745321 TI - Untangling letter confusability and word length effects in pure alexia. AB - Pure alexia is an acquired neuropsychological disorder that follows damage to the occipito-temporal lobe. This brain damage results in a severe reading impairment in which previously literate individuals are no longer able to efficiently read words, but are still able to perform other language tasks. The present study sought to identify factors of words that make it more difficult for pure alexic individuals to read, such as letter confusability and word length. Eye-tracking methodology was paired with a naming task to examine whether word length or letter confusability is a better predictor of processing difficulty. It was found that word length was a significant predictor of reading time, while summed letter confusability was not significant. This study contradicts some previous research and shows that when an orthogonal set of stimuli is used, letter confusability is not a significant factor driving this reading impairment in all individuals with pure alexia. PMID- 26745322 TI - Removal of Acid Black 194 dye from water by electrocoagulation with aluminum anode. AB - Application of an electrocoagulation process (EC) for the elimination of AB194 textile dye from synthetic and textile wastewater (effluent) contaminated with AB194 dye, was carried out using aluminum anodes at two different initial pH values. Tafel studies in the presence and absence of the dye were performed. The aluminum species formed during the electrolysis were quantified by atomic absorption, and the flocs formed in the process were analyzed by HPLC-MS. Complete removal of AB194 from 1.0 L of solution was achieved applying low densities current at initial pH values of 4.0 and 8.0. The removal of AB194 by EC was possible with a short electrolysis time, removing practically 100% of the total organic carbon content and chemical oxygen demand. The final result was completely discolored water lacking dye and organic matter. An effluent contaminated with 126 mg L(-1) AB194 dye from a Chilean textile industry was also treated by EC under optimized experimental conditions, yielding discolored water and considerably decreasing the presence of organic compounds (dye + dyeing additives), with very low concentrations of dissolved Al(3+). Analysis of flocs showed the presence of the original dye without changes in its chemical structure. PMID- 26745323 TI - A Combined Approach Employing Chlorotoxin-Nanovectors and Low Dose Radiation To Reach Infiltrating Tumor Niches in Glioblastoma. AB - Glioblastoma multiforme (GBM) is the most aggressive form of glioma, with life expectancy of around 2 years after diagnosis, due to recidivism and to the blood brain barrier (BBB) limiting the amount of drugs which reach the residual malignant cells, thus contributing to the failure of chemotherapies. To bypass the obstacles imposed by the BBB, we investigated the use of nanotechnologies combined with radiotherapy, as a potential therapeutic strategy for GBM. We used poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PNP) conjugated to chlorotoxin (CTX), a peptide reported to bind selectively to glioma cells. Silver nanoparticles were entrapped inside the functionalized nanoparticles (Ag-PNP CTX), to allow detection and quantification of the cellular uptake by confocal microscopy, both in vitro and in vivo. In vitro experiments performed with different human glioblastoma cell lines showed higher cytoplasmic uptake of Ag PNP-CTX, with respect to nonfunctionalized nanoparticles. In vivo experiments showed that Ag-NP-CTX efficiently targets the tumor, but are scarcely effective in crossing the blood brain barrier in the healthy brain, where dispersed metastatic cells are present. We show here that single whole brain X-ray irradiation, performed 20 h before nanoparticle injection, enhances the expression of the CTX targets, MMP-2 and ClC-3, and, through BBB permeabilization, potently increases the amount of internalized Ag-PNP-CTX even in dispersed cells, and generated an efficient antitumor synergistic effect able to inhibit in vivo tumor growth. Notably, the application of Ag-PNP-CTX to irradiated tumor cells decreases the extracellular activity of MMP-2. By targeting dispersed GBM cells and reducing MMP-2 activity, the combined use of CTX-nanovectors with radiotherapy may represent a promising therapeutic approach toward GBM. PMID- 26745325 TI - Disruptive Mood Dysregulation Disorder in a Community Mental Health Clinic: Prevalence, Comorbidity and Correlates. AB - OBJECTIVE: The revision of the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) added a new diagnosis of disruptive mood dysregulation disorder (DMDD) to depressive disorders. This study examines the prevalence, comorbidity, and correlates of the new disorder, with a particular focus on its overlap with oppositional defiant disorder (ODD), with which DMDD shares core symptoms. METHODS: Data were obtained from 597 youth 6-18 years of age who participated in a systematic assessment of symptoms offered to all intakes at a community mental health center (sample accrued from July 2003 to March 2008). Assessment included diagnostic, symptomatic, and functional measures. DMDD was diagnosed using a post-hoc definition from item-level ratings on the Schedule for Affective Disorders and Schizophrenia for School-Age Children that closely matches the DSM-5 definition. Caregivers rated youth on the Child Behavior Checklist. RESULTS: Approximately 31% of youth met the operational definition of DMDD, and 40% had Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnoses of ODD. Youth with DMDD almost always had ODD (odds ratio [OR] = 53.84) and displayed higher rates of comorbidity with attention deficit/hyperactivity disorder (ADHD) and conduct disorder than youth without DMDD. Caregivers of youth with DMDD reported more symptoms of aggressive behavior, rule-breaking, social problems, anxiety/depression, attention problems, and thought problems than all other youth without DMDD. Compared with youth with ODD, youth with DMDD were not significantly different in terms of categorical or dimensional approaches to comorbidity and impairment. CONCLUSIONS: The new diagnosis of DMDD might be common in community mental health clinics. Youth with DMDD displayed more severe symptoms and poorer functioning than youth without DMDD. However, DMDD almost entirely overlaps with ODD and youth with DMDD were not significantly different than youth with ODD. These findings raise concerns about the potentially confusing effects of using DMDD in clinical settings, particularly given that DSM-5 groups DMDD with depressive disorders, but ODD remains a disruptive behavior disorder, potentially changing the decision-making framework that clinicians use to select treatments. PMID- 26745326 TI - Molecular Epidemiology and Drug Resistance of Acinetobacter baumannii Isolated from Hospitals in Southern Poland: ICU as a Risk Factor for XDR Strains. AB - The objectives of the present study were to investigate the carbapenemase and metallo-beta-lactamase genes of Acinetobacter baumannii clinical isolates by polymerase chain reaction (PCR) and real time PCR and to determine the molecular epidemiology of the strains using the DiversiLab tool. From these data, correlations between drug resistance, resistance genes, and epidemiological clones may be revealed. The study was conducted on 125 A. baumannii collected over the 2013 year. The majority of the isolates from both intensive care unit (ICU) and non-ICU cases originated from pneumonia infections (79.2%), isolates from blood infections accounted for 17.6% and 3.2% were from meningitis infections. In the ICU cases compared with the non-ICU cases, bloodstream infections were more frequently diagnosed (19.2% vs. 11.5%). Sixty percent of A. baumannii strains were resistant to all the antimicrobials tested with the exception of colistin. All strains were susceptible to colistin and polymyxin B. Extensively drug-resistant (XDR) strains accounted for 80.8% of the isolates tested and these XDR strains were more frequently isolated from ICU cases than from non-ICU cases (93.9% vs. 30.8%). Among the 101 isolates of A. baumannii exhibiting the XDR pattern of resistance, 80 possessed the blaOXA-24 gene and 29 had the blaOXA-23 gene. Only two isolates possessed the blaVIM gene. The presence of the ISAba1element was confirmed among 10 strains from patients hospitalized in the ICU. Using repetitive extragenic palindromic sequence PCR (DiversiLab typing), six clones and 12 unique strains were identified, of which two clones dominated. Most isolates belonging to clone 1 (66.7%) and clone 2 (85.5%) were susceptible only to colistin. In summary, it is clear from our findings and those of other studies that carbapenem resistance among A. baumannii strains presents a serious clinical problem worldwide. Furthermore, the presence of XDR international clone II in ICUs poses a potential risk for future outbreaks of A. baumannii infection and controlling A. baumannii infections in hospitals presents a serious challenge. PMID- 26745324 TI - Real-Time Observation of Backtracking by Bacterial RNA Polymerase. AB - RNA polymerase (RNAP) backtracking is a backward sliding of the enzyme along DNA and RNA. It plays important roles in many essential processes in bacteria and in eukaryotes. We describe here a fluorescence-based approach that allows a real time observation of bacterial RNAP backtracking. A Cy3 fluorescence probe, when incorporated into a specific site in the nontemplate strand near the site of backtracking, allows RNAP movements to be monitored near the probe because of a robust enhancement of fluorescence caused by protein proximity. Using this approach, we showed that binding of NTP to the active site prior to phosphodiester bond formation inhibited backtracking, consistent with the coupling of NTP binding to translocation. The extent and the kinetics of backtracking did not show a simple correlation with the instability of the DNA RNA hybrid, indicating a more complex dependence of backtracking on DNA template sequence. Experiments with transcription through an abasic site in DNA template or neutravidin bound to biotinylated template strand base illustrated an important role of backtracking in defining how RNAP reacts to such obstacles in the DNA template. The described approach will be a useful tool in deciphering the mechanism of backtracking and in studying factors that affect the backtracking. PMID- 26745328 TI - Hyperenhancement of the Pericardium on Cardiac Magnetic Resonance Imaging: A Marker of Acute Inflammation and Neovascularization or a Chronic Fibrotic State. AB - In cardiac magnetic resonance imaging, hyperenhancement of the pericardium post gadolinium administration in acute chest pain often signifies pericarditis with an acute inflammatory response and neovascularization. In the context of constrictive pericarditis, case series have indicated that the intensity of hyperenhancement and the thickness of the pericardium imply reversibility of the physiology of the constrictive pericarditis. We present a case of intense hyperenhancement and marked thickening of the pericardium in a patient with constrictive pericarditis with antecedent chest pain. Surgical resection of the pericardium and microscopy revealed a chronic fibrotic state with no evidence of inflammation or neovascularization, thus clarifying the failure of initial medical/anti-inflammatory treatment. Our case highlights the fact that hyperenhancement of the pericardium post gadolinium is non-specific for histology and does not necessarily imply the reversibility of pericardial constriction. PMID- 26745329 TI - Role of Aggregates in the Luminescence Decay Dynamics of Conjugated Polymers. AB - Fluorescence quantum yields of conjugated polymer films are systematically lower than their counterparts in dilute solution. Films also exhibit a long "temporal tail" in their fluorescence decay dynamics not present in solution. We study the spectroscopy, excitation wavelength dependence, temperature dependence, and electric field quenching of the temporal tail of the photoluminescence in MEH-PPV on a nanosecond time scale to elucidate the relationship between those observations. We conclude that the tail represents emission from H-like aggregated regions in the polymer. Using a simple model of the photophysics, we estimate the formation yield of the aggregates responsible for the tail emission to be <20% so that they cannot account for the large reduction in fluorescence observed in densely packed films relative to that in solution. PMID- 26745327 TI - Characterization of gonadal transcriptomes from the turbot (Scophthalmus maximus). AB - The mechanisms underlying sexual reproduction and sex ratio determination remains unclear in turbot, a flatfish of great commercial value. And there is limited information in the turbot database regarding genes related to the reproductive system. Here, we conducted high-throughput transcriptome profiling of turbot gonad tissues to better understand their reproductive functions and to supply essential gene sequence information for marker-assisted selection programs in the turbot industry. In this study, two gonad libraries representing sex differences in Scophthalmus maximus yielded 453 818 high-quality reads that were assembled into 24 611 contigs and 33 713 singletons by using 454 pyrosequencing, 13 936 contigs and singletons (CS) of which were annotated using BLASTx. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses revealed that various biological functions and processes were associated with many of the annotated CS. Expression analyses showed that 510 genes were differentially expressed in males versus females; 80% of these genes were annotated. In addition, 6484 and 6036 single nucleotide polymorphisms (SNPs) were identified in male and female libraries, respectively. This transcriptome resource will serve as the foundation for cDNA or SNP microarray construction, gene expression characterization, and sex-specific linkage mapping in turbot. PMID- 26745330 TI - Connecting Metallic Nanoparticles by Optical Printing. AB - Optical printing is a simple and flexible method to bring colloidal nanoparticles from suspension to specific locations of a substrate. However, its application has been limited to the fabrication of arrays of isolated nanoparticles because, until now, it was never possible to bring nanoparticles closer together than approximately 300 nm. Here, we propose this limitation is due to thermophoretic repulsive forces generated by plasmonic heating of the NPs. We show how to overcome this obstacle and demonstrate the optical printing of connected nanoparticles with well-defined orientation. These experiments constitute a key step toward the fabrication by optical printing of functional nanostructures and microcircuits based on colloidal nanoparticles. PMID- 26745331 TI - Corrigendum. PMID- 26745333 TI - A Method for Examining Stability in Reliability. AB - A correlation structure modeling approach to the study of stability in reliability of multiple, repeatedly administered measures is outlined. The method is applicable also when it is of interest to examine relationships between model parameters in a uniform metric across all variables. The approach is illustrated on data from a fluid intelligence study (Baltes, Dittmann-Kohli, & Kliegl, 1986). PMID- 26745332 TI - Effects of Concurrent Calcium Channel Blocker on Antiplatelet Efficacy of Clopidogrel Therapy: A Systematic Review. AB - Clopidogrel is a widely used drug in clinical practice. Controversy persists as to whether it interacts with proton pump inhibitors. Recently, research interest has grown in the area concerning an interaction of clopidogrel with calcium channel blockers. Multiple studies have been conducted to evaluate the effect of calcium channel blockers on the efficacy of clopidogrel, both in vitro and in vivo. The authors aim to present a systematic review of the published studies in the literature. Various terms were searched in PubMed, Web of Science, and The Cochrane database. Abstracts of studies were read and based on strict exclusion criteria; a study was included/excluded into the review. A total of 424 studies were initially included. Based on exclusion criteria, 22 studies were finally included in the review. Various studies report widely different results regarding the effects of calcium channel blockers on antiplatelet efficacy of clopidogrel. Large prospective studies are needed to delineate the association or lack thereof. PMID- 26745335 TI - Influence of Imputation and EM Methods on Factor Analysis when Item Nonresponse in Questionnaire Data is Nonignorable. AB - This study deals with the influence of each of twelve imputation methods and two methods using the EM algorithm on the results of maximum likelihood factor analysis as compared with results obtained from the complete data factor analysis (no missing scores). Complete questionnaire rating scale data were simulated and, next, missing item scores were created under both ignorable and nonignorable nonresponse mechanisms. Next, imputation methods were used to fill the gaps and factor analysis was applied to both the original complete data and to the data sets including imputed scores. Each imputation method was implemented once with residual error and once without residual error. Also, one EM method estimated the factor loadings directly and the other estimated the complete data covariance matrix, which subsequently was factor analyzed. A design was analyzed with design factors Latent Trait Structure (technically called Mixing Configuration), Correlation Between Latent Traits, Nonresponse Mechanism, Percentage of Missingness, Sample Size, and Imputation Method. We found that, in general, methods that impute a score based on a respondent's mean score obtained from his/her observed item scores best recovered the factor loadings structure from the complete data. Moreover, for unidimensional data person mean methods with a residual error gave better results than the other imputation methods, either with or without a residual error component. For the EM methods a smaller design was analyzed. The conclusion was that both EM methods better recovered the complete data factor loadings than the imputation methods. PMID- 26745334 TI - Multidimensional Scaling Methods for Many-Object Sets: A Review. AB - Given a set of dissimilarities data between n objects, multidimensional scaling is the problem of reconstructing a geometrical pattern of these objects, using n points, so that between-points distance corresponds to between-objects dissimilarity. Often, the collection of input data requires rating the dissimilarities between all n(n - 1)/2 possible pairs of stimuli. When the number of stimuli is large, say n $ 30, the number of pairs to be compared becomes very large and the similarity task inefficient. Hence a question of major importance is how to increase the efficiency of the similarity task while maintaining satisfactory scaling solutions. This article reviews the main similarity task methods suitable for a large objects set. PMID- 26745336 TI - Modeling Intraindividual Changes in Children's Social Skills at Home and at School: A Multivariate Latent Growth Approach to Understanding Between-Settings Differences in Children's Social Skill Development. AB - Multivariate latent growth modeling was used to conceptualize and analyze intraindividual changes in children's social skills and interindividual differences in these changes in home and school settings. Parent and teacher ratings assessing children's social skills at home and school settings, respectively, were obtained for a sample of 378 children at 4 time points spaced at approximately 12-month intervals over a 4-year period from Kindergarten to Grade 3. Results showed that, in initial status at Kindergarten, there were significant individual differences in social skills in both home and school settings and a significant positive association between initial status in social skills in the two settings. Systematic between-settings differences in children's social skill development were found. Social skills development at home was best described with a nonlinear trajectory in which skills increased from Kindergarten to Grade 2 with a substantially larger increase from Grade 1 to Grade 2 than from Kindergarten to Grade 1, and then remained relatively constant from Grade 2 to Grade 3. In contrast, social skills development at school was best described with a negative linear trajectory in which skills decreased at a constant rate from Kindergarten to Grade 3. The differences in social skills development may derive form the fact that different teachers with different expectations regarding social skills provided ratings each year while the same parent was the source of at-home social skills ratings. There were significant individual differences in growth rates in the school as well as the home setting. Evidence of between settings differences in social skills development were obtained from differential patterns of associations between growth parameters (initial status and growth rate) and individual predictors (family income, parent education, child verbal skills) across settings. PMID- 26745337 TI - Multivariate Analysis of Triadic Relationst. AB - To analyze variance in a triadic variable, Bond, Horn, and Kenny (1997) have proposed a Triadic Relations Model. Here we extend this model to analyze the covariances between triadic variables. A bivariate version of the Triadic Relations Model is specified, and estimation methods are presented. These can be used to decompose the covariance between two triadic variables into thirty-three covariance components. Interpretations and an example of this analysis are offered. Applications of this model and alternative techniques are noted. PMID- 26745339 TI - Measurement of neutrophil gelatinase-associated lipocalin (NGAL) in patients with non-communicable diseases: any additional benefit? AB - AIM: Chronic kidney disease (CKD) is one of the major complication from non communicable diseases (NCD), such as diabetes or hypertension. We aimed to determine if routine measurement of neutrophil gelatinase-associated lipocalin (NGAL) in NCD patients could provide additional benefit for diagnosing kidney disease. METHODS: Fasting serum NGAL, urea, creatinine, uric acid and albumin were measured in 298 NCD patients. Estimated glomerular filtration rate (e-GFR) was calculated using the CKD-EPI equation. Multiple linear regression modeling was used for analysis. RESULTS: CKD patients have the highest levels of NGAL than the other NCD patients (p < 0.001). Although NGAL was significantly related to e GFR, creatinine, urea and albumin in CKD-patients (p < 0.001) and not in the other NCD patients (p > 0.05), only serum creatinine predicted NGAL levels in CKD patients (p < 0.001). CONCLUSION: NGAL level is best associated with serum creatinine only in patients with CKD and NGAL measurement may not be cost effective as a routine kidney function test in NCD patients in under-resourced economies. PMID- 26745338 TI - Geographic scope and accessibility of a centralized, electronic consult program for patients with recent fracture. AB - INTRODUCTON: Low-trauma, osteoporotic fractures among older men are associated with a significant increase in morbidity and mortality. Despite effective therapies for osteoporosis, several studies have demonstrated that management and treatment after a low trauma fracture remains inadequate, especially among men. Fracture liaison services have been shown to significantly improve osteoporosis evaluation and treatment. However, such programs may be less feasible and accessible in rural areas, with limited availability of specialty services. The study objective was to evaluate a centralized, electronic consult (e-consult) program serving multiple veterans administration medical centers, including the geographic scope, accessibility to rural patients, and impact on osteoporosis evaluation and treatment. METHODS: The e-consult program identified veterans with potential osteoporotic fractures from inpatient and outpatient encounter data, based on ICD9 diagnosis codes (800-829) from the central data warehouse. The medical record of an eligible patient was reviewed by a bone health specialist, and an e-consult note was sent to the patient's primary care provider that specified guideline-based recommendations for further evaluation and management. A bone health nurse liaison then coordinated the ordering and follow-up of laboratory and bone density assessment, osteoporosis education (eg medication administration and side effects, calcium and vitamin D supplementation, falls prevention, and exercise), and adherence follow-up via telephone. Patients were identified as living in a rural area if their ZIP code was not in a US Census Bureau-defined urban area (ie population density greater than approximately 386 persons per square kilometer/1000 persons per square mile). RESULTS: From October 2013 to September 2014, 2775 fractures were identified by a fracture-related ICD9 code. After exclusion of those aged less than 50 years and high-trauma fractures, 321 e-consults were completed. Of those, 171 (53.3%) were for patients residing in a rural or highly rural area. The e-consult program saved a total of 19 187 km (11 917 miles) of travel. For rural patients, bisphosphonates were recommended 51 times, with 33 (64.7%) ordered, and bone density assessments were recommended 109 times with 79 (72.5%) ordered. A nurse liaison significantly improved bisphosphonate ordering (from 39.7% to 75.8%) and bone mineral density testing completion rates (from 37.1% to 63.0%), for both rural and urban patients (p<0.01). CONCLUSIONS: A centralized e-consult program can effectively and efficiently provide specialty bone health services to patients residing in rural areas. The program was able to save substantial travel time and increase the rates of evaluation and treatment for osteoporosis. PMID- 26745340 TI - REI/SH3BP5 protein family: New GEFs for Rab11. PMID- 26745342 TI - Chiral Analysis Using Broadband Rotational Spectroscopy. AB - broadband microwave spectroscopy is a proven tool to precisely determine molecular properties of gas-phase molecules. Recent developments make it applicable to investigate chiral molecules. Enantiomers can be differentiated, and the enantiomeric excess and, indirectly, the absolute configuration can be determined in a molecule-selective manner. The resonant character and high resolution of rotational spectroscopy provide a unique mixture compatibility. Future directions, such as extending the technique to chemical analysis, are discussed. PMID- 26745343 TI - How personality, coping styles, and perceived closeness influence help-seeking attitudes in suicide-bereaved adults. AB - This study examined the impact of personality, coping, and perceived closeness on help-seeking attitudes in suicide bereaved adults. Participants (n = 418; mean age = 49.50; 90% women, 89.7% Caucasian) completed measures of personality (neuroticism, extraversion, openness, conscientiousness, and agreeableness), coping, and attitudes toward seeking mental health services. Regression analyses revealed neuroticism as the strongest predictor of help-seeking attitudes. Relatively neurotic adult women bereaved by suicide may be at-risk for developing unhealthy coping styles, low stigma indifference, and more negative help-seeking attitudes. PMID- 26745345 TI - A Potent d-Protein Antagonist of VEGF-A is Nonimmunogenic, Metabolically Stable, and Longer-Circulating in Vivo. AB - Polypeptides composed entirely of d-amino acids and the achiral amino acid glycine (d-proteins) inherently have in vivo properties that are proposed to be near-optimal for a large molecule therapeutic agent. Specifically, d-proteins are resistant to degradation by proteases and are anticipated to be nonimmunogenic. Furthermore, d-proteins are manufactured chemically and can be engineered to have other desirable properties, such as improved stability, affinity, and pharmacokinetics. Thus, a well-designed d-protein therapeutic would likely have significant advantages over l-protein drugs. Toward the goal of developing d protein therapeutics, we previously generated RFX001.D, a d-protein antagonist of natural vascular endothelial growth factor A (VEGF-A) that inhibited binding to its receptor. However, RFX001.D is unstable at physiological temperatures (Tm = 33 degrees C). Here, we describe RFX037.D, a variant of RFX001.D with extreme thermal stability (Tm > 95 degrees C), high affinity for VEGF-A (Kd = 6 nM), and improved receptor blocking. Comparison of the two enantiomeric forms of RFX037 revealed that the d-protein is more stable in mouse, monkey, and human plasma and has a longer half-life in vivo in mice. Significantly, RFX037.D was nonimmunogenic in mice, whereas the l-enantiomer generated a strong immune response. These results confirm the potential utility of synthetic d-proteins as alternatives to therapeutic antibodies. PMID- 26745346 TI - The transition from primary to secondary school as stressful life event provoking risky drinking behaviors. AB - This study is based on a drug prevention project for children in the German Polish border region known as "Pomerania." The aim of this project was to minimize risk behaviors while developing social skills as protective factors through project-specific training interventions. The present study especially investigates the development of social skills and risk behaviors at German and Polish primary schools in the critical transitional period from primary to secondary school. Data on German 4th graders and Polish 6th graders were collected by means of a longitudinal and control group design through 3rd-party assessment from teachers. The data on social skills was collected through the use of standardized assessment instruments. The study established that social skills could indeed be increased through training and that risk behaviors decreased in both of the treatment groups. The control group showed altogether an increase in risk behavior and a decrease in coping skills. In the Polish treatment group, even risk behaviors which had been detected previously decreased. The German control group showed an increase in risk behaviors and a decrease in coping skills. In the case of the younger German pupils, the effectiveness of the interventions was exhibited indirectly. Despite variations in age and cultural differences, the effects of training were noticeable in children from both countries. The intervention program offered the children adequate assistance in order to successfully cope with this stressful life event. It promoted the development of social skills while minimizing risk behaviors. PMID- 26745344 TI - Placental membrane-type metalloproteinases (MT-MMPs): Key players in pregnancy. AB - Membrane-type matrix metalloproteinases (MT-MMPs) are a sub-family of zinc dependent endopeptidases involved in the degradation of the extracellular matrix. Although MT-MMPs have been mainly characterized in tumor biology, they also play a relevant role during pregnancy. Placental MT-MMPs are required for cytotrophoblast migration and invasion of the uterine wall and in the remodeling of the spiral arteries. They are involved in the fusion of cytotrophoblasts to form the syncytiotrophoblast as well as in angiogenesis. All these processes are crucial for establishing and maintaining a successful pregnancy and, thus, MT-MMP activity has to be tightly regulated in time and space. Indeed, a de-regulation of MT-MMP expression has been linked with pregnancy complications such as preeclampsia (PE), fetal growth restriction (FGR), gestational diabetes mellitus (GDM) and was also found in maternal obesity. Here we review what is currently known about MT-MMPs in the placenta, with a focus on their general features, their localization and their involvement in pregnancy disorders. PMID- 26745347 TI - Residential Solar PV Systems in the Carolinas: Opportunities and Outcomes. AB - This paper presents a first-order analysis of the feasibility and technical, environmental, and economic effects of large levels of solar photovoltaic (PV) penetration within the services areas of the Duke Energy Carolinas (DEC) and Duke Energy Progress (DEP). A PV production model based on household density and a gridded hourly global horizontal irradiance data set simulates hourly PV power output from roof-top installations, while a unit commitment and real-time economic dispatch (UC-ED) model simulates hourly system operations. We find that the large generating capacity of base-load nuclear power plants (NPPs) without ramping capability in the region limits PV integration levels to 5.3% (6510 MW) of 2015 generation. Enabling ramping capability for NPPs would raise the limit of PV penetration to near 9% of electricity generated. If the planned retirement of coal-fired power plants together with new installations and upgrades of natural gas and nuclear plants materialize in 2025, and if NPPs operate flexibly, then the share of coal-fired electricity will be reduced from 37% to 22%. A 9% penetration of electricity from PV would further reduce the share of coal-fired electricity by 4-6% resulting in a system-wide CO2 emissions rate of 0.33 to 0.40 tons/MWh and associated abatement costs of 225-415 (2015$ per ton). PMID- 26745349 TI - Successful management of a giant anterior sacral meningocele with an endoscopic cutting stapler: case report. AB - Anterior sacral meningoceles (ASMs) are rare defects in the sacrum with thecal sac herniations and symptoms that commonly include constipation, dysmenorrhea, and urinary disturbances. An ASM causing hydronephrosis and acute renal failure from compression of the lower portion of the urinary tract is a rare clinical entity. Only one other case has been reported. The authors present the case of a 37-year-old man admitted for obstructive renal failure and hydronephrosis due to a giant ASM that measured 25 * 12 * 18 cm and compressed the ureters and bladder. The ASM was successfully treated via an anterior transabdominal approach in which the authors used a novel technique for watertight closure of the meningocele pedicle with an endoscopic cutting stapler. The authors review the literature and discuss the surgical options for the treatment of ASMs, specifically the management of ASMs in the context of obstructive renal failure and hydronephrosis. PMID- 26745348 TI - Mini-open pedicle subtraction osteotomy as a treatment for severe adult spinal deformities: case series with initial clinical and radiographic outcomes. AB - OBJECTIVE Pedicle subtraction osteotomy (PSO) is a powerful but high-risk surgical technique for destabilizing the spine for deformity correction in both the sagittal and coronal planes. Numerous reports have demonstrated the benefits of this technique for realigning the spine in a physiological posture; however, the open surgical technique is associated with a high complication rate. In this report the authors review data obtained in a series of patients who underwent PSO through a less invasive approach. METHODS Sixteen patients with severe coronal- and/or sagittal-plane deformities were treated in this series. Conservative measures had failed in all cases and patients had undergone a single-level PSO or extended PSO at L-2 or L-3. Fixation was accomplished using percutaneous instrumentation and interbody or facet joint fusions were used at the remaining levels. None of the procedures were aborted or converted to a traditional open procedure. Standard clinical and radiographic measures were used to assess patient outcomes. RESULTS Mean age was 68.8 years and mean follow-up duration was 17.7 months. An average of 7.6 levels were fused, and 50% of the patients had bilateral iliac screw fixation, with all constructs crossing both the thoracolumbar and lumbosacral junctions. Operative time averaged 356 +/- 50 minutes and there was a mean blood loss of 843 +/- 339 ml. The leg visual analog scale score improved from a mean of 5.7 +/- 2.7 to one of 1.3 +/- 1.6, and the back visual analog scale score improved from a mean of 8.6 +/- 1.3 to one of 2.4 +/- 2.1. The Oswestry Disability Index score improved from a mean of 50.1 +/- 14.4 to 16.4 +/- 12.7, representing a mean reduction of 36.0 +/- 16.9 points. The SF-36 physical component summary score changed from a mean of 43.4 +/- 2.6 to one of 47.0 +/- 4.3, and the SF-36 mental component summary score changed from a mean of 46.7 +/- 3.6 to 46.30 +/- 3.0. Coronal alignment improved from a mean of 27.9 +/- 43.6 mm to 16.0 +/- 17.2 mm. The lumbar Cobb angle improved from a mean of 41.2 degrees +/- 18.4 degrees to 15.4 degrees +/- 9.6 degrees , and lumbar lordosis improved from 23.1 degrees +/- 15.9 degrees to 48.6 degrees +/- 11.7 degrees . Pelvic tilt improved from a mean of 33.7 degrees +/- 8.6 degrees to 24.4 degrees +/- 6.5 degrees , and the sagittal vertical axis improved from 102.4 +/- 73.4 mm to 42.2 +/- 39.9 mm. The final lumbar lordosis-pelvic incidence difference averaged 8.4 degrees +/- 12.1 degrees . There were 4 patients who failed to achieve less than or equal to a 10 degrees mismatch on this parameter. Ten of the 16 patients underwent delayed postoperative CT, and 8 of these had developed a solid arthrodesis at all levels treated. A total of 6 complications occurred in this series. There were no cases of symptomatic proximal junction kyphosis. CONCLUSIONS Advancements in minimally invasive technique have resulted in the ability to manage increasingly complex deformities with hybrid approaches. In this limited series, the authors describe the results of utilizing a tissue sparing mini-open PSO to correct severe spinal deformities. This method was technically feasible in all cases with acceptable radiographic outcomes similar to open surgery. However, high complication rates associated with these deformity corrections remain problematic. PMID- 26745350 TI - Long-term outcomes of vertebral column resection for kyphosis in patients with cured spinal tuberculosis: average 8-year follow-up. AB - OBJECTIVE The authors conducted a study to evaluate the long-term clinical and radiographic outcomes of vertebral column resection (VCR) for kyphosis in patients with cured spinal tuberculosis. METHODS This was a retrospective study. Between 2003 and 2009, 28 consecutive patients with cured spinal tuberculosis underwent VCR for kyphosis in which the target vertebra was removed completely. Autologous iliac crest bone graft or titanium mesh packed with autograft was placed into the osteotomy gap to reconstruct the spine for anterior column stability. Posterior pedicle screw fixation and fusion were typically performed. Radiographic parameters, including kyphosis angle and sagittal balance, were measured, and visual analog scale score, America Spinal Injury Association grade, Scoliosis Research Society outcome instrument (SRS-22) score, Oswestry Disability Index, patient satisfaction index, and long-term complications were evaluated. RESULTS This study included 12 males and 16 females, with an average age of 20.9 years at the time of surgery. The average follow-up was 96.9 months. No deaths occurred in this study. At the final follow-up, the kyphosis angle improved from the preoperative average of 70.7 degrees to the final follow-up average of 30.2 degrees , and the average kyphosis correction loss was 8.5 degrees . The sagittal balance averaged 15.4 mm before surgery, 2.8 mm after surgery, and 5.4 mm at the final followup. Thirteen patients showed improvement of more than 1 America Spinal Injury Association grade. The visual analog scale, Oswestry Disability Index, and SRS-22 scores improved significantly, and the overall satisfaction rate was 92.9%. Adjacent-segment degeneration occurred in 3 patients. No severe instrumentation-related complications were observed. CONCLUSIONS The long-term safety and efficacy of the VCR technique for treating spinal tuberculosis-related kyphosis were favorable, and no severe late-stage complications appeared. Lumbar tubercular kyphosis showed a tendency for sagittal decompensation within the first 3 postoperative years. Cases of adjacent-segment degenerations were relatively few and mild without clinical symptoms. PMID- 26745351 TI - The effect of increased T2 signal intensity in the spinal cord on the injury severity and early neurological recovery in patients with central cord syndrome. AB - OBJECTIVE The aim of this paper was to compare the severity of the initial neurological injury as well as the early changes in the American Spinal Injury Association (ASIA) motor score (AMS) between central cord syndrome (CCS) patients with and without an increased T2 signal intensity in their spinal cord. METHODS Patients with CCS were identified and stratified based on the presence of increased T2 signal intensity in their spinal cord. The severity of the initial neurological injury and the progression of the neurological injury over the 1st week were measured according to the patient's AMS. The effect of age, sex, congenital stenosis, surgery within 24 hours, and surgery in the initial hospitalization on the change in AMS was determined using an analysis of variance. RESULTS Patients with increased signal intensity had a more severe initial neurological injury (AMS 57.6 vs 75.3, respectively, p = 0.01). However, the change in AMS over the 1st week was less severe in patients with an increase in T2 signal intensity (-0.85 vs -4.3, p = 0.07). Analysis of variance did not find that age, sex, Injury Severity Score, congenital stenosis, surgery within 24 hours, or surgery during the initial hospitalization affected the change in AMS. CONCLUSIONS The neurological injury is different between patients with and without an increased T2 signal intensity. Patients with an increased T2 signal intensity are likely to have a more severe initial neurological deficit but will have relatively minimal early neurological deterioration. Comparatively, patients without an increase in the T2 signal intensity will likely have a less severe initial injury but can expect to have a slight decline in neurological function in the 1st week. PMID- 26745353 TI - Ground-Level Ozone Following Astrophysical Ionizing Radiation Events: An Additional Biological Hazard? AB - Astrophysical ionizing radiation events such as supernovae, gamma-ray bursts, and solar proton events have been recognized as a potential threat to life on Earth, primarily through depletion of stratospheric ozone and subsequent increase in solar UV radiation at Earth's surface and in the upper levels of the ocean. Other work has also considered the potential impact of nitric acid rainout, concluding that no significant threat is likely. Not yet studied to date is the potential impact of ozone produced in the lower atmosphere following an ionizing radiation event. Ozone is a known irritant to organisms on land and in water and therefore may be a significant additional hazard. Using previously completed atmospheric chemistry modeling, we examined the amount of ozone produced in the lower atmosphere for the case of a gamma-ray burst and found that the values are too small to pose a significant additional threat to the biosphere. These results may be extended to other ionizing radiation events, including supernovae and extreme solar proton events. PMID- 26745352 TI - Microsurgical treatment of sacral perineural (Tarlov) cysts: case series and review of the literature. AB - OBJECTIVE Tarlov cysts (TCs) occur most commonly on extradural components of the sacral and coccygeal nerve roots. These lesions are often found incidentally, with an estimated prevalence of 4%-9%. Given the low estimated rates of symptomatic TC and the fact that symptoms can overlap with other common causes of low-back pain, optimal management of this entity is a matter of ongoing debate. Here, the authors investigate the effects of surgical intervention on symptomatic TCs and aim to solidify the surgical criteria for this disease process. METHODS The authors performed a retrospective review of data from consecutive patients who were surgically treated for symptomatic TCs from September 2011 to March 2013. Clinical evaluations and results from surveying pain and overall health were used. Univariate statistical analyses were performed. RESULTS Twenty-three adults (4 males, 19 females) who had been symptomatic for a mean of 47.4 months were treated with laminectomy, microsurgical exposure and/or imbrication, and paraspinous muscle flap closure. Eighteen patients (78.3%) had undergone prior interventions without sustained improvement. Thirteen patients (56.5%) underwent lumbar drainage for an average of 8.7 days following surgery. The mean follow-up was 14.4 months. Univariate analyses demonstrated that an advanced age (p = 0.045), the number of noted perineural cysts on preoperative imaging (p = 0.02), and the duration of preoperative symptoms (p = 0.03) were associated with a poor postoperative outcome. Although 47.8% of the patients were able to return to normal activities, 93.8% of those surveyed reported that they would undergo the operation again if given the choice. CONCLUSIONS This is one of the largest published studies on patients with TCs treated microsurgically. The data suggest that patients with symptomatic TCs may benefit from open microsurgical treatment. Although outcomes seem related to patient age, duration of symptoms, and extent of disease demonstrated on imaging, further study is warranted and underway. PMID- 26745354 TI - An Examination of the True Reliability of Lower Limb Stiffness Measures During Overground Hopping. AB - Evidence suggests reports describing the reliability of leg-spring (kleg) and joint stiffness (kjoint) measures are contaminated by artifacts originating from digital filtering procedures. In addition, the intraday reliability of kleg and kjoint requires investigation. This study examined the effects of experimental procedures on the inter- and intraday reliability of kleg and kjoint. Thirty-two participants completed 2 trials of single-legged hopping at 1.5, 2.2, and 3.0 Hz at the same time of day across 3 days. On the final test day a fourth experimental bout took place 6 hours before or after participants' typical testing time. Kinematic and kinetic data were collected throughout. Stiffness was calculated using models of kleg and kjoint. Classifications of measurement agreement were established using thresholds for absolute and relative reliability statistics. Results illustrated that kleg and kankle exhibited strong agreement. In contrast, kknee and khip demonstrated weak-to-moderate consistency. Results suggest limits in kjoint reliability persist despite employment of appropriate filtering procedures. Furthermore, diurnal fluctuations in lower-limb muscle tendon stiffness exhibit little effect on intraday reliability. The present findings support the existence of kleg as an attractor state during hopping, achieved through fluctuations in kjoint variables. Limits to kjoint reliability appear to represent biological function rather than measurement artifact. PMID- 26745355 TI - Diketopyrrolopyrrole-Based Ratiometric/Turn-on Fluorescent Chemosensors for Citrate Detection in the Near-Infrared Region by an Aggregation-Induced Emission Mechanism. AB - This work reports two new diketoprrrolopyrrole-based fluorescent chemosensors (DPP-Py1 and DPP-Py2) using symmetrical diamides as recognition groups for selective and fast detection of citrate in the near-infrared region. To our delight, DPP-Py1 is a ratiometric sensor, whereas DPP-Py2 is a turn-on fluorescent sensor. It is worth noting that DPP-Py1 has higher accuracy and sensitivity with a relatively lower detection limit (1.8 * 10(-7) M) and better stability in different pH buffers than DPP-Py2. Scanning electron microscopy, dynamic light scattering analyses, (1)H NMR titration, and 2D-NOESY NMR suggested that the fluorescence increment of the probes DPP-Py1 and DPP-Py2 for citrate could probably originate from aggregation-induced emission (AIE) on the basis of the complexation of the pyridinium-based symmetrical diamides, DPPs, with carboxyl anions of citrate. Our work may provide a simpler and faster means for qualitative and quantitative analysis of citrate through an AIE mechanism. PMID- 26745359 TI - SSD modeling-It's all about F! PMID- 26745356 TI - Biodegradation of cyanide wastes from mining and jewellery industries. AB - Cyanide, one of the known most toxic chemicals, is widely used in mining and jewellery industries for gold extraction and recovery from crushed ores or electroplating residues. Cyanide toxicity occurs because this compound strongly binds to metals, inactivating metalloenzymes such as cytochrome c oxidase. Despite the toxicity of cyanide, cyanotrophic microorganisms such as the alkaliphilic bacterium Pseudomonas pseudoalcaligenes CECT5344 may use cyanide and its derivatives as a nitrogen source for growth, making biodegradation of cyanurated industrial waste possible. Genomic, transcriptomic and proteomic techniques applied to cyanide biodegradation ('cyan-omics') provide a holistic view that increases the global insights into the genetic background of cyanotrophic microorganisms that could be used for biodegradation of industrial cyanurated wastes and other biotechnological applications. PMID- 26745357 TI - The reciprocal relationship between participation in leisure activities and cognitive functioning: the moderating effect of self-rated literacy level. AB - OBJECTIVE: Participation in leisure activities is beneficial for cognitive functioning of older adults, but it is less known whether it is also beneficial for those with low basic cognitive level. This study examined the reciprocal relationship between participating in leisure activities and cognitive functioning among low and higher literacy level older adults. METHOD: Respondents aged 60 years and older who participated in both first waves (2005-2006 and 2009 2010) of the Israeli component of the Survey of Health, Ageing and Retirement in Europe (SHARE-Israel) were divided into low (n = 139) and higher literacy level respondents (n = 714). They reported participation in leisure activities and completed measures of cognitive functioning at both waves. RESULTS: Cross-lagged models showed that participation in leisure activities predicted higher cognitive functioning four years later only among older adults with low literacy level. On the other hand, cognitive functioning predicted more participation in leisure activities four years later only among higher literacy level older adults. CONCLUSIONS: Participating in leisure activities may be especially beneficial to cognitive functioning among older adults with low literacy level, as their initial low cognitive level allows more room for cognitive improvement than among higher literacy level older adults. Public efforts aimed at increasing participation in leisure activities may therefore target particularly older adults with low basic cognitive level. PMID- 26745360 TI - Present, bioaccumulative, and toxic: Sufficient for PBT? PMID- 26745361 TI - Efficacy of a workplace relaxation exercise program on muscle tenderness in a working community with headache and neck pain: a longitudinal, controlled study. AB - BACKGROUND: Pericranial muscle tenderness shows a remarkable prevalence not only in tension-type headache, but also in migraine, both episodic and chronic. Neck pain is a common disorder and leads to a high rate of work disability; its prevalence increases for headache. AIM: This study aimed at examining the effects of a relaxation exercise programme on pericranial/cervical muscle tenderness in a working community with headache and neck pain. DESIGN: This was a controlled, non randomized trial. SETTING: The study was carried out in a working community, on the employees of the City of Turin's central and peripheral registry and tax offices. POPULATION: A total of 384 workers were enrolled and divided into two groups: a study group (group 1; 192 subjects) and a control group (group 2; 192 subjects). METHODS: A programme, with relaxation/posture exercises and a visual feedback, was carried out for Group 1 for 6 months and, afterwards, also for group 2 for the same follow-up period throughout. Data on head/neck pain were collected. Standard palpation of pericranial and cervical muscles was done, scoring each patient for Pericranial Muscle Tenderness (PTS) (0-3), Cervical Muscle Tenderness (CTS) (0-3) and a Cumulative Muscle Tenderness (CUM) (0-6). RESULTS: After 6 months from baseline, a significant difference was observed between the groups: i.e. group 1 had an average change from baseline of -0.19 for PTS, -0.2 for CTS and -0.36 for the CUM score - in association with a reduction in headache, neck and shoulder pain. The difference between the groups in PTS, CTS and CUM scores was no longer detectable at the end of the study, after also group 2 performed the programme. CONCLUSIONS: The administration of a workplace relaxation exercise intervention significantly decreased pericranial/cervical muscle tenderness in the working community, in association with head-neck pain benefit. CLINICAL REHABILITATION IMPACT: This relaxation exercise programme was remarkably cost-effective, yielding a relevant benefit on pericranial/cervical muscle tenderness in a working community, at a relatively low cost. PMID- 26745362 TI - Minimum data set to measure rehabilitation needs and health outcome after major trauma: application of an international framework. AB - BACKGROUND: Measurement of long term health outcome after trauma remains non standardized and ambiguous which limits national and international comparison of burden of injuries. The World Health Organization (WHO) has recommended the application of the International Classification of Function, Disability and Health (ICF) to measure rehabilitation and health outcome worldwide. No previous poly-trauma studies have applied the ICF comprehensively to evaluate outcome after injury. AIM: To apply the ICF categorization in patients with traumatic injuries to identify a minimum data set of important rehabilitation and health outcomes to enable national and international comparison of outcome data. DESIGN: A mixed methods design of patient interviews and an on-line survey. SETTING: An ethnically diverse urban major trauma center in London. POPULATION: Adult patients with major traumatic injuries (poly-trauma) and international health care professionals (HCPs) working in acute and post-acute major trauma settings. METHODS: Mixed methods investigated patients and health care professionals (HCPs) perspectives of important rehabilitation and health outcomes. Qualitative patient data and quantitative HCP data were linked to ICF categories. Combined data were refined to identify a minimum data set of important rehabilitation and health outcome categories. RESULTS: Transcribed patient interview data (N.=32) were linked to 234 (64%) second level ICF categories. Two hundred and fourteen HCPs identified 121 from a possible 140 second level ICF categories (86%) as relevant and important. Patients and HCPs strongly agreed on ICF body structures and body functions categories which include temperament, energy and drive, memory, emotions, pain and repair function of the skin. Conversely, patients prioritised domestic tasks, recreation and work compared to HCP priorities of self-care and mobility. Twenty six environmental factors were identified. Patient and HCP data were refined to recommend a 109 possible ICF categories for a minimum data set. CONCLUSIONS: The comprehensive measurement of health outcomes after trauma is important for patients, health professionals and trauma systems. An internationally applied ICF minimum data set will standardize the language used and concepts measured after major trauma to enable national and international comparison of outcome data. CLINICAL REHABILITATION IMPACT: A minimum ICF data set for trauma will standardize rehabilitation language and provide a minimum dataset to capture outcome in trauma systems to enable comparison and service improvement. PMID- 26745364 TI - Energy Budget of Liquid Drop Impact at Maximum Spreading: Numerical Simulations and Experiments. AB - The maximum spreading of an impinging droplet on a rigid surface is studied for low to high impact velocity, until the droplet starts splashing. We investigate experimentally and numerically the role of liquid properties, such as surface tension and viscosity, on drop impact using three liquids. It is found that the use of the experimental dynamic contact angle at maximum spreading in the Kistler model, which is used as a boundary condition for the CFD-VOF calculation, gives good agreement between experimental and numerical results. Analytical models commonly used to predict the boundary layer thickness and time at maximum spreading are found to be less correct, meaning that energy balance models relying on these relations have to be considered with care. The time of maximum spreading is found to depend on both the impact velocity and surface tension, and neither dependency is predicted correctly in common analytical models. The relative proportion of the viscous dissipation in the total energy budget increases with impact velocity with respect to surface energy. At high impact velocity, the contribution of surface energy, even before splashing, is still substantial, meaning that both surface energy and viscous dissipation have to be taken into account, and scaling laws depending only on viscous dissipation do not apply. At low impact velocity, viscous dissipation seems to play an important role in low-surface-tension liquids such as ethanol. PMID- 26745363 TI - Remote Ischemic Preconditioning May Attenuate Renal Ischemia-Reperfusion Injury in a Porcine Model of Supraceliac Aortic Cross-Clamping. AB - AIM: The effect of remote ischemic preconditioning (RIPC) in decreasing renal ischemia-reperfusion injury (IRI) during a suprarenal aortic cross-clamping was examined in a swine model. MATERIALS AND METHODS: Four groups of pigs were examined: (a) ischemia-reperfusion (IR) group, renal IRI produced by 30 min of supraceliac aortic cross-clamping; (b) RIPC I group, the same renal IRI following RIPC by brief occlusion of the infrarenal aorta (15 min ischemia and 15 min reperfusion); (c) RIPC II group, the same renal IRI following RIPC by brief occlusion of the infrarenal aorta (3 cycles of 5 min ischemia and 5 min reperfusion); (d) sham group. Renal function was assessed before and after IRI by examining creatinine, neutrophil gelatinase-associated lipocalin (NGAL), TNF alpha, malondialdehyde (MDA), cystatin C and C-reactive protein (CRP) from renal vein blood samples at specific time intervals. RESULTS: Both RIPC groups presented significantly less impaired results compared to the IR group when considering MDA, cystatin C, CRP and creatinine. Between the two RIPC groups, RIPC II presented a better response with regard to CRP, NGAL, TNF-alpha, MDA and cystatin C. CONCLUSIONS: Remote IR protocols and mainly repetitive short periods of cycles of IR ameliorate the biochemical kidney effects of IRI in a model of suprarenal aortic aneurysm repair. PMID- 26745365 TI - Genetic and Quantitative Trait Locus Analysis for Bio-Oil Compounds after Fast Pyrolysis in Maize Cobs. AB - Fast pyrolysis has been identified as one of the biorenewable conversion platforms that could be a part of an alternative energy future, but it has not yet received the same attention as cellulosic ethanol in the analysis of genetic inheritance within potential feedstocks such as maize. Ten bio-oil compounds were measured via pyrolysis/gas chromatography-mass spectrometry (Py/GC-MS) in maize cobs. 184 recombinant inbred lines (RILs) of the intermated B73 x Mo17 (IBM) Syn4 population were analyzed in two environments, using 1339 markers, for quantitative trait locus (QTL) mapping. QTL mapping was performed using composite interval mapping with significance thresholds established by 1000 permutations at alpha = 0.05. 50 QTL were found in total across those ten traits with R2 values ranging from 1.7 to 5.8%, indicating a complex quantitative inheritance of these traits. PMID- 26745367 TI - Effects of absolute and relative practice on n-2 repetition costs. AB - Recently, Grange and Juvina (2015) found decreasing n-2 repetition costs with increasing practice. However, in their experiment, no differentiation between absolute and relative strength of the three tasks was possible because all tasks were practiced to the same degree. To further elucidate this issue, two experiments were designed in which for one of the three tasks, aspects of the task set changed during the course of the experiment (Exp. I: Stimulus-response mapping, Exp. II: Cue-task mapping). Replicating Grange and Juvina (2015), decreasing n-2 repetition costs with increasing practice were observed, but the change of stimulus-response mappings in Exp. I did not affect n-2 repetition costs. In Exp. II, n-2 repetition costs were affected by the change of the cue task-mapping, but no effect of absolute practice was visible. These results suggest that absolute practice influences n-2 repetition costs as long as no change in relative strength is introduced on the level of mapping cues to tasks. If, however, relative task strength is varied, its impact overrides the influence of absolute practice. In addition, the data pattern points towards cue-related instead of response-related inhibitory processes causing n-2 repetition costs. PMID- 26745366 TI - Macroalgal Morphogenesis Induced by Waterborne Compounds and Bacteria in Coastal Seawater. AB - Axenic gametes of the marine green macroalga Ulva mutabilis Foyn (Ria Formosa, locus typicus) exhibit abnormal development into slow-growing callus-like colonies with aberrant cell walls. Under laboratory conditions, it was previously demonstrated that all defects in growth and thallus development can be completely abolished when axenic gametes are inoculated with a combination of two specific bacterial strains originally identified as Roseobacter sp. strain MS2 and Cytophaga sp. strain MS6. These bacteria release diffusible morphogenetic compounds (= morphogens), which act similar to cytokinin and auxin. To investigate the ecological relevance of the waterborne bacterial morphogens, seawater samples were collected in the Ria Formosa lagoon (Algarve, Southern Portugal) at 20 sampling sites and tidal pools to assess their morphogenetic effects on the axenic gametes of U. mutabilis. Specifically the survey revealed that sterile-filtered seawater samples can completely recover growth and morphogenesis of U. mutabilis under axenic conditions. Morphogenetic activities of free-living and epiphytic bacteria isolated from the locally very abundant Ulva species (i.e., U. rigida) were screened using a multiwell-based testing system. The most represented genera isolated from U. rigida were Alteromonas, Pseudoalteromonas and Sulfitobacter followed by Psychrobacter and Polaribacter. Several naturally occurring bacterial species could emulate MS2 activity (= induction of cell divisions) regardless of taxonomic affiliation, whereas the MS6 activity (= induction of cell differentiation and cell wall formation) was species-specific and is probably a feature of difficult-to-culture bacteria. Interestingly, isolated bacteroidetes such as Algoriphagus sp. and Polaribacter sp. could individually trigger complete Ulva morphogenesis and thus provide a novel mode of action for bacterial-induced algal development. This study also highlights that the accumulation of algal growth factors in a shallow water body separated from the open ocean by barrier islands might have strong implications to, for example, the wide usage of natural coastal seawater in algal (land based) aquacultures of Ulva. PMID- 26745368 TI - Speed on the dance floor: Auditory and visual cues for musical tempo. AB - Musical tempo is most strongly associated with the rate of the beat or "tactus," which may be defined as the most prominent rhythmic periodicity present in the music, typically in a range of 1.67-2 Hz. However, other factors such as rhythmic density, mean rhythmic inter-onset interval, metrical (accentual) structure, and rhythmic complexity can affect perceived tempo (Drake, Gros, & Penel, 1999; London, 2011 Drake, Gros, & Penel, 1999; London, 2011). Visual information can also give rise to a perceived beat/tempo (Iversen, et al., 2015), and auditory and visual temporal cues can interact and mutually influence each other (Soto Faraco & Kingstone, 2004; Spence, 2015). A five-part experiment was performed to assess the integration of auditory and visual information in judgments of musical tempo. Participants rated the speed of six classic R&B songs on a seven point scale while observing an animated figure dancing to them. Participants were presented with original and time-stretched (+/-5%) versions of each song in audio only, audio+video (A+V), and video-only conditions. In some videos the animations were of spontaneous movements to the different time-stretched versions of each song, and in other videos the animations were of "vigorous" versus "relaxed" interpretations of the same auditory stimulus. Two main results were observed. First, in all conditions with audio, even though participants were able to correctly rank the original vs. time-stretched versions of each song, a song specific tempo-anchoring effect was observed, such that sped-up versions of slower songs were judged to be faster than slowed-down versions of faster songs, even when their objective beat rates were the same. Second, when viewing a vigorous dancing figure in the A+V condition, participants gave faster tempo ratings than from the audio alone or when viewing the same audio with a relaxed dancing figure. The implications of this illusory tempo percept for cross-modal sensory integration and working memory are discussed, and an "energistic" account of tempo perception is proposed. PMID- 26745369 TI - Transfer of an implied incompatible spatial mapping to a Simon task. AB - When location words left and right are presented in left and right locations and mapped to left and right keypress responses in the Hedge and Marsh (1975) task (Arend & Wandmacher, 1987), a compatible mapping of words to responses yields a benefit for stimulus-response location correspondence (sometimes called the Simon effect), whereas an incompatible mapping yields a benefit for noncorrespondence (called the Hedge and Marsh reversal). Experiment 1 replicated the correspondence benefit and its reversal by using Chinese location words [symbol: see text] (left) and [symbol: see text] (right) in the Hedge and Marsh task. Experiments 2 and 3 examined whether the tendency to respond with the noncorresponding response when the mapping is incompatible transfers to the task version in which the mapping is compatible, and Experiment 4 examined whether transfer similarly occurs from the compatible mapping to the task version with incompatible mapping. Transfer of the incompatible relation was apparent in a lack of correspondence benefit when the mapping was changed to compatible, but transfer of the compatible relation to the incompatible mapping did not occur. The results suggest that an association between noncorresponding stimulus-response locations is acquired when the word-response mapping is incompatible, even though this relation is only implicit, regardless of whether through misapplication of a logical recoding rule or spatial representations shared by the locations and words. These associations then continue to affect processing of location when the mapping is compatible. PMID- 26745370 TI - Computational Intelligence and Wavelet Transform Based Metamodel for Efficient Generation of Not-Yet Simulated Waveforms. AB - The design and verification of complex electronic systems, especially the analog and mixed-signal ones, prove to be extremely time consuming tasks, if only circuit-level simulations are involved. A significant amount of time can be saved if a cost effective solution is used for the extensive analysis of the system, under all conceivable conditions. This paper proposes a data-driven method to build fast to evaluate, but also accurate metamodels capable of generating not yet simulated waveforms as a function of different combinations of the parameters of the system. The necessary data are obtained by early-stage simulation of an electronic control system from the automotive industry. The metamodel development is based on three key elements: a wavelet transform for waveform characterization, a genetic algorithm optimization to detect the optimal wavelet transform and to identify the most relevant decomposition coefficients, and an artificial neuronal network to derive the relevant coefficients of the wavelet transform for any new parameters combination. The resulted metamodels for three different waveform families are fully reliable. They satisfy the required key points: high accuracy (a maximum mean squared error of 7.1x10-5 for the unity based normalized waveforms), efficiency (fully affordable computational effort for metamodel build-up: maximum 18 minutes on a general purpose computer), and simplicity (less than 1 second for running the metamodel, the user only provides the parameters combination). The metamodels can be used for very efficient generation of new waveforms, for any possible combination of dependent parameters, offering the possibility to explore the entire design space. A wide range of possibilities becomes achievable for the user, such as: all design corners can be analyzed, possible worst-case situations can be investigated, extreme values of waveforms can be discovered, sensitivity analyses can be performed (the influence of each parameter on the output waveform). PMID- 26745371 TI - Dendritic Cells Induce a Subpopulation of IL-12Rbeta2-Expressing Treg that Specifically Consumes IL-12 to Control Th1 Responses. AB - Cytokines secreted from dendritic cells (DCs) play an important role in the regulation of T helper (Th) cell differentiation and activation into effector cells. Therefore, controlling cytokine secretion from DCs may potentially regulate Th differentiation/activation. DCs also induce de-novo generation of regulatory T cells (Treg) that modulate the immune response. In the current study we used the mixed leukocyte reaction (MLR) to investigate the effect of allospecific Treg on IL-12, TNFalpha and IL-6 secretion by DCs. Treg cells were found to markedly down-regulate IL-12 secretion from DCs following stimulation with TLR7/8 agonist. This down-regulation of IL-12 was neither due to a direct suppression of its production by the DCs nor a result of marked DC death. We found that IL-12 was rather actively consumed by Treg cells. IL-12 consumption was mediated by a subpopulation of IL-12Rbeta2-expressing Treg cells and was dependent on MHC class-II expressed on dendritic cells. Furthermore, IL-12 consumption by Tregs increased their suppressive effect on T cell proliferation and Th1 activation. These results provide a new pathway of Th1 response regulation where IL-12 secreted by DCs is consumed by a sub-population of IL 12Rbeta2-expressing Treg cells. Consumption of IL-12 by Tregs not only reduces the availability of IL-12 to Th effector cells but also enhances the Treg immunosuppressive effect. This DC-induced IL-12Rbeta2-expressing Treg subpopulation may have a therapeutic advantage in suppressing Th1 mediated autoimmunity. PMID- 26745373 TI - Expression of Human NSAID Activated Gene 1 in Mice Leads to Altered Mammary Gland Differentiation and Impaired Lactation. AB - Transgenic mice expressing human non-steroidal anti-inflammatory drug activated gene 1 (NAG-1) have less adipose tissue, improved insulin sensitivity, lower insulin levels and are resistant to dietary induced obesity. The hNAG-1 expressing mice are more metabolically active with a higher energy expenditure. This study investigates female reproduction in the hNAG-1 transgenic mice and finds the female mice are fertile but have reduced pup survival after birth. Examination of the mammary glands in these mice suggests that hNAG-1 expressing mice have altered mammary epithelial development during pregnancy, including reduced occupancy of the fat pad and increased apoptosis via TUNEL positive cells on lactation day 2. Pups nursing from hNAG-1 expressing dams have reduced milk spots compared to pups nursing from WT dams. When CD-1 pups were cross-fostered with hNAG-1 or WT dams; reduced milk volume was observed in pups nursing from hNAG-1 dams compared to pups nursing from WT dams in a lactation challenge study. Milk was isolated from WT and hNAG-1 dams, and the milk was found to have secreted NAG-1 protein (approximately 25 ng/mL) from hNAG-1 dams. The WT dams had no detectable hNAG-1 in the milk. A decrease in non-esterified free fatty acids in the milk of hNAG-1 dams was observed. Altered milk composition suggests that the pups were receiving inadequate nutrients during perinatal development. To examine this hypothesis serum was isolated from pups and clinical chemistry points were measured. Male and female pups nursing from hNAG-1 dams had reduced serum triglyceride concentrations. Microarray analysis revealed that genes involved in lipid metabolism are differentially expressed in hNAG-1 mammary glands. Furthermore, the expression of Cidea/CIDEA that has been shown to regulate milk lipid secretion in the mammary gland was reduced in hNAG-1 mammary glands. This study suggests that expression of hNAG-1 in mice leads to impaired lactation and reduces pup survival due to altered milk quality and quantity. PMID- 26745372 TI - Forecasting Ecological Genomics: High-Tech Animal Instrumentation Meets High Throughput Sequencing. AB - Recent advancements in animal tracking technology and high-throughput sequencing are rapidly changing the questions and scope of research in the biological sciences. The integration of genomic data with high-tech animal instrumentation comes as a natural progression of traditional work in ecological genetics, and we provide a framework for linking the separate data streams from these technologies. Such a merger will elucidate the genetic basis of adaptive behaviors like migration and hibernation and advance our understanding of fundamental ecological and evolutionary processes such as pathogen transmission, population responses to environmental change, and communication in natural populations. PMID- 26745374 TI - A Recombinant Positive Control for Serology Diagnostic Tests Supporting Elimination of Onchocerca volvulus. AB - BACKGROUND: Serological assays for human IgG4 to the Onchocerca volvulus antigen Ov16 have been used to confirm elimination of onchocerciasis in much of the Americas and parts of Africa. A standardized source of positive control antibody (human anti-Ov16 IgG4) will ensure the quality of surveillance data using these tests. METHODOLOGY/PRINCIPAL FINDINGS: A recombinant human IgG4 antibody to Ov16 was identified by screening against a synthetic human Fab phage display library and converted into human IgG4. This antibody was developed into different positive control formulations for enzyme-linked immunosorbent assay (ELISA) and rapid diagnostic test (RDT) platforms. Variation in ELISA results and utility as a positive control of the antibody were assessed from multiple laboratories. Temperature and humidity conditions were collected across seven surveillance activities from 2011-2014 to inform stability requirements for RDTs and positive controls. The feasibility of the dried positive control for RDT was evaluated during onchocerciasis surveillance activity in Togo, in 2014. When the anti-Ov16 IgG4 antibody was used as a standard dilution in horseradish peroxidase (HRP) and alkaline phosphatase (AP) ELISAs, the detection limits were approximately 1ng/mL by HRP ELISA and 10ng/mL by AP ELISA. Positive control dilutions and spiked dried blood spots (DBS) produced similar ELISA results. Used as a simple plate normalization control, the positive control antibody may improve ELISA data comparison in the context of inter-laboratory variation. The aggregate temperature and humidity monitor data informed temperature parameters under which the dried positive control was tested and are applicable inputs for testing of diagnostics tools intended for sub-Saharan Africa. As a packaged positive control for Ov16 RDTs, stability of the antibody was demonstrated for over six months at relevant temperatures in the laboratory and for over 15 weeks under field conditions. CONCLUSIONS: The recombinant human anti-Ov16 IgG4 antibody-based positive control will benefit inter-laboratory validation of ELISA assays and serve as quality control (QC) reagents for Ov16 RDTs at different points of the supply chain from manufacturer to field use. PMID- 26745375 TI - An Extended N-Player Network Game and Simulation of Four Investment Strategies on a Complex Innovation Network. AB - As computer science and complex network theory develop, non-cooperative games and their formation and application on complex networks have been important research topics. In the inter-firm innovation network, it is a typical game behavior for firms to invest in their alliance partners. Accounting for the possibility that firms can be resource constrained, this paper analyzes a coordination game using the Nash bargaining solution as allocation rules between firms in an inter-firm innovation network. We build an extended inter-firm n-player game based on nonidealized conditions, describe four investment strategies and simulate the strategies on an inter-firm innovation network in order to compare their performance. By analyzing the results of our experiments, we find that our proposed greedy strategy is the best-performing in most situations. We hope this study provides a theoretical insight into how firms make investment decisions. PMID- 26745376 TI - Polyfunctional HIV-Specific Antibody Responses Are Associated with Spontaneous HIV Control. AB - Elite controllers (ECs) represent a unique model of a functional cure for HIV-1 infection as these individuals develop HIV-specific immunity able to persistently suppress viremia. Because accumulating evidence suggests that HIV controllers generate antibodies with enhanced capacity to drive antibody-dependent cellular cytotoxicity (ADCC) that may contribute to viral containment, we profiled an array of extra-neutralizing antibody effector functions across HIV-infected populations with varying degrees of viral control to define the characteristics of antibodies associated with spontaneous control. While neither the overall magnitude of antibody titer nor individual effector functions were increased in ECs, a more functionally coordinated innate immune-recruiting response was observed. Specifically, ECs demonstrated polyfunctional humoral immune responses able to coordinately recruit ADCC, other NK functions, monocyte and neutrophil phagocytosis, and complement. This functionally coordinated response was associated with qualitatively superior IgG3/IgG1 responses, whereas HIV-specific IgG2/IgG4 responses, prevalent among viremic subjects, were associated with poorer overall antibody activity. Rather than linking viral control to any single activity, this study highlights the critical nature of functionally coordinated antibodies in HIV control and associates this polyfunctionality with preferential induction of potent antibody subclasses, supporting coordinated antibody activity as a goal in strategies directed at an HIV-1 functional cure. PMID- 26745377 TI - Molecular Mechanisms Responsible for Neuron-Derived Conditioned Medium (NCM) Mediated Protection of Ischemic Brain. AB - The protective value of neuron-derived conditioned medium (NCM) in cerebral ischemia and the underlying mechanism(s) responsible for NCM-mediated brain protection against cerebral ischemia were investigated in the study. NCM was first collected from the neuronal culture growing under the in vitro ischemic condition (glucose-, oxygen- and serum-deprivation or GOSD) for 2, 4 or 6 h. Through the focal cerebral ischemia (bilateral CCAO/unilateral MCAO) animal model, we discovered that ischemia/reperfusion (I/R)-induced brain infarction was significantly reduced by NCM, given directly into the cistern magna at the end of 90 min of CCAO/MCAO. Immunoblocking and chemical blocking strategies were applied in the in vitro ischemic studies to show that NCM supplement could protect microglia, astrocytes and neurons from GOSD-induced cell death, in a growth factor (TGFbeta1, NT-3 and GDNF) and p-ERK dependent manner. Brain injection with TGFbeta1, NT3, GDNF and ERK agonist (DADS) alone or in combination, therefore also significantly decreased the infarct volume of ischemic brain. Moreover, NCM could inhibit ROS but stimulate IL-1beta release from GOSD-treated microglia and limit the infiltration of IL-beta-positive microglia into the core area of ischemic brain, revealing the anti-oxidant and anti-inflammatory activities of NCM. In overall, NCM-mediated brain protection against cerebral ischemia has been demonstrated for the first time in S.D. rats, due to its anti-apoptotic, anti oxidant and potentially anti-glutamate activities (NCM-induced IL-1beta can inhibit the glutamate-mediated neurotoxicity) and restriction upon the infiltration of inflammatory microglia into the core area of ischemic brain. The therapeutic potentials of NCM, TGFbeta1, GDNF, NT-3 and DADS in the control of cerebral ischemia in human therefore have been suggested and require further investigation. PMID- 26745380 TI - PCDDs, PCDFs and PCBs in farmed fish produced in Greece: Levels and human population exposure assessment. AB - Fish is among the essential components of Mediterranean diet and has beneficial effects on human health. Farmed fish is an affordable alternative to wild fish and a significant food export product for Greece. Published studies worldwide have reported significant levels of environmental pollutants in fish tissues. Especially for PCDDs/Fs and PCBs, the studies suggest that the most important contribution to human dietary intake is from fish and seafood. In the present study, we investigate the levels of PCDDs/Fs, dioxin-like and non dioxin-like PCBs in the most common farmed fish species produced in Greece i.e. sea bass, sea bream and rainbow trout. These species are widely consumed in Greece and are also exported to many countries worldwide. The mean levels found were WHO-PCDD/F-TEQ: 0.22 pg g(-1) wet weight (w.w.), WHO-PCDD/F-PCB-TEQ: 0.88 pg g(-1) w.w. for sea bream, WHO-PCDD/F-TEQ: 0.13 pg g(-1) w.w., WHO-PCDD/F-PCB-TEQ: 0.68 pg g(-1) w.w. for sea bass and WHO-PCDD/F-TEQ: 0.10 pg g(-1) w.w., WHO-PCDD/F-PCB-TEQ: 0.43 pg g(-1) w.w. for rainbow trout. For non dioxin-like PCBs, mean sum values found were 8.02 ng g(-1) w.w. for sea bream, 5.24 ng g(-1) w.w. for sea bass and 2.90 ng g(-1) w.w. for rainbow trout. All concentrations found were far below maximum levels set by the European Union and in the same range as wild-caught fish also presented for comparison. Daily intake from the consumption of farmed fish species examined is calculated at 1.3 pg WHO-TEQ kg(-1) b.w., which is at the lowest end of TDI values proposed by the WHO. PMID- 26745378 TI - The role of small RNAs in vegetative shoot development. AB - Shoot development consists of the production of lateral organs in predictable spatial and temporal patterns at the shoot apex. To properly integrate such programs of growth across different cell and tissue types, plants require highly complex and robust genetic networks. Over the last twenty years, the roles of small, non-coding RNAs (sRNAs) in these networks have become increasingly apparent, not least in vegetative shoot growth. In this review, we describe recent progress in understanding the contribution of sRNAs to the regulation of vegetative shoot growth, and outline persisting experimental limitations in the field. PMID- 26745381 TI - Electrochemical oxidation of perfluorinated compounds in water. AB - Perfluorinated compounds (PFCs) are persistent and refractory organic pollutants that have been detected in various environmental matrices and municipal wastewater. Electrochemical oxidation (EO) is a promising remediation technique for wastewater contaminated with PFCs. A number of recent studies have demonstrated that the "non-active" anodes, including boron-doped diamond, tin oxide, and lead dioxide, are effective in PFCs elimination in wastewater due to their high oxygen evolution potential. Many researchers have conducted experiments to investigate the optimal conditions (i.e., potential, current density, pH value, plate distance, initial PFCs concentration, electrolyte, and other factors) for PFCs elimination to obtain the maximal elimination efficiency and current efficiency. The EO mechanism and pathways of PFCs have been clearly elucidated, which undergo electron transfer, Kolbe decarboxylation or desulfonation, hydrolysis, and radical reaction. In addition, the safety evaluation and energy consumption evaluation of the EO technology have also been summarized to decrease toxic ion release from electrode and reduce the cost of this technique. Although the ultrasonication and hydrothermal techniques combined with the EO process can improve the removal efficiency and current efficiency significantly, these coupled techniques have not been commercialized and applied in industrial wastewater treatment. Finally, key challenges facing EO technology are listed and the directions for further research are pointed out (such as combination with other techniques, treatment for natural waters contaminated by low levels of PFCs, and reactor design). PMID- 26745382 TI - Insights into siloxane removal from biogas in biotrickling filters via process mapping-based analysis. AB - Data process mapping using response surface methodology (RSM)-based computational techniques is performed in this study for the diagnosis of a laboratory-scale biotrickling filter applied for siloxane (i.e. octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5)) removal from biogas. A mathematical model describing the process performance (i.e. Si removal efficiency, %) was obtained as a function of key operating parameters (e.g biogas flowrate, D4 and D5 concentration). The contour plots and the response surfaces generated for the obtained objective function indicate a minimization trend in siloxane removal performance, however a maximum performance of approximately 60% Si removal efficiency was recorded. Analysis of the process mapping results provides indicators of improvement to biological system performance. PMID- 26745379 TI - Factors Associated with Participation, Active Refusals and Reasons for Not Taking Part in a Mortality Followback Survey Evaluating End-of-Life Care. AB - BACKGROUND: Examination of factors independently associated with participation in mortality followback surveys is rare, even though these surveys are frequently used to evaluate end-of-life care. We aimed to identify factors associated with 1) participation versus non-participation and 2) provision of an active refusal versus a silent refusal; and systematically examine reasons for refusal in a population-based mortality followback survey. METHODS: Postal survey about the end-of-life care received by 1516 people who died from cancer (aged >=18), identified through death registrations in London, England (response rate 39.3%). The informant of death (a relative in 95.3% of cases) was contacted 4-10 months after the patient died. We used multivariate logistic regression to identify factors associated with participation/active refusals and content analysis to examine refusal reasons provided by 205 nonparticipants. FINDINGS: The odds of partaking were higher for patients aged 90+ (AOR 3.48, 95%CI: 1.52-8.00, ref: 20 49yrs) and female informants (AOR 1.70, 95%CI: 1.33-2.16). Odds were lower for hospital deaths (AOR 0.62, 95%CI: 0.46-0.84, ref: home) and proxies other than spouses/partners (AORs 0.28 to 0.57). Proxies of patients born overseas were less likely to provide an active refusal (AOR 0.49; 95% CI: 0.32-0.77). Refusal reasons were often multidimensional, most commonly study-related (36.0%), proxy related and grief-related (25.1% each). One limitation of this analysis is the large number of nonparticipants who did not provide reasons for refusal (715/920). CONCLUSIONS: Our survey better reached proxies of older patients while those dying in hospitals were underrepresented. Proxy characteristics played a role, with higher participation from women and spouses/partners. More information is needed about the care received by underrepresented groups. Study design improvements may guide future questionnaire development and help develop strategies to increase response rates. PMID- 26745383 TI - Variation of the phytotoxicity of municipal solid waste incinerator bottom ash on wheat (Triticum aestivum L.) seed germination with leaching conditions. AB - Municipal solid waste incinerator bottom ash (MSWIBA) has long been regarded as an alternative building material in the construction industry. However, the pollutants contained in the bottom ash could potentially leach out and contaminate the local environment, which presents an obstacle to the reuse of the materials. To evaluate the environmental feasibility of using MSWIBA as a recycled material in construction, the leaching derived ecotoxicity was assessed. The leaching behavior of MSWIBA under various conditions, including the extractant type, leaching time, liquid-to-solid (L/S) ratio, and leachate pH were investigated, and the phytotoxicity of these leachates on wheat (Triticum aestivum L.) seed germination was determined. Moreover, the correlation between the germination index and the concentrations of various chemical constituents in the MSWIBA leachates was assessed using multivariate statistics with principal component analysis and Pearson's correlation analysis. It was found that, heavy metal concentrations in the leachate were pH and L/S ratio dependent, but were less affected by leaching time. Heavy metals were the main pollutants present in wheat seeds. Heavy metals (especially Ba, Cr, Cu and Pb) had a substantial inhibitory effect on wheat seed germination and root elongation. To safely use MSWIBA in construction, the potential risk and ecotoxicity of leached materials must be addressed. PMID- 26745384 TI - Evaluation of hepatic biotransformation of polybrominated diphenyl ethers in the polar bear (Ursus maritimus). AB - Polar bears are at the top of the Arctic marine food chain and are subject to exposure and bioaccumulation of environmental chemicals of concern such as polybrominated diphenyl ethers (PBDEs), which were widely used as flame retardants. The aim of the present study was to evaluate the in vitro oxidative metabolism of 2,2',4,4'-tetrabrominated diphenyl ether (BDE-47) and 2,2',4,4',5 pentabrominated diphenyl ether (BDE-99) by polar bear liver microsomes. The identification and quantification of the hydroxy-brominated diphenyl ethers formed were assessed using an ultra-high performance liquid chromatography-tandem mass spectrometry-based method. Incubation of BDE-47 with archived individual liver microsomes, prepared from fifteen polar bears from northern Canada, produced a total of eleven hydroxylated metabolites, eight of which were identified using authentic standards. The major metabolites were 4'-hydroxy 2,2',4,5'-tetrabromodiphenyl ether and 5'-hydroxy-2,2',4,4'-tetrabromodiphenyl ether. Incubation of BDE-99 with polar bear liver microsomes produced a total of eleven hydroxylated metabolites, seven of which were identified using authentic standards. The major metabolites were 2,4,5-tribromophenol and 4-hydroxy 2,2',3,4',5-pentabromodiphenyl ether. Among the CYP specific antibodies tested, anti-rat CYP2B was found to be the most active in inhibiting the formation of hydroxylated metabolites of both BDE-47 and BDE-99, indicating that CYP2B was the major CYP enzyme involved in the oxidative biotransformation of these two congeners. Our study shows that polar bears are capable of forming multiple hydroxylated metabolites of BDE-47 and BDE-99 in vitro and demonstrates the role of CYP2B in the biotransformation and possibly in the toxicity of BDE-47 and BDE 99 in polar bears. PMID- 26745385 TI - Long-term exposure to caffeine and carbamazepine: Impacts on the regenerative capacity of the polychaete Diopatra neapolitana. AB - The toxicity induced in non-target organisms by pharmaceutical drugs has been the focus of several studies. In the aquatic environment, most of the studies have been devoted to fish and bivalves, while little is known on the impacts induced in polychaetes. The present study evaluated the impacts of carbamazepine and caffeine on the regenerative capacity of Diopatra neapolitana, a polychaete species with high ecological and economic relevance. Under laboratory controlled conditions polychaetes were exposed, during 28 days, to carbamazepine (Ctl-0.0; 0.3; 3.0; 6.0; 9.0 MUg/L) and caffeine (Ctl-0.0; 0.5; 3.0; 18.0 MUg/L). During the experiment, at days 11, 18, 25, 32, 39 and 46 after amputation, for each specimen, the percentage of the body width regenerated was determined and the number of new segments was counted. The regenerative capacity was assessed considering the number of days needed to achieve full regeneration and the total number of new segments. The obtained results revealed that with the increase of drugs concentrations organisms regenerated less new segments and took longer to completely regenerate. PMID- 26745387 TI - Activity, Expression, and Substrate Preference of the Delta(6)-Desaturase in Slow or Fast-Growing Rabbit Genotypes. AB - In the present paper liver fatty acid Delta(6) desaturation (fads2) activity was analyzed in two rabbit strains with slow- (S, 27.5 g/day) or fast-growing (F, 48.5 g/day) rate. The fatty acid profile of the liver showed a different PUFA profile in the two strains with a lower n-6/n-3 ratio in the S rabbits. The expression of fads2 was 2-fold higher in S than in F rabbits, whereas enzyme activity was higher in F and more oriented toward the desaturation of linoleic acid (90%). In contrast, S showed a higher preference for linolenic acid (38.9 vs 10%). This study identified a single difference in the fads2 amino acid sequence between these two strains. Such a difference consists in the substitution of Gly104 to Ser104 in the sequence of F fads2. These results indicate for the first time that genetic selection for performance may affect the preference for PUFA toward desaturation of linoleic/linolenic acid. PMID- 26745388 TI - Advances in treatment strategies for ischemia reperfusion injury. AB - INTRODUCTION: Ischemia-reperfusion injury (IRI) involves a complex sequence of events and limits the outcome of various surgical interventions. Clinical trials, based on the data of experimental models, aim to prove whether a pharmacological or technical approach could be suitable to provide a beneficial effect in humans. Due to the complexity of IRI, few pharmacological treatments have been investigated in clinical Phase III. AREAS COVERED: In this review we report clinical trials that test specific drugs in clinical trials of organ transplantation. These studies form part of Phase II trials and examine the administration of caspase inhibitors, P-selectin antagonist or an antioxidant component in order to attenuate cold IRI during transplantation. Moreover, we provide a brief description of drugs tested on trials of different clinical situations associated to IRI, such as the coronary artery bypass graft surgery and percutaneous coronary intervention. EXPERT OPINION: Future clinical trials could be centered on the application of techniques suitable for organs with increased vulnerability toward IRI. Furthermore, the standardization of reliable biomarkers and a careful estimation of the impact of high risk factors may be the key in order to achieve a more critical evaluation of the obtained results. PMID- 26745386 TI - Tetrachlorobenzoquinone exhibits neurotoxicity by inducing inflammatory responses through ROS-mediated IKK/IkappaB/NF-kappaB signaling. AB - Tetrachlorobenzoquinone (TCBQ) is a joint metabolite of persistent organic pollutants (POPs), hexachlorobenzene (HCB) and pentachlorophenol (PCP). Previous studies have been reported that TCBQ contributes to acute hepatic damage due to its pro-oxidative nature. In the current study, TCBQ showed the highest capacity on the cytotoxicity, ROS formation and inflammatory cytokines release among four compounds, i.e., HCB, PCP, tetrachlorohydroquinone (TCHQ, reduced form of TCBQ) and TCBQ, in PC 12 cells. Further mechanistic study illustrated TCBQ activates nuclear factor-kappa B (NF-kappaB) signaling. The activation of NF-kappaB was identified by measuring the protein expressions of inhibitor of nuclear factor kappa-B kinase (IKK) alpha/beta, p-IKKalpha/beta, an inhibitor of NF-kappaB (IkappaB) alpha, p-IkappaBalpha, NF-kappaB (p65) and p-p65. The translocation of NF-kappaB was assessed by Western blotting of p65 in nuclear/cytosolic fractions, electrophoretic mobility shift assay (EMSA) and luciferase reporter gene assay. In addition, TCBQ significantly induced protein and mRNA expressions of inflammatory cytokines and mediators, such as interleukin-1 beta (IL-1beta), IL 6, tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and the production of nitric oxide (NO) and prostaglandin E2 (PGE2). Pyrrolidine dithiocarbamate (PDTC), a specific NF-kappaB inhibitor inhibited these effects efficiently, further suggested TCBQ-induced inflammatory responses involve NF-kappaB signaling. Moreover, antioxidants, i.e., N-acetyl-l-cysteine (NAC), Vitamin E and curcumin, ameliorated TCBQ-induced ROS generation as well as the activation of NF-kappaB, which implied that ROS serve as the upstream molecule of NF-kappaB signaling. In summary, TCBQ exhibits a neurotoxic effect by inducing oxidative stress-mediated inflammatory responses via the activation of IKK/IkappaB/NF-kappaB pathway in PC12 cells. PMID- 26745389 TI - Monodispersed calcium carbonate nanoparticles modulate local pH and inhibit tumor growth in vivo. AB - The acidic extracellular environment of tumors potentiates their aggressiveness and metastasis, but few methods exist to selectively modulate the extracellular pH (pHe) environment of tumors. Transient flushing of biological systems with alkaline fluids or proton pump inhibitors is impractical and nonselective. Here we report a nanoparticles-based strategy to intentionally modulate the pHe in tumors. Biochemical simulations indicate that the dissolution of calcium carbonate nanoparticles (nano-CaCO3) in vivo increases pH asymptotically to 7.4. We developed two independent facile methods to synthesize monodisperse non-doped vaterite nano-CaCO3 with distinct size range between 20 and 300 nm. Using murine models of cancer, we demonstrate that the selective accumulation of nano-CaCO3 in tumors increases tumor pH over time. The associated induction of tumor growth stasis is putatively interpreted as a pHe increase. This study establishes an approach to prepare nano-CaCO3 over a wide particle size range, a formulation that stabilizes the nanomaterials in aqueous solutions, and a pH-sensitive nano platform capable of modulating the acidic environment of cancer for potential therapeutic benefits. PMID- 26745390 TI - Cross-Linked Chitosan as an Efficient Binder for Si Anode of Li-ion Batteries. AB - We investigate the use of chitosan (CS) as a new cross-linkable and water-soluble binder for the Si anode of Li-ion batteries. In contrast to the traditional binder utilizing a hydrogen bond and/or van der Waals force-linked anode electrodes, CS can easily form a 3D network to limit the movement of Si particles through the cross-linking between the amino groups of CS and the dialdehyde of glutaraldehyde (GA). Chemical, mechanical, and morphological analyses are conducted by Fourier transform infrared spectroscopy, tensile testing, and scanning electron microscopy. The cross-linked Si/CS-GA anode exhibits an initial discharge capacity of 2782 mAh g(-1) with a high initial Coulombic efficiency of 89% and maintained a capacity of 1969 mAh g(-1) at the current density of 500 mA g(-1) over 100 cycles. PMID- 26745391 TI - The impact of sperm morphology on the outcome of intrauterine insemination cycles with gonadotropins in unexplained and male subfertility. AB - OBJECTIVE: To determine the impact of sperm morphology on success of intrauterine insemination (IUI) in unexplained and male subfertility. STUDY DESIGN: Basal and post-wash normal percentage of sperm with normal morphology was assessed prospectively in 412 couples with 530 IUI cycles who underwent ovarian hyperstimulation with gonadotropins. The primary outcome was live birth per cycle. Receiver operating characteristics (ROC) curves were used to determine the effectiveness of sperm morphology to predict live birth in IUI cycles. RESULTS: Normal sperm morphology (%) after preparation was higher in patients with live birth (5.4 +/- 4.5 vs 4.3 +/- 4.1; respectively, p<.05) in study population. In male subfertile group, normal sperm morphology before and after sperm preparation was higher in patients with live birth (1.3 +/- 1.4 vs 0.6 +/- 0.9; p<0.001 and 4.6 +/- 4.4 vs 1.9 +/- 2.2; p<0.01, respectively). However, both basal and post wash normal sperm morphology (%) were similar in patients with and without live birth in unexplained group. The best cut-off value for normal sperm morphology (%) to predict live birth was 4.5% in male subfertile group with a sensitivity of 50.6% and specificity of 61.7%. CONCLUSION: Morphological evaluation is not a reliable parameter alone for predicting pregnancy outcome in unexplained infertility. In male subfertility, post-wash normal sperm morphology percentage higher than 4.5 increases the probability of live birth. PMID- 26745392 TI - Three-dimensional digital reconstruction of human placental villus architecture in normal and complicated pregnancies. AB - OBJECTIVE: This study aimed to examine the use of digital technology in the three dimensional reconstruction of human placentas. STUDY DESIGN: Placentas obtained at term elective caesarean section were sampled, formalin-fixed and embedded in paraffin. Two hundred 5 MUm consecutive sections were cut from each specimen and the resultant slides stained with haematoxylin and eosin. Slides were then scanned and the digitised images reconstructed using customised software. RESULTS: Three-dimensional reconstructions were successfully achieved in placentas from normal pregnancies and those complicated by pre-eclampsia, growth restriction, and gestational diabetes. Marked morphological differences were readily identifiable, most clearly in the stem villus architecture. CONCLUSION: This method is an emerging research tool for examining placental histoarchitecture at high resolution and gaining clinically relevant insight into the placental pathology allied to pregnancy complications such as PET, IUGR and GD. PMID- 26745394 TI - Silicate reduces cadmium uptake into cells of wheat. AB - Cadmium (Cd) is a health threat all over the world and high Cd content in wheat causes high Cd intake. Silicon (Si) decreases cadmium content in wheat grains and shoot. This work investigates whether and how silicate (Si) influences cadmium (Cd) uptake at the cellular level in wheat. Wheat seedlings were grown in the presence or absence of Si with or without Cd. Cadmium, Si, and iron (Fe) accumulation in roots and shoots was analysed. Leaf protoplasts from plants grown without Cd were investigated for Cd uptake in the presence or absence of Si using the fluorescent dye, Leadmium Green AM. Roots and shoots of plants subjected to all four treatments were investigated regarding the expression of genes involved in the Cd uptake across the plasma membrane (i.e. LCT1) and efflux of Cd into apoplasm or vacuole from the cytosol (i.e. HMA2). In addition, phytochelatin (PC) content and PC gene (PCS1) expression were analysed. Expression of iron and metal transporter genes (IRT1 and NRAMP1) were also analysed. Results indicated that Si reduced Cd accumulation in plants, especially in shoot. Si reduced Cd transport into the cytoplasm when Si was added both directly during the uptake measurements and to the growth medium. Silicate downregulated LCT1 and HMA2 and upregulated PCS1. In addition, Si enhanced PC formation when Cd was present. The IRT1 gene, which was downregulated by Cd was upregulated by Si in root and shoot facilitating Fe transport in wheat. NRAMP1 was similarly expressed, though the effect was limited to roots. This work is the first to show how Si influences Cd uptake on the cellular level. PMID- 26745393 TI - Enhanced anaerobic dechlorination of polychlorinated biphenyl in sediments by bioanode stimulation. AB - The application of a low-voltage electric field as an electron donor or acceptor to promote the bioremediation of chlorinated organic compounds represents a promising technology meeting the demand of developing an efficient and cost effective strategy for in situ treatment of PCB-contaminated sediments. Here, we reported that bioanode stimulation with an anodic potential markedly enhanced dechlorination of 2,3,4,5-tetrachlorobiphenyl (PCB 61) contained in the sediment at an electronic waste recycling site of Qingyuan, Guangdong, China. The 110-day incubation of the bioanode with a potential poised at 0.2 V relative to saturated calomel electrode enabled 58% transformation of the total PCB 61 at the initial concentration of 100 MUmol kg(-1), while only 23% was reduced in the open-circuit reference experiment. The introduction of acetate to the bioelectrochemical reactor (BER) further improved PCB 61 transformation to 82%. Analysis of the bacterial composition showed significant community shifts in response to variations in treatment. At phylum level, the bioanode stimulation resulted in substantially increased abundance of Actinobacteria, Bacteroidetes, and Chloroflexi either capable of PCB dechlorination, or detected in the PCB contaminated environment. At genus level, the BER contained two types of microorganisms: electrochemically active bacteria (EAB) represented by Geobacter, Ignavibacterium, and Dysgonomonas, and dechlorinating bacteria including Hydrogenophaga, Alcanivorax, Sedimentibacter, Dehalogenimonas, Comamonas and Vibrio. These results suggest that the presence of EAB can promote the population of dechlorinating bacteria which are responsible for PCB 61 transformation. PMID- 26745395 TI - A decision-making approach for delineating sites which are potentially contaminated by heavy metals via joint simulation. AB - This work develops a new approach for delineating sites that are contaminated by multiple soil heavy metals and applies it to a case study. First a number of contaminant sample data are transformed into multiple spatially un-correlated factors using Uniformly Weighted Exhaustive Diagonalization with Gauss iterations (U-WEDGE). Sequential Gaussian simulation (sGs) is then used to generate sets of realizations of each resultant factor. These are then transformed into sets of sGs contaminant distribution realizations, which are then used to analyze the local and spatial (global) uncertainties in the distribution and concentration of contaminants via joint simulation. Finally, Info-Gap Decision Theory (IGDT) is used to consider different monitoring and or remediation regimes based on the analysis of contaminant realization spatial uncertainty. In our case study each heavy metal contaminant was considered individually and together with all other heavy metals; as the number of heavy metals considered increased, higher critical proportion values of local probability were chosen to obtain a low global uncertainty (to provide high reliability). Info-Gap Decision Theory (IGDT) yielded the most appropriate critical proportion values which minimized information loss in terms of specific goals. When the false negative rate is set to zero, meaning that it is necessary to monitor all potentially polluted areas, the corresponding false positive rates are at least 63%, 65%, 66%, 68%, 70%, and 78% to yield robustness levels of 0.50, 0.60, 0.70, 0.80, 0.90, and 1.00 respectively. However, when the false negative rate tolerance threshold is raised to 50%, the false positive rate tolerance which yields robustness levels of 0.50, 0.60, 0.70, 0.80, 0.90 and 1.00 drop to 12%, 14%, 15%, 18%, 20%, and 39%. The case study demonstrates the effectiveness of the developed approach at making robust decisions concerning the delineation of sites contaminated by multiple heavy metals. PMID- 26745396 TI - Is there any consistency between the microplastics found in the field and those used in laboratory experiments? AB - The ubiquitous presence and persistency of microplastics (MPs) in aquatic environments are of particular concern since they represent an increasing threat to marine organisms and ecosystems. Great differences of concentrations and/or quantities in field samples have been observed depending on geographical location around the world. The main types reported have been polyethylene, polypropylene, and polystyrene. The presence of MPs in marine wildlife has been shown in many studies focusing on ingestion and accumulation in different tissues, whereas studies of the biological effects of MPs in the field are scarce. If the nature and abundance/concentrations of MPs have not been systematically determined in field samples, this is due to the fact that the identification of MPs from environmental samples requires mastery and execution of several steps and techniques. For this reason and due to differences in sampling techniques and sample preparation, it remains difficult to compare the published studies. Most laboratory experiments have been performed with MP concentrations of a higher order of magnitude than those found in the field. Consequently, the ingestion and associated effects observed in exposed organisms have corresponded to great contaminant stress, which does not mimic the natural environment. Medium contaminations are produced with only one type of polymer of a precise sizes and homogenous shape whereas the MPs present in the field are known to be a mix of many types, sizes and shapes of plastic. Moreover, MPs originating in marine environments can be colonized by organisms and constitute the sorption support for many organic compounds present in environment that are not easily reproducible in laboratory. Determination of the mechanical and chemical effects of MPs on organisms is still a challenging area of research. Among the potential chemical effects it is necessary to differentiate those related to polymer properties from those due to the sorption/desorption of organic compounds. PMID- 26745398 TI - Physicochemical transformation and algal toxicity of engineered nanoparticles in surface water samples. AB - Most studies on the behavior and toxicity of engineered nanoparticles (NPs) have been conducted in artificial water with well-controlled conditions, which are dramatically different from natural waters with complex compositions. To better understand the fate and toxicity of NPs in the natural water environment, physicochemical transformations of four NPs (TiO2, ZnO, Ag, and carbon nanotubes (CNTs)) and their toxicities towards a unicellular green alga (Chlorella pyrenoidosa) in four fresh water and one seawater sample were investigated. Results indicated that water chemistry had profound effects on aggregation, dissolution, and algal toxicity of the NPs. The strongest homoaggregation of the NPs was associated with the highest ionic strength, but no obvious correlation was observed between the homoaggregation of NPs and pH or dissolved organic matter content of the water samples. The greatest dissolution of ZnO NPs also occurred in seawater with the highest ionic strength, while the dissolution of Ag NPs varied differently from ZnO NPs. The released Zn(2+) and especially Ag(+) mainly accounted for the algal toxicity of ZnO and Ag NPs, respectively. The NP cell heteroagglomeration occurred generally for CNTs and Ag NPs, which contributed to the observed nanotoxicity. However, there was no significant correlation between the observed nanotoxicity and the type of NP or the water chemistry. It was thus concluded that the physicochemical transformations and algal toxicities of NPs in the natural water samples were caused by the combined effects of complex water quality parameters rather than any single influencing factor alone. These results will increase our knowledge on the fate and effects of NPs in the aquatic environment. PMID- 26745397 TI - Perfluorinated compounds in soil, surface water, and groundwater from rural areas in eastern China. AB - Little research on perfluorinated compounds (PFCs) has been conducted in rural areas, although rural PFC sources are less complicated than in urban and industrial areas. To determine the levels and geographical distribution of 17 PFC compounds, samples of soil, surface water, and groundwater were collected from eight rural areas in eastern China. The total PFC concentrations (?PFCs) in soils ranged from 0.34 to 65.8 ng/g ?PFCs in surface waters ranged from 7.0 to 489 ng/L and ?PFCs in groundwater ranged from 5.3 to 615 ng/L. Ratios of perfluorononanoic acid/perfluorooctanoic acid (PFNA/PFOA), perfluoro-n-butyric acid/perfluorooctanoic acid (PFBA/PFOA), and perfluoroheptanoic acid/perfluorooctanoic acid (PFHpA/PFOA) in rainwater increased due to the fluorine chemical plants in the surrounding rural and urban areas, suggesting that atmospheric precipitation may carry PFCs and their precursors from the fluorochemical industrial area to the adjacent rural areas. PMID- 26745399 TI - Metabolism of pharmaceutical and personal care products by carrot cell cultures. AB - With the increasing use of treated wastewater and biosolids in agriculture, residues of pharmaceutical and personal care products (PPCPs) in these reused resources may contaminate food produce via plant uptake, constituting a route for human exposure. Although various PPCPs have been reported to be taken up by plants in laboratories or under field conditions, at present little information is available on their metabolism in plants. In this study, we applied carrot cell cultures to investigate the plant metabolism of PPCPs. Five phase I metabolites of carbamazepine were identified and the potential metabolism pathways of carbamazepine were proposed. We also used the carrot cell cultures as a rapid screening tool to initially assess the metabolism potentials of 18 PPCPs. Eleven PPCPs, including acetaminophen, caffeine, meprobamate, primidone, atenolol, trimethoprim, DEET, carbamazepine, dilantin, diazepam, and triclocarban, were found to be recalcitrant to metabolism. The other 7 PPCPs, including triclosan, naproxen, diclofenac, ibuprofen, gemfibrozil, sulfamethoxazole, and atorvastatin, displayed rapid metabolism, with 0.4-47.3% remaining in the culture at the end of the experiment. Further investigation using glycosidase hydrolysis showed that 1.3-20.6% of initially spiked naproxen, diclofenac, ibuprofen, and gemfibrozil were transformed into glycoside conjugates. Results from this study showed that plant cell cultures may be a useful tool for initially exploring the potential metabolites of PPCPs in plants as well as for rapidly screening the metabolism potentials of a variety of PPCPs or other emerging contaminants, and therefore may be used for prioritizing compounds for further comprehensive evaluations. PMID- 26745400 TI - Reduced gait automaticity in female patients with chronic fatigue syndrome: Case control study. AB - Patients with chronic fatigue syndrome (CFS) report difficulties walking for a prolonged period of time. This study compares gait automaticity between women with CFS and nondisabled controls. The "stops walking with eyes closed with secondary cognitive task" test is based on the classic "stops walking while talking" test but compares walking with eyes closed while performing a secondary cognitive task in a female CFS population (n = 34) and in female nondisabled controls (n = 38). When initiating gate, 23.5% of patients with CFS looked toward the ground compared with only 2.6% of nondisabled controls. After 7 m, subjects were asked to close their eyes, and after another 7 m, they were asked, "How much is 100 minus 7?" Of the patients with CFS, 55.9% stopped walking compared with 5.3% of nondisabled controls. Less automated walking was observed in patients with CFS than in nondisabled controls (p < 0.001). The test-retest reliability is moderate for global stopping. This simple test observed reduced gait automaticity in patients with CFS for the first time. Dual tasking could be helpful to address the functional limitations found in this particular study. PMID- 26745401 TI - Innate myeloid cells under the control of adaptive immunity: the example of mast cells and basophils. AB - Mast cells and basophils are mostly known as the initiators of IgE-dependent allergic reactions. They, however, contribute to innate immunity against pathogens and venoms. Like other myeloid cells, they also express receptors for the Fc portion of IgG antibodies. These include activating receptors and inhibitory receptors. Because IgG antibodies are produced in exceedingly higher amounts than IgE antibodies, IgG receptors are co-engaged with IgE receptors under physiological conditions. Mast cells and basophils are examples of the many innate myeloid cells whose effector functions are used and finely tuned by antibodies. They can be thus enrolled in a variety of adaptive immune responses, their activation can be regulated, positively and negatively and their biological responses can be modulated qualitatively by antibodies. PMID- 26745402 TI - Amphipathic Helices-Wedge? Or Nae Nae? PMID- 26745403 TI - Classic Analysis of Biopolymer Dynamics Is Model Free. AB - Early analysis of biopolymer dynamics relied on a variety of motional models that were difficult to distinguish and sometimes gave contradictory results. The Lipari-Szabo model-free approach (documented in a 1980 article in Biophysical Journal, as well as in two more comprehensive 1982 articles in the Journal of the American Chemical Society, provided a simple formalism that allowed investigators to understand fluorescence and NMR experimental data without having to specify a motional model. Although the model-free method is not universally applicable (for example, its assumption of a uniform correlation time for overall molecular tumbling can be problematic for biomolecules containing areas of disorder), it remains the most popular and widely used technique for analyzing molecular motion. PMID- 26745404 TI - How Mammalian Cells Acquire Copper: An Essential but Potentially Toxic Metal. AB - Cu is an essential micronutrient, and its role in an array of critical physiological processes is receiving increasing attention. Among these are wound healing, angiogenesis, protection against reactive oxygen species, neurotransmitter synthesis, modulation of normal cell and tumor growth, and many others. Free Cu is absent inside cells, and a network of proteins has evolved to deliver this essential, but potentially toxic, metal ion to its intracellular target sites following uptake. Although the total body content is low (~100 mg), dysfunction of proteins involved in Cu homeostasis results in several well characterized human disease states. The initial step in cellular Cu handling is its transport across the plasma membrane, a subject of study for only about the last 25 years. This review focuses on the initial step in Cu homeostasis, the properties of the major protein, hCTR1, that mediates Cu uptake, and the status of our understanding of this highly specialized transport system. Although a high resolution structure of the protein is still lacking, an array of biochemical and biophysical studies have provided a picture of how hCTR1 mediates Cu(I) transport and how Cu is delivered to the proteins in the intracellular milieu. Recent studies provide evidence that the transporter also plays a key protective role in the regulation of cellular Cu via regulatory endocytosis, lowering its surface expression, in response to elevated Cu loads. PMID- 26745406 TI - Photon-HDF5: An Open File Format for Timestamp-Based Single-Molecule Fluorescence Experiments. AB - We introduce Photon-HDF5, an open and efficient file format to simplify exchange and long-term accessibility of data from single-molecule fluorescence experiments based on photon-counting detectors such as single-photon avalanche diode, photomultiplier tube, or arrays of such detectors. The format is based on HDF5, a widely used platform- and language-independent hierarchical file format for which user-friendly viewers are available. Photon-HDF5 can store raw photon data (timestamp, channel number, etc.) from any acquisition hardware, but also setup and sample description, information on provenance, authorship and other metadata, and is flexible enough to include any kind of custom data. The format specifications are hosted on a public website, which is open to contributions by the biophysics community. As an initial resource, the website provides code examples to read Photon-HDF5 files in several programming languages and a reference Python library (phconvert), to create new Photon-HDF5 files and convert several existing file formats into Photon-HDF5. To encourage adoption by the academic and commercial communities, all software is released under the MIT open source license. PMID- 26745405 TI - Voltage-Dependent Gating: Novel Insights from KCNQ1 Channels. AB - Gating of voltage-dependent cation channels involves three general molecular processes: voltage sensor activation, sensor-pore coupling, and pore opening. KCNQ1 is a voltage-gated potassium (Kv) channel whose distinctive properties have provided novel insights on fundamental principles of voltage-dependent gating. 1) Similar to other Kv channels, KCNQ1 voltage sensor activation undergoes two resolvable steps; but, unique to KCNQ1, the pore opens at both the intermediate and activated state of voltage sensor activation. The voltage sensor-pore coupling differs in the intermediate-open and the activated-open states, resulting in changes of open pore properties during voltage sensor activation. 2) The voltage sensor-pore coupling and pore opening require the membrane lipid PIP2 and intracellular ATP, respectively, as cofactors, thus voltage-dependent gating is dependent on multiple stimuli, including the binding of intracellular signaling molecules. These mechanisms underlie the extraordinary KCNE1 subunit modification of the KCNQ1 channel and have significant physiological implications. PMID- 26745408 TI - Optical Pushing: A Tool for Parallelized Biomolecule Manipulation. AB - The ability to measure and manipulate single molecules has greatly advanced the field of biophysics. Yet, the addition of more single-molecule tools that enable one to measure in a parallel fashion is important to diversify the questions that can be addressed. Here we present optical pushing (OP), a single-molecule technique that is used to exert forces on many individual biomolecules tethered to microspheres using a single collimated laser beam. Forces ranging from a few femtoNewtons to several picoNewtons can be applied with a submillisecond response time. To determine forces exerted on the tethered particles by the laser, we analyzed their measured Brownian motion using, to our knowledge, a newly derived analytical model and numerical simulations. In the model, Brownian rotation of the microspheres is taken into account, which proved to be a critical component to correctly determine the applied forces. We used our OP technique to map the energy landscape of the protein-induced looping dynamics of DNA. OP can be used to apply loading rates in the range of 10(-4)-10(6) pN/s to many molecules at the same time, which makes it a tool suitable for dynamic force spectroscopy. PMID- 26745407 TI - Nesprin-2G, a Component of the Nuclear LINC Complex, Is Subject to Myosin Dependent Tension. AB - The nucleus of a cell has long been considered to be subject to mechanical force. Despite the observation that mechanical forces affect nuclear geometry and movement, how forces are applied onto the nucleus is not well understood. The nuclear LINC (linker of nucleoskeleton and cytoskeleton) complex has been hypothesized to be the critical structure that mediates the transfer of mechanical forces from the cytoskeleton onto the nucleus. Previously used techniques for studying nuclear forces have been unable to resolve forces across individual proteins, making it difficult to clearly establish if the LINC complex experiences mechanical load. To directly measure forces across the LINC complex, we generated a fluorescence resonance energy transfer-based tension biosensor for nesprin-2G, a key structural protein in the LINC complex, which physically links this complex to the actin cytoskeleton. Using this sensor we show that nesprin-2G is subject to mechanical tension in adherent fibroblasts, with highest levels of force on the apical and equatorial planes of the nucleus. We also show that the forces across nesprin-2G are dependent on actomyosin contractility and cell elongation. Additionally, nesprin-2G tension is reduced in fibroblasts from Hutchinson-Gilford progeria syndrome patients. This report provides the first, to our knowledge, direct evidence that nesprin-2G, and by extension the LINC complex, is subject to mechanical force. We also present evidence that nesprin-2G localization to the nuclear membrane is altered under high-force conditions. Because forces across the LINC complex are altered by a variety of different conditions, mechanical forces across the LINC complex, as well as the nucleus in general, may represent an important mechanism for mediating mechanotransduction. PMID- 26745409 TI - Phase Behavior of DNA in the Presence of DNA-Binding Proteins. AB - To characterize the thermodynamical equilibrium of DNA chains interacting with a solution of nonspecific binding proteins, we implemented a Flory-Huggins free energy model. We explored the dependence on DNA and protein concentrations of the DNA collapse. For physiologically relevant values of the DNA-protein affinity, this collapse gives rise to a biphasic regime with a dense and a dilute phase; the corresponding phase diagram was computed. Using an approach based on Hamiltonian paths, we show that the dense phase has either a molten globule or a crystalline structure, depending on the DNA bending rigidity, which is influenced by the ionic strength. These results are valid at the thermodynamical equilibrium and therefore should be consistent with many biological processes, whose characteristic timescales range typically from 1 ms to 10 s. Our model may thus be applied to biological phenomena that involve DNA-binding proteins, such as DNA condensation with crystalline order, which occurs in some bacteria to protect their chromosome from detrimental factors; or transcription initiation, which occurs in clusters called transcription factories that are reminiscent of the dense phase characterized in this study. PMID- 26745410 TI - Mechanical Folding and Unfolding of Protein Barnase at the Single-Molecule Level. AB - The unfolding and folding of protein barnase has been extensively investigated in bulk conditions under the effect of denaturant and temperature. These experiments provided information about structural and kinetic features of both the native and the unfolded states of the protein, and debates about the possible existence of an intermediate state in the folding pathway have arisen. Here, we investigate the folding/unfolding reaction of protein barnase under the action of mechanical force at the single-molecule level using optical tweezers. We measure unfolding and folding force-dependent kinetic rates from pulling and passive experiments, respectively, and using Kramers-based theories (e.g., Bell-Evans and Dudko-Hummer Szabo models), we extract the position of the transition state and the height of the kinetic barrier mediating unfolding and folding transitions, finding good agreement with previous bulk measurements. Measurements of the force-dependent kinetic barrier using the continuous effective barrier analysis show that protein barnase verifies the Leffler-Hammond postulate under applied force and allow us to extract its free energy of folding, DeltaG0. The estimated value of DeltaG0 is in agreement with our predictions obtained using fluctuation relations and previous bulk studies. To address the possible existence of an intermediate state on the folding pathway, we measure the power spectrum of force fluctuations at high temporal resolution (50 kHz) when the protein is either folded or unfolded and, additionally, we study the folding transition-path time at different forces. The finite bandwidth of our experimental setup sets the lifetime of potential intermediate states upon barnase folding/unfolding in the submillisecond timescale. PMID- 26745411 TI - Direct Calculation of Protein Fitness Landscapes through Computational Protein Design. AB - Naturally selected amino-acid sequences or experimentally derived ones are often the basis for understanding how protein three-dimensional conformation and function are determined by primary structure. Such sequences for a protein family comprise only a small fraction of all possible variants, however, representing the fitness landscape with limited scope. Explicitly sampling and characterizing alternative, unexplored protein sequences would directly identify fundamental reasons for sequence robustness (or variability), and we demonstrate that computational methods offer an efficient mechanism toward this end, on a large scale. The dead-end elimination and A(*) search algorithms were used here to find all low-energy single mutant variants, and corresponding structures of a G protein heterotrimer, to measure changes in structural stability and binding interactions to define a protein fitness landscape. We established consistency between these algorithms with known biophysical and evolutionary trends for amino acid substitutions, and could thus recapitulate known protein side-chain interactions and predict novel ones. PMID- 26745412 TI - Apolipoprotein C-II Adopts Distinct Structures in Complex with Micellar and Submicellar Forms of the Amyloid-Inhibiting Lipid-Mimetic Dodecylphosphocholine. AB - The formation of amyloid deposits is a common feature of a broad range of diseases, including atherosclerosis, Alzheimer's disease, and Parkinson's disease. The basis and role of amyloid deposition in the pathogenesis of these diseases is still being defined, however an interesting feature of amyloidogenic proteins is that the majority of the pathologically associated proteins are involved in lipid homeostasis, be it in lipid transport, incorporation into membranes, or the regulation of lipid pathways. Thus, amyloid-forming proteins commonly bind lipids, and lipids are generally involved in the proper folding of these proteins. However, understanding of the basis for these lipid-related aspects of amyloidogenesis is lacking. Thus, we have used the apolipoprotein C-II amyloid model system in conjunction with x-ray and neutron scattering analyses to address this problem. Apolipoprotein C-II is a well-studied model system of systemic amyloid fibril formation, with a clear and well-defined pathway for fibril formation, where the effects of lipid interaction are characterized, particularly for the lipid mimetic dodecylphosphocholine. We show that the micellar state of an inhibitory lipid can have a very significant effect on protein conformation, with micelles stabilizing a particular alpha-helical structure, whereas submicellar lipids stabilize a very different dimeric, alpha helical structure. These results indicate that lipids may have an important role in the development and progression of amyloid-related diseases. PMID- 26745414 TI - Variable Field Analytical Ultracentrifugation: II. Gravitational Sweep Sedimentation Velocity. AB - Sedimentation velocity (SV) analytical ultracentrifugation is a classical biophysical technique for the determination of the size-distribution of macromolecules, macromolecular complexes, and nanoparticles. SV has traditionally been carried out at a constant rotor speed, which limits the range of sedimentation coefficients that can be detected in a single experiment. Recently we have introduced methods to implement experiments with variable rotor speeds, in combination with variable field solutions to the Lamm equation, with the application to expedite the approach to sedimentation equilibrium. Here, we describe the use of variable-field sedimentation analysis to increase the size range covered in SV experiments by ~100-fold with a quasi-continuous increase of rotor speed during the experiment. Such a gravitational-sweep sedimentation approach has previously been shown to be very effective in the study of nanoparticles with large size ranges. In the past, diffusion processes were not accounted for, thereby posing a lower limit of particle sizes and limiting the accuracy of the size distribution. In this work, we combine variable field solutions to the Lamm equation with diffusion-deconvoluted sedimentation coefficient distributions c(s), which further extend the macromolecular size range that can be observed in a single SV experiment while maintaining accuracy and resolution. In this way, approximately five orders of magnitude of sedimentation coefficients, or eight orders of magnitude of particle mass, can be probed in a single experiment. This can be useful, for example, in the study of proteins forming large assemblies, as in fibrillation process or capsid self assembly, in studies of the interaction between very dissimilar-sized macromolecular species, or in the study of broadly distributed nanoparticles. PMID- 26745413 TI - The C-Terminus of Human Copper Importer Ctr1 Acts as a Binding Site and Transfers Copper to Atox1. AB - Uptake of copper (Cu) ions into human cells is mediated by the plasma membrane protein Ctr1 and is followed by Cu transfer to cytoplasmic Cu chaperones for delivery to Cu-dependent enzymes. The C-terminal cytoplasmic tail of Ctr1 is a 13 residue peptide harboring an HCH motif that is thought to interact with Cu. We here employ biophysical experiments under anaerobic conditions in peptide models of the Ctr1 C-terminus to deduce Cu-binding residues, Cu affinity, and the ability to release Cu to the cytoplasmic Cu chaperone Atox1. Based on NMR assignments and bicinchoninic acid competition experiments, we demonstrate that Cu interacts in a 1:1 stoichiometry with the HCH motif with an affinity, KD, of ~10(-14) M. Removing either the Cys residue or the two His residues lowers the Cu peptide affinity, but site specificity is retained. The C-terminal peptide and Atox1 do not interact in solution in the absence of Cu. However, as directly demonstrated at the residue level via NMR spectroscopy, Atox1 readily acquires Cu from the Cu-loaded peptide. We propose that Cu binding to the Ctr1 C-terminal tail regulates Cu transport into the cytoplasm such that the metal ion is only released to high-affinity Cu chaperones. PMID- 26745415 TI - The Exact NOE as an Alternative in Ensemble Structure Determination. AB - The structure-function paradigm is increasingly replaced by the structure dynamics-function paradigm. All protein activity is steered by the interplay between enthalpy and entropy. Conformational dynamics serves as a proxy of conformational entropy. Therefore, it is essential to study not only the average conformation but also the spatial sampling of a protein on all timescales. To this purpose, we have established a protocol for determining multiple-state ensembles of proteins based on exact nuclear Overhauser effects (eNOEs). We have recently extended our previously reported eNOE data set for the protein GB3 by a very large set of backbone and side-chain residual dipolar couplings and three bond J couplings. Here, we demonstrate that at least four structural states are required to represent the complete data set by dissecting the contributions to the CYANA target function, which quantifies restraint violations in structure calculation. We present a four-state ensemble of GB3, which largely preserves the characteristics obtained from eNOEs only. Due to the abundance of the input data, the ensemble and chi(1) angles in particular are well suited for cross-validation of the input data and comparison to x-ray structures. Principal component analysis is used to automatically identify and validate relevant states of the ensembles. Overall, our findings suggest that eNOEs are a valuable alternative to traditional NMR probes in spatial elucidation of proteins. PMID- 26745416 TI - Determinants of Cx43 Channel Gating and Permeation: The Amino Terminus. AB - Separate connexin domains partake in proposed gating mechanisms of gap junction channels. The amino-terminus (NT) domains, which contribute to voltage sensing, may line the channel's cytoplasmic-facing funnel surface, stabilize the channel's overall structure through interactions with the transmembrane domains and each other, and integrate to form a compound particle to gate the channel closed. Interactions of the carboxyl-terminus (CT) and cytoplasmic loop (CL) domains underlie voltage- and low pH-triggered channel closure. To elucidate potential cooperation of these gating mechanisms, we replaced the Cx43NT with the Cx37NT (chimera Cx43(*)NT37), leaving the remainder of the Cx43 sequence, including the CT and CL, unchanged. Compared to wild-type Cx43 (Cx43WT), Cx43(*)NT37 junctions exhibited several functional alterations: extreme resistance to halothane- and acidification-induced uncoupling, absence of voltage-dependent fast inactivation, longer channel open times, larger unitary channel conductances, low junctional dye permeability/permselectivity, and an overall cation selectivity more typical of Cx37WT than Cx43WT junctions. Together, these results suggest a cohesive model of channel function wherein: 1) channel conductance and size selectivity are largely determined by pore diameter, whereas charge selectivity results from the NT domains, and 2) transition between fully open and (multiple) closed states involves global changes in structure of the pore-forming domains transduced by interactions of the pore-forming domains with either the NT, CT, or both, with the NT domains forming the gate of the completely closed channel. PMID- 26745417 TI - Nanoscale, Voltage-Driven Application of Bioactive Substances onto Cells with Organized Topography. AB - With scanning ion conductance microscopy (SICM), a noncontact scanning probe technique, it is possible both to obtain information about the surface topography of live cells and to apply molecules onto specific nanoscale structures. The technique is therefore widely used to apply chemical compounds and to study the properties of molecules on the surfaces of various cell types. The heart muscle cells, i.e., the cardiomyocytes, possess a highly elaborate, unique surface topography including transverse-tubule (T-tubule) openings leading into a cell internal system that exclusively harbors many proteins necessary for the cell's physiological function. Here, we applied isoproterenol into these surface openings by changing the applied voltage over the SICM nanopipette. To determine the grade of precision of our application we used finite-element simulations to investigate how the concentration profile varies over the cell surface. We first obtained topography scans of the cardiomyocytes using SICM and then determined the electrophoretic mobility of isoproterenol in a high ion solution to be -7 * 10(-9) m(2)/V s. The simulations showed that the delivery to the T-tubule opening is highly confined to the underlying Z-groove, and especially to the first T tubule opening, where the concentration is ~6.5 times higher compared to on a flat surface under the same delivery settings. Delivery to the crest, instead of the T-tubule opening, resulted in a much lower concentration, emphasizing the importance of topography in agonist delivery. In conclusion, SICM, unlike other techniques, can reliably deliver precise quantities of compounds to the T-tubules of cardiomyocytes. PMID- 26745418 TI - Shock Wave-Induced Damage of a Protein by Void Collapse. AB - In this study, we report on a series of molecular dynamics simulations that were used to examine the effects of shock waves on a membrane-bound ion channel. A planar shock wave was found to compress the ion channel upon impact, but the protein geometry resembles the crystal structure as soon as the solvent density begins to dissipate. When a void was placed in close proximity to the membrane, the shock wave proved to be more destructive to the protein due to formation of a nanojet that results from the asymmetric collapse of the void. The nanojet was able to cause significant structural changes to the protein even at low piston velocities that are not able to directly cause poration of the membrane. PMID- 26745419 TI - Intra- and Intersubunit Dynamic Binding in Kv4.2 Channel Closed-State Inactivation. AB - We studied the kinetics and structural determinants of closed-state inactivation (CSI) in Kv4.2 channels, considering a multistep process and the possibility that both intra- and intersubunit dynamic binding (i.e., loss and restoration of physical contact) may occur between the S4-S5 linker, including the initial S5 segment (S4S5), and the S6 gate. We expressed Kv4.2 channels in Xenopus oocytes and measured the onset of low-voltage inactivation under two-electrode voltage clamp. Indicative of a transitory state, the onset kinetics were best described by a double-exponential function. To examine the involvement of individual S4S5 and S6 amino acid residues in dynamic binding, we studied S4S5 and S6 single alanine mutants and corresponding double mutants. Both transitory and steady state inactivation were modified by these mutations, and we quantified the mutational effects based on apparent affinities for the respective inactivated states. Double-mutant cycle analyses revealed strong functional coupling of the S6 residues V404 and I412 to all tested S4S5 residues. To examine whether dynamic S4S5/S6 binding occurs within individual alpha-subunits or between neighboring alpha-subunits, we performed a double-mutant cycle analysis with Kv4.2 tandem dimer constructs. The constructs carried either an S4S5/S6 double mutation in the first alpha-subunit and no mutation in the second (concatenated) alpha-subunit or an S4S5 point mutation in the first alpha-subunit and an S6 point mutation in the second alpha-subunit. Our results support the notion that CSI in Kv4.2 channels is a multistep process that involves dynamic binding both within individual alpha subunits and between neighboring alpha-subunits. PMID- 26745421 TI - Equation of State for Phospholipid Self-Assembly. AB - Phospholipid self-assembly is the basis of biomembrane stability. The entropy of transfer from water to self-assembled micelles of lysophosphatidylcholines and diacyl phosphatidylcholines with different chain lengths converges to a common value at a temperature of 44 degrees C. The corresponding enthalpies of transfer converge at ~-18 degrees C. An equation of state for the free energy of self assembly formulated from this thermodynamic data depends on the heat capacity of transfer as the sole parameter needed to specify a particular lipid. For lipids lacking calorimetric data, measurement of the critical micelle concentration at a single temperature suffices to define an effective heat capacity according to the model. Agreement with the experimental temperature dependence of the critical micelle concentration is then good. The predictive powers should extend also to amphiphile partitioning and the kinetics of lipid-monomer transfer. PMID- 26745420 TI - Cholesterol-Enriched Domain Formation Induced by Viral-Encoded, Membrane-Active Amphipathic Peptide. AB - The alpha-helical (AH) domain of the hepatitis C virus nonstructural protein NS5A, anchored at the cytoplasmic leaflet of the endoplasmic reticulum, plays a role in viral replication. However, the peptides derived from this domain also exhibit remarkably broad-spectrum virocidal activity, raising questions about their modes of membrane association. Here, using giant lipid vesicles, we show that the AH peptide discriminates between membrane compositions. In cholesterol containing membranes, peptide binding induces microdomain formation. By contrast, cholesterol-depleted membranes undergo global softening at elevated peptide concentrations. Furthermore, in mixed populations, the presence of ~100 nm vesicles of viral dimensions suppresses these peptide-induced perturbations in giant unilamellar vesicles, suggesting size-dependent membrane association. These synergistic composition- and size-dependent interactions explain, in part, how the AH domain might on the one hand segregate molecules needed for viral assembly and on the other hand furnish peptides that exhibit broad-spectrum virocidal activity. PMID- 26745423 TI - Oxidized Phospholipids Inhibit the Formation of Cholesterol-Dependent Plasma Membrane Nanoplatforms. AB - We previously developed a single-molecule microscopy method termed TOCCSL (thinning out clusters while conserving stoichiometry of labeling), which allows for direct imaging of stable nanoscopic platforms with raft-like properties diffusing in the plasma membrane. As a consensus raft marker, we chose monomeric GFP linked via a glycosylphosphatidylinositol (GPI) anchor to the cell membrane (mGFP-GPI). With this probe, we previously observed cholesterol-dependent homo association to nanoplatforms diffusing in the plasma membrane of live CHO cells. Here, we report the release of this homo-association upon addition of 1-palmitoyl 2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) or 1-palmitoyl-2-glutaroyl sn-glycero-3-phosphocholine, two oxidized phospholipids (oxPLs) that are typically present in oxidatively modified low-density lipoprotein. We found a dose-response relationship for mGFP-GPI nanoplatform disintegration upon addition of POVPC, correlating with the signal of the apoptosis marker Annexin V-Cy3. Similar concentrations of lysolipid showed no effect, indicating that the observed phenomena were not linked to properties of the lipid bilayer itself. Inhibition of acid sphingomyelinase by NB-19 before addition of POVPC completely abolished nanoplatform disintegration by oxPLs. In conclusion, we were able to determine how oxidized lipid species disrupt mGFP-GPI nanoplatforms in the plasma membrane. Our results favor an indirect mechanism involving acid sphingomyelinase activity rather than a direct interaction of oxPLs with nanoplatform constituents. PMID- 26745424 TI - Label-free Imaging of Microtubules with Sub-nm Precision Using Interferometric Scattering Microscopy. AB - Current in vitro optical studies of microtubule dynamics tend to rely on fluorescent labeling of tubulin, with tracking accuracy thereby limited by the quantum yield of fluorophores and by photobleaching. Here, we demonstrate label free tracking of microtubules with nanometer precision at kilohertz frame rates using interferometric scattering microscopy (iSCAT). With microtubules tethered to a glass substrate using low-density kinesin, we readily detect sequential 8 nm steps in the microtubule center of mass, characteristic of a single kinesin molecule moving a microtubule. iSCAT also permits dynamic changes in filament length to be measured with <5 nm precision. Using the arbitrarily long observation time enabled by label-free iSCAT imaging, we demonstrate continuous monitoring of microtubule disassembly over a 30 min period. The ability of iSCAT to track microtubules with nm precision together with its potential for label free single protein detection and simultaneous single molecule fluorescence imaging represent a unique platform for novel approaches to studying microtubule dynamics. PMID- 26745422 TI - Anisotropic Membrane Curvature Sensing by Amphipathic Peptides. AB - Many proteins and peptides have an intrinsic capacity to sense and induce membrane curvature, and play crucial roles for organizing and remodeling cell membranes. However, the molecular driving forces behind these processes are not well understood. Here, we describe an approach to study curvature sensing by simulating the interactions of single molecules with a buckled lipid bilayer. We analyze three amphipathic antimicrobial peptides, a class of membrane-associated molecules that specifically target and destabilize bacterial membranes, and find qualitatively different sensing characteristics that would be difficult to resolve with other methods. Our findings provide evidence for direction-dependent curvature sensing mechanisms in amphipathic peptides and challenge existing theories of hydrophobic insertion. The buckling approach is generally applicable to a wide range of curvature-sensing molecules, and our results provide strong motivation to develop new experimental methods to track position and orientation of membrane proteins. PMID- 26745425 TI - A Simple Model of Multivalent Adhesion and Its Application to Influenza Infection. AB - Adhesion between biological surfaces, which is typically the result of molecular binding between receptors on one surface and ligands on another, plays a fundamental role in biology and is key to the infection mechanisms of certain viruses, including influenza. The physiological outcome of adhesion depends on both the number of bound cells (or viruses, or other biological particles) and the properties of the adhesion interface that is formed, including the equilibrium number of receptor-ligand connections. Here, we introduce a quantitative model for biological adhesion by adapting thermodynamic models developed for the related problem of multivalent molecular binding. In our model, adhesion affinity is approximated by a simple, analytical expression involving the numbers of ligands and receptors at the interface. Our model contains only two fitting parameters and is simple to interpret. When applied to the adhesion between the hemagglutinin ligands on influenza viruses and the sialic acid receptors on biosensors or on host cells, our model generates adhesion affinities consistent with experimental measurements performed over a range of numbers of receptors, and provides a semiquantitative estimate of the affinity range of the hemagglutinin-sialic acid interaction necessary for the influenza virus to successfully infect host cells. The model also provides a quantitative explanation for the experimental finding that a mutant avian virus gained transmissibility in mammals despite the mutations conferring only a less than twofold increase in the affinity of its hemagglutinin for mammalian receptors: the model predicts an order-of-magnitude improvement in adhesion to mammalian cells. We also extend our model to describe the competitive inhibition of adhesion: the model predicts that hemagglutinin inhibitors of relatively modest affinity can dramatically reduce influenza virus adhesion to host cells, suggesting that such inhibitors, if discovered, may be viable therapeutic agents against influenza. PMID- 26745426 TI - Intracellular Impedance Measurements Reveal Non-ohmic Properties of the Extracellular Medium around Neurons. AB - Determining the electrical properties of the extracellular space around neurons is important for understanding the genesis of extracellular potentials, as well as for localizing neuronal activity from extracellular recordings. However, the exact nature of these extracellular properties is still uncertain. Here, we introduce a method to measure the impedance of the tissue, one that preserves the intact cell-medium interface using whole-cell patch-clamp recordings in vivo and in vitro. We find that neural tissue has marked non-ohmic and frequency-filtering properties, which are not consistent with a resistive (ohmic) medium, as often assumed. The amplitude and phase profiles of the measured impedance are consistent with the contribution of ionic diffusion. We also show that the impact of such frequency-filtering properties is possibly important on the genesis of local field potentials, as well as on the cable properties of neurons. These results show non-ohmic properties of the extracellular medium around neurons, and suggest that source estimation methods, as well as the cable properties of neurons, which all assume ohmic extracellular medium, may need to be reevaluated. PMID- 26745427 TI - Diffusion of Bacterial Cells in Porous Media. AB - The chemotaxis signal transduction network regulates the biased random walk of many bacteria in favorable directions and away from harmful ones through modulating the frequency of directional reorientations. In mutants of diverse bacteria lacking the chemotaxis response, migration in classic motility agar, which constitutes a fluid-filled porous medium, is compromised; straight-swimming cells unable to tumble become trapped within the agar matrix. Spontaneous mutations that restore spreading have been previously observed in the enteric bacterium Escherichia coli, and recent work in other bacterial species has isolated and quantified different classes of nonchemotacting mutants exhibiting the same spreading phenotype. We present a theoretical description of bacterial diffusion in a porous medium-the natural habitat for many cell types-which elucidates how diverse modifications of the motility apparatus resulting in a nonzero tumbling frequency allows for unjamming of otherwise straight-swimming cells at internal boundaries and leads to net migration. A unique result of our analysis is increasing diffusive spread with increasing tumbling frequency in the small pore limit, consistent with earlier experimental observations but not captured by previous models. Our theoretical results, combined with a simple model of bacterial diffusion and growth in agar, are compared with our experimental measurements of swim ring expansion as a function of time, demonstrating good quantitative agreement. Our results suggest that the details of the cellular tumbling process may be adapted to enable bacteria to propagate efficiently through complex environments. For engineered, self-propelled microswimmers that navigate via alternating straight runs and changes in direction, these results suggest an optimal reorientation strategy for efficient migration in a porous environment with a given microarchitecture. PMID- 26745428 TI - Population-Dynamic Modeling of Bacterial Horizontal Gene Transfer by Natural Transformation. AB - Natural transformation is a major mechanism of horizontal gene transfer (HGT) and plays an essential role in bacterial adaptation, evolution, and speciation. Although its molecular underpinnings have been increasingly revealed, natural transformation is not well characterized in terms of its quantitative ecological roles. Here, by using Neisseria gonorrhoeae as an example, we developed a population-dynamic model for natural transformation and analyzed its dynamic characteristics with nonlinear tools and simulations. Our study showed that bacteria capable of natural transformation can display distinct population behaviors ranging from extinction to coexistence and to bistability, depending on their HGT rate and selection coefficient. With the model, we also illustrated the roles of environmental DNA sources-active secretion and passive release-in impacting population dynamics. Additionally, by constructing and utilizing a stochastic version of the model, we examined how noise shapes the steady and dynamic behaviors of the system. Notably, we found that distinct waiting time statistics for HGT events, namely a power-law distribution, an exponential distribution, and a mix of the both, are associated with the dynamics in the regimes of extinction, coexistence, and bistability accordingly. This work offers a quantitative illustration of natural transformation by revealing its complex population dynamics and associated characteristics, therefore advancing our ecological understanding of natural transformation as well as HGT in general. PMID- 26745429 TI - Quantitative Morphology of Epithelial Folds. AB - The shape of spatially modulated epithelial morphologies such as villi and crypts is usually associated with the epithelium-stroma area mismatch leading to buckling. We propose an alternative mechanical model based on intraepithelial stresses generated by differential tensions of apical, lateral, and basal sides of cells as well as on the elasticity of the basement membrane. We use it to theoretically study longitudinal folds in simple epithelia and we identify four types of corrugated morphologies: compact, invaginated, evaginated, and wavy. The obtained tissue contours and thickness profiles are compared to epithelial folds observed in invertebrates and vertebrates, and for most samples, the agreement is within the estimated experimental error. Our model establishes the groove-crest modulation of tissue thickness as a morphometric parameter that can, together with the curvature profile, be used to estimate the relative differential apicobasal tension in the epithelium. PMID- 26745430 TI - Rigorous Phenotyping of Cardiac iPSC Preparations Requires Knowledge of Their Resting Potential(s). PMID- 26745431 TI - The Fallacy of Assigning Chamber Specificity to iPSC Cardiac Myocytes from Action Potential Morphology. PMID- 26745433 TI - New and Notable Changes at Biophysical Journal. PMID- 26745432 TI - Action Potential Shape Is a Crucial Measure of Cell Type of Stem Cell-Derived Cardiocytes. PMID- 26745434 TI - Copper-Catalyzed Regioselective C-H Sulfonylation of 8-Aminoquinolines. AB - Copper(I)-catalyzed 5-sulfonation of quinolines via bidentate-chelation assistance has been developed. The reaction is compatible with a wide range of quinoline substrates and arylsulfonyl chlorides. Experimental and theoretical (DFT) investigation implicated that a single-electron-transfer process is involved in this sulfonylation transformation. PMID- 26745435 TI - Discovery of Pyrophosphate Diesters as Tunable, Soluble, and Bioorthogonal Linkers for Site-Specific Antibody-Drug Conjugates. AB - As part of an effort to examine the utility of antibody-drug conjugates (ADCs) beyond oncology indications, a novel pyrophosphate ester linker was discovered to enable the targeted delivery of glucocorticoids. As small molecules, these highly soluble phosphate ester drug linkers were found to have ideal orthogonal properties: robust plasma stability coupled with rapid release of payload in a lysosomal environment. Building upon these findings, site-specific ADCs were made between this drug linker combination and an antibody against human CD70, a receptor specifically expressed in immune cells but also found aberrantly expressed in multiple human carcinomas. Full characterization of these ADCs enabled procession to in vitro proof of concept, wherein ADCs 1-22 and 1-37 were demonstrated to afford potent, targeted delivery of glucocorticoids to a representative cell line, as measured by changes in glucocorticoid receptor mediated gene mRNA levels. These activities were found to be antibody-, linker-, and payload-dependent. Preliminary mechanistic studies support the notion that lysosomal trafficking and enzymatic linker cleavage are required for activity and that the utility for the pyrophosphate linker may be general for internalizing ADCs as well as other targeted delivery platforms. PMID- 26745436 TI - Unseen positive and negative affective information influences social perception in bipolar I disorder and healthy adults. AB - Bipolar disorder is fundamentally a disorder of emotion regulation, and associated with explicit processing biases for socially relevant emotional information in human faces. Less is known, however, about whether implicit processing of this type of emotional information directly influences social perception. We thus investigated group-related differences in the influence of unconscious emotional processing on conscious person perception judgments using a continuous flash suppression task among 22 individuals with remitted bipolar I disorder (BD; AgeM=30.82, AgeSD=7.04; 68.2% female) compared with 22 healthy adults (CTL; AgeM=20.86, AgeSD=9.91; 72.2% female). Across both groups, participants rated neutral faces as more trustworthy, warm, and competent when paired with unseen happy faces as compared to unseen angry and neutral faces; participants rated neutral faces as less trustworthy, warm, and competent when paired with unseen angry as compared to neutral faces. These findings suggest that emotion-related disturbances are not explained by early automatic processing stages, and that activity in the dorsal visual stream underlying implicit emotion processing is intact in bipolar disorder. Implications for understanding the etiology of emotion disturbance in BD are discussed. PMID- 26745438 TI - Pneumococcal-specific IgG levels after 13-valent pneumococcal conjugate vaccination in Nigerian children with sickle cell disease. AB - BACKGROUND: Children with sickle cell disease (SCD) are particularly susceptible to pneumococcal infection. Administration of the 13-valent conjugate pneumococcal vaccine which is now available in Nigeria may help to reduce the incidence. OBJECTIVES: To determine the serum level of pneumococcal-specific IgG (PIgG) in a cohort of patients with SCD after administration of a single-dose of a 13-valent pneumococcal conjugate vaccine. METHODS: The study was conducted between December 2011 and March 2012 among children with SCD aged 5 months to 5 years attending the sickle cell clinic in five public hospitals in Lagos. Altogether, 151 children with SCD and 52 without it (controls) were recruited by convenience sampling from the sickle cell clinics and well-child clinics. Blood samples were collected for PIgG concentrations before and 2 months after a single dose of the Prevenar 13 vaccine. Seroconversion was defined as a fourfold or greater increase in antibody concentration after vaccination while those with PIgG concentrations >=200 MUU/ml were considered to have protective levels. RESULTS: The age range of the total study group was 5-60 months with a mean (SD) of 39.04 (15.44) months and a median of 39 months. The mean (SD) ages of subjects with and without SCD were 38.91 (15.75) months and 16.39 (15.45) months, respectively. The PIgG concentration 2 months post-vaccination was significantly greater than the pre vaccination levels in all age categories in both groups and almost all subjects had protective PIgG concentrations 2 months after vaccination. A four-fold increase in PIgG concentration was detected more commonly in the controls than in SCD patients. CONCLUSION: Prevenar 13 provided protective immunity in all vaccinated children but those under 2 years of age who had non-protective levels pre-vaccination benefited the most. PMID- 26745439 TI - Removal of arsenic from water using manganese (III) oxide: Adsorption of As(III) and As(V). AB - Removal of arsenic from water was evaluated with manganese (III) oxide (Mn2O3) as adsorbent. Adsorption of As(III) and As(V) onto Mn2O3 was favorable according to the Langmuir and Freundlich adsorption equilibrium equations, while chemisorption of arsenic occurred according to the Dubinin-Radushkevich equation. Adsorption parameters from the Langmuir, Freundlich, and Temkin equations showed a greater adsorption and removal of As(III) than As(V) by Mn2O3. Maximum removal of As(III) and As(V) occurred at pH 3-9 and at pH 2, respectively, while removal of As(V) in the pH range of 6-9 was 93% (pH 6) to 61% (pH 9) of the maximum removal. Zeta potential measurements for Mn2O3 in As(III) was likely converted to As(V) solutions indicated that As(III) was likely converted to As(V) on the Mn2O3 surface at pH 3-9. Overall, the effective Mn2O3 sorbent rapidly removed As(III) and As(V) from water in the pH range of 6-9 for natural waters. PMID- 26745437 TI - Heterogeneity in long-term trajectories of depressive symptoms: Patterns, predictors and outcomes. AB - BACKGROUND: Evidence suggests that long-term trajectories of depressive symptoms vary greatly throughout the population, with some individuals experiencing few or no symptoms, some experiencing transient symptoms and others experiencing chronic depression. The goal of this paper is to review studies that examined heterogeneity in long-term trajectories of depressive symptoms and summarize the current knowledge regarding (a) the number and patterns of trajectories and (b) antecedents and outcomes associated with different trajectory patterns. METHODS: We conducted a systematic review of literature in the Medline and PsychINFO databases. Articles were included if they (a) modeled trajectories of depressive symptoms, (b) used a group-based trajectory modeling approach, (c) followed participants for 5+ years and (d) had a sample size of at least 200. RESULTS: We identified 25 studies from 24 separate cohorts. Most of the studies identified either 3 or 4 distinct trajectory classes. Trajectories varied in terms of severity (low, medium, high) and stability (stable, increasing, decreasing). In most studies, the majority of participants had consistently few or no depressive symptoms, but a notable minority (usually <10%) reported persistent symptoms. Predictors of trajectories with greater symptom burden included female gender, lower income/education and non-white race. Other predictors were specific to different populations (e.g. mothers, older adults). High symptom burden trajectories were associated with poor psychiatric and social outcomes. LIMITATIONS: Comparisons between studies were qualitative. CONCLUSIONS: Trajectories of depression symptoms in the general population are heterogeneous, with most individuals showing minimal symptoms but a notable minority experiencing chronic high symptom burden. PMID- 26745440 TI - Probing Spin-Orbit Coupling and Interlayer Coupling in Atomically Thin Molybdenum Disulfide Using Hydrostatic Pressure. AB - In two-dimensional transition-metal dichalcogenides, both spin-orbit coupling and interlayer coupling play critical roles in the electronic band structure and are desirable for the potential applications in spin electronics. Here, we demonstrate the pressure characteristics of the exciton absorption peaks (so called excitons A, B and C) in monolayer, bilayer, and trilayer molybdenum disulfide (MoS2) by studying the reflectance spectra under hydrostatic pressure and performing the electronic band structure calculations based on density functional theory to account for the experimental observations. We find that the valence band maximum splitting at the K point in monolayer MoS2, induced by spin orbit coupling, remains almost unchanged with increasing pressure applied up to 3.98 GPa, indicating that the spin-orbit coupling is insensitive to the pressure. For bilayer and trilayer MoS2, however, the splitting shows an increase with increasing pressure due to the pressure-induced strengthening of the interlayer coupling. The experimental results are in good agreement with the theoretical calculations. Moreover, the exciton C is identified to be the interband transition related to the van Hove singularity located at a special point which is approximately 1/4 of the total length of Gamma-K away from the Gamma point in the Brillouin zone. PMID- 26745441 TI - Photoinduced Electron Transfer Reactions for Macromolecular Syntheses. AB - Photochemical reactions, particularly those involving photoinduced electron transfer processes, establish a substantial contribution to the modern synthetic chemistry, and the polymer community has been increasingly interested in exploiting and developing novel photochemical strategies. These reactions are efficiently utilized in almost every aspect of macromolecular architecture synthesis, involving initiation, control of the reaction kinetics and molecular structures, functionalization, and decoration, etc. Merging with polymerization techniques, photochemistry has opened up new intriguing and powerful avenues for macromolecular synthesis. Construction of various polymers with incredibly complex structures and specific control over the chain topology, as well as providing the opportunity to manipulate the reaction course through spatiotemporal control, are one of the unique abilities of such photochemical reactions. This review paper provides a comprehensive account of the fundamentals and applications of photoinduced electron transfer reactions in polymer synthesis. Besides traditional photopolymerization methods, namely free radical and cationic polymerizations, step-growth polymerizations involving electron transfer processes are included. In addition, controlled radical polymerization and "Click Chemistry" methods have significantly evolved over the last few decades allowing access to narrow molecular weight distributions, efficient regulation of the molecular weight and the monomer sequence and incredibly complex architectures, and polymer modifications and surface patterning are covered. Potential applications including synthesis of block and graft copolymers, polymer-metal nanocomposites, various hybrid materials and bioconjugates, and sequence defined polymers through photoinduced electron transfer reactions are also investigated in detail. PMID- 26745442 TI - Disruptive Mood Dysregulation Disorder Symptoms and Association with Oppositional Defiant and Other Disorders in a General Population Child Sample. AB - OBJECTIVE: The new Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) diagnosis, disruptive mood dysregulation disorder (DMDD), has generated appreciable controversy since its inception, primarily in regard to its validity as a distinct disorder from oppositional defiant disorder (ODD). The goal of our study was to determine if the two DSM-5 DMDD symptoms (persistently irritable or angry mood and severe recurrent temper outbursts) occurred independently of other disorders, particularly ODD. Other DSM-5 DMDD criteria were not assessed. METHODS: Maternal ratings of the two DMDD symptoms, clinical diagnosis of ODD using DSM-5 symptom criteria, and psychological problem scores (anxiety, depression, oppositional behavior, conduct disorder, and attention deficit/hyperactivity disorder [ADHD]) on the Pediatric Behavior Scale were analyzed in a population sample, 6-12 years of age (n = 665). RESULTS: The prevalence of DMDD symptoms (irritable-angry mood and temper outbursts both rated by mothers as often or very often a problem) was 9%. In all, 92% of children with DMDD symptoms had ODD, and 66% of children with ODD had DMDD symptoms, indicating that it is very unlikely to have DMDD symptoms without ODD, but that ODD can occur without DMDD symptoms. Comorbid psychological problems (anxiety, depression, conduct disorder, and ADHD) in addition to ODD did not increase the risk of having DMDD symptoms beyond that for ODD alone. Only 3% of children with psychological problems other than ODD had DMDD symptoms. CONCLUSIONS: Our general population findings are similar to those for a psychiatric sample, suggesting that DMDD cannot be differentiated from ODD based on symptomatology. Therefore, it is important to assess all DSM criteria and to examine for comorbid psychopathology when considering a diagnosis of DMDD. Our results support the recommendation made by the World Health Organization's International Classification of Diseases, 11th Revision (ICD-11) panel of experts that DMDD symptoms may be more appropriately classified as an ODD specifier than a separate diagnosis. PMID- 26745443 TI - Holarrhena antidysenterica Extract and Its Steroidal Alkaloid, Conessine, as Resistance-Modifying Agents Against Extensively Drug-Resistant Acinetobacter baumannii. AB - Emergence and spread of antibiotic-resistant Acinetobacter baumannii have become a major public health concern. This study was designed to investigate the efficacy of Holarrhena antidysenterica extract and its major steroidal alkaloid conessine as resistance-modifying agents (RMAs) on the susceptibility of A. baumannii to novobiocin and rifampicin. A significant synergistic activity of both the extract and conessine in combination with either novobiocin or rifampicin with fractional inhibitory concentration index <=0.5 was demonstrated. Fluorescent dyes and different efflux pump inhibitors were used to further investigate the synergism. Increase in the uptake of 1-N-phenylnaphthylamine in the bacterial cells treated with the extract and conessine was not observed indicating that both substances did not act as permeabilizers. With regard to efflux pump inhibition, no accumulation in ethidium bromide (EtBr) was noticed suggesting that the AdeABC pump was not involved. In contrast, accumulation in Pyronin Y was significantly increased (p < 0.05) demonstrating that the synergism was due to interference with the AdeIJK pump. Study on frequencies of the spontaneous mutational resistance to the extract in combination with antibiotics demonstrated attenuation in drug-resistant organisms. Thus, H. antidysenterica extract and conessine as RMAs may offer a combinatory therapy to restore antibiotic susceptibility in the extensively drug-resistant A. baumannii. PMID- 26745444 TI - Using stable isotopes to resolve transit times and travel routes of river water: a case study from southern Finland. AB - The stable isotopic composition of two rivers, the Vantaanjoki River and the Kokemaenjoki River, in southern and southwestern Finland was studied to resolve the transit times and travel routes of the river water in the two different catchments. The Kokemaenjoki River is dominated by great lake basins whereas the Vantaanjoki River has been reported having a significant groundwater component. The mean residence time of the young surface flow component could be resolved by sine function fitting onto the annual fluctuations of the isotopic signal, and the amount of base flow was estimated by using the isotopic composition of the river and groundwater. In this study, we found that the methods work for simple two component catchments. In more complex cases with three different components mixing, the solution becomes increasingly difficult and requires more study. PMID- 26745446 TI - Hydrogen-Regulated Chiral Nanoplasmonics. AB - Chirality is a highly important topic in modern chemistry, given the dramatically different pharmacological effects that enantiomers can have on the body. Chirality of natural molecules can be controlled by reconfiguration of molecular structures through external stimuli. Despite the rapid progress in plasmonics, active regulation of plasmonic chirality, particularly in the visible spectral range, still faces significant challenges. In this Letter, we demonstrate a new class of hybrid plasmonic metamolecules composed of magnesium and gold nanoparticles. The plasmonic chirality from such plasmonic metamolecules can be dynamically controlled by hydrogen in real time without introducing macroscopic structural reconfiguration. We experimentally investigate the switching dynamics of the hydrogen-regulated chiroptical response in the visible spectral range using circular dichroism spectroscopy. In addition, energy dispersive X-ray spectroscopy is used to examine the morphology changes of the magnesium particles through hydrogenation and dehydrogenation processes. Our study can enable plasmonic chiral platforms for a variety of gas detection schemes by exploiting the high sensitivity of circular dichroism spectroscopy. PMID- 26745445 TI - Effect of Amyloid Imaging on the Diagnosis and Management of Patients with Cognitive Decline: Impact of Appropriate Use Criteria. AB - BACKGROUND: Published appropriate use criteria (AUC) describe patients for whom amyloid positron emission tomography (PET) might be most useful. This study compared the impact of amyloid PET on diagnosis and management in subjects likely to either meet or not meet AUC. METHODS: Physicians provided a provisional diagnosis and management plan for patients presenting with cognitive decline before and after amyloid PET imaging with florbetapir F 18. Participants were classified as AUC-like or not, based on the prescan diagnosis and demographic features. RESULTS: In all, 125 of 229 participants (55%) were classified as AUC like. Sixty-two percent of the AUC-like subjects had a change in diagnosis after scanning compared with 45% of the non-AUC subjects (p = 0.011). Both groups demonstrated high rates of change in their management plans after scanning (88.0% for AUC-like cases, 85.6% for non-AUC cases). CONCLUSIONS: The impact of amyloid imaging on diagnosis and planned management was maintained and, if anything, amplified in AUC-like patients. PMID- 26745447 TI - Derivation and Implementation of the Gradient of the R(-7) Dispersion Interaction in the Effective Fragment Potential Method. AB - The dispersion interaction energy may be expressed as a sum over R(-n) terms, with n >= 6. Most implementations of the dispersion interaction in model potentials are terminated at n = 6. Those implementations that do include higher order contributions commonly only include even power terms, despite the fact that odd power terms can be important. Because the effective fragment potential (EFP) method contains no empirically fitted parameters, the EFP method provides a useful vehicle for examining the importance of the leading R(-7) odd power term in the dispersion expansion. To fully evaluate the importance of the R(-7) contribution to the dispersion energy, it is important to have analytic energy first derivatives for all terms. In the present work, the gradients of the term E7 ~ R(-7) are derived analytically, implemented in the GAMESS software package, and evaluated relative to other terms in the dispersion expansion and relative to the total EFP interaction energy. Periodic boundary conditions in the minimum image convention are also implemented. A more accurate dispersion energy contribution can now be obtained during molecular dynamics simulations. PMID- 26745448 TI - Origin of the Zero-Field Splitting in Mononuclear Octahedral Mn(IV) Complexes: A Combined Experimental and Theoretical Investigation. AB - The aim of this work was to determine and understand the origin of the electronic properties of Mn(IV) complexes, especially the zero-field splitting (ZFS), through a combined experimental and theoretical investigation on five well characterized mononuclear octahedral Mn(IV) compounds, with various coordination spheres (N6, N3O3, N2O4 in both trans (trans-N2O4) and cis configurations (cis N2O4) and O4S2). High-frequency and -field EPR (HFEPR) spectroscopy has been applied to determine the ZFS parameters of two of these compounds, MnL(trans N2O4) and MnL(O4S2). While at X-band EPR, the axial-component of the ZFS tensor, D, was estimated to be +0.47 cm(-1) for MnL(O4S2), and a D-value of +2.289(5) cm( 1) was determined by HFEPR, which is the largest D-magnitude ever measured for a Mn(IV) complex. A moderate D value of -0.997(6) cm(-1) has been found for MnL(trans-N2O4). Quantum chemical calculations based on two theoretical frameworks (the Density Functional Theory based on a coupled perturbed approach (CP-DFT) and the hybrid Ligand-Field DFT (LF-DFT)) have been performed to define appropriate methodologies to calculate the ZFS tensor for Mn(IV) centers, to predict the orientation of the magnetic axes with respect to the molecular ones, and to define and quantify the physical origin of the different contributions to the ZFS. Except in the case of MnL(trans-N2O4), the experimental and calculated D values are in good agreement, and the sign of D is well predicted, LF-DFT being more satisfactory than CP-DFT. The calculations performed on MnL(cis-N2O4) are consistent with the orientation of the principal anisotropic axis determined by single-crystal EPR, validating the calculated ZFS tensor orientation. The different contributions to D were analyzed demonstrating that the d-d transitions mainly govern D in Mn(IV) ion. However, a deep analysis evidences that many factors enter into the game, explaining why no obvious magnetostructural correlations can be drawn in this series of Mn(IV) complexes. PMID- 26745451 TI - Protein Kinase C gamma Interneurons Mediate C-fiber-induced Orofacial Secondary Static Mechanical Allodynia, but Not C-fiber-induced Nociceptive Behavior. AB - BACKGROUND: Tissue injury enhances pain sensitivity both at the site of tissue damage and in surrounding uninjured skin (secondary hyperalgesia). Secondary hyperalgesia encompasses several pain symptoms including pain to innocuous punctate stimuli or static mechanical allodynia. How injury-induced barrage from C-fiber nociceptors produces secondary static mechanical allodynia has not been elucidated. METHODS: Combining behavioral, immunohistochemical, and Western blot analysis, the authors investigated the cell and molecular mechanisms underlying the secondary static mechanical allodynia in the rat medullary dorsal horn (MDH) using the capsaicin model (n = 4 to 5 per group). RESULTS: Intradermal injection of capsaicin (25 MUg) into the vibrissa pad produces a spontaneous pain and a secondary static mechanical allodynia. This allodynia is associated with the activation of a neuronal network encompassing lamina I-outer lamina III, including interneurons expressing the gamma isoform of protein kinase C (PKCgamma) within inner lamina II (IIi) of MDH. PKCgamma is concomitantly phosphorylated (+351.4 +/- 79.2%, mean +/- SD; P = 0.0003). Mechanical allodynia and innocuous punctate stimulus-evoked laminae I to III neuronal activation can be replicated after intracisternally applied gamma-aminobutyric acid receptor type A (GABAA) antagonist (bicuculline: 0.05 MUg) or reactive oxygen species (ROS) donor (tert-butyl hydroperoxide: 50 to 250 ng). Conversely, intracisternal PKCgamma antagonist, GABAA receptor agonist, or ROS scavenger prevent capsaicin induced static mechanical allodynia and neuronal activation. CONCLUSIONS: Sensitization of lamina IIi PKCgamma interneurons is required for the manifestation of secondary static mechanical allodynia but not for spontaneous pain. Such sensitization is driven by ROS and GABAAergic disinhibition. ROS released during intense C-fiber nociceptor activation might produce a GABAAergic disinhibition of PKCgamma interneurons. Innocuous punctate inputs carried by Adelta low-threshold mechanoreceptors onto PKCgamma interneurons can then gain access to the pain transmission circuitry of superficial MDH, producing pain. PMID- 26745449 TI - A Microfluidic Device with Integrated Sonication and Immunoprecipitation for Sensitive Epigenetic Assays. AB - Epigenetic studies increasingly require analysis of a small number of cells that are of one specific type and derived from patients or animals. In this report, we demonstrate a simple microfluidic device that integrates sonication and immunoprecipitation (IP) for epigenetic assays, such as chromatin immunoprecipitation (ChIP) and methylated DNA immunoprecipitation (MeDIP). By incorporating an ultrasonic transducer with a microfluidic chamber, we implemented microscale sonication for both shearing chromatin/DNA and mixing/washing of IP beads. Such integration allowed highly sensitive tests starting with 100 cross-linked cells for ChIP or 500 pg of genomic DNA for MeDIP (compared to 10(6)-10(7) cells for ChIP and 1-10 MUg of DNA for MeDIP in conventional assays). The entire on-chip process of sonication and IP took only 1 h. Our tool will be useful for highly sensitive epigenetic studies based on a small quantity of sample. PMID- 26745450 TI - Combined application of polyacrylate scaffold and lipoic acid treatment promotes neural tissue reparation after brain injury. AB - PRIMARY OBJECTIVE: The aim of this study was to investigate the reparative potential of a polymeric scaffold designed for brain tissue repair in combination with lipoic acid. RESEARCH DESIGN: Histological, cytological and structural analysis of a combined treatment after a brain cryo-injury model in rats. METHODS AND PROCEDURES: Adult Wistar rats were subjected to cryogenic brain injury. A channelled-porous scaffold of ethyl acrylate and hydroxyethylacrylate, p(EA-co HEA) was grafted into cerebral penumbra alone or combined with intraperitoneal LA administration. Histological and cytological evaluation was performed after 15 and 60 days and structural magnetic resonance (MRI) assessment was performed at 2 and 6 months after the surgery. MAIN OUTCOMES AND RESULTS: The scaffold was suitable for the establishment of different cellular types. The results obtained suggest that this strategy promotes blood vessels formation, decreased microglial response and neuron migration, particularly when LA was administrated. CONCLUSIONS: These evidences demonstrated that the combination of a channelled polymer scaffold with LA administration may represent a potential treatment for neural tissue repair after brain injury. PMID- 26745453 TI - Topoisomerase-Based Preparation and AFM Imaging of Multi-Interlocked Circular DNA. AB - Multi-interlocked circular DNA structures have been in high demand for fabricating complicated functional DNA architectures and nanodevices such as molecular switches, shuttles, and motors. Even though various innovative methods have been developed in the past, creation of multi-interlocked circular DNA structures with defined numbers of DNA molecules and linking patterns is still a challenging task nowadays. Here, we propose a top-down decatenation of kinetoplast DNA as a new approach for creating multi-interlocked circular DNA structures. Through optimizing the amount and reaction time of topoisomerase II, we synthesized completely mutually interlocked tricircular, tetra-circular, and oligo-circular DNA structures, which have not yet been acquirable through any other existing synthetic means. The catenation structures of multiple circular DNA were further verified through atomic force microscopic analysis of the backbone overlapping patterns and the circumference. It accordingly is our expectation that the top-down enzymatic approaches could offer a highly interlocked network with defined numbers of circular DNA with simple protocols, and could consequently be beneficial to the design and fabrication of sophisticated functional molecules and nanodevices in the areas of supramolecular chemistry, DNA nanotechnology, and material science. PMID- 26745452 TI - Unanticipated Insights into Biomedicine from the Study of Acupuncture. AB - Research into acupuncture has had ripple effects beyond the field of acupuncture. This paper identifies five exemplars to illustrate that there is tangible evidence of the way insights gleaned from acupuncture research have informed biomedical research, practice, or policy. The first exemplar documents how early research into acupuncture analgesia has expanded into neuroimaging research, broadening physiologic understanding and treatment of chronic pain. The second describes how the acupuncture needle has become a tool to enhance biomedical knowledge of connective tissue. The third exemplar, which illustrates use of a modified acupuncture needle as a sham device, focuses on emergent understanding of placebo effects and, in turn, on insights into therapeutic encounters in treatments unrelated to acupuncture. The fourth exemplar documents that two medical devices now in widespread use were inspired by acupuncture: transcutaneous electrical nerve stimulators for pain control and antinausea wrist bands. The final exemplar describes how pragmatic clinical trial designs applied in acupuncture research have informed current general interest in comparative effectiveness research. In conclusion, these exemplars of unanticipated outcomes of acupuncture research comprise an additional rationale for continued support of basic and clinical research evaluating acupuncture and other under-researched therapies. PMID- 26745455 TI - Regulation of Ca(2+) signaling in prostate cancer cells. PMID- 26745454 TI - Human placental multipotent mesenchymal stromal cells modulate placenta angiogenesis through Slit2-Robo signaling. AB - The objective of this study was to investigate whether human placental multipotent mesenchymal stromal cell (hPMSC)-derived Slit2 and endothelial cell Roundabout (Robo) receptors are involved in placental angiogenesis. The hPMSC conditioned medium and human umbilical vein endothelial cells were studied for Slit2 and Robo receptor expression by immunoassay and RT-PCR. The effect of the conditioned medium of hPMSCs with or without Slit2 depletion on endothelial cells was investigated by in vitro angiogenesis using growth factor-reduced Matrigel. hPMSCs express Slit2 and both Robo1 and Robo4 are present in human umbilical vein endothelial cells. Human umbilical vein endothelial cells do not express Robo2 and Robo3. The hPMSC-conditioned medium and Slit2 recombinant protein significantly inhibit the endothelial cell migration, but not by the hPMSC conditioned medium with Slit2 depletion. The hPMSC-conditioned medium and Slit2 significantly enhance endothelial tube formation with increased cumulated tube length, polygonal network number and vessel branching point number compared to endothelial cells alone. The tube formation is inhibited by the depletion of Slit2 from the conditioned medium, or following the expression of Robo1, Robo4, and both receptor knockdown using small interfering RNA. Furthermore, co immunoprecipitation reveals Slit2 binds to Robo1 and Robo4. Robo1 interacts and forms a heterodimeric complex with Robo4. These results suggest the implication of both Robo receptors with Slit2 signaling, which is involved in endothelial cell angiogenesis. Slit2 in the conditioned medium of hPMSCs has functional effect on endothelial cells and may play a role in placental angiogenesis. PMID- 26745456 TI - Effects of age, gender, and stimulus presentation period on visual short-term memory. AB - This study focused on age-related changes in visual short-term memory using visual stimuli that did not allow verbal encoding. Experiment 1 examined the effects of age and the length of the stimulus presentation period on visual short term memory function. Experiment 2 examined the effects of age, gender, and the length of the stimulus presentation period on visual short-term memory function. The worst memory performance and the largest performance difference between the age groups were observed in the shortest stimulus presentation period conditions. The performance difference between the age groups became smaller as the stimulus presentation period became longer; however, it did not completely disappear. Although gender did not have a significant effect on d' regardless of the presentation period in the young group, a significant gender-based difference was observed for stimulus presentation periods of 500 ms and 1,000 ms in the older group. This study indicates that the decline in visual short-term memory observed in the older group is due to the interaction of several factors. PMID- 26745459 TI - A Two Factor ANOVA-like Test for Correlated Correlations: CORANOVA. AB - Testing homogeneity of correlations with Fisher's Z is inappropriate when correlations are themselves correlated. Suppose measurements of brain activation and performance are taken before and during a verbal memory task. Of interest are changes in activity gradients in specific regions, R1, R2, R3, and performance, V. The "correlated correlations" of interest rhoV,R1 , rhoV,R2 , and rhoV,R3 , have a single variable, V, in common. We wish to compare these correlations between males and females, across regions, and to assess an interaction of the correlation. Fisher's Z can compare pairs of correlations, and Olkin and Finn's (1990) method can test homogeneity of correlated correlations across a single within factor (based on asymptotic normality), but no current procedure can test a region by gender (within by between) interaction of correlations. We propose a nonparametric method for testing this interaction and both main effects. The procedure is analogous to two-way ANOVA, but hypotheses test homogeneity of correlations, not means. The null distributions are estimated with permutations, avoiding asymptotic distributional assumptions and enhancing applicability to smaller samples and non-normal data. Simulations demonstrated maintenance of correct level (power = alpha level under the null) for normal and non-normal data and small samples. The Olkin-Finn test had inflated level for non-normal data or small samples. The Fisher's Z had inflated level for non-normal data, but not for small samples. Our method had better efficiency across contrasts and data types and sizes. Applied to correlations between regional laterality of blood flow and verbal memory performance, the method showed sensitivity to a biologically meaningful sex by region interaction in these correlations. A SAS macro for CORANOVA is available. PMID- 26745457 TI - ATP-Responsive Drug Delivery Systems. PMID- 26745458 TI - Interactive and Versatile Navigation of Structural Databases. AB - We present CSD-CrossMiner, a novel tool for pharmacophore-based searches in crystal structure databases. Intuitive pharmacophore queries describing, among others, protein-ligand interaction patterns, ligand scaffolds, or protein environments can be built and modified interactively. Matching crystal structures are overlaid onto the query and visualized as soon as they are available, enabling the researcher to quickly modify a hypothesis on the fly. We exemplify the utility of the approach by showing applications relevant to real-world drug discovery projects, including the identification of novel fragments for a specific protein environment or scaffold hopping. The ability to concurrently search protein-ligand binding sites extracted from the Protein Data Bank (PDB) and small organic molecules from the Cambridge Structural Database (CSD) using the same pharmacophore query further emphasizes the flexibility of CSD CrossMiner. We believe that CSD-CrossMiner closes an important gap in mining structural data and will allow users to extract more value from the growing number of available crystal structures. PMID- 26745460 TI - Estimating Cognitive Profiles Using Profile Analysis via Multidimensional Scaling (PAMS). AB - Two of the most popular methods of profile analysis, cluster analysis and modal profile analysis, have limitations. First, neither technique is adequate when the sample size is large. Second, neither method will necessarily provide profile information in terms of both level and pattern. A new method of profile analysis, called Profile Analysis via Multidimensional Scaling (PAMS; Davison, 1996), is introduced to meet the challenge. PAMS extends the use of simple multidimensional scaling methods to identify latent profiles in a multi-test battery. Application of PAMS to profile analysis is described. The PAMS model is then used to identify latent profiles from a subgroup (N = 357) within the sample of the Woodcock Johnson Psychoeducational Battery-Revised (WJ-R; McGrew, Werder, & Woodcock, 1991; Woodcock & Johnson, 1989), followed by a discussion of procedures for interpreting participants' observed score profiles from the latent PAMS profiles. Finally, advantages and limitations of the PAMS technique are discussed. PMID- 26745461 TI - Using Latent Class Analysis to Model Temperament Types. AB - Mixture models are appropriate for data that arise from a set of qualitatively different subpopulations. In this study, latent class analysis was applied to observational data from a laboratory assessment of infant temperament at four months of age. The EM algorithm was used to fit the models, and the Bayesian method of posterior predictive checks was used for model selection. Results show at least three types of infant temperament, with patterns consistent with those identified by previous researchers who classified the infants using a theoretically based system. Multiple imputation of group memberships is proposed as an alternative to assigning subjects to the latent class with maximum posterior probability in order to reflect variance due to uncertainty in the parameter estimation. Latent class membership at four months of age predicted longitudinal outcomes at four years of age. The example illustrates issues relevant to all mixture models, including estimation, multi-modality, model selection, and comparisons based on the latent group indicators. PMID- 26745462 TI - Evaluation of the Bayesian and Maximum Likelihood Approaches in Analyzing Structural Equation Models with Small Sample Sizes. AB - The main objective of this article is to investigate the empirical performances of the Bayesian approach in analyzing structural equation models with small sample sizes. The traditional maximum likelihood (ML) is also included for comparison. In the context of a confirmatory factor analysis model and a structural equation model, simulation studies are conducted with the different magnitudes of parameters and sample sizes n = da, where d = 2, 3, 4 and 5, and a is the number of unknown parameters. The performances are evaluated in terms of the goodness-of-fit statistics, and various measures on the accuracy of the estimates. The conclusion is: for data that are normally distributed, the Bayesian approach can be used with small sample sizes, whilst ML cannot. PMID- 26745463 TI - The Specific Analysis of Structural Equation Models. AB - Conventional structural equation modeling fits a covariance structure implied by the equations of the model. This treatment of the model often gives misleading results because overall goodness of fit tests do not focus on the specific constraints implied by the model. An alternative treatment arising from Pearl's directed acyclic graph theory checks identifiability and lists and tests the implied constraints. This approach is complete for Markov models, but has remained incomplete for models with correlated disturbances. Some new algebraic results overcome the limitations of DAG theory and give a specific form of structural equation analysis that checks identifiability, tests the implied constraints, equation by equation, and gives consistent estimators of the parameters in closed form from the equations. At present the method is limited to recursive models subject to exclusion conditions. With further work, specific structural equation modeling may yield a complete alternative to the present, rather unsatisfactory, global covariance structure analysis. PMID- 26745464 TI - Extended functional repertoire for human copper chaperones. AB - Copper (Cu) ions are cofactors in many essential enzymes. As free Cu ions are toxic, most organisms have highly specialized Cu transport systems involving dedicated proteins. The human cytoplasmic Cu chaperone Atox1 delivers Cu to P1B type ATPases in the Golgi network, for incorporation into Cu-dependent enzymes following the secretory path. Atox1 homologs are found in most organisms; it is a 68-residue ferredoxin-fold protein that binds Cu in a conserved surface-exposed CXXC motif. In addition to Atox1, the human cytoplasm also contains Cu chaperones for loading of superoxide dismutase 1 (i.e. CCS) and cytochrome c oxidase in mitochondria (i.e. Cox17). Many mechanistic aspects have been resolved with respect to how Cu ions are moved between these proteins. In addition to the primary cytoplasmic Cu chaperone function, all three cytoplasmic chaperones have been reported to have other interaction partners that are involved in signaling pathways that modulate cell growth and development. These new discoveries imply that humans have evolved a highly sophisticated network of control mechanisms that connect Cu transport with cell regulatory processes. This knowledge may eventually be exploited for future drug developments towards diseases such as cancer and neurodegenerative disorders. PMID- 26745466 TI - Biocatalytic production of D-tagatose: A potential rare sugar with versatile applications. AB - D-tagatose is a naturally existing rare monosaccharide having prebiotic properties. Minimal absorption, low metabolizing energy, and unique clinical properties are the characteristics of D-tagatose. D-tagatose gained international attention by matching the purpose of alternate sweeteners that is much needed for the control of diabetes among world population. Recent efforts in understanding tagatose bioconversion have generated essential information regarding its production and application. This article reviews the evolution of D-tagatose as an important rare sugar by appreciable improvements in production results and its significant applications resulted of its unique physical, chemical, biological, and clinical properties thus considering it an appropriate product for requisite improvements in technical viability. Based on current knowledge and technology projections, the commercialization of D-tagatose rare sugar as food additive is close to reality. PMID- 26745465 TI - The tyrosine-sorting motif of the vacuolar sorting receptor VSR4 from Arabidopsis thaliana, which is involved in the interaction between VSR4 and AP1M2, MU1 adaptin type 2 of clathrin adaptor complex 1 subunits, participates in the post Golgi sorting of VSR4. AB - MU1-Adaptin of adaptor protein (AP) 1 complex, AP1M, is generally accepted to load cargo proteins into clathrin-coated vesicles (CCVs) at the trans-Golgi network through its binding to cargo-recognition sequences (CRSs). Plant vacuolar sorting receptors (VSRs) function in sorting vacuolar proteins, which are reportedly mediated by CCV. We herein investigated the involvement of CRSs of Arabidopsis thaliana VSR4 in the sorting of VSR4. The results obtained showed the increased localization of VSR4 at the plasma membrane or vacuoles by mutations in CRSs including the tyrosine-sorting motif YMPL or acidic dileucine-like motif EIRAIM, respectively. Interaction analysis using the bimolecular fluorescence complementation (BiFC) system, V10-BiFC, which we developed, indicated an interaction between VSR4 and AP1M2, AP1M type 2, which was attenuated by a YMPL mutation, but not influenced by an EIRAIM mutation. These results demonstrated the significance of the recognition of YMPL in VSR4 by AP1M2 for the post-Golgi sorting of VSR4. PMID- 26745467 TI - The case for a sociology of dying, death, and bereavement. AB - Dying, death, and bereavement do not occur in a social vacuum. How individuals and groups experience these phenomena will be largely influenced by the social context in which they occur. To develop an adequate understanding of dying, death, and bereavement we therefore need to incorporate a sociological perspective into our analysis. This article examines why a sociological perspective is necessary and explores various ways in which sociology can be of practical value in both intellectual and professional contexts. A case study comparing psychological and sociological perspectives is offered by way of illustration. PMID- 26745468 TI - Predictors of clinical outcomes in patients with neuropsychiatric systemic lupus erythematosus. AB - INTRODUCTION: Neuropsychiatric systemic lupus erythematosus (NPSLE), a serious organ disorder with a variety of symptoms, has diverse therapeutic outcomes because of the variability of NPSLE manifestations. A comprehensive association study of NPSLE among clinical and immunopathogenic aspects and outcomes has not been conducted. METHODS: We analyzed the laboratory data, NPSLE symptoms, and clinical outcomes at 1yr post-treatment and the profiles of 27 cytokines, chemokines and growth factors in cerebrospinal fluid (CSF) samples using the Bio Plex Human 27-plex panel from 28 NPSLE patients. Univariate and multivariable competing risks regression analyses were used to determine the predictive factors of clinical response. We also tried to predict the outcome of NPSLE by the 27 cytokines/chemokines/growth factors using a weighted-voting (WV) algorithm. RESULTS: Of the two males and 26 females (92.9%), 16 were non-responders at 1yr post-treatment; in the final model, the independent predictors of non-responders were longer disease durations of SLE (odds ratio [OR]: 1.490, 95% confidence interval [CI]: 1.143-2.461, p=0.0003) and patients with more than one NPSLE symptom types (OR: 15.14, 95% CI: 1.227-452.1, p=0.0334). The pretreatment CSF interleukin (IL)-6, IL-10, interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) levels were significantly higher in the non-responders (p=0.0207, p=0.0054, p=0.0242 and p=0.0077, respectively). We identified six "minimum predictive markers:" IL-10, TNF-alpha, IL-6, IFN-gamma, IL-4 and IL-13 by a WV algorithm that showed the highest accuracy (70.83%) and highest Matthews correlation coefficient (54.23%). CONCLUSIONS: We have devised a numerical prediction scoring system that was able to separate the non-responders from responders. The patients with longer disease durations of SLE and those with more than one NPSLE symptom types had poorer outcomes. Our findings may indicate both the importance of making a diagnosis at an earlier phase for better therapeutic response and the usefulness of measuring multiple cytokines to predict NPSLE therapeutic outcomes. PMID- 26745469 TI - How to enhance route learning and visuo-spatial working memory in aging: a training for residential care home residents. AB - OBJECTIVES: This study aimed to assess the efficacy of a route-learning training in a group of older adults living in a residential care home. We verified the presence of training-specific effects in tasks similar to those trained - route learning tasks - as well as transfer effects on related cognitive processes - visuo-spatial short-term memory (VSSTM; Corsi Blocks Test (CBT), forward version), visuo-spatial working memory (VSWM; CBT, backward version; Pathway Span Tasks; Jigsaw Puzzle Test) - and in self-report measures. The maintenance of training benefits was examined after 3 months. METHOD: Thirty 70-90-year-old residential care home residents were randomly assigned to the route-learning training group or to an active control group (involved in non-visuo-spatial activities). RESULTS: The trained group performed better than the control group in the route-learning tasks, retaining this benefit 3 months later. Immediate transfer effects were also seen in visuo-spatial span tasks (i.e., CBT forward and backward version and Pathway Span Task); these benefits had been substantially maintained at the 3-month follow-up. CONCLUSION: These findings suggest that a training on route learning is a promising approach to sustain older adults' environmental learning and some related abilities (e.g., VSSTM and VSWM), even in residential care home residents. PMID- 26745470 TI - Influence of female sex on hepatitis C virus infection progression and treatment outcomes. AB - BACKGROUND: The influence of sex on hepatitis C virus (HCV)-related outcomes is often neglected. The effects of sex on liver fibrosis progression and the effect of socioeconomic status on management are unclear. PATIENTS AND METHODS: Data were evaluated from patients followed at The Ottawa Hospital and Regional Viral Hepatitis Program. RESULTS: Of 1978 chronic HCV-infected patients, 630 (32%) were women. Women had lower liver enzyme levels, HCV RNA levels, and weight compared with men. Women were more likely to be non-genotype-1 infected, Black or Asian, and immigrants from Africa and Asia (all P<0.01). Under 50 years of age, women on average had lower fibrosis scores than men. Beyond the age of 50 years, the mean fibrosis scores were similar, suggesting a 'catch-up' phase. Women were less likely to have initiated interferon-based HCV antiviral therapy (35.3 vs. 43.3%, P=0.01). Crude sustained virological responses were higher in women (65.3 vs. 56.3%, P=0.03), but were similar to men as determined by multivariable analysis (odds ratio: 0.92, 95% confidence interval: 0.58-1.46). Women of low socioeconomic status were more likely to be HIV coinfected and had higher rates of fibrosis progression. Women living in low-income neighborhoods were less likely to achieve sustained virological response (odds ratio: 0.50, 95% confidence interval: 0.34-0.75, P=0.01) compared with women in higher income regions. CONCLUSION: Sex differences have been identified as a potential barrier to overcome when managing viral infections. Our analysis suggests that sex influences fibrosis progression, likelihood of initiating HCV antiviral therapy, and treatment outcomes. PMID- 26745471 TI - Endoscopic appearances of polypoid type 1 gastric microcarcinoids by narrow-band imaging: a case series in a referral center. AB - OBJECTIVE: Narrow-band imaging (NBI) has been associated with high accuracy for the identification of gastric malignant lesions. This study aimed to investigate for the first time the endoscopic NBI appearances of type 1 gastric carcinoids in a consecutive series of patients with atrophic gastritis. METHODS: Seven consecutive patients (five women, median age 61 years) with atrophic gastritis and polypoid type 1 gastric carcinoids were included. After white-light examination, gastric antrum and body were examined by NBI for the examination of polyps and lesions. Digital images of polyps from recorded videos were extracted and reviewed for NBI features. RESULTS: Fifteen polypoid type 1 gastric microcarcinoids (median size 3 mm) were detected in the seven patients; four patients had synchronous lesions. Nine (60%) lesions showed a tubulovillous and six lesions (40%) showed an irregular mucosal pattern; a regular circular pattern was never observed. A light-blue crest was observed on six (40%) lesions. The vascular pattern was irregular in eight (53.3%) microcarcinoids. All six type 1 gastric carcinoids with an irregular mucosal pattern showed an irregular vascular pattern without light-blue crest. Of the nine carcinoids with a tubulovillous mucosal pattern, two had an irregular and seven had a regular vascular pattern. CONCLUSION: Polypoid type 1 gastric microcarcinoids always show an abnormal NBI mucosal surface pattern, but no specific features to distinguish them from other intraepithelial lesions such as intestinal metaplasia, adenomas, or low-grade and high-grade dysplasia are observed. Thus, target biopsies to diagnose the pathological nature of the lesion are advocated. PMID- 26745472 TI - Skull base chordomas: clinical outcome in a consecutive series of 45 patients with long-term follow-up and evaluation of clinical and biological prognostic factors. AB - OBJECTIVE Skull base chordomas (SBCs) are rare dysembryogenetic invasive tumors with a variable tendency for recurrence. According to previous studies, the recurrence rate seems to be affected by both clinical variables and tumor biological features. The authors present the results of treatment of SBCs in a large series of patients and investigate the role of 1p36 chromosomal region loss of heterozygosity (LOH) as a prognostic factor. METHODS Between 1990 and 2011, 45 patients were treated for SBCs. The mean follow-up was 76 months (range 1-240 months). An LOH analysis was performed in 27 cases. Survival analysis was performed to determine clinical and biological parameters correlating with clinical outcome. RESULTS The 5- and 10-year overall survival rates were 67% and 57%, respectively. Five- and 10-year progression-free survival rates were 58% and 44%, respectively. Multivariate analysis showed that extent of resection, adjuvant radiation therapy, and absence of rhinopharynx invasion were positive independent predictors of overall survival. The latter 2 variables and a younger patient age were positive independent predictors of progression-free survival. Twenty-one patients showed 1p36 LOH. All events of recurrence and death clustered in the group of patients with 1p36 LOH; however, this biological marker was not statistically significant on multivariate analysis. CONCLUSIONS Resection is the treatment of choice in primary and recurrent SBC. Patient age, rhinopharynx invasion at diagnosis, extent of tumor removal, and postoperative radiation therapy influence SBC prognosis. Genetic analysis, even while showing interesting results, did not reveal 1p36 LOH as an independent predictor of clinical outcome. PMID- 26745473 TI - Straight sinus: ultrastructural analysis aimed at surgical tumor resection. AB - OBJECTIVE Accurate knowledge of the anatomy of the straight sinus (SS) is relevant for surgical purposes. During one surgical procedure involving the removal of part of the SS wall, the authors observed that the venous blood flow was maintained in the SS, possibly through a vein-like structure within the dural sinus or dural multiple layers. This observation and its divergence from descriptions of the histological features of the SS walls motivated the present study. The authors aimed to investigate whether it is possible to dissect the SS walls while keeping the lumen intact, and to describe the histological and ultrastructural composition of the SS wall. METHODS A total of 22 cadaveric specimens were used. The SS was divided into three portions: anterior, middle, and posterior. The characteristics of the SS walls were analyzed, and the feasibility of dissecting them while keeping the SS lumen intact was assessed. The thickness and the number of collagen fibers and other tissues in the SS walls were compared with the same variables in other venous sinuses. Masson's trichrome and Verhoeff's stains were used to assess collagen and elastic fibers, respectively. The data were analyzed using Zeiss image analysis software (KS400). RESULTS A vein-like structure independent of the SS walls was found in at least one of the portions of the SS in 8 of 22 samples (36.36%). The inferior wall could be delaminated in at least one portion in 21 of 22 samples (95.45%), whereas the lateral walls could seldom be delaminated. The inferior wall of the SS was thicker (p < 0.05) and exhibited less collagen and greater amounts of other tissues-including elastic fibers, connective tissue, blood vessels, and nerve fibers (p < 0.05)-compared with the lateral walls. Transmission electron microscopy revealed the presence of muscle fibers at a level deeper than that of the subendothelial connective tissue in the inferior wall of the SS, extending from its junction with the great cerebral vein to the confluence of sinuses. CONCLUSIONS The presence of a structure within the SS that can maintain the venous blood flow despite the dural wall might be considered an anatomical variation. The greater thickness of the inferior wall of the SS compared with the lateral walls is mainly due to the presence of larger amounts of tissues other than collagen. Delamination of the inferior wall of the SS was mostly possible in its inferior wall, but an attempt to delaminate the lateral walls is not recommended. Ultrastructural assessment corroborated a recent report of the presence of muscle fibers in the inferior wall of the SS. PMID- 26745474 TI - The significant impact of framing coils on long-term outcomes in endovascular coiling for intracranial aneurysms: how to select an appropriate framing coil. AB - OBJECTIVE The importance of a framing coil (FC)-the first coil inserted into an aneurysm during endovascular coiling, also called a lead coil or a first coil-is recognized, but its impact on long-term outcomes, including recanalization and retreatment, is not well established. The purposes of this study were to test the hypothesis that the FC is a significant factor for aneurysmal recurrence and to provide some insights on appropriate FC selection. METHODS The authors retrospectively reviewed endovascular coiling for 280 unruptured intracranial aneurysms and gathered data on age, sex, aneurysm location, aneurysm morphology, maximal size, neck width, adjunctive techniques, recanalization, retreatment, follow-up periods, total volume packing density (VPD), volume packing density of the FC, and framing coil percentage (FCP; the percentage of FC volume in total coil volume) to clarify the associated factors for aneurysmal recurrence. RESULTS Of 236 aneurysms included in this study, 33 (14.0%) had recanalization, and 18 (7.6%) needed retreatment during a mean follow-up period of 37.7 +/- 16.1 months. In multivariate analysis, aneurysm size (odds ratio [OR] = 1.29, p < 0.001), FCP < 32% (OR 3.54, p = 0.009), and VPD < 25% (OR 2.96, p = 0.015) were significantly associated with recanalization, while aneurysm size (OR 1.25, p < 0.001) and FCP < 32% (OR 6.91, p = 0.017) were significant predictors of retreatment. VPD as a continuous value or VPD with any cutoff value could not predict retreatment with statistical significance in multivariate analysis. CONCLUSIONS FCP, which is equal to the FC volume as a percentage of the total coil volume and is unaffected by the morphology of the aneurysm or the measurement error in aneurysm length, width, or height, is a novel predictor of recanalization and retreatment and is more significantly predictive of retreatment than VPD. To select FCs large enough to meet the condition of FCP >= 32% is a potential relevant factor for better long-term outcomes. These findings support our hypothesis that the FC is a significant factor for aneurysmal recurrence. PMID- 26745475 TI - Temporary surgical clipping of flow-diverted arteries in an experimental aneurysm model. AB - OBJECTIVE Surgical management of recurrent aneurysms following failed flow diversion may pose difficulties in securing vascular control with temporary clips. The authors tested the efficacy and impact of different types of aneurysm clips on flow-diverted arteries. METHODS Six wide-necked experimental aneurysms were created in canines and treated with Pipeline flow diverters. In 4 aneurysms, occlusion of the artery at the level of the proximal and distal landing zones (n = 2 per aneurysm) was attempted, using temporary, fenestrated, single, and double permanent aneurysm clips. Two aneurysms served as unclipped controls. Serial angiography was performed to investigate the efficacy of clip occlusion, flow diverter deformation, and thrombus formation. After the animals were killed, the flow-diverted aneurysm constructs were opened and photographed to determine neointimal or device damage as a result of clip placement. RESULTS Angiography confirmed clip occlusion was only possible for 4 of 8 of the tested flow-diverted arterial segments. Clip application attempts led to filling defects consistent with thrombus formation in 2 of 4 flow-diverted constructs, and to minor damage of the flow diverter with neointimal fracture in 1 of 4 cases. CONCLUSIONS Aneurysm clips placed on canine parent arteries bearing a Pipeline flow diverter were unable to reliably stop blood flow. Application of aneurysm clips can cause mild damage to the device and neointima, which might translate into thromboembolic risks. If possible, vascular control should be sought beyond the terminal ends of the implanted device. PMID- 26745476 TI - Results of a prospective study (CATS) on the effects of thalamic stimulation in minimally conscious and vegetative state patients. AB - OBJECTIVE Deep brain stimulation of the thalamus was introduced more than 40 years ago with the objective of improving the performance and attention of patients in a vegetative or minimally conscious state. Here, the authors report the results of the Cortical Activation by Thalamic Stimulation (CATS) study, a prospective multiinstitutional study on the effects of bilateral chronic stimulation of the anterior intralaminar thalamic nuclei and adjacent paralaminar regions in patients affected by a disorder of consciousness. METHODS The authors evaluated the clinical and radiological data of 29 patients in a vegetative state (unresponsive wakefulness syndrome) and 11 in a minimally conscious state that lasted for more than 6 months. Of these patients, 5 were selected for bilateral stereotactic implantation of deep brain stimulating electrodes into their thalamus. A definitive consensus for surgery was obtained for 3 of the selected patients. All 3 patients (2 in a vegetative state and 1 in a minimally conscious state) underwent implantation of bilateral thalamic electrodes and submitted to chronic stimulation for a minimum of 18 months and a maximum of 48 months. RESULTS In each case, there was an increase in desynchronization and the power spectrum of electroencephalograms, and improvement in the Coma Recovery Scale Revised scores was found. Furthermore, the severity of limb spasticity and the number and severity of pathological movements were reduced. However, none of these patients returned to a fully conscious state. CONCLUSIONS Despite the limited number of patients studied, the authors confirmed that bilateral thalamic stimulation can improve the clinical status of patients affected by a disorder of consciousness, even though this stimulation did not induce persistent, clinically evident conscious behavior in the patients. Clinical trial registration no.: NCT01027572 ( ClinicalTrials.gov ). PMID- 26745477 TI - Neuroendoscopic stent placement for cerebrospinal fluid pathway obstructions in adults. AB - OBJECTIVE Since its revival in the early 1990s, neuroendoscopy has become an integral component of modern neurosurgery. Endoscopic stent placement for treatment of CSF pathway obstruction is a rarely used and underestimated procedure. The authors present the first series of neuroendoscopic intracranial stenting for CSF pathway obstruction in adults with associated results and complications spanning a long-term follow-up of 20 years. METHODS The authors retrospectively reviewed a prospectively maintained clinical database for endoscopic stent placement performed in adults between 1993 and 2013. RESULTS Of 526 endoscopic intraventricular procedures, stents were placed for treatment of CSF disorders in 25 cases (4.8%). The technique was used in the management of arachnoid cysts (ACs; n = 8), tumor-related CSF disorders (n = 13), and hydrocephalus due to stenosis of the foramen of Monro (n = 2) or aqueduct (n = 2). The mean follow-up was 87.1 months. No deaths or infections occurred that were related to endoscopic placement of intracranial stents. Late stent dislocation or migration was observed in 3 patients (12%). CONCLUSIONS Endoscopic intracranial stent placement in adults is rarely required but is a safe and helpful technique in select cases. It is indicated when reliable and long-lasting restoration of CSF pathway obstructions cannot be achieved with standard endoscopic techniques. In the treatment of tumor-related hydrocephalus, it is a good option to avoid reclosure of the restored CSF pathway by tumor growth. Currently, routine stent placement after endoscopic fenestration of ACs is not recommended. Stent placement for treatment of CSF disorders due to tumor is a good option for avoiding CSF shunting. To avoid stent migration and dislocation, and to allow for easy removal if needed, the device should be fixed to a bur hole reservoir. PMID- 26745478 TI - Epidural hematomas after the implantation of thoracic paddle spinal cord stimulators. AB - OBJECTIVE There is little information on the frequency of symptomatic epidural hematomas after the implantation of paddle spinal cord stimulators (SCSs) in the thoracic spine. The purpose of this paper is to provide this metric and compare it to the frequency of symptomatic epidural hematomas for all other thoracic laminectomies combined. METHODS This study involved retrospectively analyzing the experience of a single surgeon in a consecutive series of patients who underwent the implantation of a thoracic paddle SCS with respect to the occurrence of a symptomatic epidural hematoma. For comparison, the occurrence of a symptomatic epidural hematoma in non-SCS thoracic laminectomies done during the same period of time was determined. RESULTS One hundred fifty-four thoracic paddle SCSs were implanted between May 2002 and February 2015. Despite perfect hemostasis and no preoperative risk factors, 4 of 154 patients (2.60%) developed postoperative lower-extremity weakness caused by an epidural hematoma. There were no other causes of a neurological deficit. In 3 of the 4 patients, the symptoms were delayed. Over the same time period, only 1 of 119 patients (0.84%) developed a postoperative motor deficit from a symptomatic epidural hematoma after a non-SCS laminectomy. CONCLUSIONS The occurrence of epidural hematomas after thoracic paddle SCS implantation may be underreported. Suggestions are given to decrease its incidence. It seems paradoxical that an epidural hematoma occurred 3 times more often after small SCS thoracic laminectomies than after larger non-SCS thoracic laminectomies. If confirmed by future studies, this finding may suggest that the intrusion of instruments into a confined epidural sublaminar space or the presence of a paddle and a hematoma in this restricted space may account for this differential. PMID- 26745479 TI - Erratum: Stroke prevention by direct revascularization for patients with adult onset moyamoya disease presenting with ischemia. PMID- 26745480 TI - Extruded contents of colloid cysts after endoscopic removal. AB - OBJECTIVE Mineralized or desiccated colloid cysts pose some unique challenges to endoscopic removal. The extrusion of the solid matrix into the intraventricular compartment has not been previously reported and, as such, no guidance exists regarding its predilection, prevention, and fate. METHODS Postoperative imaging studies in a registry of patients undergoing endoscopic removal of colloid cyst were reviewed to detect any solid matrix within the ventricular compartment. Preoperative images and operative notes were used to determine if any features were predictive. Serial postoperative images and clinical notes were used to characterize the implications of these findings. RESULTS From a review of 94 patients, 10 (10.6%) patients had evidence of an extruded intraventricular solid fragment (median follow-up 4 months; range 0.5-115 months). Of the evaluable patients, 7 of 9 patients had T1-weighted hyperintense and T2-weighted hypointense cysts on preoperative scans. Seventy-eight percent of the extrusions were on the same side as the endoscopic entry. Three patients demonstrated early fragment migration, but not after 8 months of radiological follow-up. All evaluable patients demonstrated improvement in their hydrocephalus, and none suffered a complication attributable to the intraventricular extruded fragments. CONCLUSIONS Intraventricular extruded colloid fragments can occur after endoscopic resection, with the possible risk demonstrated as cyst hypointensity on preoperative T2-weighted images. The finding does not seem to result in any clinical morbidity, and radiographic involution is the rule. Migratory capacity, however, does exist and justifies a more frequent imaging surveillance schedule and consideration for removal. PMID- 26745481 TI - Transmastoid reshaping of the sigmoid sinus: preliminary study of a novel surgical method to quiet pulsatile tinnitus of an unrecognized vascular origin. AB - OBJECTIVE A dominant sigmoid sinus with focal dehiscence or thinning (DSSD/T) of the overlying bony wall is a commonly encountered, but frequently overlooked, cause of vascular pulsatile tinnitus (VPT). Also, the pathophysiological mechanism of sound perception in patients with VPT remains poorly understood. In the present study, a novel surgical method, termed transmastoid SS-reshaping surgery, was introduced to ameliorate VPT in patients with DSSD/T. The authors reviewed a case series, analyzed the surgical outcomes, and suggested the pathophysiological mechanism of sound perception. The theoretical background underlying VPT improvement after transmastoid SS-reshaping surgery was also explored. METHODS Eight patients with VPT that was considered attributable to DSSD/T underwent transmastoid SS-reshaping surgery between February 2010 and February 2015. The mean postoperative follow-up period was 9.5 months (range 4-13 months). Transmastoid SS-reshaping surgery featured simple mastoidectomy, partial compression of the SS using harvested cortical bone chips, and reinforcement of the bony SS wall with bone cement. Perioperative medical records, imaging results, and audiological findings were comprehensively reviewed. RESULTS In 7 of the 8 patients (87.5%), the VPT abated immediately after surgery. Statistically significant improvements in tinnitus loudness and distress were evident on numeric rating scales. Three patients with preoperative ipsilesional low frequency hearing loss exhibited postoperative improvements in their low frequency hearing thresholds. No major postoperative complications were encountered except in the first subject, who experienced increased intracranial pressure postoperatively. This subsided after a revision operation for partial decompression of the SS. CONCLUSIONS Transmastoid SS-reshaping surgery may be a good surgical option in patients with DSSD/T, a previously unrecognized cause of VPT. Redistribution of severely asymmetrical blood flow, reinforcement of the bony SS wall with bone cement to reconstruct a soundproof barrier, and disconnection of a problematic sound conduction route via simple mastoidectomy silence VPT. PMID- 26745482 TI - Hearing subclassification may predict long-term auditory outcomes after radiosurgery for vestibular schwannoma patients with good hearing. AB - OBJECTIVE In the era of MRI, vestibular schwannomas are often recognized when patients still have excellent hearing. Besides success in tumor control rate, hearing preservation is a main goal in any procedure for management of this population. The authors evaluated whether modified auditory subclassification prior to radiosurgery could predict long-term hearing outcome in this population. METHODS The authors reviewed a quality assessment registry that included the records of 1134 vestibular schwannoma patients who had undergone stereotactic radiosurgery during a 15-year period (1997-2011). The authors identified 166 patients who had Gardner-Robertson Class I hearing prior to stereotactic radiosurgery. Fifty-three patients were classified as having Class I-A (no subjective hearing loss) and 113 patients as Class I-B (subjective hearing loss). Class I-B patients were further stratified into Class I-B1 (pure tone average <= 10 dB in comparison with the contralateral ear; 56 patients), and I-B2 (> 10 dB compared with the normal ear; 57 patients). At a median follow-up of 65 months, the authors evaluated patients' hearing outcomes and tumor control. RESULTS The median pure tone average elevations after stereotactic radiosurgery were 5 dB, 13.5 dB, and 28 dB in Classes I-A, I-B1, and I-B2, respectively. The median declines in speech discrimination scores after stereotactic radiosurgery were 0% for Class I-A (p = 0.33), 8% for Class I-B1 (p < 0.0001), and 40% for Class I-B2 (p < 0.0001). Serviceable hearing preservation rates were 98%, 73%, and 33% for Classes I-A, I-B1, and I-B2, respectively. Gardner-Robertson Class I hearing was preserved in 87%, 43%, and 5% of patients in Classes I-A, I-B1, and I-B2, respectively. CONCLUSIONS Long-term hearing preservation was significantly better if radiosurgery was performed prior to subjective hearing loss. In patients with subjective hearing loss, the difference in pure tone average between the affected ear and the unaffected ear was an important factor in long-term hearing preservation. PMID- 26745483 TI - Microsurgical resectability, outcomes, and tumor control in meningiomas occupying the cavernous sinus. AB - OBJECTIVE Cavernous sinus meningiomas (CSMs) represent a cohort of challenging skull base tumors. Proper management requires achieving a balance between optimal resection, restoration of cranial nerve (CN) function, and maintaining or improving quality of life. The objective of this study was to assess the pre-, intra-, and postoperative factors related to clinical and neurological outcomes, morbidity, mortality, and tumor control in patients with CSM. METHODS A retrospective review of a single surgeon's experience with microsurgical removal of CSM in 65 patients between January 1996 and August 2013 was done. Sekhar's classification, modified Kobayashi grading, and the Karnofsky Performance Scale were used to define tumor extension, tumor removal, and clinical outcomes, respectively. RESULTS Preoperative CN dysfunction was evident in 64.6% of patients. CN II deficits were most common. The greatest improvement was seen for CN V deficits, whereas CN II and CN IV deficits showed the smallest degree of recovery. Complete resection was achieved in 41.5% of cases and was not significantly associated with functional CN recovery. Internal carotid artery encasement significantly limited the complete microscopic resection of CSM (p < 0.0001). Overall, 18.5% of patients showed symptomatic recurrence after their initial surgery (mean follow-up 60.8 months [range 3-199 months]). The use of adjuvant stereotactic radiosurgery (SRS) after microsurgery independently decreased the recurrence rate (p = 0.009; OR 0.036; 95% CI 0.003-0.430). CONCLUSIONS Modified Kobayashi tumor resection (Grades I-IIIB) was possible in 41.5% of patients. CN recovery and tumor control were independent of extent of tumor removal. The combination of resection and adjuvant SRS can achieve excellent tumor control. Furthermore, the use of adjuvant SRS independently decreases the recurrence rates of CSM. PMID- 26745484 TI - ADAMTS genes and the risk of cerebral aneurysm. AB - OBJECTIVE Cerebral aneurysms (CAs) affect 2%-5% of the population, and familial predisposition plays a significant role in CA pathogenesis. Several lines of evidence suggest that genetic variations in matrix metalloproteinase genes (MMP) are involved in the etiopathology of CAs. The authors performed a case-control study to investigate the effect of 4 MMP variants from the ADAMTS family on the pathogenesis of CAs. METHODS To identify susceptible genetic variants, the authors investigated 8 single nucleotide polymorphisms (SNPs) in 4 genes from the ADAMTS family (ADAMTS2, -7, -12, and -13) known to be associated with vascular diseases. The study included 353 patients with CAs and 1055 healthy adults. RESULTS The authors found significant associations between CA susceptibility and genetic variations in 3 members of the ADAMTS family. The largest risk for CA (OR 1.32, p = 0.006) was observed in carriers of the ADAMTS2 variant rs11750568, which has been previously associated with pediatric stroke. Three SNPs under investigation are associated with a protective effect in CA pathogenesis (ADAMTS12 variant rs1364044: OR 0.65, p = 0.0001; and ADAMTS13 variants rs739469 and rs4962153: OR 0.77 and 0.63, p = 0.02 and 0.0006, respectively), while 2 other ADAMTS13 variants may confer a significant risk (rs2301612: OR 1.26, p = 0.011; rs2285489: OR 1.24, p = 0.02). CONCLUSIONS These results suggest that reduced integrity of the endothelial wall, as conferred by ADAMTS variants, together with inflammatory processes and defective vascular remodeling plays an important role in CA pathogenesis, although the mechanism of action remains unknown. The authors' findings may lead to specific screening of at-risk populations in the future. PMID- 26745485 TI - Submaximal angioplasty for symptomatic intracranial atherosclerosis: a prospective Phase I study. AB - OBJECTIVE Intracranial atherosclerotic disease (ICAD) accounts for approximately 10% of ischemic strokes. The recent Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study demonstrated a high incidence of perioperative complications (15%) for treatment of ICAD with stenting. Although the incidence of stroke was lower in the medical arm, recurrent stroke was found in 12% of patients despite aggressive medical management, suggesting that intervention may remain a viable option for ICAD if perioperative risk is minimized. Angioplasty without stenting represents an alternative and understudied revascularization treatment for ICAD. Submaximal angioplasty limits the risks of thromboembolism, vessel perforation, and reperfusion hemorrhage that were frequently reported with stenting in the SAMMPRIS trial. The authors conducted a prospective Phase I trial designed to assess the safety of submaximal angioplasty in patients with symptomatic ICAD. METHODS This study was approved by the local institutional review board. Demographic and clinical data were prospectively collected. Angioplasty was performed with a balloon undersized to approximately 50%-70% of the nondiseased vessel diameter in patients with symptomatic ICAD who had angiographically significant stenosis of >= 70%. The primary outcome measure was the incidence of periprocedural complications (combined rate of death, stroke, and hemorrhage occurring within 30 days and at 1 year). RESULTS Among the 65 patients with symptomatic ICAD who were screened, 24 had significant angiographic stenosis that met the inclusion criteria of this study. The mean age was 64.08 years (median 65 years; SD +/- 11.24 years), most were men (62.5%), and most were white (66.67%). Many patients had concomitants of vascular disease, including hypertension (95.8%), hyperlipidemia (70.83%), smoking history (54.1%), and diabetes mellitus (50.0%). Coronary artery disease (41.66%) and previous stroke or transient ischemic attack (45.83%) were frequently present. Most patients (75%) had anterior circulation stenosis. The mean preprocedure stenosis was 80.16% (median 80%, range 70%-95%). Submaximal angioplasty was performed in patients who met the inclusion criteria, with a mean postangioplasty stenosis rate of 54.62% (median 55.5%, range 31%-78%). Rates of ischemic stroke in the territory of the treated artery were 0% within 30 days and 5.55% (in the only patient who presented with recurrent stroke) at 1 year. The mortality and hemorrhage rates in this series were 0%. CONCLUSIONS This study demonstrates the safety of the submaximal angioplasty technique, with no permanent periprocedural complications in 24 treated patients. PMID- 26745486 TI - A new comorbidities index for risk stratification for treatment of unruptured cerebral aneurysms. AB - OBJECTIVE Comorbidities have an impact on risk stratification for outcomes in analyses of large patient databases. Although the Charlson Comorbidity Index (CCI) and the Elixhauser Comorbidity Index (ECI) are the most commonly used comorbidity indexes, these have not been validated for patients with unruptured cerebral aneurysms; therefore, the authors created a comorbidity index specific to these patients. METHODS The authors extracted all records involving unruptured cerebral aneurysms treated with clipping, coiling, or both from the Nationwide Inpatient Sample (2002-2010). They assessed the effect of 37 variables on poor outcome and used the results to create a risk score for these patients. The authors used a validation data set and bootstrapping to evaluate the new index and compared it to CCI and ECI in prediction of poor outcome, mortality, length of stay, and hospital charges. RESULTS The index assigns integer values (-2 to 7) to 20 comorbidities: neurological disorder, renal insufficiency, gastrointestinal bleeding, paralysis, acute myocardial infarction, electrolyte disorder, weight loss, metastatic cancer, drug abuse, arrhythmia, coagulopathy, cerebrovascular accident, psychosis, alcoholism, perivascular disease, valvular disease, tobacco use, hypothyroidism, depression, and hypercholesterolemia. Values are summed to determine a patient's risk score. The new index was better at predicting poor outcome than CCI or ECI (area under the receiver operating characteristic curve [AUC] 0.814 [95% CI 0.798-0.830], vs 0.694 and 0.712, respectively, for the other indices), and it was also better at predicting mortality (AUC 0.775 [95% CI 0.754 0.792], vs 0.635 and 0.657, respectively, for CCI and ECI). CONCLUSIONS This new comorbidity index outperforms the CCI and ECI in predicting poor outcome, mortality, length of stay, and total charges for patients with unruptured cerebral aneurysm. Reevaluation of other patient cohorts is warranted to determine the impact of more accurate patient stratification. PMID- 26745487 TI - Malignant peripheral nerve sheath tumors of the eighth cranial nerve arising without prior irradiation. AB - OBJECTIVE Malignant peripheral nerve sheath tumors (MPNSTs) of the eighth cranial nerve (CN) are exceedingly rare. To date the literature has focused on MPNSTs occurring after radiation therapy for presumed benign vestibular schwannomas (VSs), while MPNSTs arising without prior irradiation have received little attention. The objectives of the current study are to characterize the epidemiology, clinical presentation, disease course, and outcome using a large national cancer registry database and a systematic review of the English literature. Additionally, a previously unreported case is presented. METHODS The authors conducted an analysis of the Surveillance, Epidemiology, and End Results (SEER) database, a systematic review of the literature, and present a case report. Data from all patients identified in the SEER database with a diagnosis of MPNST involving the eighth CN, without a history of prior radiation, were analyzed. Additionally, all cases reported in the English literature between January 1980 and March 2015 were reviewed. Finally, 1 previously unreported case is presented. RESULTS The SEER registries identified 30 cases between 1992 and 2012. The average incidence was 0.017 per 1 million persons per year (range 0.000 0.0687 per year). The median age at diagnosis was 55 years, and 16 (53%) were women. Thirteen cases were diagnosed upon autopsy. Of the 17 cases diagnosed while alive, the median follow-up was 118 days, with 3 deaths (18%) observed. When compared with the incidence of benign VS, 1041 VSs present for every 1 MPNST arising from the eighth CN. Including a previously unreported case from the authors' center, a systematic review of the English literature yielded 24 reports. The median age at diagnosis was 44 years, 50% were women, and the median tumor size at diagnosis was 3 cm. Eleven patients (46%) reported isolated audiovestibular complaints typical for VS while 13 (54%) exhibited facial paresis or other signs of a more aggressive process. Treatment included microsurgery alone, microsurgery with adjuvant radiation, or microsurgery with chemoradiation. Sixty-one percent of patients receiving treatment experienced recurrence, 22% of which were diagnosed with drop metastases to the spine. Ultimately, 13 patients (54%) died of progressive disease at a median of 3 months following diagnosis. The ability to achieve gross-total resection was the only feature that was associated with improved disease-specific survival. CONCLUSIONS MPNSTs of the eighth CN are extremely rare and portend a poor prognosis. Nearly half of patients initially present with findings consistent with a benign VS, often making an early diagnosis challenging. In light of these data, early radiological and clinical follow-up should be considered in those who elect nonoperative treatment, particularly in patients with a short duration of symptoms or atypical presentation. These data also provide a baseline rate of malignancy that should be considered when estimating the risk of malignant transformation following stereotactic radiosurgery for VS. PMID- 26745488 TI - Lateral orbitotomy for a maxillary nerve schwannoma: case report. AB - Authors of this report describe a Fukushima Type D(b) or Kawase Type ME2 trigeminal schwannoma involving the right maxillary division in a 59-year-old woman who presented with intermittent right-sided facial numbness and pain. This tumor was successfully resected via a right lateral orbitotomy without the need for craniotomy. This novel approach to a lesion of this type has not yet been described in the scientific literature. The outcome in this case was good, and the patient's intra- and postoperative courses proceeded without complication. The epidemiology of trigeminal schwannomas and some technical aspects of lateral orbitotomy, including potential advantages of this approach over traditional transcranial as well as fully endoscopic dissections in appropriately selected cases, are also briefly discussed. PMID- 26745489 TI - Supratentorial hemispheric ependymomas: an analysis of 109 adults for survival and prognostic factors. AB - OBJECTIVE Survival rates and prognostic factors for supratentorial hemispheric ependymomas have not been determined. The authors therefore designed a retrospective study to determine progression-free survival (PFS), overall survival (OS), and prognostic factors for hemispheric ependymomas. METHODS The study population consisted of 8 patients from our institution and 101 patients from the literature with disaggregated survival information (n = 109). Patient age, sex, tumor side, tumor location, extent of resection (EOR), tumor grade, postoperative chemotherapy, radiation, time to recurrence, and survival were recorded. Kaplan-Meier survival analyses and Cox proportional hazard models were completed to determine survival rates and prognostic factors. RESULTS Anaplastic histology/WHO Grade III tumors were identified in 62% of cases and correlated with older age. Three-, 5-, and 10-year PFS rates were 57%, 51%, and 42%, respectively. Three-, 5-, and 10-year OS rates were 77%, 71%, and 58%, respectively. EOR and tumor grade were identified on both Kaplan-Meier log-rank testing and univariate Cox proportional hazard models as prognostic for PFS and OS. Both EOR and tumor grade remained prognostic on multivariate analysis. Subtotal resection (STR) predicted a worse PFS (hazard ratio [HR] 4.764, p = 0.001) and OS (HR 4.216, p = 0.008). Subgroup survival analysis of patients with STR demonstrated a 5- and 10-year OS of 28% and 0%, respectively. WHO Grade III tumors also had worse PFS (HR 10.2, p = 0.004) and OS (HR 9.1, p = 0.035). Patients with WHO Grade III tumors demonstrated 5- and 10-year OS of 61% and 46%, respectively. Postoperative radiation was not prognostic for PFS or OS. CONCLUSIONS A high incidence of anaplastic histology was found in hemispheric ependymomas and was associated with older age. EOR and tumor grade were prognostic factors for PFS and OS on multivariate analysis. STR or WHO Grade III pathology, or both, predicted worse overall prognosis in patients with hemispheric ependymoma. PMID- 26745490 TI - Three-dimensional SPACE fluid-attenuated inversion recovery at 3 T to improve subthalamic nucleus lead placement for deep brain stimulation in Parkinson's disease: from preclinical to clinical studies. AB - OBJECTIVE Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well established therapy for motor symptoms in patients with pharmacoresistant Parkinson's disease (PD). However, the procedure, which requires multimodal perioperative exploration such as imaging, electrophysiology, or clinical examination during macrostimulation to secure lead positioning, remains challenging because the STN cannot be reliably visualized using the gold standard, T2-weighted imaging (T2WI) at 1.5 T. Thus, there is a need to improve imaging tools to better visualize the STN, optimize DBS lead implantation, and enlarge DBS diffusion. METHODS Gradient-echo sequences such as those used in T2WI suffer from higher distortions at higher magnetic fields than spin-echo sequences. First, a spin-echo 3D SPACE (sampling perfection with application optimized contrasts using different flip angle evolutions) FLAIR sequence at 3 T was designed, validated histologically in 2 nonhuman primates, and applied to 10 patients with PD; their data were clinically compared in a double-blind manner with those of a control group of 10 other patients with PD in whom STN targeting was performed using T2WI. RESULTS Overlap between the nonhuman primate STNs segmented on 3D-histological and on 3D-SPACE-FLAIR volumes was high for the 3 most anterior quarters (mean [+/- SD] Dice scores 0.73 +/- 0.11, 0.74 +/- 0.06, and 0.60 +/- 0.09). STN limits determined by the 3D-SPACE-FLAIR sequence were more consistent with electrophysiological edges than those determined by T2WI (0.9 vs 1.4 mm, respectively). The imaging contrast of the STN on the 3D-SPACE FLAIR sequence was 4 times higher (p < 0.05). Improvement in the Unified Parkinson's Disease Rating Scale Part III score (off medication, on stimulation) 12 months after the operation was higher for patients who underwent 3D-SPACE FLAIR-guided implantation than for those in whom T2WI was used (62.2% vs 43.6%, respectively; p < 0.05). The total electrical energy delivered decreased by 36.3% with the 3D-SPACE-FLAIR sequence (p < 0.05). CONCLUSIONS 3D-SPACE-FLAIR sequences at 3 T improved STN lead placement under stereotactic conditions, improved the clinical outcome of patients with PD, and increased the benefit/risk ratio of STN DBS surgery. PMID- 26745492 TI - Comparison of the effectiveness of using the optic strut and tuberculum sellae as radiological landmarks in diagnosing paraclinoid aneurysms with CT angiography. AB - OBJECTIVE The treatment of paraclinoid aneurysms remains challenging. It is important to determine the exact location of the paraclinoid aneurysm when considering treatment options. The authors herein evaluated the effectiveness of using the optic strut (OS) and tuberculum sellae (TS) as radiographic landmarks for distinguishing between intradural and extradural paraclinoid aneurysms on source images from CT angiography (CTA). METHODS Between January 2010 and September 2013, a total of 49 surgical patients with the preoperative diagnoses of paraclinoid aneurysm and 1 symptomatic cavernous-clinoid aneurysm were retrospectively identified. With the source images from CTA, the OS and the TS were used as landmarks to predict the location of the paraclinoid aneurysm and its relation to the distal dural ring (DDR). The operative findings were examined to confirm the definitive location of the paraclinoid aneurysm. Statistical analysis was performed to determine the diagnostic effectiveness of the landmarks. RESULTS Nineteen patients without preoperative CTA were excluded. The remaining 30 patients comprised the current study. The intraoperative findings confirmed 12 intradural, 12 transitional, and 6 extradural paraclinoid aneurysms, the diagnoses of which were significantly related to the type of aneurysm (p < 0.05) but not factors like sex, age, laterality of aneurysm, or relation of the aneurysm to the ophthalmic artery on digital subtraction angiography. To measure agreement with the correct diagnosis, the OS as a reference point was far superior to the TS (Cohen's kappa coefficients 0.462 and 0.138 for the OS and the TS, respectively). For paraclinoid aneurysms of the medial or posterior type, using the base of the OS as a reference point tended to overestimate intradural paraclinoid aneurysms. The receiver operating characteristic curve indicated that if the aneurysmal neck traverses the axial plane 2 mm above the base of the OS, the aneurysm is most likely to grow across the DDR and present as a transitional aneurysm (sensitivity 0.806; specificity 0.792). CONCLUSIONS High-resolution thin cut CTA is a fast and crucial tool for diagnosing paraclinoid aneurysms. The OS serves as an effective landmark in CTA source images for distinguishing between intradural and extradural paraclinoid aneurysms. The DDR is supposed to be located 2 mm above the base of the OS in axial planes. PMID- 26745493 TI - "One-Shot" CT image navigated circumferential fusion in a single lateral decubitus position: surgical technique. AB - The purpose of this paper was to summarize the surgical peculiarities of a combined approach for minimally invasive lateral retroperitoneal interbody fusion and posterior percutaneous pedicle screw instrumentation in the same lateral decubitus position using intraoperative computed tomography-based navigation. PMID- 26745491 TI - Surgical outcomes following encephaloduroarteriosynangiosis in adult moyamoya disease associated with Type 2 diabetes. AB - OBJECTIVE Debate exists regarding the merits and shortcomings of an indirect bypass procedure for treating adult patients with moyamoya disease (MMD). Considerable variation in neovascularization occurs among different organs in patients with diabetes mellitus. Here, the effect of encephaloduroarteriosynangiosis on MMD associated with Type 2 diabetes mellitus (T2DM) is evaluated. METHODS A retrospective and 1:2 matched case-control study was conducted in moyamoya patients with or without T2DM (n = 180). Postoperative collateral formations were graded according to the Modified Collateral Grading System that originated from the Matsushima Angiographic Stage Classification. Neurological function outcomes before and after the operation were evaluated according to the modified Rankin Scale. Univariate and multivariate logistic regression analyses were performed to determine the risk factors for clinical outcome. RESULTS There was no statistically significant difference in the constituent ratios of initial symptom and preoperative Suzuki stage between patients with and without T2DM. Progression of angiopathy around the circle of Willis was postoperatively observed in bilateral internal carotid arteries in both groups. Patients with T2DM had a higher postoperative Suzuki stage (p < 0.01) and more frequent development of collateral angiogenesis germinating from the external carotid after indirect revascularization procedures in the surgical cerebral hemisphere (82.7% vs 72.2%; p < 0.05). The extent of postoperative collateral formation in patients with diabetes mellitus was significantly higher (p < 0.01). Postoperative clinical improvement in the diabetes group was more common after revascularization procedures (p < 0.05), and the diabetes group had lower modified Rankin Scale scores (p < 0.05) in comparison with the nondiabetes group. Late postoperative stroke and posterior cerebral artery involvement were identified as predictors of unfavorable clinical outcome in both groups, while T2DM was associated with a favorable clinical outcome. CONCLUSIONS Encephaloduroarteriosynangiosis is an efficacious treatment for adult patients with MMD. Patients with T2DM could achieve better collateral circulation and clinical improvement following surgery. PMID- 26745494 TI - Increased VEGF levels in one case of papillary tumor of the pineal region with intracranial haemorrhage at presentation: a potential surrogate indicator of tumor angiogenesis and aggressiveness? AB - Pineal tumors are rare, about 1% of all intracranial tumors. At variance with pineocytomas, usually characterized by a good prognosis, papillary tumors behave more aggressively. Owing to their rarity, little is known about their biology and clinical behavior, moreover conflicting data on prognosis have been reported. Here we present an unusual case of papillary neuroepithelial tumor of the pineal region in a 40-years old man who was admitted in a state of unconsciousness due to the presence of intracranial haemorrhage. After 21 days from admission, he underwent third ventriculostomy for hydrocephalus and biopsy of the lesion. Since bleeding manifestations are uncommonly associated with this kind of tumors, we performed some additional non routine laboratory tests in order to identify biological indicators of disease course and abnormal angiogenesis. Coagulation screening tests were performed to rule out the presence of coagulopathy and vascular endothelial growth factor (VEGF) levels measured in plasma as marker of tumor angiogenic potential. Histologic evaluation confirmed the diagnosis of a papillary tumor of the pineal region with the presence of tiny vessel lumens that may account for increased angiogenesis Coagulation screening was normal and VEGF levels were extremely high if compared to healthy individuals. After 20 months of follow-up the tumor mass, radiotherapy treated, appeared dramatically reduced at MRI evaluation, and, interestingly, VEGF levels, although still higher than in healthy individuals, resulted significantly decreased as compared to those measured at time of first hospital admission suggesting a role for VEGF as indicator of tumor aggressiveness. In conclusion, measurement of angiogenesis circulating soluble markers could have an additional feedback in the diagnosis, therapy and monitoring the disease in patients with very rare CNS tumors as papillary tumors of pineal region that have non univocal clinical behavior and prognosis. PMID- 26745495 TI - Selective Depletion Interactions in Mixtures of Rough and Smooth Silica Spheres. AB - The depletion interaction as induced between colloids by the addition of a polymer depletant is one of the few ways in which short-ranged attractions between particles can be controlled. Due to these tunable interactions, colloid polymer mixtures have contributed to a better understanding of the role of attractions both in equilibrium phenomena such as phase transitions and liquid surfaces as well as in systems out of equilibrium such as gelation and the glass transition. It is known that, by simple geometric effects, surface roughness decreases the strength of the depletion interaction. In this study, we demonstrate both by Monte Carlo simulations and experiments that it is possible to generate enough difference in attraction strength to induce phase separation in smooth particles but not in rough particles. Roughness was induced by coating smooth particles with smaller spherical colloids. We indicate how effective potentials can be obtained through simulations and how the interplay between gravity and the depletion interaction with a flat container wall can be used to obtain a simple measure of the interaction strengths as a function of roughness. PMID- 26745497 TI - Gut Microbiota and Metabolic Endotoxemia in Young Obese Mexican Subjects. AB - BACKGROUND: The gut microbiota plays an important role in human metabolism; previous studies suggest that the imbalance can cause a metabolic endotoxemia that may be linked to weight gain and insulin resistance. The purpose of this study was to investigate the relationship between the gut microbiota composition, the lipopolysaccharide levels and the metabolic profile in obese and normal weight young subjects. METHODS: We studied 32 obese (BMI >= 30 kg/m2) and 32 normal-weight subjects (BMI = 18.5-24.9 kg/m2), aged 18-25 years. Quantification of intestinal bacteria was performed by real-time PCR. Endotoxin units were determined with the test QCL-1000, and biochemical profile was performed under a standard protocol of Spinreact. RESULTS: Obese individuals had a BMI of 34.5 (32.9-36.45) kg/m2, increased triglycerides (123 vs. 70 mg/dl), total cholesterol (168 vs. 142 mg/dl), and LDL-cholesterol (114 vs. 96.5 mg/dl). In obese subjects body temperature was higher than in normal-weight subjects. We found a greater number of Clostridum leptum and Lactobacillus (p < 0.001) and lower numbers of Prevotella and Escherichia coli (p < 0.001) in the obese group. A decrease of E. coli was associated with an increased risk of lipopolysaccharide levels ranging from 1 to 1.3 EU/ml. A positive correlation was found between serum lipopolysaccharides and BMI (r = 0.46, p = 0.008), triglyceride levels (r = 0.44, p = 0.011) as well as waist circumference (r = 0.34, p = 0.040), being more evident in young obese females. CONCLUSION: Subclinical metabolic endotoxemia determined by serum concentration of lipopolysaccharides was related to the smallest amount of E. coli, high triglyceride levels, and central adiposity in obese young persons. PMID- 26745496 TI - Expression Profiles of Long Noncoding RNAs and Messenger RNAs in Mn-Exposed Hippocampal Neurons of Sprague-Dawley Rats Ascertained by Microarray: Implications for Mn-Induced Neurotoxicity. AB - Manganese (Mn) is an essential trace element, while excessive expose may induce neurotoxicity. Recently, lncRNAs have been extensively studied and it has been confirmed that lncRNAs participate in neural functions and aberrantly expressed lncRNAs are involved in neurological diseases. However, the pathological effects of lncRNAs on Mn-induced neurotoxicity remain unclear. In this study, the expression profiles of lncRNAs and messenger RNAs (mRNAs) were identified in Mn treated hippocampal neurons and control neurons via microarray. Bioinformatic methods and intersection analysis were also employed. Results indicated that 566, 1161, and 1474 lncRNAs meanwhile 1848, 3228, and 4022 mRNAs were aberrantly expressed in low, intermediate, and high Mn-exposed groups compared with the control group, respectively. Go analysis determined that differentially expressed mRNAs were targeted to biological processes, cellular components, and molecular functions. Pathway analysis indicated that these mRNAs were enriched in insulin secretion, cell cycle, and DNA replication. Intersection analysis denominated that 135 lncRNAs and 373 mRNAs were consistently up-regulated while 150 lncRNAs and 560 mRNAs were consistently down-regulated. Meanwhile, lncRNA BC079195 was significantly up-regulated while lncRNAs uc.229- and BC089928 were significantly down-regulated in three comparison groups. The relative expression levels of 3 lncRNAs and 4 mRNAs were validated through qRT-PCR. To the best of our knowledge, this study is the first to identify the expression patterns of lncRNAs and mRNAs in hippocampal neurons of Sprague-Dawley rats. The results may provide evidence on underlying mechanisms of Mn-induced neurotoxicity, and aberrantly expressed lncRNAs/mRNAs may be useful in further investigations to detect early symptoms of Mn-induced neuropsychiatric disorders in the central nervous system. PMID- 26745498 TI - Quantifying Neural Oscillatory Synchronization: A Comparison between Spectral Coherence and Phase-Locking Value Approaches. AB - Synchronization or phase-locking between oscillating neuronal groups is considered to be important for coordination of information among cortical networks. Spectral coherence is a commonly used approach to quantify phase locking between neural signals. We systematically explored the validity of spectral coherence measures for quantifying synchronization among neural oscillators. To that aim, we simulated coupled oscillatory signals that exhibited synchronization dynamics using an abstract phase-oscillator model as well as interacting gamma-generating spiking neural networks. We found that, within a large parameter range, the spectral coherence measure deviated substantially from the expected phase-locking. Moreover, spectral coherence did not converge to the expected value with increasing signal-to-noise ratio. We found that spectral coherence particularly failed when oscillators were in the partially (intermittent) synchronized state, which we expect to be the most likely state for neural synchronization. The failure was due to the fast frequency and amplitude changes induced by synchronization forces. We then investigated whether spectral coherence reflected the information flow among networks measured by transfer entropy (TE) of spike trains. We found that spectral coherence failed to robustly reflect changes in synchrony-mediated information flow between neural networks in many instances. As an alternative approach we explored a phase locking value (PLV) method based on the reconstruction of the instantaneous phase. As one approach for reconstructing instantaneous phase, we used the Hilbert Transform (HT) preceded by Singular Spectrum Decomposition (SSD) of the signal. PLV estimates have broad applicability as they do not rely on stationarity, and, unlike spectral coherence, they enable more accurate estimations of oscillatory synchronization across a wide range of different synchronization regimes, and better tracking of synchronization-mediated information flow among networks. PMID- 26745499 TI - Endocrine Mechanisms Regulating Post-Diapause Development in the Cabbage Armyworm, Mamestra brassicae. AB - Diapause, a programmed developmental arrest at a specific stage, is common in insects and is regulated by hormones. It is well established that in pupal diapause, cessation of ecdysteroid secretion from the prothoracic glands (PGs) after pupal ecdysis leads to diapause initiation, while resumption of its secretion induces post-diapause development. However, what regulates the activity of the glands is poorly understood, especially for the glands of diapause terminated pupae. In the present study, we investigate the mechanisms by which post-diapause development is regulated in the cabbage armyworm Mamestra brassicae. We demonstrate that the brain is necessary for the initiation of post diapause development and that the factor in the brain responsible for the activation of the PGs is the prothoracicotropic hormone (PTTH). Further, through measuring the hemolymph PTTH titers by time-resolved fluoroimmunoassay, we show that PTTH is actually released into the hemolymph prior to the activation of the PGs. Although its peak titer is much lower than expected, this low concentration of PTTH is most likely still effective to activate the PGs of post-diapause pupae, because the responsiveness to PTTH of the glands at this stage is very high compared to that of nondiapause pupal PGs. These results strongly suggest that in M. brassicae, PTTH serves as a trigger to initiate pupa-adult development after diapause termination by stimulating the PGs to secrete ecdysteroid. PMID- 26745500 TI - Seeing Minds in Others - Can Agents with Robotic Appearance Have Human-Like Preferences? AB - Ascribing mental states to non-human agents has been shown to increase their likeability and lead to better joint-task performance in human-robot interaction (HRI). However, it is currently unclear what physical features non-human agents need to possess in order to trigger mind attribution and whether different aspects of having a mind (e.g., feeling pain, being able to move) need different levels of human-likeness before they are readily ascribed to non-human agents. The current study addresses this issue by modeling how increasing the degree of human-like appearance (on a spectrum from mechanistic to humanoid to human) changes the likelihood by which mind is attributed towards non-human agents. We also test whether different internal states (e.g., being hungry, being alive) need different degrees of humanness before they are ascribed to non-human agents. The results suggest that the relationship between physical appearance and the degree to which mind is attributed to non-human agents is best described as a two linear model with no change in mind attribution on the spectrum from mechanistic to humanoid robot, but a significant increase in mind attribution as soon as human features are included in the image. There seems to be a qualitative difference in the perception of mindful versus mindless agents given that increasing human-like appearance alone does not increase mind attribution until a certain threshold is reached, that is: agents need to be classified as having a mind first before the addition of more human-like features significantly increases the degree to which mind is attributed to that agent. PMID- 26745501 TI - Evidence for Functional Groupings of Vibrissae across the Rodent Mystacial Pad. AB - During natural exploration, rats exhibit two particularly conspicuous vibrissal mediated behaviors: they follow along walls, and "dab" their snouts on the ground at frequencies related to the whisking cycle. In general, the walls and ground may be located at any distance from, and at any orientation relative to, the rat's head, which raises the question of how the rat might determine the position and orientation of these surfaces. Previous studies have compellingly demonstrated that rats can accurately determine the horizontal angle at which a vibrissa first touches an object, and we therefore asked whether this parameter could provide the rat with information about the pitch, distance, and yaw of a surface relative to its head. We used a three-dimensional model of the whisker array to construct mappings between the horizontal angle of contact of each vibrissa and every possible (pitch, distance, and yaw) configuration of the head relative to a flat surface. The mappings revealed striking differences in the patterns of contact for vibrissae in different regions of the array. The exterior (A, D, E) rows provide information about the relative pitch of the surface regardless of distance. The interior (B, C) rows provide distance cues regardless of head pitch. Yaw is linearly correlated with the difference between the number of right and left whiskers touching the surface. Compared to the long reaches that whiskers can make to the side and below the rat, the reachable distance in front of the rat's nose is relatively small. We confirmed key predictions of these functional groupings in a behavioral experiment that monitored the contact patterns that the vibrissae made with a flat vertical surface. These results suggest that vibrissae in different regions of the array are not interchangeable sensors, but rather functionally grouped to acquire particular types of information about the environment. PMID- 26745502 TI - Proteomics-Based Identification and Analysis of Proteins Associated with Helicobacter pylori in Gastric Cancer. AB - Helicobacter pylori (H. pylori) is a spiral-shaped Gram-negative bacterium that causes the most common chronic infection in the human stomach. Approximately 1% 3% of infected individuals develop gastric cancer. However, the mechanisms by which H. pylori induces gastric cancer are not completely understood. The available evidence indicates a strong link between the virulence factor of H. pylori, cytotoxin-associated gene A (CagA), and gastric cancer. To further characterize H. pylori virulence, we established three cell lines by infecting the gastric cancer cell lines SGC-7901 and AGS with cagA+ H. pylori and transfecting SGC-7901 with a vector carrying the full-length cagA gene. We detected 135 differently expressed proteins from the three cell lines using proteome technology, and 10 differential proteins common to the three cell lines were selected and identified by LC-MS/MS as well as verified by western blot: beta-actin, L-lactate dehydrogenase (LDH), dihydrolipoamide dehydrogenase (DLD), pre-mRNA-processing factor 19 homolog (PRPF19), ATP synthase, calmodulin (CaM), p64 CLCP, Ran-specific GTPase-activating protein (RanGAP), P43 and calreticulin. Detection of the expression of these proteins and genes encoding these proteins in human gastric cancer tissues by real-time PCR (RT-qPCR) and western blot revealed that the expression of beta-ACTIN, LDH, DLD, PRPF19 and CaM genes were up-regulated and RanGAP was down-regulated in gastric cancer tissues and/or metastatic lymph nodes compared to peri-cancerous tissues. High gene expression was observed for H. pylori infection in gastric cancer tissues. Furthermore, the LDH, DLD and CaM genes were demethylated at the promoter -2325, -1885 and -276 sites, respectively, and the RanGAP gene was highly methylated at the promoter 570 and -170 sites in H. pylori-infected and cagA-overexpressing cells. These results provide new insights into the molecular pathogenesis and treatment targets for gastric cancer with H. pylori infection. PMID- 26745504 TI - Glucosamine suppresses platelet-activating factor-induced activation of microglia through inhibition of store-operated calcium influx. AB - Microglia activation and subsequent release of inflammatory mediators are implicated in the pathophysiology of neurodegenerative diseases. Platelet activating factor (PAF), a potent lipid mediator synthesized by microglia, is known to stimulate microglia functional responses. In this study, we determined that endogenous PAF exert autocrine effects on microglia activation, as well as the underlying mechanism involved. We also investigated the effect of D glucosamine (GlcN) on PAF-induced cellular activation in human HMO6 microglial cells. PAF induced sustained intracellular Ca(2+) ([Ca(2+)]i) increase through store-operated Ca(2+) channels (SOC) and reactive oxygen species (ROS) generation. PAF also induced pro-inflammatory markers through NFkappaB/COX-2 signaling. GlcN significantly inhibited PAF-induced Ca(2+) influx and ROS generation without significant cytotoxicity. GlcN downregulated excessive expression of pro-inflammatory markers and promoted filopodia formation through NFkappaB/COX-2 inhibition in PAF-stimulated HMO6 cells. Taken together, these data suggest that GlcN may offer substantial therapeutic potential for treating inflammatory and neurodegenerative diseases accompanied by microglial activation. PMID- 26745503 TI - In Vitro Mode of Action and Anti-thrombotic Activity of Boophilin, a Multifunctional Kunitz Protease Inhibitor from the Midgut of a Tick Vector of Babesiosis, Rhipicephalus microplus. AB - BACKGROUND: Hematophagous mosquitos and ticks avoid host hemostatic system through expression of enzyme inhibitors targeting proteolytic reactions of the coagulation and complement cascades. While most inhibitors characterized to date were found in the salivary glands, relatively few others have been identified in the midgut. Among those, Boophilin is a 2-Kunitz multifunctional inhibitor targeting thrombin, elastase, and kallikrein. However, the kinetics of Boophilin interaction with these enzymes, how it modulates platelet function, and whether it inhibits thrombosis in vivo have not been determined. METHODOLOGY/PRINCIPAL FINDINGS: Boophilin was expressed in HEK293 cells and purified to homogeneity. Using amidolytic assays and surface plasmon resonance experiments, we have demonstrated that Boophilin behaves as a classical, non-competitive inhibitor of thrombin with respect to small chromogenic substrates by a mechanism dependent on both exosite-1 and catalytic site. Inhibition is accompanied by blockade of platelet aggregation, fibrin formation, and clot-bound thrombin in vitro. Notably, we also identified Boophilin as a non-competitive inhibitor of FXIa, preventing FIX activation. In addition, Boophilin inhibits kallikrein activity and the reciprocal activation, indicating that it targets the contact pathway. Furthermore, Boophilin abrogates cathepsin G- and plasmin-induced platelet aggregation and partially affects elastase-mediated cleavage of Tissue Factor Pathway Inhibitor (TFPI). Finally, Boophilin inhibits carotid artery occlusion in vivo triggered by FeCl3, and promotes bleeding according to the mice tail transection method. CONCLUSION/SIGNIFICANCE: Through inhibition of several enzymes involved in proteolytic cascades and cell activation, Boophilin plays a major role in keeping the midgut microenvironment at low hemostatic and inflammatory tonus. This response allows ticks to successfully digest a blood meal which is critical for metabolism and egg development. Boophilin is the first tick midgut FXIa anticoagulant also found to inhibit thrombosis. PMID- 26745505 TI - Identification of the inhibitory mechanism of FDA approved selective serotonin reuptake inhibitors: an insight from molecular dynamics simulation study. AB - Antidepressants selectively inhibiting serotonin reuptake (SSRIs) represent a highly effective drug class, and novel therapeutic strategies were proposed to improve SSRIs' drug efficacy. The knowledge of the inhibitory mechanism of FDA approved SSRIs could provide great insights and act as important starting points to discover privileged drug scaffolds with improved efficacy. However, the structure of human serotonin transporter (hSERT) is yet to be determined and the inhibitory mechanism underlying SSRIs still needs to be further explored. In this study, the inhibitory mechanism of 4 approved SSRIs treating major depression (fluoxetine, sertraline, paroxetine and escitalopram) was identified by integrating multiple computational methods. Firstly, a recently published template with high sequence identity was adopted for the first time to generate hSERT's homology model. Then, docking poses of 4 SSRIs were used as the initial conformation for molecular dynamics (MD) simulation followed by MM/GBSA binding free energy calculation and per-residue free energy decomposition. Finally, the binding mode shared by the 4 studied SSRIs was identified by hierarchically clustering per-residue free energies. The identified binding mode was composed of collective interactions between 3 chemical groups in SSRIs and 11 hot spot residues in hSERT. 6 out of these 11 were validated by previous mutagenesis studies or pharmacophore models, and the remaining 5 (Ala169, Ala173, Thr439, Gly442 and Leu443) found in this work were not yet been identified as common determinants of all the 4 studied SSRIs in binding hSERT. Moreover, changes in SSRIs' binding induced by mutation on hot spot residues were further explored, and 3 mechanisms underlining their drug sensitivity were summarized. In summary, the identified binding mode provided important insights into the inhibitory mechanism of approved SSRIs treating major depression, which could be further utilized as a framework for assessing and discovering novel lead scaffolds. PMID- 26745506 TI - A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics. AB - AIM: This study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to individually refine warfarin dosing in Caribbean Hispanic patients. PATIENTS & METHODS: A multiple linear regression analysis of effective warfarin doses versus relevant genotypes, admixture, clinical and demographic factors was performed in 255 patients and further validated externally in another cohort of 55 individuals. RESULTS: The admixture-adjusted, genotype-guided warfarin dosing refinement algorithm developed in Caribbean Hispanics showed better predictability (R2 = 0.70, MAE = 0.72mg/day) than a clinical algorithm that excluded genotypes and admixture (R2 = 0.60, MAE = 0.99mg/day), and outperformed two prior pharmacogenetic algorithms in predicting effective dose in this population. For patients at the highest risk of adverse events, 45.5% of the dose predictions using the developed pharmacogenetic model resulted in ideal dose as compared with only 29% when using the clinical non-genetic algorithm (p<0.001). The admixture-driven pharmacogenetic algorithm predicted 58% of warfarin dose variance when externally validated in 55 individuals from an independent validation cohort (MAE = 0.89 mg/day, 24% mean bias). CONCLUSIONS: Results supported our rationale to incorporate individual's genotypes and unique admixture metrics into pharmacogenetic refinement models in order to increase predictability when expanding them to admixed populations like Caribbean Hispanics. TRIAL REGISTRATION: ClinicalTrials.gov NCT01318057. PMID- 26745508 TI - Accuracy in HIV Rapid Testing among Laboratory and Non-laboratory Personnel in Zambia: Observations from the National HIV Proficiency Testing System. AB - BACKGROUND: Despite rapid task-shifting and scale-up of HIV testing services in high HIV prevalence countries, studies evaluating accuracy remain limited. This study aimed to assess overall accuracy level and factors associated with accuracy in HIV rapid testing in Zambia. METHODS: Accuracy was investigated among rural and urban HIV testing sites participating in two annual national HIV proficiency testing (PT) exercises conducted in 2009 (n = 282 sites) and 2010 (n = 488 sites). Testers included lay counselors, nurses, laboratory personnel and others. PT panels of five dry tube specimens (DTS) were issued to testing sites by the national reference laboratory (NRL). Site accuracy level was assessed by comparison of reported results to the expected results. Non-parametric rank tests and multiple linear regression models were used to assess variation in accuracy between PT cycles and between tester groups, and to examine factors associated with accuracy respectively. RESULTS: Overall accuracy level was 93.1% (95% CI: 91.2-94.9) in 2009 and 96.9% (95% CI: 96.1-97.8) in 2010. Differences in accuracy were seen between the tester groups in 2009 with laboratory personnel being more accurate than non-laboratory personnel, while in 2010 no differences were seen. In both PT exercises, lay counselors and nurses had more difficulties interpreting results, with more occurrences of false-negative, false-positive and indeterminate results. Having received the standard HIV rapid testing training and adherence to the national HIV testing algorithm were positively associated with accuracy. CONCLUSION: The study showed an improvement in tester group and overall accuracy from the first PT exercise to the next. Average number of incorrect test results per 1000 tests performed was reduced from 69 to 31. Further improvement is needed, however, and the national HIV proficiency testing system seems to be an important tool in this regard, which should be continued and needs to be urgently strengthened. PMID- 26745507 TI - A Higher Activation Threshold of Memory CD8+ T Cells Has a Fitness Cost That Is Modified by TCR Affinity during Tuberculosis. AB - T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naive CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4 specific retrogenic CD8+ T cells. We find that the primary (naive) response outnumbers the secondary (memory) response during Mtb challenge, an effect moderated by increased TCR affinity. To determine whether the expansion of polyclonal memory T cells is restrained following Mtb challenge, we used TCRbeta deep sequencing to track TB10.4-specific CD8+ T cells after vaccination and subsequent challenge in intact mice. Successful memory T cells, defined by their clonal expansion after Mtb challenge, express similar CDR3beta sequences suggesting TCR selection by antigen. Thus, both TCR-dependent and -independent factors affect the fitness of memory CD8+ responses. The impaired expansion of the majority of memory T cell clonotypes may explain why some TB vaccines have not provided better protection. PMID- 26745510 TI - Successive ratio subtraction coupled with constant multiplication spectrophotometric method for determination of hydroquinone in complex mixture with its degradation products, tretinoin and methyl paraben. AB - A sensitive and selective stability-indicating successive ratio subtraction coupled with constant multiplication (SRS-CM) spectrophotometric method was studied and developed for the spectrum resolution of five component mixture without prior separation. The components were hydroquinone in combination with tretinoin, the polymer formed from hydroquinone alkali degradation, 1,4 benzoquinone and the preservative methyl paraben. The proposed method was used for their determination in their pure form and in pharmaceutical formulation. The zero order absorption spectra of hydroquinone, tretinoin, 1,4 benzoquinone and methyl paraben were determined at 293, 357.5, 245 and 255.2 nm, respectively. The calibration curves were linear over the concentration ranges of 4.00-46.00, 1.00 7.00, 0.60-5.20, and 1.00-7.00 MUg mL(-1) for hydroquinone, tretinoin, 1,4 benzoquinone and methyl paraben, respectively. The pharmaceutical formulation was subjected to mild alkali condition and measured by this method resulting in the polymerization of hydroquinone and the formation of toxic 1,4 benzoquinone. The proposed method was validated according to ICH guidelines. The results obtained were statistically analyzed and compared with those obtained by applying the reported method. PMID- 26745509 TI - Acetate selective fluorescent turn-on sensors derived using vitamin B6 cofactor pyridoxal-5-phosphate. AB - Two new Schiff base receptors have been synthesized by condensation of pyridoxal 5-phosphate with 2-aminophenol (L(1)) or aniline (L(2)). In DMSO, the receptors showed both chromogenic and 'turn-on' fluorescence responses selectively in the presence of AcO(-) and F(-). However, in mixed DMSO-H2O medium, the receptors showed AcO(-) selective 'turn-on' fluorescence without any interference from other tested anions including F(-). The detection limit for AcO(-) was found to be 7.37 MUM and 22.9 MUM using the receptors L(1) and L(2), respectively. PMID- 26745511 TI - Spectroscopic studies of the fish fossils (Cladocyclus gardneri and Vinctifer comptoni) from the Ipubi Formation of the Cretaceous Period. AB - Fossils are mineralized remains or traces from animals, plants and other organisms aged to about 10(8)years. The chemical processes of fossilization are dated back from old geological periods on Earth. The understanding of these processes and the structure of the fossils are one of the goals of paleontology and geology in the sedimentary environments. Many researches have tried to unveil details about special kinds of biological samples; however, a lack of data is noticed for various other specimens. This study reports the investigations through infrared spectroscopy, X-ray fluorescence and X-ray diffraction measurements for two types of fish fossils from the Cretaceous Period. The sample of Cladocyclus gardneri and Vinctifer comptoni fossils were collected from the Ipubi Formation, being one of the less studied, among the formations that constitute the important Santana group in the Araripe Basin, Brazil. The results obtained through different techniques, showed that the C. gardneri fish fossil contains hydroxyapatite and calcite as constituents whereas its rock matrix was formed by calcite, quartz and pyrite. Regarding the V. comptoni, the measurements confirmed the presence of hydroxyapatite in the fossil and its rock matrix gypsum, pyrite, quartz and calcite. The above scientific data contributed to the understanding the fossil formation in the Ipubi Formation, an important environment of the Cretaceous Period, which is rich in well-preserved fossils from different species. PMID- 26745513 TI - Nanoscale bio-platforms for living cell interrogation: current status and future perspectives. AB - The living cell is a complex entity that dynamically responds to both intracellular and extracellular environments. Extensive efforts have been devoted to the understanding intracellular functions orchestrated with mRNAs and proteins in investigation of the fate of a single-cell, including proliferation, apoptosis, motility, differentiation and mutations. The rapid development of modern cellular analysis techniques (e.g. PCR, western blotting, immunochemistry, etc.) offers new opportunities in quantitative analysis of RNA/protein expression up to a single cell level. The recent entries of nanoscale platforms that include kinds of methodologies with high spatial and temporal resolution have been widely employed to probe the living cells. In this tutorial review paper, we give insight into background introduction and technical innovation of currently reported nanoscale platforms for living cell interrogation. These highlighted technologies are documented in details within four categories, including nano biosensors for label-free detection of living cells, nanodevices for living cell probing by intracellular marker delivery, high-throughput platforms towards clinical current, and the progress of microscopic imaging platforms for cell/tissue tracking in vitro and in vivo. Perspectives for system improvement were also discussed to solve the limitations remains in current techniques, for the purpose of clinical use in future. PMID- 26745514 TI - Graphene Oxide-Assisted Synthesis of Microsized Ultrathin Single-Crystalline Anatase TiO2 Nanosheets and Their Application in Dye-Sensitized Solar Cells. AB - High-quality microsized ultrathin single-crystalline anatase TiO2 nanosheets (MS TiO2) with exposed {001} facets were synthesized by a facile and low-cost two step process that combines a graphene oxide (GO)-assisted hydrothermal method with calcination. Both GO and HF play an important role in the formation of well dispersed MS-TiO2. As a novel microsized (1-4 MUm) ultrathin two-dimensional (2D) material, MS-TiO2 possesses much higher lateral size and aspect ratio compared to common 2D nanosized (30-60 nm) ultrathin TiO2 nanosheets (NS-TiO2), resulting in excellent electronic conductivity and superior electron transfer and diffusion properties. Here, we fabricated MS-TiO2 and NS-TiO2, both of which were incorporated with the TiO2 nanoparticles (P25) to constitute the hybrid photoanode of dye-sensitized solar cells (DSSCs), and explored the effect of the lateral size (nano- and micro-) of ultrathin TiO2 nanosheets on their electron transfer and diffusion properties. Benefiting from the faster electron transfer rate and short diffusion path of the MS-TiO2, the MS-TiO2/P25 gains the more superior performance compared to pure P25 and NS-TiO2/P25 in the application of DSSCs. Moreover, it is expected that the novel high aspect ratio MS-TiO2 may be applied in diverse fields including photocatalysis, photodetectors, lithium-ion batteries and others concerning the environment and energy. PMID- 26745515 TI - A quantitative study of intracranial hypotensive syndrome by magnetic resonance. AB - OBJECTIVES: The study aims to investigate the magnetic resonance imaging (MRI) findings of intracranial hypotension syndrome (IHS) and the change of quantitative indicators, so as to yield a deeper understanding of the disease. PATIENTS AND METHODS: The clinical data and MRI findings of 26 cases of IHS which were confirmed by lumbar puncture were retrospectively analyzed. Two physicians evaluated the MRI findings including thickening and enhancement of dural, pituitary enlargement, subdural effusion (hematocele), venous engorgement and brain sagging, and measured the quantitative indicators including mamillopontine distance and pontomesencephalic angle. The consistency between the two results of the physicians was assessed by Kappa consistency test. The differences of mamillopontine distance and pontomesencephalic angle between the patient group and the control group were determined by paired t-test. The diagnostic efficiency of mamillopontine distance and pontomesencephalic angle was assessed by area under the ROC curve, and their best diagnostic thresholds were also determined, respectively. Age- and sex-matched healthy volunteers controls (n=26) were recruited and served as the control group. RESULTS: All of the 26 patients suffered from the characterized by orthostatic headache of IHS. The clinical evaluations of dural thickening and enhancement, pituitary enlargement, subdural effusion (hematocele), venous engorgement by the two physicians showed excellent agreements (kappa=0.808, 1 and 0.906, P<0.01), and the clinical evaluations of brain sagging showed medium agreements (kappa=0.606, P<0.01). The mamillopontine distance and pontomesencephalic angle of the patient group were 5.4 +/- 1.6mm and 47.8 +/- 8.7 degrees , respectively, which were obviously less than those of the control group (6.9 +/- 1.1mm and 61.0 +/- 6.1 degrees , respectively), and the differences were statistically significant (t=-4.563, P<0.01; t=-.329, P<0.01). The area under ROC curve of mamillopontine distance and pontomesencephalic angle were 0.774 and 0.908, respectively, and the diagnostic value of pontomesencephalic angle was higher than that of the mamillopontine distance. The sensitivity and specificity were 73.1% and 73.1%, respectively, when diagnostic threshold of mamillopontine distance was 6.4mm. The sensitivity and specificity were 76.9% and 96.2%, when diagnostic threshold of pontomesencephalic angle was 51.7 degrees . CONCLUSION: The MRI findings presented characteristic features of IHS. The quantitative indicators including mamillopontine distance and pontomesencephalic angle were helpful for clinical diagnosis of subjective findings of IHS. PMID- 26745512 TI - Vimentin-Mediated Steroidogenesis Induced by Phthalate Esters: Involvement of DNA Demethylation and Nuclear Factor kappaB. AB - Di-n-butyl phthalate (DBP) and its active metabolite, monobutyl phthalate (MBP) are the most common endocrine disrupting chemicals. Many studies indicate that high-doses of DBP and/or MBP exhibit toxicity on testicular function, however, little attention have been paid to the effects of low levels of DBP/MBP on steroidogenesis. As we all know, the steroidogenic acute regulatory protein (StAR) is a key regulator involved in the steroidogenesis. Here we found that, in addition to StAR, MBP/DBP increased the steroidogenesis by a cytoskeletal protein, vimentin. Briefly, in murine adrenocortical tumor (Y1) and the mouse Leydig tumor (MLTC-1) cells, vimentin regulated the secretion of progesterone. When these two cells were exposure to MBP, the DNA demethylation in the vimentin promoter was observed. In addition, MBP also induced the activation of nuclear factor kappa B (NF-kappaB, a transcriptional regulator of vimentin). These two processes improved the transcriptional elevation of vimentin. Knockdown of NF kappaB/vimentin signaling blocked the DBP/MBP-induced steroidogenesis. These in vitro results were also confirmed via an in vivo model. By identifying a mechanism whereby DBP/MBP regulates vimentin, our results expand the understanding of the endocrine disrupting potential of phthalate esters. PMID- 26745517 TI - A systematic review of sleep disturbance in anxiety and related disorders. AB - Recent research suggests that sleep disturbance may be a transdiagnostic process, and there is increasing interest in examining how sleep disturbance may contribute to anxiety and related disorders. The current review summarizes and synthesizes the extant research assessing sleep in anxiety and related disorders. The findings suggest that sleep disturbance exacerbates symptom severity in the majority of anxiety and related disorders. However, the nature of sleep disturbance often varies as a function of objective versus subjective assessment. Although sleep disturbance is a correlate of most anxiety and related disorders, a causal role for sleep disturbance is less clear. A model of potential mechanisms by which sleep disturbance may confer risk for the development of anxiety and related disorders is discussed. Future research integrating findings from basic sleep research with current knowledge of anxiety and related disorders may facilitate the development of novel treatments for comorbid sleep disturbance and clinical anxiety. PMID- 26745518 TI - Degradation of cis- and trans-(4-methylcyclohexyl) methanol in activated sludge. AB - Crude (4-methylcyclohexyl)methanol (MCHM) caused extensive contamination of drinking water, wastewater, and the environment during the 2014 West Virginia Chemical Spill. However, information related to the environmental degradation of cis- and trans-4-MCHM, the main components of the crude 4-MCHM mixture, remains largely unknown. This study is among the first to investigate the degradation kinetics and transformation of 4-MCHM isomers in activated sludge. The 4-MCHM loss was mainly due to biodegradation to form carbon dioxide (CO2), plus acetic, propionic, isobutyric, and isovaleric acids with little contribution from adsorption. The biodegradation of 4-MCHM isomers followed the first-order kinetic model with half-lives higher than 0.50 days. Nitrate augmented the degradation of 4-MCHM isomers, while glucose and acetate decreased their degradation. One 4-MCHM degrading bacterium isolated from activated sludge was identified as Acinetobacter bouvetii strain EU40 based on 16S rRNA gene sequences. This study will enhance the prediction of the environmental fate of 4-MCHM in water treatment systems. PMID- 26745520 TI - The Usefulness of Combined B Mode and Doppler Ultrasonography to Guide Treatment of Appendicitis. AB - Introduction We have succeeded in classifying the severity of appendicitis by evaluating the structure of the submucosal layer and blood flow in the appendix wall with ultrasonography (US). Here, we propose a new preoperative classification system to guide treatment strategy. Materials and Methods Between February 2005 and December 2011, a total of 440 acute appendicitis cases were diagnosed, and 407 met inclusion criteria for this study. US and Doppler findings were used to classify cases as Grade I, IIa, IIb, III, or appendiceal mass. Grades I and IIa were treated conservatively without antibiotics. Appendectomy for Grades IIb and III and interval appendectomy for appendiceal mass were performed. Results Of 407 cases, 38 were Grade I, 132 were Grade IIa, 130 were Grade IIb, 57 were Grade III, and 50 were appendiceal mass. Improvement occurred without antibiotics in 37 (97.3%) Grade I and 129 (97.7%) Grade IIa cases. Recurrence occurred postdischarge in 9 (23.6%) Grade I and 35 (26.5%) Grade IIa cases. All Grades IIb and III patients had gangrenous or phlegmonous appendicitis. There were no negative appendectomies. Conclusion Even if US findings reveal swelling or an irregular submucosal layer, when power Doppler identifies abundant blood flow, inflammation may improve spontaneously. Decreased appendiceal wall blood flow indicates irreversible necrotic change. Doppler and B mode US used together improve acute appendicitis treatment. PMID- 26745519 TI - Misdiagnosis of Acute Appendicitis in Children Attending the Emergency Department: The Experience of a Large, Tertiary Care Pediatric Hospital. AB - Background Missed appendicitis is a frequent cause of professional liability for emergency department (ED) physicians. Our objective was to assess and compare the presentations of patients in whom the diagnosis of appendicitis was missed with those in whom it was correctly diagnosed on their first ED visit and to identify the clinical features that characterized the two groups. Methods This study is a retrospective review of all ED children with proven appendicitis between January 2010 and December 2013. Historical, clinical, and laboratory features of patients missed and correctly diagnosed during their first ED visit were compared. The literature on this subject was also reviewed. Results A total of 400 patients were included in this study. Fifteen (3.75%) patients were considered to be misdiagnoses, the most common misdiagnosis being acute gastroenteritis (26.6%). Thirty-three percent of misdiagnosed patients had undergone an ultrasound compared with 87% of correctly diagnosed patients (p < 0.05). Conclusion Our incidence of missed appendicitis compares favorably with the 6.9 to 27.6% incidence reported in the literature. Our relatively low incidence may be a result of medical practice, especially during night shifts, and the availability of ultrasound 24 hours a day. PMID- 26745521 TI - Dynamic Compression System: An Effective Nonoperative Treatment for Pectus Carinatum: A Single Center Experience in Basel, Switzerland. AB - Background Several nonoperative treatments are currently available for the correction of pectus carinatum (PC). Objective The objective of this study is to report our single center experience with the dynamic compression system (DCS). Materials and Methods The DCS is a rigid aluminum brace. PC is reshaped into a normal appearance through anterior-posterior pressure and lateral expansion of the chest. Patients with chondrogladiolar PC were considered suitable for the nonoperative treatment with DCS. Results In this study, 53 of 68 children (78%) with chondrogladiolar PC were assessed retrospectively: 2 children were corrected by surgery, 12/53 (23%) treated by a conventional orthesis, 11/53 (21%) remained without therapy because of minor PC, and 36/53 (68%) were treated using the DCS. Of these 36 patients, 17 (47%) are already cured with a good (7/17) to excellent (10/17) cosmetic result after a median treatment period of 9 months (range, 2.5 16 months). The mean daily time of wearing of the device for those 17 patients was 9 hours (range, 5-18). None abandoned the treatment and there were almost no complications. Conclusions Lateral expansion of the chest and the possibility to measure the applied pressure seemed to be the key to DCSs success. We propose the DCS as first choice in the treatment of chondrogladiolar PC in children. PMID- 26745516 TI - An analysis of inhibitory functioning in individuals with chronic posttraumatic stress disorder. AB - Cognitive abnormalities in posttraumatic stress disorder (PTSD) may be a function of underlying inhibitory deficits. Prepulse inhibition (PPI) and attentional blink (AB) are paradigms thought to assess inhibition. Using a sample of 28 individuals with PTSD compared to 20 trauma-exposed and 19 healthy individuals, PPI was examined using white noise that was preceded by a tone, and AB was examined using a presentation of letters in a stream of numbers. Relative to the control group, the PTSD and trauma-exposed groups did not follow the u-shaped pattern in AB, suggesting trauma-exposure and subsequent PTSD are associated with similar impairment in attention. Individuals with PTSD showed reduced PPI compared to trauma-exposed and healthy individuals, suggesting individuals with PTSD exhibit faulty automatic processing. For individuals with PTSD, PTSD severity was associated with a decline in PPI. These findings suggest a general faulty inhibitory mechanism associated with trauma exposure and PTSD. PMID- 26745522 TI - Laparoscopic Sleeve Gastrectomy versus Gastric Bypass in Late Adolescents: What Is the Optimal Surgical Strategy for Morbid Obesity? AB - Introduction Interest in bariatric surgery in adolescents is increasing, because adolescent obesity equals increased health risks in adult life. To define the preferred procedure in adolescents, this study compares outcomes of LSG and LRYGB in late adolescents in our center. Materials and methods Data on baseline characteristics, operative details, and follow-up were collected retrospectively in all patients (age 18-20 years) who underwent LSG or LRYGB in our clinic. Outcomes were analyzed using nonparametric tests. Results Total 65 adolescents (54 females; median age 19 years) were included, 45 patients underwent LSG, and 20 underwent LRYGB.Significant differences in %EWL were observed at 2-year follow up; 81.0% in LRYGB (n = 11) versus 96.8% in LSG (n = 23), p = 0.007. No differences were observed in postoperative mortality, complication rate, and resolution of comorbidities between both procedures. Discussion LSG showed significant better results than LRYGB in terms of %EWL after 2 years in this selected group of late adolescents. Considering these results in LSG patients and the theoretical advantages of LSG (normal diet options, preservation of an intact GI-tract, less vitamin disturbances, and better quality of life), LSG may be an appropriate bariatric technique to perform in morbidly obese adolescents. PMID- 26745523 TI - Cosmetic Outcomes of Sutureless Closure in Gastroschisis. AB - Purpose A sutureless gastroschisis repair allows for spontaneous closure of abdominal wall defect. We report our experience focusing on final esthetic outcome. Methods Retrospective data were collected from medical reports of all neonates with gastroschisis operated from January 2009 to December 2013. Variables recorded included patients descriptors, management modality, and cosmetic outcome. Results From the overall group of 38 patients with gastroschisis, 20 infants treated with sutureless closure were included in this study. In the analyzed cohort, 17 (85%) children were operated under general anesthesia and 3 (15%) without intubation. Primary reduction was possible in 15 (75%) cases, and in 5 (25%) we used silo. There were two (10%) deaths in late postoperative course due to septic complications. Three (15%) infants needed laparotomy because of adhesions and bowel obstruction. There were no infectious complications of the wound. Only 55% (10/18) of children presented umbilical hernia prior to discharge. Only two (11%) children with umbilical hernia were operated until now. Almost all patients (16/18; 89%) present excellent final cosmetic result without scar formation. Conclusion Sutureless closure of uncomplicated gastroschisis is a safe technique that reduces need of intubation and provides excellent cosmetic results. PMID- 26745524 TI - Synthesis of Isocoumarins via Silver(I)-Mediated Annulation of Enol Esters. AB - Silver-mediated annulation of 2-iodo enol esters leading to 4- and 3,4 substituted isocoumarins was accomplished selectively at room temperature. Coupling of 2-iodo benzoic acids with enolates that were produced in situ from the simple esters was also performed to produce isocoumarins under analogous reaction conditions. Owing to the mildness of the current protocol, 4-acyl 3 substituted isocoumarins were efficiently produced without any deacylation. PMID- 26745525 TI - Feeding Anthrax: The Crystal Structure of Bacillus anthracis InhA Protease. AB - Pathogenic bacteria secrete proteases to evade host defense and to acquire nutrients. In this issue of Structure, Arolas et al. (2016) describe the structural basis of activation and latency of InhA, a major secreted protease of Bacillus anthracis. PMID- 26745526 TI - PhnK: Another Piece of the Carbon-Phosphorus Lyase Puzzle. AB - Despite the fact that carbon-phosphorus lyase activity was first documented more than 50 years ago, we are yet to completely understand the details of how this enzyme system functions or what it looks like. In this issue of Structure, Yang et al. (2016) now provide a step forward with a view of how PhnK fits into the bigger picture of carbon-phosphorus lyase. PMID- 26745527 TI - Let the Powers Combine. AB - Lipoproteins play a variety of roles in bacterial physiology and virulence. Correct localization is essential for lipoprotein function, yet the mechanisms by which this occurs are not yet fully understood. In this issue of Structure, East et al. (2016) describe the factors that govern secretion of the PulA lipoprotein. PMID- 26745528 TI - Structural Basis for the Non-catalytic Functions of Protein Kinases. AB - Protein kinases are known primarily for their ability to phosphorylate protein substrates, which constitutes an essential biological process. Recently, compelling evidence has accumulated that the functions of many protein kinases extend beyond phosphorylation and include an impressive spectrum of non-catalytic roles, such as scaffolding, allosteric regulation, or even protein-DNA interactions. How the conserved kinase fold shared by all metazoan protein kinases can accomplish these diverse tasks in a specific and regulated manner is poorly understood. In this review, we analyze the molecular mechanisms supporting phosphorylation-independent signaling by kinases and attempt to identify common and unique structural characteristics that enable kinases to perform non catalytic functions. We also discuss how post-translational modifications, protein-protein interactions, and small molecules modulate these non-canonical kinase functions. Finally, we highlight current efforts in the targeted design of small-molecule modulators of non-catalytic kinase functions, a new pharmacological challenge for which structural considerations are more important than ever. PMID- 26745529 TI - Structural Basis for Latency and Function of Immune Inhibitor A Metallopeptidase, a Modulator of the Bacillus anthracis Secretome. AB - Immune inhibitor A(InhA)-type metallopeptidases are potential virulence factors secreted by members of the Bacillus cereus group. Two paralogs from anthrax causing Bacillus anthracis (BaInhA1 and BaInhA2) were shown to degrade host tissue proteins with broad substrate specificity. Analysis of their activation mechanism and the crystal structure of a zymogenic BaInhA2 variant revealed a ~750-residue four-domain structure featuring a pro-peptide, a catalytic domain, a domain reminiscent of viral envelope glycoproteins, and a MAM domain grafted into the latter. This domain, previously found only in eukaryotes, is required for proper protein expression in B. anthracis and evinces certain flexibility. Latency is uniquely modulated by the N-terminal segment of the pro-peptide, which binds the catalytic zinc through its alpha-amino group and occupies the primed side of the active-site cleft. The present results further our understanding of the modus operandi of an anthrax secretome regulator. PMID- 26745531 TI - Year of Reflection. PMID- 26745532 TI - Writing for Publication: Is It for You? PMID- 26745530 TI - New Dynamic Rotamer Libraries: Data-Driven Analysis of Side-Chain Conformational Propensities. AB - Most rotamer libraries are generated from subsets of the PDB and do not fully represent the conformational scope of protein side chains. Previous attempts to rectify this sparse coverage of conformational space have involved application of weighting and smoothing functions. We resolve these limitations by using physics based molecular dynamics simulations to determine more accurate frequencies of rotameric states. This work forms part of our Dynameomics initiative and uses a set of 807 proteins selected to represent 97% of known autonomous protein folds, thereby eliminating the bias toward common topologies found within the PDB. Our Dynameomics derived rotamer libraries encompass 4.8 * 10(9) rotamers, sampled from at least 51,000 occurrences of each of 93,642 residues. Here, we provide a backbone-dependent rotamer library, based on secondary structure phi/psi regions, and an update to our 2011 backbone-independent library that addresses the doubling of our dataset since its original publication. PMID- 26745533 TI - Exposing Compassion Fatigue and Burnout Syndrome in a Trauma Team: A Qualitative Study. AB - Compassion fatigue (CF) and burnout syndrome (BOS) are identified in trauma, emergency, and critical care nursing practices. The purpose of this qualitative study was to measure CF and BOS in a trauma team and allow them to share perceptions of related stress triggers and coping strategies. Surveys to measure CF and BOS and a focus group allowed a trauma team (12 practitioners) to share perceptions of related stress triggers and coping strategies. More than half scored at risk for CF and BOS. Stress triggers were described as situation (abuse, age of patient) versus injury-related. Personal coping mechanisms were most often reported. Both CF and BOS can be assessed with a simple survey tool. Strategies for developing a program culturally sensitive to CF and BOS are provided. PMID- 26745534 TI - Personalized Medicine and Pharmacogenomics: Is Trauma Ready? PMID- 26745535 TI - Effectiveness of the Rural Trauma Team Development Course for Educating Nurses and Other Health Care Providers at Rural Community Hospitals. AB - The study evaluates (1) health care provider perception of the Rural Trauma Team Development Course (RTTDC); (2) improvement in acute trauma emergency care knowledge; and (3) early transfer of trauma patients from rural emergency departments (EDs) to a verified trauma center. A 1-day, 8-hour RTTDC was given to 101 nurses and other health care providers from nine rural community hospitals from 2011 to 2013. RTTDC participants completed questionnaires to address objectives (1) and (2). ED and trauma registry data were queried to achieve objective (3) for assessing reduction in ED time (EDT), from patient arrival to decision to transfer and ED length of stay (LOS). The RTTDC was positively perceived by health care providers (96.3% of them completed the program). Significant improvement in 13 of the 19 knowledge items was observed in nurses. Education intervention was an independent predictor in reducing EDT by 28 minutes and 95% confidence interval (CI) [-57, -0.1] at 6 months post-RTTDC, and 29 minutes and 95% CI [-53, -6] at 12 months post-RTTDC. Similar results were observed with ED LOS. The RTTDC is well-perceived as an education program. It improves acute trauma emergency care knowledge in rural health care providers. It promotes early transfer of severely injured patients to a higher level of care. PMID- 26745536 TI - Diving Into Blunt Aortic Injury: A Case Review. AB - Although many advances in trauma care have occurred, traumatic aortic injuries remain a leading cause of death in trauma patients. For those who survive long enough to receive treatment, rapid identification of injuries, surgical intervention, and definitive care are critical. Assessment findings and diagnostic imaging are both necessary to rapidly identify aortic injury and select the proper intervention. Surgical options are now available that, for the appropriate patient with aortic injury, can eliminate the need for invasive surgery, decrease complications, and decrease recovery time. PMID- 26745537 TI - Implementation and Evaluation of a Ward-Based eLearning Program for Trauma Patient Management. AB - The majority of trauma nursing education is focused on the emergency phases of care. We describe the development and evaluation of a trauma eLearning module for the ward environment. The module was developed using adult learning principles and implemented in 2 surgical wards. There were 3 phases of evaluation: (1) self efficacy of nurses; (2) relevance and usability of the module and; (3) application of knowledge learnt. The majority indicated they had applied new knowledge, particularly when performing a physical assessment (85.7%), communicating (91.4%), and identifying risk of serious illness (90.4%). Self efficacy relating to confidence in caring for patients, communication, and escalating clinical deterioration improved (p = .023). An eLearning trauma patient assessment module for ward nursing staff improves nursing knowledge and self-efficacy. PMID- 26745538 TI - Geriatric Trauma: A Clinical and Ethical Review. AB - Because of advances in medicine and other sciences, the average human life span is longer now than any other time in history. The physiologic effects of aging as well as multimorbidity, polypharmacy, and other geriatric-specific syndromes create additional challenges when elderly patients experience a traumatic injury. However, there is a growing evidence base that can inform the clinical decision making process. This narrative review of the literature addresses the state of the science regarding geriatric syndromes, guidelines and protocols, indices and models for prognostication, outcomes and ethical concerns in the treatment of geriatric trauma. PMID- 26745539 TI - Case Report: Traumatic Carotid-Cavernous Fistula. AB - Carotid-cavernous fistulae (CCFs) are a rare complication of head trauma, with potentially serious consequences. We report the case of a 45-year-old male patient who presented with posttraumatic CCF 2 months after sustaining a head injury. Appropriate imaging in the form of computed tomography of the head, magnetic resonance imaging of the head, and digital subtraction angiography of the intracranial vessels was performed, and the CCF was successfully coil embolized. This resulted in good resolution of the patient's symptoms. We discuss the cause, presentation, diagnosis, and treatment of CCFs. Carotid-cavernous fistulae are a rare sequela of craniofacial trauma; therefore, a high index of suspicion must be maintained to establish a diagnosis and prevent serious consequences. PMID- 26745540 TI - Identifying Obstacles for the Obese Trauma Patient. AB - With the prevalence of obesity and the incidence of trauma increasing, acute care practitioners need to be better prepared to manage this special population. Numerous obstacles exist that complicate and delay the care for this population. Recognizing the obese patient as a special population by trauma organizations and health care facilities can help educate providers in the external, anatomical, and physiological obstacles that may delay care. The purpose of this article is to identify these obstacles that may complicate the assessment, diagnosis, and treatment of the obese trauma patient in the acute care setting. By identifying these obstacles, care givers can have the necessary staff, equipment, and protocols in place to expedite care and improve outcomes. PMID- 26745543 TI - Suppression of Experimental Arthritis and Associated Bone Loss by a Tissue Selective Estrogen Complex. AB - In addition to the systemic inflammation present in rheumatoid arthritis (RA), decreased estradiol levels in postmenopausal RA patients further accelerate bone loss in these patients. The tissue-selective estrogen complex (TSEC), an estrogen combined with a selective estrogen receptor modulator, is a new hormone replacement therapy option. The first approved TSEC, containing conjugated estrogens and bazedoxifene (BZA), reduces menopausal symptoms and prevents osteoporosis with an improved safety profile compared with conventional hormone replacement therapy. Previous studies have shown that estrogens strongly inhibit experimental arthritis whereas BZA is mildly suppressive. In this study the antiarthritic potential of combined BZA and estradiol is explored for the first time. Female ovariectomized DBA/1 mice were subjected to collagen-induced arthritis, an experimental postmenopausal RA model, and treated with BZA, 17beta estradiol (E2), combined BZA and E2 (BZA/E2), or vehicle. BZA/E2 suppressed arthritis severity and frequency, synovitis, and joint destruction, equally efficient as E2 alone. Unwanted estrogenic proliferative effects on the endometrium were blocked by the addition of BZA, determined by collecting uterine weights. Bone mineral density was measured by peripheral quantitative computed tomography, and all treatments protected collagen-induced arthritis mice from both trabecular and cortical bone loss. Moreover, BZA/E2, but not E2 alone, inhibited preosteoclast formation and reduced serum anticollagen type II antibodies. In conclusion, a TSEC, herein combined BZA/E2, suppresses experimental arthritis and prevents associated bone loss as efficiently as E2 alone but with minimal uterine effects, highlighting the need for clinical trials that evaluate the addition of a TSEC to conventional postmenopausal RA treatment. PMID- 26745544 TI - Light Emission as a Probe of Energy Losses in Molecular Junctions. AB - Visible light emission was observed for molecular junctions containing 5-19 nm thick layers of aromatic molecules between carbon contacts and correlated with their current-voltage behaviors. Their emission was compared to that from Al/AlOx/Au tunnel junctions, which has been previously attributed to transport of carriers across the AlOx layer to yield "hot carriers" which emit light as they relax within the Au contact. The maximum emitted photon energy is equal to the applied bias for the case of coherent tunneling, and such behavior was observed for light emission from AlOx and thin (<5 nm) molecular junctions. For thicker films, the highest energy observed for emitted photons is less than eVapp and exhibits an energy loss that is strongly dependent on molecular layer structure and thickness. For the case of nitroazobenzene junctions, the energy loss is linear with the molecular layer thickness, with a slope of 0.31 eV/nm. Energy loss rules out coherent tunneling as a transport mechanism in the thicker films and provides a direct measure of the electron energy after it traverses the molecular layer. The transition from elastic transport in thin films to "lossy" transport in thick films confirms that electron hopping is involved in transport and may provide a means to distinguish between various hopping mechanisms, such as activated electron transport, variable range hopping, and Poole Frankel transport. PMID- 26745545 TI - Estimating Children's Soil/Dust Ingestion Rates through Retrospective Analyses of Blood Lead Biomonitoring from the Bunker Hill Superfund Site in Idaho. AB - BACKGROUND: Soil/dust ingestion rates are important variables in assessing children's health risks in contaminated environments. Current estimates are based largely on soil tracer methodology, which is limited by analytical uncertainty, small sample size, and short study duration. OBJECTIVES: The objective was to estimate site-specific soil/dust ingestion rates through reevaluation of the lead absorption dose-response relationship using new bioavailability data from the Bunker Hill Mining and Metallurgical Complex Superfund Site (BHSS) in Idaho, USA. METHODS: The U.S. Environmental Protection Agency (EPA) in vitro bioavailability methodology was applied to archived BHSS soil and dust samples. Using age specific biokinetic slope factors, we related bioavailable lead from these sources to children's blood lead levels (BLLs) monitored during cleanup from 1988 through 2002. Quantitative regression analyses and exposure assessment guidance were used to develop candidate soil/dust source partition scenarios estimating lead intake, allowing estimation of age-specific soil/dust ingestion rates. These ingestion rate and bioavailability estimates were simultaneously applied to the U.S. EPA Integrated Exposure Uptake Biokinetic Model for Lead in Children to determine those combinations best approximating observed BLLs. RESULTS: Absolute soil and house dust bioavailability averaged 33% (SD +/- 4%) and 28% (SD +/- 6%), respectively. Estimated BHSS age-specific soil/dust ingestion rates are 86-94 mg/day for 6-month- to 2-year-old children and 51-67 mg/day for 2- to 9-year-old children. CONCLUSIONS: Soil/dust ingestion rate estimates for 1- to 9-year-old children at the BHSS are lower than those commonly used in human health risk assessment. A substantial component of children's exposure comes from sources beyond the immediate home environment. CITATION: von Lindern I, Spalinger S, Stifelman ML, Stanek LW, Bartrem C. 2016. Estimating children's soil/dust ingestion rates through retrospective analyses of blood lead biomonitoring from the Bunker Hill Superfund Site in Idaho. Environ Health Perspect 124:1462-1470; http://dx.doi.org/10.1289/ehp.1510144. PMID- 26745546 TI - Empathy and visual perspective-taking performance. AB - This study examined the extent to which visual perspective-taking performance is modulated by trait-level empathy. Participants completed a third-person visual perspective-taking task in which they judged the perspectives of two simultaneously presented avatars, designated "Self" and "Other." Depending on the trial, these avatars either held the same view (i.e., congruent) or a different view (i.e., incongruent). Analyses focused on the relationship between empathy and two perspective-taking phenomena: Selection between competing perspectives (i.e., perspective-congruence effects) and prioritization of the Self avatar's perspective. Empathy was related to improved overall performance on this task and a reduced cost of selecting between conflicting perspectives (i.e., smaller perspective-congruence effects). This effect was asymmetric, with empathy (i.e., empathic concern) levels predicting reduced interference from a conflicting perspective, especially when adopting the Self (vs. Other) avatar's perspective. Taken together, these results highlight the importance of the self-other distinction and mental flexibility components of empathy. PMID- 26745548 TI - Switching the Magnetic Vortex Core in a Single Nanoparticle. AB - Imaging and manipulating the spin structure of nano- and mesoscale magnetic systems is a challenging topic in magnetism, yielding a wide range of spin phenomena such as skyrmions, hedgehog-like spin structures, or vortices. A key example has been provided by the vortex spin texture, which can be addressed in four independent states of magnetization, enabling the development of multibit magnetic storage media. Most of the works devoted to the study of the magnetization reversal mechanisms of the magnetic vortices have been focused on micrometer-size magnetic platelets. Here we report the experimental observation of the vortex state formation and annihilation in individual 25 nm molecular based magnetic nanoparticles measured by low-temperature variable-field magnetic force microscopy. Interestingly, in these nanoparticles the switching of the vortex core can be induced with very small values of the applied static magnetic field. PMID- 26745547 TI - Evaluation of urban environment pollution based on the accumulation of macro- and trace elements in epiphytic lichens. AB - Nitrogen, phosphorus, potassium, magnesium, zinc, nickel, copper, manganese, iron and lead accumulation properties of three epiphytic lichen species (Hypogymnia physodes (L.) Nyl., Parmelia sulcata Taylor and Xanthoria parietina (L.) Th. Fr.) were compared. An assessment of pollution of the municipal environment in Slupsk (Poland) according to macro- and trace elements was also done. Lichen samples were taken in Autumn 2013 from Betula pendula, Fraxinus excelsior, Acer platanoides, A. pseudoplatanus and Populus sp. trees. Sampling stations comprised of house development areas, green urban parks, vicinity of streets with heavy traffic and industrial enterprises. It was found that lichens represent diverse accumulation properties to pollutants according to the species. X. parietina indicated the highest bioaccumulation in relation to N, K, Mg, Zn and Fe, the thalli of H. physodes accumulated the largest amounts of Ni and Pb, while P. sulcata P and Cu. Manganese was accumulated in similar quantities by all species. Evidences acquired by the use of factor analysis proved that pollution in Slupsk municipal environment is a serious issue with three major sources domination: street dust, marine factor and residual oil combustion. The high-risk areas were detected and visualized using surface maps based on Kriging algorithm. It was seen that the highest pollution occurs in the town centre, while the smallest happened on its outskirts and in urban parks. PMID- 26745549 TI - Mitochondrial Dysfunction, Disruption of F-Actin Polymerization, and Transcriptomic Alterations in Zebrafish Larvae Exposed to Trichloroethylene. AB - Trichloroethylene (TCE) is primarily used as an industrial degreasing agent and has been in use since the 1940s. TCE is released into the soil, surface, and groundwater. From an environmental and regulatory standpoint, more than half of Superfund hazardous waste sites on the National Priority List are contaminated with TCE. Occupational exposure to TCE occurs primarily via inhalation, while environmental TCE exposure also occurs through ingestion of contaminated drinking water. Current literature links TCE exposure to various adverse health effects including cardiovascular toxicity. Current studies aiming to address developmental cardiovascular toxicity utilized rodent and avian models, with the majority of studies using relatively higher parts per million (mg/L) doses. In this study, to further investigate developmental cardiotoxicity of TCE, zebrafish embryos were treated with 0, 10, 100, or 500 parts per billion (ppb; MUg/L) TCE during embryogenesis and/or through early larval stages. After the appropriate exposure period, angiogenesis, F-actin, and mitochondrial function were assessed. A significant dose-response decrease in angiogenesis, F-actin, and mitochondrial function was observed. To further complement this data, a transcriptomic profile of zebrafish larvae was completed to identify gene alterations associated with the 10 ppb TCE exposure. Results from the transcriptomic data revealed that embryonic TCE exposure caused significant changes in genes associated with cardiovascular disease, cancer, and organismal injury and abnormalities with a number of targets in the FAK signaling pathway. Overall, results from our study support TCE as a developmental cardiovascular toxicant, provide molecular targets and pathways for investigation in future studies, and indicate a need for continued priority for environmental regulation. PMID- 26745550 TI - Maternal cardiac troponin levels in pre-eclampsia: a systematic review. AB - OBJECTIVE: We systematically review the literature for potential alterations in cardiac troponin I (cTnI) in patients who suffer from pre-eclampsia. METHODS: We used the Medline (1966-2015), Scopus (2004-2015), Popline (1974-2015), ClinicalTrials.gov (2008-2015) and Cochrane Central Register of Controlled Trials (CENTRAL) (1999-2015) databases for our primary search; we also employed the reference lists of the full-text articles that we retrieved electronically. RESULTS: We included nine studies involving 719 women. Five of these studies suggested that cTnI increases in pre-eclamptic patients above the normal threshold. However, all studies reported outcomes at a single time point, and they failed to perform consecutive measurements to observe whether this effect was long lasting and whether it evolved during the course of pregnancy. CONCLUSIONS: Current evidence suggests that cTnI might be elevated in pre eclamptic pregnant women, although this observation is not always reported. Future studies are necessary to consistently observe cTnI levels throughout the prenatal period and during the first few postnatal weeks. A concurrent evaluation of other cardiovascular hemodynamic parameters could be of use in mechanistic models for predicting future cardiovascular morbidity in these women. PMID- 26745551 TI - A Matrix Isolation and Computational Study of Molecular Palladium Fluorides: Does PdF6 Exist? AB - Palladium atoms generated by thermal evaporation and laser ablation were reacted with and trapped in F2/Ar, F2/Ne, and neat F2 matrices. The products were characterized by electronic absorption and infrared spectroscopy, together with relativistic density functional theory calculations as well as coupled cluster calculations. Vibrational modes at 540 and 617 cm(-1) in argon matrices were assigned to molecular PdF and PdF2, and a band at 692 cm(-1) was assigned to molecular PdF4. A band at 624 cm(-1) can be assigned to either PdF3 or PdF6, with the former preferred from experimental considerations. Although calculations might support the latter assignment, our conclusion is that in these detailed experiments there is no convincing evidence for PdF6. PMID- 26745552 TI - Spontaneous Coassembly of Biologically Active Nanoparticles via Affinity Binding of Heparin-Binding Proteins to Alginate-Sulfate. AB - Controlled delivery of heparin-binding (HB) proteins represents a challenge in regenerative medicine strategies. Here, we describe the features of novel nanoparticles (NPs), spontaneously coassembled due to affinity interactions between HB proteins and the semisynthetic anionic polysaccharide, alginate sulfate. The NPs efficiently encapsulated and protected the proteins from proteolysis. Injection of a combination of NPs encapsulating multiple therapeutic growth factors promoted effective and long-term tissue repair in animal models of severe ischemia (murine model of hindlimb ischemia and acute myocardial infarction in rats). This simple yet efficient NP fabrication method is amenable for clinical use. PMID- 26745553 TI - In vivo effects of high dietary copper levels on hepatocellular mitochondrial respiration and electron transport chain enzymes in broilers. AB - The diet of broiler chickens supplemented with increasing concentrations of copper (Cu) was assessed for the effect of Cu on liver mitochondrial function. A total of 160, 1-d-old Cobb 500 broilers (Gallus domesticus) were randomly assigned in equal numbers into 4 groups, which differed in the concentration of copper supplements in the diet; 11 (control), 110, 220 and 330 mg of Cu/kg dry matter. Liver mitochondrial function was recorded at 12, 24, 36, 48 and 60 d of age. Supplementation with 110 mg Cu/kg dry matter enhanced mitochondrial function and activities of complexes I-V, and this was significant at 36 d of age compared with the other diets (P < 0.05). Supplementation with 220 mg Cu/kg dry matter and 330 mg Cu/kg dry matter enhanced mitochondrial function and activities of complexes I-V at 12, 24 and 36 d of age, but displayed reduced function (P < 0.05) at 48 and 60 d of age except in complex IV (P > 0.05). Mitochondrial hydrogen peroxide (H2O2) production was also increased (P < 0.05) with an increase of copper supplementation in the diet. The results indicate that appropriate dietary copper supplements are sufficient for improving mitochondrial function and activities of the respiratory complexes. Higher concentrations of copper, on the other hand, lead to copper toxicity by affecting certain respiratory complexes. PMID- 26745554 TI - The past, present and future of genomic scans for selection. PMID- 26745556 TI - Chemical constituents from the flowering buds of Bauhinia tomentosa Linn (FBBT). AB - Isolation and characterisation of compounds, 1-(2'-hydroxy-4'-methoxyphenyl)-3 (4"-methoxyphenyl)-2-hydroxypropane-1,3-dione (1), 5-hydroxyflavone (2), 3,5,7,3',4'-pentahydroxyflavone (3), 3,5,7,2',4'-pentahydroxyflavone (4) and 5,7,3',4'-tetrahydroxyflavone-3-O-rhamnoside (5) are reported from the air dried flowering buds of Bauhinia tomentosa Linn. Their structures are determined on the basis of extensive chemical and spectral evidences. Compound (1) is reported for the first time from the plant source. While compounds (2) and (4) are reported for the first time from this genus, compound (2) is reported for the second time from the natural source. PMID- 26745555 TI - Reduction of Caloric Intake Might Override the Prosteatotic Effects of the PNPLA3 p.I148M and TM6SF2 p.E167K Variants in Patients with Fatty Liver: Ultrasound Based Prospective Study. AB - BACKGROUND: The adiponutrin (PNPLA3) p.I148M and transmembrane 6 superfamily member 2 (TM6SF2) p.E167K variants represent risk factors for non-alcoholic fatty liver disease (NAFLD). In this study, we assessed the effects of caloric restriction on liver phenotypes in NAFLD patients in relation to the PNPLA3 and TM6SF2 genotypes. METHODS: We genotyped both variants in 143 individuals with NAFLD (55 females, age 18-74 years) and 180 controls (85 females, age 33-66 years). Liver steatosis was assessed using the ultrasound-based Hamaguchi score. A 4-month dietetic intervention, consisting of restriction of daily caloric intake without changes in physical activity, was performed. RESULTS: Both PNPLA3 (p = 0.002) and TM6SF2 (p = 0.041) variants were associated with NAFLD before intervention. Overall, 88 patients completed the intervention, which led to a significant decrease of steatosis, ALT activities, body mass index, hip and waist circumferences, and waist-hip ratio (all p < 0.0001). Hepatic steatosis and anthropometric traits improved significantly (p < 0.05) in carriers of either PNPLA3 or TM6SF2 risk genotype. The improvement of phenotypic traits, apart from WHR (p = 0.02), was not modified by the presence of PNPLA3 or TM6SF2 variants. CONCLUSIONS: The PNPLA3 and TM6SF2 polymorphisms are associated with NAFLD assessed by the Hamaguchi score. Neither PNPLA3 nor TM6SF2 risk alleles impair the response to dietetic intervention in NAFLD. PMID- 26745558 TI - Insights into the Mechanistic Role of Diphenylphosphine Selenide, Diphenylphosphine, and Primary Amines in the Formation of CdSe Monomers. AB - The formation mechanism of CdSe monomers from the reaction of cadmium oleate (Cd(OA)2) and SePPh2H in the presence of HPPh2 and RNH2 was studied systematically at the M06//B3LYP/6-31++G(d,p),SDD level in 1-octadecene solution. Herein, SePPh2H, HPPh2, and RNH2 act as hydrogen/proton donors with a decreased capacity, leading to the release of oleic acid (RCOOH). The longer the radius of the coordinated atom is, the larger the size of the cyclic transition state is, which lowers the activation strain and the Gibbs free energy of activation for the release of RCOOH. From the resulting RCOOCdSe-PPh2, for the formation of Ph2P CdSe-PPh2 (G), SePPh2H acts as a catalyst, in which the turnover frequency determining transition state (TDTS) is characteristic of the Se-P bond cleavage. For the formation of RHN-CdSe-PPh2 (H), SePPh2H also serves as a catalyst, in which the TDTS is representative of the N-H bond cleavage. For the formation of Ph2PSe-CdSe-NHR (I), HPPh2 behaves as a catalyst, in which the TDTS is typical of the Se-P and N-H bond cleavage. The rate constants increase as kI < kH < kG, which is in good agreement with our previous experimental observations reported. The present study brings insight into the use of additives such as HPPh2 and RNH2 to synthesize colloidal quantum dots. PMID- 26745557 TI - The Protective Role of Anise Oil in Oxidative Stress and Genotoxicity Produced in Favism. AB - The metabolic disease favism is an acute hemolytic anemia. Anise oil was obtained from Pimpinella anisum L. seeds (family Apiaceae). The objective of this study was to establish the protective effect of anise oil in favism disorders. Forty eight male albino rats were divided into six groups: group 1 orally administrated 1 mL distilled water, group 2 orally received 300 mg/kg anise oil, and group 3 orally administrated 100 mg/kg anethole over a seven-day period, group 4 favism induced rats, group 5 orally administrated 300 mg/kg anise oil and group 6 orally administrated 100 mg/kg anethole once a day over a seven-day period prior to favism induction. The result obtained revealed that oral administration of either anise oil or anethole into normal rats over a seven-day period did not induce any change. Following favism induction, hemoglobin, hematocrit, red and white blood cell counts, serum glucose, blood glutathione, glucose-6-phosphate dehydrogenase, total protein, globulin, alanine and aspartate aminotransferases levels were significantly decreased, while serum alkaline phosphatase and bilirubin showed significant increase. Pretreatment with either anise oil or anethole into favism induced rats prevented these changes. Favism also induced deoxyribonucleic acid (DNA) damage and prior treatment of anise oil maintained liver DNA content. These results were supported by histopathological evaluation. In conclusion, anise oil pretreatment into favism-induced rats decreased the favism disorders, and this effect was related to the anethole ingredient of the oil. PMID- 26745559 TI - Hepatitis C Virus Infection Screening Within Community Health Centers. AB - CONTEXT: Approximately 2.7 million people in the United States currently live with chronic hepatitis C virus (HCV) infection, and many are unaware that they have the disease. Community health centers (CHCs) serve as the primary care safety net for more than 22 million patients who are at risk for health inequities and represent an important frontline resource for early screening and treatment for HCV infection. OBJECTIVE: To understand HCV infection screening rates among CHC patients, and to quantify the screening gap by demographic characteristics. METHODS: The authors analyzed a deidentified dataset obtained through electronic health records from a large national network of CHCs. All adults at risk for HCV infection, according to the US Preventive Services Task Force (USPSTF) birth cohort screening guidelines for HCV infection, were considered eligible if they had a patient office visit between January 1, 2013, and December 31, 2013. Data were reviewed to determine the documentation of HCV infection screening from January 1, 2010, to December 31, 2013, and HCV infection screening rates were analyzed by age, race/ethnicity, and sex. RESULTS: Among 60,722 eligible patients, 5033 (8.3%) had an HCV infection screen in accordance with USPSTF birth cohort screening guidelines. Women were less likely to be screened than men in every race/ethnic group, including white Hispanic (9.3% in women vs 5.4% in men), black Hispanic (15.1% in women vs 9.0% in men), white non Hispanic (13.6% in women vs 8.1% in men), black non-Hispanic (14.9% in women vs 8.9% in men), Caribbean Islander or Haitian (6.5% in women vs 3.7% in men), and other races/ethnicities (6.3% in women vs 3.6% in men). CONCLUSION: To the authors' knowledge, this is the first large-scale study among CHCs to assess the screening gap of the USPSTF birth cohort screening guidelines for HCV infection. This study suggests that CHCs should consider opportunities to improve HCV infection screening, thereby contributing to the reduction of health inequities resulting from untreated HCV infection. PMID- 26745560 TI - Primo Vascular System: A Unique Biological System Shifting a Medical Paradigm. AB - The primo vascular system has a specific anatomical and immunohistochemical signature that sets it apart from the arteriovenous and lymphatic systems. With immune and endocrine functions, the primo vascular system has been found to play a large role in biological processes, including tissue regeneration, inflammation, and cancer metastases. Although scientifically confirmed in 2002, the original discovery was made in the early 1960s by Bong-Han Kim, a North Korean scientist. It would take nearly 40 years after that discovery for scientists to revisit Kim's research to confirm the early findings. The presence of primo vessels in and around blood and lymph vessels, nerves, viscera, and fascia, as well as in the brain and spinal cord, reveals a common link that could potentially open novel possibilities of integration with cranial, lymphatic, visceral, and fascial approaches in manual medicine. PMID- 26745561 TI - Gamification and Multimedia for Medical Education: A Landscape Review. AB - BACKGROUND: Medical education is rapidly evolving. Students enter medical school with a high level of technological literacy and an expectation for instructional variety in the curriculum. In response, many medical schools now incorporate technology-enhanced active learning and multimedia education applications. Education games, medical mobile applications, and virtual patient simulations are together termed gamified training platforms. OBJECTIVE: To review available literature for the benefits of using gamified training platforms for medical education (both preclinical and clinical) and training. Also, to identify platforms suitable for these purposes with links to multimedia content. METHODS: Peer-reviewed literature, commercially published media, and grey literature were searched to compile an archive of recently published scientific evaluations of gamified training platforms for medical education. Specific educational games, mobile applications, and virtual simulations useful for preclinical and clinical training were identified and categorized. Available evidence was summarized as it related to potential educational advantages of the identified platforms for medical education. RESULTS: Overall, improved learning outcomes have been demonstrated with virtual patient simulations. Games have the potential to promote learning, increase engagement, allow for real-word application, and enhance collaboration. They can also provide opportunities for risk-free clinical decision making, distance training, learning analytics, and swift feedback. A total of 5 electronic games and 4 mobile applications were identified for preclinical training, and 5 electronic games, 10 mobile applications, and 12 virtual patient simulation tools were identified for clinical training. Nine additional gamified, virtual environment training tools not commercially available were also identified. CONCLUSION: Many published studies suggest possible benefits from using gamified media in medical curriculum. This is a rapidly growing field. More research is required to rigorously evaluate the specific educational benefits of these interventions. This archive of hyperlinked tools can be used as a resource for all levels of medical trainees, providers, and educators. PMID- 26745562 TI - Linking Community Hospital Initiatives With Osteopathic Medical Students' Quality Improvement Training: A Pilot Program. AB - Quality improvement (QI) continues to be a health care challenge, and the literature indicates that osteopathic medical students need more training. To qualify for portions of managed care reimbursement, hospitals are required to meet measures intended to improve quality of care and patient satisfaction, which may be challenging for small community hospitals with limited resources. Because osteopathic medical training is grounded on community hospital experiences, an opportunity exists to align the outcomes needs of hospitals and QI training needs of students. In this pilot program, 3 sponsoring hospitals recruited and mentored 1 osteopathic medical student each through a QI project. A mentor at each hospital identified a project that was important to the hospital's patient care QI goals. This pilot program provided osteopathic medical students with hands-on QI training, created opportunities for interprofessional collaboration, and contributed to hospital initiatives to improve patient outcomes. PMID- 26745564 TI - Management of Acute Isolated Soleal Vein Thrombosis in a Pregnant Patient With an Osteopathic Approach to Evaluation. AB - In pregnant women, the risk of venous thromboembolism increases 4 to 5 fold over that in nonpregnant women. Deep vein thromboses in the calf occur in approximately 6% of cases, with a 20% incidence of propagation, but new imaging methods suggest a higher rate. Nevertheless, the management of isolated soleal vein thrombosis is currently one of the most debated issues in the field of venous thromboembolism, and a clear set of principles for the management of this unique clinical problem remains undefined. The authors present the case of a 37 year-old woman with a history of recurrent spontaneous abortions and cervical insufficiency who presented with a short cervix and acute right isolated soleal vein thrombosis. Long-term anticoagulantion therapy was recommended. Future studies on the risk of isolated soleal vein thrombosis propagation in the setting of pregnancy are required to identify the most effective treatment options for this clinical problem. PMID- 26745563 TI - Effective Patient-Physician Communication Based on Osteopathic Philosophy in Caring for Elderly Patients. AB - The objective of this article is to discuss effective communication strategies between elderly patients and their physicians from the perspective of osteopathic heritage. The patient-physician communication styles of Andrew Taylor Still, MD, DO, and early osteopathic physicians (ie, DOs) may have influenced how DOs today communicate with their patients. Historical literature describes how Still would discuss with his patients the causes of their health problems using analogies and language they would understand, and how, when caring for a patient at the end of life, he empathically provided emotional support for both patients and their families. Early DOs advocated setting clear expectations for patients regarding clinical outcomes and carefully listening to patients to build trust. The Osteopathic Oath, which calls for the DO to view the patient as a friend, may also affect patient-physician communication. Early osteopathic philosophy and culture, as modeled by Dr Still in his approach to elderly patients, should inspire today's DOs in their communication with their elderly patients. PMID- 26745572 TI - Incidental Adenomyomatosis of Gallbladder With Renal Cell Carcinoma. PMID- 26745573 TI - Not on the First Date. PMID- 26745574 TI - Determining the Feasibility of Managing Erectile Dysfunction in Humans With Placental-Derived Stem Cells. AB - INTRODUCTION: Stem cell therapy is thought to improve wound healing and promote vasculogenesis and has also been investigated as a treatment for patients with erectile dysfunction (ED), which is usually caused by a microvascular disease such as diabetes mellitus or hypertension. OBJECTIVE: To determine the feasibility and effects of using placental matrix-derived mesenchymal stem cells (PM-MSCs) in the treatment of patients with ED. METHODS: Participants were recruited from a private practice urology in Coral Springs, Florida. Each patient received an injection of PM-MSCs and was followed up with at 6 weeks, 3 months, and 6 months to assess peak systolic velocity (PSV), end diastolic velocity, stretched penile length, penile width, and erectile function status based on the International Index of Erectile Function questionnaire. RESULTS: Eight patients were injected with PM-MSCs. At the 6-week follow-up, PSV ranged from 25.5 cm/s to 56.5 cm/s; at 3 months, PSV ranged from 32.5 cm/s to 66.7 cm/s. Using unpaired t tests, the increase in PSV was statistically significant (P<.05). At 6 months, PSV ranged from 50.7 cm/s to 73.9 cm/s (P<.01). Changes in measured end diastolic velocity, stretched penile length, penile width, and International Index of Erectile Function scores were not statistically significant. At the 6-week follow up, 2 patients for whom previous oral therapies failed had the ability to sustain erections on their own. At the 3-month follow-up, 1 additional patient was able to achieve erections on his own. CONCLUSION: To our knowledge, this is one of the first human studies to report on the feasibility of using stem cell therapy to treat patients with ED. The results indicate that this treatment may be beneficial, and further investigations with larger sample sizes should be conducted. (ClinicalTrials.gov number NCT02398370). PMID- 26745575 TI - Modern Still Life. PMID- 26745576 TI - Individual Variation in Alcohol Intake Predicts Reinforcement, Motivation, and Compulsive Alcohol Use in Rats. AB - BACKGROUND: Alcohol is one of the most commonly used psychoactive substances. Prolonged alcohol use can result in alcohol use disorder (AUD), characterized by excessive and compulsive alcohol consumption. Importantly, however, the development of AUD only happens in a minority of individuals who consume alcohol. To understand the individual vulnerability for AUD, models that capture both the individual variability in alcohol consumption and the transition from casual to compulsive alcohol use are essential. METHODS: Individual variability in voluntary alcohol intake and the preference for alcohol were assessed under continuous alcohol access (CAA) and intermittent-every-other-day alcohol access (IAA) schedules in the home cage using outbred Lister Hooded rats. Subsequently, the reinforcing properties of alcohol were tested in an operant setting. In subsequent experiments, we performed a quinine adulteration experiment to assess inflexible alcohol consumption and blood alcohol levels (BALs) were assessed after voluntary alcohol consumption. RESULTS: We found marked individual differences in alcohol consumption and preference under both access schedules, whereby subgroups of high- and low-alcohol-drinking rats (HD and LD) could be identified. HD with IAA increased their alcohol intake over days in the first month, whereas LD did not. Moreover, when alcohol access time was extended from 7 to 24 h/d for rats with IAA, alcohol intake profoundly increased in HD with IAA, whereas LD with IAA maintained low levels of alcohol intake. Furthermore, HD earned more alcohol than LD under both fixed ratio and progressive ratio schedules of reinforcement. We further found that HD continued their intake of a quinine-adulterated alcohol solution to a larger extent than LD and HD showed higher BALs after 30 minutes of alcohol consumption. CONCLUSIONS: These profound individual differences in alcohol intake, reinforcement, motivation, and AUD-like behavior provide a promising tool to unravel the neurobehavioral underpinnings of individual vulnerability for AUD. PMID- 26745577 TI - Controllable Cobalt Oxide/Au Hierarchically Nanostructured Electrode for Nonenzymatic Glucose Sensing. AB - By electrodeposition and galvanic replacement reaction, we developed a facile, time-saving, cost-effective, and environmentally friendly, two-step synthesis route to obtain a controllable cobalt oxide/Au hierarchically nanostructured electrode for glucose sensing. The nanomaterials were characterized by transmission electron microscopy, scanning electron microscopy, Raman spectroscopy, energy-dispersive spectrometry, and X-ray photoelectron spectroscopy, meanwhile, the sensing performance was investigated by cyclic voltammetry and amperometric response. The results revealed that this novel electrode exhibited excellent electrocatalytic performance toward glucose oxidation, with a wide double-linear range from 0.2 MUM to 20 mM and a low detection limit of 0.1 MUM based on a signal-to-noise ratio of 3, which was mainly attributed to the ability of loading a small amount of Au with good electron conductivity on the surface of cobalt oxide nanosheets with large active surface area and synergistic electrocatalytic activity of Au and cobalt oxide toward glucose electrooxidation. This facile, sensitive, and selective glucose sensor is also proven to be suitable for the detection of glucose in human serum. PMID- 26745578 TI - Insight into microbial mannosidases: a review. AB - Mannan is the major constituent of hemicelluloses in softwoods. Mannan hydrolyzing enzymes cleave the 1,4-beta-mannopyranosyl linkages of the hetero-1,4 beta-d-mannans to yield mannose. beta-Mannosidases are mandatory for the complete depolymerization of mannan, these are exo-acting enzymes, which acts on non reducing end of mannooligomers and on mannobiose removing mannose residues. Some plants and actinomycetes produce mannosidases but mainly these enzymes are produced by bacteria and fungi. The majority of microorganisms produce these enzymes extracellularly and their activity is in a wide range of pH and temperature. They have found potential applications in bioethanol production, synthesis of alkyl glycosides and, as pharmaceutical agents. Comprehensive information will be helpful for the effective understanding and application of these enzymes. This manuscript is an exhaustive review of microbial mannosidases reported to date. All the aspects such as sources, production conditions, characterization, cloning and biotechnological applications are considered. PMID- 26745592 TI - Mindfulness-based interventions with social workers and the potential for enhanced patient-centered care: A systematic review of the literature. AB - The use of mindfulness-based interventions (MBIs) is well documented in the mental health, medical, and education literature. There is minimal research on the use of mindfulness with social workers. As demonstrated in other professional and helping fields, mindfulness may enhance clinical skills, reduce burnout, and increase job satisfaction among social workers. In the health care field mindfulness appears integral to patient and family relationships and personal resilience. The evolving and expanding role of hospital social workers may lead to increased work stress and greater demands from both the medical system and patients and families. Research with medical providers, such as physicians and nurses, suggests mindfulness may help in reducing stress, enhancing relationships, and fostering the self-reflection required to provide patient centered care. We systematically reviewed the existing literature to begin understanding both mindfulness qualities and practices and the effectiveness of MBIs among social workers as well as the relationship of mindfulness to patient centered care. PMID- 26745591 TI - Modulation of Cav3.2 T-type calcium channel permeability by asparagine-linked glycosylation. AB - Low-voltage-gated T-type calcium channels are expressed throughout the nervous system where they play an essential role in shaping neuronal excitability. Defects in T-type channel expression have been linked to various neuronal disorders including neuropathic pain and epilepsy. Currently, little is known about the cellular mechanisms controlling the expression and function of T-type channels. Asparagine-linked glycosylation has recently emerged as an essential signaling pathway by which the cellular environment can control expression of T type channels. However, the role of N-glycans in the conducting function of T type channels remains elusive. In the present study, we used human Cav3.2 glycosylation-deficient channels to assess the role of N-glycosylation on the gating of the channel. Patch-clamp recordings of gating currents revealed that N glycans attached to hCav3.2 channels have a minimal effect on the functioning of the channel voltage-sensor. In contrast, N-glycosylation on specific asparagine residues may have an essential role in the conducting function of the channel by enhancing the channel permeability and / or the pore opening of the channel. Our data suggest that modulation of N-linked glycosylation of hCav3.2 channels may play an important physiological role, and could also support the alteration of T type currents observed in disease states. PMID- 26745595 TI - Understanding Linkages Among Mixture Models. AB - The methodological literature on mixture modeling has rapidly expanded in the past 15 years, and mixture models are increasingly applied in practice. Nonetheless, this literature has historically been diffuse, with different notations, motivations, and parameterizations making mixture models appear disconnected. This pedagogical review facilitates an integrative understanding of mixture models. First, 5 prototypic mixture models are presented in a unified format with incremental complexity while highlighting their mutual reliance on familiar probability laws, common assumptions, and shared aspects of interpretation. Second, 2 recent extensions-hybrid mixtures and parallel-process mixtures-are discussed. Both relax a key assumption of classic mixture models but do so in different ways. Similarities in construction and interpretation among hybrid mixtures and among parallel-process mixtures are emphasized. Third, the combination of both extensions is motivated and illustrated by means of an example on oppositional defiant and depressive symptoms. By clarifying how existing mixture models relate and can be combined, this article bridges past and current developments and provides a foundation for understanding new developments. PMID- 26745593 TI - LPS-induced CXCR4-dependent migratory properties and a mesenchymal-like phenotype of colorectal cancer cells. AB - Colorectal cancer (CRC) is the most commonly diagnosed cancer worldwide, and over 50% of patients will develop hepatic metastasis during the course of their disease. CXCR4 and its ligand, stromal cell-derived factor 1alpha (SDF 1alpha)/chemokine (C-X-C motif) ligand 12 (CXCL12) have been revealed as regulatory molecules involved in the spreading and progression of a variety of tumors. Here we have shown that lipopolysaccharides (LPS) promoted the migratory capacity of colon cancer cells in vivo and in vitro, which correlated with the activation of SDF-1alpha/CXCR4 axis and epithelial-mesenchymal transition (EMT) occurrence. Additionally, we found that LPS-induced CXCR4 expression and EMT through NF-kappaB signaling pathway activation. And inhibition of NF-kappaB pathway, which recovered the epithelial phenotype and attenuated CXCR4 expression, inhibited cell migratory capacity. Clinically, high levels of CXCR4 always correlated with metastasis and poor prognosis of CRC patients. In conclusion, LPS participate in the whole process of hepatic metastasis of CRC, not only causing liver damage resulting in the production of SDF-1alpha, but also enhancing the invasive potential of CRC cells by promoting CXCR4 expression and EMT occurrence, which would contribute to the enhancement of cell migration and invasion. PMID- 26745594 TI - Bicalutamide causes heart failure in an elderly patient with prostate cancer. AB - OBJECTIVE: To examine the molecular mechanisms by which bicalutamide may cause heart failure in an elderly patient. METHODS: Retrospective analysis of bicalutamide as a cause of heart failure in Mr FD, an 82 years old with prostate cancer. RESULTS: Following months of therapy, Mr FD was diagnosed with heart failure. Bicalutamide has been ceased, but 21 months later, Mr FD was still on heart failure medications, and passed away months later probably due to complications of prostate cancer. The Naranjo ADR probability scale gave this case a score of seven. CONCLUSION: The Naranjo scale strongly suggests that bicalutamide was the cause of heart failure. Apoptosis seems to be one of the mechanisms mediating heart failure, with the involvement of many molecular actors, such as ET-1, Bcl-2 and cyclin-A. The author believes this to be the first analysis describing bicalutamide as a probable cause of heart failure. PMID- 26745597 TI - Flexible Mediation Analysis in the Presence of Nonlinear Relations: Beyond the Mediation Formula. AB - In the social sciences, mediation analysis has typically been formulated in the context of linear models using the Baron & Kenny (1986) approach. Extensions to nonlinear models have been considered but lack formal justification. By placing mediation analysis within the counterfactual framework of causal inference one can define causal mediation effects in a way that is not tied to a specific statistical model and identify them under certain no unmeasured confounding assumptions. Corresponding estimation procedures using parametric or nonparametric models, based on the so-called mediation formula, have recently been proposed in the psychological literature and made accessible through the R package mediation. A number of limitations of the latter approach are discussed and a more flexible approach using natural effects models is proposed as an alternative. The latter builds on the same counterfactual framework but enables interpretable and parsimonious modeling of direct and mediated effects and facilitates tests of hypotheses that would otherwise be difficult or impossible to test. We illustrate the approach in a study of individuals who ended a romantic relationship and explore whether the effect of attachment anxiety during the relationship on unwanted pursuit behavior after the breakup is mediated by negative affect during the breakup. PMID- 26745596 TI - Contextualized Personality Questionnaires: A Case for Copulas in Structural Equation Models for Categorical Data. AB - For structural equation models (SEMs) with categorical data, correlated measurement residuals are not easily implemented. The problem lies mainly in the absence of a categorical analogue to the multivariate normal distribution and the absence of closed form formulas in SEMs for categorical data. We present a novel technique to handle measurement residuals that keeps the attractive SEM mainframe intact yet adds flexibility in dependence modeling without excessive computational burden. The technique is based upon the concept of copula functions and is introduced with a data set of ordinal responses originating from a contextualized personality study on aggression. Focus is on models arising in a multitrait-multimethod context, where the flexibility in dependence structures allows for method effects that can vary across the latent trait dimension. The empirical application illustrates that ignoring design-implied correlated measurement residuals can potentially influence study results and conclusions in both a quantitative as well as a qualitative way. Model parameter estimates can be biased, but more important, model inferences can be heavily distorted. PMID- 26745598 TI - ANCOVA Versus CHANGE From Baseline in Nonrandomized Studies: The Difference. AB - The pretest-posttest control group design can be analyzed with the posttest as dependent variable and the pretest as covariate (ANCOVA) or with the difference between posttest and pretest as dependent variable (CHANGE). These 2 methods can give contradictory results if groups differ at pretest, a phenomenon that is known as Lord's paradox. Literature claims that ANCOVA is preferable if treatment assignment is based on randomization or on the pretest and questionable for preexisting groups. Some literature suggests that Lord's paradox has to do with measurement error in the pretest. This article shows two new things: First, the claims are confirmed by proving the mathematical equivalence of ANCOVA to a repeated measures model without group effect at pretest. Second, correction for measurement error in the pretest is shown to lead back to ANCOVA or to CHANGE, depending on the assumed absence or presence of a true group difference at pretest. These two new theoretical results are illustrated with multilevel (mixed) regression and structural equation modeling of data from two studies. PMID- 26745599 TI - The Effect of the Raters' Marginal Distributions on Their Matched Agreement: A Rescaling Framework for Interpreting Kappa. AB - Cohen's kappa measures the improvement in classification above chance level and it is the most popular measure of interjudge agreement. Yet, there is considerable confusion about its interpretation. Specifically, researchers often ignore the fact that the observed level of matched agreement is bounded from above and below and the bounds are a function of the particular marginal distributions of the table. We propose that these bounds should be used to rescale the components of kappa (observed and expected agreement). Rescaling kappa in this manner results in kappa', a measure that was originally proposed by Cohen (1960) and was largely ignored in both research and practice. This measure provides a common scale for agreement measures of tables with different marginal distributions. It reaches the maximal value of 1 when the judges show the highest level of agreement possible, given their marginal disagreements. We conclude that kappa' should be used to measure the level of matched agreement contingent on a particular set of marginal distributions. The article provides a framework and a set of guidelines that facilitate comparisons between various types of agreement tables. We illustrate our points with simulations and real data from two studies one involving judges' ratings of baseball players and one involving ratings of essays in high-stakes tests. PMID- 26745601 TI - Serum CA125 is a novel predictive marker for pancreatic cancer metastasis and correlates with the metastasis-associated burden. AB - This study evaluated potential of serum tumor markers to predict the incidence and intensity of pancreatic cancer metastasis as well as patient survival. Retrospective records from 905 patients and prospective data from 142 patients were collected from two high-volume institutions. The levels of eight serum tumor markers (CA19-9, CEA, CA242, CA72-4, CA50, CA125, CA153, and AFP) commonly used in gastroenterological cancer were analyzed in all stages of pancreatic cancer. Serum CA125 levels were the most strongly associated with pancreatic cancer metastasis and were higher in patients with metastatic disease than those without. CA125 levels increased with increasing metastasis to lymph nodes and distant organs, especially the liver. High baseline CA125 levels predicted early distant metastasis after pancreatectomy and were associated with the presence of occult metastasis before surgery. An optimal CA125 cut-off value of 18.4 U/mL was identified; patients with baseline CA125 levels of 18.4 U/mL or higher had poor surgical outcomes. In addition, high serum CA125 levels coincided with the expression of a metastasis-associated gene signature and with alterations in "driver" gene expression involved in pancreatic cancer metastasis. CA125 may therefore be a promising, noninvasive, metastasis-associated biomarker for monitoring pancreatic cancer prognosis. PMID- 26745604 TI - Evaluation of allergenic potential for rice seed protein components utilizing a rice proteome database and an allergen database in combination with IgE-binding of recombinant proteins. AB - Among 131 rice endosperm proteins previously identified by MS-based proteomics, most of the proteins showed low or almost no sequence similarity to known allergens in databases, whereas nine proteins did it significantly. The sequence of two proteins showed high overall identity with Hsp70-like hazel tree pollen allergen (Cor a 10) and barley alpha-amylase (Hor v 16), respectively, whereas the others showed low identity (28-58%) with lemon germin-like protein (Cit l 1), corn zein (Zea m 50 K), wheat chitinase-like xylanase inhibitor (Tri a XI), and kinase-like pollen allergen of Russian thistle (Sal k 1). Immuno-dot blot analysis showed that recombinant proteins for these rice seed homologs were positive in the IgE-binding, but not necessarily similarity dependent, from some allergic patients. These results suggest that utilization of proteome and sequence databases in combination with IgE-binding analysis was effective to screen and evaluate allergenic potential of rice seed protein components. PMID- 26745603 TI - MiR-let-7a inhibits cell proliferation, migration, and invasion by down regulating PKM2 in gastric cancer. AB - In contrast to normal differentiated cells that depend on aerobicoxidation for energy production, cancer cells use aerobic glycolysis as the main source (Warburg's effect). The M2 splice isoform of pyruvate kinase (PKM2) is the key regulator for the aerobic glycolysis, high expression of PKM2 contributes to the aerobic glycolysis, promotes the growth of tumors. In the present study, we found that PKM2 was highly expressed in gastric cancer (GC) tissues and had a strongly inverse correlation with the expression of microRNA-let-7a (miR-let-7a). Furthermore, we found that the overexpression of miR-let-7a markedly suppressed the proliferation, migration, and invasion of GC cells by down-regulating the expression of PKM2. MicroRNAs (miRNAs) are important regulators play key roles in tumorigenesis and tumor progression. Although previous reports showed that let-7 family members act as tumor suppressors in many cancers. The specific regulatory mechanism of miR-let-7a to PKM2 in gastric cancer is still unclear. In this study, we revealed that miR-let-7a function as the antitumor and gene regulatory effects of PKM2 in GC cells. PMID- 26745605 TI - Quality analysis, classification, and authentication of liquid foods by near infrared spectroscopy: A review of recent research developments. AB - Nowadays, near-infrared spectroscopy (NIR) has become one of the most efficient and advanced techniques for analysis of food products. Many relevant researches have been conducted in this regard. However, no reviews about the applications of NIR for liquid food analysis are reported. Therefore, this review summarizes the recent research developments of NIR technology in the field of liquid foods, focusing on the detection of quality attributes of various liquid foods, including alcoholic beverages (red wines, rice wines, and beer), nonalcoholic beverages (juice, fruit vinegars, coffee beverages, and cola beverages), dairy products (milk and yogurt), and oils (vegetable, camellia, peanut, and virgin olive oils and frying oil). In addition, the classification and authentication detection of adulteration are also covered. It is hoped that the current paper can serve as a reference source for the future liquid food analysis by NIR techniques. PMID- 26745606 TI - Psychological adaptation to spousal bereavement in old age: The role of trait resilience, marital history, and context of death. AB - This research examined the effect of marital status and gender on various indicators of psychological adaptation, namely depressive symptoms, loneliness, and life satisfaction. It further explores the role of trait resilience, marital history, and context of death for predicting these outcomes in bereaved individuals. Four hundred eighty widowed individuals aged between 60 and 89 were compared with 759 married peers. Main effects were found for marital status and gender for all indicators. The regression analyses illustrate the multifaceted structure of psychological adaptation. Trait resilience is a key factor in adapting to spousal bereavement, whereas marital history and the context are secondary. PMID- 26745602 TI - HDAC3 mediates smoking-induced pancreatic cancer. AB - Smoking is a major risk factor for developing pancreatic adenocarcinoma (PDAC); however, little is known about the mechanisms involved. Here we employed a genetic animal model of early stages of PDAC that overexpresses oncogenic Kras in the pancreas to investigate the mechanisms of smoking-induced promotion of the disease in vivo. We confirmed the regulation of the interactions between the tumor microenvironment cells using in vitro cellular systems. Aerial exposure to cigarette smoke stimulated development of pancreatic intraepithelial neaoplasia (PanIN) lesions associated with a tumor microenvironment-containing features of human PDAC including fibrosis, activated stellate cells, M2-macrophages and markers of epithelial-mesenchymal transition (EMT). The pro-cancer effects of smoking were prevented by Histone Deacetylase HDAC I/II inhibitor Saha. Smoking decreased histone acetylation associated with recruitment of and phenotypic changes in macrophages; which in turn, stimulated survival and induction of EMT of the pre-cancer and cancer cells. The interaction between the cancer cells and macrophages is mediated by IL-6 produced under the regulation of HDAC3 translocation to the nucleus in the cancer cells. Pharmacological and molecular inhibitions of HDAC3 decreased IL-6 levels in cancer cells. IL-6 stimulated the macrophage phenotype change through regulation of the IL-4 receptor level of the macrophage. This study demonstrates a novel pathway of interaction between cancer cells and tumor promoting macrophages involving HDAC3 and IL-6. It further demonstrates that targeting HDAC3 prevents progression of the disease and could provide a strategy for treating the disease considering that the HDAC inhibitor we used is FDA approved for a different disease. PMID- 26745608 TI - Rashba magnetic resonance in 2D electron gas induced by microwave electric field. AB - The electric component of microwave radiation acting on the electrons causes an alternating current which induces electron spin resonance. The oscillating part of kinetic energy of electrons is converted into Zeeman energy via Rashba magnetic field, according to oscillating electron current. Description of this energy conversion is presented and its negative contribution to the resonance signal is explained. PMID- 26745607 TI - Using Videoconferencing to Deliver Individual Therapy and Pediatric Psychology Interventions with Children and Adolescents. AB - BACKGROUND: Because of the widening access gap between need for individual and pediatric psychology services and child specialist availability, secure videoconferencing options are more needed than ever to address access challenges across underserved settings. METHODS: The authors summarize real-time videoconferencing evidence to date across individual therapy with children and pediatric psychology interventions using videoconferencing. The authors summarize emerging guidelines that inform best practices for individual child therapy over videoconferencing. RESULTS: The authors present three case examples to illustrate best practices. The first behavioral pediatrics case summarizes evidence-based approaches in treating a rural young adolescent with attention deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and hearing impairment. The second pediatric psychology case describes similarities and difference between on-site and videoconferencing services in treating a rural child with toileting concerns. The third adolescent case describes treatment of an urban honors student with depression. CONCLUSIONS: Videoconferencing is an effective approach to improving access to individual and pediatric psychology interventions for children and adolescents. Videoconferencing approaches are well accepted by families and show promise for disseminating evidence-based treatments to underserved communities. PMID- 26745612 TI - Identification of Individuals With Undiagnosed Diabetes and Pre-Diabetes in a Danish Cohort Attending Dental Treatment. AB - BACKGROUND: It is estimated that 3.6% and 13.6% of the Danish population have undiagnosed type 2 diabetes mellitus and prediabetes, respectively. Periodontitis is an established complication associated with diabetes (DM). Identification of individuals with DM and prediabetes is important to reduce DM-related complications, including periodontitis. The objective of this study is to identify individuals with undiagnosed DM or prediabetes among patients attending a dental setting for diagnosis and treatment. METHODS: A total of 291 adults with no history of DM was included in the study (periodontitis patients: n = 245; non periodontitis control individuals: n = 46). Participants answered questionnaires concerning general health, including family history of DM. Body mass index, waist circumference, fat percentage, and glycated hemoglobin (HbA1c) level were recorded chairside. Periodontal examination was performed and radiographic bone level measured. All individuals were informed about their HbA1c test result and were referred to their physician if HbA1c level was above guideline levels for DM or prediabetes according to the American Diabetes Association. RESULTS: Nine (3.1%) and 79 (27.1%) individuals were identified with HbA1c levels corresponding to guideline levels for DM and prediabetes, respectively. Higher proportions of patients with undiagnosed DM and prediabetes were observed in the periodontitis group (32.7%) than in the control group (17.4%) (P = 0.054). Identification of DM and prediabetes based on a diagnosis of periodontitis yielded a sensitivity of 0.91 and a specificity of 0.19. CONCLUSIONS: This study confirms that individuals with undiagnosed DM and prediabetes can be identified in the dental office by chairside recordings of HbA1c levels. Routine measurement of HbA1c levels in dental offices, eventually restricted to those at risk, may help identification of individuals with DM and prediabetes at early stages of disease, which may prevent future complications. PMID- 26745609 TI - Risk of Cardiovascular Disease from Cumulative Cigarette Use and the Impact of Smoking Intensity. AB - BACKGROUND: Relative risks (RRs) for cardiovascular disease (CVD) by smoking rate exhibit a concave pattern, with RRs in low rate smokers exceeding a linear extrapolation from higher rate smokers. However, cigarettes/day does not by itself fully characterize smoking-related risks. A reexamination of the concave pattern using a comprehensive representation of smoking may enhance insights. METHODS: Data were from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective cohort enrolled in four areas of the US in 1987-1989. Follow-up was through 2008. Analyses included 14,233 participants, 245,915 person-years, and 3,411 CVD events. RESULTS: The concave RRs with cigarettes/day were consistent with cigarettes/day modifying a linear RR association of pack-years with CVD (i.e., strength of the pack-years association depended on cigarettes/day, indicating that the manner of pack-years accrual impacted risk). Smoking fewer cigarettes/day for longer duration was more deleterious than smoking more cigarettes/day for shorter duration (P < 0.01). For 50 pack-years (365,000 cigarettes), estimated RRs of CVD were 2.1 for accrual at 20 cigarettes/day and 1.6 for accrual at 50 cigarettes/day. Years since smoking cessation did not alter the diminishing strength of association with increasing cigarettes/day. Analyses that accounted for competing risks did not affect findings. CONCLUSION: Pack years remained the primary determinant of smoking-related CVD risk; however, accrual influenced RRs. For equal pack-years, smoking fewer cigarettes/day for longer duration was more deleterious than smoking more cigarettes/day for shorter duration. This observation provides clues to better understanding the biological mechanisms, and reinforces the importance of cessation rather than smoking less to reduce CVD risk. PMID- 26745615 TI - Inflatable Penile Prosthesis Washout. PMID- 26745610 TI - Prenatal Phthalate Exposures and Body Mass Index Among 4- to 7-Year-old Children: A Pooled Analysis. AB - BACKGROUND: Phthalates are hypothesized to cause obesity, but few studies have assessed whether prenatal phthalate exposures are related to childhood body mass index (BMI). METHODS: We included 707 children from three prospective cohort studies enrolled in the US between 1998 and 2006 who had maternal urinary phthalate metabolite concentrations measured during pregnancy, and measures of weight and height at ages 4 to 7 years. We calculated age- and sex-standardized BMI z scores and classified children with BMI percentiles >=85 as overweight/obese. We used mixed effects regression models to estimate associations between a 1 standard deviation increase in natural log phthalate metabolite concentrations and BMI z scores and overweight/obesity. We estimated associations in multiple metabolite models adjusted for confounders, and evaluated heterogeneity of associations by child's sex, race/ethnicity, and cohort. RESULTS: Mono-3-carboxypropyl phthalate concentrations were positively associated with overweight/obese status in children (odds ratio [95% credible interval] = 2.1 [1.2, 4.0]) but not with BMI z scores (beta = -0.02 [-0.15, 0.11]). We did not observe evidence of obesogenic effects for other metabolites. However, monoethyl phthalate and summed di-(2-ethylhexyl) phthalate metabolites (?DEHP) concentrations were inversely associated with BMI z scores among girls (monoethyl phthalate beta = -0.14 [-0.28, 0.00]; ?DEHP beta = -0.12 [-0.27, 0.02]). CONCLUSIONS: Maternal urinary mono-3-carboxypropyl phthalate, a nonspecific metabolite of several phthalates, was positively associated with childhood overweight/obesity. Metabolites of diethyl phthalate and DEHP were associated with lower BMI in girls but not in boys, suggesting that prenatal exposures may have sexually dimorphic effects on physical development. PMID- 26745614 TI - Prospective Clinical and Radiographic Study of Alveolar Ridge Preservation Combining Freeze-Dried Bone Allograft With Two Xenogeneic Collagen Matrices. AB - BACKGROUND: Tooth extractions are followed by significant dimensional changes in the alveolar crest that may preclude implant placement. This randomized, controlled, prospective compares the preservation of soft and hard tissue dimensional changes after alveolar ridge preservation (ARP) using two membranes consisting of collagen matrix (CM) or extracellular matrix (ECM) as barriers over freeze-dried bone allograft (FDBA). METHODS: Standardized clinical and radiographic measurements of soft and hard tissues were recorded by means of a stent before and 4 months after ARP. The surgery entailed sulcular incisions with minimal flap elevation and repositioning without advancement. RESULTS: Of 11 patients in the CM group and 12 in the ECM group who completed the study, gingival thickness (GT) increased from 0.1 to 0.2 mm for both groups along with a 0.5-mm decrease in the width of keratinized tissue after healing. Reductions in ridge width were most pronounced on the coronal aspect, 1.8 mm for CM and 2.0 mm for ECM, whereas vertical reduction was most pronounced on the buccal aspect, 0.7 to 1.0 mm. Differences between groups were not statistically significant. However, significant correlation for changes in GT (P = 0.001) and crestal bone width (P = 0.002) with preoperative buccal plate thickness (BPT) was observed. CONCLUSIONS: Both xenogeneic collagen matrices combined with FDBA were effective in maintaining soft tissues and minimizing ridge resorption in all dimensions after ARP. BPT was an important determinant for amount of change in crestal GT and ridge width. PMID- 26745613 TI - Combination of Controlled Release Platelet-Rich Plasma Alginate Beads and Bone Morphogenetic Protein-2 Genetically Modified Mesenchymal Stem Cells for Bone Regeneration. AB - BACKGROUND: Platelet-rich plasma (PRP) consists of platelet-derived growth factor and transforming growth factor-beta that increase proliferation of mesenchymal stem cells (MSCs), whereas bone morphogenetic protein-2 (BMP2) promotes osteogenic differentiation of MSCs. However, the high degradation rate of fibrin leads to the dissociation of cytokines even before the process of bone regeneration begins. To the best of the authors' knowledge, this is the first study to examine the combined effect of sustained release of PRP from alginate beads on BMP2-modified MSC osteogenic differentiation in vitro and sustained release of PRP alone on a fracture defect model ex vivo as well as its effect on calvarial suture closure. METHODS: After optimizing the alginate concentration for microspheres, the combined osteogenic and mineralization effect of PRP and BMP2 on MSCs was studied. Self-setting alginate hydrogel carrying PRP was tested on a femur defect model ex vivo. The effect of PRP at day 15 on the closure of the embryonic mouse calvaria sutures ex vivo was also studied. RESULTS: Increase of PRP concentration promoted proliferation of MSCs, and 2.5% to 10% of PRP gradually increased alkaline phosphatase (ALP) activity in the cells in a dose dependent manner. Sustained release of PRP and BMP2 demonstrated significantly higher ALP and mineralization activity (P <0.05). Radiographs of alginate hydrogel with PRP-treated bone demonstrated nearly complete healing of the fracture, and histologic sections of the embryonic calvaria revealed that PRP leads to suture fusion. CONCLUSION: Sustained release of PRP along with BMP2 modified MSCs can significantly promote bone regeneration. PMID- 26745617 TI - Erectile Dysfunction, Boredom, and Hypersexuality among Coupled Men from Two European Countries. AB - INTRODUCTION: Much of the research on the association between erectile dysfunction (ED) and possible clinical relevant hypersexuality up to now has been only descriptive in nature. AIM: The present study aimed to explore the relationships among hypersexuality, ED, and sexual boredom in a sample of coupled community men. METHODS: An Internet-based survey was conducted in two European countries. The sample included 911 Croatian and 210 German coupled men. The survey comprised the Hypersexual Disorder Screening Inventory, the International Index of Erectile Function and the Sexual Boredom Scale. Poisson regression analysis was used to examine how ED, solitary sexual activities and sexual boredom were associated with hypersexuality. RESULTS: Among Croatian and German men, hypersexuality was significantly correlated with proneness to sexual boredom and more problems with erectile function. CONCLUSIONS: In some men, hypersexual behavior may serve as a coping mechanism for sexual fantasy poverty-associated boredom. In addition, ED within an intimate relationship can accompany this simultaneously. PMID- 26745616 TI - Efficacy and Safety of Flibanserin in Women with Hypoactive Sexual Desire Disorder: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: Flibanserin, is a postsynaptic agonist of serotonin receptor 1A and an antagonist of serotonin receptor 2A, has been shown to increase sexual desire and reduce distress in women with hypoactive sexual desire disorder (HSDD). AIM: We carried out a systematic review and meta-analysis to assess the efficacy and safety of the drug in women with HSDD. METHODS: A literature review was performed to identify all published randomized double-blind, placebo-controlled trials of flibanserin for the treatment of HSDD. The search included the following databases: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. MAIN OUTCOME MEASURES: Four publications involving a total of 3,414 patients were used in the analysis, including four randomized controlled trials that compared flibanserin with placebo. RESULTS: For the comparison of flibanserin with placebo, primary efficacy endpoints: satisfying sexual events (the standardized mean difference [SMD] = 0.59, 95% confidence interval [CI] = 0.37-0.80, P < 0.00001); sexual desire score (the SMD = 1.91, 95% CI = 0.21 to 3.60, P = 0.03) and Female Sexual Function Index (FSFI) desire domain score (the SMD = 0.32, 95% CI = 0.19-0.46, P < 0.00001) and key secondary efficacy endpoints: FSFI total score, Female Sexual Distress Scale-Revised (FSDS-R) total score, FSDS-R Item 13 score, Patient's Global Impression of Improvement score and Patient Benefit Evaluation indicated that flibanserin was more effective than the placebo. Safety assessments included the proportion of women who experienced an adverse event (odds ratio = 1.54, 95% CI = .34 to 1.76, P < 0.00001), nervous system disorders and fatigue indicated that flibanserin was well tolerated. CONCLUSIONS: This meta-analysis indicates that flibanserin to be an effective and safe treatment for HSDD in women. PMID- 26745618 TI - Active and Passive Components of Pelvic Floor Muscle Tone in Women with Provoked Vestibulodynia: A Perspective Based on a Review of the Literature. AB - AIM: Pelvic floor muscle (PFM) dysfunctions, especially elevated tone or tension, are suggested to play an important role in the pathophysiology of provoked vestibulodynia (PVD). However, the involvement of the PFMs remains misunderstood as the assessment of muscle tone is complex and requires a thorough understanding of muscle physiology in relation to the characteristics and limitations of current PFM assessment tools. The aim of this review was to describe the structures and mechanisms involved in muscle tone in normally innervated muscle, and to discuss and relate these concepts to the PFM findings in women with PVD. METHODS: A narrative overview of the literature retrieved from searches of electronic databases and hand searches. RESULTS: Muscle tone in a normally innervated muscle comprises both active (contractile) and passive (viscoelastic) components. Current methods for evaluating PFM tone such as digital palpation, ultrasound imaging, pressure perineometry, dynamometry, and electromyography may evaluate different components. Research findings suggestive of PFM hypertonicity in women with PVD include elevated general PFM tone, changes in viscoelastic properties, and at least in some women, abnormal increases in electrogenic activity. CONCLUSION: There is a growing body of evidence to support the involvement of PFM hypertonicity in the pathophysiology of PVD. Limitations of the instruments as well as their properties should be considered when evaluating PFM tone in order to obtain better insight into which component of PFM tone is assessed. Future research is required for further investigating the underlying mechanisms of PFM hypertonicity, and studying the specific effects of physiotherapeutic interventions on PFM tone in women with PVD. PMID- 26745619 TI - Risk factors for ventilator associated pneumonia due to carbapenemase-producing Klebsiella pneumoniae in mechanically ventilated patients with tracheal and rectal colonization. AB - BACKGROUND: The aim of this study was to identify the risk factors for ventilator associated pneumonia (VAP) due to Klebsiella pneumoniae carbapenemase-producing K (KPC-Kp) development in ICU patients with documented rectal and tracheal colonization. METHODS: We performed a retrospective, matched case-control study in a medical-surgical ICU (January 2011-December 2013) comparing 30 patients who developed KPC-Kp VAP during the ICU stay to 60 colonized patients not developing KPC-Kp VAP. Analysed risk factors included: age, sex, SAPS II and SOFA scores, comorbidities, type and length of antibiotic therapy, previous non KPC-Kp infections, time between admission to rectal and tracheal colonization. RESULTS: Several risk factors were more frequent among patients who developed KPC-Kp pneumonia versus matched colonized controls: previous infection not related to KPC-Kp (P<0.001), duration of previous antibiotic therapy before (P<0.001) and after (P=0.002) KPC-Kp colonization. Amoxicillin/clavulanic acid prophylaxis was administered in 17% of VAP patients versus 73% of patients not developing VAP (P<0.001). Multivariate conditional logistic regression analysis identified several significant independent risk factors favoring KPC-Kp VAP in patients colonized at multiple sites: previous non KPC-Kp infections (OR: 2.046), duration of previous antibiotic therapy before (OR: 1.309) and after (OR: 1.122) KPC-Kp colonization; antibiotic therapy with amoxicillin/clavulanic acid prophylaxis (<48 hours) was associated with reduced risk of KPC-Kp VAP (OR: 0.987). CONCLUSIONS: In rectal and tracheal KPC-Kp colonized patients, prolonged antibiotic therapy administered for non KPC-Kp infection predisposes patients to subsequent KPC-Kp VAP. Short prophylaxis of early pneumonia with amoxicillin/clavulanic acid, reducing the need for subsequent antibiotic use, may be associated with reduced risk for KPC-Kp VAP. PMID- 26745622 TI - Mindfulness-based therapy and behavioral activation: A randomized controlled trial with depressed college students. AB - Major Depressive Disorder (MDD) manifests in 20-30% of college students, with increased incidence in recent decades. Very limited research has assessed the efficacy of evidence-based interventions for MDD in college students. Mindfulness Based Therapy (MBT) and Behavioral Activation (BA) are two interventions with significant potential to meet demands of college counseling clinics and effectively treat college students with MDD. This study utilized a randomized controlled research design (n = 50) to examine the efficacy of four-sessions of abbreviated MBT and BA relative to a wait-list control condition with depressed college students. Intent-to-treat data analyses on depression outcome measures suggested both treatments were superior to the control group. There were significant pre-post treatment improvements across measures of depression, rumination, stress, and mindfulness, gains largely maintained at 1-month follow up. Neither active treatment effectively reduced somatic anxiety. Both treatments generally had moderate-strong effect sizes relative to the control group, and based on depression response and remission criteria, 56-79% of patients exhibited clinically significant improvement. Based on reliable change indices, 75-85% experienced clinically significant reductions in depression. There was strong therapist competence and adherence to treatment protocols and high patient satisfaction with both interventions. Study limitations and implications for the assessment and treatment of depressed college students are discussed. PMID- 26745623 TI - High Coke-Resistance Pt/Mg1-xNixO Catalyst for Dry Reforming of Methane. AB - A highly active and stable nano structured Pt/Mg1-xNixO catalysts was developed by a simple co-precipitation method. The obtained Pt/Mg1-xNixO catalyst exhibited cubic structure nanocatalyst with a size of 50-80 nm and realized CH4 and CO2 conversions as high as 98% at 900 degrees C with excellent stability in the dry reforming of methane. The characterization of catalyst was performed using various kinds of analytical techniques including XRD, BET, XRF, TPR-H2, TGA, TEM, FESEM, FT-IR, and XPS analyses. Characterization of spent catalyst further confirms that Pt/Mg1-xNixO catalyst has high coke-resistance for dry reforming. Thus, the catalyst demonstrated in this study, offers a promising catalyst for resolving the dilemma between dispersion and reducibility of supported metal, as well as activity and stability during high temperature reactions. PMID- 26745621 TI - For whom the bell tolls: Neurocognitive individual differences in the acute stress-reduction effects of an attention bias modification game for anxiety. AB - The efficacy of attention bias modification training (ABMT) for anxiety is debated, in part because individual differences in task engagement and pre training threat bias impact training efficacy. In the present study, an engaging, gamified ABMT mobile application, or "app," was utilized in 42 (21 females) trait anxious adults. EEG was recorded during pre- and post-training threat bias assessment to generate scalp-recorded event-related potentials (ERPs) reflecting neurocognitive responses to threat. Following app play (ABMT versus placebo), subjective anxiety and stress responses (observed and self-reported) were measured. ABMT, versus placebo, resulted in improved behavioral performance during the stress task for females, and in potentiation of the N2 ERP to threat for males, suggesting increased attention control. Training groups did not differ in self-reported anxiety. ABMT also resulted in improved performance during the stress task among those evidencing specific pre-training ERP responses: decreased P1, suggesting less attention allocation, but potentiated N170, suggesting enhanced attention selection and discrimination. Differences in behavioral threat bias did not moderate training effects. Results suggest that efficient allocation of attention to threat combined with enhanced discrimination between threat and non-threat may facilitate stress-reduction effects of ABMT. Targeting neurocognitive responses to threat to personalize ABMT and develop more effective methods of treatment delivery, such as gamification, are discussed. PMID- 26745624 TI - Refeeding Syndrome: An Important Complication Following Obesity Surgery. AB - BACKGROUND: Refeeding syndrome (RFS) is an important and well-known complication in malnourished patients, but the incidence of RFS after obesity surgery is unknown and the awareness of RFS in obese patients as a postsurgical complication must be raised. We present a case of RFS subsequent to biliopancreatic diversion in a morbidly obese patient. CASE REPORT: A 48-year-old female patient with a BMI of 41.5 kg/m2 was transferred to our hospital due to Wernicke's Encephalopathy in a global malabsorptive syndrome after biliopancreatic diversion. Parenteral nutrition, vitamin supplementation and high-dosed intravenous thiamine supplementation were initiated. After 14 days, the patient started to develop acute respiratory failure, and neurological functions were impaired. Blood values showed significant electrolyte disturbances. RFS was diagnosed and managed according to the NICE guidelines. After 14 days, phosphate levels had returned to normal range, and neurological symptoms were improved. CONCLUSION: Extreme weight loss following obesity surgery has been shown to be associated with undernutrition. These patients are at high risk for evolving RFS, even though they may still be obese. Awareness of RFS as a postsurgical complication, the identification of patients at risk as well as prevention and correct management should be routinely performed at every bariatric center. PMID- 26745625 TI - The Efficacy of Continued Sorafenib Treatment after Radiologic Confirmation of Progressive Disease in Patients with Advanced Hepatocellular Carcinoma. AB - BACKGROUND: Whether radiologically detected progressive disease (PD) is an accurate metric for discontinuing sorafenib treatment in patients with hepatocellular carcinoma (HCC) is unclear. We investigated the efficacy of sorafenib treatment after radiologic confirmation of PD in patients with advanced HCC. METHODS: We retrospectively analyzed HCC patients treated with sorafenib at Kyushu Medical Center. Six of the 92 patients with radiologically confirmed PD were excluded because they were classified as Child-Pugh C or had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) >=3; 86 patients were ultimately enrolled. RESULTS: Among the 86 patients, 47 continued sorafenib treatment after radiologic confirmation of PD (the continuous group), whereas 39 did not (the discontinuous group). The median survival time (MST) in the continuous group after confirmation was 12.9 months compared with 4.5 months in the discontinuous group (p <0.01). The time to progression in the continuous group after confirmation was 2.6 months compared with 1.4 months in the discontinuous group (p <0.01); it was 4.2 months and 2.1 months in patients who had received sorafenib >=4 months and <4 months, respectively, before confirmation (p = 0.03). In these subgroups, the post-PD MST was 16.7 months and 9.6 months, respectively (p < 0.01). Independent predictors of overall survival after radiologic detection of PD were (hazard ratio, confidence interval): ECOG PS <2 (0.290, 0.107-0.880), Barcelona Clinical Liver Cancer stage B (0.146, 0.047 0.457), serum alpha-fetoprotein level >=400 ng/mL (2.801, 1.355-5.691), and post PD sorafenib administration (0.279, 0.150-0.510). CONCLUSION: Continuing sorafenib treatment after radiologic confirmation of PD increased survival in patients with advanced HCC. Therefore, radiologically detected PD is not a metric for discontinuation of sorafenib treatment in such patients. PMID- 26745626 TI - A 36,000-Year-Old Volcanic Eruption Depicted in the Chauvet-Pont d'Arc Cave (Ardeche, France)? AB - Among the paintings and engravings found in the Chauvet-Pont d'Arc cave (Ardeche, France), several peculiar spray-shape signs have been previously described in the Megaloceros Gallery. Here we document the occurrence of strombolian volcanic activity located 35 km northwest of the cave, and visible from the hills above the cave entrance. The volcanic eruptions were dated, using 40Ar/39Ar, between 29 +/- 10 ka and 35 +/- 8 ka (2sigma), which overlaps with the 14C AMS and thermoluminescence ages of the first Aurignacian occupations of the cave in the Megaloceros Gallery. Our work provides the first evidence of an intense volcanic activity between 40 and 30 ka in the Bas-Vivarais region, and it is very likely that Humans living in the Ardeche river area witnessed one or several eruptions. We propose that the spray-shape signs found in the Chauvet-Pont d'Arc cave could be the oldest known depiction of a volcanic eruption, predating by more than 34 ka the description by Pliny the Younger of the Vesuvius eruption (AD 79) and by 28 ka the Catalhoyuk mural discovered in central Turkey. PMID- 26745627 TI - Effects of BmCPV Infection on Silkworm Bombyx mori Intestinal Bacteria. AB - The gut microbiota has a crucial role in the growth, development and environmental adaptation in the host insect. The objective of our work was to investigate the microbiota of the healthy silkworm Bombyx mori gut and changes after the infection of B. mori cypovirus (BmCPV). Intestinal contents of the infected and healthy larvae of B. mori of fifth instar were collected at 24, 72 and 144 h post infection with BmCPV. The gut bacteria were analyzed by pyrosequencing of the 16S rRNA gene. 147(135) and 113(103) genera were found in the gut content of the healthy control female (male) larvae and BmCPV-infected female (male) larvae, respectively. In general, the microbial communities in the gut content of healthy larvae were dominated by Enterococcus, Delftia, Pelomonas, Ralstonia and Staphylococcus, however the abundance change of each genus was depended on the developmental stage and gender. Microbial diversity reached minimum at 144 h of fifth instar larvae. The abundance of Enterococcus in the females was substantially lower and the abundance of Delftia, Aurantimonas and Staphylococcus was substantially higher compared to the males. Bacterial diversity in the intestinal contents decreased after post infection with BmCPV, whereas the abundance of both Enterococcus and Staphylococcus which belongs to Gram-positive were increased. Therefore, our findings suggested that observed changes in relative abundance was related to the immune response of silkworm to BmCPV infection. Relevance analysis of plenty of the predominant genera showed the abundance of the Enterococcus genus was in negative correlation with the abundance of the most predominant genera. These results provided insight into the relationship between the gut microbiota and development of the BmCPV-infected silkworm. PMID- 26745628 TI - Josephin Domain Structural Conformations Explored by Metadynamics in Essential Coordinates. AB - The Josephin Domain (JD), i.e. the N-terminal domain of Ataxin 3 (At3) protein, is an interesting example of competition between physiological function and aggregation risk. In fact, the fibrillogenesis of Ataxin 3, responsible for the spinocerebbellar ataxia 3, is strictly related to the JD thermodynamic stability. Whereas recent NMR studies have demonstrated that different JD conformations exist, the likelihood of JD achievable conformational states in solution is still an open issue. Marked differences in the available NMR models are located in the hairpin region, supporting the idea that JD has a flexible hairpin in dynamic equilibrium between open and closed states. In this work we have carried out an investigation on the JD conformational arrangement by means of both classical molecular dynamics (MD) and Metadynamics employing essential coordinates as collective variables. We provide a representation of the free energy landscape characterizing the transition pathway from a JD open-like structure to a closed like conformation. Findings of our in silico study strongly point to the closed like conformation as the most likely for a Josephin Domain in water. PMID- 26745629 TI - Largescale Transcriptomics Analysis Suggests Over-Expression of BGH3, MMP9 and PDIA3 in Oral Squamous Cell Carcinoma. AB - Oral squamous cell carcinoma (OSCC) has been reported as the most prevalent cancer of the head and neck region, while early diagnosis remains challenging. Here we took a comprehensive bioinformatics study on microarray data of 326 OSCC clinical samples with control of 165 normal tissues. The cell interaction pathways of ECM-receptor interaction and focal adhesion were found to be significantly regulated in OSCC samples. Further analysis of the topological properties and expression consistency identified that three hub genes in the gene interaction network, MMP9, PDIA3 and BGH3, were consistently up-expressed in OSCC samples. When being validated on additional microarray datasets of 41 OSCC samples, the validation rate of over-expressed BGH3, MMP9, and PDIA3 reached 90%, 90% and 84% respectively. At last, immuno-histochemical assays were done to test the protein expression of the three genes on newly collected clinical samples of 35 OSCC, 20 samples of pre-OSCC stage, and 12 normal oral mucosa specimens. Their protein expression levels were also found to progressively increase from normal mucosa to pre-OSCC stage and further to OSCC (ANOVA p = 0.000), suggesting their key roles in OSCC pathogenesis. Based on above solid validation, we propose BGH3, MMP9 and PDIA3 might be further explored as potential biomarkers to aid OSCC diagnosis. PMID- 26745631 TI - Feasibility and acceptability of smartphone applications for seizure self management in China: Questionnaire study among people with epilepsy. AB - OBJECTIVE: The aim of this report was to assess the feasibility and acceptability of using smartphone apps for seizure self-management in China. METHODS: All patients with epilepsy were consecutively recruited from the Neurology Epilepsy Prevention and Cure Center of West China Hospital from January 2015 to June 2015. Data on patients' clinical characteristics, mobile phone utilization habits, preferences for contents of apps for seizure self-management, medication adherence, and attitudes toward the use of smartphone apps were collected from 502 patients with epilepsy by questionnaire. RESULTS: Among 502 participants, 96.8% had their own mobile phones, and 94.4% owned a smartphone. Although only 9.5% (48/502) of participants had prior knowledge of apps for managing chronic illness, 66.7% (335/502) of participants reported that managing their seizure through an app would be useful. Sixty-five point five percent of participants reported that they would use a smartphone app for seizure self-management if it were free. Patients who were more likely to use an app were those with a low Morisky Scale score (patients with poor medicine adherence), young patients, patients who lived in cities, and patients with frequent seizures (P<0.001, P=0.002, P<0.001, P=0.01). Patients with higher education and with stable employment were also more likely to use an app (P=0.001, P<0.001). CONCLUSIONS: This is the first study on the feasibility and acceptability of smartphone apps for seizure self-management in China. The findings of this study indicate that there is a positive attitude toward using epilepsy apps among patients with epilepsy. Based on patients' positive attitudes toward using epilepsy apps and the current development of mobile health in China, the use of smartphone apps could be a promising strategy for seizure self-management. PMID- 26745630 TI - Costs of Three Wolbachia Infections on the Survival of Aedes aegypti Larvae under Starvation Conditions. AB - The mosquito Aedes aegypti, the principal vector of dengue virus, has recently been infected experimentally with Wolbachia: intracellular bacteria that possess potential as dengue biological control agents. Wolbachia depend on their hosts for nutrients they are unable to synthesize themselves. Consequently, competition between Wolbachia and their host for resources could reduce host fitness under the competitive conditions commonly experienced by larvae of Ae. aegypti in the field, hampering the invasion of Wolbachia into natural mosquito populations. We assess the survival and development of Ae. aegypti larvae under starvation conditions when infected with each of three experimentally-generated Wolbachia strains: wMel, wMelPop and wAlbB, and compare their fitness to wild-type uninfected larvae. We find that all three Wolbachia infections reduce the survival of larvae relative to those that are uninfected, and the severity of the effect is concordant with previously characterized fitness costs to other life stages. We also investigate the ability of larvae to recover from extended food deprivation and find no effect of Wolbachia on this trait. Aedes aegypti larvae of all infection types were able to resume their development after one month of no food, pupate rapidly, emerge at a large size, and exhibit complete cytoplasmic incompatibility and maternal transmission. A lowered ability of Wolbachia infected larvae to survive under starvation conditions will increase the threshold infection frequency required for Wolbachia to establish in highly competitive natural Ae. aegypti populations and will also reduce the speed of invasion. This study also provides insights into survival strategies of larvae when developing in stressful environments. PMID- 26745633 TI - Correction: STAT2 Knockout Syrian Hamsters Support Enhanced Replication and Pathogenicity of Human Adenovirus, Revealing an Important Role of Type I Interferon Response in Viral Control. AB - [This corrects the article DOI: 10.1371/journal.ppat.1005084.]. PMID- 26745632 TI - RAGE and AGEs in Mild Cognitive Impairment of Diabetic Patients: A Cross Sectional Study. AB - OBJECTIVE: Receptor for advanced glycation end products (AGEs; RAGE) binds to both AGEs and amyloid-beta peptides. RAGE is involved in chronic complications of type 2 diabetes and Alzheimer's disease. We aimed to investigate the roles of RAGE, AGEs and the Gly82Ser polymorphism of RAGE in mild cognitive impairment (MCI) among type 2 diabetes patients. METHODS: Of the 167 hospitalized type 2 diabetes patients recruited, 82 satisfied the diagnostic criteria for MCI, and 85 matched control individuals were classified as non-MCI. Demographic data were collected, and the soluble RAGE (sRAGE) concentrations, serum AGE-peptide (AGE-P) levels, RAGE Gly82Ser genotype and neuropsychological test results were examined. RESULTS: The MCI group exhibited a decreased sRAGE level (0.87+/-0.35 vs. 1.05+/ 0.52 ng/ml, p<0.01) and an increased serum AGE-P level (3.54+/-1.27 vs. 2.71+/ 1.18 U/ml, p<0.01) compared with the control group. Logistic regression analysis indicated that each unit reduction in the sRAGE concentration increased the MCI risk by 54% (OR 0.46[95% CI 0.22-0.96], p = 0.04) and that each unit increase in the AGE-P level increased the MCI risk by 72% in the type 2 diabetes patients (OR 1.72[95% CI 1.31-2.28], p<0.01). The serum sRAGE level was negatively correlated with the score on the trail making test-B (TMT-B) (r = -0.344, p = 0.002), which indicates early cognitive deficits related to diabetes. Moreover, the AGE-P level was positively correlated with multiple cognitive domains (all p<0.05). No significant differences in the neuropsychological test results or serum RAGE concentrations between the different RAGE genotypes or in the RAGE genotype frequencies between the MCI and control groups were identified (all p>0.05). CONCLUSIONS: The RAGE pathway partially mediates AGE-induced MCI in diabetic patients. The serum AGE-P level may serve as a serum biomarker of MCI in these individuals, and sRAGE represents a predictor and even a potential intervention target of early cognitive decline in type 2 diabetes patients. TRIAL REGISTRATION: Advanced Glycation End Products Induced Cognitive Impairment in Diabetes: BDNF Signal Meditated Hippocampal Neurogenesis ChiCTR-OCC-15006060. PMID- 26745636 TI - Nanostructured SnS with inherent anisotropic optical properties for high photoactivity. AB - In view of the worldwide energy challenge in the 21(st) century, the technology of semiconductor-based photoelectrochemical (PEC) water splitting has received considerable attention as an alternative approach for solar energy harvesting and storage. Two-dimensional (2D) structures such as nanosheets have the potential to tap the solar energy by unlocking the functional properties at the nanoscale. Tin(ii) sulfide is a fascinating solar energy material due to its anisotropic material properties. In this manuscript, we report on exploiting the 2D structure modulated optical properties of nanocrystalline SnS thin film synthesized by chemical spray pyrolysis using ambient transport in the harvesting of solar energy. We obtained the nanostructured SnS with well-preserved dimensions and morphologies with one step processing. The work demonstrates that the intrinsically ordered SnS nanostructure on FTO coated glass can tap the incident radiation in an efficient manner. The structure-property relationship to explain the photo-response in nanocrystalline-SnS is verified experimentally and theoretically. The novel design scheme for antireflection coating along with the anisotropic properties of SnS is conceived for realizing a PEC cell. The developed PEC cell consists of a SnS photoanode which shows considerably high photocurrent density of 7 mA cm(-2) with aqueous media under AM 1.5G, 100 mW cm( 2) exposure with notably stable operation. Electrochemical impedance spectroscopy revealed that a non-ideal capacitive behavior as well as drift assisted transport across the solid-state interface is responsible for such a high photo-current density in the nanocrystalline-SnS photoanode. PMID- 26745634 TI - A Role of Medial Olivocochlear Reflex as a Protection Mechanism from Noise Induced Hearing Loss Revealed in Short-Practicing Violinists. AB - Previous studies have indicated that extended exposure to a high level of sound might increase the risk of hearing loss among professional symphony orchestra musicians. One of the major problems associated with musicians' hearing loss is difficulty in estimating its risk simply on the basis of the physical amount of exposure, i.e. the exposure level and duration. The aim of this study was to examine whether the measurement of the medial olivocochlear reflex (MOCR), which is assumed to protect the cochlear from acoustic damage, could enable us to assess the risk of hearing loss among musicians. To test this, we compared the MOCR strength and the hearing deterioration caused by one-hour instrument practice. The participants in the study were music university students who are majoring in the violin, whose left ear is exposed to intense violin sounds (broadband sounds containing a significant number of high-frequency components) during their regular instrument practice. Audiogram and click-evoked otoacoustic emissions (CEOAEs) were measured before and after a one-hour violin practice. There was a larger exposure to the left ear than to the right ear, and we observed a left-ear specific temporary threshold shift (TTS) after the violin practice. Left-ear CEOAEs decreased proportionally to the TTS. The exposure level, however, could not entirely explain the inter-individual variation in the TTS and the decrease in CEOAE. On the other hand, the MOCR strength could predict the size of the TTS and CEOAE decrease. Our findings imply that, among other factors, the MOCR is a promising measure for assessing the risk of hearing loss among musicians. PMID- 26745635 TI - siMS Score: Simple Method for Quantifying Metabolic Syndrome. AB - OBJECTIVE: To evaluate siMS score and siMS risk score, novel continuous metabolic syndrome scores as methods for quantification of metabolic status and risk. MATERIALS AND METHODS: Developed siMS score was calculated using formula: siMS score = 2*Waist/Height + Gly/5.6 + Tg/1.7 + TAsystolic/130-HDL/1.02 or 1.28 (for male or female subjects, respectively). siMS risk score was calculated using formula: siMS risk score = siMS score * age/45 or 50 (for male or female subjects, respectively) * family history of cardio/cerebro-vascular events (event = 1.2, no event = 1). A sample of 528 obese and non-obese participants was used to validate siMS score and siMS risk score. Scores calculated as sum of z-scores (each component of metabolic syndrome regressed with age and gender) and sum of scores derived from principal component analysis (PCA) were used for evaluation of siMS score. Variants were made by replacing glucose with HOMA in calculations. Framingham score was used for evaluation of siMS risk score. RESULTS: Correlation between siMS score with sum of z-scores and weighted sum of factors of PCA was high (r = 0.866 and r = 0.822, respectively). Correlation between siMS risk score and log transformed Framingham score was medium to high for age groups 18+,30+ and 35+ (0.835, 0.707 and 0.667, respectively). CONCLUSIONS: siMS score and siMS risk score showed high correlation with more complex scores. Demonstrated accuracy together with superior simplicity and the ability to evaluate and follow up individual patients makes siMS and siMS risk scores very convenient for use in clinical practice and research as well. PMID- 26745637 TI - Cell-Capture and Release Platform Based on Peptide-Aptamer-Modified Nanowires. AB - Nanowires have attracted much attention due to their potential bioapplications, such as delivery of drugs or sensing devices. Here we report the development of a unique cell-capture and release platform based on nanowires. The combination of nanowires, surface-binding peptides, and cell-targeting aptamers leads to specific and efficient capture of cancer cells. Moreover, the binding processes are reversible, which is not only useful for downstream analysis but also for reusability of the substrate. Our work provides a new method in the design of the cell-capture and release platform, which may open up new opportunities of developing cell-separation and diagnosis systems based on cell-capture techniques. PMID- 26745639 TI - [Levers in Primary Health Care - Identifying Strategic Success Factors for Improved Primary Care in Upper Austria]. AB - Current and projected general practitioner (GP) and primary care in Austria shows structural and process inadequacies in the quality as well as assurance of healthcare supply. The aim is therefore to develop solution- and patient-oriented measures that take patient-related requirements and medical perspectives into account. Using an effect matrix, subjective expert and user priorities were ascertained, cause and effect relationships were examined, and an expanded circle of success for the optimization of GP and primary care in Upper Austria was developed. Through this, the relevant levers for target-oriented development and optimization of the complex system of GP and primary care in Upper Austria were identified; these are training to become general practitioners, entrepreneurs as well as management and coordination. It is necessary to further adapt the identified levers conceptually and operationally in a targeted approach. This is to be achieved by means of the primary health care (PHC) concept as well as management tools and information and communication technologies (ICT) associated with it. PMID- 26745638 TI - Polyethylenimine-polyacrylic acid nanocomposites: Type of bonding does influence the gene transfer efficacy and cytotoxicity. AB - The main aim of the current study is to compare the physicochemical properties, cytotoxicity and gene-transfer ability of electrostatically and covalently linked nanocomposites of polyethylenimine (PEI) and polyacrylic acid (PAA) on mammalian cells. Two series of nanocomposites, ionic PEI-PAA (iPP) and covalent PEI-PAA (cPP), were synthesized by varying the amounts of polyacrylic acid (PAA). Physicochemical characterization revealed that iPP nanopcomposites were of bigger sized than cPP nanocomposites with zeta potential almost comparable. Nucleic acid binding assay displayed that iPP and cPP nanocomposites, having sufficient cationic charge, efficiently interacted with plasmid DNA and completely retarded its electrophoretic mobility on agarose gel. In vitro MTT assay showed slightly higher cell viability of cPP/pDNA complexes over their ionic counterparts. Both the series of nanocomposite/pDNA complexes exhibited considerably higher transfection efficacy compared to pDNA complexes of native bPEI and the standard transfection reagent, Lipofectamine, with cPP/pDNA complexes performed much better than iPP/pDNA complexes. Flow cytometry further confirmed these findings where cPP-4/pDNA complex showed transfection in ~ 85% HEK293 cells, while iPP 2/pDNA complex transfected ~ 67% HEK293 cells. Lipofectamine/pDNA and bPEI/pDNA complexes could transfect just ~ 35% and ~ 26% HEK293 cells. All these results demonstrate the superiority of covalently linked nanocomposites (cPP) which could be used as efficient carriers for nucleic acids in future gene delivery applications. PMID- 26745640 TI - Trichloromethanesulfonyl Chloride: A Chlorinating Reagent for Aldehydes. AB - Trichloromethanesulfonyl chloride (CCl3SO2Cl), a commercially available reagent, has been found to perform efficiently in the alpha-chlorination of aldehydes, including its catalytic asymmetric version, under very mild reaction conditions. Under our reaction conditions, this compound outperforms typical chlorinating reagents for organic synthesis, facilitates workup and purification of the product, and minimizes the formation of toxic, chlorinated organic waste. PMID- 26745643 TI - Metal-Free CH-CH-Type Cross-Coupling of Arenes and Alkynes Directed by a Multifunctional Sulfoxide Group. AB - A metal-free CH-CH-type coupling of arenes and alkynes, mediated by a multifunctional sulfoxide directing group, exploits nonprefunctionalized coupling partners, proceeds under mild conditions, is operationally simple, and exhibits high functional group tolerance. The products of the CH-CH coupling are highly versatile, and the metal-free process can be used for the construction and late stage modification of important molecular scaffolds. PMID- 26745642 TI - Environmental Remediation to Address Childhood Lead Poisoning Epidemic due to Artisanal Gold Mining in Zamfara, Nigeria. AB - BACKGROUND: From 2010 through 2013, integrated health and environmental responses addressed an unprecedented epidemic lead poisoning in Zamfara State, northern Nigeria. Artisanal gold mining caused widespread contamination resulting in the deaths of > 400 children. Socioeconomic, logistic, and security challenges required remediation and medical protocols within the context of local resources, labor practices, and cultural traditions. OBJECTIVES: Our aim was to implement emergency environmental remediation to abate exposures to 17,000 lead poisoned villagers, to facilitate chelation treatment of children <= 5 years old, and to establish local technical capacity and lead health advocacy programs to prevent future disasters. METHODS: U.S. hazardous waste removal protocols were modified to accommodate local agricultural practices. Remediation was conducted over 4 years in three phases, progressing from an emergency response by international personnel to comprehensive cleanup funded and accomplished by the Nigerian government. RESULTS: More than 27,000 m3 of contaminated soils and mining waste were removed from 820 residences and ore processing areas in eight villages, largely by hand labor, and disposed in constructed landfills. Excavated areas were capped with clean soils (<= 25 mg/kg lead), decreasing soil lead concentrations by 89%, and 2,349 children received chelation treatment. Pre chelation geometric mean blood lead levels for children <= 5 years old decreased from 149 MUg/dL to 15 MUg/dL over the 4-year remedial program. CONCLUSIONS: The unprecedented outbreak and response demonstrate that, given sufficient political will and modest investment, the world's most challenging environmental health crises can be addressed by adapting proven response protocols to the capabilities of host countries. CITATION: Tirima S, Bartrem C, von Lindern I, von Braun M, Lind D, Anka SM, Abdullahi A. 2016. Environmental remediation to address childhood lead poisoning epidemic due to artisanal gold mining in Zamfara, Nigeria. Environ Health Perspect 124:1471-1478; http://dx.doi.org/10.1289/ehp.1510145. PMID- 26745641 TI - SNaPP: Simplified Nanoproteomics Platform for Reproducible Global Proteomic Analysis of Nanogram Protein Quantities. AB - Global proteomic analyses of complex protein samples in nanogram quantities require a fastidious approach to achieve in-depth protein coverage and quantitative reproducibility. Biological samples are often severely mass limited and can preclude the application of more robust bulk sample processing workflows. In this study, we present a system that minimizes sample handling by using online immobilized trypsin digestion and solid phase extraction to create a simple, sensitive, robust, and reproducible platform for the analysis of nanogram-size proteomic samples. To demonstrate the effectiveness of our simplified nanoproteomics platform, we used the system to analyze preimplantation blastocysts collected on day 4 of pregnancy by flushing the uterine horns with saline. For each of our three sample groups, blastocysts were pooled from three mice resulting in 22, 22, and 25 blastocysts, respectively. The resulting proteomic data provide novel insight into mouse blastocyst protein expression on day 4 of normal pregnancy because we characterized 348 proteins that were identified in at least two sample groups, including 59 enzymes and blastocyst specific proteins (eg, zona pellucida proteins). This technology represents an important advance in which future studies could perform global proteomic analyses of blastocysts obtained from an individual mouse, thereby enabling researchers to investigate interindividual variation as well as increase the statistical power without increasing animal numbers. This approach is also easily adaptable to other mass-limited sample types. PMID- 26745645 TI - Letter to the Editor: Filum terminale in tethered cord syndrome. PMID- 26745644 TI - Assessment of metal exposure, ecological status and required water quality monitoring strategies in small- to medium-size temperate rivers. AB - The present study was undertaken to obtain a better understanding of the seasonal variability of total dissolved metal/metalloid levels and physicochemical parameters within small- to medium-size freshwater ecosystems in temperate climate region. The research was conducted in four seasons in the Sutla River, medium-size polluted, and the Crnomerec Stream, small-size unpolluted watercourse in Croatia. In the Sutla River, characterized by the rural/industrial catchment, physicochemical parameters and total dissolved metal concentrations of 21 trace and 4 macro elements were analysed downstream of the point source of pollution, the glass production facility, indicating for the first time their variability across four seasons. Based on dissolved oxygen, total dissolved solids, nutrient concentrations, conductivity and total chemical oxygen demand, quality status of the Sutla River was good, but moderate to poor during summer, what was additionally confirmed by the highest levels of the most of 25 measured metals/metalloids in summer. Comparison with the reference small-size watercourse, the Crnomerec Stream, indicated significant anthropogenic impact on the Sutla River, most evident for Fe, Mn, Mo, Ni, Pb, Rb and Tl levels (3-70-fold higher in the Sutla River across all seasons). Generally, presented results indicated significant decrease of the water quality in the anthropogenically impacted small- to medium-size watercourses in summer, regarding physicochemical water parameters and total dissolved metal/metalloid concentrations, and pointed to significant seasonality of these parameters. Confirmed seasonality of river ecological status indicates that seasonal assessment represents a prerequisite for proper classification of the water quality in small- to medium-size temperate rivers. PMID- 26745648 TI - Unilateral coronal synostosis: can we trust the sagittal suture as a landmark for the underlying superior sagittal sinus? AB - OBJECTIVE The sagittal suture is usually considered an external anatomical landmark, indicating the location of the superior sagittal sinus (SSS) for surgical approaches. Children with unilateral coronal synostosis (UCS) often present with an important deviation of the sagittal suture. Because these patients usually undergo frontal reconstruction or even endoscope-assisted minimally invasive procedures, it is imperative to know the location of the SSS. The aim of this investigation was to study the anatomical relationship between the SSS and the sagittal suture in children with anterior plagiocephaly. METHODS The authors retrospectively studied the relationship between the sagittal sinus and the sagittal suture at 5 points: nasion, midpoint nasion-bregma, bregma, midpoint bregma-lambda, and lambda. The study analyzed CT scans of 50 children with UCS admitted to the craniofacial unit of Necker Enfants Malades Hospital between March 2006 and March 2013 and compared them with 50 control children with no evidence of craniosynostosis, bone disease, or genetic syndromes. The authors also analyzed the presence of extracerebral fluid collection and ventricular asymmetry in children with UCS. RESULTS Fifty-six percent of patients had anterior right UCS and 44% had left-sided UCS. Type I UCS was seen in 1 patient, Type IIA in 20 patients, Type IIB in 20 patients, and Type III in 9 patients. The authors found that the nasion is usually deviated to the ipsilateral side of the synostosis, the bregma contralaterally, and the lambda ipsilaterally. The gap distances between the reference point and the SSS were 0-7.3 mm (mean 1.4 mm) at the nasion; 0-16.7 mm (mean 3.8 mm) at the midpoint nasion-bregma; 0-12 mm (mean 5.8 mm) at the bregma; 0-9.5 mm (mean 3 mm) at the midpoint bregma-lambda; and 0 11.6 mm (mean 5.5 mm) at the lambda. Conversely, a discrepancy of more than 1 mm between the SSS and the position of the suture was found only in 7 control cases (14%). Of patients with UCS, 38% presented with an extracerebral fluid collection contralateral to the fused coronal suture. Fifty-two percent had a ventricular asymmetry, which was characterized by reduced ventricular volume ipsilateral to the synostosis in all but 1 patient. CONCLUSIONS In this study, the SSS was usually deviated contralaterally to the closed coronal suture. It tended to be in the midline of the cranial vault and could be projected virtually along an imaginary line passing through the midline of the cranial base. The authors recommend a distance of 37 mm from the sagittal suture as a safety margin during surgery. PMID- 26745646 TI - Regression of ventriculomegaly following medical management of a patient with Hurler syndrome. AB - Hurler syndrome is the most severe form of mucopolysaccharidosis (MPS) Type 1. Progressive neurocognitive decline in this condition can be accompanied by macrocephaly, ventriculomegaly, and/or periventricular signal changes on MRI, which often leads to a neurosurgical referral. In this case, the authors describe a 2-year-old boy with ventriculomegaly and periventricular T2 signal changes, both of which decreased following medical management of Hurler syndrome. The authors discuss the possible mechanisms for this finding and the implications for neurosurgical treatment of this condition. PMID- 26745649 TI - Scalable Preparation of Multifunctional Fire-Retardant Ultralight Graphene Foams. AB - Traditional flame-retardant materials often show poor tolerance to oxidants, strong acidic/alkaline reagents, organic solvents, along with toxicity problems. Herein, highly fire-retardant ultralight graphene foam has been developed, which possesses not only ultralight and compressible characteristics but also efficient flame-retardant properties, outperforming those traditional polymer, metallic oxide, and metal hydroxide based flame retardant materials and their composites. The newly developed unconventional refractory materials are promising for specific applications as demonstrated by the observed high temperature resistant microwave absorption capability. PMID- 26745647 TI - Frequency and long-term follow-up of trapped fourth ventricle following neonatal posthemorrhagic hydrocephalus. AB - OBJECTIVE Intraventricular hemorrhage (IVH) is a common complication of premature neonates with small birth weight, which often leads to hydrocephalus and treatment with ventriculoperitoneal (VP) shunting procedures. Trapped fourth ventricle (TFV) can be a devastating consequence of the subsequent occlusion of the cerebral aqueduct and foramina of Luschka and Magendie. METHODS The authors retrospectively reviewed 8 consecutive cases involving pediatric patients with TFV following VP shunting for IVH due to prematurity between 2003 and 2012. The patients ranged in gestational age from 23.0 to 32.0 weeks, with an average age at first shunting procedure of 6.1 weeks (range 3.1-12.7 weeks). Three patients were managed with surgery. Patients received long-term radiographic (mean 7.1 years; range 3.4-12.2 years) and clinical (mean 7.8 years; range 4.6-12.2 years) follow-up. RESULTS The frequency of TFV following VP shunting for neonatal posthemorrhagic hydrocephalus was found to be 15.4%. Three (37.5%) patients presented with symptoms of posterior fossa compression and were treated surgically. All of these patients showed signs of radiographic improvement with stable or improved clinical examinations during postoperative follow-up. Of the 5 patients treated conservatively, 80% experienced stable ventricular size and 1 patient experienced a slight increase (3 mm) on imaging. All of the nonsurgical patients showed stable to improved clinical examinations over the follow-up period. CONCLUSIONS The frequency of TFV among premature IVH patients is relatively high. Most patients with TFV are asymptomatic at presentation and can be managed without surgery. Symptomatic patients may be treated surgically for decompression of the fourth ventricle. PMID- 26745650 TI - Use of the electrosurgical unit in a carbon dioxide atmosphere. AB - The electrosurgical unit (ESU) utilizes an electrical discharge to cut and coagulate tissue and is often held above the surgical site, causing a spark to form. The voltage at which the spark is created, termed the breakdown voltage, is governed by the surrounding gaseous environment. Surgeons are now utilizing the ESU laparoscopically with carbon dioxide insufflation, potentially altering ESU operating characteristics. This study examines the clinical implications of altering gas composition by measuring the spark gap distance as a marker of breakdown voltage and use of the ESU on a biologic model, both in room air and carbon dioxide. Paschen's Law predicted a 35% decrease in gap distance in carbon dioxide, while testing revealed an average drop of 37-47% as compared to air. However, surgical model testing revealed no perceivable clinical difference. Electrosurgery can be performed in carbon dioxide environments, although surgeons should be aware of potentially altered ESU performance. PMID- 26745652 TI - Bi(3n+1)Ti7Fe(3n-3)O(9n+11) Homologous Series: Slicing Perovskite Structure with Planar Interfaces Containing Anatase-like Chains. AB - The n = 3-6 members of a new perovskite-based homologous series Bi(3n+1)Ti7Fe(3n 3)O(9n+11) are reported. The crystal structure of the n = 3 Bi10Ti7Fe6O38 member is refined using a combination of X-ray and neutron powder diffraction data (a = 11.8511(2) A, b = 3.85076(4) A, c = 33.0722(6) A, S.G. Immm), unveiling the partially ordered distribution of Ti(4+) and Fe(3+) cations and indicating the presence of static random displacements of the Bi and O atoms. All Bi(3n+1)Ti7Fe(3n-3)O(9n+11) structures are composed of perovskite blocks separated by translational interfaces parallel to the (001)p perovskite planes. The thickness of the perovskite blocks increases with n, while the atomic arrangement at the interfaces remains the same. The interfaces comprise chains of double edge-sharing (Fe,Ti)O6 octahedra connected to the octahedra of the perovskite blocks by sharing edges and corners. This configuration shifts the adjacent perovskite blocks relative to each other over a vector 1/2[110]p and creates S-shaped tunnels along the [010] direction. The tunnels accommodate double columns of the Bi(3+) cations, which stabilize the interfaces owing to the stereochemical activity of their lone electron pairs. The Bi(3n+1)Ti7Fe(3n 3)O(9n+11) structures can be formally considered either as intergrowths of perovskite modules and polysynthetically twinned modules of the Bi2Ti4O11 structure or as intergrowths of the 2D perovskite and 1D anatase fragments. Transmission electron microscopy (TEM) on Bi10Ti7Fe6O38 reveals that static atomic displacements of Bi and O inside the perovskite blocks are not completely random; they are cooperative, yet only short-range ordered. According to TEM, the interfaces can be laterally shifted with respect to each other over +/-1/3a, introducing an additional degree of disorder. Bi10Ti7Fe6O38 is paramagnetic in the 1.5-1000 K temperature range due to dilution of the magnetic Fe(3+) cations with nonmagnetic Ti(4+). The n = 3, 4 compounds demonstrate a high dielectric constant of 70-165 at room temperature. PMID- 26745653 TI - Spontaneous Internalization of Cell Penetrating Peptide-Modified Nanowires into Primary Neurons. AB - Semiconductor nanowire (NW) devices that can address intracellular electrophysiological events with high sensitivity and spatial resolution are emerging as key tools in nanobioelectronics. Intracellular delivery of NWs without compromising cellular integrity and metabolic activity has, however, proven difficult without external mechanical forces or electrical pulses. Here, we introduce a biomimetic approach in which a cell penetrating peptide, the trans activating transcriptional activator (TAT) from human immunodeficiency virus 1, is linked to the surface of Si NWs to facilitate spontaneous internalization of NWs into primary neuronal cells. Confocal microscopy imaging studies at fixed time points demonstrate that TAT-conjugated NWs (TAT-NWs) are fully internalized into mouse hippocampal neurons, and quantitative image analyses reveal an ca. 15% internalization efficiency. In addition, live cell dynamic imaging of NW internalization shows that NW penetration begins within 10-20 min after binding to the membrane and that NWs become fully internalized within 30-40 min. The generality of cell penetrating peptide modification method is further demonstrated by internalization of TAT-NWs into primary dorsal root ganglion (DRG) neurons. PMID- 26745654 TI - The Complex Role of Anticoagulation in Cirrhosis: An Updated Review of Where We Are and Where We Are Going. AB - Venous thromboembolism (VTE) in cirrhotic patients is an increasingly encountered problem in the daily clinical practice; there is still a debate on the ideal measures to be followed for prophylaxis and treatment of VTE among this population. Although traditionally, liver cirrhosis has been considered a disease with hypocoagulability state and increasing bleeding tendency due to severe homeostatic disruption in liver disease, until recently there is increasing awareness and evidence that cirrhotic patients are not completely protected from thrombotic events although they have an elevated international normalized ratio and auto anticoagulation. Furthermore, hypercoagulability is now an increasingly recognized aspect of chronic liver disease (CLD), and the bleeding risk of VTE prophylaxis and treatment remains unclear. In this review, we provide an updated discussion on the mechanisms involved in hemostasis in CLD as well as on the benefits and complications of anticoagulant therapy in cirrhotic patients. Overall, sufficient evidence exists, promoting the use of anticoagulation in cirrhotic patients for both VTE prophylaxis and treatment in carefully selected patients after consideration of pharmacologic or endoscopic variceal bleeding prophylaxis. PMID- 26745656 TI - Finely Formed, Kinetically Modulated Wrinkle Structures in UV-Crosslinkable Liquid Prepolymers. PMID- 26745651 TI - Recommendations and Standardization of Biomarker Quantification Using NMR-Based Metabolomics with Particular Focus on Urinary Analysis. AB - NMR-based metabolomics has shown considerable promise in disease diagnosis and biomarker discovery because it allows one to nondestructively identify and quantify large numbers of novel metabolite biomarkers in both biofluids and tissues. Precise metabolite quantification is a prerequisite to move any chemical biomarker or biomarker panel from the lab to the clinic. Among the biofluids commonly used for disease diagnosis and prognosis, urine has several advantages. It is abundant, sterile, and easily obtained, needs little sample preparation, and does not require invasive medical procedures for collection. Furthermore, urine captures and concentrates many "unwanted" or "undesirable" compounds throughout the body, providing a rich source of potentially useful disease biomarkers; however, incredible variation in urine chemical concentrations makes analysis of urine and identification of useful urinary biomarkers by NMR challenging. We discuss a number of the most significant issues regarding NMR based urinary metabolomics with specific emphasis on metabolite quantification for disease biomarker applications and propose data collection and instrumental recommendations regarding NMR pulse sequences, acceptable acquisition parameter ranges, relaxation effects on quantitation, proper handling of instrumental differences, sample preparation, and biomarker assessment. PMID- 26745659 TI - Chemical simulation of greywater. AB - Sustainable water resources management attracts considerable attention in today's world. Recycling and reuse of both wastewater and greywater are becoming more attractive. The strategy is to protect ecosystem services by balancing the withdrawal of water and the disposal of wastewater. In the present study, a timely and novel synthetic greywater composition has been proposed with respect to the composition of heavy metals, nutrients and organic matter. The change in water quality of the synthetic greywater due to increasing storage time was monitored to evaluate the stability of the proposed chemical formula. The new greywater is prepared artificially using analytical-grade chemicals to simulate either low (LC) or high (HC) pollutant concentrations. The characteristics of the synthetic greywater were tested (just before starting the experiment, after two days and a week of storage under real weather conditions) and compared to those reported for real greywater. Test results for both synthetic greywater types showed great similarities with the physiochemical properties of published findings concerning real greywater. Furthermore, the synthetic greywater is relatively stable in terms of its characteristics for different storage periods. However, there was a significant (p < .05) reduction in 5-day biochemical oxygen demand (BOD5) for both low (LC) and high (HC) concentrations of greywater after two days of storage with reductions of 62% and 55%, respectively. A significant (p < .05) change was also noted for the reduction (70%) of nitrate-nitrogen (NO3 N) concerning HC greywater after seven days of storage. PMID- 26745660 TI - Altered energy intake and the amplitude of the body temperature rhythm are associated with changes in phase, but not amplitude, of clock gene expression in the rat suprachiasmatic nucleus in vivo. AB - Circadian rhythms in mammals are driven by a central clock in the suprachiasmatic nucleus (SCN). In vitro, temperature cycles within the physiological range can act as potent entraining cues for biological clocks. We altered the body temperature (Tc) rhythm in rats by manipulating energy intake (EI) to determine whether EI-induced changes in Tc oscillations are associated with changes in SCN clock gene rhythms in vivo. Male Wistar rats (n = 16 per diet) were maintained on either an ad libitum diet (CON), a high energy cafeteria diet (CAF), or a calorie restricted diet (CR), and Tc was recorded every 30 min for 6-7 weeks. SCN tissue was harvested from rats at zeitgeber time (ZT) 0, ZT6, ZT12, or ZT18. Expression of the clock genes Bmal1, Per2, Cry1, and Rev-erbalpha, the heat shock transcription factor Hsf1, and the heat shock protein Hsp90aa1, were determined using qPCR. The circadian profile of gene expression for each gene was characterized using cosinor analysis. Compared to the CON rats, the amplitude of Tc was decreased in CAF rats by 0.1 degrees C (p < 0.001), and increased in CR rats by 0.3 degrees C (p < 0.001). The amplitude of Hsp90aa1 expression was lowest in CAF rats and highest in CR rats (p = 0.045), but the amplitude of all of the clock genes and Hsf1 were unaffected by diet (p > 0.25). Compared to CON, phase advances of the Tc, Bmal1, and Per2 rhythms were observed with CR feeding (p < 0.05), but CAF feeding elicited no significant changes in phase. The present results indicate that in vivo, the SCN is largely resistant to entrainment by EI induced changes in the Tc rhythm, although some phase entrainment may occur. PMID- 26745661 TI - Volumetric muscle loss leads to permanent disability following extremity trauma. AB - Extremity injuries comprise the majority of battlefield injuries and contribute the most to long-term disability of servicemembers. The purpose of this study was to better define the contribution of muscle deficits and volumetric muscle loss (VML) to the designation of long-term disability in order to better understand their effect on outcomes for limb-salvage patients. Medically retired servicemembers who sustained a combat-related type III open tibia fracture (Orthopedic cohort) were reviewed for results of their medical evaluation leading to discharge from military service. A cohort of battlefield-injured servicemembers (including those with nonorthopedic injuries) who were medically retired because of various injuries (General cohort) was also examined. Muscle conditions accounted for 65% of the disability of patients in the Orthopedic cohort. Among the General cohort, 92% of the muscle conditions were identified as VML. VML is a condition that contributes significantly to long-term disability, and the development of therapies addressing VML has the potential to fill a significant void in orthopedic care. PMID- 26745662 TI - Sterols and squalene in apricot (Prunus armeniaca L.) kernel oils: the variety as a key factor. AB - The profile of sterols and squalene content in oils recovered from the kernels of 15 apricot (Prunus armeniaca L.) varieties were investigated. Nine sterols (campesterol, beta-sitosterol, Delta5-avenasterol, 24-methylene-cycloartanol, cholesterol, gramisterol, Delta7-stigmasterol, Delta7-avenasterol and citrostadienol) were identified in apricot kernel oils. The beta-sitosterol was the predominant sterol in each cultivar and consisted of 76-86% of the total detected sterols. The content of total sterols and squalene were significantly affected by the variety and ranged between 215.7-973.6 and 12.6-43.9 mg/100 g of oil, respectively. PMID- 26745664 TI - Effect of Four Weeks of beta-alanine Supplementation on Muscle Carnosine and Blood Serum Lactate during Exercise in Male Rats. AB - beta-alanine (BA) supplementation may increase muscle buffering capacity and affect physiological responses during exercise. We examined the effects of 4 weeks of BA supplementation on muscle carnosine and serum lactate in male rats. Rats (n = 24, age: 2 months, body weight: 265+/-22 g) were divided into a BA supplementation or control group. Along with aerobic acclimatization exercise (15 m.min(-1), 8-10 min.day(-1), 4 days.week(-1) for 4 weeks), the BA group had access to BA powder in their drinking water (1.8%) with the control group having access to plain water for 4 weeks. After 4 weeks, rats ran on a treadmill at speeds of 15, 20, 25, 30, and 35 m.min(-1), respectively, each for 4 min, in order to measure post-exercise serum lactate. Muscle carnosine and serum lactate levels were measured with high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbant assay (ELISA) procedures, respectively. Following BA supplementation, carnosine content in the m.rectus femoris increased by 117% (p < .01) and serum lactate decreased by 7.4% (p < .01). It was concluded that beta alanine supplementation increases muscle carnosine content and reduces serum lactate; these changes may indicate an adaptation of rat skeletal muscles to postpone peripheral muscle fatigue during high-intensity exercise. PMID- 26745665 TI - Deep-sequencing of the T-cell receptor repertoire in patients with haplo-cord and matched-donor transplants. AB - Haplo-cord transplant has emerged as a feasible and reliable approach for haematopoietic stem cell transplant in patients who are unable to find matched donor. This approach provides fast myeloid recovery, low incidence of graft vs host disease (GVHD) and favorable graft versus leukemia (GVL) effects. T cell recovery plays an important role in preventing infectious complications; it also mediates the GVHD and the GVL effects. Here, we utilized a novel RNA-based sequencing approach to quantitatively characterize the T cell receptor (TCRs) repertoire in patients underwent haplo-cord transplant in comparison with those underwent matched-donor transplant. Our study shows that higher percentage of cord cells early post transplant were associated with significantly higher TCR diversity. TCR diversity was significantly lower in patients with GVHD and in relapsed patients. A larger cohort study is needed to validate these data and to provide useful information on the specific TCR clones correlated with clinical outcome. PMID- 26745663 TI - Mechanisms of trophoblast migration, endometrial angiogenesis in preeclampsia: The role of decorin. AB - The objective of the present review is to synthesize the information on the cellular and molecular players responsible for maintaining a homeostatic balance between a naturally invasive human placenta and the maternal uterus in pregnancy; to review the roles of decorin (DCN) as a molecular player in this homeostasis; to list the common maladies associated with a break-down in this homeostasis, resulting from a hypo-invasive or hyper-invasive placenta, and their underlying mechanisms. We show that both the fetal components of the placenta, represented primarily by the extravillous trophoblast, and the maternal component represented primarily by the decidual tissue and the endometrial arterioles, participate actively in this balance. We discuss the process of uterine angiogenesis in the context of uterine arterial changes during normal pregnancy and preeclampsia. We compare and contrast trophoblast growth and invasion with the processes involved in tumorigenesis with special emphasis on the roles of DCN and raise important questions that remain to be addressed. Decorin (DCN) is a small leucine-rich proteoglycan produced by stromal cells, including dermal fibroblasts, chondrocytes, chorionic villus mesenchymal cells and decidual cells of the pregnant endometrium. It contains a 40 kDa protein core having 10 leucine-rich repeats covalently linked with a glycosaminoglycan chain. Biological functions of DCN include: collagen assembly, myogenesis, tissue repair and regulation of cell adhesion and migration by binding to ECM molecules or antagonising multiple tyrosine kinase receptors (TKR) including EGFR, IGF-IR, HGFR and VEGFR-2. DCN restrains angiogenesis by binding to thrombospondin-1, TGFbeta, VEGFR-2 and possibly IGF-IR. DCN can halt tumor growth by antagonising oncogenic TKRs and restraining angiogenesis. DCN actions at the fetal-maternal interface include restraint of trophoblast migration, invasion and uterine angiogenesis. We demonstrate that DCN overexpression in the decidua is associated with preeclampsia (PE); this may have a causal role in PE by compromising endovascular differentiation of the trophoblast and uterine angiogenesis, resulting in poor arterial remodeling. Elevated DCN level in the maternal blood is suggested as a potential biomarker in PE. PMID- 26745666 TI - Diastolic Dysfunction Increases the Risk of Primary Graft Dysfunction after Lung Transplant. AB - RATIONALE: Primary graft dysfunction (PGD) is a significant cause of early morbidity and mortality after lung transplant and is characterized by severe hypoxemia and infiltrates in the allograft. The pathogenesis of PGD involves ischemia-reperfusion injury. However, subclinical increases in pulmonary venous pressure due to left ventricular diastolic dysfunction may contribute by exacerbating capillary leak. OBJECTIVES: To determine whether a higher ratio of early mitral inflow velocity (E) to early diastolic mitral annular velocity (e), indicative of worse left ventricular diastolic function, is associated with a higher risk of PGD. METHODS: We performed a retrospective cohort study of patients in the Lung Transplant Outcomes Group who underwent bilateral lung transplant at our institution between 2004 and 2014 for interstitial lung disease, chronic obstructive pulmonary disease, or pulmonary arterial hypertension. Transthoracic echocardiograms obtained during evaluation for transplant listing were analyzed for E/e and other measures of diastolic function. PGD was defined as PaO2/FiO2 less than or equal to 200 with allograft infiltrates at 48 or 72 hours after reperfusion. The association between E/e and PGD was assessed with multivariable logistic regression. MEASUREMENTS AND MAIN RESULTS: After adjustment for recipient age, body mass index, mean pulmonary arterial pressure, and pretransplant diagnosis, higher E/e and E/e greater than 8 were associated with an increased risk of PGD (E/e odds ratio, 1.93; 95% confidence interval, 1.02-3.64; P = 0.04; E/e >8 odds ratio, 5.29; 95% confidence interval, 1.40-20.01; P = 0.01). CONCLUSIONS: Differences in left ventricular diastolic function may contribute to the development of PGD. Future trials are needed to determine whether optimization of left ventricular diastolic function reduces the risk of PGD. PMID- 26745667 TI - Structural Analysis on the Pathologic Mutant Glucocorticoid Receptor Ligand Binding Domains. AB - Glucocorticoid receptor (GR) gene mutations may cause familial or sporadic generalized glucocorticoid resistance syndrome. Most of the missense forms distribute in the ligand-binding domain and impair its ligand-binding activity and formation of the activation function (AF)-2 that binds LXXLL motif-containing coactivators. We performed molecular dynamics simulations to ligand-binding domain of pathologic GR mutants to reveal their structural defects. Several calculated parameters including interaction energy for dexamethasone or the LXXLL peptide indicate that destruction of ligand-binding pocket (LBP) is a primary character. Their LBP defects are driven primarily by loss/reduction of the electrostatic interaction formed by R611 and T739 of the receptor to dexamethasone and a subsequent conformational mismatch, which deacylcortivazol resolves with its large phenylpyrazole moiety and efficiently stimulates transcriptional activity of the mutant receptors with LBP defect. Reduced affinity of the LXXLL peptide to AF-2 is caused mainly by disruption of the electrostatic bonds to the noncore leucine residues of this peptide that determine the peptide's specificity to GR, as well as by reduced noncovalent interaction against core leucines and subsequent exposure of the AF-2 surface to solvent. The results reveal molecular defects of pathologic mutant receptors and provide important insights to the actions of wild-type GR. PMID- 26745668 TI - Research Resource: Genetic Labeling of Human Islet Alpha Cells. AB - The 2 most abundant human pancreatic islet cell types are insulin-producing beta cells and glucagon-producing alpha-cells. Defined cis-regulatory elements from rodent Insulin genes have permitted genetic labeling of human islet beta-cells, enabling lineage tracing and generation of human beta-cell lines, but analogous elements for genetically labeling human alpha-cells with high specificity do not yet exist. To identify genetic elements that specifically direct reporter expression to human alpha-cells, we investigated noncoding sequences adjacent to the human GLUCAGON and ARX genes, which are expressed in islet alpha-cells. Elements with high evolutionary conservation were cloned into lentiviral vectors to direct fluorescent reporter expression in primary human islets. Based on the specificity of reporter expression for alpha- and beta-cells, we found that rat glucagon promoter was not specific for human alpha-cells but that addition of human GLUCAGON untranslated region sequences substantially enhanced specificity of labeling in both cultured and transplanted islets to a degree not previously reported, to our knowledge. Specific transgene expression from these cis regulatory sequences in human alpha-cells should enable targeted genetic modification and lineage tracing. PMID- 26745670 TI - Retraction. PMID- 26745671 TI - Estimating the Expected Replicability of a Pattern of Correlations and Other Measures of Association. AB - Replication is at the heart of all empirical sciences. However, there are no standard procedures for establishing the replicability of a pattern of correlations found linking a particular variable to an inventory or battery of other measures. This article introduces 2 statistics for quantifying the expected replicability of a pattern of associations (i.e., correlations, slope coefficients) between a variable of interest and a SET of other variables, items, measures, and so on. Using simulations and real data, we illustrate that these statistics are highly accurate estimates of the expected replicability of an observed pattern of correlations. These statistics can readily be used to indicate the replicability of patterns of association indexed by other statistics (e.g., regression slopes or covariances) and can be applied to other contexts, such as estimating the reliability of profile correlations. It is recommended that these statistics are regularly reported in such studies. PMID- 26745672 TI - The Relationships between Individualism, Nationalism, Ethnocentrism, and Authoritarianism in Flanders: A Continuous Time-Structural Equation Modeling Approach. AB - This article analyzes the relationships among nationalism (N), individualism (I), ethnocentrism (E), and authoritarianism (A) in continuous time (CT), estimated as a structural equation model. The analysis is based on the General Election Study for Flanders, Belgium, for 1991, 1995, and 1999. We find reciprocal effects between A and E and between E and I as well as a unidirectional effect from A on I. We furthermore find relatively small, but significant, effects from both I and E on N but no effect from A on N or from N on any of the other variables. Because of its central role in the N-I-E-A complex, mitigation of authoritarianism has the largest potential to reduce the spread of nationalism, ethnocentrism, and racism in Flanders. PMID- 26745669 TI - Research Resource: Hormones, Genes, and Athleticism: Effect of Androgens on the Avian Muscular Transcriptome. AB - Male vertebrate social displays vary from physically simple to complex, with the latter involving exquisite motor command of the body and appendages. Studies of these displays have, in turn, provided substantial insight into neuromotor mechanisms. The neotropical golden-collared manakin (Manacus vitellinus) has been used previously as a model to investigate intricate motor skills because adult males of this species perform an acrobatic and androgen-dependent courtship display. To support this behavior, these birds express elevated levels of androgen receptors (AR) in their skeletal muscles. Here we use RNA sequencing to explore how testosterone (T) modulates the muscular transcriptome to support male manakin courtship displays. In addition, we explore how androgens influence gene expression in the muscles of the zebra finch (Taenopygia guttata), a model passerine bird with a limited courtship display and minimal muscle AR. We identify androgen-dependent, muscle-specific gene regulation in both species. In addition, we identify manakin-specific effects that are linked to muscle use during the manakin display, including androgenic regulation of genes associated with muscle fiber contractility, cellular homeostasis, and energetic efficiency. Overall, our results point to numerous genes and gene networks impacted by androgens in male birds, including some that underlie optimal muscle function necessary for performing acrobatic display routines. Manakins are excellent models to explore gene regulation promoting athletic ability. PMID- 26745674 TI - Analyzing Multiple Multivariate Time Series Data Using Multilevel Dynamic Factor Models. AB - Multivariate time series data offer researchers opportunities to study dynamics of various systems in social and behavioral sciences. Dynamic factor model (DFM), as an idiographic approach for studying intraindividual variability and dynamics, has typically been applied to time series data obtained from a single unit. When multivariate time series data are collected from multiple units, how to synchronize dynamical information becomes a silent issue. To address this issue, the current study presented a multilevel dynamic factor model (MDFM) that analyzes multiple multivariate time series in multilevel SEM frameworks. MDFM not only disentangles within- and between-person variability but also models dynamics of the intraindividual processes. To illustrate the uses of MDFMs, we applied lag0, lag1, and lag2 MDFMs to empirical data on affect collected from 205 dating couples who had at least 50 consecutive days of observations. We also considered a model extension where the dynamical coefficients were allowed to be randomly varying in the population. The empirical analysis yielded interesting findings regarding affect regulation and coregulation within couples, demonstrating promising uses of MDFMs in analyzing multiple multivariate time series. In the end, we discussed a number of methodological issues in the applications of MDFMs and pointed out possible directions for future research. PMID- 26745673 TI - The Joint Multivariate Modeling of Multiple Mixed Response Sources: Relating Student Performances with Feedback Behavior. AB - The present study concerns a Dutch computer-based assessment, which includes an assessment process about information literacy and a feedback process for students. The assessment is concerned with the measurement of skills in information literacy and the feedback process with item-based support to improve student learning. To analyze students' feedback behavior (i.e. feedback use and attention time), test performance, and speed of working, a multivariate hierarchical latent variable model is proposed. The model can handle multivariate mixed responses from multiple sources related to different processes and comprehends multiple measurement components for responses and response times. A flexible within-subject latent variable structure is defined to explore multiple individual latent characteristics related to students' test performance and feedback behavior. Main results of the computer-based assessment showed that feedback-information pages were less visited by well-performing students when they relate to easy items. Students' attention paid to feedback was positively related to working speed but not to the propensity to use feedback. PMID- 26745675 TI - Increased serum NKG2D-ligands and downregulation of NKG2D in peripheral blood NK cells of patients with major burns. AB - Immune suppression following major thermal injury directly impacts the recovery potential. Limited data from past reports indicate that natural killer cells might be suppressed due to a putative soluble factor that has remained elusive up to date. Here we comparatively study cohorts of patients with Major and Non-Major Burns as well as healthy donors. MICB and ULBP1 are stress ligands of NKG2D that can be induced by heat stress. Remarkably, serum concentration levels of MICB and ULBP1 are increased by 3-fold and 20-fold, respectively, already within 24h post major thermal injury, and are maintained high for 28 days. In contrast, milder thermal injuries do not similarly enhance the serum levels of MICB and ULBP1. This kinetics coincides with a significant downregulation of NKG2D expression among peripheral blood NK cells. Downregulation of NKG2D by high concentration of soluble MICB occurs in cancer patients and during normal pregnancy due to over production by cancer cells or extravillous trophoblasts, respectively, as an active immune-evasion mechanism. In burn patients this seems an incidental outcome of extensive thermal injury, leading to reduced NKG2D expression. Enhanced susceptibility of these patients to opportunistic viral infections, particularly herpes viruses, could be explained by the reduced NKG2D expression. Further studies are warranted for translation into innovative diagnostic or therapeutic technologies. PMID- 26745676 TI - Gastro-duodenal fluid induced nuclear factor-kappaappaB activation and early pre malignant alterations in murine hypopharyngeal mucosa. AB - We recently described the role of gastro-duodenal fluids (GDFs) in generating changes consistent with hypopharyngeal neoplasia through activation of NF-kappaB pathway, using an in vitro model of human hypopharyngeal normal keratinocytes. Here, we further provide evidence that gastro-duodenal reflux is a risk factor for early pre-malignant alterations in hypopharyngeal mucosa (HM) related to an activated NF-kappaB oncogenic pathway, using both an in vitro and a novel in vivo model of C57Bl/6J mice. Histological, immunohistochemical and automated quantitative analysis documents significant NF-kappaB activation and early pre malignant alterations in HM topically exposed to GDFs, compared to acid alone and other controls. Early pre-malignant histologic lesions exhibited increased Ki67, CK14 and DeltaNp63, cell proliferation markers, changes of cell adhesion molecules, E-Cadherin and beta-catenin, and STAT3 activation. The in vivo effect of NF-kappaB activation is positively correlated with p-STAT3, Ki67, CK14 or beta catenin expression, while GDFs induce significant transcriptional activation of RELA(p65), bcl-2, TNF-alpha, STAT3, EGFR and wnt5A, in vivo. Our in vivo model demonstrates selectively activated NF-kappaB in response to topically administrated GDFs, leading to early pre-malignant events in HM. PMID- 26745677 TI - Polo-like kinase 1 mediates BRCA1 phosphorylation and recruitment at DNA double strand breaks. AB - Accurate repair of DNA double-strand breaks (DSB) caused during DNA replication and by exogenous stresses is critical for the maintenance of genomic integrity. There is growing evidence that the Polo-like kinase 1 (Plk1) that plays a number of pivotal roles in cell proliferation can directly participate in regulation of DSB repair. In this study, we show that Plk1 regulates BRCA1, a key mediator protein required to efficiently repair DSB through homologous recombination (HR). Following induction of DSB, BRCA1 concentrates in distinctive large nuclear foci at damage sites where multiple DNA repair factors accumulate. First, we found that inhibition of Plk1 shortly before DNA damage sensitizes cells to ionizing radiation and reduces DSB repair by HR. Second, we provide evidence that BRCA1 foci formation induced by DSB is reduced when Plk1 is inhibited or depleted. Third, we identified BRCA1 as a novel Plk1 substrate and determined that Ser1164 is the major phosphorylation site for Plk1 in vitro. In cells, mutation of Plk1 sites on BRCA1 significantly delays BRCA1 foci formation following DSB, recapitulating the phenotype observed upon Plk1 inhibition. Our data then assign a key function to Plk1 in BRCA1 foci formation at DSB, emphasizing Plk1 importance in the HR repair of human cells. PMID- 26745678 TI - TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun. AB - Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have shown promising clinical efficacy in non-squamous non-small cell lung cancer (NSCLC); however, resistance is frequently observed in malignant cells, operating through a mechanism that remains largely unknown. The present study shows that T-lymphokine-activated killer cell-originated protein kinase (TOPK) is upregulated in NSCLC and excessively activated in TKI-refractory cells. TOPK dictates the responsiveness of lung cancers to the EGFR-targeted TKI gefitinib through the transcription factor AP-1 component c-Jun. TOPK binds directly to and phosphorylates c-Jun, which consequently activates the transcription of AP-1 target genes, including CCND1 and CDC2. TOPK silencing sensitizes EGFR-TKI resistant lung cancer cells to gefitinib and increases gefitinib efficacy in preclinical lung adenocarcinoma xenograft models. These findings represent a novel mechanism of lung cancer resistance to TKIs and suggest that TOPK may have value both as a predictive biomarker and as a therapeutic target: TOPK-targeted therapy may synergize with EGFR-targeted therapy in lung cancers. PMID- 26745681 TI - Anti-inflammatory effects of omega 3 and omega 6 polyunsaturated fatty acids in cardiovascular disease and metabolic syndrome. AB - A lipid excess produces a systemic inflammation process due to tumor necrosis factor-alpha, interleukin-6 and C-reactive protein synthesis. Simultaneously, this fat excess promotes the appearance of insulin resistance. All this contributes to the development of atherosclerosis and increases the risk of cardiovascular diseases (CVDs). On the other hand, polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid and docosahexaenoic acid (omega 3), and arachidonic acid (omega 6) have shown anti-inflammatory properties. Lately, an inverse relationship between omega-3 fatty acids, inflammation, obesity and CVDs has been demonstrated. To check fatty acids effect, the levels of some inflammation biomarkers have been analyzed. Leptin, adiponectin and resistin represent a group of hormones associated with the development of CVDs, obesity, type 2 diabetes mellitus and insulin resistance and are modified in obese/overweight people comparing to normal weight people. Omega-3 PUFAs have been shown to decrease the production of inflammatory mediators, having a positive effect in obesity and diabetes mellitus type-2. Moreover, they significantly decrease the appearance of CVD risk factors. Regarding omega-6 PUFA, there is controversy whether their effects are pro- or anti-inflammatory. The aim of this manuscript is to provide a comprehensive overview about the role of omega-3 and omega-6 PUFAs in CVDs and metabolic syndrome. PMID- 26745680 TI - High-performance liquid chromatographic method for profiling 2-oxo acids in urine and its application in evaluating vitamin status in rats. AB - B-group vitamins are involved in the catabolism of 2-oxo acids. To identify the functional biomarkers of B-group vitamins, we developed a high-performance liquid chromatographic method for profiling 2-oxo acids in urine and applied this method to urine samples from rats deficient in vitamins B1 and B6 and pantothenic acid. 2-Oxo acids were reacted with 1,2-diamino-4,5-methylenebenzene to produce fluorescent derivatives, which were then separated using a TSKgel ODS-80Ts column with 30 mmol/L of KH2PO4 (pH 3.0):acetonitrile (7:3) at a flow rate of 1.0 mL/min. Vitamin B1 deficiency increased urinary levels of all 2-oxo acids, while vitamin B6 deficiency only increased levels of sum of 2-oxaloacetic acid and pyruvic acid, and pantothenic acid deficiency only increased levels of 2 oxoisovaleric acid. Profiles of 2-oxo acids in urine samples might be a non invasive way of clarifying the functional biomarker of B-group vitamins. PMID- 26745683 TI - A Practical Guide to Assessing Adult Firesetters' Fire-Specific Treatment Needs Using the Four Factor Fire Scales. AB - OBJECTIVE: Practitioners working with offenders who have set fires have access to very few measures examining fire-specific treatment needs (e.g., fire interest, fire attitudes). In this article we examine the new Four Factor Fire Scales (O Ciardha et al., 2015), which may be used by practitioners to examine fire specific treatment needs for offenders who have set deliberate fires. We present a standardized scoring procedure when using these scales, as well as an associated scoring template for practitioner use. METHOD: Norm data are based on male and female firesetters (n = 378) and nonfiresetters (n = 187) recruited from 19 prison establishments (including six female establishments, one young offender institution) and 12 secure mixed-gender mental health settings. RESULTS: We present a full overview of all data we have collected to date relating to the Four Factor Fire Scales across prison, mental health, and young offending participants. For each population, we present mean scores as well as associated cutoff scores and reliable change indices to aid practitioners in their interpretation of scores. CONCLUSIONS: The Four Factor Fire Scales provide professionals working in the area with a robust template for administering, scoring, and interpreting the fire-specific factors currently identified as playing a role in deliberate firesetting behavior. Strengths and limitations of the measure are discussed. PMID- 26745682 TI - Behavioral Interventions for Anger, Irritability, and Aggression in Children and Adolescents. AB - OBJECTIVE: Anger, irritability, and aggression are among the most common reasons for child mental health referrals. This review is focused on two forms of behavioral interventions for these behavioral problems: Parent management training (PMT) and cognitive-behavioral therapy (CBT). METHODS: First, we provide an overview of anger/irritability and aggression as the treatment targets of behavioral interventions, followed by a discussion of the general principles and techniques of these treatment modalities. Then we discuss our current work concerning the transdiagnostic approach to CBT for anger, irritability, and aggression. RESULTS: PMT is aimed at improving aversive patterns of family interactions that engender children's disruptive behavior. CBT targets deficits in emotion regulation and social problem-solving that are associated with aggressive behavior. Both forms of treatment have received extensive support in randomized controlled trials. Given that anger/irritability and aggressive behavior are common in children with a variety of psychiatric diagnoses, a transdiagnostic approach to CBT for anger and aggression is described in detail. CONCLUSIONS: PMT and CBT have been well studied in randomized controlled trials in children with disruptive behavior disorders, and studies of transdiagnostic approaches to CBT for anger and aggression are currently underway. More work is needed to develop treatments for other types of aggressive behavior (e.g., relational aggression) that have been relatively neglected in clinical research. The role of callous-unemotional traits in response to behavioral interventions and treatment of irritability in children with anxiety and mood disorders also warrants further investigation. PMID- 26745679 TI - Phosphorylation of 4EBP by oral leucine administration was suppressed in the skeletal muscle of PGC-1alpha knockout mice. AB - Leucine is known to increase mTOR-mediated phosphorylation of 4EBP. In this study, leucine was administered to skeletal muscle-PGC-1alpha knockout mice. We observed attenuated 4EBP phosphorylation in the skeletal muscle, but not in the liver, of the PGC-1alpha knockout mice. These data suggest that skeletal muscle PGC-1alpha is important for leucine-mediated mTOR activation and protein biosynthesis. PMID- 26745685 TI - Comparison of Attachments in Real-World and Virtual-World Relationships. AB - OBJECTIVE: The burgeoning of online social networks raises questions about the quality and value of these interpersonal relationships. The present study employed an established measure of attachment security to compare the nature of individuals' attachments in virtual-world relationships with those in real-world relationships and also examined the relative strength of attachments in the two types of relationships. METHOD: Participants were 125 volunteers recruited online who had established relationships in Second Life, a popular virtual world. Participants consented and completed all measures anonymously online. RESULTS: The findings indicate that equally strong attachments are formed in virtual- and real-world relationships; there is modest correspondence in the quality of attachment in the two types of relationship; the strength of attachments in the virtual world is influenced by capacity to immerse oneself in fantasy; duration of the relationship is correlated with strength of attachment in both worlds; and emotional well-being relates to strength of attachment in real-world relationships and lower attachment anxiety in virtual-world relationships. CONCLUSIONS: The value of attachment relationships in virtual worlds calls for further investigation. Moreover, consistent with the growing employment of telemedicine, the potential for clinical interventions in virtual worlds merits consideration. PMID- 26745684 TI - Individual Psychotherapy and Changes in Self-Experience in Schizophrenia: A Qualitative Comparison of Patients in Metacognitively Focused and Supportive Psychotherapy. AB - OBJECTIVE: Deficits in metacognition, or the ability to form complex ideas about self and others, may be a root cause of dysfunction in schizophrenia. Accordingly, forms of psychotherapy have been proposed to address metacognitive deficits. This study explored whether metacognitively focused individual psychotherapy can affect self-experience by conducting narrative interviews of patients with a schizophrenia spectrum disorder enrolled in either metacognitively oriented psychotherapy (n = 12) or supportive psychotherapy (n = 13) in a naturalistic setting. METHOD: Participants in both groups completed a narrative interview consisting of questions that focused on perceptions and process of psychotherapy and its impact on outcomes. Interviews were audiotaped, transcribed, and coded using an inductive process informed by grounded theory. RESULTS: Qualitative analyses revealed all participants reported psychotherapy led to improvements in self-esteem and the ability to think more clearly and set meaningful goals. The group receiving metacognitively oriented therapy, in contrast to those receiving supportive therapy, reported being able to integrate their current experiences into the larger narratives of their lives and an increased experience of sense of agency and the ability to understand and manage pain. CONCLUSIONS: Results provide evidence that metacognitively oriented psychotherapy may promote subjective forms of recovery. PMID- 26745686 TI - Examination of the Content Specificity of Posttraumatic Cognitions in Combat Veterans With Posttraumatic Stress Disorder. AB - OBJECTIVE: Cognitive theories have proposed the idea of content specificity, which holds that emotional disorders are associated with unique sets of negative cognitions. The existent research exploring the content specificity related to posttraumatic stress disorder (PTSD) and depression is sparse, and research is especially needed in veteran samples. The purpose of this study was to examine the associations of PTSD symptom clusters and comorbid depressive symptoms with posttraumatic cognitions. METHOD: This study was cross-sectional in design, and the sample consisted of data from 150 male combat veterans with PTSD drawn from the baseline assessments of a large clinical trial. Analyses involved a series of separate and simultaneous linear regressions to examine the unique associations of comorbid depressive symptoms and PTSD symptom clusters with posttraumatic cognitions, as well as post hoc analyses to examine the mediational role of comorbid depressive symptoms. RESULTS: Findings demonstrated that posttraumatic negative cognitions about the self and self-blame were most strongly associated with comorbid depressive symptoms and the depression-related PTSD numbing cluster. Comorbid depressive symptoms also partially mediated nearly all the relationships between posttraumatic cognitions and PTSD symptom clusters. CONCLUSIONS: The findings of this study suggest that posttraumatic cognitions about the self and self-blame are not specific to PTSD but rather are more strongly related to symptoms of depression and negative affect. The results also suggest a potential pathway from posttraumatic cognitions to PTSD through the partially mediating influence of comorbid depression, and highlight the need to assess and treat comorbid depression in veterans with PTSD. PMID- 26745687 TI - Humor and Trauma-Related Psychopathology Among Survivors of Terror Attacks and Their Spouses. AB - The goal of this study was to examine the bidirectional relationships between humor and trauma-related psychopathology (posttraumatic stress disorder [PTSD], depression, and anxiety symptoms) among 105 dyads consisting of Israelis who were injured during terror attacks and their spouses (N = 210). An actor-partner interdependence model (APIM) was applied as part of a structural equation modeling (SEM) analysis aimed at examining the associations between the use of different styles of humor and trauma-related psychopathology. Consistent with our hypotheses, results suggested that benign styles of humor were associated with survivors' lower levels of trauma-related symptoms (actor effects) and also had a buffering effect for the spouse (partner effects). More specifically, the use of self-enhancing humor by survivors was negatively associated with spousal symptoms and the use of affiliative humor by spouses was negatively associated with psychopathology symptoms reported by survivors. The results of this study shed light on the role that benign humor may play in coping with traumatic events while taking into account the dyadic relationships among survivors and their spouses. Theoretical and clinical implications of the findings are discussed. PMID- 26745688 TI - Somatic Complaints and Attachment in Former Prisoners of War: A Longitudinal Study. AB - OBJECTIVE: War captivity includes a unique constellation of simultaneous somatic and interpersonal assaults. This raises questions about the link between attachment and somatic complaints among ex-prisoners of war (ex-POWs). Although the attachment literature assumes that attachment affects somatic complaints and not vice versa, to date no empirical studies assess the association between the two variables over time. In this article we prospectively examine the association between attachment and somatic complaints over time among ex-POWs and comparable veterans. METHOD: The current study included two groups of male Israeli veterans of the 1973 Yom Kippur War: ex-POWs and comparable veterans who were not taken captive. Both groups were assessed via self-report measures at three times: T1 (1991), T2 (2003), and T3 (2008)--18, 30, and 35 years after the war, respectively. RESULTS: Ex-POWs reported higher levels of somatic complaints and attachment insecurities. These levels increased over time compared to combatant veterans. Moreover, while there was a unidirectional influence of somatic complaints on attachment security over time among combatant veterans, this relationship was bidirectional among ex-POWs. CONCLUSIONS: The present study suggests that the combined physical and interpersonal assaults experienced during captivity have adverse effects on combatants and on attachment security, even three decades later. More important, in ex-POWs the relationship between these domains appears to be interactive and mutual, with one reinforcing the other, and vice versa. PMID- 26745689 TI - Traumatic Life Events Prior to Alcohol-Related Admission of Injured Acute Care Inpatients: A Brief Report. AB - OBJECTIVE: Approximately 30 million Americans present to acute care medical settings annually after incurring traumatic injuries. Posttraumatic stress disorder (PTSD) and depressive symptoms are endemic among injury survivors. Our article is a replication and extension of a previous report documenting a pattern of multiple traumatic life events across patients admitted to Level I trauma centers for an alcohol-related injury. METHOD: This study is a secondary analysis of a nationwide 20-site randomized trial of an alcohol brief intervention with 660 traumatically injured inpatients. Pre-injury trauma history was assessed using the National Comorbidity Survey trauma history screen at the six-month time point. RESULTS: Most common traumatic events experienced by our population of alcohol-positive trauma survivors were having had someone close unexpectedly die, followed by having seen someone badly beaten or injured. Of particular note, there is high reported prevalence of rape/sexual assault, and childhood abuse and neglect among physically injured trauma survivors. Additional trauma histories are increasingly common among alcohol-positive patients admitted for a traumatic injury. CONCLUSIONS: Due to the high rate of experienced multiple traumatic events among acutely injured inpatients, the trauma history screen could be productively integrated into screening and brief intervention procedures developed for acute care settings. PMID- 26745694 TI - A Phase 2, Single Arm Study of Iniparib in Patients With BRCA1 or BRCA2 Associated Advanced Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. AB - OBJECTIVE: The aim of the study was to evaluate the activity and tolerability of iniparib monotherapy in women with BRCA1 or BRCA2-associated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. METHODS AND MATERIALS: Eligible patients had advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer, germline BRCA1 or BRCA2 mutation, measurable disease, and at least 1 previous treatment regimen of platinum/taxane chemotherapy. Patients received iniparib 8 mg/kg intravenously on days 1 and 4 weekly, with imaging every 8 weeks. Treatment continued until disease progression or adverse events (AEs) prohibited further therapy. Common Terminology Criteria for AEs v3.0 was used to grade AEs. The primary endpoint was tumor response. The study was conducted with a Simon 2-stage design with 12 and 23 patients planned in the first and second stage, respectively. The study was designed to distinguish between 10% and 30% responding with types 1 and 2 error of 0.10. RESULTS: Twelve patients were treated on study, with median exposure to iniparib of 7.5 weeks. The median number of previous chemotherapeutic regimens was 7. Treatment-related AEs (>=10%) included asthenia (83.3%), constipation (25%), diarrhea (25%), nausea (25%), abdominal pain (16.7%), and decreased hemoglobin (16.7%). All treatment related AEs were grades 1 or 2 with the following 2 exceptions: 1 grade 3 diarrhea and 1 grade 3 hypertension. One patient had stable disease lasting 2 cycles; the remaining 11 patients had progressive disease. The study did not proceed to second stage enrollment. CONCLUSIONS: Iniparib did not show significant activity in this heavily pretreated ovarian cancer population, all of whom had BRCA1 or BRCA2 mutations. PMID- 26745696 TI - Routine Clinical Practice for Patients With Recurrent Ovarian Carcinoma: Results From the TROCADERO Study. AB - OBJECTIVE: Treatment options for patients with recurrent ovarian carcinoma are diverse, and different therapies are recommended based on platinum-free interval (PFI). Data examining the association between platinum sensitivity, treatment strategy, and outcomes are limited, particularly for partially platinum-sensitive (PPS) patients. This study characterized clinical features and outcomes in patients with recurrent ovarian carcinoma in the context of sensitivity to platinum-based therapy. METHODS: Anonymized case records were obtained from eligible European medical sites. Eligible patients were 18 years or older with epithelial ovarian carcinoma who had received 1 or more platinum-based therapies and had 1 or more subsequent relapses. Patient records were categorized by PFI and analyzed based on demographic and clinical data using descriptive statistics. RESULTS: There was no difference between PFI in PPS patients receiving platinum versus nonplatinum therapy (8.9 [range, 6.0-12.0] and 8.3 [range, 6.0-11.3] months, respectively). Overall survival in patients with platinum-sensitive, PPS, platinum-resistant, and platinum-refractory disease was 43.0 (95% confidence interval [95% CI], 25.1-42.3), 20.5 (95% CI, 17.7-24.8), 12.7 (95% CI, 10.4 14.2), and 9.8 (95% CI, 6.6-14.9) months, respectively. Among PPS patients, overall survival was 23.5 (95% CI, 18.4-37.3) and 18.7 (95% CI, 11.0-23.5) months for those who received platinum and nonplatinum-based therapy, respectively. No demographic or clinical characteristics were identified that indicated a difference between PPS patients who received platinum-based therapy versus those who did not. CONCLUSIONS: Partially platinum-sensitive patients with recurrent ovarian carcinoma who received platinum-based therapy had improved outcomes compared with those who did not. No clear demographic criteria for choosing platinum- versus nonplatinum-based therapy for PPS patients were identified from patient records. PMID- 26745697 TI - Risk of Parametrial Spread in Small Stage I Cervical Carcinoma: Pathology Review of 223 Cases With a Tumor Diameter of 20 mm or Less. AB - BACKGROUND: Considering the morbidity of radical hysterectomy, the advent of fertility-sparing approaches, and the low risk of parametrial involvement in patients with early stage I cervical tumors, the benefit from parametrial resection is debatable. Objectives of this study were to determine factors predicting parametrial tumor spread and to define a group of patients who might be safely spared parametrial resection. METHODS: Pathology review was done on patients with stages IA2 and small IB1, treated by radical hysterectomy and pelvic lymph node dissection. Analysis was performed to determine factors associated with parametrial spread and to define risks of obeying parametrial resection. RESULTS: A total of 223 patients with tumors less than 20 mm in diameter were identified. Parametrial metastases were documented in 8 patients (3.6%); nodes, 1.3%; lymphovascular space invasion (LVSI), 1.8%; contiguous spread, 0.9%. Of 211 (94.6%) patients with negative pelvic nodes, none had parametrial nodal involvement, 0.9% had LVSI, and 0.4% had contiguous spread. Factors associated with parametrial disease were deep cervical invasion, LVSI, tumor volume, and pelvic lymph node metastases (P < 0.01 for each). In patients without tumor LVSI and the depth of invasion was within the inner third, the rate of parametrial spread was 0.45%. CONCLUSIONS: Our data show a risk of parametrial spread of 0.45% for tumors less than 20 mm in diameter, no LVSI, and a depth of invasion within the inner third. Patients wanting fertility preservation might be prepared to take this risk of recurrence. Morbidity after nerve-sparing radical hysterectomy is tolerably low, and for patients in whom fertility preservation is not an issue, this should be considered the standard of care. PMID- 26745695 TI - Pilot Clinical Evaluation of a Confocal Microlaparoscope for Ovarian Cancer Detection. AB - OBJECTIVE: The aim of this study is to evaluate the performance of a confocal fluorescence microlaparoscope for in vivo detection of ovarian cancer. METHODS/MATERIALS: Seventy-one patients scheduled for open or laparoscopic oophorectomy were consented for the imaging study. High-resolution confocal microlaparoscopic images of the epithelial surface of the ovary were acquired in vivo or ex vivo after tissue staining using acridine orange. Standard histologic evaluation of extracted tissue samples was performed and used as the gold standard of disease diagnosis. Trained human observers from different specialties viewed the microlaparoscopic images, rating each image on a 6-point scale ranging from "definitely not cancer" to "definitely cancer." Receiver operating characteristic curves were generated using these scores and the gold standard histopathologic diagnosis. Area under the receiver operating characteristic curve (AUC) was calculated as a performance metric. RESULTS: Forty-five of the consented patients were used in the final evaluation study. From these 45 patients, 63 tissue locations or samples were identified and imaged with the confocal microlaparoscope. Twenty of the samples were high-grade cancers, and the remaining 43 samples were normal or noncancerous. Twenty-three of the samples were imaged in vivo, and the remaining 40 samples were imaged ex vivo. The average AUC score and standard error (SE) for detection of cancer in all images were 0.88 and 0.02, respectively. An independent-samples t test was conducted to compare AUC scores for in vivo and ex vivo conditions. No statistically significant difference in the AUC score for in vivo (AUC, 0.850; SE, 0.049) and ex vivo (AUC, 0.888; SE, 0.027) conditions was observed, t(6) = 1.318, P = 0.2355. CONCLUSIONS: Area under the receiver operating characteristic curve scores indicate that high-resolution in vivo images obtained by the confocal laparoscope can distinguish between normal and malignant ovarian surface epithelium. In addition, in vivo performance is similar to that which can be obtained from ex vivo tissue. PMID- 26745698 TI - Adjuvant Treatment and Clinical Trials in Elderly Patients With Endometrial Cancer: A Time for Change? AB - OBJECTIVES: The aim of the study were to evaluate the gap between recommended and received adjuvant therapy in elderly patients with endometrial cancer (EC) and to determine the percent of women 70 years and older who would meet enrollment criteria for representative Gynecologic Oncology Group (GOG) trials. METHODS AND MATERIALS: An institutional review board approved retrospective chart review of all EC cases from a tertiary care institution from 2005 to 2010 was performed. Clinical, surgical, and pathologic data were abstracted from electronic medical records. Gynecologic Oncology Group protocols 249, 209, and 229L were selected as representative national EC trials. Patients were evaluated for eligibility by each protocol's criteria. RESULTS: Twenty-six percent (280/1064) of patients with EC were older than 70 years. More than 60% (181/280) of elderly patients with EC were recommended to undergo adjuvant therapy. By therapy type, 64% (48/75) of elderly patients who were recommended adjuvant radiation received it, 53% (49/92) of elderly patients who were recommended combination chemotherapy and radiation received it, and 29% (4/14) of elderly patients who were recommended chemotherapy received it. In evaluating enrollment criteria for GOG 249, 30% (40/134) of pathologically eligible patients would have been eliminated for medical clearance; for GOG 209, 31% (26/86) would have been eliminated, and for GOG 229L, 9% (4/45) would have been eliminated purely for medical reasons. CONCLUSIONS: More adjuvant treatment is recommended in the elderly patients because of a higher incidence of advanced disease and aggressive histopathology. Approximately half of the elderly patients who were recommended treatment actually received it. In addition, clinical trial data are limited for elderly patients because approximately one third of the women aged 70 years and older who meet pathologic enrollment criteria for trials were excluded because of complex medical disease. PMID- 26745699 TI - Adjuvant Chemotherapy and Vaginal Vault Brachytherapy With or Without Pelvic Radiotherapy for Stage 1 Papillary Serous or Clear Cell Endometrial Cancer. AB - OBJECTIVE: The aim of this study was to assess and compare adjuvant chemotherapy followed by either high-dose-rate vaginal vault brachytherapy (VBT) alone or combined with pelvic external beam radiotherapy (EBRT) for International Federation of Gynaecology and Obstetrics stage 1 serous or clear cell (CC) endometrial cancer. METHODS: Between 2006 and 2012, 84 women with stage 1 serous or CC endometrial cancer were evaluated postoperatively for adjuvant treatment at our hospital. More than 80% of patients had pelvic lymphadenectomy. Patients declining or not completing adjuvant treatments were excluded. Twenty-five women received 4 to 6 cycles of carboplatin/paclitaxel followed by EBRT and VBT. Thirty two women received 6 cycles of carboplatin/paclitaxel followed by VBT. Locoregional control and toxicities were assessed during follow-up. RESULTS: The 3-year disease-free survival and overall survival rates for the VBT group compared with the EBRT + VBT group were 88% versus 84%, P = 0.6, and 100% versus 94%, P = 0.6, respectively. Only 1 patient in the EBRT + VBT group developed a distant recurrence. One patient had grade 3 toxicity (chronic gastrointestinal [GI] toxicity) in the EBRT + VBT group. Acute grade 1-to-2 GI and grade 1 genitourinary (GU) toxicities were less frequent in the VBT group compared with the EBRT + VBT group (P = 0.008 and P = 0.019, respectively). Late GI and GU toxicities were comparable. Grade 1 vaginal toxicity was similar in both groups. No acute or late grade 2 GU or vaginal toxicities were reported. CONCLUSIONS: According to this study, VBT alone seems to be as effective as EBRT and VBT for stage 1 serous and CC endometrial cancer treated with surgery and adjuvant chemotherapy. Furthermore, less acute GI and GU toxicities were seen in the VBT group. PMID- 26745700 TI - Salvage Versus Adjuvant Radiation Treatment for Women With Early-Stage Endometrial Carcinoma: A Matched Analysis. AB - OBJECTIVES: Adjuvant radiation treatment (ART) has been shown to reduce local recurrences in early-stage endometrial carcinoma (EC); however, this has not translated into improved overall survival (OS) benefit. As a result, some physicians forgo ART, citing successful salvage rates in cases of recurrence. Survival end points were compared between women treated with salvage RT (SRT) for locoregional recurrence and similarly matched women treated upfront with ART. MATERIALS AND METHODS: We identified 40 patients with stage I to II type 1 EC who underwent hysterectomy and received no adjuvant RT but later developed locoregional recurrence and subsequently received SRT. An additional 374 patients who underwent hysterectomy followed by ART during the same period were identified. Patients in the SRT group were matched to those in the ART group based on FIGO (International Federation of Gynecology and Obstetrics) stage and tumor grade in a 1:3 ratio. Disease-specific survival (DSS) and OS were calculated. RESULTS: A total of 156 women were matched (39:117). Median follow-up was 56 months. The 2 groups were generally well balanced. With regard to the site of tumor recurrence, it was commonly vaginal in the SRT group (74.3% vs 28.6%, P = 0.01). More SRT patients received a combination of pelvic external-beam RT with vaginal brachytherapy (94.8% vs 35%, P < 0.001). The ART group had significantly better 5-year DSS (95% vs 77%, P < 0.001) and 5-year OS (79% vs 72%, P = 0.005) compared with those of the SRT group. CONCLUSIONS: Our study suggests that women who receive SRT for their locoregional recurrence have worse DSS and OS compared with those matched patients who received ART. Further studies are warranted to develop a high-quality cost-effectiveness analysis as well as accurate predictive models of tumor recurrence. Until then, ART should at least be considered in the management of early-stage EC patients with adverse prognostic factors. PMID- 26745701 TI - Three-Dimensional Power Doppler Ultrasound for Predicting Response and Local Recurrence After Concomitant Chemoradiation Therapy for Locally Advanced Carcinoma of the Cervix. AB - OBJECTIVE: The aim of this study was to assess the potential role of 3 dimensional power Doppler ultrasound (3D-PDUS) for predicting clinical response and recurrence after chemoradiotherapy in advanced-stage cervical cancer. METHODS: This is a prospective study comprising a series of women with histological proven diagnosis of locally advanced stage (stage IB2-IVA) carcinoma of the cervix and submitted to chemoradiaton therapy. Before the start of chemoradiation therapy, all women were submitted to undergo transvaginal 3D-PDUS for assessing tumor volume and tumor vascularization. After finishing chemoradiation, all women were evaluated to assess clinical response. Complete clinical response was determined when no residual tumor was apparent. Partial clinical response (PCR) was determined when persistent residual tumor was observed and confirmed by histological analysis. Patients with PCR underwent salvage surgery. Local recurrence was defined as reappearance of the tumor within the pelvis at any time during follow-up. RESULTS: Thirty-nine women (mean age, 50.3 years; ranging from 30 to 81 years) were included in the study. Complete clinical response was achieved in 29 women (70.7%), whereas 10 women (24.4%) had PCR. Eight women (20.5%) had local recurrence during follow-up. We did not find statistical significant differences in tumor size, volume, and vascularization between those women who had complete clinical response and those who had PCR and between those who had local recurrence and those who had not. CONCLUSIONS: A single 3D-PDUS assessment of tumor size and vascularization before treatment seems to be of limited value for predicting tumor response to chemoradiation therapy and for predicting tumor recurrence in women with locally advanced carcinoma of the cervix. PMID- 26745702 TI - An orthodontic bracket embedded in the medial pterygoid surface: a case report. AB - There is a potential risk that orthodontic brackets can become dislodged into the aerodigestive tract. This case illustrates the management of an orthodontic bracket, which became embedded in the deep tissues of the oropharynx. We aim to highlight the potential risk misplaced dental instruments and materials pose, including that they may become embedded in the soft tissues of the throat and suggest that that this possibility should be considered when they cannot be localized. PMID- 26745704 TI - Troubleshooting the NIHSS: question-and-answer session with one of the designers. PMID- 26745705 TI - The Multi-National survey on Epidemiology, Morbidity, and Outcomes iN Intracerebral Haemorrhage (MNEMONICH). PMID- 26745706 TI - Exploring cerebral small vessel disease research using informetrics: a first glimpse into microbleeds. PMID- 26745707 TI - Dural arteriovenous fistula presenting as a seizure mimicking transient ischemic attack: advantages of susceptibility-weighted imaging. PMID- 26745708 TI - Effect of atorvastatin co-treatment on inhibition of platelet activation by clopidogrel in patients with ischemic stroke. PMID- 26745709 TI - Recurrent abdominal pain in children: underlying pathologies in the absence of "alarm" symptoms. AB - BACKGROUND: Recurrent abdominal pain (RAP) is a common disorder in childhood. However, it is not clear what the incidence of organic disease is, in the absence of "alarm" symptoms or signs. The aim of this study was to clarify if the performance of diagnostic tests can be useful in revealing underlying organic disorders. METHODS: The participants were 4- to 16-year-old children, who had been referred to our tertiary care pediatric center. A total of 98 children (48 males, 50 females) with RAP but without any alarm symptoms or signs were selected. In the 98 selected children, the performance of diagnostic tests for suspected organic diseases was recommended. RESULTS: Fourteen children refused diagnostic tests. Forty-eight out of 84 children with RAP without any alarm symptoms and signs received a diagnosis of organic disease. Nineteen (22.6%) patients resulted positive for lactose intolerance. Seventeen patients (20.2%) were affected by celiac disease. Two (2.4%) patients were positive for cow milk allergy. Nine (10.7%) patients resulted positive for ureteral calculosis. One (1.2%) was affected by teniasis. Thirty-three children of the 38 children tested positive for lactose intolerance, celiac disease or cow-milk allergy were completely symptom-free at the 6 months follow-up and the remaining five patients reported a significant lower mean level of pain severity overall. Seven of 9 children with calculosis improved symptomatology. At the next follow-up six children were again suffering from RAP. CONCLUSIONS: Children with RAP should be referred to pediatric gastroenterologists if symptoms persist; testing should be performed even in the absence of alarm signs because of the high prevalence of underlying organic pathologies. PMID- 26745710 TI - Bidirectional relations between phonological awareness and letter knowledge in preschool revisited: A growth curve analysis of the relation between two code related skills. AB - Despite the importance of phonological awareness for the development of reading in alphabetic languages, little attention has been paid to its developmental origins. In this study, dual-process, latent growth models were used to examine patterns of bidirectional relations between letter knowledge and phonological awareness during preschool. The sample comprised 358 children (mean age=48.60 months, SD=7.26). Growth models were used to quantify the unique longitudinal relations between the initial level of each skill and growth in the other skill during the preschool year, after controlling for initial level of the same skill, vocabulary, age, and growth in the code-related skill being used as a predictor. Letter-name knowledge and phonological awareness were bidirectionally related; the initial level of each uniquely predicted growth in the other. Initial letter sound knowledge and phonological awareness growth were not uniquely related, and vocabulary was not related to growth in phonological awareness. These findings extend the evidence of the relation between letter knowledge and phonological awareness to supra-phonemic tasks, indicating that this bidirectional relation begins at an earlier point in the development of phonological awareness than previously reported. In addition, these findings help to rule out general growth in letter knowledge and phonological awareness as an alternative explanation for the bidirectional relation between these two code-related skills. PMID- 26745711 TI - Elevated Progesterone Levels on the Day of Oocyte Maturation May Affect Top Quality Embryo IVF Cycles. AB - In contrast to the impact of elevated progesterone on endometrial receptivity, the data on whether increased progesterone levels affects the quality of embryos is still limited. This study retrospectively enrolled 4,236 fresh in vitro fertilization (IVF) cycles and sought to determine whether increased progesterone is associated with adverse outcomes with regard to top quality embryos (TQE). The results showed that the TQE rate significantly correlated with progesterone levels on the day of human chorionic gonadotropin (hCG) trigger (P = 0.009). Multivariate linear regression analysis of factors related to the TQE rate, in conventional IVF cycles, showed that the TQE rate was negatively associated with progesterone concentration on the day of hCG (OR was -1.658, 95% CI: -2.806 to 0.510, P = 0.005). When the serum progesterone level was within the interval 2.0 2.5 ng/ml, the TQE rate was significantly lower (P <0.05) than when the progesterone level was < 1.0 ng/ml; similar results were obtained for serum progesterone levels >2.5 ng/ml. Then, we choose a progesterone level at 1.5ng/ml, 2.0 ng/ml and 2.5 ng/ml as cut-off points to verify this result. We found that the TQE rate was significantly different (P <0.05) between serum progesterone levels < 2.0 ng/ml and >2.0 ng/ml. In conclusion, the results of this study clearly demonstrated a negative effect of elevated progesterone levels on the day of hCG trigger, on TQE rate, regardless of the basal FSH, the total gonadotropin, the age of the woman, or the time of ovarian stimulation. These data demonstrate that elevated progesterone levels (>2.0 ng/ml) before oocyte maturation were consistently detrimental to the oocyte. PMID- 26745712 TI - 4,7-Dimethoxy-5-methyl-1,3-benzodioxole from Antrodia camphorata inhibits LPS induced inflammation via suppression of NF-kappaB and induction HO-1 in RAW264.7 cells. AB - Several benzenoid compounds have been isolated from Antrodia camphorata are known to have excellent anti-inflammatory activity. In this study, we investigated the anti-inflammatory potential of 4,7-dimethoxy-5-methyl-1,3-benzodioxole (DMB), one of the major benzenoid compounds isolated from the mycelia of A. camphorata. DMB significantly decreased the LPS-induced production of pro-inflammatory molecules, such as nitric oxide (NO), interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha) in RAW264.7 cells. In addition, DMB suppressed the protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in a dose dependent manner. Moreover, DMB significantly suppressed LPS induced nuclear translocation of nuclear factor-kappaB (NF-kappaB), and this inhibition was found to be associated with decreases in the phosphorylation and degradation of its inhibitor, inhibitory kappaB-alpha (IkappaB-alpha). Moreover, we found that DMB markedly inhibited the protein expression level of Toll-like receptor 4 (TLR4). Furthermore, treatment with DMB significantly increased hemoxygenase-1 (HO-1) expression in RAW264.7 cells, which is further confirmed by hemin, a HO-1 enhancer, significantly attenuated the LPS-induced pro-inflammatory molecules and iNOS and TLR4 protein levels. Taken together, the present study suggests that DMB may have therapeutic potential for the treatment of inflammatory diseases. PMID- 26745713 TI - Suppression of macrophage-mediated phagocytosis of apoptotic cells by soluble beta-glucan due to a failure of PKC-betaII translocation. AB - If apoptotic cells are not removed efficiently, they may proceed to the stage of secondary necrosis, which would cause inflammation. Therefore, identification of cause(s) and agent(s) for down-modulating phagocytosis of apoptotic cells would help understand the pathologies. In this study we found that macrophage-mediated phagocytosis of apoptotic cells was suppressed by both soluble and particulate beta-glucan. This suppression was not observed when secondary necrotic cells were used. The adhesion of apoptotic cells to macrophages was not suppressed by soluble beta-glucan, suggesting that soluble beta-glucan suppresses phagocytosis at a post-adhesion step. Experiments involving PKC inhibitors suggested that PKC betaII is required for phagocytosis of apoptotic cells but not secondary necrotic ones by macrophages. Translocation of GFP-PKC-betaII from the cytoplasm to membranes occurred upon interaction with apoptotic cells but not secondary necrotic ones. Such translocation was inhibited by soluble beta-glucan. Overall, this study suggests that suppression of macrophage-mediated phagocytosis of apoptotic cells by soluble beta-glucan is due to a failure of PKC-betaII translocation. PMID- 26745714 TI - BDNF Serum Levels with Respect to Multidimensional Assessment in Amyotrophic Lateral Sclerosis. AB - BACKGROUND: The clinical presentation of amyotrophic lateral sclerosis (ALS) is characterized by high heterogeneity, the greatest part of which still remains unexplained. OBJECTIVE: To assess serum levels of brain-derived neurotrophic factor (BDNF) in ALS patients, implementing a multidimensional characterization focused on four a priori chosen elements of phenotypic variability: ALS bulbar/spinal subtype, cognitive impairment, mood dysfunction and disease progression speed. METHODS: Serum samples were obtained from 45 ALS outpatients (16% bulbar onset) and 22 healthy controls. Each patient underwent the Montreal Cognitive Assessment (MoCA) and the Beck Depression Inventory (BDI), and disease progression speed was estimated by calculating the decay of the ALSFRS-R score over time. RESULTS: BDNF serum levels did not differ between patients and controls, although ~25% lower levels characterized those patients carrying a depressive trait. Finally, BDNF serum levels were significantly lower in ALS patients expressing lower ALSFRS-R scores (r = 0.39, p < 0.01). No differences were found when considering cognitive impairment, disease progression speed and site of onset. CONCLUSION: BDNF serum levels might mark and possibly contribute in part to ALS phenotypic variability. PMID- 26745715 TI - Predictors of Dropout by Female Obese Patients Treated with a Group Cognitive Behavioral Therapy to Promote Weight Loss. AB - OBJECTIVE: To investigate predictors of dropout from a group cognitive behavioral therapy (CBT) intervention for overweight or obese women. METHODS: 119 overweight and obese Japanese women aged 25-65 years who attended an outpatient weight loss intervention were followed throughout the 7-month weight loss phase. Somatic characteristics, socioeconomic status, obesity-related diseases, diet and exercise habits, and psychological variables (depression, anxiety, self-esteem, alexithymia, parenting style, perfectionism, and eating attitude) were assessed at baseline. Significant variables, extracted by univariate statistical analysis, were then used as independent variables in a stepwise multiple logistic regression analysis with dropout as the dependent variable. RESULTS: 90 participants completed the weight loss phase, giving a dropout rate of 24.4%. The multiple logistic regression analysis demonstrated that compared to completers the dropouts had significantly stronger body shape concern, tended to not have jobs, perceived their mothers to be less caring, and were more disorganized in temperament. Of all these factors, the best predictor of dropout was shape concern. CONCLUSION: Shape concern, job condition, parenting care, and organization predicted dropout from the group CBT weight loss intervention for overweight or obese Japanese women. PMID- 26745716 TI - The Combination of X-Ray Crystallography and Cryo-Electron Microscopy Provides Insight into the Overall Architecture of the Dodecameric Rvb1/Rvb2 Complex. AB - The Rvb1/Rvb2 complex is an essential component of many cellular pathways. The Rvb1/Rvb2 complex forms a dodecameric assembly where six copies of each subunit form two heterohexameric rings. However, due to conformational variability, the way the two rings pack together is still not fully understood. Here, we present the crystal structure and two cryo-electron microscopy reconstructions of the dodecameric, full-length Rvb1/Rvb2 complex, all showing that the interaction between the two heterohexameric rings is mediated through the Rvb1/Rvb2-specific domain II. Two conformations of the Rvb1/Rvb2 dodecamer are present in solution: a stretched conformation also present in the crystal, and a compact conformation. Novel asymmetric features observed in the reconstruction of the compact conformation provide additional insight into the plasticity of the Rvb1/Rvb2 complex. PMID- 26745718 TI - HABP2 G534E Variant in Papillary Thyroid Carcinoma. AB - The main nonmedullary form of thyroid cancer is papillary thyroid carcinoma (PTC) that accounts for 80-90% of all thyroid malignancies. Only 3-10% of PTC patients have a positive family history of PTC yet the familiality is one of the highest of all cancers as measured by case control studies. A handful of genes have been implicated accounting for a small fraction of this genetic predisposition. It was therefore of considerable interest that a mutation in the HABP2 gene was recently implicated in familial PTC. The present work was undertaken to examine the extent of HABP2 variant involvement in PTC. The HABP2 G534E variant (rs7080536) was genotyped in blood DNA from 179 PTC families (one affected individual per family), 1160 sporadic PTC cases and 1395 controls. RNA expression of HABP2 was tested by qPCR in RNA extracted from tumor and normal thyroid tissue from individuals that are homozygous wild-type or heterozygous for the variant. The variant was found to be present in 6.1% familial cases, 8.0% sporadic cases (2 individuals were homozygous for the variant) and 8.7% controls. The variant did not segregate with PTC in one large and 6 smaller families in which it occurred. In keeping with data from the literature and databases the expression of HABP2 was highest in the liver, much lower in 3 other tested tissues (breast, kidney, brain) but not found in thyroid. Given these results showing lack of any involvement we suggest that the putative role of variant HABP2 in PTC should be carefully scrutinized. PMID- 26745717 TI - Long-Term Clinical Outcome of Internal Globus Pallidus Deep Brain Stimulation for Dystonia. AB - BACKGROUND: GPi (Internal globus pallidus) DBS (deep brain stimulation) is recognized as a safe, reliable, reversible and adjustable treatment in patients with medically refractory dystonia. OBJECTIVES: This report describes the long term clinical outcome of 36 patients implanted with GPi DBS at the Neurosurgery Department of Seoul National University Hospital. METHODS: Nine patients with a known genetic cause, 12 patients with acquired dystonia, and 15 patients with isolated dystonia without a known genetic cause were included. When categorized by phenomenology, 29 patients had generalized, 5 patients had segmental, and 2 patients had multifocal dystonia. Patients were assessed preoperatively and at defined follow-up examinations postoperatively, using the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) for movement and functional disability assessment. The mean follow-up duration was 47 months (range, 12-84). RESULTS: The mean movement scores significantly decreased from 44.88 points preoperatively to 26.45 points at 60-month follow up (N = 19, P = 0.006). The mean disability score was also decreased over time, from 11.54 points preoperatively to 8.26 points at 60 month follow up, despite no statistical significance (N = 19, P = 0.073). When analyzed the movement and disability improvement rates at 12-month follow up point, no significant difference was noted according to etiology, disease duration, age at surgery, age of onset, and phenomenology. However, the patients with DYT-1 dystonia and isolated dystonia without a known genetic cause showed marked improvement. CONCLUSIONS: GPi DBS is a safe and efficient therapeutic method for treatment of dystonia patients to improve both movement and disability. However, this study has some limitations caused by the retrospective design with small sample size in a single-center. PMID- 26745721 TI - Strengthening of Mg based alloy through grain refinement for orthopaedic application. AB - Magnesium is presently attracting a lot of interest as a replacement to clinically used orthopaedic implant materials, due to its ability to solve the stress shielding problems, biodegradability and osteocompatibility. However, the strength of Mg is still lower than the requirement and it becomes worse after it starts degrading fast, while being exposed in living body environment. This research explores the effectiveness of 'grain refinement through deformation', as a tool to modify the strength (while keeping elastic modulus unaffected) of Mg based alloys in orthopaedic application. Hot rolled Mg-3wt% Zn alloy (MZ3) has been investigated for its potential in orthopaedic implant. Microstructure, mechanical properties, bio-corrosion properties and biocompatibility of the rolled samples are probed into. Grain size gets refined significantly with increasing amount of deformation. The alloy experiences a marked improvement in hardness, yield strength, ultimate tensile strength, strain and toughness with finer grain size. An increment in accelerated corrosion rate is noted with decreasing grain size, which is correlated to the increased grain boundary area and mechano-chemical dissolution. However, immersion test in simulated body fluid (SBF) reveals reduction in corrosion rate after third day of immersion. This was possible owing to precipitation of protective hydroxyapatite (HA) layer, formed out of the interaction of SBF and the alloy. More nucleation sites at the grain boundary for fine grained samples help in forming more HA and thus reduce the corrosion rate. Human osteosarcoma cells show less viability and adhesion on grain refined alloy. PMID- 26745720 TI - Cytocompatibility, mechanical and dissolution properties of high strength boron and iron oxide phosphate glass fibre reinforced bioresorbable composites. AB - In this study, Polylactic acid (PLA)/phosphate glass fibres (PGF) composites were prepared by compression moulding. Fibres produced from phosphate based glasses P2O5-CaO-MgO-Na2O (P45B0), P2O5-CaO-MgO-Na2O-B2O3 (P45B5), P2O5-CaO-MgO-Na2O Fe2O3 (P45Fe3) and P2O5-CaO-MgO-Na2O-B2O3-Fe2O3 (P45B5Fe3) were used to reinforce the bioresorbable polymer PLA. Fibre mechanical properties and degradation rate were investigated, along with the mechanical properties, degradation and cytocompatibility of the composites. Retention of the mechanical properties of the composites was evaluated during degradation in PBS at 37 degrees C for four weeks. The fibre volume fraction in the composite varied from 19 to 23%. The flexural strength values (ranging from 131 to 184MPa) and modulus values (ranging from 9.95 to 12.29GPa) obtained for the composites matched those of cortical bone. The highest flexural strength (184MPa) and modulus (12.29GPa) were observed for the P45B5Fe3 composite. After 28 days of immersion in PBS at 37 degrees C, ~35% of the strength profile was maintained for P45B0 and P45B5 composites, while for P45Fe3 and P45B5Fe3 composites ~40% of the initial strength was maintained. However, the overall wet mass change of P45Fe3 and P45B5Fe3 remained significantly lower than that of the P45B0 and P45B5 composites. The pH profile also revealed that the P45B0 and P45B5 composites degraded quicker, correlating well with the degradation profile. From SEM analysis, it could be seen that after 28 days of degradation, the fibres in the fractured surface of P45B5Fe3 composites remain fairly intact as compared to the other formulations. The in vitro cell culture studies using MG63 cell lines revealed both P45Fe3 and P45B5Fe3 composites maintained and showed higher cell viability as compared to the P45B0 and P45B5 composites. This was attributed to the slower degradation rate of the fibres in P45Fe3 and P45B5Fe3 composites as compared with the fibres in P45B0 and P45B5 composites. PMID- 26745722 TI - Analysis of the Maize dicer-like1 Mutant, fuzzy tassel, Implicates MicroRNAs in Anther Maturation and Dehiscence. AB - Sexual reproduction in plants requires development of haploid gametophytes from somatic tissues. Pollen is the male gametophyte and develops within the stamen; defects in the somatic tissues of the stamen and in the male gametophyte itself can result in male sterility. The maize fuzzy tassel (fzt) mutant has a mutation in dicer-like1 (dcl1), which encodes a key enzyme required for microRNA (miRNA) biogenesis. Many miRNAs are reduced in fzt, and fzt mutants exhibit a broad range of developmental defects, including male sterility. To gain further insight into the roles of miRNAs in maize stamen development, we conducted a detailed analysis of the male sterility defects in fzt mutants. Early development was normal in fzt mutant anthers, however fzt anthers arrested in late stages of anther maturation and did not dehisce. A minority of locules in fzt anthers also exhibited anther wall defects. At maturity, very little pollen in fzt anthers was viable or able to germinate. Normal pollen is tricellular at maturity; pollen from fzt anthers included a mixture of unicellular, bicellular, and tricellular pollen. Pollen from normal anthers is loaded with starch before dehiscence, however pollen from fzt anthers failed to accumulate starch. Our results indicate an absolute requirement for miRNAs in the final stages of anther and pollen maturation in maize. Anther wall defects also suggest that miRNAs have key roles earlier in anther development. We discuss candidate miRNAs and pathways that might underlie fzt anther defects, and also note that male sterility in fzt resembles water deficit-induced male sterility, highlighting a possible link between development and stress responses in plants. PMID- 26745719 TI - CFLAP1 and CFLAP2 Are Two bHLH Transcription Factors Participating in Synergistic Regulation of AtCFL1-Mediated Cuticle Development in Arabidopsis. AB - The cuticle is a hydrophobic lipid layer covering the epidermal cells of terrestrial plants. Although many genes involved in Arabidopsis cuticle development have been identified, the transcriptional regulation of these genes is largely unknown. Previously, we demonstrated that AtCFL1 negatively regulates cuticle development by interacting with the HD-ZIP IV transcription factor HDG1. Here, we report that two bHLH transcription factors, AtCFL1 associated protein 1 (CFLAP1) and CFLAP2, are also involved in AtCFL1-mediated regulation of cuticle development. CFLAP1 and CFLAP2 interact with AtCFL1 both in vitro and in vivo. Overexpression of either CFLAP1 or CFLAP2 led to expressional changes of genes involved in fatty acids, cutin and wax biosynthesis pathways and caused multiple cuticle defective phenotypes such as organ fusion, breakage of the cuticle layer and decreased epicuticular wax crystal loading. Functional inactivation of CFLAP1 and CFLAP2 by chimeric repression technology caused opposite phenotypes to the CFLAP1 overexpressor plants. Interestingly, we find that, similar to the transcription factor HDG1, the function of CFLAP1 in cuticle development is dependent on the presence of AtCFL1. Furthermore, both HDG1 and CFLAP1/2 interact with the same C-terminal C4 zinc finger domain of AtCFL1, a domain that is essential for AtCFL1 function. These results suggest that AtCFL1 may serve as a master regulator in the transcriptional regulation of cuticle development, and that CFLAP1 and CFLAP2 are involved in the AtCFL1-mediated regulation pathway, probably through competing with HDG1 to bind to AtCFL1. PMID- 26745723 TI - Socio-Environmental Factors Associated with the Risk of Contracting Buruli Ulcer in Tiassale, South Cote d'Ivoire: A Case-Control Study. AB - BACKGROUND: Buruli ulcer (BU) is a cutaneous infectious disease caused by Mycobacterium ulcerans. The exact mode of transmission remains elusive; yet, some studies identified environmental, socio-sanitary, and behavioral risk factors. The purpose of this study was to assess the association of such factors to contracting BU in Tiassale, south Cote d'Ivoire. METHODOLOGY: A case-control study was conducted in 2012. Cases were BU patients diagnosed according to clinical definition put forth by the World Health Organization, readily confirmed by IS2404 polymerase chain reaction (PCR) analysis prior to our study and recruited at one of the health centers of the district. Two controls were matched for each control, by age group (to the nearest 5 years), sex, and living community. Participants were interviewed after providing oral witnessed consent, assessing behavioral, environmental, and socio-sanitary factors. PRINCIPAL FINDINGS: A total of 51 incident and prevalent cases and 102 controls were enrolled. Sex ratio (male:female) was 0.9. Median age was 25 years (range: 5-70 years). Regular contact with unprotected surface water (adjusted odds ratio (aOR) = 6.5; 95% confidence interval (CI) = 2.1-19.7) and absence of protective equipment during agricultural activities (aOR = 18.5, 95% CI = 5.2-66.7) were identified as the main factors associated with the risk of contracting BU. Etiologic fractions among exposed to both factors were 84.9% and 94.6%, respectively. Good knowledge about the risks that may result in BU (aOR = 0.3, 95% CI = 0.1-0.8) and perception about the disease causes (aOR = 0.1, 95% CI = 0.02-0.3) showed protection against BU with a respective preventive fraction of 70% and 90%. CONCLUSIONS/SIGNIFICANCE: Main risk factors identified in this study were the contact with unprotected water bodies through daily activities and the absence of protective equipment during agricultural activities. An effective strategy to reduce the incidence of BU should involve compliance with protective equipment during agricultural activities and avoidance of contact with surface water and community capacity building through training and sensitization. PMID- 26745725 TI - Novel Anderson-type [TeMo6O24](6-)-based metal-organic complexes tuned by different species and their coordination modes: assembly, various architectures and properties. AB - Four novel Anderson-type polyoxometalates (POMs) [TeMo6O24](6-) (TeMo6)-based metal-organic complexes (MOCs), namely, H2[Zn4(3-Hdpyp)2(TeMo6O24)2(H2O)16].6H2O (1), [Zn3(3-dpyb)2(TeMo6O24)(H2O)12].8H2O (2), [Cu2(4 Hdpyp)2(TeMo6O24)(H2O)6].4H2O (3), and [Cu3(3-dpyp)2(TeMo6O24)(H2O)8].4H2O (4) (3 dpyp = N,N'-bis(3-pyridinecarboxamide)-1,3-propane, 3-dpyb = N,N'-bis(3 pyridinecarboxamide)-1,4-butane, 4-dpyp = N,N'-bis(4-pyridinecarboxamide)-1,3 propane), were hydrothermally synthesized and structurally characterized by single-crystal X-ray diffraction, IR spectra, powder X-ray diffraction (PXRD) and thermogravimetric analyses (TGA). In complex 1, two TeMo6 polyoxoanions bridge Zn(II) ions to generate a discrete tetranuclear zinc complex H2[Zn4(3 Hdpyp)2(TeMo6O24)2(H2O)16]. In 2, the TeMo6 anions connect the metal-organic units [Zn3(3-dpyb)2](6+) to form an Anderson-type TeMo6-based wave-like metal organic chain. Both the discrete tetranuclear subunits in 1 and 1D wavy chains in 2 were further extended to 2D supramolecular networks through the hydrogen bonding interactions. In complex 3, the TeMo6 anions link the metal-organic units [Cu2(4-Hdpyp)2](6+) to construct a 2D layer, which is further extended to a 3D supramolecular framework by the hydrogen bonding interactions. In complex 4, the TeMo6 polyoxoanions bridge the Cu(II) ions to generate a 2D Cu-TeMo6 inorganic layer, which is further linked by the MU2-bridging 3-dpyp ligands to form a 3D metal-organic framework. The effects of various coordination modes of TeMo6 polyanions and the bis-pyridyl-bis-amide ligands, as well as the central metals on the structures of the title complexes have been discussed. Besides, the fluorescence, electrochemical properties and photocatalytic activities of the title complexes have been investigated in detail. PMID- 26745724 TI - Phospholipid Scramblase 1 Modulates FcR-Mediated Phagocytosis in Differentiated Macrophages. AB - Phospholipid Scramblase 1 (PLSCR1) was initially characterized as a type II transmembrane protein involved in bilayer movements of phospholipids across the plasma membrane leading to the cell surface exposure of phosphatidylserine, but other cellular functions have been ascribed to this protein in signaling processes and in the nucleus. In the present study, expression and functions of PLSCR1 were explored in specialized phagocytic cells of the monocyte/macrophage lineage. The expression of PLSCR1 was found to be markedly increased in monocyte derived macrophages compared to undifferentiated primary monocytes. Surprisingly, this 3-fold increase in PLSCR1 expression correlated with an apparent modification in the membrane topology of the protein at the cell surface of differentiated macrophages. While depletion of PLSCR1 in the monocytic THP-1 cell line with specific shRNA did not inhibit the constitutive cell surface exposure of phosphatidylserine observed in differentiated macrophages, a net increase in the FcR-mediated phagocytic activity was measured in PLSCR1-depleted THP-1 cells and in bone marrow-derived macrophages from PLSCR1 knock-out mice. Reciprocally, phagocytosis was down-regulated in cells overexpressing PLSCR1. Since endogenous PLSCR1 was recruited both in phagocytic cups and in phagosomes, our results reveal a specific role for induced PLSCR1 expression in the modulation of the phagocytic process in differentiated macrophages. PMID- 26745726 TI - Correction: A Conserved NS3 Surface Patch Orchestrates NS2 Protease Stimulation, NS5A Hyperphosphorylation and HCV Genome Replication. AB - [This corrects the article DOI: 10.1371/journal.ppat.1004736.]. PMID- 26745727 TI - Graphene Oxide Papers Simultaneously Doped with Mg(2+) and Cl(-) for Exceptional Mechanical, Electrical, and Dielectric Properties. AB - This paper reports simultaneous modification of graphene oxide (GO) papers by functionalization with MgCl2. The Mg(2+) ions enhance both the interlayer cross links and lateral bridging between the edges of adjacent GO sheets by forming Mg O bonds. The improved load transfer between the GO sheets gives rise to a maximum of 200 and 400% increases in Young's modulus and tensile strength of GO papers. The intercalation of chlorine between the GO layers alters the properties of GO papers in two ways by forming ionic Cl(-) and covalent C-Cl bonds. The p-doping effect arising from Cl contributes to large enhancements in electrical conductivities of GO papers, with a remarkable 2500-fold surge in the through thickness direction. The layered structure and the anisotropic electrical conductivities of reduced GO papers naturally create numerous nanocapacitors that lead to charge accumulation based on the Maxwell-Wagner (MW) polarization. The combined effect of much promoted dipolar polarizations due to Mg-O, C-Cl, and Cl( ) species results in an exceptionally high dielectric constant greater than 60 000 and a dielectric loss of 3 at 1 kHz by doping with 2 mM MgCl2. The excellent mechanical and electrical properties along with unique dielectric performance shown by the modified GO and rGO papers open new avenues for niche applications, such as electromagnetic interference shielding materials. PMID- 26745728 TI - Social Welfare Centers Protect Outpatients with Mood Disorders from Risk of Hospital Admission. AB - BACKGROUND: South Korea faces difficulties in the management of mental disorders, and those difficulties are expected to gradually worsen. Therefore, we analyzed the relationship between social welfare centers and hospital admission after outpatient treatment for mood disorders. METHODS: We used data from the National Health Insurance Service National Sample Cohort 2002-2013, which included all medical claims filed for the 50,160 patients who were newly diagnosed with a mood disorder among the 1,025,340 individuals in a nationally representative sample. We performed a logistic regression analysis using generalized estimating equation (GEE) models to examine the relationship between social welfare centers and hospital admission after outpatient treatment for mood disorders (ICD-10: F3). RESULTS: There was a 3.9% admission rate among a total of 99,533 person-years. Outpatients who lived in regions with more social welfare centers were less likely to be admitted to a hospital (per increase of five social welfare centers per 100,000 people; OR: 0.958; 95% CI: 0.919-0.999). Social welfare centers had an especially strong protective effect on patients with relatively mild mood disorders and those who were vulnerable to medical expenditures. CONCLUSIONS: Considering the protective role of social welfare centers in managing patients with mood disorders, health-policy makers need to consider strategies for activating mental healthcare. PMID- 26745729 TI - Development and Application of a High Throughput Protein Unfolding Kinetic Assay. AB - The kinetics of folding and unfolding underlie protein stability and quantification of these rates provides important insights into the folding process. Here, we present a simple high throughput protein unfolding kinetic assay using a plate reader that is applicable to the studies of the majority of 2 state folding proteins. We validate the assay by measuring kinetic unfolding data for the SH3 (Src Homology 3) domain from Actin Binding Protein 1 (AbpSH3) and its stabilized mutants. The results of our approach are in excellent agreement with published values. We further combine our kinetic assay with a plate reader equilibrium assay, to obtain indirect estimates of folding rates and use these approaches to characterize an AbpSH3-peptide hybrid. Our high throughput protein unfolding kinetic assays allow accurate screening of libraries of mutants by providing both kinetic and equilibrium measurements and provide a means for in depth phi-value analyses. PMID- 26745731 TI - The Use of Finite Element Analysis to Enhance Research and Clinical Practice in Orthopedics. AB - Finite element analysis (FEA) is a very powerful tool for the evaluation of biomechanics in orthopedics. Finite element (FE) simulations can effectively and efficiently evaluate thousands of variables (such as implant variation, surgical techniques, and various pathologies) to optimize design, screening, prediction, and treatment in orthopedics. Additionally, FEA can be used to retrospectively evaluate and troubleshoot complications or failures to prevent similar future occurrences. Finally, FE simulations are used to evaluate implants, procedures, and techniques in a time- and cost-effective manner. In this work, an overview of the development of FE models is provided and an example application is presented to simulate knee biomechanics for a specimen with medial meniscus insufficiency. FE models require the development of the geometry of interest, determination of the material properties of the tissues simulated, and an accurate application of a numerical solver to produce an accurate solution and representation of the field variables. The objectives of this work are to introduce the reader to the application of FEA in orthopedic analysis of the knee joint. A brief description of the model development process as well as a specific application to the investigation of knee joint stability in geometries with normal or compromised medial meniscal attachment is included. Significant increases in stretch of the anterior cruciate ligament were predicted in specimens with medial meniscus insufficiency (such behavior was confirmed in corresponding biomechanical testing). It can be concluded from this work that FE analysis of the knee can provide significant new information with which more effective clinical decisions can be made. PMID- 26745730 TI - Infrared and skin: Friend or foe. AB - In the last decade, it has been proposed that the sun's IR-A wavelengths might be deleterious to human skin and that sunscreens, in addition to their desired effect to protect against UV-B and UV-A, should also protect against IR-A (and perhaps even visible light). Several studies showed that NIR may damage skin collagen content via an increase inMMP-1 activity in the same manner as is known for UVR. Unfortunately, the artificial NIR light sources used in such studies were not representative of the solar irradiance. Yet, little has been said about the other side of the coin. This article will focus on key information suggesting that IR-A may be more beneficial than deleterious when the skin is exposed to the appropriate irradiance/dose of IR-A radiation similar to daily sun exposure received by people in real life.IR-A might even precondition the skin--a process called photo prevention--from an evolutionary standpoint since exposure to early morning IR-A wavelengths in sunlight may ready the skin for the coming mid-day deleterious UVR. Consequently IR-A appears to be the solution, not the problem. It does more good than bad for the skin. It is essentially a question of intensity and how we can learn from the sun. (c) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). PMID- 26745732 TI - Oxidative burden of fine particulate air pollution and risk of cause-specific mortality in the Canadian Census Health and Environment Cohort (CanCHEC). AB - BACKROUND: Fine particulate air pollution (PM2.5) is known to contribute to cardiorespiratory mortality but it is not clear how PM2.5 oxidative burden (i.e. the ability of PM2.5 to cause oxidative stress) may influence long-term mortality risk. METHODS: We examined the relationship between PM2.5 oxidative burden and cause-specific mortality in Ontario, Canada. Integrated PM2.5 samples were collected from 30 provincial monitoring sites between 2012 and 2013. The oxidative potential (% depletion/ug) of regional PM2.5 was measured as the ability of filter extracts to deplete antioxidants (glutathione and ascorbate) in a synthetic respiratory tract lining fluid. PM2.5oxidative burden was calculated as the product of PM2.5 mass concentrations and regional estimates of oxidative potential. In total, this study included 193,300 people who completed the Canadian long-form census in 1991 and who lived within 5km of a site where oxidative potential was measured. Deaths occurring between 1991 and 2009 were identified through record linkages and Cox proportional hazard models were used to estimate hazard ratios (and 95% confidence intervals) for interquartile changes in exposure adjusting for individual-level covariates and indirect adjustment for smoking and obesity. RESULTS: Glutathione-related oxidative burden was associated with cause-specific mortality. For lung cancer specifically, this metric was associated with a 12% (95% CI: 5.0-19) increased risk of mortality whereas a 5.0% (95% CI: 0.1, 10) increase was observed for PM2.5. Indirect adjustment for smoking and obesity decreased the lung cancer hazard ratio for glutathione-related oxidative burden but it remained significantly elevated (HR=1.07, 95% CI: 1.005, 1.146). Ascorbate-related oxidative burden was not associated with mortality. CONCLUSIONS: Our findings suggest that glutathione related oxidative burden may be more strongly associated with lung cancer mortality than PM2.5 mass concentrations. PMID- 26745736 TI - Managing drug-resistant organisms in acute care. AB - The purpose of this article is to provide practitioners with therapeutic considerations for infections caused by drug-resistant organisms in the acute care setting. Proper identification of organisms and appropriate use of antibiotics are imperative strategies to help reduce the development and spread of antimicrobial resistance. PMID- 26745733 TI - Mercury exposure and a shift toward oxidative stress in avid seafood consumers. AB - Mechanisms of mercury (Hg) toxicity at low doses from seafood consumption, the most common exposure route, are not well understood. We tested the hypothesis that seafood Hg exposure is related to a shift in redox status, indicated by a decrease in the ratio of reduced to oxidized glutathione (GSH:GSSG) in blood, or increase in redox potential (Eh). We also examined whether key seafood nutrients (selenium (Se), omega-3 fatty acids) confound or modify this shift. We measured blood concentrations of total Hg, Se, GSH, GSSG, and the Omega-3 Index (% omega 3s of total fatty acids in red blood cell membranes) in seafood consumers in Long Island, NY. We examined relationships between Hg, GSH:GSSG ratio and Eh. Elevated blood Hg (>5.8ugL(-1)) was associated with lower GSH:GSSG (beta=-116.73, p=0.01), with no evidence of confounding by Se or Omega-3 Index. However, in models stratified by Omega-3 Index levels, Hg-GSH:GSSG associations were weakened among those with high Omega-3 Index levels (>6% of fatty acids, beta=-63.46, p=0.28), and heightened among those with low Omega-3 Index (beta=-182.53, p<0.01). We observed comparable patterns for Eh in relation to Hg. These results support the hypothesis that Hg exposure from seafood is linked to a shift in redox status toward oxidative stress, modified by omega-3 fatty acids in this population. Further work should examine the role of different seafood nutrients and Hg induced shifts in redox status in the diverse health effects associated with elevated Hg exposure. PMID- 26745735 TI - Encapsulation of Vitamin B(1) and Its Phosphate Derivatives by Cucurbit[7]uril: Tunability of the Binding Site and Affinity by the Presence of Phosphate Groups. AB - Vitamin B1 (1) and its phosphate derivatives, thiamine monophosphate (2) and thiamine pyrophosphate (3), are shown to form stable 1:1 host-guest complexes with cucurbit[7]uril (CB[7]) in aqueous solution. The binding sites of CB[7] on these guests shift from the ethylthiazolium region of 1 to the pyrimidine moiety of 2 and 3 due to the presence of phosphate groups, leading to variations of binding affinities as well as C(2)-H/D exchange rate constants and C(2)-H pKa values with these guest molecules. PMID- 26745737 TI - The Million Hearts initiative: Guidelines and best practices. AB - Million Hearts is a national initiative to improve the nation's cardiovascular health through evidence-based practices and prevention. This article reviews the ABCS of Million Hearts with an emphasis on NP-led care models. Recommendations for clinical practice, education, research, and health policy are highlighted. PMID- 26745738 TI - Optimization of methane production in anaerobic co-digestion of poultry litter and wheat straw at different percentages of total solid and volatile solid using a developed response surface model. AB - Poultry litter (PL) can be good feedstock for biogas production using anaerobic digestion. In this study, methane production from batch co-digestion of PL and wheat straw (WS) was investigated for two factors, i.e., total solid (2%, 5%, and 10%) and volatile solid (0, 25, and 50% of WS), constituting a 3 * 3 experimental design. The results showed that the maximum specific methane volume [197 mL (g VS)(-1)] was achieved at 50% VS from WS at 5% TS level. It was estimated that the inhibitory threshold of free ammonia was about 289 mg L(--1), beyond which reduction of methanogenic activity by at least 54% was observed. The specific methane volume and COD removal can be expressed using two response surface models (R(2) = 0.9570 and 0.9704, respectively). Analysis of variance of the experimental results indicated that the C/N ratio was the most significant factor influencing the specific methane volume and COD removal in the co-digestion of these two materials. PMID- 26745734 TI - Environmental stress in the Gulf of Mexico and its potential impact on public health. AB - The Deepwater Horizon (DWH) oil spill in the Gulf of Mexico was the largest maritime oil spill in history resulting in the accumulation of genotoxic substances in the air, soil, and water. This has potential far-reaching health impacts on cleanup field workers and on the populations living in the contaminated coastal areas. We have employed portable airborne particulate matter samplers (SKC Biosampler Impinger) and a genetically engineered bacterial reporter system (umu-ChromoTest from EBPI) to determine levels of genotoxicity of air samples collected from highly contaminated areas of coastal Louisiana including Grand Isle, Port Fourchon, and Elmer's Island in the spring, summer and fall of 2011, 2012, 2013 and 2014. Air samples collected from a non-contaminated area, Sea Rim State Park, Texas, served as a control for background airborne genotoxic particles. In comparison to controls, air samples from the contaminated areas demonstrated highly significant increases in genotoxicity with the highest values registered during the month of July in 2011, 2013, and 2014, in all three locations. This seasonal trend was disrupted in 2012, when the highest genotoxicity values were detected in October, which correlated with hurricane Isaac landfall in late August of 2012, about five weeks before a routine collection of fall air samples. Our data demonstrate: (i) high levels of air genotoxicity in the monitored areas over last four years post DWH oil spill; (ii) airborne particulate genotoxicity peaks in summers and correlates with high temperatures and high humidity; and (iii) this seasonal trend was disrupted by the hurricane Isaac landfall, which further supports the concept of a continuous negative impact of the oil spill in this region. PMID- 26745739 TI - Iridium-Catalyzed, Hydrosilyl-Directed Borylation of Unactivated Alkyl C-H Bonds. AB - We report the iridium-catalyzed borylation of primary and secondary alkyl C-H bonds directed by a Si-H group to form alkylboronate esters site selectively. The reactions occur with high selectivity at primary C-H bonds gamma to the hydrosilyl group to form primary alkyl bisboronate esters. In the absence of such primary C-H bonds, the borylation occurs selectively at a secondary C-H bond gamma to the hydrosilyl group, and these reactions of secondary C-H bonds occur with high diastereoselectivity. The hydrosilyl-containing alkyl boronate esters formed by this method undergo transformations selectively at the carbon-boron or carbon-silicon bonds of these products under distinct conditions to give the products of amination, oxidation, and arylation. PMID- 26745740 TI - Dynamic and structural correlations in nanocomposites of silica with modified surface and carboxylated nitrile rubber. AB - Distinct affinities between the organic and inorganic phases were observed in nanocomposites prepared through a colloidal route with carboxylated nitrile rubber and modified silica nanoparticles, which resulted in variable mechanical properties and improved thermal stability. Nanoparticles with modified surface affected the macromolecular arrangements of the elastomeric matrix, changing the final mechanical behavior of the nanocomposite, which could be predicted by the spin-lattice relaxation time measured by solid-state NMR. It was also possible to identify how each different nanoparticle affected the molecular dynamic of nanocomposite, correlating the dynamic-mechanical analysis with the NMR data of the saturated carbons of the elastomer. PMID- 26745741 TI - Composite microparticles of halloysite clay nanotubes bound by calcium carbonate. AB - Natural halloysite clay nanotubes with 15 nm inner and 75 nm outer diameters have been used as vehicles for sustained release of drugs in composite hollow microparticles "glued" with CaCO3. We used a layer-by layer assembly accomplished alginate binding with Ca(2+) followed by CO2 bubbling to prepare the composite microspheres of CaCO3 and polyelectrolytes (PE) modified halloysite nanotubes (HNTs-PE2/CaCO3) with the diameter of about 5-10 MUm. These microparticles have empty spherical structure and abundant pore distributions with maxima at 2.5, 3.9, 6.0 and 13.3 nm, and higher surface area of 82.3 m(2) g(-1) as characterized by SEM and BET test. We loaded drugs in these micro-nano carriers of tight piles of halloysite nanotube with end clogged with CaCO3. The sustained release of Nifedipine drug from HNTs-PE2/CaCO3 composite microspheres was slower than for pristine halloysite nanotubes. PMID- 26745742 TI - CeO2 nanorods-supported transition metal catalysts for CO oxidation. AB - A catalytically active oxide support in combination with metal catalysts is required in order to achieve better low temperature activity and selectivity. Here, we report that CeO2 nanorods with a superior surface oxygen release/storage capability were used as an active support of transition metal (TM) catalysts (Mn, Fe, Co, Ni, Cu) for CO oxidation reaction. The as-prepared CeO2 nanorods supported 10 wt% TM catalysts were highly active for CO oxidation at low temperature, except for the Fe sample. It is found that the 10%Cu-CeO2 catalyst performed best, and it provided a lower light-off temperature with T50 (50% conversion) at 75 degrees C and T100 (100% conversion) of CO to CO2 at 194 degrees C. The atomic level surface structure of CeO2 nanorods was investigated in order to understand the improved low temperature catalytic activity. The richness of surface roughness and various defects (voids, lattice distortion, bending, steps, twinning) on CeO2 nanorods could facilitate oxygen release and storage. According to XRD and Raman analysis, copper species migrate into the bulk CeO2 nanorods to a greater degree. Since CO adsorbed over the surface of the catalyst/support is detrimental to its catalytic activity, the surface defects on the CeO2 nanorods and CeO2-TM interactions were critical to the enhanced activity. PMID- 26745743 TI - Construction of carbon nanodots/tungsten trioxide and their visible-light sensitive photocatalytic activity. AB - Herein we designed a simple and effective method for synthesizing carbon nanodots/tungsten trioxide nanocomposite with high photocatalytic activity. The as-prepared carbon nanodots/ tungsten trioxide has strong photoabsorption under visible light irradiation. Then, carbon nanodots/tungsten trioxide was successfully applied to the degradation of methylene blue. The photodegradation efficiency of methylene blue can be reached as high as 100% after 0.5 h visible light illumination. In addition, carbon nanodots/tungsten trioxide could also be used to degrade rhodamine B and methyl orange. Most importantly, the photocatalytic activity of carbon nanodots/tungsten trioxide did not exhibit obvious changes after five cycles. The results indicate that carbon nanodots/tungsten trioxide has potential applications in the degradation of organic pollutants in industrial waste water. PMID- 26745744 TI - Assembly of porous hierarchical copolymers/resin proppants: New approaches to smart proppant immobilization via molecular anchors. AB - HYPOTHESIS: The assembly of temperature/pH sensitive complex microparticle structures through chemisorption and physisorption provides a responsive system that offers application as routes to immobilization of proppants in-situ. EXPERIMENTS: Thermogravimetric analysis (TGA) and scanning electron microscopy (SEM) along with energy dispersive X-ray analysis (EDX) have been used to characterize a series of bi-functionalized monolayers and/or multilayers grown on alumina microparticles and investigate the reactive nature of both temperature sensitive cross-linker (epoxy resin) with the layers and pH-responsive bridging layer (polyetheramine). FINDINGS: The bifunctional acids, behaving as molecular anchors, allow for a controlled reaction with a cross-linker (resin or polymer) with the formation of networks, which is either irreversible or reversible based on the nature of the cross-linker. The networks results in formation of porous hierarchical particles that offer a potential route to the creation of immobile proppant pack. PMID- 26745745 TI - Novel visible-light-responsive Ag/AgCl@MIL-101 hybrid materials with synergistic photocatalytic activity. AB - In this paper, a novel visible-light responsive photocatalyst of Ag/AgCl@MIL-101 was synthesized via vapor diffusion-photoreduction strategy. The as-prepared composite material was characterized using X-ray diffraction, scanning electron microscopy, energy dispersive X-ray spectroscopy, transmission electron microscopy, ultraviolet-visible diffuse reflection spectra and X-ray photoelectron spectroscopy. Due to the synergistic effect between Ag/AgCl and MIL 101, the composite photocatalyst exhibited an enhanced and stable photoactivity for the degradation of Rhodamine B under visible light irradiation. The relationship between the photocatalytic activity and the structure of Ag/AgCl@MIL 101 hybrid material was discussed and the possible reaction mechanism was proposed. PMID- 26745746 TI - Prediction of exacerbation onset in chronic obstructive pulmonary disease patients. AB - The objective of this study was to develop an algorithm for prediction of exacerbation onset in Chronic Obstructive Pulmonary Disease (COPD) patients based on continuous self-monitoring of physiological parameters from telehome-care monitoring. 151 physiological parameters of COPD patients were monitored on a daily/weekly basis for up to 2 years. Data were segmented in 30-day periods leading up to an exacerbation (exacerbation episode) and starting from a 14-day recovery period post-exacerbation (control episode) and tested in 6 intervals to predict exacerbation onset using k-nearest neighbour (k = 1, 3, 5). A classifier with sensitivity of 73%, specificity of 74%, positive predictive value of 69%, negative predictive value of 78% and an accuracy of 74% was achieved using data intervals consisting of 5 days. Intelligent processing of physiological recordings have potential for predicting exacerbation onset. PMID- 26745747 TI - Ag2CO3/CA-AA-AmidPhos Multifunctional Catalysis in the Enantioselective 1,3 Dipolar Cycloaddition of Azomethine Ylides. AB - The new Ag2CO3/CA-AA-amidphos complexes have been demonstrated as highly efficient multifunctional catalysts in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides. Under optimal conditions, highly functionalized endo-4 pyrrolidines were obtained with excellent yields (up to 99% yield) and enantioselectivities (up to 96% ee). PMID- 26745748 TI - Enantioselective Synthesis of Atropisomeric Vinyl Arene Compounds by Palladium Catalysis: A Carbene Strategy. AB - An efficient palladium-catalyzed asymmetric synthesis of axially chiral vinyl arenes from aryl bromides and hydrazones is reported. The products were easily oxidized to axially chiral biaryl compounds, and the phosphine oxides were readily reduced to phosphine ligands. PMID- 26745749 TI - Administration of the glial cell modulator, minocycline, in the nucleus accumbens attenuated the maintenance and reinstatement of morphine-seeking behavior. AB - Relapse to drug use is one of the most difficult clinical problems in treating addiction. Glial activation has been linked with the drug abuse, and the glia modulators such as minocycline can modulate the drug abuse effects. The aim of the present study was to determine whether minocycline could attenuate the maintenance and reinstatement of morphine. Conditioned place preference (CPP) was induced by subcutaneous injection of morphine (5 mg/kg) for 3 days. Following the acquisition of the CPP, the rats were given daily bilateral intra-NAc injections of either minocycline (1, 5, and 10 MUg/0.5 MUL) or saline (0.5 MUL). The animals were tested for conditioning score 60 min after each injection. To induce the reinstatement, a priming dose of morphine (1 mg/kg) was injected 1 day after the final extinction day. The morphine-induced CPP lasted for 7 days after cessation of morphine treatment. Our data revealed that a priming dose of morphine could reinstate the extinguished morphine-induced CPP. Daily intra-accumbal injection of minocycline during the extinction period blocked the maintenance of morphine CPP and also attenuated the priming-induced reinstatement. Our findings indicated that minocycline could facilitate the extinction and attenuate the reinstatement of morphine. These results provided new evidence that minocycline might be considered as a promising therapeutic agent for the treatment of several symptoms associated with morphine abuse. PMID- 26745750 TI - Reproducibility of fractional ventilation derived by Fourier decomposition after adjusting for tidal volume with and without an MRI compatible spirometer. AB - PURPOSE: To reduce the influence of tidal volume on fractional ventilation (FV) derived by Fourier decomposition (FD). METHODS: Twelve volunteers were examined on a 1.5 Tesla scanner. Spoiled gradient echo imaging of coronal and sagittal slices of the lung were performed. The tidal volume variations between different acquisitions were studied by reproducibility and repeatability measurements. To adjust the FV derived by FD for tidal volume differences between the measurements, during all acquisitions, the lung volume changes were measured by a spirometer and used to calculate a global FV parameter. As an alternative, using the FD data, the lung area changes were calculated and used for the adjustment. RESULTS: Reproducibility analysis of unadjusted coronal FV showed a determination coefficient of R2 = 71% and an intraclass correlation coefficient of ICC = 93%. Differences in the measurements could be ascribed to different tidal volumes. Area adjusted values exhibited an increased R2 of 84% and a higher ICC of 97%. For the coronal middle slice/sagittal slices in free breathing, the inter volunteer coefficient of variation was reduced from 0.23/0.28 (unadjusted) to 0.16/0.20 (spirometer) or 0.12/0.13 (area). CONCLUSION: The calculation of lung area changes is sufficient to increase the reproducibility of FV in a volunteer cohort avoiding the need for an MRI compatible spirometer. Magn Reson Med 76:1542 1550, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26745751 TI - Adverse Effects of Intraoperative Blood Loss on Long-Term Outcomes after Curative Gastrectomy of Patients with Stage II/III Gastric Cancer. AB - BACKGROUND/AIMS: Gastrectomy with systemic lymphadenectomy sometimes causes excessive bleeding even by experienced surgeons. The aim of this study was to evaluate how intraoperative estimated blood loss (EBL) affected the long-term outcomes after curative surgery of patients with stage II/III gastric cancer (GC). METHODS: This study included 203 patients with stage II/III GC who did not receive perioperative blood transfusion between 1999 and 2015. The optimal cutoff and the prognostic significance of EBL were determined retrospectively. RESULTS: The median EBL was 285 ml. Receiver operating characteristic curve analysis identified 400 ml as an optimal cutoff. Patients with EBL >=400 ml were more likely to have hepatic relapse and worse prognosis compared to those with EBL <400 ml. EBL >=400 ml was identified as an independent prognostic factor for mortality by multivariable analysis. When patients were subdivided according to administration of adjuvant chemotherapy, there was a significant difference between the EBL >=400 and <400 ml groups in patients who underwent surgery alone, whereas the prognosis was similar for patients of both groups who received adjuvant chemotherapy. CONCLUSION: EBL serves as a useful predictor for risk stratification after curative gastrectomy in patients with stage II/III GC. PMID- 26745752 TI - A unique, fast-forwards rotating schedule with 12-h long shifts prevents chronic sleep debt. AB - Sleep debt--together with circadian misalignment--is considered a central factor for adverse health outcomes associated with shift work. Here, we describe in detail sleep-wake behavior in a fast-forward rotating 12-h shift schedule, which involves at least 24 hours off after each shift and thus allows examining the role of immediate recovery after shift-specific sleep debt. Thirty-five participants at two chemical plants in Germany were chronotyped using the Munich ChronoType Questionnaire for Shift-Workers (MCTQ(Shift)) and wore actimeters throughout the two-week study period. From these actimetry recordings, we computed sleep and nap duration, social jetlag (a measure of circadian misalignment), and the daily timing of activity and sleep (center of gravity and mid-sleep, respectively). We observed that the long off-work periods between each shift create a fast alternation between shortened (mean +/- standard deviation, 5h 17min +/- 56min) and extended (8h 25min +/- 72min) sleep episodes resulting in immanent reductions of sleep debt. Additionally, extensive napping of early chronotypes (up to 3 hours before the night shift) statistically compensated short sleep durations after the night shift. Partial rank correlations showed chronotype-dependent patterns of sleep and activity that were similar to those previously described in 8-h schedules; however, sleep before the day shift did not differ between chronotypes. Our findings indicate that schedules preventing a build-up of chronic sleep debt may reduce detrimental effects of shift work irrespective of shift duration. Prospective studies are needed to further elucidate the relationship between sleep, the circadian system, and health and safety hazards. PMID- 26745753 TI - Ambulation and independence among Veterans with nontraumatic bilateral lower-limb loss. AB - In describing functional outcomes and independent living in a cohort of bilateral major amputees, we sought to provide current estimates of function and independence after a second major amputation in an elderly Veteran population with peripheral arterial disease and/or diabetes. After retrospectively reviewing and excluding the electronic health records of those failing to meet the inclusion criteria, we identified 40 patients with a history of unilateral major amputation who underwent a second major amputation during the defined study period. Of these, 43% (17) were bilateral transfemoral amputations (TFAs); bilateral transtibial amputations (TTAs) and TFA-TTA accounted for the rest (33% and 25%, respectively). Of the 19 (48%) patients who were ambulatory prior to bilateral amputation, only 2 (11%) remained ambulatory after the second amputation, while 17 (89%) patients lost ambulatory capabilities. Compared with those who were 10 bpm in 6 of 9 patients. Based on all RR samples observed, the default alarm thresholds, to serve as a starting point for each patient, would be a low RR of 6 (>10 years of age) and 10 (4-9 years of age). CONCLUSIONS: In this study, the use of RR monitoring did not improve the detection of respiratory depression. An RR threshold, which would have been predictive of desaturations, would have resulted in an unacceptably high false alarm rate. Future research using a combination of variables (e.g., SpO2 and RR), or the measurement of tidal volumes, may be needed to improve patient safety in the postoperative ward. PMID- 26745755 TI - Incomplete Spontaneous Recovery from Airway Obstruction During Inhaled Anesthesia Induction: A Computational Simulation. AB - BACKGROUND: Inhaled induction with spontaneous respiration is a technique used for difficult airways. One of the proposed advantages is if airway patency is lost, the anesthetic agent will spontaneously redistribute until anesthetic depth is reduced and airway patency can be recovered. There are little and conflicting clinical or experimental data regarding the kinetics of this anesthetic technique. We used computer simulation to investigate this situation. METHODS: We used GasMan, a computer simulation of inhaled anesthetic kinetics. For each simulation, alveolar ventilation was initiated with a set anesthetic induction concentration. When the vessel-rich group level reached the simulation specified airway obstruction threshold, alveolar ventilation was set at 0 to simulate complete airway obstruction. The time until the vessel-rich group anesthetic level decreased below the airway obstruction threshold was designated time to spontaneous recovery. We varied the parameters for each simulation, exploring the use of sevoflurane and halothane, airway obstruction threshold from 0.5 to 2 minimum alveolar concentration (MAC), anesthetic induction concentration 2 to 4 MAC sevoflurane and 4 to 6 MAC halothane, cardiac output 2.5 to 10 L/min, functional residual capacity 1.5 to 3.5 L, and relative vessel-rich group perfusion 67% to 85%. RESULTS: In each simulation, there were 3 general phases: anesthetic wash-in, obstruction and overshoot, and then slow redistribution. During the first 2 phases, there was a large gradient between the alveolar and vessel-rich group. Alveolar do not reflect vessel-rich group anesthetic levels until the late third phase. Time to spontaneous recovery varied between 35 and 749 seconds for sevoflurane and 13 and 222 seconds for halothane depending on the simulation parameters. Halothane had a faster time to spontaneous recovery because of the lower alveolar gradient and less overshoot of the vessel-rich group, not faster redistribution. Higher airway obstruction thresholds, decreased anesthetic induction, and higher cardiac output reduced time to spontaneous recovery. To a lesser effect, decreased functional residual capacity and the decreased relative vessel-rich groups' perfusion also reduced the time to spontaneous recovery. CONCLUSIONS: Spontaneous recovery after complete airway obstruction during inhaled induction is plausible, but the recovery time is highly variable and depends on the clinical and physiologic situation. These results emphasize that induction is a non-steady-state situation, thus effect site anesthetic levels should be modeled in future research, not alveolar concentration. Finally, this study provides an example of using computer simulation to explore situations that are difficult to investigate clinically. PMID- 26745757 TI - Advanced molecular diagnostic techniques for detection of food-borne pathogens: Current applications and future challenges. AB - The elimination of disease-causing microbes from the food supply is a primary goal and this review deals with the overall techniques available for detection of food-borne pathogens. Now-a-days conventional methods are replaced by advanced methods like Biosensors, Nucleic Acid-based Tests (NAT), and different PCR-based techniques used in molecular biology to identify specific pathogens. Bacillus cereus, Staphylococcus aureus, Proteus vulgaris, Escherichia coli, Campylobacter, Listeria monocytogenes, Salmonella spp., Aspergillus spp., Fusarium spp., Penicillium spp., and pathogens are detected in contaminated food items that cause always diseases in human in any one or the other way. Identification of food-borne pathogens in a short period of time is still a challenge to the scientific field in general and food technology in particular. The low level of food contamination by major pathogens requires specific sensitive detection platforms and the present area of hot research looking forward to new nanomolecular techniques for nanomaterials, make them suitable for the development of assays with high sensitivity, response time, and portability. With the sound of these, we attempt to highlight a comprehensive overview about food borne pathogen detection by rapid, sensitive, accurate, and cost affordable in situ analytical methods from conventional methods to recent molecular approaches for advanced food and microbiology research. PMID- 26745758 TI - First Isolation of Severe Fever with Thrombocytopenia Syndrome Virus from Haemaphysalis longicornis Ticks Collected in Severe Fever with Thrombocytopenia Syndrome Outbreak Areas in the Republic of Korea. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease that is endemic to China, Japan, and the Republic of Korea (ROK). In this study, 8313 ticks collected from SFTS outbreak areas in the ROK in 2013 were used to detect the SFTS virus (SFTSV). A single SFTSV was isolated in cell culture from one pool of Haemaphysalis longicornis ticks collected from Samcheok-si, Gangwon Province, in the ROK. Phylogenetic analysis showed that the SFTSV isolate was clustered with the SFTSV strain from Japan, which was isolated from humans. To the best of our knowledge, this is the first isolation in the world of SFTSV in ticks collected from vegetation. PMID- 26745759 TI - LKB1 acts as a critical gatekeeper of ovarian primordial follicle pool. AB - Liver Kinase b1 (LKB1/STK11)is a tumor suppressor responsible for the Peutz Jeghers syndrome, an autosomal-dominant, cancer-prone disorder in which patients develop neoplasms in several organs, including the oviduct, ovary, and cervix. Besides, the C allele of a SNP in the Lkb1 gene impedes the likelihood of ovulation in polycystic ovary syndrome (PCOS) in women treated with metformin, a known LKB1-AMPK activator. It is very likely that LKB1 plays roles in female fertility. To identify the physiological functions of LKB1 in the mouse ovary, we selectively disrupted LKB1 in oocytes by the Cre-LoxP conditional knockout system and found that Lkb1fl/fl; Gdf9-Cre mice were severely subfertile with significantly enlarged ovaries compared to Lkb1fl/fl mice. Interestingly, without Lkb1 expression in oocytes from the primordial follicle stage, the entire primordial follicle pool was activated but failed to mature and ovulate, subsequently causing premature ovarian failure (POF). Further investigation demonstrated that elevated mTOR signaling regulated by an AKT-independent LKB1 AMPK pathway was responsible for the excessive follicle activation and growth. Our findings reveal the role of LKB1 as an indispensable gatekeeper for the primordial follicle pool, offer new functional understanding for the tumor suppressor genes in reproductive organs, and might also provide valuable information for understanding POF and infertility. PMID- 26745761 TI - Facilitating cells: Translation of hematopoietic chimerism to achieve clinical tolerance. AB - For over 50 y the association between hematopoietic chimerism and tolerance has been recognized. This originated with the brilliant observation by Dr. Ray Owen that freemartin cattle twins that shared a common placental blood supply were red blood cell chimeras, which led to the discovery that hematopoietic chimerism resulted in actively acquired tolerance. This was first confirmed in neonatal mice by Medawar et al. and subsequently in adult rodents. Fifty years later this concept has been successfully translated to solid organ transplant recipients in the clinic. The field is new, but cell-based therapies are being used with increasing frequency to induce tolerance and immunomodulation. The future is bright. This review focuses on chimerism and tolerance: past, present and prospects for the future. PMID- 26745763 TI - Multi-oriented windowed harmonic phase reconstruction for robust cardiac strain imaging. AB - The purpose of this paper is to develop a method for direct estimation of the cardiac strain tensor by extending the harmonic phase reconstruction on tagged magnetic resonance images to obtain more precise and robust measurements. The extension relies on the reconstruction of the local phase of the image by means of the windowed Fourier transform and the acquisition of an overdetermined set of stripe orientations in order to avoid the phase interferences from structures outside the myocardium and the instabilities arising from the application of a gradient operator. Results have shown that increasing the number of acquired orientations provides a significant improvement in the reproducibility of the strain measurements and that the acquisition of an extended set of orientations also improves the reproducibility when compared with acquiring repeated samples from a smaller set of orientations. Additionally, biases in local phase estimation when using the original harmonic phase formulation are greatly diminished by the one here proposed. The ideas here presented allow the design of new methods for motion sensitive magnetic resonance imaging, which could simultaneously improve the resolution, robustness and accuracy of motion estimates. PMID- 26745764 TI - Annual patient and caregiver burden of oncology clinic visits for granulocyte colony stimulating factor therapy in the US. AB - OBJECTIVE: Prophylactic treatment with granulocyte-colony stimulating factors (G CSFs) is indicated for chemotherapy patients with a significant risk of febrile neutropenia. This study estimates the annual economic burden on patients and caregivers of clinic visits for prophylactic G-CSF injections in the US. METHODS: Annual clinic visits for prophylactic G-CSF injections (all cancers) were estimated from national cancer incidence, chemotherapy treatment and G-CSF utilization data, and G-CSF sales and pricing information. Patient travel times, plus time spent in the clinic, were estimated from patient survey responses collected during a large prospective cohort study (the Prospective Study of the Relationship between Chemotherapy Dose Intensity and Mortality in Early-Stage (I III) Breast Cancer Patients). Economic models were created to estimate travel costs, patient co-pays and the economic value of time spent by patients and caregivers in G-CSF clinic visits. RESULTS: Estimated total clinic visits for prophylactic G-CSF injections in the US were 1.713 million for 2015. Mean (SD) travel time per visit was 62 (50) min; mean (SD) time in the clinic was 41 (68) min. Total annual time for travel to and from the clinic, plus time at the clinic, is estimated at 4.9 million hours, with patient and caregiver time valued at $91.8 million ($228 per patient). The estimated cumulative annual travel distance for G-CSF visits is 60.2 million miles, with a total transportation cost of $28.9 million ($72 per patient). Estimated patient co-pays were $61.1 million, ~$36 per visit, $152 per patient. The total yearly economic impact on patients and caregivers is $182 million, ~$450 per patient. LIMITATIONS: Data to support model parameters were limited. Study estimates are sensitive to the assumptions used. CONCLUSIONS: The burden of clinic visits for G-CSF therapy is a significant addition to the total economic burden borne by cancer patients and their families. PMID- 26745760 TI - Potential role of epigenetic mechanisms in regulation of trophoblast differentiation, migration, and invasion in the human placenta. AB - The proper establishment and organogenesis of the placenta is crucial for intrauterine fetal growth and development. Endometrial invasion by the extravillous trophoblast cells, as well as formation of the syncytiotrophoblast (STB), are of vital importance for placental function. Trophoblast migration and invasion is often compared to tumor metastasis, which uses many of the same molecular mechanisms. However, unlike cancer cells, both initiation and the extent of trophoblast invasion are tightly regulated by feto-maternal cross-talk, which when perturbed, results in a wide range of abnormalities. Multiple factors control the trophoblast, including cytokines and hormones, which are subject to transcriptional regulatory networks. The relevance of epigenetics in transcriptional regulation of trophoblast differentiation and invasion, as well as in the onset of placenta-related pregnancy disorders, became recognized decades ago. Although, there has been tremendous progress in uncovering the molecular foundation of placental development, there is still much to be learned about the epigenetic machinery, and its role in trophoblast differentiation and invasion. This review will provide an overview of the epigenetic control of trophoblast differentiation and invasion. It will also highlight the major epigenetic mechanisms involved in pregnancy complications related to placental deficiencies. PMID- 26745765 TI - Plasma Fibrinogen Qualification as a Drug Development Tool in Chronic Obstructive Pulmonary Disease. Perspective of the Chronic Obstructive Pulmonary Disease Biomarker Qualification Consortium. AB - The COPD Foundation Biomarker Qualification Consortium (CBQC) is a unique public private partnership established in 2010 between the COPD Foundation, the pharmaceutical industry, and academic chronic obstructive pulmonary disease (COPD) experts with advisors from the U.S. NHLBI and the Food and Drug Administration (FDA). This was a direct response to the 2009 publication of a guidance on qualification of drug development tools by the FDA. Although data were believed to be available from publicly funded and industry-funded studies that could support qualification of several tools, the necessary data resided in disparate databases. The initial intent of the CBQC was to integrate these data and submit a dossier for the qualification. This led to the FDA qualification of plasma fibrinogen as a prognostic or enrichment biomarker for all-cause mortality and COPD exacerbations in July 2015. It is the first biomarker drug development tool qualified for use in COPD under the FDA's drug development tool qualification program. This perspective summarizes the FDA's qualification process, the formation of the CBQC, and the effort that led to a successful outcome for plasma fibrinogen and discusses implications for future biomarker qualification efforts. PMID- 26745766 TI - Development of Autotaxin Inhibitors: An Overview of the Patent and Primary Literature. AB - The autotaxin-lysophophatidic acid (ATX-LPA) signaling pathway is implicated in a variety of human disease states including angiogenesis, autoimmune diseases, cancer, fibrotic diseases, inflammation, neurodegeneration, and neuropathic pain, among others. As a result, ATX-LPA has become of significant interest within both the industrial and the academic communities. This review aims to provide a concise overview of the development of novel ATX inhibitors, including the disclosure of the first ATX clinical trial data. PMID- 26745767 TI - The effects of acetaldehyde, glyoxal and acetic acid on the heterogeneous reaction of nitrogen dioxide on gamma-alumina. AB - Heterogeneous reactions of nitrogen oxides on the surface of aluminium oxide result in the formation of adsorbed nitrite and nitrate. However, little is known about the effects of other species on these heterogeneous reactions and their products. In this study, diffuse reflectance infrared spectroscopy (DRIFTS) was used to analyze the process of the heterogeneous reaction of NO2 on the surface of aluminium oxide particles in the presence of pre-adsorbed organic species (acetaldehyde, glyoxal and acetic acid) at 298 K and reveal the influence of these organic species on the formation of adsorbed nitrite and nitrate. It was found that the pre-adsorption of organic species (acetaldehyde, glyoxal and acetic acid) on gamma-Al2O3 could suppress the formation of nitrate to different extents. Under the same experimental conditions, the suppression of the formation of nitrate by the pre-adsorption of acetic acid is much stronger than that by pre adsorption of acetaldehyde and glyoxal, indicating that the influence of acetic acid on the heterogeneous reaction of NO2 is different from that of acetaldehyde and glyoxal. Surface nitrite is formed and identified to be an intermediate product. For the heterogeneous reaction of NO2 on the surface of gamma-Al2O3 with and without the pre-adsorption of acetaldehyde and glyoxal, it is firstly formed and then gradually disappears as the reaction proceeds, but for the reaction with the pre-adsorption of acetic acid, it is the final main product besides nitrate. This indicates that the pre-adsorption of acetic acid would promote the formation of nitrite, while the others would not change the trend of the formation of nitrite. The possible influence mechanisms of the pre-adsorption of acetaldehyde, glyoxal and acetic acid on the heterogeneous conversion of NO2 on gamma-Al2O3 are proposed and atmospheric implications based on these results are discussed. PMID- 26745768 TI - Genetic variation in the tryptophan hydroxylase 2 gene moderates depressive symptom trajectories and remission over 8 weeks of escitalopram treatment. AB - The serotonin system plays an important role in the pathogenesis of major depressive disorder (MDD) and genetic variations in serotonin-related genes affect the efficacy of antidepressants. The aim of this study was to investigate the relationship between genotypic variation in six candidate serotonergic genes (ADCY9, HTR1B, GNB3, HTR2A, TPH2, SLC6A4) and depressive and anxiety symptom severity trajectories as well as remission following escitalopram treatment. A total of 166 Chinese patients with MDD were treated with escitalopram (open label) for 8 weeks. TPH2 rs4570625 GG carriers were more likely to achieve depressive and anxiety symptom remission compared with T-allele carriers. At the trend level (P(corrected)=0.05), depressive symptom severity trajectories were moderated by TPH2 rs4570625. Patients with the GT or the GG genotype showed more favorable depressive symptom severity trajectories compared with TT genotype carriers. Polymorphisms in ADCY9, HTR1B, and HTR2A were nominally associated with symptom remission, but did not withstand correction for multiple comparisons. The HTTLPR polymorphism was not included in our final analysis because of a high percentage of missing data. These results suggested that genotypic variation in TPH2 may moderate the therapeutic response to esciatlopram among Chinese patients with MDD. PMID- 26745769 TI - Affective differences in Iowa Gambling Task performance associated with sexual risk taking and substance use among HIV-positive and HIV-negative men who have sex with men. AB - We investigated the relationship between emotional distress and decision making in sexual risk and substance use behavior among 174 (ages 25 to 50 years, 53% black) men who have sex with men (MSM), a population at increased risk for HIV. The sample was stratified by HIV status. Measures of affective decision making, depression, anxiety, sex acts, and substance use during the past 60 days were collected at our research center. Negative binomial regression models were used to examine the relationship between age, HIV status, anxiety, depression, and IGT performance in the prediction of number of risky sex acts and substance use days. Among those without anxiety or depression, both number of risky sex acts and drug use days decreased with better performance during risky trials (i.e., last two blocks) of the IGT. For those with higher rates of anxiety, but not depression, IGT risk trial performance and risky sex acts increased concomitantly. Anxiety also interacted with IGT performance across all trials to predict substance use, such that anxiety was associated with greater substance use among those with better IGT performance. The opposite was true for those with depression, but only during risk trials. HIV-positive participants reported fewer substance use days than HIV-negative participants, but there was no difference in association between behavior and IGT performance by HIV status. Our findings suggest that anxiety may exacerbate risk-taking behavior when affective decision-making ability is intact. The relationship between affective decision making and risk taking may be sensitive to different profiles of emotional distress, as well as behavioral context. Investigations of affective decision making in sexual risk taking and substance use should examine different distress profiles separately, with implications for HIV prevention efforts. PMID- 26745772 TI - THE MULTIFACTOR BEHAVIORAL APPROACH TO THE GENETIC-ETIOLOGICAL DIAGNOSIS OF MENTAL RETARDATION. AB - This study explored the feasibility of discriminating among subtypes of mental retardation on the basis of observable behavior. The major focus was on discrimination between Ss whose low I.Q. could be attributed to normal chromosomal or single locus genetic defects. Concurrently the study sought t o distinguish among diagnostic subgroups of the second category. Three groups of institutionalized subjects were used: Undifferentiated (presumed polygenic segregants), PKU, and Down's Syndrome. PMID- 26745771 TI - Telepharmacotherapy for Child and Adolescent Psychiatric Patients. AB - OBJECTIVE: The purpose of this study is to review and discuss the status of telepsychiatry practice, particularly as applied to treating children and adolescents with psychotropic medications, which is termed "telepharmacotherapy." METHODS: The literature pertinent to telepsychiatry practice is reviewed, followed by a presentation of the challenges to implementing telepharmacotherapy, potential solutions, current controversies, and future directions, combining insights from the literature with the authors' own experiences. RESULTS: Telepsychiatry services for children and adolescents are expanding, and provide needed pharmacotherapy for patients who are underserved by available resources. The evidence base supporting the effectiveness of telepsychiatry practice and telepharmacotherapy is still emerging, and consists mainly of feasibility and satisfaction studies with limited outcome data. Although a number of challenges to this mode of care delivery currently exist, the authors outline potential solutions for those challenges that are consistent with existing guidelines for clinical practice. CONCLUSIONS: Telepsychiatry appears to be a feasible and satisfactory alternative to in-person care, and a valid option for increasing access to psychopharmacotherapy for children and adolescents. Although the evidence base is still emerging, and practitioners may face a number of challenges, solutions are presented that may help to overcome those challenges. PMID- 26745773 TI - A COMPARISON OF TWO MODELS REPRESENTING TASTE MIXTURE SIMILARITIES IN A CROSS MODAL MATCHING TASK. AB - Comparisons between two alternative psychophysical models of taste mixture similarity perception are made, using data from a cross-modal matching task where taste mixtures were compared serially with histogram picture representations of other taste mixtures. The problems of generalizing results are indicated. PMID- 26745774 TI - DIMENSIONAL INTERPRETATION AND CONFIGURATION INVARIANCE IN MULTIDIMENSIONAL SCALING: AN EMPIRICAL STUDY. AB - This paper is concerned with: a ) the invariance of nonmetric multi- dimensional scaling soludions over changes in stimulus domain; and b) pro- cedures for assisting the researcher in interpreting the axes of multidimen- sional scaling configurations. The stimuli consisted of the names of 17 popular brands of automobiles. Similarities and preference judgments were obtained from 37 subjects, divided into two groups of approximately equal size. Each group received 11 of the 17 stimuli. A core set of 6 stimuli was common over both groups. Each group also rated the 11 car models on 20 semantic differential scales. Results of the study suggested that the interpoint distances of bhe core set of 5 stimuli remained stable over subject groups and differences in stimulus set composition. Semantic differential ratings were used to find directions in the configurational space (obtained from overall similarity judg- ments) whose projections were maximally correlated with the outside (property) vectors. Stimulus configurations developed from the semantic differential space were highly congruent with those found by the analysis of direct similarity judgments. However, attempts to develop stimulus configurations by the "unfolding" of preference data alone did not lead to configurations which closely matched those found by the analysis of direct similarities data. PMID- 26745775 TI - A SET OF FACTOR ANALYTICALLY DERIVED SCALES FOR SCORING THE M-B HISTORY RECORD. AB - A study was made of the factor structure underlying items from a standard social history questionnaire, The Briggs M-B History Record (MBHR). Relatives of 187 psychiatric patients completed the MBHR. An orthogonal factor analysis yielded 7 factors identified on the basis of item content as Condbct Disorder, Home Instability, Poor Family Atmosphere, Low Educational Achievement, Lack of Social Interest, Hypochondriasis, and Learning Difficulty. The factors were scored in order to determine the reliabilities of the factor scale scores and to compare the factors with the item clusters obtained by Briggs. PMID- 26745776 TI - FACTORIAL INVARIANCE OF BIOGRAPHICAL FACTORS. AB - A biographical information blank (BIB) was administered to students in grades 7, 9, and 11, and was subsequently analyzed to determine the stability of both its factor pattern and structure. This was done by deriving a single average factor pattern matrix which was rotated to simple structure and then to similarity to each of three factor matrices at each grade level. Of 11 factors extracted, all but three showed reasonably good stability. Those factors that showed the greatest change, in terms of their presence over the three grade levels, were General Appreciation of School Courses, Social Activities, and High Level Literary Activities. Implications of stability in factor pattern and structure for further BIB development and for utilization in the framework of a longitudinal study are discussed. PMID- 26745770 TI - The impact of oculomotor functioning on neuropsychological performance in Huntington disease. AB - Huntington disease (HD) is a neurodegenerative condition with prominent motor (including oculomotor), cognitive, and psychiatric effects. While neuropsychological deficits are present in HD, motor impairments may impact performance on neuropsychological measures, especially those requiring a speeded response, as has been demonstrated in multiple sclerosis and schizophrenia. The current study is the first to explore associations between oculomotor functions and neuropsychological performance in HD. Participants with impaired oculomotor functioning performed worse than those with normal oculomotor functioning on cognitive tasks requiring oculomotor involvement, particularly on psychomotor speed tasks, controlling for covariates. Consideration of oculomotor dysfunction on neuropsychological performance is critical, particularly for populations with motor deficits. PMID- 26745777 TI - PERSONAL STYLES OF REACTION TO THE FRUSTRATION OF OTHERS AS PORTRAYED BY MULTIDIMENSIONAL SCALOGRAM ANALYSIS. AB - A questionnaire for the assessment of reactions to the frustration of others was constructed and administered to 56 Ss. This questionnaire concentrated on the reported intensity of eight reactions, namely: Pity, Attempt to Help, Reproach, Withdrawal, Disgust, Mockery, Anger, and Malicious Joy. Each one of the 56 Ss had a total profile of the eight reactions, and these profiles were analyzed by Multidimensional Scalogram Analysis (MSA). MSA led to the conclusion that the personal styles of reaction could be characterized as a Cartesian product of two facets: a ) Activity-Passivity of the reaction, b) High vs. Low Intensity of the reaction. A third facet was hinted, which relates to the time-sequence of the reactions. PMID- 26745778 TI - NEUROTICISM (CATTELL) AND ITS RELATIONSHIP TO THE PRESENCE OF NEUROTIC SYMPTOMATOLOGY. AB - The Neuroticism Scale Questionnaire and the Symptom-Sign Inventory were investigated by means of multiple regression analysis and principal com- ponent analysis. The results provided evidence for the validity of the dimension which Cattell and Scheier call Neuroticism. In a patient population this dimension was very closely related to the number of neurotic symptoms affirmed by the patient. It is also shown that neurotic disturbance can be divided into two comparitively independent components: (i) symptoms, and (ii) personality. These findings are discussed with regard to their theoretical and practical implications. PMID- 26745779 TI - ON THE METHODS AND THEORY OF CLUSTERING. AB - The need for methods of clustering individuals into homogeneous groups seems clear. One hopes, by applying them to his data, to discover clusterings which may prove to be important. This aim appears straightforward, but the methods which exist do not necessarily satisfy them. The procedures which employ the correlation measure of profile similarity, and those which employ the distance measure are discussed. Technical and logical problems are shown to exist for both measures. The key defect in almost all clustering procedures seems to be the absence of a statistical model. The suggestion is made that the clustering problem be stated as a mixture problem. The need for further work by psychologists and statisticians is pointed out. PMID- 26745780 TI - BRIEF REPORT: COMMENTS ON EBER'S MAXPLANE MEETS THURSTONE'S FACTORIALLY INVARIANT BOX PROBLEM. PMID- 26745782 TI - Cardiorespiratory demands during an inline speed skating marathon race: a case report. AB - This study was designed to investigate the intensity profile during an inline speed skating marathon road race. A highly-trained male athlete (20 y, 73.4 kg, 178 cm, VO2 peak: 60.8 mL.kg-1.min-1) participated in a marathon road race. Oxygen uptake (VO2), respiratory exchange ratio (RER), heart rate (HR) and speed were measured using a portable gas analysis system with a HR monitor and GPS Sensor integrated. The athlete's peak VO2, HR and speed at ventilatory thresholds were assessed during an incremental field test (22 km.h-1, increase 2 km.h-1 every 5 min) one week before the race. During the race, the absolute time spent in the "easy intensity zone" (VO2 below VT1) was 1 min, 49 min "moderate intensity zone" (VO2 between VT1 and VT2), and 26 min in the "hard intensity zone" (VO2 above VT2). The average HR was 171+/-6 bpm, corresponding to 95% of the maximum. This study shows that inline speed skating road races over a marathon are conducted at moderate to high VO2 and heart rate levels. The physiological racing pattern is very intermittent, requiring both a high level of aerobic and anaerobic capacity. PMID- 26745781 TI - Burning mouth syndrome. AB - INTRODUCTION: Burning mouth syndrome mainly affects women, particularly after the menopause, when its prevalence may be 18% to 33%. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of selected treatments for burning mouth syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2015 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 70 studies. After deduplication and removal of conference abstracts, 45 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 25 studies and the further review of 20 full publications. Of the 20 full articles evaluated, one systematic review and nine RCTs were added at this update. We performed a GRADE evaluation for five PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for six interventions based on information about the effectiveness and safety of alphalipoic acid, benzodiazepines, benzydamine hydrochloride, cognitive behavioural therapy (CBT), selective serotonin re-uptake inhibitors (SSRIs), and tricyclic antidepressants. PMID- 26745783 TI - Development of the Malocclusion Impact Questionnaire (MIQ) to measure the oral health-related quality of life of young people with malocclusion: part 2 - cross sectional validation. AB - OBJECTIVE: To test the items, identified through qualitative inquiry that might form the basis of a new Malocclusion Impact Questionnaire (MIQ) to measure the oral health-related quality of life (OHQoL) of young people with malocclusion. METHODS: Piloting with 13 young people reduced the number of items from 37 to 28. Cross-sectional testing involved a convenience sample aged 10-16 years, attending the Orthodontic Department of the Charles Clifford Dental Hospital, Sheffield. The fit and function of the initial MIQ questions were examined using item response theory. RESULTS: 184 participants (113 females; 71 males) completed a questionnaire (response 85%), seven participants were excluded due to missing responses. The mean age of participants was 12.9 years (SD 1.4) and they had a wide range of malocclusions. The majority were White British (67.4%). Data from 47 participants were used to analyse test-retest reliability. Rasch analysis was undertaken, which further reduced the number of items in the questionnaire from 28 to 17. Unidimensionality of the scale was confirmed. The analysis also identified that the original 5-point response scale could be reduced to three points. The new measure demonstrated good criterion validity (r = 0.751; P < 0.001) and construct validity with the two global questions ('Overall bother' rho = 0.733 and 'Life overall' rho = 0.701). Internal consistency (Cronbach's alpha = 0.906) and test-retest reliability Intraclass correlation coefficient (ICC = 0.78; 95% CI 0.61-0.88) were also good. CONCLUSION: Cross-sectional testing has shown the new MIQ to be both valid and reliable. Further evaluation is required to confirm the generalisability as well as the ability of the new measure to detect change over time (responsiveness). PMID- 26745784 TI - Self-Assembly-Induced Alternately Stacked Single-Layer MoS2 and N-doped Graphene: A Novel van der Waals Heterostructure for Lithium-Ion Batteries. AB - In this article, a simple self-assembly strategy for fabricating van der Waals heterostructures from isolated two-dimensional atomic crystals is presented. Specifically, dopamine (DOPA), an excellent self-assembly agent and carbon precursor, was adsorbed on exfoliated MoS2 monolayers through electrostatic interaction, and the surface-modified monolayers self-assembled spontaneously into DOPA-intercalated MoS2. The subsequent in situ conversion of DOPA to highly conductive nitrogen-doped graphene (NDG) in the interlayer space of MoS2 led to the formation of a novel NDG/MoS2 nanocomposite with well-defined alternating structure. The NDG/MoS2 was then studied as an anode for lithium-ion batteries (LIBs). The results show that alternating arrangement of NDG and MoS2 triggers synergistic effect between the two components. The kinetics and cycle life of the anode are greatly improved due to the enhanced electron and Li(+) transport as well as the effective immobilization of soluble polysulfide by NDG. A reversible capacity of more than 460 mAh/g could be delivered even at 5 A/g. Moreover, the abundant voids created at the MoS2-NDG interface also accommodate the volume change during cycling and provide additional active sites for Li(+) storage. These endow the NDG/MoS2 heterostructure with low charge-transfer resistance, high sulfur reservation, and structural robustness, rendering it an advanced anode material for LIBs. PMID- 26745785 TI - Phototransformation of pesticides in prairie potholes: effect of dissolved organic matter in triplet-induced oxidation. AB - Photochemical reactions involving a variety of photosensitizers contribute to the abiotic transformation of pesticides in prairie pothole lakes (PPLs). Despite the fact that triplet excited state dissolved organic matter (DOM) enhances phototransformation of pesticides by acting as a photosensitizer, it may also decrease the overall phototransformation rate through various mechanisms. In this study, the effect of DOM on the phototransformation of four commonly applied pesticides in four different PPL waters was investigated under simulated sunlight using photoexcited benzophenone-4-carboxylate as the oxidant with DOM serving as an anti-oxidant. For atrazine and mesotrione, a decrease in phototransformation rates was observed, while phototransformations of metolachlor and isoproturon were not affected by DOM inhibition. Phototransformation rates and the extent of inhibition/enhancement by DOM varied spatially and temporally across the wetlands studied. Characterization of DOM from the sites and different seasons suggested that the DOM type and variations in the DOM structure are important factors controlling phototransformation rates of pesticides in PPLs. PMID- 26745786 TI - Viability of aromatic all-pnictogen anions. AB - Aromaticity in novel cyclic all-pnictogen heterocyclic anions, P2N3(-) and P3N2( ), and in their heavier analogues is studied using quantum mechanical computations. All geometrical parameters from optimized geometry, bonding, electron density analysis from quantum theory of atoms in molecules, nucleus independent chemical shift, and ring current density plots support their aromaticity. The aromatic nature of these molecules closely resembles that of the prototypical aromatic anion, C5H5(-). These singlet C2v symmetric molecules are comprised of five distinct canonical structures and are stable up to at least 1000 fs without any significant distortion. Mechanistic study revealed a plausible synthetic pathway for P3N2(-) - a click reaction between N2 and P3(-), through a C2v symmetric transition state. Besides this, the possibility of P3N2( ) as a eta(5)-ligand in metallocenes is studied and the nature of bonding in metallocenes is discussed through the energy decomposition analysis. PMID- 26745787 TI - Effects of resveratrol on the structure and fluidity of lipid bilayers: a membrane biophysical study. AB - Resveratrol is a natural active compound which has been attracting increasing interest due to its several pharmacological effects in cancer prevention, cardiovascular protection and treatment of neurodegenerative disorders and diabetes. The current work investigates how resveratrol affects membrane order and structure, gathering information determined by X-ray scattering analysis, derivative spectrophotometry, fluorescence quenching and fluorescence anisotropy studies. The results indicate that resveratrol is able to be incorporated into DMPC liposome model systems, either fluidizing or stiffening the bilayer, which largely depends on the membrane fluidity state. These findings suggest that the effects of resveratrol resemble cholesterol action on biological membranes, thereby contributing to the regulation of cell membrane structure and fluidity, which may influence the activity of transmembrane proteins and hence control the cell signaling pathways. The regulation of a number of cellular functions, thus may contribute to the pharmacological and therapeutic activities of this compound, explaining its pleiotropic action. PMID- 26745788 TI - Social cognition makes an independent contribution to peer relations in children with Specific Language Impairment. AB - BACKGROUND: Language is important for developing and maintaining social relationships, and also for understanding others minds. Separate studies have shown that children with Specific Language Impairment (SLI) present difficulties in both abilities, although the role of social cognition (SC) on peers' perception remains unexplored. AIMS: The present study aims to assess specific sociometric features of children with SLI through peer nominations of liking and disliking, and also to explore their relationship to the children's SC. METHODS AND PROCEDURES: Thirty-five children with SLI attending ordinary schools (3;10 to 8;00 years old) and thirty-five age-matched children (AM) were assessed with language, SC and sociometric measures. RESULTS: SLI group received more disliked nominations and had lower scores on SC tasks compared to the AM group. After controlling for age and language, SC made an independent contribution to disliked nominations within the SLI group. CONCLUSIONS: Difficulties with peers of children with SLI are related to their language level but also with their SC abilities. Consequently, only resolving language impairments will not necessarily improve early peer acceptance in children with SLI. IMPLICATION: This finding stresses the importance of early intervention programmes aimed at reducing deleterious effects in later development and socialization with peers. PMID- 26745789 TI - Towards high power output of scaled-up benthic microbial fuel cells (BMFCs) using multiple electron collectors. AB - This study aimed at achieving high power output of benthic microbial fuel cells (BMFCs) with novel geometric anode setups (inverted tube granular activated charcoal (IT-GAC) and carbon cloth roll (CCR)) and multiple anodes/electron collectors. The lab-scale tests showed the power density of IT-GAC and CCR anodes achieved at 2.92 and 2.55 W m(-2), the highest value ever reported in BMFCs. The power density of BMFCs substantially increased with electron collector number (titanium rods) in anodes. The connection of multiple electron collectors with multiple cathodes had much higher total voltage/current output than that with single cathode. The possibility of maintaining high power density at scaled-up BMFCs was explored by arranging multiple anodes in sediment. The compact configuration of multiple CCR anodes contacting each other did not deteriorate the performance of individual anodes, showing the feasibility of maximizing anode numbers per sediment footprint and achieving high power output. Multiple IT-GAC and CCR anodes with multiple collectors effectively utilized sediment at both horizontal and vertical directions and enhanced electron collection efficiency. This study demonstrated that bacterial adhesion and electron collection should be optimized on small anodes in order to maintain high power density and achieve high power output in the scaled-up BMFCs. PMID- 26745790 TI - Analytical development of a binuclear oxo-manganese complex bio-inspired on oxidase enzyme for doping control analysis of acetazolamide. AB - A bio-inspired electrochemical sensor using a binuclear oxo-manganese complex was evaluated and applied in the detection of a substance associated with doping in sports: acetazolamide (ACTZ). Investigation was made of the influence of different experimental variables on the electrocatalytic oxidation of ACTZ by the bio-inspired sensor, such as pH and interfering species. The bio-inspired sensor showed the best response in the range from 5.00*10(-9) to 7.00*10(-8) mol L(-1) ACTZ, with a linear range from 5.00*10(-9) to 2.50*10(-8) mol L(-1) and a detection limit of 4.76*10(-9) mol L(-1). The sensor exhibited characteristics similar to the Michaelis-Menten model of an enzymatic electrode, due to the use of a multinucleated complex of manganese with MU-oxo units, which was able to mimic the properties of enzymes with manganese as a cofactor in their composition, such as Mn-containing oxidase. The determination of ACTZ with the bio-inspired sensor was evaluated using three different synthetic biological fluids (plasma, saliva, and urine), demonstrating its viability for use with real samples. The analysis of ACTZ in real urine samples using the bio-inspired sensor, simulating the method adopted by the World Anti-Doping Agency, which revealed viable, suggesting a new and promising platform to be used in these analysis. PMID- 26745791 TI - Ultrasensitive detection of superoxide anion released from living cells using a porous Pt-Pd decorated enzymatic sensor. AB - Considering the critical roles of superoxide anion (O2(?-)) in pathological conditions, it is of great urgency to establish a reliable and durable approach for real-time determination of O2(?-). In this study, we propose a porous Pt-Pd decorated superoxide dismutase (SOD) sensor for qualitative and quantitative detection O2(?-). The developed biosensor exhibits a fast, selective and linear amperometric response upon O2(?-) in the concentration scope of 16 to 1,536 MUM (R(2)=0.9941), with a detection limit of 0.13 MUM (S/N=3) and a low Michaelis Menten constant of 1.37 MUM which indicating a high enzymatic activity and affinity to O2(?-). Inspiringly, the proposed sensor possesses an ultrahigh sensitivity of 1270 MUA mM(-1)cm(-2). In addition, SOD/porous Pt-Pd sensor exhibits excellent anti-interference property, reproducibility and long-term storage stability. Beyond our expectation, the trace level of O2(?-) released from living cells has also been successfully captured. These satisfactory results are mainly ascribed to (1) the porous interface with larger surface area and more active sites to provide a biocompatible environment for SOD (2) the specific biocatalysis of SOD towards O2(?-) and (3) porous Pt-Pd nanomaterials fastening the electron transfer. The superior electrochemical performance makes SOD/porous Pt-Pd sensor a promising candidate for monitoring the dynamic changes of O2(?-)in vivo. PMID- 26745792 TI - Nitrogen-doped multiple graphene aerogel/gold nanostar as the electrochemical sensing platform for ultrasensitive detection of circulating free DNA in human serum. AB - Graphene aerogel has attracted increasing attention due to its large specific surface area, high-conductivity and electronic interaction. The paper reported a facile synthesis of nitrogen-doped multiple graphene aerogel/gold nanostar (termed as N-doped MGA/GNS) and its use as the electrochemical sensing platform for detection of double stranded (dsDNA). On the one hand, the N-doped MGA offers a much better electrochemical performance compared with classical graphene aerogel. Interestingly, the performance can be enhanced by only increasing the cycle number of graphene oxide gelation. On the other hand, the hybridization with GNS further enhances the electrocatalytic activity towards Fe(CN)6(3-/4-). In addition, the N-doped MGA/GNS provides a well-defined three-dimensional architecture. The unique structure make it is easy to combine with dsDNA to form the electroactive bioconjugate. The integration not only triggers an ultrafast DNA electron and charge transfer, but also realizes a significant synergy between N-doped MGA, GNS and dsDNA. As a result, the electrochemical sensor based on the hybrid exhibits highly sensitive differential pulse voltammetric response (DPV) towards dsDNA. The DPV signal linearly increases with the increase of dsDNA concentration in the range from 1.0*10(-)(21) g ml(-)(1) to 1.0*10(-16) g ml(-1) with the detection limit of 3.9*10(-22) g ml(-1) (S/N=3). The sensitivity is much more than that of all reported DNA sensors. The analytical method was successfully applied in the electrochemical detection of circulating free DNA in human serum. The study also opens a window on the electrical properties of multiple graphene aerogel and DNA as well their hybrids to meet the needs of further applications as special nanoelectronics in molecule diagnosis, bioanalysis and catalysis. PMID- 26745793 TI - A simple turn on fluorescent sensor for the selective detection of thiamine using coconut water derived luminescent carbon dots. AB - In this study microwave-assisted hydrothermal method was used to prepare highly luminescent carbon dots (1-6 nm size) within a minute from tender coconut (Cocos nucifera) water. The synthesized carbon dots (C-dots) exhibit emission of blue and green lights while excited at 390 and 450 nm wavelengths, respectively. As an application, these C-dots were tested for a simple "turn on" fluorescent sensor for rapid detection of thiamine (vitamin B1). The detection of thiamine in human body is very important to prevent various diseases such as beriberi, neurological disorders, optic neuropathy, etc. The fluorescence emission intensity of C-dots quenches after addition of Cu(2+) ion and then again increases selectively (turn on) after the addition of thiamine. The fluorescence emission intensity enhancement of Cu(2+) ion modified C-dots in the presence of thiamine exhibits a linear relationship within the thiamine concentration range of 10-50 MUM. The limit of detection was found to be 280 nM from this study. The selectivity of the detection was also tested in the presence of different organic molecules and inorganic ions (Ca(2+), Mg(2+), Na(+), K(+), Cl(-), SO4(2-), and NO3(-)) which are present in blood serum and urine and found to be almost no interference in the detection. Finally, to see the applicability in real samples a commercial vitamin capsule was tested and found less than 3% error in the detected concentration. The C-dots were also used for bioimaging of fungus and the results show they are also suitable for this application too. PMID- 26745794 TI - Synthesis, modification, bioconjugation of silica coated fluorescent quantum dots and their application for mycotoxin detection. AB - To create bright and stable fluorescent biolabels for immunoassay detection of mycotoxin deoxynivalenol in food and feed, CdSe/CdS/ZnS core-shell quantum dots (QDs) were encapsulated in silica nanoparticles through a water-in-oil reverse microemulsion process. The optical properties and stability of the obtained silica coated QDs (QD@SiO2), modified with amino, carboxyl and epoxy groups and stabilized with polyethylene glycol fragments, were characterized in order to assess their bioapplicability. The developed co-condensation techniques allowed maintaining 80% of the initial fluorescent properties and yielded stable fluorescent labels that could be easily activated and bioconjugated. Further, the modified QD@SiO2 were efficiently conjugated with antibodies and applied as a novel label in a microtiter plate based immunoassay and a quantitative column based rapid immunotest for deoxynivalenol detection with IC50 of 473 and 20 ng/ml, respectively. PMID- 26745797 TI - Rotational Spectrum and Structure of the 1,1-Difluoroethylene...Carbon Dioxide Complex. AB - Rotational spectra for five isotopologues of the 1:1 weak complex between 1,1 difluoroethylene (H2C?CF2) and carbon dioxide (CO2) have been measured using 480 MHz bandwidth chirped-pulse and resonant cavity Fourier-transform microwave spectroscopy between 5.5 and 18.5 GHz. The observed structure of the complex is planar, with the CO2 aligned roughly parallel to the C?C bond, and experimental structural parameters derived from rotational constants are consistent with the most stable geometry predicted by basis set superposition error and zero point energy corrected ab initio geometry optimizations at the MP2/6-311++G(2d,2p) level. Comparisons with the recently characterized vinyl fluoride...carbon dioxide complex reveal slightly longer intermolecular distances in the present complex, but very similar binding energies. PMID- 26745796 TI - Energy driven cascade recognition for selective detection of nucleic acids with high discrimination factor at room temperature. AB - In this article, we demonstrated a cascade recognition strategy for the detection of single strand nucleic acid with high discrimination factor at room temperature. The cascade recognition strategy contains a toehold mediated strand displacement and a double-toehold mediated double strand displacement reaction, thus enable the high ability to discern point mutation of target. The discrimination factor of the model target is between 45 and 109, with the medium of 70. This strategy is homogeneous, easy operation, enzyme-free, isothermal, and can be easily adapted to high-throughput devices without the need of designing complicated instruments. PMID- 26745795 TI - Sandwich-type electrochemical immunosensor for the detection of AFP based on Pd octahedral and APTES-M-CeO2-GS as signal labels. AB - In the present work, an ultrasensitive sandwich-type electrochemical immunosensor based on a novel signal amplification strategy was designed for quantitative detection of alpha fetoprotein (AFP). Au nanoparticles with biocompatibility were electrodeposited on the surface of glassy carbon electrode (GCE) which can effectively capture and immobilize primary anti-AFP (Ab1) to significantly amplify the electrochemical signal. Graphene Oxide and CeO2 mesoporous nanocomposite functionalized by the 3-aminopropyltriethoxysilane supported Pd octahedral nanoparticles (Pd/APTES-M-CeO2-GS) were utilized as labels of detection anti-AFP (Ab2). Pd octahedral nanoparticles presented good catalytic activity towards the reduction of H2O2. Due to the large specific surface area and good adsorption properties of APTES-CeO2-GS nanocomposite, large amount of Pd octahedral nanoparticles could be immobilized, which could amplify the electrochemical signal and improve the sensitivity of the immunosensor. Under optimal conditions, the immunosensor exhibited wide linear range from 0.1 pg/mL to 50 ng/mL with a low detection limit of 0.033 pg/mL (S/N=3) for AFP detection. In addition, high sensitivity, excellent selectivity, good reproducibility and stability were obtained for the immunosensor, which has a promising application for quantitative detection of other tumor markers in clinical diagnosis. PMID- 26745798 TI - Proteomic Analysis of Minimally Damaged Renal Tubular Tissue from Two-Kidney-One Clip Hypertensive Rats Demonstrates Extensive Changes Compared to Tissue from Controls. AB - BACKGROUND: Tubular atrophy and interstitial fibrosis mark the final stage in most forms of progressive kidney diseases. Little is known regarding changes in the tubular proteome. In this study, we investigated changes in the tubular proteome of normal or minimally damaged tubular tissue in the non-clipped kidney from rats with two-kidney one-clip (2K1C) hypertension. METHODS: Formalin-fixed paraffin-embedded kidney sections from four 2K1C rats with hypertensive kidney damage and 6 sham rats were used. Tubulointerstitial tissue without discernable interstitial expansion or pronounced tubular alterations was microdissected and this was assumed to represent an early stage of chronic tubular damage in 2K1C. Samples were analyzed by mass spectrometry and relative protein abundances were compared between 2K1C and sham. RESULTS: A total of 1,160 proteins were identified with at least 2 unique peptides, allowing for relative quantitation between samples. Among these, 151 proteins were more abundant, and 192 proteins were less abundant in 2K1C compared with sham. Transgelin, vimentin and creatine kinase B-type were among the proteins that were most increased in 2K1C. Ingenuity Pathway Analysis showed increased abundance of proteins related to Rho signaling and protein turnover (eIF2 signaling and protein ubiquitination), and decreased abundance of proteins related to fatty acid beta-oxidation. CONCLUSION: Tubular tissue from normal or minimally damaged hypertensive kidney damage demonstrate extensive proteomic changes with upregulation of pathways associated with progressive kidney damage, such as Rho signaling and protein turnover. Thus, proteomics presents itself to be a promising tool for the discovery of early damage markers from not yet morphologically visible tubular damage. PMID- 26745800 TI - MiR-124 Promote Neurogenic Transdifferentiation of Adipose Derived Mesenchymal Stromal Cells Partly through RhoA/ROCK1, but Not ROCK2 Signaling Pathway. AB - OBJECTIVE: Some recent studies suggest that multiple miRNAs might regulate neurogenic transdifferentiation of mesenchymal stromal cells (MSCs). In the present study, we hypothesized that the miR-124 can repress the expression of RhoA upon the neurogenesis of adipose derived MSCs (ADMSCs). METHODS: MiRNA expression dynamics during neurogenic transdifferentiation of ADMSCs were measured. The expression of neuron-specific enolase (NSE), Tuj-1 (Neuron-specific class III beta-tubulin) and glial fibrillary acidic protein (GFAP), as well as electrophysiological properties, were detected after neurogenic transdifferentiation. The targeting of miR-124 over RhoA was verified by dual luciferase assay, qRT-PCR and western blot. The functions of miR-124 and the RhoA/ROCK signaling pathway were studied using gain and loss of function experiments in vitro. RESULTS: MiR-124 is significantly upregulated during neurogenic transdifferentiation of ADMSCs. Knockdown of endogenous miR-124 hampered neurogenic transdifferentiation and the acquired electrophysiological properties. MiR-124 could directly target RHOA mRNA and repress its expression, through which it increased the proportion of transdifferentiated (transdiff.) cells with positive NSE, Tuj-1 and GFAP. RhoA/ROCK1, but not ROCK2 is a downstream signaling pathway of miR-124 in the process of transdifferentiation. CONCLUSION: MiR-124 is an important miRNA modulating neurogenic transdifferentiation of ADMSCs at least partly via the miR-124/RhoA/ROCK1 signaling pathway. These findings provided some fundamental information for future use of ADMSCs as an agent for regenerative medicine and cell therapy for neurological diseases. PMID- 26745803 TI - Functionally Brain Network Connected to the Retrosplenial Cortex of Rats Revealed by 7T fMRI. AB - Functional networks are regarded as important mechanisms for increasing our understanding of brain function in healthy and diseased states, and increased interest has been focused on extending the study of functional networks to animal models because such models provide a functional understanding of disease progression, therapy and repair. In rodents, the retrosplenial cortex (RSC) is an important cortical region because it has a large size and presents transitional patterns of lamination between the neocortex and archicortex. In addition, a number of invasive studies have highlighted the importance of the RSC for many functions. However, the network based on the RSC in rodents remains unclear. Based on the critical importance of the RSC, we defined the bilateral RSCs as two regions of interest and estimated the network based on the RSC. The results showed that the related regions include the parietal association cortex, hippocampus, thalamus nucleus, midbrain structures, and hypothalamic mammillary bodies. Our findings indicate two possible major networks: a sensory-cognitive network that has a hub in the RSCs and processes sensory information, spatial learning, and episodic memory; and a second network that is involved in the regulation of visceral functions and arousal. In addition, functional asymmetry between the bilateral RSCs was observed. PMID- 26745799 TI - Chemical Composition and Biological Activity of Extracts Obtained by Supercritical Extraction and Ethanolic Extraction of Brown, Green and Red Propolis Derived from Different Geographic Regions in Brazil. AB - The variations in the chemical composition, and consequently, on the biological activity of the propolis, are associated with its type and geographic origin. Considering this fact, this study evaluated propolis extracts obtained by supercritical extraction (SCO2) and ethanolic extraction (EtOH), in eight samples of different types of propolis (red, green and brown), collected from different regions in Brazil. The content of phenolic compounds, flavonoids, in vitro antioxidant activity (DPPH and ABTS), Artepillin C, p-coumaric acid and antimicrobial activity against two bacteria were determined for all extracts. For the EtOH extracts, the anti-proliferative activity regarding the cell lines of B16F10, were also evaluated. Amongst the samples evaluated, the red propolis from the Brazilian Northeast (states of Sergipe and Alagoas) showed the higher biological potential, as well as the larger content of antioxidant compounds. The best results were shown for the extracts obtained through the conventional extraction method (EtOH). However, the highest concentrations of Artepillin C and p-coumaric acid were identified in the extracts from SCO2, indicating a higher selectivity for the extraction of these compounds. It was verified that the composition and biological activity of the Brazilian propolis vary significantly, depending on the type of sample and geographical area of collection. PMID- 26745801 TI - Deletion of Dystrophin In-Frame Exon 5 Leads to a Severe Phenotype: Guidance for Exon Skipping Strategies. AB - Duchenne and Becker muscular dystrophy severity depends upon the nature and location of the DMD gene lesion and generally correlates with the dystrophin open reading frame. However, there are striking exceptions where an in-frame genomic deletion leads to severe pathology or protein-truncating mutations (nonsense or frame-shifting indels) manifest as mild disease. Exceptions to the dystrophin reading frame rule are usually resolved after molecular diagnosis on muscle RNA. We report a moderate/severe Becker muscular dystrophy patient with an in-frame genomic deletion of DMD exon 5. This mutation has been reported by others as resulting in Duchenne or Intermediate muscular dystrophy, and the loss of this in frame exon in one patient led to multiple splicing events, including omission of exon 6, that disrupts the open reading frame and is consistent with a severe phenotype. The patient described has a deletion of dystrophin exon 5 that does not compromise recognition of exon 6, and although the deletion does not disrupt the reading frame, his clinical presentation is more severe than would be expected for classical Becker muscular dystrophy. We suggest that the dystrophin isoform lacking the actin-binding sequence encoded by exon 5 is compromised, reflected by the phenotype resulting from induction of this dystrophin isoform in mouse muscle in vivo. Hence, exon skipping to address DMD-causing mutations within DMD exon 5 may not yield an isoform that confers marked clinical benefit. Additional studies will be required to determine whether multi-exon skipping strategies could yield more functional dystrophin isoforms, since some BMD patients with larger in-frame deletions in this region have been reported with mild phenotypes. PMID- 26745802 TI - Mutations of Arabidopsis TBL32 and TBL33 Affect Xylan Acetylation and Secondary Wall Deposition. AB - Xylan is a major acetylated polymer in plant lignocellulosic biomass and it can be mono- and di-acetylated at O-2 and O-3 as well as mono-acetylated at O-3 of xylosyl residues that is substituted with glucuronic acid (GlcA) at O-2. Based on the finding that ESK1, an Arabidopsis thaliana DUF231 protein, specifically mediates xylan 2-O- and 3-O-monoacetylation, we previously proposed that different acetyltransferase activities are required for regiospecific acetyl substitutions of xylan. Here, we demonstrate the functional roles of TBL32 and TBL33, two ESK1 close homologs, in acetyl substitutions of xylan. Simultaneous mutations of TBL32 and TBL33 resulted in a significant reduction in xylan acetyl content and endoxylanase digestion of the mutant xylan released GlcA-substituted xylooligomers without acetyl groups. Structural analysis of xylan revealed that the tbl32 tbl33 mutant had a nearly complete loss of 3-O-acetylated, 2-O-GlcA substituted xylosyl residues. A reduction in 3-O-monoacetylated and 2,3-di-O acetylated xylosyl residues was also observed. Simultaneous mutations of TBL32, TBL33 and ESK1 resulted in a severe reduction in xylan acetyl level down to 15% of that of the wild type, and concomitantly, severely collapsed vessels and stunted plant growth. In particular, the S2 layer of secondary walls in xylem vessels of tbl33 esk1 and tbl32 tbl33 esk1 exhibited an altered structure, indicating abnormal assembly of secondary wall polymers. These results demonstrate that TBL32 and TBL33 play an important role in xylan acetylation and normal deposition of secondary walls. PMID- 26745804 TI - Frequency, Magnitude, and Possible Causes of Stranding and Mass-Mortality Events of the Beach Clam Tivela mactroides (Bivalvia: Veneridae). AB - Stranding combined with mass-mortality events of sandy-beach organisms is a frequent but little-understood phenomenon, which is generally studied based on discrete episodes. The frequency, magnitude, and possible causes of stranding and mass-mortality events of the trigonal clam Tivela mactroides were assessed based on censuses of stranded individuals, every four days from September 2007 through December 2008, in Caraguatatuba Bay, southeastern Brazil. Stranded clams were classified as dying (closed valves did not open when forced) or dead (closed valves were easily opened). Information on wave parameters and the living intertidal clam population was used to assess possible causes of stranding. This fine-scale monitoring showed that stranding occurred widely along the shore and year-round, with peaks interspersed with periods of low or no mortality. Dead clams showed higher mean density than dying individuals, but a lower mean shell length, attributed to a higher tolerance to desiccation of larger individuals. Wave height had a significant negative relationship to the density of dying individuals, presumed to be due to the accretive nature of low-energy waves: when digging out, clams would be more prone to be carried upward and unable to return; while larger waves, breaking farther from the beach and with a stronger backwash, would prevent stranding in the uppermost areas. This ecological finding highlights the need for refined temporal studies on mortality events, in order to understand them more clearly. Last, the similar size structure of stranded clams and the living population indicated that the stranded individuals are from the intertidal or shallow subtidal zone, and reinforces the ecological and behavioral components of this process, which have important ecological and socioeconomic implications for the management of this population. PMID- 26745805 TI - Structural and Functional Interactions between Transient Receptor Potential Vanilloid Subfamily 1 and Botulinum Neurotoxin Serotype A. AB - BACKGROUND: Botulinum neurotoxins are produced by Clostridium botulinum bacteria. There are eight serologically distinct botulinum neurotoxin isoforms (serotypes A H). Currently, botulinum neurotoxin serotype A (BoNT/A) is commonly used for the treatment of many disorders, such as hyperactive musculoskeletal disorders, dystonia, and pain. However, the effectiveness of BoNT/A for pain alleviation and the mechanisms that mediate the analgesic effects of BoNT/A remain unclear. To define the antinociceptive mechanisms by which BoNT/A functions, the interactions between BoNT/A and the transient receptor potential vanilloid subfamily 1 (TRPV1) were investigated using immunofluorescence, co-immunoprecipitation, and western blot analysis in primary mouse embryonic dorsal root ganglion neuronal cultures. RESULTS: 1) Three-week-old cultured dorsal root ganglion neurons highly expressed transient TRPV1, synaptic vesicle 2A (SV2A) and synaptosomal-associated protein 25 (SNAP-25). SV2A and SNAP-25 are the binding receptor and target protein, respectively, of BoNT/A. 2) TRPV1 colocalized with both BoNT/A and cleaved SNAP 25 when BoNT/A was added to dorsal root ganglia neuronal cultures. 3) After 24 hours of BoNT/A treatment (1 nmol/l), both TRPV1 and BoNT/A positive bands were detected in western blots of immunoprecipitated pellets. 4) Blocking TRPV1 with a specific antibody decreased the cleavage of SNAP-25 by BoNT/A. CONCLUSION: BoNT/A interacts with TRPV1 both structurally and functionally in cultured mouse embryonic dorsal root ganglion neurons. These results suggest that an alternative mechanism is used by BoNT/A to mediate pain relief. PMID- 26745808 TI - Influence of Anterior Cruciate Ligament Tear on Thigh Muscle Strength and Hamstring-to-Quadriceps Ratio: A Meta-Analysis. AB - Theoretical compensation after anterior cruciate ligament (ACL) tear could cause quadriceps weakness and hamstring activation, preventing anterior tibial subluxation and affecting the expected hamstring-to-quadriceps ratio. Although quadriceps weakness often occurs after ACL tears, it remains unclear whether hamstring strength and hamstring-to-quadriceps ratio increase in ACL deficient knees. This meta-analysis compared the isokinetic muscle strength of quadriceps and hamstring muscles, and the hamstring-to-quadriceps ratio, of the injured and injured limbs of patients with ACL tears. This meta-analysis included all studies comparing isokinetic thigh muscle strengths and hamstring-to-quadriceps ratio in the injured and uninjured legs of patients with ACL tear, without or before surgery. Thirteen studies were included in the meta-analysis. Quadriceps and hamstring strengths were 22.3 N?m (95% CI: 15.2 to 29.3 N?m; P<0.001) and 7.4 N?m (95% CI: 4.3 to 10.5 N?m; P<0.001) lower, respectively, on the injured than on the uninjured side. The mean hamstring-to-quadriceps ratio was 4% greater in ACL deficient than in uninjured limbs (95% CI: 1.7% to 6.3%; P<0.001). Conclusively, Decreases were observed in both the quadriceps and hamstring muscles of patients with ACL tear, with the decrease in quadriceps strength being 3-fold greater. These uneven reductions slightly increase the hamstring-to-quadriceps ratio in ACL deficient knees. PMID- 26745807 TI - Prevalence of Overweight and Obesity among Chinese Adults: Role of Adiposity Indicators and Age. AB - OBJECTIVES: The role of different body fat indicators and age in assessing the prevalence of obesity is unclear. We aimed to examine to what extent different body fat indicators including BMI, waist circumference (WC) and waist-to-hip ratio (WHR) affect the prevalence of overweight and obesity among Chinese adults taking age into account. METHODS: This population-based cross-sectional study included a random sample of 7,603 adults aged 20-79 years across entire Tianjin, China. BMI, WC, and WHR were used to define overweight and obesity following standard criteria. Prevalence rates were calculated and standardized using local age- and gender-specific census data. Logistic regression was used in data analysis. RESULTS: Using the combination of BMI, WC, and WHR, the prevalence of overweight and obesity was 69.8%, and increased with age till the age of 60 and a decline thereafter. The prevalence of overweight assessed by BMI was higher than that assessed by WC and WHR, while the prevalence of obesity defined by BMI was much lower than that defined by WC or WHR. CONCLUSION: The prevalence of overweight and obesity is about 70% among Chinese adults. Adiposity indicators and age play an important role in the prevalence of overweight and obesity. PMID- 26745806 TI - Waterpipe Tobacco Use in the United Kingdom: A Cross-Sectional Study among University Students and Stop Smoking Practitioners. AB - INTRODUCTION: Despite cigarette-like adverse health outcomes associated with waterpipe tobacco smoking and increase in its use among youth, it is a much underexplored research area. We aimed to measure the prevalence and patterns of waterpipe tobacco use and evaluate tobacco control policy with respect to waterpipe tobacco, in several universities across the UK. We also aimed to measure stop smoking practitioners' encounter of waterpipe tobacco smoking. METHODS: We distributed an online survey to six UK universities, asking detailed questions on waterpipe tobacco. Multivariable logistic regression models, adjusted for age, gender, ethnicity, graduate status, university and socioeconomic status (SES) assessed associations between waterpipe tobacco smoking (single use and dual use with cigarettes) and sociodemographic variables. SES was ascertained by average weekly self-spend on non-essentials. We also descriptively analysed data from a 2012 survey of stop smoking practitioners to assess the proportion of clients that used waterpipe regularly. RESULTS: f 2217 student responses, 66.0% (95% CI 63.9-68.0%) had tried waterpipe tobacco smoking; 14.3% (95% CI 12.8-15.8%) reported past-30 day use, and 8.7% (95% CI 7.6-9.9%) reported at least monthly users. Past-30 day waterpipe-only use was associated with being younger (AOR 0.95, 95% CI 0.91-0.99), male (AOR 1.44, 95% CI 1.08 1.94), higher SES (AOR 1.16, 95% CI 1.06-1.28) and belonging to non-white ethnicities (vs. white, AOR 2.24, 95% CI 1.66-3.04). Compared to less than monthly users, monthly users were significantly more likely to have urges to smoke waterpipe (28.1% vs. 3.1%, p<0.001) report difficulty in quitting (15.5% vs. 0.8%, p<0.001), report feeling guilty, and annoyed when criticised about waterpipe smoking (19.2% vs. 9.2%, p<0.001). Nearly a third (32.5%) of respondents who had tried waterpipe had violated the UK smokefree law and a quarter (24.5%) reporting seeing health warnings on waterpipe tobacco packaging or apparatuses. Of 1,282 smoking cessation practitioners, a quarter (23.4%, 95% CI 21.5-26.1%) reported having some clients who regularly use waterpipes, but 69.5% (95% CI 67.0-72.0%) never ask clients about waterpipe use. Three quarters (74.8%, 95% CI 72.4-77.1%) want more information about waterpipe tobacco smoking. CONCLUSIONS: While two thirds of university students have ever tried waterpipe tobacco, at least monthly use is less common. Regular users display features of waterpipe tobacco dependence, and a substantial minority of SSS practitioners encounter clients who regularly use waterpipe. The lack of training on waterpipe for SSS practitioners and reported violations of smokefree laws for waterpipe highlight the need for regular surveillance of and a coordinated tobacco control strategy for waterpipe use. PMID- 26745810 TI - Evaluation of local bone turnover in painful hip by 18F-fluoride positron emission tomography. AB - OBJECTIVE: The diagnosis of painful hip without remarkable radiographic findings is still challenging. In recent years, femoroacetabular impingement (FAI) has been recognized as an important cause of painful hip. The hypothesis of this study was that local bone turnover may be accelerated in painful hip, especially in FAI lesions. To test this, patients with unilateral symptomatic hip underwent F-fluoride PET, which directly correlates with osteoblast activity and therefore bone turnover. PATIENTS AND METHODS: In total, 27 patients with unilateral symptomatic painful hip were enrolled. The diagnosis included 15 cam-type FAI cases, six labral tear cases, and six early-stage osteoarthritis cases. The region of interest for cam and pincer lesions was identified and the maximum standardized uptake value (SUVmax) in these regions and the contralateral asymptomatic regions were measured by F-fluoride PET. The SUVmax ratio was defined as symptomatic side SUVmax/asymptomatic side SUVmax. The alpha angle and center-edge angle were measured by plain radiograph. RESULTS: The SUVmax of both cam and pincer lesions were significantly higher than the SUVmax of the contralateral regions (P<0.0001). The cam SUVmax ratio correlated positively with the alpha angle (r=0.5, P=0.007). Patients with an alpha angle of more than or equal to 60 degrees had a significantly higher cam SUVmax ratio than the less than 60 degrees group (P=0.017). CONCLUSION: This study showed the accelerated local bone turnover in painful hip, partly in FAI cases. Accelerated bone turnover may play a significant role in FAI pathophysiology; therefore, its recognition by imaging modality may contribute toward a more sensitive diagnosis in painful hip. PMID- 26745811 TI - Diagnostic performance of 18F-FDG PET/contrast-enhanced CT versus contrast enhanced CT alone for post-treatment detection of ovarian malignancy. AB - OBJECTIVE: The aim of this study was to evaluate the diagnostic performance of combined fluorine-18 fluorodeoxyglucose (F-FDG) PET/contrast-enhanced computed tomography (Ce-CT) in comparison with Ce-CT alone for the detection of residual/recurrent tumor after initial treatment of malignant ovarian tumors. PATIENTS AND METHODS: The study prospectively recruited 111 patients with a clinical suspicion of ovarian tumor recurrence. Each patient underwent F-FDG PET/computed tomography (CT) with low-dose CT, followed immediately by Ce-CT. Study-based analyses for a total of 136 scans were carried out. For each study, 11 subsites were assessed on a four-point score (score 0=definitely benign, score 1=probably benign, score 2=probably malignant, and score 3=definitely malignant). The subsites were collectively categorized into four groups: local tumor site, peritoneum, pelvi-abdominal lymph nodes, and other sites (e.g. liver, lung, bone, brain, etc). The final diagnosis of disease status was made on subsequent follow up by conventional imaging (CT/MRI), F-FDG PET/CT, or histopathology whenever possible. RESULTS: Of the 136 studies evaluated, 97 (71%) studies had recurrent/residual disease and 39 (29%) studies were disease free on the basis of the final diagnosis. F-FDG PET/Ce-CT and Ce-CT had a sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of 96 versus 84%, 92 versus 59%, 90 versus 59%, 97 versus 84%, and 95 versus 76%, respectively. F-FDG PET/Ce-CT was significantly more sensitive, specific, and accurate compared with Ce-CT, with P-values of 0.002, 0.001, and less than 0.0001, respectively. Site-based analyses also showed significant differences. CONCLUSION: CombinedF-FDG PET/Ce-CT significantly outperforms Ce-CT alone in the post-treatment detection of malignant ovarian tumors. PMID- 26745812 TI - Arylpiperidines as a new class of oxidosqualene cyclase inhibitors. AB - The cyclization of oxidosqualene to lanosterol, catalyzed by the enzyme oxidosqualene cyclase (OSC), goes through a number of carbocationic high energy intermediates (HEI), and mimicking these intermediates is a promising approach for the development of OSC inhibitors. 3-Arylpiperidines (or tetrahydropyridines) were designed as steroidomimetic rings A + C equivalents containing two protonable amino groups for mimicking both the pro-C4 HEI and the pro-C20 HEI of the OSC-mediated cyclization cascade. Inhibitory activity is strongly dependent on the nature of the lipophilic substituent representing an equivalent of the sterol side chain. Here aromatic residues (substituted benzyl, cinnamyl, naphthylmethyl) were found to be most suitable. Docking experiments on a first optimized 3-arylpiperidine compound led to an isomeric 4-arylpiperidine with submicromolar activity on human OSC. This inhibitor reduced total cholesterol biosynthesis in a cellular assay with an IC50 value of 0.26 MUM. PMID- 26745809 TI - Arabidopsis ERF1 Mediates Cross-Talk between Ethylene and Auxin Biosynthesis during Primary Root Elongation by Regulating ASA1 Expression. AB - The gaseous phytohormone ethylene participates in the regulation of root growth and development in Arabidopsis. It is known that root growth inhibition by ethylene involves auxin, which is partially mediated by the action of the WEAK ETHYLENE INSENSITIVE2/ANTHRANILATE SYNTHASE alpha1 (WEI2/ASA1), encoding a rate limiting enzyme in tryptophan (Trp) biosynthesis, from which auxin is derived. However, the molecular mechanism by which ethylene decreases root growth via ASA1 is not understood. Here we report that the ethylene-responsive AP2 transcription factor, ETHYLENE RESPONSE FACTOR1 (ERF1), plays an important role in primary root elongation of Arabidopsis. Using loss- and gain-of-function transgenic lines as well as biochemical analysis, we demonstrate that ERF1 can directly up-regulate ASA1 by binding to its promoter, leading to auxin accumulation and ethylene induced inhibition of root growth. This discloses one mechanism linking ethylene signaling and auxin biosynthesis in Arabidopsis roots. PMID- 26745813 TI - Improving Transgender Healthcare in the New York City Correctional System. AB - PURPOSE: Correctional settings create unique challenges for patients with special needs, including transgender patients, who have an increased rate of overall discrimination, sexual abuse, healthcare disparities, and improper housing. As part of our correctional health quality improvement process, we sought to review and evaluate the adequacy of care for transgender patients in the New York City jail system. METHODS: Using correctional pharmacy records, transgender patients receiving hormonal treatment were identified. A brief in-person survey was conducted to evaluate their care in the community before incarceration, medical care in jail, and experience in the jail environment. RESULTS: Survey findings and analysis of transgender patient healthcare-related complaints revealed opportunities for improvements in the provision of care and staff understanding of this population. Utilizing these findings, we conducted lesbian, gay, bisexual, and transgender (LGBT) trainings in all 12 jail clinics for medical, nursing, and mental health staff. Three months after LGBT training, patient complaints dropped by over 50%. After the development and implementation of a newly revised transgender healthcare policy, complaints dropped to zero within 6 months. CONCLUSION: Our efforts to assess the quality of care provided to transgender patients revealed significant areas for improvement. Although we have made important gains in providing quality care through the implementation of policies and procedures rooted in community standards and the express wishes of our patients, we continue to engage this patient population to identify other issues that impact their health and well-being in the jail environment. PMID- 26745814 TI - Manganese Electrocatalysts with Bulky Bipyridine Ligands: Utilizing Lewis Acids To Promote Carbon Dioxide Reduction at Low Overpotentials. AB - Earth-abundant manganese bipyridine (bpy) complexes are well-established molecular electrocatalysts for proton-coupled carbon dioxide (CO2) reduction to carbon monoxide (CO). Recently, a bulky bipyridine ligand, 6,6'-dimesityl-2,2' bipyridine (mesbpy), was utilized to significantly lower the potential necessary to access the doubly reduced states of these manganese catalysts by eliminating their ability to dimerize after one-electron reduction. Although this Mn mesbpy catalyst binds CO2 at very low potentials, reduction of a resulting Mn(I)-COOH complex at significantly more negative potentials is required to achieve fast catalytic rates. Without reduction of Mn(I)-COOH, catalysis occurs slowly via a alternate catalytic pathway-protonation of Mn(I)-COOH to form a cationic tetracarbonyl complex. We report the use of Lewis acids, specifically Mg(2+) cations, to significantly increase the rate of catalysis (by over 10-fold) at these low overpotentials (i.e., the same potential as CO2 binding). Reduction of CO2 occurs at one of the lowest overpotentials ever reported for molecular electrocatalysts (eta = 0.3-0.45 V). With Mg(2+), catalysis proceeds via a reductive disproportionation reaction of 2CO2 + 2e(-) -> CO and CO3(2-). Insights into the catalytic mechanism were gained by using variable concentration cyclic voltammetry, infrared spectroelectrochemistry, and bulk electrolysis studies. The catalytic Tafel behavior (log turnover frequency vs overpotential relationship) of [Mn(mesbpy)(CO)3(MeCN)](OTf) with added Mg(2+) is compared with those of other commonly studied CO2 reduction catalysts. PMID- 26745815 TI - Redox Reactions between Mn(II) and Hexagonal Birnessite Change Its Layer Symmetry. AB - Birnessite, a phyllomanganate and the most common type of Mn oxide, affects the fate and transport of numerous contaminants and nutrients in nature. Birnessite exhibits hexagonal (HexLayBir) or orthogonal (OrthLayBir) layer symmetry. The two types of birnessite contain contrasting content of layer vacancies and Mn(III), and accordingly have different sorption and oxidation abilities. OrthLayBir can transform to HexLayBir, but it is still vaguely understood if and how the reverse transformation occurs. Here, we show that HexLayBir (e.g., delta-MnO2 and acid birnessite) transforms to OrthLayBir after reaction with aqueous Mn(II) at low Mn(II)/Mn (in HexLayBir) molar ratios (5-24%) and pH >= 8. The transformation is promoted by higher pH values, as well as smaller particle size, and/or greater stacking disorder of HexLayBir. The transformation is ascribed to Mn(III) formation via the comproportionation reaction between Mn(II) adsorbed on vacant sites and the surrounding layer Mn(IV), and the subsequent migration of the Mn(III) into the vacancies with an ordered distribution in the birnessite layers. This study indicates that aqueous Mn(II) and pH are critical environmental factors controlling birnessite layer structure and reactivity in the environment. PMID- 26745816 TI - Arrhythmias and sudden death. PMID- 26745817 TI - 2015 European Society of Cardiology Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death summarized by co-chairs. AB - The present European Society of Cardiology (ESC) Guidelines is a European update to the 2006 European/American guidelines for the management of patients with ventricular arrhythmias (VA) and the prevention of sudden cardiac death (SCD). The update is timely considering new insights into the natural history of diseases predisposing to SCD especially for younger individuals and also with the completion of major trials that have impacted management strategies for heart failure (HF). PMID- 26745818 TI - EHJ's new impact factor of 15.2: a global strategy is paying off. PMID- 26745820 TI - The Complement System in Hemodialysis Patients: Getting to the Heart of the Matter. PMID- 26745819 TI - Distinct decalcification process of dentin by different cariogenic organic acids: Kinetics, ultrastructure and mechanical properties. AB - OBJECTIVES: We studied artificial dentin lesions in human teeth generated by lactate and acetate buffers (pH 5.0), the two most abundant acids in caries. The objective of this study was to determine differences in mechanical properties, mineral density profiles and ultrastructural variations of two different artificial lesions with the same approximate depth. METHODS: 0.05M (pH 5.0) acetate or lactate buffer was used to create 1) 180MUm-deep lesions in non carious human dentin blocks (acetate 130h; lactate 14days); (2) demineralized, ~180MUm-thick non-carious dentin discs (3 weeks). We performed nanoindentation to determine mechanical properties across the hydrated lesions, and micro X-ray computed tomography (MicroXCT) to determine mineral profiles. Ultrastructure in lesions was analyzed by TEM/selected area electron diffraction (SAED). Demineralized dentin discs were analyzed by small angle X-ray scattering (SAXS). RESULTS: Diffusion-dominated demineralization was shown based on the linearity between lesion depths versus the square root of exposure time in either solution, with faster kinetics in acetate buffer. Nanoindentation revealed lactate induced a significantly sharper transition in reduced elastic modulus across the lesions. MicroXCT showed lactate demineralized lesions had swelling and more disorganized matrix structure, whereas acetate lesions had abrupt X-ray absorption near the margin. At the ultrastructural level, TEM showed lactate was more effective in removing minerals from the collagenous matrix, which was confirmed by SAXS analysis. CONCLUSIONS: These findings indicated the different acids yielded lesions with different characteristics that could influence lesion formation resulting in their distinct predominance in different caries activities, and these differences may impact strategies for dentin caries remineralization. PMID- 26745821 TI - What Do We Learn from Spheroid Culture Systems? Insights from Tumorspheres Derived from Primary Colon Cancer Tissue. AB - Due to their self-renewal and tumorigenic properties, tumor-initiating cells (TICs) have been hypothesized to be important targets for colorectal cancer (CRC). However the study of TICs is hampered by the fact that the identification and culturing of TICs is still a subject of extensive debate. Floating three dimensional spheroid cultures (SC) that grow in serum-free medium supplemented with growth factors are supposed to be enriched in TICs. We generated SC from fresh clinical tumor specimens and compared them to SC isolated from CRC cell lines as well as to adherent differentiated counterparts. Patient-derived SC display self-renewal capacity and can induce serial transplantable tumors in immuno-deficient mice, which phenotypically resemble the tumor of origin. In addition, the original tumor tissue and established SC retain several similar CRC relevant mutations. Primary SC express key stemness proteins such as SOX2, OCT4, NANOG and LGR5 and importantly show increased chemoresistance ability compared to their adherent differentiated counterparts and to cell line-derived SC. Strikingly, cells derived from spheroid or adherent differentiating culture conditions displayed similar self-renewal capacity and equally formed tumors in immune-deficient mice, suggesting that self-renewal and tumor-initiation capacity of TICs is not restricted to phenotypically immature spheroid cells, which we describe to be highly plastic and able to reacquire stem-cell traits even after long differentiation processes. Finally, we identified two genes among a sphere gene expression signature that predict disease relapse in CRC patients. Here we propose that SC derived from fresh patient tumor tissue present interesting phenotypic features that may have clinical relevance for chemoresistance and disease relapse and therefore represent a valuable tool to test for new CRC therapies that overcome drug resistance. PMID- 26745823 TI - Gibbs-ringing artifact removal based on local subvoxel-shifts. AB - PURPOSE: To develop a fast and stable method for correcting the gibbs-ringing artifact. METHODS: Gibbs-ringing is a well-known artifact which manifests itself as spurious oscillations in the vicinity of sharp image gradients at tissue boundaries. The origin can be seen in the truncation of k-space during MRI data acquisition. Correction techniques like Gegenbauer reconstruction or extrapolation methods aim at recovering these missing data. Here, we present a simple and robust method which exploits a different view on the Gibbs-phenomenon: The truncation in k-space can be interpreted as a convolution of the underlying image with a sinc-function. As the image is reconstructed on a discretized grid, the severity of the ringing artifacts depends on how this grid is located with respect to the edge and the oscillation pattern of the function. We propose to reinterpolate the image based on local, subvoxel-shifts to sample the ringing pattern at the zero-crossings of the oscillating sinc-function. RESULTS: With the proposed method, the artifact can simply, effectively, and robustly be removed with a minimal amount of image smoothing. CONCLUSIONS: The robustness of the method suggests it as a suitable candidate for an implementation in the standard image processing pipeline in clinical routine. Magn Reson Med 76:1574-1581, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26745824 TI - Role of Histone-Modifying Enzymes and Their Complexes in Regulation of Chromatin Biology. AB - In 1964, Alfrey and colleagues proposed that acetylation and methylation of histones may regulate RNA synthesis and described "the possibility that relatively minor modifications of histone structure, taking place on the intact protein molecule, offer a means of switching-on or off RNA synthesis at different loci along the chromosome" [Allfrey, V., Faulkner, R., and Mirsky, A. (1964) Proc. Natl. Acad. Sci. U.S.A. 51, 786]. Fifty years later, this prescient description provides a simple but conceptually accurate model for the biological role of histone post-translational modifications (PTMs). The basic unit of chromosomes is the nucleosome, with double-stranded DNA wrapped around a histone protein oligomer. The "tails" of histone proteins are post-translationally modified, which alters the physical properties of nucleosomes in a manner that impacts gene accessibility for transcription and replication. Enzymes that catalyze the addition and removal of histone PTMs, histone-modifying enzymes (HMEs), are present in large protein complexes, with DNA-binding proteins, ATP dependent chromatin remodeling enzymes, and epigenetic reader proteins that bind to post-translationally modified histone residues [Arrowsmith, C. H., Bountra, C., Fish, P. V., Lee, K., and Schapira, M. (2012) Nat. Rev. Drug Discovery 11, 384-400]. The activity of HME complexes is coordinated with that of other chromatin-associated complexes that, together, regulate gene transcription, DNA repair, and DNA replication. In this context, the enzymes that catalyze addition and removal of histone PTMs are an essential component of the highly regulated mechanism for accessing compacted DNA. To fully understand the function of HMEs, the structure of nucleosomes, their natural substrate, will be described. Each major class of HMEs subsequently will be discussed with regard to its biochemistry, enzymatic mechanism, and biological function in the context of a prototypical HME complex. PMID- 26745822 TI - Family Chaos and Child Functioning in Relation to Sleep Problems Among Children at Risk for Obesity. AB - This study evaluated the influence of child and family functioning on child sleep behaviors in low-income minority families who are at risk for obesity. A cross sectional study was utilized to measure child and family functioning from 2013 to 2014. Participants were recruited from Head Start classrooms while data were collected during home visits. A convenience sample of 72 low-income Hispanic (65%) and African American (32%) families of preschool-aged children were recruited for this study. We assessed the association of child and family functioning with child sleep behaviors using a multivariate multiple linear regression model. Bootstrap mediation analyses examined the effects of family chaos between child functioning and child sleep problems. Poorer child emotional and behavioral functioning related to total sleep behavior problems. Chaos associated with bedtime resistance significantly mediated the relationship between Behavioral and Emotional Screening System (BESS) and Bedtime Resistance. Families at high risk for obesity showed children with poorer emotional and behavioral functioning were at higher risk for problematic sleep behaviors, although we found no link between obesity and child sleep. Family chaos appears to play a significant role in understanding part of these relationships. Future longitudinal studies are necessary to establish causal relationships between child and family functioning and sleep problems to further guide obesity interventions aimed at improving child sleep routines and increasing sleep duration. PMID- 26745825 TI - Measuring negative emotionality using the infant behavior questionnaire-revised very short form in a low income, diverse sample. PMID- 26745826 TI - Resolving Conflicting Predictions from Multimapping Reads. AB - The first step in the analysis of data produced by ultra-high-throughput next generation sequencing technology is to map short sequence "reads" to a reference genome, if available. Sequencing errors, repeat regions, and polymorphisms may lead a read to align to multiple locations in the genome reasonably well. While ignoring such multimapping reads, or some of their alignments, will reduce the sensitivity of almost any type of downstream analysis (e.g., detecting structural variants), erroneous mappings will typically yield false positive predictions. Here we propose a framework that aims to identify true predictions among a large set of candidate predictions by selecting for each read a unique mapping that collectively imply conflict-free predictions. We formulate this problem as the maximum facility location problem, for which we propose LP-rounding heuristics. We provide a theoretic guarantee on the quality of the solution and demonstrate the utility of our algorithm in resolving conflicting deletions implied by simulated reads mapping ambiguously to Craig Venter's genome model and Illumina sequencing reads of the well-studied NA12878 individual. PMID- 26745827 TI - Incidence of HIV Infection and Sexually Transmitted Infections and Related Risk Factors Among Very Young Men Who Have Sex With Men. AB - INTRODUCTION: The HIV epidemic continues to disproportionately affect men who have sex with men (MSM) in the United States, with over a third of new infections in MSM occurring in younger men. Very few studies have reported on HIV and sexually transmitted infection (STI) incidence and related risks among younger MSM, particularly among minors under 18 years of age. METHODS: Data analyzed herein are from a longitudinal study of HIV risk among 450 very young MSM in Chicago aged 16 to 20, recruited via respondent-driven sampling and followed-up for 2 years, with annual HIV and STI testing. We report estimated cumulative HIV and STI incidence over the 24-month follow-up using Kaplan-Meier methods and evaluated associations with incident infections using Cox proportional hazards regression. RESULTS: The final analytic sample was primarily non-white (83%); median age was 19; 25% of the sample was under age 18. Twenty-six new HIV infections were detected over 632 person-years of follow-up. HIV incidence was 4.11/100 person-years [95% confidence interval (CI): 2.80 to 6.04] and STI incidence was 6.22/100 person-years (95% CI: 4.54 to 8.51). Cumulative HIV incidence over 24 months of follow-up was 7.32% (95% CI: 5.05 to 10.57), with higher incidence among racial/ethnic minorities. In multivariate analyses, non white race and recent sexual partner concurrency were associated with both HIV and STI infection; HIV testing history and sex with an HIV-positive partner were associated with increased risk of HIV infection. DISCUSSION: High rates of incident HIV infection and STIs among very young MSM and the relationship between incidence and race/ethnicity, concurrency and partner characteristics indicate potential focal points of future intervention and the need for continued vigilance. PMID- 26745829 TI - Naturally acquired immunity to malaria. PMID- 26745828 TI - Lamivudine Monotherapy-Based cART Is Efficacious for HBV Treatment in HIV/HBV Coinfection When Baseline HBV DNA <20,000 IU/mL. AB - BACKGROUND: Although combination antiretroviral therapy (cART) including tenofovir (TDF)+lamivudine (3TC) or emtricitabine (FTC) is recommended for treatment of HIV/HBV coinfected patients, TDF is unavailable in some resource limited areas. Some data suggest that 3TC monotherapy-based cART may be effective in patients with low pretreatment HBV DNA. METHODS: Prospective study of 151 Chinese HIV/HBV coinfected subjects of whom 60 received 3TC-based cART and 91 received TDF+3TC-based cART. Factors associated with HBV DNA suppression at 24 and 48 weeks, including anti-HBV drugs, baseline HBV DNA, and baseline CD4 cell count, were evaluated overall and stratified by baseline HBV DNA using Poisson regression with a robust error variance. RESULTS: Baseline HBV DNA >=20,000 IU/mL was present in 48.3% and 44.0% of subjects in the 3TC and TDF groups, respectively (P = 0.60). After 48 weeks of treatment, HBV DNA suppression rates were similar between these 2 groups (96.8% vs. 98.0% for 3TC and TDF+3TC, P > 0.999) in subjects with baseline HBV DNA <20,000 IU/mL; whereas in those with baseline HBV DNA >=20,000 IU/mL, TDF+3TC was associated with higher suppression rates (34.5% vs. 72.5% in 3TC and TDF+3TC groups, respectively, P = 0.002). In stratified multivariate regression, TDF use (RR 1.98, P = 0.010) and baseline HBV DNA (per 1 log increase in International Units Per Milliliter, RR 0.74, P < 0.001) were associated with HBV DNA suppression only when baseline HBV DNA >=20,000 IU/mL. CONCLUSION: This study suggests that 3TC monotherapy-based cART is efficacious for HBV treatment through 48 weeks in HIV/HBV coinfection when baseline HBV DNA <20,000 IU/mL. Studies with long-term follow-up are warranted to determine if this finding persists. PMID- 26745830 TI - Fulminant hepatic failure attributed to infection with human herpesvirus 6 (HHV 6) in an immunocompetent woman: A case report and review of the literature. AB - Mild disease due to human herpesvirus-6 (HHV-6) has been reported in healthy children. Severe disease due to this virus can occur in immunocompromised patients but is rarely reported in previously healthy adults. We report the case of a previously healthy woman who presented with a skin rash, mild upper respiratory symptoms, and abdominal pain and succumbed to fulminant hepatic failure attributed to infection with HHV-6B. HHV-6 may be more commonly associated with fulminant hepatitis in immunocompetent patients than previously thought and should be considered in the differential diagnosis of patients presenting with skin rash, upper respiratory symptoms, and unexplained hepatitis. PMID- 26745831 TI - Biogeochemical transformations of mercury in solid waste landfills and pathways for release. AB - Mercury (Hg) is present in a variety of solid wastes including industrial wastes, household products, consumer electronics, and medical wastes, some of which can be disposed in conventional landfills. The presence of this neurotoxic metal in landfills is a concern due to the potential for it to leach or volatilize from the landfill and impact local ecosystems. The objective of this review is to describe general practices for the disposal of mercury-bearing solid wastes, summarize previous studies on the release of mercury from landfills, and delineate the expected transformations of Hg within landfill environments that would influence transport of Hg via landfill gas and leachate. A few studies have documented the emissions of Hg as landfill gas, primarily as gaseous elemental Hg(0) and smaller amounts as methylated Hg species. Much less is known regarding the release of Hg in leachate. Landfill conditions are unique from other subsurface environments in that they can contain water with very high conductivity and organic carbon concentration. Landfills also experience large changes in redox potential (and the associated microbial community) that greatly influence Hg speciation, transformations, and mobilization potential. Generally, Hg is not likely to persist in large quantities as dissolved species, since Hg(0) tends to evolve in the gas phase and divalent Hg(ii) sorbs strongly to particulate phases including organic carbon and sulfides. However, Hg(ii) has the potential to associate with or form colloidal particles that can be mobilized in porous media under high organic carbon conditions. Moreover, the anaerobic conditions within landfills can foster the growth of microorganisms that produced monomethyl- and dimethyl-Hg species, the forms of mercury with high potential for bioaccumulation. Much advancement has recently been made in the mercury biogeochemistry research field, and this study seeks to incorporate these findings for landfill settings. PMID- 26745833 TI - ESTIMATING TOXOPLASMA GONDII EXPOSURE IN ARCTIC FOXES (VULPES LAGOPUS) WHILE NAVIGATING THE IMPERFECT WORLD OF WILDLIFE SEROLOGY. AB - Although the protozoan parasite Toxoplasma gondii is ubiquitous in birds and mammals worldwide, the full suite of hosts and transmission routes is not completely understood, especially in the Arctic. Toxoplasma gondii occurrence in humans and wildlife can be high in Arctic regions, despite apparently limited opportunities for transmission of oocysts shed by felid definitive hosts. Arctic foxes (Vulpes lagopus) are under increasing anthropogenic and ecologic pressure, leading to population declines in parts of their range. Our understanding of T. gondii occurrence in arctic foxes is limited to only a few regions, but mortality events caused by this parasite have been reported. We investigated the exposure of arctic foxes to T. gondii in the Karrak Lake goose colony, Queen Maud Gulf Migratory Bird Sanctuary, Nunavut, Canada. Following an occupancy-modeling framework, we performed replicated antibody testing on serum samples by direct agglutination test (DAT), indirect fluorescent antibody test (IFAT), and an indirect enzyme-linked immunosorbent assay (ELISA) that can be used in multiple mammalian host species. As a metric of test performance, we then estimated the probability of detecting T. gondii antibodies for each of the tests. Occupancy estimates for T. gondii antibodies in arctic foxes under this framework were between 0.430 and 0.758. Detection probability was highest for IFAT (0.716) and lower for DAT (0.611) and ELISA (0.464), indicating that the test of choice for antibody detection in arctic foxes might be the IFAT. We document a new geographic record of T. gondii exposure in arctic foxes and demonstrate an emerging application of ecologic modeling techniques to account for imperfect performance of diagnostic tests in wildlife species. PMID- 26745832 TI - An Open Pilot Study of Training Hostile Interpretation Bias to Treat Disruptive Mood Dysregulation Disorder. AB - OBJECTIVE: Irritability in disruptive mood dysregulation disorder (DMDD) may be associated with a biased tendency to judge ambiguous facial expressions as angry. We conducted three experiments to explore this bias as a treatment target. We tested: 1) whether youth with DMDD express this bias; 2) whether judgment of ambiguous faces can be altered in healthy youth by training; and 3) whether such training in youth with DMDD is associated with reduced irritability and associated changes in brain function. METHODS: Participants in all experiments made happy versus angry judgments of faces that varied along a happy to angry continuum. These judgments were used to quantify a "balance point," the facial expression at which a participant's judgment switches from predominantly happy to predominantly angry. We first compared balance points in youth with DMDD (n = 63) versus healthy youth (n = 26). We then conducted a double-blind, randomized controlled trial of active versus sham balance-point training in 19 healthy youth. Finally, we piloted open, active balance-point training in 14 youth with DMDD, with 10 completing an implicit functional MRI (fMRI) face-emotion processing task. RESULTS: Relative to healthy youth, DMDD youth manifested a shifted balance point, expressed as a tendency to classify ambiguous faces as angry rather than happy. In both healthy and DMDD youth, active training is associated with a shift in balance point toward more happy judgments. In DMDD, evidence suggests that active training may be associated with decreased irritability and changes in activation in the lateral orbitofrontal cortex. CONCLUSIONS: These results set the stage for further research on computer-based treatment targeting interpretation bias of angry faces in DMDD. Such treatment may decrease irritability and alter neural responses to subtle expressions of happiness and anger. PMID- 26745834 TI - Parasitic and Bacterial Infections of Myocastor coypus in a Metropolitan Area of Northwestern Italy. AB - Coypus (Myocastor coypus) are widespread throughout Europe. In northern Italy, they are abundant in the flatland areas, and their high population densities can cause economic loss and ecosystem damage. We examined 153 coypus for selected parasitic and bacterial infections. We found Strongyloides myopotami (63.4% prevalence), Trichostrongylus duretteae (28.1%), Eimeria coypi (86.3%), and Eimeria seideli (6.8%), but did not find Giardia duodenalis or Cryptosporidium spp. We also isolated Staphylococcus aureus (10.1%), Escherichia coli (4.5%), and Streptococcus spp. (3.4%) from lung samples; no Salmonella spp. were isolated from fecal samples. Coypus had antibodies to Toxoplasma gondii (28.9%) and to four serovars of Leptospira interrogans (44.9%); Australis/Bratislava was the serovar most frequently detected. It is clear that coypu can be infected with pathogens of human and veterinary importance. PMID- 26745835 TI - Detection of Snake Fungal Disease Due to Ophidiomyces ophiodiicola in Virginia, USA. AB - Snake fungal disease (SFD) is an emerging disease of wildlife believed to be caused by Ophidiomyces ophiodiicola. Although geographic and host ranges have yet to be determined, this disease is characterized by crusty scales, superficial pustules, and subcutaneous nodules, with subsequent morbidity and mortality in some snake species. To confirm the presence of SFD and O. ophiodiicola in snakes of eastern Virginia, US, we clinically examined 30 free-ranging snakes on public lands from April to October 2014. Skin biopsy samples were collected from nine snakes that had gross lesions suggestive of SFD; seven of these biopsies were suitable for histologic interpretation, and eight were suitable for culture and PCR detection of O. ophiodiicola. Seven snakes had histologic features consistent with SFD and eight were positive for O. ophiodiicola by PCR or fungal culture. PMID- 26745836 TI - A quick guide to CRISPR sgRNA design tools. AB - Targeted genome editing is now possible in nearly any organism and is widely acknowledged as a biotech game-changer. Among available gene editing techniques, the CRISPR-Cas9 system is the current favorite because it has been shown to work in many species, does not necessarily result in the addition of foreign DNA at the target site, and follows a set of simple design rules for target selection. Use of the CRISPR-Cas9 system is facilitated by the availability of an array of CRISPR design tools that vary in design specifications and parameter choices, available genomes, graphical visualization, and downstream analysis functionality. To help researchers choose a tool that best suits their specific research needs, we review the functionality of various CRISPR design tools including our own, the CRISPR Genome Analysis Tool (CGAT; http://cropbioengineering.iastate.edu/cgat ). PMID- 26745837 TI - Evaluation of custom energy expenditure models for SenseWear armband in manual wheelchair users. AB - Physical activity monitors are increasingly used to help the general population lead a healthy lifestyle by keeping track of their daily physical activity (PA) and energy expenditure (EE). However, none of the commercially available activity monitors can accurately estimate PA and EE in people who use wheelchairs as their primary means of mobility. Researchers have recently developed custom EE prediction models for manual wheelchair users (MWUs) with spinal cord injuries (SCIs) based on a commercial activity monitor--the SenseWear armband. This study evaluated the performance of two custom EE prediction models, including a general model and a set of activity-specific models among 45 MWUs with SCI. The estimated EE was obtained by using the two custom models and the default manufacturer's model, and it was compared with the gold standard measured by the K4b2 portable metabolic cart. The general, activity-specific, and default models had a mean signed percent error (mean +/- standard deviation) of -2.8 +/- 26.1%, -4.8 +/- 25.4%, and -39.6 +/- 37.8%, respectively. The intraclass correlation coefficient was 0.86 (95% confidence interval [CI] = 0.82 to 0.89) for the general model, 0.83 (95% CI = 0.79 to 0.87) for the activity-specific model, and 0.62 (95% CI = 0.16 to 0.81) for the default model. The custom models for the SenseWear armband significantly improved the EE estimation accuracy for MWUs with SCI. PMID- 26745840 TI - PATTERN PERCEPTION, CONCEPTUAL SPACES, AND DIMENSIONAL LIMITATIONS ON INFORMATION PROCESSING. AB - A conceptual space was defined as the collection of all linearly inde- pendent psychological dimensions underlying the multidimensional scaling of a set of tasks. When a single subject scaled a sample of random polygons under fifteen different task conditions, a total of ten linearly independent dimensions was obtained. The number of obtained dimensions in individual tasks ranged between 1 and 3. The results suggest the existence o f a dimensional limitation upon information processing in MDS studies. PMID- 26745841 TI - A TWIN STUDY OF SPATIAL ABILITY. AB - A battery of spatial visualization land form percepthn plus some tests of arithmetic, vocabulary and social perception has been administered to 274 pairs of identical and 198 pairs of frabmal twins. To assess the importance of hereditary components in the individual differences observed, the within pair variance for fraternal paim was compared with the within pair vazianw for identical pains by the F ratio test. The results for 123 pairs of identiml twins and 91 pairs of fraternal twins on the spatial task, were classified in terms of the apparent psychological task requirements of the test. It appears that tests requiring three-dimensional manipdadion of drawings demonstrate more frequently a statistically significant hereditary component. PMID- 26745842 TI - ASSESSMENT OF A PROPOSED EXPANSION OF THE COMREY PERSONALITY FACTOR SYSTEM. AB - Six major factors of personality have been identified repeatedly in factor analytic studies by Comrey and his coworkers: Shyness, Dependence, Em- paths, Neuroticism, Compulsion, and Hostility. Analysis of the Guilford-Zimmerman test suggested that this system of six factors could be enlarged to include three additional factors : General Activity, Thoughtfulness, and Mas- culinity. An inventory designed to measure all these factors was administered to 259 volunteers, mostly from the general population. Analysis of the results by factor analytic methods showed that General Activity was well enough defined and confirmed to warrant adding it to the Comrey factor system. The other two additional factors failed to achieve this level of confirmation. PMID- 26745843 TI - A DIMENSIONAL ANALYSIS OF MMPI ITEMS. AB - A method of analysis specifically designed for binary data was applied to 100 MMPI items. Sixty, items were carefully chosen to represent the nine major clinical scales with respect to direction of keying, social desirability scale value and endorsement frequency. The remaining 40 items were randomly chosen from items not appearing on any of these scales. Although a complete solution was obtained in five dimensions, only three were retained. The three dimensions were related to scale membership, gender of the respondent and various item characteristics. The results clearly support the two major MMPI factors obtained on a scale level and additionally show a strong gender dimension. PMID- 26745839 TI - New insights on the role of microglia in synaptic pruning in health and disease. AB - Recent genome-wide association studies implicate microglia in Alzheimer's disease (AD) pathogenesis; however, their biological significance remains poorly understood. Synapse loss is a significant correlate of cognitive decline that serves as a critical hallmark of AD and other neurodegenerative diseases; however, mechanisms underlying synaptic vulnerability remain elusive. Emerging research on microglia function in the healthy brain is providing new insight into fundamental roles of microglia and immune molecules in brain wiring. Among their many roles, microglia prune developing synapses and regulate synaptic plasticity and function. Here, we review and discuss how this emerging work may provide new insight into how disruptions in microglia-synapse interactions could contribute to synapse loss and dysfunction, and consequently cognitive impairment, in AD. PMID- 26745844 TI - A FACTOR ANALYTIC STUDY OF THE AI AND THE CCI. AB - While the AI contains 13 common factors and the CCI contains 11 common factors, these factors together span only 22 dimensions. The lost dimensions may be associated with simple combinations of certain AI factors, and apparently result from differential tendencies of certain personalities to choose different colleges. One dimension of choice lies in the realm of academic interests and another in the realm of social relationships. In contrast with one another, the CCI is primarily a measure of college environment independent of the personality of the respondent, while the AI is primarily a measure of the individual reporting about himself. PMID- 26745846 TI - THE MULTIFACTOR BEHAVIORAL APPROACH TO THE GENETIC-ETIOLOGICAL DIAGNOSIS OF MENTAL RETARDATION. PMID- 26745845 TI - A NOTE ON THE EXPECTED VALUE OF A COEFFICIENT OF REPRODUCIBILITY. AB - In a recent study of the sensitivity of Coefficients of Reproducibility, Cotton (1969) found a lower bound for the expected value of the Green-Sagi (1953, 1959) Coefficient of Reproducibility under the assumption of response independence. It is the purpose of this note to show that the lower bound found by Cotton holds more generally. An appendix gives a nomograph for testing the significance of this coefficient of reproducibility. PMID- 26745847 TI - BRIEF REPORT: BARTLETT'S TEST OF SPHERICITY AND CHANCE FINDINGS IN FACTOR ANALYSIS. AB - Bartlett's test of sphericitg: was applied to a correlation matrix computed on random normal deviates by Armstrong and Soelberg (1968), and returned a chi square value indicating that the matrix could have been generated from a population where the correlation coefficients are zero. These results re- emphasize the desirability of computing this test prior to proceeding t o factor extraction, and in accord with the findings of other writers, indicate this test to be sensitive in detecting results which can be ascribed to chance. PMID- 26745848 TI - Consumer acceptance of reformulated food products: A systematic review and meta analysis of salt-reduced foods. AB - Food product reformulation is promoted as an effective strategy to reduce population salt intake and address the associated burden of chronic disease. Salt has a number of functions in food processing, including impacting upon physical and sensory properties. Manufacturers must ensure that reformulation of foods to reduce salt does not compromise consumer acceptability. The aim of this systematic review is to determine to what extent foods can be reduced in salt without detrimental effect on consumer acceptability. Fifty studies reported on salt reduction, replacement or compensation in processed meats, breads, cheeses, soups, and miscellaneous products. For each product category, levels of salt reduction were collapsed into four groups: <40%, 40-59%, 60-79% and >=80%. Random effects meta-analyses conducted on salt-reduced products showed that salt could be reduced by approximately 40% in breads [mean change in acceptability for reduction <40% (-0.27, 95% confidence interval (CI) -0.62, 0.08; p = 0.13)] and approximately 70% in processed meats [mean change in acceptability for reductions 60-69% (-0.18, 95% CI -0.44, 0.07; p = 0.15)] without significantly impacting consumer acceptability. Results varied for other products. These results will support manufacturers to make greater reductions in salt when reformulating food products, which in turn will contribute to a healthier food supply. PMID- 26745850 TI - Development of a simulator for the validation of noninvasive blood pressure monitoring devices. AB - This research aimed to develop a simulator capable of oscillometric pressure pulses recorded from the participants for the validation of oscillometric noninvasive blood pressure (NIBP) devices. The simulator generates the pressure pulses to the cuff connected to NIBP devices depending on the oscillometric waveforms obtained from the participants. Device readings were compared with auscultatory references (systolic and diastolic blood pressures) of the participants. A total of 94 oscillometric waveforms from participants were used in the simulator for the validation of two automated NIBP devices (Omron HEM-7221 and UA-787Plus). For Omron HEM-7221, the differences between device readings and auscultation references for systolic and diastolic blood pressures were 2.82+/ 7.27 and -4.74+/-6.73 mmHg, respectively. UA-787Plus showed differences of 3.26+/ 5.69 and -3.53+/-6.61 mmHg, respectively. Although the number of individual measurements did not fulfill the ISO 81060-2 requirement for clinical validation, criterion 1, where the average of the difference and SD should be lower than +/-5 and -8 mmHg, was fulfilled. Although the simulator still needs extensive comparative studies to be verified, it could be a potential candidate for a simple and robust tool for the validation and quality control of NIBP devices. PMID- 26745849 TI - [3 + 2]-Annulations of N-Hydroxy Allenylamines with Nitrosoarenes: One-Pot Synthesis of Substituted Indole Products. AB - In the presence of O2 and an IPrCuCl additive (5 mol %), [3 + 2]-annulation reactions of N-hydroxyaniline with nitrosobenzenes in cold toluene form isoxazolidin-5-ol derivatives. Heating the same reaction mixture with DBU in toluene affords highly functionalized indole products efficiently. This method provides short synthesis of several bioactive molecules including WIN 48098, WIN 53365, and JWH 015. PMID- 26745851 TI - PPARgamma ligands increase antileukemic activity of second- and third-generation tyrosine kinase inhibitors in chronic myeloid leukemia cells. PMID- 26745852 TI - Evaluating results from the multiple myeloma patient subset treated with denosumab or zoledronic acid in a randomized phase 3 trial. AB - In a phase 3 trial of denosumab vs zoledronic acid in patients (n=1776) with bone metastases and solid tumors or multiple myeloma, denosumab was superior to zoledronic acid for the primary end point of prevention of skeletal-related events. There was no difference in overall survival between the two groups; however, an ad hoc overall survival analysis in the multiple myeloma subset of patients (n=180) favored zoledronic acid (hazard ratio (HR) 2.26; 95% confidence interval (CI) 1.13-4.50; P=0.014). In the present analysis, we found imbalances between the groups with respect to baseline risk characteristics. HRs with two sided 95% CIs were estimated using the Cox model. After adjustment in a covariate analysis, the CI crossed unity (HR 1.86; 95% CI 0.90-3.84; P=0.0954). Furthermore, we found a higher rate of early withdrawals for the reasons of lost to follow-up and withdrawal of consent in the zoledronic acid group; after accounting for these, the HR was 1.31 (95% CI 0.80-2.15; P=0.278). In conclusion, the survival results in multiple myeloma patients in this trial were confounded and will eventually be resolved by an ongoing phase 3 trial. PMID- 26745854 TI - Novobiocin Analogues That Inhibit the MAPK Pathway. AB - Heat shock protein 90 (Hsp90) inhibition by modulation of its N- or C-terminal binding site has become an attractive strategy for the development of anticancer chemotherapeutics. The first Hsp90 C-terminus inhibitor, novobiocin, manifested a relatively high IC50 value of ~700 MUM. Therefore, investigation of the novobiocin scaffold has led to analogues with improved antiproliferative activity (nanomolar concentrations) against several cancer cell lines. During these studies, novobiocin analogues that do not inhibit Hsp90 were identified; however, these analogues demonstrated potent antiproliferative activity. Compound 2, a novobiocin analogue, was identified as a MAPK pathway signaling disruptor that lacked Hsp90 inhibitory activity. In addition, structural modifications of compound 2 were identified that segregated Hsp90 inhibition from MAPK signaling disruption. These studies indicate that compound 2 represents a novel scaffold for disruption of MAPK pathway signaling and may serve as a useful structure for the generation of new anticancer agents. PMID- 26745853 TI - RUNX1 haploinsufficiency results in granulocyte colony-stimulating factor hypersensitivity. AB - RUNX1/AML1 is among the most commonly mutated genes in human leukemia. Haploinsufficiency of RUNX1 causes familial platelet disorder with predisposition to myeloid malignancies (FPD/MM). However, the molecular mechanism of FPD/MM remains unknown. Here we show that murine Runx1(+/-) hematopoietic cells are hypersensitive to granulocyte colony-stimulating factor (G-CSF), leading to enhanced expansion and mobilization of stem/progenitor cells and myeloid differentiation block. Upon G-CSF stimulation, Runx1(+/-) cells exhibited a more pronounced phosphorylation of STAT3 as compared with Runx1(+/+) cells, which may be due to reduced expression of Pias3, a key negative regulator of STAT3 signaling, and reduced physical sequestration of STAT3 by RUNX1. Most importantly, blood cells from a FPD patient with RUNX1 mutation exhibited similar G-CSF hypersensitivity. Taken together, Runx1 haploinsufficiency appears to predispose FPD patients to MM by expanding the pool of stem/progenitor cells and blocking myeloid differentiation in response to G-CSF. PMID- 26745857 TI - Effects of Nanoporous Anodic Alumina Oxide on the Crystallization and Melting Behavior of Poly(vinylidene fluoride). AB - Poly(vinylidene fluoride) (PVDF) nanotubes were fabricated by melt-wetting into porous anodic aluminum oxide (AAO) templates with two different interfacial properties: one is pristine AAO, and the other is modified by FOTS (AAO-F). Their crystallization and melting behaviors are compared with those of a bulk sample. For the PVDF in AAO-F, the nonisothermal crystallization temperature is slightly lower than that of bulk, and the melting temperature is similar to that of bulk. For the PVDF in pristine AAO, when the pore diameter is 200 nm, the crystallization is induced by two kinds of nucleation: heterogeneous nucleation and interface-induced nucleation. On the contrary, in the AAO template with pore diameter smaller than 200 nm, only interface-induced nucleation occurs. The melting temperature of PVDF crystals in the pristine AAO is much higher than that of bulk which can be attributed to the presence of an interfacial layer of PVDF on the template inner surface. The interaction between PVDF and AAO template produces the interfacial layer. Such an interfacial layer plays an important role in enhancing the melting temperature of PVDF crystals. The higher melting peak is always observed when the PVDF is nonisothermally crystallized in the AAO template irrespective of the thermal erasing temperature suggesting the interfacial layer is very stable on the AAO template surface. If the PVDF nanostructures are released from AAO template, the higher melting peak disappears with the enhancement of thermal erasing temperature. PMID- 26745855 TI - The role of CX3CL1 in fetal-maternal interaction during human gestation. AB - Embryo implantation and subsequent placentation require a fine balanced fetal maternal cross-talk of hormones, cytokines and chemokines. Amongst the group of chemokines, CX3CL1 (also known as fractalkine) has recently attracted attention in the field of reproductive research. It exists both as membrane-bound and soluble isoforms. On the basis of current experimental evidence, fractalkine is suggested to regulate adhesion and migration processes in fetal-maternal interaction at different stages of human pregnancy. Expressed by uterine glandular epithelial cells, predominantly during the mid-secretory phase of the menstrual cycle, fractalkine appears to prime the blastocyst for forthcoming implantation. After implantation, fractalkine is suggested to regulate invasion of extravillous trophoblasts by altering their expression profile of adhesion molecules. With onset of perfusion of the intervillous space at the end of first trimester, fractalkine present at the apical microvillous plasma membrane of the syncytiotrophoblast may mediate close interaction of placental villi with circulating maternal blood cells. PMID- 26745858 TI - Equol Effectively Inhibits Toxic Activity of Human Neutrophils without Influencing Their Viability. AB - Equol (7,4'-dihydroxy-isoflavan, or 4',7-isoflavandiol) is a chroman derivative produced by intestinal bacteria in response to soy isoflavone intake in some, but not in all, humans. Equol shows strong anti-oxidant, anti-estrogenic, anti cancerous and anti-inflammatory properties. The antioxidative capacity of equol has recently received considerable attention, and it has been used for preventing and treating several diseases. We investigated the effect of equol on human neutrophils, extra- and intracellular formation of oxidants, the phosphorylation of protein regulating NADPH oxidase and its effect on apoptosis. Neutrophils, isolated from blood from healthy subjects, were tested upon activation with various stimulants, proper for reactive oxygen species (ROS) production and treated by equol. Equol has the ability to reduce the toxic action of neutrophils. With increasing concentrations, equol decreased the amount of oxidants produced by neutrophils both extra- and intracellularly. The phosphorylation of p40(phox) (a component of NADPH oxidase, responsible for the assembly of functional oxidase in intracellular membranes) was reduced in the presence of equol. The experiments showed that equol did not change the number of viable, apoptotic or dead neutrophils significantly in all concentrations used. These results indicate the promising effect of equol in the operation of ROS in different mechanisms in the model of inflammation. PMID- 26745859 TI - Imaging Tests for the Diagnosis and Staging of Pancreatic Adenocarcinoma: A Meta Analysis. AB - Imaging tests are central to the diagnosis and staging of pancreatic adenocarcinoma. We performed a systematic review and meta-analysis of the pertinent evidence on 5 imaging tests (computed tomography (CT), magnetic resonance imaging, CT angiography, endoscopic ultrasound with fine-needle aspiration, and combined positron emission tomography with CT). Searches of several databases up to March 1, 2014, yielded 9776 articles, and 24 provided comparative effectiveness of 2 or more imaging tests. Multiple reviewers applied study inclusion criteria, extracted data from each study, rated the risk of bias, and graded the strength of evidence. Data included accuracy of diagnosis and resectability in primary untreated pancreatic adenocarcinoma, including tumor stage, nodal stage, metastases, and vascular involvement. Where possible, study results were combined using bivariate meta-analysis. Studies were at low or moderate risk of bias. Most comparisons between imaging tests were insufficient to permit conclusions, due to imprecision or inconsistency among study results. However, moderate-grade evidence revealed that CT and magnetic resonance imaging had similar sensitivities and specificities for both diagnosis and vascular involvement. Other conclusions were based on low-grade evidence. In general, more direct evidence is needed to inform decisions about imaging tests for pancreatic adenocarcinoma. PMID- 26745856 TI - Ozone Exposure Increases Circulating Stress Hormones and Lipid Metabolites in Humans. AB - RATIONALE: Air pollution has been associated with increased prevalence of type 2 diabetes; however, the mechanisms remain unknown. We have shown that acute ozone exposure in rats induces release of stress hormones, hyperglycemia, leptinemia, and glucose intolerance that are associated with global changes in peripheral glucose, lipid, and amino acid metabolism. OBJECTIVES: To examine ozone-induced metabolic derangement in humans using serum metabolomic assessment, establish human-to-rodent coherence, and identify novel nonprotein biomarkers. METHODS: Serum samples were obtained from a crossover clinical study that included two clinic visits (n = 24 each) where each subject was blindly exposed in the morning to either filtered air or 0.3 parts per million ozone for 2 hours during 15 minute on-off exercise. Serum samples collected within 1 hour after exposure were assessed for changes in metabolites using a metabolomic approach. MEASUREMENTS AND MAIN RESULTS: Metabolomic analysis revealed that ozone exposure markedly increased serum cortisol and corticosterone together with increases in monoacylglycerol, glycerol, and medium- and long-chain free fatty acids, reflective of lipid mobilization and catabolism. Additionally, ozone exposure increased serum lysolipids, potentially originating from membrane lipid breakdown. Ozone exposure also increased circulating mitochondrial beta-oxidation derived metabolites, such as acylcarnitines, together with increases in the ketone body 3-hydroxybutyrate. These changes suggested saturation of beta oxidation by ozone in exercising humans. CONCLUSIONS: As in rodents, acute ozone exposure increased stress hormones and globally altered peripheral lipid metabolism in humans, likely through activation of a neurohormonally mediated stress response pathway. The metabolomic assessment revealed new biomarkers and allowed for establishment of rodent-to-human coherence. Clinical trial registered with www.clinicaltrials.gov (NCT 01492517). PMID- 26745860 TI - Recent Trends in Survival of Patients With Pancreatic Cancer in Germany and the United States. AB - OBJECTIVES: Survival improvement for pancreatic cancer has not been observed in the last 4 decades. We report the most up-to-date population-based relative survival (RS) estimates and recent trends in Germany and the United States. METHODS: Data for patients diagnosed in 1997 to 2010 and followed up to 2010 were drawn from 12 population-based German cancer registries and the US SEER (Surveillance, Epidemiology and End Results) 13 registries database. Using period analysis, 5-year RS for 2007 to 2010 was derived. Model-based period analysis was used to assess 5-year RS time trends, 2002-2010. RESULTS: In total 28,977 (Germany) and 34,793 (United States) patients aged 15 to 74 years were analyzed. Five-year RS was 10.7% and 10.3% in Germany and the United States, respectively, and strongly decreased with age and tumor spread. Prognosis slightly improved from the period 2002-2004 to 2008-2010 (overall age-adjusted RS: +2.5% units in Germany and +3.4% units in the United States); improvement was particularly strong for regional stage and head and body subsites in Germany and for localized and regional stages and tail subsite in the United States. CONCLUSIONS: Although pancreatic cancer survival continues to be poor for advanced-stage patients, our study disclosed encouraging indications of first improvements in 5-year RS after decades of stagnation. PMID- 26745861 TI - Preoperative Computerized Tomography and Magnetic Resonance Imaging of the Pancreas Predicts Pancreatic Mass and Functional Outcomes After Total Pancreatectomy and Islet Autotransplant. AB - OBJECTIVES: Approximately two thirds of patients will remain on insulin therapy after total pancreatectomy with islet autotransplant (TPIAT) for chronic pancreatitis. We investigated the relationship between measured pancreas volume on computerized tomography or magnetic resonance imaging and features of chronic pancreatitis on imaging, with subsequent islet isolation and diabetes outcomes. METHODS: Computerized tomography or magnetic resonance imaging was reviewed for pancreas volume (Vitrea software) and presence or absence of calcifications, atrophy, and dilated pancreatic duct in 97 patients undergoing TPIAT. Relationship between these features and (1) islet mass isolated and (2) diabetes status at 1-year post-TPIAT were evaluated. RESULTS: Pancreas volume correlated with islet mass measured as total islet equivalents (r = 0.50, P < 0.0001). Mean islet equivalents were reduced by more than half if any one of calcifications, atrophy, or ductal dilatation were observed. Pancreatic calcifications increased the odds of insulin dependence 4.0 fold (1.1, 15). Collectively, the pancreas volume and 3 imaging features strongly associated with 1-year insulin use (P = 0.07), islet graft failure (P = 0.003), hemoglobin A1c (P = 0.0004), fasting glucose (P = 0.027), and fasting C-peptide level (P = 0.008). CONCLUSIONS: Measures of pancreatic parenchymal destruction on imaging, including smaller pancreas volume and calcifications, associate strongly with impaired islet mass and 1-year diabetes outcomes. PMID- 26745862 TI - The Establishment of a Hyperactive Structure Allows the Tumour Suppressor Protein p53 to Function through P-TEFb during Limited CDK9 Kinase Inhibition. AB - CDK9 is the catalytic subunit of positive elongation factor b (P-TEFb) that controls the transition of RNA polymerase II (RNAPII) into elongation. CDK9 inhibitors block mRNA synthesis and trigger activation of the stress-sensitive p53 protein. This in turn induces transcription of CDKN1A (p21) and other cell cycle control genes. It is presently unclear if and how p53 circumvents a general P-TEFb-requirement when it activates its target genes. Our investigations using a panel of specific inhibitors reason for a critical role of CDK9 also in the case of direct inhibition of the kinase. At the prototypic p21 gene, the activator p53 initially accumulates at the pre-bound upstream enhancer followed-with significant delay-by de novo binding to a secondary enhancer site within the first intron of p21. This is accompanied by recruitment of the RNAPII initiation machinery to both elements. ChIP and functional analyses reason for a prominent role of CDK9 itself and elongation factor complexes PAF1c and SEC involved in pause and elongation control. It appears that the strong activation potential of p53 facilitates gene activation in the situation of global repression of RNAPII transcription. The data further underline the fundamental importance of CDK9 for class II gene transcription. PMID- 26745865 TI - The Education-health Nexus: Fact and fiction. AB - This paper examines the link between schooling and health. We provide new evidence on the relationship between formal schooling completed and several aspects of health by using Finnish twin data matched to individual information on schooling. Health is measured in 1990 (and 1981). Schooling is defined using comprehensive register-based information. All models account for initial health endowment in 1975. The sample sizes vary from 2542 to 4402 identical twins, depending on the specification. Using twin design, we find that unobserved family and genetic factors drive the cross-sectional correlations between schooling and many health measures, especially for females. Our within-MZ twin results for males show that high school (or vocational) or lowest level tertiary education reduces BMI and medication use. High school (or vocational) or university graduated males also exercise more than males who have completed primary education only. Given that high school or basic tertiary education have the strongest positive health effects for males, our results suggest that policies that prevent secondary school dropout alone may yield social benefits in the form of better health. PMID- 26745864 TI - Better the donor you know? A qualitative study of renal patients' views on 'altruistic' live-donor kidney transplantation. AB - BACKGROUND: In the UK there is a short-fall between individuals requiring a renal transplant and kidneys available for transplantation. Non-directed 'altruistic' living kidney donation has emerged as a strategy for bridging this gap between supply and demand, with the number increasing each year. OBJECTIVE: This study aimed to explore the views of potential recipients towards non-directed 'altruistic' live-donor kidney transplantation. METHODS: Semi-structured interviews with 32 UK deceased-donor kidney transplant recipients were performed. Interviews explored willingness to consider directed and non-directed live-donor kidney transplants (LDKTs). Interviews were recorded, transcribed verbatim and transcripts were analysed using the constant comparison method described in Grounded Theory. RESULTS: For those not willing to accept a non-directed 'altruistic' LDKT, the following themes were identified: i) Prioritising other recipients above self; ii) Fear of acquiring an unknown donor's characteristics, and iii) Concern for the donor - unnecessary risk. For those willing to accept a non-directed 'altruistic' LDKT the following themes were identified: iv) Prioritising known above unknown persons, v) Belief that they are as deserving as other potential recipients, and vi) Advantages of a LDKT. CONCLUSIONS: Drawing on 'gift exchange theory', this study contributes to our understanding of the experience of the intended recipient of a gift. The anonymity of the donor recipient appears to be seen as a benefit of non-directed 'altruistic' live-donor transplants, freeing recipients from the obligations of the gift. However, those who feel unworthy of the 'gifted transplant' are concerned about the donor and by the lack of opportunity for direct reciprocity. Highlighting the 'reciprocal benefits' reported by donors may allow individuals whose preference is a live donor transplant to accept one if offered. These insights provide the transplant community with targets for intervention, through which the concerns of potential recipients might be addressed. PMID- 26745866 TI - "Doctor my eyes": A natural experiment on the demand for eye care services. AB - Preventive health care is promoted by many organisations from the World Health Organisation (WHO) to regional and national governments. The degree of cost sharing between individuals and the health care service affects preventive service use. For instance, out-of-pocket fees that are paid by individuals for curative services reduce preventive care demand. We examine the impact of subsidised preventive care on demand. We motivate our analysis with a theoretical model of inter-temporal substitution in which individuals decide whether to have a health examination in period one and consequently whether to be treated if required in period two. We derive four testable hypotheses. We test these using the subsidised eye care policy introduced in Scotland in 2006. This provides a natural experiment that allows us to identify the effect of the policy on the demand for eye examinations. We also explore socio-economic differences in the response to the policy. The analysis is based on a sample from the British Household Panel Survey of 52,613 observations of people, aged between 16 and 59 years, living in England and Scotland for the period 2001-2008. Using the difference-in-difference methodology, we find that on average the policy did not affect demand for eye examinations. We find that demand for eye examinations only increased among high income households, and consequently, inequalities in eye care services demand have widened in Scotland since the introduction of the policy. PMID- 26745863 TI - A Shh-Foxf-Fgf18-Shh Molecular Circuit Regulating Palate Development. AB - Cleft palate is among the most common birth defects in humans. Previous studies have shown that Shh signaling plays critical roles in palate development and regulates expression of several members of the forkhead-box (Fox) family transcription factors, including Foxf1 and Foxf2, in the facial primordia. Although cleft palate has been reported in mice deficient in Foxf2, whether Foxf2 plays an intrinsic role in and how Foxf2 regulates palate development remain to be elucidated. Using Cre/loxP-mediated tissue-specific gene inactivation in mice, we show that Foxf2 is required in the neural crest-derived palatal mesenchyme for normal palatogenesis. We found that Foxf2 mutant embryos exhibit altered patterns of expression of Shh, Ptch1, and Shox2 in the developing palatal shelves. Through RNA-seq analysis, we identified over 150 genes whose expression was significantly up- or down-regulated in the palatal mesenchyme in Foxf2-/- mutant embryos in comparison with control littermates. Whole mount in situ hybridization analysis revealed that the Foxf2 mutant embryos exhibit strikingly corresponding patterns of ectopic Fgf18 expression in the palatal mesenchyme and concomitant loss of Shh expression in the palatal epithelium in specific subdomains of the palatal shelves that correlate with where Foxf2, but not Foxf1, is expressed during normal palatogenesis. Furthermore, tissue specific inactivation of both Foxf1 and Foxf2 in the early neural crest cells resulted in ectopic activation of Fgf18 expression throughout the palatal mesenchyme and dramatic loss of Shh expression throughout the palatal epithelium. Addition of exogenous Fgf18 protein to cultured palatal explants inhibited Shh expression in the palatal epithelium. Together, these data reveal a novel Shh-Foxf-Fgf18-Shh circuit in the palate development molecular network, in which Foxf1 and Foxf2 regulate palatal shelf growth downstream of Shh signaling, at least in part, by repressing Fgf18 expression in the palatal mesenchyme to ensure maintenance of Shh expression in the palatal epithelium. PMID- 26745867 TI - Understanding the role of Indigenous community participation in Indigenous prenatal and infant-toddler health promotion programs in Canada: A realist review. AB - PURPOSE: Striking disparities in Indigenous maternal-child health outcomes persist in relatively affluent nations such as Canada, despite significant health promotion investments. The aims of this review were two-fold: 1. To identify Indigenous prenatal and infant-toddler health promotion programs in Canada that demonstrate positive impacts on prenatal or child health outcomes. 2. To understand how, why, for which outcomes, and in what contexts Indigenous prenatal and infant-toddler health promotion programs in Canada positively impact Indigenous health and wellbeing. METHODS: We systematically searched computerized databases and identified non-indexed reports using key informants. Included literature evaluated a prenatal or child health promoting program intervention in an Indigenous population in Canada. We used realist methods to investigate how, for whom, and in what circumstances programs worked. We developed and appraised the evidence for a middle range theory of Indigenous community investment ownership-activation as an explanation for program success. FINDINGS: Seventeen articles and six reports describing twenty programs met final inclusion criteria. Program evidence of local Indigenous community investment, community perception of the program as intrinsic (mechanism of community ownership) and high levels of sustained community participation and leadership (community activation) was linked to positive program change across a diverse range of outcomes including: birth outcomes; access to pre- and postnatal care; prenatal street drug use; breast-feeding; dental health; infant nutrition; child development; and child exposure to Indigenous languages and culture. CONCLUSIONS: These findings demonstrate Indigenous community investment-ownership-activation as an important pathway for success in Indigenous prenatal and infant-toddler health programs. PMID- 26745868 TI - Abdominal Muscle Activity during Mechanical Ventilation Increases Lung Injury in Severe Acute Respiratory Distress Syndrome. AB - OBJECTIVE: It has proved that muscle paralysis was more protective for injured lung in severe acute respiratory distress syndrome (ARDS), but the precise mechanism is not clear. The purpose of this study was to test the hypothesis that abdominal muscle activity during mechanically ventilation increases lung injury in severe ARDS. METHODS: Eighteen male Beagles were studied under mechanical ventilation with anesthesia. Severe ARDS was induced by repetitive oleic acid infusion. After lung injury, Beagles were randomly assigned into spontaneous breathing group (BIPAPSB) and abdominal muscle paralysis group (BIPAPAP). All groups were ventilated with BIPAP model for 8h, and the high pressure titrated to reached a tidal volume of 6ml/kg, the low pressure was set at 10 cmH2O, with I:E ratio 1:1, and respiratory rate adjusted to a PaCO2 of 35-60 mmHg. Six Beagles without ventilator support comprised the control group. Respiratory variables, end-expiratory volume (EELV) and gas exchange were assessed during mechanical ventilation. The levels of Interleukin (IL)-6, IL-8 in lung tissue and plasma were measured by qRT-PCR and ELISA respectively. Lung injury scores were determined at end of the experiment. RESULTS: For the comparable ventilator setting, as compared with BIPAPSB group, the BIPAPAP group presented higher EELV (427+/-47 vs. 366+/-38 ml) and oxygenation index (293+/-36 vs. 226+/-31 mmHg), lower levels of IL-6(216.6+/-48.0 vs. 297.5+/-71.2 pg/ml) and IL-8(246.8+/-78.2 vs. 357.5+/-69.3 pg/ml) in plasma, and lower express levels of IL-6 mRNA (15.0+/ 3.8 vs. 21.2+/-3.7) and IL-8 mRNA (18.9+/-6.8 vs. 29.5+/-7.9) in lung tissues. In addition, less lung histopathology injury were revealed in the BIPAPAP group (22.5+/-2.0 vs. 25.2+/-2.1). CONCLUSION: Abdominal muscle activity during mechanically ventilation is one of the injurious factors in severe ARDS, so abdominal muscle paralysis might be an effective strategy to minimize ventilator induce lung injury. PMID- 26745869 TI - Concomitant Sleep Disorders Significantly Increase the Risk of Cardiovascular Disease in Patients with Psoriasis. AB - BACKGROUND: The increased rates of cardiovascular morbidity and mortality in patients with psoriasis are not adequately explained by traditional risk factors. Whether concomitant sleep disorders (SDs) modify the risk of cardiovascular disease (CVD) in patients with psoriasis remains unknown. METHODS: Using the Taiwan National Health Insurance Research Database (NHIRD), we conducted a cohort study to investigate the association between concomitant SDs and CVD risk in patients with psoriasis. Data from 99,628 adults who received a psoriasis diagnosis during the period from 2004 to 2010 were analyzed. Cox proportional hazards regression analysis models were used to compare the risks of ischemic heart disease (IHD) and stroke between patients with and without SDs. RESULTS: Psoriasis patients with a concomitant SD had significantly higher risks of IHD (adjusted hazard ratio [aHR], 1.25; 95% confidence interval [CI], 1.22-1.28) and stroke (aHR, 1.24; 95% CI, 1.16-1.33) as compared with psoriasis patients without SDs. All psoriasis patient subgroups, including those with mild and severe psoriasis and those with and without arthritis, had increased HRs for IHD and stroke. The increases in IHD and stroke risks conferred by SDs were proportional to the dose of hypnotics used. The effect of SDs on the risks of IHD and stroke was greater in young adults than in middle-aged and older adults. CONCLUSIONS: The risks of IHD and stroke were higher for psoriasis patients with SDs than for those without SDs. Clinicians should carefully evaluate CVD risk, particularly in young patients with psoriasis. PMID- 26745870 TI - Marine Fouling Assemblages on Offshore Gas Platforms in the Southern North Sea: Effects of Depth and Distance from Shore on Biodiversity. AB - Offshore platforms are known to act as artificial reefs, though there is on-going debate on whether this effect is beneficial or harmful for the life in the surrounding marine environment. Knowing what species exist on and around the offshore platforms and what environmental variables influence this species assemblage is crucial for a better understanding of the impact of offshore platforms on marine life. Information on this is limited for offshore platforms in the southern North Sea. This study aims to fill this gap in our knowledge and to determine how the composition and the abundance of species assemblages changes with depth and along a distance-from-shore gradient. The species assemblages on five offshore gas platforms in the southern North Sea have been inventoried using Remotely Operated Vehicles inspection footage. A total of 30 taxa were identified. A Generalised Additive Model of the species richness showed a significant non-linear relation with water depth (p = 0.001): from a low richness in shallow waters it increases with depth until 15-20 m, after which richness decreases again. Using PERMANOVA, water depth (p<=0.001), community age (p<=0.001) and the interaction between distance from shore and community age (p<=0.001) showed a significant effect on the species assemblages. Future research should focus on the effect additional environmental variables have on the species assemblages. PMID- 26745871 TI - Knowledge of Bovine Tuberculosis, Cattle Husbandry and Dairy Practices amongst Pastoralists and Small-Scale Dairy Farmers in Cameroon. AB - BACKGROUND: Control of bovine tuberculosis (bTB) and zoonotic tuberculosis (zTB) has relied upon surveillance and slaughter of infected cattle, milk pasteurisation and public health education. In Cameroon, like many other sub Saharan African countries, there is limited understanding of current cattle husbandry or milk processing practices or livestock keepers awareness of bTB. This paper describes husbandry and milk processing practices within different Cameroonian cattle keeping communities and bTB awareness in comparison to other infectious diseases. STUDY DESIGN: A population based cross-sectional sample of herdsmen and a questionnaire were used to gather data from pastoralists and dairy farmers in the North West Region and Vina Division of Cameroon. RESULTS: Pastoralists were predominately male Fulanis who had kept cattle for over a decade. Dairy farmers were non-Fulani and nearly half were female. Pastoralists went on transhumance with their cattle and came into contact with other herds and potential wildlife reservoirs of bTB. Dairy farmers housed their cattle and had little contact with other herds or wildlife. Pastoralists were aware of bTB and other infectious diseases such as foot-and-mouth disease and fasciolosis. These pastoralists were also able to identify clinical signs of these diseases. A similar proportion of dairy farmers were aware of bTB but fewer were aware of foot-and-mouth and fasciolosis. In general, dairy farmers were unable to identify any clinical signs for any of these diseases. Importantly most pastoralists and dairy farmers were unaware that bTB could be transmitted to people by consuming milk. CONCLUSIONS: Current cattle husbandry practices make the control of bTB in cattle challenging especially in mobile pastoralist herds. Routine test and slaughter control in dairy herds would be tractable but would have profound impact on dairy farmer livelihoods. Prevention of transmission in milk offers the best approach for human risk mitigation in Cameroon but requires strategies that improved risk awareness amongst producers and consumers. PMID- 26745872 TI - KDAC8 with High Basal Velocity Is Not Activated by N-Acetylthioureas. AB - Lysine deacetylases (KDACs) are enzymes that reverse the post-translational modification of lysine acetylation. Recently, a series of N-acetylthioureas were synthesized and reported to enhance the activity of KDAC8 with a fluorogenic substrate. To determine if the activation was general, we synthesized three of the most potent N-acetylthioureas and measured their effect with peptide substrates and the fluorogenic substrate under multiple reaction conditions and utilizing two enzyme purification approaches. No activation was observed for any of the three N-acetylthioureas under any assayed conditions. Further characterization of KDAC8 kinetics with the fluorogenic substrate yielded a kcat/KM of 164 +/- 17 in the absence of any N-acetylthioureas. This catalytic efficiency is comparable to or higher than that previously reported when KDAC8 was activated by the N-acetylthioureas, suggesting that the previously reported activation effect may be due to use of an enzyme preparation that contains a large fraction of inactive enzyme. Further characterization with a less active preparation and additional substrates leads us to conclude that N-acetylthioureas are not true activators of KDAC8 and only increase activity if the enzyme preparation is below the maximal basal activity. PMID- 26745873 TI - Grey Matter Atrophy in Multiple Sclerosis: Clinical Interpretation Depends on Choice of Analysis Method. AB - BACKGROUND: Studies disagree on the location of grey matter (GM) atrophy in the multiple sclerosis (MS) brain. AIM: To examine the consistency between FSL, FreeSurfer, SPM for GM atrophy measurement (for volumes, patient/control discrimination, and correlations with cognition). MATERIALS AND METHODS: 127 MS patients and 50 controls were included and cortical and deep grey matter (DGM) volumetrics were performed. Consistency of volumes was assessed with Intraclass Correlation Coefficient/ICC. Consistency of patients/controls discrimination was assessed with Cohen's d, t-tests, MANOVA and a penalized double-loop logistic classifier. Consistency of association with cognition was assessed with Pearson correlation coefficient and ANOVA. Voxel-based morphometry (SPM-VBM and FSL-VBM) and vertex-wise FreeSurfer were used for group-level comparisons. RESULTS: The highest volumetry ICC were between SPM and FreeSurfer for cortical regions, and the lowest between SPM and FreeSurfer for DGM. The caudate nucleus and temporal lobes had high consistency between all software, while amygdala had lowest volumetric consistency. Consistency of patients/controls discrimination was largest in the DGM for all software, especially for thalamus and pallidum. The penalized double-loop logistic classifier most often selected the thalamus, pallidum and amygdala for all software. FSL yielded the largest number of significant correlations. DGM yielded stronger correlations with cognition than cortical volumes. Bilateral putamen and left insula volumes correlated with cognition using all methods. CONCLUSION: GM volumes from FreeSurfer, FSL and SPM are different, especially for cortical regions. While group-level separation between MS and controls is comparable, correlations between regional GM volumes and clinical/cognitive variables in MS should be cautiously interpreted. PMID- 26745874 TI - Delays in Human-Computer Interaction and Their Effects on Brain Activity. AB - The temporal contingency of feedback is an essential requirement of successful human-computer interactions. The timing of feedback not only affects the behavior of a user but is also accompanied by changes in psychophysiology and neural activity. In three fMRI experiments we systematically studied the impact of delayed feedback on brain activity while subjects performed an auditory categorization task. In the first fMRI experiment, we analyzed the effects of rare and thus unexpected delays of different delay duration on brain activity. In the second experiment, we investigated if users can adapt to frequent delays. Therefore, delays were presented as often as immediate feedback. In a third experiment, the influence of interaction outage was analyzed by measuring the effect of infrequent omissions of feedback on brain activity. The results show that unexpected delays in feedback presentation compared to immediate feedback stronger activate inter alia bilateral the anterior insular cortex, the posterior medial frontal cortex, the left inferior parietal lobule and the right inferior frontal junction. The strength of this activation increases with the duration of the delay. Thus, delays interrupt the course of an interaction and trigger an orienting response that in turn activates brain regions of action control. If delays occur frequently, users can adapt, delays become expectable, and the brain activity in the observed network diminishes over the course of the interaction. However, introducing rare omissions of expected feedback reduces the system's trustworthiness which leads to an increase in brain activity not only in response to such omissions but also following frequently occurring and thus expected delays. PMID- 26745875 TI - BRCA somatic and germline mutation detection in paraffin embedded ovarian cancers by next-generation sequencing. AB - BRCA mutated ovarian cancers respond better to platinum-based therapy and to the recently approved PARP-inhibitors. There is the need for efficient and timely methods to detect both somatic and germline mutations using formalin-fixed paraffin-embedded (FFPE) tissues and commercially available technology. We used a commercial kit exploring all exons and 50bp exon-intron junctions of BRCA1 and BRCA2 genes, and semiconductor next-generation sequencing (NGS) on DNA from 47 FFPE samples of high-grade serous ovarian cancers. Pathogenic mutations were found in 13/47 (28%) cancers: eight in BRCA1 and five in BRCA2. All BRCA1 and two BRCA2 mutations were germline; three BRCA2 mutations were somatic. All mutations were confirmed by Sanger sequencing. To evaluate the performance of the NGS panel, we assessed its capability to detect the 6,953 variants described for BRCA1 and BRCA2 in ClinVar and COSMIC databases using callability analysis. 6,059 (87.1%) variants were identified automatically by the software; 829 (12.0%) required visual verification. The remaining 65 (0.9%) variants were uncallable, and would require 15 Sanger reactions to be resolved. Thus, the sensitivity of the NGS-panel was 99.1%. In conclusion, NGS performed with a commercial kit is highly efficient for detection of germline and somatic mutations in BRCA genes using routine FFPE tissue. PMID- 26745877 TI - Neuromuscular control of curved walking in people with stroke: Case report. AB - People are required to adapt their basic walking pattern to turn and change directions safely for activities of daily living. This case study describes the changes in neuromuscular control among individuals with stroke on walking paths of different curvatures. Two men with hemiparetic stroke and one control subject walked along a straight, wide curved, and tight curved pathway while muscle activation of the medial and lateral gastrocnemius was recorded, along with the trajectory of the center of pressure (COP) during the single support phase. Balance, sensorimotor control, and functional ambulation were also evaluated. The subject with greater lower-limb sensorimotor impairment displayed a larger difference in the anterior-posterior COP displacement between limbs, which exacerbated as the path curvature increased. In addition, while the control subject demonstrated a lateral shift in the medial-lateral COP position, this person was unable to adapt the COP position on the nonparetic side. The second participant with a stroke demonstrated better balance and lateral shifting of the COP position. Modulation of the COP trajectory is required to safely perform curved walking. Further study is required to confirm the role of stroke-related gait deficits in the ability to adapt to curved walking. PMID- 26745878 TI - Strategies in Development of an mHealth Technology for Low Socioeconomic Groups in Free Healthcare Clinics. PMID- 26745876 TI - Clinical and Pathophysiological Characteristics of Cirrhotic Patients with Grade 1 and Minimal Hepatic Encephalopathy. AB - BACKGROUND AND AIMS: EASL/AASLD hepatic encephalopathy (HE) guidelines proposed the alternative use of the term 'Covert HE' combining minimal HE (mHE) and Grade 1 HE into a single entity. However, longitudinal data to indicate that these are indeed a single entity are lacking. The aims of this study were to determine whether the occurrence of complications of cirrhosis requiring hospital admission and mortality were similar in these sub-groups of patients. METHODS: Clinically stable cirrhotic patients (n = 106) with no previous history of 'Overt HE' were included over a 2-year period and classified as having no HE (n = 23), mHE (n = 39) or Grade 1 HE (n = 44). Standard biochemistry, venous ammonia, bacterial DNA and neutrophil function were measured at inclusion and the patients were followed for a mean of 230+/-95 days. RESULTS: Patients with Grade 1 HE had significantly more complications requiring hospitalisation (infection 9/18/34%; HE 4/8/18%; other 13/10/11%; P = 0.02) and significantly greater mortality (4/5/20%; P = 0.04) compared to patients with no HE or mHE respectively. Patients with mHE and grade 1 HE had similar ammonia levels, but higher than the no HE group (P<0.001). MELD score was similar between groups but Grade 1 HE patients had increased frequency of bacterial translocation (P = 0.06) and neutrophil spontaneous respiratory burst (P = 0.02) compared to patients with mHE. CONCLUSIONS: The results of this study show for the first time that 'Covert HE' is a heterogeneous entity with significantly greater hospitalisations and mortality in the Grade 1 HE patients compared with mHE. Further prospective longer-term studies are required before EASL/AASLD guidance is fully implemented. PMID- 26745879 TI - ANI Emerging Leader Project: Enhancing the Role of Nurses in Zambia Through mHealth. PMID- 26745881 TI - Systemic Inflammatory Response Syndrome Following Percutaneous Nephrolithotomy: Assessment of Risk Factors and Their Impact on Patient Outcomes. AB - OBJECTIVES: To identify perioperative risk factors for postoperative systemic inflammatory response syndrome (SIRS) and suggest possible modifications to reduce morbidity. MATERIAL AND METHODS: We prospectively analysed perioperative data such as history of pervious stone surgery, number and configuration of stones, presence of stent or nephrostomy, any previous positive urine culture, intraoperative renal pelvic urine and stone culture, aspiration of turbid urine on initial puncture, number of tracts required and clearance of stones, operative time and intraoperative hypotension and tachycardia of all patients who underwent percutaneous nephrolithotomy over a period of 15 months. RESULTS: A total of 182 patients were included, average stone size was 2.8 cm, 36.2% had staghorn stones and 15.9% had an indwelling stent or nephrostomy. Despite sterile preoperative urine culture, renal pelvic urine culture (RPUC) was positive in 14.8% (27 patients) and stone culture was positive in 21.9% (40 patients). SIRS developed in 17.5% (32 patients) and septic shock in 1.09% (2 patients). On analysis younger age, positive RPUC and stone culture, longer operative time and intraoperative tachycardia correlated significantly with the development of SIRS. CONCLUSION: Intra-operative cultures are only therapy-guiding cultures during SIRS, as preoperative urine cultures seldom accurately depict bacteriological status of upper tracts and thus should be obtained in all patients. PMID- 26745882 TI - Assessing the Effects of Indigenous Migration on Zootherapeutic Practices in the Semiarid Region of Brazil. AB - Human migration implies adaptations to new environments, such as ways to benefit from the available biodiversity. This study focused on the use of animal-derived remedies, and we investigated the effects of migration on the traditional medical system of the indigenous Truka people. This ethnic group lives in Northeast Brazil and is currently distributed in four distinct villages. In these villages, the zootherapeutic knowledge of 54 indigenous people was determined through semi structured questionnaires given from September 2013 to January 2014. The interviewees indicated 137 zootherapeutic uses involving 21 animal species. The variety of species and their uses have a higher similarity between villages that are closer to each other, which can be a reflection of geographic and environmental factors. However, even close villages showed a low similarity in the zootherapeutic uses recorded, which reflects a strong idiosyncrasy regarding the knowledge of each village. Hence, each village may be influenced by the physical environment and contact with other cultures, which may maintain or reduce the contact of younger villages with the original village. PMID- 26745883 TI - Comparative Analysis of Xenorhabdus koppenhoeferi Gene Expression during Symbiotic Persistence in the Host Nematode. AB - Species of Xenorhabdus and Photorhabdus bacteria form mutualistic associations with Steinernema and Heterorhabditis nematodes, respectively and serve as model systems for studying microbe-animal symbioses. Here, we profiled gene expression of Xenorhabdus koppenhoeferi during their symbiotic persistence in the newly formed infective juveniles of the host nematode Steinernema scarabaei through the selective capture of transcribed sequences (SCOTS). The obtained gene expression profile was then compared with other nematode-bacteria partnerships represented by Steinernema carpocapsae-Xenorhabdus nematophila and Heterorhabditis bacteriophora-Photorhabdus temperata. A total of 29 distinct genes were identified to be up-regulated and 53 were down-regulated in X. koppenhoeferi while in S. scarabaei infective juveniles. Of the identified genes, 8 of the up regulated and 14 of the down-regulated genes were similarly expressed in X. nematophila during persistence in its host nematode S. carpocapsae. However, only one from each of these up- and down-regulated genes was common to the mutualistic partnership between the bacterium P. temperata and the nematode H. bacteriophora. Interactive network analysis of the shared genes between X. koppenhoeferi and X. nematophila demonstrated that the up-regulated genes were mainly involved in bacterial survival and the down-regulated genes were more related to bacterial virulence and active growth. Disruption of two selected genes pta (coding phosphotransacetylase) and acnB (coding aconitate hydratase) in X. nematophila with shared expression signature with X. koppenhoeferi confirmed that these genes are important for bacterial persistence in the nematode host. The results of our comparative analyses show that the two Xenorhabdus species share a little more than a quarter of the transcriptional mechanisms during persistence in their nematode hosts but these features are quite different from those used by P. temperata bacteria in their nematode host H. bacteriophora. PMID- 26745884 TI - Radiation Inhibits Interleukin-12 Production via Inhibition of C-Rel through the Interleukin-6/ Signal Transducer and Activator of Transcription 3 Signaling Pathway in Dendritic Cells. AB - Radiotherapy (RT) is a potent anti-tumor modality. However, unwanted effects including increased recurrence and metastasis that involve factors such as cytokines, which induce complex molecular mechanisms, have also been reported. In a previous study, we showed that interleukin (IL)-12 and radiotherapy combination treatment suppressed tumor growth and metastasis in a hepatoma mouse model. In this study, we investigated the mechanism underlying the IL-12 anti-tumor effect during radiotherapy. In tumor-bearing mice, irradiation decreased IL-12 expression in the tumors and spleens. However, a number of dendritic cells infiltrated into the tumors in which IL-12 expression did not decrease. To further study the underlying detailed mechanism for this decrease in IL-12, LPS stimulated bone marrow-derived dendritic cells (BMDCs) were irradiated, and then IL-12- and IL-6-associated molecules were examined in irradiated tumors and BMDCs. Irradiation resulted in IL-12 suppression and IL-6 increase. IL-6 and signal transducer and activator of transcription 3 (STAT3) inhibitors restored the irradiation-induced IL-12 decrease via suppression of C-Rel activation. Taken together, our study suggests that irradiation-induced IL-6 can decrease IL-12 production through the inhibition of C-Rel phosphorylation by the IL-6/STAT3 signaling pathway. PMID- 26745885 TI - Evaluation of Anticancer and Antioxidant Activity of a Commercially Available CO2 Supercritical Extract of Old Man's Beard (Usnea barbata). AB - There is a worldwide ongoing investigation for novel natural constituents with cytotoxic and antioxidant properties. The aim of this study was to investigate chemical profile and stated biological activities of the supercritical CO2 extract (SCE) of old man's beard compared to the extracts obtained using the conventional techniques (Soxhlet extracts and macerate). The most abundant compound identified was usnic acid, which content was inversely proportional to the polarity of the solvent used and was the highest in the SCE, which was the sample revealing the highest cytotoxic activity in tested tumor cell lines (B16 mouse melanoma and C6 rat glioma), with lower IC50 values compared to pure usnic acid. Further investigations suggested both SCE and usnic acid to induce apoptosis and/or autophagy in B16 and C6, indicating higher cytotoxicity of SCE to be related to the higher degree of ROS production. A good correlation of usnic acid content in the extracts and their antioxidant capacity was established, extricating SCE as the most active one. Presented results support further investigations of SCE of old man's beard as a prospective therapeutic agent with potential relevance in the treatment of cancer and/or in oxidative stress mediated conditions. PMID- 26745886 TI - Intrauterine Growth Restriction Alters Mouse Intestinal Architecture during Development. AB - Infants with intrauterine growth restriction (IUGR) are at increased risk for neonatal and lifelong morbidities affecting multiple organ systems including the intestinal tract. The underlying mechanisms for the risk to the intestine remain poorly understood. In this study, we tested the hypothesis that IUGR affects the development of goblet and Paneth cell lineages, thus compromising the innate immunity and barrier functions of the epithelium. Using a mouse model of maternal thromboxane A2-analog infusion to elicit maternal hypertension and resultant IUGR, we tested whether IUGR alters ileal maturation and specifically disrupts mucus-producing goblet and antimicrobial-secreting Paneth cell development. We measured body weights, ileal weights and ileal lengths from birth to postnatal day (P) 56. We also determined the abundance of goblet and Paneth cells and their mRNA products, localization of cellular tight junctions, cell proliferation, and apoptosis to interrogate cellular homeostasis. Comparison of the murine findings with human IUGR ileum allowed us to verify observed changes in the mouse were relevant to clinical IUGR. At P14 IUGR mice had decreased ileal lengths, fewer goblet and Paneth cells, reductions in Paneth cell specific mRNAs, and decreased cell proliferation. These findings positively correlated with severity of IUGR. Furthermore, the decrease in murine Paneth cells was also seen in human IUGR ileum. IUGR disrupts the normal trajectory of ileal development, particularly affecting the composition and secretory products of the epithelial surface of the intestine. We speculate that this abnormal intestinal development may constitute an inherent "first hit", rendering IUGR intestine susceptible to further injury, infection, or inflammation. PMID- 26745888 TI - Correction: Spatial Homogeneity of Bacterial Communities Associated with the Surface Mucus Layer of the Reef-Building Coral Acropora palmata. PMID- 26745887 TI - Diurnal Variations of Circulating Extracellular Vesicles Measured by Nano Flow Cytometry. AB - The identification of extracellular vesicles (EVs) as intercellular conveyors of biological information has recently emerged as a novel paradigm in signaling, leading to the exploitation of EVs and their contents as biomarkers of various diseases. However, whether there are diurnal variations in the size, number, and tissue of origin of blood EVs is currently not known, and could have significant implications when using EVs as biomarkers for disease progression. Currently available technologies for the measurement of EV size and number are either time consuming, require specialized equipment, or lack sufficient accuracy across a range of EV sizes. Flow cytometry represents an attractive alternative to these methods; however, traditional flow cytometers are only capable of measuring particles down to 500 nm, which is significantly larger than the average and median sizes of plasma EVs. Utilizing a Beckman Coulter MoFlo XDP flow cytometer with NanoView module, we employed nanoscale flow cytometry (termed nanoFCM) to examine the relative number and scatter distribution of plasma EVs at three different time points during the day in 6 healthy adults. Analysis of liposomes and plasma EVs proved that nanoFCM is capable of detecting biologically-relevant vesicles down to 100 nm in size. With this high resolution configuration, we observed variations in the relative size (FSC/SSC distributions) and concentration (proportions) of EVs in healthy adult plasma across the course of a day, suggesting that there are diurnal variations in the number and size distribution of circulating EV populations. The use of nanoFCM provides a valuable tool for the study of EVs in both health and disease; however, additional refinement of nanoscale flow cytometric methods is needed for use of these instruments for quantitative particle counting and sizing. Furthermore, larger scale studies are necessary to more clearly define the diurnal variations in circulating EVs, and thus further inform their use as biomarkers for disease. PMID- 26745890 TI - Descriptive study of 896 Oral squamous cell carcinomas from the only University based Oral Pathology Diagnostic Service in Sri Lanka. AB - BACKGROUND: The main objective of this study was to describe selected clinico pathological characteristics of Oral Squamous Cell Carcinoma (OSCC) in Sri-Lanka. MATERIALS & METHODS: The study sample comprised of eight hundred and ninety six biopsies diagnosed as OSCC. The clinical and histopathological features were analyzed using the Chi-square test. RESULTS: Of the 896 biopsies, 801 were primary OSCCs, while 95 were recurrent OSCCs. Majority of the patients (78 %) were in the 5(th) to 7(th) decades of life and showed a male predilection. The buccal mucosa was the commonest site of primary OSCC comprising of 43 % of the sample. Of the primary OSCCs, with known TNM stage, 86 % were in stage 3&4 and majority (59 %) of stage 4 tumours showed tumour at one or more excision margins. Of the recurrent OSCC, 46 % developed their recurrences within one year of the excision of the primary tumour. CONCLUSION: In Sri-Lanka, OSCC is a major problem. Only half the patients had completely excised tumours (with clearance of >5 mm at all excision margins) at operation, and recurrences appeared early. This data should be considered in the future management policy of OSCC in Sri-Lanka. PMID- 26745889 TI - Loss of Y Chromosome in Peripheral Blood of Colorectal and Prostate Cancer Patients. AB - BACKGROUND: Although age-related loss of chromosome Y (LOY) in normal hematopoietic cells is a well-known phenomenon, the phenotypic consequences of LOY have been elusive. However, LOY has been found in association with smoking, shorter survival and higher risk of cancer. It was suggested that LOY in blood cells could become a predictive biomarker of male carcinogenesis. AIMS, METHODS & FINDINGS: To investigate the association of LOY in blood cells with the risk for development of colorectal (CC) and prostate cancers (PC), we have analyzed DNA samples from peripheral blood of 101 CC male patients (mean age 60.5+/-11.9 yrs), 70 PC patients (mean age 68.8+/-8.0 yrs) and 93 healthy control males (mean age 65.8+/-16.6 yrs). The methodology included co-amplification of homologous sequences on chromosome Y and other chromosomes using multiplex quantitative fluorescent (QF) PCR followed by automatic detection and analysis on ABI 3500 Genetic Analyzer. The mean Y/X ratio was significantly lower in the whole group of cancer patients (0.907+/-0.12; p = 1.17x10-9) in comparison to the controls (1.015+/-0.15), as well as in CC (0.884+/-0.15; p = 3.76x10-9) and PC patients (0.941+/-0.06; p = 0.00012), when analyzed separately. Multivariate logistic regression analysis adjusting for LOY and age showed that LOY is a more significant predictor of cancer presence than age, and that age probably does not contribute to the increased number of subjects with detectable LOY in cancer patients cohort. CONCLUSION: In conclusion, our results support the recent findings of association of LOY in blood cells with carcinogenesis in males. PMID- 26745893 TI - Medical physicist assistants are a bad idea. PMID- 26745891 TI - Patients' willingness to participate in clinical trials and their views on aspects of cancer research: results of a prospective patient survey. AB - BACKGROUND: Recruitment to clinical trials can be challenging and slower than anticipated. This prospective patient survey aimed to investigate the proportion of patients approached about a trial who agree to participate, their motivations for trial participation and their views on aspects of cancer research. METHODS: Patients who had been approached about participation in any clinical trials in the Gastrointestinal and Lymphoma Unit at the Royal Marsden were invited to complete a questionnaire. The statistical analysis is mainly descriptive, with percentages being reported. Univariate logistic regression analysis was used to determine any associations between patient characteristics and patient responses. RESULTS: From August 2013-July 2014, 276 patients received 298 clinical trial patient information sheets and were asked to complete the questionnaire. The majority of patients (263 patients, 88 %) consented to a clinical trial and 249 of the 263 patients (95 %) completed the questionnaire. Multiple factors influenced decisions to participate in clinical trials, with patients stating that the most important reasons were that the trial offered the best treatment available and that the trial results could benefit others. Of the 249 questionnaire respondents, 78 % would donate their tissue for genetic research, 75 % would consider participating in studies requiring a research biopsy and 75 % felt that patients should be informed of trial results. Patients treated with palliative intent and those who had received multiple lines of treatment were more willing to consider research biopsies. Of the patients approached about a clinical trial of an investigational medicinal product, 48-50 % would have liked more information on the study drugs/procedures. CONCLUSION: The majority of patients approached about a clinical trial consented to one or more trials. Patients' motivations for trial participation included potential personal benefit and altruistic reasons. A high proportion of patients were willing to donate tissue for research and to consider trials involving repeat biopsies. The majority of patients feel that participants should be informed of trial results and there is a group of patients who would like more detailed trial information. PMID- 26745892 TI - Rapid dissemination of human T-lymphotropic virus type 1 during primary infection in transplant recipients. AB - BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) infects an estimated 10 million persons globally with transmission resulting in lifelong infection. Disease, linked to high proviral load, occurs in a minority. In established infection HTLV-1 replicates through infectious spread and clonal expansion of infected lymphocytes. Little is known about acute HTLV-1 infection. The kinetics of early HTLV-1 infection, following transplantation-acquired infection in three recipients from one HTLV-1 infected donor, is reported. The recipients were treated with two HTLV-1 enzyme inhibitors 3 weeks post exposure following the detection of HTLV-1 provirus at low level in each recipient. HTLV-1 infection was serially monitored by serology, quantification of proviral load and HTLV-1 2LTR DNA circles and by HTLV-1 unique integration site analysis. RESULTS: HTLV-1 antibodies were first detected 16-39 days post-transplantation. HTLV-1 provirus was detected by PCR on day 16-23 and increased by 2-3 log by day 38-45 with a peak proviral doubling time of 1.4 days, after which steady state was reached. The rapid proviral load expansion was associated with high frequency of HTLV-1 2LTR DNA circles. The number of HTLV-1 unique integration sites was high compared with established HTLV-1 infection. Clonal expansion of infected cells was detected as early as day 37 with high initial oligoclonality index, consistent with early mitotic proliferation. CONCLUSIONS: In recipients infected through organ transplantation HTLV-1 disseminated rapidly despite early anti-HTLV-1 treatment. Proviral load set point was reached within 6 weeks. Seroconversion was not delayed. Unique integration site analysis and HTLV-1 2LTR DNA circles indicated early clonal expansion and high rate of infectious spread. PMID- 26745894 TI - A self-powered thin-film radiation detector using intrinsic high-energy current. AB - PURPOSE: The authors introduce a radiation detection method that relies on high energy current (HEC) formed by secondary charged particles in the detector material, which induces conduction current in an external readout circuit. Direct energy conversion of the incident radiation powers the signal formation without the need for external bias voltage or amplification. The detector the authors consider is a thin-film multilayer device, composed of alternating disparate electrically conductive and insulating layers. The optimal design of HEC detectors consists of microscopic or nanoscopic structures. METHODS: Theoretical and computational developments are presented to illustrate the salient properties of the HEC detector and to demonstrate its feasibility. In this work, the authors examine single-sandwiched and periodic layers of Cu and Al, and Au and Al, ranging in thickness from 100 nm to 300 MUm and separated by similarly sized dielectric gaps, exposed to 120 kVp x-ray beam (half-value thickness of 4.1 mm of Al). The energy deposition characteristics and the high-energy current were determined using radiation transport computations. RESULTS: The authors found that in a dual-layer configuration, the signal is in the measurable range. For a defined total detector thickness in a multilayer structure, the signal sharply increases with decreasing thickness of the high-Z conductive layers. This paper focuses on the computational results while a companion paper reports the experimental findings. CONCLUSIONS: Significant advantages of the device are that it does not require external power supply and amplification to create a measurable signal; it can be made in any size and geometry, including very thin (sub-millimeter to submicron) flexible curvilinear forms, and it is inexpensive. Potential applications include medical dosimetry (both in vivo and external), radiation protection, and other settings where one or more of the above qualities are desired. PMID- 26745895 TI - Prototypes of self-powered radiation detectors employing intrinsic high-energy current. AB - PURPOSE: The authors experimentally investigate the effect of direct energy conversion of x-rays via selfpowered Auger- and photocurrent, potentially suitable to practical radiation detection and dosimetry in medical applications. Experimental results are compared to computational predictions. The detector the authors consider is a thin-film multilayer device, composed of alternating disparate electrically conductive and insulating layers. This paper focuses on the experiments while a companion paper introduces the fundamental concepts of high-energy current (HEC) detectors. METHODS: The energy of ionizing radiation is directly converted to detector signal via electric current induced by high-energy secondary electrons generated in the detector material by the incident primary radiation. The HEC electrons also ionize the dielectric and the resultant charge carriers are selfcollected due to the contact potential of the disparate electrodes. Thus, an electric current is induced in the conductors in two different ways without the need for externally applied bias voltage or amplification. Thus, generated signal in turn is digitized by a data acquisition system. To determine the fundamental properties of the HEC detector and to demonstrate its feasibility for medical applications, the authors used a planar geometry composed of multilayer microstructures. Various detectors with up to seven conducting layers with different combinations of materials (250 MUm Al, 35 MUm Cu, 100 MUm Pb) and air gaps (100 MUm) were exposed to nearly plane-parallel 60-120 kVp x-ray beams. For the experimental design and verification, the authors performed coupled electron-photon radiation transport computations. The detector signal was measured using a commercial data acquisition system with 24 bits dynamic range, 0.4 fC sensitivity, and 0.9 ms sampling time. RESULTS: Measured signals for the prototype detector varied depending on the number of layers, material type, and incident photon energy, and it was in the range of 30-150 nA/cm(2) for unit air kerma (1 Gy), which is viable for practical applications. The experiments had an excellent agreement with the computations. Within the examined range of 60-120 kVp, the energy dependence of the HEC (normalized to the x-ray tube output) was relatively small. CONCLUSIONS: Based on the experimental results for 100 ms sampling time, it would be possible to measure the time dependence of x-ray beams for x-ray tube current of 0.1 mA or higher. Significant advantages of the HEC device are that generation of its signal does not require external power supply, it can be made in any size and shape, including flexible curvilinear forms, and it is inexpensive. It remains to be determined, which of the potential applications in medical dosimetry (both in vivo and external), or radiation protection would benefit from such selfpowered detectors. PMID- 26745897 TI - Estimating lung ventilation directly from 4D CT Hounsfield unit values. AB - PURPOSE: Computed tomography ventilation imaging (CTVI) aims to visualize air volume changes in the lung by quantifying respiratory motion in 4DCT using deformable image registration (DIR). A problem is that DIR-based CTVI is sensitive both to 4DCT image artifacts and DIR parameters, hindering clinical validation of the technique. To address this, the authors present a streamlined CTVI approach that estimates blood-gas exchange in terms of time-averaged 4DCT Hounsfield unit (HU) values without relying on DIR. The purpose of this study is to quantify the accuracy of the HU-based CTVI method using high-resolution (68)Ga positron emission tomography ("Galligas PET") scans in lung cancer patients. METHODS: The authors analyzed Galligas 4D-PET/CT scans acquired for 25 lung cancer patients at up to three imaging timepoints during lung cancer radiation therapy. For each 4DCT scan, the authors produced three types of CTVIs: (i) the new method (CTV IHU-), which takes the 4D time-averaged product of regional air and tissue densities at each voxel, and compared this to DIR-based estimates of (ii) breathing-induced density changes (CTV IDIR-HU), and (iii) breathing-induced volume changes (CTV IDIR-Jac) between the exhale/inhale phase images. The authors quantified the accuracy of CTV IHU-, CTV IDIR-HU and CTV IDIR-Jac versus Galligas PET in terms of voxel-wise Spearman correlation (r) and the separation of mean voxel values between clinically defined defect/nondefect regions. RESULTS: Averaged over 62 scans, CTV IHU- showed better accuracy than CTV IDIR-HU and CTV IDIR-Jac in terms of Spearman correlation with Galligas PET, with (mean +/- SD) r values of (0.50 +/- 0.17), (0.42 +/- 0.20), and (0.19 +/- 0.23), respectively. A two-sample Kolmogorov-Smirnov test indicates that CTV IHU- shows statistically significant separation of mean ventilation values between clinical defect/nondefect regions. Qualitatively, CTV IHU- appears concordant with Galligas PET for emphysema related defects, but differences arise in tumor obstructed regions (where aeration is overestimated due to motion blur) and for other abnormal morphology (e.g., fluid-filled or peritumoral lung with HU ? - 600) where the assumptions of the HU model may break down. CONCLUSIONS: The HU based CTVI method can improve voxel-wise correlations with Galligas PET compared to DIR-based methods and may be a useful approximation for voxels with HU values in the range (-1000, - 600). With further clinical verification, HU-based CTVI could provide a straightforward and reproducible means to estimate lung ventilation using free-breathing 4DCT. PMID- 26745896 TI - Population of 224 realistic human subject-based computational breast phantoms. AB - PURPOSE: To create a database of highly realistic and anatomically variable 3D virtual breast phantoms based on dedicated breast computed tomography (bCT) data. METHODS: A tissue classification and segmentation algorithm was used to create realistic and detailed 3D computational breast phantoms based on 230 + dedicated bCT datasets from normal human subjects. The breast volume was identified using a coarse three-class fuzzy C-means segmentation algorithm which accounted for and removed motion blur at the breast periphery. Noise in the bCT data was reduced through application of a postreconstruction 3D bilateral filter. A 3D adipose nonuniformity (bias field) correction was then applied followed by glandular segmentation using a 3D bias-corrected fuzzy C-means algorithm. Multiple tissue classes were defined including skin, adipose, and several fractional glandular densities. Following segmentation, a skin mask was produced which preserved the interdigitated skin, adipose, and glandular boundaries of the skin interior. Finally, surface modeling was used to produce digital phantoms with methods complementary to the XCAT suite of digital human phantoms. RESULTS: After rejecting some datasets due to artifacts, 224 virtual breast phantoms were created which emulate the complex breast parenchyma of actual human subjects. The volume breast density (with skin) ranged from 5.5% to 66.3% with a mean value of 25.3% +/- 13.2%. Breast volumes ranged from 25.0 to 2099.6 ml with a mean value of 716.3 +/- 386.5 ml. Three breast phantoms were selected for imaging with digital compression (using finite element modeling) and simple ray-tracing, and the results show promise in their potential to produce realistic simulated mammograms. CONCLUSIONS: This work provides a new population of 224 breast phantoms based on in vivo bCT data for imaging research. Compared to previous studies based on only a few prototype cases, this dataset provides a rich source of new cases spanning a wide range of breast types, volumes, densities, and parenchymal patterns. PMID- 26745898 TI - Quantitatively accurate activity measurements with a dedicated cardiac SPECT camera: Physical phantom experiments. AB - PURPOSE: Recently, there has been increased interest in dedicated cardiac single photon emission computed tomography (SPECT) scanners with pinhole collimation and improved detector technology due to their improved count sensitivity and resolution over traditional parallel-hole cameras. With traditional cameras, energy-based approaches are often used in the clinic for scatter compensation because they are fast and easily implemented. Some of the cardiac cameras use cadmium-zinc-telluride (CZT) detectors which can complicate the use of energy based scatter correction (SC) due to the low-energy tail-an increased number of unscattered photons detected with reduced energy. Modified energy-based scatter correction methods can be implemented, but their level of accuracy is unclear. In this study, the authors validated by physical phantom experiments the quantitative accuracy and reproducibility of easily implemented correction techniques applied to (99m)Tc myocardial imaging with a CZT-detector-based gamma camera with multiple heads, each with a single-pinhole collimator. METHODS: Activity in the cardiac compartment of an Anthropomorphic Torso phantom (Data Spectrum Corporation) was measured through 15 (99m)Tc-SPECT acquisitions. The ratio of activity concentrations in organ compartments resembled a clinical (99m)Tc-sestamibi scan and was kept consistent across all experiments (1.2:1 heart to liver and 1.5:1 heart to lung). Two background activity levels were considered: no activity (cold) and an activity concentration 1/10th of the heart (hot). A plastic "lesion" was placed inside of the septal wall of the myocardial insert to simulate the presence of a region without tracer uptake and contrast in this lesion was calculated for all images. The true net activity in each compartment was measured with a dose calibrator (CRC-25R, Capintec, Inc.). A 10 min SPECT image was acquired using a dedicated cardiac camera with CZT detectors (Discovery NM530c, GE Healthcare), followed by a CT scan for attenuation correction (AC). For each experiment, separate images were created including reconstruction with no corrections (NC), with AC, with attenuation and dual energy window (DEW) scatter correction (ACSC), with attenuation and partial volume correction (PVC) applied (ACPVC), and with attenuation, scatter, and PVC applied (ACSCPVC). The DEW SC method used was modified to account for the presence of the low-energy tail. RESULTS: T-tests showed that the mean error in absolute activity measurement was reduced significantly for AC and ACSC compared to NC for both (hot and cold) datasets (p < 0.001) and that ACSC, ACPVC, and ACSCPVC show significant reductions in mean differences compared to AC (p <= 0.001) without increasing the uncertainty (p > 0.4). The effect of SC and PVC was significant in reducing errors over AC in both datasets (p < 0.001 and p < 0.01, respectively), resulting in a mean error of 5% +/- 4%. CONCLUSIONS: Quantitative measurements of cardiac (99m)Tc activity are achievable using attenuation and scatter corrections, with the authors' dedicated cardiac SPECT camera. Partial volume corrections offer improvements in measurement accuracy in AC images and ACSC images with elevated background activity; however, these improvements are not significant in ACSC images with low background activity. PMID- 26745900 TI - Design and evaluation of an MRI-compatible linear motion stage. AB - PURPOSE: To develop and evaluate a tool for accurate, reproducible, and programmable motion control of imaging phantoms for use in motion sensitive magnetic resonance imaging (MRI) appli cations. METHODS: In this paper, the authors introduce a compact linear motion stage that is made of nonmagnetic material and is actuated with an ultrasonic motor. The stage can be positioned at arbitrary positions and orientations inside the scanner bore to move, push, or pull arbitrary phantoms. Using optical trackers, measuring microscopes, and navigators, the accuracy of the stage in motion control was evaluated. Also, the effect of the stage on image signal-to-noise ratio (SNR), artifacts, and B0 field homogeneity was evaluated. RESULTS: The error of the stage in reaching fixed positions was 0.025 +/- 0.021 mm. In execution of dynamic motion profiles, the worst-case normalized root mean squared error was below 7% (for frequencies below 0.33 Hz). Experiments demonstrated that the stage did not introduce artifacts nor did it degrade the image SNR. The effect of the stage on the B0 field was less than 2 ppm. CONCLUSIONS: The results of the experiments indicate that the proposed system is MRI-compatible and can create reliable and reproducible motion that may be used for validation and assessment of motion related MRI applications. PMID- 26745899 TI - Characterization of deformation and physical force in uniform low contrast anatomy and its impact on accuracy of deformable image registration. AB - PURPOSE: Little is known about the effect of force on organ deformation and consequently its impact on precision dose delivery. The purpose of this study was to evaluate the fundamental relationship between anatomic deformation and its causative physical force to ascertain if a threshold limit exists for deformable image registration (DIR) accuracy in uniform low contrast anatomy, beyond which its applicability may be clinically inappropriate. METHODS: To simulate a simplified model, a tissue equivalent deformable bladder phantom with 21 implanted fiducial markers was developed using a viscoelastic polymer. The bladder phantom was deformed by applying a force in increments from 10 to 70 N. DIR accuracy was studied using intensity based mim and Velocity B-spline algorithms by comparing the 3D vector of the 21 marker locations at the original target image with the synthetically derived marker positions from each target image obtained from DIR. RESULTS: The relationship between applied force in 1D deformation along the axis of applied force and 3D deformation of the phantom showed a linear response. The maximum and average displacements of markers exhibited a nonlinear response to the applied force. In the absence of implanted markers, DIR performance was suboptimal with a threshold limit of only 20 N (5 mm deformation) beyond which the average marker error was >=3 mm. DIR performance improved significantly with the addition of only one marker for the intensity based mim algorithm. In contrast, the Velocity B-spline algorithm showed reduced sensitivity to the number of markers introduced in both the source and target images. CONCLUSIONS: The limits of applicability of DIR are strongly dependent on the magnitude of deformation. There is a threshold limit beyond which the accuracy of DIR fails in uniform low contrast anatomy. The sensitivity of the DIR performance to the number of fiducial markers present indicates that if DIR performance is solely assessed with the contrast rich features present in clinical anatomy, the results may not be reflective of the true DIR performance in uniform low contrast anatomy. PMID- 26745901 TI - Evaluation of a silicon photomultiplier PET insert for simultaneous PET and MR imaging. AB - PURPOSE: In this study, the authors present a silicon photomultiplier (SiPM) based positron emission tomography (PET) insert dedicated to small animal imaging with high system performance and robustness to temperature change. METHODS: The insert consists of 64 LYSO-SiPM detector blocks arranged in 4 rings of 16 detector blocks to yield a ring diameter of 64 mm and axial field of view of 55 mm. Each detector block consists of a 9 * 9 array of LYSO crystals (1.2 * 1.2 * 10 mm(3)) and a monolithic 4 * 4 SiPM array. The temperature of each monolithic SiPM is monitored, and the proper bias voltage is applied according to the temperature reading in real time to maintain uniform performance. The performance of this PET insert was characterized using National Electrical Manufacturers Association NU 4-2008 standards, and its feasibility was evaluated through in vivo mouse imaging studies. RESULTS: The PET insert had a peak sensitivity of 3.4% and volumetric spatial resolutions of 1.92 (filtered back projection) and 0.53 (ordered subset expectation maximization) mm(3) at center. The peak noise equivalent count rate and scatter fraction were 42.4 kcps at 15.08 MBq and 16.5%, respectively. By applying the real-time bias voltage adjustment, an energy resolution of 14.2% +/- 0.3% was maintained and the count rate varied <=1.2%, despite severe temperature changes (10-30 degrees C). The mouse imaging studies demonstrate that this PET insert can produce high-quality images useful for imaging studies on the small animals. CONCLUSIONS: The developed MR-compatible PET insert is designed for insertion into a narrow-bore magnetic resonance imaging scanner, and it provides excellent imaging performance for PET/MR preclinical studies. PMID- 26745902 TI - A computer-aided diagnosis system for breast DCE-MRI at high spatiotemporal resolution. AB - PURPOSE: With novel MRI sequences, high spatiotemporal resolution has become available in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the breast. Since benign structures in the breast can show enhancement similar to malignancies in DCE-MRI, characterization of detected lesions is an important problem. The purpose of this study is to develop a computer-aided diagnosis (CADx) system for characterization of breast lesions imaged with high spatiotemporal resolution DCE-MRI. METHODS: The developed CADx system is composed of four main parts: semiautomated lesion segmentation, automated computation of morphological and dynamic features, aorta detection, and classification between benign and malignant categories. Lesion segmentation is performed by using a "multiseed smart opening" algorithm. Five morphological features were computed based on the segmentation of the lesion. For each voxel, contrast enhancement curve was fitted to an exponential model and dynamic features were computed based on this fitted curve. Average and standard deviations of the dynamic features were computed over the entire segmented area, in addition to the average value in an automatically selected smaller "most suspicious region." To compute the dynamic features for an enhancement curve, information of aortic enhancement is also needed. To keep the system fully automated, the authors developed a component which automatically detects the aorta and computes the aortic enhancement time. The authors used random forests algorithm to classify benign lesions from malignant. The authors evaluated this system in a dataset of breast MRI scans of 325 patients with 223 malignant and 172 benign lesions and compared its performance to an existing approach. The authors also evaluated the classification performances for ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), and invasive lobular carcinoma (ILC) lesions separately. The classification performances were measured by receiver operating characteristic (ROC) analysis in a leave-one-out cross validation scheme. RESULTS: The area under the ROC curve (AUC) obtained by the proposed CADx system was 0.8543, which was significantly higher (p = 0.007) than the performance obtained by the previous CADx system (0.8172) on the same dataset. The AUC values for DCIS, IDC, and ILC lesions were 0.7924, 0.8688, and 0.8650, respectively. CONCLUSIONS: The authors developed a CADx system for high spatiotemporal resolution DCE-MRI of the breast. This system outperforms a previously proposed system in classifying benign and malignant lesions, while it requires less user interactions. PMID- 26745904 TI - Development of computational small animal models and their applications in preclinical imaging and therapy research. AB - The development of multimodality preclinical imaging techniques and the rapid growth of realistic computer simulation tools have promoted the construction and application of computational laboratory animal models in preclinical research. Since the early 1990s, over 120 realistic computational animal models have been reported in the literature and used as surrogates to characterize the anatomy of actual animals for the simulation of preclinical studies involving the use of bioluminescence tomography, fluorescence molecular tomography, positron emission tomography, single-photon emission computed tomography, microcomputed tomography, magnetic resonance imaging, and optical imaging. Other applications include electromagnetic field simulation, ionizing and nonionizing radiation dosimetry, and the development and evaluation of new methodologies for multimodality image coregistration, segmentation, and reconstruction of small animal images. This paper provides a comprehensive review of the history and fundamental technologies used for the development of computational small animal models with a particular focus on their application in preclinical imaging as well as nonionizing and ionizing radiation dosimetry calculations. An overview of the overall process involved in the design of these models, including the fundamental elements used for the construction of different types of computational models, the identification of original anatomical data, the simulation tools used for solving various computational problems, and the applications of computational animal models in preclinical research. The authors also analyze the characteristics of categories of computational models (stylized, voxel-based, and boundary representation) and discuss the technical challenges faced at the present time as well as research needs in the future. PMID- 26745903 TI - A framework for optimization of diffusion-weighted MRI protocols for large field of-view abdominal-pelvic imaging in multicenter studies. AB - PURPOSE: To develop methods for optimization of diffusion-weighted MRI (DW-MRI) in the abdomen and pelvis on 1.5 T MR scanners from three manufacturers and assess repeatability of apparent diffusion coefficient (ADC) estimates in a temperature-controlled phantom and abdominal and pelvic organs in healthy volunteers. METHODS: Geometric distortion, ghosting, fat suppression, and repeatability and homogeneity of ADC estimates were assessed using phantoms and volunteers. Healthy volunteers (ten per scanner) were each scanned twice on the same scanner. One volunteer traveled to all three institutions in order to provide images for qualitative comparison. The common volunteer was excluded from quantitative analysis of the data from scanners 2 and 3 in order to ensure statistical independence, giving n = 10 on scanner 1 and n = 9 on scanners 2 and 3 for quantitative analysis. Repeatability and interscanner variation of ADC estimates in kidneys, liver, spleen, and uterus were assessed using within patient coefficient of variation (wCV) and Kruskal-Wallis tests, respectively. RESULTS: The coefficient of variation of ADC estimates in the temperature controlled phantom was 1%-4% for all scanners. Images of healthy volunteers from all scanners showed homogeneous fat suppression and no marked ghosting or geometric distortion. The wCV of ADC estimates was 2%-4% for kidneys, 3%-7% for liver, 6%-9% for spleen, and 7%-10% for uterus. ADC estimates in kidneys, spleen, and uterus showed no significant difference between scanners but a significant difference was observed in liver (p < 0.05). CONCLUSIONS: DW-MRI protocols can be optimized using simple phantom measurements to produce good quality images in the abdomen and pelvis at 1.5 T with repeatable quantitative measurements in a multicenter study. PMID- 26745905 TI - Technical Note: A novel leaf sequencing optimization algorithm which considers previous underdose and overdose events for MLC tracking radiotherapy. AB - PURPOSE: Multileaf collimator (MLC) tracking radiotherapy is complex as the beam pattern needs to be modified due to the planned intensity modulation as well as the real-time target motion. The target motion cannot be planned; therefore, the modified beam pattern differs from the original plan and the MLC sequence needs to be recomputed online. Current MLC tracking algorithms use a greedy heuristic in that they optimize for a given time, but ignore past errors. To overcome this problem, the authors have developed and improved an algorithm that minimizes large underdose and overdose regions. Additionally, previous underdose and overdose events are taken into account to avoid regions with high quantity of dose events. METHODS: The authors improved the existing MLC motion control algorithm by introducing a cumulative underdose/overdose map. This map represents the actual projection of the planned tumor shape and logs occurring dose events at each specific regions. These events have an impact on the dose cost calculation and reduce recurrence of dose events at each region. The authors studied the improvement of the new temporal optimization algorithm in terms of the L1-norm minimization of the sum of overdose and underdose compared to not accounting for previous dose events. For evaluation, the authors simulated the delivery of 5 conformal and 14 intensity-modulated radiotherapy (IMRT)-plans with 7 3D patient measured tumor motion traces. RESULTS: Simulations with conformal shapes showed an improvement of L1-norm up to 8.5% after 100 MLC modification steps. Experiments showed comparable improvements with the same type of treatment plans. CONCLUSIONS: A novel leaf sequencing optimization algorithm which considers previous dose events for MLC tracking radiotherapy has been developed and investigated. Reductions in underdose/overdose are observed for conformal and IMRT delivery. PMID- 26745906 TI - Weekly response assessment of involved lymph nodes to radiotherapy using diffusion-weighted MRI in oropharynx squamous cell carcinoma. AB - PURPOSE: Patients with cancers of oropharynx have a favorable prognosis and are an ideal candidate for adaptive therapy. A replan to improve coverage or escalate/de-escalate dose based on morphological information alone may not be adequate as the grossly involved lymph nodes (LNs) of a subset of these patients tend to become cystic and often do not regress. Functional adaptation may be a better approach when considering replanning for these patients. The purpose of this study was to evaluate the weekly trends in treatment related morphological and physiological changes for these LNs using diffusion-weighted MRI (DW-MRI) and evaluate its implications for adaptive replanning. METHODS: Ten patients with histologically proven oropharynx HNSCC undergoing concurrent chemoradiation were analyzed in this study. MR imaging protocol included axial T1w, T2w, and DW-MRI using a 3 T Philips MR scanner. The patients were scanned weekly in radiation treatment planning position using a 16 element phased-array anterior coil and a 44 element posterior coil. A total of 65 DWI and T2w scans were analyzed. DWI was performed using an optimized single-shot echo planar imaging sequence (TR/TE = 5000/65 ms, slice thickness = 5 mm; slices = 28; b values = 0 and 800 s/mm(2)). Quantification of the DW-MRI images was performed by calculating the apparent diffusion coefficient (ADC). T2w and DWI scans were imported into the Eclipse treatment planning system and gross tumor volumes (GTVs) corresponding to grossly involved LNs were contoured on each axial slice by physician experts. An attempt was made to remove any cystic or necrotic components so that the ADC analysis was of viable tumor only. A pixel-by-pixel fit of signal intensities within the GTVs was performed assuming monoexponential behavior. From each GTV histogram mean, median, standard deviation, skewness, and kurtosis were calculated. Absolute and percent change in weekly ADC histogram parameters and percent change in T2w GTV were also calculated. RESULTS: For all nodes, an immediate change in ADC was observed during first 2-3 weeks after which ADC values either continued to increase or plateaued. A few nodal volumes had a slightly decreased ADC value during later weeks. Percent increase in median ADC from weeks 1 to 6 with respect to baseline was 14%, 25%, 41%, 42%, 45%, and 58%. The corresponding change in median T2 volumes was 8%, 10%, 16%, 22%, 40%, and 42%, respectively. The ADC distribution of the viable tumors was initially highly kurtotic; however, the kurtosis decreased as treatment progressed. The ADC distribution also showed a higher degree of skewness in the first 2 weeks, progressively becoming less skewed as treatment progressed so as to slowly approach a more symmetric distribution. CONCLUSIONS: Physiological changes in LNs represented by changes in ADC evaluated using DW-MRI are evident sooner than the morphological changes calculated from T2w MRI. The decisions for adaptive replanning may need to be individualized and should be based primarily on tumor functional information. The authors' data also suggest that for many patients, week 3 maybe the optimal time to intervene and replan. Larger studies are needed to confirm their findings. PMID- 26745908 TI - Improving the accuracy in detection of clustered microcalcifications with a context-sensitive classification model. AB - PURPOSE: In computer-aided detection of microcalcifications (MCs), the detection accuracy is often compromised by frequent occurrence of false positives (FPs), which can be attributed to a number of factors, including imaging noise, inhomogeneity in tissue background, linear structures, and artifacts in mammograms. In this study, the authors investigated a unified classification approach for combating the adverse effects of these heterogeneous factors for accurate MC detection. METHODS: To accommodate FPs caused by different factors in a mammogram image, the authors developed a classification model to which the input features were adapted according to the image context at a detection location. For this purpose, the input features were defined in two groups, of which one group was derived from the image intensity pattern in a local neighborhood of a detection location, and the other group was used to characterize how a MC is different from its structural background. Owing to the distinctive effect of linear structures in the detector response, the authors introduced a dummy variable into the unified classifier model, which allowed the input features to be adapted according to the image context at a detection location (i.e., presence or absence of linear structures). To suppress the effect of inhomogeneity in tissue background, the input features were extracted from different domains aimed for enhancing MCs in a mammogram image. To demonstrate the flexibility of the proposed approach, the authors implemented the unified classifier model by two widely used machine learning algorithms, namely, a support vector machine (SVM) classifier and an Adaboost classifier. In the experiment, the proposed approach was tested for two representative MC detectors in the literature [difference-of-Gaussians (DoG) detector and SVM detector]. The detection performance was assessed using free-response receiver operating characteristic (FROC) analysis on a set of 141 screen-film mammogram (SFM) images (66 cases) and a set of 188 full-field digital mammogram (FFDM) images (95 cases). RESULTS: The FROC analysis results show that the proposed unified classification approach can significantly improve the detection accuracy of two MC detectors on both SFM and FFDM images. Despite the difference in performance between the two detectors, the unified classifiers can reduce their FP rate to a similar level in the output of the two detectors. In particular, with true positive rate at 85%, the FP rate on SFM images for the DoG detector was reduced from 1.16 to 0.33 clusters/image (unified SVM) and 0.36 clusters/image (unified Adaboost), respectively; similarly, for the SVM detector, the FP rate was reduced from 0.45 clusters/image to 0.30 clusters/image (unified SVM) and 0.25 clusters/image (unified Adaboost), respectively. Similar FP reduction results were also achieved on FFDM images for the two MC detectors. CONCLUSIONS: The proposed unified classification approach can be effective for discriminating MCs from FPs caused by different factors (such as MC-like noise patterns and linear structures) in MC detection. The framework is general and can be applicable for further improving the detection accuracy of existing MC detectors. PMID- 26745907 TI - Application of a novel Kalman filter based block matching method to ultrasound images for hand tendon displacement estimation. AB - PURPOSE: Information about tendon displacement is important for allowing clinicians to not only quantify preoperative tendon injuries but also to identify any adhesive scaring between tendon and adjacent tissue. The Fisher-Tippett (FT) similarity measure has recently been shown to be more accurate than the Laplacian sum of absolute differences (SAD) and Gaussian sum of squared differences (SSD) similarity measures for tracking tendon displacement in ultrasound B-mode images. However, all of these similarity measures can easily be influenced by the quality of the ultrasound image, particularly its signal-to-noise ratio. Ultrasound images of injured hands are unfortunately often of poor quality due to the presence of adhesive scars. The present study investigated a novel Kalman-filter scheme for overcoming this problem. METHODS: Three state-of-the-art tracking methods (FT, SAD, and SSD) were used to track the displacements of phantom and cadaver tendons, while FT was used to track human tendons. These three tracking methods were combined individually with the proposed Kalman-filter (K1) scheme and another Kalman-filter scheme used in a previous study to optimize the displacement trajectories of the phantom and cadaver tendons. The motion of the human extensor digitorum communis tendon was measured in the present study using the FT-K1 scheme. RESULTS: The experimental results indicated that SSD exhibited better accuracy in the phantom experiments, whereas FT exhibited better performance for tracking real tendon motion in the cadaver experiments. All three tracking methods were influenced by the signal-to-noise ratio of the images. On the other hand, the K1 scheme was able to optimize the tracking trajectory of displacement in all experiments, even from a location with a poor image quality. The human experimental data indicated that the normal tendons were displaced more than the injured tendons, and that the motion ability of the injured tendon was restored after appropriate rehabilitation sessions. CONCLUSIONS: The obtained results show the potential for applying the proposed FT-K1 method in clinical applications for evaluating the tendon injury level after metacarpal fractures and assessing the recovery of an injured tendon during rehabilitation. PMID- 26745909 TI - Failure mode and effects analysis based risk profile assessment for stereotactic radiosurgery programs at three cancer centers in Brazil. AB - PURPOSE: The goal of this study was to evaluate the safety and quality management program for stereotactic radiosurgery (SRS) treatment processes at three radiotherapy centers in Brazil by using three industrial engineering tools (1) process mapping, (2) failure modes and effects analysis (FMEA), and (3) fault tree analysis. METHODS: The recommendations of Task Group 100 of American Association of Physicists in Medicine were followed to apply the three tools described above to create a process tree for SRS procedure for each radiotherapy center and then FMEA was performed. Failure modes were identified for all process steps and values of risk priority number (RPN) were calculated from O, S, and D (RPN = O * S * D) values assigned by a professional team responsible for patient care. RESULTS: The subprocess treatment planning was presented with the highest number of failure modes for all centers. The total number of failure modes were 135, 104, and 131 for centers I, II, and III, respectively. The highest RPN value for each center is as follows: center I (204), center II (372), and center III (370). Failure modes with RPN >= 100: center I (22), center II (115), and center III (110). Failure modes characterized by S >= 7, represented 68% of the failure modes for center III, 62% for center II, and 45% for center I. Failure modes with RPNs values >=100 and S >= 7, D >= 5, and O >= 5 were considered as high priority in this study. CONCLUSIONS: The results of the present study show that the safety risk profiles for the same stereotactic radiotherapy process are different at three radiotherapy centers in Brazil. Although this is the same treatment process, this present study showed that the risk priority is different and it will lead to implementation of different safety interventions among the centers. Therefore, the current practice of applying universal device-centric QA is not adequate to address all possible failures in clinical processes at different radiotherapy centers. Integrated approaches to device-centric and process specific quality management program specific to each radiotherapy center are the key to a safe quality management program. PMID- 26745911 TI - Penalized maximum likelihood reconstruction for x-ray differential phase-contrast tomography. AB - PURPOSE: The purpose of this work is to propose a cost function with regularization to iteratively reconstruct attenuation, phase, and scatter images simultaneously from differential phase contrast (DPC) acquisitions, without the need of phase retrieval, and examine its properties. Furthermore this reconstruction method is applied to an acquisition pattern that is suitable for a DPC tomographic system with continuously rotating gantry (sliding window acquisition), overcoming the severe smearing in noniterative reconstruction. METHODS: We derive a penalized maximum likelihood reconstruction algorithm to directly reconstruct attenuation, phase, and scatter image from the measured detector values of a DPC acquisition. The proposed penalty comprises, for each of the three images, an independent smoothing prior. Image quality of the proposed reconstruction is compared to images generated with FBP and iterative reconstruction after phase retrieval. Furthermore, the influence between the priors is analyzed. Finally, the proposed reconstruction algorithm is applied to experimental sliding window data acquired at a synchrotron and results are compared to reconstructions based on phase retrieval. RESULTS: The results show that the proposed algorithm significantly increases image quality in comparison to reconstructions based on phase retrieval. No significant mutual influence between the proposed independent priors could be observed. Further it could be illustrated that the iterative reconstruction of a sliding window acquisition results in images with substantially reduced smearing artifacts. CONCLUSIONS: Although the proposed cost function is inherently nonconvex, it can be used to reconstruct images with less aliasing artifacts and less streak artifacts than reconstruction methods based on phase retrieval. Furthermore, the proposed method can be used to reconstruct images of sliding window acquisitions with negligible smearing artifacts. PMID- 26745912 TI - Discontinuous finite element space-angle treatment of the first order linear Boltzmann transport equation with magnetic fields: Application to MRI-guided radiotherapy. AB - PURPOSE: The advent of magnetic resonance imaging (MRI) guided radiotherapy systems demands the incorporation of the magnetic field into dose calculation algorithms of treatment planning systems. This is due to the fact that the Lorentz force of the magnetic field perturbs the path of the relativistic electrons, hence altering the dose deposited by them. Building on the previous work, the authors have developed a discontinuous finite element space-angle treatment of the linear Boltzmann transport equation to accurately account for the effects of magnetic fields on radiotherapy doses. METHODS: The authors present a detailed description of their new formalism and compare its accuracy to geant4 Monte Carlo calculations for magnetic fields parallel and perpendicular to the radiation beam at field strengths of 0.5 and 3 T for an inhomogeneous 3D slab geometry phantom comprising water, bone, and air or lung. The accuracy of the authors' new formalism was determined using a gamma analysis with a 2%/2 mm criterion. RESULTS: Greater than 98.9% of all points analyzed passed the 2%/2 mm gamma criterion for the field strengths and orientations tested. The authors have benchmarked their new formalism against Monte Carlo in a challenging radiation transport problem with a high density material (bone) directly adjacent to a very low density material (dry air at STP) where the effects of the magnetic field dominate collisions. CONCLUSIONS: A discontinuous finite element space-angle approach has been proven to be an accurate method for solving the linear Boltzmann transport equation with magnetic fields for cases relevant to MRI guided radiotherapy. The authors have validated the accuracy of this novel technique against geant4, even in cases of strong magnetic field strengths and low density air. PMID- 26745910 TI - Accuracy of respiratory motion measurement of 4D-MRI: A comparison between cine and sequential acquisition. AB - PURPOSE: The authors have recently developed a cine-mode T2*/T1-weighted 4D-MRI technique and a sequential-mode T2-weighted 4D-MRI technique for imaging respiratory motion. This study aims at investigating which 4D-MRI image acquisition mode, cine or sequential, provides more accurate measurement of organ motion during respiration. METHODS: A 4D digital extended cardiac-torso (XCAT) human phantom with a hypothesized tumor was used to simulate the image acquisition and the 4D-MRI reconstruction. The respiratory motion was controlled by the given breathing signal profiles. The tumor was manipulated to move continuously with the surrounding tissue. The motion trajectories were measured from both sequential- and cine-mode 4D-MRI images. The measured trajectories were compared with the average trajectory calculated from the input profiles, which was used as references. The error in 4D-MRI tumor motion trajectory (E) was determined. In addition, the corresponding respiratory motion amplitudes of all the selected 2D images for 4D reconstruction were recorded. Each of the amplitude was compared with the amplitude of its associated bin on the average breathing curve. The mean differences from the average breathing curve across all slice positions (D) were calculated. A total of 500 simulated respiratory profiles with a wide range of irregularity (Ir) were used to investigate the relationship between D and Ir. Furthermore, statistical analysis of E and D using XCAT controlled by 20 cancer patients' breathing profiles was conducted. Wilcoxon Signed Rank test was conducted to compare two modes. RESULTS: D increased faster for cine-mode (D = 1.17 * Ir + 0.23) than sequential-mode (D = 0.47 * Ir + 0.23) as irregularity increased. For the XCAT study using 20 cancer patients' breathing profiles, the median E values were significantly different: 0.12 and 0.10 cm for cine- and sequential-modes, respectively, with a p-value of 0.02. The median D values were significantly different: 0.47 and 0.24 cm for cine- and sequential modes, respectively, with a p-value < 0.001. CONCLUSIONS: Respiratory motion measurement may be more accurate and less susceptible to breathing irregularity in sequential-mode 4D-MRI than that in cine-mode 4D-MRI. PMID- 26745913 TI - Flattening filter free beams from TrueBeam and Versa HD units: Evaluation of the parameters for quality assurance. AB - PURPOSE: Flattening filter free (FFF) beams generated by medical linear accelerators are today clinically used for stereotactical and non-stereotactical radiotherapy treatments. Such beams differ from the standard flattened beams (FF) in the high dose rate and the profile shape peaked on the beam central axis. Definition of new parameters as unflatness and slope for FFF beams has been proposed based on a renormalization factor for FFF profiles. The present study aims to assess the dosimetric differences between FFF beams generated by linear accelerators from different vendors, and to provide renormalization and parameter data of the two kinds of units. METHODS: Dosimetric data from two Varian TrueBeam and two Elekta Versa HD linear accelerators, all with 6 and 10 MV nominal accelerating potentials, FF and FFF modes have been collected. Renormalization factors and related fit parameters according to Fogliata et al. ["Definition of parameters for quality assurance of flattening filter free (FFF) photon beams in radiation therapy," Med. Phys. 39, 6455-6464 (2012)] have been evaluated for FFF beams of both units and energies. Unflatness and slope parameters from profile curves were evaluated. Dosimetric differences in terms of beam penetration and near-the-surface dose were also assessed. RESULTS: FFF profile parameters have been updated; renormalization factors and unflatness from the Varian units are consistent with the published data. Elekta FFF beam qualities, different from the Varian generated beams, tend to express similar behaviour as the FF beam of the corresponding nominal energy. TPR20,10 for 6 and 10 MV FF and FFF TrueBeam beams are 0.665, 0.629 (6 MV) and 0.738, 0.703 (10 MV). The same figures for Versa HD units are 0.684, 0.678 (6 MV) and 0.734, 0.721 (10 MV). CONCLUSIONS: Renormalization factor and unflatness parameters evaluated from Varian and Elekta FFF beams are provided, in particular renormalization factors table and fit parameters. PMID- 26745915 TI - Osmotic potential calculations of inorganic and organic aqueous solutions over wide solute concentration levels and temperatures. AB - PURPOSE: To demonstrate that the authors' new "aqueous solution vs pure water" equation to calculate osmotic potential may be used to calculate the osmotic potentials of inorganic and organic aqueous solutions over wide ranges of solute concentrations and temperatures. Currently, the osmotic potentials of solutions used for medical purposes are calculated from equations based on the thermodynamics of the gas laws which are only accurate at low temperature and solute concentration levels. Some solutions used in medicine may need their osmotic potentials calculated more accurately to take into account solute concentrations and temperatures. METHODS: The authors experimented with their new equation for calculating the osmotic potentials of inorganic and organic aqueous solutions up to and beyond body temperatures by adjusting three of its factors; (a) the volume property of pure water, (b) the number of "free" water molecules per unit volume of solution, "Nf," and (c) the "t" factor expressing the cooperative structural relaxation time of pure water at given temperatures. Adequate information on the volume property of pure water at different temperatures is available in the literature. However, as little information on the relative densities of inorganic and organic solutions, respectively, at varying temperatures needed to calculate Nf was available, provisional equations were formulated to approximate values. Those values together with tentative t values for different temperatures chosen from values calculated by different workers were substituted into the authors' equation to demonstrate how osmotic potentials could be estimated over temperatures up to and beyond bodily temperatures. RESULTS: The provisional equations formulated to calculate Nf, the number of free water molecules per unit volume of inorganic and organic solute solutions, respectively, over wide concentration ranges compared well with the calculations of Nf using recorded relative density data at 20 degrees C. They were subsequently used to estimate Nf values at temperatures up to and excess of body temperatures. Those values, together with t values at temperatures up to and in excess of body temperatures recorded in the literature, were substituted in the authors' equation for the provisional calculation of osmotic potentials. The calculations indicated that solution temperatures and solute concentrations have a marked effect on osmotic potentials. CONCLUSIONS: Following work to measure the relative densities of aqueous solutions for the calculation of Nf values and the determination of definitive t values up to and beyond bodily temperatures, the authors' equation would enable the accurate estimations of the osmotic potentials of wide concentrations of aqueous solutions of inorganic and organic solutes over the temperature range. The study illustrates that not only solute concentrations but also temperatures have a marked effect on osmotic potentials, an observation of medical and biological significance. PMID- 26745914 TI - The impact of system matrix dimension on small FOV SPECT reconstruction with truncated projections. AB - PURPOSE: A dedicated cardiac hybrid single photon emission computed tomography (SPECT)/CT scanner that uses cadmium zinc telluride detectors and multiple pinhole collimators for stationary acquisition offers many advantages. However, the impact of the reconstruction system matrix (SM) dimension on the reconstructed image quality from truncated projections and 19 angular samples acquired on this scanner has not been extensively investigated. In this study, the authors aimed to investigate the impact of the dimensions of SM and the use of body contour derived from adjunctive CT imaging as an object support in reconstruction on this scanner, in relation to background extracardiac activity. METHODS: The authors first simulated a generic SPECT/CT system to image four NCAT phantoms with various levels of extracardiac activity and compared the reconstructions using SM in different dimensions and with/without body contour as a support for quantitative evaluations. The authors then compared the reconstructions of 18 patient studies, which were acquired on a GE Discovery NM570c scanner following injection of different radiotracers, including (99m)Tc Tetrofosmin and (123)I-mIBG, comparing the scanner's default SM that incompletely covers the body with a large SM that incorporates a patient specific full body contour. RESULTS: The simulation studies showed that the reconstructions using a SM that only partially covers the body yielded artifacts on the edge of the field of view (FOV), overestimation of activity and increased nonuniformity in the blood pool for the phantoms with higher relative levels of extracardiac activity. However, the impact on the quantitative accuracy in the high activity region, such as the myocardium, was subtle. On the other hand, an excessively large SM that enclosed the entire body alleviated the artifacts and reduced overestimation in the blood pool, but yielded slight underestimation in myocardium and defect regions. The reconstruction using the larger SM with body contour yielded the most quantitatively accurate results in all the regions of interest for a range of uptake levels in the extracardiac regions. In patient studies, the SM incorporating patient specific body contour minimized extracardiac artifacts, yielded similar myocardial activity, lower blood pool activity, and subsequently improved myocardium-to-blood pool contrast (p < 0.0001) by an average of 7% (range 0%-18%) across all the patients, compared to the reconstructions using the scanner's default SM. CONCLUSIONS: Their results demonstrate that using a large SM that incorporates a CT derived body contour in the reconstruction could improve quantitative accuracy within the FOV for clinical studies with high extracardiac activity. PMID- 26745916 TI - Effect of deformable registration uncertainty on lung SBRT dose accumulation. AB - PURPOSE: Deformable image registration (DIR) plays an important role in dose accumulation, such as incorporating breathing motion into the accumulation of the delivered dose based on daily 4DCBCT images. However, it is not yet well understood how the uncertainties associated with DIR methods affect the dose calculations and resulting clinical metrics. The purpose of this study is to evaluate the impact of DIR uncertainty on the clinical metrics derived from its use in dose accumulation. METHODS: A biomechanical model based DIR method and a biomechanical-intensity-based hybrid method, which reduced the average registration error by 1.6 mm, were applied to ten lung cancer patients. A clinically relevant dose parameter [minimum dose to 0.5 cm(3) (Dmin)] was calculated for three dose scenarios using both algorithms. Dose scenarios included static (no breathing motion), predicted (breathing motion at the time of planning), and total accumulated (interfraction breathing motion). The relationship between the dose parameter and a combination of DIR uncertainty metrics, tumor volume, and dose heterogeneity of the plan was investigated. RESULTS: Depending on the dose heterogeneity, tumor volume, and DIR uncertainty, in over 50% of the patients, differences greater than 1.0 Gy were observed in the Dmin of the tumor in the static dose calculation on exhale phase of the 4DCT. Such differences were due to the errors in propagating the tumor contours from the reference planning 4DCT phase onto a subsequent 4DCT phase using each DIR algorithm and calculating the dose on that phase. The differences in predicted dose were more subtle when breathing motion was modeled explicitly at the time of planning with only one patient exhibiting a greater than 1.0 Gy difference in Dmin. Dmin differences of up to 2.5 Gy were found in the total accumulated delivered dose due to difference in quantifying the interfraction variations. Such dose uncertainties could potentially be clinically significant. CONCLUSIONS: Reductions in average uncertainty in DIR algorithms by 1.6 mm may have a clinically significant impact on the decision-making metrics used in dose planning and dose accumulation assessment. PMID- 26745918 TI - Frame average optimization of cine-mode EPID images used for routine clinical in vivo patient dose verification of VMAT deliveries. AB - PURPOSE: The in vivo 3D dose delivered to a patient during volumetric modulated arc therapy (VMAT) delivery can be calculated using electronic portal imaging device (EPID) images. These images must be acquired in cine-mode (i.e., "movie" mode) in order to capture the time-dependent delivery information. The angle subtended by each cine-mode EPID image during an arc can be changed via the frame averaging number selected within the image acquisition software. A large frame average number will decrease the EPID's angular resolution and will result in a decrease in the accuracy of the dose information contained within each image. Alternatively, less EPID images acquired per delivery will decrease the overall 3D patient dose calculation time, which is appealing for large-scale clinical implementation. Therefore, the purpose of this study was to determine the optimal frame average value per EPID image, defined as the highest frame averaging that can be used without an appreciable loss in 3D dose reconstruction accuracy for VMAT treatments. METHODS: Six different VMAT plans and six different SBRT-VMAT plans were delivered to an anthropomorphic phantom. Delivery was carried out on a Varian 2300ix model linear accelerator (Linac) equipped with an aS1000 EPID running at a frame acquisition rate of 7.5 Hz. An additional PC was set up at the Linac console area, equipped with specialized frame-grabber hardware and software packages allowing continuous acquisition of all EPID frames during delivery. Frames were averaged into "frame-averaged" EPID images using matlab. Each frame averaged data set was used to calculate the in vivo dose to the patient and then compared to the single EPID frame in vivo dose calculation (the single frame calculation represents the highest possible angular resolution per EPID image). A mean percentage dose difference of low dose (<20% prescription dose) and high dose regions (>80% prescription dose) was calculated for each frame averaged scenario for each plan. The authors defined their unacceptable loss of accuracy as no more than a +/-1% mean dose difference in the high dose region. Optimal frame average numbers were then determined as a function of the Linac's average gantry speed and the dose per fraction. RESULTS: The authors found that 9 and 11 frame averages were suitable for all VMAT and SBRT-VMAT treatments, respectively. This resulted in no more than a 1% loss to any of the dose region's mean percentage difference when compared to the single frame reconstruction. The optimized number was dependent on the treatment's dose per fraction and was determined to be as high as 14 for 12 Gy/fraction (fx), 15 for 8 Gy/fx, 11 for 6 Gy/fx, and 9 for 2 Gy/fx. CONCLUSIONS: The authors have determined an optimal EPID frame averaging number for multiple VMAT-type treatments. These are given as a function of the dose per fraction and average gantry speed. These optimized values are now used in the authors' clinical, 3D, in vivo patient dosimetry program. This provides a reduction in calculation time while maintaining the authors' required level of accuracy in the dose reconstruction. PMID- 26745917 TI - Influence of geometric and material properties on artifacts generated by interventional MRI devices: Relevance to PRF-shift thermometry. AB - PURPOSE: Magnetic resonance imaging (MRI) is capable of providing valuable real time feedback during medical procedures, partly due to the excellent soft-tissue contrast available. Several technical hurdles still exist to seamless integration of medical devices with MRI due to incompatibility of most conventional devices with this imaging modality. In this study, the effect of local perturbations in the magnetic field caused by the magnetization of medical devices was examined using finite element analysis modeling. As an example, the influence of the geometric and material characteristics of a transurethral high-intensity ultrasound applicator on temperature measurements using proton resonance frequency (PRF)-shift thermometry was investigated. METHODS: The effect of local perturbations in the magnetic field, caused by the magnetization of medical device components, was examined using finite element analysis modeling. The thermometry artifact generated by a transurethral ultrasound applicator was simulated, and these results were validated against analytic models and scans of an applicator in a phantom. Several parameters were then varied to identify which most strongly impacted the level of simulated thermometry artifact, which varies as the applicator moves over the course of an ablative high-intensity ultrasound treatment. RESULTS: Key design parameters identified as having a strong influence on the magnitude of thermometry artifact included the susceptibility of materials and their volume. The location of components was also important, particularly when positioned to maximize symmetry of the device. Finally, the location of component edges and the inclination of the device relative to the magnetic field were also found to be important factors. CONCLUSIONS: Previous design strategies to minimize thermometry artifact were validated, and novel design strategies were identified that substantially reduce PRF-shift thermometry artifacts for a variety of device orientations. These new strategies are being incorporated into the next generation of applicators. The general strategy described in this study can be applied to the design of other interventional devices intended for use with MRI. PMID- 26745919 TI - Accuracy of UTE-MRI-based patient setup for brain cancer radiation therapy. AB - PURPOSE: Radiation therapy simulations solely based on MRI have advantages compared to CT-based approaches. One feature readily available from computed tomography (CT) that would need to be reproduced with MR is the ability to compute digitally reconstructed radiographs (DRRs) for comparison against on board radiographs commonly used for patient positioning. In this study, the authors generate MR-based bone images using a single ultrashort echo time (UTE) pulse sequence and quantify their 3D and 2D image registration accuracy to CT and radiographic images for treatments in the cranium. METHODS: Seven brain cancer patients were scanned at 1.5 T using a radial UTE sequence. The sequence acquired two images at two different echo times. The two images were processed using an in house software to generate the UTE bone images. The resultant bone images were rigidly registered to simulation CT data and the registration error was determined using manually annotated landmarks as references. DRRs were created based on UTE-MRI and registered to simulated on-board images (OBIs) and actual clinical 2D oblique images from ExacTracTM. RESULTS: UTE-MRI resulted in well visualized cranial, facial, and vertebral bones that quantitatively matched the bones in the CT images with geometric measurement errors of less than 1 mm. The registration error between DRRs generated from 3D UTE-MRI and the simulated 2D OBIs or the clinical oblique x-ray images was also less than 1 mm for all patients. CONCLUSIONS: UTE-MRI-based DRRs appear to be promising for daily patient setup of brain cancer radiotherapy with kV on-board imaging. PMID- 26745921 TI - SIFT-based dense pixel tracking on 0.35 T cine-MR images acquired during image guided radiation therapy with application to gating optimization. AB - PURPOSE: To first demonstrate the viability of applying an image processing technique for tracking regions on low-contrast cine-MR images acquired during image-guided radiation therapy, and then outline a scheme that uses tracking data for optimizing gating results in a patient-specific manner. METHODS: A first generation MR-IGRT system-treating patients since January 2014-integrates a 0.35 T MR scanner into an annular gantry consisting of three independent Co-60 sources. Obtaining adequate frame rates for capturing relevant patient motion across large fields-of-view currently requires coarse in-plane spatial resolution. This study initially (1) investigate the feasibility of rapidly tracking dense pixel correspondences across single, sagittal plane images (with both moderate signal-to-noise and spatial resolution) using a matching objective for highly descriptive vectors called scale-invariant feature transform (SIFT) descriptors associated to all pixels that describe intensity gradients in local regions around each pixel. To more accurately track features, (2) harmonic analysis was then applied to all pixel trajectories within a region-of-interest across a short training period. In particular, the procedure adjusts the motion of outlying trajectories whose relative spectral power within a frequency bandwidth consistent with respiration (or another form of periodic motion) does not exceed a threshold value that is manually specified following the training period. To evaluate the tracking reliability after applying this correction, conventional metrics-including Dice similarity coefficients (DSCs), mean tracking errors (MTEs), and Hausdorff distances (HD)-were used to compare target segmentations obtained via tracking to manually delineated segmentations. Upon confirming the viability of this descriptor-based procedure for reliably tracking features, the study (3) outlines a scheme for optimizing gating parameters including relative target position and a tolerable margin about this position derived from a probability density function that is constructed using tracking results obtained just prior to treatment. RESULTS: The feasibility of applying the matching objective for SIFT descriptors toward pixel-by-pixel tracking on cine-MR acquisitions was first retrospectively demonstrated for 19 treatments (spanning various sites). Both with and without motion correction based on harmonic analysis, sub-pixel MTEs were obtained. A mean DSC value spanning all patients of 0.916 +/- 0.001 was obtained without motion correction, with DSC values exceeding 0.85 for all patients considered. While most patients show accurate tracking without motion correction, harmonic analysis does yield substantial gain in accuracy (defined using HDs) for three particularly challenging subjects. An application of tracking toward a gating optimization procedure was then demonstrated that should allow a physician to balance beam-on time and tissue sparing in a patient-specific manner by tuning several intuitive parameters. CONCLUSIONS: Tracking results show high fidelity in assessing intrafractional motion observed on cine-MR acquisitions. Incorporating harmonic analysis during a training period improves the robustness of the tracking for challenging targets. The concomitant gating optimization procedure should allow for physicians to quantitatively assess gating effectiveness quickly just prior to treatment in a patient-specific manner. PMID- 26745920 TI - An interprojection sensor fusion approach to estimate blocked projection signal in synchronized moving grid-based CBCT system. AB - PURPOSE: A preobject grid can reduce and correct scatter in cone beam computed tomography (CBCT). However, half of the signal in each projection is blocked by the grid. A synchronized moving grid (SMOG) has been proposed to acquire two complimentary projections at each gantry position and merge them into one complete projection. That approach, however, suffers from increased scanning time and the technical difficulty of accurately merging the two projections per gantry angle. Herein, the authors present a new SMOG approach which acquires a single projection per gantry angle, with complimentary grid patterns for any two adjacent projections, and use an interprojection sensor fusion (IPSF) technique to estimate the blocked signal in each projection. The method may have the additional benefit of reduced imaging dose due to the grid blocking half of the incident radiation. METHODS: The IPSF considers multiple paired observations from two adjacent gantry angles as approximations of the blocked signal and uses a weighted least square regression of these observations to finally determine the blocked signal. The method was first tested with a simulated SMOG on a head phantom. The signal to noise ratio (SNR), which represents the difference of the recovered CBCT image to the original image without the SMOG, was used to evaluate the ability of the IPSF in recovering the missing signal. The IPSF approach was then tested using a Catphan phantom on a prototype SMOG assembly installed in a bench top CBCT system. RESULTS: In the simulated SMOG experiment, the SNRs were increased from 15.1 and 12.7 dB to 35.6 and 28.9 dB comparing with a conventional interpolation method (inpainting method) for a projection and the reconstructed 3D image, respectively, suggesting that IPSF successfully recovered most of blocked signal. In the prototype SMOG experiment, the authors have successfully reconstructed a CBCT image using the IPSF-SMOG approach. The detailed geometric features in the Catphan phantom were mostly recovered according to visual evaluation. The scatter related artifacts, such as cupping artifacts, were almost completely removed. CONCLUSIONS: The IPSF-SMOG is promising in reducing scatter artifacts and improving image quality while reducing radiation dose. PMID- 26745922 TI - X-ray focal spot reconstruction by circular penumbra analysis-Application to digital radiography systems. AB - PURPOSE: The quality of a radiography system is affected by several factors, a major one being the focal spot size of the x-ray tube. In fact, the measurement of such size is recognized to be of primary importance during acceptance tests and image quality evaluations of clinical radiography systems. The most common device providing an image of the focal spot emission distribution is a pin-hole camera, which requires a high tube loading in order to produce a measurable signal. This work introduces an alternative technique to obtain an image of the focal spot, through the processing of a single radiograph of a simple test object, acquired with a suitable magnification. METHODS: The radiograph of a magnified sharp edge is a well-established method to evaluate the extension of the focal spot profile along the direction perpendicular to the edge. From a single radiograph of a circular x-ray absorber, it is possible to extract simultaneously the radial profiles of several sharp edges with different orientations. The authors propose a technique that allows to obtain an image of the focal spot through the processing of these radial profiles by means of a pseudo-CT reconstruction technique. In order to validate this technique, the reconstruction has been applied to the simulated radiographs of an ideal disk shaped absorber, generated by various simulated focal spot distributions. Furthermore, the method has been applied to the focal spot of a commercially available mammography unit. RESULTS: In the case of simulated radiographs, the results of the reconstructions have been compared to the original distributions, showing an excellent agreement for what regards both the overall distribution and the full width at half maximum measurements. In the case of the experimental test, the method allowed to obtain images of the focal spot that have been compared with the results obtained through standard techniques, namely, pin-hole camera and slit camera. CONCLUSIONS: The method was proven to be effective for simulated images and the results of the experimental test suggest that it could be considered as an alternative technique for focal spot distribution evaluation. The method offers the possibility to measure the actual focal spot size and emission distribution at the same exposure conditions as clinical routine, avoiding high tube loading as in the case of the pin-hole imaging technique. PMID- 26745923 TI - Technical Note: On the analytical proton dose evaluation in compounds and mixtures. AB - PURPOSE: By combining the physical processes occurring due to the interaction of protons with matter, analytical theories published so far have provided acceptable models for calculating depth-dose distributions in homogeneous media. As a well-defined and comprehensive theory, the formula derived by Bortfeld models the dose transferred to the target in terms of the parabolic cylinder function. The model also includes three parameters with values specified for an initial proton energy and for the target material. These parameters are obtainable through the data gathered in nuclear data tables. The analytical studies using this interesting model are therefore restricted to those materials for which the data have been provided in these tables. This study aims to find general solutions for calculation of these parameters for a compound or mixture composed of an arbitrary choice of constituent elements. METHODS: Inspired by formulas dedicated for calculating the range and the probability of undergoing nonelastic nuclear interactions for protons in desired compounds, the analytical methods for finding the three mentioned parameters are investigated. The accuracy of the methods suggested is examined through comparison of the results with those which are calculated using the data taken from nuclear data tables. By employing the calculated parameters using the derived formulas in the Bortfeld model, the dose distribution at depth in a chosen target is calculated. RESULTS: For an arbitrary selection of compounds, the predictions of the analytical depth-dose model using these parameters have been found to closely match the results employing the parameters calculated using the data reported in nuclear data tables. CONCLUSIONS: The formulas presented are general, mathematically easy to handle, and valid for almost every compound or mixture including materials of interest for proton radiotherapy purposes, making the Bortfeld model more practical and advantageous. PMID- 26745924 TI - Technical Note: Radiation properties of tissue- and water-equivalent materials formulated using the stoichiometric analysis method in charged particle therapy. AB - PURPOSE: Five tissue- and water-equivalent materials (TEMs) mimicking ICRU real tissues have been formulated using a previously established stoichiometric analysis method (SAM) to be applied in charged particle therapy. The purpose of this study was an experimental verification of the TEMs-SAM against charged particle beam measurements and for different computed tomography (CT) scanners. The potential of the TEMs-SAM to be employed in the dosimetry was also investigated. METHODS: Experimental verification with three CT scanners was carried out to validate the calculated Hounsfield units (HUs) of the TEMs. Water equivalent path lengths (WEPLs) of the TEMs for proton (106.8 MeV/u), helium (107.93 MeV/u), and carbon (200.3 MeV/u) ions were measured to be compared with the computed relative stopping powers. HU calibration curves were also generated. RESULTS: Differences between the measured HUs of the TEMs and the calculated HUs of the ICRU real tissues for all CT scanners were smaller than 4 HU except for the skeletal tissues which deviated up to 21 HU. The measured WEPLs verified the calculated WEPLs of the TEMs (maximum deviation was 0.17 mm) and were in good agreement with the calculated WEPLs of the ICRU real tissues (maximum deviation was 0.23 mm). Moreover, the relative stopping powers converted from the measured WEPLs differed less than 0.8% and 1.3% from the calculated values of the SAM and the ICRU, respectively. Regarding the relative nonelastic cross section per unit of volume for 200 MeV protons, the ICRU real tissues were generally well represented by the TEMs except for adipose which differed 3.8%. Further, the HU calibration curves yielded the mean and the standard deviation of the errors not larger than 0.5% and 1.9%, respectively. CONCLUSIONS: The results of this investigation implied the potential of the TEMs formulated using the SAM to be employed for both, beam dosimetry and HU calibration in charged particle therapy. PMID- 26745925 TI - Commissioning optically stimulated luminescence in vivo dosimeters for fast neutron therapy. AB - PURPOSE: Clinical in vivo dosimeters intended for use with photon and electron therapies have not been utilized for fast neutron therapy because they are highly susceptible to neutron damage. The objective of this work was to determine if a commercial optically stimulated luminescence (OSL) in vivo dosimetry system could be adapted for use in fast neutron therapy. METHODS: A 50.5 MeV fast neutron beam generated by a clinical neutron therapy cyclotron was used to irradiate carbon doped aluminum oxide (Al2O3:C) optically simulated luminescence dosimeters (OSLDs) in a solid water phantom under standard calibration conditions, 150 cm SAD, 1.7 cm depth, and 10.3 * 10.0 cm field size. OSLD fading and electron trap depletion studies were performed with the OSLDs irradiated with 20 and 50 cGy and monitored over a 24-h period to determine the optimal time for reading the dosimeters during calibration. Four OSLDs per group were calibrated over a clinical dose range of 0-150 cGy. RESULTS: OSLD measurement uncertainties were lowered to within +/-2%-3% of the expected dose by minimizing the effect of transient fading that occurs with neutron irradiation and maintaining individual calibration factors for each dosimeter. Dose dependent luminescence fading extended beyond the manufacturer's recommended 10 min period for irradiation with photon or electron beams. To minimize OSL variances caused by inconsistent fading among dosimeters, the observed optimal time for reading the OSLDs postirradiation was between 30 and 90 min. No field size, wedge factor, or gantry angle dependencies were observed in the OSLDs irradiated by the studied fast neutron beam. CONCLUSIONS: Measurements demonstrated that uncertainties less than +/-3% were attainable in OSLDs irradiated with fast neutrons under clinical conditions. Accuracy and precision comparable to clinical OSL measurements observed with photons can be achieved by maintaining individual OSLD calibration factors and minimizing transient fading effects. PMID- 26745926 TI - Automated selection of the optimal cardiac phase for single-beat coronary CT angiography reconstruction. AB - PURPOSE: Reconstructing a low-motion cardiac phase is expected to improve coronary artery visualization in coronary computed tomography angiography (CCTA) exams. This study developed an automated algorithm for selecting the optimal cardiac phase for CCTA reconstruction. The algorithm uses prospectively gated, single-beat, multiphase data made possible by wide cone-beam imaging. The proposed algorithm differs from previous approaches because the optimal phase is identified based on vessel image quality (IQ) directly, compared to previous approaches that included motion estimation and interphase processing. Because there is no processing of interphase information, the algorithm can be applied to any sampling of image phases, making it suited for prospectively gated studies where only a subset of phases are available. METHODS: An automated algorithm was developed to select the optimal phase based on quantitative IQ metrics. For each reconstructed slice at each reconstructed phase, an image quality metric was calculated based on measures of circularity and edge strength of through-plane vessels. The image quality metric was aggregated across slices, while a metric of vessel-location consistency was used to ignore slices that did not contain through-plane vessels. The algorithm performance was evaluated using two observer studies. Fourteen single-beat cardiac CT exams (Revolution CT, GE Healthcare, Chalfont St. Giles, UK) reconstructed at 2% intervals were evaluated for best systolic (1), diastolic (6), or systolic and diastolic phases (7) by three readers and the algorithm. Pairwise inter-reader and reader-algorithm agreement was evaluated using the mean absolute difference (MAD) and concordance correlation coefficient (CCC) between the reader and algorithm-selected phases. A reader-consensus best phase was determined and compared to the algorithm selected phase. In cases where the algorithm and consensus best phases differed by more than 2%, IQ was scored by three readers using a five point Likert scale. RESULTS: There was no statistically significant difference between inter-reader and reader algorithm agreement for either MAD or CCC metrics (p > 0.1). The algorithm phase was within 2% of the consensus phase in 15/21 of cases. The average absolute difference between consensus and algorithm best phases was 2.29% +/- 2.47%, with a maximum difference of 8%. Average image quality scores for the algorithm chosen best phase were 4.01 +/- 0.65 overall, 3.33 +/- 1.27 for right coronary artery (RCA), 4.50 +/- 0.35 for left anterior descending (LAD) artery, and 4.50 +/- 0.35 for left circumflex artery (LCX). Average image quality scores for the consensus best phase were 4.11 +/- 0.54 overall, 3.44 +/- 1.03 for RCA, 4.39 +/- 0.39 for LAD, and 4.50 +/- 0.18 for LCX. There was no statistically significant difference (p > 0.1) between the image quality scores of the algorithm phase and the consensus phase. CONCLUSIONS: The proposed algorithm was statistically equivalent to a reader in selecting an optimal cardiac phase for CCTA exams. When reader and algorithm phases differed by >2%, image quality as rated by blinded readers was statistically equivalent. By detecting the optimal phase for CCTA reconstruction, the proposed algorithm is expected to improve coronary artery visualization in CCTA exams. PMID- 26745927 TI - Automated segmentation of dental CBCT image with prior-guided sequential random forests. AB - PURPOSE: Cone-beam computed tomography (CBCT) is an increasingly utilized imaging modality for the diagnosis and treatment planning of the patients with craniomaxillofacial (CMF) deformities. Accurate segmentation of CBCT image is an essential step to generate 3D models for the diagnosis and treatment planning of the patients with CMF deformities. However, due to the image artifacts caused by beam hardening, imaging noise, inhomogeneity, truncation, and maximal intercuspation, it is difficult to segment the CBCT. METHODS: In this paper, the authors present a new automatic segmentation method to address these problems. Specifically, the authors first employ a majority voting method to estimate the initial segmentation probability maps of both mandible and maxilla based on multiple aligned expert-segmented CBCT images. These probability maps provide an important prior guidance for CBCT segmentation. The authors then extract both the appearance features from CBCTs and the context features from the initial probability maps to train the first-layer of random forest classifier that can select discriminative features for segmentation. Based on the first-layer of trained classifier, the probability maps are updated, which will be employed to further train the next layer of random forest classifier. By iteratively training the subsequent random forest classifier using both the original CBCT features and the updated segmentation probability maps, a sequence of classifiers can be derived for accurate segmentation of CBCT images. RESULTS: Segmentation results on CBCTs of 30 subjects were both quantitatively and qualitatively validated based on manually labeled ground truth. The average Dice ratios of mandible and maxilla by the authors' method were 0.94 and 0.91, respectively, which are significantly better than the state-of-the-art method based on sparse representation (p-value < 0.001). CONCLUSIONS: The authors have developed and validated a novel fully automated method for CBCT segmentation. PMID- 26745929 TI - Experimental evaluation of neutron dose in radiotherapy patients: Which dose? AB - PURPOSE: The evaluation of peripheral dose has become a relevant issue recently, in particular, the contribution of secondary neutrons. However, after the revision of the Recommendations of the International Commission on Radiological Protection, there has been a lack of experimental procedure for its evaluation. Specifically, the problem comes from the replacement of organ dose equivalent by the organ-equivalent dose, being the latter "immeasurable" by definition. Therefore, dose equivalent has to be still used although it needs the calculation of the radiation quality factor Q, which depends on the unrestricted linear energy transfer, for the specific neutron irradiation conditions. On the other hand, equivalent dose is computed through the radiation weighting factor wR, which can be easily calculated using the continuous function provided by the recommendations. The aim of the paper is to compare the dose equivalent evaluated following the definition, that is, using Q, with the values obtained by replacing the quality factor with wR. METHODS: Dose equivalents were estimated in selected points inside a phantom. Two types of medical environments were chosen for the irradiations: a photon- and a proton-therapy facility. For the estimation of dose equivalent, a poly-allyl-diglicol-carbonate-based neutron dosimeter was used for neutron fluence measurements and, additionally, Monte Carlo simulations were performed to obtain the energy spectrum of the fluence in each point. RESULTS: The main contribution to dose equivalent comes from neutrons with energy higher than 0.1 MeV, even when they represent the smallest contribution in fluence. For this range of energy, the radiation quality factor and the radiation weighting factor are approximately equal. Then, dose equivalents evaluated using both factors are compatible, with differences below 12%. CONCLUSIONS: Quality factor can be replaced by the radiation weighting factor in the evaluation of dose equivalent in radiotherapy environments simplifying the practical procedure. PMID- 26745928 TI - A robust noise reduction technique for time resolved CT. AB - PURPOSE: To develop a noise reduction method for time resolved CT data, especially those with significant patient motion. METHODS: PArtial TEmporal Nonlocal (PATEN) means is a technique that uses the redundant information in time resolved CT data to achieve noise reduction. In this method, partial temporal profiles are used to determine the similarity (or weight) between pixels, and the similarity search makes use of both spatial and temporal information, providing robustness to patient motion. The performance of the PATEN filter was qualitatively and quantitatively evaluated with nine cardiac CT patient data sets and five CT brain perfusion patient data sets. In cardiac CT, PATEN was applied to reduce noise primarily in the reduced-dose phases created with electrocardiographic (ECG) pulsing. CT number accuracy and noise reduction were evaluated in both full-dose phases and reduced-dose phases between filtered backprojection images and PATEN filtered images. In CT brain perfusion, simulated quarter dose data were obtained by adding noise to the raw data of a routine dose scan. PATEN was applied to the simulated low-dose images. Image noise, time intensity profile accuracy, and perfusion parameter maps were compared among low dose, low-dose+PATEN filter, and full-dose images. The noise reduction performance of PATEN was compared to a previously proposed noise reduction method, time-intensity profile similarity (TIPS) bilateral filtering. RESULTS: In 4D cardiac CT, after PATEN filtering, the image noise in the reduced-dose phases was greatly reduced, making anatomical structures easier to identify. The mean decreases in noise values between the original and PATEN images were 11.0% and 53.8% for the full and reduced-dose phases of the cardiac cycle, respectively. TIPS could not achieve effective noise reduction. In CT brain perfusion, PATEN achieved a 55.8%-66.3% decrease in image noise in the low-dose images. The contrast to noise ratio in the axial images was increased and was comparable to the full-dose images. Differentiation of anatomical structure in the PATEN images and corresponding quantitative perfusion parameter maps were preferred by two neuroradiologists compared to the simulated low-dose and TIPS results. The mean perfusion parameters calculated from the PATEN images agreed with those determined from full-dose data to within 12% and 20% for normal and diseased regions. CONCLUSIONS: In ECG-gated cardiac CT, where the dose had already been reduced by a factor of 5 in the reduced-dose phases, PATEN achieved a 53.8% noise reduction, which decreased the noise level in the reduced-dose phases close to that of the full-dose phases. In CT brain perfusion, a fourfold dose reduction was demonstrated to be achievable by PATEN filtering, which improved quantitative perfusion analysis. PATEN can be used to effectively reduce image noise to improve image quality, even when significant motion occurred between temporal samples. PMID- 26745931 TI - Knowledge-based prediction of three-dimensional dose distributions for external beam radiotherapy. AB - PURPOSE: To demonstrate knowledge-based 3D dose prediction for external beam radiotherapy. METHODS: Using previously treated plans as training data, an artificial neural network (ANN) was trained to predict a dose matrix based on patient-specific geometric and planning parameters, such as the closest distance (r) to planning target volume (PTV) and organ-at-risks (OARs). Twenty-three prostate and 43 stereotactic radiosurgery/radiotherapy (SRS/SRT) cases with at least one nearby OAR were studied. All were planned with volumetric-modulated arc therapy to prescription doses of 81 Gy for prostate and 12-30 Gy for SRS. Using these clinically approved plans, ANNs were trained to predict dose matrix and the predictive accuracy was evaluated using the dose difference between the clinical plan and prediction, deltaD = Dclin - Dpred. The mean (), standard deviation (sigmadeltaDr ), and their interquartile range (IQR) for the training plans were evaluated at a 2-3 mm interval from the PTV boundary (rPTV) to assess prediction bias and precision. Initially, unfiltered models which were trained using all plans in the cohorts were created for each treatment site. The models predict approximately the average quality of OAR sparing. Emphasizing a subset of plans that exhibited superior to the average OAR sparing during training, refined models were created to predict high-quality rectum sparing for prostate and brainstem sparing for SRS. Using the refined model, potentially suboptimal plans were identified where the model predicted further sparing of the OARs was achievable. Replans were performed to test if the OAR sparing could be improved as predicted by the model. RESULTS: The refined models demonstrated highly accurate dose distribution prediction. For prostate cases, the average prediction bias for all voxels irrespective of organ delineation ranged from -1% to 0% with maximum IQR of 3% over rPTV ? [ - 6, 30] mm. The average prediction error was less than 10% for the same rPTV range. For SRS cases, the average prediction bias ranged from -0.7% to 1.5% with maximum IQR of 5% over rPTV ? [ - 4, 32] mm. The average prediction error was less than 8%. Four potentially suboptimal plans were identified for each site and subsequent replanning demonstrated improved sparing of rectum and brainstem. CONCLUSIONS: The study demonstrates highly accurate knowledge-based 3D dose predictions for radiotherapy plans. PMID- 26745930 TI - Dose enhancement in radiotherapy of small lung tumors using inline magnetic fields: A Monte Carlo based planning study. AB - PURPOSE: To report on significant dose enhancement effects caused by magnetic fields aligned parallel to 6 MV photon beam radiotherapy of small lung tumors. Findings are applicable to future inline MRI-guided radiotherapy systems. METHODS: A total of eight clinical lung tumor cases were recalculated using Monte Carlo methods, and external magnetic fields of 0.5, 1.0, and 3 T were included to observe the impact on dose to the planning target volume (PTV) and gross tumor volume (GTV). Three plans were 6 MV 3D-CRT plans while 6 were 6 MV IMRT. The GTV's ranged from 0.8 to 16 cm(3), while the PTV's ranged from 1 to 59 cm(3). In addition, the dose changes in a 30 cm diameter cylindrical water phantom were investigated for small beams. The central 20 cm of this phantom contained either water or lung density insert. RESULTS: For single beams, an inline magnetic field of 1 T has a small impact in lung dose distributions by reducing the lateral scatter of secondary electrons, resulting in a small dose increase along the beam. Superposition of multiple small beams leads to significant dose enhancements. Clinically, this process occurs in the lung tissue typically surrounding the GTV, resulting in increases to the D98% (PTV). Two isolated tumors with very small PTVs (3 and 6 cm(3)) showed increases in D98% of 23% and 22%. Larger PTVs of 13, 26, and 59 cm(3) had increases of 9%, 6%, and 4%, describing a natural fall-off in enhancement with increasing PTV size. However, three PTVs bounded to the lung wall showed no significant increase, due to lack of dose enhancement in the denser PTV volume. In general, at 0.5 T, the GTV mean dose enhancement is around 60% lower than that at 1 T, while at 3 T, it is 5%-60% higher than 1 T. CONCLUSIONS: Monte Carlo methods have described significant and predictable dose enhancement effects in small lung tumor plans for 6 MV radiotherapy when an external inline magnetic field is included. Results of this study indicate that future clinical inline MRI-guided radiotherapy systems will be able to deliver a dosimetrically superior treatment to small (PTV < 15 cm(3)), isolated lung tumors over non-MRI-Linac systems. This increased efficacy coincides with the reimbursement in the United States of lung CT screening and the likely rapid growth in the number of patients with small lung tumors to be treated with radiotherapy. PMID- 26745932 TI - Improved accuracy of quantitative parameter estimates in dynamic contrast enhanced CT study with low temporal resolution. AB - PURPOSE: A previously proposed method to reduce radiation dose to patient in dynamic contrast-enhanced (DCE) CT is enhanced by principal component analysis (PCA) filtering which improves the signal-to-noise ratio (SNR) of time concentration curves in the DCE-CT study. The efficacy of the combined method to maintain the accuracy of kinetic parameter estimates at low temporal resolution is investigated with pixel-by-pixel kinetic analysis of DCE-CT data. METHODS: The method is based on DCE-CT scanning performed with low temporal resolution to reduce the radiation dose to the patient. The arterial input function (AIF) with high temporal resolution can be generated with a coarsely sampled AIF through a previously published method of AIF estimation. To increase the SNR of time concentration curves (tissue curves), first, a region-of-interest is segmented into squares composed of 3 * 3 pixels in size. Subsequently, the PCA filtering combined with a fraction of residual information criterion is applied to all the segmented squares for further improvement of their SNRs. The proposed method was applied to each DCE-CT data set of a cohort of 14 patients at varying levels of down-sampling. The kinetic analyses using the modified Tofts' model and singular value decomposition method, then, were carried out for each of the down-sampling schemes between the intervals from 2 to 15 s. The results were compared with analyses done with the measured data in high temporal resolution (i.e., original scanning frequency) as the reference. RESULTS: The patients' AIFs were estimated to high accuracy based on the 11 orthonormal bases of arterial impulse responses established in the previous paper. In addition, noise in the images was effectively reduced by using five principal components of the tissue curves for filtering. Kinetic analyses using the proposed method showed superior results compared to those with down-sampling alone; they were able to maintain the accuracy in the quantitative histogram parameters of volume transfer constant [standard deviation (SD), 98th percentile, and range], rate constant (SD), blood volume fraction (mean, SD, 98th percentile, and range), and blood flow (mean, SD, median, 98th percentile, and range) for sampling intervals between 10 and 15 s. CONCLUSIONS: The proposed method of PCA filtering combined with the AIF estimation technique allows low frequency scanning for DCE-CT study to reduce patient radiation dose. The results indicate that the method is useful in pixel by-pixel kinetic analysis of DCE-CT data for patients with cervical cancer. PMID- 26745933 TI - Medical image segmentation via atlases and fuzzy object models: Improving efficacy through optimum object search and fewer models. AB - PURPOSE: Statistical object shape models (SOSMs), known as probabilistic atlases, are popular in medical image segmentation. They register an image into the atlas coordinate system, such that a desired object can be delineated from the constraints of its shape model. While this strategy facilitates segmenting objects with even weak-boundary contrast, it tends to require more models per object to cope with possible registration errors. Fuzzy object shape models (FOSMs) gain substantial speed by avoiding image registration and placing more relaxed model constraints with optimum object search. However, they tend to require stronger object boundary contrast for effective delineation. In this work, the authors show that optimum object search, the essential underpinning of FOSMs, can improve segmentation efficacy of SOSMs with fewer models per object. METHODS: For the sake of efficiency, the authors use three atlases per object (SOSM-3) as baseline for segmentation based on the best match with posterior probability maps. A novel strategy for SOSM with a single atlas and optimum object search (SOSM-S) is presented. When registering an image to the atlas system, one should expect that the object's boundary falls within the uncertainty region of the model-region wherein voxels show probabilities greater than 0 and less than 1 to be in the object. Since registration may fail, SOSM-S translates the atlas locally and, at each location, delineates and scores a candidate object in the uncertainty region. Segmentation is defined by the candidate with the highest score. The presented FOSM also uses a single model per object, but model construction uses only shape translations, building a fuzzy object model with larger uncertainty region. Optimum object search requires estimation of the object's location and/or optimization algorithms to speed-up segmentation. RESULTS: The authors evaluate SOSM-3, SOSM-S, and FOSM on 75 CT-images of the thorax and 35 MR T1-weighted images of the brain, with nine objects of interest. The results show that SOSM-S and FOSM can segment seven out of the nine objects with higher accuracy than SOSM-3, according to the average symmetric surface distance and statistical test. SOSM-S was consistently more accurate than FOSM, FOSM being 2-3 orders of magnitude faster than SOSM-S and SOSM-3 for model construction and hundreds of times faster than them for segmentation. CONCLUSIONS: Although multiple models per object can usually improve segmentation efficacy, the optimum object search has shown to reduce the number of required models. The efficiency gain of FOSM over SOSM-S motivates its use for interactive applications and studies with large image data sets. FOSM and SOSM impose different degrees of shape constraints from the model, making one approach more suitable than the other, depending on contrast. This suggests the use of hybrid models that can take advantage from the strengths of fuzzy and statistical models. PMID- 26745934 TI - Small field detector correction factors kQclin,Qmsr (fclin,fmsr) for silicon diode and diamond detectors with circular 6 MV fields derived using both empirical and numerical methods. AB - PURPOSE: The use of radiotherapy fields smaller than 3 cm in diameter has resulted in the need for accurate detector correction factors for small field dosimetry. However, published factors do not always agree and errors introduced by biased reference detectors, inaccurate Monte Carlo models, or experimental errors can be difficult to distinguish. The aim of this study was to provide a robust set of detector-correction factors for a range of detectors using numerical, empirical, and semiempirical techniques under the same conditions and to examine the consistency of these factors between techniques. METHODS: Empirical detector correction factors were derived based on small field output factor measurements for circular field sizes from 3.1 to 0.3 cm in diameter performed with a 6 MV beam. A PTW 60019 microDiamond detector was used as the reference dosimeter. Numerical detector correction factors for the same fields were derived based on calculations from a geant4 Monte Carlo model of the detectors and the Linac treatment head. Semiempirical detector correction factors were derived from the empirical output factors and the numerical dose-to-water calculations. RESULTS: The PTW 60019 microDiamond was found to over-respond at small field sizes resulting in a bias in the empirical detector correction factors. The over-response was similar in magnitude to that of the unshielded diode. Good agreement was generally found between semiempirical and numerical detector correction factors except for the PTW 60016 Diode P, where the numerical values showed a greater over-response than the semiempirical values by a factor of 3.7% for a 1.1 cm diameter field and higher for smaller fields. CONCLUSIONS: Detector correction factors based solely on empirical measurement or numerical calculation are subject to potential bias. A semiempirical approach, combining both empirical and numerical data, provided the most reliable results. PMID- 26745935 TI - Low drive field amplitude for improved image resolution in magnetic particle imaging. AB - PURPOSE: Magnetic particle imaging (MPI) is a new imaging technology that directly detects superparamagnetic iron oxide nanoparticles. The technique has potential medical applications in angiography, cell tracking, and cancer detection. In this paper, the authors explore how nanoparticle relaxation affects image resolution. Historically, researchers have analyzed nanoparticle behavior by studying the time constant of the nanoparticle physical rotation. In contrast, in this paper, the authors focus instead on how the time constant of nanoparticle rotation affects the final image resolution, and this reveals nonobvious conclusions for tailoring MPI imaging parameters for optimal spatial resolution. METHODS: The authors first extend x-space systems theory to include nanoparticle relaxation. The authors then measure the spatial resolution and relative signal levels in an MPI relaxometer and a 3D MPI imager at multiple drive field amplitudes and frequencies. Finally, these image measurements are used to estimate relaxation times and nanoparticle phase lags. RESULTS: The authors demonstrate that spatial resolution, as measured by full-width at half-maximum, improves at lower drive field amplitudes. The authors further determine that relaxation in MPI can be approximated as a frequency-independent phase lag. These results enable the authors to accurately predict MPI resolution and sensitivity across a wide range of drive field amplitudes and frequencies. CONCLUSIONS: To balance resolution, signal-to-noise ratio, specific absorption rate, and magnetostimulation requirements, the drive field can be a low amplitude and high frequency. Continued research into how the MPI drive field affects relaxation and its adverse effects will be crucial for developing new nanoparticles tailored to the unique physics of MPI. Moreover, this theory informs researchers how to design scanning sequences to minimize relaxation-induced blurring for better spatial resolution or to exploit relaxation-induced blurring for MPI with molecular contrast. PMID- 26745937 TI - Limited-angle effect compensation for respiratory binned cardiac SPECT. AB - PURPOSE: In cardiac single photon emission computed tomography (SPECT), respiratory-binned study is used to combat the motion blur associated with respiratory motion. However, owing to the variability in respiratory patterns during data acquisition, the acquired data counts can vary significantly both among respiratory bins and among projection angles within individual bins. If not properly accounted for, such variation could lead to artifacts similar to limited angle effect in image reconstruction. In this work, the authors aim to investigate several reconstruction strategies for compensating the limited-angle effect in respiratory binned data for the purpose of reducing the image artifacts. METHODS: The authors first consider a model based correction approach, in which the variation in acquisition time is directly incorporated into the imaging model, such that the data statistics are accurately described among both the projection angles and respiratory bins. Afterward, the authors consider an approximation approach, in which the acquired data are rescaled to accommodate the variation in acquisition time among different projection angles while the imaging model is kept unchanged. In addition, the authors also consider the use of a smoothing prior in reconstruction for suppressing the artifacts associated with limited-angle effect. In our evaluation study, the authors first used Monte Carlo simulated imaging with 4D NCAT phantom wherein the ground truth is known for quantitative comparison. The authors evaluated the accuracy of the reconstructed myocardium using a number of metrics, including regional and overall accuracy of the myocardium, uniformity and spatial resolution of the left ventricle (LV) wall, and detectability of perfusion defect using a channelized Hotelling observer. As a preliminary demonstration, the authors also tested the different approaches on five sets of clinical acquisitions. RESULTS: The quantitative evaluation results show that the three compensation methods could all, but to different extents, reduce the reconstruction artifacts over no compensation. In particular, the model based approach reduced the mean-squared error of the reconstructed myocardium by as much as 40%. Compared to the approach of data rescaling, the model based approach further improved both the overall and regional accuracy of the myocardium; it also further improved the lesion detectability and the uniformity of the LV wall. When ML reconstruction was used, the model based approach was notably more effective for improving the LV wall; when MAP reconstruction was used, the smoothing prior could reduce the noise level and artifacts with little or no increase in bias, but at the cost of a slight resolution loss of the LV wall. The improvements in image quality by the different compensation methods were also observed in the clinical acquisitions. CONCLUSIONS: Compensating for the uneven distribution of acquisition time among both projection angles and respiratory bins can effectively reduce the limited angle artifacts in respiratory-binned cardiac SPECT reconstruction. Direct incorporation of the time variation into the imaging model together with a smoothing prior in reconstruction can lead to the most improvement in the accuracy of the reconstructed myocardium. PMID- 26745938 TI - Temporal regularization of ultrasound-based liver motion estimation for image guided radiation therapy. AB - PURPOSE: Ultrasound-based motion estimation is an expanding subfield of image guided radiation therapy. Although ultrasound can detect tissue motion that is a fraction of a millimeter, its accuracy is variable. For controlling linear accelerator tracking and gating, ultrasound motion estimates must remain highly accurate throughout the imaging sequence. This study presents a temporal regularization method for correlation-based template matching which aims to improve the accuracy of motion estimates. METHODS: Liver ultrasound sequences (15 23 Hz imaging rate, 2.5-5.5 min length) from ten healthy volunteers under free breathing were used. Anatomical features (blood vessels) in each sequence were manually annotated for comparison with normalized cross-correlation based template matching. Five sequences from a Siemens AcusonTM scanner were used for algorithm development (training set). Results from incremental tracking (IT) were compared with a temporal regularization method, which included a highly specific similarity metric and state observer, known as the alpha-beta filter/similarity threshold (ABST). A further five sequences from an Elekta ClarityTM system were used for validation, without alteration of the tracking algorithm (validation set). RESULTS: Overall, the ABST method produced marked improvements in vessel tracking accuracy. For the training set, the mean and 95th percentile (95%) errors (defined as the difference from manual annotations) were 1.6 and 1.4 mm, respectively (compared to 6.2 and 9.1 mm, respectively, for IT). For each sequence, the use of the state observer leads to improvement in the 95% error. For the validation set, the mean and 95% errors for the ABST method were 0.8 and 1.5 mm, respectively. CONCLUSIONS: Ultrasound-based motion estimation has potential to monitor liver translation over long time periods with high accuracy. Nonrigid motion (strain) and the quality of the ultrasound data are likely to have an impact on tracking performance. A future study will investigate spatial uniformity of motion and its effect on the motion estimation errors. PMID- 26745936 TI - Low Z target switching to increase tumor endothelial cell dose enhancement during gold nanoparticle-aided radiation therapy. AB - PURPOSE: Previous studies have introduced gold nanoparticles as vascular disrupting agents during radiation therapy. Crucial to this concept is the low energy photon content of the therapy radiation beam. The authors introduce a new mode of delivery including a linear accelerator target that can toggle between low Z and high Z targets during beam delivery. In this study, the authors examine the potential increase in tumor blood vessel endothelial cell radiation dose enhancement with the low Z target. METHODS: The authors use Monte Carlo methods to simulate delivery of three different clinical photon beams: (1) a 6 MV standard (Cu/W) beam, (2) a 6 MV flattening filter free (Cu/W), and (3) a 6 MV (carbon) beam. The photon energy spectra for each scenario are generated for depths in tissue-equivalent material: 2, 10, and 20 cm. The endothelial dose enhancement for each target and depth is calculated using a previously published analytic method. RESULTS: It is found that the carbon target increases the proportion of low energy (<150 keV) photons at 10 cm depth to 28% from 8% for the 6 MV standard (Cu/W) beam. This nearly quadrupling of the low energy photon content incident on a gold nanoparticle results in 7.7 times the endothelial dose enhancement as a 6 MV standard (Cu/W) beam at this depth. Increased surface dose from the low Z target can be mitigated by well-spaced beam arrangements. CONCLUSIONS: By using the fast-switching target, one can modulate the photon beam during delivery, producing a customized photon energy spectrum for each specific situation. PMID- 26745939 TI - Fast leaf-fitting with generalized underdose/overdose constraints for real-time MLC tracking. AB - PURPOSE: Real-time multileaf collimator (MLC) tracking is a promising approach to the management of intrafractional tumor motion during thoracic and abdominal radiotherapy. MLC tracking is typically performed in two steps: transforming a planned MLC aperture in response to patient motion and refitting the leaves to the newly generated aperture. One of the challenges of this approach is the inability to faithfully reproduce the desired motion-adapted aperture. This work presents an optimization-based framework with which to solve this leaf-fitting problem in real-time. METHODS: This optimization framework is designed to facilitate the determination of leaf positions in real-time while accounting for the trade-off between coverage of the PTV and avoidance of organs at risk (OARs). Derived within this framework, an algorithm is presented that can account for general linear transformations of the planned MLC aperture, particularly 3D translations and in-plane rotations. This algorithm, together with algorithms presented in Sawant et al. ["Management of three-dimensional intrafraction motion through real-time DMLC tracking," Med. Phys. 35, 2050-2061 (2008)] and Ruan and Keall [Presented at the 2011 IEEE Power Engineering and Automation Conference (PEAM) (2011) (unpublished)], was applied to apertures derived from eight lung intensity modulated radiotherapy plans subjected to six-degree-of-freedom motion traces acquired from lung cancer patients using the kilovoltage intrafraction monitoring system developed at the University of Sydney. A quality-of-fit metric was defined, and each algorithm was evaluated in terms of quality-of-fit and computation time. RESULTS: This algorithm is shown to perform leaf-fittings of apertures, each with 80 leaf pairs, in 0.226 ms on average as compared to 0.082 and 64.2 ms for the algorithms of Sawant et al., Ruan, and Keall, respectively. The algorithm shows approximately 12% improvement in quality-of-fit over the Sawant et al. approach, while performing comparably to Ruan and Keall. CONCLUSIONS: This work improves upon the quality of the Sawant et al. approach, but does so without sacrificing run-time performance. In addition, using this framework allows for complex leaf-fitting strategies that can be used to account for PTV/OAR trade-off during real-time MLC tracking. PMID- 26745940 TI - Accurate assessment and prediction of noise in clinical CT images. AB - PURPOSE: The objectives of this study were (a) to devise a technique for measuring quantum noise in clinical body computed tomography (CT) images and (b) to develop a model for predicting that noise with high accuracy. METHODS: The study included 83 clinical image sets at two dose levels (clinical and 50% reduced dose levels). The quantum noise in clinical images was measured by subtracting sequential slices and filtering out edges. Noise was then measured in the resultant uniform area. The noise measurement technique was validated using 17 clinical image cases and a turkey phantom. With a validated method to measure noise in clinical images, this noise was predicted by establishing the correlation between water-equivalent diameter (Dw) and noise in a variable-sized phantom and ascribing a noise level to the patient based on Dw estimated from CT image. The accuracy of this prediction model was validated using 66 clinical image sets. RESULTS: The error in noise measurement was within 1.5 HU across two reconstruction algorithms. In terms of noise prediction, across the 83 clinical image sets, the average discrepancies between predicted and measured noise were 6.9% and 6.6% for adaptive statistical iterative reconstruction and filtered back projection reconstruction, respectively. CONCLUSIONS: This study proposed a practically applicable method to assess quantum noise in clinical images. The image-based measurement technique enables automatic quality control monitoring of image noise in clinical practice. Further, a phantom-based model can accurately predict quantum noise level in patient images. The prediction model can be used to quantitatively optimize individual protocol to achieve targeted noise level in clinical images. PMID- 26745942 TI - Comparison of proton therapy treatment planning for head tumors with a pencil beam algorithm on dual and single energy CT images. AB - PURPOSE: Dual energy CT (DECT) has recently been proposed as an improvement over single energy CT (SECT) for stopping power ratio (SPR) estimation for proton therapy treatment planning (TP), thereby potentially reducing range uncertainties. Published literature investigated phantoms. This study aims at performing proton therapy TP on SECT and DECT head images of the same patients and at evaluating whether the reported improved DECT SPR accuracy translates into clinically relevant range shifts in clinical head treatment scenarios. METHODS: Two phantoms were scanned at a last generation dual source DECT scanner at 90 and 150 kVp with Sn filtration. The first phantom (Gammex phantom) was used to calibrate the scanner in terms of SPR while the second served as evaluation (CIRS phantom). DECT images of five head trauma patients were used as surrogate cancer patient images for TP of proton therapy. Pencil beam algorithm based TP was performed on SECT and DECT images and the dose distributions corresponding to the optimized proton plans were calculated using a Monte Carlo (MC) simulation platform using the same patient geometry for both plans obtained from conversion of the 150 kVp images. Range shifts between the MC dose distributions from SECT and DECT plans were assessed using 2D range maps. RESULTS: SPR root mean square errors (RMSEs) for the inserts of the Gammex phantom were 1.9%, 1.8%, and 1.2% for SECT phantom calibration (SECTphantom), SECT stoichiometric calibration (SECTstoichiometric), and DECT calibration, respectively. For the CIRS phantom, these were 3.6%, 1.6%, and 1.0%. When investigating patient anatomy, group median range differences of up to -1.4% were observed for head cases when comparing SECTstoichiometric with DECT. For this calibration the 25th and 75th percentiles varied from -2% to 0% across the five patients. The group median was found to be limited to 0.5% when using SECTphantom and the 25th and 75th percentiles varied from -1% to 2%. CONCLUSIONS: Proton therapy TP using a pencil beam algorithm and DECT images was performed for the first time. Given that the DECT accuracy as evaluated by two phantoms was 1.2% and 1.0% RMSE, it is questionable whether the range differences reported here are significant. PMID- 26745941 TI - Therapeutic analysis of high-dose-rate (192)Ir vaginal cuff brachytherapy for endometrial cancer using a cylindrical target volume model and varied cancer cell distributions. AB - PURPOSE: To evaluate high-dose-rate (HDR) vaginal cuff brachytherapy (VCBT) in the treatment of endometrial cancer in a cylindrical target volume with either a varied or a constant cancer cell distributions using the linear quadratic (LQ) model. METHODS: A Monte Carlo (MC) technique was used to calculate the 3D dose distribution of HDR VCBT over a variety of cylinder diameters and treatment lengths. A treatment planning system (TPS) was used to make plans for the various cylinder diameters, treatment lengths, and prescriptions using the clinical protocol. The dwell times obtained from the TPS were fed into MC. The LQ model was used to evaluate the therapeutic outcome of two brachytherapy regimens prescribed either at 0.5 cm depth (5.5 Gy * 4 fractions) or at the vaginal mucosal surface (8.8 Gy * 4 fractions) for the treatment of endometrial cancer. An experimentally determined endometrial cancer cell distribution, which showed a varied and resembled a half-Gaussian distribution, was used in radiobiology modeling. The equivalent uniform dose (EUD) to cancer cells was calculated for each treatment scenario. The therapeutic ratio (TR) was defined by comparing VCBT with a uniform dose radiotherapy plan in term of normal cell survival at the same level of cancer cell killing. Calculations of clinical impact were run twice assuming two different types of cancer cell density distributions in the cylindrical target volume: (1) a half-Gaussian or (2) a uniform distribution. RESULTS: EUDs were weakly dependent on cylinder size, treatment length, and the prescription depth, but strongly dependent on the cancer cell distribution. TRs were strongly dependent on the cylinder size, treatment length, types of the cancer cell distributions, and the sensitivity of normal tissue. With a half Gaussian distribution of cancer cells which populated at the vaginal mucosa the most, the EUDs were between 6.9 Gy * 4 and 7.8 Gy * 4, the TRs were in the range from (5.0)(4) to (13.4)(4) for the radiosensitive normal tissue depending on the cylinder size, treatment lengths, prescription depth, and dose as well. However, for a uniform cancer cell distribution, the EUDs were between 6.3 Gy * 4 and 7.1 Gy * 4, and the TRs were found to be between (1.4)(4) and (1.7)(4). For the uniformly interspersed cancer and radio-resistant normal cells, the TRs were less than 1. The two VCBT prescription regimens were found to be equivalent in terms of EUDs and TRs. CONCLUSIONS: HDR VCBT strongly favors cylindrical target volume with the cancer cell distribution following its dosimetric trend. Assuming a half Gaussian distribution of cancer cells, the HDR VCBT provides a considerable radiobiological advantage over the external beam radiotherapy (EBRT) in terms of sparing more normal tissues while maintaining the same level of cancer cell killing. But for the uniform cancer cell distribution and radio-resistant normal tissue, the radiobiology outcome of the HDR VCBT does not show an advantage over the EBRT. This study strongly suggests that radiation therapy design should consider the cancer cell distribution inside the target volume in addition to the shape of target. PMID- 26745943 TI - Experimental evaluation of neural probe's insertion induced injury based on digital image correlation method. AB - PURPOSE: The application of neural probes in clinic has been challenged by probes' short lifetime when implanted into brain tissue. The primary goal is to develop an evaluation system for testing brain tissue injury induced by neural probe's insertion using microscope based digital image correlation method. METHODS: A brain tissue phantom made of silicone rubber with speckle pattern on its surface was fabricated. To obtain the optimal speckle pattern, mean intensity gradient parameter was used for quality assessment. The designed testing system consists of three modules: (a) load module for simulating neural electrode implantation process; (b) data acquisition module to capture micrographs of speckle pattern and to obtain reactive forces during the insertion of the probe; (c) postprocessing module for extracting tissue deformation information from the captured speckle patterns. On the basis of the evaluation system, the effects of probe wedge angle, insertion speed, and probe streamline on insertion induced tissue injury were investigated. RESULTS: The optimal quality speckle pattern can be attained by the following fabrication parameters: spin coating rate-1000 r/min, silicone rubber component A: silicone rubber component B: softener: graphite = 5 ml: 5 ml: 2 ml: 0.6 g. The probe wedge angle has a significant effect on tissue injury. Compared to wedge angle 40 degrees and 20 degrees , maximum principal strain of 60 degrees wedge angle was increased by 40.3% and 87.5%, respectively; compared with a relatively higher speed (500 MUm/s), the maximum principle strain within the tissue induced by slow insertion speed (100 MUm/s) was increased by 14.3%; insertion force required by probe with convex streamline was smaller than the force of traditional probe. Based on the experimental results, a novel neural probe that has a rounded tip covered by a biodegradable silk protein coating with convex streamline was proposed, which has both lower insertion and micromotion induced tissue injury. CONCLUSIONS: The established evaluation system has provided a simulation environment for testing brain tissue injury produced by various insertion conditions. At the same time, it eliminates the adverse effect of biological factors on tissue deformation during the experiment, improving the repeatability of measurement results. As a result, the evaluation system will provide support on novel neural probe design that can reduce the acute tissue injury during the implantation of the probe. PMID- 26745944 TI - Technical Note: Improved CT number stability across patient size using dual energy CT virtual monoenergetic imaging. AB - PURPOSE: The purpose of this study was to evaluate, over a wide range of phantom sizes, CT number stability achieved using two techniques for generating dual energy computed tomography (DECT) virtual monoenergetic images. METHODS: Water phantoms ranging in lateral diameter from 15 to 50 cm and containing a CT number test object were scanned on a DSCT scanner using both single-energy (SE) and dual energy (DE) techniques. The SE tube potentials were 70, 80, 90, 100, 110, 120, 130, 140, and 150 kV; the DE tube potential pairs were 80/140, 70/150Sn, 80/150Sn, 90/150Sn, and 100/150Sn kV (Sn denotes that the 150 kV beam was filtered with a 0.6 mm tin filter). Virtual monoenergetic images at energies ranging from 40 to 140 keV were produced from the DECT data using two algorithms, monoenergetic (mono) and monoenergetic plus (mono+). Particularly in large phantoms, water CT number errors and/or artifacts were observed; thus, datasets with water CT numbers outside +/-10 HU or with noticeable artifacts were excluded from the study. CT numbers were measured to determine CT number stability across all phantom sizes. RESULTS: Data exclusions were generally limited to cases when a SE or DE technique with a tube potential of less than 90 kV was used to scan a phantom larger than 30 cm. The 90/150Sn DE technique provided the most accurate water background over the large range of phantom sizes evaluated. Mono and mono+ provided equally improved CT number stability as a function of phantom size compared to SE; the average deviation in CT number was only 1.4% using 40 keV and 1.8% using 70 keV, while SE had an average deviation of 11.8%. CONCLUSIONS: The authors' report demonstrates, across all phantom sizes, the improvement in CT number stability achieved with mono and mono+ relative to SE. PMID- 26745945 TI - Force balancing in mammographic compression. AB - PURPOSE: In mammography, the height of the image receptor is adjusted to the patient before compressing the breast. An inadequate height setting can result in an imbalance between the forces applied by the image receptor and the paddle, causing the clamped breast to be pushed up or down relative to the body during compression. This leads to unnecessary stretching of the skin and other tissues around the breast, which can make the imaging procedure more painful for the patient. The goal of this study was to implement a method to measure and minimize the force imbalance, and to assess its feasibility as an objective and reproducible method of setting the image receptor height. METHODS: A trial was conducted consisting of 13 craniocaudal mammographic compressions on a silicone breast phantom, each with the image receptor positioned at a different height. The image receptor height was varied over a range of 12 cm. In each compression, the force exerted by the compression paddle was increased up to 140 N in steps of 10 N. In addition to the paddle force, the authors measured the force exerted by the image receptor and the reaction force exerted on the patient body by the ground. The trial was repeated 8 times, with the phantom remounted at a slightly different orientation and position between the trials. RESULTS: For a given paddle force, the obtained results showed that there is always exactly one image receptor height that leads to a balance of the forces on the breast. For the breast phantom, deviating from this specific height increased the force imbalance by 9.4 +/- 1.9 N/cm (6.7%) for 140 N paddle force, and by 7.1 +/- 1.6 N/cm (17.8%) for 40 N paddle force. The results also show that in situations where the force exerted by the image receptor is not measured, the craniocaudal force imbalance can still be determined by positioning the patient on a weighing scale and observing the changes in displayed weight during the procedure. CONCLUSIONS: In mammographic breast compression, even small changes in the image receptor height can lead to a severe imbalance of the applied forces. This may make the procedure more painful than necessary and, in case the image receptor is set too low, may lead to image quality issues and increased radiation dose due to undercompression. In practice, these effects can be reduced by monitoring the force imbalance and actively adjusting the position of the image receptor throughout the compression. PMID- 26745946 TI - A method for normalizing pathology images to improve feature extraction for quantitative pathology. AB - PURPOSE: With the advent of digital slide scanning technologies and the potential proliferation of large repositories of digital pathology images, many research studies can leverage these data for biomedical discovery and to develop clinical applications. However, quantitative analysis of digital pathology images is impeded by batch effects generated by varied staining protocols and staining conditions of pathological slides. METHODS: To overcome this problem, this paper proposes a novel, fully automated stain normalization method to reduce batch effects and thus aid research in digital pathology applications. Their method, intensity centering and histogram equalization (ICHE), normalizes a diverse set of pathology images by first scaling the centroids of the intensity histograms to a common point and then applying a modified version of contrast-limited adaptive histogram equalization. Normalization was performed on two datasets of digitized hematoxylin and eosin (H&E) slides of different tissue slices from the same lung tumor, and one immunohistochemistry dataset of digitized slides created by restaining one of the H&E datasets. RESULTS: The ICHE method was evaluated based on image intensity values, quantitative features, and the effect on downstream applications, such as a computer aided diagnosis. For comparison, three methods from the literature were reimplemented and evaluated using the same criteria. The authors found that ICHE not only improved performance compared with un-normalized images, but in most cases showed improvement compared with previous methods for correcting batch effects in the literature. CONCLUSIONS: ICHE may be a useful preprocessing step a digital pathology image processing pipeline. PMID- 26745948 TI - Computer-aided diagnosis for classifying benign versus malignant thyroid nodules based on ultrasound images: A comparison with radiologist-based assessments. AB - PURPOSE: To develop a semiautomated computer-aided diagnosis (cad) system for thyroid cancer using two-dimensional ultrasound images that can be used to yield a second opinion in the clinic to differentiate malignant and benign lesions. METHODS: A total of 118 ultrasound images that included axial and longitudinal images from patients with biopsy-confirmed malignant (n = 30) and benign (n = 29) nodules were collected. Thyroid cad software was developed to extract quantitative features from these images based on thyroid nodule segmentation in which adaptive diffusion flow for active contours was used. Various features, including histogram, intensity differences, elliptical fit, gray-level co occurrence matrixes, and gray-level run-length matrixes, were evaluated for each region imaged. Based on these imaging features, a support vector machine (SVM) classifier was used to differentiate benign and malignant nodules. Leave-one-out cross-validation with sequential forward feature selection was performed to evaluate the overall accuracy of this method. Additionally, analyses with contingency tables and receiver operating characteristic (ROC) curves were performed to compare the performance of cad with visual inspection by expert radiologists based on established gold standards. RESULTS: Most univariate features for this proposed cad system attained accuracies that ranged from 78.0% to 83.1%. When optimal SVM parameters that were established using a grid search method with features that radiologists use for visual inspection were employed, the authors could attain rates of accuracy that ranged from 72.9% to 84.7%. Using leave-one-out cross-validation results in a multivariate analysis of various features, the highest accuracy achieved using the proposed cad system was 98.3%, whereas visual inspection by radiologists reached 94.9% accuracy. To obtain the highest accuracies, "axial ratio" and "max probability" in axial images were most frequently included in the optimal feature sets for the authors' proposed cad system, while "shape" and "calcification" in longitudinal images were most frequently included in the optimal feature sets for visual inspection by radiologists. The computed areas under curves in the ROC analysis were 0.986 and 0.979 for the proposed cad system and visual inspection by radiologists, respectively; no significant difference was detected between these groups. CONCLUSIONS: The use of thyroid cad to differentiate malignant from benign lesions shows accuracy similar to that obtained via visual inspection by radiologists. Thyroid cad might be considered a viable way to generate a second opinion for radiologists in clinical practice. PMID- 26745949 TI - Estimating local noise power spectrum from a few FBP-reconstructed CT scans. AB - PURPOSE: Traditional ways to estimate 2D CT noise power spectrum (NPS) involve an ensemble average of the power spectrums of many noisy scans. When only a few scans are available, regions of interest are often extracted from different locations to obtain sufficient samples to estimate the NPS. Using image samples from different locations ignores the nonstationarity of CT noise and thus cannot accurately characterize its local properties. The purpose of this work is to develop a method to estimate local NPS using only a few fan-beam CT scans. METHODS: As a result of FBP reconstruction, the CT NPS has the same radial profile shape for all projection angles, with the magnitude varying with the noise level in the raw data measurement. This allows a 2D CT NPS to be factored into products of a 1D angular and a 1D radial function in polar coordinates. The polar separability of CT NPS greatly reduces the data requirement for estimating the NPS. The authors use this property and derive a radial NPS estimation method: in brief, the radial profile shape is estimated from a traditional NPS based on image samples extracted at multiple locations. The amplitudes are estimated by fitting the traditional local NPS to the estimated radial profile shape. The estimated radial profile shape and amplitudes are then combined to form a final estimate of the local NPS. We evaluate the accuracy of the radial NPS method and compared it to traditional NPS methods in terms of normalized mean squared error (NMSE) and signal detectability index. RESULTS: For both simulated and real CT data sets, the local NPS estimated with no more than six scans using the radial NPS method was very close to the reference NPS, according to the metrics of NMSE and detectability index. Even with only two scans, the radial NPS method was able to achieve a fairly good accuracy. Compared to those estimated using traditional NPS methods, the accuracy improvement was substantial when a few scans were available. CONCLUSIONS: The radial NPS method was shown to be accurate and efficient in estimating the local NPS of FBP-reconstructed 2D CT images. It presents strong advantages over traditional NPS methods when the number of scans is limited and can be extended to estimate the in-plane NPS of cone-beam CT and multislice helical CT scans. PMID- 26745950 TI - Energy dependent calibration of XR-QA2 radiochromic film with monochromatic and polychromatic x-ray beams. AB - PURPOSE: This work investigates the energy response and dose-response curve determinations for XR-QA2 radiochromic film dosimetry system used for synchrotron radiation work and for quality assurance in diagnostic radiology, in the range of effective energies 18-46.5 keV. METHODS: Pieces of XR-QA2 films were irradiated, in a plane transverse to the beam axis, with a monochromatic beam of energy in the range 18-40 keV at the ELETTRA synchrotron radiation facility (Trieste, Italy) and with a polychromatic beam from a laboratory x-ray tube operated at 80, 100, and 120 kV. The film calibration curve was expressed as air kerma (measured free-in-air with an ionization chamber) versus the net optical reflectance change (netDeltaR) derived from the red channel of the RGB scanned film image. Four functional relationships (rational, linear exponential, power, and logarithm) were tested to evaluate the best curve for fitting the calibration data. The adequacy of the various fitting functions was tested by using the uncertainty analysis and by assessing the average of the absolute air kerma error calculated as the difference between calculated and delivered air kerma. The sensitivity of the film was evaluated as the ratio of the change in net reflectance to the corresponding air kerma. RESULTS: The sensitivity of XR-QA2 films increased in the energy range 18-39 keV, with a maximum variation of about 170%, and decreased in the energy range 38-46.5 keV. The present results confirmed and extended previous findings by this and other groups, as regards the dose response of the radiochromic film XR-QA2 to monochromatic and polychromatic x-ray beams, respectively. CONCLUSIONS: The XR-QA2 radiochromic film response showed a strong dependence on beam energy for both monochromatic and polychromatic beams in the range of half value layer values from 0.55 to 6.1 mm Al and corresponding effective energies from 18 to 46.5 keV. In this range, the film response varied by 170%, from a minimum sensitivity of 0.0127 to a maximum sensitivity of 0.0219 at 10 mGy air kerma in air. The more suitable function for air kerma calibration of the XR-QA2 radiochromic film was the power function. A significant batch-to batch variation, up to 55%, in film response at 120 kV (46.5 keV effective energy) was observed in comparison with published data. PMID- 26745947 TI - Comparative performance evaluation of automated segmentation methods of hippocampus from magnetic resonance images of temporal lobe epilepsy patients. AB - PURPOSE: Segmentation of the hippocampus from magnetic resonance (MR) images is a key task in the evaluation of mesial temporal lobe epilepsy (mTLE) patients. Several automated algorithms have been proposed although manual segmentation remains the benchmark. Choosing a reliable algorithm is problematic since structural definition pertaining to multiple edges, missing and fuzzy boundaries, and shape changes varies among mTLE subjects. Lack of statistical references and guidance for quantifying the reliability and reproducibility of automated techniques has further detracted from automated approaches. The purpose of this study was to develop a systematic and statistical approach using a large dataset for the evaluation of automated methods and establish a method that would achieve results better approximating those attained by manual tracing in the epileptogenic hippocampus. METHODS: A template database of 195 (81 males, 114 females; age range 32-67 yr, mean 49.16 yr) MR images of mTLE patients was used in this study. Hippocampal segmentation was accomplished manually and by two well known tools (FreeSurfer and hammer) and two previously published methods developed at their institution [Automatic brain structure segmentation (ABSS) and LocalInfo]. To establish which method was better performing for mTLE cases, several voxel-based, distance-based, and volume-based performance metrics were considered. Statistical validations of the results using automated techniques were compared with the results of benchmark manual segmentation. Extracted metrics were analyzed to find the method that provided a more similar result relative to the benchmark. RESULTS: Among the four automated methods, ABSS generated the most accurate results. For this method, the Dice coefficient was 5.13%, 14.10%, and 16.67% higher, Hausdorff was 22.65%, 86.73%, and 69.58% lower, precision was 4.94%, -4.94%, and 12.35% higher, and the root mean square (RMS) was 19.05%, 61.90%, and 65.08% lower than LocalInfo, FreeSurfer, and hammer, respectively. The Bland-Altman similarity analysis revealed a low bias for the ABSS and LocalInfo techniques compared to the others. CONCLUSIONS: The ABSS method for automated hippocampal segmentation outperformed other methods, best approximating what could be achieved by manual tracing. This study also shows that four categories of input data can cause automated segmentation methods to fail. They include incomplete studies, artifact, low signal-to-noise ratio, and inhomogeneity. Different scanner platforms and pulse sequences were considered as means by which to improve reliability of the automated methods. Other modifications were specially devised to enhance a particular method assessed in this study. PMID- 26745951 TI - A nanocomposite of Au-AgI core/shell dimer as a dual-modality contrast agent for x-ray computed tomography and photoacoustic imaging. AB - PURPOSE: To develop a core/shell nanodimer of gold (core) and silver iodine (shell) as a dual-modal contrast-enhancing agent for biomarker targeted x-ray computed tomography (CT) and photoacoustic imaging (PAI) applications. METHODS: The gold and silver iodine core/shell nanodimer (Au/AgICSD) was prepared by fusing together components of gold, silver, and iodine. The physicochemical properties of Au/AgICSD were then characterized using different optical and imaging techniques (e.g., HR- transmission electron microscope, scanning transmission electron microscope, x-ray photoelectron spectroscopy, energy dispersive x-ray spectroscopy, Z-potential, and UV-vis). The CT and PAI contrast enhancing effects were tested and then compared with a clinically used CT contrast agent and Au nanoparticles. To confer biocompatibility and the capability for efficient biomarker targeting, the surface of the Au/AgICSD nanodimer was modified with the amphiphilic diblock polymer and then functionalized with transferrin for targeting transferrin receptor that is overexpressed in various cancer cells. Cytotoxicity of the prepared Au/AgICSD nanodimer was also tested with both normal and cancer cell lines. RESULTS: The characterizations of prepared Au/AgI core/shell nanostructure confirmed the formation of Au/AgICSD nanodimers. Au/AgICSD nanodimer is stable in physiological conditions for in vivo applications. Au/AgICSD nanodimer exhibited higher contrast enhancement in both CT and PAI for dual-modality imaging. Moreover, transferrin functionalized Au/AgICSD nanodimer showed specific binding to the tumor cells that have a high level of expression of the transferrin receptor. CONCLUSIONS: The developed Au/AgICSD nanodimer can be used as a potential biomarker targeted dual-modal contrast agent for both or combined CT and PAI molecular imaging. PMID- 26745952 TI - A linear, separable two-parameter model for dual energy CT imaging of proton stopping power computation. AB - PURPOSE: To evaluate the accuracy and robustness of a simple, linear, separable, two-parameter model (basis vector model, BVM) in mapping proton stopping powers via dual energy computed tomography (DECT) imaging. METHODS: The BVM assumes that photon cross sections (attenuation coefficients) of unknown materials are linear combinations of the corresponding radiological quantities of dissimilar basis substances (i.e., polystyrene, CaCl2 aqueous solution, and water). The authors have extended this approach to the estimation of electron density and mean excitation energy, which are required parameters for computing proton stopping powers via the Bethe-Bloch equation. The authors compared the stopping power estimation accuracy of the BVM with that of a nonlinear, nonseparable photon cross section Torikoshi parametric fit model (VCU tPFM) as implemented by the authors and by Yang et al. ["Theoretical variance analysis of single- and dual energy computed tomography methods for calculating proton stopping power ratios of biological tissues," Phys. Med. Biol. 55, 1343-1362 (2010)]. Using an idealized monoenergetic DECT imaging model, proton ranges estimated by the BVM, VCU tPFM, and Yang tPFM were compared to International Commission on Radiation Units and Measurements (ICRU) published reference values. The robustness of the stopping power prediction accuracy of tissue composition variations was assessed for both of the BVM and VCU tPFM. The sensitivity of accuracy to CT image uncertainty was also evaluated. RESULTS: Based on the authors' idealized, error free DECT imaging model, the root-mean-square error of BVM proton stopping power estimation for 175 MeV protons relative to ICRU reference values for 34 ICRU standard tissues is 0.20%, compared to 0.23% and 0.68% for the Yang and VCU tPFM models, respectively. The range estimation errors were less than 1 mm for the BVM and Yang tPFM models, respectively. The BVM estimation accuracy is not dependent on tissue type and proton energy range. The BVM is slightly more vulnerable to CT image intensity uncertainties than the tPFM models. Both the BVM and tPFM prediction accuracies were robust to uncertainties of tissue composition and independent of the choice of reference values. This reported accuracy does not include the impacts of I-value uncertainties and imaging artifacts and may not be achievable on current clinical CT scanners. CONCLUSIONS: The proton stopping power estimation accuracy of the proposed linear, separable BVM model is comparable to or better than that of the nonseparable tPFM models proposed by other groups. In contrast to the tPFM, the BVM does not require an iterative solving for effective atomic number and electron density at every voxel; this improves the computational efficiency of DECT imaging when iterative, model-based image reconstruction algorithms are used to minimize noise and systematic imaging artifacts of CT images. PMID- 26745955 TI - A new look for Medical Physics and refocused editorial vision. PMID- 26745953 TI - Automatic anatomy recognition in whole-body PET/CT images. AB - PURPOSE: Whole-body positron emission tomography/computed tomography (PET/CT) has become a standard method of imaging patients with various disease conditions, especially cancer. Body-wide accurate quantification of disease burden in PET/CT images is important for characterizing lesions, staging disease, prognosticating patient outcome, planning treatment, and evaluating disease response to therapeutic interventions. However, body-wide anatomy recognition in PET/CT is a critical first step for accurately and automatically quantifying disease body wide, body-region-wise, and organwise. This latter process, however, has remained a challenge due to the lower quality of the anatomic information portrayed in the CT component of this imaging modality and the paucity of anatomic details in the PET component. In this paper, the authors demonstrate the adaptation of a recently developed automatic anatomy recognition (AAR) methodology [Udupa et al., "Body-wide hierarchical fuzzy modeling, recognition, and delineation of anatomy in medical images," Med. Image Anal. 18, 752-771 (2014)] to PET/CT images. Their goal was to test what level of object localization accuracy can be achieved on PET/CT compared to that achieved on diagnostic CT images. METHODS: The authors advance the AAR approach in this work in three fronts: (i) from body-region-wise treatment in the work of Udupa et al. to whole body; (ii) from the use of image intensity in optimal object recognition in the work of Udupa et al. to intensity plus object-specific texture properties, and (iii) from the intramodality model building-recognition strategy to the intermodality approach. The whole-body approach allows consideration of relationships among objects in different body regions, which was previously not possible. Consideration of object texture allows generalizing the previous optimal threshold-based fuzzy model recognition method from intensity images to any derived fuzzy membership image, and in the process, to bring performance to the level achieved on diagnostic CT and MR images in body-region-wise approaches. The intermodality approach fosters the use of already existing fuzzy models, previously created from diagnostic CT images, on PET/CT and other derived images, thus truly separating the modality independent object assembly anatomy from modality-specific tissue property portrayal in the image. RESULTS: Key ways of combining the above three basic ideas lead them to 15 different strategies for recognizing objects in PET/CT images. Utilizing 50 diagnostic CT image data sets from the thoracic and abdominal body regions and 16 whole-body PET/CT image data sets, the authors compare the recognition performance among these 15 strategies on 18 objects from the thorax, abdomen, and pelvis in object localization error and size estimation error. Particularly on texture membership images, object localization is within three voxels on whole-body low-dose CT images and 2 voxels on body-region-wise low-dose images of known true locations. Surprisingly, even on direct body-region wise PET images, localization error within 3 voxels seems possible. CONCLUSIONS: The previous body-region-wise approach can be extended to whole-body torso with similar object localization performance. Combined use of image texture and intensity property yields the best object localization accuracy. In both body region-wise and whole-body approaches, recognition performance on low-dose CT images reaches levels previously achieved on diagnostic CT images. The best object recognition strategy varies among objects; the proposed framework however allows employing a strategy that is optimal for each object. PMID- 26745956 TI - Device malfunction caused by "auto-oversensing" of transthoracic impedance measurement test pulses in a modern minute ventilation dual-chamber pacemaker. AB - Oversensing of physiologic and non-physiologic electrical signals is a relevant cause of malfunctions in subjects with CIED. Physicians taking care of CIED patients must be aware of the potential causes of oversensing and their pattern in EGMs. The present case describes an uncommon source and unique underlying root cause for oversensing in a modern dual-chamber MV rate-adaptive pacemaker. PMID- 26745957 TI - Effect of Cysteamine on Mutant ASL Proteins with Cysteine for Arginine Substitutions. AB - INTRODUCTION: Cysteamine is used to treat cystinosis via the modification of cysteine residues substituting arginine in mutant proteins. OBJECTIVES: We investigated the effect of cysteamine on mutant argininosuccinate lyase (ASL), the second most common defect in the urea cycle. METHODS: In an established mammalian expression system, 293T cell lysates were produced after transfection with all known cysteine for arginine mutations in the ASL gene (p.Arg94Cys, p.Arg95Cys, p.Arg168Cys, p.Arg379Cys, and p.Arg385Cys), allowing testing of the effect of cysteamine over 48 h in the culture medium as well as for 1 h immediately prior to the enzyme assay. RESULTS: Cysteamine at low concentrations showed no effect on 293T cell viability, ASL protein expression, or ASL activity when applied during cell culture. However, incubation of transfected cells with 0.05 mM cysteamine immediately before the enzyme assay resulted in increased ASL activity of p.Arg94Cys, p.Arg379Cys, and p.Arg385Cys by 64, 20, and 197 %, respectively, and this result was significant (p < 0.01). Cell lysates carrying p.Arg385Cys and treated with cysteamine recover enzyme activity that is similar to the untreated designed mutation p.Arg385Lys, providing circumstantial evidence for the assumed cysteamine-induced change of a cysteine to a lysine analogue. CONCLUSION: Since 12 % of all known genotypes in ASL deficiency are affected by a cysteine for arginine mutation, we conclude that the potential of cysteamine or of related substances as remedy for this disease should be investigated further. PMID- 26745958 TI - The effect of amidation on the behaviour of antimicrobial peptides. AB - Aurein 2.6-COOH and aurein 3.1-COOH were studied along with their naturally occurring C-terminally amidated analogues. Circular dichroism (CD) and molecular dynamic (MD) simulations were used to study the effects of amidation on the interaction of antimicrobial peptides (AMPs) with lipid bilayers. CD measurements and MD analysis suggested that both peptide analogues were predominantly random coil and adopted low levels of alpha-helical structure in solution (<30%) and in the presence of a lipid bilayer the peptides formed a stable alpha-helical structure. In general, amidated analogues have a greater propensity than the non amidated peptides to form a alpha-helical structure. MD simulations predicted that aurein 2.6-COOH and aurein 3.1-CHOOH destabilised lipid bilayers from 1,2 dimyristoyl-sn-glycero-3-phosphocholine and 1,2-dimyristoyl-sn-glycero-3 phosphoserine via angled bilayer penetration. They also showed that aurein 2.6 CONH2 and aurein 3.1-CONH2 formed a helix horizontal to the plane of an asymmetric interface. PMID- 26745959 TI - Comparison of flowable bulk-fill and flowable resin-based composites: an in vitro analysis. AB - OBJECTIVES: Flowable bulk-fill resin bonded composites (RBCs) are supposed to show improved abrasion resistance and fracture toughness in comparison to flowable conventional RBCs. MATERIALS AND METHODS: Specimens of eight flowable RBCs (5* flowable conventional, 3* flowable bulk-fill) were fabricated for testing relative fracture toughness (SENB), relative three-body wear, the Vickers hardness, glass transition Tg (differential scanning calorimetry; DSC) and filler mass fraction (thermal gravimetric analysis; TGA). A laboratory veneering composite was used as a reference. Fracture toughness and wear values were related to this reference. Scanning electron microscope images were evaluated for fraktographical and microstructural investigations. Statistical analyses were performed using one-way Anova, the Bonferroni post hoc test and the Pearson correlation test (alpha =0.05). RESULTS: Relative fracture toughness varied between 0.64 and 1.34 (1.00 = 1.69 MPam1/2) and relative wear rates between 1.24 and 0.55 (1.00 = 134 MUm). The Vickers hardness ranged between 14.4 and 57.2 HV. TGA showed filler fractions between 55 and 77 wt.%. Tg values varied between 67.8 and -40.9 degrees C. None of the tests identified clear differences between flowable bulk-fills or conventional flowable RBCs. The Pearson correlation coefficient (cc) showed significant correlations (cc > 0.583; p < 0.001) between relative fracture toughness and hardness or filler content. There was a significant correlation (cc = 0.757; p = 0.005) between relative wear and glass transition temperature or between filler fraction and the Vickers hardness (cc > 0.702; p < 0.001). For all filler sizes breakdown was found, where clusters and pre-polymerized particles were partly disintegrated. CONCLUSIONS: Flowable bulk fill RBCs showed no improved abrasion resistance and fracture toughness in comparison to flowable conventional RBCs. CLINICAL RELEVANCE: Differences in the properties were higher between the individual materials than between the material groups. Therefore the appropriate material selection may be essential for a clinical success. PMID- 26745961 TI - Using diffusion of innovation theory to describe perceptions of a passive positioning alarm among persons with mild dementia: a repeated interview study. AB - BACKGROUND: Problems with memory and decline in cognitive abilities are common during development of dementia. Different kinds of technologies may be useful in supporting persons with dementia and their relatives in daily life. Tracking technologies have the potential to improve independence among persons with dementia. Consequently, the aim of the present study was to describe perceptions of a passive positioning alarm (PPA) among persons with mild dementia. METHODS: A repeated interview study was conducted in Sweden with a strategic sample of 11 persons with mild dementia. Roger's Diffusion of Innovation Theory was used to deductively analyse the data. RESULTS: Regarding the advantages of the PPA, participants described perceived safety and security for, both themselves, and their relatives, as well as freedom and independence. However, they also expressed concern about the cost of the PPA, reflected on who might be the receiver of the alarm from the PPA, emphasized the importance of opportunities to test the device before becoming a user and early introduction before their problems start, thus allowing them to decide for themselves. CONCLUSIONS: Supporting persons with dementia in their own homes using, e.g., a PPA may enable them and their relatives to remain longer in their own homes and be safer in their own neighbourhoods. PMID- 26745960 TI - Effect of ultrasonic tip and root-end filling material on bond strength. AB - OBJECTIVES: The objective of this study was to evaluate the bond strength of three root-end filling materials (MTAA-MTA Angelus, MTAS-experimental MTA Sealer, and ZOE- zinc oxide and eugenol cement) in retrograde preparations performed with different ultrasonic tips (CVD, Trinity, and Satelec). MATERIALS AND METHOD: Ninety 2-mm root sections from single-rooted human teeth were used. The retrograde cavities were prepared by using the ultrasonic tips, coupled to a device for position standardization. The specimens were randomly divided into nine groups: CVD MTAA; CVD MTAS; CVD ZOE; Trinity MTAA; Trinity MTAS; Trinity ZOE; Satelec MTAA; Satelec MTAS; Satelec ZOE. Each resin disc/dentin/root-end filling material was placed in the machine to perform the push-out test. The specimens were examined in a stereomicroscope to evaluate the type of failure. Data were submitted to statistical analysis using ANOVA and Tukey tests (alpha = 0.05). RESULTS: The highest bond strength was observed for the CVD tip irrespective of the material used (P < 0.05). There was no significant difference for the Trinity TU-18 diamond and S12 Satelec tips (P > 0.05). MTAA and MTAS showed highest bond strength. The most common type of failure was adhesion between the filling material and dentin wall, except for ZOE, where mixed failure was predominant. CONCLUSIONS: The CVD tip favored higher bond strength of the root-end filling materials. MTA Angelus and experimental MTAS presented bond strength to dentin prepared with ultrasonic tips. CLINICAL RELEVANCE: Root-end preparation with the CVD tip positively influences the bond strength of root-end filling materials. MTA Angelus and experimental MTAS present bond strength to be used as root-end filling materials. PMID- 26745962 TI - The effects of tourniquet use in total knee arthroplasty: a randomized, controlled trial. AB - PURPOSE: Tourniquets are still widely used in total knee arthroplasty (TKA), although they may be associated with several adverse effects. An observer blinded, randomized, controlled trial was performed to evaluate the effects of tourniquet use in TKA. METHODS: Fifty participants who underwent staged bilateral TKA were recruited for this study. The first-side TKA was randomly allocated to either long-duration tourniquet use or short-duration tourniquet use followed by a 3-month washout period and crossover to the other tourniquet strategy for the opposite-side TKA. Blood loss was monitored perioperatively. The operating time, allogeneic blood transfusion rate, thigh pain, knee pain, limb swelling, clinical outcome as measured by the Likert-type Western Ontario and McMaster University (WOMAC) score, straight leg raising and knee active range of motion (ROM) were also recorded. RESULTS: The long-duration tourniquet group exhibited reduced total blood loss [-99.1 ml, 95 % confidence interval (CI) -168.1 to -30.1, P = 0.0411] and intraoperative blood loss (-225.2 ml, 95 % CI -369.5 to -80.9, P = 0.0071) compared with the short-duration tourniquet group. However, there were greater postoperative blood loss (69.6 ml, 95 % CI 21.1 to 118.2, P = 0.0282) and hidden blood loss (52.8 ml, 95 % CI 10.5 to 95.1, P = 0.0332) in the long duration tourniquet group. The short-duration tourniquet group showed better outcomes for thigh and knee pain, limb swelling, WOMAC score at 6-week follow-up, straight leg raising and knee ROM. Similar allogeneic blood transfusion rates were observed for both groups. CONCLUSION: Total and intraoperative blood losses were reduced with the long-duration tourniquet use, whereas the short-duration tourniquet use would reduce postoperative and hidden blood losses without increasing the allogeneic blood transfusion rate. In addition, short-duration tourniquet use would result in faster recovery and less pain during the early rehabilitation period following TKA. LEVEL OF EVIDENCE: I. PMID- 26745963 TI - A new wide-angle arthroscopic system: a comparative study with a conventional 30 degrees arthroscopic system. AB - PURPOSE: To compare users' hand movements in performing validated shoulder arthroscopic tasks between a 30 degrees and a wide-angle arthroscopic system, using phantom models with an optical motion analysis system. METHODS: Twelve orthopaedic residents were enrolled and randomly allocated into two groups. In order to compensate for any learning effect, a Latin square counterbalancing technique was used. An optical motion analysis system was used with markers affixed to pre-designed sites; each participant conducted four validated shoulder arthroscopic tasks using both arthroscopic systems. Each participant was instructed to perform the experiment three times with each arthroscope. The time taken, total path length, number of movements, and average acceleration were analysed. RESULTS: Significant differences were observed for the time taken, number of movements, and average acceleration between the two arthroscopic systems (P < 0.05 for all). However, the time taken was not significant. The mean total path length measured 53 +/- 38 cm with the 30 degrees arthroscope, while the mean with the wide-angle arthroscope was significantly shorter, at 36 +/- 22 cm. The mean number of movements with the 30 degrees and wide-angle arthroscopes were 1974 +/- 1305 and 1233 +/- 990, respectively, while the average accelerations were 2.6 +/- 1.3 and 1.2 +/- 0.6 cm/s(2), respectively. The mean time taken was 13 % faster when using the wide-angle arthroscopic system, although this was not statistically significant. CONCLUSION: The wide-angle arthroscopic system improved the arthroscope manoeuvre in terms of the total path length, number of movements, and average acceleration required for experimental arthroscopy. This system may help surgeons triangulate the arthroscope and surgical instruments during surgery by expanding the field of view. PMID- 26745964 TI - Open Latarjet versus arthroscopic Latarjet: clinical results and cost analysis. AB - PURPOSE: The aim of this study was to compare the clinical results between open and arthroscopic Latarjet and perform a cost analysis of the two techniques. MATERIALS AND METHODS: A systematic review of articles present in PubMed and MEDLINE was performed in accordance with PRISMA guidelines. Studies concerning post-operative outcomes following Latarjet procedures for chronic anterior shoulder instability were selected for analysis. The clinical and radiographic results as well as the costs of the open and arthroscopic techniques were evaluated. RESULTS: Twenty-three articles, describing a total of 1317 shoulders, met the inclusion criteria: 17 studies were related to open Latarjet, and 6 to the arthroscopic technique. Despite the heterogeneity of the evaluation scales, the clinical results seemed very satisfactory for both techniques. We detected a statistically significant difference in the percentage of bone graft healing in favour of the open technique (88.6 vs 77.6 %). Recurrent dislocation was more frequent following open surgery (3.3 % after open surgery vs 0.3 % after arthroscopy), but this finding was biased by the large difference in follow-up duration between the two techniques. The direct costs of the arthroscopic procedure were double in comparison to open surgery (?2335 vs ?1040). A lack of data prevented evaluation of indirect costs and, therefore, a cost-effectiveness analysis. CONCLUSIONS: The open and arthroscopic Latarjet techniques showed excellent and comparable clinical results. However, the much higher direct costs of the arthroscopic procedure do not seem, at present, to be justified by a benefit to the patient. LEVEL OF EVIDENCE: III. PMID- 26745966 TI - Vitamin D deficiency and length of pediatric intensive care unit stay: a prospective observational study. AB - BACKGROUND: Due to the limited data available in the pediatric population and lack of interventional studies to show that administration of vitamin D indeed improves clinical outcomes, opinion is still divided as to whether it is just an innocent bystander or a marker of severe disease. Our objective was therefore to estimate the prevalence of vitamin D deficiency in children admitted to intensive care unit (ICU) and to examine its association with duration of ICU stay and other key clinical outcomes. METHODS: We prospectively enrolled children aged 1 month-17 years admitted to the ICU over a period of 8 months (n = 101). The primary objectives were to estimate the prevalence of vitamin D deficiency (serum 25 (OH) <20 ng/mL) at 'admission' and to examine its association with length of ICU stay. RESULTS: The prevalence of vitamin D deficiency was 74 % (95 % CI: 65 88). The median (IQR) duration of ICU stay was significantly longer in 'vitamin D deficient' children (7 days; 2-12) than in those with 'no vitamin D deficiency' (3 days; 2-5; p = 0.006). On multivariable analysis, the association between length of ICU stay and vitamin D deficiency remained significant, even after adjusting for key baseline variables, diagnosis, illness severity (PIM-2), PELOD, and need for fluid boluses, ventilation, inotropes and mortality [adjusted mean difference (95 % CI): 3.5 days (0.50-6.53); p = 0.024]. CONCLUSIONS: We observed a high prevalence of vitamin D deficiency in critically ill children in our study population. Vitamin D deficient children had a longer duration of ICU stay as compared to others. PMID- 26745965 TI - Impaired voluntary quadriceps force control following anterior cruciate ligament reconstruction: relationship with knee function. AB - PURPOSE: Impairments in quadriceps force control and altered quadriceps and hamstring muscle activation strategies have been observed following anterior cruciate ligament reconstruction; however, the functional implications of these impairments are unclear. This study examined the cross-sectional associations between quadriceps force control, quadriceps activation, hamstring coactivation and clinically assessed knee function following anterior cruciate ligament reconstruction with a hamstring graft. METHODS: Sixty-six patients (18 +/- 3 months following surgery) and 41 uninjured individuals participated. Quadriceps force control was assessed using an isometric knee extension task. Participants cyclically increased and decreased quadriceps force at slow speeds between 5 and 30 % maximum voluntary isometric contraction matching a moving target displayed on a screen. Quadriceps activation and hamstring coactivation were assessed concurrently using surface electromyography. Knee function was assessed with the Cincinnati Knee Rating Scale and three single-leg hop tests. RESULTS: The reconstructed group completed the task with 48 % greater root-mean-square error (RMSE), indicating significantly worse quadriceps force control (p < 0.001). In a multivariable model adjusted for sex, greater RMSE and greater lateral hamstring coactivation were significantly associated with worse knee function that is greater odds of scoring <85 % on one or more knee functional assessment. CONCLUSIONS: Less-accurate quadriceps force output and greater hamstring coactivation are associated with worse knee joint function following anterior cruciate ligament reconstruction and may contribute to irregular knee joint loading and the onset or progression of knee osteoarthritis. Impairments in quadriceps force control and altered muscle activation strategies may be modifiable through neuromuscular training, and this is an area for future research. LEVEL OF EVIDENCE: Case-control study, Level III. PMID- 26745967 TI - Sandalwood: basic biology, tissue culture, and genetic transformation. AB - MAIN CONCLUSION: Sustainable resource preservation of Santalum species that yield commercially important forest products is needed. This review provides an understanding of their basic biology, propagation, hemi-parasitic nature, reproductive biology, and biotechnology. Many species of the genus Santalum (Santalaceae) have been exploited unremittingly for centuries, resulting in the extinction of one and the threatened status of three other species. This reduction in biodiversity of sandalwood has resulted from the commercial exploitation of its oil-rich fragrant heartwood. In a bid to conserve the remaining germplasm, biotechnology provides a feasible, and effective, means of propagating members of this genus. This review provides a detailed understanding of the biological mechanisms underlying the success or failure of traditional propagation, including a synopsis of the process of hemi-parasitism in S. album, and of the suitability of host plants to sustain the growth of seedlings and plants under forestry production. For the mass production of economically important metabolites, and to improve uniformity of essential oils, the use of clonal material of similar genetic background for cultivation is important. This review summarizes traditional methods of sandalwood production with complementary and more advanced in vitro technologies to provide a basis for researchers, conservationists and industry to implement sustainable programs of research and development for this revered genus. PMID- 26745970 TI - The Doppler Effect: A Century from Red Shift to Red Spot. PMID- 26745971 TI - Inauguration speech: 27 October 2015 at the Van Swieten Hall of the Medical University of Vienna. PMID- 26745968 TI - Doxycycline Suppresses Microglial Activation by Inhibiting the p38 MAPK and NF-kB Signaling Pathways. AB - In neurodegenerative diseases, the inflammatory response is mediated by activated glial cells, mainly microglia, which are the resident immune cells of the central nervous system. Activated microglial cells release proinflammatory mediators and neurotoxic factors that are suspected to cause or exacerbate these diseases. We recently demonstrated that doxycycline protects substantia nigra dopaminergic neurons in an animal model of Parkinson's disease. This effect was associated with a reduction of microglial cell activation, which suggests that doxycycline may operate primarily as an anti-inflammatory drug. In the present study, we assessed the anti-inflammatory potential of doxycycline using lipopolysaccharide (LPS)-activated primary microglial cells in culture as a model of neuroinflammation. Doxycycline attenuated the expression of key activation markers in LPS-treated microglial cultures in a concentration-dependent manner. More specifically, doxycycline treatment lowered the expression of the microglial activation marker IBA-1 as well as the production of ROS, NO, and proinflammatory cytokines (TNF-alpha and IL-1beta). In primary microglial cells, we also found that doxycycline inhibits LPS-induced p38 MAP kinase phosphorylation and NF-kB nuclear translocation. The present results indicate that the effect of doxycycline on LPS-induced microglial activation probably occurs via the modulation of p38 MAP kinase and NF-kB signaling pathways. These results support the idea that doxycycline may be useful in preventing or slowing the progression of PD and other neurodegenerative diseases that exhibit altered glia function. PMID- 26745972 TI - Short-term pacemaker dependency after transcatheter aortic valve implantation. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a less invasive technique for the treatment of severe aortic stenosis in high-risk patients. Occurrence of conduction disturbances requiring permanent pacemaker (PPM) implantation after TAVI is frequently observed. METHODS: The retrospective analysis comprised 153 patients (96 women, aged from 65 to 97 years) who underwent TAVI due to high-grade aortic stenosis. The aim was to evaluate the incidence of high-grade atrioventricular (AV) block after TAVI and the percentage of ventricular pacing and pacemaker (PM)-dependency at the first follow-up 6-8 weeks after implantation. RESULTS: Out of the 153 patients (age 81 +/- 6 years) who underwent TAVI, 144 (94 %) had a transfemoral and 9 (6 %) patients a transapical approach. A PPM was implanted in 31 (20 %) patients, 24 (16 %) were implanted with the Medtronic CoreValve(r) and 7 (5 %) with the Edwards Sapien(r) valve (p = n.s.). Complete AV block was the indication in 21 patients (68 %), second-degree AV block in 1 patient (3 %), slow atrial fibrillation in 3 patients (10 %), new left bundle branch block (LBBB) plus sustained ventricular tachycardia (VT) in 1 patient (3 %), sick sinus syndrome in 2 patients (7 %), whereas in 3 patients (10 %) a PPM was inserted for safety reasons because of new LBBB and first-grade AV block. All of the nine patients (6 %) with a preexisting bundle branch block developed total AV block after TAVI. At follow-up PM dependency (intrinsic rhythm < 30 bpm) occurred in 11/30 patients (37 %), whereas an intrinsic rhythm > 50 bpm was seen in 17 patients (57 %). At nominal device programming the percentage of ventricular stimulation (VP) during the short-term observation period was 60 +/- 44 % in dual-chamber devices (N = 18), and 70 +/- 36 % in single-chamber PPM (N = 5). CONCLUSION: The PPM implantation rate of about 20 % after TAVI is comparable to previously published data. The need for permanent pacing is linked to the valve type and preexistence of a right bundle branch block. At short-term more than half of the patients implanted with a device were not strictly PM-dependent, but presented an underlying intrinsic rhythm, indicating that temporary AV conduction disturbances may recover over time. This might justify a more conservative approach in some patients under watchful waiting. From another point of view, ventricular pacing at a regular or sensor-modulated rate may provide rhythm stability and chronotropy during the short-term period post-TAVI. PMID- 26745974 TI - Leeuwenhoekiella nanhaiensis sp. nov., isolated from deep-sea water. AB - A novel heterotrophic, aerobic, Gram-stain-negative, rod-shaped and yellow bacterium, designated strain G18T, was isolated from a water sample collected from the deep South China Sea. Strain G18T grew at 4-40 degrees C (optimum 28-32 degrees C), at pH 6.0-8.0 (optimum pH 6.5-7.5) and with 0-12 % (w/v) NaCl (optimum 3-4 %). The organism was mesophilic and piezotolerant, its optimal growth pressure was 0.1 MPa, which was lower than that at the depth from which it was isolated. Its optimal growth temperature was higher than that at the depth of its isolation. The predominant cellular fatty acids were C15 : 0iso, C17 : 0iso 3 OH and C15 : 1iso. The major polar lipids were composed of phosphatidylethanolamine, one unknown aminolipid and one unknown polar lipid. The major respiratory quinone was menaquinone 6. The G+C content of the genomic DNA was 35 mol%. Phylogenetic analysis, based on 16S rRNA gene sequences, revealed that strain G18T clustered with species of the genus Leeuwenhoekiella with validly published names within the family Flavobacteriaceae with 95.9-98.2 % sequence similarity. DNA-DNA reassociation values ranged from 9 to 42 %. Differential phenotypic properties, together with the phylogenetic distinctiveness, suggest that strain G18T differs from species of the genus Leeuwenhoekiella with validly published names. On the basis of the polyphasic evidence, strain G18T represents a novel species, isolated from deep-sea, of the genus Leeuwenhoekiella for which the name Leeuwenhoekiella nanhaiensis sp. nov. is proposed. The type strain is G18T ( = CCTCC AB 2015204T = KCTC 42729T). PMID- 26745973 TI - Results of a prospective dose intensity and neutropenia prophylaxis evaluation programme (DIEPP) in cancer patients at risk of febrile neutropenia due to myelosuppressive chemotherapy. AB - OBJECTIVE: To describe the incidence of febrile neutropenia (FN) and use of pegfilgrastim in cancer patients with high overall risk of FN and to investigate the relationship between granulocyte-colony stimulating factor (G-CSF) guideline adherence and chemotherapy delivery in Central and Eastern Europe (CEE) and Austria. METHODS: Dose Intensity Evaluation Program and Prophylaxis (DIEPP) was a multicentre, prospective, and observational study of adult patients with breast cancer, lymphoma, lung cancer, gastric cancer, and ovarian cancer, who received chemotherapy with pegfilgrastim support and who had an overall risk of FN >= 20 %. Physicians assessed patient risk factors and reported their reasons for administering pegfilgrastim. RESULTS: Patients were enrolled from 113 centres in CEE and Austria between August 2010 and July 2013, and data were analysed from 1072 patients. The most common tumour types were breast cancer (50 %) and lymphoma (24 %). FN incidence was 5 % overall. FN occurred in 3 % of patients (28/875) who received pegfilgrastim as primary prophylaxis (PP) and 13 % of patients (19/142) who received it as secondary prophylaxis (SP); 79 % of FN events in SP patients occurred in the first cycle before pegfilgrastim was administered. The three most frequently chosen reasons for using pegfilgrastim were planned chemotherapy with high FN risk, female gender, and advanced disease. Overall, 40 % of patients received > 90 % of their planned chemotherapy dose within 3 days of the planned schedule. CONCLUSION: FN incidence was relatively low with pegfilgrastim PP in patients with a physician-assessed overall FN risk of >= 20 %. The most important reasons for pegfilgrastim use were consistent with the investigators' risk assessment and international guidelines. PMID- 26745969 TI - Are Polyphenols Strong Dietary Agents Against Neurotoxicity and Neurodegeneration? AB - Life expectancy of most human populations has greatly increased as a result of factors including better hygiene, medical practice, and nutrition. Unfortunately, as humans age, they become more prone to suffer from neurodegenerative diseases and neurotoxicity. Polyphenols can be cheaply and easily obtained as part of a healthy diet. They present a wide range of biological activities, many of which have relevance for human health. Compelling evidence has shown that dietary phytochemicals, particularly polyphenols, have properties that may suppress neuroinflammation and prevent toxic and degenerative effects in the brain. The mechanisms by which polyphenols exert their action are not fully understood, but it is clear that they have a direct effect through their antioxidant activities. They have also been shown to modulate intracellular signaling cascades, including the PI3K-Akt, MAPK, Nrf2, and MEK pathways. Polyphenols also interact with a range of neurotransmitters, illustrating that these compounds can promote their health benefits in the brain through a direct, indirect, or complex action. We discuss whether polyphenols obtained from diet or food supplements are an effective strategy to prevent or treat neurodegeneration. We also discuss the safety, mechanisms of action, and the current and future relevance of polyphenols in clinical treatment of neurodegenerative diseases. As populations age, it is important to discuss the dietary strategies to avoid or counteract the effects of incurable neurodegenerative disorders, which already represent an enormous financial and emotional burden for health care systems, patients, and their families. PMID- 26745977 TI - Control of Alginate Core Size in Alginate-Poly (Lactic-Co-Glycolic) Acid Microparticles. AB - Core-shell alginate-poly (lactic-co-glycolic) acid (PLGA) microparticles are potential candidates to improve hydrophilic drug loading while facilitating controlled release. This report studies the influence of the alginate core size on the drug release profile of alginate-PLGA microparticles and its size. Microparticles are synthesized through double-emulsion fabrication via a concurrent ionotropic gelation and solvent extraction. The size of alginate core ranges from approximately 10, 50, to 100 MUm when the emulsification method at the first step is homogenization, vortexing, or magnetic stirring, respectively. The second step emulsification for all three conditions is performed with magnetic stirring. Interestingly, although the alginate core has different sizes, alginate-PLGA microparticle diameter does not change. However, drug release profiles are dramatically different for microparticles comprising different-sized alginate cores. Specifically, taking calcein as a model drug, microparticles containing the smallest alginate core (10 MUm) show the slowest release over a period of 26 days with burst release less than 1 %. PMID- 26745976 TI - A Simple and Easy Process for the Determination of Estimated Plasma Glucose Level in Patients Presenting to Hospital: An Example of Multicentric Data Mining. AB - The aim of the present study was to determine the relation between the simultaneous fasting plasma glucose level and HbA1c in a large population of patients presenting to the hospital, based on various measurement methods available for HbA1c. HbA1c levels of 162,210 patients presenting to various hospitals and laboratories were measured based on seven different systems, and at the same time, eAG levels were calculated based on HbA1c levels. The correlation coefficients (r) between serum plasma glucose and HbA1c levels were found to be 0.809, 0.774, 0.779, 0.817, 0.704, 0.796, and 0.747 in Bio-Rad Variant II, Tosoh G8, ADAMS A1c, Trinity Boronate Affinity, Chromsystems HPLC, Roche Tina-quant, and Abbott Architect, respectively. The concordance correlation coefficients between the eAG levels as calculated with the formulas provided in the text and the eAG levels as calculated according to NGSP directions (where eAG = (28.7*HbA1c) - 46.7) were found to be between 0.9339 and 0.9866. Despite the progress made for the standardization of HbA1c measurements, the relation between serum glucose and HbA1c still demonstrated certain discrepancies pertaining to the differences in measurement methodologies. As a conclusion, each laboratory could determine different eAG levels depending on the data originated by their individual analyzer. PMID- 26745975 TI - XPC intron11 C/A polymorphism as a risk factor for prostate cancer. AB - OBJECTIVES: DNA repair genes play an important role in protection against environmental and endogenous DNA damage, and constitute the first line of defense against cancer. Xeroderma pigmentosum complementation group C (XPC) is involved in the damage recognition step during nucleotide excision repair. The relationship between XPC intron11 C/A polymorphism and cancer risk has not been widely studied. Hence, this study evaluated the relationship between the XPC intron11 C/A polymorphism and prostate cancer risk. MATERIALS AND METHODS: This hospital-based cohort consisted of 152 patients with prostate cancer and 142 male controls. The XPC intron11 C/A genotype was determined using the PCR-RFLP method. Medical, occupational, and cigarette-smoking history was obtained from each participant using questionnaires. RESULTS: Logistic regression analysis revealed that compared to controls, the frequencies of the A/A and C/A genotypes were significantly higher than those of the C/C genotype in cancer patients (OR = 2.03, 95% confidence interval (CI) 1.03-3.98 and OR = 1.91, 95% CI 1.13-3.24, respectively). We also found that the frequency of the A/A genotype was significantly higher in cancer cases than in controls among non-smokers (OR = 7.7, 95% CI 1.38-42.88, compared to the C/C genotype). CONCLUSION: We found that the XPC intron11 C/A polymorphism was associated with an increased risk of prostate cancer. Among non-smokers, the A/A genotype was significantly more prevalent in prostate cancer patients than in controls. PMID- 26745978 TI - Morphological and molecular characterization of yellow oyster mushroom, Pleurotus citrinopileatus, hybrids obtained by interspecies mating. AB - Pleurotus citrinopileatus (yellow oyster mushroom) has an attractive shape and yellow colour but the fragile texture complicates packaging, and its strong aroma is unappealing to consumers. This study aimed to improve the characteristics and yield of P. citrinopileatus by interspecies mating between monokaryotic cultures of P. citrinopileatus and P. pulmonarius. Ten monokaryon cultures of the parental lines were crossed in all combinations to obtain hybrids. Eleven compatible mating pairs were obtained and cultivated to observe their sporophore morphology and yield. The selected hybrid, i.e. P1xC9, was beige in colour while hybrid P3xC8 was yellow in colour. Their sporophores had less offensive aroma, improved texture and higher yield. The DNA sequences of these hybrids were found to be in the same clade as the P. citrinopileatus parent with a bootstrap value of 99%. High bootstrap values indicate high genetic homology between hybrids and the P. citrinopileatus parent. The biological efficiencies of these hybrids P1xC9 (70.97%) and P3xC8 (52.14%) were also higher than the P. citrinopileatus parent (35.63%). Interspecies hybrids obtained by this mating technique can lead to better strains of mushrooms for genetic improvement of the Pleurotus species. PMID- 26745979 TI - Dual symbiosis between Piriformospora indica and Azotobacter chroococcum enhances the artemisinin content in Artemisia annua L. AB - At present, Artemisia annua L. is the major source of artemisinin production. To control the outbreaks of malaria, artemisinin combination therapies (ACTs) are recommended, and hence an ample amount of artemisinin is required for ACTs manufacture to save millions of lives. The low yield of this antimalarial drug in A. annua L. plants (0.01-1.1%) ensues its short supply and high cost, thus making it a topic of scrutiny worldwide. In this study, the effects of root endophyte, Piriformospora indica strain DSM 11827 and nitrogen fixing bacterium, Azotobacter chroococcum strain W-5, either singly and/or in combination for artemisinin production in A. annua L. plants have been studied under poly house conditions. The plant growth was monitored by measuring parameters like height of plant, total dry weight and leaf yield with an increase of 63.51, 52.61 and 79.70% respectively, for treatment with dual biological consortium, as compared to that of control plants. This significant improvement in biomass was associated with higher total chlorophyll content (59.29%) and enhanced nutrition (especially nitrogen and phosphorus, 55.75 and 86.21% respectively). The concentration of artemisinin along with expression patterns of artemisinin biosynthesis genes were appreciably higher in dual treatment, which showed positive correlation. The study suggested the potential use of the consortium P. indica strain DSM 11827 and A. chroococcum strain W-5 in A. annua L. plants for increased overall productivity and sustainable agriculture. PMID- 26745981 TI - A novel enterocin T1 with anti-Pseudomonas activity produced by Enterococcus faecium T1 from Chinese Tibet cheese. AB - An enterocin-producing Enterococcus faecium T1 was isolated from Chinese Tibet cheese. The enterocin was purified by SP-Sepharose and reversed phase HPLC. It was identified as unique from other reported bacteriocins based on molecular weight (4629 Da) and amino acid compositions; therefore it was subsequently named enterocin T1. Enterocin T1 was stable at 80-100 degrees C and over a wide pH range, pH 3.0-10.0. Protease sensitivity was observed to trypsin, pepsin, papain, proteinase K, and pronase E. Importantly, enterocin T1 was observed to inhibit the growth of numerous Gram-negative and Gram-positive bacteria including Pseudomonas putida, Pseudomonas aeruginosa, Pseudomonas fluorescens, Escherichia coli, Salmonella typhimurium, Shigella flexneri, Shigella sonnei, Staphylococcus aureus, Listeria monocytogenes. Take together, these results suggest that enterocin T1 is a novel bacteriocin with the potential to be used as a bio preservative to control Pseudomonas spp. in food. PMID- 26745980 TI - Isolation, diversity and acetylcholinesterase inhibitory activity of the culturable endophytic fungi harboured in Huperzia serrata from Jinggang Mountain, China. AB - Huperzia serrata has many important medicinal properties with proven pharmacological potential. Some of these properties may be mediated by its endophytic fungi. To test this hypothesis, in the present study, we provided a first insights into evaluating the species composition and acetylcholinesterase (AChE) inhibitory activity of the culturable endophytic fungi of H. serrata from the regional at Jinggang Mountain in southeastern China. A total number of 885 fungal isolates distributed across 44 genera and 118 putative species were obtained from 1422 fragments of fine H. serrata roots, stems and leaves base on ITS-rDNA sequences BLAST analysis. The endophytic fungi were phylogenetically diverse and species-rich, with high rate of colonization and isolation. The assemble of endophytic fungi consisted mainly of Ascomycota (97.15%), followed by Basidiomycota (1.92%) and unknown fungal species (0.90%). Colletotrichum (64.29%), Phyllosticta (3.39%), Hypoxylon (2.81%), Xylaria (2.25%) and Nigrospora (2.04%) were the most abundant genera, whereas the remaining genera were infrequent groups. Although, roots yielded low abundance strains, the diverse and species-rich were both higher than that of stems and leaves. In addition, out of the 247 endophytic fungi strains determinated, 221 fungal extracts showed AChE inhibition activities in vitro. Among them, 22 endophytic fungi strains achieved high inhibitory activity (>=50%) on AChE which belongs to 13 genera and five incertae sedis strains. Four endophytic fungi designated as JS4 (Colletotrichum spp.), FL14 (Ascomycota spp.), FL9 (Sarcosomataceae spp.) and FL7 (Dothideomycetes spp.) were displayed highly active (>=80%) against AChE, which the inhibition effects were even more intense than the positive control. Our findings highlight that H. serrata grown in Jinggang Mountain harbors a rich and fascinating endophytic fungus community with potential AChE inhibitory activity, which could further broaden the natural acetylcholinesterase inhibitors resources used for Alzheimer's disease treatment. PMID- 26745982 TI - Salmonella typhimurium-induced M1 macrophage polarization is dependent on the bacterial O antigen. AB - Recently, macrophages were shown to be capable of differentiating toward two phenotypes after antigen stimulation: a classically activated (M1) or an alternatively activated phenotype (M2). To investigate the effect of Salmonella enteric serovar typhimurium (S. typhimurium) on macrophage differentiation, we compared macrophage phenotypes after infection of murine bone marrow-derived macrophages with wild-type S. typhimurium and its isogenic rfc mutant. S. typhimurium C5 induced M1 macrophage polarization and enhanced inducible nitric oxide synthase expression by macrophages; this induction was dependent on Toll like receptor 4. In contrast, the Deltarfc mutant (S. typhimurium C5 rfc::Km(r)) lost this function and induced an M2 response in the macrophages. Here, we propose that S. typhimurium C5 is capable of polarizing macrophages towards the M1 phenotype and that this polarization is dependent on the O antigen encoded by rfc. Our finding indicates that M1 macrophage polarization induced by S. typhimurium may be related to the ability of this intracellular bacterium to survive and replicate within macrophages, which is essential for systemic disease. PMID- 26745983 TI - Glyceryl trinitrate and caprylic acid for the mitigation of the Desulfovibrio vulgaris biofilm on C1018 carbon steel. AB - Microbiologically influenced corrosion (MIC), also known as biocorrosion, is caused by corrosive biofilms. MIC is a growing problem, especially in the oil and gas industry. Among various corrosive microbes, sulfate reducing bacteria (SRB) are often the leading culprit. Biofilm mitigation is the key to MIC mitigation. Biocide applications against biofilms promote resistance over time. Thus, it is imperative to develop new biodegradable and cost-effective biocides for large scale field applications. Using the corrosive Desulfovibrio vulgaris (an SRB) biofilm as a model biofilm, this work demonstrated that a cocktail of glyceryl trinitrate (GTN) and caprylic acid (CA) was very effective for biofilm prevention and mitigation of established biofilms on C1018 carbon steel coupons. The most probable number sessile cell count data and confocal laser scanning microscope biofilm images proved that the biocide cocktail of 25 ppm (w/w) GTN + 0.1% (w/w) CA successfully prevented the D. vulgaris biofilm establishment on C1018 carbon steel coupons while 100 ppm GTN + 0.1% CA effectively mitigated pre-established D. vulgaris biofilms on C1018 carbon steel coupons. In both cases, the cocktails were able to reduce the sessile cell count from 10(6) cells/cm(2) to an undetectable level. PMID- 26745984 TI - Analysis on evolutionary relationship of amylases from archaea, bacteria and eukaryota. AB - Amylase is one of the earliest characterized enzymes and has many applications in clinical and industrial settings. In biotechnological industries, the amylase activity is enhanced through modifying amylase structure and through cloning and expressing targeted amylases in different species. It is important to understand how engineered amylases can survive from generation to generation. This study used phylogenetic and statistical approaches to explore general patterns of amylases evolution, including 3118 alpha-amylases and 280 beta-amylases from archaea, eukaryota and bacteria with fully documented taxonomic lineage. First, the phylogenetic tree was created to analyze the evolution of amylases with focus on individual amylases used in biofuel industry. Second, the average pairwise p distance was computed for each kingdom, phylum, class, order, family and genus, and its diversity implies multi-time and multi-clan evolution. Finally, the variance was further partitioned into inter-clan variance and intra-clan variance for each taxonomic group, and they represent horizontal and vertical gene transfer. Theoretically, the results show a full picture on the evolution of amylases in manners of vertical and horizontal gene transfer, and multi-time and multi-clan evolution as well. Practically, this study provides the information on the surviving chance of desired amylase in a given taxonomic group, which may potentially enhance the successful rate of cloning and expression of amylase gene in different species. PMID- 26745985 TI - Evaluation of economically feasible, natural plant extract-based microbiological media for producing biomass of the dry rot biocontrol strain Pseudomonas fluorescens P22Y05 in liquid culture. AB - The production of microbial biomass in liquid media often represents an indispensable step in the research and development of bacterial and fungal strains. Costs of commercially prepared nutrient media or purified media components, however, can represent a significant hurdle to conducting research in locations where obtaining these products is difficult. A less expensive option for providing components essential to microbial growth in liquid culture is the use of extracts of fresh or dried plant products obtained by using hot water extraction techniques. A total of 13 plant extract-based media were prepared from a variety of plant fruits, pods or seeds of plant species including Allium cepa (red onion bulb), Phaseolus vulgaris (green bean pods), and Lens culinaris (lentil seeds). In shake flask tests, cell production by potato dry rot antagonist Pseudomonas fluorescens P22Y05 in plant extract-based media was generally statistically indistinguishable from that in commercially produced tryptic soy broth and nutrient broth as measured by optical density and colony forming units/ml produced (P <= 0.05, Fisher's protected LSD). The efficacy of biomass produced in the best plant extract-based media or commercial media was equivalent in reducing Fusarium dry rot by 50-96% compared to controls. In studies using a high-throughput microbioreactor, logarithmic growth of P22Y05 in plant extract-based media initiated in 3-5 h in most cases but specific growth rate and the time of maximum OD varied as did the maximum pH obtained in media. Nutrient analysis of selected media before and after cell growth indicated that nitrogen in the form of NH4 accumulated in culture supernatants, possibly due to unbalanced growth conditions brought on by a scarcity of simple sugars in the media tested. The potential of plant extract-based media to economically produce biomass of microbes active in reducing plant disease is considerable and deserves further research. PMID- 26745986 TI - beta-1,3-1,4-glucanase gene from Bacillus velezensis ZJ20 exerts antifungal effect on plant pathogenic fungi. AB - Bacillus velezensis is a known antifungal bacteria. To understand the role of beta-1, 3-1, 4-glucanase played on B. velezensis about the mechanism which exerts effect on fungi, we isolated and cloned the beta-1, 3-1, 4-glucanase gene (Bglu1) from B. velezensis ZJ20. The Bglu1 open reading frame was 732 bp that encoded a protein with 243 amino acids and a calculated molecular weight of 27.3 kDa. The same gene without the signal peptide, termed Bglu2, was also cloned and expressed in E. coli BL21. Among the two variants, only Bglu2 protein was expressed. Purified Bglu2 could be eluted with imidazole solution at concentrations ranging from 100 to 500 mM although the highest expression was observed at 150 and 200 mM and the purest was at 500 mM. In addition, activity of the crude enzyme was 1527 U ml(-1) and the highest activity of the purified enzyme was 1706 U ml(-1). The purified beta-1, 3-1, 4-glucanase had activity on a wide range of pH and temperatures and displayed optimal activity at pH 5.0 and 35 degrees C. More importantly, the mycelial morphology of three pathogenic fungi was destroyed by the purified beta-1, 3-1, 4-glucanase. In conclusion, beta-1, 3-1, 4-glucanase from B. velezensis ZJ20 can be highly expressed in E. coli BL21 and the recombinant protein is pathogenic to fungi. PMID- 26745989 TI - Abstract Book: Society of Surgical Oncology 69(th) Annual Cancer Symposium. PMID- 26745988 TI - United Kingdom National Guideline on the Management of the viral hepatitides A, B and C 2015. PMID- 26745987 TI - Effect of context exposure after fear learning on memory generalization in mice. AB - BACKGROUND: The conditions under which memory generalization occurs are not well understood. Although it is believed that fear memory generalization is gradually established after learning, it is not clear whether experiences soon after learning affect generalization. RESULTS: Using a contextual fear conditioning paradigm in mice, we found that fear memory generalization occurred when mice were exposed to a familiar, unconditioned context soon after fear learning. CONCLUSIONS: Our results suggest that the familiarity of contexts and the timing of their exposure influences memory generalization, which increases our understanding of the mechanisms of generalization. PMID- 26745991 TI - Colorful Polyelectrolytes: An Atom Transfer Radical Polymerization Route to Fluorescent Polystyrene Sulfonate. AB - A labeled green fluorescent polystyrene sulfonate (LNaPSS) has been synthesized using atom transfer radical polymerization of a styrene sulfonate monomer with a fluorescent co-monomer, fluorescein thiocyanate-vinyl aniline. As a result this 100 % sulfonated polymer contains no hydrophobic patches along the chain backbone besides the fluorescent marker itself. The concentration of the fluorescent monomer was kept low to maintain the characteristic properties of the anionic polyelectrolyte, LNaPSS. ATRP conditions facilitated the production of polymers spanning a range of molecular weights from 35,000 to 175,000 in gram-scale batches with polydispersity indices of 1.01-1.24. Molecular weight increased with the monomer to initiator ratio. Gel permeation chromatography results show a unimodal distribution, and the polymer structure was also confirmed by (1)H NMR and FT-IR spectroscopy. Fluorescence spectroscopy confirmed covalent bonding of fluorescein isothiocyanate to the polymer, indicating that the polymer is suitable as a probe in fluorescence microscopy. To demonstrate this ability, the polymer was used to locate structural features in salt crystals formed during drying, as in the evaporation of sea mist. A second application to probe diffusion studies is also demonstrated. PMID- 26745990 TI - Optical and electron microscopy study of laser-based intracellular molecule delivery using peptide-conjugated photodispersible gold nanoparticle agglomerates. AB - BACKGROUND: Cell-penetrating peptides (CPPs) can act as carriers for therapeutic molecules such as drugs and genetic constructs for medical applications. The triggered release of the molecule into the cytoplasm can be crucial to its effective delivery. Hence, we implemented and characterized laser interaction with defined gold nanoparticle agglomerates conjugated to CPPs which enables efficient endosomal rupture and intracellular release of molecules transported. RESULTS: Gold nanoparticles generated by pulsed laser ablation in liquid were conjugated with CPPs forming agglomerates and the intracellular release of molecules was triggered via pulsed laser irradiation (gamma = 532 nm, tau pulse = 1 ns). The CPPs enhance the uptake of the agglomerates along with the cargo which can be co-incubated with the agglomerates. The interaction of incident laser light with gold nanoparticle agglomerates leads to heat deposition and field enhancement in the vicinity of the particles. This highly precise effect deagglomerates the nanoparticles and disrupts the enclosing endosomal membrane. Transmission electron microscopy images confirmed this rupture for radiant exposures of 25 mJ/cm2 and above. Successful intracellular release was shown using the fluorescent dye calcein. For a radiant exposure of 35 mJ/cm2 we found calcein delivery in 81 % of the treated cells while maintaining a high percentage of cell viability. Furthermore, cell proliferation and metabolic activity were not reduced 72 h after the treatment. CONCLUSION: CPPs trigger the uptake of the gold nanoparticle agglomerates via endocytosis and co-resident molecules in the endosomes are released by applying laser irradiation, preventing their intraendosomal degradation. Due to the highly localized effect, the cell membrane integrity is not affected. Therefore, this technique can be an efficient tool for spatially and temporally confined intracellular release. The utilization of specifically designed photodispersible gold nanoparticle agglomerates (65 nm) can open novel avenues in imaging and molecule delivery. Due to the induced deagglomeration the primary, small particles (~5 nm) are more likely to be removed from the body. PMID- 26745993 TI - Use of Transalveolar Sutures in Conjunction With Grafting to Preserve Vestibular Depth and Augment Gingival Thickness Around Mandibular Implants. AB - Preservation or reconstruction of the soft tissues around dental implants is an essential component of implant dentistry. Increased width and thickness of the keratinized tissue surrounding dental implants has been recognized as an important factor associated with long-term implant success. When extractions and ridge reduction are performed concurrently with implant placement, maintaining vestibular depth also is of utmost importance. A previous report described a technique for applying bone-anchoring sutures to preserve keratinized tissue and vestibular depth around implants. The present report describes a variation of the procedure for the simultaneous correction of situations in which the existing keratinized tissue is thin and narrow and preserving and apically positioning it might not provide an appropriate gingival cuff. PMID- 26745994 TI - Editors' Overview: Experiments, Ethics, and New Technologies. PMID- 26745992 TI - Catechol-O-Methyltransferase Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis. AB - BACKGROUND: The catechol-O-methyltransferase (COMT) enzyme plays a crucial role in dopamine degradation, and the COMT Val158Met polymorphism (rs4680) is associated with significant differences in enzymatic activity and consequently dopamine concentrations in the prefrontal cortex. Multiple studies have analyzed the COMT Val158Met variant in relation to antipsychotic response. Here, we conducted a meta-analysis examining the relationship between COMT Val158Met and antipsychotic response. METHODS: Searches using PubMed, Web of Science, and PsycInfo databases (03/01/2015) yielded 23 studies investigating COMT Val158Met variation and antipsychotic response in schizophrenia and schizo-affective disorder. Responders/nonresponders were defined using each study's original criteria. If no binary response definition was used, authors were asked to define response according to at least 30% Positive and Negative Syndrome Scale score reduction (or equivalent in other scales). Analysis was conducted under a fixed effects model. RESULTS: Ten studies met inclusion criteria for the meta-analysis. Five additional antipsychotic-treated samples were analyzed for Val158Met and response and included in the meta-analysis (ntotal=1416). Met/Met individuals were significantly more likely to respond than Val-carriers (P=.039, ORMet/Met=1.37, 95% CI: 1.02-1.85). Met/Met patients also experienced significantly greater improvement in positive symptoms relative to Val-carriers (P=.030, SMD=0.24, 95% CI: 0.024-0.46). Posthoc analyses on patients treated with atypical antipsychotics (n=1207) showed that Met/Met patients were significantly more likely to respond relative to Val-carriers (P=.0098, ORMet/Met=1.54, 95% CI: 1.11-2.14), while no difference was observed for typical-antipsychotic-treated patients (n=155) (P=.65). CONCLUSIONS: Our findings suggest that the COMT Val158Met polymorphism is associated with response to antipsychotics in schizophrenia and schizo-affective disorder patients. This effect may be more pronounced for atypical antipsychotics. PMID- 26745996 TI - Understanding an Ebola outbreak: Social representations of emerging infectious diseases. AB - This study examined the collective image of the 2014-2015 Ebola outbreak, to understand how people incorporate this epidemic in their everyday thinking. A free association exercise elicited by Ebola was answered by 294 people from Spain and the content was analysed using Alceste software. First, results showed that Ebola was represented as inherently African. Second, it was also depicted as a global threat creating fear. People also felt anger, and they blamed political authorities and the mass media for the failure to manage this crisis. Finally, this research underlines the importance of the social representations to understand how current outbreaks are cognitively represented and emotionally faced as a key factor to appropriately manage future epidemics. PMID- 26745995 TI - [Anesthesia in obstetrics: Tried and trusted methods, current standards and new challenges]. AB - Obstetric analgesia and anesthesia have some specific aspects, which in particular are directly related to pathophysiological alterations during pregnancy and also to the circumstance that two or even more individuals are always affected by complications or therapeutic measures. This review article deals with some evergreens and hot topics of obstetric anesthesia and essential new knowledge on these aspects is described. The article summarizes the talks given at the 16th symposium on obstetric anesthesia organized by the Scientific Committee for Regional Anaesthesia and Obstetric Anaesthesia within the German Society of Anaesthesiology. The topics are in particular, special features and pitfalls of informed consent in the delivery room, challenges in education and training in obstetric anesthesia, expedient inclusion of simulation-assisted training and further education on risk minimization, knowledge and recommendations on fasting for the delivery room and cesarean sections, monitoring in obstetric anesthesia by neuraxial and alternative procedures, the possibilities and limitations of using ultrasound for lumbal epidural catheter positioning in the delivery room, recommended approaches in preparing peridural catheters for cesarean section, basic principles of cardiotocography, postoperative analgesia after cesarean section, the practice of early bonding in the delivery room during cesarean section births and the management of postpartum hemorrhage. PMID- 26745997 TI - [The intervention mapping protocol: A structured process to develop, implement and evaluate health promotion programs]. AB - BACKGROUND: Health promotion programs are expected to improve population health and reduce social inequalities in health. However, their theoretical foundations are frequently ill-defined, and their implementation faces many obstacles. The aim of this article is to describe the intervention mapping protocol in health promotion programs planning, used recently in several countries. METHODS: The challenges of planning health promotion programs are presented, and the six steps of the intervention mapping protocol are described with an example. Based on a literature review, the use of this protocol, its requirements and potential limitations are discussed. RESULTS: The intervention mapping protocol has four essential characteristics: an ecological perspective (person-environment), a participative approach, the use of theoretical models in human and social sciences and the use of scientific evidence. It comprises six steps: conduct a health needs assessment, define change objectives, select theory-based change techniques and practical applications, organize techniques and applications into an intervention program (logic model), plan for program adoption, implementation, and sustainability, and generate an evaluation plan. This protocol was used in different countries and domains such as obesity, tobacco, physical activity, cancer and occupational health. Although its utilization requires resources and a critical stance, this protocol was used to develop interventions which efficacy was demonstrated. CONCLUSION: The intervention mapping protocol is an integrated process that fits the scientific and practical challenges of health promotion. It could be tested in France as it was used in other countries, in particular to reduce social inequalities in health. PMID- 26745999 TI - [Point of view of older adults on the potentially inappropriate medications prescribing in primary care facilities in Bobo-Dioulasso, Burkina Faso]. AB - BACKGROUND: Little is known about the organization of primary care facilities in sub-Saharan Africa that might lead to potentially inappropriate prescribing. The aim of this study was to analyze the factors that could lead to potentially inappropriate prescribing in primary care facilities in Bobo-Dioulasso (Burkina Faso), taking into consideration the patient's perspective. METHODS: A cross sectional qualitative study was conducted in primary care facilities from November 2013 to February 2014. People aged 60 years or more with at least one chronic disease were included. Individual interviews were conducted. An analysis of the thematic content of the interviews was conducted. RESULTS: Our results showed that the patient referral system was insufficient. We also found many different prescribers for older people seeking care and poor communication between prescribers and patients. This caused some consequences such as the absence of review of drugs consumed before a new prescription, a lack of exchange on medication changes and repeated treatment change during hospitalization. Most of the persons who prescribed potentially inappropriate medications were nurses. CONCLUSION: The poor communication between prescribers and patients is a challenge for the prevention of prescribing potentially inappropriate medications. Teamwork is an important feature of the organizational care system, strengthening it could be a way to improve rational prescription. PMID- 26746000 TI - Health department beefed up Keogh strike letter, says Independent. PMID- 26745998 TI - Reference centres for adults with rare and complex cancers - Policy recommendations to improve the organisation of care in Belgium. AB - BACKGROUND: Rare and/or complex cancers call for a very specific expertise and adequate infrastructure. In Belgium, every hospital with a programme in oncology can deliver care for adults with rare and/or complex cancer types, without having demonstrated a specific know-how to adequately manage these patients. Therefore, the Minister of Health ordered a scenario for the organisation of care for adults with rare and/or complex cancers, taking into account the current Belgian situation and relevant foreign experience. METHODS: Combined methods were used in this study: a literature review, the consultation of stakeholders, in depth discussions in 14 multidisciplinary groups leading to concrete proposals for several rare/complex cancers and the consultation of a panel of expert pathologists. RESULTS: The core recommendation is the set-up of shared care networks around reference centres, with multidisciplinary teams of recognised expertise in specific rare/complex cancers. The definition of minimum caseloads for hospitals and medical specialists, the evaluation of the quality of care, a model of diagnostic confirmation and the set-up of a national portal website which provides information on rare and/or complex cancers and reference centres are highly recommended. CONCLUSION: It is no longer practicable, efficient or ethical that every hospital or every practitioner continues to offer care for every rare/complex cancer. Improving the quality of rare/complex cancer care requires to concentrate expertise and sophisticated infrastructure in reference centres. Furthermore, the formation of networks between reference centres and peripheral centres will allow a delivery of care combining expertise and proximity. The next step is the translation of the recommendations into policy decisions. It is very well realised that this will take some courage and that a certain degree of resistance will have to be surmounted, but eventually, the best interest of the patient should prevail. PMID- 26746001 TI - Quality of Life after Bladder Cancer: A Prospective Study Comparing Patient related Outcomes after Radical Surgery or Radical Radiotherapy for Bladder Cancer. PMID- 26746002 TI - Evaluating the Need for Daily Image Guidance in Head and Neck Cancers Treated with Helical Tomotherapy: A Retrospective Analysis of a Large Number of Daily Imaging-based Corrections. AB - AIMS: Clinical implementation of image-guided intensity-modulated radiotherapy is rapidly evolving. Helical tomotherapy treatment delivery involves daily imaging before intensity-modulated radiotherapy delivery. This can be a time consuming resource-intensive process, which may not be essential in head and neck radiotherapy, where effective immobilisation is possible. This study aimed to evaluate whether an offline protocol implementing the shifts derived from the first few fractions can be an acceptable alternative to daily imaging for helical tomotherapy. MATERIALS AND METHODS: We retrospectively analysed the set-up data of 2858 fractions of 100 head and neck cancer patients who were treated with daily online image guidance. Using summary data from all treatment fractions, we calculated the systematic error (?) and random error (sigma) in each of the three axes, i.e. mediolateral (x), craniocaudal (y), anteroposterior (z). We also calculated the translational vector of each fraction of individual patients. We then simulated two no-action-level offline protocols where set-up errors of the first three (protocol F3) or five fractions (protocol F5) were averaged and implemented for the remaining fractions. The residual errors in each axis for these fractions were determined together with the residual ? and sigma. Planning target volume (PTV) margins using the van Herk formula were generated based on the uncorrected errors as well as for the F3 and F5 protocols. For each scenario, we tabulated the number of fractions where the residual errors were more than 5 mm (our default PTV margin). We also tried to evaluate whether errors tended to differ based on intent (radical or adjuvant), anatomical subsite or weight loss during treatment. RESULTS: Analysis from this large dataset revealed that in the tomotherapy platform, the highest set-up errors were in the anteroposterior (z) axis. The global mean was 5.4 mm posterior shift, which can be partly attributed to couch sag on this system. Uncorrected set-up errors resulted in systematic and random errors of ?x,y,z of 1.8, 1.7 and 2 mm and sigmax,y,z of 1.7, 1.5 and 1.9 mm, with a required PTV margin in x, y, z axes of 5.7, 5.3 and 6.2 mm. Implementing average shifts from the first three or five fractions resulted in a substantial reduction in the residual systematic errors, whereas random errors remained constant. The PTV margins required for the residual errors after three and five fraction corrections were 3.8, 3.4 and 5.1 mm for F3 and 3.3, 2.9, 4.8 mm for F5. The proportions of fractions where there was >5 mm residual error were 1.6%, 1.1%, 2.9% in x, y and z axes in the F3 protocol and 1.5%, 0.8% and 2.6% with the F5 protocol. Although there was no difference in residual shifts > 5 mm, there was a statistically higher chance of residual errors > 3 mm larynx/hypopharynx subsites versus other sites. In patients who had more than 5% weight loss, there was no significant increase in residual errors with the F5 protocol and the required PTV margin was within our default PTV margins expansion. CONCLUSIONS: Correction of systematic errors by implementing average shifts from the first five fractions enables us to safely avoid daily imaging in this retrospective analysis. If this is validated in a prospective group it could lead to implementation of a resource sparing image-guided radiotherapy protocol both in terms of time and imaging dose. Patients with larynx/hypopharynx subsites may require more careful evaluation and daily online matching. PMID- 26746003 TI - What Is Chronic or Persistent Diabetic Macular Edema and How Should It Be Treated? PMID- 26746004 TI - The Logistics and Coordination of Respiratory Syncytial Virus Immunoprophylaxis Use Among US Pediatric Specialists. AB - This study was conducted to survey US pediatric specialists about administration of respiratory syncytial virus (RSV) immunoprophylaxis, communication patterns among physicians and parents, and barriers to access. Separate surveys were sent to neonatologists, pediatricians, pediatric pulmonologists, and pediatric cardiologists. Most physicians (>=93.5%) routinely recommended immunoprophylaxis to high-risk children. Most respondents (>=71.8%) reported that >50.0% of eligible infants and young children received each monthly dose throughout the RSV season, with the first dose most commonly administered before discharge from the birth hospitalization. To ensure receipt of subsequent doses, specialists frequently scheduled a follow-up visit at the end of the current appointment. All specialists reported insurance denials as the biggest obstacle to the administration of immunoprophylaxis to high-risk children. These findings may be used to improve adherence to immunoprophylaxis by enhancing education and physician-parent communications about severe RSV disease prevention, and by reducing known barriers to use of this preventive therapy. PMID- 26746005 TI - Crystal structure of nanoKAZ: The mutated 19 kDa component of Oplophorus luciferase catalyzing the bioluminescent reaction with coelenterazine. AB - The 19 kDa protein (KAZ) of Oplophorus luciferase is a catalytic component, that oxidizes coelenterazine (a luciferin) with molecular oxygen to emit light. The crystal structure of the mutated 19 kDa protein (nanoKAZ) was determined at 1.71 A resolution. The structure consists of 11 antiparallel beta-strands forming a beta-barrel that is capped by 4 short alpha-helices. The structure of nanoKAZ is similar to those of fatty acid-binding proteins (FABPs), even though the amino acid sequence similarity was very low between them. The coelenterazine-binding site and the catalytic site for the luminescence reaction might be in a central cavity of the beta-barrel structure. PMID- 26746006 TI - High affinity nucleotide-binding mutant of the epsilon subunit of thermophilic F1 ATPase. AB - Specific ATP binding to the epsilon subunit of thermophilic F1-ATPase has been utilized for the biosensors of ATP in vivo. I report here that the epsilon subunit containing R103A/R115A mutations can bind ATP with a dissociation constant at 52 nM, which is two orders of magnitude higher affinity than the wild type. The mutant retained specificity for ATP; ADP and GTP bound to the mutant with dissociation constants 16 and 53 MUM, respectively. Thus, the mutant would be a good platform for various types of nucleotide biosensor with appropriate modifications. PMID- 26746007 TI - Differentiation of protein species of alpha-2u-globulin according to database entries: A half-theoretical approach. AB - The alpha-2u-globulin protein, the main subject of this study, is the most abundant protein in adult male rat urine. In this investigation there are 19 spots identified as alpha-2u-globulin by 2-DE and MALDI-TOF/TOF-MS. All of them are in the low molecular weight region, at approximately 15-25kDa. Searches within both, SwissProt and NCBI databases gave different from each other, but on the majority the same database entry as the highest ranked result for all spots. For this half-theoretical approach all entries from the NCBI database for the protein alpha-2u-globulin were considered in more detail. The sequences and the masses of the theoretically resulting tryptic peptides were compared with the PMF spectra of the spots identified as alpha-2u-globulin. This study presents a trial to distinguish between different protein species of that protein, only on the amino acid level. Other modifications like phosphorylation, glycosylation or any other group modification could not be considered here. Different protein species can be predicted for groups of closer positioned spots. Statements about which spot contains which peptide variant can be done, too. But it was found that several spots contain more than one protein species. BIOLOGICAL SIGNIFICANCE: In this investigation a half-theoretically approach was shown to differentiate between protein species of different spots identified as the same protein. Different positions of spots in 2-DE gels mean different contents of protein species. Here, peptide masses from sequences of protein database entries were searched in the PMF spectra of alpha-2u-globulin. Different peptide variants could be assigned to different spots. It was also found that several spots contain more than one peptide variant and therefore more than one protein species. In addition, the insufficiency of the database has been demonstrated. PMID- 26746009 TI - Comparative analysis of Brassica napus plasma membrane proteins under phosphorus deficiency using label-free and MaxQuant-based proteomics approaches. AB - Phosphorus (P) deficiency is a primary constraint for plant growth in terrestrial ecosystems. To better understand the genotypic differences in the adaptation mechanism of Brassica napus to P deficiency, we purified the plasma membrane (PM) from the roots of two genotypes: P-efficient "Eyou Changjia" and P-inefficient "B104-2". Combining label-free quantitative proteomics with the MaxQuant approach, a total of 71 proteins that significantly changed in abundances were identified in the two genotypes in response to P-free starvation, including 31 in "Eyou Changjia" and 40 in "B104-2". Based on comparative genomics study, 28 proteins were mapped to the confidence intervals of quantitative trait loci (QTLs) for P efficiency related traits. Seven decreased proteins with transporter activity were found to be located in the PM by subcellular localization analyses. These proteins involved in intracellular protein transport and ATP hydrolysis coupled proton transport were mapped to the QTL for P content and dry weight. Compared with "B104-2", more decreased proteins referring to transporter activity were found in "Eyou Changjia", showing that substance exchange was decreased in response to short-term P-free starvation. Together with the finding, more decreased proteins functioning in signal transduction and protein synthesis/degradation suggested that "Eyou Changjia" could slow the progression of growth and save more P in response to short-term P-free starvation. BIOLOGICAL SIGNIFICANCE: P deficiency seriously limits the production and quality of B. napus. Roots absorb water and nutrients and anchor the plant in the soil. Therefore, to study root PM proteome under P stress would be helpful to understand the adaptation mechanism for P deficiency. However, PM proteome analysis in B. napus has been seldom reported due to the high hydrophobicity and low abundance of PM. Thus, we herein investigated the PM proteome alteration of roots in two B. napus genotypes, with different P deficient tolerances, in response to P-free starvation. The present study offers new insights and novel information for better understanding the adaptative response to P deficiency in B. napus. PMID- 26746008 TI - iTRAQ-based quantitative proteomic analysis of Macrobrachium rosenbergii hemocytes during Spiroplasma eriocheiris infection. AB - Spiroplasma eriocheiris, as a novel aquaculture pathogen, has led into catastrophic economic losses in aquaculture. The Macrobrachium rosenbergii hemocytes were major target cells in S. eriocheiris infection. Our study was designed to examine the hemocytes' immune response at the protein levels. The differential proteomes of the prawn hemocytes were analyzed immediately prior to injection with the pathogen, and at 192h post-injection by isobaric tags for relative and absolute quantization (iTRAQ) labeling, followed by liquid chromatogramphytandem mass spectrometry (LC-MS/MS). A total of 69 differentially expressed proteins were identified. Forty-nine proteins were up-regulated and 20 proteins were down-regulated resulting from a S. eriocheiris infection. Up regulated proteins included vertebrate gliacolin-like protein, vitellogenin, Gram negative binding protein 1, alpha2 macroglobulin isoform 2 (a2M), etc. Down regulated proteins, involved with beta-1,3-glucan-binding protein (BGBP), immunoglobulin like, Rab7, lipopolysaccharide and beta-1,3-glucan (LGBP), actin related protein, etc. Selected bioactive factors (tachylectin, alpha2M and vitellogenin, BGBP, C-type lectin, LGBP and Rab7) were verified by their immune roles in the S. eriocheiris infection using real-time PCR. The present work could serve as a basis for future studies on the proteins implicated in the susceptibility/resistance of M. rosenbergii to S. eriocheiris, as well as contribute to our understanding of disease processes in prawns. BIOLOGICAL SIGNIFICANCE: This is the first time using an iTRAQ approach to analyze proteomes of M. rosenbergii mobilized against S. eriocheiris infection and substantiated the hemocytes' proteomic changes in M. rosenbergii using an infection model. The results reported here can provide a significant step forward toward a more complete elucidation of the immune relationship between M. rosenbergii and the pathogen S. eriocheiris. PMID- 26746010 TI - Ciliary muscle contraction force and trapezius muscle activity during manual tracking of a moving visual target. AB - Previous studies have shown an association of visual demands during near work and increased activity of the trapezius muscle. Those studies were conducted under stationary postural conditions with fixed gaze and artificial visual load. The present study investigated the relationship between ciliary muscle contraction force and trapezius muscle activity across individuals during performance of a natural dynamic motor task under free gaze conditions. Participants (N=11) tracked a moving visual target with a digital pen on a computer screen. Tracking performance, eye refraction and trapezius muscle activity were continuously measured. Ciliary muscle contraction force was computed from eye accommodative response. There was a significant Pearson correlation between ciliary muscle contraction force and trapezius muscle activity on the tracking side (0.78, p<0.01) and passive side (0.64, p<0.05). The study supports the hypothesis that high visual demands, leading to an increased ciliary muscle contraction during continuous eye-hand coordination, may increase trapezius muscle tension and thus contribute to the development of musculoskeletal complaints in the neck-shoulder area. Further experimental studies are required to clarify whether the relationship is valid within each individual or may represent a general personal trait, when individuals with higher eye accommodative response tend to have higher trapezius muscle activity. PMID- 26746011 TI - Anticipation of direction and time of perturbation modulates the onset latency of trunk muscle responses during sitting perturbations. AB - Trunk muscles are responsible for maintaining trunk stability during sitting. However, the effects of anticipation of perturbation on trunk muscle responses are not well understood. The objectives of this study were to identify the responses of trunk muscles to sudden support surface translations and quantify the effects of anticipation of direction and time of perturbation on the trunk neuromuscular responses. Twelve able-bodied individuals participated in the study. Participants were seated on a kneeling chair and support surface translations were applied in the forward and backward directions with and without direction and time of perturbation cues. The trunk started moving on average approximately 40ms after the perturbation. During unanticipated perturbations, average latencies of the trunk muscle contractions were in the range between 103.4 and 117.4ms. When participants anticipated the perturbations, trunk muscle latencies were reduced by 16.8+/-10.0ms and the time it took the trunk to reach maximum velocity was also reduced, suggesting a biomechanical advantage caused by faster muscle responses. These results suggested that trunk muscles have medium latency responses and use reflexive mechanisms. Moreover, anticipation of perturbation decreased trunk muscles latencies, suggesting that the central nervous system modulated readiness of the trunk based on anticipatory information. PMID- 26746012 TI - New Insights in the Optic Radiations Connectivity in the Human Brain. AB - PURPOSE: To study optic radiations connectivity by means of advanced magnetic resonance imaging (MRI) approaches, noninvasively, in vivo, in healthy human brains. METHODS: Sixteen healthy subjects (nine males, age range, 25-40 years) were included in this study. Morphologic and diffusion data were acquired by means of a 3T MRI scanner. Using an advanced tractographic technique, based on probabilistic constrained spherical deconvolution algorithm, postprocessing analyses were performed. Statistical analysis was carried out using the 2-tailed Wilcoxon rank sum test. Outcome measure was the percentage distribution of optic radiations streamlines in different cortical visual areas (V1-V5). The latter were detected by means of Juelich probabilistic histologic atlas. RESULTS: Average connectivity analyses revealed that the optic radiations are mainly distributed in V1 (47.46% +/- 5.5) and V2 (32.45% +/- 3.98); furthermore, direct connections with V3 (7.81 +/- 3.06), V4 (4.22% +/- 1.82), and V5 (8.06% +/- 2.65) were also detected. CONCLUSIONS: In the present study, the connectivity profile of optic radiations, obtained by means of algorithms not affected by the limitations of other tractographic techniques, such as diffusion tensor imaging, was shown in healthy human brains. Interestingly, direct connections with V4 were detected for the first time in humans; moreover, further support on the possible existence of V5 connections was provided. Our findings showed new connections between lateral geniculate nuclei and cortical visual areas, giving a further possible comprehension of the phenomena leading to the visual signals elaboration. PMID- 26746014 TI - MicroRNA-124 Controls Transforming Growth Factor beta1-Induced Epithelial Mesenchymal Transition in the Retinal Pigment Epithelium by Targeting RHOG. AB - PURPOSE: MicroRNA-124 (miR-124) is thought to be involved in the epithelial mesenchymal transition (EMT) of RPE. We investigated the regulation of TGF-beta1 induced EMT by miR-124 in human RPE cells (ARPE-19). METHODS: Expression of miR 124 was evaluated after TGF-beta1 treatment by quantitative RT-PCR. Phenotypic alterations were analyzed by Western blot analysis and immunocytochemical staining. Target validation was performed by a luciferase reporter assay to identify the putative target of miR-124. RESULTS: The expression level of miR-124 was downregulated during the progression of EMT. Overexpression of miR-124 upregulated the levels of zonular occludens 1 and occludin, and downregulated those of fibronectin, alpha-smooth muscle actin, and vimentin. Furthermore, inhibition of endogenous miR-124 increased and decreased the levels of mesenchymal and epithelial factors, respectively. TargetScan predicted two well conserved and two vertebrate-only conserved miR-124 target sequences in the 3' untranslated region (UTR) of the Ras homology Growth-related (RHOG) mRNA. Direct targeting of this 3' UTR by miR-124 was demonstrated using a luciferase assay. Silencing of RHOG using a specific siRNA had identical effects on EMT regulation. Overexpression of miR-124 repressed TGF-beta1-induced RPE cell-collagen gel lattice contraction by altering cell spreading/cell-to-cell adhesion. CONCLUSIONS: This study describes the regulation of EMT in RPE cells by TGF beta1/miR-124/RHOG signaling and suggests that the supplement of miR-124 exogenously would be a valuable therapeutic approach for the prevention or treatment of proliferative vitreoretinopathy. PMID- 26746013 TI - Aqueous Angiopoietin-Like 4 Levels Correlate With Nonperfusion Area and Macular Edema in Branch Retinal Vein Occlusion. AB - PURPOSE: To investigate whether macular edema (ME) due to branch retinal vein occlusion (BRVO) associates with retinal overexpression of angiopoietin-like 4 (ANGPTL4). The aqueous ANGPTL4 and vascular endothelial growth factor (VEGF) levels in patients with ME due to BRVO were measured, and the relationships between ANGPTL4 levels and the degree of retinal ischemia and edema were determined. METHODS: The study and control groups consisted of all consecutive patients who were scheduled to undergo intravitreal bevacizumab injection for treatment-naive BRVO with ME and senile cataract surgery, respectively. The study group was divided into the major BRVO and macular BRVO subgroups on the basis of the involved retinal area. The aqueous ANGPTL4 and VEGF levels were measured by enzyme-linked immunosorbent assay. In the patients with BRVO, capillary nonperfusion area by fluorescein angiography and central subfield macular thickness (CSMT) and total macular volume (TMV) by spectral-domain optical coherence tomography were determined. RESULTS: Patients with ME due to BRVO (50 eyes) had higher aqueous ANGPTL4 and VEGF levels than the controls (61 eyes) (both P < 0.001). The major BRVO had higher ANGPTL4 and VEGF levels than the macular BRVO (both P < 0.001). The aqueous ANGPTL4 levels of all BRVO patients correlated positively with nonperfusion area (r = 0.901, P < 0.001), CSMT (r = 0.574, P < 0.001), and TMV (r = 0.453, P = 0.001), even after adjustment for VEGF levels. CONCLUSIONS: The aqueous ANGPTL4 levels correlated significantly with phenotypes of BRVO with ME. This suggests that ANGPTL4 may be a candidate biomarker and treatment target in ischemia-induced retinopathies, including BRVO. PMID- 26746016 TI - Inhibition by the Antimicrobial Peptide LL37 of Lipopolysaccharide-Induced Innate Immune Responses in Human Corneal Fibroblasts. AB - PURPOSE: The synthesis of cytokines and adhesion molecules by corneal fibroblasts contributes to the innate immune response to corneal infection. The effects of the antimicrobial peptide LL37 on cytokine and adhesion molecule expression induced by bacterial lipopolysaccharide (LPS) in human corneal fibroblasts were examined. METHODS: The release of the cytokines IL-6 and IL-8 into culture supernatants and the expression of intercellular adhesion molecule (ICAM)-1 at the cell surface were measured with ELISAs and by flow cytometry. The abundance of mRNAs was quantitated by RT and real-time PCR analysis, and the phosphorylation of signaling proteins was examined by immunoblot analysis. The subcellular localization of ICAM-1 and the transcription factor nuclear factor (NF)-kappaB was determined by immunofluorescence analysis. Neutrophil infiltration in a mouse model of LPS-induced keratitis was evaluated by immunohistofluorescence analysis. RESULTS: The antimicrobial peptide LL37 inhibited the up-regulation of IL-6, IL-8, and ICAM-1 both at protein and mRNA levels in corneal fibroblasts induced by LPS without affecting those elicited by TNF-alpha. Furthermore, LL37 attenuated the LPS-induced phosphorylation of the NF kappaB inhibitor IkappaBalpha and the mitogen-activated protein kinases extracellular signal-regulated kinase, p38, and c-Jun NH2-terminal kinase, as well as the translocation of NF-kappaB to the nucleus in corneal fibroblasts. Lipopolysaccharide-induced keratitis in mice was also suppressed by topical application of LL37. CONCLUSIONS: The inhibition of LPS-induced cytokine and adhesion molecule expression in human corneal fibroblasts by LL37 suggests that this peptide might promote the resolution of corneal inflammation associated with bacterial infection. PMID- 26746015 TI - The Pupillary Light Reflex in Idiopathic Intracranial Hypertension. AB - PURPOSE: To evaluate the effects of idiopathic intracranial hypertension (IIH) on rod-, cone-, and melanopsin-mediated pupillary light reflexes (PLRs). METHODS: Pupillary light reflexes elicited by full-field, brief-flash stimuli were recorded in 13 IIH patients and 13 normal controls. Subjects were dark-adapted for 10 minutes and the PLR was recorded in response to short-wavelength flashes (0.001 cd/m2: rod condition; 450 cd/m2: melanopsin condition). Subjects were then exposed to a rod-suppressing field and 10 cd/m2 long-wavelength flashes were presented (cone condition). Pupillary light reflexes were quantified as the maximum transient constriction (rod and cone conditions) and the post illumination pupil constriction (melanopsin condition), relative to the baseline pupil size. Diagnostic power was evaluated using receiver operating characteristic (ROC) analysis. RESULTS: The IIH patients had significantly smaller PLRs under the melanopsin (P < 0.001) and rod (P = 0.04) paradigms; a trend for reduced cone-mediated PLRs was also found (P = 0.08). Receiver operating characteristic analysis indicated areas under the curves (AUC) of 0.83 (melanopsin-meditated; P = 0.001), 0.71 (rod-mediated; P = 0.07), and 0.77 (cone mediated; P = 0.02). The AUC (0.90, P < 0.001), sensitivity (85%), and specificity (85%) were high for ROC analysis performed on the mean of the rod, cone, and melanopsin PLRs. CONCLUSIONS: Pupillary light reflex reductions in IIH patients indicate compromised RGC function. PLR measurement, particularly under rod- and melanopsin-mediated conditions, may be a useful adjunct to standard clinical measures of visual function in IIH. PMID- 26746019 TI - Thriving With Mindfulness. PMID- 26746017 TI - Vitreous Microparticle Shedding in Retinal Detachment: A Prospective Comparative Study. AB - PURPOSE: Microparticles (MPs) are membrane-derived vesicles measuring less than 1 MUm in diameter. They are shed from nearly every activated or preapoptotic cell and may exhibit biologic activities in inflammation or apoptosis settings. The main purpose of this study was to determine whether MP shedding was higher in the vitreous of patients with retinal detachment (RD). METHODS: This was a prospective, comparative study. Levels of vitreous MPs (including phosphatidylserine [PS]-expressing MPs, photoreceptor cell-derived MPs, and photoreceptor cell-derived MPs expressing PS) and soluble proinflammatory factors (i.e., monocyte chemoattractant protein-1, intercellular adhesion molecule-1, and IL-6) were analyzed by flow cytometry. Samples were obtained from 49 eyes undergoing RD surgery and 41 control eyes. RESULTS: Vitreous levels of all the MPs studied were significantly increased in the RD group. Vitreous MP levels were correlated with levels of at least one proinflammatory factor depending on MP subsets. Concerning clinical parameters, vitreous PS-expressing MP and PS expressing photoreceptor cell-derived MP levels were higher depending on the duration of RD at surgery, the detached retina surface, and the macula status and were found more sensitive than proinflammatory factors only for the duration of RD at surgery. CONCLUSIONS: Vitreous concentrations of MPs (mainly derived from photoreceptor cells) are higher after rhegmatogenous RD and found to be correlated with soluble proinflammatory factors. PMID- 26746018 TI - Assessment of blood lead level declines in an area of historical mining with a holistic remediation and abatement program. AB - Lead exposure and blood lead levels (BLLs) in the United States have declined dramatically since the 1970s as many widespread lead uses have been discontinued. Large scale mining and mineral processing represents an additional localized source of potential lead exposure in many historical mining communities, such as Butte, Montana. After 25 years of ongoing remediation efforts and a residential metals abatement program that includes blood lead monitoring of Butte children, examination of blood lead trends offers a unique opportunity to assess the effectiveness of Butte's lead source and exposure reduction measures. This study examined BLL trends in Butte children ages 1-5 (n= 2796) from 2003-2010 as compared to a reference dataset matched for similar demographic characteristics over the same period. Blood lead differences across Butte during the same period are also examined. Findings are interpreted with respect to effectiveness of remediation and other factors potentially contributing to ongoing exposure concerns. REFERENCE POPULATION COMPARISON: BLLs from Butte were compared with a reference dataset (n=2937) derived from the National Health and Nutrition Examination Survey. The reference dataset was initially matched for child age and sample dates. Additional demographic factors associated with higher BLLs were then evaluated. Weights were applied to make the reference dataset more consistent with the Butte dataset for the three factors that were most disparate (poverty-to-income ratio, house age, and race/ethnicity). A weighted linear mixed regression model showed Butte geometric mean BLLs were higher than reference BLLs for 2003-2004 (3.48vs. 2.05ug/dL), 2005-2006 (2.65vs. 1.80ug/dL), and 2007-2008 (2.2vs. 1.72ug/dL), but comparable for 2009-2010 (1.53vs. 1.51ug/dL). This trend suggests that, over time, the impact of other factors that may be associated with Butte BLLs has been reduced. COMPARISON ACROSS BUTTE: Neighborhood differences were examined by dividing the Butte dataset into the older area called "Uptown", located at higher elevation atop historical mine workings, and "the Flats", at lower elevation and more recently developed. Significant declines in BLLs were observed over time in both areas, though Uptown had slightly higher BLLs than the Flats (2003-2004: 3.57vs. 3.45ug/dL, p=0.7; 2005-2006: 2.84vs. 2.52ug/dL, p=0.1; 2007-2008: 2.58vs. 1.99ug/dL, p=0.001; 2009-2010: 1.71vs. 1.44ug/dL, p=0.02). BLLs were higher when tested in summer/fall than in winter/spring for both neighborhoods, and statistically higher BLLs were found for children in Uptown living in properties built before 1940. Neighborhood differences and the persistence of a greater percentage of high BLLs (>5ug/dL) in Butte vs. the reference dataset support continuation of the home lead abatement program. CONCLUSIONS: Butte BLL declines likely reflect the cumulative effectiveness of screening efforts, community-wide remediation, and the ongoing metals abatement program in Butte in addition to other factors not accounted for by this study. As evidenced in Butte, abatement programs that include home evaluations and assistance in addressing multiple sources of lead exposure can be an important complement to community-wide soil remediation activities. PMID- 26746020 TI - Perioperative Nurse Engagement in Lifelong Learning. PMID- 26746021 TI - The Iowa Model. PMID- 26746022 TI - AORN Surgical Conference & Expo 2016 Speaker Interviews. PMID- 26746028 TI - AORN's Revised Model for Evidence Appraisal and Rating. AB - AORN perioperative practice specialists responsible for authoring the Guidelines for Perioperative Practice have spent several years using evidence-based practice tools adapted from other organizations. AORN now has its own evidence appraisal tools and model for evidence-based practice that can be used by nurses and students to appraise research and nonresearch articles and assign an evidence rating to help inform perioperative practice decisions. The new and revised tools include a new evidence rating model, hierarchy of evidence, and expanded appraisal tools. PMID- 26746029 TI - Patient Abuse in the Health Care Setting: The Nurse as Patient Advocate. AB - Incidents of verbal and physical patient abuse in health care settings continue to occur, with some making headline news. Nurses have a professional and ethical responsibility to advocate for their patients when incidents of abuse occur. Tolerating or ignoring inappropriate behaviors occurs for multiple reasons, including ignorance, fear of retaliation, the need for peer acceptance, and concerns for personal advancement. Nurses need to reflect on their biases before they can truly respect patients' autonomy. Through the examination of reported cases of patient abuse, the need for a change in hospital culture becomes evident. The primary steps in eliminating patient abuse are opening communication, providing education, establishing competency, eliminating tolerance of unacceptable behavior, and creating a code of mutual respect. A change in culture to one of mutual respect and dignity for staff members and patients will lead to the best outcomes for all involved. PMID- 26746030 TI - Reducing OR Traffic Using Education, Policy Development, and Communication Technology. AB - A bundled approach to surgical site infection (SSI) prevention strategies includes reducing OR traffic. A nurse-led quality improvement (QI) team sought to reduce OR traffic through education and a process change that included wireless communication technology and policy development. The team measured OR traffic by counting the frequency of door openings per hour in seven surgical suites during 305 surgical procedures conducted during similar 22-week periods before and after the QI project intervention. Door openings decreased significantly (P < 0.05) from an average of 37.8 per hour to 32.8 per hour after the QI project intervention. This suggests that our multifaceted approach reduces OR traffic. The next steps of this project include analyzing automatically captured video to understand OR traffic patterns and expanding education to departments and external personnel frequently present in our surgical suites. Future research evaluating the effectiveness of this OR traffic initiative on SSI incidence is recommended. PMID- 26746031 TI - Student Nurses in the OR: Improving Recruitment and Retention. AB - Changes in nursing education have made it difficult for students to find or participate in perioperative clinical experiences, which makes it difficult for employers to find experienced perioperative nurses. We developed a perioperative preceptorship for senior-level nursing students, to provide them with the opportunity to learn RN circulator skills based on AORN's Guidelines for Perioperative Practice. Senior nursing students had the opportunity to demonstrate critical thinking skills within the context of patient-centered care while integrating knowledge and skills learned in the classroom. The students applied the knowledge and skills learned in the classroom in the OR setting during a required minimum 210-hour clinical commitment. We believe the course has been successful in providing the foundation needed to become a competent perioperative nurse, because, to date, all students who were hired are still employed in the OR. PMID- 26746032 TI - Back to Basics: Surgical Skin Antisepsis. AB - The fundamental basis for preventing surgical site infections is the antiseptic preparation of the skin at the surgical site. All perioperative nurses must learn this skill. The goal of surgical skin antisepsis, frequently referred to as prepping the skin, is to remove soil and transient (ie, temporary) microorganisms living on the skin that could pose a risk for surgical site infections. This Back to Basics article examines the origin of surgical skin antisepsis and the steps perioperative nurses should take to provide the patient with an aseptic surgical site before any surgical or other invasive procedure. PMID- 26746033 TI - Bullying in the Workplace: A Leadership Perspective. PMID- 26746034 TI - Social Media in the OR: More Than Just Cell Phones. PMID- 26746036 TI - Fire in the Hole!--An OR Fire. PMID- 26746037 TI - Preparing the Next Generation of Perioperative Nurses. AB - Perioperative nursing faces a workforce crisis. There are too few perioperative nurses entering the workforce to replace those who will reach retirement age. Further, the costs of orienting perioperative nurses is high, and turnover rates in the first year after graduation are significant. To address these issues, nursing leaders at Theda Clark Medical Center, Neenah, Wisconsin, and the University of Wisconsin Oshkosh College of Nursing partnered with local medical centers to form a precepted clinical immersion program intended to orient senior baccalaureate nursing students to the perioperative setting. The students were hired after graduation, and the cost savings for orienting each new employee was estimated at $16,000 to $25,000 per student. Other benefits include identifying students who are and are not a good fit for perioperative nursing. The collaboration of health care and academic leaders is one solution for addressing the perioperative nursing workforce crisis. PMID- 26746038 TI - Factors Disrupting the Preference Card Management Process: A Root Cause Analysis. AB - Preference cards, the nexus of an efficient OR, help ensure that OR personnel have what they need to safely and efficiently care for surgical patients. In June 2013, a new electronic health record (EHR) was implemented in the ORs of the Duke University Health System, Durham, North Carolina. Although it was an integrated system, the EHR disrupted supply management in the OR, which affected the availability of correct resources. The project team performed a process improvement project using root cause analysis (RCA) to identify the factors that led to the disruption in the preference card management process for orthopedic surgical procedures. Team members identified that a chief cause of resource disruption was the mistiming of interface messages that created the pick lists and requisition forms. Based on the results of the RCA, the project team developed and implemented recommendations for process improvement. PMID- 26746039 TI - Patellar instability and quadriceps avoidance affect walking knee moments. AB - PURPOSE: To classify patients with patellofemoral (PF) instability on the basis of their mechanical gait characteristics, and to relate gait deficits to patellofemoral congruence. METHODS: Thirteen patients awaiting patellar stabilisation surgery were recruited for gait analysis and magnetic resonance imaging, MRI assessment of PF congruence. Patients were grouped into two subgroups (P1, P2) based on knee joint moment during stance, and their total support moments (TSMs) during stance were compared against eight healthy Control subjects. PF congruence was compared between groups from MRI data captured at 0, 20 and 40 degrees of passive knee flexion and during dynamic extension. RESULTS: Five patients were classified into group P1 because they demonstrated a knee extensor moment during early stance, and eight patients into group P2 because they did not. The TSM of the more affected limb in group P1 was not significantly different from Control values in early stance but the difference was significant (P<.05) in late stance. In group P2, both the less and more affected limbs were significantly different from Control TSM values in early stance, but only the more affected limb in late stance. Patellofemoral contact areas as measured by MRI were greatest for the Control patients, and least for patient group P2 especially during the active extension trials. CONCLUSIONS: Patients with patellofemoral pain and instability walked with a slightly flexed knee, avoiding extension. The MRI measurements of joint contact agreed with the patient groupings according to gait mechanics. Cartilage contact across the PF joint can be an objective measure of instability. PMID- 26746040 TI - Inter-observer reliability of measurements performed on digital long-leg standing radiographs and assessment of validity compared to 3D CT-scan. AB - BACKGROUND: Long-leg radiographs (LLR) are often used in orthopaedics to assess limb alignment in patients undergoing total knee arthroplasty (TKA). However, there are still concerns about the adequacy of measurements performed on LLR. We assessed the reliability and validity of measurements on LLR using three dimensional computed tomography (3D CT)-scan as a gold standard. METHODS: Six different surgeons measured the mechanical axis and position of the femoral and tibial components individually on 24 LLR. Intraclass correlation coefficients (ICC) were calculated to obtain reliability and Bland-Altman plots were constructed to assess agreement between measurements on LLR and measurements on 3D CT-scan. RESULTS: ICC agreement for the six observer measurements on LLR was 0.70 for the femoral component and 0.80 for the tibial component. The mean difference between measurements performed on LLR and 3D CT-scan was 0.3 degrees for the femoral component and -1.1 degrees for the tibial component. Variation of the difference between LLR and 3D CT-scan for the femoral component was 1.1 degrees and 0.9 degrees for the tibial component. 95% of the differences between measurements performed on LLR and 3D CT-scan were between -1.9 and 2.4 degrees (femoral component) and between -2.9 and 0.7 (tibial component). CONCLUSION: Measurements on LLR show moderate to good reliability and, when compared to 3D CT-scan, show good validity. CLINICAL TRIAL REGISTRATION NUMBER: institutional review board Atrium-Orbis-Zuyd, number: 11-T-15. LEVEL OF EVIDENCE: Prospective cohort study, Level II. PMID- 26746041 TI - Polypropylene mesh augmentation for complete quadriceps rupture after total knee arthroplasty. AB - INTRODUCTION: Polypropylene mesh has previously been shown to be an effective treatment for failed patellar tendon repairs after total knee arthroplasty (TKA), but there have been few reports of this synthetic mesh used in complete quadriceps rupture after TKA. METHODS: We retrospectively reviewed seven consecutive cases in six patients with complete quadriceps tears after TKA who had their quadriceps tendon repaired with suture and polypropylene mesh augmentation. All but two patients had previously failed primary suture repair. Patient outcomes were evaluated using the Knee Society Score. Standardized anterior-posterior (AP), lateral and merchant radiographs were evaluated preoperatively and at final follow-up. RESULTS: Seven knees in six patients were evaluated with a mean follow-up of 34+/-10 (range 24 to 49months) months. There were only four clinical successes defined as an extensor lag less than 30 degrees . Of the functioning knees at final follow-up (n=5) the overall extensor lag in this group did significantly improve from 50+/-13 degrees to 20+/-15 degrees (range 5 to 40 degrees ) (p=.01). Mean postoperative flexion at final follow-up was 115+/-8 degrees . Mean Knee Society Score for function improved from 20+/-30 to 45+/-54 (p=.03) as did the mean Knee Society Score for pain (44+/-18 vs. 74+/ 78, p=.02). DISCUSSION: Polypropylene mesh offered limited postoperative functional results when used as an augment to the multiply operated knee that sustains a complete quadriceps rupture after TKA, but did allow for significant improvement in postoperative pain outcomes. LEVEL OF EVIDENCE: IV. PMID- 26746042 TI - The impact of custom cutting guides on patient satisfaction and residual symptoms following total knee arthroplasty. AB - BACKGROUND: Custom cutting guides (CCGs) in total knee arthroplasty (TKA) use preoperative three-dimensional (3-D) imaging to manufacture cutting blocks specific to a patient's anatomy. The purpose of this study was to evaluate the impact of CCGs versus standard intramedullary and extramedullary guides on patient-reported satisfaction and residual symptoms following TKA. METHODS: A retrospective, multicenter study was performed to compare a magnetic resonance imaging-based CCG system versus standard instrumentation. All patients received the same, cemented, fixed-bearing, cruciate-retaining component, and had a primary diagnosis of osteoarthritis. Data was collected by an independent, third party survey center blinded to surgical technique that administered telephone questionnaires assessing patient satisfaction and symptoms. Patient age, gender, minority status, education level, income, length of follow-up, and pre-arthritic UCLA scores were considered potential confounders and accounted for using multivariate logistic regression analyses. RESULTS: 448 patients (107 CCGs, 341 standard) were successfully interviewed. At a mean follow-up of threeyears, there was no difference in percentage of patients reporting their knee to feel "normal" (74% CCG versus 78% standard, p=0.37). Residual symptoms including knee stiffness (37% CCG versus 28% standard, p=0.08) and difficulty getting in and out of car (34% CCG versus 30% standard, p=0.40) remained high. Multivariate regression analyses demonstrated no differences between the two cohorts for both patient reported satisfaction and residual symptoms (odds ratios 0.72 to 1.48; p=0.10 to 0.81). CONCLUSION: When interviewed by an independent, blinded third party, the use of CCGs in TKA did not improve patient-reported satisfaction or residual symptoms versus the use of standard alignment guides. PMID- 26746043 TI - Focal intratendinous radiolucency: A new radiographic method for diagnosing patellar tendon ruptures. AB - BACKGROUND: Diagnosis of patellar tendon rupture is usually based on clinical history and examination. In equivocal cases, imaging may be required. Lateral radiograph is a simple and cost-effective method for prompt diagnosis. However, no specific radiological sign has been described. Rather than utilising patella alta as an indirect measure of patellar tendon rupture, we hypothesise that a focal intratendinous radiolucency is another reliable and accurate radiological sign for diagnosis. Sensitivity and specificity analysis was undertaken to evaluate the diagnostic value of this radiographic sign. METHODS: Lateral radiographs of mid-substance patellar tendon ruptures from 19 patients were analysed. These were then randomised with another 19 normal knee radiographs from age-matched patients to create a pool of 38 radiographs for interpretation. Six independent interpreters who were blinded to the diagnosis were requested to indicate whether rupture was present or absent based on the visualisation of a focal intratendinous radiolucency in the patellar tendon. The Insall-Salvati (IS), Caton-Deschamps (CD) and Blackburne-Peel (BP) ratios were measured in the same radiographs. Sensitivity and specificity for each of the radiographic measurements were calculated. Inter- and intraobserver correlations were reported in kappa statistics. RESULTS: The average sensitivity and specificity for focal radiolucency in the patellar tendon substance were 82.5% and 95.2%, respectively. Sensitivity and specificity for the IS ratio were 84.2% and 78.9%, for CD was 68.4% and 84.2% and for BP was 68.4% and 89.4% respectively. CONCLUSION: The presence of a focal intratendinous radiolucency in the patellar tendon is both accurate and reliable in diagnosing patellar tendon ruptures. PMID- 26746044 TI - Intravenous versus intra-articular tranexamic acid in total knee arthroplasty: A double-blinded randomised controlled noninferiority trial. AB - BACKGROUND: Despite the proven efficacy of both intravenous (IV) and intra articular (IA) tranexamic acid (TXA) in reducing blood loss during total knee arthroplasty (TKA), the ideal route of administration remained debatable. This study aimed to compare the effect of IV versus IA TXA on transfusion incidences, perioperative blood loss and postoperative lower limb swelling during TKA. METHODS: One hundred patients were prospectively randomised into two groups: 1) IV TXA; and 2) IA TXA. In both groups, TXA was administered intraoperatively after cementing the prostheses. The perioperative blood loss was calculated using the haemoglobin balance method. The thigh, suprapatellar, and calf girths were measured preoperatively and on postoperative day (POD) 4. RESULTS: Two patients in the IV group and one patient in the IA group required blood transfusion (p=0.500). The median and interquartile range (IQR) of perioperative blood loss on POD1 and POD4 was 530 (IQR 386,704) and 730 (IQR 523,925) ml for the IV group, compared with 613 (IQR 506,703) and 799 (IQR 563,1067) ml for the IA group (p=0.090 and p=0.232 respectively). The median increment in thigh, suprapatellar, and calf girths were 1.5 (IQR 0, 3.0), 2.0 (IQR 0.5, 4.0) and 0 (IQR 0, 1.0) cm for the IV group, compared to 2.0 (IQR 1.0, 4.0), 2.0 (IQR 0, 4.5) and 0 (IQR 0, 1.5) cm for the IA group (p=0.246, p=0.562, and p=0.937 respectively). CONCLUSIONS: Both IV and IA TXA had comparable effect on transfusion incidences, perioperative blood loss, and postoperative lower limb swelling during TKA. IA TXA is an alternative to IV TXA. LEVEL OF EVIDENCE: I. PMID- 26746045 TI - Inter- and intra-rater reliability of patellofemoral kinematic and contact area quantification by fast spin echo MRI and correlation with cartilage health by quantitative T1rho MRI. AB - BACKGROUND: Patellar maltracking is a leading cause of patellofemoral pain syndrome (PFPS). The aim of this study was to determine the inter- and intra rater reliability of a semi-automated program for magnetic resonance imaging (MRI) based patellofemoral kinematics. METHODS: Sixteen subjects (10 with PFPS [mean age 32.3; SD 5.2; eight females] and six controls without PFPS 19 [mean age 28.6; SD 2.8; three females]) participated in the study. One set of T2-weighted, fat-saturated fast spin-echo (FSE) MRIs were acquired from each subject in full extension and 30 degrees of knee flexion. MRI including axial T1rho relaxation time mapping sequences was also performed on each knee. Following image acquisitions, regions of interest for kinematic MRI, and patellar and trochlear cartilage were segmented and quantified with in-house designed spline- based MATLAB semi-automated software. RESULTS: Intraclass Correlations Coefficients (ICC) of calculated kinematic parameters were good to excellent, ICC > 0.8 in patellar flexion, rotation, tilt, and translation (anterior -posterior, medial lateral, and superior -inferior), and contact area translation. Only patellar tilt in the flexed position and motion from extended to flexed state was significantly different between PFPS and control patients (p=0.002 and p=0.006, respectively). No significant correlations were identified between patellofemoral kinematics and contact area with T1rho relaxation times. CONCLUSIONS: A semi automated, spline-based kinematic MRI technique for patellofemoral kinematic and contact area quantification is highly reproducible with the potential to help better understand the role of patellofemoral maltracking in PFPS and other knee disorders. LEVEL OF EVIDENCE: Level IV. PMID- 26746046 TI - Antisense Oligonucleotides for Duchenne Muscular Dystrophy: Why No Neurologist Should Skip This. PMID- 26746047 TI - Phospholipase Cbeta connects G protein signaling with RNA interference. AB - Phosphoinositide-specific-phospholipase Cbeta (PLCbeta) is the main effector of Galphaq stimulation which is coupled to receptors that bind acetylcholine, bradykinin, dopamine, angiotensin II as well as other hormones and neurotransmitters. Using a yeast two-hybrid and other approaches, we have recently found that the same region of PLCbeta that binds Galphaq also interacts with Component 3 Promoter of RNA induced silencing complex (C3PO), which is required for efficient activity of the RNA-induced silencing complex. In purified form, C3PO competes with Galphaq for PLCbeta binding and at high concentrations can quench PLCbeta activation. Additionally, we have found that the binding of PLCbeta to C3PO inhibits its nuclease activity leading to reversal of RNA-induced silencing of specific genes. In cells, we found that PLCbeta distributes between the plasma membrane where it localizes with Galphaq, and in the cytosol where it localizes with C3PO. When cells are actively processing small interfering RNAs the interaction between PLCbeta and C3PO gets stronger and leads to changes in the cellular distribution of PLCbeta. The magnitude of attenuation is specific for different silencing RNAs. Our studies imply a direct link between calcium responses mediated through Galphaq and post-transcriptional gene regulation through PLCbeta. PMID- 26746090 TI - Real-time in vivo assessment of radiofrequency ablation of human colorectal liver metastases using diffuse reflectance spectroscopy. AB - BACKGROUND: The success of radiofrequency (RF) ablation is limited by the inability to assess thermal tissue damage achieved during or immediately after the procedure. The goal of this proof-of-principle study was to investigate whether diffuse reflectance (DR) spectroscopy during and after RF ablation of liver tumours could aid in detecting complete tissue ablation. MATERIAL AND METHODS: DR spectra were acquired in vivo in eight patients undergoing RF ablation for unresectable colorectal liver metastases, using a disposable spectroscopy needle. Intraoperative ultrasound imaging was used for accurate positioning of the RF electrode and the spectroscopy needle. Spectral changes were quantified and correlated to tissue histopathology and follow-up CT imaging. RESULTS: For the lesions in which ablation was monitored by DR spectroscopy (N = 8), median tumour size was 1.6 cm (range 0.8-3.3 cm). We found an excellent correlation (97-99%) between thermal damage suggested by spectral changes and histology. DR spectroscopy allowed discrimination between non-ablated and ablated tissue, regardless whether the needle was placed in tumour tissue or in surrounding liver tissue. Additional measurements performed continuously during ablation confirmed that the magnitude of spectral change correlates with the histochemical degree of thermal damage. CONCLUSIONS: Diffuse reflectance spectroscopy allows accurate quantification of thermal tissue damage during and after RF ablation. Real-time feedback by DR spectroscopy could improve the accuracy and quality of the RF procedures by lowering incomplete ablation rates. PMID- 26746089 TI - Stapled orthotopic ileal neobladder after radical cystectomy for bladder cancer: Functional results and complications over a 20-year period. AB - AIMS: To present the long term-results and complications of a large series of stapled ileal orthotopic neobladders. MATERIALS AND METHODS: From 1992 to 2012 we performed 606 radical cystectomies with stapled orthotopic neobladder substitution in male patients. The median patient age was 65 years (interquartile range [IQR]: 58-71). RESULTS: Median operative time was 205 min (IQR: 180-225). The overall survival rates at 5, 10, 15, and 20 yr were 68% (336 of 494), 55% (207 of 376), 38% (98 of 259), and 23% (14 of 62), respectively, and the disease specific survival rates were 75% (371 of 494), 59% (222 of 376), 50% (130 of 259), and 35% (22 of 62), respectively. After a median follow-up of 81 months (IQR: 30-144), a total of 147 early (less than 90 days) complications (38 diversion related, 109 diversion unrelated) occurred in 144 patients (24%); 163 late complications (141 diversion related, 22 diversion unrelated) affected 141 patients (23%). At 60 months, daytime and nighttime continence was complete in 96% and 72% of cases, respectively. Urodynamic studies showed that maximum capacity, residual volume, maximum flow rate, pressure at maximum capacity, and maximum outlet closure pressure were not statistically different at 12 and 60 months postoperatively. CONCLUSIONS: The use of a stapler when performing orthotopic neobladders significantly reduces the operating time, and offers good functional results with acceptable complication rates. Our results could encourage the use of a stapler when performing an ileal neobladder during laparoscopic and robotic radical cystectomies. PMID- 26746091 TI - Sentinel node biopsy after neoadjuvant treatment in breast cancer: Five-year follow-up of patients with clinically node-negative or node-positive disease before treatment. AB - PURPOSE: It is controversial whether sentinel node biopsy (SNB) without axillary dissection (AD) should be performed in cN1/2 breast cancer patients who become cN0 after neoadjuvant treatment, since the false negative rate (FNR) may be unacceptably high. We assessed outcomes to address this issue. METHODS: We retrospectively assessed 396 cT1-4, cN0/1/2 patients, who became or remained cN0 after neoadjuvant treatment and underwent SNB with at least one sentinel node (SN) found, and AD not performed if the SN was negative. RESULTS: After a median follow-up of 61 months (interquartile range 38-82), five-year overall survival was 90.7% (95% CI, 87.7-93.7) in the whole cohort, 93.3% (95% CI, 90.0-96.6) in those initially cN0, and 86.3% (95% CI, 80.6-92.1) in those initially cN1/2 (P = 0.12). Axillary failure occurred in only 1 (0.7%) initially cN1/2 patient who became cN0. In initially cN0 patients, and also initially cN1/2 patients who responded well to neoadjuvant treatment (ypT0/ypTx), SN-negativity was a significant predictor of good outcome, consistent with the known prognostic significance of axillary status, and suggesting that SN status accurately reflected axillary status. By contrast, in initially cN1/2 patients found to be ypT1/2/3, SN status (and whether or not AD was performed) had no influence on survival. CONCLUSIONS: These findings suggest that SNB is acceptable in cN1/2 patients who become cN0 after neoadjuvant therapy. PMID- 26746104 TI - Enrichment of hydrophobic membrane proteins using Triton X-114 and subsequent analysis of their N-glycosylation. AB - BACKGROUND: Numerous proteins depend on correct glycosylation for their proper function and nearly all membrane, as well as secreted, proteins are glycosylated. Glycosylation of membrane proteins plays a crucial role in many processes including the intercellular recognition and intermolecular interactions on the cell surface. The composition of N-glycans attached to membrane proteins has not been sufficiently studied due to the lack of efficient and reproducible analytical methods. METHODS: The aim of this study was to optimise cloud-point extraction (CPE) of membrane proteins with the non-ionic detergent Triton X-114 and analyse their N-glycosylation using hydrophilic interaction liquid chromatography (HILIC-UPLC). Purification of isolated proteins from the excess of detergent proved to be the key step. Therefore, several purification procedures were tested to efficiently remove detergent, while retaining maximum protein recoveries. RESULTS: CPE showed to be an efficient method to simultaneously extract membrane and soluble proteins, which subsequently resulted in different N glycan profiles of the aforementioned protein groups. The resulting protocol showed satisfactory reproducibility and potential for N-glycan analysis of both membrane and intracellular (soluble) proteins from different kinds of biological material. CONCLUSIONS: This method can be used as a new analytical tool for reliable detection and quantification of oligomannose and complex type N-glycans attached to membrane proteins, thus serving to distinguish between differences in cell types and states. GENERAL SIGNIFICANCE: The simple method was successfully optimised to generate reliable HILIC-UPLC profiles of N-glycans released from membrane proteins. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc. PMID- 26746105 TI - Depression as a risk factor for Alzheimer's disease: Genes, steroids, cytokines and neurogenesis - What do we need to know? AB - Depression (MDD) is prodromal to, and a component of, Alzheimer's disease (AD): it may also be a trigger for incipient AD. MDD is not a unitary disorder, so there may be particular subtypes of early life MDD that pose independent high risks for later AD, though the identification of these subtypes is problematical. There may either be a common pathological event underlying both MDD and AD, or MDD may sensitize the brain to a second event ('hit') that precipitates AD. MDD may also accelerate brain ageing, including altered DNA methylation, increased cortisol but decreasing DHEA and thus the risk for AD. So far, genes predicting AD (e.g. APOEepsilon4) are not risk factors for MDD, and those implicated in MDD (e.g. SLC6A4) are not risks for AD, so a common genetic predisposition looks unlikely. There is as yet no strong indication that an epigenetic event occurs during some forms of MDD that predisposes to later AD, though the evidence is limited. Glucocorticoids (GCs) are disturbed in some cases of MDD and in AD. GCs have marked degenerative actions on the hippocampus, a site of early beta-amyloid deposition, and rare genetic variants of GC-regulating enzymes (e.g. 11beta-HSD) predispose to AD. GCs also inhibit hippocampal neurogenesis and plasticity, and thus episodic memory, a core symptom of AD. Disordered GCs in MDD may inhibit neurogenesis, but the contribution of diminished neurogenesis to the onset or progression of AD is still debated. GCs and cytokines also reduce BDNF, implicated in both MDD and AD and hippocampal neurogenesis, reinforcing the notion that those cases of MDD with disordered GCs may be a risk for AD. Cytokines, including IL1beta, IL6 and TNFalpha, are increased in the blood in some cases of MDD. They also reduce hippocampal neurogenesis, and increased cytokines are a known risk for later AD. Inflammatory changes occur in both MDD and AD (e.g. raised CRP, TNFalpha). Both cytokines and GCs can have pro inflammatory actions in the brain. Inflammation (e.g. microglial activation) may be a common link, but this has not been systematically investigated. We lack substantial, rigorous and comprehensive follow-up studies to better identify possible subtypes of MDD that may represent a major predictor for later AD. This would enable specific interventions during critical episodes of these subtypes of MDD that should reduce this substantial risk. PMID- 26746106 TI - Effect of maternal exposure to Tityus bahiensis scorpion venom during lactation on the offspring of rats. AB - Scorpion stings are a public health problem in Brazil and lactating women may be affected. We aimed to study the effects of Tityus bahiensis venom in the offspring of rats treated during lactation. Mothers received a subcutaneous injection of saline (1.0ml/kg) or venom (2.5mg/kg) or an intraperitoneal injection of LPS (lipopolysaccharide) (100MUg/kg) on postnatal (PN) days 2 (PN2), 10 (PN10) or 16 (PN16). The offspring were evaluated during the childhood and adulthood. Pups showed a delay in physical and reflexological development, and a decrease in motor activity. Adults displayed low anxiety. There was an increase in the number of viable neuronal cells in hippocampal areas CA1 and CA4. The levels of IFN-gamma (interferon-gamma) increased in the experimental groups. Several of the parameters analyzed showed important differences between the sexes. Thus, the scorpion venom affects the development in the offspring of mothers envenomed during the lactation. PMID- 26746107 TI - Inhibition of serotonin reuptake in the prepubertal rat ovary by fluoxetine and effects on ovarian functions. AB - Fluoxetine (FLX), a selective serotonin reuptake inhibitor is an antidepressant in the treatment of mood disorders. Its impact on reproductive processes is incompletely known. The present study analyzed the reproductive effects of FLX in prepubertal female rats. Two experiments were conducted. First (acute administration), 30-day-old female rats were injected intraperitoneally with 5mg/kg of fluoxetine-hydrochloride, and were terminated 24, 48 or 72h after the treatment. Second (subchronic administration), FLX was injected on days 30-33 of age, and the animals were terminated the day of first estrus. In acute treatment estradiol concentration increased to 72h. In subchronic treatment increased serotonin concentration in ovaries and decreased the number of ova shed. An increase in number of atretic follicles and oocyte fragmentation was observed in these animals. The results suggest that FLX acts on the ovary or hypothalamus pituitary axis resulting in modifications of the follicular development and ovulation. PMID- 26746108 TI - The effects of in utero bisphenol A exposure on the ovaries in multiple generations of mice. AB - Bisphenol A is used in polycarbonate plastics and epoxy resins. Previous studies show that in utero BPA exposure inhibits germ cell nest breakdown in the F1 generation of mice, but its effects on germ cell nest breakdown and on the ovary in the F2-F3 generations were unknown. Thus, we tested the hypothesis that BPA has transgenerational effects on the ovary. Mice were exposed to BPA in utero (BPA 0.5, 20, or 50MUg/kg/day), and ovaries were collected at postnatal days (PND) 4 and 21 from the F1-F3 generations and subjected to histological evaluation and gene expression analyses. In utero BPA exposure did not have transgenerational effects on germ cell nest breakdown and gene expression on PND 4, but it caused transgenerational changes in expression in multiple genes on PND 21. Collectively, these data indicate that in utero BPA exposure has some transgenerational effects in mice. PMID- 26746109 TI - Cytotoxicity and mitogenicity assays with real-time and label-free monitoring of human granulosa cells with an impedance-based signal processing technology intergrating micro-electronics and cell biology. AB - A recently developed technology (xCelligence) integrating micro-electronics and cell biology allows real-time, uninterrupted and quantitative analysis of cell proliferation, viability and cytotoxicity by measuring the electrical impedance of the cell population in the wells without using any labeling agent. In this study we investigated if this system is a suitable model to analyze the effects of mitogenic (FSH) and cytotoxic (chemotherapy) agents with different toxicity profiles on human granulosa cells in comparison to conventional methods of assessing cell viability, DNA damage, apoptosis and steroidogenesis. The system generated the real-time growth curves of the cells, and determined their doubling times, mean cell indices and generated dose-response curves after exposure to cytotoxic and mitogenic stimuli. It accurately predicted the gonadotoxicity of the drugs and distinguished less toxic agents (5-FU and paclitaxel) from more toxic ones (cisplatin and cyclophosphamide). This platform can be a useful tool for specific end-point assays in reproductive toxicology. PMID- 26746110 TI - Characterization of contact offenders and child exploitation material trafficking on five peer-to-peer networks. AB - We provide detailed measurement of the illegal trade in child exploitation material (CEM, also known as child pornography) from mid-2011 through 2014 on five popular peer-to-peer (P2P) file sharing networks. We characterize several observations: counts of peers trafficking in CEM; the proportion of arrested traffickers that were identified during the investigation as committing contact sexual offenses against children; trends in the trafficking of sexual images of sadistic acts and infants or toddlers; the relationship between such content and contact offenders; and survival rates of CEM. In the 5 P2P networks we examined, we estimate there were recently about 840,000 unique installations per month of P2P programs sharing CEM worldwide. We estimate that about 3 in 10,000 Internet users worldwide were sharing CEM in a given month; rates vary per country. We found an overall month-to-month decline in trafficking of CEM during our study. By surveying law enforcement we determined that 9.5% of persons arrested for P2P based CEM trafficking on the studied networks were identified during the investigation as having sexually offended against children offline. Rates per network varied, ranging from 8% of arrests for CEM trafficking on Gnutella to 21% on BitTorrent. Within BitTorrent, where law enforcement applied their own measure of content severity, the rate of contact offenses among peers sharing the most severe CEM (29%) was higher than those sharing the least-severe CEM (15%). Although the persistence of CEM on the networks varied, it generally survived for long periods of time; e.g., BitTorrent CEM had a survival rate near 100%. PMID- 26746111 TI - Diagnostic agreement when comparing still and video imaging for the medical evaluation of child sexual abuse. AB - Still photo imaging is often used in medical evaluations of child sexual abuse (CSA) but video imaging may be superior. We aimed to compare still images to videos with respect to diagnostic agreement regarding hymenal deep notches and transections in post-pubertal females. Additionally, we evaluated the role of experience and expertise on agreement. We hypothesized that videos would result in improved diagnostic agreement of multiple evaluators as compared to still photos. This was a prospective quasi-experimental study using imaging modality as the quasi-independent variable. The dependent variable was diagnostic agreement of participants regarding presence/absence of findings indicating penetrative trauma on non-acute post-pubertal genital exams. Participants were medical personnel who regularly perform CSA exams. Diagnostic agreement was evaluated utilizing a retrospective selection of videos and still photos obtained directly from the videos. Videos and still photos were embedded into an on-line survey as sixteen cases. One-hundred sixteen participants completed the study. Participant diagnosis was more likely to agree with study center diagnosis when using video (p<0.01). Use of video resulted in statistically significant changes in diagnosis in four of eight cases. In two cases, the diagnosis of the majority of participants changed from no hymenal transection to transection present. No difference in agreement was found based on experience or expertise. Use of video vs. still images resulted in increased agreement with original examiner and changes in diagnostic impressions in review of CSA exams. Further study is warranted, as video imaging may have significant impacts on diagnosis. PMID- 26746112 TI - Community implementation outcomes of Attachment and Biobehavioral Catch-up. AB - Bringing evidence-based treatments to community practice is a critical challenge for the field. When implemented in the community, evidence-based treatments often fail to provide the benefits shown in laboratory settings. Therefore, when evidence-based treatments are transported to the community, it is essential to investigate implementation process and outcomes. The present study assessed whether Attachment and Biobehavioral Catch-up (ABC), an intervention for high risk parents that has been shown to be efficacious in randomized clinical trials (RCTs), changed parent behavior in a community-based setting. This study examined data collected from 78 cases by 9 parent coaches in a diverse community setting in Hawaii, and compared data to benchmarks from RCTs. Parent coach fidelity was coded from intervention session video clips, and was also compared with benchmarks. Caregivers participating in ABC were primarily birth parents, and most were referred through Child Protective Services involvement or for reasons of harsh parenting or neglect. Parental behavior was assessed before and after intervention using a semi-structured play task. Increases in parental following the lead and delight, and decreases in parental intrusiveness, were observed; these changes were comparable to effect sizes observed in RCTs. Intent to treat analyses were conducted using behavioral data from videotaped sessions, and suggested that ABC also improved following the lead in parents who subsequently dropped out of treatment. These results support the viability of ABC for enhancing parenting behavior among parents at high risk for maltreatment, and demonstrate that parent coaches in community agencies can successfully implement ABC. PMID- 26746113 TI - Antigen Binding and Site-Directed Labeling of Biosilica-Immobilized Fusion Proteins Expressed in Diatoms. AB - The diatom Thalassiosira pseudonana was genetically modified to express biosilica targeted fusion proteins comprising either enhanced green fluorescent protein (EGFP) or single chain antibodies engineered with a tetracysteine tagging sequence. Of interest were the site-specific binding of (1) the fluorescent biarsenical probe AsCy3 and AsCy3e to the tetracysteine tagged fusion proteins and (2) high and low molecular mass antigens, the Bacillus anthracis surface layer protein EA1 or small molecule explosive trinitrotoluene (TNT), to biosilica immobilized single chain antibodies. Analysis of biarsenical probe binding using fluorescence and structured illumination microscopy indicated differential colocalization with EGFP in nascent and mature biosilica, supporting the use of either EGFP or bound AsCy3 and AsCy3e in studying biosilica maturation. Large increases in the lifetime of a fluorescent analogue of TNT upon binding single chain antibodies provided a robust signal capable of discriminating binding to immobilized antibodies in the transformed frustule from nonspecific binding to the biosilica matrix. In conclusion, our results demonstrate an ability to engineer diatoms to create antibody-functionalized mesoporous silica able to selectively bind chemical and biological agents for the development of sensing platforms. PMID- 26746114 TI - PSD-95 regulates synaptic kainate receptors at mouse hippocampal mossy fiber-CA3 synapses. AB - Kainate-type glutamate receptors (KARs) are the third class of ionotropic glutamate receptors whose activation leads to the unique roles in regulating synaptic transmission and circuit functions. In contrast to AMPA receptors (AMPARs), little is known about the mechanism of synaptic localization of KARs. PSD-95, a major scaffold protein of the postsynaptic density, is a candidate molecule that regulates the synaptic KARs. Although PSD-95 was shown to bind directly to KARs subunits, it has not been tested whether PSD-95 regulates synaptic KARs in intact synapses. Using PSD-95 knockout mice, we directly investigated the role of PSD-95 in the KARs-mediated components of synaptic transmission at hippocampal mossy fiber-CA3 synapse, one of the synapses with the highest density of KARs. Mossy fiber EPSCs consist of AMPA receptor (AMPAR) mediated fast component and KAR-mediated slower component, and the ratio was significantly reduced in PSD-95 knockout mice. The size of KARs-mediated field EPSP reduced in comparison with the size of the fiber volley. Analysis of KARs mediated miniature EPSCs also suggested reduced synaptic KARs. All the evidence supports critical roles of PSD-95 in regulating synaptic KARs. PMID- 26746115 TI - Human upright posture control models based on multisensory inputs; in fast and slow dynamics. AB - Posture control to maintain an upright stance is one of the most important and basic requirements in the daily life of humans. The sensory inputs involved in posture control include visual and vestibular inputs, as well as proprioceptive and tactile somatosensory inputs. These multisensory inputs are integrated to represent the body state (body schema); this is then utilized in the brain to generate the motion. Changes in the multisensory inputs result in postural alterations (fast dynamics), as well as long-term alterations in multisensory integration and posture control itself (slow dynamics). In this review, we discuss the fast and slow dynamics, with a focus on multisensory integration including an introduction of our study to investigate "internal force control" with multisensory integration-evoked posture alteration. We found that the study of the slow dynamics is lagging compared to that of fast dynamics, such that our understanding of long-term alterations is insufficient to reveal the underlying mechanisms and to propose suitable models. Additional studies investigating slow dynamics are required to expand our knowledge of this area, which would support the physical training and rehabilitation of elderly and impaired persons. PMID- 26746116 TI - A Geometric Capacity-Demand Analysis of Maternal Levator Muscle Stretch Required for Vaginal Delivery. AB - Because levator ani (LA) muscle injuries occur in approximately 13% of all vaginal births, insights are needed to better prevent them. In Part I of this paper, we conducted an analysis of the bony and soft tissue factors contributing to the geometric "capacity" of the maternal pelvis and pelvic floor to deliver a fetal head without incurring stretch injury of the maternal soft tissue. In Part II, we quantified the range in demand, represented by the variation in fetal head size and shape, placed on the maternal pelvic floor. In Part III, we analyzed the capacity-to-demand geometric ratio, g, in order to determine whether a mother can deliver a head of given size without stretch injury. The results of a Part I sensitivity analysis showed that initial soft tissue loop length (SL) had the greatest effect on maternal capacity, followed by the length of the soft tissue loop above the inferior pubic rami at ultimate crowning, then subpubic arch angle (SPAA) and head size, and finally the levator origin separation distance. We found the more caudal origin of the puborectal portion of the levator muscle helps to protect it from the stretch injuries commonly observed in the pubovisceral portion. Part II fetal head molding index (MI) and fetal head size revealed fetal head circumference values ranging from 253 to 351 mm, which would increase up to 11 mm upon face presentation. The Part III capacity-demand analysis of g revealed that, based on geometry alone, the 10th percentile maternal capacity predicted injury for all head sizes, the 25th percentile maternal capacity could deliver half of all head sizes, while the 50th percentile maternal capacity could deliver a head of any size without injury. If ultrasound imaging could be operationalized to make measurements of ratio g, it might be used to usefully inform women on their level of risk for levator injury during vaginal birth. PMID- 26746118 TI - Assessment of Left Ventricular Mass in Children and Adolescents: Current Status. PMID- 26746119 TI - Pulse Oximetry Screening for Critical Congenital Heart Disease after Home Birth and Early Discharge. AB - OBJECTIVES: To assess the feasibility of pulse oximetry (PO) screening in settings with home births and very early discharge. We assessed this with an adapted protocol in The Netherlands. STUDY DESIGN: PO screening was performed in the Leiden region in hospitals and by community midwives. Measurements were taken >= 1 hour after birth and on day 2 or 3 during the midwife visit. Primary outcome was the percentage of screened infants with parental consent. The time point of screening, oxygen saturation, false positive (FP) screenings, critical congenital heart defects (CCHDs), and other detected pathology were registered. RESULTS: In a 1-year period, 3625 eligible infants were born. Parents of 491 infants were not approached for consent, and 44 refused the screening. PO screening was performed in 3059/3090 (99%) infants with obtained consent. Median (IQR) time points of the first and second screening were 1.8 (1.3-2.8) and 37 (27-47) hours after birth. In 394 infants with screening within 1 hour after birth, the median pre- and postductal oxygen saturations were 99% (98%-100%) and 99% (97%-100%). No CCHD was detected. The FP prevalence was 1.0% overall (0.6% in the first hours after birth). After referral, important noncritical cardiac and other noncardiac pathology was found in 62% of the FP screenings. CONCLUSIONS: PO screening for CCHD is feasible after home births and very early discharge from hospital. Important neonatal pathology was detected at an early stage, potentially increasing the safety of home births and early discharge policy. PMID- 26746117 TI - Patient-Level DNA Damage and Repair Pathway Profiles and Prognosis After Prostatectomy for High-Risk Prostate Cancer. AB - IMPORTANCE: A substantial number of patients diagnosed with high-risk prostate cancer are at risk for metastatic progression after primary treatment. Better biomarkers are needed to identify patients at the highest risk to guide therapy intensification. OBJECTIVE: To create a DNA damage and repair (DDR) pathway profiling method for use as a prognostic signature biomarker in high-risk prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: A cohort of 1090 patients with high-risk prostate cancer who underwent prostatectomy and were treated at 3 different academic institutions were divided into a training cohort (n = 545) and 3 pooled validation cohorts (n = 232, 130, and 183) assembled for case-control or case-cohort studies. Profiling of 9 DDR pathways using 17 gene sets for GSEA (Gene Set Enrichment Analysis) of high-density microarray gene expression data from formalin-fixed paraffin-embedded prostatectomy samples with median 10.3 years follow-up was performed. Prognostic signature development from DDR pathway profiles was studied, and DDR pathway gene mutation in published cohorts was analyzed. MAIN OUTCOMES AND MEASURES: Biochemical recurrence-free, metastasis free, and overall survival. RESULTS: Across the training cohort and pooled validation cohorts, 1090 men were studied; mean (SD) age at diagnosis was 65.3 (6.4) years. We found that there are distinct clusters of DDR pathways within the cohort, and DDR pathway enrichment is only weakly correlated with clinical variables such as age (Spearman rho [rho], range, -0.07 to 0.24), Gleason score (rho, range, 0.03 to 0.20), prostate-specific antigen level (rho, range, -0.07 to 0.10), while 13 of 17 DDR gene sets are strongly correlated with androgen receptor pathway enrichment (rho, range, 0.33 to 0.82). In published cohorts, DDR pathway genes are rarely mutated. A DDR pathway profile prognostic signature built in the training cohort was significantly associated with biochemical recurrence-free, metastasis-free, and overall survival in the pooled validation cohorts independent of standard clinicopathological variables. The prognostic performance of the signature for metastasis-free survival appears to be stronger in the younger patients (HR, 1.67; 95% CI, 1.12-2.50) than in the older patients (HR, 0.77; 95% CI, 0.29-2.07) on multivariate Cox analysis. CONCLUSIONS AND RELEVANCE: DNA damage and repair pathway profiling revealed patient-level variations and the DDR pathways are rarely affected by mutation. A DDR pathway signature showed strong prognostic performance with the long-term outcomes of metastasis-free and overall survival that may be useful for risk stratification of high-risk prostate cancer patients. PMID- 26746120 TI - Sperm Retrieval in Adolescents and Young Adults with Klinefelter Syndrome: A Prospective, Pilot Study. AB - OBJECTIVE: To assess sperm retrieval rates in adolescents and young adults with Klinefelter syndrome, with the ultimate goal of improving fertility in this population. Secondary aims were to evaluate other clinical characteristics of the cohort and identify predictors of sperm retrieval. STUDY DESIGN: Patients 12-25 years of age with Klinefelter syndrome (47,XXY) were recruited at the Boston Children's Hospital. Physical examination, biochemical evaluation, scrotal ultrasonography, and semen analysis were performed. Neurocognitive data were collected. Microdissection sperm extraction (unilateral micro-testicular sperm extraction) was offered to individuals with no sperm in their ejaculates. Given the small sample size, analysis was primarily descriptive. RESULTS: Fifteen patients were enrolled. None had sperm in their ejaculates. Ten patients underwent unilateral micro-testicular sperm extraction. Sperm retrieval rate was 50%. From a neurocognitive standpoint, subjects reported problems with peers, conduct, and overall difficulties. Incidentally, one-third of the patients were found to have testicular microlithiasis and 17% of subjects with renal ultrasound imaging had bilateral renal medullary nephrocalcinosis. CONCLUSIONS: This pilot study suggests that sperm retrieval rates in adolescents and young adults with Klinefelter syndrome are comparable with those reported in older men. However, larger studies are needed to confirm our findings. The clinical significance of the scrotal and renal ultrasound findings merits further investigation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01817296. PMID- 26746122 TI - A Sweet Addition for the Treatment of Neonatal Hypoglycemia. PMID- 26746123 TI - Does the Medical Home Really Matter? PMID- 26746124 TI - Standard Outcome Measures in Facial Paralysis: Getting on the Same Page. PMID- 26746125 TI - Design and application of model for training ultrasound-guided vascular cannulation in pediatric patients. AB - Central vascular cannulation is not a risk-free procedure, especially in pediatric patients. Newborn and infants are small and low-weighted, their vascular structures have high mobility because of tissue laxity and their vessels are superficial and with small diameter. These characteristics, together with the natural anatomical variability and poor collaboration of small children, make this technique more difficult to apply. Therefore, ultrasound imaging is increasingly being used to locate vessels and guide vascular access in this population. OBJECTIVE: (a) To present a model that simulates the vascular system for training ultrasound-guided vascular access in pediatrics patients; (b) to ultrasound-guided vascular cannulation in the model. RESULTS: The model consisted of two components: (a) muscular component: avian muscle, (b) vascular component: elastic tube-like structure filled with fluid. 864 ecoguided punctures was realized in the model at different vessel depth and gauge measures were simulated, for two medical operators with different degree of experience. The average depth and diameter of vessel cannulated were 1.16 (0.42)cm and 0.43 (0.1)cm, respectively. The average number of attempts was of 1.22 (0.62). The percentage of visualization of the needle was 74%. The most frequent maneuver used for the correct location, was the modification of the angle of the needle and the relocation of the guidewire in 24% of the cases. The average time for the correct cannulations was 41 (35.8)s. The more frequent complications were the vascular perforation (11.9%) and the correct vascular puncture without possibility of introducing the guidewire (1.2%). The rate of success was 96%. CONCLUSIONS: The model simulates the anatomy (vascular and muscular structures) of a pediatric patient. It is cheap models, easily reproducible and a useful tool for training in ultrasound-guided puncture and cannulation. PMID- 26746126 TI - Update in the management of critically ill burned patients. AB - The management of critically ill burn patients is challenging. These patients have to be managed in specialized centers, where the expertise of physicians and nursing personnel guarantees the best treatment. Mortality of burn patients has improved over the past decades due to a better understanding of burn shock pathophysiology, optimal surgical management, infection control and nutritional support. Indeed, a more aggressive resuscitation, early excision and grafting, the judicious use of topical antibiotics, and the provision of an adequate calorie and protein intake are key to attain best survival results. General advances in critical care have also to be implemented, including protective ventilation, glycemic control, selective decontamination of the digestive tract, and implementation of sedation protocols. PMID- 26746127 TI - Mortality in patients with respiratory distress syndrome. AB - INTRODUCTION: Mortality in Acute Respiratory Distress Syndrome (ARDS) is decreasing, although its prognosis after hospital discharge and the prognostic accuracy of Berlin's new ARDS stratification are uncertain. METHODS: We did a restrospective analysis of hospital and 6 month mortality of patients with ARDS admitted to the Intensive Care Unit of a Univeristy Hospital in Buenos Aires, between January 2008 and June 2011. ARDS was defined by PaO2/FiO2 lower than 200 mmHg under ventilation with at least 10 cm H2O of PEEP and a FiO2 higher or equal than 0.5. and the presence of bilateral infiltrates in chest radiography, in the absence of cardiogenic acute pulmonary edema, during the first 72 hs of mechanical ventilation. Mortality associated risk factors, the use of rescue therapies and Berlin's stratification for moderate and severe ARDS patients were considered. RESULTS: Ninety eight patients were included; mean age was 59+/-19 years old, 42,9% had mayor co-morbidities; APACHE II at admission was 22+/-7; SOFA at day 1 was 8+/-3. Prone position ventilation was applied in 20,4% and rescue measures in 12,2% (12 patients with nitric oxide and 1 with extracorporeal membrane oxygenation). Hospital and 6 months mortality were 37.7 and 43.8% respectively. After logistic regression analysis, only age, the presence of septic shock at admission, Ppl >30 cmH2O, and major co-morbidities were independently associated with hospital outcome. There was no difference between moderate and severe groups (41,2 and 36,8% respectively; p=0,25). CONCLUSION: In this cohort, including patients with severe hypoxemia and high percentage of mayor co-morbidities, ARDS associated mortality was lower than some previous studies. There was no increase in mortality after hospital discharge. There was no difference in mortality between moderate and severe groups according to Berlin's definition. PMID- 26746128 TI - Exploring variation in dimensions of obstetric forceps. PMID- 26746121 TI - Efficacy of Low-Dose Buspirone for Restricted and Repetitive Behavior in Young Children with Autism Spectrum Disorder: A Randomized Trial. AB - OBJECTIVES: To determine safety and efficacy of the 5HT1A serotonin partial agonist buspirone on core autism and associated features in children with autism spectrum disorder (ASD). STUDY DESIGN: Children 2-6 years of age with ASD (N = 166) were randomized to receive placebo or 2.5 or 5.0 mg of buspirone twice daily. The primary objective was to evaluate the effects of 24 weeks of buspirone on the Autism Diagnostic Observation Schedule (ADOS) Composite Total Score. Secondary objectives included evaluating the effects of buspirone on social competence, repetitive behaviors, language, sensory dysfunction, and anxiety and to assess side effects. Positron emission tomography measures of tryptophan metabolism and blood serotonin concentrations were assessed as predictors of buspirone efficacy. RESULTS: There was no difference in the ADOS Composite Total Score between baseline and 24 weeks among the 3 treatment groups (P = .400); however, the ADOS Restricted and Repetitive Behavior score showed a time-by treatment effect (P = .006); the 2.5-mg buspirone group showed significant improvement (P = .003), whereas placebo and 5.0-mg buspirone groups showed no change. Children in the 2.5-mg buspirone group were more likely to improve if they had fewer foci of increased brain tryptophan metabolism on positron emission tomography (P = .018) or if they showed normal levels of blood serotonin (P = .044). Adverse events did not differ significantly among treatment groups. CONCLUSIONS: Treatment with 2.5 mg of buspirone in young children with ASD might be a useful adjunct therapy to target restrictive and repetitive behaviors in conjunction with behavioral interventions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00873509. PMID- 26746131 TI - Men's health: a benefit for men or a marketing opportunity? PMID- 26746130 TI - Epidemiology of human coronavirus NL63 infection among hospitalized patients with pneumonia in Taiwan. AB - BACKGROUND/PURPOSE: Human coronavirus (HCoV) NL63 is recognized in association with upper or lower respiratory tract illnesses in children. This study surveyed the prevalence of HCoV-NL63 and influenza viruses in patients with influenza-like illness in Taiwan during 2010-2011. METHODS: Throat samples from 107 hospitalized patients with pneumonia and 175 outpatients with influenza-like illness were examined using real-time polymerase chain reaction assays with virus-specific primers, and then virus-positive specimens were confirmed by sequencing the polymerase chain reaction products. RESULTS: HCoV-NL63 infection was identified in 8.4% (9/107) of hospitalized patients with pneumonia, but not found in outpatients with influenza-like illness. Age distribution of HCoV-NL63 infection in hospitalized patients with pneumonia indicated that the group aged 16-25 years (20%) had the highest positive rate compared with the other groups, and exhibited a similar age-specific pattern to influenza A/H1N1 infection, but not influenza A/H3N2 and B infections in hospitalized patients. Seasonal prevalence of HCoV NL63 infection was late winter, overlapping the highest peak of the influenza A/H1N1 epidemic during December 2010 to March 2011 in Taiwan. Co-infection of HCoV-NL63 and influenza A/H1N1 was detected in three hospitalized patients. Clinical manifestation analysis indicated that the main symptoms for HCoV-NL63 infection included fever (88.9%), cough (77.8%), and pneumonia (100%). Co infection caused significantly higher rates of breathing difficulties, cough, and sore throat than those of single infection with HCoV-NL63 and influenza A/H1N1. Phylogenetic analysis indicated a low level of heterogeneity between Taiwan and global HCoV-NL63 strains. CONCLUSION: Understanding epidemiology of HCoV-NL63 in Taiwan provides an insight for worldwide surveillance of HCoV-NL63 infection. PMID- 26746129 TI - Target validation of highly conserved Amblyomma americanum tick saliva serine protease inhibitor 19. AB - Amblyomma americanum tick serine protease inhibitor (serpin, AAS) 19, is a highly conserved protein that is characterized by its functional domain being 100% conserved across tick species. We also reported that AAS19 was an immunogenic tick saliva protein with anti-haemostatic functions and an inhibitor of trypsin like proteases including five of the eight serine protease factors in the blood clotting cascade. In this study the goal was to validate the importance of AAS19 in A. americanum tick physiology, assess immunogenicity and investigate tick vaccine efficacy of yeast-expressed recombinant (r) AAS19. We confirm that AAS19 is important to A. americanum fitness and blood meal feeding. AAS19 mRNA disruption by RNAi silencing caused ticks to obtain blood meals that were 50% smaller than controls, and treated ticks being morphologically deformed with 100% of the deformed ticks dying in incubation. We show that rAAS19 is highly immunogenic in that two 500 MUg inoculations mixed with TiterMax Gold adjuvant provoked antibody titers of more than 1:320,000 that specifically reacted with native AAS19 in unfed and partially fed tick tissue. Since AAS19 is injected into animals during tick feeding, we challenge infested immunized rabbits twice to test if tick infestations of immunized rabbits could act as booster. While in the first infestation significantly smaller tick blood meals were observed on one of the two immunized rabbits, smaller blood meals were observed on both rabbits, but 60% of ticks that engorged on immunized rabbits in the second infestation failed to lay eggs. It is notable that ticks fed faster on immunized animals despite obtaining smaller blood meals. We conclude that rAAS19 is a potential component of cocktail tick vaccine. PMID- 26746132 TI - Endometriosis-related infertility: assisted reproductive technology has no adverse impact on pain or quality-of-life scores. AB - OBJECTIVE: To evaluate the impact of assisted reproduction technology (ART) on painful symptoms and quality of life (QoL) in women who have endometriosis as compared with disease-free women. DESIGN: Prospective controlled, observational cohort study. SETTING: University hospital. PATIENT(S): Two hundred and sixty four matched-pairs of endometriosis and disease-free women undergoing ART. INTERVENTION(S): Assessment of pain evolution using visual analogue scale (VAS) during ART; QoL assessment with the Fertility Quality of Life (FertiQoL) tool. MAIN OUTCOME MEASURE(S): VAS pain intensities relative to dysmenorrhea, dyspareunia, noncyclic chronic pelvic pain (NCCPP), gastrointestinal pain, lower urinary tract pain; trends for VAS change between postretrieval and baseline evaluation; FertiQoL score; and statistical analyses conducted using univariate and adjusted multiple linear regression models. RESULT(S): After excluding canceled cycles and patients lost to follow-up observation, 102 women with endometriosis and 104 disease-free women were retained for the study. The trends for VAS change between the postretrieval and baseline evaluations in the women with endometriosis compared with the disease-free women revealed a statistically significant pain decrease for dysmenorrhea (-1.35 +/- 3.23 and 0.61 +/- 4.00) and dyspareunia (-1.19 +/- 2.58 and 0.14 +/- 2.06). For NCCPP, gastrointestinal symptoms, and lower urinary tract symptoms, there were no statistically significant differences between the groups. After multiple linear regression, no worsening of pain was observed in the endometriosis group as compared with disease-free group. In addition subgroup analysis according to endometriosis phenotype failed to show any increase of pain. The quality of life in the endometriosis group was comparable to that of the disease-free group. CONCLUSION(S): Assisted reproduction technology did not exacerbate the symptoms of endometriosis or negatively impact QoL in women with endometriosis as compared with disease-free women. PMID- 26746134 TI - Introduction: Male fertility preservation: innovations and questions. AB - It is now well established that many benign or malignant diseases may by themselves or as result of treatment, impair male fertility. Therefore, preserving the potential of becoming a genetic father represents a major issue. Besides sperm cryopreservation, which is the most reliable method for male fertility preservation, other strategies have more recently emerged, especially in prepubertal boys. Prepubertal germ cell storage from testicular sperm extraction and derivation of male gametes from stem cells may represent a future hope, although raising many ethical issues. PMID- 26746135 TI - Time-lapse: the remaining questions to be answered. PMID- 26746136 TI - Correct coding for laboratory procedures during assisted reproductive technology cycles. AB - This document provides updated coding information for services related to assisted reproductive technology procedures. This document replaces the 2012 ASRM document of the same name. PMID- 26746137 TI - Human somatic cell nuclear transfer and reproductive cloning: an Ethics Committee opinion. AB - This document presents arguments that conclude that it is unethical to use somatic cell nuclear transfer (SCNT) for infertility treatment due to concerns about safety; the unknown impact of SCNT on children, families, and society; and the availability of other ethically acceptable means of assisted reproduction. This document replaces the ASRM Ethics Committee report titled, "Human somatic cell nuclear transfer and cloning," last published in Fertil Steril 2012;98:804 7. PMID- 26746138 TI - Painful Right Inguinal Swelling. PMID- 26746133 TI - Experimental methods to preserve male fertility and treat male factor infertility. AB - Infertility is a prevalent condition that has insidious impacts on the infertile individuals, their families, and society, which extend far beyond the inability to have a biological child. Lifestyle changes, fertility treatments, and assisted reproductive technology (ART) are available to help many infertile couples achieve their reproductive goals. All of these technologies require that the infertile individual is able to produce at least a small number of functional gametes (eggs or sperm). It is not possible for a person who does not produce gametes to have a biological child. This review focuses on the infertile man and describes several stem cell-based methods and gene therapy approaches that are in the research pipeline and may lead to new fertility treatment options for men with azoospermia. PMID- 26746139 TI - Diego and Giorgina Vergani: The two hearts of translational autoimmunity. AB - Since the publication of the first textbook on autoimmune diseases in 1963, the knowledge in the field has exponentially grown into numerous tracks of research, particularly at benchside. Systemic and organ-specific autoimmune diseases, as in the case of the liver, have witnessed notable advances in terms of epidemiology, genetics, effector and regulatory mechanisms, and ultimately treatment. While the available tools for communication have provided accelerating progress rates, we recognize that key opinion leaders continue to provide significant contributions to the field. The present issue is dedicated to celebrate Giorgina Mieli-Vergani and Diego Vergani as two of the finest examples of excellence in autoimmune liver diseases and the broader field of autoimmunity. Diego and Giorgina are extremely well-liked Colleagues who fully represent the translational efforts between laboratory research and clinically relevant questions in the practice of pediatric liver diseases and autoimmune hepatitis. PMID- 26746140 TI - Association of Oxygen Target and Growth Status With Increased Mortality in Small for Gestational Age Infants: Further Analysis of the Surfactant, Positive Pressure and Pulse Oximetry Randomized Trial. PMID- 26746141 TI - Comparison of Ex Vivo and In Vivo Dermoscopy in Dermatopathologic Evaluation of Skin Tumors. AB - IMPORTANCE: Ex vivo dermoscopy (EVD) can be a valuable tool in routine diagnostic dermatopathologic evaluation. OBJECTIVES: To compare in vivo dermoscopy (IVD) and EVD and to provide guidance for routine dermatopathologic evaluations. DESIGN, SETTING, AND PARTICIPANTS: This observational study collected 101 consecutive IVD and EVD images of skin tumors from a private dermatology practice from March 1 to September 30, 2013. Four observers (3 dermatologists and 1 dermatopathologist) blinded to the histopathologic diagnoses independently scored and compared the colors, structures, and vessels of EVD images with those of the corresponding IVD images. Data were analyzed from January 1 to March 31, 2014. MAIN OUTCOMES AND MEASURES: Concordance between the EVD and IVD images and gain or loss of colors, structures, and vessels on EVD relative to IVD images. RESULTS: The final analysis included 404 observations of 101 images. The EVD image was generally similar to the corresponding IVD image but clearly darker, with new areas of blue in 130 of 404 observations (32.2%) and white in 100 of 404 observations (24.8%) and loss of red in 283 of 404 observations (70.0%). Most structures were well preserved. New structureless areas were found in 78 of 404 observations of EVD images (19.3%), and new crystalline structures were detected in 68 of 404 observations of EVD images (16.8%). On EVD images, squames and crusts were lost in 56 of 404 observations (13.9%) and 43 of 404 observations (10.6%), respectively. Blood vessels were lost in 142 of 404 observations of EVD images (35.1%). CONCLUSIONS AND RELEVANCE: The EVD image is an important new tool in dermatopathology and may give direction to targeted tissue processing and examination of skin tumors. PMID- 26746143 TI - Exosomes derived from dendritic cells improve cardiac function via activation of CD4(+) T lymphocytes after myocardial infarction. AB - CD4(+) T cell activation plays a key role in facilitating wound healing after myocardial infarction (MI). Exosomes (EXs) secreted from dendritic cells (DCs) can activate T cells in tumor models; however, whether DEXs (DC-EXs) can mediate CD4(+) T cell activation and improve wound healing post-MI remains unknown. This study sought to determine whether DEXs mediate CD4(+) T cell activation and improve cardiac function post-MI in mice. We used supernatants of hypoxic primary or necrotic HL-1 cardiomyocytes to simulate the post-MI cardiomyocyte microenvironment in vitro. Cultured bone marrow-derived DCs (BMDCs) from mice were stimulated with the supernatants of normal (Control group), hypoxic primary or necrotic HL-1 cardiomyocytes (MI group); a subset of BMDCs remained unstimulated (Negative group). DEXs were then isolated from the BMDC supernatants and either incubated with CD4(+) T cells or injected into mice via the tail vein. In this study, we found that the supernatants of both hypoxic primary and necrotic HL-1 cardiomyocytes upregulate DC maturation markers. After the injection of DEXs, a greater number of MI-DEXs are recruited by the mouse spleen and with greater rapidity than control- or negative-DEXs. Confocal imaging and flow cytometry revealed that MI-DEXs exhibited higher uptake by splenic CD4(+) T cells than the control- and negative-DEXs, and this increase was correlated with significantly greater increases in the expression of chemokines and the inflammatory cytokines IFN-gamma and TNF by the CD4(+) T cells in vitro and in vivo. In addition, the injection of MI-DEXs improved cardiac function in mice post-MI. These results suggest that DEXs could mediate the activation of CD4(+) T cells through an endocrine mechanism and improve cardiac function post-MI. Our findings provide the basis for a novel strategy for the treatment of MI through the systemic delivery of DEXs. PMID- 26746142 TI - AMPK is critical for mitochondrial function during reperfusion after myocardial ischemia. AB - AMP-activated kinase (AMPK) is a stress responsive kinase that regulates cellular metabolism and protects against cardiomyocyte injury during ischemia-reperfusion (IR). Mitochondria play an important role in cell survival, but the specific actions of activated AMPK in maintaining mitochondrial integrity and function during reperfusion are unknown. Thus, we assessed the consequences of AMPK inactivation on heart mitochondrial function during reperfusion. Mouse hearts expressing wild type (WT) or kinase-dead (KD) AMPK were studied. Mitochondria isolated from KD hearts during reperfusion had intact membrane integrity, but demonstrated reduced oxidative capacity, increased hydrogen peroxide production and decreased resistance to mitochondrial permeability transition pore opening compared to WT. KD hearts showed increased activation of the mitogen activated protein kinase kinase 4 (MKK4) and downstream c-Jun terminal kinase (JNK) and greater necrosis during reperfusion after coronary occlusion. Transgenic expression of mitochondrial catalase (MCAT) prevented the excessive cardiac JNK activation and attenuated the increased myocardial necrosis observed during reperfusion in KD mice. Inhibition of JNK increased the resistance of KD hearts to mPTP opening, contractile dysfunction and necrosis during IR. Thus, intrinsic activation of AMPK is critical to prevent excess mitochondrial reactive oxygen production and consequent JNK signaling during reperfusion, thereby protecting against mPTP opening, irreversible mitochondrial damage and myocardial injury. PMID- 26746144 TI - Cyclophilin D regulates mitochondrial flashes and metabolism in cardiac myocytes. AB - Cyclophilin D (CyP-D) is the mitochondrial-specific member of the evolutionally conserved cyclophilin family, and plays an important role in the regulation of mitochondrial permeability transition (MPT) under stress. Recently we have demonstrated that respiratory mitochondria undergo mitochondrial flash ("mitoflash") activity which is coupled with transient MPT under physiological conditions. However, whether and how CyP-D regulates mitoflashes remain incompletely understood. By using both loss- and gain-of-function approaches in isolated cardiomyocytes, beating hearts, and skeletal muscles in living mice, we revisited the role of CyP-D in the regulation of mitoflashes. Overexpression of CyP-D increased, and knockout of it halved, cardiac mitoflash frequency, while mitoflash amplitude and kinetics remained unaffected. However, CyP-D ablation did not alter mitoflash frequency, with mitoflash amplitude increased, in gastrocnemius muscles. This disparity was accompanied by 4-fold higher CyP-D expression in mouse cardiac than skeletal muscles. The mitochondrial maximal respiration rate and reserved capacity were reduced in CyP-D-null cardiomyocytes. These data indicate that CyP-D is a significant regulator of mitoflash ignition and mitochondrial metabolism in heart. In addition, tissue-specific CyP-D expression may partly explain the differential regulation of mitoflashes in the two types of striated muscles. PMID- 26746145 TI - Genome-wide DNA methylation profile implicates potential cartilage regeneration at the late stage of knee osteoarthritis. AB - OBJECTIVE: The aim of this work was to characterize the genome-wide DNA methylation profile of cartilage from three regions of tibial plateau isolated from patients with primary knee osteoarthritis (OA), providing the first DNA methylation study that reflects OA progression. METHODS: The unique model system was used to section three regions of tibial plateau: the outer lateral tibial plateau (oLT), the inner lateral tibial plateau (iLT) and the inner medial tibial plateau (iMT) regions which represented the early, intermediate and late stages of OA, respectively. Genome-wide DNA methylation profile was examined using Illumina Infinium HumanMethylation450 BeadChip array. Comparisons of the iLT/oLT and iMT/oLT groups were carried out to identify differentially methylated (DM) probes (DMPs) associated with OA progression. DM genes were analyzed to identify the gene ontologies (GO), pathways, upstream regulators and networks. RESULTS: No significant DMPs were identified in iLT/oLT group, while 519 DMPs were identified in iMT/oLT group. Over half of them (68.2%) were hypo-methylated and enriched in enhancers and OpenSea. Upstream regulator analysis identified many microRNAs. DM genes were enriched in transcription factors, especially homeobox genes and in Wnt/beta-catenin signaling pathway. These genes also showed changes in expression when analyzed with expression profiles generated from previous studies. CONCLUSION: Our data suggested the changes in DNA methylation occurred at the late stage of OA. Pathways and networks enriched in identified DM genes highlighted potential etiologic mechanism and implicated the potential cartilage regeneration in the late stage of knee OA. PMID- 26746147 TI - Changes in ultrasound assessed markers of inflammation following intra-articular steroid injection combined with exercise in knee osteoarthritis: exploratory outcome from a randomized trial. AB - OBJECTIVE: Knee osteoarthritis (KOA) is a multifactorial joint disease affecting many people worldwide. Recommended treatments for KOA include exercise and steroid injections, or a combination of these. The objective of this exploratory outcome analysis of a randomized trial was to assess changes in inflammation markers assessed by ultrasound imaging (US) in KOA secondary to intra-articular corticosteroid injection given prior to exercise therapy. DESIGN: This study is a sub-study to a larger clinical trial which compared the clinical effects of steroid injection in KOA to placebo injection, both given prior to exercise therapy. The US outcomes were changes from baseline in US-assessed synovial size, Doppler activity presence in the synovial membrane, and numbers of US-detected Baker's cysts. US was performed at baseline, week 14 (exercise stop), and week 26 (follow-up). RESULTS: Fifty participants received steroid injection, and 50 received placebo injection. All participants received 12 weeks of exercise. Forty five and 44, respectively, completed the study. At week 14, the group difference in the change in synovium thickness was 2.2 mm (95%, confidence interval (CI) 0.5 to 4.8), P = 0.11. There were no group differences in the changes in distribution of patients with presence of synovial Doppler activity (P = 0.98) or Baker's cysts (P = 0.35). There were no statistically significant differences between groups at week 26 in any outcome. CONCLUSION: Intra-articular steroid injection of KOA-patients prior to a 3 months exercise programme did not reduce synovial hypertrophy, synovial Doppler activity, or Baker's cyst presence more than a placebo saline injection according to US-assessments. TRIAL REGISTRATION: EudraCT: 2012-002607-18. PMID- 26746146 TI - Model-based evaluation of cost-effectiveness of nerve growth factor inhibitors in knee osteoarthritis: impact of drug cost, toxicity, and means of administration. AB - OBJECTIVE: Studies suggest nerve growth factor inhibitors (NGFi) relieve pain but may accelerate disease progression in some patients with osteoarthritis (OA). We sought cost and toxicity thresholds that would make NGFi a cost-effective treatment for moderate-to-severe knee OA. DESIGN: We used the Osteoarthritis Policy (OAPol) model to estimate the cost-effectiveness of NGFi compared to standard of care (SOC) in OA, using Tanezumab as an example. Efficacy and rates of accelerated OA progression were based on published studies. We varied the price/dose from $200 to $1000. We considered self-administered subcutaneous (SC) injections (no administration cost) vs provider-administered intravenous (IV) infusion ($69-$433/dose). Strategies were defined as cost-effective if their incremental cost-effectiveness ratio (ICER) was less than $100,000/quality adjusted life year (QALY). In sensitivity analyses we varied efficacy, toxicity, and costs. RESULTS: SOC in patients with high levels of pain led to an average discounted quality-adjusted life expectancy of 11.15 QALYs, a lifetime risk of total knee replacement surgery (TKR) of 74%, and cumulative discounted direct medical costs of $148,700. Adding Tanezumab increased QALYs to 11.42, reduced primary TKR utilization to 63%, and increased costs to between $155,400 and $199,500. In the base-case analysis, Tanezumab at $600/dose was cost-effective when delivered outside of a hospital. At $1000/dose, Tanezumab was not cost effective in all but the most optimistic scenario. Only at rates of accelerated OA progression of 10% or more (10-fold higher than reported values) did Tanezumab decrease QALYs and fail to represent a viable option. CONCLUSIONS: At $100,000/QALY, Tanezumab would be cost effective if priced <=$400/dose in all settings except IV hospital delivery. PMID- 26746150 TI - Impaired muscle function in a mouse surgical model of post-traumatic osteoarthritis. AB - OBJECTIVES: Using a mouse surgical model of post-traumatic osteoarthritis (OA), we sought to determine if muscle function is altered following acute joint injury and whether this relates to OA progression. DESIGN: Male C57BL/6 mice underwent surgical transection of the medio-meniscal tibial ligament destabilisation of the medial meniscus (DMM) or sham surgery on one knee. Tibialis anterior (TA) muscle function was assessed in situ at 1, 4 and 8 weeks post-surgery. Cartilage damage and joint inflammation were assessed by histologic scoring. Muscle mRNA expression was quantified by qRT-PCR. RESULTS: Tetanic and twitch force production between DMM and sham muscle did not differ at 1 week post-surgery. Muscle function improved in both groups with time, but specific force production in DMM muscles was 18% and 22% lower than sham muscles at 4 and 8 weeks post surgery respectively. At 8 weeks post-surgery, DMM muscles had a 40% slower relaxation rate and reduced expression of sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase (Serca) pump mRNA compared to sham muscles; both observations indicate likely alterations in muscle Ca(2+) handling. There were no histologic signs of muscle atrophy or inflammation in DMM TA muscles. Specific force production in both sham and DMM mice showed a negative correlation with the severity of joint inflammation. CONCLUSIONS: Acute knee injury in the DMM model of post-traumatic OA leads to a persistent deficit in TA muscle function that occurs in the absence of muscle atrophy. This study highlights that the impact of acute knee injury is unlikely to be limited to the muscles controlling knee movement. PMID- 26746148 TI - Phlpp1 facilitates post-traumatic osteoarthritis and is induced by inflammation and promoter demethylation in human osteoarthritis. AB - OBJECTIVE: Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability. OA is characterized by articular chondrocyte deterioration, subchondral bone changes and debilitating pain. One strategy to promote cartilage regeneration and repair is to accelerate proliferation and matrix production of articular chondrocytes. We previously reported that the protein phosphatase Phlpp1 controls chondrocyte differentiation by regulating the activities of anabolic kinases. Here we examined the role of Phlpp1 in OA progression in a murine model. We also assessed PHLPP1 expression and promoter methylation. DESIGN: Knee joints of WT and Phlpp1(-/-) mice were surgically destabilized by transection of the medial meniscal ligament (DMM). Mice were assessed for signs of OA progression via radiographic and histological analyses, and pain assessment for mechanical hypersensitivity using the von Frey assay. Methylation of the PHLPP1 promoter and PHLPP1 expression were evaluated in human articular cartilage and chondrocyte cell lines. RESULTS: Following DMM surgeries, Phlpp1 deficient mice showed fewer signs of OA and cartilage degeneration. Mechanical allodynia associated with DMM surgeries was also attenuated in Phlpp1(-/-) mice. PHLPP1 was highly expressed in human articular cartilage from OA patients, but was undetectable in cartilage specimens from femoral neck fractures (FNFxs). Higher PHLPP1 levels correlated with less PHLPP1 promoter CpG methylation in cartilage from OA patients. Blocking cytosine methylation or treatment with inflammatory mediators enhanced PHLPP1 expression in human chondrocyte cell lines. CONCLUSION: Phlpp1 deficiency protects against OA progression while CpG demethylation and inflammatory cytokines promote PHLPP1 expression. PMID- 26746149 TI - Influences on the decision to use an osteoarthritis diagnosis in primary care: a cohort study with linked survey and electronic health record data. AB - OBJECTIVE: Clinicians may record patients presenting with osteoarthritis (OA) symptoms with joint pain rather than an OA diagnosis. This may have implications for OA research studies and patient care. The objective was to assess whether older adults recorded with joint pain are similar to those with a recorded OA diagnosis. METHOD: A study of adults aged >=50 years in eight United Kingdom general practices, with electronic health records linked to survey data. Patients with a recorded regional OA diagnosis were compared to those with a recorded joint pain symptom on socio-demographics, risk factors, body region, pain severity, prescribed analgesia, and potential differential diagnoses. A sub-group was compared on radiographic knee OA. RESULTS: Thirteen thousand eight hundred and thirty-one survey responders consented to record review. One thousand four hundred and twenty-seven (10%) received an OA (n = 616) or joint pain (n = 811) code with wide practice variation. Receiving an OA diagnosis was associated with age (75+ compared to 50-64 OR 3.25; 95% Credible intervals (CrI) 2.36, 4.53), obesity (1.72; 1.22, 2.33), and pain interference (1.45; 1.09, 1.92). Analgesia management was similar. Radiographic OA was common in both groups. A quarter of those with a joint pain record received an OA diagnosis in the following 6 years. CONCLUSION: Recording OA diagnoses are less common than recording a joint pain symptom and associated with risk factors and severity. OA studies in primary care need to consider joint pain symptoms to understand the burden and quality of care across the spectrum of OA. Patients recorded with joint pain may represent early cases of OA with need for early intervention. PMID- 26746152 TI - Turning Pain Into Cues for Goal-Directed Behavior: Implementation Intentions Reduce Escape-Avoidance Behavior on a Painful Task. AB - Pain automatically elicits escape-avoidance behavior to avert bodily harm. In patients with chronic pain, long-term escape-avoidance behavior may increase the risk of chronic disability. The aim of the presents study was to examine whether implementation intentions reduce escape-avoidance behavior during painful tasks in healthy individuals. Implementation intentions are "if-then" self-statements associating situational cues with goal-directed behaviors. Seventy healthy participants performed a painful finger pressing task, preceded by either implementation intention instructions with pain or a nonpain cue as a cue for goal-directed behavior, or control instructions. Escape-avoidance behavior was operationalized as task duration and response rate. Inhibitory control was measured using the Stop Signal Task. The pain implementation intentions resulted in the longest task duration (P = .02), and thus less escape-avoidance behavior. Low inhibitory control was associated with shorter task duration (P = .03), and thus more escape-avoidance behavior. The nonpain implementation intentions resulted in the highest response rate, but only when inhibitory control was low (P = .04). Implementation intentions referring to pain or nonpain reduce escape avoidance behavior on a painful task. It is worthwhile to examine whether individuals in pain and with low inhibitory control benefit from interventions that incorporate implementation intentions. PERSPECTIVE: To our knowledge, this study is the first to show that forming implementation intentions reduces escape avoidance behavior during pain and fosters nonpain goal pursuit. The use of implementation intentions is indicated to be an intervention that could be of use in patients with pain, particularly when inhibitory control is low. PMID- 26746159 TI - Ultrasonic guided wave tomography for ice detection. AB - Of great concern for many structures, particularly critical sections of rotary and fixed wing aircrafts, is the ability to detect ice either on grounded or in flight vehicles. As a consequence, some work is reported here that could be useful for a variety of different industries where ice formation is an important problem. This paper presents experimental validations of a probability-based reconstruction algorithm (PRA) on ice detection of plate-like structures. The ice detection tests are performed for three different specimens: a single layer aluminum plate with a circular ice sensing array, a titanium plate with a sparse rectangular ice sensing array, and a carbon-fiber-reinforced titanium plate with an embedded ice sensing array mounted on a carbon fiber back plate. Cases from the simple to the more challenging exemplify that special modes can be used to differentiate ice from water, a sparse rectangular array could also be used for ice detection, and an ice sensing array could be further used to detect the ice on the sensor free side, a very useful application of ice sensing for aircraft wings, for example. Ice detection images for the respective cases are reconstructed to investigate the feasibility of ice sensing with ultrasonic guided wave tomography technology. The results show that the PRA based ultrasonic guided wave tomography method successfully detected and showed ice spots correctly for all three cases. This corroborates the fact that ultrasonic guided wave imaging technology could be a potential useful ice sensing tool in plate like structures. PMID- 26746160 TI - Guided wave mode selection for inhomogeneous elastic waveguides using frequency domain finite element approach. AB - This article describes the use of the frequency domain finite element (FDFE) technique for guided wave mode selection in inhomogeneous waveguides. Problems with Rayleigh-Lamb and Shear-Horizontal mode excitation in isotropic homogeneous plates are first studied to demonstrate the application of the approach. Then, two specific cases of inhomogeneous waveguides are studied using FDFE. Finally, an example of guided wave mode selection for inspecting disbonds in composites is presented. Identification of sensitive and insensitive modes for defect inspection is demonstrated. As the discretization parameters affect the accuracy of the results obtained from FDFE, effect of spatial discretization and the length of the domain used for the spatial fast Fourier transform are studied. Some recommendations with regard to the choice of the above parameters are provided. PMID- 26746151 TI - Unilateral anterior crossbite induces aberrant mineral deposition in degenerative temporomandibular cartilage in rats. AB - OBJECTIVE: To investigate whether mechanical stress induces mineral deposits that contribute to matrix degradation at the onset of osteoarthritis (OA) in temporomandibular joint (TMJ) cartilage. DESIGN: Female Spraguee-Dawley rats were subjected to an unilateral anterior crossbite (UAC) procedure. Histology, electron microscopy, and energy dispersive spectrometer (EDS) were used to examine cartilage matrix structures and composition of mineral deposit in the affected TMJ cartilage. Protein and/or RNA expression of phenotypic markers and mineralization modulators and matrix degradation was analyzed by immunohistochemistry and/or real-time PCR. Synthetic basic calcium phosphate (BCP) and calcium pyrophosphate dehydrate (CPPD) crystals were used to stimulate ATDC5 cells for their impact on cell differentiation and gene expression. RESULTS: Fragmented and disorganized collagen fibers, expanded fibrous spaces, and enhancement of matrix vesicle production and mineral deposition were observed in matrices surrounding hypertrophic chondrocytes in cartilage as early as 2 weeks post-UAC and exacerbated with time. The mineral deposits in TMJ cartilage at 12- and 20-weeks post-UAC had Ca/P ratios of 1.42 and 1.44, which are similar to the ratios for BCP. The expression of mineralization inhibitors, NPP1, ANK, CD73, and Matrix gla protein (MGP) was decreased from 2 to 8 weeks post-UAC, so were the chondrogenic markers, Col-2, Col-X and aggrecan. In contrast, the expression of tissue-nonspecific alkaline phosphatase (TNAP) and MMP13 was increased 4-weeks post-UAC. Treating ADTC5 cells with BCP crystals increased MMPs and ADAMTS5 expression, but reduced matrix production in a time-dependent manner. CONCLUSION: UAC induces deposition of BCP-like minerals in osteoarthritic cartilage, which can stimulate matrix degradation by promoting the expression of cartilage-degrading enzymes to facilitate OA progression. PMID- 26746161 TI - Conjugated gold nanoparticles as a tool for probing the bacterial cell envelope: The case of Shewanella oneidensis MR-1. AB - The bacterial cell envelope forms the interface between the interior of the cell and the outer world and is, thus, the means of communication with the environment. In particular, the outer cell surface mediates the adhesion of bacteria to the surface, the first step in biofilm formation. While a number of ligand-based interactions are known for the attachment process in commensal organisms and, as a result, opportunistic pathogens, the process of nonspecific attachment is thought to be mediated by colloidal, physiochemical, interactions. It is becoming clear, however, that colloidal models ignore the heterogeneity of the bacterial surface, and that the so-called nonspecific attachment may be mediated by specific regions of the cell surface, whether or not the relevant interaction is ligand-mediate. The authors introduce surface functionalized gold nanoparticles to probe the surface chemistry of Shewanella oneidensis MR-1 as it relates to surface attachment to omega-substituted alkanethiolates self-assembled monolayers (SAMs). A linear relationship between the attachment of S. oneidensis to SAM modified planar substrates and the number of similarly modified nanoparticles attached to the bacterial surfaces was demonstrated. In addition, the authors demonstrate that carboxylic acid-terminated nanoparticles attach preferentially to the subpolar region of the S. oneidensis and obliteration of that binding preference corresponds in loss of attachment to carboxylic acid terminated SAMs. Moreover, this region corresponds to suspected functional regions of the S. oneidensis surface. Because this method can be employed over large numbers of cells, this method is expected to be generally applicable for understanding cell surface organization across populations. PMID- 26746162 TI - Chemical physics of water-water interfaces. AB - A brief review is given on recent progress in experimental and theoretical investigations of the interface between coexisting aqueous phases of biopolymers. The experimental aspects are introduced using results obtained from a model system consisting of aqueous mixtures of nongelling gelatin and dextran. The focus is on the interfacial tension and interfacial electric potential (Donnan potential). These quantities are experimentally accessible and can be shown to be closely related. PMID- 26746164 TI - Probing carbonyl-water hydrogen-bond interactions in thin polyoxazoline brushes. AB - Temperature-responsive oxazoline-based polymer brushes have gained increased attention as biocompatible surfaces. In aqueous environment, they can be tuned between hydrophilic and hydrophobic behavior triggered by a temperature stimulus. This transition is connected with changes in molecule-solvent interactions and results in a switching of the brushes between swollen and collapsed states. This work studies the temperature-dependent interactions between poly(2-oxazoline) brushes and water. In detail, thermoresponsive poly(2-cyclopropyl-2-oxazoline), nonresponsive hydrophilic poly(2-methyl-2-oxazoline), as well as a copolymer of the two were investigated with in situ infrared ellipsometry. Focus was put on interactions of the brushes' carbonyl groups with water molecules. Different polymer-water interactions could be observed and assigned to hydrogen bonding between C=O groups and water molecules. The switching behavior of the brushes in the range of 20-45 degrees C was identified by frequency shifts and intensity changes of the amide I band. PMID- 26746163 TI - Hydration force fluctuations in hydrophilic planar systems. AB - Utilizing all-atom simulations with explicit solvent, the authors model hydrophilic surfaces interacting across water at a fixed chemical potential. They extract the hydration forces acting between the surfaces and assess force fluctuations as well as interlamellar water number fluctuations. The trends obtained from the simulations are captured by a continuum-based description with effective model parameters. The significance of fluctuations depends on surface hydrophilicity and rigidity. The authors show that the force fluctuations play an important role in kinetic processes in systems with lateral sizes smaller than several tens of nanometers. PMID- 26746165 TI - Ionic strength dependent vesicle adsorption and phase behavior of anionic phospholipids on a gold substrate. AB - The authors report on the effect of ionic strength on the formation of supported vesicle layers of anionic phospholipids 1,2-dimyristoyl-sn-glycero-3-phospho-rac glycerol (DMPG) and dimyristoylphosphatidylserine (DMPS) onto gold. Using quartz crystal microbalance with dissipation monitoring the authors show that vesicle adsorption is mainly governed by NaCl concentration, reflecting the importance of electrostatic interactions in anionic lipids, as compared to zwitterionic 1,2 dimyristoyl-sn-glycero-3-phosphocholine. At low ionic strength, low or no adsorption is observed as a result of vesicle-vesicle electrostatic repulsion. At medium ionic strength, the negative charges of DMPG and DMPS are screened resulting in larger adsorption and a highly dissipative intact vesicle layer. In addition, DMPS exhibits a peculiar behavior at high ionic strength that depends on the temperature of the process. PMID- 26746167 TI - Segment fusion of ToF-SIMS images. AB - The imaging capabilities of time-of-flight secondary ion mass spectrometry (ToF SIMS) have not been used to their full potential in the analysis of polymer and biological samples. Imaging has been limited by the size of the dataset and the chemical complexity of the sample being imaged. Pixel and segment based image fusion algorithms commonly used in remote sensing, ecology, geography, and geology provide a way to improve spatial resolution and classification of biological images. In this study, a sample of Arabidopsis thaliana was treated with silver nanoparticles and imaged with ToF-SIMS. These images provide insight into the uptake mechanism for the silver nanoparticles into the plant tissue, giving new understanding to the mechanism of uptake of heavy metals in the environment. The Munechika algorithm was programmed in-house and applied to achieve pixel based fusion, which improved the spatial resolution of the image obtained. Multispectral and quadtree segment or region based fusion algorithms were performed using ecognition software, a commercially available remote sensing software suite, and used to classify the images. The Munechika fusion improved the spatial resolution for the images containing silver nanoparticles, while the segment fusion allowed classification and fusion based on the tissue types in the sample, suggesting potential pathways for the uptake of the silver nanoparticles. PMID- 26746166 TI - Evaluation of biomolecular distributions in rat brain tissues by means of ToF SIMS using a continuous beam of Ar clusters. AB - Time-of-flight secondary ion mass spectrometry (ToF-SIMS) provides detailed chemical structure information and high spatial resolution images. Therefore, ToF SIMS is useful for studying biological phenomena such as ischemia. In this study, in order to evaluate cerebral microinfarction, the distribution of biomolecules generated by ischemia was measured with ToF-SIMS. ToF-SIMS data sets were analyzed by means of multivariate analysis for interpreting complex samples containing unknown information and to obtain biomolecular mapping indicated by fragment ions from the target biomolecules. Using conventional ToF-SIMS (primary ion source: Bi cluster ion), it is difficult to detect secondary ions beyond approximately 1000 u. Moreover, the intensity of secondary ions related to biomolecules is not always high enough for imaging because of low concentration even if the masses are lower than 1000 u. However, for the observation of biomolecular distributions in tissues, it is important to detect low amounts of biological molecules from a particular area of tissue. Rat brain tissue samples were measured with ToF-SIMS (J105, Ionoptika, Ltd., Chandlers Ford, UK), using a continuous beam of Ar clusters as a primary ion source. ToF-SIMS with Ar clusters efficiently detects secondary ions related to biomolecules and larger molecules. Molecules detected by ToF-SIMS were examined by analyzing ToF-SIMS data using multivariate analysis. Microspheres (45 MUm diameter) were injected into the rat unilateral internal carotid artery (MS rat) to cause cerebral microinfarction. The rat brain was sliced and then measured with ToF-SIMS. The brain samples of a normal rat and the MS rat were examined to find specific secondary ions related to important biomolecules, and then the difference between them was investigated. Finally, specific secondary ions were found around vessels incorporating microspheres in the MS rat. The results suggest that important biomolecules related to cerebral microinfarction can be detected by ToF-SIMS. PMID- 26746168 TI - Three-dimensional imaging of cholesterol and sphingolipids within a Madin-Darby canine kidney cell. AB - Metabolic stable isotope incorporation and secondary ion mass spectrometry (SIMS) depth profiling performed on a Cameca NanoSIMS 50 were used to image the (18)O cholesterol and (15)N-sphingolipid distributions within a portion of a Madin Darby canine kidney (MDCK) cell. Three-dimensional representations of the component-specific isotope distributions show clearly defined regions of (18)O cholesterol and (15)N-sphingolipid enrichment that seem to be separate subcellular compartments. The low levels of nitrogen-containing secondary ions detected at the (18)O-enriched regions suggest that these (18)O-cholesterol-rich structures may be lipid droplets, which have a core consisting of cholesterol esters and triacylglycerides. PMID- 26746171 TI - Correction. AB - Gu W, Jiang W, He J, et al. Blockade of the brachial plexus abolishes activation of specific brain regions by electroacupuncture at LI4: a functional MRI study. Acupunct Med 2015;33:457-64. On page 2 in the Methods subsection entitled "Experimental protocol", the pulse width should have been stated as 0.5 ms and not 30 ms as published. PMID- 26746170 TI - Toward Rational Donor Selection in Faecal Microbiota Transplantation for IBD. PMID- 26746172 TI - Contributions of ADP and ATP to the increase in skeletal muscle blood flow after manual acupuncture stimulation in rats. AB - OBJECTIVE: To investigate the contributions of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to the increase in skeletal muscle blood flow (MBF) observed following manual acupuncture (MA) stimulation in rats. METHODS: Male Sprague-Dawley rats were used as experimental animals (300-370 g, n=40). MA was applied to the right tibialis anterior muscle (TA) for 1 min using a stainless steel acupuncture needle. In eight rats, high-performance liquid chromatography with the microdialysis technique was used to measure local extracellular concentrations of ATP, ADP, adenosine monophosphate (AMP), and adenosine in the TA. In the remaining 32 rats, fluorescent microspheres (15 um in diameter) were used to measure MBF in the TA following pre-treatment with either the P2 receptor antagonist suramin (100 mg/kg intra-arterially) or saline (control) (n=16 each). Rats receiving MA (Suramin+MA and Saline+MA groups, n=8 each) were compared with untreated rats (Suramin and Saline groups, n=8). RESULTS: MA significantly increased the local extracellular concentration of ATP, ADP, and adenosine (p<0.05, before MA vs 30 min after MA). In addition, MA significantly increased MBF in rats pre-treated with saline or suramin (p<0.01, Saline vs Saline+MA; p<0.05, Suramin vs Suramin+MA, respectively). However, suramin significantly suppressed this MA-induced increase in MBF (p<0.05, Saline+MA vs Suramin+MA). CONCLUSIONS: These results suggest that both ATP and ADP partially contribute to the MA-induced increase in MBF via P2 receptors. However, further studies are needed to clarify the contributions of other vasodilators. PMID- 26746169 TI - Systematic Review and Meta-analysis: Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis. AB - BACKGROUND AND AIMS: Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool. RESULTS: In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7-13%) and 33% [95% CI 29-37%], respectively. Corresponding values for maintenance trials were 19% [95% CI 11 30%] and 22% [95% CI 17-28%]. Trials enrolling patients with more active disease confirmed by endoscopy [endoscopy subscore >= 2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits. CONCLUSIONS: Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials. PMID- 26746173 TI - Trigger point dry needling versus strain-counterstrain technique for upper trapezius myofascial trigger points: a randomised controlled trial. AB - BACKGROUND: Treatment of active myofascial trigger points includes both invasive and non-invasive techniques. OBJECTIVES: To compare the effects of upper trapezius trigger point dry needling (DN) and strain-counterstrain (SCS) techniques versus sham SCS. STUDY DESIGN: Randomised controlled trial. METHOD: 34 study subjects with active trigger points were randomly assigned to one of three treatment groups, and received either three sessions of DN (n=12), six sessions of SCS (n=10), or sham SCS (n=12) over a 3-week period. Subjective pain response and subjects' own ratings of perceived disability were measured. RESULTS: The analysis of variance mixed model showed a significant time effect for pain (p<0.001), elicited pain (p<0.001), pain pressure threshold (p<0.01), and neck disability index (p=0.016). Pain at rest decreased in all groups, as follows: DN 18.5 mm (95% CI 4.3 to 32.7 mm); SCS 28.3 mm (95% CI 12.4 to 44.1 mm); sham SCS 21.9 mm (95% CI 3.5 to 40.1 mm). Reductions in disability score (points) were significant in the SCS group (5.5, 95% CI 1.6 to 9.4) but not in the DN (1.4, 95% CI -4.9 to 2.1) or sham SCS (1.8, 95% CI -6.4 to 2.7) groups. There was no significant group*time interaction effect for any variables studied. CONCLUSIONS: There were no differences between the sham SCS, SCS, and DN groups in any of the outcome measures. DN relieved pain after fewer sessions than SCS and sham SCS, and thus may be a more efficient technique. Future studies should include a larger sample size. TRIAL REGISTRATION NUMBER: NCT01290653. PMID- 26746174 TI - Pleurochrysome: A Web Database of Pleurochrysis Transcripts and Orthologs Among Heterogeneous Algae. AB - Pleurochrysis is a coccolithophorid genus, which belongs to the Coccolithales in the Haptophyta. The genus has been used extensively for biological research, together with Emiliania in the Isochrysidales, to understand distinctive features between the two coccolithophorid-including orders. However, molecular biological research on Pleurochrysis such as elucidation of the molecular mechanism behind coccolith formation has not made great progress at least in part because of lack of comprehensive gene information. To provide such information to the research community, we built an open web database, the Pleurochrysome (http://bioinf.mind.meiji.ac.jp/phapt/), which currently stores 9,023 unique gene sequences (designated as UNIGENEs) assembled from expressed sequence tag sequences of P. haptonemofera as core information. The UNIGENEs were annotated with gene sequences sharing significant homology, conserved domains, Gene Ontology, KEGG Orthology, predicted subcellular localization, open reading frames and orthologous relationship with genes of 10 other algal species, a cyanobacterium and the yeast Saccharomyces cerevisiae. This sequence and annotation information can be easily accessed via several search functions. Besides fundamental functions such as BLAST and keyword searches, this database also offers search functions to explore orthologous genes in the 12 organisms and to seek novel genes. The Pleurochrysome will promote molecular biological and phylogenetic research on coccolithophorids and other haptophytes by helping scientists mine data from the primary transcriptome of P. haptonemofera. PMID- 26746176 TI - Body Mass Index, Abdominal Fatness, and Heart Failure Incidence and Mortality: A Systematic Review and Dose-Response Meta-Analysis of Prospective Studies. AB - BACKGROUND: Obesity has been associated with increased risk of heart failure, but whether overweight also increases risk is unclear. It is also unclear whether abdominal adiposity is more strongly associated with heart failure risk than general adiposity. We conducted a systematic review and meta-analysis of prospective studies to clarify the strength and shape of the dose-response relationship between general and abdominal adiposity and the risk of heart failure. METHODS AND RESULTS: PubMed and Embase databases were searched up to October 10, 2014. Summary relative risks were calculated using random-effects models. A total of 28 studies (27 publications) were included. Twenty-three prospective studies with >15 905 incident cases among 647 388 participants were included in the analysis of body mass index and heart failure incidence, and 4 studies were included for heart failure mortality. The summary relative risk for a 5-unit increment in body mass index was 1.41 (95% confidence interval, 1.34 1.47; I(2)=83%) for heart failure incidence and 1.26 (95% confidence interval, 0.85-1.87; I(2)=95%) heart failure mortality. Although the test for nonlinearity was significant (P<0.0001), this appeared to be attributable to a threshold at a body mass index of ~23 to 24 kg/m(2); however, there was evidence of increased risk even in the overweight body mass index range. The summary relative risk for a 10-cm increase in waist circumference was 1.29 (95% confidence interval, 1.21 1.37; I(2)=89%) and per 0.1-unit increase in waist-to-hip ratio was 1.29 (95% confidence interval, 1.13-1.47; I(2)=82%). CONCLUSION: Overweight and obesity and abdominal adiposity are associated with increased risk of heart failure. PMID- 26746175 TI - N-Terminal Pro-Brain Natriuretic Peptide and Heart Failure Risk Among Individuals With and Without Obesity: The Atherosclerosis Risk in Communities (ARIC) Study. AB - BACKGROUND: Obesity is a risk factor for heart failure (HF) but is associated with lower N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. It is unclear whether the prognostic value and implications of NT-proBNP levels for HF risk differ across body mass index (BMI) categories. METHODS AND RESULTS: We followed up 12 230 ARIC participants free of prior HF at baseline (visit 2, 1990 1992) with BMI >=18.5 kg/m(2). We quantified and compared the relative and absolute risk associations of NT-proBNP with incident HF across BMI categories. There were 1861 HF events during a median 20.6 years of follow-up. Despite increased HF risk in obesity, a weak inverse association was seen between baseline BMI and NT-proBNP levels (r=-0.10). Nevertheless, higher baseline NT proBNP was associated with increased HF risk in all BMI categories. NT-proBNP improved HF risk prediction overall, even among those with severe obesity (BMI >=35 kg/m(2); improvement in C statistic, 0.032; 95% confidence interval, 0.011 0.053). However, given the higher HF rates among those with obesity, at each NT proBNP level, higher BMI was associated with greater absolute HF risk. Indeed, among those with NT-proBNP of 100 to <200 pg/mL, the average 10-year HF risk was <5% among normal-weight individuals but >10% among the severely obese. CONCLUSIONS: Despite its inverse relationship with BMI, NT-proBNP provides significant prognostic information on the risk of developing HF even among individuals with obesity. Given the higher baseline HF risk among persons with obesity, even slight elevations in NT-proBNP may have implications for increased absolute HF risk in this population. PMID- 26746177 TI - Atrial Fibrillation Begets Heart Failure and Vice Versa: Temporal Associations and Differences in Preserved Versus Reduced Ejection Fraction. AB - BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) frequently coexist and together confer an adverse prognosis. The association of AF with HF subtypes has not been well described. We sought to examine differences in the temporal association of AF and HF with preserved versus reduced ejection fraction. METHODS AND RESULTS: We studied Framingham Heart Study participants with new-onset AF or HF between 1980 and 2012. Among 1737 individuals with new AF (mean age, 75+/-12 years; 48% women), more than one third (37%) had HF. Conversely, among 1166 individuals with new HF (mean age, 79+/-11 years; 53% women), more than half (57%) had AF. Prevalent AF was more strongly associated with incident HF with preserved ejection fraction (multivariable-adjusted hazard ratio [HR], 2.34; 95% confidence interval [CI], 1.48-3.70; no AF as referent) versus HF with reduced ejection fraction (HR, 1.32; 95% CI, 0.83-2.10), with a trend toward difference between HF subtypes (P for difference=0.06). Prevalent HF was associated with incident AF (HR, 2.18; 95% CI, 1.26-3.76; no HF as referent). The presence of both AF and HF portended greater mortality risk compared with neither condition, particularly among individuals with new HF with reduced ejection fraction and prevalent AF (HR, 2.72; 95% CI, 2.12-3.48) compared with new HF with preserved ejection fraction and prevalent AF (HR, 1.83; 95% CI, 1.41-2.37; P for difference=0.02). CONCLUSIONS: AF occurs in more than half of individuals with HF, and HF occurs in more than one third of individuals with AF. AF precedes and follows HF with both preserved and reduced ejection fraction, with some differences in temporal association and prognosis. Future studies focused on underlying mechanisms of these dual conditions are warranted. PMID- 26746179 TI - 'Imagined guilt' vs 'recollected guilt': implications for fMRI. AB - Guilt is thought to maintain social harmony by motivating reparation. This study compared two methodologies commonly used to identify the neural correlates of guilt. The first, imagined guilt, requires participants to read hypothetical scenarios and then imagine themselves as the protagonist. The second, recollected guilt, requires participants to reflect on times they personally experienced guilt. In the fMRI scanner, participants were presented with guilt/neutral memories and guilt/neutral hypothetical scenarios. Contrasts confirmed a priori predictions that guilt memories, relative to guilt scenarios, were associated with significantly greater activity in regions associated with affect [anterior cingulate cortex (ACC), Caudate, Insula, orbital frontal cortex (OFC)] and social cognition [temporal pole (TP), precuneus). Similarly, results indicated that guilt memories, relative to neutral memories, were also associated with greater activity in affective (ACC, amygdala, Insula, OFC) and social cognition (mPFC, TP, precuneus, temporo-parietal junction) regions. There were no significant differences between guilt hypothetical scenarios and neutral hypothetical scenarios in either affective or social cognition regions. The importance of distinguishing between different guilt inductions inside the scanner is discussed. We offer explanations of our results and discuss ideas for future research. PMID- 26746180 TI - Proximal vocal threat recruits the right voice-sensitive auditory cortex. AB - The accurate estimation of the proximity of threat is important for biological survival and to assess relevant events of everyday life. We addressed the question of whether proximal as compared with distal vocal threat would lead to a perceptual advantage for the perceiver. Accordingly, we sought to highlight the neural mechanisms underlying the perception of proximal vs distal threatening vocal signals by the use of functional magnetic resonance imaging. Although we found that the inferior parietal and superior temporal cortex of human listeners generally decoded the spatial proximity of auditory vocalizations, activity in the right voice-sensitive auditory cortex was specifically enhanced for proximal aggressive relative to distal aggressive voices as compared with neutral voices. Our results shed new light on the processing of imminent danger signaled by proximal vocal threat and show the crucial involvement of the right mid voice sensitive auditory cortex in such processing. PMID- 26746183 TI - A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN. AB - OBJECTIVE: To classify the patterns of functional decline in patients with sporadic amyotrophic lateral sclerosis (ALS) and explore the genetic backgrounds that modified these patterns. METHODS: We included 465 patients with sporadic ALS in the analysis and clustered the longitudinal functional scores in the registered patients, using a mixture approach of a non-linear mixed-effects model. We conducted a genome-wide analysis of 572 983 single nucleotide polymorphisms (SNPs). We then assessed the association between the clusters of longitudinal functional scores and SNPs. RESULTS: We identified the following four clusters of longitudinal functional decline in the cases: a rapid decline cluster, an intermediate decline cluster, a sigmoidal decline cluster and a moderate decline cluster. We identified seven SNPs associated with the rapid decline cluster, using a recessive model (p=3.47-8.34*10(-8)). The OR for the probabilities of the rapid decline cluster ranged from 5.5 to 5.84. Homozygosity for the minor alleles in the seven SNPs, which constituted a linkage disequilibrium (LD) block, was associated with decreased expression of TTN (encoding Titin, a large sarcomere protein) in the expression quantitative trait loci database of a large-scale Japanese genetic variation database (p=8.6*10(-10) 1.1*10(-7)). TTN expression in immortalised lymphocyte lines was decreased in patients who were homozygous for the minor alleles compared with those who were homozygous for the major alleles (n=19 in each group, p=0.002). CONCLUSIONS: We detected an LD block associated with a rapid functional decline in patients with sporadic ALS, which is linked to decreased expression of TTN. PMID- 26746182 TI - Converging evidence for an impact of a functional NOS gene variation on anxiety related processes. AB - Being a complex phenotype with substantial heritability, anxiety and related phenotypes are characterized by a complex polygenic basis. Thereby, one candidate pathway is neuronal nitric oxide (NO) signaling, and accordingly, rodent studies have identified NO synthase (NOS-I), encoded by NOS1, as a strong molecular candidate for modulating anxiety and hippocampus-dependent learning processes. Using a multi-dimensional and -methodological replication approach, we investigated the impact of a functional promoter polymorphism (NOS1-ex1f-VNTR) on human anxiety-related phenotypes in a total of 1019 healthy controls in five different studies. Homozygous carriers of the NOS1-ex1f short-allele displayed enhanced trait anxiety, worrying and depression scores. Furthermore, short-allele carriers were characterized by increased anxious apprehension during contextual fear conditioning. While autonomous measures (fear-potentiated startle) provided only suggestive evidence for a modulatory role of NOS1-ex1f-VNTR on (contextual) fear conditioning processes, neural activation at the amygdala/anterior hippocampus junction was significantly increased in short-allele carriers during context conditioning. Notably, this could not be attributed to morphological differences. In accordance with data from a plethora of rodent studies, we here provide converging evidence from behavioral, subjective, psychophysiological and neuroimaging studies in large human cohorts that NOS-I plays an important role in anxious apprehension but provide only limited evidence for a role in (contextual) fear conditioning. PMID- 26746181 TI - Pain empathy in schizophrenia: an fMRI study. AB - Although it has been proposed that schizophrenia is characterized by impaired empathy, several recent studies found intact neural responses on tasks measuring the affective subdomain of empathy. This study further examined affective empathy in 21 schizophrenia outpatients and 21 healthy controls using a validated pain empathy paradigm with two components: (i) observing videos of people described as medical patients who were receiving a painful sound stimulation treatment; (ii) listening to the painful sounds (to create regions of interest). The observing videos component incorporated experimental manipulations of perspective taking (instructions to imagine 'Self' vs 'Other' experiencing pain) and cognitive appraisal (information about whether treatment was 'Effective' vs 'Not Effective'). When considering activation across experimental conditions, both groups showed similar dorsal anterior cingulate cortex (dACC) and anterior insula (AI) activation while merely observing others in pain. However, there were group differences associated with perspective taking: controls showed relatively greater dACC and AI activation for the Self vs Other contrast whereas patients showed relatively greater activation in these and additional regions for the Other vs Self contrast. Although patients demonstrated grossly intact neural activity while observing others in pain, they showed more subtle abnormalities when required to toggle between imagining themselves vs others experiencing pain. PMID- 26746184 TI - Prognostic significance of delayed intraventricular haemorrhage in the INTERACT studies. AB - BACKGROUND AND PURPOSE: Intraventricular extension of intracerebral haemorrhage (ICH) predicts poor outcome, but the significance of delayed intraventricular haemorrhage (dIVH) is less well defined. We determined the prognostic significance of dIVH in the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trials (INTERACT 1 and 2). METHODS: Pooled analyses of the INTERACT CT substudies-international, multicentre, prospective, open, blinded end point, randomised controlled trials of patients with acute spontaneous ICH and elevated systolic blood pressure (SBP)-randomly assigned to intensive (<140 mm Hg) or guideline-based (<180 mm Hg) SBP management. Participants had blinded central analyses of baseline and 24 h CTs, with dIVH defined as new intraventricular haemorrhage (IVH) on the latter scan. Outcomes of death and major disability were defined by modified Rankin Scale scores at 90 days. RESULTS: There were 349 (27%) of 1310 patients with baseline IVH, and 107 (11%) of 961 initially IVH-free patients who developed dIVH. Significant associations of dIVH were prior warfarin anticoagulation, high (>=15) baseline National Institutes of Health Stroke Scale score, larger (>=15 mL) ICH volume, greater ICH growth and higher achieved SBP over 24 h. Compared with those who were IVH-free, dIVH had greater odds of 90-day death or major disability versus initial IVH (adjusted ORs 2.84 (95% CI 1.52 to 5.28) and 1.87 (1.36 to 2.56), respectively (p trend <0.0001)). CONCLUSIONS: Although linked to factors determining greater ICH growth including poor SBP control, dIVH is independently associated with poor outcome in acute small to moderate-size ICH. TRIAL REGISTRATION NUMBERS: NCT00226096 and NCT00716079. PMID- 26746185 TI - Selective vulnerability in neurodegeneration: insights from clinical variants of Alzheimer's disease. AB - Selective vulnerability in the nervous system refers to the fact that subpopulations of neurons in different brain systems may be more or less prone to abnormal function or death in response to specific types of pathological states or injury. The concept has been used extensively as a potential way of explaining differences in degeneration patterns and the clinical presentation of different neurodegenerative diseases. Yet the increasing complexity of molecular histopathology at the cellular level in neurodegenerative disorders frequently appears at odds with phenotyping based on clinically-directed, macroscopic regional brain involvement. While cross-disease comparisons can provide insights into the differential vulnerability of networks and neuronal populations, we focus here on what is known about selective vulnerability-related factors that might explain the differential phenotypic expressions of the same disease-in this case, typical and atypical forms of Alzheimer's disease. Whereas considerable progress has been made in this area, much is yet to be elucidated; further studies comparing different phenotypic variants aimed at identifying both vulnerability and resilience factors may provide valuable insights into disease pathogenesis, and suggest novel targets for therapy. PMID- 26746178 TI - Dietary and Policy Priorities for Cardiovascular Disease, Diabetes, and Obesity: A Comprehensive Review. AB - Suboptimal nutrition is a leading cause of poor health. Nutrition and policy science have advanced rapidly, creating confusion yet also providing powerful opportunities to reduce the adverse health and economic impacts of poor diets. This review considers the history, new evidence, controversies, and corresponding lessons for modern dietary and policy priorities for cardiovascular diseases, obesity, and diabetes mellitus. Major identified themes include the importance of evaluating the full diversity of diet-related risk pathways, not only blood lipids or obesity; focusing on foods and overall diet patterns, rather than single isolated nutrients; recognizing the complex influences of different foods on long-term weight regulation, rather than simply counting calories; and characterizing and implementing evidence-based strategies, including policy approaches, for lifestyle change. Evidence-informed dietary priorities include increased fruits, nonstarchy vegetables, nuts, legumes, fish, vegetable oils, yogurt, and minimally processed whole grains; and fewer red meats, processed (eg, sodium-preserved) meats, and foods rich in refined grains, starch, added sugars, salt, and trans fat. More investigation is needed on the cardiometabolic effects of phenolics, dairy fat, probiotics, fermentation, coffee, tea, cocoa, eggs, specific vegetable and tropical oils, vitamin D, individual fatty acids, and diet microbiome interactions. Little evidence to date supports the cardiometabolic relevance of other popular priorities: eg, local, organic, grass-fed, farmed/wild, or non-genetically modified. Evidence-based personalized nutrition appears to depend more on nongenetic characteristics (eg, physical activity, abdominal adiposity, gender, socioeconomic status, culture) than genetic factors. Food choices must be strongly supported by clinical behavior change efforts, health systems reforms, novel technologies, and robust policy strategies targeting economic incentives, schools and workplaces, neighborhood environments, and the food system. Scientific advances provide crucial new insights on optimal targets and best practices to reduce the burdens of diet-related cardiometabolic diseases. PMID- 26746186 TI - A large-scale multicentre cerebral diffusion tensor imaging study in amyotrophic lateral sclerosis. AB - OBJECTIVE: Damage to the cerebral tissue structural connectivity associated with amyotrophic lateral sclerosis (ALS), which extends beyond the motor pathways, can be visualised by diffusion tensor imaging (DTI). The effective translation of DTI metrics as biomarker requires its application across multiple MRI scanners and patient cohorts. A multicentre study was undertaken to assess structural connectivity in ALS within a large sample size. METHODS: 442 DTI data sets from patients with ALS (N=253) and controls (N=189) were collected for this retrospective study, from eight international ALS-specialist clinic sites. Equipment and DTI protocols varied across the centres. Fractional anisotropy (FA) maps of the control participants were used to establish correction matrices to pool data, and correction algorithms were applied to the FA maps of the control and ALS patient groups. RESULTS: Analysis of data pooled from all centres, using whole-brain-based statistical analysis of FA maps, confirmed the most significant alterations in the corticospinal tracts, and captured additional significant white matter tract changes in the frontal lobe, brainstem and hippocampal regions of the ALS group that coincided with postmortem neuropathological stages. Stratification of the ALS group for disease severity (ALS functional rating scale) confirmed these findings. INTERPRETATION: This large-scale study overcomes the challenges associated with processing and analysis of multiplatform, multicentre DTI data, and effectively demonstrates the anatomical fingerprint patterns of changes in a DTI metric that reflect distinct ALS disease stages. This success paves the way for the use of DTI-based metrics as read-out in natural history, prognostic stratification and multisite disease-modifying studies in ALS. PMID- 26746188 TI - Naive Donor NK Cell Repertoires Associated with Less Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation. AB - Acute and latent human CMV cause profound changes in the NK cell repertoire, with expansion and differentiation of educated NK cells expressing self-specific inhibitory killer cell Ig-like receptors. In this study, we addressed whether such CMV-induced imprints on the donor NK cell repertoire influenced the outcome of allogeneic stem cell transplantation. Hierarchical clustering of high resolution immunophenotyping data covering key NK cell parameters, including frequencies of CD56(bright), NKG2A(+), NKG2C(+), and CD57(+) NK cell subsets, as well as the size of the educated NK cell subset, was linked to clinical outcomes. Clusters defining naive (NKG2A(+)CD57(-)NKG2C(-)) NK cell repertoires in the donor were associated with decreased risk for relapse in recipients with acute myeloid leukemia and myelodysplastic syndrome (hazard ratio [HR], 0.09; 95% confidence interval [CI]: 0.03-0.27; p < 0.001). Furthermore, recipients with naive repertoires at 9-12 mo after hematopoietic stem cell transplantation had increased disease-free survival (HR, 7.2; 95% CI: 1.6-33; p = 0.01) and increased overall survival (HR, 9.3; 95% CI: 1.1-77, p = 0.04). Conversely, patients with a relative increase in differentiated NK cells at 9-12 mo displayed a higher rate of late relapses (HR, 8.41; 95% CI: 6.7-11; p = 0.02), reduced disease-free survival (HR, 0.12; 95% CI: 0.12-0.74; p = 0.02), and reduced overall survival (HR, 0.07; 95% CI: 0.01-0.69; p = 0.02). Thus, our data suggest that naive donor NK cell repertoires are associated with protection against leukemia relapse after allogeneic HSCT. PMID- 26746187 TI - High-resolution intracranial vessel wall imaging: imaging beyond the lumen. AB - Accurate and timely diagnosis of intracranial vasculopathies is important due to significant risk of morbidity with delayed and/or incorrect diagnosis both from the disease process as well as inappropriate therapies. Conventional vascular imaging techniques for analysis of intracranial vascular disease provide limited information since they only identify changes to the vessel lumen. New advanced MR intracranial vessel wall imaging (IVW) techniques can allow direct characterisation of the vessel wall. These techniques can advance diagnostic accuracy and may potentially improve patient outcomes by better guided treatment decisions in comparison to previously available invasive and non-invasive techniques. While neuroradiological expertise is invaluable in accurate examination interpretation, clinician familiarity with the application and findings of the various vasculopathies on IVW can help guide diagnostic and therapeutic decision-making. This review article provides a brief overview of the technical aspects of IVW and discusses the IVW findings of various intracranial vasculopathies, differentiating characteristics and indications for when this technique can be beneficial in patient management. PMID- 26746191 TI - Pivotal Role for CD16+ Monocytes in Immune Surveillance of the Central Nervous System. AB - Monocytes represent a heterogeneous population of primary immune effector cells. At least three different subsets can be distinguished based on expression of the low-affinity FcgammaRIII: CD14(++)CD16 -: classical monocytes, CD14(++)CD16(+) intermediate monocytes, and CD14(+)CD16 ++: non-classical monocytes. Whereas CD16 -: classical monocytes are considered key players in multiple sclerosis (MS), little is known on CD16(+) monocytes and how they contribute to the disease. In this study, we examined the frequency and phenotype of monocyte subpopulations in peripheral blood, cerebrospinal fluid (CSF), and brain biopsy material derived from MS patients and controls. Furthermore, we addressed a possible monocyte dysfunction in MS and analyzed migratory properties of monocyte subsets using human brain microvascular endothelial cells. Our ex vivo studies demonstrated that CD16(+) monocyte subpopulations are functional but numerically reduced in the peripheral blood of MS patients. CD16(+) monocytes with an intermediate-like phenotype were found to be enriched in CSF and dominated the CSF monocyte population under noninflammatory conditions. In contrast, an inversed CD16(+) to CD16 -: CSF monocyte ratio was observed in MS patients with relapsing-remitting disease. Newly infiltrating, hematogenous CD16(+) monocytes were detected in a perivascular location within active MS lesions, and CD16(+) monocytes facilitated CD4(+) T cell trafficking in a blood -: brain barrier model. Our findings support an important role of CD16(+) monocytes in the steady-state immune surveillance of the CNS and suggest that CD16(+) monocytes shift to sites of inflammation and contribute to the breakdown of the blood-brain barrier in CNS autoimmune diseases. PMID- 26746190 TI - Allergy-Protective Arabinogalactan Modulates Human Dendritic Cells via C-Type Lectins and Inhibition of NF-kappaB. AB - Arabinogalactan (AG) isolated from dust of a traditional farm prevents disease in murine models of allergy. However, it is unclear whether this polysaccharide has immune regulatory properties in humans. The aim of this study was to test the influence of AG on the immune-stimulating properties of human dendritic cells (DCs). Moreover, we sought to identify the receptor to which AG binds. AG was produced from plant callus tissue under sterile conditions to avoid the influence of pathogen-associated molecular patterns in subsequent experiments. The influence of AG on the human immune system was investigated by analyzing its impact on monocyte-derived DCs. To analyze whether the T cell stimulatory capacity of AG-stimulated DCs is altered, an MLR with naive Th cells was performed. We revealed that AG reduced T cell proliferation in a human MLR. In the search for a molecular mechanism, we found that AG binds to the immune modulatory receptors DC-specific ICAM-3 -: grabbing non integrin (DC-SIGN) and macrophage mannose receptor 1 (MMR-1). Stimulation of these receptors with AG simultaneously with TLR4 stimulation with LPS increased the expression of the E3 ubiquitin-protein ligase tripartite motif -: containing protein 21 and decreased the phosphorylation of NF-kappaB p65 in DCs. This led to a reduced activation profile with reduced costimulatory molecules and proinflammatory cytokine production. Blocking of MMR-1 or DC-SIGN with neutralizing Abs partially inhibits this effect. We conclude that AG dampens the activation of human DCs by LPS via binding to DC-SIGN and MMR-1, leading to attenuated TLR signaling. This results in a reduced T cell activation capacity of DCs. PMID- 26746189 TI - IRF4 and IRF8 Act in CD11c+ Cells To Regulate Terminal Differentiation of Lung Tissue Dendritic Cells. AB - Dendritic cells (DCs) initiate immune responses in barrier tissues including lung and skin. Conventional DC (cDC) subsets, CD11b(-) (cDC1s) or CD11b(+) (cDC2s), arise via distinct networks of transcription factors involving IFN regulatory factor 4 (IRF4) and IRF8, and are specialized for unique functional responses. Using mice in which a conditional Irf4 or Irf8 allele is deleted in CD11c(+) cells, we determined whether IRF4 or IRF8 deficiency beginning in CD11c(+) cDC precursors (pre-cDCs) changed the homeostasis of mature DCs or pre-DCs in the lung, dermis, and spleen. CD11c-cre-Irf4(-/-) mice selectively lacked a lung resident CD11c(hi)CD11b(+)SIRPalpha(+)CD24(+) DC subset, but not other lung CD11b(+) DCs or alveolar macrophages. Numbers of CD11b(+)CD4(+) splenic DCs, but not CD11b(+) dermal DCs, were reduced, indicating cDC2s in the lung and dermis develop via different pathways. Irf4 deficiency did not alter numbers of cDC1s. CD11c-cre-Irf8(-/-) mice lacked lung-resident CD103(+) DCs and splenic CD8alpha(+) DCs, yet harbored increased IRF4-dependent DCs. This correlated with a reduced number of Irf8(-/-) pre-cDCs, which contained elevated IRF4, suggesting that Irf8 deficiency diverts pre-cDC fate. Analyses of Irf4 and Irf8 haploinsufficient mice showed that, although one Irf4 allele was sufficient for lung cDC2 development, two functional Irf8 alleles were required for differentiation of lung cDC1s. Thus, IRF8 and IRF4 act in pre-cDCs to direct the terminal differentiation of cDC1 and cDC2 subsets in the lung and spleen. These data suggest that variation in IRF4 or IRF8 levels resulting from genetic polymorphisms or environmental cues will govern tissue DC numbers and, therefore, regulate the magnitude of DC functional responses. PMID- 26746192 TI - Real-Time Analysis of Calcium Signals during the Early Phase of T Cell Activation Using a Genetically Encoded Calcium Biosensor. AB - Proper T cell activation is promoted by sustained calcium signaling downstream of the TCR. However, the dynamics of calcium flux after stimulation with an APC in vivo remain to be fully understood. Previous studies focusing on T cell motility suggested that the activation of naive T cells in the lymph node occurs in distinct phases. In phase I, T cells make multiple transient contacts with dendritic cells before entering a phase II, where they exist in stable clusters with dendritic cells. It has been suggested that T cells signal during transient contacts of phase I, but this has never been shown directly. Because time dependent loss of calcium dyes from cells hampers long-term imaging of cells in vivo after antigenic stimulation, we generated a knock-in mouse expressing a modified form of the Cameleon fluorescence resonance energy transfer reporter for intracellular calcium and examined calcium flux both in vitro and in situ. In vitro, we observed transient, oscillatory, and sustained calcium flux after contact with APC, but these behaviors were not affected by the type of APC or Ag quantity, but were, however, moderately dependent on Ag quality. In vivo, we found that during phase I, T cells exhibit weak calcium fluxes and detectable changes in cell motility. This demonstrates that naive T cells signal during phase I and support the hypothesis that accumulated calcium signals are required to signal the beginning of phase II. PMID- 26746193 TI - CD46 Activation Regulates miR-150-Mediated Control of GLUT1 Expression and Cytokine Secretion in Human CD4+ T Cells. AB - CD46 is a cell surface complement inhibitor widely expressed in human tissues, in contrast to mice, where expression is limited to the testes. In humans, it has been identified as an important T cell costimulatory receptor, and patients deficient in CD46 or its endogenous ligands are unable to mount effective Th1 T cell responses. Stimulation of human CD4(+) T cells with CD3 and CD46 also leads to the differentiation of a "switched" Th1 population, which shuts down IFN-gamma secretion and upregulates IL-10 and is thought to be important for negative feedback regulation of the Th1 response. In the present study, we show that CD46 costimulation leads to amplified microRNA (miR) expression changes in human CD4(+) T cells, with associated increases in activation more potent than those mediated by the "classic" costimulator CD28. Blockade of cell surface CD46 inhibited CD28-mediated costimulation, identifying autocrine CD46 signaling as downstream of CD28. We also identify a downregulation of miR-150 in CD46 costimulated T cells and identify the glucose transporter 1 encoding transcript SLC2A1 as a target of miR-150 regulation, connecting miR-150 with modulation of glucose uptake. We also investigated microRNA expression profiles of CD46-induced switched IL-10-secreting Th1 T cells and found increased expression of miR-150, compared with IFN-gamma-secreting Th1 cells. Knockdown of miR-150 led to a reduction in IL-10 but not IFN-gamma. CD46 therefore controls both Th1 activation and regulation via a miR-150-dependent mechanism. PMID- 26746194 TI - Microsphere-based antibody assays for human parvovirus B19V, CMV and T. gondii. AB - BACKGROUND: Human parvovirus B19 (B19V), cytomegalovirus (CMV) and Toxoplasma gondii (T. gondii) may cause intrauterine infections with potentially severe consequences to the fetus. Current serodiagnosis of these infections is based on detection of antibodies most often by EIA and individually for each pathogen. We developed singleplex and multiplex microsphere-based Suspension Immuno Assays (SIAs) for the simultaneous detection of IgG antibodies against B19V, CMV and T. gondii. METHODS: We tested the performances of SIAs as compared to in-house and commercial reference assays using serum samples from well-characterized cohorts. RESULTS: The IgG SIAs for CMV and T. gondii showed good concordance with the corresponding Vidas serodiagnostics. The B19V IgG SIA detected IgG in all samples collected >10 days after onset of symptoms and showed high concordance with EIAs (in-house and Biotrin). The serodiagnostics for these three pathogens performed well in multiplex format. CONCLUSIONS: We developed singleplex and multiplex IgG SIAs for the detection of anti-B19V, -CMV and -T. gondii antibodies. The SIAs were highly sensitive and specific, and had a wide dynamic range. These components thus should be suitable for construction of a multiplex test for antibody screening during pregnancy. PMID- 26746196 TI - Response to the Reply on behalf of the 'Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area' (MAK Commission) by Andrea Hartwig Karlsruhe Institute of Technology (KIT). PMID- 26746195 TI - Comparative effectiveness of antihypertensive treatment for older children with primary hypertension: study protocol for a series of n-of-1 randomized trials. AB - BACKGROUND: Children are increasingly being diagnosed with primary hypertension. The absence of comparative effectiveness research of antihypertensive medications in children has contributed to considerable differences in prescribing practices among physicians treating children with primary hypertension. Even if parallel group trials had established a best overall choice for most of these children, the best medication for an individual may differ from the best overall medication. METHODS/DESIGN: This project consists of a series of systematically administered n-of-1 trials among older children to verify the need for ongoing antihypertensive treatment and, if so, to identify the preferred single drug therapy from among the three major classes of drugs commonly used for primary hypertension (angiotensin-converting enzyme inhibitors, calcium channel blockers, and diuretics). We will determine whether one of these is the preferred therapy for the great majority of patients. The "preferred" therapy is the drug which produces normal ambulatory blood pressure, with the greatest reduction in blood pressure without unacceptable side effects. We will recruit 50 patients from the Houston Pediatric and Adolescent Hypertension Program clinic. For each patient, the three drugs will be prescribed in random order and each drug will be taken for 2 weeks. The effectiveness of each therapy will be measured with 24-h ambulatory blood pressure monitoring, and tolerability will be assessed using a side effect questionnaire. Participants will rotate through treatment periods, repeating drugs and adjusting doses until the preferred therapy is identified. In assessing whether one of the medications is most effective for the majority of subjects, the primary outcome will be the percentage of participants for whom each drug is selected as the preferred therapy. We hypothesize that no drug will be selected for the great majority of the subjects, a finding that would support consideration of clinical use of n-of-1 trials. Secondary analyses will explore whether patient characteristics predict which medication will be selected as a preferred drug. DISCUSSION: This study will help optimize care of participating patients and provide evidence regarding the usefulness of n-of-1 trials in identifying appropriate treatment for children with hypertension and potentially other disorders. TRIAL REGISTRATION: Clinicaltrials.gov NCT02412761 (registered 4/8/2015). PMID- 26746197 TI - Stakeholders' perceptions of rehabilitation services for individuals living with disability: a survey study. AB - BACKGROUND: The World Health Organization (WHO) was tasked with developing health system guidelines for the implementation of rehabilitation services. Stakeholders' perceptions are an essential factor to take into account in the guideline development process. The aim of this study was to assess stakeholders' perceived feasibility and acceptability of eighteen rehabilitation services and the values they attach to ten rehabilitation outcomes. METHODS: We disseminated an online self-administered questionnaire through a number of international and regional organizations from the different WHO regions. Eligible individuals included persons with disability, caregivers of persons with disability, health professionals, administrators and policy makers. The answer options consisted of a 9-point Likert scale. RESULTS: Two hundred fifty three stakeholders participated. The majority of participants were health professional (64 %). In terms of outcomes, 'Increasing access' and 'Optimizing utilization' were the top service outcomes rated as critical (i.e., 7, 8 or 9 on the Likert scale) by >70 % of respondents. 'Fewer hospital admissions', 'Decreased burden of care' and 'Increasing longevity' were the services rated as least critical (57 %, 63 % and 58 % respectively). In terms of services, 'Community based rehabilitation' and 'Home based rehabilitation' were found to be both definitely feasible and acceptable (75 % and 74 % respectively). 'Integrated and decentralized rehabilitation services' was found to be less feasible than acceptable according to stakeholders (61 % and 71 % respectively). As for 'Task shifting', most stakeholders did not appear to find task shifting as either definitely feasible or definitely acceptable (63 % and 64 % respectively). CONCLUSION: The majority of stakeholder's perceived 'Increasing access' and 'Optimizing utilization' as most critical amongst rehabilitation outcomes. The feasibility of the 'Integrated and decentralized rehabilitation services' was perceived to be less than their acceptability. The majority of stakeholders found 'Task shifting' as neither feasible nor acceptable. PMID- 26746200 TI - A swollen wrist. PMID- 26746198 TI - ASIC subunit ratio and differential surface trafficking in the brain. AB - BACKGROUND: Acid-sensing ion channels (ASICs) are key mediators of acidosis induced responses in neurons. However, little is known about the relative abundance of different ASIC subunits in the brain. Such data are fundamental for interpreting the relative contribution of ASIC1a homomers and 1a/2 heteromers to acid signaling, and essential for designing therapeutic interventions to target these channels. We used a simple biochemical approach and semi-quantitatively determined the molar ratio of ASIC1a and 2 subunits in mouse brain. Further, we investigated differential surface trafficking of ASIC1a, ASIC2a, and ASIC2b. RESULTS AND CONCLUSIONS: ASIC1a subunits outnumber the sum of ASIC2a and ASIC2b. There is a region-specific variation in ASIC2a and 2b expression, with cerebellum and striatum expressing predominantly 2b and 2a, respectively. Further, we performed surface biotinylation and found that surface ASIC1a and ASIC2a ratio correlates with their total expression. In contrast, ASIC2b exhibits little surface presence in the brain. This result is consistent with increased co localization of ASIC2b with an ER marker in 3T3 cells. Our data are the first semi-quantitative determination of relative subunit ratio of various ASICs in the brain. The differential surface trafficking of ASICs suggests that the main functional ASICs in the brain are ASIC1a homomers and 1a/2a heteromers. This finding provides important insights into the relative contribution of various ASIC complexes to acid signaling in neurons. PMID- 26746201 TI - Left clavicular fracture. Pyknodysostosis. PMID- 26746199 TI - In situ remineralisation response of different artificial caries-like enamel lesions to home-care and professional fluoride treatments. AB - BACKGROUND: Artificial lesions produced by different protocols might directly influence the response to different remineralising treatments. This study compared the response of different artificial caries-like enamel lesions to home care and professional fluoride based-remineralising treatments in situ. METHODS: The tested demineralising protocols were methylcellulose- MC gel, polyacrylic acid - PA gel, tetraethyl methylene diphosphanate - TEMDP solution, and acetate- Buffer solution. The lesions were remineralised using an in situ model, following a crossover and double blind design. Twelve subjects wore intra-oral appliances during 3 phases (3 d each): control (C) (saliva); home-care F(-) treatment (FD) (1,100 ppm F(-) dentifrice, 2x1 min/day); and professional (FVD) (22,600 ppm F(-) varnish) plus FD. The de-remineralisation was measured by transverse microradiography-TMR and hardness (surface hardness/cross-sectional hardness, SH/CSH, respectively). RESULTS: For SH, lesions produced by PA gel were the only one showing significant differences among the remineralising treatments (C x FD x FVD); while the TEMDP lesion were not responsive to any fluoride treatment (for both SH/CSH). For TMR, there were no differences among the remineralising treatments, regardless of the type of lesion. Generally, the most responsive lesions to fluoride were the less demineralised lesions (considering hardness: PA gel and Buffer). CONCLUSIONS: The type of lesion has influence on the surface remineralisation degree induced by home-care and professional fluoride treatments using this in situ model. PMID- 26746202 TI - Rapid palatal expansion effects on mandibular transverse dimensions in unilateral posterior crossbite patients: a three-dimensional digital imaging study. AB - BACKGROUND: The purpose of this controlled study was to investigate indirect effects on mandibular arch dimensions, 1 year after rapid palatal expansion (RPE) therapy. METHODS: Thirty-three patients in mixed dentition (mean age 8.8 years) showing unilateral posterior crossbite and maxillary deficiency were treated with a RPE (Haas type) cemented on the first permanent molars. Treatment protocol consisted of two turns per day until slight overcorrection of the molar transverse relationship occurred. The Haas expander was kept on the teeth as a passive retainer for an average of 6 months. Study models were taken prior (T1) and 15 months on average (T2) after expansion. A control group of 15 untreated subjects with maxillary deficiency (mean age 8.3 years) was also recorded with a 12-month interval. Stone casts were digitized with a 3D scanner (3Shape, DK). RESULTS: In the treated group, both mandibular intermolar distance (+1.9 mm) and mandibular molar angulation (+9 degrees ) increased. Mandibular incisor angulation showed an increase of 1.9 degrees . There was little effect on intercanine distance and canine angulation. Controls showed a reduction in transverse arch dimension and a decrease in molar and canine angulation values. CONCLUSIONS: RPE protocol has indirect widening effects on the mandibular incisors and first molars. PMID- 26746203 TI - 'Papillary' solitary fibrous tumor/hemangiopericytoma with nuclear STAT6 expression and NAB2-STAT6 fusion. AB - This report describes clinicopathological findings, including genetic data of STAT6, in a solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) of the central nervous system in an 83-year-old woman with a bulge in the left forehead. She noticed it about 5 months before, and it had grown rapidly for the past 1 month. Neuroradiological studies disclosed a well-demarcated tumor that accompanied the destruction of the skull. The excised tumor showed a prominent papillary structure, where atypical cells were compactly arranged along the fibrovascular core ('pseudopapillary'). There was rich vasculature, some of which resembled 'staghorn' vessels. Mitotic figures were occasionally found. Whorls, psammoma bodies, or intra-nuclear pseudoinclusions were not identified. By immunohistochemistry, CD34 was strongly positive in the tumor cells, and STAT6 was localized in their nuclei. By reverse transcription-polymerase chain reaction (RT-PCR), an NAB2-STAT6 fusion gene, NAB2 exon6-STAT6 exon17, was detected, establishing a definite diagnosis of SFT/HPC. 'Papillary' SFT/HPC needs to be recognized as a possible morphological variant of SFT/HPC, and should be borne in mind in its diagnostic practice. PMID- 26746204 TI - Analysis of EZH2: micro-RNA network in low and high grade astrocytic tumors. AB - Enhancer of Zeste homologue2 (EZH2) is an epigenetic regulator that functions as oncogene in astrocytic tumors, however, EZH2 regulation remains little studied. In this study, we measured EZH2 levels in low (Gr-II,DA) and high grade (Gr IV,GBM) astrocytic tumors and found significant increased EZH2 transcript level with grade(median DA-8.5, GBM-28.9).However, a different trend was reflected in protein levels, with GBMs showing high EZH2 LI(median-26.5) compared to DA (median 0.3). This difference in correlation of EZH2 protein and RNA levels suggested post-transcriptional regulation of EZH2, likely mediated by miRNAs. We selected eleven miRNAs that strongly predicted to target EZH2 and measured their expression. Three miRNAs (miR-26a-5p,miR27a-3p and miR-498) showed significant correlation with EZH2 protein, suggesting them as regulators of EZH2, however miR 26a-5p levels decreased with grade. ChIP analyses revealed H3K27me3 modifications in miR-26a promoter suggesting feedback loop between EZH2 and miR26a. We further measured six downstream miRNA targets of EZH2 and found significant downregulation of four (miR-181a/b and 200b/c) in GBM. Interestingly, EZH2 associated miRNAs were predicted to target 25 genes in glioma-pathway, suggesting their role in tumor formation or progression. Collectively, our work suggests EZH2 and its miRNA interactors may serve as promising biomarkers for progression of astrocytic tumors and may offer novel therapeutic strategies. PMID- 26746205 TI - Healthcare Communication Barriers and Self-Rated Health in Older Chinese American Immigrants. AB - Older Chinese immigrants are a growing population in the United States who experience multiple healthcare communication barriers such as limited English proficiency and low health literacy. Each of these obstacles has been associated with poor health outcomes but less is known about their effects in combination. This study examined the association between healthcare communication barriers and self-rated health among older Chinese immigrants. Cross-sectional survey data were obtained from 705 Chinese American immigrants ages 50-75 living in San Francisco, California. Communication barriers examined included spoken English proficiency, medical interpreter needs, and health literacy in written health information. The study sample (81 % females, mean age = 62) included 67 % who spoke English poorly or not at all, 34 % who reported needing a medical interpreter, and 37 % who reported "often" or "always" needing assistance to read health information. Two-thirds reported poor self-rated health; many reported having access to racial-concordant (74 %) and language-concordant (86 %) healthcare services. Both poor spoken English proficiency and low health literacy were associated with poor self-rated health, independent of other significant correlates (unemployment, chronic health conditions, and having a primary doctor who was ethnic Chinese). Results revealed that spoken English proficiency and print health literacy are independent communication barriers that are directly associated with health status among elderly Chinese American immigrants. Access to racial- or language-concordant health care services did not appear to resolve these barriers. These findings underscore the importance of addressing both spoken and written healthcare communication needs among older Chinese American immigrants. PMID- 26746207 TI - Effects of wortmannin on cardioprotection exerted by ischemic preconditioning in rat hearts subjected to ischemia-reperfusion. AB - Ischemic preconditioning (IPC) is one of the most powerful interventions to reduce ischemia-reperfusion injury. The aim of the present study was to investigate the involvement of the phosphatidylinositol-3-kinases (PI3Ks) family in cardioprotection exerted by IPC and the relationship between preservation of mitochondrial morphology and ATP synthesis capacity. In this regard, macroautophagy (autophagy) is considered a dynamic process involved in the replacement of aged or defective organelles under physiological conditions. IPC consisted of four 5-min cycles of ischemia-reperfusion followed by sustained ischemia. Wortmannin (W), a PI3K family inhibitor, was added to the perfusion medium to study the involvement of autophagy in the beneficial effects of IPC. In the present study, LC3-II/I expression was significantly increased in the IPC group when compared with the control group. The hearts subjected to IPC showed greater degradation of p62 than control groups, establishing the existence of an autophagic flow. Electron microscopy showed that IPC preserves the structural integrity of mitochondria after ischemia and at the end of reperfusion. Moreover, hearts subjected to IPC exhibited increased mitochondrial ATP synthesis. The beneficial effects of IPC were abolished by W in all trials of this study, abolishing the differences between the IPC and control groups. These results suggest that IPC could partly reduce injury by ischemia-reperfusion (I/R) by decreasing mitochondrial damage and promoting autophagy. Since W is a nonspecific inhibitor of the PI3Ks family, further research is required to confirm participation of PI3K in the response to IPC. PMID- 26746206 TI - Comparative metabonomic analysis of hepatotoxicity induced by acetaminophen and its less toxic meta-isomer. AB - The leading cause of drug-induced liver injury in the developed world is overdose with N-acetyl-p-aminophenol (APAP). A comparative metabonomic approach was applied to the study of both xenobiotic and endogenous metabolic profiles reflective of in vivo exposure to APAP (300 mg/kg) and its structural isomer N acetyl-m-aminophenol (AMAP; 300 mg/kg) in C57BL/6J mice, which was anchored with histopathology. Liver and urine samples were collected at 1 h, 3 h and 6 h post treatment and analyzed by 1H nuclear magnetic resonance (NMR) spectroscopy and gas chromatography-mass spectrometry (liver only). Histopathology revealed the presence of centrilobular necrosis from 3 h post-APAP treatment, while an AMAP mediated necrotic endpoint was not observed within the timescale of this study, yet two of five treated mice showed minimal centrilobular eosinophilia. The 1H NMR xenobiotic metabolic profile of APAP-treated animals comprised of mercapturate (urine and liver) and glutathionyl (liver) conjugates detected at 1 h post-treatment. This finding corroborated the hepatic endogenous metabolic profile which showed depletion of glutathione from 1 h onwards. In contrast, AMAP glutathionyl conjugates were not detected, nor was AMAP-induced depletion of hepatic glutathione observed. APAP administration induced significant endogenous hepatic metabolic perturbations, primarily linked to oxidative and energetic stress, and perturbation of amino acid metabolism. Early depletion of glutathione was followed by depletion of additional sulfur-containing metabolites, while altered levels of mitochondrial and glycolytic metabolites indicated a disruption of energy homeostasis. In contrast, AMAP administration caused minimal, transient, distinct metabolic perturbations and by 6 h the metabolic profiles of AMAP-treated mice were indistinguishable from those of controls. PMID- 26746208 TI - Protective effect of mycophenolate mofetil against nephrotoxicity and hepatotoxicity induced by tacrolimus in Wistar rats. AB - Tacrolimus (TAC), a calcineurin inhibitor (CNI), is clinically used as an immunosuppressive agent in the transplant recipient; however, the use of TAC is greatly limited by its nephrotoxicity and hepatotoxicity. Mycophenolate mofetil (MMF), an inhibitor of the purine synthesis, has been used in combination with many immunosuppressive drugs such as TAC. The association TAC/MMF was used in organ transplantation to increase the efficiency and reduce acute rejection rates, but the effects of MMF on TAC-induced kidney and liver injuries are still not well investigated. The aims of this study are to explore whether MMF co administration with TAC has a renoprotective and hepatoprotective effect against TAC-induced renal and hepatic injuries and to check the implication of oxidative stress in the MMF's possible protective effect. Our results showed that MMF (at 50 mg kg(-1) body weight (b.w.)) restored creatinine, in addition to increased AST and ALT levels by TAC (at 60 mg kg(-1) b.w.). Furthermore, MMF decreased DNA damage induced by TAC in the kidney and liver of rats as assessed by comet assay. This renoprotective and hepatoprotective effect of MMF was associated with an antioxidant effect. In fact, MMF co-treatment with TAC decreased oxidative damage induced by TAC. It reduced malondialdehyde (MDA) and protein carbonyl (PC) levels as well as catalase and superoxide dismutase (SOD) activities. We conclude that the co-administration MMF with TAC protect liver and kidney against TAC toxicity via an antioxidant process. PMID- 26746209 TI - Nausea as a sentinel symptom for cytotoxic chemotherapy effects on the gut-brain axis among women receiving treatment for recurrent ovarian cancer: an exploratory analysis. AB - PURPOSE: Nausea is a common and potentially serious effect of cytotoxic chemotherapy for recurrent ovarian cancer and may function as a sentinel symptom reflecting adverse effects on the gut-brain axis (GBA) more generally, but research is scant. As a first exploratory test of this GBA hypothesis, we compared women reporting nausea to women not reporting nausea with regard to the severity of other commonly reported symptoms in this patient population. METHODS: A secondary analysis of data systematically collected from women in active chemotherapy treatment for recurrent ovarian cancer (n = 158) was conducted. The Symptom Representation Questionnaire (SRQ) provided severity ratings for 22 common symptoms related to cancer and chemotherapy. Independent sample t tests and regression analyses were used to compare women with and without nausea with regard to their experience of other symptoms. RESULTS: Nausea was reported by 89 (56.2 %) women. Symptoms that were significantly associated with nausea in bivariate and regression analyses included abdominal bloating, bowel disturbances, dizziness, depression, drowsiness, fatigue, headache, lack of appetite, memory problems, mood swings, shortness of breath, pain, sleep disturbance, urinary problems, vomiting, and weight loss. Symptoms that were not associated with nausea included hair loss, numbness and tingling, sexuality concerns, and weight gain. CONCLUSIONS: Nausea experienced during chemotherapy for recurrent ovarian cancer may be an indicator of broader effects on the gut brain axis. A better understanding of the mechanisms underlying these effects could lead to the development of novel supportive therapies to increase the tolerability and effectiveness of cancer treatment. PMID- 26746210 TI - Identifying functional impairment and rehabilitation needs in patients newly diagnosed with inoperable lung cancer: a structured literature review. AB - PURPOSE: Patients newly diagnosed with inoperable lung cancer experience a symptom distress burden that may impact upon functional performance in daily activities. This structured review examines empirical evidence to see how functional limitation and rehabilitation needs are represented in the supportive care literature in this population. Early access to rehabilitation services may ameliorate the impact, but evidence of need following diagnosis is required. METHOD: Electronic databases Medline, Web-of-Science, Cinahl, AMED and PsychINFO were searched in April 2014. Hawker's criteria were used to assess methodological quality. The World Health Organization International Classification for Functioning Disability and Health (WHO-ICF) guided framework analysis and narrative synthesis. RESULTS: Thirty-two articles selected for further analysis included heterogeneous studies exploring the following conceptually diverse dimensions: quality of life, symptoms, functional performance and unmet supportive care needs at diagnosis and first treatment phase. Studies, mostly utilising patient self-report measures, reveal functional impairments, limitations and restrictions influenced by personal and environmental factors across all WHO-ICF domains. Two studies included objective evaluations of function. Six studies explored functional performance as a primary aim. Five studies suggested specific or general rehabilitation interventions to address identified needs. CONCLUSIONS: Needs associated with a diagnosis of inoperable lung cancer impact on daily life in the peri and early post-diagnostic period across all WHO-ICF domains. Specific functional impairments, limitations and restrictions and the potential role of rehabilitation services are rarely explored objectively or discussed in the supportive care literature for this population. Research is needed to guide the development of effective rehabilitation interventions acceptable to patients, health care commissioners and providers that address the impact of a new lung cancer diagnosis on functional performance. PMID- 26746211 TI - Thymidine 5'-O-monophosphorothioate induces HeLa cell migration by activation of the P2Y6 receptor. AB - ATP, ADP, UTP, and UDP acting as ligands of specific P2Y receptors activate intracellular signaling cascades to regulate a variety of cellular processes, including proliferation, migration, differentiation, and cell death. Contrary to a widely held opinion, we show here that nucleoside 5'-O-monophosphorothioate analogs, containing a sulfur atom in a place of one nonbridging oxygen atom in a phosphate group, act as ligands for selected P2Y subtypes. We pay particular attention to the unique activity of thymidine 5'-O-monophosphorothioate (TMPS) which acts as a specific partial agonist of the P2Y6 receptor (P2Y6R). We also collected evidence for the involvement of the P2Y6 receptor in human epithelial adenocarcinoma cell line (HeLa) cell migration induced by thymidine 5'-O monophosphorothioate analog. The stimulatory effect of TMPS was abolished by siRNA-mediated P2Y6 knockdown and diisothiocyanate derivative MRS 2578, a selective antagonist of the P2Y6R. Our results indicate for the first time that increased stability of thymidine 5'-O-monophosphorothioate as well as its affinity toward the P2Y6R may be responsible for some long-term effects mediated by this receptor. PMID- 26746212 TI - Using Ecological Momentary Assessment (EMA) to Study Sex Events Among Very High Risk Men Who Have Sex with Men (MSM). AB - MSM continue to represent the largest share of new HIV infections in the United States each year due to high infectivity associated with unprotected anal sex. Ecological momentary assessment (EMA) has the potential to provide a unique view of how high-risk sexual events occur in the real world and can impart detailed information about aspects of decision-making, antecedents, and consequences that accompany these events. EMA may also produce more accurate data on sexual behavior by assessing it soon after its occurrence. We conducted a study involving 12 high-risk MSM to explore the acceptability and feasibility of a 30 day, intensive EMA procedure. Results suggest this intensive assessment strategy was both acceptable and feasible to participants. All participants provided response rates to various assessments that approached or were in excess of their targets: 81.0 % of experience sampling assessments and 93.1 % of daily diary assessments were completed. However, comparing EMA reports with a Timeline Followback (TLFB) of the same 30 day period suggested that participants reported fewer sexual risk events on the TLFB compared to EMA, and reported a number of discrepancies about specific behaviors and partner characteristics across the two methods. Overall, results support the acceptability, feasibility, and utility of using EMA to understand sexual risk events among high-risk MSM. Findings also suggest that EMA and other intensive longitudinal assessment approaches could yield more accurate data about sex events. PMID- 26746213 TI - Surgical treatment of secondary peritonitis : A continuing problem. AB - Secondary peritonitis remains associated with high mortality and morbidity rates. Treatment of secondary peritonitis is challenging even in modern medicine. Surgical intervention for source control remains the cornerstone of treatment, beside adequate antimicrobial therapy and resuscitation. A randomized clinical trial showed that relaparotomy on demand (ROD) after initial emergency surgery is the preferred treatment strategy, irrespective of the severity and extent of peritonitis. The effective and safe use of ROD requires intensive monitoring of the patient in a setting where diagnostic tests and decision making about relaparotomy are guaranteed round the clock. The lack of knowledge on timely and adequate patient selection, together with the lack of use of easy but reliable monitoring tools, seems to hamper full implementation of ROD. The accuracy of the relap decision tool is reasonable for prediction of ongoing peritonitis and selection for computer tomography (CT). The value of CT in an early postoperative phase is unclear. Future research and innovative technologies should focus on the additive value of CT in cases of operated secondary peritonitis and on the further optimization of bedside prediction tools to enhance adequate patient selection for intervention in a multidisciplinary setting. PMID- 26746214 TI - Targeting BRAF mutants in clear-cell sarcomas of soft tissue: beyond sarcoma or melanoma classification. PMID- 26746215 TI - The Bioactive Secondary Metabolites from Talaromyces species. AB - The focus of this review is placed on the chemical structures from the species of the genus Talaromyces reported with reference to their biological activities. 221 secondary metabolites, including 43 alkaloids and peptides, 88 esters, 31 polyketides, 19 quinones, 15 steroid and terpenoids, and 25 other structure type compounds, have been included, and 66 references are cited. PMID- 26746217 TI - Exploring stochasticity and imprecise knowledge based on linear inequality constraints. AB - This paper explores the stochastic dynamics of a simple foodweb system using a network model that mimics interacting species in a biosystem. It is shown that the system can be described by a set of ordinary differential equations with real valued uncertain parameters, which satisfy a set of linear inequality constraints. The constraints restrict the solution space to a bounded convex polytope. We present results from numerical experiments to show how the stochasticity and uncertainty characterizing the system can be captured by sampling the interior of the polytope with a prescribed probability rule, using the Hit-and-Run algorithm. The examples illustrate a parsimonious approach to modeling complex biosystems under vague knowledge. PMID- 26746216 TI - Antiproliferative Triterpenoid Saponins from Leptaulus citroides Baill. from the Madagascar Rain Forest. AB - Bioassay-guided fractionation of EtOH extracts obtained from the roots and wood of the Madagascan plant Leptaulus citroides Baill. (Cardiopteridaceae) led to the isolation of ethyl esters of three new triterpenoid saponins (1-3) and the known sesquiterpenoid cinnamosmolide (4). The structures of 1-3 were elucidated by extensive 1D and 2D NMR experiments and mass spectrometry. Compounds 1, 2, and 4 showed moderate cytotoxicity against the A2780 human ovarian cancer cell line with IC50 values of 2.8, 10.2 and 2.0 uM, respectively. PMID- 26746218 TI - Strong association of relatively low and extremely excessive iodine intakes with thyroid cancer in an iodine-replete area. AB - PURPOSE: The relationship between iodine intake and development of thyroid diseases shows a U-shaped curve with an increase of risk in both deficient and excessive iodine intakes. Our aim was to investigate the relationship between iodine intake and thyroid cancer in patients with thyroid nodules in an iodine replete area. METHODS: Retrospective analysis of 1170 patients with thyroid nodules was performed. Urinary iodine concentration (UIC) was measured by inductively-coupled plasma mass spectrometry. Predictive factors for thyroid cancer were evaluated using multivariate logistic regression models. RESULTS: The median UIC in all patients with thyroid nodules was 360 MUg/L (range from 4 to 9631 MUg/L). More than half of the patients (650/1170, 56 %) belonged to the category of excessive iodine intake (UIC >= 300 MUg/L) according to WHO iodine recommendations. Patients with thyroid cancer were more likely to be distributed in UIC < 300 MUg/L and in UIC >= 2500 MUg/L than those with benign thyroid nodules. Male gender (OR 1.528, p = 0.028) and UIC were independent predictors for thyroid cancer. The multivariate-adjusted OR (95 % CI) in the relatively low (UIC < 300 MUg/L) and extremely excessive (UIC >= 2500 MUg/L) iodine intake groups for thyroid cancer were 1.519 (1.099-2.098) and 1.874 (1.094-3.208), respectively, compared to the other iodine intake group (300-2499 MUg/L). CONCLUSION: Male gender and UIC were independent predictors of thyroid cancer in patients with thyroid nodules. This study suggests that relatively low and extremely excessive iodine intakes are associated with thyroid cancer in an iodine-replete area. PMID- 26746219 TI - Compliance with dietary guidelines affects capillary recruitment in healthy middle-aged men and women. AB - PURPOSE: Healthy microcirculation is important to maintain the health of tissues and organs, most notably the heart, kidney and retina. Single components of the diet such as salt, lipids and polyphenols may influence microcirculation, but the effects of dietary patterns that are consistent with current dietary guidelines are uncertain. It was hypothesized that compliance to UK dietary guidelines would have a favourable effect on skin capillary density/recruitment compared with a traditional British diet (control diet). METHODS: A 12-week randomized controlled trial in men and women aged 40-70 years was used to test whether skin microcirculation, measured by skin video-capillaroscopy on the dorsum of the finger, influenced functional capillary density (number of capillaries perfused under basal conditions), structural capillary density (number of anatomical capillaries perfused during finger cuff inflation) and capillary recruitment (percentage difference between structural and functional capillary density). RESULTS: Microvascular measures were available for 137 subjects out of the 165 participants randomized to treatment. There was evidence of compliance to the dietary intervention, and participants randomized to follow dietary guidelines showed significant falls in resting supine systolic, diastolic and mean arterial pressure of 3.5, 2.6 and 2.9 mmHg compared to the control diet. There was no evidence of differences in capillary density, but capillary recruitment was 3.5 % (95 % CI 0.2, 6.9) greater (P = 0.04) on dietary guidelines compared with control. CONCLUSIONS: Adherence to dietary guidelines may help maintain a healthy microcirculation in middle-aged men and women. This study is registered at www.isrctn.com as ISRCTN92382106. PMID- 26746220 TI - Independent associations of vitamin D metabolites with anemia in patients referred to coronary angiography: the LURIC study. AB - PURPOSE: Anemia and vitamin D deficiency are both frequent in adult patients. Whether low vitamin D metabolite levels are an independent risk factor for different subtypes of anemia remains to be studied in detail. METHODS: In 3299 patients referred for coronary angiography, we investigated the association of 25 hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D [1,25(OH)2D] with anemia [hemoglobin (Hb) <12.5 g/dl] of specific subtypes. RESULTS: Compared with patients with 25OHD levels in the adequate range (50-125 nmol/l), patients with deficient 25OHD concentrations (<30 nmol/l; 33.6 % of patients) had 0.6 g/dl lower Hb levels. Hb values were 1.3 g/dl lower in patients with 1,25(OH)2D levels <40 pmol/l (5.4 % of patients), compared with patients in the highest 1,25(OH)2D category (>70 pmol/l). Of the participants, 16.7 % met the criteria for anemia. In multivariate-adjusted regression analyses, the odds ratios for anemia in the lowest 25OHD and 1,25(OH)2D categories were 1.52 (95 % CI 1.15-2.02) and 3.59 (95 % CI 2.33-5.52), compared with patients with 25OHD levels in the adequate range and patients with 1,25(OH)2D levels >70 pmol/l. The probability of anemia was highest in patients with combined 25OHD and 1,25(OH)2D deficiency [multivariable adjusted odds ratio 5.11 (95 % CI 2.66-9.81)]. Patients with anemia of chronic kidney disease had the highest prevalence of 25OHD deficiency and 1,25(OH)2D concentrations of <40 pmol/l. CONCLUSIONS: Low 25OHD and 1,25(OH)2D concentrations are independently associated with anemia. Patients with poor kidney function are most affected. Interventional trials are warranted to prove whether administration of plain or activated vitamin D can prevent anemia. PMID- 26746221 TI - Do dry roasting, lightly salting nuts affect their cardioprotective properties and acceptability? AB - PURPOSE: Previous studies have reported improvements in cardiovascular disease (CVD) risk factors with the consumption of raw nuts. However, around one-third of nuts consumed are roasted and salted. Thus, it is important to determine whether roasting and salting nuts affect the health benefits observed with raw nuts. This study aimed to compare the effects of consuming two different forms of hazelnuts on cardiovascular risk factors and acceptance. METHODS: Using a randomised crossover design, 72 participants were asked to consume 30 g/day of either raw or dry roasted, lightly salted hazelnuts for 28 days each. CVD risk factors were measured at the beginning and end of each treatment period. "Desire to consume" and "overall liking" for both forms of hazelnuts were assessed daily using a 150 mm visual analogue scale. RESULTS: Body composition, blood pressure, plasma total and low-density lipoprotein-cholesterol, apolipoprotein A1 and B100, glucose and alpha-tocopherol concentrations did not differ between forms of hazelnuts (all P >= 0.054). High-density lipoprotein (HDL)-cholesterol (P = 0.037) and triacylglycerol (P < 0.001) concentrations were significantly lower following the consumption of dry roasted, lightly salted hazelnuts when compared to the raw hazelnuts. Compared with baseline, consuming both forms of hazelnuts significantly improved HDL-cholesterol and apolipoprotein A1 concentrations, total-C/HDL-C ratio, and systolic blood pressure without significantly changing body composition. Acceptance ratings did not differ between forms of hazelnuts and remained high throughout the study. CONCLUSION: Dry roasting and lightly salting nuts do not appear to negate the cardioprotective effects observed with raw nut consumption, and both forms of nuts are resistant to monotony. Public health messages could be extended to include dry roasted and lightly salted nuts as part of a heart healthy diet. PMID- 26746222 TI - Prevalence of K65R in patients treated with tenofovir disoproxil fumarate: recommendations based on the Frankfurt HIV Cohort Study Resistance Database (FHCS RD). AB - Mutations in the genome of HIV-1 can compromise the success of antiretroviral treatments (ARTs) in HIV-1-infected individuals. The Frankfurt HIV Cohort Study Resistance Database (FHCS-RD) has previously documented a decline in the burden of resistance-associated mutations (RAMs) following the implementation of several new antiretroviral therapy regimens in 2007. In the current study, the annual burden of RAMs documented in the FHCS-RD in 2005-2013 was set in relation to the annual number of all cohort patients, drug regimens, available resistance tests, and prevalence for each RAM on relevant codons of reverse transcriptase (RT) and protease (PR) genes. A specific focus was put on the prevalence of the tenofovir disoproxil fumarate (TDF) signature mutation K65R in HIV-1 RT in relation to the application of TDF within ART. Between 2005 and 2012, a total of 4423 HIV genotyping data sets from 4509 patients were analysed. All mutations show a consistent decline, and the most impressive decrease was observed for thymidine analogue mutations (TAMs). The frequency of non-TAMs and PR mutations also decreased, but generally to a lower extent. The prevalence of K65R decreased from 2.6 % in 2005 to 0.2 % in 2012 despite increased use of TDF-containing ART. Both the improved strategic use of TDF in ARTs and generally more effective ART regimens may have resulted in decreasing RAM prevalences in FHCS-RD since 2007. These trends challenge the cost-effectiveness of resistance testing prior to failing ART. PMID- 26746223 TI - Mesenteric Torsion as a Cause of Late Abdominal Pain after Gastric Bypass Surgery. AB - Gastric bypass (GBP) has been the most common surgical way to treat obesity and its comorbidities. Late abdominal pain may occur by gastro-jejunal ulcers, gallstones, internal herniation or, rarely, intussusception. In an area with more than 1000 GBPs performed yearly, three patients with primary small bowel volvulus causing abdominal pain and requiring emergency or semi-urgent surgery were identified. Patients' histories, radiology, and surgery performed are presented. Weight loss followed by mesenteric narrowing of the root and thus relative elongation may make rotation of the small bowel mesentery possible. Such a torsion might be an overlooked differential diagnosis in obscure abdominal pain after GBP. PMID- 26746224 TI - Laparoscopic Conversion of One Anastomosis Gastric Bypass to Roux-en-Y Gastric Bypass for Chronic Bile Reflux. AB - BACKGROUND: One anastomosis gastric bypass (OAGB) demonstrated similar results to traditional Roux-en-Y procedures. A possible concern is how to manage a chronic bile reflux when medical therapy results ineffective. Revision of the gastro jejunal anastomosis, obtaining a Roux-en-Y reconstruction, has already been proposed, but technical details have not been elucidated yet. This video shows how to revise a 200-cm OAGB to treat chronic bile reflux, by converting the procedure to Roux-en-Y, having a short gastric pouch and a long efferent limb. METHODS: A 51-year-old patient complained of recurrent heartburns 2 months after OAGB. A gastroscopy witnessed the presence of a 6-cm long gastric pouch with pouchitis and bile reflux in esophagus. Specific medications were ineffective. He underwent a revisional laparoscopic procedure. The efferent limb was measured and consisted of 650 cm. The afferent limb was then divided next to the previous gastro-jejunal anastomosis and a jejuno-jejunal anastomosis was performed distally at 70 cm on the alimentary limb. RESULTS: Total operative time was 50 min. The postoperative stay was uneventful and the patient was discharged in postoperative day four. At 6 months follow-up he is still free of medications without symptoms. CONCLUSIONS: The ideal scenario for the presented technique is the finding of a long efferent limb, in order to fashion a Roux-en-Y limb without the risk of postoperative malabsorption. To reach this goal, we suggest the measurement of the whole small bowel intra-operatively, in order to assess the length of the common channel left in place. PMID- 26746226 TI - Withdrawal Notice. PMID- 26746225 TI - Older Parents Benefit More in Health Outcome From Daughters' Than Sons' Emotional Care in China. AB - OBJECTIVE: To examine whether older parents in China would benefit more from daughters' care than from sons' emotional care. METHOD: Analysis of the unique data sets of the Chinese Longitudinal Healthy Longevity Survey conducted in 2002, 2005, and 2008-2009 in 22 provinces. RESULTS: As compared with having son(s), having daughter(s) is significantly more beneficial at older ages in China, with regard to maintaining higher cognitive capacity and reducing mortality risk. Such daughter advantages in providing emotional care to older parents are more profound among the oldest-old aged 80+ as compared with the young-old aged 65 to 79 and surprisingly more profound in rural areas as compared with urban areas, even though son preference is much more common among rural residents. DISCUSSION: We describe how educational campaigns aimed at informing the public about the benefits of daughter(s) for older parents' health outcome could help promote gender equality and reduce traditional son preference, especially in rural China. PMID- 26746228 TI - Physicians' attitudes and knowledge concerning antibiotic prescription and resistance: questionnaire development and reliability. AB - BACKGROUND: Understanding physicians' antibiotic-prescribing behaviour is fundamental when it comes to improving antibiotic use and tackling the growing rates of antimicrobial resistance. The aim of the study was to develop and validate--in terms of face validity, content validity and reliability--an instrument designed to assess the attitudes and knowledge underlying physician antibiotic prescribing. METHODS: The questionnaire development and validation process comprised two different steps, namely: (1) content and face validation, which included a literature review and validation both by physicians and by Portuguese language and clinical psychology experts; and (2) reliability analysis, using the test-retest method, to assess the questionnaire's internal consistency (Cronbach's alpha) and reproducibility (intraclass correlation coefficient--ICC). The questionnaire includes 17 items assessing attitudes and knowledge about antibiotic prescribing and resistances and 9 items evaluating the importance of different sources of knowledge. The study was conducted in the catchment area covered by Portugal's Northern Regional Health Administration and used a convenience sample of 61 primary-care and 50 hospital-care physicians. RESULTS: Response rate was 64% (49% to retest) for primary-care physicians and 66% (60% to retest) for hospital-care physicians. Content validity resulted in 9 changes to professional concepts. Face validity assessment resulted in 19 changes to linguistic and interpretative terms. In the case of the reliability analysis, the ICC values indicated a minimum of fair to good reproducibility (ICC > 0.4), and the Cronbach alpha values were satisfactory (alpha > 0.70). CONCLUSIONS: The questionnaire developed is valid--in terms of face validity, content validity and reliability--for assessing physicians' attitudes to and knowledge of antibiotic prescribing and resistance, in both hospital and primary-care settings, and could be a very useful tool for characterising physicians' antibiotic-prescribing behaviour. PMID- 26746229 TI - Protection of dogs against canine heartworm infection 28 days after four monthly treatments with Advantage Multi(r) for Dogs. AB - BACKGROUND: Monthly heartworm preventives are designed to protect dogs by killing heartworms acquired the month prior to their administration, and after treatment with most products, the drug levels rapidly dissipate to very low levels. Work with Advantage Multi(r) for Dogs (imidacloprid + moxidectin) topical solution showed protection against hookworm infection throughout the month after administration of several monthly doses suggesting that similar protection might occur with heartworms. This study assessed the amount of protection afforded to dogs by the administration of four monthly doses of Advantage Multi for Dogs prior to infection with third-stage heartworm larvae (Dirofilaria immitis) 28 days after the last (fourth) treatment. METHODS: There were 16 purpose-bred mongrel dogs in the study that were divided into two groups, 8 control and 8 treated dogs. Dogs were housed in a manner preventing contact between animals and groups, and personal protective gear worn by staff minimised the chance spread of the topically applied product between runs. The dogs in the treated group received monthly applications of Advantage Multi for Dogs as per label instructions on Study Days 0, 28, 56, and 84. On Study Day 112, all 16 dogs received 50 third-stage larvae of D. immitis ("Missouri" isolate) via subcutaneous inoculation in the inguinal region. The study was terminated on Day 264, and the number of heartworms per dog was determined at necropsy. RESULTS: Moxidectin levels after 4 treatments 28 days apart were near steady state on Study Day 112 when the dogs were inoculated with D. immitis third-stage larvae. At necropsy, 152 days after infection, all the control dogs had adult worms in their pulmonary arteries (geometric mean = 33.9; range 25-41), and none of the dogs treated four times prior to infection, with the last treatment 30 days prior to infection, harbored worms at necropsy. CONCLUSIONS: The efficacy of prevention was 100% when the dogs were infected 28 days after the last monthly treatment. When dogs receive consecutive doses of Advantage Multi for Dogs as prescribed, heartworm infections will be prevented throughout the monthly dosing interval after administration of several monthly doses. PMID- 26746227 TI - Normative values for carotid intima media thickness and its progression: Are they transferrable outside of their cohort of origin? AB - BACKGROUND: The clinical use of carotid intima media thickness (cIMT) requires normal values, which may be subject to variation of geographical factors, ethnicity or measurement details. The influence of these factors has rarely been studied. The aim of this study was to determine whether normative cIMT values and their association with event risk are generalizable across populations. DESIGN: Meta-analysis of individual participant data. METHOD: From 22 general population cohorts from Europe, North America and Asia we selected subjects free of cardiovascular disease. Percentiles of cIMT and cIMT progression were assessed separately for every cohort. Cox proportional hazards models for vascular events were used to estimate hazard ratios for cIMT in each cohort. The estimates were pooled across Europe, North America and Asia, with random effects meta-analysis. The influence of geography, ethnicity and ultrasound protocols on cIMT values and on the hazard ratios was examined by meta-regression. RESULTS: Geographical factors, ethnicity and the ultrasound protocol had influence neither on the percentiles of cIMT and its progression, nor on the hazard ratios of cIMT for vascular events. Heterogeneity for percentiles of cIMT and cIMT progression was too large to create meaningful normative values. CONCLUSIONS: The distribution of cIMT values is too heterogeneous to define universal or regional population reference values. CIMT values vary widely between different studies regardless of ethnicity, geographic location and ultrasound protocol. Prediction of vascular events with cIMT values was more consistent across all cohorts, ethnicities and regions. PMID- 26746230 TI - Evidence-Based Plastic Surgery: Its Rise, Importance, and a Practical Guide. AB - There is a perfect storm developing in 21st century healthcare; rising complexity and patient expectations in the context of fiscal restraint. Evidence-based medicine (EBM) may be the best-kept secret in dealing with the "storm." Such an approach prefers management pathways that deliver better outcomes at less relative cost. In this article, the rise of EBM, its significance, a guide to practicing it, and its future in the field of plastic, reconstructive, and aesthetic surgery are presented. PMID- 26746231 TI - Safety performance testing of climbing helmet-mounted cameras. AB - BACKGROUND: No research establishing the effects of climbing helmet-mounted cameras on head injury biomechanics. OBJECTIVE: Establish the potential effects of climbing helmet-mounted cameras on the injury risks associated with falling object strikes and falls onto flat and angled surfaces. METHODS: Three experimental studies were developed via the adaptation of European helmet testing standards and regulations. Study 1 performed falling striker tests to the helmet, Study 2 performed linear headform drop tests onto a flat anvil and Study 3 performed oblique headform drop tests onto an anvil angled 15 degrees from vertical. Three helmet categories (hard-shell, foam and hybrid) were impacted at three locations (vertex, front and side), using five camera mounting combinations and three control helmets. Data was collected for the forces, linear accelerations, rotational velocities and rotational accelerations experienced by the headform. RESULTS: All helmet and camera combinations investigated by this project complied with current legislative performance criteria, while no combination exceeded published injury thresholds. No increase in head injury risk was observed for the forces transferred to the head during falling object strikes or with the linear accelerations experienced during falls onto flat and angled surfaces. Finally, although greater rotational head velocities and accelerations were observed with falls onto flat and angled surfaces, no injury threshold was exceeded by any investigated helmet and camera combination. CONCLUSIONS: All helmet and camera combinations investigated by this project complied with current legislative performance criteria, while no combination exceeded published injury thresholds. Further research may be required to establish the effects of additional impact mechanism, helmet or camera mounting configurations. PMID- 26746232 TI - How different is the care of terminal pancreatic cancer patients in inpatient palliative care units and acute hospital wards? A nationwide population-based study. AB - BACKGROUND: Inpatient palliative care is important for patients with terminal pancreatic cancer. However, the differences between inpatient palliative care and acute hospital care for inpatients with pancreatic cancer have not been explored in a population-based study. METHODS: This population-based nationwide study was conducted using data from the Taiwan National Health Insurance database to analyze the differences between inpatient palliative care and acute hospital care for inpatients with pancreatic cancer. We identified 854 patients with terminal pancreatic cancer, who had received in-hospital end-of-life care between January 2003 and December 2006. These patients were then sub-divided and matched 1:1 (using propensity score matching) according to whether they received inpatient palliative care (n = 276) or acute hospital care (n = 276). These groups were subsequently compared to evaluate any differences in the use of aggressive procedures, prescribed medications, and medical costs. RESULTS: Inpatient palliative care was typically provided by family physicians (39%) and oncologists (25%), while acute hospital care was typically provided by oncologists (29%) and gastroenterologists (24%). The inpatient palliative care group used natural opium alkaloids significantly more frequently than the acute hospital care group (84.4% vs. 56.5%, respectively; P < 0.001). The inpatient palliative care group also had shorter hospital stays (10.6 +/- 11.1 days vs. 20.6 +/- 16.3 days, respectively; P < 0.001), fewer aggressive procedures, and lower medical costs (both, P < 0.005). CONCLUSIONS: Compared to patients in acute hospital wards, patients with pancreatic cancer in inpatient palliative care units received more frequent pain control treatments, underwent fewer aggressive procedures, and incurred lower medical costs. Therefore, inpatient palliative care should be considered a viable option for patients with terminal pancreatic cancer. PMID- 26746233 TI - Abortion numbers halve in Northern Ireland as doctors fear prison. PMID- 26746234 TI - Balancing benefits and risks of glucocorticoids in rheumatic diseases and other inflammatory joint disorders: new insights from emerging data. An expert consensus paper from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). AB - PURPOSE: This consensus review article considers the question of whether glucocorticoid (GC) therapy is still relevant in the treatment of rheumatic diseases, with a particular focus on rheumatoid arthritis (RA), and whether its side effects can be adequately managed. Recent basic and clinical research on the molecular, cellular and clinical effects of GCs have considerably advanced our knowledge in this field. An overview of the subject seems appropriate. METHODS: This review is the result of a multidisciplinary expert working group, organised by European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis. The recent literature was surveyed and the salient evidence synthetized. RESULTS: The pathophysiological basis of RA (and other inflammatory rheumatic diseases) now strongly implicates the adaptive immune system in addition to innate mechanisms. The molecular effect of GCs and differential GC sensitivity is better understood, although exploiting this knowledge is still in its infancy. The newer treatment strategies of early and aggressive control of RA have gr eatly improved clinical outcomes, but improvements are still possible. Newer targeted anti-inflammatory drugs have made an important impact, yet they too are associated with numerous side effects. DISCUSSION: Short durations of moderate doses of GCs are generally well tolerated and have a positive benefit/risk ratio. Patients should be assessed for fracture risk and bone preserving agents and be prescribed calcium and vitamin D supplementation. CONCLUSIONS: Within a strategy of a disease modifying approach to inflammatory disease, combination therapy including a GC is effective approach. PMID- 26746236 TI - Validation of a German version of the International Hip Outcome Tool 12 (iHOT12) according to the COSMIN checklist. AB - BACKGROUND: Patient Reported Outcome (PRO) measurements have become an important tool to evaluate disease-related quality of life. The "International Hip Outcome Tool" (iHOT12) is a self-administered patient-reported outcome tool, which includes questions on the patient's symptoms, functional and sports limitations as well as social, emotional, and occupational limitations. The purpose of this study was to adapt and validate a German version of the iHOT12 according to the COSMIN checklist. METHODS: In order to validate the German translation of the iHOT12, we conducted a prospective multicenter cohort study on patients with hip disorders and a score >=4 on the modified Tegner Activity Scale (mTAS). The patients completed the German iHOT12 questionnaire and other functional scores (Hip Outcome Score, modified Tegner Activity Scale, EuroQol-5D) twice at intervals of at least two weeks. Evaluation of psychometric properties was conducted following the COSMIN checklist for validation of health status measurement instruments. The methodical testing for reliability included internal consistency, test-retest reliability, and measurement error. For testing of validity, we analyzed construct validity, hypotheses testing, interpretability and responsiveness. RESULTS: Between December 2013 and December 2014, eighty three consecutive patients completed both questionnaires and were available for data analysis. Cronbach's alpha was 0.94 (95 %-CI: 0.91, 0.95) confirming internal consistency and test-retest reliability of the iHOT-12 was high with an ICC = 0.94 (95 %-CI: 0.89, 0.97). All a priori hypotheses were confirmed. Further, no relevant floor- or ceiling effects occurred. The iHOT12 showed good responsiveness with a minimal important change (MIC) under 14 points. CONCLUSIONS: The German translation of the iHOT-12 is a reliable, valid, and responsive tool for the evaluation of disease-related quality of life in active patients with a hip disorder. We could show that the minimal important change, a change of health condition the patient discerns, is less than 14 points in the iHOT12 scale. PMID- 26746235 TI - PINK1 expression increases during brain development and stem cell differentiation, and affects the development of GFAP-positive astrocytes. AB - BACKGROUND: Mutation of PTEN-induced putative kinase 1 (PINK1) causes autosomal recessive early-onset Parkinson's disease (PD). Despite of its ubiquitous expression in brain, its roles in non-neuronal cells such as neural stem cells (NSCs) and astrocytes were poorly unknown. RESULTS: We show that PINK1 expression increases from embryonic day 12 to postnatal day 1 in mice, which represents the main period of brain development. PINK1 expression also increases during neural stem cell (NSC) differentiation. Interestingly, expression of GFAP (a marker of astrocytes) was lower in PINK1 knockout (KO) mouse brain lysates compared to wild type (WT) lysates at postnatal days 1-8, whereas there was little difference in the expression of markers for other brain cell types (e.g., neurons and oligodendrocytes). Further experiments showed that PINK1-KO NSCs were defective in their differentiation to astrocytes, producing fewer GFAP-positive cells compared to WT NSCs. However, the KO and WT NSCs did not differ in their self renewal capabilities or ability to differentiate to neurons and oligodendrocytes. Interestingly, during differentiation of KO NSCs there were no defects in mitochondrial function, and there were not changes in signaling molecules such as SMAD1/5/8, STAT3, and HES1 involved in differentiation of NSCs into astrocytes. In brain sections, GFAP-positive astrocytes were more sparsely distributed in the corpus callosum and substantia nigra of KO animals compared with WT. CONCLUSION: Our study suggests that PINK1 deficiency causes defects in GFAP-positive astrogliogenesis during brain development and NSC differentiation, which may be a factor to increase risk for PD. PMID- 26746238 TI - Hyperbaric oxygen therapy for the treatment of traumatic brain injury: a meta analysis. AB - Compelling evidence suggests the advantage of hyperbaric oxygen therapy (HBOT) in traumatic brain injury. The present meta-analysis evaluated the outcomes of HBOT in patients with traumatic brain injury (TBI). Prospective studies comparing hyperbaric oxygen therapy vs. control in patients with mild (GCS 13-15) to severe (GCS 3-8) TBI were hand-searched from medical databases using the terms "hyperbaric oxygen therapy, traumatic brain injury, and post-concussion syndrome". Glasgow coma scale (GCS) was the primary outcome, while Glasgow outcome score (GOS), overall mortality, and changes in post-traumatic stress disorder (PTSD) score, constituted the secondary outcomes. The results of eight studies (average age of patients, 23-41 years) reveal a higher post-treatment GCS score in the HBOT group (pooled difference in means = 3.13, 95 % CI 2.34-3.92, P < 0.001), in addition to greater improvement in GOS and lower mortality, as compared to the control group. However, no significant change in the PTSD score was observed. Patients undergoing hyperbaric therapy achieved significant improvement in the GCS and GOS with a lower overall mortality, suggesting its utility as a standard intensive care regimen in traumatic brain injury. PMID- 26746237 TI - Attention deficit hyperactivity disorder: genetic association study in a cohort of Spanish children. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) has a strong genetic component. The study is aimed to test the association of 34 polymorphisms with ADHD symptomatology considering the role of clinical subtypes and sex in a Spanish population. METHODS: A cohort of ADHD 290 patients and 340 controls aged 6-18 years were included in a case-control study, stratified by sex and ADHD subtype. Multivariate logistic regression was used to detect the combined effects of multiple variants. RESULTS: After correcting for multiple testing, we found several significant associations between the polymorphisms and ADHD (p value corrected <=0.05): (1) SLC6A4 and LPHN3 were associated in the total population; (2) SLC6A2, SLC6A3, SLC6A4 and LPHN3 were associated in the combined subtype; and (3) LPHN3 was associated in the male sample. Multivariable logistic regression was used to estimate the influence of these variables for the total sample, combined and inattentive subtype, female and male sample, revealing that these factors contributed to 8.5, 14.6, 2.6, 16.5 and 8.5 % of the variance respectively. CONCLUSIONS: We report evidence of the genetic contribution of common variants to the ADHD phenotype in four genes, with the LPHN3 gene playing a particularly important role. Future studies should investigate the contribution of genetic variants to the risk of ADHD considering their role in specific sex or subtype, as doing so may produce more predictable and robust models. PMID- 26746240 TI - COMP-assisted collagen secretion--a novel intracellular function required for fibrosis. AB - Cartilage oligomeric matrix protein (COMP) is an abundant component in the extracellular matrix (ECM) of load-bearing tissues such as tendons and cartilage. It provides adaptor functions by bridging different ECM structures. We have previously shown that COMP is also a constitutive component of healthy human skin and is strongly induced in fibrosis. It binds directly and with high affinity to collagen I and to collagen XII that decorates the surface of collagen I fibrils. We demonstrate here that lack of COMP-collagen interaction in the extracellular space leads to changes in collagen fibril morphology and density, resulting in altered skin biomechanical properties. Surprisingly, COMP also fulfills an important intracellular function in assisting efficient secretion of collagens, which were retained in the endoplasmic reticulum of COMP-null fibroblasts. Accordingly, COMP-null mice showed severely attenuated fibrotic responses in skin. Collagen secretion was fully restored by introducing wild-type COMP. Hence, our work unravels a new, non-structural and intracellular function of the ECM protein COMP in controlling collagen secretion. PMID- 26746239 TI - Flagellar pocket restructuring through the Leishmania life cycle involves a discrete flagellum attachment zone. AB - Leishmania promastigote parasites have a flagellum, which protrudes from the flagellar pocket at the cell anterior, yet, surprisingly, have homologs of many flagellum attachment zone (FAZ) proteins--proteins used in the related Trypanosoma species to laterally attach the flagellum to the cell body from the flagellar pocket to the cell posterior. Here, we use seven Leishmania mexicana cell lines that expressed eYFP fusions of FAZ protein homologs to show that the Leishmania flagellar pocket includes a FAZ structure. Electron tomography revealed a precisely defined 3D organisation for both the flagellar pocket and FAZ, with striking similarities to those of Trypanosoma brucei. Expression of two T. brucei FAZ proteins in L. mexicana showed that T. brucei FAZ proteins can assemble into the Leishmania FAZ structure. Leishmania therefore have a previously unrecognised FAZ structure, which we show undergoes major structural reorganisation in the transition from the promastigote (sandfly vector) to amastigote (in mammalian macrophages). Morphogenesis of the Leishmania flagellar pocket, a structure important for pathogenicity, is therefore intimately associated with a FAZ; a finding with implications for understanding shape changes involving component modules during evolution. PMID- 26746241 TI - Recommended administered activities for (68)Ga-labelled peptides in paediatric nuclear medicine. AB - PURPOSE: The aim of this study was to establish a method for determining administered activities for (68)Ga-labelled peptides. Dose calculations were based on the weight-independent effective dose model proposed by the EANM paediatric dosage card for use in paediatric nuclear medicine. METHODS: Previously published time-integrated activity coefficients for (68)Ga-DOTATATE, (68)Ga-DOTATOC and (68)Ga-pentixafor were used to calculate age-independent effective doses. Consequently, the corresponding weight-dependent effective dose coefficients were rescaled according to the formalism of the EANM dosage card to determine the radiopharmaceutical class of (68)Ga-labelled peptides ("multiples") and to calculate the baseline activities based on an upper limit for administered activity (185 MBq) in an adult. RESULTS: All calculated normalization factors suggest that the (68)Ga-labelled peptides are class "B" radiopharmaceuticals. The baseline activity for all compounds is 12.8 MBq. In analogy to (18)F-fluoride, we recommend a minimum activity of 14 MBq. CONCLUSION: For paediatric nuclear medicine applications involving (68)Ga-labelled peptides, we suggest determining administered activities based on the formalism proposed in this work. The corresponding effective doses from these procedures will remain age-independent. PMID- 26746243 TI - Inequality in Black and White High School Students' Perceptions of School Support: An Examination of Race in Context. AB - Supportive relationships with adults at school are critical to student engagement in adolescence. Additional research is needed to understand how students' racial backgrounds interact with the school context to shape their perceptions of school support. This study employed multilevel, latent variable methods with a sample of Black and White students (N = 19,726, 35.8 % Black, 49.9 % male, mean age = 15.9) in 58 high schools to explore variation in perceived caring, equity, and high expectations by student race, school diversity, and socioeconomic context. The results indicated that Black students perceived less caring and equity relative to White students overall, and that equity and high expectations were lower in diverse schools for both Black and White students. Nonetheless, racial disparities were attenuated in more diverse schools. The findings point to the need for intervention to improve perceptions of school support for Black youth and for all students in lower income and more diverse schools. PMID- 26746242 TI - Shared Risk Factors for the Perpetration of Physical Dating Violence, Bullying, and Sexual Harassment Among Adolescents Exposed to Domestic Violence. AB - The high risk of perpetrating physical dating violence, bullying, and sexual harassment by adolescents exposed to domestic violence points to the need for programs to prevent these types of aggression among this group. This study of adolescents exposed to domestic violence examined whether these forms of aggression share risk factors that could be targeted for change in single programs designed to prevent all three types of aggression. Analyses were conducted on 399 mother victims of domestic violence and their adolescents, recruited through community advertising. The adolescents ranged in age from 12 to 16 years; 64 % were female. Generalized estimating equations was used to control for the covariation among the aggression types when testing for shared risk factors. Approximately 70 % of the adolescents reported perpetrating at least one of the three forms of aggression. In models examining one risk factor at a time, but controlling for demographics, adolescent acceptance of sexual violence, mother-adolescent discord, family conflict, low maternal monitoring, low mother adolescent closeness, low family cohesion, depressed affect, feelings of anger, and anger reactivity were shared across all three aggression types. In multivariable models, which included all of the risk factors examined and the demographic variables, low maternal monitoring, depressed affect and anger reactivity remained significant shared risk factors. Our findings suggest that programs targeting these risk factors for change have the potential to prevent all three forms of aggression. In multivariable models, poor conflict management skills was a risk for bullying and sexual harassment, but not dating violence; acceptance of dating violence was a risk for dating violence and bullying, but not sexual harassment; and none of the examined risk factors were unique to aggression type. The study's implications for the development of interventions and future research are discussed. PMID- 26746311 TI - Trunk muscles contribute as functional groups to directionality of reaching during stance. AB - Muscle activity preceding the onset of voluntary movement has been shown to reduce centre of mass (CoM) displacement and stabilise the body during self induced 'perturbations'. However, based on recent findings in the lower limb, where preparatory muscle activity creates the dynamics necessary for the initiation of movement, this study sought to investigate whether trunk musculature acted consistently to minimise the displacement of the CoM, or in contrast, contribute to the movement. While standing, nine healthy participants made single-step (point-to-point) reaching movements to 13 visual targets throughout a 180 degrees range (target interval = 15 degrees ). Full-body kinematics and electromyographic activity from 'focal' arm and 'postural' trunk muscles were analysed for a preparatory phase of 250-ms preceding movement onset (termed pPA). Akin to lower limb findings, direction-specific patterns of anticipatory trunk muscle activity accompanied the onset of rotational kinematics and CoM acceleration in the direction of the desired target. When arranged in terms of peak activation, we found functionally relevant groupings aligned to either ipsi-, central or contra-lateral reaching directions. Contrary to traditional approaches, which focus on CoM stabilisation, this spatial recruitment was in favour of assisting initiation of movement. Such activity suggests that the central nervous system may rely on synergic patterns of muscle activation within an undistinguishable and shared focal/postural motor command for functional voluntary movements. PMID- 26746313 TI - The Interaction of Learning Disability Status and Student Demographic Characteristics on Mathematics Growth. AB - This study examined mathematics achievement growth of students without disabilities (SWoD) and students with learning disabilities (LD) and tested whether growth and LD status interacted with student demographic characteristics. Growth was estimated in a statewide sample of 79,554 students over Grades 3 to 7. The LD group was significantly lower in achievement in each grade and had less growth than the SWoD group. We also found that student demographic characteristics were significantly related to mathematics growth, but only three demographic characteristics were statistically significant as interactions. We found that LD-SWoD differences at Grade 3 were moderated by student sex, while Black race/ethnicity and free or reduced lunch (FRL) status moderated LD-SWoD differences at all grades. These results provide practitioners and policy makers with more specific information about which particular LD students show faster or slower growth in mathematics. Our results show that simply including predictors in a regression equation may produce different results than direct testing of interactions and achievement gaps may be larger for some LD subgroups of students than previously reported. PMID- 26746312 TI - Emotion and reward are dissociable from error during motor learning. AB - Although emotion is known to reciprocally interact with cognitive and motor performance, contemporary theories of motor learning do not specifically consider how dynamic variations in a learner's affective state may influence motor performance during motor learning. Using a prism adaptation paradigm, we assessed emotion during motor learning on a trial-by-trial basis. We designed two dart throwing experiments to dissociate motor performance and reward outcomes by giving participants maximum points for accurate throws and reduced points for throws that hit zones away from the target (i.e., "accidental points"). Experiment 1 dissociated motor performance from emotional responses and found that affective ratings tracked points earned more closely than error magnitude. Further, both reward and error uniquely contributed to motor learning, as indexed by the change in error from one trial to the next. Experiment 2 manipulated accidental point locations vertically, whereas prism displacement remained horizontal. Results demonstrated that reward could bias motor performance even when concurrent sensorimotor adaptation was taking place in a perpendicular direction. Thus, these experiments demonstrate that affective states were dissociable from error magnitude during motor learning and that affect more closely tracked points earned. Our findings further implicate reward as another factor, other than error, that contributes to motor learning, suggesting the importance of incorporating affective states into models of motor learning. PMID- 26746315 TI - Relationships of Attention and Executive Functions to Oral Language, Reading, and Writing Skills and Systems in Middle Childhood and Early Adolescence. AB - Relationships between attention/executive functions and language learning were investigated in students in Grades 4 to 9 ( N = 88) with and without specific learning disabilities (SLDs) in multiword syntax in oral and written language (OWL LD), word reading and spelling (dyslexia), and subword letter writing (dysgraphia). Prior attention-deficit/hyperactivity disorder (ADHD) diagnosis was correlated only with impaired handwriting. Parental ratings of inattention, but not hyperactivity, correlated with measures of written language but not oral language. Sustaining switching attention correlated with writing the alphabet from memory in manuscript or by keyboard and fast copying of a sentence with all the letters of the alphabet. Multiple regressions based on a principal component for composites of multiple levels of language (subword, word, and syntax/text) showed that measures of attention and executive function involving language processing rather than ratings of attention and executive function not specifically related to language accounted for more variance and identified more unique predictors in the composite outcomes for oral language, reading, and writing systems. Inhibition related to focused attention uniquely predicted outcomes for the oral language system. Findings are discussed in reference to implications for assessing and teaching students who are still learning to pay attention to heard and written language and self-regulate their language learning during middle childhood and adolescence. PMID- 26746316 TI - [Congres de la Societe de pathologie exotique : parasitoses, mycoses et cancer 18 novembre 2015, Institut Pasteur, Paris]. PMID- 26746314 TI - Executive Function, Self-Regulated Learning, and Reading Comprehension: A Training Study. AB - The goal of this study was to evaluate the extent to which training that emphasizes the process of executive function (EF) and self-regulated learning (SRL) would result in increased reading comprehension; we also evaluated interrelationships of EF, SRL, and reading. We report an experiment ( N = 75 fourth graders) that contrasted two researcher-implemented conditions (text-based reading [TB] and text-based reading plus executive function [TB+EF]) to a control. We also evaluated relationships among measures of SRL, EF, and reading. Both the TB and TB+EF groups outperformed the control group for proximal text comprehension (where the topic was similar to that covered in training) and background knowledge related to it, but the two researcher-led groups performed similarly. There were no significant differences for less proximal text, and again similar performance for both TB and TB+EF. Correlations among measures were weak in general, although the pattern was similar to that found in the extant literature. The findings speak to the difficulty in separating these components from those of strong instruction more generally. The relationships of these constructs to reading comprehension will likely be enhanced by more sensitive measurement of EF and reading comprehension, particularly where tied to active treatment components. PMID- 26746317 TI - [Time perceptions and representations]. AB - Representations of time and time measurements depend on subjective constructs that vary according to changes in our concepts, beliefs, societal needs and technical advances. Similarly, the past, the future and the present are subjective representations that depend on each individual's psychic time and biological time. Therefore, there is no single, one-size-fits-all time for everyone, but rather a different, subjective time for each individual. We need to acknowledge the existence of different inter-individual times but also intra individual times, to which different functions and different rhythms are attached, depending on the system of reference. However, the construction of these time perceptions and representations is influenced by objective factors (physiological, physical and cognitive) related to neuroscience which will be presented and discussed in this article. Thus, studying representation and perception of time lies at the crossroads between neuroscience, human sciences and philosophy. Furthermore, it is possible to identify several constants among the many and various representations of time and their corresponding measures, regardless of the system of time reference. These include the notion of movements repeated in a stable rhythmic pattern involving the recurrence of the same interval of time, which enables us to define units of time of equal and invariable duration. This rhythmicity is also found at a physiological level and contributes through circadian rhythms, in particular the melatonin rhythm, to the existence of a biological time. Alterations of temporality in mental disorders will be also discussed in this article illustrated by certain developmental disorders such as autism spectrum disorders. In particular, the hypothesis will be developed that children with autism would need to create discontinuity out of continuity through stereotyped behaviors and/or interests. This discontinuity repeated at regular intervals could have been fundamentally lacking in their physiological development due to possibly altered circadian rhythms, including arhythmy and asynchrony. Time measurement, based on the repetition of discontinuity at regular intervals, involves also a spatial representation. It is our own trajectory through space-time, and thus our own motion, including the physiological process of aging, that affords us a representation of the passing of time, just as the countryside seems to be moving past us when we travel in a vehicle. Chinese and Indian societies actually have circular representations of time, and linear representations of time and its trajectory through space-time are currently a feature of Western societies. Circular time is collective time, and its metaphysical representations go beyond the life of a single individual, referring to the cyclical, or at least nonlinear, nature of time. Linear time is individual time, in that it refers to the scale of a person's lifetime, and it is physically represented by an arrow flying ineluctably from the past to the future. An intermediate concept can be proposed that acknowledges the existence of linear time involving various arrows of time corresponding to different lifespans (human, animal, plant, planet lifespans, etc.). In fact, the very notion of time would depend on the trajectory of each arrow of time, like shooting stars in the sky with different trajectory lengths which would define different time scales. The time scale of these various lifespans are very different (for example, a few decades for humans and a few days or hours for insects). It would not make sense to try to understand the passage of time experienced by an insect which may live only a few hours based on a human time scale. One hour in an insect's life cannot be compared to one experienced by a human. Yet again, it appears that there is a coexistence of different clocks based here on different lifespans. Finally, the evolution of our society focused on the present moment and choosing the cesium atom as the international reference unit of time measurement (cesium has a transition frequency of 9.192.631.77000 oscillations per second), will be questioned. We can consider that focusing on the present moment, in particular on instantaneity rather than infinity, prevents us from facing our own finitude. In conclusion, the question is raised that the current representation of time might be a means of managing our fear of death, giving us the illusion of controlling the uncontrollable, in particular the passage of time, and a means of avoiding to represent what many regard as non representable, namely our own demise. PMID- 26746318 TI - [Role of rhythmicity in infant development]. AB - This article deals with rhythm in the experiences of infants, focusing in particular on the function of rhythmicity in the baby's sense of being and its continuity. Infants are inevitably subjected to experiences of discontinuity. These experiences are necessary to development, but they expose the child to chaotic experiences when a basic rhythmicity is not ensured. The rhythmicity of childcare experiences gives the illusion of permanence and enables anticipation. This nourishes the basic feeling of security and supports the development of thought. Interactive and intersubjective exchanges must be rhythmic and must be in keeping with the rhythm of the baby, who needs to withdraw regularly from the interaction to internalize the experience of the exchange. Without this retreat, the interaction is over-stimulating and prevents internalization. Object presence/ absence must also be rhythmic, to enable the infant to keep the object alive inside him/ herself. Observation of babies has demonstrated their ability to manage experiences of discontinuity: they are able to sustain a continuous link via their gaze, look for clues indicating the presence of a lost object, search for support in sensations, and fabricate rhythmicity to remain open to the self and the world. The author gives some examples of infant observations that provide evidence of these capacities. One observation shows how a baby defends itself against a discontinuity by actively maintaining a link via his/her gaze. Another example shows an infant holding on to "hard sensations" in order to stay away from "soft" ones, which represent the fragility of the separation experience. This example pertains to a seven-month-old's prelanguage and "prosodic tonicity". The author takes this opportunity to propose the notion of "psychic bisensuality" to describe these two sensation poles, which must be harmoniously articulated to guarantee an inner sense of security. Such repairs of discontinuity are only possible if the experience of discontinuity is not overly disorganizing. For instance, if an object is absent for more than a certain amount of time, it is no longer alive in the infant's mind and despair is inevitable. This prompts us to think carefully about the separation experiences we impose upon babies and their duration. Rhythms of security set in right from the beginning of early childhood, or even in utero. The author gives an example of recourse to inner rhythmicity in an 8 - or 9-month-old baby, which serves to ground the baby's sense of security. In infants, as in each one of us, rhythmicity organizes a foundation of permanence and bridges the gap created by separation. If leaning on sensations and creating neo-rhythms fails to repair the discontinuities, the baby will plunge into experiences of chaos and confusion, as seen, for example, in inconsolability. Even in this latter case, one can find a rhythmicity in the infant's crying, for example, as if the baby didn't want to be separated from the sorrow, a sort of paradoxical companion. Traces of all these primitive defenses can be found in the older child and in adult psychopathology. The importance of rhythmicity is stressed in relation to learning, which involves the experience of otherness and reality, and the rhythmic patterns of engagement and withdrawal support the integration process. The same holds true for the caretaking relationship: rhythmic involvement supports coming together, sharing, and understanding. In all of these situations, the parent, the teacher, the caregiver, must adapt to the child, the pupil, the patient; the external rhythms must fit the internal rhythm of the subject. PMID- 26746319 TI - [Temporal meaning of suffering]. AB - If we had to find a few simple words to express what a suffering human being experiences, no matter what ills are causing the suffering and no matter what circumstances underlie the ills themselves, we could unmistakably say that it is the experience of not being able to go on like this. Suffering can be described, in this same sense, as an alteration in temporality. However, describing suffering as such only makes sense if we already have a conception of normal temporality. Yet for this, philosophical tradition offers not one but four competing conceptions. In the present article, we begin by briefly presenting these different conceptions. We then show how each one sheds light, by way of contrast, on a phenomenon whose meaning thus appears to be essentially negative. But does this phenomenon have a negative meaning only? Doesn't it correspond as much to a transformation as an alteration of temporality? This is what we will strive to establish in the third part of the article by relating suffering to hope, in a paradoxical sense of the term. Of the four conceptions of time likely to shed a contrasting light on the upheavals that suffering introduces into our life experience, the one described by Aristotle in Physics is historically the first. In particular, the notion of succession originates therein. But this conception does not account for what makes time the unit of a past, a present, and a future. In Book XI of Confessions, St. Augustine situated this unit not in nature but in the human mind. Hence, his definition of time as a distension of the soul and the necessary division into physical time and psychic time it entails. Husserl's Lessons on the phenomenology of the consciousness of internal time lend credit to this division, but they illuminate only the internal constitution of the "present", which is at the heart of the psychological conception of time. In Being and Time, Heidegger breaks away from this long standing tradition; in his view, physical time and psychic also time take root in the temporality of "planning", understood to be a general form of openness to the world. But in our minds, "being" means more than "being in the world"; it also means, and by that very token, "being for death". Anguish is the fundamental experience that brings out this structural identity. As such, it lies at the core of Heidegger's conception of temporality. Nonetheless, is death the ultimate truth of time? This is what Paul Ricoeur denies in establishing an internal relationship between time and narration, for narration not only produces a synthesis of time, it also allows us to assume a future which, granted, presupposes death but does not remain its captive. This supports a fourth conception of time, that summarized by the notion of "narrated time". Narrative resources do not; however, cancel the multiple alterations that suffering introduces into temporality, which, by contrast, can be reduced - as we show in the second part of the article in reference to the preceding conceptions - to four descriptive features: dechronologization, reduction of the present to the instant, breakdown of the plan, and disintegration of the narrative. They explain why, in the presence of suffering, life seems more impossible than death. But at the same time, it leaves us with an enigma: Why doesn't the suffering human being always choose death? This enigma, above all, is the enigma of melancholic suffering. Hence, the privileged place given to melancholy in the last part of the article, where psychiatry encounters philosophy and justifies some distinctions that philosophy alone would not have dared make. A case in point is Minkowski's distinction, in Lived Time, between "activity" and "waiting", and also holds for our own distinction, following Minkowski, between planning time and hoping time, where hoping is to be taken in the deeper sense than implied by the common opposition between "hope" and "despair". PMID- 26746320 TI - [Seasons, circadian rhythms, sleep and suicidal behaviors vulnerability]. AB - INTRODUCTION: Suicidal behaviors are common in the general population and are so a major public health problem. In order to improve suicide prevention and to reduce the mortality by suicide, it appears essential to better identify suicide risk factors. Seasonality, circadian rhythms and sleep abnormalities have been already associated with numerous psychiatric disorders. This review aimed to characterize the associations between seasonality, circadian rhythms, sleep and suicidal behaviors including suicide attempts and completed suicides. METHODS: We conducted a literature search between 1973 and 2015 in PubMed databases using the following terms: ("suicide" OR "suicidality" OR "suicide attempts" OR "suicidal behavior") AND ("circadian rhythms" OR "seasons" OR "sleep"). RESULTS: Many studies confirm a specific seasonality for suicide with a higher peak of suicides in spring for both sex and a lower peak in autumn especially for women. This distribution seems to correlate with depressive symptoms (especially for the autumn peak), gender and different types of suicide. Regarding gender and type of suicide differences, males more commonly commit violent suicide with a higher rate of suicides in spring. Suicide behaviors appear to be influenced by climatic and biological factors like sunshine, daylight cycles, temperature, air pollutants, viruses, parasites and aeroallergens. Circadian variations exist in suicide rates depending on age with a morning peak for elder and an evening peak for youth. In addition, completed suicide peak in early morning whereas suicide attempts peak rather in later afternoon. Several biomarkers dysregulation like melatonin, serotonin and cortisol may be implicated in suicide circadian variations. Furthermore, specific sleep disorders like insomnia, nightmares and sleep deprivation are common risk factors of suicide and possibly independently of the presence of depressive symptoms. Finally, the efficacy of chronotherapeutics (such as luminotherapy, dark therapy, sleep deprivation and melatonin drugs) has been suggested in the reduction of suicidal behaviors. CONCLUSION: The suicide seasonality is very well documented showing a main peak in spring and another one in autumn. A suicide circadian distribution also exists depending of the suicidal behavior intensity and of the age. Numerous sleep disorders are also suicide risk factors and can be treated with chronotherapeutics. A better identification of seasonality, circadian rhythms and sleep abnormalities in suicidal behaviors could allow a better prevention in suicidal attempts and a reduction in death by suicide. PMID- 26746321 TI - [Circadian markers and genes in bipolar disorder]. AB - INTRODUCTION: Bipolar disorder is a severe and complex multifactorial disease, characterized by alternance of acute episodes of depression and mania/hypomania, interspaced by euthymic periods. The etiological determinants of bipolar disorder yet, are still poorly understood. For the last 30 years, chronobiology is an important field of investigation to better understand the pathophysiology of bipolar disorder. METHODS: We conducted a review using Medline, ISI Database, EMBase, PsyInfo up to January 2015, using the following keywords combinations: "mood disorder", "bipolar disorder", "depression", "unipolar disorder", "major depressive disorder", "affective disorder", for psychiatric conditions; and "circadian rhythms", "circadian markers", "circadian gene", "clock gene", "melatonin" for circadian rhythms. The search critera was presence of word in any field of the article. RESULTS: Quantitative and qualitative circadian abnormalities are associated with bipolar disorders both during acute episodes and euthymic periods, suggesting that these altered circadian rhythms may represent biological trait markers of the disorder. These circadian dysfunctions were assessed by various validated tools including polysomnography, actigraphy, sleep diaries, chronotype assessments and blood melatonin/cortisol measures. Other altered endogenous circadian activities have also been reported in bipolar patients, such as hormones secretion, core body temperature or fibroblasts activity. Moreover, these markers were also altered in healthy relatives of bipolar patients, suggesting a degree of heritability. Several genetic association studies have also showed associations between multiple circadian genes and bipolar disorder, such as CLOCK, ARTNL1, GSK3beta, PER3, NPAS2, NR1D1, TIMELESS, RORA, RORB, and CSNK1epsilon. Thus, these circadian gene variants may contribute to the genetic susceptibility of the disease. Furthermore, the study of the clock system may help to better understand some phenotypic aspects like the mechanisms of pharmacological treatments used in bipolar disorder, in particular lithium carbonate. CONCLUSION: Several clinical, physiological and genetic data suggest that circadian rhythms dysregulations are involved in the pathophysiology of bipolar disorder. The circadian model has led to the development of new therapeutic strategies such as chronotherapeutics or Inter Personal Social and Rhythms Therapies. Further studies are needed in this promising research field to keep exploring the relationship between these circadian markers, genes and the clinical aspects of the disease. PMID- 26746323 TI - [Temporality and psychological debriefing of groups: a variant of logical time]. AB - OBJECTIVE: Group debriefing has been a topic of controversy regarding its temporal dimension. What is the opportune time for using this communication device and when is it the most effective? In practice, group debriefing is generally used after the fact, in post-event interventions. What is the rationale for delaying the debriefing process? Debriefing follows a logical progression that goes from evocation of the event to the expression of a possible future. How should one view this progression in relation to the subject's logical temporality? Finally, are the temporalities of the subjects and the group compatible? The objective of this paper is to show that one of the particularities of group debriefing is that it associates group temporality and subjective logical time. METHODOLOGY: This study describes the temporal modalities of group debriefing practiced at the Emergency Medical-Psychological Unit of the Ille-et-Vilaine Department of France, based on the analysis of a clinical case. The debriefing situation presented here took place in a firm following a suicide. Four female employees of the firm saw the body of a person committing suicide as it fell from the higher floors of the building. The psychoanalytic research on subjective time, used as a basis for this study, points out two dimensions of time, prograde and retrograde. Retrograde time produces a feedback effect via which the subject reorganizes his/her past. Psychoanalysis also describes a logical time specific to each subject, which can be broken down into three time frames: seeing, understanding, and concluding. In group debriefing, the time course is group-specific. RESULTS: We show that the subjects' temporality is interconnected with the temporal progression of the group during debriefing. We present some elements showing how subjective and group positioning evolved in relation to the shared temporal unfolding of the debriefing. The debriefing consisted of three time frames. The first involved evoking the tragic experience of the event; it brought out the common points in the women's experience of the event, and a solution of "withdrawal" as a protection mechanism. Individual experiences, such as the desire to avoid or see the scene, or the ability or inability to call for help, were also present. The second time frame pertained to the symptomatology and subsequent experience of the event; here, we observed evocation of similar symptoms among some of the participants but also after the event, depending on individual subjectivity. The relationship to the event was also addressed in terms of the ability or inability of each individual to cope with the event and overcome it. The third time frame involved projection into the future; a sense of relief became manifest as the debriefing progressed. This third time frame permitted evocation of a possible way of "breaking away" from the event, linked to each person's history and connected in particular to the relationship with death evoked during the second time frame. The debriefing also helped in acknowledging the pain brought about by the traumatic event, a beneficial factor in psychic processing. CONCLUSION: Group debriefing articulates subjective time and group time. In practice, debriefing follows chronological time, at the same time as it mobilizes logical time. It brings to bear a double temporality that must be taken into account during both the implementation and unfolding phases of the debriefing process, but also in the objectives set for this device. The clinician-debriefer must consider this double temporality in order to direct the debriefing in a way suited to the clinical implications that justify its use, and must do so with tact and moderation, without imposition on the subjects'individual temporalities and defenses. PMID- 26746322 TI - [Temporality and trauma: Towards an articulation between the judicial, educational and psychological times in repeat teenage offenders]. AB - Within the past few years, the problem of repeat teenage offenders has raised troubling questions among the various institutions in charge of this population. The temporalities of these adolescents are marked by immediacy, urgency, and repetition that circumvent a linear view of time and the programs set up to handle them. Studies on repeat teenage aggressors (notably, sexual aggressors) have shown that these young people often have a history of an acknowledged or unacknowledged trauma. The fact of having been a victim of abuse during childhood is thought to be a factor leading to later acting out. Our objective is to inquire into these juvenile delinquents and their treatment using a temporal framework of their life pathway that will influence the ways in which they are treated by professionals. By tracing back through the lives of these young authors of violence, we can find out whether they were themselves victims. Repeated acts of violence by a youth could then be seen not as isolated acts but as expressions of ill-being, of having been a victim, whether recognized or not. The act thus represents a link between the present and the past that can be analyzed by looking at occurrences of acting out. It would be interesting, moreover, to reflect upon how continuity could be created there where disruption strikes the youth and often the institutions too. We provide a detailed description of the notion of trauma by recalling its definition and its possible immediate and deferred effects on these youths. In the immediate time frame, the subject may present a physical reaction to the trauma. The psychological reaction will determine a psychic time frame expressed in several ways, whether immediately or at a distance from the traumatic event. Posttraumatic reactions may hamper the development of the teenager's personality. Some traumatized adolescents will express their ill-being by aggressiveness, as they replay the traumatic scene by staging violent and dangerous actions. Next we examine the different intertwined and interacting temporalities of the concerned institutions - namely, the legal, educational, and psychological therapeutic time frames - and how they contribute to creating a link between the past and the present in order to reconstruct the subject's life history. Legal time corresponds to the time during which the committed act is put into words, its significance is determined and judged, and a penal response to the offense is issued. Judgment time constitutes a waiting period for the subject; once the legal decision is made, the subject can mentally return to the present. The subject may experience this waiting period as a time to think about his/her act, in which case it may initiate a time for psychotherapy. Other youths will deny the posited act, thereby preventing any projection into the future. Educational time can only become fully meaningful once the legal decisions have been announced; its purpose is to help these youths project into a future in which their acts will repeatedly end in failure. Lastly, psychological therapy time can constitute a period of reconstruction and repair by making sense out of the acted-out events in the subject's life history. Repetition of delinquent acts, then, should be understand not as the repetition of isolated acts leading to disruptions that call for a response each time, but more as a means of finding meaning by reintegrating a repressed history that perturbs the present and prevents the adolescent from making a life plan. The complexity and interaction of these different temporalities (legal, educational, and psychological) prompt us to reflect upon the interconnections that should be set up, in the form of networks, to best accompany these teenagers and make their time meaningful, notably by enabling them to project into the future. PMID- 26746325 TI - Hepatitis B vaccination and adolescents: A lost generation. PMID- 26746324 TI - [Time perception and schizophrenia: Phenomenological and neuropsychological approach]. AB - OBJECTIVES: Based on clinical, phenomenological and neurobiological observations, psychiatrists often report a deficit in time estimation in patients with schizophrenia. Cognitive models of time estimation in healthy subjects have been proposed and developed for approximately 30 years. The investigation of time perception is pertinent to the understanding of neurobiological and cognitive abnormalities in schizophrenia. Brain lesions and neuroimaging studies have shown that the critical brain structures engaged in time perception include the prefrontal and parietal lobes, thalamus, basal ganglia and cerebellum. These brain areas have been implicated in the physiopathology of schizophrenia in that there is impaired coordination of activity among these regions. Clinical and experimental date strongly suggest that patients with schizophrenia are less accurate in their ability to estimate time than healthy subjects. The specificity of these clinical and behavioral impairments is still in question. The aims of this article are to present an overview of the literature regarding time estimation and schizophrenia, to discuss specific issues related to how perceptual dysfunction in schizophrenia may lead to abnormalities in time perception, and to propose new perspectives towards an integrative approach between phenomenology and neuroscience. METHODS: We present a review of the literature describing the current theory in the field of time perception, which is supported by a connectionist model, postulating that temporal judgment is based upon a pacemaker-counter device that depends mostly upon memory and attentional resources. The pacemaker emits pulses that are accumulated in a counter, and the number of pulses determines the perceived length of an interval. Patients with schizophrenia are known to display attentional and memory dysfunctions. Moreover, dopamine regulation mechanisms are involved in both the temporal perception and schizophrenia. DISCUSSION: It is still unclear if temporal impairments in schizophrenia are related to a specific disturbance in central temporal processes or are due to certain cognitive problems, such as attentional and memory dysfunctions, or biological abnormalities. While psychopathological and phenomenological work strongly suggests that time perception disturbance may be the key or core symptom in schizophrenia, neuroscience studies have failed to do the same. The question of specificity of temporal perception impairments in schizophrenia remains contested. Neuroscience studies suggest that time symptoms in patients with schizophrenia are only secondary to thought disorders and primary cognitive impairments. This debate refers to the etiologic/organic versus psychogenesis/psychological dichotomy and may be over-taken. CONCLUSION: Clinical evidence associated with psychopathological, biological and cognitive theories strongly suggests that patients with schizophrenia have a deficit in time perception. Discrimination and reproduction of durations have been found to be constantly impaired and disorganized. There is still much work to be done to identify the exact sources of variability in temporal judgments in schizophrenia, and the study of developmental course of time perception could be an interesting route. Regardless of the role of temporal deficits in the pathogenesis of schizophrenia (as a general cognitive disorder or a core role), clinical and phenomenological data encourage us to conduct further studies, especially in the field of developmental psychology. PMID- 26746326 TI - Vaccine strategies against bacterial pathogens in cystic fibrosis patients. AB - A large number of cystic fibrosis pathogens such as bacteria of the Burkholderia cepacia complex, Pseudomonas aeruginosa, or Mycobacterium abscessus are associated with complex therapeutic problems due to their inherent resistance to antibiotics. No vaccine is currently available against those pathogens. Vaccines are therefore crucial to combat these multidrug-resistant bacteria in specific clinical situations including cystic fibrosis. Various strategies may be considered to develop these vaccines. Similar virulence factors are expressed during the infection with various pathogens; they could thus be used as antigen to assess cross-protection. Many clinical trials are currently being conducted to try and develop a prophylactic treatment for patients presenting with cystic fibrosis. PMID- 26746327 TI - Toxoplasmic ventriculitis. PMID- 26746328 TI - Inferior Vena Cava Filters in Pregnancy: A Systematic Review. AB - During pregnancy, patients have an increased risk of venous thromboembolism (VTE). This is an important cause of maternal mortality. Inferior vena cava (IVC) filters can be used to prevent pulmonary embolism in complicated cases of VTE during pregnancy. The present systematic review includes all patients reported in the literature who had an IVC filter placed during pregnancy. The indications for IVC filters are discussed, along with practical considerations for placement during pregnancy, filter effectiveness, and maternal and fetal mortality and morbidity. IVC filters can be used safely when appropriate during pregnancy, with complication rates similar to those in nonpregnant patients. PMID- 26746331 TI - A Modern Radiotherapy Series of Survival in Hispanic Patients with Glioblastoma. AB - BACKGROUND: Studies have shown racial differences in cancer outcomes. We investigate whether survival differences existed in Hispanic patients with glioblastoma (GBM) compared with other ethnicities from our modern radiotherapy series, because no study to date has focused on outcomes in this group after radiation therapy. METHODS: We retrospectively evaluated 428 patients diagnosed with GBM from 1996 to 2014 at our institution, divided into 4 groups based on self-report: white, black, Hispanic, and Asian/Indian. The primary outcome was overall survival. We analyzed differences in prognostic factors among the whole cohort compared with the Hispanic cohort alone. RESULTS: Baseline characteristics of the 4 racial groups were comparable. With a median follow-up of 387 days, no survival differences were seen by Kaplan-Meier analysis. Median overall survival for Hispanic patients was 355 days versus 450 days for the entire cohort. Factors significant for patient outcomes in the entire cohort differed slightly from those specific to Hispanic patients. Low Karnofsky Performance Status was significant on multivariate analysis in the whole population, but not in Hispanic patients. Extent of resection, recursive partitioning analysis class, and radiation therapy total dose were significant on multivariate analysis in both the whole population and Hispanic patients. CONCLUSIONS: We found that Hispanic patients with GBM had no difference in survival compared with other ethnicities in our cohort. Differences exist in factors associated with outcomes on single and multivariate analysis for Hispanic patients with GBM compared with the entire cohort. Additional studies focusing on Hispanic patients will aid in more personalized treatment approaches in this group. PMID- 26746332 TI - Thoracolumbar Arteriovenous Malformations Presenting with Intracranial Subarachnoid Hemorrhage: Case Series and Review of Literature. AB - OBJECTIVE: Cryptogenic intracranial subarachnoid hemorrhage accounts for approximately 15% of all subarachnoid hemorrhage cases. Diagnostic workup after negative cerebral digital subtraction angiogram typically includes magnetic resonance imaging of the brain and cervical spine for arteriovenous malformations, tumors, and fistulae. Only a few cases of thoracolumbar spinal vascular malformations have been associated with intracranial subarachnoid hemorrhage. METHODS: Case series and review of the literature. RESULTS: We found 3 patients at our institution who had nontraumatic, nonaneurysmal intracranial subarachnoid hemorrhage with isolated spinal vascular malformation in the thoracolumbar region. Including our 3 cases, we found a total of 15 similar cases in the literature. Most of the patients were younger, most having concurrent spinal cord symptoms of radiculopathy (27%), myelopathy (20%), or bladder bowel involvement (20%). Most of the spinal vascular malformations were intramedullary or conus medullaris type. Locations of intracranial subarachnoid hemorrhage were mostly isolated to the perimesencephalic area and posterior fossa. CONCLUSIONS: In younger populations presenting with nonaneurysmal intracranial subarachnoid hemorrhage and symptoms related to the spinal cord, evaluation for thoracolumbar spinal vascular malformations must be included in the initial workup. PMID- 26746333 TI - Lumbar Spinal Fixation with Cortical Bone Trajectory Pedicle Screws in 79 Patients with Degenerative Disease: Perioperative Outcomes and Complications. AB - OBJECTIVE: Biomechanical studies demonstrate that cortical bone trajectory pedicle screws (CBTPS) have greater pullout strength than traditional pedicle screws with a lateral-medial trajectory. CBTPS start on the pars and angulate in a mediolateral-caudocranial direction. To our knowledge, no large series exists evaluating the perioperative outcomes and safety of CBTPS. METHODS: We retrospectively reviewed all patients who received lumbar CBTPS at our institution. Data were collected regarding patient demographics, use of image guidance, operative blood loss, hospital stay, and postoperative complications. RESULTS: A total of 79 patients undergoing CBTPS fusion for degenerative lumbosacral disease with back pain were included in the analysis (42 female, 37 male; October 2011-January 2015). Twenty patients (25.3%) had previous lumbar spine surgery, 39 (49.4%) had a smoking history, and mean body mass index was 28.7. Mean length of stay was 3.5 days, and mean operative blood loss was 306.3 mL. Image guidance was used in 69 (87.3%) cases. A total of 66 (83.5%) fusions were single level, and 54 (68.4%) fusions were single level without previous surgery. There were 9 complications in 7 (8.9%) patients; these included hardware failure, pseudarthrosis, deep vein thrombosis, pulmonary embolism, epidural hematoma, and wound infection. No complications were caused by misplaced screws. Mean follow-up was 13.2 months. CONCLUSIONS: As CBTPS becomes increasingly popular among spine surgeons performing lumbar fusion, this report provides an important evaluation of technique safety and acceptable perioperative outcomes. PMID- 26746335 TI - Incidence of Headache After Traumatic Brain Injury in China: A Large Prospective Study. AB - BACKGROUND: There have yet to be any large-scale studies in China on headaches after traumatic brain injury (TBI). We evaluate the incidence of headache after TBI and investigate risk factors and functional outcome in a large tertiary center with a high caseload. METHODS: A total of 543 patients (82% men, 18% women) with a mean age of 48.4 +/- 18.6 years presenting with TBI were prospectively enrolled in this study between March 2011 and July 2013. Patient demographics, severity of TBI, incidence and classification of headache, and treatment information were collected during initial hospitalization and at 3, 6, and 12 months follow-up. RESULTS: Of our 543 patients (82% men, 18% women), 62% were injured in motor vehicle collisions and 27% in falls. Most patients (97%) were considered to have mild TBI. Follow-up rates at 3, 6, and 12 months were 91%, 75%, and 61%, respectively. Only 12% of patients reported pre-TBI headaches, whereas 58% of respondents reported headache at 3 months follow-up, 54% at 6 months follow-up, and 49% at 1 year follow-up. No statistically significant correlations between age, sex, or TBI severity and posttraumatic headaches were observed. CONCLUSIONS: We present the findings of the first study on headaches after TBI in China. Headaches were found to occur in most patients with TBI and persisted through the first year after injury. The incidence of posttraumatic headache observed here is comparable with previously published studies outside China. PMID- 26746336 TI - Neurofibromas of the Phrenic Nerve: A Case Report and Review of the Literature. AB - BACKGROUND: Phrenic neurofibromas are a rare pathologic entity, with 9 cases described in the English literature. They may occur in conjunction with or independently of neurofibromatosis type 1. Phrenic neurofibromas pose distinct therapeutic challenges compared with the more common phrenic schwannoma. We describe here a 12-year-old boy with neurofibroma of the left phrenic nerve presenting as dextroposition of the heart after paralysis of the left hemidiaphragm allowed herniation of abdominal contents into the left hemithorax and displaced the heart. METHOD: Surgical resection of the tumor followed by diaphragmatic plication was performed to assess its degree of malignancy, reduce abdominal herniation, and improve lung capacity. RESULTS: The operation markedly improved his hemidiaphragmatic elevation. CONCLUSIONS: The spectrum of management options ranges from conservative surveillance to open thoracic surgery. Functional preservation of the phrenic nerve is technically challenging, and although phrenic neurofibromas often present with absent function that cannot be recovered, surgical intervention can be fruitful in restoring lung capacity through diaphragmatic reconstruction. PMID- 26746334 TI - Venous Thromboembolism Prophylaxis in Meningioma Surgery: A Population-Based Comparative Effectiveness Study of Routine Mechanical Prophylaxis with or without Preoperative Low-Molecular-Weight Heparin. AB - OBJECTIVES: Venous thromboembolism (VTE) is a serious complication after intracranial meningioma surgery. To what extent systemic prophylaxis with pharmacotherapy is beneficial with respect to VTE risk, or associated with increased risk of bleeding and postoperative hemorrhage, remains debated. The current study aimed to clarify the risk/benefit ratio of prophylactic pharmacotherapy initiated the evening before craniotomy for meningioma. METHODS: In a Scandinavian population-based cohort, we conducted a retrospective review of 979 operations for intracranial meningioma between 2007 and 2013 at 3 neurosurgical centers with population-based referral. We compared 2 different treatment strategies analyzing frequencies of VTE and proportions of postoperative intracranial hematomas requiring surgery or intensified subsequent observation or care (intensive care unit or other intensified observation or treatment). One neurosurgical center favored preoperative prophylaxis with low molecular-weight heparin (LMWH) (LMWH routine group) in addition to mechanical prophylaxis, and 2 centers favored mechanical prophylaxis with LMWH only given as needed in cases of delayed mobilization (LMWH as needed group). RESULTS: In the LMWH routine group, VTE was diagnosed after 24/626 operations (3.9%), and VTE was diagnosed after 11/353 (3.1%) operations in the LMWH as needed group (P = 0.56). Clinically relevant postoperative hematomas occurred after 57/626 operations (9.1%) in the LMWH routine group compared with 23/353 (6.5%) in the LMWH as needed group (P = 0.16). Surgically evacuated postoperative hematomas occurred after 19/626 operations (3.0%) in the LMWH routine group compared with 8/353 operations (2.3%) in the LMWH as needed group (P = 0.26). CONCLUSIONS: There is no benefit of routine preoperative LMWH starting before intracranial meningioma surgery. Neither could we for primary outcomes detect a significant increase in clinically relevant postoperative hematomas secondary to this regimen. We suggest that as needed perioperative administration of LMWH, reserved for patients with excess risk because of delayed mobilization, is effective and also appears to be the safest strategy. PMID- 26746337 TI - Supplementary Motor Cortical Changes Explored by Resting-State Functional Connectivity in Brachial Plexus Injury. AB - BACKGROUND: Brachial plexus injury (BPI) is a serious peripheral nerve injury, and clinical outcomes are generally unsatisfactory. It has been reported that cortical plasticity could influence the restoration of motor function. However, the neurologic mechanism of BPI is unclear, which provides a basis for further investigation. The supplementary motor area (SMA) plays an important role in the regulation of motor function. This study aims to explore SMA-whole brain functional connectivity after deafferentation of the brachial plexus. METHODS: Study subjects included 16 patients with BPI and 8 healthy volunteers. The seed region was defined by a block-design functional magnetic resonance imaging program that used unilateral imaginary hand grasp motion as a task stimulus. Next, the voxel-wise functional connectivity between the predefined region and the other regions of the brain was calculated. RESULTS: We discovered decreased voxel-wise functional connectivity between the SMA and multiple brain regions, including precuneus, posterior cingulum cortex, and anterior cingulum cortex, that are closely associated with information integration or motor processing in patients with BPI. CONCLUSIONS: Patients with BPI showed weakened functional connectivity between hand grasp-related areas and the SMA and multiple regions associated with motor processing or information integration. A clear image of the functional status of the brain after deafferentation was provided. On the basis of this discovery, a relationship between changes in neuroimaging measurements and clinical outcomes can be determined in future studies. PMID- 26746338 TI - Astrocytic role in synapse formation after injury. AB - In 1969 a paper entitled Neuronal plasticity in the septal nuclei of the adult rat proposed that new synapses are formed in the adult brain after injury (Raisman, 1969). The quantitative electron microscopic study of the timed responses to selective partial denervation of the neuropil of the adult rat septal nuclei after distant transection of the hippocampal efferent axons in the fimbria showed that the new synapses arise by sprouting of surviving adjacent synapses which selectively take over the previously denervated sites and thus restore the number of synapses to normal. This article presents the evidence for the role of perisynaptic astrocytic processes in the removal and formation of synapses and considers its significance as one of the three major divisions of the astrocytic surface in terms of the axonal responses to injury and regeneration. This article is part of a Special Issue entitled SI:50th Anniversary Issue. PMID- 26746339 TI - Heterogeneous organization and function of the central noradrenergic system. PMID- 26746340 TI - Caffeine treatment aggravates secondary degeneration after spinal cord injury. AB - Spinal cord injury (SCI) often results in some form of paralysis. Recently, SCI therapy has been focused on preventing secondary injury to reduce both neuroinflammation and lesion size so that functional outcome after an SCI may be improved. Previous studies have shown that adenosine receptors (AR) are a major regulator of inflammation after an SCI. The current study was performed to examine the effect of caffeine, a pan-AR blocker, on spontaneous functional recovery after an SCI. Animals were assigned into 3 groups randomly, including sham, PBS and caffeine groups. The rat SCI was generated by an NYU impactor with a 10 g rod dropped from a 25 mm height at thoracic 9 spinal cord level. Caffeine and PBS were injected daily during the experiment period. Hind limb motor function was evaluated by the Basso, Beattie, Bresnahan (BBB) locomotor rating scale at 1 week and 4 weeks after the SCI. Spinal cord segments were collected after final behavior evaluation for morphological analysis. The tissue sparing was evaluated by luxol fast blue staining. Immunofluorescence stain was employed to assess astrocyte activation and neurofilament positioning, while microglia activation was examined by immunohistochemistry stain.The results showed that spontaneous functional recovery was blocked after the animals were subjected caffeine daily. Moreover, caffeine administration increased the demyelination area, promoted astrocyte and microglia activation and decreased the quantity of neurofilaments. These findings suggest that the neurotoxicity effect of caffeine may be associated with the inhibition of neural repair and the promotion of neuroinflammation. PMID- 26746341 TI - The GLP-1 receptor agonist liraglutide reduces pathology-specific tau phosphorylation and improves motor function in a transgenic hTauP301L mouse model of tauopathy. AB - In addition to a prominent role in glycemic control, glucagon-like peptide 1 (GLP 1) receptor agonists exhibit neuroprotective properties. There is mounting experimental evidence that GLP-1 receptor agonists, including liraglutide, may enhance synaptic plasticity, counteract cognitive deficits and ameliorate neurodegenerative features in preclinical models of Alzheimer's disease (AD), predominantly in the context of beta-amyloid toxicity. Here we characterized the effects of liraglutide in a transgenic mutant tau (hTauP301L) mouse tauopathy model, which develops age-dependent pathology-specific neuronal tau phosphorylation and neurofibrillary tangle formation with progressively compromised motor function (limb clasping). Liraglutide (500 ug/kg/day, s.c., q.d., n=18) or vehicle (n=18) was administered to hTauP301L mice for 6 months from the age of three months. Vehicle-dosed wild-type FVB/N mice served as normal control (n=17). The onset and severity of hind limb clasping was markedly different in liraglutide and vehicle-dosed transgenic mice. Clasping behavior was observed in 61% of vehicle-dosed hTauP301L mice with a 55% survival rate in 9 month old transgenic mice. In contrast, liraglutide treatment reduced the clasping rate to 39% of hTauP301L mice, and fully prevented clasping-associated lethality resulting in a survival rate of 89%. Stereological analyses demonstrated that hTauP301L mice exhibited hindbrain-dominant neuronal accumulation of phosphorylated tau closely correlated to the severity of clasping behavior. In correspondence, liraglutide treatment significantly reduced neuronal phospho-tau load by 61.9+/-10.2% (p<0.001) in hTauP301L mice, as compared to vehicle-dosed controls. In conclusion, liraglutide significantly reduced tau pathology in a transgenic mouse tauopathy model. PMID- 26746344 TI - Recent developments in agrochemistry. PMID- 26746343 TI - New hybrid molecules with anticonvulsant and antinociceptive activity derived from 3-methyl- or 3,3-dimethyl-1-[1-oxo-1-(4-phenylpiperazin-1-yl)propan-2 yl]pyrrolidine-2,5-diones. AB - The purpose of this study was to synthetize the focused library of 34 new piperazinamides of 3-methyl- and 3,3-dimethyl-(2,5-dioxopyrrolidin-1-yl)propanoic or butanoic acids as potential new hybrid anticonvulsants. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5-38 were prepared in a coupling reaction of the 3-methyl- or 3,3-dimethyl-2-(2,5-dioxopyrrolidin-1 yl)propanoic (1, 2) or butanoic acids (3, 4) with the appropriately substituted secondary amines in the presence of the N,N-carbonyldiimidazole reagent. The initial anticonvulsant screening was performed in mice (ip) using the 'classical' maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests as well as in the six-Hertz (6Hz) model of pharmacoresistant limbic seizures. The acute neurological toxicity was determined applying the chimney test. The broad spectra of activity across the preclinical seizure models in mice ip displayed compounds 7, 15, and 36. The most favorable anticonvulsant properties demonstrated 15 (ED50 MES=74.8mg/kg, ED50scPTZ=51.6mg/kg, ED50 6Hz=16.8mg/kg) which showed TD50=213.3mg/kg in the chimney test that yielded satisfying protective indexes (PI MES=2.85, PI scPTZ=4.13, PI 6Hz=12.70) at time point of 0.5h. As a result, compound 15 displayed comparable or better safety profile than clinically relevant AEDs: ethosuximide, lacosamide or valproic acid. In the in vitro assays compound 15 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and L-type calcium channels. Beyond the anticonvulsant properties, 6 compounds diminished the pain responses in the formalin model of tonic pain in mice. PMID- 26746345 TI - Synthesis, structure, and evaluation of a beta-cyclodextrin-artificial carbohydrate conjugate for use as a doxorubicin-carrying molecule. AB - This paper describes the synthesis of a beta-cyclodextrin (beta-CyD) derivative conjugated with a C,C-glucopyranoside containing a benzene unit. Its doxorubicin inclusion ability and structure are also discussed. SPR analysis revealed that the beta-CyD conjugate had a high inclusion association value of 3.8*10(6)M(-1) for immobilized doxorubicin. NMR structural analysis suggested that its high doxorubicin-inclusion ability was due to the formation of the inclusion complex as a result of the pi-pi stacking interaction between the benzene ring of the conjugate and the A ring of doxorubicin. PMID- 26746342 TI - Therapeutic hypothermia and targeted temperature management in traumatic brain injury: Clinical challenges for successful translation. AB - The use of therapeutic hypothermia (TH) and targeted temperature management (TTM) for severe traumatic brain injury (TBI) has been tested in a variety of preclinical and clinical situations. Early preclinical studies showed that mild reductions in brain temperature after moderate to severe TBI improved histopathological outcomes and reduced neurological deficits. Investigative studies have also reported that reductions in post-traumatic temperature attenuated multiple secondary injury mechanisms including excitotoxicity, free radical generation, apoptotic cell death, and inflammation. In addition, while elevations in post-traumatic temperature heightened secondary injury mechanisms, the successful implementation of TTM strategies in injured patients to reduce fever burden appear to be beneficial. While TH has been successfully tested in a number of single institutional clinical TBI studies, larger randomized multicenter trials have failed to demonstrate the benefits of therapeutic hypothermia. The use of TH and TTM for treating TBI continues to evolve and a number of factors including patient selection and the timing of the TH appear to be critical in successful trial design. Based on available data, it is apparent that TH and TTM strategies for treating severely injured patients is an important therapeutic consideration that requires more basic and clinical research. Current research involves the evaluation of alternative cooling strategies including pharmacologically-induced hypothermia and the combination of TH or TTM approaches with more selective neuroprotective or reparative treatments. This manuscript summarizes the preclinical and clinical literature emphasizing the importance of brain temperature in modifying secondary injury mechanisms and in improving traumatic outcomes in severely injured patients. This article is part of a Special Issue entitled SI:Brain injury and recovery. PMID- 26746346 TI - Ventricular septal rupture in a case of myocardial infarction with normal coronary arteries: Case report. AB - Ventricular wall rupture has become an infrequent complication of myocardial infarction due to widespread use of prompt reperfusion strategies. Patients suffering myocardial infarction with normal coronary arteries seldom develop severe mechanical complications. We present the case of a patient who developed a ventricular septal rupture following an anteroseptal myocardial infarction and who presented normal coronary arteries at the time of coronary angiography. PMID- 26746347 TI - Misleading ST-segment elevation myocardial infarction pattern in ketoacidosis. PMID- 26746355 TI - Acoustic radiation force impulse with shear wave speed quantification of pancreatic masses: A prospective study. AB - BACKGROUND: Acoustic Radiation Force Impulse (ARFI) is a new ultrasound technique that evaluates mechanical properties of tissues. To evaluate the use of ARFI with shear waves speed quantification for pancreatic masses characterization during the ultrasound examination. METHODS: 123 pancreatic lesions were prospectively evaluated. Median shear waves speeds were compared with Mann-Whitney U test. Two reading methods were applied for the characterization of adenocarcinoma: more than one measurement above the top shear waves speed (SWS) value. Two reading methods were applied to diagnose mucinous lesion: at least 2 (method 1) or 3 (method 2) numerical measurements. Sensitivity, specificity, positive and negative predictive values and accuracy of each reading method were calculated. Forty volunteers were included for normal ARFI values. RESULTS: In the adenocarcinoma group median SWS value was 2.74 m/s. In the volunteers group the median SWS value was 1.17 m/s. Significant difference between SWS median values of adenocarcinoma and normal pancreas was found (P < 0.05). For the diagnosis of pancreatic solid masses if more than one measurement is above the top SWS value of 4.00 m/s results in the study, the diagnosis of ductal adenocarcinoma is highly specific with specificity and PPV of 100%. Good sensitivity (73.3%) and specificity (83.3%) were obtained for the characterization of mucinous cystic lesions. CONCLUSIONS: Acoustic Radiation Force Impulse imaging could help in the non-invasive characterization of solid and cystic lesions of the pancreas during a conventional US examination. PMID- 26746354 TI - Higenamine protects ischemia/reperfusion induced cardiac injury and myocyte apoptosis through activation of beta2-AR/PI3K/AKT signaling pathway. AB - Cardiomyocyte apoptosis contributes to ischemic cardiac injury and the development of heart failure. Higenamine is a key component of the Chinese herb aconite root that has been prescribed for treating symptoms of heart failure for thousands of years in the oriental Asian countries. It has been shown that higenamine has anti-apoptotic effects in a few cell types including cardiomyocytes. However, the pharmacological target and molecular mechanism of higenamine in the heart are still not fully illustrated. Herein, we report that higenamine protected myocyte apoptosis and ischemia/reperfusion (I/R) injury through selective activation of beta2-adrenergic receptor (beta2-AR). In particular, we show that higenamine significantly reduced I/R-induced myocardial infarction in mice. In both primary neonatal rat and adult mouse ventricular myocytes, we show higenamine inhibited cell apoptosis and also reduced biochemical markers of apoptosis such as cleaved caspase 3 and 9. More importantly, we show that the anti-apoptotic effects of higenamine in cardiomyocytes were completely abolished by beta2-AR but not beta1-AR antagonism. Furthermore, we confirmed that higenamine attenuated I/R-induced myocardial injury and reduced cleaved caspases in a beta2-AR dependent manner in intact mouse hearts. Higenamine stimulated AKT phosphorylation and required PI3K activation for the anti-apoptotic effect in cardiomyocytes. These findings together suggest that anti-apoptotic and cardiac protective effects of higenamine are mediated by the beta2-AR/PI3K/AKT cascade. PMID- 26746356 TI - Comment on: "Fire in the vein: Heroin acidity and its proximal effect on users' health" by Ciccarone and Harris. PMID- 26746358 TI - Differential expression of six chicken genes associated with fatness traits in a divergently selected broiler population. AB - A genome-wide association study has shown a number of chicken (Gallus gallus) single nucleotide polymorphism (SNP) markers to be significantly associated with abdominal fat content in Northeast Agricultural University (NEAU) broiler lines selected divergently for abdominal fat content (NEAUHLF). The six significant SNPs are located in the kinase insert domain receptor (KDR), tumor suppressor candidate 3 (TUSC3), phosphoribosyl pyrophosphate amidotransferase (PPAT), exocyst complex component 1 (EXOC1), v-myb myeloblastosis viral oncogene homolog (avian)-like 2 (MYBL2) and KIAA1211 (undefined) genes. In this study, the expression levels of these genes were investigated in both abdominal fat and liver tissues using 32 14th generation chickens from the NEAUHLF. The levels of expression of KDR in abdominal fat and KDR and TUSC3 in liver differed significantly between the two lines. The expression level of KDR in the abdominal fat was significantly correlated with the abdominal fat weight (AFW) and abdominal fat percentage (AFP). The expression levels of KDR, TUSC3 and PPAT in liver were significantly correlated with AFW and AFP, indicating that the six genes, especially KDR and TUSC3, could be associated with fat traits in domestic chickens. This study could provide insight into the mechanisms underlying the formation of abdominal fat in chickens. PMID- 26746359 TI - Whole genome sequencing of diverse Shiga toxin-producing and non-producing Escherichia coli strains reveals a variety of virulence and novel antibiotic resistance plasmids. AB - The genomes of a diverse set of Escherichia coli, including many Shiga toxin producing strains of various serotypes were determined. A total of 39 plasmids were identified among these strains, and many carried virulence or putative virulence genes of Shiga toxin-producing E. coli strains, virulence genes for other pathogenic E. coli groups, and some had combinations of these genes. Among the novel plasmids identified were eight that carried resistance genes to aminoglycosides, carbapenems, penicillins, cephalosporins, chloramphenicol, dihydrofolate reductase inhibitors, sulfonamides, tetracyclines and resistance to heavy metals. Two of the plasmids carried six of these resistance genes and two novel IncHI2 plasmids were also identified. The results of this study showed that plasmids carrying diverse resistance and virulence genes of various pathogenic E. coli groups can be found in E. coli strains and serotypes regardless of the isolate's source and therefore, is consistent with the premise that these mobile elements carrying these traits may be broadly disseminated among E. coli. PMID- 26746368 TI - [Squamous cell carcinoma, basaloid squamous cell carcinoma and adenosquamous carcinoma in the lung]. AB - The precise distinction between adenocarcinoma and squamous cell carcinoma (SqCC) has become very important for determining the appropriate therapy for patients and more specifically to drive the use of tyrosine kinase inhibitors, pemetrexed, anti-VEGF monoclonal antibody and crizotinib. Squamous pearls and distinct intercellular bridges identify keratinizing SqCC. In non-keratinizing SqCC, immuno-histochemistry is required. Recent studies have shown p40 and TTF1 to be the two best markers of SqCC and adenocarcinoma respectively. Many morphological variants of SqCC have been described. Basaloid SqCC is a poorly differentiated epithelial tumor lacking squamous morphology but showing immuno-histochemical expression of squamous makers. The pronostic of basaloid carcinoma is considered poorer than that of other non-small cell lung cancers. Adenosquamous carcinoma shows components of both SqCC and adenocarcinoma. Both components must be clearly identified either on H&E or by immuno-histochemistry. The adenocarcinoma components justified a screening for gene rearrangements. Finally, the recent WHO classification of lung tumors did not change the criteria applying for the grading of preinvasive bronchial lesion. PMID- 26746366 TI - Squamous Cell Carcinoma "Transformation" Concurrent with Secondary T790M Mutation in Resistant EGFR-Mutated Adenocarcinomas. AB - The authors report two cases of epidermal growth factor receptor gene (EGFR) mutant stage IV lung adenocarcinomas developing immunohistochemically proven squamous cell carcinoma (SCC) "transformation" concurrently with T790M EGFR mutation, leading to acquired resistance to EGFR inhibitors. Moreover, the histologic change of EGFR-mutant lung adenocarcinoma into SCC has been recently reported in literature. The histological transformation to SCC appears as a novel mechanism of acquired EGFR TKI resistance in EGFR-mutated adenocarcinomas and it may be challenging for treatment. PMID- 26746367 TI - Incidence of Brain Metastasis at the Initial Diagnosis of Lung Squamous Cell Carcinoma on the Basis of Stage, Excluding Brain Metastasis. AB - INTRODUCTION: Current National Comprehensive Cancer Network guidelines recommend routine brain magnetic resonance imaging (MRI) screening in patients with stage II to IV non-small cell carcinoma, regardless of histological subtype. This recommendation might not be universally applicable, however, because brain metastasis (BM) is seen less frequently in patients with lung squamous cell carcinoma (SCC) than in those with a histological diagnosis of nonsquamous cell carcinoma. METHODS: The cases of 564 patients with lung SCC in our institution between January 2012 and December 2013 were reviewed prospectively for comprehensive staging. All subjects' lung SCC, but not their BM, was staged on the basis of the seventh edition of the guidelines of the American Joint Committee on Cancer. We evaluated the incidence of BM across the stages and clinical factors associated with BM. RESULTS: Of the 564 patients, 28 (5.0%) had BM. BM did not occur in patients with stage Ia or Ib disease; however, it increased significantly as the disease progressed from stage IIa to IV (p < 0.001, trend test). Multivariate analysis showed that tumor involvement in N3 lymph nodes and distant metastasis other than BM (M1b) was independently associated with the development of BM. CONCLUSIONS: Routine brain MRI screening in patients with lung SCC in stage II to IV can help to evaluate asymptomatic BM. By contrast, we did not find any evidence supporting routine brain MRI screening in patients with stage I disease. PMID- 26746369 TI - [Why proposing a new histomolecular classification of lung cancers in 2015?]. PMID- 26746370 TI - [Cardiovascular involvement in Loeys-Dietz syndrome]. PMID- 26746357 TI - Calcium regulation of HCN channels supports persistent activity in a multiscale model of neocortex. AB - Neuronal persistent activity has been primarily assessed in terms of electrical mechanisms, without attention to the complex array of molecular events that also control cell excitability. We developed a multiscale neocortical model proceeding from the molecular to the network level to assess the contributions of calcium (Ca(2+)) regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in providing additional and complementary support of continuing activation in the network. The network contained 776 compartmental neurons arranged in the cortical layers, connected using synapses containing AMPA/NMDA/GABAA/GABAB receptors. Metabotropic glutamate receptors (mGluR) produced inositol triphosphate (IP3) which caused the release of Ca(2+) from endoplasmic reticulum (ER) stores, with reuptake by sarco/ER Ca(2+)-ATP-ase pumps (SERCA), and influence on HCN channels. Stimulus-induced depolarization led to Ca(2+) influx via NMDA and voltage-gated Ca(2+) channels (VGCCs). After a delay, mGluR activation led to ER Ca(2+) release via IP3 receptors. These factors increased HCN channel conductance and produced firing lasting for ~1min. The model displayed inter-scale synergies among synaptic weights, excitation/inhibition balance, firing rates, membrane depolarization, Ca(2+) levels, regulation of HCN channels, and induction of persistent activity. The interaction between inhibition and Ca(2+) at the HCN channel nexus determined a limited range of inhibition strengths for which intracellular Ca(2+) could prepare population-specific persistent activity. Interactions between metabotropic and ionotropic inputs to the neuron demonstrated how multiple pathways could contribute in a complementary manner to persistent activity. Such redundancy and complementarity via multiple pathways is a critical feature of biological systems. Mediation of activation at different time scales, and through different pathways, would be expected to protect against disruption, in this case providing stability for persistent activity. PMID- 26746372 TI - Does What Happens During Sleep Matter for the Failing Heart? PMID- 26746371 TI - Influenza Vaccination in Patients With Chronic Heart Failure: The PARADIGM-HF Trial. AB - OBJECTIVES: This study sought to examine the prevalence and predictors of influenza vaccination among participants in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) study and investigate associations between receiving influenza vaccine and cardiovascular death or heart failure hospitalizations, all cause hospitalizations, and cardiopulmonary or influenza-related hospitalizations. BACKGROUND: Influenza is associated with an increased risk for cardiovascular events in patients with heart failure. METHODS: We used data from the PARADIGM-HF trial in which patients with heart failure were randomized to the angiotensin receptor neprilysin inhibitor LCZ696 (sacubitril/valsartan) or enalapril. We assessed predictors of receiving influenza vaccination, and examined the relationship between influenza vaccination and outcomes in a propensity-adjusted model. RESULTS: Of 8,099 study participants, 1,769 (21%) received influenza vaccination. We observed significant regional variation in vaccination rates, with highest rates in the Netherlands (77.5%), Great Britain (77.2%), and Belgium (67.5%), and lowest rates in Asia (2.6%), with intermediate rates in North America (52.8%). Top predictors of vaccination included enrolling country, white race, implanted defibrillator, older age, lower New York Heart Association functional class, lower heart rate, and a history of diabetes mellitus. Influenza vaccination was associated with a reduced risk for all-cause mortality in propensity-adjusted (hazard ratio: 0.81; 95% confidence interval: 0.67 to 0.97; p = 0.015) models. CONCLUSIONS: Influenza vaccination rates varied widely in patients with heart failure with reduced ejection fraction enrolled in the PARADIGM-HF trial, and vaccination was associated with reduced risk for death, although whether this association was causal cannot be determined. PMID- 26746373 TI - Spinal Cord Stimulation for Heart Failure in the DEFEAT-HF Study: Lost Battle or Lasting Opportunities? PMID- 26746374 TI - What Medicare Knows About the Takotsubo Cardiomyopathy. PMID- 26746375 TI - The "Obesity Paradox" Is Not a Paradox: Time to Focus on Effective Treatments. PMID- 26746376 TI - Worsening Renal Function in Acute Decompensated Heart Failure: The Puzzle is Still Incomplete. PMID- 26746378 TI - Hemodynamic Ramp Tests in Patients With Left Ventricular Assist Devices. AB - OBJECTIVES: This study tested whether combined invasive hemodynamic and echocardiographic ramp tests can help optimize patient management. BACKGROUND: Guidelines for optimizing speed and medications in continuous flow ventricular assist device (cfLVAD) patients are mainly based on expert opinion. METHODS: Thirty-five cfLVAD patients (21 HeartMate II [Thoratec, Pleasanton, California] and 14 HVAD [HeartWare International, Framingham, Massachusetts]) underwent ramp tests with right heart catheterization (including central venous pressure [CVP], pulmonary artery pressure, pulmonary capillary wedge pressure [PCWP], and blood pressure) and echocardiography. Data were recorded at up to 9 speed settings. Speed changes were in steps of 400 revolutions per minute (RPM) for HeartMate II (8,000 to 12,000 RPM) and 100 RPM for HVAD (2,300 to 3,200 RPM) patients. RESULTS: Only 42.9% of patients had normal CVPs and PCWPs at their original RPM settings. Going from lowest to highest speeds, cardiac output improved by 0.16 +/ 0.19 l/min/step (total change 1.28 +/- 1.41 l/min) and PCWP decreased by 1.23 +/ 0.85 mm Hg/step (total change 9.9 +/- 6.5 mm Hg). CVP and systolic blood pressure did not change significantly with RPM. RPM were adjusted based on test results to achieve CVPs and PCWPs as close to normal limits as possible, which was feasible in 56% of patients. For the remainder, results indicated which type of medical management should be pursued. CONCLUSIONS: Use of combined hemodynamic and echocardiographic ramp tests in patients provides objective means of optimizing RPM, and has the potential to guide medical management. It remains to be tested whether this strategy has a beneficial impact on quality of life or clinical outcomes. PMID- 26746379 TI - Reduced resilience of a globally distributed coccolithophore to ocean acidification: Confirmed up to 2000 generations. AB - Ocean acidification (OA), induced by rapid anthropogenic CO2 rise and its dissolution in seawater, is known to have consequences for marine organisms. However, knowledge on the evolutionary responses of phytoplankton to OA has been poorly studied. Here we examined the coccolithophore Gephyrocapsa oceanica, while growing it for 2000 generations under ambient and elevated CO2 levels. While OA stimulated growth in the earlier selection period (from generations ~700 to ~1550), it reduced it in the later selection period up to 2000 generations. Similarly, stimulated production of particulate organic carbon and nitrogen reduced with increasing selection period and decreased under OA up to 2000 generations. The specific adaptation of growth to OA disappeared in generations 1700 to 2000 when compared with that at 1000 generations. Both phenotypic plasticity and fitness decreased within selection time, suggesting that the species' resilience to OA decreased after 2000 generations under high CO2 selection. PMID- 26746377 TI - Trends in Short- and Long-Term Outcomes for Takotsubo Cardiomyopathy Among Medicare Fee-for-Service Beneficiaries, 2007 to 2012. AB - OBJECTIVES: The aim of this study was to assess trends in hospitalizations and outcomes for Takotsubo cardiomyopathy (TTC). BACKGROUND: There is a paucity of nationally representative data on trends in short- and long-term outcomes for patients with TTC. METHODS: The authors examined hospitalization rates; in hospital, 30-day, and 1-year mortality; and all-cause 30-day readmission for Medicare fee-for-service beneficiaries with principal and secondary diagnoses of TTC from 2007 to 2012. RESULTS: Hospitalizations for principal or secondary diagnosis of TTC increased from 5.7 per 100,000 person-years in 2007 to 17.4 in 2012 (p for trend < 0.001). Patients were predominantly women and of white race. For principal TTC, in-hospital, 30-day, and 1-year mortality was 1.3% (95% confidence interval [CI]: 1.1% to 1.6%), 2.5% (95% CI: 2.2% to 2.8%), and 6.9% (95% CI: 6.4% to 7.5%), and the 30-day readmission rate was 11.6% (95% CI: 10.9% to 12.3%). For secondary TTC, in-hospital, 30-day, and 1-year mortality was 3% (95% CI: 2.7% to 3.3%), 4.7% (95% CI: 4.4% to 5.1%), and 11.4% (95% CI: 10.8% to 11.9%), and the 30-day readmission rate was 15.8% (95% CI: 15.1% to 16.4%). Over time, there was no change in mortality or readmission rate for both cohorts. Patients >=85 years of age had higher in-hospital, 30-day, and 1-year mortality and 30-day readmission rates. Among patients with principal TTC, male and nonwhite patients had higher 1-year mortality than their counterparts, whereas in those with secondary TTC, mortality was worse at all 3 time points. Nonwhite patients had higher 30-day readmission rates for both cohorts. CONCLUSIONS: Hospitalization rates for TTC are increasing, but short- and long-term outcomes have not changed. At 1 year, 14 in 15 patients with principal TTC and 8 in 9 with secondary TTC are alive. Older, male, and nonwhite patients have worse outcomes. PMID- 26746381 TI - Reliability of Abdominal Muscle Stiffness Measured Using Elastography during Trunk Rehabilitation Exercises. AB - The aim of this study was to assess the intra-session and inter-rater reliability of shear modulus measured in abdominal muscles during two commonly used trunk stability exercises. Thirty healthy volunteers performed a series of abdominal hollow and abdominal brace tasks. Supersonic shear imaging was used to measure the shear modulus (considered an index of muscle tension) of the four anterior trunk muscles: obliquus externus abdominis, obliquus internus abdominis, transversus abdominis and rectus abdominis. Because of measurement artifacts, internus abdominis and transversus abdominis data were not analyzed for 36.7% and 26.7% of the participants, respectively. These participants exhibited thicker superficial fat layers than the others. For the remaining participants, fair to excellent intra-session and inter-rater reliability was observed with moderate to high intra-class coefficients (0.45-0.97) and low to moderate standard error of measurement values (0.38-3.53 kPa). Reliability values were consistently greater for superficial than for deeper muscles. PMID- 26746380 TI - Loss and self-restoration of macrobenthic diversity in reclamation habitats of estuarine islands in Yangtze Estuary, China. AB - In this study, macrobenthic diversity data were collected from intertidal habitats of island wetlands in Yangtze Estuary before and after reclamation. Three survey regions based on habitat features were investigated: protected region, normal region, and self-restored region. The pattern of diversity variation showed a sharp decrease in reclamation sites and an obvious increase in vegetated sites of the self-restored region before and after reclamation. A declining trend in habitat health was observed in reclamation sites, but the degree of perturbation was relatively weaker in protected region than in normal region. The vegetated site showed a better self-restoration of biodiversity than the bald site. These results suggest that reclamation may have a negative influence on biodiversity and habitat health status in the intertidal wetland. Also, there is a possibility of self-restoration in tidal flats disturbed by reclamation and the resistance effect in nature reserve may reduce the disturbances resulting from reclamation. PMID- 26746382 TI - Supersonic Shear Wave Elastography of Response to Anti-cancer Therapy in a Xenograft Tumor Model. AB - Our objective was to determine if supersonic shear wave elastography (SSWE) can detect changes in stiffness of a breast cancer model under therapy. A human invasive carcinoma was implanted in 22 mice. Eleven were treated with an anti angiogenic therapy and 11 with glucose for 24 d. Tumor volume and stiffness were assessed during 2 wk before treatment and 0, 7, 12, 20 and 24 d after the start of therapy using SSWE. Pathology was assessed after 12 and 24 d of treatment. We found that response to therapy was associated with early softening of treated tumors only, resulting in a significant difference from non-treated tumors after 12 d of treatment (p = 0.03). On pathology, large areas of necrosis were observed at 12 d in treated tumors. Although treatment was still effective, treated tumors subsequently stiffened during a second phase of the treatment (days 12-24), with a small amount of necrosis observed on pathology on day 24. In conclusion, SSWE was able to measure changes in the stiffness of tumors in response to anti-cancer treatment. However, stiffness changes associated with good response to treatment may change over time, and increased stiffness may also reflect therapy efficacy. PMID- 26746384 TI - The role of NIV in chronic hypercapnic COPD following an acute exacerbation: the importance of patient selection? AB - Recently, clear benefits have been shown from long-term noninvasive ventilation (NIV) in stable chronic obstructive pulmonary disease (COPD) patients with chronic hypercapnic respiratory failure. In our opinion, these benefits are confirmed and nocturnal NIV using sufficiently high inspiratory pressures should be considered in COPD patients with chronic hypercapnic respiratory failure in stable disease, preferably combined with pulmonary rehabilitation. In contrast, clear benefits from (continuing) NIV at home after an exacerbation in patients who remain hypercapnic have not been shown. In this review we will discuss the results of five trials investigating the use of home nocturnal NIV in patients with prolonged hypercapnia after a COPD exacerbation with acute hypercapnic respiratory failure. Although some uncontrolled trials might have shown some benefits of this therapy, the largest randomized controlled trial did not show benefits in terms of hospital readmission or death. However, further studies are necessary to select the patients that optimally benefit, select the right moment to initiate home NIV, select the optimal ventilatory settings, and to choose optimal follow up programmes. Furthermore, there is insufficient knowledge about the optimal ventilatory settings in the post-exacerbation period. Finally, we are not well informed about exact reasons for readmission in patients on NIV, the course of the exacerbation and the treatment instituted. A careful follow up might probably be necessary to prevent deterioration on NIV early. PMID- 26746385 TI - Functional expression of choline transporter like-protein 1 (CTL1) and CTL2 in human brain microvascular endothelial cells. AB - In this study, we examined the molecular and functional characterization of choline transporter in human brain microvascular endothelial cells (hBMECs). Choline uptake into hBMECs was a saturable process that was mediated by a Na(+) independent, membrane potential and pH-dependent transport system. The cells have two different [(3)H]choline transport systems with Km values of 35.0 +/- 4.9 MUM and 54.1 +/- 8.1 MUM, respectively. Choline uptake was inhibited by choline, acetylcholine (ACh) and the choline analog hemicholinium-3 (HC-3). Various organic cations also interacted with the choline transport system. Choline transporter-like protein 1 (CTL1) and CTL2 mRNA were highly expressed, while mRNA for high-affinity choline transporter 1 (CHT1) and organic cation transporters (OCTs) were not expressed in hBMECs. CTL1 and CTL2 proteins were localized to brain microvascular endothelial cells in human brain cortical sections. Both CTL1 and CTL2 proteins were expressed on the plasma membrane and mitochondria. CTL1 and CTL2 proteins are mainly expressed in plasma membrane and mitochondria, respectively. We conclude that choline is mainly transported via an intermediate affinity choline transport system, CTL1 and CTL2, in hBMECs. These transporters are responsible for the uptake of extracellular choline and organic cations. CTL2 participate in choline transport mainly in mitochondria, and may be the major site for the control of choline oxidation. PMID- 26746383 TI - Comparative efficacy of fixed-dose combinations of long-acting muscarinic antagonists and long-acting beta2-agonists: a systematic review and network meta analysis. AB - BACKGROUND: A number of long-acting muscarinic antagonist (LAMA)/long-acting beta2-agonist (LABA) fixed-dose combinations (FDCs) for treatment of moderate-to very severe chronic obstructive pulmonary disease (COPD) have recently become available, but none have been directly compared in head-to-head randomized controlled trials (RCTs). The purpose of this study was to assess the relative clinical benefit of all currently available LAMA/LABA FDCs using a Bayesian network meta-analysis (NMA). METHODS: A systematic literature review identified RCTs investigating the efficacy, safety and quality of life associated with licensed LAMA/LABA FDCs for the treatment of moderate-to-very severe COPD. RCTs were screened for inclusion in the NMA using prespecified eligibility criteria. Data were extracted for outcomes of interest, including change in trough forced expiratory volume in 1 second (tFEV1) from baseline, St. George Respiratory Questionnaire (SGRQ) percentage of responders, Transition Dyspnea Index (TDI) percentage of responders, change in SGRQ score from baseline, change in TDI focal score from baseline, moderate-to-severe exacerbations, all-cause discontinuation, and discontinuation due to adverse events. RESULTS: Following screening, a total of 27 trials from 26 publications with 30,361 subjects were eligible for inclusion in the NMA. Nonsignificant results were seen in most analyses comparing efficacy, exacerbations and discontinuation rates of included LAMA/LABA FDCs (i.e. aclidinium/formoterol 400/12 ug, glycopyrronium/indacaterol 110/50 ug, tiotropium + olodaterol 5/5 ug, umeclidinium/vilanterol 62.5/25 ug). Meta regression controlling for post-bronchodilator percentage of tFEV1 predicted at baseline as well as meta-regression adjusting for concomitant use of inhaled corticosteroids at baseline was performed to assess the magnitude of effect modification and produced similar results as observed in the base case analysis. CONCLUSION: All LAMA/LABA FDCs were found to have similar efficacy and safety. Definitive assessment of the relative efficacy of different treatments can only be performed through direct comparison in head-to-head RCTs. In the absence of such data, this indirect comparison may be of value in clinical and health economic decision-making. PMID- 26746386 TI - Brain cholinergic alterations in rats subjected to repeated immobilization or forced swim stress on lambda-cyhalothrin exposure. AB - Role of immobilization stress (IMS), a psychological stressor and forced swim stress (FSS), a physical stressor was investigated on the neurobehavioral toxicity of lambda-cyhalothrin (LCT), a new generation type-II synthetic pyrethroid. Pre-exposure of rats to IMS (15 min/day) or FSS (3 min/day) for 28 days on LCT (3.0 mg/kg body weight, p.o.) treatment for 3 days resulted to decrease spatial learning and memory and muscle strength associated with cholinergic-muscarinic receptors in frontal cortex and hippocampus as compared to those exposed to IMS or FSS or LCT alone. Decrease in acetylcholinesterase activity, protein expression of ChAT and PKC-beta1 associated with decreased mRNA expression of CHRM2, AChE and ChAT in frontal cortex and hippocampus was also evident in rats pre-exposed to IMS or FSS on LCT treatment, compared to rats exposed to IMS or FSS or LCT alone. Interestingly, changes both in behavioral and neurochemical endpoints were marginal in rats subjected to IMS or FSS for 28 days or those exposed to LCT for 3 days alone, compared to controls. The results suggest that stress is an important contributor in LCT induced cholinergic deficits. PMID- 26746387 TI - Survival of the ovine footrot pathogen Dichelobacter nodosus in different soils. AB - Dichelobacter nodosus (D. nodosus) is the causative agent of footrot in sheep; one of the most important health and welfare issues of sheep worldwide. For control programmes to be effective, it is essential that the transmission cycle of D. nodosus is understood and bacterial reservoirs in the environment are better defined. This study evaluated the survival of D. nodosus in different soils using soil microcosms. Cultivation independent and dependent methods were used to detect D. nodosus over 40 days from seeding in soil. A D. nodosus specific probe was used for quantification by qPCR and viability was assessed by cell permeability to an intercalating dye, PMA, and by culture. Survival varied dramatically depending on soil type, matric potential (MP) and temperature. Our findings indicate that D. nodosus survival was higher at 5 degrees C compared with 25 degrees C in all soils and significantly longer at both temperatures in clay soil (>44% clay) compared with other soil types. Survival under all conditions was longer than 30 days for both culture independent and dependent methods, this is substantially longer than previous studies and, if this is an infectious dose, longer than the current recommendation of resting a field for 14 days to prevent onward infection. PMID- 26746388 TI - Analyzing fractal property of species abundance distribution and diversity indexes. AB - Community diversity is usually characterized by numerical indexes; however it indeed depends on the species abundance distribution (SAD). Diversity indexes and SAD are based on the same information but treating as separate themes. Ranking species abundance from largest to smallest, the decreasing pattern can give the information about the SAD. Frontier proposed such SAD might be a fractal structure, and first applied the Zipf-Mandelbrot model to the SAD study. However, this model fails to include the Zipf model, and also fails to ensure an integer rank. In this study, a fractal model of SAD was reconstructed, and tested with 104 community samples from 8 taxonomic groups. The results show that there was a good fit of the presented model. Fractal parameter (p) determines the SAD of a community. The ecological significance of p relates to the "dominance" of a community. The correlation between p and classical diversity indexes show that Shannon index decreases and Simpson index increases as p increases. The main purpose of this paper is not to compare with other SADs models; it simply provides a new interpretation of SAD model construction, and preliminarily integrates diversity indexes and SAD model into a broader perspective of community diversity. PMID- 26746390 TI - Foreword. PMID- 26746391 TI - Chapter 5: Evaluation and treatment of kidney transplant bone disease. PMID- 26746392 TI - Chapter 6: Summary and research recommendations. PMID- 26746389 TI - Eel green fluorescent protein is associated with resistance to oxidative stress. AB - Green fluorescent protein (GFP) from eel (Anguilla japonica) muscle (eelGFP) is unique in the vertebrates and requires bilirubin as a ligand to emit fluorescence. This study was performed to clarify the physiological function of the unique GFP. Investigation of susceptibility to oxidative stress was carried out using three types of cell lines including jellyfish (Aequorea coerulescens) GFP (jfGFP)-, or eel GFP (eelGFP)-expressing HEK293 cells, and control vector transfected HEK293 cells. Binding of eelGFP to bilirubin was confirmed by the observation of green fluorescence in HEK293-eelGFP cells. The growth rate was compared with the three types of cells in the presence or absence of phenol red which possessed antioxidant activity. The growth rates of HEK293-CV and HEK293 jfGFP under phenol red-free conditions were reduced to 52 and 31% of those under phenol red. Under the phenol red-free condition, HEK293-eelGFP had a growth rate of approximately 70% of the phenol red-containing condition. The eelGFP expressing cells were approximately 2-fold resistant to oxidative stress such as H2O2 exposure. The fluorescence intensity partially decreased or disappeared after exposure to H2O2, and heterogeneous intensity of fluorescence was also observed in isolated eel skeletal muscle cells. These results suggested eelGFP, but not jfGFP, coupled with bilirubin provided the antioxidant activity to the cells as compared to non-bound free bilirubin. PMID- 26746393 TI - Biographic and disclosure information. PMID- 26746395 TI - Chapter 3.1: Diagnosis of CKD-MBD: biochemical abnormalities. PMID- 26746396 TI - Chapter 1: Introduction and definition of CKD-MBD and the development of the guideline statements. PMID- 26746397 TI - Chapter 4.1: Treatment of CKD-MBD targeted at lowering high serum phosphorus and maintaining serum calcium. PMID- 26746398 TI - Chapter 2: Methodological approach. PMID- 26746400 TI - Pillow height for i-gel((r)) insertion: a randomized clinical trial. PMID- 26746399 TI - Ischaemic and inflammatory injury in renal graft from brain death donation: an update review. AB - Renal transplantation remains an important therapy in treating renal failure and can be considered to be a curative treatment. The demand for renal grafts outstrips supply available each year, making it increasingly important to look at improving the treatment of both renal grafts and recipients, and thereby improving patient outcomes and increasing the pool of potential donor grafts. Important to this, however, is knowledge of the underlying mechanisms leading to damage to the graft and rejection from the recipient. This includes ischaemia and consequently the priming of the organ during storage for ischaemia reperfusion injury (IRI) on implantation and the importance of the innate immune system which can be activated via multiple pathways, often via TLR-4, and the consequent production of danger-associated molecular patterns. This makes the time period involving both explantation and storage an important therapeutic window for improving outcomes. Other windows explored include treatment of IRI and improvement in immunosuppressive therapy. The multiple windows of potential therapeutic input have spawned a large body of work exploring both the underlying mechanisms and also how to exploit these mechanisms to improve overall outcomes and to allow for more marginal organs to be used. PMID- 26746402 TI - Characterization of pH-fractionated humic acids with respect to their dissociation behaviour. AB - Humic acids were divided into several fractions using buffer solutions as extraction agents with different pH values. Two methods of fractionation were used. The first one was subsequent dissolution of bulk humic acids in buffers adjusted to different pH. The second one was sequential dissolution in buffers with increasing pH values. Experimental data were compared with hypothesis of partial solubility of humic acids in aqueous solutions. Behaviour of humic fractions obtained by sequential dissolution, original bulk sample and residual fractions obtained by subsequent dissolution at pH 10 and 12 agrees with the hypothesis. Results demonstrated that regardless the common mechanism, solubility and dissociation degree of various humic fractions may be very different and can be estimated using parameters of the model based on the proposed mechanism. Presented results suggest that dissolving of solid humic acids in water environment is more complex than conventional solubility behaviour of sparingly soluble solids. PMID- 26746401 TI - Impact of the biocide Irgarol on meiofauna and prokaryotes from the sediments of the Bizerte lagoon-an experimental study. AB - The biocide Irgarol 1051 has been reported to have negative effects on a large number of living components including non-target organisms, but information on its impact on the marine meiofauna and benthic prokaryotes is completely lacking. Here, we report the results of long-term experimental studies in which we determined the effects of increasing Irgarol concentrations (from 11.5 to 315 ng g(-1) sediment dry weight) on meiofauna and benthic prokaryotes. We found that this biocide had a significant impact on meiofauna abundance, even at the lowest concentrations, causing a drastic decline in the abundance of nematodes (the dominant meiofaunal taxon) and an increase of the relative importance of oligochaetes. Even if no direct effects of Irgarol were found on prokaryotic abundance and biomass, the molecular fingerprinting analyses (automated ribosomal intergenic spacer analysis) showed that the prokaryotic diversity was significantly altered by the biocide. The results of the present study indicate that Irgarol 1051 in marine sediments has a significant impact on the smallest eukaryotic and microbial components also at very low concentrations (ca 12 ng g( 1)). PMID- 26746404 TI - Turner Syndrome and Celiac Disease: A Case-Control Study. AB - OBJECTIVE: Turner syndrome (TS) is the most common sex chromosome abnormality in females. Previous research has indicated a high prevalence of celiac disease (CD) in TS, but data have mostly been limited to case series at tertiary centers. We aimed to examine the risk for CD in individuals with TS compared with the general population. METHODS: This Swedish nationwide case-control study included individuals with CD and controls born in 1973-2006. The study consisted of 2 groups: (1) 7548 females with biopsy-verified CD (villous atrophy; Marsh stage 3) diagnosed until January 2008 according to histopathology report data from all 28 Swedish pathology departments and (2) 34 492 population-based controls matched by gender, age, calendar year of birth, and county of residence. TS, diagnosed by the end of 2009, was identified using prospectively recorded data from 3 nationwide health registries. Odds ratios (ORs) for CD were calculated using conditional logistic regression. RESULTS: Of the 7548 females with CD, 20 had a diagnosis of TS (0.26%) compared with 21 of 34 492 controls (0.06%), corresponding to an OR of 3.29 (95% confidence interval [CI] 1.94-5.56) for CD in individuals with TS. The risk of CD in females with TS ranged from twofold (OR 2.16; 95% CI 0.91-5.11) in the first 5 years of life to a more than fivefold increase in females aged >10 years at CD diagnosis (OR 5.50; 95% CI 1.53-19.78). The association between TS and CD was largely unaffected by concurrent type 1 diabetes. CONCLUSIONS: Females with TS are more likely to develop CD. This study supports active case-finding for CD in TS. PMID- 26746403 TI - [Methods for measuring skin aging]. AB - Aging affects human skin and is becoming increasingly important with regard to medical, social and aesthetic issues. Detection of intrinsic and extrinsic components of skin aging requires reliable measurement methods. Modern techniques, e.g., based on direct imaging, spectroscopy or skin physiological measurements, provide a broad spectrum of parameters for different applications. PMID- 26746406 TI - Hyperthyroidism Presenting With Pathologic Fractures. AB - Previous studies have shown that thyroid hormone directly stimulates bone resorption in in vitro organ culture, and in adults excess thyroid hormone is associated with decreased bone mineral density. There are limited data in children regarding the effect of hyperthyroidism on bone metabolism and even fewer instances in the literature of hyperthyroidism presenting with bone demineralization and fracture. We report a case of an 11-year-old boy with undiagnosed hyperthyroidism presenting with fractures and osteoporosis. This case emphasizes the importance of maintaining a broad differential diagnosis when a patient presents with a pathologic fracture. PMID- 26746405 TI - Incidence of Concussion in Youth Ice Hockey Players. AB - BACKGROUND: Ice hockey is a fast-paced collision sport that entails both intentional (ie, body checking) and incidental contact that may involve the head. The objective of this study was to determine the incidence of concussions in relation to games/practices and age among competition-level youth ice hockey players (ages 12-18 years). METHODS: Participants included 397 youth ice hockey players from Western Pennsylvania; Boston, Massachusetts; and Birmingham, Alabama, during the 2012-2013 and 2013-2014 youth ice hockey seasons. Incidence rates (IRs) and incidence rate ratios (IRRs) of concussion were calculated for games/practices and age groups. RESULTS: A total of 23 369 (12 784 practice/10 585 game) athletic exposures (AEs) involving 37 medically diagnosed concussions occurred. More than 40% of concussions involved illegal contact. The combined IR for games and practices was 1.58 concussions per 1000 AEs. The IRR was 2.86 times (95% confidence interval 0.68-4.42) higher during games (2.49 per 1000 AEs) than practices (1.04 per 1000 AEs). CONCLUSIONS: The overall IR for concussion in youth ice hockey was comparable to those reported in other youth collision sports. The game-to-practice IRR was lower than previously reported in ice hockey and other youth sports, although more concussions per exposure occurred in games compared with practices. Younger players had a higher rate of concussions than older players. PMID- 26746409 TI - Adopting 'ng/L' as the units for high-sensitivity cardiac troponin assays and commitment by the entire health-care team could be the key for adopting recommendations. PMID- 26746408 TI - Vagal Nerve Stimulation Evoked Heart Rate Changes and Protection from Cardiac Remodeling. AB - This study investigated whether vagal nerve stimulation (VNS) leads to improvements in ischemic heart failure via heart rate modulation. At 7 +/- 1 days post left anterior descending artery (LAD) ligation, 63 rats with myocardial infarctions (MI) were implanted with ECG transmitters and VNS devices (MI + VNS, N = 44) or just ECG transmitters (MI, N = 17). VNS stimulation was active from 14 +/- 1 days to 8 +/- 1 weeks post MI. The average left ventricular (LV) end diastolic volumes at 8 +/- 1 weeks were MI = 672.40 MUl and MI + VNS = 519.35 MUl, p = 0.03. The average heart weights, normalized to body weight (+/- std) at 14 +/- 1 weeks were MI = 3.2 +/- 0.6 g*kg(-1) and MI + VNS = 2.9 +/- 0.3 g*kg( 1), p = 0.03. The degree of cardiac remodeling was correlated with the magnitude of acute VNS-evoked heart rate (HR) changes. Further research is required to determine if the acute heart rate response to VNS activation is useful as a heart failure biomarker or as a tool for VNS therapy characterization. PMID- 26746410 TI - Clinical need-directed blood tests: a step in saving the NHS? AB - BACKGROUND: Unnecessary blood tests are estimated to contribute to 25% of wastage in the National Health Service. The aim of this study was to assess the financial implication of clinical need-focused blood tests guided by a senior clinician in a district general hospital. METHODS: We conducted an observational longitudinal study over six months with pre- and postanalysis of a vetting intervention. A colorectal firm (Team A) implemented a vetting system that required a registrar or consultant to discuss which blood tests needed to be requested for each in patient with junior doctors. Another colorectal firm (Team B) with a similar caseload was blinded to the study and was used as a control. RESULTS: The vetting initiative demonstrated a reduction of 33% of blood test requests, translating to a cost-saving of L2406 over three months. Following the intervention, the median number of tests requested per patient per day by Team A for C-reactive protein reduced from 0.8 to 0.63 (P = 0.0074), full blood counts reduced from 0.8 to 0.67 (P = 0.0138), liver function tests decreased from 0.8 to 0.6 (P = 0.0021) and urea and electrolytes fell from 0.8 to 0.63 (P = 0.0083). The number of tests per patient per day after the intervention was significantly less than the control group (P < 0.001). The length of hospital stay and admission to critical care were not adversely affected in the group that had less blood tests, P = 0.808 and P = 0.58, respectively. CONCLUSION: The direction, by a senior clinician, of the requesting of blood tests by junior doctors to ensure that requests were based on clinical need, reduced the number of inappropriate blood tests and resulted in some reduction in laboratory costs. PMID- 26746407 TI - Metabolic Diseases Downregulate the Majority of Histone Modification Enzymes, Making a Few Upregulated Enzymes Novel Therapeutic Targets--"Sand Out and Gold Stays". AB - To determine whether the expression of histone modification enzymes is regulated in physiological and pathological conditions, we took an experimental database mining approach pioneered in our labs to determine a panoramic expression profile of 164 enzymes in 19 human and 17 murine tissues. We have made the following significant findings: (1) Histone enzymes are differentially expressed in cardiovascular, immune, and other tissues; (2) our new pyramid model showed that heart and T cells are among a few tissues in which histone acetylation/deacetylation, and histone methylation/demethylation are in the highest varieties; and (3) histone enzymes are more downregulated than upregulated in metabolic diseases and regulatory T cell (Treg) polarization/ differentiation, but not in tumors. These results have demonstrated a new working model of "Sand out and Gold stays," where more downregulation than upregulation of histone enzymes in metabolic diseases makes a few upregulated enzymes the potential novel therapeutic targets in metabolic diseases and Treg activity. PMID- 26746413 TI - Update on bedside ultrasound diagnosis of pericardial effusion. AB - Pericardial effusion (PE) is the presence of an excess of fluid in the pericardial cavity. PE symptoms depend from the rate of fluid accumulation, ranging from mild dyspnea on exertion to shock due to cardiac tamponade. Echocardiography is usually the primary diagnostic tool when PE is suspected, as it is accurate, non-invasive, widely available, and feasible also with pocket size devices. Studies have shown a high degree of sensitivity and specificity in the detection of PE using focused cardiac ultrasound (FOCUS), which can be performed also by non-cardiologist in emergency setting or at bedside. A PE is visualized as an echo-free space between the heart and the parietal layer of the pericardium. A semi-quantification of the PE may be obtained measuring the distance between the two pericardial layers. Once PE diagnosis has been made, characterization of fluid and search for signs of possible cardiac tamponade have to be performed. While unechogenic space is usually associated with serous fluid, hemorrhagic, and purulent effusions may be suspected in the presence of corpuscolated/echogenic fluid. Echocardiography may identify cardiac tamponade before it is clinically evident, and can guide pericardiocentesis. B-mode echocardiographic signs of cardiac tamponade include cardiac chambers collapse (with right chambers collapse occurring at earlier stages), opposite changes in right and left cardiac chamber filling during respiratory cycle, inferior vena cava and hepatic vein plethora. Doppler analysis of tricuspidalic and mitral flow velocities are used for a more detailed analysis of ventricular interdependence, even though more advanced operator expertise is required. PMID- 26746411 TI - [Mesenchymal tumors of the urinary bladder]. AB - Mesenchymal tumors and tumor-like lesions of the urinary bladder are rare. They encompass a heterogeneous group of reactive pseudosarcomatous tumor-like changes and benign neoplastic lesions as well as malignant neoplasms (sarcomas) with variable biological behavior. The well-known differential diagnostic difficulties related to these conditions are mainly due to their rarity and thus limited experience and familiarity with their histological features and due to the significant morphological overlap between fully benign reactive conditions and aggressive malignant neoplasms. The distinction between them may on occasion represent a real challenge and is associated with several pitfalls. This overview summarizes the clinicopathological and differential diagnostic aspects of the most important lesions and discuss their differential diagnosis in the light of current knowledge. PMID- 26746414 TI - Clinical decision where evidence is lacking. PMID- 26746416 TI - In vitro assessment of the effect of proportional assist ventilation on the work of breathing. AB - During proportional assist ventilation, elastic and resistive unloading can be delivered to reduce the work of breathing (WOB). Our aim was to determine the effects of different levels of elastic and resistive unloading on the WOB in lung models designed to mimic certain neonatal respiratory disorders. Two dynamic lung models were used, one with a compliance of 0.4 ml/cm H2O to mimic an infant with respiratory distress syndrome and one with a resistance of 300 cm H2O/l/s to mimic an infant with bronchopulmonary dypslasia. Pressure volume curves were constructed at each unloading level. Elastic unloading in the low compliance model was highly effective in reducing the WOB measured in the lung model; the effective compliance increased from 0.4 ml/cm H2O at baseline to 4.1 ml/cm H2O at maximum possible elastic unloading (2.0 cm H2O/ml). Maximum possible resistive unloading (200 cm H2O/l/s) in the high-resistance model only reduced the effective resistance from 300 to 204 cm H2O/l/s. At maximum resistive unloading, oscillations appeared in the airway pressure waveform. CONCLUSION: Our results suggest that elastic unloading will be helpful in respiratory conditions characterised by a low compliance, but resistive unloading as currently delivered is unlikely to be of major clinical benefit. WHAT IS KNOWN: * During PAV, the ventilator can provide elastic and resistive unloading. What is New: * Elastic unloading was highly effective in reducing the work of breathing. * Maximum resistive unloading only partially reduced the effective resistance. PMID- 26746417 TI - Effects of combined UV and chlorine treatment on chloroform formation from triclosan. AB - The co-exposure to UV irradiation and free chlorine may occur in certain drinking water and wastewater treatment systems. This study investigated the effects of simultaneous low pressure ultraviolet (LPUV) irradiation and free chlorination on the formation of chloroform from triclosan which is a commonly used antibacterial agent. Different treatment systems (i.e., combined UV/chlorine, UV alone, and chlorine alone) were applied to examine the degradation of triclosan and formation of chloroform. The fate of representative intermediates, including chlorinated triclosan, dechlorinated triclosan intermediates and 2,4 dichlorophenol, were tracked to deduce the effect of combined UV/chlorine on the transformation of chloroform formation precursors. The relation between intermediates degradation and chloroform formation was investigated in depth by conducting stepwise experiments with UV and chlorine in different sequences. Results indicate that the combined UV/chlorine notably enhanced the chloroform formation from triclosan. From the reaction mechanism perspective the combined UV/chlorine, where the direct photolysis may play an important role, could accelerate the decay of intermediates and facilitate the generation of productive chloroform precursors. The radicals had modest influence on the degradation of triclosan and intermediates and partly hindered the formation of chloroform. These results emphasize the necessity of considering disinfection by-products formation in the application of combined UV/chlorine technology during water treatment. PMID- 26746418 TI - Fate of three anti-influenza drugs during ozonation of wastewater effluents - degradation and formation of transformation products. AB - Anti-influenza drugs constitute a key component of pandemic preparedness plans against influenza. However, the occurrence of such drugs in water environments, the potential of resistance development in the natural hosts, and the risk for transmission of antiviral resistance to humans call for measures to increase removal in wastewater treatment plants (WWTPs). In this study, removal of three anti-influenza drugs; amantadine (AM), oseltamivir carboxylate (OC) and zanamivir (ZA), and formation/removal of their transformation products during ozonation of wastewater effluents from two Swedish WWTPs in Uppsala and Stockholm were studied. The removal profile of target antivirals and formation/removal of their transformation products were studied by liquid chromatography/high resolution mass spectrometry. 3.5 h of ozone exposure (total dose of ozone 5.95 g) led to complete removal of the three anti-influenza drugs with a degradation in the following order ZA > OC > AM. Two, five and one transformation products were identified and semi-quantified for AM, OC and ZA, respectively. Increasing and later decreasing transformation products concentration followed the decrease in concentration of target compounds. All transformation products detected, except one of AM in wastewater from Stockholm WWTP, were removed at the end of the experiment. The removal efficiency was higher for all studied compounds in wastewater from Uppsala WWTP, which had lower TOC and COD values, less phosphorus, and also higher pH in the water. Ozonation thus offers multiple benefits through its potential to degrade influenza antivirals, hence decrease the risk of environmental resistance development, in addition to degrading other pharmaceuticals and resistant microorganisms. PMID- 26746415 TI - Socioeconomic Status, Risk of Obesity, and the Importance of Albert J. Stunkard. AB - Albert J. Stunkard's influential career in obesity research spanned over 50 years and included several landmark studies on social factors related to obesity. This review discusses the important contributions Stunkard made to research on the relationship between socioeconomic status socioeconomic status and obesity, extensions of his work, and reflects on Stunkard's role in the mentoring of succeeding generations of scientists. PMID- 26746420 TI - Uncovering Some of the Hidden Costs and Burdens of Glaucoma. PMID- 26746419 TI - Redox effects on release kinetics of arsenic, cadmium, cobalt, and vanadium in Wax Lake Deltaic freshwater marsh soils. AB - The impact of redox potential (EH), pH, iron (Fe), manganese (Mn), chloride (Cl( )), aliphatic and aromatic dissolved organic carbon (DOC), and sulfate ( [Formula: see text] ) on the release of dissolved arsenic (As), cadmium (Cd), cobalt (Co), and vanadium (V) were studied in Louisiana freshwater marsh Wax Lake Delta soil (Mississippi River) using an automated biogeochemical microcosm apparatus. The experiment was conducted from reducing (-60 mV) to stepwise oxidizing (+491 mV) conditions. The initial pH was 7.4 and decreased under reducing conditions to 4.9, and remained constant during the increase of EH. Concentrations of As (1.3-120.5 MUg L(-1)), V (0.9-48.6 MUg L(-1)), Fe, DOC, and the specific UV absorbance increased under reducing conditions and decreased with rising EH. Release of As and V appeared to be related to changes of EH/pH, co precipitation with Fe oxides, and the release of dissolved aromatic carbon compounds. Concentrations of soluble Cd (4.8-11.2 MUg L(-1)), Mn, [Formula: see text] , and Cl(-) increased under oxidizing conditions. Release of Co (166.6 258.2 MUg L(-1)) was related to the chemistry of Fe, Mn and DOC. Phospholipid fatty acids analysis indicated the potential for the microbial community to be involved in biogeochemical processes such as the formation of sulfides, oxidation and reduction of compounds, and the bio-methylation of elements such as As. Overall, we measured a release of As and V under anoxic conditions, while oxic conditions favored the release of Cd. These results outline concern on the potential risk of mobilization of toxic elements in temporary waterlogged soils for agricultural purposes in deltaic ecosystems. PMID- 26746421 TI - Lysobacter aestuarii sp. nov., isolated from estuary sediment. AB - A Gram-stain-negative, strictly aerobic, non-motile bacterium, designated strain S2-CT, was isolated from an estuary sediment in South Korea and subjected to a polyphasic taxonomic investigation. Cells were catalase- and oxidase-positive rods without gliding motility. Growth of strain S2-CT was observed at 15-40 degrees C (optimum, 30 degrees C), at pH 5.5-9.0 (optimum, pH 6.5-7.5) and in the presence of 0-7.0 % (w/v) NaCl (optimum, 0-2 %). Only ubiquinone-8 (Q-8) was detected as the isoprenoid quinone and iso-C16 : 0, iso-C15 : 0, summed feature 9 (comprising iso-C17 : 1omega9c and/or C16 : 0 10-methyl), iso-C11 : 0, iso-C11 : 0 3-OH and iso-C14 : 0 were found to be the major cellular fatty acids. Strain S2 CT contained phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol as the major polar lipids. The G+C content of the genomic DNA was 63.8 mol%. Phylogenetic analysis, based on 16S rRNA gene sequences, revealed that strain S2-CT formed a distinct phyletic lineage within the genus Lysobacter. Strain S2-CT was most closely related to Lysobacter daejeonensis GH1 9T with 97.1 % 16S rRNA gene sequence similarity and the DNA-DNA relatedness value between strain S2-CT and the type strain of L. daejeonensis was 45.7 +/- 2.2 %. On the basis of the phenotypic, chemotaxonomic and molecular features, strain S2-CT clearly represents a novel species of the genus Lysobacter, for which the name Lysobacter aestuarii sp. nov. is proposed. The type strain is S2 CT ( = KACC 18502T = JCM 31130T). PMID- 26746422 TI - Retinal and Optic Nerve Damage is Associated with Early Glial Responses in an Experimental Autoimmune Glaucoma Model. AB - It is well established that the immunization with ocular antigens causes a retinal ganglion cell (RGC) decline, which is accompanied by glia alterations. In this study, the degenerative effects of the immunization with an optic nerve homogenate (ONA) and its purified compound S100 were analyzed on retinas and optic nerves. Since a participation of glia cells in cell death mechanisms is currently discussed, rats were immunized with S100 or ONA. At 14 and 28 days, immune-histological and Western blot analyses were performed to investigate the optic nerve structure (SMI-32), retinal ganglion cells (Brn-3a), apoptosis (cleaved caspase 3, FasL), and glial profile (Iba1, ED1, GFAP, vimentin). Neurofilament dissolution in S100 animals was evident at 14 days (p = 0.047) and increased at 28 days (p = 0.01). ONA optic nerves remained intact at early stages and degenerated later on (p = 0.002). In both groups, RGC loss was detected via immune-histology and Western blot at 28 days (ONA: p = 0.02; S100: p = 0.005). Additionally, more Iba1(+) retinal microglia could be detected at early stages (ONA: p = 0.006; S100: p = 0.028). A slight astrocyte response was detected on Western blots only on ONA retinas (p = 0.01). Hence, the RGC and optic nerve decline was partly antigen dependent, while neuronal loss is paralleled by an early microglial response. PMID- 26746423 TI - Improved monitoring of clinical response in Systemic Lupus Erythematosus by longitudinal trend in soluble vascular cell adhesion molecule-1. AB - BACKGROUND: To determine whether optimal use of serial measurements of serum levels of soluble cell adhesion molecules (CAM) can improve monitoring of disease activity in SLE. METHODS: Serum levels of soluble CAM and conventional SLE biomarkers were measured in serial samples (n = 80) from 21 SLE patients during and after flare and correlated in longitudinal analysis with disease activity determined by ECLAM score. Blood samples from a second cohort of 34 SLE patients were subject to flow cytometry to correlate serum biomarkers with B cell subsets. RESULTS: By adjusting for the baseline level (at the first visit), delta soluble vascular cell adhesion molecule-1 (sVCAM-1) showed stronger correlation with changes in ECLAM score and improved sensitivity and specificity for identifying SLE responders versus non-responders compared to conventional SLE biomarkers including anti-dsDNA antibody titre and complement C3. Multiple regression analysis identified delta sVCAM-1 as the best marker of SLE clinical response. sVCAM-1 levels were significantly correlated with CD95(+)CD27(+) activated memory B cells, CD95(+) plasmablasts and circulating plasma cell numbers in SLE patients. CONCLUSION: Subtracting a baseline level of sVCAM-1 for each individual substantially improved its utility as a biomarker. Delta sVCAM-1 was superior to conventional SLE biomarkers for monitoring changes in disease activity. This suggests that serial monitoring of serum sVCAM-1 trends should be considered in SLE patients to document responses to treatment. We hypothesise that the correlation between activated B cell subsets and circulating plasma cell numbers with soluble VCAM-1 serum levels in SLE may relate to the important role of VCAM 1 in B lymphocyte survival and maturation in bone marrow and secondary lymphoid tissues. PMID- 26746424 TI - Persistent Racial Disparities in HIV Infection in the USA: HIV Prevalence Matters. AB - OBJECTIVES: Despite increased funding and efforts to prevent and control HIV infections in the black and Hispanic communities, racial disparities persist in the USA. We used a mathematical model to explain the phenomena. METHODS: A mathematical model was constructed to project HIV prevalence ratio (PR), incidence rate ratio (IRR), and HIV-specific mortality rate ratio (MRR) among blacks and Hispanics vs. whites in two scenarios: (1) an annual reduction in HIV incidence rate at the 2007-2010 level and (2) an annual reduction in HIV incidence rate at the 2007-2010 level among whites (4.2 %) and twice that of whites among blacks and Hispanics (8.4 %). RESULTS: In scenario no. 1, the PR, IRR, and MRR among blacks would decrease from 7.6 to 5.8, 7.9 to 5.9, and 11.3 to 5.3 and among Hispanics from 2.8 to 1.8, 3.1 to 1.9, and 2.3 to 1.0, respectively. In scenario no. 2, the PR, IRR, and MRR among blacks would decrease from 7.6 to 5.1, 7.9 to 2.5, and 11.3 to 4.7 and among Hispanics from 2.8 to 1.6, 3.1 to 0.8, and 2.3 to 0.9, respectively. CONCLUSIONS: Much of the persistent racial disparities in HIV infection in the USA, as measured by PR, IRR, and MRR, can be explained by higher HIV prevalence among blacks and Hispanics. The public health community should continue its efforts to reduce racial disparities, but also need to set realistic goals and measure progress with sensitive indicators. PMID- 26746426 TI - Differentiation of sarcoidosis-lymphoma syndrome lesions: a case report on the use of two different positron emission tomography tracers. AB - BACKGROUND: Sarcoidosis-lymphoma syndrome (SLS) is a rare disease in which both entities coexist. We aimed to study the role of (18)F-fluorodeoxyglucose (FDG) and L-[3-(18)F] alpha-methyltyrosine (FAMT) positron emission tomography (PET)/computed tomography (CT) in differentiating between these two lesions. CASE PRESENTATION: A 54-year-old female with large liver tumors was referred to our Nuclear Medicine Department for staging using FDG PET/CT. She had a history of primary biliary cirrhosis (PBC) for 15 years and developed lung and mediastinal sarcoidosis 1 year before the liver tumors were noted. Abdominal dynamic CT revealed two well-circumscribed, peripherally-enhancing, low-density masses in the right lobe of the liver with intensive ring-form FDG uptakes at maximum standard uptake values (SUVmax) of 18.3 and 19.5, respectively. In the arterial phase, a hepatic artery was seen penetrating the tumor, a phenomenon known as "angiogram sign". Chest PET/CT findings showed irregular thickening of the bronchovascular bundles, central peribronchial shaggy consolidations in the right middle and lower lobes (SUVmax, 4.6), and mediastinal and hilar lymphadenopathies (SUVmax, 2.7). After assessment, chemotherapy with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) was administered for eight cycles. Follow-up imaging studies using FDG and FAMT PET/CT were performed 3 months after the last cycle of chemotherapy, which showed that the two highly FDG-avid tumors in the liver had disappeared. However, faint FDG uptake persisted in the lung consolidations (SUVmax, 6.3), and FDG uptake for the mediastinal lymphadenopathies increased (SUVmax of 5.8). In contrast, there was no significant uptake of FAMT in the liver, as well as in the lungs and the bilateral mediastinal lymphadenopathies. These discrepant uptakes between FDG and FAMT were compatible with sarcoidosis. CONCLUSION: Combination of FDG and FAMT in PET/CT studies may play an important role in the management of SLS patients, especially in differentiating between sarcoidosis and lymphoma lesions. PMID- 26746428 TI - Margaret McCartney: Bruce Keogh's letter to junior doctors: the importance of independence. PMID- 26746427 TI - Less cost by using hanging maneuver and Pringle maneuver in left lateral hepatectomy through small laparotomy wound--experience of Southern Taiwan. AB - BACKGROUND: Laparoscopic segmentectomy for liver tumor located in the left lateral segment (LLS) is thought to be a standard protocol nowadays with several advantages, such as small wound, few blood loss, and short hospital stay. However, there are still many disadvantages during executing laparoscopic LLS segmentectomy. This manuscript aims to present the technique to execute LLS segmentectomy with small incision, hanging maneuver without Pringle maneuver in patients with tumor at LLS of the liver. MATERIAL AND METHODS: Between November 2010 and July 2011, hepatectomies through small incision for nine patients with benign and malignant tumors were performed at Kaohsiung Chang Gung Memorial Hospital, Taiwan. Perioperative and postoperative results, such as operation time, blood loss, incisional width, and postoperative stay were used to determine consequents for this technique. RESULT: Results demonstrated that modified LLS segmentectomy by the author's team was performed successfully in patient with liver tumor with fewer blood loss, smaller incisional width, and lower hospital cost than traditional open surgery. In addition, the instrument cost and blood loss in our series were less than that in laparoscopic LLS segmentectomy in published literature. CONCLUSION: Authors concluded that minimally incisional segmentectomy, with less cost and technical demanding, could be an alternative choice in patient with liver tumor at LLS. PMID- 26746429 TI - Nebivolol Acts as a S-Nitrosoglutathione Reductase Inhibitor: A New Mechanism of Action. AB - BACKGROUND AND PURPOSE: Published data on nebivolol reveal selective beta1 adrenergic selectively along with novel nitric oxide (NO)-dependent vasodilatory properties. However, the exact molecular mechanism is unknown. Protein S nitrosylation constitutes a large part of the ubiquitous influence of NO on cellular signal transduction and is involved in a number of human diseases. More recently, protein denitrosylation has been shown to play a major role in controlling cellular S-nitrosylation (SNO). Several enzymes have been reported to catalyze the reduction of SNOs and are viewed as candidate denitrosylases. One of the first described is known as S-nitrosoglutathione reductase (GSNOR). Importantly, GSNOR has been shown to play a role in regulating SNO signaling downstream of the beta-adrenergic receptor and is therefore operative in cellular signal transduction. Pharmacological inhibition or genetic deletion of GSNOR leads to enhanced vasodilation and characteristic of known effects of nebivolol. Structurally, nebivolol is similar to known inhibitors of GSNOR. Therefore, we hypothesize that some of the known effects of nebivolol may occur through this mechanism. EXPERIMENTAL APPROACH: Using cell culture systems, tissue organ bath, and intact animal models, we report that nebivolol treatment leads to a dose dependent accumulation of nitrosothiols in cells, and this is associated with an enhanced vasodilation by S-nitrosoglutathione. KEY RESULTS: These data suggest a new mechanism of action of nebivolol that may explain in part the reported NO activity. CONCLUSIONS AND IMPLICATIONS: Because exogenous mediators of protein SNO or denitrosylation can substantially affect the development or progression of disease, this may call for new utility of nebivolol. PMID- 26746425 TI - Diversification of behavior and postsynaptic properties by netrin-G presynaptic adhesion family proteins. AB - BACKGROUND: Vertebrate-specific neuronal genes are expected to play a critical role in the diversification and evolution of higher brain functions. Among them, the glycosylphosphatidylinositol (GPI)-anchored netrin-G subfamily members in the UNC6/netrin family are unique in their differential expression patterns in many neuronal circuits, and differential binding ability to their cognate homologous post-synaptic receptors. RESULTS: To gain insight into the roles of these genes in higher brain functions, we performed comprehensive behavioral batteries using netrin-G knockout mice. We found that two netrin-G paralogs that recently diverged in evolution, netrin-G1 and netrin-G2 (gene symbols: Ntng1 and Ntng2, respectively), were responsible for complementary behavioral functions. Netrin G2, but not netrin-G1, encoded demanding sensorimotor functions. Both paralogs were responsible for complex vertebrate-specific cognitive functions and fine scale regulation of basic adaptive behaviors conserved between invertebrates and vertebrates, such as spatial reference and working memory, attention, impulsivity and anxiety etc. Remarkably, netrin-G1 and netrin-G2 encoded a genetic "division of labor" in behavioral regulation, selectively mediating different tasks or even different details of the same task. At the cellular level, netrin-G1 and netrin G2 differentially regulated the sub-synaptic localization of their cognate receptors and differentiated the properties of postsynaptic scaffold proteins in complementary neural pathways. CONCLUSIONS: Pre-synaptic netrin-G1 and netrin-G2 diversify the complexity of vertebrate behaviors and differentially regulate post synaptic properties. Our findings constitute the first genetic analysis of the behavioral and synaptic diversification roles of a vertebrate GPI protein and presynaptic adhesion molecule family. PMID- 26746430 TI - Expression Characterization of Stress Genes Under High and Low Temperature Stresses in the Pacific Oyster, Crassostrea gigas. AB - As a characteristic sessile inhabitant of the intertidal zone, the Pacific oyster Crassostrea gigas occupies one of the most physically stressful environments on earth. With high exposure to terrestrial conditions, oysters must tolerate broad fluctuations in temperature range. However, oysters' cellular and molecular responses to temperature stresses have not been fully characterized. Here, we analyzed oyster transcriptome data under high and low temperatures. We also identified over 30 key temperature stress-responsive candidate genes, which encoded stress proteins such as heat shock proteins and apoptosis-associated proteins. The expression characterization of these genes under short-term cold and hot environments (5 and 35 degrees C) and long-term cold environments (5 degrees C) was detected by quantitative real-time PCR. Most of these genes reached expression peaks during the recovery stage after 24 h of heat stress, and these genes were greatly induced around day 3 in long-term cold stress while responded little to short-term cold stress. In addition, in the second heat stress after 2 days of recovery, oysters showed milder expression in these genes and a lower mortality rate, which indicated the existence of plasticity in the oyster's response to heat stress. We confirmed that homeostatic flexibility and anti-apoptosis might be crucial centers of temperature stress responses in oysters. Furthermore, we analyzed stress gene families in 11 different species and found that the linage-specific expansion of stress genes might be implicated in adaptive evolution. These results indicated that both plasticity and evolution played an important role in the stress response adaptation of oysters. PMID- 26746431 TI - Protective effects of Arctium lappa L. root extracts (AREs) on high fat diet induced quail atherosclerosis. AB - BACKGROUND: This study was designed to evaluate the protective effects of Arctium lappa L. root extracts (AREs) from different extraction methods (aqueous, ethanol, chloroform and flavone) on atherosclerosis. METHODS: Quails (Coturnix coturnix) were subjected to high fat diet, with or without one of the four different AREs or positive control simvastatin. Blood samples were collected before treatment, after 4.5 weeks or ten weeks to assess lipid profile (Levels of total cholesterol (TC), Triacylglycerol (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL)). After ten weeks, the serum levels of nitric oxide (NO) as well as antioxidant and pro-oxidative status (Levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione peroxidase (GSH-Px)) were measured. Furthermore, aortas were collected after ten weeks treatment, aorta lipid contents (TC, TG and LDL) were assessed, and histology was used to confirm atherosclerotic changes. RESULTS: The results indicated that high fat diet significantly deteriorated lipid profile and antioxidant status in quail serum, while all the extracts significantly reverted the changes similar to simvastatin. Aorta lipid profile assessment revealed similar results. Histology on aortas from quails treated for ten weeks confirmed atherosclerotic changes in high fat diet group, while the extracts significantly alleviated the atherosclerotic changes similar to simvastatin. Among the different extracts, flavones fraction exerted best protective effects. CONCLUSIONS: Our data suggest that the protective effects of AREs were medicated via hypolipidemic and anti-oxidant effects. Underlying molecular mechanisms are under investigation. PMID- 26746432 TI - Validation of Models Used to Inform Colorectal Cancer Screening Guidelines: Accuracy and Implications. AB - BACKGROUND: Microsimulation models synthesize evidence about disease processes and interventions, providing a method for predicting long-term benefits and harms of prevention, screening, and treatment strategies. Because models often require assumptions about unobservable processes, assessing a model's predictive accuracy is important. METHODS: We validated 3 colorectal cancer (CRC) microsimulation models against outcomes from the United Kingdom Flexible Sigmoidoscopy Screening (UKFSS) Trial, a randomized controlled trial that examined the effectiveness of one-time flexible sigmoidoscopy screening to reduce CRC mortality. The models incorporate different assumptions about the time from adenoma initiation to development of preclinical and symptomatic CRC. Analyses compare model predictions to study estimates across a range of outcomes to provide insight into the accuracy of model assumptions. RESULTS: All 3 models accurately predicted the relative reduction in CRC mortality 10 years after screening (predicted hazard ratios, with 95% percentile intervals: 0.56 [0.44, 0.71], 0.63 [0.51, 0.75], 0.68 [0.53, 0.83]; estimated with 95% confidence interval: 0.56 [0.45, 0.69]). Two models with longer average preclinical duration accurately predicted the relative reduction in 10-year CRC incidence. Two models with longer mean sojourn time accurately predicted the number of screen-detected cancers. All 3 models predicted too many proximal adenomas among patients referred to colonoscopy. CONCLUSION: Model accuracy can only be established through external validation. Analyses such as these are therefore essential for any decision model. Results supported the assumptions that the average time from adenoma initiation to development of preclinical cancer is long (up to 25 years), and mean sojourn time is close to 4 years, suggesting the window for early detection and intervention by screening is relatively long. Variation in dwell time remains uncertain and could have important clinical and policy implications. PMID- 26746433 TI - Multiple sclerosis-like diagnosis as a complication of previously treated malaria in an iron and vitamin D deficient Nigerian patient. AB - In contrast to malaria, multiple sclerosis (MS) is infrequently found in Black Africans. We describe a 29 year old Nigerian female who developed an MS-like condition with symptoms similar to relapsing-remitting MS following malaria infection, leading to a diagnosis of MS. However, absence of hyperintense lesions in the brain and spinal cord presented a conundrum since not all the diagnostic criteria for MS were met. Pathology supported genetic testing (PSGT) was applied to combine family and personal medical history, lifestyle factors, and biochemical test results for interpretation of genetic findings. This approach provides a means of identifying risk factors for different subtypes of demyelinating disease. The patient was subsequently treated according to an individualised intervention program including nutritional supplementation as well as a change in diet and lifestyle. Deficiencies of vitamin B12, iron and vitamin D were addressed. Genetic analysis revealed absence of the HLA DRB1*1501 allele, considered to be the most prominent genetic risk factor for MS. Extended mutation analysis identified variations in three genes in the folate-vitamin B12 metabolic pathway, which could have increased the patient's sensitivity to the antifolate drugs used to treat the malaria. A glutathione-S-transferase GSTM1 null allele, previously associated with neurological complications of malaria, was also detected. Furthermore, a heterozygous variation in the iron-related transmembrane protease serine 6 (TMPRSS6) gene, rs855791 was found, which could have impacted the patient's iron status following two successive blood donations and exposure to malaria preceding the MS diagnosis. PSGT identifies relevant risk factors for demyelinating disorders resembling MS and uses the data for individualised treatment programs, and to systematically build a database that can provide evidence in large patient cohorts. Follow-up investigations may be suggested, such as whole exome sequencing in selected cases, to ensure that remyelination and restoration of function are achieved. PMID- 26746435 TI - Examining Infertility Treatment and Early Childhood Development in the Upstate KIDS Study. AB - IMPORTANCE: An increasing percentage of births are conceived with assisted reproductive technology (ART) and other infertility treatment. Despite findings that such treatments may be associated with diminished gestation and birth size, scarce data exist regarding infertility treatments and children's development in the United States. OBJECTIVE: To assess the use and type of infertility treatment in relation to children's development through age 36 months. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study (conducted 2008-2014) that sampled based on infertility treatment and plurality. Included in the study were infants born between 2008 and 2010 in New York state (excluding New York City) whose parents completed developmental screening instruments through 36 months of age. A total of 4824 mothers (97% of 4989) completed 1 or more developmental screening instruments for 5841 children, including 1830 conceived with infertility treatment and 2074 twins. EXPOSURES: Maternal self-report of any infertility treatment was further categorized into ART and ovulation induction/intrauterine insemination. Assisted reproductive technology use was previously validated by linkage with the Society for Assisted Reproductive Technology-Clinical Outcome Reporting System. MAIN OUTCOMES AND MEASURES: Five developmental domains (fine motor, gross motor, communication, personal-social functioning, and problem solving ability), as measured by the parental completion of the Ages and Stages Questionnaires at 4, 8, 12, 18, 24, 30, and 36 months of age. Generalized linear mixed modeling techniques estimated adjusted odds ratios (aORs) and 95% CIs for use and type of infertility treatment in relation to failing a developmental domain. Data were stratified by plurality and weighted for the sampling scheme. RESULTS: There were 1422 mothers (29.5%; mean [SD], age, 34.1 [5.2] years) who underwent infertility treatment. Infertility treatment was not associated with risk of their children failing any developmental domain (aOR, 1.33; 95% CI, 0.94 1.89). Assisted reproductive technology was associated with increased risk for failing any developmental domain but only when singletons and twins were evaluated together (aOR, 1.81; 95% CI, 1.21-2.72). Adjustment for birth weight further attenuated this estimate (aOR, 1.26; 95% CI, 0.82-1.93). After stratifying by plurality, type of treatment also was not significantly associated with failing any developmental domain for ovulation induction/intrauterine insemination (aOR, 1.00; 95% CI, 0.57-1.77 for singletons and aOR, 1.30; 95% CI, 0.76-2.21 for twins) or ART (aOR, 1.38; 95% CI, 0.78-2.43 for singletons and aOR, 1.58; 95% CI, 0.94-2.65 for twins). CONCLUSIONS AND RELEVANCE: After considering plurality, children's development through age 3 years was similar irrespective of infertility treatment or specific type. To our knowledge, these findings are among the first to focus on non-ART treatments in the United States. PMID- 26746439 TI - Day of Sounds: Alice Baber. PMID- 26746440 TI - Can Nonhormonal Treatments Dial Down the Heat During Menopause? PMID- 26746436 TI - Cytopathology whole slide images and adaptive tutorials for senior medical students: a randomized crossover trial. AB - BACKGROUND: Diagnostic cytopathology is an essential part of clinical decision making. However, due to a combination of factors including curriculum reform and shortage of pathologists to teach introductory cytopathology, this area of pathology receives little or no formal attention in most medical school curricula. We have previously described the successful use of efficient and effective digital learning resources, including whole slide images (WSI) and virtual microscopy adaptive tutorials (VMATs), to teach cytopathology to pathology specialist trainees - a group that had prior exposure to cytopathology in their day to day practice. Consequently, in the current study we attempted to demonstrate the efficiency and efficacy of this eLearning resource in a cohort of senior medical students that was completely naive to the subject matter (cytopathology). METHODS: We evaluated both the quantitative and qualitative impact of these digital educational materials for learning cytopathology compared with existing resources (e-textbooks and online atlases). The senior medical students were recruited from The University of New South Wales Australia for a randomized cross-over trial. Online assessments, administered after each arm of the trial, contained questions which related directly to a whole slide image. Two categories of questions in the assessments (focusing on either diagnosis or identification of cellular features) were utilized to determine efficacy. User experience and perceptions of efficiency were evaluated using online questionnaires containing Likert scale items and open-ended questions. RESULTS: For this cohort of senior medical students, virtual microscopy adaptive tutorials (VMATs) proved to be at least as effective as existing digital resources for learning cytopathology. Importantly, virtual microscopy adaptive tutorials had superior efficacy in facilitating accurate diagnosis on whole slide images. Student perceptions of VMATs were positive, particularly regarding the immediate feedback, interactivity and equity of learning which this learning resource provides. CONCLUSIONS: Virtual microscopy adaptive tutorials have the potential to improve the efficacy of learning microscopic pathology for medical students. The enhanced learning experience provided by these eLearning tools merits further investigation of their utility for other cohorts, including specialist trainees. PMID- 26746434 TI - Cerebral malaria--clinical manifestations and pathogenesis. AB - One of the most common central nervous system diseases in tropical countries is cerebral malaria (CM). Malaria is a common protozoan infection that is responsible for enormous worldwide mortality and economic burden on the society. Episodes of Plasmodium falciparum (Pf) caused CM may be lethal, while survivors are likely to suffer from persistent debilitating neurological deficits, especially common in children. In this review article, we have summarized the various symptoms and manifestations of CM in children and adults, and entailed the molecular basis of the disease. We have also emphasized how pathogenesis of the disease is effected by the parasite and host responses including blood brain barrier (BBB) disruption, endothelial cell activation and apoptosis, nitric oxide bioavailability, platelet activation and apoptosis, and neuroinflammation. Based on a few recent studies carried out in experimental mouse malaria models, we propose a basis for the neurological deficits and sequelae observed in human cerebral malaria, and summarize how existing drugs may improve prognosis in affected individuals. PMID- 26746441 TI - Campaign Wars: Health Policy in a Fantasy World. PMID- 26746450 TI - Reimagining Electronic Clinical Communication in the Post-Pager, Smartphone Era. PMID- 26746451 TI - Delivery Models for High-Risk Older Patients: Back to the Future? PMID- 26746453 TI - Innovations in Health Care Delivery and the Future of Medicine. PMID- 26746452 TI - A PIECE OF MY MIND. Thinking Outside the (Lunch) Box. PMID- 26746454 TI - Lifestyle Interventions to Improve Exercise Tolerance in Obese Older Patients With Heart Failure and Preserved Ejection Fraction. PMID- 26746455 TI - Establishing the Clinical Validity of Arrhythmia-Related Genetic Variations Using the Electronic Medical Record: A Valid Take on Precision Medicine? PMID- 26746456 TI - Effect of Caloric Restriction or Aerobic Exercise Training on Peak Oxygen Consumption and Quality of Life in Obese Older Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial. AB - IMPORTANCE: More than 80% of patients with heart failure with preserved ejection fraction (HFPEF), the most common form of heart failure among older persons, are overweight or obese. Exercise intolerance is the primary symptom of chronic HFPEF and a major determinant of reduced quality of life (QOL). OBJECTIVE: To determine whether caloric restriction (diet) or aerobic exercise training (exercise) improves exercise capacity and QOL in obese older patients with HFPEF. DESIGN, SETTING, AND PARTICIPANTS: Randomized, attention-controlled, 2 * 2 factorial trial conducted from February 2009 through November 2014 in an urban academic medical center. Of 577 initially screened participants, 100 older obese participants (mean [SD]: age, 67 years [5]; body mass index, 39.3 [5.6]) with chronic, stable HFPEF were enrolled (366 excluded by inclusion and exclusion criteria, 31 for other reasons, and 80 declined participation). INTERVENTIONS: Twenty weeks of diet, exercise, or both; attention control consisted of telephone calls every 2 weeks. MAIN OUTCOMES AND MEASURES: Exercise capacity measured as peak oxygen consumption (VO2, mL/kg/min; co-primary outcome) and QOL measured by the Minnesota Living with Heart Failure (MLHF) Questionnaire (score range: 0-105, higher scores indicate worse heart failure-related QOL; co-primary outcome). RESULTS: Of the 100 enrolled participants, 26 participants were randomized to exercise; 24 to diet; 25 to exercise + diet; 25 to control. Of these, 92 participants completed the trial. Exercise attendance was 84% (SD, 14%) and diet adherence was 99% (SD, 1%). By main effects analysis, peak VO2 was increased significantly by both interventions: exercise, 1.2 mL/kg body mass/min (95% CI, 0.7 to 1.7), P < .001; diet, 1.3 mL/kg body mass/min (95% CI, 0.8 to 1.8), P < .001. The combination of exercise + diet was additive (complementary) for peak VO2 (joint effect, 2.5 mL/kg/min). There was no statistically significant change in MLHF total score with exercise and with diet (main effect: exercise, -1 unit [95% CI, -8 to 5], P = .70; diet, -6 units [95% CI, -12 to 1], P = .08). The change in peak VO2 was positively correlated with the change in percent lean body mass (r = 0.32; P = .003) and the change in thigh muscle:intermuscular fat ratio (r = 0.27; P = .02). There were no study-related serious adverse events. Body weight decreased by 7% (7 kg [SD, 1]) in the diet group, 3% (4 kg [SD, 1]) in the exercise group, 10% (11 kg [SD, 1] in the exercise + diet group, and 1% (1 kg [SD, 1]) in the control group. CONCLUSIONS AND RELEVANCE: Among obese older patients with clinically stable HFPEF, caloric restriction or aerobic exercise training increased peak VO2, and the effects may be additive. Neither intervention had a significant effect on quality of life as measured by the MLHF Questionnaire. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00959660. PMID- 26746458 TI - Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth. AB - IMPORTANCE: Vaginal candidiasis is common during pregnancy. Although intravaginal formulations of topical azole antifungals are first-line treatment for pregnant women, oral fluconazole is often used despite limited safety information. OBJECTIVE: To study the association between oral fluconazole exposure during pregnancy and the risk of spontaneous abortion and stillbirth. DESIGN, SETTING, AND PARTICIPANTS: Nationwide register-based cohort study in Denmark, 1997-2013. From a cohort of 1,405,663 pregnancies, oral fluconazole-exposed pregnancies were compared with up to 4 unexposed pregnancies matched on propensity score, maternal age, calendar year, and gestational age (based on gestational age at first day of treatment with eligible controls surviving through this date). To test for confounding by indication, pregnancies exposed to intravaginal formulations of topical azoles were used as an additional comparator group. EXPOSURES: Filled prescriptions for oral fluconazole were obtained from the National Prescription Register. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) for spontaneous abortion and stillbirth, estimated using proportional hazards regression. RESULTS: Among 3315 women exposed to oral fluconazole from 7 through 22 weeks' gestation, 147 experienced a spontaneous abortion, compared with 563 among 13,246 unexposed matched women. There was a significantly increased risk of spontaneous abortion associated with fluconazole exposure (HR, 1.48; 95% CI, 1.23-1.77). Among 5382 women exposed to fluconazole from gestational week 7 to birth, 21 experienced a stillbirth, compared with 77 among 21,506 unexposed matched women. There was no significant association between fluconazole exposure and stillbirth (HR, 1.32 [95% CI, 0.82-2.14]). Using topical azole exposure as the comparison, 130 of 2823 women exposed to fluconazole vs 118 of 2823 exposed to topical azoles had a spontaneous abortion (HR, 1.62 [95% CI, 1.26-2.07]); 20 of 4301 women exposed to fluconazole vs 22 of 4301 exposed to topical azoles had a stillbirth (HR, 1.18 [95% CI, 0.64-2.16]). CONCLUSIONS AND RELEVANCE: In this nationwide cohort study in Denmark, use of oral fluconazole in pregnancy was associated with a statistically significant increased risk of spontaneous abortion compared with risk among unexposed women and women with topical azole exposure in pregnancy. Until more data on the association are available, cautious prescribing of fluconazole in pregnancy may be advisable. Although the risk of stillbirth was not significantly increased, this outcome should be investigated further. PMID- 26746460 TI - Computed Tomography Screening for Lung Cancer: A High-Value Proposition? PMID- 26746461 TI - Erythematous Plaques on the Buttock. PMID- 26746457 TI - Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records. AB - IMPORTANCE: Large-scale DNA sequencing identifies incidental rare variants in established Mendelian disease genes, but the frequency of related clinical phenotypes in unselected patient populations is not well established. Phenotype data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants. OBJECTIVE: To determine the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 2022 individuals recruited for nonantiarrhythmic drug exposure phenotypes from October 5, 2012, to September 30, 2013, for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 US academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes, were assessed for potential pathogenicity by 3 laboratories with ion channel expertise and by comparison with the ClinVar database. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014. EXPOSURES: One or more variants designated as pathogenic in SCN5A or KCNH2. MAIN OUTCOMES AND MEASURES: Arrhythmia or electrocardiographic (ECG) phenotypes defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, ECG data, and manual EMR review. RESULTS: Among 2022 study participants (median age, 61 years [interquartile range, 56-65 years]; 1118 [55%] female; 1491 [74%] white), a total of 122 rare (minor allele frequency <0.5%) nonsynonymous and splice-site variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11% of the study cohort). Forty-two variants in 63 participants were designated potentially pathogenic by at least 1 laboratory or ClinVar, with low concordance across laboratories (Cohen kappa = 0.26). An ICD-9 code for arrhythmia was found in 11 of 63 (17%) variant carriers vs 264 of 1959 (13%) of those without variants (difference, +4%; 95% CI, -5% to +13%; P = .35). In the 1270 (63%) with ECGs, corrected QT intervals were not different in variant carriers vs those without (median, 429 vs 439 milliseconds; difference, -10 milliseconds; 95% CI, -16 to +3 milliseconds; P = .17). After manual review, 22 of 63 participants (35%) with designated variants had any ECG or arrhythmia phenotype, and only 2 had corrected QT interval longer than 500 milliseconds. CONCLUSIONS AND RELEVANCE: Among laboratories experienced in genetic testing for cardiac arrhythmia disorders, there was low concordance in designating SCN5A and KCNH2 variants as pathogenic. In an unselected population, the putatively pathogenic genetic variants were not associated with an abnormal phenotype. These findings raise questions about the implications of notifying patients of incidental genetic findings. PMID- 26746459 TI - Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. AB - IMPORTANCE: Estimates of familial cancer risk from population-based studies are essential components of cancer risk prediction. OBJECTIVE: To estimate familial risk and heritability of cancer types in a large twin cohort. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 80,309 monozygotic and 123,382 same-sex dizygotic twin individuals (N = 203,691) within the population-based registers of Denmark, Finland, Norway, and Sweden. Twins were followed up a median of 32 years between 1943 and 2010. There were 50,990 individuals who died of any cause, and 3804 who emigrated and were lost to follow-up. EXPOSURES: Shared environmental and heritable risk factors among pairs of twins. MAIN OUTCOMES AND MEASURES: The main outcome was incident cancer. Time-to-event analyses were used to estimate familial risk (risk of cancer in an individual given a twin's development of cancer) and heritability (proportion of variance in cancer risk due to interindividual genetic differences) with follow-up via cancer registries. Statistical models adjusted for age and follow-up time, and accounted for censoring and competing risk of death. RESULTS: A total of 27,156 incident cancers were diagnosed in 23,980 individuals, translating to a cumulative incidence of 32%. Cancer was diagnosed in both twins among 1383 monozygotic (2766 individuals) and 1933 dizygotic (2866 individuals) pairs. Of these, 38% of monozygotic and 26% of dizygotic pairs were diagnosed with the same cancer type. There was an excess cancer risk in twins whose co-twin was diagnosed with cancer, with estimated cumulative risks that were an absolute 5% (95% CI, 4%-6%) higher in dizygotic (37%; 95% CI, 36%-38%) and an absolute 14% (95% CI, 12%-16%) higher in monozygotic twins (46%; 95% CI, 44%-48%) whose twin also developed cancer compared with the cumulative risk in the overall cohort (32%). For most cancer types, there were significant familial risks and the cumulative risks were higher in monozygotic than dizygotic twins. Heritability of cancer overall was 33% (95% CI, 30%-37%). Significant heritability was observed for the cancer types of skin melanoma (58%; 95% CI, 43%-73%), prostate (57%; 95% CI, 51%-63%), nonmelanoma skin (43%; 95% CI, 26%-59%), ovary (39%; 95% CI, 23%-55%), kidney (38%; 95% CI, 21%-55%), breast (31%; 95% CI, 11%-51%), and corpus uteri (27%; 95% CI, 11%-43%). CONCLUSIONS AND RELEVANCE: In this long-term follow-up study among Nordic twins, there was significant excess familial risk for cancer overall and for specific types of cancer, including prostate, melanoma, breast, ovary, and uterus. This information about hereditary risks of cancers may be helpful in patient education and cancer risk counseling. PMID- 26746462 TI - Antitissue Transglutaminase IgA for Celiac Disease Testing. PMID- 26746463 TI - Subsequent Maltreatment in Children With Disabilities After an Unsubstantiated Report for Neglect. PMID- 26746464 TI - Mindfulness-Based Stress Reduction for Veterans With PTSD. PMID- 26746465 TI - Mindfulness-Based Stress Reduction for Veterans With PTSD--Reply. PMID- 26746466 TI - Bedside Ultrasonography for Diagnosis of Septic Shock. PMID- 26746467 TI - Bedside Ultrasonography for Diagnosis of Septic Shock--Reply. PMID- 26746468 TI - Value Errors in Tables and Abstract. PMID- 26746469 TI - Incomplete Dosage Information. PMID- 26746470 TI - Incorrect Data in Tables and eFigure. PMID- 26746472 TI - Coffee and Protein Metabolism. PMID- 26746473 TI - JAMA PATIENT PAGE. Treatment of Liver Cancer. PMID- 26746474 TI - Vitamin D Supplementation and Increased Risk of Falling: A Cautionary Tale of Vitamin Supplements Retold. PMID- 26746475 TI - ACMT Position Statement: The Use of Methadone as an Analgesic. PMID- 26746478 TI - Omitted Minus Sign. PMID- 26746476 TI - Effect of Concurrent Use of Whole-Body Vibration and Parathyroid Hormone on Bone Structure and Material Properties of Ovariectomized Mice. AB - This study was designed to determine the effectiveness of whole-body vibration (WBV) and intermittent parathyroid hormone (iPTH) in combination against estrogen deficiency-induced osteoporosis. Female C57BL/6J mice were bilaterally ovariectomized (OVX, n = 40) or sham-operated (sham-OVX, n = 8) at 9 weeks of age. Two weeks later, the OVX mice were randomly divided into four groups (n = 10 each): the control group (c-OVX) and groups treated with iPTH (p-OVX), WBV (w OVX) and both (pw-OVX). The p-OVX and pw-OVX groups were given human PTH (1-34) at a dose of 30 ug/kg/day. The w-OVX and pw-OVX groups were exposed to WBV at an acceleration of 0.3 g and 45 Hz for 20 min/day. All mice were euthanized after the 18-day treatment, and the left tibiae were harvested. The proximal metaphyseal region was uCT-scanned, and its cortical bone cross-section was analyzed by Fourier transform infrared microspectroscopy and nanoindentation testing. A single application of iPTH or WBV to OVX mice had no effect on bone structure or material properties of cortical bone, which were compromised in comparison to those in sham-OVX mice. The combination of iPTH and WBV improved trabecular bone volume, thickness, and connectivity in OVX mice. Although the combined treatment failed to improve cortical bone structure, its mineral maturity and hardness were restored to the levels observed in sham-OVX mice. There was no evidence of interaction between the two treatments, and the combined effects seemed to be additive. These results suggest combining WBV with iPTH has great potential for treating postmenopausal osteoporosis. PMID- 26746477 TI - Current and Future Incidence and Costs of Osteoporosis-Related Fractures in The Netherlands: Combining Claims Data with BMD Measurements. AB - This study aims to estimate the incidence and costs of osteoporosis-related fractures in The Netherlands in 2010 and project them to 2030. The incidence and costs of five different types of fractures (spine, hip, upper extremity, lower extremity, wrist/distal forearm, other) were derived from claims data of all Dutch healthcare insurers. Given that fracture-codes in claims data do not indicate whether fractures are related to osteoporosis, we used a large dataset with DXA measurements to attribute fractures to osteoporosis. Future projections used four scenarios: (1) demographic, (2) demographic + annual trend in incidence rates, (3) demographic + annual trend in incidence rates + annual trend in costs, and (4) treatment. Of all registered fractures, 32 % was attributed to osteoporosis (36 % in women and 21 % in men). Over time (2010-2030) the increase in incidence of osteoporosis-related fractures was estimated to be 40 % (scenario 1); for the hip 60-79 % (scenario 1-2). In 2010, approximately ?200 million was spent on treatment of osteoporosis-related fractures, most on fractures of the hip followed by wrist/distal forearm. In both men and women, the excess costs due to osteoporosis-related fractures were highest for hip fractures (?11,000-?13,000 per person), followed by spine fractures (?6000-?7000).The costs for osteoporosis related fractures were projected to increase with 50 % from 2010 to 2030 (scenario 1); for the hip 60-148 % (scenario 1-3). Pharmacotherapeutic prevention can lead to cost-savings of ?377 million in 2030 (scenario 1 and 4 combined). The projected increase in incidence and costs of osteoporosis-related fractures calls for a wider use of prevention and treatment. PMID- 26746480 TI - A Real-Time Surface Enhanced Raman Spectroscopy Study of Plasmonic Photothermal Cell Death Using Targeted Gold Nanoparticles. AB - Plasmonic nanoparticles are increasingly utilized in biomedical applications including imaging, diagnostics, drug delivery, and plasmonic photothermal therapy (PPT). PPT involves the rapid conversion of light into heat by plasmonic nanoparticles targeted to a tumor, causing hyperthermia-induced cell death. These nanoparticles can be passively targeted utilizing the enhanced permeability and retention effect, or actively targeted using proteins, peptides, or other small molecules. Here, we report the use of actively targeted spherical gold nanoparticles (AuNPs), both to induce PPT cell death, and to monitor the associated molecular changes through time-dependent surface enhanced Raman spectroscopy within a single cell. We monitored these changes in real-time and found that heat generated from the aggregated nanoparticles absorbing near infrared (NIR) laser light of sufficient powers caused modifications in the protein and lipid structures within the cell and ultimately led to cell death. The same molecular changes were observed using different nanoparticle sizes and laser intensities, indicating the consistency of the molecular changes throughout PPT-induced cell death from actively targeted AuNPs. We also confirmed these observations by comparing them to reference spectra obtained by cell death induced by oven heating at 100 degrees C. The ability to monitor PPT-induced cell death in real-time will help understand the changes on a molecular level and offers us a basis to understand the molecular mechanisms involved in photothermal cancer cell death. PMID- 26746479 TI - Cancer Mortality Among Recipients of Solid-Organ Transplantation in Ontario, Canada. AB - IMPORTANCE: Solid-organ transplant recipients (SOTRs) are at greater risk of developing some cancers than the general population; however, because they are also at increased risk of mortality from noncancer causes, the effect of transplantation on cancer mortality is unclear. OBJECTIVE: To describe cancer mortality in SOTRs and to assess whether SOTRs are at increased risk of cancer mortality compared with the general population. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study of patients who underwent solid-organ transplantation in Ontario, Canada, between 1991 and 2010 with 85 557 person years of follow-up through December 31, 2011. Solid-organ transplantation was identified using the national transplant register and linked to the provincial cancer registry and administrative databases. The analysis was conducted between November 2013 and February 2015. EXPOSURE: Solid-organ transplantation. MAIN OUTCOMES AND MEASURES: Cancer mortality for SOTRs was compared with that of the general population using standardized mortality ratios (SMRs). Mortality and cause of death were ascertained by record linkage between the Canadian Organ Replacement Register, the Ontario Cancer Registry, and the Office of the Registrar General of Ontario death database. RESULTS: A total of 11 061 SOTRs were identified, including 6516 kidney, 2606 liver, 929 heart, and 705 lung transplantations. Recipients had a median (interquartile range) age of 49 (37-58) years, and 4004 (36.2%) were women. Of 3068 deaths, 603 (20%) were cancer related. Cancer mortality in SOTRs was significantly elevated compared with the Ontario population (SMR, 2.84 [95% CI, 2.61-3.07]). The risk remained elevated when patients with pretransplant malignant neoplasms (n = 1124) were excluded (SMR, 1.93 [95% CI, 1.75-2.13]). The increased risk was observed irrespective of transplanted organ. The SMR for cancer death after solid-organ transplantation was higher in children (SMR, 84.61 [95% CI, 52.00-128.40]) and lower in patients older than 60 years (SMR, 1.88 [95% CI, 1.62-2.18]) but remained elevated compared with the general population at all ages. CONCLUSIONS AND RELEVANCE: Cancer death rate in SOTRs was increased compared with that expected in the general population; cancer was the second leading cause of death in these patients. Advances in prevention, clinical surveillance, and cancer treatment modalities for SOTRs are needed to reduce the burden of cancer mortality in this population. PMID- 26746564 TI - Neuraxial catheter and antithrombotic therapy for myocardial infarction: When can we remove it? PMID- 26746491 TI - Mechanical Characterization of a Dynamic and Tunable Methacrylated Hyaluronic Acid Hydrogel. AB - Hyaluronic acid (HA) is a commonly used natural polymer for cell scaffolding. Modification by methacrylate allows it to be polymerized by free radicals via addition of an initiator, e.g., light-sensitive Irgacure, to form a methacrylated hyaluronic acid (MeHA) hydrogel. Light-activated crosslinking can be used to control the degree of polymerization, and sequential polymerization steps allow cells plated onto or in the hydrogel to initially feel a soft and then a stiff matrix. Here, the elastic modulus of MeHA hydrogels was systematically analyzed by atomic force microscopy (AFM) for a number of variables including duration of UV exposure, monomer concentration, and methacrylate functionalization. To determine how cells would respond to a specific two-step polymerization, NIH 3T3 fibroblasts were cultured on the stiffening MeHA hydrogels and found to reorganize their cytoskeleton and spread area upon hydrogel stiffening, consistent with cells originally cultured on substrates of the final elastic modulus. PMID- 26746565 TI - Ex vivo lung graft perfusion. AB - This review proposes an update of the state of the art and the ongoing clinical trials of ex vivo lung perfusion for lung transplantation in patients. Ex vivo lung perfusion techniques (EVLP) can be used to evaluate a lung graft outside of the body. The goal of EVLP is to study the functional status of lung grafts that were first rejected for transplantation because they did not match all criteria for a conventional transplantation. After an EVLP evaluation, some of these lungs may be requalified for a possible transplantation in patients. This article proposes an overview of the developments of EVLP techniques. During EVLP, the perfusion and ventilation of the isolated lung preparation are very progressive in order to avoid oedema due to ischaemia-reperfusion injuries. Lung evaluation is mainly based on gasometric (PaO2/FiO2) and rheological criteria (low pulmonary arterial resistance). Several series of patients transplanted with EVLP evaluated lungs have been recently published with promising results. EVLP preparations also allow a better understanding of the physiopathology and treatments of ischaemia reperfusion injuries. Organ procurements from "non-heart-beating" donors will probably require a wider application of these ex vivo techniques. The development of semi-automated systems might facilitate the clinical use of EVLP techniques. PMID- 26746566 TI - Validation of the 30-Day Postoperative Mortality Standard and Its Relevance. PMID- 26746567 TI - Hepatitis C status and infectious complications in the surgical intensive care unit: a retrospective analysis of 1,941 consecutive patients. AB - BACKGROUND: Hepatitis C virus (HCV) infection is thought to be associated with immune dysfunction. We hypothesized that HCV status would be associated with increased infectious complications in the surgical intensive care unit (SICU). METHODS: All patients admitted to our SICU between 2008 and 2012 were included. We evaluated 90-day mortality and infectious complications in the SICU. Multivariate logistic regression was performed to identify predictors of infectious complications and 90-day mortality. RESULTS: A total of 1,941 patients were included. The HCV-positive group had a higher overall incidence of infectious complications (25% vs 18%), particularly ventilator-associated pneumonia (VAP) and bacteremia. The increased incidences of VAP and bacteremia persisted when cirrhotic patients were excluded. Prolonged intubation (Odds Ratio [OR] = 2.1), abdominal surgery (OR = 1.6), and model for end-stage liver disease >= 15 (OR = 1.4) were independent predictors of SICU infectious complications. CONCLUSIONS: The HCV-positive group had an increased incidence of infectious complications in the SICU, particularly VAP and bacteremia. This effect persisted when cirrhotic patients were excluded. PMID- 26746568 TI - Surgeon specialization impacts the management but not outcomes of acute complicated diverticulitis. AB - BACKGROUND: The management and outcomes of patients receiving nonelective surgical treatment of acute complicated diverticulitis by surgeon specialization have received little attention. METHODS: A retrospective review was performed of consecutive patients with acute complicated diverticulitis who underwent surgery from 2006 to 2013. Patients were analyzed based on surgeon specialty: general surgery (GS) or colorectal surgery (CRS). RESULTS: One hundred fifteen patients met criteria for study; 62 patients in the CRS and 53 in the GS group. GS were more likely to perform Hartmann's procedures or primary anastomosis and less likely to perform primary anastomosis with diverting ileostomy than CRS. There were no differences between groups for any outcome measures on univariate analysis. CRS patients had shorter operative time (P = .001) and length of stay (P <= .001) for stoma reversal procedures. Surgeon specialization was not associated with morbidity, readmission, or length of stay on multivariate analysis. CONCLUSIONS: Although surgical management differed significantly between CRS and GS, comparable outcomes were observed at the index hospital admission. PMID- 26746569 TI - Precise Longitudinal Tracking of Microscopic Structures in Melanocytic Nevi Using Reflectance Confocal Microscopy: A Feasibility Study. AB - IMPORTANCE: Reflectance confocal microscopy (RCM), a cellular-level, in vivo imaging technique, may be potentially used for monitoring melanocytic neoplasms for microscopic stability vs changes over time. OBJECTIVE: To test feasibility of using RCM to track specific microscopic structures within nevi over 1 year. DESIGN, SETTING, AND PARTICIPANTS: This was an observational study, a review of prospectively acquired RCM images, performed at a tertiary academic medical center. Seventeen patients were enrolled from adult patients presenting to pigmented lesion clinic; from each participant, 3 confirmed benign nevi were randomly selected from the upper and lower back and from the lower extremity. EXPOSURES: Nevi underwent standardized RCM imaging at baseline and after 1 year. MAIN OUTCOMES AND MEASURES: We tested interobserver reproducibility in recognition of tissue anchors, RCM structures that can be identified at 2 time points. We used 2 tests to measure concordance between independent readers: (1) In the multiple choice matching test (n = 43 nevi), readers were shown a tissue anchor in a baseline RCM image (<= 1 * 1-mm field-of-view) and asked to identify the same structure in 1 of 4 equally sized RCM images obtained from the same nevus at follow-up. (2) In the annotation test (n = 29 nevi), readers were shown a tissue anchor in a follow-up RCM image (<= 1 * 1-mm field-of-view) and asked to annotate the corresponding location of this structure in the baseline RCM mosaic image (<= 5 * 5-mm field-of-view) from the same nevus; good agreement was defined as annotations deviant by less than 10% of the mosaic's width. RESULTS: In total, 17 patients (mean age, 45 years [range, 28-70 years]; 10 [59%] were women) contributed a total of 51 nevi, of which 44 nevi (86%) were used for the study. Images from 7 nevi (14%) were suboptimal in quality. Tissue anchors were identified at both time points in all 44 nevi. Selected tissue anchors were located at a mean depth of 54.3 um; the most commonly selected anchors (37 of 44 images [84.1%]) were dermal papillae. In the multiple choice matching test, compared with a reference reader, 2 readers correctly matched baseline to follow up tissue anchors in 40 of 43 nevi (93%; P < .01) and 42 of 43 nevi (98%; P < .01), respectively. In the annotation test, there was good agreement between 2 readers in all 29 cases (100%); the mean deviation was 2% (range, 0%-7.5%). CONCLUSIONS AND RELEVANCE: Precise longitudinal tracking of microscopic structures in melanocytic nevi using RCM is feasible. PMID- 26746570 TI - A Comparison of 5 Models of Total Knee Arthroplasty in Young Patients. AB - BACKGROUND: Several different total knee implants were introduced in an attempt to potentially improve outcomes of total knee arthroplasty in young patients. The object of this study was to compare the clinical outcomes of 5 models of total knee implants. METHODS: We compared 172 patients who received posterior substituting knee implants with an average 13.2-year follow-up, 182 patients who received high-flex knees with an average 11.8-year follow-up, 190 patients who received mobile-bearing knees with an average 13.9-year follow-up, 170 patients who received gender-specific knees with an average 10.8-year follow-up, and 192 patients who received oxidized zirconium knees with an average 13.5-year follow up. There were 186 men and 720 women (mean age, 53.3 years; range, 40-60). The mean follow-up was 12.6 years. RESULTS: We found similar postoperative Knee Society knee and function scores (P = .693 and P = .698, respectively), postoperative Western Ontario MacMaster Universities Osteoarthritis Index score (P = .523), University of California, Los Angeles activity score (P = .651) and range of knee motion (P = .417), radiographic results (P > .05), revision rates (P = .241), and survivorship (P = .981) of the implants. CONCLUSIONS: Range of knee motion, prevalence of polyethylene wear, osteolysis, revision rates, and survivorship of 5 models of total knee arthroplasties were similar. We believe that good designs with a good quality of polyethylene and defined surgical techniques provided good clinical and radiographic outcomes of these 5 models of total knee arthroplasties at this length of follow-up. PMID- 26746571 TI - [Integrated approach to a complex chronic case through an interdisciplinary team in primary care]. AB - This article tends to illustrate the coordination mechanisms used through an example centred on a case study of a 65 year-old patient who presents obesity, hypertension, high cardiovascular risk, alcoholism, smoking and silent ischaemic strokes; divorced twice and with five children. After his last separation 8 years ago he moved to his father's house. While his father was still alive his health situation was stable and monitored by professionals of the primary care team. He was recently referred to the Social Worker at the Health Centre due to his lack of personal hygiene and housing. The interdisciplinary work of the Social Worker and Community Nurse Case Manager resulted in a shared action plan. His father died a year ago and since then there was no news of the patient in the health centre and also he did not collect his medication from the pharmacy. The house was owned by inheritance by the smallest of the four brothers, who had threatened to expel him. In the interview, the brother claimed that he didn't want to be helped and only received visits from one of his sons occasionally to receive money. Primary care professionals visited him several times at home. The patient was cooperative and engaged when preparing a joint plan with the professionals involved. This joint plan allowed to activate the care coordination for a successful management of his chronic conditions. PMID- 26746572 TI - Aptamers as radiopharmaceuticals for nuclear imaging and therapy. AB - Today, radiopharmaceuticals belong to the standard instrumentation of nuclear medicine, both in the context of diagnosis and therapy. The majority of radiopharmaceuticals consist of targeting biomolecules which are designed to interact with a disease-related molecular target. A plethora of targeting biomolecules of radiopharmaceuticals exists, including antibodies, antibody fragments, proteins, peptides and nucleic acids. Nucleic acids have some significant advantages relative to proteinaceous biomolecules in terms of size, production, modifications, possible targets and immunogenicity. In particular, aptamers (non-coding, synthetic, single-stranded DNA or RNA oligonucleotides) are of interest because they can bind a molecular target with high affinity and specificity. At present, few aptamers have been investigated preclinically for imaging and therapeutic applications. In this review, we describe the use of aptamers as targeting biomolecules of radiopharmaceuticals. We also discuss the chemical modifications which are needed to turn aptamers into valuable (radio )pharmaceuticals, as well as the different radiolabeling strategies that can be used to radiolabel oligonucleotides and, in particular, aptamers. PMID- 26746574 TI - Emerging role of tumor markers and biochemistry in the preoperative invasive assessment of intraductal papillary mucinous neoplasm of the pancreas. AB - BACKGROUND: We explored the significance of laboratory examinations in predicting invasive carcinoma derived from intraductal papillary mucinous neoplasm (IPMN). METHODS: We retrospectively reviewed preoperative laboratory examination data and postoperative pathological data for 87 patients with IPMN who underwent surgical resection at Peking Union Medical College Hospital from February 2008 to March 2015. RESULTS: Histological review of 87 patients with surgical resection revealed 4 cases of mild-grade dysplasia (4.6%), 34 cases of intermediate dysplasia (39.1%), 16 cases of high-grade dysplasia (18.4%) and 33 cases of invasive carcinoma (37.9%). The first 3 grades were considered noninvasive. In univariate analyses, increased serum concentrations of CA19-9 (p<0.001), CA24-2 (p<0.001), CEA (p<0.001) and hsCRP (p=0.027) were significantly associated with invasive carcinoma. Multivariate analysis showed that increased serum concentrations of CA19-9 (p=0.009) and CEA (p=0.042) were significant independent predictors of invasiveness. The combination of CA19-9, CA 24-2 and CEA improved the accuracy of prediction, and the sensitivity and specificity were 71.0% and 87.7% respectively. CONCLUSIONS: The development of diagnostic laboratory tests has important implications for pre-operative IPMN evaluation. Increased serum CA19-9 and CEA concentrations are independent predictors of invasive carcinoma derived from IPMN, and increased serum CA24-2 and hsCRP concentrations are significantly associated with the risk of invasiveness. Combined detection of CA19-9+CA24-2+CEA proved to be the most accurate in predicting the invasiveness of IPMN. PMID- 26746576 TI - Factors Affecting Poststroke Sleep Disorders. AB - OBJECTIVE: The aim of this study is to evaluate the sleep quality of stroke patients, to present the influencing factors, and thus to provide more effective rehabilitation in hospitals' inpatient clinics. MATERIALS AND METHODS: Twenty three stroke patients who received inpatient treatment at Bolu Physical Therapy and Rehabilitation Hospital were retrospectively evaluated in the study. Educational background, occupation, body mass index, symptom duration, etiology, dominant hemisphere, affected hemisphere, comorbid diseases, and Brunnstrom recovery stages (9), Pittsburgh Sleep Quality Index (PSQI) score, Beck Depression Inventory (BDI) score, and Functional Independence Measure score were assessed. RESULTS: In multivariate linear regression analysis, we found that BDI score (P = .030) and comorbid diseases (P = .040) had the highest effect on change in PSQI. CONCLUSIONS: Depression and comorbid diseases were the most effective factors on poststroke sleep disorder in patients who underwent neurological rehabilitation and they should be managed to increase the efficacy of the neurological rehabilitation. PMID- 26746575 TI - Antimicrobial cathelicidin peptide LL-37 inhibits the pyroptosis of macrophages and improves the survival of polybacterial septic mice. AB - LL-37 is the only known member of the cathelicidin family of antimicrobial peptides in humans. In addition to its broad spectrum of antimicrobial activities, LL-37 can modulate various inflammatory reactions. We previously revealed that LL-37 suppresses the LPS/ATP-induced pyroptosis of macrophages in vitro by both neutralizing the action of LPS and inhibiting the response of P2X7 (a nucleotide receptor) to ATP. Thus, in this study, we further evaluated the effect of LL-37 on pyroptosis in vivo using a cecal ligation and puncture (CLP) sepsis model. As a result, the intravenous administration of LL-37 improved the survival of the CLP septic mice. Interestingly, LL-37 inhibited the CLP-induced caspase-1 activation and pyroptosis of peritoneal macrophages. Moreover, LL-37 modulated the levels of inflammatory cytokines (IL-1beta, IL-6 and TNF-alpha) in both peritoneal fluids and sera, and suppressed the activation of peritoneal macrophages (as evidenced by the increase in the intracellular levels of IL 1beta, IL-6 and TNF-alpha). Finally, LL-37 reduced the bacterial burdens in both peritoneal fluids and blood samples. Together, these observations suggest that LL 37 improves the survival of CLP septic mice by possibly suppressing the pyroptosis of macrophages, and inflammatory cytokine production by activated macrophages and bacterial growth. Thus, the present findings imply that LL-37 can be a promising candidate for sepsis because of its many functions, such as the inhibition of pyroptosis, modulation of inflammatory cytokine production and antimicrobial activity. PMID- 26746577 TI - Five-year results of Small Incision Lenticule Extraction (ReLEx SMILE). AB - BACKGROUND: To evaluate the 5-year results of Refractive Lenticule Extraction (ReLEx) as Small Incision Lenticule Extraction (SMILE) technique for treatment of myopia and myopic astigmatism. METHODS: In 2008/2009, the worldwide first 91 eyes were treated using a novel surgical technique (SMILE), where a refractive lenticule of intrastromal corneal tissue is removed though a small incision completely eliminating flap-cutting. 56 out of 91 eyes of the original treatment group volunteered for re-examination 5 years after surgery. Uncorrected distance visual acuity and corrected distance visual acuity after 5 years, objective and manifest refractions as well as evaluation of the interface and corneal surface by slit-lamp examination were documented. Late side effects like corneal scars, corneal ectasia, persistent dry eye symptoms or cataract were documented. RESULTS: 5 years postoperatively, no significant change to the 6-month data was found. Spherical equivalent was -0.375 D and therefore close to target refraction (emmetropia). 32 of the 56 eyes had gained 1-2 Snellen lines. There was no loss of 2 or more lines over the 5-year period. Regression in the long term was 0.48 D. CONCLUSIONS: This first long-term study demonstrates SMILE to be an effective, stable and safe procedure for treatment of myopia and myopic astigmatism. CLINICAL TRIAL NUMBER: DE/CA93/KP/07/001. Post-results. PMID- 26746578 TI - CFH Y402H polymorphism and the complement activation product C5a: effects on NF kappaB activation and inflammasome gene regulation. AB - BACKGROUND/AIMS: The Y402H polymorphism in the complement factor H (CFH) gene is an important risk factor for age-related macular degeneration (AMD). Complement activation products and proinflammatory cytokines are associated with this polymorphism at the systemic level, but less is known of the associations in the outer retina of the genotyped eye. Here we investigate complement activation products and their role in nuclear factor (NF)-kappaB activation and gene expression of the NLRP3 inflammasome pathway. METHODS: Postmortem donor eyes were genotyped for the CFH Y402H polymorphism and assessed for complement C3a, C5a, interleukin (IL)-18 and tumour necrosis factor (TNF)-alpha. ARPE19 cells were stimulated basolaterally with C5a or TNF-alpha in polarised cultures. NF-kappaB activation was assessed with a reporter cell line. Gene expression of inflammasome-related (NLRP3, caspase-1, IL-1beta and IL-18) and classic inflammatory (IL-6 and IL-8) genes was studied. The distribution of inflammasome products, IL-1beta and IL-18, was studied in postmortem donor eyes with AMD pathologies. RESULTS: Eyes with the homozygous at-risk variant demonstrated higher levels of C5a, IL-18 and TNF-alpha in Bruch's membrane and choroid. C5a promoted NF-kappaB activation and upregulation of IL-18 in polarised ARPE19. TNF alpha promoted NF-kappaB activation and gene expression of caspase-1, IL-1beta, IL-18, IL-6 and IL-8, but downregulated NLRP3. In eyes with geographic atrophy, strong immunoreactivity was observed for inflammasome products IL-1beta and IL-18 compared with age-matched controls. CONCLUSION: The at-risk polymorphism of the CFH Y402H may contribute to AMD disease process through increased complement and NF-kappaB activation, and the upregulation of IL-18, a product of inflammasome activation. PMID- 26746580 TI - The effects of gratitude expression on neural activity. AB - Gratitude is a common aspect of social interaction, yet relatively little is known about the neural bases of gratitude expression, nor how gratitude expression may lead to longer-term effects on brain activity. To address these twin issues, we recruited subjects who coincidentally were entering psychotherapy for depression and/or anxiety. One group participated in a gratitude writing intervention, which required them to write letters expressing gratitude. The therapy-as-usual control group did not perform a writing intervention. After three months, subjects performed a "Pay It Forward" task in the fMRI scanner. In the task, subjects were repeatedly endowed with a monetary gift and then asked to pass it on to a charitable cause to the extent they felt grateful for the gift. Operationalizing gratitude as monetary gifts allowed us to engage the subjects and quantify the gratitude expression for subsequent analyses. We measured brain activity and found regions where activity correlated with self-reported gratitude experience during the task, even including related constructs such as guilt motivation and desire to help as statistical controls. These were mostly distinct from brain regions activated by empathy or theory of mind. Also, our between groups cross-sectional study found that a simple gratitude writing intervention was associated with significantly greater and lasting neural sensitivity to gratitude - subjects who participated in gratitude letter writing showed both behavioral increases in gratitude and significantly greater neural modulation by gratitude in the medial prefrontal cortex three months later. PMID- 26746579 TI - Accumulation of iron in the putamen predicts its shrinkage in healthy older adults: A multi-occasion longitudinal study. AB - Accumulation of non-heme iron is believed to play a major role in neurodegeneration of the basal ganglia. In healthy aging, however, the temporal relationship between change in brain iron content and age-related volume loss is unclear. Here, we present the first long-term longitudinal multi-occasion investigation of changes in iron content and volume in the neostriatum in a sample of healthy middle-aged and older adults (N=32; ages 49-83years at baseline). Iron content, estimated via R2* relaxometry, increased in the putamen, but not the caudate nucleus. In the former, the rate of accumulation was coupled with change in volume. Moreover, greater baseline iron content predicted faster shrinkage and smaller volumes seven years later. Older age partially accounted for individual differences in neostriatal iron content and volume, but vascular risk did not. Thus, brain iron content may be a promising biomarker of impending decline in normal aging. PMID- 26746583 TI - High-Content Analysis of Breast Cancer Using Single-Cell Deep Transfer Learning. AB - High-content analysis has revolutionized cancer drug discovery by identifying substances that alter the phenotype of a cell, which prevents tumor growth and metastasis. The high-resolution biofluorescence images from assays allow precise quantitative measures enabling the distinction of small molecules of a host cell from a tumor. In this work, we are particularly interested in the application of deep neural networks (DNNs), a cutting-edge machine learning method, to the classification of compounds in chemical mechanisms of action (MOAs). Compound classification has been performed using image-based profiling methods sometimes combined with feature reduction methods such as principal component analysis or factor analysis. In this article, we map the input features of each cell to a particular MOA class without using any treatment-level profiles or feature reduction methods. To the best of our knowledge, this is the first application of DNN in this domain, leveraging single-cell information. Furthermore, we use deep transfer learning (DTL) to alleviate the intensive and computational demanding effort of searching the huge parameter's space of a DNN. Results show that using this approach, we obtain a 30% speedup and a 2% accuracy improvement. PMID- 26746582 TI - Human Adenine Nucleotide Translocase (ANT) Modulators Identified by High Throughput Screening of Transgenic Yeast. AB - Transport of ADP and ATP across mitochondria is one of the primary points of regulation to maintain cellular energy homeostasis. This process is mainly mediated by adenine nucleotide translocase (ANT) located on the mitochondrial inner membrane. There are four human ANT isoforms, each having a unique tissue specific expression pattern and biological function, highlighting their potential as drug targets for diverse clinical indications, including male contraception and cancer. In this study, we present a novel yeast-based high-throughput screening (HTS) strategy to identify compounds inhibiting the function of ANT. Yeast strains generated by deletion of endogenous proteins with ANT activity followed by insertion of individual human ANT isoforms are sensitive to cell permeable ANT inhibitors, which reduce proliferation. Screening hits identified in the yeast proliferation assay were characterized in ADP/ATP exchange assays employing recombinant ANT isoforms expressed in isolated yeast mitochondria and Lactococcus lactis as well as by oxygen consumption rate in mammalian cells. Using this approach, closantel and CD437 were identified as broad-spectrum ANT inhibitors, whereas leelamine was found to be a modulator of ANT function. This yeast "knock-out/knock-in" screening strategy is applicable to a broad range of essential molecular targets that are required for yeast survival. PMID- 26746585 TI - PGC-1alpha overexpression via local transfection attenuates mitophagy pathway in muscle disuse atrophy. AB - Loss of mitochondrial structural and functional integrity plays a critical role in the pathogenesis of muscle disuse atrophy. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) has been suggested to modulate autophagy-lysosome pathway (mitophagy) during muscle atrophy, but clear evidence is still lacking. In the current study, we tested the hypothesis that overexpression of PGC-1alpha via in vivo transfection would ameliorate mitophagy in mouse tibialis anterior muscle subjected to two weeks of immobilization (IM), followed by remobilization (RM). While mitochondrial biogenesis and antioxidant enzymes are decreased, all autophagic and mitophagic protein markers such as Beclin-1, Bnip3, PINK1, parkin, Mul1 and the LC3II/LC3I ratio were increased in IM-RM muscle together with activation of FoxO pathway. Overexpression of PGC 1alpha significantly increased mitochondrial DNA proliferation and oxidative enzyme activity, whereas it mitigated oxidative stress and mitochondrial ubiquination in IM-RM muscle. Protein contents of PINK1, parkin and Mul1 in mitochondria decreased by approximately 50% with PGC-1alpha treatment. Furthermore, PGC-1alpha overexpression suppressed FoxO1 and FoxO3 activation along with a decreased LC3II/LC3I ratio. Importantly, PGC-1alpha attenuated IM-RM induced ubiquination and degradation of mitofusion protein Mfn2. Muscle apoptotic tendency, measured by Bax/Bcl2 ratio and caspase-3 activity, were elevated with IM-RM, but unaffected by PGC-1alpha. We conclude that overexpression of PGC 1alpha by in vivo transfection can inhibit activation of mitophagy pathway in the atrophying muscle caused by immobilization. PMID- 26746584 TI - Phenotypic Screening of Drug Library in Actively Differentiating Mouse Embryonic Stem Cells. AB - Phenotypic screening enables the discovery of new drug leads with novel targets. ES cells differentiate into different lineages by successively making use of different subsets of the genome's possible macromolecular interactions. If a compound effectively targets just one of these interactions, it derails the developmental pathway to produce a phenotypical change. The OTRADI microsource spectrum library of 2000 approved drug components, natural products, and bioactive components was screened for compounds that can induce phenotypic changes in ES cell cultures at 10 uM after 3 days. Twenty-one compounds that induced specific morphologies also induced unique changes to an expression profile of a dozen markers of early embryonic development, indicating that each compound has derailed the molecular developmental process in a characteristic way. Phenotypic screens conducted with ES cultures differentiating along different lineages can be used to efficiently prescreen compounds able to regulate cell differentiation lineage. PMID- 26746581 TI - Quantitative proteomic analysis of Shigella flexneri and Shigella sonnei Generalized Modules for Membrane Antigens (GMMA) reveals highly pure preparations. AB - Outer membrane blebs are naturally shed by Gram-negative bacteria and are candidates of interest for vaccines development. Genetic modification of bacteria to induce hyperblebbing greatly increases the yield of blebs, called Generalized Modules for Membrane Antigens (GMMA). The composition of the GMMA from hyperblebbing mutants of Shigella flexneri 2a and Shigella sonnei were quantitatively analyzed using high-sensitivity mass spectrometry with the label free iBAQ procedure and compared to the composition of the solubilized cells of the GMMA-producing strains. There were 2306 proteins identified, 659 in GMMA and 2239 in bacteria, of which 290 (GMMA) and 1696 (bacteria) were common to both S. flexneri 2a and S. sonnei. Predicted outer membrane and periplasmic proteins constituted 95.7% and 98.7% of the protein mass of S. flexneri 2a and S. sonnei GMMA, respectively. Among the remaining proteins, small quantities of ribosomal proteins collectively accounted for more than half of the predicted cytoplasmic protein impurities in the GMMA. In GMMA, the outer membrane and periplasmic proteins were enriched 13.3-fold (S. flexneri 2a) and 8.3-fold (S. sonnei) compared to their abundance in the parent bacteria. Both periplasmic and outer membrane proteins were enriched similarly, suggesting that GMMA have a similar surface to volume ratio as the surface to periplasmic volume ratio in these mutant bacteria. Results in S. flexneri 2a and S. sonnei showed high reproducibility indicating a robust GMMA-producing process and the low contamination by cytoplasmic proteins support the use of GMMA for vaccines. Data are available via ProteomeXchange with identifier PXD002517. PMID- 26746586 TI - Peroxynitrite deteriorates oocyte quality through disassembly of microtubule organizing centers. AB - Previous theoretical studies have suggested that utilization of 3-D imaging to acquire morphologic parameters of meiotic spindles may be useful in infertility related procedures as an assessment of oocyte quality. However, our results show that treatment of oocytes with increasing concentrations of peroxynitrite (ONOO( )) caused a dramatic alteration in spindle shape in which morphologic parameters are not measurable or are uninformative in terms of oocyte quality. Metaphase II mouse oocytes (n=520) were treated with increasing concentrations of ONOO(-), after which all oocytes were fixed and subjected to indirect immunofluorescence. Oocyte quality was assessed by alterations in the microtubule-organizing center (MTOC), pericentrin location, microtubule morphology, and chromosomal alignment. In untreated oocytes, pericentrin is primarily assembled utilizing the acentrosomal MTOC, which appears as a condensation at both spindle poles. The spindle has a symmetrical pointed barrel shape, assembled around the chromosomal plate at the spindle equator. Oocytes treated with low concentrations of ONOO(-) (<2.5 MUM) showed shortening of the spindle apparatus, while pericentrin scatters from a tight condensation to a dispersed cluster around each spindle pole. At higher ONOO(-) concentrations (>2.5MUM) the central attachments between microtubules are strained and bend or unevenly break, and the MTOC proteins are further dispersed or undetectable. Peroxynitrite mediated MTOC damage, which deranges the chromosomal scaffold at the time of assembly and separation, caused the deterioration in oocyte quality. These results provide a link between reactive oxygen species and poor reproductive outcomes and elucidate the underlying etiology, which could be used as a superior biomarker for oocyte quality compared to existing assessment tools. PMID- 26746587 TI - Attention to irrelevant contexts decreases as training increases: Evidence from eye-fixations in a human predictive learning task. AB - Participants were trained in a human predictive learning task in which they had to predict whether the ingestion of a given food (cue) by the imaginary customer of an imaginary restaurant (context) was followed by gastric malaise (outcome). One food was always followed by gastric malaise in one of the contexts, while other foods were not followed by gastric malaise in the same, or in an alternative context. Predictive responses and eye-fixations were recorded throughout the 48 training trials with each cue involved in the task. In agreement with the predictions of the Attentional Theory of Context Processing, attention to the contexts measured through eye-fixations decreased while attention to the cues increased as training progressed. The results of this study give support to the idea that contexts are actively processed at the beginning of acquisition, and that this processing decreases as training increases. PMID- 26746588 TI - Process optimization and kinetics for leaching of rare earth metals from the spent Ni-metal hydride batteries. AB - Nickel-metal hydride batteries (Ni-MH) contain not only the base metals, but valuable rare earth metals (REMs) viz. La, Sm, Nd, Pr and Ce as well. In view of the importance of resource recycling and assured supply of the contained metals in such wastes, the present study has focussed on the leaching of the rare earth metals from the spent Ni-MH batteries. The conditions for the leaching of REMs from the spent batteries were optimized as: 2M H2SO4, 348K temperature and 120min of time at a pulp density (PD) of 100g/L. Under this condition, the leaching of 98.1% Nd, 98.4% Sm, 95.5% Pr and 89.4% Ce was achieved. Besides the rare earth metals, more than 90% of base metals (Ni, Co, Mn and Zn) were also leached out in this condition. Kinetic data for the dissolution of all the rare earth metals showed the best fit to the chemical control shrinking core model. The leaching of metals followed the mechanism involving the chemical reaction proceeding on the surface of particles by the lixiviant, which was corroborated by the XRD phase analysis and SEM-EDS studies. The activation energy of 7.6, 6.3, 11.3 and 13.5kJ/mol was acquired for the leaching of neodymium, samarium, praseodymium and cerium, respectively in the temperature range 305-348K. From the leach liquor, the mixed rare earth metals were precipitated at pH~1.8 and the precipitated REMs was analyzed by XRD and SEM studies to determine the phases and the morphological features. PMID- 26746589 TI - Adelta-fiber low threshold mechanoreceptors innervating mammalian hairy skin: A review of their receptive, electrophysiological and cytochemical properties in relation to Adelta-fiber high threshold mechanoreceptors. AB - The sensation of gentle touch of the mammalian hairy skin is mediated by morphologically and physiologically distinct classes of low-threshold mechanoreceptors (LTMs) which are classified, according to their axonal conduction velocities, into Abeta-, Adelta- and C-LTMs. Although Adelta-LTMs (D hair cells) were first described about five decades ago, and have been found in hairy skin of every species examined including humans, it is commonly assumed that all Adelta-fiber neurons are nociceptors. This view is endorsed by many textbooks. This article reviews the evidence that Adelta-LTMs exist in substantial proportions in different species, and that their peripheral and central axonal endings, molecular markers, receptive, electrophysiological and cytochemical properties are distinct from those of Adelta-high-threshold mechanoreceptors (Adelta-HTMs). A brief overview of some of the ion channels and markers that are expressed by the two populations of primary afferent neurons is also provided. Failure to recognize the existence and properties of Adelta-LTMs might lead/have led to misinterpretations of data. Abeta-LTMs and C-LTMs have been reviewed elsewhere and are not subject of this review. PMID- 26746590 TI - Neuroimaging in moderate MDMA use: A systematic review. AB - MDMA ("ecstasy") is widely used as a recreational drug, although there has been some debate about its neurotoxic effects in humans. However, most studies have investigated subjects with heavy use patterns, and the effects of transient MDMA use are unclear. In this review, we therefore focus on subjects with moderate use patterns, in order to assess the evidence for harmful effects. We searched for studies applying neuroimaging techniques in man. Studies were included if they provided at least one group with an average of <50 lifetime episodes of ecstasy use or an average lifetime consumption of <100 ecstasy tablets. All studies published before July 2015 were included. Of the 250 studies identified in the database search, 19 were included. There is no convincing evidence that moderate MDMA use is associated with structural or functional brain alterations in neuroimaging measures. The lack of significant results was associated with high methodological heterogeneity in terms of dosages and co-consumption of other drugs, low quality of studies and small sample sizes. PMID- 26746591 TI - Mentored peer reviewing for PhD faculty and students. AB - There is a need for scholars to be prepared as peer reviewers in order to ensure the continual publication of quality science. However, developing the skills to craft a constructive critique can be difficult. In this commentary, we discuss the use of a group peer review mentoring model for PhD students to gain experience in peer review from a faculty member who is experienced in peer review. Central to this model, was the opportunity for each student and faculty mentor to openly discuss their critique of the manuscript. Through this enriching experience, novice researchers were able to learn the elements of a good peer review, better determine a manuscript's substantive contribution to science, and advance the quality of their own manuscript writing. PMID- 26746592 TI - Confidence and authority through new knowledge: An evaluation of the national educational programme in paediatric oncology nursing in Sweden. AB - BACKGROUND: There is a lack of nurse specialists in many paediatric hospitals in Sweden. This lack of competence is devastating for childhood cancer care because it is a highly specialised area that demands specialist knowledge. Continuing education of nurses is important to develop nursing practice and also to retain them. OBJECTIVES: The aim of this study was to evaluate a Swedish national educational programme in paediatric oncology nursing. SETTINGS AND PARTICIPANTS: The nurses who participated came from all of the six paediatric oncology centres as well as from general paediatric wards. At the time of the evaluation, three groups of registered nurses (n=66) had completed this 2year, part-time educational programme. DESIGN AND METHODS: A study specific questionnaire, including closed and open-ended questions was sent to the 66 nurses and 54 questionnaires were returned. Answers were analysed using descriptive statistics and qualitative content analysis. RESULTS: The results show that almost all the nurses (93%) stayed in paediatric care after the programme. Furthermore, 31% had a position in management or as a consultant nurse after the programme. The vast majority of the nurses (98%) stated that the programme had made them more secure in their work. The nurses were equipped, through education, for paediatric oncology care which included: knowledge generating new knowledge; confidence and authority; national networks and resources. They felt increased confidence in their roles as paediatric oncology nurses as well as authority in their encounters with families and in discussions with co-workers. New networks and resources were appreciated and used in their daily work in paediatric oncology. CONCLUSIONS: The programme was of importance to the career of the individual nurse and also to the quality of care given to families in paediatric oncology. The national educational programme for nurses in Paediatric Oncology Care meets the needs of the highly specialised care. PMID- 26746593 TI - Five-Year Incidence and Visual Outcomes in Postintravitreal Injection Endophthalmitis. PMID- 26746594 TI - Prevalence, Awareness, and Risk Factors of Primary Open-Angle Glaucoma: Korea National Health and Nutrition Examination Survey 2008-2011. AB - PURPOSE: To investigate the prevalence, awareness, and risk factors for primary open-angle glaucoma (POAG) in the Korean population. DESIGN: The Korea National Health and Nutrition Examination Survey (KNHANES), a population-based cross sectional study using a complex, stratified, multistage, probability-cluster survey. PARTICIPANTS: A total of 13,831 participants 40 years of age or older were included from the KNHANES database for the years 2008 through 2011. METHODS: Glaucoma diagnosis was based on the International Society of Geographical and Epidemiological Ophthalmology criteria. The prevalence of POAG and the proportion of POAG patients previously informed of the disease were calculated using KNHANES sample weights. Ocular and systemic factors were compared between the POAG and control groups. Univariate and multivariate logistic regression analyses were used to evaluate the risk factors for POAG. MAIN OUTCOME MEASURES: Weighted prevalence, awareness, and risk factors for POAG. RESULTS: The prevalence of POAG in the Korean population was 4.7% (95% confidence interval, 4.2-5.1): 5.5% in men and 3.9% in women, respectively, which increased with age (P < 0.001). The mean intraocular pressure (IOP) in POAG eyes was 15.0+/-0.4 mmHg, which was higher than that of the control group (14.0+/-0.1 mmHg; P < 0.001). Multivariate logistic regression analysis revealed that older age (P < 0.001), male gender (P < 0.001), higher IOP (P < 0.001), myopia (P < 0.001), hypertension (P = 0.031), and nonoverweight status (P = 0.017) were associated significantly with POAG in the Korean population. Among the 710 study participants diagnosed with POAG, only 8.0% were aware of the disease. CONCLUSIONS: This was the first study to examine the prevalence, awareness, and risk factors of POAG in the Korean population using 4-year KNHANES data. Koreans with higher IOP, myopia, older age, male gender, hypertension, and nonoverweight status require more attention and support from the glaucoma screening and surveillance systems. PMID- 26746595 TI - Rates of Vitrectomy among Enrollees in a United States Managed Care Network, 2001 2012. AB - PURPOSE: To determine whether vitrectomy surgery rates have changed over the past decade and factors affecting the odds of undergoing this procedure. DESIGN: Retrospective, longitudinal cohort study. PARTICIPANTS: All enrollees 21 years of age or older between 2001 and 2012 in a United States managed care network. METHODS: Claims data from a managed care network were analyzed to identify all enrollees who underwent 1 vitrectomy or more each year from 2001 through 2012. Rates of vitrectomy per 1000 enrollees were computed each year from 2001 through 2012 for the entire group and separately for patients with and without diabetes mellitus. Multivariate logistic regression assessed factors affecting the odds of undergoing vitrectomy surgery. MAIN OUTCOME MEASURES: Annual rates of vitrectomy surgery from 2001 through 2012 and odds ratios (ORs) of undergoing a vitrectomy with 95% confidence intervals (CIs). RESULTS: Among the 11 161 907 eligible enrollees, 40 892 (0.4%) underwent vitrectomy over the 12-year period. The average age of those undergoing vitrectomy was 57+/-13 years. Overall vitrectomy rates increased 31% from 2001 to 2012 (from 1.47 to 1.92 per 1000 patients). During this same period, the vitrectomy rate among persons with diabetes mellitus decreased by 43% (from 5.84 to 3.31 per 1000 patients with diabetes). Women had 24% decreased odds of undergoing vitrectomy (adjusted odds ratio [OR], 0.76; 95% confidence interval [CI], 0.72-0.79). The odds of undergoing a vitrectomy were 17% greater for black persons (adjusted OR, 1.17; 95% CI, 1.07-1.27) and 7% higher for persons with diabetes (adjusted OR, 1.07; 95% CI, 1.01-1.14). CONCLUSIONS: Overall, we observed an increase in the vitrectomy rates per 1000 enrollees in this large managed care network over the course of the past decade. However, among persons with diabetes mellitus, vitrectomy rates declined substantially over this period. These changes may be explained, in part, by advances in surgical instrumentation and imaging methods to detect retinal diseases changing indications for surgery, improvements in diabetes care, and alternative treatment options for managing retinal conditions. These results may be useful for future planning of manpower needs and highlight the need for aggressive prevention of complications in black persons with diabetes. PMID- 26746596 TI - A Retrospective Comparison of Primary Baerveldt Implantation versus Trabeculectomy with Mitomycin C. AB - PURPOSE: To compare the safety and efficacy of Baerveldt implantation (Abbott Medical Optics, Santa Ana, CA) and trabeculectomy with mitomycin C (MMC) in patients who have not undergone prior incisional ocular surgery. DESIGN: Retrospective, comparative case series. PARTICIPANTS: A total of 125 patients with low-risk glaucoma undergoing primary glaucoma surgery, including 55 patients who received a 350-mm(2) Baerveldt glaucoma implant and 70 patients who underwent trabeculectomy with MMC. METHODS: Eligible patients were identified using Current Procedural Terminology codes, and their medical records were reviewed retrospectively. MAIN OUTCOME MEASURES: The primary outcome measure was surgical success (intraocular pressure [IOP] <=21 mmHg and reduced >=20% from baseline, IOP >5 mmHg, no reoperation for glaucoma, no loss of light-perception vision). Secondary outcome measures included visual acuity, IOP, number of glaucoma medications, and complications. RESULTS: The cumulative probability of success at 3 years with or without medical therapy was 87% in the Baerveldt group and 76% in the trabeculectomy group (P = 0.23). Postoperative complications occurred in 11 patients (20%) in the Baerveldt group and 20 patients (29%) in the trabeculectomy group (P = 0.27). Mean follow-up +/- standard deviation was 27+/-19 months in the Baerveldt group and 34+/-20 months in the trabeculectomy group (P = 0.053). CONCLUSIONS: Similar rates of surgical success and postoperative complications were observed in patients undergoing trabeculectomy with MMC and in those undergoing Baerveldt implantation during 3 years of follow-up. Both are viable primary glaucoma procedures in patients who have not undergone prior ocular surgery. PMID- 26746597 TI - Rate and Pattern of Rim Area Loss in Healthy and Progressing Glaucoma Eyes. AB - PURPOSE: To characterize the rate and pattern of age-related and glaucomatous neuroretinal rim area changes in subjects of African and European descent. DESIGN: Prospective longitudinal study. PARTICIPANTS: Two hundred ninety-six eyes of 157 healthy subjects (88 patients of African descent and 69 of European descent) and 73 progressing glaucoma eyes of 67 subjects (24 patients of African descent and 43 of European descent) from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study were included. METHODS: Global and sectoral rim areas were measured using confocal laser scanning ophthalmoscopy. Masked stereophotograph review determined progression of glaucomatous optic disc damage. The rates of absolute rim area loss and percentage rim area loss in healthy and progressing glaucomatous eyes were compared using multivariate, nested, mixed-effects models. MAIN OUTCOME MEASURES: Rate of rim area loss over time. RESULTS: The median follow-up time was 5.0 years (interquartile range, 2.0-7.4 years) for healthy eyes and 8.3 years (interquartile range, 7.5-9.9 years) for progressing glaucoma eyes. The mean rate of global rim area loss was significantly faster in progressing glaucomatous eyes compared with healthy eyes for both rim area loss (-10.2*10(-3) vs. -2.8*10(-3) mm(2)/year, respectively; P < 0.001) and percentage rim area loss (-1.1% vs. 0.2%/year, respectively; P < 0.001), but considerable overlap existed between the 2 groups. Sixty-three percent of progressing glaucoma eyes had a rate of change faster than the fifth quantile of healthy eyes. For both healthy and progressing eyes, the pattern of rim area loss and percentage rim area loss were similar, tending to be fastest in the superior temporal and inferior temporal sectors. The rate of change was similar in progressing eyes of patients of African or European descent. CONCLUSIONS: Compared with healthy eyes, the mean rate of global rim area loss was 3.7 times faster and the mean rate of global percentage rim area loss was 5.4 times faster in progressing glaucoma eyes. A reference database of healthy eyes can be used to help clinicians distinguish age-related rim area loss from rim area loss resulting from glaucoma. PMID- 26746600 TI - Acro-osteolysis as an indicator of severity in systemic sclerosis. AB - INTRODUCTION: Systemic sclerosis is a rare disease that predominantly affects women. The Medsger severity scale has been used to assess the severity, but it requires expensive and poorly accessible studies and it does not include complications such acrosteolysis, calcinosis, pericardial disease or hypothyroidism that occur on a relatively frequent basis in this disease. There is no study that considers if comorbidities, such as primary biliary cirrhosis, are related to gravity. OBJECTIVES: To determine the correlation between severity and the presence of such complications. METHODS: 40 patients with systemic sclerosis, dividing them into tertiles according to severity were studied. Dichotomous variables were described using percentages, while dimensional by averages+SD. Statistical inference was performed using chi square test or Kruskal Wallis test with Dunn post-test, as appropriate. A significance at P<.05 was set. RESULTS: Of all the complications studied there were only differences in severity with acrosteolysis. Within comorbidities, primary biliary cirrhosis is not associated with gravity. PMID- 26746599 TI - Periodic fever, aphtous stomatitis, pharyngitis and adenopathy syndrome and vitamin D: A possible treatment option? PMID- 26746601 TI - [Microbial contamination of the implant-abutment connections: Review of the literature]. AB - Today manufacturing process of dental implant parts allows for a precision of fit between implant and abutment of several microns. This microgap opens and closes under occlusal forces, leading to a pumping effect and to a contamination of the implant from bacteria and oral fluids. This kind of contamination is seen in all systems even if less often with internal connections that offers a better fit. Apart from this junction area, the screw well is another contamination pathway if the filling materials do not guarantee a hermetic sealing. The nature of contamination depends on the surrounding oral flora. When present, contamination leads to a persistent inflammatory reaction nearby the seal. The use of antiseptics or other materials for sealing the microgap decreases the risk of contamination and improves the gingival reaction. However, these solutions are time-limited. PMID- 26746598 TI - Spectral-Domain Optical Coherence Tomography Imaging in 67 321 Adults: Associations with Macular Thickness in the UK Biobank Study. AB - PURPOSE: To derive macular thickness measures and their associations by performing rapid, automated segmentation of spectral-domain optical coherence tomography (SD OCT) images collected and stored as part of the UK Biobank (UKBB) study. DESIGN: Large, multisite cohort study in the United Kingdom. Analysis of cross-sectional data. PARTICIPANTS: Adults from the United Kingdom aged 40 to 69 years. METHODS: Participants had nonmydriatic SD OCT (Topcon 3D OCT-1000 Mark II; Topcon GB, Newberry, Berkshire, UK) performed as part of the ocular assessment module. Rapid, remote, automated segmentation of the images was performed using custom optical coherence tomography (OCT) image analysis software (Topcon Advanced Boundary Segmentation [TABS]; Topcon GB) to generate macular thickness values. We excluded people with a history of ocular or systemic disease (diabetes or neurodegenerative diseases) and eyes with reduced vision (<0.1 logarithm of the minimum angle of resolution) or with low SD OCT signal-to-noise ratio and low segmentation success certainty. MAIN OUTCOME MEASURES: Macular thickness values across 9 Early Treatment of Diabetic Retinopathy Study (ETDRS) subfields. RESULTS: The SD OCT scans of 67 321 subjects were available for analysis, with 32 062 people with at least 1 eye meeting the inclusion criteria. There were 17 274 women and 14 788 men, with a mean (standard deviation [SD]) age of 55.2 (8.2) years. The mean (SD) logarithm of the minimum angle of resolution visual acuity was -0.075 (0.087), and the refractive error was -0.071 (+1.91) diopters (D). The mean (SD) central macular thickness (CMT) in the central 1-mm ETDRS subfield was 264.5 (22.9) MUm, with 95% confidence limits of 220.8 and 311.5 MUm. After adjusting for covariates, CMT was positively correlated with older age, female gender, greater myopia, smoking, body mass index (BMI), and white ethnicity (all P < 0.001). Of note, macular thickness in other subfields was negatively correlated with older age and greater myopia. CONCLUSIONS: We report macular thickness data derived from SD OCT images collected as part of the UKBB study and found novel associations among older age, ethnicity, BMI, smoking, and macular thickness. PMID- 26746602 TI - Otorhinolaryngological, audiovestibular and swallowing manifestations of patients with Niemann-Pick disease Type C. AB - OBJECTIVES: The aim of this study is to evaluate audiovestibular and swallowing impairment of patients with NPC. METHODS: Audiovestibular and swallowing evaluation were performed on patients with Niemann-Pick disease type C (NPC) at Hacettepe University between 20013 and 2015 prospectively. Pure-tone audiometry (PTA), Auditory Brain stem response (ABR), Flexible endoscopic evaluation of swallowing (FEES) test and posturography were done. Hearing, swallowing and balance states were measured. RESULTS: There were 16 patients (5 male and 11 female, with a median age of 6.5 years old). The most common ABR abnormalities observed were absent waves I and III (%70 absent I waves, %43.75 absent III waves). Twelve of sixteen patients (%75) had an ABR abnormality in at least one ear, of these, four patients had normal hearing and three of them had periferal hearing loss. 12 (75%) patients had complaint of postural imbalance. 11(69%) of patients had peripheral and one (6%) patient had central impairment. Nine of sixteen patients (56.25%) show some degree of dysphagia (either penetration or aspiration). Two patients (12.5%) showed aspiration both liquid and viscous nutrition. Three patients (18.75%) showed aspiration primarily in liquids and two of them had penetration with viscous nutrition. Three patients (18.75%) had penetration with no aspiration neither liquid nor viscous nutrition (PEN-ASP score was 3, 3, 5, respectively). CONCLUSION: There is no curative treatment for this devastating and fatal disorder and hearing impairment, balance and swallowing disorders can be seen especially late onset form of disease. PMID- 26746603 TI - Sevoflurane and bradycardia in infants with trisomy 21: A case report and review of the literature. AB - Various perioperative concerns have been reported in patients with trisomy 21 including associated congenital heart disease, atlantoaxial instability, tracheal and subglottic stenosis, a predisposition to respiratory complications, hypothyroidism, and macroglossia leading to sleep disordered breathing. The recent literature has also suggested a propensity for the development of significant bradycardia during inhalation induction with sevoflurane. We present a 2-year-old girl with trisomy 21 who developed the rapid onset of bradycardia during anesthetic induction with sevoflurane. Previous reports are reviewed, postulated mechanisms discussed, and preventative strategies presented. PMID- 26746604 TI - A proteomic characterization of NTHi lysates. AB - BACKGROUND: Non-typeable Haemophilus influenzae (NTHi) is a ubiquitous bacterial pathogen which accounts for a majority of human upper respiratory tract infections. Laboratory lysate preparations from this bacterium are commonly utilized to investigate the promulgation of inflammatory responses in respiratory and middle ear epithelium both in vivo and in vitro. We undertook an unbiased proteomics based analysis of NTHi lysate preps to: (a) identify abundant bacterial proteins present in these lysates that could play a role in NTHi biological effects and (b) determine the protein content variability in different lysate prep batches from the same NTHI strain. STUDY DESIGN: Proteomic analysis of laboratory NTHi lysate preparations from clinical strain 12. METHODS: NTHi lysates were denatured, gel-fractionated, digested by trypsin and the generated peptides were identified using a liquid chromatography tandem mass spectrometry (LC-MS/MS). Western blot analyses for the important proinflammatory enhancer, outer membrane protein 6 (OMP6), was performed to validate the MS findings. Luciferase assays for NF-kB activation were used to measure the pro-inflammatory biologic effects from each NTHi lysate preparation. RESULTS: The MS identified 793 unique NTHi proteins. Most common and abundant proteins found have been described to either contribute to biofilm formation, elude the innate immune system, or activate epithelial pro-inflammatory pathways such as Toll Like Receptor 2 (TLR-2) signaling and NF-kB transcription factor. Strong positive signal for OMP6 was found in each of the NTHi lysate preparations. Significant NF kB promoter response activation as expected with NTHi stimulation over control was also noted for each NTHi lysate preparation. CONCLUSIONS: Proteomics was a successful technique to broadly define the protein content of NTHi lysates. This is the first report of the proteome of NTHi lysates widely used in laboratories to study the biological effect of NTHi. Despite the variability of the protein composition from different preps, all the batches of NTHi lysates induced similar NFkappaB activation. LEVEL OF EVIDENCE: NA. PMID- 26746605 TI - Hospital cost of pediatric patients with complicated acute sinusitis. AB - OBJECTIVE: Review costs for pediatric patients with complicated acute sinusitis. METHODS: A retrospective case series of patients in a pediatric hospital was created to determine hospital costs using a standardized activity-based accounting system for inpatient treatment between November 2010 and December 2014. Children less than 18 years of age who were admitted for complicated acute sinusitis were included in the study. Demographics, length of stay, type of complication and cost of care were determined for these patients. RESULTS: The study included 64 patients with a mean age of 10 years. Orbital cellulitis (orbital/preseptal/postseptal cellulitis) accounted for 32.8% of patients, intracranial complications (epidural/subdural abscess, cavernous sinus thrombosis) for 29.7%, orbital abscesses (subperiosteal/intraorbital abscesses) for 25.0%, potts puffy tumor for 7.8%, and other (including facial abscess and dacryocystitis) for 4.7%. The average length of stay was 5.7 days. The mean cost per patient was $20,748. Inpatient floor costs (31%) and operating room costs (18%) were the two greatest expenditures. The major drivers in variation of cost between types of complications included pediatric intensive care unit stays and pharmacy costs. CONCLUSION: Although complicated acute sinusitis in the pediatric population is rare, this study demonstrates a significant financial impact on the health care system. Identifying ways to reduce unnecessary costs for these visits would improve the value of care for these patients. PMID- 26746607 TI - Congenital hairy polyp of the oropharynx presenting as an esophageal mass in a neonate, a case report and literature review. AB - PURPOSE: To review the literature of congenital hairy polyps and describe the clinical presentation, operative management, and histologic findings of a congenital hairy polyp arising from the palatopharyngeus muscle in a neonate with recurrent choking episodes. METHODS: Chart review of a 2-month-old male referred to a tertiary care pediatric hospital. RESULTS: We present a case of a 2-month old male who presented to the emergency room with recurrent episodes of choking and vomiting. The patient was previously healthy with no prior medical or neonatal history. The parents noted a small fleshy mass in the patient's oropharynx that he would chew on and swallow after several minutes. However, on physical exam, there was no evidence of oropharyngeal mass. The patient did not have respiratory distress. Imaging revealed a 22*7*11mm oblong, fatty mass in the lower cervical and upper thoracic esophagus with a thin stalk extending proximally to the upper collapsed esophagus. Intraoperative recorded laryngoscopy revealed a pedunculated soft palate mass attached to the right superior palatopharyngeus muscle. Histopathology revealed ectodermal and mesodermal elements in a polypoid structure lined by keratinizing squamous epithelium with adnexal structures and central mature adipose tissue, consistent with congenital hairy polyp resembling an accessory tragus of the ear and branchial anomaly. At 6 week follow up, the patient was doing well and gaining weight appropriately with no further choking episodes. There was no evidence of velopharyngeal dysfunction on follow up exam. The surgical site was completely healed and there was no evidence of recurrence. DISCUSSION: Congenital hairy polyps of the naso- and oropharynx are rare but may present as airway or esophageal masses, causing respiratory distress or choking episodes in a pediatric patient. The pathologic findings of keratinizing squamous epithelium, adnexal structures, adipose and cartilage tissues resemble congenital accessory tragus and may be considered a branchial arch anomaly. PMID- 26746608 TI - Stridor and apnea as the initial presentation of primary hypoparathyroidism. AB - We present a previously undescribed case of stridor and apnea as the initial presentation of primary hypoparathyroidism. A neonate presenting with these symptoms was initially diagnosed with laryngopharyngeal reflux and laryngomalacia. After failing medical management, she underwent supraglottoplasty with improvement of stridor, but persistent apneic events. Further work-up showed severe hypocalcemia due to hypoparathyroidism. Subsequent genetic testing revealed a diagnosis of Bartter Syndrome Type V, a rare cause of primary hypoparathyroidism. Although uncommon, hypocalcemic tetany can present as apneic episodes in the setting of unrecognized primary hypoparathyroidism. Electrolyte abnormalities should be explored in neonates with recurrent apnea of unknown etiology. PMID- 26746609 TI - Zinc effect on human lymphatic malformation cells in vitro. AB - OBJECTIVES: Lymphatic malformations (LM) are clinically characterized by episodes of inflammatory episodes. Often, an upper respiratory illness or trauma will lead to painful swelling in the distribution of the LM. Zinc is an element involved in numerous aspects of cellular metabolism and is a common dietary supplement and cold remedy. We surmise that zinc may act as a therapeutic anti-inflammatory agent for lymphatic malformations and their cellular components. We investigate the apparent cytotoxic effect of zinc ion on lymphatic malformation cells in vitro. METHODS: Fresh surgical lymphatic malformation specimens from 10 patients were collected and processed in a laboratory. Tissues were processed and lymphatic malformation cells were isolated and grown. Immunohistochemistry and cell morphology were used to confirm LM cells. HUVEC cells were used as controls. Zinc chloride solution was added to the cells and its effect observed. RESULTS: LM cells were isolated from five of the 10 specimens. Of these, the cells of only one specimen were able to be amplified to confluence. Five specimens were contaminated. Immunohistochemical staining (CD31, D2-40, and LYVE-1) and cell morphology of our specimens were consistent with lymphatic malformation while HUVEC control cells were negative. Zinc has a cytotoxic effect on BEL isolates in vitro with no obvious effect on cell morphology or growth rate of the control HUVEC cells. When compared with the published toxic zinc concentration for most cell types in the literature (100MUM total zinc in vitro), our result indicates that LM cells may have a lower tolerance to zinc (10MUM total zinc in vitro). CONCLUSION: Zinc has an apparent morphological effect on lymphatic malformation cells in vitro. Compared with other cell types, LM cells have a lower tolerance to zinc. While this result looks very promising for future therapeutic use of zinc in acute lymphangitis, further studies are necessary, such as finding the IC50 of zinc for lymphatic malformation in vitro and also in vivo. PMID- 26746610 TI - Serum 25-hydroxyvitamin D3 levels in children with allergic or nonallergic rhinitis. AB - OBJECTIVES: The relationship between vitamin D and allergic diseases such as asthma and atopic dermatitis is shown in several studies. But there is a lack of knowledge about vitamin D status in children with allergic rhinitis (AR). We aimed to investigate serum vitamin D levels of children with AR or nonallergic rhinitis (NAR), to compare with normal subjects and to evaluate the relationship between vitamin D and the severity of AR. METHODS: The study included a total of 141 children (76 patients with rhinitis and 65 control subjects), who applied to the Pediatric allergy immunology outpatient. Skin prick tests were performed using the same antigens for all patients. Serum 25-hydroxyvitamin D3 (25OHD3) levels were measured. AR was classified according to the ARIA guidelines. RESULTS: Mean 25OHD3 levels were 18.07+/-6.1ng/mL in the AR group, 14.81+/-4.86 in the NAR, and 24.03+/-9.43ng/mL in the control group. These differences among groups were statistically significant (p=0.001). Vitamin D status was determined as deficient in 32 (66.7%) patients, insufficient in 14 (29.2%) and normal in 2 (4.2%) of the AR group. These frequencies for NAR and control groups are 25 (89.3%), 3 (10.7%), 0, and 25 (38.5%), 32 (49.2%), 8 (12.3%), respectively. Vitamin D status was found to be different among groups (p=0.001). There were not any association between 25OHD3 levels and allergen sensitivity (p>0.05). The comparison of the mean 25OHD3 levels according to the severity and duration of AR did not detect statistically significant difference among groups (respectively, p=0.384, p=0.23 Denburg J, Fokkens WJ, Togias A5). CONCLUSIONS: The mean serum 25OHD3 levels of the children both with AR and NAR were lower than control group. No association between 25OHD3 levels and allergen sensitivities was found in our study. We did not find any relationship between 25OHD3 levels and the severity and duration of allergic rhinitis. PMID- 26746606 TI - Improved behavior after adenotonsillectomy in children with higher and lower IQ. AB - OBJECTIVES: To examine whether high intellectual ability, in comparison to average or lower performance, reflects the consequences of sleep-disordered breathing and limits behavioral benefit observed 6 months after adenotonsillectomy. METHODS: Children aged 3-12 years (n=147) recruited from otolaryngology practices at two hospitals and assessed with Conners' Parent Rating Scales and an age range-appropriate intellectual measure, the Stanford Binet Intelligence Scale at baseline and 6 months after clinically-indicated adenotonsillectomy. Subjects were classified as having high (IQ>=110), average (90<=IQ<110), or low (IQ<90) cognitive ability. RESULTS: After adenotonsillectomy, improvements in Conners' internalizing, externalizing, hyperactivity, and cognitive domains were observed across IQ groups (main effects for time, all p<0.01 or better), with no evidence for differential improvements among the groups (no significant time by IQ group interactions). The magnitude of behavioral improvement among children with high IQ resembled that observed among the other two groups. Changes in the Conners' domains were not significantly correlated with baseline IQ, age, socioeconomic status, body mass index z-score, or respiratory disturbance index. CONCLUSION: Behavioral function can improve after adenotonsillectomy even among children with relatively high intellectual ability at baseline. Diagnosis and treatment with expectation of neurobehavioral benefit should be considered among high-performing children as readily as it is more traditionally among their lower-performing peers. PMID- 26746611 TI - Prevalence and ethnic variation of pre-auricular sinuses in children. AB - OBJECTIVES: Pre-auricular sinus (PAS) describes a congenital ear malformation presenting as a pit or sinus that may become infected, often requiring antibiotics and/or surgical excision. Although the presentation of PAS in otolaryngology clinics is not uncommon, there is limited epidemiological data regarding this malformation in children. Some evidence also suggests a potential ethnic variation in prevalence rates and potential heritability patterns within families, however these have yet to be proven. This study is the first to use pediatric population level data to investigate prevalence rate, ethnic variation, and to explore the unproven hypotheses of a genetic basis of PAS. METHODS: In this prospective cross-sectional study, we enrolled 1106 subjects (mean age=6.8, male-to-female ratio=1.15:1) between June and September 2014. Subjects were recruited from B.C. Children's Hospital in Vancouver, Canada. Inclusion criteria was children <18 years of age; exclusion criteria was those seeking care for PAS. Subjects were visually inspected for the presence of PAS by clinical observers followed by verbal questionnaire (demographics, self-identified ethnicity, family history of PAS, chronic medical conditions). Data analysis utilized Pearson Chi Square Test to determine the potential ethnic variation, and odds ratios of family history were used to determine a potential genetic basis. RESULTS: 26 (7 bilateral, 19 unilateral) of 1106 subjects were positive for PAS (2.4%). Using Pearson Chi-Square Test, a significant ethnic variation was found to exist (chi(2) (6,N=1106)=22.80, p<0.0001), with Asians having the highest prevalence (6.6%), followed by African Americans (4.5%), Middle Easterners (3.4%), First Nations (2.0%), and Caucasians (1.2%). None were found in South Asians (n=124) or Latin Americans (n=18). Subjects with positive family history of PAS had greater likelihood of having PAS (OR=16.7, 95% CI=7.3-38.5, p<0.0001). There was also stronger association between family history and bilateral PAS (OR=26.5, 95% CI=5.8-121.7, p<0.0001) compared to unilateral PAS (OR=12.2, 95% CI=4.6-32.5, p<0.0001). CONCLUSIONS: This was the largest pediatric population level study to date, and showed the prevalence of PAS was 2.4% in this pediatric population, whose ethnic diversity was representative of B.C.'s community. A significant ethnic variation existed and associations between family history and PAS suggested a potential genetic basis, particularly with bilateral PAS. PMID- 26746612 TI - Characterization of B-Cells in tonsils of patients diagnosed with pediatric autoimmune neuropsychiatric disorder associated streptococcus. AB - OBJECTIVE: To determine if Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS) patients demonstrate a significantly different number of B-Cells or markers of activity when compared to recurrent Group A Streptococcus or Obstructive Sleep Apnea patients. STUDY DESIGN: Prospective Cohort Study. STUDY SETTING: Academic University Hospital. METHODS: Tonsil tissue was collected from twenty-two patients in the operating room and organized into three groups. Ten clinically diagnosed PANDAS, six Group A Streptococcus and six Obstructive Sleep Apnea patients were included in this study. Each tissue sample was extracted with MSD Tris Lysis Buffer and protein lysates were analyzed for CD 19, B-Cell Activating Factor and B-Cell Activating Receptor by western blot methods. RESULTS: Based on ANOVA analysis, there was no significant difference in the expression of B-Cell Activating Factor, B-Cell Activating Receptor or CD 19 when comparing the three study groups by western blot analysis methods. CONCLUSIONS: In this prospective cohort study, it appears that PANDAS patients do not demonstrate increased number of B-Cells, expression of B-Cell Activating Factor or B-Cell Activating Receptor when compared to Group A Streptococcus or Obstructive Sleep Apnea cohorts. As a result, further evaluation of the cell-mediated immune system is warranted to provide further insight into the pathophysiology of PANDAS. In addition, we must investigate if PANDAS patients only demonstrate increased B-Cell number or activity when undergoing an acute Tic/OCD exacerbation. PMID- 26746613 TI - The Galker test of speech reception in noise; associations with background variables, middle ear status, hearing, and language in Danish preschool children. AB - PURPOSE: We tested "the Galker test", a speech reception in noise test developed for primary care for Danish preschool children, to explore if the children's ability to hear and understand speech was associated with gender, age, middle ear status, and the level of background noise. METHODS: The Galker test is a 35-item audio-visual, computerized word discrimination test in background noise. Included were 370 normally developed children attending day care center. The children were examined with the Galker test, tympanometry, audiometry, and the Reynell test of verbal comprehension. Parents and daycare teachers completed questionnaires on the children's ability to hear and understand speech. As most of the variables were not assessed using interval scales, non-parametric statistics (Goodman Kruskal's gamma) were used for analyzing associations with the Galker test score. For comparisons, analysis of variance (ANOVA) was used. Interrelations were adjusted for using a non-parametric graphic model. RESULTS: In unadjusted analyses, the Galker test was associated with gender, age group, language development (Reynell revised scale), audiometry, and tympanometry. The Galker score was also associated with the parents' and day care teachers' reports on the children's vocabulary, sentence construction, and pronunciation. Type B tympanograms were associated with a mean hearing 5-6dB below that of than type A, C1, or C2. In the graphic analysis, Galker scores were closely and significantly related to Reynell test scores (Gamma (G)=0.35), the children's age group (G=0.33), and the day care teachers' assessment of the children's vocabulary (G=0.26). CONCLUSIONS: The Galker test of speech reception in noise appears promising as an easy and quick tool for evaluating preschool children's understanding of spoken words in noise, and it correlated well with the day care teachers' reports and less with the parents' reports. PMID- 26746615 TI - Management of pediatric cholesteatoma based on presentations, complications, and outcomes. AB - OBJECTIVES: To highlight important aspects and paradigms in the management of paediatric cholesteatoma in a developing world setting. METHODS: A retrospective audit was conducted of paediatric cholesteatomas that underwent tympanomastoid surgery between 2008 and 2012 at the Red Cross War Memorial Children's Hospital in Cape Town. The following was audited: initial presentation; cholesteatoma complications; types of surgery, intraoperative findings and outcomes of surgery in terms of hearing, otorrhoea and recidivism; and the reliability of follow-up and how this might influence the type of surgery. RESULTS: Fifty-seven children aged 2-13 years with 61 cholesteatomas (4 bilateral) were reviewed. Fifty-five mastoidectomies were done; 11% presented with complicated cholesteatoma. Referrals from primary care were significantly delayed (>6 months) in 76%. Canal wall down surgery was done in 71%. Forty-five percent had improved hearing (within 15dB of better hearing ear) and a further 15% had no or only mild hearing loss. Ossicular chain involvement and ossicles encased in inflammatory tissue were associated with poorer hearing outcomes. Sixty-four percent of ears remained dry. Forty-five percent of the canal wall up, and 23% of canal wall down mastoidectomies had recidivism. Twenty-six percent of patients were lost to follow-up. CONCLUSIONS: Children are likely to present with advanced cholesteatoma with ossicular chain involvement. The children present with high rates of complications, poor pre-operative hearing and have high recurrence rates post-surgery. Referral from primary health care is delayed. Canal wall down procedures may be appropriate in a setting where patient follow-up is unreliable and access to operating theatre is limited. PMID- 26746614 TI - Rat model of chronic tympanic membrane perforation: Ventilation tube with mitomycin C and dexamethasone. AB - OBJECTIVE: Chronic tympanic membrane perforation (TMP) in a clinical setting may attract surgical intervention. With the advent of modern biomaterials, new options are available for myringoplasty but safety and efficacy need evaluation in a chronic TMP animal model. The aim of this study was to evaluate the efficacy of ventilation tube (VT) insertion in conjunction with topical application of mitomycin C/dexamethasone (M/D) for the creation of chronic TMP in rats. METHODS: Thirty male Sprague-Dawley rats underwent myringotomy of the right tympanic membrane (TM) and were divided into three experimental groups: spontaneous healing (myringotomy control), VT insertion for 2 weeks and VT insertion for 2 weeks in conjunction with topical application of M/D (VT-M/D). All TMs were regularly assessed by otoscopy for 10 weeks and then animals were sacrificed for histological evaluation. RESULTS: In the VT-M/D group, seven out of ten (70%) perforations were patent at 10 weeks (mean patency, 57.9 days; P<0.01). The VT group had two out of ten (20%) perforations patent at 10 weeks (mean patency, 26.5 days; P<0.01), while all TMPs from the myringotomy control group were closed by day 9 (mean patency, 7.2 days). Histologically, the TMPs patent at week 10 had a stratified squamous epithelialized rim, keratinocyte layer thickening around the perforation edge as well as increased collagen deposition and macrophage infiltration. CONCLUSION: Chronic TMP in a rat model was successfully created by VT insertion and the efficacy was increased in combination with topical application of M/D. PMID- 26746617 TI - Identification of a nonsense mutation in the STRC gene in a Korean family with moderate hearing loss. AB - Hereditary hearing loss is a heterogeneous disorder that results in a common sensorineural disorder. To date, more than 150 loci and 89 genes have been reported for non-syndromic hearing loss. Next generation sequencing has recently been developed as a powerful genetic strategy for identifying pathogenic mutations in heterogeneous disorders with various causative genes. In this study, we performed targeted sequencing to identify the causative mutation in a Korean family that had moderate hearing loss. We targeted 64 genes associated with non syndromic hearing loss and sorted the homozygous variations according to the autosomal recessive inheritance pattern of the family. Implementing a bioinformatic platform for filtering and detecting variations allowed for the identification of two variations within different genes (c.650G>A in TRIOBP and c.4057C>T in STRC). These variants were selected for further analysis. Among these, c.4057C>T (p.Q1353X) was a divergent sequence variation between the STRC gene and the STRC pseudogene. This was the critical difference that resulted in loss of the protein-coding ability of the pseudogene. Therefore, we hypothesized that the p.Q1353X variation in the STRC gene is the causative mutation for hearing loss. This result suggests that application of targeted sequencing will be valuable for the diagnosis of heterogeneous disorders. PMID- 26746616 TI - Decreased salivary matrix metalloproteinase-8 reflecting a defensive potential in juvenile parotitis. AB - OBJECTIVE: Matrix metalloproteinases MMP-2 and MMP-9 have been associated with juvenile parotitis. However, the role of MMP-8 has not been addressed previously. This work focuses on salivary MMP-8 and -9 levels in juvenile parotitis. METHODS: During a five-year period at Helsinki University Hospital, a tertiary care hospital, 41 patients aged 17 or under, were identified as having parotitis; from 36 of these patients, saliva samples were collected for MMP-8 IFMA (time-resolved immunofluorometric assay) analyses. Control saliva samples were collected from 34 age- and gender-matched children admitted for an elective surgery who had no history of parotitis. For comparison, salivary levels of MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP-1), MMP-8/TIMP-1 ratio, human neutrophil elastase (HNE), and myeloperoxidase (MPO) were analyzed by ELISA. Additionally, salivary MMP-8 levels were compared to historical saliva samples from 18 adult gingivitis patients as well as to 10 healthy adult controls. RESULTS: The median (25%, 75% percentile) MMP-8 concentration in saliva of parotitis patients was significantly lower than MMP-8 concentration in saliva of their controls [50.4ng/ml (37.5, 72.9) vs. 148.5ng/ml (101.2, 178.5) p<0.0001] and lower than in patients with gingivitis [347.9ng/ml (242.6, 383.2) p<0.0001] or healthy adult controls [257.2ng/ml (164.9, 320.7) p<0.0001]. The MMP-8/TIMP-1 ratio was lower than in controls [0.13 (0.05-0.02) vs. 0.3 (0.17-0.46) p<0.0001]. The median MMP 9 concentration in saliva of parotitis patients was significantly higher than in controls [143.9ng/m (68.8-189.0) vs. 34.9ng/ml (16.3-87.6) p<0.0001]. Neither HNE, MPO, nor TIMP-1 alone separated the patients from the control groups. CONCLUSIONS: MMP-9 was up-regulated in juvenile parotitis saliva, suggesting that MMP-9 may play a destructive role in juvenile parotitis, as others have suggested. The present novel findings reveal a decreased salivary MMP-8 concentration, suggesting that MMP-8 may reflect in juvenile parotitis down regulated or anti-inflammatory immune characteristics. PMID- 26746618 TI - Adenoid hypertrophy and chronic rhinosinusitis: Helicobacter pylori on antral lavages, adenoid tissue and salival inmunoglobuline A on paediatric patients. AB - OBJECTIVE: To determine Helicobacter pylori presence on antral lavages, adenoids and salival inmunoglobuline A on paediatric patients with chronic rhinosinusitis without nasal polyps (CRSsNP) and adenoid hypertrophy. METHODS: Adenoid tissue, liquid obtained from antral lavages and saliva from 28 children diagnosed with CRSsNP, from the paediatric otorhinolaryngology practice of "Dr. Domingo Luciani" Hospital was taken and processed by means of polymerase chain reaction (PCR) using cagA, vacA and babA primers, also anatomopathological examination using Giemsa stain of the adenoids, determination of salivary specific secretory inmunoglobuline A (sIgA), socio-economic condition using the Graffar scale and associated gastrointestinal symptoms were assessed. RESULTS: No evidence of Helicobacter pylori neither in antral lavages liquid nor adenoid tissue was found using PCR and Giemsa stain. sIgA was present in 28.6% of the subjects. The most frequently found symptoms were, diarrhea in 17.9%, distension and abdominal pain in 10.7%, 64.3% of the patients were in working (28.6%) and low middle (35.7%) classes. CONCLUSIONS: Helicobacter pylori is not present neither in maxillary sinuses nor adenoid tissue of the evaluated patients, sIgA it is a non-invasive method for assessment of immunologic challenge with the bacteria, not the presence of acute or chronic infection. PMID- 26746619 TI - Quality of life outcomes for children with hearing impairment in Singapore. AB - OBJECTIVES: This study aimed to investigate the hearing-related quality of life (hearing-QOL) of children with hearing loss in Singapore using hearing aids (HAs) and/or cochlear implants (CIs). Their health-related QOL (health-QOL) as well as their families' health-QOL were compared with normally hearing (NH) children and their families. METHODS: This cross-sectional study recruited families (i.e., children aged 2-18 years and their parents) of NH children (n=44), children wearing HAs (n=22) and children wearing CIs (n=14). Hearing-QOL was assessed using the parent-reported Children Using Hearing Devices QOL questionnaire. General health-QOL was assessed using parent and child-reported measures from the PedsQL inventory consisting of the Generic Core Scales, General Well-being Scale and Family Impact Module. The questionnaires were self-administered for children aged 8-18 years, and interviewer-administered for children aged 5-7 years. RESULTS: The NH children and their families had significantly higher general health-QOL scores compared to the children with hearing loss and their families. This indicates that hearing loss significantly impacts on the well-being of children and their families. Congruence between parent and child reports was only observed in the NH group. Parents of children wearing HAs rated their child's overall hearing-QOL significantly higher than parents of children wearing CIs. Family household income was the only significant predictor of child hearing-QOL scores with parents from the middle income families rating their child's hearing QOL significantly poorer than parents from high income families. CONCLUSION: Overall, NH children and their families have higher self-rated general health-QOL than children with hearing loss and their families, with children using HAs providing higher hearing-QOL than those using CIs. Evaluating both general health and hearing specific QOL from both the child and their parent/caregiver is worthwhile, allowing a more holistic measure of real-life outcomes and better individualised clinical care. PMID- 26746620 TI - Origins of the binocular head mirror: The mystery of Dr. Clar, clarified. AB - BACKGROUND: The origin of Dr. Clar's forehead mirror remains a mystery. The aim of this study is to track the roots of this eponym anew to find a definitive answer. METHODS: Historical, notably by the analysis of the reports of medical meetings and the content of instrument trade catalogs of the corresponding epoch. RESULTS: Konrad or Conrad Clar (1844-1904) was an Austrian balneologist and geologist particularly interested in laryngological examination. He notably invented a lighting apparatus in 1874, his famous forehead mirror in 1886, and a handgrip for laryngological instruments in 1901. CONCLUSIONS: Konrad Clar is the man behind the eponymous Dr. Clar's mirror. This study allowed to definitively confirm this statement. PMID- 26746621 TI - The Global Tracheostomy Collaborative: one institution's experience with a new quality improvement initiative. AB - OBJECTIVE: Given the low frequency of adverse events after tracheostomy, individual institutions struggle to collect outcome data to generate effective quality improvement protocols. The Global Tracheostomy Collaborative (GTC) is a multi-institutional, multi-disciplinary organization that utilizes a prospective database to collect data on patients undergoing tracheostomy. We describe our institution's preliminary experience with this collaborative. It was hypothesized that entry into the database would be non-burdensome and could be easily and accurately initiated by skilled specialists at the time of tracheostomy placement and completed at time of patient discharge. METHODS: Demographic, diagnostic, and outcome data on children undergoing tracheostomy at our institution from January 2013 to June 2015 were entered into the GTC database, a database collected and managed by REDCap (Research Electronic Data Capture). All data entry was performed by pediatric otolaryngology fellows and all post-operative updates were completed by a skilled tracheostomy nurse. Tracked outcomes included accidental decannulation, failed decannulation, tracheostomy tube obstruction, bleeding/tracheoinnominate fistula, and tracheocutaneous fistula. RESULTS: Data from 79 patients undergoing tracheostomy at our institution were recorded. Database entry was straightforward and entry of patient demographic information, medical comorbidities, surgical indications, and date of tracheostomy placement was completed in less than 5min per patient. The most common indication for surgery was facilitation of ventilation in 65 patients (82.3%). Average time from admission to tracheostomy was 62.6 days (range 0-246). Stomal breakdown was seen in 1 patient. A total of 72 patients were tracked to hospital discharge with 53 patients surviving (88.3%). No mortalities were tracheostomy-related. CONCLUSION: The Global Tracheostomy Collaborative is a multi-institutional, multi disciplinary collaborative that collects data on patients undergoing tracheostomy. Our experience proves proof of concept of entering demographics and outcome data into the GTC database in a manner that was both accurate and not burdensome to those participating in data entry. In our tertiary care, pediatric academic medical center, tracheostomy continues to be a safe procedure with no major tracheostomy-related morbidities occurring in this patient population involvement with the GTC has shown opportunities for improvement in communication and coordination with other tracheostomy-related disciplines. PMID- 26746622 TI - Splitting One Kidney into Two: Robotic Partial Kidney Transplant in a Porcine Model. PMID- 26746623 TI - Outcomes for Patients with Metastatic Renal Cell Carcinoma Achieving a Complete Response on Targeted Therapy: A Registry-based Analysis. AB - BACKGROUND: It is currently not known whether treatment with anti-vascular endothelial growth factor agents for metastatic renal cell carcinoma (mRCC) can be safely discontinued in patients achieving a complete response (CR). OBJECTIVE: To assess outcomes for patients with mRCC achieving CR on targeted therapy (TT) and the survival of patients discontinuing TT after CR. DESIGN, SETTING, AND PARTICIPANTS: A national registry was used to identify patients achieving CR during first-line TT using bevacizumab, sunitinib, sorafenib, or pazopanib. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships with outcomes were analysed using a log-rank test. RESULTS AND LIMITATIONS: A total of 100 patients achieving CR were identified out of 2803 patients. The median time to CR was 10.1 mo. Median progression-free survival (PFS) from TT initiation was 3.8 yr (95% confidence interval [CI] 2.9-4.6 yr) and the 5-yr overall survival (OS) was 80% (95% CI 70-91%). Patients discontinuing TT within 1 mo after achieving CR and those continuing TT beyond CR had similar OS (CI for difference in 2-yr post-CR OS -13% to 19%; p=0.3) and PFS (CI for difference in 2-yr post-CR PFS -29% to 17%; p=0.7). The limitations include the retrospective, registry-based data analysis. CONCLUSIONS: Achievement of CR on TT for mRCC was associated with excellent long-term prognosis. No significant differences in post-CR survival were observed between patients discontinuing TT after the date of CR and those who continued on TT, although the wide CIs cannot exclude important differences between the groups. PATIENT SUMMARY: According to this registry-based analysis, patients with metastatic renal cancer with no signs of disease (complete response) after treatment with targeted agents experience excellent long-term survival even if the treatment does not continue beyond the date of complete response. PMID- 26746625 TI - FCRL3 gene polymorphisms as risk factors for rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is a common chronic systemic autoimmune disease. As a member of FCRLs clusters, Fc receptor-like 3 (FCRL3) has been recognized as a neoteric autoimmune activation factor for RA. The aim of our study is to evaluate the correlation between four single-nucleotide polymorphisms (SNPs) on FCRL3 and RA risk in a Chinese Han population. MATERIAL AND METHODS: The hospital-based case-control study included 630 RA patients together with 696 healthy individuals as the control group and all subjects are Chinese ancestry. Four tagging single-nucleotide polymorphisms (tag-SNPs) on FCRL3 were selected and genotyped by TaqMan assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were employed to evaluate the correlations between FCRL3 polymorphisms and RA. A systematic meta-analysis was also carried out based on the present study and previously published studies to further examine the association between FCRL3 variations and RA risk. RESULTS: Significant association was found between 169T/C SNP and RA risk (CC vs. TT, OR=1.62, 95% CI=1.18-2.22; TC/CC vs. TT, OR=1.47, 95% CI=1.18-1.84; C vs. T, OR=1.32, 95% CI=1.12-1.54). Apart from that, mutations of -169T/C was significantly correlated with rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) positive status. The meta analysis also suggested that -169T/C mutation might have positive correlation with risk of RA in the overall population, particularly for Asian. Stratified analysis based on clinical characteristics of RF and ACPA also provided evidence that -169T/C polymorphisms could alter phenotypes of RA. CONCLUSION: The FCRL3 169T/C variant was significantly linked with an increased RA risk in the Chinese Han population. Moreover, this meta-analysis also provides notion that -169T/C variant could act as a susceptible factor for RA. However, further investigations about the functional impacts of this polymorphism are essential to confirm the above conclusions. PMID- 26746624 TI - Functional connectivity of the amygdala and subgenual cingulate during cognitive reappraisal of emotions in children with MDD history is associated with rumination. AB - Major Depressive Disorder (MDD) is characterized by poor emotion regulation. Rumination, a maladaptive strategy for dealing with negative emotions, is common in MDD, and is associated with impaired inhibition and cognitive inflexibility that may contribute to impaired emotion regulation abilities. However, it is unclear whether rumination is differently associated with emotion regulation in individuals with MDD history (MDD-ever) and healthy individuals. In this study, children (8-15 years old) performed a cognitive reappraisal task in which they attempted to decrease their emotional response to sad images during fMRI scanning. Functional connectivity (FC) between both the amygdala and subgenual anterior cingulate (sACC) increased with cortical control regions during reappraisal as rumination increased in MDD-ever, while connectivity between those regions decreased during reappraisal as rumination increased in healthy controls. As the role of cortical control regions is to down-regulate activity of emotion processing regions during reappraisal, this suggests that rumination in MDD-ever, but not controls, is associated with inefficient regulation. This finding suggests that rumination may be particularly associated with poor emotion regulation in MDD-ever, and may also indicate qualitative group differences in whether rumination is maladaptive. These differences in rumination may provide important insight into depressive risk and potential avenues for treatment. PMID- 26746626 TI - The clinical and biochemical characteristics of Yemeni adults and children with visceral leishmaniasis and the differences between them: a prospective cross sectional study before and after treatment. AB - OBJECTIVES: To determine the clinical and biochemical characteristics of Yemeni adults and children with visceral leishmaniasis (VL) and the differences between them. METHODS: A prospective cross-sectional study on patients with bone marrow aspirate confirmed VL evaluated at Al-Jomhori Teaching Hospital in Sana'a, Yemen. RESULTS: Twenty-eight (59.6%) patients were adults with a mean age (+/- SD) of 24.3 years +/- 9.2 and 19 (40.4%) patients were children with a mean age (+/- SD) of 7.1 years +/- 4.7. Fever, pallor, splenomegaly and hepatomegaly were the most common clinical findings. Hypoalbuminaemia, hyperglobulinaemia, elevated LDH, hypocalcaemia and elevated CRP were common biochemical abnormalities. There was no significant difference in splenomegaly size or biochemical parameters with regard to grade of parasitic load. Both children and adults showed similar significant improvement after treatment. CONCLUSION: Biochemical abnormalities were not related to degree of parasitic load and there were no clinical, biochemical or treatment differences between adults and children. PMID- 26746628 TI - Four-year follow-up of acquired aorto-right ventricular fistula after transcatheter aortic valve implantation. PMID- 26746627 TI - Effects of paediatric HIV infection on childhood vasculature. AB - AIMS: Human immunodeficiency virus (HIV) infection may alter childhood vascular properties and influence future cardiovascular risk. Whether vascular changes are associated with HIV infection per se or antiretroviral therapy (ART) is unknown. We investigated the effects of ART-naive or ART-exposed HIV infection in children on childhood vascular characteristics. METHODS AND RESULTS: We performed vascular ultrasound to measure carotid intima media thickness (cIMT), distensibility, and elastic modulus on 114 children with vertically acquired HIV infection (56 ART naive, 58 ART treated) and 51 healthy children in Jakarta, Indonesia. Children also underwent clinical and blood examinations. We used general linear modelling to estimate associations between HIV infection/treatment status and vascular characteristics with adjustment for confounders or possible mediators. Vascular measurements were successful in 42 ART-naive HIV-infected [median age 4.0 years (min 0.4-max 11.5)]; 53 ART-treated HIV infected [5.7 years (0.6-12.2), median ART duration 2.4 years (0.1-9.9)]; and 48 healthy children, 6.5 years (2.4-14.0). The ART-naive HIV infected had thicker cIMT (difference 70.4 um, 95% CI 32.1 108.7, P < 0.001), adjusted for age, sex, socioeconomic status, parental smoking, body mass index, systolic and diastolic blood pressure, LDL cholesterol, and HbA1c. Addition of high-sensitivity C-reactive protein (hs-CRP) level to the model did not affect the results (71.6 um, 31.9-111.2, P = 0.001). The ART exposed children had similar cIMT dimensions to healthy children. Distensibility was not significantly different between HIV infected, either ART-naive or exposed, and healthy children, but adjusted analysis including only ART-exposed children with controlled HIV (CD4+ >=200/mm3 or CD4+ >=15%) showed that the ART exposed had an increased elastic modulus (difference 37.9 kPa, 95% CI 6.5-69.3, P = 0.02), and following adjustment for hs-CRP (35.5 kPa, 95% CI 4.2-66.8, P = 0.03). CONCLUSION: ART-naive HIV infection in children is associated with increased cIMT. Children with ART-controlled HIV may have increased arterial stiffness, although further confirmation is required. PMID- 26746630 TI - A young woman with shortness of breath. PMID- 26746629 TI - Clinical usefulness of gene-expression profile to rule out acute rejection after heart transplantation: CARGO II. AB - AIMS: A non-invasive gene-expression profiling (GEP) test for rejection surveillance of heart transplant recipients originated in the USA. A European based study, Cardiac Allograft Rejection Gene Expression Observational II Study (CARGO II), was conducted to further clinically validate the GEP test performance. METHODS AND RESULTS: Blood samples for GEP testing (AlloMap((r)), CareDx, Brisbane, CA, USA) were collected during post-transplant surveillance. The reference standard for rejection status was based on histopathology grading of tissue from endomyocardial biopsy. The area under the receiver operating characteristic curve (AUC-ROC), negative (NPVs), and positive predictive values (PPVs) for the GEP scores (range 0-39) were computed. Considering the GEP score of 34 as a cut-off (>6 months post-transplantation), 95.5% (381/399) of GEP tests were true negatives, 4.5% (18/399) were false negatives, 10.2% (6/59) were true positives, and 89.8% (53/59) were false positives. Based on 938 paired biopsies, the GEP test score AUC-ROC for distinguishing >=3A rejection was 0.70 and 0.69 for >=2-6 and >6 months post-transplantation, respectively. Depending on the chosen threshold score, the NPV and PPV range from 98.1 to 100% and 2.0 to 4.7%, respectively. CONCLUSION: For >=2-6 and >6 months post-transplantation, CARGO II GEP score performance (AUC-ROC = 0.70 and 0.69) is similar to the CARGO study results (AUC-ROC = 0.71 and 0.67). The low prevalence of ACR contributes to the high NPV and limited PPV of GEP testing. The choice of threshold score for practical use of GEP testing should consider overall clinical assessment of the patient's baseline risk for rejection. PMID- 26746631 TI - Calcium imaging and selective computed tomography angiography in comparison to functional testing for suspected coronary artery disease: the multicentre, randomized CRESCENT trial. AB - AIMS: To compare the effectiveness and safety of a cardiac computed tomography (CT) algorithm with functional testing in patients with symptoms suggestive of coronary artery disease (CAD). METHODS AND RESULTS: Between April 2011 and July 2013, 350 patients with stable angina, referred to the outpatient clinic of four Dutch hospitals, were prospectively randomized between cardiac CT and functional testing (2 : 1 ratio). The tiered cardiac CT protocol included a calcium scan followed by CT angiography if the Agatston calcium score was between 1 and 400. Patients with test-specific contraindications were not excluded from study participation. By 1 year, fewer patients randomized to cardiac CT reported anginal complaints (P = 0.012). The cumulative radiation dose was slightly higher in the CT group (6.6 +/- 8.7 vs. 6.1 +/- 9.3 mSv; P < 0.0001). After 1.2 years, event-free survival was 96.7% for patients randomized to CT and 89.8% for patients randomized to functional testing (P = 0.011). After CT, the final diagnosis was established sooner (P < 0.0001), and additional downstream testing was required less frequently (25 vs. 53%, P < 0.0001), resulting in lower cumulative diagnostic costs (?369 vs. ?440; P < 0.0001). CONCLUSION: For patients with suspected stable CAD, a tiered cardiac CT protocol offers an effective and safe alternative to functional testing. Incorporating the calcium scan into the diagnostic workup was safe and lowered diagnostic expenses and radiation exposure. PMID- 26746632 TI - Long-term clinical outcome after alcohol septal ablation for obstructive hypertrophic cardiomyopathy: results from the Euro-ASA registry. AB - AIMS: The first cases of alcohol septal ablation (ASA) for obstructive hypertrophic cardiomyopathy (HCM) were published two decades ago. Although the outcomes of single-centre and national ASA registries have been published, the long-term survival and clinical outcome of the procedure are still debated. METHODS AND RESULTS: We report long-term outcomes from the as yet largest multinational ASA registry (the Euro-ASA registry). A total of 1275 (58 +/- 14 years, median follow-up 5.7 years) highly symptomatic patients treated with ASA were included. The 30-day post-ASA mortality was 1%. Overall, 171 (13%) patients died during follow-up, corresponding to a post-ASA all-cause mortality rate of 2.42 deaths per 100 patient-years. Survival rates at 1, 5, and 10 years after ASA were 98% (95% CI 96-98%), 89% (95% CI 87-91%), and 77% (95% CI 73-80%), respectively. In multivariable analysis, independent predictors of all-cause mortality were age at ASA (P < 0.01), septum thickness before ASA (P < 0.01), NYHA class before ASA (P = 0.047), and the left ventricular (LV) outflow tract gradient at the last clinical check-up (P = 0.048). Alcohol septal ablation reduced the LV outflow tract gradient from 67 +/- 36 to 16 +/- 21 mmHg (P < 0.01) and NYHA class from 2.9 +/- 0.5 to 1.6 +/- 0.7 (P < 0.01). At the last check-up, 89% of patients reported dyspnoea of NYHA class <=2, which was independently associated with LV outflow tract gradient (P < 0.01). CONCLUSIONS: The Euro-ASA registry demonstrated low peri-procedural and long-term mortality after ASA. This intervention provided durable relief of symptoms and a reduction of LV outflow tract obstruction in selected and highly symptomatic patients with obstructive HCM. As the post-procedural obstruction seems to be associated with both worse functional status and prognosis, optimal therapy should be focused on the elimination of LV outflow tract gradient. PMID- 26746634 TI - Giant apparently not dissecting aneurysm and severe aortic valve insufficiency in an elite athlete. PMID- 26746635 TI - Sleep-disordered breathing: how should we judge its severity? PMID- 26746636 TI - Case Series: Vaginal Rupture Injuries after Sexual Assault in Children and Adolescents. AB - BACKGROUND: Vaginal rupture after sexual assault is a rare but life-threatening occurrence requiring prompt recognition and treatment. Herein, we describe four such cases in children. Our purposes are to increase clinicians' awareness of the physical trauma that a sexual abuse victim can suffer and increase recognition that these victims require immediate trauma services. CASES: Each patient had obvious hymenal and vaginal lacerations with a vaginal apical rupture injury and secondary acute blood loss. None of the four victims sustained infectious sequelae. SUMMARY AND CONCLUSION: Providers should have a low threshold for managing sexual abuse victims as trauma cases when they have obvious hymenal and vaginal lacerations and genital bleeding, proceeding expeditiously to examination using general anesthesia when appropriate. PMID- 26746633 TI - Coping strategies and risk of cardiovascular disease incidence and mortality: the Japan Public Health Center-based prospective Study. AB - AIMS: Coping strategies may be significantly associated with health outcomes. This is the first study to investigate the association between baseline coping strategies and cardiovascular disease (CVD) incidence and mortality in a general population cohort. METHODS AND RESULTS: The Japan Public Health Center-based prospective Study asked questions on coping in its third follow-up survey (2000 04). Analyses on CVD incidence and mortality included 57 017 subjects aged 50-79 without a history of CVD and who provided complete answers on approach- and avoidance-oriented coping behaviours and strategies. Cox regression models, adjusted for confounders, were used to determine hazard ratios (HRs) according to coping style. Mean follow-up time was 7.9 years for incidence and 8.0 years for mortality.The premorbid use of an approach-oriented coping strategy was inversely associated with incidence of stroke (HR = 0.85; 95% CI, 0.73-1.00) and CVD mortality (HR = 0.74; 95% CI, 0.55-0.99). Stroke subtype analyses revealed an inverse association between the approach-oriented coping strategy and incidence of ischaemic stroke (HR = 0.79; 95% CI, 0.64-0.98) and a positive association between the combined coping strategy and incidence of intra-parenchymal haemorrhage (HR = 2.03; 95% CI, 1.01-4.10). Utilizing an avoidance coping strategy was associated with increased mortality from ischaemic heart disease (IHD) only in hypertensive individuals (HR = 3.46; 95% CI, 1.07-11.18). The coping behaviours fantasizing and positive reappraisal were associated with increased risk of CVD incidence (HR = 1.24; 95% CI, 1.03-1.50) and reduced risk of IHD mortality (HR = 0.63; 95% CI, 0.40-0.99), respectively. CONCLUSION: An approach-oriented coping strategy, i.e. proactively dealing with sources of stress, may be associated with significantly reduced stroke incidence and CVD mortality in a Japanese population-based cohort. PMID- 26746638 TI - Innovative Graduate Research Education for Advancement of Implementation Science in Adolescent Behavioral Health. AB - An innovative approach to research education that integrates the theory and principles of implementation science, participatory research, and service learning in the area of adolescent behavioral health is presented. Qualitative interviews and surveys of program participants have been conducted to assess the program's curricula, service-learning partnerships, student (scholar) satisfaction, and views of community partnerships and academic mentors. The Institute has experienced the successful completion of its first and second cohorts and enrollment of a third cohort of scholars. Community partners are utilizing results of service-learning projects to influence agency operations. Institute scholars have identified research and service learning experiences as key factors in the decision to apply to the Institute graduate certificate program. The availability of tuition support is identified as valuable but not ranked as the most important reason for scholar interest in the program. Academic mentors report positive relationships with community agencies. Future iterations of the program will expand options for distance learning and alternatives to traditional graduate education for community-based scholars. Community partner agency capacity for participation is expected to change over time. Methods are being identified to both sustain existing partnerships and develop new community partnership relationships. PMID- 26746637 TI - Update on our investigation of malignant tumors associated with Peutz-Jeghers syndrome in Japan. AB - PURPOSE: To investigate the recent incidence of malignant tumors associated with Peutz-Jeghers syndrome (PJS) in Japan to clarify if there are any differences in malignant tumor risk and the spectrum of malignancies by reviewing the literature on this subject. METHODS: We reviewed PJS cases reported in 1115 papers in Japan between January, 1989 and December, 2014. RESULTS: Malignant tumors were identified in 186 of the total 583 PJS cases from 523 evaluable studies. The estimated cumulative risk of a malignant tumor was 83.0 % at 70 years of age. Compared with a previous study, on a collective 91 cases reported up until 1988 in Japan, the reported proportion of gastrointestinal malignancies decreased, from 82.4 to 48.3 %, whereas that of gynecological malignancies increased, from 8.8 to 34.3 % (P < 0.01). Moreover, breast cancers were occasionally reported (4.8 %), even though none were reported in the previous study. Adenocarcinoma of the uterine cervix was the most common malignant tumor (46.8 %) among women with PJS. CONCLUSIONS: The increased number of reports of cervical adenocarcinoma in women with PJS is the prominent trend in Japan, and a subject of concern among gynecologists. The risk of breast cancer seems to be increasing, but confirmation of this trend will require further investigation. PMID- 26746639 TI - [Current methods for modelling voice production]. AB - BACKGROUND: Many details of the phonatory process are not yet fully understood. Besides observational research, scientists have long since been trying to explain the physical fundamentals of voicing using simulations. This approach is commonly called modeling. However, the knowledge gained often failed to find its way to professionals working with the voice, such as singing teachers, voice therapists, and voice coaches, and sometimes also to otorhinolaryngologists and phoniatricians. The reason for this is that scientific publications on this topic mostly contain very detailed mathematical and physical descriptions, which are often hard to understand. OBJECTIVE: A simplified presentation and explanation of current methods for modeling the phonatory process, which have contributed greatly to uncovering and understanding the relationships involved in voicing during recent years. METHODS: The presented methods cover a wide spectrum, ranging from numerically rather simple to mathematically highly complex models. Experimental models are based on self-oscillating silicon or static vocal folds. Cadaver models have the advantage of being representative of the natural phonation process. RESULTS: An overview of different kinds of models is given to show the diversity of modeling approaches without going into mathematical or physical details. CONCLUSION: Numerical and experimental models for simulating the phonatory process enable causalities and correlations to be uncovered, which can be used in the future to adapt conservative and surgical voice therapies, or even to suggest entire new treatment strategies. PMID- 26746640 TI - [The role of microRNAs in head and neck squamous cell carcinoma : Biomarkers for prognosis, therapy selection, and novel therapeutics]. AB - Despite recent advances in radiochemotherapy, treatment of locally advanced head and neck squamous cell carcinoma is still challenging, and survival rates have improved only slightly. This is due to the high frequency of metastases and local and/or regional tumor recurrences that have acquired radio- or chemoresistance. MiRNAs regulate diverse processes in tumorigenesis, metastasis, and therapy resistance in head and neck squamous cell carcinoma. Hence, miRNAs are highly valued in biomarker studies. Establishment of the miRNA profiles of oropharyngeal tumors enables personalized treatment selection, since expression of distinct miRNAs can predict the response to two different radiochemotherapy regimens. Development of novel miRNA therapeutics has a high clinical potential for further improving treatment of cancerous disease. The use of nanoparticles with distinct surface modifications as miRNA vectors permits prolonged bioavailability, high efficacy in tumor targeting, and low toxicity. Nevertheless, the efficacy of miRNA therapy has only been shown in animal models to date. PMID- 26746643 TI - [In Process Citation]. PMID- 26746641 TI - Functional and cytometric examination of different human lung epithelial cell types as drug transport barriers. AB - To develop inhaled medications, various cell culture models have been used to examine the transcellular transport or cellular uptake properties of small molecules. For the reproducible high throughput screening of the inhaled drug candidates, a further verification of cell architectures as drug transport barriers can contribute to establishing appropriate in vitro cell models. In the present study, side-by-side experiments were performed to compare the structure and transport function of three lung epithelial cells (Calu-3, normal human bronchial primary cells (NHBE), and NL-20). The cells were cultured on the nucleopore membranes in the air-liquid interface (ALI) culture conditions, with cell culture medium in the basolateral side only, starting from day 1. In transport assays, paracellular transport across all three types of cells appeared to be markedly different with the NHBE or Calu-3 cells, showing low paracellular permeability and high TEER values, while the NL-20 cells showed high paracellular permeability and low TEER. Quantitative image analysis of the confocal microscope sections further confirmed that the Calu-3 cells formed intact cell monolayers in contrast to the NHBE and NL-20 cells with multilayers. Among three lung epithelial cell types, the Calu-3 cell cultures under the ALI condition showed optimal cytometric features for mimicking the biophysical characteristics of in vivo airway epithelium. Therefore, the Calu-3 cell monolayers could be used as functional cell barriers for the lung-targeted drug transport studies. PMID- 26746644 TI - [Radicalism and feminism: The case of Poulain de la Barre]. AB - Early modern radicalism and its criteria are described and defined by Jonathan Israel in various works. Poulain de la Barre, one of the first modern feminist thinkers, first is used by Israel as an example of the so-called radical Enlightenment and finally is rejected as such. This case study exhibed the necessity of questionning the coherence of the required criteria for defining a " radical " thinker, especially when examinating carefully the last paragraph of Spinoza's Political Treatise. PMID- 26746645 TI - [Life and death of captive eastern gorillas (Gorilla beringei) (1923-2012)]. AB - The evolving channels through which zoos acquire animals is an important-albeit often ignored-part of the history of these institutions, allowing a better understanding of human-animal relationships. Following current developments in animal history, this essay focuses on animals themselves, their experience of capture, and of captivity. A micro-historical approach based on the case of Eastern gorillas'capture highlights human practices and policies, their effects on gorillas and the evolution towards a decrease of captures. PMID- 26746642 TI - A mutation in the Cc.arp9 gene encoding a putative actin-related protein causes defects in fruiting initiation and asexual development in the agaricomycete Coprinopsis cinerea. AB - Agaricomycetes exhibit a remarkable morphological differentiation from vegetative mycelia to huge fruiting bodies. To investigate the molecular mechanism underlying the fruiting body development, we have isolated and characterized many Coprinopsis cinerea mutant strains defective in fruiting initiation to date. Dikaryon formation in agaricomycetes, which is followed by fruiting development, is governed by the mating type loci, A and B. Recently, mutations in the Cc.snf5 gene, which encodes a putative component of the chromatin remodeling complex switch/sucrose non-fermentable (SWI/SNF), were shown to cause defects in A regulated clamp cell morphogenesis, as well as in fruiting initiation. Here, we demonstrate that Cc.arp9, which encodes a putative actin-related protein associated with two chromatin remodeling complexes, SWI/SNF and remodels the structure of chromatin (RSC), is also essential for fruiting initiation. In contrast to Cc.snf5 mutants, Cc.arp9 mutants were not defective in clamp cell formation. The effects of mutations in Cc.arp9 and Cc.snf5 on oidia production and the transcriptional expression levels of clp1 and pcc1, which are under the control of the A gene, were also examined. These indicated that Cc.Snf5 is involved in A-regulated pathways, whereas Cc.Arp9 is not apparently. Cc.arp9/Cc.snf5 double-gene disruptants were generated and their phenotypes were analyzed, which suggested a complicated developmental regulation mechanism mediated by chromatin remodeling. PMID- 26746646 TI - [The theory of order from poinsot to Bourgoin: Mathematics, philosophy, ornemental art]. AB - The aim of this paper is to understand the dynamics of the theory of order in the nineteenth century and to reveal a specific approach to mathematics, science, philosophy and decorative art in which order plays a prominent role. We will analyze the singular meaning that Poinsot assigns to the notion of order in the mathematical sciences, before describing the circulation of his writings on the order in the nineteenth century. Poinsot is one of the main sources of Cournot, who places the notions of order and form as the basis of his knowledge system. Then we will study the writings of Bourgoin who develops a combinatorics of ornaments based on the categories of order and form. PMID- 26746647 TI - [Eleven thesis on the archive of scientific research, for a new patrimonial and scientific policy]. AB - Abstracting the main content of a recent report on the bad state of the archives of scientific research, this paper puts forward eleven thesis likely to feed, in this time of numeric transition to a new documentary regime and to a new patrimonial policy. The recent numeric conditions impose to set new archival pratices, more proactive, anticipative and prospective. Archives of scientific research must be thought in a double memorial and scientific dimension, and not only as a patrimonial or historical one. PMID- 26746648 TI - Simplex didactics: A non-linear trajectory for research in education. AB - The concept of simplexity, as proposed by Alain Berthoz, is based on the assumption that solutions elaborated by living organisms to decipher and face complexity could be applicable to all complex adaptive systems. Within the pedagogical and didactic context the proposal of the French physiologist could provide a scientific research trajectory aiming at solving the tension between theory, praxis, descriptive approaches and practical needs. Thus, simplexity seems to be an operational strategy based on the identification of the principles that rule and guide the didactic action through patterns of adaptation, which allow to decipher complexity in terms of data elaboration and decision making among different opportunities. PMID- 26746649 TI - [In Process Citation]. PMID- 26746650 TI - [Not Available]. PMID- 26746652 TI - Tenofovir Disoproxil Fumarate Fails to Prevent HIV Acquisition or the Establishment of a Viral Reservoir: Two Case Reports. AB - The use of antiretrovirals as pre-exposure prophylaxis (PrEP) is highly efficacious in HIV prevention. The World Health Organization recently recommended Truvada((r)) (Gilead Sciences, Inc.) or tenofovir disoproxil fumarate (TDF) for high-risk individuals, with limited data for single-agent TDF PrEP in men who have sex with men (MSM). We report two cases of TDF PrEP failure in MSM who had received long-term TDF for hepatitis B infection and had therapeutic levels of drug immediately after HIV acquisition. Rapid antiretroviral intensification at diagnosis of acute HIV infection failed to limit immune dysfunction or prevent the establishment of a viral reservoir. PMID- 26746653 TI - Assessment of bone marrow lymphocytic status during tyrosine kinase inhibitor therapy and its relation to therapy response in chronic myeloid leukaemia. AB - PURPOSE: Tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukaemia have been reported to induce immunomodulatory effects. We aimed to assess peripheral blood (PB) and bone marrow (BM) lymphocyte status at the diagnosis and during different TKI therapies and correlate it with treatment responses. METHODS: BM and PB samples were acquired from 105 first-line TKI treated patients. Relative number of BM lymphocytes was evaluated from MGG stained BM aspirates, and immunophenotypic analyses were performed with multicolour flow cytometry. RESULTS: Early 3-month expansion of BM lymphocytes was found during all different TKIs (imatinib n = 71, 20 %; dasatinib n = 25, 21 %; nilotinib n = 9, 22 %; healthy controls n = 14, 12 %, p < 0.0001). Increased PB lymphocyte count was only observed during dasatinib therapy. The BM lymphocyte expansion was associated with early molecular response; patients with 3-month BCR ABL1 <10 % showed higher lymphocyte counts than patients with BCR-ABL1 >10 % (23 vs. 17 %, p < 0.05). Detailed phenotypic analysis showed that BM lymphocyte expansion consisted of various lymphocyte subclasses, but especially the proportion of CD19+ B cells and CD3negCD16/56+ NK cells increased from diagnostic values. During dasatinib treatment, the lymphocyte balance in both BM and PB was shifted more to cytotoxic direction (increased CD8+CD57+ and CD8+HLA-DR+ cells, and low T regulatory cells), whereas no major immunophenotypic differences were observed between imatinib and nilotinib patients. CONCLUSIONS: Early BM lymphocytosis occurs with all current first-line TKIs and is associated with better treatment responses. PB and BM immunoprofile during dasatinib treatment markedly differs from both imatinib- and nilotinib-treated patients. PMID- 26746654 TI - Survival advantage of lymphadenectomy in endometrial cancer. AB - BACKGROUND: The lymphadenectomy in the treatment of endometrial cancer is a topic of ongoing debate. The direct comparison between no lymphadenectomy, pelvic lymphadenectomy, and pelvic/para-aortic lymphadenectomy regarding overall survival of patients with endometrial cancer is missing. METHODS: We performed a multicenter, retrospective, registry-based study of 1502 patients with endometrial cancer treated with no lymphadenectomy (n = 697), systemic pelvic lymphadenectomy (n = 543) and systemic pelvic/para-aortic lymphadenectomy (n = 262). The patients were divided into three groups of recurrence risk: low, intermediate, and high. The outcome measure was overall survival. RESULTS: Median follow-up was 78 months. Lymphadenectomy did not improve overall survival of patients with low risk of recurrence. The survival effect of systemic lymphadenectomy was significant in patients with intermediate and high risk of recurrence. Multivariate analysis showed that both pelvic (HR 0.63, CI 0.38-0.82, p = 0.001) and combination of pelvic/para-aortic lymphadenectomy (HR 0.50, CI 0.43-0.81, p < 0.0001) significantly reduced the mortality risk in patients with intermediate risk compared to the patients who underwent no lymphadenectomy. In patients with high risk, only combined pelvic/para-aortic lymphadenectomy (HR 0.62, CI 0.48-0.82, p = 0.005) was associated with decreased mortality rate compared with no lymphadenectomy. Among patients with intermediate and high risk of recurrence who did not receive any adjuvant therapy, pelvic/para-aortic lymphadenectomy significantly reduced the mortality risk (HR 0.52, CI 0.37-0.73, p < 0.0001) in comparison with no lymphadenectomy. This management was superior to pelvic lymphadenectomy alone. In patients with low risk of recurrence, lymphadenectomy had no effect on overall survival. CONCLUSIONS: Pelvic/para aortic lymphadenectomy should be performed in all patients with endometrial cancer at intermediate and high risk of recurrence. PMID- 26746656 TI - Novel insights into the link between fetal cell microchimerism and maternal cancers. AB - INTRODUCTION: Fetal cell microchimerism (FCM) is defined as the persistence of fetal cells in the mother for decades after pregnancy without any apparent rejection. Fetal microchimeric cells (fmcs) engraft the maternal bone marrow and are able to migrate through the circulation and to reach tissues. In malignancies, the possible role of fmcs is still controversial, several studies advising a protective and repairing function, and other postulating a beneficial role in the progression of the disease. At the peripheral blood level, FCM is less frequently observed in women with several solid and hematological neoplasia with respect to healthy controls, suggesting a beneficial role in cancer surveillance. At the tissue level, fmcs were documented in neoplastic lesions of thyroid, breast, cervix, lung and melanoma, displaying epithelial, hematopoietic, mesenchymal and endothelial lineage differentiation. Fmcs expressing hematopoietic markers were hypothesized to have a role in the attack to neoplastic cells, whereas those expressing epithelial or mesenchymal antigens could be involved in repair and replacement of damaged cells. On the other hand, fetal cells showing an endothelial phenotype could have a role in tumor evolution and progression. The positive effect of FCM is supported by findings in animal models. CONCLUSIONS: This review provides an extensive overview of the link between fetal cell microchimerism and maternal cancers. Moreover, biological mechanisms by which fetal cell microchimerism is believed to modulate the protection against cancer development or tumor progression will be discussed, together with findings in animal models. PMID- 26746657 TI - Spatial driving forces of dominant land use/land cover transformations in the Dongjiang River watershed, Southern China. AB - Information about changes in, and causes of, land use/land cover (LULC) is crucial for land use resource planning. We investigated the processes involved in LULC change (LUCC) in the Dongjiang Watershed, in Southern China, over a 15-year period to gain a better understanding of the causes of the main types of LUCC. Using a depth transition matrix and redundancy analysis (RDA), the major types and causes of LUCC for each LULC type over the past 15 years were identified. LUCC exhibited obvious net change, relatively low persistence, and high swap change. The swap changes in most LULC types were considered as a strong signal of LULC transformations. The driving forces behind swap changes were quantified and identified through RDA. The results showed that all driving forces played important roles in explaining swap changes of LULC, although the relative effects of these drivers varied widely with both LULC type and time period. Swap changes of the LULC types were generally classified into two categories. Some, e.g., built-up land and wetland, were affected mostly by landform and/or distance factors, while others, e.g., grassland and woodland, were modulated mostly by climate and/or socioeconomic factors. Selected spatial driving forces and local land use policies played important roles in explaining the dominant LUCC types, but on different timescales. These findings may improve understanding of the detailed processes involved in LUCC, landscape transformation, and the causes of LUCC in other areas with extensive LUCC and could help managers plan, design, and implement land resource management. PMID- 26746655 TI - Prostate tumor overexpressed 1 expression in invasive urothelial carcinoma. AB - PURPOSE: To determine the expression patterns of the proliferation marker prostate tumor overexpressed 1 (PTOV1) in invasive urothelial cancer (UC). METHODS: Corresponding UC and benign samples from paraffin-embedded tissue of 102 patients treated with cystectomy for invasive UC were immunohistochemically (IHC) assessed for PTOV1. Expression was evaluated gradually separated for cytoplasmic and nuclear staining. Results were correlated to histological and clinical data. To correlate PTOV1 expression with molecular subtypes of UC, analysis of PTOV1 RNA expression data of the Cancer Genome Atlas UC cohort was performed. RESULTS: PTOV1 expression was present in UC and benign urothelium, whereby nuclear staining was significantly more frequent in UC tissue (p = 0.0004). Lower cytoplasmic expression was significantly associated with pathological stage >pT2 (p = 0.0014) and grade >=G3 (p = 0.0041), respectively. IHC expression patterns did not show correlation to survival data. PTOV1 RNA expression correlated with features of the luminal UC subtype. CONCLUSIONS: Subcellular distribution seems to be the most important feature of PTOV1 expression in UC. Nuclear localization of PTOV1 along with cytoplasmic decrease in PTOV1 expression was identified as putative surrogate for PTOV1-associated cellular proliferation and dedifferentiation in UC. The functional relevance as well as the potential role of PTOV1 as a biomarker in UC remains to be specified in future studies. PMID- 26746658 TI - The serine protease inhibitor of Kazal-type 9 (SPINK9) is expressed in lichen simplex chronicus, actinic keratosis and squamous cell carcinoma. AB - The serine protease inhibitor of Kazal-type (SPINK) 9 was reported to be exclusively expressed in palmoplantar skin. SPINK9 is a specific inhibitor of the serine protease kallikrein-related peptidase 5 (KLK5), which contributes to the desquamation process of the stratum corneum. Herein, we demonstrated that SPINK9 is also expressed in lichen simplex chronicus. Moreover, we observed expression of SPINK9 in 51 % of lesions of actinic keratosis and squamous cell carcinoma. In conclusion, we demonstrate that SPINK9 is not only expressed in healthy palmoplantar skin, but also in dermatologic disorders like lichen simplex chronicus, actinic keratosis and squamous cell carcinoma. PMID- 26746659 TI - Paradoxical E-cadherin increase in 5FU-resistant colon cancer is unaffected during mesenchymal-epithelial reversion induced by gamma-secretase inhibition. AB - AIM: Presenilin-1 (PS1), the main component of gamma-secretase activity support a key role during Epithelial-Mesenchymal Transition (EMT) and chemoresistance acquisition by triggering a complex sequence of molecular events, including E cadherin down-regulation. However, we hypothesize that EMT and chemoresistance should be deemed separate processes in HCT-8 colon cancer cells. MAIN METHODS: HCT-8 and HCT-8FUres invasion was evaluated by trans-well assay. uPA activity was detected by zymography. Prostaglandin E2 levels were quantified using an ELISA kit. E-cadherin FL and CTF2, PS1, Notch1, Cyclin D1, COX2, SNAI1 and alpha-SMA expression were determined using Western blot technique. beta-Catenin localization was observed by confocal microscopy. Cell apoptosis was evaluated by cytofluorimetric assay, and measurement of caspase-3 and cl-PARP. gamma-Secretase activity was inhibited by DAPT, a gamma-secretase inhibitor. KEY FINDINGS: Chemoresistant HCT-8 underwent EMT that can be efficiently reversed by inhibiting PS1 activity, leading thus to a normalization of mostly of the pivotal features showed by the invasive cancer phenotype. Indeed, we observed decreased SNAI1 and Notch 1 activation, altogether with reduced E-cadherin cleavage. Concomitantly, resistant HCT-8 invasiveness was almost completely abolished. However, such reversion was not followed by any increase in apoptotic rate, not by changes in E cadherin levels. Indeed, despite HCT-8FUres underwent an undeniable EMT, full length E-cadherin levels were found remarkably higher than those observed in wild HCT-8. SIGNIFICANCE: High E-cadherin concentration in presence of enhanced gamma secretase activity is incontestably a paradoxically result, highlighting that E cadherin loss is not a pre-requisite for EMT. Additionally, EMT and chemoresistance acquisition in HCT-8 should be considered as distinct processes. PMID- 26746660 TI - Discovery of novel dual inhibitors against Mdm2 and Mdmx proteins by in silico approaches and binding assay. AB - AIMS: The p53 protein, also called guardian of the genome, has a key role in cell cycle regulation. It is activated under stressful circumstances, such as DNA damage which results in permanent arrest or cell death. The protein is disabled in several types of human cancer due to over-expression of the two regulators, Mdm2 and Mdmx. As a result, inhibiting Mdm subtypes could reactivate p53 and bring about a promising therapeutic strategy in cancers. MAIN METHODS: Here a structure-based pharmacophore search and docking simulation are presented in order to filter our in-house library which contains 1035 compounds to find novel scaffolds that inhibit Mdm2 and Mdmx concomitantly. Afterwards, fluorescence polarization binding assay was used to obtain inhibition constant of final compounds. KEY FINDINGS: Thirty two ligands were introduced to bioassay as a result of in-silico methods. Twelve of them inhibit both proteins with almost balanced Ki value ranging from 18 to 162MUM for Mdm2 and 18 to 233MUM for Mdmx. It was observed that all compounds fill Phe19 and Trp23 pockets of Mdm2/x binding sites and form a hydrogen bond with Trp23 pocket's neighbor amino acids in a manner similar to p53 protein. Additionally, it was concluded that Trp23 pocket of Mdmx has a bigger hydrophobic volume comparing with the one of Mdm2. SIGNIFICANCE: Three structure-activity relationship patterns are supposed which one of them presents usefulness features and can be used in future studies. This study presents first qualitative SAR for dual inhibitors against Mdm2/x. PMID- 26746665 TI - Promicromonospora alba sp. nov., an actinomycete isolated from the cuticle of Camponotus japonicas Mayr. AB - A novel actinomycete, designated strain 1C-HV12T, was isolated from the cuticle of Camponotus japonicas Mayr and characterized using a polyphasic approach. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that the organism should be assigned to the genus Promicromonospora and that it forms a monophyletic clade with the closest relatives Promicromonospora umidemergens JCM 17975T(99.17 % 16S rRNA gene sequence similarity), Promicromonospora vindobonensis V45T (98.88 %) and Promicromonospora iranensis HM 792T (98.85 %). Moreover, morphological and chemotaxonomic properties of strain 1C-HV12T also confirmed the affiliation of the isolate to the genus Promicromonospora. The peptidoglycan hydrolysates contained alanine, glutamic acid and lysine, and whole cell sugars were galactose, glucose, rhamnose and ribose. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside, an unidentified phosphoglycolipid, an unidentified phospholipid and an unidentified glycolipid. The major menaquinones were MK-9(H4) and MK-9(H2). The predominant cellular fatty acids were anteiso-C15 : 0, iso-C15 : 0 and anteiso-C17 : 0. The DNA G+C content was 71.6 mol%. However, the low level of DNA-DNA relatedness and some phenotypic characteristics allowed the isolate to be differentiated from closely related species. Therefore, it is concluded that strain 1C-HV12T represents a novel species of the genus Promicromonospora, for which the name Promicromonospora alba sp. nov. is proposed. The type strain is 1C-HV12T ( = CGMCC 4.7283T = DSM 100490T). PMID- 26746661 TI - Effects of Living Alone on Social Capital and Health Among Older Adults in China. AB - Social capital has been connected with positive health outcomes across countries, including China. Given the rise in the number of seniors living alone, there is a need to examine the health benefits of social capital, accounting for living arrangements. Data from the 2005 Chinese General Social Survey were used to test research hypotheses. Controlling for demographics, elders living alone possessed similar level of social capital compared with elders living with others. While bonding and linking social capital were significant factors in urban areas and linking social capital was a significant factor in rural areas, the relationship between living alone and health did not differ based on the level of social capital possession. When the traditional intergenerational living arrangement has not been a valid option for many older adults in China, seeking new way of family caring, and developing appropriate social and institutional structures to assist elders living alone, becomes critical. PMID- 26746666 TI - Progesterone Changes VEGF and BDNF Expression and Promotes Neurogenesis After Ischemic Stroke. AB - Studies have shown that progesterone enhances functional recovery after ischemic stroke, but the underlying mechanisms are not completely understood. Therefore, we investigated the effect of progesterone on vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and neurogenesis in a rodent stroke model. Rats underwent permanent middle cerebral artery occlusion (pMCAO) and then received intraperitoneal injections of progesterone (15 mg/kg) or vehicle at 1 h followed by subcutaneous injections at 6, 24, and 48 h. We examined VEGF and BDNF expression by Western blotting and/or immunostaining and microvessel density by lectin immunostaining. Neurogenesis in the subventricular zone was determined by immunostaining of Ki67 and doublecortin, and double BrdU/Nestin immunostaining. We calculated brain water content with the wet-dry weight method on day 3 and assessed neurologic deficits with the modified neurological severity score on days 1, 3, 7, and 14. Progesterone-treated rats showed a significant decrease in VEGF expression, but an increase in BDNF expression, compared with that of vehicle-treated pMCAO rats on day 3 post occlusion. Progesterone did not alter the microvessel density, but it reduced brain water content compared with that in vehicle-treated rats on day 3 post occlusion. Progesterone treatment increased the numbers of newly generated neurons in the subventricular zone and doublecortin-positive cells in the peri infarct region on day 7 post-occlusion. In addition, progesterone improved neurologic function on days 7 and 14 post-occlusion. Our data suggest that the enhancement of endogenous BDNF and subsequent neurogenesis could partially underlie the neuroprotective effects of progesterone. PMID- 26746668 TI - Alzheimer's Disease Variants with the Genome-Wide Significance are Significantly Enriched in Immune Pathways and Active in Immune Cells. AB - The existing large-scale genome-wide association studies (GWAS) datasets provide strong support for investigating the mechanisms of Alzheimer's disease (AD) by applying multiple methods of pathway analysis. Previous studies using selected single nucleotide polymorphisms (SNPs) with several thresholds of nominal significance for pathway analysis determined that the threshold chosen for SNPs can reflect the disease model. Presumably, then, pathway analysis with a stringent threshold to define "associated" SNPs would test the hypothesis that highly associated SNPs are enriched in one or more particular pathways. Here, we selected 599 AD variants (P < 5.00E-08) to investigate the pathways in which these variants are enriched and the cell types in which these variants are active. Our results showed that AD variants are significantly enriched in pathways of the immune system. Further analysis indicated that AD variants are significantly enriched for enhancers in a number of cell types, in particular the B-lymphocyte, which is the most substantially enriched cell type. This cell type maintains its dominance among the strongest enhancers. AD SNPs also display significant enrichment for DNase in 12 cell types, among which the top 6 significant signals are from immune cell types, including 4 B cells (top 4 significant signals) and CD14+ and CD34+ cells. In summary, our results show that these AD variants with P < 5.00E-08 are significantly enriched in pathways of the immune system and active in immune cells. To a certain degree, the genetic predisposition for development of AD is rooted in the immune system, rather than in neuronal cells. PMID- 26746667 TI - Deletion of Nuclear Localizing Signal Attenuates Proinflammatory Activity of Prothymosin-Alpha and Enhances Its Neuroprotective Effect on Transient Ischemic Stroke. AB - Post-ischemic inflammation plays an important role in the progression of ischemia/reperfusion injuries. Prothymosin-alpha (ProT) can protect cells from necrotic death following ischemia; however, its immunostimulatory actions may counteract the neuroprotective effect. We proposed that ProTDeltaNLS, synthesized by deleting its nuclear localizing signal (NLS) at the C-terminal of ProT, can attenuate the immunostimulatory activity and has more salient neuroprotective effect. In this study, we examined the therapeutic effects of ProT and ProTDeltaNLS in a transient middle cerebral artery occlusion (tMCAO) model of rats. Rats that had sustained 90 min of tMCAO were treated with GST-vehicle, ProT, or ProTDeltaNLS. Therapeutic outcomes were evaluated by infarction volume assay and behavioral assessment. Changes to inflammatory mediators, including tumor necrosis factor alpha (TNF-alpha), interleukin-10 (IL-10), and myeloperoxidase (MPO) were evaluated by enzyme-linked immunosorbent assay. Activated matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9) levels were evaluated by gelatin zymography. Microglial activation was identified by double immunostaining for Iba-1 and CD68. Our results showed that while both ProT and ProTDeltaNLS reduce infarction volume and improve functional outcome, ProTDeltaNLS provides the best therapeutic outcome. ProT increases TNF-alpha but decreases IL-10 secretion after ischemic injury, reflecting its pro-inflammatory activity. ProTDeltaNLS suppresses expression of TNF-alpha, MPO, and activity of MMPs in ischemic brain tissue. It also suppresses activation of microglia in penumbral cortex. These data demonstrate the immunesuppressive activities of ProTDeltaNLS. In conclusion, ProT has pro-inflammatory effect that may counteract its neuroprotective effect. Deletion of NLS from ProT may attenuate post-ischemic inflammation and enhance the neuroprotective effects of ProT. PMID- 26746671 TI - Formalizing the Austrian Procedure Catalogue: A 4-step methodological analysis approach. AB - OBJECTIVES: Due to the lack of an internationally accepted and adopted standard for coding health interventions, Austria has established its own country-specific procedure classification system - the Austrian Procedure Catalogue (APC). Even though the APC is an elaborate coding standard for medical procedures, it has shortcomings that limit its usability. In order to enhance usability and usefulness, especially for research purposes and e-health applications, we developed an ontologized version of the APC. In this paper we present a novel four-step approach for the ontology engineering process, which enables accurate extraction of relevant concepts for medical ontologies from written text. METHODS: The proposed approach for formalizing the APC consists of the following four steps: (1) comparative pre-analysis, (2) definition analysis, (3) typological analysis, and (4) ontology implementation. The first step contained a comparison of the APC to other well-established or elaborate health intervention coding systems in order to identify strengths and weaknesses of the APC. In the second step, a list of definitions of medical terminology used in the APC was obtained. This list of definitions was used as input for Step 3, in which we identified the most important concepts to describe medical procedures using the qualitative typological analysis approach. The definition analysis as well as the typological analysis are well-known and effective methods used in social sciences, but not commonly employed in the computer science or ontology engineering domain. Finally, this list of concepts was used in Step 4 to formalize the APC. RESULTS: The pre-analysis highlighted the major shortcomings of the APC, such as the lack of formal definition, leading to implicitly available, but not directly accessible information (hidden data), or the poor procedural type classification. After performing the definition and subsequent typological analyses, we were able to identify the following main characteristics of health interventions: (1) Procedural type, (2) Anatomical site, (3) Medical device, (4) Pathology, (5) Access, (6) Body system, (7) Population, (8) Aim, (9) Discipline, (10) Technique, and (11) Body Function. These main characteristics were taken as input of classes for the formalization of the APC. We were also able to identify relevant relations between classes. CONCLUSIONS: The proposed four-step approach for formalizing the APC provides a novel, systematically developed, strong framework to semantically enrich procedure classifications. Although this methodology was designed to address the particularities of the APC, the included methods are based on generic analysis tasks, and therefore can be re used to provide a systematic representation of other procedure catalogs or classification systems and hence contribute towards a universal alignment of such representations, if desired. PMID- 26746669 TI - In Vitro Differentiation of Human iPS Cells into Neural like Cells on a Biomimetic Polyurea. AB - Human-induced pluripotent stem cells (hiPSCs) have the pluripotency to differentiate into all three germ layers in vitro and have been considered potent candidates for regenerative medicine as an unlimited source of cells for therapeutic applications. Neural tissue engineering is an important area of research in the field of tissue-engineering especially for neurodegenerative disease. Here, we investigated the use of poly lactic acid/gelatin (PLA/gelatin) scaffold as three-dimensional (3D) system which increase neural cell differentiation. Through neural induction, neural-like cells (NLCs) were derived from hiPSCs on nanofibrous PLA/gelatin scaffold. Enhanced numbers of neural structures and staining of neural markers were observed with hiPS cell-seeded nanofibrous scaffolds when compared with control medium. The results revealed that hiPSCs attach and grow on the nanofibrous PLA/gelatin scaffold, and hiPSCs cultured on scaffold have the potential to differentiate in neuronal cells in the presence of growth factors. The result of this study may have impact in tissue engineering and cells-base therapy of neurodegenerative diseases and have a great potential for wide application. PMID- 26746670 TI - Leukemia Inhibitory Factor Protects Neurons from Ischemic Damage via Upregulation of Superoxide Dismutase 3. AB - Leukemia inhibitory factor (LIF) has been shown to protect oligodendrocytes from ischemia by upregulating endogenous antioxidants. The goal of this study was to determine whether LIF protects neurons during stroke by upregulating superoxide dismutase 3 (SOD3). Animals were administered phosphate-buffered saline (PBS) or 125 MUg/kg LIF at 6, 24, and 48 h after middle cerebral artery occlusion or sham surgery. Neurons were isolated from rat pups on embryonic day 18 and used between 7 and 15 days in culture. Cells were treated with LIF and/or 10 MUM Akt inhibitor IV with PBS and 0.1 % DMSO acting as vehicle controls. Neurons transfected with scrambled or SOD3 small interfering RNA (siRNA) were subjected to 24-h ischemia after PBS or LIF treatment. LIF significantly increased superoxide dismutase activity and SOD3 expression in ipsilateral brain tissue compared to PBS. Following 24-h ischemia, LIF reduced cell death and increased SOD3 messenger RNA (mRNA) in vitro compared to PBS. Adding Akt inhibitor IV with LIF counteracted the decrease in cell death. Partially silencing the expression of SOD3 using siRNA prior to LIF treatment counteracted the protective effect of LIF-alone PBS treatment. These results indicate that LIF protects neurons in vivo and in vitro via upregulation of SOD3. PMID- 26746672 TI - Adaptability of structured forms for CSII initiation in patients with type 2 diabetes the Getting2Goal(SM) concept. AB - BACKGROUND: The goal is to assess the usability and satisfaction of implementing the Getting2Goal(SM) protocol by physicians transitioning patients with type 2 diabetes (T2DM) from multiple daily injections (MDI) to continuous subcutaneous insulin infusion (CSII). METHODS: T2DM patients from three diabetes clinics were switched from MDI to CSII. Physicians used the Getting2Goal type 2 pumping protocol to prescribe and manage insulin pump therapy for T2DM. Surveys were conducted in which the physicians rated their feedback related to acceptability of the Getting2Goal on a 5-point Likert scale. RESULTS: 17 patients with T2DM were switched from MDI to CSII treatment. Mean (+/-standard deviation) age was 61.2 +/- 7.7 (46-77) years, weight was 91.4 +/- 21 (66-147) kg, BMI was 31.9 +/- 7.6, A1C was 9.2 +/- 1.4 % (7.2-12.3) and TDD on MDI was 109.1 +/- 53.1 units. Surveys completed by physicians indicated Getting2Goal type 2 pumping protocol to be more efficient, time saving, and structured compared to their current processes. In addition, the primarily prescribed TDD on pump was 98.1 +/- 50.0 units and the TDD at first download was 81.4 +/- 36.4 units, representing a 25.4 % reduction in TDD At first download. The percentage of all blood glucose readings below 70 mg/dL was also very low. CONCLUSIONS: The data indicate Getting2Goal materials as a standard approach that is simple and efficient to initiate pump therapy for T2DM. At the same time, it is safe and a useful tool for physicians that are starting to prescribe pump therapy for T2DM. PMID- 26746674 TI - Optimising value from the soft re-use of brownfield sites. AB - Soft re-use of brownfields describes intended temporary or final re-uses of brownfield sites which are not based on built constructions or infrastructure ('hard' re-use). Examples of soft re-uses include the creation of public green space. These are essentially uses where the soil is not sealed. Often the case for soft re-use of brownfields has not been easy to demonstrate in strictly financial terms. The purpose of this paper is to describe a value based approach to identify and optimise services provided by the restoration of brownfields to soft re-uses, on a permanent or interim basis. A 'Brownfield Opportunity Matrix' is suggested as means of identifying and discussing soft restoration opportunities. The use of 'sustainability linkages' is suggested as a means of understanding the sustainability of the services under consideration and providing a structure for the overall valuation of restoration work, for example as part of design or option appraisal processes, or to support the solicitation of interest in a project. PMID- 26746673 TI - Transient receptor potential ankyrin 1 (TRPA1) receptor is involved in chronic arthritis: in vivo study using TRPA1-deficient mice. AB - BACKGROUND: The transient receptor potential ankyrin 1 (TRPA1) is a calcium permeable cation channel that is expressed on capsaicin-sensitive sensory neurons, endothelial and inflammatory cells. It is activated by a variety of inflammatory mediators, such as methylglyoxal, formaldehyde and hydrogen sulphide. Since only few data are available about the role of TRPA1 in arthritis and related pain, we investigated its involvement in inflammation models of different mechanisms. METHODS: Chronic arthritis was induced by complete Freund's adjuvant (CFA), knee osteoarthritis by monosodium iodoacetate (MIA) in TRPA1 knockout (KO) mice and C57Bl/6 wildtype mice. For comparison, carrageenan- and CFA-evoked acute paw and knee inflammatory changes were investigated. Thermonociception was determined on a hot plate, cold tolerance in icy water, mechanonociception by aesthesiometry, paw volume by plethysmometry, knee diameter by micrometry, weight distribution with incapacitance tester, neutrophil myeloperoxidase activity and vascular leakage by in vivo optical imaging, and histopathological alterations by semiquantitative scoring. RESULTS: CFA-induced chronic mechanical hypersensitivity, tibiotarsal joint swelling and histopathological alterations, as well as myeloperoxidase activity in the early phase (day 2), and vascular leakage in the later stage (day 7), were significantly reduced in TRPA1 KO mice. Heat and cold sensitivities did not change in this model. Although in TRPA1 KO animals MIA-evoked knee swelling and histopathological destruction were not altered, hypersensitivity and impaired weight bearing on the osteoarthritic limb were significantly decreased. In contrast, carrageenan- and CFA-induced acute inflammation and pain behaviours were not modified by TRPA1 deletion. CONCLUSIONS: TRPA1 has an important role in chronic arthritis/osteoarthritis and related pain behaviours in the mouse. Therefore, it might be a promising target for novel analgesic/anti-inflammatory drugs. PMID- 26746677 TI - Serum folate levels and fatality among diabetic adults: A 15-y follow-up study of a national cohort. AB - OBJECTIVE: Folate is involved in carbohydrate metabolism, a process that can have clinical implications regarding diabetes management. The aim of this study was to assess the relationship between serum folate and fatality among adults with diabetes. METHODS: A retrospective cohort study was conducted with 532 adults with diabetes who participated in Phase II of NHANES III (National Health and Nutrition Examination Survey III; 1991-1994). This study served as baseline and was linked to the National Death Index database for a 15-y (1991-2006) follow-up study. Estimates of hazard ratios (HRs) for all-cause and cancer-related deaths, cardiovascular disease (CVD), and diabetes for individuals with different serum folate levels were obtained from Cox proportional hazards regression. RESULTS: The mean age of adults with diabetes and detected serum folate at baseline was 63.2 y (SD 13.8 y). During follow-up, diabetes was listed as a contributor for 138 of 299 deaths. For all-cause deaths, the fatality rate of the upper quartile (74.30/1000 person-years [PY]) was almost twofold higher than the lower quartile (41.75/1000 PY) of serum folate levels. After adjusting for several covariates, including serum vitamin B12, cotinine, homocysteine and CVD history at baseline; the HRs for all-cause fatalities were 1.00 (reference), 1.62 (95% confidence interval [CI], 1.06-2.47) and 1.76 (95% CI, 1.09-2.83) among adults with diabetes in the lower, intermediate, and upper quartiles of serum folate levels, respectively. CONCLUSION: Results indicate that high serum folate concentrations are associated with an increased fatality risk among adults with diabetes. Further studies are warranted to determine the mechanism(s) of this phenomenon. PMID- 26746676 TI - Associations among circulating branched-chain amino acids and tyrosine with muscle volume and glucose metabolism in individuals without diabetes. AB - OBJECTIVES: Amino acid metabolites, including branched-chain amino acids (BCAA) and tyrosine (Tyr), affect glucose metabolism. The effects of BCAA on insulin resistance in patients with diabetes seem to conflict with mechanisms determined in animal models and cultured cells. The aim of this study was to clarify the controversy surrounding the effects of BCAA by investigating the physiological effects of BCAA and Tyr on glucose metabolism in healthy community dwellers. METHODS: We investigated associations among BCAA and Tyr and metabolic parameters in 78 residents (median age, 52 y) of Mie, Japan, who did not have prediabetes, diabetes, or a body mass index >30 kg/m(2). RESULTS: Muscle volume, serum BCAA, and Tyr levels were higher in men than in women (n = 32 and 46, respectively; all P < 0.0001). Stepwise multiple regression analysis associated BCAA positively with muscle volume (regression coefficient/t/p/95% confidence interval, 281.8/3.7/0.0004/129.7-433.8), fasting blood glucose (FBG; 12699.4/3.22/0.0020/4830.9-20567.8), fasting immunoreactive insulin (IRI; 8505.1/2.75/0.0078/2322.5-14687.6), and homeostasis model assessment of beta-cell function (HOMA-beta; 893.6/2.58/0.0122/201.8-1585.5), and negatively with the HOMA-insulin resistance (HOMA-IR; -9294.1/-2.89/0.0052/-15711.0 to -2877.1). Tyr positively correlated with fasting IRI (26/2.77/0.0072/7.3-44.7). CONCLUSIONS: Insulin sensitivity and muscle volume are positively associated with BCAA in individuals without diabetes. In turn, BCAA correlate with increased FBG and fasting IRI levels. Tyr correlated with fasting IRI, but not with insulin sensitivity. PMID- 26746678 TI - Special postoperative diet orders: Irrational, obsolete, and imprudent. AB - There are no indications to prescribed special diets for postoperative patients. Low-sodium and low-fat or low-cholesterol diets are examples of restricted diets, especially in patients with heart disease and atherosclerosis. These restricted diets are unpalatable. Postoperative nausea, paralytic ileus, and vomiting caused by residual anesthetic effects and opioids used for pain control further contribute to the problem. Long-term adherence to these diets is necessary to derive benefits. Prescribing regular and palatable diets in the immediate postoperative period to meet protein and energy goals is important for wound healing and is commensurate with best clinical practices. In the following, we review the pertinent literature and offer clinical evidence that routine special diet orders for postoperative patients are not necessary. PMID- 26746675 TI - Anti-tumor effects of pigment epithelium-derived factor (PEDF): implication for cancer therapy. A mini-review. AB - Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein and a non inhibitory member of the serine protease inhibitor (serpin) family. It is widely expressed in human fetal and adult tissues but its expression decreases with age and in malignant tissues. The main anti-cancer activities of PEDF derive from its dual effects, either indirectly on the tumor microenvironment (indirect antitumor action) or directly on the tumor itself (direct antitumor influence). The indirect antitumor activities of PEDF were uncovered from the early findings that it stimulates retinoblastoma cell differentiation and that additionally it possesses anti-angiogenic, anti-tumorigenic and anti-metastatic properties. The mechanisms of its direct antitumor effect, however, have not been fully elucidated. This review highlights recent progress in our understanding of the multifunctional activities of PEDF and, in particular, its anti-cancer signaling mechanisms. Additionally, we discuss the possibility of using novel phosphaplatin compounds that can upregulate PEDF expression as a chemotherapy for cancer treatment. PMID- 26746679 TI - Abnormal fatty acids in Canadian children with autism. AB - OBJECTIVE: Fatty acids are critical for pediatric neurodevelopment and are abnormal in autism, although prior studies have demonstrated conflicting results and methodological differences. To our knowledge, there are no published data on fatty acid in Canadian children with autism. The aim of this study was to investigate red blood cell and serum fatty acid status to identify whether abnormalities exist in Canadian children with autism, and to enhance future cross study comparison. METHODS: Eleven Canadian children with autism (3 girls, 8 boys; age 3.05 +/- 0.79 y) and 15 controls (9 girls, 6 boys; age 3.87 +/- 1.06 y) met inclusion criteria, which included prior Diagnostic and Statistical Manual diagnosis of autism spectrum disorder, no recent medication or supplements, no specialty diets, and no recent illness. RESULTS: The children with autism demonstrated lower red blood cell docosahexaenoic acid (P < 0.0003), eicosapentaenoic acid (P < 0.03), arachidonic acid (P < 0.002), and omega-3/omega 6 ratios (P < 0.001). They also demonstrated lower serum docosahexaenoic acid (P < 0.02), arachidonic acid (P < 0.05), and linoleic acid (P < 0.02) levels. CONCLUSIONS: Fatty acids in both serum and red blood cells were abnormal in this small group of Canadian children with autism than in controls, underlining a need for larger age- and sex-matched investigations in this community. A potential role for fatty acid abnormalities within the complex epigenetic etiology of autism is proposed in relation to emerging understanding of relationships between cobalamin metabolism, gut microbiota, and propionic acid production. PMID- 26746680 TI - Job preferences among clinical officers in public sector facilities in rural Kenya: a discrete choice experiment. AB - BACKGROUND: Clinical officers (COs), a mid-level cadre of health worker, are the backbone of healthcare provision in rural Kenya. However, the vacancy rate for COs in rural primary healthcare facilities is high. Little is known about factors motivating COs' preferences for rural postings. METHODS: A discrete choice experiment (DCE) questionnaire was used with 57 COs at public health facilities in nine districts of Nyanza Province, Kenya. The questionnaire was developed on the basis of formative qualitative interviews with COs (n = 5) and examined how five selected job attributes influenced COs' preferences for working in rural areas. Conditional logit models were employed to examine the relative importance of different job attributes. RESULTS: Analysis of the qualitative data revealed five important job attributes influencing COs' preferences: quality of the facility, educational opportunities, housing, monthly salary and promotion. Analysis of the DCE indicated that a 1-year guaranteed study leave after 3 years of service would have the greatest impact on retention, followed by good quality health facility infrastructure and equipment and a 30% salary increase. Sub-group analysis shows that younger COs demonstrated a significantly stronger preference for study leave than older COs. Female COs placed significantly higher value on promotion than male COs. CONCLUSIONS: Although both financial incentives and non financial incentives were effective in motivating COs to stay in post, the study leave intervention was shown to have the strongest impact on COs' retention in our study. Further research is required to examine appropriate interventions at each career stage that might boost COs' professional identity and status but without leading to larger deficits in the availability of generalist COs. PMID- 26746682 TI - Effectiveness and Value of Treatment Options for Obesity--A Report for the California Technology Assessment Forum. PMID- 26746681 TI - Clinical-Pathological Correlation of Vogt-Koyanagi-Harada Disease. PMID- 26746683 TI - Envisioning future cognitive telerehabilitation technologies: a co-design process with clinicians. AB - Purpose Cognitive telerehabilitation is the concept of delivering cognitive assessment, feedback, or therapeutic intervention at a distance through technology. With the increase of mobile devices, wearable sensors, and novel human-computer interfaces, new possibilities are emerging to expand the cognitive telerehabilitation paradigm. This research aims to: (1) explore design opportunities and considerations when applying emergent pervasive computing technologies to cognitive telerehabilitation and (2) develop a generative co design process for use with rehabilitation clinicians. Methods We conducted a custom co-design process that used design cards, probes, and design sessions with traumatic brain injury (TBI) clinicians. All field notes and transcripts were analyzed qualitatively. Results Potential opportunities for TBI cognitive telerehabilitation exist in the areas of communication competency, executive functioning, emotional regulation, energy management, assessment, and skill training. Designers of TBI cognitive telerehabilitation technologies should consider how technologies are adapted to a patient's physical/cognitive/emotional state, their changing rehabilitation trajectory, and their surrounding life context (e.g. social considerations). Clinicians were receptive to our co-design approach. Conclusion Pervasive computing offers new opportunities for life situated cognitive telerehabilitation. Convivial design methods, such as this co design process, are a helpful way to explore new design opportunities and an important space for further methodological development. Implications for Rehabilitation Designers of rehabilitation technologies should consider how to extend current design methods in order to facilitate the creative contribution of rehabilitation stakeholders. This co-design approach enables a fuller participation from rehabilitation clinicians at the front-end of design. Pervasive computing has the potential to: extend the duration and intensity of cognitive telerehabilitation training (including the delivery of 'booster' sessions or maintenance therapies); provide assessment and treatment in the context of a traumatic brain injury (TBI) patient's everyday life (thereby enhancing generalization); and permit time-sensitive interventions. Long-term use of pervasive computing for TBI cognitive telerehabilitation should take into account a patient's changing recovery trajectory, their meaningful goals, and their journey from loss to redefinition. PMID- 26746684 TI - Functional decomposition of the human ERG based on the discrete wavelet transform. AB - The morphology of the electroretinogram (ERG) can be altered as a result of normal and pathological processes of the retina. However, given that the ERG is almost solely assessed in terms of its amplitude and timing, defining the shape of the ERG waveform so that subtle, physiologically driven, morphological changes can be systematically and reproducibly detected remains a challenging problem. We examined if the discrete wavelet transform (DWT) could meet this challenge. Normal human photopic ERGs evoked to a broad range of luminance intensities (to yield waveforms of various shapes, amplitudes, and timings) were analyzed using DWT descriptors of the ERG. Luminance-response curves that were generated using the various DWT descriptors revealed distinct (p < 0.05) luminance-dependence patterns, indicating that the stimulus luminance differently modulates the various time-frequency components of the ERG and thus its morphology. The latter represents the first attempt to study the luminance-dependence of ERG descriptors obtained with the DWT. Analyses of ERGs obtained from patients affected with ON or OFF retinal pathway anomalies were also presented. We show here for the first time that distinct time-frequency descriptors can be specifically associated to the function of the ON and OFF cone pathway. Therefore, in this study, the DWT revealed reproducible, physiologically meaningful and diagnostically relevant descriptors of the ERG over a wide range of signal amplitudes and morphologies. The DWT analysis thus represents a valuable addition to the electrophysiologist's armamentarium that will improve the quantification and interpretation of normal and pathological ERG responses. PMID- 26746685 TI - Surveillance and Screening for Social Determinants of Health: The Medical Home and Beyond. PMID- 26746686 TI - White Coat Adherence in Pediatric Patients With Type 1 Diabetes Who Use Insulin Pumps. AB - BACKGROUND: The purpose was to assess the occurrence of white coat adherence, defined as an increase in adherence to treatment regimens prior to a clinic appointment, in children and adolescents with type 1 diabetes (T1D) who use insulin pumps. METHODS: Blood glucose monitoring (BGM) data, carbohydrate inputs, and insulin boluses delivered were downloaded from the insulin pumps of children and adolescents, aged 7-19 years with T1D, at 2 consecutive routine diabetes clinic visits. Linear mixed models were used to analyze patterns of BGM, carbohydrate inputs, and insulin boluses delivered in patients who had >=28 days of data stored in their insulin pumps. RESULTS: In general, younger children engaged in more frequent BGM, carbohydrate inputs, and insulin boluses delivered than older children and adolescents. White coat adherence occurred with frequency of BGM, carbohydrate inputs, and insulin boluses delivered, but only in younger children. CONCLUSIONS: Diabetes care providers need to be aware that white coat adherence may occur, particularly in young children. Providers routinely download meter and insulin pump data for the 1- to 2-week period before the clinic visit. For patients exhibiting white coat adherence, their data will overestimate the patient's actual adherence. PMID- 26746688 TI - Erratum to: Preoperative predictive factors and further risk stratification of biochemical recurrence in clinically localized high-risk prostate cancer. PMID- 26746687 TI - Cells of renin lineage express hypoxia inducible factor 2alpha following experimental ureteral obstruction. AB - BACKGROUND: Recent studies indicate that mural cells of the preglomerular vessels, known as cells of renin lineage (CoRL), contribute to repair and regeneration of injured kidney glomeruli. However, their potential roles in tubulointerstitial disease are less understood. The aim of this study was to better understand CoRL number and distribution following UUO so that future mechanistic studies could be undertaken. METHODS: We mapped the fate of CoRL in adult Ren1cCreER x Rs-tdTomato-R reporter mice that underwent UUO. Kidney biopsies from sham and UUO-subjected mice on days 3, 7, and 14 were evaluated by immunohistochemistry. RESULTS: In sham animals, CoRL were restricted to juxtaglomerular location. At day 7 following UUO, CoRL increased two-fold, were perivascular in location, and co-expressed pericyte markers (PDGFbetaR, NG2), but did not express renin. At day 14 post UUO, labeled CoRL detached from vessels and were present in the interstitium, in areas of fibrosis, where they now expressed the myofibroblast marker alpha-smooth muscle actin. The increase in CoRL was likely due to proliferation as marked by BrdU labeling, and migration from the cortex. Following UUO starting from day 3, active hypoxia inducible factor-2alpha was detected in nuclei in labeled CoRL, in the cortex, but not those cells found in medulla. CONCLUSIONS: We have demonstrated that arteriolar CoRL are potential kidney progenitors that may contribute to the initial vascular regeneration. However, in chronic kidney injury (>=14 days post UUO), perivascular CoRL transition to myofibroblast-like cells. PMID- 26746690 TI - The medical students' perspective of faculty and informal mentors: a questionnaire study. AB - BACKGROUND: Student mentoring is an important aspect of undergraduate medical education. While medical schools often assign faculty advisors to medical students as mentors to support their educational experience, it is possible for the students to pursue mentors informally. The possible role of these informal mentors and their interactions with the students in a faculty mentorship program has not been reported. This study builds upon previous work that suggested many students have informal mentors, and that there might be interplay between these two types of mentors. This study was conducted to report the experience of undergraduate medical students in a faculty mentorship program of their faculty mentors and if applicable, of their informal mentors. METHODS: One month before residency (post-graduate training for Canadians) ranking, the survey was administered to the graduating class of 2014 at the University of Calgary's Cumming School of Medicine. The survey was created from focus groups of the previous graduating class of 2013. The survey investigated meeting characteristics and the students' perceptions of faculty advisors and informal mentors, and the students' intended choice for residency. RESULTS: The study response rate was 86% (95 of 111); 58% (54 of 93) of the students reported having an informal mentor. There was no reported difference in satisfaction ratings of the Faculty mentorship program between students with only faculty mentors and those with also informal mentors. Students' reporting of their satisfaction with the Faculty mentorship program and the faculty mentors did not differ between the students with informal mentors and those with faculty mentors only. The students' meeting frequency, discussed topics, and perceived characteristics of faculty mentors were not associated with having an informal mentor. The students generally perceived their informal mentors more positively than their faculty mentors. The reported student career intention was associated with the discipline of informal mentors and not with the discipline of faculty mentors. CONCLUSIONS: Informal mentorship was common for medical students. The presence of an informal mentor was not associated with dissatisfaction with the Faculty advisor or with the mentorship program. It is likely students may pursue informal mentorship for career-related reasons. PMID- 26746689 TI - S-1 and irinotecan plus bevacizumab as second-line chemotherapy for patients with oxaliplatin-refractory metastatic colorectal cancer: a multicenter phase II study in Japan (KSCC1102). AB - BACKGROUND: Combination chemotherapy with S-1 and irinotecan is one of the standard treatments for metastatic colorectal cancer (mCRC) in Japan. However, there are few alternative practical second-line therapies. We conducted a phase II trial to evaluate the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab as a second-line treatment for oxaliplatin-refractory mCRC. METHODS: Patients with mCRC who were previously treated with oxaliplatin containing regimens were enrolled. Oral S-1 at a dose of 40 mg/m(2) was administered twice daily for 2 weeks, followed by a 1-week drug-free interval. Irinotecan at a dose of 150 mg/m(2) and bevacizumab at a dose of 7.5 mg/kg were administered on day 1. The primary endpoint was progression-free survival (PFS). RESULTS: Thirty-seven patients were enrolled, and 34 and 36 patients were assessed for response and safety, respectively. The overall response rate was 20.6 % (95 % confidence interval [CI] 8.7-37.9), and the disease control rate was 76.5 % (95 % CI 58.8-89.3). The median PFS was 5.6 months (95 % CI 3.8-7.0). The median overall survival was 16.4 months (95 % CI 8.1-20.0). The most common grade 3/4 adverse events included neutropenia (25.0 %), anorexia (22.2 %), anemia (16.7 %), and fatigue/malaise (16.7 %). The most common grade 3/4 adverse event of special interest for bevacizumab was hypertension (30.6 %). One treatment-related death caused by gastrointestinal bleeding occurred. CONCLUSIONS: The findings suggest that the combination of S-1 and irinotecan plus bevacizumab is effective and tolerable as second-line chemotherapy for patients with oxaliplatin refractory mCRC. PMID- 26746691 TI - Multiparametric MR imaging of tumor response to intraarterial chemotherapy in orthotopic xenograft models of human metastatic brain tumor. AB - The purpose of our study was to investigate the therapeutic efficacy of intraarterial (IA) chemotherapy via multiparametric magnetic resonance imaging (MRI) analysis in orthotopic mouse brain tumor models. Stereotactic-guided intracranial inoculation of MDA-MB-231 cells was performed in nude mice. Thirty tumor bearing mice were randomized into three groups, and each group received either IA docetaxel administration (n = 10), intravenous (IV) docetaxel administration (n = 10), or IA solvent injection (n = 10) as control. Treatment response was monitored by diffusion-weighted imaging and dynamic contrast enhanced-MRI obtained 1 day before and 8 days after therapy initiation. Imaging results were correlated with histopathology. In the results, IA chemotherapy showed a significant decrease in tumor volume (86.5 +/- 15.6 %) compared to the IV chemotherapy (121.1 +/- 39.6%) and control (126.2 +/- 22.0%) 8 days after therapy (p < 0.05). Furthermore, IA chemotherapy resulted in a significant increase in mean tumor apparent diffusion coefficient (ADC) values (116.8 +/- 44.9%); in contrary IV chemotherapy (66.6 +/- 26.9%) and control (69.1 +/- 29.5%) showed a significant decrease in ADC values corresponding to further tumor growth (p < 0.05). However, there was no significant difference in perfusion parameters including initial area under the curve, K(trans), K(ep), and V(e) between the groups (p > 0.05). Histopathology confirmed necrosis and necroptosis in the tumors after IA chemotherapy. In conclusion, IA chemotherapy may lead to effective inhibition of tumor cell proliferation and offer potential benefit of inducing higher degree of treatment response than IV chemotherapy. PMID- 26746694 TI - Precision Medicine and Low- to Middle-Income Countries. PMID- 26746693 TI - Small vessel microembolization and acute glomerulonephritis following infection of aesthetic filler implants. AB - BACKGROUND: The systemic consequences of esthetic filler injections are poorly understood. CASE PRESENTATION: We report a patient with a past history of subcutaneous injection of aesthetic filler material in the lower legs, who presented with post-infectious glomerulonephritis following necrotic leg ulcers at the injection site. Kidney biopsy revealed the presence of translucent, non birefringent microspherical bodies compatible with polymethylmetacrylate (PMMA) microspheres in some capillary lumens. This had not previously been described. PMMA is a biphasic aesthetical filler composed of polymethylmetacrylate microspheres suspended in a biodegradable bovine collagen carrier. The solid phase (PMMA microspheres) persists in tissues for years. Although PMMA was thought to not disseminate systemically, tissue necrosis may have favored systemic dissemination of the microspheres, although entry in the circulation and microembolization at the time of administration cannot be ruled out. CONCLUSIONS: In conclusion, aesthetic filler implants may cause microembolization into small vessels. Recognition of the characteristic morphology may expedite diagnosis and avoid unnecessary further testing. PMID- 26746695 TI - Shifting Paradigms About Hormonal Risk Factors for Postmenopausal Depression: Age at Menopause as an Indicator of Cumulative Lifetime Exposure to Female Reproductive Hormones. PMID- 26746692 TI - Initial evidence that blood-borne microvesicles are biomarkers for recurrence and survival in newly diagnosed glioblastoma patients. AB - The purpose of this pilot study was to determine whether blood-borne microvesicles from newly diagnosed glioblastoma patients could be used as biomarkers. We collected 2.8 mL blood from 16 post-operative patients at the time that they were being simulated for chemoradiation therapy (radiation with concurrent temozolomide). Two additional samples were collected during chemoradiation therapy and a final sample was collected at the end of chemoradiation therapy. Patients continued with the therapy suggested by their physicians, based on tumor conference consensus and were followed for recurrence and overall survival. Microvesicles were isolated using serial centrifugation and stained for surface markers (Annexin V for phosphotidyl serine, CD41 for platelets, anti-EGFR for tumor cells, and CD235 for red blood cells). Flow cytometry analysis was performed. Our findings provide initial evidence that increases in Annexin V positive microvesicle levels during chemoradiation therapy are associated with earlier recurrence and shorter overall survival in newly diagnosed glioblastoma patients. The effect is dramatic, with over a four-fold increase in the hazard ratio for an individual at the 75th versus the 25th percentile. Moreover the pattern of Annexin V positive microvesicles remain significant after adjustment for confounding clinical variables that have previously been shown to be prognostic for recurrence and survival. Inclusion of neutrophil levels at the start of chemoradiation therapy in the model yielded the largest attenuation of the observed association. Further studies will be needed to verify and further investigate the association between these two entities. PMID- 26746705 TI - Shisan C. Chen and his research on goldfish genetics. PMID- 26746696 TI - Highly Sensitive and Selective Determination of Tertiary Butylhydroquinone in Edible Oils by Competitive Reaction Induced "On-Off-On" Fluorescent Switch. AB - As one of most common synthetic phenolic antioxidants, tertiary butylhydroquinone (TBHQ) has received increasing attention due to the potential risk for liver damage and carcinogenesis. Herein, a simple and rapid fluorescent switchable methodology was developed for highly selective and sensitive determination of TBHQ by utilizing the competitive interaction between the photoinduced electron transfer (PET) effect of carbon dots (CDs)/Fe(III) ions and the complexation reaction of TBHQ/Fe(III) ions. This novel fluorescent switchable sensing platform allows determining TBHQ in a wider range from 0.5 to 80 MUg mL(-1) with a low detection limit of 0.01 MUg mL(-1). Furthermore, high specificity and good accuracy with recoveries ranging from 94.29 to 105.82% in spiked edible oil samples are obtained with the present method, confirming its applicability for the trace detection of TBHQ in a complex food matrix. Thus, the present method provides a novel and effective fluorescent approach for rapid and specific screening of TBHQ in common products, which is beneficial for monitoring and reducing the risk of TBHQ overuse during food storage. PMID- 26746707 TI - Dietary Guidelines for Americans. PMID- 26746708 TI - Overlap and Differences in Brain Networks Underlying the Processing of Complex Sentence Structures in Second Language Users Compared with Native Speakers. AB - When we learn a second language later in life, do we integrate it with the established neural networks in place for the first language or is at least a partially new network recruited? While there is evidence that simple grammatical structures in a second language share a system with the native language, the story becomes more multifaceted for complex sentence structures. In this study, we investigated the underlying brain networks in native speakers compared with proficient second language users while processing complex sentences. As hypothesized, complex structures were processed by the same large-scale inferior frontal and middle temporal language networks of the brain in the second language, as seen in native speakers. These effects were seen both in activations and task-related connectivity patterns. Furthermore, the second language users showed increased task-related connectivity from inferior frontal to inferior parietal regions of the brain, regions related to attention and cognitive control, suggesting less automatic processing for these structures in a second language. PMID- 26746706 TI - Parkin promotes proteasomal degradation of p62: implication of selective vulnerability of neuronal cells in the pathogenesis of Parkinson's disease. AB - Mutations or inactivation of parkin, an E3 ubiquitin ligase, are associated with familial form or sporadic Parkinson's disease (PD), respectively, which manifested with the selective vulnerability of neuronal cells in substantia nigra (SN) and striatum (STR) regions. However, the underlying molecular mechanism linking parkin with the etiology of PD remains elusive. Here we report that p62, a critical regulator for protein quality control, inclusion body formation, selective autophagy and diverse signaling pathways, is a new substrate of parkin. P62 levels were increased in the SN and STR regions, but not in other brain regions in parkin knockout mice. Parkin directly interacts with and ubiquitinates p62 at the K13 to promote proteasomal degradation of p62 even in the absence of ATG5. Pathogenic mutations, knockdown of parkin or mutation of p62 at K13 prevented the degradation of p62. We further showed that parkin deficiency mice have pronounced loss of tyrosine hydroxylase positive neurons and have worse performance in motor test when treated with 6-hydroxydopamine hydrochloride in aged mice. These results suggest that, in addition to their critical role in regulating autophagy, p62 are subjected to parkin mediated proteasomal degradation and implicate that the dysregulation of parkin/p62 axis may involve in the selective vulnerability of neuronal cells during the onset of PD pathogenesis. PMID- 26746710 TI - Relative Abundance of Nitrotoga spp. in a Biofilter of a Cold-Freshwater Aquaculture Plant Appears To Be Stimulated by Slightly Acidic pH. AB - The functioning of recirculation aquaculture systems (RAS) is essential to maintain water quality for fish health, and one crucial process here is nitrification. The investigated RAS was connected to a rainbow trout production system and operated at an average temperature of 13 degrees C and pH 6.8. Community analyses of the nitrifying biofilm revealed a coexistence of Nitrospira and Nitrotoga, and it is hypothesized that a slightly acidic pH in combination with lower temperatures favors the growth of the latter. Modification of the standard cultivation approach toward lower pH values of 5.7 to 6.0 resulted in the successful enrichment (99% purity) of Nitrotoga sp. strain HW29, which had a 16S rRNA sequence similarity of 99.0% to Nitrotoga arctica. Reference cultures of Nitrospira defluvii and the novel Nitrotoga sp. HW29 were used to confirm differentiation of these nitrite oxidizers in distinct ecological niches. Nitrotoga sp. HW29 revealed pH and temperature optima of 6.8 and 22 degrees C, respectively, whereas Nitrospira defluvii displayed the highest nitrite oxidation rate at pH 7.3 and 32 degrees C. We report here the occurrence of Nitrotoga as one of the main nitrite-oxidizing bacteria in freshwater aquaculture systems and indicate that a slightly acidic pH, in addition to temperatures below 20 degrees C, can be applied as a selective isolation criterion for this microorganism. PMID- 26746709 TI - The Female Post-Mating Response Requires Genes Expressed in the Secondary Cells of the Male Accessory Gland in Drosophila melanogaster. AB - Seminal proteins from the Drosophila male accessory gland induce post-mating responses (PMR) in females. The PMR comprise behavioral and physiological changes that include increased egg laying, decreased receptivity to courting males, and changes in the storage and use of sperm. Many of these changes are induced by a "sex peptide" (SP) and are maintained by SP's binding to, and slow release from, sperm. The accessory gland contains two secretory cell types with distinct morphological and developmental characteristics. Products of these "main" and "secondary" cells work interdependently to induce and maintain the PMR. To identify individual genes needed for the morphology and function of secondary cells, we studied iab-6(cocu) males, whose secondary cells have abnormal morphology and fail to provide products to maintain the PMR. By RNA-seq, we identified 77 genes that are downregulated by a factor of >5* in iab-6(cocu) males. By functional assays and microscopy, we tested 20 candidate genes and found that at least 9 are required for normal storage and release of SP in mated females. Knockdown of each of these 9 genes consequently leads to a reduction in egg laying and an increase in receptivity over time, confirming a role for the secondary cells in maintaining the long-term PMR. Interestingly, only 1 of the 9 genes, CG3349, encodes a previously reported seminal fluid protein (Sfp), suggesting that secondary cells may perform essential functions beyond the production and modification of known Sfps. At least 3 of the 9 genes also regulate the size and/or abundance of secondary cell vacuoles, suggesting that the vacuoles' contents may be important for the machinery used to maintain the PMR. PMID- 26746711 TI - Loop-Mediated Isothermal Amplification (LAMP) for Rapid Detection and Quantification of Dehalococcoides Biomarker Genes in Commercial Reductive Dechlorinating Cultures KB-1 and SDC-9. AB - Real-time quantitative PCR (qPCR) protocols specific to the reductive dehalogenase (RDase) genes vcrA, bvcA, and tceA are commonly used to quantify Dehalococcoides spp. in groundwater from chlorinated solvent-contaminated sites. In this study, loop-mediated isothermal amplification (LAMP) was developed as an alternative approach for the quantification of these genes. LAMP does not require a real-time thermal cycler (i.e., amplification is isothermal), allowing the method to be performed using less-expensive and potentially field-deployable detection devices. Six LAMP primers were designed for each of three RDase genes (vcrA, bvcA, and tceA) using Primer Explorer V4. The LAMP assays were compared to conventional qPCR approaches using plasmid standards, two commercially available bioaugmentation cultures, KB-1 and SDC-9 (both contain Dehalococcoides species). DNA was extracted over a growth cycle from KB-1 and SDC-9 cultures amended with trichloroethene and vinyl chloride, respectively. All three genes were quantified for KB-1, whereas only vcrA was quantified for SDC-9. A comparison of LAMP and qPCR using standard plasmids indicated that quantification results were similar over a large range of gene concentrations. In addition, the quantitative increase in gene concentrations over one growth cycle of KB-1 and SDC-9 using LAMP was comparable to that of qPCR. The developed LAMP assays for vcrA and tceA genes were validated by comparing quantification on the Gene-Z handheld platform and a real-time thermal cycler using DNA isolated from eight groundwater samples obtained from an SDC-9-bioaugmented site (Tulsa, OK). These assays will be particularly useful at sites subject to bioaugmentation with these two commonly used Dehalococcoides species-containing cultures. PMID- 26746712 TI - Evaluation of Ultrasound-Induced Damage to Escherichia coli and Staphylococcus aureus by Flow Cytometry and Transmission Electron Microscopy. AB - As a nonthermal sterilization technique, ultrasound has attracted great interest in the field of food preservation. In this study, flow cytometry and transmission electron microscopy were employed to investigate ultrasound-induced damage to Escherichia coli and Staphylococcus aureus. For flow cytometry studies, single staining with propidium iodide (PI) or carboxyfluorescein diacetate (cFDA) revealed that ultrasound treatment caused cell death by compromising membrane integrity, inactivating intracellular esterases, and inhibiting metabolic performance. The results showed that ultrasound damage was independent of initial bacterial concentrations, while the mechanism of cellular damage differed according to the bacterial species. For the Gram-negative bacterium E. coli, ultrasound worked first on the outer membrane rather than the cytoplasmic membrane. Based on the double-staining results, we inferred that ultrasound treatment might be an all-or-nothing process: cells ruptured and disintegrated by ultrasound cannot be revived, which can be considered an advantage of ultrasound over other nonthermal techniques. Transmission electron microscopy studies revealed that the mechanism of ultrasound-induced damage was multitarget inactivation, involving the cell wall, cytoplasmic membrane, and inner structure. Understanding of the irreversible antibacterial action of ultrasound has great significance for its further utilization in the food industry. PMID- 26746713 TI - Prokaryotic Community Structure Driven by Salinity and Ionic Concentrations in Plateau Lakes of the Tibetan Plateau. AB - The prokaryotic community composition and diversity and the distribution patterns at various taxonomic levels across gradients of salinity and physiochemical properties in the surface waters of seven plateau lakes in the Qaidam Basin, Tibetan Plateau, were evaluated using Illumina MiSeq sequencing. These lakes included Lakes Keluke (salinity, <1 g/liter), Qing (salinity, 5.5 to 6.6 g/liter), Tuosu (salinity, 24 to 35 g/liter), Dasugan (salinity, 30 to 33 g/liter), Gahai (salinity, 92 to 96 g/liter), Xiaochaidan (salinity, 94 to 99 g/liter), and Gasikule (salinity, 317 to 344 g/liter). The communities were dominated by Bacteria in lakes with salinities of <100 g/liter and by Archaea in Lake Gasikule. The clades At12OctB3 and Salinibacter, previously reported only in hypersaline environments, were found in a hyposaline lake (salinity, 5.5 to 6.6 g/liter) at an abundance of ~1.0%, indicating their ecological plasticity. Salinity and the concentrations of the chemical ions whose concentrations covary with salinity (Mg(2+), K(+), Cl(-), Na(+), SO4 (2-), and Ca(2+)) were found to be the primary environmental factors that directly or indirectly determined the composition and diversity at the level of individual clades as well as entire prokaryotic communities. The distribution patterns of two phyla, five classes, five orders, five families, and three genera were well predicted by salinity. The variation of the prokaryotic community structure also significantly correlated with the dissolved oxygen concentration, pH, the total nitrogen concentration, and the PO4 (3-) concentration. Such correlations varied depending on the taxonomic level, demonstrating the importance of comprehensive correlation analyses at various taxonomic levels in evaluating the effects of environmental variable factors on prokaryotic community structures. Our findings clarify the distribution patterns of the prokaryotic community composition in plateau lakes at the levels of individual clades as well as whole communities along gradients of salinity and ionic concentrations. PMID- 26746714 TI - Long-Term Colonization by bla(CTX-M)-Harboring Escherichia coli in Healthy Japanese People Engaged in Food Handling. AB - The actual state of intestinal long-term colonization by extended-spectrum beta lactamase (ESBL)-producing Escherichia coli in healthy Japanese people remains unclear. Therefore, a total of 4,314 fecal samples were collected from 2,563 food handlers from January 2010 to December 2011. Approximately 0.1 g of each fecal sample was inoculated onto a MacConkey agar plate containing cefotaxime (1 MUg/ml). The bacterial colonies that grew on each plate were checked for ESBL production by the double-disk synergy test, as recommended by the Clinical and Laboratory Standards Institute. The bacterial serotype, antimicrobial susceptibility, pulsotype, sequence type (ST), and ESBL genotype were checked, and the replicon types of plasmids harboring the ESBL gene were also determined after conjugation experiments. ESBL producers were recovered from 70 (3.1%) of 2,230 participants who were checked only once. On the other hand, ESBL producers were isolated at least once from 52 (15.6%) of 333 participants who were checked more than twice, and 13 of the 52 participants carried ESBL producers for from more than 3 months to up to 2 years. Fluoroquinolone (FQ)-resistant E. coli strains harboring bla(CTX-M) were repeatedly recovered from 11 of the 13 carriers of bla(CTX-M)-harboring E. coli. A genetically related FQ-resistant E. coli O25b:H4-ST131 isolate harboring bla(CTX-M)-27 was recovered from 4 of the 13 carriers for more than 6 months. Three FQ-resistant E. coli O1:H6-ST648 isolates that harbored bla(CTX-M-15) or bla(CTX-M)-14 were recovered from 3 carriers. Moreover, multiple CTX-M-14- or CTX-M-15-producing E. coli isolates with different serotypes were recovered from 2 respective carriers. These findings predict a provable further spread of ESBL producers in both community and clinical settings. PMID- 26746715 TI - The Bacteriome of Bat Flies (Nycteribiidae) from the Malagasy Region: a Community Shaped by Host Ecology, Bacterial Transmission Mode, and Host-Vector Specificity. AB - The Nycteribiidae are obligate blood-sucking Diptera (Hippoboscoidea) flies that parasitize bats. Depending on species, these wingless flies exhibit either high specialism or generalism toward their hosts, which may in turn have important consequences in terms of their associated microbial community structure. Bats have been hypothesized to be reservoirs of numerous infectious agents, some of which have recently emerged in human populations. Thus, bat flies may be important in the epidemiology and transmission of some of these bat-borne infectious diseases, acting either directly as arthropod vectors or indirectly by shaping pathogen communities among bat populations. In addition, bat flies commonly have associations with heritable bacterial endosymbionts that inhabit insect cells and depend on maternal transmission through egg cytoplasm to ensure their transmission. Some of these heritable bacteria are likely obligate mutualists required to support bat fly development, but others are facultative symbionts with unknown effects. Here, we present bacterial community profiles that were obtained from seven bat fly species, representing five genera, parasitizing bats from the Malagasy region. The observed bacterial diversity includes Rickettsia, Wolbachia, and several Arsenophonus-like organisms, as well as other members of the Enterobacteriales and a widespread association of Bartonella bacteria from bat flies of all five genera. Using the well-described host specificity of these flies and data on community structure from selected bacterial taxa with either vertical or horizontal transmission, we show that host/vector specificity and transmission mode are important drivers of bacterial community structure. PMID- 26746717 TI - A 1,3-1,4-beta-Glucan Utilization Regulon in Paenibacillus sp. Strain JDR-2. AB - Paenibacillus sp. strain JDR-2 (Paenibacillus JDR-2) secretes a multimodular cell associated glycoside hydrolase family 10 (GH10) endoxylanase (XynA10A1) that catalyzes the depolymerization of methylglucuronoxylan (MeGXn) and rapidly assimilates the products of depolymerization. Efficient utilization of MeGXn has been postulated to result from the coupling of the processes of exocellular depolymerization and assimilation of oligosaccharide products, followed by intracellular metabolism. Growth and substrate utilization patterns with barley glucan and laminarin similar to those observed with MeGXn as a substrate suggest similar processes for 1,3-1,4-beta-glucan and 1,3-beta-glucan depolymerization and product assimilation. The Paenibacillus JDR-2 genome includes a cluster of genes encoding a secreted multimodular GH16 beta-glucanase (Bgl16A1) containing surface layer homology (SLH) domains, a secreted GH16 beta-glucanase with only a catalytic domain (Bgl16A2), transporter proteins, and transcriptional regulators. Recombinant Bgl16A1 and Bgl16A2 catalyze the formation of trisaccharides, tetrasaccharides, and larger oligosaccharides from barley glucan and of mono-, di , tri-, and tetrasaccharides and larger oligosaccharides from laminarin. The lack of accumulation of depolymerization products during growth and a marked preference for polymeric glucan over depolymerization products support a process coupling extracellular depolymerization, assimilation, and intracellular metabolism for beta-glucans similar to that ascribed to the GH10/GH67 xylan utilization system in Paenibacillus JDR-2. Coordinate expression of genes encoding GH16 beta-glucanases, transporters, and transcriptional regulators supports their role as a regulon for the utilization of soluble beta-glucans. As in the case of the xylan utilization regulons, this soluble beta-glucan regulon provides advantages in the growth rate and yields on polymeric substrates and may be exploited for the efficient conversion of plant-derived polysaccharides to targeted products. PMID- 26746716 TI - Functions of VPA1418 and VPA0305 Catalase Genes in Growth of Vibrio parahaemolyticus under Oxidative Stress. AB - The marine foodborne enteropathogen Vibrio parahaemolyticus has four putative catalase genes. The functions of two katE-homologous genes, katE1 (VPA1418) and katE2 (VPA0305), in the growth of this bacterium were examined using gene deletion mutants with or without complementary genes. The growth of the mutant strains in static or shaken cultures in a rich medium at 37 degrees C or at low temperatures (12 and 4 degrees C), with or without competition from Escherichia coli, did not differ from that of the parent strain. When 175 MUM extrinsic H2O2 was added to the culture medium, bacterial growth of the DeltakatE1 strain was delayed and growth of the DeltakatE1 DeltakatE2 and DeltakatE1 DeltaahpC1 double mutant strains was completely inhibited at 37 degrees C for 8 h. The sensitivity of the DeltakatE1 strain to the inhibition of growth by H2O2 was higher at low incubation temperatures (12 and 22 degrees C) than at 37 degrees C. The determined gene expression of these catalase and ahpC genes revealed that katE1 was highly expressed in the wild-type strain at 22 degrees C under H2O2 stress, while the katE2 and ahpC genes may play an alternate or compensatory role in the DeltakatE1 strain. This study demonstrated that katE1 encodes the chief functional catalase for detoxifying extrinsic H2O2 during logarithmic growth and that the function of these genes was influenced by incubation temperature. PMID- 26746718 TI - Strong Seasonality of Marine Microbial Eukaryotes in a High-Arctic Fjord (Isfjorden, in West Spitsbergen, Norway). AB - The Adventfjorden time series station (IsA) in Isfjorden, West Spitsbergen, Norway, was sampled frequently from December 2011 to December 2012. The community composition of microbial eukaryotes (size, 0.45 to 10 MUm) from a depth of 25 m was determined using 454 sequencing of the 18S V4 region amplified from both DNA and RNA. The compositional changes throughout the year were assessed in relation to in situ fjord environmental conditions. Size fractionation analyses of chlorophyll a showed that the photosynthetic biomass was dominated by small cells (<10 MUm) most of the year but that larger cells dominated during the spring and summer. The winter and early-spring communities were more diverse than the spring and summer/autumn communities. Dinophyceae were predominant throughout the year. The Arctic Micromonas ecotype was abundant mostly in the early-bloom and fall periods, whereas heterotrophs, such as marine stramenopiles (MASTs), Picozoa, and the parasitoid marine alveolates (MALVs), displayed higher relative abundance in the winter than in other seasons. Our results emphasize the extreme seasonality of Arctic microbial eukaryotic communities driven by the light regime and nutrient availability but point to the necessity of a thorough knowledge of hydrography for full understanding of their succession and variability. PMID- 26746719 TI - Microbial and Functional Diversity within the Phyllosphere of Espeletia Species in an Andean High-Mountain Ecosystem. AB - Microbial populations residing in close contact with plants can be found in the rhizosphere, in the phyllosphere as epiphytes on the surface, or inside plants as endophytes. Here, we analyzed the microbiota associated with Espeletia plants, endemic to the Paramo environment of the Andes Mountains and a unique model for studying microbial populations and their adaptations to the adverse conditions of high-mountain neotropical ecosystems. Communities were analyzed using samples from the rhizosphere, necromass, and young and mature leaves, the last two analyzed separately as endophytes and epiphytes. The taxonomic composition determined by performing sequencing of the V5-V6 region of the 16S rRNA gene indicated differences among populations of the leaf phyllosphere, the necromass, and the rhizosphere, with predominance of some phyla but only few shared operational taxonomic units (OTUs). Functional profiles predicted on the basis of taxonomic affiliations differed from those obtained by GeoChip microarray analysis, which separated community functional capacities based on plant microenvironment. The identified metabolic pathways provided insight regarding microbial strategies for colonization and survival in these ecosystems. This study of novel plant phyllosphere microbiomes and their putative functional ecology is also the first step for future bioprospecting studies in search of enzymes, compounds, or microorganisms relevant to industry or for remediation efforts. PMID- 26746721 TI - Severe liver injury due to a homemade flower pollen preparation in a patient with high CYP3A enzyme activity: a case report. PMID- 26746720 TI - Microbial Diversity in the Early In Vivo-Formed Dental Biofilm. AB - Although the mature dental biofilm composition is well studied, there is very little information on the earliest phase of in vivo tooth colonization. Progress in dental biofilm collection methodologies and techniques of large-scale microbial identification have made new studies in this field of oral biology feasible. The aim of this study was to characterize the temporal changes and diversity of the cultivable and noncultivable microbes in the early dental biofilm. Samples of early dental biofilm were collected from 11 healthy subjects at 0, 2, 4, and 6 h after removal of plaque and pellicle from tooth surfaces. With the semiquantitative Human Oral Microbiome Identification Microarray (HOMIM) technique, which is based on 16S rRNA sequence hybridizations, plaque samples were analyzed with the currently available 407 HOMIM microbial probes. This led to the identification of at least 92 species, with streptococci being the most abundant bacteria across all time points in all subjects. High-frequency detection was also made with Haemophilus parainfluenzae, Gemella haemolysans, Slackia exigua, and Rothia species. Abundance changes over time were noted for Streptococcus anginosus and Streptococcus intermedius (P = 0.02), Streptococcus mitis bv. 2 (P = 0.0002), Streptococcus oralis (P = 0.0002), Streptococcus cluster I (P = 0.003), G. haemolysans (P = 0.0005), and Stenotrophomonas maltophilia (P = 0.02). Among the currently uncultivable microbiota, eight phylotypes were detected in the early stages of biofilm formation, one belonging to the candidate bacterial division TM7, which has attracted attention due to its potential association with periodontal disease. PMID- 26746778 TI - Eating disorders, menstrual dysfunction, weight change and DMPA use predict bone density change in college-aged women. AB - INTRODUCTION: There are limited longitudinal studies that have evaluated bone mineral density (BMD) changes in college-aged women. Our objective was to simultaneously evaluate factors influencing 4-year BMD change. METHODS: This was a longitudinal cohort study of healthy, physically active women in the US Military Academy (n=91; average age=18.4years). Assessments over four years included: height, weight, calcium intake, physical fitness, menstrual function (annual number cycles), oral contraceptives (OCs) or depot-medroxyprogesterone acetate (DMPA) use, and eating disorder behavior (Eating Disorder Inventory; (EDI)). BMD was measured annually at the lumbar spine and total hip by dual X-ray absorptiometry and calcaneal BMD by PIXI. Slope of 4year BMD change at each skeletal site (spine total hip and calcaneus) was calculated for each woman. RESULTS: BMD gains occurred at the spine in 50% and the hip in 36% of women. In unadjusted analyses, spine bone gain was positively related to menstrual cycle frequency (p=0.04). Spine and hip BMD loss occurred in those using DMPA (p<0.01) and those with the highest EDI quartile scores (p<0.05). BMD change was unrelated to OC use. Hip and calcaneus BMD decreased with weight loss (average 4.8+2.2lb/year) as compared to those with stable weight/weight gain (p<0.05). In multivariable analysis, spine BMD increase was significantly related to African American (AA) race, normal EDI score and normal menses. Hip BMD increase was related to AA race, weight increase and normal menses. DMPA use was associated with spine, hip, and calcaneus bone loss. CONCLUSION: On average, BMD may modestly increase in college-aged women, in the absence of risk factors. However, risk factors including subclinical eating disorders, weight loss, menstrual dysfunction and DMPA use can have significant detrimental effects on BMD in young healthy physically active women. PMID- 26746781 TI - Deliberate Self-harm Following Bariatric Surgery. PMID- 26746782 TI - Should We Leave the Skin Biopsies to the Dermatologists? PMID- 26746779 TI - Congenital insensitivity to pain: Fracturing without apparent skeletal pathobiology caused by an autosomal dominant, second mutation in SCN11A encoding voltage-gated sodium channel 1.9. AB - Congenital insensitivity to pain (CIP) comprises the rare heritable disorders without peripheral neuropathy that feature inability to feel pain. Fracturing and joint destruction are common complications, but lack detailed studies of mineral and skeletal homeostasis and bone histology. In 2013, discovery of a heterozygous gain-of-function mutation in SCN11A encoding voltage-gated sodium channel 1.9 (Nav1.9) established a distinctive CIP in three unrelated patients who suffered multiple painless fractures, self-inflicted mutilation, chronic diarrhea, and hyperhidrosis. Here, we studied a mother and two children with CIP by physical examination, biochemical testing, radiological imaging including DXA, iliac crest histology, and mutation analysis. She suffered fractures primarily of her lower extremities beginning at age two years, and had Charcot deformity of both ankles and joint hypermobility. Nerve conduction velocity together with electromyography were normal. Her children had recurrent major fractures beginning in early childhood, joint hypermobility, and chronic diarrhea. She had an excoriated external nare, and both children had hypertrophic scars from scratching. Skin collagen studies were normal. Radiographs revealed fractures and deformities. However, lumbar spine and total hip BMD Z-scores, biochemical parameters of mineral and skeletal homeostasis, and iliac crest histology of the mother (after in vivo tetracycline labeling) were normal. Genomic DNA from the children revealed a unique heterozygous missense mutation in exon 23 (c.3904C>T, p.Leu1302Phe) of SCN11A that is absent in SNP databases and alters an evolutionarily conserved amino acid. This autosomal dominant CIP reflects the second gain-of-function mutation of SCN11A. Perhaps joint hypermobility is an unreported feature. How mutation of Nav1.9 causes fracturing remains unexplained. Lack of injury awareness is typically offered as the reason, and was supported by our unremarkable biochemical, radiological, and histological findings indicating no skeletal pathobiology. However, low-trauma fracturing in these patients suggests an uncharacterized defect in bone quality. PMID- 26746780 TI - Posttranslational processing of FGF23 in osteocytes during the osteoblast to osteocyte transition. AB - FGF23 is an O-glycosylated circulating peptide hormone with a critical role in phosphate homeostasis; it is inactivated by cellular proprotein convertases in a pre-release degradative pathway. We have here examined the metabolism of FGF23 in a model bone cell line, IDG-SW3, prior to and following differentiation, as well as in regulated secretory cells. Labeling experiments showed that the majority of (35)S-labeled FGF23 was cleaved to smaller fragments which were constitutively secreted by all cell types. Intact FGF23 was much more efficiently stored in differentiated than in undifferentiated IDG-SW3 cells. The prohormone convertase PC2 has recently been implicated in FGF23 degradation; however, FGF23 was not targeted to forskolin-stimulatable secretory vesicles in a regulated cell line, suggesting that it lacks a targeting signal to PC2-containing compartments. In vitro, PC1/3 and PC2, but not furin, efficiently cleaved glycosylated FGF23; surprisingly, PC5/6 accomplished a small amount of conversion. FGF23 has recently been shown to be phosphorylated by the kinase FAM20C, a process which was shown to reduce FGF23 glycosylation and promote its cleavage; our in vitro data, however, show that phosphorylation does not directly impact cleavage, as both PC5/6 and furin were able to efficiently cleave unglycosylated, phosphorylated FGF23. Using qPCR, we found that the expression of FGF23 and PC5/6, but not PC2 or furin, increased substantially following osteoblast to osteocyte differentiation. Western blotting confirmed the large increase in PC5/6 expression upon differentiation. FGF23 has been linked to a variety of bone disorders ranging from autosomal dominant hypophosphatemic rickets to chronic kidney disease. A better understanding of the biosynthetic pathway of this hormone may lead to new treatments for these diseases. PMID- 26746783 TI - Spinal Cord Stroke Presenting With Acute Monoplegia in a 17-Year-Old Tennis Player. AB - BACKGROUND: Acute monoplegia is a rare presentation for spinal cord stroke, which usually presents with paraplegia or paraparesis. PATIENT DESCRIPTION: We describe an athletic girl who presented after a week of heavy athletic activity complaining of back and left leg pain, followed by flaccid left leg paralysis. RESULTS: The prothrombotic evaluation was unremarkable. Cerebrospinal fluid studies demonstrated elevated myelin basic protein but no oligoclonal bands. Magnetic resonance imaging revealed a lesion in the anterior cord from T9 to T11 with T2 hyperintensity, contrast enhancement, and diffusion restriction, suggesting infarction. There was a herniated disc at T10-T11 contacting the spinal cord and Schmorl's nodes at T11 and T12. Magnetic resonance angiography of the spinal cord was limited by movement artifact. CONCLUSIONS: The combination of our patient's clinical presentation, imaging studies, and laboratory evaluation suggests that our patient had a spinal cord infarct. A fibrocartilaginous embolism was the likely mechanism of infarct due to the presence of Schmorl's nodes and disc herniation on imaging. In addition to spinal cord stroke, other possible mechanisms leading to presentation with monoplegia, such as transverse myelitis, neuromyelitis optica, and multiple sclerosis, are discussed. PMID- 26746784 TI - Hypertension is Associated With Increased Mortality in Children Hospitalized With Arterial Ischemic Stroke. AB - BACKGROUND: Recently a single-center study suggested that hypertension after stroke in children was a risk factor for mortality. Our goal was to assess the association between hypertension and outcome after arterial ischemic stroke in children from a large national sample. METHODS: Using the Healthcare Cost and Utilization Project Kids' Inpatient Database, children (1-18 years) with a primary diagnosis of ischemic stroke (International Classification of Diseases, Ninth Revision [ICD-9] codes 433-437.1) who also had a diagnosis of elevated blood pressure (ICD-9 code 796.2) or hypertension (ICD-9 codes 401 and 405) from 2003, 2006, and 2009 were identified. Clinical characteristics, discharge outcomes, and length of stay were assessed. Multivariable logistic regression was used to assess the relationship between hypertension and in-hospital mortality or discharge outcomes. RESULTS: Of 2590 children admitted with arterial ischemic stroke, 156 (6%) also had a diagnosis of hypertension. Ten percent of children with hypertension also had renal failure. Among patients with arterial ischemic stroke, hypertension was associated with increased mortality (7.4% vs. 2.8%; P = 0.01) and increased length of stay (mean 11 +/- 17 vs. 7 +/- 12 days; P = 0.004) compared with those without hypertension. After adjusting for age, sex, intubation, presence of a fluid and electrolyte disorder, and renal failure, children with hypertension had an increased odds of in-hospital death (odds ratio 1.2, 95% confidence interval [1.1-3.3, P = 0.04]). CONCLUSION: Hypertension was associated with an increased risk of in-hospital death for children presenting with arterial ischemic stroke. Further prospective study of blood pressure in children with stroke is needed. PMID- 26746785 TI - Chemometric and conformational approach to the analysis of the aggregation capabilities in a set of bile salts of the allo and normal series. AB - Bile salts are steroid biosurfactants that have a significant role in fat digestion, cholesterol micellar solubilization, and regulation of metabolism. They are important in pharmaceutical studies as modulators of the transport permeability of drugs or as ligands for certain receptors. For the rational application of bile salts in medicine, it is necessary to have detailed knowledge of their aggregation capabilities (which determine their membranotoxicity and solubilization capacity). From the examination of bile salt derivatives, the in plane of lnk (RPHPLC) and micelle aggregation number n, as well as the anion of 7 oxodeoxycholic acid (7-OxD) and anion of cholic acid (C), are considered to be outliers, related to linear hydrophobic congeneric groups, which means that their micelles, in addition to being determined by hydrophobic interactions, are determined by hydrogen bonds, i.e., they form micelles with higher aggregation numbers than would be expected from the hydrophobicity of their steroid skeleton. For bile salts of the normal series in the formation of hydrogen bonds in secondary micelles, the crucial structural elements of the steroid skeleton are: alpha-equatorial-C3-OH group and alpha-axial-C12-OH group. Bile salts of the allo series, including allocholic (aC), allodeoxycholic (aDC) and allochenodeoxycholic acid (aCD), belong to the linear hydrophobic congeneric group. Their micelles are determined by hydrophobic interactions. It is assumed that for the analyzed allo derivatives, the A ring of the steroid skeleton is in the twisted boat conformation, which explains the spatial sheltering of their C3-OH group in micelles. PMID- 26746786 TI - Integrating 400 million variants from 80,000 human samples with extensive annotations: towards a knowledge base to analyze disease cohorts. AB - BACKGROUND: Data from a plethora of high-throughput sequencing studies is readily available to researchers, providing genetic variants detected in a variety of healthy and disease populations. While each individual cohort helps gain insights into polymorphic and disease-associated variants, a joint perspective can be more powerful in identifying polymorphisms, rare variants, disease-associations, genetic burden, somatic variants, and disease mechanisms. DESCRIPTION: We have set up a Reference Variant Store (RVS) containing variants observed in a number of large-scale sequencing efforts, such as 1000 Genomes, ExAC, Scripps Wellderly, UK10K; various genotyping studies; and disease association databases. RVS holds extensive annotations pertaining to affected genes, functional impacts, disease associations, and population frequencies. RVS currently stores 400 million distinct variants observed in more than 80,000 human samples. CONCLUSIONS: RVS facilitates cross-study analysis to discover novel genetic risk factors, gene disease associations, potential disease mechanisms, and actionable variants. Due to its large reference populations, RVS can also be employed for variant filtration and gene prioritization. AVAILABILITY: A web interface to public datasets and annotations in RVS is available at https://rvs.u.hpc.mssm.edu/. PMID- 26746787 TI - [Correlation between ICIQ-UI-SF score and personality testing results over a urinary incontinent population]. AB - OBJECTIVE: We found out the personality pattern of an incontinent population and proceeded to a correlation between the personality inventory and the ICIQ-UI-SF (International Consultation Incontinence Questionnaire Urinary Incontinence Short Form) to demonstrate reliability and sincerity of the answers and to establish that a personality disturbance may impact the physiopathology of micturition. MATERIALS AND METHODS: We performed an observational prospective study. It included patient's answers to a computed questionnaire combining a double ICIQ-UI SF questionnaire and the 71 questions of the Minimult questionnaire. Forty-seven patients were asked to participate. RESULTS: Over 37 patients included, Wilcoxon Mann-Whitney non parametric test confirmed agreement of the two ICIQ-UI-SF questionnaires with P=0.1792. Twenty-three patients were validated to the Minimult inventory with F scale<70. We analysed variability of the two global ICIQ-UI-SF score in regard with the validity scale using ROC analysis. We observed an AUC of 0.559 with sensitivity 78.6% and specificity 43.5%. No L score was above 70 demonstrating absence of lie. No personality disturbance was found in 9 cases. We observed six cases with a high hypochondric value, five with a high depressive value, and four with a high hysteric value. This neurotic triad was found in two cases. We noticed five cases with psychopathic deviance relative to antisocial behaviour while values of paranoia and hypomania were high in one case without any association of these personality aspects, which demonstrated absence of behavioural problem. Psychotic profile associating schizophrenia, paranoia, depression and hypomania was not found. We outlined in half of the valid population a significant high psycho-asthenic pattern. CONCLUSION: We conclude that a correlation between the personality inventory and the ICIQ-UI-SF is feasible. The comparative study demonstrate reliability of answers. Sincerity is established by the Minimult L scale. We confirm and precise literature information over clinical personality pattern of this population and observe relevant elements concerning the psycho-asthenic pattern which depicts an anxious personality with an important feeling of the problem. These elements permit to suspect that a personality disturbance may impact the physiopathology of the micturition. LEVEL OF EVIDENCE: 4. PMID- 26746788 TI - Effect of C-5 position on the photochemical properties and phototoxicity of antofloxacin and levofloxacin: A stable and transient study. AB - The photochemistry of two structure-related fluoroquinolones (FQs), antofloxacin (ANT) and levofloxacin (LEV), was studied in aqueous solution using stable and transient methods. The properties for energy transfer and electron transfer of these two FQs were also studied. The transient absorption spectra of FQs were observed, and transient species were assigned. The LEV triplet state ((3)LEV(*)) spectra (lambdamax = 610 nm) were determined, whereas the transient absorption of ANT could not be observed. The decay rate constant of (3)LEV(*) via unimolecular attenuation, self-quenching, and quenching by oxygen was 3.2 * 10(5) s(-1), 6.72 * 10(8) M(-1) s(-1), and 1.01 * 10(9) M(-1) s(-1), respectively. A reasonable diagram showing the decay of (1)FQs* consisting of various substituents at the C 5 position was proposed. The phototoxicity of LEV and ANT was investigated and compared. Insertion of an amino group at the C-5 position made ANT relatively photostable and non-phototoxic compared with LEV. PMID- 26746791 TI - WITHDRAWN: Editor's Forum. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published in , http://dx.doi.org/10.1016/j.redox.2015.08.002, http://dx.doi.org/10.1016/j.redox.2015.08.003, http://dx.doi.org/10.1016/j.redox.2015.08.004. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26746792 TI - WITHDRAWN: Editor's Forum. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published in , http://dx.doi.org/10.1016/j.redox.2015.08.002, http://dx.doi.org/10.1016/j.redox.2015.08.003, http://dx.doi.org/10.1016/j.redox.2015.08.004. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26746789 TI - Nogo-B receptor deficiency causes cerebral vasculature defects during embryonic development in mice. AB - Nogo-B receptor (NgBR) was identified as a receptor specific for Nogo-B. Our previous work has shown that Nogo-B and its receptor (NgBR) are essential for chemotaxis and morphogenesis of endothelial cells in vitro and intersomitic vessel formation via Akt pathway in zebrafish. Here, we further demonstrated the roles of NgBR in regulating vasculature development in mouse embryo and primitive blood vessel formation in embryoid body culture systems, respectively. Our results showed that NgBR homozygous knockout mice are embryonically lethal at E7.5 or earlier, and Tie2Cre-mediated endothelial cell-specific NgBR knockout (NgBR ecKO) mice die at E11.5 and have severe blood vessel assembly defects in embryo. In addition, mutant embryos exhibit dilation of cerebral blood vessel, resulting in thin-walled endothelial caverns. The similar vascular defects also were detected in Cdh5(PAC)-CreERT2 NgBR inducible ecKO mice. Murine NgBR gene targeting embryonic stem cells (ESC) were generated by homologous recombination approaches. Homozygous knockout of NgBR in ESC results in cell apoptosis. Heterozygous knockout of NgBR does not affect ESC cell survival, but reduces the formation and branching of primitive blood vessels in embryoid body culture systems. Mechanistically, NgBR knockdown not only decreases both Nogo-B and VEGF stimulated endothelial cell migration by abolishing Akt phosphorylation, but also decreases the expression of CCM1 and CCM2 proteins. Furthermore, we performed immunofluorescence (IF) staining of NgBR in human cerebral cavernous malformation patient tissue sections. The quantitative analysis results showed that NgBR expression levels in CD31 positive endothelial cells is significantly decreased in patient tissue sections. These results suggest that NgBR may be one of important genes coordinating the cerebral vasculature development. PMID- 26746793 TI - WITHDRAWN: Editor's Forum. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published in , http://dx.doi.org/10.1016/j.redox.2015.08.002, http://dx.doi.org/10.1016/j.redox.2015.08.003, http://dx.doi.org/10.1016/j.redox.2015.08.004. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26746794 TI - Rare Cause of New Mitral Regurgitation After Aortic Valve Replacement. PMID- 26746795 TI - Cortical Blindness After Cardiac Surgery: Just an Ischemic Mechanism? PMID- 26746796 TI - A Complex Atrial Septal Defect and Three-Dimensional Echocardiography: A Question and an Answer. PMID- 26746790 TI - MEMO1 drives cranial endochondral ossification and palatogenesis. AB - The cranial base is a component of the neurocranium and has a central role in the structural integration of the face, brain and vertebral column. Consequently, alteration in the shape of the human cranial base has been intimately linked with primate evolution and defective development is associated with numerous human facial abnormalities. Here we describe a novel recessive mutant mouse strain that presented with a domed head and fully penetrant cleft secondary palate coupled with defects in the formation of the underlying cranial base. Mapping and non complementation studies revealed a specific mutation in Memo1 - a gene originally associated with cell migration. Expression analysis of Memo1 identified robust expression in the perichondrium and periosteum of the developing cranial base, but only modest expression in the palatal shelves. Fittingly, although the palatal shelves failed to elevate in Memo1 mutants, expression changes were modest within the shelves themselves. In contrast, the cranial base, which forms via endochondral ossification had major reductions in the expression of genes responsible for bone formation, notably matrix metalloproteinases and markers of the osteoblast lineage, mirrored by an increase in markers of cartilage and extracellular matrix development. Concomitant with these changes, mutant cranial bases showed an increased zone of hypertrophic chondrocytes accompanied by a reduction in both vascular invasion and mineralization. Finally, neural crest cell-specific deletion of Memo1 caused a failure of anterior cranial base ossification indicating a cell autonomous role for MEMO1 in the development of these neural crest cell derived structures. However, palate formation was largely normal in these conditional mutants, suggesting a non-autonomous role for MEMO1 in palatal closure. Overall, these findings assign a new function to MEMO1 in driving endochondral ossification in the cranium, and also link abnormal development of the cranial base with more widespread effects on craniofacial shape relevant to human craniofacial dysmorphology. PMID- 26746799 TI - PEP-on-DEP: A competitive peptide-based disposable electrochemical aptasensor for renin diagnostics. AB - Antibody-based immunosensors are relatively less accessible to a wide variety of unreachable targets, such as low-molecular-weight biomarkers that represent a rich untapped source of disease-specific diagnostic information. Here, we present a peptide aptamer-based electrochemical sensor technology called 'PEP-on-DEP' to detect less accessible target molecules, such as renin, and to improve the quality of life. Peptide-based aptamers represent a relatively smart class of affinity binders and show great promise in biosensor development. Renin is involved in the regulation of arterial blood pressure and is an emerging biomarker protein for predicting cardiovascular risk and prognosis. To our knowledge, no studies have described aptamer molecules that can be used as new potent probes for renin. Here, we describe a portable electrochemical biosensor platform based on the newly identified peptide aptamer molecules for renin. We constructed a randomized octapeptide library pool with diversified sequences and selected renin specific peptide aptamers using cDNA display technology. We identified a few peptide aptamer sequences with a KD in the uM binding affinity range for renin. Next, we grafted the selected peptide aptamers onto gold nanoparticles and detected renin in a one-step competitive assay using our originally developed DEP (Disposable Electrochemical Printed) chip and a USB powered portable potentiostat system. We successfully detected renin in as little as 300ngmL(-1) using the PEP-on-DEP method. Thus, the generation and characterization of novel probes for unreachable target molecules by merging a newly identified peptide aptamer with electrochemical transduction allowed for the development of a more practical biosensor that, in principle, can be adapted to develop a portable, low-cost and mass-producible biosensor for point-of-care applications. PMID- 26746798 TI - Inner nuclear membrane protein Lem2 facilitates Rad3-mediated checkpoint signaling under replication stress induced by nucleotide depletion in fission yeast. AB - DNA replication checkpoint is a highly conserved cellular signaling pathway critical for maintaining genome integrity in eukaryotes. It is activated when DNA replication is perturbed. In Schizosaccharomyces pombe, perturbed replication forks activate the sensor kinase Rad3 (ATR/Mec1), which works cooperatively with mediator Mrc1 and the 9-1-1 checkpoint clamp to phosphorylate the effector kinase Cds1 (CHK2/Rad53). Phosphorylation of Cds1 promotes autoactivation of the kinase. Activated Cds1 diffuses away from the forks and stimulates most of the checkpoint responses under replication stress. Although this signaling pathway has been well understood in fission yeast, how the signaling is initiated and thus regulated remains incompletely understood. Previous studies have shown that deletion of lem2(+) sensitizes cells to the inhibitor of ribonucleotide reductase, hydroxyurea. However, the underlying mechanism is still not well understood. This study shows that in the presence of hydroxyurea, Lem2 facilitates Rad3-mediated checkpoint signaling for Cds1 activation. Without Lem2, all known Rad3-dependent phosphorylations critical for replication checkpoint signaling are seriously compromised, which likely causes the aberrant mitosis and drug sensitivity observed in this mutant. Interestingly, the mutant is not very sensitive to DNA damage and the DNA damage checkpoint remains largely intact, suggesting that the main function of Lem2 is to facilitate checkpoint signaling in response to replication stress. Since Lem2 is an inner nuclear membrane protein, these results also suggest that the replication checkpoint may be spatially regulated inside the nucleus, a previously unknown mechanism. PMID- 26746800 TI - Preparation and in vivo evaluation of insulin-loaded biodegradable nanoparticles prepared from diblock copolymers of PLGA and PEG. AB - The aim of this study was to design a controlled release vehicle for insulin to preserve its stability and biological activity during fabrication and release. A modified, double emulsion, solvent evaporation, technique using homogenisation force optimised entrapment efficiency of insulin into biodegradable nanoparticles (NP) prepared from poly (DL-lactic-co-glycolic acid) (PLGA) and its PEGylated diblock copolymers. Formulation parameters (type of polymer and its concentration, stabiliser concentration and volume of internal aqueous phase) and physicochemical characteristics (size, zeta potential, encapsulation efficiency, in vitro release profiles and in vitro stability) were investigated. In vivo insulin sensitivity was tested by diet-induced type II diabetic mice. Bioactivity of insulin was studied using Swiss TO mice with streptozotocin-induced type I diabetic profile. Insulin-loaded NP were spherical and negatively charged with an average diameter of 200-400 nm. Insulin encapsulation efficiency increased significantly with increasing ratio of co-polymeric PEG. The internal aqueous phase volume had a significant impact on encapsulation efficiency, initial burst release and NP size. Optimised insulin NP formulated from 10% PEG-PLGA retained insulin integrity in vitro, insulin sensitivity in vivo and induced a sustained hypoglycaemic effect from 3h to 6 days in type I diabetic mice. PMID- 26746801 TI - Hot melt extrusion based solid solution approach: Exploring polymer comparison, physicochemical characterization and in-vivo evaluation. AB - The objective of this study was to develop solid solution (SSL) using hot-melt extrusion as a continuous manufacturing method. Powder blends of artesunate (ARS) a water insoluble drug with either Soluplus (SOL) or Kollidon VA64 (VA64) and additives in the form of surfactants or plasticizers were extruded to manufacture extrudes. The incorporation of surfactant or plasticizers facilitates smooth extrusion processing of the drug-excipient blend which directly reduced the residence time to form extrudes and works as parameter to control flow of the drug-excipients melt inside the extruder barrel. Differential scanning calorimetry (DSC) and X-ray diffraction (TXRD) analysis revealed the existence of the drug within the extrudes in amorphous state. Scanning electron microscopy (SEM), Raman spectroscopy (RS), Raman imaging (RI) and Atomic force microscopy (AFM) analytical characterization were carry out on the SSL formulations showed a homogeneous drug distribution within the extrudes. (2)D NMR and (1)H NMR studies were undertaken to reveal the possible drug-excipient interactions. The SSL produced via continuous HME processing showed significantly faster release of ARS compared to the pure drug substance. It is observed that F1 SSL (soluplus based) have 66.44 times higher AUC(0-72) and 16.60 times higher Cmax than pure ARS. Also K1 SSL (Kollidon VA64 based) have 62.20 times higher AUC(0-72) and 13.40 times higher Cmax than pure ARS. PMID- 26746802 TI - Andrographolide stimulates p38 mitogen-activated protein kinase-nuclear factor erythroid-2-related factor 2-heme oxygenase 1 signaling in primary cerebral endothelial cells for definite protection against ischemic stroke in rats. AB - Stroke pathogenesis involves complex oxidative stress-related pathways. The nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) pathways have been considered molecular targets in pharmacologic intervention for ischemic diseases. Andrographolide, a labdane diterpene, has received increasing attention in recent years because of its various pharmacologic activities. We determined that andrographolide modulates the mitogen-activated protein kinase (MAPK)-Nrf2-HO-1 signaling cascade in primary cerebral endothelial cells (CECs) to provide positive protection against middle cerebral artery occlusion (MCAO) induced ischemic stroke in rats. In the present study, andrographolide (10 MUM) increased HO-1 protein and messenger RNA expressions, Nrf2 phosphorylation, and nuclear translocation in CECs, and these activities were disrupted by a p38 MAPK inhibitor, SB203580, but not by the extracellular signal-regulated kinase inhibitor PD98059 or c-Jun amino-terminal kinase inhibitor SP600125. Similar results were observed in confocal microscopy analysis. Moreover, andrographolide induced Nrf2 and HO-1 protein expressions were significantly inhibited by Nrf2 small interfering RNA. Moreover, HO-1 knockdown attenuated the protective effect of andrographolide against oxygen-glucose deprivation-induced CEC death. Andrographolide (0.1 mg/kg) significantly suppressed free radical formation, blood-brain barrier disruption, and brain infarction in MCAO-insulted rats, and these effects were reversed by the HO-1 inhibitor zinc protoporphyrin IX. The mechanism is attributable to HO-1 activation, as directly evidenced by andrographolide-induced pronounced HO-1 expression in brain tissues, which was highly localized in the cerebral capillary. In conclusion, andrographolide increased Nrf2-HO-1 expression through p38 MAPK regulation, confirming that it provides protection against MCAO-induced brain injury. These findings provide strong evidence that andrographolide could be a therapeutic agent for treating ischemic stroke or neurodegenerative diseases. PMID- 26746803 TI - Evaluation of intraoperative fluorescence imaging-guided surgery in cancer bearing dogs: a prospective proof-of-concept phase II study in 9 cases. AB - The objective was to prospectively evaluate the application of intraoperative fluorescence imaging (IOFI) in the surgical excision of malignant masses in dogs, using a novel lipid nanoparticle contrast agent. Dogs presenting with spontaneous soft-tissue sarcoma or subcutaneous tumors were prospectively enrolled. Clinical staging and whole-body computed tomography (CT) were performed. All the dogs received an intravenous injection of dye-loaded lipid nanoparticles, LipImage 815. Wide or radical resection was realized after CT examination. Real-time IOFI was performed before skin incision and after tumor excision. In cases of radical resection, the lymph nodes (LNs) were imaged. The margin/healthy tissues fluorescence ratio or LN/healthy tissues fluorescence ratio was measured and compared with the histologic margins or LN status. Nine dogs were included. Limb amputation was performed in 3 dogs, and wide resection in 6. No adverse effect was noted. Fluorescence was observed in all 9 of the tumors. The margins were clean in 5 of 6 dogs after wide surgical resection, and the margin/healthy tissues fluorescence ratio was close to 1.0 in all these dogs. Infiltrated margins were observed in 1 case, with a margin/healthy tissues fluorescence ratio of 3.2. Metastasis was confirmed in 2 of 3 LNs, associated with LN/healthy tissues fluorescence ratios of 2.1 and 4.2, whereas nonmetastatic LN was associated with a ratio of 1.0. LipImage 815 used as a contrast agent during IOFI seemed to allow for good discrimination between tumoral and healthy tissues. Future studies are scheduled to evaluate the sensitivity and specificity of IOFI using LipImage 815 as a tracer. PMID- 26746804 TI - Novel immunologic tolerance of human cancer cell xenotransplants in zebrafish. AB - Immune deficiency or suppression in host animals is an essential precondition for the success of cancer cell xenotransplantation because the host immune system has a tendency to reject implanted cells. However, in such animals, the typical tumor microenvironment seen in cancer subjects does not form because of the lack of normal immunity. Here, we developed a novel zebrafish (Danio rerio) model based on 2 rounds of cancer cell xenotransplantation that achieved cancer-specific immunologic tolerance without immunosuppression. We irradiated human cancer cells (PC-3, K562 and HepG2) to abolish their proliferative abilities and implanted them into zebrafish larvae. These cells survived for 2 weeks in the developing host. Three months after the first implantation, the zebrafish were implanted with the same, but nonirradiated, cell lines. These cancer cells proliferated and exhibited metastasis without immune suppression. To reveal the transcriptional mechanism of this immune tolerance, we conducted dual RNA-seq of the tumor with its surrounding tissues and identified several regulatory zebrafish genes that are involved in immunity; the expression of plasminogen activator, urokinase, and forkhead box P3 was altered in response to immunologic tolerance. In conclusion, this xenograft method has potential as a platform for zebrafish-based anticancer drug discovery because it can closely mimic human clinical cancers without inducing immune suppression. PMID- 26746805 TI - Prenatal cigarette smoke exposure effects on apoptotic and nicotinic acetylcholine receptor expression in the infant mouse brainstem. AB - Infants exposed to cigarette smoked during pregnancy into infancy have increased respiratory and cardiac abnormalities. Nicotine, the major neurotoxic component of cigarette smoke, induces its actions by binding to nicotinic acetylcholine receptors (nAChR), with one downstream effect being increased apoptosis. Using a pre- into post- natal cigarette smoke exposure mouse model (SE), we studied the immunohistochemical expression of nAChR subunits alpha2, alpha3, alpha4, alpha5, alpha7, alpha9, beta1 and beta2 and two markers of apoptosis, active caspase-3 and TUNEL, in seven nuclei of the medulla and facial nucleus of the pons in male mice. Pups of dams exposed to two cigarettes (nicotine <=1.2mg, CO <=15mg) twice daily for six weeks prior to mating, during gestation and lactation (n=5; SE), were compared to pups exposed to air under the same condition (n=5; SHAM) at P20. Results showed that the hypoglossal nucleus had increased alpha3, alpha4, alpha7, alpha9, Casp-3 and TUNEL, dorsal motor nucleus of the vagus had increased alpha3, alpha5, alpha7, beta1 and Casp-3, nucleus of the solitary tract had increased alpha3 but decreased alpha4, alpha5, beta1 and apoptosis, cuneate nucleus had increased alpha3, beta2 and Casp- 3, but decreased alpha5, nucleus of the spinal trigeminal tract had increased alpha3, alpha7, beta1, lateral reticular nucleus had decreased beta1, inferior olivary nucleus had increased beta1 but decreased apoptosis, and the facial had increased alpha2, alpha3 and alpha7. This is the first study to demonstrate that nAChR subunits are affected following pre- into post-natal SE and that they simultaneously coincided with changes in apoptotic expression. PMID- 26746807 TI - Banning Trophy Hunting Will Exacerbate Biodiversity Loss. AB - International pressure to ban trophy hunting is increasing. However, we argue that trophy hunting can be an important conservation tool, provided it can be done in a controlled manner to benefit biodiversity conservation and local people. Where political and governance structures are adequate, trophy hunting can help address the ongoing loss of species. PMID- 26746806 TI - Complex Homology and the Evolution of Nervous Systems. AB - We examine the complex evolution of animal nervous systems and discuss the ramifications of this complexity for inferring the nature of early animals. Although reconstructing the origins of nervous systems remains a central challenge in biology, and the phenotypic complexity of early animals remains controversial, a compelling picture is emerging. We now know that the nervous system and other key animal innovations contain a large degree of homoplasy, at least on the molecular level. Conflicting hypotheses about early nervous system evolution are due primarily to differences in the interpretation of this homoplasy. We highlight the need for explicit discussion of assumptions and discuss the limitations of current approaches for inferring ancient phenotypic states. PMID- 26746810 TI - Self-rated health in women prior to clinical onset of multiple sclerosis: A study within the Danish National Birth Cohort. AB - BACKGROUND: It has been suggested that onset of multiple sclerosis (MS) is preceded by a clinically silent period of up to 10 years. OBJECTIVES: Examine whether such a period should be associated with poor self-rated health (SRH). METHODS: Information on SRH before pregnancy was ascertained among 80,848 women participating in the Danish National Birth Cohort (DNBC) 1996-2002. Women were followed for MS from enrolment in DNBC in the 16th week of pregnancy until 31 December 2011. Associations between SRH and MS were evaluated by means of hazard ratios (HR) with 95% confidence intervals (CIs) using Cox proportional hazard models. RESULTS: During on average 11.7 years of follow-up, 239 women were diagnosed with MS. Overall, neither women with fair (HR = 1.09 (95% CI = 0.83 1.41), n = 113) nor poor pre-pregnancy SRH (HR = 0.94 (95% CI = 0.47-1.87), n = 9) were at an increased risk of MS compared with women reporting very good pre pregnancy SRH. Supplementary analyses showed no significant differences in MS risk in consecutive periods of follow-up. CONCLUSION: In this first prospective cohort study assessing MS risk as a function of SRH, we found no indication of a long period of poor SRH prior to MS. Our findings based on pregnant women may not necessarily apply to all women. PMID- 26746809 TI - Characterizing the phenotype of multiple sclerosis-associated depression in comparison with idiopathic major depression. AB - BACKGROUND: Depression is a common co-morbidity in patients with multiple sclerosis (MS). While somatic symptoms of MS correlate with depression levels, it is unclear whether the clinical presentation of MS-associated depression differs from patients with "idiopathic" major depressive disorder (MDD). OBJECTIVE: To compare the clinical phenotype of depression among MS and idiopathic MDD patients. METHODS: Mean relative contribution of individual Beck Depression Inventory-II (BDI-II) items was evaluated among n = 139 patients with relapsing remitting MS and n = 85 MDD patients without somatic illness. Next, comparisons were repeated in n = 38 MS with clinically relevant depressive symptoms (BDI-II > 19) and n = 38 MDD patients matched for sex, age, and depression severity. Finally, the underlying construct of depression was compared across groups using confirmatory factor analysis (CFA). RESULTS: Comparisons on a whole-group level produced the expected differences along somatic/non-somatic symptoms. However, when appropriately controlling for depression severity, age, and sex, only four items contributed differentially to BDI-II total scores in MS versus MDD. CFA suggested that the underlying depression construct is essentially identical in both groups. CONCLUSION: The clinical phenotype of "idiopathic" MDD and MS associated depression appears similar when adequately examined. The relevance of these findings for psychotherapeutic approaches for MS-associated depression should be explored in future studies. PMID- 26746808 TI - Heme-bound SiaA from Streptococcus pyogenes: Effects of mutations and oxidation state on protein stability. AB - The protein SiaA (HtsA) is part of a heme uptake pathway in Streptococcus pyogenes. In this report, we present the heme binding of the alanine mutants of the axial histidine (H229A) and methionine (M79A) ligands, as well as a lysine (K61A) and cysteine (C58A) located near the heme propionates (based on homology modeling) and a control mutant (C47A). pH titrations gave pKa values ranging from 9.0 to 9.5, close to the value of 9.7 for WT SiaA. Resonance Raman spectra of the mutants suggested that the ferric heme environment may be distinct from the wild type; spectra of the ferrous states were similar. The midpoint reduction potential of the K61A mutant was determined by spectroelectrochemical titration to be 61+/-3mV vs. SHE, similar to the wild-type protein (68+/-3mV). The addition of guanidine hydrochloride showed two processes for protein denaturation, consistent with heme loss from protein forms differing by the orientation of the heme in the binding pocket (the half-life for the slower process ranged from less than half a day to two days). The ease of protein unfolding was related to the strength of interaction of the residues with the heme. We hypothesize that kinetically facile but only partial unfolding, followed by a very slow approach to the completely unfolded state, may be a fundamental attribute of heme trafficking proteins. Small motions to release/transfer the heme accompanied by resistance to extensive unfolding may preserve the three dimensional form of the protein for further uptake and release. PMID- 26746811 TI - Erratum. AB - Sbardella E, Tona F, Petsas N, et al. Functional connectivity changes and their relationship with clinical disability and white matter integrity in patients with relapsing-remitting multiple sclerosis. Multiple Sclerosis Journal 2015; 21(13): 1681-1692. DOI: 10.1177/1352458514568826The above article that appeared in the November 2015 issue of Multiple Sclerosis Journal contained incorrect affiliations for two of the authors.The correct affiliation for Patrizia Pantano is Department of Neurology and Psychiatry, University of Rome, Italy / IRCSS Neuromed, Italy.The correct affiliation for Nicola Filippini is FMRIB Centre, John Radcliffe Hospital, UK. PMID- 26746812 TI - Review: Clinical aspects of hereditary DNA Mismatch repair gene mutations. AB - Inherited mutations of the DNA Mismatch repair genes MLH1, MSH2, MSH6 and PMS2 can result in two hereditary tumor syndromes: the adult-onset autosomal dominant Lynch syndrome, previously referred to as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and the childhood-onset autosomal recessive Constitutional Mismatch Repair Deficiency syndrome. Both conditions are important to recognize clinically as their identification has direct consequences for clinical management and allows targeted preventive actions in mutation carriers. Lynch syndrome is one of the more common adult-onset hereditary tumor syndromes, with thousands of patients reported to date. Its tumor spectrum is well established and includes colorectal cancer, endometrial cancer and a range of other cancer types. However, surveillance for cancers other than colorectal cancer is still of uncertain value. Prophylactic surgery, especially for the uterus and its adnexa is an option in female mutation carriers. Chemoprevention of colorectal cancer with aspirin is actively being investigated in this syndrome and shows promising results. In contrast, the Constitutional Mismatch Repair Deficiency syndrome is rare, features a wide spectrum of childhood onset cancers, many of which are brain tumors with high mortality rates. Future studies are very much needed to improve the care for patients with this severe disorder. PMID- 26746813 TI - 18F-FDG PET/CT in gastric lymphoepithelioma-like carcinoma. PMID- 26746816 TI - Four-dimensional computed tomography prediction of inter- and intrafractional upper gastrointestinal tumor motion during fractionated stereotactic body radiation therapy. AB - PURPOSE: Respiratory-induced tumor motion of upper gastrointestinal (GI) tumors during radiation therapy is often assessed using a single 4-dimensional computed tomography (4D-CT) and presumed to be representative during fractionated treatment regimens. The purpose of this study was to examine the intra- and interfraction correlations of tumor motion between pretreatment 4D-CT and real time fiducial-based motion tracking in patients treated with fractionated stereotactic body radiation therapy (SBRT) for upper GI malignancies. METHODS AND MATERIALS: Fourteen patients with upper GI tumors underwent fractionated SBRT using the CyberKnife radiosurgical system with Synchrony respiratory motion management. Before treatment, each patient underwent a free-breathing 4D-CT scan and fiducial motion was tracked for each phase of the respiratory cycle. Real time fiducial positions recorded during delivery of each SBRT fraction were extracted from the CyberKnife planning system. Displacements were compared between those predicted by 4D-CT and those recorded by Synchrony during treatment in the left-right (LR), anteroposterior (AP), and superoinferior (SI) directions. RESULTS: The 4D-CT scans demonstrated little correlation with real-time mean fiducial displacement as determined by Pearson correlation with coefficients of 0.45, 0.52, and 0.63 in the SI, AP, and LR directions, respectively. Cohort averaged maximum fiducial displacements based on 4D-CT and real-time tracking were measured to be 3.86 +/- 1.40 mm versus 10.73 +/- 7.03 mm, 2.29 +/- 1.02 mm versus 4.44 +/- 3.33 mm, and 1.45 +/- 0.49 mm versus 2.67 +/- 2.49 mm in the SI, AP, and LR directions, respectively. Mean fiducial displacements were greater than that predicted by the maximum displacements on the corresponding 4D-CT scan in 39%, 22%, and 25% of SBRT fractions in the SI, AP, and LR directions, respectively. CONCLUSIONS: Comparison of 4D-CT with real-time fiducial tracking demonstrated significant inter- and intrafractional discrepancies, particularly in the SI direction, which could result in compromise of target coverage when planning with a single free-breathing 4D-CT. PMID- 26746815 TI - Enhancing safety and quality through preplanning peer review for patients undergoing stereotactic body radiation therapy. AB - PURPOSE: Because of its high dose per fraction delivery, stereotactic body radiation therapy (SBRT) requires real-time process assurance to promote safe, high-quality treatments. In an effort to assure safety and first-time quality, we instituted a pilot, single-institution, SBRT peer review process before treatment planning. Here, we present a summary of the results of that process over a 26 month period. METHODS AND MATERIALS: Before planning, all patients were presented at an SBRT "rounds" that required, at a minimum, the treating attending or resident physician, an independent attending physician, a physicist, and a dosimetrist. Items reviewed included imaging, image registration, target contours, prescription, and planning goals. The results of peer review were prospectively recorded and logistic regression models were used to assess the relationship between various physician and case characteristics and the odds of a change being made. RESULTS: A total of 513 SBRT cases were peer reviewed before planning. In 22.6% of cases, at least 1 change was made because of this process. A lower change rate was observed in higher volume SBRT body sites (lung and liver). In all body sites, gross and planning target volume contours were changed 8.2% and 5.5% of the time, respectively. The prescription was changed 4.9% of the time, and organs at risk goals were changed 7.2% of the time. The odds of having a change were significantly lower when the treating oncologist had more SBRT experience. CONCLUSIONS: Preplanning peer review by an independent physician, physicist, and dosimetrist resulted in changes in nearly one-quarter of SBRT patients, potentially preventing suboptimal treatments. The odds of a change being required were decreased in higher volume body sites and when the treating oncologist was more experienced with SBRT, underscoring the potential importance of peer review in uncommon SBRT sites and at low-volume SBRT centers. PMID- 26746817 TI - Externally applied high-dose-rate brachytherapy for deeply invasive cutaneous squamous cell carcinoma in an older patient. PMID- 26746818 TI - Occurrence of polybrominated diphenyl ethers (PBDEs) in foodstuffs in Italy and implications for human exposure. AB - Polybrominated diphenyl ethers (PBDEs) were determined in various foodstuffs in Italy and the dietary intake was estimated. PBDEs were detected in all analysed samples at concentrations that spanned over five orders of magnitude. The most abundant congeners were the BDE-209, followed by BDE-47 and BDE-99. Fish oil and milk samples showed the highest PBDE concentrations among all samples. The daily dietary intake values were found to be in good agreement or higher to literature values, impacted mainly from the contribution of the analysed dairy products. The cancer risk values estimated for BDE-209 indicated that this specific risk associated with the studied foodstuffs is limited. Italy is one of the world leading countries in the production of furniture and clothes and has extremely developed medium enterprise industrial sector, where PBDEs were historically used suggesting that their occurrence may be linked to these activities. PMID- 26746819 TI - What They Want: Inclusion of Blood and Marrow Transplantation Survivor Preference in the Development of Models of Care for Long-Term Health in Sydney, Australia. AB - Four hundred forty-one adult allogeneic blood and marrow transplantation (BMT) survivors participated in a cross-sectional survey to assess long-term follow-up (LTFU) model of care preference. Survey instruments included the Sydney Post BMT Survey, Functional Assessment of Cancer Therapy-BMT, Depression Anxiety Stress Scales 21, the Chronic GVHD Activity Assessment-Patient Self Report (Form B), the Lee Chronic GVHD Symptom Scale and the Post-Traumatic Growth Inventory. We found most BMT survivors (74%) would prefer LTFU with their transplantation physicians alone or in combination with transplantation center-linked services (satellite clinics or telemedicine) Over one-quarter indicated a preference for receiving comprehensive post-transplantation care in a "satellite" clinic staffed by their BMT team situated closer to their place of residence, with higher income, higher educational level, and sexual morbidity being significant social factors influencing this preference. Regular exercise was reported less often in those who preferred telemedicine, which may reflect reduced mobility. The factor most strongly associated with a preference for transplantation center follow-up was the severity of chronic graft-versus-host disease. Full- and part-time work were negatively associated with transplantation center follow-up, possibly implying decreased dependency on the center and some return to normalcy. This study is the first to explore the preferences of BMT survivors for long-term post transplantation care. These data provides the basis for LTFU model of care development and health service reform consistent with the preferences of BMT survivors. PMID- 26746821 TI - The Reed-Stanton press rig for the generation of reproducible fingermarks: Towards a standardised methodology for fingermark research. AB - In the search for better or new methods/techniques to visualise fingermarks or to analyse them exploiting their chemical content, fingermarks inter-variability may hinder the assessment of the method effectiveness. Variability is due to changes in the chemical composition of the fingermarks between different donors and within the same donor, as well as to differential contact time, pressure and angle. When validating a method or comparing it with existing ones, it is not always possible to account for this type of variability. One way to compensate for these issues is to employ, in the early stages of the method development, a device generating reproducible fingermarks. Here the authors present their take on such device, as well as quantitatively describing its performance and benefits against the manual production of marks. Finally a short application is illustrated for the use of this device, at the method developmental stages, in an emerging area of fingerprinting research concerning the retrieval of chemical intelligence from fingermarks. PMID- 26746820 TI - The retrieval of fingerprint friction ridge detail from elephant ivory using reduced-scale magnetic and non-magnetic powdering materials. AB - An evaluation of reduced-size particle powdering methods for the recovery of usable fingermark ridge detail from elephant ivory is presented herein for the first time as a practical and cost-effective tool in forensic analysis. Of two reduced-size powder material types tested, powders with particle sizes <= 40 MUm offered better chances of recovering ridge detail from unpolished ivory in comparison to a conventional powder material. The quality of developed ridge detail of these powders was also assessed for comparison and automated search suitability. Powder materials and the enhanced ridge detail on ivory were analysed by scanning electron microscopy and energy dispersive X-ray spectroscopy and interactions between their constituents and the ivory discussed. The effect of ageing on the quality of ridge detail recovered showed that the best quality was obtained within 1 week. However, some ridge detail could still be developed up to 28 days after deposition. Cyanoacrylate and fluorescently-labelled cyanoacrylate fuming of ridge detail on ivory was explored and was less effective than reduced-scale powdering in general. This research contributes to the understanding and potential application of smaller scale powdering materials for the development of ridge detail on hard, semi-porous biological material typically seized in wildlife-related crimes. PMID- 26746822 TI - 10 years of 1:1 taping in Belgium - A selection of murder cases involving fibre examination. AB - Since 2002, the 1:1 tape lifting technique on murder victims has been introduced in Belgium. Thirty-six murder cases for which a fibre examination was carried out in our laboratory between 2002 and 2012 are reviewed. These cases all involved the collection of microtraces on 39 victims using a 1:1 taping or similar technique, called semi 1:1 taping. The degree of "positive outcomes" for investigative and comparative fibre cases is high. Especially in cases where the modus operandi of suspects had to be verified, the examination of the 1:1 tape lifting led to very useful fibre results. The findings from some of these fibre cases are used to illustrate the advantages, drawbacks and points of interest of the two collection techniques. These are also compared with the zonal taping technique, another microtrace collection technique applied on victims at the crime scene. PMID- 26746823 TI - Identification and persistence of Pinus pollen DNA on cotton fabrics: A forensic application. AB - Advances in plant genomics have had an impact on the field of forensic botany. However, the use of pollen DNA profiling in forensic investigations has yet to be applied. Five volunteers wore a jacket with Pinus echinata pollen-containing cotton swatches for a 14-day period. Pollen decay was evaluated at days 0, 3, 6, 9 and 14 by microscopy. Pollen grains were then transferred to slides using a portable forensic vacuum handle. Ten single grains per swatch were isolated for DNA analysis. DNA was extracted using a high throughput extraction method. A nine locus short tandem repeat (STR) multiplex system, including previously published primers from Pinus taeda, was developed. DNA was amplified by PCR using fluorescent dyes and analyzed by capillary electrophoresis. Pollen counts from cotton swatches in a 14-day period exhibited an exponential decay from 100% to 17%. The success rate of PCR amplification was 81.2%. Complete and partial STR profiles were generated from 250 pollen grains analyzed (44% and 37%, respectively). Due to the limited amount of DNA, drop-in events were observed (1.87%). However, the rate of contamination with pollen from other pine individuals originating from environmental sources was 4.4%. In conclusion, this study has shown that pollen can be a stable source of forensic DNA evidence, as a proof-of-principle, and that may persist on cotton clothing for at least 14 days of wear. This method can be applied in forensic cases where pollen grains larger than 10 MUm (e.g., from herbs or trees) may be transferred to clothing (worn by suspect or victim) by primary contact. PMID- 26746824 TI - Seized cannabis seeds cultivated in greenhouse: A chemical study by gas chromatography-mass spectrometry and chemometric analysis. AB - Cannabis sativa L. is cultivated in most regions of the world. In 2013, the Brazilian Federal Police (BFP) reported 220 tons of marijuana seized and about 800,000 cannabis plants eradicated. Efforts to eradicate cannabis production may have contributed to the development of a new form of international drug trafficking in Brazil: the sending of cannabis seeds in small amounts to urban centers by logistics postal. This new and increasing panorama of cannabis trafficking in Brazil, encouraged the chemical study of cannabis seeds cultivated in greenhouses by gas-chromatography coupled with mass spectrometry (GC-MS) associated with exploratory and discriminant analysis. Fifty cannabis seeds of different varieties and brands, seized by the BFP were cultivated under predefined conditions for a period of 4.5 weeks, 5.5 weeks, 7.5 weeks, 10 weeks and 12 weeks. Aerial parts were analyzed and cannabigerol, cannabinol, cannabidiol, cannabichromene Delta9-tetrahydrocannabinol (THC) and other terpenoids were detected. The chromatographic chemical profiles of the samples were significantly different, probably due to different variety, light exposition and age. THC content increased with the age of the plant, however, for other cannabinoids, this correlation was not observed. The chromatograms were plotted in a matrix with 50 rows (samples) and 3886 columns (abundance in a retention time) and submitted to PCA, HCA and PLS-DA after pretreatment (normalization, first derivative and autoscale). The PCA and HCA showed age separation between samples however it was not possible to verify the separation by varieties and brands. The PLS-DA classification provides a satisfactory prediction of plant age. PMID- 26746825 TI - A demonstration of the application of the new paradigm for the evaluation of forensic evidence under conditions reflecting those of a real forensic-voice comparison case. AB - The new paradigm for the evaluation of the strength of forensic evidence includes: The use of the likelihood-ratio framework. The use of relevant data, quantitative measurements, and statistical models. Empirical testing of validity and reliability under conditions reflecting those of the case under investigation. Transparency as to decisions made and procedures employed. The present paper illustrates the use of the new paradigm to evaluate strength of evidence under conditions reflecting those of a real forensic-voice-comparison case. The offender recording was from a landline telephone system, had background office noise, and was saved in a compressed format. The suspect recording included substantial reverberation and ventilation system noise, and was saved in a different compressed format. The present paper includes descriptions of the selection of the relevant hypotheses, sampling of data from the relevant population, simulation of suspect and offender recording conditions, and acoustic measurement and statistical modelling procedures. The present paper also explores the use of different techniques to compensate for the mismatch in recording conditions. It also examines how system performance would have differed had the suspect recording been of better quality. PMID- 26746826 TI - Increased Risk of Mortality Due to Interpersonal Violence in Foreign-Born Women of Reproductive Age: A Swedish Register-Based Study. AB - Violence against women is an increasing public health concern, with assault leading to death as the most extreme outcome. Previous findings indicate that foreign-born women living in Sweden are more exposed to interpersonal violence than Swedish-born women. The current study investigates mortality due to interpersonal violence in comparison with other external causes of death among women of reproductive age in Sweden, with focus on country of birth. Foreign-born women and especially those from countries with low and very low gender equity levels had increased risk of mortality due to interpersonal violence, thus implicating lack of empowerment as a contributing factor. PMID- 26746827 TI - Purely endoscopic removal of a parasagittal/falx meningioma. AB - BACKGROUND: Endoscopic techniques are an integral part of the neurosurgical armamentarium with a growing list of indications. We describe the purely endoscopic removal of an atypical parasagittal meningioma in a patient who could not undergo standard craniotomy due to severe scalp atrophy following childhood irradiation for tinea capitis. METHODS: A 68-year-old man in good general health presented with a parasagittal meningioma that recurred following subtotal removal and adjuvant fractionated stereotactic radiosurgery (FSR). The scalp above the tumor location was very diseased and precluded a regular craniotomy for tumor removal. A 4-cm craniotomy was made in the midline forehead, where the skin was normal. A rigid endoscope was advanced under neuronavigation through the interhemispheric fissure, which provided good access with limited retraction, until the tumor was encountered at a depth of 7-8 cm. Two surgeons performed the surgery using a "four-hands technique". The tumor was removed and the insertion area was resected and coagulated. RESULTS: The surgery was uneventful, with no coagulation or transection of major veins. A subtotal resection was achieved, and the patient recovered with no neurological deficit. CONCLUSIONS: Safe resection of parasagittal meningiomas with a purely endoscopic technique is feasible. This option needs further exploration as an alternative strategy in patients with severely atrophic scalp skin that greatly increases the risk of significant healing complications with calvarian craniotomy. PMID- 26746829 TI - An exceptional outcome from a rare cause of postpartum haemodynamic collapse. AB - We present a case of a 26-year-old woman presenting with haemorrhagic shock without any overt bleeding on postpartum day 2. Work up revealed intra-abdominal haemorrhage from an unclear source in the pelvis. She was intubated, resuscitated with mostly crystalloids, and started on norepinephrine and dopamine, in a rural hospital with limited resources. She was then transferred to the closest tertiary care centre 3 h away by air. On arrival, she was hypothermic (34.9 degrees C) and had developed severe metabolic acidosis (pH 6.89). A massive transfusion protocol was initiated. She underwent an emergency laparotomy and the origin of the active bleeding was believed to be a branch of the right internal iliac artery. Haemostasis was achieved with packing. She was subsequently taken to interventional radiology for angioembolisation of the right uterine artery as an alternative to haemostatic hysterectomy. Her final diagnosis was rupture of an extrauterine uterine artery pseudoaneurysm. PMID- 26746828 TI - Hemodynamic alterations after stent implantation in 15 cases of intracranial aneurysm. AB - BACKGROUND: Stent-assisted coiling technology has been widely used in the treatment of intracranial aneurysms. In the current study, we investigated the intra-aneurysmal hemodynamic alterations after stent implantation and their association with the aneurysm location. METHODS: We first retrospectively studied 15 aneurysm cases [8 internal carotid artery-ophthalmic artery (ICA-OphA) aneurysms and 7 posterior communicating artery (PcoA) aneurysms] treated with Enterprise stents and coils. Then, based on the patient-specific geometries before and after stenting, we built virtual stenting computational fluid dynamics (CFD) simulation models. RESULTS: Before and after the stent deployment, the average wall shear stress (WSS) on the aneurysmal sac at systolic peak changed from 7.04 Pa (4.14 Pa, 15.77 Pa) to 6.04 Pa (3.86 Pa, 11.13 Pa), P = 0.001; the spatially averaged flow velocity in the perpendicular plane of the aneurysm dropped from 0.5 m/s (0.28 m/s, 0.7 m/s) to 0.33 m/s (0.25 m/s, 0.49 m/s), P = 0.001, respectively. Post stent implantation, the WSS in ICA-OphA aneurysms and PcoA aneurysms decreased by 14.4 % (P = 0.012) and 16.6 % (P = 0.018), respectively, and the flow velocity also reduced by 10.3 % (P = 0.029) and 10.5 % (P = 0.013), respectively. Changes in the WSS, flow velocity, and pressure were not significantly different between ICA-OphA and PcoA aneurysms (P > 0.05). Stent implantation did not significantly change the peak systolic pressure in either aneurysm type. CONCLUSION: After the stent implantation, both the intra aneurysmal flow velocity and WSS decreased independently of aneurysm type (ICA OphA and PcoA). Little change was observed in peak systolic pressure. PMID- 26746831 TI - Recurrent pancreatitis after unremarkable colonoscopy, temporalised by CT imaging: an unusual case. AB - Acute pancreatitis is a common surgical presentation, frequently caused by gallstones and alcohol. Here we present an unusual case of a recurrent episode of pancreatitis after an unremarkable colonoscopy, in a patient with several pre existing risk factors for pancreatitis. Before and after abdominal CT scans clearly demonstrate the acute inflammatory process affecting the pancreas and temporalise its development. Early resuscitation and appropriate involvement of high dependency care is advocated by all current guidelines to improve patient outcome. We consider possible aetiology and how early diagnosis and recognition of possible high-risk situations can expedite its investigation and management, helping to provide the best possible care. PMID- 26746830 TI - Is congenital melanocytic naevus a link between Hirayama disease and moyamoya pattern: a new syndrome or a co-incidence? AB - A 22-year-old man presented with a history of progressive weakness and wasting of the right hand and forearm for 12 months followed by similar symptoms in the left upper limb for the past 5 months. He also gave a history of episodes of loss of consciousness for the past 5 years with a frequency of one per 3 months. On examination, there were melanocytic naevi-one large lesion in the nape of the neck and multiple satellite lesions. On investigation, the cervical cord MRI was normal. The brain MRI and angiography showed a moyamoya pattern. Thus, this patient had congenital melanocytic naevi with Hirayama disease and moyamoya pattern. He was treated with extracranial-intracranial bypass for moyamoya disease. During 6-month follow-up, he has been stable. Although moyamoya syndrome has been associated with several systemic diseases and conditions, the coexistence of a moyamoya pattern with Hirayama disease and melanocytic naevi has not been described so far. PMID- 26746832 TI - Ischiofemoral impingement due to a lipoma of the ischiofemoral space. AB - Non-focal hip and groin pain can frequently be a diagnostic problem, particularly if it is related to uncommon causes such as ischiofemoral impingement. The vast majority of published cases of ischiofemoral impingement are caused by osseous changes of the ischiofemoral interval. We describe an unusual case of ischiofemoral impingement caused by an intermuscular lipoma. Surgical resection of the tumour and histology confirmed the lipomatous nature of the tumour, with subsequent resolution of symptoms. To the best of our knowledge, this is the first case of a lipoma causing ischiofemoral impingement described in the English literature and emphasises that impingement can occur on the basis of a soft tissue mass occupying the interval of otherwise normal osseous interval and boundaries. PMID- 26746833 TI - An unusual cause of focal hand dystonia due to a retained implant of the distal radius. AB - Focal hand dystonia (FHD) is characterised clinically by a task-specific symptom and typical electromyography findings of a characteristic pattern of cocontraction of the agonist and antagonist muscles of the hand and forearm. The aetiopathogenesis of this condition is still not clear. We present a case of a patient with an unusual aetiology for this condition, in the form of retained hardware in the distal radius. This patient had complete resolution of symptoms after removal of a retained radial plate. Thorough history-taking, clinical examination and necessary investigations are the cornerstones for making a diagnosis of FHD. PMID- 26746835 TI - Seminal vesicle involvement: a rare extranodal manifestation of non-Hodgkin's lymphoma. PMID- 26746834 TI - A large, benign prostatic cyst presented with an extremely high serum prostate specific antigen level. AB - We report a case of a patient who presented with an extremely high serum prostate specific antigen (PSA) level and underwent radical prostatectomy for presumed prostate cancer. Surprisingly, the whole mount prostatectomy specimen showed only small volume, organ-confined prostate adenocarcinoma and a large, benign intraprostatic cyst, which was thought to be responsible for the PSA elevation. PMID- 26746836 TI - Hepatic portal venous gas with associated bowel ischaemia and intra-abdominal sepsis after recent chemotherapy. PMID- 26746837 TI - Hypothenar hammer syndrome. PMID- 26746838 TI - Unusual cause of flare in antineutrophil cytoplasmic antibody-associated vasculitis. AB - A 53-year-old woman attended for a routine outpatient appointment for follow-up of antineutrophil cytoplasmic antibody-positive vasculitis. Her disease had relapsed despite appropriate medical management with mycophenolate mofetil (MMF), as evidenced by rising acute phase response and antimyeloperoxidase titre with ongoing symptoms. On further questioning, she had been taking oral charcoal as part of a detoxification diet, which we postulate was causing significantly impaired MMF absorption. This case report summarises the presentation and highlights the importance of a thorough drug history, and should prompt the reader to keep an open mind with regard to drug interactions and treatment regimen adherence when treatment is, unexpectedly, seemingly failing. PMID- 26746839 TI - Loa loa in the vitreous cavity of the eye. AB - A 25-year-old man presented with painful diminution of vision (20/160), accompanied by redness, pain and floaters, over a period of 2 weeks, in his left eye. On examination, the anterior segment revealed moderate inflammation. Posterior segment examination showed a grade one vitreous haze with a fairly long live worm moving around in a haphazard and relentless manner throughout the vitreous cavity. The media was slightly hazy due to corneal oedema. The worm was clearly visible in the fundus photo taken. So we planned the patient for vitrectomy, and removal of the worm was performed under steroid cover. The worm was sent to the microbiology department for examination and it was found to be the species of Loa loa. The patient was administered a course of diethylcarbamazine and, on follow-up after 2 weeks, his vision had improved to 20/40. PMID- 26746840 TI - Infrequent presentation of giant cell arteritis. PMID- 26746841 TI - Topochemistry of Internuclear and Intranuclear Interneurons of the Vasomotor Area in the Medulla Oblongata of Hypertensive Rats. AB - Immunohistochemical examination with the antiserum against neuronal NO synthase and cystathionine beta-synthase was used to study the following two pools of interneurons in Wistar rats at various periods after the development of renovascular hypertension: intranuclear interneurons (lying in the projection of the solitary nucleus, reticular gigantocellular nucleus, and parvocellular nucleus) and 2 groups of internuclear interneurons (small interneurons, area 50 300 MU(2); and large interneurons, area above 350 MU(2)). Intranuclear and internuclear interneurons probably play a role in the central mechanisms of hemodynamics regulation. These interneurons differ by not only in topochemical parameters, but also functional properties (different resistances to BP changes). Intranuclear interneurons are characterized by high sensitivity of the gas transmitter systems to a continuous increase in BP, which results in remodeling and dysfunction of the bulbar part of the cardiovascular center. Large internuclear interneurons demonstrate a strong reaction to BP rise, which confirms their involvement into hemodynamics regulation. By contrast, small internuclear interneurons retain their characteristics in arterial hypertension and probably perform an integrative function. PMID- 26746842 TI - Bright-field HER2 dual in situ hybridization (DISH) assay on breast cancer cell blocks: a comparative study with histological sections. AB - BACKGROUND: HER2 testing for samples from recurrent or metastatic disease is recommended by the 2013 update of the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines and cytological analysis can be applied to several types of metastatic lesions. However, the practical method to assess the HER2 testing of breast cancer cytology specimens has yet to be resolved. Therefore, we conducted the bright-field HER2 dual in situ hybridization (DISH) assay on cell blocks (CBs) prepared from breast cancer cell samples as a validation study before clinical use. METHODS: CBs were prepared from tumor cell samples collected from 54 surgically excised breast tumors. The cells were fixed in 10 % buffered formalin for 16-28 h, and embedded in paraffin. The INFORM HER2/neu Dual ISH DNA Probe Cocktail was used for the DISH assay on the Ventana BenchMark ULTRA (Roche Diagnostics). RESULTS: Successful results were obtained in 51 of 54 CB specimens, and the results from the CB specimens were in agreement with those from the histological sections in 48 of the 51 cases (concordance rate, 94 %; kappa, 0.846). The intraclass correlation coefficient (ICC) between the CB and histological specimens in the continuous HER2/CEP17 signal count ratio was 0.89 (95 % CI 0.81-0.93), and the Pearson's CC was 0.91 (95 % CI 0.85-0.94). CONCLUSION: The HER2 DISH assay, utilizing 10 % buffered formalin-fixed CB, would be a reliable and ideal method to assess the HER2 gene status of breast cancer cytological specimens. PMID- 26746843 TI - A structured literature review of the burden of illness and unmet needs in patients with rheumatoid arthritis: a current perspective. AB - While rheumatologists often focus on treatment targets, for many patients with rheumatoid arthritis (RA), control over pain and fatigue, as well as sustaining physical function and quality of life (QoL), is of primary importance. This literature review aimed at examining patients' and physicians' treatment aspirations, and identifying the unmet needs for patients with RA receiving ongoing treatment. Searches were performed using MEDLINE, Embase, PsycINFO, and Econlit literature databases for articles published from 2004 to 2014 in the English language. Published literature was screened to identify articles reporting the unmet needs in RA. We found that, despite the wide range of available treatments, RA continues to pose a substantial humanistic and economic burden on patients, and there are still unmet needs across key domains such as pain, physical function, mental function, and fatigue. These findings suggest that there is a need for further treatment advances in RA that address these domains of contemporary unmet need. PMID- 26746845 TI - When things go wrong: Cysticercus longicollis in an adult wild red fox (Vulpes vulpes). AB - First case of Cysticercus longicollis, larval stage of Taenia crassiceps, was diagnosed in a wild adult male red fox (Vulpes vulpes). The fox was killed by dogs at Nature Park Medvednica and presented to the University of Zagreb Faculty of Veterinary Medicine with history of being unable to run away and having skin lesions on legs that resembled to those of mange. Necropsy revealed whitish fluctuant mass full of cysticercus-like structures, surrounded by fibrous capsule and placed between the leg muscles, and numerous of spherical cysts in the subcutis and in the peritoneal cavity. Cysticerci were identified as C. longicollis based on their size, number and size of the rostellar hooks, mode of proliferation and DNA analysis. To our knowledge, this is the first case of T. crassiceps cysticercosis in a wild carnivore. PMID- 26746846 TI - Immunohistochemical localization of renin-containing cells in two elasmobranch species. AB - Renin immunoreactivity was localized at the light and electron microscopic level in two elasmobranch fish species, the Atlantic stingray, Dasyatis sabina, and river ray, Potamotrygon humerosa. At the light microscopic level, the peroxidase anti-peroxidase method showed a positive immunoreactivity in modified smooth muscle cells in kidney afferent arterioles as well as in arterioles of several organs: rectal gland, inter-renal gland, conus arteriosus, and gill. Electron microscopic renin-positive immunogold localization was confined to the contents of membrane bound granules in the modified smooth muscle cells of these arterioles. The presence of renin-containing granules in the modified smooth muscle, "granular cells," of the renal glomerular afferent arteriole of these two stingray species adds support to earlier studies which showed the structural components of a complete juxtaglomerular apparatus and some of the biochemical and molecular components of a renin-angiotensin system (RAS) as found in teleost fish, reptiles, birds, and mammals. A notable result, however, was the renin positive immunoreaction in the arteriolar wall of all other organs studied here. The presence of this "diffuse renin system" in the connective tissue of various organs suggests that in these two stingray species in addition to local organ specific functions, the RAS may act as a systemic mechanism to regulate blood pressure and blood flow in the body. PMID- 26746847 TI - Long-term feeding a plant-based diet devoid of marine ingredients strongly affects certain key metabolic enzymes in the rainbow trout liver. AB - Incorporation of a plant blend in the diet can affect growth parameters and metabolism in carnivorous fish. We studied for the first time the long-term (1 year) metabolic response of rainbow trout fed from first feeding with a plant based diet totally devoid of marine ingredients. Hepatic enzymes were analyzed at enzymatic and molecular levels, at 3, 8 and 24 h after the last meal to study both the short-term effects of the last meal and long-term effects of the diet. The results were compared with those of fish fed a control diet of fish meal and fish oil. Growth, feed intake, feed efficiency and protein retention were lower in the group fed the plant-based diet. Glucokinase and pyruvate kinase activity were lower in the livers of trout fed the plant-based diet which the proportion of starch was lower than in the control diet. Glutamate dehydrogenase was induced by the plant-based diet, suggesting an imbalance of amino acids and a possible link with the lower protein retention observed. Gene expression of delta 6 desaturase was higher in fish fed the plant-based diet, probably linked to a high dietary level of linolenic acid and the absence of long-chain polyunsaturated fatty acids in vegetable oils. Hydroxymethylglutaryl-CoA synthase expression was also induced by plant-based diet because of the low rate of cholesterol in the diet. Changes in regulation mechanisms already identified through short-term nutritional experiments (<12 weeks) suggest that metabolic responses are implemented at short term and remain in the long term. PMID- 26746848 TI - Dim-light photoreceptor of chub mackerel Scomber japonicus and the photoresponse upon illumination with LEDs of different wavelengths. AB - To study the absorption characteristics of rhodopsin, a dim-light photoreceptor, in chub mackerel (Scomber japonicus) and the relationship between light wavelengths on the photoresponse, the rod opsin gene was cloned into an expression vector, pMT4. Recombinant opsin was transiently expressed in COS-1 cells and reconstituted with 11-cis-retinal. Cells containing the regenerated rhodopsin were solubilized and subjected to UV/Vis spectroscopic analysis in the dark and upon illumination. Difference spectra from the lysates indicated an absorption maximum of mackerel rhodopsin around 500 nm. Four types of light emitting diode (LED) modules with different wavelengths (red, peak 627 nm; cyan, 505 nm; blue, 442 nm; white, 447 + 560 nm) were constructed to examine their effects on the photoresponse in chub mackerel. Behavioral responses of the mackerels, including speed and frequencies acclimated in the dark and upon LED illumination, were analyzed using an underwater acoustic camera. Compared to an average speed of 22.25 +/- 1.57 cm/s of mackerel movement in the dark, speed increased to 22.97 +/- 0.29, 24.66 +/- 1.06, 26.28 +/- 2.28, and 25.19 +/- 1.91 cm/s upon exposure to red, blue, cyan, and white LEDs, respectively. There were increases of 103.48 +/- 1.58, 109.37 +/- 5.29, 118.48 +/- 10.82, and 109.43 +/- 3.92 %, respectively, in the relative speed of the fishes upon illumination with red, blue, cyan, and white LEDs compared with that in the dark (set at 100 %). Similar rate of wavelength-dependent responses was observed in a frequency analysis. These results indicate that an LED emitting a peak wavelength close to an absorption maximum of rhodopsin is more effective at eliciting a response to light. PMID- 26746844 TI - Insights into Group 2 Innate Lymphoid Cells in Human Airway Disease. AB - Recent discoveries have led to the identification of a novel group of immune cells, the innate lymphoid cells (ILCs). The members of this group are divided into three subpopulations: ILC1s, ILC2s, and ILC3s. ILC2s produce Th2 cytokines, IL-4, IL-5, and IL-13, upon activation by epithelial cell-derived cytokines, lipid mediators (cysteinyl leukotrienes and prostaglandin D2), and TNF family member TL1A and promote structural and immune cell responses in the airways after antigen exposure. In addition, ILC2 function is also influenced by inducible T cell costimulator (ICOS)/ICOS-ligand (ICOS-L) interactions via direct contact between immune cells. The most common airway antigens are allergens and viruses which are highly linked to the induction of airway diseases with underlying type 2 inflammation including asthma and allergic rhinitis. Based on recent findings linking ILC2s and airway Th2 responses, there is intensive investigation into the role of ILC2s in human disease with the hope of a better understanding of the pathophysiology and the discovery of novel potential therapeutic targets. This review summarizes the recent advances made in elucidating ILC2 involvement in human Th2 airway disease. PMID- 26746849 TI - Ceftolozane/Tazobactam: A Review in Complicated Intra-Abdominal and Urinary Tract Infections. AB - Globally, the increasing prevalence of multidrug-resistant pathogens continues to pose major problems in healthcare systems and, at least in part, is driving an initiative to develop new antibacterials, such as ceftolozane (a cephalosporin beta-lactam). Adding a beta-lactamase inhibitor (e.g. tazobactam) to a beta lactam extends its spectrum of activity against beta-lactamase-producing microorganisms (a key mechanism of resistance to beta-lactams). Ceftolozane/tazobactam (ZerbaxaTM), a beta-lactam/beta-lactamase inhibitor combination, is indicated for the treatment of adults with complicated intra abdominal infections (cIAI) or complicated urinary tract infections (cUTI), including pyelonephritis. In multinational, phase 3 noninferiority trials, intravenous ceftolozane/tazobactam was an effective and generally well tolerated treatment in patients with cIAI or cUTI. In the ASPECT-cIAI trial, ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in terms of clinical cure rates at the test-of-cure (TOC) visit, with clinical cure rates in subgroup analyses consistent with those in the primary analysis. In the ASPECT cUTI trial, ceftolozane/tazobactam was superior to levofloxacin in terms of composite cure rates (clinical cure plus microbiological eradiation) at the TOC visit. Further clinical experience should help to more definitively position ceftolozane/tazobactam in the treatment of cIAI and cUTI, including in patients with renal impairment. In the meantime, given its very good in vitro activity against extended-spectrum beta-lactamase-producing Enterobacteriaceae and drug resistant Pseudomonas aeruginosa isolates, ceftolozane/tazobactam provides a potential alternative to currently approved antibacterials for empirical treatment of cIAI and cUTI in adults. PMID- 26746850 TI - Comparative study of titrated oral misoprostol solution and vaginal dinoprostone for labor induction at term pregnancy. AB - OBJECTIVE: To evaluate effectiveness and safety of titrated oral misoprostol solution (OMS) in comparison with vaginal dinoprostone for cervix ripening and labor induction in term pregnant women. METHODS: A multicenter randomized controlled trial of women with term singleton pregnancy with indications for labor induction; 481 participants were allocated to receive titrated OMS with different doses by hourly administration according to the procedure or insert vaginal dinoprostone for cervix ripening and labor induction to compare maternal outcomes including indication of labor induction, mode of outcome of delivery, maternal morbidity, and neonatal outcomes between two groups for evaluating the efficacy and safety of titrated oral misoprostol induction. RESULT: Proportion of delivery within 12 h of titrated oral misoprostol is significantly less than vaginal dinoprostone (p = 0.03), but no difference of total vaginal delivery rate (p = 0.93); the mean time of first treatment to vaginal delivery was longer in OMS group (21.3 +/- 14.5 h) compared with the vaginal dinoprostone group (15.7 +/ 9.6 h). Although the proportion of cesarean section between the two groups showed no statistically significant difference, OMS group showed significantly lower frequency of uterine hyperstimulation, hypertonus, partus precipitatus and non-reassuring fetal heart rate than dinoprostone group. Neonatal outcomes were similar evaluating from Apgar score and NICU admission. Our study also showed that labor induction of women with cervix Bishop score <=3 needed increased dosage of misoprostol solution. CONCLUSION: Titrated OMS is as effective as vaginal dinoprostone in labor induction for term pregnant women, with safer effect for its lower rate of adverse effect for women. PMID- 26746852 TI - Agile CD22 nanoclusters run rings around fenced BCR. PMID- 26746851 TI - HDAC6 regulates cellular viral RNA sensing by deacetylation of RIG-I. AB - RIG-I is a key cytosolic sensor that detects RNA viruses through its C-terminal region and activates the production of antiviral interferons (IFNs) and proinflammatory cytokines. While posttranslational modification has been demonstrated to regulate RIG-I signaling activity, its significance for the sensing of viral RNAs remains unclear. Here, we first show that the RIG-I C terminal region undergoes deacetylation to regulate its viral RNA-sensing activity and that the HDAC6-mediated deacetylation of RIG-I is critical for viral RNA detection. HDAC6 transiently bound to RIG-I and removed the lysine 909 acetylation in the presence of viral RNAs, promoting RIG-I sensing of viral RNAs. Depletion of HDAC6 expression led to impaired antiviral responses against RNA viruses, but not against DNA viruses. Consequently, HDAC6 knockout mice were highly susceptible to RNA virus infections compared to wild-type mice. These findings underscore the critical role of HDAC6 in the modulation of the RIG-I mediated antiviral sensing pathway. PMID- 26746854 TI - A Cripavirus in the brown planthopper, Nilaparvata lugens. AB - A Cripavirus-like long unique sequence was identified during transcriptome sequencing of the brown planthopper (BPH), Nilaparvata lugens. This unique sequence demonstrated high similarity with the whole-genome sequence of cricket paralysis virus, including 5' and 3' untranslated regions; thus we considered it the whole genome of a new virus. We propose that the virus be named Nilaparvata lugens C virus (NlCV). The plus-strand RNA genome spanned 9144 nt, excluding a 3' poly(A) tail with two large ORFs encoding structural and non-structural proteins, respectively. Detection of NlCV in BPH honeydew raised the hypothesis of horizontal transmission of the virus. Honeydew from viruliferous BPHs was used to feed non-viruliferous insects, the results of which indicated that the BPH could acquire NlCV through feeding and that the virus could multiply in the insect body. A tissue-specific distribution test using real-time quantitative PCR demonstrated that NlCV was mainly present in the reproductive organs, and the virus was detected in eggs laid by viruliferous female insects using nested PCR, indicating the possibility of vertical transmission as well. As no significant symptom was detected in the viruliferous BPH, NlCV is considered a new commensal virus of BPH. Interestingly, this virus was also detected in two other hemipteran insects, the white-backed planthopper and the horned gall aphid, indicating that NlCV might be present in many other hemipteran insects and have a wide host range. PMID- 26746855 TI - 50 Years of Research and Discovery in Chronic Kidney Disease and Mineral & Bone Disorder: The Central Role of Phosphate. PMID- 26746853 TI - Change of concept about the regulation of angiotensin II-induced monocyte chemoattractant protein-1 production in human endothelial cells. AB - AIMS: Some intriguing clinical observations about the anti-inflammatory effects of angiotensin type 1 (AT1) receptor blockers and angiotensin converting enzyme inhibitors in cardiovascular patients brought us to study the signalling pathways which lead to angiotensin II (ANG)-induced monocyte chemoattractant protein-1 (MCP-1) production in human endothelial cells. METHODS: MCP-1 production in human umbilical vein endothelial cells (HUVECs) under treatments with ANG, AT1 and angiotensin type 2 (AT2) receptor blockers and pravastatin was measured by ELISA. The expression of AT1 and AT2 receptors and NADPH oxidase catalytic subunits (NOX 1-5) was analysed at mRNA and protein levels. Nuclear factor-kappa B (NF-kappaB) activation was studied by p65 subunit translocation to the cellular nucleus. Cell viability was tested by the MTT method. Nox4 subcellular distribution was analysed by subcellular protein fractionation and by immunoprecipitation followed by matrix-assisted laser desorption/ionization mass spectrometry analysis. RESULTS: ANG-induced MCP-1 production was mediated by AT2 receptor, but not AT1 receptor in HUVECs in culture, which in turn activated NF-kappaB, promoting p65 subunit translocation to the nucleus. Reactive oxygen species produced by NADPH oxidase participated in this activation, mainly by the Nox4 subunit, ubiquitously expressed in all the compartments of HUVECs. Pravastatin inhibited ANG-induced MCP-1 production. CONCLUSIONS: Our results support that ANG-induced MCP-1 production in HUVECs is mediated by AT2 instead AT1 receptor activation, which in turn activates NF-kappaB involving reactive oxygen species produced by the NADPH oxidase complex. Statins can also block ANG-induced MCP-1 production, probably by their inhibitory effects on NADPH oxidase activity. PMID- 26746856 TI - Bone: from a reservoir of minerals to a regulator of energy metabolism. AB - Besides locomotion, organ protection, and calcium-phosphorus homeostasis, the three classical functions of the skeleton, bone remodeling affects energy metabolism through uncarboxylated osteocalcin, a recently discovered hormone secreted by osteoblasts. This review traces how energy metabolism affects osteoblasts through the central control of bone mass involving leptin, serotoninergic neurons, the hypothalamus, and the sympathetic nervous system. Next, the role of osteocalcin (insulin secretion, insulin sensitivity, and pancreas beta-cell proliferation) in the regulation of energy metabolism is described. Then, the connections between insulin signaling on osteoblasts and the release of uncarboxylated osteocalcin during osteoclast bone resorption through osteoprotegerin are reported. Finally, the understanding of this new bone endocrinology will provide some insights into bone, kidney, and energy metabolism in patients with chronic kidney disease. PMID- 26746857 TI - Phosphate and Klotho. AB - Klotho is a putative aging suppressor gene encoding a single-pass transmembrane co-receptor that makes the fibroblast growth factor (FGF) receptor specific for FGF-23. In addition to multiple endocrine organs, Klotho is expressed in kidney distal convoluted tubules and parathyroid cells, mediating the role of FGF-23 in bone-kidney-parathyroid control of phosphate and calcium. Klotho(-/-)mice display premature aging and chronic kidney disease-associated mineral and bone disorder (CKD-MBD)-like phenotypes mediated by hyperphosphatemia and remediated by phosphate-lowering interventions (diets low in phosphate or vitamin D; knockouts of 1alpha-hydroxylase, vitamin D receptor, or NaPi cotransporter). CKD can be seen as a state of hyperphosphatemia-induced accelerated aging associated with Klotho deficiency. Humans with CKD experience decreased Klotho expression as early as stage 1 CKD; Klotho continues to decline as CKD progresses, causing FGF 23 resistance and provoking large FGF-23 and parathyroid hormone increases, and hypovitaminosis D. Secreted Klotho protein, formed by extracellular clipping, exerts FGF-23-independent phosphaturic and calcium-conserving effects through its paracrine action on the proximal and distal tubules, respectively. We contend that decreased Klotho expression is the earliest biomarker of CKD and the initiator of CKD-MBD pathophysiology. Maintaining normal phosphate levels with phosphate binders in patients with CKD with declining Klotho expression is expected to reduce mineral and vascular derangements. PMID- 26746858 TI - Phosphate and FGF-23. AB - Fibroblast growth factor (FGF)-23 is probably the most important regulator of serum phosphate and calcitriol (1,25(OH)2D3) levels. It is secreted by osteocytes and osteoblasts in response to oral phosphate loading or increased serum 1,25(OH)2D3 levels. In human chronic kidney disease (CKD), plasma FGF-23 appears to be a sensitive biomarker of abnormal renal phosphate handling, as FGF-23 levels increase during early stages of kidney malfunction. In humans and animals with CKD, elevated FGF-23 levels increase fractional phosphate excretion, reduce serum phosphate levels, and reduce 1alpha-hydroxylase activity, which reduces 1,25(OH)2D3 formation thereby increasing parathyroid hormone (PTH) secretion. FGF 23 thus has a key adaptive role in maintaining normophosphatemia. Plasma FGF-23 continues to increase as CKD progresses, increasing by orders of magnitude in end stage renal disease. At the same time, responsiveness to FGF-23 declines as the number of intact nephrons declines, which is associated with reduced expression of Klotho, the co-receptor required for FGF-23 signaling. In late CKD, FGF-23 cannot reduce serum phosphate levels, and abnormally high plasma FGF-23 concentrations appear to exert unwarranted off-target effects, including left ventricular hypertrophy, faster CKD progression, and premature mortality. Lowering serum phosphate levels through the use of oral phosphate binders and/or long-acting PTH agents may reduce FGF-23 levels in early CKD stages, thereby limiting off-target effects, which may improve patient outcomes. PMID- 26746859 TI - The intact nephron hypothesis: the concept and its implications for phosphate management in CKD-related mineral and bone disorder. AB - Mechanistic understanding of secondary hyperparathyroidism, vascular calcification, and regulation of phosphate metabolism in chronic kidney disease (CKD) has advanced significantly in the past five decades. In 1960, Bricker developed the 'intact nephron hypothesis', opening the door for hundreds of investigations. He emphasized that 'as the number of functioning nephrons decreases, each remaining nephron must perform a greater fraction of total renal excretion'. Phosphate per se, independent of Ca(2+) and calcitriol, directly affects the development of parathyroid gland hyperplasia and secondary hyperparathyroidism. Vitamin D receptor, Ca(2+) sensing receptor, and Klotho fibroblast growth factor (FGF) receptor-1 complex are all significantly decreased in the parathyroid glands of patients with CKD. Duodenal instillation of phosphate rapidly decreases parathyroid hormone release without changes in calcium or calcitriol. The same procedure also rapidly increases renal phosphate excretion independently of FGF-23, suggesting the possibility of an 'intestinal phosphatonin'. These observations suggest a possible 'phosphate sensor' in the parathyroid glands and gastrointestinal tract, although as yet there is no proof for the existence of such a sensor. Evidence shows that phosphate has a key role in parathyroid hyperplasia by activating the transforming growth factor-alpha epidermal growth factor receptor complex. Thus, control of serum phosphorus early in the course of CKD will significantly ameliorate the pathological manifestations observed during progressive deterioration of renal function. PMID- 26746860 TI - Cardiovascular risk factors in chronic kidney disease: does phosphate qualify? AB - Risk factors for disease states are rigorously defined. This analysis considers the definition of a risk factor as applied to the question of whether the serum phosphorus level is a risk factor for cardiovascular disease. Observational studies strongly suggest that phosphorus is associated with cardiovascular risk, and definitive prospective animal studies are supportive. A plausible mechanism of action has been discovered demonstrating that phosphorus stimulates osteoblastic transition of cells in the neointima of atherosclerotic plaques, which, if prevented, blocks vascular calcification. However, prospective studies demonstrating that modulation of the putative risk factor affects clinical outcomes are lacking, and phosphorus, as yet, does not qualify as a cardiovascular risk factor. This is a clarion call for additional research. PMID- 26746861 TI - Relaxin in paraventricular nucleus contributes to sympathetic overdrive and hypertension via PI3K-Akt pathway. AB - Relaxin is recognized as an ovarian polypeptide hormone. Abundant relaxin binding sites are observed in hypothalamic paraventricular nucleus (PVN). This study was conducted to determine the roles and underlying mechanisms of relaxin in the PVN in sympathetic activation and hypertension in spontaneously hypertensive rats (SHR). Experiments were performed in normotensive Wistar-Kyoto rats (WKY) and SHR. Relaxin and its RXFP1 receptors in PVN were up-regulated in SHR. Relaxin positive neurons existed in both parvocellular and magnocellular parts of the PVN. Presympathetic neurons and AVP neurons in the PVN expressed RXFP1, but not relaxin. Bilateral PVN microinjection of human relaxin-2 increased but anti relaxin IgG reduced renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), plasma norepinephrine (NE) and arginine vasopressin (AVP) levels in SHR. The effects of relaxin-2 on RSNA and MAP were abolished by intravenous infusion of ganglionic blocker hexamethonium, and attenuated by AVP V1 receptor antagonist AAVP. Akt phosphorylation was enhanced in SHR, and relaxin-2 stimulated Akt phosphorylation and p85alpha subunit of PI3K expression. PI3K inhibitor LY294002 or Akt inhibitor MK-2206 abolished the effects of relaxin-2 on the RSNA, MAP and plasma NE, and attenuated the relaxin-2-induced AVP secretion. STAT5a and polymerase II (Pol II) binding to relaxin-promoter were significantly increased in SHR. Chronic PVN infusion of relaxin-2 with osmotic pumps in normal rats induced sympathetic activation, AVP secretion and hypertension accompanied with cardiovascular remodeling. Relaxin in the PVN contributes to sympathetic overdrive and hypertension via PI3K-Akt pathway. PMID- 26746862 TI - The interactive effects of negative symptoms and social role functioning on suicide ideation in individuals with schizophrenia. AB - Findings regarding the protective effect of social role functioning on suicide ideation in individuals with schizophrenia have been mixed. One reason for such inconsistencies in the literature may be that individuals with prominent negative symptoms of schizophrenia may not experience a desire for social closeness, and therefore social role functioning may not influence suicide risk in these individuals. The aim of this study was to examine the moderating effects of self reported desire for social closeness and interviewer-rated negative symptoms on the relationship between social role functioning and suicide ideation. Our sample consisted of 162 individuals who had been diagnosed with schizophrenia-spectrum disorders; all participants completed self-report questionnaires and clinician administered interviews, and moderation hypotheses were tested with a non parametric procedure. The results indicated that motivation and pleasure-related negative symptoms moderated the relationship between social role functioning and suicide ideation; self-reported desire for social closeness and negative symptoms related to expression did not have such a moderating effect. Specifically, better social role functioning was associated with less suicide ideation only in those individuals who had low motivation and pleasure-related negative symptoms; no significant relationship was observed between social role functioning and suicide ideation among those with elevated motivation and pleasure-related negative symptoms. These findings suggest that assessing for negative symptoms and social role functioning may inform suicide risk assessments in individuals with schizophrenia, and improving social role functioning may reduce suicide ideation among those with few motivation and pleasure-related negative symptoms. PMID- 26746863 TI - Immunoreactivities of IL-1beta and IL-1R in oviduct of Chinese brown frog (Rana dybowskii) during pre-hibernation and the breeding period. AB - The Chinese brown frog (Rana dybowskii) has one special physiological phenomenon, which is that its oviduct goes through expansion prior to hibernation instead of during the breeding period. In this study, we investigated the localization and expression level of interleukin-1 (IL-1beta) and its functional membrane receptor type I (IL1R1) proteins in the oviduct of R. dybowskii during pre-hibernation and the breeding period. There were significant differences in both oviductal weight and pipe diameter, with values markedly higher in pre-hibernation than in the breeding period. Histologically, epithelium cells, glandular cells and tubule lumen were identified in the oviduct during pre-hibernation and the breeding period, while sizes of both cell types are larger in the pre-hibernation than those of the breeding period. IL-1beta was immunolocalized in the cytoplasm of epithelial and glandular cells in both periods, whereas IL-1R1 was observed in the membrane of epithelial and glandular cells in the breeding period, whereas only in epithelial cells during pre-hibernation. Consistently, the protein levels of IL-1beta and IL-1R1 were higher in pre-hibernation as compared to the breeding period. These results suggested that IL-1beta may play an important autocrine or paracrine role in oviductal cell proliferation and differentiation of R. dybowskii. PMID- 26746864 TI - Neuronal HIF-1alpha and HIF-2alpha deficiency improves neuronal survival and sensorimotor function in the early acute phase after ischemic stroke. AB - Hypoxia-inducible factors mediate adaptive responses to ischemia, among others, by induction of anti- and pro-survival genes. Thus, the impact of HIF on neuronal survival upon stroke is controversial. Therefore, neuron-specific knockout mice deficient for Hif1a and Hif2a were exposed to inspiratory hypoxia or ischemia reperfusion injury. Both Hif1a- and Hif2a-deficient mice showed no altered infarct and edema size, suggesting that both HIF-alpha subunits might compensate for each other. Accordingly, hypoxic HIF-target gene regulation was marginally affected with exception of anti-survival Bnip3 and pro-survival erythropoietin. In the early acute stage upon stroke, Hif1a/Hif2a double knockout mice exhibited significantly reduced expression of the anti-survival Bnip3, Bnip3L, and Pmaip1 Accordingly, global cell death and edema were significantly reduced upon 24 h but not 72 h reperfusion. Behavioral assessment indicated that Hif1a/Hif2a-deficient mice initially performed better, but became significantly more impaired after 72 h accompanied by increased apoptosis and reduced angiogenesis. Our findings suggest that in neurons HIF-1 and HIF-2 have redundant functions for cellular survival under ischemic conditions. By contrast, lack of anti-survival factors in Hif1a/Hif2a-deficient mice might protect from early acute neuronal cell death and neurological impairment, indicating a benefit of HIF-pathway inhibition in neurons in the very acute phase after ischemic stroke. PMID- 26746865 TI - Neuroprotective effects of adenosine deaminase in the striatum. AB - Adenosine deaminase (ADA) is a ubiquitous enzyme that catabolizes adenosine and deoxyadenosine. During cerebral ischemia, extracellular adenosine levels increase acutely and adenosine deaminase catabolizes the increased levels of adenosine. Since adenosine is a known neuroprotective agent, adenosine deaminase was thought to have a negative effect during ischemia. In this study, however, we demonstrate that adenosine deaminase has substantial neuroprotective effects in the striatum, which is especially vulnerable during cerebral ischemia. We used temporary oxygen/glucose deprivation (OGD) to simulate ischemia in rat corticostriatal brain slices. We used field potentials as the primary measure of neuronal damage. For stable and efficient electrophysiological assessment, we used transgenic rats expressing channelrhodopsin-2, which depolarizes neurons in response to blue light. Time courses of electrically evoked striatal field potential (eFP) and optogenetically evoked striatal field potential (optFP) were recorded during and after oxygen/glucose deprivation. The levels of both eFP and optFP decreased after 10 min of oxygen/glucose deprivation. Bath-application of 10 ug/ml adenosine deaminase during oxygen/glucose deprivation significantly attenuated the oxygen/glucose deprivation-induced reduction in levels of eFP and optFP. The number of injured cells decreased significantly, and western blot analysis indicated a significant decrease of autophagic signaling in the adenosine deaminase-treated oxygen/glucose deprivation slices. These results indicate that adenosine deaminase has protective effects in the striatum. PMID- 26746866 TI - Cerebroprotection by the neuronal PGE2 receptor EP2 after intracerebral hemorrhage in middle-aged mice. AB - Inflammatory responses mediated by prostaglandins such as PGE2 may contribute to secondary brain injury after intracerebral hemorrhage (ICH). However, the cell specific signaling by PGE2 receptor EP2 differs depending on whether the neuropathic insult is acute or chronic. Using genetic and pharmacologic approaches, we investigated the role of EP2 receptor in two mouse models of ICH induced by intrastriatal injection of collagenase or autologous arterial whole blood. We used middle-aged male mice to enhance the clinical relevance of the study. EP2 receptor was expressed in neurons but not in astrocytes or microglia after collagenase-induced ICH. Brain injury after collagenase-induced ICH was associated with enhanced cellular and molecular inflammatory responses, oxidative stress, and matrix metalloproteinase (MMP)-2/9 activity. EP2 receptor deletion exacerbated brain injury, brain swelling/edema, neuronal death, and neurobehavioral deficits, whereas EP2 receptor activation by the highly selective agonist AE1-259-01 reversed these outcomes. EP2 receptor deletion also exacerbated brain edema and neurologic deficits in the blood ICH model. These findings support the premise that neuronal EP2 receptor activation by PGE2 protects brain against ICH injury in middle-aged mice through its anti inflammatory and anti-oxidant effects and anti-MMP-2/9 activity. PGE2/EP2 signaling warrants further investigation for potential use in ICH treatment. PMID- 26746869 TI - Abstracts--HCV infection and disease, APASL STC Conference, Dec 18-20, New Delhi. PMID- 26746868 TI - Persistent Macular Thickening After Ranibizumab Treatment for Diabetic Macular Edema With Vision Impairment. AB - IMPORTANCE: The prevalence of persistent diabetic macular edema (DME) after months of anti-vascular endothelial growth factor therapy and its effect on visual acuity are unknown. OBJECTIVE: To assess subsequent outcomes of eyes with DME persisting for 24 weeks after initiating treatment with 0.5 mg of ranibizumab. DESIGN, SETTING, AND PARTICIPANTS: We performed post hoc, exploratory analyses of a randomized clinical trial from March 20, 2007, through January 29, 2014, from 117 of 296 eyes (39.5%) randomly assigned to receive ranibizumab with persistent DME (central subfield thickness >=250 MUm on time domain optical coherence tomography) through the 24-week visit. INTERVENTIONS: Four monthly intravitreous injections of ranibizumab and then as needed per protocol. MAIN OUTCOMES AND MEASURES: Cumulative 3-year probabilities of chronic persistent DME (failure to achieve a central subfield thickness <250 MUm and at least a 10% reduction from the 24-week visit on at least 2 consecutive study visits) determined by life-table analyses, and at least 10 letter (>=2 line) gain or loss of visual acuity among those eyes. RESULTS: The probability of chronic persistent DME among eyes with persistent DME at the 24-week visit decreased from 100% at the 32-week visit to 81.1% (99% CI, 69.6%-88.6%), 55.8% (99% CI, 42.9% 66.9%), and 40.1% (99% CI, 27.4%-52.4%) at the 1-, 2-, and 3-year visits, respectively. At 3 years, visual acuity improved in eyes with and without chronic persistent DME through the follow-up period, respectively, by a mean of 7 letters and 13 letters from baseline. Among 40 eyes with chronic persistent edema through 3 years, 17 (42.5%) (99% CI, 23.1%-63.7%) gained 10 letters or more from baseline, whereas 5 (12.5%) (99% CI, 2.8%-31.5%) lost 10 letters or more from baseline. CONCLUSIONS AND RELEVANCE: These data suggest less than half of eyes treated for DME with intravitreous ranibizumab have persistent central-involved DME through 24 weeks after initiating treatment. Among the 40% that then have chronic persistent central-involved DME through 3 years, longer-term visual acuity outcomes appear to be slightly worse than in the 60% in which DME does not persist. Nevertheless, when following the treatment protocol used in this trial among eyes with vision impairment from DME, long-term improvement in visual acuity from baseline is typical and substantial (>=2-line) loss of visual acuity is likely uncommon through 3 years, even when central-involved DME chronically persists. PMID- 26746871 TI - Variability in DXA Reporting and Other Challenges in Osteoporosis Evaluation. PMID- 26746867 TI - Magnetic Resonance investigation into the mechanisms involved in the development of high-altitude cerebral edema. AB - Rapid ascent to high altitude commonly results in acute mountain sickness, and on occasion potentially fatal high-altitude cerebral edema. The exact pathophysiological mechanisms behind these syndromes remain to be determined. We report a study in which 12 subjects were exposed to a FiO2 = 0.12 for 22 h and underwent serial magnetic resonance imaging sequences to enable measurement of middle cerebral artery velocity, flow and diameter, and brain parenchymal, cerebrospinal fluid and cerebral venous volumes. Ten subjects completed 22 h and most developed symptoms of acute mountain sickness (mean Lake Louise Score 5.4; p < 0.001 vs. baseline). Cerebral oxygen delivery was maintained by an increase in middle cerebral artery velocity and diameter (first 6 h). There appeared to be venocompression at the level of the small, deep cerebral veins (116 cm3 at 2 h to 97 cm3 at 22 h; p < 0.05). Brain white matter volume increased over the 22-h period (574 ml to 587 ml; p < 0.001) and correlated with cumulative Lake Louise scores at 22 h (p < 0.05). We conclude that cerebral oxygen delivery was maintained by increased arterial inflow and this preceded the development of cerebral edema. Venous outflow restriction appeared to play a contributory role in the formation of cerebral edema, a novel feature that has not been observed previously. PMID- 26746870 TI - Carbon dioxide receptor genes and their expression profile in Diabrotica virgifera virgifera. AB - BACKGROUND: Diabrotica virgifera virgifera, western corn rootworm, is one of the most devastating species in North America. D. v. virgifera neonates crawl through the soil to locate the roots on which they feed. Carbon dioxide (CO2) is one of the important volatile cues that attract D. v. virgifera larvae to roots. RESULTS: In this study, we identified three putative D. v. virgifera gustatory receptor genes (Dvv_Gr1, Dvv_Gr2, and Dvv_Gr3). Phylogenetic analyses confirmed their orthologous relationships with known insect CO2 receptor genes from Drosophila, mosquitoes, and Tribolium. The phylogenetic reconstruction of insect CO2 receptor proteins and the gene expression profiles were analyzed. Quantitative analysis of gene expression indicated that the patterns of expression of these three candidate genes vary among larval tissues (i.e., head, integument, fat body, and midgut) and different development stages (i.e., egg, three larval stages, adult male and female). CONCLUSION: The Dvv_Gr2 gene exhibited highest expression in heads and neonates, suggesting its importance in allowing neonate larvae to orient to its host plant. Similar expression patterns across tissues and developmental stages for Dvv_Gr1 and Dvv_Gr3 suggest a potentially different role. Findings from this study will allow further exploration of the functional role of specific CO2 receptor proteins in D. v. virgifera. PMID- 26746872 TI - The Purdue Pegboard test: normative data for older adults with low vision. AB - Purpose The usability of assistive technologies depends, in part, on the user's ability to manipulate the device. In the context of aging and visual impairment, the visibility of any device and its components becomes crucial, and often users rely on tactile information in order to overcome visibility barriers. The purpose of this study was to establish performance norms for older adults with low vision on a common measure of manual dexterity: the Purdue Pegboard Test. Method The Purdue Pegboard was completed visually with the dominant, non-dominant and both hands by 134 older adults (age 60-97) with various levels of low vision, ranging from 20/30 to 20/604 in the better eye. Results Scores decreased significantly as age increased. In addition, performance using the dominant hand was generally best. Compared to previously published values, scores were lower than the norms for healthy older adults as well as those for younger visually impaired individuals. Conclusions The present values for older adults with low vision add to the already existing standards and allow for comparison among future studies with this population. Systematic examination of manual dexterity in low vision clients will enable rehabilitation specialists to make more informed recommendations in terms of usable low-vision devices. Implications for rehabilitation Older adults with visual impairment often rely on tactile cues when using assistive devices. The Purdue Pegboard provides a systematic evaluation of manual dexterity, whereby age norms exist for older adults and for visually impaired younger adults. We present normative data on the Purdue Pegboard test for older adults with low vision in order to facilitate comparison of performance. Systematic evaluation of manual dexterity will inform whether some assistive devices are suitable for older adults with a visual impairment. PMID- 26746874 TI - Rethinking Attention-Deficit/Hyperactivity Disorder. PMID- 26746873 TI - A national research agenda for pre-hospital emergency medical services in the Netherlands: a Delphi-study. AB - BACKGROUND: In pre-hospital Emergency Medical Services (EMS) more research is needed to direct and underpin care delivery and inform policy. To target future research efforts, this study aimed to determine future research priorities with representatives of the EMS field. METHODS: A four-round online Delphi survey was used to discuss different viewpoints and reach consensus on research priorities. A multidisciplinary panel of experts was recruited in the field of pre-hospital EMS and adjoining (scientific) professional organisations (n = 62). 48 research topics were presented in Delphi I, and the panel was asked to rate their importance on a 5-point scale. In Delphi II and III the panel selected their priority research topics, and arguments why and suggestions for research questions were collected and reported back. In Delphi IV appropriateness of the remaining topics and agreement within the expert panel was taken into account to make up the final list of research priorities. RESULTS: The response on the Delphi-survey was high: 95% (n = 59; Delphi I); 97% (n = 60, Delphi II); 94% (n = 58, Delphi III); 97% (n = 60, Delphi IV). The panel reduced the number of research topics from 48 topics in Delphi I to 12 topics in Delphi III. A variety of arguments and suggestions for research questions were collected, giving insight in reasons why research on these topics in the near future is needed. Delphi IV showed an adequate level of agreement with respect to the 12 presented research topics. The following 9 topics were rated as appropriate for the national pre-hospital EMS research agenda: Non-conveyance to the hospital (ranked highest); Performance measures for quality of care; Hand over/registration/exchange of patient data; Care and task substitution; Triage; Assessment of acute neurologic signs & symptoms; Protocols and protocol adherence; Immobilisation; and Open/secure airway. DISCUSSIONS: The research priorities identified in our study resemble those in other studies. However, the topic 'non-conveyance to the hospital' was determined as a priority in this study but not in other studies. CONCLUSIONS: The national pre-hospital EMS research agenda can focus future research efforts to improve the evidence base and clinical practice of pre-hospital emergency medical services. Dissemination and implementation of the research agenda deserves careful attention. PMID- 26746875 TI - A comparison of form processing involved in the perception of biological and nonbiological movements. AB - Although there is evidence for specialization in the human brain for processing biological motion per se, few studies have directly examined the specialization of form processing in biological motion perception. The current study was designed to systematically compare form processing in perception of biological (human walkers) to nonbiological (rotating squares) stimuli. Dynamic form-based stimuli were constructed with conflicting form cues (position and orientation), such that the objects were perceived to be moving ambiguously in two directions at once. In Experiment 1, we used the classification image technique to examine how local form cues are integrated across space and time in a bottom-up manner. By comparing with a Bayesian observer model that embodies generic principles of form analysis (e.g., template matching) and integrates form information according to cue reliability, we found that human observers employ domain-general processes to recognize both human actions and nonbiological object movements. Experiments 2 and 3 found differential top-down effects of spatial context on perception of biological and nonbiological forms. When a background does not involve social information, observers are biased to perceive foreground object movements in the direction opposite to surrounding motion. However, when a background involves social cues, such as a crowd of similar objects, perception is biased toward the same direction as the crowd for biological walking stimuli, but not for rotating nonbiological stimuli. The model provided an accurate account of top-down modulations by adjusting the prior probabilities associated with the internal templates, demonstrating the power and flexibility of the Bayesian approach for visual form perception. PMID- 26746877 TI - ICU Deaths in Patients With Advanced Cancer. AB - BACKGROUND: A significant number of advanced cancer admissions to the intensive care unit (ICU) are inappropriate in that they do not result in prolonged survival. No clear consensus criteria for reasonable admissions of advanced cancer patients have been developed. METHOD: We established four criteria for reasonable admissions to ICU in patients who suffered from advanced, incurable cancer: post procedure complication, recent notification of cancer, ECOG performance status of 0-1, and life expectancy of more than 6 months. Based on these criteria, we reviewed the charts of all patients who died in the ICU at the University of Tennessee Health Science Center (UTHSC) affiliated Veteran's Affairs Medical Center between 10/2005 and 10/2010. We identified patients with advanced, incurable cancer and performed an in depth review of their charts. RESULTS: In the 421 charts of patients who died in our ICU between October 2005 and October 2010 we identified 52 patients admitted to the ICU with advanced, incurable cancer. 14 patients were diagnosed with cancer one month or less prior to admission. 21 patients had ECOG performance status of 0-1. 14 patients had life expectancy of more than 6 months and 8 patients were admitted for post procedure complication. 47% of patients who did not satisfy any of our reasonable admission criteria had APDs. CONCLUSIONS: Incorporating proposed admission criteria in ICU admission guidelines may prevent 37% of inappropriate, advanced cancer admissions to the ICU. A simple increase in numbers of APDs would not likely change significantly the numbers of inappropriate ICU admissions. PMID- 26746878 TI - An Observational Study to Explore the Feasibility of Assessing Bereaved Relatives' Experiences Before and After a Quality Improvement Project to Improve Care of Dying Medical Inpatients. AB - Although hospitals are the most likely place of death, the quality of care received by dying inpatients remains variable. This is concerning for both the dying person and their relatives, with poorer bereavement outcomes likely for those who perceived their family member suffered unduly. There is a real need to consider how this situation can be improved. This work was conducted with the aim of exploring the feasibility of including bereaved relatives' experiences as part of a larger project exploring the use of a care bundle to improve care of the dying inpatients. Fifty relatives of inpatients who had died previously in hospital were contacted by letter with a request for interview before the implementation of a care bundle for the dying, with a care bundle being a collection of care processes that are implemented together. After this project had been in place for 6 months, a further 50 families were contacted who had died on the bundle. Ten families responded initially to the first request and 10 the second, with the interviews based on the Quality of Dying and Death (QODD) tool and a final open-ended question. Although all families who agree to be interviewed completed the session, with regard to the QODD, some families indicated that they would rather talk than provide numeric scores. No major differences in the prescores and postscores were noted. When invited to share their experiences, without prompting, families spoke of consistent concerns that included communication, place of death, and symptom control. This work confirms that it is highly feasible to incorporate assessments of bereaved family members' opinions as part of the wider assessment of research into end-of-life care. PMID- 26746876 TI - Efficacy of the Lunch is in the Bag intervention to increase parents' packing of healthy bag lunches for young children: a cluster-randomized trial in early care and education centers. AB - BACKGROUND: Lunches that parents pack for their young children to eat at school or the Early Care and Education (ECE) center fall short of recommended standards. Lunch is in the Bag is a multi-level behavioral nutrition intervention to increase parents' packing of fruit, vegetables, and whole grains in their children's lunches. Designed for implementation in ECE centers, the five-week long intervention is followed three months later with a one-week booster. METHODS: Efficacy of Lunch is in the Bag was tested in cluster randomized trial. Participants were 633 families from 30 ECE centers (15 intervention, 15 control) across Austin, San Antonio, and Houston, Texas, USA. Primary outcomes were servings of fruit, vegetables, and whole grains observed in the children's parent packed bag lunches. Servings of refined grains, meats/beans/eggs/nuts, dairy, chips, and sweets also were observed. Data were collected at baseline, post intervention (6-week follow-up), pre-booster (22-weeks follow-up), and post booster (28-week follow-up). Time-by-treatment interactions were analyzed separately for each of the food groups using multi-level models to compare changes from baseline. Analyses were adjusted for relevant demographic variables and clustering within centers and parents. RESULTS: The intervention effected increases from baseline to 6-week follow-up in vegetables (0.17 servings, SE = 0.04, P < 0.001) and whole grains (0.30 servings, SE = 0.13, P = 0.018). The increase in whole grains was maintained through the 28-week follow-up (0.34 servings, SE = 0.13, P = 0.009). Fruit averaged more than 1.40 servings with no differences between groups or across time. The intervention prevented increase in sweets (-0.43 servings, SE = 0.11, P < .001, at the 22-week follow-up). Parents persisted, however, in packing small amounts of vegetables (averages of 0.41 to 0.52 servings) and large amounts of sweets and chips (averages of 1.75 to 1.99 servings). CONCLUSIONS: The need for and positive effects of the Lunch is in the Bag intervention at ECE centers where parents send bag lunch for their preschool aged children was confirmed. An important direction for future research is discovery of more options for leveraging the partnership of ECE centers and families to help young children learn to eat and enjoy vegetables and other healthy foods in preference to less healthy choices such as chips and sweets. TRIAL REGISTRATION: The Clinical Trials Number is NCT01292434 . PMID- 26746879 TI - Interrupting Ebola Transmission in Liberia Through Community-Based Initiatives. PMID- 26746881 TI - Palladium-Catalyzed Decarboxylative Acylation of N-Nitrosoanilines with alpha Oxocarboxylic Acids. AB - A palladium-catalyzed oxidative C-H bond decarboxylative acylation of N nitrosoanilines using alpha-oxocarboxylic acid as the acyl source is described. The catalyst Pd(OAc)2 and oxidant (NH4)2S2O8 enabled ortho-acylation of N nitrosoanilines at room temperature, affording an array of N-nitroso-2 aminobenzophenones in moderate to excellent yields. PMID- 26746880 TI - Dopamine, Striatum, Antipsychotics, and Questions About Weight Gain. PMID- 26746882 TI - Characterization of Breast Implant Surfaces, Shapes, and Biomechanics: A Comparison of High Cohesive Anatomically Shaped Textured Silicone, Breast Implants from Three Different Manufacturers. AB - Several companies offer anatomically shaped breast implants but differences among manufacturers are often misunderstood. The shell texture is a crucial parameter for anatomically shaped implants to prevent rotation and to decrease the risk of capsular contracture, even though concerns have recently been raised concerning the complications associated with textured breast implants. The aim of this study was to characterize differences in terms of texture, cell adhesion, shape, and stiffness between some commonly used anatomically shaped implants from three different manufacturers. METHODS: Five commercially available anatomically shaped breast implants from 3 different manufacturers (Allergan, Mentor, and Sebbin) were used. Scanning electron microscopy, X-ray microtomography, and scanning mechanical microscopy were used to characterize the shell texture. Human fibroblast adhesion onto the shells was evaluated. 3D models of the implants were obtained using CT-scan acquisitions to analyze their shape. Implant stiffness was evaluated using a tractiometer. RESULTS: Major differences were observed in the topography of the textures of the shells, but this was not conveyed by a statistically significant fibroblast adhesion difference. However, fibroblasts adhered better on anatomically shaped textured implants than on smooth implants (p < 0.01). Our work pointed out differences in the Biocell(r) texture in comparison with older studies. The 3D analysis showed significant shape differences between the anatomically shaped implants of the 3 companies, despite similar dimensions. Implant stiffness was comparable among the 3 brands. CONCLUSIONS: Each texture had its specific topography, and this work is the first description of Sebbin anatomic breast implant texturation. Moreover, major discrepancies were found in the analysis of the Biocell(r) texture when comparing our results with previous reports. These differences may have clinical implications and are discussed. This study also highlighted major shape differences among breast implants from different manufacturers, which is quite counterintuitive. The clinical impact of these differences however needs further investigation. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26746883 TI - Predicting the growth of glioblastoma multiforme spheroids using a multiphase porous media model. AB - Tumor spheroids constitute an effective in vitro tool to investigate the avascular stage of tumor growth. These three-dimensional cell aggregates reproduce the nutrient and proliferation gradients found in the early stages of cancer and can be grown with a strict control of their environmental conditions. In the last years, new experimental techniques have been developed to determine the effect of mechanical stress on the growth of tumor spheroids. These studies report a reduction in cell proliferation as a function of increasingly applied stress on the surface of the spheroids. This work presents a specialization for tumor spheroid growth of a previous more general multiphase model. The equations of the model are derived in the framework of porous media theory, and constitutive relations for the mass transfer terms and the stress are formulated on the basis of experimental observations. A set of experiments is performed, investigating the growth of U-87MG spheroids both freely growing in the culture medium and subjected to an external mechanical pressure induced by a Dextran solution. The growth curves of the model are compared to the experimental data, with good agreement for both the experimental settings. A new mathematical law regulating the inhibitory effect of mechanical compression on cancer cell proliferation is presented at the end of the paper. This new law is validated against experimental data and provides better results compared to other expressions in the literature. PMID- 26746899 TI - Measurements of C-reactive protein (CRP) and nerve-growth-factor (NGF) concentrations in serum and urine samples of dogs with neurologic disorders. AB - BACKGROUND: The purpose of this study was to prove the hypothesis that C-reactive protein (CRP) and nerve growth factor (NGF) may be potential biomarkers for lower urinary tract disorders and may be able to distinguish between micturition dysfunctions of different origin in dogs with spinal cord diseases. NGF- and CRP- concentrations were measured in serum and urine samples using specific ELISA Kits. Results in urine were standardized by urine-creatinine levels. RESULTS: CRP in serum was detectable in 32/76 and in urine samples in 40/76 patients. NGF could be measured in all serum and in 70/76 urine samples. Urinary CRP concentrations were significantly higher in dogs with micturition dysfunction (p = 0.0009) and in dogs with different neurological diseases (p = 0.0020) compared to the control group. However, comparing dogs with spinal cord disorders with and without associated micturition dysfunction no significant difference could be detected for NGF and CRP values in urine or serum samples. Additionally, levels did not decrease significantly, when measured at the time when the dogs regained the ability to urinate properly (urinary NGF p = 0.7962; urinary CRP p = 0.078). Urine samples with bacteria and/or leukocytes had no significant increase in urinary NGF (p = 0.1112) or CRP (p = 0.0534) concentrations, but higher CRP levels in urine from dogs with cystitis were found compared to dogs without signs of cystitis. CONCLUSIONS: From these data we conclude that neither CRP nor NGF in urine or serum can be considered as reliable biomarkers for micturition disorders in dogs with spinal cord disorders in a clinical setting, but their production might be part of the pathogenesis of such disorders. Significantly higher levels of CRP could be found in the urine of dogs with micturition dysfunctions compared to control dogs. This phenomenon could potentially be explained by unspecific extrahepatic CRP production by smooth muscle cells in the dilated bladder. PMID- 26746901 TI - Sagittal Fluoroscopy for the Assessment of Hindfoot Kinematics. AB - Current methods of quantifying foot kinematics during gait typically use markers placed externally on bony anatomic locations. These models are unable to analyze talocrural or subtalar motion because the talus lacks palpable landmarks to place external markers. Alternative methods of measuring these clinically relevant joint motions are invasive and have been limited to research purposes only. This study explores the use of fluoroscopy to noninvasively quantify talocrural and subtalar sagittal plane kinematics. A fluoroscopy system (FS) was designed and built to synchronize with an existing motion analysis system (MAS). Simultaneous fluoroscopic, marker motion, and ground reaction force (GRF) data were collected for five subjects to demonstrate system application. A hindfoot sagittal plane model was developed to evaluate talocrural and subtalar joint motion. Maximum talocrural plantar and dorsiflexion angles averaged among all the subjects occur at 12% and 83% of stance, respectively, with a range of motion of 20.1 deg. Maximum talocrural plantar and dorsiflexion angles averaged among all the subjects occur at toe-off and 67% of stance, respectively, with a range of motion of 8.7 deg. Based on the favorable comparison between the current fluoroscopically measured kinematics and previously reported results from alternative methods, it is concluded that fluoroscopic technology is well suited for measuring the sagittal plane hindfoot motion. PMID- 26746900 TI - Assessment of Pradosia huberi effects on the reproductive system of male rats. AB - Pradosia huberi is a species found in the Amazon region and used as an antiulcerogenic and gastroprotective agent; however, phytochemical analysis has revealed the presence of compounds with potential toxic effects on the reproductive system. For the evaluation of the toxicity of P. huberi on male fertility, male Wistar rats were divided into four groups: one control (distilled water p.o.) and three treated (hydroalcoholic extract of the stem bark of P. Huberi (PH-HAE) at doses of 1.22, 6.1, and 30.5 mg/kg p.o.) once daily, for 63 days. In the last week of treatment (from the 57th to the 63rd day), the rats were mated with untreated virgin females (n = 30/group) and were killed on day 64. To investigate the toxic potential of PH-HAE on the reproductive system of rats the following parameters were evaluated: sperm production, genotoxicity, and general development. The production of gametes and their morphology did not differ between control and treated groups. Treatment with PH-HAE did not result in fewer vaginal plugs formed, indicating that the ability to mate was not impaired, but caused an increase of 14.3 and 10.8% in the preimplantation loss index, a reduction of 14.3 and 10.8% in the implantation index, and a reduction of 5.6 and 8.2% in the postimplantation loss index of female rats mated with rats treated with 6.1 and 30.5 mg/kg, respectively, indicating a possible toxic action of PH-HAE on the reproductive system of rats. PMID- 26746903 TI - Post discharge medicines use review service for older patients: recruitment issues in a feasibility study. AB - BACKGROUND: The community pharmacy medicines use review (MUR) service in England has been identified as a way of providing support with medication to recently discharged patients; however initial uptake of post-discharge MUR has been low. OBJECTIVE: To identify barriers to recruitment into a randomised controlled feasibility study of a hospital referral system to older patients' regular community pharmacists. METHOD: Ward pharmacists at Southport District General Hospital identified patients aged over 65 to be approached by a researcher to assess eligibility and discuss involvement in the trial. Participants were randomised to referral for a post discharge MUR with their regular community pharmacist, or to standard discharge care. Reasons for patients not participating were collected. RESULTS: Over a 9-month period 337 potential participants were identified by ward pharmacists. Of these, 132 were eligible and 60 were recruited. Barriers to recruitment included competing priorities among ward pharmacists, and national restrictions placed on MURs e.g. housebound patients and those requiring carer support with medication. Lack of expected benefit resulted in a high proportion of patient refusals. CONCLUSION: The current provisions for post discharge MURs exclude many older people from participation, including those possibly in greatest need. Unfamiliarity with the role of the pharmacist in transitional care may have affected patients' perceived 'cost benefit' of taking part in this study. PMID- 26746902 TI - Free phenytoin assessment in patients: measured versus calculated blood serum levels. AB - BACKGROUND: Total serum drug levels are routinely determined for the therapeutic drug monitoring of selected, difficult-to-dose drugs. For some of these drugs, however, knowledge of the free fraction is necessary to adapt correct dosing. Phenytoin, with its non-linear pharmacokinetics, >90 % albumin binding and slow elimination rate, is such a drug requiring individualization in patients, especially if rapid intravenous loading and subsequent dose adaptation is needed. In a prior long-term investigation, we showed the excellent performance of pharmacy-assisted Bayesian forecasting support for optimal dosing in hospitalized patients treated with phenytoin. In a subgroup analysis, we evaluated the suitability of the Sheiner-Tozer algorithm to calculate the free phenytoin fraction in hypoalbuminemic patients. OBJECTIVE: To test the usefulness of the Sheiner-Tozer algorithm for the correct estimation of the free phenytoin concentrations in hospitalized patients. SETTING: A Swiss tertiary care hospital. METHOD: Free phenytoin plasma concentration was calculated from total phenytoin concentration in hypoalbuminemic patients and compared with the measured free phenytoin. The patients were separated into a low (35 <= albumin >= 25 g/L) and a very low group (albumin <25 g/L) for comparing and statistically analyzing the calculated and the measured free phenytoin concentration. MAIN OUTCOME MEASURES: Calculated and the measured free phenytoin concentration. RESULTS: The calculated (1.2 mg/L (SD = 0.7) and the measured (1.1 mg/L (SD = 0.5) free phenytoin concentration correlated. The mean difference in the low and the very low albumin group was: 0.10 mg/L (SD = 1.4) (n = 11) and 0.13 mg/L (SD = 0.24) (n = 12), respectively. Although the variability of the data could be a bias, no statistically significant difference between the groups was found: t test (p = 0.78), the Passing-Bablok regression, the Spearman's rank correlation coefficient of r = 0.907 and p = 0.00. The Bland-Altman plot including the regression analysis revealed no systematic differences between the calculated and the measured value [M = 0.11 (SD = 0.28)]. CONCLUSION: In absence of a free phenytoin plasma concentration measurement also in hypoalbuminemic patients, the Sheiner Tozer algorithm represents a useful tool to assist therapeutic monitoring to calculate or control free phenytoin by using total phenytoin and the albumin concentration. PMID- 26746904 TI - Demographic factors in hip fracture incidence and mortality rates in California, 2000-2011. AB - BACKGROUND: Hip fractures result in both health and cost burdens from a public health perspective and have a major impact on the health care system in the USA. The purpose was to examine whether there were systematic differences in hip fracture incidence and 30-, 90-, and 365-day mortality after hip fracture in the California population as a function of age, gender, and race/ethnicity from 2000 2011. METHODS: This was a population-based study from 2000 to 2011 using data from the California Office of Statewide Health and Planning and Development (OSHPD, N = 317,677), California State Death Statistical Master File records (N = 224,899), and the US Census 2000 and 2010. There were a total of 317,677 hospital admissions for hip fractures over the 12-year span and 24,899 deaths following hip fractures. All participants without linkage (substituted for social security) numbers were excluded from mortality rate calculations. Variation in incidence and mortality rates across time, gender, race/ethnicity, and age were assessed using Poisson regression models. Odds ratio and 95 % confidence intervals are provided. RESULTS: The incidence rate of hip fractures decreased between 2000 and 2011 (odds ratio (OR) = 0.98, 95 % confidence interval (CI) 0.98, 0.98). Mortality rates also decreased over time. There were gender, race/ethnicity, and age group differences in both incidence and mortality rates. CONCLUSIONS: Males were half as likely to sustain a hip fracture, but their mortality within a year of the procedure is almost twice the rate than women. As age increased, the prevalence of hip fracture increased dramatically, but mortality did not increase as steeply. Caucasians were more likely to sustain a hip fracture and to die within 1 year after a hip fracture. The disparities in subpopulations will allow for targeted population interventions and opportunities for further research. PMID- 26746905 TI - Step training improves reaction time, gait and balance and reduces falls in older people: a systematic review and meta-analysis. AB - OBJECTIVE: To examine the effects of stepping interventions on fall risk factors and fall incidence in older people. DATA SOURCE: Electronic databases (PubMed, EMBASE, CINAHL, Cochrane, CENTRAL) and reference lists of included articles from inception to March 2015. STUDY SELECTION: Randomised (RCT) or clinical controlled trials (CCT) of volitional and reactive stepping interventions that included older (minimum age 60) people providing data on falls or fall risk factors. RESULTS: Meta-analyses of seven RCTs (n=660) showed that the stepping interventions significantly reduced the rate of falls (rate ratio=0.48, 95% CI 0.36 to 0.65, p<0.0001, I2=0%) and the proportion of fallers (risk ratio=0.51, 95% CI 0.38 to 0.68, p<0.0001, I2=0%). Subgroup analyses stratified by reactive and volitional stepping interventions revealed a similar efficacy for rate of falls and proportion of fallers. A meta-analysis of two RCTs (n=62) showed that stepping interventions significantly reduced laboratory-induced falls, and meta analysis findings of up to five RCTs and CCTs (n=36-416) revealed that stepping interventions significantly improved simple and choice stepping reaction time, single leg stance, timed up and go performance (p<0.05), but not measures of strength. CONCLUSIONS: The findings indicate that both reactive and volitional stepping interventions reduce falls among older adults by approximately 50%. This clinically significant reduction may be due to improvements in reaction time, gait, balance and balance recovery but not in strength. Further high-quality studies aimed at maximising the effectiveness and feasibility of stepping interventions are required. SYSTEMATIC REVIEWS REGISTRATION NUMBER: CRD42015017357. PMID- 26746906 TI - Four biomechanical and anthropometric measures predict tibial stress fracture: a prospective study of 1065 Royal Marines. AB - BACKGROUND: Tibial stress fractures (TSFs) cause a significant burden to Royal Marines recruits. No prospective running gait analyses have previously been performed in military settings. AIM: We aimed to identify biomechanical gait factors and anthropometric variables associated with increased risk of TSF. METHODS: 1065 Royal Marines recruits were assessed in week 2 of training. Bilateral plantar pressure and three-dimensional lower limb kinematics were obtained for barefoot running at 3.6 m/s, providing dynamic arch index, peak heel pressure and lower limb joint angles. Age, bimalleolar breadth, calf girth, passive hip internal/external range of motion and body mass index (BMI) were also recorded. 10 recruits who sustained a TSF during training were compared with 120 recruits who completed training injury-free using a binary logistic regression model to identify injury risk factors. RESULTS: 4 variables significantly (p<0.05) predicted increased risk of TSF (ORs and 95% CI): smaller bimalleolar width (0.73, 0.58 to 0.93), lower BMI (0.56, 0.33 to 0.95), greater peak heel pressure (1.25, 1.07 to 1.46) and lower range of tibial rotation (0.78, 0.63 to 0.96). SUMMARY: Reduced impact attenuation and ability to withstand load were implicated in tibial stress fracture risk. PMID- 26746907 TI - Injury risk in runners using standard or motion control shoes: a randomised controlled trial with participant and assessor blinding. AB - BACKGROUND/AIM: This randomised controlled trial investigated if the usage of running shoes with a motion control system modifies injury risk in regular leisure-time runners compared to standard shoes, and if this influence depends on foot morphology. METHODS: Recreational runners (n=372) were given either the motion control or the standard version of a regular running shoe model and were followed up for 6 months regarding running activity and injury. Foot morphology was analysed using the Foot Posture Index method. Cox regression analyses were used to compare injury risk between the two groups, based on HRs and their 95% CIs, controlling for potential confounders. Stratified analyses were conducted to evaluate the effect of motion control system in runners with supinated, neutral and pronated feet. RESULTS: The overall injury risk was lower among the participants who had received motion control shoes (HR=0.55; 95% CI 0.36 to 0.85) compared to those receiving standard shoes. This positive effect was only observed in the stratum of runners with pronated feet (n=94; HR=0.34; 95% CI 0.13 to 0.84); there was no difference in runners with neutral (n=218; HR=0.78; 95% CI 0.44 to 1.37) or supinated feet (n=60; HR=0.59; 95% CI 0.20 to 1.73). Runners with pronated feet using standard shoes had a higher injury risk compared to those with neutral feet (HR=1.80; 95% CI 1.01 to 3.22). CONCLUSIONS: The overall injury risk was lower in participants who had received motion control shoes. Based on secondary analysis, those with pronated feet may benefit most from this shoe type. PMID- 26746908 TI - Hamstring injuries have increased by 4% annually in men's professional football, since 2001: a 13-year longitudinal analysis of the UEFA Elite Club injury study. AB - BACKGROUND: There are limited data on hamstring injury rates over time in football. AIM: To analyse time trends in hamstring injury rates in male professional footballers over 13 consecutive seasons and to distinguish the relative contribution of training and match injuries. METHODS: 36 clubs from 12 European countries were followed between 2001 and 2014. Team medical staff recorded individual player exposure and time-loss injuries. Injuries per 1000 h were compared as a rate ratio (RR) with 95% CI. Injury burden was the number of lay off days per 1000 h. Seasonal trend for injury was analysed using linear regression. RESULTS: A total of 1614 hamstring injuries were recorded; 22% of players sustained at least one hamstring injury during a season. The overall hamstring injury rate over the 13-year period was 1.20 injuries per 1000 h; the match injury rate (4.77) being 9 times higher than the training injury rate (0.51; RR 9.4; 95% CI 8.5 to 10.4). The time-trend analysis showed an annual average 2.3% year on year increase in the total hamstring injury rate over the 13 year period (R(2)=0.431, b=0.023, 95% CI 0.006 to 0.041, p=0.015). This increase over time was most pronounced for training injuries-these increased by 4.0% per year (R(2)=0.450, b=0.040, 95% CI 0.011 to 0.070, p=0.012). The average hamstring injury burden was 19.7 days per 1000 h (annual average increase 4.1%) (R(2)=0.437, b=0.041, 95% CI 0.010 to 0.072, p=0.014). CONCLUSIONS: Training related hamstring injury rates have increased substantially since 2001 but match related injury rates have remained stable. The challenge is for clubs to reduce training-related hamstring injury rates without impairing match performance. PMID- 26746909 TI - Intra-articular hip injections: is there a role for ultrasound? PMID- 26746910 TI - Physical performance tests predict injury in National Collegiate Athletic Association athletes: a three-season prospective cohort study. AB - BACKGROUND: The ability to predict injury is difficult. Prior injury is the only risk factor that has been reported consistently in multiple research studies. Convenient and easy to perform, physical performance tests (PPTs) have great allure as prognostic factors. METHODS: 11 PPTs were issued to 359 participants over the course of three seasons of National Collegiate Athletic Association Division I athletic competition. Injuries were monitored and reported in a centralised university tracking system. Exploratory factor analysis was performed in order to group the PPTs into constructs. The relationship between injury and these PPT-based constructs and other known predictors of injury was explored using univariate and multivariate regression. RESULTS: PPTs clustered into five constructs: (1) active motion, (2) power, (3) hip stability, (4) flexibility and (5) motor control. When these five were placed into a multiple regression equation along with known risk factors (age, body mass index (BMI), gender, excessive flexibility and past injury), hip stability and active motion were predicted injury. In addition, motor control predicted non-traumatic injury. Past injury did not predict injury in the multivariate model. SUMMARY: In college athletes, hip stability, active motion and motor control as assessed through PPTs can be useful as part of preseason screening. These PPT-related constructs seem to have a mediating effect on the relationship between past injury and future injury. This study provides the rationale to test targeted interventions to address these limitations. CLINICAL TRIAL REGISTRATION NUMBER: NCT01804894. PMID- 26746975 TI - The new Interventional Radiology/Diagnostic Radiology dual certificate: "higher standards, better education". AB - The American Board of Medical Specialties (ABMS) has approved a "new" residency: dual Certification in Interventional Radiology (IR) / Diagnostic Radiology (DR). This IR/DR program intends to better prepare future IR doctors. Residency programs can apply for the IR/DR program beginning in 2015, with full nationwide implementation of the IR/DR residency likely to ramp up by 2022. The IR/DR dual certificate can be attained via an "Integrated" or "Independent" IR/DR residency pathway. The IR/DR training pathway may lead the way to the future training of IR/DR physicians worldwide. Certainly, the ABMS approval of a "new" residency is rare and worth attention; however, as with all things new, questions and concerns will be raised. MAIN MESSAGES: * The ABMS approved a "new" residency, the IR/DR dual Certification. * This IR/DR program intends to better prepare future IR doctors. * Full nationwide implementation of the IR/DR Residency is likely by 2022. * The IR/DR certificate can be attained via the Integrated or the Independent residency pathway. * These programs may lead the way to the future training of IR/DR physicians worldwide. PMID- 26746976 TI - MR-arthrography and CT-arthrography in sports-related glenolabral injuries: a matched descriptive illustration. AB - The combination of a large range of motion and insufficient bony stabilization makes the glenohumeral joint susceptible to injuries including dislocation in young athletes. Magnetic resonance arthrography (MR-arthrography) and computed tomography arthrography (CT-arthrography) play an important role in the preoperative workup of labroligametous injuries. This paper illustrates MR arthrography and CT-arthrography findings acquired at the same time on the same subjects to illustrate common causes and sequelae of shoulder instability. Teaching Points * MR-arthrography and CT-arthrography are equivalent for SLAP and full-thickness rotator cuff tears.* CT-arthrography is superior in evaluating osseous defects and cartilage surface lesions.* MR-arthrography is superior in evaluating intrasubstance and extra-articular tendinous injuries. PMID- 26746978 TI - Deliberate Self-harm Following Bariatric Surgery. PMID- 26746977 TI - Designing an Electronic Patient Management System for Multiple Sclerosis: Building a Next Generation Multiple Sclerosis Documentation System. AB - BACKGROUND: Technologies like electronic health records or telemedicine devices support the rapid mediation of health information and clinical data independent of time and location between patients and their physicians as well as among health care professionals. Today, every part of the treatment process from diagnosis, treatment selection, and application to patient education and long term care may be enhanced by a quality-assured implementation of health information technology (HIT) that also takes data security standards and concerns into account. In order to increase the level of effectively realized benefits of eHealth services, a user-driven needs assessment should ensure the inclusion of health care professional perspectives into the process of technology development as we did in the development process of the Multiple Sclerosis Documentation System 3D. After analyzing the use of information technology by patients suffering from multiple sclerosis, we focused on the needs of neurological health care professionals and their handling of health information technology. OBJECTIVE: Therefore, we researched the status quo of eHealth adoption in neurological practices and clinics as well as health care professional opinions about potential benefits and requirements of eHealth services in the field of multiple sclerosis. METHODS: We conducted a paper-and-pencil-based mail survey in 2013 by sending our questionnaire to 600 randomly chosen neurological practices in Germany. The questionnaire consisted of 24 items covering characteristics of participating neurological practices (4 items), the current use of network technology and the Internet in such neurological practices (5 items), physicians' attitudes toward the general and MS-related usefulness of eHealth systems (8 items) and toward the clinical documentation via electronic health records (4 items), and physicians' knowledge about the Multiple Sclerosis Documentation System (3 items). RESULTS: From 600 mailed surveys, 74 completed surveys were returned. As much as 9 of the 10 practices were already connected to the Internet (67/74), but only 49% preferred a permanent access. The most common type of HIT infrastructure was a complete practice network with several access points. Considering data sharing with research registers, 43% opted for an online interface, whereas 58% decided on an offline method of data transmission. eHealth services were perceived as generally useful for physicians and nurses in neurological practices with highest capabilities for improvements in clinical documentation, data acquisition, diagnosis of specific MS symptoms, physician patient communication, and patient education. Practices specialized in MS in comparison with other neurological practices presented an increased interest in online documentation. Among the participating centers, 91% welcomed the opportunity of a specific clinical documentation for MS and 87% showed great interest in an extended and more interconnected electronic documentation of MS patients. Clinical parameters (59/74) were most important in documentation, followed by symptomatic parameters like measures of fatigue or depression (53/74) and quality of life (47/74). CONCLUSIONS: Physicians and nurses may significantly benefit from an electronically assisted documentation and patient management. Many aspects of patient documentation and education will be enhanced by eHealth services if the most informative measures are integrated in an easy-to-use and easily connectable approach. MS-specific eHealth services were highly appreciated, but the current level of adoption is still behind the level of interest in an extended and more interconnected electronic documentation of MS patients. PMID- 26746979 TI - A New Era for the Journal. PMID- 26746981 TI - Pharmacokinetics of intravenous moxifloxacin in the cerebrospinal fluid of a patient with central nervous system shunt infection. AB - We report the first case describing the pharmacokinetics of moxifloxacin in the cerebrospinal fluid after multiple-dose intravenous administration in a patient with central nervous system shunt infection. The ratio of the area under the concentration-time curve over 24h (AUC) in cerebrospinal fluid to the AUC in serum was 0.7 in this patient. PMID- 26746982 TI - Regarding "Development of a postgraduate interventional cardiac nursing curriculum" by Currey et al. PMID- 26746980 TI - Prediction of Protein Submitochondrial Locations by Incorporating Dipeptide Composition into Chou's General Pseudo Amino Acid Composition. AB - Mitochondrion is the key organelle of eukaryotic cell, which provides energy for cellular activities. Submitochondrial locations of proteins play crucial role in understanding different biological processes such as energy metabolism, program cell death, and ionic homeostasis. Prediction of submitochondrial locations through conventional methods are expensive and time consuming because of the large number of protein sequences generated in the last few decades. Therefore, it is intensively desired to establish an automated model for identification of submitochondrial locations of proteins. In this regard, the current study is initiated to develop a fast, reliable, and accurate computational model. Various feature extraction methods such as dipeptide composition (DPC), Split Amino Acid Composition, and Composition and Translation were utilized. In order to overcome the issue of biasness, oversampling technique SMOTE was applied to balance the datasets. Several classification learners including K-Nearest Neighbor, Probabilistic Neural Network, and support vector machine (SVM) are used. Jackknife test is applied to assess the performance of classification algorithms using two benchmark datasets. Among various classification algorithms, SVM achieved the highest success rates in conjunction with the condensed feature space of DPC, which are 95.20 % accuracy on dataset SML3-317 and 95.11 % on dataset SML3-983. The empirical results revealed that our proposed model obtained the highest results so far in the literatures. It is anticipated that our proposed model might be useful for future studies. PMID- 26746983 TI - A threshold regression model to predict return to work after traumatic limb injury. AB - OBJECTIVE: The study aims to examine the severity of initial impairment and recovery rate of return-to-work (RTW) predictors among workers with traumatic limb injury. METHODS: This 2-year prospective cohort study recruited 1124 workers with traumatic limb injury during the first 2 weeks of hospital admission. Baseline data were obtained by questionnaire and chart review. Patient follow-up occurred at 1, 3, 6, 12, 18, and 24 months post injury. The primary outcome was the time of first RTW. The impact of potential predictors on initial impairment and rate of recovery towards RTW was estimated by threshold regression (TR). RESULTS: A total of 846 (75.27%) participants returned to work during the follow up period. Our model revealed that the initial impairment level in elderly workers and lower limb injuries were 33% and 35% greater than their counterparts, respectively. Workers with >12 years of education, part-time job, and moderate and higher self-efficacy were less impaired at initial injury compared with their counterparts. In terms of the rate of recovery leading to RTW, workers with older age, part-time jobs, lower limbs, or combined injuries had a significantly slower recovery rate, while workers with 9-12 years of education and >12 years of education had a significantly faster recovery rate. CONCLUSIONS: Our study provides researchers and clinicians with evidence to understand the baseline impairment and rate of recovery towards RTW by explaining the predictors of RTW among workers with traumatic limb injuries. PMID- 26746984 TI - Impact of socio-economic status on unplanned readmission following injury: A multicenter cohort study. AB - BACKGROUND: Unplanned readmissions cost the US economy approximately $17 billion in 2009 with a 30-day incidence of 19.6%. Despite the recognised impact of socio economic status (SES) on readmission in diagnostic populations such as cardiovascular patients, its impact in trauma patients is unclear. We examined the effect of SES on unplanned readmission following injury in a setting with universal health insurance. We also evaluated whether additional adjustment for SES influenced risk-adjusted readmission rates, used as a quality indicator (QI). STUDY DESIGN: We conducted a multicenter cohort study in an integrated Canadian trauma system involving 56 adult trauma centres using trauma registry and hospital discharge data collected between 2005 and 2010. The main outcome was unplanned 30-day readmission; all cause, due to complications of injury and due to subsequent injury. SES was determined using ecological indices of material and social deprivation. Odds ratios of readmission and 95% confidence intervals adjusted for covariates were generated using multivariable logistic regression with a correction for hospital clusters. We then compared a readmission QI validated previously (original QI) to a QI with additional adjustment for SES (SES-adjusted QI) using the mean absolute difference. RESULTS: The cohort consisted of 52,122 trauma admissions of which 6.5% were rehospitalised within 30 days of discharge. Compared to patients in the lowest quintile of social deprivation, those in the highest quintile had a 20% increase in the odds of all cause unplanned readmission (95% CI=1.06-1.36) and a 27% increase in the odds of readmission due to complications of injury (95% CI=1.04-1.54). No association was observed for material deprivation or for readmissions due to subsequent injuries. We observed a strong agreement between the original and SES-adjusted readmission (mean absolute difference= 0.04%). CONCLUSIONS: Patients admitted for traumatic injury who suffer from social deprivation have an increased risk of unplanned rehospitalisation due to complications of injury in the 30 days following discharge. Better discharge planning or follow up for such patients may improve patient outcome and resource use for trauma admissions. Despite observed associations, results suggest that the trauma QI based on unplanned readmission does not require additional adjustment for SES. PMID- 26746987 TI - Reaching the brain: Advances in optic nerve regeneration. AB - The optic nerve has been widely used to investigate factors that regulate axon regeneration in the mammalian CNS. Although retinal ganglion cells (RGCs), the projection neurons of the eye, show little capacity to regenerate their axons following optic nerve damage, studies spanning the 20th century showed that some RGCs can regenerate axons through a segment of peripheral nerve grafted to the optic nerve. More recently, some degree of regeneration has been achieved through the optic nerve itself by factors associated with intraocular inflammation (oncomodulin) or by altering levels of particular transcription factors (Klf-4, 9, c-myc), cell-intrinsic suppressors of axon growth (PTEN, SOCS3), receptors to cell-extrinsic inhibitors of axon growth (Nogo receptor, LAR, PTP-sigma) or the intracellular signaling pathway activated by these receptors (RhoA). Other regulators of regeneration and cell survival continue to be identified in this system at a rapid pace. Combinatorial treatments that include two or more of these factors enable some retinal ganglion cells to regenerate axons from the eye through the entire length of the optic nerve and across the optic chiasm. In some cases, regenerating axons have been shown to innervate the appropriate central target areas and elicit postsynaptic responses. Many discoveries made in this system have been found to enhance axon regeneration after spinal cord injury. Thus, progress in optic nerve regeneration holds promise not only for visual restoration but also for improving outcome after injury to other parts of the mature CNS. PMID- 26746985 TI - Altered long non-coding RNA transcriptomic profiles in brain microvascular endothelium after cerebral ischemia. AB - The brain endothelium is an important therapeutic target for the inhibition of cerebrovascular dysfunction in ischemic stroke. Previously, we documented the important regulatory roles of microRNAs in the cerebral vasculature, in particular the cerebral vascular endothelium. However, the functional significance and molecular mechanisms of other classes of non-coding RNAs in the regulation of cerebrovascular endothelial pathophysiology after stroke are completely unknown. Using RNA sequencing (RNA-seq) technology, we profiled long non-coding RNA (lncRNA) expressional signatures in primary brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation (OGD), an in vitro mimic of ischemic stroke conditions. After 16h of OGD exposure, the expression levels for 362 of the 10,677 lncRNAs analyzed changed significantly, including a total of 147 lncRNAs increased and 70 lncRNAs decreased by more than 2-fold. Among them, the most highly upregulated lncRNAs include Snhg12, Malat1, and lnc OGD 1006, whereas the most highly downregulated lncRNAs include 281008D09Rik, Peg13, and lnc-OGD 3916. Alteration of the most highly upregulated/downregulated ODG-responsive lncRNAs was further confirmed in cultured BMECs after OGD as well as isolated cerebral microvessels in mice following transient middle cerebral artery occlusion (MCAO) and 24h reperfusion by the quantitative real-time PCR approach. Moreover, promoter analysis of altered ODG-responsive endothelial lncRNA genes by bioinformatics showed substantial transcription factor binding sites on lncRNAs, implying potential transcriptional regulation of those lncRNAs. These findings are the first to identify OGD-responsive brain endothelial lncRNAs, which suggest potential pathological roles for these lncRNAs in mediating endothelial responses to ischemic stimuli. Endothelial-selective lncRNAs may function as a class of novel master regulators in cerebrovascular endothelial pathologies after ischemic stroke. PMID- 26746986 TI - C9orf72 promoter hypermethylation is reduced while hydroxymethylation is acquired during reprogramming of ALS patient cells. AB - Among several genetic mutations known to cause amyotrophic lateral sclerosis (ALS), a hexanucleotide repeat expansion in the C9orf72 gene is the most common. In approximately 30% of C9orf72-ALS cases, 5-methylcytosine (5mC) levels within the C9orf72 promoter are increased, resulting in a modestly attenuated phenotype. The developmental timing of C9orf72 promoter hypermethylation and the reason why it occurs in only a subset of patients remain unknown. In order to model the acquisition of C9orf72 hypermethylation and examine the potential role of 5 hydroxymethylcytosine (5hmC), we generated induced pluripotent stem cells (iPSCs) from an ALS patient with C9orf72 promoter hypermethylation. Our data show that 5mC levels are reduced by reprogramming and then re-acquired upon neuronal specification, while 5hmC levels increase following reprogramming and are highest in iPSCs and motor neurons. We confirmed the presence of 5hmC within the C9orf72 promoter in post-mortem brain tissues of hypermethylated patients. These findings show that iPSCs are a valuable model system for examining epigenetic perturbations caused by the C9orf72 mutation and reveal a potential role for cytosine demethylation. PMID- 26746988 TI - Phylogenetic analyses suggest that diversification and body size evolution are independent in insects. AB - BACKGROUND: Skewed body size distributions and the high relative richness of small-bodied taxa are a fundamental property of a wide range of animal clades. The evolutionary processes responsible for generating these distributions are well described in vertebrate model systems but have yet to be explored in detail for other major terrestrial clades. In this study, we explore the macro evolutionary patterns of body size variation across families of Hexapoda (insects and their close relatives), using recent advances in phylogenetic understanding, with an aim to investigate the link between size and diversity within this ancient and highly diverse lineage. RESULTS: The maximum, minimum and mean-log body lengths of hexapod families are all approximately log-normally distributed, consistent with previous studies at lower taxonomic levels, and contrasting with skewed distributions typical of vertebrate groups. After taking phylogeny and within-tip variation into account, we find no evidence for a negative relationship between diversification rate and body size, suggesting decoupling of the forces controlling these two traits. Likelihood-based modeling of the log mean body size identifies distinct processes operating within Holometabola and Diptera compared with other hexapod groups, consistent with accelerating rates of size evolution within these clades, while as a whole, hexapod body size evolution is found to be dominated by neutral processes including significant phylogenetic conservatism. CONCLUSIONS: Based on our findings we suggest that the use of models derived from well-studied but atypical clades, such as vertebrates may lead to misleading conclusions when applied to other major terrestrial lineages. Our results indicate that within hexapods, and within the limits of current systematic and phylogenetic knowledge, insect diversification is generally unfettered by size-biased macro-evolutionary processes, and that these processes over large timescales tend to converge on apparently neutral evolutionary processes. We also identify limitations on available data within the clade and modeling approaches for the resolution of trees of higher taxa, the resolution of which may collectively enhance our understanding of this key component of terrestrial ecosystems. PMID- 26746996 TI - Skin disease in United Nations peacekeepers in Lebanon. AB - OBJECTIVES: Skin disease is one of the major components of health problems for soldiers either during war or peacetime. Despite increased numbers and scale of military missions, dermatological survey is limited. The aim of this study was to outline the dermatological profile in international peacekeepers in Lebanon and to explore the features of disease pattern. METHODS: The dermatological records of peacekeepers visiting a Chinese Level 2 hospital during a 7-year period were retrospectively assessed. Comparisons with previous reports of skin disease in military personnel were performed. RESULTS: A total of 1658 patients (91% men, with a mean age of 32 years) were included. More than half of them were Asian (62%). Dermatitis and eczema (27%) was the leading category. Tinea pedis (13%), lichen simplex chronicus (9%), unspecified dermatitis (8%), verruca vulgaris (7%) and alopecia areata (5%) were the top five complaints. Dermatitis and eczematous eruptions appeared to be the most common condition in troops deployed in the Middle East, whereas fungal infection was highly prevalent in tropical regions. Additionally, a remarkably high rate of alopecia areata was noted in two studies including ours. CONCLUSIONS: Environment, group living, occupational activities and work-related stress act as initiating and/or aggravating factors in the development and/or spread of some conditions. The knowledge of disease profile empowers doctors to enforce preventive measures and prepare for treatment modalities. In particular, the underlying psychological component in lichen simplex chronicus and alopecia areata should be addressed appropriately. PMID- 26746989 TI - Statin therapy is not associated with improved outcomes after heart transplantation in children and adolescents. AB - BACKGROUND: Although used routinely, the pleiotropic benefits of statins remain understudied in children after heart transplantation. We hypothesized that statin therapy would reduce the incidence of rejection, cardiac allograft vasculopathy (CAV) and post-transplant lymphoproliferative disease (PTLD). METHODS: This study was a retrospective review of 964 pediatric (ages 5 to 18 years) heart transplant recipients in the multicenter Pediatric Heart Transplant Study registry from 2001 to 2012. Patients were excluded if they were undergoing re-transplantation, survived <1 year post-transplant, or had missing data regarding statin use. The effects of statins beyond the first year were estimated by Kaplan-Meier and Cox regression multivariable analysis for freedom from PTLD, rejection requiring treatment, any severity of CAV, and survival. RESULTS: Statin use was variable among participating centers with only 30% to 35% of patients >=10 years of age started on a statin at <1 year post-transplant. After the first year post transplant, statin-treated children (average age at transplant 13.24 +/- 3.29 years) had significantly earlier rejection (HR 1.42, 95% CI 1.11 to 1.82, p = 0.006) compared with untreated children (transplanted at 12 +/- 3.64 years) after adjusting for conventional risk factors for rejection. Freedom from PTLD, CAV and overall survival up to 5 years post-transplant were not affected by statin use, although the number of events was small. CONCLUSIONS: Statin therapy did not confer a survival benefit and was not associated with delayed onset of PTLD or CAV. Early (<1 year post-transplant) statin therapy was associated with increased later frequency of rejection. These findings suggest that a prospective trial evaluating statin therapy in pediatric heart transplant recipients is warranted. PMID- 26746997 TI - The use of breathing techniques for the management of Eustachian tube dysfunction. AB - INTRODUCTION: Eustachian tube dysfunction (ETD) is a common condition faced by primary care physicians with a variety of available treatments, none of which are particularly efficacious. CASE REPORT: A 28 year old male soldier presented with ETD following swimming at depth which did not resolve with initial therapies. His condition resolved rapidly after implementation of the Modified Butyenko Breathing technique. DISCUSSION: The breathing technique offers a series of methods that can be used to treat patients who are refractory to conventional treatments and can add to the range of non-surgical treatments for this common condition. PMID- 26746998 TI - Simple Renal Cysts as Markers of Thoracic Aortic Disease. AB - BACKGROUND: Thoracic aortic aneurysm is usually a clinically silent disease; timely detection is largely dependent upon identification of clinical markers of thoracic aortic disease (TAD); (bicuspid aortic valve, intracranial aortic aneurysm, bovine aortic arch, or positive family history). Recently, an association of simple renal cysts (SRC) with abdominal aortic aneurysm and aortic dissection was established. The aim of our study was to evaluate the prevalence of SRC in patients with TAD in order to assess whether the presence of SRC can be used as a predictor of TAD. METHODS AND RESULTS: We evaluated the prevalence of SRC in 842 patients with TAD (64.0% males) treated at our institution from 2004 to 2013 and compared to a control group of patients (n=543; 56.2% males). Patients were divided into 4 groups: ascending aortic aneurysm (456; 54.2%); descending aortic aneurysm (86; 10.2%); type A aortic dissection (118; 14.0%); and type B aortic dissection (182; 21.6%). SRC were identified by abdominal computed tomography or magnetic resonance imaging of these patients. Prevalence of SRC is 37.5%, 57.0%, 44.1%, and 47.3% for patients with ascending aneurysm, descending aneurysm, type A dissection, and type B dissection, respectively. Prevalence of SRC in the control group was 15.3%. Prevalence of SRC was not significantly different between male and female aortic disease patients, despite reported general male predominance (2:1), which was also observed in our control group (1.7:1). CONCLUSIONS: This study establishes an increased prevalence of SRC in patients with TAD. SRC can potentially be used as a marker for timely detection of patients at risk of TAD. PMID- 26747007 TI - Spatial distribution, risk factors and haemato-biochemical alterations associated with Theileria equi infected equids of Punjab (India) diagnosed by indirect ELISA and nested PCR. AB - Equine piroplasmosis is a febrile, tick-borne disease of equids predominately caused by obligatory intra-erythrocytic protozoa Theileria equi in the Indian sub continent. A cross-sectional study was carried out on 464 equids (426 horses and 38 donkeys/mules) in Punjab, India to assess the level of exposure to equine piroplasmosis by 18S rRNA gene nested polymerase chain reaction (nPCR) and equine merozoite antigen-2 (EMA2) indirect-ELISA (enzyme linked immunosorbent assay), to investigate risk factors and haemato-biochemical alterations associated with the infection. The endemicity of the disease was confirmed by positive PCR amplification in 21.77% and positive antibody titers in 49.78% equid samples. There was a fair agreement between these two diagnostic techniques (Kappa coefficient=0.326). The spatial distribution analysis revealed an increasing trend of T. equi prevalence from north-eastern to south-western region of Punjab by both the techniques correspondingly, which proffered a direct relation with temperature and inverse with humidity variables. The relatively prominent risk factor associated with sero-positivity was the presence of other domestic animals in the herd, while the propensity of finding a positive PCR amplification was higher in donkeys/mules, animal kept at unorganised farm or those used for commercial purposes as compared to their counterparts. There was a significant increase in globulins, gamma glutamyl-transferase, total bilirubin, direct bilirubin, indirect bilirubin, glucose levels and decrease in total erythrocyte count, haemoglobin, packed cell volume by animals, which were revealed positive by nPCR (may or may not positive by indirect-ELISA) and increase in creatinine, total bilirubin, direct bilirubin, glucose and decrease in total erythrocytes count by animals, which were revealed positive by indirect-ELISA (alone). To our knowledge, this study, for the first time, brings out a comprehensive report on the status on spatial distribution of T. equi in Punjab (India) state, thoroughly investigated by molecular and serological techniques, evaluating various environmental and demographic risk factors along with the haemato-biochemical alterations in the exposed animals. PMID- 26746999 TI - Testosterone Antagonizes Doxorubicin-Induced Senescence of Cardiomyocytes. AB - BACKGROUND: Chronic cardiotoxicity is less common in male than in female patients receiving doxorubicin and other anthracyclines at puberty and adolescence. We hypothesized that this sex difference might be secondary to distinct activities of sex hormones on cardiomyocyte senescence, which is thought to be central to the development of long-term anthracycline cardiomyopathy. METHODS AND RESULTS: H9c2 cells and neonatal mouse cardiomyocytes were exposed to doxorubicin with or without prior incubation with testosterone or 17beta-estradiol, the main androgen and estrogen, respectively. Testosterone, but not 17beta-estradiol, counteracted doxorubicin-elicited senescence. Downregulation of telomere binding factor 2, which has been pinpointed previously as being pivotal to doxorubicin-induced senescence, was also prevented by testosterone, as were p53 phosphorylation and accumulation. Pretreatment with the androgen receptor antagonist flutamide, the phosphatidylinositol 3 kinase inhibitor LY294002, and the nitric oxide synthase inhibitor L-NG-nitroarginine methyl ester abrogated the reduction in senescence and the normalization of telomere binding factor 2 levels attained by testosterone. Consistently, testosterone enhanced the phosphorylation of AKT and nitric oxide synthase 3. In H9c2 cells, doxorubicin-stimulated senescence was still observed up to 21 days after treatment and increased further when cells were rechallenged with doxorubicin 14 days after the first exposure to mimic the schedule of anthracycline-containing chemotherapy. Remarkably, these effects were also inhibited by testosterone. CONCLUSIONS: Testosterone protects cardiomyocytes against senescence caused by doxorubicin at least in part by modulating telomere binding factor 2 via a pathway involving the androgen receptor, phosphatidylinositol 3 kinase, AKT, and nitric oxide synthase 3. This is a potential mechanism by which pubescent and adolescent boys are less prone to chronic anthracycline cardiotoxicity than girls. PMID- 26747000 TI - Interferon-beta Modulates Inflammatory Response in Cerebral Ischemia. AB - BACKGROUND: Stroke is a leading cause of death in the world. In >80% of strokes, the initial acute phase of ischemic injury is due to the occlusion of a blood vessel resulting in severe focal hypoperfusion, excitotoxicity, and oxidative damage. Interferon-beta (IFNbeta), a cytokine with immunomodulatory properties, was approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis for more than a decade. Its anti inflammatory properties and well-characterized safety profile suggest that IFNbeta has therapeutic potential for the treatment of ischemic stroke. METHODS AND RESULTS: We investigated the therapeutic effect of IFNbeta in the mouse model of transient middle cerebral artery occlusion/reperfusion. We found that IFNbeta not only reduced infarct size in ischemic brains but also lessened neurological deficits in ischemic stroke animals. Further, multiple molecular mechanisms by which IFNbeta modulates ischemic brain inflammation were identified. IFNbeta reduced central nervous system infiltration of monocytes/macrophages, neutrophils, CD4(+) T cells, and gammadelta T cells; inhibited the production of inflammatory mediators; suppressed the expression of adhesion molecules on brain endothelial cells; and repressed microglia activation in the ischemic brain. CONCLUSIONS: Our results demonstrate that IFNbeta exerts a protective effect against ischemic stroke through its anti-inflammatory properties and suggest that IFNbeta is a potential therapeutic agent, targeting the reperfusion damage subsequent to the treatment with tissue plasminogen activator. PMID- 26747008 TI - Molecular detection and identification of Leishmania spp. in naturally infected Phlebotomus tobbi and Sergentomyia dentata in a focus of human and canine leishmaniasis in western Turkey. AB - Human visceral leishmaniasis (VL) is reported from 38 provinces of Turkey and dogs are accepted as main reservoir hosts. Kusadasi town, belonging to Aydin province and located in western part of Turkey, is endemic for human and canine visceral leishmaniasis caused by Leishmania infantum MON1 and MON98. In this study, phlebotomine survey was conducted to determine the vector sand fly species and to identify sand fly blood meal sources. In August and September 2012, 1027 sand fly specimens were caught using CDC light traps. Eight Phlebotomus and two Sergentomyia species with the dominancy of Phlebotomus tobbi (61.34%) were detected. A total of 622 female sand flies (571 Phlebotomus; 51 Sergentomyia) were checked for Leishmania infection by direct dissection of the midgut. The half of the midgut content was inoculated into NNN culture for isolation of the parasite. Leishmania species-specific ITS1 real time PCR, conventional PCR assays of ITS1 and hsp70 genes and subsequent sequencing were performed from extracted DNAs. A region of cytochrome b (cyt-b) gene of vertebrates based PCR was used to determine the source of blood meal of sand flies. In microscopical examinations, two female specimens (0.32%) were found naturally infected with high number and different stages of promastigotes. No growth was observed in NNN culture but Leishmania DNA was obtained from both specimens. First positive specimen was identified as P. tobbi and L. infantum DNA was detected. Second specimen was Sergentomyia dentata, but Leishmania DNA could not be identified on species level. A total of 16 blood-fed female P. tobbi specimens were used for blood meal analysis and eight, three and one specimens were positive for human, dog and mouse, respectively. This is the first detection of Leishmania promastigotes using microscopical examination in P. tobbi and S. dentata in human and canine visceral leishmaniasis endemic area in western part of Turkey. Our results indicate that, (i) P. tobbi is the principal vector species and (ii) human and dogs are main blood sources. The detection of Leishmania sp. in Sergentomyia species may be an evidence for natural cycle of Sauro-leishmania agents in the area. PMID- 26747009 TI - Current drug therapy and pharmaceutical challenges for Chagas disease. AB - One of the most significant health problems in the American continent in terms of human health, and socioeconomic impact is Chagas disease, caused by the protozoan parasite Trypanosoma cruzi. Infection was originally transmitted by reduviid insects, congenitally from mother to fetus, and by oral ingestion in sylvatic/rural environments, but blood transfusions, organ transplants, laboratory accidents, and sharing of contaminated syringes also contribute to modern day transmission. Likewise, Chagas disease used to be endemic from Northern Mexico to Argentina, but migrations have earned it global. The parasite has a complex life cycle, infecting different species, and invading a variety of cells - including muscle and nerve cells of the heart and gastrointestinal tract in the mammalian host. Human infection outcome is a potentially fatal cardiomyopathy, and gastrointestinal tract lesions. In absence of a vaccine, vector control and treatment of patients are the only tools to control the disease. Unfortunately, the only drugs now available for Chagas' disease, Nifurtimox and Benznidazole, are relatively toxic for adult patients, and require prolonged administration. Benznidazole is the first choice for Chagas disease treatment due to its lower side effects than Nifurtimox. However, different strategies are being sought to overcome Benznidazole's toxicity including shorter or intermittent administration schedules-either alone or in combination with other drugs. In addition, a long list of compounds has shown trypanocidal activity, ranging from natural products to specially designed molecules, re purposing drugs commercialized to treat other maladies, and homeopathy. In the present review, we will briefly summarize the upturns of current treatment of Chagas disease, discuss the increment on research and scientific publications about this topic, and give an overview of the state-of-the-art research aiming to produce an alternative medication to treat T. cruzi infection. PMID- 26747010 TI - Seroprevalence and risk factors of human cysticercosis and taeniasis prevalence in a highly endemic area of epilepsy in Bangoua, west Cameroon. AB - Cysticercosis caused by the larvae of Taenia solium is a serious and emerging threat to public health in the endemic areas as well as in the non-endemic areas. Neurocysticercosis, an affection of the central nervous system is a leading cause of epilepsy in endemic areas. This study was carried out to investigate human cysticercosis, taeniasis and risk factors, and also their association with epilepsy in Bangoua, west Cameroon where epilepsy is highly prevalent. Out of 384 people investigated, 12 (3.1%) exhibited antibody response against low molecular weight antigens of T. solium by ELISA. Immunoblot revealed that six persons (1.6%) were seropositive with the same antigens. Among 61 epileptic patients, only one was seropositive by immunoblot and the study did not find any statistically significant difference (P>0.05) in seropositivity to T. solium between epileptic persons (1/61, 1.6%) and non-epileptic group (5/323, 1.5%). In addition, cysticercosis was associated with households eating pork meat from pigs slaughtered at home, but not with other factors. The risk factors including pig farming, the consumption of pork meat, vegetables, and non-drinkable water were attenuated by the relatively good hygiene and pig husbandry practices of the population. No egg of Taenia was found in stool by microscopic examination. All data obtained in this study suggested that cysticercosis might not be the principal causative agent of epilepsy in this area. PMID- 26747011 TI - Can separation of the scrotal sac in proximal hypospadias reliably predict the need for urethral plate transection? AB - INTRODUCTION: One of the main challenges in proximal hypospadias repair is correcting curvature. The best technique to achieve this remains the object of debate. Indeed, some authors believe the urethral plate should be kept and used as often as possible. In some cases, however, even after extensive mobilization and dorsal plication, significant curvature remains and it is necessary to transect the urethral plate. Having a reliable pre-dissection marker of the need for urethral transection would be useful in choosing a technique.We wanted to determine if presence of marked separation of the scrotal sac (SSS), also referred to as bifid scrotum, could reliably predict the need for urethral plate transection. STUDY DESIGN: We prospectively enrolled a series of boys with proximal hypospadias. We noted age, degree of hypospadias, meatal position, presence of cryptorchidism, and presence or absence of SSS. During surgery we fully degloved the penile shaft, freeing all ventral tissues, and radically dissected the more proximal bulbar urethra. We then performed an erection test. If there was residual curvature <30 degrees we performed a dorsal plication, if it was >30 degrees we transected the urethral plate. RESULTS: Twenty-nine patients were included, of whom 18 presented SSS. The average age was comparable in both groups, as was type of hypospadias and meatal position. We estimated transection of the urethral plate to be necessary in 15 out of the 18 children with SSS, and 2 out of the 11 children without SSS. The relative risk for requiring urethral plate transection in case of SSS in this series was 4.58. CONCLUSION: Techniques that commit to urethral plate transection are criticized because they preclude using the urethral plate. In our study presence of SSS was predictive for the need to transect the plate. Obviously one can decide to keep the urethral plate at all cost, and mobilize it more than we did, or accept more residual curvature, but in reality our aim was to determine a preoperative marker allowing us to define a patient category. We believe presence of SSS is a marker of severity, and that this "severity" translates into "a less usable urethra". As recent studies caution us about the evolution of the reconstructed native urethra and the possibility that it may not grow as well as the other penile tissues, we believe this extra information could influence the surgeon's decision as to the most appropriate technique for each patient. PMID- 26747012 TI - Outcomes of complex robot-assisted extravesical ureteral reimplantation in the pediatric population. AB - INTRODUCTION AND OBJECTIVE: While open ureteral reimplantation remains the gold standard for surgical treatment of vesicoureteral reflux (VUR), minimally invasive approaches offer potential benefits. This study evaluated the outcomes of children undergoing complex robot-assisted laparoscopic ureteral reimplantation (RALUR) for failed previous anti-reflux surgery, complex anatomy, or ureterovesical junction obstruction (UVJO), and compared them with patients undergoing open extravesical repair. STUDY DESIGN: Children undergoing complex RALUR or open extravesical ureteral reimplantation (OUR) were identified. Reimplantation was classified as complex if ureters: 1) had previous anti-reflux surgery, 2) required tapering and/or dismembering, or 3) had associated duplication or diverticulum. RESULTS: Seventeen children underwent complex RALUR during a 24-month period, compared with 41 OUR. The mean follow-up was 16.6 +/- 6.5 months. The RALUR children were significantly older (9.3 +/- 3.7 years) than the OUR patients (3.1 +/- 2.7 years; P < 0.001). All RALUR patients were discharged on postoperative day one, while 24.4% of children in the open group required longer hospitalization (mean 1.3 +/- 0.7 days; P = 0.03). Adjusting for age, there was no significant difference in inpatient analgesic usage between the two cohorts. Three OUR patients (7.3%) developed postoperative febrile urinary tract infection compared with a single child (5.9%) undergoing RALUR (P = 1.00). There was no significant difference in complication rate between the two groups (12.2% OUR versus 11.8% RALUR; P = 1.00). A postoperative cystogram was performed in the majority of RALUR patients, with no persistent VUR detected, and one child (6.7%) was diagnosed with contralateral reflux. DISCUSSION: Reported VUR resolution rates following robot-assisted ureteral reimplantation are varied. In the present series, children undergoing RALUR following failed previous anti reflux surgery, with complex anatomy, or UVJO experienced a shorter length of stay but had similar analgesic requirements to those undergoing open repair. Radiographic, clinical success rates and complication risk were comparable. This study had several limitations, aside from lack of randomization. Analgesic use was limited to an inpatient setting, and pain scores were not assessed. Not all children underwent a postoperative VCUG, so the true radiographic success rate is unknown. A larger patient cohort with longer follow-up is necessary to determine predictors of radiographic and clinical failure. CONCLUSION: Older children with a previous history of anti-reflux surgery were more likely to undergo RALUR. These children had success and complication rates comparable to younger patients following complex open extravesical reimplantation, which underscores the expanding role of robot-assisted lower urinary tract reconstructive surgery in the pediatric population. PMID- 26747014 TI - Micromorts--what is the risk? AB - The effective communication of risk, which is central to the process of consent, can be difficult, and can be hard for patients to understand. We introduce the potential utility of the micromort, a unit of risk defined as a one-in-a-million chance of sudden death, which allows clinicians to compare the risks of an intervention with those of different activities, making them easier to understand. PMID- 26747013 TI - Concurrent epidemics of influenza A/H3N2 and A/H1N1pdm in Southern China: A serial cross-sectional study. AB - OBJECTIVES: This study aimed to elucidate the antibody response pattern of multiple influenza subtypes through a 4-year serological study of a general population in Shenzhen, Southern China. METHODS: A serial cross-sectional serological survey was conducted at eight time points between 2009 and 2012. A total number of 5876 subjects were recruited from all age groups. The influenza subtypes tested were A/H1N1, A/H3N2, B/Yamagata, B/Victoria, and A/H1N1pdm. Genetic sequencing and phylogenetic analysis were performed on 127 H3 genes and 28 H1pdm genes. RESULTS: We found concurrent epidemics of A/H3N2 and A/H1N1pdm with simultaneous peak times at March 2011. A/H3N2 was the dominant subtype. Ten residue substitutions (S61N, T64I, K78E, K160N, N161S, A214S, T228A, A229V, V239I, N294K, and N328S) were found in the H3 gene that might underlie its epidemic. The elderly group showed an antibody response cycle that was weaker in magnitude and slower in peak time than in younger groups. CONCLUSIONS: The study provides a broad transmission picture and epidemiological characteristics of the major flu subtypes. The findings suggest that it may be necessary to include the A/H1N1pdm strain to the current trivalent or quadrivalent vaccine design. The delayed antibody response cycle in the elderly group indicates the need for better protection of elderly people that might be achieved by an earlier vaccination at a higher dose. PMID- 26747015 TI - Skull reshaping with fat-grafting surgery. PMID- 26747016 TI - [Multifocal serous chorioretinopathy secondary to the use of MEK inhibitors: Illustration and example of management through two case reports]. AB - New targeted treatments are being used for patients affected by certain types of cancers with specific gene dysregulation. These new treatments transform the prognosis for the patients but the exact way in which they work is often incompletely known. This can prove to be problematic with regard to potential side effects. Ophthalmologic side effects are particularly difficult to detect in animal models. MEK inhibitors are among these new targeted treatments for which the indications are broad. One of the reported side effects of MEK inhibitors is the appearance of atypical multifocal serous chorioretinopathies which, when present, occur rapidly after starting the treatment and disappear soon after stopping it. We report two documented cases of serous chorioretinopathies secondary to the use of selumetinib, an MEK inhibitor. Both patients were followed for several months after initiating the treatment, using angiography, OCT, and filtered photographs. Only a very few cases have been reported, and the detailed description of two clear-cut cases and their management, as well as a review of the current literature, seems a good way to approach the management of this complication. PMID- 26747017 TI - [Overview of medical practices in wet AMD in France]. AB - BACKGROUND AND OBJECTIVES: Wet AMD is characterized by the formation of choroidal neovascularization, mediated by vascular endothelial growth factor (VEGF) and responsible for a decrease in visual acuity and metamorphopsia of sudden onset. Intravitreal anti-VEGF can stabilize or even improve visual acuity. Although there is a consensus among ophthalmologists about the induction phase injection of anti-VEGF, there appear to be differences in practice regarding therapeutic treatment modalities. The goal of this work was to explore this hypothesis and to better understand real life practices. METHOD: The Ipsos institute conducted a qualitative survey of 16 retinal specialists and 9 general ophthalmologists in September and October 2013, using a questionnaire developed by a scientific committee of experts. Fifteen telephone interviews and 4 face-to-face meetings with a retina specialist and an ophthalmologist were conducted. This qualitative study allowed the development of a quantitative survey of 200 retina specialists and general ophthalmologists, conducted between November 2013 and January 2014, to describe practices in diagnosis, treatment and follow-up of wet AMD. RESULTS: A distribution of roles between the ophthalmologist making the initial diagnosis and the retinal specialists responsible for treatment and follow-up was noted. Treatment was initiated within 10 days of diagnosis as recommended by the HAS in only one third of patients. After the induction phase of treatment, i.e. three monthly injections of anti-VEGF, treatment and monitoring practices were heterogeneous with 74% of physicians using a PRN treatment protocol, 22% a bimonthly protocol (with monthly monitoring in 19.4% of cases) and 4% a "treat and extend" protocol. There was little change in the protocol chosen in the case of recurrence. CONCLUSION: Three quarters of ophthalmologists report using a PRN protocol, and over 90% report seeing their patients monthly, either for injection or for a check-up. This apparent uniformity is in reality more complex: for the large majority, they prefer to closely follow the patient so as to treat the slightest recurrence, but with great variability in practices with regard to individualization of treatment. PMID- 26747018 TI - Recent advances in polymeric micelles for anti-cancer drug delivery. AB - Block co-polymeric micelles receive increased attention due to their ability to load therapeutics, deliver the cargo to the site of action, improve the pharmacokinetic of the loaded drug and reduce off-target cytotoxicity. While polymeric micelles can be developed with improved drug loading capabilities by modulating hydrophobicity and hydrophilicity of the micelle forming block co polymers, they can also be successfully cancer targeted by surface modifying with tumor-homing ligands. However, maintenance of the integrity of the self-assembled system in the circulation and disassembly for drug release at the site of drug action remain a challenge. Therefore, stimuli-responsive polymeric micelles for on demand drug delivery with minimal off-target effect has been developed and extensively investigated to assess their sensitivity. This review focuses on discussing various polymeric micelles currently utilized for the delivery of chemotherapeutic drugs. Designs of various stimuli-sensitive micelles that are able to control drug release in response to specific stimuli, either endogenous or exogenous have been delineated. PMID- 26747019 TI - A PK-PD model-based assessment of sugammadex effects on coagulation parameters. AB - Exposure-response analyses of sugammadex on activated partial thromboplastin time (APTT) and prothrombin time international normalized ratio (PT(INR)) were performed using data from two clinical trials in which subjects were co-treated with anti-coagulants, providing a framework to predict these responses in surgical patients on thromboprophylactic doses of low molecular weight or unfractionated heparin. Sugammadex-mediated increases in APTT and PT(INR) were described with a direct effect model, and this relationship was similar in the presence or absence of anti-coagulant therapy in either healthy volunteers or surgical patients. In surgical patients on thromboprophylactic therapy, model based predictions showed 13.1% and 22.3% increases in respectively APTT and PT(INR) within 30min after administration of 16mg/kg sugammadex. These increases remain below thresholds seen following treatment with standard anti-coagulant therapy and were predicted to be short-lived paralleling the rapid decline in sugammadex plasma concentrations. PMID- 26747020 TI - UHPLC/Q-TOFMS-based metabolomics for the characterization of cold and hot properties of Chinese materia medica. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The cold/hot property of Chinese materia medica (CMM) and the application of its corresponding knowledge in the diagnosis, differentiation and treatment of diseases have been considered to be the extremely important part of traditional Chinese medicine (TCM). As highly abstracted TCM theory, the cold/hot property of CMMs is still not fully understood and remains to be elucidated by systems biology approach. The cold and hot properties of CMM are mainly defined by the response of the body to a given CMM. Metabolomics is a promising systems biology method to profile entire endogenous metabolites and monitor their fluctuations related to an exogenous stimulus. Thus, a metabolomics approach was applied to characterize the cold and hot properties of CMMs. MATERIAL AND METHODS: Mice were intragastrically administered three selected cold property CMMs (i.e., Rheum palmatum L., radix et rhizoma; Coptis chinensis Franch, rhizome and Scutellaria baicalensis Georgi, radix) and three hot property CMMs (i.e., Cinnamomum cassia (L.) J. Presl, cortex; Zingiber officinale Roscoe, rhizoma and Evodia rutaecarpa (Juss.) Benth., fructus) once daily for one week. The comprehensive metabolome changes in the plasma of mice after treatment with cold or hot property CMMs were characterized by ultra-high performance liquid chromatography/time of flight mass spectrometry (UHPLC/Q-TOF-MS), and the potential biomarkers related to cold and hot properties of CMM were explored. RESULTS: Metabolites perturbation in plasma occurs after treatment with cold CMMs and hot CMMs in mice, and 15 and 16 differential biomarkers were identified to be associated with the cold and hot properties of CMMs, respectively. Among them, LPC (18:0), LPC (18:1), LPC (20:4) and LPC (20:5) showed decreased trends in the cold property CMM treated groups, but increased in the hot property CMM treated groups. CONCLUSIONS: There is a strong connection between the cold/hot property of CMMs and lysophosphatidylcholines metabolism. This study offers new insight into CMM properties and their clinical application. PMID- 26747021 TI - [Re-analysis of construct validity of the brief-version of the University of California Performance Skills Assessment (Sp-UPSA-Brief) of Garcia-Portilla et al]. PMID- 26747022 TI - Historical evolution of our knowledge of firefly eyes. Potential optical functions of the prothorax. PMID- 26747023 TI - Botulinum toxin type A as treatment of partially accommodative esotropia. AB - OBJECTIVE: To determine the effectiveness of a botulinum toxin type A injection in both medial rectus muscles in patients with partially accommodative esotropia. Residual deviation and stability of strabismus were evaluated at 18 months follow up. METHOD: A prospective, analytical, quasi-experimental study was conducted on a cohort of 21 patients who underwent total cycloplegic refraction and with a residual deviation of at least 14 DP. A botulinum toxin type A dose of 5 IU was injected into each medial rectus muscle for a residual deviation greater than 18 DP, with a dose of 2.5 IU being used for a deviation between 14 and 18 DP. Multivariate logistic regression analyses were performed to relate residual deviation to variables recorded as potential predictors. RESULTS: A total of 21 patients were included, 33.3% (n=7) males and 66.6% (n=14) females. Mean visual acuity was -.28+/-.25 logMAR for right eye (range 0 to -1) and -.42+/-.31 logMAR for left eye (range 0 to -1.3). Mean angle of residual deviation before application of botulinum toxin was 40.95+/-8.6DP without spectacles correction, and 22.3+/-7.99 DP with full cycloplegic refraction. Adverse effects were ptosis in 14.2% (n=3), diplopia 23.8% (n=5), and vertical deviation in 33% (n=7). One patient had a poor outcome, therefore required surgical treatment. At one year follow up, 85.71% of patients showed good results with esotropia of 12 DP or less, dropping to 71.43% at 18 months of follow up. CONCLUSION: Botulinum toxin type A is an effective long-term treatment with a good response in 71.43% of patients. No predictors of good response were demonstrated. PMID- 26747024 TI - Impact of parent-related factors on dental caries in the permanent dentition of 6 12-year-old children: A systematic review. AB - OBJECTIVE: To synthesise data from the literature on the effects of various parent-related characteristics (socio-demographic, behavioural and family environment) on dental caries in the permanent dentition of children. DATA: Available studies in which the effects of parent-related characteristics on dental caries experience in the permanent dentition of children aged 6-12 years were evaluated. SOURCES: PubMed, Medline via OVID and CINAHL Plus via EBSCO, restricted to scientific articles, were searched in April 2015. English language and time filters (articles published from 2000) were used. STUDY SELECTION: A total of 4162 titles were retrieved, of which 2578 remained after duplicates were removed. After review of titles and their abstracts by two independent reviewers, 114 articles were considered relevant for full text review. Of these, 48 were considered for final inclusion. Data extraction was performed by two authors using piloted data extraction sheets. CONCLUSIONS: Most of the literature on determinants of dental caries has been limited to socio-economic and behavioural aspects: we found few studies evaluating the effects of family environment and parental oral hygiene behaviour. Children belonging to lower socio-economic classes experienced more caries. In more than half the studies, children of highly educated, professional and high income parents were at lower risk for dental caries. There were conflicting results from studies on the effect of variables related to family environment, parents' oral hygiene behaviour and parent's disease status on dental caries in their children. PMID- 26747025 TI - In vitro aerodynamic characterization of the dose emitted during nebulization of tobramycin high strength solution by novel and jet nebulizer delivery systems. AB - BACKGROUND: Chronic infections with Pseudomonas aeruginosa are a leading cause of morbidity in patients with cystic fibrosis (CF). The aim of tobramycin inhalation therapy in CF patients with chronic pulmonary infection is to deliver high amounts of drug directly to the site of infection. TOBI((r)) is a tobramycin nebulizer solution (300 mg/5 ml) approved by FDA for maintenance therapy for patient with CF. The 20% tobramycin sulfate solution was reported as the optimal and maximal concentration. METHODS: Nebulization of high strength tobramycin solution (20% tobramycin sulfate) (HSTS) has been assessed in this study by using different selected high performance nebulizer delivery systems: two different designs of jet nebulizers, and three new nebulizers based on vibrating mesh technology. The aerosol particle size distribution and output characteristics were measured for in vitro performance assessment of the nebulizer systems. The methodology was adapted from the current European standard, EN 13544-1:2001E. RESULTS: The particle size distribution characteristic measurements showed that all tested nebulizers may be suitable for inhalation of HSTS. The mean (SD) of highest percentage of fine particles (<5 MUm) was 77.64 (2.3) % for Sidestream((r)), at flow rate 16 L/min. The highest respirable inhaled mass was for Pari LC Plus((r)) combined with PariBoyN((r)) compressor, with mean (SD) 90.85 (8.6) mg. The mean (SD) of highest drug wastage percentage was 63.9 (3.9) % for Sidestream((r)) jet nebulizer combined with compressed air cylinder at flow rate 16 L/min, while the lowest was 2.3 (0.26) % for NE-U22 Omron((r)) (high frequency). CONCLUSIONS: The HSTS can be nebulized by all tested nebulisers but the high frequency NE-U22 Omron((r)) and Aeroneb Go((r)) are more efficient. When the HSTS compared to TOBI((r)), the respirable inhaled dose was increased to more than 73%. PMID- 26747026 TI - Potential mechanisms for low uric acid in Parkinson disease. AB - Several epidemiologic studies have described an association between low serum uric acid (UA) and Parkinson disease (PD). Uric acid is a known antioxidant, and one proposed mechanism of neurodegeneration in PD is oxidative damage of dopamine neurons. However, other complex metabolic pathways may contribute. The purpose of this study is to elucidate potential mechanisms of low serum UA in PD. Subjects who met diagnostic criteria for definite or probable PD (n = 20) and controls (n = 20) aged 55-80 years were recruited. Twenty-four hour urine samples were collected from all participants, and both uric acid and allantoin were measured and corrected for body mass index (BMI). Urinary metabolites were compared using a twoway ANOVA with diagnosis and sex as the explanatory variables. There were no significant differences between PD and controls for total UA (p = 0.60), UA corrected for BMI (p = 0.37), or in the interaction of diagnosis and sex on UA (p = 0.24). Similarly, there were no significant differences between PD and controls for allantoin (p = 0.47), allantoin corrected for BMI (p = 0.57), or in the interaction of diagnosis and sex on allantoin (p = 0.78). Allantoin/UA ratios also did not significantly differ by diagnosis (p = 0.99). Our results imply that low serum UA in PD may be due to an intrinsic mechanism that alters the homeostatic set point for serum UA in PD, and may contribute to relatively lower protection against oxidative damage. These findings provide indirect support for neuroprotection trials aimed at raising serum UA. PMID- 26747028 TI - Response of dogs with urinary tract obstructions secondary to prostatic carcinomas to the alpha-1 antagonist prazosin. PMID- 26747030 TI - Vaginal birth after caesarean section: why is uptake so low? Insights from a meta ethnographic synthesis of women's accounts of their birth choices. AB - OBJECTIVE: To identify what women report influences their preferred mode of birth after caesarean section. DESIGN: Systematic review of qualitative literature using meta-ethnography. DATA SOURCES: Medline, EMBASE, ASSIA, CINAHL and PsycINFO (1996 until April 2013; updated September 2015). Hand-searched journals, reference lists and abstract authors. STUDY SELECTION: Primary qualitative studies reporting women's accounts of what influenced their preferred mode of birth after caesarean section. DATA EXTRACTION AND SYNTHESIS: Primary data (quotations from study participants) and authors' interpretations of these were extracted, compared and contrasted between studies, and grouped into themes to support the development of a 'line of argument' synthesis. RESULTS: 20 papers reporting the views of 507 women from four countries were included. Distinctive clusters of influences were identified for each of three groups of women. Women who confidently sought vaginal birth after a caesarean section were typically driven by a long-standing anticipation of vaginal birth. Women who sought a repeat caesarean section were strongly influenced by distressing previous birth experiences, and at times, by encouragement from social contacts. Women who were more open to information and professional guidance had fewer strong preconceptions and concerns, and viewed a range of considerations as potentially important. CONCLUSIONS: Women's attitudes towards birth after caesarean section appear to be shaped by distinct clusters of influences, suggesting that opportunities exist for clinicians to stratify and personalise decision support by addressing relevant ideas, concerns and experiences from the first caesarean section birth onwards. PMID- 26747029 TI - Factors associated with declining under-five mortality rates from 2000 to 2013: an ecological analysis of 46 African countries. AB - OBJECTIVE: Inadequate overall progress has been made towards the 4th Millennium Development Goal of reducing under-five mortality rates by two-thirds between 1990 and 2015. Progress has been variable across African countries. We examined health, economic and social factors potentially associated with reductions in under-five mortality (U5M) from 2000 to 2013. SETTING: Ecological analysis using publicly available data from the 46 nations within the WHO African Region. OUTCOME MEASURES: We assessed the annual rate of change (ARC) of 70 different factors and their association with the annual rate of reduction (ARR) of U5M rates using robust linear regression models. RESULTS: Most factors improved over the study period for most countries, with the largest increases seen for economic or technological development and external financing factors. The median (IQR) U5M ARR was 3.6% (2.8 to 5.1%). Only 4 of 70 factors demonstrated a strong and significant association with U5M ARRs, adjusting for potential confounders. Higher ARRs were associated with more rapidly increasing coverage of seeking treatment for acute respiratory infection (beta=0.22 (ie, a 1% increase in the ARC was associated with a 0.22% increase in ARR); 90% CI 0.09 to 0.35; p=0.01), increasing health expenditure relative to gross domestic product (beta=0.26; 95% CI 0.11 to 0.41; p=0.02), increasing fertility rate (beta=0.54; 95% CI 0.07 to 1.02; p=0.07) and decreasing maternal mortality ratio (beta=-0.47; 95% CI -0.69 to -0.24; p<0.01). The majority of factors showed no association or raised validity concerns due to missing data from a large number of countries. CONCLUSIONS: Improvements in sociodemographic, maternal health and governance and financing factors were more likely associated with U5M ARR. These underscore the essential role of contextual factors facilitating child health interventions and services. Surveillance of these factors could help monitor which countries need additional support in reducing U5M. PMID- 26747027 TI - Involvement of glutamatergic neurotransmission in the antidepressant-like effect of zinc in the chronic unpredictable stress model of depression. AB - Stress and excessive glutamatergic neurotransmission have been implicated in the pathophysiology of depression. Therefore, this study was aimed at investigating the influence of zinc on depressive-like behavior induced by chronic unpredictable stress (CUS), on alterations in glutamate-induced toxicity and immunocontent of proteins involved in the control of glutamatergic neurotransmission in the hippocampus of mice. Mice were subjected to CUS procedure for 14 days. From the 8th to the 14th day, mice received zinc chloride (ZnCl2) (10 mg/kg) or fluoxetine (10 mg/kg, positive control) once a day by oral route. CUS caused a depressive-like behavior evidenced by the increased immobility time in the tail suspension test (TST), which was prevented by treatment with ZnCl2 or fluoxetine. Ex vivo exposure of hippocampal slices to glutamate (10 mM) resulted in a significant decrease on cell viability; however, neither CUS procedure nor drug treatments altered this reduction. No alterations in the immunocontents of GLT-1 and GFAP or p-Akt were observed in any experimental group. The ratio of p-Akt/AKT was also not altered in any group. However, Akt immunocontent was increased in stressed mice and in animals treated with ZnCl2 (stressed or non-stressed mice) and EAAC1 immunocontent was increased in stressed mice treated with ZnCl2, fluoxetine or vehicle and in non-stressed mice treated with ZnCl2 and fluoxetine. These findings indicate a robust effect of zinc in reversing behavioral alteration induced by CUS in mice, through a possible modulation of the glutamatergic neurotransmission, extending literature data regarding the mechanisms underlying its antidepressant-like action. PMID- 26747032 TI - Are there long-term benefits of experiential, interprofessional education for non specialists on clinical behaviours and outcomes in diabetes care? A cohort study. AB - OBJECTIVES: Our aim was to assess the impact of an educational initiative for non specialist, healthcare professionals in the community on the process and quality measures of diabetes care delivered, and changes in their learning experiences and clinical management behaviour in the short and long term. SETTING: Single locality of 26 primary care practices associated with one secondary centre. PARTICIPANTS: General practitioners and practice nurses managing 4167 patients with diabetes. INTERVENTION: A rolling 10-week, experiential, interprofessional education programme delivered to 57 practitioners and observations in practice. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were changes in the proportion of patients receiving foot care, urine albumin:creatinine ratio assessments and achieving National Quality Outcome Framework targets for blood pressure (<145/80 mm Hg), glycated haemoglobin (HbA1c; >86 mmol/mol (10%) and <57.4 mmol/mol (7.4%)) and total cholesterol (<5 mmol/L) thresholds. Secondary outcomes were evidence of sustained learning and changes in the number of patients referred to secondary care. RESULTS: Evaluation of care processes and quality outcomes took place 15 months after the programme was initiated. The proportion of patients with a HbA1c of <57.4 mmol/mol (7.4%) and >85 mmol/mol (10%) was significantly higher (44% vs 53% p=0.0001) and lower (12.5% vs 10%; p=0.002) respectively. There was an increase in the proportion (95% CI) of patients receiving foot care reviews (+26.0% (24.0% to 28.1%)), microalbuminuria screening (+29.8% (27.7% to 31.9%)) and who achieved targets for blood pressure (+9.6% (7.5% to 11.6%)) and total cholesterol (+14.4% (12.3% to 16.5%); p<0.001). 241 fewer patients were referred to secondary care. Increases in the healthcare professional's confidence and collaborative clinical behaviour were evident 3 years after completing the programme. CONCLUSIONS: An experiential, interprofessional intervention can result in significant improvements in quality outcomes in association with a sustained impact on behaviours and practices. PMID- 26747031 TI - Patient-centredness as a quality domain in Swedish healthcare: results from the first national surveys in different Swedish healthcare settings. AB - OBJECTIVES: Patients' perception of the quality and patient-centredness of healthcare has gained increasing interest in the last decade in Sweden, as in other countries. The purpose of the study was to evaluate to what extent patients perceived Swedish healthcare as patient-centred and to explore the satisfaction levels related to gender, education level and to having or not having Swedish as one's mother tongue. DESIGN AND SETTINGS: This study has a cross-sectional design. Analyses were based on the first national patient surveys in Sweden, conducted between 2009 and 2010. The surveys included responses from 232,518 patients who had been in contact with primary, outpatient, inpatient, or emergency care units. Survey questions related to indicators of patient-centred care and sociodemographic variables were selected for the analysis. The patients' level of satisfaction in the selected indicators was analysed and compared by sociodemographic and background factors. Multivariable logistic regression models were used for analysis. RESULTS: The patients expressed high levels of satisfaction in questions related to the 'Respect' indicator (81-96% satisfied) but lower levels in most of the other indicators of patient-centred care. Only 25 30% of the patients reported they had been told about possible warning signs of their condition or treatment and 58-66% said they had received enough information about their condition. Group differences were detected. The most satisfied patient groups were men, individuals with low levels of education and those with Swedish as their mother tongue. CONCLUSIONS: According to these first national patient surveys, achieving patient-centred healthcare for all citizens is a challenge for Swedish healthcare authorities. Future analyses of national patient surveys should show whether national efforts to encourage acceptance of patient centred approaches and strategies for equal care will give intended results. PMID- 26747033 TI - Calcium channel blockers and cancer: a risk analysis using the UK Clinical Practice Research Datalink (CPRD). AB - OBJECTIVE: The evidence of an association between calcium channel blockers (CCBs) and cancer is conflicting. The objective of the present study was to evaluate the risk of cancer (all, breast, prostate and colon cancers) in association with exposure to CCB. METHODS: This is a population-based cohort study in patients exposed to CCBs from across the UK, using two comparison cohorts: (1) patients with no exposure to CCB (non-CCB) matched on age and gender and (2) unmatched patients unexposed to CCB and at least one other antihypertensive (AHT) prescription. Cancer incidence rates computed in the exposed and the two unexposed groups were compared using HRs and 95% CIs obtained from multivariate Cox regression analyses. RESULTS: Overall, 150,750, 557,931 and 156,966 patients were included, respectively, in the CCB, non-CCB and AHT cohorts. Crude cancer incidence rates per 1000 person-years were 16.51, 15.75 and 10.62 for the three cohorts, respectively. Adjusted HRs (CI) for all cancers comparing CCB, non-CCB and AHT cohorts were 0.88 (0.86 to 0.89) and 1.01 (0.98 to 1.04), respectively. Compared to the AHT cohort, adjusted HRs (CI) for breast, prostate and colon cancer for the CCB cohort were 0.95 (0.87 to 1.04), 1.07 (0.98 to 1.16) and 0.89 (0.81 to 0.98), respectively. Analyses by duration of exposure to CCB did not show excess risk. CONCLUSIONS: This large population-based study provides strong evidence that CCB use is not associated with an increased risk of cancer. The analyses yielded robust results across all types of cancer and different durations of exposure to CCBs. PMID- 26747035 TI - Validation of targeted next-generation sequencing for RAS mutation detection in FFPE colorectal cancer tissues: comparison with Sanger sequencing and ARMS Scorpion real-time PCR. AB - OBJECTIVE: To validate the targeted next-generation sequencing (NGS) platform-Ion Torrent PGM for KRAS exon 2 and expanded RAS mutations detection in formalin fixed paraffin-embedded (FFPE) colorectal cancer (CRC) specimens, with comparison of Sanger sequencing and ARMS-Scorpion real-time PCR. SETTING: Beijing, China. PARTICIPANTS: 51 archived FFPE CRC samples (36 men, 15 women) were retrospectively randomly selected and then checked by an experienced pathologist for sequencing based on histological confirmation of CRC and availability of sufficient tissue. METHODS: RAS mutations were detected in the 51 FFPE CRC samples by PGM analysis, Sanger sequencing and the Therascreen KRAS assay, respectively. Agreement among the 3 methods was assessed. Assay sensitivity was further determined by sequencing serially diluted DNA from FFPE cell lines with known mutation statuses. RESULTS: 13 of 51 (25.5%) cases had a mutation in KRAS exon 2, as determined by PGM analysis. PGM analysis showed 100% (51/51) concordance with Sanger sequencing (kappa=1.000, 95% CI 1 to 1) and 98.04% (50/51) agreement with the Therascreen assay (kappa=0.947, 95% CI 0.844 to 1) for detecting KRAS exon 2 mutations, respectively. The only discrepant case harboured a KRAS exon 2 mutation (c.37G>T) that was not covered by the Therascreen kit. The dilution series experiment results showed that PGM was able to detect KRAS mutations at a frequency of as low as 1%. Importantly, RAS mutations other than KRAS exon 2 mutations were also detected in 10 samples by PGM. Furthermore, mutations in other CRC-related genes could be simultaneously detected in a single test by PGM. CONCLUSIONS: The targeted NGS platform is specific and sensitive for KRAS exon 2 mutation detection and is appropriate for use in routine clinical testing. Moreover, it is sample saving and cost-efficient and time-efficient, and has great potential for clinical application to expand testing to include mutations in RAS and other CRC-related genes. PMID- 26747036 TI - Competing priorities in treatment decision-making: a US national survey of individuals with depression and clinicians who treat depression. AB - OBJECTIVE: To identify information priorities for consumers and clinicians making depression treatment decisions and assess shared decision-making (SDM) in routine depression care. DESIGN: 20 questions related to common features of depression treatments were provided. Participants were initially asked to select which features were important, and in a second stage they were asked to rank their top 5 'important features' in order of importance. Clinicians were asked to provide rankings according to both consumer and clinician perspectives. Consumers completed CollaboRATE, a measure of SDM. Multiple logistic regression analysis identified consumer characteristics associated with CollaboRATE scores. SETTING: Online cross-sectional surveys fielded in September to December 2014. PARTICIPANTS: We administered surveys to convenience samples of US adults with depression and clinicians who treat depression. Consumer sampling was targeted to reflect age, gender and educational attainment of adults with depression in the USA. PRIMARY OUTCOME MEASURES: Information priority rankings; CollaboRATE, a 3 item consumer-reported measure of SDM. RESULTS: 972 consumers and 244 clinicians completed the surveys. The highest ranked question for both consumers and clinicians was 'Will the treatment work?' Clinicians were aware of consumers' priorities, yet did not always prioritise that information themselves, particularly insurance coverage and cost of treatment. Only 18% of consumers reported high levels of SDM. Working with a psychiatrist (OR 1.87; 95% CI 1.07 to 3.26) and female gender (OR 2.04; 95% CI 1.25 to 3.34) were associated with top CollaboRATE scores. CONCLUSIONS: While clinicians know what information is important to consumers making depression treatment decisions, they do not always address these concerns. This mismatch, coupled with low SDM, adversely affects the quality of depression care. Development of a decision support intervention based on our findings can improve levels of SDM and provide clinicians and consumers with a tool to address the existing misalignment in information priorities. PMID- 26747034 TI - Associations of vitamin D status, bone health and anthropometry, with gross motor development and performance of school-aged Indian children who were born at term with low birth weight. AB - OBJECTIVES: There is little information regarding motor development of children born at term with low birth weight (LBW), a group that constitutes a large proportion of children in South Asia. We used data from infancy and at school age from a LBW cohort to investigate children's motor performance using causal inference. DESIGN: Cross-sectional follow-up study. SETTING: Delhi, India. PARTICIPANTS: We recruited 912 children aged 5 years who had participated in a trial of vitamin D for term LBW infants in the first 6 months of life. OUTCOME MEASURES: We focused on gross motor development, using the Ages and Stages Questionnaire (ASQ) gross motor scale and several measures of motor performance. We examined the effects on these of current anthropometry, vitamin D status and bone health, controlling for age, sex, season of interview, socioeconomic variables, early growth, recent morbidity, sun exposure and animal food intake. RESULTS: In adjusted analyses, stunted children (height-for-age Z (HAZ) <-2) took longer to run 20 m (0.52 s, 95% CI 0.35 to 0.70; p<0.001) and had greater odds of a failing score on the ASQ (OR 3.00, 95% CI 1.41 to 6.38, p=0.004). Greater arm muscle area was associated with faster run time, and the ability to perform more stands and squats in 15 s. Poorer vitamin D status was associated with the ability to perform more stands and squats. Lower tibia ultrasound Z score was associated with greater hand grip strength. Early growth and current body mass index had no associations with motor outcomes. CONCLUSIONS: Current HAZ and arm muscle area showed the strongest associations with gross motor outcomes, likely due to a combination of simple physics and factors associated with stunting. The counterintuitive inverse associations of tibia health and vitamin D status with outcomes may require further research. PMID- 26747037 TI - The harms of smoking and benefits of smoking cessation in women compared with men with type 2 diabetes: an observational analysis of the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron modified release Controlled Evaluation) trial. AB - OBJECTIVES: In general populations, the adverse effects of smoking on coronary risk have been demonstrated to be greater in women than in men; whether this is true for individuals with diabetes is unclear. DESIGN: Cohort study. SETTING: 20 countries worldwide participating in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron modified release Controlled Evaluation) trial. PARTICIPANTS: 11,140 patients with type 2 diabetes aged >= 55 years and in cardiovascular risk at the time of randomisation. PRIMARY AND SECONDARY OUTCOME MEASURES: Major cardiovascular events (death from cardiovascular disease, non fatal stroke or non-fatal myocardial infarction (MI)), all cardiovascular events (major cardiovascular event or peripheral arterial disease or transient ischaemic attack), and all-cause mortality. Secondary outcome measures were major coronary events (fatal and non-fatal MI), major cerebrovascular events (fatal and non fatal stroke), nephropathy (new or worsening renal disease), and all cancer. RESULTS: At baseline, 6466 (56% women) participants were never-smokers, 1550 (28% women) were daily smokers and 3124 (21% women) were former smokers. Median follow up time was 5 years. In Cox regression models after multiple adjustments, compared with never smoking, daily smoking was associated with increased risk of all primary and secondary outcomes with the exception of major cerebrovascular disease. Only for major coronary events was there any evidence of a stronger effect in women than in men (ratio of the adjusted HRs women:men; 1.64 (0.83 to 3.26) p=0.08). For all other outcomes considered, the hazards of smoking were similar in men and women. Quitting smoking was associated with a 30% reduction in all-cause mortality (p=0.001) in both sexes. CONCLUSIONS: In individuals with diabetes, the effects of smoking on all major forms of cardiovascular disease are equally as hazardous in women and men with the possible exception of major coronary events where there was some evidence of a greater hazard in women. TRIAL REGISTRATION NUMBER: NCT00145925. PMID- 26747039 TI - A qualitative assessment of the impact of a uterine balloon tamponade package on decisions regarding the role of emergency hysterectomy in women with uncontrolled postpartum haemorrhage in Kenya and Senegal. AB - OBJECTIVES: To assess the impact of a every second matters for mothers and babies uterine balloon tamponade package (ESM-UBT) on provider decisions regarding emergency hysterectomy in cases of uncontrolled postpartum haemorrhage (PPH). DESIGN: Qualitative assessment and analysis of a subgroup extracted from a larger database that contains all UBT device uses among ESM-UBT trained health providers. SETTING: Health facilities in Kenya and Senegal with ESM-UBT training and capable of performing emergency hysterectomies. PARTICIPANTS: All medical doctors who had placed a UBT for uncontrolled PPH subsequent to implementation of ESM-UBT at their facility, and who also had the capabilities of performing emergency hysterectomies. PRIMARY OUTCOME MEASURES: The impact of ESM-UBT on decisions regarding emergency hysterectomy in cases of uncontrolled PPH. RESULTS: 30 of the 31 medical doctors (97%) who fulfilled the inclusion criteria were independently interviewed. Collectively the interviewed medical doctors had placed over 80 UBT devices for uncontrolled PPH since ESM-UBT implementation. All 30 responded that UBT devices immediately controlled haemorrhage and prevented women from being taken to emergency hysterectomy. All 30 would continue to use UBT devices in future cases of uncontrolled PPH. CONCLUSIONS: These preliminary data suggest that following ESM-UBT implementation, emergency hysterectomy for uncontrolled PPH may be averted by use of uterine balloon tamponade. PMID- 26747038 TI - Lessons learnt from the Bristol Girls Dance Project cluster RCT: implications for designing and implementing after-school physical activity interventions. AB - OBJECTIVE: To consider implementation issues associated with the delivery of Bristol Girls Dance Project (BGDP) and to identify improvements that may aid the design of after-school physical activity (PA) interventions. DESIGN: Two-armed cluster randomised control trial. The BGDP was a 20-week school-based intervention, consisting of two 75 min after-school dance sessions per week, which aimed to support Year 7 girls to be more physically active. SETTING: 18 secondary schools (nine intervention, nine control) in the Greater Bristol area (as an indication of deprivation, children eligible for the pupil premium in participant schools ranged from 6.9 to 53.3%). PARTICIPANTS: 571 Year 7 girls. This article reports on qualitative data collected from 59 girls in the intervention arm of the trial, 10 dance instructors and 9 school contacts involved in the delivering of the BGDP. METHODS: Data were obtained from nine focus groups with girls (one per intervention school), and interviews with dance instructors and school contacts. Focus groups sought views of girls' motivation to participate, teaching styles and experiences of the intervention. Interviews explored views on implementation and dissemination. Framework analysis was used to analyse data. RESULTS: Qualitative data elicited three themes associated with the delivery of BGDP that affected implementation: project design, session content and project organisation. 'Project design' found issues associated with recruitment, timetabling and session quantity to influence the effectiveness of BGDP. 'Session content' found that dance instructors delivered a range of content and that girls enjoyed a variety of dance. Themes within 'project organisation' suggested an 'open enrolment' policy and greater parental involvement may facilitate better attendance. CONCLUSIONS: After-school PA interventions have potential for increasing PA levels among adolescent girls. There is a need to consider the context in which interventions are delivered and implement them in ways that are appropriate to the needs of participants. TRIAL REGISTRATION NUMBER: ISRCTN52882523. PMID- 26747040 TI - Adolescent girls and young adult women's perceptions of superslims cigarette packaging: a qualitative study. AB - OBJECTIVES: To explore perceptions of superslims packaging, including compact 'lipstick' packs, in line with 3 potential impacts identified within the impact assessment of the European Union (EU) Tobacco Products Directive: appeal, harm perceptions and the seriousness of warning of health risks. DESIGN: Qualitative focus group study. SETTING: Informal community venues in Scotland, UK. PARTICIPANTS: 75 female non-smokers and occasional smokers (age range 12-24). RESULTS: Compact 'lipstick'-type superslims packs were perceived most positively and rated as most appealing. They were also viewed as less harmful than more standard sized cigarette packs because of their smaller size and likeness to cosmetics. Additionally, 'lipstick' packs were rated as less serious in terms of warning about the health risks associated with smoking, either because the small font size of the warnings was difficult to read or because the small pack size prevented the text on the warnings from being displayed properly. Bright pack colours and floral designs were also thought to detract from the health warning. CONCLUSIONS: As superslims packs were found to increase appeal, mislead with respect to level of harm, and undermine the on-pack health warnings, this provides support for the decision to ban 'lipstick'-style cigarette packs in the EU and has implications for policy elsewhere. PMID- 26747041 TI - Assessing access to paediatric trauma centres in Canada, and the impact of the golden hour on length of stay at the hospital: an observational study. AB - OBJECTIVES: In Canada injuries are a leading cause of death and morbidity among the paediatric population. Trauma systems have been established across North America to provide comprehensive injury care and to lead injury control efforts. However, not all populations have equal access to trauma care services. This is an observational study with the aim of assessing the impact of geographical access to paediatric trauma centres (PTCs) on patient outcomes, and to determine spatial access to PTCs across Canada. SETTING: To examine the relationship between access to PTC and injury outcome, length of stay at the PTC was determined for all injured patients who live within and outside of 60 min driving time of the PTC. To determine spatial access to PTCs across Canada, a list of level 1 and 2 PTCs was identified across Canada. A 1 h driving time catchment was created around each PTC in order to estimate spatial accessibility. PARTICIPANTS: Hospital administration data sets from British Columbia (BC) and the Nova Scotia (NS) trauma registry were used to assess the impact of spatial access on paediatric injury (ages 0-15 years) outcomes. The data sets provided case-level data including the Injury Severity Score, postal code of place of residence, age and length of hospital stay. RESULTS: In NS and BC, average length of stay at the hospital is significantly lower inside 60 min driving time compared to outside of 60 min driving time from a PTC (p<0.05, using a non-parametric t test). In Canada, approximately 65% of the paediatric population resides within 1 h of a PTC. CONCLUSIONS: This paper highlights differences in injury outcomes as a result of access. However, further investigation is needed as other considerations such as type of injury, age and/or gender may also affect injury outcomes. PMID- 26747043 TI - Local True Discovery Rate Weighted Polygenic Scores Using GWAS Summary Data. AB - A polygenic score is commonly derived using genome-wide genotype data to summarize the genetic contribution to a particular disease at the individual level. Usually it is constructed as a linear combination of SNP genotype weighted by the SNP-wise regression coefficient of the SNP to the phenotype using SNPs with p values smaller than a particular threshold. Commonly a range of thresholds are used which can pose problems with multiple comparisons as well as over fitting. Here, an alternative weighting scheme is proposed, making use of the local true discovery rate, estimated from summary statistics. Two methods of estimation are proposed-maximum likelihood and kernel density estimation. Simulation studies using real and artificial data suggest this new weighting scheme is highly comparable with standard polygenic scores using the best possible p value threshold in prediction, even though this threshold is not normally known in practice. PMID- 26747042 TI - Morphometric analysis of stab wounds by MSCT and MRI after the instillation of contrast medium. AB - OBJECTIVE: To analyze the morphology and depth of stab wounds experimentally produced on human legs amputated for medical reasons using multislice computed tomography (MSCT) and magnetic resonance imaging (MRI) after the instillation of a single contrast medium solution (CMS). MATERIALS AND METHODS: For morphological analysis, MSCT and MRI scans were performed before and after the instillation of CMS into the wound cavity. Depth measurements were performed on the sagittal view only after CMS instillation. Subsequently, each wound was dissected using the layer-by-layer technique and the depth was measured by a ruler. One-way between groups pairwise analysis of variance (ANOVA) and Bland-Altman plot analysis were used for comparing radiological and anatomical measurements. RESULTS: Unenhanced MSCT images did not identify the wound channels, whereas unenhanced MRI evidenced the wound cavity in 50 % of cases. After the instillation of CMS, both MSCT and MRI depicted the wound channel in all the investigated stabbings, although the morphology of the cavity was irregular and did not resemble the shape of the blade. The radiological measurements of the wounds' depth, after the application of CMS, exhibited a high level of agreement (about 95 % at Bland-Altman plot analysis) with the anatomical measurements at dissection. A similar systematic underestimation, however, has been evidenced for MSCT (average 11.4 %; 95 % CI 7 17) and MRI (average 9.6 %; 95 % CI 6-13) data after the instillation of CMS with respect to wound dissection measurements. CONCLUSION: MSCT and MRI after the instillation of CMS can be used for depicting the morphometric features of stab wounds, although depth measurements are affected by a slight systematic underestimation compared to layer-by-layer dissection. PMID- 26747044 TI - Detection of QTLs for cold tolerance of rice cultivar 'Kuchum' and effect of QTL pyramiding. AB - KEY MESSAGE: A QTL for cold tolerance at the booting stage of rice cultivar 'Kuchum' was detected and delimited into a 1.36 Mb region, and a cold-tolerant line was developed by QTL pyramiding. Low temperature in summer causes pollen sterility in rice, resulting in a serious loss of yield. The second most widely grown rice cultivar in Japan, 'Hitomebore', has been developed as a cultivar highly tolerant to low temperature at the booting stage. However, even 'Hitomebore' exhibits sterility at a temperature lower than 18.5 degrees C. Further improvement of cold tolerance of rice is required. In the present study, QTLs for cold tolerance in a Bhutanese rice variety, 'Kuchum', were analyzed using backcrossed progenies and a major QTL, named qCT-4, was detected on chromosome 4. Evaluating cold tolerance of seven types of near isogenic lines having 'Kuchum' alleles around qCT-4 with a 'Hitomebore' genetic background, qCT 4 was delimited to a region of ca. 1.36 Mb between DNA markers 9_1 and 10_13. Homozygous 'Kuchum' alleles at qCT-4 showed an effect of increasing seed fertility by ca. 10 % under cold-water treatment. Near isogenic lines of 'Hitomebore' having 'Silewah' alleles of Ctb1 and Ctb2 and a 'Hokkai PL9' allele of qCTB8 did not exhibit higher cold tolerance than that of 'Hitomebore'. On the other hand, a qLTB3 allele derived from a Chinese cultivar 'Lijiangxintuanheigu' increased cold tolerance of 'Hitomebore', and pyramiding of the qCT-4 allele and the qLTB3 allele further increased seed fertility under cold-water treatment. Since NILs of 'Hitomebore' with the 'Kuchum' allele of qCT-4 were highly similar to 'Hitomebore' in other agronomic traits, the qCT-4 allele is considered to be useful for developing a cold-tolerant cultivar. PMID- 26747045 TI - Fine genetic mapping of spot blotch resistance gene Sb3 in wheat (Triticum aestivum). AB - KEY MESSAGE: Spot blotch disease resistance gene Sb3 was mapped to a 0.15 centimorgan (cM) genetic interval spanning a 602 kb physical genomic region on chromosome 3BS. Wheat spot blotch disease, caused by B. sorokiniana, is a devastating disease that can cause severe yield losses. Although inoculum levels can be reduced by planting disease-free seed, treatment of plants with fungicides and crop rotation, genetic resistance is likely to be a robust, economical and environmentally friendly tool in the control of spot blotch. The winter wheat line 621-7-1 confers immune resistance against B. sorokiniana. Genetic analysis indicates that the spot blotch resistance of 621-7-1 is controlled by a single dominant gene, provisionally designated Sb3. Bulked segregant analysis (BSA) and simple sequence repeat (SSR) mapping showed that Sb3 is located on chromosome arm 3BS linked with markers Xbarc133 and Xbarc147. Seven and twelve new polymorphic markers were developed from the Chinese Spring 3BS shotgun survey sequence contigs and 3BS reference sequences, respectively. Finally, Sb3 was mapped in a 0.15 cM genetic interval spanning a 602 kb physical genomic region of Chinese Spring chromosome 3BS. The genetic and physical maps of Sb3 provide a framework for map-based cloning and marker-assisted selection (MAS) of the spot blotch resistance. PMID- 26747046 TI - Introgression of genes from bread wheat enhances the aluminium tolerance of durum wheat. AB - KEY MESSAGE: The aluminium tolerance of durum wheat was markedly enhanced by introgression of TaALMT1 and TaMATE1B from bread wheat. In contrast to bread wheat, TaMATE1B conferred greater aluminium tolerance than TaALMT1. Durum wheat (tetraploid AABB, Triticum turgidum) is a species that grows poorly on acid soils due to its sensitivity of Al(3+). By contrast, bread wheat (hexaploid AABBDD, T. aestivum) shows a large variation in Al(3+) tolerance which can be attributed to a major gene (TaALMT1) located on chromosome 4D as well as to other genes of minor effect such as TaMATE1B. Genotypic variation for Al(3+) tolerance in durum germplasm is small and the introgression of genes from bread wheat is one option for enhancing the ability of durum wheat to grow on acid soils. Introgression of a large fragment of the 4D chromosome previously increased the Al(3+) tolerance of durum wheat demonstrating the viability of transferring the TaALMT1 gene to durum wheat to increase its Al(3+) tolerance. Here, we used a ph1 (pairing homoeologous) mutant of durum wheat to introgress a small fragment of the 4D chromosome harboring the TaALMT1 gene. The size of the 4D chromosomal fragment introgressed into durum wheat was estimated by markers, fluorescence in situ hybridisation and real-time quantitative PCR. In a parallel strategy, we introgressed TaMATE1B from bread wheat into durum wheat using conventional crosses. Both genes separately increased the Al(3+) tolerance of durum wheat in both hydroponics and soil cultures. In contrast to bread wheat, the TaMATE1B gene was more effective than TaALMT1 in increasing the Al(3+) tolerance of durum wheat grown on acid soil. PMID- 26747047 TI - Genetics and mapping of a novel downy mildew resistance gene, Pl(18), introgressed from wild Helianthus argophyllus into cultivated sunflower (Helianthus annuus L.). AB - KEY MESSAGE: A novel downy mildew resistance gene, Pl(18), was introgressed from wild Helianthus argophyllus into cultivated sunflower and genetically mapped to linkage group 2 of the sunflower genome. The new germplasm, HA-DM1, carrying Pl(18) has been released to the public. Sunflower downy mildew (DM) is considered to be the most destructive foliar disease that has spread to every major sunflower-growing country of the world, except Australia. A new dominant downy mildew resistance gene (Pl 18) transferred from wild Helianthus argophyllus (PI 494573) into cultivated sunflower was mapped to linkage group (LG) 2 of the sunflower genome using bulked segregant analysis with 869 simple sequence repeat (SSR) markers. Phenotyping 142 BC1F2:3 families derived from the cross of HA 89 and H. argophyllus confirmed the single gene inheritance of resistance. Since no other Pl gene has been mapped to LG2, this gene was novel and designated as Pl (18). SSR markers CRT214 and ORS203 flanked Pl(18) at a genetic distance of 1.1 and 0.4 cM, respectively. Forty-six single nucleotide polymorphism (SNP) markers that cover the Pl(18) region were surveyed for saturation mapping of the region. Six co-segregating SNP markers were 1.2 cM distal to Pl(18), and another four co segregating SNP markers were 0.9 cM proximal to Pl(18). The new BC2F4-derived germplasm, HA-DM1, carrying Pl(18) has been released to the public. This new line is highly resistant to all Plasmopara halstedii races identified in the USA providing breeders with an effective new source of resistance against downy mildew in sunflower. The molecular markers that were developed will be especially useful in marker-assisted selection and pyramiding of Pl resistance genes because of their close proximity to the gene and the availability of high-throughput SNP detection assays. PMID- 26747049 TI - Erratum to: Separation and Characterization of Epithelial and Mesenchymal-like Murine Mammary Tumor Cells Reveals Epithelial Cell Differentiation Plasticity and Enhanced Tumorigenicity of Epithelial-enriched Tumor Cells. PMID- 26747048 TI - Genomic selection in a commercial winter wheat population. AB - KEY MESSAGE: Genomic selection models can be trained using historical data and filtering genotypes based on phenotyping intensity and reliability criterion are able to increase the prediction ability. We implemented genomic selection based on a large commercial population incorporating 2325 European winter wheat lines. Our objectives were (1) to study whether modeling epistasis besides additive genetic effects results in enhancement on prediction ability of genomic selection, (2) to assess prediction ability when training population comprised historical or less-intensively phenotyped lines, and (3) to explore the prediction ability in subpopulations selected based on the reliability criterion. We found a 5 % increase in prediction ability when shifting from additive to additive plus epistatic effects models. In addition, only a marginal loss from 0.65 to 0.50 in accuracy was observed using the data collected from 1 year to predict genotypes of the following year, revealing that stable genomic selection models can be accurately calibrated to predict subsequent breeding stages. Moreover, prediction ability was maximized when the genotypes evaluated in a single location were excluded from the training set but subsequently decreased again when the phenotyping intensity was increased above two locations, suggesting that the update of the training population should be performed considering all the selected genotypes but excluding those evaluated in a single location. The genomic prediction ability was substantially higher in subpopulations selected based on the reliability criterion, indicating that phenotypic selection for highly reliable individuals could be directly replaced by applying genomic selection to them. We empirically conclude that there is a high potential to assist commercial wheat breeding programs employing genomic selection approaches. PMID- 26747050 TI - The efficacy and safety of low-dose radiotherapy on pain and functioning in patients with osteoarthritis: a systematic review. AB - Low-dose radiotherapy (LD-RT) has been widely used for treatment of non-malignant disorders since its introduction and animal studies show anti-inflammatory effects in osteoarthritis (OA). However, the evidence for its effect in clinical practice remains unclear. Therefore, the aim of this study is to systematically summarise the literature on effectiveness of LD-RT on pain and functioning in patients with OA and its safety. Broad search terms were used to search PubMed, EMBASE and Web of Science. Primary inclusion criteria were osteoarthritis as indication, radiotherapy as intervention, written in English, German or Dutch and published since 1980. Study quality was assessed using the EPHPP Quality Assessment Tool for Quantitative Studies (scale: strong, moderate, weak). Seven studies were suitable for inclusion, all with retrospective uncontrolled observational design. Methodological quality of all studies was judged as weak. Most studies used 2-3 RT sessions per week for 2 weeks, some with booster session after 6 weeks. Generally, non-validated single-item measurement instruments were used to evaluate the effect of LD-RT on pain and function. Across the studies, in 25-90 and 29-71 % of the patients pain and functioning improved, respectively. Side effects were described in one study, none were reported. Our results show that there is insufficient evidence for efficacy or to confirm the safety of LD RT in treatment of OA, due to absence of high-quality studies. Therefore, a well designed, sham-controlled and blinded randomised trial, using validated outcome measures is warranted to demonstrate the value of LD-RT for OA in clinical practice. PMID- 26747051 TI - Determining the effects and challenges of incorporating genetic testing into primary care management of hypertensive patients with African ancestry. AB - People of African ancestry (Blacks) have increased risk of kidney failure due to numerous socioeconomic, environmental, and clinical factors. Two variants in the APOL1 gene are now thought to account for much of the racial disparity associated with hypertensive kidney failure in Blacks. However, this knowledge has not been translated into clinical care to help improve patient outcomes and address disparities. GUARDD is a randomized trial to evaluate the effects and challenges of incorporating genetic risk information into primary care. Hypertensive, non diabetic, adults with self-reported African ancestry, without kidney dysfunction, are recruited from diverse clinical settings and randomized to undergo APOL1 genetic testing at baseline (intervention) or at one year (waitlist control). Providers are educated about genomics and APOL1. Guided by a genetic counselor, trained staff return APOL1 results to patients and provide low-literacy educational materials. Real-time clinical decision support tools alert clinicians of their patients' APOL1 results and associated risk status at the point of care. Our academic-community-clinical partnership designed a study to generate information about the impact of genetic risk information on patient care (blood pressure and renal surveillance) and on patient and provider knowledge, attitudes, beliefs, and behaviors. GUARDD will help establish the effective implementation of APOL1 risk-informed management of hypertensive patients at high risk of CKD, and will provide a robust framework for future endeavors to implement genomic medicine in diverse clinical practices. It will also add to the important dialog about factors that contribute to and may help eliminate racial disparities in kidney disease. PMID- 26747052 TI - Metabolic Syndrome in Children and Adolescents: a Critical Approach Considering the Interaction between Pubertal Stage and Insulin Resistance. AB - Pediatricians increasingly diagnose the metabolic syndrome (MetS) in recent years to describe cardiovascular risk and to guide management of the obese child. However, there is an ongoing discussion about how to define the MetS in childhood and adolescence. Since insulin resistance-the major driver of MetS-is influenced by pubertal stage, it is questionable to use definitions for MetS in children and adolescents that do not take into account pubertal status. A metabolic healthy status in prepubertal stage does not predict a metabolic healthy status during puberty. Furthermore, cardiovascular risk factors improve at the end of puberty without treatment. However, having a uniform internationally accepted definition of the MetS for children and adolescents would be very helpful for the description of populations in different studies. Therefore, the concept of MetS has to be revisited under the influence of puberty stage. PMID- 26747054 TI - No difference in compensation for sugar in a drink versus sugar in semi-solid and solid foods. AB - It is claimed that sugar consumed in a drink is poorly compensated for by a reduction in subsequent energy intake, however very little research has tested directly the effect on appetite of adding sugar to a drink versus food. In this between subjects study, 144 participants (72 men) consumed preloads sweetened with either sucrose or the low-energy sweetener, sucralose (preload energy difference 162kcal) in the form of a blackcurrant drink, jelly or candy. The different preload viscosities were achieved by varying the amount of thickener (carrageenan) and water in the recipes. Participants completed hunger ratings before and 5, 10 and 20min after consuming their preload. After the 20-minute rating they were served a test-meal comprising an excess of bite-sized sandwiches and a sweet dessert. Energy intake measured for the same meal consumed the previous day (baseline day, no preload consumed) was used in the data analyses to control for individual differences in energy intake. Overall, there was 36% compensation for the energy difference in the preloads, but this did not vary with preload viscosity - if anything compensation was greater for the drink preload, and greater in men. The drink preload also showed an effect of sucrose versus sucralose for hunger. The lack of the predicted effect of viscosity on compensation could not be explained by differences in blood-glucose concentration 20min after the preload (measured in a separate study) or by differences in preload sweetness, flavour intensity, liking or familiarity. Comparison of baseline and test-meal food intakes indicated that, irrespective of energy content, the sweet drinks reduced the relative intake of sweet food. In conclusion, short-term energy compensation did not differ across a set of realistic drink and food stimuli. PMID- 26747053 TI - Ribosomal protein genes are highly enriched among genes with allele-specific expression in the interspecific F1 hybrid catfish. AB - Interspecific hybrids provide a rich source for the analysis of allele-specific expression (ASE). In this work, we analyzed ASE in F1 hybrid catfish using RNA Seq datasets. While the vast majority of genes were expressed with both alleles, 7-8 % SNPs exhibited significant differences in allele ratios of expression. Of the 66,251 and 177,841 SNPs identified from the datasets of the liver and gill, 5420 (8.2 %) and 13,390 (7.5 %) SNPs were identified as significant ASE-SNPs, respectively. With these SNPs, a total of 1519 and 3075 ASE-genes were identified. Gene Ontology analysis revealed that genes encoding cytoplasmic ribosomal proteins (RP) were highly enriched among ASE genes. Parent-of-origin was determined for 27 and 30 ASE RP genes in the liver and gill, respectively. The results indicated that genes from both channel catfish and blue catfish were involved in ASE. However, each RP gene appeared to be almost exclusively expressed from only one parent, indicating that ribosomes in the hybrid catfish were in the "hybrid" form. Overall representation of RP transcripts among the transcriptome appeared lower in the F1 hybrid catfish than in channel catfish or blue catfish, suggesting that the "hybrid" ribosomes may work more efficiently for translation in the F1 hybrid catfish. PMID- 26747055 TI - Structural characterization and biological activities of two alpha-glucans from radix paeoniae alba. AB - Radix Paeoniae Alba is widely used in Chinese traditional medicine to treat various diseases such as gastrointestinal disorders, cancer, and other diseases. In this study, two polysaccharides RPAPW1 and RPAPW2 were isolated from Radix Paeoniae Alba by DEAE-52 cellulose chromatography and G-25 sephadex. According to physicochemical methods, NMR and methylation analysis, RPAPW1 and RPAPW2 were established to be alpha-glucans consisting of predominant 4-linked alpha- Glc residues branched at O-6 and contained trace amount of protein and uronic acid. Immunological tests indicated that RPAPW1, RPAPW2 and could promote splenocyte proliferation and RAW264.7 phagocytic activity. In vitro, RPAPW1 and RPAPW2 elicited a week reducing power, DPPH scavenging activity and could not protect the PC12 cells from H2O2 damage. These data implied polysaccharides RPAPW1 and RPAPW2 had the potential to be a natural immunopotentiating and antioxidant supplement for preparing functional foods and nutraceuticals. PMID- 26747056 TI - The role of altered cutaneous immune responses in the induction and persistence of rosacea. AB - Rosacea is a chronic inflammatory skin condition that predominantly affects the skin of the face and the eyes. Several factors are associated with the onset and persistence of the condition, including an altered immune response in the skin and elevated levels of Demodex mites. Alterations in the immune response include elevated levels of LL-37 in rosacea skin, increased expression of TLR-2 and increased amounts of vitamin D3 in epidermal tissue. The combined effect of these changes may make the skin more sensitive to external and internal stimuli. External stimuli that may trigger or sustain rosacea inflammation include exposure to ultraviolet light, while internal factors may include the presence of elevated numbers of Demodex mites. These mites may directly stimulate an immune response or release bacteria within the pilosebaceous unit that act as a trigger for inflammation. This review will highlight the changes that occur in the immune response of the skin and describe how Demodex mites and associated bacteria may activate this response and lead to the characteristics of rosacea. PMID- 26747057 TI - Juglone up-regulates sirt1 in skin cells under normal and UVB irradiated conditions. PMID- 26747058 TI - CGRP and migraine. PMID- 26747059 TI - Comment on: Pharmacokinetics of Tramadol and O-Desmethyltramadol Enantiomers Following Administration of Extended-Release Tablets to Elderly and Young Subjects. PMID- 26747060 TI - Self-reported Function, Health Resource Use, and Total Health Care Costs Among Medicare Beneficiaries With Glaucoma. AB - IMPORTANCE: The effect of glaucoma on nonglaucomatous medical conditions and resultant secondary health care costs is not well understood. OBJECTIVE: To assess self-reported medical conditions, the use of medical services, and total health care costs among Medicare beneficiaries with glaucoma. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal observational study of 72,587 Medicare beneficiaries in the general community using the Medicare Current Beneficiary Survey (2004-2009). Coding to extract data started in January 2015, and analyses were performed between May and July 2015. MAIN OUTCOMES AND MEASURES: Self reported health, the use of health care services, adjusted mean annual total health care costs per person, and adjusted mean annual nonoutpatient costs per person. RESULTS: Participants were 72,587 Medicare beneficiaries 65 years or older with (n = 4441) and without (n = 68,146) a glaucoma diagnosis in the year before collection of survey data. Their mean age was 76.9 years, and 43.2% were male. Patients with glaucoma who responded to survey questions on visual disability were stratified into those with (n = 1748) and without (n = 2639) self reported visual disability. Medicare beneficiaries with glaucoma had higher adjusted odds of inpatient hospitalizations (odds ratio [OR], 1.27; 95% CI, 1.17 1.39; P < .001) and home health aide visits (OR, 1.27; 95% CI, 1.13-1.43; P < .001) compared with Medicare beneficiaries without glaucoma. Furthermore, patients with glaucoma with self-reported visual disability were more likely to report depression (OR, 1.47; 95% CI, 1.26-1.71; P < .001), falls (OR, 1.34; 95% CI, 1.09-1.66; P = .006), and difficulty walking (OR, 1.22; 95% CI, 1.02-1.45; P = .03) compared with those without self-reported visual disability. In the risk adjusted model, Medicare beneficiaries with glaucoma incurred an additional $2903 (95% CI, $2247-$3558; P < .001) annual total health care costs and $2599 (95% CI, $1985-$3212; P < .001) higher costs for nonoutpatient services compared with Medicare beneficiaries without glaucoma. CONCLUSIONS AND RELEVANCE: Glaucoma is associated with greater use of inpatient and home health aide services and with higher annual total and nonoutpatient medical costs. Perception of vision loss among patients with glaucoma may be associated with depression, falls, and difficulty walking. Reducing the prevalence and severity of glaucoma may result in improvements in associated nonglaucomatous medical conditions and resultant reduction in health care costs. PMID- 26747061 TI - Characterization of carbapenem-resistant Acinetobacter calcoaceticus-baumannii complex isolates from nosocomial bloodstream infections in southern Iran. AB - Acinetobacter baumannii is an important opportunistic bacterial pathogen responsible for serious infections in hospitalized patients. From a total of 78 consecutive non-repetitive Acinetobacter spp. isolates from patients with blood infections, 61 were carbapenem resistant, which were positive for blaOXA-51-like (96.7%), blaOXA-23-like (77 %), blaOXA-58-like (8.1%) and blaOXA-40-like genes (32.8%) by multiplex PCR. The isolates were identified as A. baumannii (n = 59) and Acinetobacter nosocomialis (n = 2). Also, we found a case of Acinetobacter junii, causing bacteraemia, that possessed the IMP gene. High levels of resistance were observed to fluoroquinolones, aminoglycosides, tigecycline and to the beta-lactam antibiotics, including piperacillin/tazobactam and ampicillin/sulbactam. ISAba1 was present in 96.7% of all Acinetobacter calcoaceticus-baumannii complex (Acb) isolates. Also, 33 (54.1%) and 23 (37.7%) isolates harboured ISAba1 upstream of blaOXA-23-like and blaOXA-51-like genes, respectively, though this was not observed in A. nosocomialis isolates. No relationship was observed between the presence of ISAba1 upstream of oxacillinase genes and the level of carbapenem resistance in all Acb isolates. Only two genes encoding metallo-beta-lactamase (VIM, SPM) were detected in all Acb isolates. This suggests that carbapenem resistance in blood-isolate Acb is mostly due to the presence of acquired carbapenemases. This is the first report from Iran on the identification of A. nosocomialis isolates that possess multiple oxacillinase genes and lack upstream ISAba1. PMID- 26747062 TI - Osteoporosis Overtreatment in a Regional Health Care System. PMID- 26747064 TI - The Long Drive Ahead to Better Understanding Chronic Traumatic Encephalopathy: First (Case) and 10 (Years Later). PMID- 26747063 TI - Social cognition in schizophrenia: factor structure, clinical and functional correlates. AB - BACKGROUND: Social cognition is consistently impaired in people with schizophrenia, separable from general neurocognition, predictive of real-world functioning and amenable to psychosocial treatment. Few studies have empirically examined its underlying factor structure. AIMS: This study (1) examines the factor structure of social cognition in both a sample of individuals with schizophrenia-spectrum disorders and non-clinical controls and (2) explores relationships of factors to neurocognition, symptoms and functioning. METHOD: A factor analysis was conducted on social cognition measures in a sample of 65 individuals with schizophrenia or schizoaffective disorder, and 50 control participants. The resulting factors were examined for their relationships to symptoms and functioning. RESULTS: Results suggested a two-factor structure in the schizophrenia sample (social cognition skill and hostile attributional style) and a three-factor structure in the non-clinical sample (hostile attributional style, higher-level inferential processing and lower-level cue detection). In the schizophrenia sample, the social cognition skill factor was significantly related to negative symptoms and social functioning, whereas hostile attributional style predicted positive and general psychopathology symptoms. CONCLUSIONS: The factor structure of social cognition in schizophrenia separates hostile attributional style and social cognition skill, and each show differential relationships to relevant clinical variables in schizophrenia. PMID- 26747065 TI - The Environmental Domain of Quality of Life in Patients with Chronic Respiratory Diseases. AB - The literature lacks reports on the role played by the Environmental domain of quality of life (QoL) in care for patients with chronic respiratory diseases. Such information has a high potential for implementation in modern medicine based on a 'tailor-made' holistic healthcare model. The purpose of this study was to determine the components that shape the Environmental domain of QoL in patients with chronic respiratory diseases. The study group consisted of 305 adult patients (median age 65 years) with at least one chronic respiratory disease. The greatest contribution to a high value of QoL in the Environmental domain among patients with chronic respiratory diseases was made by the coexistence of high QoL levels in other domains and in satisfaction with QoL. Programs for preventing a decline in QoL in the Environmental domain should include patients with low scores for the above variables as well as those with a low level of education, those who have not shown an improvement in their psychological well-being in the past 12 months, those with a low level of positive mental attitudes or healthy eating habits, a low Camberwell index, and low levels of overall pro-health behavior. PMID- 26747066 TI - Chronic Cough as a Female Gender Issue. AB - Cough accompanying acute respiratory tract disorders is a self-limiting phenomenon, and it usually does not require sophisticated management. Chronic cough, in contrast, is a bothersome problem, considerably influencing the quality of life of affected individuals. Specialized cough clinics report that substantial proportion of their patients are middle aged-to-postmenopausal females who cough for years in response to otherwise non-tussigenic stimuli, without a clear underlying disease reason. A newly established entity - 'cough hypersensitivity syndrome' explains pathogenesis of this problem. However, the syndrome has not been generally accepted, and the guidelines regarding the diagnostic protocols and treatment are not yet available. The reason why females cough more than males do is unclear, but the analysis of literature and experience with the chronic cough patients allows selecting three main targets of hormonal background which can contribute to the enhanced coughing in females. They are as follows: increased activity of transient receptor potential (TRP) channels expressed on vagal C-fibers mediating cough, laryngeal hypersensitivity and laryngeal dysfunction with paradoxical vocal cord movement, and mast cells which are known to express receptors for female sexual hormones and are frequently found in the bronchoalveolar lavage in chronic cough patients. In this review we analyze the potential contribution of the factors above outlined to excessive cough in female subjects. PMID- 26747067 TI - Treatment Options for Central Sleep Apnea: Comparison of Ventilator, Oxygen, and Drug Therapies. AB - Central sleep apnea (CSA) is a sleep-related disorder characterized by pauses in breathing during sleep when the brain respiratory network momentarily interrupts transmission of impulses to the respiratory musculature. CSA presents significant problems being an independent risk factor for cardiovascular events and death. There are several available treatment options according to CSA severity. Currently, adaptive servo-ventilation is considered best for CSA patients. The goal of the present study was to retrospectively investigate different treatment methods employed for CSA, such as different modes of ventilation, oxygen therapy, and drugs to determine the most effective one. Data were obtained from hospital records during 2010-2015. The diagnosis of CSA and the optimal treatment method were supported by polysomnography examinations. Devices used during sleep to support breathing included continuous positive airway pressure, bi-level positive airway pressure, or adaptive servo-ventilation. We classified 71 (2.9 %) patients as having CSA from 2,463 patients with sleep-disordered breathing. Of those 71 patients, 54 (76.1 %, 95 % CI 66.2-86.0 %) were male and 17 (23.9 %, 95 % CI 14.0 33.8 %) were female, and they had a mean age of 67.1 +/- 14.1. Four (5.6 %) patients underwent a combination therapy, 39 (54.9 %) received a ventilator in proper ventilation mode, 25 (35.2 %) received oxygen therapy, 7 (9.9 %) received medication, and 4 (5.6 %) received no treatment. We conclude that although the majority of patients needed treatment for central sleep apnea, a clear advantage in using ventilators when compared to oxygen therapy or drug therapy could not be found. PMID- 26747069 TI - Next-Generation Sequencing of 5' Untranslated Region of Hepatitis C Virus in Search of Minor Viral Variant in a Patient Who Revealed New Genotype While on Antiviral Treatment. AB - The role of mixed infections with different hepatitis C virus (HCV) genotypes in viral persistence, treatment effects, and tissue tropism is unclear. Next generation sequencing (NGS), which is suitable for analysis of large, genetically diverse populations offers unparalleled advantages for the study of mixed infections. The aim of the study was to determine, using two different deep sequencing strategies (pyrosequencing - 454 Life Sciences/Roche and reversible terminator sequencing-by-synthesis by Illumina), the origin of a novel HCV genotype transiently detectable during antiviral therapy (pre-existing minor population vs. de novo superinfection). Secondly, we compared 5' untranslated region (5'-UTR) variants obtained by the two NGS approaches. 5' UTR amplification products from 9 samples collected from genotype 1b infected patient before, during, and after treatment (4 serum and 5 peripheral blood mononuclear cell - PBMC - samples) were subjected to the next-generation sequencing. The sequencing revealed the presence of two (454/Roche) and one (Illumina) genotype 4 variants in PBMC at Week 16. None of these variants were present either in the preceding or following samples as revealed by both platforms. 454/Roche sequencing detected 24 different 5'-UTR variants: 8 were present in serum and PBMC, 4 only in serum and 12 only in PBMC. Illumina sequencing detected 11 different 5'-UTR variants: 5 in serum and PBMC, 4 only in serum and 2 only in PBMC. Six variants were identical for both sequencing platforms. The difference in variants number was primarily due to variability in two 5'-UTR homopolymeric regions. In conclusion, longitudinal analysis of HCV variants, employing two independent deep sequencing methods, suggests that the transient presence of a different genotype strain in PBMC was a result of superinfection and not a selection of pre-existing minor variant. PMID- 26747070 TI - Respiratory Toxicity of Dimethyl Sulfoxide. AB - Dimethyl sulfoxide (DMSO) is one of the most commonly used solvents for hydrophobic substances in biological experiments. In addition, the compound exhibits a plethora of bioactivities, which makes it of potential pharmacological use of its own. The influence on respiration, and thus on arterial blood oxygenation, of DMSO is unclear, contentious, and an area of limited study. Thus, in the present investigation we set out to determine the influence on lung ventilation of cumulated doses of DMSO in the amount of 0.5, 1.5, 3.5, 7.5, and 15.5 g/kg; each dose given intraperitoneally at 1 h interval in conscious mice. Ventilation and its responses to 7 % hypoxia (N(2) balanced) were recorded in a whole body plethsymograph. We demonstrate a dose-dependent inhibitory effect of DMSO on lung ventilation and its hypoxic responsiveness, driven mostly by changes in the tidal component. The maximum safe dose of DMSO devoid of meaningful consequences for respiratory function was 3.5 g/kg. The dose of 7.5 g/kg of DMSO significantly dampened respiration, with yet well preserved hyperventilatory response to hypoxia. The highest dose of 15.5 g/kg severely impaired ventilation and its responses. The study delineates the safety profile of DMSO regarding the respiratory function which is essential for maintaining proper tissue oxygenation. Caution should be exercised concerning dose concentration of DMSO. PMID- 26747068 TI - Growing Antibiotic Resistance in Fatal Cases of Staphylococcal Pneumonia in the Elderly. AB - Older people are often especially susceptible to pneumonia and bacteria may develop resistance to antibiotics quicker in the elderly, whose immune systems gradually diminish. This study analyses, retrospectively, resistance to antibiotics in high-risk elderly patients with fatal pneumonia. Records of all patients aged over 65 who did not survive a bout with pneumonia were gathered from the records of the Department of Pneumology of HELIOS Clinic in Wuppertal, Germany from the period of 2004-2014. Susceptibility testing was executed for the study population, whose pneumonia was triggered by various kinds of bacteria. We detected 936 pneumonia patients of the overall mean age of 68.0 +/- 13.6 years, with the following pneumonia types: 461 (49.3 %) community-acquired, 354 (37.8 %) nosocomial-acquired, and 121 (12.9 %) aspiration pneumonia. There were 631 (67.4 %) males and 305 (32.6 %) females there. We identified 672 (71.8 %) patients who had a high risk for pneumonia, especially staphylococcal pneumonia (p < 0.0001). The elderly patients had a higher risk of dying from pneumonia (2.9 odds ratio, 95 % confidence interval 1.8-4.6; p < 0.0001); of the 185 pneumonia-related deaths, 163 (88.1 %) were in the elderly. In those with fatal staphylococcal pneumonia, a high antibiotic resistance rate was found for piperacillin tazobactam (p = 0.044), cefuroxime (p = 0.026), cefazolin (p = 0.043), levofloxacin (p = 0.018), erythromycin (p = 0.004), and clindamycin (p = 0.025). We conclude that elderly patients with staphylococcal pneumonia show resistance to common antibiotics. However, no significant antibiotic resistance could be ascribed for other types of pneumonia in these patients. PMID- 26747071 TI - Coexpression of Galanin and Nestin in the Chemoreceptor Cells of the Human Carotid Body. AB - The carotid body is a highly specialized chemoreceptive organ of neural crest origin whose role is to detect changes in arterial oxygen content. The sensory units are the chemoreceptor cells, which are neuronal-like cells, surrounded by sustentacular or glial-like cells. It is suggested that the carotid body contains self-renewing multipotent stem cells, which are putatively represented by glial like sustentacular cells. The mechanisms of renewal of neuronal-like cells are unclear. Recently, we have demonstrated the expression of galanin, a peptide promoting neurogenesis, in chemoreceptor cells in the human CB. Thus, in the present study we seek to determine whether galanin expression in chemoreceptor cells could be matched with that of nestin, a peptide that is a marker of multipotent neural stem cells, or rather with the glial fibrillary acidic protein (GFAP), a marker for glial cells. The latter would underscore the pluasibly essential role of sustentacular cells in the self-renewal capability of chemorecetors. We found that galanin expression is matched with nestin in chemoreceptor cells of the human carotid body, but not with that of GFAP. Thus, galanin expression in chemoreceptor cells could provide a signal for neurogenesis and chemoreceptor cell differentiation in the carotid body. PMID- 26747074 TI - A 15-Year-Old Boy With Trisomy 21 and Postoperative Weakness. PMID- 26747075 TI - JAMA Pediatrics Patient Page. Atopic Diseases in Children. PMID- 26747076 TI - Effect of the Healthy Hunger-Free Kids Act on the Nutritional Quality of Meals Selected by Students and School Lunch Participation Rates. AB - IMPORTANCE: Effective policies have potential to improve diet and reduce obesity. School food policies reach most children in the United States. OBJECTIVE: To assess the nutritional quality of foods chosen by students and meal participation rates before and after the implementation of new school meal standards authorized through the Healthy Hunger-Free Kids Act. DESIGN, SETTING, AND PARTICIPANTS: This descriptive, longitudinal study examined changes in the nutritional quality of 1,741,630 school meals at 3 middle schools and 3 high schools in an urban school district in Washington state. Seventy two hundred students are enrolled in the district; 54% are eligible for free and reduced-price meals. Student food selection data were collected daily from January 2011 through January 2014 during the 16 months prior to and the 15 months after implementation of the Healthy Hunger-Free Kids Act. EXPOSURE: The Healthy Hunger-Free Kids Act. MAIN OUTCOMES AND MEASURES: Nutritional quality was assessed by calculating monthly mean adequacy ratio and energy density of the foods selected by students each day. Six nutrients were included in the mean adequacy ratio calculations: calcium, vitamin C, vitamin A, iron, fiber, and protein. Monthly school meal participation was calculated as the mean number of daily meals served divided by student enrollment. Mean monthly values of mean adequacy ratio, energy density, and participation were compared before and after policy implementation. RESULTS: After implementation of the Healthy Hunger-Free Kids Act, change was associated with significant improvement in the nutritional quality of foods chosen by students, as measured by increased mean adequacy ratio from a mean of 58.7 (range, 49.6-63.1) prior to policy implementation to 75.6 (range, 68.7-81.8) after policy implementation and decreased energy density from a mean of 1.65 (range, 1.53-1.82) to 1.44 (range, 1.29-1.61), respectively. There was negligible difference in student meal participation following implementation of the new meal standards with 47% meal participation (range, 40.4%-49.5%) meal participation prior to the implemented policy and 46% participation (range, 39.1%-48.2%) afterward. CONCLUSIONS AND RELEVANCE: Food policy in the form of improved nutrition standards was associated with the selection of foods that are higher in nutrients that are of importance in adolescence and lower in energy density. Implementation of the new meal standards was not associated with a negative effect on student meal participation. In this district, meal standards effectively changed the quality of foods selected by children. PMID- 26747077 TI - Radiograph-Negative Lateral Ankle Injuries in Children: Occult Growth Plate Fracture or Sprain? AB - IMPORTANCE: Lateral ankle injuries without radiographic evidence of a fracture are a common pediatric injury. These children are often presumed to have a Salter Harris type I fracture of the distal fibula (SH1DF) and managed with immobilization and orthopedic follow-up. However, previous small studies suggest that these injuries may represent ankle sprains rather than growth plate fractures. OBJECTIVES: To determine the frequency of SH1DF using magnetic resonance imaging (MRI) and compare the functional recovery of children with fractures identified by MRI vs those with isolated ligament injuries. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study was conducted between September 2012 and August 2014 at 2 tertiary care pediatric emergency departments. We screened 271 skeletally immature children aged 5 to 12 years with a clinically suspected SH1DF; 170 were eligible and 140 consented to participate. INTERVENTIONS: Children underwent MRI of both ankles within 1 week of injury. Children were managed with a removable brace and allowed to return to activities as tolerated. MAIN OUTCOMES AND MEASURES: The proportion with MRI-confirmed SH1DF. A secondary outcome included the Activity Scale for Kids score at 1 month. RESULTS: Of the 135 children who underwent ankle MRI, 4 (3.0%; 95% CI, 0.1%-5.9%) demonstrated MRI-confirmed SH1DF, and 2 of these were partial growth plate injuries. Also, 108 children (80.0%) had ligament injuries and 27 (22.0%) had isolated bone contusions. Of the 108 ligament injuries, 73 (67.6%) were intermediate to high-grade injuries, 38 of which were associated with radiographically occult fibular avulsion fractures. At 1 month, the mean (SD) Activity Scale for Kids score of children with MRI-detected fibular fractures (82.0% [17.2%]) was not significantly different from those without fractures (85.8% [12.5%]) (mean difference, -3.8%; 95% CI, -1.7% to 9.2%). CONCLUSIONS AND RELEVANCE: Salter-Harris I fractures of the distal fibula are rare in children with radiograph fracture-negative lateral ankle injuries. These children most commonly have ligament injuries (sprains), sometimes associated with radiographically occult avulsion fractures. Children with fractures detectable only by MRI had a comparable recovery with those with sprains when treated with a removable ankle brace and self-regulated return to activities. This work has the potential to simplify the care of these common injuries, safely minimizing the inconveniences and costs of overtreatment. PMID- 26747078 TI - Revisiting Radiograph-Negative Ankle Injuries in Children: Is It a Fracture or a Sprain? PMID- 26747079 TI - Successes of the Healthy Hunger-Free Kids Act. PMID- 26747080 TI - Sick Neonate Score: Better than Others in Resource Restricted Settings? PMID- 26747081 TI - Approach to Joint Pain in Children. AB - It is not uncommon in pediatric clinical practice to encounter children with musculoskeletal symptoms. A number of disparate conditions can present with joint complaints in children. In this article, the author describes the clinical approach to a child presenting with joint complaints. A detailed clinical history, including the family history, along with a complete physical examination can provide vital clues to the underlying condition in most cases. A structured screening examination of the musculoskeletal system that has been recently developed (i.e., pGALS) is also discussed. It is also pointed out that the pattern of joint involvement gives us one of the most important clues to the etiology of arthritis. The pediatrician has to be aware of the conditions that can have arthritis as one of the manifestations so as to investigate and treat the child accordingly. PMID- 26747082 TI - Exchange Transfusion in Severe Neonatal Sepsis: Is it Beneficial? PMID- 26747083 TI - Use of a Cumulative Risk Scale to Predict Poor Intellectual and Academic Outcomes in Childhood Epilepsy. AB - Discrete risk factors for poor outcomes in childhood epilepsy have been identified, but it is unclear whether the combined effect of several risk factors better predicts outcome. The Epilepsy Cumulative Risk Scale was developed to quantify cumulative risk for poor outcomes in childhood epilepsy. Participants included 156 clinic-referred children with epilepsy. The Epilepsy Cumulative Risk Scale was developed using variables previously associated with functional outcomes. Scale utility was examined through its association with intellectual and academic functioning. All Epilepsy Cumulative Risk Scale variables were significantly associated with functioning. The Total Score (ie, cumulative effect) was most strongly correlated with cognition and academic skills. A Total Score >= 5 had the best sensitivity and specificity for differentiating those at high risk for poor outcomes. The Epilepsy Cumulative Risk Scale shows promise as a practical, data-driven tool for quantification of cumulative risk for poor outcomes in childhood epilepsy and may be helpful in detecting those needing referral for additional services. PMID- 26747084 TI - Genetic studies of Polish migraine patients: screening for causative mutations in four migraine-associated genes. AB - BACKGROUND AND AIM: Migraine is the most common neurological disorder, affecting approximately 12 % of the adult population worldwide, caused by both environmental and genetic factors. Three causative genes have been identified in familial hemiplegic migraine (FHM) families: CACNA1A, ATP1A2, and SCNA1A. Recently, several mutations in KCNK18 have also been found as causative factors in migraine development. The aim of our study was to identify the genetic background of migraine in the Polish population. MATERIAL AND METHODS: Sixty patients with migraine without aura (MO) or with different types of migraine with aura (MA), including sporadic hemiplegic, familial hemiplegic, and probable familial hemiplegic, were screened for mutations in the four genes previously linked with different types of migraine (ATP1A2, CACNA1A, SCN1A, and KCNK18). RESULTS: Two missense mutations were found. One novel mutation in SCN1A, encoding alpha subunit of sodium channel, causing amino acid change M1500V localized to a region encoding inactivation loop between transmembrane domains III and IV of the channel, was detected in a female FHM patient. The M1500V mutation was absent in a group of 62 controls, as well as in the ExAC database. The second, already known missense mutation S231P in KCNK18 was found in a female MA patient. Additionally, a novel intronic polymorphism possibly affecting alternative splicing of SCN1A, at chr2:16685249, g.77659T>C, and c.4581+32A>G, located between exons 24 and 25, in a region encoding the inactivation loop of the sodium channel was found in a female MO patient. No mutations in ATP1A2 or CACNA1A were found in the study group. CONCLUSIONS: The presence of SCN1A mutations and absence of mutations in ATP1A2 or CACNA1A suggest that the Polish patients represent FHM type 3. On the other hand, the presence of KCNK18 mutation indicated another FHM subtype. It could be speculated that contrary to other European populations, the genetic basis of migraine in the Polish population involves mutations in genes not included in the study. Next-generation sequencing methods should be implemented to identify other migraine-associated variants. PMID- 26747085 TI - Influence of EMS-physician presence on survival after out-of-hospital cardiopulmonary resuscitation: systematic review and meta-analysis. AB - BACKGROUND: Evidence suggests that EMS-physician-guided cardiopulmonary resuscitation (CPR) in out-of-hospital cardiac arrest (OOHCA) may be associated with improved outcomes, yet randomized controlled trials are not available. The goal of this meta-analysis was to determine the association between EMS-physician versus paramedic-guided CPR and survival after OOHCA. METHODS AND RESULTS: Studies that compared EMS-physician- versus paramedic-guided CPR in OOHCA published until June 2014 were systematically searched in MEDLINE, EMBASE and Cochrane databases. All studies were required to contain survival data. Data on study characteristics, methods, and as well as survival outcomes were extracted. A random-effects model was used for the meta-analysis due to a high degree of heterogeneity among the studies (I(2) = 44%). Return of spontaneous circulation [ROSC], survival to hospital admission, and survival to hospital discharge were the outcome measures. Out of 3,385 potentially eligible studies, 14 met the inclusion criteria. In the pooled analysis (n = 126,829), EMS-physician-guided CPR was associated with significantly improved outcomes compared to paramedic guided CPR: ROSC 36.2% (95% confidence interval [CI] 31.0 - 41.7%) vs. 23.4% (95% CI 18.5 - 29.2%) (pooled odds ratio [OR] 1.89, 95% CI 1.36 - 2.63, p < 0.001); survival to hospital admission 30.1 % (95% CI 24.2 - 36.7%) vs. 19.2% (95% CI 12.7 - 28.1%) (pooled OR 1.78, 95% CI 0.97 - 3.28, p = 0.06); and survival to discharge 15.1% (95% CI 14.6 - 15.7%) vs. 8.4% (95% CI 8.2 - 8.5%) (pooled OR 2.03, 95% CI 1.48 - 2.79, p < 0.001). CONCLUSIONS: This systematic review suggests that EMS-physician-guided CPR in out-of-hospital cardiac arrest is associated with improved survival outcomes. PMID- 26747086 TI - Cardiac Outcomes in Adult Survivors of Childhood Cancer Exposed to Cardiotoxic Therapy: A Cross-sectional Study. AB - BACKGROUND: Studies of cardiac disease among adult survivors of childhood cancer have generally relied on self-reported or registry-based data. OBJECTIVE: To systematically assess cardiac outcomes among survivors of childhood cancer. DESIGN: Cross-sectional study. SETTING: St. Jude Children's Research Hospital. PATIENTS: 1853 adult survivors of childhood cancer, aged 18 years or older, who received cancer-related cardiotoxic therapy at least 10 years earlier. MEASUREMENTS: Baseline history and physical examination, fasting metabolic and lipid panels, echocardiography, electrocardiography, and 6-minute walk test. RESULTS: One half of the survivors (52.3%) were men with a median age of 8 years (range, 0 to 24 years) at cancer diagnosis and 31 years (range, 18 to 60 years) at evaluation. Cardiomyopathy was present in 7.4% survivors (newly identified at the time of evaluation in 4.7%), coronary artery disease in 3.8% (newly identified in 2.2%), valvular regurgitation or stenosis in 28.0% (newly identified in 24.8%), and conduction or rhythm abnormalities in 4.4% (newly identified in 1.4%). Nearly all survivors were asymptomatic. The prevalence of cardiac conditions increased with age at evaluation, ranging from 3% to 24% among survivors aged 30 to 39 years to 10% to 37% among those aged 40 years or older. In multivariable analysis, survivors exposed to anthracycline doses of 250 mg/m2 or more had greater odds of cardiomyopathy (odds ratio, 2.7 [95% CI, 1.1 to 6.9]) than those who were not exposed. Survivors exposed to heart radiation also had increased odds of cardiomyopathy (odds ratio, 1.9 [CI, 1.1 to 3.7]) compared with those who were not exposed. Radiation exposure greater than 1500 cGy with any anthracycline exposure conferred the greatest odds for valve findings. LIMITATIONS: Sixty-one percent of survivors exposed to anthracycline chemotherapy or cardiac-directed radiation participated. A comparison group and longitudinal assessments were not available. CONCLUSION: Cardiovascular screening identified considerable subclinical disease among adult survivors of childhood cancer. PRIMARY FUNDING SOURCE: National Cancer Institute, American Lebanese Syrian Associated Charities. PMID- 26747089 TI - Coarse-Grained Model for Water Involving a Virtual Site. AB - In this work, we propose a new coarse-grained (CG) model for water by combining the features of two popular CG water models (BMW and MARTINI models) as well as by adopting a topology similar to that of the TIP4P water model. In this CG model, a CG unit, representing four real water molecules, consists of a virtual site, two positively charged particles, and a van der Waals (vdW) interaction center. Distance constraint is applied to the bonds formed between the vdW interaction center and the positively charged particles. The virtual site, which carries a negative charge, is determined by the locations of the two positively charged particles and the vdW interaction center. For the new CG model of water, we coined the name "CAVS" (charge is attached to a virtual site) due to the involvment of the virtual site. After being tested in molecular dynamic (MD) simulations of bulk water at various time steps, under different temperatures and in different salt (NaCl) concentrations, the CAVS model offers encouraging predictions for some bulk properties of water (such as density, dielectric constant, etc.) when compared to experimental ones. PMID- 26747088 TI - Striatal Reward Activity and Antipsychotic-Associated Weight Change in Patients With Schizophrenia Undergoing Initial Treatment. AB - IMPORTANCE: Weight gain is a common and serious adverse effect of antipsychotic treatment. A variable individual predisposition to development of metabolic disturbances calls for predictive biological markers. OBJECTIVES: To investigate whether attenuated striatal activity during reward anticipation is associated with amisulpride-induced weight change in antipsychotic-naive patients with schizophrenia undergoing initial treatment and to examine the association between weight change and changes in reward anticipation activity after treatment. DESIGN, SETTING, AND PARTICIPANTS: Sixty-nine antipsychotic-naive inpatients and outpatients with schizophrenia were included in a multimodal longitudinal cohort study from December 16, 2008, to December 11, 2013. Fifty-eight patients underwent functional magnetic resonance imaging (fMRI) while performing a monetary reward task. After 6 weeks of treatment with amisulpride, a relatively selective dopamine D2 antagonist, 39 patients underwent a second fMRI scan and measurement of change in body weight. Final follow-up was completed on January 14, 2014, and data were analyzed from October 25, 2014, to June 15, 2015 and August 31 to September 19, 2015. EXPOSURES: Six weeks of individually dosed amisulpride treatment. MAIN OUTCOMES AND MEASURES: Reward-anticipation activity in the striatum before and after treatment and weight change. RESULTS: Of the 69 patients who consented to the study, 39 underwent the follow-up fMRI and weight measurement (age range, 18-45 years; 17 women and 22 men). The mean (SD) daily dose of amisulpride was 272 (168; range, 50-800) mg, and patients gained a mean (SD) of 2.3 (2.8; range, -4 to 8) kg in body weight. Improvement from baseline to follow-up was found on the mean (SD) positive (19.9 [4.1] to 14.3 [3.8]), general (39.7 [7.7] to 30.5 [7.7]), and total (78.5 [15.3] to 63.2 [13.9]) scores on the Positive and Negative Syndrome Scale (P < .001). Weight gain was predicted by low mean (SD) baseline reward-related activity in the right-sided putamen (0.20 [0.93]; F35,3 = 5.64; P = .003). After 6 weeks, weight gain was associated with an increase in mean (SD) reward activity in the same region during treatment (0.28 [0.74]; F37,1 = 4.48; P = .04). CONCLUSIONS AND RELEVANCE: Activity in striatal regions of the reward system appears to be associated with the individual variability in the predisposition for antipsychotic-associated weight gain. Moreover, pharmacologic modulation of the reward system may play a role in antipsychotic-associated weight gain. PMID- 26747090 TI - CRISPR/Cas-mediated genome editing to treat EGFR-mutant lung cancer: a personalized molecular surgical therapy. PMID- 26747087 TI - Both HDAC5 and HDAC6 are required for the proliferation and metastasis of melanoma cells. AB - BACKGROUND: Histone deacetylase (HDAC) inhibitors are widely used in clinical investigation as novel drug targets. For example, panobinostat and vorinostat have been used to treat patients with melanoma. However, HDAC inhibitors are small-molecule compounds without a specific target, and their mechanism of action is unclear. Therefore, it is necessary to investigate which HDACs are required for the proliferation and metastasis of melanoma cells. METHODS: We used overexpression and knocking down lentivirus to clarify the influence of HDAC5 and HDAC6 in melanoma development. Also, we introduced stable HDAC5 or HDAC6 knockdown cells into null mice and found that the knockdown cells were unable to form solid tumors. Finally, we tested HDAC5 and HDAC6 expression and sub-location in clinical melanoma tissues and tumor adjacent tissues. RESULTS: In this study, and found that HDAC5 and HDAC6 were highly expressed in melanoma cells but exhibited low expression levels in normal skin cells. Furthermore, we knocked down HDAC5 or HDAC6 in A375 cells and demonstrated that both HDAC5 and HDAC6 contributed to the proliferation and metastasis of melanoma cells. CONCLUSIONS: This study demonstrated both HDAC5 and HDAC6 were required for melanoma cell proliferation and metastasis through different signaling pathways. PMID- 26747091 TI - Pancreatic cancer microenvironment, to target or not to target? AB - We have collectively been spoiled by the astounding clinical benefit of antimicrobials. Much like the discovery and use of penicillin to eradicate once deadly infections, we continue to desperately search for the next "magic bullet" to kill cancer while sparing the non-transformed cells. Greater appreciation for the molecular intricacies of malignancy has resulted in dedicated pursuit of cancer genomics and large-scale informatics to identify "drugable" targets within the cancer cell itself. However, studies at the bench elucidating a dynamic relationship between tumor and microenvironment have become more common and demonstrate promise for novel therapeutic intervention. PMID- 26747092 TI - Backbones versus core agents in initial ART regimens: one game, two players. AB - The advances seen in ART during the last 30 years have been outstanding. Treatment has evolved from the initial use of single agents as monotherapy. The ability to use HIV RNA as a surrogate marker for clinical outcomes allowed the more rapid evaluation of new therapies. This led to the understanding that triple drug regimens, including a core agent (an NNRTI or a boosted PI) and two NRTIs, are optimal. These combinations have demonstrated continued improvements in their efficacy and toxicity as initial therapy. However, the need for pharmacokinetic boosting, with potential drug-drug interactions, or residual issues of efficacy or toxicity have persisted for some agents. Most recently, integrase strand transfer inhibitors, particularly dolutegravir, have shown unparalleled safety and efficacy and are currently the core agents of choice. Regimens that included only core agents or only backbone agents have not been as successful as combined therapy in antiretroviral-naive patients. It appears that at least one NRTI is needed for optimal performance and lamivudine and emtricitabine may be the ideal candidates. Several studies are ongoing of agents with longer dosing intervals, lower cost and new NRTI-saving strategies to address unmet needs. PMID- 26747093 TI - Comment on: Subcutaneous ivermectin use in the treatment of severe Strongyloides stercoralis infection: two case reports and a discussion of the literature. PMID- 26747094 TI - The purine analogues abacavir and didanosine increase acetaminophen-induced hepatotoxicity by enhancing mitochondrial dysfunction. AB - BACKGROUND: NRTIs are essential components of HIV therapy with well-documented, long-term mitochondrial toxicity in hepatic cells, but whose acute effects on mitochondria are unclear. As acetaminophen-induced hepatotoxicity also involves mitochondrial interference, we hypothesized that it would be exacerbated in the context of ART. METHODS: We evaluated the acute effects of clinically relevant concentrations of the most widely used NRTIs, alone or combined with acetaminophen, on mitochondrial function and cellular viability. RESULTS: The purine analogues abacavir and didanosine produced an immediate and concentration dependent inhibition of oxygen consumption and complex I and III activity. This inhibition was accompanied by an undermining of mitochondrial function, with increased production of reactive oxygen species and reduction of mitochondrial membrane potential and intracellular ATP levels. However, this interference did not compromise cell survival. Co-administration with concentrations of acetaminophen below those considered hepatotoxic exacerbated the deleterious effects of both compounds on mitochondrial function and compromised cellular viability, showing a clear correlation with diminished glutathione levels. CONCLUSIONS: The simultaneous presence of purine analogues and low concentrations of acetaminophen significantly potentiates mitochondrial dysfunction, increasing the risk of liver injury. This new mechanism is relevant given the liver's susceptibility to mitochondrial dysfunction-related toxicity and the tendency of the HIV infection to increase oxidative stress. PMID- 26747095 TI - qnrA6 genetic environment and quinolone resistance conferred on Proteus mirabilis. AB - OBJECTIVES: To determine the genetic location and environment of the qnrA6 gene in Proteus mirabilis PS16 where it was first described and to characterize the quinolone resistance qnrA6 confers. METHODS: Transformation experiments and Southern blotting were performed for plasmid and genomic DNA of P. mirabilis PS16 to determine the qnrA6 location. Combinatorial PCRs with primers in qnrA6 and genes usually surrounding qnrA genes were used to determine the genetic environment. The qnrA6 coding region, including or not the promoter region, was cloned into vectors pTOPO and pBR322 and the MICs of six quinolones were measured for transformants of Escherichia coli TOP10 and P. mirabilis ATCC 29906 Rif(R). RESULTS: qnrA6 was shown to be chromosomally encoded in P. mirabilis PS16 and its genetic environment was 81%-87% similar to that of qnrA2 in the Shewanella algae chromosome. The 5138 bp region up- and downstream of qnrA6 contained an IS10 sequence surrounded by two ISCR1. This resulted in qnrA6 being displaced 1.9 kb from its native promoter but supplied a promoter present in ISCR1. qnrA6 cloned into pTOPO and pBR322 conferred a 4-32-fold increase in fluoroquinolone MICs when expressed in E. coli but only 2-3-fold in P. mirabilis. When including the promoter region, a further increase in resistance was observed in both species, reaching MIC values above clinical breakpoints for only P. mirabilis. CONCLUSIONS: qnrA6 is the first chromosomally located qnrA gene described in Enterobacteriaceae. The quinolone resistance conferred by qnrA6 depends on the proximity of an efficient promoter and the host strain where it is expressed. PMID- 26747097 TI - In vitro antifungal activity and in vivo antibiofilm activity of cerium nitrate against Candida species. PMID- 26747096 TI - Comparative analysis of an IncR plasmid carrying armA, blaDHA-1 and qnrB4 from Klebsiella pneumoniae ST37 isolates. AB - OBJECTIVES: The objective of this study was to conduct a comparative analysis with reported IncR plasmids of a Klebsiella pneumoniae IncR plasmid carrying an MDR region. METHODS: MDR K. pneumoniae isolates were serially identified from two inpatients at a hospital in the USA in 2014. MDR plasmid pYDC676 was fully sequenced, annotated and compared with related plasmids. Antimicrobial susceptibility testing, PFGE and MLST were also conducted. RESULTS: The K. pneumoniae isolates were identical by PFGE, belonged to ST37 and harboured an identical ~50 kb IncR plasmid (pYDC676). pYDC676 possessed the backbone and multi IS loci closely related to IncR plasmids reported from aquatic bacteria, as well as animal and human K. pneumoniae strains, and carried an MDR region consisting of armA, blaDHA-1 and qnrB4, a combination that has been reported in IncR plasmids from K. pneumoniae ST11 strains in Europe and Asia. A plasmid with the identical IncR backbone and a similar MDR region containing blaDHA-1 and qnrB4 has also been reported in ST37 strains from Europe, suggesting potential dissemination of this lineage of IncR plasmids in K. pneumoniae ST37. CONCLUSIONS: K. pneumoniae ST37 strains with an MDR IncR plasmid carrying armA, blaDHA-1 and qnrB4 were identified in a hospital in the USA, where these resistance genes remain rare. The IncR backbone may play a role in the global dissemination of these resistance genes. PMID- 26747098 TI - Simultaneous assessment of the pharmacokinetics of a pleuromutilin, lefamulin, in plasma, soft tissues and pulmonary epithelial lining fluid. AB - BACKGROUND: Lefamulin is a pleuromutilin antibiotic under evaluation for the treatment of bacterial infections, including respiratory tract infections. Currently, there are no high-quality pharmacokinetic data on drug tissue concentrations of lefamulin available. METHODS: A single dose of intravenous lefamulin (150 mg) was given to 12 healthy men. The registered EudraCT number for this study was 2010-021938-54. Lefamulin concentrations were simultaneously measured in plasma, skeletal muscle tissue, subcutaneous adipose tissue and epithelial lining fluid (ELF) over 24 h, and corresponding pharmacokinetic parameters were calculated. Microdialysis was used to measure unbound lefamulin concentrations in skeletal muscle tissue and subcutaneous adipose tissue, which were similar to unbound lefamulin concentrations in plasma. Bronchoalveolar lavage was performed 1, 2, 4 and 8 h post-dose to determine lefamulin concentrations in ELF. RESULTS: Unbound lefamulin levels showed a 5.7-fold higher exposure in ELF compared with that in plasma, demonstrating good penetration to the target site. CONCLUSIONS: Lefamulin may be an addition to the therapeutic armamentarium for the treatment of infections. Simultaneous measurements of unbound drug concentration can guide target attainment for future therapeutic trials. PMID- 26747099 TI - Drug-drug interactions between bedaquiline and the antiretrovirals lopinavir/ritonavir and nevirapine in HIV-infected patients with drug-resistant TB. AB - OBJECTIVES: Bedaquiline is a new anti-TB drug, which is metabolized by cytochrome P450 (CYP) 3A4. Concomitant ART is important for all HIV-infected patients treated for TB, but several antiretrovirals inhibit or induce CYP3A4. Single-dose drug-drug interaction studies found no significant interactions with nevirapine or lopinavir/ritonavir, but these findings could be misleading, especially because of bedaquiline's long terminal t1/2. We evaluated the effect of nevirapine and lopinavir/ritonavir on bedaquiline exposure. METHODS: We conducted a parallel-group pharmacokinetic study of three groups of participants who were on bedaquiline as part of therapy for drug-resistant TB: no ART (HIV seronegative); nevirapine-based ART; and lopinavir/ritonavir-based ART. Non compartmental analyses were done and exposure of bedaquiline and its M2 metabolite compared between the no-ART group and the two ART groups. RESULTS: We enrolled 48 participants: 17 in the no-ART group, 17 in the nevirapine group and 14 in the lopinavir/ritonavir group. The following median bedaquiline pharmacokinetic parameters were significantly higher in the lopinavir/ritonavir group than in the no-ART group: AUC(0-48) (67 002 versus 34 730 ng . h/mL; P = 0.003); Tmax (6 versus 4 h; P = 0.003); and t1/2 (55 versus 31 h; P = 0.004). On multivariate analysis, bedaquiline exposure was increased by lopinavir/ritonavir, male sex and time on bedaquiline. Bedaquiline exposure was not significantly different between the nevirapine group and the no-ART group. M2 metabolite exposure was not significantly different in either of the antiretroviral groups compared with the no-ART group. CONCLUSIONS: Lopinavir/ritonavir significantly increased bedaquiline exposure. The clinical significance of this interaction remains to be determined. PMID- 26747100 TI - Temocillin in vitro activity against recent clinical isolates of Neisseria gonorrhoeae compared with penicillin, ceftriaxone and ciprofloxacin. PMID- 26747102 TI - An update on faecal carriage of ESBL-producing Enterobacteriaceae by Portuguese healthy humans: detection of the H30 subclone of B2-ST131 Escherichia coli producing CTX-M-27. PMID- 26747101 TI - Identification and characterization of haemofungin, a novel antifungal compound that inhibits the final step of haem biosynthesis. AB - OBJECTIVES: During recent decades, the number of invasive fungal infections among immunosuppressed patients has increased significantly, whereas the number of effective systemic antifungal drugs remains low and unsatisfactory. The aim of this study was to characterize a novel antifungal compound, CW-8/haemofungin, which we previously identified in a screen for compounds affecting fungal cell wall integrity. METHODS: The in vitro characteristics of haemofungin were investigated by MIC evaluation against a panel of pathogenic and non-pathogenic fungi, bacteria and mammalian cells in culture. Haemofungin mode-of-action studies were performed by screening an Aspergillus nidulans overexpression genomic library for resistance-conferring plasmids and biochemical validation of the target. In vivo efficacy was tested in the Galleria mellonella and Drosophila melanogaster insect models of infection. RESULTS: We demonstrate that haemofungin causes swelling and lysis of growing fungal cells. It inhibits the growth of pathogenic Aspergillus, Candida, Fusarium and Rhizopus isolates at micromolar concentrations, while only weakly affecting the growth of mammalian cell lines. Genetic and biochemical analyses in A. nidulans and Aspergillus fumigatus indicate that haemofungin primarily inhibits ferrochelatase (HemH), the last enzyme in the haem biosynthetic pathway. Haemofungin was non-toxic and significantly reduced mortality rates of G. mellonella and D. melanogaster infected with A. fumigatus and Rhizopus oryzae, respectively. CONCLUSIONS: Further development and in vivo validation of haemofungin is warranted. PMID- 26747103 TI - Extended-spectrum antibodies protective against carbapenemase-producing Enterobacteriaceae. AB - BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) are responsible for worldwide outbreaks and antibiotic treatments are problematic. The polysaccharide poly-(beta-1,6)-N-acetyl glucosamine (PNAG) is a vaccine target detected on the surface of numerous pathogenic bacteria, including Escherichia coli. Genes encoding PNAG biosynthetic proteins have been identified in two other main pathogenic Enterobacteriaceae, Enterobacter cloacae and Klebsiella pneumoniae. We hypothesized that antibodies to PNAG might be a new therapeutic option for the different pan-resistant pathogenic species of CRE. METHODS: PNAG production was detected by confocal microscopy and its role in the formation of the biofilm (for E. cloacae) and as a virulence factor (for K. pneumoniae) was analysed. The in vitro (opsonophagocytosis killing assay) and in vivo (mouse models of peritonitis) activity of antibodies to PNAG were studied using antibiotic susceptible and -resistant E. coli, E. cloacae and K. pneumoniae. A PNAG producing strain of Pseudomonas aeruginosa, an organism that does not naturally produce this antigen, was constructed by adding the pga locus to a strain with inactive alg genes responsible for the production of P. aeruginosa alginate. Antibodies to PNAG were tested in vitro and in vivo as above. RESULTS: PNAG is a major component of the E. cloacae biofilm and a virulence factor for K. pneumoniae. Antibodies to PNAG mediated in vitro killing (>50%) and significantly protected mice against the New Delhi metallo-beta-lactamase-producing E. coli (P = 0.02), E. cloacae (P = 0.0196) and K. pneumoniae (P = 0.006), against K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae (P = 0.02) and against PNAG-producing P. aeruginosa (P = 0.0013). Thus, regardless of the Gram-negative bacterial species, PNAG expression is the sole determinant of the protective efficacy of antibodies to this antigen. CONCLUSIONS: Our findings suggest antibodies to PNAG may provide extended-spectrum antibacterial protective activity. PMID- 26747124 TI - Simplicity-Tenacity in Stroke Rehabilitation. PMID- 26747105 TI - The role of GAGE cancer/testis antigen in metastasis: the jury is still out. AB - BACKGROUND: GAGE cancer/testis antigens are frequently expressed in various types of malignancies and represent attractive targets for immunotherapy, however their role in cancer initiation and progression has remained elusive. GAGE proteins are expressed in normal cells during early development with migratory and invasive properties and were found to be upregulated in cancer cells with metastasizing potential in a gastric cancer model. METHODS: We have addressed the direct role of GAGE proteins in supporting metastasis using an isogenic metastasis model of human cancer, consisting of 4 isogenic cell lines, which are equally tumorigenic in immunodeficient mice, but differ with their ability to generate metastases in the lungs and lymph nodes. RESULTS: Although GAGE proteins were strongly upregulated in the highly metastatic clone (CL16) compared to non-metastatic (NM2C5), weakly metastatic (M4A4) and moderately metastatic clones (LM3), stable downregulation of GAGE expression did not affect the ability of CL16 cells to establish primary tumors and form metastasis in the lungs of immunodeficient mice. CONCLUSIONS: These results suggest that GAGE proteins per se do not support metastasis and that further studies are needed to clarify the contribution of GAGE proteins to the metastatic potential of different types of cancer cells. PMID- 26747125 TI - Upper Limb Rehabilitation in People With Multiple Sclerosis: A Systematic Review. AB - Background There has been an increasing research interest in upper limb rehabilitation in multiple sclerosis (MS). The current changes in the research field inquire a new literature review. Objective This systematic review aimed to provide an overview of the upper limb rehabilitation strategies in people with MS (PwMS). Methods Articles published in PubMed and Web of Knowledge were selected when written in English, published in the past 25 years, peer reviewed, that included at least 5 PwMS, and described the effects of an intervention study including rehabilitation strategies targeting the upper limbs. Included articles were screened based on title/abstract and full text by 2 independent reviewers. Results Thirty articles met the criteria and were included for data extraction. Only half of the included studies investigated the effects of a training program specially targeted toward the upper limbs, while in the other studies, a general whole body therapy was used. The therapy content and dosage varied greatly between the different included studies. Multidisciplinary and robot-based rehabilitation were the most investigated rehabilitation strategies and showed to improve upper limb capacity. Strength and endurance training improved the upper limb body functions and structures but did not influence the upper limb capacity and performance. Conclusions The results of this systematic review indicated that different types of upper limb rehabilitation strategies can improve upper limb function in PwMS. Further research is necessary to compare directly the effects of different rehabilitation strategies and to investigate the optimal therapy dosage according to the upper limb disability level. PMID- 26747126 TI - Robotic Quantification of Position Sense in Children With Perinatal Stroke. AB - Background Perinatal stroke is the leading cause of hemiparetic cerebral palsy. Motor deficits and their treatment are commonly emphasized in the literature. Sensory dysfunction may be an important contributor to disability, but it is difficult to measure accurately clinically. Objective Use robotics to quantify position sense deficits in hemiparetic children with perinatal stroke and determine their association with common clinical measures. Methods Case-control study. Participants were children aged 6 to 19 years with magnetic resonance imaging-confirmed unilateral perinatal arterial ischemic stroke or periventricular venous infarction and symptomatic hemiparetic cerebral palsy. Participants completed a position matching task using an exoskeleton robotic device (KINARM). Position matching variability, shift, and expansion/contraction area were measured with and without vision. Robotic outcomes were compared across stroke groups and controls and to clinical measures of disability (Assisting Hand Assessment) and sensory function. Results Forty stroke participants (22 arterial, 18 venous, median age 12 years, 43% female) were compared with 60 healthy controls. Position sense variability was impaired in arterial (6.01 +/- 1.8 cm) and venous (5.42 +/- 1.8 cm) stroke compared to controls (3.54 +/- 0.9 cm, P < .001) with vision occluded. Impairment remained when vision was restored. Robotic measures correlated with functional disability. Sensitivity and specificity of clinical sensory tests were modest. Conclusions Robotic assessment of position sense is feasible in children with perinatal stroke. Impairment is common and worse in arterial lesions. Limited correction with vision suggests cortical sensory network dysfunction. Disordered position sense may represent a therapeutic target in hemiparetic cerebral palsy. PMID- 26747127 TI - Effects of Pain and Pain Management on Motor Recovery of Spinal Cord-Injured Patients: A Longitudinal Study. AB - Background Approximately 60% of patients suffering from acute spinal cord injury (SCI) develop pain within days to weeks after injury, which ultimately persists into chronic stages. To date, the consequences of pain after SCI have been largely examined in terms of interfering with quality of life. Objective The objective of this study was to examine the effects of pain and pain management on neurological recovery after SCI. Methods We analyzed clinical data in a prospective multicenter observational cohort study in patients with SCI. Using mixed effects regression techniques, total motor and sensory scores were modelled at 1, 3, 6, and 12 months postinjury. Results A total of 225 individuals were included in the study (mean age: 45.8 +/- 18 years, 80% male). At 1 month postinjury, 28% of individuals with SCI reported at- or below-level neuropathic pain. While pain classification showed no effect on neurological outcomes, individuals administered anticonvulsant medications at 1 month postinjury showed significant reductions in pain intensity (2 points over 1 year; P < .05) and greater recovery in total motor scores (7.3 points over 1 year; P < .05). This drug effect on motor recovery remained significant after adjustment for injury level and injury severity, pain classification, and pain intensity. Conclusion While initial pain classification and intensity did not reveal an effect on motor recovery following acute SCI, anticonvulsants conferred a significant beneficial effect on motor outcomes. Early intervention with anticonvulsants may have effects beyond pain management and warrant further studies to evaluate the therapeutic effectiveness in human SCI. PMID- 26747128 TI - Effects of Unilateral Upper Limb Training in Two Distinct Prognostic Groups Early After Stroke: The EXPLICIT-Stroke Randomized Clinical Trial. AB - Background and Objective Favorable prognosis of the upper limb depends on preservation or return of voluntary finger extension (FE) early after stroke. The present study aimed to determine the effects of modified constraint-induced movement therapy (mCIMT) and electromyography-triggered neuromuscular stimulation (EMG-NMS) on upper limb capacity early poststroke. Methods A total of 159 ischemic stroke patients were included: 58 patients with a favorable prognosis (>10 degrees of FE) were randomly allocated to 3 weeks of mCIMT or usual care only; 101 patients with an unfavorable prognosis were allocated to 3-week EMG-NMS or usual care only. Both interventions started within 14 days poststroke, lasted up until 5 weeks, focused at preservation or return of FE. Results Upper limb capacity was measured with the Action Research Arm Test (ARAT), assessed weekly within the first 5 weeks poststroke and at postassessments at 8, 12, and 26 weeks. Clinically relevant differences in ARAT in favor of mCIMT were found after 5, 8, and 12 weeks poststroke (respectively, 6, 7, and 7 points; P < .05), but not after 26 weeks. We did not find statistically significant differences between mCIMT and usual care on impairment measures, such as the Fugl-Meyer assessment of the arm (FMA-UE). EMG-NMS did not result in significant differences. Conclusions Three weeks of early mCIMT is superior to usual care in terms of regaining upper limb capacity in patients with a favorable prognosis; 3 weeks of EMG-NMS in patients with an unfavorable prognosis is not beneficial. Despite meaningful improvements in upper limb capacity, no evidence was found that the time dependent neurological improvements early poststroke are significantly influenced by either mCIMT or EMG-NMS. PMID- 26747129 TI - Experimental Measurement of the Static Coefficient of Friction at the Ti-Ti Taper Connection in Total Hip Arthroplasty. AB - The modular taper junction in total hip replacements has been implicated as a possible source of wear. The finite-element (FE) method can be used to study the wear potential at the taper junction. For such simulations it is important to implement representative contact parameters, in order to achieve accurate results. One of the main parameters in FE simulations is the coefficient of friction. However, in current literature, there is quite a wide spread in coefficient of friction values (0.15 - 0.8), which has a significant effect on the outcome of the FE simulations. Therefore, to obtain more accurate results, one should use a coefficient of friction that is determined for the specific material couple being analyzed. In this study, the static coefficient of friction was determined for two types of titanium-on-titanium stem-adaptor couples, using actual cut-outs of the final implants, to ensure that the coefficient of friction was determined consistently for the actual implant material and surface finish characteristics. Two types of tapers were examined, Biomet type-1 and 12/14, where type-1 has a polished surface finish and the 12/14 is a microgrooved system. We found static coefficients of friction of 0.19 and 0.29 for the 12/14 and type-1 stem-adaptor couples, respectively. PMID- 26747131 TI - Erythropoietin in anemia of unknown etiology: A systematic review and meta analysis. AB - INTRODUCTION: We conducted a systematic review and meta-analysis of observational studies in order to explore the relationship between erythropoietin (EPO) and hemoglobin in elderly individuals with anemia of unknown etiology (AUE) and other forms of anemia. METHODS: We searched Medline, EMBASE, Web of Science, Biosis Previews, Dissertations, and Theses in addition to meeting abstracts of the European Hematology Association and American Society of Hematology for relevant studies. The meta-analysis was conducted using pooled ratio of means (ROM) through the generic inverse variance method. RESULTS: Six studies were included in the meta-analysis, which confirmed that EPO levels were significantly lower in AUE as compared to iron deficiency anemia (ROM 0.7210; random 95% CI 0.7052 to 0.7372; P-value < 0.00001) and anemia of chronic disease (ROM 0.8995; random 95% CI 0.8362 to 0.9677; P = 0.004). EPO levels in AUE were slightly higher than levels in anemia of chronic kidney disease (ROM 1.0940; random 95% CI 1.0557, 1.1337; P < 0.00001). The heterogeneity (I2) of all analyses was 100%. CONCLUSION: Our findings suggest that erythropoietin levels in AUE, although elevated, remain inappropriately low, particularly when compared with other forms of anemia. This suggests a relative erythropoietin deficiency or a blunted erythroid cell response. PMID- 26747104 TI - The Worldwide Antibiotic Resistance and Prescribing in European Children (ARPEC) point prevalence survey: developing hospital-quality indicators of antibiotic prescribing for children. AB - OBJECTIVES: Previously, web-based tools for cross-sectional antimicrobial point prevalence surveys (PPSs) have been used in adults to develop indicators of quality improvement. We aimed to determine the feasibility of developing similar quality indicators of improved antimicrobial prescribing focusing specifically on hospitalized neonates and children worldwide. METHODS: A standardized antimicrobial PPS method was employed. Included were all inpatient children and neonates receiving an antimicrobial at 8:00 am on the day of the PPS. Denominators included the total number of inpatients. A web-based application was used for data entry, validation and reporting. We analysed 2012 data from 226 hospitals (H) in 41 countries (C) from Europe (174H; 24C), Africa (6H; 4C), Asia (25H; 8C), Australia (6H), Latin America (11H; 3C) and North America (4H). RESULTS: Of 17,693 admissions, 6499 (36.7%) inpatients received at least one antimicrobial, but this varied considerably between wards and regions. Potential indicators included very high broad-spectrum antibiotic prescribing in children of mainly ceftriaxone (ranked first in Eastern Europe, 31.3%; Asia, 13.0%; Southern Europe, 9.8%), cefepime (ranked third in North America, 7.8%) and meropenem (ranked first in Latin America, 13.1%). The survey identified worryingly high use of critically important antibiotics for hospital-acquired infections in neonates (34.9%; range from 14.2% in Africa to 68.0% in Latin America) compared with children (28.3%; range from 14.5% in Africa to 48.9% in Latin America). Parenteral administration was very common among children in Asia (88%), Latin America (81%) and Europe (67%). Documentation of the reasons for antibiotic prescribing was lowest in Latin America (52%). Prolonged surgical prophylaxis rates ranged from 78% (Europe) to 84% (Latin America). CONCLUSIONS: Simple web-based PPS tools provide a feasible method to identify areas for improvement of antibiotic use, to set benchmarks and to monitor future interventions in hospitalized neonates and children. To our knowledge, this study has derived the first global quality indicators for antibiotic use in hospitalized neonates and children. PMID- 26747130 TI - Over-expression of Arabidopsis thaliana SFD1/GLY1, the gene encoding plastid localized glycerol-3-phosphate dehydrogenase, increases plastidic lipid content in transgenic rice plants. AB - Lipids are the major constituents of all membranous structures in plants. Plants possess two pathways for lipid biosynthesis: the prokaryotic pathway (i.e., plastidic pathway) and the eukaryotic pathway (i.e., endoplasmic-reticulum (ER) pathway). Whereas some plants synthesize galactolipids from diacylglycerol assembled in the plastid, others, including rice, derive their galactolipids from diacylglycerols assembled by the eukaryotic pathway. Arabidopsis thaliana glycerol-3-phosphate dehydrogenase (G3pDH), coded by SUPPRESSOR OF FATTY ACID DESATURASE 1 (SFD1; alias GLY1) gene, catalyzes the formation of glycerol 3 phosphate (G3p), the backbone of many membrane lipids. Here SFD1 was introduced to rice as a transgene. Arabidopsis SFD1 localizes in rice plastids and its over expression increases plastidic membrane lipid content in transgenic rice plants without any major impact on ER lipids. The results suggest that over-expression of plastidic G3pDH enhances biosynthesis of plastid-localized lipids in rice. Lipid composition in the transgenic plants is consistent with increased phosphatidylglycerol synthesis in the plastid and increased galactolipid synthesis from diacylglycerol produced via the ER pathway. The transgenic plants show a higher photosynthetic assimilation rate, suggesting a possible application of this finding in crop improvement. PMID- 26747173 TI - Assessing and Strengthening Evidence-Based Program Registries' Usefulness for Social Service Program Replication and Adaptation. AB - BACKGROUND: Government and private funders increasingly require social service providers to adopt program models deemed "evidence based," particularly as defined by evidence-based program registries, such as What Works Clearinghouse and National Registry of Evidence-Based Programs and Practices. These registries summarize the evidence about programs' effectiveness, giving near-exclusive priority to evidence from experimental-design evaluations. The registries' goal is to aid decision making about program replication, but critics suspect the emphasis on evidence from experimental-design evaluations, while ensuring strong internal validity, may inadvertently undermine that goal, which requires strong external validity as well. OBJECTIVE: The objective of this study is to determine the extent to which the registries' reports provide information about context specific program implementation factors that affect program outcomes and would thus support decision making about program replication and adaptation. METHOD: A research-derived rubric was used to rate the extent of context-specific reporting in the population of seven major registries' evidence summaries ( N = 55) for youth development programs. FINDINGS: Nearly all (91%) of the reports provide context-specific information about program participants, but far fewer provide context-specific information about implementation fidelity and other variations in program implementation (55%), the program's environment (37%), costs (27%), quality assurance measures (22%), implementing agencies (19%), or staff (15%). CONCLUSION: Evidence-based program registries provide insufficient information to guide context-sensitive decision making about program replication and adaptation. Registries should supplement their evidence base with nonexperimental evaluations and revise their methodological screens and synthesis-writing protocols to prioritize reporting-by both evaluators and the registries themselves-of context specific implementation factors that affect program outcomes. PMID- 26747132 TI - Antibody profiles to plasmodium merozoite surface protein-1 in Cambodian adults during an active surveillance cohort with nested treatment study. AB - BACKGROUND: In addition to evidence for a protective role of antibodies to the malaria blood stage antigen merozoite surface protein 1 (MSP1), MSP1 antibodies are also considered as a marker of past malaria exposure in sero-epidemiological studies. METHODS: In order to better assess the potential use of MSP1 serology in malaria chemoprophylaxis trials in endemic areas, an analysis for the prevalence of antibodies to both Plasmodium falciparum and Plasmodium vivax MSP142 in healthy Cambodian adults was conducted at two sites as part of an active, observational cohort evaluating the efficacy of dihydroartemisinin-piperaquine (DP) for uncomplicated malaria (ClinicalTrials.gov identifier NCT01280162). RESULTS: Rates of baseline sero-positivity were high (59 and 73% for PfMSP142 and PvMSP142, respectively), and titers higher in those who lived in a higher transmission area, although there was little correlation in titers between the two species. Those volunteers who subsequently went on to develop malaria had higher baseline MSP142 titers than those who did not for both species. Titers to both antigens remained largely stable over the course of the 4-6 month study, except in those infected with P. falciparum who had multiple recurrences. CONCLUSION: These findings illuminate the difficulties in using MSP142 serology as either a screening criterion and/or biomarker of exposure in chemoprophylaxis studies. Further work remains to identify useful markers of malarial infection and/or immunity. PMID- 26747174 TI - Deliberate Self-harm Following Bariatric Surgery-Reply. PMID- 26747177 TI - A Patient With DNMT1 Gene Mutation Presenting With Polyneuropathy, Hearing Loss, and Personality Changes. PMID- 26747175 TI - Efficient expression of nuclear transgenes in the green alga Chlamydomonas: synthesis of an HIV antigen and development of a new selectable marker. AB - The unicellular green alga Chlamydomonas reinhardtii has become an invaluable model system in plant biology. There is also considerable interest in developing this microalga into an efficient production platform for biofuels, pharmaceuticals, green chemicals and industrial enzymes. However, the production of foreign proteins in the nucleocytosolic compartment of Chlamydomonas is greatly hampered by the inefficiency of transgene expression from the nuclear genome. We have recently addressed this limitation by isolating mutant algal strains that permit high-level transgene expression and by determining the contributions of GC content and codon usage to gene expression efficiency. Here we have applied these new tools and explored the potential of Chlamydomonas to produce a recombinant biopharmaceutical, the HIV antigen P24. We show that a codon-optimized P24 gene variant introduced into our algal expression strains give rise to recombinant protein accumulation levels of up to 0.25% of the total cellular protein. Moreover, in combination with an expression strain, a resynthesized nptII gene becomes a highly efficient selectable marker gene that facilitates the selection of transgenic algal clones at high frequency. By establishing simple principles of successful transgene expression, our data open up new possibilities for biotechnological research in Chlamydomonas. PMID- 26747176 TI - The Effectiveness of Prompts to Promote Engagement With Digital Interventions: A Systematic Review. AB - BACKGROUND: Digital interventions have been effective in improving numerous health outcomes and health behaviors; furthermore, they are increasingly being used in different health care areas, including self-management of long-term conditions, mental health, and health promotion. The full potential of digital interventions is hindered by a lack of user engagement. There is an urgent need to develop effective strategies that can promote users' engagement with digital interventions. One potential method is the use of technology-based reminders or prompts. OBJECTIVE: To evaluate the effectiveness of technology-based strategies for promoting engagement with digital interventions. METHODS: Cochrane Collaboration guidelines on systematic review methodology were followed. The search strategy was executed across 7 electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Web of Science, the Education Resources Information Center (ERIC), PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). Databases were searched from inception to September 13, 2013, with no language or publication type restrictions, using three concepts: randomized controlled trials, digital interventions, and engagement. Gray literature and reference lists of included studies were also searched. Titles and abstracts were independently screened by 2 authors, then the full texts of potentially eligible papers were obtained and double-screened. Data from eligible papers were extracted by one author and checked for accuracy by another author. Bias was assessed using the Cochrane risk of bias assessment tool. Narrative synthesis was performed on all included studies and, where appropriate, data were pooled using meta-analysis. All findings were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: A total of 14 studies were included in the review with 8774 participants. Of the 14 studies, 9 had sufficient data to be included in the meta-analyses. The meta-analyses suggested that technology-based strategies can potentially promote engagement compared to no strategy for dichotomous outcomes (relative risk [RR] 1.27, 95% CI 1.01-1.60, I(2)=71%), but due to considerable heterogeneity and the small sample sizes in most studies, this result should be treated with caution. No studies reported adverse or economic outcomes. Only one study with a small sample size compared different characteristics; the study found that strategies promoting new digital intervention content and those sent to users shortly after they started using the digital intervention were more likely to engage users. CONCLUSIONS: Overall, studies reported borderline positive effects of technology-based strategies on engagement compared to no strategy. However, the results have to be interpreted with caution. More research is needed to replicate findings and understand which characteristics of the strategies are effective in promoting engagement and how cost-effective they are. PMID- 26747178 TI - PIK3CA and PIK3CB silencing by RNAi reverse MDR and inhibit tumorigenic properties in human colorectal carcinoma. AB - Colorectal carcinoma (CRC) is the second most common and frequent cause of cancer related deaths for men and women in the world. PIK3CA and PIK3CB that reverse multidrug resistance (MDR) can serve as predictive and prognostic markers as well as therapeutic targets for CRC treatment. In the present study, we showed that PIK3CA and PIK3CB are upregulated in CRCs and positively correlated with MDR-1, LRP, and GST-pi. Long-term monitoring of 316 CRC patients showed that PIK3CA and PIK3CB were associated with poor survival time as shown by Kaplan-Meier analysis. Furthermore, we found that the downregulation of PIK3CA and PIK3CB reversed MDR; inhibited the capability of proliferation, migration, and invasion of CRC cells; and slowed down the CRC tumor growth in nude mice. Consistent with clinical observations, PIK3CA and PIK3CB significantly increase multidrug resistance of CRC cells in vivo. Together, these results suggest that PIK3CA and PIK3CB may be used as potential therapeutic drug targets for colorectal cancer. PMID- 26747179 TI - Upregulation of CD44v6 contributes to acquired chemoresistance via the modulation of autophagy in colon cancer SW480 cells. AB - The CD44 isoform containing variant exon v6 (CD44v6) plays an important role in the progression, metastasis, and prognosis of colorectal cancer (CRC). Recently, it was found that CD44v6 is involved in acquired drug resistance. This study aimed to investigate the molecular mechanism of CD44v6 in the resistance of CRC cells to chemotherapy. A stable CD44v6 overexpression model in SW480 cells was established via lentiviral transduction. The chemosensitivity of cells to 5 fluorouracil (5-FU) and oxaliplatin (L-OHP) was determined by cell counting kit (CCK)-8, lactate dehydrogenase (LDH) release, and colony formation assays. Immunohistochemical staining of CD44v6 was performed in human CRC tissues. The key components in cell apoptosis, drug efflux and metabolism, mismatch repair, autophagy, epithelial-mesenchymal transition (EMT), and the PI3K-Akt and MAPK-Ras Erk1/2 pathways were assessed using flow cytometry, quantitative real-time polymerase chain reaction (PCR), and western blot assays. The CD44v6 overexpression cells showed a higher viability, a lower LDH release rate, and an increased clonogenicity than the control cells under drug treatment. Moreover, overexpression of CD44v6 resulted in enhanced autophagy flux, EMT, and phosphorylation of Akt and Erk in the presence of drugs. Furthermore, high CD44v6 expression in the primary tumor was closely associated with an early recurrence in CRC patients who underwent curative surgery and adjuvant chemotherapy. In conclusion, overexpression of CD44v6 contributes to chemoresistance in SW480 cells under cytotoxic stress via the modulation of autophagy, EMT, and activation of the PI3K-Akt and MAPK-Ras-Erk pathways. PMID- 26747181 TI - Testing flow diversion in animal models: a systematic review. AB - INTRODUCTION: Flow diversion (FD) is increasingly used to treat intracranial aneurysms. We sought to systematically review published studies to assess the quality of reporting and summarize the results of FD in various animal models. METHODS: Databases were searched to retrieve all animal studies on FD from 2000 to 2015. Extracted data included species and aneurysm models, aneurysm and neck dimensions, type of flow diverter, occlusion rates, and complications. Articles were evaluated using a checklist derived from the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. RESULTS: Forty-two articles reporting the results of FD in nine different aneurysm models were included. The rabbit elastase-induced aneurysm model was the most commonly used, with 3-month occlusion rates of 73.5%, (95%CI [61.9-82.6%]). FD of surgical sidewall aneurysms, constructed in rabbits or canines, resulted in high occlusion rates (100% [65.5-100%]). FD resulted in modest occlusion rates (15.4% [8.9-25.1%]) when tested in six complex canine aneurysm models designed to reproduce more difficult clinical contexts (large necks, bifurcation, or fusiform aneurysms). Adverse events, including branch occlusion, were rarely reported. There were no hemorrhagic complications. Articles complied with 20.8 +/- 3.9 of 41 ARRIVE items; only a small number used randomization (3/42 articles [7.1%]) or a control group (13/42 articles [30.9%]). CONCLUSION: Preclinical studies on FD have shown various results. Occlusion of elastase-induced aneurysms was common after FD. The model is not challenging but standardized in many laboratories. Failures of FD can be reproduced in less standardized but more challenging surgical canine constructions. The quality of reporting could be improved. PMID- 26747180 TI - Interventions to improve mental health nurses' skills, attitudes, and knowledge related to people with a diagnosis of borderline personality disorder: Systematic review. AB - OBJECTIVES: There is some evidence that mental health nurses have poor attitudes towards people with a diagnosis of borderline personality disorder and that this might impact negatively on the development of helpful therapeutic relationships. We aimed to collate the current evidence about interventions that have been devised to improve the responses of mental health nurses towards this group of people. DESIGN: Systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses statement. DATA SOURCES: Comprehensive terms were used to search CINAHL, PsycINFO, Medline, Biomedical Reference Collection: Comprehensive, Web of Science, ASSIA, Cochrane Library, EMBASE, ProQuest [including Dissertations/Theses], and Google Scholar for relevant studies. REVIEW METHODS: Included studies were those that described an intervention whose aim was to improve attitudes towards, knowledge about or responses to people with a diagnosis of borderline personality disorder. The sample described had to include mental health nurses. Information about study characteristics, intervention content and mode of delivery was extracted. Study quality was assessed, and effect sizes of interventions and potential moderators of those interventions were extracted and converted to Cohen's d to aid comparison. RESULTS: The search strategy yielded a total of eight studies, half of which were judged to be methodologically weak with the remaining four studies judged to be of moderate quality. Only one study employed a control group. The largest effect sizes were found for changes related to cognitive attitudes including knowledge; smaller effect sizes were found in relation to changes in affective outcomes. Self-reported behavioural change in the form of increased use of components of Dialectical Behaviour Therapy following training in this treatment was associated with moderate effect sizes. The largest effect sizes were found among those with poorer baseline attitudes and without previous training about borderline personality disorder. CONCLUSIONS: There is a dearth of high quality evidence about the attitudes of mental health nurses towards people with a diagnosis of borderline personality disorder. This is an important gap since nurses hold the poorest attitudes of professional disciplines involved in the care of this group. Further work is needed to ascertain the most effective elements of training programmes; this should involve trials of interventions in samples that are compared against adequately matched control groups. PMID- 26747182 TI - Tumour necrosis factor-alpha inhibits hepatic lipid deposition through GSK 3beta/beta-catenin signaling in juvenile turbot (Scophthalmus maximus L.). AB - In this study, the mechanism that TNFalpha inhibits lipid deposition through GSK 3beta/beta-catenin signaling was investigated in the liver of juvenile turbot (Scophthalmus maximus L.) by injection of TNFalpha or TNFalpha inhibitor pomalidomide (POM). It was found that TNFalpha inhibited the expression of GSK 3beta and induced beta-catenin expression. TNFalpha inhibited the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein alpha (C/EBPalpha), as well as the activity of lipoprotein lipase (LPL) and fatty acid synthetase (FAS). In addition, the level of triglyceride (TG), total cholesterol (TC), nonesterified fatty acid (NEFA), and glycerol was decreased by TNFalpha treatment in the liver. In the plasma, the level of TG, TC, low density lipoprotein cholesterol (LDL-C), NEFA, and glycerol was decreased, but high density lipoprotein cholesterol (HDL-C) was increased by TNFalpha treatment. However, compared to TNFalpha, POM had the opposite effect on the biochemical indexes and genes related to lipid deposition in the liver. The results indicated that TNFalpha may regulate hepatic lipid metabolism and fat distribution through GSK-3beta/beta-catenin signaling as well as transcription factors PPARgamma and C/EBPalpha in juvenile turbot. PMID- 26747183 TI - Impact of diagnosing diabetic complications on future hemoglobin A1c levels. AB - AIM: To assess how hemoglobin A1c (HbA1c) values might change following the diagnosis of the first complication from diabetes mellitus (DM). METHODS: Using a nationwide, longitudinal managed care network claims database (2001-2011), we identified patients with DM who experienced an initial diabetes-related complication. A paired t-test was used to compare average HbA1c levels before the initial complication was first diagnosed to average HbA1c levels following the diagnosis of the complication. RESULTS: 518 enrollees met study inclusion criteria. Patients with suboptimally controlled DM (defined as HbA1c>7% (53 mmol/mol)) prior to the diagnosis of their first diabetic complication demonstrated a clinically significant reduction in average HbA1c following the diagnosis of their first complication (mean pre-complication HbA1c=8.5 +/- 1.5% (69 +/- 17 mmol/mol) vs. mean post-complication HbA1c=7.9 +/- 1.7% (63 +/- 18 mmol/mol) (p<0.0001)). CONCLUSION: Enrollees with suboptimally controlled DM may achieve better glycemic control following the diagnosis of a complication from DM. The results from this study, if confirmed in prospective studies, may provide a rationale for the earlier detection of complications from DM to facilitate improved glycemic control among patients with DM. PMID- 26747197 TI - Recent development of allele frequencies and exclusion probabilities of microsatellites used for parentage control in the German Holstein Friesian cattle population. AB - BACKGROUND: Methods for parentage control in cattle have changed since their initial implementation in the late 1950's from blood group typing to more current single nucleotide polymorphism determination. In the early 1990's, 12 microsatellites were selected by the International Society for Animal Genetics based on their informativeness and robustness in a variety of different cattle breeds. Since then this panel is used as standard in cattle herd book breeding and its application is accompanied by recurrent international comparison tests ensuring permanent validity for the most common commercial dairy and beef cattle breeds for example Holstein Friesian, Simmental, Angus, and Hereford. Although, nearly every parentage can be resolved using these microsatellites, cases with very close relatives became an emerging resolution problem during recent years. This is mainly due to an increase of monomorphism and a trend to the fixation of alleles, although no direct selection against their variability was applied. Thus other effects must be presumed resulting in a loss of polymorphism information content, heterozygosity, and exclusion probabilities. RESULTS: To determine changes of allele frequencies and exclusion probabilities, we analyzed the development of these parameters for the 12 microsatellites from 2004 to 2014. One hundred sixty eight thousand recorded Holstein Friesian cattle genotypes were evaluated. During this period certain alleles of nine microsatellites increased significantly (t-values >5). When calculating the exclusion probabilities for 11 microsatellites, reduction was determined for the three situations, i.e. one parent is wrongly identified (p = 0.01), both parents are wrongly identified (p = 0.005), and the genotype of one parent is missing (p = 0.048). With the addition of BM1818 to the marker set in 2009, this development was corrected leading to significant increases in exclusion probabilities. Although, the exclusion probabilities for the three family situations using the 12 microsatellites are >99%, the clarification of 142 relationships in 40,000 situations where one parent is missing will still be impossible. Twenty-five sires were identified that are responsible for the most significant microsatellite allele increases in the population. The corresponding alleles are mainly associated with milk protein and fat yield, body weight at birth and weaning, as well as somatic cell score, milk fat percentage, and longissimus muscle area. CONCLUSIONS: Our data show that most of the microsatellites used for parentage control in cattle show directional changes in allele frequencies consistent with the history of artificial selection in the German Holstein population. PMID- 26747198 TI - Compression Stockings for Preventing the Postthrombotic Syndrome in Patients with Deep Vein Thrombosis. AB - OBJECTIVE: We conducted a systematic review and meta-analysis to address benefits and harms of using elastic compression stockings after lower-extremity deep vein thrombosis. METHODS: We searched 7 electronic databases through January 15, 2015, including randomized controlled trials (RCTs)/quasi-randomized trials reporting on elastic compression stocking efficacy on postthrombotic syndrome incidence, recurrent venous thromboembolism, mortality, and acute pain after deep vein thrombosis. Two reviewers independently screened records, extracted data, assessed risk of bias, and assessed confidence in effect estimates using Grading of Recommendations Assessment, Development, and Evaluation methodology. We applied random-effects meta-analysis models. RESULTS: We included 5 RCTs (n = 1418) reporting on postthrombotic syndrome. The hazard ratio (HR) for postthrombotic syndrome with elastic compression stockings was 0.69 (95% confidence interval [CI], 0.47-1.02). We have very low confidence in this estimate due to heterogeneity and inclusion of unblinded studies at high risk of bias. Excluding high risk of bias studies, a single large RCT at low risk of bias provided moderate-quality evidence of no effect on postthrombotic syndrome (HR 1.00; 95% CI, 0.81-1.24). Moderate-quality evidence including all 5 studies suggests no effect of elastic compression stockings on recurrent venous thromboembolism (relative risk [RR] 0.88; 95% CI, 0.63-1.24) or mortality (RR 1.00; 95% CI, 0.73-1.37, 5 studies). Moderate-quality evidence from one large RCT does not suggest effect on acute pain after deep vein thrombosis. CONCLUSIONS: The highest-quality evidence available suggests no effect of elastic compression stockings on postthrombotic syndrome or pain relief, from a single large RCT. However, results for preventing postthrombotic syndrome differ substantially across studies, and future guideline updates should reflect uncertainty about treatment effects. Elastic compression stockings are unlikely to prevent death or recurrent venous thromboembolism. PMID- 26747200 TI - A Cosmetic Content-Based Nutrition Education Program Improves Fruit and Vegetable Consumption Among Grade 11 Thai Students. AB - OBJECTIVE: To examine and compare the effectiveness of a cosmetic content-based nutrition education (CCBNEd) program and a health content-based nutrition education (HCBNEd) program on the promotion of fruit and vegetable (F&V) consumption. DESIGN: Quasi-experimental. SETTING: Three secondary schools in Nonthaburi, Thailand. PARTICIPANTS/INTERVENTIONS: Three classes of students were randomly assigned to 3 study groups: experimental group 1 (n = 41) participated in the CCBNEd program, experimental group 2 (n = 35) experienced the HCBNEd program, and a comparison group (n = 37) did not participate in a program. All groups received F&V information. Data were collected between July and September, 2013. MAIN OUTCOME MEASURES: Knowledge about F&V, attitude toward F&V consumption, and the amount and variety of F&V consumed were measured at baseline, posttest, and follow-up. ANALYSIS: Nonparametric statistics were used to compare the programs' effectiveness. RESULTS: After the test, experimental group 1 had significantly increased knowledge scores, attitude scores, and the amount and variety of F&V consumed compared with those at baseline (P < .001). These positive changes were maintained until follow-up. In experimental group 2, knowledge and attitude scores increased (P < .001) at posttest and then decreased at follow-up whereas the comparison group positively changed only in knowledge. CONCLUSIONS AND IMPLICATIONS: The CCBNEd program was most effective at increasing F&V consumption. PMID- 26747201 TI - S-phase-specific radiosensitization by gemcitabine for therapeutic carbon ion exposure in vitro. AB - Densely ionizing charged particle irradiation offers physical as well as biological advantages compared with photon irradiation. Radiobiological data for the combination of such particle irradiation (i.e. therapeutic carbon ions) with commonly used chemotherapeutics are still limited. Recent in vitro results indicate a general prevalence of additive cytotoxic effects in combined treatments, but an extension of established multimodal treatment regimens with photons to the inclusion of particle therapy needs to evaluate possible peculiarities of using high linear energy transfer (LET) radiation. The present study investigates the effect of combined radiochemotherapy using gemcitabine and high-LET irradiation with therapeutic carbon ions. In particular, the earlier observation of S-phase specific radiosensitization with photon irradiation should be evaluated with carbon ions. In the absence of the drug gemcitabine, carbon ion irradiation produced the typical survival behavior seen with X-rays-increased relative biological efficiency, and depletion of the survival curve's shoulder. By means of serum deprivation and subsequent replenishment, ~70% S-phase content of the cell population was achieved, and such preparations showed radioresistance in both treatment arms-,photon and carbon ion irradiation. Combined modality treatment with gemcitabine caused significant reduction of clonogenic survival especially for the S-phase cells. WIDR cells exhibited S-phase-specific radioresistance with high-LET irradiation, although this was less pronounced than for X-ray exposure. The combined treatment with therapeutic carbon ions and gemcitabine caused the resistance phenomenon to disappear phenotypically. PMID- 26747204 TI - Effective biodegradation of nitrate, Cr(VI) and p-fluoronitrobenzene by a novel three dimensional bioelectrochemical system. AB - p-Fluoronitrobenzene (p-FNB) was degraded in a novel three dimensional bioelectrochemical system (3D BES) and potentially utilized as carbon source for achieving both nitrate (NO3(-)-N) and Cr(VI) reduction. For single NO3(-)-N and Cr(VI) removal, 200 mg L(-1) NO3(-)-N and 100 mg L(-1) Cr(VI) could be almost completely converted to N2 and Cr(III) at current 50 mA. For single p-FNB degradation, 100 mg L(-1) p-FNB was completely degraded at current 50 mA. The critical current for defluorination was 40 mA, and the intermediate product p fluoroaniline (p-FA) tended to decrease when current was higher than 40 mA. When NO3(-)-N, Cr(VI), and p-FNB were both coexisted in this system, the average NO3( )-N, Cr(VI), and p-FNB removal efficiencies slightly decreased with addition of carbon source. Without carbon source, NO3(-)-N and Cr(VI) removal rates reached 34.45% and 41.38% with 91.02% p-FNB degradation, proving that NO3(-)-N and Cr(VI) could be reduced by degrading p-FNB in the BES. PMID- 26747203 TI - A Computational Approach to Estimating Nondisjunction Frequency in Saccharomyces cerevisiae. AB - Errors segregating homologous chromosomes during meiosis result in aneuploid gametes and are the largest contributing factor to birth defects and spontaneous abortions in humans. Saccharomyces cerevisiae has long served as a model organism for studying the gene network supporting normal chromosome segregation. Measuring homolog nondisjunction frequencies is laborious, and involves dissecting thousands of tetrads to detect missegregation of individually marked chromosomes. Here we describe a computational method (TetFit) to estimate the relative contributions of meiosis I nondisjunction and random-spore death to spore inviability in wild type and mutant strains. These values are based on finding the best-fit distribution of 4, 3, 2, 1, and 0 viable-spore tetrads to an observed distribution. Using TetFit, we found that meiosis I nondisjunction is an intrinsic component of spore inviability in wild-type strains. We show proof-of principle that the calculated average meiosis I nondisjunction frequency determined by TetFit closely matches empirically determined values in mutant strains. Using these published data sets, TetFit uncovered two classes of mutants: Class A mutants skew toward increased nondisjunction death, and include those with known defects in establishing pairing, recombination, and/or synapsis of homologous chromosomes. Class B mutants skew toward random spore death, and include those with defects in sister-chromatid cohesion and centromere function. Epistasis analysis using TetFit is facilitated by the low numbers of tetrads (as few as 200) required to compare the contributions to spore death in different mutant backgrounds. TetFit analysis does not require any special strain construction, and can be applied to previously observed tetrad distributions. PMID- 26747202 TI - Whole-Genome Sequencing of a Canine Family Trio Reveals a FAM83G Variant Associated with Hereditary Footpad Hyperkeratosis. AB - Over 250 Mendelian traits and disorders, caused by rare alleles have been mapped in the canine genome. Although each disease is rare in the dog as a species, they are collectively common and have major impact on canine health. With SNP-based genotyping arrays, genome-wide association studies (GWAS) have proven to be a powerful method to map the genomic region of interest when 10-20 cases and 10-20 controls are available. However, to identify the genetic variant in associated regions, fine-mapping and targeted resequencing is required. Here we present a new approach using whole-genome sequencing (WGS) of a family trio without prior GWAS. As a proof-of-concept, we chose an autosomal recessive disease known as hereditary footpad hyperkeratosis (HFH) in Kromfohrlander dogs. To our knowledge, this is the first time this family trio WGS-approach has been used successfully to identify a genetic variant that perfectly segregates with a canine disorder. The sequencing of three Kromfohrlander dogs from a family trio (an affected offspring and both its healthy parents) resulted in an average genome coverage of 9.2X per individual. After applying stringent filtering criteria for candidate causative coding variants, 527 single nucleotide variants (SNVs) and 15 indels were found to be homozygous in the affected offspring and heterozygous in the parents. Using the computer software packages ANNOVAR and SIFT to functionally annotate coding sequence differences, and to predict their functional effect, resulted in seven candidate variants located in six different genes. Of these, only FAM83G:c155G > C (p.R52P) was found to be concordant in eight additional cases, and 16 healthy Kromfohrlander dogs. PMID- 26747205 TI - Flashing light in microalgae biotechnology. AB - Flashing light can enhance photosynthesis and improve the quality and quantity of microalgal biomass, as it can increase the products of interest by magnitudes. Therefore, the integration of flashing light effect into microalgal cultivation systems should be considered. However, microalgae require a balanced mix of the light/dark cycle for higher growth rates, and respond to light intensity differently according to the pigments acquired or lost during the growth. This review highlights recently published results on flashing light effect on microalgae and its applications in biotechnology, as well as the recently developed bioreactors designed to fulfill this effect. It also discusses how this knowledge can be applied in selecting the optimal light frequencies and intensities with specific technical properties for increasing biomass production and/or the yield of the chemicals of interest by microalgae belonging to different genera. PMID- 26747206 TI - Is digit ratio (2D:4D) a reliable pointer to speech laterality? AB - The relative length of the second and fourth digits (2D:4D ratio) is sexually dimorphic and a retrospective biomarker of prenatal hormonal exposure. Low ratios indicate higher prenatal testosterone (pT) and lower estrogen exposure, whereas the reverse pattern is associated with high ratios. Elevated levels of pT exposure have long been thought to modulate hemispheric specialisation; subsequently many studies use the 2D:4D ratio as a proxy index for pT to examine the effects of prenatal hormonal exposure on lateralised cognitive abilities. Here we used Transcranial Doppler ultrasonography and digit ratio to investigate whether pT has an influence on speech laterality. We tested 34 right and 14 left handed adults. Our results indicate that speech representation is unrelated to digit characteristics and therefore purportedly pT. We discuss these findings in relation to androgen theories of lateralisation. PMID- 26747207 TI - Chronical sleep interruption-induced cognitive decline assessed by a metabolomics method. AB - Good sleep is necessary for optimal health, especially for mental health. Insomnia, sleep deprivation will make your ability to learn and memory impaired. Nevertheless, the underlying pathophysiological mechanism of sleep disorders induced cognitive decline is still largely unknown. In this study, the sleep deprivation of animal model was induced by chronical sleep interruption (CSI), the behavioral tests, biochemical index determinations, and a liquid chromatography-mass spectrometry (LC-MS) based serum metabolic profiling analysis were performed to explore the effects of CSI on cognitive function and the underlying mechanisms. After 14-days CSI, the cognitive function of the mice was evaluated by new objects preference (NOP) task and temporal order judgment (TOJ) task. Serum corticosterone (CORT), and brain Malondialdehyde (MDA), Superoxide Dismutase (SOD), and Catalase (CAT) levels were determined by ELISA kits. Data were analyzed by Principal Component Analysis (PCA), Partial Least Squares project to latent structures-Discriminant Analysis (PLS-DA), and Student's t test. We found that the cognitive function of the mice was significantly affected by CSI. Besides, levels of CORT and MDA were higher, and SOD and CAT were lower in CSI mice than those of control. Obvious body weight loss of CSI mice was also observed. Thirteen potential serum biomarkers including choline, valine, uric acid, allantoic acid, carnitines, and retinoids were identified. Affected metabolic pathways involve metabolism of purine, retinoid, lipids, and amino acid. These results showed that CSI can damage the cognitive performance notably. The cognitive decline may ascribe to excessive oxidative stress and a series of disturbed metabolic pathways. PMID- 26747208 TI - Workplace learning in midwifery education in Flanders (Belgium). AB - Workplace learning plays a crucial role in midwifery education. Twelve midwifery schools in Flanders (Belgium) implemented a new competency framework and aimed at implementing a more standardized and evidence-based method to learn and assess competencies, as well as to guide continuous competency development in practice. This paper describes the introduction of 'Embo's continuous workplace learning model', a holistic and competency-based method that integrates all workplace learning components. Available research evidence helps concluding the learning model is a feasible approach to organize workplace learning in such a way that continuous professional competency development is achieved. PMID- 26747209 TI - Baseline estradiol concentration in community-dwelling Japanese American men is not associated with intra-abdominal fat accumulation over 10 years. AB - PROBLEM: The role of plasma estradiol in the accumulation of intra-abdominal fat (IAF) in men is uncertain. Cross-sectional studies using imaging of IAF have shown either a positive or no association. In contrast, a randomised controlled trial using an aromatase inhibitor to suppress estradiol production found an association between oestrogen deficiency and short-term IAF accumulation. No longitudinal study has been conducted to examine the relationship between plasma estradiol concentration and the change in IAF area measured using direct imaging. METHODS: This is a longitudinal observational study in community-dwelling Japanese-American men (n=215, mean age 52 years, BMI 25.4kg/m2). IAF and subcutaneous fat areas were assessed using computerized tomography (CT) at baseline, 5 and 10 years. Baseline plasma estradiol concentrations were measured using liquid chromatography-tandem mass spectrometry. RESULTS: Univariate analysis found no association between baseline estradiol concentration and baseline IAF, or 5- or 10-year changes in IAF area (r=-0.05 for both time points, p=0.45 and p=0.43, respectively). Multivariate linear regression analysis of the change in IAF area by baseline estradiol concentration adjusted for age, baseline IAF area, and weight change found no association with either the 5- or 10-year IAF area change (p=0.52 and p=0.55, respectively). CONCLUSIONS: Plasma estradiol concentration was not associated with baseline IAF nor with change in IAF area over 5 or 10 years based on serial CT scans in community-dwelling Japanese American men. These results do not support a role for oestrogen deficiency in IAF accumulation in men. PMID- 26747210 TI - The relationship between aquaglyceroporin expression and development of fatty liver in diet-induced obesity and ob/ob mice. AB - Aquaporin (AQP) 7 and AQP9 are subcategorised as aquaglyceroporins which transport glycerin in addition to water. These AQPs may play a role in the homeostasis of energy metabolism. We examined the effect of AQP7, AQP9, and lipid metabolism-related gene expression in obese mice. In diet-induced obese (DIO) mice, excess lipid accumulated in the liver, which was hyperleptinemic and hyperinsulinemic. Hepatic AQP9 gene expression was significantly increased in both DIO and ob/ob mice compared to controls. The mRNA expression levels of fatty acid and triglyceride synthesis-related genes and fatty acid beta oxidation related genes in the liver were also higher in both mouse models, suggesting that triglyceride synthesis in this organ is promoted as a result of glycerol release from adipocytes. Adipose AQP7 and AQP9 gene expressions were increased in DIO mice, but there was no difference in ob/ob mice compared to wild-type mice. In summary, adipose AQP7 and AQP9 gene expressions are increased by diet-induced obesity, indicating that this is one of the mechanisms by which lipid accumulates in response to a high fat diet, not the genetic mutation of ob/ob mice. Hepatic AQP9 gene expression was increased in both obesity model mice. AQP7 and AQP9 therefore have the potential of defining molecules for the characterisation of obesity or fatty liver and may be a target molecules for the treatment of those disease. PMID- 26747211 TI - Ocular inflammation induces trigeminal pain, peripheral and central neuroinflammatory mechanisms. AB - Ocular surface diseases are among the most frequent ocular pathologies, with prevalence ranging from 20% of the general population. In addition, ocular pain following corneal injury is frequently observed in clinic. The aim of the study was to characterize the peripheral and central neuroinflammatory process in the trigeminal pathways in response to cornea alteration induced by chronic topical instillations of 0.2% benzalkonium chloride (BAC) in male C57BL/6J mice. In vitro BAC induced neurotoxicity and increases neuronal (FOS, ATF3) and pro-inflammatory (IL-6) markers in primary mouse trigeminal ganglion culture. BAC-treated mice exhibited 7days after the treatment reduced aqueous tear production and increased inflammatory cell infiltration in the cornea. Hypertonic saline-evoked eye wipe behavior was enhanced in BAC-treated animals that exhibited increased FOS, ATF3 and Iba1 immunoreactivity in the trigeminal ganglion. Ocular inflammation is associated with a significant increase in IL-6 and TNF-alpha mRNA expression in the trigeminal ganglion. We reported a strong increase in FOS and Iba1 positive cells in particular in the sensory trigeminal complex at the ipsilateral interpolaris/caudalis (Vi/Vc) transition and Vc/upper cervical cord (Vc/C1) regions. In addition, activated microglial cells were tightly wrapped around activated FOS neurons in both regions and phosphorylated p38 mitogen-activated protein kinase was markedly enhanced specifically in microglial cells during ocular inflammation. Similar data were obtained in the facial motor nucleus. These neuroanatomical data correlated with the increase in mRNA expression of pro inflammatory (TNF-alpha, IL-6, CCL2) and neuronal (FOS and ATF3) markers. Interestingly, the suppression of corneal inflammation 10days following the end of BAC treatment resulted in a marked attenuation of peripheral and central changes observed in pathological conditions. This study provides the first demonstration that corneal inflammation induces activation of neurons and microglial p38 MAPK pathway within sensory trigeminal complex. These results suggest that this altered activity in intracellular signaling caused by ocular inflammation might play a priming role in the central sensitization of ocular related brainstem circuits, which represents a significant factor in ocular pain development. PMID- 26747214 TI - Is alexithymia associated with metabolic syndrome? A study in a healthy adult population. AB - Metabolic syndrome (MetS) is a constellation of risk factors for, in particular, cardiovascular diseases and increased mortality, and it constitutes a major clinical challenge affecting millions of lives. Alexithymia is a condition that has been linked with several mental diseases and symptoms, as well as somatic illnesses, including essential hypertension and diabetes mellitus. However, there is limited research on the association of alexithymia and MetS. The aim of the present study was to comprehensively explore this association in a large (n=1648) non-clinical sample of adults. Logistic regression analyses were applied to the five separate MetS components as well as the MetS diagnosis, and the analyses included a number of sociodemographic variables and depressive symptoms as covariates. The results confirmed the previous finding of alexithymic features being independently and significantly associated with hypertension. As a new finding, this association appears to be related to two particular dimensions of alexithymia, namely difficulty describing feelings and externally oriented thinking. Interestingly, alexithymic features were also separately significantly associated with waist circumference and triglycerides as well as the MetS diagnosis. Depressive symptoms did not have any significant effect on the relations of alexithymia and MetS. PMID- 26747215 TI - Personality disorders, but not cancer severity or treatment type, are risk factors for later generalised anxiety disorder and major depressive disorder in non metastatic breast cancer patients. AB - This study aimed to determine whether personality disorders were associated with later Major Depressive Disorder (MDD) or Generalised Anxiety Disorder (GAD) in breast cancer patients. This longitudinal and multicentric study included 120 French non-metastatic breast cancer patients. After cancer diagnosis (T1) and 7 months after diagnosis (T3), we assessed MDD and GAD (Mini International Neuropsychiatric Interview 5.0). We assessed personality disorders 3 months after diagnosis (VKP). We used multiple logistic regression analysis to determine what were the factors associated with GAD and MDD at T3. At T3, prevalence rate was 10.8% for MDD and 19.2% for GAD. GAD at T3 was significantly and independently associated with GAD at T1 and with existence of a personality disorder, no matter the cluster type. MDD at T3 was significantly and independently associated with MDD at T1 and with the existence of a cluster C personality disorder. Initial cancer severity and the type of treatment used were not associated with GAD or MDD at T3. Breast cancer patients with personality disorders are at higher risk for GAD and MDD at the end of treatment. Patients with GAD should be screened for personality disorders. Specific interventions for patients with personality disorders could prevent psychiatric disorders. PMID- 26747212 TI - Dynamic structural flexibility of alpha-synuclein. AB - alpha-Synuclein is a conserved, abundantly expressed protein that is partially localized in pre-synaptic terminals in the central nervous system. The precise biological function(s) and structure of alpha-synuclein are under investigation. Recently, the native conformation and the presence of naturally occurring multimeric assemblies have come under debate. These are important deliberations because alpha-synuclein assembles into highly organized amyloid-like fibrils and non-amyloid amorphous aggregates that constitute the neuronal inclusions in Parkinson's disease and related disorders. Therefore understanding the nature of the native and pathological conformations is pivotal from the standpoint of therapeutic interventions that could maintain alpha-synuclein in its physiological state. In this review, we will discuss the existing evidence that define the physiological states of alpha-synuclein and highlight how the inherent structural flexibility of this protein may be important in health and disease. PMID- 26747213 TI - Subjective pain during NSSI as an active agent in suicide risk. AB - Non-suicidal self-injury (NSSI) has been identified as a correlate and predictor of suicidal ideation and attempts. Given the high-rates of NSSI presence among adolescents and young adults, it is important to identify specific characteristics of NSSI that might place individuals who engage in this behavior at highest risk for suicidal behavior. NSSI is thought to increase the acquired capability for suicide via habituation to self-harm, though the NSSI characteristics most responsible for this relationship are unclear. The current study examined three characteristics of NSSI (frequency, number of methods, and subjective pain) that may help to elucidate this risk relationship. University students (N=997) with a history of NSSI completed measures assessing lifetime NSSI frequency, number of NSSI methods employed, and subjective experience of pain during NSSI, as well as suicide attempt (SA) history. Results indicated that NSSI frequency, number of NSSI methods, and subjective pain experienced during NSSI were each positively associated with SA history. Further, subjective pain experienced during NSSI moderated the relationship between NSSI frequency and SA history, such that the association between NSSI frequency and SA history was stronger for individuals who experienced lower levels of subjective pain. PMID- 26747216 TI - The Institute of Medicine Says Time to Act to Improve Cardiac Arrest Survival: Here's How. PMID- 26747217 TI - The Impact of Clinical Decision Rules on Computed Tomography Use and Yield for Pulmonary Embolism: A Systematic Review and Meta-analysis. AB - STUDY OBJECTIVE: Validation studies have confirmed the accuracy of clinical decision rules for the evaluation of pretest probability of pulmonary embolism. It has been assumed that clinical decision rules will also decrease testing in actual practice, but the evidence for this is unclear. We perform a systematic review of impact analyses on clinical decision rules for pulmonary embolism. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched without language restriction for studies assessing the effect of clinical decision rules on efficiency (computed tomography [CT] angiography use and yield) and safety (missed pulmonary embolism) through October 2014. Two reviewers independently extracted data on study characteristics, methods, risk of bias, and outcomes. RESULTS: Eight studies (n=6,677) contained sufficient information, including 1 randomized trial and 7 observational studies. Because of heterogeneity, the results of 4 studies of moderate to high quality assessing the Wells criteria were pooled. The pooled CT angiography yield was 9% (95% confidence interval [CI] 6% to 12%) in the control group and 12% (95% CI 11% to 14%) in the intervention group, for a 3% increase in yield (95% CI 1% to 5%), relative risk 1.3 (95% CI 1.1 to 1.6). We were unable to report a pooled estimate of CT angiography use. Of 2 studies with sufficient information, there was no difference in the rate of missed pulmonary embolism between intervention and control groups. No studies used a cluster-randomized design. CONCLUSION: Among participants with suspected pulmonary embolism, implementation of the Wells criteria was associated with a modest increase in CT angiography yield. There is a lack of cluster-randomized trials to confirm the efficacy of clinical decision rules for the diagnosis of pulmonary embolism. PMID- 26747218 TI - Efficacy of Nasal Cannula Oxygen as a Preoxygenation Adjunct in Emergency Airway Management. AB - STUDY OBJECTIVE: Although preoxygenation for emergency airway management is usually performed with nonrebreather face masks or bag-valve-mask devices, some clinicians also deliver supplemental high-flow oxygen by nasal cannula. We aim to measure the efficacy of supplemental nasal cannula oxygen delivery to conventional bag-valve-mask and nonrebreather face mask preoxygenation both with and without a simulated face mask leak. METHODS: We conducted a randomized crossover trial using healthy volunteers. We randomized subjects to preoxygenation with bag-valve-mask or nonrebreather face mask. In random sequence, subjects underwent 3-minute trials of preoxygenation with oxygen through mask alone at 15 L/min, oxygen through mask at 15 L/min with standardized leak, oxygen through mask at 15 L/min+oxygen through nasal cannula at 10 L/min, and oxygen through mask at 15 L/min+oxygen through nasal cannula at 10 L/min with standardized leak. The primary outcome was single-breath exhalation end-tidal oxygen (eto2). We compared eto2 between preoxygenation modalities, using nonparametric techniques. RESULTS: We enrolled 60 subjects (30 nonrebreather face mask and 30 bag-valve-mask). In scenarios without a mask leak, eto2 was similar between bag-valve-mask and bag-valve-mask+nasal cannula (mean 79% versus 75%; difference -3%; 95% confidence interval [CI] -8% to 1%). In bag-valve-mask scenarios with a mask leak, eto2 was higher for bag-valve-mask+nasal cannula than bag-valve-mask alone (mean 66% versus 41%; difference 25%; 95% CI 21% to 29%). eto2 was higher for nonrebreather face mask+nasal cannula than nonrebreather face mask (mean 67% versus 52%; difference 15%; 95% CI 12% to 18%). In nonrebreather face mask scenarios with a mask leak, eto2 was higher for nonrebreather face mask+nasal cannula than nonrebreather face mask (mean 65% versus 48%; difference 17%; 95% CI 13% to 20%). CONCLUSION: Although not aiding bag-valve-mask preoxygenation with a good mask seal, supplemental nasal cannula oxygen improved preoxygenation efficacy in the presence of a bag-valve-mask mask leak. Supplemental nasal cannula oxygen improved nonrebreather face mask preoxygenation both with and without a mask leak. Supplemental nasal cannula oxygen may be helpful for preoxygenation before emergency airway management. PMID- 26747220 TI - Skin Glue Reduces the Failure Rate of Emergency Department-Inserted Peripheral Intravenous Catheters: A Randomized Controlled Trial. AB - STUDY OBJECTIVE: Peripheral intravenous catheters are the most common invasive device in health care yet have very high failure rates. We investigate whether the failure rate could be reduced by the addition of skin glue to standard peripheral intravenous catheter care. METHODS: We conducted a single-site, 2-arm, nonblinded, randomized, controlled trial of 380 peripheral intravenous catheters inserted into 360 adult patients. The standard care group received standard securement. The skin glue group received standard securement plus cyanoacrylate skin glue applied to the skin insertion site. The primary outcome was peripheral intravenous catheter failure at 48 hours, regardless of cause. Secondary outcomes were the individual modes of peripheral intravenous catheter failure: infection, phlebitis, occlusion, or dislodgement. RESULTS: Peripheral intravenous catheter failure was 10% lower (95% confidence interval -18% to -2%; P=.02) with skin glue (17%) than standard care (27%), and dislodgement was 7% lower (95% confidence interval -13% to 0%; P=.04). Phlebitis and occlusion were less with skin glue but were not statistically significant. There were no infections. CONCLUSION: This study supports the use of skin glue in addition to standard care to reduce peripheral intravenous catheter failure rates for adult emergency department patients admitted to the hospital. PMID- 26747219 TI - STONE PLUS: Evaluation of Emergency Department Patients With Suspected Renal Colic, Using a Clinical Prediction Tool Combined With Point-of-Care Limited Ultrasonography. AB - STUDY OBJECTIVE: We determine whether renal point-of-care limited ultrasonography (PLUS) used in conjunction with the Sex, Timing, Origin, Nausea, Erythrocytes (STONE) clinical prediction score can aid identification of emergency department (ED) patients with uncomplicated ureteral stone or need for urologic intervention. METHODS: This was a prospective observational study of adult ED patients undergoing computed tomography (CT) scan for suspected ureteral stone. The previously validated STONE score classifies patients into risk categories of low (~10%), moderate (~50%), or high (~90%) for symptomatic stone. Renal PLUS assessed for presence of hydronephrosis before CT scanning. The primary outcomes of symptomatic ureteral stone or acutely important alternative finding were abstracted from CT reports. The secondary outcome, urologic intervention, was assessed by 90-day follow-up interview and record review. RESULTS: Of 835 enrolled patients, ureteral stone was identified in 53%, whereas 6.5% had an acutely important alternative finding on CT. Renal PLUS modestly increased sensitivity for symptomatic stone among low and moderate STONE score categories. Moderate or greater hydronephrosis improved specificity from 67% (62% to 72%) to 98% (93% to 99%) and 42% (37% to 47%) to 92% (86% to 95%) in low- and moderate risk patients, with likelihood ratios of 22 (95% CI, 4.2-111) and 4.9 (95% CI, 2.9-8.3), respectively. Test characteristics among high-risk patients were unchanged by renal PLUS. For urologic intervention, any hydronephrosis was 66% sensitive (57% to 74%), whereas moderate or greater hydronephrosis was 86% specific overall (83% to 89%) and 81% (69% to 90%) sensitive and 79% 95% CI, (73 84) specific among patients with the highest likelihood of symptomatic stone. CONCLUSION: Hydronephrosis on renal PLUS modestly improved risk stratification in low- and moderate-risk STONE score patients. The presence or absence of hydronephrosis among high-risk patients did not significantly alter likelihood of symptomatic stone but may aid in identifying patients more likely to require urologic intervention. PMID- 26747221 TI - Tracheal diverticula in cystic fibrosis-A potentially important underreported finding on chest CT. AB - BACKGROUND: We aim to assess the prevalence and describe characteristics of tracheal diverticula (TD) in patients with cystic fibrosis (CF). METHODS: This retrospective study included 92 patients with known CF treated in our medical center who had available chest CT, performed between 2001 and 2013. Presence, number, size, and location of TD were recorded on the most recent chest CT. The severity of CF-related pulmonary CT findings and pulmonary function tests were recorded and correlated with the presence of the diverticula. RESULTS: Twenty-six (28%) of the 92 patients (17 males, 9 females, age range 5-59years) had one or more TD. The size of TD ranged from 2mm to 32mm. TDs were on the right posterolateral aspect of the upper tracheain nearly all patients. Small TDs appeared as a focal paratracheal lucency and larger ones as a soft tissue mass with central air bubbles. There was no significant difference in the Bhalla score between patients with and without TD. There was no correlation between the Bhalla score and patients' age, size, or number of diverticula. Pulmonary function tests were worse and declined faster in patients with TD compared to those without. CONCLUSIONS: TDs are quite common on chest CT of CF patients. Those with diverticula have significantly worse pulmonary function tests than those without. PMID- 26747222 TI - Cell specific differences in the protein abundances of GAPDH and Na(+),K(+) ATPase in skeletal muscle from aged individuals. AB - Na(+), K(+)-ATPase (NKA) isoforms (alpha1,alpha2,alpha3,beta1,beta2,beta3) are involved in the maintenance of membrane potential and hence are important regulators of cellular homeostasis. Given the age-related decline in skeletal muscle function, we investigated whether the natural physiological process of aging is associated with altered abundance of NKA isoforms (alpha1,alpha2,alpha3,beta1,beta2,beta3) or of the commonly used control protein, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Importantly, measurements were made in both whole muscle or specific fiber types obtained from skeletal muscle biopsies. Seventeen healthy older (AGED, 69.4 +/- 3.5 years, mean +/- SD) and 14 younger (YOUNG, 25.5 +/- 2.8 years) adults underwent a muscle biopsy for biochemical analyses. Comparing homogenates from AGED and YOUNG individuals revealed higher beta3 isoform (p<0.05) and lower GAPDH (p<0.05). Analysis of individual fibers in muscle from YOUNG individuals, showed greater alpha3 and beta2 isoforms, and more GAPDH in Type II compared with Type I fibers (p<0.05). In the AGED, GAPDH was higher in Type II compared with Type I fibers (p<0.05), there were no fiber type differences in the NKA isoforms (p>0.05). Compared with the same fiber type in YOUNG, alpha1 was greater (Type I) and alpha3 lower (Type II), while in both fiber types, beta2 was lower, beta3 greater and GAPDH lower, in muscle from AGED individuals (all p<0.05). Overall, we demonstrate that (i) GAPDH is an inappropriate choice of protein for normalization in all skeletal muscle research and (ii) full understanding of the role of NKA isoforms in human skeletal muscle requires consideration of age and muscle fiber type. PMID- 26747223 TI - Changing paradigms in the surgical management of cystic liver hydatidosis improve the postoperative outcomes. AB - AIM OF THE STUDY: Our aim was to propose and examine the outcomes of a comprehensive strategy for the management of cystic liver hydatidosis (CLH) based on extensive intraoperative assessments and optimal management of cystobiliary communications. BACKGROUND DATA: Although operative intervention remains the preferred treatment for CLH, and the presence of a cystobiliary communication remains a well-established predictive factor for postoperative complications, no internationally accepted management strategy integrates the specific management of cystobiliary communication into the choice of surgical approach. METHODS: Early postoperative outcomes were compared before (1990-2004; P1 group; n = 664) and after (2005-2013; P2 group; n = 156) the implementation of a CLH surgical management strategy for CLH in our overall group of patients in subgroups selected by risk factors (as determined by multivariate analysis), and in 2 propensity score-matched groups. RESULTS: Specific complications related to the hepatic procedure (intraabdominal complications) were independently associated with the presence of >= 3 cysts (P = .013), a fibrotic pericyst (P = .005), a cystobiliary communication (P < .001), and the P1 treatment period (P = .002). Between P1 and P2 groups, the rate of specific complications decreased in the overall group of patients with CLH (18.3% vs 4.5%; P < .001). The rate also decreased in risk factor-based subgroups: patients with >= 3 cysts (31.0% vs 4.0%; P = .005), a fibrotic pericyst (23.1% vs 9.2%; P = .011), and a cystobiliary communication (33.0% vs 13.2%; P = .006). After propensity score matching among 123 well-balanced matched pairs of patients, the overall complication rate, specific hepatic surgery-related complication rate, and median duration of hospital stay decreased between the P1 and P2 groups: 23.6% vs 12.2% (P = .02), 21.1% vs 4.9% (P < .001), and 7 vs 5 days (P < .001), respectively. CONCLUSION: Implementation of a CLH surgical management strategy based on specific intraoperative assessment and optimal management of cystobiliary communications improved early postoperative outcomes. PMID- 26747225 TI - Reply to: Accuracy of scoring systems for suspected choledocholithiasis. PMID- 26747224 TI - Evaluation of the efficacy of daikenchuto (TJ -100) for the prevention of paralytic ileus after pancreaticoduodenectomy: A multicenter, double-blind, randomized, placebo-controlled trial. AB - BACKGROUND: We assessed the efficacy of TJ-100 taken perioperatively to recovery among patients with periampullary tumor or tumor of the head of the pancreas who underwent pancreaticoduodenectomy (PD). PATIENTS AND METHODS: In this multicenter, randomized, double-blinded, placebo-controlled, phase II trial (JAPAN-PD Study), patients were assigned randomly in a 1:1 ratio to receive TJ 100 or placebo. The coprimary endpoints were (1) incidence of postoperative paralytic ileus lasting >72 hours after surgery and (2) time to occurrence of postoperative paralytic ileus. This trial is registered at the UMIN Clinical Trials Registry (000007975) and at ClinicalTrials.gov (NCT01607307). RESULTS: From August 2012 through July 2013, we assessed 273 patients for eligibility, and 224 underwent randomization; 112 patients received TJ-100, and 112 patients received placebo. The population for analysis consisted of 104 patients who received TJ-100 and 103 who received placebo. Paralytic ileus occurred 35 (33.7%) in the TJ-100 group and 38 (36.9%) in the placebo group (P = .626). Time to first flatus was 2.25 (2.00-2.50) days in the TJ-100 group and 2.50 (1.50-2.50) days in the placebo group (P = .343). Among 23 patients who underwent a pylorus ring preserving PD, time to first flatus was lower in the TJ-100 group than in the placebo group: 0.50 (0.50-1.00) days versus 1.50 (0.50-3.00) days (P = .034). CONCLUSION: Our findings suggest that use of TJ-100 did not improve recovery from paralytic ileus after PD, and may preclude the routine use of TJ-100 in clinical practice after PD operation. PMID- 26747226 TI - The impact of chronic liver disease on the risk assessment of ACS NSQIP morbidity and mortality after hepatic resection. AB - BACKGROUND: The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) risk-adjustment model for patients who require hepatic resection does not include metrics of underlying chronic liver disease. The applicability of the current risk adjustment model is under debate. This study aims to assess the impact of chronic liver disease on the ACS NSQIP estimates of postoperative morbidity and mortality. STUDY DESIGN: This retrospective cohort study included all cases of hepatic resection at our quaternary referral institution between 2006 and 2013. Metrics of chronic liver disease were abstracted and linked with the ACS NSQIP risk-adjustment model estimated probabilities of morbidity and mortality for each case. Sequential general linear models were used to estimate differences in ACS NSQIP probabilities of morbidity and mortality associated with measures of underlying chronic liver disease. RESULTS: A total of 522 hepatic resections were performed during the study period. The patient cohort included 91 patients with fibrosis (17%) and 38 patients with cirrhosis (7%). The mean ACS NSQIP estimated probability of morbidity was 0.24 +/- 0.11 and probability of mortality was 0.02 +/- 0.02. Fibrosis was associated with increased probability of morbidity (0.26 +/- 0.11; P = .019); cirrhosis was also associated with increased probability of morbidity (0.27 +/- 0.10; P = .059). Parenchymal liver disease was not associated with increased probability of mortality (all P >= .62). Increased probabilities of mortality were associated with diagnosis and extent of resection (both P < .001). CONCLUSIONS: In patients selected for hepatectomy, metrics of chronic liver disease were associated with differences in ACS NSQIP estimated probability of morbidity. Incorporation of metrics of chronic liver disease into the ACS NSQIP targeted hepatectomy modules should improve estimates of risk after hepatic resection. PMID- 26747228 TI - Assessment of two different diagnostic guidelines criteria (National Cholesterol Education Adult Treatment Panel III [ATP III] and International Diabetes Federation [IDF]) for the evaluation of metabolic syndrome remission in a longitudinal cohort of patients undergoing Roux-en-Y gastric bypass. AB - BACKGROUND: Bariatric surgery has proven to provide durable weight loss and control of comorbid conditions, including the metabolic syndrome (MS). Existing definitions of MS have caused substantial confusion regarding their concordance for identifying the same individuals. The aim of this study was to assess the value of 2 different diagnostic guidelines criteria (National Cholesterol Education Adult Treatment Panel III [ATP III] and International Diabetes Federation [IDF]) for the evaluation of remission of MS after Roux-en-Y gastric bypass (RYGB). PATIENTS AND METHODS: A cohort of 381 patients who underwent a primary RYGB, satisfied the criteria for MS, and had at least o1 postoperative visit were selected. Weight loss and MS remission were analyzed 6 and 12 months after surgery by ATP III and IDF criteria. RESULTS: Before surgery, 381 (48.9%) and 354 (45.4%) patients fulfilled the criteria for MS according to the ATP III and IDF, respectively. According to the ATP III definition, remission of MS after bariatric surgery occurred in 209 of 239 (87.4%) and 98/102 (96.1%) patients at 6 and 12 months, respectively. According to the IDF definition, this occurred in 180 of 232 (77.6%) and 54 of 64 (84.4%) at the same time periods. On the basis of different percentage of excess body weight loss cut-off values, the area under the curve in receiver operating characteristic analysis at 12 months was slightly better for ATP III (0.77) than IDF criteria (0.68) for remission of MS. CONCLUSIONS: With the use of the IDF definition, the remission rate of MS was 10% more rigorous than with use of the ATP-III criteria. This feature is attributable to a greater discrimination of patients with high blood pressure, glycemia, and dyslipidemia. The IDF criteria seem more accurate to evaluate MS remission. PMID- 26747227 TI - Effectiveness of routine ultrasonographic surveillance of patients with low-risk papillary carcinoma of the thyroid. AB - BACKGROUND: Over the last 15 years, there has been a change in clinical practice for the detection of recurrence in all patients with papillary thyroid cancer (PTC). In the past, recurrence was detected by clinical examination supplemented with fine-needle aspiration cytology; however, routine neck ultrasonography (US) and measurements of serum thyroglobulin were introduced for follow-up in 2000 and are now used widely for recurrence surveillance. The aim of this study was to describe the effectiveness of this changing trend in the use of routine surveillance ultrasonography for the detection of recurrence in low-risk PTC at a single institution. METHODS: Patients undergoing total thyroidectomy for PTC between January 2000 and December 2010 were identified from an institutional database. Of these, 752 (43.1%) were categorized as low risk by the risk stratification of the American Thyroid Association and included for analysis. The number of US examinations per patient per year of follow-up was then determined. The number of recurrences and deaths from disease was recorded similarly. RESULTS: The median age was 48 years (range, 16-83) and the median follow-up was 34 months (range, 1-148). Between 2003 and 2012, the number of US examinations per patient-year of follow-up increased by 5.3-fold. Over the same time period, 3 structural recurrences (clinically evident neck masses or nodes) were detected with no disease-related deaths. CONCLUSION: At our institution, the annual rate of neck US examination increased by 5.3-fold per low-risk PTC patients between 2003 and 2012. Despite this increase, only 3 structural recurrences were detected. The routine use of neck US for surveillance of low-risk PTC patients requires review. PMID- 26747229 TI - Variations and adaptations of associated liver partition and portal vein ligation for staged hepatectomy (ALPPS): Many routes to the summit. AB - BACKGROUND: Our aim was to review variations from the originally described associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure and relevant clinical outcomes. METHODS: A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (ie, PRISMA) guidelines. A search of PubMed and Google Scholar was conducted until March 2015. Inclusion criteria were any publications reporting technical variations and descriptions of ALPPS. Exclusion criteria were insufficient technical description, data repeated elsewhere, or data that could not be accessed in English. RESULTS: Initial search results returned 790 results; 46 studies were included in the final qualitative analysis. There were several alternatives described to the first stage of complete parenchymal split. Variations included partial ALPPS (partial split; hypertrophy of future liver remnant [FLR] 80-90%), radiofrequency-assisted liver partition and portal vein ligation (mean FLR hypertrophy 62%), laparoscopic microwave ablation and portal vein ligation (FLR hypertrophy 78-90%), associating liver tourniquet and portal ligation for staged hepatectomy (median FLR hypertrophy 61%), and sequential associating liver tourniquet and portal ligation for staged hepatectomy (FLR hypertrophy 77%) with a potential decrease in morbidity particularly after stage I. We analyzed several other variations, including considerations for segment IV, operative maneuvers, use of laparoscopy, identification of biliary complications, and liver containment. CONCLUSION: The current literature demonstrates a large variability in techniques of ALPPS that limits meaningful statistical comparisons of outcomes. Not physically splitting the liver at the first stage may decrease morbidity; however, randomized controlled trials are needed to determine benefits in technical variations. PMID- 26747230 TI - Recurrence of gastric cancer in patients who are disease-free for more than 5 years after primary resection. AB - BACKGROUND: Late recurrence of gastric cancer is rare and there are few data on recurrence in patients who are disease free for >5 years after gastrectomy. The aim of this study was to evaluate the predictors and status of tumor recurrence among these patients. METHODS: Clinicopathologic characteristics, patterns of recurrence, and postrecurrence survival were analyzed in patients who were diagnosed as disease free at 5 years postoperatively and thereafter experienced recurrence. Independent factors associated with the late recurrence were analyzed. RESULTS: Among 1,573 patients who underwent curative surgery from June 1992 to December 2006, 348 patients had recurrence. Of them, 7.6% (n = 25) suffered from late recurrence after 5 years after gastrectomy. Among patients who were diagnosed as disease free at 5 years after surgery, it accounted for 2.8% (25/902). Cases with late recurrence were characterized by more aggressive clinicopathologic features than those without recurrence. The median time to recurrence was 88.8 months (range, 64.8-238.0); of the 25 patients, 18 (72.0%) had recurrence within 8 years after surgery. The most common pattern was peritoneal recurrence (n = 19; 76.0%). The estimated median survival after recurrence was 9.4 months. On multivariate analysis, pT4 classification was the only independent risk factor for late recurrence. There were 185 patients with pT4 tumor who had no recurrence at 5 years after surgery; 19 (10.3%) had late recurrence. CONCLUSION: pT4 tumor was the only important predictor of late recurrence. Whether extended follow-up for T4 tumors affects survival needs to be demonstrated in more large-scale studies. PMID- 26747231 TI - Coronary CT angiography derived fractional flow reserve: Methodology and evaluation of a point of care algorithm. AB - BACKGROUND: Recently several publications described the diagnostic value of coronary CT angiography (coronary CTA) derived fractional flow reserve (CTA-FFR). For a recently introduced on-site CTA-FFR application, detailed methodology and factors potentially affecting performance have not yet been described. OBJECTIVE: To provide a methodological background for an on-site CTA-FFR application and evaluate the effect of patient and acquisition characteristics. METHODS: The on site CTA-FFR application utilized a reduced-order hybrid model applying pressure drop models within stenotic regions. In 116 patients and 203 vessels the diagnostic performance of CTA-FFR was investigated using invasive FFR measurements as a reference. The effect of several potentially relevant factors on CTA-FFR was investigated. RESULTS: 90 vessels (44%) had a hemodynamically relevant stenosis according to invasive FFR (threshold <=0.80). The overall vessel-based sensitivity, specificity and accuracy of CTA-FFR were 88% (CI 95%:79 94%), 65% (55-73%) and 75% (69-81%). The specificity was significantly lower in the presence of misalignment artifacts (25%, CI: 6-57%). A non-significant reduction in specificity from 74% (60-85%) to 48% (26-70%) was found for higher coronary artery calcium scores. Left ventricular mass, diabetes mellitus and large vessel size increased the discrepancy between invasive FFR and CTA-FFR values. CONCLUSIONS: On-site calculation of CTA-FFR can identify hemodynamically significant CAD with an overall per-vessel accuracy of 75% in comparison to invasive FFR. The diagnostic performance of CTA-FFR is negatively affected by misalignment artifacts. CTA-FFR is potentially affected by left ventricular mass, diabetes mellitus and vessel size. PMID- 26747232 TI - Differential effects of the recombinant toxin PnTx4(5-5) from the spider Phoneutria nigriventer on mammalian and insect sodium channels. AB - The toxin PnTx4(5-5) from the spider Phoneutria nigriventer is extremely toxic/lethal to insects but has no macroscopic behavioral effects observed in mice after intracerebral injection. Nevertheless, it was demonstrated that it inhibits the N-methyl-d-aspartate (NMDA) - subtype of glutamate receptors of cultured rat hippocampal neurons. PnTx4(5-5) has 63% identity to PnTx4(6-1), another insecticidal toxin from P. nigriventer, which can slow down the sodium current inactivation in insect central nervous system, but has no effect on Nav1.2 and Nav1.4 rat sodium channels. Here, we have cloned and heterologous expressed the toxin PnTx4(5-5) in Escherichia coli. The recombinant toxin rPnTx4(5-5) was tested on the sodium channel NavBg from the cockroach Blatella germanica and on mammalian sodium channels Nav1.2-1.6, all expressed in Xenopus leavis oocytes. We showed that the toxin has different affinity and mode of action on insect and mammalian sodium channels. The most remarkable effect was on NavBg, where rPnTx4(5-5) strongly slowed down channel inactivation (EC50 = 212.5 nM), and at 1 MUM caused an increase on current peak amplitude of 105.2 +/- 3.1%. Interestingly, the toxin also inhibited sodium current on all the mammalian channels tested, with the higher current inhibition on Nav1.3 (38.43 +/- 8.04%, IC50 = 1.5 MUM). Analysis of activation curves on Nav1.3 and Nav1.5 showed that the toxin shifts channel activation to more depolarized potentials, which can explain the sodium current inhibition. Furthermore, the toxin also slightly slowed down sodium inactivation on Nav1.3 and Nav1.6 channels. As far as we know, this is the first araneomorph toxin described which can shift the sodium channel activation to more depolarized potentials and also slows down channel inactivation. PMID- 26747233 TI - Systematic prophylactic oxytocin injection and the incidence of postpartum hemorrhage: A before-and-after study. AB - OBJECTIVE: Assess the impact of routine injection of 5 units of oxytocin as soon as the anterior shoulder is delivered on the incidence of postpartum haemorrhage (PPH) in a context of daily practice. MATERIALS AND METHODS: Single-centre before and-after study evaluating the effect of a change in the protocol for PPH prevention as applied in our obstetrical unit. During the first period, oxytocin (5 units) was to be injected only in case of PPH risk factors. During the second period, the injection was systematic. RESULTS: In the "before" study period, there were 1953 patients vaginal deliveries and 843 (43%) oxytocin injections, with a protocol compliance of 85%. In the "after" study period, 2018 women had vaginal deliveries and 1911 (95%) had an oxytocin injection (protocol compliance: 95%). The whole study period was associated with a reduced risk of moderate haemorrhage (13.4% vs. 9.2%, P<0.001), but no significant reduced risk of severe haemorrhage was observed (2.1% vs. 2.0%, P=0.79). After logistic regression, the study period remained associated with a significant reduction in the risk of moderate PPH (OR=0.72 [0.58-0.89]). CONCLUSION: Routine injection of 5 units of oxytocin makes it possible to reduce the risk of moderate PPH, but it does not affect the risk of severe PPH. PMID- 26747235 TI - Lack of p47(phox) in Akita Diabetic Mice Is Associated with Interstitial Pneumonia, Fibrosis, and Oral Inflammation. AB - Excess reactive oxygen species production is central to the development of diabetic complications. The contribution of leukocyte reactive oxygen species produced by the NADPH oxidase to altered inflammatory responses associated with uncontrolled hyperglycemia is poorly understood. To get insight into the role of phagocytic superoxide in the onset of diabetic complications, we used a model of periodontitis in mice with chronic hyperglycemia and lack of leukocyte p47(phox) (Akita/Ncf1) bred from C57BL/6-Ins2(Akita)/J (Akita) and neutrophil cytosolic factor 1 knockout (Ncf1) mice. Akita/Nfc1 mice showed progressive cachexia starting at early age and increased mortality by six months. Their lungs developed infiltrative interstitial lesions that obliterated air spaces as early as 12 weeks when fungal colonization of lungs also was observed. Neutrophils of Akita/Ncf1 mice had normal degranulation and phagocytic efficiency when compared with wild-type mice. Although Akita/Ncf1 mice had increased prevalence of oral infections and more severe periodontitis compared with wild-type mice, bone loss was only marginally higher compared with Akita and Ncf1 null mice. Altogether these results indicate that lack of leukocyte superoxide production in mice with chronic hyperglycemia results in interstitial pneumonia and increased susceptibility to infections. PMID- 26747234 TI - Cyclooxygenase- and cytochrome P450-derived eicosanoids in stroke. AB - Arachidonic acid (AA) is metabolized by cyclooxygenase (COX) and cytochrome P450 (CYP) enzymes into eicosanoids, which are involved in cardiovascular diseases and stroke. Evidence has demonstrated the important functions of these eicosanoids in regulating cerebral vascular tone, cerebral blood flow, and autoregulation of cerebral circulation. Although COX-2 inhibitors have been suggested as potential treatments for stroke, adverse events, including an increased risk of stroke, occur following long-term use of coxibs. It is important to note that prolonged treatment with rofecoxib increased circulating levels of 20 hydroxyeicosatetraenoic acid (20-HETE), and 20-HETE blockade is a possible strategy to prevent coxib-induced stroke events. It appears that 20-HETE has detrimental effects in the brain, and that its blockade exerts cerebroprotection against ischemic stroke and subarachnoid hemorrhage (SAH). There is clear evidence that activation of EP2 and EP4 receptors exerts cerebroprotection against ischemic stroke. Several elegant studies have contributed to defining the importance of stabilizing the levels of epoxyeicosatrienoic acids (EETs), by inhibiting or deleting soluble epoxide hydrolase (sEH), in stroke research. These reports support the notion that sEH blockade is cerebroprotective against ischemic stroke and SAH. Here, we summarize recent findings implicating these eicosanoid pathways in cerebral vascular function and stroke. We also discuss the development of animal models with targeted gene deletion and specific enzymatic inhibitors in each pathway to identify potential targets for the treatment of ischemic stroke and SAH. PMID- 26747244 TI - Genotyping of feline leukemia virus in Mexican housecats. AB - Feline leukemia virus (FeLV) is a retrovirus with variable rates of infection globally. DNA was obtained from cats' peripheral blood mononuclear cells, and proviral DNA of pol and env genes was detected using PCR. Seventy-six percent of cats scored positive for FeLV using env-PCR; and 54 %, by pol-PCR. Phylogenetic analysis of both regions identified sequences that correspond to a group that includes endogenous retroviruses. They form an independent branch and, therefore, a new group of endogenous viruses. Cat gender, age, outdoor access, and cohabitation with other cats were found to be significant risk factors associated with the disease. This strongly suggests that these FeLV genotypes are widely distributed in the studied feline population in Mexico. PMID- 26747242 TI - Assessment of EGFR Mutation Status in Matched Plasma and Tumor Tissue of NSCLC Patients from a Phase I Study of Rociletinib (CO-1686). AB - PURPOSE: The evaluation of plasma testing for the EGFR resistance mutation T790M in NSCLC patients has not been broadly explored. We investigated the detection of EGFR activating and T790M mutations in matched tumor tissue and plasma, mostly from patients with acquired resistance to first-generation EGFR inhibitors. EXPERIMENTAL DESIGN: Samples were obtained from two studies, an observational study and a phase I trial of rociletinib, a mutant-selective inhibitor of EGFR that targets both activating mutations and T790M. Plasma testing was performed with the cobas EGFR plasma test and BEAMing. RESULTS: The positive percent agreement (PPA) between cobas plasma and tumor results was 73% (55/75) for activating mutations and 64% (21/33) for T790M. The PPA between BEAMing plasma and tumor results was 82% (49/60) for activating mutations and 73% (33/45) for T790M. Presence of extrathoracic (M1b) versus intrathoracic (M1a/M0) disease was found to be strongly associated with ability to identify EGFR mutations in plasma (P < 0.001). Rociletinib objective response rates (ORR) were 52% [95% confidence interval (CI), 31 - 74%] for cobas tumor T790M-positive and 44% (95% CI, 25 - 63%) for BEAMing plasma T790M-positive patients. A drop in plasma-mutant EGFR levels to <=10 molecules/mL was seen by day 21 of treatment in 7 of 8 patients with documented partial response. CONCLUSIONS: These findings suggest the cobas and BEAMing plasma tests can be useful tools for noninvasive assessment and monitoring of the T790M resistance mutation in NSCLC, and could complement tumor testing by identifying T790M mutations missed because of tumor heterogeneity or biopsy inadequacy. Clin Cancer Res; 22(10); 2386-95. (c)2016 AACR. PMID- 26747245 TI - Epidemiological and molecular features of hepatitis B and hepatitis delta virus transmission in a remote rural community in central Africa. AB - Hepatitis B virus (HBV) and hepatitis delta virus (HDV) occur worldwide and are prevalent in both urban and remote rural communities. In a remote village in Gabon, central Africa, we observed a high prevalence of HBsAg carriage and HDV infection, particularly in children and adolescents. The prevalence of HBsAg differed significantly by gender and age, females being more likely than males to carry the HBsAg during the first 10 years of life, while the prevalence was higher among males than females aged 11-20 years. We also characterised HBV and HDV strains circulating in the village. The principal HBV strains belonged to genotype HBV-E and subgenotype QS-A3. Complete genome analysis revealed for the first time the presence of the HBV-D genotype in Gabon, in the form of an HBV-D/E recombinant. Molecular analysis of HDV strains and their complete genomic characterisation revealed two distinct groups within the dominant HDV clade 8. Molecular analysis of HBV and HDV strains did not reveal vertical transmission within the families studied but rather horizontal, intrafamilial transmission among children aged 0-10 years. Our findings indicate that HBV is transmitted in early childhood by body fluids rather than by sexual contact. Health education adapted to the different age groups might therefore help to reduce HBV transmission. Young children should be vaccinated to control HBV infection in areas of extremely high prevalence. PMID- 26747243 TI - Relationship Between Serum Albumin Levels and Infections in Newborn Late Preterm Infants. AB - BACKGROUND: We aimed to evaluate the clinical value of serum albumin levels for the evaluation and prognosis of late preterm infants with infections. MATERIAL/METHODS: This was a retrospective study performed in late preterm infants admitted at the neonatal intensive care unit (NICU) of the Liaocheng People's Hospital between July 2012 and March 2013. Data, including laboratory test results, neonatal critical illness score (NCIS), perinatal complications and prognosis, were analyzed. The newborn infants were divided into 3 groups according to their serum albumin levels, (>=30 g/L, 25-30 g/L and <=25 g/L for high, moderate, and low, respectively). RESULTS: Among 257 patients, birth weight was 2003+/-348 g, gestational age was 35.7+/-2.3 weeks, and 59.1% were male. In addition, 127 (49.4%) were in the low albumin group. There were 32 patients with sepsis, 190 with infections, and 35 without infection, and their rates of hypoalbuminemia were 86.0%, 50.5%, and 30.7%, respectively (P<0.05). Albumin levels of the patients who survived were higher than those of the patients who died. In the low albumin group, the number of individual-event-critical NCIS cases and the frequency of multiple organs injuries were 63.8% and 28.3%, respectively, and were higher than in the 2 other groups. Mortality was higher in patients with sepsis. Hypoalbuminemia was associated with severe adverse outcomes (odds ratio=6.3, 95% confidence interval: 3.7-10.9, P<0.001). CONCLUSIONS: Hypoalbuminemia was frequent among neonates with sepsis. Lower albumin levels might be associated with a poorer prognosis. Albumin levels could be appropriate for the diagnosis and prognosis of late preterm neonates with infections. PMID- 26747246 TI - Redundant and nonredundant roles for Cdc42 and Rac1 in lymphomas developed in NPM ALK transgenic mice. AB - Increasing evidence suggests that Rho family GTPases could have a critical role in the biology of T-cell lymphoma. In ALK-rearranged anaplastic large cell lymphoma (ALCL), a specific subtype of T-cell lymphoma, the Rho family GTPases Cdc42 and Rac1 are activated by the ALK oncogenic activity. In vitro studies have shown that Cdc42 and Rac1 control rather similar phenotypes of ALCL biology such as the proliferation, survival, and migration of lymphoma cells. However, their role and possible redundancy in ALK-driven lymphoma development in vivo are still undetermined. We genetically deleted Cdc42 or Rac1 in a mouse model of ALK rearranged ALCL to show that either Cdc42 or Rac1 deletion impaired lymphoma development, modified lymphoma morphology, actin filament distribution, and migration properties of lymphoma cells. Cdc42 or Rac1 deletion primarily affected survival rather than proliferation of lymphoma cells. Apoptosis of lymphoma cells was equally induced following Cdc42 or Rac1 deletion, was associated with upregulation of the proapoptotic molecule Bid, and was blocked by Bcl2 overexpression. Remarkably, Cdc42/Rac1 double deletion, but not Cdc42 or Rac1 single deletions, completely prevented NPM-ALK lymphoma dissemination in vivo. Thus, Cdc42 and Rac1 have nonredundant roles in controlling ALK-rearranged lymphoma survival and morphology but are redundant for lymphoma dissemination, suggesting that targeting both GTPases could represent a preferable therapeutic option for ALCL treatment. PMID- 26747247 TI - PET-CT for staging and early response: results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study. AB - International guidelines recommend that positron emission tomography-computed tomography (PET-CT) should replace CT in Hodgkin lymphoma (HL). The aims of this study were to compare PET-CT with CT for staging and measure agreement between expert and local readers, using a 5-point scale (Deauville criteria), to adapt treatment in a clinical trial: Response-Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL). Patients were staged using clinical assessment, CT, and bone marrow biopsy (RATHL stage). PET-CT was performed at baseline (PET0) and after 2 chemotherapy cycles (PET2) in a response-adapted design. PET-CT was reported centrally by experts at 5 national core laboratories. Local readers optionally scored PET2 scans. The RATHL and PET-CT stages were compared. Agreement among experts and between expert and local readers was measured. RATHL and PET0 stage were concordant in 938 (80%) patients. PET-CT upstaged 159 (14%) and downstaged 74 (6%) patients. Upstaging by extranodal disease in bone marrow (92), lung (11), or multiple sites (12) on PET-CT accounted for most discrepancies. Follow-up of discrepant findings confirmed the PET characterization of lesions in the vast majority. Five patients were upstaged by marrow biopsy and 7 by contrast-enhanced CT in the bowel and/or liver or spleen. PET2 agreement among experts (140 scans) with a kappa (95% confidence interval) of 0.84 (0.76-0.91) was very good and between experts and local readers (300 scans) at 0.77 (0.68-0.86) was good. These results confirm PET-CT as the modern standard for staging HL and that response assessment using Deauville criteria is robust, enabling translation of RATHL results into clinical practice. PMID- 26747248 TI - CARMA1- and MyD88-dependent activation of Jun/ATF-type AP-1 complexes is a hallmark of ABC diffuse large B-cell lymphomas. AB - A hallmark of the diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) type, a molecular subtype characterized by adverse outcome, is constitutive activation of the transcription factor nuclear factor-kappaB (NF-kappaB), which controls expression of genes promoting cellular survival and proliferation. Much less, however, is known about the role of the transcription factor activator protein-1 (AP-1) in ABC DLBCL. Here, we show that AP-1, like NF-kappaB, was controlled by constitutive activation of the B-cell receptor signaling component caspase recruitment domain-containing membrane-associated guanylate kinase 1 (CARMA1) and/or the Toll-like receptor signaling component myeloid differentiation primary response gene 88 (MyD88) in ABC DLBCL cell lines. In contrast to germinal center (GC) B-cell (GCB) DLBCL, ABC DLBCL cell lines expressed high levels of the AP-1 family members c-Jun, JunB, and JunD, which formed heterodimeric complexes with the AP-1 family members activating transcription factor (ATF) 2, ATF3, and ATF7. Inhibition of these complexes by a dominant-negative approach led to impaired growth of a majority of ABC DLBCL cell lines. Individual silencing of c-Jun, ATF2, or ATF3 decreased cellular survival and revealed c-Jun/ATF2-dependent control of ATF3 expression. As a consequence, ATF3 expression was much higher in ABC vs GCB DLBCL cell lines. Samples derived from DLBCL patients showed a clear trend toward high and nuclear ATF3 expression in nodal DLBCL of the non-GC or ABC subtype. These findings identify the activation of AP-1 complexes of the Jun/ATF-type as an important element controlling the growth of ABC DLBCL. PMID- 26747250 TI - CD4+ T cells from patients with acquired thrombotic thrombocytopenic purpura recognize CUB2 domain-derived peptides. AB - Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder resulting from the development of autoantibodies against ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). HLA-DRB1*11 provides a risk factor for developing acquired TTP. Pulsing of antigen-presenting cells from HLA-DRB1*11- and HLA-DRB1*03-positive individuals with ADAMTS13 resulted in presentation of peptides derived from the CUB2 domain of ADAMTS13 with core sequences FINVAPHAR or ASYILIRD. Here, we assessed whether FINVAPHAR- or ASYILIRD-reactive CD4(+)T cells are present in peripheral blood mononuclear cells from HLA-DRB1*11 and HLA-DRB1*03-positive subjects with acquired TTP. The presence of ADAMTS13-reactive CD4(+)T cells was addressed by flow cytometry and the expression of activation marker CD40 ligand by CD4(+)T cells. FINVAPHAR reactive CD4(+)T cells were identified in an HLA-DRB1*11-positive patient during the acute phase of the disease whereas ASYILIRD-positive CD4(+)T cells were identified in a DRB1*03-positive patient with acquired TTP. Frequencies of CUB2 domain-reactive CD4(+)T cells ranged from 3.3% to 4.5%. Control peptides in which the anchor residues were modified did not induce activation of CD4(+)T cells. Taken together, our data provide evidence for the involvement of CUB2 domain reactive CD4(+)T cells in the etiology of acquired TTP. PMID- 26747249 TI - Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype. AB - Early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL/LBL) is a recently recognized high-risk T lymphoblastic leukemia/lymphoma (T-ALL/LBL) subgroup. The optimal therapeutic approaches to adult patients with ETP-ALL/LBL are poorly characterized. In this study, we compared the outcomes of adults with ETP-ALL/LBL who received treatment on frontline regimens with those of patients with other T-ALL/LBL immunophenotypic subtypes. Patients with newly diagnosed T ALL/LBL who received frontline chemotherapy between the years 2000 and 2014 at The University of Texas MD Anderson Cancer Center were identified and immunophenotypically categorized into early, thymic, and mature per the World Health Organization (WHO) classification using CD1a and surface CD3 status. Patients with ETP-ALL/LBL were identified on the basis of the following immunophenotypes: CD1a(-), CD8(-), CD5(-)(dim), and positivity for 1 or more stem cell or myeloid antigens. A total of 111 patients with T-ALL/LBL (68% T-ALL; 32% T-LBL) with adequate immunophenotype data were identified. The median age was 30 years (range, 13-79). There was no difference in the outcomes of patients based on the WHO subtypes. Nineteen patients (17%) had ETP-ALL/LBL. The complete remission rate /complete remission with incomplete platelet recovery rate in patients with ETP-ALL/LBL was significantly lower than that of non-ETP-ALL/LBL patients (73% vs 91%;P= .03). The median overall survival for patients with ETP ALL/LBL was 20 months vs not reached for the non-ETP-ALL/LBL patients (P= .008). ETP-ALL/LBL represents a high-risk disease subtype of adult ALL. Novel treatment strategies are needed to improve treatment outcomes in this T-ALL/LBL subset. PMID- 26747251 TI - UV photolysis for enhanced phenol biodegradation in the presence of 2,4,6 trichlorophenol (TCP). AB - A bacterial strain isolated from activated sludge and identified as Bacillus amyloliquefaciens could biodegrade phenol, but 2,4,6-trichlorophenol (TCP) inhibited phenol biodegradation and biomass growth. UV photolysis converted TCP into dichlorocatechol, monochlorophenol, and dichlorophenol, and this relieved inhibition by TCP. Phenol-removal and biomass-growth rates were significantly accelerated after UV photolysis: the monod maximum specific growth rate (MU(max)) increased by 9% after TCP photolysis, and the half-maximum-rate concentration (K(S)) decreased by 36%. Thus, the major benefit of UV photolysis in this case was to transform TCP into a set of much-less-inhibitory products. PMID- 26747252 TI - Cost-Effectiveness of Ranibizumab Versus Aflibercept for Macular Edema Secondary to Branch Retinal Vein Occlusion: A UK Healthcare Perspective. AB - INTRODUCTION: Ranibizumab and aflibercept are anti-vascular endothelial growth factor agents licensed for the treatment of visual impairment due to macular edema secondary to branch retinal vein occlusion (BRVO). The aim of this study was to estimate, from a UK healthcare payer's perspective, the cost-effectiveness of ranibizumab versus aflibercept in this indication. METHODS: A Markov model was used to simulate the outcomes and costs of treating BRVO. Patient baseline characteristics and efficacy data for ranibizumab were obtained from the BRAVO trial. The relative efficacy of aflibercept was derived from a published network meta-analysis. Injection frequencies were derived from ranibizumab and aflibercept studies included in the network meta-analysis. Health states were defined by increments of 10 letters in best corrected visual acuity (BCVA). Patients could gain or lose a maximum of two health states between cycles. The first cycle was 6 months, followed by monthly cycles. Different utility values were assigned to the better-seeing and worse-seeing eyes based on BCVA. A 2-year treatment time frame and a lifetime time horizon were used. Future costs and health outcomes were discounted at 3.5% per annum. Sensitivity analyses were used to test the robustness of the model. RESULTS: The lifetime cost per patient treated was L15,273 with ranibizumab and L17,347 with aflibercept. Ranibizumab was dominant over aflibercept, producing incremental health gains of 0.0120 quality-adjusted life-years (QALYs) and cost savings of L2074. Net monetary benefit for ranibizumab at a willingness-to-pay threshold of L20,000/QALY was L2314. Sensitivity analyses showed that the results were robust to variations in model parameters. CONCLUSIONS: Ranibizumab provides greater health gains at a lower overall cost than aflibercept in the treatment of visual impairment due to macular edema secondary to BRVO. Ranibizumab is therefore cost-effective from a UK healthcare payer's perspective. FUNDING: Novartis Pharma AG, Basel, Switzerland. PMID- 26747253 TI - The impact of domestic violence and depressive symptoms on preterm birth in South India. AB - PURPOSE: India has the highest absolute number of maternal deaths, preterm birth cases, and under-5 mortality in the world, as well as high domestic violence (DV) rates. We sought to examine the impact of DV and its psychosocial correlates on pregnancy and birth outcomes. METHODS: Women seeking antenatal care in Tamil Nadu, South India (N = 150) were assessed during pregnancy, and birth outcomes were abstracted from medical records after the babies were born. RESULTS: We found that psychological abuse (OR 3.9; 95% CI 1.19-12.82) and mild or greater depressive symptoms (OR 3.3; 95% CI 0.99-11.17) were significantly associated with increased risk of preterm birth. Physical abuse was also associated with increased risk of preterm birth, but this was not statistically significant (OR 1.9; 95% CI 0.59-6.19). In each of the above adjusted models, low maternal education was associated with increased risk of preterm birth, in the analysis with depressive symptoms OR 0.18, CI 0.04-0.86 and in the analyses with psychological abuse OR 0.19, CI 0.04-0.91. CONCLUSIONS: These findings suggest that future research should focus on understanding the psychosocial antecedents to preterm birth, to better target interventions and improve maternal child health in limited resource settings. PMID- 26747255 TI - Computed tomography compared to magnetic resonance imaging in occult or suspect hip fractures. A retrospective study in 44 patients. AB - BACKGROUND: Computed tomography (CT) for evaluation of occult and suspect hip fractures has been proposed as a good second-line investigation. The diagnostic precision compared to magnetic resonance imaging (MRI) is unclear. PURPOSE: To compare the diagnostic performance of CT and MRI in a retrospective study on patients with suspect and occult hip fractures. MATERIAL AND METHODS: Forty-four elderly consecutive patients with low-energy trauma to the hip were identified where negative or suspect CT was followed by MRI. Primary reporting and review by two observers as well as the diagnostic performance of the two modalities were compared. Surgical treatment and clinical course were used as outcomes. RESULTS: Compared to the primary reports, the CT reviewers found fewer normal and no suspect cases. MRI changed the primary diagnoses in 27 cases, and in 14 and 15 cases, respectively, at review. There was no disagreement on MRI diagnoses. CONCLUSION: In our patient population, MRI was deemed a more reliable modality for hip fracture diagnosis in comparison to CT. For clinical decision making, MRI seems to have a higher accuracy than CT. A negative CT finding cannot completely rule out a hip fracture in patients where clinical findings of hip fracture persevere. KEY POINTS: * Experience is highly influential in diagnosing occult or suspect hip fractures at CT * Inconclusive hip CT shows high inter-rater reliability at experienced review * There was low diagnostic accuracy via CT compared to MRI for all interpreters * Hip fractures can readily be diagnosed at MRI regardless of radiological experience. PMID- 26747256 TI - Application of ultrasound-guided core biopsy to minimize the non-diagnostic results and the requirement of diagnostic surgery in extrapulmonary tuberculosis of the head and neck. AB - PURPOSE: Head and neck extrapulmonary tuberculosis (ETB) presenting as lymphadenopathy poses a great threat by potentially increasing the deterioration of clinical outcomes. Tissue sampling for diagnostic confirmation of ETB is the only invasive procedure during the entire clinical course. It is, therefore, necessary to establish ETB sampling methods with accuracy and minimal invasiveness. METHODS: From 2009 to 2014, consecutive patients suspected of ETB receiving ultrasound-guided core biopsy (USCB), fine needle aspiration (FNA), and open biopsy (OB) were enrolled for comparison. RESULTS: There were 52 cases in the USCB group, 58 cases in the FNA group, and 78 cases in the OB group. For USCB, FNA, and OB groups, the diagnostic rates were 84.6 %, 8.6 %, and 100 % and the positive rates of acid-fast stain were 28.6 %, 0 %, and 37.5 %, respectively. The diagnostic rates of culture were 9.6 %, 0 %, and 50 %, respectively. For head and neck ETB, USCB procedure is timesaving, without leaving poor-healing wounds, scars, and the need for general anaesthesia and hospitalization. CONCLUSIONS: This study helps to optimize the ETB sampling method in head and neck based on diagnostic accuracy and minimal invasiveness. USCB can serve as the first-line diagnostic tool for ETB by reducing non-diagnostic results and the need for diagnostic surgery. KEY POINTS: * USCB shows higher diagnostic accuracy of ETB than FNA (84.6 % vs. 8.6 %). * USCB diminishes wound complications caused by surgical intervention for ETB. * USCB avoids general anaesthesia and hospitalization for diagnosing ETB. * USCB saves time and reduces the medical costs of diagnosing ETB. PMID- 26747254 TI - 3D-Flair sequence at 3T in cochlear otosclerosis. AB - PURPOSE: To assess the capability of three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) sequences in detecting signal alterations of the endolabyrinthine fluid in patients with otosclerosis. MATERIALS AND METHODS: 3D FLAIR before and after (-/+) gadolinium (Gd) administration was added to the standard MR protocol and acquired in 13 patients with a clinical/audiological diagnosis of severe/profound hearing loss in otosclerosis who were candidates for cochlear implantation and in 11 control subjects using 3-T magnetic resonance imaging (MRI) equipment. The MRI signal of the fluid-filled cochlea was assessed both visually and calculating the signal intensity ratio (SIR = signal intensity cochlea/brainstem). RESULTS: We revealed no endocochlear signal abnormalities on T1-weighted -/+ Gd images for either group, while on 3D-FLAIR we found bilateral hyperintensity with enhancement after Gd administration in eight patients and bilateral hyperintensity without enhancement in one patient. No endocochlear signal abnormalities were detected in other patients or the control group. CONCLUSION: Using 3-T MRI equipment, the 3D-FLAIR -/+ Gd sequence is able to detect the blood-labyrinth barrier (BLB) breakdown responsible for alterations of the endolabyrinthine fluid in patients with cochlear otosclerosis. We believe that 3D-FLAIR +/- Gd is an excellent imaging modality to assess the intra cochlear damage in otosclerosis patients. KEY POINTS: * Gd-enhanced T1-weighted MRI has limited application to detect intra-cochlear damage. * 3D-FLAIR is less sensitive to flux artefacts and allows multiplanar reconstruction. * Post-Gd 3D FLAIR is advantageous as it may highlight the BLB breakdown. * Using 3D-FLAIR -/+ Gd, we were able to identify intra-cochlear signal hyperintensities. * 3D-FLAIR might be applied for monitoring disease progression and treatment response. PMID- 26747257 TI - Anterolateral ligament abnormalities in patients with acute anterior cruciate ligament rupture are associated with lateral meniscal and osseous injuries. AB - OBJECTIVE: To determine the frequency of anterolateral ligament (ALL) injury in patients with acute anterior cruciate ligament (ACL) rupture and to analyse its associated injury patterns. METHODS: Ninety patients with acute ACL rupture for which MRI was obtained within 8 weeks after the initial trauma were retrospectively identified. Two radiologists assessed the status of the ALL on MRI by consensus. The presence or absence of an ALL abnormality was compared with the existence of medial and lateral meniscal tears diagnosed during arthroscopy. Associated collateral ligament and osseous injuries were documented with MRI. RESULTS: Forty-one of 90 knees (46 %) demonstrated ALL abnormalities on MRI. Of 49 knees with intact ALL, 15 (31 %) had a torn lateral meniscus as compared to 25 torn lateral menisci in 41 knees (61 %) with abnormal ALL (p = 0.008). Collateral ligament (p <= 0.05) and osseous injuries (p = 0.0037) were more frequent and severe in ALL-injured as compared with ALL-intact knees. CONCLUSION: ALL injuries are fairly common in patients with acute ACL rupture and are statistically significantly associated with lateral meniscal, collateral ligament and osseous injuries. KEY POINTS: * ALL injuries are fairly common in patients with acute ACL rupture. * ALL injuries are highly associated with lateral meniscal and osseous injuries. * MRI assessment of ACL-injured knees should include evaluation of the ALL. PMID- 26747258 TI - The effectiveness of acupuncture as a treatment for tinnitus: a randomized controlled trial using (99m)Tc-ECD SPECT. AB - OBJECTIVE: Investigate the effect of acupuncture on brain perfusion using ethyl cysteinate dimer single-photon emission computed tomography ((99m)Tc-ECD SPECT) in patients with tinnitus. METHODS: This randomized, single-blind, sham-control study examined patients (18-60 years old) with normal hearing and chronic, idiopathic, continuous tinnitus. Fifty-seven subjects were randomly assigned to true (n = 30) or sham (n = 27) acupuncture (ACP); (99m)Tc-ECD SPECT examinations were performed before and after 12 twice-weekly ACP sessions. Secondary outcomes included changes in the Tinnitus Handicap Inventory (THI), Visual Analog Scale (VAS), Hamilton Anxiety Scale (HAS) and Beck Depression Inventory (BDI). Imaging data were analysed using Statistical Parametric Mapping (SPM8) software. Regression models were used to examine secondary outcomes via two paradigms: intention-to-treat (ITT; where multiple imputations were conducted because of study attrition) and complete cases. RESULTS: No between-group brain perfusion differences were observed. However, a significant improvement in THI scores was observed at the end of true ACP treatment for all domains (all p values < 0.01) except the catastrophic scale. CONCLUSIONS: ACP might reduce the effects of tinnitus on daily life; however, additional studies should be conducted to verify the effects of ACP on the neural architecture and brain function of tinnitus patients. KEY POINTS: * Efficacy of acupuncture on brain perfusion and symptoms of tinnitus patients. * Acupuncture improved the Tinnitus Handicap Inventory scores in tinnitus patients. * No significant changes in brain perfusion were observed after 12 twice-weekly sessions. * Perfusion changes would reflect changes in neuronal function. PMID- 26747259 TI - Extended monitoring of coiled aneurysms completely occluded at 6-month follow-up: late recanalization rate and related risk factors. AB - OBJECTIVES: To estimate long-term durability in coiled aneurysms completely occluded at 6-month follow-up imaging, focusing on late recanalization rate and the risk factors involved. METHODS: A cohort of 620 patients harbouring 698 completely occluded coiled aneurysms at 6-month follow-up was subjected to extended monitoring (mean, 24.5 +/- 7.9 months). Cumulative recanalization rate and related risk factors were analysed using Cox proportional hazards regression and Kaplan-Meier product-limit estimator. RESULTS: Forty-three aneurysms (6.2 %) occluded completely at 6-months displayed recanalization (3.02 % per aneurysm year) during continued surveillance (1425.5 aneurysm-years), with 26 (60.5 %) surfacing in another 6 months, 15 (34.9 %) within 18 months and 2 (4.6 %) within 30 months. Cumulative survival rates without recanalization were significantly lower in subjects with aneurysms >7 mm (p = 0.014), with bifurcation aneurysms (p = 0.009) and with subarachnoid haemorrhage (SAH) at presentation (p < 0.001). Multivariate analysis indicated that aneurysms >7 mm (HR = 2.37, p = 0.02) and bifurcation aneurysms (HR = 2.70, p = 0.03) were significant factors in late recanalization, whereas a link with SAH at presentation was marginal (HR = 1.92, p = 0.06) and stent placement fell short of statistical significance (HR = 0.47; p = 0.12). CONCLUSION: Most (93.8 %) coiled aneurysms showing complete occlusion at 6 months post-procedure were stable in long-term monitoring. However, aneurysms >7 mm and bifurcation aneurysms were predisposed to late recanalization. KEY POINTS: * Most coiled aneurysms showing complete occlusion at 6 months were stable. * Forty-three aneurysms (6.2 %) occluded completely at 6 month follow-up displayed late recanalization. * Late recanalization rate was 3.02 % per aneurysm-year during follow-up of 1425.5 aneurysm-years. * Aneurysms over 7 mm and bifurcation aneurysms were predisposed to late recanalization. PMID- 26747260 TI - Assessment of intracardiac flow and vorticity in the right heart of patients after repair of tetralogy of Fallot by flow-sensitive 4D MRI. AB - OBJECTIVES: To comprehensively and quantitatively analyse flow and vorticity in the right heart of patients after repair of tetralogy of Fallot (rTOF) compared with healthy volunteers. METHODS: Time-resolved flow-sensitive 4D MRI was acquired in 24 rTOF patients and 12 volunteers. Qualitative flow evaluation was based on consensus reading of two observers. Quantitative analysis included segmentation of the right atrium (RA) and ventricle (RV) in a four-chamber view to extract volumes and regional haemodynamic information for computation of regional mean and peak vorticity. RESULTS: Right heart intra-atrial, intraventricular and outflow tract flow patterns differed considerably between rTOF patients and volunteers. Peak RA and mean RV vorticity was significantly higher in patients (p = 0.02/0.05). Significant negative correlations were found between patients' maximum and mean RV and RA vorticity and ventricular volumes (p < 0.05). The main pulmonary artery (MPA) regurgitant flow was associated with higher RA and RV vorticity, which was significant for RA maximum and RV mean vorticity (p = 0.01/0.03). CONCLUSION: The calculation of vorticity based on 4D flow data is an alternative approach to assess intracardiac flow changes in rTOF patients compared with qualitative flow visualization. Alterations in intracardiac vorticity could be relevant with regard to the development of RV dilation and impaired function. KEY POINTS: * 4D flow MRI with vorticity calculation enables a novel approach to assess intracardiac flow. * Significantly higher intracardiac vorticity occurred in patients after repair of tetralogy of Fallot. * Regurgitant flow in the main pulmonary artery is associated with higher right heart vorticity. PMID- 26747261 TI - Validation and reappraisal of the assessment for retreatment with transarterial chemoembolization score for unresectable non-metastatic hepatocellular carcinoma in a hepatitis b virus-endemic region. AB - OBJECTIVES: To validate and reappraise the Assessment for Retreatment with Transarterial chemoembolization (ART) score comprising three parameters (>25 % increase in aspartate aminotransferase [AST], increase in Child-Pugh score and tumour response), determined prior to subsequent transarterial chemoembolization (TACE). METHODS: Enrolled patients were diagnosed with unresectable non metastatic hepatocellular carcinoma and underwent multiple TACEs between June 2006 and December 2007 (N = 153). Subgroupings were classified according to the established cut-off (<=1.5 vs. >=2.5). Survival analysis using the Kaplan-Meier curve was performed. RESULTS: The original ART score dichotomized patients according to their overall survival (P = 0.004). We found several patients who actually survived longer than others were assigned to a poor prognostic group due to the AST component. Parameter estimates for AST obtained from our analysis were much lower than the original version (0.5 vs. 2.1). We adjusted the component according to the value of our parameter estimates, and patients with >25 % AST increase received 1.0 point. After this modification, patients assigned to the favourable prognostic group were more likely to have a better survival outcome (median 23.9 vs. 12.2 months, P < 0.001). CONCLUSIONS: In hepatitis B virus endemic regions, the ART score is valid and can better predict post-TACE survival after the AST component is modified. KEY POINTS: * The ART score was validated in a HBV-endemic region. * The modified ART score improved prognostic performance by reappraising the AST component. * The modified ART score helps physicians make decisions for further TACE. PMID- 26747262 TI - Magnetic resonance imaging with gadoxetic acid for local tumour progression after radiofrequency ablation in patients with hepatocellular carcinoma. AB - OBJECTIVES: To develop and validate a prediction model using magnetic resonance imaging (MRI) for local tumour progression (LTP) after radiofrequency ablation (RFA) in hepatocellular carcinoma (HCC) patients. METHODS: Two hundred and eleven patients who had received RFA as first-line treatment for HCC were retrospectively analyzed. They had undergone gadoxetic acid-enhanced MRI before treatment, and parameters including tumour size; margins; signal intensities on T1-, T2-, and diffusion-weighted images, and hepatobiliary phase images (HBPI); intratumoral fat or tumoral capsules; and peritumoural hypointensity in the HBPI were used to develop a prediction model for LTP after treatment. This model to discriminate low-risk from high-risk LTP groups was constructed based on Cox regression analysis. RESULTS: Our analyses produced the following model: 'risk score = 0.617 * tumour size + 0.965 * tumour margin + 0.867 * peritumoural hypointensity on HBPI'. This was able to predict which patients were at high risk for LTP after RFA (p < 0.001). Patients in the low-risk group had a significantly better 5-year LTP-free survival rate compared to the high-risk group (89.6 % vs. 65.1 %; hazard ratio, 3.60; p < 0.001). CONCLUSION: A predictive model based on MRI before RFA could robustly identify HCC patients at high risk for LTP after treatment. KEY POINTS: * Tumour size, margin, and peritumoural hypointensity on HBPI were risk factors for LTP. * The risk score model can predict which patients are at high risk for LTP. * This prediction model could be helpful for risk stratification of HCC patients. PMID- 26747263 TI - Four-dimensional flow MRI for evaluation of post-stenotic turbulent flow in a phantom: comparison with flowmeter and computational fluid dynamics. AB - OBJECTIVES: To validate 4D flow MRI in a flow phantom using a flowmeter and computational fluid dynamics (CFD) as reference. METHODS: Validation of 4D flow MRI was performed using flow phantoms with 75 % and 90 % stenosis. The effect of spatial resolution on flow rate, peak velocity and flow patterns was investigated in coronal and axial scans. The accuracy of flow rate with 4D flow MRI was evaluated using a flowmeter as reference, and the peak velocity and flow patterns obtained were compared with CFD analysis results. RESULTS: 4D flow MRI accurately measured the flow rate in proximal and distal regions of the stenosis (percent error <=3.6 % in axial scanning with 1.6-mm resolution). The peak velocity of 4D flow MRI was underestimated by more than 22.8 %, especially from the second half of the stenosis. With 1-mm isotropic resolution, the maximum thickness of the recirculating flow region was estimated within a 1-mm difference, but the turbulent velocity fluctuations mostly disappeared in the post-stenotic region. CONCLUSION: 4D flow MRI accurately measures the flow rates in the proximal and distal regions of a stenosis in axial scan but has limitations in its estimation of peak velocity and turbulent characteristics. KEY POINTS: * 4D flow MRI accurately measures the flow rate in axial scan. * The peak velocity was underestimated by 4D flow MRI. *4D flow MRI demonstrates the principal pattern of post-stenotic flow. PMID- 26747264 TI - Double versus single reading of mammograms in a breast cancer screening programme: a cost-consequence analysis. AB - OBJECTIVES: To assess the costs and health-related outcomes of double versus single reading of digital mammograms in a breast cancer screening programme. METHODS: Based on data from 57,157 digital screening mammograms from women aged 50-69 years, we compared costs, false-positive results, positive predictive value and cancer detection rate using four reading strategies: double reading with and without consensus and arbitration, and single reading with first reader only and second reader only. Four highly trained radiologists read the mammograms. RESULTS: Double reading with consensus and arbitration was 15 % (Euro 334,341) more expensive than single reading with first reader only. False-positive results were more frequent at double reading with consensus and arbitration than at single reading with first reader only (4.5 % and 4.2 %, respectively; p < 0.001). The positive predictive value (9.3 % and 9.1 %; p = 0.812) and cancer detection rate were similar for both reading strategies (4.6 and 4.2 per 1000 screens; p = 0.283). CONCLUSIONS: Our results suggest that changing to single reading of mammograms could produce savings in breast cancer screening. Single reading could reduce the frequency of false-positive results without changing the cancer detection rate. These results are not conclusive and cannot be generalized to other contexts with less trained radiologists. KEY POINTS: * Double reading of digital mammograms is more expensive than single reading. * Compared to single reading, double reading yields a higher proportion of false-positive results. * The cancer detection rate was similar for double and single readings. * Single reading may be a cost-effective strategy in breast cancer screening programmes. PMID- 26747265 TI - Pentoxifylline for Diabetic Nephropathy: an Important Opportunity to Re-purpose an Old Drug? AB - Diabetic nephropathy, or diabetic kidney disease (DKD), is the most serious complication of diabetes mellitus (DM). Despite recent advances in therapy, DKD still often progresses to end-stage renal disease (ESRD). Recent studies have suggested that pentoxifylline (PTX) may be efficacious in the treatment of DKD. PTX is a rheologic modifier approved for use in the USA for the symptomatic relief of claudication. It competitively inhibits phosphodiesterase (PDE), resulting in increased intracellular cyclic AMP (cAMP), activation of protein kinase A (PKA), inhibition of interleukin (IL) and tumor necrosis factor (TNF) synthesis, and reduced inflammation. PTX improves red blood cell deformability, reduces blood viscosity, and decreases platelet aggregation. In combination with renin-angiotensin-aldosterone (RAAS) blockers, PTX may help prevent progression to ESRD in patients with DKD. This review focuses on the possible mechanisms of action of PTX in DKD and studies suggesting possible efficacy of this old drug for a new indication. PMID- 26747266 TI - Contrasting effects of fish predation on benthic versus emerging prey: a meta analysis. AB - Predator-prey interactions are often studied entirely within the ecosystem of the predator. However, many prey transition between ecosystems during development, expanding the effects of predators across ecosystems. Prey are often vulnerable to predation during this transition, facing a predator gauntlet as they leave their source ecosystem. As a result of predation during this transition, predators may have stronger effects on prey fluxes to the neighboring ecosystem than on prey densities in the predator's own ecosystem. I used meta-analysis of predator (fish) and prey (invertebrate) interactions in freshwater ecosystems to test the hypothesis that fish have stronger effects on prey flux to the terrestrial ecosystem, by reducing insect emergence biomass, than on prey densities in the aquatic ecosystem, by reducing benthic insect/invertebrate biomass. Fish reduced insect emergence by 39 % on average, more than twice as strong as their reductions of benthic prey (16 % reduction; averages are variance weighted). In fact, fish effects on benthic prey were not significantly different from zero, but were significant for emergence. These results indicate that predator effects can not only cascade from one ecosystem to another but also that effects can be stronger outside than within the ecosystem of the predator. Failure to account for this may underestimate the effects of predators on prey. PMID- 26747267 TI - Seed predation and climate impacts on reproductive variation in temperate forests of the southeastern USA. AB - Climatic effects on tree recruitment will be determined by the interactive effects of fecundity and seed predation. Evaluating how insect and vertebrate seed predators mediate tree reproductive responses to climate depends on long term studies of seed production, development, and predation. In this study, our objectives were to (1) assess the effects of interannual climate variation on seed abortion rates, (2) assess the impact of seed density on predation rates, and (3) examine the degree to which density-dependent seed predation would amplify or dampen interannual variation in fecundity associated with seed abortion. We used a 19-year study of seed abortion and pre-dispersal predation rates by insects and vertebrates (birds and rodents) for five temperate tree species across forest plots from the North Carolina Piedmont to the Southern Appalachian Mountains in the southeastern USA. We found that rates of seed abortion and predation increased reproductive variation for oaks (Quercus species). Probability of seed abortion was greatest during years with cool, dry springs. Responses of seed predation on Quercus species to current year's seed density varied by species, but exhibited positive density-dependence to previous year's seed density consistent with numerical responses of seed predators. Seed abortion and predation rates for two drupe species responded little to variation in climate or seed density, respectively. Given that predation increased interannual variation in seed availability and the negative density-dependence to previous year's seed density, our results indicate that consistent numerical responses of oak seed predators may amplify interannual variation due to climate mediated processes like seed abortion. PMID- 26747268 TI - Impacts of leguminous shrub encroachment on neighboring grasses include transfer of fixed nitrogen. AB - Shrub encroachment induced by global change and human disturbance strongly affects ecosystem structure and function. In this study, we explore the degree to which invading leguminous shrubs affected neighboring grasses, including via the transfer of fixed nitrogen (N). We measured N concentrations and natural abundance (15)N of shoot tissues from three dominant grasses from different plant functional groups across seven distances along a local transect (up to 500 cm) to the leguminous shrub, Caragana microphylla. C. microphylla did transfer fixed N to neighboring grasses, but the amount and distance of N transferred were strongly species-specific. Shoot N concentrations decreased significantly with distance from C. microphylla, for a rhizomatous grass, Leymus chinensis, and a bunchgrass, Achnatherum sibiricum. However, N concentrations of another bunchgrass, Stipa grandis, were higher only directly underneath the shrub canopy. Shoot delta(15)N values of L. chinensis were enriched up to 500 cm from the shrub, but for S. grandis were enriched only below the shrub canopy. In contrast, delta(15)N of A. sibiricum did not change along the 500-cm transect. Our results indicated the rhizomatous grass transferred fixed N over long distances while bunchgrasses did not. The presence of C. microphylla increased the shoot biomass of L. chinensis but decreased that of S. grandis and A. sibiricum. These findings highlight the potential role of nutrient-acquisition strategies of neighboring grasses in moderating the interspecific variation of fixed N transfer from the leguminous shrub. Overall, leguminous shrubs have either positive or negative effects on the neighboring grasses and dramatically affect plant community composition and structure. PMID- 26747269 TI - Coupled long-term summer warming and deeper snow alters species composition and stimulates gross primary productivity in tussock tundra. AB - Climate change is expected to increase summer temperature and winter precipitation throughout the Arctic. The long-term implications of these changes for plant species composition, plant function, and ecosystem processes are difficult to predict. We report on the influence of enhanced snow depth and warmer summer temperature following 20 years of an ITEX experimental manipulation at Toolik Lake, Alaska. Winter snow depth was increased using snow fences and warming was accomplished during summer using passive open-top chambers. One of the most important consequences of these experimental treatments was an increase in active layer depth and rate of thaw, which has led to deeper drainage and lower soil moisture content. Vegetation concomitantly shifted from a relatively wet system with high cover of the sedge Eriophorum vaginatum to a drier system, dominated by deciduous shrubs including Betula nana and Salix pulchra. At the individual plant level, we observed higher leaf nitrogen concentration associated with warmer temperatures and increased snow in S. pulchra and B. nana, but high leaf nitrogen concentration did not lead to higher rates of net photosynthesis. At the ecosystem level, we observed higher GPP and NEE in response to summer warming. Our results suggest that deeper snow has a cascading set of biophysical consequences that include a deeper active layer that leads to altered species composition, greater leaf nitrogen concentration, and higher ecosystem-level carbon uptake. PMID- 26747272 TI - Comparison of the Anti-inflammatory Effects of Proanthocyanidin, Quercetin, and Damnacanthal on Benzo(a)pyrene Exposed A549 Alveolar Cell Line. AB - Phytochemical compounds are emerging as a new group of anti-inflammatory, antioxidant, and anti-cancer agents that help minimize toxicity in patients with pulmonary diseases. The goal of this study was to investigate the potential curative effects of Quercetin (QC), Damnacanthal (DAM), and Proanthocyanidine (PA) on inflammatory mediators and oxidative stress parameters and to examine the viability of the A549 cell line treated with benzo(a)pyrene (BaP) in vitro. The A549 cell line was treated with BaP, a BaP/QC combination, a BaP/DAM combination, and BaP/PA combination. Inflammatory markers, oxidative stress parameters, mRNA expression levels of apoptotic and antiapoptotic proteins, and cell viability were assessed, and the results were compared. There were higher levels of lactate dehydrogenase after BaP treatment of A549 cell lines. Interferon-gamma level significantly decreased in the QC, DAM, and PA-treated group (P < 0.001). IL 1beta and TNF-alpha levels significantly decreased after PA and QC treatments (P < 0.001). Some of the oxidative stress markers (NO, MDA, TOS) and OSI decreased, while antioxidant (GSH) levels increased after treatment with QC, DAM, and PA. The QC and DAM treatments profoundly upregulated apoptotic gene expression and downregulated antiapoptotic gene expression. Viability of QC, DAM, and PA-treated cells was found to be significantly higher in comparison to the control and BaP treated groups (p < 0.001). Our results revealed that A549 cell lines treated with BaP-stimulated necrosis produced higher level of inflammatory cytokines and oxidative stress parameters. Treatments with PA, QC, and DAM reduced inflammatory response induced by BaP exposure. PMID- 26747273 TI - Revisiting tumor angiogenesis: vessel co-option, vessel remodeling, and cancer cell-derived vasculature formation. AB - Tumor growth and metastasis depend on the establishment of tumor vasculature to provide oxygen, nutrients, and other essential factors. The well-known vascular endothelial growth factor (VEGF) signaling is crucial for sprouting angiogenesis as well as recruitment of circulating progenitor endothelial cells to tumor vasculature, which has become therapeutic targets in clinical practice. However, the survival benefits gained from targeting VEGF signaling have been very limited, with the inevitable development of treatment resistance. In this article, we discuss the most recent findings and understanding on how solid tumors evade VEGF-targeted therapy, with a special focus on vessel co-option, vessel remodeling, and tumor cell-derived vasculature establishment. Vessel co option may occur in tumors independently of sprouting angiogenesis, and sprouting angiogenesis is not always required for tumor growth. The differences between vessel-like structure and tubule-like structure formed by tumor cells are also introduced. The exploration of the underlying mechanisms of these alternative angiogenic approaches would not only widen our knowledge of tumor angiogenesis but also provide novel therapeutic targets for better controlling cancer growth and metastasis. PMID- 26747275 TI - Cadmium uptake capacity of an indigenous cyanobacterial strain, Nostoc entophytum ISC32: new insight into metal uptake in microgravity-simulating conditions. AB - Among nine cyanobacterial strains isolated from oil-contaminated regions in southern Iran, an isolate with maximum cadmium uptake capacity was selected and identified on the basis of analysis of morphological criteria and 16S rRNA gene sequence similarity as Nostoc entophytum (with 99% similarity). The isolate was tentatively designated N. entophytum ISC32. The phylogenetic affiliation of the isolates was determined on the basis of their 16S rRNA gene sequence. The maximum amount of Cd(II) adsorbed by strain ISC32 was 302.91 mg g(-1) from an initial exposure to a solution with a Cd(II) concentration of 150 mg l(-1). The cadmium uptake by metabolically active cells of cyanobacterial strain N. entophytum ISC32, retained in a clinostat for 6 days to simulate microgravity conditions, was examined and compared with that of ground control samples. N. entophytum ISC32 under the influence of microgravity was able to take up cadmium at amounts up to 29% higher than those of controls. The activity of antioxidant enzymes including catalase and peroxidase was increased in strain ISC32 exposed to microgravity conditions in a clinostat for 6 days, as catalase activity of the cells was more than three times higher than that of controls. The activity of the peroxidase enzyme increased by 36% compared with that of the controls. Membrane lipid peroxidation was also increased in the cells retained under microgravity conditions, up to 2.89-fold higher than in non-treated cells. Images obtained using scanning electron microscopy showed that cyanobacterial cells form continuous filaments which are drawn at certain levels, while the cells placed in a clinostat appeared as round-shaped, accumulated together and distorted to some extent. PMID- 26747274 TI - Induction of initial steps of angiogenic differentiation and maturation of endothelial cells by pericytes in vitro and the role of collagen IV. AB - Activation of endothelial cells and recruitment of mural cells define critical steps during the formation of stable vascular elements. Both events are reflected by cocultures of endothelial cells and isolated murine pericyte-like cells and define a versatile platform for the analysis of distinct steps during the angiogenic process in vitro. Isolated pericyte-like cells promote the survival of endothelial cells, induce the assembly of endothelial cells as well as establish direct contacts with forming endothelial alignments. More importantly, they also induce characteristic steps of maturation including the assembly of stable cell cell junctions, deposition of basement membrane-like matrices and local formation of a central lumen. The presence of pericyte-like cells induces the secretion of extracellular matrices enriched in collagen IV by endothelial cells, which improves endothelial tube formation and provides the adhesive substrate for mural cell recruitment. Collagen-binding integrins contribute differentially to the process, with alpha1beta1 involved in the adhesion of pericyte-like cells to collagen IV and alpha2beta1 mainly involved in endothelial cord formation. These data indicate that pericyte-like cells are essential for the survival of endothelial cells, the efficient formation of endothelial alignments as well as initial steps of maturation of capillary-like structures. PMID- 26747280 TI - Exercise in a bottle: Elucidating how exercise conveys health benefits might lead to new therapeutic options for a range of diseases from cancer to metabolic syndrome. PMID- 26747278 TI - Efficacy of omalizumab (Xolair(r)) in patients with moderate to severe predominately chronic oral steroid dependent asthma in Taiwan: a retrospective, population-based database cohort study. AB - BACKGROUND: Omalizumab (Xolair(r)), a recombinant monoclonal anti-IgE antibody, has demonstrated efficacy in clinical trials conducted in patients with moderate to severe persistent allergic asthma. We aimed to investigate the efficacy, discontinuation and medical resource utilization of omalizumab in the real-life setting in Taiwan. METHODS: This study was a retrospective, population-based database cohort study using the Taiwan NHIRD from 2007 to 2011 assessing the efficacy of omalizumab therapy over 4 months on changes in asthma medication, asthma control, frequency of exacerbations and hospitalization rates at baseline and after omalizumab discontinuation. RESULTS: There was a reduction in asthma medication post omalizumab therapy and severe exacerbations and hospitalizations from baseline (31.2%, n = 282) to the end of follow-up (11.8%, n = 144, p < 0.001). Nearly all the patients received chronic oral corticosteroids at baseline (92.4%). The number of ER visits decreased from 1.13 +/- 2.04 to 0.29 +/- 0.83, and the mean number of admissions decreased from 5.93 +/- 16.16 to 2.75 +/- 12.02 from baseline to the end of follow-up (p < 0.001). After discontinuation of omalizumab, the cost of ER medical expenses decreased from New Taiwan dollars (NTD) 3934 at 2 months to NTD 2860 at 12 months. CONCLUSIONS: Patients who received omalizumab therapy for over 4 months were more likely to reduce the use of other asthma medications and less likely to experience an asthma exacerbation, ER visits, and hospitalization, even after the discontinuation of omalizumab. These data suggest that omalizumab has efficacy in improving health outcomes in patients with moderate to severe predominately chronic oral steroid dependent asthma in the real-life setting in Taiwan. PMID- 26747276 TI - Post-CNS-inflammation expression of CXCL12 promotes the endogenous myelin/neuronal repair capacity following spontaneous recovery from multiple sclerosis-like disease. AB - BACKGROUND: Demyelination and axonal degeneration, hallmarks of multiple sclerosis (MS), are associated with the central nervous system (CNS) inflammation facilitated by C-X-C motif chemokine 12 (CXCL12) chemokine. Both in MS and in experimental autoimmune encephalomyelitis (EAE), the deleterious CNS inflammation has been associated with upregulation of CXCL12 expression in the CNS. We investigated the expression dynamics of CXCL12 in the CNS with progression of clinical EAE and following spontaneous recovery, with a focus on CXCL12 expression in the hippocampal neurogenic dentate gyrus (DG) and in the corpus callosum (CC) of spontaneously recovered mice, and its potential role in promoting the endogenous myelin/neuronal repair capacity. METHODS: CNS tissue sections from mice with different clinical EAE phases or following spontaneous recovery and in vitro differentiated adult neural stem cell cultures were analyzed by immunofluorescent staining and confocal imaging for detecting and enumerating neuronal progenitor cells (NPCs) and oligodendrocyte precursor cells (OPCs) and for expression of CXCL12. RESULTS: Our expression dynamics analysis of CXCL12 in the CNS with EAE progression revealed elevated CXCL12 expression in the DG and CC, which persistently increases following spontaneous recovery even though CNS inflammation has subsided. Correspondingly, the numbers of NPCs and OPCs in the DG and CC, respectively, of EAE-recovered mice increased compared to that of naive mice (NPCs, p < 0.0001; OPCs, p < 0.00001) or mice with active disease (OPCs, p < 0.0005). Notably, about 30 % of the NPCs and unexpectedly also OPCs (~50 %) express CXCL12, and their numbers in DG and CC, respectively, are higher in EAE-recovered mice compared with naive mice and also compared with mice with ongoing clinical EAE (CXCL12(+) NPCs, p < 0.005; CXCL12(+) OPCs, p < 0.0005). Moreover, a significant proportion (>20 %) of the CXCL12(+) NPCs and OPCs co-express the CXCL12 receptor, CXCR4, and their numbers significantly increase with recovery from EAE not only relative to naive mice (p < 0.0002) but also to mice with ongoing EAE (p < 0.004). CONCLUSIONS: These data link CXCL12 expression in the DG and CC of EAE-recovering mice to the promotion of neuro/oligodendrogenesis generating CXCR4(+) CXCL12(+) neuronal and oligodendrocyte progenitor cells endowed with intrinsic neuro/oligondendroglial differentiation potential. These findings highlight the post-CNS-inflammation role of CXCL12 in augmenting the endogenous myelin/neuronal repair capacity in MS like disease, likely via CXCL12/CXCR4 autocrine signaling. PMID- 26747281 TI - Feasibility and acceptability of injectable artesunate for the treatment of severe malaria in the Democratic Republic of Congo. AB - BACKGROUND: The Democratic Republic of the Congo (DRC) changed its national policy for the treatment of severe malaria in both children and adults in 2012 from intravenous quinine to injectable artesunate. The country is now planning to deploy nationwide injectable artesunate as the preferred treatment for the management of severe malaria. To support this process, the feasibility and acceptability of the use of injectable artesunate in the context of the DRC was assessed, from the perspective of both health care providers and patients/caretakers. METHODS: Questionnaires and observations were used to collect information from health care providers and patients/caretakers in eight health facilities in the Province of Kinshasa and in the Province of Bas-Congo. RESULTS: A total of 31 health care providers and 134 patients/care takers were interviewed. Seventy five percent (75%) of health care providers found it less difficult to prepare injectable artesunate compared to quinine. None of them encountered problems during preparation and administration of injectable artesunate. The large majority of care providers (93%) and patients/caretakers (93%) answered that injectable artesunate took less time than quinine to cure the symptoms of the patients. 26 (84%) health care providers reported that the personnel workload had diminished with the use of injectable artesunate. 7 (22.6%) health workers reported adverse drug reactions, of which a decrease in the haemoglobin rate was the most common (71.4%). All care providers and the vast majority of patients/caretakers (96%, N = 128) were either satisfied or very satisfied with injectable artesunate. CONCLUSIONS: These findings show that the use of injectable artesunate for the treatment of severe malaria is feasible and acceptable in the context of DRC, with appropriate training of care providers. Both care providers and patients/caretakers perceived injectable artesunate to be effective and safe, thus promoting acceptability. PMID- 26747277 TI - Increased peri-ductal collagen micro-organization may contribute to raised mammographic density. AB - BACKGROUND: High mammographic density is a therapeutically modifiable risk factor for breast cancer. Although mammographic density is correlated with the relative abundance of collagen-rich fibroglandular tissue, the causative mechanisms, associated structural remodelling and mechanical consequences remain poorly defined. In this study we have developed a new collaborative bedside-to-bench workflow to determine the relationship between mammographic density, collagen abundance and alignment, tissue stiffness and the expression of extracellular matrix organising proteins. METHODS: Mammographic density was assessed in 22 post menopausal women (aged 54-66 y). A radiologist and a pathologist identified and excised regions of elevated non-cancerous X-ray density prior to laboratory characterization. Collagen abundance was determined by both Masson's trichrome and Picrosirius red staining (which enhances collagen birefringence when viewed under polarised light). The structural specificity of these collagen visualisation methods was determined by comparing the relative birefringence and ultrastructure (visualised by atomic force microscopy) of unaligned collagen I fibrils in reconstituted gels with the highly aligned collagen fibrils in rat tail tendon. Localised collagen fibril organisation and stiffness was also evaluated in tissue sections by atomic force microscopy/spectroscopy and the abundance of key extracellular proteins was assessed using mass spectrometry. RESULTS: Mammographic density was positively correlated with the abundance of aligned periductal fibrils rather than with the abundance of amorphous collagen. Compared with matched tissue resected from the breasts of low mammographic density patients, the highly birefringent tissue in mammographically dense breasts was both significantly stiffer and characterised by large (>80 MUm long) fibrillar collagen bundles. Subsequent proteomic analyses not only confirmed the absence of collagen fibrosis in high mammographic density tissue, but additionally identified the up-regulation of periostin and collagen XVI (regulators of collagen fibril structure and architecture) as potential mediators of localised mechanical stiffness. CONCLUSIONS: These preliminary data suggest that remodelling, and hence stiffening, of the existing stromal collagen microarchitecture promotes high mammographic density within the breast. In turn, this aberrant mechanical environment may trigger neoplasia-associated mechanotransduction pathways within the epithelial cell population. PMID- 26747282 TI - Segmentation and characterization of interscapular brown adipose tissue in rats by multi-parametric magnetic resonance imaging. AB - OBJECTIVE: The aim was to auto-segment and characterize brown adipose, white adipose and muscle tissues in rats by multi-parametric magnetic resonance imaging with validation by histology and UCP1. MATERIALS AND METHODS: Male Wistar rats were randomized into two groups for thermoneutral (n = 8) and cold exposure (n = 8) interventions, and quantitative MRI was performed longitudinally at 7 and 11 weeks. Prior to imaging, rats were maintained at either thermoneutral body temperature (36 +/- 0.5 degrees C), or short term cold exposure (26 +/- 0.5 degrees C). Neural network based automatic segmentation was performed on multi parametric images including fat fraction, T2 and T2* maps. Isolated tissues were subjected to histology and UCP1 analysis. RESULTS: Multi-parametric approach showed precise delineation of the interscapular brown adipose tissue (iBAT), white adipose tissue (WAT) and muscle regions. Neural network based segmentation results were compared with manually drawn regions of interest, and showed 96.6 and 97.1% accuracy for WAT and BAT respectively. Longitudinal assessment of the iBAT volumes showed a reduction at 11 weeks of age compared to 7 weeks. The cold exposed group showed increased iBAT volume compared to thermoneutral group at both 7 and 11 weeks. Histology and UCP1 expression analysis supported our imaging results. CONCLUSION: Multi-parametric MR based neural network auto-segmentation provides accurate separation of BAT, WAT and muscle tissues in the interscapular region. The cold exposure improves the classification and quantification of heterogeneous BAT. PMID- 26747283 TI - Chloroplast Activity and 3'phosphadenosine 5'phosphate Signaling Regulate Programmed Cell Death in Arabidopsis. AB - Programmed cell death (PCD) is a crucial process both for plant development and responses to biotic and abiotic stress. There is accumulating evidence that chloroplasts may play a central role during plant PCD as for mitochondria in animal cells, but it is still unclear whether they participate in PCD onset, execution, or both. To tackle this question, we have analyzed the contribution of chloroplast function to the cell death phenotype of the myoinositol phosphate synthase1 (mips1) mutant that forms spontaneous lesions in a light-dependent manner. We show that photosynthetically active chloroplasts are required for PCD to occur in mips1, but this process is independent of the redox state of the chloroplast. Systematic genetic analyses with retrograde signaling mutants reveal that 3'-phosphoadenosine 5'-phosphate, a chloroplast retrograde signal that modulates nuclear gene expression in response to stress, can inhibit cell death and compromises plant innate immunity via inhibition of the RNA-processing 5'-3' exoribonucleases. Our results provide evidence for the role of chloroplast derived signal and RNA metabolism in the control of cell death and biotic stress response. PMID- 26747284 TI - Nuclear Function of Subclass I Actin-Depolymerizing Factor Contributes to Susceptibility in Arabidopsis to an Adapted Powdery Mildew Fungus. AB - Actin-depolymerizing factors (ADFs) are conserved proteins that function in regulating the structure and dynamics of actin microfilaments in eukaryotes. In this study, we present evidence that Arabidopsis (Arabidopsis thaliana) subclass I ADFs, particularly ADF4, functions as a susceptibility factor for an adapted powdery mildew fungus. The null mutant of ADF4 significantly increased resistance against the adapted powdery mildew fungus Golovinomyces orontii. The degree of resistance was further enhanced in transgenic plants in which the expression of all subclass I ADFs (i.e. ADF1-ADF4) was suppressed. Microscopic observations revealed that the enhanced resistance of adf4 and ADF1-4 knockdown plants (ADF1 4Ri) was associated with the accumulation of hydrogen peroxide and cell death specific to G. orontii-infected cells. The increased resistance and accumulation of hydrogen peroxide in ADF1-4Ri were suppressed by the introduction of mutations in the salicylic acid- and jasmonic acid-signaling pathways but not by a mutation in the ethylene-signaling pathway. Quantification by microscopic images detected an increase in the level of actin microfilament bundling in ADF1-4Ri but not in adf4 at early G. orontii infection time points. Interestingly, complementation analysis revealed that nuclear localization of ADF4 was crucial for susceptibility to G. orontii. Based on its G. orontii-infected-cell-specific phenotype, we suggest that subclass I ADFs are susceptibility factors that function in a direct interaction between the host plant and the powdery mildew fungus. PMID- 26747285 TI - Affinity Purification and Characterization of Functional Tubulin from Cell Suspension Cultures of Arabidopsis and Tobacco. AB - Microtubules assemble into several distinct arrays that play important roles in cell division and cell morphogenesis. To decipher the mechanisms that regulate the dynamics and organization of this versatile cytoskeletal component, it is essential to establish in vitro assays that use functional tubulin. Although plant tubulin has been purified previously from protoplasts by reversible taxol induced polymerization, a simple and efficient purification method has yet to be developed. Here, we used a Tumor Overexpressed Gene (TOG) column, in which the tubulin-binding domains of a yeast (Saccharomyces cerevisiae) TOG homolog are immobilized on resin, to isolate functional plant tubulin. We found that several hundred micrograms of pure tubulin can readily be purified from cell suspension cultures of tobacco (Nicotiana tabacum) and Arabidopsis (Arabidopsis thaliana). The tubulin purified by the TOG column showed high assembly competence, partly because of low levels of polymerization-inhibitory phosphorylation of alpha tubulin. Compared with porcine brain tubulin, Arabidopsis tubulin is highly dynamic in vitro at both the plus and minus ends, exhibiting faster shrinkage rates and more frequent catastrophe events, and exhibits frequent spontaneous nucleation. Furthermore, our study shows that an internal histidine tag in alpha tubulin can be used to prepare particular isotypes and specifically engineered versions of alpha-tubulin. In contrast to previous studies of plant tubulin, our mass spectrometry and immunoblot analyses failed to detect posttranslational modification of the isolated Arabidopsis tubulin or detected only low levels of posttranslational modification. This novel technology can be used to prepare assembly-competent, highly dynamic pure tubulin from plant cell cultures. PMID- 26747286 TI - Genome-Wide Characterization of Maize Small RNA Loci and Their Regulation in the required to maintain repression6-1 (rmr6-1) Mutant and Long-Term Abiotic Stresses. AB - Endogenous small RNAs (sRNAs) contribute to gene regulation and genome homeostasis, but their activities and functions are incompletely known. The maize genome has a high number of transposable elements (TEs; almost 85%), some of which spawn abundant sRNAs. We performed sRNA and total RNA sequencing from control and abiotically stressed B73 wild-type plants and rmr6-1 mutants. RMR6 encodes the largest subunit of the RNA polymerase IV complex and is responsible for accumulation of most 24-nucleotide (nt) small interfering RNAs (siRNAs). We identified novel MIRNA loci and verified miR399 target conservation in maize. RMR6-dependent 23-24 nt siRNA loci were specifically enriched in the upstream region of the most highly expressed genes. Most genes misregulated in rmr6-1 did not show a significant correlation with loss of flanking siRNAs, but we identified one gene supporting existing models of direct gene regulation by TE derived siRNAs. Long-term drought correlated with changes of miRNA and sRNA accumulation, in particular inducing down-regulation of a set of sRNA loci in the wild-typeleaf. PMID- 26747290 TI - Omitted Author Affiliation. PMID- 26747287 TI - Deficiency of Starch Synthase IIIa and IVb Alters Starch Granule Morphology from Polyhedral to Spherical in Rice Endosperm. AB - Starch granule morphology differs markedly among plant species. However, the mechanisms controlling starch granule morphology have not been elucidated. Rice (Oryza sativa) endosperm produces characteristic compound-type granules containing dozens of polyhedral starch granules within an amyloplast. Some other cereal species produce simple-type granules, in which only one starch granule is present per amyloplast. A double mutant rice deficient in the starch synthase (SS) genes SSIIIa and SSIVb (ss3a ss4b) produced spherical starch granules, whereas the parental single mutants produced polyhedral starch granules similar to the wild type. The ss3a ss4b amyloplasts contained compound-type starch granules during early developmental stages, and spherical granules were separated from each other during subsequent amyloplast development and seed dehydration. Analysis of glucan chain length distribution identified overlapping roles for SSIIIa and SSIVb in amylopectin chain synthesis, with a degree of polymerization of 42 or greater. Confocal fluorescence microscopy and immunoelectron microscopy of wild-type developing rice seeds revealed that the majority of SSIVb was localized between starch granules. Therefore, we propose that SSIIIa and SSIVb have crucial roles in determining starch granule morphology and in maintaining the amyloplast envelope structure. We present a model of spherical starch granule production. PMID- 26747291 TI - Omission in Byline and Errors in Affiliation and Table. PMID- 26747288 TI - Singlet Oxygen-Induced Cell Death in Arabidopsis under High-Light Stress Is Controlled by OXI1 Kinase. AB - Studies of the singlet oxygen ((1)O2)-overproducing flu and chlorina1 (ch1) mutants of Arabidopsis (Arabidopsis thaliana) have shown that (1)O2-induced changes in gene expression can lead to either programmed cell death (PCD) or acclimation. A transcriptomic analysis of the ch1 mutant has allowed the identification of genes whose expression is specifically affected by each phenomenon. One such gene is OXIDATIVE SIGNAL INDUCIBLE1 (OXI1) encoding an AGC kinase that was noticeably induced by excess light energy and (1)O2 stress conditions leading to cell death. Photo-induced oxidative damage and cell death were drastically reduced in the OXI1 null mutant (oxi1) and in the double mutant ch1*oxi1 compared with the wild type and the ch1 single mutant, respectively. This occurred without any changes in the production rate of (1)O2 but was cancelled by exogenous applications of the phytohormone jasmonate. OXI1-mediated (1)O2 signaling appeared to operate through a different pathway from the previously characterized OXI1-dependent response to pathogens and H2O2 and was found to be independent of the EXECUTER proteins. In high-light-stressed plants, the oxi1 mutation was associated with reduced jasmonate levels and with the up regulation of genes encoding negative regulators of jasmonate signaling and PCD. Our results show that OXI1 is a new regulator of (1)O2-induced PCD, likely acting upstream of jasmonate. PMID- 26747293 TI - The Extended Mirror Neuron Network: Anatomy, Origin, and Functions. AB - Mirror neurons (MNs) are a fascinating class of cells originally discovered in the ventral premotor cortex (PMv) and, subsequently, in the inferior parietal lobule (IPL) of the macaque, which become active during both the execution and observation of actions. In this review, I will first highlight the mounting evidence indicating that mirroring others' actions engages a broad system of reciprocally connected cortical areas, which extends well beyond the classical IPL-PMv circuit and might even include subcortical regions such as the basal ganglia. Then, I will present the most recent findings supporting the idea that the observation of one's own actions, which might play a role in the ontogenetic origin and tuning of MNs, retains a particular relevance within the adult MN system. Finally, I will propose that both cortical and subcortical mechanisms do exist to decouple MN activity from the motor output, in order to render it exploitable for high-order perceptual, cognitive, and even social functions. The findings reviewed here provide an original framework for envisaging the main challenges and experimental directions of future neurophysiological and neuroanatomical studies of the monkey MN system. PMID- 26747294 TI - Effect of Obesity on Outcomes of Forefoot Surgery. AB - BACKGROUND: Forefoot surgery typically is elective, so it is important to define risk factors to educate patients on potential complications. The purpose of this study was to determine if obesity is an independent risk factor that contributes to increased complication rates after forefoot surgery. METHODS: Through a retrospective review of records, 633 patients were identified who had forefoot surgery at one institution between 2008 and 2010. All patients who currently smoked or smoked in the past were excluded to eliminate a confounding factor, as smoking is known to increase complication rates, leaving 427 patients for inclusion, 299 nonobese (BMI less than 30) and 128 obese (BMI more than 30). Medical records were reviewed for the occurrence of complications, including nonunion, delayed union, delayed wound healing, infection, and persistent pain. RESULTS: The overall complication rate was 9%, with similar rates between obese (10%) and nonobese patients (9%). The only specific complication approaching significance (P = .13) was a higher rate of infection in obese patients (4 % compared to 1%), which could be attributed to the higher percentage of diabetic patients in the obese group. Diabetic patients, regardless of weight, had significantly higher rates of infection (P = .03), with a trend toward higher rates of overall complications and delayed wound healing (P = .08 and P < .06, respectively). CONCLUSION: Obesity was not shown to lead to more frequent complications after forefoot surgery. Diabetes was associated with significantly higher rates of infection, regardless of weight. Though not significant, there was a trend toward higher rates of overall complications and delayed wound healing in diabetic patients as well. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 26747295 TI - Comment on "Neutrophil to lymphocyte ratio improves the risk assessment of ISS staging in newly diagnosed MM patients treated upfront with novel agents". PMID- 26747297 TI - Interval debulking surgery for advanced epithelial ovarian cancer. AB - BACKGROUND: Interval debulking surgery (IDS), following induction or neoadjuvant chemotherapy, may have a role in treating advanced epithelial ovarian cancer (stage III to IV) where primary debulking surgery is not an option. OBJECTIVES: To assess the effectiveness and complications of IDS for women with advanced stage epithelial ovarian cancer. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) 2012, Issue 6, MEDLINE and EMBASE for the original review in to June 2012. We updated the searches in June 2009, 2012 and 2015 for the review updates. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing survival of women with advanced epithelial ovarian cancer, who had IDS performed between cycles of chemotherapy after primary surgery with survival of women who had conventional treatment (primary debulking surgery and adjuvant chemotherapy). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Searches for additional information from study authors were attempted. We performed meta-analysis of overall and progression-free survival (PFS), using random-effects models. MAIN RESULTS: Three RCTs randomising 853 women, of whom 781 were evaluated, met the inclusion criteria. Meta-analysis of three trials for overall survival (OS) found no statistically significant difference between IDS and chemotherapy alone (hazard ratio (HR) = 0.80, 95% confidence interval (CI) 0.61 to 1.06, I2 = 58%). Subgroup analysis for OS in two trials, where the primary surgery was not performed by gynaecologic oncologists or was less extensive, showed a benefit of IDS (HR = 0.68, 95% CI 0.53 to 0.87, I2 = 0%). Meta-analysis of two trials for PFS found no statistically significant difference between IDS and chemotherapy alone (HR = 0.88, 95% CI 0.57 to 1.33, I2 = 83%). Rates of toxic reactions to chemotherapy were similar in both arms (risk ratio = 1.19, 95% CI 0.53 to 2.66, I2 = 0%), but little information was available for other adverse events or quality or life (QoL). AUTHORS' CONCLUSIONS: We found no conclusive evidence to determine whether IDS between cycles of chemotherapy would improve or decrease the survival rates of women with advanced ovarian cancer, compared with conventional treatment of primary surgery followed by adjuvant chemotherapy. IDS appeared to yield benefit only in women whose primary surgery was not performed by gynaecologic oncologists or was less extensive. Data on QoL and adverse events were inconclusive. PMID- 26747298 TI - The Survival of Cone Photoreceptors in Retinitis Pigmentosa. PMID- 26747296 TI - Viral co-infections and paraproteins in HIV: effect on development of hematological malignancies. AB - The role of viral co-infections and paraproteins in the development of hematological malignancies (HMs) in HIV remains unclear. Using our large database of HIV+ patients, we investigated whether co-infection and paraproteinemia increase the risk of HM. Data on demographics, hepatitis B (HBV) and hepatitis C virus (HCV) co-infections, paraproteinemia, HIV characteristics, and biopsy proven malignant hematological disorders for HIV+ patients were collected over a 10-year period in a large urban hospital setting. We identified 10,293 HIV+ patients who were followed for a median duration of 53 months. Of the 10,293 patients with HIV, 229 (2.2 %) were diagnosed with a HM. Over 85 % of patients in both groups were tested; no significant difference in the prevalence of chronic HBV or HCV was noted between the HM positive (n = 229) and HM negative (n = 9992) patients. The serum protein electrophoresis test was performed for 1371 of the 10,221 patients. HM positive patients, compared to HM negative, were more likely to be tested for paraproteins (OR 3.3, 95 % CI 2.5-4.4) and more likely to have a discrete paraprotein band (OR 3.3, 95 % CI 1.2-8.9). Discrete paraproteins exclusively correlated with the development of plasma cell malignancies. Faint or oligoclonal protein bands were seen in high grade B cell lymphomas but did not show a significant correlation with HM development. Chronic hepatitis B or C infections did not correlate with the development of HM in HIV; however, viral influence on host gene transformation may have been impacted by anti-viral therapy limiting the duration of high viremic states. PMID- 26747299 TI - Erratum to: Periparturient stress and immune suppression as a potential cause of retained placenta in highly productive dairy cows: examples of prevention. PMID- 26747300 TI - Dioscin alleviates BDL- and DMN-induced hepatic fibrosis via Sirt1/Nrf2-mediated inhibition of p38 MAPK pathway. AB - Oxidative stress is involved in hepatic stellate cells (HSCs) activation and extracellular matrix overproduction. We previously reported the promising effects of dioscin against CCl4-induced liver fibrosis, but its effects and mechanisms on BDL- and DMN-induced liver fibrosis remain unknown. The results in the present study indicated that dioscin significantly inhibited HSCs activation and attenuated hepatic fibrosis in rats. Furthermore, dioscin markedly up-regulated the levels of sirtuin 1 (Sirt1), HO-1, GST, GCLC and GCLM via increasing the nuclear translocation of nuclear erythroid factor 2-related factor 2 (Nrf2), which in turn inhibited mitogen-activated protein kinase 14 (p38 MAPK) phosphorylation and reduced the levels of COL1A1, COL3A1, alpha-SMA and fibronectin. These results were further validated by knockdown of Sirt1 and Nrf2 using siRNAs silencing, and abrogation of p38 MAPK using SB-203580 (a p38 MAPK inhibitor) in HSC-T6 and LX-2 cells. Collectively, our findings confirmed the potent effects of dioscin against liver fibrosis and also provided novel insights into the mechanisms of this compound as a candidate for the prevention of liver fibrosis in the future. PMID- 26747301 TI - The combination of ethanol with mephedrone increases the signs of neurotoxicity and impairs neurogenesis and learning in adolescent CD-1 mice. AB - A new family of psychostimulants, under the name of cathinones, has broken into the market in the last decade. In light of the fact that around 95% of cathinone consumers have been reported to combine them with alcoholic drinks, we sought to study the consequences of the concomitant administration of ethanol on mephedrone -induced neurotoxicity. Adolescent male Swiss-CD1 mice were administered four times in one day, every 2h, with saline, mephedrone (25mg/kg), ethanol (2; 1.5; 1.5; 1g/kg) and their combination at a room temperature of 26+/-2 degrees C. The combination with ethanol impaired mephedrone-induced decreases in dopamine transporter and tyrosine hydroxylase in the frontal cortex; and in serotonin transporter and tryptophan hydroxylase in the hippocampus by approximately 2 fold, 7days post-treatment. Furthermore, these decreases correlated with a 2-fold increase in lipid peroxidation, measured as concentration of malondialdehyde (MDA), 24h post-treatment, and were accompanied by changes in oxidative stress related enzymes. Ethanol also notably potentiated mephedrone-induced negative effects on learning and memory, as well as hippocampal neurogenesis, measured through the Morris water maze (MWM) and 5-bromo-2'-deoxyuridine staining, respectively. These results are of special significance, since alcohol is widely co-abused with amphetamine derivatives such as mephedrone, especially during adolescence, a crucial stage in brain maturation. Given that the hippocampus is greatly involved in learning and memory processes, normal brain development in young adults could be affected with permanent behavioral consequences after this type of drug co-abuse. PMID- 26747305 TI - A New Pair of Lungs. PMID- 26747306 TI - Shining a Light on the Dark Side. PMID- 26747302 TI - The History and Future of Treatment of Hypothyroidism. AB - Thyroid hormone replacement has been used for more than a century to treat hypothyroidism. Natural thyroid preparations (thyroid extract, desiccated thyroid, or thyroglobulin), which contain both thyroxine (T4) and triiodothyronine (T3), were the first pharmacologic treatments available and dominated the market for the better part of the 20th century. Dosages were adjusted to resolve symptoms and to normalize the basal metabolic rate and/or serum protein-bound iodine level, but thyrotoxic adverse effects were not uncommon. Two major developments in the 1970s led to a transition in clinical practice: 1) The development of the serum thyroid-stimulating hormone (TSH) radioimmunoassay led to the discovery that many patients were overtreated, resulting in a dramatic reduction in thyroid hormone replacement dosage, and 2) the identification of peripheral deiodinase-mediated T4-to-T3 conversion provided a physiologic means to justify l-thyroxine monotherapy, obviating concerns about inconsistencies with desiccated thyroid. Thereafter, l-thyroxine monotherapy at doses to normalize the serum TSH became the standard of care. Since then, a subgroup of thyroid hormone-treated patients with residual symptoms of hypothyroidism despite normalization of the serum TSH has been identified. This has brought into question the inability of l-thyroxine monotherapy to universally normalize serum T3 levels. New research suggests mechanisms for the inadequacies of l-thyroxine monotherapy and highlights the possible role for personalized medicine based on deiodinase polymorphisms. Understanding the historical events that affected clinical practice trends provides invaluable insight into formulation of an approach to help all patients achieve clinical and biochemical euthyroidism. PMID- 26747307 TI - Shining a Light on the Dark Side. PMID- 26747308 TI - Shining a Light on the Dark Side. PMID- 26747309 TI - Shining a Light on the Dark Side. PMID- 26747310 TI - Shining a Light on the Dark Side. PMID- 26747311 TI - Shining a Light on the Dark Side. PMID- 26747312 TI - Shining a Light on the Dark Side. PMID- 26747313 TI - Correction: Ultrasonography Screening for Abdominal Aortic Aneurysms. PMID- 26747314 TI - Annals for Educators - 5 January 2016. PMID- 26747316 TI - Web Exclusives. Annals Graphic Medicine - She Never Woke Up. PMID- 26747315 TI - In the Clinic. Alcohol Use. AB - This issue provides a clinical overview of alcohol use, focusing on health benefits, harms, prevention, screening, diagnosis, treatment, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers. PMID- 26747318 TI - Frailty predicts trajectories of quality of life over time among British community-dwelling older people. AB - PURPOSE: To investigate associations between baseline frailty status and subsequent changes in QOL over time among community-dwelling older people. METHODS: Among 363 community-dwelling older people >=65 years, frailty was measured using Frailty Index (FI) constructed from 40 deficits at baseline. QOL was measured using Older People's Quality of Life Questionnaire (OPQOL) six times over 2.5 years. Two-level hierarchical linear models were employed to predict QOL changes over time according to baseline frailty. RESULTS: At baseline, mean age was 73.1 (range 65-90) and 62.0 % were women. Mean FI was 0.17 (range 0.00-0.66), and mean OPQOL was 130.80 (range 93-163). The hierarchical linear model adjusted for age, gender, ethnicity, education, and enrollment site predicted that those with higher FI at baseline have lower QOL than those with lower FI (regression coefficient = -47.64, p < 0.0001) and that QOL changes linearly over time with slopes ranging from 0.80 (FI = 0.00) to -1.15 (FI = 0.66) as the FI increases. A FI of 0.27 is the cutoff point at which improvements in QOL over time change to declines in QOL. CONCLUSIONS: Frailty was associated with lower QOL among British community-dwelling older people. While less frail participants had higher QOL at baseline and QOL improved over time, QOL of frailer participants was lower at baseline and declined. PMID- 26747317 TI - Paving the way for the use of the SDQ in economic evaluations of school-based population health interventions: an empirical analysis of the external validity of SDQ mapping algorithms to the CHU9D in an educational setting. AB - PURPOSE: The Strengths and Difficulties Questionnaire (SDQ) is a behavioural screening tool for children. The SDQ is increasingly used as the primary outcome measure in population health interventions involving children, but it is not preference based; therefore, its role in allocative economic evaluation is limited. The Child Health Utility 9D (CHU9D) is a generic preference-based health related quality of-life measure. This study investigates the applicability of the SDQ outcome measure for use in economic evaluations and examines its relationship with the CHU9D by testing previously published mapping algorithms. The aim of the paper is to explore the feasibility of using the SDQ within economic evaluations of school-based population health interventions. METHODS: Data were available from children participating in a cluster randomised controlled trial of the school-based roots of empathy programme in Northern Ireland. Utility was calculated using the original and alternative CHU9D tariffs along with two SDQ mapping algorithms. t tests were performed for pairwise differences in utility values from the preference-based tariffs and mapping algorithms. RESULTS: Mean (standard deviation) SDQ total difficulties and prosocial scores were 12 (3.2) and 8.3 (2.1). Utility values obtained from the original tariff, alternative tariff, and mapping algorithms using five and three SDQ subscales were 0.84 (0.11), 0.80 (0.13), 0.84 (0.05), and 0.83 (0.04), respectively. Each method for calculating utility produced statistically significantly different values except the original tariff and five SDQ subscale algorithm. CONCLUSION: Initial evidence suggests the SDQ and CHU9D are related in some of their measurement properties. The mapping algorithm using five SDQ subscales was found to be optimal in predicting mean child health utility. Future research valuing changes in the SDQ scores would contribute to this research. PMID- 26747329 TI - Profiling of rectal cancers MRI in pathological complete remission states after neoadjuvant concurrent chemoradiation therapy. AB - AIM: To fully characterise the magnetic resonance imaging (MRI) traits of rectal cancers in a large sample of patients, each experiencing pathological complete remission (pCR) after neoadjuvant concurrent chemoradiation therapy (CCRT). MATERIALS AND METHODS: A total of 120 patients (77 male, 43 female; median age, 59.5 years; range, 32-81 years) with rectal cancers in CCRT-induced pCR states who underwent pre- and post-CCRT MRI and eventual surgery between July, 2005 and September, 2014 were retrospectively reviewed. In most (n=100), diffusion weighted imaging was also performed. Tumour volume, tumour regression grade (TRG), T-stage, mesorectal fascia (MRF) status, and T2 signal intensity (T2-SI) were analysed. Paired t-test and McNemar's test were applied for statistical comparisons. RESULTS: Tumour volume declined sharply after CCRT (pre-CCRT, 21.5 +/- 22.4 cm(3); post-CCRT, 6.6 +/- 8.4 cm(3); p<0.001). TRG distribution was as follows: G1 (clinical CR), 3; G2, 38; G3, 78; G4, 1; and G5 (marked progression), 0. Downstaging of T-stage (34%,16/47) and MRF status (19.7%,13/66) did occur; but on post-CCRT MRI, 25.8% (31/120) remained at T3 >= 5 mm or T4 stage, and 44.2% (53/120) were MRF-positive. A majority (88.3%, 106/120) of patients displayed intermediate T2-SI prior to CCRT. Most converted to dark T2-SI after CCRT, with 12.5% (15/120) unchanged. On post-CCRT MRI, 11% (11/100) of patients showed diffusion restriction. CONCLUSION: MRI findings in CCRT-induced pCR-status rectal cancers were highly variable. Tumour volume and T2-SI mostly decreased; however, such lesions occasionally presented with unexpected atypical features, such as large residual volume and/or intermediate T2-SI. PMID- 26747330 TI - Cost savings associated with transfer of trauma patients within an accountable care organization. AB - BACKGROUND: The Patient Protection and Affordable Care Act supports the establishment of accountable care organizations (ACOs) as care delivery models designed to save costs. The potential for these cost savings has been demonstrated in the primary care and inpatient populations, but not for patients with emergency conditions or traumatic injuries. METHODS: Our study evaluated adult trauma patients transferred to the tertiary care hospitals of a pioneer ACO, comparing those who were transferred from within the ACO to those from outside the ACO in terms of overall cost of hospitalization. Hospital length of stay and number of imaging studies were predetermined secondary outcomes. RESULTS: The study population included 7696 hospitalizations for traumatic injuries over a 5-year period, 85.1% of which were for patients transferred from outside the ACO. Patients transferred from within the ACO had a 7.2% lower overall cost of hospitalization (P = .032). Mean injury severity scores were not significantly different between groups. Differences in mortality, intensive care unit length of stay, and overall hospital length of stay were not significant. However, analysis of radiology studies performed during the hospitalization revealed that patients transferred from within the ACO had, on average, 0.47 fewer advanced imaging studies per hospitalization than did those transferred from outside the ACO (3.55 vs 4.02 studies per hospitalization, P = .003). CONCLUSIONS: Adult trauma patients transferred from within an ACO have significantly lower total costs of hospitalization than do those transferred from outside the system, without significant differences in disease burden, hospital length of stay, or mortality. PMID- 26747331 TI - Thirty-Day Postoperative Mortality Risk Estimates and 1-Year Survival in Veterans Health Administration Surgery Patients. AB - IMPORTANCE: For more than 2 decades, the Veterans Health Administration (VHA) has relied on risk-adjusted, postoperative, 30-day mortality data as a measure of surgical quality of care. Recently, the use of 30-day mortality data has been criticized based on a theory that health care professionals manage patient care to meet the metric and that other outcome metrics are available. OBJECTIVES: To determine whether postoperative mortality data identify a delay in care to meet a 30-day mortality metric and to evaluate whether 30-day mortality risk score groups stratify survival patterns up to 365 days after surgery in surgical procedures assessed by the Veterans Affairs Surgical Quality Improvement Program (VASQIP). DESIGN, SETTING, AND PARTICIPANTS: Patients undergoing VASQIP-assessed surgical procedures within the VHA from October 1, 2011, to September 30, 2013, were evaluated. Data on 365-day survival follow-up of 212 733 surgical cases using VHA Vital Status and admission records were obtained with 10 947 mortality events. Data analysis was conducted from September 3, 2014, to November 9, 2015. MAIN OUTCOMES AND MEASURES: Survival up to 365 days after surgery for the overall cohort divided into 10 equal groups (deciles). RESULTS: There were 10 947 mortality events identified in a cohort of 212 733 surgical patients. The mean probability of death was 1.03% (95% CI, 1.01%-1.04%). Risk estimate groups in the 212 733 surgical cases analyzed showed significantly different postoperative survival, with consistency beyond the time frame for which they were developed. The lowest risk decile had the highest 365-day survival probability (99.74%; 95% CI, 99.66%-99.80%); the highest risk decile had the lowest 365-day survival probability (72.04%; 95% CI, 71.43%-72.64%). The 9 lowest risk deciles had linear survival curves from 0 to 365 postoperative days, with the highest risk decile having early survival risk and becoming more linear after the first 180 days. Survival curves between 25 and 35 days were consistent for all risk deciles and showed no evidence that mortality rates were affected in the immediate period beyond day 30. The setting of mortality varied by postoperative day ranges, with index hospitalization events declining and deaths outside of the hospital increasing up to 365 days. CONCLUSIONS AND RELEVANCE: Deciles of 30-day mortality estimates are associated with significantly different survival outcomes at 365 days even after removing patients who died within the first 30 postoperative days. No evidence of delays in patient care and treatment to meet a 30-day metric were identified. These findings reinforce the usefulness of 30-day mortality risk stratification as a surrogate for long-term outcomes. PMID- 26747332 TI - A trial for the design and optimization of pH-sensitive microparticles for intestinal delivery of cinnarizine. AB - The aim of this study was to formulate a microparticulate delivery system to deliver cinnarizine (CIN) directly to its site of absorption to overcome its low oral bioavailability. Enteric microparticles were prepared by varying ratios of pH-sensitive polymers (Eudragit L100 and Eudragit S100). A full 3(3) factorial experimental design was adopted to evaluate the effect of variables (CIN concentration as well as Eudragit's concentration) on the tested parameters, namely, particle size (p.s.), drug entrapment efficiency (E.E.), and release efficiency (R.E.). Optimization was done using Design Expert(r) software to maximize E.E. and R.E. and minimize p.s. The optimized formula was characterized using scanning electron microscopy, differential scanning calorimetry, and X-ray diffractometry. In vivo studies conducted on human volunteers using LC-MS analysis revealed improved bioavailability of CIN-loaded enteric microparticles compared to the market product as detected from calculated pharmacokinetic parameters. This study reveals the usefulness of site-specific delivery of CIN. PMID- 26747333 TI - Monthly High-Dose Vitamin D Treatment for the Prevention of Functional Decline: A Randomized Clinical Trial. AB - IMPORTANCE: Vitamin D deficiency has been associated with poor physical performance. OBJECTIVE: To determine the effectiveness of high-dose vitamin D in lowering the risk of functional decline. DESIGN, SETTING, AND PARTICIPANTS: One year, double-blind, randomized clinical trial conducted in Zurich, Switzerland. The screening phase was December 1, 2009, to May 31, 2010, and the last study visit was in May 2011. The dates of our analysis were June 15, 2012, to October 10, 2015. Participants were 200 community-dwelling men and women 70 years and older with a prior fall. INTERVENTIONS: Three study groups with monthly treatments, including a low-dose control group receiving 24,000 IU of vitamin D3 (24,000 IU group), a group receiving 60,000 IU of vitamin D3 (60,000 IU group), and a group receiving 24,000 IU of vitamin D3 plus 300 MUg of calcifediol (24,000 IU plus calcifediol group). MAIN OUTCOMES AND MEASURES: The primary end point was improving lower extremity function (on the Short Physical Performance Battery) and achieving 25-hydroxyvitamin D levels of at least 30 ng/mL at 6 and 12 months. A secondary end point was monthly reported falls. Analyses were adjusted for age, sex, and body mass index. RESULTS: The study cohort comprised 200 participants (men and women >= 70 years with a prior fall). Their mean age was 78 years, 67.0% (134 of 200) were female, and 58.0% (116 of 200) were vitamin D deficient (<20 ng/mL) at baseline. Intent-to-treat analyses showed that, while 60,000 IU and 24,000 IU plus calcifediol were more likely than 24,000 IU to result in 25 hydroxyvitamin D levels of at least 30 ng/mL (P = .001), they were not more effective in improving lower extremity function, which did not differ among the treatment groups (P = .26). However, over the 12-month follow-up, the incidence of falls differed significantly among the treatment groups, with higher incidences in the 60,000 IU group (66.9%; 95% CI, 54.4% to 77.5%) and the 24,000 IU plus calcifediol group (66.1%; 95% CI, 53.5%-76.8%) group compared with the 24,000 IU group (47.9%; 95% CI, 35.8%-60.3%) (P = .048). Consistent with the incidence of falls, the mean number of falls differed marginally by treatment group. The 60,000 IU group (mean, 1.47) and the 24,000 IU plus calcifediol group (mean, 1.24) had higher mean numbers of falls compared with the 24,000 IU group (mean, 0.94) (P = .09). CONCLUSIONS AND RELEVANCE: Although higher monthly doses of vitamin D were effective in reaching a threshold of at least 30 ng/mL of 25 hydroxyvitamin D, they had no benefit on lower extremity function and were associated with increased risk of falls compared with 24,000 IU. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01017354. PMID- 26747334 TI - Development of the Malocclusion Impact Questionnaire (MIQ) to measure the oral health-related quality of life of young people with malocclusion: part 1 - qualitative inquiry. AB - OBJECTIVES: To seek the views of adolescents with malocclusion about how the appearance and arrangement of their teeth affects their everyday life and to incorporate these views into a new Malocclusion Impact Questionnaire (MIQ). METHODS: Semi-structured interviews were undertaken with a purposive sample of 30 young people (10-16 years) referred for orthodontic treatment to two dental teaching hospitals. The interviews were recorded, transcribed and analysed using framework analysis. Several themes and sub themes were identified and these were used to identify items to include in the new measure. RESULTS: Three themes emerged which were: concerns about the appearance of their teeth, effect on social interactions and oral health/function. Participants expressed the view that their teeth did not look normal, causing them embarrassment and a lack of confidence, particularly when they were with their peers or having their photograph taken. Concerns regarding the potential effect of a malocclusion on oral health, in terms of food becoming stuck between crooked teeth, interferences when chewing and increased risk of damaging the teeth were also identified. The themes were used to generate individual items for inclusion in the questionnaire. CONCLUSIONS: Common themes relating to the impact of malocclusion on the lives of young people were identified and generated items for the new MIQ to measure the oral health-related quality of life of young people with malocclusion. Part 2 outlines the further development and testing of the MIQ. PMID- 26747335 TI - Altered Brain Computed Tomography Perfusion in Patients With Fluctuating Lacunar Syndrome and Normal Magnetic Resonance Imaging. PMID- 26747336 TI - Dendrimers in anticancer drug delivery: mechanism of interaction of drug and dendrimers. AB - Dendrimers represents a novel class of macromolecules, which are derived from branches upon branches type structural design. Dendrimers are emerging as promising drug-delivery molecule because of their extraordinary properties including membrane interaction, monodispersity, well-defined size, shape and molecular weight, etc. Drugs interact with dendrimers in three ways; (a) physical encapsulation, (b) electrostatic interactions, and (c) covalent conjugations. Due to compact, globular structure and availability of interior cavity spaces and multiple surface functional groups, drug molecules can be encapsulated both in the interior of the dendrimers (physical encapsulation) as well as attached to the surface functional groups (covalent conjugations). PMID- 26747370 TI - The fatty acid amide hydrolase inhibitor URB597 modulates serotonin-dependent emotional behaviour, and serotonin1A and serotonin2A/C activity in the hippocampus. AB - The fatty acid amide hydrolase (FAAH) inhibitor URB597 increases anandamide, resulting in antidepressant/anxiolytic-like activity, likely via CB1 receptor mediated modulation of serotonin (5-HT) and norepinephrine (NE) neurotransmission. However, the relative importance of the 5-HT and NE systems in these effects and on effects of URB597 on postsynaptic 5-HT receptors remain to be determined. Using behavioural and electrophysiological approaches, we assessed the effects of acute-single and repeated URB597 treatment on responses predicting antidepressant/anxiolytic activity, and on hippocampal 5-HT1A and 5-HT2A/C receptor sensitivity. Acute-single or serial URB597 treatment, compared to vehicle, reduced immobility in the forced swim test (FST), increased open arm visits in the elevated plus maze and shortened feeding latency in the novelty suppressed feeding test (NSFT). Repeated URB597 treatment yielded more profound behavioural effects, which were associated with an increase in hippocampal brain derived neurotrophic factor (BDNF). The 5-HT synthesis inhibitor para chlorophenylalanine (pCPA), but not the NE neurotoxin N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP4) prevented URB597-mediated antidepressant/anxiolytic-like response in the FST and NSFT, while DSP4 did not further affect URB597-mediated increase in raphe 5-HT neuron firing. Repeated URB597 administration decreased hippocampal pyramidal firing in response to 5-HT2A/C and 5-HT1A stimulation with 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) and 8-hydroxy-2 dipropylaminotetralin (8-OH-DPAT), respectively, suggesting plastic adaptation of these receptors. The effects of acute-single and repeated URB597 administration on hippocampal cell firing in response to DOI or 8-OH-DPAT were similar in magnitude and intensity to the positive control citalopram. These data indicate that URB597 acts, either directly or indirectly, on the 5-HT system, increases hippocampal BDNF expression, and modifies 5-HT1A and 5-HT2A/C function. PMID- 26747372 TI - Summaries for Patients. Heart Problems in Adults Who Survived Cancer as Children. PMID- 26747373 TI - Association of Age at Menopause and Duration of Reproductive Period With Depression After Menopause: A Systematic Review and Meta-analysis. AB - IMPORTANCE: Estrogens have neuroprotective and antidepressive effects; however, associations between indices of reduced endogenous estrogens and risk for postmenopausal depression have not been systematically explored. OBJECTIVE: To investigate the association of age at menopause and the duration of the reproductive period with the risk for depression among postmenopausal women with naturally occurring menopause. DATA SOURCES: A search strategy for use of MEDLINE was developed (through January 1, 2015) using the key terms menopause, climacteric, reproductive period, depression, and mood disorders. References of included studies and reviews were also screened; authors were contacted to maximize synthesized evidence. STUDY SELECTION: A total of 12,323 articles, without language restriction, were screened by pairs of reviewers to identify observational studies related to the study hypothesis; 14 studies were eligible for meta-analysis. DATA EXTRACTION AND SYNTHESIS: Pairs of reviewers independently extracted information on study design and type of analysis by participants' characteristics and methods of depression ascertainment. Study quality was assessed using the Newcastle-Ottawa Scale, and fixed- or random effects models were implemented. MAIN OUTCOMES AND MEASURES: Pooled-effect estimates for depression, defined by psychiatric evaluation or validated instruments, by age at menopause and duration of the reproductive period. RESULTS: The 14 studies included in the meta-analysis represented 67,714 women. An inverse association (reported as odds ratio [OR]; 95% CI of 2-year increments) with depression in postmenopausal women was shown for increasing age at menopause (0.98; 0.96-0.99 [67,434 unique participants; 13 studies]) and duration of the reproductive period (0.98; 0.96-0.99 [54,715 unique participants; 5 studies]). Menopause at age 40 or more years compared with premature menopause was associated with a 50% decreased risk for depression (3033 unique participants; 4 studies). Pooling of studies examining severe depression showed a 5% decrease in risk of severe depression with increasing (2-year increment) age at menopause (52,736 unique participants; 3 studies); sensitivity analysis of studies controlling for past depression revealed similar results for age at menopause (0.98; 0.96-1.00 [48,894 unique participants; 3 studies). No heterogeneity or publication bias was evident in the main analyses. CONCLUSIONS AND RELEVANCE: Longer exposure to endogenous estrogens, expressed as older age at menopause and longer reproductive period, is associated with a lower risk of depression in later life. Identifying women at higher risk for depression due to early menopause who could benefit from psychiatric intervention or estrogen-based therapies could be useful in the clinical setting. PMID- 26747371 TI - Common mechanisms in development and disease: BMP signaling in craniofacial development. AB - BMP signaling is one of the key pathways regulating craniofacial development. It is involved in the early patterning of the head, the development of cranial neural crest cells, and facial patterning. It regulates development of its mineralized structures, such as cranial bones, maxilla, mandible, palate, and teeth. Targeted mutations in the mouse have been instrumental to delineate the functional involvement of this signaling network in different aspects of craniofacial development. Gene polymorphisms and mutations in BMP pathway genes have been associated with various non-syndromic and syndromic human craniofacial malformations. The identification of intricate cellular interactions and underlying molecular pathways illustrate the importance of local fine-regulation of Bmp signaling to control proliferation, apoptosis, epithelial-mesenchymal interactions, and stem/progenitor differentiation during craniofacial development. Thus, BMP signaling contributes both to shape and functionality of our facial features. BMP signaling also regulates postnatal craniofacial growth and is associated with dental structures life-long. A more detailed understanding of BMP function in growth, homeostasis, and repair of postnatal craniofacial tissues will contribute to our ability to rationally manipulate this signaling network in the context of tissue engineering. PMID- 26747374 TI - Survival and Growth of Freshwater Pulmonate and Nonpulmonate Snails in 28-Day Exposures to Copper, Ammonia, and Pentachlorophenol. AB - We performed toxicity tests with two species of pulmonate snails (Lymnaea stagnalis and Physa gyrina) and four taxa of nonpulmonate snails in the family Hydrobiidae (Pyrgulopsis robusta, Taylorconcha serpenticola, Fluminicola sp., and Fontigens aldrichi). Snails were maintained in static-renewal or recirculating culture systems with adults removed periodically to isolate cohorts of offspring for toxicity testing. This method successfully produced offspring for both species of pulmonate snails and for two hydrobiid species, P. robusta and Fluminicola sp. Toxicity tests were performed for 28 days with copper, ammonia, and pentachlorophenol in hard reconstituted water with endpoints of survival and growth. Tests were started with 1-week-old L. stagnalis, 2-week-old P. gyrina, 5- to 13-week-old P. robusta and Fluminicola sp., and older juveniles and adults of several hydrobiid species. For all three chemicals, chronic toxicity values for pulmonate snails were consistently greater than those for hydrobiid snails, and hydrobiids were among the most sensitive taxa in species sensitivity distributions for all three chemicals. These results suggest that the toxicant sensitivity of nonpulmonate snails in the family Hydrobiidae would not be adequately represented by results of toxicity testing with pulmonate snails. PMID- 26747376 TI - Fast Folding Dynamics of an Intermediate State in RNase H Measured by Single Molecule FRET. AB - We have studied the folding kinetics of the core intermediate (I) state of RNase H by using a combination of single-molecule FRET (smFRET) and hidden Markov model analysis. To measure fast dynamics in thermal equilibrium as a function of the concentration of the denaturant GdmCl, a special FRET labeled variant, RNase H 60 113, which is sensitive to folding of the protein core, was immobilized on PEGylated surfaces. Conformational transitions between the unfolded (U) state and the I state could be described by a two-state model within our experimental time resolution, with millisecond mean residence times. The I state population was always a minority species in the entire accessible range of denaturant concentrations. By introducing the measured free energy differences between the U and I states as constraints in global fits of the GdmCl dependence of FRET histograms of a differently labeled RNase H variant (RNase H 3-135), we were able to reveal the free energy differences and, thus, population ratios of all three macroscopic state ensembles, U, I and F (folded state) as a function of denaturant concentration. PMID- 26747375 TI - Antagonism of V1b receptors promotes maternal motivation to retrieve pups in the MPOA and impairs pup-directed behavior during maternal defense in the mpBNST of lactating rats. AB - Recent studies using V1b receptor (V1bR) knockout mice or central pharmacological manipulations in lactating rats highlighted the influence of this receptor for maternal behavior. However, its role in specific brain sites known to be important for maternal behavior has not been investigated to date. In the present study, we reveal that V1bR mRNA (qPCR) and protein levels (Western blot) within either the medial preoptic area (MPOA) or the medial-posterior part of the bed nucleus of the stria terminalis (mpBNST) did not differ between virgin and lactating rats. Furthermore, we characterized the effects of V1bR blockade via bilateral injections of the receptor subtype-specific antagonist SSR149415 within the MPOA or the mpBNST on maternal behavior (maternal care under non-stress and stress conditions, maternal motivation to retrieve pups in a novel environment, maternal aggression) and anxiety-related behavior in lactating rats. Blocking V1bR within the MPOA increased pup retrieval, whereas within the mpBNST it decreased pup-directed behavior, specifically licking/grooming the pups, during the maternal defense test. In addition, immediately after termination of the maternal defense test, V1bR antagonism in both brain regions reduced nursing, particularly arched back nursing. Anxiety-related behavior was not affected by V1bR antagonism in either brain region. In conclusion our data indicate that V1bR antagonism significantly modulates different aspects of maternal behavior in a brain region-dependent manner. PMID- 26747377 TI - Prevalence and Risk Factors of Chronic Rhinosinusitus, Allergic Rhinitis, and Nasal Septal Deviation: Results of the Korean National Health and Nutrition Survey 2008-2012. AB - IMPORTANCE: Chronic rhinosinusitis (CRS), allergic rhinitis (AR), and nasal septal deviation (NSD) are frequent rhinologic diseases that consume considerable health care resources. OBJECTIVE: To determine the prevalence and risk factors of CRS, AR, and NSD in Korea. DESIGN, SETTING, AND PARTICIPANTS: This study analyzed 5-year cross-sectional data from the Korean National Health and Nutrition Examination Survey (KNHANES) 2008-2012. A total of 35 511 participants, who underwent an interview regarding nasal symptoms and a nasal examination, were enrolled and subsequently divided into 3 groups: children (aged 7-12 years), adolescents (aged 13-19 years), and adults (aged >=20 years). MAIN OUTCOMES AND MEASURES: Adult CRS was classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). Diagnosis of AR was based on symptoms and serum levels of specific IgE for 3 allergens, including Dermatophagoides farinae. The precise prevalence of AR was reestimated by multiplying the reciprocal of D farinae frequency based on a conventional skin prick test. Nasal septal deviation was diagnosed via nasal endoscopy after nasal decongestion. This study estimated the association of the 3 diseases with demographic data, including sex, age, obesity, level of education, socioeconomic status, residence, smoking, and alcohol. RESULTS: The prevalence of CRSwNP and CRSsNP in 28 912 adults was 2.6% and 5.8%, respectively. An association was found between CRSwNP and age (odds ratio [OR], 1.03; 95% CI, 1.02-1.04; P < .001), lower level of education (OR, 1.40; 95% CI, 1.02-1.92; P = .04), and obesity (OR, 1.46; 95% CI, 1.16-1.84; P = .001). Symptom-based and allergy test result-based AR had a prevalence of 27.5% (n = 35 511) and 16.1% (n = 2298), respectively. The reestimated prevalence of AR was 18.5% for all ages. Urban residence increased the risk of AR (OR, 1.21; 95% CI, 1.06-1.38; P = .005), but age was associated with a decreased risk (OR, 0.99; 95% CI, 0.98-0.99; P < .001). The prevalence of NSD was 48.0% and increased with age. In addition, NSD was a risk factor for CRSsNP (adjusted OR, 1.16; 95% CI, 1.02-1.32; P = .03) but not for CRSwNP. CONCLUSIONS AND RELEVANCE: In KNHANES 2008-2012, older age was associated with increased risk for CRSwNP and NSD but associated with a decreased risk for AR. Obesity was another risk factor for CRSwNP. PMID- 26747378 TI - Reducing Depression Through an Online Intervention: Benefits From a User Perspective. AB - BACKGROUND: Internet interventions are increasingly being recognized as effective in the treatment and prevention of mental health conditions; however, the usefulness of such programs from the perspective of the participants is often not reported. OBJECTIVE: This study explores the experiences of participants of a 12 week randomized controlled trial of an automated self-help training program (e couch), with and without an Internet support group, targeting depression. METHODS: The study comprised a community sample of 298 participants who completed an online survey both prior to and on completion of an intervention for preventing or reducing depressive symptoms. RESULTS: Overall, participants reported a high level of confidence in the ability of an online intervention to improve a person's understanding of depression. However, confidence that a website could help people learn skills for preventing depression was lower. Benefits reported by participants engaged in the intervention included increased knowledge regarding depression and its treatment, reduced depressive symptoms, increased work productivity, and improved ability to cope with everyday stress. A minority of participants reported concerns or problems resulting from participation in the interventions. CONCLUSIONS: The findings provide consumer support for the effectiveness of this online intervention. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 65657330;http://www.isrctn.com/ISRCTN65657330 (Archived by WebCite at http://www.webcitation.org/6cwH8xwF0). PMID- 26747379 TI - Incorporating Health-related Quality of Life Into the Assessment of Outcome Following Strabismus Surgery. AB - PURPOSE: To evaluate changes in health-related quality of life (HRQOL) in adult strabismus patients classified as surgical failures by standard motor and diplopia criteria. DESIGN: Prospective cohort study evaluating outcomes. METHODS: Adults undergoing strabismus surgery in a single clinical practice, with preoperative and 1-year-postoperative Adult Strabismus-20 HRQOL questionnaires, were included. Motor and diplopia criteria were applied to classify outcomes (success, partial success, or failure). For those classified as failure, the medical record of the 1-year examination was reviewed to determine whether the patient reported subjective improvement. We evaluated improvement in HRQOL, defined as exceeding 95% limits of agreement on at least 1 of the 4 Adult Strabismus-20 domains. We compared proportions exceeding 95% limits of agreement in those reporting subjective improvement vs those who did not. RESULTS: Forty of 227 patients (18%) were classified as failure by motor and diplopia criteria, with 39 of 40 able to exceed Adult Strabismus-20 95% limits of agreement. Overall, 21 of 39 (54%) showed improved HRQOL by exceeding 95% limits of agreement on at least 1 of the 4 Adult Strabismus-20 domains (54% vs predicted 10% by chance alone; P < .0001). Twenty-five patients (64%) reported subjective improvement, of whom 16 (64%) showed improved HRQOL exceeding 95% limits of agreement. CONCLUSIONS: Many apparent surgical failures report subjective improvement, often reflected in improved HRQOL scores. We propose incorporating quantitative HRQOL criteria into the assessment of strabismus surgery outcomes, defining success as either meeting motor and diplopia criteria or showing improvement in HRQOL beyond test-retest variability. PMID- 26747389 TI - Global burden of CVD: focus on secondary prevention of cardiovascular disease. AB - Despite encouraging advances in prevention and treatment of atherothrombosis, cardiovascular disease (CVD) remains a major cause of deaths and disability worldwide and will continue to grow mainly due to the increase in incidence in low and middle income countries (LMIC). In Europe and the United States of America (USA), coronary heart disease (CHD) mortality rates have decreased since the mid-1990s due to improvements in acute care, however the prevalence of CHD is increasing largely in part due to the overall aging of the population, increased prevalence of cardiovascular (CV) risk factors, and improved survival of patients after a CV event. Data from clinical trials has consistently proven the efficacy of pharmacologic interventions with aspirin, statins, and blood pressure (BP) lowering agents in reducing the risk of CV events and total mortality in the ever growing pool of patients in secondary prevention. However, large gaps between indicated therapy and prescribed medication can be observed worldwide, with very low rates of use of effective therapies in LMIC countries. Adherence to medication is very poor in chronic patients, especially those treated with multiple pharmacologic agents, and has been directly correlated to a greater incidence of recurrent CV events and increase in direct and indirect healthcare costs. In this article, we review the global burden of CV disease, status of secondary prevention therapy and major barriers for treatment adherence. PMID- 26747388 TI - QuickRNASeq lifts large-scale RNA-seq data analyses to the next level of automation and interactive visualization. AB - BACKGROUND: RNA sequencing (RNA-seq), a next-generation sequencing technique for transcriptome profiling, is being increasingly used, in part driven by the decreasing cost of sequencing. Nevertheless, the analysis of the massive amounts of data generated by large-scale RNA-seq remains a challenge. Multiple algorithms pertinent to basic analyses have been developed, and there is an increasing need to automate the use of these tools so as to obtain results in an efficient and user friendly manner. Increased automation and improved visualization of the results will help make the results and findings of the analyses readily available to experimental scientists. RESULTS: By combing the best open source tools developed for RNA-seq data analyses and the most advanced web 2.0 technologies, we have implemented QuickRNASeq, a pipeline for large-scale RNA-seq data analyses and visualization. The QuickRNASeq workflow consists of three main steps. In Step #1, each individual sample is processed, including mapping RNA-seq reads to a reference genome, counting the numbers of mapped reads, quality control of the aligned reads, and SNP (single nucleotide polymorphism) calling. Step #1 is computationally intensive, and can be processed in parallel. In Step #2, the results from individual samples are merged, and an integrated and interactive project report is generated. All analyses results in the report are accessible via a single HTML entry webpage. Step #3 is the data interpretation and presentation step. The rich visualization features implemented here allow end users to interactively explore the results of RNA-seq data analyses, and to gain more insights into RNA-seq datasets. In addition, we used a real world dataset to demonstrate the simplicity and efficiency of QuickRNASeq in RNA-seq data analyses and interactive visualizations. The seamless integration of automated capabilites with interactive visualizations in QuickRNASeq is not available in other published RNA-seq pipelines. CONCLUSION: The high degree of automation and interactivity in QuickRNASeq leads to a substantial reduction in the time and effort required prior to further downstream analyses and interpretation of the analyses findings. QuickRNASeq advances primary RNA-seq data analyses to the next level of automation, and is mature for public release and adoption. PMID- 26747390 TI - The Fuster-CNIC-Ferrer Cardiovascular Polypill: a polypill for secondary cardiovascular prevention. AB - During the last decade, there has been a tremendous effort to develop different cardiovascular polypills in response to the upsurge in global cardiovascular disease worldwide. The pharmacological development of such a strategy has proven to be extremely complex from a formulation standpoint. Not all drugs are suitable for use in a polypill because of potential drug incompatibilities between them. Candidate agents must be safe, well tolerated, effective, guideline recommended and physiochemically compatible with the other components of the pill. The Fuster CNIC-Ferrer cardiovascular (CV) polypill has been found to be the first-in-class polypill to be approved and commercialized in Europe and Latinamerican Countries. In this article, we review the pharmacological properties of its three components, including the clinical evidence supporting their use in patients with established cardiovascular disease, their pharmacokinetic properties, adverse effects, drug interactions and contraindications. PMID- 26747391 TI - The cardiovascular polypill: clinical data and ongoing studies. AB - Cardiovascular risk modification in terms of comprehensive medical therapy (antithrombotic therapy, lipid-lowering therapy, antihypertensive medication) and lifestyle modification (healthy diet, regular exercise, weight loss, smoking cessation) is the cornerstone of secondary prevention. It is now clear that even in those undergoing PCI or bypass surgery, appropriate lifestyle modification and aggressive medical therapy are paramount for optimizing long-term outcomes. However, what has emerged from studies that examined the role of medical therapy in the context of coronary heart disease is that only ~50% of the patients in these studies are achieving target treatment goals for blood pressure, lipid and glycemic control. Non-adherence is thought to be a very large contributor to this problem; across all health-care categories, non-adherence is estimated to account for $290 billion of annual health-care expenditure in the United States and ?1.25 billion in European Union, with poor adherence to CVD medication accounting for 9% of all European CVD events. Socioeconomic factors may have a role in patients' discontinuing their medications, and a major initiative to combat this problem is the increasing focus on the polypill. The idea of combining numerous medications into a single tablet to reduce CV risk was first proposed more than a decade ago. This combined formulation not only significantly enhances patient convenience and adherence but also drives savings for the healthcare systems. Several randomized clinical trials have consistently demonstrated the effects of polypills on CV risk factors and adherence, and major trials are underway to study the effect on hard clinical outcomes. PMID- 26747392 TI - Exclusion of Gastrointestinal Cancer Patients With Prior Cancer From Clinical Trials: Is This Justified? AB - BACKGROUND: Strict eligibility criteria are necessary to maintain patient safety and scientific validity in clinical trials. However, this may lead to impaired generalizability of results. As survival in gastrointestinal (GI) cancer relates mainly to the GI malignancy, we hypothesized that previous cancers do not impact on survival and are not a rational exclusion criterion. MATERIALS AND METHODS: Patients treated with chemotherapy for a GI cancer in 2006 were identified from the electronic patient record at the Royal Marsden Hospital, London. Chart review was performed and patient age, gender, GI cancer stage, prior cancer stage, clinical trial availability/eligibility, and dates of cancer recurrence, death, and last follow-up were collated. RESULTS: A total of 697 patients were identified. Fifty-four patients (8%) had a prior cancer; commonly breast (26%), prostate (17%), or colon (9%); most were stage I (42%) or II (37%). Two hundred ninety-seven (65%) patients had GI cancer recurrence, 7 (12%) patients had relapse of a prior cancer. Five hundred four (72%) patients have died, 170 (24%) are alive with no cancer, and 23 (3%) patients are alive with cancer. A total of 476 (94%) died of GI cancer, 2 (0.3%) of their prior cancer. Of all patients, 489 (70%) had an available trial, but 30% of patients with a prior cancer were ineligible for this reason. Overall and GI-cancer-specific survival were comparable for patients with/without a prior cancer. CONCLUSIONS: Survival for patients with a GI cancer requiring chemotherapy relates to the GI cancer and rarely a prior cancer. These patients should not be excluded from clinical trial participation. PMID- 26747393 TI - Discovery and preclinical evaluation of potent, orally bioavailable, metabolically stable cyclopropylindolobenzazepine acylsulfonamides as thumb site 1 inhibitors of the hepatitis c virus NS5B RNA-dependent, RNA polymerase. AB - Herein, we describe the synthesis, antiviral structure-activity relationships (SAR), metabolic stability, and pharmacokinetic (PK) properties for a series of cyclopropylindolobenzazepine acylsulfonamide HCV NS5B polymerase inhibitors. Optimization of SAR, metabolic stability and PK led to the identification of compound 19 which was advanced into pre-IND enabling toxicology studies. PMID- 26747394 TI - Identification of a small molecule HIV-1 inhibitor that targets the capsid hexamer. AB - The HIV-1 CA protein is an attractive therapeutic target for the development of new antivirals. An inter-protomer pocket within the hexamer configuration of the CA, which is a binding site for key host dependency factors, is an especially appealing region for small molecule targeting. Using a field-based pharmacophore derived from an inhibitor known to interact with this region, coupled to biochemical and biological assessment, we have identified a new compound that inhibits HIV-1 infection and that targets the assembled CA hexamer. PMID- 26747396 TI - Muscle activation timing and balance response in chronic lower back pain patients with associated radiculopathy. AB - BACKGROUND: Patients with chronic low back pain and associated radiculopathy present with neuromuscular symptoms both in their lower back and down their leg; however, investigations of muscle activation have so far been isolated to the lower back. During balance perturbations, it is necessary that lower limb muscles activate with proper timing and sequencing along with the lower back musculature to efficiently regain balance control. METHODS: Patients with chronic low back pain and radiculopathy and matched controls completed a series of balance perturbations (rapid bilateral arm raise, unanticipated and anticipated sudden loading, and rapid rise to toe). Muscle activation timing and sequencing as well as kinetic response to the perturbations were analyzed. FINDINGS: Patients had significantly delayed lower limb muscle activation in rapid arm raise trials as compared to controls. In sudden loading trials, muscle activation timing was not delayed in patients; however, some differences in posterior chain muscle activation sequencing were present. Patients demonstrated less anterior-posterior movement in unanticipated sudden loading trials, and greater medial-lateral movement in rise to toe trials. INTERPRETATION: Patients with low back pain and radiculopathy demonstrated some significant differences from control participants in terms of muscle activation timing, sequencing, and overall balance control. The presence of differences between patients and controls, specifically in the lower limb, indicates that radiculopathy may play a role in altering balance control in these patients. PMID- 26747395 TI - Expression of nicotinic acetylcholine receptor subunits from parasitic nematodes in Caenorhabditis elegans. AB - The levamisole-sensitive nicotinic acetylcholine receptor present at nematode neuromuscular junctions is composed of multiple different subunits, with the exact composition varying between species. We tested the ability of two well conserved nicotinic receptor subunits, UNC-38 and UNC-29, from Haemonchus contortus and Ascaris suum to rescue the levamisole-resistance and locomotion defects of Caenorhabditis elegans strains with null deletion mutations in the unc 38 and unc-29 genes. The parasite cDNAs were cloned downstream of the relevant C. elegans promoters and introduced into the mutant strains via biolistic transformation. The UNC-38 subunit of H. contortus was able to completely rescue both the locomotion defects and levamisole resistance of the null deletion mutant VC2937 (ok2896), but no C. elegans expressing the A. suum UNC-38 could be detected. The H. contortus UNC-29.1 subunit partially rescued the levamisole resistance of a C. elegans null mutation in unc-29 VC1944 (ok2450), but did cause increased motility in a thrashing assay. In contrast, only a single line of worms containing the A. suum UNC-29 subunit showed a partial rescue of levamisole resistance, with no effect on thrashing. PMID- 26747398 TI - Retained garden fork following cranial stab injury. AB - Retained garden fork is a rare complication of penetrating cranial trauma. Retained knife blade is the most commonly reported presentation. We report an unusual case of a 30-year-old male patient treated at our institution, who presented with a retained garden fork following a stab to the head, with no associated neurological deficits. Computerized tomographic scan of the brain was performed preoperatively to assess the trajectory of the weapon and parenchymal injury. A craniectomy was performed to facilitate removal of the weapon in the operating theatre under general anaesthesia. Intravenous prophylactic antibiotics were administered pre- and postoperatively to prevent septic complications. The patient recovered well and was discharged home. PMID- 26747397 TI - In vitro initial stability of a stemless humeral implant. AB - BACKGROUND: Stemless humeral prostheses have been recently introduced. We measured for the first time their in vitro primary stability and analyzed the influence of three clinically important parameters (bone quality, implant size and post-operative loading) on micromotion. We also assessed if displacement sensors are appropriate to measure implant micromotion. METHODS: A stemless humeral implant (Sidus(r) Stem-Free Shoulder, Zimmer GmbH, Winterthur, Switzerland) was implanted in 18 cadaveric humeri. Three-dimensional motion of the implant was measured under dynamic loading at three load magnitudes with displacement sensors. Additionally, the relative motion at the bone-implant interface was measured with an optical system in four specimens. RESULTS: Micromotion values derived from the displacement sensors were significantly higher than those measured by the optical system (P<0.005). Analysis of variance (ANOVA) indicated that bone density (P<0.0005) and load (P<0.0001) had a significant effect on implant micromotion, however the effect of implant size was not statistically significant (P=0.123). INTERPRETATION: Micromotion of this stemless design was shown to be significantly dependent on cancellous bone density. Patients must therefore have adequate bone quality for this procedure. The influence of load magnitude on micromotion emphasizes the need for controlled post-operative rehabilitation. Measurements with displacement sensors overestimate true interface micromotion by up to 50% and correction by an optical system is strongly recommended. PMID- 26747399 TI - Population data of 24 STRs in Mexican-Mestizo population from Monterrey, Nuevo Leon (Northeast, Mexico) based on Powerplex((r)) Fusion and GlobalFiler((r)) kits. AB - The STR loci included into new commercial human identification kits compels geneticists estimating forensic parameters for interpretation purposes in forensic casework. Therefore, we studied for the first time in Mexico the GlobalFiler((r)) and Powerplex((r)) Fusion systems in 326 and 682 unrelated individuals, respectively. These individuals are resident of the Monterrey City of the Nuevo Leon state (Northeast, Mexico). Population data from 23 autosomal STRs and the Y-STR locus DYS391 are reported and compared against available STR data from American ethnic groups and the unique Mexican population studied with Powerplex((r)) Fusion. PMID- 26747400 TI - Mfsd2a-based pharmacological strategies for drug delivery across the blood-brain barrier. AB - The blood-brain barrier (BBB) keeps the central nervous system (CNS) safe from various brain diseases, while the BBB makes it difficult for effective drugs to enter the CNS. Mfsd2a is specifically expressed on the cell membrane of brain microvascular endothelial cell (BMEC) and is implicated in the delivery of some substances across the BBB. Mfsd2a is the first inhibitor of the transcytosis and the first transporter for lysophosphatidylcholine-docosahexaenoic acid (LPC-DHA) in BMECs. The crucial dual function of Mfsd2a puts forward two kinds of Mfsd2a based strategies for carrying drugs from blood to the CNS. First, the reversible inhibition of Mfsd2a may temporarily induce a general disinhibition of the transcytosis in BMECs to transport macromolecular drugs across the BBB (Strategy One). Second, Mfsd2a could be used for the transport of some small-molecule drugs chemically coupled to LPC across the BBB (Strategy Two), which is quite similar to the carrier-mediated transport (CMT) via the glucose transporter (GluT1) and the L-type amino acid transporter 1 (LAT1). We here analyze and discuss the clinical significance of the two Mfsd2a-based strategies, including therapeutic potential, available pharmaceuticals, side effects, administration procedures, and disease types. In summary, the regulatory role of Mfsd2a deepens our knowledge of the function of the BBB, potentially contributing to the effective drug delivery in the treatments for neurodegenerative diseases, brain tumors, and life-threatening infections in the CNS. PMID- 26747401 TI - Kinin B1 receptor antagonist BI113823 reduces allergen-induced airway inflammation and mucus secretion in mice. AB - Kinin B1 receptors are implicated in asthmatic airway inflammation. Here we tested this hypothesis by examining the anti-inflammatory effects of BI113823, a novel non-peptide orally active kinin B1 receptor antagonist in mice sensitized to ovalbumin (OVA). Male Balb-c mice were randomly assigned to four study groups: (1) control, (2) OVA+vehicle, (3) OVA+BI113823, (4) OVA+dexamethasone. Mice were sensitized intraperitoneally with 75MUg ovalbumin on days 1 and 8. On days 15-17, mice were challenged intranasally with 50MUg of ovalbumin. Mice received vehicle, BI113823, or dexamethasone (positive control) on days 16-18. On day 19, bronchoalveolar lavage (BAL) and lung tissue were collected for biochemical and immuno-histological analysis. Compared to controls treatment with BI113823 significantly reduced the numbers of BAL eosinophils, macrophages, neutrophils and lymphocytes by 58.3%, 61.1%, 66.4% and 56.0%, respectively. Mice treated with dexamethasone showed similar reductions in BAL cells. Treatment with BI113823 and dexamethasone also significantly reduced total protein content, IgE, TNF-alpha and IL-1beta in lavage fluid, reduced myeloperoxidase activity, mucus secretion in lung tissues, and reduced the expression of B1 receptors, matrix metalloproteinase (MMP)-2 and cyclooxygenase (COX)-2 compared to vehicle-treated mice. Only BI113823 reduced MMP-9 and inducible nitric oxide synthase (iNOS). BI113823 effectively reduced OVA-induced inflammatory cell, mediator and signaling pathways equal to or greater than that seen with steroids in a mouse asthma model. BI113823 might be useful in modulating inflammation in asthma. PMID- 26747402 TI - Small bowel protection against NSAID-injury in rats: Effect of rifaximin, a poorly absorbed, GI targeted, antibiotic. AB - Nonsteroidal anti-inflammatory drugs, besides exerting detrimental effects on the upper digestive tract, can also damage the small and large intestine. Although the underlying mechanisms remain unclear, there is evidence that enteric bacteria play a pivotal role. The present study examined the enteroprotective effects of a delayed-release formulation of rifaximin-EIR (R-EIR, 50mg/kg BID, i.g.), a poorly absorbed antibiotic with a broad spectrum of antibacterial activity, in a rat model of enteropathy induced by indomethacin (IND, 1.5mg/kg BID for 14 days) administration. R-EIR was administered starting 7 days before or in concomitance with IND administration. At the end of treatments, blood samples were collected to evaluate hemoglobin (Hb) concentration (as an index of digestive bleeding). Small intestine was processed for: (1) histological assessment of intestinal damage (percentage length of lesions over the total length examined); (2) assay of tissue myeloperoxidase (MPO) and TNF levels, as markers of inflammation; (3) assay of tissue malondialdehyde (MDA) and protein carbonyl concentrations, as an index of lipid and protein peroxidation, respectively; (4) evaluation of the major bacterial phyla. IND significantly decreased Hb levels, this effect being significantly blunted by R-EIR. IND also induced the occurrence of lesions in the jejunum and ileum. In both intestinal regions, R-EIR significantly reduced the percentage of lesions, as compared with rats receiving IND alone. Either the markers of inflammation and tissue peroxidation were significantly increased in jejunum and ileum from IND-treated rats. However, in rats treated with R-EIR, these parameters were not significantly different from those observed in controls. R-EIR was also able to counterbalance the increase in Proteobacteria and Firmicutes abundance induced by INDO. To summarize, R-EIR treatment significantly prevents IND-induced intestinal damage, this enteroprotective effect being associated with a decrease in tissue inflammation, oxidative stress and digestive bleeding as well as reversal of NSAID-induced alterations in bacterial population. PMID- 26747403 TI - Neurobiological actions by three distinct subtypes of brain-derived neurotrophic factor: Multi-ligand model of growth factor signaling. AB - Brain-derived neurotrophic factor (BDNF) is one of the most active members of the neurotrophin family. BDNF not only regulates neuronal survival and differentiation, but also functions in activity-dependent plasticity processes such as long-term potentiation (LTP), long-term depression (LTD), learning, and memory. Like other growth factors, BDNF is produced by molecular and cellular mechanisms including transcription and translation, and functions as a bioactive molecule in the nervous system. Among these mechanisms, a particular post translational mechanism, namely the conversion of precursor BDNF into mature BDNF by proteolytic cleavage, was not fully understood. In this review, we discuss the manner through which this post-translational mechanism alters the biological actions of BDNF protein. In addition to the initially elucidated findings on BDNF, the biological roles of precursor BDNF and the BDNF pro-peptide, especially synaptic plasticity, will be extensively discussed. Recent findings on the BDNF pro-peptide will provide new insights for understanding the mechanisms of action of the pro-peptides of growth factors. PMID- 26747404 TI - The HNO donor Angeli's salt offers potential haemodynamic advantages over NO or dobutamine in ischaemia-reperfusion injury in the rat heart ex vivo. AB - Available inotropic pharmacotherapy for acute heart failure (HF) remains largely ineffective at ameliorating marked impairments in contractile function. Nitroxyl (HNO), the redox sibling of NO*, has recently attracted interest as a therapeutic approach for acute HF. We now compare the impact of ischaemia-reperfusion (I-R) injury on acute haemodynamic responsiveness of the HNO donor, Angeli's salt (AS), to that of NO and dobutamine. Dose-response curves to bolus doses of AS, diethylamine NONOate (DEA/NO, both 0.001-MUmol) and dobutamine (0.1-100 nmol) were performed in rat isolated hearts, following I-R or normoxic perfusion. An additional 10MUmol dose of Angeli's salt was included, to permit roughly equivalent inotropic responses to dobutamine. Changes in cardiac contraction, heart rate and coronary flow (CF) were determined. Although AS and DEA/NO elicited comparable dose-dependent increases in CF in normoxic hearts, only AS vasodilation was preserved after I-R. AS and dobutamine elicited dose-dependent inotropic responses in normoxic hearts and I-R blunted inotropic responses to both. Dobutamine however increased heart rate, which was exacerbated by I-R; this was not evident with AS. Further, AS infusion during reperfusion (1MUM), in a separate cohort of rat hearts, improved recovery of cardiac contractility, with lower incidence of I-R-induced ventricular fibrillation. In conclusion, these observations suggest that HNO offers haemodynamic advantages over NO following I R. Although I-R suppresses inotropy to both agents, residual contractile responses to AS following I-R is likely free of concomitant pro-arrhythmic events. HNO donors may thus offer haemodynamic advantages over existing pharmacotherapy in acute HF. PMID- 26747405 TI - Impact of self-tongue brushing on taste perception in Thai older adults: A pilot study. AB - Oral hygiene influences taste, affecting appetite and nutrition in older adults. However, the impact of self-administered tongue brushing on their taste perceptions was unclear. This pilot study (N = 44) was aimed to observe the changes in taste thresholds using Filter Paper Disc after tongue brushing in Thai older adults. Based on the results, continuous tongue brushing for 3 months reduced tongue coat (p < 0.01) and improved subjective taste in 74% of participants. Sweet and salty recognition thresholds were reduced in both anterior and posterior tongue, while sour and bitter thresholds were reduced only in posterior tongue. No changes in umami (savory) were observed. Daily brushing was more effective than weekly brushing in improving the sweet and bitter tastes. The data suggested that tongue brushing could improve perception of multiple tastes and daily tongue brushing was recommended as routine personal care for older adults. This study supports further investigation in a randomized controlled setting. PMID- 26747406 TI - Microstructural abnormalities of the trigeminal nerve correlate with pain severity and concomitant emotional dysfunctions in idiopathic trigeminal neuralgia: A randomized, prospective, double-blind study. AB - OBJECTIVE: To compare cross-sectional area (CSA) and volume (V) between the trigeminal nerves (TGNs) of the affected side and the unaffected side in patients with idiopathic trigeminal neuralgia (ITN), and both nerves in normal controls, and to correlate these morphological data with degree of facial pain and emotional disorder severity in ITN patients. METHODS: Forty ITN patients and 40 matched healthy volunteers underwent three-dimensional fast imaging employing steady state acquisition (3D-FIESTA) and time-of-flight magnetic resonance angiography (TOF-MRA) focusing on CSA and V of the TGN cisternal segment. Correlations between the morphological results and scores of visual analogue scale (VAS), Hamilton Depression Rating Scale (HAMD), and Hamilton Anxiety Rating Scale (HAMA) were analyzed in two groups. RESULTS: CSA and V of the affected TGN were significantly smaller than in the unaffected TGN and both sides in controls. No statistical differences were observed between morphological data of the unaffected TGN and control TGNs. CSA and V of the affected TGN were significantly associated with VAS scores in ITN patients, and intermediate correlations were detected with HAMD and HAMA scores. CONCLUSION: Degree of atrophy in the affected TGN can be effective for evaluating facial pain and assessing emotional deficits in ITN patients. PMID- 26747407 TI - RF system calibration for global Q matrix determination. AB - The use of multiple transmission channels (known as Parallel Transmission, or PTx) provides increased control of the MRI signal formation process. This extra flexibility comes at a cost of uncertainty of the power deposited in the patient under examination: the electric fields produced by each transmitter can interfere in such a way to lead to excessively high heating. Although it is not possible to determine local heating, the global Q matrix (which allows the whole-body Specific Absorption Rate (SAR) to be known for any PTx pulse) can be measured in situ by monitoring the power incident upon and reflected by each transmit element during transmission. Recent observations have shown that measured global Q matrices can be corrupted by losses between the coil array and location of power measurement. In this work we demonstrate that these losses can be accounted for, allowing accurate global Q matrix measurement independent of the location of the power measurement devices. PMID- 26747408 TI - Single-breath-hold thin-slice gadoxetic acid-enhanced hepatobiliary MR imaging using a newly developed three-dimensional fast spoiled gradient-echo sequence. AB - PURPOSE: To prospectively evaluate the efficacy of a new three-dimensional gradient-echo sequence (Turbo LAVA) that uses undersampled k-space acquisition combined with a two-dimensional parallel imaging technique for hepatobiliary MRI. MATERIALS AND METHODS: Sixty patients underwent T1-weighted gadoxetic acid enhanced hepatobiliary axial MRI during a single breath-hold using both Turbo LAVA (thickness/interval=1.6/0.8mm) and conventional three-dimensional gradient echo (4/2mm; LAVA) sequences at 3T. Axial 4-mm-thick reformation was performed from Turbo LAVA images. Portal vein-to-liver contrast (PLC), bile duct-to-liver contrast (BLC), and lesion-to-liver contrast (LLC) were compared. Two radiologists independently assessed image quality using a five-point scale. Sagittal 4-mm-thick multiplanar reconstructions (MPR) were performed from both sequences and assessed together with directly obtained 4-mm-thick sagittal LAVA images in terms of sharpness. The paired t-test was used to compare PLC, BLC, and LLC. The Wilcoxon signed rank test was used to compare five-point scales. RESULTS: The mean PLC (P<0.001), BLC (P<0.001), and LLC (P<0.005) were significantly higher for Turbo LAVA than for LAVA; the scores for image noise and sharpness were inferior (P=0.000 and 0.005) and superior (0.005 and 0.157) for Turbo LAVA. There were no significant differences in the scores for bile duct visualization, artifacts, fat suppression quality, overall quality, and focal lesion conspicuity. For sagittal images, MPR Turbo LAVA showed significantly better sharpness than MPR LAVA but showed significantly worse sharpness compared with directly obtained LAVA. CONCLUSION: High-spatial-resolution single-breath hold hepatobiliary MRI using Turbo LAVA was feasible. Diagnostic-quality MPR images can be obtained using this sequence. PMID- 26747409 TI - Comparison of CAIPIRINHA-VIBE, Radial-VIBE, and conventional VIBE sequences for dynamic contrast-enhanced (DCE) MRI: A validation study using a DCE-MRI phantom. AB - OBJECTIVE: To validate radial acquisition of volumetric interpolated breath hold examination (Radial-VIBE) and the controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA-VIBE) sequences for dynamic contrast-enhanced MRI (DCE-MRI) by comparing them to conventional VIBE sequence using a phantom. METHODS: On a DCE-MRI phantom containing various concentrations of NiCl2 solutions, six minutes of dynamic series and T1 mapping with variable flip angle methods were acquired using conventional VIBE, Radial-VIBE, and CAIPIRINHA-VIBE sequences on 3.0-T scanners. Signal stability and signal linearity were tested for dynamic series and the precision of R1 values were tested for T1 mapping series. The scans were repeatedly performed at two weeks and three months to test repeatability/reproducibility, assessed by within-subject coefficient of variation (WSCV). RESULTS: Signal stability over six minutes was excellent in all three sequences. Regarding the signal linearity, CAIPIRINHA-VIBE demonstrated the highest linear correlation (r=0.963), followed by conventional VIBE (r=0.959) and Radial-VIBE (r=0.953). Regarding the R1 precision, CAIPIRINHA-VIBE (r=0.985) was the most accurate, followed by conventional VIBE (r=0.861) and Radial-VIBE (r=0.442). CAIPIRINHA-VIBE showed excellent repeatability/reproducibility (WSCV, 1.79-6.71%) compared with Radial-VIBE (WSCV, 2.04-67.2%) and conventional VIBE (WSCV, 3.4-31.9%). CONCLUSION: In terms of signal stability, signal linearity, R1 precision, and repeatability/reproducibility, CAIPIRINHA-VIBE demonstrated outstanding performance for DCE-MRI compared with Radial-VIBE and conventional VIBE. PMID- 26747410 TI - Non-enhanced magnetic resonance imaging of the small bowel at 7 Tesla in comparison to 1.5 Tesla: First steps towards clinical application. AB - OBJECTIVE: To perform non-enhanced (NE) magnetic resonance imaging (MRI) of the small bowel at 7 Tesla (7T) and to compare it with 1.5 Tesla (1.5T). MATERIAL AND METHODS: Twelve healthy subjects were prospectively examined using a 1.5T and 7T MRI system. Coronal and axial true fast imaging with steady-state precession (TrueFISP) imaging and a coronal T2-weighted (T2w) half-Fourier acquisition single-shot turbo spin-echo (HASTE) sequence were acquired. Image analysis was performed by 1) visual evaluation of tissue contrast and detail detectability, 2) measurement and calculation of contrast ratios and 3) assessment of artifacts. RESULTS: NE MRI of the small bowel at 7T was technically feasible. In the vast majority of the cases, tissue contrast and image details were equivalent at both field strengths. At 7T, two cases revealed better detail detectability in the TrueFISP, and better contrast in the HASTE. Susceptibility artifacts and B1 inhomogeneities were significantly increased at 7T. CONCLUSION: This study provides first insights into NE ultra-high field MRI of the small bowel and may be considered an important step towards high quality T2w abdominal imaging at 7T MRI. PMID- 26747412 TI - Butylbenzyl phthalate induces spermatogenic cell apoptosis in prepubertal rats. AB - Butylbenzyl phthalate (BBP), a suspected endocrine disruptor, adversely affects male reproductive function. In this study, morphological alterations of prepubertal rat testes caused by single administration of BBP, were examined by light microscopy. Three-week-old male rats were given a single dose of 500 mg/kg BBP by oral gavage and sacrificed at 3, 12, and 24 h after administration. Histopathological examination revealed progressive detachment and sloughing of spermatogenic cells into the lumen, and a significant increase in the number of TUNEL-positive (apoptotic) spermatogenic cells in the treated groups, compared to the control. Semithin sections confirmed the apoptotic cells by their prominent basophilia, condensed chromatin, and shrunken cytoplasm, hallmarks of apoptotic cell death. Immunohistochemistry identified disruption of Sertoli cell vimentin and actin filaments in the treated groups. To elucidate the recovery effects of BBP, rats were treated in the same way and were sacrificed at D1-12h after administration. The apoptotic index returned to normal at D9. While, the testes revealed lower weight gain until D12. These results show for the first time that BBP induces collapse of vimentin filaments in Sertoli cells which may lead to disruption of Sertoli-spermatogenic cell physical interaction and induces spermatogenic cell apoptosis. PMID- 26747411 TI - Cellular mechanisms of human atherosclerosis: Role of cell-to-cell communications in subendothelial cell functions. AB - The present study was undertaken in order to extend of our earlier work, focusing on the analysis of roles of cell-to-cell communications in the regulation of the subendothelial cell function. In present study, we have found that the expression of connexin43 (Cx43) is dramatically reduced in human atherosclerotic lesions, compared with undiseased intima. In atherosclerotic lesions, the number of so called 'connexin plaques' was found to be lower in lipid-laden cells than in cells which were free from lipid inclusions. In primary cell culture, subendothelial intimal cells tended to create multicellular structures in the form of clusters. Cluster creation was accompanied by the formation of gap junctions between cells; the degree of gap junctional communication correlated with the density of cells in culture. We found that atherosclerosis-related processes such as DNA synthesis, protein synthesis and accumulation of intracellular cholesterol correlated with the degree of cell-to-cell communication. The relation of DNA and protein synthesis with cell-to-cell communication could be described as "bell-shaped". We further incubated cells, cultured from undiseased subendothelial intima, with various forms of modified LDL causing intracellular cholesterol accumulation. After the incubation of intimal cells with modified LDL, intercellular communication has "dropped" considerably. The findings indicate that intracellular lipid accumulation might be a reason for a decrease of the number of gap junctions. The findings also suggest that the disintegration of cellular network is associated with foam cell formation, the process known as a key event of atherogenesis. PMID- 26747413 TI - Quality of life and psychological affect related to sport participation in children and youth athletes with physical disabilities: A parent and athlete perspective. AB - BACKGROUND: Adapted sport, with its recreational, therapeutic, and competitive characteristics is increasingly serving as a forum through which to develop and maintain physical and psychological functioning, promote good health by developing a healthy lifestyle, and enhance health related quality of life (HRQoL) and life satisfaction of persons with disabilities. OBJECTIVE: This study examined the relationship between athlete and parent perceptions of health related quality of life (HRQoL) and the relationship between the athletes' perceived HRQoL and subjective exercise evaluations. METHODS: A total of 70 youth athletes with physical disabilities (Mage = 15, SD = 2.92) and a parent completed the pediatric quality of life inventory (PedsQL). Participants also completed the subjective exercise experience scale (SEES) prior to and immediately after a sport practice. RESULTS: Athletes with disabilities reported higher perceptions of HRQoL than their parents reported for them on physical (t = 4.42, p = .000), emotional (t = 2.78, p = .006) and social (t = 3.26, p = .000) functioning subscales with moderate to high effect sizes (d = .81, .51-1.30, respectively). Positive well-being subscale from the SEES was significantly related to overall HRQoL (r = .49, p = .001) and was a significant predictor (R(2) = .238, F Change = 13.42 (1, 42) p = .001) of overall HRQoL. CONCLUSIONS: Since parents, specifically for younger children, primarily make decisions about program and therapeutic treatments, understanding differences in perceptions of HRQoL between parent and athlete is essential to improving athlete recruitment and structuring program interventions directed at improving HRQoL and emotional well-being of children with disabilities. PMID- 26747414 TI - Impacts of motivational valence on the error-related negativity elicited by full and partial errors. AB - Affect and motivation influence the error-related negativity (ERN) elicited by full errors; however, it is unknown whether they also influence ERNs to correct responses accompanied by covert incorrect response activation (partial errors). Here we compared a neutral condition with conditions, where correct responses were rewarded or where incorrect responses were punished with gains and losses of small amounts of money, respectively. Data analysis distinguished ERNs elicited by full and partial errors. In the reward and punishment conditions, ERN amplitudes to both full and partial errors were larger than in the neutral condition, confirming participants' sensitivity to the significance of errors. We also investigated the relationships between ERN amplitudes and the behavioral inhibition and activation systems (BIS/BAS). Regardless of reward/punishment condition, participants scoring higher on BAS showed smaller ERN amplitudes in full error trials. These findings provide further evidence that the ERN is related to motivational valence and that similar relationships hold for both full and partial errors. PMID- 26747415 TI - Heart rate variability and self-control--A meta-analysis. AB - Heart rate variability (HRV) has been suggested as a biological correlate of self control. Whereas many studies found a relationship between HRV at rest and self control, effect sizes vary substantially across studies in magnitude and direction. This meta-analysis evaluated the association between HRV at rest and self-control in laboratory tasks, with a particular focus on the identification of moderating factors (task characteristics, methodological aspects of HRV assessment, demographics). Overall, 24 articles with 26 studies and 132 effects (n=2317, mean age=22.44, range 18.4-57.8) were integrated (random effects model with robust variance estimation). We found a positive average effect of r=0.15, 95% CI [0.088; 0.221], p<0.001 with a moderate heterogeneity (I(2)=56.10%), but observed evidence of publication bias. Meta-regressions did not reveal significant moderators. Due to the presence of potential publication bias, our results have to be interpreted cautiously. PMID- 26747417 TI - Attentional bias and executive control in treatment-seeking substance-dependent adolescents: A cross-sectional and follow-up study. AB - BACKGROUND: Research in adults shows that substance dependent individuals demonstrate attentional bias (AB) for substance-related stimuli. This study investigated the role of AB in adolescents diagnosed with alcohol, cannabis, amphetamine or GHB dependency on entering therapy and six months later, and the role of executive control (EC) as a moderator of the relationship between problem severity and AB. METHODS: Seventy-eight young substance-dependent (SD) patients (mean age=19.5), and 64 healthy controls (HC; mean age=19.0) were tested. Thirty eight SD patients took part at 6-month follow-up (FU). AB was indexed by a visual probe task, EC by the attention network task, problem severity by the short alcohol (or drug) use disorder identification test and the severity of dependence questionnaire. RESULTS: SD patients demonstrated an AB for substance stimuli presented for 500 ms and 1250 ms, with the latter related to severity of dependence. There was a nonsignificant tendency indicating that EC was higher in HC than SD participants, but EC did not moderate the relationship between AB and dependency. Substance use, dependency, EC and AB remained unchanged in the 6 month FU period. CONCLUSIONS: Young SD patients showed a stronger relatively early as well as maintained AB toward substance cues. A stronger maintained attention was related to higher severity of dependence. Further, there were some indications that EC might play a role in adolescent substance use. The finding that at FU AB and problem severity were not decreased, and EC was not increased underlines the persistent character of addiction. PMID- 26747416 TI - Moderators and mediators of the relationship between receiving versus being denied a pregnancy termination and subsequent binge drinking. AB - BACKGROUND: Women who terminate pregnancies drink more subsequent to the pregnancy than women who give birth, including women who give birth after seeking to terminate a pregnancy. METHODS: Data are from the Turnaway Study, a prospective, longitudinal study of 956 women who sought to terminate pregnancies at 30 U.S. facilities. This paper focuses on the 452 women who received terminations just below facility gestational limits and 231 who were denied terminations because they presented just beyond facility gestational limits. This study examined whether baseline characteristics moderate the relationship between termination and subsequent binge drinking and whether stress, feelings about the pregnancy, and number of social roles mediate the relationship. RESULTS: Only having had a previous live birth modified the termination-binge drinking relationship. Among women with previous live births, binge drinking was reduced among women carrying to term compared to terminating the pregnancy. Among women who had not had a previous live birth, however, the reduction in binge drinking among those denied termination was not sustained over time, and binge drinking of those who had and had not had terminations converged by 2.5 years. Neither stress, negative emotions, nor social roles mediated effects on binge drinking. Positive emotions at one week mediated effects on binge drinking at six months, although positive emotions at two years did not mediate effects on binge drinking at 2.5 years. CONCLUSIONS: Higher levels of binge drinking among those who terminate pregnancies do not appear due to stress or to negative emotions. Only parous women - and not nulliparous women - denied terminations experienced sustained reductions in binge drinking over time. PMID- 26747418 TI - A novel ELISA using a recombinant outer membrane protein, rTp0663, as the antigen for serological diagnosis of syphilis. AB - BACKGROUND: The lack of Treponema pallidum-specific antigens with highly accurate diagnosis makes the diagnosis of syphilis challenging. METHODS: A soluble recombinant version of a new diagnostic protein Tp0663 has been produced. The serodiagnostic potential of this protein was assessed by screening 3326 serum samples simultaneously evaluated by rapid plasma reagin and T. pallidum particle agglutination tests. Kappa (kappa) coefficients were used to compare the concordance between clinical diagnosis and the Tp0663-based ELISA or the ARCHITECT Syphilis TP chemiluminescent immunoassay (Abbott GmbH and Co. KG). RESULTS: Using the results of clinical diagnosis as the gold standard, the sensitivity and specificity of Tp0663 were found to be 98.83% (95% confidence interval (CI) 96.61-99.60%) and 100% (95% CI 99.88-100%), respectively. In comparison, the ARCHITECT Syphilis TP assay was found to have a lower sensitivity (97.27%, 95% CI 94.46-98.67%) and specificity (99.61%, 95% CI 99.32-99.78%). In particular, the ARCHITECT Syphilis TP exhibited a false-positive rate of 0.39%. Moreover, the ELISA was in perfect agreement with the gold standard, with a kappa value of 0.99, comparable to that of ARCHITECT Syphilis TP (0.96). CONCLUSION: These results identified Tp0663 as a novel serodiagnostic candidate with great potential for developing novel tests for the diagnosis of syphilis. PMID- 26747420 TI - Association between Bone Mass and Dental Hypomineralization. AB - The aim of this study was to examine the association between the bone mass (bone mineral content [BMC]) and hypomineralized second primary molars (HSPMs)/molar incisor hypomineralization (MIH) in 6-y-old children. This cross-sectional study was embedded in the Generation R Study, a population-based prospective cohort study, starting from fetal life until adulthood in Rotterdam, Netherlands. The European Academy of Pediatric Dentistry criteria were used to score the intraoral photographs on the presence or absence of HSPMs and MIH. Bone mass was measured with a dual-energy x-ray absorptiometry (DXA) scan. Intraoral photographs and DXA scans were available in 6,510 6-y-old children. Binary logistic regression models were used to study the association between the bone mass and HSPMs/MIH. In total, 5,586 children had their second primary molars assessed and a DXA scan made; 507 children were diagnosed with HSPM. Of 2,370 children with data on their permanent first molars, 203 were diagnosed with MIH. In the fully adjusted model, children with lower BMC (corrected for bone area) were more likely to have HSPMs (odds ratio, 1.13; 95% confidence interval, 1.02 to 1.26 per 1-standard deviation decrease). A lower BMC (corrected for bone area) was not associated with MIH (odds ratio, 1.02; 95% confidence interval, 0.87 to 1.20 per 1-standard deviation decrease). We observed a negative association between BMC (corrected for bone area) and HSPMs. No association was found between BMC (corrected for bone area) and MIH. Future research should focus on investigating the mechanism underlying the negative association between the bone mass and HSPMs. Our study, in a large population of 6-y-old children, adds the finding that BMC (corrected for bone size) is associated with HSPMs but not with MIH in childhood. PMID- 26747421 TI - Probiotic Compared with Standard Milk for High-caries Children: A Cluster Randomized Trial. AB - The aim of this study was to compare milk supplemented with probiotic lactobacilli with standard milk for the increment of caries in preschool children after 10 mo of intervention. The study was a triple-blind, placebo-controlled randomized trial. Participants were children aged 2 and 3 y (n = 261) attending 16 nursery schools in a metropolitan region in Chile. Nursery schools were randomly assigned to 2 parallel groups: children in the intervention group were given 150 mL of milk supplemented with Lactobacillus rhamnosus SP1 (10(7) CFU/mL), while children in the control group were given standard milk. Interventions took place on weekdays for 10 mo. Data were collected through a clinical examination of participants. The primary outcome measure was the increment of caries in preschool children. This was assessed using the International Caries Detection and Assessment System (ICDAS). The dropout rate was 21%. No differences in caries prevalence were detected between the groups at baseline (P = 0.68). After 10 mo of probiotic intake, the caries prevalence was 54.4% in the probiotic group and 65.8% in the control group. The percentage of new individuals who developed cavitated lesions (ICDAS 5-6) in the control group (24.3%) was significantly higher than that in the probiotic group (9.7%). The increment of dental caries showed an odds ratio of 0.35 (P < 0.05) in favor of the probiotic group. At the cavitated lesion level, the increment of new caries lesions within the groups showed 1.13 new lesions per child in the probiotic group compared with 1.75 lesions in the control group (P < 0.05). The probiotic group showed an increment of 0.58 +/- 1.17 new lesions compared with 1.08 +/- 1.70 new lesions observed in the control group. The difference in caries increment was significant at the cavitated lesion level (P < 0.01). In conclusion, the regular long-term intake of probiotic-supplemented milk may reduce caries development in high-caries preschool children (ClinicalTrials.gov: NCT01648075). PMID- 26747423 TI - Letter to the Editor, "The Role of Membrane Attack Complex Formation against Gram positive Bacteria". PMID- 26747422 TI - Innate Immunity and Saliva in Candida albicans-mediated Oral Diseases. AB - The oral cavity is a unique niche where Candida albicans infections occur in immunocompetent as well as immunosuppressed individuals. Here we critically review the significance of human innate immune response in preventing oral candidiasis. One important line of defense against oropharyngeal candidiasis is the oral microbiota that prevents infection by competing for space and nutrients as well as by secreting antagonistic molecules and triggering local inflammatory responses. C. albicans is able to induce mucosal defenses through activation of immune cells and production of cytokines. Also, saliva contains various proteins that affect C. albicans growth positively by promoting mucosal adherence and negatively through immune exclusion and direct fungicidal activity. We further discuss the role of saliva in unifying host innate immune defenses against C. albicans as a communicating medium and how C. albicans overgrowth in the oral cavity may be a result of aberrations ranging from microbial dysbiosis and salivary dysfunction to epithelial damage. Last we underscore select oral diseases in which C. albicans is a contributory microorganism in immune-competent individuals. PMID- 26747424 TI - Response to Letter to the Editor, "The Role of Membrane Attack Complex Formation against Gram-positive Bacteria". PMID- 26747426 TI - Urinary beta-galactosidase stimulates Ca2+ transport by stabilizing TRPV5 at the plasma membrane. AB - Transcellular Ca(2+)transport in the late distal convoluted tubule and connecting tubule (DCT2/CNT) of the kidney is a finely controlled process mediated by the transient receptor potential vanilloid type 5 (TRPV5) channel. A complex-type-N glycan bound at the extracellular residue Asn358 of TRPV5 through post translational glycosylation has been postulated to regulate the activity of TRPV5 channels. Using in vitro Ca(2+)transport assays, immunoblot analysis, immunohistochemistry, patch clamp electrophysiology and total internal reflection fluorescence microscopy, it is demonstrated that the glycosidase beta galactosidase (beta-gal), an enzyme that hydrolyzes galactose, stimulates TRPV5 channel activity. However, the activity of the non-glycosylated TRPV(N358Q)mutant was not altered in the presence of beta-gal, showing that the stimulation is dependent on the presence of the TRPV5N-glycan. In addition, beta-gal was found to stimulate transcellular Ca(2+)transport in isolated mouse primary DCT2/CNT cells. beta-gal expression was detected in the apical membrane of the proximal tubules, and the protein was found in mouse urine. In summary, beta-gal is present in the pro-urine from where it is thought to stimulate TRPV5 activity. PMID- 26747425 TI - Galectins are human milk glycan receptors. AB - The biological recognition of human milk glycans (HMGs) is poorly understood. Because HMGs are rich in galactose we explored whether they might interact with human galectins, which bind galactose-containing glycans and are highly expressed in epithelial cells and other cell types. We screened a number of human galectins for their binding to HMGs on a shotgun glycan microarray consisting of 247 HMGs derived from human milk, as well as to a defined HMG microarray. Recombinant human galectins (hGal)-1, -3, -4, -7, -8 and -9 bound selectively to glycans, with each galectin recognizing a relatively unique binding motif; by contrast hGal-2 did not recognize HMGs, but did bind to the human blood group A Type 2 determinants on other microarrays. Unlike other galectins, hGal-7 preferentially bound to glycans expressing a terminal Type 1 (Galbeta1-3GlcNAc) sequence, a motif that had eluded detection on non-HMG glycan microarrays. Interactions with HMGs were confirmed in a solution setting by isothermal titration microcalorimetry and hapten inhibition experiments. These results demonstrate that galectins selectively bind to HMGs and suggest the possibility that galectin HMG interactions may play a role in infant immunity. PMID- 26747427 TI - Comparison of biological activities of human antithrombins with high-mannose or complex-type nonfucosylated N-linked oligosaccharides. AB - The structure of the N-linked oligosaccharides attached to antithrombin (AT) has been shown to affect its anticoagulant activity and pharmacokinetics. Human AT has biantennary complex-type oligosaccharides with the unique feature of lacking a core fucose, which affects its biological activities by changing its heparin binding affinity. In human plasma, AT circulates as a mixture of the alpha-form bearing four oligosaccharides and the beta-form lacking an oligosaccharide at Asn135. However, it remains unclear how the immature high-mannose-type oligosaccharides produced by mammalian cells affect biological activities of AT. Here, we succeeded in directly comparing the activities between the high-mannose and complex types. Interestingly, although there were no substantial differences in thrombin inhibitory activity, the high-mannose type showed higher heparin binding affinity. The anticoagulant activities were increased by heparin and correlated with the heparin-binding affinity, resulting in the strongest anticoagulant activity being displayed in the beta-form with the high-mannose type. In pharmacokinetic profiling, the high-mannose type showed a much shorter plasma half-life than the complex type. The beta-form was found to have a prolonged plasma half-life compared with the alpha-form for the high-mannose type; conversely, the alpha-form showed a longer half-life than the beta-form for the complex-type. The present study highlights that AT physiological activities are strictly controlled not only by a core fucose at the reducing end but also by the high-mannose-type structures at the nonreducing end. The beta-form with the immature high-mannose type appears to function as a more potent anticoagulant than the AT typically found in human plasma, once it emerges in the blood. PMID- 26747431 TI - Three-dimensional analysis of the accuracy of optic and electromagnetic navigation systems using surface registration in live endoscopic sinus surgery. AB - BACKGROUND: This study presents the first report in the same patients on the time efficiency of surface registration as well as the navigational accuracy using optic and electromagnetic tracking systems. METHODS: Thirty patients with bilateral chronic paranasal pansinusitis underwent endoscopic sinus surgery. After surface registration, the surgeries were performed on one side using optic navigation guidance and on the other side using electromagnetic navigation guidance. The intraoperative measurements performed included the time taken for the surface registration and surgical procedure on each side, as well as the navigation errors at the different locations. RESULTS: The time for surface registration was significantly longer in the optic navigation group than the electromagnetic group. A comparison of the navigation errors along the 3 axes showed that the deviation in the medial-lateral direction was significantly less than that in the anterior-posterior and cranial-caudal directions in the optic navigation group as well as the electromagnetic group. CONCLUSIONS: The procedure for surface registration in both optic and electromagnetic guidance is efficient and convenient. The accuracy of both navigation systems is comparable and within acceptable ranges for clinical use. In addition, the best accuracy was measured in the medial-lateral direction compared with the other two axes. PMID- 26747430 TI - Improvement in Agrobacterium-mediated transformation of chickpea (Cicer arietinum L.) by the inhibition of polyphenolics released during wounding of cotyledonary node explants. AB - Agrobacterium-mediated transformation of chickpea (Cicer arietinum L.) has been performed using cotyledonary node explants (CNs), which release phenolics upon excision that are detrimental to the viability of Agrobacterium tumefaciens and result in low transformation frequency. Twelve low molecular weight phenolic compounds and salicylic acid were identified in the exudates released upon excision during the preparation of cotyledonary nodes by reverse phase high performance liquid chromatography (RP-HPLC). Zone inhibition assays performed with the explant exudates released at periodic intervals after excision showed the inhibition of A. tumefaciens. Agroinoculation of freshly excised cotyledonary nodes of chickpea showed 98-99 % inhibition of colony forming units (cfu). Osmium tetraoxide fixation of excised tissues showed enhanced accumulation of phenolics in the sub-epidermal regions causing enzymatic browning, affecting the viability and performance of A. tumefaciens for T-DNA delivery. The periodic analysis of exudates released from excised CNs showed enhanced levels of gallic acid (0.2945 +/- 0.014 MUg/g), chlorogenic acid (0.0978 +/- 0.0046 MUg/g), and quercetin (0.0971 +/- 0.0046 MUg/g) fresh weight, which were detrimental to A. tumefaciens. Quantitative assays and the elution profile showed the maximum leaching of phenolics, flavonoids, and salicylic acid immediately after the excision of explants and continued till 4 to 8 h post-excision. Pre-treatment of excised explants with inhibitors of polyphenol oxidase like L-cysteine, DTT, and sodium thiosulfate before co-cultivation showed the recovery of A. tumefaciens cfu, decreased the accumulation of phenolics, and improved transformation frequency. Our results show the hypersensitive response of excision stress for the expression of defense response-related genes and synthesis of metabolites in grain legume chickpea against pathogen infestation including Agrobacterium. PMID- 26747432 TI - Targeted exercise for muscles that support the spine reduces low back pain, Cochrane review shows. PMID- 26747433 TI - Congenital anatomic variants of the kidney and ureter: a pictorial essay. AB - Congenital renal parenchymal and pelvicalyceal abnormalities have a wide spectrum. Most of them are asymptomatic, like that of ectopia, cross fused kidney, horseshoe kidney, etc., while a few of them become complicated, leading to renal failure and death. It is very important for the radiologist to identify these anatomic variants and guide the clinicians for surgical and therapeutic procedures. Cross-sectional imaging with a volume rendered technique/maximum intensity projection has overcome ultrasonography and IVU for identification and interpretation of some of these variants. PMID- 26747435 TI - Ventricular asynchrony: A shift to the right? PMID- 26747434 TI - Facile and cost-effective production of microscale PDMS architectures using a combined micromilling-replica moulding (MUMi-REM) technique. AB - We describe a cost-effective and simple method to fabricate PDMS-based microfluidic devices by combining micromilling with replica moulding technology. It relies on the following steps: (i) microchannels are milled in a block of acrylic; (ii) low-cost epoxy adhesive resin is poured over the milled acrylic block and allowed to cure; (iii) the solidified resin layer is peeled off the acrylic block and used as a mould for transferring the microchannel architecture onto a PDMS layer; finally (iv) the PDMS layer is plasma bonded to a glass surface. With this method, microscale architectures can be fabricated without the need for advanced technological equipment or laborious and time-consuming intermediate procedures. In this manuscript, we describe and validate the microfabrication procedure, and we illustrate its applicability to emulsion and microbubble production. PMID- 26747436 TI - Statin impact on disease activity and C-reactive protein concentrations in systemic lupus erythematosus patients: A systematic review and meta-analysis of controlled trials. AB - BACKGROUND AND PURPOSE: Efficacy and safety of statin therapy in patients with systemic lupus erythematosus (SLE) is controversial. The aim of this meta analysis was to evaluate whether statin therapy affects SLE disease activity and systemic inflammation (C-reactive protein, CRP) according to the evidence from controlled clinical trials. EXPERIMENTAL APPROACH: A systematic review followed by a bibliographic search in Medline and SCOPUS (up to March 2015) was performed. Quantitative data synthesis was performed using a random-effects model and the generic inverse variance weighting method. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI). KEY RESULTS: Meta-analysis of five controlled trials reporting statin impact on SLE disease activity did not suggest any significant effect of statin therapy on SLEDAI. Evaluation of seven controlled trials with reported effects on CRP levels suggested a significant reduction of plasma CRP concentrations in patients with SLE independent of the treatment duration. The effect size on plasma CRP concentrations was significant with lipophilic (atorvastatin) but not hydrophilic (pravastatin and rosuvastatin) statins. CONCLUSION AND IMPLICATIONS: The present results suggest that statin therapy is likely to be safe in patients with SLE. In addition, statin-treated SLE patients may benefit from CRP reduction in terms of managing severe cardiovascular complications associated with the disease. PMID- 26747437 TI - Organic UV Filters in the Surface Water of Nanjing, China: Occurrence, Distribution and Ecological Risk Assessment. AB - Organic UV filters (OUV-Fs) are increasingly used for protection against UV irradiation. The widespread occurrence of OUV-Fs residues in aquatic systems has been reported, but little is known regarding their distribution and potential impact to the surface water in China. This study reports the occurrence, distribution and risk assessment of eight widely used OUV-Fs in the surface water of Nanjing. The results indicated butyl-methoxydibenzoylmethane, octyl-dimethyl PABA and benzophenone-types (BP3, BP4 and BP1) were the most frequently detected compounds at concentrations of 3.63-104 ng/L. In general, the concentrations of OUV-Fs were decreased along the rivers; however, due to a substantial pollution load from the tributaries, higher concentrations of OUV-Fs were observed near the tributary inlet, compared to the other study areas. The risk assessment based on the calculated risk quotients (RQs) demonstrated that all OUV-Fs posed at least low risks to certain sensitive aquatic organisms, and BP3 posed high risk with RQ values of 1.64. It should be noted that the exclusion of adsorbed OUV-Fs might have contributed to an underestimation of the risk, therefore, it's necessary to assess both adsorbed and dissolved OUV-Fs in further studies. PMID- 26747440 TI - Immobilization of horseradish peroxidase onto kaolin. AB - Kaolin showed as a very perspective carrier for the enzyme immobilization and it was used for the adsorption of horseradish peroxidase (HRP). The effects of the enzyme concentration and pH on the immobilization efficiency were studied in the reaction with pyrogallol and anthraquinone dye C.I. Acid Violet 109 (AV 109). In addition, Fourier transform infrared spectroscopy, scanning electron microscopy and analysis by Brunauer-Emmett-Teller were performed for kaolin, thermally activated kaolin and the immobilized enzyme. It has been shown that 0.1 IU of HRP kaolin decolorized 87 % of dye solution, under the optimal conditions (pH 5.0, temperature 24 degrees C, dye concentration 40 mg/L and 0.2 mM of H2O2) within 40 min. The immobilized HRP decolorization follows the Ping Pong Bi-Bi mechanism with dead-end inhibition by the dye. The biocatalyst retained 35 +/- 0.9 % of the initial activity after seven cycles of reuse in the decolorization reaction of AV 109 under optimal conditions in a batch reactor. The obtained kinetic parameters and reusability study confirmed improvement in performances of k-HRP compared to free, indicating that k-HRP has a great potential for environmental purposes. PMID- 26747438 TI - Long-term outcome and chest pain in patients with true versus non-true bifurcation lesions treated with second-generation drug-eluting stents in the TWENTE trial. AB - The objective of this study is to assess 3-year clinical outcome of patients with true bifurcation lesions (TBLs) versus non-true bifurcation lesions (non-TBLs) following treatment with second-generation drug-eluting stents (DES). TBLs are characterized by the obstruction of both main vessel and side-branch. Limited data are available on long-term clinical outcome following TBL treatment with newer-generation DES. We performed an explorative sub-study of the randomized TWENTE trial among 287 patients who had bifurcated target lesions with side branches >=2.0 mm. Patients were categorized into TBL (Medina classes: 1.1.1; 1.0.1; 0.1.1) versus non-TBL to compare long-term clinical outcome. A total of 116 (40.4 %) patients had TBL, while 171 (59.6 %) had non-TBL only. Target-lesion revascularization rates were similar (3.5 vs. 3.5 %; p = 1.0), and definite-or probable stent thrombosis rates were low (both <1.0 %). The target-vessel myocardial infarction (MI) rate was 11.3 versus 5.3 % (p = 0.06), mostly driven by (periprocedural) MI <=48 h from PCI. All-cause mortality and cardiac death rates were 8.7 versus 3.5 % (p = 0.06) and 3.5 versus 1.2 % (p = 0.22), respectively. The 3-year major adverse cardiac event rate for patients with TBL versus non-TBL was 20.0 versus 11.7 % (p = 0.05). At 1-, 2-, and 3-year follow up, 6.5, 13.0, and 11.0 % of patients reported chest pain at less than or equal moderate physical effort, respectively, without any between-group difference. Patients treated with second-generation DES for TBL had somewhat higher adverse event rates than patients with non-TBL, but dissimilarities did not reach statistical significance. Up to 3-year follow-up, the vast majority of patients of both groups remained free from chest pain. PMID- 26747439 TI - Endomyocardial fibrosis: missing tricuspid valve and Fontan-like circulation. AB - Endomyocardial fibrosis (EMF) is a progressive type of obliterative/restrictive cardiomyopathy characterized by fibrosis of the apical endomyocardium of the ventricles. Although the prognosis of EMF patients is poor in tropical regions, the exact clinical course and pathogenesis of patients with EMF are not known. Here, we report the rare case with EMF in the seventh decade, who showed the disappearance of papillary muscles, chordae tendineae, and part of the tricuspid valves due to massive right ventricular thrombus. Because of those unusual findings of the isolated RV involvement, we observed continuous forward pulmonary artery flow, as occurring in a Fontan circulation. PMID- 26747441 TI - Cost-effective copper removal by electrosorption powered by microbial fuel cells. AB - This work studied a cost-effective electrosorption that driven by microbial fuel cells (MFC-sorption) to remove Cu(2+) from wastewater without an external energy supply. The impact factors, adsorption isotherms and kinetics of the novel process were investigated. It indicated that a low electrolyte concentration and a high solution pH could enhance the Cu(2+) removal efficiency, while the adsorption capacity increased with the increase of numbers of MFCs in series and the initial Cu(2+) concentration. The adsorption isotherms study indicated that the monolayer adsorption in MFC-sorption was dominant. The kinetics study suggested the increase of initial Cu(2+) concentration could enhance the initial adsorption rate. The electrode characterizations verified the existence of Cu2O and Cu on the electrode surface of active carbon fibers (ACFs), suggesting that MFC-sorption was not only an adsorption process, but also a redox reaction process. PMID- 26747442 TI - Reclassification of Wolbachia persica as Francisella persica comb. nov. and emended description of the family Francisellaceae. AB - The taxonomic status of the bacterium Wolbachia persica is described, and based on the evidence presented, transfer of this species to the genus Francisella as Francisella persica comb. nov. is proposed. This reclassification is supported by data generated from genomic comparisons of W. persica ATCC VR-331T ( = FSC845T = DSM 101678T) to other near neighbours, including Francisella tularensis subsp. novicida. The full-length 16S rRNA gene sequence of strain ATCC VR-331T had 98.5 % nucleotide identity to the cognate gene in F. tularensis, with the highest similarity to subspecies novicida. Phylogenetic trees of full-length 16S rRNA gene, gyrA and recA sequences from species of the genera Wolbachia (class Alphaproteobacteria) and Francisella (class Gammaproteobacteria) indicated that W. persica ATCC VR-331T was most closely related to members of the genus Francisella and not Wolbachia. Local collinear blocks within the chromosome of strain ATCC VR-331T had considerable similarity with F. tularensis subsp. novicida, but not with any Wolbachia strain. The genomes of strain ATCC VR-331T and F. tularensis subsp. novicida Utah 112T ( = ATCC 15482T) contained an average nucleotide identity mean of 88.72 % and median of 89.18 %. Importantly, the genome of strain ATCC VR-331T contained one Francisella Pathogenicity Island, similar to F. tularensis subsp. novicida, as well as the Francisella-specific gene fopA1 and F. tularensis-specific genes fopA2 and lpnA (also referred to as tul4). In contrast to the obligate intracellular genus Wolbachia, strain ATCC VR 331T and facultative intracellular Francisella can replicate in specialized cell free media. Collectively, these results demonstrate that Wolbachia persica should be reclassified in the genus Francisella as Francisella persica comb. nov. The type strain of Francisella persica comb. nov. is ATCC VR-331T ( = FSC845T = DSM 101678T). An emended description of the family Francisellaceae is also provided. PMID- 26747444 TI - Numerical simulations of multicomponent ecological models with adaptive methods. AB - BACKGROUND: The study of dynamic relationship between a multi-species models has gained a huge amount of scientific interest over the years and will continue to maintain its dominance in both ecology and mathematical ecology in the years to come due to its practical relevance and universal existence. Some of its emergence phenomena include spatiotemporal patterns, oscillating solutions, multiple steady states and spatial pattern formation. METHODS: Many time dependent partial differential equations are found combining low-order nonlinear with higher-order linear terms. In attempt to obtain a reliable results of such problems, it is desirable to use higher-order methods in both space and time. Most computations heretofore are restricted to second order in time due to some difficulties introduced by the combination of stiffness and nonlinearity. Hence, the dynamics of a reaction-diffusion models considered in this paper permit the use of two classic mathematical ideas. As a result, we introduce higher order finite difference approximation for the spatial discretization, and advance the resulting system of ODE with a family of exponential time differencing schemes. We present the stability properties of these methods along with the extensive numerical simulations for a number of multi-species models. RESULTS: When the diffusivity is small many of the models considered in this paper are found to exhibit a form of localized spatiotemporal patterns. Such patterns are correctly captured in the local analysis of the model equations. An extended 2D results that are in agreement with Turing typical patterns such as stripes and spots, as well as irregular snakelike structures are presented. We finally show that the designed schemes are dynamically consistent. CONCLUSION: The dynamic complexities of some ecological models are studied by considering their linear stability analysis. Based on the choices of parameters in transforming the system into a dimensionless form, we were able to obtain a well-balanced system that is biologically meaningful. The accuracy and reliability of the schemes are justified via the computational results presented for each of the diffusive multi species models. PMID- 26747443 TI - Opportunistic Neurologic Infections in Patients with Acquired Immunodeficiency Syndrome (AIDS). AB - Infections of the central nervous system (CNS) in individuals with human immunodeficiency virus (HIV) remain a substantial cause of morbidity and mortality despite the introduction of highly active antiretroviral therapy (HAART) especially in the resource-limited regions of the world. Diagnosis of these infections may be challenging because findings on cerebrospinal fluid (CSF) analysis and brain imaging are nonspecific. While brain biopsy provides a definitive diagnosis, it is an invasive procedure associated with a relatively low mortality rate, thus less invasive modalities have been studied in recent years. Diagnosis, therefore, can be established based on a combination of a compatible clinical syndrome, radiologic and CSF findings, and understanding of the role of HIV in these infections. The most common CNS opportunistic infections are AIDS-defining conditions; thus, treatment of these infections in combination with HAART has greatly improved survival. PMID- 26747445 TI - Paper-Based Quantification of Male Fertility Potential. AB - BACKGROUND: More than 70 million couples worldwide are affected by infertility, with male-factor infertility accounting for about half of the cases. Semen analysis is critical for determining male fertility potential, but conventional testing is costly and complex. Here, we demonstrate a paper-based microfluidic approach to quantify male fertility potential, simultaneously measuring 3 critical semen parameters in 10 min: live and motile sperm concentrations and sperm motility. METHODS: The device measures the colorimetric change of yellow tetrazolium dye to purple formazan by the diaphorase flavoprotein enzyme present in metabolically active human sperm to quantify live and motile sperm concentration. Sperm motility was determined as the ratio of motile to live sperm. We assessed the performance of the device by use of clinical semen samples, in parallel with standard clinical approaches. RESULTS: Detection limits of 8.46 and 15.18 million/mL were achieved for live and motile sperm concentrations, respectively. The live and motile sperm concentrations and motility values from our device correlated with those of the standard clinical approaches (R(2) >= 0.84). In all cases, our device provided 100% agreement in terms of clinical outcome. The device was also robust and could tolerate conditions of high absolute humidity (22.8 g/m(3)) up to 16 weeks when packaged with desiccant. CONCLUSIONS: Our device outperforms existing commercial paper based assays by quantitatively measuring live and motile sperm concentrations and motility, in only 10 min. This approach is applicable to current clinical practices as well as self-diagnostic applications. PMID- 26747446 TI - Pharmacists in the Laboratory Space: Friends or Foes? PMID- 26747447 TI - The mysterious orphans of Mycoplasmataceae. AB - BACKGROUND: The length of a protein sequence is largely determined by its function. In certain species, it may be also affected by additional factors, such as growth temperature or acidity. In 2002, it was shown that in the bacterium Escherichia coli and in the archaeon Archaeoglobus fulgidus, protein sequences with no homologs were, on average, shorter than those with homologs (BMC Evol Biol 2:20, 2002). It is now generally accepted that in bacterial and archaeal genomes the distributions of protein length are different between sequences with and without homologs. In this study, we examine this postulate by conducting a comprehensive analysis of all annotated prokaryotic genomes and by focusing on certain exceptions. RESULTS: We compared the distribution of lengths of "having homologs proteins" (HHPs) and "non-having homologs proteins" (orphans or ORFans) in all currently completely sequenced and COG-annotated prokaryotic genomes. As expected, the HHPs and ORFans have strikingly different length distributions in almost all genomes. As previously established, the HHPs, indeed are, on average, longer than the ORFans, and the length distributions for the ORFans have a relatively narrow peak, in contrast to the HHPs, whose lengths spread over a wider range of values. However, about thirty genomes do not obey these rules. Practically all genomes of Mycoplasma and Ureaplasma have atypical ORFans distributions, with the mean lengths of ORFan larger than the mean lengths of HHPs. These genera constitute over 80 % of atypical genomes. CONCLUSIONS: We confirmed on a ubiquitous set of genomes that the previous observation of HHPs and ORFans have different gene length distributions. We also showed that Mycoplasmataceae genomes have very distinctive distributions of ORFans lengths. We offer several possible biological explanations of this phenomenon, such as an adaptation to Mycoplasmataceae's ecological niche, specifically its "quiet" co existence with host organisms, resulting in long ABC transporters. PMID- 26747448 TI - No Significant Evidence of Cognitive Biases for Emotional Stimuli in Children At Risk of Developing Anxiety Disorders. AB - This paper explores whether the increased vulnerability of children of anxious parents to develop anxiety disorders may be partially explained by these children having increased cognitive biases towards threat compared with children of non anxious parents. Parents completed questionnaires about their child's anxiety symptoms. Children aged 5-9 (n = 85) participated in two cognitive bias tasks: 1) an emotion recognition task, and 2) an ambiguous situations questionnaire. For the emotion recognition task, there were no significant differences between at risk children and children of non-anxious parents in their cognitive bias scores for reaction times or for accuracy in identifying angry or happy facial expressions. In addition, there were no significant differences between at-risk children and children of non-anxious parents in the number of threat interpretations made for the ambiguous situations questionnaire. It is possible that these cognitive biases only become present subsequent to the development of an anxiety disorder, or only in older at-risk children. PMID- 26747449 TI - Longitudinal and Incremental Relation of Cybervictimization to Negative Self Cognitions and Depressive Symptoms in Young Adolescents. AB - Adolescents are among the most frequent users of social media websites, raising concern about the dangers of cyber bullying or cybervictimization (CV). A 12 month longitudinal study examined the unique, prospective relation of CV to the development of negative self-cognitions and depressive symptoms in a community sample of 827 children and young adolescents (ages 8-13; 55.1 % female) from the southeastern United States. Over and above conventional types of peer victimization, CV significantly predicted changes in self-referential negative cognitions, victimization-related cognitive reactions, and depressive symptoms, even after controlling for baseline levels of the dependent variables. Results also showed that CV was significantly less stable than other forms of victimization and tended to increase slightly with time. The study highlights the unique effects of CV and has implications for research and practice. PMID- 26747450 TI - Early Childhood Precursors and School age Correlates of Different Internalising Problem Trajectories Among Young Children. AB - It is unclear why trajectories of internalising problems vary between groups of young children. This is the first attempt in the United Kingdom to identify and explain different trajectories of internalising problems from 46 to 94 months. Using both mother- and child-reported data from the large Growing Up in Scotland (GUS) birth cohort (N = 2901; male N = 1497, female N = 1404), we applied growth mixture modelling and multivariable multinomial regression models. Three trajectories were identified: low-stable, high-decreasing and medium-increasing. There were no gender differences in trajectory shape, membership, or importance of covariates. Children from both elevated trajectories shared several early risk factors (low income, poor maternal mental health, poor partner relationship, pre school behaviour problems) and school-age covariates (low mother-child warmth and initial school maladjustment) and reported fewer supportive friendships at 94 months. However, there were also differences in covariates between the two elevated trajectories. Minority ethnic status and pre-school conduct problems were more strongly associated with the high-decreasing trajectory; and covariates measured after school entry (behaviour problems, mother-child conflict and school maladjustment) with the medium-increasing trajectory. This suggests a greater burden of early risk for the high-decreasing trajectory, and that children with moderate early problem levels were more vulnerable to influences after school transition. Our findings largely support the sparse existing international evidence and are strengthened by the use of child-reported data. They highlight the need to identify protective factors for children with moderate, as well as high, levels of internalising problems at pre-school age, but suggest different approaches may be required. PMID- 26747451 TI - HybriFree: a robust and rapid method for the development of monoclonal antibodies from different host species. AB - BACKGROUND: The production of recombinant monoclonal antibodies in mammalian cell culture is of high priority in research and medical fields. A critical step in this process is the isolation of the antigen-binding domain sequences of antibodies possessing the desired properties. Many different techniques have been described to achieve this goal, but all have shortcomings; most techniques have problems with robustness, are time-consuming and costly, or have complications in the transfer from isolation to production phase. Here, we report a novel HybriFree technology for the development of monoclonal antibodies from different species that is robust, rapid, inexpensive and flexible and can be used for the subsequent production of antibodies in mammalian cell factories. RESULTS: HybriFree technology is illustrated herein via detailed examples of isolating mouse, rabbit and chicken monoclonal antibody sequences from immunized animals. Starting from crude spleen samples, antigen capturing of specific B-cells is performed initially. cDNA of antibody variable domains is amplified from the captured cells and used a source material for simple and rapid restriction/ligation free cloning of expression vector library in order to produce scFv-Fc or intact IgG antibodies. The vectors can be directly used for screening purposes as well as for the subsequent production of the developed monoclonal antibodies in mammalian cell culture. The antibodies isolated by the method have been shown to be functional in different immunoassays, including ELISA, immunofluorescence and Western blot. In addition, we demonstrate that by using a modified method including a negative selection step, we can isolate specific antibodies targeting the desired epitope and eliminate antibodies directed to undesired off-targets. CONCLUSIONS: HybriFree can be used for the reliable development of monoclonal antibodies and their subsequent production in mammalian cells. This simple protocol requires neither the culturing of B-cells nor single-cell manipulations, and only standard molecular biology laboratory equipment is needed. In principle, the method is applicable to any species for which antibody cDNA sequence information is available. PMID- 26747454 TI - Applicability of a Single Time Point Strategy for the Prediction of Area Under the Concentration Curve of Linezolid in Patients: Superiority of Ctrough- over Cmax-Derived Linear Regression Models. AB - BACKGROUND AND OBJECTIVES: Linezolid, a oxazolidinone, was the first in class to be approved for the treatment of bacterial infections arising from both susceptible and resistant strains of Gram-positive bacteria. Since overt exposure of linezolid may precipitate serious toxicity issues, therapeutic drug monitoring (TDM) may be required in certain situations, especially in patients who are prescribed other co-medications. METHODS: Using appropriate oral pharmacokinetic data (single dose and steady state) for linezolid, both maximum plasma drug concentration (Cmax) versus area under the plasma concentration-time curve (AUC) and minimum plasma drug concentration (Cmin) versus AUC relationship was established by linear regression models. The predictions of the AUC values were performed using published mean/median Cmax or Cmin data and appropriate regression lines. The quotient of observed and predicted values rendered fold difference calculation. The mean absolute error (MAE), root mean square error (RMSE), correlation coefficient (r), and the goodness of the AUC fold prediction were used to evaluate the two models. RESULTS: The Cmax versus AUC and trough plasma concentration (Ctrough) versus AUC models displayed excellent correlation, with r values of >0.9760. However, linezolid AUC values were predicted to be within the narrower boundary of 0.76 to 1.5-fold by a higher percentage by the Ctrough (78.3%) versus Cmax model (48.2%). The Ctrough model showed superior correlation of predicted versus observed values and RMSE (r = 0.9031; 28.54%, respectively) compared with the Cmax model (r = 0.5824; 61.34%, respectively). CONCLUSIONS: A single time point strategy of using Ctrough level is possible as a prospective tool to measure the AUC of linezolid in the patient population. PMID- 26747457 TI - A renewed challenge. PMID- 26747453 TI - Current and Emerging Therapies for the Treatment of Cystic Fibrosis or Mitigation of Its Symptoms. AB - Clinical presentation of the chronic, heritable condition cystic fibrosis (CF) is complex, with a diverse range of symptoms often affecting multiple organs with varying severity. The primary source of morbidity and mortality is due to progressive destruction of the airways attributable to chronic inflammation arising from microbial colonisation. Antimicrobial therapy combined with practises to remove obstructive mucopurulent deposits form the cornerstone of current therapy. However, new treatment options are emerging which offer, for the first time, the opportunity to effect remission from the underlying cause of CF. Here, we discuss these therapies, their mechanisms of action, and their successes and failures in order to illustrate the shift in the nature of how CF will likely be managed into the future. PMID- 26747452 TI - Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer. AB - BACKGROUND: While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). METHODS: The primary patient set (Set 1) included 14 independent EOC studies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta analyses (73,203 variants and 13,163 genes overlapped). RESULTS: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta = 1.1E-6, HRSet1 = 1.17, HRSet2 = 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01). CONCLUSIONS: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. IMPACT: This study represents the first exome-wide association study of EOC survival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446-54. (c)2016 AACR. PMID- 26747455 TI - Comparison of Lactobacillus crispatus isolates from Lactobacillus-dominated vaginal microbiomes with isolates from microbiomes containing bacterial vaginosis associated bacteria. AB - Vaginal lactobacilli can inhibit colonization by and growth of other bacteria, thereby preventing development of bacterial vaginosis (BV). Amongst the lactobacilli, Lactobacillus crispatus appears to be particularly effective at inhibiting growth of BV-associated bacteria. Nonetheless, some women who are colonized with this species can still develop clinical BV. Therefore, we sought to determine whether strains of L. crispatus that colonize women with lactobacilli-dominated vaginal microbiomes are distinct from strains that colonize women who develop BV. The genomes of L. crispatus isolates from four women with lactobacilli-dominated vaginal microbiomes ( <1% 16S rRNA reads above threshold from genera other than Lactobacillus) and four women with microbiomes containing BV-associated bacteria (>12% 16S rRNA reads from bacterial taxa associated with BV) were sequenced and compared. Lactic acid production by the different strains was quantified. Phage induction in the strains was also analysed. There was considerable genetic diversity between strains, and several genes were exclusive to either the strains from Lactobacillus-dominated microbiomes or those containing BV-associated bacteria. Overall, strains from microbiomes dominated by lactobacilli did not differ from strains from microbiomes containing BV-associated bacteria with respect to lactic acid production. All of the strains contained multiple phage, but there was no clear distinction between the presence or absence of BV-associated bacteria with respect to phage-induced lysis. Genes found to be exclusive to the Lactobacillus dominated versus BV-associated bacteria-containing microbiomes could play a role in the maintenance of vaginal health and the development of BV, respectively. PMID- 26747456 TI - Prevalence and determinants of insufficient work ability in older HIV-positive and HIV-negative workers. AB - PURPOSE: To explore whether the prevalence and determinants of insufficient work ability (WA) of older HIV-positive workers differ from a comparable group of HIV negative workers. METHODS: Cross-sectional data from 359 HIV-negative and 264 HIV positive middle-aged individuals (45-65 years) participating in paid labor, collected within the AGEhIV Cohort Study between October 2010-September 2012, were selected. Data were collected by self-administered questionnaires and physical examination. Participants self-rated their current WA, ranging from 0 to 10. WA was dichotomized into insufficient (<6) and sufficient (>=6). Using univariable and multivariable logistic regression, we studied the independent effect of HIV status on insufficient WA and determinants of insufficient WA. RESULTS: Overall, 8% of participants reported insufficient WA (HIV-positive 9 vs. HIV-negative 7%, P = 0.20). Twice as many HIV-positive as HIV-negative individuals were declared partly unfit for work (6 vs. 3%, P = 0.02). HIV status itself was not associated with WA in univariable and multivariable analyses. Multivariable analyses revealed that low educational level, working fewer hours, being partly unfit for work, experiencing a high need for recovery after work, staying home from work >=2 times in the past 6 months, and reporting depressive symptoms were associated with insufficient WA, independent of HIV status. CONCLUSIONS: HIV-positive individuals aged 45-65 years participating in paid labor seem to function as well at work as HIV-negative individuals. HIV-positive participants were more often formally declared partly unfit for work, but percentages were low in both groups. Knowledge of determinants of insufficient WA may help employers and professionals to optimize WA. PMID- 26747458 TI - Single-blind, placebo controlled randomised clinical study of chitosan for body weight reduction. AB - BACKGROUND: Chitosan is a dietary fibre which acts by reducing fat absorption and thus used as a means for controlling weight. Weight loss clinical trial outcomes, however, have contradictory results regarding its efficacy. The primary objective of the present study was to evaluate the efficacy and safety of a chitosan from fungal origin in treatment of excess weight in the absence of dietary restrictions. METHODS: A phase IV, randomised, multicentre, single-blind, placebo controlled, clinical study was conducted by administering chitosan capsules (500 mg, five/day) and indistinguishable placebo capsules as daily supplements to 96 overweight and obese subjects for 90 days. The study participants were divided in 2:1 ratio to receive either chitosan (n = 64) or placebo (n = 32). Efficacy was assessed by measuring body weight, body composition parameters, anthropometric measurements, HbA1C level and lipid profile at day 45 and day 90. Also, short form-36 quality of life (QoL) questionnaire was assessed to evaluate improvement in life-style and dietary habits were recorded for calorie intake. Safety was assessed by evaluating safety parameters and monitoring adverse events. RESULTS: The mean changes in body weight were -1.78 +/- 1.37 kg and -3.10 +/- 1.95 kg at day 45 and day 90 respectively in chitosan group which were significantly different (p < 0.0001) as compared to placebo. BMI was decreased by10.91 fold compared to placebo after 90 day administration. In concert with this, there was also reduction in body composition and anthropometric parameters together with improvement in QoL score. Chitosan was also able to reduce HbA1C levels (below 6 %) in subjects who had initial higher values. The mean caloric intake shows that there was no change in dietary habits of subjects in both groups. Lipid levels were unaffected and all adverse events were mild in nature and unrelated to study treatment. CONCLUSION: Chitosan from fungal origin was able to reduce the mean body weight up to 3 kg during the 90 day study period. Together with this, there was also improvement in body composition, anthropometric parameters and HbA1C, reflecting overall benefits for the overweight individuals. Additionally, there was also improvement in QoL score. It was safe and well tolerated by all subjects. TRIAL REGISTRATION: CTRI/2014/08/004901. PMID- 26747459 TI - Desmoplastic Melanocytic Nevus of Oral Mucosa. AB - The desmoplastic melanocytic nevus is an uncommon variant that easily may be confused with a fibrohistiocytic neoplasm or a desmoplastic melanoma. It is believed that the following report describes the first known example of a desmoplastic melanocytic nevus arising in the oral mucosa. The histopathologic and immunohistochemical features that allow separation from other microscopically similar pathoses are stressed. PMID- 26747461 TI - Collecting standardised urban health indicator data at an individual level for adults living in urban areas: methodology from EURO-URHIS 2. AB - Background: An aim of the EURO-URHIS 2 project was to collect standardised data on urban health indicators (UHIs) relevant to the health of adults resident in European urban areas. This article details development of the survey instruments and methodologies to meet this aim. 32 urban areas from 11 countries conducted the adult surveys. Using a participatory approach, a standardised adult UHI survey questionnaire was developed mainly comprised of previously validated questions, followed by translation and back-translation. An evidence-based survey methodology with extensive training was employed to ensure standardised data collection. Comprehensive UK piloting ensured face validity and investigated the potential for response bias in the surveys. Each urban area distributed 800 questionnaires to age-sex stratified random samples of adults following the survey protocols. Piloting revealed lower response rates in younger males from more deprived areas. Almost 19500 adult UHI questionnaires were returned and entered from participating urban areas. Response rates were generally low but varied across Europe. The participatory approach in development of survey questionnaires and methods using an evidence-based approach and extensive training of partners has ensured comparable UHI data across heterogeneous European contexts. The data provide unique information on health and determinants of health in adults living in European urban areas that could be used to inform urban health policymaking. However, piloting has revealed a concern that non response bias could lead to under-representation of younger males from more deprived areas. This could affect the generalisability of findings from the adult surveys given the low response rates. PMID- 26747460 TI - Head and Neck Schwannomas: 20-Year Experience of a Single Institution Excluding Cutaneous and Acoustic Sites. AB - While head and neck sites comprise the most common location of schwannomas, clinicopathologic data regarding those tumors occurring in non-acoustic and non cutaneous locations are relatively sparse. In this study, therefore, we sought to examine retrospectively the clinical and pathologic features of head and neck schwannomas excised at our institution over a 20-year period. During this period, we identified a total cohort of 85 patients, which included 36 males (42.4 %) and 49 females with average age of 41.3 years, the majority of which presented asymptomatically with a mass. Localized symptoms were, however, associated with all of the schwannomas that arose in the oral cavity and larynx, while tumors within or adjacent to bone were often associated with neurologic complaints (7 of 15 such tumors [46.7 %]). Clinical follow-up data was available in 86.4 % of all cases and demonstrated no recurrences or mortality. Pathologically, the microscopic features were characteristic of those well-described for schwannomas in other sites, including alternating Antoni A and B areas and the presence of degenerative changes. Tumor encapsulation, however, was variable and was completely absent in schwannomas of the nasal cavity, paranasal sinuses, and larynx. Additionally, a significant minority of the tumors (28.2 %) exhibited foci that resembled neurofibroma. Non-acoustic, non-cutaneous schwannomas of the head and neck appear to have clinicopathologic features similar to their soft tissue counterparts with some subsite variation in presentation and/or microscopic features. PMID- 26747462 TI - Imageability and semantic association in the representation and processing of event verbs. AB - This study examined the relative salience of imageability (the degree to which a word evokes mental imagery) versus semantic association (the density of semantic network in which a word is embedded) in the representation and processing of four types of event verbs: sensory, cognitive, speech, and motor verbs. ERP responses were recorded, while 34 university students performed on a lexical decision task. Analysis focused primarily on amplitude differences across verb conditions within the N400 time window where activities are considered representing meaning activation. Variation in N400 amplitude across four types of verbs was found significantly associated with the level of imageability, but not the level of semantic association. The findings suggest imageability as a more salient factor relative to semantic association in the processing of these verbs. The role of semantic association and the representation of speech verbs are also discussed. PMID- 26747465 TI - Numbers game: Researchers explore whether fewer than 3 doses of HPV vaccine are effective. PMID- 26747466 TI - Cancer still leading cause of death for US Hispanics. PMID- 26747463 TI - The impact of epistemological beliefs and cognitive ability on recall and critical evaluation of scientific information. AB - Scientific research findings are frequently picked up by the mainstream media, but it is largely unclear which factors have an impact on laypeople's processing of the presented scientific information. In this study, we investigated the influence of cognitive and metacognitive inter-individual differences on recall and on critical evaluation of new scientific information that was presented in a journalistic article. Sixty-three participants (80 % female; mean age 24.1 +/- 3.3 years) read a newspaper article reporting research findings on a recently developed and yet unproven treatment for depression. We found that more sophisticated, domain-specific epistemological beliefs and a higher cognitive ability were independently associated with better recall of content from the article. Additionally, participants with more sophisticated epistemological beliefs displayed a more critical evaluation of the article. Cognitive ability was unrelated to critical evaluation and to epistemological beliefs. There were also no interaction effects of cognitive ability and epistemological beliefs on recall or on critical evaluation. Based on our preliminary findings and previous evidence of epistemological beliefs as a modifiable feature, we discuss this inter-individual characteristic as a potential target for the promotion of better understanding of scientific topics by the general public. PMID- 26747468 TI - Xiu-Yi Zhi, Jin-Ming Yu, and Yuan-Kai Shi. Chinese Guidelines on the Diagnosis and Treatment of Primary Lung Cancer (2015 Version). Cancer. 2015;121:3165-3181. PMID- 26747467 TI - Wide variation in cancer deaths mapped by congressional district. PMID- 26747469 TI - Translational Childhood Cancer Genomics: The Future Is Now. PMID- 26747470 TI - A systematic literature review of the key challenges for developing the structure of public health economic models. AB - OBJECTIVES: To identify the key methodological challenges for public health economic modelling and set an agenda for future research. METHODS: An iterative literature search identified papers describing methodological challenges for developing the structure of public health economic models. Additional multidisciplinary literature searches helped expand upon important ideas raised within the review. RESULTS: Fifteen articles were identified within the formal literature search, highlighting three key challenges: inclusion of non-healthcare costs and outcomes; inclusion of equity; and modelling complex systems and multi component interventions. Based upon these and multidisciplinary searches about dynamic complexity, the social determinants of health, and models of human behaviour, six areas for future research were specified. CONCLUSIONS: Future research should focus on: the use of systems approaches within health economic modelling; approaches to assist the systematic consideration of the social determinants of health; methods for incorporating models of behaviour and social interactions; consideration of equity; and methodology to help modellers develop valid, credible and transparent public health economic model structures. PMID- 26747471 TI - Characterization and structural analysis of a potent anticoagulant phospholipase A2 from Pseudechis australis snake venom. AB - Pseudechis australis is one of the most venomous and lethal snakes in Australia. Numerous phospholipase A2 (PLA2) isoforms constitute a major portion of its venom, some of which have previously been shown to exhibit not only enzymatic, but also haemolytic, neurotoxic and anticoagulant activities. Here, we have purified a potent anticoagulant PLA2 (identified as PA11) from P. australis venom to investigate its phospholipase, anticoagulant, haemolytic and cytotoxic activities and shown that addition of 11 nM PA11 resulted in a doubling of the clotting time of recalcified whole blood. We have also demonstrated that PA11 has high PLA2 enzymatic activity (10.9 * 10(4) Units/mg), but low haemolytic activity (0.6% of red blood cells hydrolysed in the presence of 1 nM PA11). PA11 at a concentration lower than 600 nM is not cytotoxic towards human cultured cells. Chemical modification experiments using p-bromophenacyl bromide have provided evidence that the catalytic histidine of PA11 is critical for the anticoagulant activity of this PLA2. PA11 that was subjected to trypsin digestion without previous reduction and alkylation of the disulfide bonds maintained enzymatic and anticoagulant activity, suggesting that proteolysis alone cannot abolish these properties. Consistent with these results, administration of PA11 by gavage in a rabbit stasis thrombosis model increased the clotting time of recalcified citrated whole blood by a factor of four. These data suggest that PA11 has potential to be developed as an anticoagulant in a clinical setting. PMID- 26747472 TI - Protection against Amorimia septentrionalis poisoning in goats by the continuous administration of sodium monofluoroacetate-degrading bacteria. AB - The intraruminal inoculation of sodium monofluoroacetate (MFA)-degrading bacteria has been proposed as a method to prevent poisoning by MFA-containing plants. In previous experiments, MFA-degrading bacteria were inoculated intraruminally before or concurrent with plant challenge, with both strategies conferring partial protection to poisoning. To evaluate the protection to Amorimia septentrionalis poisoning provided by the continuous inoculation of MFA-degrading bacteria isolated from plants and soils, 18 goats were divided into three experimental groups of six animals each: Group 1 goats received daily doses of a mixture of Paenibacillus sp. and Cupriavidus sp., and Group 2 goats received a mixture of Ralstonia sp. and Burkholderia sp., for 40 days, while Group 3 goats were not inoculated. Ten days after initiation of bacterial inoculation in Groups 1 and 2, all goats were challenged daily with 5 g/kg body weight of green leaves from A. septentrionalis. Four goats from Group 1 consumed the leaves throughout the 30-day consumption period and showed clinical signs such as transient tachycardia and engorgement of the jugular. The two remaining animals from Group 1 showed obvious signs of intoxication, and plant administration was suspended on days 17 and 19. The goats in Group 2 consumed the leaves throughout the 30-day study without showing signs of poisoning. The goats from Group 3 (control) manifested severe clinical signs of poisoning between the 3rd and 10th days following the start of the A. septentrionalis challenge. Under the conditions of this experiment continuous intraruminal administration of Ralstonia sp. and Burkholderia sp. provided complete protection to poisoning by A. septentrionalis in goats, while continuous intraruminal administration of Paenibacillus sp. and Cupriavidus sp. provided partial protection. PMID- 26747473 TI - Spectral characteristics of caries-related autofluorescence spectra and their use for diagnosis of caries stage. PMID- 26747474 TI - Empirical mode decomposition-based motion artifact correction method for functional near-infrared spectroscopy. PMID- 26747475 TI - In vivo use of hyperspectral imaging to develop a noncontact endoscopic diagnosis support system for malignant colorectal tumors. PMID- 26747476 TI - Optoacoustic image reconstruction and system analysis for finite-aperture detectors under the wavelet-packet framework. PMID- 26747477 TI - GPU acceleration of time-domain fluorescence lifetime imaging. PMID- 26747478 TI - Photodynamic antimicrobial chemotherapy using zinc phthalocyanine derivatives in treatment of bacterial skin infection. PMID- 26747496 TI - Age-related changes in intraventricular kinetic energy: a physiological or pathological adaptation? AB - Aging has important deleterious effects on the cardiovascular system. We sought to compare intraventricular kinetic energy (KE) in healthy subjects of varying ages with subjects with ventricular dysfunction to understand if changes in energetic momentum may predispose individuals to heart failure. Four-dimensional flow MRI was acquired in 35 healthy subjects (age: 1-67 yr) and 10 patients with left ventricular (LV) dysfunction (age: 28-79 yr). Healthy subjects were divided into age quartiles (1st quartile: <16 yr, 2nd quartile: 17-32 yr, 3rd quartile: 33-48 yr, and 4th quartile: 49-64 yr). KE was measured in the LV throughout the cardiac cycle and indexed to ventricular volume. In healthy subjects, two large peaks corresponding to systole and early diastole occurred during the cardiac cycle. A third smaller peak was seen during late diastole in eight adults. Systolic KE (P = 0.182) and ejection fraction (P = 0.921) were preserved through all age groups. Older adults showed a lower early peak diastolic KE compared with children (P < 0.0001) and young adults (P = 0.025). Subjects with LV dysfunction had reduced ejection fraction (P < 0.001) and compared with older healthy adults exhibited a similar early peak diastolic KE (P = 0.142) but with the addition of an elevated KE in diastasis (P = 0.029). In healthy individuals, peak diastolic KE progressively decreases with age, whereas systolic peaks remain constant. Peak diastolic KE in the oldest subjects is comparable to those with LV dysfunction. Unique age-related changes in ventricular diastolic energetics might be physiological or herald subclinical pathology. PMID- 26747497 TI - Morphometric and hemodynamic analysis of atherosclerotic progression in human carotid artery bifurcations. AB - Although atherosclerosis has been widely investigated at carotid artery bifurcation, there is a lack of morphometric and hemodynamic data at different stages of the disease. The purpose of this study was to determine the lesion difference in patients with carotid artery disease compared with healthy control subjects. The three-dimensional (3D) geometry of carotid artery bifurcation was reconstructed from computed tomography angiography (CTA) images of Chinese control subjects (n = 30) and patients with carotid artery disease (n = 30). We defined two novel vector angles (i.e., angles 1 and 2) that were tangential to the reconstructed contour of the 3D vessel. The best-fit diameter was computed along the internal carotid artery (ICA) center line. Hemodynamic analysis was performed at various bifurcations. Patients with stenotic vessels have larger angles 1 and 2 (151 +/- 11 degrees and 42 +/- 20 degrees ) and smaller diameters of the external carotid artery (ECA) (4.6 +/- 0.85 mm) compared with control subjects (144 +/- 13 degrees and 36 +/- 16 degrees , 5.2 +/- 0.57 mm) although there is no significant difference in the common carotid artery (CCA) (7.1 +/- 1.2 vs. 7.5 +/- 1.0 mm, P = 0.18). In particular, all patients with carotid artery disease have a stenosis at the proximal ICA (including both sinus and carina regions), while 20% of patients have stenosis at the middle ICA and 20% have stenosis expansion to the entire cervical ICA. Morphometric and hemodynamic analyses suggest that atherosclerotic plaques initiate at both sinus and carina regions of ICA and progress downstream. PMID- 26747498 TI - Left atrial aging: a cardiac magnetic resonance feature-tracking study. AB - Importance of left atrial (LA) phasic function evaluation is increasingly recognized for its incremental value in terms of prognosis and risk stratification. LA phasic deformation in the pathway of normal aging has been characterized using echocardiographic speckle tracking. However, no data are available regarding age-related variations using feature-racking (FT) techniques from standard cine magnetic resonance imaging (MRI). We studied 94 healthy adults (41 +/- 14 yr, 47 women), who underwent MRI and Doppler echocardiography on the same day for left ventricular (LV) diastolic function evaluation. From cine MRI, longitudinal strain and strain rate, radial motion fraction, and radial relative velocity, respectively, corresponding to the reservoir, conduit, and LA contraction phases, were measured using dedicated FT software. Longitudinal strain and radial motion fraction decreased gradually and significantly with aging for both reservoir (r > 0.31, P < 0.003) and conduit (r > 0.54, P < 0.001) phases, whereas they remained unchanged during the LA contraction phase. Subsequently, the LA contraction-to-reservoir ratio increased significantly with age (r > 0.44, P < 0.001). Longitudinal strain rate and radial relative velocity significantly decreased with age (reservoir: r = 0.39, P < 0.001, conduit: r > 0.54, P < 0.001), and these associations tended to be stronger in women than in men. Finally, associations of LA functional indexes with age were stronger in individuals with lower transmitral early-to-atrial maximal velocity ratio and mitral annulus maximal longitudinal velocity, as well as higher transmitral early maximal-to-mitral annulus maximal longitudinal velocity ratio, highlighting the LV-LA interplay. Age-related changes in LA phasic function indexes were quantified by cine MRI images using a FT technique and were significantly related to age and LV diastolic function. PMID- 26747499 TI - Sex differences in clinical characteristics and long-term outcome in acute decompensated heart failure patients with preserved and reduced ejection fraction. AB - In patients with acute decompensated heart failure (ADHF), sex differences considering clinical and pathophysiologic features are not fully understood. We investigated sex differences in left ventricular (LV) ejection fraction (LVEF), plasma B-type natriuretic peptide (BNP) levels, and prognostic factors in patients with ADHF in Japan. We studied 748 consecutive ADHF patients of 821 patients registered in the ADHF registry between January 2007 and December 2014. Patients were divided into four groups based on sex and LVEF [reduced (ejection fraction, or EF, <50%, heart failure with reduced EF, or HFrEF) or preserved (EF >=50%, heart failure with preserved LVEF, or HFpEF)]. The primary endpoint was the combination of cardiovascular death and heart failure (HF) admission. The present study consisted of 311 female patients (50% HFrEF, 50% HFpEF) and 437 male patients (63% HFrEF, 37% HFpEF). There was significant difference between sexes in the LVEF distribution profile. The ratio of HFpEF patients was significantly higher in female patients than in male patients (P= 0.0004). Although there were no significant sex differences in median plasma BNP levels, the prognostic value of BNP levels was different between sexes. Kaplan-Meier analysis revealed that the high BNP group had worse prognosis than the low BNP group in male but not in female patients. In multivariate analysis, log transformed BNP at discharge predicted cardiovascular events in male but not in female HF patients (female, hazard ratio: 1.169; 95% confidence interval: 0.981 1.399;P= 0.0806; male, hazard ratio: 1.289; 95% confidence interval: 1.120 1.481;P= 0.0004). In patients with ADHF, the distribution of LV function and the prognostic significance of plasma BNP levels for long-term outcome were different between the sexes. PMID- 26747500 TI - Oxidative stress contributes to the enhanced expression of Gqalpha/PLCbeta1 proteins and hypertrophy of VSMC from SHR: role of growth factor receptor transactivation. AB - We showed previously that vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHRs) exhibit overexpression of Gqalpha/PLCbeta1 proteins, which contribute to increased protein synthesis through the activation of MAP kinase signaling. Because oxidative stress has been shown to be increased in hypertension, the present study was undertaken to examine the role of oxidative stress and underlying mechanisms in enhanced expression of Gqalpha/PLCbeta1 proteins and VSMC hypertrophy. Protein expression was determined by Western blotting, whereas protein synthesis and cell volume, markers for VSMC hypertrophy, were determined by [(3)H]-leucine incorporation and three dimensional confocal imaging, respectively. The increased expression of Gqalpha/PLCbeta1 proteins, increased protein synthesis, and augmented cell volume exhibited by VSMCs from SHRs were significantly attenuated by antioxidants N acetyl-cysteine (NAC), a scavenger of superoxide anion, DPI, an inhibitor of NAD(P)H oxidase. In addition, PP2, AG1024, AG1478, and AG1295, inhibitors of c Src, insulin-like growth factor receptor (IGFR), epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor (PDGFR), respectively, also attenuated the enhanced expression of Gqalpha/PLCbeta1 proteins and enhanced protein synthesis in VSMCs from SHRs toward control levels. Furthermore, the levels of IGF-1R and EGFR proteins and not of PDGFR were also enhanced in VSMCs from SHRs, which were attenuated significantly by NAC, DPI, and PP2. In addition, NAC, DPI, and PP2 also attenuated the enhanced phosphorylation of IGF-1R, PDGFR, EGFR, c-Src, and EKR1/2 in VSMCs from SHRs. These data suggest that enhanced oxidative stress in VSMCs from SHRs activates c-Src, which through the transactivation of growth factor receptors and MAPK signaling contributes to enhanced expression of Gqalpha/PLCbeta1 proteins and resultant VSMC hypertrophy. PMID- 26747501 TI - Consequences of intravascular lymphatic valve properties: a study of contraction timing in a multi-lymphangion model. AB - The observed properties of valves in collecting lymphatic vessels include transmural pressure-dependent bias to the open state and hysteresis. The bias may reduce resistance to flow when the vessel is functioning as a conduit. However, lymphatic pumping implies a streamwise increase in mean pressure across each valve, suggesting that the bias is then potentially unhelpful. Lymph pumping by a model of several collecting lymphatic vessel segments (lymphangions) in series, which incorporated these properties, was investigated under conditions of adverse pressure difference while varying the refractory period between active muscular contractions and the inter-lymphangion contraction delay. It was found that many combinations of the timing parameters and the adverse pressure difference led to one or more intermediate valves remaining open instead of switching between open and closed states during repetitive contraction cycles. Cyclic valve switching was reliably indicated if the mean pressure in a lymphangion over a cycle was higher than that in the lymphangion upstream, but either lack of or very brief valve closure could cause mean pressure to be lower downstream. Widely separated combinations of refractory period and delay time were found to produce the greatest flow-rate for a given pressure difference. The efficiency of pumping was always maximized by a long refractory period and lymphangion contraction starting when the contraction of the lymphangion immediately upstream was peaking. By means of an ex vivo experiment, it was verified that intermediate valves in a chain of pumping lymphangions can remain open, while the lymphangions on either side of the open valve continue to execute contractions. PMID- 26747502 TI - Combination of angiotensin II and l-NG-nitroarginine methyl ester exacerbates mitochondrial dysfunction and oxidative stress to cause heart failure. AB - Mitochondrial dysfunction has been implicated as a cause of energy deprivation in heart failure (HF). Herein, we tested individual and combined effects of two pathogenic factors of nonischemic HF, inhibition of nitric oxide synthesis [with l-N(G)-nitroarginine methyl ester (l-NAME)] and hypertension [with angiotensin II (AngII)], on myocardial mitochondrial function, oxidative stress, and metabolic gene expression. l-NAME and AngII were administered individually and in combination to mice for 5 wk. Although all treatments increased blood pressure and reduced cardiac contractile function, the l-NAME + AngII group was associated with the most severe HF, as characterized by edema, hypertrophy, oxidative stress, increased expression of Nppa and Nppb, and decreased expression of Atp2a2 and Camk2b. l-NAME + AngII-treated mice exhibited robust deterioration of cardiac mitochondrial function, as observed by reduced respiratory control ratios in subsarcolemmal mitochondria and reduced state 3 levels in interfibrillar mitochondria for complex I but not for complex II substrates. Cardiac myofibrils showed reduced ADP-supported and oligomycin-inhibited oxygen consumption. Mitochondrial functional impairment was accompanied by reduced mitochondrial DNA content and activities of pyruvate dehydrogenase and complex I but increased H2O2 production and tissue protein carbonyls in hearts from AngII and l-NAME + AngII groups. Microarray analyses revealed the majority of the gene changes attributed to the l-NAME + AngII group. Pathway analyses indicated significant changes in metabolic pathways, such as oxidative phosphorylation, mitochondrial function, cardiac hypertrophy, and fatty acid metabolism in l-NAME + AngII hearts. We conclude that l-NAME + AngII is associated with impaired mitochondrial respiratory function and increased oxidative stress compared with either l-NAME or AngII alone, resulting in nonischemic HF. PMID- 26747504 TI - Increased postflight carotid artery stiffness and inflight insulin resistance resulting from 6-mo spaceflight in male and female astronauts. AB - Removal of the normal head-to-foot gravity vector and chronic weightlessness during spaceflight might induce cardiovascular and metabolic adaptations related to changes in arterial pressure and reduction in physical activity. We tested hypotheses that stiffness of arteries located above the heart would be increased postflight, and that blood biomarkers inflight would be consistent with changes in vascular function. Possible sex differences in responses were explored in four male and four female astronauts who lived on the International Space Station for 6 mo. Carotid artery distensibility coefficient (P = 0.005) and beta-stiffness index (P = 0.006) reflected 17-30% increases in arterial stiffness when measured within 38 h of return to Earth compared with preflight. Spaceflight-by-sex interaction effects were found with greater changes in beta-stiffness index in women (P = 0.017), but greater changes in pulse wave transit time in men (P = 0.006). Several blood biomarkers were changed from preflight to inflight, including an increase in an index of insulin resistance (P < 0.001) with a spaceflight-by-sex term suggesting greater change in men (P = 0.034). Spaceflight by-sex interactions for renin (P = 0.016) and aldosterone (P = 0.010) indicated greater increases in women than men. Six-month spaceflight caused increased arterial stiffness. Altered hydrostatic arterial pressure gradients as well as changes in insulin resistance and other biomarkers might have contributed to alterations in arterial properties, including sex differences between male and female astronauts. PMID- 26747503 TI - Endothelial fibroblast growth factor receptor signaling is required for vascular remodeling following cardiac ischemia-reperfusion injury. AB - Fibroblast growth factor (FGF) signaling is cardioprotective in various models of myocardial infarction. FGF receptors (FGFRs) are expressed in multiple cell types in the adult heart, but the cell type-specific FGFR signaling that mediates different cardioprotective endpoints is not known. To determine the requirement for FGFR signaling in endothelium in cardiac ischemia-reperfusion injury, we conditionally inactivated the Fgfr1 and Fgfr2 genes in endothelial cells with Tie2-Cre (Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice). Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice had normal baseline cardiac morphometry, function, and vessel density. When subjected to closed-chest, regional cardiac ischemia reperfusion injury, Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice showed a significantly increased hypokinetic area at 7 days, but not 1 day, after reperfusion. Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice also showed significantly worsened cardiac function compared with controls at 7 days but not 1 day after reperfusion. Pathophysiological analysis showed significantly decreased vessel density, increased endothelial cell apoptosis, and worsened tissue hypoxia in the peri-infarct area at 7 days following reperfusion. Notably, Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice showed no impairment in the cardiac hypertrophic response. These data demonstrate an essential role for FGFR1 and FGFR2 in endothelial cells for cardiac functional recovery and vascular remodeling following in vivo cardiac ischemia-reperfusion injury, without affecting the cardiac hypertrophic response. This study suggests the potential for therapeutic benefit from activation of endothelial FGFR pathways following ischemic injury to the heart. PMID- 26747506 TI - Impaired microcirculatory perfusion in a rat model of cardiopulmonary bypass: the role of hemodilution. AB - Although hemodilution is attributed as the main cause of microcirculatory impairment during cardiopulmonary bypass (CPB), this relationship has never been investigated. We investigated the distinct effects of hemodilution with or without CPB on microvascular perfusion and subsequent renal tissue injury in a rat model. Male Wistar rats (375-425 g) were anesthetized, prepared for cremaster muscle intravital microscopy, and subjected to CPB (n = 9), hemodilution alone (n = 9), or a sham procedure (n = 6). Microcirculatory recordings were performed at multiple time points and analyzed for perfusion characteristics. Kidney and lung tissue were investigated for mRNA expression for genes regulating inflammation and endothelial adhesion molecule expression. Renal injury was assessed with immunohistochemistry. Hematocrit levels dropped to 0.24 +/- 0.03 l/l and 0.22 +/- 0.02 l/l after onset of hemodilution with or without CPB. Microcirculatory perfusion remained unaltered in sham rats. Hemodilution alone induced a 13% decrease in perfused capillaries, after which recovery was observed. Onset of CPB reduced the perfused capillaries by 40% (9.2 +/- 0.9 to 5.5 +/- 1.5 perfused capillaries per microscope field; P < 0.001), and this reduction persisted throughout the experiment. Endothelial and inflammatory activation and renal histological injury were increased after CPB compared with hemodilution or sham procedure. Hemodilution leads to minor and transient disturbances in microcirculatory perfusion, which cannot fully explain impaired microcirculation following cardiopulmonary bypass. CPB led to increased renal injury and endothelial adhesion molecule expression in the kidney and lung compared with hemodilution. Our findings suggest that microcirculatory impairment during CPB may play a role in the development of kidney injury. PMID- 26747507 TI - An integrated mathematical model of the human cardiopulmonary system: model validation under hypercapnia and hypoxia. AB - A novel integrated physiological model of the interactions between the cardiovascular and respiratory systems has been in development for the past few years. The model has hundreds of parameters and variables representing the physical and physiological properties of the human cardiopulmonary system. It can simulate many dynamic states and scenarios. The description of the model and the results in normal resting conditions were presented in a companion paper (Albanese A, Cheng L, Ursino M, Chbat NW.Am J Physiol Heart Circ Physiol 310: 2016; doi:10.1152/ajpheart.00230.2014), where model predictions were compared against average population data from literature. However, it is also essential to test the model in abnormal or pathological conditions to prove its consistency. Hence, in this paper, we concentrate on testing the cardiopulmonary model under hypercapnic and hypoxic conditions, by comparing model's outputs to population averaged cardiorespiratory data reported in the literature. The utility of this comprehensive model is demonstrated by testing the internal consistency of the simulated responses of a significant number of cardiovascular variables (heart rate, arterial pressure, and cardiac output) and respiratory variables (tidal volume, respiratory rate, minute ventilation, alveolar O2 and CO2 partial pressures) over a wide range of perturbations and conditions; namely, hypercapnia at 3-7% CO2 levels and hypoxia at 7-9% O2 levels with controlled CO2(isocapnic hypoxia) and without controlled CO2(hypocapnic hypoxia). Finally, a sensitivity analysis is performed to analyze the role of the main cardiorespiratory control mechanisms triggered by hypercapnia and hypoxia. PMID- 26747505 TI - beta-Adrenergic-mediated vasodilation in young men and women: cyclooxygenase restrains nitric oxide synthase. AB - We tested the hypothesis that women exhibit greater vasodilator responses to beta adrenoceptor stimulation compared with men. We further hypothesized women exhibit a greater contribution of nitric oxide synthase and cyclooxygenase to beta adrenergic-mediated vasodilation compared with men. Forearm blood flow (Doppler ultrasound) was measured in young men (n = 29, 26 +/- 1 yr) and women (n = 33, 25 +/- 1 yr) during intra-arterial infusion of isoproterenol (beta-adrenergic agonist). In subset of subjects, isoproterenol responses were examined before and after local inhibition of nitric oxide synthase [N(G)-monomethyl-l-arginine (l NMMA); 6 male/10 female] and/or cyclooxygenase (ketorolac; 5 male/5 female). Vascular conductance (blood flow / mean arterial pressure) was calculated to assess vasodilation. Vascular conductance increased with isoproterenol infusion (P < 0.01), and this effect was not different between men and women (P = 0.41). l NMMA infusion had no effect on isoproterenol-mediated dilation in men (P > 0.99) or women (P = 0.21). In contrast, ketorolac infusion markedly increased isoproterenol-mediated responses in both men (P < 0.01) and women (P = 0.04) and this rise was lost with subsequent l-NMMA infusion (men, P < 0.01; women, P < 0.05). beta-Adrenergic vasodilation is not different between men and women and sex differences in the independent contribution of nitric oxide synthase and cyclooxygenase to beta-mediated vasodilation are not present. However, these data are the first to demonstrate beta-adrenoceptor activation of cyclooxygenase suppresses nitric oxide synthase signaling in human forearm microcirculation and may have important implications for neurovascular control in both health and disease. PMID- 26747508 TI - Endothelial dysfunction following prolonged sitting is mediated by a reduction in shear stress. AB - We and others have recently reported that prolonged sitting impairs endothelial function in the leg vasculature; however, the mechanism(s) remain unknown. Herein, we tested the hypothesis that a sustained reduction in flow-induced shear stress is the underlying mechanism by which sitting induces leg endothelial dysfunction. Specifically, we examined whether preventing the reduction in shear stress during sitting would abolish the detrimental effects of sitting on popliteal artery endothelial function. In 10 young healthy men, bilateral measurements of popliteal artery flow-mediated dilation were performed before and after a 3-h sitting period during which one foot was submerged in 42 degrees C water (i.e., heated) to increase blood flow and thus shear stress, whereas the contralateral leg remained dry and served as internal control (i.e., nonheated). During sitting, popliteal artery mean shear rate was reduced in the nonheated leg (pre-sit, 42.9 +/- 4.5 s(-1); and 3-h sit, 23.6 +/- 3.3 s(-1); P < 0.05) but not in the heated leg (pre-sit, 38.9 +/- 3.4 s(-1); and 3-h sit, 63.9 +/- 16.9 s(-1); P > 0.05). Popliteal artery flow-mediated dilation was impaired after 3 h of sitting in the nonheated leg (pre-sit, 7.1 +/- 1.4% vs. post-sit, 2.8 +/- 0.9%; P < 0.05) but not in the heated leg (pre-sit: 7.3 +/- 1.5% vs. post-sit, 10.9 +/- 1.8%; P > 0.05). Collectively, these data suggest that preventing the reduction of flow-induced shear stress during prolonged sitting with local heating abolishes the impairment in popliteal artery endothelial function. Thus these findings are consistent with the hypothesis that sitting-induced leg endothelial dysfunction is mediated by a reduction in shear stress. PMID- 26747509 TI - "I Kicked the Hard Way. I Got Incarcerated." Withdrawal from Methadone During Incarceration and Subsequent Aversion to Medication Assisted Treatments. AB - Incarceration is a common experience for individuals with opioid use disorder, including those receiving medication assisted treatments (MAT), such as buprenorphine or methadone. In the United States, MAT is rarely available during incarceration. We were interested in whether challenges with methadone maintenance treatment during incarceration affected subsequent attitudes toward MAT following release. We conducted semi-structured interviews with 21 formerly incarcerated individuals with opioid use disorder in community substance abuse treatment settings. Interviews were audio recorded, transcribed, and analyzed using a grounded theory approach. Themes that emerged upon iterative readings of transcripts were discussed by the research team. The three main themes relating to methadone were: 1) rapid dose reduction during incarceration; 2) discontinuity of methadone during incarceration; and 3) post incarceration aversion to methadone. Participants who received methadone maintenance treatment prior to incarceration reported severe and prolonged withdrawal symptoms from rapid dose reductions or disruption of their methadone treatment during incarceration. The severe withdrawal during incarceration contributed to a subsequent aversion to methadone and adversely affected future decisions regarding reengagement in MAT. Though MAT is the most efficacious treatment for opioid use disorder, current penal policy, which typically requires cessation of MAT during incarceration, may dissuade individuals with opioid use disorder from considering and engaging in MAT after release from incarceration. PMID- 26747510 TI - Prevalence of Self-reported Symptoms After Gastric Bypass Surgery for Obesity. AB - IMPORTANCE: Population-based studies on the prevalence of symptoms after Roux-en Y gastric bypass (RYGB) surgery are sparse. Knowledge about possible predictors of these symptoms is important for prevention. OBJECTIVES: To examine patients' overall well-being and the prevalence and predictors of medical, nutritional, and surgical symptoms after RYGB surgery, and their association with quality of life. DESIGN, SETTING, AND PARTICIPANTS: A survey was conducted from March 3 to July 31, 2014, among 2238 patients who underwent RYGB surgery between January 1, 2006, and December 31, 2011, in the Central Denmark Region. A comparison cohort of 89 individuals who were matched with patients according to sex and body mass index but who did not undergo RYGB surgery were surveyed as a point of reference. Data analysis was conducted from September 1, 2014, to June 25, 2015. MAIN OUTCOMES AND MEASURES: Prevalence and severity (based on contacts with health care system, ranging from no contact to hospitalization) of self-reported symptoms following RYGB surgery. Prevalence ratios (PRs) of symptoms associated with different predictors were computed. The association between number of symptoms and quality of life was investigated using the Spearman rank correlation coefficient. RESULTS: Of 2238 patients undergoing RYGB surgery, 1429 (63.7%) responded to the survey. Among these patients, 1266 (88.6%) reported 1 or more symptoms a median of 4.7 years after RYGB surgery. Mean age at the time of the survey was 47.1 years (range, 26.9-68.0 years), and 286 were men (20.0%). A total of 1219 of 1394 patients (87.4%) reported that their well-being was improved after vs before RYGB surgery, while 113 (8.1%) reported reduced well-being. Symptoms after RYGB surgery were reported by 1266 patients (88.6%); 966 patients (67.6%) had been in contact with the health care system about their symptoms vs 31 [34.8%] of those in the comparison group, and 416 (29.1%) had been hospitalized vs 6 [6.7%] of those in the comparison group. The symptoms most commonly leading to health care contact after RYGB surgery were abdominal pain (489 [34.2%]), fatigue (488 [34.1%]), and anemia (396 [27.7%]). The risk of symptoms was higher among women (crude PR, 1.23; 95% CI, 1.11-1.37), among patients younger than 35 years (PR, 1.24; 95% CI, 1.13-1.36), among smokers (PR, 1.11; 95% CI, 1.02-1.20), among unemployed persons (PR, 1.15; 95% CI, 1.06-1.24), and in those with surgical symptoms before RYGB surgery (PR, 1.34; 95% CI, 1.25-1.43). Quality of life was inversely associated with the number of symptoms (r = -0.30; P < .001). CONCLUSIONS AND RELEVANCE: Most patients reported improved well-being after RYGB surgery, but the prevalence of symptoms was high and nearly one-third of patients were hospitalized, 4- to 5-fold more than among the comparison group. Predictors of symptoms included young age, female sex, smoking, and experiencing symptoms before RYGB surgery. Development of weight loss procedures with fewer subsequent symptoms should be a high priority. PMID- 26747512 TI - My Weight Loss Journey: Unasked and Unanswered Questions. PMID- 26747511 TI - Activation of protein kinase A in the amygdala modulates anxiety-like behaviors in social defeat exposed mice. AB - BACKGROUND: Social defeat (SD) stress induces social avoidance and anxiety-like phenotypes. Amygdala is recognized as an emotion-related brain region such as fear, aversion and anxiety. It is conceivable to hypothesize that activation of amygdala is involved in SD-dependent behavioral defects. RESULTS: SD model was established using C57BL/6J mice that were physically defeated by different CD-1 mice for 10 days. Stressed mice exhibited decreased social interaction level in social interaction test and significant anxiety-like behaviors in elevated plus maze and open field tests. Meanwhile, a higher phosphorylation of PKA and CREB with a mutually linear correlation, and increased Fos labeled cells in the basolateral amygdala (BLA) were observed. Activation of PKA in the BLA by 8-Br cAMP, a PKA activitor, significantly upregulated pCREB and Fos expression. To address the role of PKA activation on SD stress-induced social avoidance and anxiety-like behaviors, 8-Br-cAMP or H-89, a PKA inhibitor, was continuously administered into the bilateral BLA by a micro-osmotic pump system during the 10 day SD period. Neither H-89 nor 8-Br-cAMP affected the social behavior. Differently, 8-Br-cAMP significantly relieved anxiety-like behaviors in both general and moderate SD protocols. H-89 per se did not have anxiogenic effect in naive mice, but aggravated moderate SD stress-induced anxiety-like behaviors. The antidepressant clomipramine reduced SD-induced anxiety and up-regulated pPKA level in the BLA. CONCLUSIONS: These results suggest that SD-driven PKA activation in the basolateral amygdala is actually a compensatory rather than pathogenic response in the homeostasis, and modulating amygdaloid PKA may exhibit potency in the therapy of social derived disorders. PMID- 26747513 TI - Mechanobiology of cell migration in the context of dynamic two-way cell-matrix interactions. AB - Migration of cells is integral in various physiological processes in all facets of life. These range from embryonic development, morphogenesis, and wound healing, to disease pathology such as cancer metastasis. While cell migratory behavior has been traditionally studied using simple assays on culture dishes, in recent years it has been increasingly realized that the physical, mechanical, and chemical aspects of the matrix are key determinants of the migration mechanism. In this paper, we will describe the mechanobiological changes that accompany the dynamic cell-matrix interactions during cell migration. Furthermore, we will review what is to date known about how these changes feed back to the dynamics and biomechanical properties of the cell and the matrix. Elucidating the role of these intimate cell-matrix interactions will provide not only a better multi scale understanding of cell motility in its physiological context, but also a more holistic perspective for designing approaches to regulate cell behavior. PMID- 26747514 TI - Time-elapsed screw insertion with microCT imaging. AB - Time-elapsed analysis of bone is an innovative technique that uses sequential image data to analyze bone mechanics under a given loading regime. This paper presents the development of a novel device capable of performing step-wise screw insertion into excised bone specimens, within the microCT environment, whilst simultaneously recording insertion torque, compression under the screw head and rotation angle. The system is computer controlled and screw insertion is performed in incremental steps of insertion torque. A series of screw insertion tests to failure were performed (n=21) to establish a relationship between the torque at head contact and stripping torque (R(2)=0.89). The test-device was then used to perform step-wise screw insertion, stopping at intervals of 20%, 40%, 60% and 80% between screw head contact and screw stripping. Image data-sets were acquired at each of these time-points as well as at head contact and post failure. Examination of the image data revealed the trabecular deformation as a result of increased insertion torque was restricted to within 1mm of the outer diameter of the screw thread. Minimal deformation occurred prior to the step between the 80% time-point and post-failure. The device presented has allowed, for the first time, visualization of the micro-mechanical response in the peri implant bone with increased tightening torque. Further testing on more samples is expected to increase our understanding of the effects of increased tightening torque at the micro-structural level, and the failure mechanisms of trabeculae. PMID- 26747517 TI - Pediatric Radiology editorial board - acknowledgments and updates. PMID- 26747520 TI - Cross-Shelf Exchange. AB - Cross-shelf exchange dominates the pathways and rates by which nutrients, biota, and materials on the continental shelf are delivered and removed. This follows because cross-shelf gradients of most properties are usually far greater than those in the alongshore direction. The resulting transports are limited by Earth's rotation, which inhibits flow from crossing isobaths. Thus, cross-shelf flows are generally weak compared with alongshore flows, and this leads to interesting observational issues. Cross-shelf flows are enabled by turbulent mixing processes, nonlinear processes (such as momentum advection), and time dependence. Thus, there is a wide range of possible effects that can allow these critical transports, and different natural settings are often governed by different combinations of processes. This review discusses examples of representative transport mechanisms and explores possible observational and theoretical paths to future progress. PMID- 26747515 TI - The effect of parameters of equilibrium-based 3-D biomechanical models on extracted muscle synergies during isometric lumbar exertion. AB - A hallmark of more advanced models is their higher details of trunk muscles represented by a larger number of muscles. The question is if in reality we control these muscles individually as independent agents or we control groups of them called "synergy". To address this, we employed a 3-D biomechanical model of the spine with 18 trunk muscles that satisfied equilibrium conditions at L4/5, with different cost functions. The solutions of several 2-D and 3-D tasks were arranged in a data matrix and the synergies were computed by using non-negative matrix factorization (NMF) algorithms. Variance accounted for (VAF) was used to evaluate the number of synergies that emerged by the analysis, which were used to reconstruct the original muscle activations. It was showed that four and six muscle synergies were adequate to reconstruct the input data of 2-D and 3-D torque space analysis. The synergies were different by choosing alternative cost functions as expected. The constraints affected the extracted muscle synergies, particularly muscles that participated in more than one functional tasks were influenced substantially. The compositions of extracted muscle synergies were in agreement with experimental studies on healthy participants. The following computational methods show that the synergies can reduce the complexity of load distributions and allow reduced dimensional space to be used in clinical settings. PMID- 26747521 TI - Nitrogen and Oxygen Isotopic Studies of the Marine Nitrogen Cycle. AB - The marine nitrogen cycle is a complex web of microbially mediated reactions that control the inventory, distribution, and speciation of nitrogen in the marine environment. Because nitrogen is a major nutrient that is required by all life, its availability can control biological productivity and ecosystem structure in both surface and deep-ocean communities. Stable isotopes of nitrogen and oxygen in nitrate and nitrite have provided new insights into the rates and distributions of marine nitrogen cycle processes, especially when analyzed in combination with numerical simulations of ocean circulation and biogeochemistry. This review highlights the insights gained from dual-isotope studies applied at regional to global scales and their incorporation into oceanic biogeochemical models. These studies represent significant new advances in the use of isotopic measurements to understand the modern nitrogen cycle, with implications for the study of past ocean productivity, oxygenation, and nutrient status. PMID- 26747522 TI - Enhanced anti-cancer and antimicrobial activities of curcumin nanoparticles. AB - Background Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over the last 50 years has demonstrated that these polyphenols play an important role in the maintenance of health and prevention of diseases, in addition to its therapeutic benefits such as anti-tumor, anti-inflammatory, and anti-oxidant activities. Materials and methods This study is devoted to the enhancement of the solubility and bioavailability of curcumin nanoparticles prepared by a process based on a wet-milling technique and then examine in vitro against prostate cancer cell line 3 (PC3), human embryonic kidney cell line (HEK), human erythrocytes (red blood cells (RBCs)), and against fourth different bacterial strains two gram-positive (Micrococcus luteus ATCC 9341, Staphylococcus aureus ATCC 29213), two gram negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853). Results The cell viability curve, the half maximal inhibitory concentration (IC50), and the minimum bactericidal concentration (MBC) were evaluated. Nanocurcumin displayed significant activity against cancer cell line (PC3) and low toxicity against normal cells (HEK) compared with parent curcumin in favor of PC3 (P < 0.05). In addition, it was found that the efficiency of toxicity for nanocurcumin against PC3 (E% = 59.66%) was much better than HEK (E% = 36.07%) compared with parent curcumin. The results also demonstrate that, although nanocurcumin has a little more ability to lays RBCs than parent curcumin after incubated 60 min, but the hemolysis % remained very low and there was no significant difference between hemolysis % of nanocurcumin and parent curcumin (P > 0.05). On the other hand, the results demonstrate that, the MBCs of nanocurcumin were lower than curcumin for all different bacterial strains. Moreover, the selected gram-positive bacteria had higher sensitivity than the selected gram-negative bacteria for both curcumin and nanocurcumin. In conclusion, all these findings not only indicate that nanocurcumin safe compound has a potent ability as anti-cancer and antimicrobial activities, but also well justify the avail of using nanocurcumin as prostate cells PC3 anti-cancer, and antimicrobial agent for nanocurcumin are markedly improved by decreasing particle size to the nano-scale regime. PMID- 26747523 TI - Should We Abandon Routine Visits? There Is Little Evidence for or Against. PMID- 26747524 TI - Early Intervention for Psychotic Disorders: Building Population Health Systems. PMID- 26747525 TI - IL-10 and integrin signaling pathways are associated with head and neck cancer progression. AB - BACKGROUND: Head and neck cancer is morbid with a poor prognosis that has not significantly improved in the past several decades. The purpose of this study was to identify biological pathways underlying progressive head and neck cancer to inform prognostic and adjuvant strategies. We identified 235 head and neck cancer patients in The Cancer Genome Atlas (TCGA) with sufficient clinical annotation regarding therapeutic treatment and disease progression to identify progressors and non-progressors. We compared primary tumor gene expression and mutational status between these two groups. RESULTS: 105 genes were differentially expressed between progressors and nonprogressors (FDR < 0.05). Pathway analyses revealed deregulation (FDR < 0.05) of multiple pathways related to integrin signaling as well as IL-10 signaling. A number of genes were uniquely mutated in the progressor cohort including increased frequency of truncating mutations in CTCF (P = 0.007). An 11-gene signature derived from a combination of unique mutations and differential expression was identified (PAGE4, SMTNL1, VTN, CA5A, C1orf43, KRTAP19-1, LEP, HRH4, PAGE5, SEZ6L, CREB3). This signature was associated with decreased overall survival (Logrank Test; P = 0.03443). Cox modeling of both key clinical features and the signature was significant (P = 0.032) with the greatest prognostic improvement seen in the model based on nodal extracapsular spread and alcohol use alone (P = 0.004). CONCLUSIONS: Molecular analyses of head and neck cancer tumors that progressed despite treatment, identified IL-10 and integrin pathways to be strongly associated with cancer progression. In addition, we identified an 11-gene signature with implications for patient prognostication. Mutational analysis highlighted a potential role for CTCF, a crucial regulator of long-range chromatin interactions, in head and neck cancer progression. PMID- 26747561 TI - Technical advances in trigger-induced RNA interference gene silencing in the parasite Entamoeba histolytica. AB - Entamoeba histolytica has a robust endogenous RNA interference (RNAi) pathway. There are abundant 27 nucleotide (nt) anti-sense small RNAs (AS sRNAs) that target genes for silencing and the genome encodes many genes involved in the RNAi pathway such as Argonaute proteins. Importantly, an E. histolytica gene with numerous AS sRNAs can function as a "trigger" to induce silencing of a gene that is fused to the trigger. Thus, the amebic RNAi pathway regulates gene expression relevant to amebic biology and has additionally been harnessed as a tool for genetic manipulation. In this study we have further improved the trigger-induced gene silencing method. We demonstrate that rather than using the full-length gene, a short portion of the coding region fused to a trigger is sufficient to induce silencing; the first 537 bp of the E. histolytica rhomboid gene (EhROM1) fused in-frame to the trigger was sufficient to silence EhROM1. We also demonstrated that the trigger method could silence two amebic genes concomitantly; fusion of the coding regions of EhROM1 and transcription factor, EhMyb, in-frame to a trigger gene resulted in both genes being silenced. Alternatively, two genes can be silenced sequentially: EhROM1-silenced parasites with no drug selection plasmid were transfected with trigger-EhMyb, resulting in parasites with both EhROM1 and EhMyb silenced. With all approaches tested, the trigger-mediated silencing was substantive and silencing was maintained despite loss of the G418 selectable marker. All gene silencing was associated with generation of AS sRNAs to the silenced gene. We tested the reversibility of the trigger system using inhibitors of histone modifications but found that the silencing was highly stable. This work represents a technical advance in the trigger gene silencing method in E. histolytica. Approaches that readily silence multiple genes add significantly to the genetic toolkit available to the ameba research community. PMID- 26747562 TI - Pathologically Confirmed Chronic Traumatic Encephalopathy in a 25-Year-Old Former College Football Player. PMID- 26747564 TI - Comment on Three X-ray Crystal Structure Papers. PMID- 26747563 TI - Comparative Study of Early Cold-Regulated Proteins by Two-Dimensional Difference Gel Electrophoresis Reveals a Key Role for Phospholipase Dalpha1 in Mediating Cold Acclimation Signaling Pathway in Rice. AB - To understand the early signaling steps that regulate cold responses in rice, two dimensional difference gel electrophoresis (2-D DIGE)(1)was used to study early cold-regulated proteins in rice seedlings. Using mass spectrometry, 32 spots, which represent 26 unique proteins that showed an altered expression level within 5 min of cold treatment were identified. Among these proteins, Western blot analyses confirmed that the cellular phospholipase D alpha1 (OsPLDalpha1) protein level was increased as early as 1 min after cold treatment. Genetic studies showed that reducing the expression ofOsPLDalpha1makes rice plants more sensitive to chilling stress as well as cold acclimation increased freezing tolerance. Correspondingly, cold-regulated proteomic changes and the expression of the cold responsive C repeat/dehydration-responsive element binding 1 (OsDREB1) family of transcription factors were inhibited in thepldalpha1mutant. We also found that the expression ofOsPLDalpha1is directly regulated by OsDREB1A. This transcriptional regulation ofOsPLDalpha1could provide positive feedback regulation of the cold signal transduction pathway in rice. OsPLDalpha1 hydrolyzes phosphatidylcholine to produce the signal molecule phosphatidic acid (PA). By lipid-overlay assay, we demonstrated that the rice cold signaling proteins, MAP kinase 6 (OsMPK6) and OsSIZ1, bind directly to PA. Taken together, our results suggest that OsPLDalpha1 plays a key role in transducing cold signaling in rice by producing PA and regulatingOsDREB1s' expression by OsMPK6, OsSIZ1, and possibly other PA-binding proteins. PMID- 26747565 TI - Comments from the Editor-in-Chief. PMID- 26747566 TI - Response to Comment on Three X-ray Crystal Structure Papers. PMID- 26747567 TI - Additional Comment on Three X-ray Crystal Structure Papers. PMID- 26747568 TI - Comment on "Cutting Edge: Inhibiting TBK1 by Compound II Ameliorates Autoimmune Disease in Mice". PMID- 26747569 TI - Response to Additional Comment on Three X-ray Crystal Structure Papers. PMID- 26747570 TI - Response to Comment on "Cutting Edge: Inhibiting TBK1 by Compound II Ameliorates Autoimmune Disease in Mice". PMID- 26747571 TI - Posttranscriptional and Translational Control of Gene Regulation in CD4+ T Cell Subsets. AB - The immune system is under strict regulatory control to ensure homeostasis of inflammatory responses, lying dormant when not needed but quick to act when called upon. Small changes in gene expression can lead to drastic changes in lineage commitment, cellular function, and immunity. Conventional assessment of these changes centered on the analysis of mRNA levels through a variety of methodologies, including microarrays. However, mRNA synthesis does not always correlate directly to protein synthesis and downstream functional activity. Work conducted in recent years has begun to shed light on the various posttranscriptional changes that occur in response to a dynamic external environment that a given cell type encounters. We provide a critical review of key posttranscriptional mechanisms (i.e., microRNA) and translational mechanisms of regulation of gene expression in the immune system, with a particular emphasis on these regulatory processes in various CD4(+) T cell subsets. PMID- 26747577 TI - Effects of breed, age, season, and multiple ovulations on cyclic, PGF2alpha induced, and postpartum estrus characteristics in Spanish jennies. AB - This retrospective, population-based, cross-sectional study analyzed data for a total of 104 jennies reared in southern Spain over the period 1995 to 2014. Intervals to ovulation and incidence of multiple ovulation and pregnancy were charted for spontaneous, PGF2alpha-induced, and postpartum estrous cycles. In spontaneous estrous cycles, the interovulatory interval varied as a function of breed (P < 0.03) and month of ovulation (P < 0.01), and duration of estrus signs was longer in older jennies (0.04). Spontaneous cycles were also associated with higher ovulation rates from September to January (P < 0.006). When PGF2alpha was used to induce the estrus, not only did estrus signs last longer in old (P < 0.004) and in polyovular (0.02) jennies but old jennies also displayed significantly higher ovulation rates (P < 0.03). In postpartum jennies, no variations were observed as a function of any of the independent variables analyzed. Comparison of ovulation rates between different types of cycle revealed that postpartum jennies exhibited significantly lower ovulation rates (1.32 +/- 0.07) and a lower incidence of multiple ovulation (30.4%) than spontaneous (1.62 +/- 0.04, 55.0%) and PGF2alpha-induced (1.74 +/- 0.08, 65.5%) groups. No differences were observed in the incidence of ovulation or pregnancy depending on the location of ovulation in polyovular cycles, and ovulation occurred at similar rates in the right and left ovaries. These findings shed further light on reproductive physiology in jennies and may be of value in improving animal management. PMID- 26747578 TI - Involvement of cAMP-dependent unique signaling cascades in the decrease of serine/threonine-phosphorylated proteins in boar sperm head. AB - We previously suggested that protein phosphatase-dependent decrease of postacrosomal phosphorylated proteins may be necessary for the occurrence of acrosome reaction in livestock spermatozoa (Adachi et al., J Reprod Dev 54, 171 176, 2008; Mizuno et al., Mol Reprod Dev 82, 232-250, 2015). The aim of this study was to examine the involvement of the intracellular cAMP signaling cascades in the regulation of the decrease of postacrosomal phosphorylated proteins in boar spermatozoa. Boar ejaculated spermatozoa were incubated with cAMP analogs and then used for the immunodetection of serine/threonine-phosphorylated proteins and assessment of acrosome morphology. The protein phosphatase-dependent decrease of postacrosomal phosphorylated proteins was greatly promoted by the incubation with a cAMP analog Sp-5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole-3',5' monophosphorothioate (cBiMPS). This decrease was induced before the initiation of acrosome reaction and did not require the millimolar concentration of extracellular Ca(2+) which was necessary for the initiation of acrosome reaction. Moreover, suppression of protein kinase A activity with an inhibitor (H89) had almost no influence on both decrease of phosphorylated proteins and occurrence of acrosome reaction in the spermatozoa incubated with cBiMPS. In addition, the prolonged incubation with a potentially exchange protein directly activated by cAMP-selective cAMP analog (8pM) could only partially mimic effects of cBiMPS on these events. These results indicate that the cAMP-dependent signaling cascades which are less dependent on protein kinase A may regulate the decrease of postacrosomal phosphorylated proteins in boar spermatozoa before the extracellular Ca(2+)-triggered initiation of acrosome reaction. PMID- 26747580 TI - Primary Aortocaval Fistula and Juxtarenal Aortic Aneurysm. PMID- 26747579 TI - A DTI study on the corpus callosum of treatment-naive boys with 'pure' Tourette syndrome. AB - Disturbances in the corpus callosum (CC) indicating altered interhemispheric connectivity have been associated with Tourette syndrome (TS). The objective of the present study was to refine knowledge about interhemispheric connectivity in TS by analyzing four different diffusion tensor imaging (DTI) parameters in a very homogeneous group of treatment-naive boys with pure TS in comparison to male healthy controls (HC). Fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) and mean diffusivity (MD) of five CC-segments were assessed from DTI of 26 treatment-naive boys with pure TS and 24 HC. We observed no group differences in both FA and RD. However, we found a significant effect for AD and a trend for MD, being both reduced in boys with TS in comparison to HC. Moreover, a negative correlation between AD and the Yale Global Tic Severity Scale total score was observed. Reduced AD of the CC in treatment-naive boys with pure TS in comparison to HC may indicate that significant alterations in white matter microstructure of the CC contribute to tic symptomatology per se and seem not to be related to confounders such as consequences of long-term medication, tic performance or tic suppression. PMID- 26747581 TI - The Interplay of Dengue Virus Morphological Diversity and Human Antibodies. AB - Dengue virus (DENV) infects ~400 million people annually, and there is no available vaccine or therapeutics. It is not clear why candidate vaccines provide only modest protection. In addition to the presence of four different dengue serotypes, there is also structural heterogeneity in DENV infectious particles, even within a strain. This severely complicates the development of vaccines and therapeutics. The currently known different morphologies of DENV are: immature, partially mature, compact mature, and expanded mature forms of the virus. In this review I describe these forms of the virus, their infectivity, and how antibodies could recognize these morphologies. I also discuss possible vaccine and antibody therapeutic formulations to protect against all morphologies. PMID- 26747582 TI - Salivary Transmission of the Chikungunya Arbovirus. AB - The emergence of Chikungunya virus (CHIKV) has prompted a re-think of how preventative solutions should be approached since recent studies support the notion of salivary transmission. With the threat of significant health and economic burden, new control strategies aimed at limiting salivary transmission are needed to avoid further outbreaks. PMID- 26747583 TI - Relation between Neospora caninum and abortion in dairy cows: Risk factors and pathogenesis of disease. AB - Neosporosis is a parasitic disease cause by Neospora caninum, a parasite of great importance in livestock. This study aimed to evaluate the presence of antibody against N. caninum in dairy cattle with history of abortion, as well as to identify associated risk factors for neosporosis. Animals suspected of neosporosis (n = 130) after clinical examination were randomly selected. Sera samples from 29 farms were submitted to indirect immunofluorescence technique (IFA) in order to detect antibodies against N. caninum, and animals were considered positive if >= IFA 1:200. An epidemiological questionnaire was used to verify probable risk factors for neosporosis and their cause-effect relation. Serological results showed that 43.8% of the animals were seropositives for N. caninum. The univariate statistical analysis found a significant relation between neoporosis and age. The number of pregnancies and the number of years that the farms had been producing milk were found as associated risk factors for the disease either by univariate or by multivariate analyses. The cause-effect model found a possible relation between reproductive problems and positive serology for neosporosis (P = 0.06). Therefore, it was concluded that approximately 44% of dairy cows with history of abortion were seropositives for N. caninum and that age and the number of years that the farms had been producing milk are risk factors for parasite infection in dairy cattle. PMID- 26747584 TI - Antimicrobial resistance pattern and genetic correlation in Enterococcus faecium isolated from healthy volunteers. AB - Enterococci are known as a cause of nosocomial infections and this aptitude is intensified by the growth of antibiotic resistance. In the present study, Enterococcus faecium isolates from healthy volunteers were considered to determine the antibiotic resistance profiles and genetic correlation. A total 91 normal flora isolates of enterococci were included in this study. Identification of Enterococcus genus and species were done by biochemical and PCR methods, respectively. Sensitivity for 10 antibiotics was determined and genetic relatedness of all isolates was assessed using Repetitive Element Palindromic PCR (REP-PCR) followed by Pulse Field Gel Electrophoresis (PFGE) on the representative patterns. None of the isolates were resistant to teicoplanin, vancomycin, quinupristin-dalfopristin, linezolid, chloramphenicol, ampicillin and high-level gentamicin. On the other hand, the resistance rate was detected in 30.7%, 23%, and 3.29% of isolates for erythromycin, tetracycline and ciprofloxacin, respectively. The results of PFGE showed 19 (61.5% of our isolates) common types (CT) and 35 (38.5%) single types (ST) amongst the isolates. This is the first study to describe antibiotic resistance pattern and genetic relationship among normal flora enterococci in Iran. This study showed no prevalence of Vancomycin Resistant Enterococci (VRE) and high degrees of diversity among normal flora isolates by genotyping using PFGE. PMID- 26747585 TI - External Quality Assessment for Detection of Fetal Trisomy 21, 18, and 13 by Massively Parallel Sequencing in Clinical Laboratories. AB - An external quality assessment for detection of trisomy 21, 18, and 13 by massively parallel sequencing was implemented by the National Center for Clinical Laboratories of People's Republic of China in 2014. Simulated samples were prepared by mixing fragmented abnormal DNA with plasma from non-pregnant women. The external quality assessment panel, comprising 5 samples from pregnant healthy women, 2 samples with sex chromosome aneuploidies, and 13 samples with different concentrations of fetal fractions positive for trisomy 21, 18, and 13, was then distributed to participating laboratories. In total, 55.6% (47 of 84) of respondents correctly identified each of the samples in the panel. Seventeen false-negative and 87 gray zone results were reported, most [102 of 104 (98.1%)] of which were derived from for trisomy samples with effective fetal fractions <4%. No laboratories generated false-positive results. In addition, we observed varied diagnostic capabilities of different assays, with the assay on the basis of NextSeq CN500 performing better than others, whereas Z values generated by BGISEQ-100 fluctuated greatly. There were no significant correlations between the numbers of unique sequence reads and Z values from any trisomy sample generated by BGISEQ-100. Overall, most clinical laboratories detected samples containing effective fetal fractions >4%. Our study shows need for further laboratory training in the management of samples with low fetal fractions. For some assays, precision of Z values needs to be improved. PMID- 26747586 TI - A Multiplexed Amplicon Approach for Detecting Gene Fusions by Next-Generation Sequencing. AB - Chromosomal rearrangements that result in oncogenic gene fusions are clinically important drivers of many cancer types. Rapid and sensitive methods are therefore needed to detect a broad range of gene fusions in clinical specimens that are often of limited quantity and quality. We describe a next-generation sequencing approach that uses a multiplex PCR-based amplicon panel to interrogate fusion transcripts that involve 19 driver genes and 94 partners implicated in solid tumors. The panel also includes control assays that evaluate the 3'/5' expression ratios of 12 oncogenic kinases, which might be used to infer gene fusion events when the partner is unknown or not included on the panel. There was good concordance between the solid tumor fusion gene panel and other methods, including fluorescence in situ hybridization, real-time PCR, Sanger sequencing, and other next-generation sequencing panels, because 40 specimens known to harbor gene fusions were correctly identified. No specific fusion reads were observed in 59 fusion-negative specimens. The 3'/5' expression ratio was informative for fusions that involved ALK, RET, and NTRK1 but not for BRAF or ROS1 fusions. However, among 37 ALK or RET fusion-negative specimens, four exhibited elevated 3'/5' expression ratios, indicating that fusions predicted solely by 3'/5' read ratios require confirmatory testing. PMID- 26747598 TI - Special issue on animal models in endocrine neoplasia. PMID- 26747599 TI - Classification of Cholesteatoma According to Growth Patterns. AB - IMPORTANCE: Several classifications of cholesteatoma exist, but there are controversies about their clinical application. OBJECTIVE: To classify cholesteatomas and describe the prevalence of the subtypes. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional comparative study of 414 ears in 356 consecutive patients with middle ear cholesteatoma and no history of ear surgery treated at a tertiary hospital was conducted from March 8, 2000, to March 30, 2015. Data analysis was conducted from March 30, 2014, to March 30, 2015. INTERVENTION: Otoendoscopy was conducted, and findings for both ears were recorded. MAIN OUTCOMES AND MEASURES: Cholesteatoma growth patterns were classified as anterior epitympanic, posterior epitympanic, posterior mesotympanic, 2 routes (both the pars flaccida and the pars tensa are involved), and undetermined. RESULTS: Among the 356 patients in this study, mean (SD) patient age was 33.23 (19.81) years (range, 4-82 years), and 125 patients (35.1%) were female. The right ear was identified as the affected ear in 220 patients (61.8%). A total of 272 (65.7%) ears were from adults. Of the 414 ears that underwent otoendoscopy, posterior epitympanic (142 [34.3%]) and posterior mesotympanic (140 [33.8%]) were the most frequent types of cholesteatoma observed, followed by undetermined (67 [16.2%]) and 2 routes (57 [13.8%]). Anterior epitympanic type was the least frequent (8 [1.9%]). Posterior epitympanic cholesteatoma was more prevalent in adults (111 [40.8%]), whereas posterior mesotympanic cholesteatoma was more frequent in children (43.0%) (P < .001). Anterior epitympanic cholesteatoma was observed only in children. CONCLUSIONS AND RELEVANCE: Classifying cholesteatomas according to the growth pattern (anterior epitympanic, posterior epitympanic, posterior mesotympanic, 2 routes, and undetermined) includes all existing types of cholesteatomas of the middle ear. In general, the prevalence of posterior epitympanic and posterior mesotympanic cholesteatoma were similar. Whereas anterior epitympanic and posterior mesotympanic cholesteatomas were more prevalent in children, posterior epitympanic cholesteatoma was more frequent in adults. PMID- 26747600 TI - Leo P. Kadanoff (1937-2015): An appreciation. PMID- 26747601 TI - H1N1 infection of sleep/wake regions results in narcolepsy-like symptoms. PMID- 26747602 TI - Driven to metastasize: Kinases as potential therapeutic targets in prostate cancer. PMID- 26747603 TI - Dating the origin of dinosaurs. PMID- 26747604 TI - Ligand steals spotlight from metal to orchestrate hydrogen production. PMID- 26747605 TI - Human phosphatase CDC14A is recruited to the cell leading edge to regulate cell migration and adhesion. AB - Cell adhesion and migration are highly dynamic biological processes that play important roles in organ development and cancer metastasis. Their tight regulation by small GTPases and protein phosphorylation make interrogation of these key processes of great importance. We now show that the conserved dual specificity phosphatase human cell-division cycle 14A (hCDC14A) associates with the actin cytoskeleton of human cells. To understand hCDC14A function at this location, we manipulated native loci to ablate hCDC14A phosphatase activity (hCDC14A(PD)) in untransformed hTERT-RPE1 and colorectal cancer (HCT116) cell lines and expressed the phosphatase in HeLa FRT T-Rex cells. Ectopic expression of hCDC14A induced stress fiber formation, whereas stress fibers were diminished in hCDC14A(PD) cells. hCDC14A(PD) cells displayed faster cell migration and less adhesion than wild-type controls. hCDC14A colocalized with the hCDC14A substrate kidney- and brain-expressed protein (KIBRA) at the cell leading edge and overexpression of KIBRA was able to reverse the phenotypes of hCDC14A(PD) cells. Finally, we show that ablation of hCDC14A activity increased the aggressive nature of cells in an in vitro tumor formation assay. Consistently, hCDC14A is down-regulated in many tumor tissues and reduced hCDC14A expression is correlated with poorer survival of patients with cancer, to suggest that hCDC14A may directly contribute to the metastatic potential of tumors. Thus, we have uncovered an unanticipated role for hCDC14A in cell migration and adhesion that is clearly distinct from the mitotic and cytokinesis functions of Cdc14/Flp1 in budding and fission yeast. PMID- 26747606 TI - Actin-interacting Protein 1 Promotes Disassembly of Actin-depolymerizing Factor/Cofilin-bound Actin Filaments in a pH-dependent Manner. AB - Actin-interacting protein 1 (AIP1) is a conserved WD repeat protein that promotes disassembly of actin filaments when actin-depolymerizing factor (ADF)/cofilin is present. Although AIP1 is known to be essential for a number of cellular events involving dynamic rearrangement of the actin cytoskeleton, the regulatory mechanism of the function of AIP1 is unknown. In this study, we report that two AIP1 isoforms from the nematode Caenorhabditis elegans, known as UNC-78 and AIPL 1, are pH-sensitive in enhancement of actin filament disassembly. Both AIP1 isoforms only weakly enhance disassembly of ADF/cofilin-bound actin filaments at an acidic pH but show stronger disassembly activity at neutral and basic pH values. However, a severing-defective mutant of UNC-78 shows pH-insensitive binding to ADF/cofilin-decorated actin filaments, suggesting that the process of filament severing or disassembly, but not filament binding, is pH-dependent. His 60 of AIP1 is located near the predicted binding surface for the ADF/cofilin actin complex, and an H60K mutation of AIP1 partially impairs its pH sensitivity, suggesting that His-60 is involved in the pH sensor for AIP1. These biochemical results suggest that pH-dependent changes in AIP1 activity might be a novel regulatory mechanism of actin filament dynamics. PMID- 26747607 TI - Determination of the Oligomeric State of SecYEG Protein Secretion Channel Complex Using in Vivo Photo- and Disulfide Cross-linking. AB - SecYEG protein of bacteria or Sec61alphabetagamma of eukaryotes is a universally conserved heterotrimeric protein channel complex that accommodates the partitioning of membrane proteins into the lipid bilayer as well as the secretion of proteins to the trans side of the plasma or endoplasmic reticular membrane, respectively. SecYEG function is facilitated by cytosolic partners, mainly a nascent chain-ribosome complex or the SecA ATPase motor protein. Extensive efforts utilizing both biochemical and biophysical approaches have been made to determine whether SecYEG functions as a monomer or a dimer, but such approaches have often generated conflicting results. Here we have employed site-specific in vivo photo-cross-linking or cysteine cross-linking, along with co immunoprecipitation or SecA footprinting techniques to readdress this issue. Our findings show that the SecY dimer to monomer ratio is relatively constant regardless of whether translocons are actively engaged with protein substrate or not. Under the former conditions the SecY dimer can be captured associated with a translocon-jammed substrate, indicative of SecY dimer function. Furthermore, SecA ATPase can be cross-linked to two copies of SecY when the complex contains a translocation intermediate. Collectively, our results suggest that SecYEG dimers are functional units of the translocon. PMID- 26747609 TI - Opposing Chromatin Signals Direct and Regulate the Activity of Lysine Demethylase 4C (KDM4C). AB - Histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 9 trimethylation (H3K9me3) are epigenetic marks with opposing roles in transcription regulation. Whereas colocalization of these modifications is generally excluded in the genome, how this preclusion is established remains poorly understood. Lysine demethylase 4C (KDM4C), an H3K9me3 demethylase, localizes predominantly to H3K4me3-containing promoters through its hybrid tandem tudor domain (TTD) (1, 2), providing a model for how these modifications might be excluded. We quantitatively investigated the contribution of the TTD to the catalysis of H3K9me3 demethylation by KDM4C and demonstrated that TTD-mediated recognition of H3K4me3 stimulates demethylation of H3K9me3 in cis on peptide and mononucleosome substrates. Our findings support a multivalent interaction mechanism, by which an activating mark, H3K4me3, recruits and stimulates KDM4C to remove the repressive H3K9me3 mark, thus facilitating exclusion. In addition, our work suggests that differential TTD binding properties across the KDM4 demethylase family may differentiate their targets in the genome. PMID- 26747608 TI - Mechanistic Insights into Hsp104 Potentiation. AB - Potentiated variants of Hsp104, a protein disaggregase from yeast, can dissolve protein aggregates connected to neurodegenerative diseases such as Parkinson disease and amyotrophic lateral sclerosis. However, the mechanisms underlying Hsp104 potentiation remain incompletely defined. Here, we establish that 2-3 subunits of the Hsp104 hexamer must bear an A503V potentiating mutation to elicit enhanced disaggregase activity in the absence of Hsp70. We also define the ATPase and substrate-binding modalities needed for potentiated Hsp104(A503V) activity in vitro and in vivo. Hsp104(A503V) disaggregase activity is strongly inhibited by the Y257A mutation that disrupts substrate binding to the nucleotide-binding domain 1 (NBD1) pore loop and is abolished by the Y662A mutation that disrupts substrate binding to the NBD2 pore loop. Intriguingly, Hsp104(A503V) disaggregase activity responds to mixtures of ATP and adenosine 5'-(gamma-thio)-triphosphate (a slowly hydrolyzable ATP analogue) differently from Hsp104. Indeed, an altered pattern of ATP hydrolysis and altered allosteric signaling between NBD1 and NBD2 are likely critical for potentiation. Hsp104(A503V) variants bearing inactivating Walker A or Walker B mutations in both NBDs are inoperative. Unexpectedly, however, Hsp104(A503V) retains potentiated activity upon introduction of sensor-1 mutations that reduce ATP hydrolysis at NBD1 (T317A) or NBD2 (N728A). Hsp104(T317A/A503V) and Hsp104(A503V/N728A) rescue TDP-43 (TAR DNA-binding protein 43), FUS (fused in sarcoma), and alpha-synuclein toxicity in yeast. Thus, Hsp104(A503V) displays a more robust activity that is unperturbed by sensor-1 mutations that greatly reduce Hsp104 activity in vivo. Indeed, ATPase activity at NBD1 or NBD2 is sufficient for Hsp104 potentiation. Our findings will empower design of ameliorated therapeutic disaggregases for various neurodegenerative diseases. PMID- 26747611 TI - Outcomes of a Mobile Health Coaching Platform: 12-Week Results of a Single-Arm Longitudinal Study. AB - BACKGROUND: The number of mobile health coaching applications is expanding at a rapid rate. An application that uses a guiding intelligence to deliver an individualized structured program has the potential to provide a significant benefit. However, there are few studies of this approach that examine multiple clinical outcomes in a longitudinal manner. OBJECTIVE: The objective of the study was to conduct a 12-week evaluation of participants using the YouPlus Health mobile coaching platform, specifically examining the effects on body weight, waist measurement, blood pressure, lipid profile, glycohemoglobin (A1C), and maximum volume of oxygen consumption (VO2 max). METHODS: A quasi-experimental research design was used. This included a single-arm pre and post intervention assessment of outcomes. Participants underwent a 12-week intervention in which they received the entirety of the mobile health coaching program via an application on their mobile phones and were evaluated in the same physician's office setting every two weeks. Data regarding app usage was continuously collected and maintained in a database. RESULTS: 10 subjects were enrolled in and completed the pilot study. The mean weight loss was 13.5 lbs. which represented 7.3% of baseline (P=.005). Mean waist circumference was reduced by 7.2 cm or 6.6% of baseline (P=.005). Both systolic (SBP) and diastolic (DBP) blood pressure measures were significantly lower after 12 weeks of intervention. Mean SBP fell 18.6 mmHg (P=.005) and mean DBP declined 6.4 mmHg (P=.005). VO2 max increased by an average of 3.13 ml/kg/min from baseline to study end (P=.005). From baseline to end-of-study HDL levels increased significantly by 4.0 mg/dL (P=.04) Total cholesterol, LDL, triglycerides, and glycohemoglobin (A1C) trended in the desired direction but did not meet statistical significance. All of the participants in the study completed the necessary in-app tutorials and also completed the in-app questions and received feedback. Every individual completed the appropriate amount of program levels necessary to give the specifics of the program, and the mean weekly app open rate ranged from 5.1 to 18.4. CONCLUSIONS: Users of the YouPlus Health mobile coaching platform experienced significant reductions in body weight, waist circumference, and both systolic and diastolic blood pressures, while attaining significant increases in HDL and VO2 Max. PMID- 26747612 TI - Characterization and comparison of osteoblasts derived from mouse embryonic stem cells and induced pluripotent stem cells. AB - New developments in stem cell biology offer alternatives for the reconstruction of critical-sized bone defects. One of these developments is the use of induced pluripotent stem (iPS) cells. These stem cells are similar to embryonic stem (ES) cells, but can be generated from adult somatic cells and therefore do not raise ethical concerns. Proper characterization of iPS-derived osteoblasts is important for future development of safe clinical applications of these cells. For this reason, we differentiated mouse ES and iPS cells toward osteoblasts using osteogenic medium and compared their functionality. Immunocytochemical analysis showed significant expression of bone markers (osteocalcin and collagen type I) in osteoblasts differentiated from ES and iPS cells on days 7 and 30. An in vitro mineralization assay confirmed the functionality of osteogenically differentiated ES and iPS cells. Gene expression arrays focusing on osteogenic differentiation were performed in order to compare the gene expression pattern in both differentiated and undifferentiated ES cells and iPS cells. We observed a significant upregulation of osteogenesis-related genes such as Runx2, osteopontin, collagen type I, Tnfsf11, Csf1, and alkaline phosphatase upon osteogenic differentiation of the ES and iPS cells. We further validated the expression of key osteogenic genes Runx2, osteopontin, osteocalcin, collagen type I, and osterix in both differentiated and undifferentiated ES and iPS cells by means of quantified real-time polymerase chain reaction. We conclude that ES and iPS cells are similar in their osteogenic differentiation capacities, as well as in their gene expression patterns. PMID- 26747610 TI - Homodimeric PHD Domain-containing Rco1 Subunit Constitutes a Critical Interaction Hub within the Rpd3S Histone Deacetylase Complex. AB - Recognition of histone post-translational modifications is pivotal for directing chromatin-modifying enzymes to specific genomic regions and regulating their activities. Emerging evidence suggests that other structural features of nucleosomes also contribute to precise targeting of downstream chromatin complexes, such as linker DNA, the histone globular domain, and nucleosome spacing. However, how chromatin complexes coordinate individual interactions to achieve high affinity and specificity remains unclear. The Rpd3S histone deacetylase utilizes the chromodomain-containing Eaf3 subunit and the PHD domain containing Rco1 subunit to recognize nucleosomes that are methylated at lysine 36 of histone H3 (H3K36me). We showed previously that the binding of Eaf3 to H3K36me can be allosterically activated by Rco1. To investigate how this chromatin recognition module is regulated in the context of the Rpd3S complex, we first determined the subunit interaction network of Rpd3S. Interestingly, we found that Rpd3S contains two copies of the essential subunit Rco1, and both copies of Rco1 are required for full functionality of Rpd3S. Our functional dissection of Rco1 revealed that besides its known chromatin-recognition interfaces, other regions of Rco1 are also critical for Rpd3S to recognize its nucleosomal substrates and functionin vivo. This unexpected result uncovered an important and understudied aspect of chromatin recognition. It suggests that precisely reading modified chromatin may not only need the combined actions of reader domains but also require an internal signaling circuit that coordinates the individual actions in a productive way. PMID- 26747615 TI - Gut Microbiota Cool-Down Burning Fat! The Immune Hypothesis. AB - Obesity is characterized by gut microbiota dysbiosis and reduced thermogenic activity of brown adipose tissue. A recent study reveals that gut microbiota hampers the emergence of thermogenic brown fat cells named beige cells within white fat depots via a mechanism that involves the control of macrophages and eosinophil infiltration. PMID- 26747613 TI - Bone mineral density and its determinants in men with opioid dependence. AB - Data on the influence of opioid substitution therapy (OST) on skeletal health in men is limited. This cross-sectional study aimed to determine the prevalence of low bone mass in male drug users and to evaluate the relationship between endogenous testosterone and bone mass. We recruited 144 men on long-term opioid maintenance therapy followed in the Center of Addiction Medicine in Basel, Switzerland. Data on medical and drug history, fracture risk and history of falls were collected. Bone mineral density (BMD) was evaluated by densitometry and serum was collected for measurements of gonadal hormones and bone markers. 35 healthy age- and BMI-matched men served as the control group. The study participants received OST with methadone (69 %), morphine (25 %) or buprenorphine (6 %). Overall, 74.3 % of men had low bone mass, with comparable bone mass irrespective of OST type. In older men (>=40 years, n = 106), 29.2 % of individuals were osteoporotic (mean T-score -3.0 +/- 0.4 SD) and 48.1 % were diagnosed with osteopenia (mean T-score -1.7 +/- 0.4 SD). In younger men (n = 38), 65.8 % of men had low bone mass. In all age groups, BMD was significantly lower than in age-and BMI-matched controls. In multivariate analyses, serum free testosterone (fT) was significantly associated with low BMD at the lumbar spine (p = 0.02), but not at the hip. When analysed by quartiles of fT, lumbar spine BMD decreased progressively with decreasing testosterone levels. We conclude that low bone mass is highly prevalent in middle-aged men on long-term opioid dependency, a finding which may partly be determined by partial androgen deficiency. PMID- 26747616 TI - Prevalence and predictors of left intraventricular dyssynchrony determined by phase analysis in patients undergoing gatedSPECT myocardial perfusion imaging. AB - Left ventricular dyssynchrony (LVD) is an independent predictor of adverse cardiovascular events, death, and progression to heart failure. Myocardial perfusion imaging (MPI) with ECG-gated single-photon emission computed tomography (SPECT) can be used to diagnose LVD rapidly and automatically using phase analysis (PA). The objective of this study was to evaluate the prevalence and predictors of LVD in patients undergoing MPI. Clinical, electrocardiographic, and scintigraphic data from 1000 patients who underwent MPI with ECG-gated SPECT over a period of 1 year were analyzed retrospectively. TheEmoryCardiac Toolboxsoftware was used for PA, and LVD was diagnosed based on the following criteria: standard deviation of LV phase distribution >=43 degrees and/or phase histogram >=140 degrees in the resting and/or stress phase of the examination. Several variables were evaluated using univariate and multivariate analyses. The prevalence of LVD in the study population was 6.5 %, and the average age was 63.6 +/- 12 years. The variables significantly associated with LVD were male gender, obesity, hypertension, diabetes, dyslipidemia, coronary artery disease (CAD), QRS interval >=120 ms, LV dysfunction, and myocardial perfusion defects (especially fixed defects) on MPI. Although the PA parameters were greater at rest, both phases could be used for diagnosis. Multivariate analysis revealed that the variables significantly associated with LVD were male sex, obesity, history of CAD, and QRS interval >=120 ms. The overall prevalence of LVD was 6.5 % in patients undergoing MPI in this study, and it reached 42 % in the presence of certain risk factors. PMID- 26747617 TI - Fetal Persistent Left Superior Vena Cava with Trisomy 21: A Case Report and Literature Review. PMID- 26747618 TI - Risk Factors for Intracardiac Thrombosis in the Right Atrium and Superior Vena Cava in Critically Ill Neonates who Required the Installation of a Central Venous Catheter. AB - BACKGROUND: Central venous catheter (CVC) installation is essential for the treatment of critically ill neonates; however, it is associated with the development of neonatal intracardiac thrombosis, which is a complication that is associated with a poor prognosis. We aimed to identify specific risk factors for the development of intracardiac thrombosis in the right atrium (RA) and superior vena cava (SVC) related to the use of CVC in critically ill neonates. METHODS: A case-control study was conducted at the tertiary referral neonatal intensive care unit of the Pediatric Hospital Siglo XXI in Mexico City, Mexico from 2008 to 2013. The included cases (n = 43) were de novo patients with intracardiac thrombosis in the RA and SVC diagnosed by echocardiography. The controls (n = 43) were neonates without intracardiac thrombosis or thrombosis at other sites. A logistic regression analysis was conducted, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: The independent risk factors for intracardiac thrombosis in the RA and SVC were the surgical cut-down insertion technique (OR = 2.98; 95% CI: 1.18-9.10), a maternal history of gestational diabetes/diabetes mellitus (OR = 10.64; 95% CI: 1.13-121.41), Staphylococcus epidermidis infection (OR = 7.09; 95% CI: 1.09-45.92), and CVC placement in the SVC (OR = 5.77; 95% CI: 1.10-30.18). CONCLUSION: This study allowed us to identify several contributing factors to the development of intracardiac thrombosis in the RA and SVC related to the installation of a CVC in a subgroup of critically ill neonates. Multicenter and well-designed studies with a larger number of patients could help validate our findings and/or identify other risk factors that were not identified in the present study. PMID- 26747619 TI - Herpes Simplex Virus-related Transverse Myelitis and Polyneuritis. PMID- 26747614 TI - An overview of osteocalcin progress. AB - An increasing amount of data indicate that osteocalcin is an endocrine hormone which regulates energy metabolism, male fertility and brain development. However, the detailed functions and mechanism of osteocalcin are not well understood and conflicting results have been obtained from researchers worldwide. In the present review, we summarize the progress of osteocalcin studies over the past 40 years, focusing on the structure of carboxylated and undercarboxylated osteocalcin, new functions and putative receptors, the role of osteocalcin in bone remodeling, specific expression and regulation in osteoblasts, and new indices for clinical studies. The complexity of osteocalcin in completely, uncompletely and non carboxylated forms may account for the discrepancies in its tertiary structure and clinical results. Moreover, the extensive expression of osteocalcin and its putative receptor GPRC6A imply that there are new physiological functions and mechanisms of action of osteocalcin to be explored. New discoveries related to osteocalcin function will assist its potential clinical application and physiological theory, but comprehensive investigations are required. PMID- 26747620 TI - Thoracic Insufficiency Syndrome. AB - Thoracic insufficiency syndrome (TIS) is a broad grouping of disorders that have a substantial impact on the chest wall, spine, and in many situations, both. While the conditions are varied, they share a potentially substantial impact on respiratory capacity and development over time and a presentation and need for intervention that is often in early childhood. Addressing these conditions has required a new paradigm that involves both deformity correction and a preservation of growth capacity. While there are now a number of options to treat severe spinal deformity early in life, when the deformity causes or is caused by a chest wall deformity, the Vertical Expandable Prosthetic Titanium Rib(VEPTR) is able to support surgical correction of both. The skeletal correction is often quite dramatic, but the functional measurements of quality of life and pulmonary function often do not show as dramatic and improvement, but consistently show a stabilization indicating control of the progressive thoracospinal disorder that produced TIS. PMID- 26747621 TI - Letter to the editor re: ICP monitoring guidelines for TBI. PMID- 26747622 TI - Long-term survival of an infant with an atypical teratoid/rhabdoid tumor following subtotal resection and low-cumulative dose chemotherapy: a case report. AB - INTRODUCTION: Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive embryonal tumor of the central nervous system with a generally dismal prognosis, especially in patients younger than 12 months. DISCUSSION: We here describe the unusual case of an infant with AT/RT with long-term survival despite low-cumulative dose chemotherapy after subtotal resection. Due to a poor neurological situation and an unfavorable oncological prognosis, therapy was halted after two partial surgical resections and four of the nine chemotherapy courses recommended by the European Rhabdoid Registry, without the patient receiving either radiotherapy or high-dose chemotherapy. The patient is alive without evidence of disease 52 months after diagnosis. CONCLUSION: This case report highlights that independent prognostic factors are urgently needed for optimizing treatment stratification and preventing overtreatment. PMID- 26747623 TI - Congenital myotonic dystrophy: ventriculomegaly and shunt considerations for the pediatric neurosurgeon. AB - PURPOSE: Ventriculomegaly in infants with congenital myotonic dystrophy (CDM) is common, and the neurosurgical determination of shunting is complex. The natural history of CDM-associated ventriculomegaly from prenatal to natal to postnatal stages is poorly known. The relationship between macrocephaly and ventriculomegaly, incidence of shunt necessity, and early mortality outcomes lack pooled data analysis. This study aims to review clinical features and pathophysiology of CDM, with emphasis on ventriculomegaly progression, ventriculomegaly association with macrocephaly, and incidence of shunting. METHODS: This is a literature review with pooled data analysis and case report. RESULTS: One hundred four CDM patients were reviewed in 13 articles that mentioned CDM with ventriculomegaly and/or head circumference. Data was very limited: only 7 patients had data on the presence or absence of prenatal ventriculomegaly, 97 on ventriculomegaly at birth, and 32 on whether or not the ventricles enlarged post-natally. Three patients of 7 (43 %) had pre-natally diagnosed ventriculomegaly, 43 of 97 (44 %) had ventriculomegaly at birth, and only 5 of 32 (16 %) had progressive enlargement of ventricles post-natally. Only 5 of 104 patients had a documented shunt placement: 1 for obstructive, 1 for a post-hemorrhagic communicating, 2 for a communicating hydrocephalus without hemorrhage, and 1 with unknown indication. Of 13 macrocephalic patients with data about ventricular size, 12 had ventriculomegaly. CONCLUSIONS: Ventriculomegaly occurs regularly with CDM but most often does not require CSF diversion. Decisions regarding neurosurgical intervention will necessarily be based on limited information, but shunting should only occur once dynamic data confirms hydrocephalus. PMID- 26747625 TI - Development of a multiplex Q-PCR to detect Trichoderma harzianum Rifai strain T22 in plant roots. AB - The fungal species Trichoderma harzianum is widely used as a biological agent in crop protection. To verify the continued presence of this fungus on plant roots manually inoculated with T. harzianum strain T22, a Q-PCR was designed using specific probes for this particular strain. To develop these molecular diagnostic tools, genome mining was first carried out to retrieve putative new regions by which different strains of T. harzianum could be distinguished. Subsequently, Sanger sequencing of the L-aminoacid oxidase gene (aox1) in T. harzianum was applied to determine the mutations differing between various strains isolated from the Trichoderma collection of Koppert Biological Systems. Based on the sequence information obtained, a set of hydrolysis probes was subsequently developed which discriminated T. harzianum T22 strains varying in only a single nucleotide. Probes designed for two strains uniquely recognized the respective strains in Q-PCR with a detection limit of 12,5ng DNA. Titration assays in which T. harzianum DNA from distinct strains was varied further underscored the specificity of the probes. Lastly, fungal DNA extracted from roots of greenhouse cultured tomato plants was analyzed using the probe-based assay. DNA from T. harzianum strain T22 could readily be identified on roots of greenhouse reared tomato plants inoculated with varying concentrations up to one week after treatment with a detection limit of 3e6 colony forming units of T. harzianum T22. We conclude that the Q-PCR method is a reliable and robust method for assessing the presence and quantity of T. harzianum strain T22 in manually inoculated plant material. Our method provides scope for the development of DNA based strain specific identification of additional strains of Trichoderma and other fungal biological control agents. PMID- 26747624 TI - Impaired phosphorylation of JAK2-STAT5b signaling in fibroblasts from uremic children. AB - BACKGROUND: Chronic kidney disease (CKD) in children is characterized by severe growth failure. The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis in uremic animals shows a post-receptor impaired phosphorylation of Janus kinase 2/signal transducer and activator of transcription (JAK-STAT) proteins. The objective of our study was to characterize the intracellular phosphorylation of JAK-STAT signaling in fibroblasts from children with CKD on chronic peritoneal dialysis (PD). METHODS: Serum GH-binding protein (GHBP), IGF-1 and IGFBP3 were measured in 15 prepubertal CKD stage-5 children on PD. Cytoplasmic JAK2, cytoplasmic/nuclear STAT5b and nuclear IGFBP3, acid-labile subunit (ALS) and IGF 1 mRNA expression were quantified in fibroblasts obtained from skin biopsies before and after stimulation with 200 ng/ml recombinant human growth hormone (rhGH). Phosphorylation activity at both the cytoplasmic and nuclear level was expressed as the ratio phosphorylated (p)/total (t) abundance of the product (p/t) at 30 and 60 min. Fifteen healthy children were recruited as the control group. Values were expressed in arbitrary units (AU) and normalized for comparison. Significance was defined as p < 0.05. RESULTS: Thirty minutes after rhGH stimulus, the cytoplasmic (p/t) JAK2 ratio was significantly lower in patients than in controls [median and interquartile range (IQR): 7.4 (4.56) vs. 20.5 (50.06) AU]. At 60 min after rhGH stimulation, median JAK2 phosphorylation activity was still significantly lower in the patients [7.14 (IQR 3.8) vs. 10.2 (IQR 29.8) AU; p < 0.05]. The increase in the cytoplasmic (p/t) STAT5b/beta-actin ratio was lower at both measurement points in the patients compared to the controls, without reaching statistical significance between groups. Median IGFBP3 mRNA abundance was significantly decreased in fibroblasts from uremic patients 24 h after rhGH stimulation compared to the healthy controls [1.27 (IQR 0.83) vs. 2.37 (IQR 0.80) AU]. Median ALS and IGF-1 mRNA expression changed in response to rhGH stimuli at 24 and 48 h. CONCLUSION: In this study, children with CKD undergoing PD therapy showed an impaired phosphorylation of JAK2/STAT5b signaling in fibroblasts after GH stimulation, as well as impaired IGFBP3 mRNA abundance. Both impairments may be partially responsible for the observed resistance to the growth-promoting actions of GH in chronic kidney failure. PMID- 26747626 TI - Management of Cognitive Impairment in Heart Failure. AB - OPINION STATEMENT: Cognitive impairment (CI) is an inclusive term to describe trouble with memory, learning, concentration, or decision-making. CI is highly prevalent in patients with heart failure (HF) and is known to be associated with a variety of poor outcomes. While published HF guidelines recommend screening for CI, they do not indicate how, due to a lack of consensus in the literature about which instrument to use. Our recommendation is to use the Mini-Cog for this purpose because of its brevity and utility in identifying patients with HF at high risk for hospitalization or mortality. At this time, there is minimal published clinical trial evidence about how to manage CI in patients with HF. Reasonable approaches to management may include following guideline-directed medical therapy for HF, treatment of hypertension and atrial fibrillation, management of depression, proactive diagnosis and treatment of sleep apnea, and encouragement of aerobic exercise and weight loss. Left ventricular assist device (LVAD) therapy in patients with Stage D HF may improve CI in the short term after implantation, though there is a risk of worsening CI in the intermediate and long term. Clinicians who care for patients with HF should routinely screen for CI and when identified should encourage interventions to support self-care, increase family involvement, and arrange for more frequent follow-up. PMID- 26747627 TI - Approach to Treatment of Bifurcation Lesions. AB - OPINION STATEMENT: Bifurcation lesions are frequently encountered in the cath lab [1] and remain a challenge for conventional percutaneous coronary intervention (PCI) techniques. Although provisional stenting remains the default approach for most bifurcation lesions [2-6], the two-stent technique is more appropriate in certain situations. If a two-stent strategy is selected, then final kissing balloon inflation (KBI) should be performed. Adjunctive assessment with intravascular imaging (intravascular ultrasound (IVUS)/optical coherence tomography (OCT)) and physiologic testing (fractional flow reserve, FFR) should be performed liberally. Drug-eluting stents (DES) are typically utilized to reduce the risk of restenosis in bifurcation disease. PMID- 26747628 TI - Training Future Physicians to Deliver Tobacco Cessation Treatment. PMID- 26747629 TI - Myeloperoxidase-Antineutrophil Cytoplasmic Antibody-Positive Otitis Media and Rhinosinusitis With Pathological Features of Immunoglobulin G4-Related Disease: A Case Report. AB - BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have different clinical and pathological features. However, differentiation between these 2 disorders is sometimes difficult. OBJECTIVE: To report a case involving a patient with characteristics of both IgG4-RD and AAV. METHODS: Case report with literature review. RESULTS: We report a case of myeloperoxidase-ANCA-positive otitis media and rhinosinusitis with pathological features of IgG4-RD in a 73-year-old man. The patient was first clinically suspected to have granulomatosis with polyangiitis. All of the main characteristic pathological features of IgG4-RD were present: dense lymphoplasmacytic infiltration, increased numbers of IgG4 positive plasma cells, storiform-type fibrosis, and obliterative phlebitis. CONCLUSIONS: The simultaneous presence of the characteristics of both IgG4-RD and AAV makes diagnosis and treatment difficult. PMID- 26747630 TI - Device Life of Two Generations of Provox Voice Prostheses. AB - BACKGROUND: Tracheoesophageal voice prostheses are invaluable for speech rehabilitation in patients who have received total laryngectomy, but device failure impedes communication and creates psychosocial and financial burdens. This study compares the Provox 2 and Provox Vega voice prostheses on the parameter of device life. METHODS: This was a retrospective observational study of 21 patients with 181 device replacements at an academic tertiary care medical center. Disparity in device life and factors that may influence device life were analyzed. RESULTS: The mean device life for Provox 2, at 115.6 days (SE = 5.8), was longer than for Provox Vega, at 65.1 days (SE = 7.5) (P < .001). CONCLUSIONS: Device longevity was greater for Provox 2 over Provox Vega. These results will facilitate the design of prospective studies to assess reasons for variations in device life between patients and device types. PMID- 26747631 TI - Median artery of the forearm in human fetuses in northeastern Brazil: anatomical study and review of the literature. AB - A persistent median artery is a rare anomaly. It accompanies the median nerve along its course in the forearm and is of variable origin. It is associated with other local anatomical variations and may contribute significantly towards formation of the superficial palmar arch. In embryos, it is responsible mainly for the blood supply to the hand. The objective of this study was to research the frequency, type (forearm or palmar) and origin of the median artery in fetuses, correlating its presence with sex and body side. Red-colored latex was injected into 32 brachial arteries of human fetuses until its arrival in the hand could be seen. Twenty-four hours after the injection, the median arteries were dissected without the aid of optical instruments. Among the 32 forearms dissected, the median artery was present in 81.25 % (26) of the cases, and it was found more frequently in females and on the left side. Regarding origin, most of the median arteries originated in the common interosseous artery (38.5 %) and anterior interosseous artery (34.6 %). The mean length of the median arteries was 21.1 mm for the palmar type and 19.8 mm for the forearm type. The median artery has a high rate of persistence. It is important to be aware of this anatomical variation, since its presence may give rise to difficulties during routine surgical procedures on the wrist. Its presence may cause serious functional complications in the carpal tunnel, anterior interosseous nerve, round pronator syndromes, and ischemia of the hand. PMID- 26747632 TI - High rate of symptoms is seen five years after gastric bypass surgery for obesity. PMID- 26747633 TI - Familial Factors, Low Birth Weight, and Development of ESRD: A Nationwide Registry Study. AB - BACKGROUND: Previous studies have demonstrated that low birth weight (LBW) is associated with higher risk for end-stage renal disease (ESRD). However, both LBW and ESRD cluster in families. The present study investigates whether familial factors explain the association between LBW and ESRD. STUDY DESIGN: Retrospective registry-based cohort study. SETTING & PARTICIPANTS: Since 1967, the Medical Birth Registry of Norway has recorded medical data for all births in the country. Sibling data are available through the Norwegian Population Registry. Since 1980, all patients with ESRD in Norway have been registered in the Norwegian Renal Registry. Individuals registered in the Medical Birth Registry with at least 1 registered sibling were included. PREDICTOR: LBW in the participant and/or LBW in at least 1 sibling. OUTCOME: ESRD. RESULTS: Of 1,852,080 included individuals, 527 developed ESRD. Compared with individuals without LBW and with no siblings with LBW, individuals without LBW but with a sibling with LBW had an HR for ESRD of 1.20 (95% CI, 0.91-1.59), individuals with LBW but no siblings with LBW had an HR of 1.59 (95% CI, 1.18-2.14), and individuals with LBW and a sibling with LBW had an HR of 1.78 (95% CI, 1.26-2.53). Similar results were observed for individuals who were small for gestational age (SGA). Separate analyses for the association of age 18 to 42 years and noncongenital ESRD showed stronger associations for SGA than for LBW, and the associations were not statistically significant for age 18 to 42 years for LBW. LIMITATIONS: Follow-up only until 42 years of age. CONCLUSIONS: LBW and SGA are associated with higher risk for ESRD during the first 40 years of life, and the associations were not explained by familial factors. Our results support the hypothesis that impaired intrauterine nephron development may be a causal risk factor for progressive kidney disease. PMID- 26747634 TI - Zolmitriptan Nasal Spray: A Review in Acute Migraine in Pediatric Patients 12 Years of Age or Older. AB - The intranasal formulation of zolmitriptan, a selective serotonin 5-HT1B/1D agonist, was recently approved by the US Food and Drug Administration for the treatment of acute migraine in pediatric patients 12 years of age or older. This article summarizes the efficacy and tolerability of zolmitriptan (Zomig((r))) nasal spray (NS) in acute migraine in this patient group. Zolmitriptan NS 5 mg was more effective in relieving headache pain than placebo in two double-blind studies in pediatric patients 12-17 years of age with acute migraine. Furthermore, zolmitriptan NS 2.5 and 5 mg effectively relieved photophobia and phonophobia, and was associated with a faster return to normal daily activities than placebo. Zolmitriptan NS is rapidly absorbed from the nasal mucosa and is associated with a fast onset of action, with one study showing a significant difference versus placebo with regard to headache response 15 min after administration. In both trials, zolmitriptan NS was generally well tolerated, with no serious adverse events. In conclusion, zolmitriptan NS provides rapid, effective and generally well tolerated treatment of acute migraine in pediatric patients 12 years of age or older and may be of particular benefit for those with nausea or not easily able to swallow tablets. PMID- 26747635 TI - Long-Term Follow-Up on a Cohort Temporary Utilization Authorization (ATU) Survey of Patients Treated with Pheburane (Sodium Phenylbutyrate) Taste-Masked Granules. AB - OBJECTIVES: The aim was to describe the status of patients with urea cycle disorders (UCD) at the latest long-term clinical follow-up of treatment with a new taste-masked formulation of sodium phenylbutyrate (NaPB) granules (Pheburane). These patients are a subset of those treated under a cohort temporary utilisation study (ATU) previously reported and now followed for 2 years. METHODS: From a French cohort temporary utilization authorization (ATU) set up to monitor the use of Pheburane on a named-patient basis in UCD patients in advance of its marketing authorization, a subset of patients were followed up in the long term. Data on demographics, dosing characteristics of NaPB, concomitant medications, adverse events and clinical outcomes were collected at a follow-up visit after 1-2 years of treatment with the drug administered under marketing conditions. This paper reports on the subset of patients who were included in further long-term follow-up at the principal recruiting metabolic reference center involved in the original cohort. RESULTS: No episode of metabolic decompensation was observed over a treatment period ranging from 8 to 30 months with Pheburane, and the range of ammonia and glutamine levels continued to improve and remained within the normal range, thus adding valuable longer-term feedback to the original ATU report. In all, no adverse events were reported with Pheburane treatment. These additional data demonstrate the maintenance of the safety and efficacy of Pheburane over time. CONCLUSIONS: The recently developed taste-masked formulation of NaPB granules (Pheburane) improved the quality of life for UCD patients. The present post-marketing report on the use of the product confirms the original observations of improved compliance, efficacy and safety with this taste-masked formulation of NaPB. PMID- 26747637 TI - On chirality of slime mould. AB - Left-right patterning and lateralised behaviour is an ubiquitous aspect of plants and animals. The mechanisms linking cellular chirality to the large-scale asymmetry of multicellular structures are incompletely understood, and it has been suggested that the chirality of living cells is hardwired in their cytoskeleton. We examined the question of biased asymmetry in a unique organism: the slime mould Physarum polycephalum, which is unicellular yet possesses macroscopic, complex structure and behaviour. In laboratory experiment using a T shape, we found that Physarum turns right in more than 74% of trials. The results are in agreement with previously published studies on asymmetric movement of muscle cells, neutrophils, liver cells and growing neural filaments, and for the first time reveal the presence of consistently-biased laterality in the fungi kingdom. Exact mechanisms of the slime mould's direction preference remain unknown. PMID- 26747636 TI - Disentangling the influence of cell phone usage in the dilemma zone: An econometric approach. AB - This paper focuses on developing an analysis framework to study the impact of cell phone treatment (cell phone type and call status) on driver behavior in the presence of a dilemma zone. Specifically, we examine how the treatment influences the driver maneuver decision at the intersection (stop or cross) and the eventual success of the maneuver. For a stop maneuver, success is defined as stopping before the stop line. Similarly, for a cross maneuver, success is defined as clearing the intersection safely before the light turns red. The eventual success or failure of the driver's decision process is dependent on the factors that affected the maneuver decision. Hence it is important to recognize the interconnectedness of the stop or cross decision with its eventual success (or failure). Toward this end, we formulate and estimate a joint framework to analyze the stop/cross decision with its eventual success (or failure) simultaneously. The study is conducted based on driving simulator data provided online for the 2014 Transportation Research Board Data Contest at http://depts.washington.edu/hfsm/upload.php. The model is estimated to analyze drivers' behavior at the onset of yellow by employing exogenous variables from three broad categories: driver characteristics, cell phone attributes and driving attributes. We also generate probability surfaces to identify dilemma zone distribution associated with different cell phone treatment types. The plots clearly illustrate the impact of various cellphone treatments on driver dilemma zone behavior. PMID- 26747638 TI - Population-reaction model and microbial experimental ecosystems for understanding hierarchical dynamics of ecosystems. AB - Understanding ecosystem dynamics is crucial as contemporary human societies face ecosystem degradation. One of the challenges that needs to be recognized is the complex hierarchical dynamics. Conventional dynamic models in ecology often represent only the population level and have yet to include the dynamics of the sub-organism level, which makes an ecosystem a complex adaptive system that shows characteristic behaviors such as resilience and regime shifts. The neglect of the sub-organism level in the conventional dynamic models would be because integrating multiple hierarchical levels makes the models unnecessarily complex unless supporting experimental data are present. Now that large amounts of molecular and ecological data are increasingly accessible in microbial experimental ecosystems, it is worthwhile to tackle the questions of their complex hierarchical dynamics. Here, we propose an approach that combines microbial experimental ecosystems and a hierarchical dynamic model named population-reaction model. We present a simple microbial experimental ecosystem as an example and show how the system can be analyzed by a population-reaction model. We also show that population-reaction models can be applied to various ecological concepts, such as predator-prey interactions, climate change, evolution, and stability of diversity. Our approach will reveal a path to the general understanding of various ecosystems and organisms. PMID- 26747639 TI - Identification and characterization of an apoptosis-stimulating protein of p53 (ASPP) gene from Branchiostoma belcheri: Insights into evolution of ASPP gene family. AB - The ASPP (apoptosis-stimulating protein of p53) protein family plays very key roles in apoptosis regulation, in both p53-dependent and p53-independent pathways. However, the ASPP homologous gene has not been identified in amphioxus to date. Here, we identified and characterized an ASPP gene from Branchiostoma belcheri (designed as AmphiASPP) and extensively studied its evolution and roles involved in innate immunity. The results showed that the amphioxus genome has an ASPP homolog gene with an ORF of 3285 bp, encoding 1094 amino acids which contains ANK repeats and SK3 domain. The evolutionary analyses indicated that the members of ASPP protein family might be present in a common ancestor of Nematostella vectensis and underwent positive selective in the evolutionary history. In addition, the amphioxus ASPP gene was ubiquitously and differentially expressed in five investigated tissues, and the amphioxus ASPP gene was involved in the innate immune response of LPS and LTA stimulation. Finally, bioinformatic analyses displayed that amphioxus ASPP protein could interact with REL protein by conserved binding sites compared with human ASPP2 protein, which seemed to further suggest that the amphioxus ASPP protein involve in innate immunity through NF-kB signaling pathway. Taken together, our findings provided an insight into the evolution and innate immunity function of the ASPP family. PMID- 26747640 TI - First comparative characterization of three distinct ferritin subunits from a teleost: Evidence for immune-responsive mRNA expression and iron depriving activity of seahorse (Hippocampus abdominalis) ferritins. AB - Ferritins play an indispensable role in iron homeostasis through their iron withholding function in living beings. In the current study, cDNA sequences of three distinct ferritin subunits, including a ferritin H, a ferritin M, and a ferritin L, were identified from big belly seahorse, Hippocampus abdominalis, and molecularly characterized. Complete coding sequences (CDS) of seahorse ferritin H (HaFerH), ferritin M (HaFerM), and ferritin L (HaFerL) subunits were comprised of 531, 528, and 522 base pairs (bp), respectively, which encode polypeptides of 177, 176, and 174 amino acids, respectively, with molecular masses of ~20-21 kDa. Our in silico analyses demonstrate that these three ferritin subunits exhibit the typical characteristics of ferritin superfamily members including iron regulatory elements, domain signatures, and reactive centers. The coding sequences of HaFerH, M, and L were cloned and the corresponding proteins were overexpressed in a bacterial system. Recombinantly expressed HaFer proteins demonstrated detectable in vivo iron sequestrating (ferroxidase) activity, consistent with their putative iron binding capability. Quantification of the basal expression of these three HaFer sequences in selected tissues demonstrated a gene-specific ubiquitous spatial distribution pattern, with abundance of mRNA in HaFerM in the liver and predominant expression of HaFerH and HaFerL in blood. Interestingly, the basal expression of all three ferritin genes was found to be significantly modulated against pathogenic stress mounted by lipopolysaccharides (LPS), poly I:C, Streptococcus iniae, and Edwardsiella tarda. Collectively, our findings suggest that the three HaFer subunits may be involved in iron (II) homeostasis in big belly seahorse and that they are important in its host defense mechanisms. PMID- 26747641 TI - Cellular phenotyping of chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: Defining the phenotypes of chronic rhinosinusitis with nasal polyps (CRSwNP) with prognosis may lead to delivery of personalized treatment. This study aimed to identify cellular phenotypes of CRSwNP using cluster analysis and define an algorithm for different clusters associated with polyp recurrence. METHODS: Overall, 366 patients with CRSwNP were enrolled in this retrospective analysis. Eighteen variables, including clinical characteristics and tissue/peripheral inflammatory cells assessments, were selected for factor analysis. Unsupervised cluster analysis was performed after variables reduction and standardization and differences in polyp recurrence during follow-up for a minimum of 24 months were analysed among clusters. Discriminant analysis was further used to develop a clinically useful algorithm for predicting clustering. RESULTS: Five phenotypic clusters were identified. Clusters 1 and 2 were plasma cell-dominant and lymphocyte-dominant phenotypes, respectively. Cluster 3 revealed a mixed inflammatory pattern. Cluster 4 was characterized by infiltration of predominantly neutrophils. Cluster 5 was characterized by a marked tissue eosinophilia and highest recurrence rate of 98.5%. The clinical algorithm predicted clustering with 93.7% accuracy. CONCLUSIONS: Chinese CRSwNP patients may be classified into five phenotypes with different polyp recurrence rates, based on the presence of predominantly plasma cells, lymphocytes, neutrophils, eosinophils or mixed inflammatory cells in polyps. PMID- 26747642 TI - Conformational changes of recombinant monoclonal antibodies by limited proteolytic digestion, stable isotope labeling, and liquid chromatography-mass spectrometry. AB - Limited proteolytic digestion is a method with a long history that has been used to study protein domain structures and conformational changes. A method of combining limited proteolytic digestion, stable isotope labeling, and mass spectrometry was established in the current study to investigate protein conformational changes. Recombinant monoclonal antibodies with or without the conserved oligosaccharides, and with or without oxidation of the conserved methionine residues, were used to test the newly proposed method. All of the samples were digested in ammonium bicarbonate buffer prepared in normal water. The oxidized deglycosylated sample was also digested in ammonium bicarbonate buffer prepared in (18)O-labeled water. The sample from the digestion in (18)O water was spiked into each sample digested in normal water. Each mixed sample was subsequently analyzed by liquid chromatography-mass spectrometry (LC-MS). The molecular weight differences between the peptides digested in normal water versus (18)O-water were used to differentiate peaks from the samples. The relative peak intensities of peptides with or without the C-terminal incorporation of (18)O atoms were used to determine susceptibility of different samples to trypsin and chymotrypsin. The results demonstrated that the method was capable of detecting local conformational changes of the recombinant monoclonal antibodies caused by deglycosylation and oxidation. PMID- 26747643 TI - Serum metabolomics strategy for understanding pharmacological effects of ShenQi pill acting on kidney yang deficiency syndrome. AB - Kidney yang deficiency syndrome, a diagnostic pattern in Chinese medicine, is similar with clinical features of the glucocorticoid withdrawal syndrome. The aim of this present study was to explore low molecular mass differentiating metabolites between control group and model group of kidney yang deficiency rats induced with corticosterone as well as the therapeutic effect of Shen Qi Pill, a classic traditional Chinese medicine formula for treating Kidney yang deficiency syndrome in China. This study utilized ultra-performance liquid chromatography coupled with electrospray ionization synapt quadrupole time-of-flight high definition mass spectrometry (UPLC/ESI-SYNAPT-QTOF-HDMS) to identify the underlying biomarkers for clarifying mechanism of Shen Qi Pill in treating Kidney yang deficiency syndrome based on metabolite profiling of the serum samples and in conjunction with multivariate and pathway analysis. Meanwhile, blood biochemistry assay and histopathology were examined to identify specific changes in the model group rats. Distinct changes in the pattern of metabolites were observed by UPLC-HDMS. The changes in metabolic profiling were restored to their baseline values after treatment with Shen Qi Pill according to the combined with a principal component analysis (PCA) score plots. Altogether, the current metabolomics approach based on UPLC-HDMS and orthogonal projection to latent structures discriminate analysis (OPLS-DA) demonstrated 27 ions (18 in the negative mode, 9 in the positive mode, 17 ions restored by Shen Qi Pill). These results indicated that effectiveness of Shen Qi Pill in Kidney yang deficiency syndrome rats induced a substantial change in the metabolic profiles by regulating the biomarkers and adjusting the metabolic disorder. It suggested that the metabolomics approach was a powerful approach for elucidation of pathologic changes of Chinese medicine syndrome and action mechanisms of traditional Chinese medicine. PMID- 26747645 TI - Asthma prevalence and risk factors in early childhood at Northern Portugal. AB - Asthma is the commonest and most important chronic non-infectious disease in childhood and it has become more prevalent in recent years. There is a shortage of studies in relation to early childhood and so, as part of the INAIRCHILD project, this cross-sectional study aimed to assess the prevalence of asthma and its associated risk factors, namely demographic, environmental, psychosocial and clinical factors for infants and preschoolers living in Northern Portugal. Data concerning asthma prevalence were collected through questionnaires based on those from the International Study of Asthma and Allergies in Childhood (ISAAC derived), the questionnaires were distributed to 1042 children attending the 17 nurseries involved in the INAIRCHILD project (10 in urban and suburban context, and 7 in rural context). The response rate was 48%. Prevalence of asthma based on symptomatology and odds ratio was calculated. Around 52% of the studied children presented at least one of the respiratory symptoms investigated (wheeze, dyspnea and cough) in the absence of upper respiratory infections. The prevalence of asthma was 10.7%, comparable to the figures for Portuguese schoolchildren (6-7 years old) reported by the national Directorate-General of Health, thus showing that an early diagnosis might be possible and helpful for the mitigation of childhood asthma. Environmental context (urban, suburban or rural), gender and family asthma history showed clear associations with asthma prevalence, namely non-rural location, male gender, and having an asthmatic parent were found to be risk factors. PMID- 26747646 TI - Membrane lipid compositional sensing by the inducible amphipathic helix of CCT. AB - The amphipathic helical (AH) membrane binding motif is recognized as a major device for lipid compositional sensing. We explore the function and mechanism of sensing by the lipid biosynthetic enzyme, CTP:phosphocholine cytidylyltransferase (CCT). As the regulatory enzyme in phosphatidylcholine (PC) synthesis, CCT contributes to membrane PC homeostasis. CCT directly binds and inserts into the surface of bilayers that are deficient in PC and therefore enriched in lipids that enhance surface charge and/or create lipid packing voids. These two membrane physical properties induce the folding of the CCT M domain into a >=60 residue AH. Membrane binding activates catalysis by a mechanism that has been partially deciphered. We review the evidence for CCT compositional sensing, and the membrane and protein determinants for lipid selective membrane-interactions. We consider the factors that promote the binding of CCT isoforms to the membranes of the ER, nuclear envelope, or lipid droplets, but exclude CCT from other organelles and the plasma membrane. The CCT sensing mechanism is compared with several other proteins that use an AH motif for membrane compositional sensing. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon. PMID- 26747647 TI - On the molecular mechanism of flippase- and scramblase-mediated phospholipid transport. AB - Phospholipid flippases are key regulators of transbilayer lipid asymmetry in eukaryotic cell membranes, critical to many trafficking and signaling pathways. P4-ATPases, in particular, are responsible for the uphill transport of phospholipids from the exoplasmic to the cytosolic leaflet of the plasma membrane, as well as membranes of the late secretory/endocytic pathways, thereby establishing transbilayer asymmetry. Recent studies combining cell biology and biochemical approaches have improved our understanding of the path taken by lipids through P4-ATPases. Additionally, identification of several protein families catalyzing phospholipid 'scrambling', i.e. disruption of phospholipid asymmetry through energy-independent bi-directional phospholipid transport, as well as the recent report of the structure of such a scramblase, opens the way to a deeper characterization of their mechanism of action. Here, we discuss the molecular nature of the mechanism by which lipids may 'flip' across membranes, with an emphasis on active lipid transport catalyzed by P4-ATPases. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon. PMID- 26747650 TI - The binding versatility of plant acyl-CoA-binding proteins and their significance in lipid metabolism. AB - Acyl-CoA esters are the activated form of fatty acids and play important roles in lipid metabolism and the regulation of cell functions. They are bound and transported by nonenzymic proteins such as the acyl-CoA-binding proteins (ACBPs). Although plant ACBPs were so named by virtue of amino acid homology to existing yeast and mammalian counterparts, recent studies revealed that ligand specificities of plant ACBPs are not restricted to acyl-CoA esters. Arabidopsis and rice ACBPs also interact with phospholipids, and their affinities to different acyl-CoA species and phospholipid classes vary amongst isoforms. Their ligands also include heavy metals. Interactors of plant ACBPs are further diversified due to the evolution of protein-protein interacting domains. This review summarizes our current understanding of plant ACBPs with a focus on their binding versatility. Their broad ligand range is of paramount significance in serving a multitude of functions during development and stress responses as discussed herein. This article is part of a Special Issue entitled: Plant Lipid Biology edited by Kent D. Chapman and Ivo Feussner. PMID- 26747649 TI - Identification of a triacylglycerol lipase in the diatom Phaeodactylum tricornutum. AB - Diatoms accumulate triacylglycerols (TAGs) as storage lipids, but the knowledge about the molecular mechanisms of lipid metabolism is still sparse. Starting from a partial sequence for a putative TAG-lipase of the diatom Phaeodactylum tricornutum retrieved from the data bases, we have identified the full length coding sequence, tgl1. The gene encodes an 813 amino acid sequence that shows distinct motifs for so called "true" TAG-lipases [EC 3.1.1.3] that have been functionally characterized in model organisms like Arabidopsis thaliana and Saccharomyces cerevisiae. These lipases mediate the first initial step of TAG breakdown from storage lipids. To test whether Tgl1 can act as a TAG-lipase, a His-tagged version was overexpressed in Escherichia coli and the protein indeed showed esterase activity. To identify the TAG degrading function of Tgl1 in P. tricornutum, knock-down mutant strains were created using an antisense RNA approach. In the mutant cell lines the relative tgl1-mRNA-level was reduced up to 20% of that of the wild type, accompanied by a strong increase of TAG in the lipid extracts. In spite of the TAG accumulation, the polar lipid species pattern appeared to be unchanged, confirming the TAG-lipase function of Tgl1. PMID- 26747648 TI - Taming the sphinx: Mechanisms of cellular sphingolipid homeostasis. AB - Sphingolipids are important structural membrane components of eukaryotic cells, and potent signaling molecules. As such, their levels must be maintained to optimize cellular functions in different cellular membranes. Here, we review the current knowledge of homeostatic sphingolipid regulation. We describe recent studies in Saccharomyces cerevisiae that have provided insights into how cells sense changes in sphingolipid levels in the plasma membrane and acutely regulate sphingolipid biosynthesis by altering signaling pathways. We also discuss how cellular trafficking has emerged as an important determinant of sphingolipid homeostasis. Finally, we highlight areas where work is still needed to elucidate the mechanisms of sphingolipid regulation and the physiological functions of such regulatory networks, especially in mammalian cells. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon. PMID- 26747651 TI - MicroRNA-192* impairs adipocyte triglyceride storage. AB - We investigated the expression of miR-192* (miR-192-3p) in the visceral adipose tissue (VAT) of obese subjects and its function in cultured human adipocytes. This miRNA is a 3' arm derived from the same pre-miRNA as miR-192 (miR-192-5p) implicated in type 2 diabetes, liver disease and cancers, and is predicted to target key genes in lipid metabolism. In morbidly obese subjects undergoing bariatric surgery preceded by a very low calorie diet, miR-192* in VAT correlated negatively (r=-0.387; p=0.046) with serum triglyceride (TG) and positively with high-density lipoprotein (HDL) concentration (r=0.396; p=0.041). In a less obese patient cohort, the miRNA correlated negatively with the body mass index (r= 0.537; p=0.026). To characterize the function of miR-192*, we overexpressed it in cultured adipocytes and analyzed the expression of adipogenic differentiation markers as well as cellular TG content. Reduced TG and expression of the adipocyte marker proteins aP2 (adipocyte protein 2) and perilipin 1 were observed. The function of miR-192* was further investigated by transcriptomic profiling of adipocytes expressing this miRNA, revealing impacts on key lipogenic genes. A number of the mRNA alterations were validated by qPCR. Western analysis confirmed a marked reduction of the lipogenic enzyme SCD (stearoyl coenzyme A desaturase-1), the fatty aldehyde dehydrogenase ALDH3A2 (aldehyde dehydrogenase 3 family member A2) and the high-density lipoprotein receptor SCARB1 (scavenger receptor B, type I). SCD and ALDH3A2 were demonstrated to be direct targets of miR-192*. To conclude, the present data identify miR-192* as a novel controller of adipocyte differentiation and lipid homeostasis. PMID- 26747653 TI - Proof of concept: hypovolemic hyponatremia may precede and augment creatine kinase elevations during an ultramarathon. AB - PURPOSE: It is not known if exercise-associated hyponatremia (EAH) is a cause or consequence of exertional rhabdomyolysis (ER).We hypothesized that osmotic stress (EAH) coupled with mechanical stress (running) potentiated muscle cell breakdown (ER). This concept would be supported if a nadir in serum sodium concentration ([Na(+)]) temporally preceded peak creatine kinase levels (CK) during an ultramarathon run. METHODS: Fifteen participants ran >=104 km and had blood drawn: prior to start; 53; 104 km; and 24-h post run. Serum [Na(+)], CK, urea, creatinine and estimated glomerular filtration rate (eGFR) were measured from serial blood samples. Two-way repeated-measures ANOVA was used to examine differences regarding both race distance and natremia status. RESULTS: Ten of 15 participants demonstrated EAH (serum [Na(+)] <135 mmol/L) at least once during serial testing. Participants were categorized post hoc into one of three natremia groups based on lowest recorded [Na(+)]: (1) <129 mmol/L (n = 3; moderate EAH); (2) between 129 and 134 mmol/L (n = 7; mild EAH); and (3) >134 mmol/L (n = 5; normonatremia). Participants with lowest [Na(+)] demonstrated highest CK values at subsequent checkpoints. Significant natremia group differences noted at the 53 km point (p = 0.0002) for [Na(+)] while significant natremia group effect noted for CK seen at the 24-h post-finish testing point (p = 0.02). Significant natremia group effects noted for renal biomarkers, with the moderate EAH group documenting the lowest eGFR (p = 0.005), and highest serum urea (p = 0.0006) and creatinine (p < 0.0001) levels. Hyponatremic runners had lower post-race urine [Na(+)] than normonatremic runners (26 +/- 15 vs. 89 +/- 79 mmol/L; p = 0.03). CONCLUSIONS: Preliminary data support the possibility that transient hypovolemic EAH may precede and augment CK during an ultramarathon. PMID- 26747656 TI - Nexplanon(r) removals in a community sexual and reproductive health service. PMID- 26747655 TI - Simultaneous acquisition of (99m)Tc- and (123)I-labeled radiotracers using a preclinical SPECT scanner with CZT detectors. AB - OBJECTIVE: Simultaneous acquisition of (99m)Tc and (123)I was evaluated using a preclinical SPECT scanner with cadmium zinc telluride (CZT)-based detectors. METHODS: 10-ml cylindrical syringes contained about 37 MBq (99m)Tc-tetrofosmin ((99m)Tc-TF) or 37 MBq (123)I-15-(p-iodophenyl)-3R,S-methyl pentadecanoic acid ((123)I-BMIPP) were used to assess the relationship between these SPECT radioactive counts and radioactivity. Two 10-ml syringes contained 100 or 300 MBq (99m)Tc-TF and 100 MBq (123)I-BMIPP to assess the influence of (99m)Tc upscatter and (123)I downscatter, respectively. A rat-sized cylindrical phantom also contained both 100 or 300 MBq (99m)Tc-TF and 100 MBq (123)I-BMIPP. The two 10-ml syringes and phantom were scanned using a pinhole collimator for rats. Myocardial infarction model rats were examined using 300 MBq (99m)Tc-TF and 100 MBq (123)I BMIPP. Two 1-ml syringes contained 105 MBq (99m)Tc-labeled hexamethylpropyleneamine oxime ((99m)Tc-HMPAO) and 35 MBq (123)I-labeled N-omega fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl) nortropane ((123)I-FP-CIT). The two 1-ml syringes were scanned using a pinhole collimator for mice. Normal mice were examined using 105 MBq (99m)Tc-HMPAO and 35 MBq (123)I-FP-CIT. RESULTS: The relationship between SPECT radioactive counts and radioactivity was excellent. Downscatter contamination of (123)I-BMIPP exhibited fewer radioactive counts for 300 MBq (99m)Tc-TF without scatter correction (SC) in 125-150 keV. There was no upscatter contamination of (99m)Tc-TF in 150-175 keV. In the rat sized phantom, the radioactive count ratio decreased to 4.0 % for 300 MBq (99m)Tc TF without SC in 125-150 keV. In the rats, myocardial images and radioactive counts of (99m)Tc-TF with the dual tracer were identical to those of the (99m)Tc TF single injection. Downscatter contamination of (123)I-FP-CIT was 4.2 % without SC in 125-150 keV. In the first injection of (99m)Tc-HMPAO and second injection of (123)I-FP-CIT, brain images and radioactive counts of (99m)Tc-HMPAO with the dual tracer in normal mice also were the similar to those of the (99m)Tc-HMPAO single injection. In the first injection of (123)I-FP-CIT and second injection of (99m)Tc-HMPAO, the brain images and radioactive counts with the dual tracer were not much different from those of the (123)I-FP-CIT single injection. CONCLUSIONS: Dual-tracer imaging of (99m)Tc- and (123)I-labeled radiotracers is feasible in a preclinical SPECT scanner with CZT detector. When higher radioactivity of (99m)Tc labeled radiotracers relative to (123)I-labeled radiotracers is applied, correction methods are not necessarily required for the quantification of (99m)Tc and (123)I-labeled radiotracers when using a preclinical SPECT scanner with CZT detector. PMID- 26747654 TI - Call it Worm Sleep. AB - The nematode Caenorhabditis elegans stops feeding and moving during a larval transition stage called lethargus and following exposure to cellular stressors. These behaviors have been termed 'sleep-like states'. We argue that these behaviors should instead be called sleep. Sleep during lethargus is similar to sleep regulated by circadian timers in insects and mammals, and sleep in response to cellular stress is similar to sleep induced by sickness in other animals. Sleep in mammals and Drosophila shows molecular and functional conservation with C. elegans sleep. The simple neuroanatomy and powerful genetic tools of C. elegans have yielded insights into sleep regulation and hold great promise for future research into sleep regulation and function. PMID- 26747657 TI - Photodynamic therapy using Photofrin and excimer dye laser treatment for superficial oral squamous cell carcinomas with long-term follow up. AB - OBJECTIVES: Photodynamic therapy (PDT) is a very effective treatment for superficial malignancies that does not result in loss of normal tissue. Here, we report successful PDT treatment of superficial oral cancers and its clinical outcome with long-term follow up. MATERIALS AND METHODS: Thirty-four superficial oral squamous cell carcinomas were treated with PDT, and the effects were evaluated. Each patient received Photofrin (2mg/kg) intravenously 48h prior to light irradiation. Photoradiation was performed at doses of 100-150J/cm(2) using a 630-nm wavelength excimer dye laser. RESULTS: Six months after PDT, 30 patients (88.2%) showed complete responses while 9 patients (26.5%) had local relapses during long-term follow-up. The 5-year overall survival, disease-specific survival, and disease-free survival rates were 76.5%, 84.6%, and 63.3%, respectively. Lesions with red patches had a significantly higher recurrence rate than lesions with white patches. Accurate evaluation of the extent of lesions and appropriate photoradiation were important in improving outcomes. Adverse events observed included sunburn and sequestrum formation of alveolar bone. No abnormal laboratory values or systemic complications were observed. CONCLUSION: PDT using Photofrin as the photosensitizer is an effective treatment modality for superficial oral carcinomas, with excellent healing and minimal side effects. PMID- 26747658 TI - A complex postnatal mental health intervention: Australian translational formative evaluation. AB - Reducing the burden of postnatal maternal mental health problems is an international public health priority. We developed What Were We Thinking (WWWT), a psychoeducation programme for primary postnatal health care that addresses known but neglected risks. We then demonstrated evidence of its effects in a before-and-after controlled study in preventing maternal postnatal mental health problems among women without a psychiatric history participating in the intervention compared to usual care (AOR 0.43; 95% CI 0.21, 0.89) when conducted by specialist nurses. Testing its effectiveness when implemented in routine primary care requires changes at practitioner, organizational and health system levels. This paper describes a programme of translational formative evaluation to inform the protocol for a cluster RCT. Following the UK Medical Research Council (MRC) Guidance for evaluating complex interventions, we conducted a translational formative evaluation using mixed methods. Collection and analysis of postnatal health service documents, semi-structured interviews, group discussions and an online survey were used to investigate service provision, consumers' needs and expectations, clinicians' attitudes and clinical practice, and the implications for health service delivery. Participants were expectant parents, health care providers, health service managers and government policy makers. Results documented current clinical practice, staff training needs, necessary service modifications to standardize advice to parents and include fathers, key priorities and drivers of government health policy, and informed a model of costs and expected health and social outcomes. Implementation of WWWT into routine postnatal care requires adjustments to clinical practice. Staff training, modifications to service opening hours and economic implications for the health system also need to be considered. The MRC Guidance for developing and evaluating complex interventions is a useful framework for conceptualizing and reporting translational formative evaluation, which is an essential step in the evidence trajectory. The results of the evaluation will inform the protocol for a cluster RCT of WWWT and associated health economic evaluation. PMID- 26747659 TI - Can the sociology of social problems help us to understand and manage 'lifestyle drift'? AB - Lifestyle drift is increasingly seen as a barrier to broad action on the social determinants of health. The term is currently used in the population health literature to describe how broad policy initiatives for tackling inequalities in health that start off with social determinants (upstream) approach drift downstream to largely individual lifestyle factors, as well as the general trend of investing a the individual level. Lifestyle drift occurs despite the on-going efforts of public health advocates, such as anti-obesity campaigners, to draw attention to the social factors which shape health behavior and outcomes. In this article, we explore whether the sociology of social problems can help understand lifestyle drift in the context of obesity. Specifically, we apply Jamrozik and Nocella's residualist conversion model to the problem of obesity in order to explore whether such an approach can provide greater insight into the processes that underpin lifestyle drift and inform our attempts to mitigate it. PMID- 26747660 TI - Vertical dimension of occlusion (VDO): cephalometric norms for a Moroccan population. AB - OBJECTIVES: The purpose of this work was to develop cephalometric standards of the vertical dimension of occlusion (VDO) in Moroccan adults. METHODS: Our data consisted of standardized lateral cephalometric radiographs of 98 students at the Casablanca Faculty of Dentistry. These included 74 women and 24 men aged 18-34 years, who were selected on the basis of a well-proportioned face, acceptable profile, Class I occlusion, minor or no crowding, and no history of orthodontic treatment. Mean values of seven (six angle and one linear) dentoskeletal parameters were determined from lateral cephalometric radiographs. RESULTS: These Moroccans tended to exhibit an opening in the VDO in comparison with the standards of Steiner and Wylie and those of other populations: GoGn/SN: 35.4 degrees +/- 5.3 degrees , FMA: 25.6 degrees +/- 5.1 degrees , Occ/SN: 19.3 degrees +/- 4.7 degrees , Occ/Fr: 9.1 degrees +/- 4 degrees , SGn/Fr: 59.2 degrees +/- 3.4 degrees , ENA-Xi-Pm: 46.2 degrees +/- 4.4 degrees , ENA-Me: 69.7 +/- 5.9 mm. CONCLUSION: Moroccans have distinct cephalometric characteristics, which should be used as the reference in future orthodontic and prosthetic treatments. PMID- 26747661 TI - Evaluation of maxillary arch morphology in children with unilaterally impacted incisors via three-dimensional analysis of digital dental casts: a controlled study. AB - OBJECTIVE: The purpose of this work was to analyze variations in maxillary arch dimensions in subjects presenting unilaterally impacted maxillary permanent central incisors compared with a control group of subjects without eruption anomalies. METHODS: A group of 23 Caucasian children [8 females and 15 males, mean age 9.7 years, standard deviation (SD) 1.6 years] displaying unilaterally impacted maxillary permanent central incisors (impacted incisor group: IIG) were compared with a control group (CG) of 23 subjects (9 females; 14 males, mean age 8.8 years, SD 1.9 years) presenting no eruption disorders. Pretreatment dental casts were taken from each subject and the upper arch was scanned using a three dimensional scanner. Linear measurements were taken on each digital model to analyze maxillary arch dimensions. Significant between-group differences were tested with the Student's t test (p < 0.05). RESULTS: The transverse and sagittal upper-arch measurements were significantly smaller in the IIG than in the CG. In particular, the anterior arch was 1.35 mm shorter in the IIG, while intercanine width was decreased by 2.51 mm on the impacted side. CONCLUSION: Children revealing unilaterally impacted maxillary central incisors demonstrated a significantly constricted maxillary transverse width and shorter arch on the impacted side compared with subjects with no eruption disorders. PMID- 26747662 TI - Radiation dose of cone-beam computed tomography compared to conventional radiographs in orthodontics. AB - OBJECTIVES: The aim of this study was to determine radiation doses of different cone-beam computed tomography (CBCT) scan modes in comparison to a conventional set of orthodontic radiographs (COR) by means of phantom dosimetry. MATERIALS AND METHODS: Thermoluminescent dosimeter (TLD) chips (3 * 1 * 1 mm) were used on an adult male tissue-equivalent phantom to record the distribution of the absorbed radiation dose. Three different scanning modes (i.e., portrait, normal landscape, and fast scan landscape) were compared to CORs [i.e., conventional lateral (LC) and posteroanterior (PA) cephalograms and digital panoramic radiograph (OPG)]. RESULTS: The following radiation levels were measured: 131.7, 91, and 77 MUSv in the portrait, normal landscape, and fast landscape modes, respectively. The overall effective dose for a COR was 35.81 MUSv (PA: 8.90 MUSv; OPG: 21.87 MUSv; LC: 5.03 MUSv). DISCUSSION: Although one CBCT scan may replace all CORs, one set of CORs still entails 2-4 times less radiation than one CBCT. Depending on the scan mode, the radiation dose of a CBCT is about 3-6 times an OPG, 8-14 times a PA, and 15-26 times a lateral LC. Finally, in order to fully reconstruct cephalograms including the cranial base and other important structures, the CBCT portrait mode must be chosen, rendering the difference in radiation exposure even clearer (131.7 vs. 35.81 MUSv). Shielding radiation-sensitive organs can reduce the effective dose considerably. CONCLUSION: CBCT should not be recommended for use in all orthodontic patients as a substitute for a conventional set of radiographs. In CBCT, reducing the height of the field of view and shielding the thyroid are advisable methods and must be implemented to lower the exposure dose. PMID- 26747663 TI - Thoughts Toward a Theory of Natural Selection: The Importance of Microbial Experimental Evolution. AB - Natural selection should no longer be thought of simply as a primitive (magical) concept that can be used to support all kinds of evolutionary theorizing. We need to develop causal theories of natural selection; how it arises. Because the factors contributing to the creation of natural selection are expected to be complex and intertwined, theories explaining the causes of natural selection can only be developed through the experimental method. Microbial experimental evolution provides many benefits that using other organisms does not. Microorganisms are small, so millions can be housed in a test tube; they have short generation times, so evolution over hundreds of generations can be easily studied; they can grow in chemically defined media, so the environment can be precisely defined; and they can be frozen, so the fitness of strains or populations can be directly compared across time. Microbial evolution experiments can be divided into two types. The first is to measure the selection coefficient of two known strains over the first 50 or so generations, before advantageous mutations rise to high frequency. This type of experiment can be used to directly test hypotheses. The second is to allow microbial cultures to evolve over many hundreds or thousands of generations and follow the genetic changes, to infer what phenotypes are selected. In the last section of this article, I propose that selection coefficients are not constant, but change as the population becomes fitter, introducing the idea of the selection space. PMID- 26747667 TI - Korean National Health Insurance Database. PMID- 26747668 TI - Korean National Health Insurance Database--Reply. PMID- 26747669 TI - Supplementing the Role of Primary Care Physicians. PMID- 26747664 TI - Adult Neurogenesis in Fish. AB - Teleost fish have a remarkable neurogenic and regenerative capacity in the adult throughout the rostrocaudal axis of the brain. The distribution of proliferation zones shows a remarkable conservation, even in distantly related teleost species, suggesting a common teleost ground plan of proliferation zones. There are different progenitor populations in the neurogenic niches-progenitors positive for radial glial markers (dorsal telencephalon, hypothalamus) and progenitors with neuroepithelial-like characteristics (ventral telencephalon, optic tectum, cerebellum). Definition of these progenitors has allowed studying their role in normal growth of the adult brain, but also when challenged following a lesion. From these studies, important roles have emerged for intrinsic mechanisms and extrinsic signals controlling the activation of adult neurogenesis that enable regeneration of the adult brain to occur, opening up new perspectives on rekindling regeneration also in the context of the mammalian brain. PMID- 26747670 TI - The Safe Use of Propofol. PMID- 26747671 TI - Unreliable Conclusions of Breast Cancer Screening, Incidence, and Mortality. PMID- 26747672 TI - The Safe Use of Propofol--Reply. PMID- 26747673 TI - Unreliable Conclusions of Breast Cancer Screening, Incidence, and Mortality- Reply. PMID- 26747674 TI - Cardiopulmonary Resuscitation and Benefit to Patients With Metastatic Cancer. PMID- 26747675 TI - Cardiopulmonary Resuscitation and Benefit to Patients With Metastatic Cancer- Reply. PMID- 26747676 TI - Error in Table. PMID- 26747677 TI - Outcomes of Ureteroscopic Management of Pediatric Urolithiasis: A Comparative Analysis of Prepubertal and Adolescent Patients. AB - OBJECTIVE: To compare the outcomes of ureteroscopic intervention in terms of both the stone-free rate and complications in both prepubertal and adolescent patients. Although safety of pediatric ureteroscopic intervention is well established, a comparative outcome of prepubertal and adolescent patients is lacking. MATERIALS AND METHODS: Pediatric patients who underwent ureteroscopic treatment of a renal or ureteral stone at our institution from July 2005 to August 2014 were retrospectively identified. Patients were classified by age either as prepubertal (<=11 years) or adolescent (>11 years) for purposes of comparison. Demographic and intraoperative variables as well as 30-day postoperative complication rates were compared between groups. Data were analyzed using chi(2) and Fisher's exact tests as appropriate. RESULTS: A total of 104 patients were identified, of whom 64 (62%) were prepubertal and 40 (38%) were adolescent. Ureteroscopic failure occurred in a minority of patients (5% vs 4.7%, P > .9). Complication rates including ureteral perforation (0% vs 1.6%, P > .9), postoperative urinary tract infection (2.5% vs 4.7%, P > .9), hematuria with clot passage (0% vs 7.8%, P = .15), and persistent flank pain (15% vs 17%, P = .85) were not significantly different between adolescent and prepubertal patients, respectively. CONCLUSION: In spite of small size and small body habitus, the ureteroscopic management of pediatric urolithiasis can be performed successfully in both the prepubertal and adolescent patients with acceptable and equivalent morbidity as well as successful clearance of stone. PMID- 26747678 TI - DNA Damage and Repair Pathway Profiles as Biomarkers in High-Risk Prostate Cancer. PMID- 26747680 TI - Risk factors and outcomes of postoperative ischemic colitis in contemporary open and endovascular abdominal aortic aneurysm repair. AB - OBJECTIVE: Postoperative ischemic colitis (IC) can be a serious complication following infrarenal abdominal aortic aneurysm (AAA) repair. We sought to identify risk factors and outcomes in patients developing IC after open AAA repair and endovascular aneurysm repair (EVAR). METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was used to examine clinical data of patients undergoing AAA repair from 2011 to 2012 who developed postoperative IC. Multivariate regression analysis was performed to identify risk factors and outcomes. RESULTS: We evaluated a cohort of 3486 patients who underwent AAA repair (11.6% open repair and 88.4% EVAR). The incidence of postoperative IC was 2.2% (5.2% for open repair and 1.8% for EVAR). Surgical treatment was needed in 49.3% of patients who developed IC. The mortality of patients with IC was higher than that of patients without IC (adjusted odds ratio [AOR], 4.23; 95% confidence interval [CI], 2.26-7.92; P < .01). The need for surgical treatment (AOR, 7.77; 95% CI, 2.08-28.98; P < .01) and age (AOR, 1.11; 95% CI, 1.01-1.22; P = .01) were mortality predictors of IC patients. Predictive factors of IC included need for intraoperative or postoperative transfusion (AOR, 6; 95% CI, 3.08-11.72; P < .01), rupture of the aneurysm before surgery (AOR, 4.07; 95% CI, 1.78-9.31; P < .01), renal failure requiring dialysis (AOR, 3.86; 95% CI, 1.18-12.62; P = .02), proximal extension of the aneurysm (AOR, 2.19; 95% CI, 1.04-4.59; P = .03), diabetes (AOR, 1.87; 95% CI, 1.01-3.46; P = .04), and female gender (AOR, 1.75; 95% CI, 1.01-3.02; P = .04). Although open AAA repair had three times higher rate of postoperative IC compared with endovascular repair, in multivariate analysis we did not find any statistically significant difference between open repair and EVAR in the development of IC (5.2% vs 1.8%; AOR, 1.25; 95% CI, 0.70-2.25; P = .43). CONCLUSIONS: Postoperative IC has a rate of 2.2% after AAA repair. However, it is associated with 38.7% mortality rate. Rupture of the aneurysm before surgery, need for transfusion, proximal extension of the aneurysm, renal failure requiring dialysis, diabetes, and female gender were significant predictors of postoperative IC. AAA patients who develop IC have four times higher mortality compared with those without IC. Surgical treatment is needed in nearly 50% of IC patients and is a predictor of higher mortality. PMID- 26747679 TI - Abdominal aortic aneurysms in women. AB - Abdominal aortic aneurysm (AAA) has long been recognized as a condition predominantly affecting males, with sex-associated differences described for almost every aspect of the disease from pathophysiology and epidemiology to morbidity and mortality. Women are generally spared from AAA formation by the immunomodulating effects of estrogen, but once they develop, the natural history of AAAs in women appears to be more aggressive, with more rapid expansion, a higher tendency to rupture at smaller diameters, and higher mortality following rupture. However, simply repairing AAAs at smaller diameters in women is a debatable solution, as even elective endovascular AAA repair is fraught with higher morbidity and mortality in women compared to men. The goal of this review is to summarize what is currently known about the effect of gender on AAA presentation, treatment, and outcomes. Additionally, we aim to review current controversies over screening recommendations and threshold for repair in women. PMID- 26747681 TI - Complete regression of a symptomatic, mycotic juxtarenal abdominal aortic aneurysm after treatment with fenestrated endovascular aneurysm repair. AB - Mycotic abdominal aortic aneurysms are rare and present unique challenges when potential treatment options are considered. Although aortic resection with in situ grafting techniques or extra-anatomic reconstruction are the treatments of choice, endovascular aortic repair has emerged as a suitable alternative in critically ill patients. We report the successful endovascular repair of a symptomatic, mycotic juxtarenal aortic aneurysm using a physician-modified fenestrated endograft. In this patient, with >6 months of follow-up, the aneurysm has completely regressed, illustrating that in select patients with complex mycotic aneurysms, endovascular repair combined with appropriate medical management is a viable treatment strategy. PMID- 26747683 TI - Perpetuating the cycle of violence in South African low-income communities: attraction to violence in young men exposed to continuous threat. AB - BACKGROUND: Life in the low-income urban communities of South Africa is imprinted by a cycle of violence in which young males predominantly are in the roles of both victim and perpetrator. There is some evidence that adolescents who show an attraction to cruelty can display high levels of psychosocial functioning despite the presence of posttraumatic stress symptoms. However, the role of appetitive aggression in the context of ongoing threats and daily hassles is not yet fully understood. OBJECTIVE: In this study, we examine the role of attraction to violence in areas of continuous traumatic stress exposure and its effect on posttraumatic stress disorder (PTSD) severity and violence perpetration. METHOD: A sample of 290 young males from two low-income Cape Town communities was surveyed. We assessed appetitive aggression with the Appetitive Aggression Scale (AAS), PTSD symptoms with the PTSD Symptom Scale-Interview, the number of witnessed and self-experienced traumatic event types with an adaptation of the Child Exposure to Community Violence questionnaire, and the number of perpetrated violence event types with an adapted offence checklist from the AAS. RESULTS: Appetitive aggression scores were predicted by witnessed as well as self experienced traumatic events. Higher appetitive aggression scores resulted in higher levels of PTSD severity and perpetrated violence. CONCLUSIONS: Young males living in the low-income areas of South Africa may develop an attraction to cruelty in response to exposure to violence. Their willingness to fight in turn can increase the likelihood of continued violent behaviour. In contrast to previous research from postconflict areas, appetitive aggression and engagement in violence do not prevent the development of PTSD, but are instead associated with higher levels of posttraumatic stress. PTSD symptoms such as avoidance and hyperarousal, as well as an attraction to cruelty and thus the willingness to fight, might support survival in areas of ongoing conflict, but at the same time they could fuel the cycle of violence. PMID- 26747684 TI - Contemporary Multidisciplinary Care--Who Is the Captain of the Ship, and Does It Matter? PMID- 26747682 TI - Smoking cessation counseling in vascular surgical practice using the results of interviews and focus groups in the Vascular Surgeon offer and report smoking cessation pilot trial. AB - OBJECTIVE: Although smoking cessation is a key priority emphasized by professional societies and multidisciplinary consensus guidelines, significant variation exists in the methods and efficacy of smoking cessation treatment practiced by vascular surgeons. We conducted a series of patient, surgeon, and nonpatient stakeholder focus groups to identify important domains for establishment of a successful smoking cessation program. METHODS: As part of a planning effort for a randomized clinical trial on usual care vs a standardized, evidence-based smoking cessation intervention, our group performed a series of interviews and focus groups. These were four 1-hour interviews, conducted with stakeholders such as tobacco cessation counselors (n = 2), a Quit Line representative (n = 1), and a Vascular Quality Initiative leader (n = 1), as well as two 90-minute, formal, professionally moderated focus groups, one with vascular surgeons (n = 7), and another with patients (n = 4). Transcripts and audio recordings were qualitatively reviewed for themes to establish the most important domains perceived to be associated with a successful smoking cessation program. RESULTS: Patients emphasized four domains critical for a successful smoking cessation program: the motivation to quit, an individualized approach, the timing of an intervention, and the tone of the physician who offers counseling. Although surgeons and nonpatient stakeholders also emphasized the importance of a compassionate physician tone, surgeons and nonpatient stakeholders differed from patients in their remaining domains. They emphasized the feasibility of a brief intervention in a busy clinical practice, implementation of the effort, and necessary infrastructure for smoking cessation programs. All focus group participants described a brief, evidence-based smoking cessation intervention as feasible in routine vascular practice. CONCLUSIONS: Differences in motivation and significance exist for patients, surgeons, and stakeholders when they considered the specific domains most important in building a successful smoking cessation program. Despite these differences, all parties involved agreed that a brief, standardized intervention can be successful delivered in a busy vascular clinic setting. PMID- 26747686 TI - Percutaneous approach to the treatment of a totally occluded abdominal aortic stent graft. AB - Aorto femoral bypass is usually the recommended therapy for diffuse disease involving the aorta and iliac arteries. In this case report, a case involving a chronic endovascular abdominal aortic stent graft occlusion in which percutaneous angioplasty was performed via a transbrachial and transfemoral approach is presented. This case emphasized that occlusion of an endovascular abdominal aortic stent graft can also be treated, primarily, with an endovascular technique. PMID- 26747687 TI - A Patient With Blue Ears. PMID- 26747688 TI - In-cell clean-up pressurized liquid extraction and gas chromatography-tandem mass spectrometry determination of hydrophobic persistent and emerging organic pollutants in coastal sediments. AB - The main goal of this work was to develop, optimize and validate a multi-residue method for the simultaneous determination of 97 contaminants, including fragrances, UV filters, repellents, endocrine disruptors, biocides, polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), organophosphorus flame retardants, and several types of pesticides in marine sediment samples. Extraction and cleanup were integrated into the same step using pressurized liquid extraction (PLE) with in-cell clean-up (1g of alumina). The extraction was performed using dichloromethane at 100 degrees C, 1500 psi and 3 extraction cycles (5 min per cycle). Extracts were derivatized with N-(tert butyldimethylsilyl)-N-methyltrifluoroacetamide (MTBSTFA) to improve the signal and sensitivity of some target compounds (i.e., triclosan, 2 hydroxybenzophenone). Separation, identification and quantification of analytes were carried out by gas chromatography (GC) coupled to tandem mass spectrometry. Under optimal conditions, the optimized protocol showed good recovery percentages (70-100%), linearity (>0.99) and limits of detection below 1 ng g(-1) for all compounds. Finally, the method was applied to the analysis of sediment samples from different coastal areas from Andalusia (Spain), where occurrence and distribution of emerging contaminants in sediments is very scarce. Twenty five compounds out of 98 were detected in all samples, with the endocrine disruptor nonylphenol and the fragrance galaxolide showing the highest concentrations, up to 377.6 ng g(-1) and 237.4 ng g(-1), respectively. PMID- 26747689 TI - Multimodal charge-induction chromatography for antibody purification. AB - Hydrophobic charge-induction chromatography (HCIC) has advantages of high capacity, salt-tolerance and convenient pH-controlled elution. However, the binding specificity might be improved with multimodal molecular interactions. New ligand W-ABI that combining tryptophan and 5-amino-benzimidazole was designed with the concept of mutimodal charge-induction chromatography (MCIC). The indole and benzimidazole groups of the ligand could provide orientated mutimodal binding to target IgG under neutral pH, while the imidazole groups could induce the electrostatic repulsion forces for efficient elution under acidic pH. W-ABI ligand was coupled successfully onto agarose gel, and IgG adsorption behaviors were investigated. High affinity to IgG was found with the saturated adsorption capacity of 70.4 mg/ml at pH 7, and the flow rate of mobile phase showed little impact on the dynamic binding capacity. In addition, efficient elution could be achieved at mild acidic pH with high recovery. Two separation cases (IgG separation from albumin containing feedstock and monoclonal antibody purification from cell culture supernatant) were verified with high purity and recovery. In general, MCIC with the specially-designed ligand is an expanding of HCIC with improved adsorption selectivity, which would be a potential alternative to Protein A-based capture for the cost-effective purification of antibodies. PMID- 26747690 TI - Determination of salivary cotinine through solid phase extraction using a bead injection lab-on-valve approach hyphenated to hydrophilic interaction liquid chromatography. AB - Cotinine, the first metabolite of nicotine, is often used as a biomarker in the monitoring of environmental tobacco smoke (ETS) exposure due to its long half life. This paper reports on the development of an at-line automatic micro-solid phase extraction (MUSPE) method for the determination of salivary cotinine followed by its analysis via hydrophilic interaction liquid chromatography (HILIC). The SPE methodology is based on the bead injection (BI) concept in a mesofluidic lab-on-valve (LOV) flow system to automatically perform all SPE steps. Three commercially available reversed-phase sorbents were tested, namely, Oasis HLB, Lichrolut EN and Focus, and the spherically shaped sorbents (i.e., Oasis HLB and Focus) provided better packing within the SPE column and hence higher column efficiency. An HILIC column was chosen based on its potential for achieving higher sensitivity and better retention of polar compounds such as cotinine. The method uses an isocratic program with acetonitrile:100mM ammonium acetate buffer, pH 5.8 in 95:5 v/v ratio as the mobile phase at a flow rate of 1.0 mL min(-1). Using this approach, the linear calibration range was from 10 to 1000 ng which corresponded to 5-500 MUg L(-1). The corresponding MUSPE-BI-LOV system was proven to be reliable in the handing and analysis of viscous biological samples such as saliva, achieving a sampling rate of 6h(-1) and a limit of detection and quantification of 1.5 and 3MUgL(-1), respectively. PMID- 26747685 TI - Reference Ranges of Left Ventricular Strain Measures by Two-Dimensional Speckle Tracking Echocardiography in Children: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Establishment of the range of reference values and associated variations of two-dimensional speckle-tracking echocardiography (2DSTE)-derived left ventricular (LV) strain is a prerequisite for its routine clinical adoption in pediatrics. The aims of this study were to perform a meta-analysis of normal ranges of LV global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) measurements derived by 2DSTE in children and to identify confounding factors that may contribute to variance in reported measures. METHODS: A systematic review was launched in MEDLINE, Embase, Scopus, the Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library. Search hedges were created to cover the concepts of pediatrics, STE, and left-heart ventricle. Two investigators independently identified and included studies if they reported 2DSTE-derived LV GLS, GCS, or GRS. The weighted mean was estimated by using random effects models with 95% CIs, heterogeneity was assessed using the Cochran Q statistic and the inconsistency index (I(2)), and publication bias was evaluated using the Egger test. Effects of demographic (age), clinical, and vendor variables were assessed in a metaregression. RESULTS: The search identified 2,325 children from 43 data sets. The reported normal mean values of GLS among the studies varied from -16.7% to -23.6% (mean, -20.2%; 95% CI, -19.5% to -20.8%), GCS varied from -12.9% to -31.4% (mean, -22.3%; 95% CI, -19.9% to 24.6%), and GRS varied from 33.9% to 54.5% (mean, 45.2%; 95% CI, 38.3% to 51.7%). Twenty-six studies reported longitudinal strain only from the apical four-chamber view, with a mean of -20.4% (95% CI, -19.8% to -21.7%). Twenty-three studies reported circumferential strain (mean, -20.3%; 95% CI, -19.4% to -21.2%) and radial strain (mean, 46.7%; 95% CI, 42.3% to 51.1%) from the short-axis view at the midventricular level. A significant apex-to-base segmental longitudinal strain gradient (P < .01) was observed in the LV free wall. There was significant between-study heterogeneity and inconsistency (I(2) > 94% and P < .001 for each strain measure), which was not explained by age, gender, body surface area, blood pressure, heart rate, frame rate, frame rate/heart rate ratio, tissue-tracking methodology, location of reported strain value along the strain curve, ultrasound equipment, or software. The metaregression showed that these effects were not significant determinants of variations among normal ranges of strain values. There was no evidence of publication bias (P = .40). CONCLUSIONS: This study defines reference values of 2DSTE-derived LV strain in children on the basis of a meta-analysis. In healthy children, mean LV GLS was -20.2% (95% CI, -19.5% to 20.8%), mean GCS was -22.3% (95% CI, -19.9% to -24.6%), and mean GRS was 45.2% (95% CI, 38.3% to 51.7%). LV segmental longitudinal strain has a stable apex-to base gradient that is preserved throughout maturation. Although variations among different reference ranges in this meta-analysis were not dependent on differences in demographic, clinical, or vendor parameters, age- and vendor specific referenced ranges were established as well. PMID- 26747691 TI - MISER chiral supercritical fluid chromatography for high throughput analysis of enantiopurity. AB - MISER chromatographic analysis (Multiple Injections in a Single Experimental Run) using supercritical fluid chromatography (SFC) with pressurized carbon dioxide based eluents is well suited to the high throughput analysis of enantiopurity. SFC is currently the preferred method for fast enantiopurity analysis, with analysis times of only a few seconds achievable in some cases. Injector programming using both the Agilent Infinity and Shimadzu Nexera UC instruments permitted MISER SFC experiments to be performed. Several case studies are presented, showcasing the power and versatility of the technique, with 'plate analysis times' (the time required for analysis of enantiopurity of 96 samples) of less than 33-34 min achievable in the best cases. PMID- 26747693 TI - Paralympism, Paralympic values and disability sport: a conceptual and ethical critique. AB - PURPOSE: This paper explores the conceptual content of Paralympism. It exists by exploring the nascent normative framework that the International Paralympic Committee (IPC) has begun to construct around its constituent sports. The IPC sets out four values: Courage, Determination, Inspiration and Equality. METHOD: Drawing on philosophical ethical methods it offers a critical evaluation of the four values that comprise the IPC position. CONCLUSION: While courage is undoubtedly a moral virtue, there is more than one conception that might inform Paralympism with either/both active and passive content. It is argued that Determination is an instrumental character trait that is not necessarily ethically praiseworthy. While potentially inspiring, the efforts and abilities of Paralympic athletes need not depend on the reception of spectators whom they have no control over. Finally, being an important ethical idea, it is neither clear what kind of equality is aimed for nor how it would be operationalized within sports with respect to access to expensive technology that is often the precondition of Paralympic sporting success. It is concluded that the Paralympic movement has not yet invested sufficient intellectual effort to articulate its ethical basis, and while these four values may have something to do with Paralympism, they are insufficient to articulate the concept. Implications for Rehabilitation Athletes with disabilities are governed by a range of normative frameworks that affect their preparation for and participation in the Paralympic games and associated events. Medical models often espouse a conception of biostatistical normality that derogates persons with disabilities, yet in elite sports abnormalities in structure and function can be highly valued. There is a lack of clarity about the ethical goals for those assisting Paralympic athletes. Governing bodies in disability sports, such as the International Paralympic Committee need to more critically and coherently spell out their ethical vision for Paralympic sports, which should guide athletes and rehabilitation professionals to behave in ways that would command the general public's admiration. Paralympism, Paralympic values and disability sport: a conceptual and ethical critique. PMID- 26747694 TI - Role of the FDA in Affordability of Off-Patent Pharmaceuticals. PMID- 26747692 TI - Hydrophilic interaction chromatography combined with dispersive liquid-liquid microextraction as a preconcentration tool for the simultaneous determination of the panel of underivatized neurotransmitters in human urine samples. AB - A simple and sensitive method using dispersive liquid-liquid microextraction (DLLME) followed by liquid chromatography coupled to mass spectrometry (LC-MS) with a hydrophilic interaction chromatography (HILIC) column was developed for the simultaneous determination of 13 compounds of different polarities, comprising monoamine neurotransmitters (dopamine, norepinephrine, epinephrine and serotonin) along with their respective precursors and metabolites, in human urine samples. The microextraction procedure was based on the fast injection of a mixture of ethanol (disperser solvent) and dichloromethane (extraction solvent) into a human urine sample, forming a cloudy solution in the Eppendorf tube. After centrifugation, the sedimented phase was collected and subsequently analyzed by LC-HILIC-MS in about 12min without a derivatization step. The separation was performed on an XBridge AmideTM BEH column 3.0*100mm, 3.5mm and the mobile phase consisted of phase A: 10mM ammonium formate buffer in water pH 3.0 and phase B: 10 mM ammonium formate buffer in acetonitrile, under gradient program elution. Tyrosine, tryptophan, 5-hydroxytryptophan, dopamine, epinephrine, norepinephrine, serotonin, 3-methoxytyramine, 5-hydroxyindole-3-acetic acid, 3,4-dihydroxy-l phenylalanine and norvaline (internal standard) were detected in the positive ionization mode. While vanillylmandelic acid, homovanillic acid, 3,4 dihydroxyphenylacetic acid and 3,4-dihydroxybenzylamine (internal standard) were detected in the negative ionization mode. Parameters influencing DLLME and LC HILIC-MS were investigated. Under the optimum conditions, the proposed method exhibited a low detection limit (5-10ngmL(-1)), and good linearity with R between 0.9991 and 0.9998. The recoveries in human urine samples were 99.0%+/-3.6%. for the 13 studied biogenic amines with intra- and inter-day RSDs of 0.24-9.55% and 0.31-10.0%, respectively. The developed DLLME-LC-MS method could be successfully applied for the determination of trace amounts of polar endogenous compounds, such as neurotransmitters, in human urine samples, including samples with a reduced volume obtained from pediatric patients. PMID- 26747695 TI - An Adjuvant Role for Mobile Health in Psychiatry. PMID- 26747696 TI - Establishment of Two Mouse Models for CEDNIK Syndrome Reveals the Pivotal Role of SNAP29 in Epidermal Differentiation. AB - Loss-of-function mutations in the synaptosomal-associated protein 29 (SNAP29) gene cause the cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome. In this study, we created total (Snap29(-/-)) as well as keratinocyte specific (Snap29(fl/fl)/K14-Cre) Snap29 knockout mice. Both mutant mice exhibited a congenital distinct ichthyotic phenotype resulting in neonatal lethality. Mutant mice revealed acanthosis and hyperkeratosis as well as abnormal keratinocyte differentiation and increased proliferation. In addition, the epidermal barrier was severely impaired. These results indicate an essential role of SNAP29 in epidermal differentiation and barrier formation. Markedly decreased deposition of lamellar body contents in mutant mice epidermis and the observation of malformed lamellar bodies indicate severe impairments in lamellar body function due to the Snap29 knockout. We also found increased microtubule associated protein-1 light chain 3, isoform B-II levels, unchanged p62/SQSTM1 protein amounts, and strong induction of the endoplasmic reticulum stress marker C/EBP homologous protein in mutant mice. This emphasizes a role of SNAP29 in autophagy and endoplasmic reticulum stress. Our murine models serve as powerful tools for investigating keratinocyte differentiation processes and provide insights into the essential contribution of SNAP29 to epidermal differentiation. PMID- 26747698 TI - Controlling Hydrogen Activation, Spillover, and Desorption with Pd-Au Single-Atom Alloys. AB - Key descriptors in hydrogenation catalysis are the nature of the active sites for H2 activation and the adsorption strength of H atoms to the surface. Using atomically resolved model systems of dilute Pd-Au surface alloys and density functional theory calculations, we determine key aspects of H2 activation, diffusion, and desorption. Pd monomers in a Au(111) surface catalyze the dissociative adsorption of H2 at temperatures as low as 85 K, a process previously expected to require contiguous Pd sites. H atoms preside at the Pd sites and desorb at temperatures significantly lower than those from pure Pd (175 versus 310 K). This facile H2 activation and weak adsorption of H atom intermediates are key requirements for active and selective hydrogenations. We also demonstrate weak adsorption of CO, a common catalyst poison, which is sufficient to force H atoms to spill over from Pd to Au sites, as evidenced by low-temperature H2 desorption. PMID- 26747697 TI - p53 Is a Direct Transcriptional Repressor of Keratin 17: Lessons from a Rat Model of Radiation Dermatitis. AB - The intermediate filament protein keratin 17 (Krt17) shows highly dynamic and inducible expression in skin physiology and pathology. Because Krt17 exerts physiologically important functions beyond providing structural stability to keratinocytes whereas abnormal Krt17 expression is a key feature of dermatoses such as psoriasis and pachyonychia congenita, the currently unclear regulation of Krt17 expression needs to be better understood. Using a rat model of radiation dermatitis, we report here that Krt17 expression initially is down-regulated but later is strongly up-regulated by ionizing radiation. The early down-regulation correlates with the activation of p53 signaling. Deletion of p53 abolishes the initial down-regulation but not its subsequent up-regulation, suggesting that p53 represses Krt17 transcription. Because previous work reported up-regulation of Krt17 by ultraviolet irradiation, which also activates p53 signaling, the effect of ultraviolet radiation was reexamined. This revealed that the initial down regulation of Krt17 is conserved, but the up-regulation comes much faster. Chromatin immunoprecipitation analysis in vivo and electromobility shift assay in vitro identified two p53-binding sites in the promoter region of Krt17. Thus, p53 operates as a direct Krt17 repressor, which invites therapeutic targeting in dermatoses characterized by excessive Krt17 expression. PMID- 26747699 TI - Transient Neurological Symptoms in Patients With Intracerebral Hemorrhage. AB - IMPORTANCE: Transient symptoms from an intracerebral hemorrhage (ICH) are not well recognized and have previously not been reported. OBJECTIVE: To describe the clinical presentations and neuroimaging findings in a subset of patients with ICH presenting with transient neurological signs and symptoms. DESIGN, SETTING, AND PARTICIPANTS: Clinical case series in which the hospital database of a large academic center in Boston, Massachusetts, was searched using International Classification of Diseases, Ninth Revision code 431 from June 1, 2000, to August 31, 2014, to identify patients with ICH who had transient deficits that resolved completely within 24 hours of symptom onset. MAIN OUTCOMES AND MEASURES: Clinical presentation, neuroimaging findings, and prognosis. RESULTS: Among 3207 consecutive patients with ICH initially screened, 17 fulfilled study criteria (median age, 65 years [interquartile range, 56-73 years]; 11 male). In most patients, recovery from neurological symptoms started within a few hours after onset. Most hemorrhages in this cohort were small, with a mean (SD) hematoma volume of 17 (9.9) mL, and were subcortical in location. One patient died of hemorrhage recurrence. CONCLUSIONS AND RELEVANCE: Patients with ICH can present with rapidly resolving deficits resembling transient ischemic attacks. Recognition of these instances is important to avoid delays in investigations and to manage these cases appropriately. PMID- 26747701 TI - Rhythm of Silence. AB - Speech is a complex sound sequence containing statistical regularities on multiple timescales. New research manipulates long-timescale statistical regularities of speech by jittering the duration of silence periods. It provides evidence that low-frequency neural activity (<4 Hz) is tuned to the statistical regularities of natural speech. PMID- 26747702 TI - Appropriateness of oral drugs for long-term treatment of lower urinary tract symptoms in older persons. PMID- 26747700 TI - Genome-wide binding analysis of the transcriptional regulator TrmBL1 in Pyrococcus furiosus. AB - BACKGROUND: Several in vitro studies document the function of the transcriptional regulator TrmBL1 of Pyrococcus furiosus. These data indicate that the protein can act as repressor or activator and is mainly involved in transcriptional control of sugar uptake and in the switch between glycolysis and gluconeogenesis. The aim of this study was to complement the in vitro data with an in vivo analysis using ChIP-seq to explore the genome-wide binding profile of TrmBL1 under glycolytic and gluconeogenic growth conditions. RESULTS: The ChIP-seq analysis revealed under gluconeogenic growth conditions 28 TrmBL1 binding sites where the TGM is located upstream of coding regions and no binding sites under glycolytic conditions. The experimental confirmation of the binding sites using qPCR, EMSA, DNase I footprinting and in vitro transcription experiments validated the in vivo identified TrmBL1 binding sites. Furthermore, this study provides evidence that TrmBL1 is also involved in transcriptional regulation of additional cellular processes e.g. amino acid metabolism, transcriptional control or metabolic pathways. In the initial setup we were interested to include the binding analysis of TrmB, an additional member of the TrmB family, but western blot experiments and the ChIP-seq data indicated that the corresponding gene is deleted in our Pyrococcus strain. A detailed analysis of a new type strain demonstrated that a 16 kb fragment containing the trmb gene is almost completely deleted after the first re-cultivation. CONCLUSIONS: The identified binding sites in the P. furiosus genome classified TrmBL1 as a more global regulator as hitherto known. Furthermore, the high resolution of the mapped binding positions enabled reliable predictions, if TrmBL1 activates (binding site upstream of the promoter) or represses transcription (binding site downstream) of the corresponding genes. PMID- 26747703 TI - Should AED Devices Be Routinely Included in Wilderness Medical Kits? PMID- 26747704 TI - Diabetes and cervical myelopathy. AB - Diabetes may affect the typical physical findings associated with cervical spondylotic myelopathy, as coexisting diabetic neuropathy may dampen expected hyperreflexia and also produce non-dermatomal extremity numbness. Most large studies of surgically treated diabetic patients with cervical spondylotic myelopathy have focused upon infection rates rather than exploring any differences in the presenting physical signs. We conducted a retrospective study of the pattern of presenting neurological signs and symptoms and of the clinical outcomes in 438 patients surgically treated for cervical spondylotic myelopathy, 79 of whom had diabetes. Compared with non-diabetic patients, those with diabetes were slightly older and had lower preoperative modified Japanese Orthopaedic Association (mJOA) scores. Those with diabetes also had a significantly higher incidence of hyporeflexia and a higher incidence of a positive Babinski sign, but there was no difference in the appearance of the Hoffman sign. The magnitude of mJOA improvement after surgery was comparable. We conclude that diabetes may alter the typical signs and symptoms of cervical spondylotic myelopathy and suggest that knowledge of the differences may aid in securing a prompt and accurate diagnosis. PMID- 26747706 TI - miR-137 Regulates the Tumorigenicity of Colon Cancer Stem Cells through the Inhibition of DCLK1. AB - miRNAs have important roles in regulating cancer stem cell (CSC) properties and are considered to be potential therapeutic targets. However, few studies have focused on miRNAs which are specifically related to colon CSCs. Here, a PCR-based miRNA profiling analysis of normal colon stem cells (NCSC) and colon CSCs (EpCAM+/CD44+/CD66a-) identified miRNAs which regulate colon CSC properties. Interestingly, miRNA-137 (miR-137) expression was downregulated in the colon CSCs compared with NCSCs, while doublecortin-like kinase 1(DCLK1) mRNA was highly expressed in the colon CSCs but low in the NCSCs. In fact, DCLK1-positive cancer cells were widely distributed in clinically resected colon cancer specimens, while DCLK1-positve epithelial cells were rarely detected in normal colon tissues including the crypt bottoms. Luciferase assay and immunoblot analysis revealed that miR-137 regulated DCLK1 gene expression. Transduction of exogenous miR-137 suppressed the development of colon cancer organoids in vitro and the tumorigenicity of colon cancer cells in vivo without affecting the growth of normal intestinal organoids. Furthermore, the suppression of miR-137 enhanced the organoid development of normal colon cells. These data demonstrate that miR-137 has the capacity to suppress the tumorigenicity of colon CSCs and that maintained expression of miR-137 in NCSCs contributes to suppressing uncontrolled cell proliferation through the inhibition of DCLK1 expression. IMPLICATIONS: The miR 137/DCLK1 axis as an important regulator in NCSCs and colon CSCs; further understanding of this axis may foster the development of potential gene therapeutic strategies targeting colon CSCs. PMID- 26747705 TI - TGF-beta/SMAD Pathway and Its Regulation in Hepatic Fibrosis. AB - Transforming growth factor-beta1 (TGF-beta1), a key member in the TGF-beta superfamily, plays a critical role in the development of hepatic fibrosis. Its expression is consistently elevated in affected organs, which correlates with increased extracellular matrix deposition. SMAD proteins have been studied extensively as pivotal intracellular effectors of TGF-beta1, acting as transcription factors. In the context of hepatic fibrosis, SMAD3 and SMAD4 are pro-fibrotic, whereas SMAD2 and SMAD7 are protective. Deletion of SMAD3 inhibits type I collagen expression and blocks epithelial-myofibroblast transition. In contrast, disruption of SMAD2 upregulates type I collagen expression. SMAD4 plays an essential role in fibrosis disease by enhancing SMAD3 responsive promoter activity, whereas SMAD7 negatively mediates SMAD3-induced fibrogenesis. Accumulating evidence suggests that divergent miRNAs participate in the liver fibrotic process, which partially regulates members of the TGF-beta/SMAD signaling pathway. In this review, we focus on the TGF-beta/SMAD and other relative signaling pathways, and discussed the role and molecular mechanisms of TGF-beta/SMAD in the pathogenesis of hepatic fibrosis. Moreover, we address the possibility of novel therapeutic approaches to hepatic fibrosis by targeting to TGF-beta/SMAD signaling. PMID- 26747707 TI - Transcriptional Regulation of miR-31 by Oncogenic KRAS Mediates Metastatic Phenotypes by Repressing RASA1. AB - Activating KRAS mutations are nearly ubiquitous in pancreatic cancer occurring in more than 95% of clinical cases. miRNAs are small noncoding RNAs that regulate gene expression by binding sequences within the 3'UTRs of target mRNAs. An integral role for miRNAs in cancer pathogenesis is well established; however, the role of miRNAs in KRAS-mediated tumorigenesis is poorly characterized. Here it is demonstrated that expression of miR-31 is coupled to the expression of oncogenic KRAS and activity of the MAPK pathway. miR-31 is highly expressed in patient derived xenografts and a panel of pancreatic and colorectal cancer cells harboring activating KRAS mutations. The miR-31 host gene is a large noncoding RNA that correlates with miR-31 expression and enabled identification of the putative miR-31 promoter. Using luciferase reporters, a minimal RAS-responsive miR-31 promoter was found to drive robust luciferase activity dependent on expression of mutant KRAS and the transcription factor ELK1. Furthermore, ELK1 interacts directly with the endogenous miR-31 promoter in a MAPK-dependent manner. Expression of enforced miR-31 significantly enhanced invasion and migration of multiple pancreatic cancer cells resulting from the activation of RhoA through regulation of the miR-31 target gene RASA1. Importantly, acute knockdown of RASA1 phenocopied enforced miR-31 expression on the migratory behavior of pancreatic cancer cells through increased RhoA activation. IMPLICATIONS: Oncogenic KRAS can activate Rho through the miR-31-mediated regulation of RASA1 indicating miR-31 acts as a KRAS effector to modulate invasion and migration in pancreatic cancer. PMID- 26747708 TI - A Borrelia burgdorferi Surface-Exposed Transmembrane Protein Lacking Detectable Immune Responses Supports Pathogen Persistence and Constitutes a Vaccine Target. AB - Borrelia burgdorferi harbors a limited set of transmembrane surface proteins, most of which constitute key targets of humoral immune responses. Here we show that BB0405, a conserved membrane-spanning protein of unknown function, fails to evoke detectable antibody responses despite its extracellular exposure. bb0405 is a member of an operon and ubiquitously expressed throughout the rodent-tick infection cycle. The gene product serves an essential function in vivo, as bb0405 deletion mutants are unable to transmit from ticks and establish infection in mammalian hosts. Despite the lack of BB0405-specific immunoglobulin M or immunoglobulin G antibodies during natural infection, mice immunized with a recombinant version of the protein elicited high-titer and remarkably long lasting antibody responses, conferring significant host protection against tick borne infection. Taken together, these studies highlight the essential role of an apparently immune-invisible borrelial transmembrane protein in facilitating infection and its usefulness as a target of protective host immunity blocking the transmission of B. burgdorferi. PMID- 26747709 TI - Genomic Analysis of Serogroup Y Neisseria meningitidis Isolates Reveals Extensive Similarities Between Carriage-Associated and Disease-Associated Organisms. AB - BACKGROUND: Neisseria meningitidis is a frequent colonizer of the human nasopharynx, with asymptomatic carriage providing the reservoir for invasive, disease-causing strains. Serogroup Y (MenY) strains are a major cause of meningococcal disease. High-resolution genetic analyses of carriage and disease isolates can establish epidemiological relationships and identify potential virulence factors. METHODS: Whole-genome sequence data were obtained for 99 MenY carriage isolates recovered in the United Kingdom during 1997-2010. Sequences were compared to those of 73 MenY invasive isolates recovered during 2010-2011, using a gene-by-gene approach. RESULTS: Comparisons across 1605 core genes resolved 91% of isolates into one of 8 clusters containing closely related disease and carriage isolates. Six clusters contained carried meningococci isolated during 1997-2001, suggesting temporal stability. One cluster of isolates, predominately sharing the designation Y: P1.5-1,10-1: F4-1: ST-1655 (cc23), was resolved into one subcluster with 86% carriage isolates and a second with 90% invasive isolates. These subclusters were defined by specific allelic differences in 5 core genes encoding glycerate kinase (glxK), valine-pyruvate transaminase (avtA), superoxide dismutase (sodB), and 2 hypothetical proteins. CONCLUSIONS: High-resolution genetic analyses detected long-term temporal stability and temporally overlapping carriage and disease populations for MenY clones but also evidence of a disease-associated clone. PMID- 26747712 TI - Raising the Bar at Health Education & Behavior: A Five-Year Retrospective and Look Ahead. PMID- 26747711 TI - Histopathologic Evaluation of Vascular Findings in the Cochlea in Patients With Presbycusis. AB - IMPORTANCE: Age-related changes in cochlear vessel wall thickness in human temporal bones have not been described previously. OBJECTIVES: To compare thickness of the spiral modiolar artery and strial capillaries and to investigate strial atrophy and vessel loss in temporal bones with and without presbycusis. DESIGN, SETTING, AND PARTICIPANTS: This retrospective case-control study examined the autopsy reports of 1024 patients in the temporal bone collection at the University of Minnesota. Inclusion criteria consisted of being 60 years or older with sensorineural hearing loss and progression of hearing loss with age (presbycusis group). Age-matched controls had no record of hearing loss. All patients underwent pure-tone audiometry. Exclusion criteria included a history of otologic disease, ototoxic drug use, head or acoustic trauma, or systemic disease. Data were collected from October 1, 2013, to October 1, 2014. MAIN OUTCOMES AND MEASURES: Vessel wall thickness in the modiolar artery and strial vessels, the strial area, and number of strial vessels were measured under light microscopy. RESULTS: Among the 1024 autopsy reports examined, 11 patients (19 temporal bones) with presbycusis (7 men and 4 women; age range, 67-88 years; mean [SD] age, 78 [7] years]) and 15 controls (24 temporal bones) (7 men and 8 women; age range, 67-94 years; mean [SD] age, 79 [8] years) met the inclusion criteria. Compared with the control group, the presbycusis group had significantly increased mean (SD) thickness of vessel walls in the modiolar arteries (6.73 [2.39] vs 5.55 [0.86] MUm; P = .02) and the strial capillaries in the lower basal (1.57 [0.21] vs 1.39 [0.15] MUm; P = .005), upper basal (1.62 [0.28] vs 1.40 [0.13] MUm; P < .001), lower middle (1.68 [0.22] vs 1.39 [0.20] MUm; P < .001), upper middle (1.74 [0.39] vs 1.40 [0.19] MUm; P = .01), and apical (1.70 [0.36] vs 1.47 [0.21] MUm; P = .04) turns of the cochlea. Compared with the control group, the presbycusis group had significant loss of strial area in the lower basal (6614 [1559] vs 8790 [1893] MUm2; P = .002), upper basal (6387 [2211] vs 9105 [2700] MUm2; P < .001), lower middle (5140 [1471] vs 7269 [2181] MUm2; P = .003), upper middle, (5583 [1742] vs 7206 [2258] MUm2; P = .02), and apical (4286 [1604] vs 6535 [2454] MUm2; P < .001) turns of the cochlea; in the vessel area in the lower basal turn (74.65 [127.74] vs 124.92 [89.04] MUm2; P = .01); and in the number of vessels in the lower basal (1.00 [0.78] vs 1.94 [0.93]; P = .008) and lower middle (1.00 [0.78] vs 1.94 [0.93]; P = .04) turns of the cochlea. CONCLUSIONS AND RELEVANCE: The histopathologic findings of increased thickness of the vascular walls of the modiolar arteries and stria vascularis, increased strial atrophy, and decreased number of strial vessels may have led to decreased cochlear microcirculation. Deficiency in the circulation and perfusion of the cochlea may be a factor in presbycusis. PMID- 26747713 TI - Navigating Government Service as a Physician. AB - Working in government can be a remarkable life experience for anyone but particularly for those who have trained in the worlds of medicine and public health. This article describes some lessons learned from a physician initially based in academic medicine and public health who has since spent more than a decade serving in leadership positions at the state and federal levels. Many of the described themes about policy making can guide health professionals who wish to understand and ultimately contribute to the public sector. Certainly, the challenges and risks are noteworthy. However, for those willing and able to take the leap, government service can offer extraordinary opportunities not only for tremendous personal growth but also for making broader contributions to public health. PMID- 26747710 TI - Loss of neutral ceramidase protects cells from nutrient- and energy -deprivation induced cell death. AB - Sphingolipids are a family of lipids that regulate the cell cycle, differentiation and cell death. Sphingolipids are known to play a role in the induction of apoptosis, but a role for these lipids in necroptosis is largely unknown. Necroptosis is a programmed form of cell death that, unlike apoptosis, does not require ATP. Necroptosis can be induced under a variety of conditions, including nutrient deprivation and plays a major role in ischaemia/reperfusion injury to organs. Sphingolipids play a role in ischaemia/reperfusion injury in several organs. Thus, we hypothesized that sphingolipids mediate nutrient deprivation-induced necroptosis. To address this, we utilized mouse embryonic fibroblast (MEFs) treated with 2-deoxyglucose (2DG) and antimycin A (AA) to inhibit glycolysis and mitochondrial electron transport. 2DG/AA treatment of MEFs induced necroptosis as it was receptor- interacting protein (RIP)-1/3 kinase dependent and caspase-independent. Ceramides, sphingosine (Sph) and sphingosine 1 phosphate (S1P) were increased following 2DG/AA treatment. Cells lacking neutral ceramidase (nCDase(-/-)) were protected from 2DG/AA. Although nCDase(-/-) cells generated ceramides following 2DG/AA treatment, they did not generate Sph or S1P. This protection was stimulus-independent as nCDase(-/-) cells were also protected from endoplasmic reticulum (ER) stressors [tunicamycin (TN) or thapsigargin (TG)]. nCDase(-/-) MEFs had higher autophagic flux and mitophagy than wild-type (WT) MEFs and inhibition of autophagy sensitized them to necroptosis. These data indicate that loss of nCDase protects cells from nutrient- deprivation-induced necroptosis via autophagy, and clearance of damaged mitochondria. Results suggest that nCDase is a mediator of necroptosis and might be a novel therapeutic target for protection from ischaemic injury. PMID- 26747714 TI - Reflections on Government Service Rotations by an Academic Health Education Professional. AB - This reflection is on a health education professional's rotation from professor in a school of public health to a government position and back parallels that of Professor Howard Koh's journey to Assistant Secretary of Health, one level higher in the same federal bureaucracy. We both acknowledge the steep learning curve and some bureaucratic hassles and mazes that can attend government service, but similarly conclude that ". . . it was worth it." In this personalized case, I weigh some of the specific learning experiences and challenges I faced while in the government against the needs of the field of health promotion for more such revolving-door experiences among academic public health professionals. From my argument that to get more evidence-based practice we need more practice-based evidence, I conclude that more experience in practice among those returning to academia will render their teaching and research more relevant to the needs for evidence in policy and practice. PMID- 26747715 TI - Translating the Socio-Ecological Perspective Into Multilevel Interventions: Gaps Between Theory and Practice. AB - Multilevel interventions are inspired by socio-ecological models, and seek to create change on various levels-for example by increasing the health literacy of individuals as well as modifying the social norms within a community. Despite becoming a buzzword in public health, actual multilevel interventions remain scarce. In this commentary, we explore the operational and empirical barriers to designing and implementing multilevel interventions, and argue that the current theoretical framework based on the socio-ecological model is insufficient to guide those seeking to design multilevel interventions. We consider two theories, namely, the complementarity principle theory and the risk compensation theory-to address the gap between theory and translation into practice. PMID- 26747716 TI - Metformin as firstline treatment for type 2 diabetes: are we sure? AB - Remy Boussageon and colleagues ask whether metformin is bringing practical benefit to patients and question the focus on surrogate measures. PMID- 26747717 TI - Improving the performance of reflex Human Papilloma Virus (HPV) testing in triaging women with atypical squamous cells of undetermined significance (ASCUS): A restrospective study in a tertiary hospital in United Arab Emirates (UAE). AB - INTRODUCTION: Cervical cancer is the second commonest cancer in women worldwide. Infection with oncogenic types of human Papillomavirus (HPV) is the most important risk factor for developing cervical cancer. Reflex High risk HPV (HR HPV) testing is of significant value in the assessment of Papanicolaou (Pap) smear results where ASCUS are identified. OBJECTIVE: To improve the performance of reflex HR-HPV testing in triage of ASCUS and analyze the factors impacting it. METHODOLOGY: In this study, we generated a database of 9641 women who had cervical smears collected during the study period from the cytopathology record in a large tertiary hospital in UAE. These included 297 smears with ASCUS diagnosis. All cases were retrospectively followed up with a mean duration of 2.44 years. We analyzed data according to the outcome based on several follow-up Pap smear analysis as the reference assessment. RESULTS: We detected HR-HPV infection in 17.9% of cases. 9.1% <25, 28.8% 25-34 and 62.1% >=35 years old. HR HPV prevalence was higher among premenopausal women (20.7%) compared to postmenopausal women (9.5%) (P-value=0.044). The rate of progression to high grade lesions was also higher (28.7%) in the premenopausal group compared to (12.8%) in the postmenopausal group. Reflex HPV testing had an overall sensitivity of 41.1%, specificity of 88.2%, positive predictive value (PPV) of 62.1%, and negative predictive value (NPV) of 75.9% in detection of cervical lesions. These figures were higher on combining premenopausal status and complaint of abnormal bleeding or discharge/itching (66.7%, 93.3%, 66.8% and 93.3% respectively). CONCLUSIONS: The sensitivity, specificity and NPV of reflex HPV testing in the triage of ASCUS cases can be more accurate in premenopausal women upon adding age group and presenting complaint as a triage item. This improves the performance of reflex HPV testing and the subsequent selection of high risk patients for colposcopy. PMID- 26747718 TI - Humoral immune responses in koalas (Phascolarctos cinereus) either naturally infected with Chlamydia pecorum or following administration of a recombinant chlamydial major outer membrane protein vaccine. AB - The development of a vaccine is a key strategy to combat the widespread and debilitating effects of chlamydial infection in koalas. One such vaccine in development uses recombinant chlamydial major outer membrane protein (rMOMP) as an antigen and has shown promising results in several koala trials. Previous chlamydial vaccine studies, primarily in the mouse model, suggest that both cell mediated and antibody responses will be required for adequate protection. Recently, the important protective role of antibodies has been highlighted. In our current study, we conducted a detailed analysis of the antibody-mediated immune response in koalas that are either (a) naturally-infected, and/or (b) had received an rMOMP vaccine. Firstly, we observed that naturally-infected koalas had very low levels of Chlamydia pecorum-specific neutralising antibodies. A strong correlation between low IgG total titers/neutralising antibody levels, and higher C. pecorum infection load was also observed in these naturally-infected animals. In vaccinated koalas, we showed that the vaccine was able to boost the humoral immune response by inducing strong levels of C. pecorum-specific neutralising antibodies. A detailed characterisation of the MOMP epitope response was also performed in naturally-infected and vaccinated koalas using a PepScan epitope approach. This analysis identified unique sets of MOMP epitope antibodies between naturally-infected non-protected and diseased koalas, versus vaccinated koalas, with the latter group of animals producing a unique set of specific epitope-directed antibodies that we demonstrated were responsible for the in vitro neutralisation activity. Together, these results show the importance of antibodies in chlamydial infection and immunity following vaccination in the koala. PMID- 26747719 TI - Topical Docosahexaenoic Acid (DHA) Accelerates Skin Wound Healing in Rats and Activates GPR120. AB - BACKGROUND: The development of methods for improving skin wound healing may have an impact on the outcomes of a number of medical conditions. The topical use of polyunsaturated fatty acids (PUFAs) can accelerate skin wound healing through mechanisms that involve, at least in part, the modulation of inflammatory activity. PURPOSE: We evaluated whether G-protein-coupled receptor 120 (GPR120), a recently identified receptor for docosahexaenoic acid (DHA) with anti inflammatory activity, is expressed in the skin and responds to topical DHA. METHOD: Male Wistar rats were submitted to an 8.0-mm wound on the back and were immediately administered a topical treatment of a solution containing 30 MUM of DHA once a day. The healing process was photodocumented, and tissues were collected on Days 5, 9, and 15 for protein and RNA analyses and histological evaluation. RESULTS: GPR120 was expressed in the intact skin and in the wound. Keratinocytes expressed the most skin GPR120, while virtually no expression was detected in fibroblasts. Upon DHA topical treatment, wound healing was significantly accelerated and was accompanied by the molecular activation of GPR120, as determined by its association with beta-arrestin-2. In addition, DHA promoted a reduction in the expression of interleukin (IL) 1beta and an increase in the expression of IL-6. Furthermore, there was a significant increase in expression of transforming growth factor beta (TGF-beta) and the keratinocyte marker involucrin. DISCUSSION: Topical DHA improved skin wound healing. The activation of GPR120 is potentially involved in this process. PMID- 26747720 TI - Unhappiness and the Radiologist. PMID- 26747721 TI - Patient Motion During Clinical MR Examinations, Beyond the Economic Burden. PMID- 26747722 TI - The Not-All-That-Invisible College. PMID- 26747724 TI - What Are Women Being Exposed to? A Review of the Quality, Content and Ownership of Websites on Premenstrual Dysphoric Disorder. AB - BACKGROUND: An increasing number of people are now turning to the Internet for health information. Internet use is especially likely in women with the clinical condition premenstrual dysphoric disorder (PMDD), which affects approximately 8% of premenopausal women. However, to date, there has not been a review of the quality of these online resources on PMDD. The aim of the present study was to address this gap by reviewing websites containing PMDD information. METHODS: A search was conducted on three commonly used search engines (Google, Yahoo, and Bing). The first 50 results were extracted and compared across each search engine results to determine unique resources. After removing inaccessible links, a total of 69 unique websites were reviewed to evaluate their general quality, condition specific content quality, and ownership. RESULTS: The websites varied widely in terms of their quality and ownership. Most returned websites were from web providers, U.S. health care providers, and media companies. General quality (e.g., design) was modest; yet, condition-specific content quality was far poorer. CONCLUSIONS: Women are being exposed to a varying degree of quality information about PMDD. Health professionals and website owners of this information should consider this and encourage better online resources to help this patient group. The paper presents the five highest scoring websites that may be used by those with a vested interest in PMDD, such as health professionals or women with PMDD. PMID- 26747723 TI - Clusters of Multiple Complex Chronic Conditions: A Latent Class Analysis of Children at End of Life. AB - CONTEXT: Children at end of life often experience multiple complex chronic conditions with more than 50% of children reportedly having two or more conditions. These complex chronic conditions are unlikely to occur in an entirely uniform manner in children at end of life. Previous work has not fully accounted for patterns of multiple conditions when evaluating care among these children. OBJECTIVES: The objective of the study was to understand the clusters of complex chronic conditions present among children in the last year of life. METHODS: Participants were 1423 pediatric decedents from the 2007 to 2008 California Medicaid data. A latent class analysis was used to identify clusters of children with multiple complex chronic conditions (neurological, cardiovascular, respiratory, renal, gastrointestinal, hematologic, metabolic, congenital, cancer). Multinomial logistic regression analysis was used to examine the relationship between demographic characteristics and class membership. RESULTS: Four latent classes were yielded: medically fragile (31%); neurological (32%); cancer (25%); and cardiovascular (12%). Three classes were characterized by a 100% likelihood of having a complex chronic condition coupled with a low or moderate likelihood of having the other eight conditions. The four classes exhibited unique demographic profiles. CONCLUSION: This analysis presented a novel way of understanding patterns of multiple complex chronic conditions among children that may inform tailored and targeted end-of-life care for different clusters. PMID- 26747725 TI - Combining Persuasive Technology With Behavioral Theory to Support Weight Maintenance Through a Mobile Phone App: Protocol for the MotiMate App. AB - BACKGROUND: The prevalence of health-focused mobile phone apps available for download increases daily, with weight management apps being among the most proliferative. However, most lack theoretic grounding or evidence of efficacy. There is a significant body of literature which provides evidence for behaviors which are associated with successful weight loss maintenance. Behavioral theory also provides further insight regarding successful behavior change and maintenance. OBJECTIVE: We aimed to apply this knowledge to the development of the functionality of an app targeting weight loss maintenance. METHODS: We have subsequently undertaken the development of a persuasive and behavior targeting mobile app (MotiMate) to assist in maintenance of weight loss. MotiMate combines persuasive and behavior change theories in a practical targeted tool through its motivational messages, personalized feedback, and intelligent supportive tools to manage weight, food, exercise, mood and stress. RESULTS: The development and trial of MotiMate received funding support in May 2014. All 88 volunteers started the trial by December 2014 and were in the process of completing their final visits when this paper was submitted (May 2015). Data analysis is currently underway. CONCLUSIONS: The paper has presented a scientifically informed mobile phone app to support weight loss maintenance. Further evaluation of its efficacy is in progress. TRIAL REGISTRATION: ANZCTR 12614000474651; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366120 (Archived by WebCite at http://www.webcitation.org/6eJeQiKxi). PMID- 26747726 TI - Fatty acid induced metabolic memory involves alterations in renal histone H3K36me2 and H3K27me3. AB - Accumulating evidence suggest that diabetic complications persist even after the maintenance of normal glucose levels. However, the molecular mechanisms involved are still unclear. In the present study, we have investigated the molecular mechanism behind the presence of insulin resistance (IR) condition even after normalization of circulating lipids levels both in vivo and in vitro. Persistent inhibition of insulin signalling in absence of elevated circulating lipids level confirms the presence of metabolic memory in our model of IR. IR in human urine derived podocyte-like epithelial cells (HUPECs) was developed by incubating cells with palmitate (750 MUM) for 24 h and in SD rats by feeding high fat diet for 16 weeks. Inhibition of insulin induced FOXO1 (regulator of gluconeogenic genes) degradation persisted even after 48 h of palmitate removal from the culture media. Metabolic memory by palmitate was found to be associated with increased FOXO1 activity as evident from increased expression of FOXO1 target genes such as PDK4, p21, G6Pc and IGFBP1. To understand the reason for prolonged activation of FOXO1 and its target genes, chromatin immuno-precipitation (ChIP) was performed with histone H3K36me2 and H3K27me3 antibodies. ChIP assay shows persistent increase in abundance of histone H3K36me2 on promoter region of FOXO1. We also show decreased abundance of histone H3K27me3 on promoter region of FOXO1, in the kidneys of HFD fed rats, which persisted even after 8 weeks of diet reversal. Taken together, we provide first evidence that circulating lipids generate metabolic memory possibly by altering the abundance of histone H3K36me2 and H3K27me3 on FOXO1 promoter. PMID- 26747729 TI - A novel rat model of gestational diabetes induced by intrauterine programming is associated with alterations in placental signaling and fetal overgrowth. AB - A family history of diabetes predisposes to gestational diabetes mellitus (GDM). We hypothesized that female offspring of rats with pre-gestational diabetes will develop GDM, a pathology associated with fetal overgrowth and altered placental signaling. We found normal glycemia and insulinemia in the offspring from pre gestational diabetic rats at three months of age. However, consistent with GDM, maternal hyperglycemia and hyperinsulinemia and increased fetal weight were evident when compared to controls. In this intrauterine programmed GDM model, the placentas showed alterations in mTOR pathway: unchanged phosphorylation of 4EBP-1 and PKCalpha despite reduced total expression of 4EBP-1 and PKCalpha, and increased phosphorylation of SGK1. GDM placentas also showed reduced expression of PPARalpha and PPARgamma, and increased lipoperoxidation, nitric oxide production and peroxynitrite-induced damage. We conclude that exposure of maternal diabetes in utero programs GDM in the female offspring, leading to a GDM model associated with impaired placental signaling pathways, increased pro oxidant/pro-inflammatory environment and fetal overgrowth. PMID- 26747728 TI - Genetic control of bone mass. AB - Bone mineral density (BMD) is a quantitative traits used as a surrogate phenotype for the diagnosis of osteoporosis, a common metabolic disorder characterized by increased fracture risk as a result of a decreased bone mass and deterioration of the microarchitecture of the bone. Normal variation in BMD is determined by both environmental and genetic factors. According to heritability studies, 50-85% of the variance in BMD is controlled by genetic factors which are mostly polygenic. In contrast to the complex etiology of osteoporosis, there are disorders with deviating BMD values caused by one mutation with a large impact. These mutations can result in monogenic bone disorders with either an extreme high (sclerosteosis, Van Buchem disease, osteopetrosis, high bone mass phenotype) or low BMD (osteogenesis imperfecta, juvenile osteoporosis, primary osteoporosis). Identification of the disease causing genes, increased the knowledge on the regulation of BMD and highlighted important signaling pathways and novel therapeutic targets such as sclerostin, RANKL and cathepsin K. Genetic variation in genes involved in these pathways are often also involved in the regulation of normal variation in BMD and osteoporosis susceptibility. In the last decades, identification of genetic factors regulating BMD has proven to be a challenge. Several approaches have been tested such as linkage studies and candidate and genome wide association studies. Although, throughout the years, technological developments made it possible to study increasing numbers of genetic variants in populations with increasing sample sizes at the same time, only a small fraction of the genetic impact can yet be explained. In order to elucidate the missing heritability, the focus shifted to studying the role of rare variants, copy number variations and epigenetic influences. This review summarizes the genetic cause of different monogenic bone disorders with deviating BMD and the knowledge on genetic factors explaining normal variation in BMD and osteoporosis risk. PMID- 26747727 TI - All-trans retinoic acid modulates Wnt3A-induced osteogenic differentiation of mesenchymal stem cells via activating the PI3K/AKT/GSK3beta signalling pathway. AB - Osteogenic differentiation of mesenchymal stem cells (MSCs) is a vital process for the maintenance of healthy bone tissue and is mediated by numerous factors. Canonical Wnt signalling is essential for MSC osteogenic differentiation, and it interacts with several nuclear receptors, including the retinoic acid receptor, vitamin D receptor, and glucocorticoid receptor. Here, we explored whether Wnt3A and all-trans-retinoic acid (ATRA) play synergistic roles in MSC osteogenic differentiation. We found that ATRA potentiated the Wnt3A-induced expression of early and late osteogenic markers as well as matrix mineralization and further confirmed the phenomena using foetal limb explant culture and MSC implantation experiments. Mechanistically, ATRA cooperated with Wnt3A to induce beta-catenin translocation from cell-cell contacts into the cytosol and nucleus, thereby activating Wnt/beta-catenin signalling. Additionally, Wnt3A attenuated ATRA induced Cyp26a1 expression, inhibiting the degradation of ATRA into its oxidative forms. beta-catenin silencing abolished the stimulatory effect of ATRA on Wnt3A induced alkaline phosphatase (ALP) activity and reversed its inhibitory effect on Cyp26a1 expression. Furthermore, ATRA and Wnt3A synergistically promoted AKT phosphorylation, enhancing beta-catenin-dependent transcription through GSK3beta inhibition or direct beta-catenin phosphorylation at Ser552. This event was largely abolished by LY294002 pre-treatment, suggesting that ATRA and Wnt3A at least partially promote osteogenic differentiation via activating the PI3K/AKT/GSK3beta signalling pathway. Thus, crosstalk between the Wnt/beta catenin and retinoic acid signalling pathways may be an effective therapeutic target for bone diseases, such as osteoporosis. PMID- 26747730 TI - Individual differences in face processing captured by ERPs. AB - A rapid neural adaptation procedure and Event Related Potentials (ERPs) were employed to study individual differences in Good and Bad recognizers in face perception. The major goal was to characterize the sensitivity of the P100 and the N170 to the identity repetition effect as a function of inter-individual perceptual abilities. For these purposes an integrated methodological approach was used in which a self-report, a standardized test and behavioral performances were combined with ERPs measures. Specifically, two groups of face recognizers (Good and Bad recognizers) were selected by means of a self-report questionnaire on face recognition abilities (The Italian Face Abilities Questionnaire) and the scoring at the Cambridge Face Memory Test. The P100 showed an early neural tuning for faces in Good recognizers. The N170 triggered by the adaptor showed face specificity compared to cars but, importantly, only Good recognizers showed a decreased amplitude of N170 for test faces of the same identity compared to test faces of different identity while this was not the case for Bad recognizers. These results show that ERPs are a suitable and sensitive tool to tap individual differences in face recognition. In conclusion, our results show the importance of considering inter-individual different perceptual abilities in face processing research. PMID- 26747731 TI - Impact of a pre-operative pulmonary rehabilitation program on functional performance in patients undergoing video-assisted thoracic surgery for lung cancer. PMID- 26747732 TI - Chronic lung infection caused by Trichosporon mycotoxinivorans and tricosporin mucoides in an immunocompetent cystic fibrosis patient. PMID- 26747733 TI - Assessment of Inducible Myocardial Ischemia, Quality of Life, and Functional Status After Successful Percutaneous Revascularization in Patients With Chronic Total Coronary Occlusion. AB - The benefits of chronic total coronary occlusion (CTO) revascularization are not well established. In this prospective cohort study, 47 consecutive patients with successful percutaneous recanalization of CTO underwent adenosine stress cardiac magnetic resonance (CMR), 6-minute walk test (6MWT), and the Short Form-36 Health Survey before and 6 months after the procedure. Successful recanalization of a CTO was followed by significant improvement of (1) global physical and mental health status; (2) the distance walked in the 6MWT; (3) the incidence of chest pain at the end of the 6MWT; and (4) the score of a novel CMR ischemic burden index on the basis of the characteristics of adenosine stress perfusion defects (extension, persistence, transmurality, and induced contractile regional dysfunction). Patients with greater CMR ischemic index before percutaneous revascularization showed better improvement in the 6MWT. In conclusion, successful recanalization of a CTO leads to a concurrent improvement in ischemic burden, exercise tolerance, angina frequency, and quality of life scores. Patients with a high ischemic CMR score before CTO recanalization showed the better improvement in exercise tolerance. PMID- 26747734 TI - Relation of Depressive Symptoms With Coronary Artery Calcium Determined by Electron-Beam Computed Tomography (from the Rancho Bernardo Study). AB - Studies linking depressive symptoms and coronary artery calcium (CAC), a measure of subclinical atherosclerosis, have yielded mixed results. No longitudinal studies of depressive symptoms and CAC have included older adults of both genders. This study examined the association of depressive symptoms with CAC and CAC progression in older men and women. Participants were 417 community-dwelling older adults (mean age = 67 +/- 7) with no history of heart disease who attended a 1997 to 1999 research clinic visit when depressive symptoms were assessed using the Beck Depression Inventory (BDI). CAC was measured using electron-beam computed tomography in 2000 to 2002 and again in 2005 to 2007. Median BDI was 3, range = 0 to 37; 39% of men and 10% of women had severe CAC (Agatston score >= 400) in 2000 to 2002. Ordinal logistic regression analyses examining the odds of greater compared with lesser CAC severity by BDI quartiles showed an unexpected negative association whereby women with the lowest depressive symptoms had 2.4 times the odds of increasing CAC severity compared with women in the second BDI quartile (95% CI 1.1 to 5.4). A nonlinear, U-shaped association was observed in men with those in the first and fourth BDI quartiles having 2.6 and 3.0 times higher odds of increasing CAC severity than subjects in the second quartile (95% CI 1.2 to 5.6 and 1.3 to 6.9, respectively) after adjustment for coronary heart disease risk factors. No significant associations were observed for CAC progression although similar nonlinear patterns were observed in men. In conclusion, our results suggest that depressive symptoms have a gender-specific, cross-sectional association with CAC but no statistically significant associations with CAC progression. PMID- 26747735 TI - Acute high-grade acromioclavicular joint injuries treatment: Arthroscopic non rigid coracoclavicular fixation provides better quality of life outcomes than hook plate ORIF. AB - INTRODUCTION: Treatment of acute high-grade acromioclavicular joint (ACJ) injuries with metal hardware alters the biomechanics of the ACJ, implying a second surgery for hardware removal. The period during which the plate is present involves functional limitations, pain and a risk factor for the development of hardware-related-injuries. Arthroscopy-assisted procedures compared to open-metal hardware techniques offer: less morbidity, the possibility to treat associated lesions and no need for a second operation. The aim was to compare the Quality of life (QoL) of patients with acute high-grade ACJ injuries (Rockwood grade III-V), managed arthroscopically with a non-rigid coracoclavicular (CC) fixation versus the QoL of patients managed with a hook plate, 24 months or more after their shoulder injury. PATIENTS AND METHODS: A retrospective revision of high-grade ACJ injuries managed in three institutions was performed. Patients treated by means of an arthroscopy-assisted CC fixation or by means of a hook plate were included. The inclusion period was between 2008 and 2012. The QoL was evaluated at the last follow-up visit by means of the SF36, the visual analog scale (VAS), the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, the Constant score and the global satisfaction (scale from 0 to 10). The presence of scapular dyskinesis and remaining vertical instability were evaluated. Comparison between groups was performed. RESULTS: Thirty-one patients were included: 20 arthroscopy group (ARTH group: 3 Rockwood III, 3 IV and 14 V) and 11 hook plate-group (HOOK group: 5 Rockwood III and 6 V). The mean age was 36 [25-52] year-old for the ARTH group and 41 [19-55] for the HOOK group (P=0.185). The mean results of the questionnaires were: (1) physical SF36 score (ARTH group 58.24+/-2.16 and HOOK group 53.70+/-4.33, P<0.001); (2) mental SF36 score (ARTH group 56.15+/-2.21 and HOOK group 53.06+/-6.10, P=0.049); (3) VAS (ARTH group 0.40+/-0.50 and HOOK group 1.45+/-1.51, P=0.007); (4) DASH (ARTH group 2.98+/-2.03 and HOOK group 4.79+/ 5.60, P=0.200); (5) Constant score (ARTH group 95.30+/-2.45 and HOOK group 91.36+/-6.84, P=0.026); (6) global satisfaction (ARTH group 8.85+/-0.93 and HOOK group 8.00+/-1.18, P=0.035). There was evidence of scapular dyskinesis in 15% (3/20) of the patients of the ARTH group and in 18% (2/11) of the patients of the HOOK group (P=1.000). Remaining vertical ACJ instability was observed in 40% (8/20) of the patients of the ARTH group and in 36.36% (4/11) of the patients of the HOOK group (P=1.000). CONCLUSION: Patients with acute high-grade ACJ injuries managed arthroscopically with a non-rigid CC fixation seem to have a better QoL than patients managed with a hook plate. LEVEL OF EVIDENCE: Level IV therapeutic; retrospective comparative study. PMID- 26747736 TI - Analysis of circulating CD14+/CD16+ monocyte-derived macrophages (MDMs) in the peripheral blood of patients with oral squamous cell carcinoma. AB - OBJECTIVES: Monocytes/macrophages are regarded as the first line of defense in tumors. Therefore, analyzing monocyte subtypes in oral squamous cell carcinoma (OSCC) may be of value in disease monitoring and to explore immunotherapeutic strategies for cancer patients. STUDY DESIGN: Circulating peripheral blood CD14+/CD16+ monocyte-derived macrophages (MDMs) were evaluated in OSCC patients with oral squamous cell carcinoma (n = 44) compared with controls (n = 85). Moreover, epitope detection in monocytes (EDIM) technology was used to detect biomarkers Apo10 and transketolase-like-1 in CD14+/CD16+ MDMs. RESULTS: Compared with controls, no significant (P = .3646) difference (control group 9.8%, OSCC group 8.8%) in CD14+/CD16+ MDM were noted in OSCC. However, EDIM-Apo10 and EDIM TKTL1 scores detected in the CD14+/CD16+ MDMs were increased in OSCC compared with controls (P < .0001). CONCLUSIONS: Analyzing CD14+/CD16+ MDMs represents a stable cell population for detecting biomarkers in cancer disease monitoring. PMID- 26747744 TI - Current trends in protein crystallization. AB - Proteins belong to the most complex colloidal system in terms of their physicochemical properties, size and conformational-flexibility. This complexity contributes to their great sensitivity to any external change and dictate the uncertainty of crystallization. The need of 3D models to understand their functionality and interaction mechanisms with other neighbouring (macro)molecules has driven the tremendous effort put into the field of crystallography that has also permeated other fields trying to shed some light into reluctant-to crystallize proteins. This review is aimed at revising protein crystallization from a regular-laboratory point of view. It is also devoted to highlight the latest developments and achievements to produce, identify and deliver high quality protein crystals for XFEL, Micro-ED or neutron diffraction. The low likelihood of protein crystallization is rationalized by considering the intrinsic polypeptide nature (folded state, surface charge, etc) followed by a description of the standard crystallization methods (batch, vapour diffusion and counter-diffusion), including high throughput advances. Other methodologies aimed at determining protein features in solution (NMR, SAS, DLS) or to gather structural information from single particles such as Cryo-EM are also discussed. Finally, current approaches showing the convergence of different structural biology techniques and the cross-methodologies adaptation to tackle the most difficult problems, are presented. SYNOPSIS: Current advances in biomacromolecules crystallization, from nano crystals for XFEL and Micro-ED to large crystals for neutron diffraction, are covered with special emphasis in methodologies applicable at laboratory scale. PMID- 26747737 TI - Altered signaling in systemic juvenile idiopathic arthritis monocytes. AB - Systemic juvenile idiopathic arthritis (sJIA) is characterized by systemic inflammation and arthritis. Monocytes are implicated in sJIA pathogenesis, but their role in disease is unclear. The response of sJIA monocytes to IFN may be dysregulated. We examined intracellular signaling in response to IFN type I (IFNalpha) and type II (IFNgamma) in monocytes during sJIA activity and quiescence, in 2 patient groups. Independent of disease activity, monocytes from Group 1 (collected between 2002 and 2009) showed defective STAT1 phosphorylation downstream of IFNs, and expressed higher transcript levels of SOCS1, an inhibitor of IFN signaling. In the Group 2 (collected between 2011 and 2014), monocytes of patients with recent disease onset were IFNgamma hyporesponsive, but in treated, quiescent subjects, monocytes were hyperresponsive to IFNgamma. Recent changes in medication in sJIA may alter the IFN hyporesponsiveness. Impaired IFN/pSTAT1 signaling is consistent with skewing of sJIA monocytes away from an M1 phenotype and may contribute to disease pathology. PMID- 26747745 TI - Directional patterns of cross frequency phase and amplitude coupling within the resting state mimic patterns of fMRI functional connectivity. AB - Functional imaging investigations into the brain's resting state interactions have yielded a wealth of insight into the intrinsic and dynamic neural architecture supporting cognition and behavior. Electrophysiological studies however have highlighted the fact that synchrony across large-scale cortical systems is composed of spontaneous interactions occurring at timescales beyond the traditional resolution of fMRI, a feature that limits the capacity of fMRI to draw inference on the true directional relationship between network nodes. To approach the question of directionality in resting state signals, we recorded resting state functional MRI (rsfMRI) and electrocorticography (ECoG) from four human subjects undergoing invasive epilepsy monitoring. Using a seed-point based approach, we employed phase-amplitude coupling (PAC) and biPhase Locking Values (bPLV), two measures of cross-frequency coupling (CFC) to explore both outgoing and incoming connections between the seed and all non-seed, site electrodes. We observed robust PAC between a wide range of low-frequency phase and high frequency amplitude estimates. However, significant bPLV, a CFC measure of phase phase synchrony, was only observed at specific narrow low and high frequency bandwidths. Furthermore, the spatial patterns of outgoing PAC connectivity were most closely associated with the rsfMRI connectivity maps. Our results support the hypothesis that PAC is relatively ubiquitous phenomenon serving as a mechanism for coordinating high-frequency amplitudes across distant neuronal assemblies even in absence of overt task structure. Additionally, we demonstrate that the spatial distribution of a seed-point rsfMRI sensorimotor network is strikingly similar to specific patterns of directional PAC. Specifically, the high frequency activities of distal patches of cortex owning membership in a rsfMRI sensorimotor network were most likely to be entrained to the phase of a low frequency rhythm engendered from the neural populations at the seed-point, suggestive of greater directional coupling from the seed out to the site electrodes. PMID- 26747747 TI - Laser-evoked cortical responses in freely-moving rats reflect the activation of C fibre afferent pathways. AB - The limited success of translating basic animal findings into effective clinical treatments of pain can be partly ascribed to the use of sub-optimal models. Murine models of pain often consist in recording (1) threshold responses (like the tail-flick reflex) elicited by (2) non-nociceptive specific inputs in (3) anaesthetized animals. The direct cortical recording of laser-evoked potentials (LEPs) elicited by stimuli of graded energies in freely-moving rodents avoids these three important pitfalls, and has thus the potential of improving such translation. Murine LEPs are classically reported to consist of two distinct components, reflecting the activity of Adelta- and C-fibre afferent pathways. However, we have recently demonstrated that the so-called "Adelta-LEPs" in fact reflect the activation of the auditory system by laser-generated ultrasounds. Here we used ongoing white noise to avoid the confound represented by the early auditory response, and thereby comprehensively characterized the physiological properties of C-fibre LEPs recorded directly from the exposed surface of the rat brain. Stimulus-response functions indicated that response amplitude is positively related to the stimulus energy, as well as to nocifensive behavioral score. When displayed using average reference, murine LEPs consist of three distinct deflections, whose polarity, order, and topography are surprisingly similar to human LEPs. The scalp topography of the early N1 wave is somatotopically-organized, likely reflecting the activity of the primary somatosensory cortex, while topographies of the later N2 and P2 waves are more centrally distributed. These results indicate that recording LEPs in freely moving rats is a valid model to improve the translation of animal results to human physiology and pathophysiology. PMID- 26747746 TI - Heritability and reliability of automatically segmented human hippocampal formation subregions. AB - The human hippocampal formation can be divided into a set of cytoarchitecturally and functionally distinct subregions, involved in different aspects of memory formation. Neuroanatomical disruptions within these subregions are associated with several debilitating brain disorders including Alzheimer's disease, major depression, schizophrenia, and bipolar disorder. Multi-center brain imaging consortia, such as the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium, are interested in studying disease effects on these subregions, and in the genetic factors that affect them. For large-scale studies, automated extraction and subsequent genomic association studies of these hippocampal subregion measures may provide additional insight. Here, we evaluated the test-retest reliability and transplatform reliability (1.5T versus 3T) of the subregion segmentation module in the FreeSurfer software package using three independent cohorts of healthy adults, one young (Queensland Twins Imaging Study, N=39), another elderly (Alzheimer's Disease Neuroimaging Initiative, ADNI-2, N=163) and another mixed cohort of healthy and depressed participants (Max Planck Institute, MPIP, N=598). We also investigated agreement between the most recent version of this algorithm (v6.0) and an older version (v5.3), again using the ADNI-2 and MPIP cohorts in addition to a sample from the Netherlands Study for Depression and Anxiety (NESDA) (N=221). Finally, we estimated the heritability (h(2)) of the segmented subregion volumes using the full sample of young, healthy QTIM twins (N=728). Test-retest reliability was high for all twelve subregions in the 3T ADNI-2 sample (intraclass correlation coefficient (ICC)=0.70-0.97) and moderate-to-high in the 4T QTIM sample (ICC=0.5-0.89). Transplatform reliability was strong for eleven of the twelve subregions (ICC=0.66-0.96); however, the hippocampal fissure was not consistently reconstructed across 1.5T and 3T field strengths (ICC=0.47-0.57). Between-version agreement was moderate for the hippocampal tail, subiculum and presubiculum (ICC=0.78-0.84; Dice Similarity Coefficient (DSC)=0.55-0.70), and poor for all other subregions (ICC=0.34-0.81; DSC=0.28-0.51). All hippocampal subregion volumes were highly heritable (h(2)=0.67-0.91). Our findings indicate that eleven of the twelve human hippocampal subregions segmented using FreeSurfer version 6.0 may serve as reliable and informative quantitative phenotypes for future multi-site imaging genetics initiatives such as those of the ENIGMA consortium. PMID- 26747749 TI - Glucose consumption of inflammatory cells masks metabolic deficits in the brain. AB - Inflammatory cells such as microglia need energy to exert their functions and to maintain their cellular integrity and membrane potential. Subsequent to cerebral ischemia, inflammatory cells infiltrate tissue with limited blood flow where neurons and astrocytes died due to insufficient supply with oxygen and glucose. Using dual tracer positron emission tomography (PET), we found that concomitant with the presence of inflammatory cells, transport and consumption of glucose increased up to normal levels but returned to pathological levels as soon as inflammatory cells disappeared. Thus, inflammatory cells established sufficient glucose supply to satisfy their energy demands even in regions with insufficient supply for neurons and astrocytes to survive. Our data suggest that neurons and astrocytes died from oxygen deficiency and inflammatory cells metabolized glucose non-oxidatively in regions with residual availability. As a consequence, glucose metabolism of inflammatory cells can mask metabolic deficits in neurodegenerative diseases. We further found that the PET tracer did not bind to inflammatory cells in severely hypoperfused regions and thus only a part of the inflammation was detected. We conclude that glucose consumption of inflammatory cells should be taken into account when analyzing disease-related alterations of local cerebral metabolism. PMID- 26747753 TI - The role of Coxsackievirus A16 in a case of sudden unexplained death in an infant - A SUDI case. AB - The Coxsackievirus A16 (CV-A16) is one of the main pathogens causing hand-foot and-mouth disease in young children. It is a low-virulence virus rarely involved in serious illness. It is seen sporadically or in outbreaks all over the world. We report a case of sudden unexplained death in infancy, SUDI, in a 3 and 1/2 months old infant, in which a thorough post mortem investigation pointed at a fatal infection with CV-A16 as the most likely cause of death. Only five cases of fatal CV-A16 infection have been published and none of these presented as sudden death. The fatal cases involved two infants, two young children and an elderly man. Post mortem, pre-autopsy CT-scan and C-reactive protein analysis allowed for an autopsy procedure targeted at a microbiological cause of death. The case illustrates the usefulness of supplementary testing during autopsy. PMID- 26747748 TI - The role of blood vessels in high-resolution volume conductor head modeling of EEG. AB - Reconstruction of the electrical sources of human EEG activity at high spatio temporal accuracy is an important aim in neuroscience and neurological diagnostics. Over the last decades, numerous studies have demonstrated that realistic modeling of head anatomy improves the accuracy of source reconstruction of EEG signals. For example, including a cerebro-spinal fluid compartment and the anisotropy of white matter electrical conductivity were both shown to significantly reduce modeling errors. Here, we for the first time quantify the role of detailed reconstructions of the cerebral blood vessels in volume conductor head modeling for EEG. To study the role of the highly arborized cerebral blood vessels, we created a submillimeter head model based on ultra-high field-strength (7T) structural MRI datasets. Blood vessels (arteries and emissary/intraosseous veins) were segmented using Frangi multi-scale vesselness filtering. The final head model consisted of a geometry-adapted cubic mesh with over 17*10(6) nodes. We solved the forward model using a finite-element-method (FEM) transfer matrix approach, which allowed reducing computation times substantially and quantified the importance of the blood vessel compartment by computing forward and inverse errors resulting from ignoring the blood vessels. Our results show that ignoring emissary veins piercing the skull leads to focal localization errors of approx. 5 to 15mm. Large errors (>2cm) were observed due to the carotid arteries and the dense arterial vasculature in areas such as in the insula or in the medial temporal lobe. Thus, in such predisposed areas, errors caused by neglecting blood vessels can reach similar magnitudes as those previously reported for neglecting white matter anisotropy, the CSF or the dura - structures which are generally considered important components of realistic EEG head models. Our findings thus imply that including a realistic blood vessel compartment in EEG head models will be helpful to improve the accuracy of EEG source analyses particularly when high accuracies in brain areas with dense vasculature are required. PMID- 26747755 TI - Altered expression and signalling of EP2 receptor in nasal polyps of AERD patients: role in inflammation and remodelling. AB - BACKGROUND: Down-regulation of the E-prostanoid (EP)2 receptor has been reported in aspirin exacerbated respiratory disease (AERD). We aimed to evaluate the expression and activation of EP receptors in AERD and their role in prostaglandin (PG) E2 signalling. METHODS: Samples were obtained from nasal mucosa of control subjects (NM-C, n=7) and from nasal polyps of AERD patients (NP-AERD, n=7). Expression of EP1-4 was assessed at baseline. Fibroblasts were stimulated with receptor agonists to measure cAMP levels, cell proliferation and granulocyte macrophage colony-stimulating factor (GM-CSF) release. RESULTS: NM-C and NP-AERD samples and fibroblasts expressed EP2, EP3 and EP4 at baseline. Lower expression of EP2 and higher expression of EP4 was observed in NP-AERD compared with NM-C. Stimulation with PGE2 and butaprost caused a higher increase in cAMP in NM-C than in NP-AERD. On the contrary, CAY10598 produced a higher production of cAMP in NP AERD compared with NM-C. The anti-proliferative effect of PGE2 and butaprost was lower in NP-AERD than in NM-C fibroblasts. Similarly, the capacity of PGE2 and butaprost to inhibit GM-CSF release was lower in NP-AERD than in NM-C. CONCLUSIONS: The altered expression of EP2 in AERD may contribute to reduce the capacity of PGE2 to mediate anti-proliferative and anti-inflammatory effects. PMID- 26747754 TI - AISF position paper on liver disease and pregnancy. AB - The relationship between liver disease and pregnancy is of great clinical impact. Severe liver disease in pregnancy is rare; however, pregnancy-related liver disease is the most frequent cause of liver dysfunction during pregnancy and represents a severe threat to foetal and maternal survival. A rapid differential diagnosis between liver disease related or unrelated to pregnancy is required in women who present with liver dysfunction during pregnancy. This report summarizes the recommendation of an expert panel established by the Italian Association for the Study of the Liver (AISF) on the management of liver disease during pregnancy. The article provides an overview of liver disease occurring in pregnancy, an update on the key mechanisms involved in its pathogenesis, and an assessment of the available treatment options. The report contains in three sections: (1) specific liver diseases of pregnancy; (2) liver disease occurring during pregnancy; and (3) pregnancy in patients with pre-existing chronic liver disease. Each topic is discussed considering the most relevant data available in literature; the final statements are formulated according to both scientific evidence and clinical expertise of the involved physicians, and the AISF expert panel recommendations are reported. PMID- 26747756 TI - Early and late effects of radiochemotherapy on cerebral blood flow in glioblastoma patients measured with non-invasive perfusion MRI. AB - BACKGROUND AND PURPOSE: To provide a systematic measure of changes of brain perfusion in healthy tissue following a fractionated radiotherapy of brain tumors. MATERIALS AND METHODS: Perfusion was assessed before and after radiochemotherapy using arterial spin labeling in a group of 24 patients (mean age 54.3 +/- 14.1 years) with glioblastoma multiforme. Mean relative perfusion change in gray matter in the hemisphere contralateral to the tumor was obtained for the whole hemisphere and also for six regions created by thresholding the individual dose maps at 10 Gy steps. RESULTS: A significant decrease of perfusion of -9.8 +/- 20.9% (p=0.032) compared to the pre-treatment baseline was observed 3 months after the end of radiotherapy. The decrease was more pronounced for high dose regions above 50 Gy (-16.8 +/- 21.0%, p=0.0014) than for low-dose regions below 10 Gy (-2.3 +/- 20.0%, p=0.54). No further significant decrease compared to the post-treatment baseline was observed 6 months (-0.4 +/- 18.4%, p=0.94) and 9 months (2.0 +/- 15.4%, p=0.74) after the end of radiotherapy. CONCLUSIONS: Perfusion decreased significantly during the course of radiochemotherapy. The decrease was higher in regions receiving a higher dose of radiation. This suggests that the perfusion decrease is at least partly caused by radiotherapy. Our results suggest that the detrimental effects of radiochemotherapy on perfusion occur early rather than later. PMID- 26747758 TI - In vitro degradation of biodegradable polylactic acid/magnesium composites: Relevance of Mg particle shape. AB - Absorbable medical devices must be developed in order to have an appropriate degradation rate in agreement with the healing rate of bone in the implantation site. In this work, biodegradable composites formed by a polylactic acid matrix reinforced with 10%wt. magnesium microparticles were processed and their in vitro degradation investigated during 28 days. A joint analysis of the amount of H2 released, the changes in pH in buffered (PBS) and non-buffered media (distilled water), the variations in mass, microstructure and the mechanical performance of the specimens was developed. The main aim was to elucidate the relevance of Mg particles shape on tailoring the degradation kinetics of these novel composites. The results show that the shape of the Mg reinforcing particles plays a crucial role in the degradation rate of PLA/Mg composites, with spherical particles promoting a lower degradation rate than irregular particles. This fact is only partially due to the smaller surface area to volume ratio of the spherical particles. Irregular particles promote a faster formation of cracks and, therefore, an increasingly faster degradation of the polymeric matrix. In every case, the amount of H2 released by the composites was well below that released by monolithic Mg. The pH of PBS during degradation remained always within 7.2 and 7.4. PLA/Mg reinforced with spherical particles retains more than 90% of its mechanical properties after 7 days of immersion and more than 60% after 28 days. STATEMENT OF SIGNIFICANCE: The increasing demand for temporary orthopaedic implants is the driving force to seek new strategies to decrease costs and simultaneously improve patients comfort as well as simplify surgical procedures. Resorbable medical devices must be developed in order to have an appropriate degradation rate in agreement with the healing rate of bone. We are presenting for the first time results of the degradation kinetics of a new material based on polylactic acid reinforced with 10%wt. Mg microparticles. This work analyzes the relevance of Mg particle shape (irregular and spherical) on tailoring the degradation behaviour of these composites. Conclusions withdrawn from this study help to customize bioabsorbable materials in order to meet the requirements for a specific application and patient. PMID- 26747757 TI - Growth inhibition and chemo-radiosensitization of head and neck squamous cell carcinoma (HNSCC) by survivin-siRNA lentivirus. AB - BACKGROUND: Survivin expression is often associated with aggressive tumor behavior and therapy resistance. In this study, we investigated the effect of survivin knockdown by survivin-siRNA lentiviral vector (Svv-Lent) on the response of HNSCC to chemo-radiotherapy, tumor growth and metastasis. METHODS: Four human HNSCC (OSC19, Cal27, Cal33 and FaDu) and one normal HOK cell lines were included in the study, and survivin knockdown was achieved with Svv-Lent treatment. Cell proliferation and apoptosis were measured by MTT and TUNEL assay, respectively. Transwell assays were performed to measure in vitro cell migration and matrigel invasion. Xenograft tumors were developed in nude mice by injecting Cal27 cells subcutaneously and following tail-vein injection of lung and liver metastasis. RESULTS: Knockdown of survivin significantly suppressed HNSCC cell proliferation and induced apoptosis in vitro. Survivin inhibition could also significantly reduce in vitro cell migration and matrigel invasion that might be due to inactivation of matrix metalloproteinases. In vivo studies showed significant repression of Cal27 xenograft tumor growth and tissue metastasis leading to improvement in mice survival in the Svv-Lent treated group compared to controls. Our data indicated that survivin expression in HNSCC cells contributed to chemo radioresistance, and its down-regulation increased anti-cancer effects of paclitaxel, cisplatin and radiation. CONCLUSIONS: Our findings suggest that sustained survivin expression facilitates HNSCC tumor growth and confers resistance to chemo-radiotherapy. Svv-Lent therapy may be able to enhance the cytotoxic effect of commonly used anticancer drugs such as cisplatin and paclitaxel, and radiotherapy that could provide a promising strategy for the effective control of resistant head and neck cancer. PMID- 26747760 TI - Association of ATG5 Gene Polymorphisms With Behcet's Disease and ATG10 Gene Polymorphisms With VKH Syndrome in a Chinese Han Population. AB - PURPOSE: This study was conducted to explore the association of autophagy-related genes (ATGs) single nucleotide polymorphisms (SNPs) with Behcet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome in a Chinese Han population. METHODS: A two-stage association study was carried out in 940 BD, 1061 VKH, and 2007 healthy controls. Genotyping for genetic variants of 10 autophagy family genes (ATG5, ATG7, ATG10, ATG16L1, IRGM, LKKR2, ATG2A, DAP, ULK1, and TSC1) was performed using PCR-restriction fragment length polymorphism (PCR-RFLP) or TaqMan SNP assays. Gene expression was quantified by real-time PCR. RESULTS: In the cohort of BD patients, we observed that the TT genotype of rs573775/ATG5 decreased susceptibility to BD (Pc = 8.35 * 10-6, OR = 0.490). In the case of VKH patients, the AC genotype of rs4703863/ATG10 increased susceptibility to VKH syndrome (Pc = 9.94 * 10-5, OR = 1.444), whereas the A allele and AA genotype of rs4703863 (Pc = 7.06 * 10-5, OR = 0.745; Pc = 6.34 * 10-6, OR = 0.669, respectively) acted as protective factors for VKH. Functional experiments showed an increased ATG5 expression by LPS stimulated PBMCs in TT cases of rs573775 compared with controls. The level of ATG5 mRNA in active BD patients not receiving immunosuppression was significantly higher than that in healthy controls. CONCLUSIONS: This study demonstrated an association of ATG5 rs573775 with BD and ATG10 rs4703863 with VKH syndrome in a Chinese Han population. Furthermore, a variant of the ATG5 gene was shown to be correlated with ATG5 expression. PMID- 26747759 TI - High content analysis platform for optimization of lipid mediated CRISPR-Cas9 delivery strategies in human cells. AB - Non-viral gene-editing of human cells using the CRISPR-Cas9 system requires optimized delivery of multiple components. Both the Cas9 endonuclease and a single guide RNA, that defines the genomic target, need to be present and co localized within the nucleus for efficient gene-editing to occur. This work describes a new high-throughput screening platform for the optimization of CRISPR Cas9 delivery strategies. By exploiting high content image analysis and microcontact printed plates, multi-parametric gene-editing outcome data from hundreds to thousands of isolated cell populations can be screened simultaneously. Employing this platform, we systematically screened four commercially available cationic lipid transfection materials with a range of RNAs encoding the CRISPR-Cas9 system. Analysis of Cas9 expression and editing of a fluorescent mCherry reporter transgene within human embryonic kidney cells was monitored over several days after transfection. Design of experiments analysis enabled rigorous evaluation of delivery materials and RNA concentration conditions. The results of this analysis indicated that the concentration and identity of transfection material have significantly greater effect on gene editing than ratio or total amount of RNA. Cell subpopulation analysis on microcontact printed plates, further revealed that low cell number and high Cas9 expression, 24h after CRISPR-Cas9 delivery, were strong predictors of gene editing outcomes. These results suggest design principles for the development of materials and transfection strategies with lipid-based materials. This platform could be applied to rapidly optimize materials for gene-editing in a variety of cell/tissue types in order to advance genomic medicine, regenerative biology and drug discovery. STATEMENT OF SIGNIFICANCE: CRISPR-Cas9 is a new gene-editing technology for "genome surgery" that is anticipated to treat genetic diseases. This technology uses multiple components of the Cas9 system to cut out disease causing mutations in the human genome and precisely suture in therapeutic sequences. Biomaterials based delivery strategies could help transition these technologies to the clinic. The design space for materials based delivery strategies is vast and optimization is essential to ensuring the safety and efficacy of these treatments. Therefore, new methods are required to rapidly and systematically screen gene-editing efficacy in human cells. This work utilizes an innovative platform to generate and screen many formulations of synthetic biomaterials and components of the CRISPR-Cas9 system in parallel. On this platform, we watch genome surgery in action using high content image analysis. These capabilities enabled us to identify formulation parameters for Cas9 material complexes that can optimize gene-editing in a specific human cell type. PMID- 26747761 TI - Predictive Value of Outer Retina En Face OCT Imaging for Geographic Atrophy Progression. AB - PURPOSE: We determined if the ellipsoid zone (EZ) disruption pattern could be predictive of the geographic atrophy (GA) pattern at 1 year in dry age-related macular degeneration (AMD). METHODS: A retrospective study was done of dry eyes in patients with AMD and GA from July to November 2013. Eyes with previous choroidal neovascularization were excluded. Based on spectral domain optical coherence tomography (SD-OCT), the GA was assessed at each timepoint, using a sub RPE slab derived from the Cirrus Advanced RPE Analysis software encompassing the RPE (sub-RPE slab). Disruption of the EZ also was assessed at baseline, using en face extraction of a 20-MUm-thick slab, 20 MUm above the RPE (EZ slab) encompassing the EZ band using two different algorithms (RPE and RPE-fit). The EZ disruption area surrounding GA at baseline was quantified using ImageJ software. Primary endpoint was to identify en face pattern similarities between the baseline EZ disruption and the 1-year GA. Secondary endpoint was to correlate the baseline EZ disruption area surrounding GA with the GA enlargement over 1 year. Statistical analysis was performed using a correlation test (Pearson) and a t test. RESULTS: We included 37 eyes of 31 patients with dry AMD. En face EZ disruption pattern correlated in two-thirds of cases with the 1-year GA pattern using both algorithms. The EZ disruption area surrounding GA at baseline and GA enlargement over 1 year were poorly correlated when RPE-fit algorithm (R = 0.17) was used. The correlation was still poor using an RPE algorithm (R = 0.38), but increased after selection of eyes without reticular pseudodrusen (R = 0.79). CONCLUSIONS: The EZ disruption pattern could be an indicator for GA pattern progression, but is not a good quantitative tool to predict the size of GA in the overall population over a 1-year period except for patients without reticular pseudodrusen. The results in this specific population must be confirmed by further studies. PMID- 26747762 TI - Effect of Stratification on Surface Properties of Corneal Epithelial Cells. AB - PURPOSE: The purpose of this study was to determine the influence of mucin expression in an immortalized human corneal epithelial cell line (hTCEpi) on the surface properties of cells, such as wettability, contact angle, and surface heterogeneity. METHODS: hTCEpi cells were cultured to confluence in serum-free medium. The medium was then replaced by stratification medium to induce mucin biosynthesis. The mucin expression profile was analyzed using quantitative PCR and Western blotting. Contact angles were measured using a two-immiscible liquid method, and contact angle hysteresis was evaluated by tilting the apparatus and recording advancing and receding contact angles. The spatial distribution of mucins was evaluated with fluorescently labeled lectin. RESULTS: hTCEpi cells expressed the three main ocular mucins (MUC1, MUC4, and MUC16) with a maximum between days 1 and 3 of the stratification process. Upon stratification, cells caused a very significant increase in contact angle hysteresis, suggesting the development of spatially discrete and heterogeneously distributed surface features, defined by topography and/or chemical functionality. Although atomic force microscopy measurements showed no formation of appreciable topographic features on the surface of the cells, we observed a significant increase in surface chemical heterogeneity. CONCLUSIONS: The surface chemical heterogeneity of the corneal epithelium may influence the dynamic behavior of tear film by "pinning" the contact line between the cellular surface and aqueous tear film. Engineering the surface properties of corneal epithelium could potentially lead to novel treatments in dry eye disease. PMID- 26747764 TI - Treatment of Inherited Eye Defects by Systemic Hematopoietic Stem Cell Transplantation. PMID- 26747763 TI - Proteomic Analysis of Lipid Raft-Like Detergent-Resistant Membranes of Lens Fiber Cells. AB - PURPOSE: Plasma membranes of lens fiber cells have high levels of long-chain saturated fatty acids, cholesterol, and sphingolipids-key components of lipid rafts. Thus, lipid rafts are expected to constitute a significant portion of fiber cell membranes and play important roles in lens biology. The purpose of this study was to characterize the lens lipid raft proteome. METHODS: Quantitative proteomics, both label-free and iTRAQ methods, were used to characterize lens fiber cell lipid raft proteins. Detergent-resistant, lipid raft membrane (DRM) fractions were isolated by sucrose gradient centrifugation. To confirm protein localization to lipid rafts, protein sensitivity to cholesterol removal by methyl-beta-cyclodextrin was quantified by iTRAQ analysis. RESULTS: A total of 506 proteins were identified in raft-like detergent-resistant membranes. Proteins identified support important functions of raft domains in fiber cells, including trafficking, signal transduction, and cytoskeletal organization. In cholesterol-sensitivity studies, 200 proteins were quantified and 71 proteins were strongly affected by cholesterol removal. Lipid raft markers flotillin-1 and flotillin-2 and a significant fraction of AQP0, MP20, and AQP5 were found in the DRM fraction and were highly sensitive to cholesterol removal. Connexins 46 and 50 were more abundant in nonraft fractions, but a small fraction of each was found in the DRM fraction and was strongly affected by cholesterol removal. Quantification of modified AQP0 confirmed that fatty acylation targeted this protein to membrane raft domains. CONCLUSIONS: These data represent the first comprehensive profile of the lipid raft proteome of lens fiber cells and provide information on membrane protein organization in these cells. PMID- 26747765 TI - Tailoring Myopic CNV Treatment Based on Preexisting Ophthalmic Condition. PMID- 26747766 TI - Choroidal Response to Anti-VEGF Therapy in Subgroups Classified by Preexisting Ophthalmic or Systemic Condition. PMID- 26747767 TI - Exome Sequencing on 298 Probands With Early-Onset High Myopia: Approximately One Fourth Show Potential Pathogenic Mutations in RetNet Genes. AB - PURPOSE: To investigate mutations in 234 genes associated with retinal dystrophies in a cohort of 298 probands with early-onset high myopia using whole exome sequencing. METHODS: Genomic DNA from 298 probands with early-onset high myopia was analyzed by whole exome sequencing. Variants from 234 genes were selected and analyzed by multistep bioinformatics analyses. RESULTS: Systematic analysis of variants in the 234 genes identified potential pathogenic mutations in 34 of 234 genes in 71 of 298 (23.8%) probands. Of the 71 probands, 44 (62.0%) had mutations in 11 genes responsible for ocular diseases accompanied by high myopia, including COL2A1, COL11A1, PRPH2, FBN1, GNAT1, OPA1, PAX2, GUCY2D, TSPAN12, CACNA1F, and RPGR. Initial clinical records of the 71 patients with mutations did not show recognizable signs of original diseases other than high myopia. CONCLUSIONS: Mutations in genes known to be responsible for retinal diseases were found in approximately one-fourth of the probands with early-onset high myopia. The high mutation frequency of RetNet genes in these patients can provide clues for genetic screening and further specific clinical examinations of high myopia to promote long-term follow-up assessment and prompt treatment of some diseases. PMID- 26747768 TI - The Dorsal Raphe Nucleus Receives Afferents From Alpha-Like Retinal Ganglion Cells and Intrinsically Photosensitive Retinal Ganglion Cells in the Rat. AB - PURPOSE: A retinal projection into the dorsal raphe nucleus (DRN), namely, the retino-raphe projection, exists in many species. The rat is one of several species in which a retino-raphe projection has been described; however, the retinal ganglion cell (RGC) types that contribute to this pathway are unknown. METHODS: Retrograde tracing via cholera toxin subunit B (CTB) was used to reveal DRN-projecting RGCs in rats, combined with intracellular injection in vitro, melanopsin immunostaining in whole-mounted retinas, and serotonin immunostaining to define the DRN. We modified methods of CTB injection into DRN used previously in order to avoid possible contamination with other retinorecipient regions, particularly the superior colliculus (SC). RESULTS: The majority of DRN projecting RGCs showed alpha-like morphology, and some CTB-positive RGCs were colabeled with melanopsin. Approximately 80% of the total population of CTB labeled DRN-projecting RGCs was alpha-like cells including ON alpha cells and OFF alpha cells; these alpha-like cells were melanopsin immunonegative. Approximately 10% of the remaining DRN-projecting RGCs were melanopsin immunopositive, in which the M1 subtype of intrinsically photosensitive retinal ganglion cell (ipRGC) provided the dominant projection of ipRGCs into DRN, with only few non-M1 ipRGCs involved. The DRN-projecting ipRGCs could be retrogradely labeled following tracer injection into all rostrocaudal aspects of the DRN. CONCLUSIONS: Both conventional RGCs with alpha-like morphology and melanopsin-expressing ipRGCs project into the rat DRN. Approximately 10% of DRN-projecting RGCs were colabeled with melanopsin, and the majority of these were the M1 subtype of ipRGCs. An ipRGC component of the retino-raphe projection may contribute to a sustained light-mediated modulation of DRN serotonin release. PMID- 26747769 TI - Effects of Oxidative Stress on the Conjunctiva in Cu, Zn-Superoxide Dismutase-1 (Sod1)-Knockout Mice. AB - PURPOSE: A healthy conjunctiva secreting mucins is essential for maintaining the integrity of the ocular surface epithelium. We used Cu, Zn-superoxide dismutase 1 deficient mice (Sod1-/- mice) and investigated the effect of oxidative stress on the tear function, conjunctival phenotype, and ocular surface mucin expression. METHODS: Fifty-week-old C57/B6 wild-type (WT) and Sod1-/- mice were used for evaluations of the tear film breakup time and periodic acid Schiff staining of the conjunctival specimens to detect goblet cell densities in the conjunctiva. Immunohistochemistry stainings with anti-Muc5AC, anti-Muc1, anti-4-hydroxy-2 nonenal, and anti-8-hydroxy-2'-deoxyguanosine antibodies were also performed. The mRNA expression levels of Muc1, Muc5AC, Spdef, involcurin, and transglutaminase 1 were quantified with real-time RT-PCR. RESULTS: The mean goblet cell density in the aged Sod1-/- mice was significantly lower than the aged WT mice. The mean number of Muc5ac-positive cells was significantly lower in the aged Sod1-/- mice compared with the aged WT mice. The conjunctival epithelium in the aged Sod1-/- mice displayed marked staining with lipid and DNA oxidative stress markers. The mRNA expression of transglutaminase 1 and involcurin in the aged Sod1-/- mice was significantly higher than the aged WT mice. The Spdef mRNA expression in the aged Sod1-/- mice was also significantly lower than the aged WT mice. CONCLUSIONS: Elevated oxidative stress status appears to affect the conjunctival differentiation and alter the conjunctival epithelial phenotype with aging in the Sod1-/- mice. PMID- 26747771 TI - Modulating the Transport Characteristics of Bruch's Membrane With Steroidal Glycosides and its Relevance to Age-Related Macular Degeneration (AMD). AB - PURPOSE: Beneficial expectations of supplement therapies to increase the transport of nutrients, vitamins, and antioxidants across Bruch's membrane in AMD, by mass action alone, remain inconclusive. Therefore, the potential for targeting the transport pathways themselves to improve bidirectional exchange using amphipathic steroidal glycosides (ginsenosides) has been investigated. METHODS: Bruch's choroid preparations were mounted in modified Ussing chambers and basal levels of hydraulic conductivity (23 donors, age range, 12-89 years) and diffusional transport of FITC-albumin (21 donors, age range, 12-92 years) quantified. Then, following a 24-hour incubation with ginsenoside preparations, the transport parameters were re-evaluated and the resulting data analyzed with respect to aging and modulation by ginsenosides. RESULTS: Basal hydraulic conductivity of Bruch's showed an age-related exponential decline with a half life of 19 years. Incubation with ginsenosides improved hydraulic conductivity with levels equivalent to donors 19 years younger. Across the age range examined, hydraulic conductivities were increased to 2.05-fold +/- 0.38 (P < 0.001) of basal values. Diffusional transport of albumin across Bruch's also showed an age related exponential decline with a half-life of 18 years. The decay curves were elevated on incubation with ginsenosides and diffusional rates were equivalent to donors 15 years younger. Diffusional rates were elevated 2.01-fold +/- 0.49 over basal values (P < 0.001). CONCLUSIONS: Transport characteristics of human Bruch's can be improved by ginsenosides, facilitating the bidirectional exchange of nutrients and waste products across the membrane. With improved transport pathways, the need for supplement therapies becomes redundant. Slowed aging of Bruch's is expected to delay the onset and/or progression of AMD. PMID- 26747770 TI - Lacrimal Gland Inflammation Deregulates Extracellular Matrix Remodeling and Alters Molecular Signature of Epithelial Stem/Progenitor Cells. AB - PURPOSE: The adult lacrimal gland (LG) is highly regenerative and is able to repair itself even after substantial damage; however, this ability to regenerate is lost with the development of dry eye conditions in chronically inflamed LGs.This study compares changes in the cell adhesion and cell matrix molecules and stem cell transcription factors in the LGs of healthy mice and of two mouse models of Sjogren's syndrome: nonobese diabetic (NOD) and MRL-lpr/lpr (MRL/lpr) mice during the early stage of inflammation. METHODS: The LGs from 12- to 13-week old female MRL/lpr and male NOD mice along with their respective control strains were harvested and divided into three pieces and processed for quantitative (q) RT-PCR and qRT-PCR Arrays, histology, immunohistochemistry, and Western blotting. RESULTS: The extracellular matrix (ECM) and adhesion molecules RT2-PCR array combined with protein expression data revealed changes in the expression of integrins, matrix metalloproteinases, and other molecules, which are associated largely with invasion, attachment, and expansion of the lymphocytic cells, whereas changes in the stem cell transcription factors revealed substantial decrease in expression of transcription factors associated with epithelial stem/progenitor cell lineage. CONCLUSIONS: We concluded that the expression of several important ECM components is significantly deregulated in the LG of two murine models of Sjogren's syndrome, suggesting an alteration of the epithelial stem/progenitor cell niche. This may result in profound effects on localization, activation, proliferation, and differentiation of the LG stem/progenitor cells and, therefore, LG regeneration. PMID- 26747772 TI - MicroRNA-483-3p Inhibits Extracellular Matrix Production by Targeting Smad4 in Human Trabecular Meshwork Cells. AB - PURPOSE: This study investigated the effects of microRNA-483-3p (miR-483-3p) on extracellular matrix (ECM) production, and clarified the regulatory mechanism of microRNA-483-3p in human trabecular meshwork cells (HTMCs) under oxidative stress. METHODS: The expression levels of ECM (fibronectin, laminin, collagen I) in HTMCs under oxidative stress were measured by Western blot. Changes of miR-483 3p expression in HTMCs were evaluated by quantitative polymerase chain reaction (qPCR). After using lentivirus stably expressing pri-miR-483, the effects of miR 483-3p on the ECM were assessed by qPCR and Western blot. Smad4, the potential target of miR-483-3p according to mRNA target-predicting algorithms, was confirmed by luciferase assay and Western blot. Furthermore, the effects of Smad4 knockdown on ECM expression were investigated by qPCR and Western blot. RESULTS: The mRNA and protein levels of ECM (fibronectin, laminin, collagen I) were upregulated in HTMCs induced by oxidative stress. The expression level of miR-483 3p decreased in HTMCs under oxidative stress, and the ectopic expression of miR 483-3p decreased the levels of ECM. In addition, miR-483-3p targeted Smad4 through two binding sites, resulting in a decrease of Smad4 expression. Furthermore, knockdown of Smad4 reduced the levels of ECM in HTMCs. CONCLUSIONS: MicroRNA-483-3p has an inhibitory effect on ECM production in HTMCs through downregulating Smad4, which indicates that miR-483-3p may serve as a potential therapeutic target in glaucoma. PMID- 26747774 TI - Photoreceptor Mitochondrial Reserve Capacity: Is It the Etiology for Differential Compartmental Vulnerability? PMID- 26747773 TI - Quantification of Oxygen Consumption in Retina Ex Vivo Demonstrates Limited Reserve Capacity of Photoreceptor Mitochondria. AB - PURPOSE: Cell death in neurodegeneration occurs at the convergence of diverse metabolic pathways. In the retina, a common underlying mechanism involves mitochondrial dysfunction since photoreceptor homeostasis and survival are highly susceptible to altered aerobic energy metabolism. We sought to develop an assay to directly measure oxygen consumption in intact retina with the goal of identifying alterations in respiration during photoreceptor dysfunction and degeneration. METHODS: Circular punches of freshly isolated mouse retina, adjacent to the optic nerve head, were used in the microplate-based Seahorse Extracellular Flux Analyzer to measure oxygen consumption. Tissue integrity was evaluated by propidium iodide staining and live imaging. Different substrates were tested for mitochondrial respiration. Basal and maximal respiration were expressed as oxygen consumption rate (OCR) and respectively measured in Ames' medium before and after the addition of mitochondrial uncoupler, BAM15. RESULTS: We show that glucose is an essential substrate for retinal mitochondria. At baseline, mitochondria respiration in the intact wild-type retina was close to maximal, with limited reserve capacity. Similar OCR and limited mitochondrial reserve capacity was also observed in cone-only Nrl-/- retina. However, the retina of Pde6brd1/rd1, Cep290rd16/rd16 and Rpgrip1-/- mice, all with dysfunctional or no photoreceptors, had reduced OCR and higher mitochondrial reserve capacity. CONCLUSIONS: We have optimized a method to directly measure oxygen consumption in acutely isolated, ex vivo mouse retina and demonstrate that photoreceptors have low mitochondrial reserve capacity. Our data provide a plausible explanation for the high vulnerability of photoreceptors to altered energy homeostasis caused by mutations or metabolic challenges. PMID- 26747775 TI - Primed Mycobacterial Uveitis (PMU): Histologic and Cytokine Characterization of a Model of Uveitis in Rats. AB - PURPOSE: The purpose of this study was to compare the histologic features and cytokine profiles of experimental autoimmune uveitis (EAU) and a primed mycobacterial uveitis (PMU) model in rats. METHODS: In Lewis rats, EAU was induced by immunization with interphotoreceptor binding protein peptide, and PMU was induced by immunization with a killed mycobacterial extract followed by intravitreal injection of the same extract. Clinical course, histology, and the cytokine profiles of the aqueous and vitreous were compared using multiplex bead fluorescence immunoassays. RESULTS: Primed mycobacterial uveitis generates inflammation 2 days after intravitreal injection and resolves spontaneously 14 days later. CD68+ lymphocytes are the predominant infiltrating cells and are found in the anterior chamber, surrounding the ciliary body and in the vitreous. In contrast to EAU, no choroidal infiltration or retinal destruction is noted. At the day of peak inflammation, C-X-C motif ligand 10 (CXCL10), IL-1beta, IL-18, and leptin were induced in the aqueous of both models. Interleukin-6 was induced 2-fold in the aqueous of PMU but not EAU. Cytokines elevated in the aqueous of EAU exclusively include regulated on activation, normal T cell expressed and secreted (RANTES), lipopolysaccharide-induced CXC chemokine (LIX), growth-related oncogene/keratinocyte chemokine (GRO/KC), VEGF, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha), and IL-17A. In the vitreous, CXCL10, GRO/KC, RANTES, and MIP-1alpha were elevated in both models. Interleukin-17A and IL-18 were elevated exclusively in EAU. CONCLUSIONS: Primed mycobacterial uveitis generates an acute anterior and intermediate uveitis without retinal involvement. Primed mycobacterial uveitis has a distinct proinflammatory cytokine profile compared with EAU, suggesting PMU is a good complementary model for study of immune-mediated uveitis. CXCL10, a proinflammatory cytokine, was increased in the aqueous and vitreous of both models and may be a viable therapeutic target. PMID- 26747776 TI - Comparative Proteomic Analysis of Two Uveitis Models in Lewis Rats. AB - PURPOSE: Inflammation generates changes in the protein constituents of the aqueous humor. Proteins that change in multiple models of uveitis may be good biomarkers of disease or targets for therapeutic intervention. The present study was conducted to identify differentially-expressed proteins in the inflamed aqueous humor. METHODS: Two models of uveitis were induced in Lewis rats: experimental autoimmune uveitis (EAU) and primed mycobacterial uveitis (PMU). Differential gel electrophoresis was used to compare naive and inflamed aqueous humor. Differentially-expressed proteins were separated by using 2-D gel electrophoresis and excised for identification with matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF). Expression of select proteins was verified by Western blot analysis in both the aqueous and vitreous. RESULTS: The inflamed aqueous from both models demonstrated an increase in total protein concentration when compared to naive aqueous. Calprotectin, a heterodimer of S100A8 and S100A9, was increased in the aqueous in both PMU and EAU. In the vitreous, S100A8 and S100A9 were preferentially elevated in PMU. Apolipoprotein E was elevated in the aqueous of both uveitis models but was preferentially elevated in EAU. Beta-B2-crystallin levels decreased in the aqueous and vitreous of EAU but not PMU. CONCLUSIONS: The proinflammatory molecules S100A8 and S100A9 were elevated in both models of uveitis but may play a more significant role in PMU than EAU. The neuroprotective protein beta-B2-crystallin was found to decline in EAU. Therapies to modulate these proteins in vivo may be good targets in the treatment of ocular inflammation. PMID- 26747777 TI - Targeted Cancer Screening After Solid-Organ Transplantation. PMID- 26747778 TI - Comparison of a sentinel lymph node and a selective lymphadenectomy algorithm in patients with endometrioid endometrial carcinoma and limited myometrial invasion. AB - OBJECTIVES: To assess clinicopathologic outcomes between two nodal assessment approaches in patients with endometrioid endometrial carcinoma and limited myoinvasion. METHODS: Patients with endometrial cancer at two institutions were reviewed. At one institution, a complete pelvic and para-aortic lymphadenectomy to the renal veins was performed in select cases deemed at risk for nodal metastasis due to grade 3 cancer and/or primary tumor diameter>2cm (LND cohort). This is a historic approach at this institution. At the other institution, a sentinel lymph node mapping algorithm was used per institutional protocol (SLN cohort). Low risk was defined as endometrioid adenocarcinoma with myometrial invasion <50%. Macrometastasis, micrometastasis, and isolated tumor cells were all considered node-positive. RESULTS: Of 1135 cases identified, 642 (57%) were managed with an SLN approach and 493 (43%) with an LND approach. Pelvic nodes (PLNs) were removed in 93% and 58% of patients, respectively (P<0.001); para aortic nodes (PANs) were removed in 14.5% and 50% of patients, respectively (P<0.001). Median number of PLNs removed was 6 and 34, respectively; median number of PANs removed was 5 and 16, respectively (both P<0.001). Metastasis to PLNs was detected in 5.1% and 2.6% of patients, respectively (P=0.03), and to PANs in 0.8% and 1.0%, respectively (P=0.75). The 3-year disease-free survival rates were 94.9% (95% CI, 92.4-97.5) and 96.8% (95% CI, 95.2-98.5), respectively. CONCLUSIONS: Our findings support the use of either strategy for endometrial cancer staging, with no apparent detriment in adhering to the SLN algorithm. The clinical significance of disease detected on ultrastaging and the role of adjuvant therapy is yet to be determined. PMID- 26747779 TI - Lipopolysaccharide induces ICAM-1 expression via a c-Src/NADPH oxidase/ROS dependent NF-kappaB pathway in human pulmonary alveolar epithelial cells. AB - Upregulation of intercellular adhesion molecule-1 (ICAM-1) is frequently implicated in lung inflammation. Lipopolysaccharide (LPS) has been shown to play a key role in inflammation via adhesion molecule induction and then causes lung injury. However, the mechanisms underlying LPS-induced ICAM-1 expression in human pulmonary alveolar epithelial cells (HPAEpiCs) remain unclear. We showed that LPS induced ICAM-1 expression in HPAEpiCs, revealed by Western blotting, RT-PCR, real time PCR, and promoter assay. Pretreatment with the inhibitor of c-Src (protein phosphatase-1, PP1), reactive oxygen species (ROS) (Edaravone), NADPH oxidase (apocynin and diphenyleneiodonium chloride), EGFR (AG1478), PDGFR (AG1296), phosphatidylinositol-3-kinase (PI3K) (LY294002), MEK1/2 (U0126), or NF-kappaB (Bay11-7082) and transfection with siRNAs of c-Src, EGFR, PDGFR, Akt, p47(phox), Nox2, Nox4, p42, and p65 markedly reduced LPS-induced ICAM-1 expression and monocyte adherence to HPAEpiCs challenged with LPS. In addition, we established that LPS stimulated phosphorylation of c-Src, EGFR, PDGFR, Akt, or p65, which was inhibited by pretreatment with their respective inhibitors. LPS induced Toll-like receptor 4 (TLR4), MyD88, TNF receptor-associated factor 6 (TRAF6), c-Src, p47(phox), and Rac1 complex formation 2, which was attenuated by transfection with c-Src or TRAF6 siRNA. Furthermore, LPS markedly enhanced NADPH oxidase activation and intracellular ROS generation, which were inhibited by PP1. We established that LPS induced p42/p44 MAPK activation via a c-Src/NADPH oxidase/ROS/EGFR, PDGFR/PI3K/Akt-dependent pathway in these cells. Finally, we observed that LPS significantly enhanced NF-kappaB and IkappaBalpha phosphorylation, NF-kappaB translocation, and NF-kappaB promoter activity, which were inhibited by PP1, Edaravone, apocynin, diphenyleneiodonium chloride, AG1478, AG1296, LY294002, or U0126. These results demonstrated that LPS induces p42/p44 MAPK activation mediated through the TLR4/MyD88/TRAF6/c-Src/NADPH oxidase/ROS/EGFR, PDGFR/PI3K/Akt pathway, which in turn initiates the activation of NF-kappaB and ultimately induces ICAM-1 expression in HPAEpiCs. PMID- 26747780 TI - Genetic ablation of interleukin-18 does not attenuate hypobaric hypoxia-induced right ventricular hypertrophy. AB - Interleukin-18 (IL-18), a proinflammatory cytokine, has been implicated in pathologic left ventricular hypertrophy and is elevated in plasma of heart failure patients. However, IL-18 blockade strategies have been conflicting. The purpose of these experiments was to determine whether genetic ablation of IL-18 would protect mice against hypobaric hypoxia (HH)-induced right ventricular (RV) hypertrophy, a condition in which chamber-specific inflammation is prominent. We hypothesized that IL-18 knockout (KO) mice would be protected while wild-type (WT) mice would demonstrate RV hypertrophy in response to HH exposure. KO and WT mice were exposed to HH for 7 wk, and control mice were exposed to normoxic ambient air. Following echocardiography, the RV was dissected and flash-frozen for biochemical analyses. HH exposure increased IL-18 mRNA (P = 0.08) in RV from WT mice. Genetic ablation of IL-18 mildly attenuated RV hypertrophy as assessed by myocyte size. However, IL-18 KO mice were not protected against HH-induced organ-level remodeling, as evidenced by higher RV weights, elevated RV systolic pressure, and increased RV anterior wall thickness compared with normoxic KO mice. These RV changes were similar to those seen in HH-exposed WT mice. Compensatory upregulation of other proinflammatory cytokines IL-2 and stromal cell-derived factor-1 was seen in the HH-KO animals, suggesting that activation of parallel inflammatory pathways might mitigate the effect of IL-18 KO. These data suggest targeted blockade of IL-18 alone is not a viable therapeutic strategy in this model. PMID- 26747781 TI - The role of hyaluronan in the pathobiology and treatment of respiratory disease. AB - Hyaluronan, a ubiquitous naturally occurring glycosaminoglycan, is a major component of the extracellular matrix, where it participates in biological processes that include water homeostasis, cell-matrix signaling, tissue healing, inflammation, angiogenesis, and cell proliferation and migration. There are emerging data that hyaluronan and its degradation products have an important role in the pathobiology of the respiratory tract. We review the role of hyaluronan in respiratory diseases and present evidence from published literature and from clinical practice supporting hyaluronan as a novel treatment for respiratory diseases. Preliminary data show that aerosolized exogenous hyaluronan has beneficial activity against airway inflammation, protects against bronchial hyperreactivity and remodeling, and disrupts the biofilm associated with chronic infection. This suggests a role in airway diseases with a predominant inflammatory component such as rhinosinusitis, asthma, chronic obstructive pulmonary disease, cystic fibrosis, and primary ciliary dyskinesia. The potential for hyaluronan to complement conventional therapy will become clearer when data are available from controlled trials in larger patient populations. PMID- 26747782 TI - Alcohol abuse and smoking alter inflammatory mediator production by pulmonary and systemic immune cells. AB - Alcohol use disorders (AUDs) and tobacco smoking are associated with an increased predisposition for community-acquired pneumonia and the acute respiratory distress syndrome. Mechanisms are incompletely established but may include alterations in response to pathogens by immune cells, including alveolar macrophages (AMs) and peripheral blood mononuclear cells (PBMCs). We sought to determine the relationship of AUDs and smoking to expression of IFNgamma, IL 1beta, IL-6, and TNFalpha by AMs and PBMCs from human subjects after stimulation with lipopolysaccharide (LPS) or lipoteichoic acid (LTA). AMs and PBMCs from healthy subjects with AUDs and controls, matched on smoking, were cultured with LPS (1 MUg/ml) or LTA (5 MUg/ml) in the presence and absence of the antioxidant precursor N-acetylcysteine (10 mM). Cytokines were measured in cell culture supernatants. Expression of IFNgamma, IL-1beta, IL-6, and TNFalpha in AMs and PBMCs was significantly increased in response to stimulation with LPS and LTA. AUDs were associated with augmented production of proinflammatory cytokines, particularly IFNgamma and IL-1beta, by AMs and PBMCs in response to LPS. Smoking diminished the impact of AUDs on AM cytokine expression. Expression of basal AM and PBMC Toll-like receptors-2 and -4 was not clearly related to differences in cytokine expression; however, addition of N-acetylcysteine with LPS or LTA led to diminished AM and PBMC cytokine secretion, especially among current smokers. Our findings suggest that AM and PBMC immune cell responses to LPS and LTA are influenced by AUDs and smoking through mechanisms that may include alterations in cellular oxidative stress. PMID- 26747784 TI - Targeting host calpain proteases decreases influenza A virus infection. AB - Influenza A viruses (IAV) trigger contagious acute respiratory diseases. A better understanding of the molecular mechanisms of IAV pathogenesis and host immune responses is required for the development of more efficient treatments of severe influenza. Calpains are intracellular proteases that participate in diverse cellular responses, including inflammation. Here, we used in vitro and in vivo approaches to investigate the role of calpain signaling in IAV pathogenesis. Calpain expression and activity were found altered in IAV-infected bronchial epithelial cells. With the use of small-interfering RNA (siRNA) gene silencing, specific synthetic inhibitors of calpains, and mice overexpressing calpastatin, we found that calpain inhibition dampens IAV replication and IAV-triggered secretion of proinflammatory mediators and leukocyte infiltration. Remarkably, calpain inhibition has a protective impact in IAV infection, since it significantly reduced mortality of mice challenged not only by seasonal H3N2- but also by hypervirulent H5N1 IAV strains. Hence, our study suggests that calpains are promising therapeutic targets for treating IAV acute pneumonia. PMID- 26747783 TI - p53- and PAI-1-mediated induction of C-X-C chemokines and CXCR2: importance in pulmonary inflammation due to cigarette smoke exposure. AB - We previously demonstrated that tumor suppressor protein p53 augments plasminogen activator inhibitor-1 (PAI-1) expression in alveolar epithelial cells (AECs) during chronic cigarette smoke (CS) exposure-induced lung injury. Chronic lung inflammation with elevated p53 and PAI-1 expression in AECs and increased susceptibility to and exacerbation of respiratory infections are all associated with chronic obstructive pulmonary disease (COPD). We recently demonstrated that preventing p53 from binding to the endogenous PAI-1 mRNA in AECs by either suppressing p53 expression or blockading p53 interactions with the PAI-1 mRNA mitigates apoptosis and lung injury. Within this context, we now show increased expression of the C-X-C chemokines (CXCL1 and CXCL2) and their receptor CXCR2, and the intercellular cellular adhesion molecule-1 (ICAM-1), in the lung tissues of patients with COPD. We also found a similar increase in lung tissues and AECs from wild-type (WT) mice exposed to passive CS for 20 wk and in primary AECs treated with CS extract in vitro. Interestingly, passive CS exposure of mice lacking either p53 or PAI-1 expression resisted an increase in CXCL1, CXCL2, CXCR2, and ICAM-1. Furthermore, inhibition of p53-mediated induction of PAI-1 expression by treatment of WT mice exposed to passive CS with caveolin-1 scaffolding domain peptide reduced CXCL1, CXCL2, and CXCR2 levels and lung inflammation. Our study reveals that p53-mediated induction of PAI-1 expression due to chronic CS exposure exacerbates lung inflammation through elaboration of CXCL1, CXCL2, and CXCR2. We further provide evidence that targeting this pathway mitigates lung injury associated with chronic CS exposure. PMID- 26747788 TI - Unilateral Axillary Toxic Erythema of Chemotherapy in a Patient With Previous Axillary Lymph Node Dissection: Implications for Pathophysiology and Therapy. PMID- 26747787 TI - Exudative Macular Detachment After Viral Illness With Rash. PMID- 26747785 TI - miR-185 mediates lung epithelial cell death after oxidative stress. AB - Lung epithelial cell death is a prominent feature involved in the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Hyperoxia induced ALI is an established animal model mimicking human ARDS. Small noncoding RNAs such as microRNAs (miRNAs) have potent physiological and pathological functions involving multiple disease processes. Emerging interests focus on the potential of miRNAs to serve as novel therapeutic targets and diagnostic biomarkers. We found that hyperoxia highly induces miR-185 and its precursor in human lung epithelial cells in a time-dependent manner, and this observation is confirmed using mouse primary lung epithelial cells. The hyperoxia-induced miR 185 is mediated by reactive oxygen species. Furthermore, histone deacetylase 4 (HDAC4) locates in the promoter region of miR-185. We found that hyperoxia suppresses HDAC4 specifically in a time-dependent manner and subsequently affects histone deacetylation, resulting in an elevated miR-185 transcription. Using MC1586, an inhibitor of class IIa HDACs, we showed that inhibition of class IIa HDACs upregulates the expression of miR-185, mimicking the effects of hyperoxia. Functionally, miR-185 promotes hyperoxia-induced lung epithelial cell death through inducing DNA damage. We confirmed functional roles of miR-185 using both the loss- and gain-of-function approaches. Moreover, multiple 14-3-3delta pathway proteins are highly attenuated by miR-185 in the presence of hyperoxia. Taken together, hyperoxia-induced miR-185 in lung epithelial cells contributes to oxidative stress-associated epithelial cell death through enhanced DNA damage and modulation of 14-3-3delta pathways. PMID- 26747786 TI - Deletion of P2X7 attenuates hyperoxia-induced acute lung injury via inflammasome suppression. AB - Increasing evidence shows that hyperoxia is a serious complication of oxygen therapy in acutely ill patients that causes excessive production of free radicals leading to hyperoxia-induced acute lung injury (HALI). Our previous studies have shown that P2X7 receptor activation is required for inflammasome activation during HALI. However, the role of P2X7 in HALI is unclear. The main aim of this study was to determine the effect of P2X7 receptor gene deletion on HALI. Wild type (WT) and P2X7 knockout (P2X7 KO) mice were exposed to 100% O2 for 72 h. P2X7 KO mice treated with hyperoxia had enhanced survival in 100% O2 compared with the WT mice. Hyperoxia-induced recruitment of inflammatory cells and elevation of IL 1beta, TNF-alpha, monocyte chemoattractant protein-1, and IL-6 levels were attenuated in P2X7 KO mice. P2X7 deletion decreased lung edema and alveolar protein content, which are associated with enhanced alveolar fluid clearance. In addition, activation of the inflammasome was suppressed in P2X7-deficient alveolar macrophages and was associated with suppression of IL-1beta release. Furthermore, P2X7-deficient alveolar macrophage in type II alveolar epithelial cells (AECs) coculture model abolished protein permeability across mouse type II AEC monolayers. Deletion of P2X7 does not lead to a decrease in epithelial sodium channel expression in cocultures of alveolar macrophages and type II AECs. Taken together, these findings show that deletion of P2X7 is a protective factor and therapeutic target for the amelioration of hyperoxia-induced lung injury. PMID- 26747789 TI - The development of a framework for high-quality, sustainable and accessible rural private therapy under the Australian National Disability Insurance Scheme. AB - PURPOSE: The Australian National Disability Insurance Scheme (NDIS) will provide people with individual funding with which to purchase services such as therapy from private providers. This study developed a framework to support rural private therapists to meet the anticipated increase in demand. METHOD: The study consisted of three stages utilizing focus groups, interviews and an online expert panel. Participants included private therapists delivering services in rural New South Wales (n = 28), disability service users (n = 9) and key representatives from a range of relevant consumer and service organizations (n = 16). We conducted a thematic analysis of focus groups and interview data and developed a draft framework which was subsequently refined based on feedback from stakeholders. RESULTS: The framework highlights the need for a 'rural-proofed' policy context in which service users, therapists and communities engage collaboratively in a therapy pathway. This collaborative engagement is supported by enablers, including networks, resources and processes which are influenced by the drivers of time, cost, opportunity and motivation. CONCLUSIONS: The framework identifies factors that will facilitate delivery of high-quality, sustainable, individualized private therapy services for people with a disability in rural Australia under the NDIS and emphasizes the need to reconceptualize the nature of private therapy service delivery. Implications for Rehabilitation Rural private therapists need upskilling to work with individuals with disability who have individual funding such as that provided by the Australian National Disability Insurance Scheme. Therapists working in rural communities need to consider alternative ways of delivering therapy to individuals with disability beyond the traditional one-on-one therapy models. Rural private therapists need support to work collaboratively with individuals with disability and the local community. Rural private therapists should harness locally available and broader networks, resources and processes to meet the needs and goals of individuals with disability. PMID- 26747790 TI - Cost-effectiveness of Corticosteroid Nasal Spray vs Surgical Therapy in Patients With Severe to Extreme Anatomical Nasal Obstruction. AB - IMPORTANCE: Health insurance companies commonly require a trial of corticosteroid nasal spray prior to authorizing nasal surgery, even in patients with severe to extreme anatomical nasal obstruction, despite lack of data supporting such medical therapy. OBJECTIVES: To provide a model for the comparative analysis of medical vs surgical treatment for nasal obstruction to help maximize health care benefit per dollar spent and to explore the cost-effectiveness of corticosteroid nasal spray in patients with severe to extreme nasal airway obstruction on Nasal Obstruction Symptom Evaluation (NOSE) scores. DESIGN, SETTING, AND PARTICIPANTS: A cost-efficiency frontier economic evaluation was performed. The economic perspective was that of the health care third-party payer. Effectiveness data were obtained from NOSE score questionnaires in 179 patients. An incremental cost effectiveness ratio was determined from the cost and efficacy data. Comparative treatment groups were medical therapy with corticosteroid nasal spray vs surgical therapy for nasal airway obstruction. The study was conducted between January 1, 2011, and December 30, 2013. The time horizon included 1, 2, and 5 years. Data analysis was completed June 1, 2015. MAIN OUTCOMES AND MEASURES: The primary outcome was cost per quality-adjusted life-year (QALY). A modified Markov decision tree model was used. Costs were obtained from the Medicare 2015 physician fee schedule, and the mean was determined (owing to geographic disparity) along with wholesale and generic pharmaceutical pricing. RESULTS: Among 100 men and 79 women evaluated (mean [SD] age, 37.9 [12.9] years), surgical repair of severe nasal airway obstruction cost $6537 and produced a total of 1.15 QALYs at 1 year. Medical treatment involved a trial of corticosteroid nasal sprays, which cost $520 and produced a total of 1.03 QALYs. The surgical approach was markedly more effective but at greater short-term cost. In cases of extreme nasal obstruction, medical treatment cost $520.73 with 1.004 QALYs, demonstrating an incremental cost-effectiveness ratio (ICER) of $354 693 per QALY compared with no treatment. Conversely, surgical treatment cost $6536.64 and produced 1.136 QALYs, with an ICER of $45 633 compared with medical therapy. At 5 years, the ICER decreased from $45 634 to $8110 per QALY for surgical treatment of extreme nasal obstruction. The medical treatment ICER decreased from $354 693 per QALY at 1 year to $273 704 per QALY at 5 years. An ICER was performed and demonstrated a cost threshold of $50 554 per QALY for surgical treatment compared with $67 518 per QALY for medical treatment at 1 year for severe nasal obstruction. If the evaluation is extended to 5 years, surgical treatment cost $8984 per QALY compared with $52 571 per QALY for medical treatment. Owing to the improved effectiveness outcomes, greater cost savings per ICER was demonstrated in patients with extreme nasal obstruction. CONCLUSIONS AND RELEVANCE: Surgical treatment for patients with severe to extreme anatomical nasal obstruction demonstrates increased short-term expense but is cost-effective in the long term. These data suggest that treatment with corticosteroid nasal spray in patients with documented severe to extreme anatomical nasal obstruction is unnecessary and results in a delay in treatment. LEVEL OF EVIDENCE: NA. PMID- 26747791 TI - Three-Dimensional-Printing of Bio-Inspired Composites. AB - Optimized for millions of years, natural materials often outperform synthetic materials due to their hierarchical structures and multifunctional abilities. They usually feature a complex architecture that consists of simple building blocks. Indeed, many natural materials such as bone, nacre, hair, and spider silk, have outstanding material properties, making them applicable to engineering applications that may require both mechanical resilience and environmental compatibility. However, such natural materials are very difficult to harvest in bulk, and may be toxic in the way they occur naturally, and therefore, it is critical to use alternative methods to fabricate materials that have material functions similar to material function as their natural counterparts for large scale applications. Recent progress in additive manufacturing, especially the ability to print multiple materials at upper micrometer resolution, has given researchers an excellent instrument to design and reconstruct natural-inspired materials. The most advanced 3D-printer can now be used to manufacture samples to emulate their geometry and material composition with high fidelity. Its capabilities, in combination with computational modeling, have provided us even more opportunities for designing, optimizing, and testing the function of composite materials, in order to achieve composites of high mechanical resilience and reliability. In this review article, we focus on the advanced material properties of several multifunctional biological materials and discuss how the advanced 3D-printing techniques can be used to mimic their architectures and functions. Lastly, we discuss the limitations of 3D-printing, suggest possible future developments, and discuss applications using bio-inspired materials as a tool in bioengineering and other fields. PMID- 26747794 TI - Communication: Configuration interaction combined with spin-projection for strongly correlated molecular electronic structures. AB - We present single and double particle-hole excitations in the recently revived spin-projected Hartree-Fock. Our motivation is to treat static correlation with spin-projection and recover the residual correlation, mostly dynamic in nature, with simple configuration interaction (CI). To this end, we introduce the Wick theorem for nonorthogonal determinants, which enables an efficient implementation in conjunction with the direct CI scheme. The proposed approach, termed spin extended CI with singles and doubles, achieves a balanced treatment between dynamic and static correlations. To approximately account for the quadruple excitations, we also modify the well-known Davidson correction. We report that our approaches yield surprisingly accurate potential curves for HF, H2O, N2, and a hydrogen lattice, compared to traditional single reference wave function methods at the same computational scaling as regular CI. PMID- 26747795 TI - Sign Learning Kink-based (SiLK) Quantum Monte Carlo for molecular systems. AB - The Sign Learning Kink (SiLK) based Quantum Monte Carlo (QMC) method is used to calculate the ab initio ground state energies for multiple geometries of the H2O, N2, and F2 molecules. The method is based on Feynman's path integral formulation of quantum mechanics and has two stages. The first stage is called the learning stage and reduces the well-known QMC minus sign problem by optimizing the linear combinations of Slater determinants which are used in the second stage, a conventional QMC simulation. The method is tested using different vector spaces and compared to the results of other quantum chemical methods and to exact diagonalization. Our findings demonstrate that the SiLK method is accurate and reduces or eliminates the minus sign problem. PMID- 26747792 TI - Factors Associated With Recurrent Ischemic Stroke in the Medical Group of the SAMMPRIS Trial. AB - IMPORTANCE: The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) Trial showed that aggressive medical therapy was more effective than stenting for preventing stroke in patients with symptomatic intracranial stenosis. However, 15% of patients in the medical group still experienced a primary end point during a median follow-up of 32.7 months. OBJECTIVE: To determine baseline features that were associated with a high rate of a primary end point in the medical arm of the SAMMPRIS Trial. DESIGN, SETTING, AND PARTICIPANTS: A post hoc analysis of patients in the medical arm only of the SAMMPRIS trial. Enrollment occurred between October 2008 and April 2013 and included 227 patients randomized to medical management alone. Baseline demographic features, vascular risk factors, qualifying event, brain imaging, and angiographic features were analyzed. Bivariate and multivariable proportional hazard regression modeling was performed to relate baseline features to the time until a primary end point. The post hoc analysis was conducted from November 2014 to June 2015. INTERVENTIONS: The SAMMPRIS Trial compared stenting with aggressive medical management in patients with a stroke or transient ischemic attack attributed to 70% to 99% stenosis of a major intracranial artery. MAIN OUTCOMES AND MEASURES: The primary outcome was any of the following: stroke or death within 30 days of enrollment, ischemic stroke in the territory of the symptomatic intracranial artery beyond 30 days after enrollment, or any stroke or death within 30 days after stenting a patient in the medical group during follow up. RESULTS: A total of 227 patients were included in the study, 82 of whom were female, and the mean (SD) age was 59.5 (11.8) years. Being female (hazard ratio [HR], 1.9; 95% CI, 0.96-3.7), having diabetes mellitus (HR, 1.8; 95% CI, 0.9 3.5), not taking a statin at enrollment (HR, 2.6; 95% CI, 1.2-5.7), stroke as the qualifying event (HR, 2.5; 95% CI, 1.03-6.0), Rankin grade of 1 or greater (HR, 2.3; 95% CI, 0.9-5.5), old infarct in the territory of the stenotic artery (HR, 2.6; 95% CI, 1.3-5.1), and greater than 80% stenosis (HR, 1.9; 95% CI, 0.9-3.7) were associated (P < .10) with higher risk on bivariate analysis. Factors that were significantly associated with a primary end point on multivariable analyses were old infarct in the territory (HR, 2.6; 95% CI, 1.3-5.3; P = .006), stroke as the qualifying event (HR, 3.0; 95% CI, 1.1-7.7; P = .03), and no statin use at enrollment (HR, 2.4; 95% CI, 1.1-5.2; P = .03). CONCLUSIONS AND RELEVANCE: Old infarct in the territory of the stenosis, new stroke presentation, and absence of statin use at enrollment were independently associated with high rates of the primary end point in the medical group in the SAMMPRIS Trial. These features may be useful for selecting high-risk patients for future clinical trials evaluating alternative therapies for intracranial stenosis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00576693. PMID- 26747796 TI - Quantifying local exciton, charge resonance, and multiexciton character in correlated wave functions of multichromophoric systems. AB - A new method for quantifying the contributions of local excitation, charge resonance, and multiexciton configurations in correlated wave functions of multichromophoric systems is presented. The approach relies on fragment-localized orbitals and employs spin correlators. Its utility is illustrated by calculations on model clusters of hydrogen, ethylene, and tetracene molecules using adiabatic restricted-active-space configuration interaction wave functions. In addition to the wave function analysis, this approach provides a basis for a simple state specific energy correction accounting for insufficient description of electron correlation. The decomposition scheme also allows one to compute energies of the diabatic states of the local excitonic, charge-resonance, and multi-excitonic character. The new method provides insight into electronic structure of multichromophoric systems and delivers valuable reference data for validating excitonic models. PMID- 26747793 TI - Blood pressure variability and its association with echocardiographic parameters in hypertensive diabetic patients. AB - BACKGROUND: Blood pressure (BP) variability is associated with target organ damage in hypertension and diabetes. The 24 h ambulatory blood pressure monitoring (24 h-ABPM) has been proposed as an evaluation for BP variability using several indexes [standard deviation (SD) of mean BP, coefficient of variation (CV), BP variation over time (time-rate index)]. METHODS: We evaluated the association between BP variability measured by 24 h-ABPM indexes and echocardiographic variables in a cross-sectional study in 305 diabetic hypertensive patients. RESULTS: Two groups were defined by the median (0.55 mmHg/min) of time-rate systolic BP (SBP) index and classified as low or high variability. Age was 57.3 +/- 6.2 years, 196 (64.3%) were female. Diabetes duration was 10.0 (5.0-16.2) years, HbA1c was 8.2 +/- 1.9%. Baseline clinical characteristics were similar between low (n = 148) and high (n = 157) variability groups. Office SBP and systolic 24 h-ABPM were higher in the high variability group (139.9 mmHg vs 146.0 mmHg, P = 0.006; 128.3 mmHg vs 132.9 mmHg, P = 0.019, respectively). Time-rate index, SD and CV of SBP, were higher in high variability group (P < 0.001; P < 0.001 and P = 0.003, respectively). Time-rate index was not independently associated with the echocardiography's variables in multiple linear model when adjusting for age, 24 h-ABPM, diabetes duration and HbA1c. The multiple linear regression model revealed that the significant and independent determinants for septum thickness, relative wall thickness and posterior wall thickness (parameters of left ventricular hypertrophy) were: age (p = 0.025; p = 0.010; p = 0.032, respectively) and 24 h-SBP (p < 0.001 in the three parameters). CONCLUSION: BP variability estimated by 24 h-ABPM is not independently associated with echocardiographic parameters in diabetic-hypertensive patients. PMID- 26747797 TI - A generalized Poisson and Poisson-Boltzmann solver for electrostatic environments. AB - The computational study of chemical reactions in complex, wet environments is critical for applications in many fields. It is often essential to study chemical reactions in the presence of applied electrochemical potentials, taking into account the non-trivial electrostatic screening coming from the solvent and the electrolytes. As a consequence, the electrostatic potential has to be found by solving the generalized Poisson and the Poisson-Boltzmann equations for neutral and ionic solutions, respectively. In the present work, solvers for both problems have been developed. A preconditioned conjugate gradient method has been implemented for the solution of the generalized Poisson equation and the linear regime of the Poisson-Boltzmann, allowing to solve iteratively the minimization problem with some ten iterations of the ordinary Poisson equation solver. In addition, a self-consistent procedure enables us to solve the non-linear Poisson Boltzmann problem. Both solvers exhibit very high accuracy and parallel efficiency and allow for the treatment of periodic, free, and slab boundary conditions. The solver has been integrated into the BigDFT and Quantum-ESPRESSO electronic-structure packages and will be released as an independent program, suitable for integration in other codes. PMID- 26747798 TI - Oscillatory reaction cross sections caused by normal mode sampling in quasiclassical trajectory calculations. AB - The quasiclassical trajectory (QCT) method is an efficient and important tool for studying the dynamics of bimolecular reactions. In this method, the motion of the atoms is simulated classically, and the only quantum effect considered is that the initial vibrational states of reactant molecules are semiclassically quantized. A sensible expectation is that the initial ensemble of classical molecular states generated this way should be stationary, similarly to the quantum state it is supposed to represent. The most widely used method for sampling the vibrational phase space of polyatomic molecules is based on the normal mode approximation. In the present work, it is demonstrated that normal mode sampling provides a nonstationary ensemble even for a simple molecule like methane, because real potential energy surfaces are anharmonic in the reactant domain. The consequences were investigated for reaction CH4 + H -> CH3 + H2 and its various isotopologs and were found to be dramatic. Reaction probabilities and cross sections obtained from QCT calculations oscillate periodically as a function of the initial distance of the colliding partners and the excitation functions are erratic. The reason is that in the nonstationary ensemble of initial states, the mean bond length of the breaking C-H bond oscillates in time with the frequency of the symmetric stretch mode. We propose a simple method, one period averaging, in which reactivity parameters are calculated by averaging over an entire period of the mean C-H bond length oscillation, which removes the observed artifacts and provides the physically most reasonable reaction probabilities and cross sections when the initial conditions for QCT calculations are generated by normal mode sampling. PMID- 26747799 TI - Application of a convergent, composite coupled cluster approach to bound state, adiabatic electron affinities in atoms and small molecules. AB - Benchmark quality adiabatic electron affinities for a collection of atoms and small molecules were obtained with the Feller-Peterson-Dixon composite coupled cluster theory method. Prior applications of this method demonstrated its ability to accurately predict atomization energies/heats of formation for more than 170 molecules. In the current work, the 1-particle expansion involved very large correlation consistent basis sets, ranging up to aug-cc-pV9Z (aug-cc-pV10Z for H and H2), with the goal of minimizing the residual basis set truncation error that must otherwise be approximated with extrapolation formulas. The n-particle expansion begins with coupled cluster calculations through iterative single and double excitations plus a quasiperturbative treatment of "connected" triple excitations (CCSD(T)) pushed to the complete basis set limit followed by CCSDT, CCSDTQ, or CCSDTQ5 corrections. Due to the small size of the systems examined here, it was possible in many cases to extend the n-particle expansion to the full configuration interaction wave function limit. Additional, smaller corrections associated with core/valence correlation, scalar relativity, anharmonic zero point vibrational energies, and non-adiabatic effects were also included. The overall root mean square (RMS) deviation was 0.005 eV (0.12 kcal/mol). This level of agreement was comparable to what was found with molecular heats of formation. A 95% confidence level corresponds to roughly twice the RMS value or 0.01 eV. While the atomic electron affinities are known experimentally to high accuracy, the molecular values are less certain. This contributes to the difficulty of gauging the accuracy of the theoretical results. A limited number of electron affinities were determined with the explicitly correlated CCSD(T)-F12b method. After extending the VnZ-F12 orbital basis sets with additional diffuse functions, the F12b method was found to accurately reproduce the best F/F(-) value obtained with standard methods, but it underestimated the CH3/CH3 (-) value by 0.01 eV. PMID- 26747800 TI - The origins of intra- and inter-molecular vibrational couplings: A case study of H2O-Ar on full and reduced-dimensional potential energy surface. AB - The origin and strength of intra- and inter-molecular vibrational coupling is difficult to probe by direct experimental observations. However, explicitly including or not including some specific intramolecular vibrational modes to study intermolecular interaction provides a precise theoretical way to examine the effects of anharmonic coupling between modes. In this work, a full-dimension intra- and inter-molecular ab initio potential energy surface (PES) for H2O-Ar, which explicitly incorporates interdependence on the intramolecular (Q1, Q2, Q3) normal-mode coordinates of the H2O monomer, has been calculated. In addition, four analytic vibrational-quantum-state-specific PESs are obtained by least squares fitting vibrationally averaged interaction energies for the (v1, v2, v3) = (0, 0, 0), (0, 0, 1), (1, 0, 0), (0, 1, 0) states of H2O to the three-dimensional Morse/long-range potential function. Each vibrationally averaged PES fitted to 442 points has root-mean-square (rms) deviation smaller than 0.15 cm(-1), and required only 58 parameters. With the 3D PESs of H2O-Ar dimer system, we employed the combined radial discrete variable representation/angular finite basis representation method and Lanczos algorithm to calculate rovibrational energy levels. This showed that the resulting vibrationally averaged PESs provide good representations of the experimental infrared data, with rms discrepancies smaller than 0.02 cm(-1) for all three rotational branches of the asymmetric stretch fundamental transitions. The infrared band origin shifts associated with three fundamental bands of H2O in H2O Ar complex are predicted for the first time and are found to be in good agreement with the (extrapolated) experimental values. Upon introduction of additional intramolecular degrees of freedom into the intermolecular potential energy surface, there is clear spectroscopic evidence of intra- and intermolecular vibrational couplings. PMID- 26747801 TI - Manipulation of a neutral and nonpolar nanoparticle in water using a nonuniform electric field. AB - The manipulation of nanoparticles in water is of essential importance in chemical physics, nanotechnology, medical technology, and biotechnology applications. Generally, a particle with net charges or charge polarity can be driven by an electric field. However, many practical particles only have weak and even negligible charge and polarity, which hinders the electric field to exert a force large enough to drive these nanoparticles directly. Here, we use molecular dynamics simulations to show that a neutral and nonpolar nanoparticle in liquid water can be driven directionally by an external electric field. The directed motion benefits from a nonuniform water environment produced by a nonuniform external electric field, since lower water energies exist under a higher intensity electric field. The nanoparticle spontaneously moves toward locations with a weaker electric field intensity to minimize the energy of the whole system. Considering that the distance between adjacent regions of nonuniform field intensity can reach the micrometer scale, this finding provides a new mechanism of manipulating nanoparticles from the nanoscale to the microscale. PMID- 26747802 TI - Involvement of a low-lying Rydberg state in the ultrafast relaxation dynamics of ethylene. AB - We present a measurement of the time-resolved photoelectron kinetic energy spectrum of ethylene using 156 nm and 260 nm laser pulses. The 156 nm pulse first excites ethylene to the (1)B1u (pipi(*)) electronic state where 260 nm light photoionizes the system to probe the relaxation dynamics with sub-30 fs resolution. Recent ab initio calculations by Mori et al. [J. Phys. Chem. A 116, 2808-2818 (2012)] have predicted an ultrafast population transfer from the initially excited state to a low-lying Rydberg state during the relaxation of photoexcited ethylene. The measured photoelectron kinetic energy spectrum reveals wave packet motion on the valence state and shows indications that the low-lying pi3s Rydberg state is indeed transiently populated via internal conversion following excitation to the pipi(*) state, supporting the theoretical predictions. PMID- 26747804 TI - Substituent effects on dynamics at conical intersections: Allene and methyl allenes. AB - We report a joint experimental and theoretical study on the ultrafast excited state dynamics of allene and a series of its methylated analogues (1,2-butadiene, 1,1-dimethylallene, and tetramethylallene) in order to elucidate the conical intersection mediated dynamics that give rise to ultrafast relaxation to the ground electronic state. We use femtosecond time-resolved photoelectron spectroscopy (TRPES) to probe the coupled electronic-vibrational dynamics following UV excitation at 200 nm (6.2 eV). Ab initio multiple spawning (AIMS) simulations are employed to determine the mechanistic details of two competing dynamical pathways to the ground electronic state. In all molecules, these pathways are found to involve as follows: (i) twisting about the central allenic C-C-C axis followed by pyramidalization at one of the terminal carbon atoms and (ii) bending of allene moiety. Importantly, the AIMS trajectory data were used for ab initio simulations of the TRPES, permitting direct comparison with experiment. For each molecule, the decay of the TRPES signal is characterized by short (30 fs, 52 fs, 23 fs) and long (1.8 ps, 3.5 ps, [306 fs, 18 ps]) time constants for 1,2-butadiene, 1,1-dimethylallene, and tetramethylallene, respectively. However, AIMS simulations show that these time constants are only loosely related to the evolution of electronic character and actually more closely correlate to large amplitude motions on the electronic excited state, modulating the instantaneous vertical ionization potentials. Furthermore, the fully substituted tetramethylallene is observed to undergo qualitatively different dynamics, as displacements involving the relatively massive methyl groups impede direct access to the conical intersections which give rise to the ultrafast relaxation dynamics observed in the other species. These results show that the branching between the "twisting" and "bending" pathways can be modified via the selective methylation of the terminal carbon atoms of allene. The interplay between inertial and potential effects is a key to understanding these dynamical branching pathways. The good agreement between the simulated and measured TRPES confers additional confidence to the dynamical picture presented here. PMID- 26747803 TI - IR-induced conformational isomerization of a helical peptide in a cold ion trap. AB - In this work, we use laser-induced population transfer techniques to study the conformational isomerization of a helical peptide, Ac-Phe-(Ala)5-LysH(+), in a cold ion trap. In one scheme, called IR-UV hole-filling spectroscopy, a single conformation is selectively excited with an IR pump laser via a distinct NH stretch vibration. After giving the vibrationally excited ions sufficient time to isomerize and re-cool in the trap, the new conformational redistribution is detected by UV photofragment spectroscopy. While we clearly observe a redistribution of the conformer populations due to isomerization, only those conformations that initially have population participate in this redistribution we do not form conformers that were not initially present in the trap. In a second scheme, called IR-induced population transfer spectroscopy, we determine the fractional populations of the four stable conformations of Ac-Phe-(Ala)5 LysH(+) by scanning the IR laser while selectively detecting a specific conformation using UV photofragment spectroscopy. PMID- 26747805 TI - Phase-only laser control in the weak-field limit: Two-pulse control of IBr photofragmentation revisited. AB - We demonstrate theoretically that laser-induced coherent quantum interference control of asymptotic states of dissociating molecules is possible, starting from a single vibrational eigenstate, after the interaction with two laser pulses-at a fixed time delay-both operating in the weak-field limit. Thus, phase dependence in the interaction with the second fixed-energy phase-modulated pulse persists after the pulse is over. This is illustrated for the nonadiabatic process: I + Br(*)<-IBr -> I + Br, where the relative yield of excited Br(*) can be changed by pure phase modulation. Furthermore, a strong frequency dependence of the branching ratio is observed and related to the re-crossing dynamics of the avoided crossing in the above-mentioned process. PMID- 26747806 TI - Observations of the high vibrational levels of the B('')B (1)Sigma(u)(+) state of H2. AB - Double-resonance laser spectroscopy via the EF (1)Sigmag (+),v(')=6,J(')=0-2 state was used to probe the high vibrational levels of the B('')B (1)Sigmau (+) state of molecular hydrogen. Resonantly enhanced multiphoton ionization spectra were recorded by detecting ion production as a function of energy using a time of flight mass spectrometer. New measurements of energies for the v = 51-66 levels for the B('')B state of H2 are reported, which, taken with previous results, span the v = 46-69 vibrational levels. Results for energy levels are compared to theoretical close-coupled calculations [L. Wolniewicz, T. Orlikowski, and G. Staszewska, J. Mol. Spectrosc. 238, 118-126 (2006)]. The average difference between the 84 measured energies and calculated energies is -3.8 cm(-1) with a standard deviation of 5.3 cm(-1). This level of agreement showcases the success of the theoretical calculations in accounting for the strong rovibronic mixing of the (1)Sigmau (+) and (1)Piu (+) states. Due to the ion-pair character of the outer well, the observed energies of the vibrational levels below the third dissociation limit smoothly connect with previously observed energies of ion-pair states above this limit. The results provide an opportunity for testing a heavy Rydberg multi-channel quantum defect analysis of the high vibrational states below the third dissociation limit. PMID- 26747807 TI - Rotating effects on the Landau quantization for an atom with a magnetic quadrupole moment. AB - Based on the single particle approximation [Dmitriev et al., Phys. Rev. C 50, 2358 (1994) and C.-C. Chen, Phys. Rev. A 51, 2611 (1995)], the Landau quantization associated with an atom with a magnetic quadrupole moment is introduced, and then, rotating effects on this analogue of the Landau quantization is investigated. It is shown that rotating effects can modify the cyclotron frequency and breaks the degeneracy of the analogue of the Landau levels. PMID- 26747808 TI - Excited state non-adiabatic dynamics of N-methylpyrrole: A time-resolved photoelectron spectroscopy and quantum dynamics study. AB - The dynamics of N-methylpyrrole following excitation at wavelengths in the range 241.5-217.0 nm were studied using a combination of time-resolved photoelectron spectroscopy (TRPES), ab initio quantum dynamics calculations using the multi layer multi-configurational time-dependent Hartree method, as well as high-level photoionization cross section calculations. Excitation at 241.5 and 236.2 nm results in population of the A2(pisigma(*)) state, in agreement with previous studies. Excitation at 217.0 nm prepares the previously neglected B1(pi3py) Rydberg state, followed by prompt internal conversion to the A2(pisigma(*)) state. In contrast with the photoinduced dynamics of pyrrole, the lifetime of the wavepacket in the A2(pisigma(*)) state was found to vary with excitation wavelength, decreasing by one order of magnitude upon tuning from 241.5 nm to 236.2 nm and by more than three orders of magnitude when excited at 217.0 nm. The order of magnitude difference in lifetimes measured at the longer excitation wavelengths is attributed to vibrational excitation in the A2(pisigma(*)) state, facilitating wavepacket motion around the potential barrier in the N-CH3 dissociation coordinate. PMID- 26747809 TI - Some considerations on the transport properties of water-glycerol suspensions. AB - We study the self-diffusion coefficient and viscosity of a water-glycerol mixture for several glycerol molar fractions as a function of temperature well inside the metastable supercooled regime. We perform NMR experiments and verify that the system has at different concentration a fragile-to-strong crossover accompanied by the violation of the Stokes-Einstein relation. We observe that the crossover temperature depends on the water amount. Studying the fractional representation of the Stokes-Einstein relation, we find that in these systems dynamical arrest does not exhibit criticality and the transport parameters have a universal behavior. PMID- 26747810 TI - Prediction of binary nanoparticle superlattices from soft potentials. AB - Driven by the hypothesis that a sufficiently continuous short-ranged potential is able to account for shell flexibility and phonon modes and therefore provides a more realistic description of nanoparticle interactions than a hard sphere model, we compute the solid phase diagram of particles of different radii interacting with an inverse power law potential. From a pool of 24 candidate lattices, the free energy is optimized with respect to additional internal parameters and the p exponent, determining the short-range properties of the potential, is varied between p = 12 and p = 6. The phase diagrams contain the phases found in ongoing self-assembly experiments, including DNA programmable self-assembly and nanoparticles with capping ligands assembled by evaporation from an organic solvent. The resulting phase diagrams can be mapped quantitatively to existing experiments as a function of only two parameters: Nanoparticle radius ratio (gamma) and softness asymmetry. PMID- 26747811 TI - Quasielastic neutron scattering measurements and ab initio MD-simulations on single ion motions in molten NaF. AB - The ionic stochastic motions in the molten alkali halide NaF are investigated by quasielastic neutron scattering and first principles molecular dynamics simulation. Quasielastic neutron scattering was employed to extract the diffusion behavior of the sodium ions in the melt. An extensive first principles based simulation on a box of up to 512 particles has been performed to complement the experimental data. From that large box, a smaller 64-particle box has then been simulated over a runtime of 60 ps. A good agreement between calculated and neutron data on the level of spectral shape has been obtained. The obtained sodium diffusion coefficients agree very well. The simulation predicts a fluorine diffusion coefficient similar to the sodium one. Applying the Nernst-Einstein equation, a remarkable large cross correlation between both ions can be deduced. The velocity cross correlations demonstrate a positive correlation between the ions over a period of 0.1 ps. That strong correlation is evidence that the unlike ions do not move completely statistically independent and have a strong association over a short period of time. PMID- 26747812 TI - On the wettability transparency of graphene-coated silicon surfaces. AB - In order to better understand the behavior and governing characteristics of the wetting transparency phenomenon observed in graphene-coated surfaces, molecular dynamics simulations were coupled with a theoretical model. Graphene-coated silicon was selected for this analysis, due to potential applications of hybrid silicon-graphene materials as detectors in aqueous environments. The results indicate good agreement between the theory and simulations at the macroscopic conditions required to observe wetting transparency. A microscopic analysis was also conducted in order to identify the parameters, such as the interaction potential energy landscape and the interfacial liquid structure that govern the wetting behavior of graphene-coated surfaces. The interfacial liquid structure was found to be different between uncoated Si(100) and the graphene-coated version and very similar between uncoated Si(111) and the graphene-coated version. However, the concentration of liquid particles for both silicon surfaces was found to be very similar under transparent wetting conditions. PMID- 26747813 TI - Pyridine on flat Pt(111) and stepped Pt(355)--An in situ HRXPS investigation of adsorption and thermal evolution. AB - We investigated the adsorption and reaction of pyridine on flat Pt(111) and stepped Pt(355) surfaces via high-resolution in situ x-ray photoelectron spectroscopy. The surfaces were exposed to pyridine at temperatures between 112 and 300 K while simultaneously recording XP spectra. Subsequently, the crystals were annealed and the temperature dependencies of the N 1s and C 1s core levels were studied again in a continuous and quantitative way. Various surface species were found, namely, physisorbed, flat-lying and end-on pyridine, alpha-pyridyl species on the terraces and on the steps and several unidentified high temperature species. We were able to show an influence of the steps of Pt(355) by pre-adsorbing silver next to the step, which selectively suppresses the step adsorption. PMID- 26747814 TI - Insight into interfacial effect on effective physical properties of fibrous materials. I. The volume fraction of soft interfaces around anisotropic fibers. AB - With advances in interfacial properties characterization technologies, the interfacial volume fraction is a feasible parameter for evaluating effective physical properties of materials. However, there is a need to determine the interfacial volume fraction around anisotropic fibers and a need to assess the influence of such the interfacial property on effective properties of fibrous materials. Either ways, the accurate prediction of interfacial volume fraction is required. Towards this end, we put forward both theoretical and numerical schemes to determine the interfacial volume fraction in fibrous materials, which are considered as a three-phase composite structure consisting of matrix, anisotropic hard spherocylinder fibers, and soft interfacial layers with a constant dimension coated on the surface of each fiber. The interfacial volume fraction actually represents the fraction of space not occupied by all hard fibers and matrix. The theoretical scheme that adopts statistical geometry and stereological theories is essentially an analytic continuation from spherical inclusions. By simulating such three-phase chopped fibrous materials, we numerically derive the interfacial volume fraction. The theoretical and numerical schemes provide a quantitative insight that the interfacial volume fraction depends strongly on the fiber geometries like fiber shape, geometric size factor, and fiber size distribution. As a critical interfacial property, the present contribution can be further drawn into assessing effective physical properties of fibrous materials, which will be demonstrated in another paper (Part II) of this series. PMID- 26747815 TI - Theoretical prediction of the band offsets at the ZnO/anatase TiO2 and GaN/ZnO heterojunctions using the self-consistent ab initio DFT/GGA-1/2 method. AB - The band offsets of the ZnO/anatase TiO2 and GaN/ZnO heterojunctions are calculated using the density functional theory/generalized gradient approximation (DFT/GGA)-1/2 method, which takes into account the self-energy corrections and can give an approximate description to the quasiparticle characteristics of the electronic structure of semiconductors. We present the results of the ionization potential (IP)-based and interfacial offset-based band alignments. In the interfacial offset-based band alignment, to get the natural band offset, we use the surface calculations to estimate the change of reference level due to the interfacial strain. Based on the interface models and GGA-1/2 calculations, we find that the valence band maximum and conduction band minimum of ZnO, respectively, lie 0.64 eV and 0.57 eV above those of anatase TiO2, while lie 0.84 eV and 1.09 eV below those of GaN, which agree well with the experimental data. However, a large discrepancy exists between the IP-based band offset and the calculated natural band offset, the mechanism of which is discussed. Our results clarify band alignment of the ZnO/anatase TiO2 heterojunction and show good agreement with the GW calculations for the GaN/ZnO heterojunction. PMID- 26747816 TI - Reaction paths of phosphine dissociation on silicon (001). AB - Using density functional theory and guided by extensive scanning tunneling microscopy (STM) image data, we formulate a detailed mechanism for the dissociation of phosphine (PH3) molecules on the Si(001) surface at room temperature. We distinguish between a main sequence of dissociation that involves PH2+H, PH+2H, and P+3H as observable intermediates, and a secondary sequence that gives rise to PH+H, P+2H, and isolated phosphorus adatoms. The latter sequence arises because PH2 fragments are surprisingly mobile on Si(001) and can diffuse away from the third hydrogen atom that makes up the PH3 stoichiometry. Our calculated activation energies describe the competition between diffusion and dissociation pathways and hence provide a comprehensive model for the numerous adsorbate species observed in STM experiments. PMID- 26747817 TI - Energy barriers for dipole moment flipping in PVDF-related ferroelectric polymers. AB - Energy barriers for flipping the transverse dipole moments in poly(vinylidene fluoride) (PVDF) and related copolymers and terpolymers are predicted using the nudged elastic band method. The dipole moments flip individually along the chain, with an order and energy barrier magnitudes (0.1-1.2 eV) that depend on the chain composition and environment. Trifluoroethylene (TrFE) and chlorofluoroethylene (CFE) monomers have larger energy barriers than VDF monomers, while a chain in an amorphous environment has a similar transition pathway as that of an isolated molecule. In a crystalline environment, TrFE and CFE monomers expand the lattice and lower the energy barriers for flipping VDF monomers. This finding is consistent with experimental observations of a large electrocaloric effect in P(VDF-TrFE-CFE) terpolymers. PMID- 26747818 TI - Coarse-grained model of water diffusion and proton conductivity in hydrated polyelectrolyte membrane. AB - Using dissipative particle dynamics (DPD), we simulate nanoscale segregation, water diffusion, and proton conductivity in hydrated sulfonated polystyrene (sPS). We employ a novel model [Lee et al. J. Chem. Theory Comput. 11(9), 4395 4403 (2015)] that incorporates protonation/deprotonation equilibria into DPD simulations. The polymer and water are modeled by coarse-grained beads interacting via short-range soft repulsion and smeared charge electrostatic potentials. The proton is introduced as a separate charged bead that forms dissociable Morse bonds with the base beads representing water and sulfonate anions. Morse bond formation and breakup artificially mimics the Grotthuss mechanism of proton hopping between the bases. The DPD model is parameterized by matching the proton mobility in bulk water, dissociation constant of benzenesulfonic acid, and liquid-liquid equilibrium of water-ethylbenzene solutions. The DPD simulations semi-quantitatively predict nanoscale segregation in the hydrated sPS into hydrophobic and hydrophilic subphases, water self diffusion, and proton mobility. As the hydration level increases, the hydrophilic subphase exhibits a percolation transition from isolated water clusters to a 3D network. The analysis of hydrophilic subphase connectivity and water diffusion demonstrates the importance of the dynamic percolation effect of formation and breakup of temporary junctions between water clusters. The proposed DPD model qualitatively predicts the ratio of proton to water self-diffusion and its dependence on the hydration level that is in reasonable agreement with experiments. PMID- 26747820 TI - Confinement and diffusion modulate bistability and stochastic switching in a reaction network with positive feedback. AB - Positive feedback is a common feature in signal transduction networks and can lead to phenomena such as bistability and signal propagation by domain growth. Physical features of the cellular environment, such as spatial confinement and the mobility of proteins, play important but inadequately understood roles in shaping the behavior of signaling networks. Here, we use stochastic, spatially resolved kinetic Monte Carlo simulations to explore a positive feedback network as a function of system size, system shape, and mobility of molecules. We show that these physical properties can markedly alter characteristics of bistability and stochastic switching when compared with well-mixed simulations. Notably, systems of equal volume but different shapes can exhibit qualitatively different behaviors under otherwise identical conditions. We show that stochastic switching to a state maintained by positive feedback occurs by cluster formation and growth. Additionally, the frequency at which switching occurs depends nontrivially on the diffusion coefficient, which can promote or suppress switching relative to the well-mixed limit. Taken together, the results provide a framework for understanding how confinement and protein mobility influence emergent features of the positive feedback network by modulating molecular concentrations, diffusion-influenced rate parameters, and spatiotemporal correlations between molecules. PMID- 26747819 TI - Binding of ACE-inhibitors to in vitro and patient-derived amyloid-beta fibril models. AB - Currently, no drugs exist that can prevent or reverse Alzheimer's disease, a neurodegenerative disease associated with the presence, in the brain, of plaques that are composed of beta-amyloid (Abeta) peptides. Recent studies suggest that angiotensin-converting enzyme (ACE) inhibitors, a set of drugs used to treat hypertension, may inhibit amyloid formation in vitro. In the present study, we investigate through computer simulations the binding of ACE inhibitors to patient derived Abeta fibrils and contrast it with that of ACE inhibitors binding to in vitro generated fibrils. The binding affinities of the ACE inhibitors are compared with that of Congo red, a dye that is used to identify amyloid structures and that is known to be a weak inhibitor of Abeta aggregation. We find that ACE inhibitors have a lower binding affinity to the patient-derived fibrils than to in vitro generated ones. For patient-derived fibrils, their binding affinities are even lower than that of Congo red. Our observations raise doubts on the hypothesis that these drugs inhibit fibril formation in Alzheimer patients by interacting directly with the amyloids. PMID- 26747821 TI - Softness and non-spherical shape define the phase behavior and the structural properties of lysozyme in aqueous solutions. AB - In this study, Boltzmann inversion is applied in conjunction with molecular dynamics simulations to derive inter-molecular potential for protein lysozyme in aqueous solution directly from experimental static structure factor. The potential has a soft repulsion at short distances and an attraction well at intermediate distances that give rise to the liquid-liquid phase separation. Moreover, Gibbs ensemble Monte Carlo simulations demonstrate that a non-spherical description of lysozyme is better suited to correctly reproduce the experimentally observed properties of such a phase separation. Our findings shed new light on the common problem in molecular and cell biology: "How to model proteins in their natural aqueous environments?" PMID- 26747823 TI - The effect of TiO2 concentration on properties of apatite-mullite glass-ceramics for dental use. AB - OBJECTIVE: The aim of this study was to evaluate the effect of TiO2 concentration on the properties of apatite-mullite glass-ceramics namely strength and the chemical solubility to comply with the ISO standard recommendations for dental ceramics (BS EN ISO 6872-2008). METHODS: Ten novel glass-ceramic materials were produced based on the general formula (4.5SiO2-3Al2O3-1.5P2O5-3CaO-CaF2-xTiO2) where x varied from 0.5 to 5 wt%. Glass with no TiO2 added (HG1T0.0) was used as a reference. Discs of 12 mm diameter and 1.6 mm (+/-0.2 mm) thickness were prepared for both biaxial flexural strength (BFS) and chemical solubility testing, in accordance with the BS EN ISO 6872-2008 for dental ceramics. All produced materials were investigated using differential thermal analysis (DTA), X ray diffraction (XRD), and scanning electron microscopy (SEM). Energy dispersive X-ray analysis (EDS) was also carried out on some samples to identify the element composition of samples. RESULTS: Increasing the concentration of TiO2 from 0.5 wt% to 2 wt% significantly (P<0.05) increased the chemical solubility of the material. With the material containing 2.5 wt% of TiO2, the solubility significantly reduced (P<0.05) and resulted in a solubility value of 228.3 MUm/cm(2) and BFS value of 197.9 MPa. Increasing the TiO2 concentration more than 2.5 wt%, led to a significant (P<0.05) increase in solubility and a reduction in BFS. CONCLUSIONS: TiO2 is an effective agent for improving the durability and the mechanical properties of an apatite-mullite glass-ceramic only up to 2.5 wt% concentration. PMID- 26747822 TI - On the stiffness of demineralized dentin matrices. AB - Resin bonding to dentin requires the use of self-etching primers or acid etching to decalcify the surface and expose a layer of collagen fibrils of the dentin matrix. Acid-etching reduces the stiffness of demineralized dentin from approximately 19 GPa-1 MPa, requiring that it floats in water to prevent it from collapsing during bonding procedures. Several publications show that crosslinking agents like gluteraladehyde, carbodiimide or grape seed extract can stiffen collagen and improve resin-dentin bond strength. OBJECTIVE: The objective was to assess a new approach for evaluating the changes in stiffness of decalcified dentin by polar solvents and a collagen cross-linker. METHODS: Fully demineralized dentin beams and sections of etched coronal dentin were subjected to indentation loading using a cylindrical flat indenter in water, and after treatment with ethanol or ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). The stiffness was measured as a function of strain and as a function of loading rate from 1 to 50 MUm/s. RESULTS: At a strain of 0.25% the elastic modulus of the fully demineralized dentin was approximately 0.20 MPa. It increased to over 0.90 MPa at strains of 1%. Exposure to ethanol caused an increase in elastic modulus of up to four times. Increasing the loading rate from 1 to 50 MUm/s caused an increase in the apparent modulus of up to three times in both water and ethanol. EDC treatment caused increases in the stiffness in fully demineralized samples and in acid-etched demineralized dentin surfaces in situ. SIGNIFICANCE: Changes in the mechanical behavior of demineralized collagen matrices can be measured effectively under hydration via indentation with cylindrical flat indenters. This approach can be used for quantifying the effects of bonding treatments on the properties of decalcified dentin after acid etching, as well as to follow the loss of stiffness over time due to enzymatic degradation. PMID- 26747824 TI - Editorial Commentary: Quantitative Molecular Approach to Diagnosing Pneumonia. PMID- 26747826 TI - Editorial Commentary: The Modern Quest for the "Holy Grail" of Pneumonia Etiology. PMID- 26747828 TI - Tinnitus and its current treatment--Still an enigma in medicine. AB - Tinnitus is a phantom auditory perception that occurs in humans. Tinnitus, which is a distressing problem affecting many people around the world, is commonly referred to as ringing in the ears. No effective drug therapy is available for this elusive disease, although much research work into mechanism and possible treatment is underway. As yet, there are no Food and Drug Administration approved drugs available and the quest for a new treatment option for tinnitus focus on important challenges in tinnitus management. A number of options have been used to treat patients with tinnitus, but outcomes have been limited. A new, curative modality will provide a turning point in the management of tinnitus. The purpose of this review article is to discuss the pathophysiology, global burden, current treatment, and prevention of tinnitus, with future prospective studies in new drug therapy for this elusive condition. PMID- 26747825 TI - Comprehensive Molecular Testing for Respiratory Pathogens in Community-Acquired Pneumonia. AB - BACKGROUND: The frequent lack of a microbiological diagnosis in community acquired pneumonia (CAP) impairs pathogen-directed antimicrobial therapy. This study assessed the use of comprehensive multibacterial, multiviral molecular testing, including quantification, in adults hospitalized with CAP. METHODS: Clinical and laboratory data were collected for 323 adults with radiologically confirmed CAP admitted to 2 UK tertiary care hospitals. Sputum (96%) or endotracheal aspirate (4%) specimens were cultured as per routine practice and also tested with fast multiplex real-time polymerase-chain reaction (PCR) assays for 26 respiratory bacteria and viruses. Bacterial loads were also calculated for 8 bacterial pathogens. Appropriate pathogen-directed therapy was retrospectively assessed using national guidelines adapted for local antimicrobial susceptibility patterns. RESULTS: Comprehensive molecular testing of single lower respiratory tract (LRT) specimens achieved pathogen detection in 87% of CAP patients compared with 39% with culture-based methods. Haemophilus influenzae and Streptococcus pneumoniae were the main agents detected, along with a wide variety of typical and atypical pathogens. Viruses were present in 30% of cases; 82% of these were codetections with bacteria. Most (85%) patients had received antimicrobials in the 72 hours before admission. Of these, 78% had a bacterial pathogen detected by PCR but only 32% were culture-positive (P < .0001). Molecular testing had the potential to enable de-escalation in number and/or spectrum of antimicrobials in 77% of patients. CONCLUSIONS: Comprehensive molecular testing significantly improves pathogen detection in CAP, particularly in antimicrobial-exposed patients, and requires only a single LRT specimen. It also has the potential to enable early de-escalation from broad-spectrum empirical antimicrobials to pathogen-directed therapy. PMID- 26747830 TI - A rare cause of weakness. PMID- 26747829 TI - Prepregnancy Obesity Class Is a Risk Factor for Failure to Exclusively Breastfeed at Hospital Discharge among Latinas. AB - BACKGROUND: Suboptimal infant feeding practices, including the failure to exclusively breastfeed, are modifiable risk factors that affect multiple maternal and child health outcomes. Women who are overweight or obese prenatally are more likely to fail to exclusively breastfeed. In the United States, Latinas represent a high-risk population with respect to overweight, obesity, and suboptimal infant feeding practices. OBJECTIVES: Examine whether exclusive breastfeeding status at hospital discharge among overweight and obese Latinas was associated with (1) prepregnancy body mass index (BMI) and gestational weight gain and (2) sociodemographic, psychosocial, and maternal/infant biomedical factors. METHODS: An electronic medical records review was conducted to determine exclusive breastfeeding status at hospital discharge among Latinas who gave birth at Hartford Hospital, Hartford, Connecticut, USA (N = 480). Eligible participants were >= 16 years, Latina, overweight or obese (BMI >= 25.0 kg/m(2)) and delivered a healthy full-term (>= 37 weeks) singleton. RESULTS: In the multivariable model, obese class II (BMI, 35.0-39.9 kg/m(2)) women had increased odds of failing to exclusively breastfeed at hospital discharge compared with overweight women. Planned formula use/partial breastfeeding was the single strongest predictor of nonexclusive breastfeeding status. Other risk factors included Puerto Rican ethnicity and parity. CONCLUSION: Maternal prepregnancy obesity class is an important predictor of exclusive breastfeeding status at hospital discharge among overweight and obese Latinas. Future research should examine why in-hospital exclusive breastfeeding behaviors differ by obesity class to subsequently inform the design of breastfeeding promotion and support interventions tailored to the needs of Latinas by obesity class. Culturally appropriate prenatal breastfeeding promotion interventions emphasizing action and coping planning should be considered. PMID- 26747831 TI - Cut drinking to reduce risk of cancer, says new guidance. PMID- 26747832 TI - Articulating the Case for the Longevity Dividend. AB - The survival of large segments of human populations to advanced ages is a crowning achievement of improvements in public health and medicine. But, in the 21st century, our continued desire to extend life brings forth a unique dilemma. The risk of death from cardiovascular diseases and many forms of cancer have declined, but even if they continue to do so in the future, the resulting health benefits and enhanced longevities are likely to diminish. It is even possible that healthy life expectancy could decline in the future as major fatal diseases wane. The reason is that the longer we live, the greater is the influence of biological aging on the expression of fatal and disabling diseases. As long as the rates of aging of our bodies continues without amelioration, the progress we make on all major disease fronts must eventually face a point of diminishing returns. Research in the scientific study of aging has already showed that the aging of our bodies is inherently modifiable, and that a therapeutic intervention that slows aging in people is a plausible target for science and public health. Given the speed with which population aging is progressing and chronic fatal and disabling conditions are challenging health care costs across the globe, the case is now being made in the scientific literature that delayed aging could be one of the most efficient and promising ways to combat disease, extend healthy life, compress morbidity, and reduce health care costs. A consortium of scientists and nonprofit organizations has devised a plan to initiate an accelerated program of scientific research to develop, test for safety and efficacy, and then disseminate a therapeutic intervention to delay aging if proven to be safe and effective; this is referred to as the Longevity Dividend Initiative Consortium (LDIC). In this review, I articulate the case for the LDIC. PMID- 26747834 TI - GABAergic Synchronization in Epilepsy. AB - gamma-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the cerebral cortex. GABAergic inhibition enables synchronization of activity in cortical networks, and contributes to generation of variety of brain activity patterns. In relation to epilepsy, GABAergic inhibition has been traditionally viewed as the main mechanism counterbalancing glutamatergic excitation and preventing hypersynchronous neuronal discharges. Indeed, deficits in GABAergic functions most commonly result in a hyperexcitable epileptic state, and many of the currently used antiepileptic drugs act through enhancement of GABAergic functions. However, a number of observations show that some epileptiform activity patterns involve synchronization by GABAergic mechanisms. These include two main categories that will be reviewed here: (1) synchronization of epileptiform oscillations based on GABAergic inhibition, and (2) epileptiform events driven by depolarizing and excitatory GABA. The conclusion is reached that GABAergic control of spike timing, either through inhibition or excitation under certain conditions, may work as a powerful synchronizing mechanism during epilepsy. PMID- 26747833 TI - Hepatitis B Virus X and Regulation of Viral Gene Expression. AB - The efficient replication of hepatitis B virus (HBV) requires the HBV regulatory hepatitis B virus X (HBx) protein. The exact contributions of HBx are not fully understood, in part because of the limitations of the assays used for its study. When HBV replication is driven from a plasmid DNA, the contribution of HBx is modest. However, there is an absolute requirement for HBx in assays that recapitulate the infectious virus life cycle. There is much evidence that HBx can contribute directly to HBV replication by acting on viral promoters embedded within protein coding sequences. In addition, HBx may also contribute indirectly by modulating cellular pathways to benefit virus replication. Understanding the mechanism(s) of HBx action during virus replication may provide insight into novel ways to disrupt chronic HBV replication. PMID- 26747836 TI - Antileishmanial Activities of Greek Juniper (Juniperus excelsa M.Bieb.) Against Leishmania major Promastigotes. AB - Petroleum ether, chloroform, ethyl acetate, and n-butanol fractions of Greek juniper (Juniperus excelsa M.Bieb. from the family Cupressaceae) were evaluated for antileishmanial activities against Leishmania major promastigotes compared to meglumine antimoniate (Glucantime). In vitro toxicity assay was performed using 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and microplate ELISA reader. Extracts were prepared in ethanol/dimethyl sulfoxide (80/20) at 10 to 0.62 mg/mL. The standard was prepared in phosphate-buffered saline at 500 to 15.62 mg/mL. Both leaf and fruit extracts and related fractions showed strong inhibitory effects against promastigotes, significantly different from that of the standard. The leaf extract and the respective petroleum ether fraction showed maximum effectiveness compared to other fractions and also fruit extract and fractions (IC90 = 1.89 +/- 0.03 and 0.90 +/- 0.03 mg/mL, respectively). Regarding the potent activities of nonpolar fractions of Greek juniper leaf extract, these fractions can be suggested for further investigation. PMID- 26747837 TI - Src family kinase expression and subcellular localization in macrophages: implications for their role in CSF-1-induced macrophage migration. AB - A major role of colony-stimulating factor-1 is to stimulate the differentiation of mononuclear phagocytic lineage cells into adherent, motile, mature macrophages. The colony-stimulating factor-1 receptor transduces colony stimulating factor-1 signaling, and we have shown previously that phosphatidylinositol 3-kinase p110delta is a critical mediator of colony stimulating factor-1-stimulated motility through the colony-stimulating factor-1 receptor pY721 motif. Src family kinases are also implicated in the regulation of macrophage motility and in colony-stimulating factor-1 receptor signaling, although functional redundancy of the multiple SFKs expressed in macrophages makes it challenging to delineate their specific functions. We report a comprehensive analysis of individual Src family kinase expression in macrophage cell lines and primary macrophages and demonstrate colony-stimulating factor-1 induced changes in Src family kinase subcellular localization, which provides clues to their distinct and redundant functions in macrophages. Moreover, expression of individual Src family kinases is both species specific and dependent on colony-stimulating factor-1-induced macrophage differentiation. Hck associated with the activated colony-stimulating factor-1 receptor, whereas Lyn associated with the receptor in a constitutive manner. Consistent with this, inhibitor studies revealed that Src family kinases were important for both colony stimulating factor-1 receptor activation and colony-stimulating factor-1-induced macrophage spreading, motility, and invasion. Distinct colony-stimulating factor 1-induced changes in the subcellular localization of individual SFKs suggest specific roles for these Src family kinases in the macrophage response to colony stimulating factor-1. PMID- 26747835 TI - A Molecular Perspective on Procedures and Outcomes with Assisted Reproductive Technologies. AB - The emerging association of assisted reproductive technologies with adverse perinatal outcomes has prompted the in-depth examination of clinical and laboratory protocols and procedures and their possible effects on epigenetic regulatory mechanism(s). The application of various approaches to study epigenetic regulation to problems in reproductive medicine has the potential to identify relative risk indicators for particular conditions, diagnostic biomarkers of disease state, and prognostic indicators of outcome. Moreover, when applied genome-wide, these techniques are likely to find novel pathways of disease pathogenesis and identify new targets for intervention. The analysis of DNA methylation, histone modifications, transcription factors, enhancer binding and other chromatin proteins, DNase-hypersensitivity and, micro- and other noncoding RNAs all provide overlapping and often complementary snapshots of chromatin structure and resultant "gene activity." In terms of clinical application, the predictive power and utility of epigenetic information will depend on the power of individual techniques to discriminate normal levels of interindividual variation from variation linked to a disease state. At present, quantitative analysis of DNA methylation at multiple loci seems likely to hold the greatest promise for achieving the level of precision, reproducibility, and throughput demanded in a clinical setting. PMID- 26747838 TI - Mincle suppresses Toll-like receptor 4 activation. AB - Regulation of Toll-like receptor responses is critical for limiting tissue injury and autoimmunity in both sepsis and sterile inflammation. We found that Mincle, a C-type lectin receptor, regulates proinflammatory Toll-like receptor 4 signaling. Specifically, Mincle ligation diminishes Toll-like receptor 4-mediated inflammation, whereas Mincle deletion or knockdown results in marked hyperresponsiveness to lipopolysaccharide in vitro, as well as overwhelming lipopolysaccharide-mediated inflammation in vivo. Mechanistically, Mincle deletion does not up-regulate Toll-like receptor 4 expression or reduce interleukin 10 production after Toll-like receptor 4 ligation; however, Mincle deletion decreases production of the p38 mitogen-activated protein kinase dependent inhibitory intermediate suppressor of cytokine signaling 1, A20, and ABIN3 and increases expression of the Toll-like receptor 4 coreceptor CD14. Blockade of CD14 mitigates the increased sensitivity of Mincle(-/-) leukocytes to Toll-like receptor 4 ligation. Collectively, we describe a major role for Mincle in suppressing Toll-like receptor 4 responses and implicate its importance in nonmycobacterial models of inflammation. PMID- 26747839 TI - Can Hospital Form Trigger Fear Response? AB - OBJECTIVE: To examine whether exposure to curve versus sharp contours in the built healthcare setting produces systematic and identifiable patterns of amygdala activation and behavioral response in healthy adults. BACKGROUND: Recent studies in cognitive neuroscience suggest that humans prefer objects with a curved contour compared with objects that have pointed features and a sharp angled contour. An implicit perception of threat represented by sharp objects, in humans, was hypothesized to explain this bias. METHOD: The study adopted a within subject experimental design, where 36 subjects (representing three age-groups and both sexes) were exposed to a randomized order of 312 real-life images (objects, interiors, exteriors, landscape, and a set of control images). Amygdala activation was simultaneously captured using functional magnetic resonance imaging technology. Subjects' preference (like/dislike) data were also collected while in the scanner. Data were collected in 2013. RESULTS: In case of images depicting landscape and healthcare objects, brain scans show significant higher amygdala activation associated with sharp contours. However, in relation to images depicting hospital interiors and exterior envelops, brain scans show significant higher amygdala activation associated with curve contours. These activations pertain to exposure during the precognitive stages of the subjects' perception. CONCLUSION: Hospital forms do have systematic impact on fear response during precognitive stages of human perception. Whether this first impression colors the subsequent experience of an actual patient with real illness or injury is unknown. PMID- 26747840 TI - Design to Improve Visibility: Impact of Corridor Width and Unit Shape. AB - OBJECTIVE: This study analyzes 10 intensive care units (ICUs) to understand the associations between design features of space layout and nurse-to-patient visibility parameters. BACKGROUND: Previous studies have explored how different hospital units vary in their visibility relations and how such varied visibility relations result in different nurse behaviors toward patients. However, more limited research has examined the specific design attributes of the layouts that determine the varied visibility relations in the unit. Changes in size, geometry, or other attributes of design elements in nursing units, which might affect patient observation opportunities, require more research. METHODS: This article reviews the literature to indicate evidence for the impact of hospital unit design on nurse/patient visibility relations and to identify design parameters shown to affect visibility. It further focuses on 10 ICUs to investigate how different layouts diverge regarding their visibility relations using a set of metrics developed by other researchers. Shape geometry and corridor width, as two selected design features, are compared. RESULTS: Corridor width and shape characteristics of ICUs are positively correlated with visibility. Results suggest that floor plans, which are repeatedly broken down into smaller convex (higher convex fragmentation values), or units, which have longer distances between their rooms or between their two opposite ends (longer relative grid distances), might have lower visibility levels across the unit. The findings of this study also suggest that wider corridors positively affect visibility of patient rooms. CONCLUSION: Changes in overall shape configuration and corridor width of nursing units may have important effects on patient observation and monitoring opportunities. PMID- 26747841 TI - Toward a Safer and Cleaner Way: Dealing With Human Waste in Healthcare. AB - Organizations must evaluate their infection control plans in a holistic and inclusive manner to continue reducing healthcare-associated infection (HAI) rates, including giving consideration to the manner of collecting and disposing of patient waste. Manual washing of bedpans and other containers poses a risk of spreading infection via caregivers, the environment, and the still-contaminated bedpan. Several alternative disposal methods are available and have been tested in some countries for decades, including options such as bedpan washer disinfector machines, macerator machines, and disposable bedpans. This article reviews methods and issues related to human waste disposal in healthcare settings. Healthcare organizations must evaluate the options thoroughly and then consistently implement the option most in line with its goals and culture. PMID- 26747842 TI - Space Syntax Analysis: Tools for Augmenting the Precision of Healthcare Facility Spatial Analysis. AB - AIM: This article reviews and addresses various spatial measures that provide and facilitate accurate descriptions of different layout typologies with particular focus on healthcare facilities. BACKGROUND: Evidence-based design is a field of study that emphasizes the importance of using credible data in order to influence the design process. It addresses whether/how the design and operation of buildings support positive health outcomes through a growing collection of solutions informed by research and practical knowledge. In order to acquire this knowledge, we must consider the environment in a very precise and measurable way, which can then be investigated quantitatively with regard to various human behaviors and cognitive processes. TOPICAL HEADINGS: Space Syntax theory and methods are concerned with understanding how spaces are arranged and connected to one another. It provides quantitative measures of individual spaces and of the entire layout, thereby achieving great accuracy. Space Syntax researchers have used graph theory to define spatial measures and have produced computer tools to quantify the relational properties of spaces and to provide numerical and display values for each. Moreover, they have developed more precise tools that can be embedded within basic Space Syntax concepts in order to augment the credibility of the acquired data. CONCLUSION: The study elaborates on the effectiveness of Space Syntax and its newly developed measures for the field of healthcare facility design and research. We present a comprehensive model that brings together these measures with their correlated behavioral and perceptual consequences, thereby providing a point of departure for further investigation and exploration. PMID- 26747843 TI - Predicting the genetic consequences of future climate change: The power of coupling spatial demography, the coalescent, and historical landscape changes. AB - PREMISE OF THE STUDY: Climate change is a widely accepted threat to biodiversity. Species distribution models (SDMs) are used to forecast whether and how species distributions may track these changes. Yet, SDMs generally fail to account for genetic and demographic processes, limiting population-level inferences. We still do not understand how predicted environmental shifts will impact the spatial distribution of genetic diversity within taxa. METHODS: We propose a novel method that predicts spatially explicit genetic and demographic landscapes of populations under future climatic conditions. We use carefully parameterized SDMs as estimates of the spatial distribution of suitable habitats and landscape dispersal permeability under present-day, past, and future conditions. We use empirical genetic data and approximate Bayesian computation to estimate unknown demographic parameters. Finally, we employ these parameters to simulate realistic and complex models of responses to future environmental shifts. We contrast parameterized models under current and future landscapes to quantify the expected magnitude of change. KEY RESULTS: We implement this framework on neutral genetic data available from Penstemon deustus. Our results predict that future climate change will result in geographically widespread declines in genetic diversity in this species. The extent of reduction will heavily depend on the continuity of population networks and deme sizes. CONCLUSIONS: To our knowledge, this is the first study to provide spatially explicit predictions of within-species genetic diversity using climatic, demographic, and genetic data. Our approach accounts for climatic, geographic, and biological complexity. This framework is promising for understanding evolutionary consequences of climate change, and guiding conservation planning. PMID- 26747844 TI - How do general practitioners identify inflammatory arthritis? A cohort analysis of Dutch general practitioner electronic medical records. AB - OBJECTIVE: To examine the symptoms, signs and additional investigations that general practitioners (GPs) used in the process of diagnosing recent-onset inflammatory arthritis. Here, we assumed that the recorded information was crucial in the diagnostic process of arthritis. METHODS: A database including electronic medical records of 16 Dutch general practices with 44,350 patients was studied. Patients with an episode of RA and allied conditions according to the International Classification of Primary Care-1 code L88 (here summarized as inflammatory arthritis) in the period 2009-2013 were selected. Frequencies of symptoms, signs and performed additional investigations were evaluated and compared between referred and non-referred patients. RESULTS: A total of 126 patients were diagnosed with inflammatory arthritis. Information on symptom duration, symptom location, swelling, loss of function, redness and warmth were recorded in, respectively, 64, 90, 80, 52, 48 and 41% of patients. Information on morning stiffness, family history or the squeeze-test was provided in 20, 18 and 17% of patients. Symmetry, inflammatory type arthralgia and fist closure were not recorded. Acute phase reactants and auto-antibody tests were performed in 40-46% and 8-11%, respectively. Eighty-four patients (67%) were referred to secondary care. Symptoms located in the foot, morning stiffness, family history, myalgia, absence of redness and elevated acute phase reactants were associated with referral (all P < 0.05). CONCLUSION: GPs mainly used classical signs of inflammation to diagnose inflammatory arthritis. Other items that are regularly assessed in secondary care (morning stiffness, squeeze-test, family history) were infrequently recorded by GPs. PMID- 26747846 TI - Re: "The Influence of Screening For Precancerous Lesions on Family-Based Genetic Association Tests: An Example of Colorectal Polyps and Cancer". PMID- 26747847 TI - A PRACTICAL APPROACH TO PERFORM THE ISOTROPY TEST FOR EXTREMITY DOSEMETERS. AB - The requirements for determining extremity dosemeter performance have evolved over the past decade. In 2010, the Spanish Nuclear Safety Council (CSN) adopted a national protocol with performance requirements based on ISO 12794. Because of the lack of symmetry of ISO 4037-3 calibration phantoms, the isotropy test set up in the sagittal plane presented several challenges both for individual monitoring services and for calibration labs. This article proposes and validates a practical approach to reduce the number of irradiations. Results show that wrist and ring dosemeters in this study meet the ISO 12794 requirements for the isotropy test. However, additional studies would be needed to verify the newer IEC 62387 Standard. PMID- 26747845 TI - A Randomized Implementation Study of Trauma-Focused Cognitive Behavioral Therapy for Adjudicated Teens in Residential Treatment Facilities. AB - Adjudicated youth in residential treatment facilities (RTFs) have high rates of trauma exposure and post-traumatic stress disorder (PTSD). This study evaluated strategies for implementing trauma-focused cognitive behavioral therapy (TF-CBT) in RTF. Therapists (N = 129) treating adjudicated youth were randomized by RTF program (N = 18) to receive one of the two TF-CBT implementation strategies: (1) web-based TF-CBT training + consultation (W) or (2) W + 2 day live TF-CBT workshop + twice monthly phone consultation (W + L). Youth trauma screening and PTSD symptoms were assessed via online dashboard data entry using the University of California at Los Angeles PTSD Reaction Index. Youth depressive symptoms were assessed with the Mood and Feelings Questionnaire-Short Version. Outcomes were therapist screening; TF-CBT engagement, completion, and fidelity; and youth improvement in PTSD and depressive symptoms. The W + L condition resulted in significantly more therapists conducting trauma screening (p = .0005), completing treatment (p = .03), and completing TF-CBT with fidelity (p = .001) than the W condition. Therapist licensure significantly impacted several outcomes. Adjudicated RTF youth receiving TF-CBT across conditions experienced statistically and clinically significant improvement in PTSD (p = .001) and depressive (p = .018) symptoms. W + L is generally superior to W for implementing TF-CBT in RTF. TF-CBT is effective for improving trauma-related symptoms in adjudicated RTF youth. Implementation barriers are discussed. PMID- 26747848 TI - Defect Characteristics of Reverse Hill-Sachs Lesions. AB - BACKGROUND: Little scientific evidence regarding reverse Hill-Sachs lesions (RHSLs) in posterior shoulder instability exists. Recently, standardized measurement methods of the size and localization were introduced, and the biomechanical effect of the extent and position of the defects on the risk of re engagement was determined. PURPOSE: To analyze the characteristics and patterns of RHSLs in a large case series using standardized measurements and to interpret the results based on the newly available biomechanical findings. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: In this multicenter study, 102 cases of RHSLs in 99 patients were collected from 7 different shoulder centers between 2004 and 2013. Patient- as well as injury-specific information was gathered, and defect characteristics in terms of the size, localization, and depth index were determined on computed tomography or magnetic resonance imaging scans by means of standardized measurements. Additionally, the position (gamma angle) of the posterior defect margin as a predictor of re-engagement was analyzed. RESULTS: Three types of an RHSL were distinguished based on the pathogenesis and chronicity of the lesion: dislocation (D), locked dislocation (LD), and chronic locked dislocation (CLD). While the localization of the defects did not vary significantly between the subgroups (P = .072), their mean size differed signficantly (D: 32.6 degrees +/- 11.7 degrees , LD: 49.4 degrees +/- 17.2 degrees , CLD: 64.1 degrees +/- 20.7 degrees ; P < .001). The mean gamma angle as a predictor of re-engagement was similarly significantly different between groups (D: 83.8 degrees +/- 14.5 degrees , LD: 96.5 degrees +/- 17.9 degrees , CLD: 108.7 degrees +/- 18.4 degrees ; P < .001). The orientation of the posterior defect margin was consistently quite parallel to the humeral shaft axis, with a mean difference of 0.3 degrees +/- 8.1 degrees . CONCLUSION: The distinction between the 3 different RHSL types based on the pathogenesis and chronicity of the defect helps identify defects prone to re-engagement. The gamma angle as a measurement of the position of the posterior defect margin and therefore a predictor of re-engagement varies significantly between the defect types. PMID- 26747849 TI - Bivalirudin Is Associated With Improved In-Hospital Outcomes Compared With Heparin in Percutaneous Vascular Interventions: Observational, Propensity-Matched Analysis From the Premier Hospital Database. AB - BACKGROUND: Peripheral vascular interventions are increasingly preferred for the treatment of patients with symptomatic peripheral arterial disease because they are associated with similar clinical outcomes and lower morbidity than open surgical procedures. The objective of this study was to assess the comparative effectiveness of procedural anticoagulation with bivalirudin compared with unfractionated heparin in patients undergoing peripheral vascular interventions. METHODS AND RESULTS: This was a retrospective, observational study using the Premier Hospital administrative database. We examined 23,934 consecutive patients undergoing lower extremity peripheral vascular interventions between January 2008 and December 2012 who were treated with either bivalirudin or unfractionated heparin. In-hospital end points included death, myocardial infarction, transfusion, stroke, amputation, and the composite end points of major adverse cardiovascular events, and net adverse clinical events. Propensity score matching was performed to control for baseline imbalances and yielded 3649 matched pairs. After propensity score matching, patients treated with bivalirudin had lower in hospital event rates with significantly lower mortality (odds ratio, 0.40; P=0.017), need for blood product transfusion (odds ratio, 0.74; P=0.009), major adverse cardiovascular events (odds ratio, 0.64; P=0.003), and net adverse clinical events (odds ratio, 0.72; P<0.001). These associations were observed consistently across clinically relevant subgroups. CONCLUSIONS: In patients undergoing peripheral vascular interventions, procedural anticoagulation with bivalirudin may result in more favorable in-hospital outcomes compared with unfractionated heparin, the current standard of care. These observations will require prospective confirmation in a randomized, controlled trial. PMID- 26747851 TI - Will Bivalirudin Have an Impact in Peripheral Vascular Interventions? PMID- 26747852 TI - Widespread synaptic loss in multiple sclerosis. PMID- 26747850 TI - Safety and Efficacy of New-Generation Drug-Eluting Stents in Women at High Risk for Atherothrombosis: From the Women in Innovation and Drug-Eluting Stents Collaborative Patient-Level Pooled Analysis. AB - BACKGROUND: The safety and efficacy of new-generation drug-eluting stents (DES) in women with multiple atherothrombotic risk (ATR) factors is unclear. METHODS AND RESULTS: We pooled patient-level data for women enrolled in 26 randomized trials. Study population was categorized based on the presence or absence of high ATR, which was defined as having history of diabetes mellitus, prior percutaneous or surgical coronary revascularization, or prior myocardial infarction. The primary end point was major adverse cardiovascular events defined as a composite of all-cause mortality, myocardial infarction, or target lesion revascularization at 3 years of follow-up. Out of 10,449 women included in the pooled database, 5333 (51%) were at high ATR. Compared with women not at high ATR, those at high ATR had significantly higher risk of major adverse cardiovascular events (15.8% versus 10.6%; adjusted hazard ratio: 1.53; 95% confidence interval: 1.34-1.75; P=0.006) and all-cause mortality. In high-ATR risk women, the use of new generation DES was associated with significantly lower risk of 3-year major adverse cardiovascular events (adjusted hazard ratio: 0.69; 95% confidence interval: 0.52-0.92) compared with early-generation DES. The benefit of new generation DES on major adverse cardiovascular events was uniform between high ATR and non-high-ATR women, without evidence of interaction (Pinteraction=0.14). At landmark analysis, in high-ATR women, stent thrombosis rates were comparable between DES generations in the first year, whereas between 1 and 3 years, stent thrombosis risk was lower with new-generation devices. CONCLUSIONS: Use of new generation DES even in women at high ATR is associated with a benefit consistent over 3 years of follow-up and a substantial improvement in very-late thrombotic safety. PMID- 26747854 TI - What lies beneath grey matter atrophy in multiple sclerosis? PMID- 26747853 TI - Cerebellar damage limits reinforcement learning. PMID- 26747855 TI - Altered intra- and inter-network dynamics reflect symptom dimensions in childhood onset schizophrenia. PMID- 26747856 TI - Corrigendum. PMID- 26747857 TI - Estimating Field Densities of Haematobia irritans (Diptera: Muscidae) Using Direct Visual Field Counts Versus Photographic Assessments. AB - Horn flies, Haematobia irritans (L.), were photographed on cattle and then immediately estimated visually in the field on pastured beef cattle in southern California. Horn flies were counted in the pictures later on a computer screen. For 479 counts on individual cattle, the concordance correlation coefficient between the visual and photo-based assessments was 0.790, but was better for the higher half of the counts (0.732) than for the lower half of the counts (0.217). Major axis regression indicated that visual estimates were consistently higher than the number of flies counted in the pictures across the entire density range. Based on average raw means, the visual estimates averaged 21% higher than the photo counts. Visual estimates included flies on the belly and lower legs that could not be seen in a photo, and lower densities may have been more susceptible to such error. Where flies can be seen well, e.g. for very tame animals, the visual estimates were much faster and more cost-efficient and were sufficient to track relative horn fly abundance changes. PMID- 26747858 TI - Knockdown Resistance (kdr) Mutations in Indian Anopheles stephensi (Diptera: Culicidae) Populations. AB - Knockdown resistance (kdr) in insects resulting from mutation(s) in the voltage gated sodium channel (VGSC) gene is one of the mechanisms of resistance against DDT and the pyrethroid group of insecticides. Earlier, we reported the presence of two classic kdr mutations, i.e., L1014F and L1014S in Anopheles stephensi Liston, a major Indian malaria vector affecting mainly urban areas. This report presents the distribution of these alleles in different An. stephensi populations. Seven populations of An. stephensi from six states of India were screened for the presence of two alternative kdr mutations L1014F and L1014S using allele-specific polymerase chain reaction assays. We recorded the presence of both kdr mutations in northern Indian populations (Alwar and Gurgaon), with the preponderance of L1014S, whereas only L1014F was present in Raipur (central India) and Chennai (southern India). None of the kdr mutations were found in Ranchi in eastern India and in Mangaluru and Mysuru in southern India. This study provides evidence for a focal pattern of distribution of kdr alleles in India. PMID- 26747859 TI - Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma. AB - BACKGROUND: The phase III RAINBOW trial demonstrated that the addition of ramucirumab to paclitaxel improved overall survival, progression-free survival, and tumor response rate in fluoropyrimidine-platinum previously treated patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. Here, we present results from quality-of-life (QoL) and performance status (PS) analyses. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group PS of 0/1 were randomized to receive ramucirumab (8 mg/kg i.v.) or placebo on days 1 and 15 of a 4-week cycle, with both arms receiving paclitaxel (80 mg/m(2)) on days 1, 8, and 15. Patient-reported outcomes were assessed with the QoL/health status questionnaires EORTC QLQ-C30 and EQ-5D at baseline and 6-week intervals. PS was assessed at baseline and day 1 of every cycle. Time to deterioration (TtD) in each QLQ-C30 scale was defined as randomization to first worsening of >=10 points (on 100-point scale) and TtD in PS was defined as first worsening to >=2. Hazard ratios (HRs) for treatment effect were estimated using stratified Cox proportional hazards models. RESULTS: Of the 665 patients randomized, 650 (98%) provided baseline QLQ-C30 and EQ-5D data, and 560 (84%) also provided data from >=1 postbaseline time point. Baseline scores for both instruments were similar between arms. Of the 15 QLQ-C30 scales, 14 had HR < 1, indicating similar or longer TtD in QoL for ramucirumab + paclitaxel. Treatment with ramucirumab + paclitaxel was also associated with a delay in TtD in PS to >=2 (HR = 0.798, P = 0.0941). Alternate definitions of PS deterioration yielded similar results: PS >= 3 (HR = 0.656, P = 0.0508), deterioration by >=1 PS level (HR = 0.802, P = 0.0444), and deterioration by >=2 PS levels (HR = 0.608, P = 0.0063). EQ-5D scores were comparable between treatment arms, stable during treatment, and worsened at discontinuation. CONCLUSION: In patients with previously treated advanced gastric/GEJ adenocarcinoma, addition of ramucirumab to paclitaxel prolonged overall survival while maintaining patient QoL with delayed symptom worsening and functional status deterioration. CLINICALTRIALSGOV: NCT01170663. PMID- 26747860 TI - Induction Therapy With Antithymocyte Globulin in Patients Undergoing Cardiac Transplantation Is Associated With Decreased Coronary Plaque Progression as Assessed by Intravascular Ultrasound. AB - BACKGROUND: Antithymocyte globulin (ATG) is used as induction therapy after cardiac transplant for enhancing immunosuppression and delaying the initiation of nephrotoxic drugs. It is unknown if ATG induction is associated with decreased coronary plaque progression by intravascular ultrasound (IVUS). METHODS AND RESULTS: Patients transplanted between March 2010 and December 2012 with baseline and 1-year IVUS were included. All patients transplanted were included in a secondary analysis. Change in plaque progression was measured in a blinded fashion on matched coronary segments and contrasted between patients induced with ATG and those who were not. One hundred and three patients were included in IVUS arms. Mean age at transplant was 55.8 +/- 12.6 years, and 33.0% were female. Patients induced with ATG were more sensitized (54.3% versus 14.3%). Plaque progression was attenuated in patients who received ATG by changes in maximal intimal area (1.0 +/- 1.2 versus 2.3 +/- 2.6 mm(2); P = 0.001), maximal percent stenosis (6.3 +/- 7.9 versus 12.8 +/- 12.3%; = 0.003), maximal intimal thickness (0.2 +/- 0.2 versus 0.3 +/- 0.3 mm; P = 0.035), and plaque volume (0.5 +/- 0.7 versus 1.0 +/- 1.3 mm(3)/mm; P = 0.016). Rapid plaque progression by maximal percent stenosis (>= 20%) occurred less frequently in the ATG arm (4.3% versus 26.3; P = 0.003). Survival (P = 0.242) and any treated rejection (P = 0.166) were not statistically different between groups. Patients receiving ATG had a higher rate of first-year infection (P = 0.003), perhaps related to increased intravenous antibiotic use immediately postoperatively, and a trend toward more biopsy-proven rejection (P = 0.073). CONCLUSIONS: Induction therapy with ATG is associated with reduced first-year coronary plaque progression as assessed by IVUS, despite an increased prevalence of sensitized patients with a trend toward more rejection. PMID- 26747861 TI - Cancer Therapy-Related Cardiac Dysfunction and Heart Failure: Part 1: Definitions, Pathophysiology, Risk Factors, and Imaging. AB - Advances in cancer therapy have resulted in significant improvement in long-term survival for many types of cancer but have also resulted in untoward side effects associated with treatment. One such complication that has become increasingly recognized is the development of cardiomyopathy and heart failure. Whether a previously healthy person from a cardiovascular perspective develops cancer therapy-related cardiac dysfunction or a high-risk cardiovascular patient requires cancer therapy, the team of oncologists and cardiologists must be better equipped with an evidence-based approach to care for these patients across the spectrum. Although the toxicities associated with various cancer therapies are well recognized, limitations to our understanding of the appropriate course of action remain. In this first of a 2-part review, we discuss the epidemiologic, pathophysiologic, risk factors, and imaging aspects of cancer therapy-related cardiac dysfunction and heart failure. In a subsequent second part, we discuss the prevention and treatment aspects, concluding with a section on evidence gap and future directions. We focus on adult patients in all stages of cancer therapy from pretreatment surveillance, to ongoing therapy, and long-term follow-up. PMID- 26747864 TI - Ultrasound standard of peripheral nerve block for shoulder arthroscopy: a single penetration double-injection approach targeting the superior trunk and supraclavicular nerve in the lateral decubitus position. PMID- 26747863 TI - Chromosomal microarray testing identifies a 4p terminal region associated with seizures in Wolf-Hirschhorn syndrome. AB - BACKGROUND: Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion syndrome involving variable size deletions of the 4p16.3 region. Seizures are frequently, but not always, associated with WHS. We hypothesised that the size and location of the deleted region may correlate with seizure presentation. METHODS: Using chromosomal microarray analysis, we finely mapped the breakpoints of copy number variants (CNVs) in 48 individuals with WHS. Seizure phenotype data were collected through parent-reported answers to a comprehensive questionnaire and supplemented with available medical records. RESULTS: We observed a significant correlation between the presence of an interstitial 4p deletion and lack of a seizure phenotype (Fisher's exact test p=3.59e-6). In our cohort, there were five individuals with interstitial deletions with a distal breakpoint at least 751 kbp proximal to the 4p terminus. Four of these individuals have never had an observable seizure, and the fifth individual had a single febrile seizure at the age of 1.5 years. All other individuals in our cohort whose deletions encompass the terminal 751 kbp region report having seizures typical of WHS. Additional examples from the literature corroborate these observations and further refine the candidate seizure susceptibility region to a region 197 kbp in size, starting 368 kbp from the terminus of chromosome 4. CONCLUSIONS: We identify a small terminal region of chromosome 4p that represents a seizure susceptibility region. Deletion of this region in the context of WHS is sufficient for seizure occurrence. PMID- 26747862 TI - Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology. AB - The proliferation and activation of microglial cells is a hallmark of several neurodegenerative conditions. This mechanism is regulated by the activation of the colony-stimulating factor 1 receptor (CSF1R), thus providing a target that may prevent the progression of conditions such as Alzheimer's disease. However, the study of microglial proliferation in Alzheimer's disease and validation of the efficacy of CSF1R-inhibiting strategies have not yet been reported. In this study we found increased proliferation of microglial cells in human Alzheimer's disease, in line with an increased upregulation of the CSF1R-dependent pro mitogenic cascade, correlating with disease severity. Using a transgenic model of Alzheimer's-like pathology (APPswe, PSEN1dE9; APP/PS1 mice) we define a CSF1R dependent progressive increase in microglial proliferation, in the proximity of amyloid-beta plaques. Prolonged inhibition of CSF1R in APP/PS1 mice by an orally available tyrosine kinase inhibitor (GW2580) resulted in the blockade of microglial proliferation and the shifting of the microglial inflammatory profile to an anti-inflammatory phenotype. Pharmacological targeting of CSF1R in APP/PS1 mice resulted in an improved performance in memory and behavioural tasks and a prevention of synaptic degeneration, although these changes were not correlated with a change in the number of amyloid-beta plaques. Our results provide the first proof of the efficacy of CSF1R inhibition in models of Alzheimer's disease, and validate the application of a therapeutic strategy aimed at modifying CSF1R activation as a promising approach to tackle microglial activation and the progression of Alzheimer's disease. PMID- 26747872 TI - More data needed on hysteroscopic compared with laparoscopic sterilisation. PMID- 26747873 TI - Best evidence supports topical corticosteroids and routine saline irrigations for medical treatment of chronic rhinosinusitis. PMID- 26747866 TI - The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders. AB - The deleterious effects of a disrupted copper metabolism are illustrated by hereditary diseases caused by mutations in the genes coding for the copper transporters ATP7A and ATP7B. Menkes disease, involving ATP7A, is a fatal neurodegenerative disorder of copper deficiency. Mutations in ATP7B lead to Wilson disease, which is characterized by a predominantly hepatic copper accumulation. The low incidence and the phenotypic variability of human copper toxicosis hamper identification of causal genes or modifier genes involved in the disease pathogenesis. The Labrador retriever was recently characterized as a new canine model for copper toxicosis. Purebred dogs have reduced genetic variability, which facilitates identification of genes involved in complex heritable traits that might influence phenotype in both humans and dogs. We performed a genome-wide association study in 235 Labrador retrievers and identified two chromosome regions containing ATP7A and ATP7B that were associated with variation in hepatic copper levels. DNA sequence analysis identified missense mutations in each gene. The amino acid substitution ATP7B:p.Arg1453Gln was associated with copper accumulation, whereas the amino acid substitution ATP7A:p.Thr327Ile partly protected against copper accumulation. Confocal microscopy indicated that aberrant copper metabolism upon expression of the ATP7B variant occurred because of mis-localization of the protein in the endoplasmic reticulum. Dermal fibroblasts derived from ATP7A:p.Thr327Ile dogs showed copper accumulation and delayed excretion. We identified the Labrador retriever as the first natural, non-rodent model for ATP7B-associated copper toxicosis. Attenuation of copper accumulation by the ATP7A mutation sheds an interesting light on the interplay of copper transporters in body copper homeostasis and warrants a thorough investigation of ATP7A as a modifier gene in copper metabolism disorders. The identification of two new functional variants in ATP7A and ATP7B contributes to the biological understanding of protein function, with relevance for future development of therapy. PMID- 26747874 TI - Health promotion coaching for obese individuals with serious mental illnesses produces clinically significant reductions in cardiovascular risks up to 18 months. PMID- 26747865 TI - The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders. AB - Congenital diarrheal disorders are rare, often fatal, diseases that are difficult to diagnose (often requiring biopsies) and that manifest in the first few weeks of life as chronic diarrhea and the malabsorption of nutrients. The etiology of congenital diarrheal disorders is diverse, but several are associated with defects in the predominant intestinal epithelial cell type, enterocytes. These particular congenital diarrheal disorders (CDD(ENT)) include microvillus inclusion disease and congenital tufting enteropathy, and can feature in other diseases, such as hemophagocytic lymphohistiocytosis type 5 and trichohepatoenteric syndrome. Treatment options for most of these disorders are limited and an improved understanding of their molecular bases could help to drive the development of better therapies. Recently, mutations in genes that are involved in normal intestinal epithelial physiology have been associated with different CDD(ENT). Here, we review recent progress in understanding the cellular mechanisms of CDD(ENT). We highlight the potential of animal models and patient specific stem-cell-based organoid cultures, as well as patient registries, to integrate basic and clinical research, with the aim of clarifying the pathogenesis of CDD(ENT) and expediting the discovery of novel therapeutic strategies. PMID- 26747875 TI - Prevalence of dural venous sinus stenosis and hypoplasia in a generalized population. AB - BACKGROUND AND PURPOSE: While recent literature has described the prevalence of transverse sinus stenosis in patients with idiopathic intracranial hypertension, tinnitus, and refractory headaches, it is unclear what the prevalence is in the general population. This study evaluates the prevalence of venous sinus stenosis and hypoplasia in the general patient population. MATERIALS AND METHODS: 355 of 600 consecutive patients who underwent CT angiography of the head met the inclusion criteria. The diameters of the dural venous sinuses were recorded. Each study was evaluated by a neuroradiologist for the presence of stenoses. Univariate and multivariate statistical analyses were performed by a statistician. RESULTS: The prevalence of unilateral transverse sinus stenosis or hypoplasia in a sample of patients representing the general population was 33%, the prevalence of bilateral transverse sinus stenosis was 5%, and the prevalence of unilateral stenosis with contralateral hypoplasia was 1%. A multivariate analysis identified arachnoid granulations as a predictor of stenosis (p<0.001). Gender trended toward significance (p=0.094). Race was not a significant predictor of stenosis (p=0.745). CONCLUSIONS: The prevalence of bilateral transverse sinus stenosis in the general population is not trivial. These data may be used as a reference for understanding the mechanistic role of stenoses in idiopathic intracranial hypertension, tinnitus, and refractory headaches. PMID- 26747876 TI - The safety and efficacy of low profile visualized intraluminal support (LVIS) stents in assisting coil embolization of intracranial saccular aneurysms: a single center experience. AB - BACKGROUND: The low profile visualized intraluminal support (LVIS) device is a new generation of self-expanding braided stents recently introduced into China for stent assisted coiling of intracranial aneurysms. This study assessed the clinical safety and efficacy of the LVIS stent for embolization of intracranial saccular aneurysms. METHODS: Patients with intracranial saccular aneurysms treated using the LVIS device in our center between April 2014 and December 2014 were reviewed. The primary outcomes were procedural safety, target aneurysm recurrence, and mid-term follow-up of clinical and angiographic outcomes. RESULTS: 97 patients with intracranial saccular aneurysms were treated using the LVIS stent, with 100% technical success rate. No mortality was observed. One patient had transient deficit (1/97, 1.0%). Immediate angiographic outcome evaluation showed complete occlusion in 28 (28.8%) and neck remnant in 39 (40.2%) of the 97 patients, respectively. Of the 76 (78.35%) patients who underwent angiographic follow-up at a mean of 8.1 months, complete occlusion was achieved in 64 (84.2%) patients. In the remaining patients, neck remnant in nine (11.8%) and residual sac in three (4%) patients were observed. None of the patients had any target aneurysm recurrence, and the mortality rate was 0%. CONCLUSIONS: The LVIS stent is safe and effective in the treatment of intracranial saccular aneurysms. PMID- 26747877 TI - Silent ischemic events after Pipeline embolization device: a prospective evaluation with MR diffusion-weighted imaging. AB - BACKGROUND: The development of ischemic events is relatively common after endovascular interventions, and flow diverters may pose a particular threat owing to their increased technical complexity and high metal content. OBJECTIVE: To investigate the incidence and potential risk factors for thromboembolic lesions after treatment with a Pipeline embolization device (PED). METHODS: This prospective study included a total of 59 patients electively treated with a PED over 12 months. Postprocedural diffusion-weighted imaging sequences of the brain were obtained 24 h after interventions to detect ischemic lesions. Demographic data, aneurysm characteristics, antiplatelet management, and perioperative data were correlated with the rate of ischemic events. RESULTS: The incidence of silent ischemic events after use of a PED was 62.7% (37 patients) and neurological symptoms occurred in 8.1% of affected patients. Development of ischemic events was significantly associated with older patients (>=60 years; p=0.038). Routine use of platelet function assays and newer P2Y12 receptor inhibitors (ticagrelor) were not associated with fewer thromboembolic events. CONCLUSIONS: Thromboembolic events are relatively common after treatment with a PED with an incidence comparable to stent-assisted and conventional coiling but the risk of neurological morbidity from ischemic burden is low. Older patients are at particularly increased risk of thromboembolic events. PMID- 26747878 TI - The impact of evidence: evolving therapy for acute ischemic stroke in a large healthcare system. AB - BACKGROUND: With a recent surge of clinical trials, the treatment of ischemic stroke has undergone dramatic changes. OBJECTIVE: To evaluate the impact of evidence and a revamped stroke protocol on a large healthcare system. METHODS: A retrospective review of 69 patients with ischemic stroke treated with intra arterial therapy was carried out. Cohort 1 included patients treated before implementation of a new stroke protocol, and cohort 2 after implementation. Angiographic outcome was graded using the Thrombolysis in Cerebral Infarction (TICI) score. Clinical outcomes were assessed using the National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS). RESULTS: Primary outcomes comparing cohorts demonstrated decreased arrival-to-puncture time (cohort 2: 104 vs cohort 1: 181 min, p<0.001), similar TICI 2b/3 rates (86.5% vs 81.3%, p=0.5530), and similar percentage of patients with discharge mRS 0-2 (18.9% vs 21.9%, p=0.7740). Notable secondary outcomes for cohort 2 included decreased puncture-to-first pass time (34 vs 53 min, p <0.001), increased TICI 3 rates (37.8% vs 18.8%, p=0.0290), a trend toward greater improvements in NIHSS on postoperative day 1 (6.8 vs 2.6, p=0.0980) and discharge (9.5 vs 6.7, p=0.1130), and a trend toward increased percentage of patients discharged with mRS 0-3 (48.6% vs 34.4%, p=0.3280 NS). There were similar rates of symptomatic intracerebral hemorrhage (10.8% vs 9.4%, p=0.9570) and death (10.8% vs 15.6%, p=0.5530). CONCLUSIONS: An interdisciplinary and rapid response to the emergence of strong clinical evidence can result in dramatic changes in a large healthcare system. PMID- 26747879 TI - Absence of LRRK2 mutations in a cohort of patients with idiopathic REM sleep behavior disorder. PMID- 26747880 TI - Orthostatic tremor: Clinical, electrophysiologic, and treatment findings in 184 patients. AB - OBJECTIVE: To evaluate the clinical, electrophysiologic, and treatment outcome features of orthostatic tremor (OT) in a large case series. METHODS: We performed medical record review of 184 patients who met clinical and electrodiagnostic criteria for OT from 1976 to 2013 at the Mayo Clinic. Demographic, clinical, electrophysiologic, and treatment data were extracted. RESULTS: The majority of OT cases were female (63.6%) and mean age at onset was 59.3 years (range 13-85 years). Diagnosis was delayed by a mean of 7.2 years (range 0-44 years). The average tremor frequency was 15.7 Hz (range 12.5-20 Hz), and transmitted to the arms on weight-bearing (95.5%). Patients reported a spectrum of progressive orthostatic leg symptoms, relieved by sitting or leaning. Falls were reported in 24.1%. Coexistent neurologic disorders included essential tremor (22.8%), other tremor (4.9%), and parkinsonism (8.7%). Family history of OT was noted in 4.9%. Of 46 medications trialed, 24 failed to provide any benefit. Benzodiazepines provided at least mild benefit in 55.9%, and moderate to marked benefit in 31.5%; beta-blockers (31.0%) and anticonvulsants (25.0%) provided mild benefit, and the remainder were largely ineffective. Medication benefit waned over time. Deep brain stimulation (DBS) was effective in 2 cases. CONCLUSION: OT predominantly affects female seniors, and the diagnosis should be considered with any orthostatic-induced leg symptoms, and confirmed by surface EMG. Benzodiazepines are the most efficacious treatment, followed by beta-blockers and anticonvulsants. DBS should be further explored for treatment. PMID- 26747882 TI - Real-time effects of centrotemporal spikes on cognition in rolandic epilepsy: An EEG-fMRI study. AB - OBJECTIVE: To identify the real-time effects of interictal rolandic spikes (or centrotemporal spikes [CTS]) on language, behavior, and cognitive function in patients with rolandic epilepsy (RE). METHODS: We studied 22 medication-naive patients with RE using EEG-fMRI with a 3T MRI scanner. We used simultaneous EEG to define the pre-CTS, CTS, and post-CTS periods. We analyzed the dynamic functional connectivity maps of the rolandic network during the 3 interictal CTS periods. RESULTS: The analysis of dynamic changes revealed positive correlations between the bilateral rolandic areas and the left inferior frontal gyrus (IFG; Broca area), the left inferior parietal lobe and the supramarginal gyrus (areas responsible for receptive language function), and the right IFG and left caudate. Anti-correlations were found in the default mode network (bilateral superior frontal gyrus, left middle frontal gyrus, left middle temporal gyrus, and right precuneus). CONCLUSIONS: Interictal CTS directly disrupts the functional brain networks responsible for language, behavior, and cognition in children with typical RE. It is important to suppress discharges to reduce the risk of neuropsychological impairments in children with RE. PMID- 26747883 TI - Stroke risk with symptomatic carotid stenosis: The future is not what it used to be. PMID- 26747884 TI - Sodium channel Nav1.8: Emerging links to human disease. AB - The NaV1.8 sodium channel, encoded by gene SCN10A, was initially termed sensory neuron-specific (SNS) due to prominent expression in primary sensory neurons including dorsal root ganglion (DRG) neurons. Early studies on rodent NaV1.8 demonstrated depolarized voltage dependence of channel inactivation, a slow rate of inactivation, and rapid recovery from inactivation. As a result of these biophysical properties, NaV1.8 supports repetitive firing in response to sustained depolarization. This article reviews recent studies that reveal multiple links of NaV1.8 to human disease: (1) It has recently been shown that functional attributes that distinguish NaV1.8 from other sodium channel subtypes are exaggerated in human NaV1.8; its influence on neuronal activity is thus greater than previously thought. (2) Gain-of-function mutations of NaV1.8 that produce DRG neuron hyperexcitability have been found in 3% of patients with painful neuropathy, establishing a role in pathogenesis. (3) NaV1.8 is ectopically expressed within Purkinje neurons in multiple sclerosis (MS), where it perturbs electrical activity. Recent evidence indicates that variants of SCN10A predict the degree of cerebellar dysfunction in MS. (4) Emerging evidence has linked SCN10A variants to disorders of cardiac rhythm, via mechanisms that may include an effect on cardiac innervation. Involvement of NaV1.8 in neurologic disease may have therapeutic implications. NaV1.8-specific blocking agents, under development, ameliorate pain and attenuate MS-like deficits in animal models. Recent studies suggest that pharmacogenomics may permit the matching of specific channel blocking agents to particular patients. The new links of NaV1.8 in human disease raise new questions, but also suggest new therapeutic strategies. PMID- 26747885 TI - Recurrent stroke in symptomatic carotid stenosis awaiting revascularization: A pooled analysis. AB - OBJECTIVE: We aimed to quantify the risk and predictors of ipsilateral ischemic stroke in patients with symptomatic carotid stenosis awaiting revascularization (carotid endarterectomy [CEA] or carotid artery stenting) by pooling individual patient data from recent prospective studies with high rates of treatment with modern stroke prevention medications. METHODS: Data were included from 2 prospective hospital-based registries (Umea, Barcelona) and one prospective population-based study (Dublin). Patients with symptomatic 50%-99% carotid stenosis eligible for carotid revascularization were included and followed for early recurrent ipsilateral stroke or retinal artery occlusion (RAO). RESULTS: Of 607 patients with symptomatic 50%-99% carotid stenosis, 377 met prespecified inclusion criteria. Ipsilateral recurrent ischemic stroke/RAO risk pre revascularization was 2.7% (1 day), 5.3% (3 days), 11.5% (14 days), and 18.8% (90 days). On bivariate analysis, presentation with a cerebral vs ocular event was associated with higher recurrent stroke risk (log-rank p = 0.04). On multivariable Cox regression, recurrence was associated with older age (adjusted hazard ratio [HR] per 10-year increase 1.5, p = 0.02) with a strong trend for association with cerebral (stroke/TIA) vs ocular symptoms (adjusted HR 2.7, p = 0.06), but not degree of stenosis, smoking, vascular risk factors, or medications. CONCLUSIONS: We found high risk of recurrent ipsilateral ischemic events within the 14-day time period currently recommended for CEA. Randomized trials are needed to determine the benefits and safety of urgent vs subacute carotid revascularization within 14 days after symptom onset. PMID- 26747886 TI - White matter hyperintensity patterns in cerebral amyloid angiopathy and hypertensive arteriopathy. AB - OBJECTIVE: To identify different white matter hyperintensity (WMH) patterns between 2 hemorrhage-prone cerebral small vessel diseases (SVD): cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA). METHODS: Consecutive patients with SVD-related intracerebral hemorrhage (ICH) from a single-center prospective cohort were analyzed. Four predefined subcortical WMH patterns were compared between the CAA and HA groups. These WMH patterns were (1) multiple subcortical spots; (2) peri-basal ganglia (BG); (3) large posterior subcortical patches; and (4) anterior subcortical patches. Their associations with other imaging (cerebral microbleeds [CMBs], enlarged perivascular spaces [EPVS]) and clinical markers of SVD were investigated using multivariable logistic regression. RESULTS: The cohort included 319 patients with CAA and 137 patients with HA. Multiple subcortical spots prevalence was higher in the CAA compared to the HA group (29.8% vs 16.8%; p = 0.004). Peri-BG WMH pattern was more common in the HA- vs the CAA-ICH group (19% vs 7.8%; p = 0.001). In multivariable logistic regression, presence of multiple subcortical spots was associated with lobar CMBs (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.01-1.50, p = 0.039) and high degree of centrum semiovale EPVS (OR 2.43; 95% CI 1.56-3.80, p < 0.0001). By contrast, age (OR 1.05; 95% CI 1.02-1.09, p = 0.002), deep CMBs (OR 2.46; 95% CI 1.44-4.20, p = 0.001), total WMH volume (OR 1.02; 95% CI 1.01-1.04, p = 0.002), and high BG EPVS degree (OR 8.81; 95% CI 3.37-23.02, p < 0.0001) were predictors of peri-BG WMH pattern. CONCLUSION: Different patterns of subcortical leukoaraiosis visually identified on MRI might provide insights into the dominant underlying microangiopathy type as well as mechanisms of tissue injury in patients with ICH. PMID- 26747888 TI - The Manual Work Instability Scale: development and validation. AB - BACKGROUND: Increasing awareness of the burden of absenteeism and reduced performance at work highlights the importance of early identification of individuals experiencing work instability (WI), a mismatch between functional and cognitive abilities and job demands. AIMS: To develop and validate a screening questionnaire to measure WI in manual workers. METHODS: Questionnaire items were generated via qualitative interviews with manual workers and a draft survey instrument was completed by workers in a variety of fields. Rasch analysis was used interactively to assess the psychometric aspects of the emerging scale, including unidimensionality and absence of item bias (differential item functioning). RESULTS: A total of 17 qualitative interviews generated 110 potential items for the questionnaire. The item set resolved to a 25-item scale, which satisfied model expectations (item residual mean = -0.13, SD = 1.04; person residual mean = -0.29, SD = 0.75), had good reliability (alpha = 0.86) and strict unidimensionality (t-test 7.5% confidence interval 3.8-11.2). CONCLUSIONS: The Manual Work Instability Scale is a short psychometrically robust questionnaire based on the concept of WI, which incorporates both musculoskeletal symptoms and relevant psychosocial factors. It may prove effective in screening and identifying WI in workers in predominantly physical occupations. PMID- 26747881 TI - Periventricular hyperintensities are associated with elevated cerebral amyloid. AB - OBJECTIVE: To investigate the association between periventricular white mater hyperintensities (PVWMH) and biomarkers of elevated cerebral beta-amyloid (Abeta) in the Alzheimer's Disease Neuroimaging Initiative, a large prospective multicenter observational study. METHODS: The burden of frontal, parietal, and occipital PVWMH on 3T fluid-attenuated inversion recovery MRI was evaluated in 698 cognitively normal participants and participants with mild cognitive impairment (MCI) using a novel semiquantitative visual rating scale. Results were correlated with CSF-Abeta, florbetapir-PET, and fluorodeoxyglucose (FDG)-PET. RESULTS: Increased burden of parietal, occipital, and frontal PVWMH was associated with elevated cerebral amyloid evidenced by high florbetapir-PET signal (p < 0.01) and low CSF-Abeta (p < 0.01). In logistic regression models, including PVWMH, age, sex, APOE status, vascular risk factors, pulse pressure, vascular secondary prevention medications, education, ethnicity, and race, parietal, occipital, and frontal PVWMH burden was independently associated with high florbetapir-PET uptake (p < 0.05). In a similar logistic regression model, parietal and occipital (p < 0.05) but not frontal (p = 0.05) PVWMH were independently associated with CSF-Abeta. Weaker associations were found between parieto-occipital PVWMH and elevated CSF-tau (p < 0.05) and occipital PVWMH and elevated CSF-phospho-tau (p < 0.05). PVWMH were associated with cerebral hypometabolism on FDG-PET independent of CSF-Abeta levels (p < 0.05). Absolute and consistency of agreement intraclass correlation coefficients were, respectively, 0.83 and 0.83 for frontal, 0.78 and 0.8 for parietal, and 0.45 and 0.75 for occipital PVWMH measurements. CONCLUSIONS: Increased PVWMH were associated with elevated cerebral amyloid independent of potential confounders such as age, APOE genotype, and vascular risk factors. The mechanisms underlying the association between PVWMH and cerebral amyloid remain to be clarified. PMID- 26747889 TI - Exogenous Nef is an inhibitor of Mycobacterium tuberculosis -induced tumor necrosis factor-alpha production and macrophage apoptosis. PMID- 26747892 TI - Tracking Down Response and Resistance to TRK Inhibitors. AB - Two recent studies validate the LMNA-NTRK1 fusion as an oncogenic driver and therapeutic target of TRK inhibitors. The LMNA-NTRK1 fusion occurs at low frequency across multiple tumor types. The studies highlight the increasing need to develop molecular biomarker-based clinical trials across cancer subtypes. PMID- 26747893 TI - Anticancer Teamwork: Cross-Presenting Dendritic Cells Collaborate with Therapeutic Monoclonal Antibodies. AB - Cross-presentation of tumor antigens represents a key pathway in antitumor immune responses that can be exploited to synergize not only with the already prominent "checkpoint blockade," but also with newer attempts to use T-cell stimulatory monoclonal antibodies in immunotherapy. PMID- 26747887 TI - Absorption, metabolism, and functions of beta-cryptoxanthin. AB - beta-Cryptoxanthin, a carotenoid found in fruits and vegetables such as tangerines, red peppers, and pumpkin, has several functions important for human health. Most evidence from observational, in vitro, animal model, and human studies suggests that beta-cryptoxanthin has relatively high bioavailability from its common food sources, to the extent that some beta-cryptoxanthin-rich foods might be equivalent to beta-carotene-rich foods as sources of retinol. beta Cryptoxanthin is an antioxidant in vitro and appears to be associated with decreased risk of some cancers and degenerative diseases. In addition, many in vitro, animal model, and human studies suggest that beta-cryptoxanthin-rich foods may have an anabolic effect on bone and, thus, may help delay osteoporosis. PMID- 26747894 TI - Targeting ALK: The Ten Lives of a Tumor. AB - In this issue, Infarinato and colleagues report the results of preclinical testing of a novel ALK/ROS1 inhibitor, PF-06463922, in neuroblastoma. This small molecule inhibitor was shown to efficiently inhibit the growth of patient-derived and established neuroblastoma xenograft models expressing mutated ALK. Although the in vivo data are impressive and the authors suggest that clinical trials are warranted, the presented data also suggest that it is as yet too early to welcome the new drug as a magic bullet. PMID- 26747895 TI - miR-892b Silencing Activates NF-kappaB and Promotes Aggressiveness in Breast Cancer. AB - The strength and duration of NF-kappaB signaling is tightly controlled at multiple levels under physiologic conditions, but the mechanism underlying constitutive activation of the NF-kappaB pathway in cancer remains unclear. In this study, we investigated miRNA-mediated regulation of the NF-kappaB cascade in breast cancer. We report that miR-892b expression was significantly downregulated in human breast cancer specimens and correlated with poor patient survival. Overexpression of miR-892b in breast cancer cells significantly decreased tumor growth, metastatic capacity, and the ability to induce angiogenesis, whereas miR 892b depletion enhanced these properties, in vitro and in vivo. Furthermore, we demonstrate that miR-892b attenuated NF-kappaB signaling by directly targeting and suppressing multiple mediators of NF-kappaB, including TRAF2, TAK1, and TAB3, and thus, miR-892b silencing in breast cancer cells sustains NF-kappaB activity. Moreover, miR-892b downregulation was attributed to aberrant hypermethylation of its promoter. Taken together, our results provide insight into a new mechanism by which NF-kappaB signaling becomes constitutively activated in breast cancer and suggest a tumor-suppressive role for miR-829b, prompting further investigation into miRNA mimics for cancer therapy. PMID- 26747898 TI - Repeatability of metabolic rate is lower for animals living under field versus laboratory conditions. AB - Metabolic rate has been linked to several components of fitness and is both heritable and repeatable to a certain extent. However, its repeatability can differ among studies, even after controlling for the time interval between measurements. Some of this variation in repeatability might be due to the relative stability of the environmental conditions in which the animals are living between measurements. We compared published repeatability estimates for basal, resting and maximum metabolic rate from studies of endotherms living in the laboratory with those living in the wild during the interval between measurements. We found that repeatability declines over time, as demonstrated previously, but show for the first time that estimates from free-living animals are also considerably lower than those from animals living under more stable laboratory conditions. PMID- 26747896 TI - PBX3 and MEIS1 Cooperate in Hematopoietic Cells to Drive Acute Myeloid Leukemias Characterized by a Core Transcriptome of the MLL-Rearranged Disease. AB - Overexpression of HOXA/MEIS1/PBX3 homeobox genes is the hallmark of mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML). HOXA9 and MEIS1 are considered to be the most critical targets of MLL fusions and their coexpression rapidly induces AML. MEIS1 and PBX3 are not individually able to transform cells and were therefore hypothesized to function as cofactors of HOXA9. However, in this study, we demonstrate that coexpression of PBX3 and MEIS1 (PBX3/MEIS1), without ectopic expression of a HOX gene, is sufficient for transformation of normal mouse hematopoietic stem/progenitor cells in vitro. Moreover, PBX3/MEIS1 overexpression also caused AML in vivo, with a leukemic latency similar to that caused by forced expression of MLL-AF9, the most common form of MLL fusions. Furthermore, gene expression profiling of hematopoietic cells demonstrated that PBX3/MEIS1 overexpression, but not HOXA9/MEIS1, HOXA9/PBX3, or HOXA9 overexpression, recapitulated the MLL-fusion-mediated core transcriptome, particularly upregulation of the endogenous Hoxa genes. Disruption of the binding between MEIS1 and PBX3 diminished PBX3/MEIS1-mediated cell transformation and HOX gene upregulation. Collectively, our studies strongly implicate the PBX3/MEIS1 interaction as a driver of cell transformation and leukemogenesis, and suggest that this axis may play a critical role in the regulation of the core transcriptional programs activated in MLL-rearranged and HOX-overexpressing AML. Therefore, targeting the MEIS1/PBX3 interaction may represent a promising therapeutic strategy to treat these AML subtypes. PMID- 26747897 TI - JARID1D Is a Suppressor and Prognostic Marker of Prostate Cancer Invasion and Metastasis. AB - Entire or partial deletions of the male-specific Y chromosome are associated with tumorigenesis, but whether any male-specific genes located on this chromosome play a tumor-suppressive role is unknown. Here, we report that the histone H3 lysine 4 (H3K4) demethylase JARID1D (also called KDM5D and SMCY), a male-specific protein, represses gene expression programs associated with cell invasiveness and suppresses the invasion of prostate cancer cells in vitro and in vivo. We found that JARID1D specifically repressed the invasion-associated genes MMP1, MMP2, MMP3, MMP7, and Slug by demethylating trimethyl H3K4, a gene-activating mark, at their promoters. Our additional results demonstrated that JARID1D levels were highly downregulated in metastatic prostate tumors compared with normal prostate tissues and primary prostate tumors. Furthermore, the JARID1D gene was frequently deleted in metastatic prostate tumors, and low JARID1D levels were associated with poor prognosis in prostate cancer patients. Taken together, these findings provide the first evidence that an epigenetic modifier expressed on the Y chromosome functions as an anti-invasion factor to suppress the progression of prostate cancer. Our results also highlight a preclinical rationale for using JARID1D as a prognostic marker in advanced prostate cancer. PMID- 26747899 TI - Collective selection of food patches in Drosophila. AB - The fruit fly Drosophila melanogaster has emerged as a model organism for research on social interactions. Although recent studies have described how individuals interact on foods for nutrition and reproduction, the complex dynamics by which groups initially develop and disperse have received little attention. Here we investigated the dynamics of collective foraging decisions by D. melanogaster and their variation with group size and composition. Groups of adults and larvae facing a choice between two identical, nutritionally balanced food patches distributed themselves asymmetrically, thereby exploiting one patch more than the other. The speed of the collective decisions increased with group size, as a result of flies joining foods faster. However, smaller groups exhibited more pronounced distribution asymmetries than larger ones. Using computer simulations, we show how these non-linear phenomena can emerge from social attraction towards occupied food patches, whose effects add up or compete depending on group size. Our results open new opportunities for exploring complex dynamics of nutrient selection in simple and genetically tractable groups. PMID- 26747900 TI - Wavelength discrimination in the hummingbird hawkmoth Macroglossum stellatarum. AB - Despite the strong relationship between insect vision and the spectral properties of flowers, the visual system has been studied in detail in only a few insect pollinator species. For instance, wavelength discrimination thresholds have been determined in two species only: the honeybee (Apis mellifera) and the butterfly Papilio xuthus. Here, we present the wavelength discrimination thresholds (Deltalambda) for the hawkmoth Macroglossum stellatarum. We compared the data with those found for the honeybee, the butterfly P. xuthus and the predictions of a colour discrimination model. After training moths to feed from a rewarded disc illuminated with a monochromatic light, we tested them in a dual-choice situation, in which they had to choose between light of the training wavelength and a novel unrewarded wavelength. To characterise the Deltalambda function, we decreased the difference between wavelengths in subsequent tests. We also varied the light intensity to test its effect on the discrimination capacity. In agreement with the predictions of the model, we found two expected minima of discrimination where photoreceptor sensitivities overlap, as well as a third, minor, unpredicted minimum around the peak of the blue photoreceptor. Macroglossum stellatarum is capable of discriminating between lights with a wavelength difference of 1-2 nm. These discrimination minima are similar to those found for the tetrachromatic P. xuthus, and are better than those of the honeybee. The moth is also capable of using achromatic information to discriminate between lights of long wavelengths. PMID- 26747901 TI - Measuring abnormal movements in free-swimming fish with accelerometers: implications for quantifying tag and parasite load. AB - Animal-borne data loggers allow movement, associated behaviours and energy expenditure in fish to be quantified without direct observations. As with any tagging, tags that are attached externally may adversely affect fish behaviour, swimming efficiency and survival. We report on free-swimming wild Atlantic cod (Gadus morhua) held in a large mesocosm that exhibited distinctly aberrant rotational swimming (scouring) when externally tagged with accelerometer data loggers. To quantify the phenomenon, the cod were tagged with two sizes of loggers (18 and 6 g; <2% body mass) that measured tri-axial acceleration at 50 Hz. An automated algorithm, based on body angular rotation, was designed to extract the scouring movements from the acceleration signal (98% accuracy). The algorithm also identified the frequency pattern and associated energy expenditure of scouring in relation to tag load (% body weight). The average per cent time spent scouring (5%) was independent of tag load. The vector of the dynamic body acceleration (VeDBA), used as a proxy for energy expenditure, increased with tag load (r(2)=0.51), and suggests that fish with large tags spent more energy when scouring than fish with small tags. The information allowed us to determine potential detrimental effects of an external tag on fish behaviour and how these effects may be mitigated by tag size. The algorithm can potentially identify similar rotational movements associated with spawning, courtship, feeding and parasite-load shedding in the wild. The results infer a more careful interpretation of data derived from external tags and the careful consideration of tag type, drag, buoyancy and placement, as well as animal buoyancy and species. PMID- 26747902 TI - Water deprivation increases maternal corticosterone levels and enhances offspring growth in the snake Vipera aspis. AB - Circulating glucocorticoid (GC) levels may increase as a result of reproductive effort or in response to unpredictable events. However, GC secretion can vary with the availability of vital trophic resources such as energy. While water represents another critical resource, the impact of water deprivation on GC secretion during reproduction has not yet been thoroughly investigated. Here, we examined the effects of water deprivation on plasma corticosterone (CORT) concentrations of female aspic vipers (Vipera aspis), and determined the impacts of water deprivation on offspring traits. We exposed both pregnant and non reproductive females to a 20-day water deprivation and compared their pre- and post-deprivation CORT levels with those of control females. At the end of the treatment, only water-deprived pregnant females showed a significant increase in CORT levels. In pregnant females, changes in baseline CORT level were correlated with changes in female hydration state. Changes in baseline CORT levels were also negatively influenced by maternal reproductive effort in pregnant control females, while such a relationship was not apparent in pregnant water-deprived females. Finally, we found that offspring from water-deprived females had higher growth rates than offspring from control females. Offspring growth was also positively correlated with changes in both maternal osmolality and baseline CORT levels. Together, our results suggest that dehydration increases maternal CORT levels, which may subsequently influence offspring development. Further long-term field studies are therefore required to assess whether there is an adaptive significance of this response. PMID- 26747903 TI - Spectral sensitivity, spatial resolution and temporal resolution and their implications for conspecific signalling in cleaner shrimp. AB - Cleaner shrimp (Decapoda) regularly interact with conspecifics and client reef fish, both of which appear colourful and finely patterned to human observers. However, whether cleaner shrimp can perceive the colour patterns of conspecifics and clients is unknown, because cleaner shrimp visual capabilities are unstudied. We quantified spectral sensitivity and temporal resolution using electroretinography (ERG), and spatial resolution using both morphological (inter ommatidial angle) and behavioural (optomotor) methods in three cleaner shrimp species: Lysmata amboinensis, Ancylomenes pedersoni and Urocaridella antonbruunii. In all three species, we found strong evidence for only a single spectral sensitivity peak of (mean +/- s.e.m.) 518 +/- 5, 518 +/- 2 and 533 +/- 3 nm, respectively. Temporal resolution in dark-adapted eyes was 39 +/- 1.3, 36 +/- 0.6 and 34 +/- 1.3 Hz. Spatial resolution was 9.9 +/- 0.3, 8.3 +/- 0.1 and 11 +/- 0.5 deg, respectively, which is low compared with other compound eyes of similar size. Assuming monochromacy, we present approximations of cleaner shrimp perception of both conspecifics and clients, and show that cleaner shrimp visual capabilities are sufficient to detect the outlines of large stimuli, but not to detect the colour patterns of conspecifics or clients, even over short distances. Thus, conspecific viewers have probably not played a role in the evolution of cleaner shrimp appearance; rather, further studies should investigate whether cleaner shrimp colour patterns have evolved to be viewed by client reef fish, many of which possess tri- and tetra-chromatic colour vision and relatively high spatial acuity. PMID- 26747904 TI - The importance of thermal history: costs and benefits of heat exposure in a tropical, rocky shore oyster. AB - Although thermal performance is widely recognised to be pivotal in determining species' distributions, assessment of this performance is often based on laboratory-acclimated individuals, neglecting their proximate thermal history. The thermal history of a species sums the evolutionary history and, importantly, the thermal events recently experienced by individuals, including short-term acclimation to environmental variations. Thermal history is perhaps of greatest importance for species inhabiting thermally challenging environments and therefore assumed to be living close to their thermal limits, such as in the tropics. To test the importance of thermal history, the responses of the tropical oyster Isognomon nucleus to short-term differences in thermal environments were investigated. Critical and lethal temperatures and oxygen consumption were improved in oysters that previously experienced elevated air temperatures, and were associated with an enhanced heat shock response, indicating that recent thermal history affects physiological performance as well as inducing short-term acclimation to acute conditions. These responses were, however, associated with trade-offs in feeding activity, with oysters that experienced elevated temperatures showing reduced energy gain. Recent thermal history, therefore, seems to rapidly invoke physiological mechanisms that enhance survival of short term thermal challenge but also longer term climatic changes and consequently needs to be incorporated into assessments of species' thermal performances. PMID- 26747905 TI - Activity dependence of spreading depression in the locust CNS. AB - Spreading depression (SD) is associated with large changes in extracellular ion concentrations and can be induced by impairing mechanisms of K(+) ion homeostasis. We tested activity dependence of SD in the locust model of ouabain induced SD in the metathoracic ganglion. Wind activation of thoracic circuitry resulted in small increases of K(+) concentration that took 5-10 s to be cleared from the extracellular space. In the presence of the Na(+)/K(+)-ATPase inhibitor ouabain, wind stimulation every 30 s halved the latency to the first SD event and increased its duration. Wind stimulation was able to trigger the first event, suggesting that local activity could determine the origin of successive SD events. Perfusion with calcium-free saline blocked neural activity in the ganglion and prevented the occurrence of ouabain-induced SD. We conclude that ouabain-induced SD in the locust CNS is strongly dependent on the existing level of neural activity. PMID- 26747906 TI - Reconfiguration of the immune system network during food limitation in the caterpillar Manduca sexta. AB - Dwindling resources might be expected to induce a gradual decline in immune function. However, food limitation has complex and seemingly paradoxical effects on the immune system. Examining these changes from an immune system network perspective may help illuminate the purpose of these fluctuations. We found that food limitation lowered long-term (i.e. lipid) and short-term (i.e. sugars) energy stores in the caterpillar Manduca sexta. Food limitation also: altered immune gene expression, changed the activity of key immune enzymes, depressed the concentration of a major antioxidant (glutathione), reduced resistance to oxidative stress, reduced resistance to bacteria (Gram-positive and -negative bacteria) but appeared to have less effect on resistance to a fungus. These results provide evidence that food limitation led to a restructuring of the immune system network. In severely food-limited caterpillars, some immune functions were enhanced. As resources dwindled within the caterpillar, the immune response shifted its emphasis away from inducible immune defenses (i.e. those responses that are activated during an immune challenge) and increased emphasis on constitutive defenses (i.e. immune components that are produced consistently). We also found changes suggesting that the activation threshold for some immune responses (e.g. phenoloxidase) was lowered. Changes in the configuration of the immune system network will lead to different immunological strengths and vulnerabilities for the organism. PMID- 26747907 TI - Limits to sustained energy intake. XXIII. Does heat dissipation capacity limit the energy budget of lactating bank voles? AB - Understanding factors limiting sustained metabolic rate (SusMR) is a central issue in ecological physiology. According to the heat dissipation limit (HDL) theory, the SusMR at peak lactation is constrained by the maternal capacity to dissipate body heat. To test that theory, we shaved lactating bank voles (Myodes glareolus) to experimentally elevate their capacity for heat dissipation. The voles were sampled from lines selected for high aerobic exercise metabolism (A; characterized also by increased basal metabolic rate) and unselected control lines (C). Fur removal significantly increased the peak-lactation food intake (mass-adjusted least square means +/- s.e.; shaved: 16.3 +/- 0.3 g day(-1), unshaved: 14.4 +/- 0.2 g day(-1); P<0.0001), average daily metabolic rate (shaved: 109 +/- 2 kJ day(-1), unshaved: 97 +/- 2 kJ day(-1); P<0.0001) and metabolisable energy intake (shaved: 215 +/- 4 kJ day(-1), unshaved: 185 +/- 4 kJ day(-1); P<0.0001), as well as the milk energy output (shaved: 104 +/- 4 kJ day( 1); unshaved: 93 +/- 4 kJ day(-1); P=0.021) and litter growth rate (shaved: 9.4 +/- 0.7 g 4 days(-1), unshaved: 7.7 +/- 0.7 g 4 days(-1); P=0.028). Thus, fur removal increased both the total energy budget and reproductive output at the most demanding period of lactation, which supports the HDL theory. However, digestive efficiency was lower in shaved voles (76.0 +/- 0.3%) than in unshaved ones (78.5 +/- 0.2%; P<0.0001), which may indicate that a limit imposed by the capacity of the alimentary system was also approached. Shaving similarly affected the metabolic and reproductive traits in voles from the A and C lines. Thus, the experimental evolution model did not reveal a difference in the limiting mechanism between animals with inherently different metabolic rates. PMID- 26747909 TI - Winter metabolic depression does not change arterial baroreflex control of heart rate in the tegu lizard Salvator merianae. AB - Baroreflex regulation of blood pressure is important for maintaining appropriate tissue perfusion. Although temperature affects heart rate (fH) reflex regulation in some reptiles and toads, no data are available on the influence of temperature independent metabolic states on baroreflex. The South American tegu lizard Salvator merianae exhibits a clear seasonal cycle of activity decreasing fH along with winter metabolic downregulation, independent of body temperature. Through pharmacological interventions (phenylephrine and sodium nitroprusside), the baroreflex control of fH was studied at ~ 25 degrees C in spring-summer- and winter-acclimated tegus. In winter lizards, resting and minimum fH were lower than in spring-summer animals (respectively, 13.3 +/- 0.82 versus 10.3 +/- 0.81 and 11.2 +/- 0.65 versus 7.97 +/- 0.88 beats min(-1)), while no acclimation differences occurred in resting blood pressure (5.14 +/- 0.38 versus 5.06 +/- 0.56 kPa), baroreflex gain (94.3 +/- 10.7 versus 138.7 +/- 30.3% kPa(-1)) or rate pressure product (an index of myocardial activity). Vagal tone exceeded the sympathetic tone of fH, especially in the winter group. Therefore, despite the lower fH, winter acclimation does not diminish the fH baroreflex responses or rate-pressure product, possibly because of increased stroke volume that may arise because of heart hypertrophy. Independent of acclimation, fH responded more to hypotension than to hypertension. This should imply that tegus, which have no pressure separation within the single heart ventricle, must have other protection mechanisms against pulmonary hypertension or oedema, presumably through lymphatic drainage and/or vagal vasoconstriction of pulmonary artery. Such a predominant fH reflex response to hypotension, previously observed in anurans, crocodilians and mammals, may be a common feature of tetrapods. PMID- 26747908 TI - Glucose metabolism ontogenesis in rainbow trout (Oncorhynchus mykiss) in the light of the recently sequenced genome: new tools for intermediary metabolism programming. AB - The rainbow trout (Oncorhynchus mykiss), a carnivorous fish species, displays a 'glucose-intolerant' phenotype when fed a high-carbohydrate diet. The importance of carbohydrate metabolism during embryogenesis and the timing of establishing this later phenotype are currently unclear. In addition, the mechanisms underlying the poor ability of carnivorous fish to use dietary carbohydrates as a major energy substrate are not well understood. It has recently been shown in trout that duplicated genes involved in glucose metabolism may participate in establishing the glucose-intolerant phenotype. The aim of this study was therefore to provide new understanding of glucose metabolism during ontogenesis and nutritional transition, taking into consideration the complexity of the trout genome. Trout were sampled at several stages of development from fertilization to hatching, and alevins were then fed a non-carbohydrate or a high-carbohydrate diet during first feeding. mRNA levels of all glucose metabolism-related genes increased in embryos during the setting up of the primitive liver. After the first meal, genes rapidly displayed expression patterns equivalent to those observed in the livers of juveniles. g6pcb2.a (a glucose 6-phosphatase-encoding gene) was up-regulated in alevins fed a high-carbohydrate diet, mimicking the expression pattern of gck genes. The g6pcb2.a gene may contribute to the non inhibition of the last step of gluconeogenesis and thus to establishing the glucose-intolerant phenotype in trout fed a high-carbohydrate diet as early as first feeding. This information is crucial for nutritional programming investigations as it suggests that first feeding would be too late to programme glucose metabolism in the long term. PMID- 26747911 TI - Private information alone can trigger trapping of ant colonies in local feeding optima. AB - Ant colonies are famous for using trail pheromones to make collective decisions. Trail pheromone systems are characterised by positive feedback, which results in rapid collective decision making. However, in an iconic experiment, ants were shown to become 'trapped' in exploiting a poor food source, if it was discovered earlier. This has conventionally been explained by the established pheromone trail becoming too strong for new trails to compete. However, many social insects have a well-developed memory, and private information often overrules conflicting social information. Thus, route memory could also explain this collective 'trapping' effect. Here, we disentangled the effects of social and private information in two 'trapping' experiments: one in which ants were presented with a good and a poor food source, and one in which ants were presented with a long and a short path to the same food source. We found that private information is sufficient to trigger trapping in selecting the poorer of two food sources, and may be sufficient to cause it altogether. Memories did not trigger trapping in the shortest path experiment, probably because sufficiently detailed memories did not form. The fact that collective decisions can be triggered by private information alone may require other collective patterns previously attributed solely to social information use to be reconsidered. PMID- 26747910 TI - Sex-specific nutrient use and preferential allocation of resources to a sexually selected trait in Hyalella amphipods. AB - Although sexually dimorphic traits are often well studied, we know little about sex-specific resource use strategies that should underlie such dimorphism. We measured sex-specific responses in acquisition and assimilation of two fundamental resources, carbon (C) and phosphorus (P) in juvenile and mature Hyalella amphipods given low and high supplies of inorganic phosphate, analogous to oligotrophic and eutrophic conditions, respectively. Additionally, we quantified allocation of resources to sexual traits in males. Dual radiotracer ((14)C and (33)P) assays revealed substantial age- and sex-specific differences in acquisition and assimilation. Furthermore, a phenotypic manipulation experiment revealed that amphipods fed low-P food allocated more C to all traits than those fed high-P food. Importantly, we found that amphipods preferentially allocated more C to the development of a sexually selected trait (the posterior gnathopod), compared with a serially homologous trait (the fifth pereopod) not under sexual selection. Substantial differences in how the sexes use fundamental resources, and the impact of altered nutrient supply on such differences, illuminate sexual dimorphism at the lowest level of biological organization. Such information will be important in understanding how sex- and age-specific life history demands influence nutrient processing in a biosphere characterized by rapidly changing alterations to biogeochemical cycles. PMID- 26747912 TI - Tissue loss and bone repair: Time to develop an international strategy? PMID- 26747913 TI - Bone printing: new frontiers in the treatment of bone defects. AB - Bone defects can be congenital or acquired resulting from trauma, infection, neoplasm and failed arthroplasty. The osseous reconstruction of these defects is challenging. Unfortunately, none of the current techniques for the repair of bone defects has proven to be fully satisfactory. Bone tissue engineering (BTE) is the field of regenerative medicine (RM) that focuses on alternative treatment options for bone defects that will ideally address all the issues of the traditional techniques in treating large bone defects. However, current techniques of BTE is laborious and have their own shortcomings. More recently, 2D and 3D bone printing has been introduced to overcome most of the limitations of bone grafts and BTE. So far, results are extremely promising, setting new frontiers in the management of bone defects. PMID- 26747914 TI - RIA fractions contain mesenchymal stroma cells with high osteogenic potency. AB - INTRODUCTION: The gold standard for treatment of non-union is the transplantation of autologous bone from iliac crest. As an alternative, material can be harvested by femoral reaming with the Reamer-Irrigator-Aspirator((r)) (RIA)-System. This material might be a source for human mesenchymal stroma cells (MSCs) with osteogenic potency. The aim of this study was the characterisation of cells harvested with the RIA system and the comparison of their properties with cells isolated from bone marrow ("BM") and fat tissue ("adipose"). The RIA material was separated into the liquid aspiration fraction ("liquid") and the solid RIA fraction. From the solid RIA fraction the cells were cultured either directly ("native") or after collagenase digestion and filtration ("filtrate"). Stem cell characteristics were analysed and the osteogenic potential was investigated in vitro and in vivo. MATERIALS & METHODS: Fat tissue and bone marrow were harvested from nine patients (three women, six males, with a mean of 48.1 years) with atrophic non-union RIA material. The cells were isolated and characterised by flow cytometry, three lineage differentiation capacities and colony-forming unit fibroblast assay. Gene expression profiles were performed and osteogenic differentiation in vivo was analysed. RESULTS: All three RIA fractions contained mesenchymal stromal cells (MSCs) as demonstrated by CFU-F assay, three linage differentiation and surface marker analysis. The RIA-MSCs exhibited a significantly higher osteogenic potential in vitro compared to adipose-MSCs, whereas no difference was seen compared to BM-MSCs. Quantitative RT-PCR analysis revealed an expression of osteogenic markers in all isolated cells. The implantation of MSCs with beta-TCP scaffolds into the mice muscle showed significantly higher bone formation for the filtrate RIA-MSC, native RIA-MSC and BM-MSC groups compared to the adipose-MSC group. The filtrate RIA-MSCs formed twice as much new bone in vivo compared to BM-MSCs. CONCLUSION: The present study showed high potency of cells isolated by reaming. Even in the irrigation fluid, which is normally discarded, cells with the characteristics of stromal stem cells were isolated. In comparison to adipose-MSCs and BM-MSCs, the RIA-MSCs showed a similar or even better osteogenic potential in vitro and in vivo and this supports their usability in orthopaedic surgery. PMID- 26747915 TI - Bioactive glass for long bone infection: a systematic review. AB - BACKGROUND: Long bone infection remains a challenging situation for the orthopaedic surgeon. For most, treatment comprises a thorough debridement of all the infected bone, the filling of the resultant cavity with a bone substitute, and general antibiotics for a certain time. However, the type of bone substitute to insert in the cavity is still debated. PURPOSE: In this study, we aimed to systematically review the results of studies using bioactive glass for long bone infection in the clinical setting. MATERIAL AND METHOD: We searched systematically Medline via Pubmed for studies published until August 2015 that report the results of bioactive glass for long bone infection in humans. RESULTS: Three studies, including a total of 41 patients, met the inclusion criteria. Mean age was 46.5 (16-84). Twenty-nine were male and twelve were female. Period of inclusion went from 2007 to 2013. All the patients had a clinically and radiologically diagnosed osteomyelitis. They all underwent a state of the art surgical procedure to address osteomyelitis. All the patients were implanted with BAG-S53P4 granules (BonAlive Biomaterials Ltd, Turku, Finland) to fill in the resultant cavity. Mean volume inserted was 16.8 milliliters (2-60). After a mean follow-up of 21 months (10-38), three cases of osteomyelitis recurred. In two cases, a new procedure was performed. No complication directly related to the bioactive glass was reported. DISCUSSION: Despite a limited use for long bone infection in humans, bioactive glass seems to be an interesting option as bone substitute after thorough bone debridement and skin coverage. It associates antibacterial activities, osteoconductive properties and vascular stimulation. CONCLUSION: From this review, bioactive glass seems to be a useful bone substitute for long bone infection in humans. Few recurrences occurred after its use. In these cases, the volume of bone glass to insert was frequently underestimated and/or the skin coverage not adequate. PMID- 26747916 TI - Surgical treatment of early knee osteoarthritis with a cell-free osteochondral scaffold: results at 24 months of follow-up. AB - PURPOSE: "Early Osteoarthritis (EOA)" has been defined combining clinical, imaging and surgical parameters, with the aim to identify patients in early degenerative phases, who might benefit from the use of available regenerative procedures. Aim of this first clinical trial is to prospectively evaluate the results obtained in a group of patients meeting the inclusion criteria of "EOA" as proposed by the ESSKA Cartilage Committee, and surgically treated with the implantation of a multi-phasic osteochondral scaffold. METHODS: 23 patients were prospectively evaluated at 12 and 24 months of follow-up. Etiology of the chondral or osteochondral defect was rated as microtraumatic or degenerative in 18 cases, and traumatic in 5 cases. Patients included were complaining of clinical symptoms like knee pain and affected by chondral and osteochondral lesions located at the femoral condyles or trochlea and MRI findings demonstrating articular cartilage degeneration and/or meniscal degeneration and/or subchondral bone marrow lesions. RESULTS: All patients increased significantly in any clinical score adopted. The IKDC subjective score increased from 42.8 +/- 13.8 at basal evaluation to 74.3 +/- 17.4 at 12 months' (p < 0.0005), being stable (74.9 +/- 20.4) up to the final follow-up of 24 months. Tegner score showed a statistically significant improvement in sports activity from 3.3 +/- 2.7 pre-operative to 4.6 +/- 2.2 at 12 months (p < 0.005), with a slight improvement to the final evaluation (4.7 +/- 2.1; n.s.). However, the activity level was significantly lower than the pre-injury one (6.1 +/- 2.6; p = 0.004). A significant difference was shown between patients younger versus older than 40 years, with younger patients had better clinical improvement (76.0 +/- 18.6 vs 45.1 +/- 38.8 respectively, p = 0.037). CONCLUSIONS: The implantation of a multi-phasic osteochondral scaffold represents a good option after failure of conservative management for Early OA patients, where younger age represent an important factor for a better outcome. Longer follow-up is needed to evaluate the benefit over time. LEVEL OF EVIDENCE: IV, case series. PMID- 26747917 TI - Investigating a new drug delivery nano composite membrane system based on PVA/PCL and PVA/HA(PEG) for the controlled release of biopharmaceuticals for bone infections. AB - The capability for sustained and gradual release of pharmaceuticals is a major requirement in the development of a guided antimicrobial bacterial control system for clinical applications. In this study, PVA gels with varying constituents that were manufactured via a refreeze/thawing route, were found to have excellent potential for antimicrobial delivery for bone infections. Cefuroxime Sodium with poly(ethylene glycol) was incorporated into 2 delivery systems poly(e caprolactone) (PCL) and hydroxyapatite (HA), by a modified emulsion process. Our results indicate that the Cefuroxime Sodium released from poly(e-caprolactone) in PVA was tailored to a sustained release over more than 45 days, while the release from hydroxyapatite PVA reach burst maximum after 20 days. These PVA hydrogel systems were also capable of controlled and sustained release of other biopharmaceuticals. PMID- 26747918 TI - The Masquelet technique of induced membrane for healing of bone defects. A review of 8 cases. AB - BACKGROUND: Segmental defects of long bones are notoriously difficult to treat. This study evaluates eight cases in which the Masquelet technique of induced membranes was used. The primary purpose was to assess the results compared to other types of bone reconstruction and share our tips and tricks to improve the outcome. METHOD: Retrospective study based on patient records and radiographs. Eight patients operated between 2011 and 2014 were included. Three had infected non-unions. Outcome measures were time-to full weight-bearing, time to radiographic consolidation, need for secondary bone grafting procedures and occurrence of complications. RESULTS: Time to full weight bearing seemed shorter in patients treated with nails. In two cases only partial radiographic consolidation was noted at the latest follow up visit. One patient needed secondary bone grafting and two limbs were malaligned. There were no amputations, no persistent infections, and no implant failures. DISCUSSION: The induced membrane technique is a useful tool to substitute bone loss yet consolidation time is somewhat unpredictable and prolonged non-weight bearing is required. CONCLUSION: Nailing seems to improve outcome compared to plating. It shortens treatment time, reduces the amount of bone graft needed, aligns the bone and should be considered when feasible. Further larger scale studies are welcome to throw more light into the efficacy and effectiveness of this technique. PMID- 26747919 TI - Long bone non-unions treated with the diamond concept: a case series of 64 patients. AB - The aim of this retrospective study with prospectively documented data was to report the clinical results of treatment of long bone non-unions using the "diamond concept". Over a 4-year period, patients that presented with a long bone non-union and were managed with the diamond conceptual framework of bone repair were evaluated. Exclusion criteria were hypertrophic, pathological, and infected non-unions. Fixation was revised as it was indicated whilst biological enhancement included the implantation of RIA graft, BMP-7 and concentrated bone marrow aspirate. Data recorded included patient demographics, initial fracture pattern and type of stabilisation, number of previous interventions, time to reoperation, time to union and functional outcome. Painless full weight bearing defined clinical union. Radiological union was defined as the presence of mature callous bridging to at least 3 bone cortices. The minimum follow up was 12 months (range 12-32). In total 64 patients (34 males) with a mean age of 45 years (17 83) were evaluated. Anatomical distribution of non-unions included the femur (54.68%), tibia (34.38%), humerus (4.68%), radius (3.13%) and clavicle (3.13%). The median number of previous interventions was 1 (range 1-5). The majority of patients (82.62%) underwent revision of fixation whereas only bone grafting was performed 9.38% of patients. Three patients developed superficial wound infection (one was MRSA), 1 had deep vein thrombosis and 1 developed heterotopic bone formation. Union was successful in 63/64 (98.4%) non-unions at a mean time of 6 months (range 3-12). All patients were mobilising pain free and returned to their daily living activities at the final follow up. The application of the "diamond concept" in this cohort of patients was associated with a high union rate by providing an optimal mechanical and biological environment. Such an approach should be considered in the surgeon's armamentarium particularly in such cases where difficulty of bone repair is foreseen. PMID- 26747920 TI - Clinical effectiveness of Osigraft in long-bones non-unions. AB - Current evidence, based primarily on case series, suggest that the eptotermin alfa (recombinant bone morphogenetic protein-7 (rhBM-7)), which is commercialized as Osigraft with an indication for tibial non-union, used in monotherapy or polytherapy, is a safe and effective therapy for long bones non-unions of lower and upper limbs. No previous study has compared the safety and the efficacy of Osigraft and the "gold standard" treatment for recalcitrant long-bones non-union, autologous bone graft (ABG). This study aims to compare the effectiveness of Osigraft and ABG in the treatment of post-traumatic, persistent long bone non unions. In particular, the present study will focus exclusively on complex persistent non-unions, excluding simpler cases, in which it is likely that a simple revision of the osteosynthesis will be sufficient to promote union, and extremely severe cases in which there is an indication for amputation and prosthesis. The study addresses the following research question: 1. Is the effectiveness of eptotermin alfa comparable to that of ABG in the treatment of complex long bone non-unions? 2. Are there significant differences in the prevalence of adverse events between patients treated with eptotermin alfa and those treated with ABG? The study is an observational, retrospective study, located in one Experimental Recruiting Center (Ospedale Universitario G. PINI - Milano). The study was conducted with ethics approval and according with the existing Italian law. Demographic and clinical data were collected from patients Clinical Medical Records and other existing documentation, through a web based eCRF. The treatment (surgery with Osigraft or ABG) effectiveness was evaluated comparing the number of success cases (primary endpoint) and the length for clinical and radiological healing (secondary end-points). The treatment safety was evaluating comparing the prevalence of Adverse Events. Osigraft was demonstrated to be statistically equivalent to ABG with respect to the primary and secondary end point of surgical success. The treatment success was statistically comparable across all the anatomical regions considered, both in patients treated with Osigraft and in patients treated with ABG. The use of Osigraft when compared to autograft was associated with statistically lower intraoperative blood loss and shorter operative times. In addition patients treated with Osigraft developed statistically less peri-operative and late onset adverse events, compared to ABG. The difference was substantially due to the occurrence of pain at donor site in patients treated with ABG. PMID- 26747921 TI - MRI appearances of the femur following bone graft harvesting using the Reamer Irrigator-Aspirator. AB - The reamer-irrigator-aspirator is increasingly being used to harvest autologous bone graft from the femur. The purpose of this study was to investigate the extent of neo-vascularisation and new bone formation that occurs within the medulla following the procedure, and determine if new bone formation would potentially allow a repeat bone harvest in those individuals subsequently requiring further bone graft. Eleven patients who had undergone femoral bone harvest were examined with MRI. The nature of the tissue within the medulla and the extent of neo-vascularisation were assessed. MRI was performed between 3 months and 28 months following bone graft harvest, mean 14 months. Intense vascularisation of the endostial cortical surface and neo-vascularisation of the haematoma within the canal occurred as soon as 3 months following bone harvest. From as early as 14 months the tissue was replaced by normal intramedullary bone. The formation of new bone within the medullary canal gives the potential for a repeat reaming, should further bone graft be required at a later date. PMID- 26747922 TI - Terrible triad of the elbow: is it still a troublesome injury? AB - BACKGROUND: Terrible triad injury (TTI), one of the main patterns of complex elbow instability, is difficult to treat and yields conflicting surgical results. We analyzed prospectively a series of patient affected by TTI and treated according to the current diagnostic and surgical protocols to investigate whether their application allow to obtain more predictable outcomes. MATERIAL AND METHODS: We analyzed 26 patients with a mean age of 52 years. Preoperative X-rays and CT were performed; all patients were operated by the same elbow surgeon and underwent the same surgical and rehabilitation treatment. Final functional outcome was assessed by the Mayo Elbow Performance Score (MEPS), Quick-Disability of the Arm Shoulder and Hand-score (Q-DASH) and the modified-American Shoulder and Elbow Surgeons score (m-Ases). A radiographic evaluation was also performed. RESULTS: Mean follow-up was 31 months. At final evaluation, mean flexion, extension, supination and pronation were 137 degrees , 10 degrees , 77 degrees and 79 degrees , respectively; mean MEPS, m-ASES and Q-DASH scores were respectively 96, 91 and 8 points. Complications observed after first surgery were: elbow stiffness in 5 cases, mild posterolateral instability in 3 cases, chronic subluxation in 1 case. Radiographic evaluation showed secondary arthritis in 9 cases, symptomatic HO in 3 cases and late hardware displacement in 2 cases. Six out of 26 patient underwent reoperation with final satisfactory results. CONCLUSION: The current diagnostic and therapeutic protocols allow obtaining satisfactory clinical outcomes in majority of cases but a high number of major and minor unpredictable complications persist yet. In this series, low compliance, obesity, and extensive soft elbow tissue damage caused by high-energy trauma represented negative prognostic factors unrelated to surgery. On the other hand, the strict application of current algorithms by an expert elbow surgeon appears to improve clinical results by reducing the influence of other avoidable negative prognostic factors well known in current literature, such as the incomplete recognition of injuries, delayed treatment, inadequate treatment of bony and ligamentous injuries, prolonged immobilization and, last but not least, the surgeon's inexperience. LEVEL OF EVIDENCE: Level IV, Case series, Treatment study. PMID- 26747923 TI - Colonization by methicillin resistant staphylococci of nares and skin in healthcare workers: a pilot study in spinal surgeries. AB - INTRODUCTION: Staphylococcus aureus and coagulase-negative staphylococci (CoNS) colonization among healthcare workers (HCWs) may have implications in development of infections and in spreading of resistance. This study aimed to determine the rate of methicillin-resistant staphylococci carriage in HCWs of spinal surgeries in an Italian Orthopaedic Institute. MATERIALS AND METHODS: Samples from nares, axillae and hands were inoculated onto appropriate media in order to perform colony counts of methicillin-susceptible and resistant S. aureus and CoNS. RESULTS: Prevalence of S. aureus and CNS was 42.3% and 98%, respectively. Methicillin-resistance was rather infrequent in S. aureus (13.5%) while it was detected in most of CoNS (90.4%). Methicillin resistant S. aureus were prevalently isolated from nares while axillae showed the highest methicillin resistant CoNS colonization rates. CONCLUSIONS: A relatively high rate of methicillin resistant staphylococci was found among HCWs in spinal surgeries wards, thus evidencing the need for careful prevention measures and for periodic evaluation of spread among HCWs. PMID- 26747924 TI - Risk factors for long bone fracture non-union: a stratification approach based on the level of the existing scientific evidence. AB - Non-union continues to be the most devastating complication after fracture fixation. Its treatment can be prolonged and often unpredictable. The burden to the patient, surgeon and health care system can be immense. Strategies to prevent it and or identify early its development are desirable in order to improve the clinical course of the affected patients and their outcomes. We undertook a systematic review of the literature in order to identify the most common and important risk factors based on the hierarchy of level of evidence. Accordingly, a stratification scale was formed which highlighted 10 risk factors including; an open method of fracture reduction, open fracture, presence of post-surgical fracture gap, smoking, infection, wedge or comminuted types of fracture, high degree of initial fracture displacement, lack of adequate mechanical stability provided by the implant used, fracture location in the poor zone of vascularity of the affected bone, and the presence of the fracture in the tibia. Clinicians should take in to account these findings when managing patients with long bone fractures, particularly the femur and tibia in order to minimise the risk of non union. PMID- 26747941 TI - Local mechanical forces promote polarized junctional assembly and axis elongation in Drosophila. AB - Axis elongation is a conserved process in which the head-to-tail or anterior posterior (AP) axis of an embryo extends. In Drosophila, cellular rearrangements drive axis elongation. Cells exchange neighbours by converging into transient multicellular vertices which resolve through the assembly of new cell interfaces parallel to the AP axis. We found that new interfaces elongate in pulses correlated with periodic contractions of the surrounding cells. Inhibiting actomyosin contractility globally, or specifically in the cells around multicellular vertices, disrupted the rate and directionality of new interface assembly. Laser ablation indicated that new interfaces sustained greater tension than non-elongating ones. We developed a method to apply ectopic tension and found that increasing AP tension locally increased the elongation rate of new edges by more than twofold. Increasing dorsal-ventral tension resulted in vertex resolution perpendicular to the AP direction. We propose that local, periodic contractile forces polarize vertex resolution to drive Drosophila axis elongation. PMID- 26747958 TI - The role of heme oxygenase-1 in drug metabolizing dysfunction in the alcoholic fatty liver exposed to ischemic injury. AB - This study was designed to investigate the role of heme oxygenase-1 (HO-1) in hepatic drug metabolizing dysfunction after ischemia/reperfusion (IR) in alcoholic fatty liver (AFL). Rats were fed a Lieber-DeCarli diet for five weeks to allow for development of AFL and were then subjected to 90min of hepatic ischemia and 5h of reperfusion. Rats were pretreated with hemin (HO-1 inducer) or ZnPP (HO-1 inhibitor) for 16h and 3h before hepatic ischemia. After hepatic IR, ethanol diet (ED)-fed rats had higher serum aminotransferase activities and more severe hepatic necrosis compared to the control diet (CD)-fed rats. These changes were attenuated by hemin and exacerbated by ZnPP. The activity and gene expression of HO-1 and its transcription factor (Nrf2) level increased significantly after 5h of reperfusion in CD-fed rats but not in ED-fed rats. After reperfusion, cytochrome P450 (CYP) 1A1, 1A2, and 2B1 activities were reduced to levels lower than those observed in sham group, whereas CYP2E1 activity increased. The decrease in CYP2B1 activity and the increase in CYP2E1 activity were augmented after hepatic IR in ED-fed animals. These changes were significantly attenuated by hemin but aggravated by ZnPP. Finally, CHOP expression and PERK phosphorylation, microsomal lipid peroxidation, and levels of proinflammatory mediators increased in ED-fed rats compared to CD-fed rats after reperfusion. These increases were attenuated by hemin. Our results suggest that AFL exacerbates hepatic drug metabolizing dysfunction during hepatic IR via endoplasmic reticulum stress and lipid peroxidation and this is associated with impaired HO-1 induction. PMID- 26747959 TI - A young boy with recurrent headache, lethargy, and hyponatremia. AB - BACKGROUND: To investigate and differentiate the causes of hyponatremia in an 8-y old boy. METHODS: An 8-y boy presented with headache, vomiting, and diplopia. Magnetic resonance imaging of the brain confirmed a mass in the pineal region. Pathology report demonstrated a mixed germ cell tumor with a yolk sac component. A multi-agent chemotherapy and radiation regimen was initiated. He developed hyponatremia, with sodium concentrations varying from 116 to 133 mEq/l. RESULTS: Serum levels of sodium, chloride, phosphorous, uric acid, and osmolality were low. Serum alpha-fetoprotein, beta-HCG, and lactate dehydrogenase were highly elevated. Urine sodium and osmolality were increased. CONCLUSIONS: These presentations suggest that the patient has cerebral salt-wasting syndrome caused by intracranial germ cell tumor. Recognition and differentiation of cerebral salt wasting syndrome from other disorders are essential. PMID- 26747961 TI - Role of vitamin D in female reproduction. AB - Vitamin D is a fat-soluble vitamin that belongs to the family of steroid hormones. The biological actions of vitamin D are exerted through a soluble protein, the vitamin D receptor (VDR). VDR is a transcription factor located in the nuclei of target cells that mediates the genomic action of the active form of vitamin D (1,25(OH)2D3). This transcription factor is distributed in various tissues, including the reproductive system. The presence of VDR in female reproductive tissue suggests that vitamin D is involved in female reproduction. The present article reviews the impact of vitamin D on anti-Mullerian hormone (AMH), as an ovarian reserve marker, and ovarian steroidogenesis. This article also discusses the impact of vitamin D as a factor that influences infertility and the outcome of in vitro fertilization (IVF), insulin resistance (IR), hyperandrogenism, endometriosis and polycystic ovary syndrome (PCOS). PMID- 26747960 TI - Serum albumin concentrations, effect modifiers and first incident acute myocardial infarction: A cross-sectional study of 1552 cases and 6680 controls. AB - BACKGROUND: The data regarding low serum albumin (LSA) concentrations as a risk factor of CAD have been inconsistent and previous studies also have not considered the potential presence of multicollinearity among covariates. Additionally, there has been to date no reports about the association of LSA with first incident acute myocardial infarction (AMI) in Chinese Han ethnic population. METHODS: Cross-sectional study of 1552 cases and 6680 controls was performed for identifying the association of LSA with first incident AMI and its possible interactions with risk factors on first incident AMI. RESULTS: On a continuous scale, 1SD (~5 g/l) decrease in serum albumin concentrations was significantly associated with a fully adjusted odds ratio of 1.79, 95% CI (1.54 2.04) for first incident AMI in women, 1.53, (1.41-1.69) in men, and 1.61, (1.49 1.72) in total. On a categorical scale, the association of LSA with risk of first incident AMI was stepwise significantly strengthened with the increased albumin quintiles in age categories in both sexes, without a threshold effect found. A significant interaction was found between LSA and primary hypertension, ischemic stroke and hematocrit on the risk of first incident AMI. CONCLUSIONS: LSA concentrations were significantly associated with first incident AMI in a dose response manner in age categories in both sexes in Chinese Han ethnic population. Primary hypertension and hematocrit could modify this association. Whether the albumin transfusion for first incident AMI will improve patients' outcome deserves further studies. PMID- 26747974 TI - Evaluation of possible inhibition of human liver drug metabolizing cytochromes P450 by two new acetylcholinesterase oxime-type reactivators. AB - Two non-symmetric bispyridine oxime - based reactivators of acetylcholinesterase enzyme (AChE), labeled as K027 (1-(4-carbamoylpyridinium)-3-(4 hydroxyiminomethylpyridinium)-propane dibromide) and K203 ((E)-1-(4- carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide) were tested for their potential to inhibit activities of human liver microsomal cytochromes P450 (CYP). Both oximes are very potent reactivators of organophosphate-inhibited AChE. An interaction of both compounds with CYP in human liver microsomal preparation was detected using difference spectroscopy. The compounds were shown to bind to CYP enzymes with spectral binding constants of 5.04 +/- 1.79 nM (K027) and 5.2 +/- 2.6 nM (K203). Enzymology studies were subsequently performed aimed at determining which of the nine most important CYP involved in drug is affected by this interaction. The results have shown no prominent inhibition of individual CYP activities with either compounds except in the case of CYP2E1 and K203. Diagnostic Dixon plot revealed that K203 acted as an uncompetitive inhibitor of CYP2E1. Inhibition of this activity however is not as prominent as to make a potent drug interaction likely. Hence, the interaction of K027 and K203 oxime-type AChE reactivators with human liver microsomal CYP enzymes does not seem to be of prominent clinical importance and both compounds could be safely used in this respect as antidotes with low risk of drug interactions. PMID- 26747975 TI - A two-year dietary carcinogenicity study of (2R,4R)-monatin salt in mice. AB - Groups of Crl:CD-1 (ICR) mice (60/group/sex) were fed 0 (2 control groups), 5000, 20,000, or 40,000 ppm of enzymatically sourced (2R,4R)-monatin salt ("R,R monatin") in the diet for up to two years. There were no adverse effects on survival, incidence of palpable masses and tumors, feed consumption, hematology or serum chemistry parameters, organ weights, or ophthalmic, macroscopic, and microscopic examinations. The only notable effect was statistically significantly lower mean body weights and body weight gains in all treated groups, which generally occurred throughout the study and were most likely a result of caloric dilution of the test diets and not considered adverse. There were no test article related changes in the incidence or occurrence of neoplastic diseases in mice on this study. The no-observed-effect-level (NOEL) for carcinogenicity of R,R monatin fed to mice for 24 months was 40,000 ppm, the highest dietary concentration tested, which was equivalent to approximately 6502 and 7996 mg/kg bw/day in males and females, respectively. PMID- 26747976 TI - Detection of ECG effects of (2R,4R)-monatin, a sweet flavored isomer of a component first identified in the root bark of the Sclerochitin ilicifolius plant. AB - Enzymatically-synthesized (2R,4R)-monatin has, due to its pure sweet taste, been evaluated for potential use in foods. Non-clinical studies have shown that (2R,4R)-monatin is well tolerated at high dietary concentrations, is not genotoxic/mutagenic, carcinogenic, or overtly toxic. In a pharmacokinetic and metabolism study involving 12 healthy males, consumption of a single oral dose (2 mg/kg) of (2R,4R)-monatin resulted in a small reduction of heart rate and prolongation of the QTcF interval of 20-24 ms, corresponding to the time of peak plasma levels (t(max)). These findings were evaluated in a cross-over thorough QT/QTc study with single doses of 150 mg (2R,4R)-monatin, placebo and positive control (moxifloxacin) in 56 healthy males. Peak (2R,4R)-monatin plasma concentration (1720 +/- 538 ng/mL) was reached at 3.1 h (mean tmax). The placebo corrected, change-from-baseline QTcF (DeltaDeltaQTcF) reached 25 ms three hours after dosing, with DeltaDeltaQTcF of 23 ms at two and four hours. Using exposure response (QTc) analysis, a significant slope of the relationship between (2R,4R) monatin plasma levels and DeltaDeltaQTcF was demonstrated with a predicted mean QT effect of 0.016 ms per ng/mL. While similarly high plasma levels are unlikely to be achieved by consumption of (2R,4R)-monatin in foods, QTc prolongation at this level is a significant finding. PMID- 26747977 TI - Effects of 3-monochloropropane-1,2-diol (3-MCPD) and its metabolites on DNA damage and repair under in vitro conditions. AB - 3-monochloropropane-1,2-diol (3-MCPD) is a food contaminant that occurs during industrial production processes and can be found mainly in fat and salt containing products. 3-MCPD has exhibited mutagenic activity in vitro but not in vivo, however, a genotoxic mechanism for the occurrence of kidney tumors has not so far been excluded. The main pathway of mammalian 3-MCPD metabolism is via the formation of beta--chlorolactatic acid and formation of glycidol has been demonstrated in bacterial metabolism. The aim of this study was to investigate genotoxic and oxidative DNA damaging effects of 3-MCPD and its metabolites, and to provide a better understanding of their roles in DNA repair processes. DNA damage was assessed by alkaline comet assay in target rat kidney epithelial cell lines (NRK-52E) and human embryonic kidney cells (HEK-293). Purine and pyrimidine base damage, H2O2 sensitivity and DNA repair capacity were assessed via modified comet assay. The results revealed in vitro evidence for increased genotoxicity and H2O2 sensitivity. No association was found between oxidative DNA damage and DNA repair capacity with the exception of glycidol treatment at 20 MUg/mL. These findings provide further insights into the mechanisms underlying the in vitro genotoxic potential of 3-MCPD and metabolites. PMID- 26747978 TI - A combined dietary chronic toxicity and two-year carcinogenicity study of (2R,4R) monatin salt in Sprague-Dawley rats. AB - In a combined chronic toxicity/carcinogenicity study, groups of Crl:CD(SD) rats were fed 0 (2 control groups), 5000, 20,000, or 40,000 ppm (2R,4R)-monatin salt (hereafter "R,R-monatin") in the diet for up to one year in the chronic toxicity phase and up to two years in the carcinogenicity phase. There were no adverse effects on survival, incidence of palpable masses, neoplasms, organ weights, or ophthalmic examinations. The only notable effect was statistically significantly lower mean body weights and body weight gains in all treated groups generally throughout the study, which were most likely a result of caloric dilution of the test diets. Effects of long-term R,R-monatin ingestion by rats were predominantly focused on the urinary system (i.e., clinical pathology alterations indicative of electrolyte and pH imbalances, increased incidence of renal calculi, mineralization and bone hyperostosis, and increased severity of chronic progressive nephropathy). The no-observed-adverse-effect level (NOAEL) for R,R monatin from the chronic toxicity phase was 20,000 ppm (equivalent to an exposure level of 1080 mg/kg bw/day for males and 1425 mg/kg/day for females) and from the carcinogenicity phase was 5000 ppm (equivalent to an exposure level of 238 and 302 mg/kg bw/day for males and females, respectively). PMID- 26747979 TI - 3D bioprinted extracellular matrix mimics facilitate directed differentiation of epithelial progenitors for sweat gland regeneration. AB - Sweat glands perform a vital thermoregulatory function in mammals. Like other skin appendages, they originate from epidermal progenitors. However, they have low regenerative potential in response to injury, and whether adult epidermal progenitors could be specified to differentiate to a sweat gland cell lineage remains largely unexplored. We used bioprinting technology to create a functional in vitro cell-laden 3D extracellular matrix mimics (3D-ECM) with composite hydrogels based on gelatin and sodium alginate because of chemical and structural similarity to ECM components. To achieve specific cell differentiation, mouse plantar dermis and epidermal growth factor were synchronously incorporated into the 3D-ECM mimics to create an inductive niche for epidermal progenitor cells obtained from mice. The biological 3D construct could maintain cell viability, thereby facilitating cell spreading and matrix formation. In vitro data by immunofluorescence and gene expression assay of key cell-surface markers demonstrated that the bioprinted 3D-ECM could effectively create a restrictive niche for epidermal progenitors that ensures unilateral differentiation into sweat gland cells. Furthermore, direct delivery of bioprinted 3D-ECM into burned paws of mice resulted in functional restoration of sweat glands. This study represents the rational design to enhance the specific differentiation of epidermal lineages using 3D bioprinting and may have clinical and translational implications in regenerating sweat glands. STATEMENT OF SIGNIFICANCE: Sweat gland regeneration after injury is of clinical importance but remains largely unsolved because of low regenerative potential and lack of a definite niche. Some studies have shown sweat gland regeneration with gene-based interventions or cell-based induction via embryonic components, but translation to clinic is challenging. The novelty and significance of the work lies in the fact that we design a 3D bioprinted extracellular matrix that provides the spatial inductive cues for enhancing specific differentiation of epidermal lineages to regenerate sweat glands, which is critical for treating deep burns or other wounds. Our studies are encouraging given the overwhelming advantages of our designed 3D bioprinting construct over other cell delivery technology in maintaining high cell proliferation; another interesting finding is that adult tissue components retain a gland lineage-inductive power as embryonic tissue, which can facilitate translation. PMID- 26747980 TI - On the importance of aging to the crack growth resistance of human enamel. AB - With improvements in oral health and an overall increase in quality of life, the percentage of fully or largely dentate seniors is increasing. Understanding the effects of aging on the mechanical properties of teeth is essential to the maintenance of lifelong oral health. In this investigation the effects of aging on the fracture toughness of human enamel were evaluated from incremental crack growth experiments performed on tissue of donor teeth representing "young" (17 ? age ? 25) and "old" (age ? 55) age groups. Results showed that the old enamel exhibited significantly lower resistance to fracture than that of the young tissue in two orthogonal directions of crack growth. For crack growth transverse to the enamel rods, the fracture toughness of the old enamel (0.37 +/- 0.15 MPa m(0.5)) was nearly 70% lower than that of tissue from the young teeth (1.23 +/- 0.20 MPa m(0.5)). Based on results from a mechanistic analysis of crack growth, the reduction in fracture resistance is attributed to a decrease in the degree of extrinsic toughening. The practice of restorative dentistry should account for these changes in tooth tissues in the treatment of senior patients. STATEMENT OF SIGNIFICANCE: The mechanical behavior of enamel has been studied for over 3 decades. Due to the limited volume of tissue available for evaluation, past work has been largely based on indentation methods. In this investigation we have evaluated the resistance to fracture of human enamel using a conventional fracture mechanics approach and incremental crack growth. We compared the fracture resistance of cuspal enamel obtained from the teeth of representative "young" and "old" donor groups. Our results show that there is a substantial reduction in the resistance to fracture with age, that it is anisotropic, and that the degradation is more severe than that which occurs to dentin. As such, we feel this work is a significant contribution to the field. PMID- 26747981 TI - Compounds altering fat storage in Daphnia magna. AB - The analysis of lipid disruptive effects in invertebrates is limited by our poor knowledge of the lipid metabolic pathways. A recent study showed that tributyltin activated the ecdysteroid, juvenile hormone and retinoic X receptor signaling pathways, and disrupted the dynamics of neutral lipids in the crustacean Daphnia magna impairing the transfer of triacylglycerols to eggs and hence promoting their accumulation in post-spawning females. Tributyltin disruptive effects correlated with lower fitness for offspring and adults. The present study aims to addresses effects of existing compounds on storage lipids in post-spawning females and their health effects. D. magna individuals were exposed 12 chemicals that included vertebrate obesogens (tributyltin, triphenyltin, bisphenol A, nonylphenol, di-2-ethylhexyl phthalate), other contaminants known to affect arthropods (pyriproxyfen, fenarimol, methoprene, emamectin benzoate and fluoxetine), as well as the natural hormones methyl farnesoate and 20 hydroxyecdysone. Reproductive effects were also assessed. Quantitative changes in storage lipids accumulated in lipid droplets were studied using Nile red staining, which showed a close relationship with whole organism levels of triacylglycerols. Ten compounds altered storage lipids in a concentration related manner enhancing (tributyltin, bisphenol A, methyl farnesoate, pyriproxyfen and 20-hydroxyecdysone) or decreasing (nonylphenol, fenarimol, emamectin benzoate, methoprene and fluoxetine) their levels in post-spawning females. Eight compounds that altered lipid levels also had detrimental effects on growth and/or reproduction. PMID- 26747982 TI - Antecedent conditions, hydrological connectivity and anthropogenic inputs: Factors affecting nitrate and phosphorus transfers to agricultural headwater streams. AB - This paper examines relationships between rainfall-runoff, catchment connectivity, antecedent moisture conditions and fertiliser application with nitrate-N and total phosphorus (TP) fluxes in an arable headwater catchment over three hydrological years (2012-2014). Annual precipitation totals did not vary substantially between years, yet the timing of rainfall strongly influenced runoff generation and subsequent nitrate-N and TP fluxes. The greatest nitrate-N (>250 kg N day(-1)) and TP (>10 kg TP day(-1)) fluxes only occurred when shallow groundwater was within 0.6m of the ground surface and runoff coefficients were greater than 0.1. These thresholds were reached less frequently in 2012 due to drought recovery resulting in lower annual nitrate-N (7.4 kg N ha(-1)) and TP (0.12 kg P ha(-1)) fluxes in comparison with 2013 (15.1 kg N ha(-1); 0.21 kg P ha(-1)). The wet winter of 2013 with elevated shallow groundwater levels led to more frequent activation of sub-surface pathways and tile drain flow. Throughout the period, dry antecedent conditions had a temporary effect in elevating TP loads. Evidence of TP source exhaustion after consecutive storm events can be attributed to the repeated depletion of temporarily connected critical source areas to the river network via impermeable road surfaces. Fertiliser application varied considerably across three years due to differences in crop rotation between farms, with annual N and P fertiliser inputs varying by up to 21% and 41%, respectively. Proportional reductions in annual riverine nitrate-N and TP loadings were not observed at the sub-catchment outlet as loadings were largely influenced by annual runoff. Nitrate loadings were slightly higher during fertiliser application, but there was little relationship between P fertiliser application and riverine TP load. These data indicate that this intensive arable catchment may be in a state of biogeochemical stationarity, whereby legacy stores of nutrients buffer against changes in contemporary nutrient inputs. PMID- 26747983 TI - A moni-modelling approach to manage groundwater risk to pesticide leaching at regional scale. AB - Historically, the approach used to manage risk of chemical contamination of water bodies is based on the use of monitoring programmes, which provide a snapshot of the presence/absence of chemicals in water bodies. Monitoring is required in the current EU regulations, such as the Water Framework Directive (WFD), as a tool to record temporal variation in the chemical status of water bodies. More recently, a number of models have been developed and used to forecast chemical contamination of water bodies. These models combine information of chemical properties, their use, and environmental scenarios. Both approaches are useful for risk assessors in decision processes. However, in our opinion, both show flaws and strengths when taken alone. This paper proposes an integrated approach (moni-modelling approach) where monitoring data and modelling simulations work together in order to provide a common decision framework for the risk assessor. This approach would be very useful, particularly for the risk management of pesticides at a territorial level. It fulfils the requirement of the recent Sustainable Use of Pesticides Directive. In fact, the moni-modelling approach could be used to identify sensible areas where implement mitigation measures or limitation of use of pesticides, but even to effectively re-design future monitoring networks or to better calibrate the pedo-climatic input data for the environmental fate models. A case study is presented, where the moni-modelling approach is applied in Lombardy region (North of Italy) to identify groundwater vulnerable areas to pesticides. The approach has been applied to six active substances with different leaching behaviour, in order to highlight the advantages in using the proposed methodology. PMID- 26747984 TI - Cotransport of clay colloids and viruses through water-saturated vertically oriented columns packed with glass beads: Gravity effects. AB - The cotransport of clay colloids and viruses in vertically oriented laboratory columns packed with glass beads was investigated. Bacteriophages MS2 and PhiX174 were used as model viruses, and kaolinite (KappaGa-1b) and montmorillonite (STx 1b) as model clay colloids. A steady flow rate of Q=1.5 mL/min was applied in both vertical up (VU) and vertical down (VD) flow directions. In the presence of KGa-1b, estimated mass recovery values for both viruses were higher for VD than VU flow direction, while in the presence of STx-1b the opposite was observed. However, for all cases examined, the produced mass of viruses attached onto suspended clay particles were higher for VD than VU flow direction, suggesting that the flow direction significantly influences virus attachment onto clays, as well as packed column retention of viruses attached onto suspended clays. KGa-1b hindered the transport of PhiX174 under VD flow, while STx-1b facilitated the transport of PhiX174 under both VU and VD flow directions. Moreover, KGa-1b and STx-1b facilitated the transport of MS2 in most of the cases examined except of the case where KGa-1b was present under VD flow. Also, the experimental data were used for the estimation of virus surface-coverages and virus surface concentrations generated by virus diffusion-limited attachment, as well as virus attachment due to sedimentation. Both sedimentation and diffusion limited virus attachment were higher for VD than VU flow, except the case of MS2 and STx-1b cotransport. The diffusion-limited attachment was higher for MS2 than PhiChi174 for all cases examined. PMID- 26747985 TI - Estimating cultural benefits from surface water status improvements in freshwater wetland ecosystems. AB - Freshwater wetlands provide crucial ecosystem services, though are subject to anthropogenic/natural stressors that provoke negative impacts on these ecosystems, services and values. The European Union Water Framework Directive aims to achieve good status of surface waters by 2015, through implementation of Catchment Management Plans. Implementation of Catchment Management Plans is costly, though associated benefits from improvements in surface water status are less well known. This paper establishes a functional relationship between surface water status and cultural ecosystem service values of freshwater systems. Hence, we develop a bio-economic valuation approach in which we relate ecological status and chemical status of surface waters (based on local physio-chemical and benthic macro-invertebrates survey data) to willingness-to-pay (using benefit-function transfer). Results for the Pateira de Fermentelos freshwater wetland (Portugal) show that the current status of surface waters is good from a chemical though only moderate from an ecological perspective. The current cultural ecosystem service value of the wetland is estimated at 1.54 m?/yr- increasing to 2.02 m?/yr in case good status of surface waters is obtained. Taking into account ecosystem services and values in decision making is essential to avoid costs from externalities and capture benefits from spill-overs--leading to more equitable, effective and efficient water resources management. PMID- 26747986 TI - Environmental and economic benefits of variable rate nitrogen fertilization in a nitrate vulnerable zone. AB - Agronomic input and management practices have traditionally been applied uniformly on agricultural fields despite the presence of spatial variability of soil properties and landscape position. When spatial variability is ignored, uniform agronomic management can be both economically and environmentally inefficient. The objectives of this study were to: i) identify optimal N fertilizer rates using an integrated spatio-temporal analysis of yield and site specific N rate response; ii) test the sensitivity of site specific N management to nitrate leaching in response to different N rates; and iii) demonstrate the environmental benefits of variable rate N fertilizer in a Nitrate Vulnerable Zone. This study was carried out on a 13.6 ha field near the Venice Lagoon, northeast Italy over four years (2005-2008). We utilized a validated crop simulation model to evaluate crop response to different N rates at specific zones in the field based on localized soil and landscape properties under rainfed conditions. The simulated rates were: 50 kg N ha(-1) applied at sowing for the entire study area and increasing fractions, ranging from 150 to 350 kg N ha(-1) applied at V6 stage. Based on the analysis of yield maps from previous harvests and soil electrical resistivity data, three management zones were defined. Two N rates were applied in each of these zones, one suggested by our simulation analysis and the other with uniform N fertilization as normally applied by the producer. N leaching was lower and net revenue was higher in the zones where variable rates of N were applied when compared to uniform N fertilization. This demonstrates the efficacy of using crop models to determine variable rates of N fertilization within a field and the application of variable rate N fertilizer to achieve higher profit and reduce nitrate leaching. PMID- 26747987 TI - Volatile dimethylsiloxanes in market seafood and freshwater fish from the Xuquer River, Spain. AB - Volatile dimethylsiloxanes are a family of synthetic organosilicon-compounds, which have received rising attention because of their widespread use and occurrence in the environment. In the present work, an analytical method based on ultrasound-assisted solid-liquid extraction (USAE) followed by gas chromatography coupled to tandem mass spectrometry (GC-MS/MS) has been optimized and applied to assess the presence of eight volatile dimethyl siloxanes (VMS) (hexamethylcyclotrisiloxane (D3), octamethylcyclotetra-siloxane (D4), decamethylcyclopentasiloxane (D5), dodecamethylcyclohexasiloxane (D6), octamethyltrisiloxane (MDM), decamethyltetrasiloxane (MD2M) and dodecamethylpentasiloxane (MD3M) and tetradecamethylhexasiloxane (MD4M)) in fish. The optimized method presented limits of quantification between 0.1 and 1.3 pg/g for linear volatile dimethylsiloxanes (lVMS) and between 13 and 39 pg/g for cyclic volatile dimethylsiloxanes (cVMS) and intraday relative standard deviation (between 1.9 and 7.0%). Recovery yields were between 71 and 92%. 40 fish samples collected in different markets in Barcelona, (Spain), and 16 samples of fish directly collected at the Xuquer River were analysed. cVMS were detected in almost all the river fish samples at concentrations between pg/g and ng/g, with a significant correlation between the fat content and VMS concentrations in fish. In addition, significant higher concentrations were found in market samples, suggesting sources of contamination from their manipulation and storage in indoor environments. Multivariate analyses were applied to the results and the siloxane profiles and analyte correlations are discussed. PMID- 26747988 TI - Do vineyards in contrasting landscapes contribute to conserve plant species of dry calcareous grasslands? AB - The increasing development of vineyards in Mediterranean areas worldwide is considered a major driver of conversion of several habitats of conservation concern, including calcareous dry grasslands that are targeted for biodiversity conservation by the European Union, according to Natura 2000 policies. Here, we aim at evaluating the potential of extensive vineyards located in contrasting landscapes (semi-natural vs crop-dominated) for providing suitable habitat conditions to plant species associated with dry grasslands. This study was carried out in one of the economically most important winemaking districts of Italy, characterized by a hilly landscape with steep slope vineyards. We compared plant communities of vineyards in contrasting landscapes with those of the remnants of dry grasslands. Our study demonstrates that landscape composition strongly affects local plant communities in vineyards, with a positive effect of semi-natural habitats bordering the cultivated areas. Our findings thus supply an additional tool for improving the effectiveness of viticultural landscapes for nature conservation. In particular, our results indicate that vineyards on steep slopes could provide moderate chance for the conservation of plant specialists inhabiting calcareous dry grasslands, depending on the landscape composition: vineyards embedded in semi-natural landscapes have more potential for conservation than those in crop-dominated landscapes. Our study also indicates that conservation efforts should aim at (a) decreasing the current management intensity that likely hampers the beneficial effects of semi-natural habitats in the surrounding landscape on local plant assemblages, and (b) strictly conserving the remnants of dry grasslands that are irreplaceable refugia for habitat specialists and species of conservation concern. PMID- 26747989 TI - Monitoring temporal changes in use of two cathinones in a large urban catchment in Queensland, Australia. AB - Wastewater analysis was used to examine prevalence and temporal trends in the use of two cathinones, methylone and mephedrone, in an urban population (>200,000 people) in South East Queensland, Australia. Wastewater samples were collected from the inlet of the sewage treatment plant that serviced the catchment from 2011 to 2013. Liquid chromatography coupled with tandem mass spectrometry was used to measure mephedrone and methylone in wastewater sample using direct injection mode. Mephedrone was not detected in any samples while methylone was detected in 45% of the samples. Daily mass loads of methylone were normalized to the population and used to evaluate methylone use in the catchment. Methylone mass loads peaked in 2012 but there was no clear temporal trend over the monitoring period. The prevalence of methylone use in the catchment was associated with the use of MDMA, the more popular analogue of methylone, as indicated by other complementary sources. Methylone use was stable in the study catchment during the monitoring period whereas mephedrone use has been declining after its peak in 2010. More research is needed on the pharmacokinetics of emerging illicit drugs to improve the applicability of wastewater analysis in monitoring their use in the population. PMID- 26747990 TI - Electrokinetic flushing with surrounding electrode arrangements for the remediation of soils that are polluted with 2,4-D: A case study in a pilot plant. AB - This work aimed to evaluate electrokinetic soil flushing (EKSF) technologies for the removal of 2,4-dichlorophenoxyacetic acid (2,4-D) from spiked soils using an electrode configuration consisting of one cathode surrounded by six anodes (1c6a) and one anode surrounded by 6 cathodes (1a6c). Experiments were conducted for over one month in a bench-scale set-up (175 dm(3) of capacity) that was completely automated and operated at a constant electric field (1.0V cm(-1)). The electrical current, temperature, pH, moisture and pollutant concentration in electrolyte wells were monitored daily, and at the end of the experiments, an in depth sectioned analysis of the complete soil section (post-mortem analysis) was conducted. Despite the geometric similarity, the two strategies led to very different results mainly in terms of water and herbicide mobilization, whereas pH and conductivity do not depend strongly on the electrode configuration. The volume of water extracted from cathodes with 1a6c is seven times higher than that of the 1c6a strategy. Herbicide was transported to the anode wells by electromigration and then dragged toward the cathode wells by electro-osmotic fluxes, with the first process being much more important. The configuration 1c6a was the most efficient and attained a transfer of 70% of the herbicide contained in the soil to flushing water in 35 days. These results outperform those obtained by the configuration 1a6c, for which less than 8% of the herbicide was transferred to flushing fluids in a much longer time (58 days). PMID- 26747991 TI - Fluoride: A naturally-occurring health hazard in drinking-water resources of Northern Thailand. AB - In Northern Thailand, incidences of fluorosis resulting from the consumption of high-fluoride drinking-water have been documented. In this study, we mapped the high-fluoride endemic areas and described the relevant transport processes of fluoride in enriched waters in the provinces of Chiang Mai and Lamphun. Over one thousand surface and sub-surface water samples including a total of 995 collected from shallow (depth: <= 30 m) and deep (> 30 m) wells were analysed from two unconnected high-fluoride endemic areas. At the Chiang Mai site, 31% of the shallow wells contained hazardous levels (>= 1.5 mg/L) of fluoride, compared with the 18% observed in the deep wells. However, at the Lamphun site, more deep wells (35%) contained water with at least 1.5mg/L fluoride compared with the shallow wells (7%). At the Chiang Mai site, the high-fluoride waters originate from a nearby geothermal field. Fluoride-rich geothermal waters are distributed across the area following natural hydrological pathways of surface and sub-surface water flow. At the Lamphun site, a well-defined, curvilinear high-fluoride anomalous zone, resembling that of the nearby conspicuous Mae Tha Fault, was identified. This similarity provides evidence of the existence of an unmapped, blind fault as well as its likely association to a geogenic source (biotite-granite) of fluoride related to the faulted zone. Excessive abstraction of ground water resources may also have affected the distribution and concentration of fluoride at both sites. The distribution of these high-fluoride waters is influenced by a myriad of complex natural and anthropogenic processes which thus created a challenge for the management of water resources for safe consumption in affected areas. The notion of clean and safe drinking water can be found in deeper aquifers is not necessarily true. Groundwater at any depth should always be tested before the construction of wells. PMID- 26747992 TI - NMR-based metabolomic analysis of Haliotis diversicolor exposed to thermal and hypoxic stresses. AB - Haliotis diversicolor is a commercially important cultured shellfish. It is also an important marine model organism for environmental science. High temperature accompanied with hypoxia frequently induces diseases or even death to abalones. In present study, (1)H NMR spectroscopy together with pattern recognition methods was used to investigate the responses of muscle and gill of H. diversicolor to thermal and hypoxic stresses. It was found that obvious gender-, time- and tissue specific metabolic responses were induced by thermal and hypoxic stresses. In combination with the changes of H. diversicolor in physiological features, the dual-modal stresses were suggested to mainly cause the disturbance in energy metabolism and osmotic balance in muscle and gill tissues with different mechanisms. Further, the corresponding correlation networks and metabolic pathways derived from the characteristic metabolites were used to assess the major metabolic functions of these characteristic metabolites. These findings shed some lights on the metabolic influences of environmental stresses on marine organisms. PMID- 26747993 TI - Associations between organohalogen concentrations and transcription of thyroid related genes in a highly contaminated gull population. AB - A number of studies have reported altered circulating thyroid hormone levels in birds exposed either in controlled settings or in their natural habitat to ubiquitous organohalogen compounds including organochlorines (OCs) and polybrominated diphenyl ether (PBDE) flame retardants. However, limited attention has been paid to underlying homeostatic mechanisms in wild birds such as changes in the expression of genes in the hypothalamic-pituitary-thyroid (HPT) axis. The objective of the present study was to investigate the relationships between hepatic concentrations of major organohalogens (PBDEs and OCs), and circulating thyroid hormone (free and total thyroxine (T4) and triiodothyronine (T3)) levels and transcription of 14 thyroid-related genes in three tissues (thyroid, brain, and liver) of an urban-adapted bird exposed to high organohalogen concentrations in the Montreal area (QC, Canada), the ring-billed gull (Larus delawarensis). Positive correlations were found between liver concentrations of several polychlorinated biphenyls (PCBs), PBDEs as well as chlordanes and total plasma T4 levels. Hepatic concentrations of several PBDEs were negatively correlated with mRNA levels of deiodinase type 3, thyroid peroxidase, and thyroid hormone receptor beta (TRbeta) in the thyroid gland. Liver PCB (deca-CB) correlated positively with mRNA levels of sodium-iodide symporter and TRalpha. In brain, concentrations of most PBDEs were positively correlated with mRNA levels of organic anion transporter protein 1C1 and transthyretin, while PCBs positively correlated with expression of TRalpha and TRbeta as well as deiodinase type 2. These multiple correlative linkages suggest that organohalogens operate through several mechanisms (direct or compensatory) involving gene transcription, thus potentially perturbing the HPT axis of this highly organohalogen-contaminated ring-billed gull population. PMID- 26747994 TI - Product screening for sources of halogenated flame retardants in Canadian house and office dust. AB - Human exposure to halogenated flame retardants (HFRs) such as polybrominated diphenyl ethers (PBDEs) and their replacements, can be related to exposure to indoor dust and direct contact with HFR-containing products. This study aimed to identify electronic products that contributed to HFRs measured in indoor dust and to develop a screening method for identifying HFRs in hard polymer products. Concentrations of 10 PBDEs and 12 halogenated replacements in dust and surface wipe samples of hard polymer casings of electronic products plus Br in the surfaces of those casing measured using X-ray fluorescence (XRF) were analyzed from 35 homes and 10 offices in Toronto (ON, Canada). HFR concentrations in dust and product wipes were positively correlated. Thus, we hypothesize that electronic products with the highest HFR concentrations contribute the most to concentrations in dust, regardless of the volatility of the HFR. Abundant HFRs in dust and product wipes were PBDEs (BDE-47, 99, 100, 153, 154, 183, 209), TDCPP, DBDPE, EH-TBB and BEHTBP. Older CRT TVs had the highest concentration of BDE-209 of all products tested. This was followed by higher concentrations of HFRs in PCs, Audio/Video (A/V) devices, small household appliances (HHAs) and flat screen TVs. The removal of HFRs from polymer surfaces using wipes supports concerns that HFRs could be transferred from these surfaces to hands as a result of direct contact with HFR-containing products. Surface wipe testing shows promise for screening additive HFRs. In comparison, the Br-content obtained using a handheld XRF analyzer did not correspond to concentrations obtained from surface wipe testing. PMID- 26747995 TI - Reference scenarios for exposure to plant protection products and invertebrate communities in stream mesocosms. AB - Higher tier aquatic risk assessment for plant protection products (PPPs) is often based on pond-like mesocosm studies in which transient and dynamic PPP exposure scenarios as observed in lotic systems are hardly achievable. Thus, the present study presents dynamic PPP exposure scenarios at different time scales under flow through conditions as typical for streams in agricultural landscapes. The stream mesocosm setup allows testing the influence of spatial gradients of exposure over the length of themesocosms. The use of the fluorescent tracer uranine revealed the hydraulic processes generally underlying peak- and hour-scale exposure scenarios and demonstrated an optimized application technique to achieve stable day-scale exposures. Furthermore, to account for potential reactions of invertebrates to PPP exposures in streams (e.g. avoidance behavior and drift), the present study thus aimed at a comprehensive evaluation on how PPP exposure and the establishment of invertebrates can be advanced within streammesocosm testing. For both, peak- and hour-scale exposure as well as the experiments considering the establishment of invertebrates, the presented compilation of experiments was able to highlight the influence of aquatic macrophyteswithin streammesocosms. Since the field relevance of the higher tier aquatic risk assessment for PPPs relies qualitatively on the presence of potentially sensitive or vulnerable species, those species were especially considered. Thus, the establishment of aquatic invertebrates in nondosed streams was evaluated with respect to (i) the presence of different aquatic macrophytes and (ii) the duration of the pre-experimental period. The present study highlights the beneficial influence of complex-structured macrophytes and prolonged pre experimental periods on the abundance of invertebrate taxa. Furthermore, population dynamics were evaluated statistically by simulating PPP-related declines of 30, 50 and 70%. Thereby, PMID- 26747996 TI - Lake biota response to human impact and local climate during the last 200 years: A multi-proxy study of a subalpine lake (Tatra Mountains, W Carpathians). AB - Element content, loss-on-ignition, chironomid analysis and (210)Pb dating were applied on a sediment core from a subalpine Tatra lake (Popradske pleso) to reveal the response of aquatic biota to eutrophication induced by human activities in the lake catchment. The lead dating indicates that the 0-8 cm section of the core represents the past ca 200 years, ending at ~1814 AD. Comparing the key changes of the proxies with human activities that are historically well documented, four phases of the recent lake development were distinguished: (1) a pre-tourism phase, (2) a phase of increasing touristic activity and early cottage development, (3) a phase of eutrophication, and (4) a phase of post-eutrophication. Neither touristic activity, nor early cottage development around the lake (1st and 2nd phases) had considerable influence on the chironomid assemblage structure or organic content of the lake. The most significant change both in chironomid assemblage structure and loss-on-ignition occurred during the 3rd phase, when a big tourist hotel was built close by the lake and started contaminating it via direct wastewater input. However, the structure of the chironomid assemblage has not changed significantly over time and the dominating taxa remained the same during the whole period. Parallel with the nutrient signal of the paleo assemblage, a secondary signal has been identified as the ratio of rheophilic taxa on total abundance that did not correlate with the sediment's organic content, and is most likely driven by local climatic oscillations. Changes of most of metal elements concentrations reflected rather bigger scale changes of industrial activities than local scale human disturbances. Our results indicate that hydromorphological properties can moderate the impact of organic pollution on the lake biota. PMID- 26747997 TI - Cities as selective land predators? A lesson on urban growth, deregulated planning and sprawl containment. AB - The present study investigates changes in the use of land caused by the expansion of an informal city in the Mediterranean region (Athens, Greece) and it proposes a simplified methodology to assess selective land take at the scale of municipalities. The amount of land take over twenty years (1987-2007) for cropland, sparsely vegetated areas and natural land was compared with the surface area of the respective class at the beginning of the study period (1987). Indicators of selective land take by class were correlated with socioeconomic indicators at the scale of municipalities to verify the influence of the local context and the impact of urban planning on land take processes. Evidence indicates that urban expansion into fringe land consumes primarily cropland and sparse vegetation in the case of the Athens' metropolitan region. Cropland and sparse vegetation were consumed proportionally more than the respective availability in 16 municipalities out of 60. Agricultural land take was positively correlated with population density and growth rate, rate of participation to the job market and road density. Sparse vegetation land take was observed in municipalities with predominance of high density settlements. As a result of second-home expansion in coastal municipalities, natural land was converted to urban use in proportion to the availability in the landscape. Urban planning seems to have a limited impact on selective land take. PMID- 26747998 TI - Evolution of uranium distribution and speciation in mill tailings, COMINAK Mine, Niger. AB - This study investigated the evolution of uranium distribution and speciation in mill tailings from the COMINAK mine (Niger), in production since 1978. A multi scale approach was used, which combined high resolution remote sensing imagery, ICP-MS bulk rock analyses, powder X-ray diffraction, Scanning Electron Microscopy, Focused Ion Beam--Transmission Electron Microscopy and X-ray Absorption Near Edge Spectroscopy. Mineralogical analyses showed that some ore minerals, including residual uraninite and coffinite, undergo alteration and dissolution during tailings storage. The migration of uranium and other contaminants depends on (i) the chemical stability of secondary phases and sorbed species (dissolution and desorption processes), and (ii) the mechanical transport of fine particles bearing these elements. Uranium is stabilized after formation of secondary uranyl sulfates and phosphates, and adsorbed complexes on mineral surfaces (e.g. clay minerals). In particular, the stock of insoluble uranyl phosphates increases with time, thus contributing to the long-term stabilization of uranium. At the surface, a sulfate-cemented duricrust is formed after evaporation of pore water. This duricrust limits water infiltration and dust aerial dispersion, though it is enriched in uranium and many other elements, because of pore water rising from underlying levels by capillary action. Satellite images provided a detailed description of the tailings pile over time and allow monitoring of the chronology of successive tailings deposits. Satellite images suggest that uranium anomalies that occur at deep levels in the pile are most likely former surface duricrusts that have been buried under more recent tailings. PMID- 26747999 TI - Polycyclic aromatic hydrocarbons (PAHs) concentration levels, pattern, source identification and soil toxicity assessment in urban traffic soil of Dhanbad, India. AB - Present study was carried out to assess and understand potential health risk and to examine the impact of vehicular traffic on the contamination status of urban traffic soils in Dhanbad City with respect to polycyclic aromatic hydrocarbons (PAHs). Eight urban traffic sites and two control/rural site surface soils were analyzed and the contents of 13 priority PAHs was determined. Total PAH concentration at traffic sites ranged from 1.019 MUg g(-1) to 10.856 MUg g(-1) with an average value of 3.488 MUg g(-1). At control/rural site, average concentration of total PAHs was found to be 0.640 MUg g(-1). PAH pattern was dominated by four- and five-ring PAHs (contributing >50% to the total PAHs) at all the eight traffic sites. On the other hand, rural soil showed a predominance of low molecular weight three-ring PAHs (contributing >30% to the total PAHs). Indeno[123-cd]pyrene/benz[ghi]perylene (IP/BgP) ratio indicated that PAH load at the traffic sites is predominated by the gasoline-driven vehicles. The ratio of Ant/(Ant+Phe) varied from 0.03 to 0.44, averaging 0.10; Fla/(Fla+Pyr) from 0.39 to 0.954, averaging 0.52; BaA/(BaA+Chry) from 0.156 to 0.60, averaging 0.44; and IP/(IP+BgP) from 0.176 to 0.811, averaging 0.286. The results indicated that vehicular emission was the major source for PAHs contamination with moderate effect of coal combustion and biomass combustion. Carcinogenic potency of PAH load in traffic soil was nearly 6.15 times higher as compared to the control/rural soil. PMID- 26748001 TI - Increases in soil water content after the mortality of non-native trees in oceanic island forest ecosystems are due to reduced water loss during dry periods. AB - The control of dominant, non-native trees can alter the water balance of soils in forest ecosystems via hydrological processes, which results in changes in soil water environments. To test this idea, we evaluated the effects of the mortality of an invasive tree, Casuarina equisetifolia Forst., on the water content of surface soils on the Ogasawara Islands, subtropical islands in the northwestern Pacific Ocean, using a manipulative herbicide experiment. Temporal changes in volumetric water content of surface soils at 6 cm depth at sites where all trees of C. equisetifolia were killed by herbicide were compared with those of adjacent control sites before and after their mortality with consideration of the amount of precipitation. In addition, the rate of decrease in the soil water content during dry periods and the rate of increase in the soil water content during rainfall periods were compared between herbicide and control sites. Soil water content at sites treated with herbicide was significantly higher after treatment than soil water content at control sites during the same period. Differences between initial and minimum values of soil water content at the herbicide sites during the drying events were significantly lower than the corresponding differences in the control quadrats. During rainfall periods, both initial and maximum values of soil water contents in the herbicided quadrats were higher, and differences between the maximum and initial values did not differ between the herbicided and control quadrats. Our results indicated that the mortality of non native trees from forest ecosystems increased water content of surface soils, due primarily to a slower rate of decrease in soil water content during dry periods. PMID- 26748000 TI - Chemometrics in biomonitoring: Distribution and correlation of trace elements in tree leaves. AB - The concentrations of 15 elements were measured in the leaf samples of Aesculus hippocastanum, Tilia spp., Betula pendula and Acer platanoides collected in May and September of 2014 from four different locations in Belgrade, Serbia. The objective was to assess the chemical characterization of leaf surface and in-wax fractions, as well as the leaf tissue element content, by analyzing untreated, washed with water and washed with chloroform leaf samples, respectively. The combined approach of self-organizing networks (SON) and Preference Ranking Organization Method for Enrichment Evaluation (PROMETHEE) aided by Geometrical Analysis for Interactive Aid (GAIA) was used in the interpretation of multiple element loads on/in the tree leaves. The morphological characteristics of the leaf surfaces and the elemental composition of particulate matter (PM) deposited on tree leaves were studied by using scanning electron microscopy (SEM) with energy dispersive spectroscopy (EDS) detector. The results showed that the amounts of retained and accumulated element concentrations depend on several parameters, such as chemical properties of the element and morphological properties of the leaves. Among the studied species, Tilia spp. was found to be the most effective in the accumulation of elements in leaf tissue (70% of the total element concentration), while A. hippocastanum had the lowest accumulation (54%). After water and chloroform washing, the highest percentages of removal were observed for Al, V, Cr, Cu, Zn, As, Cd and Sb (>40%). The PROMETHEE/SON ranking/classifying results were in accordance with the results obtained from the GAIA clustering techniques. The combination of the techniques enabled extraction of additional information from datasets. Therefore, the use of both the ranking and clustering methods could be a useful tool to be applied in biomonitoring studies of trace elements. PMID- 26748002 TI - Influence of oxygen content of the certain types of biodiesels on particulate oxidative potential. AB - Oxidative potential (OP) is related to the organic phase, specifically to its oxygenated organic fraction (OOA). Furthermore, the oxygen content of fuel molecules has significant influence on particulate OP. Thus, this study aimed to explore the actual dependency of the OOA and ROS to the oxygen content of the fuel. In order to reach the goal, different biodiesels blends, with various ranges of oxygen content; have been employed. The compact time of flight aerosol mass spectrometer (c-ToF AMS) enabled better identification of OOA. ROS monitored by using two assays: DTT and BPEA-nit. Despite emitting lower mass, both assays agreed that oxygen content of a biodiesel is directly correlated with its OOA, and highly related to its OP. Hence, the more oxygen included in the considered biodiesels, the higher the OP of PM emissions. This highlights the importance of taking oxygen content into account while assessing emissions from new fuel types, which is relevant from a health effects standpoint. PMID- 26748004 TI - Early atmospheric metal pollution provides evidence for Chalcolithic/Bronze Age mining and metallurgy in Southwestern Europe. AB - Although archaeological research suggests that mining/metallurgy already started in the Chalcolithic (3rd millennium BC), the earliest atmospheric metal pollution in SW Europe has thus far been dated to ~3500-3200 cal.yr. BP in paleo environmental archives. A low intensity, non-extensive mining/metallurgy and the lack of appropriately located archives may be responsible for this mismatch. We have analysed the older section (>2100 cal.yr. BP) of a peat record from La Molina (Asturias, Spain), a mire located in the proximity (35-100 km) of mines which were exploited in the Chalcolithic/Bronze Age, with the aim of assessing evidence of this early mining/metallurgy. Analyses included the determination of C as a proxy for organic matter content, lithogenic elements (Si, Al, Ti) as markers of mineral matter, and trace metals (Cr, Cu, Zn, Pb) and stable Pb isotopes as tracers of atmospheric metal pollution. From ~8000 to ~4980 cal.yr. BP the Pb composition is similar to that of the underlying sediments (Pb 15 +/- 4 MUg g(-1); (206)Pb/(207)Pb 1.204 +/- 0.002). A sustained period of low (206)Pb/(207)Pb ratios occurred from ~4980 to ~2470 cal.yr. BP, which can be divided into four phases: Chalcolithic (~4980-3700 cal.yr. BP), (206)Pb/(207)Pb ratios decline to 1.175 and Pb/Al ratios increase; Early Bronze Age (~3700-3500 cal.yr. BP), (206)Pb/(207)Pb increase to 1.192 and metal/Al ratios remain stable; Late Bronze Age (~3500-2800 cal.yr. BP), (206)Pb/(207)Pb decline to their lowest values (1.167) while Pb/Al and Zn/Al increase; and Early Iron Age (~2800-2470 cal.yr. BP), (206)Pb/(207)Pb increase to 1.186, most metal/Al ratios decrease but Zn/Al shows a peak. At the beginning of the Late Iron Age, (206)Pb/(207)Pb ratios and metal enrichments show a rapid return to pre-anthropogenic values. These results provide evidence of regional/local atmospheric metal pollution triggered by the earliest phases of mining/metallurgy in the area, and reconcile paleo environmental and archaeological records. PMID- 26748003 TI - Global DNA methylation loss associated with mercury contamination and aging in the American alligator (Alligator mississippiensis). AB - Mercury is a widespread environmental contaminant with exposures eliciting a well documented catalog of adverse effects. Yet, knowledge regarding the underlying mechanisms by which mercury exposures are translated into biological effects remains incomplete. DNA methylation is an epigenetic modification that is sensitive to environmental cues, and alterations in DNA methylation at the global level are associated with a variety of diseases. Using a liquid chromatography tandem mass spectrometry-based (LC-MS/MS) approach, global DNA methylation levels were measured in red blood cells of 144 wild American alligators (Alligator mississippiensis) from 6 sites with variable levels of mercury contamination across Florida's north-south axis. Variation in mercury concentrations measured in whole blood was highly associated with location, allowing the comparison of global DNA methylation levels across different "treatments" of mercury. Global DNA methylation in alligators across all locations was weakly associated with increased mercury exposure. However, a much more robust relationship was observed in those animals sampled from locations more highly contaminated with mercury. Also, similar to other vertebrates, global DNA methylation appears to decline with age in alligators. The relationship between age-associated loss of global DNA methylation and varying mercury exposures was examined to reveal a potential interaction. These findings demonstrate that global DNA methylation levels are associated with mercury exposure, and give insights into interactions between contaminants, aging, and epigenetics. PMID- 26748005 TI - Possible link between Hg and Cd accumulation in the brain of long-finned pilot whales (Globicephala melas). AB - The bioaccumulation of metals was investigated by analysis of liver, kidney, muscle and brain tissue of a pod of 21 long-finned pilot whales (Globicephala melas) of all ages stranded in Scotland, UK. The results are the first to report cadmium (Cd) passage through the blood-brain barrier of pilot whales and provide a comprehensive study of the long-term (up to 35 years) mammalian exposure to the environmental pollutants. Additionally, linear accumulation of mercury (Hg) was observed in all studied tissues, whereas for Cd this was only observed in the liver. Total Hg concentration above the upper neurochemical threshold was found in the sub-adult and adult brains and methylmercury (MeHg) of 2.2mg/kg was found in the brain of one individual. Inter-elemental analysis showed significant positive correlations of Hg with selenium (Se) and Cd with Se in all studied tissues. Furthermore, differences in the elemental concentrations in the liver and brain tissues were found between juvenile, sub-adult and adult groups. The highest concentrations of manganese, iron, zinc, Se, Hg and MeHg were noted in the livers, whereas Cd predominantly accumulated in the kidneys. High concentrations of Hg and Cd in the tissues of pilot whales presented in this study reflect ever increasing toxic stress on marine mammals. PMID- 26748006 TI - Trace element accumulation and trophic relationships in aquatic organisms of the Sundarbans mangrove ecosystem (Bangladesh). AB - The Sundarbans forest is the largest and one of the most diverse and productive mangrove ecosystems in the world. Located at the northern shoreline of the Bay of Bengal in the Indian Ocean and straddling India and Bangladesh, the mangrove forest is the result of three primary river systems that originate further north and northwest. During recent decades, the Sundarbans have been subject to increasing pollution by trace elements caused by the progressive industrialization and urbanization of the basins of these three rivers. As a consequence, animals and plants dwelling downstream in the mangroves are exposed to these pollutants in varying degrees, and may potentially affect human health when consumed. The aim of the present study was to analyse the concentrations of seven trace elements (Zn, Cu, Cr, Hg, Pb, Cd and As) in 14 different animal and plant species collected in the Sundarbans in Bangladesh to study their transfer through the food web and to determine whether their levels in edible species are acceptable for human consumption. delta(15)N values were used as a proxy of the trophic level. A decrease in Zn, Cu, Pb and Cd levels was observed with increasing trophic position. Trace element concentrations measured in all organisms were, in general, lower than the concentrations obtained in other field studies conducted in the same region. When examined with respect to accepted international standards, the concentrations observed in fish and crustaceans were generally found to be safe for human consumption. However, the levels of Zn in Scylla serrata and Cr and Cd in Harpadon nehereus exceeded the proposed health advisory levels and may be of concern for human health. PMID- 26748007 TI - Carbon exchange fluxes over peatlands in Western Siberia: Possible feedback between land-use change and climate change. AB - The growing demand for agricultural products has been leading to an expansion and intensification of agriculture around the world. More and more unused land is currently reclaimed in the regions of the former Soviet Union. Driven by climate change, the Western Siberian grain belt might, in a long-term, even expand into the drained peatland areas to the North. It is crucial to study the consequences of this land-use change with respect to the carbon cycling as this is still a major knowledge gap. We present for the first time data on the atmosphere ecosystem exchange of carbon dioxide and methane of an arable field and a neighboring unused grassland on peat soil in Western Siberia. Eddy covariance measurements were performed over one vegetation period. No directed methane fluxes were found due to an effective drainage of the study sites. The carbon dioxide fluxes appeared to be of high relevance for the global carbon and greenhouse gas cycles. They showed very site-specific patterns resulting from the development of vegetation: the persistent plants of the grassland were able to start photosynthesizing soon after snow melt, while the absence of vegetation on the managed field lead to a phase of emissions until the oat plants started to grow in June. The uptake peak of the oat field is much later than that of the grassland, but larger due to a rapid plant growth. Budgeting the whole measurement period, the grassland served as a carbon sink, whereas the oat field was identified to be a carbon source. The conversion from non-used grasslands on peat soil to cultivated fields in Western Siberia is therefore considered to have a positive feedback on climate change. PMID- 26748008 TI - Properties of the humic-like material arising from the photo-transformation of L tyrosine. AB - The UVB photolysis of L-tyrosine yields species with fluorescence and absorption spectra that are very similar to those of humic substances. By potentiometric measurements, chemical modeling and the application of NMR, mass spectrometry and laser flash photolysis, it was possible to get insights into the structural and chemical properties of the compounds derived by the L-tyrosine phototransformation. The photolytic process follows aromatic-ring hydroxylation and dimerization. The latter is presumably linked with the photoinduced generation of tyrosyl (phenoxy-type) radicals, which have a marked tendency to dimerize and possibly oligomerize. Interestingly, photoinduced transformation gives compounds with protogenic and complexation capabilities similar to those of the humic substances that occur naturally in surface waters. This finding substantiates a new and potentially important abiotic (photolytic) pathway for the formation of humic compounds in surface-water environments. PMID- 26748009 TI - Reductive dechlorination of tetrachloroethene in marine sediments: Biodiversity and dehalorespiring capabilities of the indigenous microbes. AB - Chlorinated compounds pose environmental concerns due to their toxicity and wide distribution in several matrices. Microorganisms specialized in leading anaerobic reductive dechlorination (RD) processes, including Dehalococcoides mccartyi (Dhc), are able to reduce chlorinated compounds to harmless products or to less toxic forms. Here we report the first detailed study dealing with the RD potential of heavy polluted marine sediment by evaluating the biodegradation kinetics together with the composition, dynamics and activity of indigenous microbial population. A microcosm study was conducted under strictly anaerobic conditions on marine sediment collected near the marine coast of Sarno river mouth, one of the most polluted river in Europe. Tetrachloroethene (PCE), used as model pollutant, was completely converted to ethene within 150 days at reductive dechlorination rate equal to 0.016 meq L(-1) d(-1). Consecutive spikes of PCE allowed increasing the degradation kinetics up to 0.1 meq L(-1)d(-1) within 20 days. Strictly anaerobiosis and repeated spikes of PCE stimulated the growth of indigenous Dhc cells (growth yield of ~7.0 E + 07 Dhc cells per MUM Cl(-1) released). Dhc strains carrying the reductive dehalogenase genes tceA and vcrA were detected in the original marine sediment and their number increased during the treatment as demonstrated by the high level of tceA expression at the end of the microcosm study (2.41 E + 05 tceA gene transcripts g(-1)). Notably, the structure of the microbial communities was fully described by Catalysed Reporter Deposition Fluorescence In Situ Hybridization (CARD-FISH) as wells as the dynamics of the dechlorinating bacteria during the microcosms operation. Interestingly, a direct role of Dhc cells was ascertained suggesting the existence of strains adapted at salinity conditions. Additionally, non-Dhc Chloroflexi were retrieved in the original sediment and were kept stable over time suggesting their likely flanking role of the RD process. PMID- 26748010 TI - Molecular evolution of fever, thrombocytopenia and leukocytopenia virus (FTLSV) based on whole-genome sequences. AB - FTLSV is a novel bunyavirus that was discovered in 2007 in the Henan province of China and has reported case fatality rates of up to 30%. Despite the high case fatality rate, knowledge of the evolution and molecular epidemiology of FTLSV is limited. In this study, detailed phylogenetic analyses were performed on whole genome sequences to examine the virus's evolutionary rates, estimate dates of common ancestry, and determine the population dynamics and selection pressure for FTLSV. The evolutionary rates of FTLSV were estimated to be 2.28*10(-4), 2.42*10( 4) and 1.19*10(-4) nucleotide substitutions/site/year for the S, M and L segments, respectively. The most recent ancestor of the viruses existed approximately 182-294 years ago. Evidence of RNA segment reassortment was found in FTLSV. A Bayesian skyline plot showed that after a period of genetic stability following high variability, the FTLSV population appeared to have contracted it. Selection pressures were estimated and revealed an abundance of negatively selected sites and sparse positively selected sites. These data will be valuable in understanding the evolution and molecular epidemiology of FTLSV, eventually helping to determine mechanisms of emergence and pathogenicity and the level of the virus's threat to public health. PMID- 26748012 TI - Let there be more light! PMID- 26748011 TI - The Path of Least Resistance: Mechanisms to Reduce Influenza's Sensitivity to Oseltamivir. PMID- 26748013 TI - 2015, A Year of Light!! PMID- 26748014 TI - Generation and vulnerability of deep cerebellar nuclei neurons in the weaver condition along the anteroposterior and mediolateral axes. AB - Production and death of deep cerebellar nuclei (DCN) neurons were investigated in the weaver condition at appropriate anatomical levels throughout the mediolateral (medial, intermediate and lateral) and rostrocaudal (rostral, middle and caudal) axes of three DCN-cell groups: the fastigial, the interposed and the dentate nuclei. Current results have denoted that the deficit of DCN neurons is always more important in the homozygous weaver than in the heterozygous weaver mice. No loss of neurons was found in the dentate nucleus. In the mediolateral axis, an intranuclear gradient of depletion was observed in the mutant mice; in a given deep nucleus, neurodegeneration was more prominent in the medial pars than in lateral ones. In the rostrocaudal axis, on the other hand, when each deep nucleus was studied and compared as a whole, neuron loss was higher in the fastigial nucleus than in the interposed nucleus, which, in turn, was more important than in the dentate nucleus. These data suggest that, in the weaver condition, an internuclear gradient of neurodegeneration exists. Moreover, neurons located in rostral parts of a given nucleus appear to be more vulnerable than those settled in middle parts and these, in turn, are more than the caudal ones. These results seem to indicate the presence of an intranuclear gradient of depletion. Current autoradiographic results have revealed that, in the rostrocaudal axis, deep neurons are settled in the weaver cerebellum following three neurogenetic gradients. The first of these is internuclear; if each deep nucleus is analyzed and compared as a whole, the fastigial nucleus has more late-generated neurons than the interposed nucleus, and this, in turn, has more than the dentate nucleus. The second gradient is also internuclear; if the proportion of late-born neurons is compared throughout the rostral levels from each deep nucleus, it is observed that proportions increase from the fastigial to the dentate nucleus. A similar picture emerges when the middle and caudal regions are taken into account. The third gradient is intranuclear; in a given deep nucleus, the rostral region always presents more late-produced neurons than the middle region and these, in turn, more than in the caudal level. PMID- 26748015 TI - The fungicide thiabendazole causes apoptosis in rat hepatocytes. AB - Many pharmaceutical drugs cause hepatotoxicity in humans leading to severe liver diseases, representing a serious public health issue. This study investigates the ability of the anthelmintic and antifungal drug thiabendazole to cause cell death by apoptosis and metabolic changes in primary cultures of rat hepatocytes. Thiabendazole (200-500 MUM) induced apoptosis in hepatocytes after 1 to 24h, causing loss of mitochondrial membrane potential, cytochrome c release from mitochondria, Fas-associated death domain (FADD) translocation from the cytosol to membranes, and activation of caspases-3, -8 and -9. Thus, thiabendazole activated both the mitochondrial and death receptor pathways of apoptosis. Under these conditions, cell death by necrosis was not detected following exposure to thiabendazole (100-500 MUM) for 24-48 h, measured by lactate dehydrogenase release and propidium iodide uptake. Furthermore, thiabendazole increased activities of cytochrome P450 (CYP) isoenzymes CYP1A and CYP2B after 24 and 48 h, determined by 7-ethoxyresorufin-O-deethylase (EROD) and 7-pentoxyresorufin-O dealkylase (PROD) activities, respectively. An important finding is that thiabendazole can eliminate hepatocytes by apoptosis, which could be a sensitive marker for hepatic damage and cell death. This study improves understanding of the mode of cell death induced by thiabendazole, which is important given that humans and animals are exposed to this compound as a pharmaceutical agent and in an environmental context. PMID- 26748016 TI - Membrane pore formation in atomistic and coarse-grained simulations. AB - Biological cells and their organelles are protected by ultra thin membranes. These membranes accomplish a broad variety of important tasks like separating the cell content from the outer environment, they are the site for cell-cell interactions and many enzymatic reactions, and control the in- and efflux of metabolites. For certain physiological functions e.g. in the fusion of membranes and also in a number of biotechnological applications like gene transfection the membrane integrity needs to be compromised to allow for instance for the exchange of polar molecules across the membrane barrier. Mechanisms enabling the transport of molecules across the membrane involve membrane proteins that form specific pores or act as transporters, but also so-called lipid pores induced by external fields, stress, or peptides. Recent progress in the simulation field enabled to closely mimic pore formation as supposed to occur in vivo or in vitro. Here, we review different simulation-based approaches in the study of membrane pores with a focus on lipid pore properties such as their size and energetics, poration mechanisms based on the application of external fields, charge imbalances, or surface tension, and on pores that are induced by small molecules, peptides, and lipids. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Rog. PMID- 26748018 TI - Fully automated one-pot two-step synthesis of 4-[(18)F]-ADAM, a potent serotonin transporter imaging agent. AB - INTRODUCTION: N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4 [(18)F]-ADAM, 2) is a potent serotonin transporter (SERT) imaging agent. In order to fulfill the demand of clinical studies, we have developed a fully automated one-pot two-step synthesis of this potent SERT imaging agent. METHODS: The 4 [(18)F]-ADAM (2) was synthesized using a commercially available GE TRACERlab FN module. Briefly, the precursor, N,N-dimethyl-2-(2,4-dinitrophenylthio) benzylamine (1) in DMSO was reacted with K[(18)F]/K2.2.2 in a glassy carbon reaction vessel at 120 degrees C for 7.5min followed by reduction of the intermediate with NaBH4/Cu(OAc)2 in EtOH in the same vessel at 80 degrees C for 20min. The reaction mixture was then purified with high-performance liquid chromatography (HPLC) and solid phase extraction (SPE) to give (2). The quality of (2) synthesized by this method was verified by HPLC and TLC as compared to its authentic sample synthesized by two-pot two-step method. RESULTS: Using this automated one-pot two-step method, the radiochemical yield (RCY) of (2) was 2.5+/ 0.8% (n=12, EOS) in a synthesis time of 100+/-6min from EOB with a specific activity of 4.4+/-1.9Ci/MUmol (n=12, EOS). Radioligand (2) was stable over 4h at room temperature. CONCLUSIONS: This fully automated one-pot two-step synthetic method using a commercially available GE TRACERlab FN module could simplify the synthesis of 4-[(18)F]-ADAM (2) and fulfill its demand for both animal and human studies, especially for study sites without a cyclotron. PMID- 26748017 TI - Auger electron-emitting (111)In-DTPA-NLS-CSL360 radioimmunoconjugates are cytotoxic to human acute myeloid leukemia (AML) cells displaying the CD123(+)/CD131(-) phenotype of leukemia stem cells. AB - Chimeric IgG1 monoclonal antibody CSL360 recognizes the CD123(+)/CD131(-) phenotype expressed by leukemic stem cells (LSC). Auger electron-emitting (111)In DTPA-NLS-CSL360 radioimmunoconjugates incorporating nuclear translocation sequence (NLS) peptides bound specifically to Raji cells transfected with CD123 and exhibited a KD of 11nmols/L in a competition receptor-binding assay using CD123-transfected CHO cells. (111)In-DTPA-NLS-CSL360 was bound, internalized and transported to the nucleus of human AML-5 myeloid leukemia cells. The clonogenic survival of AML-5 cells was reduced by (111)In-DTPA-NLS-CSL360 up to 3.7-fold. Isotype control (111)In-DTPA-chIgG1 was 2-fold less cytotoxic, and unlabeled CSL360, DTPA-NLS-CSL360 or free (111)In acetate did not decrease cell survival. These results are promising for further evaluation of (111)In-DTPA-NLS-CSL360 for Auger electron radioimmunotherapy of AML targeting the critical LSC subpopulation. PMID- 26748020 TI - Generalized evaluation of environmental radioactivity measurements with UncertRadio. Part I: Methods without linear unfolding. AB - It is shown how a generalized evaluation of a large variety of environmental radioactivity measurements, without and with using linear unfolding, can be performed with a single program, UncertRadio (UR). Using a function parser allows deriving numerical partial derivatives for ISO GUM compatible uncertainty propagation. The evaluation within UR is extended to include ISO 11929 decision thresholds and detection limits. Alternatively, propagation of distributions with MC simulation is included. Part I gives an overview considering evaluations without using linear unfolding. PMID- 26748019 TI - Study of formation of deep trapping mechanism by UV, beta and gamma irradiated Eu(3+) activated SrY2O4 and Y4Al2O9 phosphors. AB - This paper reports the thermoluminescence properties of Eu(3+) doped different host matrix phosphors (SrY2O4 and Y4Al2O9). The phosphor is prepared by high temperature solid state reaction method. The method is suitable for large scale production and fixed concentration of boric acid using as a flux. The prepared samples were characterized by X-ray diffraction technique and the crystallite size calculated by Scherer's formula. The prepared phosphor characterized by Scanning Electron Microscopic (SEM), Fourier Transform Infrared (FTIR), Energy Dispersive X-ray analysis (EDX), thermoluminescence (TL) and Transmission Electron Microscopic (TEM) techniques. The prepared phosphors for different concentration of Eu(3+) ions were examined by TL glow curve for UV, beta and gamma irradiation. The UV 254nm source used for UV irradiation, Sr(90) source was used for beta irradiation and Co(60) source used for gamma irradiation. SrY2O4:Eu(3+)and Y4Al2O9:Eu(3+) phosphors which shows both higher temperature peaks and lower temperature peaks for UV, beta and gamma irradiation. Here UV irradiated sample shows the formation of shallow trap (surface trapping) and the gamma irradiated sample shows the formation of deep trapping. The estimation of trap formation was evaluated by knowledge of trapping parameters. The trapping parameters such as activation energy, order of kinetics and frequency factor were calculated by peak shape method. Here most of the peak shows second order of kinetics. The effect of gamma, beta and UV exposure on TL studies was also examined and it shows linear response with dose which indicate that the samples may be useful for TL dosimetry. Formation of deep trapping mechanism by UV, beta and gamma irradiated Eu(3+) activated SrY2O4 and Y4Al2O9 phosphors is discussed in this paper. PMID- 26748021 TI - The time course of systems consolidation of spatial memory from recent to remote retention: A comparison of the Immediate Early Genes Zif268, c-Fos and Arc. AB - Systems consolidation is a process involving the stabilisation of memory traces in the neocortex over time. The medial prefrontal cortex becomes increasingly important during the retrieval of older memories, however the timescale of its involvement is unclear, and the contribution of other neocortical brain regions to remote memory have received little attention. The Immediate Early Genes (IEGs) Zif268, c-Fos and Arc have been utilised as markers of neural activity during spatial memory retrieval, however the lack of a direct comparison between them hinders the interpretation of results. To address these questions, we examined the expression of Zif268, Arc and c-Fos protein in the medial prefrontal cortex, as well as the hippocampus, and the entorhinal, perirhinal, retrosplenial and parietal cortices of male Wistar rats following a probe trial of the Morris water maze either one day, seven days, 14 days or 30 days after acquisition. Activity of the medial prefrontal cortex during retrieval, as measured by all three IEGs, increased in correspondence with the age of the memory, reaching significance between 14 and 30 days. Similar increases in c-Fos and Arc were observed over the course of consolidation in other neocortical and parahippocampal areas, however this pattern was not observed with Zif268. Activity of the hippocampus remained largely unchanged across retention intervals. These findings suggest that systems consolidation of spatial memory takes at least two weeks, are consistent with an ongoing role for the hippocampus in the retrieval of spatial memory, and suggest that c-Fos and Arc may be a more sensitive measure of neural activity in response to behavioural tasks than Zif268. PMID- 26748023 TI - Coordinating different representations in the hippocampus. AB - The processes that organize different thoughts and memories, allowing the separation of currently relevant and irrelevant information, are collectively known as cognitive control. The neuronal mechanisms of these processes can be investigated by place cell ensemble recordings during behaviors and environmental manipulations that present cognitive control challenges to selectively represent one of multiple possible alternative estimates of location. We review place cell studies that investigate responses to manipulations that dissociate the environment into two or more spatial frames of locations, often times to test notions of pattern separation. Manipulations, such as continuously rotating the recording chamber reveal that the ensemble discharge in hippocampus self organizes into multiple, transiently-organized representations of space, each defined by the subset of coactive cells. Ensemble discharge in the hippocampus alternates between separate representations of frame-specific positions on timescales from 25 ms to several seconds. The dynamic, functional grouping of discharge into transiently co-active subsets of cells is predicted by the animal's changing behavioral needs. In addition to identifying neural correlates of cognitive control in hippocampus, these observations demonstrate that the separation of neuronal activity into distinctive representations depends on ongoing cognitive demands and that what can appear as noise, deviations from receptive field tuning, can substantially be the result of these internal knowledge-guided fluctuations. These findings inspire a new perspective that should be taken into account when investigating pattern separation--a perspective that emphasizes changes in hippocampal neural discharge that are happening on a short timescale and does not assume that patterns of neural discharge are steady and stationary across the several minutes of the recordings. PMID- 26748026 TI - A single session of meditation reduces of physiological indices of anger in both experienced and novice meditators. AB - The goal of the present study was to explore how anger reduction via a single session of meditation might be measured using psychophysiological methodologies. To achieve this, 15 novice meditators (Experiment 1) and 12 practiced meditators (Experiment 2) completed autobiographical anger inductions prior to, and following, meditation training while respiration rate, heart rate, and blood pressure were measured. Participants also reported subjective anger via a visual analog scale. At both stages, the experienced meditators' physiological reaction to the anger induction reflected that of relaxation: slowed breathing and heart rate and decreased blood pressure. Naive meditators exhibited physiological reactions that were consistent with anger during the pre-meditation stage, while after meditation training and a second anger induction they elicited physiological evidence of relaxation. The current results examining meditation training show that the naive group's physiological measures mimicked those of the experienced group following a single session of meditation training. PMID- 26748025 TI - Finger counting habit and spatial-numerical association in children and adults. AB - Sensory-motor experiences are known to build up concrete and abstract concepts during the lifespan. The present study aimed to test how finger counting habits (right-hand vs. left-hand starters) could influence the spatial-numerical representation in number-to-position (explicit) and digit-string bisection (implicit) tasks. The subjects were Italian primary school children (N=184, from the first to the fifth year) and adults (N=42). No general preference for right- or left-starting in the finger counting was found. In the explicit task, right- or left-starting did not affect performance. In the implicit task, the right-hand starters shifted from the left to the right space when bisecting small and large numbers respectively, while the left-hand starters shifted from the right to the left space with higher leftward bias for large numbers. The finger configuration in Italian children and adults influences the spatial-numerical representation, but only when implicit number processing is required by the task. PMID- 26748032 TI - Laboratory audit as part of the quality assessment of a primary HPV-screening program. AB - BACKGROUND: As primary HPV screening programs are rolled out, methods are needed for routine quality assurance of HPV laboratory analyzes. OBJECTIVE: To explore the use of similar design for audit as currently used in cytology-based screening, to estimate the clinical sensitivity to identify women at risk for CIN 3 or worse (CIN3+). STUDY DESIGN: Population-based cohort study conducted within the cervical screening program in Stockholm, Sweden, in 2011-2012. All women with histopathologically confirmed CIN3+ in the following two years were identified by registry analysis. Primary HPV and cytology screening results were collected. For women who had not been HPV tested, biobanked cytology samples were HPV-tested. If the original HPV result had been negative, the sample and subsequent biopsies were analyzed with broad HPV typing (general primer PCR and Luminex). RESULTS: 154 women had a biobanked prediagnostic cytology sample taken up to 2 years before a histopathologically confirmed CIN3+. The high-risk HPV-positivity was 97% (148/154 women), whereas 143/154 (94%) women had had a cytological abnormality. Among the six HPV-negative samples, one sample was HPV 33 positive in repeat testing whereas the other five cases were HPV-negative also on repeat testing, but HPV-positive in the subsequent tumor tissue. CONCLUSIONS: A sensitivity of the HPV test that is higher than the sensitivity of cytology suggests adequate quality of the testing. Regular audits of clinical sensitivity, similar to those of cytology-based screening, should be used also in HPV-based screening programs, in order to continuously monitor the performance of the analyzes. PMID- 26748022 TI - Representation of memories in the cortical-hippocampal system: Results from the application of population similarity analyses. AB - Here we consider the value of neural population analysis as an approach to understanding how information is represented in the hippocampus and cortical areas and how these areas might interact as a brain system to support memory. We argue that models based on sparse coding of different individual features by single neurons in these areas (e.g., place cells, grid cells) are inadequate to capture the complexity of experience represented within this system. By contrast, population analyses of neurons with denser coding and mixed selectivity reveal new and important insights into the organization of memories. Furthermore, comparisons of the organization of information in interconnected areas suggest a model of hippocampal-cortical interactions that mediates the fundamental features of memory. PMID- 26748031 TI - Aquaporin-4 deficiency diminishes the differential degeneration of midbrain dopaminergic neurons in experimental Parkinson's disease. AB - Parkinson's disease (PD) is primarily due to the progressive, selective and irreversible loss of dopaminergic (DA) neurons in the substantia nigra (SN). Interestingly, DA neurons in the ventral and lateral SN are much more susceptible than adjacent dopamine neurons in the ventral tegmental area (VTA) not only in human PD but in many PD model systems. However, the molecular causes of regional vulnerability in PD remain unknown. In our previous studies, we established acute PD animal models by administration of MPTP (1-methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine), and found that AQP4 knockout mice were significantly more prone to MPTP-induced neurotoxicity. Here, we further observe that AQP4 deficiency resulted in the same susceptible to MPTP between SN DA neuron and VTA neurons both in acute and chronic PD model. Moreover, we show that AQP4 deficiency increased the numbers of reactive astrocytes and microglias not only in the SN and but also in the VTA under basal and MPTP-induced situations. Meanwhile, AQP4 deficiency disrupted the balance of the pro-inflammatory cytokine/neurotrophin in midbrain. Taken together, these results demonstrate that glial AQP4 is involved in the susceptibility differences of DA neurons between SN and VTA, although the precise mechanism of AQP4 remains to be explored. Moreover, these findings also suggest that these susceptibility differences are not only due to intrinsic neuronal factors, but also attribute to differences in astrocytes of these regions. PMID- 26748033 TI - Preconditioning is hormesis part II: How the conditioning dose mediates protection: Dose optimization within temporal and mechanistic frameworks. AB - In Part I, hormetic doses of a variety of agents stimulated adaptive responses that conditioned and protected cells against the subsequent toxicity resulting from a second, higher dose (called a challenging dose) of the same or different agents. Herein (Part II), the optimal conditioning (hormetic) doses of many agents are documented, cellular mechanisms and temporal profiles are examined from which the conditioning (hormetic) responses are elicited, and the optimal conditioning doses are compared to the levels at which optimal protection occurs in response to the toxic challenge dose. Entry criteria for study evaluation required a conditioning mechanism-induced endpoint response, an hormetic/biphasic dose response for the protective response following the challenging dose, and a mechanistic assessment of how the conditioning dose afforded protection against a toxic challenging dose. The conditioning dose that demonstrated the largest increase in a mechanism-related conditioning (hormetic) response (i.e., prior to administration of the challenging dose) was the same dose that was optimally protective following the challenging dose. Specific receptor antagonists and/or inhibitors of cell signaling pathways which blocked the induction of conditioning (hormetic) effects during the conditioning period abolished the protective effects following the application of a challenge dose, thus identifying a specific and essential component of the hormetic mechanism. Conditioning responses often had sufficient doses to assess the nature of the dose response. In each of the cases these mechanism-based endpoints displayed an hormetic dose response. The present analysis reveals that hormetic biphasic dose responses were associated with both the conditioning process and the protective effects elicited following the challenging dose. Furthermore, based on optimal dosage, temporal relationships and the known mediating actions of receptor-based and/or cell signaling-based mechanisms, the protective effects were shown to be directly linked to the actions of the conditioning (hormetic) doses. These findings indicate that the biological/biomedical effects induced by conditioning represent a specific type of hormetic dose response and thereby contribute significantly to a generalization of the hormetic concept. PMID- 26748024 TI - Fear potentiated startle increases phospholipase D (PLD) expression/activity and PLD-linked metabotropic glutamate receptor mediated post-tetanic potentiation in rat amygdala. AB - Long-term memory (LTM) of fear stores activity dependent modifications that include changes in amygdala signaling. Previously, we identified an enhanced probability of release of glutamate mediated signaling to be important in rat fear potentiated startle (FPS), a well-established translational behavioral measure of fear. Here, we investigated short- and long-term synaptic plasticity in FPS involving metabotropic glutamate receptors (mGluRs) and associated downstream proteomic changes in the thalamic-lateral amygdala pathway (Th-LA). Aldolase A, an inhibitor of phospholipase D (PLD), expression was reduced, concurrent with significantly elevated PLD protein expression. Blocking the PLD mGluR signaling significantly reduced PLD activity. While transmitter release probability increased in FPS, PLD-mGluR agonist and antagonist actions were occluded. In the unpaired group (UNP), blocking the PLD-mGluR increased while activating the receptor decreased transmitter release probability, consistent with decreased synaptic potentials during tetanic stimulation. FPS Post-tetanic potentiation (PTP) immediately following long-term potentiation (LTP) induction was significantly increased. Blocking PLD-mGluR signaling prevented PTP and reduced cumulative PTP probability but not LTP maintenance in both groups. These effects are similar to those mediated through mGluR7, which is co immunoprecipitated with PLD in FPS. Lastly, blocking mGluR-PLD in the rat amygdala was sufficient to prevent behavioral expression of fear memory. Thus, our study in the Th-LA pathway provides the first evidence for PLD as an important target of mGluR signaling in amygdala fear-associated memory. Importantly, the PLD-mGluR provides a novel therapeutic target for treating maladaptive fear memories in posttraumatic stress and anxiety disorders. PMID- 26748034 TI - Dopaminergic drugs in type 2 diabetes and glucose homeostasis. AB - The importance of dopamine in central nervous system function is well known, but its effects on glucose homeostasis and pancreatic beta cell function are beginning to be unraveled. Mutant mice lacking dopamine type 2 receptors (D2R) are glucose intolerant and have abnormal insulin secretion. In humans, administration of neuroleptic drugs, which block dopamine receptors, may cause hyperinsulinemia, increased weight gain and glucose intolerance. Conversely, treatment with the dopamine precursor l-DOPA in patients with Parkinson's disease reduces insulin secretion upon oral glucose tolerance test, and bromocriptine improves glycemic control and glucose tolerance in obese type 2 diabetic patients as well as in non diabetic obese animals and humans. The actions of dopamine on glucose homeostasis and food intake impact both the autonomic nervous system and the endocrine system. Different central actions of the dopamine system may mediate its metabolic effects such as: (i) regulation of hypothalamic noradrenaline output, (ii) participation in appetite control, and (iii) maintenance of the biological clock in the suprachiasmatic nucleus. On the other hand, dopamine inhibits prolactin, which has metabolic functions; and, at the pancreatic beta cell dopamine D2 receptors inhibit insulin secretion. We review the evidence obtained in animal models and clinical studies that posited dopamine receptors as key elements in glucose homeostasis and ultimately led to the FDA approval of bromocriptine in adults with type 2 diabetes to improve glycemic control. Furthermore, we discuss the metabolic consequences of treatment with neuroleptics which target the D2R, that should be monitored in psychiatric patients to prevent the development in diabetes, weight gain, and hypertriglyceridemia. PMID- 26748036 TI - Exploiting plant alkaloids. AB - Alkaloid-containing plants have been used for medicine since ancient times. Modern pharmaceuticals still rely on alkaloid extraction from plants, some of which grow slowly, are difficult to cultivate and produce low alkaloid yields. Microbial cells as alternative alkaloid production systems are emerging. Before industrial application of genetically engineered bacteria and yeasts, several steps have to be taken. Original alkaloid-forming enzymes have to be elucidated from plants. Their activity in the heterologous host cells, however, may be low. The exchange of individual plant enzymes for alternative catalysts with better performance and optimal fermentation parameters appear promising. The overall aim is enhancement and stabilization of alkaloid yields from microbes in order to replace the tedious extraction of low alkaloid concentrations from intact plants. PMID- 26748035 TI - The control of tissue fibrosis by the inflammatory molecule LIGHT (TNF Superfamily member 14). AB - The TNF Superfamily member LIGHT (TNFSF14) has recently emerged as a potential target for therapeutic interventions aiming to halt tissue fibrosis. In this perspective, we discuss how LIGHT may influence the inflammatory and remodeling steps that characterize fibrosis, relevant for many human diseases presenting with scarring such as asthma, idiopathic pulmonary fibrosis, systemic sclerosis, and atopic dermatitis. LIGHT acts through two receptors in the TNF receptor superfamily, HVEM (TNFRSF14) and LTbetaR (TNFRSF3), which are broadly expressed on hematopoietic and non-hematopoietic cells. LIGHT can regulate infiltrating T cells, macrophages, and eosinophils, controlling their trafficking or retention in the inflamed tissue, their proliferation, and their ability to produce cytokines that amplify fibrotic processes. More interestingly, LIGHT can act on structural cells, namely epithelial cells, fibroblasts, smooth muscle cells, adipocytes, and endothelial cells. By signaling through either HVEM or LTbetaR expressed on these cells, LIGHT can contribute to their proliferation and expression of chemokines, growth factors, and metalloproteinases. This will lead to hyperplasia of epithelial cells, fibroblasts, and smooth muscle cells, deposition of extracellular matrix proteins, vascular damage, and further immune alterations that in concert constitute fibrosis. Because of its early expression by T cells, LIGHT may be an initiator of fibrotic diseases, but other sources in the immune system could also signify a role for LIGHT in maintaining or perpetuating fibrotic activity. LIGHT may then be an attractive prognostic marker as well as an appealing target for fibrosis therapies relevant to humans. PMID- 26748037 TI - Biobased organic acids production by metabolically engineered microorganisms. AB - Bio-based production of organic acids via microbial fermentation has been traditionally used in food industry. With the recent desire to develop more sustainable bioprocesses for production of fuels, chemicals and materials, the market for microbial production of organic acids has been further expanded as organic acids constitute a key group among top building block chemicals that can be produced from renewable resources. Here we review the current status for production of citric acid and lactic acid, and we highlight the use of modern metabolic engineering technologies to develop high performance microbes for production of succinic acid and 3-hydroxypropionic acid. Also, the key limitations and challenges in microbial organic acids production are discussed. PMID- 26748038 TI - A novel level set model with automated initialization and controlling parameters for medical image segmentation. AB - In this paper, a level set model without the need of generating initial contour and setting controlling parameters manually is proposed for medical image segmentation. The contribution of this paper is mainly manifested in three points. First, we propose a novel adaptive mean shift clustering method based on global image information to guide the evolution of level set. By simple threshold processing, the results of mean shift clustering can automatically and speedily generate an initial contour of level set evolution. Second, we devise several new functions to estimate the controlling parameters of the level set evolution based on the clustering results and image characteristics. Third, the reaction diffusion method is adopted to supersede the distance regularization term of RSF level set model, which can improve the accuracy and speed of segmentation effectively with less manual intervention. Experimental results demonstrate the performance and efficiency of the proposed model for medical image segmentation. PMID- 26748039 TI - System models for PET statistical iterative reconstruction: A review. AB - Positron emission tomography (PET) is a nuclear imaging modality that provides in vivo quantitative measurements of the spatial and temporal distribution of compounds labeled with a positron emitting radionuclide. In the last decades, a tremendous effort has been put into the field of mathematical tomographic image reconstruction algorithms that transform the data registered by a PET camera into an image that represents slices through the scanned object. Iterative image reconstruction methods often provide higher quality images than conventional direct analytical methods. Aside from taking into account the statistical nature of the data, the key advantage of iterative reconstruction techniques is their ability to incorporate detailed models of the data acquisition process. This is mainly realized through the use of the so-called system matrix, that defines the mapping from the object space to the measurement space. The quality of the reconstructed images relies to a great extent on the accuracy with which the system matrix is estimated. Unfortunately, an accurate system matrix is often associated with high reconstruction times and huge storage requirements. Many attempts have been made to achieve realistic models without incurring excessive computational costs. As a result, a wide range of alternatives to the calculation of the system matrix exists. In this article we present a review of the different approaches used to address the problem of how to model, calculate and store the system matrix. PMID- 26748040 TI - A coronary artery segmentation method based on multiscale analysis and region growing. AB - Accurate coronary artery segmentation is a fundamental step in various medical imaging applications such as stenosis detection, 3D reconstruction and cardiac dynamics assessing. In this paper, a multiscale region growing (MSRG) method for coronary artery segmentation in 2D X-ray angiograms is proposed. First, a region growing rule incorporating both vesselness and direction information in a unique way is introduced. Then an iterative multiscale search based on this criterion is performed. Selected points in each step are considered as seeds for the following step. By combining vesselness and direction information in the growing rule, this method is able to avoid blockage caused by low vesselness values in vascular regions, which in turn, yields continuous vessel tree. Performing the process in a multiscale fashion helps to extract thin and peripheral vessels often missed by other segmentation methods. Quantitative evaluation performed on real angiography images shows that the proposed segmentation method identifies about 80% of the total coronary artery tree in relatively easy images and 70% in challenging cases with a mean precision of 82% and outperforms others segmentation methods in terms of sensitivity. The MSRG segmentation method was also implemented with different enhancement filters and it has been shown that the Frangi filter gives better results. The proposed segmentation method has proven to be tailored for coronary artery segmentation. It keeps an acceptable performance when dealing with challenging situations such as noise, stenosis and poor contrast. PMID- 26748041 TI - The Bioenergetic Health Index is a sensitive measure of oxidative stress in human monocytes. AB - Metabolic and bioenergetic dysfunction are associated with oxidative stress and thought to be a common underlying mechanism of chronic diseases such as atherosclerosis, diabetes, and neurodegeneration. Recent findings support an emerging concept that circulating leukocytes and platelets can act as sensors or biomarkers of mitochondrial function in patients subjected to metabolic diseases. It is proposed that systemic stress-induced alterations in leukocyte bioenergetics are the consequence of several factors including reactive oxygen species. This suggests that oxidative stress mediated changes in leukocyte mitochondrial function could be used as an indicator of bioenergetic health in individuals. To test this concept, we investigated the effect of the redox cycling agent, 2,3 dimethoxynaphthoquinone (DMNQ) on the bioenergetic profiles of monocytes isolated from healthy human subjects using the extracellular flux analyzer. In addition, we tested the hypothesis that the bioenergetic health index (BHI), a single value that represents the bioenergetic health of individuals, is dynamically sensitive to oxidative stress in human monocytes. DMNQ decreased monocyte ATP-linked respiration, maximal respiration, and reserve capacity and caused an increase in proton leak and non-mitochondrial respiration compared to monocytes not treated with DMNQ. The BHI was a more sensitive indicator of the DMNQ-dependent changes in bioenergetics than any individual parameter. These data suggest that monocytes are susceptible to oxidative stress mediated by DMNQ and this can be accurately assessed by the BHI. Taken together, our findings suggest that the BHI has the potential to act as a functional biomarker of the impact of systemic oxidative stress in patients with metabolic disorders. PMID- 26748044 TI - Development and Initial Validation of the Pain Resilience Scale. AB - Over the past decade, the role of positive psychology in pain experience has gained increasing attention. One such positive factor, identified as resilience, has been defined as the ability to maintain positive emotional and physical functioning despite physical or psychological adversity. Although cross situational measures of resilience have been shown to be related to pain, it was hypothesized that a pain-specific resilience measure would serve as a stronger predictor of acute pain experience. To test this hypothesis, we conducted a series of studies to develop and validate the Pain Resilience Scale. Study 1 described exploratory and confirmatory factor analyses that support a scale with 2 distinct factors, Cognitive/Affective Positivity and Behavioral Perseverance. Study 2 showed test-retest reliability and construct validity of this new scale, including moderate positive relationships with measures of positive psychological functioning and small to moderate negative relationships with vulnerability measures such as pain catastrophizing. Finally, consistent with our initial hypothesis, study 3 showed that the Pain Resilience Scale is more strongly related to ischemic pain responses than existing measures of general resilience. Together, these studies support the predictive utility of this new pain-specific measure of resilience in the context of acute experimental pain. PERSPECTIVE: The Pain Resilience Scale represents a novel measure of Cognitive/Affective Positivity and Behavioral Perseverance during exposure to noxious stimuli. Construct validity is supported by expected relationships with existing pain coping measures, and predictive validity is shown by individual differences in response to acute experimental pain. PMID- 26748042 TI - An unexplored role for Peroxiredoxin in exercise-induced redox signalling? AB - Peroxiredoxin (PRDX) is a ubiquitous oxidoreductase protein with a conserved ionised thiol that permits catalysis of hydrogen peroxide (H2O2) up to a million times faster than any thiol-containing signalling protein. The increased production of H2O2 within active tissues during exercise is thought to oxidise conserved cysteine thiols, which may in turn facilitate a wide variety of physiological adaptations. The precise mechanisms linking H2O2 with the oxidation of signalling thiol proteins (phosphates, kinases and transcription factors) are unclear due to these proteins' low reactivity with H2O2 relative to abundant thiol peroxidases such as PRDX. Recent work has shown that following exposure to H2O2 in vitro, the sulfenic acid of the PRDX cysteine can form mixed disulphides with transcription factors associated with cell survival. This implicates PRDX as an 'active' redox relay in transmitting the oxidising equivalent of H2O2 to downstream proteins. Furthermore, under oxidative stress, PRDX can form stable oxidised dimers that can be secreted into the extracellular space, potentially acting as an extracellular 'stress' signal. There is extensive literature assessing non-specific markers of oxidative stress in response to exercise, however the PRDX catalytic cycle may offer a more robust approach for measuring changes in redox balance following exercise. This review discusses studies assessing PRDX-mediated cellular signalling and integrates the recent advances in redox biology with investigations that have examined the role of PRDX during exercise in humans and animals. Future studies should explore the role of PRDX as a key regulator of peroxide mediated-signal transduction during exercise in humans. PMID- 26748043 TI - Manipulation of Neurotransmitter Levels Has Differential Effects on Formalin Evoked Nociceptive Behavior in Male and Female Mice. AB - Changes in serotonin (5-hydroxytryptamine; 5-HT), noradrenaline (NA), and gamma aminobutyric acid (GABA) levels in the spinal cord are known to occur in response to nociceptive stimuli, yet little research has examined possible underlying sex differences in these changes and how they might affect nociception. We have used pharmacological approaches in a well established model of tonic nociception, the formalin test, to explore the effects of altering neurotransmitter levels on nociceptive responses in male and female C57BL/6 mice. The monoamine oxidase (MAO) inhibitor phenelzine (PLZ), its metabolite phenylethylidenehydrazine (PEH), and a derivative compound of PLZ, N(2)-acetylphenelzine (N(2)-AcPLZ), were used to increase endogenous levels of: GABA, 5-HT, and NA (PLZ); GABA alone (PEH); or 5-HT and NA only (N(2)-AcPLZ). Although both sexes had a reduction in second phase nociceptive behaviors with PEH pretreatment, the analgesic effect of PLZ was only observed in male mice. High performance liquid chromatography analysis revealed male mice had greater spinal cord increases in 5-HT and NA levels compared with female mice. Female mice, in contrast, had greater increases in GABA levels with pretreatments. With N(2)-AcPLZ pretreatment, only male mice had a reduction in second phase nociceptive behaviors despite similar increases in 5 HT and NA levels in both sexes. These findings suggest that male mice may utilize serotonergic and noradrenergic pathways more efficiently for the attenuation of nociceptive behavior and female mice are more dependent on alternate mechanisms. To our knowledge, these findings are the first on the antinociceptive properties of altering 5-HT, NA, and GABA levels with the MAO inhibitor PLZ and its derivatives in a model of tonic pain processing. They also reveal significant underlying sex differences associated with these treatments. PERSPECTIVE: The present study found that nociception in male and female mice may be regulated by different neurotransmitter systems. These results indicate that different pharmacological approaches may be needed to treat pain in both sexes. PMID- 26748045 TI - Lead and cadmium sorption mechanisms on magnetically modified biochars. AB - This paper discusses Cd(II) and Pb(II) sorption efficiency of biochars modified by impregnation with magnetic particles. All selected biochar characteristics were significantly affected after the modification. More specifically, the cation exchange capacity increased after the modification, except for grape stalk biochar. However, the changes in the pH value, PZC, and BET surface after modification process were less pronounced. The metal loading rate was also significantly improved, especially for Cd(II) sorption on/in nut shield and plum stone biochars (10- and 16-times increase, respectively). The results indicated that cation exchange (as a metal sorption mechanism) was strengthened after Fe oxide impregnation, which limited the desorbed amount of tested metals. In contrast, the magnetization of grape stalk biochar reduced Pb(II) sorption in comparison with that of pristine biochar. Magnetic modification is, therefore, more efficient for biochars with well-developed structure and for more mobile metals, such as Cd(II). PMID- 26748046 TI - G-lignin and hemicellulosic monosaccharides distinctively affect biomass digestibility in rapeseed. AB - In this study, total 19 straw samples from four Brassica species were determined with a diverse cell wall composition and varied biomass enzymatic digestibility under sulfuric acid or lime pretreatment. Correlation analysis was then performed to detect effects of cell wall compositions and wall polymer features (cellulose crystallinity, hemicellulosic monosaccharides and lignin monomers) on rapeseeds biomass digestibility. As a result, coniferyl alcohol (G-lignin) showed a strongly negative effect on biomass saccharification, whereas hemicellulosic monosaccharides (fucose, galactose, arabinose and rhamnose) were positive factors on lignocellulose digestions. Notably, chemical analyses of four typical pairs of samples indicated that hemicellulosic monosaccharides and G-lignin may coordinately influence biomass digestibility in rapeseeds. In addition, Brassica napus with lower lignin content exhibited more efficiency on both biomass enzymatic saccharification and ethanol production, compared with Brassica junjea. Hence, this study has at first time provided a genetic strategy on cell wall modification towards bioenergy rapeseed breeding. PMID- 26748047 TI - Monitoring of the cellulosic ethanol fermentation process by near-infrared spectroscopy. AB - Rapid, efficient, and low-cost technologies for monitoring the fermentation process during second generation (2G) or cellulosic ethanol production are essential for the successful implementation of this process at the commercial scale. Here, the use of near-infrared (NIR) spectroscopy associated with partial least squares (PLS) regression was investigated as a tool for monitoring the production of 2G ethanol from lignocellulosic sugarcane residues including bagasse, straw, and tops. The spectral data was based on a set of 103 alcoholic fermentation samples. Models based on different pre-processing techniques were evaluated. The best root mean square error of prediction (RMSEP) values obtained in the external validation were around 3.02 g/L for ethanol and 6.60 g/L for glucose. The findings showed that the PLS-NIR methodology was efficient in accurately predicting the glucose and ethanol concentrations during the production of 2G ethanol, demonstrating potential for use in monitoring and control of large-scale industrial processes. PMID- 26748048 TI - What are the differences between aerobic and anaerobic toxic effects of sulfonamides on Escherichia coli? AB - Bacteria in the environment face the threat of antibiotics. However, most studies investigating the toxicity and toxicity mechanisms of antibiotics have been conducted on microorganisms in aerobic conditions, while studies examining the anaerobic toxicity and toxicity mechanisms of antibiotics are still limited. In this study, we determined the aerobic and anaerobic toxicities of sulfonamides (SAs) on Escherichia coli. Next, a comparison of the aerobic and anaerobic toxicities indicated that the SAs could be divided into three groups: Group I: log(1/EC50-anaerobic)>log(1/EC50-aerobic) (EC50-anaerobic/EC50-aerobic, the median effective concentration under anaerobic/aerobic conditions), Group II: log(1/EC50-anaerobic)~log(1/EC50-aerobic), and Group III: log(1/EC50 anaerobic)=5 letters temporally related to the dissociation. Thirty-nine implant removal surgeries were performed, 33 with replacement. Twelve dissociations were noted during implant removal surgeries in 10 participants (26%, 95% CI 15%-48%); 5 of these eyes had a decline in visual acuity >=5 letters after surgery. The time from implant placement to removal surgery was longer for the surgeries at which dissociated implants were identified than for those without one (5.7 vs 3.7 years, P < .001). Overall, visual acuity declined 15 or more letters from pre-implant values in 22% of affected eyes; declines were frequently associated with complications of uveitis or its treatment. CONCLUSION: There is an increasing risk of dissociation of Retisert implants during follow up; the risk is greater with removal/exchange surgeries, but the risk of both spontaneous and surgically related events increases with longevity of the implants. In 22% of affected eyes visual acuity declined by 15 letters. In the context of eyes with moderate to severe uveitis for years, this rate is not unexpected. PMID- 26748078 TI - Electrophysiological correlates of error initiation and response correction. AB - Adaptive, goal-directed behavior requires the ability to monitor the perception action cycle, detect errors, and make adjustments to restore volitional action. One limiting factor in gaining a clearer understanding of the functional significance of the neural correlates of error detection has been the predominant use of discrete responses (e.g., a button press) as measures of behavior that do not easily afford an assessment of online error correction. This limitation was addressed in the current study by examining the neural correlates of error initiation and correction with respect to dynamic cursor movements that permitted measurement of the initiation and correction of errant responses within individual trials. Results indicate that the ERN may reflect a general error alarm following the initiation of an error but that the Pe component may be more closely related to the initiation of corrective action. The data also reveal that the amplitude and latency of frontal midline Theta oscillations may be more closely related to corrective action, suggesting that error detection and corrective action are mediated by an overlapping neural network. PMID- 26748077 TI - Task-dependent and polarity-specific effects of prefrontal transcranial direct current stimulation on cortical activation during word fluency. AB - Targeted modulation of cortical functions by non-invasive brain stimulation is widely used for the investigation of the neurophysiological signatures of executive functions and put forward as a potential specific treatment for its disorders. To further investigate the underlying mechanisms, we performed two experiments involving 46 subjects that performed a semantic and a phonological verbal fluency task (VFT) as well as a simple speech-production task after application of 1mA anodal or cathodal transcranial direct current stimulation (tDCS) to the left inferior frontal gyrus (IFG). Brain activation was measured by functional near-infrared spectroscopy (fNIRS) during task performance. Neither preceding anodal nor cathodal tDCS was found to modulate VFT performance of either difficulty. However, preconditioning with anodal tDCS increased brain activity during the VFT whereas a trendwise decrease of activation was found after cathodal stimulation. Notably, this difference was not found with simple speech production. These findings support the notion of a polarity-specific malleability of neuronal network activity underlying speech production by tDCS. Most importantly, the task-specificity of the modulatory effect observed after the end of stimulation demonstrates lasting neurophysiological effects of tDCS that are reflected in modifications of cortical excitability by challenging cognitive tasks. PMID- 26748079 TI - A randomized comparison study regarding the impact of short-duration, high intensity exercise and traditional exercise on anthropometric and body composition measurement changes in post-menopausal women--A pilot study. AB - BACKGROUND: The mode and duration of exercise necessary to change body composition and reduce weight remains debatable. Menopause results in hormonal changes that preclude weight loss. This randomized pilot study compared the effects of short-duration, high-intensity interval training and traditional exercise on anthropometric and body composition measurement changes in post menopausal women. OBJECTIVE: To compare the effects of short-duration, high intensity interval training and traditional methods of exercise (walking) on anthropometric, body composition and body weight change over a 12-week period. MAIN OUTCOME MEASURES: Subjects (N = 18) were post-menopausal, sedentary female volunteers, randomly assigned into one of two exercise groups. Both groups exercised five out of seven days for 12 weeks. The resistance group (n = 8) (54.3 +/- 7.3 years; BMI = 28.0 +/- 2.1 kg/m(2); mean +/- SD) exercised for 15.0 +/- 3.5 min, which consisted of five different exercise routines including upper and lower extremity, a cardio segment, yoga and abdominal exercises. The walkers (n = 10) (56.6 +/- 5.2 years; BMI = 29.2 +/- 2.6 kg/m(2); mean +/- SD) exercised for 40.0 +/- 5.0 min at 65% of their age-predicted maximum heart rate. Relative (%) body fat was measured via DEXA scan, along with five anthropometric measurements, all of which were taken prior to and after 12 weeks. Independent sample t-tests were probed for differences, p <= 0.05. RESULTS: No statistically significant changes were determined between the groups for pre-and post-measurements. CONCLUSIONS: The outcomes of this study provide a foundation for future comparisons of short-duration high-intensity interval training exercise and traditional exercise, or walking, on anthropometric and body composition measurement changes in sedentary, overweight, post-menopausal females over a 12 week period. PMID- 26748080 TI - Exposure to p,p'-DDE Alters Macrophage Reactivity and Increases Macrophage Numbers in Adipose Stromal Vascular Fraction. AB - Exposure to p,p'-DDE (DDE), the main bioaccumulative metabolite of the organochlorine insecticide p,p'-DDT, is associated with a higher prevalence of obesity, dyslipidemia, insulin resistance, metabolic syndrome, and immunomodulation. The present study was carried out to determine whether DDE perturbs adipose tissue homeostasis through modulation of macrophage function. Treatment with DDE or a cyclooxygenase-2 inhibitor prior to lipopolysaccharide exposure significantly decreased production of prostaglandins (PG) from J774a.1 macrophages in vitro. Similarly, J774A.1 cell lysates incubated with DDE or a specific cyclooxygenase-2 inhibitor (NS-398) produced significantly less PGE2 and PGF2alpha. Macrophage polarization studies revealed a pattern of DDE effects that were not fully consistent with a purely pro- or purely anti- M1 or M2 effect. However, DDE suppressed expression of two M1 markers (induced by an M1 stimulus) and enhanced expression of an M2 marker (induced by an M2 stimulus). Further studies including assessment of macrophage function are needed to fully characterize the effects of DDE on macrophage polarization. Obesity is characterized by an increase in the number of resident adipose tissue macrophages. To assess monocyte/macrophage recruitment to the adipose tissue in vivo, male C57Bl/6H mice were treated with 2 mg/kg DDE or corn oil vehicle for 5 days by gavage. Epididymal fat pads were digested and macrophage populations were analyzed by flow cytometry. In DDE-treated animals, there was a significant increase (37%) in F4/80(+)CD11b(+) macrophages/g of epididymal adipose over vehicle (P < .05). Together, these results suggest a role for DDE in the enhancement of adipose tissue macrophage recruitment and/or proliferation, as well as modulation of immune cell function that may contribute to the etiology of metabolic diseases associated with organochlorine exposure. PMID- 26748083 TI - Astrocytes: The Final Frontier.... AB - In this issue of Neuron, Zhang et al. (2016) develop a novel approach to generate populations of human astrocytes to uncover their uniquely human traits. PMID- 26748081 TI - The Arabidopsis Mg Transporter, MRS2-4, is Essential for Mg Homeostasis Under Both Low and High Mg Conditions. AB - Magnesium (Mg) is an essential macronutrient, functioning as both a cofactor of many enzymes and as a component of Chl. Mg is abundant in plants; however, further investigation of the Mg transporters involved in Mg uptake and distribution is needed. Here, we isolated an Arabidopsis thaliana mutant sensitive to high calcium (Ca) conditions without Mg supplementation. The causal gene of the mutant encodes MRS2-4, an Mg transporter.MRS2-4 single mutants exhibited growth defects under low Mg conditions, whereas an MRS2-4 and MRS2-7 double mutant exhibited growth defects even under normal Mg concentrations. Under normal Mg conditions, the Mg concentration of the MRS2-4 mutant was lower than that of the wild type. The transcriptome profiles of mrs2-4-1 mutants under normal conditions were similar to those of wild-type plants grown under low Mg conditions. In addition, both mrs2-4 and mrs2-7 mutants were sensitive to high levels of Mg. These results indicate that both MRS2-4 and MRS2-7 are essential for Mg homeostasis, even under normal and high Mg conditions. MRS2-4-green fluorescent protein (GFP) was mainly detected in the endoplasmic reticulum. These results indicate that these two MRS2 transporter genes are essential for the ability to adapt to a wide range of environmental Mg concentrations. PMID- 26748084 TI - A Code for Cross-Modal Working Memory. AB - In this issue of Neuron, Vergara et al. (2016) report that neurons in the pre supplementary motor area represent the frequency of tactile and auditory stimuli held in working memory. Single neurons encode both types of information by using the same representation for both modalities. PMID- 26748082 TI - Onyx versus nBCA and coils in the treatment of intracranial dural arteriovenous fistulas. AB - BACKGROUND AND PURPOSE: Intracranial dural arteriovenous fistulas (DAVFs) with cortical venous drainage have significant morbidity and mortality. Complete closure of these lesions is necessary to reduce these risks. The purpose of our study was to compare the outcome of DAVFs treated with Onyx versus those treated with n-Butyl Cyanoacrylate (nBCA) and coil embolization in a case-control study. Compared with nBCA and coil embolization, we hypothesized that Onyx embolization for DAVF is safer and has a higher chance of complete obliteration, with no need for post-embolization surgery for the DAVF. MATERIALS AND METHODS: From 1998 to 2015, 29 patients who had DAVFs were treated with endovascular embolization. Of these, 24 patients had imaging available for analysis. Successful closure rates, complications, and procedure time were compared between the embolization techniques. RESULTS: The chance of not requiring post-embolization surgery with Onyx (81.8%) was significantly higher (p = 0.005) than with nBCA (22.22%). The complication rate with Onyx (9.1%) tended to be lower compared with that of nBCA (22.22%; p = 0.37). Procedural time was not significantly different between Onyx (mean 267 minutes) and nBCA (mean 288 minutes) (p = 0.59). The odds ratio of a DAVF being treated with Onyx and then requiring no follow-up surgery was 17.5 (95% CI 1.97-155.4). CONCLUSION: Our case-control study suggests that Onyx embolization is superior to nBCA and coil embolization in completely obliterating DAVFs, with higher odds of no post-embolization surgery. We also found that Onyx is safe for embolization of DAVFs, with no associated neurological mortality and morbidity. PMID- 26748085 TI - Pondering the Pulvinar. AB - While the function of the pulvinar remains one of the least explored among the thalamic nuclei despite occupying the most thalamic volume in primates, it has long been suspected to play a crucial role in attentive stimulus processing. In this issue of Neuron, Zhou et al. (2016) use simultaneous pulvinar-visual cortex recordings and pulvinar inactivation to provide evidence that the pulvinar is essential for intact stimulus processing, maintenance of neuronal oscillatory dynamics, and mediating the effects of attention. PMID- 26748086 TI - More than Meets the Eye: the Relationship between Pupil Size and Locus Coeruleus Activity. AB - Using both direct neural recordings and electrical microstimulation, Joshi et al. (2016) show that locus coeruleus (LC) activity closely matches moment-to-moment changes in pupil size. But what causes these two measures to be related is not straightforward. PMID- 26748087 TI - Common Brain Mechanisms of Chronic Pain and Addiction. AB - While chronic pain is considered by some to be a CNS disease, little is understood about underlying neurobiological mechanisms. Addiction models have heuristic value in this regard, because both pain and addictive disorders are characterized by impaired hedonic capacity, compulsive drug seeking, and high stress. In drug addiction such symptomatology has been attributed to reward deficiency, impaired inhibitory control, incentive sensitization, aberrant learning, and anti-reward allostatic neuroadaptations. Here we propose that similar neuroadaptations exist in chronic pain patients. PMID- 26748088 TI - White-Matter Tract Connecting Anterior Insula to Nucleus Accumbens Correlates with Reduced Preference for Positively Skewed Gambles. AB - Individuals sometimes show inconsistent risk preferences, including excessive attraction to gambles featuring small chances of winning large amounts (called "positively skewed" gambles). While functional neuroimaging research indicates that nucleus accumbens (NAcc) and anterior insula (AIns) activity inversely predict risky choice, structural connections between these regions have not been described in humans. By combining diffusion-weighted MRI with tractography, we identified the anatomical trajectory of white-matter tracts projecting from the AIns to the NAcc and statistically validated these tracts using Linear Fascicle Evaluation (LiFE) and virtual lesions. Coherence of the right AIns-NAcc tract correlated with reduced preferences for positively skewed gambles. Further, diminished NAcc activity during gamble presentation mediated the association between tract structure and choice. These results identify an unreported tract connecting the AIns to the NAcc in humans and support the notion that structural connections can alter behavior by influencing brain activity as individuals weigh uncertain gains against uncertain losses. PMID- 26748090 TI - Impaired mTORC1-Dependent Expression of Homer-3 Influences SCA1 Pathophysiology. AB - Spinocerebellar ataxia type 1 (SCA1), due to the expansion of a polyglutamine repeat within the ubiquitously expressed Ataxin-1 protein, leads to the premature degeneration of Purkinje cells (PCs), the cause of which is poorly understood. Here, we identified the unique proteomic signature of Sca1(154Q/2Q) PCs at an early stage of disease, highlighting extensive alterations in proteins associated with synaptic functioning, maintenance, and transmission. Focusing on Homer-3, a PC-enriched scaffold protein regulating neuronal activity, revealed an early decline in its expression. Impaired climbing fiber-mediated synaptic transmission diminished mTORC1 signaling, paralleling Homer-3 reduction in Sca1(154Q/2Q) PCs. Ablating mTORC1 within PCs or pharmacological inhibition of mTORC1 identified Homer-3 as its downstream target. mTORC1 knockout in Sca1(154Q/2Q) PCs exacerbated and accelerated pathology. Reinstating Homer-3 expression in Sca1(154Q/2Q) PCs attenuated cellular dysfunctions and improved motor deficits. Our work reveals that impaired mTORC1-Homer-3 activity underlies PC susceptibility in SCA1 and presents a promising therapeutic target. PMID- 26748089 TI - Prolonged Mitosis of Neural Progenitors Alters Cell Fate in the Developing Brain. AB - Embryonic neocortical development depends on balanced production of progenitors and neurons. Genetic mutations disrupting progenitor mitosis frequently impair neurogenesis; however, the link between altered mitosis and cell fate remains poorly understood. Here we demonstrate that prolonged mitosis of radial glial progenitors directly alters neuronal fate specification and progeny viability. Live imaging of progenitors from a neurogenesis mutant, Magoh(+/-), reveals that mitotic delay significantly correlates with preferential production of neurons instead of progenitors, as well as apoptotic progeny. Independently, two pharmacological approaches reveal a causal relationship between mitotic delay and progeny fate. As mitotic duration increases, progenitors produce substantially more apoptotic progeny or neurons. We show that apoptosis, but not differentiation, is p53 dependent, demonstrating that these are distinct outcomes of mitotic delay. Together our findings reveal that prolonged mitosis is sufficient to alter fates of radial glia progeny and define a new paradigm to understand how mitosis perturbations underlie brain size disorders such as microcephaly. PMID- 26748091 TI - Age-Dependent Specific Changes in Area CA2 of the Hippocampus and Social Memory Deficit in a Mouse Model of the 22q11.2 Deletion Syndrome. AB - Several neuropsychiatric disorders are associated with cognitive and social dysfunction. Postmortem studies of patients with schizophrenia have revealed specific changes in area CA2, a long-overlooked region of the hippocampus recently found to be critical for social memory formation. To examine how area CA2 is altered in psychiatric illness, we used the Df(16)A(+/-) mouse model of the 22q11.2 microdeletion, a genetic risk factor for developing several neuropsychiatric disorders, including schizophrenia. We report several age dependent CA2 alterations: a decrease in the density of parvalbumin-expressing interneurons, a reduction in the amount of feedforward inhibition, and a change in CA2 pyramidal-neuron intrinsic properties. Furthermore, we found that area CA2 is less plastic in Df(16)A(+/-) mice, making it nearly impossible to evoke action potential firing in CA2 pyramidal neurons. Finally, we show that Df(16)A(+/-) mice display impaired social cognition, providing a potential mechanism and a neural substrate for this impairment in psychiatric disorders. PMID- 26748092 TI - Pulvinar-Cortex Interactions in Vision and Attention. AB - The ventro-lateral pulvinar is reciprocally connected with the visual areas of the ventral stream that are important for object recognition. To understand the mechanisms of attentive stimulus processing in this pulvinar-cortex loop, we investigated the interactions between the pulvinar, area V4, and IT cortex in a spatial-attention task. Sensory processing and the influence of attention in the pulvinar appeared to reflect its cortical inputs. However, pulvinar deactivation led to a reduction of attentional effects on firing rates and gamma synchrony in V4, a reduction of sensory-evoked responses and overall gamma coherence within V4, and severe behavioral deficits in the affected portion of the visual field. Conversely, pulvinar deactivation caused an increase in low-frequency cortical oscillations, often associated with inattention or sleep. Thus, cortical interactions with the ventro-lateral pulvinar are necessary for normal attention and sensory processing and for maintaining the cortex in an active state. PMID- 26748093 TI - Methodology to Estimate the Longitudinal Average Attributable Fraction of Guideline-recommended Medications for Death in Older Adults With Multiple Chronic Conditions. AB - BACKGROUND: Persons with multiple chronic conditions receive multiple guideline recommended medications to improve outcomes such as mortality. Our objective was to estimate the longitudinal average attributable fraction for 3-year survival of medications for cardiovascular conditions in persons with multiple chronic conditions and to determine whether heterogeneity occurred by age. METHODS: Medicare Current Beneficiary Survey participants (N = 8,578) with two or more chronic conditions, enrolled from 2005 to 2009 with follow-up through 2011, were analyzed. We calculated the longitudinal extension of the average attributable fraction for oral medications (beta blockers, renin-angiotensin system blockers, and thiazide diuretics) indicated for cardiovascular conditions (atrial fibrillation, coronary artery disease, heart failure, and hypertension), on survival adjusted for 18 participant characteristics. Models stratified by age (<=80 and >80 years) were analyzed to determine heterogeneity of both cardiovascular conditions and medications. RESULTS: Heart failure had the greatest average attributable fraction (39%) for mortality. The fractional contributions of beta blockers, renin-angiotensin system blockers, and thiazides to improve survival were 10.4%, 9.3%, and 7.2% respectively. In age-stratified models, of these medications thiazides had a significant contribution to survival only for those aged 80 years or younger. The effects of the remaining medications were similar in both age strata. CONCLUSIONS: Most cardiovascular medications were attributed independently to survival. The two cardiovascular conditions contributing independently to death were heart failure and atrial fibrillation. The medication effects were similar by age except for thiazides that had a significant contribution to survival in persons younger than 80 years. PMID- 26748094 TI - Alcohol Consumption and Longitudinal Trajectories of Physical Functioning in Central and Eastern Europe: A 10-Year Follow-up of HAPIEE Study. AB - BACKGROUND: Physical functioning (PF) is an essential domain of older persons' health and quality of life. Health behaviors are the main modifiable determinants of PF. Cross-sectionally, alcohol consumption appears to be linked to better PF, but longitudinal evidence is mixed and very little is known about alcohol consumption and longitudinal PF trajectories. METHODS: We conducted longitudinal analyses of 28,783 men and women aged 45-69 years from Novosibirsk (Russia), Krakow (Poland), and seven towns of the Czech Republic. At baseline, alcohol consumption was measured by a graduated frequency questionnaire and problem drinking was evaluated using the CAGE questionnaire. PF was assessed using the Physical Functioning Subscale of the SF-36 instrument at baseline and three subsequent occasions. Growth curve modeling was used to estimate the associations between alcohol consumption and PF trajectories over 10-year follow-up. RESULTS: PF scores declined during follow-up in all three cohorts. Faster decline in PF over time was found in Russian female frequent drinkers, Polish female moderate drinkers, and Polish male regular heavy drinkers, in comparison with regular and/or light-to-moderate drinkers. Nondrinking was associated with a faster decline compared with light drinking only in Russian men. Problem drinking and past drinking were not related to the decline rate of PF. CONCLUSIONS: This large longitudinal study in Central and Eastern European populations with relatively high alcohol intake does not strongly support the existence of a protective effect of alcohol on PF trajectories; if anything, it suggests that alcohol consumption is associated with greater deterioration in PF over time. PMID- 26748098 TI - Differences in adults' health and health behaviour between 16 European urban areas and the associations with socio-economic status and physical and social environment. AB - Background: With a growing proportion of the European population living in urban areas (UAs), exploring health in urban areas becomes increasingly important. The objective of this study is to assess the magnitude of differences in health and health behaviour between adults living in urban areas (UAs) across Europe. We also explored whether and to what extent such differences can be explained by socio-economic status (SES) and physical or social environment. Data were obtained from a cross-sectional questionnaire survey, performed between as part of the European Urban Health Indicator System Part 2 (EURO-URHIS 2) project. Using multi-level logistic regression analysis, UA differences in psychological distress, self-assessed health, overweight and obesity, daily smoking, binge drinking and physical exercise were assessed. Median Odds Ratios (MORs) were calculated to estimate the extent to which the observed variance is attributable to UA, individual-level SES (measured by perceived financial strains, education level and employment status) and/or characteristics of physical and social environment. The dataset included 14 022 respondents in 16 UAs within 9 countries. After correction for age and gender, all MORs, except that for daily smoking, indicated statistically significant UA health differences. SES indicators (partly) explained UA differences in psychological distress, decreasing the MOR from 1.43 [95% credible interval (Cr.I.) 1.27-1.67, baseline model], to 1.25 (95% Cr.I. 1.14-1.40, SES model): a reduction of 42%. Accounting for the quality of green areas reduced the MOR for psychological distress by an additional 40%, to 1.15 (95% Cr.I. 1.05-1.28). Our study showed large differences in health and health behaviour between European UAs. Reducing socio-economic disadvantage and improving the quality of the neighbourhood's green spaces may reduce UA differences in psychological distress. PMID- 26748097 TI - Locked and proteolysis-based transcription activator-like effector (TALE) regulation. AB - Development of orthogonal, designable and adjustable transcriptional regulators is an important goal of synthetic biology. Their activity has been typically modulated through stimulus-induced oligomerization or interaction between the DNA binding and activation/repression domain. We exploited a feature of the designable Transcription activator-like effector (TALE) DNA-binding domain that it winds around the DNA which allows to topologically prevent it from binding by intramolecular cyclization. This new approach was investigated through noncovalent ligand-induced cyclization or through a covalent split intein cyclization strategy, where the topological inhibition of DNA binding by cyclization and its restoration by a proteolytic release of the topologic constraint was expected. We show that locked TALEs indeed have diminished DNA binding and regain full transcriptional activity by stimulation with the rapamycin ligand or site-specific proteolysis of the peptide linker, with much higher level of activation than rapamycin-induced heterodimerization. Additionally, we demonstrated reversibility, activation of genomic targets and implemented logic gates based on combinations of protein cyclization, proteolytic cleavage and ligand-induced dimerization, where the strongest fold induction was achieved by the proteolytic cleavage of a repression domain from a linear TALE. PMID- 26748096 TI - A higher-order entity formed by the flexible assembly of RAP1 with TRF2. AB - Telomere integrity is essential to maintain genome stability, and telomeric dysfunctions are associated with cancer and aging pathologies. In human, the shelterin complex binds TTAGGG DNA repeats and provides capping to chromosome ends. Within shelterin, RAP1 is recruited through its interaction with TRF2, and TRF2 is required for telomere protection through a network of nucleic acid and protein interactions. RAP1 is one of the most conserved shelterin proteins although one unresolved question is how its interaction may influence TRF2 properties and regulate its capacity to bind multiple proteins. Through a combination of biochemical, biophysical and structural approaches, we unveiled a unique mode of assembly between RAP1 and TRF2. The complete interaction scheme between the full-length proteins involves a complex biphasic interaction of RAP1 that directly affects the binding properties of the assembly. These results reveal how a non-DNA binding protein can influence the properties of a DNA binding partner by mutual conformational adjustments. PMID- 26748095 TI - Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of DNA damage-induced signaling upon replicative stress. AB - The Saccharomyces cerevisiae genome encodes five sirtuins (Sir2 and Hst1-4), which constitute a conserved family of NAD-dependent histone deacetylases. Cells lacking any individual sirtuin display mild growth and gene silencing defects. However, hst3Delta hst4Delta double mutants are exquisitely sensitive to genotoxins, and hst3Delta hst4Delta sir2Deltamutants are inviable. Our published data also indicate that pharmacological inhibition of sirtuins prevents growth of several fungal pathogens, although the biological basis is unclear. Here, we present genome-wide fitness assays conducted with nicotinamide (NAM), a pan sirtuin inhibitor. Our data indicate that NAM treatment causes yeast to solicit specific DNA damage response pathways for survival, and that NAM-induced growth defects are mainly attributable to inhibition of Hst3 and Hst4 and consequent elevation of histone H3 lysine 56 acetylation (H3K56ac). Our results further reveal that in the presence of constitutive H3K56ac, the Slx4 scaffolding protein and PP4 phosphatase complex play essential roles in preventing hyperactivation of the DNA damage-response kinase Rad53 in response to spontaneous DNA damage caused by reactive oxygen species. Overall, our data support the concept that chromosome wide histone deacetylation by sirtuins is critical to mitigate growth defects caused by endogenous genotoxins. PMID- 26748099 TI - Private and public modes of bicycle commuting: a perspective on attitude and perception. AB - BACKGROUND: Public bicycle-sharing initiatives can act as health enhancement strategies among urban populations. The aim of the study was to determine which attitudes and perceptions of behavioural control toward cycling and a bicycle sharing system distinguish commuters with a different adherence to bicycle commuting. METHODS: The recruitment process was conducted in 40 random points in Barcelona from 2011 to 2012. Subjects completed a telephone-based questionnaire including 27 attitude and perception statements. Based on their most common one way commute trip and willingness to commute by bicycle, subjects were classified into Private Bicycle (PB), public bicycle or Bicing Bicycle (BB), Willing Non bicycle (WN) and Non-willing Non-bicycle (NN) commuters. After reducing the survey statements through principal component analysis, a multinomial logistic regression model was obtained to evaluate associations between attitudinal and commuter sub-groups. RESULTS: We included 814 adults in the analysis [51.6% female, mean (SD): age 36.6 (10.3) years]. BB commuters were 2.0 times [95% confidence interval (CI) = 1.1-3.7] less likely to perceive bicycle as a quick, flexible and enjoyable mode compared to PB. BB, WN and NN were 2.5 (95% CI = 1.46 4.24), 2.6 (95% CI = 1.53-4.41) and 2.3 times (95% CI = 1.30-4.10) more likely to perceive benefits of using public bicycles (bicycle maintenance and parking avoidance, low cost and no worries about theft and vandalism) than did PB. CONCLUSION: Willing non-bicycle and public-bicycle commuters had more favourable perception toward public-shared bicycles compared to private cyclists. Hence, public bicycles may be the impetus for those willing to start bicycle commuting, thereby increasing physical activity levels. PMID- 26748100 TI - Mortality trends in cardiovascular causes in schizophrenia, bipolar and unipolar mood disorder in Sweden 1987-2010. AB - INTRODUCTION: People with severe mental illness have increased risk for premature mortality and thus a shorter life expectancy. Relative death rates are used to show the excess mortality among patients with mental health disorder but cannot be used for the comparisons by country, region and time. METHODS: A population based register study including all Swedish patients in adult psychiatry admitted to hospital with a main diagnosis of schizophrenia, bipolar or unipolar mood disorder in 1987-2010 (614 035 person-years). Mortality rates adjusted for age, sex and period were calculated using direct standardization methods with the 2010 Swedish population as standard. Data on all residents aged 15 years or older were used as the comparison group. RESULTS: Patients with severe mental health disorders had a 3-fold mortality compared to general population. All-cause mortality decreased by 9% for people with bipolar mood disorder and by 26-27% for people with schizophrenia or unipolar mood disorder, while the decline in the general population was 30%. Also mortality from diseases of the circulatory system declined less for people with severe mental disorder (-35% to - 42%) than for general population (-49%). The pattern was similar for other cardiovascular deaths excluding cerebrovascular deaths for which the rate declined among people with schizophrenia (-30%) and unipolar mood disorder (-41%), unlike for people with bipolar mood disorder (-3%). CONCLUSIONS: People with mental health disorder have still elevated mortality. The mortality declined faster for general population than for psychiatric patients. More detailed analysis is needed to reveal causes-of-death with largest possibilities for improvement. PMID- 26748101 TI - In-person and computer-based alcohol interventions at general hospitals: reach and retention. AB - BACKGROUND: High reach of target populations is relevant for public health impact of interventions. Concerning intervention programs requiring multiple contacts, little is known about how many persons may be kept in the intervention program over multiple time points. The aim of this study was to investigate (i) the reach of general hospital inpatients with at-risk alcohol use through screening and brief intervention and (ii) whether their continued intervention participation after hospital discharge differs by in-person vs. computer-based intervention (CO) delivery. METHODS: As part of a randomized controlled trial, general hospital inpatients aged 18-64 years were screened for at-risk alcohol use on 13 wards. Participants were allocated to in-person intervention (PE), CO and assessment only. Both interventions were provided on site, and 1 and 3 months after baseline. RESULTS: Ninety-two percent of all eligible inpatients ( N: = 6251) completed the screening. Eighty-one percent ( N: = 961) of the screening positives participated in the trial and received their allocated intervention. At months 1 and 3, interventions were delivered to 83 and 79% of the CO participants and to 74 and 64% of the PE participants. The delivery of CO and PE required an average of 5.2 and 7.7 contact attempts per delivered intervention, respectively. CONCLUSION: General hospital inpatients with at-risk alcohol use were well reached through proactive interventions. COs may result in higher retention rates over 1 and 3 months and may require less contact attempts than PEs. Public health efforts that aim to achieve high intervention retention should consider proactive COs. PMID- 26748102 TI - Development of an enzyme-linked immunosorbent assay for thrombospondin-1 and comparison of human plasma and serum concentrations. AB - BACKGROUND: Thrombospondin-1 (TSP-1) is a circulating matricellular glycoprotein produced from many cell types including platelets. Currently TSP-1 is measured in either plasma or serum, using expensive commercial assays. AIM: To develop and validate a cost effective in-house immunoassay for human TSP-1 suitable for quantitating levels from both plasma and serum. METHODS: An in-house enzyme linked immunosorbent assay (ELISA) was developed for the measurement of human TSP 1. Sixteen healthy volunteers (8 male and 8 female), mean age 29 years (range 21 49), body mass index (BMI) mean 23.3 kg/m(2) (range 17.3-26.7) had non-fasted venous blood sampled at 0800 h and 1600 h for both plasma and serum TSP-1. RESULTS: The assay limit of quantitation was 7.8 MUg/L, inter assay CV was 17 31%, intra assay CV was 3-4% for plasma and <9% for serum. Plasma TSP-1 ranged from 133 to 478 MUg/L (mean concentration 290 MUg/L) in normal volunteers. Serum TSP-1 was approximately 100-fold higher, ranging from 13,700 to 44,400 MUg/L (mean concentration 257,00 MUg/L). There was no correlation between plasma and serum TSP-1. CONCLUSIONS: TSP-1 can be readily measured in human plasma using ELISA. Serum concentrations are 100-fold higher, reflecting documented TSP-1 release by platelets, and does not provide a meaningful measure of circulating concentrations. PMID- 26748104 TI - Molecular testing for familial hypercholesterolaemia-associated mutations in a UK based cohort: development of an NGS-based method and comparison with multiplex polymerase chain reaction and oligonucleotide arrays. AB - Background Detection of disease-associated mutations in patients with familial hypercholesterolaemia is crucial for early interventions to reduce risk of cardiovascular disease. Screening for these mutations represents a methodological challenge since more than 1200 different causal mutations in the low-density lipoprotein receptor has been identified. A number of methodological approaches have been developed for screening by clinical diagnostic laboratories. Methods Using primers targeting, the low-density lipoprotein receptor, apolipoprotein B, and proprotein convertase subtilisin/kexin type 9, we developed a novel Ion Torrent-based targeted re-sequencing method. We validated this in a West Midlands UK small cohort of 58 patients screened in parallel with other mutation-targeting methods, such as multiplex polymerase chain reaction (Elucigene FH20), oligonucleotide arrays (Randox familial hypercholesterolaemia array) or the Illumina next-generation sequencing platform. Results In this small cohort, the next-generation sequencing method achieved excellent analytical performance characteristics and showed 100% and 89% concordance with the Randox array and the Elucigene FH20 assay. Investigation of the discrepant results identified two cases of mutation misclassification of the Elucigene FH20 multiplex polymerase chain reaction assay. A number of novel mutations not previously reported were also identified by the next-generation sequencing method. Conclusions Ion Torrent based next-generation sequencing can deliver a suitable alternative for the molecular investigation of familial hypercholesterolaemia patients, especially when comprehensive mutation screening for rare or unknown mutations is required. PMID- 26748103 TI - The determination of serum and urinary endocan concentrations in patients with bladder cancer. AB - Background Endocan (endothelial cell-specific molecule-1) is a proteoglycan and plays an important role in angiogenesis and inflammation. The aim of this study was to evaluate of serum and urinary concentrations of endothelial cell-specific molecule-1 in bladder cancer. Methods The study included 50 bladder cancer patients, 50 with urinary tract infection and 51 healthy volunteers. Serum and urinary endothelial cell-specific molecule-1 concentrations were measured with enzyme linked immunosorbent assay. Results In bladder cancer group, serum and urinary endothelial cell-specific molecule-1 concentrations were significantly higher than in the healthy subjects ( P = 0.003 and P < 0.0001). Urinary endothelial cell-specific molecule-1 concentrations in cases with urinary tract infection were higher than in healthy volunteers ( P = 0.002). There were no significant differences between bladder cancer and urinary tract infection groups in terms of serum and urinary endothelial cell-specific molecule-1 concentrations. Urinary endothelial cell-specific molecule-1 concentrations were higher than those of corresponding serum endothelial cell-specific molecule-1 concentrations ( P < 0.0001 for bladder cancer and urinary tract infection groups, P = 0.002 for healthy subjects). In bladder cancer group, there was a positive correlation between serum endothelial cell-specific molecule-1 and urinary endothelial cell-specific molecule-1 concentrations ( r = 0.32, P = 0.002). For serum endothelial cell-specific molecule-1, sensitivity and specificity were 50%, and 77%, and for urinary endothelial cell-specific molecule 1, 62%, and 71%, respectively. Conclusion Serum and urinary endothelial cell specific molecule-1 concentrations increase in bladder cancer. This parameter also increases in serum and urine of cases with urinary tract infection. That urinary endothelial cell-specific molecule-1 values were higher than serum endothelial cell-specific molecule-1 values in all groups may be attributed to direct exfoliation of epithelial cells in bladder to urine. PMID- 26748105 TI - 1-Adamantylamine a simple urine marker for screening for third generation adamantyl-type synthetic cannabinoids by ultra-performance liquid chromatography tandem mass spectrometry. AB - Background Synthetic cannabinoids (NOIDS) are novel psychotropic drugs (NPS) currently freely sold in the United Kingdom as 'research chemicals'. Detection of NOIDS use is not available in current routine methods. Here we describe a marker which helps determine which patients have used these substances. Methods In a test case, ultra-performance liquid chromatography mass spectrometry (UPLC-Tof) was used to screen the legal high Herbal Haze II, the contents of hand-rolled cigarettes and five patient samples for NOIDS and their metabolites. Results Analysis of legal high Herbal Haze II and cigarettes identified the third generation adamantyl-type NOIDS N-(1-adamantyl)-1-pentyl-1H-indazole-3 carboxamide (AKB-48), 5F-AKB-48 and N-adamantyl-1-fluoropentylindole-3 carboxamide (STS-135). Out of 18 potential metabolites, 1-adamantylamine (C10H17N) was detected in all five urine samples. This adamantyl-type NOID marker was incorporated into our routine LC-MS/MS urine screen. Out of 14,436 random urine samples screened over eight months, 296 (2.05%) tested positive for the adamantyl-type NOID marker. Conclusion We have discovered a urine marker for identifying patients smoking legal high products containing the third generation adamantyl-type NOIDS such as AKB-48 and its fluoropentyl analogue 5F-AKB-48, which are among the most popular NOIDS currently available in legal high products sold in UK. This marker can be incorporated into routine LC-MS/MS drug screening alongside classic drugs of abuse. Positive detection rates for this new legal high marker are greater than for established classic drugs that are routinely screened such as amphetamine. This work highlights the need for a flexible toxicology screening service capable of adapting to changes in drug use such as the growing popularity of legal highs/NPS. PMID- 26748106 TI - EpimiRBase: a comprehensive database of microRNA-epilepsy associations. AB - MicroRNAs are short non-coding RNA which function to fine-tune protein levels in all cells. This is achieved mainly by sequence-specific binding to 3' untranslated regions of target mRNA. The result is post-transcriptional interference in gene expression which reduces protein levels either by promoting destabilisation of mRNA or translational repression. Research published since 2010 shows that microRNAs are important regulators of gene expression in epilepsy. A series of microRNA profiling studies in rodent and human tissue has revealed that epilepsy is associated with wide ranging changes to microRNA levels in the brain. These are thought to influence processes including cell death, inflammation and re-wiring of neuronal networks. MicroRNAs have also been identified in the blood after injury to the brain and therefore may serve as biomarkers of epilepsy. EpimiRBase is a manually curated database for researchers interested in the role of microRNAs in epilepsy. The fully searchable database includes information on up- and down-regulated microRNAs in the brain and blood, as well as functional studies, and covers both rodent models and human epilepsy. AVAILABILITY AND IMPLEMENTATION: EpimiRBase is available at http://www.epimirbase.eu CONTACT: catherinemooney@rcsi.ie. PMID- 26748113 TI - A systematic comparison between visual cues for boundary detection. AB - The detection of object boundaries is a critical first step for many visual processing tasks. Multiple cues (we consider luminance, color, motion and binocular disparity) available in the early visual system may signal object boundaries but little is known about their relative diagnosticity and how to optimally combine them for boundary detection. This study thus aims at understanding how early visual processes inform boundary detection in natural scenes. We collected color binocular video sequences of natural scenes to construct a video database. Each scene was annotated with two full sets of ground truth contours (one set limited to object boundaries and another set which included all edges). We implemented an integrated computational model of early vision that spans all considered cues, and then assessed their diagnosticity by training machine learning classifiers on individual channels. Color and luminance were found to be most diagnostic while stereo and motion were least. Combining all cues yielded a significant improvement in accuracy beyond that of any cue in isolation. Furthermore, the accuracy of individual cues was found to be a poor predictor of their unique contribution for the combination. This result suggested a complex interaction between cues, which we further quantified using regularization techniques. Our systematic assessment of the accuracy of early vision models for boundary detection together with the resulting annotated video dataset should provide a useful benchmark towards the development of higher-level models of visual processing. PMID- 26748144 TI - A sandwich ELISA for the conformation-specific quantification of the activated form of human Bax. AB - Bcl-2 family proteins are critical regulators of mitochondrial outer membrane permeabilization (MOMP), which represents the point of no return of apoptotic cell death. The exposure of the Bax N-terminus at the mitochondria reflects Bax activation; and this activated configuration of the Bax protein is associated with MOMP. N-terminal exposure can be detected using specific monoclonal and/or polyclonal antibodies, and the onset of activated Bax has extensively been used as an early marker of apoptosis. The protocols of immunoprecipitation and/or immunocytochemistry commonly used to detect activated Bax are long and tedious, and allow semiquantification of the antigen at best. The sandwich ELISA protocol we developed has a 5 ng/mL detection limit and is highly specific for the activated conformation of Bax. This ELISA allows a rapid quantification of activated human Bax in whole cells and isolated mitochondria protein extracts. These properties grant this assay the potential to further clarify the prognostic and diagnostic value of activated Bax in disorders associated with deregulated apoptotic pathways such as degenerative diseases or cancer. PMID- 26748145 TI - pRNAm-PC: Predicting N(6)-methyladenosine sites in RNA sequences via physical chemical properties. AB - Just like PTM or PTLM (post-translational modification) in proteins, PTCM (post transcriptional modification) in RNA plays very important roles in biological processes. Occurring at adenine (A) with the genetic code motif (GAC), N(6) methyldenosine (m(6)A) is one of the most common and abundant PTCMs in RNA found in viruses and most eukaryotes. Given an uncharacterized RNA sequence containing many GAC motifs, which of them can be methylated, and which cannot? It is important for both basic research and drug development to address this problem. Particularly with the avalanche of RNA sequences generated in the postgenomic age, it is highly demanded to develop computational methods for timely identifying the N(6)-methyldenosine sites in RNA. Here we propose a new predictor called pRNAm-PC, in which RNA sequence samples are expressed by a novel mode of pseudo dinucleotide composition (PseDNC) whose components were derived from a physical-chemical matrix via a series of auto-covariance and cross covariance transformations. It was observed via a rigorous jackknife test that, in comparison with the existing predictor for the same purpose, pRNAm-PC achieved remarkably higher success rates in both overall accuracy and stability, indicating that the new predictor will become a useful high-throughput tool for identifying methylation sites in RNA, and that the novel approach can also be used to study many other RNA-related problems and conduct genome analysis. A user friendly Web server for pRNAm-PC has been established at http://www.jci bioinfo.cn/pRNAm-PC, by which users can easily get their desired results without needing to go through the mathematical details. PMID- 26748153 TI - An insulin-binding protein from the venom of a solitary wasp Eumenes pomiformis binds to apolipophorin III in lepidopteran hemolymph. AB - EpIBP, an insulin-like peptide-binding protein, is a major protein component of the venom of a solitary hunting wasp, Eumenes pomiformis. To evaluate the bioactivity, bacteria-expressed EpIBP was injected into Spodoptera exigua larvae, resulting in a higher survival rate and reduced loss of body weight under starvation conditions than control larvae. EpIBP was found to interact with apolipophorin III (apoLp III), implying that EpIBP might function by altering the apoLp III-mediated metabolism of prey. PMID- 26748154 TI - Comparative characterization of botulinum neurotoxin subtypes F1 and F7 featuring differential substrate recognition and cleavage mechanisms. AB - BoNT/F7, one of the seven subtypes of botulinum neurotoxin type F (F1 to F7), is the second-most divergent subtype of this group. Despite sharing >60% identity with BoNT/F1 at both holotoxin and enzymatic domain levels, it requires an N terminal extended peptide substrate for efficient substrate cleavage, suggesting its unique substrate recognition and specificity mechanism. Substrate mapping and saturation mutagenesis analysis revealed that VAMP2 (20-65) was likely a minimally effective substrate for LC/F7 (light chain of BoNT/F7), and in addition, LC/F7 recognized VAMP2 in a unique way, which differed significantly from that of LC/F1, although both of them share similar substrate binding and hydrolysis mode. LC/F7 utilizes distinct pockets for specific substrate binding and recognition in particular for the B1, B2 and S2 sites recognitions. Our findings provide insights into the distinct substrate recognition features of BoNT subtypes and useful information for therapy development for BoNT/F. PMID- 26748155 TI - First report of goniodomin A production by the dinoflagellate Alexandrium pseudogonyaulax developing in southern Mediterranean (Bizerte Lagoon, Tunisia). AB - The dinoflagellate Alexandrium pseudogonyaulax is widely distributed around the world including the Mediterranean waters. The objectives of this study were to determine the morphology and phylogenic affiliation of A. pseudogonyaulax strain isolated from Bizerte Lagoon (Mediterranean waters, Tunisia) and investigate its toxicity. Molecular analyses confirmed the morphological identification of the isolated strain (APBZ12) as A. pseudogonyaulax. Moreover, it showed that it is 100% identical with strains of this species found in New Zealand, Japan, China and North Sea (Norway and Denmark) suggesting that this species is cosmopolitan. Until now, no toxin studies have been conducted on fully characterized (morphologically and molecularly) A. pseudogonyaulax. Cellular toxin production was determined using high pressure liquid chromatography coupled to mass spectrometry (HPLC/MS). Results showed for the first time that A. pseudogonyaulax contains goniodomin A (GDA), a highly toxic macrolide polyether previously shown to be produced by two other dinoflagellate species Alexandrium monilatum (Hsia et al., 2006) and Alexandrium hiranoi (erroneously identified as A. pseudogonyaulax in Murakami et al., 1988) in American and Japanese waters, respectively. This biologically active toxin has been associated over decades with fish mortality. Our study showed that the cell extracts of APBZ12 showed an important bioactivity using GH4C1 rat pituitary cytotoxicity bioassay. PMID- 26748146 TI - Hospital overnight and evaluation of systems and timelines study: A point prevalence study of practice in Australia and New Zealand. AB - BACKGROUND: Diurnal variation in the performance of rapid response systems has not been fully elucidated. Afferent limb failure (ALF) is a significant problem and is an important measure of performance of rapid response systems. OBJECTIVE: To determine the diurnal variation in the detection and response to acute patient deterioration as measured by ALF, completeness of patient observations (Respiratory rate (RR); Pulse rate (PR) and Systolic blood pressure (SBP), and to explore the diurnal variation in the consequences of ALF in unanticipated admissions to the Intensive care unit (ICU) from the ward. DESIGN, SETTING AND PARTICIPANTS: Point Prevalence study conducted on two days in 2012 in 41 ICUs in Australia and New Zealand, examining emergency (unanticipated) admissions to the ICU from the ward. RESULTS: 51 patients from the ward were admitted as an emergency to the ICU following a rapid response team call, of whom 48 patients had complete datasets and were enrolled; 32 (67%) were men. The prevalence of ALF was 37.5% (18/48). Median age was 62.5 (IQR 51.5-74.0), Median APACHE II score was 21.0 (IQR 17-26). There was no diurnal variation in the prevalence of ALF (day 28% versus night 28%; p=0.92), patient observations documented over time (p=0.78 for RR, p=0.95 for PR and p=0.74 for SBP) or 28-day mortality (p=0.24). There was a significant diurnal variation between the least recorded observation (SBP) and the most recorded observation (PR) (p<0.01). ALF was more likely (day and night) if a complete set of observations had been taken (p<0.01). CONCLUSION: The prevalence of ALF amongst patients admitted to the ICU from the ward is high. SBP is the least recorded patient observation. This study was unable to identify a diurnal variation in the prevalence of ALF, its consequences (i.e. mortality) and the completeness of patient observations. Observational studies with a larger sample are required to explore this important problem. PMID- 26748156 TI - Effect of oxygen on the expression of renin-angiotensin system components in a human trophoblast cell line. AB - During the first trimester, normal placental development occurs in a low oxygen environment that is known to stimulate angiogenesis via upregulation of vascular endothelial growth factor (VEGF). Expression of the placental renin-angiotensin system (RAS) is highest in early pregnancy. While the RAS and oxygen both stimulate angiogenesis, how they interact within the placenta is unknown. We postulated that low oxygen increases expression of the proangiogenic RAS pathway and that this is associated with increased VEGF in a first trimester human trophoblast cell line (HTR-8/SVneo). HTR-8/SVneo cells were cultured in one of three oxygen tensions (1%, 5% and 20%). RAS and VEGF mRNA expression were determined by qPCR. Prorenin, angiotensin converting enzyme (ACE) and VEGF protein levels in the supernatant, as well as prorenin and ACE in cell lysates, were measured using ELISAs. Low oxygen significantly increased the expression of both angiotensin II type 1 receptor (AGTR1) and VEGF (both P < 0.05). There was a positive correlation between AGTR1 and VEGF expression at low oxygen (r = 0.64, P < 0.005). Corresponding increases in VEGF protein were observed with low oxygen (P < 0.05). Despite no change in ACE1 mRNA expression, ACE levels in the supernatant increased with low oxygen (1% and 5%, P < 0.05). Expression of other RAS components did not change. Low oxygen increased AGTR1 and VEGF expression, as well as ACE and VEGF protein levels, suggesting that the proangiogenic RAS pathway is activated. This highlights a potential role for the placental RAS in mediating the proangiogenic effects of low oxygen in placental development. PMID- 26748157 TI - Effect of folic acid on human trophoblast health and function in vitro. AB - INTRODUCTION: The combined intake of folic acid (FA) from prenatal multivitamin supplements and fortified foods can result in FA intake values that exceed the tolerable upper intake level (UL). It is unclear what impact FA intake above the UL may have on the feto-placental unit. Our objective was to determine the effects of increasing concentrations of FA on trophoblast health and function in vitro. METHODS: Two human placental cell lines [HTR-8/SVneo (n = 5 experiments) and BeWo (n = 5 experiments)] and human placenta tissue explants (n = 6 experiments) were exposed to increasing concentrations of FA (2-2000 ng/mL) for 48-h. Intracellular total folate concentration, trophoblast proliferation, viability, apoptosis, placenta cell invasion and beta-hCG hormone release were assessed. RESULTS: Exposure to increasing FA concentrations resulted in higher intracellular total folate in placental cell lines and tissue explants (p < 0.05); yet, only minimal effects of excess folic acid were observed on the primary indicators of placental health and function studied. Specifically, treatment with excess folic acid (2000 ng/mL) resulted in reduced cellular viability in the villous trophoblast BeWo cell line and increased rates of proliferation in the HT8-8/SVneo extravillous trophoblast cell line (p < 0.05). Further, deficient concentrations of folic acid (2 ng/mL) resulted in decreased cell viability and invasive capabilities of the HTR-8/SVneo extravillous trophoblast cell line (p < 0.05). DISCUSSION: Our results demonstrate that placental health and function may be compromised in conditions of folate deficiency, and not necessarily in conditions of excess FA. This finding supports the recommendation of prenatal folic acid supplementation in the North American population. Further work aimed at clarifying the therapeutic window of FA intake in the obstetrical population is warranted. PMID- 26748158 TI - Metabolic scaling and twin placentas. AB - OBJECTIVE: Do monochorionic (MC) and/or dichorionic (DC) twins show allometric scaling between placental and birth weight (PW, BW)? METHODS: We extracted BW, PW, gestational age (GA) and cord insertion type from 52 MC to 310 DC twins to calculate beta. DC twins were analyzed as summed and as individuals if placentas were separate. RESULTS: Mean beta for MC (0.78 +/- 0.02), DC summed (0.78 +/- 0.02), and DC with separate placentas (0.77 +/- 0.03 and 0.76 +/- 0.04) all non significant. GA, summed BWs, total PW, BW discordance, and cord insertion sites did not differ between twin types or with beta. CONCLUSION: MC and DC twins show allometric scaling similar to singletons. PMID- 26748159 TI - Differential expression of human placental PAPP-A2 over gestation and in preeclampsia. AB - INTRODUCTION: Pregnancy Associated Plasma Protein A2 (PAPP-A2) is a pregnancy related insulin-like growth factor binding protein-5 (IGFBP-5) protease, known to be elevated in preeclampsia. As the insulin-like growth factors are important in human implantation and placentation, we sought to determine the expression pattern of PAPP-A2 over human gestation in normal and preeclamptic pregnancies to evaluate its role in placental development and the pathogenesis of preeclampsia. METHODS: Placental basal plate and chorionic villi samples, maternal and fetal cord blood sera were obtained from preeclamptic and control pregnancies. Formalin fixed tissue sections from across gestation were stained for cytokeratin-7, HLA G, and PAPP-A2. PAPP-A2 immunoblot analysis was also performed on protein lysates and sera. RESULTS: PAPP-A2 expression is predominately expressed by differentiated trophoblasts and fetal endothelium. Chorionic villi show strong expression in the first trimester, followed by a progressive decrease in the second trimester, which returns in the third trimester. PAPP-A2 expression is not impacted by labor. PAPP-A2 is increased in the basal plate, chorionic villi and maternal sera in preeclampsia compared to controls, but is not detectable in cord blood. DISCUSSION: PAPP-A2 is differentially expressed in different trophoblast populations and shows strong down regulation in the mid second trimester in chorionic villous samples. Both maternal sera and placental tissue from pregnancies complicated by preeclampsia show increased levels of PAPP-A2. PAPP-A2 levels are not altered by labor. Additionally, PAPP-A2 cannot be detected in cord blood demonstrating that the alterations in maternal and placental PAPP-A2 are not recapitulated in the fetal circulation. PMID- 26748160 TI - Improved Treatment-Related Mortality and Overall Survival of Patients with Grade IV Acute GVHD in the Modern Years. AB - The impact of advances in supportive care and hematopoietic stem cell transplantation (HSCT) practices on the outcomes of patients who develop grade III or IV acute graft-versus-host disease (GVHD) is unknown. We performed a retrospective analysis of 427 patients with overall grade III or IV acute GVHD treated at 2 partner institutions between 1997 and 2012. We compared treatment related mortality (TRM) and overall survival (OS) in 2 cohorts based on the year of transplantation, 1997 to 2006 (n = 222) and 2007 to 2012 (n = 205), using multivariate analysis, adjusting for significant patient-, disease-, and transplantation-related factors. Recipient age, reduced-intensity conditioning, unrelated donor, and peripheral blood stem cell grafts in the patients with grade III or IV acute GVHD increased over time. In the unadjusted analysis, 12-month OS increased over time (30% in 1997 to 2006 versus 42% in 2007 to 2012; P = .003) reflecting a decrease in TRM (58% in 1997 to 2006 versus 38% in 2007 to 2012; P = .0002), and an increase in PFS (29% in 1997 to 2006 versus 43% in 2007 to 2012; P = .002). On multivariate analysis, the period of transplantation remained a significant predictor for OS (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.54 to 0.94; P = .02), progression-free survival (PFS) (HR, 0.70; 95% CI, 0.52 to 0.94; P = .02), and TRM (HR, 0.57; 95% CI, 0.39 to 0.82; P = .002). In subgroup analysis, these differences were observed mainly in patients with grade IV acute GVHD. The outcomes of patients who develop overall grade III or IV acute GVHD after allogeneic HSCT has improved over time, with lower TRM and improved OS. This improvement in outcomes was seen primarily in patients with grade IV acute GVHD. PMID- 26748161 TI - Safety of Live Attenuated High-Titer Varicella-Zoster Virus Vaccine in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients. AB - Hematopoietic stem cell transplantation (HSCT) recipients have a high risk of varicella-zoster virus (VZV) infections. Although VZV vaccination may be beneficial in preventing VZV infections, data on safety and efficacy of VZV vaccines in HSCT recipients, particularly of zoster vaccine, are limited. We report our experience with the use of a single dose of an Oka strain high-titer zoster-equivalent varicella vaccine in pediatric allogeneic HSCT recipients. We administered the high-titer VZV vaccine to 31 pediatric allogeneic HSCT recipients without vaccine-type VZV infections. One patient developed varicella due to wild-type VZV 13 days after vaccination. No zoster developed after vaccination during a median follow-up period of 4.8 years from vaccination. No other adverse effects were observed. Eighteen of the 31 patients (58.1%) were seropositive after vaccination. Seventeen patients were vaccinated within 24 months after HSCT; the seropositivity of these patients did not significantly differ from that of patients vaccinated > 24 months after HSCT. VZV vaccination may be a safe and beneficial approach in preventing VZV infections after HSCT. PMID- 26748162 TI - Correlation and Agreement of Handheld Spirometry with Laboratory Spirometry in Allogeneic Hematopoietic Cell Transplant Recipients. AB - Early detection of subclinical lung function decline may help identify allogeneic hematopoietic cell transplant (HCT) recipients who are at increased risk for late noninfectious pulmonary complications, including bronchiolitis obliterans syndrome. We evaluated the use of handheld spirometry in this population. Allogeneic HCT recipients enrolled in a single-center observational trial performed weekly spirometry with a handheld spirometer for 1 year after transplantation. Participants performed pulmonary function tests in an outpatient laboratory setting at 3 time points: before transplantation, at day 80 after transplantation, and at 1 year after transplantation. Correlation between the 2 methods was assessed by Pearson and Spearman correlations; agreement was assessed using Bland-Altman plots. A total of 437 subjects had evaluable pulmonary function tests. Correlation for forced expiratory volume in 1 second (FEV1) was r = .954 (P < .0001) at day 80 and r = .931 (P < .0001) at 1 year when the handheld and laboratory tests were performed within 1 day of each other. Correlation for handheld forced expiratory volume in 6 seconds (FEV6) with laboratory forced vital capacity was r = .914 (P < .0001) at day 80 and r = .826 (P < .0001) at 1 year. The bias, or the mean difference (handheld minus laboratory), for FEV1 at day 80 and 1 year was -.13 L (limits of agreement, -.63 to .37) and -.10 L (limits of agreement, -.77 to .56), respectively. FEV6 showed greater bias at day 80 (-.51 L [limits of agreement, -1.44 to .42]) and 1 year (-.40 L [limits of agreement, -1.81 to 1.01]). Handheld spirometry correlated well with laboratory spirometry after allogeneic HCT and may be useful for self-monitoring of patients for early identification of airflow obstruction. PMID- 26748163 TI - Fetal Rat Gubernaculum Mesenchymal Cells Adopt Myogenic and Myofibroblast-Like Phenotypes. AB - PURPOSE: Gubernaculum-cremaster complex development is hormonally regulated and abnormal in a cryptorchid rat model. Using cell tracking techniques and imaging we studied myogenic phenotypes and fates in the fetal rat gubernaculum-cremaster complex. MATERIALS AND METHODS: Embryonic day 17 gubernaculum-cremaster complexes were labeled with CellTrackerTM or the DNA synthesis marker EdU (5-ethynyl-2' deoxyuridine), or immobilized in Matrigel(r) and grown in culture. Embryonic day 17 to 21 gubernaculum-cremaster complex sections and cells were imaged using wide field and deconvolution immunofluorescence microscopy, and muscle and/or myofibroblast specific antibodies. Deconvolved image stacks were used to create a 3-dimensional model of embryonic day 21 gubernaculum-cremaster complex muscle. RESULTS: PAX7 (paired box 7) positive and myogenin positive muscle precursors were visible in a desmin-rich myogenic zone between muscle layers that elongated and became thicker during development. Gubernaculum-cremaster complex inner mesenchymal cells expressed desmin and alphaSMA (alpha smooth muscle actin) at lower levels than in the myogenic zone. After pulse labeling with CellTracker or EdU mesenchymal cells became incorporated into differentiated muscle. Conversely, mesenchymal cells migrated beyond Matrigel immobilized gubernaculum-cremaster complexes, expressed PAX7 and fused to form striated myotubes. Mesenchymal gubernaculum-cremaster complex cell lines proliferated more than 40 passages and showed contractile behavior but did not form striated muscle. Our 3-dimensional gubernaculum-cremaster complex model had 2 orthogonal ventral layers and an arcing inner layer of muscle. CONCLUSIONS: Our data suggest that mesenchymal cells in the peripheral myogenic zone of the fetal gubernaculum-cremaster complex contribute to formation of a distinctively patterned cremaster muscle. Nonmyogenic, desmin and alphaSMA positive gubernaculum-cremaster complex mesenchymal cells proliferate and have a myofibroblast-like phenotype in culture. Intrinsic mechanical properties of these divergent cell types may facilitate perinatal inversion of the gubernaculum-cremaster complex. PMID- 26748164 TI - Focal Laser Ablation of Prostate Cancer: Phase I Clinical Trial. AB - PURPOSE: Focal laser ablation is an investigational technique to treat prostate cancer in a region confined manner via coagulative necrosis. This phase I trial primarily examines the safety of transrectal magnetic resonance imaging guided (in-bore) focal laser ablation in men with intermediate risk prostate cancer. An exploratory end point is cancer control after 6 months. MATERIALS AND METHODS: In an institutional review board approved trial we studied focal laser ablation in 8 men with intermediate risk prostate cancer diagnosed using magnetic resonance ultrasound fusion. Focal laser ablation was performed by inserting a cylindrically diffusing, water cooled laser fiber into magnetic resonance visible regions of interest, followed by interstitial heating at 10 to 15 W for up to 3 minutes. Secondary safety monitors (thermal probes) were inserted to assess the accuracy of magnetic resonance thermometry. Comprehensive magnetic resonance ultrasound fusion biopsy was performed after 6 months. Adverse events and health related quality of life questionnaires were recorded. RESULTS: Focal laser ablation was successfully performed in all 8 subjects. No grade 3 or greater adverse events occurred and no changes in International Prostate Symptom Score or International Index of Erectile Function 5 were observed. Ablation zones, as measured by posttreatment magnetic resonance imaging, had a median volume of 3 cc or 7.7% of prostate volume. Prostate specific antigen decreased in 7 men (p <0.01). At followup magnetic resonance-ultrasound fusion biopsy cancer was not detected in the ablation zone in 5 men but was present outside the treatment margin in 6 men. CONCLUSIONS: Focal laser ablation of the prostate is feasible and safe in men with intermediate risk prostate cancer without serious adverse events or changes in urinary or sexual function at 6 months. Comprehensive biopsy followup indicates that larger treatment margins than previously thought necessary may be required for complete tumor ablation. PMID- 26748166 TI - Issues on medical waste management research. PMID- 26748165 TI - Treatment and Clinical Outcomes of Patients with Teratoma with Somatic-Type Malignant Transformation: An International Collaboration. AB - PURPOSE: We assessed prognostic factors, treatments and outcomes in patients with teratoma with malignant transformation, a rare occurrence among germ cell tumors. MATERIALS AND METHODS: Data on patients diagnosed with teratoma with malignant transformation between June 1981 and August 2014 were collected across 5 referral centers. Chemotherapy was dichotomized as based on germ cell tumor or teratoma with malignant transformation. Cox analyses were done to evaluate prognostic factors of overall survival, the primary end point. Each factor was evaluated in a univariable model. Forward stepwise selection was used to construct an optimal model. RESULTS: Among 320 patients the tumor primary site was gonadal in 287 (89.7%), retroperitoneal in 17 (5.3%) and mediastinal in 16 (5%). Teratoma with malignant transformation and germ cell tumor were diagnosed concurrently in 130 patients (40.6%). A total of 49 patients (16.8%) initially presented with clinical stage I. The remaining patients were at good (123 or 42.3%), intermediate (42 or 14.4%) and poor (77 or 26.5%) risk for metastasis according to IGCCCG (International Germ Cell Cancer Collaborative Group). First line chemotherapy was given for germ cell tumor in 159 patients (49.7%), chemotherapy for teratoma with malignant transformation was performed in 14 (4.4%) and only surgery was done in 147 (45.9%). Median followup was 25.1 months (IQR 5.4-63.8). Five-year overall survival was 83.4% (95% CI 61.3 to 93.5) in patients with clinical stage I and it was also worse than expected in those with metastasis. On multivariable analyses nonprimitive neuroectodermal tumor histology (overall p = 0.004), gonadal primary tumor (p = 0.005) and fewer prior chemotherapy regimens (p <0.001) were independent predictors of better overall survival. Chemotherapy was not independently prognostic. CONCLUSIONS: Less heavily pretreated teratoma with malignant transformation with a gonadal primary tumor and nonprimitive neuroectodermal tumor histology appears to be associated with longer overall survival. Generally, teratoma with malignant transformation had a worse prognosis than germ cell tumor. Uncertainties persist regarding optimal chemotherapy. PMID- 26748167 TI - Glioblastoma Presenting with Pure Alexia and Palinopsia Involving the Left Inferior Occipital Gyrus and Visual Word Form Area Evaluated with Functional Magnetic Resonance Imaging and Diffusion Tensor Imaging Tractography. AB - BACKGROUND: Rapid word recognition and reading fluency is a specialized cortical process governed by the visual word form area (VWFA), which is localized to the dominant posterior lateral occipitotemporal sulcus/fusiform gyrus. A lesion of the VWFA results in pure alexia without agraphia characterized by letter-by letter reading. Palinopsia is a visual processing distortion characterized by persistent afterimages and has been reported in lesions involving the nondominant occipitotemporal cortex. CASE DESCRIPTION: A 67-year-old right-handed woman with no neurologic history presented to our emergency department with acute cortical ischemic symptoms that began with a transient episode of receptive aphasia. She also reported inability to read, albeit with retained writing ability. She also saw afterimages of objects. During her stroke workup, an intra-axial circumscribed enhancing mass lesion was discovered involving her dominant posterolateral occipitotemporal lobe. Given the eloquent brain involvement, she underwent preoperative functional magnetic resonance imaging with diffusion tensor imaging tractography and awake craniotomy to maximize resection and preserve function. CONCLUSIONS: Many organic lesions involving these regions have been reported in the literature, but to the best of our knowledge, glioblastoma involving the VWFA resulting in both clinical syndromes of pure alexia and palinopsia with superimposed functional magnetic resonance imaging and fiber tract mapping has never been reported before. PMID- 26748168 TI - Increased Incidence of Hypovitaminosis D Among Patients Requiring Treatment for Cerebral Aneurysms. AB - OBJECTIVE: Aneurysmal subarachnoid hemorrhage management is hampered by our incomplete understanding of what variables promote aneurysm formation, growth, and rupture. Because hypovitaminosis D has been identified as a risk factor for other vascular diseases, we examined its association with cerebral aneurysms requiring treatment. METHODS: We retrospectively reviewed charts of patients with cerebral aneurysms with recorded 25-hydroxy vitamin D levels undergoing treatment at our institution from May 2010 to May 2015. We compared these patients with a group of patients without aneurysms. We used multivariable Poisson regression and backward elimination to identify factors associated with cerebral aneurysms, with a threshold P < 0.20. A propensity-matching algorithm was used, incorporating all factors with P < 0.10 in our regression model. RESULTS: Patients in the aneurysm group were older than those in the control group (P = 0.001) and more likely to be female (P = 0.004), to be tobacco users (P < 0.001), and to have a diagnosis of hypertension (P = 0.001), but ethnicity, body mass index, and diabetes rates did not differ. Vitamin D levels in the aneurysm group were lower than in the control group (23.3 +/- 12.3 vs. 28.7 +/- 14.1 ng/mL, P = 0.001), and the patients were more likely to be vitamin D deficient (P = 0.028). Multivariable Poisson regression demonstrated that vitamin D level, tobacco use, age, and sex were significantly associated with aneurysms requiring treatment (P < 0.05). The propensity-matching algorithm confirmed a significant difference in vitamin D levels between the aneurysm and control groups (P = 0.01). CONCLUSIONS: Patients with cerebral aneurysms requiring treatment have a significantly higher incidence of hypovitaminosis D compared with patients in a control group. PMID- 26748169 TI - Direct Microsurgical Embolectomy for Acute Occlusion of the Internal Carotid Artery and Middle Cerebral Artery. AB - BACKGROUND: Surgical embolectomy is the most promising therapy for physically removing emboli from major cerebral arteries. However, it requires an experienced surgical team, time-consuming steps, and is not incorporated into acute stroke therapy. METHODS: We established seamless collaboration between services, refined surgical techniques, and conducted a prospective trial of emergency surgical embolectomy. Surgical indications included the presence of acute hemispheric symptoms, absence of low-density area on computed tomography, evidence of internal carotid artery terminus or proximal middle cerebral artery occlusion, and availability of resources to start surgery within 3 hours of symptom onset. The indications were confirmed by an interdisciplinary team. We assessed revascularization rates, time from admission to surgery and from surgery to recanalization, procedural complications, and clinical outcomes. RESULTS: Between 2005 and 2014, 14 consecutive patients with acute proximal middle cerebral artery or internal carotid artery terminus occlusion underwent emergency surgical embolectomy. All patients showed complete recanalization. Twelve patients survived and 7 had fair functional outcome (Rankin Scale score, <=3). No significant procedural adverse events occurred. The mean times from admission to start of surgery, from surgery to recanalization, and from onset to recanalization were 14 minutes, 79 minutes, and 223 minutes, respectively. CONCLUSIONS: Our results suggest that microsurgical embolectomy can rapidly, safely, and effectively retrieve clots and deserves reappraisal, although the choice largely depends on local institutional expertise. PMID- 26748170 TI - Acute Paraplegia After Aneurysmal SAH: A Case Report of a Rare Complication and Review of the Literature. AB - BACKGROUND: Paraplegia after intracranial aneurysmal subarachnoid hemorrhage (SAH) is a rare condition, and its pathogenesis is still unclear. CASE DESCRIPTION: We present a case of a ruptured basilar dissecting aneurysm treated with the stent-assisted coiling procedure. Progressive weakness of the lower limbs developed within 5 days postoperatively. Spinal magnetic resonance image showed SAH accumulation in the lumbosacral area. Emergency lumbar drainage was performed, and the patient's symptoms improved dramatically. CONCLUSIONS: To the best of our knowledge, this is the first report to describe the successful treatment of paraplegia after intracranial aneurysmal SAH. PMID- 26748171 TI - Comparison of Primary Spinal Central and Peripheral Primitive Neuroectodermal Tumors in Clinical and Imaging Characteristics and Long-Term Outcome. AB - OBJECTIVE: Primary spinal primitive neuroectodermal tumors are extremely rare entities. The purpose of this study was to analyze the differences in clinical and imaging characteristics and outcomes between primary spinal central PNETs (cPNETs) and peripheral PNETs (pPNETs). METHODS: There were 25 consecutive patients with primary spinal primitive neuroectodermal tumors enrolled. The diagnosis was cPNET in 6 patients with negative CD99 expression and pPNET in 19 patients with positive CD99 expression. Gross total resection (GTR) was achieved in 12 patients, subtotal resection was performed in 9 patients, and partial resection was performed in 4 patients. Postoperative chemotherapy was given to 14 patients, and radiotherapy was given to 16 patients. RESULTS: The age at diagnosis was significantly younger in the cPNET group (mean 12.8 years) compared with the pPNET group (mean 22.5 years) (P = 0.040); the 2 pathologies did not show a significant difference in prognosis. GTR (P = 0.041), radiotherapy (P = 0.008), and GTR with radiotherapy (P = 0.009) were significant factors leading to a higher 2-year survival rate. Kaplan-Meier analysis showed that radiotherapy (P < 0.001) and GTR with radiotherapy (P = 0.040) resulted in a longer median survival time. Patients who underwent GTR, chemotherapy, and radiotherapy all together had the highest 1-year (100.0%) and 2-year (71.4%) survival rates and the longest median survival time (32 months). CONCLUSIONS: Patients with spinal cPNETs were younger compared with patients with pPNETs. The prognosis of spinal cPNETs and pPNETs was poor with no significant difference between the entities. The most beneficial treatment modality is GTR combined with adjuvant radiotherapy and chemotherapy. PMID- 26748172 TI - Vertebral Artery Transposition Via an Extreme-Lateral Approach for Anterior Foramen Magnum Meningioma or Craniocervical Junction Tumors. AB - OBJECTIVE: Vertebral artery (VA) transposition in the extreme-lateral transcondylar approach can minimize the manipulation of the low cranial nerves and the brain stem. The authors describe the surgical technique of VA transposition. METHODS: From March 2000 to December 2014, 28 of 48 patients underwent VA transposition for anterior foramen magnum meningioma (16 patients) and craniocervical junction (CCJ) tumors (12 patients). Tumor was resected via an extreme-lateral approach with partial condylectomy to expose the anterior portion of the brain stem. For intradural tumors, the VA was mobilized caudomedially after circumferential dural incision around the VA at the level of the foramen magnum. For extradural tumors involving the CCJ, VA was transposed medially from the transverse foramen of C1 without any dural incision. RESULTS: Gross total resection was achieved in 26 of 28 patients (92.9%) with VA transposition. Histologically, meningioma and schwannoma were most common. The origin of the tumors was foramen magnum (57.1%), C1 nerve root (17.9%), clivus (10.7%), jugular foramen (7.1%), posterior skull base (3.6%), and hypoglossal canal (3.6%). VA transposition was performed intradurally in 19 patients (67.9%) and extradurally in 9 patients (32.1%). Surgical morbidity was 17.9% including 4 patients with hypoglossal nerve palsy and 1 patient with quadriparesis. The mean follow-up duration after surgery was 4.2 years (range, 0.1-14.8 years). CONCLUSIONS: VA transposition can provide a wide surgical window for anterior foramen magnum meningioma or tumors involving the CCJ with the least manipulation of the neuraxis. PMID- 26748173 TI - Preoperative Predictors of Spinal Infection within the National Surgical Quality Inpatient Database. AB - BACKGROUND: Surgical-site infections (SSIs) are a major cause of morbidity and mortality, increasing the length and cost of hospitalization. In patients undergoing spine surgery, there are limited large-scale data on patient-specific risk factors for SSIs. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was reviewed for all spinal operations between 2006 and 2012. The rates of 30-day SSIs were calculated, and univariate analysis of selected preoperative risk factors was performed. Multivariate analysis was then used to identify independent predictors of SSIs. RESULTS: A total of 1110 of the 60,179 patients (1.84%) had a postoperative wound infection. There were 527 (0.87%) deep and 590 (0.98%) superficial infections. Patients with infections had greater rates of sepsis, longer lengths of stay, and more return visits to the operating room. Independent predictors of infection were female sex, inpatient status, insulin-dependent diabetes, preoperative steroid use greater than 10 days, hematocrit less than 35, body mass index greater than 30, wound class, American Society of Anesthesiologists class, and operative duration. CONCLUSIONS: Analysis of a large national patient database revealed many independent risk factors for SSIs after spinal surgery. Some of these risk factors can be modified preoperatively to reduce the risk of postoperative infection. PMID- 26748174 TI - Spontaneous Regression of Pineal Lesions: Ghost Tumor or Pineal Apoplexy? AB - BACKGROUND: Pineal apoplexy (either hemorrhagic or ischemic) may complicate the course of a tumor at this site. This event usually is characterized by an acute clinical onset and requires emergency surgical management whereas the regression of the lesion is a much rarer outcome. MATERIAL AND METHODS: Three cases of pineal vanishing tumors in the pediatric population are reported and the pertinent literature is reviewed. RESULTS: In one case, radiologic findings were consistent with a diagnosis of pineal cyst, which became symptomatic after a spontaneous hemorrhage. This event may also explain its regression after the treatment of associated hydrocephalus. In the remaining 2 cases, neuroimaging examinations disclosed a solid tumor. One of them regressed after a surgical biopsy, probably because of an ischemic evolution, whereas the last one disappeared without any medical or surgical manipulation. Neither hemorrhage nor ischemia were noticed, thus the mechanism of regression remains controversial. CONCLUSIONS: Vanishing tumors of the pineal region may occur in different circumstances, resulting from absence of any medical and surgical action to minor manipulation of the tumor to obtain a biopsy. This variety may reflect different underlying mechanisms, leading to hemorrhagic or ischemic change of the tumor and its subsequent regression, although radiological imaging may fail to document hemorrhage or ischemia. PMID- 26748177 TI - Delayed Migration of Fractured K-wire Causing Vertebral Artery Invagination After Anterior Atlantoaxial Fixation: A Case Report. AB - BACKGROUND: Most of the physician's attention during spinal surgery, when using wires and screws, is toward the avoidance of injuries of critical structures (nerves and vessels). When such wires are broken during surgery, the most important point is to take them out safely or, if it is impossible, to leaf them in secure place and follow the patient closely. Migrations of broken Kirschner wire (K-wire) are well known in literature; however, to the best of our knowledge, migration of a fractured K-wire during anterior atlantoaxial fixation of cervical spine has not been reported in the literature. CASE DESCRIPTION: We report a case in which a fractured K-wire was imbedded in the lateral mass of C1 for 3 years and then migrated to endanger the dominant right vertebral artery. By using posterior approach and drilling right part of posterior arch of C1, we manage to secure the vertebral artery. The broken K-wire was extracted successfully. In our case, with optimal follow-up, the burred wire inside hard bone was moved in delayed fashion to come out of the bone, grooving the dominant vertebral artery. CONCLUSIONS: Our recommendation is to inspect the K-wire before using it and to try retrieve as much as possible when removing it. PMID- 26748176 TI - Parametric Digital Subtraction Angiography Imaging for the Objective Grading of Collateral Flow in Acute Middle Cerebral Artery Occlusion. AB - PURPOSE: To report the feasibility of parametric color-coded digital subtraction angiography (DSA) in complementing the traditional, subjective way of leptomeningeal collateral assessment in acute middle cerebral artery (MCA) occlusions. METHODS: Thirty-three consecutive patients with acute MCA occlusion who received endovascular treatment were recruited for investigation. Eighteen of 33 consecutive patients were included. The target downstream territory (TDT) of MCA and reference point at terminal internal carotid artery of each patient was contoured by 5 raters independently on the basis of anteroposterior 2-dimensional DSA. Two parameters of relative maximum density of TDT (rDensitymax) and peak time interval (DeltaPT) between reference and TDT were extracted by the use of parametric DSA analysis software. Interrater reliability was tested with intraclass correlation coefficients. Parameters with sufficient interrater reliability entered validity evaluation. Then, the correlation test with the American Society of Interventional and Therapeutic Neuroradiology collateral grading system and efficacy in predicting favorable clinical outcome was evaluated. RESULTS: The intraclass correlation coefficient of rDensitymax and DeltaPT were 0.983, 95% confidence interval 0.968-0.993 and 0.831, 95% confidence interval 0.705-0.923, respectively. The parameter rDensitymax showed a strong correlation with the American Society of Interventional and Therapeutic Neuroradiology collateral grading system score (r of Spearman correlation test = 0.869, P < 0.001) and mRS at 3 months (partial correlation coefficient = 0.616, P = 0.009), whereas DeltaPT_average did not. A cut-off point of 0.224 in rDensitymax predicted a favorable clinical outcome with high sensitivity and specificity. CONCLUSIONS: The relative maximum contrast density of MCA territory on 2-dimensional DSA measured by parametric imaging technique appears to be a simple and reliable metric for the assessment of leptomeningeal collaterals in cases of acute MCA occlusion. PMID- 26748175 TI - Craniotomy Versus Craniectomy for Acute Traumatic Subdural Hematoma in the United States: A National Retrospective Cohort Analysis. AB - OBJECTIVE: The optimal surgical management of acute traumatic subdural hematoma (ASDH) is controversial; both craniectomy and craniotomy are performed. The purpose of this study was to determine the current management of ASDH in the United States. METHODS: This retrospective cohort study used the Nationwide Inpatient Sample from the years 2006-2011 to examine patients with a primary diagnosis of ASDH. All patients >=18 years old with a primary diagnosis of ASDH were included in the analysis. Patients with procedure codes for craniectomy and craniotomy were isolated from the database. Propensity score matching based on logistic regression was used to match craniotomy to craniectomy in a 1:1 fashion. RESULTS: There were 47,911,414 hospitalizations analyzed. Of 60,435 patients with ASDH identified, 1763 underwent craniotomy and 177 underwent craniectomy. The average age of patients who underwent craniectomy was 49.5 years (SD 20.8) compared with an average age of 68.9 years (SD 17.1) of patients who underwent craniotomy (P < 0.0001). Hospital mortality was significantly higher in patients who underwent craniectomy (35.0% vs. 10.9%, P < 0.0001). Patients who underwent craniectomy had longer hospital stays compared with patients who underwent craniotomy (median duration 14.3 days [interquartile range 25] for craniectomy vs. 10.9 days [interquartile range 9] for craniotomy, P < 0.0001). Patients who underwent craniectomy were also more likely to be discharged to a skilled nursing or rehabilitation facility (79.1% vs. 63.9%, P = 0.0011). CONCLUSIONS: Craniotomy is the preferred surgical technique for management of ASDH in the United States, being performed 10 times more frequently than craniectomy. Craniectomy was associated with significantly higher in-hospital mortality after propensity score matched analysis. PMID- 26748178 TI - Isolated Intramedullary Spinal Rosai-Dorfman Disease: A Case Report and Literature Review. AB - BACKGROUND: Rosai-Dorfman disease (RDD) is a rare histioproliferative disorder that only occasionally involves the central nervous system. CASE DESCRIPTION: We present the diagnosis and treatment of an exceedingly rare case of isolated intramedullary spinal RDD that has been reported only 3 times previously. Moreover, it is the first time that intramedullary spinal RDD has been described in a child. The patient was treated by total surgical resection and experienced no recurrence during the 12-month follow-up. Histopathologic examination showed a characteristic emperipolesis; the lymphocytes were engulfed in the S-100-protein positive histiocytes with negative expression of CD1a. CONCLUSIONS: Preoperative diagnosis of spinal RDD is still challenging because the lesion usually is a dura based lesion that mimics a meningioma. Surgical resection is an effective treatment and radiotherapy; and steroid and chemotherapy have not demonstrated reliable therapeutic efficiency. PMID- 26748182 TI - The effects of LSD1 inhibition on self-renewal and differentiation of human induced pluripotent stem cells. AB - Human induced pluripotent stem cells (hiPSCs) are capable of unlimited self renewal and can generate nearly all cells in the body. Changes induced by different LSD1 activities on the regulation of hiPSC self-renewal and differentiation and the mechanism underlying such changes were determined. We used two different LSD1 inhibitors (phenelzine sulfate and tranylcypromine) and RNAi technique to inhibit LSD1 activity, and we obtained hiPSCs showing 71.3%, 53.28%, and 31.33% of the LSD1 activity in normal hiPSCs. The cells still maintained satisfactory self-renewal capacity when LSD1 activity was at 71.3%. The growth rate of hiPSCs decreased and cells differentiated when LSD1 activity was at approximately 53.28%. The hiPSCs were mainly arrested in the G0/G1 phase and simultaneously differentiated into endodermal tissue when LSD1 activity was at 31.33%. Teratoma experiments showed that the downregulation of LSD1 resulted in low teratoma volume. When LSD1 activity was below 50%, pluripotency of hiPSCs was impaired, and the teratomas mainly comprised endodermal and mesodermal tissues. This phenomenon was achieved by regulating the critical balance between histone methylation and demethylation at regulatory regions of several key pluripotent and developmental genes. PMID- 26748183 TI - Specific role of cytoplasmic dynein in the mechanism of action of an antitumor molecule, Amblyomin-X. AB - The Kunitz-type recombinant protein, Amblyomin-X, is an antitumor recombinant molecule from a cDNA library prepared from the salivary glands of the tick Amblyomma cajennense. The primary target of this protein appears to be the proteasome. Amblyomin-X increased gene and protein expression of distinct subunits of the molecular motor dynein, which plays a key role in the intracellular transport. Herein, Amblyomin-X was specifically taken up by tumor cells through lipid-raft endocytic pathways, but not by fibroblasts. Moreover, dynein inhibitor, ciliobrevin A, decreased Amblyomin-X uptake by tumor cells. Furthermore, incubation of tumor cells with Amblyomin-X inhibited trypsin-like activity of the proteasome, which was restored upon pretreatment with ciliobrevin A. Only in tumor cells treated with Amblyomin-X, we identified proteins bounds to dynein that are related to aggresome formation, autophagy inhibition, and early and recycling endosome markers. In addition, Amblyomin-X was found to interact with dynein, increased Rab11A protein expression and Rab11A co-localization with the light-intermediate chain 2 (LIC2) of dynein. Thereby, the results provide new insights on the antitumor mechanism of Amblyomin-X and reveal an unsuspected role of cytoplasmic dynein in its uptake, intracellular trafficking and pro-apoptotic action. PMID- 26748179 TI - Development and Function of Arterial and Cardiac Macrophages. AB - Macrophages inhabit all major organs, and are capable of adapting their functions to meet the needs of their home tissues. The recent recognition that tissue macrophages derive from different sources, coupled with the notion that environmental cues and inflammatory stimuli can sculpt and agitate homeostasis, provides a frame of reference from which we can decipher the breadth and depth of macrophage activity. Here we discuss macrophages residing in the cardiovascular system, focusing particularly on their development and function in steady state and disease. Central to our discussion is the tension between macrophage ontogeny as a determinant of macrophage function, and the idea that tissues condition macrophage activities and supplant the influence of macrophage origins in favor of environmental demands. PMID- 26748184 TI - The novel HSP90 inhibitor NVP-AUY922 shows synergistic anti-leukemic activity with cytarabine in vivo. AB - HSP90 is a molecular chaperone essential for stability, activity and intracellular sorting of many proteins, including oncoproteins, such as tyrosine kinases, transcription factors and cell cycle regulatory proteins. Therefore, inhibitors of HSP90 are being investigated for their potential as anti-cancer drugs. Here we show that the HSP90 inhibitor NVP-AUY922 induced degradation of the fusion oncoprotein FOP2-FGFR1 in a human acute myeloid leukemia (AML) cell line, KG-1a. Concordantly, downstream signaling cascades, such as STAT1, STAT3 and PLCgamma were abrogated. At concentrations that caused FOP2-FGFR1 degradation and signaling abrogation, NVP-AUY922 treatment caused significant cell death and inhibition of proliferation of KG-1a cells in vitro. In an animal model for AML, NVP-AUY922 administrated alone showed no anti-leukemic activity. However, when NVP-AUY922 was administered in combination with cytarabine, the two compounds showed significant synergistic anti-leukemic activity in vivo. Thus NVP-AUY922 and cytarabine combination therapy might be a prospective strategy for AML treatment. PMID- 26748185 TI - Placental development in a mouse model of spinal muscular atrophy. AB - Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder, leading to fatal loss of motor neurons. It is caused by loss of function of the SMN gene, which is expressed throughout the body, and there is increasing evidence of dysfunction in non-neuronal tissues. Birthweight is one of most powerful prognostic factors for infants born with SMA, and intrauterine growth restriction is common. In the SMNDelta7 mouse model of SMA, pups with the disease lived 25% longer when their mothers were fed a higher fat, "breeder" diet. The placenta is responsible for transport of nutrients from mother to fetus, and is a major determinant of fetal growth. Thus, the present study tested the hypothesis that placental development is impaired in SMNDelta7 conceptuses. Detailed morphological characterization revealed no defects in SMNDelta7 placental development, and expression of key transcription factors regulating mouse placental development was unaffected. The intrauterine growth restriction observed in SMA infants likely does not result from impaired placental development. PMID- 26748191 TI - Permeabilized myocardial fibers as model to detect mitochondrial dysfunction during sepsis and melatonin effects without disruption of mitochondrial network. AB - Analysis of mitochondrial function is crucial to understand their involvement in a given disease. High-resolution respirometry of permeabilized myocardial fibers in septic mice allows the evaluation of the bioenergetic system, maintaining mitochondrial ultrastructure and intracellular interactions, which are critical for an adequate functionality. OXPHOS and electron transport system (ETS) capacities were assessed using different substrate combinations. Our findings show a severe septic-dependent impairment in OXPHOS and ETS capacities with mitochondrial uncoupling at early and late phases of sepsis. Moreover, sepsis triggers complex III (CIII)-linked alterations in supercomplexes structure, and loss of mitochondrial density. In these conditions, melatonin administration to septic mice prevented sepsis-dependent mitochondrial injury in mitochondrial respiration. Likewise, melatonin improved cytochrome b content and ameliorated the assembly of CIII in supercomplexes. These results support the use of permeabilized fibers to identify properly the respiratory deficits and specific melatonin effects in sepsis. PMID- 26748205 TI - A low-cost mullite-titania composite ceramic hollow fiber microfiltration membrane for highly efficient separation of oil-in-water emulsion. AB - Oil-in-water (O/W) emulsion is considered to be difficult to treat. In this work, a low-cost multi-layer-structured mullite-titania composite ceramic hollow fiber microfiltration membrane was fabricated and utilized to efficiently remove fine oil droplets from (O/W) emulsion. In order to reduce membrane cost, coal fly ash was effectively recycled for the first time to fabricate mullite hollow fiber with finger-like and sponge-like structures, on which a much more hydrophilic TiO2 layer was further deposited. The morphology, crystalline phase, mechanical and surface properties were characterized in details. The filtration capability of the final composite membrane was assessed by the separation of a 200 mg.L(-1) synthetic (O/W) emulsion. Even with this microfiltration membrane, a TOC removal efficiency of 97% was achieved. Dilute NaOH solution backwashing was used to effectively accomplish membrane regeneration (~96% flux recovery efficiency). This study is expected to guide an effective way to recycle waste coal fly ash not only to solve its environmental problems but also to produce a high-valued mullite hollow fiber membrane for highly efficient separation application of O/W emulsion with potential simultaneous functions of pure water production and oil resource recovery. PMID- 26748207 TI - Three degradation pathways of 1-octyl-3-methylimidazolium cation by activated sludge from wastewater treatment process. AB - The biodegradability and degradation pathways of 1-octyl-3-methylimidazolium cation [OMIM](+) by microbial community of wastewater treatment plant in Jeonju city, Korea were investigated. It was found that [OMIM](+) could be easily degraded by the microbial community. New degradation products and pathways of [OMIM](+) were identified, which are partially different from previous results (Green Chem. 2008, 10, 214-224). For the analysis of the degradation pathways and intermediates, the mass peaks observed in the range m/z of 50-300 were screened by using a tandem mass spectrometer (MS), and their fragmentation patterns were investigated by MS/MS. Surprisingly, we found three different degradation pathways of [OMIM](+), which were separated according to the initially oxidized position i.e. middle of the long alkyl chain, end of the long alkyl chain, and end of the short alkyl chain. The degradation pathways showed that the long and short alkyl chains of [OMIM](+) gradually degraded by repeating oxidation and carbon release. The results presented here shows that [OMIM](+) can be easily biodegraded through three different degradation pathways in wastewater treatment plants. PMID- 26748206 TI - Presence of helminth eggs in domestic wastewater and its removal at low temperature UASB reactors in Peruvian highlands. AB - This work studied the anaerobic sludge filtration capacity for pathogens reduction in a 29 L and 1.65 m height lab-scale UASB reactor treating domestic wastewater at low temperatures in the city of Puno (Peru). The anaerobic sludge filtration capacity was performed applying upflow velocities of 0.12, 0.14, 0.16, 0.20, 0.27 and 0.41 m/h. Results show that the HE removal varied between 89 and 95% and the most common specie was Ascaris lumbricoides. Faecal coliform and Escherichia coli removal varied in the range of 0.9-2.1 and 0.8-1.6 log10 respectively. Likely related to the low operational temperatures, the total COD removal varied between 37 and 62%. The best performance in terms of removal of HE, total COD and turbidity was obtained at the lowest upflow velocity of 0.12 m/h. In order to meet WHO standards for water reuse a post-treatment unit will be required to polish the effluent. PMID- 26748208 TI - Kinetics and pathways of ibuprofen degradation by the UV/chlorine advanced oxidation process. AB - The UV/chlorine advanced oxidation process (AOP), which forms reactive species such as hydroxyl radicals (HO) and reactive chlorine species (RCS) such as chlorine atoms (Cl) and Cl2(-), is being considered as an alternative to the UV/H2O2 AOP for the degradation of emerging contaminants. This study investigated the kinetics and pathways of the degradation of a recalcitrant pharmaceutical and personal care product (PPCP)-ibuprofen (IBP)-by the UV/chlorine AOP. The degradation of IBP followed the pseudo first-order kinetics. The first-order rate constant was 3.3 times higher in the UV/chlorine AOP than in the UV/H2O2 AOP for a given chemical molar dosage at pH 6. The first-order rate constant decreased from 3.1 * 10(-3) s(-1) to 5.5 * 10(-4) s(-1) with increasing pH from 6 to 9. Both HO and RCS contributed to the degradation, and the contribution of RCS increased from 22% to 30% with increasing pH from 6 to 9. The degradation was initiated by HO-induced hydroxylation and Cl-induced chlorine substitution, and sustained through decarboxylation, demethylation, chlorination and ring cleavage to form more stable products. Significant amounts of chlorinated intermediates/byproducts were formed from the UV/chlorine AOP, and four chlorinated products were newly identified. The yield of total organic chlorine (TOCl) was 31.6 MUM after 90% degradation of 50 MUM IBP under the experimental conditions. The known disinfection by-products (DBPs) comprised 17.4% of the TOCl. The effects of water matrix in filtered drinking water on the degradation were not significant, demonstrating the practicality of the UV/chlorine AOP for the control of some refractory PPCPs. However, the toxicity of the chlorinated products should be further assessed. PMID- 26748209 TI - Is transforaminal retrieval of intradiscal deeply seated broken surgical knife blade all time pars sparing? A case report. AB - BACKGROUND: One risk accompanying with Lumbar discectomy is breaking of the surgical scalpel during discectomy. Greatest of the broken blades can be detached during the first surgery. Conversely, in few cases, surgeon's efforts might be ineffective, causing in engaged foreign body in the disc space. Works regarding this matter is infrequent, and there are no exclusive strategies to discourse this complication. PRESENTATION OF CASE: A 26-year-old female with L5-S1 left disc sequestration and plantar flexion disturbance, underwent a one level hemilaminectomy for lumbar disc herniation. The knife blade was broken in the disc space and could not be found despite 3h consumed on its tried removal by her surgeon. Transforaminal path as an unconventional access strip for its removal is planned, but pars inter articularis was not saving intact and fusion process had done.The patient was discharged a day after blade removal and fusion surgery is doing well now. CONCLUSIONS: The transforaminal route might be a harmless and informal substitute corridor for all intradiscal retained foreign bodies including a broken blade. Sometimes because of better exposure especially in deeply seated material, resection of pars and then fusion surgery avoid inevitable. PMID- 26748210 TI - Primary peritoneal adenocarcinoma as content of an incarcerated umbilical hernia: A case-report and review of the literature. AB - INTRODUCTION: Umbilical hernia is a common finding in many cases, posing potentially life-threatening complications, such as incarceration or strangulation. The presence of malignancy in hernia sacs is, however, rather rare. PRESENTATION OF CASE: Here we report on a case of primary peritoneal adenocarcinoma found through histological examination of omental tissue, resected due to an incarcerated umbilical hernia of an 84-years-old woman. There was no macroscopic sign of malignancy during operation; only after routine examination of histological sections the diagnosis was found. DISCUSSION: To our knowledge this is the first report of primary peritoneal cancer as content of an umbilical hernia. This is a rare neoplasm and histologically identical to epithelial ovarian carcinoma. For this reason, the diagnosis is usually based on the histological finding and exclusion of a primary ovarian tumor. Primary peritoneal cancer has a poor outcome in general. Early diagnosis is, therefore, essential for effective treatment. CONCLUSION: Histological analysis of resected hernia sac or content should be performed routinely to discover malignant diseases in the background of a hernia. PMID- 26748212 TI - Hardness and microstructural variation of Al-Mg-Mn-Sc-Zr alloy. AB - Variations of Vickers hardness were observed in Al-Mg-Mn alloy and Al-Mg-Mn-Sc-Zr alloy at different ageing times, ranging from a peak value of 81.2 HV at 54 ks down to 67.4 HV at 360 ks, below the initial hardness value, 71.8 HV at 0 ks for the case of Al-Mg-Mn-Sc-Zr alloy. Microstructures of samples at each ageing stage were examined carefully by transmission electron microscopes (TEMs) both in two dimensions and three-dimensions. The presence of different types, densities, and sizes of particles were observed dispersed spherical Al3Sc1-xZrx and also block shaped Al3Sc precipitates growing along <100>Al with facets {100} and {110} of the precipitates. TEM analysis both in two-dimensions and three-dimensions, performed on various samples, confirmed the direct correlation between the hardness and the density of Al3Sc. PMID- 26748211 TI - Up regulation of A2B adenosine receptor on monocytes are crucially required for immune pathogenicity in Indian patients exposed to Leishmania donovani. AB - Adenosine, an endogenous purine nucleoside is one such extracellular signalling molecule whose role in regulation of anti-inflammatory cytokines and immune pathogenicity in visceral leishmaniasis is not fully understood. Here, we investigated the relationship between Leishmania donovani infection and expression of A2B receptor on monocytes in VL patients in their pre and post treatment stage. We also investigated the molecular mechanisms influencing the interaction between immunopathogenicity and infection by exposing Leishmania donovani pulsed macrophages to Adenosine. A direct correlation of up-regulated A2B expression on monocytes with increased parasite load was also observed. Our results also suggested that A2B receptor activation is critically required for the stimulatory effect of adenosine on IL-10 production and suppression of nitric oxide release. The stimulatory effect of adenosine on Leishmania donovani induced IL-10 production required ERK1/2 activation and is p-38 MAPK independent. PMID- 26748213 TI - Heterologous overproduction of 2[4Fe4S]- and [2Fe2S]-type clostridial ferredoxins and [2Fe2S]-type agrobacterial ferredoxin. AB - Ferredoxins are small, acidic proteins containing iron-sulfur clusters that are widespread in living organisms. They play key roles as electron carriers in various metabolic processes, including respiration, photosynthesis, fermentation, nitrogen fixation, carbon dioxide fixation, and hydrogen production. However, only several kinds of ferredoxins are commercially available now, greatly limiting the investigation of ferredoxin-related enzymes and metabolic processes. Here we describe the heterologous overproduction of 2[4Fe4S]- and [2Fe2S]-type clostridial ferredoxins and [2Fe2S]-type agrobacterial ferredoxin. Adding extra iron and sulfur sources to the medium in combination with using Escherichia coli C41(DE3) harboring pCodonplus and pRKISC plasmids as host greatly enhanced iron sulfur cluster synthesis in the three ferredoxins. After induction for 12 h in terrific broth and purification by affinity chromatography and anion exchange chromatography, approximately 3.4 mg of streptavidin (Strep)-tagged and 3.7 mg of polyhistidine (His)-tagged clostridial 2[4Fe4S] ferredoxins were obtained from 1 l of culture. Excitingly, after induction for 24 h in terrific broth, around 40 mg of His-tagged clostridial [2Fe2S] and 23 mg of His-tagged agrobacterial [2Fe2S] ferredoxins were purified from 1 l of culture. The recombinant ferredoxins apparently exhibited identical properties and physiological function to native ferredoxins. No negative impact of two different affinity tags on ferredoxin activity was found. In conclusion, we successfully developed a convenient method for heterologous overproduction of the three kinds of ferredoxins with satisfactory yields and activities, which would be very helpful for the ferredoxin-related researches. PMID- 26748214 TI - Prediction of anti-angiogenesis escape. AB - Many clinical trials have demonstrated the benefit of anti-angiogenesis therapy in the treatment of gynecologic cancer. However, these benefits have often been in terms of progression-free rather than overall survival and in some cases, the magnitude of benefit demonstrated in the pivotal phase 3 trials has been disappointing when compared with the percentage of patients who responded in earlier phase 2 trials. Two potential explanations for this are the current inability to stratify patients according to chance of benefit and the development of resistance mechanisms within the tumor. In this article, we review the prediction of response and the proposed resistance and escape mechanisms involved in anti-angiogenesis therapy, including the up-regulation of alternative proangiogenic pathways, vascular co-option, and resistance to hypoxia. These insights may offer a personalized strategy for anti-angiogenesis therapy and help us to consider the best selection of other therapies that should be combined with anti-angiogenesis therapy to improve the outcome of patients with gynecologic cancer. PMID- 26748215 TI - Mutation spectrum of POLE and POLD1 mutations in South East Asian women presenting with grade 3 endometrioid endometrial carcinomas. AB - OBJECTIVE: Somatic POLE mutations have been found in a subset of endometrioid ECs particularly in FIGO grade 3 tumors while POLD1 mutations are reportedly rare in ECs. While it has been suggested that POLE mutation confers good prognosis, the data remains conflicting. Our study aims to determine the mutation spectrum of somatic and germline POLE and POLD1 gene mutations in South East Asian (SEA) women with FIGO grade 3 endometrioid ECs. METHODS: Forty-seven patients diagnosed with FIGO grade 3 endometrioid EC, diagnosed between 2009 and 2013 were included. Next generation sequencing (NGS) using formalin fixed embedded (FFPE) tissue was utilized to sequence tumor and matched normal tissue. Tumors were also assessed for other clinicopathologic and microsatellite status phenotype. Survival curves for pathogenic somatic POLE mutated and wild-type tumors were estimated by Kaplan Meier method. RESULTS: Pathogenic POLE (somatic or germline) and POLD1 (germline) mutations were detected in 29.7% (14/47) and 4.3% (2/47) patients, respectively. Three pathogenic germline mutations; one POLE and two POLD1 mutations were novel. Pathogenic germline and somatic POLE and POLD1 mutations were associated with 100% recurrence free survival. In contrast, among the wild-type POLE and POLD1 patients, 25% (8/32) had recurrence with 15.6% (5/32) subsequently dying of the disease. Somatic POLE-mutated tumors were more commonly associated with microsatellite stable (MSS) ECs (83% vs 49%; p=0.04) and peritumoral lymphocytic infiltration (75% vs 42%; p=0.05). All tumors with tumoral infiltrating lymphocytes exhibited peritumoral lymphocytic infiltrate but not vice versa. CONCLUSION: Mutations in POLE and POLD1 in SEA women with grade 3 endometrioid ECs are associated with improved recurrence free survival. Notably, germline mutations in either POLE/POLD1 were seen in 8.5% of patients who will require appropriate genetic counseling regarding risk of developing colorectal carcinoma and on the need for additional surveillance for colonic changes. MSS and peritumoral lymphocytic infiltration may be useful histological features for distinguishing POLE mutated grade 3 endometrioid ECs. PMID- 26748216 TI - A prospective observational study on chemotherapy-induced nausea and vomiting (CINV) in patients with gynecologic cancer by the CINV Study Group of Japan. AB - OBJECTIVE: This study was performed to investigate the occurrence of and risk factors for chemotherapy-induced nausea and vomiting (CINV) in patients with gynecologic cancer. METHODS: In total, 214 patients with gynecologic cancer who underwent highly emetogenic (HEC) or moderately emetogenic chemotherapy (MEC) were evaluated. We investigated the relationship between CINV and clinical factors and the accuracy of estimation of CINV by medical staff in the acute and late phases. Vomiting was evaluated in terms of frequency, and nausea was evaluated with a 100-mm visual analog scale on days 1 to 7. We also analyzed the risk factors and changes in CINV over time using a generalized linear mixed (GLM) model. RESULTS: The multivariate analysis revealed no significant risk factors for acute CINV. The independent risk factors for delayed nausea were a morning sickness history (odds ratio [OR], 2.687; 95% confidence interval [95% CI], 1.450 4.976; p=0.0017), age (each 1-year increment) (OR, 0.97; 95% CI, 0.944-0.996; p=0.0235), and HEC (OR, 2.134; 95% CI, 1.039-4.383; p=0.0391). The GLM model demonstrated that the independent factors affecting nausea were significant morning sickness (p=0.0101) and HEC (p=0.0136). These data also showed more severe nausea from days 3 to 5, but the negative predictive value for estimation of delayed nausea by medical staff was 57.8%. CONCLUSION: Our data suggest that improvement of preventive antiemetic administration is needed for patients with risk factors to manage delayed CINV caused by HEC and by MEC. PMID- 26748217 TI - Avoidance of Fiber Is Associated With Greater Risk of Crohn's Disease Flare in a 6-Month Period. AB - BACKGROUND & AIMS: Chronic inflammatory bowel diseases (IBDs) have been associated with an abnormal mucosal response to the gastrointestinal microbiota. Although dietary fiber affects the gastrointestinal microbiota, there is limited information on the role of fiber on IBD activity. We investigated factors associated with fiber consumption and whether it was associated with flares in patients with IBD. METHODS: We collected a completed 26-item dietary survey from 1619 participants in the Crohn's and Colitis Foundation of America Partners Internet cohort (Crohn's disease, 1130; ulcerative colitis/indeterminate colitis, 489). Eligible individuals were in remission based on disease activity index at baseline and completed a follow-up survey 6 months later. Fiber and whole grain consumption were categorized into quartiles and deciles. Disease flare at 6 months was defined as a disease activity index score exceeding remission cutoff values, and/or an IBD-related surgical procedure or hospitalization since baseline. RESULTS: Participants with longer duration of disease, past history of surgery, and past IBD hospitalization ate less fiber. The risks for disease flare differed by disease type. Compared with those in the lowest quartile of fiber consumption, participants with Crohn's disease in the highest quartile were less likely to have a flare (adjusted odds ratios [OR], 0.58; 95% confidence interval [CI], 0.37-0.90). Participants with Crohn's disease who reported that they did not avoid high-fiber foods were ~40% less likely to have a disease flare than those who avoided high-fiber foods (adjusted OR, 0.59; 95% CI, 0.43-0.81). There was no association between fiber intake and flares in patients with ulcerative colitis (adjusted OR, 1.82; 95% CI, 0.92-3.60). CONCLUSIONS: Intake of dietary fiber is associated with reduced disease flares in patients with Crohn's disease, but not UC. Recommendations to limit dietary fiber should be re-evaluated. PMID- 26748218 TI - A Giant Esophageal Mass in a Patient Without Dysphagia. PMID- 26748219 TI - Endoscopic Sleeve Gastroplasty Alters Gastric Physiology and Induces Loss of Body Weight in Obese Individuals. AB - BACKGROUND & AIMS: Although bariatric surgery is the most effective therapy for obesity, only a small proportion of candidates undergo this surgery. Endoscopic sleeve gastroplasty (ESG) is a minimally invasive procedure that reduces the size of the gastric reservoir. We investigated its durability and effects on body weight and gastrointestinal function in a prospective study of obese individuals. METHODS: Twenty-five obese individuals (21 female; mean body mass index, 35.5 +/- 2.6 kg/m2; mean age, 47.6 +/- 10 years) underwent ESG with endoluminal creation of a sleeve along the gastric lesser curve from September 2012 through March 2015 at the Mayo Clinic in Rochester, Minnesota. Subjects were followed for a median period of 9 months. We measured changes in body weight and recorded adverse events; patients were assessed by endoscopy after 3 months. Four participants underwent pre-ESG and post-ESG analyses to measure solid and liquid gastric emptying, satiation (meal tolerance), and fasting and postprandial levels of insulin, glucose, and gut hormones. RESULTS: Subjects had lost 53% +/- 17%, 56% +/- 23%, 54% +/- 40%, and 45% +/- 41% of excess body weight at 6, 9, 12, and 20 months, respectively, after the procedure (P < .01). Endoscopy at 3 months showed intact gastroplasty in all subjects. After ESG, physiological analyses of 4 participants showed a decrease by 59% in caloric consumption to reach maximum fullness (P = .003), slowing of gastric emptying of solids (P = .03), and a trend toward increased insulin sensitivity (P = .06). Three patients had serious adverse events (a perigastric inflammatory collection, a pulmonary embolism, and a small pneumothorax) but made full recoveries with no need for surgical interventions. No further serious adverse events occurred after the technique was adjusted. CONCLUSIONS: ESG delays gastric emptying, induces early satiation, and significantly reduces body weight. ESG could be an alternative to bariatric surgery for selected patients with obesity. ClincialTrials.gov number: NCT 01682733. PMID- 26748220 TI - Similar Efficacies of Endoscopic Ultrasound-guided Transmural and Percutaneous Drainage for Malignant Distal Biliary Obstruction. AB - BACKGROUND & AIMS: Although percutaneous transhepatic biliary drainage (PTBD) is the standard method for draining a malignant biliary obstruction after failed endoscopic retrograde cholangiopancreatographies (ERCPs), use of endoscopic ultrasound-guided transmural biliary drainage (EUS-BD) is increasing. We performed a multicenter, open-label, randomized trial to compare EUS-BD vs PTBD for malignant distal biliary obstruction after a failed ERCP. METHODS: Patients with unresectable malignant distal biliary obstructions and failed primary ERCP, caused by inaccessible papilla, were assigned to groups that underwent EUS-BD with an all-in-one device for direct deployment of a partially covered metal stent (without further fistula tract dilation, n = 34) or PTBD (n = 32). The procedures were performed at 4 tertiary academic referral centers in South Korea from October 2014 through March 2015; patients were followed up through June 2015. The primary end point was technical success, which was calculated using a noninferiority model. Secondary end points were functional success, procedure related adverse events, rate of unscheduled re-intervention, and quality of life (QOL). RESULTS: The rates of primary technical success were 94.1% (32 of 34) in the EUS-BD group and 96.9% (31 of 32) in the PTBD group (1-sided 97.5% confidence interval lower limit, -12.7%; P = .008 for a noninferiority margin of 15%). The rates of functional success were 87.5% (28 of 32) in the EUS-BD group and 87.1% (27 of 31) in the PTBD group (P = 1.00). The proportions of procedure-related adverse events were 8.8% in the EUS-BD group vs 31.2% in the PTBD group (P = .022); the mean frequency of unscheduled re-intervention was 0.34 in the EUS-BD group vs 0.93 in the PTBD group (P = .02). The QOL was similar between groups. CONCLUSIONS: EUS-BD and PTBD had similar levels of efficacy in patients with unresectable malignant distal biliary obstruction and inaccessible papilla based on rates of technical and functional success and QOL. However, EUS-BD produced fewer procedure-related adverse events and unscheduled re-interventions. Clinical trial registration no: cris.nih.go.kr/KCT0001370. PMID- 26748221 TI - Efficacy of a Gluten-Free Diet in Subjects With Irritable Bowel Syndrome-Diarrhea Unaware of Their HLA-DQ2/8 Genotype. AB - BACKGROUND & AIMS: A gluten-containing diet alters bowel barrier function in patients with irritable bowel syndrome with diarrhea (IBS-D), particularly those who are positive for HLA allele DQ2/8. We studied the effects of a gluten-free diet (GFD) in patients with IBS-D who have not previously considered the effects of gluten in their diet and were unaware of their HLA-DQ2/8 genotype. METHODS: We performed a prospective study of 41 patients with IBS-D (20 HLA-DQ2/8-positive and 21 HLA-DQ2/8-negative) at the Royal Hallamshire Hospital in Sheffield, United Kingdom, from September 2012 through July 2015. All subjects were placed on a 6 week GFD following evaluation by a dietician. Subjects completed validated questionnaires at baseline and Week 6 of the GFD. The primary endpoint was mean change in IBS Symptom Severity Score; a 50-point reduction was considered to indicate a clinical response. Secondary endpoints were changes in hospital anxiety and depression score, fatigue impact score, and Short Form-36 results. Clinical responders who chose to continue a GFD after the study period were evaluated on average 18 months later to assess diet durability, symptom scores, and anthropometric and biochemical status. RESULTS: A 6-week GFD reduced IBS Symptom Severity Score by >=50 points in 29 patients overall (71%). The mean total IBS Symptom Severity Score decreased from 286 before the diet to 131 points after 6 weeks on the diet (P < .001); the reduction was similar in each HLA-DQ group. However, HLA-DQ2/8-negative subjects had a greater reduction in abdominal distention (P = .04). Both groups had marked mean improvements in hospital anxiety and depression scores, fatigue impact score, and Short Form-36 results, although HLA-DQ2/8-positive subjects had a greater reduction in depression score and increase in vitality score than HLA-DQ2/8-negative subjects (P = .02 and P = .03, respectively). Twenty-one of the 29 subjects with a clinical response (72%) planned to continue the GFD long term; 18 months after the study they were still on a GFD, with maintained symptom reductions, and demonstrated similar anthropometric and biochemical features compared with baseline. CONCLUSIONS: A dietitian-led GFD provided sustained benefit to patients with IBS-D. The symptoms that improved differed in magnitude according to HLA-DQ status. Clinical trials.gov no: NCT02528929. PMID- 26748222 TI - Patients With Barrett's Esophagus and Persistent Low-grade Dysplasia Have an Increased Risk for High-grade Dysplasia and Cancer. AB - BACKGROUND & AIMS: In some patients with Barrett's esophagus (BE) and a confirmed diagnosis of low-grade dysplasia (LGD), the LGD is not detected during follow-up examinations. We would like to avoid the unnecessary risks and costs of ablative treatment for these patients. Therefore, we investigated whether persistent LGD increases risk for high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) and what proportion of patients are no longer found to have dysplasia after an initial diagnosis of LGD. METHODS: In a retrospective study, we collected information on 1579 patients with BE and LGD from 2005 through 2010 by using a nationwide registry of histopathology diagnoses in the Netherlands (PALGA). Confirmed LGD was defined as a diagnosis of LGD that was confirmed by any other pathologist. Persistent LGD was defined as LGD detected at the first and follow up endoscopy. Data were collected on patients until treatment for HGD, detection of EAC, or the last endoscopy at which a biopsy was collected (through July 2014). We evaluated whether persistent LGD was a risk factor for malignant progression by using univariable and multivariable Cox regression analyses. RESULTS: Of individuals with BE and LGD in the database, the diagnosis of LGD was confirmed for 161 patients (10% of total). In these patients, the incidence of HGD and/or EAC was 5.18/100 person-years (95% confidence interval [CI], 4.32 8.10/100 person-years) compared with 1.85/100 person-years (95% CI, 1.52-2.22/100 person-years) in patients for whom LGD was not confirmed at the first endoscopy. The incidence of EAC alone in patients with confirmed LGD was 2.51/100 person years (95% CI, 1.46-3.99/100 person-years), compared with 1.01/per 100 person years (95% CI, 0.41-2.10/100 person-years) in patients for whom LGD was not confirmed at the first endoscopy. Of patients in whom LGD was confirmed at the first endoscopic examination, 51% were not found to have dysplasia at the first follow-up endoscopy, and 30% had persistent LGD. In patients with persistent LGD, the incidence of HGD and/or EAC was 7.65/100 person-years (95% CI, 4.45-12.34) and of only EAC was 2.04/100 person-years (95% CI, 0.65-4.92); in patients without persistent LGD, the incidence of HGD and/or EAC was 2.32/100 person-years (95% CI, 1.08-4.40/100 person-years) and of only EAC was 1.45 (95% CI, 0.53 3.21/100 person-years). Persistent LGD was found to be an independent risk factor for the development of HGD and/or EAC, with hazard ratio of 3.5 (95% CI, 1.48 8.28). CONCLUSIONS: In a large population-based cohort study of patients with BE and LGD, the risk of progression to HGD and/or EAC was higher in patients with confirmed LGD and highest in those with confirmed and persistent LGD. PMID- 26748223 TI - Clinical, Endoscopic, and Histologic Characteristics of Ipilimumab-Associated Colitis. AB - BACKGROUND & AIMS: Ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte-associated antigen-4, is a treatment for metastatic melanoma that can induce immune-related adverse effects, such as enterocolitis. We aimed to characterize the clinical, endoscopic, and histologic features of ipilimumab induced colitis and evaluate the efficacy of therapy for this reaction. METHODS: We performed a retrospective analysis of 27 consecutive patients who developed colitis after treatment with ipilimumab infusion therapy for castration-resistant prostate cancer or metastatic melanoma, from April 2007 through September 2012. Clinical, endoscopic, and histologic information was collected from the database of the VU University Medical Center, Amsterdam, The Netherlands. Selected cases were ascertained by cross-checking with endoscopy reports. RESULTS: All patients had diarrhea (range, 3-20 stools per day); 26% had concurrent rectal blood loss and 30% had abdominal pain. These symptoms usually started after 2 infusions of ipilimumab (range, 1-4) and all patients except for 1 (who received no treatment for colitis) were given corticosteroids. Twelve patients had steroid-refractory colitis, for which they received infliximab (5 mg/kg). Diarrhea resolved in all the patients. Colon erythema was detected by endoscopy in 84% of patients, with an absent vascular pattern in all patients. In histologic analyses, colon biopsy specimens ranged from having normal architecture to severe active inflammation. Intraepithelial neutrophilic leucocytes were detected in 72% of samples, cryptitis in 92%, and crypt abscesses in 60%. Crypt irregularities were found in 40% of colon biopsy specimens, indicating chronic disease. CONCLUSIONS: In a retrospective analysis, we associated ipilimumab-associated colitis diarrhea with a variety of endoscopic and histologic features. Treatment with corticosteroids, followed by infliximab in steroid-refractory patients, was successful for all cases. PMID- 26748224 TI - Volatile organic compounds and particulate matter in child care facilities in the District of Columbia: Results from a pilot study. AB - BACKGROUND: Many young children in the U.S. spend a significant portion of their day in child care facilities where they may be exposed to contaminants linked to adverse health effects. Exposure data on volatile organic compounds (VOCs) and particulate matter (PM) in these settings is scarce. OBJECTIVE: To guide the design of a larger exposure assessment study in urban child care facilities, we conducted a pilot study in which we characterized indoor concentrations of select VOCs and PM. METHODS: We recruited 14 child care facilities in the District of Columbia (Washington, DC) and measured indoor concentrations of seven VOCs (n=35 total samples; 2-5 samples per facility): benzene, carbon tetrachloride, chloroform, ethylbenzene, o-xylene, p-xylene, and toluene in all facilities; and collected real-time PM measurements in seven facilities. We calculated descriptive statistics for contaminant concentrations and computed intraclass correlation coefficients (ICC) to evaluate the variability of VOC levels indoors. We also administered a survey to collect general health information on the children attending these facilities, and information on general housekeeping practices and proximity of facilities to potential sources of target contaminants. RESULTS: We detected six of the seven VOCs in the majority of child care facilities with detection frequencies ranging from 71% to 100%. Chloroform and toluene were detected in all samples. Median (range) concentrations for toluene, chloroform, benzene, o-xylene, ethylbenzene, and carbon tetrachloride were: 5.6ug/m(3) (0.6-16.5ug/m(3)), 2.8ug/m(3) (0.4-53.0ug/m(3)), 1.4ug/m(3) (below the limit of detection or =Cd>Ni>=Zn>=Hg for the former and Hg>=Cu>=Ni>=Cd>=Zn for the latter methods. For phenol, the results did not differ significantly; EC50 values were 124 mg L( 1) and 108-180 mg L(-1) for the hydroponic and filter paper methods, respectively. Lettuce was less sensitive than daphnids to wastewaters, but the root elongation response appears to be wastewater-specific and is especially sensitive for detecting the presence of fluorine. The new hydroponic test thus provides many practical advantages, especially in terms of cost and time effectiveness requiring only a well plate, a small volume of distilled water and short exposure period; furthermore, no specialist expertise is required. The method is simpler than the conventional EPA technique in not using filter paper which can influence the sensitivity of the test. Additionally, plant seeds have a long shelf-life and require little or no maintenance. PMID- 26748377 TI - Using monoclonal antibodies as an international standard for the measurement of anti-adalimumab antibodies. AB - Comparing studies investigating anti-drug antibody (ADA) formation is hampered by the lack of comparability between study protocols, assay formats, and standardized reference materials. In this respect, the use of an international standard would mean a major step forward. Here we compared 11 fully human monoclonal antibodies against adalimumab in two assays commonly used for ADA measurement; the bridging ELISA and the antigen binding test (ABT). Our results show non-parallel titration of the monoclonal antibodies in both assays, which we also find for polyclonal ADA sources. Moreover, we observed that the output of the bridging ELISA depends to a large degree on the affinity of the monoclonal antibody. For the ABT, results reflect a combination of affinity and avidity. This suggests that rather than reporting ADA values in nanogram per milliliter, arbitrary units may be more appropriate. Together our data highlight the difficulty of ADA standardization by identifying several pitfalls that should be taken into account when selecting a standard for ADA testing. PMID- 26748378 TI - Uniting adolescent neuroimaging and treatment research: Recommendations in pursuit of improved integration. AB - Many clinicians who provide mental health treatment find developmental neuroscience discoveries to be exciting. However, the utility of these findings often seem far removed from everyday clinical care. Thus, the goal of this article is to offer a bridge to connect the fields of applied adolescent treatment and developmental neuroscience investigation. An overview of the relevance of developmental neuroscience in adolescent direct practice and a rationale for how and why this integration could benefit adolescent treatment outcomes is provided. Finally, a series of practical suggestions is generated for enhancing collaborative, interdisciplinary work that ultimately advances treatment response for this important clinical population. PMID- 26748379 TI - GABA-ergic cell therapy for epilepsy: Advances, limitations and challenges. AB - Diminution in the number of gamma-amino butyric acid positive (GABA-ergic) interneurons and their axon terminals, and/or alterations in functional inhibition are conspicuous brain alterations believed to contribute to the persistence of seizures in acquired epilepsies such as temporal lobe epilepsy. This has steered a perception that replacement of lost GABA-ergic interneurons would improve inhibitory synaptic neurotransmission in the epileptic brain region and thereby reduce the occurrence of seizures. Indeed, studies using animal prototypes have reported that grafting of GABA-ergic progenitors derived from multiple sources into epileptic regions can reduce seizures. This review deliberates recent advances, limitations and challenges concerning the development of GABA-ergic cell therapy for epilepsy. The efficacy and limitations of grafts of primary GABA-ergic progenitors from the embryonic lateral ganglionic eminence and medial ganglionic eminence (MGE), neural stem/progenitor cells expanded from MGE, and MGE-like progenitors generated from human pluripotent stem cells for alleviating seizures and co-morbidities of epilepsy are conferred. Additional studies required for possible clinical application of GABA-ergic cell therapy for epilepsy are also summarized. PMID- 26748381 TI - Oral tacrolimus oil formulations for enhanced lymphatic delivery and efficient inhibition of T-cell's interleukin-2 production. AB - Oral oil formulations have been reported to deliver drugs into the lymph. Lymphatic delivery of immunomodulatory drugs can more efficiently expose the drugs to T-cells in lymph, consequently induce higher efficacy and lower side effects. In this study, effects of tacrolimus oral oil formulations on drug blood exposure, and on inhibition of T-cell's interleukin-2 (IL-2) production were investigated in rats. Oil formulations (sunflower oil, cacao butter, medium chain triglyceride, and palm oil) dissolving tacrolimus showed lower drug blood concentration than a solid dispersion formulation (SDF). The sunflower oil, and cacao butter formulations suppressed drug blood exposure to 50% of the SDF, and inhibited T-cell's IL-2 production similar to the SDF. In vitro digestion tests indicated that slower digestion of the oils might reduce amount and rate of tacrolimus blood absorption. The cacao butter formulations showed 3.0 times more rapid tacrolimus absorption to lymphatic fluid than the SDF. Ratio of the rate constants of absorption into lymph to that into blood was higher in oil formulations (15 times in cacao butter, 15 times sunflower oil, and 3.5 times palm oil) than in the SDF. These results indicated that the oral oil formulations might be suitable for reduced tacrolimus blood concentration for low systemic side effects, and keep high lymph concentration for high efficacy in organ transplantation patients. PMID- 26748382 TI - Mechanistic investigation of biopharmaceutic and pharmacokinetic characteristics of surface engineering of satranidazole nanocrystals. AB - The designing of surface engineered nanocrystals for improved stability and bioavailability is a multivariate process depending on several critical formulation and process variables. The present investigation deals with formulation of stable nanocrystals of poorly soluble satranidazole (SAT) for improving dissolution rate and pharmacokinetic profiling. SAT has low polar surface area, high dose and dosing frequency. Based on goniometric and stability studies of formulations prepared with various stabilizers, a unique combination of Span 20 and HPMC E-5 was selected for detailed investigation. Lyophilization of SAT nanosuspension was explored with nine different cryoprotectants in varying amounts to obtain easily redispersible nanocrystals (SAT-NC). The mean particle size and zeta potential of SAT-NC were found to be 208.8nm and -41.3mV respectively. DSC and XRPD confirmed the crystalline state of SAT. In vitro release studies of SAT-NC showed almost complete dissolution within 20min in water. Extravascular, one compartment pharmacokinetic modeling of in vivo plasma concentration versus time studies in male Wistar rats revealed twofold increase in Cmax, and AUC0-infinity. Method of residuals was employed to calculate rate of absorption Ka and lag time. Nanosizing with appropriate stabilizers and programmed processing conditions successfully produced SAT-NC with improved pharmaceutic and pharmacokinetic characteristics. PMID- 26748383 TI - CXCR4 signaling is controlled by immobilization at the plasma membrane. AB - Understanding of the regulation mechanisms of CXCR4 signaling is essential for revealing its role in physiological and pathological processes. Though biochemical pathways following CXCR4 activation by its ligand CXCL12 are well established, knowledge about the receptor dynamics on the plasma membrane remains limited. Here we used Ewing sarcoma-derived cells to unravel the processes that are involved in regulating CXCR4 dynamics on the plasma membrane during receptor signaling. Single-molecule epi-fluorescence microscopy showed that CXCR4 was present in monomeric state on the plasma membrane independent of receptor stimulation. However, upon activation freely diffusing receptors were immobilized in a ligand concentration-dependent manner. CXCR4 immobilization was strongly correlated with the ability for G-protein signaling and was a precursor of subsequent endocytotic events. Our data suggest that, a balanced regulation of G protein dependent and independent pathways is required for controlling CXCR4 receptor mobility, and potentially subsequent controlled signal transduction. PMID- 26748380 TI - Carbon Nanotube Emissions from Arc Discharge Production: Classification of Particle Types with Electron Microscopy and Comparison with Direct Reading Techniques. AB - INTRODUCTION: An increased production and use of carbon nanotubes (CNTs) is occurring worldwide. In parallel, a growing concern is emerging on the adverse effects the unintentional inhalation of CNTs can have on humans. There is currently a debate regarding which exposure metrics and measurement strategies are the most relevant to investigate workplace exposures to CNTs. This study investigated workplace CNT emissions using a combination of time-integrated filter sampling for scanning electron microscopy (SEM) and direct reading aerosol instruments (DRIs). MATERIAL AND METHODS: Field measurements were performed during small-scale manufacturing of multiwalled carbon nanotubes using the arc discharge technique. Measurements with highly time- and size-resolved DRI techniques were carried out both in the emission and background (far-field) zones. Novel classifications and counting criteria were set up for the SEM method. Three classes of CNT-containing particles were defined: type 1: particles with aspect ratio length:width >3:1 (fibrous particles); type 2: particles without fibre characteristics but with high CNT content; and type 3: particles with visible embedded CNTs. RESULTS: Offline sampling using SEM showed emissions of CNT-containing particles in 5 out of 11 work tasks. The particles were classified into the three classes, of which type 1, fibrous CNT particles contributed 37%. The concentration of all CNT-containing particles and the occurrence of the particle classes varied strongly between work tasks. Based on the emission measurements, it was assessed that more than 85% of the exposure originated from open handling of CNT powder during the Sieving, mechanical work up, and packaging work task. The DRI measurements provided complementary information, which combined with SEM provided information on: (i) the background adjusted emission concentration from each work task in different particle size ranges, (ii) identification of the key procedures in each work task that lead to emission peaks, (iii) identification of emission events that affect the background, thereby leading to far-field exposure risks for workers other than the operator of the work task, and (iv) the fraction of particles emitted from each source that contains CNTs. CONCLUSIONS: There is an urgent need for a standardized/harmonized method for electron microscopy (EM) analysis of CNTs. The SEM method developed in this study can form the basis for such a harmonized protocol for the counting of CNTs. The size-resolved DRI techniques are commonly not specific enough to selective analysis of CNT-containing particles and thus cannot yet replace offline time-integrated filter sampling followed by SEM. A combination of EM and DRI techniques offers the most complete characterization of workplace emissions of CNTs today. PMID- 26748384 TI - Thinning effects on litterfall remaining after 8 years and improved stand resilience in Aleppo pine afforestation (SE Spain). AB - Monthly litterfall was monitored over a 3-year period in afforested Aleppo pines in the Mediterranean semiarid SE Spain with the aim of determining the long-term response of pines to reductions in tree competition and how this forest practice might influence stand resilience. Three thinning intensities applied 5 years earlier were evaluated (T75 = 75% of the basal area removed, T60 = 60% and T48 = 48%), both at the stand and at the tree level. On average, the total annual litterfall varied between 1.30 Mg ha(-1) yr(-1) (+/-0.24 SE) in T75 and 3.28 Mg ha(-1) yr(-1) (+/-0.78 SE) in the unthinned control. At the stand level, monthly differences among the treatments were found over time in the needles (F = 11.09, df = 3, P = 0.0009) and woody fraction (F = 4.36, df = 3, P = 0.0269) following the thinning gradient: T0 (control)>T48 > T60 > T75, and for the total amount of needles (chi(2) = 9.33, P = 0.025) and twigs (chi(2) = 9.11, P = 0.027) recorded at the end of the study period. High amounts of twig and needle fall were recorded during summer and beginning of autumn, whereas the main miscellanea inputs were registered during the spring, coinciding with the fall of nests and frass from caterpillar outbreaks. At the tree level, the total litterfall fluctuated between 1.5 kg tree yr(-1) in T0 (2nd yr) and 7.0 kg tree yr(-1) in T75 (3rd yr), although mean annual statistical differences among the treatments were found only for the first year of monitoring. However, needle fall was higher for larger pines (T75) than for the smaller ones in control (T0) when the data were analysed over the 3-year-period (F = 3.64, df = 3, P = 0.0247), and the same happened for the woody fraction (F = 3.63, df = 3, P = 0.0250). By contrast, pine trees in the unthinned control registered needle-fall rates (measured as kg m(-2) tree(-1)) that were similar to or higher than those of pine trees in thinned stands, suggesting that defoliation processes took place at high tree densities, especially after a severely dry period. We propose thinning as a measure to adapt high-density plantations to alterations due to climate change, in order to prevent forest decline and mortality. PMID- 26748385 TI - beta-Hydroxybutyrate supports synaptic vesicle cycling but reduces endocytosis and exocytosis in rat brain synaptosomes. AB - The ketogenic diet is used as a prophylactic treatment for different types of brain diseases, such as epilepsy or Alzheimer's disease. In such a diet, carbohydrates are replaced by fats in everyday food, resulting in an elevation of blood-borne ketone bodies levels. Despite clinical applications of this treatment, the molecular mechanisms by which the ketogenic diet exerts its beneficial effects are still uncertain. In this study, we investigated the effect of replacing glucose by the ketone body beta-hydroxybutyrate as the main energy substrate on synaptic vesicle recycling in rat brain synaptosomes. First, we observed that exposing presynaptic terminals to nonglycolytic energy substrates instead of glucose did not alter the plasma membrane potential. Next, we found that synaptosomes were able to maintain the synaptic vesicle cycle monitored with the fluorescent dye acridine orange when glucose was replaced by beta hydroxybutyrate. However, in presence of beta-hydroxybutyrate, synaptic vesicle recycling was modified with reduced endocytosis. Replacing glucose by pyruvate also led to a reduced endocytosis. Addition of beta-hydroxybutyrate to glucose containing incubation medium was without effect. Reduced endocytosis in presence of beta-hydroxybutyrate as sole energy substrate was confirmed using the fluorescent dye FM2-10. Also we found that replacement of glucose by ketone bodies leads to inhibition of exocytosis, monitored by FM2-10. However this reduction was smaller than the effect on endocytosis under the same conditions. Using both acridine orange in synaptosomes and the genetically encoded sensor synaptopHluorin in cortical neurons, we observed that replacing glucose by beta hydroxybutyrate did not modify the pH gradient of synaptic vesicles. In conclusion, the nonglycolytic energy substrates beta-hydroxybutyrate and pyruvate are able to support synaptic vesicle recycling. However, they both reduce endocytosis. Reduction of both endocytosis and exocytosis together with misbalance between endocytosis and exocytosis could be involved in the anticonvulsant activity of the ketogenic diet. PMID- 26748386 TI - MiR-23b controls TGF-beta1 induced airway smooth muscle cell proliferation via TGFbetaR2/p-Smad3 signals. AB - BACKGROUND: Abnormal proliferation of ASM (airway smooth muscle) directly contributes to the airway remodeling during development of lung diseases such as asthma. Here we report that a specific microRNA (miR-23b) controls ASMCs proliferation through directly inhibiting TGFbetaR2/p-Smad3 pathway. METHODS: The expression of miR-23b in ASMCs was detected by quantitative real-time polymerase chain reaction (RT-PCR). The effects of miR-23b on cell proliferation and apoptosis of ASMCs were assessed by transient transfection of miR-23b mimics and inhibitor. The target gene of miR-23b and the downstream pathway were further investigated. RESULTS: Overexpression of miR-23b significantly inhibited TGF beta1-induced ASMCs proliferation and promoted apoptosis. RT-PCR and Western blotting analysis showed miR-23b negatively regulates the expression of TGFbetaR2 and p-Smad3 in ASMCs. Subsequent analyses demonstrated that TGFbetaR2 was a direct and functional target of miR-23b, which was validated by the dual luciferase reporter assay. CONCLUSIONS: MiR-23b may function as an inhibitor of airway smooth muscle cells proliferation through inactivation of TGFbetaR2/p Smad3 pathway. PMID- 26748388 TI - Dosage compensation and nuclear organization: cluster to control chromosome-wide gene expression. AB - In many species, male and female animals differ in the number of X chromosomes they possess. As a consequence, large scale differences in gene dosage exist between sexes; a phenomenon that is rarely tolerated by the organism for changes in autosome dosage. Several strategies have evolved independently to balance X linked gene dosage between sexes, named dosage compensation (DC). The molecular basis of DC differs among the three best-studied examples: mammals, fruit fly and nematodes. In this short review, we summarize recent microscopic and chromosome conformation capture data that reveal key features of the compensated X chromosome and highlight the events leading to the establishment of a functional, specialized nuclear compartment, the X domain. PMID- 26748387 TI - Low frequency of broadly neutralizing HIV antibodies during chronic infection even in quaternary epitope targeting antibodies containing large numbers of somatic mutations. AB - Neutralizing antibodies (Abs) are thought to be a critical component of an appropriate HIV vaccine response. It has been proposed that Abs recognizing conformationally dependent quaternary epitopes on the HIV envelope (Env) trimer may be necessary to neutralize diverse HIV strains. A number of recently described broadly neutralizing monoclonal Abs (mAbs) recognize complex and quaternary epitopes. Generally, many such Abs exhibit extensive numbers of somatic mutations and unique structural characteristics. We sought to characterize the native antibody (Ab) response against circulating HIV focusing on such conformational responses, without a prior selection based on neutralization. Using a capture system based on VLPs incorporating cleaved envelope protein, we identified a selection of B cells that produce quaternary epitope targeting Abs (QtAbs). Similar to a number of broadly neutralizing Abs, the Ab genes encoding these QtAbs showed extensive numbers of somatic mutations. However, when expressed as recombinant molecules, these Abs failed to neutralize virus or mediate ADCVI activity. Molecular analysis showed unusually high numbers of mutations in the Ab heavy chain framework 3 region of the variable genes. The analysis suggests that large numbers of somatic mutations occur in Ab genes encoding HIV Abs in chronically infected individuals in a non-directed, stochastic, manner. PMID- 26748389 TI - Effects of pentoxifylline and platelet activating factor on sperm DNA damage. AB - OBJECTIVE: Pentoxifylline and platelet-activating factor (PAF) have been used to increase sperm motility in embryology laboratories. In the present study, we aimed to investigate whether these agents pose sperm DNA damage using DNA sperm chromatin dispersion (SCD) assay. STUDY DESIGN: Following application of pentoxifylline and PAF, sperm samples of 50 individuals with different sperm parameters were compared to baseline in terms of DNA damage using SCD assay. Furthermore, the relationship between DNA damage and sperm parameters in predicting DNA damage was assessed. RESULTS AND CONCLUSIONS: Significant increase in DNA damage was observed following application of PAF and pentoxifylline. Furthermore, DNA damage was significantly increased with application of pentoxifylline compared to PAF. Sperm motility was observed to be a statistically significant indicator in predicting alterations in DNA damage in baseline and subsequent to application of PAF and pentoxifylline independent of sperm concentration and morphology. Increased DNA damage was observed in both groups following application of pentoxifylline and PAF. Furthermore, the increase in DNA damage was higher in samples treated with pentoxifylline compared to samples treated with PAF. Thus, PAF seems to be more innocent in choosing viable sperm cells and in achieving sperm motility in the in vitro fertilization laboratory. PMID- 26748390 TI - The accuracy of endometrial sampling in women with postmenopausal bleeding: a systematic review and meta-analysis. AB - Postmenopausal bleeding (PMB) can be the first sign of endometrial cancer. In case of thickened endometrium, endometrial sampling is often used in these women. In this systematic review, we studied the accuracy of endometrial sampling for the diagnoses of endometrial cancer, atypical hyperplasia and endometrial disease (endometrial pathology, including benign polyps). We systematically searched the literature for studies comparing the results of endometrial sampling in women with postmenopausal bleeding with two different reference standards: blind dilatation and curettage (D&C) and hysteroscopy with histology. We assessed the quality of the detected studies by the QUADAS-2 tool. For each included study, we calculated the fraction of women in whom endometrial sampling failed. Furthermore, we extracted numbers of cases of endometrial cancer, atypical hyperplasia and endometrial disease that were identified or missed by endometrial sampling. We detected 12 studies reporting on 1029 women with postmenopausal bleeding: five studies with dilatation and curettage (D&C) and seven studies with hysteroscopy as a reference test. The weighted sensitivity of endometrial sampling with D&C as a reference for the diagnosis of endometrial cancer was 100% (range 100-100%) and 92% (71-100) for the diagnosis of atypical hyperplasia. Only one study reported sensitivity for endometrial disease, which was 76%. When hysteroscopy was used as a reference, weighted sensitivities of endometrial sampling were 90% (range 50-100), 82% (range 56-94) and 39% (21-69) for the diagnosis of endometrial cancer, atypical hyperplasia and endometrial disease, respectively. For all diagnosis studied and the reference test used, specificity was 98-100%. The weighted failure rate of endometrial sampling was 11% (range 1 53%), while insufficient samples were found in 31% (range 7-76%). In these women with insufficient or failed samples, an endometrial (pre) cancer was found in 7% (range 0-18%). In women with postmenopausal bleeding, the sensitivity of endometrial sampling to detect endometrial cancer and especially atypical hyperplasia and endometrial disease, including endometrial polyps, is lower than previously thought. Therefore, further diagnostic work-up for focal pathology is warranted, after a benign result of endometrial sampling. PMID- 26748391 TI - Reducing progression of knee OA features assessed by MRI in overweight and obese women: secondary outcomes of a preventive RCT. AB - OBJECTIVE: To evaluate the preventive effects of a randomized controlled trial on progression of Magnetic Resonance Imaging (MRI) features of knee osteoarthritis (OA) in overweight and obese women. DESIGN: In a 2 * 2 factorial design, 2.5 years effects of a diet and exercise program and of glucosamine sulphate (double blind, placebo-controlled) were evaluated in 407 middle-aged women with body mass index (BMI) >= 27 kg/m(2) without clinical signs of knee OA at baseline (ISRCTN 42823086). MRIs were scored with the MRI Osteoarthritis Knee Score (MOAKS). Progression was defined for bone marrow lesions (BMLs), cartilage defects, osteophytes, meniscal abnormalities and meniscal extrusion. Analyses on knee level were performed over the four intervention groups using adjusted Generalized Estimating Equations (GEE). RESULTS: 687 knees of 347 women with mean age 55.7 years (+/-3.2 SD) and mean BMI 32.3 kg/m(2) (+/-4.2 SD) were analyzed. Baseline prevalence was 64% for BMLs, 70% for cartilage defects, 24% for osteophytes, 66% for meniscal abnormalities and 52% for meniscal extrusions. The diet and exercise program + placebo intervention showed significantly less progression of meniscal extrusion compared to placebo only (12% vs 22%, OR 0.50, 95% CI [0.27-0.92]). The interventions did not result in significant differences on other OA MRI features. CONCLUSIONS: In subjects at high risk for future knee OA development, a diet and exercise program, glucosamine sulphate and their combination showed small and mainly non-significant effects on the progression of OA MRI features. Only progression of meniscal extrusion was significantly diminished by the diet and exercise program. PMID- 26748392 TI - Cerebral malaria in a man with Plasmodium vivax mono-infection: a case report. AB - Cerebral malaria (CM) is a diffuse encephalopathy associated with coma and seizures commonly caused by Plasmodium falciparum (P. falciparum) in children with severe malaria. We present a case of a 19-year-old man with CM due to Plasmodium vivax (P. vivax) infection. Cerebrospinal fluid (CSF) was negative for Japanese B encephalitis, enterovirus, herpes simplex 1 and 2, varicella and mumps viruses as determined by real-time polymerase chain reaction (PCR). P. falciparum and P. vivax species were analysed by microscopy, immunochromatography and PCR assays and confirmed mono-infection of P. vivax in the patient's blood, and P. falciparum infection was established to be negative. The patient was discharged after intensive supportive care and antimalarial treatment (intravenous artesunate and oral doxycycline). We conclude that P. vivax infection is associated with CM, a life-threatening complication rarely seen in coastal districts of Karnataka. In endemic areas, the possibility of CM should be considered even with P. vivax infection. PMID- 26748393 TI - Management of infectious diseases in remote northwestern Ontario with telemedicine videoconference consultations. AB - Northwestern Ontario in Canada provides a unique clinical challenge for providing optimal medical care. It is a large geographic area (385,000 km2) and is home to 32 remote First Nations communities, most without road access. These communities suffer a heavy burden of infectious disease and specialist consultations are difficult to obtain. The Division of Infectious Diseases at the Ottawa Hospital and the Sioux Lookout Meno Ya Win Health Centre established a telemedicine-based infectious disease consultation service in July 2014. We describe the implementation of this service, types of cases seen and patient satisfaction, as well as some of the challenges encountered. Information on visits was prospectively collected through an administrative database, and patient satisfaction surveys were administered after each initial consultation. During our first year of operation, 191 teleconsultations occurred: 76 initial consultations, 82 follow-up appointments and 33 case conferences. The scope of cases has been broad, mostly involving musculoskeletal infections (26%), followed by skin and soft tissue infections (23%). HCV, acute rheumatic fever, and respiratory infections (including pulmonary tuberculosis) were other diagnoses. Patient satisfaction has been very high and 28 telemedicine patient visits have occurred in their remote home communities, minimizing travel. The infectious disease consulting service and local clinicians have succeeded in addressing needs for care in infectious diseases in northwestern Ontario, where important gaps in service to First Nations' communities continue to exist. Regular scheduled available access to an infectious disease specialist is a well-received advancement of care in this remote region of Canada. PMID- 26748394 TI - GRP-3 and KAPP, encoding interactors of WAK1, negatively affect defense responses induced by oligogalacturonides and local response to wounding. AB - Conserved microbe-associated molecular patterns (MAMPs) and damage-associated molecular patterns (DAMPs) act as danger signals to activate the plant immune response. These molecules are recognized by surface receptors that are referred to as pattern recognition receptors. Oligogalacturonides (OGs), DAMPs released from the plant cell wall homogalacturonan, have also been proposed to act as local signals in the response to wounding. The Arabidopsis Wall-Associated Kinase 1 (WAK1), a receptor of OGs, has been described to form a complex with a cytoplasmic plasma membrane-localized kinase-associated protein phosphatase (KAPP) and a glycine-rich protein (GRP-3) that we find localized mainly in the cell wall and, in a small part, on the plasma membrane. By using Arabidopsis plants overexpressing WAK1, and both grp-3 and kapp null insertional mutant and overexpressing plants, we demonstrate a positive function of WAK1 and a negative function of GRP-3 and KAPP in the OG-triggered expression of defence genes and the production of an oxidative burst. The three proteins also affect the local response to wounding and the basal resistance against the necrotrophic pathogen Botrytis cinerea. GRP-3 and KAPP are likely to function in the phasing out of the plant immune response. PMID- 26748395 TI - The Arabidopsis tonoplast is almost devoid of glycoproteins with complex N glycans, unlike the rat lysosomal membrane. AB - The distribution of the N-glycoproteome in integral membrane proteins of the vacuolar membrane (tonoplast) or the plasma membrane of Arabidopsis thaliana and, for further comparison, of the Rattus norvegicus lysosomal and plasma membranes, was analyzed. In silico analysis showed that potential N-glycosylation sites are much less frequent in tonoplast proteins. Biochemical analysis of Arabidopsis subcellular fractions with the lectin concanavalin A, which recognizes mainly unmodified N-glycans, or with antiserum against Golgi-modified N-glycans confirmed the in silico results and showed that, unlike the plant plasma membrane, the tonoplast is almost or totally devoid of N-glycoproteins with Golgi modified glycans. Lysosomes share with vacuoles the hydrolytic functions and the position along the secretory pathway; however, our results indicate that their membranes had a divergent evolution. We propose that protection against the luminal hydrolases that are abundant in inner hydrolytic compartments, which seems to have been achieved in many lysosomal membrane proteins by extensive N glycosylation of the luminal domains, has instead been obtained in the vast majority of tonoplast proteins by limiting the length of such domains. PMID- 26748396 TI - Acceptance and Efficacy of Metacognitive Training (MCT) on Positive Symptoms and Delusions in Patients With Schizophrenia: A Meta-analysis Taking Into Account Important Moderators. AB - Metacognitive training (MCT) is a new, widely used intervention for psychosis. The present meta-analysis examines the efficacy of MCT in schizophrenia. Fifteen studies comparing effects of MCT on positive symptoms, delusions or acceptance of MCT with a control group were included in this meta-analysis. These studies comprised a total of 408 patients in the MCT condition and 399 in the control condition. The moderating effects of masking of outcome assessment, randomization, incomplete outcome data, use of an active control intervention, and individual vs group MCT were investigated. Possible effects of sensitivity analyses and publication bias were also examined. The results show a significant overall effect of MCT for positive symptoms (g = -0.34, 95% CI [-0.53, -0.15]), delusions (g = -0.41, 95% CI [-0.74, -0.07]) and acceptance of the intervention (g = -0.84, 95% CI [-1.37, -0.31]). Using only studies being at low risk for bias regarding randomization, masking and incomplete outcome data reduced effect sizes for positive symptoms and delusions (g = -0.28, 95% CI [-0.50, -0.06] and g = 0.18, 95% CI [-0.43, 0.06]), respectively. This meta-analysis demonstrates that MCT exerts a small to moderate effect on delusions and positive symptoms and a large effect on acceptance of the intervention. The effect on delusions is reduced, but remains significant when potential biases are considered. PMID- 26748397 TI - Mitochondrial involvement in propofol-induced cardioprotection: An in vitro study in human myocardium. AB - Propofol has been shown to exert cardioprotection, but the underlying mechanisms remain incompletely understood. We examined: (1) whether propofol-induced cardioprotection depended on the time and the dose of administration; (2) the role of mitochondrial adenosine triphosphate-sensitive potassium channels, nitric oxide synthase, and mitochondrial respiratory chain activity in propofol-induced cardioprotection. Human right atrial trabeculae were obtained during cardiopulmonary bypass for coronary artery bypass and aortic valve replacement. Isometric force of contraction of human right atrial trabeculae hanged in an oxygenated Tyrode's solution was recorded during 30-min hypoxia and 60-min reoxygenation (Control). Propofol 0.1, 1, and 10 uM was administered: (1) 5 min before hypoxia until the end of the experiment; (2) 5 min followed by 5-min washout before hypoxia; (3) during the reoxygenation period, propofol 10 uM was administered in presence of 5-hydroxydecanoate (antagonist of mitochondrial adenosine triphosphate-sensitive potassium channels), and NG-nitro-L-arginine methyl ester (inhibitor of nitric oxide synthase). In addition, mitochondria were isolated from human right atrial at 15 min of reoxygenation. The effect of propofol on activity of the mitochondrial respiratory chain complexes was evaluated by spectrophotometry. The force of contraction (% of baseline) and the complex activity between the different groups were compared with an analysis of variance and post hoc test. Propofol 10 uM administered during the reoxygenation period significantly improved the recovery of force of contraction at the end of reoxygenation (82 +/- 6% of baseline value vs. 49 +/- 6% in Control; P < 0.001). The beneficial effects of propofol 10 uM were abolished by co-administration with 5-hydroxydecanoate (53 +/- 8%) or NG-nitro-L-arginine methyl ester (57 +/- 6%). Propofol 10 uM significantly increased enzymatic activities of the mitochondrial respiratory chain complexes, in reoxygenation period, compared to their respective untreated controls. In conclusion, in human myocardium, propofol induced cardioprotection was mediated by mitochondrial adenosine triphosphate sensitive potassium channels opening, nitric oxide synthase activation and stimulation of mitochondrial respiratory chain complexes, in early reoxygenation period. PMID- 26748398 TI - Long-term insulin treatment restores cardioprotection induced by sufentanil postconditioning in diabetic rat heart. AB - Sufentanil, a commonly used opioid analgesic, could mimic ischemia postconditioning to attenuate ischemia reperfusion injury, but this effect might be hindered in diabetic animals by inhibition of glycogen synthase kinase-3beta phosphorylation. Also, diabetes can abrogate the cardioprotection of sevoflurane (an inhaled anesthetic) against ischemia reperfusion injury, and short-term insulin treatment does not restore protection by sevoflurane postconditioning. We hypothesized that long-term insulin treatment might restore the cardioprotective effect of sufentanil postconditioning in diabetic rats via phosphorylation of glycogen synthase kinase-3beta. Streptozotocin (55 mg/kg)-induced diabetic rats received insulin (Novolin N, 6-8 u/d) for two days or two weeks, then were exposed to 30-min ischemia and 120-min reperfusion. Sufentanil postconditioning was performed 5 min before the onset of reperfusion. Controls included non diabetic rats, sham surgery for ischemia/reperfusion, and sufentanil vehicle. Infarct size, cardiac troponin I, and phosphorylated glycogen synthase kinase 3beta were examined. Sufentanil postconditioning reduced infarct size by 46% in non-diabetic rats (P < 0.001), but diabetes prevented this protective effect. Two day insulin treatment was not effective, but two-week treatment reduced infarct size by 45% (P < 0.001), reduced cardiac troponin I by 33% (P < 0.001), and increased phosphorylated glycogen synthase kinase-3beta levels (P < 0.001) in the diabetic sufentanil postconditioning group. In conclusion, sufentanil-induced cardioprotection was restored by long-term insulin treatment. The underlying mechanism may be increased phosphorylation of glycogen synthase kinase-3beta. PMID- 26748399 TI - Epigallocatechin-3-gallate protects against tumor necrosis factor alpha induced inhibition of osteogenesis of mesenchymal stem cells. AB - Anabolic bone accruement through osteogenic differentiation is important for the maintenance of physiological bone mass and often disrupted in various inflammatory diseases. Epigallocatechin-3-gallate, as an antioxidant and anti inflammatory agent, has been suggested for potential therapeutic use in this context, possibly by the inhibition of bone resorption as well as the enhancement of bone formation through directly activating osteoblast differentiation. However, the reported effects of epigallocatechin-3-gallate modulating osteoblast differentiation are mixed, and the underlying molecular mechanism is still elusive. Moreover, there is limited information regarding the effects of epigallocatechin-3-gallate on osteogenic potential of mesenchymal stem cell in inflammation. Here, we examined the in vitro osteogenic differentiation of human mesenchymal stem cells. We found that the cell viability and osteoblast differentiation of human bone marrow-derived mesenchymal stem cells are significantly inhibited by inflammatory cytokine TNFalpha treatment. Epigallocatechin-3-gallate is able to enhance the cell viability and osteoblast differentiation of mesenchymal stem cells and is capable of reversing the TNFalpha-induced inhibition. Notably, only low doses of epigallocatechin-3 gallate have such benefits, which potentially act through the inhibition of NF kappaB signaling that is stimulated by TNFalpha. These data altogether clarify the controversy on epigallocatechin-3-gallate promoting osteoblast differentiation and further provide molecular basis for the putative clinical use of epigallocatechin-3-gallate in stem cell-based bone regeneration for inflammatory bone loss diseases, such as rheumatoid arthritis and prosthetic osteolysis. PMID- 26748400 TI - Effects of resveratrol and methoxyamine on the radiosensitivity of iododeoxyuridine in U87MG glioblastoma cell line. AB - The purpose of this study was to evaluate the combination effect of resveratrol and methoxyamine on radiosensitivity of iododeoxyuridine in spheroid culture of U87MG glioblastoma cell line using colony formation and alkaline comet assays. Spheroids on day-20 with 350 um diameters were treated with 20 uM resveratrol and/or 6 mM methoxyamine and/or 1 uM iododeoxyuridine for one volume doubling time (67 h), and then irradiated with 2 Gy gamma-radiation ((60)Co) in different groups. After treatment, viability of the cells, colony forming ability and DNA damages were obtained by blue dye exclusion, colony formation and alkaline comet assay, respectively. Our results showed that methoxyamine and resveratrol could significantly reduce colony number and induce the DNA damages of glioblastoma spheroid cells treated with iododeoxyuridine in combination with gamma-rays. Therefore, methoxyamine as base excision repair inhibitor and resveratrol as hypoxia inducible factor 1-alpha inhibitor in combination with iododeoxyuridine as radiosensitizer enhanced the radiosensitization of glioblastoma spheroid cells. PMID- 26748401 TI - LncRNA TUG1 acts as a tumor suppressor in human glioma by promoting cell apoptosis. AB - Previous studies have revealed multiple functional roles of long non-coding RNA taurine upregulated gene 1 in different types of malignant tumors, except for human glioma. Here, it was designed to study the potential function of taurine upregulated gene 1 in glioma pathogenesis focusing on its regulation on cell apoptosis. The expression of taurine upregulated gene 1 in glioma tissues was detected by quantitative RT-PCR and compared with that in adjacent normal tissues. Further correlation analysis was conducted to show the relationship between taurine upregulated gene 1 expression and different clinicopathologic parameters. Functional studies were performed to investigate the influence of taurine upregulated gene 1 on apoptosis and cell proliferation by using Annexin V/PI staining and cell counting kit-8 assays, respectively. And, caspase activation and Bcl-2 expression were analyzed to explore taurine upregulated gene 1-induced mechanism. taurine upregulated gene 1 expression was significantly inhibited in glioma and showed significant correlation with WHO Grade, tumor size and overall survival. Further experiments revealed that the dysregulation of taurine upregulated gene 1 affected the apoptosis and cell proliferation of glioma cells. Moreover, taurine upregulated gene 1 could induce the activation of caspase-3 and-9, with inhibited expression of Bcl-2, implying the mechanism in taurine upregulated gene 1-induced apoptosis. taurine upregulated gene 1 promoted cell apoptosis of glioma cells by activating caspase-3 and -9-mediated intrinsic pathways and inhibiting Bcl-2-mediated anti-apoptotic pathways, acting as a tumor suppressor in human glioma. This study provided new insights for the function of taurine upregulated gene 1 in cancer biology, and suggested a potent application of taurine upregulated gene 1 overexpression for glioma therapy. PMID- 26748403 TI - A Healthy Patient With Iron Deficiency Anemia and a Perianal Papule. PMID- 26748406 TI - Fixed Flexion Deformity After Unicompartmental Knee Arthroplasty: How Much Is Too Much. AB - BACKGROUND: The detrimental impact of postoperative fixed flexion deformity (FFD) after unicompartmental knee arthroplasty (UKA) is manifold. This study aims to define the amount of postoperative FFD that is clinically relevant after UKA. METHODS: Between 2005 and 2012, 803 patients who underwent a primary UKA at a tertiary hospital were prospectively followed up. They were categorized into 3 groups based on the amount of postoperative FFD: (1) 0 degrees (control); (2) 1 degrees -10 degrees (mild FFD); and (3) >10 degrees (severe FFD). RESULTS: There were 26 patients (3%) with severe FFD at 2 years after UKA. The Knee Society Function Score and Knee Score in the severe FFD group were 10 +/- 4 and 10 +/- 2 points lower than in the control group, respectively (P = .017 and P = .001). Similarly, the Oxford Knee Score and Physical Component Score in the severe FFD group was 5 +/- 1 and 7 +/- 2 points lower than in the control group, respectively (P = .033 and P < .001). CONCLUSION: This study suggests that postoperative FFD of >10 degrees after UKA is associated with significantly poorer functional outcomes. PMID- 26748405 TI - Multicenter Study of Highly Cross-linked vs Conventional Polyethylene in Total Knee Arthroplasty. AB - BACKGROUND: Despite substantial interest and use of highly cross-linked polyethylene (HXLPE) in total knee arthroplasty (TKA), outcomes remain largely unknown. The purpose of this study is to compare HXLPE and conventional polyethylene at 4- to 5-year follow-up. METHODS: A prospective multicenter study of 307 posterior-stabilized TKAs (168 conventional and 139 HXLPE) was performed. Short-Form-6D, Short-Form 36, Knee Society Score, Lower Extremity Activity Score, health-related quality of life outcomes, and radiographs were collected preoperatively and at routine postoperative intervals. RESULTS: Two hundred twenty-four patients obtained a minimum 4- to 5-year follow-up for analysis. There were no osteolysis or polyethylene failures in either group. Although both conventional and HXLPE poly groups showed significant improvements in all measures from preoperative baselines (P < .05), the XLPE group had slightly greater mean Knee Society Score function (P = .04), Lower Extremity Activity Score (P = .03), and Short-Form 36 Physical Composite Score (P = .03) scores and a greater improvement in Short-Form 6D health-related quality of life of 0.16 points (d = 1.02, 95% CI: 0.01-1.11) at latest follow-up. CONCLUSION: The study findings support comparative safety and outcomes of HXLPE related to mechanical failure or osteolysis in the midterm. However, longer-term follow-up is warranted to assess whether wear and mechanical properties of HXLPE are maintained in vivo. PMID- 26748407 TI - Temporal distribution of intertidal macrozoobenthic assemblages in a Nanozostera noltii-dominated area (Lagoon of Venice). AB - We describe the temporal distribution of intertidal macrozoobenthic assemblages in a small marsh pond of the Lagoon of Venice colonized by the seagrass Nanozostera noltii (Hornemman) Tomlinson et Posluzny. Three stations ranging in the degree of N. noltii cover were selected about 100 m apart and sampled 9 times at regular intervals from March 1996 to March 1997. We applied the concepts of resistance and resilience to "natural stress" (e.g. extent of protection from seagrass meadows, exposure of macrozoobenthic assemblages to high temperatures in summer) with the aim to assess the stability of a community along a gradient of seagrass coverage. Results showed that the most structured and taxa-rich macrozoobenthic assemblage occurred at the station covered by a continuous stand of N. noltii, where permanent taxa (i.e. found in 100% of samples) were almost double than those found at the other stations. During the annual cycle, the macrozoobenthic assemblages showed a cyclical pattern, with temporal fluctuations increasing as they moved further away from the seagrass beds. We propose the role of N. noltii offering structural complexity and stability as the more probable explanation to the observed differences between stations in the intertidal assemblages. PMID- 26748404 TI - The Impact of Magnetic Resonance Enterography and Capsule Endoscopy on the Re classification of Disease in Patients with Known Crohn's Disease: A Prospective Israeli IBD Research Nucleus (IIRN) Study. AB - BACKGROUND AND AIMS: The classification of Crohn's disease (CD) is usually determined at initial diagnosis and is frequently based on ileocolonoscopic and cross-sectional imaging data. Advanced endoscopic and imaging techniques such as small-bowel video capsule endoscopy (VCE) and magnetic resonance enterography (MRE) may provide additional data regarding disease extent and phenotype. Our aim was to examine whether VCE or MRE performed after the initial diagnosis may alter the original disease classification. METHODS: Consecutive patients with known small-bowel CD in clinical remission or mild disease were prospectively recruited and underwent MRE and VCE (if small-bowel patency was confirmed by a patency capsule (PC). Montreal classifications before and after evaluation were compared. RESULTS: Seventy-nine patients underwent MRE and VCE was performed in 56. Previously unrecognized disease locations were detected with VCE and MRE in 51 and 25%, respectively (p < 0.01) and by both modalities combined in 44 patients (55%). Twenty-two patients (27%) were reclassified as having an advanced phenotype (B2/B3). MRE and VCE reclassified the phenotype in 26 and 11% of cases, respectively (p < 0.05). Overall, both modalities combined altered the original Montreal classification in 49/76 patients (64%). CONCLUSION: VCE and MRE may lead to reclassification of the original phenotype in a significant percentage of CD patients in remission. VCE was more sensitive for detection of previously unrecognized locations, while MRE was superior for detection of phenotype shift. The described changes in the disease classification may have an important impact on both clinical management and long-term prognosis in these patients. PMID- 26748408 TI - Comparative effects of nodularin and microcystin-LR in zebrafish: 2. Uptake and molecular effects in eleuthero-embryos and adult liver with focus on endoplasmic reticulum stress. AB - Microcystin (MC) and nodularin are structurally similar cyanobacterial toxins that inhibit protein phosphatases. Additional modes of action are poorly known, in particular for nodularin. In our associated work, we showed that active cellular uptake is mediated by the organic anion transporting polypeptide drOatp1d1 in zebrafish (Faltermann et al., 2016). Here, we assessed the transcriptional expression of three genes encoding three uptake transporters during embryonic development from 24h post fertilization (hpf) to 168 hpf. Transcripts of drOatp1d1 and drOatp2b1 are present at 24 hpf. The abundance increased after hatching and remained about constant up to 168 hpf. Transcripts of drOatp2b1 were most abundant, while drOapt1f transcripts showed very low relative abundance compared to drOatp1d1 and drOatp2b1. We further demonstrated the uptake of fluorescent labeled MC-LR in eleuthero-embryos and its accumulation in the glomerulus of the pronephros. An important molecular effect of MC-LR in human liver cells is the induction of endoplasmic reticulum (ER)-stress. Here, we investigated, whether MC-LR and nodularin similarly lead to induction of ER stress in zebrafish by analyzing changes of mRNA levels of genes indicative of ER stress. In zebrafish liver organ cultures short- and long-term exposures to 0.15 and 0.3 MUmol L(-1) MC-LR, and 0.5 and 1 MUM L(-1) nodularin led to significant transcriptional induction of several ER-stress marker genes, including the chaperone glucose regulated protein 78 (bip), the spliced form of x-box binding protein (xbp-1s), the CCAAT-enhancer-binding protein homologous protein (chop) and activating transcription factor 4 (atf4). Furthermore, strong transcriptional changes occurred for tumor necrosis factor alpha (tnfa) and dual specificity phosphatase 5 (dusp5), associated with mitogen activated protein kinase (MAPK) pathway. However, no alterations in transcript levels of pro-apoptotic genes Bcl 2 like protein 4 (bax) and p53 occurred. In contrast to adult liver, MC-LR and nodularin did not result in detectable changes of mRNA levels of selected target genes involved in ER-stress in zebrafish eleuthero-embryos, nor was the abundance of transcripts belonging to the MAPK and pro-apoptosis pathways altered. In conclusion, our data indicate that MC-LR and nodularin have similar transcriptional effects. They lead to changes in mRNA levels of genes that suggest induction of ER-stress, and furthermore, lead to increased level of tnfalpha mRNA in the adult liver, which suggests a novel (transcriptional) mode of action in fish. However, although taken up by eleuthero-embryos, no transcriptional changes induced by these cyanobacterial toxins were detected. This is probably due to action to specific organs such as liver and kidneys that could not be identified by whole-embryo sampling. PMID- 26748409 TI - Nonmedical prescription pain reliever and alcohol consumption among cannabis users. AB - BACKGROUND: This study examined poly-drug use involving the use of cannabis with nonmedical prescription pain reliever use (NMPR) and alcohol use. METHODS: Computer-assisted survey data from the National Survey on Drug Use and Health were examined. The NSDUH is an annual, cross-sectional survey of non institutionalized citizens in the United States (ages 12+). Replicate analyses were conducted using the 2013 and 2003 survey waves. RESULTS: Higher levels of cannabis use were consistently associated with more frequent consumption of prescription pain relievers, with findings replicating in both 2013 and 2003. While the prevalence of dual users declined from 2003 (2.5%) to 2013 (2.3%), the average number of days used among dual users increased by an average of 20 days over that period. These changes largely occurred among those aged 35 or older, males, whites, and non-illicit drug users. Past-year marijuana use increased by 16% (10.8-12.6%, p-value<.001) whereas NMPR decreased by 15% (4.9-4.2%, p value<.001). The largest changes occurred after 2011. Persons using the most cannabis generally had higher levels of alcohol use relative to those using the least amount of cannabis. There was a significant increase in the prevalence of dual use between 2003 (10.2%) and 2013 (11.6%), while the prevalence of past-year alcohol use remained relatively stable. CONCLUSIONS: Clinical efforts and public health interventions should consider the possible co-ingestion of cannabis with NMPR and alcohol, as concomitant use may portend negative health effects in the short and long-term. PMID- 26748410 TI - Patterns of alcohol consumption and health-related quality of life in older adults. AB - BACKGROUND: Health-related quality of life (HRQOL) is a more powerful predictor of health services use and mortality than many objective measures of health. However, in older adults the association between main alcohol drinking patterns and HRQOL is uncertain. METHODS: A prospective cohort with 2163 community dwelling individuals aged >= 60 years was recruited in Spain in 2008-2010 and followed-up through 2012. At baseline, participants reported alcohol consumption. HRQOL was measured with the SF-12 questionnaire, at baseline and in 2012. RESULTS: In cross-sectional analyses at baseline, compared to non-drinkers, better scores on the physical component summary (PCS) of the SF-12 were reported in moderate (beta=1.59 [95% confidence interval 0.61-2.58]) and heavy drinkers (beta=2.18 [0.57-3.79]). Better scores on the PCS were also reported by drinkers who adhered to the Mediterranean drinking pattern (MDP) (beta=1.43 [0.30-2.56]) as well as those who did not (beta=1.89 [0.79-2.99]). However, no association was observed between average alcohol consumption or the MDP and the mental component summary (MCS) of the SF-12; or between beverage preference or drinking with meals and either the PCS or MCS scores. In prospective analyses, women who reportedly drank exclusively with meals showed better scores on the PCS than women who drank only outside of meals (beta=3.64 [0.79-6.50]). CONCLUSIONS: The small association between alcohol consumption and better physical HRQOL found at baseline was not apparent after a few years of follow-up. Medical advice on alcohol consumption cannot be grounded on its effects on HRQOL. PMID- 26748411 TI - Insula reactivity to negative stimuli is associated with daily cigarette use: A preliminary investigation using the Human Connectome Database. AB - BACKGROUND: Individuals who smoke more cigarettes per day are at greater risk for developing smoking-related illness and have more difficulty quitting. Withdrawal related negative mood is one factor thought to motivate drug use. However, heavy smokers are generally more sensitive to negative affect, not just negative emotion stemming from withdrawal. One possibility is that individual differences in how the brain processes negative stimuli may impact smoking use. Given the wealth of data implicating the insula in nicotine dependence and affective processing we hypothesize that the number of cigarettes an individual smokes per day will relate to insula reactivity to negative stimuli. METHODS: A functional magnetic resonance imaging (fMRI) emotional processing task collected by the Human Connectome Project was assessed in 21 daily tobacco smokers who reported smoking between 5 and 20 cigarettes per day. The number of cigarettes smoked per day was correlated with right and left anterior insula reactivity to faces expressing a negative emotion relative to a control. This anterior insula region of interest has been associated with treatment outcome and smoking cue-reactivity in our prior work. RESULTS: Those who smoked more daily cigarettes showed greater right insula reactivity to negative stimuli (r=0.564, p=0.008). Left insula reactivity was not associated with cigarettes smoked per day. CONCLUSION: Smokers who use more cigarettes per day have greater insula reactivity to negative stimuli, furthering the field's understanding of the insula's involvement in nicotine use. This preliminary work also suggests a mechanism contributing to higher rates of daily smoking. PMID- 26748413 TI - Oral and maxillofacial pathology submitted to Rizgary Teaching Hospital: a 6-year retrospective study. AB - INTRODUCTION: The majority of surveys concerning oral pathology accessions have focused on specific pathological categories or particular age groups, and few studies have analysed the whole range of specimens submitted for histopathological examination. An analysis of all oral pathology submitted to the Department of Histopathology in Rizgary Teaching Hospital in Erbil, Iraq, during the 6-year period 2008-2013, was performed. METHODS: Histopathology samples (excluding smears) from the maxillae, mandible, salivary glands, the lips and oral mucosa, the tongue, the hard and soft palate and uvula, and the pillars of the fauces were included. The specimens were grouped into six diagnostic categories: oral mucosal and skin pathology; benign neoplasms; malignant neoplasms; non-neoplastic salivary gland disorders; cysts; and miscellaneous pathology. RESULTS: The total number of oral and maxillofacial specimens was 616 of 20,571 specimens. One-third of the oral and maxillofacial specimens were in the mucosal and skin pathology category, followed by benign neoplasms (24.2%) - of which 26.8% were odontogenic tumours and 42.6% were salivary gland tumours - and malignant neoplasms (n = 100, 16.2%). Neoplastic (n = 62) and non-neoplastic (n = 41) salivary gland disorders accounted for 16.7% (n = 103) of the specimens submitted, whereas odontogenic cysts (n = 34) and tumours (n = 40) comprised 5.5% and 6.5% of all biopsies. CONCLUSIONS: Many of our findings are consistent with those reported in the literature. However, a relatively larger proportion of neoplastic lesions were found in our cohort and in other Iraqi centres. Of concern to practising clinicians in Iraq is that one in 10 biopsies submitted was a squamous cell carcinoma and three in 20 accessions were malignant. PMID- 26748414 TI - Accuracy of open-source software segmentation and paper-based printed three dimensional models. AB - In this study, we aimed to verify the accuracy of models created with the help of open-source Slicer 3.6.3 software (Surgical Planning Lab, Harvard Medical School, Harvard University, Boston, MA, USA) and the Mcor Matrix 300 paper-based 3D printer. Our study focused on the accuracy of recreating the walls of the right orbit of a cadaveric skull. Cone beam computed tomography (CBCT) of the skull was performed (0.25-mm pixel size, 0.5-mm slice thickness). Acquired DICOM data were imported into Slicer 3.6.3 software, where segmentation was performed. A virtual model was created and saved as an .STL file and imported into Netfabb Studio professional 4.9.5 software. Three different virtual models were created by cutting the original file along three different planes (coronal, sagittal, and axial). All models were printed with a Selective Deposition Lamination Technology Matrix 300 3D printer using 80 gsm A4 paper. The models were printed so that their cutting plane was parallel to the paper sheets creating the model. Each model (coronal, sagittal, and axial) consisted of three separate parts (~200 sheets of paper each) that were glued together to form a final model. The skull and created models were scanned with a three-dimensional (3D) optical scanner (Breuckmann smart SCAN) and were saved as .STL files. Comparisons of the orbital walls of the skull, the virtual model, and each of the three paper models were carried out with GOM Inspect 7.5SR1 software. Deviations measured between the models analysed were presented in the form of a colour-labelled map and covered with an evenly distributed network of points automatically generated by the software. An average of 804.43 +/- 19.39 points for each measurement was created. Differences measured in each point were exported as a .csv file. The results were statistically analysed using Statistica 10, with statistical significance set at p < 0.05. The average number of points created on models for each measurement was 804.43 +/- 19.39; however, deviation in some of the generated points could not be calculated, and those points were excluded from further calculations. From 94% to 99% of the measured absolute deviations were <1 mm. The mean absolute deviation between the skull and virtual model was 0.15 +/- 0.11 mm, between the virtual and printed models was 0.15 +/- 0.12 mm, and between the skull and printed models was 0.24 +/- 0.21 mm. Using the optical scanner and specialized inspection software for measurements of accuracy of the created parts is recommended, as it allows one not only to measure 2-dimensional distances between anatomical points but also to perform more clinically suitable comparisons of whole surfaces. However, it requires specialized software and a very accurate scanner in order to be useful. Threshold-based, manually corrected segmentation of orbital walls performed with 3D Slicer software is accurate enough to be used for creating a virtual model of the orbit. The accuracy of the paper-based Mcor Matrix 300 3D printer is comparable to those of other commonly used 3-dimensional printers and allows one to create precise anatomical models for clinical use. The method of dividing the model into smaller parts and sticking them together seems to be quite accurate, although we recommend it only for creating small, solid models with as few parts as possible to minimize shift associated with gluing. PMID- 26748412 TI - Subdimensions of social-communication impairment in autism spectrum disorder. AB - BACKGROUND: More refined dimensions of social-communication impairment are needed to elucidate the clinical and biological boundaries of autism spectrum disorders (ASD) and other childhood onset psychiatric disorders associated with social difficulties, as well as to facilitate investigations in treatment and long-term outcomes of these disorders. METHODS: This study was intended to identify separable dimensions of clinician-observed social-communication impairments by examining scores on a widely used autism diagnostic instrument. Participants included verbally fluent children ages 3-13 years, who were given a clinical diagnosis of ASD (n = 120) or non-ASD (i.e. ADHD, language disorder, intellectual disability, mood or anxiety disorder; n = 118) following a comprehensive diagnostic assessment. Exploratory and confirmatory factor analysis examined the factor structure of algorithm items from the Autism Diagnostic Observation Schedule (ADOS), Module 3. RESULTS: Results indicated that a three-factor model consisting of repetitive behaviors and two separate social-communication behavior factors had superior fit compared to a two-factor model that included repetitive behaviors and one social-communication behavior factor. In the three-factor model, impairments in 'Basic Social-Communication' behaviors (e.g. eye contact, facial expressions, gestures) were separated from impairments in 'Interaction quality.' Confirmatory factor analysis in an independent sample of children in the Simons Simplex Collection (SSC) further supported the division of social communication impairments into these two factors. Scores in Interaction Quality were significantly associated with nonverbal IQ and male sex in the ASD group, and with age in the non-ASD group, while scores in basic social communication were not significantly associated with any of these child characteristics in either diagnostic group. CONCLUSIONS: Efforts to conceptualize level, or severity, of social-communication impairment in children with neurodevelopmental disorders might be facilitated by separating the most basic (or proximal) social communication impairments from those that could arise from a range of other phenotypic variables. Identification of social-communication subdimensions also highlights potential avenues for measuring different types of social communication impairments for different purposes (e.g. for differential diagnosis vs. response to treatment). PMID- 26748415 TI - What is the optimal salvage procedure for cut-out after surgical fixation of trochanteric fractures with the PFNA or TFN?: A multicentre study. AB - PURPOSE: To evaluate the outcome after different types of revision operations for blade 'cut-out' and 'cut-through' after fixation of trochanteric fractures with proximal femoral nail antirotation (PFNA) or a trochanter fixation nail (TFN). METHODS: Twenty hospitals participated in this multicentre study. A total of 4109 patients were retrospectively screened for cut-out or cut-through complications after nailing of trochanteric fractures using PFNA or TFN. Fifty-seven patients (28 with 'cut-through' and 29 with 'cut-out') were included in the study. In the 'cut-through' group, 16 patients underwent a blade exchange, six patients had a blade exchange with bone cement augmentation, and six received total hip arthroplasty (THA). In the 'cut-out' group, three patients had a blade exchange, one had a blade exchange with augmentation, three underwent re-nailing of the fracture with a new PFNA, one had a girdlestone procedure and 21 had THA procedures. RESULTS: In the 'cut-through' group, eight patients who had a blade exchanges (50%) and two patients with blade exchange and augmentation (33%) required further revision operations. THA was the definite treatment in all 6 cases. In the 'cut-out' group, two patients (66%) who had blade exchanges and two (66%) who underwent re-nailing required additional revision operations during the subsequent course. One patient (4%) who had total hip arthroplasty needed revision surgery for acetabular replacement. Overall, a total of 81 revision procedures were performed. CONCLUSION: Based on the data from this study, we recommend THA as the only valid salvage procedure for 'cut-out' and 'cut-through' of helical blades after fixation of trochanteric fractures with the PFNA and TFN. PMID- 26748416 TI - Mammalian target of rapamycin/eukaryotic initiation factor 4F pathway regulates follicle growth and development of theca cells in mice. AB - The aim of the present study was to clarify the roles of the mammalian target of rapamycin (mTOR) signalling pathway in follicular growth and development of thecal cells. Using in vivo-grown and in vitro-cultured ovaries, histological changes were evaluated using haematoxylin and eosin (HE) staining. Differentially expressed genes (DEGs) from 0 day post partum (d.p.p.) to 8 d.p.p. ovaries were screened by microarray and verified by quantitative real-time polymerase chain reaction. Forty-two DEGs related to cell proliferation and differentiation were screened out, with most DEGs being related to the to mTOR signalling pathway. Then, 3 d.p.p. ovaries were retrieved and used to verify the role of mTOR signalling in follicle and thecal cell development using its activators (Ras homologue enriched in brain (Rheb) and GTP) and inhibitor (rapamycin). The development of follicles and thecal cells was significantly impaired in ovaries cultured in vitro Day 3 to Day 8. In in vitro-cultured ovaries, Rheb and GTP (is 100ngmL-1 Rheb and 500ngmL-1 GTP for 48h) significantly increased follicle diameter, the percentage of primary and secondary follicles and the umber of thecal cells, and upregulated expression of mTOR, phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), eukaryotic initiation factor (eIF) 4F and cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1). Rapamycin (10nM rapamycin for 24h) had opposite effects to those of Rheb and GTP, and partly abrogated (significant) the effects of Rheb and GTP when added to the culture in combination with these drugs. Thus, mTOR signalling plays an important role in follicle growth and thecal cell development. PMID- 26748417 TI - Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing. AB - Holoprosencephaly (HPE) is the most common congenital cerebral malformation, characterized by impaired forebrain cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been associated with HPE and are often inherited from an unaffected parent, underlying complex genetic bases. It is now emerging that HPE may result from a combination of multiple genetic events, rather than from a single heterozygous mutation. To explore this hypothesis, we undertook whole exome sequencing and targeted high-throughput sequencing approaches to identify mutations in HPE subjects. Here, we report two HPE families in which two mutations are implicated in the disease. In the first family presenting two foetuses with alobar and semi-lobar HPE, we found mutations in two genes involved in HPE, SHH and DISP1, inherited respectively from the father and the mother. The second reported case is a family with a 9-year-old girl presenting lobar HPE, harbouring two compound heterozygous mutations in DISP1. Together, these cases of digenic inheritance and autosomal recessive HPE suggest that in some families, several genetic events are necessary to cause HPE. This study highlights the complexity of HPE inheritance and has to be taken into account by clinicians to improve HPE genetic counselling. PMID- 26748418 TI - Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming. AB - Despite the widespread interest in direct neuronal reprogramming, the mechanisms underpinning fate conversion remain largely unknown. Our study revealed a critical time point after which cells either successfully convert into neurons or succumb to cell death. Co-transduction with Bcl-2 greatly improved negotiation of this critical point by faster neuronal differentiation. Surprisingly, mutants with reduced or no affinity for Bax demonstrated that Bcl-2 exerts this effect by an apoptosis-independent mechanism. Consistent with a caspase-independent role, ferroptosis inhibitors potently increased neuronal reprogramming by inhibiting lipid peroxidation occurring during fate conversion. Genome-wide expression analysis confirmed that treatments promoting neuronal reprogramming elicit an anti-oxidative stress response. Importantly, co-expression of Bcl-2 and anti oxidative treatments leads to an unprecedented improvement in glial-to-neuron conversion after traumatic brain injury in vivo, underscoring the relevance of these pathways in cellular reprograming irrespective of cell type in vitro and in vivo. PMID- 26748420 TI - Metal-Ligand Cooperativity in a Methandiide-Derived Iridium Carbene Complex. AB - The synthesis, electronic structure, and reactivity of the first Group 9 carbene complex, [Cp*IrL] [L=C(Ph2 PS)(SO2 Ph)] (2), based on a dilithio methandiide are reported. Spectroscopic as well as computational studies have shown that, despite using a late transition-metal precursor, sufficient charge transfer occurred from the methandiide to the metal, resulting in a stable, nucleophilic carbene species with pronounced metal-carbon double-bond character. The potential of this iridium complex in the activation of a series of E-H bonds by means of metal-ligand cooperation has been tested. These studies have revealed distinct differences in the reactivity of 2 compared to a previously reported ruthenium analogue. Whereas attempts to activate the O-H bond in different phenol derivatives resulted in ligand cleavage, H-H and Si-H activation as well as dehydrogenation of isopropanol have been accomplished. These reactions are driven by the transformation of the carbene to an alkyl ligand. Contrary to a previously reported ruthenium carbene system, the dihydrogen activation has been found to proceed by a stepwise mechanism, with the activation first taking place solely at the metal. The activated products further reacted to afford a cyclometalated complex through liberation of the activated substrates. In the case of triphenylsilane, cyclometalation could thus be induced by a substoichiometric (i.e., catalytic) amount of silane. PMID- 26748419 TI - Stepwise Clearance of Repressive Roadblocks Drives Cardiac Induction in Human ESCs. AB - Cardiac induction requires stepwise integration of BMP and WNT pathway activity. Human embryonic stem cells (hESCs) are developmentally and clinically relevant for studying the poorly understood molecular mechanisms downstream of these cascades. We show that BMP and WNT signaling drive cardiac specification by removing sequential roadblocks that otherwise redirect hESC differentiation toward competing fates, rather than activating a cardiac program per se. First, BMP and WNT signals pattern mesendoderm through cooperative repression of SOX2, a potent mesoderm antagonist. BMP signaling promotes miRNA-877 maturation to induce SOX2 mRNA degradation, while WNT-driven EOMES induction transcriptionally represses SOX2. Following mesoderm formation, cardiac differentiation requires inhibition of WNT activity. We found that WNT inhibition serves to restrict expression of anti-cardiac regulators MSX1 and CDX2/1. Conversely, their simultaneous disruption partially abrogates the requirement for WNT inactivation. These results suggest that human cardiac induction depends on multi-stage repression of alternate lineages, with implications for deriving expandable cardiac stem cells. PMID- 26748421 TI - The immune system and cancer evasion strategies: therapeutic concepts. AB - The complicated interplay between cancer and the host immune system has been studied for decades. New insights into the human immune system as well as the mechanisms by which tumours evade immune control have led to the new and innovative therapeutic strategies that are considered amongst the medical breakthroughs of the last few years. Here, we will review the current understanding of cancer immunology in general, including immune surveillance and immunoediting, with a detailed look at immune cells (T cells, B cells, natural killer cells, macrophages and dendritic cells), immune checkpoints and regulators, sialic acid-binding immunoglobulin-like lectins (Siglecs) and other mechanisms. We will also present examples of new immune therapies able to reverse immune evasion strategies of tumour cells. Finally, we will focus on therapies that are already used in daily oncological practice such as the blockade of immune checkpoints cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) in patients with metastatic melanoma or advanced lung cancer, or therapies currently being tested in clinical trials such as adoptive T-cell transfer. PMID- 26748422 TI - No increased mortality in 109,000 first-degree relatives of celiac individuals. AB - BACKGROUND: Several studies have shown an excess mortality in individuals with celiac disease (CD). However, it is unknown if also first-degree relatives (FDRs) to celiac patients are at increased risk of death. AIM: We aimed to assess mortality in FDRs to celiac patients. METHODS: Individuals with CD were identified through biopsy reports (equal to Marsh grade III). Each celiac individual was matched on sex, age, county and calendar year with up to five control individuals. Through Swedish healthcare registries we identified all FDRs (father, mother, sibling, offspring) of CD individuals and controls. Through Cox regression we calculated hazard ratios (HRs) for mortality (all-cause death, circulatory, cancer and other). RESULTS: We identified 109,309 FDRs of celiac individuals and 549,098 FDRs of controls. Overall mortality was increased in FDRs to celiac individuals (HR=1.02, 95%CI=1.00-1.04, p=0.03). This corresponded to an excess risk of 5.9 deaths per 100,000 person-years of follow-up. When limiting follow-up to time since celiac diagnosis in the index individual, we found no increased risk of death (HR=1.01; 95%CI=0.98-1.03). CONCLUSION: FDRs to individuals with CD are at increased risk of death. This excess risk is however minimal and unlikely to be of any clinical importance to the individual. PMID- 26748423 TI - Gastrointestinal symptoms and behavioral problems in preschoolers with Autism Spectrum Disorder. AB - BACKGROUND: Gastrointestinal (GI) symptoms are frequently reported in children with Autism Spectrum Disorder (ASD), and an impact of GI comorbidity on ASD behavioral problems has been hypothesized. AIMS: To explore the type and the prevalence of GI symptoms in ASD patients and typical development (TD) controls, and to investigate their possible association with behavioral problems. METHODS: A total of 230 preschoolers were included in this study. Specifically, four groups of children were evaluated: ASD individuals suffering from GI symptoms (ASD/GI+), ASD subjects without GI symptoms (ASD/GI-), TD peers with (TD/GI+) and without (TD/GI-) GI symptoms. Parental report of behavioral problems and GI symptoms were assessed through the Child Behavior Check List 11/2-5. RESULTS: A significant higher percentage of ASD (37.4%) versus TD (14.8%) with GI symptoms was observed. 'Constipated' and 'Not-Eat' were the most frequent GI symptoms both in ASD and in TD groups, but they were evaluated as more severe in ASD patients. ASD/GI+ children had more anxiety problems, somatic complaints, externalizing and total problems than ASD/GI- individuals. TD/GI+ did not show more behavioral problems than TD/GI-. CONCLUSION: Development of evidence-based guidelines for identification of GI problems in ASD preschoolers is warranted. GI symptomatology should be accurately assessed, especially in ASD children with anxiety and/or externalizing behavioral problems. PMID- 26748424 TI - Subcapsular and intra-hepatic collaterals in a patient with compensated Budd Chiari syndrome. PMID- 26748425 TI - Diagnostic yield of scope retroflexion in the right colon: A prospective cohort study. AB - BACKGROUND: Techniques have been implemented to improve colonoscopy adenoma detection rate (ADR) in the right colon. AIMS & METHODS: We prospectively examined the additional diagnostic yield of right colon examination with colonoscope retroflexion in consecutive, symptomatic and screening-surveillance patients. Right colon was examined in forward-view first and thereafter, retroflexion was performed to re-inspect it. RESULTS: Right colon examination in retroflexion was achieved in 620 (92%) patients. Increased inserted scope length to the cecum (OR: 0.48 [95% CI: 0.27-0.84]) and elderly status (OR: 0.53 [95% CI: 0.430-0.94]) predicted retrofexion failure. Forward-view colonoscopy detected 134 polyps and 112 adenomas in 105 and 85 patients, respectively. Scope retroflexion revealed 7 missed (6 adenomas--2 advanced) polyps in 7 patients; indicating 4.96 (95% CI: 1.37-8.55) % and 5.1 (95% CI: 1.12-9.05) % per-polyp and per-adenoma miss rates, respectively. In ITT analysis, per-patient polyp and adenoma miss rates were 1.041% and 0.89%, respectively. Among screening-surveillance patients, retroflexion detected 3 missed adenomas (2 advanced) in 3 patients, resulting in changed surveillance schedule in 2 of them (5.12 per 1000 screening-surveillance patients). Early study termination was favored by low right colon ADR improvement and lacking substantial surveillance interval change. CONCLUSION: The additional diagnostic yield of scope retroflexion in the right colon is questionable. PMID- 26748426 TI - PRODIGE 34-FFCD 1402-ADAGE: Adjuvant chemotherapy in elderly patients with resected stage III colon cancer: A randomized phase 3 trial. PMID- 26748427 TI - Comparison of liver transplantation outcomes in biliary atresia patients with and without prior portoenterostomy: A meta-analysis. AB - BACKGROUND: Portoenterostomy is currently the standard first procedure for biliary atresia, and liver transplantation is reserved as a complementary therapy for those with late diagnosis, rapid hepatic decompensation, or failed portoenterostomy. Many previous publications have analysed the impact of prior portoenterostomy on the clinical outcomes of liver transplantation and the conclusions are discordant. METHODS: PubMed and EMBASE were systematically searched for relevant articles, and studies published in Chinese were searched in the Wanfang China Medical Collections. The references of the retrieved studies were also reviewed. In addition, Google scholar was used to further confirm the literature search. RESULTS: Fourteen studies were included comprising 1560 patients, of which 1190 (76.3%) received portoenterostomy. Meta-analysis did not reveal significant differences in either patient survival rate (odds ratio, 0.82) or graft survival rate (odds ratio, 1.11) over a 5-year follow-up between biliary atresia patients with and without a portoenterostomy procedure prior to liver transplantation; patients who received a prior portoenterostomy procedure had a higher risk of postoperative infection (odds ratio, 2.02). CONCLUSION: Accumulated literature suggested that a prior portoenterostomy did not adversely affect outcomes of liver transplantation in children with biliary atresia. PMID- 26748428 TI - A standardized method for endoscopic necrosectomy improves complication and mortality rates. AB - OBJECTIVES: Endoscopic necrosectomy is effective in the treatment of walled-off necrosis (WON), and is preferred to surgical approaches, however complication and mortality rates remain high with few centers regularly employing the technique. Lack of a standardized approach may also contribute to these limitations. METHODS: Prior to the study, a multidisciplinary team applied standardized care assessment and management plan principles to develop and optimize a systematic approach for the management of WON. Preoperative, postoperative, and endoscopic management were standardized. Patient preparation, room set-up, technical features (EUS-guidance, cold-access with balloon dilation, fragmentation of necrosis on the initial procedure, antibiotic lavage, double pigtail stents), and discontinuation of PPIs to encourage auto-digestion of necrosis were included. This study employed a consecutive prospective clinical registry to assess the clinical outcomes of this standardized approach. RESULTS: 60 consecutive patients underwent 1.58 +/- 0.1 necrosectomies, with debridement accomplished on the initial procedure in 98.3%. 39 patients (65%) required only one session. Clinical resolution occurred in 86.7%, with radiologic confirmation. Percutaneous drainage was required in 8 patients during follow-up, and 4 of these later required surgery. Serious adverse events occurred in 3.3% of patients, and there was no mortality. CONCLUSIONS: The standardized technique employed in this series was associated with lower rates of adverse events, morbidity, and mortality than prior large series. Use of a systematic approach, and integrating elements of this method may improve the risk profile of endoscopic necrosectomy and allow broader adoption. PMID- 26748429 TI - A New Approach for the Synthesis of Highly Substituted Aromatic Rings: The Alkyne Mediated Approach. AB - Pentasubstituted aromatic rings serve as templates for drug design and can be conveniently prepared by the thermolysis of suitably substituted alkynes under microwave conditions. PMID- 26748430 TI - Bay-Annulated Perylene Tetraesters: A New Class of Discotic Liquid Crystals. AB - Selenium-annulated perylene tetraesters that stabilize the hexagonal columnar phase have been synthesized and characterized, and their thermal and photophysical behavior has been determined. The mesophase range decreased with an increase in chain length. A comparative account of the structure-property relationships of this series of compounds with respect to parent perylene tetraesters, N- and S-annulated perylene tetraesters, in terms of their thermal, photophysical and electrochemical behavior is provided. The bay-annulation of perylene tetraesters is a good option to modify the thermal and photophysical properties of perylene derivatives and it can provide a new avenue for the synthesis of several technologically important self-assembling perylene derivatives. PMID- 26748431 TI - Target-Induced and Equipment-Free DNA Amplification with a Simple Paper Device. AB - We report on a paper device capable of carrying out target-induced rolling circle amplification (RCA) to produce massive DNA amplicons that can be easily visualized. Interestingly, we observed that RCA was more proficient on paper than in solution, which we attribute to a significantly higher localized concentration of immobilized DNA. Furthermore, we have successfully engineered a fully functional paper device for sensitive DNA or microRNA detection via printing of all RCA-enabling molecules within a polymeric sugar film formed from pullulan, which was integrated with the paper device. This encapsulation not only stabilizes the entrapped reagents at room temperature but also enables colorimetric bioassays with minimal steps. PMID- 26748432 TI - External validation of IOTA simple descriptors and simple rules for classifying adnexal masses. AB - OBJECTIVE: To assess the diagnostic performance of a three-step strategy proposed by the International Ovarian Tumor Analysis (IOTA) Group for discriminating between benign and malignant adnexal masses. METHODS: This was a prospective observational study, performed at two tertiary-care university hospitals, of women diagnosed with an adnexal mass on transvaginal or transabdominal ultrasound between December 2012 and December 2014. Women were scheduled for an ultrasound evaluation, which was initially performed by non-expert examiners. The examiner had to classify the mass using 'simple descriptors' (first step) and, if not possible, using 'simple rules' (second step). For inconclusive masses, an expert examiner classified the mass according to their subjective impression (third step). Masses were managed expectantly, with serial follow-up examinations, or surgically, according to ultrasound findings and clinical symptoms. Histology was used as the reference standard. Masses that were managed expectantly with at least 1 year of follow-up were considered as benign for analytical purposes. Women with less than 1 year of follow-up were not included in the study. RESULTS: Six hundred and sixty-six women were included (median age, 41 (range, 18-81) years) of whom 514 were premenopausal and 152 were postmenopausal. Based on the three-step strategy, 362 women had surgical removal of the mass (53 malignant and 309 benign), 71 masses resolved spontaneously and 233 persisted. Four hundred and forty-eight (67.3%) of 666 masses could be classified using simple descriptors and, of the 218 that could not, 147 (67.4%) were classified using simple rules. Of the remaining 71 masses, the expert examiner classified 45 as benign, 12 as malignant and 14 as uncertain. Overall sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of the three-step strategy were 94.3%, 94.9%, 18.6 and 0.06, respectively. CONCLUSION: The IOTA three-step strategy, based on the sequential use of simple descriptors, simple rules and expert evaluation, performs well for classifying adnexal masses as benign or malignant. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26748433 TI - Persistent chemosis and periorbital edema. PMID- 26748435 TI - Current status of treating neurodegenerative disease with induced pluripotent stem cells. AB - Degenerative diseases of the brain have proven challenging to treat, let alone cure. One of the treatment options is the use of stem cell therapy, which has been under investigation for several years. However, treatment with stem cells comes with a number of drawbacks, for instance the source of these cells. Currently, a number of options are tested to produce stem cells, although the main issues of quantity and ethics remain for most of them. Over recent years, the potential of induced pluripotent stem cells (iPSCs) has been widely investigated and these cells seem promising for production of numerous different tissues both in vitro and in vivo. One of the major advantages of iPSCs is that they can be made autologous and can provide a sufficient quantity of cells by culturing, making the use of other stem cell sources unnecessary. As the first descriptions of iPSC production with the transcription factors Sox2, Klf4, Oct4 and C-Myc, called the Yamanaka factors, a variety of methods has been developed to convert somatic cells from all germ layers to pluripotent stem cells. Improvement of these methods is necessary to increase the efficiency of reprogramming, the quality of pluripotency and the safety of these cells before use in human trials. This review focusses on the current accomplishments and remaining challenges in the production and use of iPSCs for treatment of neurodegenerative diseases of the brain such as Alzheimer's disease and Parkinson's disease. PMID- 26748434 TI - How young people describe the impact of living with and beyond a cancer diagnosis: feasibility of using social media as a research method. AB - OBJECTIVE: Young people with cancer exhibit unique needs. During a time of normal physical and psychological change, multiple disease and treatment-related symptoms cause short and long-term physical and psychosocial effects. Little is known about how young people cope with the impact of cancer and its treatment on daily routines and their strategies to manage the challenges of cancer and treatments. We aimed to determine how young people describe these challenges through a social media site. METHODS: Using the principles of virtual ethnography and watching videos on a social media site we gathered data from young people describing their cancer experience. Qualitative content analysis was employed to analyse and interpret the narrative from longitudinal 'video diaries' by 18 young people equating to 156 films and 27 h and 49 min of recording. Themes were described then organized and clustered into typologies grouping commonalities across themes. RESULTS: Four typologies emerged reflective of the cancer trajectory: treatment and relenting side effects, rehabilitation and getting on with life, relapse, facing more treatment and coming to terms with dying. CONCLUSIONS: This study confirms the need for young people to strive towards normality and creating a new normal, even where uncertainty prevailed. Strategies young people used to gain mastery over their illness and the types of stories they choose to tell provide the focus of the main narrative. Social Media sites can be examined as a source of data, to supplement or instead of more traditional routes of data collection known to be practically challenging with this population. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26748436 TI - Use of recycled aggregates from construction and demolition waste in geotechnical applications: A literature review. AB - The use of recycled aggregates (RA) in construction constitutes a significant step towards a more sustainable society and also creates a new market opportunity to be exploited. In recent years, several case-studies have emerged in which RA were used in Geotechnical applications, such as filling materials and in unbound pavement layers. This paper presents a review of the most important physical properties of different types of RA and their comparison with natural aggregates (NA), and how these properties affect their hydraulic and mechanical behaviour when compacted. Specifically, the effects of compaction on grading size distribution curves and density are analysed, as well as the consequences of particle crushing on the resilient modulus, CBR and permeability. The paper also contains an analysis of the influence of incorporating different RA types on the performance of unbound road pavement layers as compared with those built with NA by means of the International Roughness Index and deflection values. The results collected from the literature indicate that the performance of most RA is comparable to that of NA and can be used in unbound pavement layers or in other applications requiring compaction. PMID- 26748437 TI - Mechanism on heavy metals vaporization from municipal solid waste fly ash by MgCl2?6H2O. AB - This work aims to study the mechanism of heavy metals vaporization by MgCl2?6H2O. Firstly, the decomposition mechanism of MgCl2?6H2O was investigated by thermodynamic equilibrium calculations, XRD and TG. Upon heating, MgCl2?6H2O went through the processes of dehydration and hydrolysis simultaneously accompanied by the release of HCl between 150 and 500 degrees C. At temperature higher than 500 degrees C, Mg(OH)Cl gradually release part of HCl. MgCl2?6H2O followed the similar processes of decomposition at both oxidative and reductive atmospheres. In oxidative atmosphere, vaporization of Zn and Cu was significantly accelerated by MgCl2?6H2O. However, in inert atmosphere, vaporization of Cu was not promoted since copper chloride was only stable in oxidative atmosphere. Under slow heating condition, vaporization of heavy metals were close to that under fast heating condition. This may be partially attributed to that most heavy metals already reacted with HCl forming metal chlorides below 500 degrees C, which can be vaporized at higher temperature. Moreover, the Mg(OH)Cl contributed to release HCl up to 800 degrees C. At such high temperature, the metal chlorides continue to be formed and then vaporized. After treatment, the leaching concentration of heavy metals from treated fly ashes were much lower than that from raw fly ash and met the regulatory limit of leachate. Since a large amount of MgSiO3 were formed during thermal treatment, the fly ash treated with MgCl2?6H2O can be used as raw materials for glass-ceramics production. PMID- 26748438 TI - A micro-temporal geospatial analysis of medical marijuana dispensaries and crime in Long Beach, California. AB - AIMS: To determine whether the density of marijuana dispensaries in California, USA, in 2012-13 was related to violent and property crimes, both locally and in adjacent areas, during a time in which local law enforcement conducted operations to reduce the number of storefront medical marijuana dispensaries. DESIGN: Data on locations of crimes and medical marijuana dispensaries as well as other covariates were collected for a sample of 333 Census block groups. SETTING: Long Beach, California, USA from January 2012 to December 2013. OBSERVATIONS: A total of 7992 space-time observations (from 333 Census block groups over 24 time points). MEASUREMENTS: Outcome measures focused on block-group counts of violent and property crimes. Predictors were numbers of local and adjacent-area medical marijuana dispensaries. Covariates included markers of alcohol availability as well as area demographic and economic characteristics. FINDINGS: After adjustment for covariates, density of medical marijuana dispensaries was unrelated to property and violent crimes in local areas but related positively to crime in spatially adjacent areas [incident rate ratio (IRR) = 1.0248, CI (1.0097, 1.0402) for violent crime, IRR = 1.0169, CI (1.0071, 1.0268) for property crime]. CONCLUSIONS: Using law enforcement to reduce medical marijuana dispensaries in California appears to have reduced crime in residential areas near to, but not in, these locations. PMID- 26748439 TI - The Indian Ocean tsunami and private donations to NGOs. AB - Non-governmental organisations (NGOs) are widely believed to raise their flag in humanitarian hotspots with a strong media presence in order to attract higher private donations. We assess this hypothesis by comparing the changes in donations between US-based NGOs with and without aid operations in the four countries most affected by the tsunami in the Indian Ocean in 2004. Simple before after comparisons tend to support the hypothesis that 'flying the flag' helps attract higher private donations. However, performing a difference-in-difference in-differences (DDD) approach, we find only weak indications that private donors systematically and strongly preferred NGOs with operations in the region. Extended specifications of the baseline regressions reveal that our major findings are robust. NGO heterogeneity matters in some respects, but the DDD results hold when accounting for proxies of the NGOs' reputation and experience. PMID- 26748440 TI - Screen-detected breast carcinoma with macroscopic dystrophic calcification: A pictorial essay with radiolological pathological correlation. AB - Breast calcifications are among the most common abnormal radiographic findings detected at screening mammography. This essay illustrates the clinico pathological features of nine screen-detected breast carcinomas, which had benign appearing macrocalcifications, as a radiographically dominant presenting feature. We aimed to demonstrate that benign-appearing calcifications within a breast lesion are not diagnostic of a benign process if the other imaging characteristics of the lesion are suspicious of malignancy. PMID- 26748441 TI - Structural basis of substrate specificity in porcine RNase 4. AB - RNase 4, a member of the RNase A superfamily with substrate preference for uridine, has roles in host defence, angiogenesis and neurodegenerative diseases. It also exhibits the highest interspecies amino acid sequence similarity amongst RNase A family members. However, compared to other members of the RNase A family, including eosinophil-derived neurotoxin, eosinophil cationic protein and angiogenin, little is known about the molecular basis of substrate specificity in RNase 4. Here we report high to medium resolution structures of native porcine RNase 4 (PL3), a 'substrate-specificity' determining mutant D80A and their respective complexes with deoxyuridine 5'-monophosphate (dUMP) and deoxycytidine 5'-monophosphate (dCMP). These structures provide insight into the structural basis of the uridine versus cytosine substrate specificity in RNase 4: in the D80A mutant (D80A*dCMP), the side chain of Arg101 is positioned further away from the substrate-binding pocket due to the loss of the Asp80 side chain, reducing the repulsion force on the less favoured dCMP from Arg101 and allowing the ligand to occupy the binding pocket. This can also explain the observation that the ligand in the D80A*dCMP complex is stabilized only by a small number of hydrogen bonds. Compared to the previously reported structure of the human RNase 4*2' deoxyuridine 3'-phosphate complex, the structure of PL3*dUMP complex shows additional hydrogen bonds between the ligand and the protein. In addition, the interaction between Arg101 and the dUMP ligand is absent. These observed differences are probably the result of the flexibility and different 'positioning' of the phosphate group among the mononucleotide ligands. DATABASE: The atomic coordinates and structure factors for PL3 (5AR6), D80A (5ARJ), PL3?dUMP (5ARK) and D80A?dCMP (5ARL) complexes have been deposited with the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ, USA (http://www.rcsb.org/). PMID- 26748442 TI - Medication administration errors from a nursing viewpoint: a formal consensus of definition and scenarios using a Delphi technique. AB - AIMS AND OBJECTIVES: To develop and achieve formal consensus on a definition of medication administration errors and scenarios that should or should not be considered as medication administration errors in hospitalised patient settings. BACKGROUND: Medication administration errors occur frequently in hospitalised patient settings. Currently, there is no formal consensus on a definition of medication administration errors or scenarios that should or should not be considered as medication administration errors. DESIGN: This was a descriptive study using Delphi technique. METHODS: A panel of experts (n = 50) recruited from major hospitals, nursing schools and universities in Palestine took part in the study. Three Delphi rounds were followed to achieve consensus on a proposed definition of medication administration errors and a series of 61 scenarios representing potential medication administration error situations formulated into a questionnaire. RESULTS: In the first Delphi round, key contact nurses' views on medication administration errors were explored. In the second Delphi round, consensus was achieved to accept the proposed definition of medication administration errors and to include 36 (59%) scenarios and exclude 1 (1.6%) as medication administration errors. In the third Delphi round, consensus was achieved to consider further 14 (23%) and exclude 2 (3.3%) as medication administration errors while the remaining eight (13.1%) were considered equivocal. Of the 61 scenarios included in the Delphi process, experts decided to include 50 scenarios as medication administration errors, exclude three scenarios and include or exclude eight scenarios depending on the individual clinical situation. CONCLUSION: Consensus on a definition and scenarios representing medication administration errors can be achieved using formal consensus techniques. RELEVANCE TO CLINICAL PRACTICE: Researchers should be aware that using different definitions of medication administration errors, inclusion or exclusion of medication administration error situations could significantly affect the rate of medication administration errors reported in their studies. Consensual definitions and medication administration error situations can be used in future epidemiology studies investigating medication administration errors in hospitalised patient settings which may permit and promote direct comparisons of different studies. PMID- 26748443 TI - Medium-dose ultraviolet A1 phototherapy improves SCORAD index and increases mRNA expression of interleukin-4 without direct effect on human beta defensin-1, interleukin-10, and interleukin-31. AB - BACKGROUND: Effectiveness of ultraviolet (UV)A1 in flares of atopic dermatitis (AD) is thought to influence the expression of cytokines involved in its pathogenesis. The aim of the study was to investigate whether mRNA expression of human beta defensin-1 (hbetaD-1) correlates with that of interleukin (IL)-4, IL 10, and IL-31 in skin lesions in AD before and after UVA1 phototherapy, to determine whether UVA1 decreases the expression of the aforementioned mediators, and to confirm whether changes in mRNA expression correspond with the clinical efficacy of UVA1. METHODS: Twenty-five patients with AD underwent medium-dose UVA1 phototherapy. Before and after UVA1, biopsies from acute skin lesions were studied using reverse transcription and real-time polymerase chain reaction. RESULTS: Levels of mRNA hbetaD-1 correlated with those of IL-10 and IL-31, levels of IL-4 mRNA correlated with those of IL-10 and IL-31, and IL-10 expression correlated with that of IL-31, both before and after UVA1. Phototherapy with UVA1 improved SCORing of Atopic Dermatitis (SCORAD) values, decreased pruritus, and increased expression of IL-4. After UVA1, no difference was found in the mRNA expression of other molecules. The SCORAD index did not correlate with the expression of any examined mRNA either before or after UVA1. CONCLUSIONS: hbetaD 1, IL-4, IL-10, and IL-31 are expressed in acute skin lesions in AD, and their levels correlate with each other. UVA1 improves SCORAD and pruritus and increases the expression of IL-4 without direct effect on other molecules. PMID- 26748444 TI - Pathophysiology of pruritus in primary localized cutaneous amyloidosis. AB - BACKGROUND: Primary localized cutaneous amyloidosis (PLCA) is a chronic pruritic dermatosis prevalent among Southern Chinese and South American populations. Pruritus is frequently present and can be debilitating; its pathophysiology is largely unknown. OBJECTIVES: To investigate if small-fibre neuropathy (SFN), which results in a reduction of intraepidermal nerve fibres (IENF) and abnormalities in quantitative thermal sensory testing (QST), is present in PLCA. METHODS: Twenty Chinese patients (10 men) and 20 ethnicity-, sex- and age-matched controls underwent QST assessments. The patients' warm detection threshold (WDT) and heat pain threshold at the typical lesional sites were determined. Serum interleukin (IL)-31 levels were measured. Lesional biopsies were stained for IENF, IL-31 and its receptor's subunits [IL-31RA and oncostatin M receptor-beta (OSMRbeta)], and nerve growth factor (NGF) and its receptor [tropomyosin receptor kinase A (TrkA)], and were compared with normal skin obtained from archival paraffin-embedded specimens. RESULTS: WDT was significantly higher in patients at all sites and correlated with itch scores (r = 0.59; P < 0.01). Patient biopsies revealed lower IENF counts (P < 0.01 using protein gene product 9.5, beta3 tubulin and Neurofilament 200 stains) and increased epidermal expression of OSMRbeta (P < 0.01) and IL-31RA (P < 0.01). Cutaneous IL-31, NGF and TrkA stains were not significantly increased in patients. Serum IL-31 was not significantly higher in patients. CONCLUSIONS: SFN is present in PLCA. Pruritus in PLCA is likely associated with hypersensitivity of cutaneous nerve fibres, which may be related to an increased expression of epidermal IL-31 receptors. Targeting IL-31 receptors is therefore a potential therapeutic approach. PMID- 26748445 TI - Evaluation of the Control Strategy for the 2010 Foot-and-Mouth Disease Outbreak in Japan Using Disease Simulation. AB - In 2010, Japan experienced a foot-and-mouth disease (FMD) epidemic where 292 premises were infected over a period of 75 days. The epidemic was controlled by stamping-out and vaccination, applied 5 weeks after the first confirmation of disease within a 10 km radius of identified infected places. This study aimed at identifying the role of emergency vaccination to epidemic control while adjusting for the dynamic pattern of local spread, and assessing alternative vaccination strategies, using a disease simulation model. Our results indicate that the overall hazard of local spread remained high throughout the silent spread phase and the first two weeks post-detection, with significant reduction occurring from week 3 onwards. The estimated effectiveness of emergency vaccination quantified as reduction in the hazard of infection was at most 81% and 44% for cattle and pig farms, respectively. The vaccination strategy reduced the simulated median number of IPs by 22%, epidemic duration by 64% and culling duration by 52%, but increased the total number of infected or vaccinated premises subject to culling by 144% compared with no vaccination. The simulation indicated that vaccination starting 2 weeks earlier (3 weeks post-first detection) with a smaller vaccination radius (3 km) was more effective for eradication of the epidemic compared with the actually implemented strategy. PMID- 26748446 TI - Preparation and evaluation of ziprasidone-phospholipid complex from sustained release pellet formulation with enhanced bioavailability and no food effect. AB - OBJECTIVES: The purpose of this work was to develop ziprasidone-phospholipid complex (ZIP-PLC) in sustained-release pellets to enhance the oral bioavailability and overcome the food effect of ziprasidone. METHODS: Ziprasidone phospholipid complex was formulated by solvent-evaporation method. The complexes were characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and solubility testing. The optimized ZIP-PLC was used to prepare ZIP-PLC sustained-release pellets via extrusion-spheronization method. The pellets were characterized by in vitro drug-release studies and administered to fasted and fed beagle dogs, and their pharmacokinetics were compared with commercial formulation Zeldox capsule as a control. KEY FINDINGS: The results of FTIR, SEM, DSC and PXRD studies confirmed the formation of phospholipid complex. Solubility studies showed there was a higher solubility in water for ZIP-PLC than monohydrate ziprasidoe. The in vitro release rate of ziprasidone from the ZIP-PLC sustained-release pellet exhibited controlled-release characteristics with over 95% total release in 12 h. Pharmacokinetic studies in beagle dogs showed ziprasidone with prolong actions, and no food effect was achieved simultaneously in ZIP-PLC sustained-release pellet compared with Zeldox capsule. CONCLUSIONS: The results indicated a sustained release with prolonged actions of schizophrenia and bipolar disorder treatment. PMID- 26748447 TI - Graphene and its nanostructure derivatives for use in bone tissue engineering: Recent advances. AB - Tissue engineering and regenerative medicine represent areas of increasing interest because of the major progress in cell and organ transplantation, as well as advances in materials science and engineering. Tissue-engineered bone constructs have the potential to alleviate the demand arising from the shortage of suitable autograft and allograft materials for augmenting bone healing. Graphene and its derivatives have attracted much interest for applications in bone tissue engineering. For this purpose, this review focuses on more recent advances in tissue engineering based on graphene-biomaterials from 2013 to May 2015. The purpose of this article was to give a general description of studies of nanostructured graphene derivatives for bone tissue engineering. In this review, we highlight how graphene family nanomaterials are being exploited for bone tissue engineering. Firstly, the main requirements for bone tissue engineering were discussed. Then, the mechanism by which graphene based materials promote new bone formation was explained, following which the current research status of main types of nanostructured scaffolds for bone tissue engineering was reviewed and discussed. In addition, graphene-based bioactive glass, as a potential drug/growth factor carrier, was reviewed which includes the composition-structure drug delivery relationship and the functional effect on the tissue-stimulation properties. Also, the effect of structural and textural properties of graphene based materials on development of new biomaterials for production of bone implants and bone cements were discussed. Finally, the present review intends to provide the reader an overview of the current state of the graphene based biomaterials in bone tissue engineering, its limitations and hopes as well as the future research trends for this exciting field of science. PMID- 26748449 TI - Functionalities of expressed messenger RNAs revealed from mutant phenotypes. AB - Total messenger RNAs mRNAs that are produced from a given gene under a certain set of conditions include both functional and nonfunctional transcripts. The high prevalence of nonfunctional mRNAs that have been detected in cells has raised questions regarding the functional implications of mRNA expression patterns and divergences. Phenotypes that result from the mutagenesis of protein-coding genes have provided the most straightforward descriptions of gene functions, and such data obtained from model organisms have facilitated investigations of the functionalities of expressed mRNAs. Mutant phenotype data from mouse tissues have revealed various attributes of functional mRNAs, including tissue-specificity, strength of expression, and evolutionary conservation. In addition, the role that mRNA expression evolution plays in driving morphological evolution has been revealed from studies designed to exploit morphological and physiological phenotypes of mouse mutants. Investigations into yeast essential genes (defined by an absence of colony growth after gene deletion) have further described gene regulatory strategies that reduce protein expression noise by mediating the rates of transcription and translation. In addition to the functional significance of expressed mRNAs as described in the abovementioned findings, the functionalities of other type of RNAs (i.e., noncoding RNAs) remain to be characterized with systematic mutations and phenotyping of the DNA regions that encode these RNA molecules. WIREs RNA 2016, 7:416-427. doi: 10.1002/wrna.1329 For further resources related to this article, please visit the WIREs website. PMID- 26748448 TI - A review of linked health data in Australian nephrology. AB - Linked health data bring together data about one person from varying sources such as administrative health datasets, death registries and clinical registries using a process that maintains patient privacy. Linked health data have been used for burden of disease estimates and health-care planning and is being increasingly use as a research methodology to study health service utilisation and patient outcomes. Within Australian nephrology, there has been limited understanding and use of linked health data so far, but we expect that with the increasing availability of data and the growing complexity of health care, the use of such data will expand. This is especially pertinent for the growing elderly population with advanced kidney disease, who are poorly represented in other types of research studies. This article summarizes the history of linked health data in Australia, the nature of available datasets in Australia, the methods of access to these data, privacy and ethical issues, along with strengths, limitations and implications for the future. PMID- 26748450 TI - Cloning, expression, and characterization of a novel sialidase from Brevibacterium casei. AB - The sialidase gene from Brevibacterium casei was cloned in pET28a and overexpressed as a histidine-tagged protein in Escherichia coli BL21(DE3). The histidine-tagged sialidase protein was purified and characterized from the crude cell extracts of isopropyl-beta-d-thiogalactopyranoside-induced cells using Ni NTA agarose chromatography. SDS-PAGE using the purified sialidase indicated a single band at 116 kDa. This sialidase showed maximum activity at a pH of 5.5 and temperature of 37 degrees C. The kinetic parameters Km and Vmax for the artificial substrate 2'-(4-methylumbelliferyl)-alpha-d-N-acetyl-neuraminic acid sodium salt hydrate were 1.69 * 10-3 mM and 244 mmol.Min-1 .mg-1 , respectively. The sialidase may catalyze the hydrolysis of terminal sialic acids linked by the alpha-(2,3) and alpha-(2,8) linkage of polysialogangliosides, but it does not act on monosialotetrahexosylganglioside (GM1), which offers it a great potential for commercially producing GM1 from polysialogangliosides. PMID- 26748451 TI - Solitary trocar laparoscopic loop sigmoid colostomy using the AirSeal IFS system- a video vignette. PMID- 26748452 TI - Highly Convergent Synthesis of Intensively Blue Emissive Furo[2,3-c]isoquinolines by a Palladium-Catalyzed Cyclization Cascade of Unsaturated Ugi Products. AB - A convergent and diversity-oriented approach to the unusual furo[2,3 c]isoquinoline scaffold is presented. This serendipity-driven approach is characterized by an Ugi multicomponent reaction, which gives the substrate for a palladium-catalyzed insertion-alkynylation-cycloisomerization cascade to provide the furo[2,3-c]isoquinolines in moderate to high yield. Upon UV excitation, all representatives are intensively blue luminescent, as observed by the naked eye, and quantitative fluorescence spectroscopy reveals a considerable effect of the substitution pattern on the quantum yields. The electronic structure is semiquantitatively rationalized by DFT and time-dependent DFT calculations. PMID- 26748453 TI - Altered Expression of Growth Associated Protein-43 and Rho Kinase in Human Patients with Parkinson's Disease. AB - Causative treatment strategies for Parkinson's disease (PD) will have to address multiple underlying pathomechanisms to attenuate neurodegeneration. Additionally, the intrinsic regenerative capacity of the central nervous system is also an important factor contributing to restoration. Extracellular cues can limit sprouting and regrowth of adult neurons, but even aged neurons have a low intrinsic regeneration capacity. Whether this capacity has been lost or if growth inhibitory cues are increased during PD progression has not been resolved yet. In this study, we assessed the regenerative potential in the nigrostriatal system in post-mortem brain sections of PD patients compared to age-matched and young controls. Investigation of the expression pattern of the regeneration-associated protein GAP-43 suggested a lower regenerative capacity in nigral dopaminergic neurons of PD patients. Furthermore, the increase in protein expression of the growth-inhibitory protein ROCK2 in astrocytes and a similar trend in microglia, suggests an important role for ROCK2 in glial PD pathology, which is initiated already in normal aging. Considering the role of astro- and microglia in PD pathogenesis as well as beneficial effects of ROCK inhibition on neuronal survival and regeneration in neurodegenerative disease models, our data strengthens the importance of the ROCK pathway as a therapeutic target in PD. PMID- 26748454 TI - Microstructural Changes in High-Protein Nutrition Bars Formulated with Extruded or Toasted Milk Protein Concentrate. AB - Milk protein concentrates with more than 80% protein (that is, MPC80) are underutilized as the primary protein source in high-protein nutrition bars as they impart crumbliness and cause hardening during storage. High-protein nutrition bar texture changes are often associated with internal protein aggregations and macronutrient phase separation. These changes were investigated in model high-protein nutrition bars formulated with MPC80 and physically modified MPC80s. High-protein nutrition bars formulated with extruded MPC80s hardened slower than those formulated with toasted or unmodified MPC80. Extruded MPC80 had reduced free sulfhydryl group exposure, whereas measurable increases were seen in the toasted MPC80. High-protein nutrition bar textural performance may be related to the number of exposed free sulfhydryl groups in MPC80. Protein aggregations resulting from ingredient modification and high-protein nutrition bar storage were studied with sodium dodecyl sulfate polyacrylamide gel electrophoresis. Disulfide-based protein aggregations and changes in free sulfhydryl concentration were not consistently relatable to high-protein nutrition bar texture change. However, the high-protein nutrition bars formulated with extruded MPC80 were less prone to phase separations, as depicted by confocal laser scanning microscopy, and underwent less texture change during storage than those formulated with toasted or unmodified MPC80. PMID- 26748455 TI - Comparative Effectiveness of Second-Generation Antidepressants in Reducing the Risk of Dementia in Elderly Nursing Home Residents with Depression. AB - STUDY OBJECTIVE: Second-generation antidepressants have been shown to improve cognition and depression symptomatology, which are the major risk factors for dementia; however, little is known about the comparative effectiveness of antidepressants in reducing the risk of dementia. Thus, the objective of this study was to evaluate the long-term comparative effectiveness of different antidepressant classes in reducing the risk of dementia in elderly nursing home residents with depression. DESIGN: Propensity score-adjusted retrospective cohort study. DATA SOURCE: Multistate Minimum Data Set-linked Medicare Parts A, B, and D data files. PATIENTS: A total of 25,108 nursing home residents (65 years and older) with a diagnosis of depression and without a dementia diagnosis who were Medicare beneficiaries and new users of selective serotonin reuptake inhibitors (SSRIs; 19,952 [79.5%]), serotonin-norepinephrine reuptake inhibitors (SNRIs; 2381 [9.5%]), or tetracyclic antidepressants (2775 [11.1%]) between 2007 and 2010. MEASUREMENTS AND MAIN RESULTS: New users of SSRIs, SNRIs, and tetracyclics were followed over a 2-year period for the occurrence of dementia. A Cox proportional hazards regression model was used to evaluate the comparative effectiveness of SNRIs and tetracyclics in reducing the risk of dementia, with the SSRI class used as the reference category after controlling for propensity scores and their interactions terms. The unadjusted incidence of dementia was 8.2% for SSRI users, 6.0% for SNRI users, and 7.2% for tetracyclic users. The propensity score-adjusted Cox model did not find any significant difference in the risk of dementia in elderly nursing home residents who used SNRIs (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.84-1.19) or tetracyclics (HR 1.01, 95% CI 0.87-1.17) compared with the SSRI users. CONCLUSION: This study did not find any significant differences in reducing the risk of dementia among the new users of second-generation antidepressant classes. Further studies are needed to evaluate the profiles of second-generation antidepressants on cognition in this vulnerable population. PMID- 26748456 TI - What is resilience? An Integrative Review of the empirical literature. AB - AIM: To use systematic methods to examine how resilience is defined in empirical research. BACKGROUND: Resilience is a term that is increasingly being used to describe and explain the complexities of individual and group responses to traumatic and challenging situations. It is now frequently mentioned in relation to many areas of nursing practice, including research. Given the increasing use of the term, it is timely to examine how resilience has been defined in empirical research. DESIGN: An integrative review of the empirical literature (2000-2015). DATA SOURCES: Three health-related databases were searched: Medline, PsycINFO and the Cumulative Index for Nursing and Allied Health (CINAHL). Reference and citation tracking was performed on all articles included in the review. REVIEW METHODS: The methods described by Whittemore and Knafl were used to guide this review. Two reviewers were involved in screening articles for inclusion and in the data extraction process. Data were synthesized using the constant comparative method of analysis. RESULTS: One hundred articles were included in the final data analysis. The most significant finding of the review was that there is no universal definition of resilience. There were, however, some common themes identified: rising above, adaptation and adjustment, dynamic process, 'ordinary magic' and mental illness as a marker of resilience. CONCLUSION: Despite the increasing use of the term 'resilience', this review has identified that there is no universal definition of resilience adopted in the research literature. Further research is required to explore this construct in the context of nursing. PMID- 26748457 TI - Ineffective quinidine therapy in early onset epileptic encephalopathy with KCNT1 mutation. PMID- 26748458 TI - Bet-hedging as a mechanism for the evolution of polyandry, revisited. AB - Females that mate with multiple males (polyandry) may reduce the risk that their eggs are fertilized by a single unsuitable male. About 25 years ago it was hypothesized that bet-hedging could function as a mechanism favoring the evolution of polyandry, but this idea is controversial because theory indicates that bet-hedging via polyandry can compensate the costs of mating only in small populations. Nevertheless, populations are often spatially structured, and even in the absence of spatial structure, mate-choice opportunity can be limited to a few potential partners. We examined the effectiveness of bet-hedging in such situations with simulations carried out under two scenarios: (1) intrinsic male quality, with offspring survival determined by male phenotype (male's ability to generate viable offspring), and (2) genetic incompatibility (offspring fitness determined nonadditively by parental genotypes). We find higher fixation probabilities for a polyandrous strategy compared to a monandrous strategy if complete reproductive failure due to male effects or parental incompatibility is pervasive in the population. Our results also indicate that bet-hedging polyandry can delay the extinction of small demes. Our results underscore the potential for bet-hedging to provide benefits to polyandrous females and have valuable implications for conservation biology. PMID- 26748459 TI - Caries-preventive self-care for children. Consistent oral health messages to the public? AB - BACKGROUND: Recommendations regarding caries-preventive self-care for children are provided by several health authorities. OBJECTIVE: To investigate recommendations given to the public regarding children's caries-preventive self care by Norwegian dentists, dental hygienists, dental nurses and public health nurses. METHODS: Questionnaires were sent by e-mail and answered by 808 of 1132 persons who provide oral preventive promotion to children in dental services and health centres. The preventive advice was obtained through questions about the preferred preventive methods, fluoride recommendations and sources of knowledge on which the personnel based the advice about caries prevention in children. The responses were analysed using logistic regression. RESULTS: The majority (59-71%) in all professions judged oral hygiene education to be the most important caries preventive method. Most personnel (84-98%) recommended all children to use fluoride toothpaste, and half of all personnel (53%) recommended fluoride lozenges for 50% or more of children. Multivariate analysis showed that dental nurses recommended lozenges to more children than dentists (OR 2.5, 95% CI 1.7 3.7), while health nurses recommended lozenges to fewer children than dentists (OR 0.5, 95% CI 0.3-0.8). The most important source of knowledge reported by dental personnel was professional education, while health nurses relied on information from dental personnel. CONCLUSIONS: Health professions' recommendations regarding caries-preventive self-care for children were mainly similar, although variation existed both between and within professions. Collaboration between professions and awareness of the evidence base for preventive oral care may improve the consistency of information given by health professionals to the public. PMID- 26748460 TI - Effect of dietary fibers on losartan uptake and transport in Caco-2 cells. AB - The objective of this study was to assess the effect of dietary fibers on the transport of losartan, an angiotensin II type 1 receptor blocker, in small intestinal cells. Using Caco-2 cells in vitro, losartan uptake and transport were evaluated in the presence of various fibers (cellulose, chitosan, sodium alginate and glucomannan). Dietary fibers caused a decrease in the uptake of losartan, with chitosan causing a significant reduction. Chitosan and glucomannan significantly reduced the transport of losartan, while cellulose or sodium alginate did not. Dietary fibers also reduced the level of free losartan; however, this did not correlate with the observed reduction in losartan uptake and transport. In summary, chitosan had the greatest inhibitory effect on losartan uptake and transport, and this potential interaction should be considered in patients taking losartan. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26748461 TI - Assembly of an Axially Chiral Dynamic Redox System with a Perfluorobiphenyl Skeleton into Dumbbell- or Tripod-type Electron Donors. AB - The incorporation of F atoms endows a diethenylbiphenyl-based electron donor with configurational stability and SN Ar reactivity. The former enables the dynamic redox pair of (Rax)-1/(Rax ,R,R)-1(2+) to exhibit drastic UV/Vis and CD spectral changes upon electrolysis, whereas the latter makes it possible for (Rax)-1 to serve as a useful chiral synthon for the production of larger assemblies [(Rax ,Rax)-2 d,p,m and (Rax ,Rax ,Rax)-3] containing two or three dyrex units. These dyads and triad also exhibit a clean electrochiroptical response with isosbestic points owing to one-wave multi-electron transfer. PMID- 26748463 TI - Promoting recognition: a personal perspective. PMID- 26748462 TI - Rapid weight gain during early childhood is associated with overweight in preadolescence: a longitudinal study in Japan. AB - BACKGROUND: The objective of this study was to examine the relationship between rapid weight gain during early childhood and overweight in preadolescence by sex. METHOD: Study subjects were 676 boys and 620 girls in fourth grade (aged 9 or 10 years) from elementary schools in Ina-town, Japan, during 2010-2012. Height and weight of subjects at birth, age 1.5 and 3 years, were collected from the Maternal and Child Health Handbook, while values at 9-10 years were measured. Rapid weight gain was defined as a change in weight-for-age standard deviation score greater than 0.67 from birth to age 1.5 years (0-1.5 years) or from age 1.5 to 3 years (1.5-3 years). RESULTS: After adjustment for confounding factors, compared with no rapid weight gain, rapid weight gain during 0-1.5 years and 1.5 3 years or rapid weight gain during 1.5-3 years but not during 0-1.5 years significantly increased the odds ratio (OR) for overweight at age 9-10 years in boys (OR, 6.21; 95% confidence interval [CI], 2.84-13.58 and OR, 3.31; 95% CI, 1.67-6.54, respectively) and girls (OR, 7.55; 95% CI, 2.99-19.07 and OR, 3.42; 95% CI, 1.38-8.49, respectively). CONCLUSION: The present study suggests that rapid weight gain during early childhood was associated with being overweight in preadolescence, regardless of sex. PMID- 26748464 TI - Chrysiasis. PMID- 26748465 TI - Circadian rhythm of salivary cortisol secretion in female zoo-kept African elephants (Loxodonta africana). AB - Salivary samples were collected over a 24-hr period from one group of six juvenile (7-12 years) and one group of three adult (24-25 years) African elephant females, Loxodonta africana, and the cortisol concentration was measured in unextracted samples by EIA. Samples were collected during May, June, and November 2012 (n = 147) using cotton swabs at 4-hr intervals from 20:00 to 20:00 of the next day (seven samples per animal in each trial). The animals are kept under standard zoo management: the herd is maintained in their indoor enclosures until 10:00 and then released into the outdoor enclosures until 21:00-21:30 (May/June) and 18:30-19:00 (November). No adult elephant bull was present at the zoo during this time. The results demonstrate a clear diurnal pattern of cortisol secretion with the lowest concentration observed at 20:00 (2.03 +/- 0.08 ng/ml saliva) and the peak concentrations at 08:00 (5.26 +/- 0.35 ng/ml saliva). Although the cortisol values were higher in the adult cows compared to the juvenile cows in the May-June period, the differences were not significant. However, the values obtained in November from the juvenile group were significantly higher (P < 0.05) than the concentrations measured in this group in June. In conclusion, salivary cortisol in zoo elephants follows a circadian rhythm (sleep-wake cycle) adapted to daily zoo husbandry routines. PMID- 26748466 TI - Soil compost amendment enhances tomato (Solanum lycopersicum L.) quality. AB - BACKGROUND: Tomato (Solanum lycopersicum L.) is one of the most important crops in the world and represents a key crop in southern Italy. With the aim to evaluate the nutritional characteristics of tomato fruits in relation to NPK and compost fertilisation, the concentrations of the main nutrients, toxic elements, primary metabolites and total phenols were determined in two varieties (Lido and San Marzano). Each variety was cultivated in a different experimental field, subjected to different agronomic techniques. RESULTS: Concentrations of toxic elements (Cd and Pb) were below the limits indicated by the EU Regulation (2011) in all the fruits analysed. Moreover, fruits obtained from San Marzano plants grown on organic amended soils showed a better overall quality than those obtained on mineral fertilised soil, being characterised by lower N (attributed to lower nitrate and nitrite concentrations), lower Cd, and higher soluble sugar concentrations. Higher concentrations of soluble sugars in fruits from organic amended soils were also observed in the Lido variety. CONCLUSIONS: The agricultural use of quality compost represents an effective strategy to obtain high quality products in an economically and environmentally sustainable way. (c) 2016 Society of Chemical Industry. PMID- 26748467 TI - Was the Effect of Obesity on the Relative Risk of Replacement Surgery in Knee Osteoarthritis Patients Overestimated? Comment on the Article by Leyland et al. PMID- 26748468 TI - Manual evaluation of tissue microarrays in a high-throughput research project: The contribution of Indian surgical pathology to the Human Protein Atlas (HPA) project. AB - The Human Protein Atlas (HPA) program (www.proteinatlas.org) is an international program that has been set up to allow for a systematic exploration of the human proteome using antibody-based proteomics. This is accomplished by combining high throughput generation of affinity-purified (mono-specific) antibodies with protein profiling in a multitude of tissues/cell types assembled in tissue microarrays. Twenty-six surgical pathologists over a seven-and-half year period have annotated and curated approximately sixteen million tissue images derived from immunostaining of normal and cancer tissues by approximately 23 000 antibodies. Web-based annotation software that allows for a basic and rapid evaluation of immunoreactivity in tissues has been utilized. Intensity, fraction of immunoreactive cells and subcellular localization were recorded for each given cell population. A text comment summarizing the characteristics for each antibody was added. The methods used and the challenges encountered for this exercise, the largest effort ever by a single group of surgical pathologists, are discussed. Manual annotation of digital images is an important tool that may be successfully utilized in high-throughput research projects. This is the first time an Indian private pathology laboratory has been associated with cutting-edge research internationally providing a classic example of developed and emerging nation collaboration. PMID- 26748469 TI - Intracorneal stromal hemorrhage in dogs and its associations with ocular and systemic disease: 39 cases. AB - OBJECTIVE: To describe clinical features of dogs diagnosed with stromal intracorneal hemorrhage (ICH). ANIMALS STUDIED: Retrospective case series of 39 dogs (44 eyes) with ICH. PROCEDURES: Medical records of dogs evaluated by the Cornell University ophthalmology service were searched to identify animals with a clinical diagnosis of ICH between 2005 and 2014. Signalment and clinical details, including concurrent ocular disease, concurrent systemic disease, diagnostic tests performed, outcome of hemorrhage, presenting client complaint, and treatment, were recorded. RESULTS: Intracorneal hemorrhage was identified in 44 eyes of 39 dogs. The mean (+/-standard deviation) age of dogs was 11.5 years (+/ 2.8 years). The Bichon Frise breed and older dogs were statistically over represented relative to the entire ophthalmology service canine referral population during the same time period. Concurrent ocular disease was present in 40 eyes (91%) and included keratoconjunctivitis sicca, cataracts, and corneal ulcers. Twenty-three dogs (59%) suffered from concurrent systemic disease, most frequently diabetes mellitus, hyperadrenocorticism, hypothyroidism, and systemic hypertension. Less commonly, life-threatening systemic conditions were identified in dogs with ICH including immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, metastatic neoplasia, and sepsis. Intracorneal hemorrhage was found in all corneal locations, and corneal vascularization was present in each affected eye. CONCLUSIONS: Intracorneal hemorrhage is an uncommon condition in dogs that occurs in association with corneal vascularization. The risk of ICH may be increased due to certain ocular and systemic diseases. Although uncommon, ICH may also be an ocular manifestation of severe immune-mediated, infectious, and neoplastic systemic diseases in dogs. PMID- 26748470 TI - Patients with large-duct primary sclerosing cholangitis and Crohn's disease have a better outcome than those with ulcerative colitis, or without IBD. AB - BACKGROUND: Approximately 20% of primary sclerosing cholangitis (PSC) patients with concomitant inflammatory bowel disease (IBD) have Crohn's disease (CD). AIM: To compare PSC/CD with other PSC patients. METHODS: Retrospective study of 240 PSC patients diagnosed between 1975 and 2012 (median follow-up 12 years). Activity of PSC at diagnosis was assessed by liver biopsy, Mayo risk and ERC scores. Survival without liver transplantation, number of transplantations and liver-related death were endpoints. RESULTS: Sixty-three per cent of patients had IBD: 105 UC, 32 CD and 14 IBD unclassified (IBDu). IBD was diagnosed before PSC in 50%. The yearly development of PSC after diagnosing IBD was similar in UC, CD or IBDu. Small-duct PSC was present in 28% of PSC/CD compared to 3% of PSC/UC. Small-duct PSC had a markedly better survival than large-duct PSC: no patient developed cholangiocarcinoma or liver-related death, but colorectal cancer occurred in three patients. In large-duct PSC, a more favourable outcome was evident in patients with CD. The liver disease was less progressive: one patient underwent liver transplantation compared to 28% and liver-related deaths were absent compared to 7% in the other PSC groups. CONCLUSIONS: The prevalence of PSC with concomitant Crohn's disease is relatively rare, but the outcome is more benign than PSC with UC or without IBD. Approximately one-fourth has small-duct PSC. In large-duct PSC/CD, liver disease is less aggressive and the outcome is much better. The outcome of PSC patients with UC resembled that of PSC without IBD. PMID- 26748472 TI - Invasive candidiasis in liver transplant patients: Incidence and risk factors in a pediatric cohort. AB - Prolonged OR, re-transplantation, and high-volume intraoperative transfusion have been associated with increased risk for IC in adult LT recipients. Antifungal prophylaxis is recommended for adult patients with these risk factors. There are limited data on the incidence of and risk factors for IC in pediatric LT recipients. A retrospective cohort study of all pediatric LT patients at the CHOP between 2000 and 2012 and the CHP between 2004 and 2012 was performed to define the incidence of IC within 30 days of LT. A 3:1 matched case-control study with incidence density sampling was performed. Conditional logistic regression analyses were used to explore risk factors associated with IC. Among 397 recipients, the incidence of IC was 2.5%. Bivariate analyses showed that ICU admission prior to transplant, OR > 10 h, intraoperative volume infusion of >300 mL/kg, and broad-spectrum antibiotics were significantly associated with IC. In a multivariate model, only ICU admission remained significantly associated with IC. Antifungal prophylaxis was not significantly protective against IC. The low incidence of IC and lack of an identified protective effect from antifungal prophylaxis suggest that prophylaxis in pediatric LT recipients should not be routinely recommended to prevent IC events in the first 30 days post-transplant. PMID- 26748471 TI - Towards higher sensitivity and stability of axon diameter estimation with diffusion-weighted MRI. AB - Diffusion-weighted MRI is an important tool for in vivo and non-invasive axon morphometry. The ActiveAx technique utilises an optimised acquisition protocol to infer orientationally invariant indices of axon diameter and density by fitting a model of white matter to the acquired data. In this study, we investigated the factors that influence the sensitivity to small-diameter axons, namely the gradient strength of the acquisition protocol and the model fitting routine. Diffusion-weighted ex. vivo images of the mouse brain were acquired using 16.4-T MRI with high (Gmax of 300 mT/m) and ultra-high (Gmax of 1350 mT/m) gradient strength acquisitions. The estimated axon diameter indices of the mid-sagittal corpus callosum were validated using electron microscopy. In addition, a dictionary-based fitting routine was employed and evaluated. Axon diameter indices were closer to electron microscopy measures when higher gradient strengths were employed. Despite the improvement, estimated axon diameter indices (a lower bound of ~ 1.8 MUm) remained higher than the measurements obtained using electron microscopy (~1.2 MUm). We further observed that limitations of pulsed gradient spin echo (PGSE) acquisition sequences and axonal dispersion could also influence the sensitivity with which axon diameter indices could be estimated. Our results highlight the influence of acquisition protocol, tissue model and model fitting, in addition to gradient strength, on advanced microstructural diffusion-weighted imaging techniques. (c) 2016 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd. PMID- 26748473 TI - Impact of malnutrition on 12-month mortality following acute hip fracture. AB - BACKGROUND: Studies investigating the relationship between malnutrition and post discharge mortality following acute hip fracture yield conflicting results. This study aimed to determine whether malnutrition independently predicted 12-month post-fracture mortality after adjusting for clinically relevant covariates. METHODS: An ethics approved, prospective, consecutive audit was undertaken for all surgically treated hip fracture inpatients admitted to a dedicated orthogeriatric unit (November 2010-October 2011). The 12-month mortality data were obtained by a dual search of the mortality registry and Queensland Health database. Malnutrition was evaluated using the Subjective Global Assessment. Demographic (age, gender, admission residence) and clinical covariates included fracture type, time to surgery, anaesthesia type, type of surgery, post-surgery time to mobilize and post-operative complications (delirium, pulmonary and deep vein thrombosis, cardiac complications, infections). The Charlson Comorbidity Index was retrospectively applied. All diagnoses were confirmed by the treating orthogeriatrician. RESULTS: A total of 322 of 346 patients were available for audit. Increased age (P = 0.004), admission from residential care (P < 0.001), Charlson Comorbidity Index (P = 0.007), malnutrition (P < 0.001), time to mobilize >48 h (P < 0.001), delirium (P = 0.003), pulmonary embolism (P = 0.029) and cardiovascular complication (P = 0.04) were associated with 12-month mortality. Logistic regression analysis demonstrated that malnutrition (odds ratio (OR) 2.4 (95% confidence interval (CI) 1.3-4.7, P = 0.007)), in addition to admission from residential care (OR 2.6 (95% CI 1.3-5.3, P = 0.005)) and pulmonary embolism (OR 11.0 (95% CI 1.5-78.7, P = 0.017)), independently predicted 12-month mortality. CONCLUSIONS: Findings substantiate malnutrition as an independent predictor of 12-month mortality in a representative sample of hip fracture inpatients. Effective strategies to identify and treat malnutrition in hip fracture should be prioritized. PMID- 26748474 TI - Experimental validation of more realistic computer models for stent-graft repair of abdominal aortic aneurysms, including pre-load assessment. AB - Although the endovascular repair of abdominal aortic aneurysms is a less invasive alternative than classic open surgery, complications such as endoleak and kinking still need to be addressed. Numerical simulation of endovascular repair is becoming a valuable tool in stent-graft (SG) optimization, patient selection and surgical planning. The experimental and numerical forces required to produce SG deformations were compared in a range of in vivo conditions in the present study. The deformation modes investigated were: bending as well as axial, transversal and radial compressions. In particular, an original method was developed to efficiently account for radial pre-load because of the pre-compression of stents to match the graft dimensions during manufacturing. This is important in order to compute the radial force exerted on the vessel after deployment more accurately. Variations of displacement between the experimental and numerical results ranged from 1.39% for simple leg bending to 5.93% for three-point body bending. Finally, radial pre-load was modeled by increasing Young's modulus of each stent. On average, it was found that Young's modulus had to be augmented by a factor of 2. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26748475 TI - PGC-1beta suppresses saturated fatty acid-induced macrophage inflammation by inhibiting TAK1 activation. AB - Inflammation of infiltrated macrophages in adipose tissue is a key contributor to the initiation of adipose insulin resistance. These macrophages are exposed to high local concentrations of free fatty acids (FFAs) and can be proinflammatory activated by saturated fatty acids (SFAs). However, the regulatory mechanisms on SFA-induced macrophage inflammation are still elusive. Peroxisome proliferator activated receptor gamma coactivator-1beta (PGC-1beta) is a member of the PGC-1 family of transcriptional coactivators and has been reported to play a key role in SFAs metabolism and in the regulation of inflammatory signaling. However, it remains unclear whether PGC-1beta is involved in SFA-induced macrophage inflammation. In this study, we found that PGC-1beta expression was significantly decreased in response to palmitic acid (PA) in macrophages in a dose dependent manner. PGC-1beta inhibited PA induced TNFalpha, MCP-1, and IL-1beta mRNA and protein expressions. Furthermore, PGC-1beta significantly antagonized PA induced macrophage nuclear factor-kappaB (NF-kappaB) p65 and JUN N-terminal kinase activation. Mechanistically, we revealed that TGF-beta-activated kinase 1 (TAK1) and its adaptor protein TAK1 binding protein 1 (TAB1) played a dominant role in the regulatory effects of PGC-1beta. We confirmed that PGC-1beta inhibited downstream inflammatory signals via binding with TAB1 and thus preventing TAB1/TAK1 binding and TAK1 activation. Finally, we showed that PGC-1beta overexpression in PA treated macrophages improved adipocytes PI3K-Akt insulin signaling in a paracrine fashion. Collectively, our results uncovered a novel mechanism on how macrophage inflammation induced by SFAs was regulated and suggest a potential target in the treatment of obesity induced insulin resistance. PMID- 26748476 TI - Serum hepatic enzyme activity in relation to semen quality and serum reproductive hormone levels among Estonian fertile Men. AB - The aim of this study was to investigate the relations of basic semen parameters and reproductive hormones with alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT). In addition, to examine possible interaction between adiposity, alcohol consumption, and liver tests in relation to male reproductive health, standard semen analysis was performed and serum levels of reproductive hormones and liver tests were measured in 245 male partners of pregnant women at a University Hospital Andrology Centres in Estonia. Quartile analysis revealed that after adjustment for covariates GGT was negatively related to sperm concentration and total sperm count. These significant changes appeared from a GGT >35.5 U/L. Next to these changes ALT was not related to sperm parameters. Both enzymes, GGT and ALT, were not related to reproductive hormones. Alcohol consumption was positively related to GGT and in cases with elevated GGT alcohol use was negatively related to sperm concentration and total sperm count. Alcohol consumption was positively related to body mass index (BMI) and waist circumference (WC). Our findings also confirm results of previous studies that BMI and WC are associated positively with ALT and GGT. According to the study, increased GGT activity might represent a possible connection between adiposity, alcohol consumption, and semen quality. PMID- 26748477 TI - Increased Conformational Flexibility of HLA-B*27 Subtypes Associated With Ankylosing Spondylitis. AB - OBJECTIVE: Dissimilarities in antigen processing and presentation are known to contribute to the differential association of HLA-B*27 subtypes with the inflammatory rheumatic disease ankylosing spondylitis (AS). In support of this notion, previous x-ray crystallographic data showed that peptides can be displayed by almost identical HLA-B*27 molecules in a subtype-dependent manner, allowing cytotoxic T lymphocytes to distinguish between these subtypes. For example, a human self-peptide derived from vasoactive intestinal peptide receptor type 1 (pVIPR; sequence RRKWRRWHL) is displayed in a single conformation by B*27:09 (which is not associated with AS), while B*27:05 (which is associated with AS) presents the peptide in a dual binding mode. In addition, differences in conformational flexibility between these subtypes might affect their stability or antigen presentation capability. This study was undertaken to investigate B*27:04 and B*27:06, another pair of minimally distinct HLA-B*27 subtypes, to assess whether dual peptide conformations or structural dynamics play a role in the initiation of AS. METHODS: Using x-ray crystallography, we determined the structures of the pVIPR-B*27:04 and pVIPR-B*27:06 complexes and used isotope edited infrared (IR) spectroscopy to probe the dynamics of these HLA-B*27 subtypes. RESULTS: As opposed to B*27:05 and B*27:09, B*27:04 (which is associated with AS) displays pVIPR conventionally and B*27:06 (which is not associated with AS) presents the peptide in a dual conformation. Comparison of the 4 HLA-B*27 subtypes using IR spectroscopy revealed that B*27:04 and B*27:05 possess elevated molecular dynamics compared to the nonassociated subtypes B*27:06 and B*27:09. CONCLUSION: Our results demonstrate that an increase in conformational flexibility characterizes the disease-associated subtypes B*27:04 and B*27:05. PMID- 26748478 TI - Nogo-A controls structural plasticity at dendritic spines by rapidly modulating actin dynamics. AB - Nogo-A and its receptors have been shown to control synaptic plasticity, including negatively regulating long-term potentiation (LTP) in the cortex and hippocampus at a fast time scale and restraining experience-dependent turnover of dendritic spines over days. However, the molecular mechanisms and the precise time course mediating these actions of Nogo-A are largely unexplored. Here we show that Nogo-A signaling in the adult nervous system rapidly modulates the spine actin cytoskeleton within minutes to control structural plasticity at dendritic spines of CA3 pyramidal neurons. Indeed, acute Nogo-A loss-of-function transiently increases F-actin stability and results in an increase in dendritic spine density and length. In addition, Nogo-A acutely restricts AMPAR insertion and mEPSC amplitude at hippocampal synaptic sites. These data indicate a crucial function of Nogo-A in modulating the very tight balance between plasticity and stability of the neuronal circuitry underlying learning processes and the ability to store long-term information in the mature CNS. (c) 2016 Wiley Periodicals, Inc. PMID- 26748480 TI - Re: Letter to editor, Clinical Anatomy. PMID- 26748479 TI - Parathyroid Hormone and the Use of Diuretics and Calcium-Channel Blockers: The Multi-Ethnic Study of Atherosclerosis. AB - Thiazide diuretic (TZ) use is associated with higher bone mineral density, whereas loop diuretic (LD) use is associated with lower bone density and incident fracture. Dihydropyridine-sensitive calcium channels are expressed on parathyroid cells and may play a role in parathyroid hormone (PTH) regulation. The potential for diuretics and calcium-channel blockers (CCBs) to modulate PTH and calcium homeostasis may represent a mechanism by which they influence skeletal outcomes. We hypothesized that the use of LD and dihydropyridine CCBs is associated with higher PTH, and TZ use is associated with lower PTH. We conducted cross-sectional analyses of participants treated for hypertension in the Multi-Ethnic Study of Atherosclerosis who did not have primary hyperparathyroidism or chronic kidney disease (n = 1888). We used adjusted regression models to evaluate the independent association between TZ, LD, and CCB medication classes and PTH. TZ use was associated with lower PTH when compared with non-TZ use (44.4 versus 46.9 pg/mL, p = 0.02), whereas the use of LD and CCBs was associated with higher PTH when compared with non-users of each medication class (LD: 60.7 versus 45.5 pg/mL, p < 0.0001; CCB: 49.5 versus. 44.4 pg/mL, p < 0.0001). Adjusted regression models confirmed independent associations between TZ use and lower PTH (beta = 3.2 pg/mL, p = 0.0007), and LD or CCB use and higher PTH (LD: beta = +12.0 pg/mL, p < 0.0001; CCB: +3.7 pg/mL, p < 0.0001). Among CCB users, the use of dihydropyridines was independently associated with higher PTH (beta = +5.0 pg/mL, p < 0.0001), whereas non-dihydropyridine use was not (beta = +0.58 pg/mL, p = 0.68). We conclude that in a large community-based cohort with normal kidney function, TZ use is associated with lower PTH, whereas LD and dihydropyridine CCB use is associated with higher PTH. These associations may provide a mechanistic explanation linking use of these medications to the development of skeletal outcomes. (c) 2016 American Society for Bone and Mineral Research. PMID- 26748482 TI - Nanoscale Engineering of Designer Cellulosomes. AB - Biocatalysts showcase the upper limit obtainable for high-speed molecular processing and transformation. Efforts to engineer functionality in synthetic nanostructured materials are guided by the increasing knowledge of evolving architectures, which enable controlled molecular motion and precise molecular recognition. The cellulosome is a biological nanomachine, which, as a fundamental component of the plant-digestion machinery from bacterial cells, has a key potential role in the successful development of environmentally-friendly processes to produce biofuels and fine chemicals from the breakdown of biomass waste. Here, the progress toward so-called "designer cellulosomes", which provide an elegant alternative to enzyme cocktails for lignocellulose breakdown, is reviewed. Particular attention is paid to rational design via computational modeling coupled with nanoscale characterization and engineering tools. Remaining challenges and potential routes to industrial application are put forward. PMID- 26748481 TI - Effect of boron oxide addition on the viscosity-temperature behaviour and structure of phosphate-based glasses. AB - In this study, nine phosphate-based glass formulations from the system P2 O5 -CaO Na2 O-MgO-B2 O3 were prepared with P2 O5 content fixed as 40, 45 and 50 mol%, where Na2 O was replaced by 5 and 10 mol% B2 O3 and MgO and CaO were fixed to 24 and 16 mol%, respectively. The effect of B2 O3 addition on the viscosity temperature behaviour, fragility index and structure of the glasses was investigated. The composition of the glasses was confirmed by ICP-AES. The viscosity-temperature behaviour of the glasses were measured using beam-bending and parallel -plate viscometers. The viscosity of the glasses investigated was found to shift to higher temperature with increasing B2 O3 content. The kinetic fragility parameter, m and F1/2 , estimated from the viscosity curve were found to decease with increasing B2 O3 content. The structural analysis was achieved by a combination of Fourier transform infrared spectroscopy and solid state nuclear magnetic resonance. 31 P solid-state magic-angle-spinning nuclear magnetic resonance (MAS-NMR) showed that the local structure of the glasses changes with increasing B2 O3 content. As B2 O3 was added to the glass systems, the phosphate connectivity increases as the as the Q1 units transforms into Q2 units. The 11 B NMR results confirmed the presence of tetrahedral boron (BO4 ) units for all the compositions investigated. Structural analysis indicates an increasing level of cross-linking with increasing B2 O3 content. Evidence of the presence of P-O-B bonds was also observed from the FTIR and 31 P NMR analysis. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 764-777, 2017. PMID- 26748483 TI - Modeling Two-Channel Speech Processing With the EPIC Cognitive Architecture. AB - An important application of cognitive architectures is to provide human performance models that capture psychological mechanisms in a form that can be "programmed" to predict task performance of human-machine system designs. Although many aspects of human performance have been successfully modeled in this approach, accounting for multitalker speech task performance is a novel problem. This article presents a model for performance in a two-talker task that incorporates concepts from psychoacoustics, in particular, masking effects and stream formation. PMID- 26748486 TI - Effects of thinning on scatter-hoarding by rodents in temperate forest. AB - Deforestation and thinning are human activities that can destabilize the forest ecological system and, consequently, impact significantly on habitat and behavior of forest-dwelling animals. This hypothesis was tested in Yugong in the Mount Taihangshan area by comparing the tracks of tagged seeds of Armeniaca sibirica. in sites of unthinned and thinned forests. Our results showed that: (i) the diversity of vegetation and rodents drastically reduced in sites with thinned forests, compared to unthinned sites; (ii) the amount of both removed and scatter hoarded seeds significantly declined in sites with thinned forests, compared with the unthinned sites; (iii) there was no significant difference observed in the distance of seed dispersal between the thinned and unthinned areas; and (iv) the thinning did not show a significant change to the model of cache size. These results suggested that the thinning of forests negatively influenced the species richness and food-hoarding behavior of rodents. In addition, the results indicated that the weakened scattered-hoarding might be disadvantageous to seedling recruitment and forest restoration. PMID- 26748484 TI - Thrombopoietin/TGF-beta1 Loop Regulates Megakaryocyte Extracellular Matrix Component Synthesis. AB - Extracellular matrix (ECM) components initiate crucial biochemical and biomechanical cues that are required for bone marrow homeostasis. In our research, we prove that a peri-cellular matrix composed primarily of type III and type IV collagens, and fibronectin surrounds human megakaryocytes in the bone marrow. The data we collected support the hypothesis that bone marrow megakaryocytes possess a complete mechanism to synthesize the ECM components, and that thrombopoietin is a pivotal regulator of this new function inducing transforming growth factor-beta1 (TGF-beta1) release and consequent activation of the downstream pathways, both in vitro and in vivo. This activation results in a dose dependent increase of ECM component synthesis by megakaryocytes, which is reverted upon incubation with JAK and TGF-beta1 receptor specific inhibitors. These data are pivotal for understanding the central role of megakaryocytes in creating their own regulatory niche within the bone marrow environment. PMID- 26748487 TI - The effects of proton pump inhibitors on autonomic tone in patients with erosive and non-erosive esophagitis. AB - BACKGROUND: Reduction in autonomic tone as measured by heart rate variability (HRV) has been associated with various inflammatory conditions including reflux disease. The nature of and permanence of this damage have not been fully assessed. METHODS: Fourteen individuals with non-erosive reflux disease (NERD) and 10 individuals with erosive reflux disease (ERD) as identified on endoscopy were assessed for HRV prior to starting a course of proton pump inhibitor (PPI) therapy and 8 weeks from the start of PPI therapy. KEY RESULTS: Reflux symptoms were significantly improved by PPI therapy (p = 0.001), with no significant difference in reflux symptoms between the NERD and ERD groups either before (p = 0.45) or following therapy (p = 0.17). The ERD group displayed reduced HRV prior to PPI therapy as compared with a non-symptomatic group. There was significant improvement of HRV resulting from PPI therapy in the ERD group as measured by inspiration/expiration ratio on forced breathing (p = 0.02), Valsalva ratio (p = 0.03), and extended metronome-guided breathing at 6 breaths per minute (p = 0.03). While a similar pattern was seen in the NERD group, the effects were not as strong and did not reach statistical significance. CONCLUSIONS & INFERENCES: The results are consistent with a growing body of evidence that cardiac autonomic neuropathy as measured by HRV is associated with gastro-esophageal reflux disease and also suggest that successful treatment of the inflammation can lead to reversal of the deterioration of autonomic tone associated with that inflammation. PMID- 26748488 TI - Combining classical molecular dynamics and quantum mechanical methods for the description of electronic excitations: The case of carotenoids. AB - Carotenoids are important actors both in light-harvesting (LH) and in photoprotection functions of photosynthetic pigment-protein complexes. A deep theoretical investigation of this multiple role is still missing owing to the difficulty of describing the delicate interplay between electronic and nuclear degrees of freedom. A possible strategy is to combine accurate quantum mechanical (QM) methods with classical molecular dynamics. To do this, however, accurate force-fields (FF) are necessary. This article presents a new FF for the different carotenoids present in LH complexes of plants. The results show that all the important structural properties described by the new FF are in very good agreement with QM reference values. This increased accuracy in the simulation of the structural fluctuations is also reflected in the description of excited states. Both the energy order and the different nature of the lowest singlet states are preserved during the dynamics when the new FF is used, whereas an unphysical mixing is found when a standard FF is used. PMID- 26748489 TI - Implementing a blood management protocol during the entire perioperative period allows a reduction in transfusion rate in major orthopedic surgery: a before after study. AB - BACKGROUND: Patient blood management (PBM) must be promoted in orthopedic surgery and relies on different strategies implemented during the entire perioperative period. Our aim was to assess whether the introduction of a pre-, intra-, and postoperative PBM protocol combining erythropoietin (EPO), ferric carboxymaltose (FCM), and tranexamic acid was effective in reducing perioperative transfusion and postoperative anemia. STUDY DESIGN AND METHODS: In a two-phase prospective observational study, all patients admitted for total hip or knee arthroplasty were included the day before surgery. In Phase 1, use of EPO, iron, and tranexamic acid was left to the discretion of the anesthesiologists. In Phase 2, a protocol combining these treatments was implemented in the perioperative period. Perioperative hemoglobin levels and transfusion rates were recorded. RESULTS: A total of 367 patients were included (184 and 183 in Phase 1 and 2, respectively). During Phase 2, implementing a PBM protocol allowed an increase in preoperative EPO prescription in targeted patients (i.e., with Hb < 13 g/dL; 18 [38%] vs. 34 [62%], p = 0.03) and in postoperative use of intravenous iron (12 [6%] vs. 32 [18%], p = 0.001) and tranexamic acid (157 [86%] vs. 171 [94%] patients, p = 0.02). In Phase 2, the number of patients who received transfusions (24 [13%] vs. 5 [3%], p = 0.0003) and of patients with a Hb level of less than 10 g/dL at discharge (46 [25%] vs. 26 [14%], p = 0.01) were reduced. CONCLUSION: Introduction of a PBM protocol, using EPO, FCM, and tranexamic acid, reduces the number of perioperative transfusions and of patients with a Hb level of less than 10 g/dL at discharge. PMID- 26748490 TI - What is the role of the 11- to 14-week ultrasound in women with negative cell free DNA screening for aneuploidy? AB - OBJECTIVE: This study aimed to examine the role of the 11- to 14-week ultrasound in women with negative cell-free DNA screening. METHODS: A retrospective cohort study of women at increased risk for aneuploidy based on age or medical history and negative cell-free DNA screening between March 2012 and March 2014 was conducted. Patients were included if they had an 11- to 14-week ultrasound and obstetrical care at our center(s). Primary outcome was an unexpected finding at ultrasound. Imaging findings were compared with obstetrical outcome by medical record review. RESULTS: Study group was composed of 1739 patients. An unexpected finding was identified in 60/1739 (3.5%). An abnormal fetal finding occurred in 37 living fetuses (2.1%); 33 had a nuchal translucency (NT) >= 3 mm, including four 'isolated' cystic hygroma and three with a structural abnormality. Four fetuses had a structural anomaly without a thick NT. Karyotype confirmed euploidy in 98.7% of available cases. Pregnancy termination was chosen by 63.6% of those with cystic hygroma or anomaly at the 11- to 14-week scan. Unexpected multiples were identified in 13 (0.7%) women and a fetal demise in 10 (0.6%). CONCLUSION: Unexpected findings at the 11- to 14-week scan occur in 3.5% of patients with negative cell-free DNA. Recognition provides options for comprehensive testing, consultation, and management. PMID- 26748491 TI - Use of robot-specific resources and operating room times: the case of Telelap Alf X robotic hysterectomy. AB - INTRODUCTION: The aim of this study was to identify, quantify and evaluate the use of robotic materials and operating theatre times in Telelap ALF-X robotic hysterectomy. MATERIALS AND METHODS: Cost analysis was performed on 81 patients who underwent a Telelap ALF-X robotic hysterectomy. Data were collected during a phase II study trial conducted at the University Hospital A. Gemelli, Catholic University, Rome. According to micro-costing technique, surgical team costs, materials and operating theatre usage were recorded during each surgical intervention. Cost data were provided by the hospital's accounting office. Probabilistic sensitivity analysis was carried out in order to test the robustness of the results by assuming an Inv-norm random variable. RESULTS: The base case analysis showed a cost/patient of ?3391.82. The new robotic device requires a low consumption of robotic materials. Sensitivity analysis showed that the most sensitive cost driver was use of the operating theatre. CONCLUSION: This study shows that Telelap ALF-X robotic hysterectomy is feasible and safe and could offer specific advantages in terms of cost. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26748492 TI - Unprovoked venous thromboembolism and subsequent cancer risk: a population-based cohort study. AB - ESSENTIALS: A relationship between unprovoked venous thromboembolism (VTE) and cancer risk was investigated. We collected 27,751 VTE patients and compared them with 110,409 frequency-matched people without VTE. This cohort study showed significantly higher risks of overall and site-specific cancers in the VTE group. There is an increased risk in the first 6 months after VTE, and VTE can be an indicator of occult cancer. SUMMARY: BACKGROUND: We investigated the relationship between unprovoked venous thromboembolism (VTE) and subsequent cancer risk in Taiwan, focusing on both short-term and long-term cancer development. METHODS: For the case group, we obtained data on 27,751 patients diagnosed with unprovoked VTE between 1 January 1998, and 31 December 2008. For the comparison group, four people without unprovoked VTE were frequency-matched with each unprovoked VTE patient according to age, sex, and index year. Cox proportional hazards regression models were employed to determine the effects of unprovoked VTE on cancer risk. RESULTS: Overall cancer risk was significantly higher in the unprovoked VTE group than in the comparison group (adjusted hazard ratio = 2.26, 95% confidence interval = 2.16-2.37). The increased risk was observed in both men and women in various age groups. The patients in the unprovoked VTE group showed a significantly increased risk of cancer at all site specific cancer sites. Analyses stratified according to follow-up duration revealed that significant differences were more evident between the two groups over a follow-up duration of < 0.5 years than over a follow-up duration of >= 3 years. Furthermore, the 1-year mortality risk of cancer patients with unprovoked VTE was significantly higher than that for cancer patients in the non-VTE group. CONCLUSION: The results of this study show that unprovoked VTE is associated with a consistently high risk of subsequent cancer diagnosis. This is particularly true in the first 6 months after VTE. It suggests that unprovoked VTE can be an indicator of occult malignancy. PMID- 26748493 TI - Is Sentinel Lymph Node Biopsy Necessary in Patients Undergoing Prophylactic Mastectomy? A Systematic Review and Meta-Analysis. AB - The gain by performing sentinel lymph node biopsy (SLNB) during prophylactic mastectomy (PM) is debatable, and we performed a meta-analysis of existing literature to evaluate that the role of SLNB in subjects undergoing PM. A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane library, Google Scholar, Science Direct, and Web of Science. The search identified 11 relevant articles reporting on patients who underwent SLNB at the time of PM. Data were abstracted from each study and used to calculate a pooled odds ratio (OR) and 95% confidence interval (95% CI). We included 14 studies comprising of 2,708 prophylactic mastectomies. Among 2,708 prophylactic mastectomies, the frequency of occult invasive cancer (51 cases) was 1.8% and the rate of positive SLNs (33 cases) was 1.2%. In 25 invasive cancers at the time of PM were found to have negative SLNs which avoided axillary lymph node dissection (ALND). In seven cases with positive SLNBs were found not to have invasive cancer at the time of PM and needed a subsequent ALND. Most of the patients with positive SLNs had locally advanced disease in the contralateral breast. SLNB may be suitable for patients with ipsilateral, locally advanced breast cancer and is not recommend for all patients undergoing PM. PMID- 26748494 TI - Patient-Centered Dialysis Care: Depression, Pain, and Quality of Life. AB - Remarkable advancements have been made in the provision of chronic dialysis therapy since its inception decades ago. A series of studies inform current dialysis dosing recommendations, while advancements in strategies to treat mineral and bone disease, acid-base and electrolyte disturbances, and anemia have facilitated the management of these well-recognized complications of ESRD. The collective result has been a model of chronic dialysis care focused principally on the achievement of metabolic and dialysis-related targets. In fact, guidelines such as the Kidney Disease Outcomes Quality Initiative put forth by the National Kidney Foundation recommend metrics that characterize successful dialysis care, including the attainment of specific solute clearance targets; maintenance of hemoglobin, calcium, phosphorous, and parathyroid hormone levels within target ranges; and the preferred use of primary arteriovenous fistulae for vascular access. This focus on serologic and dialysis-specific outcomes has helped renal providers manage the biochemical effects related to the loss of kidney function and has reduced ESRD-related morbidity and mortality. Yet, absent from this model of care is an emphasis on the treatment of bothersome symptoms and the impact of such treatment on quality of life (QOL). Among the many symptoms that affect patients on chronic dialysis, depression and pain are particularly common, strongly associated with decrements in QOL, and potentially treatable. This review discusses key research findings and unanswered questions pertaining to the prevalence, significance, and treatment of depression and pain and the effect of such treatment on QOL in patients dependent on chronic dialysis, with the broad goal of incorporating symptom management strategies into a paradigm of patient centered dialysis care. PMID- 26748495 TI - Utilization of palliative radiotherapy for bone metastases near end of life in a population-based cohort. AB - BACKGROUND: Palliative radiotherapy (PRT) can significantly improve quality of life for patients dying of cancer with bone metastases. However, an aggressive cancer treatment near end of life is an indicator of poor-quality care. But the optimal rate of overall palliative RT use near the end of life is still unknown. We sought to determine the patterns of palliative radiation therapy (RT) utilization in patients with bone metastases towards their end of life in a population-based, publicly funded health care system. METHODS: All consecutive patients with bone metastases treated with RT between 2007 and 2011 were identified in a provincial Canadian cancer registry database. Patients were categorized as receiving RT in the last 2 weeks, 2-4 weeks, or >4 weeks before their death. Associations between RT fractionation utilization by these categories, and patient and provider characteristics were assessed through logistic regression. RESULTS: Of the 16,898 courses 1734 (10.3) and 709 (4.2%) were prescribed to patients in the last 2-4 weeks and <2 weeks of their life, respectively. Primary lung (8%) and gastrointestinal (6.9%) cancers received palliative RT more commonly in the last 2 weeks of life (OR 3.72 [2.86-4.84] & 3.33 [2.42-4.58] respectively, p <0.001). Among the 709 patients who received RT in the last 2 weeks of life, 350 (49), 167 (24), and 127 (18%) were for spine, pelvis, and extremity metastases, respectively. RT was prescribed most frequently to spine (5%) and extremity (4%) metastases p <0.001 in the last two weeks of life, though only varied between 1% (sternum) and 5% (spine) by site of metastases. Single fraction RT was prescribed more commonly in the last 2 weeks of life (64.2%), compared to individuals who received RT 2-4 weeks (54.5), and >4 weeks (47.9%) before death (p <0.001). CONCLUSIONS: This population-based analysis found that only 4% of patients with bone metastases received radiation therapy during the last 2 weeks of their life in our population-based, publicly funded program, though it was significantly higher in patients with lung cancer and those with metastases to the spine or extremity. Appropriately, use of multiple fractions palliative RT was less common in patients closer to death. PMID- 26748497 TI - Assessment of Cognitive Function After Critical Care: Potential Issues. PMID- 26748496 TI - MR-proANP, MR-proADM, and PCT in Patients Presenting with Acute Dyspnea in a Medical Emergency Unit. AB - BACKGROUND: The evaluation of the role of novel biomarkers in the management of cardiac and pulmonary conditions has received particular attention in recent years. A further particular perspective is the use of biomarker panels in the evaluation of patients presenting with acute dyspnea. METHODS: We prospectively evaluated three biomarkers (MR-proANP, PCT, and MR-proADM) in consecutive patients presenting with acute dyspnea in a medical emergency unit during a 4 week period. Patients received a final diagnosis. Biomarkers were tested for their potential to predict diagnoses and survival. No intervention was done. RESULTS: Overall, n = 172 patients were included. Of these, 32.6 % had acute heart failure, 16.9 % pneumonia, and 5.8 % died. MR-proANP was the highest in patients with acute heart failure and lung embolism. Dyspnea scores and levels of MR-pro-ANP correlated positively. MR-proANP achieved an AUC of 0.83 for the diagnosis of acute heart failure. Using a cut-off of 120 pmol/l, sensitivity was 91.1 % and specificity 50 %. PPV was 46.8 % and NPV 92.1 %. In patients with MR proANP >300 pmol/l, PPV raised to 67.3 %. MR-proADM had an AUC of 0.84 for the prediction of death. PPV was 16 % and NPV 98.4 %. The AUC of PCT was 0.74 for the diagnosis of pneumonia. Using a cut-off of 0.25 ng/ml, PCT had a sensitivity of 44.8 % and a specificity of 85.3 %. PPV was 38.2 and NPV 88.4 %. Using a lower cut-off of <0.1 ng/ml, NPV reached 92.9 %. CONCLUSIONS: A panel of three biomarkers (MR-proANP, PCT, and MR-proADM) in patients presenting to the emergency unit with acute dyspnea provides information about the probability of acute heart failure, nonsurvival, and pneumonia. These biomarkers achieve low to moderate positive predictive values (PPV) and high negative predictive values (NPV). PMID- 26748498 TI - Chronic Thromboembolic Pulmonary Hypertension: Experience from a Single Center in Mexico. AB - INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by precapillary pulmonary hypertension secondary to vaso-occlusive pulmonary vasculopathy and is classified as Pulmonary Hypertension Group 4. The aim of this study is to report the clinical experience of CTEPH in Mexico. METHODS: Consecutive patients diagnosed with CTEPH were identified from the Registro de Pacientes con Hipertension Pulmonar del Instituto de Seguridad y Servicio Social de los Trabajadores del Estado (REPHPISSSTE) registry between January 2009 and February 2014. Right heart catheterization was not routinely performed prior to August 2010 in the work-up of CTEPH. RESULTS: We identified 50 patients with CTEPH; their median age was 63 years and 58 % were female. Patients had multiple associated co-morbidities and moderate hemodynamic impairment. All patients were treated with anticoagulation. Despite surgical evaluation for pulmonary endarterectomy (PEA), only one patient underwent PEA given the lack of infrastructure for post-operative care and lack of insurance for this procedure. Most of the patients were treated with sildenafil, bosentan, or both, with increasing use of rivaroxaban and sildenafil in recent years. The overall survival of the cohort was similar to that reported in other international registries, despite the limitations of care imposed by drug availability and surgical feasibility. CONCLUSION: This is the first report on the CTEPH experience in Mexico. It highlights the similarity of patients in the REPHPISSSTE registry to those in international registries as well as the challenges that clinicians face in a resource-limited setting. PMID- 26748499 TI - Microbial Signatures of Cadaver Gravesoil During Decomposition. AB - Genomic studies have estimated there are approximately 10(3)-10(6) bacterial species per gram of soil. The microbial species found in soil associated with decomposing human remains (gravesoil) have been investigated and recognized as potential molecular determinants for estimates of time since death. The nascent era of high-throughput amplicon sequencing of the conserved 16S ribosomal RNA (rRNA) gene region of gravesoil microbes is allowing research to expand beyond more subjective empirical methods used in forensic microbiology. The goal of the present study was to evaluate microbial communities and identify taxonomic signatures associated with the gravesoil human cadavers. Using 16S rRNA gene amplicon-based sequencing, soil microbial communities were surveyed from 18 cadavers placed on the surface or buried that were allowed to decompose over a range of decomposition time periods (3-303 days). Surface soil microbial communities showed a decreasing trend in taxon richness, diversity, and evenness over decomposition, while buried cadaver-soil microbial communities demonstrated increasing taxon richness, consistent diversity, and decreasing evenness. The results show that ubiquitous Proteobacteria was confirmed as the most abundant phylum in all gravesoil samples. Surface cadaver-soil communities demonstrated a decrease in Acidobacteria and an increase in Firmicutes relative abundance over decomposition, while buried soil communities were consistent in their community composition throughout decomposition. Better understanding of microbial community structure and its shifts over time may be important for advancing general knowledge of decomposition soil ecology and its potential use during forensic investigations. PMID- 26748502 TI - A case report of rod migration into cerebellum through foramen magnum after lateral mass fixation of cervical spine. AB - We report on a rare case of connecting rod migration into the posterior cranial fossa after posterior cervical decompression and lateral mass screw fixation. A 55-year-old male patient who was operated on for ossification of posterior longitudinal ligament complained of sudden-onset giddiness followed by loss of consciousness one and half year following surgery. CT scan showed migration of left-sided connecting rod into the right cerebellum through foramen magnum. The patient was operated on for rod removal but he sustained a cardiorespiratory arrest and died on the eighth postoperative day. Autopsy confirmed damage to the right cerebellum due to rod migration. The clinician should be aware that superior rod migration is a rare but potentially disastrous complication. Regular follow-up with radiological evaluation should be done to look for implant loosening, migration, and non-union even in asymptomatic patients. The implant should be subsequently removed after it has served its purpose. PMID- 26748501 TI - Comparison between paricalcitol and active non-selective vitamin D receptor activator for secondary hyperparathyroidism in chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials. AB - PURPOSE: The goal of this systematic review is to evaluate the efficacy and safety of paricalcitol versus active non-selective vitamin D receptor activators (VDRAs) for secondary hyperparathyroidism (SHPT) management in chronic kidney disease (CKD) patients. METHODS: PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), clinicaltrials.gov (inception to September 2015), and ASN Web site were searched for relevant studies. A meta-analysis of randomized controlled trials (RCTs) and quasi-RCTs that assessed the effects and adverse events of paricalcitol and active non-selective VDRA in adult CKD patients with SHPT was performed using Review Manager 5.2. RESULTS: A total of 10 trials involving 734 patients were identified for this review. The quality of included trials was limited, and very few trials reported all-cause mortality or cardiovascular calcification without any differences between two groups. Compared with active non-selective VDRAs, paricalcitol showed no significant difference in both PTH reduction (MD -7.78, 95% CI -28.59-13.03, P = 0.46) and the proportion of patients who achieved the target reduction of PTH (OR 1.27, 95% CI 0.87-1.85, P = 0.22). In addition, no statistical differences were found in terms of serum calcium, episodes of hypercalcemia, serum phosphorus, calcium * phosphorus products, and bone metabolism index. CONCLUSIONS: Current evidence is insufficient, showing paricalcitol is superior to active non-selective VDRAs in lowering PTH or reducing the burden of mineral loading. Further trials are required to prove the tissue-selective effect of paricalcitol and to overcome the limitation of current research. PMID- 26748500 TI - Significance and Roles of Proteus spp. Bacteria in Natural Environments. AB - Proteus spp. bacteria were first described in 1885 by Gustav Hauser, who had revealed their feature of intensive swarming growth. Currently, the genus is divided into Proteus mirabilis, Proteus vulgaris, Proteus penneri, Proteus hauseri, and three unnamed genomospecies 4, 5, and 6 and consists of 80 O antigenic serogroups. The bacteria are known to be human opportunistic pathogens, isolated from urine, wounds, and other clinical sources. It is postulated that intestines are a reservoir of these proteolytic organisms. Many wild and domestic animals may be hosts of Proteus spp. bacteria, which are commonly known to play a role of parasites or commensals. However, interesting examples of their symbiotic relationships with higher organisms have also been described. Proteus spp. bacteria present in soil or water habitats are often regarded as indicators of fecal pollution, posing a threat of poisoning when the contaminated water or seafood is consumed. The health risk may also be connected with drug-resistant strains sourcing from intestines. Positive aspects of the bacteria presence in water and soil are connected with exceptional features displayed by autochthonic Proteus spp. strains detected in these environments. These rods acquire various metabolic abilities allowing their adaptation to different environmental conditions, such as high concentrations of heavy metals or toxic substances, which may be exploited as sources of energy and nutrition by the bacteria. The Proteus spp. abilities to tolerate or utilize polluting compounds as well as promote plant growth provide a possibility of employing these microorganisms in bioremediation and environmental protection. PMID- 26748503 TI - "Intrasellar Balloon Technique" in intraoperative MRI guided transsphenoidal endoscopic surgery for sellar region tumors. Usefulness on image interpretation and extent of resection evaluation. Technical note. AB - BACKGROUND: Intraoperative magnetic resonance imaging (iMRI) is an effective and proven tool in transsphenoidal endoscopic surgery. However, image interpretation is not always easy and can be hindered by the presence of blood, tumor remains or the displacement of surrounding structures. In this article we present a novel technique based on using intrasellar ballons to reduce these difficulties and facilitate the surgeon's intraoperative assessment by iMRI. METHODS: Eighteen patients with pituitary macroadenomas underwent transsphenoidal surgery during 2013-2014 under low-field iMRI control (PoleStar N20, 0.15 T). Intrasellar balloons were used in all of them to assess the presence of tumoral remnants. We compared the findings in iMRI and postoperative high-field MRI control scans and also analyzed the number of intermediate imaging controls needed during surgery using this technique. RESULTS: In total, of the 18 patients, 14 underwent a complete resection. In the remaining four patients, a safe maximal resection was performed, leaving a remnant because of cavernous sinus invasion. In all cases, the balloons were a major help in distinguishing the anatomical structures from the tumoral remnants. Fewer imaging controls were required, and there were no false-positives or negative intraoperative findings. No complications related to the technique were registered. CONCLUSION: The "intrasellar balloon technique" is a useful tool that facilitates surgeons' intraoperative decision making. It is an important contribution to overcome the limitations of low-field iMRI as it provides a precise delineation of the resection margins, reduces false-positives and -negatives, and decreases the number of intermediate imaging controls required. PMID- 26748504 TI - Searchlight phenomenon: a novel artifact of the gallbladder. AB - BACKGROUND: "Searchlight phenomenon" is an ultrasound artifact that appears as thin, bright, and posteriorly extending lines in the gallbladder lumen. It mimicks the comet-tail artifact, but it does not decrease in intensity in the depth of the view field, unlike the comet-tail artifact. PURPOSE: To determine the mechanism of this unpublished ultrasound artifact on the basis of clinical ultrasound images as well as using an in vitro system. MATERIALS AND METHODS: (1) CLINICAL STUDY: to determine the detection rate of the searchlight phenomenon in 453 subjects with a normal abdominal US examination result according to the medical chart. We also analyzed the appearance of the searchlight phenomenon in which US showed the searchlight phenomenon in the gallbladder. (2) Basic study: we placed a thin (thickness: 12 MUm) polyethylene membrane at the depth of 2.5 cm from the transducer inside a water bath. Then, we inserted air bubbles (50-400 MUm) below the membrane and observed when the ring-down artifact and searchlight phenomenon appeared. RESULTS: (1) CLINICAL STUDY: the searchlight phenomenon was observed in 30 out of 453 (6.6 %) subjects. When the searchlight phenomenon was seen, duodenal gas was present dorsally in the same line of sight, and the searchlight phenomenon appeared only when duodenal gas was accompanied by the ring-down artifact on US. (2) Basic study: a stepwise increase in the number of air bubbles gave rise to (a) multiple echo spots (single layer of air bubbles), (b) ring-down artifact (two layers), and (c) ring-down artifact below the membrane and searchlight phenomenon in front of the membrane simultaneously. The ring-down artifact and searchlight phenomenon always appeared in the same line of sight. CONCLUSION: The searchlight phenomenon is thought to be a range-ambiguity artifact of the ring-down artifact. Duodenal gas is thought to give rise to this artifact. When examining the gallbladder with ultrasound, knowledge of many artifacts including the searchlight phenomenon can prevent us from making a hazardous misdiagnosis. PMID- 26748505 TI - Social Media Mining for Toxicovigilance: Automatic Monitoring of Prescription Medication Abuse from Twitter. AB - INTRODUCTION: Prescription medication overdose is the fastest growing drug related problem in the USA. The growing nature of this problem necessitates the implementation of improved monitoring strategies for investigating the prevalence and patterns of abuse of specific medications. OBJECTIVES: Our primary aims were to assess the possibility of utilizing social media as a resource for automatic monitoring of prescription medication abuse and to devise an automatic classification technique that can identify potentially abuse-indicating user posts. METHODS: We collected Twitter user posts (tweets) associated with three commonly abused medications (Adderall((r)), oxycodone, and quetiapine). We manually annotated 6400 tweets mentioning these three medications and a control medication (metformin) that is not the subject of abuse due to its mechanism of action. We performed quantitative and qualitative analyses of the annotated data to determine whether posts on Twitter contain signals of prescription medication abuse. Finally, we designed an automatic supervised classification technique to distinguish posts containing signals of medication abuse from those that do not and assessed the utility of Twitter in investigating patterns of abuse over time. RESULTS: Our analyses show that clear signals of medication abuse can be drawn from Twitter posts and the percentage of tweets containing abuse signals are significantly higher for the three case medications (Adderall((r)): 23 %, quetiapine: 5.0 %, oxycodone: 12 %) than the proportion for the control medication (metformin: 0.3 %). Our automatic classification approach achieves 82 % accuracy overall (medication abuse class recall: 0.51, precision: 0.41, F measure: 0.46). To illustrate the utility of automatic classification, we show how the classification data can be used to analyze abuse patterns over time. CONCLUSION: Our study indicates that social media can be a crucial resource for obtaining abuse-related information for medications, and that automatic approaches involving supervised classification and natural language processing hold promises for essential future monitoring and intervention tasks. PMID- 26748506 TI - Post-Marketing Benefit-Risk Assessment of Rotavirus Vaccination in Japan: A Simulation and Modelling Analysis. AB - INTRODUCTION: RotarixTM, GSK's live attenuated rotavirus vaccine, was introduced in Japan in 2011. A recent trend in reduction of rotavirus gastroenteritis (RVGE) due to this vaccine was described. However, an observed/expected analysis showed a temporal association with intussusception within 7 days post dose 1. OBJECTIVE: In this paper, we compare the benefit and risk of vaccination side-by-side in a benefit-risk analysis. METHODS: The number of vaccine-preventable RVGE-associated hospitalizations and deaths (benefit) and intussusception-associated hospitalizations and deaths (risk) following two doses of RotarixTM in Japan was compared using simulations. Source data included peer-reviewed clinical and epidemiological publications, Japanese governmental statistics (Statistics Bureau, Ministry of Internal Affairs and Communications), and market survey data. RESULTS: For a birth cohort of 1 million vaccinated Japanese children followed for 5 years, the benefit-risk analysis suggested that the vaccine would prevent ~17,900 hospitalizations and ~6.3 deaths associated with RVGE. At the same time, vaccination would be associated with about ~50 intussusception hospitalizations and ~0.017 intussusception deaths. Therefore, for every intussusception hospitalization caused by vaccination and for one intussusception-associated death, 350 (95 % CI 69-2510) RVGE-associated hospitalizations and 366 (95 % CI 59 3271) RVGE-associated deaths are prevented, respectively, by vaccination. CONCLUSIONS: The benefit-risk balance for RotarixTM is favorable in Japan. From a public health perspective, the benefits in terms of prevented RVGE hospitalizations and deaths for the vaccinated population far exceed the estimated risks due to intussusception. PMID- 26748507 TI - Performance of Stratified and Subgrouped Disproportionality Analyses in Spontaneous Databases. AB - INTRODUCTION: Disproportionality analyses are used in many organisations to identify adverse drug reactions (ADRs) from spontaneous report data. Reporting patterns vary over time, with patient demographics, and between different geographical regions, and therefore subgroup analyses or adjustment by stratification may be beneficial. OBJECTIVE: The objective of this study was to evaluate the performance of subgroup and stratified disproportionality analyses for a number of key covariates within spontaneous report databases of differing sizes and characteristics. METHODS: Using a reference set of established ADRs, signal detection performance (sensitivity and precision) was compared for stratified, subgroup and crude (unadjusted) analyses within five spontaneous report databases (two company, one national and two international databases). Analyses were repeated for a range of covariates: age, sex, country/region of origin, calendar time period, event seriousness, vaccine/non-vaccine, reporter qualification and report source. RESULTS: Subgroup analyses consistently performed better than stratified analyses in all databases. Subgroup analyses also showed benefits in both sensitivity and precision over crude analyses for the larger international databases, whilst for the smaller databases a gain in precision tended to result in some loss of sensitivity. Additionally, stratified analyses did not increase sensitivity or precision beyond that associated with analytical artefacts of the analysis. The most promising subgroup covariates were age and region/country of origin, although this varied between databases. CONCLUSIONS: Subgroup analyses perform better than stratified analyses and should be considered over the latter in routine first-pass signal detection. Subgroup analyses are also clearly beneficial over crude analyses for larger databases, but further validation is required for smaller databases. PMID- 26748508 TI - Comparative Safety and Tolerability of Prostacyclins in Pulmonary Hypertension. AB - Prostacyclin (PGI2) is a prostaglandin derived from arachidonic acid in the endothelium and smooth muscle which causes vasodilation, inhibits platelet aggregation, and has anti-inflammatory, anti-thrombotic and anti-proliferative effects. In pulmonary arterial hypertension (PAH), PGI2 levels and PGI2 synthase expression are reduced, contributing to the vasoconstriction and vascular smooth muscle cell proliferation seen in the disease. Based on these findings, PGI2 analogues were developed to target this pathway. Epoprostenol was the first targeted therapy available for treating PAH. Due to the short half-life of this drug, it requires administration via a continuous intravenous infusion, and therefore it carries the risks of central line infections and thrombosis. However, it remains the treatment of choice in patients with severe PAH as it has a proven survival benefit as well as improved functional class and exercise capacity. Subsequently, several other PGI2 analogues have been developed with differing modes of administration and varying degrees of efficacy. Beraprost is an oral PGI2 analogue for which a sustained efficacy has not been demonstrated. Iloprost is a nebulised PGI2 analogue that requires administration six to nine times a day and leads to improved functional class, exercise capacity and haemodynamics. There are inhaled, oral, subcutaneous and intravenous forms of treprostinil. Subcutaneous treprostinil avoids the risks of a continuous intravenous administration; however, this drug can cause intractable pain at the injection site. Selexipag is the new oral non-prostanoid IP prostacyclin receptor agonist that has shown improved haemodynamics and good tolerance in a phase II study. Initial results of the phase III trial are promising. Comparison of the different PGI2 agents is limited by a lack of head-to-head clinical trials. However, the development of PGI2 analogues has improved survival in patients with PAH and remains the main treatment option in advanced disease. While PGI2 analogues have good efficacy in PAH, they are not interchangeable, and their delivery systems have many limitations; in particular, they are associated with significant deleterious consequences. In the future, it is hoped that the elusive goal of developing an effective oral PGI2 analogue will be achieved. This would increase the number of people who could benefit from the treatment while reducing the associated adverse events, and as a result improve the survival and quality of life for these patients. PMID- 26748509 TI - Measurement of Perceived and Technical Quality of Care for Depression in Racially and Ethnically Diverse Groups. AB - Measurement of patient satisfaction is now considered essential for providing patient centered care and is an important tool for addressing health care disparities. However, little is known about how ethnically and racially diverse (ERD) groups differ in how they perceive quality, and widely used instruments for measuring perceived quality give little attention to cultural elements of care. This study examined the relationship between the culturally determined beliefs and expectations of four ERD groups (African Americans, Latinos, Portuguese speakers, and Haitians, total N = 160) and the technical quality of treatment for depression provided in four "culturally-specific" primary care clinics. Using data from the Experiences of Care and Health Outcomes survey, chart reviews and focus groups, the study addressed a set of questions related to the psychometric properties of perceived care measures and the technical quality of care. The groups differed in preferred cultural elements except all preferred inclusion of religion. They did not differ in overall perceived quality. Technical quality was higher for Portuguese and Haitians than for African Americans and Latinos. Implications of group differences for measuring quality are discussed. PMID- 26748511 TI - Cytomolecular characterization and origin of de novo formed maize B chromosome variants. AB - B chromosomes are dispensable elements that occur in many species, including maize. The maize B chromosome is acrocentric and highly heterochromatic and undergoes nondisjunction during the second pollen mitosis. In this study, we determined the genetic behavior and organization of two naturally occurring B chromosome variants (designated B(ta) and B(tb)). The morphology and genetic behavior of the B(ta) chromosome were similar to those of the typical B chromosome, but the B(ta) chromosome contained a deletion in the first heterochromatin region and had higher transmission frequencies through both male and female parents. The B(tb) chromosome was reduced in size, consisted primarily of heterochromatin, and had a lower transmission frequency. The B(tb) chromosome lacked nondisjunctional behavior, which was restored by the presence of normal B chromosomes in the cell. Furthermore, the B(tb) chromosome contained two centromeric regions, only one of which was active. The organization of these two naturally occurring B chromosome variants was also determined using fluorescence in situ hybridization with B-associated sequences and by amplification of B specific molecular markers to create possible evolutionary models. PMID- 26748510 TI - The Pathogenic Role of Ganglioside Metabolism in Alzheimer's Disease-Cholinergic Neuron-Specific Gangliosides and Neurogenesis. AB - Alzheimer's disease (AD) is the most common type of dementia with clinical symptoms that include deficits in memory, judgment, thinking, and behavior. Gangliosides are present on the outer surface of plasma membranes and are especially abundant in the nervous tissues of vertebrates. Ganglioside metabolism, especially the cholinergic neuron-specific gangliosides, GQ1balpha and GT1aalpha, is altered in mouse model of AD and patients with AD. Thus, alterations in ganglioside metabolism may participate in several events related to the pathogenesis of AD. Increased expressions of GT1aalpha may reflect cholinergic neurogenesis. Most changes in ganglioside metabolism occur in the specific brain areas and their lipid rafts. Targeting ganglioside metabolism in lipid rafts may represent an underexploited opportunity to design novel therapeutic strategies for AD. PMID- 26748512 TI - Oligogalacturonic acids promote tomato fruit ripening through the regulation of 1 aminocyclopropane-1-carboxylic acid synthesis at the transcriptional and post translational levels. AB - BACKGROUND: Oligogalacturonic acids (OGs) are oligomers of alpha-1,4-linked galacturonosyl residues that are released from cell walls by the hydrolysis of polygalacturonic acids upon fruit ripening and under abiotic/biotic stress. OGs may induce ethylene production and fruit ripening, however, the mechanism(s) behind these processes is unknown. RESULTS: Tomato cultivar 'Ailsa Craig' (AC) and mutant Neverripe, ripening inhibitor, non-ripening, and colorless non ripening fruits were treated with OGs at different stages. Only AC fruits at mature green stage 1 showed an advanced ripening phenomenon, although transient ethylene production was detected in all of the tomato fruits. Ethylene synthesis genes LeACS2 and LeACO1 were rapidly up-regulated, and the phosphorylated LeACS2 protein was detected after OGs treatment. Protein kinase/phosphatase inhibitors significantly affected the ripening process induced by the OGs. As a potential receptor of OGs, LeWAKL2 was also up-regulated in their presence. CONCLUSIONS: We demonstrated that OGs promoted tomato fruit ripening by inducing ethylene synthesis through the regulation of LeACS2 at transcriptional and post translational levels. PMID- 26748513 TI - Genomic Signatures of Selective Pressures and Introgression from Archaic Hominins at Human Innate Immunity Genes. AB - Human genes governing innate immunity provide a valuable tool for the study of the selective pressure imposed by microorganisms on host genomes. A comprehensive, genome-wide study of how selective constraints and adaptations have driven the evolution of innate immunity genes is missing. Using full-genome sequence variation from the 1000 Genomes Project, we first show that innate immunity genes have globally evolved under stronger purifying selection than the remainder of protein-coding genes. We identify a gene set under the strongest selective constraints, mutations in which are likely to predispose individuals to life-threatening disease, as illustrated by STAT1 and TRAF3. We then evaluate the occurrence of local adaptation and detect 57 high-scoring signals of positive selection at innate immunity genes, variation in which has been associated with susceptibility to common infectious or autoimmune diseases. Furthermore, we show that most adaptations targeting coding variation have occurred in the last 6,000 13,000 years, the period at which populations shifted from hunting and gathering to farming. Finally, we show that innate immunity genes present higher Neandertal introgression than the remainder of the coding genome. Notably, among the genes presenting the highest Neandertal ancestry, we find the TLR6-TLR1-TLR10 cluster, which also contains functional adaptive variation in Europeans. This study identifies highly constrained genes that fulfill essential, non-redundant functions in host survival and reveals others that are more permissive to change containing variation acquired from archaic hominins or adaptive variants in specific populations-improving our understanding of the relative biological importance of innate immunity pathways in natural conditions. PMID- 26748514 TI - Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors. AB - Pathogens and the diseases they cause have been among the most important selective forces experienced by humans during their evolutionary history. Although adaptive alleles generally arise by mutation, introgression can also be a valuable source of beneficial alleles. Archaic humans, who lived in Europe and Western Asia for more than 200,000 years, were probably well adapted to this environment and its local pathogens. It is therefore conceivable that modern humans entering Europe and Western Asia who admixed with them obtained a substantial immune advantage from the introgression of archaic alleles. Here we document a cluster of three Toll-like receptors (TLR6-TLR1-TLR10) in modern humans that carries three distinct archaic haplotypes, indicating repeated introgression from archaic humans. Two of these haplotypes are most similar to the Neandertal genome, and the third haplotype is most similar to the Denisovan genome. The Toll-like receptors are key components of innate immunity and provide an important first line of immune defense against bacteria, fungi, and parasites. The unusually high allele frequencies and unexpected levels of population differentiation indicate that there has been local positive selection on multiple haplotypes at this locus. We show that the introgressed alleles have clear functional effects in modern humans; archaic-like alleles underlie differences in the expression of the TLR genes and are associated with increased [corrected] microbial resistance and increased allergic disease in large cohorts. This provides strong evidence for recurrent adaptive introgression at the TLR6-TLR1 TLR10 locus, resulting in differences in disease phenotypes in modern humans. PMID- 26748515 TI - Genotype Imputation with Millions of Reference Samples. AB - We present a genotype imputation method that scales to millions of reference samples. The imputation method, based on the Li and Stephens model and implemented in Beagle v.4.1, is parallelized and memory efficient, making it well suited to multi-core computer processors. It achieves fast, accurate, and memory efficient genotype imputation by restricting the probability model to markers that are genotyped in the target samples and by performing linear interpolation to impute ungenotyped variants. We compare Beagle v.4.1 with Impute2 and Minimac3 by using 1000 Genomes Project data, UK10K Project data, and simulated data. All three methods have similar accuracy but different memory requirements and different computation times. When imputing 10 Mb of sequence data from 50,000 reference samples, Beagle's throughput was more than 100* greater than Impute2's throughput on our computer servers. When imputing 10 Mb of sequence data from 200,000 reference samples in VCF format, Minimac3 consumed 26* more memory per computational thread and 15* more CPU time than Beagle. We demonstrate that Beagle v.4.1 scales to much larger reference panels by performing imputation from a simulated reference panel having 5 million samples and a mean marker density of one marker per four base pairs. PMID- 26748516 TI - Model-free Estimation of Recent Genetic Relatedness. AB - Genealogical inference from genetic data is essential for a variety of applications in human genetics. In genome-wide and sequencing association studies, for example, accurate inference on both recent genetic relatedness, such as family structure, and more distant genetic relatedness, such as population structure, is necessary for protection against spurious associations. Distinguishing familial relatedness from population structure with genotype data, however, is difficult because both manifest as genetic similarity through the sharing of alleles. Existing approaches for inference on recent genetic relatedness have limitations in the presence of population structure, where they either (1) make strong and simplifying assumptions about population structure, which are often untenable, or (2) require correct specification of and appropriate reference population panels for the ancestries in the sample, which might be unknown or not well defined. Here, we propose PC-Relate, a model-free approach for estimating commonly used measures of recent genetic relatedness, such as kinship coefficients and IBD sharing probabilities, in the presence of unspecified structure. PC-Relate uses principal components calculated from genome screen data to partition genetic correlations among sampled individuals due to the sharing of recent ancestors and more distant common ancestry into two separate components, without requiring specification of the ancestral populations or reference population panels. In simulation studies with population structure, including admixture, we demonstrate that PC-Relate provides accurate estimates of genetic relatedness and improved relationship classification over widely used approaches. We further demonstrate the utility of PC-Relate in applications to three ancestrally diverse samples that vary in both size and genealogical complexity. PMID- 26748517 TI - Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules. AB - Intellectual disability (ID) disorders are genetically and phenotypically extremely heterogeneous. Can this complexity be depicted in a comprehensive way as a means of facilitating the understanding of ID disorders and their underlying biology? We provide a curated database of 746 currently known genes, mutations in which cause ID (ID-associated genes [ID-AGs]), classified according to ID manifestation and associated clinical features. Using this integrated resource, we show that ID-AGs are substantially enriched with co-expression, protein protein interactions, and specific biological functions. Systematic identification of highly enriched functional themes and phenotypes revealed typical phenotype combinations characterizing process-defined groups of ID disorders, such as chromatin-related disorders and deficiencies in DNA repair. Strikingly, phenotype classification efficiently breaks down ID-AGs into subsets with significantly elevated biological coherence and predictive power. Custom made functional Drosophila datasets revealed further characteristic phenotypes among ID-AGs and specific clinical classes. Our study and resource provide systematic insights into the molecular and clinical landscape of ID disorders, represent a significant step toward overcoming current limitations in ID research, and prove the utility of systematic human and cross-species phenomics analyses in highly heterogeneous genetic disorders. PMID- 26748520 TI - The importance of self-management in the prevention and treatment of excessive weight and obesity. AB - OBJECTIVES: The aim of this research into 'self-management' was to determine to what extent respondents were aware of their status as overweight or obese. For respondents who indicated that they were overweight or obese, the goal was to determine whether they tried to lose weight, what steps they took to control their, and what specific methods they used. METHODS: Information was collected using semi-structured interviews from May 31, 2014, to January 30, 2015. Data processing was performed using statistical analysis of the social data SASDM 01/04/10 software. The total study group consisted of 600 respondents, including 302 from the Roma minority, and 298 from the non-Roma majority population (control group). Respondents were selected specifically from South Bohemia Region of the Czech Republic. The sample from the Roma minority was constructed using the snowball method (Snowball Sampling). The control sample of non-Roma was selected through quota sampling. RESULTS: The results indicate that the respondents from both the Roma minority and the non-Roma control group generally recognized when they were overweight or obese, or they were aware of it to a much lesser extent than objective indicators revealed. More than two thirds of the respondents who admitted they were overweight or obese (N = 143) reported that they had suffered from overweight or obesity since they were young adults. Significantly more members of the majority population had tried to lose weight using self-management, whereas the level of effort was significantly less among members of the Roma minority (P = 0). Nevertheless, Roma respondents significantly more often reported (P < 0.01) that they had agreed on a specific weight loss plan with a doctor. CONCLUSION: The results of our research show that in the context of prevention, it is important to promote self-managed skills, habits and other characteristics that can play an important role in the prevention and treatment of obesity and overweight. PMID- 26748521 TI - Selected aspects of "safety culture" in hospitals of the Czech Republic. AB - THEORETICAL BACKGROUND: Patient safety is a strategic goal of managers of all health care facilities in the Czech Republic. The development of a safety culture in the facility helps to ensure high quality health care. GOAL OF THE SURVEY was to assess the safety culture with regard to patient safety and team cooperation. A partial goal was to confirm the hypothesis that team cooperation among health care staff significantly influences patient safety. METHODOLOGY: 772 nurses took part in a quantitative survey. The respondents were nurses working shifts in inpatient departments of hospitals in the Czech Republic. RESULTS: Patient safety was described as excellent by 17.5% of nurses. It is described as very good by 60.2% of nurses and described as acceptable by 20.5% nurses. 78% of respondents agreed with the statement that patient safety was never neglected at the expense of increased workload. More than 10% of nurses reported that there were problems with patient safety. 19.8% of respondents were reported that efforts to prevent errors were not practiced at their clinic, and, therefore, and only chance had prevent more errors from occurring. According to 64.9% of respondents, the staff on the wards supported each other and a similar number of respondents reported that they showed respect for each other (60.2%). Respondents reported that intra ward support increased the degree of patient safety. CONCLUSION: Results from the survey show that team cooperation is a precondition for providing safe patient care, which cannot be underestimated and must be refined and improved through good hospital management. PMID- 26748519 TI - Invariant TAD Boundaries Constrain Cell-Type-Specific Looping Interactions between Promoters and Distal Elements around the CFTR Locus. AB - Three-dimensional genome structure plays an important role in gene regulation. Globally, chromosomes are organized into active and inactive compartments while, at the gene level, looping interactions connect promoters to regulatory elements. Topologically associating domains (TADs), typically several hundred kilobases in size, form an intermediate level of organization. Major questions include how TADs are formed and how they are related to looping interactions between genes and regulatory elements. Here we performed a focused 5C analysis of a 2.8 Mb chromosome 7 region surrounding CFTR in a panel of cell types. We find that the same TAD boundaries are present in all cell types, indicating that TADs represent a universal chromosome architecture. Furthermore, we find that these TAD boundaries are present irrespective of the expression and looping of genes located between them. In contrast, looping interactions between promoters and regulatory elements are cell-type specific and occur mostly within TADs. This is exemplified by the CFTR promoter that in different cell types interacts with distinct sets of distal cell-type-specific regulatory elements that are all located within the same TAD. Finally, we find that long-range associations between loci located in different TADs are also detected, but these display much lower interaction frequencies than looping interactions within TADs. Interestingly, interactions between TADs are also highly cell-type-specific and often involve loci clustered around TAD boundaries. These data point to key roles of invariant TAD boundaries in constraining as well as mediating cell-type specific long-range interactions and gene regulation. PMID- 26748522 TI - Patient misidentification in nursing care. AB - GOAL: The goal of the study was to assess the opinions of nurses regarding patient safety associated with patient misidentification. The investigation was focused on actual patient misidentification as well as loss of patient materials (e.g., blood samples, X-rays, etc.). These are problems often associated with patient identification methods and/or confusing patients with the same surname assigned to the same ward. The risks of misidentification incidents pose a considerable threat to patient health especially when the confusion extends to the operating room. Our objective was to identify the potential causes of patient misidentification and offers solutions to correct the issue. METHODS: A survey as part of a sociological investigation was carried out through the use of questionnaires. The selected sample included, in accordance with the needs of the project and methodology of the Institute for Health Care Information and Statistics of the Czech Republic, registered nurses working shifts on inpatient wards. The study took place across the Czech Republic between Sept. 15 and 30, 2013. The sample consisted of 772 registered nurses. RESULTS: The potential for patient misidentification (PM) was described as negligible by 73.8% of respondents. Only 9.1% of nurses admitted problems associated with patient misidentification. Respondents reported that the greatest potential for patient misidentification was associated with patients having the same surname staying on the same ward. An absolute majority of nurses responded that patient identification wristbands were the most frequently used method to prevent PM. Over 90% (90.6%) of nurses reported that patient ID wristbands were used for all patients. Almost 80% (77.4%) reported the use of positive verbal identification in addition to ID wrist bands. Respondents reported (76.2%) that the most frequently used method to avoid PM in the operating room involved a review of patient documentation. Almost the same number of repondents (74.1%) reported the use of verbal confirmation as a method to avoid PM. Another mechanism included verification of the surgical procedure. ID wristbands and completion of an 'identification protocol' rank among other options mentioned most frequently by respondents. CONCLUSION: The study shows that registered nurses regard patient misidentification as a very rare and unlikely event. Nonetheless, statistics suggest otherwise and education, changes in protocols, and new technologies are needed to improve the precision of patient identification. PMID- 26748518 TI - Genetic Diversity and Association Studies in US Hispanic/Latino Populations: Applications in the Hispanic Community Health Study/Study of Latinos. AB - US Hispanic/Latino individuals are diverse in genetic ancestry, culture, and environmental exposures. Here, we characterized and controlled for this diversity in genome-wide association studies (GWASs) for the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We simultaneously estimated population structure principal components (PCs) robust to familial relatedness and pairwise kinship coefficients (KCs) robust to population structure, admixture, and Hardy Weinberg departures. The PCs revealed substantial genetic differentiation within and among six self-identified background groups (Cuban, Dominican, Puerto Rican, Mexican, and Central and South American). To control for variation among groups, we developed a multi-dimensional clustering method to define a "genetic-analysis group" variable that retains many properties of self-identified background while achieving substantially greater genetic homogeneity within groups and including participants with non-specific self-identification. In GWASs of 22 biomedical traits, we used a linear mixed model (LMM) including pairwise empirical KCs to account for familial relatedness, PCs for ancestry, and genetic-analysis groups for additional group-associated effects. Including the genetic-analysis group as a covariate accounted for significant trait variation in 8 of 22 traits, even after we fit 20 PCs. Additionally, genetic-analysis groups had significant heterogeneity of residual variance for 20 of 22 traits, and modeling this heteroscedasticity within the LMM reduced genomic inflation for 19 traits. Furthermore, fitting an LMM that utilized a genetic-analysis group rather than a self-identified background group achieved higher power to detect previously reported associations. We expect that the methods applied here will be useful in other studies with multiple ethnic groups, admixture, and relatedness. PMID- 26748523 TI - Prevention of patient falls in hospitals in the Czech Republic. AB - THEORY: The prevention of patient falls is one of the safety goals set forth by the Ministry of Health of the Czech Republic. GOAL: A sociological survey was carried out to (1) determine to what extent nurses identify the risk of patient falls at admission, (2) if the risk is reassessed and at what intervals, (3) what preventive measures were taken, and (4) in what way are patient falls reported. METHODOLOGY: A representative sample consisting of general nurses working shifts on inpatient wards at hospitals in the Czech Republic was surveyed. Altogether 772 nurses took part in the study. RESULTS: The survey showed that at admission, most nurses assessed the risk of falls (91.6%). Nonetheless, it should stand as a stark warning that nearly one fifth of the respondents (16.2%) did not reassess the risk of falls after admission! On the other hand, it can be perceived as a positive that most nurses (70.1%) use a multifaceted program of preventive measures for at risk patients and immediately reported fall events to the doctor in charge (71.4%). During statistical testing, the predication that a working atmosphere supporting a culture of patient safety would significantly decrease the probability of patient falls and increases the willingness of nurses to use preventive programs in daily practice. CONCLUSION: Results from the survey showed that a system to minimalize fall risks has been successfully introduced into the hospitals of the Czech Republic. The system is based on the recommendations of the Ministry of Health of the Czech Republic. PMID- 26748524 TI - Genetic and biochemical characteristics in the Roma minority in the South Bohemia Region. AB - OBJECTIVE: At present, health characteristics of Roma minority within the Czech Republic are generally unknown. Therefore we examined a Roma population for some anthropometrical, biochemical and genetic parameters. DESIGN: Groups include Roma aged above 18 years (men, women), with permanent residence in the South Bohemia Region. The Roma group (302 individuals) was selected using the snowball sampling method--the same method was used to select the non-Roma control group (78 individuals) for total cholesterol and blood sugar reference values. The main non Roma control group was selected using the quota selection method (298 individuals). All participants completed a life style questionnaire, had their body measurements taken, were weighed, had their blood pressure and heart rates measured, had a capillary blood sample taken. RESULTS: The non-Roma population had a lower Body Mass Index (BMI) (25.86 +/- 4.23 vs. 27.45 +/- 6.48 kg/m2, p = 0.0004). The difference in BMI and weight was found to be associated with the MC4R gene. The values of systolic and diastolic blood pressure, total cholesterol, blood sugar did not differ with regard to the tested polymorphisms. We did not find any difference in the prevalence of MC4R or TMEM18 between groups. CONCLUSION: Despite educational efforts to introduce healthier life styles into the Roma population, there has been only limited success; as a result, Roma are very likely to suffer from premature complications of atherosclerotic processes, mostly due to theirs life style. Intensive further research is needed to improve the health conditions of the Roma minority, while still respecting their cultural differences. PMID- 26748525 TI - Evaluation of selected indicators of overweight and obesity of Roma minority in the region of South Bohemia. AB - OBJECTIVES: The objective of our correlation study was to compare selected indicators of overweight and obesity of Roma and non-Roma (majority) populations in the South Bohemia Region or the Czech Republic. METHODS: The following indicators were chosen for evaluation of overweight and obesity: body height and weight, waistline measurement, waist/height index, waist/hips index, BMI, total fat and blood pressure. 600 participants were examined and interviewed in total, including 302 Roma and 298 non-Roma participants. Each of the participants had a personal examination performed by a general nurse, under hygienic-epidemiological conditions. The criteria for inclusion of participants into the study were consent with examination and age greater than 18 years. RESULTS: The statistical analysis showed that, at a level of significance of p < 0.001, the following values differed between the Roma and non-Roma population of the South Bohemia Region: waist/height index, waistline, total fat, body mass index (BMI), systolic and diastolic blood pressure. Differences in the incidence of the waist/hips index were significant at p < 0.01. Correlations of incidence with indicators of overweight and obesity in Roma were registered in relation to both age and gender of participants. The results show that overweight and obesity indicators were recorded more frequently in Roma female respondents. Although the results are unique, the conclusions cannot be generalized for Roma throughout the Czech Republic. CONCLUSION: The conclusions of the above findings will be implemented in strategic materials for community planning in the South Bohemia Region. The goal will be to offer services aimed at supporting a healthy life style for Roma living in the South Bohemia Region of the Czech Republic. PMID- 26748527 TI - Selected areas of health and health care utilization by immigrants living in the Czech Republic. AB - OBJECTIVE: This investigation examined to what extent a selected group of immigrants in the Czech Republic receive healthcare for primary prevention and inpatient care. A partial aim of the research was to confirm the connection between immigrant health and their social situation. METHODS: Using a quantitative study technique, 1,014 legally established immigrants (Vietnamese, Polish, Ukrainian, Russian, and Slovak) between 18-65 years of age were interviewed. The selection of respondents was conducted using purposive selection. The stratification of the group was determined by nationality, age, and gender. RESULTS: Long-term illnesses were found significantly more frequently among Ukrainian immigrants and less frequently among Vietnamese immigrants. About half of the respondents had visited a GP and dentist in the previous year and 11.5% of respondents had been hospitalized in inpatient departments. Most of the surveyed immigrants had public health insurance (77.9%), one-fifth had contractual health insurance (19.6%) and 2.5% did not have health insurance. In statistical terms, Vietnamese, Ukrainian, and Russian immigrants had commercial insurance more often than Polish and Slovak immigrants. The utilization of public health insurance and healthcare among immigrants grew significantly in correlation with length of residency. The use of GPs for preventive health care also grew in correlation with knowledge of the Czech language. We found that less than nine percent of immigrants reported needing hospitalization for an illness, but were not hospitalized. CONCLUSION: Currently, immigration represents one of the most burning and sensitive global challenges. The outcome of this research clearly shows that improving immigrant Czech language skills and giving all legally established immigrants access to Czech public health insurance are important steps needed to increase access to healthcare for immigrants in the Czech Republic. PMID- 26748526 TI - Selected parameters of social exclusion among immigrants in the Czech Republic. AB - This article deals with the issue of social exclusion of immigrants in the Czech Republic. A review of expert sources indicates that immigrants are most often excluded from the labour market, housing market, and in communication with institutions. These areas became the target of our research. We observed how they were affect by knowledge of the Czech language, length of residence and type of work performed. The study was conducted using quantitative research strategies, interviews, and a questionnaire, the clarity of which was ensured by a double translation. The research group consisted of immigrants, namely Vietnamese, Slovak, Russian, Ukrainian, and Polish nationalities, living in selected regions of the Czech Republic. Results showed that there were statistically significant differences among the immigrant groups. The Vietnamese were least satisfied with housing conditions; they often reported living in overcrowded apartments and dormitories, and saw little chance of changing their situation because of discrimination by landlords. With regard to Czech language skills, the greater difference between Czech and Vietnamese and the relative similarity between Czech and the other studied immigrant languages also played a role. As a result, this indicator also showed the greatest dissatisfaction among the Vietnamese. For employees, poor knowledge of Czech corresponds to lower socioeconomic status. PMID- 26748528 TI - Qualitative analysis of selected literature sources addressing the issue of homelessness. AB - OBJECTIVES: The objective of this article is to answer the main research question, which reads: "How is the issue of homelessness presented in the relevant literature?" Basic terms related to homelessness and homeless people are defined at the beginning of the article. Homelessness is a complex social problem, with many factors contributing to its origin and development that can, in principle, be divided into objective and subjective factors. METHODS: A qualitative research strategy was chosen to address the main research question. Analysis of documents using content analysis was used as the research tool. The research sample consisted of three articles, two chapters, and two subchapters in a monograph. The three analyzed sources were in English, three in the Slovak language, and one in the Czech language. RESULTS: It was found that the issue could be viewed from both health-related and social perspectives. None of the authors, whose publications were analyzed, preferred a "purely" health-related or a "purely" social welfare view of the issue of homelessness. We identified three types of perspectives (approaches) related to the care of homeless people: health & social, preferred health care, and preferred social care. Both components of care are more or less represented in each of the three types of care. CONCLUSION: It can be concluded that the issue of homelessness cannot be viewed from a single perspective (either health or social), since it requires an interdisciplinary approach and cooperation of both healthcare professionals and social welfare experts to address the unfavorable social situations associated with homelessness. PMID- 26748529 TI - Hegemony in the Roma family. AB - This article is intended to describe the current hegemonic masculinity within the Roma family structure in the Czech Republic, with regard to changes related to developments in the majority society and the current socioeconomic situation of the Roma. The theoretical context of this article is based on the paradigm of masculine hegemony as it exists and has existed in the Roma families. Data for the study came from semi-structured interviews with 30 Roma females and 30 Roma males living as couples, in three Czech cities. The main finding reveals a dichotomy between the traditional roles of Roma women, i.e. care for the family and the household, and the present functions, i.e. contributing to the family income through social benefits. We observed a decline in the traditional role of Roma men, who were often unemployed. We related the change in the roles of men to the "non-functionality of the men", contributing to the emerging potential for emancipation of Roma women. However, the traditional patriarchal Roma family is structured such that men are given the main decision making powers, which has slowed changes in marginalized Roma families. Additionally, social pressures against women as well as socially conditioned pressures that act to preserve hegemonic masculinity, have largely prevented the realization of the potential for emancipation of Roma women, or if a woman tries to leave her non-functioning husband. PMID- 26748530 TI - Socioeconomic status and health of immigrants. AB - The aim of this article is to acquaint the general public with select socioeconomic status (SES) parameters (type of work, education level, employment category, and net monthly income) of select nationalities (Ukrainians, Slovaks, Vietnamese, Poles, and Russians) from a total of 1,014 immigrants residing in the Czech Republic. It will also present a subjective assessment of socioeconomic status and its interconnection with subjective assessment of health status. This work was carried out as part of the "Social determinants and their impact on the health of immigrants living in the Czech Republic" project (identification number LD 13044), which was conducted under the auspices of the European Cooperation in Science and Technology (COST) agency. Quantitative methodology in the form of a questionnaire was selected to facilitate the research aim. Data was processed using the Statistical Package for Social Sciences (SPSS), version 16.0 (SPSS, Inc., Chicago, IL, USA). Statistical analyses were performed using the Pearson chi-square test, adjusted residual analysis, and multivariate correspondence analysis. The results of these tests demonstrated a statistically significant relationship between subjective assessments of socioeconomic status and the following related select characteristics: type of work performed (manual/intellectual), employment categories, education, and net monthly income. Results indicate that those situated lowest on the socioeconomic ladder feel the poorest in terms of health; not only from a subjective perspective, but also in terms of objective parameter comparisons (e.g. manual laborers who earn low wages). As the level of subjective SES assessment increases, the level of subjective health assessment increases, as well. Thus, the relationship has a natural gradient, as was described by Wilkinson and Marmot in 2003. Our study found no evidence of a healthy immigrant effect. Therefore, it was not possible to confirm that health status deteriorates with length of residence, or that the health status of immigrants with a residence duration of less than 5 to 10 years is statistically significantly better than immigrants who have resided in the Czech Republic for 10 years or more. We conclude that, by increasing the education levels of immigrants, or actively selecting qualified foreign workers (according to set criteria), the number of people in the Czech Republic who positively assess their health status will surge. In terms of prevention, it is essential to focus on manual laborers and to differentiate specific methods to improve their health status (e.g. awareness-raising campaigns in large plants and factories), given that they comprise the weakest group in this regard. PMID- 26748531 TI - A randomized controlled trial into the effects of neurofeedback, methylphenidate, and physical activity on EEG power spectra in children with ADHD. AB - BACKGROUND: The clinical and neurophysiological effects of neurofeedback (NF) as treatment for children with ADHD are still unclear. This randomized controlled trial (RCT) examined electroencephalogram (EEG) power spectra before and after NF compared to methylphenidate (MPH) treatment and physical activity (PA) - as semi active control group - during resting and active (effortful) task conditions to determine whether NF can induce sustained alterations in brain function. METHODS: Using a multicentre three-way parallel group RCT design, 112 children with a DSM IV diagnosis of ADHD, aged between 7 and 13 years, were initially included. NF training consisted of 30 sessions of theta/beta training at Cz over a 10-week period. PA training was a semi-active control group, matched in frequency and duration. Methylphenidate was titrated using a double-blind placebo controlled procedure in 6 weeks, followed by a stable dose for 4 weeks. EEG power spectra measures during eyes open (EO), eyes closed (EC) and task (effortful) conditions were available for 81 children at pre- and postintervention (n = 29 NF, n = 25 MPH, n = 27 PA). CLINICAL TRIALS REGISTRATION: Train Your Brain? Exercise and Neurofeedback Intervention for ADHD, https://clinicaltrials.gov/show/;NCT01363544, Ref. No. NCT01363544. RESULTS: Both NF and MPH resulted in comparable reductions in theta power from pre- to postintervention during the EO condition compared to PA (etap (2) = .08 and .12). For NF, greater reductions in theta were related to greater reductions in ADHD symptoms. During the task condition, only MPH showed reductions in theta and alpha power compared to PA (etap (2) = .10 and .12). CONCLUSIONS: This study provides evidence for specific neurophysiological effects after theta/beta NF and MPH treatment in children with ADHD. However, for NF these effects did not generalize to an active task condition, potentially explaining reduced behavioural effects of NF in the classroom. PMID- 26748533 TI - Effect of denture-coating composite on Candida albicans biofilm and surface degradation after disinfection protocol. AB - INTRODUCTION: Denture stomatitis is the most common pathology affecting denture wearers and its main cause is colonisation of dentures with Candida albicans. OBJECTIVE: This study investigated the effectiveness of two commercial composite surface sealants (Biscover((r)) LV and Surface Coat((r))) to reduce C. albicans biofilm colonisation on denture resin, as well as their surface integrity after disinfection cycles with 1% sodium hypochlorite solution. METHODS: Heat-cured acrylic resin specimens were manufactured (10 mm * 10 mm * 1 mm). The specimen surfaces were mechanically polished to simulate rough or smooth denture surfaces. Four surface-treatment groups were tested: smooth surfaces [0.3 MUm of mean roughness (Ra)]; rough surfaces (3 MUm of Ra); rough surfaces treated with Biscover((r)) LV; and rough surfaces treated with Surface Coat((r)). Specimens of each group were randomly divided to undergo immersion in distilled water or 1% sodium hypochlorite for 30 or 90 cycles each. Specimens of all groups in each immersion solution were tested using a crystal violet (CV) staining assay for biofilm quantification and by scanning electron microscopy for visual analyses of surface integrity and biofilm structure. CV assay data were analysed using one way analysis of variance (ANOVA) followed by Tukey's multiple comparison test (P < 0.05). RESULTS: The effectiveness and surface integrity of Biscover((r)) LV treated surfaces were similar to those of smooth surfaces, whereas Surface Coat((r)) -treated surfaces presented a similar performance to rough surfaces in all solutions and cycles. CONCLUSION: These results suggest the possibility of clinical use of Biscover((r)) LV for denture coating on surfaces in which mechanical polish is not indicated, such as the fitting surface. PMID- 26748535 TI - Mind the cancer screening gap between medical rationale and laypersons' reasoning. PMID- 26748534 TI - An Aromatic Hydroxyamide Attenuates Multiresistant Staphylococcus aureus Toxin Expression. AB - Methicillin-resistant Staphylococcus aureus (MRSA) causes severe infections with only few effective antibiotic therapies currently available. To approach this challenge, chemical entities with a novel and resistance-free mode of action are desperately needed. Here, we introduce a new hydroxyamide compound that effectively reduces the expression of devastating toxins in various S. aureus and MRSA strains. The molecular mechanism was investigated by transcriptome analysis as well as by affinity-based protein profiling. Down-regulation of several pathogenesis associated genes suggested the inhibition of a central virulence related pathway. Mass spectrometry-based chemical proteomics revealed putative molecular targets. Systemic treatment with the hydroxyamide showed significant reduction of abscess sizes in a MRSA mouse skin infection model. The absence of resistance development in vitro further underlines the finding that targeting virulence could lead to prolonged therapeutic options in comparison to antibiotics that directly address bacterial survival. PMID- 26748532 TI - Association of COL4A1 gene polymorphisms with cerebral palsy in a Chinese Han population. AB - The basement membrane (BM) is an extracellular matrix associated with overlying cells and is important for proper tissue development, stability, and physiology. COL4A1 is the most abundant component of type IV collagen in the BM, and COL4A1 variants can present with variable phenotypes that might be related to cerebral palsy (CP). We postulated, therefore, that variations in the COL4A1 gene might play an important role in the etiology of CP. In this study, six single nucleotide polymorphisms (SNPs) in the COL4A1 gene were genotyped among 351 CP patients and 220 healthy controls from the Chinese Han population. Significant association was found for an association between CP and rs1961495 (allele: p = 0.008, odds ratio (OR) = 1.387, 95% confidence interval (CI) = 1.088-1.767) and rs1411040 (allele: p = 0.009, OR = 1.746, 95% CI = 1.148-2.656) SNPs of the COL4A1 gene. Multifactor dimensionality reduction analysis suggested that these SNPs had interactive effects on the risk of CP. This study is the first attempt to investigate the contribution of polymorphisms in the COL4A1 gene to the susceptibility of CP in a Chinese Han population. This study shows an association of the COL4A1 gene with CP and suggests a potential role of COL4A1 in the pathogenesis of CP. PMID- 26748536 TI - Polyelectrolyte Complexes Formed from Conjugated Polymers: Array-Based Sensing of Organic Acids. AB - One fluorescent, positively charged poly(para-phenyleneethynylene) (PAE 1) forms electrostatic complexes with five negatively charged pyridine- or benzothiadiazole-containing poly(para-aryleneethynylene)s (PAE 2-PAE 6). The PAE 2-PAE 6 are less fluorescent in water and act as quenchers for PAE 1 in their electrostatic complexes C 1-C 5; the PAE-complexes (2 MUm) were exposed to thirteen different carboxylic acids (50 mm) in buffered aqueous solution. The fluorescence responses of the small library of electrostatic PAE-complexes towards the acids was analyzed; discrimination of all of the thirteen acids was achieved. The investigated acids include acetic, butyric, tartaric, maleic, lactic, sorbic, oxalic, aspartic, and citric acids. A random, simple, ad-hoc library of electrostatic polymer complexes, C 1-C 5, therefore discerns the thirteen carboxylic acids in water. PMID- 26748537 TI - A multivariable model to guide the decision for pessary placement to prevent preterm birth in women with a multiple pregnancy: a secondary analysis of the ProTWIN trial. AB - OBJECTIVE: The ProTWIN Trial (NTR1858) showed that, in women with a multiple pregnancy and a cervical length < 25(th) percentile (38 mm), prophylactic use of a cervical pessary reduced the risk of adverse perinatal outcome. We investigated whether other maternal or pregnancy characteristics collected at baseline can improve identification of women most likely to benefit from pessary placement. METHODS: ProTWIN is a multicenter randomized trial in which 808 women with a multiple pregnancy were assigned to pessary or control. Using these data we developed a multivariable logistic model comprising treatment, cervical length, chorionicity, pregnancy history and number of fetuses, and the interaction of these variables with treatment as predictors of adverse perinatal outcome. RESULTS: Short cervix, monochorionicity and nulliparity were predictive factors for a benefit from pessary insertion. History of previous preterm birth and triplet pregnancy were predictive factors of possible harm from pessary. The model identified 35% of women as benefiting (95% CI, 32-39%), which is 10% more than using cervical length only (25%) for pessary decisions. The model had acceptable calibration. We estimated that using the model to guide the choice of pessary placement would reduce the risk of adverse perinatal outcome significantly from 13.5% when no pessary is inserted to 8.1% (absolute risk reduction, 5.4% (95% CI, 2.1-8.6%)). CONCLUSIONS: We developed and internally validated a multivariable treatment selection model, with cervical length, chorionicity, pregnancy history and number of fetuses. If externally validated, it could be used to identify women with a twin pregnancy who would benefit from a pessary, and lead to a reduction in adverse perinatal outcomes in these women. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26748538 TI - Dimerization of Organic Dyes on Luminescent Gold Nanoparticles for Ratiometric pH Sensing. AB - Synergistic effects arising from the conjugation of organic dyes onto non luminescent metal nanoparticles (NPs) have greatly broadened their applications in both imaging and sensing. Herein, we report that conjugation of a well-known pH-insensitive dye, tetramethyl-rhodamine (TAMRA), to pH-insensitive luminescent gold nanoparticles (AuNPs) can lead to an ultrasmall nanoindicator that can fluorescently report local pH in a ratiometric way. Such synergy originated from the dimerization of TAMRA on AuNPs, of which geometry was very sensitive to surface charges of the AuNPs and can be reversely modulated through protonation of surrounding glutathione ligands. Not limited to pH-insensitive dyes, this pH dependent dimerization can also enhance the pH sensitivity of fluorescein, a well known pH-sensitive dye, within a larger pH range, opening up a new pathway to design ultrasmall fluorescent ratiometric nanoindicators with tunable wavelengths and pH response ranges. PMID- 26748539 TI - FEASIBILITY FOR USING HYPOFRACTIONATED STEREOTACTIC VOLUMETRIC MODULATED ARC RADIOTHERAPY (VMAT) WITH ADAPTIVE PLANNING FOR TREATMENT OF THYMOMA IN RABBITS: 15 CASES. AB - Thymoma is a relatively common tumor in rabbits. Treatment with surgery, radiation therapy, and chemotherapy alone or in combination has been reported with varying outcomes. Stereotactic volumetric modulated arc radiotherapy delivered in a hypofractionated manner allows high doses of radiation to be delivered to the target volume while allowing sparing of adjacent critical structures. This therapy is ideally suited for thymomas in rabbits given their size, the difficulty of multiple anesthesia episodes and the complexity of the radiotherapy plans required due to the tumor's proximity to the heart, lungs, and mediastinal structures. Fifteen rabbits with thymoma were prospectively recruited for this observational, single institution, single arm clinical study. All rabbits were imaged with both computed tomography (CT) and magnetic resonance imaging (MRI). A total dose of 40 Gy in six fractions was delivered using a single arc over an 11-day period with repeat CT simulation done every other fraction for adaptive planning. Follow-up evaluation was done through repeat CT and MRI imaging and revealed complete responses using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Two rabbits had died at 618 and 718 days, 10 were alive and three were lost to follow-up. Observed acute and late effects were graded according to the Veterinary Radiation Therapy Oncology Group (VRTOG) criteria and were found to be minimal. PMID- 26748540 TI - Caregiver's burden in disorders of consciousness: a longitudinal study. AB - OBJECTIVES: To study the changes in the burden of informal caregivers of patients with disorders of consciousness (DOC) over time. MATERIALS AND METHODS: Short Form-12, Family Strain Questionnaire, Beck Depression Inventory and Coping Orientations to Problem Experiences were administered. RESULTS: Data collected on 216 informal caregivers of patients with DOC (59.6% females, mean age 53.4 +/- 12.7 years old) were analysed at two time-points (mean distance is 2.7 years). Results of the national study revealed that caregivers' mental health improved (T0: M = 41.1, SD = 11.8; T1: M = 45.8, SD = 11.7), whereas the emotional burden (T0: M = 7.4, SD = 3.6; T1: M = 6.6, SD = 3.9) and the presence of depressive symptoms (T0: M = 14.3, SD = 9.3; T1: M = 11.7, SD = 10.2) as well as the need for information about the disease (T0: M = 2.7, SD = 1.2; T1: M = 2.2, SD = 1.4), thoughts of death (T0: M = 3.6, SD = 1.5; T1: M = 3.1, SD = 1.6) and the use of avoiding coping strategy (T0: M = 7.8, SD = 1.0; T1: M = 6.0, SD = 1.3) decreased at T1. Furthermore, depressive symptoms positively correlated with the emotional burden (0.580) and negatively with the mental health component of caregivers' self-perceived health condition (-0.473). Physical (-0.308) and mental health ( 0.444) negatively correlated with emotional burden. Finally, the acute event and patients' health condition still have a deep impact on the economic situation of the family. CONCLUSION: Although high level of burden was observed, it tends to decrease over time, except for financial burden. Hence, this study suggests the importance to plan strategies or targeted interventions in order to reduce the psychosocial and financial burden associated with caregiving. PMID- 26748541 TI - The effectiveness of telephone counselling and internet- and text-message-based support for smoking cessation: results from a randomized controlled trial. AB - AIM: To compare the effectiveness of proactive telephone counselling, reactive telephone counselling and an internet- and text-message-based intervention with a self-help booklet for smoking cessation. DESIGN: A randomized controlled trial with equal allocation to four conditions: (1) proactive telephone counselling (n = 452), (2) reactive telephone counselling (n = 453), (3) internet- and text message-based intervention (n = 453) and (4) self-help booklet (control) (n = 452). SETTING: Denmark. PARTICIPANTS: Smokers who had participated previously in two national health surveys were invited. Eligibility criteria were daily cigarette smoking, age >= 16 years, having a mobile phone and e-mail address. MEASUREMENTS: Primary outcome was prolonged abstinence to 12 months from the end of the intervention period. FINDINGS: At 12-month follow-up, higher prolonged abstinence was found in the proactive telephone counselling group compared with the booklet group [7.3 versus 3.6%, odds ratio (OR) = 2.2, 95% confidence interval (CI) = 1.2-4.0]. There was no clear evidence of a difference in prolonged abstinence between the reactive telephone counselling group or the internet-based smoking cessation program and the booklet group: 1.8 versus 3.6%, OR = 0.8, 95% CI = 0.6-1.2 and 5.3 versus 3.6%, OR = 1.6, 95% CI = 0.8-3.0, respectively. In the proactive telephone counselling group, the cost per additional 12-month quitter compared with the booklet group was L644. CONCLUSIONS: Proactive telephone counselling was more effective than a self-help booklet in achieving prolonged abstinence for 12 months. No clear evidence of an effect of reactive telephone counselling or the internet- and text-message-based intervention was found compared with the self-help booklet. PMID- 26748543 TI - Assessing climate change and health vulnerability at the local level: Travis County, Texas. AB - We created a measure to help comprehend population vulnerability to potential flooding and excessive heat events using health, built environment and social factors. Through principal component analysis (PCA), we created non-weighted sum index scores of literature-reviewed social and built environment characteristics. We created baseline poor health measures using 1999-2005 age-adjusted cardiovascular and combined diabetes and hypertension mortality rates to correspond with social-built environment indices. We mapped US Census block groups by linked age-adjusted mortality and a PCA-created social-built environment index. The goal was to measure flooding and excessive heat event vulnerability as proxies for population vulnerability to climate change for Travis County, Texas. This assessment identified communities where baseline poor health, social marginalisation and built environmental impediments intersected. Such assessments may assist targeted interventions and improve emergency preparedness in identified vulnerable communities, while fostering resilience through the focus of climate change adaptation policies at the local level. PMID- 26748542 TI - Hybrid Density Functional Study on Mono- and Codoped NaNbO3 for Visible-Light Photocatalysis. AB - Monodoping with Mo, Cr, and N atoms, and codoping with Mo-N and Cr-N atom pairs, are utilized to adjust the band structure of NaNbO3 , so that NaNbO3 can effectively make use of visible light for the photocatalytic decomposition of water into hydrogen and oxygen, as determined by using the hybrid density functional. Codoping is energetically favorable compared with the corresponding monodoping, due to strong Coulombic interactions between the dopants and other atoms, and the effective band gap and stability for codoped systems increase with decreasing dopant concentration and the distance between dopants. The molybdenum, chromium, and nitrogen monodoped systems, as well as chromium-nitrogen codoped systems, are unsuitable for the photocatalytic decomposition of water by using visible light, because defects introduced by monodoping or the presence of unoccupied states above the Fermi level, which promotes electron-hole recombination processes, suppress their photocatalytic performance. The Mo-N codoped NaNbO3 sample is a promising photocatalyst for the decomposition of water by using visible light because Mo-N codoping can reduce the band gap to a suitable value with respect to the water redox level without introducing unoccupied states. PMID- 26748544 TI - Self-induced cutaneous lesions in a patient with spinal cord injury. PMID- 26748545 TI - Perforating arteries of the thigh: An anatomical and radiological study. AB - INTRODUCTION: We aimed to advance the understanding of the anatomy of the perforating branches of the profunda femoris artery to facilitate the avoidance of iatrogenic injury in surgery around the thigh and ensure safe percutaneous embolisation. METHODS: Dissection was carried out on seven cadavers, examining the relationship of the point of origin of the perforating branches of profunda femoris, relative to lines connecting palpable bony landmarks (lines A and B). These were compared with 16 computed tomography angiograms (CTA). Left to right variation within subjects and variation between the dissection and imaged group was examined. The anatomy of the two groups was then compared with that described in anatomical textbooks. RESULTS: The side to side variation in number of perforators was not significant in the dissection (P = 0.20) nor the CT group (P = 0.70). Similarly, the point of origin of the perforating vessels along lines A and B did not demonstrate any significant difference except for the fourth perforator along line B (P = 0.03). There was no significant difference in points of origin along line B between the dissection and CT groups for the first four perforators on the left (P = 0.51, P = 0.80, P = 0.66, P = 0.09 respectively) and right (P = 0.79, P = 0.45, P = 0.56, P = 0.11 respectively). The number and distribution of perforators were then compared with commonly used anatomical texts. CONCLUSION: As in other parts of the body, textbook descriptions of anatomical structures may not be reflected consistently in vivo. However, the perforating branches of the profunda femoris demonstrate a predictable topographical relationship to palpable bony landmarks. PMID- 26748547 TI - Making time and space: the impact of mindfulness training on nursing and midwifery practice. A critical interpretative synthesis. AB - AIMS AND OBJECTIVES: To explore qualitative literature to ascertain whether and how nurses and midwives perceive that mindfulness impacts on their practice, particularly their interactions with patients. BACKGROUND: Stress and burnout, which negatively impact patient care, are widely reported among nurses and midwives, who face unique stressors as professionals who often hold little organisational power, but are expected to shoulder the burden of resource cuts and an increasingly complex workload. Mindfulness is recommended as a tool to decrease stress and burnout in health professionals, and may also increase practitioner compassion and improve patient interactions. DESIGN: A critical interpretative synthesis. METHODS: A systematic search was undertaken to identify qualitative studies where the majority of participants were qualified nurses and/or midwives who had attended mindfulness training. Retrieved literature was read and reread to identify relevant material, which was then coded into themes. Related themes were grouped into synthetic constructs, and a synthetic argument was produced to illustrate the relationships between these. RESULTS: Five relevant papers were identified. Findings indicate that mindfulness training enables nurses and midwives to gain some control over their thoughts and stress levels. This then creates a quiet mental space giving them agency and perspective and leading to improved caring, including a more patient-centred focus and increased presence and listening. Mindfulness appears to alter the way nurses and midwives operate within a stressful work environment, thereby changing the way the environment is experienced by themselves and, potentially, the people in their care. CONCLUSIONS: Further research is needed, but current qualitative research suggests mindfulness may enable nurses and midwives to work with compassion in stressful and demanding work environments. RELEVANCE TO CLINICAL PRACTICE: Mindfulness may offer an enabling way of coping with stress, in contrast to long-standing strategies such as task-orientation and depersonalisation. PMID- 26748548 TI - A rare case of facial annular bullous erythema nodosum leprosum reaction in a young boy. PMID- 26748546 TI - Kinetic and structural characterization of amyloid-beta peptide hydrolysis by human angiotensin-1-converting enzyme. AB - Angiotensin-1-converting enzyme (ACE), a zinc metallopeptidase, consists of two homologous catalytic domains (N and C) with different substrate specificities. Here we report kinetic parameters of five different forms of human ACE with various amyloid beta (Abeta) substrates together with high resolution crystal structures of the N-domain in complex with Abeta fragments. For the physiological Abeta(1-16) peptide, a novel ACE cleavage site was found at His14-Gln15. Furthermore, Abeta(1-16) was preferentially cleaved by the individual N-domain; however, the presence of an inactive C-domain in full-length somatic ACE (sACE) greatly reduced enzyme activity and affected apparent selectivity. Two fluorogenic substrates, Abeta(4-10)Q and Abeta(4-10)Y, underwent endoproteolytic cleavage at the Asp7-Ser8 bond with all ACE constructs showing greater catalytic efficiency for Abeta(4-10)Y. Surprisingly, in contrast to Abeta(1-16) and Abeta(4 10)Q, sACE showed positive domain cooperativity and the double C-domain (CC-sACE) construct no cooperativity towards Abeta(4-10)Y. The structures of the Abeta peptide-ACE complexes revealed a common mode of peptide binding for both domains which principally targets the C-terminal P2' position to the S2' pocket and recognizes the main chain of the P1' peptide. It is likely that N-domain selectivity for the amyloid peptide is conferred through the N-domain specific S2' residue Thr358. Additionally, the N-domain can accommodate larger substrates through movement of the N-terminal helices, as suggested by the disorder of the hinge region in the crystal structures. Our findings are important for the design of domain selective inhibitors as the differences in domain selectivity are more pronounced with the truncated domains compared to the more physiological full length forms. DATABASE: The atomic coordinates and structure factors for N-domain ACE with Abeta peptides 4-10 (5AM8), 10-16 (5AM9), 1-16 (5AMA), 35-42 (5AMB) and (4-10)Y (5AMC) complexes have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ, USA (http://www.rcsb.org/). PMID- 26748549 TI - Conjugation of curcumin-loaded lipid nanoemulsions with cell-penetrating peptides increases their cellular uptake and enhances the anti-inflammatory effects in endothelial cells. AB - OBJECTIVES: To prepare and characterize in vitro and in vivo lipid nanoemulsions (LN) loaded with curcumin (Cm) and functionalized with a cell-penetrating peptide. METHODS: Curcumin-loaded lipid nanoemulsions (CmLN) functionalized with a nona-arginine peptide (R9-CmLN) have been obtained, characterized and optimized for size, entrapment efficiency and in vitro Cm release. The interaction of R9 CmLN with human endothelial cells (HEC) was investigated using cultured EA.hy926 cells, and in vivo biodistribution studies were performed using C57BL6 mice. KEY FINDINGS: When used in therapeutically relevant concentration, R9-CmLN have low haemolytic activity, low cytotoxicity on HEC, and show anti-inflammatory effects by reducing the monocytes adhesion to TNF-alpha activated HEC. Moreover, HEC uptake and internalization of R9-CmLN was significantly higher compared to the non-functionalized CmLN. In vivo biodistribution studies in mice revealed a higher accumulation of R9-CmLN in the liver and the lungs compared to CmLN and the body clearance of the both nanoformulations after 72 h. CONCLUSIONS: Cell penetrating peptides-functionalized CmLN have superior characteristics compared to their non-functionalized counterparts: are more efficiently internalized by the cells, produces anti-inflammatory effects in HEC and when administrated intravenously in mice exhibit increased accumulation in the liver and the lungs, suggesting their potential therapeutic applications in different inflammatory pathologies localized in the liver or the lungs. PMID- 26748550 TI - Highly Pathogenic Avian Influenza Virus A/H5N1 Infection in Vaccinated Meat Duck Flocks in the Mekong Delta of Vietnam. AB - We investigated episodes of suspected highly pathogenic avian influenza (HPAI) like illness among 12 meat duck flocks in two districts in Tien Giang province (Mekong Delta, Vietnam) in November 2013. In total, duck samples from 8 of 12 farms tested positive for HPAI virus subtype A/haemagglutinin 5 and neuraminidase 1 (H5N1) by real-time RT-PCR. Sequencing results confirmed clade of 2.3.2.1.c as the cause of the outbreaks. Most (7/8) laboratory-confirmed positive flocks had been vaccinated with inactivated HPAI H5N1 clade 2.3.4 vaccines <6 days prior to onset of clinical signs. A review of vaccination data in relation to estimated production in the area suggested that vaccination efforts were biased towards larger flocks and that vaccination coverage was low [21.2% ducks vaccinated with two shots (range by district 7.4-34.9%)]. The low-coverage data, the experimental evidence of lack of cross-protection conferred by the currently used vaccines based on clade 2.3.4 together with the short lifespan of meat duck flocks (60-70 days), suggest that vaccination is not likely to be effective as a tool for control of H5N1 infection in meat duck flocks in the area. PMID- 26748551 TI - High prevalence of psychiatric disorders in patients with skin-restricted lupus: a case-control study. AB - BACKGROUND: Psychiatric disorders have been extensively documented in patients with systemic lupus erythematosus (SLE). However, the prevalence of psychiatric disorders in patients with skin-restricted lupus (SRL) remains unknown, although SRL is more common than SLE. OBJECTIVES: To assess current and lifetime prevalence of Axis I psychiatric disorders among outpatients with SRL and to examine the factors associated with psychiatric disorders among such patients. METHODS: A multicentre case-control study involving outpatients with SRL and controls matched for sex, age and education level. The Mini International Neuropsychiatric Interview was used for psychiatric evaluation. RESULTS: We evaluated 75 patients and 150 controls. Of these, 49% of patients vs. 13% of controls fulfilled the criteria for at least one current psychiatric disorder (P < 0.001). The following disorders were significantly more frequent among patients than controls: current and lifetime major depressive disorder (9% vs. 0%, P < 0.001 and 44% vs. 26%, P = 0.01), generalized anxiety disorder (23% vs. 3%, P < 0.001 and 35% vs. 19%, P = 0.03), panic disorder (7% vs. 0%, P = 0.004 and 21% vs. 3%, P < 0.001), current suicide risk (24% vs. 7%, P = 0.003), alcohol dependence (7% vs. 0%, P = 0.004) and lifetime agoraphobia (20% vs. 9%, P = 0.01). Lupus duration and lupus past treatment by thalidomide were significantly higher among patients with current psychiatric disorders. CONCLUSIONS: This study demonstrates a high prevalence of several psychiatric disorders (anxiety, depression, suicide risk, alcohol dependence) in patients with SRL. PMID- 26748552 TI - Binding of human coronary artery endothelial cells to plasma-treated titanium dioxide nanotubes of different diameters. AB - Nanoscale topography in improving vascular response in vitro was established previously on various titanium surfaces. In the present study different surface nanotopographies that is different diameters of titanium dioxide (TiO2 ) nanotubes (NTs) were fabricated by electrochemical anodization and conditioned with highly reactive gaseous oxygen plasma. The morphology of different diameter NTs was studied by scanning electron microscopy and atomic force microscopy, while changes in chemical composition on the surface before and after plasma treatment were determined by X-ray photoelectron spectroscopy. Performance of human coronary artery endothelial cells (HCAEC) on those conditioned surfaces was studied in regard to cell proliferation, released IL-6 protein and immunofluorescence microscopy (IFM). We show that HCAEC function is dependent on the diameter of the TiO2 NTs, functioning far less optimally when bound to 100 nm TiO2 NTs as compared to Ti foil, 15 nm NTs or 50 nm NTs. There were improved, morphological cell shape changes, observed with IFM, between HCAEC growing on oxygen-rich plasma-treated versus nontreated 100 nm NTs. These endothelialized conditioned Ti nanosurfaces could elucidate optimization conditions necessary for vascular implants in coronary arteries. PMID- 26748553 TI - Faecal lactoferrin is a useful biomarker for mucosal healing in patients with ulcerative colitis during granulocyte and monocyte adsorptive apheresis therapy. AB - AIM: The study investigated the value of faecal lactoferrin as a follow-up biomarker for mucosal healing of ulcerative colitis during granulocyte and monocyte adsorptive apheresis (GMA) therapy. METHOD: Patients with ulcerative colitis exhibiting a moderate or severe disease activity with a partial Mayo Score (pMS) of over 4 were enrolled in this study. The patients received 10 courses of GMA therapy. The pMS value and faecal lactoferrin level were monitored and compared with the findings of endoscopy until 12 months after the last dose of GMA therapy. RESULTS: Twenty patients (male:female 11:9) were enrolled in this study. Twelve had total colitis, while six had left-sided involvement and two had distal proctitis. Thirteen (65.0%) responded to GMA therapy. The faecal lactoferrin levels were significantly decreased in patients who responded to GMA therapy (P < 0.05), whereas the levels did not change in non-responders. Moreover, the faecal lactoferrin levels correlated with the endoscopic findings (r = 0.792, P < 0.01) and pMS scores (r = 0.529, P < 0.01). The correlation coefficients between the faecal lactoferrin levels and mucosal findings were higher than those observed between the pMS score and mucosal findings. CONCLUSION: The faecal lactoferrin level is a useful biomarker of the mucosal findings in ulcerative colitis. Although endoscopy is the gold standard, the faecal lactoferrin level can be used as a biomarker during GMA therapy in patients with ulcerative colitis. PMID- 26748555 TI - Ln3+ -Mediated Self-Assembly of a Collagen Peptide into Luminescent Banded Helical Nanoropes. AB - Design of biomimetic peptides to achieve the desired properties of natural collagen has much potential to build functional biomaterials. A collagen peptide/Ln3+ system has been constructed and self-assembled to form helical nanoropes with a distinct periodic banding pattern characteristic of natural collagen. The fully reversible self-assembly is specifically mediated by lanthanide ions, but not by other commonly used divalent metal ions. Lanthanide ions not only provide an external biocompatible stimulus of the assembly, but also play as a functional unit to endow the assembled materials with easily tunable photoluminescence. To our knowledge, this is the first report of collagen peptide-based materials with exquisite nanorope structure and excellent photoluminescent features. These novel luminescent nanomaterials may have great potential in cell imaging, medical diagnostics, and luminescent scaffolds for cell cultivation. PMID- 26748556 TI - Detecting outlying studies in meta-regression models using a forward search algorithm. AB - When considering data from many trials, it is likely that some of them present a markedly different intervention effect or exert an undue influence on the summary results. We develop a forward search algorithm for identifying outlying and influential studies in meta-analysis models. The forward search algorithm starts by fitting the hypothesized model to a small subset of likely outlier-free studies and proceeds by adding studies into the set one-by-one that are determined to be closest to the fitted model of the existing set. As each study is added to the set, plots of estimated parameters and measures of fit are monitored to identify outliers by sharp changes in the forward plots. We apply the proposed outlier detection method to two real data sets; a meta-analysis of 26 studies that examines the effect of writing-to-learn interventions on academic achievement adjusting for three possible effect modifiers, and a meta-analysis of 70 studies that compares a fluoride toothpaste treatment to placebo for preventing dental caries in children. A simple simulated example is used to illustrate the steps of the proposed methodology, and a small-scale simulation study is conducted to evaluate the performance of the proposed method. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26748554 TI - Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Frontal Lobe Epilepsy: A New Clinico-Pathological Entity. AB - The histopathological spectrum of human epileptogenic brain lesions is widespread including common and rare variants of cortical malformations. However, 2-26% of epilepsy surgery specimens are histopathologically classified as nonlesional. We hypothesized that these specimens include also new diagnostic entities, in particular when presurgical magnetic resonance imaging (MRI) can identify abnormal signal intensities within the anatomical region of seizure onset. In our series of 1381 en bloc resected epilepsy surgery brain specimens, 52 cases could not be histopathologically classified and were considered nonlesional (3.7%). An increase of Olig2-, and PDGFR-alpha-immunoreactive oligodendroglia was observed in white matter and deep cortical layers in 22 of these patients (42%). Increased proliferation activity as well as heterotopic neurons in white matter were additional histopathological hallmarks. All patients suffered from frontal lobe epilepsy (FLE) with a median age of epilepsy onset at 4 years and 16 years at epilepsy surgery. Presurgical MRI suggested focal cortical dysplasia (FCD) in all patients. We suggest to classify this characteristic histopathology pattern as "mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE)." Further insights into pathomechanisms of MOGHE may help to bridge the diagnostic gap in children and young adults with difficult-to-treat FLE. PMID- 26748557 TI - Effect of Hops Beta Acids on the Survival of Unstressed- or Acid-Stress-Adapted Listeria Monocytogenes and on the Quality and Sensory Attributes of Commercially Cured Ham Slices. AB - This study evaluated the antilisterial activity of hops beta acids (HBA) and their impact on the quality and sensory attributes of ham. Commercially cured ham slices were inoculated with unstressed- and acid-stress-adapted (ASA)-L. monocytogenes (2.2 to 2.5 log CFU/cm(2) ), followed by no dipping (control), dipping in deionized (DI) water, or dipping in a 0.11% HBA solution. This was followed by vacuum or aerobic packaging and storage (7.2 degrees C, 35 or 20 d). Samples were taken periodically during storage to check for pH changes and analyze the microbial populations. Color measurements were obtained by dipping noninoculated ham slices in a 0.11% HBA solution, followed by vacuum packaging and storage (4.0 degrees C, 42 d). Sensory evaluations were performed on ham slices treated with 0.05% to 0.23% HBA solutions, followed by vacuum packaging and storage (4.0 degrees C, 30 d). HBA caused immediate reductions of 1.2 to 1.5 log CFU/cm(2) (P < 0.05) in unstressed- and ASA-L. monocytogenes populations on ham slices. During storage, the unstressed-L. monocytogenes populations on HBA treated samples were 0.5 to 2.0 log CFU/cm(2) lower (P < 0.05) than control samples and those dipped in DI water. The lag-phase of the unstressed-L. monocytogenes population was extended from 3.396 to 7.125 d (control) to 7.194 to 10.920 d in the HBA-treated samples. However, the ASA-L. monocytogenes population showed resistance to HBA because they had a higher growth rate than control samples and had similar growth variables to DI water-treated samples during storage. Dipping in HBA solution did not adversely affect the color or sensory attributes of the ham slices stored in vacuum packages. These results are useful for helping ready-to-eat meat processors develop operational procedures for applying HBA on ham slices. PMID- 26748558 TI - Caught between compassion and control: exploring the challenges associated with inpatient adolescent mental healthcare in an independent hospital. AB - AIM: To extend our understanding of how healthcare assistants construct and manage demanding situations in a secure mental health setting and to explore the effects on their health and well-being, to provide recommendations for enhanced support. BACKGROUND: Contemporary literature acknowledges high rates of occupational stress and burnout among healthcare assistants, suggesting the context in which they work places them at elevated risk of physical harm and psychological distress. Yet, there is a deficit of qualitative research exploring the experiences of healthcare assistants in adolescent inpatient facilities. DESIGN: An exploratory multi-method qualitative approach was used to collect data about the challenges faced by healthcare assistants working on secure adolescent mental health wards in an independent hospital during 2014. METHOD: Fifteen sets of data were collected. Ten participants completed diary entries and five participants were also interviewed allowing for triangulation. Data were analysed using Interpretive Phenomenological Analysis. FINDINGS: The findings illustrated how inpatient mental healthcare is a unique and distinctive area of nursing, where disturbing behaviour is often normalized and detached from the outside world. Healthcare assistants often experienced tension between their personal moral code which orientate them towards empathy and support and the emotional detachment and control expected by the organization, contributing to burnout and moral distress. CONCLUSIONS: This study yielded insights into mental health nursing and specifically the phenomenon of moral distress. Given the ever increasing demand for healthcare professionals, the effects of moral distress on both the lives of healthcare assistants and patient care, merits further study. PMID- 26748559 TI - Pharmacokinetic and Pharmacodynamic Analyses of Ceftaroline in Adults with Cystic Fibrosis. AB - STUDY OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of ceftaroline in adults with cystic fibrosis (CF). DESIGN: Open-label, single center, prospective study. SETTING: University-affiliated teaching institution. PATIENTS: Eight patients with a diagnosis of CF and a history of methicillin resistant Staphylococcus aureus who were treated with ceftaroline between November 2013 and September 2014. INTERVENTION: All patients received at least three doses of intravenous ceftaroline 600 mg every 12 hours, administered as a 60-minute infusion, to achieve steady-state concentrations before blood sample collection. After an interim analysis of the first four patients' pharmacokinetic data, the remaining four patients received a change in dosage of ceftaroline to 600 mg every 8 hours. MEASUREMENTS AND MAIN RESULTS: Patients' blood samples were collected at two time points, 2 and 6 hours after infusion initiation, after administration of at least three doses of ceftaroline. Serum ceftaroline concentrations were determined by using a validated mass spectrometry, with a lower limit of detection of 20 ng/ml. These ceftaroline concentrations were used to estimate patient-specific pharmacokinetic parameters, and 10,000-patient Monte Carlo simulations were performed to determine the pharmacodynamic probability of target attainment (PTA) for ceftaroline in adults with CF. A PTA of 90% or higher for the desired pharmacodynamic target was considered adequate. The PTA for 60% or higher of the dosing interval during which free (unbound) drug concentrations exceed the minimum inhibitory concentration (%fT > MIC) was simulated for various MICs. Compared with values previously reported in other populations, the volume of distribution was increased in the study patients, and the estimated half-life was shorter. Monte Carlo simulations revealed that a dose of ceftaroline 600 mg every 8 hours, infused over 60 minutes, maintained a higher than 90% PTA for %fT > MIC of 60% or higher for an MIC at the susceptibility breakpoint of 1 mg/L. CONCLUSION: The pharmacokinetics of ceftaroline is altered in adults with CF, which suggests the need for modified dosing in this patient population to achieve adequate %fT > MIC. A dosage of intravenous ceftaroline 600 mg every 8 hours administered as a 60-minute infusion should be considered to achieve 60% fT > MIC. PMID- 26748560 TI - Smad8/9 Is Regulated Through the BMP Pathway. AB - Members of the transforming growth factor-beta (TGF-beta) family function through Smad-dependent and Smad-independent pathways. The Smad-dependent pathway is stimulated through the phosphorylation of receptor-regulated Smad (R-Smad) and inhibited through the dephosphorylation of R-Smad or the gene induction of inhibitory Smad (I-Smad). Little information is available on the regulation of R Smad gene expression. BMP4 potentiated the up-regulation of Smad8/9 expression in C2C12, H9c2, 3T3-L1, HepG2, B16, and primary fibroblasts. BMP4-induced Smad8/9 expression was cycloheximide-insensitive and LDN-193189-sensitive, suggesting a direct event mediated through BMP type I receptors. BMP4 transcriptionally stimulated the Smad8/9 gene, and BMP-responsive elements (BREs) spanning nt -121 to nt -44 are involved in the up-regulation of Smad8/9 expression in response to BMP4. Phosphorylated Smad1/5/8/9 specifically bound to the BREs of Smad8/9 gene. The present study reveals that Smad8/9 is a unique R-Smad regulated through the BMP pathway at the mRNA level. J. Cell. Biochem. 117: 1788-1796, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26748561 TI - Metal-Free Synthesis of Fluorinated Indoles Enabled by Oxidative Dearomatization. AB - Nitrogen heterocycles are found in a majority of approved small-molecule pharmaceuticals, and the number of approved fluorinated drugs is increasing each decade. Therefore, new approaches for accessing fluorinated nitrogen heterocycles are of great significance. A novel, scalable, and metal-free method for accessing a wide range of fluorinated indoles is described. This oxidative-dearomatization enabled approach assembles 2-trifluoromethyl NH-indole products from simple commercially available anilines with hexafluoroacetylacetone in the presence of an organic oxidant. The nature of the aniline N-capping group is critical for the success of this new reaction. Furthermore, the indole products contain a 3 trifluoroacetyl group, which can be exploited to access a plethora of useful functional groups. PMID- 26748564 TI - Mechanical assessment of the effects of metastatic lytic defect on the structural response of human thoracolumbar spine. AB - To investigate the effects of a clinical lytic defect on the structural response of human thoracolumbar functional spinal unit. A novel CT-compatible mechanical test system was used to image the deformation of a T12-L1 motion segment and measure the change in strain response under compressive loads ranging from 50 to 750 N. A lytic lesion (LM) with cortex involvement (33% by volume) was introduced to the upper vertebral body and the CT experiments were repeated. Finite element models, established from the CT volumes, were used to investigate the defect's effects on the structural response and the state of principal and shear stresses within the affected and adjacent vertebrae. The lytic lesion resulted in severe loss of the vertebral structural competence, resulting in significant, non linear, and asymmetric increase in the experimentally measured strains and computed stresses within both vertebrae (p < 0.01). At the cortex, the tensile strains were significantly increased, while compressive strains significantly decreased, (p < 0.05). Both the vertebral bone and cortex regions adjacent to the defect showed significant increase in computed compressive, tensile, and shear stresses (p < 0.01). Changes in stress and strain distribution within the affected and adjacent vertebral bone and the experimentally observed bulging and buckling of the vertebral cortices suggested that initiation of catastrophic vertebral failure may occur under load magnitudes encountered in daily living. Although the effect of LM on the global deformation of the spine was well predicted, our results show that FE predictions of local strain changes must be carefully assessed for clinical relevance. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1808-1819, 2016. PMID- 26748562 TI - Differential effects of Epigallocatechin-3-gallate containing supplements on correcting skeletal defects in a Down syndrome mouse model. AB - SCOPE: Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa21), is characterized by a spectrum of phenotypes including skeletal abnormalities. The Ts65Dn DS mouse model exhibits similar skeletal phenotypes as humans with DS. DYRK1A, a kinase encoded on Hsa21, has been linked to deficiencies in bone homeostasis in DS mice and individuals with DS. Treatment with Epigallocatechin-3 gallate (EGCG), a known inhibitor of Dyrk1a, improves some skeletal abnormalities associated with DS in mice. EGCG supplements are widely available but the effectiveness of different EGCG-containing supplements has not been well studied. METHODS AND RESULTS: Six commercially available supplements containing EGCG were analyzed, and two of these supplements were compared with pure EGCG for their impact on skeletal deficits in a DS mouse model. The results demonstrate differential effects of commercial supplements on correcting skeletal abnormalities in Ts65Dn mice. Different EGCG-containing supplements display differences in degradation, polyphenol content, and effects on trisomic bone. CONCLUSION: This work suggests that the dose of EGCG and composition of EGCG containing supplements may be important in correcting skeletal deficits associated with DS. Careful analyses of these parameters may lead to a better understanding of how to improve skeletal and other deficits that impair individuals with DS. PMID- 26748563 TI - Diagnostic value of liquid-based cytology with fine needle aspiration specimens for cervical lymphadenopathy. AB - BACKGROUND: Cervical lymphadenopathy is a symptom that is frequently seen among outpatients, and it is important to differentiate malignant lesions from reactive lymphoid hyperplasia. Fine needle aspiration (FNA) cytology has been widely used for the diagnosis of cervical lymphadenopathy. However, some limitations of the diagnostic accuracy using conventional smear (CS) cytology have been pointed out. The diagnostic value of liquid-based cytology (LBC) with FNA specimens has not yet been fully proven. METHODS: Forty-two patients with cervical lymphadenopathy who underwent FNA with CS cytology from 2007 to 2011 and 123 patients who underwent FNA with LBC utilizing LBCPREP2TM from 2011 to 2015 were studied. Diagnostic values were compared between the CS and the LBC groups. RESULTS: Of the total 165 patients representing the combined CS and LBC groups, 81 (49.1%) were diagnosed as benign lymph node and 84 (50.9%) were malignant diseases including 37 (22.4%) of metastatic carcinoma except for thyroid carcinoma, 30 (18.2%) of metastatic thyroid carcinoma, and 17 (10.3%) of malignant lymphoma. The overall statistical values including sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the CS were 75%, 100%, 100%, 78.9%, and 87.1%, respectively, whereas those values for LBC were 91.2%, 100%, 100%, 90.7%, and 95.3%, respectively. The sensitivity of LBC for malignant diseases tended to be higher than that of CS cytology (p = 0.081). CONCLUSION: LBC with FNA specimens from cervical lymphadenopathy is a useful and reliable method for the diagnosis of malignant diseases, especially of metastatic carcinomas, due to its increased sensitivity compared with CS cytology. PMID- 26748565 TI - Retinal neuronal and vascular function in type 1 diabetes adults during glycaemic clamps. PMID- 26748566 TI - In Vivo Evaluation of Active and Passive Physiological Control Systems for Rotary Left and Right Ventricular Assist Devices. AB - Preventing ventricular suction and venous congestion through balancing flow rates and circulatory volumes with dual rotary ventricular assist devices (VADs) configured for biventricular support is clinically challenging due to their low preload and high afterload sensitivities relative to the natural heart. This study presents the in vivo evaluation of several physiological control systems, which aim to prevent ventricular suction and venous congestion. The control systems included a sensor-based, master/slave (MS) controller that altered left and right VAD speed based on pressure and flow; a sensor-less compliant inflow cannula (IC), which altered inlet resistance and, therefore, pump flow based on preload; a sensor-less compliant outflow cannula (OC) on the right VAD, which altered outlet resistance and thus pump flow based on afterload; and a combined controller, which incorporated the MS controller, compliant IC, and compliant OC. Each control system was evaluated in vivo under step increases in systemic (SVR ~1400-2400 dyne/s/cm(5) ) and pulmonary (PVR ~200-1000 dyne/s/cm(5) ) vascular resistances in four sheep supported by dual rotary VADs in a biventricular assist configuration. Constant speed support was also evaluated for comparison and resulted in suction events during all resistance increases and pulmonary congestion during SVR increases. The MS controller reduced suction events and prevented congestion through an initial sharp reduction in pump flow followed by a gradual return to baseline (5.0 L/min). The compliant IC prevented suction events; however, reduced pump flows and pulmonary congestion were noted during the SVR increase. The compliant OC maintained pump flow close to baseline (5.0 L/min) and prevented suction and congestion during PVR increases. The combined controller responded similarly to the MS controller to prevent suction and congestion events in all cases while providing a backup system in the event of single controller failure. PMID- 26748567 TI - The effect of clove bud powder at a spice level on antioxidant and quality properties of emulsified pork sausage during cold storage. AB - BACKGROUND: Clove bud is a widely used spice in meat and meat products, and it contains high level of phenolic compounds. The effectiveness of the clove as a spice has not been fully studied at a general level of addition in the meat products. Therefore, in the present study, the antioxidant, antimicrobial, and nitrite scavenging abilities of clove bud powder (CBP) was assessed at spice level (0.1% and 0.2%) in emulsified pork sausage, during 6 weeks of cold storage. RESULTS: CBP had DPPH radical scavenging ability, but CBP addition at 0.1% and 0.2% did not decrease the TBARS value. An antimicrobial effect of CBP was also not observed during the cold storage. However, residual nitrite at storage weeks 4 and 6 was shown to be lower (P < 0.05). Addition of CBP decreased CIE L* and a* values, but it produced unacceptable sensory properties. Texture profile analysis was not affected by the addition of CBP in emulsified pork sausage (P > 0.05). CONCLUSIONS: The positive effect on nitrite scavenging could be expected by the addition of 0.2% CBP as a spice. However, antioxidant and antimicrobial abilities were not observed, as well as improvement in the quality of characteristics, in emulsified pork sausage. (c) 2016 Society of Chemical Industry. PMID- 26748568 TI - The evolution of sperm competition genes: The effect of mating system on levels of genetic variation within and between species. AB - It is widely established that proteins involved in reproduction diverge between species more quickly than other proteins. For male sperm proteins, rapid divergence is believed to be caused by postcopulatory sexual selection and/or sexual conflict. Here, we derive the expected levels of gene diversity within populations and divergence between them for male sperm protein genes evolving by postcopulatory, prezygotic fertility competition, i.e. the function imputed for some sperm and seminal fluid genes. We find that, at the mutation-selection equilibrium, both gene diversity within species and divergence between them are elevated relative to genes with similar selection coefficients expressed by both sexes. We show that their expected level of diversity is a function of the harmonic mean number of mates per female, which affects the strength of fertility selection stemming from male-male sperm competition. Our predictions provide a null hypothesis for distinguishing between other selective hypotheses accounting for the rapid evolution of male reproductive genes. PMID- 26748569 TI - Improved continuity of care in a resident clinic. AB - BACKGROUND: For residents in the out-patient clinic, continuity in patient care is an integral and vital aspect of internal medicine training, but is frequently compromised by resident in-patient schedules, the structure of the out-patient clinic and the need to comply with the increasing regulation of duty hours. METHOD: In this study, we examined whether the creation and implementation of a new team approach, the Firms Model, would improve the continuity of patient care in the internal medicine resident out-patient clinic. RESULTS: Before the implementation of the Firms Model, an examination of a consecutive clinic sample indicated that patients were seen by their assigned resident providers 41.9 per cent of the time (n = 1319 clinic visits). After implementation of the Firms Model, an examination of a consecutive clinic sample indicated that patients were seen by their assigned Firm resident providers 88.9 per cent of the time (n = 1341 clinic visits). CONCLUSION: Implementation of the Firms Model resulted in a statistically significant increase in the percentage of patients seen by assigned resident providers in an internal medicine out-patient clinic, culminating in a substantial improvement in continuity of care within our resident out-patient clinic. We discuss the implications of these findings. Continuity in patient care is an integral and vital aspect of internal medicine training, but is frequently compromised. PMID- 26748570 TI - Reply. PMID- 26748571 TI - Biocompatible Size-Defined Dendrimer-Albumin Binding Protein Hybrid Materials as a Versatile Platform for Biomedical Applications. AB - For the design of a biohybrid structure as a ligand-tailored drug delivery system (DDS), it is highly sophisticated to fabricate a DDS based on smoothly controllable conjugation steps. This article reports on the synthesis and the characterization of biohybrid conjugates based on noncovalent conjugation between a multivalent biotinylated and PEGylated poly(amido amine) (PAMAM) dendrimer and a tetrameric streptavidin-small protein binding scaffold. This protein binding scaffold (SA-ABDwt) possesses nM affinity toward human serum albumin (HSA). Thus, well-defined biohybrid structures, finalized by binding of one or two HSA molecules, are available at each conjugation step in a controlled molar ratio. Overall, these biohybrid assemblies can be used for (i) a controlled modification of dendrimers with the HSA molecules to increase their blood-circulation half life and passive accumulation in tumor; (ii) rendering dendrimers a specific affinity to various ligands based on mutated ABD domain, thus replacing tedious dendrimer-antibody covalent coupling and purification procedures. PMID- 26748572 TI - Stroke assessment with intravoxel incoherent motion diffusion-weighted MRI. AB - Intravoxel incoherent motion (IVIM) diffusion-weighted MRI can simultaneously measure diffusion and perfusion characteristics in a non-invasive way. This study aimed to determine the potential utility of IVIM in characterizing brain diffusion and perfusion properties for clinical stroke. The multi-b-value diffusion-weighted images of 101 patients diagnosed with acute/subacute ischemic stroke were retrospectively evaluated. The diffusion coefficient D, representing the water apparent diffusivity, was obtained by fitting the diffusion data with increasing high b-values to a simple mono-exponential model. The IVIM-derived perfusion parameters, pseudodiffusion coefficient D*, vascular volume fraction f and blood flow-related parameter fD*, were calculated with the bi-exponential model. Additionally, the apparent diffusion coefficient (ADC) was fitted according to the mono-exponential model using all b-values. The diffusion parameters for the ischemic lesion and normal contralateral region were measured in each patient. Statistical analysis was performed using the paired Student t test and Pearson correlation test. Diffusion data in both the ischemic lesion and normal contralateral region followed the IVIM bi-exponential behavior, and the IVIM model showed better goodness of fit than the mono-exponential model with lower Akaike information criterion values. The paired Student t-test revealed significant differences for all diffusion parameters (all P < 0.001) except D* (P = 0.218) between ischemic and normal areas. For all patients in both ischemic and normal regions, ADC was significantly positively correlated with D (both r = 1, both P < 0.001) and f (r = 0.541, P < 0.001; r = 0.262, P = 0.008); significant correlation was also found between ADC and fD* in the ischemic region (r = 0.254, P = 0.010). For all pixels within the region of interest from a representative subject in both ischemic and normal regions, ADC was significantly positively correlated with D (both r = 1, both P < 0.001), f (r = 0.823, P < 0.001; r = 0.652, P < 0.001) and fD* (r = 0.294, P < 0.001; r = 0.340, P < 0.001). These findings may have clinical implications for the use of IVIM imaging in the assessment and management of acute/subacute stroke patients. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26748573 TI - Surgical drains: what is still unlearned in everyday practice? PMID- 26748575 TI - In vitro behavior of poly-lactic-co-glycolic acid microspheres containing minocycline, metronidazole, and ciprofloxacin. AB - AIM: In the present study, we aimed to fabricate poly-lactic-co-glycolic acid (PLGA) microspheres containing a mixture of three antibiotics-minocycline, metronidazole, and ciprofloxacin (MMC)-to assess their efficacy and properties. METHODS: MMC were loaded onto PLGA biopolymer microspheres at a 1:1:1 ratio using the double emulsion technique. The morphology of microspheres was observed by a (SEM). The controlled release of antibiotics was evaluated over an 18-day period. The antibacterial efficacy of released antibiotics against Aggregatibacter actinomycetemcomitans was evaluated by measuring the diameter of the growth inhibition zone. The cytotoxicity of MMC-containing microspheres was also evaluated and compared using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. One-way anova was used for the data analysis. RESULTS: SEM micrographs confirmed the spherical shape and smooth surface of microspheres. The adequate release of antibiotics was observed from the microspheres within the desired time period of 16-18 days. The MMC-containing microspheres showed antibacterial activity for 11 days. Moreover, MMC-containing microspheres showed superior cell biocompatibility compared to the free mixture of the three antibiotics (P < 0.05). CONCLUSION: Microspheres containing triple antibiotics showed good release, antibacterial activity for 11 days, and similar cell biocompatibility compared to the empty microspheres. PMID- 26748574 TI - Successful reduced-intensity stem cell transplantation for GATA2 deficiency before progression of advanced MDS. AB - A 13-yr-old boy bearing lymphedema and congenital deafness had distinct hematological abnormalities consisting of reduced monocytes, B cells, and dendritic cells in the peripheral blood as well as MDS with normal karyotype in the bone marrow. The patient was diagnosed with Emberger syndrome by sequencing of GATA2 DNA, and underwent RIST from an HLA-matched unrelated donor. Prompt engraftment and immunological reconstitution were observed without any severe RRT. As most patients with GATA2 anomaly died due to the development of AML or active infections, RIST could be a promising treatment option before progression of advanced MDS. PMID- 26748576 TI - MEF2 and NR2F2 cooperate to regulate Akr1c14 gene expression in mouse MA-10 Leydig cells. AB - Leydig cells are essential for male reproductive development and health throughout life. Production of androgens [testosterone, dihydrotestosterone (DHT)] as well as intermediate steroids [progesterone, dihydroprogesterone (DHP)] is tightly regulated. In the mouse, the 3alpha-hydroxysteroid dehydrogenase enzyme (3alpha-HSD, AKR1C14) catalyses the interconversion of DHP and DHT into less potent steroids. Despite its importance, nothing is currently known regarding the regulation of Akr1c14 expression in Leydig cells. Recently, the transcription factors MEF2 and NR2F2 were identified in the mouse testis including in Leydig cells where they were found to regulate expression of genes involved in steroidogenesis. Analyses of transcriptomic data from MEF2- or NR2F2 deficient MA-10 Leydig cells revealed a significant decrease in Akr1c14 mRNA levels. Using qPCR, we confirmed that Akr1c14 mRNA levels were decreased in MEF2- and in NR2F2-deficient conditions. Conversely, overexpression of MEF2A or/and NR2F2 in MA-10 Leydig cells led to an increase in endogenous Akr1c14 mRNA levels. Recruitment of MEF2 and NR2F2 to the Akr1c14 promoter was confirmed by ChIP while DNA precipitation assays revealed direct binding of MEF2 but not NR2F2 to this region. In functional promoter studies, NR2F2 was found to activate the Akr1c14 promoter while MEF2A on its own had no effect. Combination of both NR2F2 and MEF2A led to a cooperative activation of the Akr1c14 promoter and this required intact MEF2 and NR2F2 elements. Finally, co-immunoprecipitation experiments showed that MEF2 and NR2F2 are present in the same protein complex. In conclusion, our results identify a novel cooperation between MEF2 factors and NR2F2 in the expression of the Akr1c14 gene involved in the regulation of DHP/DHT levels. PMID- 26748577 TI - Current trends in the management of glioblastoma in a French University Hospital and associated direct costs. AB - WHAT IS NEW AND OBJECTIVES: Trends in the care of glioblastoma in actual practice settings are poorly described. In a previous pharmacoepidemiologic study, we highlighted changes in the management of patients with glioblastoma (GBM) newly diagnosed between 2004 and 2008. Our aim was to complete and to extend the previous report with a study of a cohort of patients diagnosed in 2011 to emphasize the trends in the pharmacotherapy of GBM over the last decade. METHODS: A single-centre study was undertaken of three historic cohorts of GBM patients newly diagnosed during years 2004, 2008 and 2011 (corresponding to groups 1, 2 and 3, respectively) but limited to patients eligible for radiotherapy after initial diagnosis. The type of medical management was described and compared, as well as overall survival and total cost from diagnosis to death or the last follow-up date. Cost analysis was performed from the French sickness fund perspective using tariffs from 2014. RESULTS: Two hundred and seventeen patients (49 in Group 1, 73 in Group 2, 95 in Group 3) were selected with similar baseline characteristics. Fluorescence-guided surgery using 5-ALA was increasingly used over the three periods. There was a strong trend towards broader use of temozolomide radiochemotherapy (39%, 73% and 83% of patients, respectively) as first-line treatment as well as bevacizumab regimen at recurrence (6%, 48% and 58% of patients, respectively). The increase in overall survival between Group 2 and Group 1 was confirmed for patients in Group 3 (17.5 months vs. 10 months in Group 1). The mean total cost per patient was 53368 ? in Group 1, 70 201 ? in Group 2 and 78355 ? in Group 3. Hospital care represented the largest expenditure (75%, 59% and 60% in groups 1, 2 and 3, respectively) followed by chemotherapy drug costs (11%, 30% and 29%, respectively). WHAT IS NEW AND CONCLUSION: This is the first study to report on changes in the management of GBM in real-life practice. The ten-year study indicates an improvement in overall survival but also an increase in total cost of care. The data should be useful for informing the care of GBM patients in settings similar to ours. PMID- 26748580 TI - Editorial: Biosimilars: New or Deja Vu? PMID- 26748578 TI - Glyoxal induced structural transition of buffalo kidney cystatin to molten globule and aggregates: Anti-fibrillation potency of quinic acid. AB - In our study buffalo kidney cystatin (BKC) is transformed from native conformation to amyloid fibrils when incubated with 20 mM glyoxal for a prolonged time period. These amyloid fibrils are at the heart of a number of pathological disorders. In the presence of 10 mM glyoxal, BKC retained native-like secondary structure, decreased intrinsic and increased ANS fluorescence was observed, characteristics of molten globule state (MG), thus suggesting the occurrence of MG state at this concentration. At 20 mM glyoxal, BKC aggregates were characterized by a further decrease in ANS fluorescence attributable to internalization of hydrophobic clusters owing to protein-protein interaction. Circular dichroism and FTIR spectroscopy further revealed the existence of beta sheet structure and there was an increase in Thioflavin T fluorescence, Rayleigh light scattering, turbidity as well as red shift in congo red absorbance thus confirming the existence of aggregates. We have also studied the anti-aggregation effect of polyol, quinic acid making use of various above mentioned biophysical assays. Our proposed work strongly favors the formation of BKC aggregates in the presence of glyoxal, which is present in higher amounts in pathological conditions owing to defective glycolysis pathway and also use of polyol as an antifibrillating agent. PMID- 26748579 TI - Evidence for a Role for Nanoporosity and Pyridinoline Content in Human Mild Osteogenesis Imperfecta. AB - Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous connective tissue disorder characterized by bone fragility that arises from decreased bone mass and abnormalities in bone material quality. OI type I represents the milder form of the disease and according to the original Sillence classification is characterized by minimal skeletal deformities and near-normal stature. Raman microspectroscopy is a vibrational spectroscopic technique that allows the determination of bone material properties in bone biopsy blocks with a spatial resolution of ~1 um, as a function of tissue age. In the present study, we used Raman microspectroscopy to evaluate bone material quality in transiliac bone biopsies from children with a mild form of OI, either attributable to collagen haploinsufficiency OI type I (OI-Quant; n = 11) or aberrant collagen structure (OI-Qual; n = 5), as a function of tissue age, and compared it against the previously published values established in a cohort of biopsies from healthy children (n = 54, ages 1 to 23 years). The results indicated significant differences in bone material compositional characteristics between OI-Quant patients and healthy controls, whereas fewer were evident in the OI-Qual patients. Differences in both subgroups of OI compared with healthy children were evident for nanoporosity, mineral maturity/crystallinity as determined by maxima of the v1 PO4 Raman band, and pyridinoline (albeit in different direction) content. These alterations in bone material compositional properties most likely contribute to the bone fragility characterizing this disease. (c) 2016 American Society for Bone and Mineral Research. PMID- 26748581 TI - Carbon Nanotubes and Graphene for Flexible Electrochemical Energy Storage: from Materials to Devices. AB - Flexible electrochemical energy storage (FEES) devices have received great attention as a promising power source for the emerging field of flexible and wearable electronic devices. Carbon nanotubes (CNTs) and graphene have many excellent properties that make them ideally suited for use in FEES devices. A brief definition of FEES devices is provided, followed by a detailed overview of various structural models for achieving different FEES devices. The latest research developments on the use of CNTs and graphene in FEES devices are summarized. Finally, future prospects and important research directions in the areas of CNT- and graphene-based flexible electrode synthesis and device integration are discussed. PMID- 26748583 TI - Erratum: Pediatric post-marketing safety systems in North America: assessment of the current status. PMID- 26748582 TI - Transition in the Office of Regional Editor for Europe. PMID- 26748584 TI - The authors reply "Nebulized bronchodilators instead of metered-dose inhalers for obstructive pulmonary symptoms". PMID- 26748585 TI - Instance-Based Models of Metacognition in the Prisoner's Dilemma. AB - In this article, we examine the advantages of simple metacognitive capabilities in a repeated social dilemma. Two types of metacognitive agent were developed and compared with a non-metacognitive agent and two fixed-strategy agents. The first type of metacognitive agent (opponent perspective) takes the perspective of the opponent to anticipate the opponent's future actions and respond accordingly. The other metacognitive agent (modeler) predicts the opponent's next move based on the previous moves of the agent and the opponent. The modeler agent achieves better individual outcomes than a non-metacognitive agent and is more successful at encouraging cooperation. The opponent-perspective agent, by contrast, fails to achieve these outcomes because it lacks important information about the opponent. These simple agents provide insights regarding modeling of metacognition in more complex tasks. PMID- 26748586 TI - Truncation and microdeletion of EVC/EVC2 with missense mutation of EFCAB7 in Ellis-van Creveld syndrome. AB - Ellis-van Creveld syndrome (EvC) is a ciliopathy with cardiac anomalies, disproportionate short stature, polydactyly, dystrophic nails and oral defects. To obtain further insight into the genetics of EvC, we screened EVC/EVC2 mutations in eight Vietnamese EvC patients. All the patients had a congenital heart defect with atypical oral and/or skeletal abnormalities. One had compound heterozygous EVC2 mutations: a novel mutation c.769G > T-p.E177X in exon 6 inherited from father and another previously reported c.2476C > T-p.R826X mutation in exon 14 inherited from mother. The EVC2 mRNA expression level was significantly lower in the patient and her parents compared to controls. Another case had a novel heterozygous EVC mutation (c.1717C > G-p.S572X) in exon 12, inherited from his father. Of note, the mother without any EVC mutation on Sanger sequencing showed a lower expression level of EVC mRNA compared with controls. SNP array analysis revealed that the patient and mother had a heterozygous 16.4 kb deletion in EVC. This patient also had a heterozygous novel variant in exon 9 of EFCAB7 (c.1171 T > C-p.Y391H), inherited from his father. The atypical cardiac phenotype of this patient and the father suggested that EFCAB7 may modify the phenotype by interacting with EVC. In conclusion, we detected two novel nonsense mutations and a partial deletion of EVC/EVC2 in two Vietnamese families with EvC. Moreover, we found in one family a missense mutation of EFCAB7, a possible modifier gene in EvC and its related disorders. PMID- 26748587 TI - Cancer cell identification by bi-color ZnO and TiO2 nanowires. AB - Semiconductor nanocomposites provide advantages beyond the capability of typical fluorescent materials for cancer detection. In this work, nanowire-based probes with dual color channels are employed to demonstrate the capacity of cancer cell detection. Purple emitting ZnO/antibody probes are applied to detect cancer cells and meanwhile TiO2 /antibody probes with green light emission are applied to identify normal fibroblast cells. A series of quantitative analyses are conducted to verify the correlation between the concentrations of ZnO and TiO2 probes, cell numbers, and peak intensities of the PL spectra. The results provide a quantitative reference for developing nanowire-based cancel cell probes. PMID- 26748588 TI - Impact of sleepiness on arterial stiffness and cardio-vascular risk in men with moderate to severe obstructive sleep apnea. PMID- 26748589 TI - Effectiveness and safety of mouthpiece ventilation and nocturnal non-invasive ventilation in patients with kyphoscoliosis: Short and long-term outcomes after an episode of acute respiratory failure. AB - BACKGROUND: Kyphoscoliosis is a skeletal condition involving the hyperflexion of the thoracic spine. It is characterized by reduced chest wall compliance and impaired respiratory mechanisms leading to progressive hypo-ventilation. We evaluated the effectiveness and the safety of non-invasive ventilation (NIV) in patients after an episode of acute respiratory failure (ARF). METHODS: Eighteen patients with severe kyphoscoliosis who had been hospitalized for an episode of ARF were followed for 4 years. NIV was applied via mouthpiece (MPV) during the daytime and via mask during the night. The primary outcomes were changes in physiological and functional parameters as well as quality of life. Secondary outcomes were considered re-hospitalization and mortality rate after discharge. A set of control subjects was used for comparison. RESULTS: All patients showed a significant improvement in several clinical, physiological, functional and quality of life parameters. Four of them (22.2%) died during the four year follow up period. In the uni-variate analysis patients who died had higher cardiac co morbidity, lower MIP and SNIP, higher paCO2, and oxygen desaturation index at initial admission. CONCLUSIONS: Diurnal MPV associated with nocturnal NIV had significantly improved lung function, clinical outcomes and quality of life. It should be considered as a safe alternative to traditional administering of NIV. PMID- 26748592 TI - Possible mechanism of BN fullerene formation from a boron cluster: Density functional tight-binding molecular dynamics simulations. AB - We simulate the formation of a BN fullerene from an amorphous B cluster at 2000 K by quantum mechanical molecular dynamics based on the density-functional tight binding method. We run 30 trajectories 200 ps in length, where N atoms are supplied around the target cluster, which is initially an amorphous B36 cluster. Most of the incident N atoms are promptly incorporated into the target cluster to form B-N-B bridges or NB3 pyramidal local substructures. BN fullerene formation is initiated by alternating BN ring condensation. Spontaneous atomic rearrangement and N2 dissociation lead to the construction of an sp(2) single shelled structure, during which the BN cluster undergoes a transition from a liquid-like to a solid-like state. Continual atomic rearrangement and sporadic N2 dissociation decrease the number of defective rings in the BN cluster and increase the number of six-membered rings, forming a more regular shell structure. The number of four-membered rings tends to remain constant, and contributes to more ordered isolated-tetragon-rule ring placement. PMID- 26748590 TI - Land cover change and carbon emissions over 100 years in an African biodiversity hotspot. AB - Agricultural expansion has resulted in both land use and land cover change (LULCC) across the tropics. However, the spatial and temporal patterns of such change and their resulting impacts are poorly understood, particularly for the presatellite era. Here, we quantify the LULCC history across the 33.9 million ha watershed of Tanzania's Eastern Arc Mountains, using geo-referenced and digitized historical land cover maps (dated 1908, 1923, 1949 and 2000). Our time series from this biodiversity hotspot shows that forest and savanna area both declined, by 74% (2.8 million ha) and 10% (2.9 million ha), respectively, between 1908 and 2000. This vegetation was replaced by a fivefold increase in cropland, from 1.2 million ha to 6.7 million ha. This LULCC implies a committed release of 0.9 Pg C (95% CI: 0.4-1.5) across the watershed for the same period, equivalent to 0.3 Mg C ha(-1) yr(-1) . This is at least threefold higher than previous estimates from global models for the same study area. We then used the LULCC data from before and after protected area creation, as well as from areas where no protection was established, to analyse the effectiveness of legal protection on land cover change despite the underlying spatial variation in protected areas. We found that, between 1949 and 2000, forest expanded within legally protected areas, resulting in carbon uptake of 4.8 (3.8-5.7) Mg C ha(-1) , compared to a committed loss of 11.9 (7.2-16.6) Mg C ha(-1) within areas lacking such protection. Furthermore, for nine protected areas where LULCC data are available prior to and following establishment, we show that protection reduces deforestation rates by 150% relative to unprotected portions of the watershed. Our results highlight that considerable LULCC occurred prior to the satellite era, thus other data sources are required to better understand long-term land cover trends in the tropics. PMID- 26748591 TI - Preventing species invasion: A role for integrative taxonomy? AB - Integrative taxonomy, a multi-disciplinary approach adding modern techniques to traditional morphology-based methods (e.g. molecular and morphological criteria), can play an important role in bioinvasion research to identify introduced taxa, discover pathways of introduction and inform authorities to control and prevent future introductions. The present study is the first on introduced populations of Callosciurus, Asiatic tree squirrels, known as potentially invasive species in Europe (Italy, Belgium and France). We combined molecular (mitochondrial DNA markers: CoxI, D-loop) and morphometric analysis on skulls, comparing them to the widest morphological and molecular datasets ever assembled for Callosciurus. Squirrels collected in Italy and Belgium share the same haplotypes and skull characteristics, but are conspicuously different from the French population in Antibes. Genetic data revealed close similarity between French squirrels and Pallas's squirrels, Callosciurus erythraeus, from Taiwan, China. Italian and Belgian squirrels formed an independent taxonomic lineage in genetic analyses, whose taxonomic rank needs further investigation. The morphological and morphometric characteristics of these 2 populations are, however, similar to known specimens assigned to Callosciurus erythraeus. These results may indicate a common origin for the populations found in Belgium and Italy. In contrast, French specimens suggest an independent introduction event of squirrels originating from Asia. PMID- 26748593 TI - Erythropoiesis-stimulating agents in gynecological malignancies: A study-level meta-analysis. AB - This meta-analysis was planned to define the role of erythropoiesis-stimulating agents (ESAs) in gynecological cancer patients, receiving myelosuppressive treatment. Pubmed, Medline and Scopus were searched to select English-language articles. Only randomized controlled trials (RCTs) were included. Endpoints were incidence of transfusions, thrombotic events (TE), deaths, and failures. Odd ratio (OR) with 95% confidence interval (CI) was calculated using fixed or random effects model. In seven RCTs ESAs studies of 892 patients under treatment, use of ESAs correlates with a significant reduction of transfusions rate (OR=0.35; 95% CI: 0.19-0.65; p=0.008). OR for overall mortality was 1.10 (95% CI 0.82-1.49; p=0.53). ESAs OR for disease failure in 5 studies was 1.71 (95% CI: 0.90-3.24; p=0.1). This meta-analysis, even if limited by few RCTs, suggests that ESAs reduce transfusions without increasing mortality or disease progression in gynecological cancer patients receiving treatment. PMID- 26748595 TI - Distribution, compositional pattern and sources of polycyclic aromatic hydrocarbons in urban soils of an industrial city, Lanzhou, China. AB - The level, distribution, compositional pattern and possible sources of polycyclic aromatic hydrocarbons (PAHs) in Lanzhou urban soil of Northwest China were investigated in this study. The total level of 22 PAHs ranged from 115 to 12,100 ug kg(-1) and that of 16 priority PAHs from 82.4 to 10,900 ug kg(-1). Seven carcinogenic PAHs generally accounted for 6.18-57.4% of total 22 PAHs. Compared with data from those reported about urban areas, PAH contamination in Lanzhou urban soils was moderate. Among different functional areas, higher level of PAHs was found along roadsides and in the industrial district (p<0.01), while lower levels were detected in the commercial, park and residential districts. The composition of PAHs was characterized by high molecular weight PAHs (>=4 rings), among which fluoranthene, benz[a]anthracene and phenanthrene were the most dominant components. Correlation analysis suggested that low molecular weight PAHs and high molecular weight PAHs originated from different sources and further corroborated that TOC was an important factor in the accumulation of PAHs in soil. Isomer ratios and principal component analysis indicated that PAHs in urban soil derived primarily from emissions resulting from the combustion of biomass, coal and petroleum products. Toxic equivalent concentrations (BaP(eq)) of soil PAHs ranged from 6.12 to 1302 ug BaP(eq) kg(-1), with a mean of 138 ug BaP(eq) kg(-1). The results suggested that human exposure to those soils which polluted by high concentrations of PAHs through direct ingestion or inhalation of suspended soil particles probably poses a significant risk to human health from the carcinogenic effects of PAHs. PMID- 26748594 TI - Patient-orientated removable space maintainer as a decompression stent. PMID- 26748596 TI - Production impact & time to stability in sow herds infected with porcine epidemic diarrhea virus (PEDV). AB - PEDV was first detected in United States in May, 2013. The virus spread through the swine industry and was reported in 30 US states by June, 2014 (Morrison and Goede, 2014). There are limited data describing the impact on production in sow farms. Veterinarians attempt to control the virus in sow herds with a program that stimulates herd immunity. There are no data on how long it takes with this control program to achieve a stable state of consistently produce weaned pigs that are not infected with the virus. This study involved participants and data from an existing program called the Swine Health Monitoring Project. Veterinarians were invited to share production data from 429 herds infected with PEDV. These data, in conjunction with diagnostic reports, were used to estimate the time required for the herd to produce PEDV PCR negative pigs and the production loss. Of the 429 infected herds that achieved the stable state of weaning PEDV PCR negative pigs, the median time was 28 weeks, ranging from 7 to 64 weeks. A median of 2.7 piglets/inventoried sow were not weaned and the average time required to recover to baseline production was 10 weeks in 183 herds. Herd infected in quarters 3 or 4 of the year had approximately twice the negative impact. These data are valuable for veterinarians in advising clients on the anticipated impact and time to re-achieve a stable state with regards to PEDV. PMID- 26748597 TI - Cervical amoebiasis mimicking cervical carcinoma: A rare presentation of a common infection. AB - Cervical amoebiasis is an extremely rare diagnosis with only a small number of published case reports. This disease may present as cervical growth mimicking cervical carcinoma. Owing to the similarity of the clinical presentation of bleeding per vagina and per speculum examination showing growth or ulcers, definitive diagnosis is made on microscopic examination only. We present a rare case of cervical amoebiasis in a 28-year-old, multiparous female who presented with a history of vaginal bleeding. The patient was treated with metronidazole and diloxanide furate, after which she recovered. Awareness of this rare entity is important for clinical suspicion and for the pathologist to identify trophozoites and make a diagnosis, preventing unwarranted investigations. Accurate diagnosis also facilitates quick management of a patient; as this disease is an infective pathology that can easily be treated by antibiotics. PMID- 26748598 TI - Role of reverse phenotyping in interpretation of next generation sequencing data and a review of INPP5E related disorders. AB - INTRODUCTION: Next Generation Sequencing (NGS) is a useful tool in diagnosis of rare disorders but the interpretation of data can be challenging in clinical settings. We present results of extended studies on a family of multiple members with global developmental delay and learning disability, where another research group postulated the underlying cause to be a homozygous RABL6 missense variant. METHODS AND RESULTS: Using data from the Exome Variant Server, we show that missense RABL6 variants are unlikely to cause early onset rare developmental disorder. Protein structural analysis, cellular functional studies and reverse phenotyping proved that the condition in this family is due to a homozygous INPP5E mutation. An in-depth review of mutational and phenotypic spectrum associated with INPP5E demonstrated that mutations in this gene lead to a range of cilliopathy-phenotypes. DISCUSSION: We use this study as an example to demonstrate the importance of careful clinical evaluation of multiple family members, reverse phenotyping, considering the unknown phenotypic variability of rare diseases, utilizing publically available genomic databases and conducting appropriate bioinformatics and functional studies while interpreting results from NGS in uncertain cases. We emphasize that interpretation of NGS data is an iterative process and its dynamic nature should be explained to patients and families. Our study shows that developmental delay, intellectual disability, hypotonia and ocular motor apraxia are common in INPP5E-related disorders and considerable intra-familial phenotypic variability is possible. We have compiled the INPP5E mutational spectrum and provided novel insights into their molecular mechanisms. PMID- 26748599 TI - Behavioral and emotional problems in children and adults with cerebral palsy. AB - OBJECTIVE: In patients with cerebral palsy (CP), psychological problems influence their participation in society. Little is known about the persistence of behavioral and social problems into adulthood. MATERIALS AND METHODS: In a two center cross-sectional study, caregivers of 121 adults and 88 children were ask to assess behavior of the patients through the parent/caregiver forms of the Child Behavior Checklist (CBCL), the Strengths and Difficulties Questionnaire (SDQ), and the Vineland Adaptive Behavior Scale II (VABS). Questionnaires were returned from 43 adults and 39 children. RESULTS: In both groups we found the same frequency of abnormalities in attention problems (32.4 vs. 36.1%, p = 0.826) and social interaction problems (32.3 vs. 33.3%; p = 0.926) in the CBCL, and peer problems (38.9 vs. 75.7%; p = 0.115) in the SDQ. Children show a lower percentage of abnormal prosocial behavior (41.7 vs. 16.2%, p = 0.016) and lower abnormal rates of communication (88.2 vs. 61.5; p = 0.01) and daily living skills (90.0 vs. 71.8; p = 0.041), whereas the level of abnormalities in both groups in these dimensions of VABS notably high. CONCLUSION: The persistence of psychological and social problems from childhood into adulthood underlines the importance of focusing on early intervention. PMID- 26748600 TI - Re-evaluating the residual risk of transfusion-transmitted Ross River virus infection. AB - BACKGROUND AND OBJECTIVES: Ross River virus (RRV) is an enveloped, RNA alphavirus in the same antigenic group as chikungunya virus. Australia records an annual average of 5000 laboratory-confirmed RRV infections. While RRV is currently geographically restricted to the Western Pacific, the capacity of arboviruses for rapid expansion is well established. The first case of RRV transfusion transmission was recently described prompting a comprehensive risk assessment. MATERIALS AND METHODS: To estimate the RRV residual risk, we applied laboratory confirmed RRV notifications to two published models. This modelling generated point estimates for the risk of viraemia in the donor population, the risk of collecting a viraemic donation and the predicted number of infected components. RESULTS: The EUFRAT model estimated the risk of infection in donors as one in 95 039 (one in 311 328 to one in 32 399) to one in 14 943 (one in 48 593 to one in 5094). The point estimate for collecting a RRV viraemic donation varied from one in 166 486 (one in 659 078 to one in 49 158) (annualized national risk) to one in 26 117 (one in 103 628 to one in 7729) (area of high transmission). The modelling predicted 8-11 RRV-infected labile blood components issued in Australia during a 1-year period. CONCLUSION: Considering the uncertainty in the modelled estimates, the unknown rate of RRV donor viraemia and the low severity of any recipient RRV infection, additional risk management for RRV in Australia will initially be restricted to strengthening the messaging to donors regarding prompt reporting of any postdonation illnesses. PMID- 26748601 TI - Male urinary and sexual function after robotic pelvic autonomic nerve-preserving surgery for rectal cancer. AB - BACKGROUND: Urinary and sexual dysfunction is the potential complication of rectal cancer surgery. The aim of this study was to evaluate the urinary and sexual function in male patients with robotic surgery for rectal cancer. METHODS: This prospective study included 137 of the 336 male patients who underwent surgery for rectal cancer. Urinary and male sexual function was studied by means of a questionnaire based on the International Prostatic Symptom Score and International Index of Erectile Function. All data were collected before surgery and 12 months after surgery. RESULTS: Patients who underwent robotic surgery had significantly decreased incidence of partial or complete erectile dysfunction and sexual dysfunction than patients with laparoscopic surgery. The pre- and post operative total IPSS scores in patients with robotic surgery were significantly less than that with laparoscopic surgeries. CONCLUSIONS: Robotic surgery shows distinct advantages in protecting the pelvic autonomic nerves and relieving post operative sexual dysfunction. PMID- 26748602 TI - Founder effect is responsible for the p.Leu131Phe heparin-binding-site antithrombin mutation common in Hungary: phenotype analysis in a large cohort. AB - BACKGROUND: Antithrombin (AT) is a key regulator of the coagulation. In type II deficiency, the heparin-binding-site defect (type II HBS) is considered to be relatively low thrombosis risk. OBJECTIVES: Our aims were to search for SERPINC1 mutation(s) and to describe the clinical and laboratory phenotype of a large number of AT Budapest3 (ATBp3, p.Leu131Phe) carriers and confirm the presence of a founder effect. PATIENTS/METHODS: AT-deficient patients were recruited and carriers of ATBp3, n = 102 (63 families) were selected. To investigate the founder effect, eight intragenic single nucleotide polymorphisms, a 5'-length dimorphism, and five microsatellite markers were detected. Clinical and laboratory data of the patients were collected and analyzed. RESULTS: In AT deficiency, 16 different causative mutations were found, and the great majority of patients were of type II HBS subtype. Most of them (n = 102/118, 86.5%) carried the ATBp3 mutation. The ATBp3 mutant allele was associated with one single haplotype, while different haplotypes were detected in the case of normal allele. The anti-factor Xa-based AT activity assay that we used could detect all ATBp3 patients with high sensitivity in our cohort. ATBp3 homozygosity (n = 26) was associated with thrombosis at a young age and conferred a high thrombotic risk. Half of the heterozygotes (n = 41/76, 53.9%) also had venous and/or arterial thrombosis, and pregnancy complications were also recorded. CONCLUSION: In Hungary, the founder mutation, ATBp3, is the most common AT deficiency. Our study is the first in which the clinical characterization of ATBp3 mutation was executed in a large population. PMID- 26748603 TI - Clinical experience from Thailand: noninvasive prenatal testing as screening tests for trisomies 21, 18 and 13 in 4736 pregnancies. AB - PURPOSE: The purpose of this article is to report the clinical experience and performance of massively parallel sequencing-based noninvasive prenatal testing (NIPT) as a screening method in detecting trisomy 21, 18, and 13 (T21/T18/T13) in a mixed-risk population in Thailand. METHODS: In a 30-month period, 121 medical centers in Thailand offered NIPT as clinical screening tests for fetal T21, T18, and T13 in the mixed-risk population. All NIPT-positive cases were recommended to undergo invasive prenatal diagnosis. RESULTS: A total of 4736 participants received the NIPT test, including 2840 high-risk pregnancies, either with advanced maternal age or positive serum biochemical tests, and 1889 low-risk pregnancies without conventional indications; 99.9% (4732/4736) of the participants with a median maternal age of 35 years old received reports, and 1.3% (63/4732) were classified as test positive, including 36 T21, 19 T18, and 8 T13; 82.5% (52/63) took prenatal diagnosis, and 11.5% (6/52) false-positive cases were observed. The positive predictive values for the detection of T21, T18, and T13 were 94.4%, 79.0%, and 87.5%, respectively. CONCLUSION: With stringent protocol, our prospective large-scale multicenter nationwide study demonstrated that NIPT showed excellent performance as screening tests for the detection of fetal T21, T18, and T13 in mixed-risk pregnancies in Thailand. PMID- 26748604 TI - Healthcare students and workers' knowledge about transmission, epidemiology and symptoms of Zika fever in four cities of Colombia. PMID- 26748605 TI - Endocrine Therapy for Leptomeningeal Metastases from ER-Positive Breast Cancer: Case Report and a Review of the Literature. AB - Leptomeningeal disease is an uncommon complication of estrogen receptor positive breast cancer. While there is little consensus on the standard of care, recommendations from current clinical practice guidelines are to treat with intrathecal chemotherapy, necessitating invasive procedures and potentially resulting in a substantial incidence of serious complications and side effects. Here, we review all published evidence of the effectiveness of systemic hormonal therapy alone in treating this condition, with the advantage of requiring no invasive procedures and having virtually no serious complications or side effects. Evidence indicates that most hormonal therapies can penetrate the central nervous system and can be an effective treatment of endocrine sensitive breast cancer that is widely metastatic to the leptomeninges. PMID- 26748607 TI - Blurred Boundaries: The RNA Binding Protein Lin28A Is Also an Epigenetic Regulator. AB - Lin28A is best known as a post-transcriptional regulator of gene expression. In this issue, Zeng et al. (2016) show that Lin28A has an unexpected role as an epigenetic regulator of DNA. PMID- 26748608 TI - The c.65-2A>G splice site mutation is associated with a mild phenotype in Danon disease due to the transcription of normal LAMP2 mRNA. AB - Danon disease (DD) is a rare X-linked multisystem disorder caused by mutations of the LAMP2 gene and characterized by intellectual disability, skeletal myopathy and cardiomyopathy. The survival time is severely reduced. Contrasting with the usual disease course, we report on a family with an exceptionally mild phenotype of DD despite having two potentially damaging LAMP2 mutations. Using RNA-Seq analysis, we showed that a c.65-2A>G splice site mutation results in the tissue specific production of four different transcripts including the full-length mRNA in muscle tissue but not in leukocytes. We confirmed our results by immunohistochemistry and immunoblotting, showing the detection of LAMP2 protein only in muscle. The second mutation (c.586A>T, p.T196S) has been reported before to have an uncertain clinical significance. In our patients, however, neither of the two mutations seem to have a high enough functional impact to cause a severe phenotype. Overall, our study reveals that alternative splicing is a potential mechanism in DD with underlying splice site mutations of the LAMP2 gene in order to rescue the full-length mRNA. Moreover, our report of a mild phenotype complements the DD spectrum, which is of great importance for a rare disease suspected to be underdiagnosed. PMID- 26748609 TI - Synthesis and Characterization of 6,13-Diamino-Substituted Pentacenes. AB - A series of 6,13-diamino-substituted pentacenes 1 a-d has been prepared and characterized as a new class of pentacene derivatives with strong donor ability and enhanced solubility in common organic solvents. The spectroelectrochemical and DFT studies revealed that the two-electron oxidation process was accompanied by the substantial structural change into a butterfly-like conformation of the pentacene moiety. More importantly, the extent of deformation from the planar pentacene moiety in the dications of 6,13-diaminopentacene is tunable by varying the N-substituents. PMID- 26748606 TI - Latent class profiles of depressive symptoms from early to middle childhood: predictors, outcomes, and gender effects. AB - BACKGROUND: There has been little available data to inform the predictors and outcomes of latent class trajectories of depressive symptoms beginning during preschool and continuing throughout school age. Further, the extant literature in this domain has been limited by the use of parent report checklists of nonspecific 'internalizing' psychopathology rather than diagnostic interviews for depression. METHODS: To address these gaps in the literature, this study applied growth mixture modeling to depressive symptom severity endorsed by children and/or their caregivers (N = 348) during a structured clinical interview in a 10 year longitudinal dataset spanning from preschool into late school age. RESULTS: Three distinct trajectories of depressive symptom severity were found in boys and girls. For boys, but not girls, the high depression severity latent class increased in depressive symptoms from preschool through school age, followed by a decline in depressive symptom severity during later school age. For girls, the high depression severity latent class remained stable across time. Early childhood social adversity, familial history of affective disorder, preschool onset ODD/CD, and school age functional impairment differentiated high-risk trajectory classes among both boys and girls. CONCLUSIONS: Extending the literature on trajectories of depressive symptoms to the preschool period, these findings incorporate structured clinical interviews of depressive symptom severity and indicate gender differences as well as psychosocial predictors and functional outcomes among children in high severity latent classes. The findings from this study suggest that increased attention to screening for depressive symptoms in early childhood is of significant public health importance. PMID- 26748610 TI - Evidence-based practice among nurses in Slovenian Hospitals: a national survey. AB - AIMS: To identify the extent of evidence-based practice implementation among nurses in Slovenian hospital settings, to establish nurses' beliefs on evidence based practice and to identify possible explanatory factors. BACKGROUND: Conducting and applying research are fundamental nurses' tasks and an essential expectation in nursing practice. INTRODUCTION: Despite verified benefits of evidence-based practice, research evidence across different countries has shown extremely limited implementation of this practice among nurses. METHODS: A cross sectional research design was employed. Standardized instruments Evidence-Based Practice Beliefs and Implementation Scale were used. The sample included 534 nurses from 19 Slovenian hospitals. The obtained data were analysed using descriptive statistics, correlation and factor analysis, and linear regression. RESULTS: Nurses in Slovenian hospitals have positive beliefs about evidence-based practice, but exhibit a low level of implementation. The beliefs were explained by perceived knowledge on research, job satisfaction and length of employment, whereas a low level of implementation was explained by poor perceived knowledge on research, evidence-based practice and job satisfaction level. DISCUSSION: Nurses in Slovenian hospitals have positive beliefs about evidence-based practice, but exhibit a low level of implementation. According to the results, some resources required for improved implementation are not made sufficiently available. LIMITATIONS: A low response rate; the sample not being balanced for educational achievement; and the accuracy of self-report survey methods. CONCLUSION: In addition to the perceived knowledge and education provided, an important factor is also job satisfaction, which points to the instrumental role of management workers in determining nurses' professional development. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Nursing managers in Slovenian hospitals should promote the development of head nurses in research and evidence based care, thereby fostering a culture of evidence-based practice. PMID- 26748612 TI - Total Synthesis of the Antiviral Natural Product Houttuynoid B. AB - The first total synthesis of houttuynoid B, a powerful antiviral flavonoid glycoside from the Chinese plant Houttuynia cordata, is described. In a key step, a Baker-Venkataraman rearrangement employing an already glycosylated substrate was used to efficiently set up the fully functionalized carbon skeleton. The required benzofuran building block was prepared through a domino Sonogashira coupling/5-endo-dig cyclization and converted into a stable 1 hydroxybenzotriazole-derived active ester prior to linking with a galactosylated hydroxyacetophenone unit. The elaborated synthesis requires only nine steps (11 % overall yield) along the longest linear sequence and paves the way for the preparation of structurally related compounds for further biological evaluation. PMID- 26748611 TI - IL-33 is related to innate immune activation and sensitization to HDM in mild steroid-free asthma. AB - BACKGROUND: IL-33 represents a potential link between the airway epithelium and induction of a Th2-type inflammatory response in asthma. However, the association with markers of eosinophilic airway inflammation has not previously been reported in patients with steroid-free asthma. AIM: To describe the relationship between airway IL-33 and markers of eosinophilic airway inflammation, as well potential triggers of IL-33, in mild, steroid-free asthma. METHODS: IL-33 mRNA expression and IL-33 immunoreactivity were measured in bronchial biopsies from patients with asthma untreated with inhaled steroids and healthy individuals. Furthermore, fractional exhaled nitric oxide (FeNO) and eosinophils in sputum and BAL were measured, as well as airway hyperresponsiveness to mannitol and methacholine. Epithelial integrity was assessed by computerized image analysis on haematoxylin stained sections, and TLR mRNA expression by PCR. RESULTS: A total of 23 patients with asthma and 10 healthy individuals were examined (age: 24 years (20-40); females: 53%). The level of IL-33 mRNA expression was significantly higher in patients with asthma compared to healthy individuals (Median (IQR) 1.12 (0.78) vs. 0.86, P = 0.04). There was a positive correlation between IL-33 mRNA expression and the level of FeNO (r = 0.56, P = 0.01), whereas there was no association with airway or blood eosinophils. IL-33 expression was unrelated to loss of epithelial integrity, but correlated with an increased expression of TLR2 and TLR4 (TLR2: r = 0.47, P = 0.04; TLR4: 0.68, P < 0.001), as well allergy to house dust mites (HDMs). CONCLUSION: In mild untreated asthma, the expression of IL-33 mRNA in bronchial mucosa is related to innate immune activation and allergic sensitization to HDM, rather than epithelial damage, and correlates with FeNO. These findings suggest that in mild allergic asthma, IL-33 may represent a link between innate immune activation and FeNO production. PMID- 26748614 TI - Enlarged intracranial translucency and molar tooth sign in the first trimester as features of Joubert syndrome and related disorders. PMID- 26748613 TI - Suppressive Effect of Constructed shRNAs against Apollon Induces Apoptosis and Growth Inhibition in the HeLa Cell Line. AB - BACKGROUND: Cervical cancer is the second most common female cancer worldwide. Inhibitors of apoptosis proteins (IAPs) block apoptosis; therefore, therapeutic strategies targeting IAPs have attracted the interest of researchers in recent years. Apollon, a member of IAPs, inhibits apoptosis and cell death. RNA interference is a pathway in which small interfering RNA (siRNA) or shRNA (short hairpin RNA) inactivates the expression of target genes. The purpose of this study was to determine the effect of constructed shRNAs on apoptosis and growth inhibition through the suppression of apollon mRNA in HeLa cell line. METHODS: Three shRNAs with binding ability to three different target sites of the first region of apollon gene were designed and cloned in pRNAin-H1.2/Neo vector. shRNA plasmids were then transfected in HeLa cells using electroporation. Down regulation effects of apollon and the viability of HeLa cells were analyzed by RT PCR, lactate dehydrogenase assay, and MTT assay, respectively. Also, the induction and morphological markers of apoptosis were evaluated by caspase assay and immunocytochemistry method. RESULTS: The expression of shRNA in HeLa cells caused a significant decrease in the level of apollon mRNA1. In addition, shRNA1 effectively increased the mRNA level of Smac (as the antagonist of apollon), reduced the viability of HeLa cells and exhibited immunocytochemical apoptotic markers in this cell line. CONCLUSION: Apollon gene silencing can induce apoptosis and growth impairment in HeLa cells. In this regard, apollon can be considered a candidate therapeutic target in HeLa cells as a positive human papillomavirus cancer cell line. PMID- 26748615 TI - Electrocatalytic O2 Reduction at a Bio-inspired Mononuclear Copper Phenolato Complex Immobilized on a Carbon Nanotube Electrode. AB - An original copper-phenolate complex, mimicking the active center of galactose oxidase, featuring a pyrene group was synthesized. Supramolecular pi-stacking allows its efficient and soft immobilization at the surface of a Multi-Walled Carbon Nanotube (MWCNT) electrode. This MWCNT-supported galactose oxidase model exhibits a 4 H(+)/4 e(-) electrocatalytic activity towards oxygen reduction at a redox potential of 0.60 V vs. RHE at pH 5. PMID- 26748616 TI - ULTRASOUND-GUIDED INJECTIONS IN HORSES WITH CRANIOVENTRAL DISTENSION OF THE COXOFEMORAL JOINT CAPSULE: FEASIBILITY FOR A CRANIOVENTRAL APPROACH. AB - Intrasynovial access to the equine coxofemoral joint (CFJ) is inherently challenging. Blind injection techniques rely upon inconsistently palpable landmarks, and ultrasound guidance requires expertise for needle placement into the coxofemoral articulation. Aspiration is recommended to confirm intrasynovial placement and avoid sciatic nerve anesthesia. The aim of this observational, descriptive, retrospective study was to evaluate the feasibility for an alternative ultrasound-guided approach in horses with cranioventral distention of the CFJ identified during pelvic ultrasound. Thirteen horses with cranioventral CFJ distention, including 12 with severe pathology, were recruited from 2009 to 2014. Seven were excluded as they were not injected or underwent ultrasound guided injection using a dorsal approach. The remaining six horses underwent a total of nine injections into the cranioventral recess. With the exception of one foal, all were aged horses (15-29 years) of varying breeds and uses, with prominent lameness due to subluxation (three), luxation (two), and severe osteoarthritis (one). The cranioventral recess was imaged adjacent to the proximal femur using a low-frequency curvilinear transducer placed ventral to the cranial joint margins. Using aseptic technique, spinal needles were placed cranial to the transducer and advanced caudomedially into the distended cranioventral recess. Synovial fluid was retrieved in all cases with one needle placement. Findings indicated that, when distended, ultrasound-guided access to the cranioventral CFJ recess is a feasible alternative approach and may reduce the potential for extra-synovial placement. Distention in this sample of horses was accompanied by severe pathology, also supporting the use of this approach for therapeutic interventions. PMID- 26748617 TI - Changes in the utilization of psychiatric hospital facilities in Denmark by patients diagnosed with schizophrenia from 1970 through 2012: The advent of 'revolving door' patients. AB - OBJECTIVE: The Danish psychiatric system has gone through several structural changes in the last four decades. The deinstitutionalization of the mental healthcare system was implemented in Denmark in the late 1970s with the intention of increasing out-patient treatment. One of the aims in the reorganization was to treat the patient in the local environment rather than during long-term hospitalization. This study focuses on the changes in the utilization of hospital facilities. METHOD: Using register data from secondary healthcare treatment of patients diagnosed with schizophrenia in Denmark 1970-2012, we analysed the development in the use of hospital facilities. RESULTS: Our major finding was a 220% increase between 1970 and 2012 in the total number of hospital admissions due to schizophrenia each year, while at the same time the number of annual schizophrenia bed days was reduced by 76%. Furthermore, the readmission rate within a year after discharge with a diagnosis of schizophrenia reached 70% in 2012 compared to 51% in 1970. Finally, the total bed occupancy continued to rise over the four decades and has exceeded 100% in several years since 1999. CONCLUSION: The findings indicate that the reorganization of the Danish mental healthcare system has created a problem of 'revolving door' schizophrenia patients' who since the 1970s have been increasingly hospitalized but for shorter periods. Possible explanations of the findings are premature discharge of patients with schizophrenia due to lack of beds or/and that community psychiatry has not been providing adequate relapse prevention. PMID- 26748619 TI - Of timelines and timeliness: lessons from Typhoon Haiyan in early disaster response. AB - Typhoon Haiyan struck the Philippines on 8 November 2013 with maximum sustained winds of 235 kilometres per hour, adversely affecting at least 11 million people and displacing some 673,000 in the central regions of the country. The disaster clearly overwhelmed the Philippine government despite its seemingly well-crafted disaster management plan. Using timelines of different organisations, this paper identifies gaps in the government's response, mainly due to its failure in coordinating and managing relief operations, which adversely affected its effectiveness and efficiency in the delivery of critical goods and services following the disaster. The paper also demonstrates how non-governmental organisations (NGOs), the United Nations, foreign governments and other organisations provided assistance, mainly through aid niching, to cover the government's shortcomings. The paper recommends a paradigm shift in the government's disaster response by integrating collaborative arrangements between government agencies and NGOs, and giving local governments the lead role, with the national government as support, in disaster planning and response. PMID- 26748621 TI - Influence of Metal Oxides on Platinum Activity towards Methanol Oxidation in H2SO4 solution. AB - Pt-CeO2 /C, Pt-TiO2 /C, and Pt-ZrO2 /C electrocatalysts were prepared by using a modified microwave-assisted polyol process. Physical characterization was performed by using XRD, TEM, and EDX analyses. The incorporation of different metal oxides increased the dispersion degree of Pt nanoparticles and reduced their diameter to 2.50 and 2.33 nm when TiO2 and ZrO2 were introduced to Pt/C, respectively. The electrocatalytic activity of various electrocatalysts was examined towards methanol oxidation in H2 SO4 solution by using cyclic voltammetry, chronoamperometry, and electrochemical impedance spectroscopy. Among the studied composites, Pt-ZrO2 /C was selected to be a candidate electrocatalyst for better electrochemical performance in direct methanol fuel cells. PMID- 26748622 TI - Imaging of tarsal navicular stress injury with a focus on MRI: A pictorial essay. AB - Predominantly diagnosed in athletes, stress fracture of the tarsal navicular is becoming increasingly recognised by clinicians as a cause of midfoot pain. Delayed diagnosis can increase the significant morbidity associated with this condition. Consequently the role of MRI is increasing, given the potential to identify a stress reaction in the navicular prior to the development of a discrete stress fracture. It is necessary for radiologists to be familiar with the typical and atypical appearances of this important condition. PMID- 26748620 TI - Cuticular protein and transcription factor genes expressed during prepupal-pupal transition and by ecdysone pulse treatment in wing discs of Bombyx mori. AB - We aimed to understand the underlying mechanism that regulates successively expressed cuticular protein (CP) genes around pupation in Bombyx mori. Quantitative PCR was conducted to clarify the expression profile of CP genes and ecdysone-responsive transcription factor (ERTF) genes around pupation. Ecdysone pulse treatment was also conducted to compare the developmental profiles and the ecdysone induction of the CP and ERTF genes. Fifty-two CP genes (RR-1 13, RR-2 18, CPG 8, CPT 3, CPFL 2, CPH 8) in wing discs of B. mori were examined. Different expression profiles were found, which suggests the existence of a mechanism that regulates CP genes. We divided the genes into five groups according to their peak stages of expression. RR-2 genes were expressed until the day of pupation and RR-1 genes were expressed before and after pupation and for longer than RR-2 genes; this suggests different construction of exo- and endocuticular layers. CPG, CPT, CPFL and CPH genes were expressed before and after pupation, which implies their involvement in both cuticular layers. Expression profiles of ERTFs corresponded with previous reports. Ecdysone pulse treatment showed that the induction of CP and ERTF genes in vitro reflected developmental expression, from which we speculated that ERTFs regulate CP gene expression around pupation. PMID- 26748618 TI - Role of overlapping genetic and environmental factors in the relationship between early adolescent conduct problems and substance use in young adulthood. AB - AIMS: To determine (1) the prospective associations of conduct problems during early adolescence with tobacco, alcohol and cannabis use in young adulthood and (2) to what extent these associations are due to overlapping genetic versus environmental influences. DESIGN: A prospective twin study using biometric twin modelling. SETTING: Finland. PARTICIPANTS: A total of 1847 Finnish twins (943 males and 904 females) were interviewed in early adolescence, 73% of whom (n = 1353, 640 males and 713 females) were retained in young adulthood. MEASUREMENTS: Symptom counts of conduct disorder (CD) criteria were obtained from a semi structured clinical interview in early adolescence [age 14-15 years, mean = 14.2, standard deviation (SD) = 0.15]. Frequency of alcohol, tobacco and cannabis use was obtained from a semi-structured clinical interview in young adulthood (age 19.9-26.6 years, mean = 22.4, SD = 0.7). FINDINGS: We found modest to moderate phenotypical correlations (r = 0.16-0.35) between early adolescent CD symptoms and substance use in young adulthood. In males, the phenotypical correlations of CD symptoms with all three substance use variables are explained largely by overlapping genetic influences. In females, overlapping shared environmental influences predominantly explain the phenotypical correlation between CD symptoms and tobacco and cannabis use. CONCLUSIONS: Conduct disorder symptoms in early adolescence appear to moderately predict substance use in early adulthood. In males, genetic influences seem to be most important in explaining the relationship between conduct disorder symptoms and substance use whereas in females, shared environmental influences seem to be most important. PMID- 26748623 TI - Encoding and decoding time in neural development. AB - The development of a multicellular organism involves time-dependent changes in molecular and cellular states; therefore 'time' is an indispensable mathematical parameter of ontogenesis. Regardless of their inextricable relationship, there is a limited number of events for which the output of developmental phenomena primarily uses temporal cues that are generated through multilevel interactions between molecules, cells, and tissues. In this review, we focus on neural stem cells, which serve as a faithful decoder of temporal cues to transmit biological information and generate specific output in the developing nervous system. We further explore the identity of the temporal information that is encoded in neural development, and how this information is decoded into various cellular fate decisions. PMID- 26748624 TI - Massive petechiae as an initial symptom of Waldenstrom's macroglobulinemia. PMID- 26748625 TI - Controlled oxygen therapy at emergency department presentation increases the likelihood of achieving target oxygen saturations in patients with exacerbations of chronic obstructive pulmonary disease. AB - OBJECTIVE: This study aimed to determine whether initiation of controlled oxygen therapy at ED presentation increased the proportion of patients with chronic obstructive pulmonary disease (COPD) achieving the COPD-X guideline target SpO2 range (88-92%) at 30 min and if it impacted total hospital length of stay or in hospital mortality. METHODS: Retrospective cohort study by medical record review of patients admitted to hospital with an exacerbation of COPD. The primary outcome of interest was the proportion of patients achieving the target SpO2 range at 30 min after ED arrival. RESULTS: The proportion of patients with SpO2 in the target range at 30 min was higher in the controlled oxygen therapy group (32% vs 16%: difference between proportions 16% (95% CI 7-24%); number needed to treat 6) and less likely to be over-oxygenated (SpO2 > 95%), 29% versus 54%, difference between proportions 25% (95% CI 14-35%); number needed to harm 4, without an increased likelihood of hypoxia. Length of stay was not different between the groups. Mortality for the controlled oxygen group was 2.7% (95% CI 1.3-5.5%) versus 5.8% for the uncontrolled oxygen group (95% CI 2.9-11.6%); however, this trend was not statistically significant. CONCLUSION: Patients with exacerbations of COPD receiving controlled oxygen therapy were more likely to achieve SpO2 within the COPD-X guideline target range without being more likely to be hypoxic. The proportion of patients with SpO2 within the target range was low, suggesting that further work on processes to optimise oxygenation in this group of patients is needed. PMID- 26748626 TI - Are Type 1 metabotropic glutamate receptors a viable therapeutic target for the treatment of cerebellar ataxia? AB - The cerebellum is a key brain structure for accurate coordination of sensory and motor function. Compared with other brain regions, the cerebellum expresses a particularly high level of Type 1 metabotropic glutamate receptors (mGluR1). In this review we aim to explore the significance of these receptors for cerebellar synapse function and their potential for treating cerebellar ataxia, a poorly treated degenerative motor disorder that is often hereditary. We find a significant and historical literature showing pivotal mechanisms linking mGluR1 activity with healthy cerebellar synaptic function and motor coordination. This is best illustrated by the impaired motor behaviour in mGluR1 knockout mice that bears strong resemblance to human ataxias. More recent literature also indicates that an imbalance of mGluR1 signalling is as critical as its removal. Too much, as well as too little, mGluR1 activity contributes to ataxia in several clinically relevant mouse models, and perhaps also in humans. Given the availability and ongoing refinement of selective pharmacological tools to either reduce (negative allosteric modulation) or boost (positive allosteric modulation) mGluR1 activity, our findings suggest that pharmacological manipulation of these receptors should be explored as an exciting new approach for the treatment of a variety of human cerebellar ataxias. PMID- 26748627 TI - Protective effect of Rhei Rhizoma on reflux esophagitis in rats via Nrf2-mediated inhibition of NF-kappaB signaling pathway. AB - BACKGROUND: Rhei Rhizoma has been widely used as a traditional herbal medicine to treat various inflammatory diseases. The present study was conducted to evaluate its anti-inflammatory activity against experimental reflux-induced esophagitis (RE) in SD rats. METHODS: Rhei Rhizoma was administered at 125 or 250 mg/kg body weight per day for 7 days prior to the induction of reflux esophagitis, and its effect was compared with RE control and normal rats. RESULTS: Rhei Rhizoma administration markedly ameliorated mucosal damage on histological evaluation. The elevated reactive oxygen species in the esophageal tissue of RE control rats decreased with the administration of Rhei Rhizoma. RE control rats exhibited the down-regulation of antioxidant-related proteins, such as nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression levels, in the presence of esophagitis; however, the levels with Rhei Rhizoma treatment were significantly higher than those in RE control rats. Moreover, RE control rats exhibited the up-regulation of protein expressions related to oxidative stress in the presence of esophagitis, but Rhei Rhizoma administration significantly reduced the expression of inflammatory proteins through mitogen-activated protein kinase (MAPK)-related signaling pathways. The protein expressions of inflammatory mediators and cytokines by nuclear factor-kappa B (NF-kappaB) activation were modulated through blocking the phosphorylation of inhibitor of nuclear factor kappa B (IkappaB)alpha. CONCLUSION: Our findings support the therapeutic evidence for Rhei Rhizoma ameliorating the development of esophagitis via regulating inflammation through the activation of the antioxidant pathway. PMID- 26748628 TI - Prehospital paths and hospital arrival time of patients with acute coronary syndrome or stroke, a prospective observational study. AB - BACKGROUND: Patients with a presumed diagnosis of acute coronary syndrome (ACS) or stroke may have had contact with several healthcare providers prior to hospital arrival. The aim of this study was to describe the various prehospital paths and the effect on time delays of patients with ACS or stroke. METHODS: This prospective observational study included patients with presumed ACS or stroke who may choose to contact four different types of health care providers. Questionnaires were completed by patients, general practitioners (GP), GP cooperatives, ambulance services and emergency departments (ED). Additional data were retrieved from hospital registries. RESULTS: Two hundred two ACS patients arrived at the hospital by 15 different paths and 243 stroke patients by ten different paths. Often several healthcare providers were involved (60.8 % ACS, 95.1 % stroke). Almost half of all patients first contacted their GP (47.5 % ACS, 49.4 % stroke). Some prehospital paths were more frequently used, e.g. GP (cooperative) and ambulance in ACS, and GP or ambulance and ED in stroke. In 65 % of all events an ambulance was involved. Median time between start of symptoms and hospital arrival for ACS patients was over 6 h and for stroke patients 4 h. Of ACS patients 47.7 % waited more than 4 h before seeking medical advice compared to 31.6 % of stroke patients. Median time between seeking medical advice to arrival at hospital was shortest in paths involving the ambulance only (60 min ACS, 54 min stroke) or in combination with another healthcare provider (80 to 100 min ACS, 99 to 106 min stroke). CONCLUSIONS: Prehospital paths through which patients arrived in hospital are numerous and often complex, and various time delays occurred. Delays depend on the entry point of the health care system, and dialing the emergency number seems to be the best choice. Since reducing patient delay is difficult and noticeable differences exist between various prehospital paths, further research into reasons for these different entry choices may yield possibilities to optimize paths and reduce overall time delay. PMID- 26748629 TI - Do pancrelipase delayed-release capsules have a protective role against nonalcoholic fatty liver disease after pancreatoduodenectomy in patients with pancreatic cancer? A randomized controlled trial. AB - BACKGROUND: The aim of this randomized controlled trial (RCT) was to investigate whether pancrelipase protects against nonalcoholic fatty liver disease (NAFLD) development after pancreatoduodenectomy in patients with pancreatic cancer better than conventional pancreatic enzyme supplementation. METHODS: A total of 57 patients were randomly assigned to the study group (n = 29; pancrelipase replacement therapy) or the control group (n = 28; conventional pancreatic enzyme supplementation). NAFLD was defined as a liver-to-spleen attenuation ratio less than 0.9 on CT. Clinical and laboratory findings were also assessed. RESULTS: NAFLD was observed in 6/29 patients (21%) in the study group, and 11/28 patients (39%) in the control group, but this was not a statistically significant difference. In the control group, crossover to pancrelipase replacement therapy upon NAFLD diagnosis produced improvement in five out of 10 patients. Multivariate analysis showed that advanced age and extended resection were independent risk factors for NAFLD development. CONCLUSION: This RCT did not show a significant protective effect of pancrelipase replacement therapy over conventional pancreatic enzyme supplementation on NAFLD development after pancreatoduodenectomy for pancreatic cancer. Further studies are clearly required to investigate the etiology of and new therapeutic strategies for treatment resistant NAFLD (UMIN 000019817). PMID- 26748630 TI - Enhanced osteogenic differentiation of MC3T3-E1 cells on grid-topographic surface and evidence for involvement of YAP mediator. AB - Numerous studies have shown that surface topography can promote cell-substrate associations and deeply influence cell fate. The intracellular mechanism or how micro- or nano-patterned extracellular signal is ultimately linked to activity of nuclear transcription factors remains unknown. It has been reported that Yes associated protein (YAP) can respond to extracellular matrix microenvironment signals, thus regulates stem cell differentiation process. We propose that YAP may play a role in mediating the topography induced cell differentiation. To this end, we fabricated polydimethylsiloxane (PDMS) micropatterns with grid topology (GT) (3 MUm pattern width, 2 MUm pattern interval length, 7 MUm pattern height); nonpatterned PDMS substrates were used as the planar controls. The MC3T3-E1 cells were then cultured on these surfaces, respectively, in osteogenic inducing medium. Cell differentiation in terms of osteogenesis related gene expression, protein levels, alkaline phosphatase activity and extracellular matrix mineralization was assessed. It was shown that the cells on GT surfaces had stronger osteogenesis capacity. In addition, expression level of YAP was increased when MC3T3-E1 cells grew on GT substrates, which was similar to the levels of osteogenic differentiation markers. It was also shown that YAP knockdown attenuated GT substrates-induced MC3T3-E1 differentiation, which reduced the osteogenic differentiation effect of the GT substrates. Collectively, our findings indicate that GT substrates-induced MC3T3-E1 differentiation may be associated with YAP. This paper provides new target points for transcriptional mechanism research of microenvironment induced cell differentiation and a useful approach to obtain more biofunctionalization scaffolds for tissue engineering. PMID- 26748631 TI - Finding the clues. AB - Wu, Sheppard, and Mitchell (Br. J. Psychol., 2016; 107, 1-22) provide interesting data on the perception of empathy. Their focus on cue validity could usefully be expanded to look at what cues are used, whether they have multimodal properties, and how the perception of empathy relates to other first impressions. PMID- 26748632 TI - Efficient versus flexible mentalizing in complex social settings: Exploring signature limits. AB - Wu, Sheppard, and Mitchell (Br. J. Psychol., 2016; 107, 1-22) investigate in a fascinating study the fact that adults can detect empathic traits in others after only briefly watching or listening to a person. In this commentary, we highlight how the processes of an efficient, implicit, but inflexible mentalizing system are likely to operate in such situations. Further, we specify how testing signature limits over time-, attribute-, and protagonist-restrictions can help distinguish whether an efficient-implicit or flexible-explicit mentalizing system is of relevance when processing complex social settings. PMID- 26748633 TI - An adaptive perspective on revealed and concealed cues to empathy. AB - Wu, Sheppard, and Mitchell (Br. J. Psychol., 2016; 107, 1-22) found that observers could accurately identify people with extreme but not more average empathy scores. Here, we further consider this U-shaped discrimination function. We first examine a statistical issue regarding the construction of the average groups, which are less homogenous by definition than the extreme groups. We then consider the kinds of questions arising when these results are considered within the adaptive framework of signal theory. Some interesting questions arise relating to the signal sender, including the costs and benefits to the sender in revealing and concealing true empathy levels, and the effects of adopting behavioural norms to conceal true levels of empathy. PMID- 26748636 TI - Cardiogenic Shock Following Amplatzer Device Embolization Due to Left Ventricular Outflow Tract Obstruction. PMID- 26748634 TI - The game is afoot: A response to three insightful commentaries. AB - This is an author response to commentaries on our original article (Wu, Sheppard & Mitchell, 2016). We abstract two main themes from the commentaries, and they are as follows: (1) What kind of clues in target behaviour allow perceivers to infer target EQ? And related with this, by what process do perceivers infer the target's EQ? (2) Do features of the target group naturally lead to a U-shaped function, whereby it is easy for perceivers to identify those at the extremes but not those in the middle of the continuum? PMID- 26748637 TI - Retroperitoneal colonic perforation from a foreign body--'cannibalization' effect of a toothpick--video vignette. PMID- 26748639 TI - Interfacial chemistry in a ZnTe/CdSe superlattice studied by atom probe tomography and transmission electron microscopy strain measurements. AB - The atomic scale analysis of a ZnTe/CdSe superlattice grown by molecular beam epitaxy is reported using atom probe tomography and strain measurements from high resolution scanning transmission electron microscopy images. CdTe interfaces were grown by atomic layer epitaxy to prevent the spontaneous formation of ZnSe bonds. Both interfaces between ZnTe and CdSe are composed of alloyed layers of ZnSe. Pure CdTe interfaces are not observed and Zn atoms are also visible in the CdSe layers. This information is critical to design superlattices with the expected optoelectronic properties. PMID- 26748640 TI - Molecular-Level Understanding of Structural Changes of Organic Crystals Induced by Macroscopic Mechanical Stimulation. AB - Structural changes to molecular crystals upon mechanical stimulation have attracted attention for sensing, recording, and microactuation. Comprehensive structure information is required to understand relationships between the mechanical force applied, the crystal structure, and the bulk property changes in order to develop general design concepts for mechanoresponsive compounds. Unfortunately, mechanical stimulation of organic crystals typically deteriorates their integrity, preventing detailed structure analyses by single-crystal X-ray diffraction (XRD) methods. However, in the past three years, several interesting studies have been reported in which molecular crystals retain their integrity even after a mechanically induced crystalline structure change. These materials have allowed us to investigate how macroscopic mechanical forces affect the microscopic structures of molecular crystals by single-crystal XRD analyses. This Minireview summarizes current knowledge of mechanically induced structure changes in molecular crystals, which will facilitate research in this field. PMID- 26748641 TI - Supramolecular Nanoparticles via Single-Chain Folding Driven by Ferrous Ions. AB - Single-chain nanoparticles can be obtained via single-chain folding assisted by intramolecular crosslinking reversibly or irreversibly. Single-chain folding is also an efficient route to simulate biomacromolecules. In present study, poly(N hydroxyethylacrylamide-co-4'-(propoxy urethane ethyl acrylate)-2,2':6',2'' terpyridine) (P(HEAm-co-EMA-Tpy)) is synthesized via reversible addition fragmentation chain transfer polymerization. Single-chain folding and intramolecular crosslinking of P(HEAm-co-EMA-Tpy) are achieved via metal coordination chemistry. The intramolecular interaction is characterized on ultraviolet/visible spectrophotometer (UV-vis spectroscopy), proton nuclear magnetic resonance ((1)H NMR), and differential scanning calorimetry (DSC). The supramolecular crosslinking mediated by Fe(2+) plays an important role in the intramolecular collapsing of the single-chain and the formation of the nanoparticles. The size and morphology of the nanoparticles can be controlled reversibly via metal coordination chemistry, which can be characterized by dynamic light scattering (DLS), transmission electron microscope (TEM), and atomic force microscope (AFM). PMID- 26748638 TI - Feasibility study of chemoradiotherapy followed by amrubicin and cisplatin for limited-disease small cell lung cancer. AB - To evaluate the feasibility of amrubicin plus cisplatin (AP) following chemoradiotherapy for limited-disease small-cell lung cancer, chemo-naive patients aged 20-70 years with a performance status of 0 or 1 and normal organ functions were treated with etoposide 100 mg/m2 on days 1-3, cisplatin 80 mg/m(2) on day 1 and concurrent thoracic radiotherapy at 45 Gy/30 fractions (EP-TRT), followed by three cycles of amrubicin 40 mg/m2 on days 1-3 and cisplatin 60 mg/m2 on day 1 every 3 weeks. The EP-TRT could be completed in 21 patients (15 male and 6 female patients with a median age of 62 years). Of these, 2, 1 and 18 (86%) patients received one, two and three cycles of AP, respectively. Sixteen (76%) patients required granulocyte-colony stimulating factor (G-CSF) support. Grade 3/4 neutropenia occurred in all patients. Grade 3 febrile neutropenia was observed in 9 patients, lasting for 1 day in 5 patients. The incidences of grade 3/4 thrombocytopenia and anemia were 43 and 24%, respectively. Grade 3 infection and anorexia occurred in 2 and 3 patients, respectively. The response rate was 95%. The median (95% confidence interval [CI]) progression-free survival (PFS) was 41.9 (0-102) months, and the 5-year PFS rate (CI) was 41.9% (20.4-63.4%). The median overall survival (OS) has not been reached yet, and the 5-year OS rate (CI) was 57.8% (35.2-80.4%). In conclusion, EP-TRT followed by AP therapy was well-tolerated, although a large number of patients required G-CSF support. PMID- 26748642 TI - Stackable micropatterned hydrogels for analysis of thick tissues in vitro. PMID- 26748643 TI - Integration of CD45-positive leukocytes into newly forming lymphatics of adult mice. AB - The embryonic origin of lymphatic endothelial cells (LECs) has been a matter of controversy since more than a century. However, recent studies in mice have supported the concept that embryonic lymphangiogenesis is a complex process consisting of growth of lymphatics from specific venous segments as well as the integration of lymphangioblasts into the lymphatic networks. Similarly, the mechanisms of adult lymphangiogenesis are poorly understood and have rarely been studied. We have recently shown that endothelial progenitor cells isolated from the lung of adult mice have the capacity to form both blood vessels and lymphatics when grafted with Matrigel plugs into the skin of syngeneic mice. Here, we followed up on these experiments and studied the behavior of host leukocytes during lymphangiogenesis in the Matrigel plugs. We observed a striking co-localization of CD45(+) leukocytes with the developing lymphatics. Numerous CD45(+) cells expressed the LEC marker podoplanin and were obviously integrated into the lining of lymphatic capillaries. This indicates that, similar to inflammation-induced lymphangiogenesis in man, circulating CD45(+) cells of adult mice are capable of initiating lymphangiogenesis and of adopting a lymphvasculogenic cellular differentiation program. The data are discussed in the context of embryonic and inflammation-induced lymphangiogenesis. PMID- 26748644 TI - [Pt(O,O'-acac)(gamma-acac)(DMS)] versus cisplatin: apoptotic effects in B50 neuroblastoma cells. AB - Cisplatin is one of the most active chemotherapeutic agents used in the treatment of childhood and adult malignancies. Cisplatin induces cell death through different pathways. Despite its effectiveness, the continued clinical use of cisplatin is limited by onset of severe side effects (nephrotoxicity, ototoxicity and neurotoxicity) and drug resistance. Therefore, one of the main experimental oncology purpose is related to the search for new platinum-based drugs to create different types of adducts or more specific and effective subcellular targets. Thus, [Pt(O,O'-acac)(gamma-acac)(DMS)], which reacts preferentially with protein thiols or thioether, was synthesized. In our research, different approaches were used to compare cisplatin and [Pt(O,O'-acac)(gamma-acac)(DMS)] effects in B50 rat neuroblastoma cells. Our results, using immunocytochemical, cytometric and morphological techniques, showed that these compounds exert a cytostatic action and activate apoptosis with different pathways. Long-term effects demonstrated that [Pt(O,O'-acac)(gamma-acac)(DMS)] exerts cytotoxic effects in neuronal B50 cell line not inducing drug resistance. Analysis was performed both to compare the ability of these platinum compounds to induce cell death and to investigate the intracellular mechanisms at the basis of their cytotoxicity. PMID- 26748645 TI - Survey of current trends in postgraduate musculoskeletal ultrasound education in the United States. AB - OBJECTIVE: To determine current trends in postgraduate musculoskeletal ultrasound education across various medical specialties in the United States. MATERIALS AND METHODS: A survey regarding musculoskeletal ultrasound education was sent to all program directors for diagnostic radiology and physical medicine rehabilitation residency programs, as well as adult rheumatology and sports medicine fellowship programs in the United States. The survey, sent in July 2015, queried the presence of formal musculoskeletal ultrasound training, the components of such training and case volume for trainees. RESULTS: Response rates were 23, 25, 28 and 33% for physical medicine and rehabilitation, radiology, rheumatology and sports medicine programs, respectively. Among respondents, musculoskeletal ultrasound training was present in 65% of radiology programs, 88% of sports medicine programs, 90% of rheumatology programs, and 100% of physical medicine and rehabilitation programs. Most programs utilized didactic lectures, followed by hands-on scanning. The majority of programs without current training intend to implement such training within 5 years, although radiology programs reported the lowest likelihood of this happening. Most program directors believed that musculoskeletal ultrasound education is important for their trainees, and is of greater importance than it was 10 years ago. Case volume was lowest for radiology trainees and highest for sports medicine trainees. CONCLUSION: Among respondents, the majority of diagnostic radiology programs offer musculoskeletal ultrasound training. However, this experience is even more widespread in other medical specialties, and hands-on training and experience tend to be greater in other specialties than in radiology. PMID- 26748646 TI - Normal skeletal development and imaging pitfalls of the calcaneal apophysis: MRI features. AB - OBJECTIVE: Heel pain in children and secondary MR imaging (MRI) of the hindfoot have been increasing in incidence. Our purpose is to illustrate the, previously unreported, MRI stages in development of the posterior calcaneal apophysis, with attention to imaging pitfalls. This should aid in distinguishing normal growth from true disease. MATERIAL AND METHODS: Consecutive ankle MRIs in children <18 years, from 2008-2014, were subdivided into 0<=5, 5<=10, 10<=15 and 15<=18 age groups and retrospectively reviewed for development of the calcaneal apophysis. RESULTS: 204 ankle MRI studies in 188 children were identified. 40 studies were excluded with final cohort of 164 studies in 154 patients (82 boys, 72 girls). The calcaneal apophysis was cartilaginous until age 5. Foci of decreased as well as increased signal were embedded in cartilage, prior to ossification. Early, secondary ossification centers appeared in plantar third of the apophysis in 100% of children by age 7. Increased T2 signal in the ossifications was seen in 30% of children. Apohyseal fusion began at 12 and was complete in 78% of 14<=15 year olds and in 88% of 15<=18 year olds. Curvilinear low signal in the ossification centers, paralleling, but distinguished from growth plate, and not be confused with fracture line, was common. CONCLUSION: Development of the posterior calcaneus follows a unique sequence. Apophyseal fusion occurs earlier than reported in the literature. Familiarity with this maturation pattern, in particular the apophyseal increased T2 signal and the linear low signal paralleling the growth plate, will avoid misinterpreting it for pathology. PMID- 26748648 TI - Chronic Conditions: Beckett, Bergson and Samuel Johnson. AB - This article analyses the work of the twentieth-century late modernist Samuel Beckett, in light of the turn-of-the-century anti-rationalist Henri Bergson (1859 1941) and the eighteenth-century neoclassicist Samuel Johnson (1709-1784). What unites these three very different thinkers is a concern over habitual, automatic and involuntary behavior, which in all three cases has a distinctly neurological dimension. Beckett's writing explores the Bergsonian notion, informed by medicine and experimental psychology, of the limitations of agency, of "the deep-seated recalcitrance of matter," and of the human as always already inflicted by the mechanical, a fact that is poignantly highlighted by the case of Samuel Johnson. Through his encounter with Johnson, Beckett registers a paradigm shift in the understanding of subjectivity. Whereas Bergson aims, throughout his career, to contest the mechanical, habitual and automatic that threaten to encrust themselves upon the living, in Beckett's often uncannily Johnsonian writing, the habitual and the automatic become progressively more central, until in the late works, habit and mechanical behavior constitute a tenuous, fraught and primitive ontology, the residues of an agential self. PMID- 26748647 TI - Effects of Fostamatinib on the Pharmacokinetics of Oral Contraceptive, Warfarin, and the Statins Rosuvastatin and Simvastatin: Results From Phase I Clinical Studies. AB - BACKGROUND AND OBJECTIVES: Fostamatinib is a spleen tyrosine kinase inhibitor that has been investigated as therapy for rheumatoid arthritis and immune thrombocytopenic purpura. The present studies assessed the potential for pharmacokinetic interaction between fostamatinib and the commonly prescribed medications oral contraceptive (OC), warfarin, and statins (rosuvastatin, simvastatin) in healthy subjects. METHODS: The OC study was a crossover study over two 28-day treatment periods (Microgynon((r)) 30 plus placebo or fostamatinib). Concentrations of OC constituents (ethinyl estradiol/levonorgestrel) were measured. Effects on warfarin pharmacokinetics and pharmacodynamics were assessed (21-day study). Warfarin was administered on days 1 and 14, fostamatinib on days 8-20. The statin study was a two-period, fixed sequence study of the effects of fostamatinib on exposure to rosuvastatin or simvastatin (single doses). Safety was assessed throughout. RESULTS: Fostamatinib co-administration with OC increased exposure to ethinyl estradiol [area under the plasma concentration-time curve at steady state (AUCss) 28% [confidence interval (CI 90%) 21-36]; maximum plasma concentration (Cmax) at steady state (Cmax,ss) 34% (CI 26-43)], but not levonorgestrel (AUCss 5%; Cmax,ss -3%), while exposure to luteinizing hormone and follicle-stimulating hormone decreased (~ 20%). Fostamatinib did not affect the pharmacokinetics/pharmacodynamics of warfarin to a clinically relevant extent, but caused an upward trend in AUC for both R- and S warfarin [18% (CI 13-23) and 13% (CI 7-19)]. Fostamatinib increased rosuvastatin AUC by 96% (CI 78-115) and Cmax by 88% (CI 69-110), and increased simvastatin acid AUC by 74% (CI 50-102) and Cmax by 83% (CI 57-113). CONCLUSION: Fostamatinib exhibits drug-drug interactions when co-administered with OC, simvastatin, or rosuvastatin, with the AUC of statins almost doubling. Fostamatinib did not exhibit a clinically relevant DDI on warfarin. PMID- 26748649 TI - Hypoxia paradoxically inhibits the angiogenic response of isolated vessel explants while inducing overexpression of vascular endothelial growth factor. AB - This study was designed to investigate how changes in O2 levels affected angiogenesis in vascular organ culture. Although hypoxia is a potent inducer of angiogenesis, aortic rings cultured in collagen paradoxically failed to produce an angiogenic response in 1-4 % O2. Additionally, aortic neovessels preformed in atmospheric O2 lost pericytes and regressed at a faster rate than control when exposed to hypoxia. Aortic explants remained viable in hypoxia and produced an angiogenic response when returned to atmospheric O2. Hypoxic aortic rings were unresponsive to VEGF, while increased oxygenation of the system dose-dependently enhanced VEGF-induced angiogenesis. Hypoxia-induced refractoriness to angiogenic stimulation was not restricted to the aorta because similar results were obtained with vena cava explants or isolated endothelial cells. Unlike endothelial cells, aorta-derived mural cells were unaffected by hypoxia. Hypoxia downregulated expression in aortic explants of key signaling molecules including VEGFR2, NRP1 and Prkc-beta while upregulating expression of VEGFR1. Medium conditioned by hypoxic cultures exhibited angiostatic and anti-VEGF activities likely mediated by sVEGFr1. Hypoxia reduced expression of VEGFR1 and VEGFR2 in endothelial cells while upregulating VEGFR1 in macrophages and VEGF in both macrophages and mural cells. Thus, changes in O2 levels profoundly affect the endothelial response to angiogenic stimuli. These results suggest that hypoxia-induced angiogenesis is fine-tuned by complex regulatory mechanisms involving not only production of angiogenic factors including VEGF but also differential regulation of VEGFR expression in different cell types and production of inhibitors of VEGF function such as sVEGFR1. PMID- 26748650 TI - 25 by 25: Achieving Global Reduction in Cardiovascular Mortality. AB - Four non-communicable diseases-cardiovascular disease, chronic respiratory disease, diabetes mellitus, and cancer-account for over 60 % of all deaths globally. In recognition of this significant epidemic, the United Nations set forth a target of reducing the four major NCDs by 25 % by 2025. Cardiovascular disease alone represents half of these deaths and is the leading cause of death globally, representing as much as 60 % of all deaths in regions such as Eastern Europe. In response, the WHO set specific targets on conditions and risk factors and changes in the health systems structure in order to achieve the goals. The focus was set on lifestyle risk factors-physical activity, salt-intake, and tobacco-and established conditions-obesity, hypertension, and diabetes mellitus. Health system efforts to improve medical treatment of high risk are encouraged. Efforts to achieve the goal are being promoted by leading international CVD organizations. PMID- 26748651 TI - Creatine for neuroprotection in neurodegenerative disease: end of story? AB - Creatine (Cr) is a natural compound that plays an important role in cellular energy homeostasis. In addition, it ameliorates oxidative stress, glutamatergic excitotoxicity, and apoptosis in vitro as well as in vivo. Since these pathomechanisms are implicated to play a role in several neurodegenerative diseases, Cr supplementation as a neuroprotective strategy has received a lot of attention with several positive animal studies in models of Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). This has led to a number of randomized clinical trials (RCT) with oral Cr supplementation, with durations up to 5 years. In this paper, we review the evidence and consequences stemming from these trials. In the case of PD, the initial phase II RCT was promising and led to a large and well-designed phase III trial, which, however, turned out to be negative for all outcome measures. None of the RCTs that have examined effects of Cr in ALS patients showed any clinical benefit. In HD, Cr in high doses (up to 30 g/day) was shown to slow down brain atrophy in premanifest Huntingtin mutation carriers. In spite of this, proof is still lacking that Cr can also have beneficial clinical effects in this group of patients, who will go on to develop HD symptoms. Taken together, the use of Cr supplementation has so far proved disappointing in clinical studies with a number of symptomatic neurodegenerative diseases. PMID- 26748652 TI - Mildly acidic conditions eliminate deamidation artifact during proteolysis: digestion with endoprotease Glu-C at pH 4.5. AB - Common yet often overlooked, deamidation of peptidyl asparagine (Asn or N) generates aspartic acid (Asp or D) or isoaspartic acid (isoAsp or isoD). Being a spontaneous, non-enzymatic protein post-translational modification, deamidation artifact can be easily introduced during sample preparation, especially proteolysis where higher-order structures are removed. This artifact not only complicates the analysis of bona fide deamidation but also affects a wide range of chemical and enzymatic processes; for instance, the newly generated Asp and isoAsp residues may block or introduce new proteolytic sites, and also convert one Asn peptide into multiple species that affect quantification. While the neutral to mildly basic conditions for common proteolysis favor deamidation, mildly acidic conditions markedly slow down the process. Unlike other commonly used endoproteases, Glu-C remains active under mildly acid conditions. As such, as demonstrated herein, deamidation artifact during proteolysis was effectively eliminated by simply performing Glu-C digestion at pH 4.5 in ammonium acetate, a volatile buffer that is compatible with mass spectrometry. Moreover, nearly identical sequence specificity was observed at both pH's (8.0 for ammonium bicarbonate), rendering Glu-C as effective at pH 4.5. In summary, this method is generally applicable for protein analysis as it requires minimal sample preparation and uses the readily available Glu-C protease. PMID- 26748653 TI - CT-guided aspiration cytology of advanced silicosis and confirmation of the deposited zeolite nano particles through X ray diffraction: A novel approach. AB - Silicosis is a common occupational lung disease, resulting in fibrotic nodular lesions in the upper lobes of the lung parenchyma. Most of the pneumoconioses are diagnosed on the basis of relevant history and clinico-radiological correlation. Image-guided aspiration cytology appears to be poorly yielding and is not usually considered as a diagnostic modality. However, silicosis may sometimes offer a diagnostic challenge because of its radiological resemblance and clinical overlap with pulmonary tuberculosis and neoplastic lesions. We present a unique situation where image-guided fine needle aspiration cytology (FNAC) has been advised on the basis of nodular upper lobe opacities. The cytology smears revealed hypocellular granular material, while phase contrast and polarized light microscopy highlighted crystalline particles. History of silica dust exposure long back was available after the cytological evaluation, suggesting the diagnosis of pulmonary silicosis. X ray diffraction (XRD) crystallography was also possible on cytology smears, confirming zeolite nano particles of size as small as 40 - 50 nm as the concerned agent for the first time. Cytological evaluation by phase contrast and polarized light microscopy may be useful for the confirmation of silicosis, supplemented by clinical history and radiological evaluation. XRD on smears may help in determination of chemical nature and particle size. PMID- 26748654 TI - Suicidal Individuals and Mental Health Treatment: A Novel Approach to Engagement. AB - To determine the feasibility and acceptability of a novel, manualized problem solving and comprehensive contact intervention (PS-CCI) aimed at improving treatment engagement of suicidal individuals. The PS-CCI was administered to 44 individuals with mood disorders presenting to the ER with suicidal ideation and/or behavior. The PS-CCI has two components: (1) a problem-solving interview administered upon admission to the emergency room (ER), and (2) follow-up contact post-discharge from the ER. The average age of participants was 33.45 years (SD = +/-12.30). The PS-CCI was completed by 75 % of patients. No subject (0 %) withdrew during the 3-month follow-up period; however, 27.2 % were unable to be reached for follow-up assessment. We have concluded that the intervention has a good feasibility because of high acceptability and adherence and further testing of its efficacy seems feasible. PMID- 26748655 TI - 1H, 15N, 13C resonance assignment of human GAP-43. AB - GAP-43 is a 25 kDa neuronal intrinsically disordered protein, highly abundant in the neuronal growth cone during development and regeneration. The exact molecular function(s) of GAP-43 remains unclear but it appears to be involved in growth cone guidance and actin cytoskeleton organization. Therefore, GAP-43 seems to play an important role in neurotransmitter vesicle fusion and recycling, long term potentiation, spatial memory formation and learning. Here we report the nearly complete assignment of recombinant human GAP-43. PMID- 26748656 TI - FKBP8 interact with classical swine fever virus NS5A protein and promote virus RNA replication. AB - The non-structural 5A (NS5A) protein of classical swine fever virus (CSFV) is proven to be involved in viral replication and can also modulate cellular signaling and host cellular responses via to its ability to interact with various cellular proteins. FKBP8 is also reported to promote virus replication. Here, we show that NS5A specifically interacts with FKBP8 through coimmunoprecipitation and GST-pulldown studies. Additionally, confocal microscopy study showed that NS5A and FKBP8 colocalized in the cytoplasm. Overexpression of FKBP8 via the eukaryotic expression plasmid pDsRED N1 significantly promoted viral RNA synthesis. The cells knockdown of FKBP8 by lentivirus-mediated shRNA markedly decreased the virus replication when infected with CSFV. These data suggest that FKBP8 plays a critical role in the viral life cycle, particularly during the virus RNA replication period. The investigation of FKBP8 protein functions may be beneficial for developing new strategies to treat CSFV infection. PMID- 26748659 TI - Peter R. Schreiner. AB - If I could be anyone for a day, I would be Roger Federer at Wimbledon. My favorite musicians are Joe Bonamassa, David Gilmour, and Victor Wooten. PMID- 26748657 TI - Multimedia screening of contaminants of emerging concern (CECS) in coastal urban watersheds in southern California (USA). AB - To examine the occurrence and fate of contaminants of emerging concern (CECs) and inform future monitoring of CECs in coastal urban waterways, water, sediment, and fish tissue samples were collected and analyzed for a broad suite of pharmaceuticals and personal care products (PPCPs), commercial and/or household chemicals, current use pesticides, and hormones in an effluent-dominated river and multiple embayments in southern California (USA). In the Santa Clara River, which receives treated wastewater from several facilities, aqueous phase CECs were detectable at stations nearest discharges from municipal wastewater treatment plants but were attenuated downstream. Sucralose and the chlorinated phosphate flame retardants tris(1-chloro-2-propyl) phosphate (TCPP), tris(1,3 dichloro-2-propyl) phosphate (TDCPP), and tris(2-chloroethyl) phosphate (TCEP) were most abundant in water, with maximum concentrations of 35 MUg/L, 3.3 MUg/L, 1.4 MUg/L, and 0.81 MUg/L, respectively. Triclocarban, an antimicrobial agent in use for decades, was more prevalent in water than triclosan or nonylphenol. Maximum concentrations of bifenthrin, permethrin, polybrominated diphenyl ethers (PBDEs), and degradates of fipronil exceeded CEC-specific monitoring trigger levels recently established for freshwater and estuarine sediments by factors of 10 to 1000, respectively. Maximum fish tissue concentrations of PBDEs varied widely (370 ng/g and 7.0 ng/g for the Santa Clara River and coastal embayments, respectively), with most species exhibiting concentrations at the lower end of this range. These results suggest that continued monitoring of pyrethroids, PBDEs, and degradates of fipronil in sediment is warranted in these systems. In contrast, aqueous pharmaceutical concentrations in the Santa Clara River were not close to exceeding current monitoring trigger levels, suggesting a lower priority for targeted monitoring in this medium. Environ Toxicol Chem 2016;35:1986-1994. (c) 2016 SETAC. PMID- 26748660 TI - Living dolls and nurses without empathy. PMID- 26748658 TI - A click chemistry approach identifies target proteins of xanthohumol. AB - SCOPE: Many phytochemicals with beneficial pharmacological properties contain electrophilic sites, e.g. alpha,beta-unsaturated carbonyl (enone) groups. There is increasing evidence that many biological effects of electrophilic compounds depend on covalent conjugation to reactive protein thiols. For example, the reaction of electrophiles with cysteinyl residues of the sensor protein Keap1 activates the cell-protective Nrf2 response. Thus it is of interest to identify more generally the proteins to which small molecule electrophiles bind covalently. METHODS AND RESULTS: Here we use a Click chemistry approach to identify target proteins of the chemopreventive phytochemical xanthohumol (XN), an enone-containing chalcone from hops (Humulus lupulus L.). Using an alkynylated analog of XN (XN-alkyne), we purified covalent protein-electrophile conjugates from cell lysates. We confirm the previously described conjugation of XN to Keap1. One of the newly identified candidate target proteins is glucose-6 phosphate dehydrogenase (G6PDH). We confirm that XN attenuates intracellular G6PDH activity at low micromolar concentrations. CONCLUSION: We find support for the notion that XN modulates multiple pathways and processes by covalent modification of proteins with reactive cysteines. PMID- 26748661 TI - Tetrandrine suppresses articular inflammatory response by inhibiting pro inflammatory factors via NF-kappaB inactivation. AB - Targeting activated macrophages using anti-inflammatory phytopharmaceuticals has been proposed as general therapeutic approaches for rheumatic diseases. Besides macrophages, chondrocytes are another promising target of anti-inflammatory agents. Tetrandrine is a major bisbenzylisoquinoline alkaloid isolated from Stephania tetrandrae S. Moore which has been used for 2,000 years as an antirheumatic herbal drug in China. Although, the anti-inflammatory effect of tetrandrine has been demonstrated, the mechanism has not been clearly clarified. In this study, we designed a comprehensive anti-inflammatory evaluation system for tetrandrine, including complete Freund's adjuvant (CFA)-induced arthritis rat, LPS-induced macrophage RAW 264.7 cells, and chondrogenic ATDC5 cells. The results showed that tetrandrine alleviated CFA-induced foot swelling, synovial inflammation, and pro-inflammatory cytokines secretion. Tetrandrine could inhibit IL-6, IL-1beta, and TNF-alpha expression via blocking the nuclear translocation of nuclear factor (NF)-kappaB p65 in LPS-induced RAW 264.7 cells. Moreover, ATDC5 cells well responded to LPS induced pro-inflammatory mediators secretion and tissue degradation, and tetrandrine could also inhibit the production of nitric oxide and prostaglandin E2 , as well as the expression of matrix metalloproteinase (MMP)-3 and tissue inhibitor of metalloproteinase (TIMP)-1 via inhibiting IkappaBalpha phosphorylation and degradation. In conclusion, the results showed that one of the anti-inflammatory mechanisms of tetrandrine was inhibiting IkappaBalpha and NF-kappaB p65 phosphorylation in LPS-induced macrophage RAW 264.7 cells and chondrogenic ATDC5 cells. Moreover, we introduce a vigorous in vitro cell screening system, LPS-induced murine macrophage RAW 264.7 cells coupling chondrogenic ADTC5 cells, for screening anti-rheumatic drugs. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1557-1568, 2016. PMID- 26748662 TI - Statistical efficiency and optimal design for stepped cluster studies under linear mixed effects models. AB - In stepped cluster designs the intervention is introduced into some (or all) clusters at different times and persists until the end of the study. Instances include traditional parallel cluster designs and the more recent stepped-wedge designs. We consider the precision offered by such designs under mixed-effects models with fixed time and random subject and cluster effects (including interactions with time), and explore the optimal choice of uptake times. The results apply both to cross-sectional studies where new subjects are observed at each time-point, and longitudinal studies with repeat observations on the same subjects. The efficiency of the design is expressed in terms of a 'cluster-mean correlation' which carries information about the dependency-structure of the data, and two design coefficients which reflect the pattern of uptake-times. In cross-sectional studies the cluster-mean correlation combines information about the cluster-size and the intra-cluster correlation coefficient. A formula is given for the 'design effect' in both cross-sectional and longitudinal studies. An algorithm for optimising the choice of uptake times is described and specific results obtained for the best balanced stepped designs. In large studies we show that the best design is a hybrid mixture of parallel and stepped-wedge components, with the proportion of stepped wedge clusters equal to the cluster mean correlation. The impact of prior uncertainty in the cluster-mean correlation is considered by simulation. Some specific hybrid designs are proposed for consideration when the cluster-mean correlation cannot be reliably estimated, using a minimax principle to ensure acceptable performance across the whole range of unknown values. (c) 2016 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd. PMID- 26748663 TI - Functional topography of cardiovascular regulation along the rostrocaudal axis of the rat posterior insular cortex. AB - Cardiovascular (CV) representation has been identified within the insular cortex (IC) and a lateralization of function previously suggested. In order to further understand the role of IC on cardiovascular control, the present study compared the CV responses evoked by stimulation of N-metil-D-aspartate (NMDA) receptors in the right and left posterior IC at different rostrocaudal levels. Intracortical microinjections of NMDA were performed into the IC of male Wistar rats anaesthetized with urethane (1.4 g/kg) prepared for blood pressure, heart rate and renal sympathetic nerve activity. Gene expression of NMDA receptor subunits NR2A and NR2B in the IC was confirmed by RT-PCR. Immunofluorescence for the NMDA receptor NR1 subunit was demonstrated in the IC (coordinates anteroposterior (AP) +1.5, 0.0 and -1.5 mm). A cardiac sympathoinhibitory site was identified, more rostrally located than identified in previous studies. A site of sympathoexcitatory cardiac control was identified more caudal to this region in agreement with earlier work. Under the experimental conditions, no lateralization of cardiovascular function was identified with chemical stimulation eliciting the same responses from either left or right insular cortices. No tonic role of the insula on cardiovascular control was identified with the use of the NMDA antagonist, AP-5. Peri-insular microinjection of NMDA was without cardiovascular effect indicating the specificity of the insula as a cardiovascular regulatory site. The current study reveals a functional topography for autonomic cardiovascular control along the rostrocaudal axis of the posterior IC. PMID- 26748665 TI - The use of mobile technology in evaluation. PMID- 26748664 TI - On the Use of the Platelet Activity State Assay for the In Vitro Quantification of Platelet Activation in Blood Recirculating Devices for Extracorporeal Circulation. AB - We designed an experimental setup to characterize the thrombogenic potential associated with blood recirculating devices (BRDs) used in extracorporeal circulation (ECC). Our methodology relies on in vitro flow loop platelet recirculation experiments combined with the modified-prothrombinase platelet activity state (PAS) assay to quantify the bulk thrombin production rate of circulated platelets, which correlates to the platelet activation (PA) level. The method was applied to a commercial neonatal hollow fiber membrane oxygenator. In analogous hemodynamic environment, we compared the PA level resulting from multiple passes of platelets within devices provided with phosphorylcholine (PC) coated and noncoated (NC) fibers to account for flow-related mechanical factors (i.e., fluid-induced shear stress) together with surface contact activation phenomena. We report for the first time that PAS assay is not significantly sensitive to the effect of material coating under clinically pertinent flow conditions (500 mL/min), while providing straightforward information on shear mediated PA dynamics in ECC devices. Being that the latter is intimately dependent on local flow dynamics, according to our results, the rate of thrombin production as measured by the PAS assay is a valuable biochemical marker of the selective contribution of PA in BRDs induced by device design features. Thus, we recommend the use of PAS assay as a means of evaluating the effect of modification of specific device geometrical features and/or different design solutions for developing ECC devices providing flow conditions with reduced thrombogenic impact. PMID- 26748666 TI - Physico-chemical and physiological changes during fruit development and on-tree ripening of two Spanish jujube cultivars (Ziziphus jujuba Mill.). AB - BACKGROUND: Few studies have been performed on changes in organoleptic, nutritive, functional, and physiological properties during jujube fruit development and on-tree ripening. In this work, a comparative study on the evolution of physical, chemical, nutritive, and physiological parameters and bioactive compounds of two Spanish jujube cultivars was performed. RESULTS: Both cultivars showed a non-climacteric ripening pattern, although the JM cultivar was smaller, sweeter, softer, and more highly coloured than the JG, which was characterised by having larger and firmer fruits, although less sweet and coloured. Both cultivars showed high TAA, which was highly correlated with the concentration of total phenols, giving them great functional properties. CONCLUSION: This fruit has little economic importance in Spain and it is just marginally grown for self-consumption or for ornamental purposes. Given the excellent properties of these fruits, it could be considered a fruit species of great interest, and commercial growth of these cultivars with high yields and fruits with high functional properties should be promoted. (c) 2016 Society of Chemical Industry. PMID- 26748667 TI - Reply. PMID- 26748668 TI - A Selective Mucin/Methylcellulose Hybrid Gel with Tailored Mechanical Properties. AB - Mucin glycoproteins are key components of native mucus which serves as an initial barrier in the human body against microbial attack. Mucins are able to prevent bacterial adhesion and can trap viruses. However, the weak mechanical properties of mucin solutions have so far prevented their application in a physiological environment. Here, methylcellulose biopolymers are used as mechanical adjuvants to overcome this limitation and generate a thermoresponsive mucin/methylcellulose hybrid system. The hybrid material developed combines the selective permeability properties brought about by mucins with the thermal autogelation properties of methylcellulose. As a consequence, triggered by contact with body-warm surfaces, the hybrid material rapidly forms a gel at physiological conditions, and this external temperature stimulus can also be harnessed to stimulate drug release from incorporated thermosensitive liposomes. Finally, the hybrid gel selectively retards the release of embedded molecules which can be used to further control and prolong drug release from the material. PMID- 26748669 TI - Impact of workflow on the use of the Surgical Safety Checklist: a qualitative study. AB - BACKGROUND: Regardless of the benefits associated of the Surgical Safety Checklist, adherence across its three phases remains inconsistent. The aim of this study was to systematically identify issues around workflow that impact on surgical teams' ability to use the Surgical Safety Checklist in a large tertiary facility in Queensland, Australia. METHOD: Observational audit of 10 surgical teams and 33 semi-structured interviews with 70 participants from nursing, medicine and the community were conducted. Data were collected during 2014-2015. Inductive and deductive approaches were used to analyse field observations and interview transcripts. RESULTS: The domain, impact of workflow on checklist utilization, was identified. Within this domain, seven categories illustrated the causal conditions which determined the ways in which workflow influenced checklist use. These categories included: 'busy doing the task'; 'clashing task priorities'; 'being pressured, running out of time'; 'adapting processes to work patterns'; 'doubling up on work'; 'a domino effect, leading to delays' and 'reality of the workflow'. CONCLUSIONS: One of the greatest systemic challenges to checklist use in surgery is workflow. Process changes in the way that surgical safety checklists are used need to incorporate the temporal demands of the workflow. Any changes made must ensure the process is reliable, is easily embedded into existing work routines and is not disruptive. PMID- 26748670 TI - Adaptation of Escherichia coli to glucose promotes evolvability in lactose. AB - The selective history of a population can influence its subsequent evolution, an effect known as historical contingency. We previously observed that five of six replicate populations that were evolved in a glucose-limited environment for 2000 generations, then switched to lactose for 1000 generations, had higher fitness increases in lactose than populations started directly from the ancestor. To test if selection in glucose systematically increased lactose evolvability, we started 12 replay populations--six from a population subsample and six from a single randomly selected clone--from each of the six glucose-evolved founder populations. These replay populations and 18 ancestral populations were evolved for 1000 generations in a lactose-limited environment. We found that replay populations were initially slightly less fit in lactose than the ancestor, but were more evolvable, in that they increased in fitness at a faster rate and to higher levels. This result indicates that evolution in the glucose environment resulted in genetic changes that increased the potential of genotypes to adapt to lactose. Genome sequencing identified four genes--iclR, nadR, spoT, and rbs--that were mutated in most glucose-evolved clones and are candidates for mediating increased evolvability. Our results demonstrate that short-term selective costs during selection in one environment can lead to changes in evolvability that confer longer term benefits. PMID- 26748671 TI - Nonlethal Effects of Nematode Infection on Sirex noctilio and Sirex nigricornis (Hymenoptera: Siricidae). AB - A nonnative woodwasp, Sirex noctilio F., has established in pine forests in eastern North America. To facilitate prediction of the full range of impacts S. noctilio could have as it continues to spread in North American forest ecosystems, we studied the effects of infection by a nonsterilizing parasitic nematode on S. noctilio size, fecundity, and flight capacity and on the native woodwasp, S. nigricornis, size and fecundity. We also developed predictive models relating size to fecundity for both species. On average, S. noctilio (3.18 +/- 0.05 mm) were larger than S. nigricornis (2.19 +/- 0.04 mm). For wasps of similar size, S. nigricornis was more fecund. Nematode infection negatively affected potential fecundity by a mean difference of 36 and 49 eggs in S. noctilio and S. nigricornis, respectively. Nematode-infected males of S. noctilio, however, were larger than uninfected individuals. Nematode infection showed inconsistent results on mean speed and total distance flown by S. noctilio males and females. Nematode infection did not affect total distance flown by females, and so is unlikley to have a direct, or strong influence on S. noctilio flight capacity. Models developed to predict fecundity of Sirex spp. from body size, based on the close relationship between pronotum width and potential fecundity for both species (R(2) >= 0.69), had low measures of error when compared with true values of fecundity (+/- 25-26 eggs). PMID- 26748672 TI - Evaluation of the Effects of Light Intensity and Time Interval After the Start of Scotophase on the Female Flight Propensity of Asian Gypsy Moth (Lepidoptera: Erebidae). AB - Asian gypsy moth, Lymantria dispar L. (Lepidoptera: Erebidae), females are capable of flight, but little is known about what causes the variation in flight propensity that has been observed. The female flight propensity and capability of Asian gypsy moth from seven geographic populations (three from China, two from Russia, one from Japan, and one from Korea) were compared under all combinations of three light intensities (0.05, 0.10, and 0.40 lux) and during three time intervals after the start of scotophase. A total of 567 females were flight tested. Female flight propensity, time to initiate walking, fanning, and flying, and duration of fanning differed significantly among geographic populations. Females were less likely to voluntarily fly during the 0-1-h time interval after the start of scotophase than during the later time intervals (1-2 and 2-3 h), suggesting that the light intensity cue has to occur at the correct time after the expected start of scotophase for flight initiation. Light intensity did not significantly affect the proportion of females that voluntarily flew, but did impact the timing of the walking and fanning preflight behaviors. The interaction between light intensity and time interval after the start of scotophase had a significant effect on the proportion of females that fanned. The proportion of females with sustained flight capability varied among the populations evaluated. These results may aid in determining the risk of Asian gypsy moth dispersal, but further work is needed to assess other factors that play a role in flight propensity. PMID- 26748674 TI - Structure and photoluminescent properties of green-emitting terbium-doped GdV1-x Px O4 phosphor prepared by solution combustion method. AB - Terbium-doped gadolinium orthovanadate (GdVO4 :Tb(3+) ), orthophosphate monohydrate (GdPO4 .H2 O:Tb(3+) ) and orthovanadate-phosphate (GdV,PO4 :Tb(3+) ) powder phosphors were synthesized using a solution combustion method. X-Ray diffraction analysis confirmed the formation of crystalline GdVO4 , GdPO4 .H2 O and GdV,PO4 . Scanning electron microscopy images showed that the powder was composed of an agglomeration of particles of different shapes, ranging from spherical to oval to wire-like structures. The chemical elements present were confirmed by energy dispersive spectroscopy, and the stretching mode frequencies were determined by Fourier transform infrared spectroscopy. UV-visible spectroscopy spectra showed a strong absorption band with a maximum at 200 nm assigned to the absorption of VO4 (3-) and minor excitation bands assigned to f > f transitions of Tb(3+) . Four characteristic emission peaks were observed at 491, 546, 588 and 623 nm, and are attributed to (5) D4 -> (7) Fj (j = 6, 5, 4 and 3). The photoluminescent prominent green emission peak ((5) D4 -> (7) F5 ) was centred at 546 nm. The structure and possible mechanism of light emission from GdV1-x Px O4 :% Tb(3+) are discussed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26748673 TI - 3D spatially encoded and accelerated TE-averaged echo planar spectroscopic imaging in healthy human brain. AB - Several different pathologies, including many neurodegenerative disorders, affect the energy metabolism of the brain. Glutamate, a neurotransmitter in the brain, can be used as a biomarker to monitor these metabolic processes. One method that is capable of quantifying glutamate concentration reliably in several regions of the brain is TE-averaged (1) H spectroscopic imaging. However, this type of method requires the acquisition of multiple TE lines, resulting in long scan durations. The goal of this experiment was to use non-uniform sampling, compressed sensing reconstruction and an echo planar readout gradient to reduce the scan time by a factor of eight to acquire TE-averaged spectra in three spatial dimensions. Simulation of glutamate and glutamine showed that the 2.2-2.4 ppm spectral region contained 95% glutamate signal using the TE-averaged method. Peak integration of this spectral range and home-developed, prior-knowledge-based fitting were used for quantitation. Gray matter brain phantom measurements were acquired on a Siemens 3 T Trio scanner. Non-uniform sampling was applied retrospectively to these phantom measurements and quantitative results of glutamate with respect to creatine 3.0 (Glu/Cr) ratios showed a coefficient of variance of 16% for peak integration and 9% for peak fitting using eight-fold acceleration. In vivo scans of the human brain were acquired as well and five different brain regions were quantified using the prior-knowledge-based algorithm. Glu/Cr ratios from these regions agreed with previously reported results in the literature. The method described here, called accelerated TE averaged echo planar spectroscopic imaging (TEA-EPSI), is a significant methodological advancement and may be a useful tool for categorizing glutamate changes in pathologies where affected brain regions are not known a priori. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26748675 TI - Resveratrol Ameliorates the Components of Hepatic Inflammation and Apoptosis in a Rat Model of Streptozotocin-Induced Diabetes. AB - Preclinical Research Trans-resveratrol has a wide range of biological effects that reflect its antioxidant, anti-inflammatory, anticarcinogenic and cardioprotective properties. This study was conducted to elucidate the potential role of resveratrol on hepatic inflammation and the apoptotic pathway components Bcl-2, Bax and p53 in a streptozotocin (STZ)-induced rat model of diabetes mellitus. Inflammatory and apoptotic biomarkers indicated a reduction in hepatic erythropoietin (1.26-fold) and increased asymmetric dimethylarginine (3.9-fold), visfatin (1.6-fold), inflammatory interleukins and TNF-alpha contents (approximately twofold each) in the diabetic animals. Induction of inducible nitric oxide synthase gene (2.04-fold) and protein expression (1.24-fold) was also observed. Immunohistochemical studies showed enhancement of the apoptotic biomarkers Bax and p53 in diabetic animals. STZ-induced diabetic male Wistar rats were treated with resveratrol (20 mg/kg/day i.p.). Resveratrol succeeded to recover most of these inflammatory and apoptotic elements. Therefore, inflammatory and apoptotic pathways were proved to be affected by STZ-induced diabetes in several aspects and resveratrol might contribute hepatoprotective effects as evidenced from this study. PMID- 26748676 TI - Editorial: Extracellular Matrix: The Common Thread of Disease Progression in Fibrosis? PMID- 26748678 TI - Ten-year updated meta-analysis of the clinical characteristics of pediatric mania and hypomania. AB - OBJECTIVES: The phenomenology and diagnosis of pediatric bipolar disorder has been controversial. We aimed to update a 2005 meta analysis of the prevalence of manic symptoms in youth, in order to determine whether the picture of pediatric mania has changed as research on pediatric bipolar disorder has grown. METHODS: We conducted literature reviews in PsycINFO and PubMed; studies with the prevalence of manic symptoms in youth were included. Two raters coded each study; kappa was 0.86-1.0. RESULTS: Twenty studies were meta-analyzed (N = 2,226 youths). The most common symptoms across bipolar subtypes, using a random-effects model, were: increased energy 79%, irritability 77%, mood lability 76%, distractibility 74%, goal-directed activity 72%, euphoric/elated mood 64%, pressured speech 63%, hyperactive 62%, racing thoughts 61%, poor judgment 61%, grandiosity 57%, inappropriate laughter 57%, decreased need for sleep 56%, and flight of ideas 54%. Symptom rates were heterogeneous across samples; potential predictors were explored but no clear patterns were found. CONCLUSIONS: Debate continues about the definitions of pediatric bipolar disorder; the results of this meta-analysis suggest that there is significant heterogeneity of symptom prevalence between studies, and that symptoms vary widely across individuals. Understanding the roots of this heterogeneity could broaden understanding of the complex clinical presentation of pediatric mania, and aid in diagnosis. PMID- 26748677 TI - Influence of surface sealing on color stability and roughness of composite submitted to ultraviolet-accelerated aging. AB - AIM: In the present study, we evaluated the influence of surface sealing on color stability and surface roughness of a composite resin after accelerated artificial aging. METHODS: Thirty-two specimens of a composite were prepared. After 24 h, the specimens were polished and divided into four groups (n = 8), according to the surface sealant used, including the control, which had no sealant application. Baseline color was measured according to the CIELab system using a reflection spectrophotometer. Surface roughness was determined using a profilometer with a cut-off of 0.25 mm. After these tests, specimens were aged for 252 h in an ultraviolet (UV)-accelerated aging chamber. Color stability was determined by difference between coordinates obtained before and after the aging procedure. Data of color change and roughness were evaluated by anova and Fisher's exact test (alpha = 0.05). RESULTS: The results showed that the unsealed group had the highest color change compared to other groups (P = 0.0289), and there was no significant difference between groups sealed with surface sealant (P > 0.05). The artificial aging caused an increase in roughness values independent of the experimental group studied (P = 0.0015). CONCLUSION: The sealed composites showed lower color change after UV aging, but all groups showed clinically acceptable color change, and only liquid polish decreased roughness. PMID- 26748679 TI - Loading protocols and implant supported restorations proposed for the rehabilitation of partially and fully edentulous jaws. Camlog Foundation Consensus Report. AB - OBJECTIVES: The aim of this consensus meeting was to assess whether immediate loading protocols achieve comparable clinical outcomes when compared to conventional loading protocols depending on the type of prosthetic restoration. In addition post-loading implant loss for implant supported prostheses in edentulous jaws was analyzed regarding a potential impact of implant location (maxilla vs. mandible), implant number per patient, type of prosthesis (removable vs. fixed), and type of attachment system (screw-retained, ball vs. bar vs. telescopic crown). MATERIAL AND METHODS: Two comprehensive systematic reviews were prepared in advance of the meeting. Consensus statements, practical recommendations, and implications for future research were based on within group as well as plenary scrutinization and discussions of these systematic reviews. RESULTS: The survival rates are high for immediate loaded and conventional loaded implants, but immediate loading may impose a greater risk for implant failure. The estimated implant loss rate is influenced by the implant location, type of restoration, and implant number. CONCLUSIONS: Consistent reporting of clinical studies is necessary and high-quality studies are needed to confirm the present results. PMID- 26748680 TI - Integrative Analysis of Genomics and Transcriptome Data to Identify Potential Functional Genes of BMDs in Females. AB - Osteoporosis is known to be highly heritable. However, to date, the findings from more than 20 genome-wide association studies (GWASs) have explained less than 6% of genetic risks. Studies suggest that the missing heritability data may be because of joint effects among genes. To identify novel heritability for osteoporosis, we performed a system-level study on bone mineral density (BMD) by weighted gene coexpression network analysis (WGCNA), using the largest GWAS data set for BMD in the field, Genetic Factors for Osteoporosis Consortium (GEFOS-2), and a transcriptomic gene expression data set generated from transiliac bone biopsies in women. A weighted gene coexpression network was generated for 1574 genes with GWAS nominal evidence of association (p <= 0.05) based on dissimilarity measurement on the expression data. Twelve distinct gene modules were identified, and four modules showed nominally significant associations with BMD (p <= 0.05), but only one module, the yellow module, demonstrated a good correlation between module membership (MM) and gene significance (GS), suggesting that the yellow module serves an important biological role in bone regulation. Interestingly, through characterization of module content and topology, the yellow module was found to be significantly enriched with contractile fiber part (GO:044449), which is widely recognized as having a close relationship between muscle and bone. Furthermore, detailed submodule analyses of important candidate genes (HOMER1, SPTBN1) by all edges within the yellow module implied significant enrichment of functional connections between bone and cytoskeletal protein binding. Our study yielded novel information from system genetics analyses of GWAS data jointly with transcriptomic data. The findings highlighted a module and several genes in the model as playing important roles in the regulation of bone mass in females, which may yield novel insights into the genetic basis of osteoporosis. (c) 2016 American Society for Bone and Mineral Research. PMID- 26748681 TI - In reference to "Nebulized bronchodilators instead of metered-dose inhalers for obstructive pulmonary symptoms". PMID- 26748682 TI - Use of an epidural catheter inserted at L1-L2 in a dog undergoing pelvic limb amputation. PMID- 26748683 TI - Relative suitability of DMSO and NaHCO3 for reversal of RISUG(r) induced long term contraception. AB - Among the vas-based methods on trial, reversible inhibition of sperm under guidance (RISUG((r)) ), a co-polymer of styrene and maleic anhydride is being projected as an effective alternative to No Scalpel Vasectomy. RISUG offers long term contraception with safety, efficacy in human trials and can be delivered by no-scalpel injection. Currently, the procedure is under phase-III clinical trial. However, reversal of this vas-based drug-induced contraception needs to be established in animal models prior to clinical trials to ensure its claim as an effective alternative for vasectomy. In the present investigation, the relative suitability of dimethyl sulphoxide (DMSO) and NaHCO3 for RISUG induced long-term vas occlusion reversal was carried out in albino rats. Animals were allocated into four groups (n = 10), viz., sham-operated control (group-I), vas occlusion with RISUG for 360 days (group-II), vas occlusion with RISUG for 360 days and reversal with DMSO (group-III) and vas occlusion with RISUG for 360 days and reversal with NaHCO3 (group-IV). A variable response in fertility was observed in different groups. Absolute sterility in group III at all mating intervals, while, zero percent fertility in groups II and IV following 90 days of occlusion was observed. Following reversal restoration of fertility with DMSO at 45 days, whereas, reversal by NaHCO3 at 30 days was noticed. Ejaculated spermatozoa of RISUG injected and initial intervals of reversed animals exhibited various degrees of abnormalities. The testes exhibited focal degeneration in vas occluded animals. The occluded lumen of the vas deferens contained an eosinated polymer with exfoliated epithelium. Following vas occlusion reversal, a complete regeneration in the vas epithelium was seen. All other parameters remained unaltered. The reversal with NaHCO3 resulted into an early resumption of fertility when compared with DMSO and the procedure found to be successful, feasible and safe up to F1 generation. Thus, RISUG provides a hope for reversible male contraceptives. PMID- 26748684 TI - Flexible Nanogenerators for Energy Harvesting and Self-Powered Electronics. AB - Flexible nanogenerators that efficiently convert mechanical energy into electrical energy have been extensively studied because of their great potential for driving low-power personal electronics and self-powered sensors. Integration of flexibility and stretchability to nanogenerator has important research significance that enables applications in flexible/stretchable electronics, organic optoelectronics, and wearable electronics. Progress in nanogenerators for mechanical energy harvesting is reviewed, mainly including two key technologies: flexible piezoelectric nanogenerators (PENGs) and flexible triboelectric nanogenerators (TENGs). By means of material classification, various approaches of PENGs based on ZnO nanowires, lead zirconate titanate (PZT), poly(vinylidene fluoride) (PVDF), 2D materials, and composite materials are introduced. For flexible TENG, its structural designs and factors determining its output performance are discussed, as well as its integration, fabrication and applications. The latest representative achievements regarding the hybrid nanogenerator are also summarized. Finally, some perspectives and challenges in this field are discussed. PMID- 26748686 TI - Is There Evidence for a Mixture of Processes in Speed-Accuracy Trade-Off Behavior? AB - The speed-accuracy trade-off (SAT) effect refers to the behavioral trade-off between fast yet error-prone respones and accurate but slow responses. Multiple theories on the cognitive mechanisms behind SAT exist. One theory assumes that SAT is a consequence of strategically adjusting the amount of evidence required for overt behaviors, such as perceptual choices. Another theory hypothesizes that SAT is the consequence of the mixture of multiple categorically different cognitive processes. In this paper, these theories are disambiguated by assessing whether the fixed-point property of mixture distributions holds, in both simulations and data. I conclude that, at least for perceptual decision making, there is no evidence for a mixture of different cognitive processes to trade off accuracy of responding for speed. PMID- 26748685 TI - Association between knowledge about levonorgestrel emergency contraception and the risk of ectopic pregnancy following levonorgestrel emergency contraception failure: a comparative survey. AB - OBJECTIVE: To study the association between knowledge about levonorgestrel emergency contraception (LNG-EC) and the risk of ectopic pregnancy (EP) following LNG-EC failure. METHODS: This study included 600 women who had visited the hospital with LNG-EC failure. Of these, 300 with EP and 300 with intrauterine pregnancy (IUP) were recruited to the EP group and IUP group respectively. The participants were interviewed face-to-face using a standardized questionnaire. MAIN OUTCOME MEASURES: Pearson's chi-square tests and t-test were used to compare the sociodemographic characteristics, reproductive and gynecological history, surgical history, previous contraceptive experience, and answers to 10 questions concerning the knowledge about LNG-EC. RESULTS: Those who gave incorrect answers to the question regarding the basic mechanism and specific method of levonorgestrel emergency contraceptive pills (LNG-ECPs) were at a higher risk of EP after LNG-EC failure. Women who did not strictly follow instructions or advice from healthcare professionals were more likely to subsequently experience EP (p < 10(-4) ). Women with LNG-EC failure reported friends/peers, TV, and Internet as the main sources of information. No difference was observed with regard to the sources of knowledge on LNG-EC (p = 0.07). CONCLUSIONS: The results illustrate the importance of strictly following the doctor's guidance or drug instructions when using LNG-ECPs. The media should be used to disseminate information about responsible EC, and pharmacy staff should receive regular educational training sessions in this regard. (c) 2016 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd. PMID- 26748687 TI - Is the ballan wrasse (Labrus bergylta) two species? Genetic analysis reveals within-species divergence associated with plain and spotted morphotype frequencies. AB - The ballan wrasse (Labrus bergylta) is a marine fish belonging to the family Labridae characterized by 2 main morphotypes that occur in sympatry: spotty and plain. Previous studies have revealed differences in their life-history traits, such as growth and maturation; however, the genetic relationship between forms is presently unknown. Using 20 recently developed microsatellite markers, we conducted a genetic analysis of 41 and 48 spotty and plain ballan wrasse collected in Galicia (northwest Spain). The 2 morphotypes displayed highly significant genetic differences to each other (FST = 0.018, P < 0.0001). A similar degree of genetic differentiation (FST = 0.025, P < 0.0001) was shown using the STRUCTURE clustering approach with no priors at K = 2. In this case, the frequency of spotty and plain morphotypes was significantly different (chi(2) = 9.46, P = 0.002). It is concluded that there is significant genetic heterogeneity within this species, which appears to be highly associated with the spotty and plain forms, but not completely explained by them. Given the previously demonstrated biological differences between morphotypes, and the present genetic analyses, we speculate about the convenience of a taxonomic re evaluation of this species. PMID- 26748688 TI - Metabolic Diet App Suite for inborn errors of amino acid metabolism. AB - BACKGROUND: An increasing number of rare inborn errors of metabolism (IEMs) are amenable to targeted metabolic nutrition therapy. Daily adherence is important to attain metabolic control and prevent organ damage. This is challenging however, given the lack of information of disorder specific nutrient content of foods, the limited availability and cost of specialty products as well as difficulties in reliable calculation and tracking of dietary intake and targets. OBJECTIVES: To develop apps for all inborn errors of amino acid metabolism for which the mainstay of treatment is a medical diet, and obtain patient and family feedback throughout the process to incorporate this into subsequent versions. METHODS & RESULTS: The Metabolic Diet App Suite was created with input from health care professionals as a free, user-friendly, online tool for both mobile devices and desktop computers (http://www.metabolicdietapp.org) for 15 different IEMs. General information is provided for each IEM with links to useful online resources. Nutrient information is based on the MetabolicProTM, a North American food database compiled by the Genetic Metabolic Dietitians International (GMDI) Technology committee. After user registration, a personalized dashboard and management plan including specific nutrient goals are created. Each Diet App has a user-friendly interface and the functions include: nutrient intake counts, adding your own foods and homemade recipes and, managing a daily food diary. Patient and family feedback was overall positive and specific suggestions were used to further improve the App Suite. DISCUSSION: The Metabolic Diet App Suite aids individuals affected by IEMs to track and plan their meals. Future research should evaluate its impact on patient adherence, metabolic control, quality of life and health-related outcomes. The Suite will be updated and expanded to Apps for other categories of IEMs. Finally, this Suite is a support tool only, and does not replace medical/metabolic nutrition professional advice. PMID- 26748689 TI - Real-time endoscopic Raman spectroscopy for in vivo early lung cancer detection. AB - Currently the most sensitive method for localizing lung cancers in central airways is autofluorescence bronchoscopy (AFB) in combination with white light bronchoscopy (WLB). The diagnostic accuracy of WLB + AFB for high grade dysplasia (HGD) and carcinoma in situ is variable depending on physician's experience. When WLB + AFB are operated at high diagnostic sensitivity, the associated diagnostic specificity is low. Raman spectroscopy probes molecular vibrations and gives highly specific, fingerprint-like spectral features and has high accuracy for tissue pathology classification. In this study we present the use of a real-time endoscopy Raman spectroscopy system to improve the specificity. A spectrum is acquired within 1 second and clinical data are obtained from 280 tissue sites (72 HGDs/malignant lesions, 208 benign lesions/normal sites) in 80 patients. Using multivariate analyses and waveband selection methods on the Raman spectra, we have demonstrated that HGD and malignant lung lesions can be detected with high sensitivity (90%) and good specificity (65%). PMID- 26748690 TI - Diagnosis of sessile serrated adenomas/polyps using endocytoscopy (with videos). AB - Sessile serrated adenomas/polyps (SSA/P) are considered to be precursors of colorectal cancers. They therefore need to be distinguished from hyperplastic polyps, and should be treated similarly to adenomas. Various endoscopic classifications for discriminating SSA/P have recently been proposed and validated, including the 'Type II-O' pit pattern in magnifying chromoendoscopy and the 'varicose microvascular vessel' in narrow-band imaging. However, there is currently no diagnostic consensus on the endoscopic appearance of SSA/P. Endocytoscopy (EC) is an emerging modality with diagnostic potential for SSA/P. EC is a type of a contact light microscopy, which allows in vivo visualization of cells and nuclei facilitating precise, real-time pathological prediction. SSA/P show oval gland lumens with small round nuclei in EC, indirectly reflecting the pathological features. EC has shown a sensitivity of 83.3% and a specificity of 97.8% for the diagnosis of SSA/P. EC is also a promising tool for the diagnosis of SSA/P with cytological dysplasia because of its ability to detect morphological changes in nuclei, which is the most important factor determining the presence of dysplasia in the lesion. However, clinical data validating the usefulness of EC are lacking, and further studies are required. PMID- 26748691 TI - A systematic review of low-level light therapy for treatment of diabetic foot ulcer. AB - Diabetes mellitus (DM) is a significant international health concern affecting more than 387 million individuals. A diabetic person has a 25% lifetime risk of developing a diabetic foot ulcer (DFU), leading to limb amputation in up to one in six DFU patients. Low-level light therapy (LLLT) uses low-power lasers or light-emitting diodes to alter cellular function and molecular pathways, and may be a promising treatment for DFU. The goal of this systematic review is to examine whether the clinical use of LLLT is effective in the healing of DFU at 12 and 20 weeks in comparison with the standard of care, and to provide evidence based recommendation and future clinical guidelines for the treatment of DFU using LLLT. On September 30, 2015, we searched PubMed, EMBASE, CINAHL, and Web of Science databases using the following terms: "diabetic foot" AND "low level light therapy," OR "light emitting diode," OR "phototherapy," OR "laser." The relevant articles that met the following criteria were selected for inclusion: randomized control trials (RCTs) that investigated the use of LLLT for treatment of DFU. Four RCTs involving 131 participants were suitable for inclusion based upon our criteria. The clinical trials used sham irriadiation, low dose, or nontherapeutic LLLT as placebo or control in comparison to LLLT. The endpoints included ulcer size and time to complete healing with follow-up ranging from 2 to 16 weeks. Each article was assigned a level of evidence (LOE) and graded according to the Oxford Center for Evidence-based Medicine Levels of Evidence Grades of Recommendation criteria. Limitations of reviewed RCTs include a small sample size (N < 100), unclear allocation concealment, lack of screening phase to exclude rapid healers, unclear inclusion/exclusion criteria, short (<30 days) follow-up period, and unclear treatment settings (wavelength and treatment time). However, all reviewed RCTs demonstrated therapeutic outcomes with no adverse events using LLLT for treatment of DFU. This systematic review reports that LLLT has significant potential to become a portable, minimally invasive, easy-to-use, and cost effective modality for treatment of DFU. To enthusiastically recommend LLLT for treatment of DFU, additional studies with comparable laser parameters, screening period to exclude rapid healers, larger sample sizes and longer follow-up periods are required. We envision future stringent RCTs may validate LLLT for treatment of DFU. Systematic review registration number: PROSPERO CRD42015029825. PMID- 26748692 TI - Spatially Resolved Genome-wide Transcriptional Profiling Identifies BMP Signaling as Essential Regulator of Zebrafish Cardiomyocyte Regeneration. AB - In contrast to mammals, zebrafish regenerate heart injuries via proliferation of cardiomyocytes located near the wound border. To identify regulators of cardiomyocyte proliferation, we used spatially resolved RNA sequencing (tomo-seq) and generated a high-resolution genome-wide atlas of gene expression in the regenerating zebrafish heart. Interestingly, we identified two wound border zones with distinct expression profiles, including the re-expression of embryonic cardiac genes and targets of bone morphogenetic protein (BMP) signaling. Endogenous BMP signaling has been reported to be detrimental to mammalian cardiac repair. In contrast, we find that genetic or chemical inhibition of BMP signaling in zebrafish reduces cardiomyocyte dedifferentiation and proliferation, ultimately compromising myocardial regeneration, while bmp2b overexpression is sufficient to enhance it. Our results provide a resource for further studies on the molecular regulation of cardiac regeneration and reveal intriguing differential cellular responses of cardiomyocytes to a conserved signaling pathway in regenerative versus non-regenerative hearts. PMID- 26748693 TI - Mollisolactones A and B, novel dinormonoterpenes from the soft coral Sinularia mollis. AB - Two novel dinormonoterpenes, designated as mollisolactones A and B, were discovered from the soft coral Sinularia mollis on the basis of a chromatographic and NMR spectroscopy-based fractionation. Their structures were solved through analysis of comprehensive 1D and 2D NMR spectroscopic data and HRESIMS experiments. The biological activities of the obtained metabolites were evaluated for cytotoxicity against A-459 (human lung carcinoma), HT-29 (human colon adenocarcinoma), and P-388 (mouse lymphocytic leukemia) cancer cell lines as well as antiviral activity against HCMV (human cytomegalovirus). PMID- 26748694 TI - The influence of 5-HT(2A) activity on a 5-HT(2C) specific in vivo assay used for early identification of multiple acting SERT and 5-HT(2C) receptor ligands. AB - As a result of our exploratory programme aimed at elaborating dually acting compounds towards the serotonin (5-HT) transporter (SERT) and the 5-HT2C receptor a novel series of 3-amino-1-phenylpropoxy substituted diphenylureas was identified. From that collection two promising compounds (2 and 3) exhibiting highest 5-HT2C receptor affinity strongly inhibited the 5-HT2C receptor agonist 1 (3-chlorophenyl)piperazine (mCPP) induced hypomotility in mice. In further pursuance of that objective (2-aminoethyl)(benzyl)sulfamoyl diphenylureas and diphenylpiperazines have also been elaborated. Herein we report the synthesis of potent multiple-acting compounds from this new class. However, when two optimized representatives (6 and 14) possessing the desired in vitro profile were tested neither reduced the motor activity of mCPP treated animals. Comparative albeit limited in vitro structure-activity relationship (SAR) analysis and detailed in vivo studies are discussed and explanation for their intricate behaviour is proposed. PMID- 26748695 TI - Synthesis and evaluation of an (125)I-labeled azide prosthetic group for efficient and bioorthogonal radiolabeling of cyclooctyne-group containing molecules using copper-free click reaction. AB - Herein we report the radiosynthesis of a pyridine derived azide prosthetic group for iodine radioisotope labeling of dibenzocyclooctyne (DBCO) conjugated molecules. The radiolabeling of the stannylated precursor 2 was conducted using [(125)I]NaI and chloramine-T to give (125)I-labeled azide ([(125)I]1) with high radiochemical yield (72+/-8%, n=4) and radiochemical purity (>99%). Using (125)I labeled azide ([(125)I]1), cyclic RGD peptide and near infrared fluorescent molecule were efficiently labeled with modest to good radiochemical yields. The biodistribution study and SPECT/CT images showed that [(125)I]1 underwent rapid renal clearance. These results clearly demonstrated that [(125)I]1 could be used as an useful radiotracer for in vivo pre-targeted imaging as well as efficient in vitro radiolabeling of DBCO containing molecules. PMID- 26748696 TI - Three-component, one-pot synthesis of benzo[6,7]cyclohepta[1,2-b]pyridine derivatives under catalyst free conditions and evaluation of their anti inflammatory activity. AB - An efficient three-component protocol is described for the synthesis of benzo[6,7]cyclohepta[1,2-b]pyridine derivatives using beta-chloroacroleins, 1,3 dicarbonyls and ammonium acetate under catalyst free conditions by using ethanol as reaction media. The mild reaction conditions, operational simplicity and high yields are the advantages of this protocol and the broad scope of this one-pot reaction makes this procedure promising for practical usages. All the final compounds were screened for anti-inflammatory activity. Among the compounds tested, the compounds 5a, 5b, 5c, 5d, 5f, and 5k exhibited significant inhibition of IL-1beta and MCP-1 secretion as a measure of anti-inflammatory activity. PMID- 26748698 TI - ECM Signaling Regulates Collective Cellular Dynamics to Control Pancreas Branching Morphogenesis. AB - During pancreas development, epithelial buds undergo branching morphogenesis to form an exocrine and endocrine gland. Proper morphogenesis is necessary for correct lineage allocation of pancreatic progenitors; however, the cellular events underlying pancreas morphogenesis are unknown. Here, we employed time lapse microscopy and fluorescent labeling of cells to analyze cell behaviors associated with pancreas morphogenesis. We observed that outer bud cells adjacent to the basement membrane are pleomorphic and rearrange frequently; additionally, they largely remain in the outer cell compartment even after mitosis. These cell behaviors and pancreas branching depend on cell contacts with the basement membrane, which induce actomyosin cytoskeleton remodeling via integrin-mediated activation of FAK/Src signaling. We show that integrin signaling reduces E cadherin-mediated cell-cell adhesion in outer cells and provide genetic evidence that this regulation is necessary for initiation of branching. Our study suggests that regulation of cell motility and adhesion by local niche cues initiates pancreas branching morphogenesis. PMID- 26748697 TI - Natural product-based synthesis of novel anti-infective isothiocyanate- and isoselenocyanate-functionalized amphilectane diterpenes. AB - The marine natural product (-)-8,15-diisocyano-11(20)-amphilectene (1), isolated from the Caribbean sponge Svenzea flava, was used as scaffold to synthetize five new products, all of which were tested against laboratory strains of Plasmodium falciparum and Mycobacterium tuberculosis H37Rv. The scaffold contains two isocyanide units that are amenable to chemical manipulation, enabling them to be elaborated into a small library of sulfur and selenium compounds. Although most of the analogs prepared were less potent than the parent compound, 5 was nearly equipotent showing IC50 values of 0.0066 MUM and 0.0025 MUM, respectively, against two strains (Dd2 and 3D7) of the malaria parasite. On the other hand, when assayed against the tuberculosis bacterium, analogs 5 and 6 were found to be more potent than 1. PMID- 26748700 TI - A Dendritic Golgi Satellite between ERGIC and Retromer. AB - The local synthesis of transmembrane proteins underlies functional specialization of dendritic microdomains in neuronal plasticity. It is unclear whether these proteins have access to the complete machinery of the secretory pathway following local synthesis. In this study, we describe a probe called pGolt that allows visualization of Golgi-related organelles for live imaging in neurons. We show that pGolt labels a widespread microsecretory Golgi satellite (GS) system that is, in contrast to Golgi outposts, present throughout basal and apical dendrites of all pyramidal neurons. The GS system contains glycosylation machinery and is localized between ERGIC and retromer. Synaptic activity restrains lateral movement of ERGIC, GS, and retromer close to one another, allowing confined processing of secretory cargo. Several synaptic transmembrane proteins pass through and recycle back to the GS system. Thus, the presence of an ER-ERGIC-GS retromer microsecretory system in all neuronal dendrites enables autonomous local control of transmembrane protein synthesis and processing. PMID- 26748699 TI - The X-Linked-Intellectual-Disability-Associated Ubiquitin Ligase Mid2 Interacts with Astrin and Regulates Astrin Levels to Promote Cell Division. AB - Mid1 and Mid2 are ubiquitin ligases that regulate microtubule dynamics and whose mutation is associated with X-linked developmental disorders. We show that astrin, a microtubule-organizing protein, co-purifies with Mid1 and Mid2, has an overlapping localization with Mid1 and Mid2 at intercellular bridge microtubules, is ubiquitinated by Mid2 on lysine 409, and is degraded during cytokinesis. Mid2 depletion led to astrin stabilization during cytokinesis, cytokinetic defects, multinucleated cells, and cell death. Similarly, expression of a K409A mutant astrin in astrin-depleted cells led to the accumulation of K409A on intercellular bridge microtubules and an increase in cytokinetic defects, multinucleated cells, and cell death. These results indicate that Mid2 regulates cell division through the ubiquitination of astrin on K409, which is critical for its degradation and proper cytokinesis. These results could help explain how mutation of MID2 leads to misregulation of microtubule organization and the downstream disease pathology associated with X-linked intellectual disabilities. PMID- 26748702 TI - Cortical Sensory Responses Are Enhanced by the Higher-Order Thalamus. AB - In the mammalian brain, thalamic signals reach the cortex via two major routes: primary and higher-order thalamocortical pathways. While primary thalamocortical nuclei transmit sensory signals from the periphery, the function of higher-order thalamocortical projections remains enigmatic, in particular their role in sensory processing in the cortex. Here, by optogenetically controlling the thalamocortical pathway from the higher-order posteromedial thalamic nucleus (POm) during whisker stimulation, we demonstrate the integration of the two thalamocortical streams by single pyramidal neurons in layer 5 (L5) of the mouse barrel cortex under anesthesia. We report that POm input mainly enhances sub- and suprathreshold activity via net depolarization. Sensory enhancement is accompanied by prolongation of cortical responses over long (800-ms) periods after whisker stimulation. Thus, POm amplifies and temporally sustains cortical sensory signals, possibly serving to accentuate highly relevant sensory information. PMID- 26748701 TI - DGKtheta Catalytic Activity Is Required for Efficient Recycling of Presynaptic Vesicles at Excitatory Synapses. AB - Synaptic transmission relies on coordinated coupling of synaptic vesicle (SV) exocytosis and endocytosis. While much attention has focused on characterizing proteins involved in SV recycling, the roles of membrane lipids and their metabolism remain poorly understood. Diacylglycerol, a major signaling lipid produced at synapses during synaptic transmission, is regulated by diacylglycerol kinase (DGK). Here, we report a role for DGKtheta in the mammalian CNS in facilitating recycling of presynaptic vesicles at excitatory synapses. Using synaptophysin- and vGlut1-pHluorin optical reporters, we found that acute and chronic deletion of DGKtheta attenuated the recovery of SVs following neuronal stimulation. Rescue of recycling kinetics required DGKtheta kinase activity. Our data establish a role for DGK catalytic activity at the presynaptic nerve terminal in SV recycling. Altogether, these data suggest that DGKtheta supports synaptic transmission during periods of elevated neuronal activity. PMID- 26748704 TI - Quantitative Analysis of Delta-like 1 Membrane Dynamics Elucidates the Role of Contact Geometry on Notch Signaling. AB - Notch signaling is ubiquitously used to coordinate differentiation between adjacent cells across metazoans. Whereas Notch pathway components have been studied extensively, the effect of membrane distribution and dynamics of Notch receptors and ligands remains poorly understood. It is also unclear how cellular morphology affects these distributions and, ultimately, the signaling between cells. Here, we combine live-cell imaging and mathematical modeling to address these questions. We use a FRAP-TIRF assay to measure the diffusion and endocytosis rates of Delta-like 1 (Dll1) in mammalian cells. We find large cell to-cell variability in the diffusion coefficients of Dll1 measured in single cells within the same population. Using a simple reaction-diffusion model, we show how membrane dynamics and cell morphology affect cell-cell signaling. We find that differences in the diffusion coefficients, as observed experimentally, can dramatically affect signaling between cells. Together, these results elucidate how membrane dynamics and cellular geometry can affect cell-cell signaling. PMID- 26748703 TI - Essential Function of Dicer in Resolving DNA Damage in the Rapidly Dividing Cells of the Developing and Malignant Cerebellum. AB - Maintenance of genomic integrity is critical during neurodevelopment, particularly in rapidly dividing cerebellar granule neuronal precursors that experience constitutive replication-associated DNA damage. As Dicer was recently recognized to have an unexpected function in the DNA damage response, we examined whether Dicer was important for preserving genomic integrity in the developing brain. We report that deletion of Dicer in the developing mouse cerebellum resulted in the accumulation of DNA damage leading to cerebellar progenitor degeneration, which was rescued with p53 deficiency; deletion of DGCR8 also resulted in similar DNA damage and cerebellar degeneration. Dicer deficiency also resulted in DNA damage and death in other rapidly dividing cells including embryonic stem cells and the malignant cerebellar progenitors in a mouse model of medulloblastoma. Together, these results identify an essential function of Dicer in resolving the spontaneous DNA damage that occurs during the rapid proliferation of developmental progenitors and malignant cells. PMID- 26748705 TI - Reciprocal Regulation between SIRT6 and miR-122 Controls Liver Metabolism and Predicts Hepatocarcinoma Prognosis. AB - Mice overexpressing the longevity protein SIRT6 or deficient for the liver's most prevalent microRNA miR-122 display a similar set of phenotypes, including improved lipid profile and protection against damage linked to obesity. Here, we show that miR-122 and SIRT6 negatively regulate each other's expression. SIRT6 downregulates miR-122 by deacetylating H3K56 in the promoter region. MiR-122 binds to three sites on the SIRT6 3' UTR and reduces its levels. The interplay between SIRT6 and miR-122 is manifested in two physiologically relevant ways in the liver. First, they oppositely regulate a similar set of metabolic genes and fatty acid beta-oxidation. Second, in hepatocellular carcinoma patients, loss of a negative correlation between SIRT6 and miR-122 expression is significantly associated with better prognosis. These findings show that SIRT6 and miR-122 negatively regulate each other to control various aspects of liver physiology and SIRT6-miR-122 correlation may serve as a biomarker for hepatocarcinoma prognosis. PMID- 26748706 TI - The Acetyl Group Buffering Action of Carnitine Acetyltransferase Offsets Macronutrient-Induced Lysine Acetylation of Mitochondrial Proteins. AB - Lysine acetylation (AcK), a posttranslational modification wherein a two-carbon acetyl group binds covalently to a lysine residue, occurs prominently on mitochondrial proteins and has been linked to metabolic dysfunction. An emergent theory suggests mitochondrial AcK occurs via mass action rather than targeted catalysis. To test this hypothesis, we performed mass spectrometry-based acetylproteomic analyses of quadriceps muscles from mice with skeletal muscle specific deficiency of carnitine acetyltransferase (CrAT), an enzyme that buffers the mitochondrial acetyl-CoA pool by converting short-chain acyl-CoAs to their membrane permeant acylcarnitine counterparts. CrAT deficiency increased tissue acetyl-CoA levels and susceptibility to diet-induced AcK of broad-ranging mitochondrial proteins, coincident with diminished whole body glucose control. Sub-compartment acetylproteome analyses of muscles from obese mice and humans showed remarkable overrepresentation of mitochondrial matrix proteins. These findings reveal roles for CrAT and L-carnitine in modulating the muscle acetylproteome and provide strong experimental evidence favoring the nonenzymatic carbon pressure model of mitochondrial AcK. PMID- 26748707 TI - p75 Neurotrophin Receptor Regulates Energy Balance in Obesity. AB - Obesity and metabolic syndrome reflect the dysregulation of molecular pathways that control energy homeostasis. Here, we show that the p75 neurotrophin receptor (p75(NTR)) controls energy expenditure in obese mice on a high-fat diet (HFD). Despite no changes in food intake, p75(NTR)-null mice were protected from HFD induced obesity and remained lean as a result of increased energy expenditure without developing insulin resistance or liver steatosis. p75(NTR) directly interacts with the catalytic subunit of protein kinase A (PKA) and regulates cAMP signaling in adipocytes, leading to decreased lipolysis and thermogenesis. Adipocyte-specific depletion of p75(NTR) or transplantation of p75(NTR)-null white adipose tissue (WAT) into wild-type mice fed a HFD protected against weight gain and insulin resistance. Our results reveal that signaling from p75(NTR) to cAMP/PKA regulates energy balance and suggest that non-CNS neurotrophin receptor signaling could be a target for treating obesity and the metabolic syndrome. PMID- 26748708 TI - Deregulation of STING Signaling in Colorectal Carcinoma Constrains DNA Damage Responses and Correlates With Tumorigenesis. AB - Stimulator of interferon genes (STING) has been shown to be critical for controlling antiviral responses as well as anti-tumor adaptive immunity, but little is known regarding its regulation in human tumors. Here, we report that STING signaling is recurrently suppressed in a wide variety of cancers, including colorectal carcinoma. Loss of STING signaling impeded DNA damage responses accountable for generating key cytokines that facilitate tissue repair and anti tumor T cell priming, such as type I interferons (IFNs). Correspondingly, defective STING function was also highly predictive of effectual DNA-virus mediated oncolytic activity. Thus, impaired STING responses may enable damaged cells to evade host immunosurveillance processes, although they provide a critical prognostic measurement that could help predict the outcome of effective oncoviral therapy. PMID- 26748711 TI - Structural and Functional Analysis of the Cdk13/Cyclin K Complex. AB - Cyclin-dependent kinases regulate the cell cycle and transcription in higher eukaryotes. We have determined the crystal structure of the transcription kinase Cdk13 and its Cyclin K subunit at 2.0 A resolution. Cdk13 contains a C-terminal extension helix composed of a polybasic cluster and a DCHEL motif that interacts with the bound ATP. Cdk13/CycK phosphorylates both Ser5 and Ser2 of the RNA polymerase II C-terminal domain (CTD) with a preference for Ser7 pre phosphorylations at a C-terminal position. The peptidyl-prolyl isomerase Pin1 does not change the phosphorylation specificities of Cdk9, Cdk12, and Cdk13 but interacts with the phosphorylated CTD through its WW domain. Using recombinant proteins, we find that flavopiridol inhibits Cdk7 more potently than it does Cdk13. Gene expression changes after knockdown of Cdk13 or Cdk12 are markedly different, with enrichment of growth signaling pathways for Cdk13-dependent genes. Together, our results provide insights into the structure, function, and activity of human Cdk13/CycK. PMID- 26748709 TI - Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities. AB - ATR and CHK1 maintain cancer cell survival under replication stress and inhibitors of both kinases are currently undergoing clinical trials. As ATR activity is increased after CHK1 inhibition, we hypothesized that this may indicate an increased reliance on ATR for survival. Indeed, we observe that replication stress induced by the CHK1 inhibitor AZD7762 results in replication catastrophe and apoptosis, when combined with the ATR inhibitor VE-821 specifically in cancer cells. Combined treatment with ATR and CHK1 inhibitors leads to replication fork arrest, ssDNA accumulation, replication collapse, and synergistic cell death in cancer cells in vitro and in vivo. Inhibition of CDK reversed replication stress and synthetic lethality, demonstrating that regulation of origin firing by ATR and CHK1 explains the synthetic lethality. In conclusion, this study exemplifies cancer-specific synthetic lethality between two proteins in the same pathway and raises the prospect of combining ATR and CHK1 inhibitors as promising cancer therapy. PMID- 26748712 TI - Non-canonical PRC1.1 Targets Active Genes Independent of H3K27me3 and Is Essential for Leukemogenesis. AB - Polycomb proteins are classical regulators of stem cell self-renewal and cell lineage commitment and are frequently deregulated in cancer. Here, we find that the non-canonical PRC1.1 complex, as identified by mass-spectrometry-based proteomics, is critically important for human leukemic stem cells. Downmodulation of PRC1.1 complex members, like the DNA-binding subunit KDM2B, strongly reduces cell proliferation in vitro and delays or even abrogates leukemogenesis in vivo in humanized xenograft models. PRC1.1 components are significantly overexpressed in primary AML CD34(+) cells. Besides a set of genes that is targeted by PRC1 and PRC2, ChIP-seq studies show that PRC1.1 also binds a distinct set of genes that are devoid of H3K27me3, suggesting a gene-regulatory role independent of PRC2. This set encompasses genes involved in metabolism, which have transcriptionally active chromatin profiles. These data indicate that PRC1.1 controls specific genes involved in unique cell biological processes required for leukemic cell viability. PMID- 26748710 TI - Elucidating MicroRNA Regulatory Networks Using Transcriptional, Post transcriptional, and Histone Modification Measurements. AB - MicroRNAs (miRNAs) regulate diverse biological processes by repressing mRNAs, but their modest effects on direct targets, together with their participation in larger regulatory networks, make it challenging to delineate miRNA-mediated effects. Here, we describe an approach to characterizing miRNA-regulatory networks by systematically profiling transcriptional, post-transcriptional and epigenetic activity in a pair of isogenic murine fibroblast cell lines with and without Dicer expression. By RNA sequencing (RNA-seq) and CLIP (crosslinking followed by immunoprecipitation) sequencing (CLIP-seq), we found that most of the changes induced by global miRNA loss occur at the level of transcription. We then introduced a network modeling approach that integrated these data with epigenetic data to identify specific miRNA-regulated transcription factors that explain the impact of miRNA perturbation on gene expression. In total, we demonstrate that combining multiple genome-wide datasets spanning diverse regulatory modes enables accurate delineation of the downstream miRNA-regulated transcriptional network and establishes a model for studying similar networks in other systems. PMID- 26748713 TI - Differential Thiol-Based Switches Jump-Start Vibrio cholerae Pathogenesis. AB - Bacterial pathogens utilize gene expression versatility to adapt to environmental changes. Vibrio cholerae, the causative agent of cholera, encounters redox potential changes when it transitions from oxygen-rich aquatic reservoirs to the oxygen-limiting human gastrointestinal tract. We previously showed that the virulence regulator AphB uses thiol-based switches to sense the anoxic host environment and transcriptionally activate the key virulence activator tcpP. Here, by performing a high-throughput transposon sequencing screen in vivo, we identified OhrR as another regulator that enables V. cholerae rapid anoxic adaptation. Like AphB, reduced OhrR binds to and regulates the tcpP promoter. OhrR and AphB displayed differential dynamics in response to redox-potential changes: OhrR is reduced more rapidly than AphB. Furthermore, OhrR thiol modification is required for rapid activation of virulence and successful colonization. This reveals a mechanism whereby bacterial pathogens employ posttranslational modifications of multiple transcription factors to sense and adapt to dynamic environmental changes. PMID- 26748715 TI - Identification of a Neuronal Receptor Controlling Anaphylaxis. AB - Allergic reactions can in severe cases induce a state of circulatory shock referred to as anaphylaxis. Histamine, the primary mediator of this condition, is released from immune cells, and, therefore, anaphylaxis has so far been considered an immune system disorder. However, we here show that the glutamatergic receptor mGluR7, expressed on a subpopulation of both peripheral and spinal cord neurons, controls histamine-induced communication through calcium dependent autoinhibition with implications for anaphylaxis. Genetic ablation of mGluR7, and thus altered regulation of histamine-sensing neurons, caused an anaphylaxis-like state in mGluR7(-/-) mice, which could be reversed by antagonizing signaling between neurons and mast cells but not by antagonizing a central itch pathway. Our findings demonstrate the vital role of nervous system control by mGluR7 in anaphylaxis and open up possibilities for preventive strategies for this life-threatening condition. PMID- 26748714 TI - Endogenous TRIM5alpha Function Is Regulated by SUMOylation and Nuclear Sequestration for Efficient Innate Sensing in Dendritic Cells. AB - During retroviral infection, viral capsids are subject to restriction by the cellular factor TRIM5alpha. Here, we show that dendritic cells (DCs) derived from human and non-human primate species lack efficient TRIM5alpha-mediated retroviral restriction. In DCs, endogenous TRIM5alpha accumulates in nuclear bodies (NB) that partly co-localize with Cajal bodies in a SUMOylation-dependent manner. Nuclear sequestration of TRIM5alpha allowed potent induction of type I interferon (IFN) responses during infection, mediated by sensing of reverse transcribed DNA by cGAS. Overexpression of TRIM5alpha or treatment with the SUMOylation inhibitor ginkgolic acid (GA) resulted in enforced cytoplasmic TRIM5alpha expression and restored efficient viral restriction but abrogated type I IFN production following infection. Our results suggest that there is an evolutionary trade-off specific to DCs in which restriction is minimized to maximize sensing. TRIM5alpha regulation via SUMOylation-dependent nuclear sequestration adds to our understanding of how restriction factors are regulated. PMID- 26748716 TI - Simultaneous Multiplexed Measurement of RNA and Proteins in Single Cells. AB - Significant advances have been made in methods to analyze genomes and transcriptomes of single cells, but to fully define cell states, proteins must also be accessed as central actors defining a cell's phenotype. Methods currently used to analyze endogenous protein expression in single cells are limited in specificity, throughput, or multiplex capability. Here, we present an approach to simultaneously and specifically interrogate large sets of protein and RNA targets in lysates from individual cells, enabling investigations of cell functions and responses. We applied our method to investigate the effects of BMP4, an experimental therapeutic agent, on early-passage glioblastoma cell cultures. We uncovered significant heterogeneity in responses to treatment at levels of RNA and protein, with a subset of cells reacting in a distinct manner to BMP4. Moreover, we found overall poor correlation between protein and RNA at the level of single cells, with proteins more accurately defining responses to treatment. PMID- 26748718 TI - Structure of Human DROSHA. AB - MicroRNA maturation is initiated by RNase III DROSHA that cleaves the stem loop of primary microRNA. DROSHA functions together with its cofactor DGCR8 in a heterotrimeric complex known as Microprocessor. Here, we report the X-ray structure of DROSHA in complex with the C-terminal helix of DGCR8. We find that DROSHA contains two DGCR8-binding sites, one on each RNase III domain (RIIID), which mediate the assembly of Microprocessor. The overall structure of DROSHA is surprisingly similar to that of Dicer despite no sequence homology apart from the C-terminal part, suggesting that DROSHA may have evolved from a Dicer homolog. DROSHA exhibits unique features, including non-canonical zinc-finger motifs, a long insertion in the first RIIID, and the kinked link between Connector helix and RIIID, which explains the 11-bp-measuring "ruler" activity of DROSHA. Our study implicates the evolutionary origin of DROSHA and elucidates the molecular basis of Microprocessor assembly and primary microRNA processing. PMID- 26748717 TI - RefSOFI for Mapping Nanoscale Organization of Protein-Protein Interactions in Living Cells. AB - It has become increasingly clear that protein-protein interactions (PPIs) are compartmentalized in nanoscale domains that define the biochemical architecture of the cell. Despite tremendous advances in super-resolution imaging, strategies to observe PPIs at sufficient resolution to discern their organization are just emerging. Here we describe a strategy in which PPIs induce reconstitution of fluorescent proteins (FPs) that are capable of exhibiting single-molecule fluctuations suitable for stochastic optical fluctuation imaging (SOFI). Subsequently, spatial maps of these interactions can be resolved in super resolution in living cells. Using this strategy, termed reconstituted fluorescence-based SOFI (refSOFI), we investigated the interaction between the endoplasmic reticulum (ER) Ca(2+) sensor STIM1 and the pore-forming channel subunit ORAI1, a crucial process in store-operated Ca(2+) entry (SOCE). Stimulating SOCE does not appear to change the size of existing STIM1/ORAI1 interaction puncta at the ER-plasma membrane junctions, but results in an apparent increase in the number of interaction puncta. PMID- 26748719 TI - Patient-specific assessment of dysmorphism of the femoral head-neck junction: a statistical shape model approach. AB - BACKGROUND: Objective quantification of anatomical variations about the femur head-neck junction in pre-operative planning for surgical intervention in femoro acetabular impingement is problematic, as no clear definition of average normal anatomy for a specific subject exists. METHODS: We have defined the normal equivalent of a subject's anatomy by using a statistical shape model and geometric shape optimization for finding correspondences, while excluding the femoral head-neck junction during the fitting procedure. The presented technique was evaluated on a cohort of 20 patients. RESULTS: Difference in alpha-angle measurement between the actual morphology and the predicted normal-equivalent, averaged 1.3 degrees (SD 1.7 degrees ) in the control group versus 8 degrees (SD 7.3 degrees ) in the patient group (p < 0.05). CONCLUSIONS: Defining normal equivalent anatomy is effective in quantifying anatomical dysmorphism of the femoral head-neck junction and as such can improve presurgical analysis of patients diagnosed with femoro-acetabular impingement. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26748720 TI - Historical precipitation predictably alters the shape and magnitude of microbial functional response to soil moisture. AB - Soil moisture constrains the activity of decomposer soil microorganisms, and in turn the rate at which soil carbon returns to the atmosphere. While increases in soil moisture are generally associated with increased microbial activity, historical climate may constrain current microbial responses to moisture. However, it is not known if variation in the shape and magnitude of microbial functional responses to soil moisture can be predicted from historical climate at regional scales. To address this problem, we measured soil enzyme activity at 12 sites across a broad climate gradient spanning 442-887 mm mean annual precipitation. Measurements were made eight times over 21 months to maximize sampling during different moisture conditions. We then fit saturating functions of enzyme activity to soil moisture and extracted half saturation and maximum activity parameter values from model fits. We found that 50% of the variation in maximum activity parameters across sites could be predicted by 30-year mean annual precipitation, an indicator of historical climate, and that the effect is independent of variation in temperature, soil texture, or soil carbon concentration. Based on this finding, we suggest that variation in the shape and magnitude of soil microbial response to soil moisture due to historical climate may be remarkably predictable at regional scales, and this approach may extend to other systems. If historical contingencies on microbial activities prove to be persistent in the face of environmental change, this approach also provides a framework for incorporating historical climate effects into biogeochemical models simulating future global change scenarios. PMID- 26748721 TI - Early sex determination in the canine foetus by ultrasound and PCR. AB - Twenty bitches were seen in consultation at the Department of Reproduction at ONIRIS (College of Veterinary Medicine, Food Science and Engineering, Loire Atlantique, Nantes, France) between 25 and 50 days of gestation for early sex determination of the canine foetus using ultrasound. The genital tubercle is not visible before 26 days; between 26 and 30 days, it is visible between the pelvic limbs; between 33 and 50 days, the position of the genital tubercle enables sex determination as it migrates caudally in the female and cranially in the male. Good statistical concordance between sexing via ultrasound and sexing at birth has been established (kappa coefficient of 0.8). Macroscopic, microscopic, and histological examinations of the external genital organs were also performed on 10 foetuses at 35 days of gestation; a cartilaginous structure was visualized in the genital apparatus of the male but also in half of the females. Finally, the development of a PCR technique on the SRY gene using formaldehyde-preserved tissues has been described for the first time in this study. It served as a reference for sexing canine foetuses. PMID- 26748723 TI - Behavioral disorders after traumatic brain injury: Why and how did French recommendations for good practice emerge? PMID- 26748722 TI - CDR3beta sequence motifs regulate autoreactivity of human invariant NKT cell receptors. AB - Invariant natural killer T (iNKT) cells are a subset of T lymphocytes that recognize lipid ligands presented by monomorphic CD1d. Human iNKT T cell receptor (TCR) is largely composed of invariant Valpha24 (Valpha24i) TCRalpha chain and semi-variant Vbeta11 TCRbeta chain, where complementarity-determining region (CDR)3beta is the sole variable region. One of the characteristic features of iNKT cells is that they retain autoreactivity even after the thymic selection. However, the molecular features of human iNKT TCR CDR3beta sequences that regulate autoreactivity remain unknown. Since the numbers of iNKT cells with detectable autoreactivity in peripheral blood is limited, we introduced the Valpha24i gene into peripheral T cells and generated a de novo human iNKT TCR repertoire. By stimulating the transfected T cells with artificial antigen presenting cells (aAPCs) presenting self-ligands, we enriched strongly autoreactive iNKT TCRs and isolated a large panel of human iNKT TCRs with a broad range autoreactivity. From this panel of unique iNKT TCRs, we deciphered three CDR3beta sequence motifs frequently encoded by strongly-autoreactive iNKT TCRs: a VD region with 2 or more acidic amino acids, usage of the Jbeta2-5 allele, and a CDR3beta region of 13 amino acids in length. iNKT TCRs encoding 2 or 3 sequence motifs also exhibit higher autoreactivity than those encoding 0 or 1 motifs. These data facilitate our understanding of the molecular basis for human iNKT cell autoreactivity involved in immune responses associated with human disease. PMID- 26748724 TI - Negative regulation of the hepatic fibrogenic response by suppressor of cytokine signaling 1. AB - Suppressor of cytokine signaling 1 (SOCS1) is an indispensable regulator of IFNgamma signaling and has been implicated in the regulation of liver fibrosis. However, it is not known whether SOCS1 mediates its anti-fibrotic functions in the liver directly, or via modulating IFNgamma, which has been implicated in attenuating hepatic fibrosis. Additionally, it is possible that SOCS1 controls liver fibrosis by regulating hepatic stellate cells (HSC), a key player in fibrogenic response. While the activation pathways of HSCs have been well characterized, the regulatory mechanisms are not yet clear. The goals of this study were to dissociate IFNgamma-dependent and SOCS1-mediated regulation of hepatic fibrogenic response, and to elucidate the regulatory functions of SOCS1 in HSC activation. Liver fibrosis was induced in Socs1(-/-)Ifng(-/-) mice with dimethylnitrosamine or carbon tetrachloride. Ifng(-/-) and C57BL/6 mice served as controls. Following fibrogenic treatments, Socs1(-/-)Ifng(-/-) mice showed elevated serum ALT levels and increased liver fibrosis compared to Ifng(-/-) mice. The latter group showed higher ALT levels and fibrosis than C57BL/6 controls. The livers of SOCS1-deficient mice showed bridging fibrosis, which was associated with increased accumulation of myofibroblasts and abundant collagen deposition. SOCS1-deficient livers showed increased expression of genes coding for smooth muscle actin, collagen, and enzymes involved in remodeling the extracellular matrix, namely matrix metalloproteinases and tissue inhibitor of metalloproteinases. Primary HSCs from SOCS1-deficient mice showed increased proliferation in response to growth factors such as HGF, EGF and PDGF, and the fibrotic livers of SOCS1-deficient mice showed increased expression of the Pdgfb gene. Taken together, these data indicate that SOCS1 controls liver fibrosis independently of IFNgamma and that part of this regulation may occur via regulating HSC proliferation and limiting growth factor availability. PMID- 26748725 TI - New insights of common gamma chain in hematological malignancies. AB - The common gamma chain (gammac) receptor family of cytokines including interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21 has the common feature of sharing gammac signaling subunit of their receptors. The gammac cytokines have unique biological effects that regulate differentiation, survival and activation of multiple lymphocyte lineages and control proliferation of malignant cell by influencing tumor environment. It has been also described that different types of lymphoid leukemia and lymphoma exhibit expression of divergent gammac cytokines and their receptors, as they may promote malignant transformation of lymphoid cells or on the contrary lead to tumor regression by inducing cell-cycle arrest. Therefore, cytokine-based or cytokine-directed blockade in cancer immunotherapy has currently revolutionized the development of cancer treatment. In this review, we will discuss about the role of gammac cytokines and their signaling pathways in hematological malignancies and also propose a novel alternative approach that regulates gammac cytokine responsiveness by gammac in hematological malignancies. PMID- 26748727 TI - Therapeutic utility of the newly discovered properties of interleukin-21. AB - Since its discovery in 2000, interleukin-21 (IL-21) has been shown to display a broad spectrum of pleiotropic actions including the regulation of development, differentiation and function of lymphoid-myeloid cells. More specifically, IL-21 modulates the effector functions of T, B and NK cells, which not only have key roles in antitumoral and antiviral immunity but also in exerting major effects on inflammatory responses promoting the development of autoimmune diseases. Recent studies have unveiled an unexpected role for IL-21 in immune regulation and de novo T-cell development. While highlighting its critical role in immunity, this review will mainly focus on recent advances in IL-21 biology and how such newly discovered properties could potentially be exploited therapeutically in the establishment of future clinical trials. PMID- 26748726 TI - IFN-beta antiproliferative effect and miRNA regulation in Human Papilloma Virus E6- and E7-transformed keratinocytes. AB - Human Papilloma Viruses (HPVs) are the causative agents of cervical cancer although other types of cancers are associated with HPV infection. Type I Interferons can interfere with HPV E6- and/or E7-dependent transformation and can affect microRNA (miRNA) expression. Cancer cells show a specific pattern of miRNA expression and HPVs are able to modulate miRNAs expressed in infected cells. Keratinocytes transduced with E6 and E7 from mucosal HPV-16 or cutaneous HPV-38 (K16 and K38) were studied to analyze the involvement of HPV oncoproteins in the anti-proliferative activity of IFN-beta. In view of our previous data showing senescence induction by the cytokine in K38 cells, we observe that IFN-beta treatment leads to p53-indipendent apoptosis in K16 cells whereas induces senescence in K16 cells if E6 is silenced and p53 expression is restored. The levels of selected miRNAs, deregulated in K16 and K38 cells, can be modulated by IFN-beta when E6 and E7 proteins of HPV-16, but not HPV-38, are expressed. PMID- 26748728 TI - Prediction of patient-specific post-operative outcomes of TAVI procedure: The impact of the positioning strategy on valve performance. AB - Prosthesis positioning in transcatheter aortic valve implantation procedures represents a crucial aspect for procedure success as demonstrated by many recent studies on this topic. Possible complications, device performance, and, consequently, also long-term durability are highly affected by the adopted prosthesis placement strategy. In the present work, we develop a computational finite element model able to predict device-specific and patient-specific replacement procedure outcomes, which may help medical operators to plan and choose the optimal implantation strategy. We focus in particular on the effects of prosthesis implantation depth and release angle. We start from a real clinical case undergoing Corevalve self-expanding device implantation. Our study confirms the crucial role of positioning in determining valve anchoring, replacement failure due to intra or para-valvular regurgitation, and post-operative device deformation. PMID- 26748729 TI - Generating Purkinje networks in the human heart. AB - The Purkinje network is an integral part of the excitation system in the human heart. Yet, to date, there is no in vivo imaging technique to accurately reconstruct its geometry and structure. Computational modeling of the Purkinje network is increasingly recognized as an alternative strategy to visualize, simulate, and understand the role of the Purkinje system. However, most computational models either have to be generated manually, or fail to smoothly cover the irregular surfaces inside the left and right ventricles. Here we present a new algorithm to reliably create robust Purkinje networks within the human heart. We made the source code of this algorithm freely available online. Using Monte Carlo simulations, we demonstrate that the fractal tree algorithm with our new projection method generates denser and more compact Purkinje networks than previous approaches on irregular surfaces. Under similar conditions, our algorithm generates a network with 1219+/-61 branches, three times more than a conventional algorithm with 419+/-107 branches. With a coverage of 11+/-3mm, the surface density of our new Purkije network is twice as dense as the conventional network with 22+/-7mm. To demonstrate the importance of a dense Purkinje network in cardiac electrophysiology, we simulated three cases of excitation: with our new Purkinje network, with left-sided Purkinje network, and without Purkinje network. Simulations with our new Purkinje network predicted more realistic activation sequences and activation times than simulations without. Six-lead electrocardiograms of the three case studies agreed with the clinical electrocardiograms under physiological conditions, under pathological conditions of right bundle branch block, and under pathological conditions of trifascicular block. Taken together, our results underpin the importance of the Purkinje network in realistic human heart simulations. Human heart modeling has the potential to support the design of personalized strategies for single- or bi ventricular pacing, radiofrequency ablation, and cardiac defibrillation with the common goal to restore a normal heart rhythm. PMID- 26748730 TI - The Brief Accessibility, Responsiveness, and Engagement Scale: A Tool for Measuring Attachment Behaviors in Clinical Couples. AB - Measuring attachment behaviors is relevant to creating secure couple relationships. This article seeks to test and examine the reliability and validity of the Brief Accessibility, Responsiveness, and Engagement (BARE) Scale a practical measure of couple attachment-in a clinical sample. Couples took the BARE and other assessments measuring relationship functioning (self and partner reports of relationship satisfaction, relationship stability, positive and negative communication, and attachment styles). Results suggest that the BARE appears to be a reliable and valid tool for assessing couple attachment and can accurately predict and classify whether the couples belong in the clinical or nonclinical group, as well as their level of relationship satisfaction. Results also indicate attachment behaviors are related to relationship outcomes. PMID- 26748731 TI - Evaluation of the Bangor Dyslexia Test (BDT) for use with Adults. AB - The Bangor Dyslexia Test (BDT) is a short, easy-to-administer screener for use with a broad age range, which has been in use in the UK for over three decades. A distinctive feature of the battery is its focus on skills requiring aspects of verbal and phonological processing without, however, measuring literacy skills per se. Despite its longstanding existence and usage, there has been no evaluation of the psychometric properties of the battery as an adult dyslexia screener. We examined the psychometric properties of the BDT and evaluated its capacity to discriminate between adults with and without dyslexia. A large archival sample of university students with dyslexia (n = 193) and students with no reported literacy difficulties (n = 40) were compared on the BDT as well as on literacy and cognitive measures. Statistical analyses revealed the BDT to be a reliable (alpha = .72) and valid dyslexia screening tool with the capacity to effectively identify adults at risk of the disorder with an overall classification rate of 94% (sensitivity 96.4% and specificity 82.5%). In addition, higher indices of dyslexia risk on the BDT were associated with lower scores on standardized measures of literacy. PMID- 26748732 TI - Isolation of a lytic bacteriophage against virulent Aeromonas hydrophila from an organized equine farm. AB - A bacteriophage (VTCCBPA6) against a pathogenic strain of Aeromonas hydrophila was isolated from the sewage of an organized equine breeding farm. On the basis of TEM analysis, phage belonged to family Myoviridae. PCR amplification and sequence analysis of gp23 gene (encoding for major capsid protein) revealed phylogenetic resemblance to T4 like virus genus. Protein profiling by SDS-PAGE also indicated its resemblance to T4 like phage group. However, the comparison of its gp23 gene sequence with previously reported phages showed similarity with T4 like phages infecting Enterobacteriaceae instead of Aeromonas spp. Thus, to our knowledge, this report points toward the fact that a novel/evolved phage might exist in equine environment against A. hydrophila, which can be potentially used as a biocontrol agent. PMID- 26748733 TI - Mechano-fluorochromic Pt(II) Luminogen and Its Cysteine Recognition. AB - A new triphenylamine-based organometallic Pt(II) luminogen (1) and its analogous organic compound (2) are reported. The molecules are decorated with aldehyde functionality to improve their photophysical properties by utilising donor acceptor interactions. The single crystal X-ray structure analysis of Pt(II) analogue 1 revealed that the neighbouring molecules were loosely organised by weak intermolecular C-H???pi interactions. Because of the twisted nature of the triphenylamine backbone the compounds showed aggregation-induced emission enhancement in THF/water mixture. Due to their loose crystal packing, upon application of external stimuli these luminogens exhibited mechano-fluorochromic behaviour. The crystalline forms of the compounds displayed a more superior emission efficiency than the grinded samples. Moreover, the compounds showed crystallization-induced emission enhancement (CIEE) and exhibited chemodosimetric response towards cysteine under physiological condition. PMID- 26748734 TI - A randomized, double-blind, multicenter Phase II study comparing the efficacy and safety of oral nemonoxacin with oral levofloxacin in the treatment of community acquired pneumonia. AB - BACKGROUND/PURPOSE: To compare the clinical efficacy and safety of nemonoxacin with levofloxacin in treating community-acquired pneumonia (CAP) in a Phase II clinical trial. METHODS: One hundred ninety-two patients with CAP were randomized to receive oral nemonoxacin (500 mg or 750 mg) or levofloxacin (500 mg) once daily for 7-10 days. Clinical and bacteriological responses were determined at the test of cure (TOC) visit in the full analysis set (FAS). RESULTS: The clinical cure rate of nemonoxacin (500 mg), nemonoxacin (750 mg), and levofloxacin (500 mg) was 93.3%, 87.3%, and 88.5%, respectively, in the FAS (n = 168), and 93.0%, 93.9%, and 88.9%, respectively in the per protocol set (n = 152). At the TOC visit, nemonoxacin at 500 mg and 750 mg was proven to be noninferior to levofloxacin at 500 mg in the FAS in terms of clinical efficacy. The overall bacteriological success rate was 83.3% in both nemonoxacin groups and 80.0% in the levofloxacin 500 mg group in the bacteriological FAS. The comprehensive efficacy rate was comparable among the three groups (87.5% for the nemonoxacin 500 mg group, 93.8% for the nemonoxacin 750 mg group, and 81.3% for the levofloxacin 500 mg group). Most drug-related adverse events were mild and transient, mainly gastrointestinal symptoms such as nausea and vomiting, transient neutropenia, and elevated liver enzymes. No drug-related serious adverse events occurred. CONCLUSION: Either 500 mg or 750 mg of oral nemonoxacin taken once daily for 7-10 days demonstrated high clinical and bacteriological success rates in Chinese adult patients with CAP. Nemonoxacin at 500 mg once daily for 7-10 days is recommended for future Phase III clinical trials. ClinicalTrials.gov identifier: NCT01537250. PMID- 26748736 TI - A tool to predict suicidal ideation and behavior in bipolar disorder: The Concise Health Risk Tracking Self-Report. AB - BACKGROUND: Few brief, self-report measures exist that can reliably predict adverse suicidality outcomes in patients with BD. This study utilized the Concise Health Risk Tracking Self-Report (CHRT) to assess suicidality in patients with BD and examined its psychometric performance, clinical correlates, and prospective value in predicting adverse events related to suicidality. METHODS: The CHRT was administered at baseline and follow-up to 482 adult patients in Bipolar CHOICE, a 6-month randomized comparative effectiveness trial. The Columbia Suicide Severity Rating Scale (CSSRS) was used at baseline to assess lifetime history of suicide attempts and related behaviors. Clinician-rated measures of mood (Bipolar Inventory of Symptoms Scale) and bipolar symptoms (Clinical Global Impressions Bipolar Version) were conducted at baseline and follow-up. RESULTS: The CHRT showed excellent internal consistency and construct validity and was highly correlated with clinician ratings of depression, anxiety, and overall functioning at baseline and throughout the study. Baseline CHRT scores significantly predicted risk of subsequent suicidality-related Serious Adverse Events (sSAEs), after controlling for mood and comorbidity. Specifically, the hazard of a sSAE increased by 76% for every 10-point increase in baseline CHRT score. Past history of suicide attempts and related behaviors, as assessed by the CSSRS, did not predict subsequent sSAEs. LIMITATIONS: The CSSRS was used to assess static risk factors in terms of past suicidal behaviors and may have been a more powerful predictor over longer-term follow-up. CONCLUSIONS: The CHRT offers a quick and robust self-report tool for assessing suicidal risk and has important implications for future research and clinical practice. PMID- 26748735 TI - Quantitative analysis of tissue inflammation and responses to treatment in immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, and review of literature. AB - BACKGROUND/PURPOSE: Immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome is a severe autoimmune disease that is caused by regulatory T cell deficiency due to FOXP3 gene mutations. The long-term outcome can be variable depending on the extent of tissue damage caused by autoimmunity and infections, the use of immunosuppressive treatment or sequela of bone marrow transplantation. METHODS: We used immunohistochemical staining to analyze cell types infiltrating the tissue of affected organs from a classic IPEX patient with a splicing mutation (c.736-2A>C) in the FOXP3 gene. Expression of transcription factors that are critical for immune responses including T-bet, GATA-3, RORgammat, and FOXP3 were evaluated in various tissue samples. For objective analysis of the distribution of different cell types in tissues, we used an automated microscope-based image acquiring system to assess quantitatively the different cell types by investigating the histopathological changes in the patient's biopsy samples obtained from the intestine and the kidneys before and after treatment. RESULTS: The percentages of cells expressing the TH2-associated transcription factor GATA3 were higher in the IPEX patient before treatment than in controls, suggesting that TH2-type cells contribute to the tissue inflammation of the gut and kidneys in IPEX syndrome. Immunosuppressive treatment effectively decreased the number of effector cells in the kidneys and intestine of the IPEX patient. CONCLUSION: This study provides quantitative evidence that the inflamed intestinal and renal tissues of the IPEX patient contain TH2-type immune effector cells, which decreased in number after immunosuppressive treatment was initiated and the clinical symptoms had improved. PMID- 26748739 TI - Cognitive Behavioral Social Rhythm Group Therapy for Veterans with posttraumatic stress disorder, depression, and sleep disturbance: Results from an open trial. AB - INTRODUCTION: Cognitive Behavioral Social Rhythm Therapy (CBSRT) is a group psychotherapy tailored for Veterans with Posttraumatic Stress Disorder (PTSD), Major Depressive Disorder (MDD), and sleep disturbances. The aims of this study were to introduce and present initial outcomes of Cognitive Behavioral Social Rhythm Therapy (CBSRT), a 12-week skills group therapy designed to improve sleep and mood by reducing chaotic or isolated lifestyles in Veterans with PTSD. METHODS: Twenty-four male Veterans with at least moderate PTSD and MDD participated in this open trial. Main outcomes were the daily sleep diary for sleep disturbances, the Clinician-Administered PTSD Scale (CAPS) for PTSD, and the Hamilton Depression Rating scale for MDD. RESULTS: Veterans improved on all measures (a) with large within subject effects on PTSD symptoms, MDD symptoms, and sleep quality, and (b) with 46-58% of the sample receiving clinically significant benefits on MDD and PTSD symptoms respectively. The consistency of social rhythms was associated with the average reduction in global CAPS scores over time. Only 13% of participants dropped-out of the group therapy prematurely suggesting that this new group therapy is relatively well-tolerated by Veterans. LIMITATIONS: Future research that employs a control condition is necessary to establish efficacy of CBSRT. CONCLUSIONS: Data from this initial pilot study demonstrate that CBSRT may be an effective group treatment option for Veterans presenting with all three symptom complaints. These data also suggest that daily routine may be an important mechanism to consider in the treatment of PTSD symptoms comorbid with depression. PMID- 26748737 TI - Individualized identification of euthymic bipolar disorder using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and machine learning. AB - BACKGROUND: Previous studies have reported that patients with bipolar disorder (BD) present with cognitive impairments during mood episodes as well as euthymic phase. However, it is still unknown whether reported neurocognitive abnormalities can objectively identify individual BD patients from healthy controls (HC). METHODS: A total of 21 euthymic BD patients and 21 demographically matched HC were included in the current study. Participants performed the computerized Cambridge Neurocognitive Test Automated Battery (CANTAB) to assess cognitive performance. The least absolute shrinkage selection operator (LASSO) machine learning algorithm was implemented to identify neurocognitive signatures to distinguish individual BD patients from HC. RESULTS: The LASSO machine learning algorithm identified individual BD patients from HC with an accuracy of 71%, area under receiver operating characteristic curve of 0.7143 and significant at p=0.0053. The LASSO algorithm assigned individual subjects with a probability score (0-healthy, 1-patient). Patients with rapid cycling (RC) were assigned increased probability scores as compared to patients without RC. A multivariate pattern of neurocognitive abnormalities comprising of affective Go/No-go and the Cambridge gambling task was relevant in distinguishing individual patients from HC. LIMITATIONS: Our study sample was small as we only considered euthymic BD patients and demographically matched HC. CONCLUSION: Neurocognitive abnormalities can distinguish individual euthymic BD patients from HC with relatively high accuracy. In addition, patients with RC had more cognitive impairments compared to patients without RC. The predictive neurocognitive signature identified in the current study can potentially be used to provide individualized clinical inferences on BD patients. PMID- 26748738 TI - A nationwide population-based study of depression in Brazil. AB - INTRODUCTION: The state of mental health of the population is considered to be an important and essential component of public health. Depression is the mental disorder with greatest prevalence in several countries around the world. METHODS: This was a nationwide Brazilian survey with household-based interviews. The sampling process was at random and cluster-based, and performed in three stages: census tracts, households and individuals. One inhabitant aged >=18 years was selected per household. Individuals at greater risk of depression were identified through the Patient Health Questionnaire-9 (PHQ-9) algorithm, which uses internationally accepted diagnostic criteria. All analyses took into account sample weights. RESULTS: A total of 60,202 individuals were evaluated and the prevalence of positive screening for depression was 4.1% (95% CI: 3.8-4.4%). After adjustments for potential confounding factors, depression was found to be greater among women, individuals aged either 40-59 years or 80 years or over, individuals living in urban areas, those with lower educational level, smokers, and among individuals with arterial hypertension, diabetes and heart disorders. Skin colour, marital status and alcohol abuse were not associated with depression. LIMITATIONS: Characteristics of respondents and non-respondents in the sample could not be compared because data about non-respondents was not available. CONCLUSIONS: The prevalence of positive screening for depression in Brazil was similar to other studies conducted worldwide. In Brazil, this proportion reflects a considerable absolute number of people with greater risk of depression (~5.5 million) that may require adequate management through the health system and services. PMID- 26748740 TI - Regulation of cell reversal frequency in Myxococcus xanthus requires the balanced activity of CheY-like domains in FrzE and FrzZ. AB - The Frz pathway of Myxococcus xanthus controls cell reversal frequency to support directional motility during swarming and fruiting body formation. Previously, we showed that phosphorylation of the response regulator FrzZ correlates with reversal frequencies, suggesting that this activity represents the output of the Frz pathway. Here, we tested the effect of different expression levels of FrzZ and its cognate kinase FrzE on M. xanthus motility. FrzZ overexpression caused a slight increase in phosphorylation and reversals. By contrast, FrzE overexpression abolished phosphorylation of FrzZ; this inhibition required the response regulator domain of FrzE. FrzZ phosphorylation was restored when both FrzE and FrzZ were overexpressed together. Our results show that the response regulator domain of FrzE is a negative regulator of FrzE kinase activity. This inhibition can be modulated by FrzZ, which acts as a positive regulator. Interestingly, fluorescence microscopy revealed that FrzZ and FrzE localize differently: FrzE colocalizes with the FrzCD receptor and the nucleoid, while FrzZ shows dispersed and polar localization. However, FrzZ binds tightly to the truncated variant FrzEDelta(CheY) . This indicates that the response regulator domain of FrzE is required for the interaction between FrzE and FrzZ to be transient, providing an unexpected regulatory output to the Frz pathway. PMID- 26748741 TI - Lived experience of caring for dying patients in emergency room. AB - BACKGROUND: Dying often occurs in hospitals and frequently in emergency rooms. Understanding caring for critical and dying patients is necessary for quality nursing. PURPOSE: This study described the meaning of nurses' lived experience of caring for critical and dying patients in the emergency rooms. METHODS: This study was conducted in three emergency rooms of tertiary hospitals in southern Thailand. Twelve nurses met the inclusion criteria: nurses working in emergency room for at least 2 years, and experienced caring for critical and dying patients in an emergency department. Data were collected using in-depth individual interviews. Data transcription and analysis used van Manen's hermeneutic phenomenological approach. Trustworthiness was established following Lincoln and Guba's criteria. FINDINGS: Experiences of caring for critical and dying patients revealed four thematic categories: defying death; no time for palliative care; lacking support for family; and privacy for peaceful deaths. These thematic categories reflected van Manen's four lived worlds of body, time, relations and space. CONCLUSIONS: The study described the meaning of the experience of caring for critical and dying patients while supporting the development of nursing knowledge for palliative and end-of-life care in emergent settings. IMPLICATIONS FOR NURSING POLICY: Findings of the study influence nursing policies toward enhancing education of nurses regarding palliative and end-of-life care in emergency settings. These findings can also influence the value of caring-healing environments for critical and dying patients and their families. Policies can focus on practice and education of families particularly about end-of-life care for critical and dying patients. PMID- 26748742 TI - A computer-based model to assess costs associated with the use of factor VIII and factor IX one-stage and chromogenic activity assays. AB - BACKGROUND: Measurement of coagulation factor factor VIII (FVIII) and factor IX (FIX) activity can be associated with a high level of variability using one-stage assays based on activated partial thromboplastin time (APTT). Chromogenic assays show less variability, but are less commonly used in clinical laboratories. In addition, one-stage assay accuracy using certain reagent and instrument combinations is compromised by some modified recombinant factor concentrates. Reluctance among some in the hematology laboratory community to adopt the use of chromogenic assays may be partly attributable to lack of familiarity and perceived higher associated costs. OBJECTIVES: To identify and characterize key cost parameters associated with one-stage APTT and chromogenic assays for FVIII and FIX activity using a computer-based cost analysis model. METHODS: A cost model for FVIII and FIX chromogenic assays relative to APTT assays was generated using assumptions derived from interviews with hematologists and laboratory scientists, common clinical laboratory practise, manufacturer list prices and assay kit configurations. RESULTS: Key factors that contribute to costs are factor-deficient plasma and kit reagents for one-stage and chromogenic assays, respectively. The stability of chromogenic assay kit reagents also limits the cost efficiency compared with APTT testing. Costs for chromogenic assays might be reduced by 50-75% using batch testing, aliquoting and freezing of kit reagents. CONCLUSIONS: Both batch testing and aliquoting of chromogenic kit reagents might improve cost efficiency for FVIII and FIX chromogenic assays, but would require validation. Laboratory validation and regulatory approval as well as education and training in the use of chromogenic assays might facilitate wider adoption by clinical laboratories. PMID- 26748743 TI - Mutational spectrum of Korean patients with corneal dystrophy. AB - Corneal dystrophy typically refers to a group of rare hereditary disorders with a heterogeneous genetic background. A comprehensive molecular genetic analysis was performed to characterize the genetic spectrum of corneal dystrophies in Korean patients. Patients with various corneal dystrophies underwent thorough ophthalmic examination, histopathologic examination, and Sanger sequencing. A total of 120 probands were included, with a mean age of 50 years (SD = 18 years) and 70% were female. A total of 26 mutations in five genes (14 clearly pathogenic and 12 likely pathogenic) were identified in 49 probands (41%). Epithelial-stromal TGFBI dystrophies, macular corneal dystrophy and Schnyder corneal dystrophy (SCD) showed 100% mutation detection rates, while endothelial corneal dystrophies showed lower detection rates of 3%. Twenty six non-duplicate mutations including eight novel mutations were identified and mutations associated with SCD were identified genetically for the first time in this population. This study provides a comprehensive characterization of the genetic aberrations in Korean patients and also highlights the diagnostic value of molecular genetic analysis in corneal dystrophies. PMID- 26748746 TI - Foxd3: A Repressor, an Activator, or Both? AB - Two papers in this issue of Cell Stem Cell come to different conclusions about the role of the transcription factor Foxd3 in pluripotent cells. Here, the lead authors of both papers discuss their perspectives on the basis for these differences and how they might be reconciled. PMID- 26748745 TI - Emerging therapy in arthritis: Modulation of markers of the inflammatory process. AB - The induction of tolerance has been proposed as a therapeutic strategy for arthritis aiming to decrease progression of the pathology, probably by promoting suppressor mechanisms of the autoimmune response. This work aimed to confirm whether the treatment with vitamin D3 could synergize oral tolerance induced by hydrolyzed collagen peptides, in our experimental model of antigen induced arthritis in New Zealand rabbits. Clinical observation of the phenomenon indicates that simultaneous treatment with hydrolyzed collagen peptides and vitamin D3 was beneficial when compared with no treatment, for arthritic animals, and for arthritic animals that received treatment with only hydrolyzed collagen peptides or vitamin D3. Treatment with hydrolyzed collagen peptides caused diminished proinflammatory cytokine levels, an effect synergized significantly by the simultaneous treatment with vitamin D3. The anatomical-pathological studies of the animals that received both treatments simultaneously showed synovial tissues without lymphocytic and plasma cell infiltrates, and without vascular proliferation. Some of the synovial tissue of the animals of these groups showed a slight decrease in Galectin-3 expression. We propose that simultaneous oral treatment with vitamin D3 and hydrolyzed collagen peptides could increase the immunoregulatory effect on the process of previously triggered arthritis. We used articular cartilage hydrolysate and not collagen II because peptides best expose antigenic determinants that could induce oral tolerance. Oral tolerance may be considered in the design of novel alternative therapies for autoimmune disease and we have herein presented novel evidence that the simultaneous treatment with vitamin D3 may synergize this beneficial effect. PMID- 26748747 TI - Human Stem Cells Can Differentiate in Post-implantation Mouse Embryos. AB - The potency of human pluripotent stem cells (hPSCs) to differentiate into germ layer derivatives is conventionally assessed by teratoma induction and in vitro differentiation. In this issue of Cell Stem Cell, Mascetti and Pedersen (2016) demonstrate that the human-mouse post-implantation chimera offers an efficient avenue to test the germ layer differentiation potential of hPSCs in mouse embryos ex vivo. PMID- 26748748 TI - Lost in Translation: Preserving Satellite Cell Function with Global Translational Control. AB - Quiescence is highly regulated to preserve stem cell function. In this issue of Cell Stem Cell, Zismanov et al. (2016) show that P-eIF2alpha, a translational initiation factor, reinforces the quiescent state of muscle stem cells by safeguarding against cell-cycle entry and lineage progression. PMID- 26748749 TI - Lifting the Mist on Gastric Stem Cells. AB - In a recent issue of Cancer Cell, Hayakawa et al. (2015) demonstrate that Mist1(+) gastric stem cells are supported by a specialized niche composed of Cxcl12(+) endothelium and Wnt5a-producing Cxcr4(+) innate lymphoid cells. In diffuse-type gastric cancer this perivascular stem cell niche is expanded and can be exploited for cancer therapy. PMID- 26748750 TI - Dramatic Expansion of HSCs: New Possibilities for HSC Transplants? AB - The identification of mechanisms that regulate stem cell renewal has led to the development of innovative approaches to expand hematopoietic stem cells ex vivo. One approach reported by Wagner et al. (2016) in this issue of Cell Stem Cell has demonstrated dramatic expansion of umbilical cord blood stem cells that promote rapid engraftment while maintaining capacity for long-term hematopoiesis. PMID- 26748751 TI - To Serve and Protect: Hydrogels to Improve Stem Cell-Based Therapies. AB - Harsh environments within damaged and diseased tissues and limited retention and survival of injected stem cells pose major challenges for stem cell therapeutics today. Here, we discuss promising hydrogel-based strategies for improving engraftment and viability of transplanted stem cells and stimulating recruitment of endogenous stem cells for repair. PMID- 26748752 TI - Improving Stem Cell Therapeutics with Mechanobiology. AB - In recent years, it has become clear that mechanical cues play an integral role in maintaining stem cell functions. Here we discuss how integrating physical approaches and engineering principles in stem cell biology, including culture systems, preclinical models, and functional assessment, may improve clinical application in regenerative medicine. PMID- 26748744 TI - Prostaglandin J2: a potential target for halting inflammation-induced neurodegeneration. AB - Prostaglandins (PGs) are produced via cyclooxygenases, which are enzymes that play a major role in neuroinflammation. Epidemiological studies show that chronic treatment with low levels of cyclooxygenase inhibitors (nonsteroidal anti inflammatory drugs (NSAIDs)) lowers the risk for Alzheimer's disease (AD) and Parkinson's disease (PD) by as much as 50%. Unfortunately, inhibiting cyclooxygenases with NSAIDs blocks the synthesis of downstream neuroprotective and neurotoxic PGs, thus producing adverse side effects. We focus on prostaglandin J2 (PGJ2) because it is highly neurotoxic compared to PGA1, D2, and E2. Unlike other PGs, PGJ2 and its metabolites have a cyclopentenone ring with reactive alpha,beta-unsaturated carbonyl groups that form covalent Michael adducts with key cysteines in proteins and GSH. Cysteine-binding electrophiles such as PGJ2 are considered to play an important role in determining whether neurons will live or die. We discuss in vitro and in vivo studies showing that PGJ2 induces pathological processes relevant to neurodegenerative disorders such as AD and PD. Further, we discuss our work showing that increasing intracellular cAMP with the lipophilic peptide PACAP27 counteracts some of the PGJ2-induced detrimental effects. New therapeutic strategies that neutralize the effects of specific neurotoxic PGs downstream from cyclooxygenases could have a significant impact on the treatment of chronic neurodegenerative disorders with fewer adverse side effects. PMID- 26748753 TI - From Nano to Macro: Multiscale Materials for Improved Stem Cell Culturing and Analysis. AB - Stem cells respond to nanoscale, microscale, and macroscale cues, such as matrix, growth factors, and niche organization, which are difficult to physiologically recapitulate in culture. We discuss how utilizing bioengineering approaches to manipulate and integrate spatiotemporal cues across these discrete length scales can improve traditional methods for controlling cell fate. PMID- 26748754 TI - Engineering Stem Cell Organoids. AB - Organoid systems leverage the self-organizing properties of stem cells to create diverse multi-cellular tissue proxies. Most organoid models only represent single or partial components of a tissue, and it is often difficult to control the cell type, organization, and cell-cell/cell-matrix interactions within these systems. Herein, we discuss basic approaches to generate stem cell-based organoids, their advantages and limitations, and how bioengineering strategies can be used to steer the cell composition and their 3D organization within organoids to further enhance their utility in research and therapies. PMID- 26748755 TI - Material Cues as Potent Regulators of Epigenetics and Stem Cell Function. AB - Biophysical signals act as potent regulators of stem cell function, lineage commitment, and epigenetic status. In recent years, synthetic biomaterials have been used to study a wide range of outside-in signaling events, and it is now well appreciated that material cues modulate the epigenome. Here, we review the role of extracellular signals in guiding stem cell behavior via epigenetic regulation, and we stress the role of physicochemical material properties as an often-overlooked modulator of intracellular signaling. We also highlight promising new research tools for ongoing interrogation of the stem cell-material interface. PMID- 26748757 TI - FOXD3 Regulates Pluripotent Stem Cell Potential by Simultaneously Initiating and Repressing Enhancer Activity. AB - Early development is governed by the ability of pluripotent cells to retain the full range of developmental potential and respond accurately to developmental cues. This property is achieved in large part by the temporal and contextual regulation of gene expression by enhancers. Here, we evaluated regulation of enhancer activity during differentiation of embryonic stem to epiblast cells and uncovered the forkhead transcription factor FOXD3 as a major regulator of the developmental potential of both pluripotent states. FOXD3 bound to distinct sites in the two cell types priming enhancers through a dual-functional mechanism. It recruited the SWI/SNF chromatin remodeling complex ATPase BRG1 to promote nucleosome removal while concurrently inhibiting maximal activation of the same enhancers by recruiting histone deacetylases1/2. Thus, FOXD3 prepares cognate genes for future maximal expression by establishing and simultaneously repressing enhancer activity. Through switching of target sites, FOXD3 modulates the developmental potential of pluripotent cells as they differentiate. PMID- 26748756 TI - Genome Editing in Human Pluripotent Stem Cells: Approaches, Pitfalls, and Solutions. AB - Human pluripotent stem cells (hPSCs) with knockout or mutant alleles can be generated using custom-engineered nucleases. Transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 nucleases are the most commonly employed technologies for editing hPSC genomes. In this Protocol Review, we provide a brief overview of custom-engineered nucleases in the context of gene editing in hPSCs with a focus on the application of TALENs and CRISPR/Cas9. We will highlight the advantages and disadvantages of each method and discuss theoretical and technical considerations for experimental design. PMID- 26748760 TI - Reduction of red blood cell transfusions by implementation of a concise pretransfusion checklist. AB - BACKGROUND: This study assesses the effect of the implementation of a concise pretransfusion checklist as a means for restrictive blood transfusion strategy. OBJECTIVES: To achieve an optimal use of red blood cells and to prevent overdosing of transfusion by implementation of a decision support algorithm. METHODS: To ensure adequate use of red blood cells, physicians were obliged to complete the checklist with pretransfusion patient information before transfusion was approved. Laboratory employees checked the information and provided approval or refused to process the request. The red blood cell transfusion events, length of stay and mortality were analysed during a pre- and post-implementation period of 1 year. RESULTS: Transfusion requests decreased by 17.0%. The proportion of 1 unit and 2-unit transfusions decreased by 5.6% and 29.2%, respectively, corresponding with a total red blood cell units reduction of 22.6% and a yearly direct local cost reduction of 190.000 ?. The median length of stay of transfused patients on wards decreased by 1.07 days (P < 0.05). Average pre- and post transfusion haemoglobin levels before and after implementation of the checklist decreased by 0.32-0.35 g L(-1) (P < 0.05) for one unit red blood cell transfusions and 0.72-0.87 g L(-1) (P < 0.05) for two units of red blood cell transfusions. CONCLUSION: Decision support for transfusion necessity, in the form of a concise checklist as part of the transfusion request, is an example of a successful restricted blood transfusion strategy. The checklist can be applied in other hospitals as well. PMID- 26748761 TI - Children's Exposure to Violence: The Underlying Effect of Posttraumatic Stress Symptoms on Behavior Problems. AB - In this study we investigated whether witnessing violence and violence victimization were associated with children's internalizing and externalizing behavior problems and examined the mediating role of posttraumatic stress (PTS) symptoms in these relationships. Secondary data analysis was conducted using 3 waves of data from the National Survey of Child and Adolescent Well-Being. Path analyses were conducted to test direct and indirect effects of violence exposure on behavior problems, using 2,064 children (ages 8-15 years) reported to Child Protective Services for maltreatment. Being a victim of violence in the home was directly associated with more internalizing (beta = .06, p = .007) and externalizing behavior problems (beta = .07, p = .002), whereas witnessing violence was not directly related to either internalizing (beta = .04, p = .056) or externalizing behavior problems (beta = .03, p = .130). PTS symptoms mediated the effects of witnessing violence and violence victimization on internalizing behavior problems (beta = .02, p = .002). Our findings suggest that PTS symptoms may be a mechanism underlying the association between violence exposure and internalizing behavior problems (R(2) = .23), underscoring the potential importance of assessing PTS symptoms and providing targeted trauma-focused interventions for children exposed to violence at home. PMID- 26748763 TI - Controlled Logic Gates-Switch Gate and Fredkin Gate Based on Enzyme-Biocatalyzed Reactions Realized in Flow Cells. AB - Controlled logic gates, where the logic operations on the Data inputs are performed in the way determined by the Control signal, were designed in a chemical fashion. Specifically, the systems where the Data output signals directed to various output channels depending on the logic value of the Control input signal have been designed based on enzyme biocatalyzed reactions performed in a multi-cell flow system. In the Switch gate one Data signal was directed to one of two possible output channels depending on the logic value of the Control input signal. In the reversible Fredkin gate the routing of two Data signals between two output channels is controlled by the third Control signal. The flow devices were created using a network of flow cells, each modified with one enzyme that biocatalyzed one chemical reaction. The enzymatic cascade was realized by moving the solution from one reacting cell to another which were organized in a specific network. The modular design of the enzyme-based systems realized in the flow device allowed easy reconfiguration of the logic system, thus allowing simple extension of the logic operation from the 2-input/3-output channels in the Switch gate to the 3-input/3-output channels in the Fredkin gate. Further increase of the system complexity for realization of various logic processes is feasible with the use of the flow cell modular design. PMID- 26748762 TI - Expedient Synthesis of (+)-Lycopalhine A. AB - Two amino acids play a key role in the first total synthesis of lycopalhine A. L glutamic acid serves as a convenient chiral starting material for the 13-step synthesis, and l-proline promotes an unusual 5-endo-trig Mannich cyclization that generates the central pyrrolidine ring of the Lycopodium alkaloid. The bicyclo[3.3.0]octanol moiety of the molecule is formed through an intramolecular aldol addition that may occur spontaneously in nature. PMID- 26748758 TI - Foxd3 Promotes Exit from Naive Pluripotency through Enhancer Decommissioning and Inhibits Germline Specification. AB - Following implantation, mouse epiblast cells transit from a naive to a primed state in which they are competent for both somatic and primordial germ cell (PGC) specification. Using mouse embryonic stem cells as an in vitro model to study the transcriptional regulatory principles orchestrating peri-implantation development, here we show that the transcription factor Foxd3 is necessary for exit from naive pluripotency and progression to a primed pluripotent state. During this transition, Foxd3 acts as a repressor that dismantles a significant fraction of the naive pluripotency expression program through decommissioning of active enhancers associated with key naive pluripotency and early germline genes. Subsequently, Foxd3 needs to be silenced in primed pluripotent cells to allow re activation of relevant genes required for proper PGC specification. Our findings therefore uncover a cycle of activation and deactivation of Foxd3 required for exit from naive pluripotency and subsequent PGC specification. PMID- 26748764 TI - Postnatal craniofacial ontogeny in neandertals and modern humans. AB - OBJECTIVES: Neandertals and humans are closely related but differ noticeably in adult morphology. Previous work has been equivocal as to the contribution of postnatal growth and development to these differences. Due to disparate preservation, most analyses focus on specific anatomies, reconstructed fossils, or limited sample sizes. The objective of this research is to highlight the importance of postnatal growth in expressing Neandertal-human distinctions in the craniofacial skeleton, using a large and unreconstructed Neandertal sample. MATERIALS/METHODS: A resampling approach is utilized to compare relative size change in 20 craniofacial dimensions between Neandertals (n = 42) and humans (n = 262). The large number of immature Neandertal samples within and between dental stages provides the necessary variation to test for growth differences. Nested resampling using human-human comparisons assesses the likelihood of observing human-Neandertal growth differences under the null hypothesis of similar ontogenetic variation. RESULTS: Humans and Neandertals undergo comparable levels of overall size change. However, we identify growth differences for a number of traits, helping explain some of the unique features of this fossil taxon. Nested resampling shows it is unlikely that a Neandertal-like maturation would be observed in a random ontogenetic sample of humans. DISCUSSION: Growth during adolescence appears to be fundamental in the expression of some Neandertal anatomies. Neandertal upper facial and nasal breadths appear to have expanded rapidly after puberty to account for differences between preadolescents and adults, and Neandertals and humans. Mandibular growth differences may relate to anterior tooth use to process foods and paramastication during Neandertal maturation. PMID- 26748759 TI - No longer a nuisance: long non-coding RNAs join CENP-A in epigenetic centromere regulation. AB - Centromeres represent the basis for kinetochore formation, and are essential for proper chromosome segregation during mitosis. Despite these essential roles, centromeres are not defined by specific DNA sequences, but by epigenetic means. The histone variant CENP-A controls centromere identity epigenetically and is essential for recruiting kinetochore components that attach the chromosomes to the mitotic spindle during mitosis. Recently, a new player in centromere regulation has emerged: long non-coding RNAs transcribed from repetitive regions of centromeric DNA function in regulating centromeres epigenetically. This review summarizes recent findings on the essential roles that transcription, pericentromeric transcripts, and centromere-derived RNAs play in centromere biology. PMID- 26748765 TI - Induced pluripotent stem cells and Parkinson's disease: modelling and treatment. AB - Many neurodegenerative disorders, such as Parkinson's disease (PD), are characterized by progressive neuronal loss in different regions of the central nervous system, contributing to brain dysfunction in the relevant patients. Stem cell therapy holds great promise for PD patients, including with foetal ventral mesencephalic cells, human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). Moreover, stem cells can be used to model neurodegenerative diseases in order to screen potential medication and explore their mechanisms of disease. However, related ethical issues, immunological rejection and lack of canonical grafting protocols limit common clinical use of stem cells. iPSCs, derived from reprogrammed somatic cells, provide new hope for cell replacement therapy. In this review, recent development in stem cell treatment for PD, using hiPSCs, as well as the potential value of hiPSCs in modelling for PD, have been summarized for application of iPSCs technology to clinical translation for PD treatment. PMID- 26748768 TI - Interaction of Lysinibacillus sphaericus Cry48Aa/Cry49Aa toxin with midgut brush border membrane fractions from Culex quinquefasciatus larvae. AB - The Cry48Aa/Cry49Aa mosquitocidal toxin from Lysinibacillus sphaericus was uniquely composed of a three-domain (Cry) toxin and binary (Bin) toxin-like protein, with high toxicity against Culex spp. However, its mode of action against the target mosquitoes is still unknown. In this study, Cry48Aa, Cry49Aa and its N- and C-terminal truncated proteins were expressed and purified, and the binding affinities of the purified proteins with midgut brush-border membrane fractions (BBMFs) from Culex quin-quefasciatus larvae were performed. The results showed that both Cry48Aa and Cry49Aa have specific and high binding affinity to BBMFs, with dissociation constants of 9.5 +/- 1.8 and 25.4 +/- 3.8 nM, respectively. Competition assays demonstrated that Cry49Aa C-terminal derivatives were able to bind to the BBMFs, whereas Far-Western dot blot analysis revealed that its N-terminal constructs interacted with Cry48Aa. Nevertheless, larvicidal activity was almost lost when Cry49Aa truncated proteins, either individually or in pairs, combined with Cry48Aa. It is concluded that Cry49Aa is responsible for receptor binding and interaction with Cry48Aa and plays an important role in the mechanism of action of these two-component toxins. PMID- 26748767 TI - Retinal artery occlusion due to Bartonella henselae infection: a case series. AB - PURPOSE: To report a case series of six patients suffering from branch retinal artery occlusion due to Bartonella henselae infection, in order to raise awareness to this etiology in the differential diagnosis of retinal artery occlusion. METHODS: A retrospective case series of patients with branch retinal artery occlusion due to ocular cat scratch disease who presented at four tertiary medical centers in Israel, Turkey and Saudi Arabia between the years 2008-2014. Data retrieved from the medical records included demographic data, exposure, complaints, visual acuity, clinical findings and imaging, laboratory assessment, treatment, disease course and visual outcome. RESULTS: The study group consisted of six patients who presented with branch retinal artery occlusion with or without neuroretinitis. One patient had multiple artery occlusions. Diagnosis of cat scratch disease was established based on positive serology and accompanying systemic symptoms, after ruling out other causes of retinal artery occlusion. Treatment included various regimens of antibiotics and systemic steroids. Visual outcome depended upon the obstructed artery. CONCLUSION: Cat scratch disease may cause retinal artery occlusion in infected patients, leaving them with a permanent visual field defect. When retinal artery occlusion occurs as an early sign of the disease, prompt recognition may prevent further events. Thorough history and relevant tests may be of great value. PMID- 26748766 TI - When psychopathology matters most: identifying sensitive periods when within person changes in conduct, affective and anxiety problems are associated with male adolescent substance use. AB - BACKGROUND AND AIMS: There is a documented link between common psychiatric disorders and substance use in adolescent males. This study addressed two key questions: (1) is there a within-person association between an increase in psychiatric problems and an increase in substance use among adolescent males and (2) are there sensitive periods during male adolescence when such associations are more evident? DESIGN: Analysis of longitudinal data collected annually on boys selected randomly from schools based on a comprehensive public school enrollment list from the Pittsburgh Board of Education. SETTING: Recruitment occurred in public schools in Pittsburgh, Pennsylvania, USA. PARTICIPANTS: A total of 503 boys assessed at ages 13-19 years, average cooperation rate = 92.1%. MEASUREMENTS: Diagnostic and Statistical Manual (DSM)-oriented affective, anxiety and conduct disorder problems were measured with items from the caregiver, teacher and youth version of the Achenbach scales. Scales were converted to t scores using age- and gender-based national norms and combined by taking the average across informants. Alcohol and marijuana use were assessed semi-annually by a 16-item Substance Use Scale adapted from the National Youth Survey. FINDINGS: When male adolescents experienced a 1-unit increase in their conduct problems t-score, their rate of marijuana use subsequently increased by 1.03 [95% confidence interval (CI) = 1.01, 1.05], and alcohol quantity increased by 1.01 (95% CI = 1.0002, 1.02). When adolescents experienced a 1-unit increase in their average quantity of alcohol use, their anxiety problems t-score subsequently increased by 0.12 (95% CI = 0.05, 0.19). These associations were strongest in early and late adolescence. CONCLUSIONS: When adolescent boys experience an increase in conduct disorder problems, they are more likely to exhibit a subsequent escalation in substance use. As adolescent boys increase their intensity of alcohol use, they become more likely to develop subsequent anxiety problems. Developmental turning points such as early and late adolescence appear to be particularly sensitive periods for boys to develop comorbid patterns of psychiatric problems and substance use. PMID- 26748769 TI - Public perceptions and attitudes to biological risks: Saudi Arabia and regional perspectives. AB - Saudi Arabia has experienced frequent occurrences of biological disasters due to a wide range of generator factors, including natural disasters and epidemics. A national survey (n=1,164) was conducted across 13 regions of Saudi Arabia to examine public perceptions to the risk of a biological disaster. The primary results reveal: (a) a degree of knowledge about biological threats such as SARS and H5N1 flu, despite the lack of individual experience with disasters; (b) age, gender, education and faith are positively related to the perception of biological risk; and (c) a number of important community resilience factors exist, including faith, education and willingness. This study concludes that the development of adapted resilience strategies in disaster management can be achieved through public education and training involving cooperation with official organisations and religious authorities in the country to increase public awareness, knowledge and skills in mitigating biological threats. PMID- 26748770 TI - Timing mechanisms in neuronal pathfinding, synaptic reorganization, and neuronal regeneration. AB - Precise temporal control of neuro differentiation and post-differentiation events are necessary for the creation of appropriate wiring diagram in the brain. To make advances in the treatment of neurodevelopmental and neurodegenerative disorders, and traumatic brain injury, it is important to understand these mechanisms. Caenorhabditis elegans has emerged as a revolutionary tool for the study of neural circuits due to its genetic homology to vertebrates and ease of genetic manipulation. microRNA (miRNA), a ubiquitous class of small non-coding RNA, that inhibits the expression of target genes, has emerged as an important timing control molecule through research conducted on C. elegans. This review will focus on the temporal control of neurodifferentiation and post differentiation events exerted by two conserved miRNAs, lin-4 and let-7. We summarize recent findings on the role of lin-4 as a timing regulator controlling transition of sequential events in neuronal pathfinding and synaptic remodeling, and the role of let-7 as a timing regulator that limits the regeneration potential of post-differentiated AVM neurons as they age. PMID- 26748773 TI - A call for improved sleep research in psoriasis populations. PMID- 26748774 TI - How well does the standard body mass index or variations with a different exponent predict human lifespan? AB - OBJECTIVE: The objective was twofold: (1) to estimate for each individual the body mass index (BMI) which is associated with the lowest risk of death, and (2) to study variants of the BMI formula to determine which gives the best predictions of death. METHODS: Treating BMI = mass/height(2) as a continuous variable and estimating its interaction effects with several other variables, this study analyzed the NIH-AARP study data set of approximately 566,000 individuals and fit Cox proportional hazards models to the survival times. RESULTS: For each individual, a "personalized optimal BMI," the BMI for that individual which, according to the model, is associated with the lowest risk of death, is estimated. The average personalized optimal BMI is approximately 26, which is in the current "overweight" category. In fact, mass/height is a better predictor of death on the data set than BMI itself. CONCLUSIONS: The model suggests that an individual's "optimal" BMI depends on his or her features; "one size-fits-all" recommendations may be not best. PMID- 26748772 TI - Qualitative study of patients' choice between public and private hospital emergency departments. AB - OBJECTIVE: The aim of this study was to gather patients' perceptions regarding their choice between public and private hospital EDs for those who hold private health insurance. The findings of this study will contribute to knowledge regarding patients' decision-making processes and therefore may contribute to the development of evidence based public policies. METHODS: An in-depth semi structured guide was used to interview participants at public and private hospital EDs. Questions sought to identify the issues that were considered by the participants to decide to attend that hospital ED, previous ED experience, expectations of ED services and perceived benefits and barriers to accessing services. Interviews were audio recorded, transcribed verbatim and analysed using content and thematic approaches. RESULTS: Four core themes emerged: prior good experience with the hospital, perceived quality of care, perceived waiting times and perceived costs that may explain patients' choice. Patients' choice between public and private EDs can be explained by the interaction of these core themes. The principal issues appear to be concern for gap payments at private hospital ED and waiting times at public hospital ED. CONCLUSIONS: Patients who choose to attend public EDs appear to value financial concern over waiting time; those who choose to attend private EDs appear to value waiting time ahead of financial concerns. PMID- 26748775 TI - Fabrication of intrafibrillar and extrafibrillar mineralized collagen/apatite scaffolds with a hierarchical structure. AB - A biomimetic collagen-apatite (Col-Ap) scaffold resembling the composition and structure of natural bone from the nanoscale to the macroscale has been successfully prepared for bone tissue engineering. We have developed a bottom-up approach to fabricate hierarchically biomimetic Col-Ap scaffolds with both intrafibrillar and extrafibrillar mineralization. To achieve intrafibrillar mineralization, polyacrylic acid (PAA) was used as a sequestrating analog of noncollagenous proteins (NCPs) to form a fluidic amorphous calcium phosphate (ACP) nanoprecursor through attraction of calcium and phosphate ions. Sodium tripolyphosphate was used as a templating analog to regulate orderly deposition of apatite within collagen fibrils. Both X-ray diffraction and Fourier transform infrared spectroscopy suggest that the mineral phase was apatite. Field emission scanning electron microscopy, transmission electron microscopy, and selected area electron diffraction confirmed that hierarchical collagen-Ap scaffolds were produced with both intrafibrillar and extrafibrillar mineralization. Biomimetic Col-Ap scaffolds with both intrafibrillar and extrafibrillar mineralization (IE Col-Ap) were compared with Col-Ap scaffolds with extrafibrillar mineralization only (E-Col-Ap) as well as pure collagen scaffolds in vitro for cellular proliferation using MC3T3-E1 cells. Pure collagen scaffolds had the highest rate of proliferation, while there was no statistically significant difference between IE-Col-Ap and E-Col-Ap scaffolds. Thus, the bottom-up biomimetic fabrication approach has rendered a group of promising Col-Ap scaffolds, which bear high resemblance to natural bone in terms of composition and structure. PMID- 26748776 TI - Cranial morphology in the brachygnathic sheep. AB - BACKGROUND: Craniofacial morphology of sheep with phenotypically observed mandibular distocclusion was analysed using the multivariate techniques principle component analysis and cluster analysis in order to test whether different types of craniofacial malformations can be distinguished. RESULTS: The results showed 8 principal components with a variance of 82.72% in the database. The method creates new variables then used in the Cluster analysis indicating 7 clusters with 3 different facial types: Normal, prognathia inferior and brachygnathia inferior. CONCLUSION: The brachygnathic facial type was mainly characterised as a shortened mandible, the upper jaw is not significantly involved. The correlations to the temporomandibular joint were shown. Molar and premolar malocclusions were revealed in two of three Clusters. Phenotypical distocclusion was not a single criterion for the affected sheep. PMID- 26748771 TI - Proton detection and breathing regulation by the retrotrapezoid nucleus. AB - We discuss recent evidence which suggests that the principal central respiratory chemoreceptors are located within the retrotrapezoid nucleus (RTN) and that RTN neurons are directly sensitive to [H(+) ]. RTN neurons are glutamatergic. In vitro, their activation by [H(+) ] requires expression of a proton-activated G protein-coupled receptor (GPR4) and a proton-modulated potassium channel (TASK-2) whose transcripts are undetectable in astrocytes and the rest of the lower brainstem respiratory network. The pH response of RTN neurons is modulated by surrounding astrocytes but genetic deletion of RTN neurons or deletion of both GPR4 and TASK-2 virtually eliminates the central respiratory chemoreflex. Thus, although this reflex is regulated by innumerable brain pathways, it seems to operate predominantly by modulating the discharge rate of RTN neurons, and the activation of RTN neurons by hypercapnia may ultimately derive from their intrinsic pH sensitivity. RTN neurons increase lung ventilation by stimulating multiple aspects of breathing simultaneously. They stimulate breathing about equally during quiet wake and non-rapid eye movement (REM) sleep, and to a lesser degree during REM sleep. The activity of RTN neurons is regulated by inhibitory feedback and by excitatory inputs, notably from the carotid bodies. The latter input operates during normo- or hypercapnia but fails to activate RTN neurons under hypocapnic conditions. RTN inhibition probably limits the degree of hyperventilation produced by hypocapnic hypoxia. RTN neurons are also activated by inputs from serotonergic neurons and hypothalamic neurons. The absence of RTN neurons probably underlies the sleep apnoea and lack of chemoreflex that characterize congenital central hypoventilation syndrome. PMID- 26748777 TI - Pattern of acute poisoning at two urban referral hospitals in Lusaka, Zambia. AB - BACKGROUND: Poisoning remains an important public health problem contributing significantly to the global burden of disease. Evidence on the exact burden and pattern of acute poisoning in Zambia is limited. We aimed to characterise acute poisoning with regard to demographic and epidemiologic factors of cases reported at the University Teaching Hospital and Levy Mwanawasa General Hospital; two large referral hospitals in Lusaka, Zambia. METHODS: This was a cross-sectional study involving retrospective collection of data on all poisoning cases recorded in hospital records from 1 January to 31 December 2012. A pretested data collection form was used to extract demographic and other data such as poisonous agents used, circumstance of poisoning, route and outcome of poisoning. All analyses were performed in STATA (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP). RESULTS: A total of 873 poisoning cases were reviewed with almost similar proportions of males (52 %) and females (49 %). Poisoning cases were highest in the 0-12 years age category (36 %) followed by the 20-30 years age category (31 %). Accidental poisoning characterised most (65 %) cases in children aged < 13 years. The common route of exposure to poisonous agents was ingestion. Overall, the mortality rate was 2.6 per 100 cases, the majority of deaths were observed in men (78 %). Poisonous agents associated with most cases were pesticides (57 %) and pharmaceuticals (13 %). CONCLUSIONS: The high risk of accidental poisoning observed in children calls for special health education on chemical safety, tailored for mothers and caregivers to prevent chemical exposure in this important age group whose access to toxic agents is mainly in homes or their immediate environment. The results also call for additional regulatory controls on pesticides and pharmaceuticals, which were the most common toxic agents. PMID- 26748778 TI - Repair of Persistent Left Superior Vena Cava to Unroofed Coronary Sinus Defect by Retro-Aortic Implantation (Modified Warden Type Procedure). AB - BACKGROUND: Repair of unroofed coronary sinus defect in the presence of left superior vena cava is challenging and requires prosthetic graft material to redirect flow to the right atrium. This may potentially cause a supra-mitral gradient or pulmonary venous obstruction. METHODS: Three patients with unroofed coronary sinus in the presence of a left superior vena cava (LSVC) underwent modified cavo-atrial anastomosis (Warden technique) to achieve reimplantation of the LSVC in a retro-aortic fashion to the right atrial appendage. RESULTS: Three patients recovered well with no evidence of an intracardiac shunt. Postoperative echocardiography demonstrated normal venous flows in the LSVC. CONCLUSION: This modified technique offers correction of this systemic venous anomaly without the need for any additional graft material. PMID- 26748779 TI - EuroSurg: a new European student-driven research network in surgery. PMID- 26748782 TI - Helping hands: Organizations, institutions work to assist and mentor early career investigators. PMID- 26748780 TI - Involvement of metabotropic glutamate receptor 5 in the inhibition of methamphetamine-associated contextual memory after prolonged extinction training. AB - Addiction is thought to be a memory process between perception and environmental cues and addicted patients often relapse when they come into contact with the drug-related context once again. Here, we used a conditioned place preference protocol to seek a more effective extinction methodology of methamphetamine (METH) memory and delineate its underlying mechanism. Conditioning METH for 3 days in mice markedly increased the time spent in the METH-paired compartment. Then the mice were conditioned with saline for 6 days, from day 6 to day 11, a procedure termed extinction training. However, METH memory returned after a priming injection of METH. We prolonged extinction duration from 6 to 10 days and found that this extensive extinction (EE) training prevented priming effect. At the molecular level, we discovered that prolonged extinction training reversed the METH-conditioned place preference-induced increase in surface expression of GluA2 and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/NMDA ratio in the basolateral amygdala. In addition, we found that extinction with metabotropic glutamate receptor 5 (mGluR5) activation had similar results to EE: reduced relapse after extinction, decreased synaptic AMPA receptors AMPARs and the AMPA/NMDA ratio. On the contrary, EE with mGluR5 inhibition suppressed the results of EE. These data indicate that EE training-elicited inhibition of METH primed reinstatement is mediated by the mGluR5. Conditioning mice with methamphetamine place preference (METH CPP) increases surface expression of AMPA receptors (AMPARs) in the basolateral amygdala. We found prolongation of extinction duration from 6 to 10 days prevented priming effect. At the molecular level, we discovered that extensive extinction (EE) reversed the METH CPP-induced increase in surface expression of GluA2 and AMPA/NMDA ratio. In addition, we found that extinction with the metabotropic glutamate receptor 5 (mGluR5) activation had similar results to EE: reduced relapse after extinction, decreased synaptic AMPARs and the AMPA/NMDA ratio. On the contrary, EE with mGluR5 inhibition suppressed the results of EE. These data indicate that EE training elicited inhibition of METH-primed reinstatement is mediated by mGluR5 (PAM: positive allosteric modulator). PMID- 26748783 TI - Researchers address palliative care at ASCO symposium. PMID- 26748784 TI - Prognostic significance of CpG island methylator phenotype in surgically resected small cell lung carcinoma. AB - Methylation is closely involved in the development of various carcinomas. However, few datasets are available for small cell lung cancer (SCLC) due to the scarcity of fresh tumor samples. The aim of the present study is to clarify relationships between clinicopathological features and results of the comprehensive genome-wide methylation profile of SCLC. We investigated the genome wide DNA methylation status of 28 tumor and 13 normal lung tissues, and gene expression profiling of 25 SCLC tissues. Following unsupervised hierarchical clustering and non-negative matrix factorization, gene ontology analysis was performed. Clustering of SCLC led to the important identification of a CpG island methylator phenotype (CIMP) of the tumor, with a significantly poorer prognosis (P = 0.002). Multivariate analyses revealed that postoperative chemotherapy and non-CIMP were significantly good prognostic factors. Ontology analyses suggested that the extrinsic apoptosis pathway was suppressed, including TNFRSF1A, TNFRSF10A and TRADD in CIMP tumors. Here we revealed that CIMP was an important prognostic factor for resected SCLC. Delineation of this phenotype may also be useful for the development of novel apoptosis-related chemotherapeutic agents for treatment of the aggressive tumor. PMID- 26748785 TI - Co-Adsorption of O2 and CO on Au2- : Infrared Photodissociation Spectroscopy and Theoretical Study of [Au2 O2 (CO)n ]- (n=2-6). AB - The co-adsorption of O2 and CO on anionic sites of gold species is considered as a crucial step in the catalytic CO oxidation on gold catalysts. In this regard, the [Au2 O2 (CO)n ]- (n=2-6) complexes were prepared by using a laser vaporization supersonic ion source and were studied by using infrared photodissociation spectroscopy in the gas phase. All the [Au2 O2 (CO)n ]- (n=2-6) complexes were characterized to have a core structure involving one CO and one O2 molecule co-adsorbed on Au2- with the other CO molecules physically tagged around. The CO stretching frequency of the [Au2 O2 (CO)]- core ion is observed around nu~ =2032-2042 cm-1 , which is about 200 cm-1 higher than that in [Au2 (CO)2 ]- . This frequency difference and the analyses based on density functional calculations provide direct evidence for the synergy effect of the chemically adsorbed O2 and CO. The low lying structures with carbonate group were not observed experimentally because of high formation barriers. The structures and the stability (i.e., the inertness in a sense) of the co-adsorbed O2 and CO on Au2- may have relevance to the elementary reaction steps on real gold catalysts. PMID- 26748786 TI - Well-Defined Macromolecules Using Horseradish Peroxidase as a RAFT Initiase. AB - Enzymatic catalysis and control over macromolecular architectures from reversible addition-fragmentation chain transfer polymerization (RAFT) are combined to give a new method of making polymers. Horseradish peroxidase (HRP) is used to catalytically generate radicals using hydrogen peroxide and acetylacetone as a mediator. RAFT is used to control the polymer structure. HRP catalyzed RAFT polymerization gives acrylate and acrylamide polymers with relatively narrow molecular weight distributions. The polymerization is rapid, typically exceeding 90% monomer conversion in 30 min. Complex macromolecular architectures including a block copolymer and a protein-polymer conjugate are synthesized using HRP to catalytically initiate RAFT polymerization. PMID- 26748788 TI - An editor's tribute to his predecessor. PMID- 26748787 TI - Identification and Optimization of Anthranilic Acid Based Inhibitors of Replication Protein A. AB - Replication protein A (RPA) is an essential single-stranded DNA (ssDNA)-binding protein that initiates the DNA damage response pathway through protein-protein interactions (PPIs) mediated by its 70N domain. The identification and use of chemical probes that can specifically disrupt these interactions is important for validating RPA as a cancer target. A high-throughput screen (HTS) to identify new chemical entities was conducted, and 90 hit compounds were identified. From these initial hits, an anthranilic acid based series was optimized by using a structure guided iterative medicinal chemistry approach to yield a cell-penetrant compound that binds to RPA70N with an affinity of 812 nm. This compound, 2-(3- (N-(3,4 dichlorophenyl)sulfamoyl)-4-methylbenzamido)benzoic acid (20 c), is capable of inhibiting PPIs mediated by this domain. PMID- 26748789 TI - Designing anti-diabetic beta-cells microcapsules using polystyrenic sulfonate, polyallylamine, and a tertiary bile acid: Morphology, bioenergetics, and cytokine analysis. AB - PURPOSE: Recently sodium alginate (SA)-poly-l-ornithine (PLO) microcapsules containing pancreatic beta-cells that showed good morphology but low cell viability (<27%) was designed. In this study, two new polyelectrolytes, polystyrenic sulfonate (PSS; at 1%) and polyallylamine (PAA; at 2%) were incorporated into a microencapsulated-formulation, with the aim of enhancing the physical properties of the microcapsules. Following incorporation, the structural characteristics and cell viability were investigated. The effects of the anti inflammatory bile acid, ursodeoxycholic acid (UDCA), on microcapsule morphology, size, and stability as well as beta-cell biological functionality was also examined. METHODS: Microcapsules were prepared using PLO-PSS-PAA-SA mixture and two types of microcapsules were produced: without UDCA (control) and with UDCA (test). Microcapsule morphology, stability, and size were examined. Cell count, microencapsulation efficiency, cell bioenergetics, and activity were also examined. RESULTS: The new microcapsules showed good morphology but cell viability remained low (29% +/- 3%). UDCA addition improved cell viability post microencapsulation (42 +/- 5, P < 0.01), reduced swelling (P < 0.01), improved mechanical strength (P < 0.01), increased Zeta-potential (P < 0.01), and improved stability. UDCA addition also increased insulin production (P < 0.01), bioenergetics (P < 0.01), and decreased beta-cell TNF-alpha (P < 0.01), IFN-gamma (P < 0.01), and IL-6 (P < 0.01) secretions. CONCLUSIONS: Addition of 4% UDCA to a formulation system consisting of 1.8% SA, 1% PLO, 1% PSS, and 2% PAA enhanced cell viability post-microencapsulation and resulted in a more stable formulation with enhanced encapsulated beta-cell metabolism, bioenergetics, and biological activity with reduced inflammation. This suggests potential application of UDCA, when combined with SA, PLO, PSS, and PAA, in beta-cell microencapsulation and diabetes treatment. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:501-509, 2016. PMID- 26748792 TI - Persuasive Technology in Mobile Applications Promoting Physical Activity: a Systematic Review. AB - Persuasive technology in mobile applications can be used to influence the behaviour of users. A framework known as the Persuasive Systems Design model has been developed for designing and evaluating systems that influence the attitudes or behaviours of users. This paper reviews the current state of mobile applications for health behavioural change with an emphasis on applications that promote physical activity. The inbuilt persuasive features of mobile applications were evaluated using the Persuasive Systems Design model. A database search was conducted to identify relevant articles. Articles were then reviewed using the Persuasive Systems Design model as a framework for analysis. Primary task support, dialogue support, and social support were found to be moderately represented in the selected articles. However, system credibility support was found to have only low levels of representation as a persuasive systems design feature in mobile applications for supporting physical activity. To ensure that available mobile technology resources are best used to improve the wellbeing of people, it is important that the design principles that influence the effectiveness of persuasive technology be understood. PMID- 26748791 TI - Development of a Wearable Motor-Imagery-Based Brain-Computer Interface. AB - A motor-imagery-based brain-computer interface (BCI) is a translator that converts the motor intention of the brain into a control command to control external machines without muscles. Numerous motor-imagery-based BCIs have been successfully proposed in previous studies. However, several electroencephalogram (EEG) channels are typically required for providing sufficient information to maintain a specific accuracy and bit rate, and the bulk volume of these EEG machines is also inconvenient. A wearable motor imagery-based BCI system was proposed and implemented in this study. A wearable mechanical design with novel active comb-shaped dry electrodes was developed to measure EEG signals without conductive gels at hair sites, which is easy and convenient for users wearing the EEG machine. In addition, a wireless EEG acquisition module was also designed to measure EEG signals, which provides a user with more freedom of motion. The proposed wearable motor-imagery-based BCI system was validated using an electrical specifications test and a hand motor imagery experiment. Experimental results showed that the proposed wearable motor-imagery-based BCI system provides favorable signal quality for measuring EEG signals and detecting motor imagery. PMID- 26748793 TI - Diabetes Distress Among Adolescents with Type 1 Diabetes: a Systematic Review. AB - Diabetes distress (DD) refers to the negative emotions arising from living with diabetes and the burden of self-management. Among adults, the prevalence and significance of DD are well established, but this is not the case among adolescents. This systematic review investigated among adolescents with type 1 diabetes: the prevalence of DD; demographic, clinical, behavioral and psychosocial correlates of DD and interventions that reduce DD. Consistent with adult studies, around one third of adolescents experience elevated DD and this is frequently associated with suboptimal glycemic control, low self-efficacy and reduced self-care. Three measures of DD have been developed specifically for adolescents, as those designed for adults may not be sufficiently sensitive to adolescent concerns. Interventions reducing DD in the short term include strategies such as cognitive restructuring, goal setting and problem solving. Further work is needed to investigate sustainability of effect. Rigorous research is needed to progress this field among adolescents. PMID- 26748790 TI - Optimizing the Use of Antibacterial Agents in the Neonatal Period. AB - Antibiotics are invaluable in the management of neonatal infections. However, overuse or misuse of antibiotics in neonates has been associated with adverse outcomes, including increased risk for future infection, necrotizing enterocolitis, and mortality. Strategies to optimize the use of antibiotics in the neonatal intensive care unit include practicing effective infection prevention, improving the diagnostic evaluation and empiric therapy for suspected infections, timely adjustment of therapy as additional information becomes available, and treating proven infections with an effective, narrow-spectrum agent for the minimum effective duration. Antibiotic stewardship programs provide support for these strategies but require the participation and input of neonatologists as stakeholders to be most effective. PMID- 26748796 TI - Ecotoxicological evaluation of low-concentration bisphenol A exposure on the soil nematode Caenorhabditis elegans and intrinsic mechanisms of stress response in vivo. AB - As a representative species of nematodes, Caenorhabditis elegans is an attractive animal model for evaluating ecotoxicological effects and intrinsic mechanisms of the stress response in vivo. To acquire a better knowledge of environmental effects of bisphenol A (BPA), ecotoxicological evaluations were conducted using C. elegans on the physiological (growth, locomotion behaviors, and reproduction), biochemical (lipofuscin accumulation, reactive oxygen species production, and cell apoptosis), and molecular (stress-related gene expression) responses. Nematodes were exposed to BPA (0.001-10 uM) in 2 assay systems (L4 larvae for 24 h and L1 larvae for 72 h). Exposure to BPA could significantly (p < 0.05) alter body length, locomotion behaviors, brood size, cell apoptosis, and selected stress-related gene expression. At the physiological level, BPA exerted adverse effects on nematodes at the microgram per liter level in both assay systems, with head thrashes as the most sensitive endpoint. At the biochemical level, apoptosis degree showed increases at concentrations above 0.1 uM in both assay systems. At the molecular level, BPA induced increases in selected stress-related gene expression, even at the lowest tested concentration. In addition, BPA-induced cell apoptosis was suggested as a potential mode of action, resulting in adverse physiological effects. Therefore, BPA exposure was speculated to impose developmental, reproductive, and neurobehavioral toxicities on C. elegans and caused variations of stress-related gene expression. Environ Toxicol Chem 2016;35:2041-2047. (c) 2016 SETAC. PMID- 26748802 TI - Erratum to: Impact of three phthalate esters on the sexual reproduction of the Monogonont rotifer, Brachionus calyciflorus. PMID- 26748794 TI - Investigation of the interactions between Pt(II) and Pd(II) derivatives of 5,10,15,20-tetrakis (N-methyl-4-pyridyl) porphyrin and G-quadruplex DNA. AB - G-quadruplexes are non-canonical DNA structures formed by guanine-rich DNA sequences that are implicated in cancer and aging. Understanding how small molecule ligands interact with quadruplexes is essential both to the development of novel anticancer therapeutics and to the design of new quadruplex-selective probes needed for elucidation of quadruplex biological functions. In this work, UV-visible, fluorescence, and circular dichroism spectroscopies, fluorescence resonance energy transfer (FRET) melting assays, and resonance light scattering were used to investigate how the Pt(II) and Pd(II) derivatives of the well studied 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP4) interact with quadruplexes formed by the human telomeric DNA, Tel22, and by the G-rich sequences from oncogene promoters. Our results suggest that Pt- and PdTMPyP4 interact with Tel22 via efficient pi-pi stacking with a binding affinity of 10(6) 10(7) M(-1). Under porphyrin excess, PtTMPyP4 aggregates using Tel22 as a template; the aggregates reach maximum size at [PtTMPyP4]/[Tel22] ~8 and dissolve at [PtTMPyP4]/[Tel22] <= 2. FRET assays reveal that both porphyrins are excellent stabilizers of human telomeric DNA, with stabilization temperature of 30.7 +/- 0.6 degrees C for PtTMPyP4 and 30.9 +/- 0.4 degrees C for PdTMPyP4 at [PtTMPyP4]/[Tel22] = 2 in K(+) buffer, values significantly higher as compared to those for TMPyP4. The porphyrins display modest selectivity for quadruplex vs. duplex DNA, with selectivity ratios of 150 and 330 for Pt- and PdTMPyP4, respectively. This selectivity was confirmed by observed 'light switch' effect: fluorescence of PtTMPyP4 increases significantly in the presence of a variety of DNA secondary structures, yet the strongest effect is produced by quadruplex DNA. PMID- 26748795 TI - Orange protein from Desulfovibrio alaskensis G20: insights into the Mo-Cu cluster protein-assisted synthesis. AB - A novel metalloprotein containing a unique [S2MoS2CuS2MoS2](3-) cluster, designated as Orange Protein (ORP), was isolated for the first time from Desulfovibrio gigas, a sulphate reducer. The orp operon is conserved in almost all sequenced Desulfovibrio genomes and in other anaerobic bacteria, however, so far D. gigas ORP had been the only ORP characterized in the literature. In this work, the purification of another ORP isolated form Desulfovibrio alaskensis G20 is reported. The native protein is monomeric (12443.8 +/- 0.1 Da by ESI-MS) and contains also a MoCu cluster with characteristic absorption bands at 337 and 480 nm, assigned to S-Mo charge transfer bands. Desulfovibrio alaskensis G20 recombinant protein was obtained in the apo-form from E. coli. Cluster reconstitution studies and UV-visible titrations with tetrathiomolybdate of the apo-ORP incubated with Cu ions indicate that the cluster is incorporated in a protein metal-assisted synthetic mode and the protein favors the 2Mo:1Cu stoichiometry. In Desulfovibrio alaskensis G20, the orp genes are encoded by a polycistronic unit composed of six genes whereas in Desulfovibrio vulgaris Hildenborough the same genes are organized into two divergent operons, although the composition in genes is similar. The gene expression of ORP (Dde_3198) increased 6.6 +/- 0.5 times when molybdate was added to the growth medium but was not affected by Cu(II) addition, suggesting an involvement in molybdenum metabolism directly or indirectly in these anaerobic bacteria. PMID- 26748803 TI - Connexin 43 (Cx43) Expression in Laryngeal Squamous Cell Carcinomas: Preliminary Data on Its Possible Prognostic Role. AB - The aim of the report is to evaluate the prognostic and predictive role of Connexin 43 (Cx43) expression in laryngeal squamous cell carcinomas. Eighty-seven previously untreated patients submitted to laryngectomy +/- neck dissection +/- radiotherapy were enrolled in this retrospective study. The original primary tumor slides were reassessed, tumor grade and stage reviewed, and Cx43 immunohistochemical analysis performed: only cytoplasmic membranous staining of Cx43 has been shown. Neither significant correlation has been showed for clinical T (p = 0.75) and N (p = 0.81), while significant correlation has been found with grading (p < 0.0001) and pathological N (p < 0.0001). Five year overall survival (OS) of the 87 patients was 54 %; 5 year OS was 59.6 % in Cx43 positive patients and 37.1 % in Cx43 negative patients, but also this difference did not reach statistical significance (p = 0.058). Our best findings were: poorly differentiated carcinomas had low or negative Cx43 expression; moderately differentiated tumors without node metastasis and no radiotherapy but with Cx43 expression had a better outcome; moderately differentiated tumors without node metastasis and no radiotherapy but without Cx43 expression had a worse outcome; moderately differentiated tumors with node metastasis and radiotherapy but without Cx43 expression had a better outcome. Interestingly, in G2 head and neck squamous cell carcinomas with lymph node metastasis at the time of diagnosis, Cx43 aberrant overexpression could identify a subset of patients with poor prognosis, far less responsive to radio/chemotherapy. PMID- 26748804 TI - Inorganic polyphosphate in the microbial world. Emerging roles for a multifaceted biopolymer. AB - Inorganic polyphosphates (polyP) are linear polymers of tens to hundreds orthophosphate residues linked by phosphoanhydride bonds. These fairly abundant biopolymers occur in all extant forms of life, from prokaryotes to mammals, and could have played a relevant role in prebiotic evolution. Since the first identification of polyP deposits as metachromatic or volutin granules in yeasts in the nineteenth century, an increasing number of varied physiological functions have been reported. Due to their "high energy" bonds analogous to those in ATP and their properties as polyanions, polyP serve as microbial phosphagens for a variety of biochemical reactions, as a buffer against alkalis, as a storage of Ca(2+) and as a metal-chelating agent. In addition, recent studies have revealed polyP importance in signaling and regulatory processes, cell viability and proliferation, pathogen virulence, as a structural component and chemical chaperone, and as modulator of microbial stress response. This review summarizes the current status of knowledge and future perspectives of polyP functions and their related enzymes in the microbial world. PMID- 26748806 TI - Protons and pleomorphs: aerobic hydrogen production in Azotobacters. AB - As obligate aerobic soil organisms, the ability of Azotobacter species to fix nitrogen is unusual given that the nitrogenase complex requires a reduced cellular environment. Molecular hydrogen is an unavoidable byproduct of the reduction of dinitrogen; at least one molecule of H2 is produced for each molecule of N2 fixed. This could be considered a fault in nitrogenase efficiency, essentially a waste of energy and reducing equivalents. Wild-type Azotobacter captures this hydrogen and oxidizes it with its membrane-bound uptake hydrogenase complex. Strains lacking an active hydrogenase complex have been investigated for their hydrogen production capacities. What is the role of H2 in the energy metabolism of nitrogen-fixing Azotobacter? Is hydrogen production involved in Azotobacter species' protection from or tolerance to oxygen, or vice versa? What yields of hydrogen can be expected from hydrogen-evolving strains? Can the yield of hydrogen be controlled or increased by changing genetic, environmental, or physiological conditions? We will address these questions in the following mini review. PMID- 26748805 TI - Diversity and ecology of oxalotrophic bacteria. AB - Oxalate is present in environments as diverse as soils or gastrointestinal tracts. This organic acid can be found as free acid or forming metal salts (e.g. calcium, magnesium). Oxalotrophy, the ability to use oxalate as carbon and energy sources, is mainly the result of bacterial catabolism, which can be either aerobic or anaerobic. Although some oxalotrophic bacterial strains are commonly used as probiotics, little is known about the diversity and ecology of this functional group. This review aims at exploring the taxonomic distribution and the phylogenetic diversity of oxalotrophic bacteria across biomes. In silico analyses were conducted using the two key enzymes involved in oxalotrophy: formyl coenzyme A (CoA) transferase (EC 2.8.3.16) and oxalyl-CoA decarboxylase (EC 4.1.1.8), encoded by the frc and oxc genes, respectively. Our analyses revealed that oxalate-degrading bacteria are restricted to three phyla, namely Actinobacteria, Firmicutes and Proteobacteria and originated from terrestrial, aquatic and clinical environments. Diversity analyses at the protein level suggest that total Oxc diversity is more constrained than Frc diversity and that bacterial oxalotrophic diversity is not yet fully described. Finally, the contribution of oxalotrophic bacteria to ecosystem functioning as well as to the carbon cycle is discussed. PMID- 26748807 TI - alpha-1,3-Glucanase: present situation and prospect of research. AB - alpha-1,3-Glucanases hydrolyze alpha-1,3-glucan which is an insoluble linear alpha-1,3-linked homopolymer of glucose and these enzymes are classified into two families of glycoside hydrolases on the basis of amino acid sequence similarity; type-71 alpha-1,3-glucanases found in fungi and type-87 enzymes in bacteria. alpha-1,3-Glucan (also called 'mutan') is a major component of dental plaque formed by oral Streptococci and has important physiological roles in various fungal species, including as a component of cell walls, an endogenous carbon source for sexual development, and a virulent factor. Considering these backgrounds, alpha-1,3-glucanases have been investigated from the perspectives of applications to dental care and development of cell-wall lytic enzymes. Compared with information regarding other glycoside hydrolases such as amylases, cellulases, chitinases, and beta-glucanases, there is limited biochemical and structural information available regarding alpha-1,3-glucanase. Further research on alpha-1,3-glucanases on enzyme application to dental care and biological control of pathogenic fungi is expected. In this mini-review, we briefly describe how alpha-1,3-glucanases are categorized and characterized and present our study findings regarding alpha-1,3-glucanase from Bacillus circulans KA-304. Furthermore, we briefly discuss potential future applications of alpha-1,3 glucanases. PMID- 26748810 TI - Influence of Pre-organised Architecture on Cell Adhesion by Using Multivalent RGD Compounds. AB - Multimeric RGD-containing compounds were designed to study the influence of ligand architecture on binding avidity. We report the synthesis of a series of tetrameric RGD compounds and their in vitro biological evaluation. The further application of molecular dynamic simulations for structural studies of RGD derivatives reveals that the observed affinities correlate with the accessibility of segregated RGD motif. PMID- 26748808 TI - Archetypal tryptophan-rich antimicrobial peptides: properties and applications. AB - Drug-resistant microorganisms ('superbugs') present a serious challenge to the success of antimicrobial treatments. Subsequently, there is a crucial need for novel bio-control agents. Many antimicrobial peptides (AMPs) show a broad spectrum activity against bacteria, fungi or viruses and are strong candidates to complement or substitute current antimicrobial agents. Some AMPs are also effective against protozoa or cancer cells. The tryptophan (Trp)-rich peptides (TRPs) are a subset of AMPs that display potent antimicrobial activity, credited to the unique biochemical properties of tryptophan that allow it to insert into biological membranes. Further, many Trp-rich AMPs cross bacterial membranes without compromising their integrity and act intracellularly, suggesting interactions with nucleic acids and enzymes. In this work, we overview some archetypal TRPs derived from natural sources, i.e., indolicidin, tritrpticin and lactoferricin, summarising their biochemical properties, structures, antimicrobial activities, mechanistic studies and potential applications. PMID- 26748811 TI - Body image disturbance in adults treated for cancer - a concept analysis. AB - AIM: To report an analysis of the concept of body image disturbance in adults who have been treated for cancer as a phenomenon of interest to nurses. BACKGROUND: Although the concept of body image disturbance has been clearly defined in adolescents and adults with eating disorders, adults who have been treated for cancer may also experience body image disturbance. In this context, the concept of body image disturbance has not been clearly defined. DESIGN: Concept analysis. DATA SOURCES: PubMed, Psychological Information Database and Cumulative Index of Nursing and Allied Health Literature were searched for publications from 1937 - 2015. Search terms included body image, cancer, body image disturbance, adult and concept analysis. METHODS: Walker and Avant's 8-step method of concept analysis was used. RESULTS: The defining attributes of body image disturbance in adults who have been treated for cancer are: (1) self-perception of a change in appearance and displeasure with the change or perceived change in appearance; (2) decline in an area of function; and (3) psychological distress regarding changes in appearance and/or function. CONCLUSIONS: This concept analysis provides a foundation for the development of multidimensional assessment tools and interventions to alleviate body image disturbance in this population. A better understanding of body image disturbance in adults treated for cancer will assist nurses and other clinicians in identifying this phenomenon and nurse scientists in developing instruments that accurately measure this condition, along with interventions that will promote a better quality of life for survivors. PMID- 26748812 TI - A two-stage approach for dynamic prediction of time-to-event distributions. AB - Dynamic prediction uses longitudinal biomarkers for real-time prediction of an individual patient's prognosis. This is critical for patients with an incurable disease such as cancer. Biomarker trajectories are usually not linear, nor even monotone, and vary greatly across individuals. Therefore, it is difficult to fit them with parametric models. With this consideration, we propose an approach for dynamic prediction that does not need to model the biomarker trajectories. Instead, as a trade-off, we assume that the biomarker effects on the risk of disease recurrence are smooth functions over time. This approach turns out to be computationally easier. Simulation studies show that the proposed approach achieves stable estimation of biomarker effects over time, has good predictive performance, and is robust against model misspecification. It is a good compromise between two major approaches, namely, (i) joint modeling of longitudinal and survival data and (ii) landmark analysis. The proposed method is applied to patients with chronic myeloid leukemia. At any time following their treatment with tyrosine kinase inhibitors, longitudinally measured BCR-ABL gene expression levels are used to predict the risk of disease progression. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26748809 TI - Sugar uptake by the solventogenic clostridia. AB - The acetone-butanol-ethanol fermentation of solventogenic clostridia was operated as a successful, worldwide industrial process during the first half of the twentieth century, but went into decline for economic reasons. The recent resurgence in interest in the fermentation has been due principally to the recognised potential of butanol as a biofuel, and development of reliable molecular tools has encouraged realistic prospects of bacterial strains being engineered to optimise fermentation performance. In order to minimise costs, emphasis is being placed on waste feedstock streams containing a range of fermentable carbohydrates. It is therefore important to develop a detailed understanding of the mechanisms of carbohydrate uptake so that effective engineering strategies can be identified. This review surveys present knowledge of sugar uptake and its control in solventogenic clostridia. The major mechanism of sugar uptake is the PEP-dependent phosphotransferase system (PTS), which both transports and phosphorylates its sugar substrates and plays a central role in metabolic regulation. Clostridial genome sequences have indicated the presence of numerous phosphotransferase systems for uptake of hexose sugars, hexose derivatives and disaccharides. On the other hand, uptake of sugars such as pentoses occurs via non-PTS mechanisms. Progress in characterization of clostridial sugar transporters and manipulation of control mechanisms to optimise sugar fermentation is described. PMID- 26748813 TI - The double stitch everting technique in end-to-side vascular anastomoses. PMID- 26748814 TI - Effects of autonomic balance and fluid and electrolyte changes on cardiac function in infarcted rats: A serial study of sexual dimorphism. AB - Premenopausal women are known to show lower incidence of cardiovascular disease than men. During myocardial infarction (MI), homeostatic responses are activated, including the sympathetic autonomic nervous system and the rennin-angiotensin aldosterone system, which is related to the fluid and electrolyte balance, both aiming to maintain cardiac output. This study sought to perform a serial evaluation of sexual dimorphism in cardiac autonomic control and fluid and electrolyte balance during the development of MI-induced heart failure in rats. Experimental MI was induced in male (M) and female (F) adult (7-9 weeks of age) Wistar rats. The animals were placed in metabolic cages to assess fluid intake and urine volume 1 and 4 weeks after inducing MI (male myocardial infarction (MMI) and female myocardial infarction (FMI) groups). They subsequently underwent echocardiographic evaluation and spectral analysis of heart rate variability. After completing each protocol, the animals were killed for postmortem evaluation and histology. The MMI group showed earlier and more intense cardiac morphological and functional changes than the FMI group, although the extent of MI did not differ between groups (P > 0.05). The MMI group showed higher sympathetic modulation and sodium and water retention than the FMI group (P < 0.05), which may partly explain both the echocardiographic and pathological findings. Females subjected to infarction seem to show attenuation of sympathetic modulation, more favourable fluid and electrolyte balances, and better preserved cardiac function compared to males subjected to the same infarction model. PMID- 26748815 TI - Ticagrelor in Triple Antithrombotic Therapy: Predictors of Ischemic and Bleeding Complications. AB - BACKGROUND: Patients on dual antiplatelet therapy following percutaneous coronary intervention often have indications for concurrent oral anticoagulation or triple antithrombotic therapy (TT). Although TT may decrease ischemic complications, it may confer increased bleeding risk. HYPOTHESIS: We hypothesize that the use of ticagrelor in TT is associated with higher risk of complications; accordingly, we sought to determine predictors of complications in patients on TT. METHODS: Patients discharged on TT after percutaneous coronary intervention were followed prospectively for 12 months. The primary endpoint was a composite of ischemic (death, myocardial infarction, stroke) and major bleeding complications or net adverse clinical event (NACE). A major secondary endpoint was BARC (Bleeding Academic Research Consortium) types 2, 3, or 5 bleeding. Outcomes were compared between ticagrelor- and clopidogrel-treated patients. Multivariable analyses were performed to elucidate predictors of complications. RESULTS: Twenty-seven of 152 patients discharged on TT were on ticagrelor. NACE occurred in 52% of patients and BARC 2, 3, or 5 bleeding occurred in 18%. There was no difference in the primary or secondary outcome between ticagrelor vs clopidogrel subgroup. On logistic regressions, use of TT in patients with acute coronary syndrome (P = 0.002) and bridging in with ticagrelor (P = 0.02) were associated with increased NACE. Low estimated glomerular filtration rate was an independent predictor of bleeding (P = 0.03). CONCLUSIONS: The risk of bleeding and ischemic complications among patients on TT is similar between those on ticagrelor and clopidogrel. However, caution with use of bridging anticoagulation should be taken when using ticagrelor. PMID- 26748817 TI - Influence of yeast strain, priming solution and temperature on beer bottle conditioning. AB - BACKGROUND: Recently, there has been a significant increase in the number of microbreweries. Usually, craft beers are bottle conditioned; however, few studies have investigated beer refermentation. One of the objectives of this study was to evaluate the impacts of different experimental conditions, specifically yeast strain, priming solution and temperature, on the standard quality attributes, the volatile compounds and the sensory profile of the bottle-conditioned beer. The other aim was to monitor the evolution of volatile compounds and amino acids consumption throughout the refermentation process to check if it is possible to reduce the time necessary for bottle conditioning. RESULTS: The results indicate that the volatile profile was mainly influenced by the strain of yeast, and this may have obscured the possible impacts of the other parameters. Our results also confirm that the two yeast strains showed different metabolic activity, particularly with respect to esters production. Moreover, we found the Safbrew S 33(r) strain when primed with Siromix(r) and refermented at 30 degrees C yielded the fastest formation of higher alcohols while maintaining low production of off flavours. CONCLUSIONS: These results suggest a formulation that may reduce the time needed for bottle conditioning without affecting the quality of the final beer which may simultaneously improve efficiency and economic profits. (c) 2016 Society of Chemical Industry. PMID- 26748818 TI - Catastrophic Antiphospholipid Syndrome Triggered by Fulminant Chikungunya Infection in a Patient With Systemic Lupus Erythematosus. PMID- 26748816 TI - Thyroid hormone reduces inflammatory cytokines improving glycaemia control in alloxan-induced diabetic wistar rats. AB - AIM: This study aimed at evaluating whether thyroid hormone treatment could improve glycaemia and insulin response in alloxan-induced diabetic rats by altering cytokine expression in the skeletal muscle and epididymal white adipose tissue (eWAT) as well as altering inflammatory cell infiltration in eWAT. METHODS: Diabetes mellitus (DM) was induced in male Wistar rats by alloxan injection, and a subset of the diabetic rats was treated with T3 (1.5 MUg per 100 g body weight) for a 28-day period (DT3 ). Cytokines were measured in serum (MILIplex assay kit) as well as in soleus and EDL skeletal muscles and eWAT by Western blotting. Thyroid function was evaluated by morphological, molecular and biochemical parameters. Cardiac function was assessed by measuring heart rate, blood pressure, maximal rate of pressure development (dp/dtmax ) and decline (dp/dtmin ) as well as the contractility index (CI). Sixty rats were used in the study. RESULTS: Diabetic rats exhibited decreased thyroid function and increased inflammatory cytokines in serum, soleus muscle and eWAT. T3 treatment decreased glycaemia and improved insulin sensitivity in diabetic animals. These alterations were accompanied by decreased TNF-alpha and IL-6 content in soleus muscle and eWAT, and inflammatory cell infiltration in eWAT. T3 treatment did not affect cardiac function of diabetic rats. CONCLUSIONS: The present data provide evidence that T3 treatment reduces glycaemia and improves insulin sensitivity in diabetic rats, and that at least part of this effect could result from its negative modulation of inflammatory cytokine expression. PMID- 26748819 TI - Purification and biochemical characterization of phytocystatin from Brassica alba. AB - Phytocystatins belong to the family of cysteine proteinases inhibitors. They are ubiquitously found in plants and carry out various significant physiological functions. These plant derived inhibitors are gaining wide consideration as potential candidate in engineering transgenic crops and in drug designing. Hence it is crucial to identify these inhibitors from various plant sources. In the present study a phytocystatin has been isolated and purified by a simple two-step procedure using ammonium sulfate saturation and gel filtration chromatography on Sephacryl S-100HR from Brassica alba seeds (yellow mustard seeds).The protein was purified to homogeneity with 60.3% yield and 180-fold of purification. The molecular mass of the mustard seed cystatin was estimated to be nearly 26,000 Da by sodium dodecyl sulfate polyacrylamide gel electrophoresis as well as by gel filtration chromatography. The stokes radius and diffusion coefficient of the mustard cystatin were found to be 23A degrees and 9.4 * 10(-7) cm(2) s(-1) respectively. The isolated phytocystatin was found to be stable in the pH range of 6-8 and is thermostable up to 60 degrees C. Kinetic analysis revealed that the phytocystatin exhibited non-competitive type of inhibition and inhibited papain more efficiently (K(i) = 3 * 10(-7) M) than ficin (K(i) = 6.6 * 10(-7) M) and bromelain (K(i) = 7.7 * 10(-7) M respectively). CD spectral analysis shows that it possesses 17.11% alpha helical content. PMID- 26748821 TI - Pleiotropy and the low cost of individual traits promote cooperation. AB - The evolution of cooperation is thought to be promoted by pleiotropy, whereby cooperative traits are coregulated with traits that are important for personal fitness. However, this hypothesis faces a key challenge: what happens if mutation targets a cooperative trait specifically rather than the pleiotropic regulator? Here, we explore this question with the bacterium Pseudomonas aeruginosa, which cooperatively digests complex proteins using elastase. We empirically measure and theoretically model the fate of two mutants--one missing the whole regulatory circuit behind elastase production and the other with only the elastase gene mutated--relative to the wild-type (WT). We first show that, when elastase is needed, neither of the mutants can grow if the WT is absent. And, consistent with previous findings, we show that regulatory gene mutants can grow faster than the WT when there are no pleiotropic costs. However, we find that mutants only lacking elastase production do not outcompete the WT, because the individual cooperative trait has a low cost. We argue that the intrinsic architecture of molecular networks makes pleiotropy an effective way to stabilize cooperative evolution. Although individual cooperative traits experience loss-of-function mutations, these mutations may result in weak benefits, and need not undermine the protection from pleiotropy. PMID- 26748820 TI - Recent Strategies in Tissue Engineering for Guided Peripheral Nerve Regeneration. AB - The repair of large crushed or sectioned segments of peripheral nerves remains a challenge in regenerative medicine due to the complexity of the biological environment and the lack of proper biomaterials and architecture to foster reconstruction. Traditionally such reconstruction is only achieved by using fresh human tissue as a surrogate for the absence of the nerve. However, recent focus in the field has been on new polymer structures and specific biofunctionalization to achieve the goal of peripheral nerve regeneration by developing artificial nerve prostheses. This review presents various tested approaches as well their effectiveness for nerve regrowth and functional recovery. PMID- 26748822 TI - Pneumatosis intestinalis with cyst perforation. PMID- 26748824 TI - Investigation on the interaction between isorhamnetin and bovine liver catalase by spectroscopic techniques under different pH conditions. AB - The binding of isorhamnetin to bovine liver catalase (BLC) was first investigated at 302, 310 and 318 K at pH 7.4 using spectroscopic methods including fluorescence spectra, circular dichroism (CD) and UV-vis absorption. Spectrophotometric observations are rationalized mainly in terms of a static quenching process. The binding constants and binding sites were evaluated by fluorescence quenching methods. Enzymatic activity of BLC in the absence and presence of isorhamnetin was measured using a UV/vis spectrophotometer. The result revealed that the binding of isorhamnetin to BLC led to a reduction in the activity of BLC. The positive entropy change and enthalpy change indicated that the interaction of isorhamnetin with BLC was mainly driven by hydrophobic forces. The distance r between the donor (BLC) and acceptor (isorhamnetin) was estimated to be 2.99 nm according to fluorescence resonance energy transfer. Fluorescence, synchronous fluorescence, and CD spectra showed no obvious change in the conformation of BLC upon the binding of isorhamnetin. In addition, the influence of pH on the binding of isorhamnetin to BLC was investigated and the binding ability of the drug to BLC deceased under other pH conditions (pH 9.0, 6.5, 5.0, 3.5, or 2.0) as compared with that at pH 7.4. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26748823 TI - The well-being of laboratory non-human primates. AB - The well-being of non-human primates in captivity is of joint concern to scientists, veterinarians, colony managers, caretakers, and researchers working with non-human primates in biomedical research. With increased regulatory, accreditation, and research focus on optimizing the use of social housing for laboratory primates, as well as the advent of techniques to assess indices of chronic stress and related measures of well-being, there is no better time to present the most current advances in the field of non-human primate behavioral management. The collective body of research presented here was inspired in part by a 2014 symposium entitled, "Chronic Hormones and Demographic Variables: Center Wide Studies on Non-Human Primate Well-Being" held at the American Society of Primatologists' 37th Annual Meeting in Decatur, GA. By aiming to target readership with scientific and/or management oversight of captive primate behavioral management programs, this special issue provides badly-needed guidance for implementing social housing programs in a research environment and leverages collaboration across multiple facilities to address key components of behavioral management, explore refinements in how well-being can be measured, and identify the interrelationships between varying indices. Am. J. Primatol. 79:e22520, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26748825 TI - Does the Clinical Context Improve the Reliability of Rheumatologists Grading Digital Ulcers in Systemic Sclerosis? AB - OBJECTIVE: Digital ulcers (DUs) are often a primary end point in systemic sclerosis (SSc; scleroderma) clinical trials, although the reliability of rheumatologists grading DUs is poor to moderate at best. DU assessment in recent trials has been based upon visual inspection alone, which potentially misses "real-world" clinical contextual information. Our aim was to investigate whether this clinical information improves the reliability of rheumatologists grading DUs. A secondary aim was to assess agreement between patients and rheumatologists. METHODS: Eighty images of a range of digital lesions were collected from patients with SSc with the clinical context: pain (severity and temporal relationship), lesion duration, and discharge (patient reported and clinician observed). Raters received all images either with or without the clinical context, and graded these images (using a custom-built interface) on an ordinal scale of severity: no ulcer, inactive ulcer, or active ulcer. Patients also graded their lesion(s) on the same scale. RESULTS: Fifty-one rheumatologists from 15 countries completed the study (26 without and 25 with context): 4,590 (including 510 repeated) image gradings were obtained. Context did not significantly increase (without and with context) either intra- (0.64, 0.71) or interrater (0.32, 0.36) reliability. Pain (visual analog scale and temporal relationship) and discharge (patient reported and clinician observed) were associated with increased lesion severity, and duration with reduced severity. Agreement between individual patients and rheumatologists was poor without and with context (0.19, 0.28). CONCLUSION: The overall intra- and interrater reliability of DU grading did not significantly improve with the clinical context. Agreement between patients and rheumatologists was poor. PMID- 26748826 TI - Reply. PMID- 26748827 TI - MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Stemness-Promoting Chromatin Modifications Independent of p53. AB - The MDM2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53 independent functions. Here we report that MDM2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the absence of p53. Similarly, MDM2 depletion in the context of p53 deficiency also promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the MDM2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. MDM2 physically associated with EZH2 on chromatin, enhancing the trimethylation of histone 3 at lysine 27 and the ubiquitination of histone 2A at lysine 119 (H2AK119) at its target genes. Removing MDM2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. In conclusion, MDM2 supports the Polycomb-mediated repression of lineage-specific genes, independent of p53. PMID- 26748829 TI - Is the change in body mass index among children newly diagnosed with type 1 diabetes mellitus associated with obesity at transition from pediatric to adult care? AB - BACKGROUND: Insulin therapy is lifesaving treatment for individuals with type 1 diabetes (T1D). Its initiation maybe associated with significant weight gain because of change from a catabolic to an anabolic state. Excessive weight-gain increases the risk of obesity and is associated with chronic disease. OBJECTIVE: To examine if change in body mass index (BMI) among children in the 6 months after diagnosis with type 1 diabetes mellitus is associated with long-term obesity. METHODS: This was a population-based retrospective study of 377 children (aged 2-18 yr) with type 1 diabetes. Measured heights and weights were used to calculate BMI z-scores based on Centers for Disease Control and Prevention (CDC) cut-points. Generalized Linear Models using BMI group, and age group at diagnosis; postdiagnosis weight change; and sex were applied to assess associations between postdiagnosis weight change and BMI z-score at transition to adult care. RESULTS: Mean BMI z-score increased from 0.28 at diagnosis, to 0.53 at 6 months and 0.66 at transition to adult care. Change in BMI z-scores differed by initial BMI group and magnitude of postdiagnosis weight change. Younger children (<11 yr) had higher (p = 0.004) BMI z-scores at diagnosis but not at last visit (p = 0.1) than older (>=11 yr) children at diagnosis. BMI z-score at diagnosis, postdiagnosis weight change, female sex, and longer duration with TID were associated with higher BMI z-score at time of transition. CONCLUSIONS: BMI z score at diagnosis was the strongest predictor of BMI z-score at time of transition to adult care, however; its effect was mediated by magnitude of weight change 6 months after diagnosis, sex, and age group at diagnosis. PMID- 26748830 TI - Galapagos land iguana (Conolophus subcristatus) as a seed disperser. AB - The role of the most common land iguana (Conolophus subcristatus) in the Galapagos Islands as an effective seed disperser is explored in this study. A total of 5705 seeds of 32 plant species were identified from 160 scats, 4545 of which (80%) appeared visually undamaged. Germination trials of 849 seeds from 29 species revealed that at least 10 species remained viable after passing through the iguana's gut, although only a small proportion of those seeds (4%) germinated. In any case, we argue that C. subcristatus exerts an important role on the 7 Galapagos islands where it occurs because of its abundance and capacity to ingest and disperse seeds at long distances. Our results strongly suggest that the Galapagos C. subcristatus plays an important role as a seed disperser of not only of native species but also some introduced plants in the Galapagos Islands. PMID- 26748828 TI - Targeting BRCA1 and BRCA2 Deficiencies with G-Quadruplex-Interacting Compounds. AB - G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers. Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double strand breaks (DSBs) arising at collapsed forks. We have previously shown that HR facilitates telomere replication. Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR. Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability. Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency. PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7. Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition. PMID- 26748831 TI - Effect of poly (lactide-co-glycolide) (PLGA)-coated beta-tricalcium phosphate on the healing of rat calvarial bone defects: a comparative study with pure-phase beta-tricalcium phosphate. AB - OBJECTIVES: To investigate the effect of poly (lactide-co-glycolide) (PLGA) coated beta-tricalcium phosphate (TCP) as a scaffold on bone regeneration in rat calvaria. MATERIAL AND METHODS: Bilateral critical-sized defects were created in the calvaria of 20 Sprague Dawley rats. Defects of each rat were filled with pure phase beta-TCP or PLGA/beta-TCP, or left as unfilled control. The healing was evaluated by micro-computed tomography, histological, and immunohistochemical analyses. Tartrate-resistant acid phosphatase (TRAP) staining was also performed to assess the resorption activity. RESULTS: At 4 weeks, ingrowth of cells from the surrounding tissue into the beta-TCP and PLGA/beta-TCP biomaterials were observed in the defect area, and new bone formation had started. At 6 weeks, the value for defect closure in the beta-TCP group was significantly greater than that in the unfilled control (P < 0.01). A significantly greater level of new bone formation was found in the beta-TCP group (P < 0.01) and PLGA/beta-TCP group (P < 0.05) than that in the control group, while no significant difference was found between the beta-TCP and PLGA/beta-TCP groups. At both time points, the height of new tissue/biomaterial in the central third of the defect was significantly increased when the beta-TCP or PLGA/beta-TCP was used. Proliferating cell nuclear antigen -positive cells were observed around and inside the beta-TCP or PLGA/beta-TCP, and TRAP-positive cells were found at the surface of the biomaterials, suggesting that remodeling was occurring. CONCLUSION: The application of PLGA-coated beta-TCP could promote bone regeneration to similar extent as the beta-TCP biomaterial in this in vivo model. PMID- 26748832 TI - Lewy body pathology involves the olfactory cells in Parkinson's disease and related disorders. AB - BACKGROUND: The "dual-hit" and propagation hypotheses of alpha-synuclein suggests that the olfactory cells of the olfactory epithelium are among the earliest sites of involvement in Parkinson's disease (PD). We investigated the olfactory epithelium in consecutive cases that had been registered with a brain bank. OBJECTIVES: This study was undertaken to check the presence or absence of Lewy body pathology in olfactory cells. METHODS: Thirty-six male and 11 female patients were examined, including eight with PD, two with dementia with Lewy bodies, 11 with incidental Lewy body disease, and 26 with no Lewy-related alpha synucleinopathy. The olfactory epithelium was sampled by craniotomy followed by resection of the cribriform plate, which was fixed in formalin and decalcified with ethylenediaminetetra-acetate. Coronal paraffin-embedded sections of the plate were stained with hematoxylin and eosin or immunohistochemically stained with antibodies against phosphorylated alpha-synuclein to detect Lewy body pathology and neuronal markers of protein gene product 9.5, phosphorylated neurofilament, and tyrosine hydroxylase. RESULTS: Lewy body pathology was detected in the olfactory cells of the olfactory epithelium in a single patient with incidental Lewy body disease and in six patients with PD, but it was not detected in patients who had dementia with Lewy bodies. CONCLUSIONS: We detected Lewy body pathology in the olfactory epithelium in six of the eight patients with Parkinson's disease and in one patient with incidental Lewy body pathology. PMID- 26748835 TI - Molecularly Dispersed Donors in Acceptor Molecular Crystals for Photon Upconversion under Low Excitation Intensity. AB - For real-world applications of photon upconversion based on the triplet-triplet annihilation (TTA-UC), it is imperative to develop solid-state TTA-UC systems that work effectively under low excitation power comparable to solar irradiance. As an approach in this direction, aromatic crystals showing high triplet diffusivity are expected to serve as a useful platform. However, donor molecules inevitably tend to segregate from the host acceptor crystals, and this inhomogeneity results in the disappointing performance of crystalline state TTA UC. In this work, a series of cast-film-forming acceptors was developed, which provide both regular acceptor alignment and soft domains of alkyl chains that accommodate donor molecules without segregation. A typical triplet sensitizer, PtII octaethylporphyrin (PtOEP), was dispersed in these acceptor crystals without aggregation. As a result, efficient triplet energy transfer from the donor to the acceptor and diffusion of triplet excitons among regularly aligned anthracene chromophores occurred. It resulted in TTA-UC emission at low excitation intensities, comparable to solar irradiance. PMID- 26748833 TI - Effectiveness of bevacizumab exposure beyond disease progression in patients with non-small-cell lung cancer: analyses of the ARIES observational cohort study. AB - PURPOSE: Bevacizumab used in combination with first-line chemotherapy confers an overall survival (OS) benefit for patients with non-squamous non-small-cell lung cancer (NSCLC). This analysis from the ARIES observational cohort study (OCS) was initiated to evaluate the effect of bevacizumab use beyond disease progression (BBP) on clinical outcomes in patients with NSCLC receiving first-line treatment with bevacizumab and chemotherapy. METHODS: The ARIES OCS prospectively enrolled patients from 2006 to 2009 in the United States who had advanced non-squamous NSCLC, received bevacizumab with chemotherapy in the first-line setting, and survived progressive disease (PD). A dichotomous landmark analysis examined post PD OS (ppOS) in patients who received BBP versus no BBP within 30 days post PD. A time-dependent Cox model assessed the effect of cumulative BBP exposure on ppOS. RESULTS: The ARIES OCS enrolled 1967 patients with first-line NSCLC; 1358 patients had first PD and were alive at the 30-day landmark (351 patients with BBP and 1007 patients with no BBP). The landmark analysis showed that BBP was associated with a lower risk of death (BBP versus No-BBP); hazard ratio [HR], 0.75; 95% confidence interval 0.65-0.86. In the cumulative exposure analysis of 1461 patients who had PD, HRs for ppOS decreased by approximately 4% for each additional 21-day interval of bevacizumab received. Protocol-specified bevacizumab-select adverse events occurred in 14% of BBP patients. CONCLUSIONS: BBP was associated with a lower risk of death in patients with NSCLC treated with first-line bevacizumab and chemotherapy. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26748834 TI - Effect of preheating and shade on surface microhardness of silorane-based composites. AB - AIM: The aim of the present study was to evaluate the effect of preheating and shade on the surface microhardness of silorane-based composites. METHODS: Three shades of two different types of composites were evaluated: a silorane-based composite and a methacrylate-based composite. The composites were tested at 23 degrees C, and after preheating at 55 degrees C. Five specimens were prepared for each experimental group. The top surface of the specimens was irradiated for 20 s using an LED unit. Vickers microhardness test was used to evaluate both top and bottom surfaces of the specimens, followed by 24-h storage in the dark. Statistical analysis was performed using one-way anova and Tukey's post-hoc test at a level of significance of alpha = 0.05. RESULTS: There was a significant rise in microhardness as the temperature increased from 23 to 55 degrees C for both the top and bottom surfaces of the tested composites (P < 0.05). The C2 shade of both composites exhibited the lowest microhardness (P < 0.05), while the A2 and A3 shades did not show significant differences compared to each other (P > 0.05) Filtek Silorane presented significantly lower microhardness than Filtek Z250 (P < 0.05), regardless of the temperature, shade, or depth of measurement. CONCLUSIONS: Preheating, shade, and composition of the tested composite resins affected their surface microhardness. PMID- 26748836 TI - Combined autologous platelet-rich plasma with microneedling verses microneedling with distilled water in the treatment of atrophic acne scars: a concurrent split face study. AB - BACKGROUND: Acne scarring causes cosmetic discomfort, depression, low self-esteem and reduced quality of life. Microneedling is an established treatment for scars, although the efficacy of platelet-rich plasma (PRP) has not been explored much. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of platelet-rich plasma (PRP) combined with microneedling for the treatment of atrophic acne scars. METHODS: Fifty patients of 17-32 years of age with atrophic acne scars were enrolled. Microneedling was performed on both halves of the face. Intradermal injections as well as topical application of PRP was given on right half of the face, while the left half of the face was treated with intradermal administration of distilled water. Three treatment sessions were given at an interval of 1 month consecutively. Goodman's Quantitative scale and Quantitative scale were used for the final evaluation of results. RESULTS: Right and left halves showed 62.20% and 45.84% improvement, respectively, on Goodman's Quantitative scale. Goodman's Qualitative scale showed excellent response in 20 (40%) patients and good response in 30 (60%) patients over right half of the face, while the left half of the face showed excellent response in 5 (10%) patients, good response in 42 (6%) patients and poor response in three patients. CONCLUSION: We conclude that PRP has efficacy in the management of atrophic acne scars. It can be combined with microneedling to enhance the final clinical outcomes in comparison with microneedling alone. PMID- 26748837 TI - Fast synthesis and bioconjugation of (68) Ga core-doped extremely small iron oxide nanoparticles for PET/MR imaging. AB - Combination of complementary imaging techniques, like hybrid PET/MRI, allows protocols to be developed that exploit the best features of both. In order to get the best of these combinations the use of dual probes is highly desirable. On this sense the combination of biocompatible iron oxide nanoparticles and 68Ga isotope is a powerful development for the new generation of hybrid systems and multimodality approaches. Our objective was the synthesis and application of a chelator-free 68Ga-iron oxide nanotracer with improved stability, radiolabeling yield and in vivo performance in dual PET/MRI. We carried out the core doping of iron oxide nanoparticles, without the use of any chelator, by a microwave-driven protocol. The synthesis allowed the production of extremely small (2.5 nm) 68Ga core-doped iron oxide nanoparticles. The microwave approach allowed an extremely fast synthesis with a 90% radiolabeling yield and T1 contrast in MRI. With the same microwave approach the nano-radiotracer was functionalized in a fast and efficient way. We finally evaluated these dual targeting nanoparticles in an angiogenesis murine model by PET/MR imaging. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26748838 TI - An Individual's Rate of Forgetting is Stable Over Time but Differs Across Materials. AB - One of the goals of computerized tutoring systems is to optimize the learning of facts. Over a hundred years of declarative memory research have identified two robust effects that can improve such systems: the spacing and the testing effect. By making optimal use of both and adjusting the system to the individual learner using cognitive models based on declarative memory theories, such systems consistently outperform traditional methods (Van Rijn, Van Maanen, & Van Woudenberg, 2009). This adjustment process is driven by a continuously updated estimate of the rate of forgetting for each item and learner on the basis of the learner's accuracy and response time. In this study, we investigated to what extent these estimates of individual rates of forgetting are stable over time and across different materials. We demonstrate that they are stable over time but not across materials. Even though most theories of human declarative memory assume a single underlying rate of forgetting, we show that, in practice, it makes sense to assume different materials are forgotten at different rates. If a computerized, adaptive fact-learning system allowed different rates of forgetting for different materials, it could adapt to individual learners more readily. PMID- 26748839 TI - Effectiveness of color intensity analysis using updated autofluorescence imaging systems for serrated lesions. AB - BACKGROUND AND AIM: We previously reported the effectiveness of color intensity analysis using autofluorescence imaging (AFI) for differentiating colorectal neoplastic lesions from non-neoplastic lesions. However, the ability of AFI systems for differentiating serrated lesions has not been evaluated. In the present study, we assessed the effectiveness of color intensity analysis using updated AFI systems for evaluating serrated lesions. METHODS: We retrospectively reviewed the data for 48 consecutive patients with 87 serrated lesions that were examined using updated AFI systems and resected at Jikei University Hospital. The mean green/red (G/R) ratio, which is obtained by dividing the mean green color intensities by the mean red color intensities, was calculated for each serrated lesion and compared between hyperplastic polyps, sessile serrated adenomas/polyps (SSA/P) with cytological dysplasia, and SSA/P without cytological dysplasia. We also assessed the area under the receiver operating characteristic curve (AUC) for determining SSA/P (both with and without cytological dysplasia) and SSA/P with cytological dysplasia. RESULTS: The AUC for determining SSA/P was 0.68; however, the AUC for determining SSA/P with cytological dysplasia was 0.97. With a cut-off for the G/R ratio of <0.93, the sensitivity, specificity, positive predictive value, and negative predictive value for SSA/P with cytological dysplasia were 95.5%, 91.0%, 77.8%, and 98.3%, respectively. CONCLUSION: Color intensity analysis of serrated lesions using updated AFI systems could effectively distinguish SSA/P with cytological dysplasia from hyperplastic polyps and SSA/P without cytological dysplasia. PMID- 26748842 TI - Voiding urosonography with second-generation contrast as a main tool for examining the upper and lower urinary tract in children. Pilot Study. AB - INTRODUCTION: In this series, we analyse the diagnostic efficacy of serial voiding urosonography (VUS) with second-generation contrast, combined harmoniously and specifically with contrast technology, in the examination of the urinary tract in children. This examination includes the diagnosis and follow-up for vesicoureteral reflux (VUR) and urethral disorders, mainly those of the posterior urethral valve (PUV). PATIENTS AND METHODS: After obtaining informed consent, a prospective study was conducted using urosonography with second generation contrast (sulphur hexafluoride microbubbles, SonoVue(r)) from November 2014 to October 2015 (1 year) in paediatric patients with suspected VUR or PUV impairment. For patients with a high suspicion of VUR and in cases of PUV, we also conducted simultaneous voiding cystourethrography (VCUG). RESULTS: We studied 40 patients (80 renal units) between the ages of 2 months and 13 years (median age, 14 months). The indication for the test was a suspected VUR (36 patients, group A) and PUV follow-up (4 patients, group B). The test was correlated with VCUG in 16 patients (12 cases with high suspicion of VUR in group A and with 4 cases of PUV in group B). The visualisation of the urethra was appropriate in cases of dilation or urethral stricture. For 3 of these patients with bilateral VUR demonstrated in the serial VUS, the VCUG showed only unilateral VUR in 2 of the patients and no VUR in 1 of the patients (kappa=.73). DISCUSSION: We have shown that the visualisation of the urethra is no longer a limitation and that serial VUS can be superior to conventional VCUG in diagnosing VUR. PMID- 26748843 TI - Microcytic carcinoma of the urinary bladder: Experience over 22 years. AB - INTRODUCTION: Microcytic carcinoma of the urinary bladder or bladder Small Cell Carcinoma (SCC) is a rare entity, characterised by an aggressive behaviour, with a poor prognosis, elevated metastatic potential, and is commonly found in older patients and in advanced disease stages. Here we present our experiences with the behaviour of the disease and the treatments applied. MATERIAL AND METHOD: This was a retrospective study on patients diagnosed with bladder SCC in our hospital between February 1992 and February 2014. We analysed the demographic and clinical characteristics of the tumour, the applied treatments and survival. We performed a descriptive statistical analysis of the median follow-up time, Overall Survival (OS) and Cancer-Specific Survival (CSS), using the SPSS statistical package v. 15.0. RESULTS: Over 22 years, 20 patients with an average age of 75 years were diagnosed with bladder SCC (2 female). The predominant symptom was macroscopic haematuria (75%). After the first transurethral resection (TUR) of the bladder and the histological diagnosis, 35% (7 patients) did not receive additional treatment, 15% (3 patients) were treated with chemoradiotherapy (CRT), 10% (2 patients) with TUR, 15% (3 patients) with chemotherapy (QT), 5% (1 patient) with TUR associated to CRT, 5% (1 patient) with radical surgery, 5% (1 patient) with radical surgery treatment followed by adjuvant CRT, 5% (1 patient) with palliative surgery (hypogastric arteriae ligation) followed by adjuvant QT and 5% (1 patient) with hemostatic radiotherapy (RT). With a median follow-up time of 13.8 months, the OS was 14.48 months (95% CI: 6.22 - 22.75) and the CSS 18.04 months (95% CI: 6.51-29.57). Only 10% (2 patients) survived till the end of the study. CONCLUSION: Microcytic carcinoma of the urinary bladder is a rare and aggressive entity commonly diagnosed in males of advanced age and in advanced disease stages. It has a poor prognosis and reduced survival. Due to its aggressiveness previous to the initial diagnosis, a cystectomy is only possible in very few cases; therefore multimodal treatment is necessary. This treatment is yet to be defined. PMID- 26748844 TI - Statins may be associated with six-week diabetic foot ulcer healing. AB - Diabetic foot ulcers (DFUs) affect 1.5 million Americans annually, of which only a minority heal with standard care, and they commonly lead to amputation. To improve care, investigations are underway to better understand DFU pathogenesis and develop more effective therapies. Some currently used medications may improve healing. One small, randomized clinical trial found statins improve DFU healing. In this secondary analysis of a large multisite prospective observational cohort of 139 patients with DFUs receiving standard care, we investigated whether there was an association between 6-week DFU wound size reduction and use of a variety of medications including alpha-blockers, beta-blockers, angiotensin converting enzyme inhibitors (ACEi) and statins. We found no significant (p < 0.05) association between six-week wound reduction and use of any of the evaluated drugs; however, statins did trend toward an association (p = 0.057). This suggests a potential benefit of statins on DFU healing, and larger, targeted studies are warranted. PMID- 26748846 TI - Selective serotonin re-uptake inhibitor use during pregnancy: association with offspring birth size and gestational age. AB - BACKGROUND: Depression around the time of pregnancy affects at least 1 in 8 women and treatment with selective serotonin re-uptake inhibitors (SSRIs) in pregnant women has been increasing, but research on adverse effects on the fetus have so far commonly used designs unable to account for confounding. We aimed to examine the effects of prenatal SSRI exposure on offspring size outcomes and gestational age, and disentangle whether associations observed were due to the medication or other factors. METHODS: We used a Swedish population-based cohort of 392,029 children and national registers to estimate the associations between prenatal exposure to SSRIs and depression on the outcomes birthweight, birth length, birth head circumference, gestational age at birth and preterm birth. A sub-sample of 1007 children was analysed in a within-family design that accounts for unmeasured parental genetic and environmental confounders. RESULTS: Crude analyses revealed associations between prenatal SSRI exposure, and offspring birth size and gestational age. However, in the within-family analyses, only the association between SSRI exposure and reduced gestational age (-2.3 days; 95% confidence interval -3.8 to -0.8) was observed. CONCLUSIONS: This study indicates that prenatal SSRI exposure may not be causally related to offspring birth size. Rather, our analyses suggest that the association could be caused by other underlying differences instead of the medication per se. A small reduction of gestational age was associated with SSRI exposure in the within-family analysis and could be due to either the exposure, or other factors changing between pregnancies. PMID- 26748845 TI - Parental smoking during pregnancy and the risk of gestational diabetes in the daughter. AB - BACKGROUND: Fetal exposure to parental smoking may have long-term impact on the development of disease in adulthood. We examined the association of parental smoking during pregnancy with risk of gestational diabetes mellitus (GDM) in the daughter. METHODS: We included 15,665 singleton pregnancies from 10,152 women in the Nurses' Health Study II cohort whose mothers participated in the Nurses' Mothers' Cohort Study. Data on maternal and paternal smoking during pregnancy and associated covariates were recalled by the mothers. GDM diagnosis was self reported by the daughters and was validated by medical record review in a previous study. We used log-binomial models with generalized estimating equations to estimate relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: We observed a positive association between maternal heavy smoking during pregnancy and risk of GDM in the daughter. The multivariable-adjusted RRs (95% CIs) of GDM among women whose mothers did not smoke during pregnancy, continued smoking 1-14, 15-24, and >= 25 cigarettes/day were 1.00 (reference), 1.05 (0.81-1.35), 1.27 (0.95-1.70) and 1.98 (1.18-3.30), respectively (P for trend = 0.01). Further adjustment for the women's perinatal variables, adult-life characteristics and body mass index during various periods of life modestly attenuated the association. No association was observed between paternal smoking during the pregnancy period and risk of GDM in the daughter. CONCLUSIONS: Maternal heavy smoking (>= 25 cigarettes/day) during pregnancy was associated with higher risk of gestational diabetes in the daughter. Further studies are warranted to confirm our findings and to elucidate the underlying mechanisms. PMID- 26748847 TI - Multiple liver adenomatosis with (18)F-FDG uptake: A rare manifestation of an infrequent entity. PMID- 26748849 TI - An Enantiornithine with a Fan-Shaped Tail, and the Evolution of the Rectricial Complex in Early Birds. AB - The most basal avians Archaeopteryx and Jeholornis have elongate reptilian tails. However, all other birds (Pygostylia) have an abbreviated tail that ends in a fused element called the pygostyle. In extant birds, this is typically associated with a fleshy structure called the rectricial bulb that secures the tail feathers (rectrices) [1]. The bulbi rectricium muscle controls the spread of the rectrices during flight. This ability to manipulate tail shape greatly increases flight function [2, 3]. The Jehol avifauna preserves the earliest known pygostylians and a diversity of rectrices. However, no fossil directly elucidates this important skeletal transition. Differences in plumage and pygostyle morphology between clades of Early Cretaceous birds led to the hypothesis that rectricial bulbs co evolved with the plough-shaped pygostyle of the Ornithuromorpha [4]. A newly discovered pengornithid, Chiappeavis magnapremaxillo gen. et sp. nov., preserves strong evidence that enantiornithines possessed aerodynamic rectricial fans. The consistent co-occurrence of short pygostyle morphology with clear aerodynamic tail fans in the Ornithuromorpha, the Sapeornithiformes, and now the Pengornithidae strongly supports inferences that these features co-evolved with the rectricial bulbs as a "rectricial complex." Most parsimoniously, rectricial bulbs are plesiomorphic to Pygostylia and were lost in confuciusornithiforms and some enantiornithines, although morphological differences suggest three independent origins. PMID- 26748848 TI - A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas. AB - Half of all human cancers lose p53 function by missense mutations, with an unknown fraction of these containing p53 in a self-aggregated amyloid-like state. Here we show that a cell-penetrating peptide, ReACp53, designed to inhibit p53 amyloid formation, rescues p53 function in cancer cell lines and in organoids derived from high-grade serous ovarian carcinomas (HGSOC), an aggressive cancer characterized by ubiquitous p53 mutations. Rescued p53 behaves similarly to its wild-type counterpart in regulating target genes, reducing cell proliferation and increasing cell death. Intraperitoneal administration decreases tumor proliferation and shrinks xenografts in vivo. Our data show the effectiveness of targeting a specific aggregation defect of p53 and its potential applicability to HGSOCs. PMID- 26748850 TI - Genomic Evidence Establishes Anatolia as the Source of the European Neolithic Gene Pool. AB - Anatolia and the Near East have long been recognized as the epicenter of the Neolithic expansion through archaeological evidence. Recent archaeogenetic studies on Neolithic European human remains have shown that the Neolithic expansion in Europe was driven westward and northward by migration from a supposed Near Eastern origin [1-5]. However, this expansion and the establishment of numerous culture complexes in the Aegean and Balkans did not occur until 8,500 before present (BP), over 2,000 years after the initial settlements in the Neolithic core area [6-9]. We present ancient genome-wide sequence data from 6,700-year-old human remains excavated from a Neolithic context in Kumtepe, located in northwestern Anatolia near the well-known (and younger) site Troy [10]. Kumtepe is one of the settlements that emerged around 7,000 BP, after the initial expansion wave brought Neolithic practices to Europe. We show that this individual displays genetic similarities to the early European Neolithic gene pool and modern-day Sardinians, as well as a genetic affinity to modern-day populations from the Near East and the Caucasus. Furthermore, modern-day Anatolians carry signatures of several admixture events from different populations that have diluted this early Neolithic farmer component, explaining why modern-day Sardinian populations, instead of modern-day Anatolian populations, are genetically more similar to the people that drove the Neolithic expansion into Europe. Anatolia's central geographic location appears to have served as a connecting point, allowing a complex contact network with other areas of the Near East and Europe throughout, and after, the Neolithic. PMID- 26748851 TI - Transcriptional Memory in the Drosophila Embryo. AB - Transmission of active transcriptional states from mother to daughter cells has the potential to foster precision in the gene expression programs underlying development. Such transcriptional memory has been specifically proposed to promote rapid reactivation of complex gene expression profiles after successive mitoses in Drosophila development [1]. By monitoring transcription in living Drosophila embryos, we provide the first evidence for transcriptional memory in animal development. We specifically monitored the activities of stochastically expressed transgenes in order to distinguish active and inactive mother cells and the behaviors of their daughter nuclei after mitosis. Quantitative analyses reveal that there is a 4-fold higher probability for rapid reactivation after mitosis when the mother experienced transcription. Moreover, memory nuclei activate transcription twice as fast as neighboring inactive mothers, thus leading to augmented levels of gene expression. We propose that transcriptional memory is a mechanism of precision, which helps coordinate gene activity during embryogenesis. PMID- 26748853 TI - USP9X Controls EGFR Fate by Deubiquitinating the Endocytic Adaptor Eps15. AB - Following activation by its cognate ligand(s), the epidermal growth factor receptor (EGFR) is rapidly routed to the lysosome for degradation in a ubiquitination-dependent fashion. This pathway represents the major mechanism of long-term attenuation of EGFR signaling, and its deregulation is a significant feature in different types of cancers. Here we demonstrate, through a systematic RNAi-based approach, that several deubiquitinating (DUB) enzymes extend or decrease EGFR half-life upon EGF stimulation. We focus on USP9X, whose depletion severely affects EGFR turnover, interfering with its internalization and trafficking. We identify the endocytic protein Eps15 as one of the critical substrates of USP9X, and we map the Eps15 ubiquitination sites. We found that Eps15 monoubiquitination occurs already at minimal dose of EGF stimulation and is essential for EGFR internalization. Overall, our findings identify USP9X as a novel regulator of EGFR endocytosis and suggest a model whereby cycles of ubiquitination and deubiquitination events on endocytic accessory proteins may regulate the internalization and trafficking of the EGFR toward the lysosomes. PMID- 26748852 TI - Evidence that Environmental Heterogeneity Maintains a Detoxifying Enzyme Polymorphism in Drosophila melanogaster. AB - Environmental heterogeneity is thought to be an important process maintaining genetic variation in populations [1-4]: if alternative alleles are favored in different environments, a stable polymorphism can be maintained [1, 5, 6]. This situation has been hypothesized to occur in genes encoding multi-substrate enzymes [7], in which changes that increase activity with one substrate typically decrease activity with others [8-10], but examples of polymorphisms maintained by this mechanism are rare. Here, we present evidence that a polymorphism in an enzyme gene in Drosophila melanogaster is maintained by such a trade-off. The mitochondrially localized aldehyde dehydrogenase in D. melanogaster has two important functions: detoxifying acetaldehyde derived from dietary ethanol [11] and detoxifying larger aldehydes produced as byproducts of oxidative phosphorylation [12]. A derived variant of the enzyme, Leu479Phe, is present in moderate frequencies in most temperate populations but is rare in more ethanol averse tropical populations. Using purified recombinant protein, we show that the Leu-Phe substitution increases turnover rate of acetaldehyde but decreases turnover rate of larger aldehydes. Furthermore, using transgenic fly lines, we show that the substitution increases lifetime fitness on medium supplemented with an ecologically relevant ethanol concentration but decreases fitness on medium lacking ethanol. The strong, opposing selection pressures, coupled with documented highly variable ethanol concentrations in breeding sites of temperate populations, implicate an essential role for environmental heterogeneity in maintaining the polymorphism. PMID- 26748854 TI - Shining a Light on Exploitative Host Control in a Photosynthetic Endosymbiosis. AB - Endosymbiosis allows hosts to acquire new functional traits such that the combined host and endosymbiont can exploit vacant ecological niches and occupy novel environments [1, 2]; consequently, endosymbiosis affects the structure and function of ecosystems [3, 4]. However, for many endosymbioses, it is unknown whether their evolutionary basis is mutualism or exploitation [5-9]. We estimated the fitness consequences of symbiosis using the interaction between the protist host Paramecium bursaria and the algal symbiont Chlorella sp. [10]. Host fitness was strongly context dependent: whereas hosts benefited from symbiosis at high light intensity, carrying endosymbionts was costly to hosts in the dark and conferred no benefit over growing autonomously at intermediate light levels. Autonomous Chlorella densities increased monotonically with light intensity, whereas per-host symbiont load and symbiont abundance peaked at intermediate light levels and were lowest at high light intensity. This suggests that hosts controlled the costs of symbiosis by manipulating symbiont load according to light intensity. Photosynthetic efficiency was consistently lower for symbiotic compared to autonomous algae, suggesting nutritional constraints upon algae in symbiosis. At intermediate light levels, we observed the establishment of small populations of free-living algae alongside the hosts with endosymbionts, suggesting that symbionts could escape symbiosis, but only under conditions where hosts didn't benefit from symbiosis. Together, these data suggest that hosts exerted strong control over endosymbionts and that there were no conditions where this nutritional symbiosis was mutually beneficial. Our findings support theoretical predictions (e.g., [5, 9]) that controlled exploitation is an important evolutionary pathway toward stable endosymbiosis. PMID- 26748855 TI - Seedlings Transduce the Depth and Mechanical Pressure of Covering Soil Using COP1 and Ethylene to Regulate EBF1/EBF2 for Soil Emergence. AB - The survival of seed plants in natural environments requires the successful emergence from the soil. In this process, the ethylene signaling pathway is utilized by plants to sense and respond to the mechanical resistance of the soil. Here, we report that constitutive photomorphogenesis 1 (COP1), a central repressor of light signaling, is a key component required for seedlings to sense the depth of soil overlay. Mutation in COP1 causes severe defects in penetrating soil, due to decreased level of EIN3, a master transcription factor in ethylene pathway that mediates seedling emergence. We show that COP1 directly targets the F box proteins EBF1 and EBF2 for ubiquitination and degradation, thus stabilizing EIN3. As seedlings grow toward the surface, the depth of soil overlay decreases, resulting in a gradual increase of light fluences. COP1 channels the light signals, while ethylene transduces the information on soil mechanical conditions, which cooperatively control EIN3 protein levels to promote seedling emergence from the soil. The COP1-EBF1/2-EIN3 module reveals a mechanism by which plants sense the depth to surface and uncovers a novel regulatory paradigm of an ubiquitin E3 ligase cascade. PMID- 26748857 TI - Severe anemia in cats with urethral obstruction: 17 cases (2002-2011). AB - OBJECTIVE: To characterize clinical parameters of cats with severe anemia due to suspected urinary bladder hemorrhage associated with urethral obstruction. DESIGN: Retrospective case-control study. SETTING: University teaching hospital. ANIMALS: Seventeen cats with urethral obstruction and severe anemia (group "UO A") that required transfusion were identified via medical record database search. Thirty cats with urethral obstruction and mild or no anemia (group "UO") were included as controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The median PCV of all cases at presentation was 28% (range, 9%-47%). Seven cats had PCV <=20% at presentation, and all transfused cats had PCV <=20% at the time of transfusion. Three cats did not receive a transfusion despite PCV <=18%. Cats in the UO-A group had a significantly longer duration of clinical signs (P = 0.001), and were more likely to have a history of previous urethral obstruction (P = 0.011), have a heart murmur (P = 0.002), have a gallop rhythm (P = 0.005), and have lower blood pressure (P = 0.007) compared to those in the UO group. Additionally, UO-A cats had significantly lower pH, more negative base excess, higher BUN, and higher creatinine compared to UO cats. Duration of urinary catheterization was significantly (P = 0.016) longer in UO-A cats. All UO cats survived to discharge, whereas 4/17 (23.5%) UO-A cats were euthanized (P = 0.013). CONCLUSIONS: A history of previous urethral obstruction and longer duration of clinical signs may be important risk factors for severe anemia in UO cats. Additionally, UO-A cats appeared to be more severely affected, as evidenced by lower blood pressure, more severe metabolic acidosis, higher BUN and creatinine, and worse outcome. PMID- 26748858 TI - [Osteo-cutaneous Mycobacterium marinum infection of the elbow and reconstruction with radial collateral artery perforator-based propeller flap]. AB - Mycobacterium marinum is an atypical and non-tuberculosis mycobacterium that mainly leads to cutaneous infections. Infections occur through inoculation of the organism through injury to the skin in the presence of contaminated water or fish. The patient often presents with unspecific symptoms and the evolution, in the absence of adequate treatment, is characterized by an expansion of the cutaneous lesion and a spread to deep structures. Infections of tendon sheaths and joints are described, rarely osteomyelitis. Sure diagnosis is hard to obtain and is established from the medical history and microbiological examination. There are no specific therapeutic guidelines. Double or triple antibiotherapy is often effective and should be continued several months after complete resolution of clinical signs. Surgical debridement is required in cases of invasive or resistant infections. We report the case of a young immunocompetent fishmonger with a rare osteocutaneous M. marinum infection of the elbow. Treatment included large surgical excision of infected skin and bone areas and a triple antibiotics administration. Reconstruction have been ensured by a radial collateral artery perforator-based propeller flap, satisfying appropriates functional and cosmetical concerns of this anatomical region. Surgery and appropriate antibiotics treatment were effective and allowed healing of an invasive cutaneous and bone M. marinum infection. PMID- 26748859 TI - Induction of autoimmune gastritis by neonatal thymectomy requires autoantibodies and is prevented by anti-FcgammaR antibodies. AB - The autoantibodies (auto-Abs) that are a hallmark of neonatally thymectomized (NTx) mice with autoimmune gastritis (AIG) have been poorly explored. We investigated their immune significance using B cell-deficient (B(-)) mice and found that B(-) mice are totally resistant to AIG but become susceptible to AIG after receiving bone marrow cells from B(+) mice. This susceptibility is most likely caused by the production of auto-Abs by B cells because B(-) pups also became susceptible to AIG when nourished by an AIG dam producing auto-Abs of the IgG class during the suckling period. NTx B(-) mice receiving purified IgG auto Abs at this developmental stage similarly developed AIG. Auto-Abs probably act on antigen handling for antigen presentation because the treatment of NTx B(+) mice with anti-FcgammaR Abs prevented the development of AIG. Auto-Abs are indispensable for AIG development but are not sufficient because auto-Ab treatment did not increase AIG incidence in NTx B(+) mice above the baseline. PMID- 26748861 TI - First-trimester spontaneous pregnancy loss - molecular analysis using multiplex ligation-dependent probe amplification. AB - Spontaneous miscarriages are the most frequent complications of pregnancy and, in at least half of cases, are caused by chromosomal abnormalities, mainly aneuploidies. We present the preliminary results of the implementation of multiplex ligation-dependent probe amplification (MLPA) in the detection of chromosomal aberrations in the tissue derived from first-trimester miscarriage and evaluate the limitations and requirements of the method. We studied 181 MLPA analyses with subtelomeric and subcentromeric probe kits for all chromosomes (SALSA P070 and SALSA P181) performed on the first-trimester spontaneous miscarriage products in our Department of Genetics between September 2012 and December 2014. Conclusive MLPA results were obtained in 97.2% of samples. Chromosomal aberrations were detected in 40.3% of samples: 61.8% samples of good quality and 12.6% samples of poor quality (p < 0.001). The normal female karyotype was detected in 14.7% of good quality samples and 84.8% of poor quality samples (p < 0.001). MLPA is a useful tool for the detection of chromosomal aberrations in first-trimester miscarriage products. However, the tissue has to be well prepared before testing and the results 46,XX should be interpreted with caution. PMID- 26748856 TI - period-Regulated Feeding Behavior and TOR Signaling Modulate Survival of Infection. AB - Most metazoans undergo dynamic, circadian-regulated changes in behavior and physiology. Currently, it is unknown how circadian-regulated behavior impacts immunity against infection. Two broad categories of defense against bacterial infection are resistance, control of microbial growth, and tolerance, control of the pathogenic effects of infection. Our study of behaviorally arrhythmic Drosophila circadian period mutants identified a novel link between nutrient intake and tolerance of infection with B. cepacia, a bacterial pathogen of rising importance in hospital-acquired infections. We found that infection tolerance in wild-type animals is stimulated by acute exposure to dietary glucose and amino acids. Glucose-stimulated tolerance was induced by feeding or direct injection; injections revealed a narrow window for glucose-stimulated tolerance. In contrast, amino acids stimulated tolerance only when ingested. We investigated the role of a known amino-acid-sensing pathway, the TOR (Target of Rapamycin) pathway, in immunity. TORC1 is circadian regulated and inhibition of TORC1 decreased resistance, as in vertebrates. Surprisingly, inhibition of the less well-characterized TOR complex 2 (TORC2) dramatically increased survival, through both resistance and tolerance mechanisms. This work suggests that dietary intake on the day of infection by B. cepacia can make a significant difference in long term survival. We further demonstrate that TOR signaling mediates both resistance and tolerance of infection and identify TORC2 as a novel potential therapeutic target for increasing survival of infection. PMID- 26748862 TI - Modelling the introduction and spread of non-native species: international trade and climate change drive ragweed invasion. AB - Biological invasions are a major driver of global change, for which models can attribute causes, assess impacts and guide management. However, invasion models typically focus on spread from known introduction points or non-native distributions and ignore the transport processes by which species arrive. Here, we developed a simulation model to understand and describe plant invasion at a continental scale, integrating repeated transport through trade pathways, unintentional release events and the population dynamics and local anthropogenic dispersal that drive subsequent spread. We used the model to simulate the invasion of Europe by common ragweed (Ambrosia artemisiifolia), a globally invasive plant that causes serious harm as an aeroallergen and crop weed. Simulations starting in 1950 accurately reproduced ragweed's current distribution, including the presence of records in climatically unsuitable areas as a result of repeated introduction. Furthermore, the model outputs were strongly correlated with spatial and temporal patterns of ragweed pollen concentrations, which are fully independent of the calibration data. The model suggests that recent trends for warmer summers and increased volumes of international trade have accelerated the ragweed invasion. For the latter, long distance dispersal because of trade within the invaded continent is highlighted as a key invasion process, in addition to import from the native range. Biosecurity simulations, whereby transport through trade pathways is halted, showed that effective control is only achieved by early action targeting all relevant pathways. We conclude that invasion models would benefit from integrating introduction processes (transport and release) with spread dynamics, to better represent propagule pressure from native sources as well as mechanisms for long-distance dispersal within invaded continents. Ultimately, such integration may facilitate better prediction of spatial and temporal variation in invasion risk and provide useful guidance for management strategies to reduce the impacts of invasion. PMID- 26748860 TI - Vaccine-mediated immunity to experimental Mycobacterium tuberculosis is not impaired in the absence of Toll-like receptor 9. AB - Accumulating evidence indicates that inflammatory signals required for maximizing effector T cell generation have opposing effects on the development of memory T cell precursors. Toll-like receptor (TLR)2, and TLR9 significantly contribute to the inflammatory milieu and therefore in this study we examined whether the absence of TLR9 alone or the combined absence of TLR2 and TLR9 would affect vaccine-mediated immunity to Mtb. We found that TLR9KO and TLR2/9DKO mice vaccinated with a live Mtb auxotroph, akin to vaccinated WT mice, exhibited early control of Mtb growth in the lungs compared to their naive counterparts. The granulomatous response, IFNgamma production and cellular recruitment to the lungs were also similar in all the vaccinated groups of mice. These findings indicate that there is minimal contribution from TLR2 and TLR9 in generating memory immunity to Mtb with live vaccines. Defining the innate milieu that can drive maximal memory T cell generation with a tuberculosis vaccine needs further inquiry. PMID- 26748863 TI - Prolonged Stay of Stroke Patients in the Emergency Department May Lead to an Increased Risk of Complications, Poor Recovery, and Increased Mortality. AB - BACKGROUND AND AIM: Following an acute stroke (AS), patients are at an increased risk of developing complications that may affect prognosis. With overcrowding in the emergency department (ED), patients stay longer hours to days before transfer to a proper stroke ward. The aim of this study was to evaluate the effect of increasing length of stay (LOS) in the ED on the risk of stroke-related complications. METHODS: We analyzed data from our stroke registry of patients admitted with AS during 2014. Stay in ED was divided into 2 groups: less than 8 hours and more than 8 hours. Data regarding demographics, stroke type, severity of stroke, ED (LOS) in hours, total LOS in hospital, number and types of complications, and prognosis were collected. RESULTS: Mean age was 54.8 years and 78.9% were males (total n = 894). Prior to ward admission, 265 (29.5%) patients remained in the ED for less than 8 hours and 629 (70.4%) remained for more than 8 hours. There was no significant difference in comorbidities or the severity of stroke at admission between the 2 groups. An ED LOS of less than 8 hours was associated with reduced risk of complications (14.3% versus 19.2%, P = .06), reduced LOS in hospital, better prognosis at discharge (72.5% versus 57.6% had modified Rankin Scale of <=2, P = .001) and at 90 days (89% versus 78.8%, P = .007) and lower in-hospital mortality (1.5% versus 5.4 %, P = .004). CONCLUSION: Delays in transferring AS patients from the ED may lead to an increase in complications resulting in an increased LOS and slower recovery. PMID- 26748864 TI - A novel approach to neoplasms medial to the condyle: a condylectomy with anterior displacement of the condyle. AB - Resecting neoplasms involving the infratemporal space has a high risk of damaging critical nerves and vessels, in addition to joint form and function. The purpose of this study was to introduce a novel approach to lesions medial to the condyle, which comprises a condylectomy with anterior displacement of the condyle. The indications evaluated using digital surgical simulation, the critical surgical technique, and the preliminary clinical effects are presented here. Five cases underwent this approach between January 2006 and December 2014. The common characteristics of the five masses were (1) that they were non-malignant neoplasms involving the posterior-medial region of the condyle; (2) the upper and lower borders were between the skull base and the lingula, while the anterior border did not exceed the coronoid process. All masses were resected successfully with no damage to any critical nerves or vessels. The average follow-up period was 29.8 months (range 6-56 months). There was no recurrence, secondary deformity, or facial paralysis. The average mouth opening improved from an original 27 mm to 34 mm after surgery. The condyles were well fixed, with no resorption, as shown on computed tomography scans. PMID- 26748865 TI - Expression profile of interferon tau-stimulated genes in ovine peripheral blood leukocytes during embryonic death. AB - Early and efficient detection of embryonic death (ED) has a valuable impact as important as early pregnancy diagnosis in ruminants. Among early pregnancy diagnosis methods, detection of the expression of interferon tau-stimulated genes (ISGs) in peripheral blood leukocytes (PBLs) is well documented in cows and ewes. Therefore, we hypothesized that the expression profile of ISGs in PBLs might also be useful for detecting ED in these animals. For this purpose, pregnant ewes were used as an experimental model. Pregnancy was detected on Day 18 after mating by transrectal ultrasonography. Pregnant ewes were divided into a control group (sham injection on Day 18, n = 10) and ED group (treated with 75 MUg synthetic PGF2alpha on Day 18, n = 12). PBLs and plasma were collected on Days 0 (mating day), 15, 18, 19, 20, 21, 23, and 25 by jugular venipuncture. Total RNA was isolated from PBLs. ISGs expression levels were determined by real-time polymerase chain reaction in triplicate. Electrochemiluminescence immunoassay was used to measure progesterone (P4) levels in plasma. In the ED group, the P4 level declined to less than 1 ng/mL on Day 19 and remained at a low level until the end of the study. Compared with that on Day 0, receptor transporter protein 4 (RTP4) and ISG15 expression was upregulated on Day 15 and remained high until Day 21 in both groups, and RTP4 and ISG15 mRNA levels were attenuated on Days 23 and 25 only in the ED group (P < 0.001). Myxovirus resistance 1 expression was upregulated on Day 15 and remained high until Day 23 in both groups, but was attenuated on Day 25 in the ED group (P < 0.05). The B2-microglobulin mRNA level did not change significantly during the study in either group. These results indicate that the decline in P4 concentration was an immediate response to PGF2alpha and that the embryo may have survived longer than the CL on the basis of the extended period of ISGs expression. This suggests that the absence of P4 could be the reason for ED rather than a direct effect of PGF2alpha. In conclusion, the expression of ISGs, including ISG15, RTP4, and myxovirus resistance 1, but not B2-microglobulin, in PBLs may serve as a marker of ED. PMID- 26748866 TI - Development of a sampling method for carbonyl compounds released due to the use of electronic cigarettes and quantitation of their conversion from liquid to aerosol. AB - In this study, an experimental method for the collection and analysis of carbonyl compounds (CCs) released due to the use of electronic cigarettes (e-cigarettes or ECs) was developed and validated through a series of laboratory experiments. As part of this work, the conversion of CCs from a refill solution (e-solution) to aerosol also was investigated based on mass change tracking (MCT) approach. Aerosol samples generated from an e-cigarette were collected manually using 2,4 dinitrophenylhydrazine (DNPH) cartridges at a constant sampling (puffing) velocity of 1 L min(-1) with the following puff conditions: puff duration (2s), interpuff interval (10s), and puff number (5, 10, and 15 times). The MCT approach allowed us to improve the sampling of CCs through critical evaluation of the puff conditions in relation to the consumed quantities of refill solution. The emission concentrations of CCs remained constant when e-cigarettes were sampled at or above 10 puff. Upon aerosolization, the concentrations of formaldehyde and acetaldehyde increased 6.23- and 58.4-fold, respectively, relative to their concentrations in e-solution. Furthermore, a number of CCs were found to be present in the aerosol samples which were not detected in the initial e-solution (e.g., acetone, butyraldehyde, and o-tolualdehyde). PMID- 26748867 TI - Ion-exchange chromatographic analysis of peroxynitric acid. AB - Ion-exchange chromatographic analysis of peroxynitric acid (O2NOOH) was performed by combining an acidic eluate with an UV-vis detector and immersing the separation column in an ice-water bath. The decomposition behavior of peroxynitric acid in the solution was also studied using this system. The fraction for the peroxynitric acid peak was collected. Ion-exchange chromatographic analysis of this fraction, after standing at room temperature for 24h, showed that the decomposition products were mainly nitrate ions with a very small amount of nitrous acid. The peroxynitric acid peak area correlated perfectly with the total amount of decomposition products. The ion-exchange chromatographic isolation allowed us to evaluate the molar extinction coefficient of peroxynitric acid precisely in a wider wavelength range than previous reports. The value decreases monotonically from 1729+/-26M(-1)cm(-1) at 200nm to 12.0+/ 0.5M(-1)cm(-1) at 290nm. PMID- 26748868 TI - A multifunctional contrast dye for morphological research. AB - OBJECTIVES: We sought to devise and test a multifunctional contrast dye agent for X-ray based digital radiography (DR) or computer tomography (CT), magnetic resonance imaging (MRI), and colored staining in ex vivo validation part of animal experiments. MATERIALS AND METHODS: The custom-formulated contrast dye namely red iodized oil (RIO) was prepared by solubilizing a lipophilic dye Oil Red O in iodized poppy seed oil (Lipiodol or LPD) followed by physicochemical characterizations. To explore and test the utility of RIO, normal rats (n = 10) and rabbits (n = 10) with myocardial infarction (MI) were euthanized by overdose of pentobarbital for infusion of RIO through catheterization. The bodies and/or excised organs including heart, liver, spleen, kidneys, pancreas, and intestines of the rats and rabbits were imaged at clinical mammography, CT and MRI units. These images were qualitatively studied and quantitatively analyzed using Wilcoxon Rank test with a P value < 0.05 being considered of a statistically significant difference. Imaging findings were verified by histomorphology. RESULTS: All experimental procedures were carried out successfully with the use of RIO. T1 and T2 relaxation time was 234.2 +/- 2.6 ms and 141.9 +/- 3.0 ms for RIO, close to that of native LPD. Proton ((1) H) NMR spectroscopy revealed almost identical profiles between RIO and native LPD. The clinical mammography unit, 128 slice CT scanner and 3.0T MRI magnet were well adapted for the animal experiments. Combined use of RIO with DR, MRI, CT and histology enabled microangiography of the organs, 3D visualization of rat pancreas, validation of in vivo cardiac quantification of MI and cause determination of the rabbit death after coronary occlusion. RIO appeared as red droplets and vacuoles in vessels by frozen and paraffin sections. Image analysis showed the superiority of DR images, which provided better overall image quality (4.35 +/- 0.49) for all analyzed liver vessel segments. MRI images revealed moderate to good overall image quality ratings (3.45 +/- 0.52). Comparing the signal intensities of vessel and liver with different MRI sequences, all P values were <0.01. CONCLUSIONS: RIO proved to be a multifunctional contrast dye, which could be applied as an imaging biomarker for tissue vascularity or blood perfusion, for visualization of organ anatomy and for ex vivo validation of in vivo animal experiments. PMID- 26748869 TI - Sympathetic Nervous System Synchrony in Couple Therapy. AB - The aim of this study was to test whether there is statistically significant sympathetic nervous system (SNS) synchrony between participants in couple therapy. To our knowledge, this is the first study to measure psychophysiological synchrony during therapy in a multiactor setting. The study focuses on electrodermal activity (EDA) in the second couple therapy session from 10 different cases (20 clients, 10 therapists working in pairs). The EDA concordance index was used as a measure of SNS synchrony between dyads, and synchrony was found in 85% of all the dyads. Surprisingly, co-therapists exhibited the highest levels of synchrony, whereas couples exhibited the lowest synchrony. The client therapist synchrony was lower than that of the co-therapists, but higher than that of the couples. A Video Abstract is available next to the online version of this article on the JMFT web site. PMID- 26748870 TI - Tilting and Tumbling in Transmembrane Anion Carriers: Activity Tuning through n Alkyl Substitution. AB - Anion transport by synthetic carriers (anionophores) holds promise for medical applications, especially the treatment of cystic fibrosis. Among the factors which determine carrier activity, the size and disposition of alkyl groups is proving remarkably important. Herein we describe a series of dithioureidodecalin anionophores, in which alkyl substituents on one face are varied from C0 to C10 in two-carbon steps. Activities increase then decrease as the chain length grows, peaking quite sharply at C6 . Molecular dynamics simulations showed the transporter chloride complexes releasing chloride as they approach the membrane aqueous interface. The free transporter then stays at the interface, adopting an orientation that depends on the alkyl substituent. If chloride release is prevented, the complex is positioned similarly. Longer chains tilt the binding site away from the interface, potentially freeing the transporter or complex to move through the membrane. However, chains which are too long can also slow transport by inhibiting movement, and especially reorientation, within the phospholipid bilayer. PMID- 26748871 TI - A putative marker for human pathogenic strains of Anaplasma phagocytophilum correlates with geography and host, but not human tropism. AB - Anaplasma phagocytophilum is an Ixodes species tick-transmitted bacterium that is capable of infecting a variety of host species, although there is a diversity of bacterial strains with differing host tropism. Recent analysis of A. phagocytophilum strains suggested that "drhm", a gene locus designated "distantly related to human marker" (drhm), which was predicted to be an integral membrane protein with possible transporter functions was not present in available canine and human isolates. By assessing 117 strains from 14 host species from across the US, we extended this analysis. Phylogenetic clades were associated with geography, but not host species. Additionally, a virulent clade that lacks drhm and infects dogs, horses, and humans in northeastern US was identified. PMID- 26748872 TI - Long-term efficacy of rituximab in IgM anti-myelin-associated glycoprotein neuropathy: RIMAG follow-up study. AB - The Rituximab vs. Placebo in Polyneuropathy Associated With Anti-MAG IgM Monoclonal Gammopathy (RIMAG) study showed no improvement using the inflammatory neuropathy cause and treatment sensory score (ISS) as primary outcome in patients with IgM anti-myelin-associated glycoprotein neuropathy (IgM anti-MAG neuropathy) treated with rituximab, when compared with placebo. However, some secondary outcomes seemed to improve in the per protocol analysis. Patients from one participating center in the RIMAG study underwent a new evaluation after a median follow-up of 6 (interquartile range (IQR) 4.9; 6.5) years, using the same outcome measures used in the original study. Data were recorded in seven rituximab patients (group 1) and in eight placebo patients (group 2). In group 2, six of eight patients received immunotherapy during follow-up, while only two of seven did in group 1. No significant change was observed in either the ISS or the secondary outcomes in both groups, with the exception of worsening in the 10-m walk time in group 2 (p = 0.016). The RIMAG follow-up study failed to find any significant change in most outcome measures in patients from the RIMAG study, some of them having received new immunotherapies. This study stresses the lack of useful clinical scales sensitive enough to capture small, even meaningful, improvement in IgM anti-MAG neuropathy. PMID- 26748873 TI - Impulsivity and risky decision making among taxi drivers in Hong Kong: An event related potential study. AB - Taxi drivers play an important role in providing safe and professional public transport services. However, they tend to be more involved than other professional driver groups in accidents caused by deliberate recklessness. This study used an event-related potential (ERP) experiment to examine risk-taking behavior arising from impulsivity by comparing the underlying neural processes of taxi drivers with and without traffic offence records in Hong Kong. A sample of 15 traffic offenders and 15 nonoffenders, matched by sociodemographic characteristics, was recruited. The results show that the offender group demonstrated significantly less negative-going (less negative) feedback-related negativity but more positive-going (more positive) feedback-related P300 when than with their nonoffending counterparts. These findings show that taxi drivers with traffic offence records were less sensitive to the consequences of behavior and more attuned to the magnitude of potential reward. In addition, behavioral data revealed that they were more willing to make risky decisions. All these characteristics pertain to impulsive personality traits. Based on these findings, we can conclude that the offenders in this sample were more impulsive than their nonoffending counterparts. PMID- 26748874 TI - [Autologous "blood patch" pleurodesis: A safe and useful treatment for persistent pneumothorax in children]. PMID- 26748875 TI - Allosterism-based simultaneous, dual anticoagulant and antiplatelet action: allosteric inhibitor targeting the glycoprotein Ibalpha-binding and heparin binding site of thrombin. AB - BACKGROUND: Allosteric inhibition is a promising approach for developing a new group of anticoagulants with potentially reduced bleeding consequences. Recently, we designed sulfated beta-O4 lignin (SbO4L) as an allosteric inhibitor that targets exosite 2 of thrombin to reduce fibrinogen cleavage through allostery and compete with glycoprotein Ibalpha to reduce platelet activation. OBJECTIVE: To assess: (i) the antithrombotic potential of a novel approach of simultaneous exosite 2-dependent allosteric inhibition of thrombin and competitive inhibition of platelet activation; and (ii) the promise of SbO4L as the first-in-class antithrombotic agent. METHODS: A combination of whole blood thromboelastography, hemostasis analysis, mouse arterial thrombosis models and mouse tail bleeding studies were used to assess antithrombotic potential. RESULTS AND CONCLUSIONS: SbO4L extended the clot initiation time, and reduced maximal clot strength, platelet contractile force, and the clot elastic modulus, suggesting dual anticoagulant and antiplatelet effects. These effects were comparable to those observed with enoxaparin. A dose of 1 mg of SbO4L per mouse prevented occlusion in 100% of arteries, and lower doses resulted in a proportionally reduced response. Likewise, the time to occlusion increased by ~ 70% with a 0.5-mg dose in the mouse Rose Bengal thrombosis model. Finally, tail bleeding studies demonstrated that SbO4L does not increase bleeding propensity. In comparison, a 0.3-mg dose of enoxaparin increased the bleeding time and blood volume loss. Overall, this study highlights the promise of the allosteric inhibition approach, and presents SbO4L as a novel anticoagulant with potentially reduced bleeding side effects. PMID- 26748879 TI - Calcium signalling in malaria parasites. AB - Ca(2+) is a ubiquitous intracellular messenger in malaria parasites with important functions in asexual blood stages responsible for malaria symptoms, the preceding liver-stage infection and transmission through the mosquito. Intracellular messengers amplify signals by binding to effector molecules that trigger physiological changes. The characterisation of some Ca(2+) effector proteins has begun to provide insights into the vast range of biological processes controlled by Ca(2+) signalling in malaria parasites, including host cell egress and invasion, protein secretion, motility and cell cycle regulation. Despite the importance of Ca(2+) signalling during the life cycle of malaria parasites, little is known about Ca(2+) homeostasis. Recent findings highlighted that upstream of stage-specific Ca(2+) effectors is a conserved interplay between second messengers to control critical intracellular Ca(2+) signals throughout the life cycle. The identification of the molecular mechanisms integrating stage transcending mechanisms of Ca(2+) homeostasis in a network of stage-specific regulator and effector pathways now represents a major challenge for a meaningful understanding of Ca(2+) signalling in malaria parasites. PMID- 26748880 TI - Comparison of Australian specialty nurse standards with registered nurse standards. AB - AIM: This study aimed to determine whether registered nurse Australian specialty competency standards identified unique capabilities of nursing practice. BACKGROUND: Use of the term specialist in nursing commenced early in the twentieth century with the growth and diversification of postgraduate nursing education. Courses in speciality nursing were associated with the development of specialty competency standards in Australia. METHOD: Australian specialty standards were mapped against the current national competency standards for the registered nurse. Content analysis was used to cross-map the standards to the national standard domains of professional practice, critical thinking and analysis, provision and coordination of care, and collaborative and therapeutic practice. FINDINGS: Of the 28 sourced speciality standards, only the nursing informatics standards displayed unique elements of nursing practice. Other nursing capabilities such as leadership and person-centred care were prominent in speciality standards, while more difficult to interpret in the national standards. In addition, developmental and intellectual disability nursing was not evident in the national competency standards. DISCUSSION: The findings above identified that nursing informatics were the only specialty standards that displayed unique capabilities of nursing practice when compared with the national competency standards. This raises the question of the value add specialty standards have on practice. CONCLUSION: Very few unique capabilities of specialty nursing were expressed in these standards. The study identified that they had more potential in assisting registered nurses to interpret their national competency standards into specialist practice contexts. IMPLICATIONS FOR NURSING AND HEALTH POLICY: It is proposed that specific performance indicators of how the registered nurse standards are applied in the specialty context are developed in place of multiple specialty standards. PMID- 26748878 TI - Converting cell fates: generating hematopoietic stem cells de novo via transcription factor reprogramming. AB - Even though all paradigms of stem cell therapy and regenerative medicine emerged from the study of hematopoietic stem cells (HSCs), the inability to generate these cells de novo or expand them in vitro persists. Initial efforts to obtain these cells began with the use of embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) technologies, but these strategies have yet to yield fully functional cells. Subsequently, more recent approaches involve transcription factor (TF) overexpression to reprogram PSCs and various somatic cells. The induction of pluripotency with just four TFs by Yamanaka informs our ability to convert cell fates and demonstrates the feasibility of utilizing terminally differentiated cells to generate cells with multilineage potential. In this review, we discuss the recent efforts undertaken using TF-based reprogramming strategies to convert several cell types into HSCs. PMID- 26748881 TI - Clinical and economic impact of non-adherence to antidepressants in major depressive disorder: A systematic review. AB - BACKGROUND: Medication non-adherence is one of the major challenges in treating patients with depression. This systematic review aims to determine the clinical and economic outcomes of non-adherence in depression. METHODS: A systematic search was performed across the following databases: PubMed, EMBASE, DARE, CINAHL, PsycINFO, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews; from database inception to March 31, 2015. Studies must report on the association between adherence and outcomes, and English full texts needed to be available. The quality of each study was assessed using the Newcastle-Ottawa scale. RESULTS: A total of 11 articles were included, with eight reporting on clinical outcomes, two reporting on economic outcomes, and one reporting on both. The majority of studies were retrospective cohort studies. The mean quality of all included studies was 7, with a range from 3 to 9. Results clearly indicate that patients who were non-adherent were more likely to experience increased risks of relapse and/or recurrence, emergency department visits, and hospitalization rates; increased severity of depression, and a decrease in response and remission rates. The worsening of clinical outcomes in patients who were non-adherent subsequently translated to an increase in healthcare utilization and charges. LIMITATIONS: No standardized adherence measurement tools were used, and few studies looked at the economic impact of non adherence in depression. CONCLUSION: There is a strong association between non adherence to antidepressants and a worsening of patients' clinical and economic outcomes. Cost-effective interventions should be directed to this group of patients to improve medication adherence. PMID- 26748882 TI - Effect of lie labelling on children's evaluation of selfish, polite, and altruistic lies. AB - This study investigates how 5- and 6-year-olds' evaluations of selfish, polite, and altruistic lies change as a result of whether these false statements are explicitly labelled as lies. We are also interested in how interpretive theory of mind may correlate with such evaluations with and without a lie label. Our results showed that labelling lowered children's evaluations for the polite and altruistic lies, but not for the selfish lies. Interpretive theory of mind correlated positively with the evaluation difference between the polite and altruistic lies and that between the selfish and altruistic lies in the label, but not in the non-label condition. Correlation between the selfish and altruistic lies and that between the polite and altruistic lies were stronger with than without labelling, after controlling for age, and verbal and non-verbal intelligence. We conclude that lie labelling biases children towards more negative evaluations for non-selfish lies and makes them see lies of different motives as more similar. If a lie label is applied, whether lies of different motives are still evaluated differently depends on interpretive theory of mind, which reflects the child's ability to represent and allow different interpretations of an ambiguous reality. PMID- 26748883 TI - 5-Hz Transcranial Magnetic Stimulation for Comorbid Posttraumatic Stress Disorder and Major Depression. AB - Current treatment options for posttraumatic stress disorder (PTSD) offer modest benefits, underscoring the need for new treatments. Repetitive transcranial magnetic stimulation (rTMS) depolarizes neurons in a targeted brain region with magnetic fields typically pulsed at low (1 Hz) or high (10 Hz) frequency to relieve major depressive disorder (MDD). Prior work suggests an intermediate pulse frequency, 5 Hz, is also efficacious for treating comorbid depressive and anxiety symptoms. In this chart review study, we systematically examined the clinical and safety outcomes in 10 patients with comorbid MDD and PTSD syndromes who received 5-Hz rTMS therapy at the Providence VA Medical Center Neuromodulation Clinic. Self-report scales measured illness severity prior to treatment, after every 5 treatments, and upon completion of treatment. Results showed significant reduction in symptoms of PTSD (p = .003, effect size = 1.12, 8/10 with reliable change) and MDD (p = .005, effect size = 1.09, 6/10 with reliable change). Stimulation was well tolerated and there were no serious adverse events. These data indicate 5-Hz rTMS may be a useful option to treat these comorbid disorders. Larger, controlled trials are needed to confirm the benefits of 5-Hz protocols observed in this pilot study. PMID- 26748885 TI - Aspergillus otitis in small animals--a retrospective study of 17 cases. AB - BACKGROUND: Aspergillus spp. are saprophytic opportunistic fungal organisms and are a common cause of otomycosis in humans. Although there have been case reports of Aspergillus otitis externa in dogs, to the best of the authors' knowledge, this is the first retrospective case series describing Aspergillus otitis in dogs and cats. OBJECTIVE: To characterize signalment, putative risk factors, treatments and outcomes of a case series of dogs and cats with Aspergillus otitis. ANIMALS: Eight dogs and nine cats diagnosed with Aspergillus otitis. METHODS: A retrospective review of medical records from 1989 to 2014 identified animals diagnosed with Aspergillus otitis based on culture. RESULTS: All dogs weighed greater than 23 kg. The most common putative risk factors identified in this study were concurrent diseases, therapy causing immunosuppression or a history of an otic foreign body. Aspergillus otitis was unilateral in all study dogs and most cats. Concurrent otitis media was confirmed in three dogs and one cat, and suspected in two additional cats. Aspergillus fumigatus was the most common isolate overall and was the dominant isolate in cats. Aspergillus niger and A. terreus were more commonly isolated from dogs. Animals received various topical and systemic antifungal medications; however, otic lavage under anaesthesia and/or surgical intervention increased the likelihood of resolution of the fungal infection. CONCLUSION: Aspergillus otitis is uncommon, typically seen as unilateral otitis externa in cats and larger breed dogs with possible risk factors that include immunosuppression and otic foreign bodies; previous antibiotic usage was common. PMID- 26748884 TI - A de novo protein confers copper resistance in Escherichia coli. AB - To survive environmental challenges, biological systems rely on proteins that were selected by evolution to function in particular cellular and conditional settings. With the advent of protein design and synthetic biology, it is now possible to construct novel proteins that are not biased by eons of selection in natural hosts. The availability of these sequences prompts us to ask whether natural biological organisms can use naive-non-biological-proteins to enhance fitness in stressful environments. To address this question, we transformed a library of DNA sequences encoding ~1.5 * 10(6) binary patterned de novo proteins into E. coli, and selected for sequences that enable growth in concentrations of copper that would otherwise be toxic. Several novel sequences were discovered, and one of them, called Construct K (ConK), was studied in detail. Cells expressing ConK accumulate approximately 50% less copper than control cells. The function of ConK does not involve an oxidase, nor does it require two of the best characterized copper efflux systems. However, the ability of ConK to rescue cells from toxic concentrations of copper does require an active proton motive force. Further selections for growth in higher concentrations of copper led to the laboratory evolution of variants of ConK with enhanced levels of activity in vivo. These studies demonstrate that novel proteins, unbiased by evolutionary history in the natural world, can enhance the fitness of biological systems. SYNOPSIS: Living systems evolve to adapt to potentially lethal environmental changes. This normally involves repurposing existing genetic information (i.e. sequences that were selected by billions of years of evolution). Here we show that a completely de novo protein, not derived from nature, can enable E. coli cells to grow in otherwise toxic concentrations of copper, demonstrating that living systems also have the capacity to incorporate and protopurpose entirely novel genetic information. PMID- 26748886 TI - Increased numbers of FoxP3-expressing CD4+ CD25+ regulatory T cells in peripheral blood from dogs with atopic dermatitis and its correlation with disease severity. AB - BACKGROUND: Atopic dermatitis (AD) is a common chronic inflammatory skin disease of humans and dogs. Regulatory T cells (Tregs) are essential controllers of immune homeostasis and have been shown to play a key role in human AD, even though frequencies of Tregs in atopic human patients vary greatly. Only two studies have reported Treg numbers in the peripheral blood of dogs with canine AD (CAD). OBJECTIVES: This study aimed to assess the numbers of circulating Tregs in healthy and atopic dogs, and to determine whether Treg numbers correlate with age, sex, disease severity or pre-treatment. ANIMALS: Client-owned dogs including 14 healthy dogs and 35 dogs with CAD. METHODS: Expression of Tregs in peripheral blood mononuclear cells was evaluated by flow cytometry. Tregs were phenotypically identified as T cells triple positive for CD4, CD25 and FoxP3. RESULTS: The percentage of circulating CD4(+) CD25(+) FoxP3(+) Tregs in atopic dogs was increased significantly compared to healthy dogs (mean 2.1% versus 1%, P = 0.002) and correlated with disease severity (Pruritus Scale: r = 0.48, P = 0.003; CADESI-04: r = 0.34, P = 0.044). No significant differences in age or sex were found in either group and pre-treatment had no influence on results for atopic dogs. CONCLUSIONS: Data suggest that, as in humans, CD4(+) CD25(+) FoxP3(+) Tregs may contribute to the pathogenesis of CAD as indicated by an association between Treg frequency and disease severity. Further investigation is required to improve the understanding of the role of Tregs in atopic dogs. PMID- 26748888 TI - Associations of demographic and behavioural factors with glycaemic control in young adults with type 1 diabetes mellitus. AB - BACKGROUND: Despite recognised benefits of optimal glycaemic control in patients with type 1 diabetes mellitus (T1DM), good control is still difficult to achieve, particularly for adolescents and young adults. Recognition of factors that may assist early optimisation of glycaemic control is therefore important. AIMS: We explored associations of demographic, social and behavioural factors with glycosylated haemoglobin (HbA1c) levels in participants with T1DM aged 18-25 years. METHODS: A cross-sectional analysis was performed on young adults attending a dedicated multidisciplinary clinic at Fremantle Hospital, Western Australia from January to August 2014. RESULTS: Data from 93 participants were analysed. Mean age was 21.4 +/- 2.3 years, and 39.8% of the cohort were female. Longer duration of diabetes was associated with higher HbA1c (r = 0.25, P = 0.04). Men had lower HbA1c than women (8.2 +/- 1.6 vs 9.2 +/- 2.0%, P = 0.01). Increased frequency of clinic attendance was associated with lower HbA1c (r = 0.27, P = 0.02). Those engaged in work or study had better HbA1c compared with those who were not (8.9 +/- 2.1 vs 10.5 +/- 2.1%, P = 0.03). Socioeconomic disadvantage, risk-taking behaviour, insulin pump use and distance travelled to clinic were not associated with differences in HbA1c. CONCLUSION: In young adults with T1DM, geographical separation, socioeconomic disadvantage and risk-taking behaviours did not influence glycaemic control. Longer duration of diabetes identifies young adults at higher risk of poor control, while attendance at a multidisciplinary clinic and engagement in work or study was associated with better glycaemic control. Additional studies are warranted to clarify the role of behavioural interventions to improve diabetes management in young adults. PMID- 26748887 TI - Potential cutaneous hypersensitivity reaction to an inactive ingredient of thyroid hormone supplements in a dog. AB - BACKGROUND: Although discussions about allergic reactions to thyroid supplements abound on professional forums, there is almost no information in the literature on these specific idiosyncratic drug reactions. ANIMAL: A dog with a history of hypothyroidism-associated weight gain and mild lethargy was prescribed levothyroxine tablets (0.018 mg/kg twice daily). After 19 days the dog developed a severe skin condition that was responsive to levothyroxine withdrawal, and antibiotic and glucocorticoid therapy. Three weeks later a different levothyroxine tablet was prescribed. Within 48 h the dog developed a more severe cutaneous reaction that resolved with drug discontinuation and appropriate topical care. OBJECTIVES: To confirm a possible hypersensitivity reaction and identify its chemical target. METHODS AND RESULTS: The two prescribed levothyroxine formulations shared two inactive ingredients: magnesium stearate and polyvinylpyrrolidone. Nine months after discontinuation of thyroid supplement, a formulation without either of these two compounds was used for a second re-challenge. There was no recurrence of the drug reaction and after 1.5 years of treatment the dog remains normal. CONCLUSIONS AND CLINICAL IMPORTANCE: These elements strongly suggest that this dog had an idiosyncratic reaction (likely immune-mediated) against one or both inactive ingredients in the first two formulations of levothyroxine. We are not aware of any previous confirmed delayed hypersensitivity to a thyroid supplement in a dog with the likely chemical trigger being an inactive ingredient rather than the therapeutic agent itself. We hope that this case will raise awareness about allergic reactions to thyroid supplements and allergic reactions to inactive formulation components. PMID- 26748889 TI - The transformer genes in the fig wasp Ceratosolen solmsi provide new evidence for duplications independent of complementary sex determination. AB - Transformer (tra) is the key gene that turns on the sex-determination cascade in Drosophila melanogaster and in some other insects. The honeybee Apis mellifera has two duplicates of tra, one of which (complementary sex determiner, csd) is the primary signal for complementary sex-determination (CSD), regulating the other duplicate (feminizer). Two tra duplicates have been found in some other hymenopteran species, resulting in the assumption that a single ancestral duplication of tra took place in the Hymenoptera. Here, we searched for tra homologues and pseudogenes in the Hymenoptera, focusing on five newly published hymenopteran genomes. We found three tra copies in the fig wasp Ceratosolen solmsi. Further evolutionary and expression analyses also showed that the two duplicates (Csoltra-B and Csoltra-C) are under positive selection, and have female-specific expression, suggesting possible sex-related functions. Moreover, Aculeata species exhibit many pseudogenes generated by lineage-specific duplications. We conclude that phylogenetic reconstruction and pseudogene screening provide novel evidence supporting the hypothesis of independent duplications rather an ancestral origin of multiple tra paralogues in the Hymenoptera. The case of C. solmsi is the first example of a non-CSD species with duplicated tra, contrary to the previous assumption that derived tra paralogues function as the CSD locus. PMID- 26748890 TI - Structure-Based Development of an Affinity Probe for Sirtuin 2. AB - Sirtuins are NAD(+)-dependent protein deacylases that cleave off acetyl groups, as well as other acyl groups, from the E-amino group of lysines in histones and other substrate proteins. Dysregulation of human Sirt2 activity has been associated with the pathogenesis of cancer, inflammation, and neurodegeneration, thus making Sirt2 a promising target for pharmaceutical intervention. Here, based on a crystal structure of Sirt2 in complex with an optimized sirtuin rearranging ligand (SirReal) that shows improved potency, water solubility, and cellular efficacy, we present the development of the first Sirt2-selective affinity probe. A slow dissociation of the probe/enzyme complex offers new applications for SirReals, such as biophysical characterization, fragment-based screening, and affinity pull-down assays. This possibility makes the SirReal probe an important tool for studying sirtuin biology. PMID- 26748891 TI - Technical note: Performance of semi and fully automated approaches for registration of 3D surface coordinates in geometric morphometric studies. AB - OBJECTIVES: One of the biggest challenges in the study of complex morphologies is to adequately describe shape variation. Here, we assess how the random sampling of surface points automatically obtained performs, when compared with observer guided sampling procedures, and also evaluate the effect of sliding surface points by bending energy and minimum Procrustes distance. MATERIAL AND METHODS: Three datasets comprising structures with disparate levels of complexity and intrasample variation are as follows: mouse molars, mouse brains, and primate endocasts. Different configurations of 3D coordinates on curves and surfaces were digitized from MRI images and CT scans using semi and fully automated procedures. Shape variables were obtained by Generalized Procrustes Superpositions before and after sliding the pseudolandmarks. Multivariate analyses were used to summarize and compare shape variation. RESULTS: For the primate endocast, the semiautomated and automated strategies yield similar ordinations of specimens. Conversely, the semiautomated strategy better discriminates molar shapes between mouse groups. Shape differences among specimens are not adequately represented by the PCs calculated with surface pseudolandmarks. This is improved when the points are converted into semilandmarks by a sliding criterion. DISCUSSION: Surface semilandmarks automatically obtained from 3D models are promising although they should be used with some caution in complex structures. This approach can be taken as complementary of semiautomated procedures which perform better for assessing shape variation in localized traits previously selected while automated procedures are suitable in studies aimed at comparing overall variation in shape and when there is no previous information about highly variable anatomical regions. PMID- 26748892 TI - Impacts of drinking-age legislation on alcohol-impaired driving crimes among young people in Canada, 2009-13. AB - BACKGROUND AND AIM: In Canada, the minimum legal drinking age (MLDA) is 18 years in Alberta, Manitoba and Quebec and 19 in the rest of the country. Given that public health organizations have not only recommended increasing the MLDA to 19 years, but also have identified 21 years as ideal, the current study tested whether drivers slightly older than the MLDA had significant and abrupt increases in alcohol-impaired driving (AID) crimes, compared with their counterparts just younger than the MLDA. DESIGN: Regression-discontinuity approach. SETTING: Canada. SAMPLE: AID criminal incidents by drivers aged 15-23 years (female, n = 10 706; male, n = 44 973). MEASUREMENTS: Police-reported AID incidents from the Canadian 2009-13 Uniform Crime Reporting Survey. FINDINGS: Significant gender * MLDA effects supported gender-specific models. Compared with males slightly younger than the MLDA, those just older had abrupt increases in AID incidents of 42.8% [95% confidence interval (CI) = 20.4-66.3%, P < 0.001], 28.1% (95% CI = 16.0-40.7%, P < 0.001) and 35.1% (95% CI = 22.4-48.4%, P < 0.001) in provinces with an MLDA of 18 years, 19 years and across the country, respectively. Among females, AID incidents increased by 39.9% (95% CI = 1.9-79.6%, P = 0.040) in provinces with an MLDA of 18 years, and by 19.4% (95% CI = 2.1-37.4%, P = 0.028) at the national level. CONCLUSION: Release from drinking-age restrictions appears to be associated with increases in alcohol-impaired driving offenses among young drivers in Canada, ranging from 28 to 43% among males and from 19 to 40% among females. PMID- 26748893 TI - Prevalence and clinical impact of antiretinal antibodies in uveitis. AB - PURPOSE: To determine the prevalence of serum antiretinal antibodies (ARAs) among patients with uveitis and establish their clinical relevance. METHODS: This prospective study assessed the presence of ARAs by indirect immunofluorescence (IIF) using primate retina in 126 patients with uveitis and 60 healthy controls. Clinical data of uveitis patients were collected from medical charts and included the classification of uveitis, cause of uveitis or its association with systemic disease, stage and activity of uveitis and specific retinal features. Correlations between the presence of specific ARAs and various clinical characteristics were analysed. RESULTS: The presence of ARAs was observed in 49 of 104 (47%) of patients with uveitis and in 10 of 59 (17%) of healthy controls (p < 0.001). Staining of the nuclear layers or the photoreceptors were both more often observed in patients with uveitis compared to healthy controls (p = 0.002 and p = 0.018, respectively). No specific associations were found between the presence of serum ARAs and various clinical characteristics. CONCLUSION: Serum ARAs were more frequent in patients with uveitis compared to healthy controls, but their clinical role remains elusive. The assessment of intraocular production of specific ARAs may provide further insight into the role of ocular autoantibodies in diverse uveitis entities. PMID- 26748896 TI - In Memoriam: Hanneke De Boer (1946-2015). PMID- 26748897 TI - Reproductive disorders in patients with epilepsy; we need high-quality studies. PMID- 26748899 TI - An exercise to map patient-centred care networks. PMID- 26748894 TI - Spleen enlargement is a risk factor for thrombosis in essential thrombocythemia: Evaluation on 1,297 patients. AB - Spleen enlargement, present in 10-20% of Essential Thrombocythemia (ET) patients at diagnosis, is a feature clinically easy to assess, confirmable by echography with a very low chance of misinterpretation. Nonetheless, the clinical and prognostic role of splenomegaly has been seldom evaluated. From 1979 to 2013, 1297 ET patients retrospectively collected in the database of the Lazio Cooperative Group and Bologna University Hospital were evaluable for spleen enlargement at diagnosis and included in the analysis. On the whole, spleen was enlarged in 172/1297 (13.0%) patients; in most cases (94.8%) splenomegaly was mild (<=5 cm). Patients with splenomegaly were younger, predominantly male, presented higher platelet count and JAK2V617F allele burden and had a lower incidence of concomitant cardiovascular risk factors. At least one thrombotic event during follow-up occurred in 97/1,125 (8.6%) patients without spleen enlargement compared to 27/172 (15.7%) patients with spleen enlargement (P = 0.003). Despite comparable use of cytoreductive/antiplatelet therapies in the two groups, the cumulative risk of thrombosis at 5 years was significantly higher in patients with baseline splenomegaly (9.8% versus 4.4% in patients without splenomegaly, P = 0.012). In multivariate analysis exploring risk factors for thrombosis, splenomegaly retained its negative prognostic role, together with previous thrombosis, leucocyte count and male gender. Baseline splenomegaly seems to be an independent additional risk factor for thrombosis in nonstrictly WHO defined ET patients. This data could be useful in the real-life clinical management of these patients. PMID- 26748898 TI - The relevance of "diagnostic delay" in epilepsy. PMID- 26748900 TI - Hypercalcaemia secondary to elevated 1,25 dihydroxycholecalciferol in a dog with immune-mediated polyarthritis. AB - A seven-year-old male entire Bearded Collie was referred following a three-week history of pyrexia, lethargy and stiffness, which was poorly responsive to antibiotic therapy. The most significant laboratory abnormalities included marked neutrophilia and ionised hypercalcaemia. The dog was diagnosed with primary immune-mediated polyarthritis, which responded to prednisolone and azathioprine, and resulted in resolution of the elevated 1,25 hydroxycholecalciferol, hypercalcaemia and neutrophilia. To the authors' knowledge, this represents the first case report of hypercalcaemia secondary to immune-mediated polyarthritis. PMID- 26748901 TI - Expression of pro-angiogenic genes in mesenchymal stem cells derived from dermis of patients with psoriasis. AB - BACKGROUND: Recent experimental studies revealed that angiogenesis and lymphangiogenesis are closely related to psoriasis. Our microarray analysis suggested that the pro-angiogenic genes platelet endothelial cell adhesion molecule-1 (PECAM1), facio-genital dysplasia-5 (FGD5), prostaglandin-endoperoxide synthase-1 (PTGS1), melanoma cell adhesion molecule (MCAM), vasohibin-2 (VASH2), and stabilin-1 (STAB1) are differentially expressed in dermal mesenchymal stem cells in psoriasis. OBJECTIVES: The aim of this study was to investigate the mRNA and protein expression of PECAM1, FGD5, PTGS1, MCAM, VASH2, and STAB1 for angiogenesis and the possible mechanisms in psoriasis. METHODS: We studied 12 patients with plaque psoriasis and 14 healthy controls matched for age and sex. Dermal mesenchymal stem cells were expanded, passaged, and identified by cellular morphology, immunophenotyping, and multipotential differentiation. The mRNA and protein expression of the above-mentioned six genes were confirmed by quantitative real-time reverse transcription-polymerase chain reaction and Western blotting. RESULTS: The significantly decreased expression of PECAM1, PTGS1, FGD5, and MCAM at both mRNA and protein level (except VASH2 and STAB1) were demonstrated in mesenchymal stem cells from psoriatic skin lesions compared with non-lesional from healthy controls. CONCLUSIONS: We provide the first report that pro-angiogenic genes PECAM1, PTGS1, FGD5, and MCAM rather than VASH2 and STAB1 may be play a vital role in pathological dermal angiogenesis disorders of psoriasis. Therefore, anti-angiogenesis is attractive and offers future potential for application in patients with psoriasis. PMID- 26748902 TI - Development of tools to study personal weight control strategies: OxFAB taxonomy. AB - OBJECTIVE: To describe the development of the Oxford Food and Activity Behaviors (OxFAB) taxonomy and questionnaire to explore the cognitive and behavioral strategies used by individuals during weight management attempts. METHODS: The taxonomy was constructed through a qualitative analysis of existing resources and a review of existing behavior change taxonomies and theories. The taxonomy was translated into a questionnaire to identify strategies used by individuals. Think aloud interviews were conducted to test the face/concept validity of the questionnaire, and test-retest reliability was assessed in a sample of 138 participants. RESULTS: The OxFAB taxonomy consists of 117 strategies grouped into 23 domains. Compared to taxonomies used to describe interventions, around half of the domains and strategies identified are unique to the OxFAB taxonomy. The OxFAB questionnaire consists of 117 questions, one for each strategy from the taxonomy. Test-retest resulted in a mean PABAK score of 0.61 (SD 0.15). Questions were revised where appropriate. CONCLUSIONS: The OxFAB taxonomy and questionnaire provide a conceptual framework to identify the cognitive and behavioral strategies used by individuals during attempts at weight control. PMID- 26748904 TI - Tricuspid Valve Annular Dilation as a Predictor of Right Ventricular Failure After Implantation of a Left Ventricular Assist Device. AB - BACKGROUND: Tricuspid annular (TA) dilation has been suggested as a more reliable marker of concomitant advanced right ventricular failure (RVF) than severity of tricuspid regurgitation (TR). Our objective was to examine the impact of TA dilation on occurrence of RVF and in-hospital mortality following left ventricular assist device (LVAD) implant. METHODS: Consecutive patients undergoing implantation of a continuous-flow LVAD implant were grouped according to the presence or absence of preoperative dilated TA. Clinical characteristics, hemodynamics, and short-term postoperative outcomes were compared between groups. RVF was defined as unplanned right ventricular assist device (RVAD) or postoperative use of inotropes for >14 days. Linear and logistic regressions were used to explore associations of TA with occurrence of RVF and duration of inotrope use. RESULTS: We included 69 patients who had continuous-flow LVAD implanted between 2006 and 2013 (50 +/- 13 years old; 69% males; 37% ischemic etiology; 69% bridge-to-transplant LVAD; 18% INTERMACS 1-2; 48% with significant TR). RVF occurred in nine cases, and overall in-hospital mortality rate was 14%. Tricuspid valve repair was performed in ten cases. Dilated TA (OR 4.86; 95% CI 1.05-22.33; p = 0.04) was associated with RVF. In an adjusted multivariable analysis, indexed TA was an independent predictor of increased days of inotrope use (0.8-day increase in inotrope use for every 1 mm/m2 increase; p = 0.04). CONCLUSION: In this cohort, TA dilation was a predictor of RVF after LVAD implant. The potential benefit of concomitant TVR in selected patients with a dilated TA undergoing LVAD implantation remains to be determined. PMID- 26748906 TI - Partial prostatectomy for anterior low rectal cancer: how to do it. A response to Frasson et al. PMID- 26748905 TI - Validation of soluble amyloid-beta precursor protein assays as diagnostic CSF biomarkers for neurodegenerative diseases. AB - Analytical validation of a biomarker assay is essential before implementation in clinical practice can occur. In this study, we analytically validated the performance of assays detecting soluble amyloid-beta precursor protein (sAPP) alpha and beta in CSF in two laboratories according to previously standard operating procedures serving this goal. sAPPalpha and sAPPbeta ELISA assays from two vendors (IBL-international, Meso Scale Diagnostics) were validated. The performance parameters included precision, sensitivity, dilutional linearity, recovery, and parallelism. Inter-laboratory variation, biomarker comparison (sAPPalpha vs. sAPPbeta) and clinical performance was determined in three laboratories using 60 samples of patients with subjective memory complaints, Alzheimer's disease, or frontotemporal dementia. All performance parameters of the assays were similar between labs and within predefined acceptance criteria. The only exceptions were minor out-of-range results for recovery at low concentrations and, despite being within predefined acceptance criteria, non comparability of the results for evaluation of the dilutional linearity and hook effect. Based on the inter-laboratory correlation between Lab #1 and Lab #2, the IBL-international assays were more robust (sAPPalpha: r(2) = 0.92, sAPPbeta: r(2) = 0.94) than the Meso Scale Diagnostics (MSD) assay (sAPPalpha: r(2) = 0.70, sAPPbeta: r(2) = 0.80). Specificity of assays was confirmed using assay-specific peptide competitors. Clinical validation showed consistent results across the clinical groups in the different laboratories for all assays. The validated sAPP assays appear to be of sufficient technical quality and perform well. Moreover, the study shows that the newly developed standard operating procedures provide highly useful tools for the validation of new biomarker assays. A recommendation was made for renewed instructions to evaluate the dilutional linearity and hook effect. We analytically validated the performance of assays detecting soluble amyloid-beta precursor protein (sAPP) alpha and beta in CSF according to SOPs in agreement with ISO15189 guidelines. The validated sAPP assays appear to be of sufficient technical quality and perform well. Moreover, this study proofs that the newly developed SOPs, with a minor modification, provide highly useful tools for the validation of new biomarker assays. PMID- 26748903 TI - Tuning microenvironment modulus and biochemical composition promotes human mesenchymal stem cell tenogenic differentiation. AB - Mesenchymal stem cells (MSCs) are promising for the regeneration of tendon and ligament tissues. Toward realizing this potential, microenvironment conditions are needed for promoting robust lineage-specific differentiation into tenocytes/ligament fibroblasts. Here, we utilized a statistical design of experiments approach to examine combinations of matrix modulus, composition, and soluble factors in human MSC tenogenic/ligamentogenic differentiation. Specifically, well-defined poly(ethylene glycol)-based hydrogels were synthesized using thiol-ene chemistry providing a bioinert base for probing cell response to extracellular matrix cues. Monomer concentrations were varied to achieve a range of matrix moduli (E ~ 10-90 kPa), and different ratios of integrin-binding peptides were incorporated (GFOGER and RGDS for collagen and fibronectin, respectively), mimicking aspects of developing tendon/ligament tissue. A face centered central composite response surface design was utilized to understand the contributions of these cues to human MSC differentiation in the presence of soluble factors identified to promote tenogenesis/ligamentogenesis (BMP-13 and ascorbic acid). Increasing modulus and collagen mimetic peptide content increased relevant gene expression and protein production or retention (scleraxis, collagen I, tenascin-C). These findings could inform the design of materials for tendon/ligament regeneration. More broadly, the design of experiments enabled efficient data acquisition and analysis, requiring fewer replicates than if each factor had been varied one at a time. This approach can be combined with other stimuli (for example, mechanical stimulation) toward a better mechanistic understanding of differentiation down these challenging lineages. PMID- 26748907 TI - Health-related quality of life and health care use in cancer survivors compared with patients with chronic diseases. AB - BACKGROUND: The number of cancer survivors is steadily increasing and these patients often experience long-lasting health problems. To make care for cancer survivors sustainable for the future, it would be relevant to put the effects of cancer in this phase into perspective. Therefore, the authors compared health related quality of life (HRQOL) and health care use among cancer survivors with that of patients with chronic diseases. METHODS: Patients diagnosed at age >18 years with a cancer with a 5-year survival rate > 20% and no distant metastases at the time of diagnosis and patients aged >18 years with physician-diagnosed somatic chronic diseases without cancer were sent a questionnaire. HRQOL was measured with the RAND-36, a measure of HRQOL. Self-reported health care use was measured for general practitioner care, specialist care, rehabilitative care, physical therapy, ambulatory mental health care, and occupational health care. RESULTS: A total of 601 cancer survivors and 1052 patients with chronic diseases without cancer were included in the current study. Multimorbidity was observed in 63% of the cancer survivors and 61% of the patients with chronic diseases. The HRQOL of the cancer survivors was significantly better than that of patients with chronic diseases after adjustment for age and sex. For the mental functioning subscale, no significant differences were found between the 2 groups. Cancer survivors were found to be less likely to have visited a general practitioner or cardiologist compared with patients with chronic diseases. CONCLUSIONS: When considering physical HRQOL and health care use, cancer survivors appear to fare better than the average patient with chronic diseases. No difference in mental functioning was observed in the current study. PMID- 26748908 TI - Reporting back environmental exposure data and free choice learning. AB - Reporting data back to study participants is increasingly being integrated into exposure and biomonitoring studies. Informal science learning opportunities are valuable in environmental health literacy efforts and report back efforts are filling an important gap in these efforts. Using the University of Arizona's Metals Exposure Study in Homes, this commentary reflects on how community-engaged exposure assessment studies, partnered with data report back efforts are providing a new informal education setting and stimulating free-choice learning. Participants are capitalizing on participating in research and leveraging their research experience to meet personal and community environmental health literacy goals. Observations from report back activities conducted in a mining community support the idea that reporting back biomonitoring data reinforces free-choice learning and this activity can lead to improvements in environmental health literacy. By linking the field of informal science education to the environmental health literacy concepts, this commentary demonstrates how reporting data back to participants is tapping into what an individual is intrinsically motivated to learn and how these efforts are successfully responding to community-identified education and research needs. PMID- 26748909 TI - The comparison of the commonly used surrogates for baseline renal function in acute kidney injury diagnosis and staging. AB - BACKGROUND: Baseline serum creatinine (SCr) level is frequently not measured in clinical practice. The aim of this study was to investigate the effect of various methods of baseline SCr determination measurement on accuracy of acute kidney injury (AKI) diagnosis in critically ill patients. METHODS: This was a retrospective cohort study. All adult intensive care unit (ICU) patients admitted at a tertiary referral hospital from January 1, 2011 through December 31, 2011, with at least one measured SCr value during ICU stay, were included in this study. The baseline SCr was considered either an admission SCr (SCrADM) or an estimated SCr, using MDRD formula, based on an assumed glomerular filtration rate (GFR) of 75 ml/min/1.73 m(2) (SCrGFR-75). Determination of AKI was based on the KDIGO SCr criterion. Propensity score to predict the likelihood of missing SCr was used to generate a simulated cohort of 3566 patients with baseline outpatient SCr, who had similar characteristics with patients whose outpatient SCr was not available. RESULTS: Of 7772 patients, 3504 (45.1 %) did not have baseline outpatient SCr. Among patients without baseline outpatient SCr, AKI was detected in 571 (16.3 %) using the SCrADM and 997 (28.4 %) using SCrGFR-75 (p < .001). Compared with non-AKI patients, patients who met AKI only by SCrADM, but not SCrGFR-75, were significantly associated with 60-day mortality (OR 2.90; 95 % CI 1.66-4.87), whereas patients who met AKI only by SCrGFR-75, but not SCrADM, had a non-significant increase in 60-day mortality risk (OR 1.33; 95 % CI 0.94-1.88). In a simulated cohort of patients with baseline outpatient SCr, SCrGFR-75 yielded a higher sensitivity (77.2 vs. 50.5 %) and lower specificity (87.8 vs. 94.8 %) for the AKI diagnosis in comparison with SCrADM. CONCLUSIONS: When baseline outpatient SCr was not available, using SCrGFR-75 as surrogate for baseline SCr was found to be more sensitive but less specific for AKI diagnosis compared with using SCrADM. This resulted in higher incidence of AKI with larger likelihood of false-positive cases. PMID- 26748911 TI - Coated/Sandwiched rGO/CoSx Composites Derived from Metal-Organic Frameworks/GO as Advanced Anode Materials for Lithium-Ion Batteries. AB - Rational composite materials made from transition metal sulfides and reduced graphene oxide (rGO) are highly desirable for designing high-performance lithium ion batteries (LIBs). Here, rGO-coated or sandwiched CoSx composites are fabricated through facile thermal sulfurization of metal-organic framework/GO precursors. By scrupulously changing the proportion of Co(2+) and organic ligands and the solvent of the reaction system, we can tune the forms of GO as either a coating or a supporting layer. Upon testing as anode materials for LIBs, the as prepared CoSx -rGO-CoSx and rGO@CoSx composites demonstrate brilliant electrochemical performances such as high initial specific capacities of 1248 and 1320 mA h g(-1) , respectively, at a current density of 100 mA g(-1) , and stable cycling abilities of 670 and 613 mA h g(-1) , respectively, after 100 charge/discharge cycles, as well as superior rate capabilities. The excellent electrical conductivity and porous structure of the CoSx /rGO composites can promote Li(+) transfer and mitigate internal stress during the charge/discharge process, thus significantly improving the electrochemical performance of electrode materials. PMID- 26748910 TI - RAP80 regulates epithelial-mesenchymal transition related with metastasis and malignancy of cancer. AB - Epithelial-mesenchymal transition (EMT) has been closely related with invasive and metastatic properties of cancer. Recently, the convergence of DNA damage response and EMT in cancer development has received a great amount of scientific attention. Here, we showed that EMT is induced by the downregulation of RAP80, a well-known regulator for DNA damage response. The knockdown of RAP80 leads to EMT like morphological changes and the increase of tumor sphere formation in non adhesive culture. Mechanistically, RAP80 controls a reciprocal regulatory axis of ZEB1 (for EMT activation) and miR200c (for EMT inhibition). The downregulation of RAP80 increases ZEB1 protein and decreases miR200c expression to activate EMT signaling in the form of drastic inhibitions of E-cadherin, p16 and p21 expression. Using in vivo metastasis analysis, RAP80 knockdown cells are shown to dramatically metastasize into the lung and generate more malignant phenotype compared to controls. Interestingly, the expression level of RAP80 was positively correlated with the survival rate in lung adenocarcinoma and breast cancer patients. These findings indicate that RAP80 is a critical gatekeeper in impeding EMT-induced metastasis and malignant phenotypes of cancer as well as preserving DNA integrity. PMID- 26748912 TI - Obstructive sleep apnoea in children with obesity. AB - AIMS: The aim of this study was to identify factors that predict risk of obstructive sleep apnoea (OSA) in obese children, which could aid in prioritising sleep studies. METHODS: A retrospective chart review was undertaken of obese children seen in the KOALA weight management clinic and Sleep clinic. Data collected included demographics, clinical history, examination findings, biochemical markers, and polysomnogram results. RESULTS: Two hundred seventy-two obese children were seen in the KOALA clinic out of which 54 (20%) were also seen in the Sleep clinic because of snoring. Thirty-two were referred by the KOALA clinic; the remaining 22 were referred by other medical practitioners prior to being seen in the KOALA clinic. Thirty-nine had polysomnograms. The time from referral to Sleep clinic ranged from 10 days to 1.5 years with 50% seen within 6 months; with similar time gap between the blood tests and time of polysomnograms. Thirty-six percent (14/39) were reported to have OSA. Six children were Aboriginal/Torres Strait Islander (ATSI) and all had OSA, which was statistically significant (P = 0.004). There was a statistically significant correlation between high-sensitivity C-reactive protein (hs-CRP) and obstructive event index (OEI) in rapid eye movement (REM) sleep. (r = 0.50, P = 0.04). Correlation between low-density lipoprotein (LDL) and OEI in REM was r = 0.36, P = 0.06, which approached significance. CONCLUSIONS: Ethnicity was a significant factor with more obese ATSI children having OSA. The significant correlation between hs CRP with OEI is consistent with findings of previous studies. Several factors (glycosylated haemoglobin, LDL) approached significance. PMID- 26748913 TI - Physiological and molecular analysis on root growth associated with the tolerance to aluminum and drought individual and combined in Tibetan wild and cultivated barley. AB - MAIN CONCLUSION: The drought-stimulated gene expression of NCED, SUS, and KS - DHN and ABA signal cross-talk with other phytohormones maintains barley root growth under drought stress at pH 4.0 plus polyethylene glycol plus aluminum. Aluminum (Al) toxicity and drought are two major factors that limit barley production. In this work, the individual and combined effects of Al/acid and polyethylene glycol (PEG 6000) induced drought stress that suppressed root growth and caused oxidative damage as characterized by increased H2O2 and O2(.-) accumulation. The wild-barley genotypes, XZ5 and XZ29, exhibited a higher tolerance than the two cultivars Dayton (Al tolerant) and Tadmor (drought tolerant) under combined stress (pH 4.0 + PEG + Al). The oxidative damage induced by PEG was more severe at pH 4.0 than at pH 6.0. In XZ29, the highest root secretion of malate and citrate was recorded, and the least Al uptake in the four genotypes. In XZ5, a peak accumulation of ABA and minor synthesis of zeatin riboside and ethylene were found being essential in maintaining primary root elongation and root hair development. PEG-induced drought stress repressed Al uptake in root tips, with a lower increase in callose formation and HvMATE (Hordeum vulgare multidrug and toxic compound exudation) expression compared to Al-induced callose production. Stress by pH 4.0 + PEG + Al up-regulated 9-cis epoxycarotenoid dioxygenase (NCED) which is involved in ABA biosynthesis. Such treatment stimulated the regulation of ABA-dependent genes sucrose synthase (SUS) and KS-type dehydrin (KS-DHN) in root tips. Our results suggest that the tolerance ranking to pH 4.0 + PEG + Al stress in Tibetan wild barley by gene expression is closely correlated to physiological indices. The results show that acclimatisation to pH 4.0 + PEG + Al stress involves specific responses in XZ5 and XZ29. The present study provides insights into the effects of Al/acid and drought combined stress on the abundance of physiological indices in the roots of barley varieties. PMID- 26748914 TI - Functional analysis of the Arabidopsis thaliana MUTE promoter reveals a regulatory region sufficient for stomatal-lineage expression. AB - MAIN CONCLUSION: The MUTE promoter contains a 175-bp region rich in Dof regulatory elements (AAAG) that is necessary and sufficient for initiation of transcription in meristemoids and the stomatal lineage. The molecular mechanism underlying the decision to divide or differentiate is a central question in developmental biology. During stomatal development, expression of the master regulator MUTE triggers the differentiation of meristemoids into stomata. In this study, we carried out MUTE promoter deletion analysis to define a regulatory region that promotes the initiation of expression in meristemoids. Expression constructs with truncated promoter fragments fused to beta-glucuronidase (GUS) were developed. The full-length promoter and promoter truncations of at least 500 bp from the translational start site exhibited normal spatiotemporal expression patterns. Further truncation revealed a 175-bp promoter fragment that was necessary and sufficient for stomatal-lineage expression. Known cis-elements were identified and tested for functional relevance. Comparison of orthologous MUTE promoters suggested DNA binding with one finger (Dof) regulatory elements and novel motifs may be important for regulation. Our data highlight the complexity and combinatorial control of gene regulation and provides tools to further investigate the genetic control of stomatal development. PMID- 26748915 TI - The plastidial starch phosphorylase from rice endosperm: catalytic properties at low temperature. AB - MAIN CONCLUSION: Consistent with its essential role in starch biosynthesis at low temperatures, the plastidial starch phosphorylase from rice endosperm is highly active at low temperature. Moreover, contrary to results on other higher plant phosphorylases, the L80 peptide, a domain unique to plant phosphorylases and not present in orthologous phosphorylases from other organisms, is not involved in enzyme catalysis. Starch phosphorylase (Pho) is an essential enzyme in starch synthesis in developing rice endosperm as the enzyme plays a critical role in both the early and maturation phases of starch granule formation especially at low temperature. In this study, we demonstrated that the rice Pho1 maintains substantial enzyme activity at low temperature (<20 degrees C) and its substrate affinities for branched alpha-glucans and glucose-1-phosphate were significantly increased at the lower reaction temperatures. Under sub-saturating substrate conditions, OsPho1 displayed higher catalytic activities at 18 degrees C than at optimal 36 degrees C, supporting the prominent role of the enzyme in starch synthesis at low temperature. Removal of the highly charged 80-amino acid sequence L80 peptide, a region found exclusively in the plastidial Pho1 of higher plants, did not significantly alter the catalytic and regulatory properties of OsPho1 but did affect heat stability. Our kinetic results support the low temperature biosynthetic role of OsPho1 in rice endosperm and indicate that its L80 region is unlikely to have a direct enzymatic role but provides stability of the enzyme under heat stress. PMID- 26748916 TI - Acylcarnitines participate in developmental processes associated to lipid metabolism in plants. AB - MAIN CONCLUSION: Plant acylcarnitines are present during anabolic processes of lipid metabolism. Their low contents relatively to the corresponding acyl-CoAs suggest that they are associated to specific pools of activated fatty acids. The non-proteinaceous amino acid carnitine exists in plants either as a free form or esterified to fatty acids. To clarify the biological significance of acylcarnitines in plant lipid metabolism, we have analyzed their content in plant extracts using an optimized tandem mass spectrometry coupled to liquid chromatography method. We have studied different developmental processes (post germination, organogenesis, embryogenesis) targeted for their high requirement for lipid metabolism. The modulation of the acylcarnitine content was compared to that of the lipid composition and lipid biosynthetic gene expression level in the analyzed materials. Arabidopsis mutants were also studied based on their alteration in de novo fatty acid partitioning between the prokaryotic and eukaryotic pathways of lipid biosynthesis. We show that acylcarnitines cannot specifically be associated to triacylglycerol catabolism but that they are also associated to anabolic pathways of lipid metabolism. They are present during membrane and storage lipid biosynthesis processes. A great divergence in the relative contents of acylcarnitines as compared to the corresponding acyl-CoAs suggests that acylcarnitines are associated to very specific process(es) of lipid metabolism. The nature of their involvement as the transport form of activated fatty acids or in connection with the management of acyl-CoA pools is discussed. Also, the occurrence of medium-chain entities suggests that acylcarnitines are associated with additional lipid processes such as protein acylation for instance. This work strengthens the understanding of the role of acylcarnitines in plant lipid metabolism, probably in the management of specific acyl-CoA pools. PMID- 26748917 TI - On the extinction probability in models of within-host infection: the role of latency and immunity. AB - Not every exposure to virus establishes infection in the host; instead, the small amount of initial virus could become extinct due to stochastic events. Different diseases and routes of transmission have a different average number of exposures required to establish an infection. Furthermore, the host immune response and antiviral treatment affect not only the time course of the viral load provided infection occurs, but can prevent infection altogether by increasing the extinction probability. We show that the extinction probability when there is a time-dependent immune response depends on the chosen form of the model specifically, on the presence or absence of a delay between infection of a cell and production of virus, and the distribution of latent and infectious periods of an infected cell. We hypothesise that experimentally measuring the extinction probability when the virus is introduced at different stages of the immune response, alongside the viral load which is usually measured, will improve parameter estimates and determine the most suitable mathematical form of the model. PMID- 26748918 TI - Mutational pattern of a sample from a critical branching population. AB - We study a universal object for the genealogy of a sample in populations with mutations: the critical birth-death process with Poissonian mutations, conditioned on its population size at a fixed time horizon. We show how this process arises as the law of the genealogy of a sample in a large class of nearly critical branching populations with rare mutations at birth, namely populations converging, in a large population asymptotic, towards the continuum random tree. We extend this model to populations with random foundation times, with (potentially improper) prior distributions [Formula: see text], [Formula: see text], including the so-called uniform ([Formula: see text]) and log-uniform ([Formula: see text]) priors. We first investigate the mutational patterns arising from these models, by studying the site frequency spectrum of a sample with fixed size, i.e. the number of mutations carried by k individuals in the sample. Explicit formulae for the expected frequency spectrum of a sample are provided, in the cases of a fixed foundation time, and of a uniform and log uniform prior on the foundation time. Second, we establish the convergence in distribution, for large sample sizes, of the (suitably renormalized) tree spanned by the sample with prior [Formula: see text] on the time of origin. We finally prove that the limiting genealogies with different priors can all be embedded in the same realization of a given Poisson point measure. PMID- 26748919 TI - Systematic Review of Modelling Approaches for the Cost Effectiveness of Hepatitis C Treatment with Direct-Acting Antivirals. AB - BACKGROUND: New direct-acting antivirals (DAAs) are highly effective for hepatitis C virus (HCV) treatment. However, their prices have been widely debated. Decision-analytic models can project the long-term value of HCV treatment. Therefore, understanding of the methods used in these models and how they could influence results is important. OBJECTIVE: Our objective was to describe and systematically review the methodological approaches in published cost-effectiveness models of chronic HCV treatment with DAAs. DATA SOURCES: We searched several electronic databases, including Medline, Embase and EconLit, from 2011 to 2015. STUDY ELIGIBILITY: Study selection was performed by two reviewers independently. We included any cost-effectiveness analysis comparing DAAs with the old standard of care for HCV treatment. We excluded non-English language studies and studies not reporting quality-adjusted life-years. STUDY APPRAISAL AND SYNTHESIS METHOD: One reviewer collected data and assessed the quality of reporting, using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. Another reviewer crosschecked the abstracted information. The development methods of the included studies were synthetized on the basis of good modelling practice recommendations. RESULTS: Review of 304 citations revealed 36 cost-effectiveness analyses. The reporting quality scores of most articles were rated as acceptable, between 67 and 100 %. The majority of the studies were conducted in Europe (50 %), followed by the USA (44 %). Fifty six percent of the 36 studies evaluated the cost effectiveness of HCV treatment in both treatment-naive and treatment-experienced patients, 97 % included genotype 1 patients and 53 % evaluated the cost effectiveness of second generation or oral DAAs in comparison with the previous standard of care or other DAAs. Twenty-one models defined health states in terms of METAVIR fibrosis scores. Only one study used a discrete-event simulation approach, and the remainder used state-transition models. The time horizons varied; however, 89 % of studies used a lifetime horizon. One study was conducted from a societal perspective. Thirty-three percent of studies did not conduct any model validation. We also noted that none of the studies modelled HCV treatment as a prevention strategy, 86 % of models did not consider the possibility of re infection with HCV after successful treatment, 97 % of studies did not consider indirect economic benefits resulting from HCV treatment and none of the studies evaluating oral DAAs used real-world data. LIMITATIONS: The search was limited by date (from 1 January 2011 to 8 September 2015) and was also limited to English language and published reports. CONCLUSIONS: Most modelling studies used a similar modelling structure and could have underestimated the value of HCV treatment. Future modelling efforts should consider the benefits of HCV treatment in preventing transmission, extra-hepatic and indirect economic benefits of HCV treatment, real-world cost-effectiveness analysis and cost effectiveness of HCV treatment in low- and middle-income countries. PMID- 26748920 TI - Disparities in Depressive Symptoms Between Heterosexual and Lesbian, Gay, and Bisexual Youth in a Dutch Cohort: The TRAILS Study. AB - Lesbian, gay, and bisexual (LGB) youth experience elevated levels of depressive symptoms compared to heterosexual youth. This study examined how differences in depressive symptoms between heterosexual and LGB youth developed from late childhood to early adulthood. The association between sexual orientation and depressive symptoms was estimated from age 11 to 22 using data from the TRacking Adolescents' Individual Lives Survey, a longitudinal Dutch cohort study. Of the 1738 respondents (54.8 % girls) that provided information on sexual orientation, 151 self-identified as LGB. In line with the Minority Stress Framework, it was tested whether self-reported peer victimization and parental rejection mediated the association between sexual orientation and depressive symptoms. Results indicated that LB girls and bisexuals were at increased risk of depressive symptoms already at age 11. The difference increased over time and was related to pubertal development in girls and bisexual individuals. Furthermore, self reported peer victimization (for both boys and girls), as well as parental rejection (for girls/bisexuals), mediated the association between sexual orientation and depressive symptoms. The authors conclude that already in late childhood, associations between sexual orientation and depressive symptoms are found, partly due to minority stress mechanisms. PMID- 26748922 TI - Dual Trajectories of Gang Affiliation and Delinquent Peer Association During Adolescence: An Examination of Long-Term Offending Outcomes. AB - Prior research has demonstrated that both adolescent gang affiliation and perceived delinquent peer association are important predictors of individual offending. A crucial question is whether and how youth gang affiliation contributes to a spectrum of criminal acts above and beyond the influence of associating with delinquent peers. Using 14 waves of data from the Rochester Youth Developmental Study, an ongoing longitudinal panel study aimed at understanding the causes and consequences of delinquency and drug use in an urban sample of adolescents, the current study employs a relatively new modeling technique-dual trajectory analysis-to illustrate the dynamic relationship between these two measures among 666 male youth. The results suggest that the two measures, while overlapping, may constitute distinct concepts that operate in different ways. The most convincing evidence of gang effects, above and beyond the influence of perceived peer delinquency, is for violent behavior and by extension police arrest. Our findings contribute to developmental research and provide information that informs future gang control efforts. PMID- 26748923 TI - Contribution of the thermotolerance genomic island to increased thermal tolerance in Cronobacter strains. AB - Cronobacter spp. are opportunistic pathogens associated with serious infections in neonates. Increased stress tolerance, including the thermotolerance of some Cronobacter strains, can promote their survival in production facilities and thus raise the possibility of contamination of dried infant formula which has been identified as a potential source of infection. Some Cronobacter strains contain a genomic island, which might be responsible for increased thermotolerance. By analysis of Cronobacter sequenced genomes this determinant was found to be present in only 49/73 Cronobacter sakazakii strains and in 9/14 Cronobacter malonaticus strains. The island was also found in 16/17 clinical isolates originating from two hospitals. Two configurations of the locus were detected; the first one with the size of 18 kbp containing the thrB-Q genes and a shorter version (6 kbp) harbouring only the thrBCD and thrOP genes. Strains containing the thermotolerance island survived significantly better at 58 degrees C comparing to a C. sakazakii isogenic mutant lacking the island and strains with the longer version of the island were 2-10 times more tolerant than those with the shortened sequence. The function of the genomic island was further confirmed by its cloning into a low-copy vector and transforming it into the isogenic mutant. Different levels of rpoS, encoding for stress-response sigma factor, expression were also associated with variability in strain thermotolerance. PMID- 26748921 TI - Family Resources as Protective Factors for Low-Income Youth Exposed to Community Violence. AB - Exposure to community violence is a risk factor for internalizing and externalizing problems; however, resources within the family can decrease the likelihood that adolescents will experience internalizing and externalizing problems as a result of such exposure. This study investigates the potential moderating effects of kinship support (i.e., emotional and tangible support from extended family) and parental involvement on the relation between exposure to community violence (i.e., witnessing violence and violent victimization) and socioemotional adjustment (i.e., internalizing and externalizing problems) in low income adolescents. The sample included 312 (50 % female; 71 % African American and 29 % White) low-income youth who participated in a longitudinal investigation when adolescents were age 14 (M age = 14.49 years) and again when they were 16 (M age = 16.49 years). Exposure to community violence at age 14 was related to more internalizing and externalizing problems at age 16. High levels of kinship support and parental involvement appeared to function as protective factors, weakening the association between exposure to violence and externalizing problems. Contrary to prediction, none of the hypothesized protective factors moderated the association between exposure to violence and internalizing problems. The results from this study suggest that both kinship support and parental involvement help buffer adolescents from externalizing problems that are associated with exposure to community violence. PMID- 26748924 TI - How lithium atoms affect the first hyperpolarizability of BN edge-doped graphene. AB - How do lithium atoms affect the first hyperpolarizability (beta0) of boron nitrogen (BN) edge-doped graphene. In this work, using pentacene as graphene model, Lin@BN-1 edge-doped pentacene and Lin@BN-2 edge-doped pentacene (n = 1, 5) were designed to study this problem. First, two models (BN-1 edge-doped pentacene, and BN-2 edge-doped pentacene ) were formed by doping the BN into the pentacene with different order, and then Li@BN-1 edge-doped pentacene and Li@ BN 2 edge-doped pentacene were obtained by substituting the H atom in BN edge-doped pentacene with a Li atom. The results show that the first hyperpolarizabilities of BN-1 edge-doped pentacene and Li@BN-1 edge-doped pentacene were 4059 a.u. and 6249 a.u., respectively; the first hyperpolarizabilities of BN-2 edge-doped pentacene and Li@BN-2 edge-doped pentacene were 2491 a.u. and 4265 a.u., respectively. The results indicate that the effect of Li substitution is to greatly increase the beta0 value. To further enhance the first hyperpolarizability, Li5@ BN-1 edge-doped pentacene and Li5@BN-2 edge-doped pentacene were designed, and were found to exhibit considerably larger first hyperpolarizabilities (beta0) (12,112 a.u. and 7921a.u., respectively). This work may inspire further study of the nonlinear properties of BN edge-doped graphene. PMID- 26748925 TI - Self-stability of C60 nanocapsules with radio-iodide content and its interaction with calcium atoms. AB - This paper inquires the C60 capabilities to contain radio-iodide ((131)I2) molecules. The encapsulation conditions are investigated applying first principles method to simulate with geometric optimizations and molecular dynamics at 310 K and atmospheric pressure. We find that the n(131)I2@C60 system, where n = 1, 2, 3..., is stable if the content does not exceed three molecules of radio iodide. The application of density functional theory allows us to determine that, the nanocapsules content limit is related with the amount of charge that is transferred from the iodine (131)I2 molecules to the carbon atoms in the fullerene surface. The Mulliken population analysis reveals that the excess of charge increases the repulsive forces between atoms and the bond length average in the C60 structure. The weakened bonds easily break and will critically damage the encapsulation properties. Additionally, we test the interaction nanocapsules with different amounts of radioactive iodine diatomic molecules content with calcium atoms, and find that only the fullerene containing one radioactive iodine diatomic molecule was able to interact with up to nine atoms of calcium without disrupting or cracking. Other fullerenes with two and three radio iodine diatomic molecules cannot resist the interaction with a single calcium atom without cracking or being broken. PMID- 26748926 TI - Germline BAP1 mutations misreported as somatic based on tumor-only testing. AB - We present three unrelated patients with germline mutations in BAP1 misreported as somatic mutations. All had strong family histories of cancer. One of these patients presented with an invasive breast cancer with the tumor tissue showing partial loss of the mutant rather than the wild type allele, suggesting that the germline BAP1 mutation didn't contribute to breast cancer development in this patient. This data highlights the importance of sequencing matching germline and tumor DNA for proper assessment of somatic versus germline mutation status. In patients with somatic mutations reported from laboratories carrying out tumor only genomic testing, the possibility that a variant may be a germline mutation should be considered, especially if the personal and/or family history suggests hereditary cancer predisposition. Since tumor-only testing can reveal germline mutations, ethical issues for patients being tested should be considered including proper consent and genetic counseling. PMID- 26748927 TI - The impact of an interventional counselling procedure in families with a BRCA1/2 gene mutation: efficacy and safety. AB - BACKGROUND: Predictive genetic testing has high impact on cancer prevention for BRCA carriers and passing this information in BRCA families is important. Mostly, this is proband-mediated but this path is defective and denies relatives lifesaving information. OBJECTIVE: To assess the efficacy/safety of an intervention, in which relatives are actively informed. DESIGN: Sequential prospective study in new BRCA families. The proband informed relatives about predictive testing (phase I). After 6 months, a letter was sent to adult relatives who had not been reached (phase II). Then a phone call was made to obtain a final notion of their wishes. All subjects received psychometric testing (State-Trait Anxiety Inventory, STAI), an interview and routine counselling. RESULTS: Twenty families were included. Twenty-four of the relatives could not be reached, 59 were 'decliners', 47 participated by the proband and 42 by the letter. Predictive testing was performed in 98% of the participants of which 30 were mutation carriers. The intervention is psychologically safe: the 95% CI for the estimated mean difference in STAI DY1 between phase II/I subjects (mean difference -1.07, 95% CI -4.4 to 2.35, p = 0.53) shows that the mean STAI DY1 score (measured at first consult) for phase II is no more than 2.35 units higher than for phase I, which is not relevant. CONCLUSIONS: A protocol directly informing relatives nearly doubles the number of relatives tested and is psychologically safe. This should lead to a change in counselling guidelines in families with a strong germline predisposition for cancer. PMID- 26748928 TI - Acrosome markers of human sperm. AB - Molecular biomarkers that can assess sperm acrosome status are very useful for evaluating sperm quality in the field of assisted reproductive technology. In this review, we introduce and discuss the localization and function of acrosomal proteins that have been well studied. Journal databases were searched using keywords, including "human acrosome", "localization", "fertilization-related protein", "acrosomal membrane", "acrosomal matrix", "acrosome reaction", "knockout mouse", and "acrosome marker". PMID- 26748929 TI - Regeneration complexities of Pinus gerardiana in dry temperate forests of Indian Himalaya. AB - Pinus gerardiana is considered an important species in dry temperate forests of North-Western Indian Himalaya because of its influence on ecological processes and economic dependence of local people in the region. But, large numbers of biotic and abiotic factors have affected P. gerardiana in these forests; hence, there is a crucial need to understand the regeneration dynamics of this tree species. The present investigation was conducted in P. gerardiana forests to understand vegetation pattern and regeneration processes on different sites in the region. Statistical analysis was performed to know variability in growing stock and regeneration on sample plots, while correlation coefficients and regression models were developed to find the relationship between regeneration and site factors. The vegetation study showed dominance of P. gerardiana, which is followed by Cedrus deodara, Pinus wallichiana and Quercus ilex in the region. The growing stock of P. gerardiana showed steep increasing and then steadily declining trend from lower to higher diameter class. The distribution of seedling, sapling, pole and trees was not uniform at different sites and less number of plots in each site were observed to have effective conditions for continuous regeneration, but mostly showed extremely limited regeneration. Regeneration success ranging from 8.44 to 15.93 % was recorded in different sites of the region, which suggests that in different sites regeneration success is influenced by collection of cone for extracting seed, grazing/browsing and physico-chemical properties of soil. Regeneration success showed significant correlation and relationship with most of abiotic and biotic factors. The regeneration success is lower than the requirement of sustainable forest, but varies widely among sites in dry temperate forests of Himalaya. More forest surveys are required to understand the conditions necessary for greater success of P. gerardiana in the region. PMID- 26748930 TI - Optimization of norovirus virus-like particle production in Pichia pastoris using a real-time near-infrared bioprocess monitor. AB - The production of norovirus virus-like particles (NoV VLPs) displaying NY-ESO-1 cancer testis antigen in Pichia pastoris BG11 Mut(+) has been enhanced through feed-strategy optimization using a near-infrared bioprocess monitor (RTBio((r)) Bioprocess Monitor, ASL Analytical, Inc.), capable of monitoring and controlling the concentrations of glycerol and methanol in real-time. The production of NoV VLPs displaying NY-ESO-1 in P. pastoris has potential as a novel cancer vaccine platform. Optimization of the growth conditions resulted in an almost two-fold increase in the expression levels in the fermentation supernatant of P. pastoris as compared to the starting conditions. We investigated the effect of methanol concentration, batch phase time, and batch to induction transition on NoV VLP-NY ESO-1 production. The optimized process included a glycerol transition phase during the first 2 h of induction and a methanol concentration set point of 4 g L(-1) during induction. Utilizing the bioprocess monitor to control the glycerol and methanol concentrations during induction resulted in a maximum NoV VP1-NY-ESO 1 yield of 0.85 g L(-1) . (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:518-526, 2016. PMID- 26748931 TI - Virtual Screening and Experimental Validation Identify Novel Inhibitors of the Plasmodium falciparum Atg8-Atg3 Protein-Protein Interaction. AB - New therapies are needed against malaria, a parasitic infection caused by Plasmodium falciparum, as drug resistance emerges against the current treatment, artemisinin. We previously characterized the Atg8-Atg3 protein-protein interaction (PPI), which is essential for autophagy and parasite survival. Herein we illustrate the use of virtual library screening to selectively block the PPI in the parasite without inhibiting the homologous interaction in humans by targeting the A-loop of PfAtg8. This A-loop is important for Atg3 binding in Plasmodium, but is absent from the human Atg8 homologues. In this proof-of concept study, we demonstrate a shift in lipidation state of PfAtg8 and inhibition of P. falciparum growth in both blood- and liver-stage cultures upon drug treatment. Our results illustrate how in silico screening and structure aided drug design against a PPI can be used to identify new hits for drug development. Additionally, as we targeted a region of Atg8 that is conserved within apicomplexans, we predict that our small molecule will have cross reactivity against other disease-causing apicomplexans, such as Toxoplasma, Cryptosporidium, Theileria, Neospora, Eimeria, and Babesia. PMID- 26748932 TI - Prognostic Factors for Chronic Lymphocytic Leukemia. AB - As novel strategies for treatment and prognostication of chronic lymphocytic leukemia (CLL) evolve, the traditional Rai and Binet systems can now be updated with more modern prognostic markers. This is a review of the latest articles which combine studies from major CLL centers to summarize major prognostic factors for patients diagnosed with CLL. The prognostic information can be categorized into three categories: genetic abnormalities which include 17p, 11q, and immunoglobulin heavy chain variable (IGHV) abnormalities; biochemical abnormalities and cell surface markers which include serum thymidine kinase, beta 2-microglobulin, CD49d, CD38, and ZAP-70 levels; and patient characteristics which include sex, age, and performance status. PMID- 26748933 TI - A Competitive Enzyme-Linked Immunosorbent Assay System for Adenylation Domains in Nonribosomal Peptide Synthetases. AB - We describe a proof-of-concept study of a competitive enzyme-linked immunosorbent assay (ELISA) system for the adenylation (A) domains of nonribosomal peptide synthetases (NRPSs) with active-site-directed probes coupled to a 5'-O-N (aminoacyl)sulfamoyladenosine scaffold. A biotin functionality immobilizes the probes onto a streptavidin-coated solid support. Dissociation constants were determined with a series of ligands, including enzyme substrates and a library of sulfamoyloxy-linked aminoacyl/aryl-AMP analogues. As it enables direct readout of protein-ligand interaction, the competitive ELISA technique provided information on comparative structure- activity relationships and insights into the enzyme active-site architecture of NRPS A-domains. These studies indicate that the ELISA technique can accelerate the discovery of small-molecule inhibitors of the A domains with new scaffolds that perturb the production of NRPS-related virulence factors. PMID- 26748934 TI - The effects of bupropion on hybrid striped bass brain chemistry and predatory behavior. AB - Increased use of antidepressants has led to an increase in their detection in final treated wastewater effluents and receiving streams. Antidepressants are intended to modify human behavior by altering brain chemistry, and because of the high functional conservation of antidepressant target receptors in vertebrates, aquatic organisms may be at risk. The antidepressant bupropion is designed to alter brain norepinephrine and dopamine concentrations in humans. The objective of the present study was to understand if alteration of dopaminergic neurotransmitter concentrations in the hybrid striped bass (Morone saxatilis * Morone chrysops) brain by bupropion would alter this predator's ability to capture prey. The authors exposed hybrid striped bass to bupropion in a static system for 6 d, followed by a 6-d recovery period. During the present study's 12 d experiment, each hybrid striped bass was fed 4 unexposed fathead minnows every 3 d, and the time it took the hybrid striped bass to consume each of those 4 fathead minnows was quantified. After each feeding event, hybrid striped bass brains were harvested and analyzed for changes in several brain neurotransmitter concentrations, including serotonin, norepinephrine, dopamine, and many of their metabolites. Although bupropion altered the concentration of dopamine and many of the dopaminergic neurotransmitter metabolite concentrations in the brains on day 3 of the exposure, it did not alter the time to capture prey. This suggests that alteration of dopaminergic neurotransmitter concentrations in the hybrid striped bass brain does not alter a predator's ability to capture prey. Environ Toxicol Chem 2016;35:2058-2065. (c) 2016 SETAC. PMID- 26748935 TI - Silent Monosodium Urate Crystal Deposits Are Associated With Severe Coronary Calcification in Asymptomatic Hyperuricemia: An Exploratory Study. AB - OBJECTIVE: To evaluate the association between monosodium urate (MSU) crystal deposits in patients with asymptomatic hyperuricemia and the severity and extension of coronary artery disease (CAD). METHODS: In this cross-sectional study, consecutive inpatients with a non-ST elevation acute coronary event and asymptomatic hyperuricemia (serum uric acid concentration of >=7.0 mg/dl) or normouricemia (serum uric acid concentration of <7.0 mg/dl) were enrolled. In patients with asymptomatic hyperuricemia, the presence of MSU crystals was determined by ultrasound evaluation of both knees and first metatarsophalangeal joints and by compensated polarized light microscopy. CAD was assessed by coronary angiography, and the following variables were considered: 1) the presence of moderate-to-severe coronary artery calcification, 2) the number of significant coronary stenoses, and 3) the presence of multivessel disease. The association between variables indicating the severity of CAD and the presence of MSU crystals was analyzed by multivariate regression. RESULTS: One hundred forty patients were enrolled. After ultrasonography and microscopic analyses were performed, the patients were classified as having normouricemia (n = 66), asymptomatic hyperuricemia alone (n = 61), and asymptomatic hyperuricemia with MSU crystals (n = 13). The prevalence of moderate-to-severe coronary calcification was significantly higher in the patients with asymptomatic hyperuricemia with MSU crystals compared with patients with asymptomatic hyperuricemia alone and patients with normouricemia (P = 0.003). An independent association was observed between the presence of moderate-to-severe calcification and asymptomatic hyperuricemia with crystals (odds ratio 16.8, P = 0.002). No significant association was observed for the other variables. CONCLUSION: Silent deposition of MSU crystals in patients with asymptomatic hyperuricemia was associated with more severe coronary calcification, which suggests more severe CAD in relation to crystal deposition. PMID- 26748936 TI - Reducing the Incidence of Falls: The Never-ending Journey. PMID- 26748937 TI - Pain medication in German nursing homes: a whole lot of metamizole. AB - PURPOSE: Prescribing of metamizole (dipyrone), an analgesic that has been withdrawn from the market or never approved in many countries owing to safety concerns, is high in elder persons in Germany. This study assessed the use of pain medications in German nursing homes with a special focus on prescribing patterns of metamizole. METHODS: Using data of the 'Inappropriate Medication in Patients with Renal Insufficiency in Nursing Homes' (IMREN) study conducted between October 2014 and April 2015 in nursing homes in Bremen and Lower Saxony, we studied prescribing of analgesics including both scheduled and as-needed medications. For residents with scheduled medication, dosage and duration of use were analysed. RESULTS: A total of 852 residents from 21 nursing homes were included. They were on average 83.5 years old, and 76.5% were women; 73.8% received at least one analgesic with 70.3% obtaining World Health Organization step I drugs. The most frequently prescribed substances were metamizole (for 40.6%) and paracetamol (acetaminophen; 35.6%), with paracetamol given mostly as needed. The proportion of residents receiving metamizole increased with age (up to 47.4% in persons aged 90 years and over). Of 143 residents with scheduled metamizole (16.8%), the mean daily dosage was 1843 mg (interquartile range [IQR]: 1500-2250); 66.9% received metamizole for at least 90 days and 23.2% for at least 365 days (mean duration 276 days; IQR: 59-314). DISCUSSION: There is a discrepancy between prescribing of metamizole for older persons, on the one hand, and evidence on comparative effectiveness and safety as well as approval and recommendations, on the other hand. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26748938 TI - Emerging role of thyroid hormone metabolites. AB - Thyroid hormones (THs) are essential for the regulation of development and metabolism in key organs. THs produce biological effects both by directly affecting gene expression through the interaction with nuclear receptors (genomic effects) and by activating protein kinases and/or ion channels (short-term effects). Such activations can be either direct, in the case of ion channels, or mediated by membrane or cytoplasmic receptors. Short-term-activated signalling pathways often play a role in the regulation of genomic effects. Several TH intermediate metabolites, which were previously considered without biological activity, have now been associated with a broad range of actions, mostly attributable to short-term effects. Here, we give an overview of the physiological roles and mechanisms of action of THs, focusing on the emerging position that TH metabolites are acquiring as important regulators of physiology and metabolism. PMID- 26748939 TI - EXPRESSION PATTERNS OF THE GLYCOGEN PHOSPHORYLASE GENE RELATED TO LARVAL DIAPAUSE IN Ostrinia furnacalis. AB - Glycogen phosphorylase (GP) acts in the first step in release of glucose from glycogen, a form of energy storage for most organisms. To investigate the characteristics and expression pattern of GP gene (Ofgp) in the Asian corn borer, Ostrinia furnacalis (Guenee), larvae, we cloned and analyzed tissue transcription of Ofgp. The results indicate that the open reading frame (ORF) is 2,526 bp, encoding 841 amino acid. The calculated three-dimensional structure shows 33 alpha-helices and 24 beta-sheets. Ofgp transcription levels varied significantly during the second to fifth instars under long-day (28 degrees C, 16:8 L:D photoperiod, and 70-80% relative humidity (RH)) and short-day (24.5 degrees C, 11:13 L:D photoperiod, and 70-80% RH) conditions, remained low during the prediapause phase, and then increased after about 36 d under short-day photoperiod. In the larvae reared under long-day condition, hemolymph ranked the highest in the transcript level of Ofgp. The highest transcription was recorded in the fat body and was lower in the other tissues in larvae reared under short day condition. We found that Ofgp transcription increased linearly from October 2012 to January 2013. The transcript level was negatively correlated with environmental temperature. We infer the higher Ofgp transcription may enhance the cold hardiness of the diapause larvae. PMID- 26748940 TI - In Situ Fabrication of Vertical Multilayered MoS2/Si Homotype Heterojunction for High-Speed Visible-Near-Infrared Photodetectors. AB - c2D transition metal dichalcogenides (TMDCs)-based heterostructures have been demonstrated to achieve superior light absorption and photovoltaic effects theoretically and experimentally, making them extremely attractive for realizing optoelectronic devices. In this work, a vertical multilayered n-MoS2/n-silicon homotype heterojunction is fabricated, which takes advantage of multilayered MoS2 grown in situ directly on plane silicon. Electrical characterization reveals that the resultant device exhibits high sensitivity to visible-near-infrared light with responsivity up to 11.9 A W(-1). Notably, the photodetector shows high-speed response time of ~ 30.5 us/71.6 us and capability to work under higher pulsed light irradiation approaching 100 kHz. The high response speed could be attributed to a good quality of the multilayer MoS2 , as well as in situ device fabrication process. These findings suggest that the multilayered MoS2 /Si homotype heterojunction have great potential application in the field of visible near-infrared detection and might be used as elements for construction of high speed integrated optoelectronic sensor circuitry. PMID- 26748941 TI - Spatiotemporal environmental heterogeneity and the maintenance of the tailspot polymorphism in the variable platyfish (Xiphophorus variatus). AB - Genetic variation is critical for adaptive evolution. Despite its importance, there is still limited evidence in support of some prominent theoretical models explaining the maintenance of genetic polymorphism within populations. We examined 84 populations of Xiphophorus variatus, a livebearing fish with a genetic polymorphism associated with physiological performance, to test: (1) whether niche differentiation explains broad-scale maintenance of polymorphism, (2) whether polymorphism is maintained among populations by local adaptation and migration, or (3) whether heterogeneity in explicit environmental variables could be linked to levels of polymorphism within populations. We found no evidence of climatic niche differentiation that could generate or maintain broad geographic variation in polymorphism. Subsequently, hierarchical partitioning of genetic richness and partial mantel tests revealed that 76% of the observed genetic richness was partitioned within populations with no effect of geographic distance on polymorphism. These results strongly suggest a lack of migration-selection balance in the maintenance of polymorphism, and model selection confirmed a significant relationship between environmental heterogeneity and genetic richness within populations. Few studies have demonstrated such effects at this scale, and additional studies in other taxa should examine the generality of gene-by environment interactions across populations to better understand the dynamics and scale of balancing selection. PMID- 26748942 TI - ASVCP guidelines: quality assurance for portable blood glucose meter (glucometer) use in veterinary medicine. AB - Portable blood glucose meters (PBGM, glucometers) are a convenient, cost effective, and quick means to assess patient blood glucose concentration. The number of commercially available PBGM is constantly increasing, making it challenging to determine whether certain glucometers may have benefits over others for veterinary testing. The challenge in selection of an appropriate glucometer from a quality perspective is compounded by the variety of analytic methods used to quantify glucose concentrations and disparate statistical analysis in many published studies. These guidelines were developed as part of the ASVCP QALS committee response to establish recommendations to improve the quality of testing using point-of-care testing (POCT) handheld and benchtop devices in veterinary medicine. They are intended for clinical pathologists and laboratory professionals to provide them with background knowledge and specific recommendations for quality assurance (QA) and quality control (QC), and to serve as a resource to assist the provision of advice to veterinarians and technicians to improve the quality of results obtained when using PBGM. These guidelines are not intended to be all-inclusive; rather they provide a minimum standard for management of PBGM in the veterinary setting. PMID- 26748943 TI - The function of small RNAs in plant biotic stress response. AB - Small RNAs (sRNAs) play essential roles in plants upon biotic stress. Plants utilize RNA silencing machinery to facilitate pathogen-associated molecular pattern-triggered immunity and effector-triggered immunity to defend against pathogen attack or to facilitate defense against insect herbivores. Pathogens, on the other hand, are also able to generate effectors and sRNAs to counter the host immune response. The arms race between plants and pathogens/insect herbivores has triggered the evolution of sRNAs, RNA silencing machinery and pathogen effectors. A great number of studies have been performed to investigate the roles of sRNAs in plant defense, bringing in the opportunity to utilize sRNAs in plant protection. Transgenic plants with pathogen-derived resistance ability or transgenerational defense have been generated, which show promising potential as solutions for pathogen/insect herbivore problems in the field. Here we summarize the recent progress on the function of sRNAs in response to biotic stress, mainly in plant-pathogen/insect herbivore interaction, and the application of sRNAs in disease and insect herbivore control. PMID- 26748944 TI - The Effects of Free-Living Physical Activity on Mortality After Coronary Artery Disease Diagnosis. AB - BACKGROUND: Previous research demonstrates greater survival among coronary artery disease (CAD) patients who engage in cardiac rehabilitation. No national prospective studies, however, have examined the effects of objectively measured free-living physical activity on mortality among CAD patients, which is important because only 25% of eligible cardiac patients participate in cardiac rehabilitation. Therefore, the purpose of this study was to examine the association between objectively measured free-living physical activity on all cause mortality among a national sample of CAD patients. HYPOTHESIS: We hypothesize that free-living physical activity will be inversely associated with all-cause mortality risk among CAD patients. METHODS: Data from the 2003 to 2006 National Health and Nutrition Examination Survey were used, with follow-up through 2011. Physical activity was assessed over 7 days during waking hours using the ActiGraph 7164 accelerometer. RESULTS: Among the 256 CAD adults (representative of 6.5 million CAD patients in the United States), 68 died over the follow-up period (26.56%). The median follow-up period was 76.5 months (interquartile range = 62-91 months). After adjustment, for every 60-minute increase in daily free-living physical activity, CAD patients had a 16% reduced risk of all-cause mortality (hazard ratio: 0.84, 95% confidence interval: 0.72 0.97). CONCLUSIONS: Free-living objectively measured physical activity is associated with greater survival among CAD patients in the United States. If confirmed by future research, development of strategies to not only increase participation in supervised cardiac rehabilitation, but also increase participation in free-living physical activity, are needed. PMID- 26748945 TI - Embedding a physical health nurse consultant within mental health services: Consumers' perspectives. AB - The life expectancy of people living with mental illness is significantly shorter than that of the rest of the population. Despite the profound impact of physical health issues on both quality of life and life expectancy, the perspectives of mental health consumers have yet to be thoroughly explored. Furthermore, research has focused far more on describing barriers than on identifying solutions. This paper reports on findings from a qualitative exploratory research study, with the aim to examine the potential role of a specialist nurse with advanced physical health-care skills. Focus groups were conducted with 31 consumers. Data were analysed thematically. The concept of a role like this was supported; however, participants stressed: (i) the importance of integration between health professionals and various components of the health-care system; and (ii) the need for culture change for nurses to work from a less medically-dominated approach. Previous research literature suggests that a nursing position dedicated to physical health care and coordination might produce positive outcomes for mental health consumers. The findings from the current research project emphasize the need for consumers to be identified as key stakeholders in a solution-focused approach to improved physical health care for mental health consumers. PMID- 26748946 TI - Dietary Salt Restriction: How Much Education Is Enough? PMID- 26748948 TI - Dental microwear of sympatric rodent species sampled across habitats in southern Africa: Implications for environmental influence. AB - Dental microwear textures have proven to be a valuable tool for reconstructing the diets of a wide assortment of fossil vertebrates. Nevertheless, some studies have recently questioned the efficacy of this approach, suggesting that aspects of habitat unrelated to food preference, especially environmental grit load, might have a confounding effect on microwear patterning that obscures the diet signal. Here we evaluate this hypothesis by examining microwear textures of 3 extant sympatric rodent species that vary in diet breadth and are found in a variety of habitat types: Mastomys coucha, Micaelamys namaquensis and Rhabdomys pumilio. We sample each of these species from 3 distinct environmental settings in southern Africa that differ in rainfall and vegetative cover: Nama-Karoo shrublands (semi-desert) and Dry Highveld grasslands in the Free State Province of South Africa, and Afromontane (wet) grasslands in the highlands of Lesotho. While differences between habitat types are evident for some of the species, inconsistency in the pattern suggests that the microwear signal is driven by variation in foods eaten rather than grit-level per se. It is clear that, at least for species and habitats sampled in the current study, environmental grit load does not swamp diet-related microwear signatures. PMID- 26748947 TI - Neuroelectrophysiological approaches in heroin addiction research: A review of literatures. AB - Neuroelectrophysiological properties have been used in human heroin addiction studies. These studies vary in their approach, experimental conditions, paradigms, and outcomes. However, it is essential to integrate previous findings and experimental methods for a better demonstration of current issues and challenges in designing such studies. This Review examines methodologies and experimental conditions of neuroelectrophysiological research among heroin addicts during withdrawal, abstinence, and methadone maintenance treatment and presents the findings. The results show decrements in attentional processing and dysfunctions in brain response inhibition as well as brain activity abnormalities induced by chronic heroin abuse. Chronic heroin addiction causes increased beta and alpha2 power activity, latency of P300 and P600, and diminished P300 and P600 amplitude. Findings confirm that electroencephalography (EEG) band power and coherence are associated with craving indices and heroin abuse history. First symptoms of withdrawal can be seen in high-frequency EEG bands, and the severity of these symptoms is associated with brain functional connectivity. EEG spectral changes and event-related potential (ERP) properties have been shown to be associated with abstinence length and tend to normalize within 3-6 months of abstinence. From the conflicting criteria and confounding effects in neuroelectrophysiological studies, the authors suggest a comprehensive longitudinal study with a multimethod approach for monitoring EEG and ERP attributes of heroin addicts from early stages of withdrawal until long-term abstinence to control the confounding effects, such as nicotine abuse and other comorbid and premorbid conditions. PMID- 26748949 TI - Antibody humanization by molecular dynamics simulations-in-silico guided selection of critical backmutations. AB - Monoclonal antibodies represent the fastest growing class of biotherapeutic proteins. However, as they are often initially derived from rodent organisms, there is a severe risk of immunogenic reactions, hampering their applicability. The humanization of these antibodies remains a challenging task in the context of rational drug design. "Superhumanization" describes the direct transfer of the complementarity determining regions to a human germline framework, but this humanization approach often results in loss of binding affinity. In this study, we present a new approach for predicting promising backmutation sites using molecular dynamics simulations of the model antibody Ab2/3H6. The simulation method was developed in close conjunction with novel specificity experiments. Binding properties of mAb variants were evaluated directly from crude supernatants and confirmed using established binding affinity assays for purified antibodies. Our approach provides access to the dynamical features of the actual binding sites of an antibody, based solely on the antibody sequence. Thus we do not need structural data on the antibody-antigen complex and circumvent cumbersome methods to assess binding affinities. (c) 2016 The Authors Journal of Molecular Recognition Published by John Wiley & Sons Ltd. PMID- 26748950 TI - Insulin pump use and discontinuation in children and teens: a population-based cohort study in Ontario, Canada. AB - OBJECTIVE: To describe insulin pump use by youth since introduction of universal funding in Ontario, Canada and to explore the relationship between pump use and pediatric diabetes center characteristics and the relationship between discontinuation and center and patient characteristics. RESEARCH DESIGN AND METHODS: Observational, population-based cohort study of youth with type 1 diabetes (<19 yr) who received pump funding from 2006 to 2013 (n = 3700). We linked 2012 survey data from 33 pediatric diabetes centers to health administrative databases. We tested the relationship between center-level pump uptake and center characteristics (center type, physician model, and availability of 24-h support) using an adjusted negative binomial model; we studied center- and patient-level factors (socioeconomic status and baseline glycemic control) associated with discontinuation using a Cox proportional hazards model with generalized estimating equations. RESULTS: Pump users were more likely to be in the highest income quintile than non-pump users (29.6 vs. 19.1%, p < 0.0001). In 2012, mean percent pump use was 38.0% with variability across centers. There was no association between uptake and center characteristics. Discontinuation was low (0.42/100 person-yr) and was associated with being followed at a small community center [hazard ratio (HR): 2.24 (1.05-4.76)] and being more deprived [HR: 2.36 (1.14-1.48)]. Older age was associated with a lower rate of discontinuation [HR: 0.31 (0.14-0.66)]. CONCLUSIONS: Rates of pump use have increased since 2006 and discontinuation is rare. Large variation in uptake across centers was not explained by the factors we examined but may reflect variation in patient populations or practice patterns, and should be further explored. PMID- 26748951 TI - Effect of PTPN22 Gene Variant R620W on Type I Interferon Production Stimulated by Different Toll-like Receptor 7 Agonists: Comment on the Article by Wang et al. PMID- 26748952 TI - Reversal of rocuronium-induced neuromuscular blockade by sugammadex allows for optimization of neural monitoring of the recurrent laryngeal nerve. AB - OBJECTIVES/HYPOTHESIS: The use of neuromuscular blocking agent may effect intraoperative neuromonitoring (IONM) during thyroid surgery. An enhanced neuromuscular-blockade (NMB) recovery protocol was investigated in a porcine model and subsequently clinically applied during human thyroid neural monitoring surgery. STUDY DESIGN: Prospective animal and retrospective clinical study. METHODS: In the animal experiment, 12 piglets were injected with rocuronium 0.6 mg/kg and randomly allocated to receive normal saline, sugammadex 2 mg/kg, or sugammadex 4 mg/kg to compare the recovery of laryngeal electromyography (EMG). In a subsequent clinical application study, 50 patients who underwent thyroidectomy with IONM followed an enhanced NMB recovery protocol-rocuronium 0.6 mg/kg at anesthesia induction and sugammadex 2 mg/kg at the operation start. The train-of-four (TOF) ratio was used for continuous quantitative monitoring of neuromuscular transmission. RESULTS: In our porcine model, it took 49 +/- 15, 13.2 +/- 5.6, and 4.2 +/- 1.5 minutes for the 80% recovery of laryngeal EMG after injection of saline, sugammadex 2 mg/kg, and sugammadex 4 mg/kg, respectively. In subsequent clinical human application, the TOF ratio recovered from 0 to >0.9 within 5 minutes after administration of sugammadex 2 mg/kg at the operation start. All patients had positive and high EMG amplitude at the early stage of the operation, and intubation was without difficulty in 96% of patients. CONCLUSIONS: Both porcine modeling and clinical human application demonstrated that sugammadex 2 mg/kg allows effective and rapid restoration of neuromuscular function suppressed by rocuronium. Implementation of this enhanced NMB recovery protocol assures optimal conditions for tracheal intubation as well as IONM in thyroid surgery. LEVEL OF EVIDENCE: NA. PMID- 26748953 TI - Volumetric analysis of chin and mandibular retromolar region as donor sites for cortico-cancellous bone blocks. AB - AIM: To test whether the mandibular retromolar region renders different results from the chin region with respect to the amount of bone available for the harvesting of block grafts. MATERIAL AND METHODS: Sixty cone beam computed tomography (CBCT) scans of mandibles of adult patients without pathologic findings in the chin and retromolar region were included. According to the number of mandibular teeth, 20 CBCT data sets were allocated to each of the following groups: group M1: dentition 36-46; group M2: dentition 37-47; and group M3: dentition 38-48. For the potential donor sites in the chin and the retromolar regions, the volume (VChin , VRetro ), the length (LChin , LRetro ), the height (HChin , HRetro ) and the width (HChin , HRetro ) were assessed using a computer software. Moreover, the chin was examined for the presence and the localization of the mandibular incisive canal. To compare the donor sites in the chin and in the retromolar regions, the quotients VRetro /VChin , LRetro /LChin , HRetro /HChin and WRetro /WChin were calculated and tested using the Wilcoxon signed rank test or the sign test. RESULTS: The mean bone volume VChin measured 3.5 +/- 1.3 cm(3) (SD), whereas the overall VRetro amounted to 1.8 +/- 1.1 cm(3) (SD). VRetro amounted to 2.6 +/- 1.4 cm(3) (SD) in the group M1, 1.8 +/- 0.5 cm(3) in the group M2 and 1.0 +/- 0.4 cm(3) in the group M3. For the group M1, VRetro /VChin measured 82 +/- 39% (P = 0.036). VRetro /VChin reached 57 +/- 20% in the group M2 and 32 +/- 12% in the group M3 (P < 0.001). The mandibular incisive canal was detected in 97% of the CBCT scans. The distance between the mandibular incisive canal and the apices of the central incisors measured 10.5 +/- 3.5 mm. CONCLUSION: The amount of bone available for the harvesting of cortico-cancellous blocks in the chin region was superior in comparison with the mandibular retromolar region. In the absence of the second and the third molars, the amount of bone harvestable in the retromolar region reached approximately 80% of the bone volume available in the chin region. In the majority of the cases, the mandibular incisive canal was detected within the donor site in the chin region. PMID- 26748954 TI - Cross-Sectional and Longitudinal Associations Between Serum Levels of High Sensitivity C-Reactive Protein, Knee Bone Marrow Lesions, and Knee Pain in Patients With Knee Osteoarthritis. AB - OBJECTIVE: To describe associations between serum high-sensitivity C-reactive protein (hsCRP), knee bone marrow lesions (BMLs), and knee pain, cross sectionally and longitudinally, in patients with knee osteoarthritis (OA). METHODS: Patients (n = 192) with symptomatic knee OA (mean age 63 years, range 50 79, women 53%) were assessed at baseline and after 24 months. Serum hsCRP was measured using enzyme-linked immunosorbent assay. Knee BMLs were scored using the modified Whole-Organ Magnetic Resonance Imaging (MRI) Score from T2-weighted fat supressed fast spin-echo MRI. Knee pain was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index. RESULTS: Quartiles of baseline serum hsCRP were associated with the presence of knee BMLs (prevalence ratio 1.07 per quartile [95% confidence interval (95% CI) 1.00, 1.15]) and total knee pain scores (beta 13.66 per quartile [95% CI 2.26, 25.07]) in multivariable analyses. Longitudinally, higher baseline hsCRP was associated with an increase in BML score (risk ratio 1.37 per quartile [95% CI 1.10, 1.70]), and change in hsCRP was positively associated with change in BML score (beta 0.19 [95% CI 0.05, 0.34]) in adjusted analyses. Baseline hsCRP was not associated with change in total knee pain, but change in hsCRP was positively and significantly associated with change in total knee pain (beta 4.71 [95% CI 0.48, 8.94]). This became nonsignificant after adjustment for changes in BML score. CONCLUSION: In patients with knee OA, serum hsCRP is associated with knee BML scores and, to a lesser extent, pain both cross-sectionally and longitudinally, suggesting that inflammation is linked with BMLs and their associated pain. PMID- 26748955 TI - Reconciling Two Computational Models of Working Memory in Aging. AB - It is well known that working memory performance changes with age. Two recent computational models of working memory, TBRS* and SOB-CS, developed from young adults WM performances are opposed regarding the postulated causes of forgetting, namely time-based decay and interference for TBRS* and SOB-CS, respectively. In the present study, these models are applied on a set of complex span data produced by young and older adults. As expected, these models are unable to account for the older adult data. An investigation on the effect of the main parameters of these models showed that the poorer performance of older adults does not come from a weaker encoding of item but rather from difficulties during the free time that immediately follows each distractor, as well as from a higher level of confusion between items. These results are discussed with respect to the current theories of working memory and aging. PMID- 26748956 TI - Anomalous position of femoral dialysis catheters. PMID- 26748957 TI - Use of enteral salbutamol in spinal shock. PMID- 26748958 TI - Chimeric Allografts Induced by Short-Term Treatment With Stem Cell Mobilizing Agents Result in Long-Term Kidney Transplant Survival Without Immunosuppression: II, Study in Miniature Swine. AB - Transplantation is now lifesaving therapy for patients with end-stage organ failure but requires lifelong immunosuppression with resultant morbidity. Current immunosuppressive strategies inhibit T cell activation and prevent donor recipient engagement. Therefore, it is not surprising that few host cells are demonstrated in donor grafts. However, our recent small animal studies found large numbers of recipient stem cells present after transplantation and pharmacological mobilization, resulting in a chimeric, repopulated organ. We now confirm these findings in a well-characterized large animal preclinical model. Here, we show that AMD3100 and FK506 mobilization of endogenous stem cells immediately post kidney transplantation combined with repeat therapy at 1, 2, and 3 months led to drug-free long-term survival in maximally immunologically mismatched swine. Three long-term recipients have stable chimeric transplants, preserved antidonor skin graft responses, and normal serum creatinine levels despite withdrawal of all medication for 3 years. PMID- 26748960 TI - PET-based quantification of statistical properties of hypoxic tumor subvolumes in head and neck cancer. AB - PURPOSE: PET hypoxia imaging of head and neck cancer (HNC) has the potential to stratify the response to radiochemotherapy. The aim of this work was to quantify the statistical properties of hypoxic tumor subvolumes measured by PET, and their impact on failure rate of standard chemoradiation. METHODS: A PubMed search was undertaken to identify relevant publications between 2001 and July 2015, containing original data regarding the properties of HNC hypoxic subvolumes and their evolution during therapy, measured using specific PET tracers. RESULTS: The number and intensity of hypoxic voxels is significantly reduced during therapy. Patients are 4.2 times more likely to have negative outcome if baseline hypoxic. The change of the hypoxic volume during therapy, as well as the statistical distribution of the hypoxic fraction (HF), is quantified and analyzed. HF strongly correlates with the median T/M (tumor-to-muscle) SUV (standard uptake value) ratio, but not with gross tumor volume. Hypoxia is 2.2 times more frequently manifest in T3 + T4 than in T1 + T2 primary tumors. Calculated quantities are presented for primary and nodal tumors separately, where available. CONCLUSIONS: Although hypoxia diminishes during chemoradiation, it is a major predictor of outcome. HF, if large enough, can be predicted from the median T/M SUV ratio. CT-delineated gross tumor size does not influence the percentage of hypoxic voxels. Primary tumors are less likely hypoxic at an earlier stage. PMID- 26748959 TI - Cuprous Oxide as a Potential Low-Cost Hole-Transport Material for Stable Perovskite Solar Cells. AB - Inorganic hole-transport materials are commercially desired to decrease the fabrication cost of perovskite solar cells. Here, Cu2O is introduced as a potential hole-transport material for stable, low-cost devices. Considering that Cu2O formation is highly sensitive to the underlying mixture of perovskite precursors and their solvents, we proposed and engineered a technique for reactive magnetron sputtering. The rotational angular deposition of Cu2O yields high surface coverage of the perovskite layer for high rate of charge extraction. Deposition of this Cu2O layer on the pinhole-free perovskite layer produces devices with power conversion efficiency values of up to 8.93%. The engineered Cu2O layers showed uniform, compact, and crack-free surfaces on the perovskite layer without affecting the perovskite structure, which is desired for deposition of the top metal contact and for surface shielding against moisture and mechanical damages. PMID- 26748961 TI - A comparison of electronic portal dosimetry verification methods for use in stereotactic radiotherapy. AB - Three methods of transit dosimetry using Electronic Portal Imaging Devices (EPIDs) were investigated for use in routine in-vivo dosimetry for cranial stereotactic radiosurgery and radiotherapy. The approaches examined were (a) A full Monte Carlo (MC) simulation of radiation transport through the linear accelerator and patient; (b) Calculation of the expected fluence by a treatment planning system (TPS); (c) Point doses calculated along the central axis compared to doses calculated using parameters acquired using the EPID. A dosimetric comparison of each of the three methods predicted doses at the imager plane to within +/-5% and a gamma comparison for the MC and TPS based approaches showed good agreement for a range of dose and distance to agreement criteria. The MC technique was most time consuming, followed by the TPS calculation with the point dose calculation significantly quicker than the other methods. PMID- 26748962 TI - Invisible Killers. PMID- 26748964 TI - Studies of a Large Odd-Numbered Odd-Electron Metal Ring: Inelastic Neutron Scattering and Muon Spin Relaxation Spectroscopy of Cr8 Mn. AB - The spin dynamics of Cr8 Mn, a nine-membered antiferromagnetic (AF) molecular nanomagnet, are investigated. Cr8 Mn is a rare example of a large odd-membered AF ring, and has an odd-number of 3d-electrons present. Odd-membered AF rings are unusual and of interest due to the presence of competing exchange interactions that result in frustrated-spin ground states. The chemical synthesis and structures of two Cr8 Mn variants that differ only in their crystal packing are reported. Evidence of spin frustration is investigated by inelastic neutron scattering (INS) and muon spin relaxation spectroscopy (MUSR). From INS studies we accurately determine an appropriate microscopic spin Hamiltonian and we show that MUSR is sensitive to the ground-spin-state crossing from S=1/2 to S=3/2 in Cr8 Mn. The estimated width of the muon asymmetry resonance is consistent with the presence of an avoided crossing. The investigation of the internal spin structure of the ground state, through the analysis of spin-pair correlations and scalar-spin chirality, shows a non-collinear spin structure that fluctuates between non-planar states of opposite chiralities. PMID- 26748965 TI - Effect of fiber reinforcement on microleakage of class II cavities restored with a novel G-aenial posterior composite, silorane composite, and nanohybrid composite: an in vitro comparative study. AB - AIM: The aim of the present study was to compare G-aenial, silorane, and nanoceramic composites and the effect of polyethylene fiber inserts in reducing gingival microleakage in class II composite restorations placed apical to the cementoenamel junction. METHODS: Standardized class II cavities were prepared on extracted molars and randomly divided into six groups (n = 20 each): group 1, Ceram X mono; group 2, Ceram X mono + Ribbond; group 3, Filtek P90; group 4, Filtek P90 + Ribbond; group 5, G-aenial posterior; and group 6, G-aenial posterior + Ribbond. All specimens were subjected to a thermocycling regime, immersed in 2% methylene blue dye for 24 h, sectioned longitudinally, and examined under a stereomicroscope to assess dye penetration on a six-point scale. The score data were subjected to statistical analysis, whereby the Kruskal-Wallis analysis of variance was used for multiple group comparisons and the Mann-Whitney test for groupwise comparisons at a significance level of P <= 0.05. RESULTS: A statistically-significant decrease in microleakage was found when Ribbond fiber was used: group 2 vs group 1 (P < 0.001), group 4 vs group 3 (P < 0.001), and group 6 vs group 5 (P < 0.001). A significant decrease in microleakage scores was found in the silorane and G-aenial posterior composites when compared to the nanoceramic composite (P < 0.001). CONCLUSION: The use of polyethylene fiber, silorane composite, and G-aenial posterior composite reduces microleakage in class II composite restorations with gingival margins below the cementoenamel junction. PMID- 26748963 TI - Microsensor and transcriptomic signatures of oxygen depletion in biofilms associated with chronic wounds. AB - Biofilms have been implicated in delayed wound healing, although the mechanisms by which biofilms impair wound healing are poorly understood. Many species of bacteria produce exotoxins and exoenzymes that may inhibit healing. In addition, oxygen consumption by biofilms and by the responding leukocytes, may impede wound healing by depleting the oxygen that is required for healing. In this study, oxygen microsensors to measure oxygen transects through in vitro cultured biofilms, biofilms formed in vivo within scabs from a diabetic (db/db) mouse wound model, and ex vivo human chronic wound specimens was used. The results showed that oxygen levels within mouse scabs had steep gradients that reached minima ranging from 17 to 72 mmHg on live mice and from 6.4 to 1.1 mmHg on euthanized mice. The oxygen gradients in the mouse scabs were similar to those observed for clinical isolates cultured in vitro and for human ex vivo specimens. To characterize the metabolic activities of the bacteria in the mouse scabs, transcriptomics analyses of Pseudomonas aeruginosa biofilms associated with the db/db mice wounds was performed. The results demonstrated that the bacteria expressed genes for metabolic activities associated with cell growth. Interestingly, the transcriptome results also indicated that the bacteria within the wounds experienced oxygen-limitation stress. Among the bacterial genes that were expressed in vivo were genes associated with the Anr-mediated hypoxia-stress response. Other bacterial stress response genes highly expressed in vivo were genes associated with stationary-phase growth, osmotic stress, and RpoH-mediated heat shock stress. Overall, the results supported the hypothesis that bacterial biofilms in chronic wounds promote chronicity by contributing to the maintenance of localized low oxygen tensions, through their metabolic activities and through their recruitment of cells that consume oxygen for host defensive processes. PMID- 26748967 TI - What is type II-open pit pattern? PMID- 26748966 TI - Absence of Tau triggers age-dependent sciatic nerve morphofunctional deficits and motor impairment. AB - Dementia is the cardinal feature of Alzheimer's disease (AD), yet the clinical symptoms of this disorder also include a marked loss of motor function. Tau abnormal hyperphosphorylation and malfunction are well-established key events in AD neuropathology but the impact of the loss of normal Tau function in neuronal degeneration and subsequent behavioral deficits is still debated. While Tau reduction has been increasingly suggested as therapeutic strategy against neurodegeneration, particularly in AD, there is controversial evidence about whether loss of Tau progressively impacts on motor function arguing about damage of CNS motor components. Using a variety of motor-related tests, we herein provide evidence of an age-dependent motor impairment in Tau-/- animals that is accompanied by ultrastructural and functional impairments of the efferent fibers that convey motor-related information. Specifically, we show that the sciatic nerve of old (17-22-months) Tau-/- mice displays increased degenerating myelinated fibers and diminished conduction properties, as compared to age matched wild-type (Tau+/+) littermates and younger (4-6 months) Tau-/- and Tau+/+ mice. In addition, the sciatic nerves of Tau-/- mice exhibit a progressive hypomyelination (assessed by g-ratio) specifically affecting large-diameter, motor-related axons in old animals. These findings suggest that loss of Tau protein may progressively impact on peripheral motor system. PMID- 26748968 TI - Septal Junctions in Filamentous Heterocyst-Forming Cyanobacteria. AB - In the filaments of heterocyst-forming cyanobacteria, septal junctions that traverse the septal peptidoglycan join adjacent cells, allowing intercellular communication. Perforations in the septal peptidoglycan have been observed, and proteins involved in the formation of such perforations and putative protein components of the septal junctions have been identified, but their relationships are debated. PMID- 26748969 TI - Persistent gross lipemia and suspected corneal lipidosis following intravenous lipid therapy in a cat with permethrin toxicosis. AB - OBJECTIVE: To describe the observation of persistent gross lipemia and suspected corneal lipidosis following intravenous lipid therapy (IVLT) in a cat with permethrin toxicosis. CASE SUMMARY: A 5-year-old, spayed female, domestic short haired cat with permethrin toxicosis was treated with a high dose of IVLT as an adjunct treatment when it remained severely obtunded following traditional supportive care. The cat received intravenous 20% lipid emulsion as a 1.5 mL/kg bolus given over 10 minutes followed by a constant rate infusion of 0.25 mL/kg/min for 2 hours. The cat developed gross lipemia that persisted at least 48 hours after the single dose of IVLT. Changes consistent with corneal lipidosis were observed and resolved within 1 week after IVLT. NEW OR UNIQUE INFORMATION PROVIDED: This is the first report documenting the complications of persistent gross lipemia and suspected corneal lipidosis in a cat following IVLT. This report underscores the off-label, experimental nature of IVLT as a treatment for intoxication in cats. PMID- 26748970 TI - A communicating pelvic cyst with hip capsule in neglected developmental hip dysplasia: case report. PMID- 26748971 TI - [Social representations of public health among healthcare workers within the French Armed Forces]. AB - BACKGROUND: Public health is a multidisciplinary activity whose fields of action are acquiring an increasingly broad. The Service de sante des armees (SSA) has always had a culture of public health problems thanks to doctors specialized in the treatment of major diseases. Often involved in public health activities, health professionals nevertheless have a fragmented vision. The objective was to describe the social representations of public health of military healthcare workers. METHOD: The responders were doctors, nurses, veterinarians and pharmacists practicing in different areas of SSA (caregivers, administrators, policy makers) and were interviewed by telephone. A question of spontaneous evocation on the representations of public health in the army was asked. The overall lexical analysis was performed according to the method of rank-frequency. Categorical analysis was conducted to better understand the whole lexical field use. RESULTS: There were 90 responders. The most salient terms were "prevention, epidemiological surveillance and vaccination". The categorical analysis showed that doctors used a lexical field primarily focused on diseases and risk behaviors, nurses on the specifics of military surveillance and policy makers about the cross-discipline. CONCLUSION: Public health in the army is mainly represented by epidemiological surveillance and prevention. Given the non mentioned fields, a strengthening of communication on the current challenges of public health would probably improve adherence of healthcare professionals since public health takes on more and more importance in the development of the national health policy and management of health crises. PMID- 26748972 TI - Public health impact of Infanrix hexa (DTPa-HBV-IPV/Hib) reimbursement: A study programme in France. Part 1: Evolution of hepatitis B vaccine coverage rates in infants aged less than 27 months, in the general population - the PopCorn study. AB - BACKGROUND: Reimbursement of the hexavalent vaccine (Infanrix hexa) comprising the DTPa-IPV-Hib components and the hepatitis B valence in a single vaccine was decided in March 2008 in France. The impact of its reimbursement on the hepatitis B vaccine coverage rate was assessed in a study conducted in the general population prior to and after implementation of the reimbursement policy. METHODS: The PopCorn study (NCT01782794) was a national, cross-sectional and repeated study, with four assessment periods over 3 years, from 2009 to 2012, to assess the hepatitis B vaccine coverage in 12- to 15- and 24- to 27-month-old children, vaccinated between 2007 and 2011 and selected by the quota sampling method. Face-to-face interviews were conducted at their homes and vaccination status was collected using their child's health record. Parents were also interviewed on their perceptions and acceptance of hepatitis B vaccination. Three indicators were calculated to assess hepatitis B vaccination coverage: proportions of infants with at least one dose before 6 months of age, with at least two doses before 6 months of age and with a complete schedule at 24 months of age. RESULTS: A total of 4903 children were enrolled in the study. An overall significant increase (P-value [P<0.05]) of the three indicators of interest over the four periods of time was observed for both age groups. The proportion of children receiving hepatitis B vaccination before 6 months increased from 21% at baseline (before vaccine reimbursement) to almost 75% at the last assessment period in 2012. More than 60% of 24- to 27-month-old children received a complete schedule in 2012 compared to 33% at baseline. No significant increases in the proportions of parents "favourable" and "moderately in favour" of hepatitis B vaccination were observed across the four evaluation periods (respectively, 17 22% and 48-50%, P=0.09). CONCLUSION: The rapid increase of hepatitis B vaccination coverage suggests a significant change in hepatitis B vaccination practice related to the hexavalent vaccine's reimbursement. This change was observed in a context of stability regarding parents' perceptions and acceptance of hepatitis B vaccination and of coverage rates for other infant vaccinations. PMID- 26748974 TI - High prevalence of metabolic syndrome in patients with psoriasis in Lebanon: a prospective study. AB - BACKGROUND: Psoriasis is a chronic inflammatory disease that affects not only the skin but also other organs as well. Genetic factors play an important role in individual predisposition. Lately, a positive association has been confirmed between psoriasis and metabolic syndrome (MBS), in western as well as in Middle Eastern countries. AIM: Assess the prevalence of MBS in Lebanese patients with psoriasis and the differential effect according to types and disease severity. METHODS: This was a case-control study including 150 psoriasis patients and 150 age- and gender-matched controls admitted to the dermatology clinics at the American University of Beirut-Medical Center, a tertiary care center in Beirut. Psoriasis severity was assessed by the Psoriasis Area Severity Index (PASI). Blood samples were collected from fasting subjects and tested for glucose, HDL cholesterol, triglycerides, and C-reactive protein (CRP). Multivariate binary logistic regression models were built to assess the relationship between MBS and psoriasis, after adjustment for smoking as a possible confounding variable. RESULTS: Patients with psoriasis were two times more likely to have MBS as compared to controls (35.3% vs 18.0%, P < 0.001) with an odds ratio (OR) of 2.4. All components of MBS were more prevalent in psoriasis patients than in controls. PASI score was greater in patients with MBS than those without MBS (10.5 +/- 11.5 vs. 7.0 +/- 8.1, P = 0.05). MBS prevalence tended to be higher in the inverse type than in others (52.2% versus 32.3%; P = 0.06) and in patients with nail pitting versus those without (45.3% vs. 28.2%; P = 0.03). CONCLUSIONS: This was the first study to assess the prevalence of MBS in Lebanese subjects with psoriasis and, to our knowledge, the first study that showed a higher likelihood of MBS in patients with inverse psoriasis and with nail pitting. PMID- 26748973 TI - 5'UTR +24T>C CR2 is not associated with nasopharyngeal carcinoma development in the North Region of Portugal. AB - OBJECTIVE: We have analysed the association of the +24T>C polymorphism (rs3813946) in CR2, the cellular receptor for Epstein-Barr virus (EBV), in the susceptibility for the development of nasopharyngeal carcinoma (NPC). METHODS: A retrospective case-control study was developed with peripheral blood samples from 111 individuals with NPC and 608 healthy individuals (controls) from the North region of Portugal. The genotyping analysis was performed by allelic discrimination real-time PCR using a TaqMan((r)) SNP Genotyping Assay. RESULTS: The genotype distribution was 62.2% TT, 34.2% TC and 3.6% CC for NPC patients; and 65.0%, 30.6% and 4.4%, respectively, for controls. Our study showed no statistical association between the genotype distribution in controls and all types of NPC (P = 0.717); nevertheless, the analysis showed statistically significant differences (P = 0.038) regarding cases with well- or moderately differentiated types of NPC suggesting that +24CC/CT genotypes are associated with increased risk (OR = 4.16; 95% CI 1.28-15.7; P = 0.016). CONCLUSIONS: This is the first study in Western populations to characterize the association of the CR2 +24T>C polymorphism in NPC development, and our results suggest that more studies are required to clarify the impact on NPC susceptibility in different populations. PMID- 26748975 TI - A Single-Lung Transplantation Complicated by Torsion of the Donor Lung: Diagnosis by Intraoperative Transesophageal Echocardiography. PMID- 26748976 TI - The Effect of Cardiopulmonary Bypass on Dabigatran Levels. PMID- 26748977 TI - CASE 3--2016: Cardiopulmonary Instability Following Single-Lung Transplant. PMID- 26748979 TI - A study to investigate and compare the physicomechanical properties of experimental and commercial temporary crown and bridge materials. AB - OBJECTIVES: To develop two experimental temporary crown and bridge materials with improved physicomechanical properties. METHODS: Commercial materials: Trim (TR, monomethacrylate, Bosworth) and Quicktemp2 (QT, dimethacrylate, Schottlander). EXPERIMENTAL MATERIALS: isobutyl methacrylate/poly(ethyl methacrylate) (IBMA/PEM) and n-butyl methacrylate/PEM (nBMA/PEM), both monomethacrylates. For water absorption/desorption studies rectangular samples (40 mm * 10 mm * 1 mm) of each material were prepared, immersed in deionized water (DW, control) and artificial saliva (AS), and weighed at regular time intervals. %solubility and diffusion coefficients (D) for uptake/loss processes were calculated and compared with theoretical predictions. Polymerization exotherm (cylindrical samples 10 mm * 18 mm) and flexural moduli were measured (three point bending; rectangular samples 80 mm * 10 mm * 4 mm, dry and after 9 days storage in DW). The data were compared statistically. RESULTS: QT and nBMA/PEM had lower %equilibrium uptakes/loss in DW (0.68%/0.884% and 0.64%/0.895% respectively). QT had the lowest water absorption/desorption D (P<0.05) compared to the three monomethacrylates, in DW and AS. %solubility for all systems showed no differences in DW (P>0.05), but a difference for QT in AS (P<0.05). QT reached its maximum temperature rapidly (~2 min; 3 monomethacrylates ~7-13 min). The commercial materials exhibited high peak temperatures (~51 degrees C, P<0.05; experimental materials ~43 degrees C). QT had a higher flexural modulus (~4 GPa; 3 monomethacrylates ~0.7-1 GPa) for dry and wet samples. The moduli for commercial materials reduced significantly after immersion in DW; there was no difference between the dry and wet experimental materials samples (P>0.05). SIGNIFICANCE: The experimental materials merit further studies since they presented with lower setting exotherms, and contained no phthalate plasticizer, thus being less of a risk to patients. PMID- 26748978 TI - Influence of dermal exposure to ultraviolet radiation and coal tar (polycyclic aromatic hydrocarbons) on the skin aging process. AB - BACKGROUND: Ultraviolet radiation (UVR) and crude coal tar (CCT) containing PAHs can accelerate the skin-aging process (SAP). However, UVR induces the formation of an important protective factor in SAP (vitamin D). OBJECTIVE: To determine the relation of SAP to selected risks and benefits of combined dermal exposure to UVR and coal tar (PAHs). METHODS: The study group consisted of patients with chronic stable plaque psoriasis and treated by Goeckerman therapy (GT; daily dermal application of UVR and 5% CCT ointment). The levels of urinary 1-hydroxypyrene (1 OHP), oxidative stress (DNA and RNA damage), genotoxic damage (chromosomal aberration in peripheral lymphocytes; ABC), 25-hydroxy-vitamin D [25(OH)D] and the PASI score were evaluated before and after GT. RESULTS: Intensive dermal absorption of PAHs was confirmed by increased levels of 1-OHP (p<0.01). After the therapy, we found an increased level of oxidative stress (p<0.05), an increased level of genotoxic damage (ABC; p<0.001), a high efficiency of the treatment (p<0.001) and an elevated production of 25(OH)D (p<0.01). We also found a relationship between the duration of UVR and the genotoxic damage (p<0.01), vitD (p<0.05) and the PASI score (p<0.05). Furthermore, we found a relationship between oxidative stress and 25(OH)D (p<0.05) and between genotoxic damage and the PASI score (p<0.05). CONCLUSION: Dermal exposure to UVR and coal tar (PAHs) enhances the level of oxidative stress and genotoxic damage and thus contributes to SAP. However, the exposure is very effective as a treatment and elevates the production of 25(OH)D, the protective factor in SAP. According to our results, UVR is probably a more hazardous factor in SAP. PMID- 26748981 TI - Monitoring Susceptibility of Western Bean Cutworm (Lepidoptera: Noctuidae) Field Populations to Bacillus thuringiensis Cry1F Protein. AB - Zea mays L. (maize) hybrids producing the Cry1F protein from Bacillus thuringiensis were first commercialized in the United States in 2003. These products demonstrated varying levels of moderate control, but not immunity to Striacosta albicosta (Smith) (Lepidoptera: Noctuidae) (western bean cutworm). Susceptibility of western bean cutworm to Cry1F protein was assessed in field populations collected in the mid- and western United States in 2003, 2004, 2013, and 2014 using diet bioassay. A meta-analysis of 32 western bean cutworm field collections assessed for susceptibility to Cry1F was conducted to investigate changes in susceptibility over time. Based on meta-analysis results, these data suggest a 5.2-fold increase in median lethal concentration (LC50) response to Cry1F in the 2013-2014 populations compared with collections that were assessed 10 yr earlier. Widespread use of Cry1F-producing maize hybrids over the past 10 yr may have contributed to favoring western bean cutworm populations with tolerance to the Cry1F protein. PMID- 26748980 TI - Confocal laser scanning microscopy and area-scale analysis used to quantify enamel surface textural changes from citric acid demineralization and salivary remineralization in vitro. AB - OBJECTIVES: This paper investigates the application of confocal laser scanning microscopy to determine the effect of acid-mediated erosive enamel wear on the micro-texture of polished human enamel in vitro. METHODS: Twenty polished enamel samples were prepared and subjected to a citric acid erosion and pooled human saliva remineralization model. Enamel surface microhardness was measured using a Knoop hardness tester, which confirmed that an early enamel erosion lesion was formed which was then subsequently completely remineralized. A confocal laser scanning microscope was used to capture high-resolution images of the enamel surfaces undergoing demineralization and remineralization. Area-scale analysis was used to identify the optimal feature size following which the surface texture was determined using the 3D (areal) texture parameter Sa. RESULTS: The Sa successfully characterized the enamel erosion and remineralization for the polished enamel samples (P<0.001). SIGNIFICANCE: Areal surface texture characterization of the surface events occurring during enamel demineralization and remineralization requires optical imaging instrumentation with lateral resolution <2.5 MUm, applied in combination with appropriate filtering in order to remove unwanted waviness and roughness. These techniques will facilitate the development of novel methods for measuring early enamel erosion lesions in natural enamel surfaces in vivo. PMID- 26748982 TI - Bacterial Volatiles Attract Gravid Secondary Screwworms (Diptera: Calliphoridae). AB - Bovine blood inoculated and incubated with bacteria was tested to determine if secondary screwworm, Cochliomyia macellaria (F.), would be attracted to the incubated substrate for oviposition. Five species of bacteria, Klebsiella oxytoca (Flugge), Proteus mirabilis Hauser, Proteus vulgaris Hauser, Providencia rettgeri Hadley, Elkins and Caldwell, and Providencia stuartii Ewing, previously isolated from animal wounds infested by primary screwworms, Cochliomyia hominivorax (Coquerel), were used. Incubated substrates were tested in a two-choice cage bioassay to study landing response and oviposition by gravid C. macellaria. Significantly more flies landed on substrates containing P. mirabilis than on substrates with other species of bacteria. Klebsiella oxytoca-treated substrates attracted the least flies. Substrates containing bacteria incubated for 72 h attracted significantly more flies than those incubated for 24-, 48-, or 96-h period. In 3-h duration oviposition tests, substrates with P. rettgeri attracted significantly more flies to oviposit than the other four species. The most eggs were recorded when substrates treated with all five species of bacteria were offered for oviposition. It is likely that multiple active chemicals present in the volatiles from substrates treated with all five species result in greater response than those in a single species. At least 72-h incubation seems to be necessary to obtain the most active volatile chemicals. Results suggest that C. macellaria uses similar chemical cues as C. hominivorax from bacteria volatiles as oviposition attractant/stimulant. PMID- 26748983 TI - The substrate promiscuity of a phosphopantetheinyl transferase SchPPT for coenzyme A derivatives and acyl carrier proteins. AB - Phosphopantetheinyl transferases (PPTases) catalyze the posttranslational modification of acyl carrier proteins (ACPs) in fatty acid synthases (FASs), ACPs in polyketide synthases, and peptidyl carrier proteins (PCPs) in nonribosomal peptide synthetases (NRPSs) in all organisms. Some bacterial PPTases have broad substrate specificities for ACPs/PCPs and/or coenzyme A (CoA)/CoA analogs, facilitating their application in metabolite production in hosts and/or labeling of ACPs/PCPs, respectively. Here, a group II PPTase SchPPT from Streptomyces chattanoogensis L10 was characterized to accept a heterologous ACP and acetyl CoA. Thus, SchPPT is a promiscuous PPTase and may be used on polyketide production in heterologous bacterial host and labeling of ACPs. PMID- 26748984 TI - Idiopathic Ulcerative Laryngitis: An uncommon disease. PMID- 26748985 TI - Nuclear AgNOR protein enhancement in nucleoplasms of peripheral blood lymphocytes of babies/children with Down syndrome. AB - Down syndrome (DS) is one of the most common chromosomal disorders. The factors contributing to the mental retardation together with other defects in this syndrome have not been fully explained. Individuals with DS have extra rRNA gene family since they carry an extra chromosome 21. The few reports available are on the relationship between the nucleolus organizer regions (NORs) and DS phenotype. The in vivo regulation of NORs expression on the extra chromosome 21 is not completely understood. Previous studies have shown that nucleoli of lymphocytes from infants (mostly neonates) with DS contain more in vivo and in vitro nucleolar AgNOR proteins when compared with healthy infants. The objective of this study is to compare the in vivo nuclear AgNOR protein level in nucleoplasms (also called as karyoplasm) of nonstimulated peripheral blood lymphocytes from babies/children with DS and healthy controls. Peripheral blood samples obtained from 20 babies/children with DS and 20 matched healthy controls were smeared on clean glass slides and then AgNOR staining was performed. The AgNOR protein level in nucleoplasms of lymphocytes from both groups was calculated using a computer program. Nearly 100 interphase nuclei per individual were analysed. Average nuclear AgNOR protein levels in nucleoplasms of lymphocytes from babies/children with DS were found to be significantly higher than those of the controls (P < 0.001). On the basis of our present results, we propose that the increase of nuclear AgNOR protein in in vivo conditions may contribute to the formation of DS phenotypes. PMID- 26748986 TI - Short time efficacy and safety of focused monopolar radiofrequency device for labial laxity improvement-noninvasive labia tissue tightening. A prospective cohort study. AB - BACKGROUND AND OBJECTIVE: To evaluate safety and efficacy of focused monopolar radio frequency (RF) device for non-invasive labia tissue tightening and improvement of labial laxity. METHODS: This prospective cohort study participants were 17 female subjects aged between 27 and 56 years with lax skin at the labia area. All subjects received four consecutive treatments at 7-day intervals with RF device (Exilis Protege IntimaR, BTL Industries Inc., Boston, MA). The primary efficacy outcome measure was defined as one or more point improvement on 1-4 scale for vulva appearance determined by three blinded evaluators. Digital photographs were taken at the baseline and 1 month after the last treatment. Sexual gratification was assessed with Female Sexual Functioning Index (FSFI) and patient discomfort by Visual Analogue Scale (VAS). RESULTS: An average 2.9 (of maximum 4) points improvement rate in vulvar appearance was observed (P < 0.01). Mean of the total FSFI score enhanced from initial 75-87% (P < 0.001). Resultant 4.7 (18%) points increase was achieved. Ninety four percent of subjects reported mild to none discomfort during the treatment. No adverse events during the study course were reported. CONCLUSION: The present study demonstrates the positive effect of focused monopolar RF device for non-invasive labia tissue tightening. The treatment is effective and safe with high patient satisfaction. PMID- 26748987 TI - Diabetes in the Cohen Rat Intensifies the Fetal Pancreatic Damage Induced by the Diabetogenic High Sucrose Low Copper Diet. AB - Intrauterine hyperglycemic environment could harm the fetus making it more susceptible to develop postnatal glucose intolerance. A possible mechanism is compromise of the fetal pancreatic development. We previously found that a high sucrose low copper diabetogenic diet induces type 2 diabetes in the Cohen diabetic sensitive rats, but not in the Sabra control rats. However, oxidative stress was observed in the placenta and term fetal liver of diabetic and nondiabetic controls. We now investigated whether the fetal pancreas is affected by this diet and whether the effects result from oxidative stress, maternal hyperglycemia, or both. Term fetal pancreases were evaluated for morphology, beta cells, oxidative stress, apoptosis, and DNA methylation. There were no microscopic changes in hematoxylin and eosin stained sections and beta cells immunostaining in the pancreas of fetuses of both strains. Fetuses of the sensitive strain fed diabetogenic diet had significantly higher activity of superoxide dismutase and catalase, elevated levels of low molecular weight antioxidants, and more intense immunostaining for nuclear factor kappa-B and hypoxia inducing factor-1alpha. Both strains fed diabetogenic diet had increased immunostaining for Bcl-2-like protein and caspase 3 and decreased immunostaining for 5-methylcytosine in their islets and acini. Our data suggest that maternal diabetogenic diet alters apoptotic rate and epigenetic steady states in the term fetal pancreas, unrelated to maternal diabetes. Maternal hyperglycemia further increases pancreatic oxidative stress, aggravating the pancreatic damage. The diet-induced insults to the fetal pancreas may be an important contributor to the high susceptibility to develop diabetes following metabolic intrauterine insults. PMID- 26748989 TI - Mitochondrial pyruvate carrier in Trypanosoma brucei. AB - Pyruvate is a key product of glycolysis that regulates the energy metabolism of cells. In Trypanosoma brucei, the causative agent of sleeping sickness, the fate of pyruvate varies dramatically during the parasite life cycle. In bloodstream forms, pyruvate is mainly excreted, whereas in tsetse fly forms, pyruvate is metabolized in mitochondria yielding additional ATP molecules. The character of the molecular machinery that mediates pyruvate transport across mitochondrial membrane was elusive until the recent discovery of mitochondrial pyruvate carrier (MPC) in yeast and mammals. Here, we characterized pyruvate import into mitochondrion of T. brucei. We identified mpc1 and mpc2 homologs in the T. brucei genome with attributes of MPC protein family and we demonstrated that both proteins are present in the mitochondrial membrane of the parasite. Investigations of mpc1 or mpc2 gene knock-out cells proved that T. brucei MPC1/2 proteins facilitate mitochondrial pyruvate transport. Interestingly, MPC is expressed not only in procyclic trypanosomes with fully activated mitochondria but also in bloodstream trypanosomes in which most of pyruvate is excreted. Moreover, MPC appears to be essential for bloodstream forms, supporting the recently emerging picture that the functions of mitochondria in bloodstream forms are more diverse than it was originally thought. PMID- 26748988 TI - NGF eye-drops topical administration in patients with retinitis pigmentosa, a pilot study. AB - BACKGROUND: Preclinical trials have shown beneficial effects of nerve growth factor (NGF) administration on visual function in animal models of retinitis pigmentosa (RP). The aim of this pilot study was to explore the potential efficacy of short term NGF eye drops treatment in patients affected by RP. METHODS: The trial consisted in 10 days daily administration of murine NGF as eye drops for a total dose of 1 mg NGF/pt. Eight RP patients at an advanced stage of the disease were included in the trial. To monitor safety and potential adverse effects subjects underwent standard clinical measures and were requested to report any general or topic alterations following NGF assumption. Retinal function was assessed at baseline and after treatment by best-corrected visual acuity measurement (BCVA), macular focal electroretinogram (fERG) recording and Goldmann visual field testing. RESULTS: A transient tolerable local corneal irritation was the only adverse effect reported. fERG and BCVA remained within the limits determined by test-retest analysis of a large cohort of RP patients. Three patients reported a subjective feeling of improved visual performance. This was associated to a temporary enlargement of the visual field in all three patients and to improved fERG in two of the three. CONCLUSIONS: Short-term administration of NGF eye-drops caused neither significant adverse effects nor visual function losses in the tested RP patients. A minority of patients experienced an improvement of visual performance as shown by Goldmann visual field and fERG. This study supports the safety and possible efficacy of NGF eye drops administration in RP patients. TRIAL REGISTRATION: EudraCT n. 2008-004561 26. PMID- 26748990 TI - Large-Scale Synthesis of Enantiopure Molecular Cages: Chiroptical and Recognition Properties. AB - A convenient and efficient gram-scale synthesis for enantiopure hemicryptophane tren (tren=tris(2-aminoethyl)amine) derivatives has been developed. The four-step synthesis is based on the optical resolution of a key intermediate, cyclotriveratrylene, for which the energy barrier for racemization has been measured to ensure that no racemization occurs during the two last steps of the synthetic pathway. The assignments of the absolute configurations have been performed by electronic circular dichroism and the enantiopurity was determined by NMR spectroscopy in the presence of enantiopure camphor sulfonic acid. To highlight the interest of such compounds, the recognition of norephedrine neurotransmitter was investigated and showed a remarkable enantioselectivity towards the C3 symmetrical hosts. Finally, this highly modular synthetic pathway was used to provide eight enantiopure hemicryptophanes with different sizes, shapes, and functionalities. These results underline the high potential of this approach, which could lead to many applications in chiral recognition or asymmetric supramolecular catalysis. PMID- 26748991 TI - Intimate Partner Violence PTSD and Neural Correlates of Inhibition. AB - Posttraumatic stress disorder (PTSD) has been linked to deficits in response inhibition, and neuroimaging research suggests this may be due to differences in prefrontal cortex recruitment. The current study examined relationships between PTSD from intimate partner violence (IPV) and neural responses during inhibition. There were 10 women with PTSD from IPV and 12 female control subjects without trauma history who completed the stop signal task during functional magnetic resonance imaging. Linear mixed models were used to investigate group differences in activation (stop-nonstop and hard-easy trials). Those with PTSD exhibited greater differential activation to stop-nonstop trials in the right dorsolateral prefrontal cortex and the anterior insula and less differential activation in several default mode regions (d = 1.12-1.22). Subjects with PTSD exhibited less differential activation to hard-easy trials in the lateral frontal and the anterior insula regions (driven by less activation to hard trials) and several default mode regions (i.e., medial prefrontal cortex, posterior cingulate; driven by greater activation to easy trials; d = 1.23-1.76). PTSD was associated with difficulties disengaging default mode regions during cognitive tasks with relatively low cognitive demand, as well as difficulties modulating executive control and salience processing regions with increasing cognitive demand. Together, these results suggest that PTSD may relate to decreased neural flexibility during inhibition. PMID- 26748993 TI - Multiplex cytokine levels of aqueous humor in acute primary angle-closure patients: fellow eye comparison. AB - BACKGROUND: The existing literature contains no information regarding inflammatory cytokine expression in unilateral acute primary angle-closure (APAC) affected eyes and fellow eyes with primary angle closure suspect (PACS). To measure levels of various inflammatory cytokines in the aqueous humor (AH) of APAC affected eyes and fellow eyes with a diagnosis of PACS (18 unilateral APAC eyes and 18 fellow eyes with PACS), and determine the underlying correlation between them. METHODS: The total levels of 12 cytokines including granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1, MCP-3, macrophage-derived chemokine (MDC), macrophage inflammatory protein (MIP)-1beta, and vascular endothelial growth factor (VEGF) etc. were assessed using the multiplex bead immunoassay technique. The level of cytokines in different groups was analyzed by a 2-related-samples nonparametric test. Data on patient demographics, preoperative intraocular pressure (IOP), number of glaucoma medications, as well as several ocular biological parameters were also collected for correlation analysis. RESULTS: The APAC patients had significantly higher levels of G-CSF, IL-6, IL-8, MCP-1, MCP-3, MDC, MIP-1beta, and VEGF in the AH samples from unilateral APAC affected eyes than in fellow eyes with PACS (all P < 0.05). The cytokines showed positive correlations between each other (P < 0.0071). CONCLUSIONS: Cytokine networks in the AH may have critical roles in the progression of APAC. Thus, different cytokine expression in both eyes of the same patient may help us to understand the different pathology in APAC and PACS. PMID- 26748994 TI - The psychosocial status of the family members of rheumatoid arthritis patients in Korea. AB - To investigate the psychosocial aspect of the family members of the patients with rheumatoid arthritis (RA), we conducted a population-based analysis to examine the psychosocial characteristics of family members of RA patients in comparison with the general population. From the Fifth Korea National Health and Nutrition Examination Survey dataset (KNHANES V) (2010-2012), we identified 363 RA patients and selected family members of these patients who were aged 20 years or older (n = 367). The control group was randomly sampled from members of families without RA patients and matched for sex and age (n = 1101). We compared the psychosocial characteristics of family members of RA patients with the control group. Additionally, serial conditional logistic regression models were performed to evaluate the factors that affect psychosocial status of the RA family members, after adjusting for covariates. No significant differences were found in socioeconomic status between the two groups. For psychological factors, stress (85.8 vs 74.7 %, p < 0.001) and depression (7.9 vs 3.3 %, p < 0.001) were more common in the family members of RA patients. The presence of a RA patient in the family showed a positive association with stress [odds ratio (OR) 2.07; 95 % confidence interval (CI) 1.48-2.88, p < 0.001] and depression (OR 2.59, CI 1.55 4.32, p < 0.001), after adjusting for socioeconomic status. Our data show that the family members of RA patients have an increased prevalence of stress and depression. Physicians who treat RA patients should also consider the needs and the burden of family members. PMID- 26748995 TI - Inter and intra-population phenotypic and genotypic structuring in the European whitefish Coregonus lavaretus, a rare freshwater fish in Scotland. AB - This study revealed between-lake genetic structuring between Coregonus lavaretus collected from the only two native populations of this species in Scotland, U.K. (Lochs Eck and Lomond) evidenced by the existence of private alleles (12 in Lomond and four in Eck) and significant genetic differentiation (FST = 0.056) across 10 microsatellite markers. Juvenile C. lavaretus originating from eggs collected from the two lakes and reared in a common-garden experiment showed clear phenotypic differences in trophic morphology (i.e. head and body shape) between these populations indicating that these characteristics were, at least partly, inherited. Microsatellite analysis of adults collected from different geographic regions within Loch Lomond revealed detectable and statistically significant but relatively weak genetic structuring (FST = 0.001-0.024) and evidence of private alleles related to the basin structure of the lake. Within lake genetic divergence patterns suggest three possibilities for this observed pattern: (1) differential selection pressures causing divergence into separate gene pools, (2) a collapse of two formerly divergent gene pools and (3) a stable state maintained by balancing selection forces resulting from spatial variation in selection and lake heterogeneity. Small estimates of effective population sizes for the populations in both lakes suggest that the capacity of both populations to adapt to future environmental change may be limited. PMID- 26748996 TI - Improving the safety and quality of nursing care through standardized operating procedures in Bosnia and Herzegovina. AB - AIM: We explored how selected 'positive deviant' healthcare facilities in Bosnia and Herzegovina approach the continuous development, adaptation, implementation, monitoring and evaluation of nursing-related standard operating procedures. BACKGROUND: Standardized nursing care is internationally recognized as a critical element of safe, high-quality health care; yet very little research has examined one of its key instruments: nursing-related standard operating procedures. INTRODUCTION: Despite variability in Bosnia and Herzegovina's healthcare and nursing care quality, we assumed that some healthcare facilities would have developed effective strategies to elevate nursing quality and safety through the use of standard operating procedures. METHODS: Guided by the 'positive deviance' approach, we used a multiple-case study design to examine a criterion sample of four facilities (two primary healthcare centres and two hospitals), collecting data via focus groups and individual interviews. FINDINGS: In each studied facility, certification/accreditation processes were crucial to the initiation of continuous development, adaptation, implementation, monitoring and evaluation of nursing-related SOPs. In one hospital and one primary healthcare centre, nurses working in advanced roles (i.e. quality coordinators) were responsible for developing and implementing nursing-related standard operating procedures. Across the four studied institutions, we identified a consistent approach to standard operating procedures-related processes. CONCLUSIONS: The certification/accreditation process is enabling necessary changes in institutions' organizational cultures, empowering nurses to take on advanced roles in improving the safety and quality of nursing care. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Standardizing nursing procedures is key to improve the safety and quality of nursing care. Nursing and Health Policy are needed in Bosnia and Herzegovina to establish a functioning institutional framework, including regulatory bodies, educational systems for developing nurses' capacities or the inclusion of nursing-related standard operating procedures in certification/accreditation standards. PMID- 26748992 TI - Vision loss in juvenile neuronal ceroid lipofuscinosis (CLN3 disease). AB - Juvenile neuronal ceroid lipofuscinosis (JNCL; also known as CLN3 disease) is a devastating neurodegenerative lysosomal storage disorder and the most common form of Batten disease. Progressive visual and neurological symptoms lead to mortality in patients by the third decade. Although ceroid-lipofuscinosis, neuronal 3 (CLN3) has been identified as the sole disease gene, the biochemical and cellular bases of JNCL and the functions of CLN3 are yet to be fully understood. As severe ocular pathologies manifest early in disease progression, the retina is an ideal tissue to study in the efforts to unravel disease etiology and design therapeutics. There are significant discrepancies in the ocular phenotypes between human JNCL and existing murine models, impeding investigations on the sequence of events occurring during the progression of vision impairment. This review focuses on current understanding of vision loss in JNCL and discusses future research directions toward molecular dissection of the pathogenesis of the disease and associated vision problems in order to ultimately improve the quality of patient life and cure the disease. PMID- 26748997 TI - Silibinin derivatives as anti-prostate cancer agents: Synthesis and cell-based evaluations. AB - This study aims to systematically explore the alkylation effect of 7-OH in silibinin and 2,3-dehydrosilibinin on the antiproliferative potency toward three prostate cancer cell lines. Eight 7-O-alkylsilibinins, eight 7-O-alkyl-2,3 dehydrosilibinins, and eight 3,7-O-dialkyl-2,3-dehydrosilibinins have been synthesized from commercially available silibinin for the in vitro cell-based evaluation. The WST-1 cell proliferation assay indicates that nineteen out of twenty-four silibinin derivatives have significantly improved antiproliferative potency when compared with silibinin. 7-O-Methylsilibinin (2) and 7-O ethylsilibinin (3) have been identified as the most potent compounds with 98- and 123-fold enhanced potency against LNCaP human androgen-dependent prostate cancer cell line. Among 2,3-dehydrosilibinin derivatives, 7-O-methyl-2,3 dehydrosilibinin (10) and 7-O-ethyl-2,3-dehydrosilibinin (11) have been identified as the optimal compounds with the highest potency towards both androgen-dependent LNCaP and androgen-independent PC-3 prostate cancer cell lines. 7-O-Ethyl-2,3-dehydrosilibinin (11) was demonstrated to arrest PC-3 cell cycle at the G0/G1 phase and to induce PC-3 cell apoptosis. The findings in this study suggest that antiproliferative potency of silibinin and 2,3 dehydrosilibinin can be appreciably enhanced through suitable chemical modifications on the phenolic hydroxyl group at C-7 and that introduction of a chemical moiety with the potential to improve bioavailability through a linker to 7-OH in silibinin and 2,3-dehydrosilibinin would be a feasible strategy for the development of silibinin derivatives as anti-prostate cancer agents. PMID- 26749000 TI - Does public health advocacy seek to redress health inequities? A scoping review. AB - The public health (PH) sector is ideally situated to take a lead advocacy role in catalysing and guiding multi-sectoral action to address social determinants of health inequities, but evidence suggests that PH's advocacy role has not been fully realised. The purpose of this review was to determine the extent to which the PH advocacy literature addresses the goal of reducing health and social inequities, and to increase understanding of contextual factors shaping the discourse and practice of PH advocacy. We employed scoping review methods to systematically examine and chart peer-reviewed and grey literature on PH advocacy published from January 1, 2000 to June 30, 2015. Databases and search engines used included: PubMed, CINAHL, PsycINFO, Social Sciences Citation Index, Google Scholar, Google, Google Books, ProQuest Dissertations and Theses, Grey Literature Report. A total of 183 documents were charted, and included in the final analysis. Thematic analysis was both inductive and deductive according to the objectives. Although PH advocacy to address root causes of health inequities is supported theoretically and through professional practice standards, the empirical literature does not reflect that this is occurring widely in PH practice. Tensions within the discourse were noted and multiple barriers to engaging in PH advocacy for health equity were identified, including a preoccupation with individual responsibilities for healthy lifestyles and behaviours, consistent with the emergence of neoliberal governance. If the PH sector is to fulfil its advocacy role in catalysing action to reduce health inequities, it will be necessary to address advocacy barriers at multiple levels, promote multi-sectoral efforts that implicate the state and corporations in the production of health inequities, and rally state involvement to redress these injustices. PMID- 26748999 TI - Co-delivery with nano-quercetin enhances doxorubicin-mediated cytotoxicity against MCF-7 cells. AB - Quercetin, the plant-derived phenolic compounds, plays a pivotal role in controlling hemostasis, by having potent antioxidant and free-radical scavenging properties. This flavonoid in combination with chemotherapeutic drugs improves the efficacy of these agents in induction of apoptosis in cancer cells. This study investigated the role of nano-quercetin (phytosome) in doxorubicin-induced apoptosis. Nanoparticles were characterized for particle size, zeta potential, scanning electron microscopy (SEM) and differential scanning calorimetric assessments. Anti-proliferative effect of formulations was evaluated by MTT assay. mRNA expression levels of target genes were measured by real time RT-PCR. The mean size of nanoparticles was 85 +/- 2 nm with nearly narrow size distribution which was confirmed by SEM analysis. Our results showed that co treatment of MCF-7 breast cancer cells with nano-quercetin and doxorubicin increased the percentage of apoptosis from 40.11 +/- 7.72-58 +/- 7.13 (p < 0.05). Furthermore, mRNA expression levels for downstream genes including NQO1 and MRP1 showed a marked decrease (p < 0.05). Taken together, our results suggest that phytosome technology can elevate the efficacy of chemotherapeutics by increasing the permeability of tumor cells to chemical agents. Our findings introduce a novel phytosome-dependent strategy to improve delivery of doxorubicin to the breast cancerous tissues. PMID- 26748998 TI - De novo development and characterization of polymorphic microsatellite markers in a schilbid catfish, Silonia silondia (Hamilton, 1822) and their validation for population genetic studies. AB - The stock characterization of wild populations of Silonia silondia is important for its scientific management. At present, the information on genetic parameters of S. silondia is very limited. The species-specific microsatellite markers were developed in current study. The validated markers were used to genotype individuals from four distant rivers. To develop de novo microsatellite loci, an enriched genomic library was constructed for S. silondia using affinity-capture approach. The markers were validated for utility in population genetics. A total number of 76 individuals from four natural riverine populations were used to generate data for population analysis. The screening of isolated repeat sequences yielded eleven novel polymorphic microsatellite loci. The microsatellite loci exhibited high level of polymorphism, with 6-24 alleles per locus and the PIC value ranged from 0.604 to 0.927. The observed (Ho) and expected (He) heterozygosities ranged from 0.081 to 0.84 and 0.66 to 0.938, respectively. The AMOVA analysis indicated significant genetic differentiation among riverine populations (overall FST = 0.075; P < 0.0001) with maximum variation (92.5%) within populations. Cross-priming assessment revealed successful amplification (35-38 %) of heterologous loci in four related species viz. Clupisoma garua, C. taakree, Ailia coila and Eutropiichthys vacha. The results demonstrated that these de novo polymorphic microsatellite loci are promising for population genetic variation and diversity studies in S. silondia. Cross-priming results indicated that these primers can help to get polymorphic microsatellite loci in the related catfish species of family Schilbidae. PMID- 26749001 TI - Scholarship improved by case report curriculum. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) requires that residents participate in scholarly activity. Case reports are an accessible form of resident scholarship, given the time required relative to other forms of research. Our paediatric residency lacked a curriculum for writing and presenting case reports. METHODS: We created and implemented a brief curriculum for writing case reports and scientific posters. The curriculum consisted of two 1-hour didactic sessions, followed by mentoring during the writing process. The impact of the curriculum was measured via resident surveys about the material presented and by the rate of presentations of case reports made by residents at our departmental research day, before and after implementation. RESULTS: In the year of curriculum implementation, there were 15 case reports presented at the departmental research day, compared with an average of 4.7 per year in the three prior years. The resident (n = 85) participation rate increased from an average of 0.06 case reports per resident per year before implementation to 0.18 case reports per resident per year after implementation (p = 0.0023). DISCUSSION: Implementation of a case report curriculum with subsequent mentoring was associated with a marked increase in resident case report presentations at the departmental research day. These results suggest that even brief instruction and subsequent faculty mentorship in preparation of case reports can significantly improve resident participation in scholarly activity. PMID- 26749002 TI - Variations in Performance of Mental Health Providers in the English NHS: An Analysis of the Relationship Between Readmission Rates and Length-of-Stay. AB - Length-of-stay (LOS) for inpatient mental health care is a major driver of variation in resource use internationally. We explore determinants of LOS in England, focusing on the impact of emergency readmission rates which can serve as a measure of the quality of care. Data for 2009/2010 and 2010/2011 are analysed using hierarchical and non-hierarchical models. Unexplained residual variation among providers is quantified using Empirical Bayes techniques. Diagnostic, treatment and patient-level demographic variables are key drivers of LOS. Higher emergency readmission rates are associated with shorter LOS. Ranking providers by residual variation reveals significant differences, suggesting some providers can improve performance. PMID- 26749004 TI - Expression of mep50 in adult and embryos of medaka fish (Oryzias latipes). AB - Protein arginine methylation is important for gene regulation and biological processes. Methylosome protein 50 (Mep50) is identified as a partner of protein arginine methyltransferase 5 (Prmt5), a major enzyme capable of symmetric dimethylation, in mammals and Xenopus. The isolation and characterization of medaka mep50 were reported in this paper. Medaka Mep50 is a homolog of human MEP50 with six WD40 domains. Medaka mep50 was ubiquitously expressed in the adult tissues and had maternal origin with continuous and dynamical expression during embryonic development detected by RT-PCR and in situ hybridization. A strong interaction of medaka Mep50 and Prmt5 was shown by yeast two hybridization. The expression pattern of mep50 is similar to that of prmt5 in medaka. The results suggested that medaka Mep50 could be a partner of Prmt5 and might play major roles in a variety of tissues in medaka. PMID- 26749005 TI - Role of gene expression profiling in defining indeterminate thyroid nodules in addition to BRAF analysis. AB - Fine-needle aspiration (FNA) is routinely used in the preoperative evaluation of thyroid nodules. However, 15% to 30% of aspirations yield indeterminate cytologic findings. Because the assessment of BRAF mutations seems to improve the diagnostic accuracy, this study evaluated BRAF mutations with Sanger sequencing and real-time methods in 650 consecutive thyroid aspirates. In addition, the expression of a large number of genes involved in basement membrane remodeling, extracellular matrix proteolysis, and cell adhesion was studied in both benign and malignant nodules to identify new diagnostic tools. In this prospective series, despite the use of a very sensitive BRAF mutational testing method, the frequency of a BRAF alteration being identified in indeterminate FNA samples was 3 of 68. Expression analysis revealed several genes that were differentially expressed between benign and malignant nodules (transforming growth factor, cadherin 1, collagen alpha1, catenin alpha1, integrin alpha3, and fibronectin 1 [FN1]), between follicular adenomas and follicular variant of papillary thyroid carcinoma (FN1, laminin gamma1, integrin beta2, connective tissue growth factor, catenin delta1, and integrin alphaV), and between BRAF-wild-type and BRAF-mutated papillary thyroid carcinomas (TIMP metallopeptidase inhibitor 1; catenin alpha1; secreted phosphoprotein 1; FN1; ADAM metallopeptidase with thrombospondin type 1 motif, 1; and selectin L). These data were partially confirmed with real-time polymerase chain reaction analysis and immunohistochemistry. When the cost/benefit ratio of the procedures was taken into account, BRAF mutational testing failed to increase diagnostic accuracy in cytologically indeterminate nodules. However, the additional analysis of the expression of specific molecular markers could have possible utility as a diagnostic tool, although further evidence based on a large series of samples is needed before definitive conclusions can be drawn. Cancer Cytopathol 2016;124:340-9. (c) 2015 American Cancer Society. PMID- 26749003 TI - Brain structure-function associations identified in large-scale neuroimaging data. AB - The relationships between structural and functional measures of the human brain remain largely unknown. A majority of our limited knowledge regarding structure function associations has been obtained through comparisons between specific groups of patients and healthy controls. Unfortunately, a direct and complete view of the associations across multiple structural and functional metrics in normal population is missing. We filled this gap by learning cross-individual co variance among structural and functional measures using large-scale neuroimaging datasets. A discover-confirm scheme was applied to two independent samples (N = 184 and N = 340) of multi-modal neuroimaging datasets. A data mining tool, gRAICAR, was employed in the discover stage to generate quantitative and unbiased hypotheses of the co-variance among six functional and six structural imaging metrics. These hypotheses were validated using an independent dataset in the confirm stage. Fifteen multi-metric co-variance units, representing different co variance relationships among the 12 metrics, were reliable across the two sets of neuroimaging datasets. The reliable co-variance units were summarized into a database, where users can select any location on the cortical map of any metric to examine the co-varying maps with the other 11 metrics. This database characterized the six functional metrics based on their co-variance with structural metrics, and provided a detailed reference to connect previous findings using different metrics and to predict maps of unexamined metrics. Gender, age, and handedness were associated to the co-variance units, and a sub study of schizophrenia demonstrated the usefulness of the co-variance database. PMID- 26749006 TI - Dietary patterns and retinal vascular calibre in children and adolescents with type 1 diabetes. AB - PURPOSE: To examine the association between dietary patterns and retinal vascular calibre in children and adolescents with type 1 diabetes. METHODS: A hospital based cross-sectional study of 83 children and adolescents with type 1 diabetes was conducted over an 8-month period. Dietary patterns were extracted using principal components analysis from completed food frequency questionnaires. Retinal vascular calibre was measured by a trained grader using a standardized protocol and later summarized as central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) using a semi-automated computer program. RESULTS: Three major dietary patterns were identified as follows: (1) processed foods, (2) plant-based foods and (3) vegetable/fish avoidance pattern. The processed pattern had high component loadings for processed meats and high fat takeaway foods. The plant-based pattern had high component loadings for a number of fruits including, but not limited to, pineapple, grapes oranges and mangos as well as a smaller number of vegetables, including beans and leeks. The vegetable and fish avoidance pattern had high inverse component loadings for canned and fresh fish as well as a number of vegetables including, but not limited to, pumpkin, green beans, broccoli, sweet potato and cabbage. Adjusted regression analysis revealed the 'vegetable/fish avoidance' dietary pattern was associated with a wider CRVE (ExpB = 3.67, 95% CI = 0.11/7.24, p = 0.039). After multivariable adjustments, a vascular risk profile that included: older age, higher BMI, higher systolic blood pressure, greater gestational age, longer screen viewing time, lower maternal education level, lower physical activity levels and lower high-density lipoproteins concentrations were more likely to display narrower CRAE (ExpB = -2.43, 95% CI = -4.92/0.06, p = 0.041). CONCLUSIONS: This study provides the first evidence for a diet-calibre relationship in children and adolescents with type 1 diabetes. This outcome has potential public health implications, as promotion of healthy eating patterns in children and adolescents might attenuate changes in microvasculature that have been related to an increased risk of microvascular disease, such as retinopathy, in adulthood. Additional studies are warranted to explore and validate this novel finding. PMID- 26749007 TI - NMR reveals structural rearrangements associated to substrate insertion in nucleotide-adding enzymes. AB - The protein NP_344798.1 from Streptococcus pneumoniae TIGR4 exhibits a head and base-interacting neck domain architecture, as observed in class II nucleotide adding enzymes. Although it has less than 20% overall sequence identity with any member of this enzyme family, the residues involved in substrate-recognition and catalysis are highly conserved in NP_344798.1. NMR studies showed binding affinity of NP_344798.1 for nucleotides and revealed MUs to ms time scale rate processes involving residues constituting the active site. The results thus obtained indicate that large-amplitude rearrangements of regular secondary structures facilitate the penetration of the substrate into the occluded nucleotide-binding site of NP_344798.1 and, by inference based on sequence and structural homology, probably a wide range of other nucleotide-adding enzymes. PMID- 26749008 TI - Effect of carbodiimide-derivatized hyaluronic acid gelatin on preventing postsurgical intra-abdominal adhesion formation and promoting healing in a rat model. AB - Adhesions often occur after abdominal surgery. It could cause chronic pelvic pain, intestinal obstruction, and infertility. A hydrogel biomaterial, carbodiimide-derivatized hyaluronic acid gelatin (cd-HA gelatin), has been successfully used to reduce adhesion formation after flexor tendon grafting. This study investigated the efficacy of cd-HA gelatin in preventing postsurgical peritoneal adhesions in a rat model. The surgical traumas were created on the underlying muscle of the abdominal wall and the serosal layer of the cecum. The wounds were covered with or without cd-HA gelatin. Animals were euthanized at day 14 after surgery. Adhesion formation was assessed with adhesion degree and adhesion breaking strength. The healing of abdominal wall was evaluated with biomechanical testing and histological analysis. The adhesions occurred in all rats (n = 12) without cd-HA gelatin treatment. The application of cd-HA gelatin significantly reduced the adhesion rate from 100% to 58%. The decrease of adhesion breaking strength also manifested that cd-HA gelatin could reduce postsurgical intra-abdominal adhesion formation. Moreover, it was found that cd HA gelatin was a safe material and could promote tissue healing. The cd-HA gelatin hydrogel could reduce the formation of intra-abdominal adhesions without adversely effects on wound healing. PMID- 26749009 TI - Prognostic factors of primary resected retroperitoneal soft tissue sarcoma: Analysis from a single asian tertiary center and external validation of gronchi's nomogram. AB - BACKGROUND: Surgery is the potentially curative treatment for retroperitoneal sarcoma (RS), but complete resectability is frequently a challenge. This study aimed to characterize the clinical features, prognostic factors and treatment outcomes. METHODS: A cohort of 144 patients with RS was surveyed retrospectively from January 1st, 2000 to July 30th, 2011. The prognostic influence of clinicopathological characteristics as well as treatments on local recurrence free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS), were examined by univariate and multivariate analyses. A histology specific nomogram developed by Gronchi et al was used for validation. RESULTS: Liposarcoma, leiomyosarcoma, and malignant peripheral sheath tumor (MPNST) were the most common histologies (70%). Multivariate analysis revealed FNCLCC tumor grade was the most significant prognostic factor for OS (P = 0.001) and DMFS (P < 0.001) and complete resection was the only significant prognostic factor for LRFS (P = 0.043). Incomplete resection of grade 3 tumor was significantly associated with a worse OS. Despite some differences in characteristics between our patients and Gronchi's cohort, external validation of Gronchi's nomogram demonstrated excellent concordance in predicting survival. CONCLUSIONS: Our study demonstrated tumor grade and surgical margins had significant prognostic influence and the Gronchi's nomogram has an excellent applicability in predicting survival of STS patients. J. Surg. Oncol. 2016;113:355-360. (c) 2016 Wiley Periodicals, Inc. PMID- 26749011 TI - Introduction-Epilepsy Research UK expert workshop 2014: SUDEP: Time for prevention-evidence and clinical translation Proceedings from the Epilepsy Research UK 2014 Expert Workshop. AB - We offer Epilepsia readers this supplement based on the proceedings of an international workshop on sudden death in epilepsy (SUDEP) held in 2014 at St Anne's College at Oxford and hosted by Epilepsy Research UK (ERUK). This is the second Epilepsia supplement dedicated to SUDEP and its focus is on prevention. As workshop co-chairs, in this introduction we outline why we believe we are on the threshold of a new era of prevention in SUDEP. PMID- 26749010 TI - Single neuron transcriptome analysis can reveal more than cell type classification: Does it matter if every neuron is unique? AB - A recent single cell mRNA sequencing study by Dueck et al. compares neuronal transcriptomes to the transcriptomes of adipocytes and cardiomyocytes. Single cell omic approaches such as those used by the authors are at the leading edge of molecular and biophysical measurement. Many groups are currently employing single cell sequencing approaches to understand cellular heterogeneity in cancer and during normal development. These single cell approaches also are beginning to address long-standing questions regarding nervous system diversity. Beyond an innate interest in cataloging cell type diversity in the brain, single cell neuronal diversity has important implications for neurotypic neural circuit function and for neurological disease. Herein, we review the authors' methods and findings, which most notably include evidence of unique expression profiles in some single neurons. PMID- 26749012 TI - Who to target in sudden unexpected death in epilepsy prevention and how? Risk factors, biomarkers, and intervention study designs. AB - The risk of dying suddenly and unexpectedly is increased 24- to 28-fold among young people with epilepsy compared to the general population, but the incidence of sudden unexpected death in epilepsy (SUDEP) varies markedly depending on the epilepsy population. This article first reviews risk factors and biomarkers for SUDEP with the overall aim of enabling identification of epilepsy populations with different risk levels as a background for a discussion of possible intervention strategies. The by far most important clinical risk factor is frequency of generalized tonic-clonic seizures (GTCS), but nocturnal seizures, early age at onset, and long duration of epilepsy have been identified as additional risk factors. Lack of antiepileptic drug (AED) treatment or, in the context of clinical trials, adjunctive placebo versus active treatment is associated with increased risks. Despite considerable research, reliable electrophysiologic (electrocardiography [ECG] or electroencephalography [EEG]) biomarkers of SUDEP risk remain to be established. This is an important limitation for prevention strategies and intervention studies. There is a lack of biomarkers for SUDEP, and until validated biomarkers are found, the endpoint of interventions to prevent SUDEP must be SUDEP itself. These interventions, be they pharmacologic, seizure-detection devices, or nocturnal supervision, require large numbers. Possible methods for assessing prevention measures include public health community interventions, self-management, and more traditional (and much more expensive) randomized clinical trials. PMID- 26749014 TI - From unwitnessed fatality to witnessed rescue: Nonpharmacologic interventions in sudden unexpected death in epilepsy. AB - Sudden unexpected death in epilepsy (SUDEP) risk reduction remains a critical aim in epilepsy care. To date, only aggressive medical and surgical efforts to control seizures have been demonstrated to be of benefit. Incomplete understanding of SUDEP mechanisms limits the development of more specific interventions. Periictal cardiorespiratory dysfunction is implicated in SUDEP; postictal electroencephalography (EEG) suppression, coma, and immobility may also play a role. Nocturnal supervision is protective against SUDEP, presumably by permitting intervention in the case of a life-threatening event. Resuscitative efforts were implemented promptly in near-SUDEP cases but delayed in SUDEP deaths in the Mortality in Epilepsy Monitoring Unit Study (MORTEMUS) study. Nursing interventions--including repositioning, oral suctioning, and oxygen administration--reduce seizure duration, respiratory dysfunction, and EEG suppression in the epilepsy monitoring unit (EMU), but have not been studied in outpatients. Cardiac pacemakers or cardioverter-defibrillator devices may be of benefit in a few select individuals. A role for implantable neurostimulators has not yet been established. Seizure detection devices, including those that monitor generalized tonic-clonic seizure-associated movements or cardiorespiratory parameters, may provide a means to permit timely periictal intervention. However, these and other devices, such as antisuffocation pillows, have not been adequately investigated with respect to SUDEP prevention. PMID- 26749016 TI - After sudden unexpected death in epilepsy: Lessons learned and the road forward. AB - The devastating effects of sudden unexpected death in epilepsy (SUDEP) can be difficult to navigate, even for experienced clinicians. Mounting evidence supports full disclosure of the risks of epilepsy to those affected and their caregivers, and recommendations from regulatory and professional groups encourage the same. Following a death, families are faced with tragedy, guilt, and sometimes anger. Clinicians are often called upon to provide information and support. The development of a comprehensive approach to SUDEP education requires careful consideration of the people living with epilepsy, facts about SUDEP and known risk factors, as well as experiences of families and care providers. In this article, we share the experiences of those working in SUDEP education and epilepsy care, including the voluntary sector. We explore the experience of bereaved families and clinicians, derive lessons from published research, highlight areas where more research is needed, and report on preliminary data from a nationwide study from France. PMID- 26749018 TI - Pulmonary Artery Aneurysm Compressing the Tracheobronchial Tree Following an Arterial Switch Operation. AB - A neonate developed severe dyspnea following an arterial switch operation due to compression of the trachea and left main bronchus by a dilated pulmonary artery. This was relieved by a second procedure in which the dilated pulmonary artery was excised and reconstructed with bovine pericardium. PMID- 26749013 TI - Sudden unexpected death in epilepsy genetics: Molecular diagnostics and prevention. AB - Epidemiologic studies clearly document the public health burden of sudden unexpected death in epilepsy (SUDEP). Clinical and experimental studies have uncovered dynamic cardiorespiratory dysfunction, both interictally and at the time of sudden death due to epilepsy. Genetic analyses in humans and in model systems have facilitated our current molecular understanding of SUDEP. Many discoveries have been informed by progress in the field of sudden cardiac death and sudden infant death syndrome. It is becoming apparent that SUDEP genomic complexity parallels that of sudden cardiac death, and that there is a pauci1ty of analytically useful postmortem material. Because many challenges remain, future progress in SUDEP research, molecular diagnostics, and prevention rests in international, collaborative, and transdisciplinary dialogue in human and experimental translational research of sudden death. PMID- 26749019 TI - Polymerizable Molecular Silsesquioxane Cage Armored Hybrid Microcapsules with In Situ Shell Functionalization. AB - We prepared core-shell polymer-silsesquioxane hybrid microcapsules from cage-like methacryloxypropyl silsesquioxanes (CMSQs) and styrene (St). The presence of CMSQ can moderately reduce the interfacial tension between St and water and help to emulsify the monomer prior to polymerization. Dynamic light scattering (DLS) and TEM analysis demonstrated that uniform core-shell latex particles were achieved. The polymer latex particles were subsequently transformed into well-defined hollow nanospheres by removing the polystyrene (PS) core with 1:1 ethanol/cyclohexane. High-resolution TEM and nitrogen adsorption-desorption analysis showed that the final nanospheres possessed hollow cavities and had porous shells; the pore size was approximately 2-3 nm. The nanospheres exhibited large surface areas (up to 486 m2 g-1 ) and preferential adsorption, and they demonstrated the highest reported methylene blue adsorption capacity (95.1 mg g-1 ). Moreover, the uniform distribution of the methacryloyl moiety on the hollow nanospheres endowed them with more potential properties. These results could provide a new benchmark for preparing hollow microspheres by a facile one-step template-free method for various applications. PMID- 26749017 TI - Specific transport of 3-fluoro-l-alpha-methyl-tyrosine by LAT1 explains its specificity to malignant tumors in imaging. AB - 3-(18)F-l-alpha-methyl-tyrosine ([18F]FAMT), a PET probe for tumor imaging, has advantages of high cancer-specificity and lower physiologic background. FAMT-PET has been proved useful in clinical studies for the prediction of prognosis, the assessment of therapy response and the differentiation of malignant tumors from inflammation and benign lesions. The tumor uptake of [18F]FAMT in PET is strongly correlated with the expression of L-type amino acid transporter 1 (LAT1), an isoform of system L upregulated in cancers. In this study, to assess the transporter-mediated mechanisms in FAMT uptake by tumors, we examined amino acid transporters for FAMT transport. We synthesized [14C]FAMT and measured its transport by human amino acid transporters expressed in Xenopus oocytes. The transport of FAMT was compared with that of l-methionine, a well-studied amino acid PET probe. The significance of LAT1 in FAMT uptake by tumor cells was confirmed by siRNA knockdown. Among amino acid transporters, [14C]FAMT was specifically transported by LAT1, whereas l-[14C]methionine was taken up by most of the transporters. Km of LAT1-mediated [14C]FAMT transport was 72.7 MUM, similar to that for endogenous substrates. Knockdown of LAT1 resulted in the marked reduction of [14C]FAMT transport in HeLa S3 cells, confirming the contribution of LAT1 in FAMT uptake by tumor cells. FAMT is highly specific to cancer-type amino acid transporter LAT1, which explains the cancer-specific accumulation of [18F]FAMT in PET. This, vice versa, further supports the cancer specific expression of LAT1. This study has established FAMT as a LAT1-specific molecular probe to monitor the expression of a potential tumor biomarker LAT1. PMID- 26749020 TI - Clinical and immunological responses of dust mite sensitive, atopic dogs to treatment with sublingual immunotherapy (SLIT). AB - BACKGROUND: Sublingual immunotherapy (SLIT) has been reported to be beneficial in people with atopic dermatitis (AD) and dust mite sensitivity. Evaluation of this therapy has not been reported in spontaneous canine AD. OBJECTIVES: The objective of this study was to preliminarily evaluate the effectiveness of an established SLIT protocol, as used in human patients, in dogs with AD. ANIMALS: Ten dust mite sensitive dogs with spontaneous AD. METHODS: Dogs underwent a 6 month open trial of SLIT concurrently with decreasing dose oral methylprednisolone. Clinical evaluations and quantitative serum anti-mite IgE and IgG levels were performed every 2 months. RESULTS: Mean methylprednisolone use from the first 2 months of the study to the final 2 months declined from 10.2 to 4.3 mg/kg/2 months (P < 0.001, Student's paired t-test); at 6 months, four dogs required no oral corticosteroid administration. Over the course of the study, median Canine Atopic Dermatitis Extent and Severity Index (CADESI)-03 scores declined from 76.5 to 59; median pruritus scores declined from 65 to 37 (P < 0.02 and P < 0.01, respectively; Wilcoxon signed-rank test). Pre- and post-SLIT intradermal test scores for mite allergen were not significantly different over time. Median Dermatophagoides farinae (DF)-specific IgE levels declined significantly from 150.2 * 10(3) AU/mL to 3.6 * 10(3) AU/mL (P < 0.05). Concurrently, median DF specific IgG levels increased from 18.5 * 10(6) AU/mL to 3923.4 * 10(6) AU/mL (P < 0.05; Wilcoxon signed-rank tests). CONCLUSIONS AND CLINICAL IMPORTANCE: SLIT treatment produced clinical improvement in dogs with dust mite-associated AD and was associated with serological changes supporting this improvement. Further studies in larger numbers of dogs and those with polysensitization are warranted. PMID- 26749021 TI - Complications of inguinal herniotomy are comparable in term and premature infants. AB - PURPOSE: Inguinal hernias are common, and prevalence is highest in premature males. Recognised complications include recurrence, iatrogenic cryptorchidism and testicular atrophy. We reviewed complication rates following inguinal herniotomy (IH), comparing premature (gestation <36 weeks) and term infants. METHODS: A retrospective case note review of infants aged 0-12 months undergoing IH between January 2006 and December 2010. Data collected included demographics, side of hernia, incarceration, complications, duration of follow-up and need for further surgery. Comparison was made using unpaired student t test and Fishers exact test. RESULTS: Four hundred and eight patients underwent IH (365 male, 42 female, 1 complete androgen insensitivity); 197 were premature (prem), mean weight 3.81 kg (1.02-9.4); 211 were term (gestation >=36 weeks), mean weight 5.85 kg (2.4 11.7), p = 0.0001 versus prem. Total herniotomies performed = 472 (131 Left, 213 Right, 64 bilateral); 89 hernias were incarcerated at presentation (60 prem vs. 29 term, p = 0.0001). Bowel resection was required in six patients (5 prem vs. 1 term, p = 0.1109), and 14 had simultaneous orchidopexy (12 prem vs. 2 term, p = 0.0049). Early post-operative complication rate 2.8 % (8 prem vs. 5 term; p = 0.4037). Two hundred and forty patients attended follow-up; 58.8 % (125 prem, 115 term). This group accounted for 279 IH (264 male, 15 female). Mean follow-up = 5 months (0.5-36). Complication rates: recurrence 2.7 %, metachronous hernia 7.5 %, iatrogenic cryptorchidism 3.8 % and testicular atrophy 0.7 %. CONCLUSION: No significant difference was found in complication rates between premature and term infants despite significantly more premature infants presenting with incarcerated hernias. PMID- 26749015 TI - From unwitnessed fatality to witnessed rescue: Pharmacologic intervention in sudden unexpected death in epilepsy. AB - The mechanisms of sudden unexpected death in epilepsy (SUDEP) have been difficult to define, as most cases occur unwitnessed, and physiologic recordings have been obtained in only a handful of cases. However, recent data obtained from human cases and experimental studies in animal models have brought us closer to identifying potential mechanisms. Theories of SUDEP should be able to explain how a seizure starting in the forebrain can sometimes lead to changes in brainstem cardiorespiratory control mechanisms. Herein we focus on three major themes of work on the causes of SUDEP. First, evidence is reviewed identifying postictal hypoventilation as a major contributor to the cause of death. Second, data are discussed that brainstem serotonin and adenosine pathways may be involved, as well as how they may contribute. Finally, parallels are drawn between SIDS and SUDEP, and we highlight similarities pointing to the possibility of shared pathophysiology involving combined failure of respiratory and cardiovascular control mechanisms. Knowledge about the causes of SUDEP may lead to potential pharmacologic approaches for prevention. We end by describing how translation of this work may result in future applications to clinical care. PMID- 26749024 TI - The distinctive micromegakaryocytes of transformed chronic myeloid leukemia. PMID- 26749023 TI - Psychological morbidities in adolescent and young adult blood cancer patients during curative-intent therapy and early survivorship. AB - BACKGROUND: Adolescents and young adults (AYAs) with cancer face unique psychosocial challenges. This pilot study was aimed at describing the prevalence of psychological morbidities among AYAs with hematologic malignancies during curative-intent therapy and early survivorship and at examining provider perceptions of psychological morbidities in their AYA patients. METHODS: Patients aged 15 to 39 years with acute leukemia, non-Hodgkin lymphoma, or Hodgkin lymphoma who were undergoing curative-intent therapy (on-treatment group) or were in remission within 2 years of therapy completion (early survivors) underwent a semistructured interview that incorporated measures of anxiety, depression, and posttraumatic stress (PTS). A subset of providers (n = 15) concomitantly completed a survey for each of the first 30 patients enrolled that evaluated their perception of each subject's anxiety, depression, and PTS. RESULTS: Sixty one of 77 eligible AYAs participated. The median age at diagnosis was 26 years (range, 15-39 years), 64% were male, and 59% were non-Hispanic white. On treatment demographics differed significantly from early-survivor demographics only in the median time from diagnosis to interview. Among the 61 evaluable AYAs, 23% met the criteria for anxiety, 28% met the criteria for depression, and 13% met the criteria for PTS; 46% demonstrated PTS symptomatology. Thirty-nine percent were impaired in 1 or more psychological domains. Psychological impairments were as frequent among early survivors as AYAs on treatment. Provider perceptions did not significantly correlate with patient survey results. CONCLUSIONS: AYAs with hematologic malignancies experience substantial psychological morbidities while they are undergoing therapy and during early survivorship, with more than one-third of the patients included in this study meeting the criteria for anxiety, depression, or traumatic stress. This psychological burden may not be accurately identified by their oncology providers. PMID- 26749022 TI - Transcriptome profiling of immune tissues reveals habitat-specific gene expression between lake and river sticklebacks. AB - The observation of habitat-specific phenotypes suggests the action of natural selection. The three-spined stickleback (Gasterosteus aculeatus) has repeatedly colonized and adapted to diverse freshwater habitats across the northern hemisphere since the last glaciation, while giving rise to recurring phenotypes associated with specific habitats. Parapatric lake and river populations of sticklebacks harbour distinct parasite communities, a factor proposed to contribute to adaptive differentiation between these ecotypes. However, little is known about the transcriptional response to the distinct parasite pressure of those fish in a natural setting. Here, we sampled wild-caught sticklebacks across four geographical locations from lake and river habitats differing in their parasite load. We compared gene expression profiles between lake and river populations using 77 whole-transcriptome libraries from two immune-relevant tissues, the head kidney and the spleen. Differential expression analyses revealed 139 genes with habitat-specific expression patterns across the sampled population pairs. Among the 139 differentially expressed genes, eight are annotated with an immune function and 42 have been identified as differentially expressed in previous experimental studies in which fish have been immune challenged. Together, these findings reinforce the hypothesis that parasites contribute to adaptation of sticklebacks in lake and river habitats. PMID- 26749025 TI - What could you do with 400 years of biological history on african americans? Evaluating the potential scientific benefit of systematic studies of dental and skeletal materials on African Americans from the 17th through 20th centuries. AB - OBJECTIVES: How important is it to be able to reconstruct the lives of a highly diverse, historically recent macroethnic group over the course of 400 years? How many insights into human evolutionary biology and disease susceptibilities could be gained, even with this relatively recent window into the past? In this article, we explore the potential ramifications of a newly constructed dataset of Four Centuries of African American Biological Variation (4Cs). METHODS: This article provides initial lists of digitized variables formatted as SQL tables for the 17th and 18th century samples and for the 19th and 20th century samples. RESULTS: This database is dynamic and new information is added yearly. The database provides novel opportunities for significant insights into the past biological history of this group and three case study applications are detailed for comparative computational systems biology studies of (1) hypertension, (2) the oral microbiome, and (3) mental health disorders. CONCLUSIONS: The 4Cs dataset is ideal for interdisciplinary "next generation" science research and these data represent a unique step toward the accumulation of historically contextualized Big Data on an underrepresented group known to have experienced differential survival over time. Am. J. Hum. Biol. 28:510-513, 2016. (c) 2016 The Authors American Journal of Human Biology Published byWiley Periodicals, Inc. PMID- 26749026 TI - A randomised controlled trial of peri-operative lidocaine infusions for open radical prostatectomy. AB - We allocated 76 men scheduled for radical retropubic prostatectomy to peri operative lidocaine 2% or saline 0.9%: a pre-operative 0.075 ml.kg(-1) intravenous bolus; an intra-operative intravenous infusion at 0.075 ml.kg(-1) .h( 1) ; and 24 hours' postoperative subcutaneous infusion at 0.075 ml.kg(-1) .h(-1) . Lidocaine reduced the postoperative hospital stay by a mean (95% CI) of 1.3 (0.3-2.4) days, p = 0.017, from a mean (SD) of 4.6 (3.2) days with saline. There were no significant differences in pain at rest or on coughing at 24 h. [corrected]. Lidocaine reduced 24-h morphine consumption by a mean (95% CI) of 13.9 (2.2-25.7) mg, p = 0.021, from a mean (SD) of 52.3 (26.9) mg with saline. There were no differences in other outcomes. PMID- 26749027 TI - Progress in the Development of non-BET Bromodomain Chemical Probes. AB - The bromodomain and extra terminal (BET) family of bromodomains have been the focus of extensive research, leading to the development of many potent, selective chemical probes and recent clinical assets. The profound biology associated with BET bromodomain inhibition has provided a convincing rationale for targeting bromodomains for the treatment of disease. However, the BET family represents just eight of the at least 56 human bromodomains identified to date. Until recently, there has been significantly less interest in non-BET bromodomains, leaving a vast area of research and the majority of this new target class yet to be thoroughly investigated. It has been widely reported that several non-BET bromodomain containing proteins are associated with various diseases including cancer and HIV. Therefore, the development of chemical probes for non-BET bromodomains will facilitate elucidation of their precise biological roles and potentially lead to the development of new medicines. This review summarises the progress made towards the development of non-BET bromodomain chemical probes to date. In addition, we highlight the potential for future work in this new and exciting area. PMID- 26749028 TI - High mortality rates after nonelective colon cancer resection: results of a national audit. AB - AIM: Colon cancer resection in a nonelective setting is associated with high rates of morbidity and mortality. The aim of this retrospective study is to identify risk factors for overall mortality after colon cancer resection with a special focus on nonelective resection. METHOD: Data were obtained from the Dutch Surgical Colorectal Audit. Patients undergoing colon cancer resection in the Netherlands between January 2009 and December 2013 were included. Patient, treatment and tumour factors were analysed in relation to the urgency of surgery. The primary outcome was 30-day postoperative mortality. RESULTS: The study included 30 907 patients. A nonelective colon cancer resection was performed in 5934 (19.2%) patients. There was a 4.4% overall mortality rate, with significantly more deaths after nonelective surgery (8.5% vs 3.4%, P < 0.001). Older patients, male patients and patients with high comorbidity, advanced tumours, perforated tumours, a tumour in the right or transverse colon and postoperative anastomotic leakage were at risk of postoperative death. In nonelective resections, a right-sided tumour and postoperative anastomotic leakage were associated with high mortality. CONCLUSION: Nonelective colon cancer resection is associated with high mortality. In particular, right-sided resections and patients with tumour perforation are at particularly high risk. The optimization of patients prior to surgery and expeditious operation after diagnosis might prevent the need for a nonelective resection. PMID- 26749029 TI - Recognition and Sensing of Creatinine. AB - Current methods for creatinine quantification suffer from significant drawbacks when aiming to combine accuracy, simplicity, and affordability. Here, an unprecedented synthetic receptor, an aryl-substituted calix[4]pyrrole with a monophosphonate bridge, is reported that displays remarkable affinity for creatinine and the creatininium cation. The receptor works by including the guest in its deep and polar aromatic cavity and establishing directional interactions in three dimensions. When incorporated into a suitable polymeric membrane, this molecule acts as an ionophore. A highly sensitive and selective potentiometric sensor suitable for the determination of creatinine levels in biological fluids, such as urine or plasma, in an accurate, fast, simple, and cost-effective way has thus been developed. PMID- 26749031 TI - The endocrine effects of dietary brominated diphenyl ether-47 exposure, measured across multiple levels of biological organization, in breeding fathead minnows. AB - The goal of the present study was to evaluate the reproductive function of fathead minnows (Pimephales promelas) exposed to brominated diphenyl ether-47 (BDE-47) at doses lower than those used in previous studies. This was accomplished by evaluating the impacts of BDE-47 exposures across multiple levels of biological organization. Breeding pairs were exposed to BDE-47 via diet for 21 d, during which reproductive success was monitored. At the conclusion of the exposure, fish were euthanized to assess the effects of BDE-47 on sex steroid related and thyroid-related transcripts, plasma androgen levels, gonadosomatic index (GSI), and secondary sexual characteristics. Several alterations in gene expression were noted including a >2.1-fold decrease in hepatic estrogen receptor alpha (eralpha) and a 2.9-fold decrease in ovarian aromatase (arom). In addition, BDE-47-exposed males experienced increases in deiodinase 2 (dio2) expression in brain tissue (~1.5-fold) and decreases in hepatic transthyretin (ttr) expression (~1.4-fold). Together, these gene expression alterations suggest the potential for BDE-47 to disrupt endocrine signaling. There were no significant differences in plasma hormone levels, GSI, secondary sexual characteristics, or reproductive success. Overall, the present study demonstrates that exposure to BDE-47 is capable of altering both sex steroid-related and thyroid-related transcripts but that these observed alterations do not necessarily manifest themselves at higher levels of biological organization for the endpoints selected. Environ Toxicol Chem 2016;35:2048-2057. (c) 2016 SETAC. PMID- 26749030 TI - Acute selective serotonin reuptake inhibitors regulate the dorsal raphe nucleus causing amplification of terminal serotonin release. AB - Selective serotonin reuptake inhibitors (SSRIs) were designed to treat depression by increasing serotonin levels throughout the brain via inhibition of clearance from the extracellular space. Although increases in serotonin levels are observed after acute SSRI exposure, 3-6 weeks of continuous use is required for relief from the symptoms of depression. Thus, it is now believed that plasticity in multiple brain systems that are downstream of serotonergic inputs contributes to the therapeutic efficacy of SSRIs. The onset of antidepressant effects also coincides with desensitization of somatodendritic serotonin autoreceptors in the dorsal raphe nucleus (DRN), suggesting that disrupting inhibitory feedback within the serotonin system may contribute to the therapeutic effects of SSRIs. Previously, we showed that chronic SSRI treatment caused a frequency-dependent facilitation of serotonin signaling that persisted in the absence of uptake inhibition. In this work, we use in vivo fast-scan cyclic voltammetry in mice to investigate a similar facilitation after a single treatment of the SSRI citalopram hydrobromide. Acute citalopram hydrobromide treatment resulted in frequency-dependent increases of evoked serotonin release in the substantia nigra pars reticulata. These increases were independent of changes in uptake velocity, but required SERT expression. Using microinjections, we show that the frequency dependent enhancement in release is because of SERT inhibition in the DRN, demonstrating that SSRIs can enhance serotonin release by inhibiting uptake in a location distal to the terminal release site. The novel finding that SERT inhibition can disrupt modulatory mechanisms at the level of the DRN to facilitate serotonin release will help future studies investigate serotonin's role in depression and motivated behavior. In this work, stimulations of the dorsal raphe nucleus (DRN) evoke serotonin release that is recorded in the substantia nigra pars reticulata (SNpr) using in vivo fast-scan cyclic voltammetry. Systemic administration of a selective serotonin reuptake inhibitor (SSRI) causes both an increase in t1/2 and an increase in [5-HT]max in the SNpr. Local application of SSRI to the DRN recapitulates the increase in [5-HT]max observed in the SNpr without affecting uptake. Thus, SSRIs increase serotonin signaling via two distinct SERT-mediated mechanisms. PMID- 26749037 TI - Ultrasound-assisted dilute acid hydrolysis of tea processing waste for production of fermentable sugar. AB - Lignocellulosic materials that are the most abundant plant biomass in the world have the potential to become sustainable sources of the produced value added products. Tea processing waste (TPW) is a good lignocellulosic source to produce the value added products from fermentable sugars (FSs). Therefore, the present study is undertaken to produce FSs by using ultrasound-assisted dilute acid (UADA) and dilute acid (DA) hydrolysis of TPW followed by enzymatic hydrolysis. UADA hydrolysis of TPW was optimized by response surface methodology (RSM) at maximum power (900 W) for 2 h. The optimum conditions were determined as 50 degrees C, 1:6 (w/v) solid:liquid ratio, and 1% (w/v) DA concentration, which yielded 20.34 g/L FS concentration. Furthermore, its DA hydrolysis was also optimized by using RSM for comparison and the optimized conditions were found as 120 degrees C, 1:8 solid:liquid ratio, and 1% acid concentration, which produced 25.3 g/L FS yield. Even though the produced sugars with UADA hydrolysis are slightly less, but it can provide significant cost saving due to the lower temperature requirement and less liquid consumption. Besides, enzymatic hydrolysis applied after pretreatments of TPW were very more economic than the conventional enzymatic hydrolysis in the literature due to shorter time requiring. In conclusion, ultrasound-assisted is a promising technology that can be successfully applied for hydrolysis of biomass and can be an alternative to the other hydrolysis procedures and also TPW can be considered as suitable carbon source for the production of value-added products like biofuels, organic acids, and polysaccharides. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:393-403, 2016. PMID- 26749038 TI - Estimation of clinical and economic effects of prophylaxis against venous thromboembolism in medical patients, including the effect of targeting patients at high-risk. AB - BACKGROUND: The clinical and economic effects of medical thromboprophylaxis (MT) using low molecular weight heparin in Australia are unknown. AIM: To estimate the effects of MT in Australia. METHODS: A decision tree model of MT was populated with national data for medical admissions. The Prevention of Recurrent Venous Thromboembolism (PREVENT) trial was chosen as the primary data source because its design uniquely avoided bias caused by treatment of sub-clinical events. Clinical efficacy and costs were estimated compared with no prophylaxis, assuming full compliance and according to three definitions of eligibility. Effectiveness was estimated as thrombotic events saved, mortality from bleeding or pulmonary embolus (PE), cost and $/year of life saved. Model outputs were subjected to sensitivity analysis. RESULTS: MT decreased thrombotic events, and the numbers avoided increased as eligibility broadened (deep vein thrombosis (DVT): 2597, 2771 and 3232 at restricted, intermediate and broad eligibility; PE: 454, 484 and 565 respectively). The annual cost of no prophylaxis was $88.7 m. Costs were reduced at most restricted eligibility (-$7.9 m), but increased by $3.0 and $32.1 m at broader eligibility. PE deaths declined, but this was offset by deaths from haemorrhage, causing a net increase (158, 299 and 672 respectively). Estimates were sensitive to the incidence of venous thromboembolic event (VTE), case fatality rates for PE and bleeds and the relative risk reduction for PE with prophylaxis. CONCLUSIONS: Under PREVENT trial conditions, MT avoids up to 3200 DVT and 565 PE events annually, but may increase mortality. PMID- 26749040 TI - Quality of life in patients with vitiligo: an analysis of the dermatology life quality index outcome over the past two decades. AB - Vitiligo is one of the most important skin disorders that does not cause much physical impairment, but due to its disfiguring appearance, patients have disturbances in mental health and quality of life (QoL). The dermatology life quality index (DLQI), as one of the most specific QoL instruments, is now used widely for patients with vitiligo. The main objective of this review is to collect and present detailed information about issues and disturbances related to the QoL of patients with vitiligo by reviewing the DLQI studies worldwide in the past 20 years. The impact of vitiligo assessed by the DLQI varies according to the clinical and demographic characteristics of patients. In the majority of our reviewed studies, women showed more QoL impairment than men did, as did young patients compared to elderly ones, married women with vitiligo than singles, and patients with involvement on exposed sites than those on unexposed sites. Dark skinned people showed more life quality effects than white people did. Dermatologists should pay particular attention to such patients who experience insufficient QoL, as they require more effort to cure their disease. PMID- 26749039 TI - Reserve network planning for fishes in the middle and lower Yangtze River basin by systematic conservation approaches. AB - Although China has established more than 600 wetland nature reserves, conservation gaps still exist for many species, especially for freshwater fishes. Underlying this problem is the fact that top-level planning is missing in the construction of nature reserves. To promote the development of nature reserves for fishes, this study took the middle and lower reaches of the Yangtze River basin (MLYRB) as an example to carry out top-level reserve network planning for fishes using approaches of systematic conservation planning. Typical fish species living in freshwater habitats were defined and considered in the planning. Based on sample data collected from large quantities of literatures, continuous distribution patterns of 142 fishes were obtained with species distribution modeling and subsequent processing, and the distributions of another eleven species were artificially designated. With the distribution pattern of species, Marxan was used to carry out conservation planning. To obtain ideal solutions with representativeness, persistence, and efficiency, parameters were set with careful consideration regarding existing wetland reserves, human disturbances, hydrological connectivity, and representation targets of species. Marxan produced the selection frequency of planning units (PUs) and a best solution. Selection frequency indicates the relative protection importance of a PU. The best solution is a representative of ideal fish reserve networks. Both of the PUs with high selection frequency and those in the best solution have low proportions included in existing wetland nature reserves, suggesting that there are significant conservation gaps for fish species in MLYRB. The best solution could serve as a reference for establishing a fish reserve network in the MLYRB. There is great flexibility for replacing selected PUs in the solution, and such flexibility facilitates the implementation of the solution in reality in case of unexpected obstacles. Further, we suggested adopting a freshwater management framework in the implementation of such solution. PMID- 26749042 TI - Retained basal cells in metastatic prostate cancer. PMID- 26749041 TI - Characterization of the Shigella and Salmonella Type III Secretion System Tip Translocon Protein-Protein Interaction by Paramagnetic Relaxation Enhancement. AB - Many Gram-negative pathogens, such as Shigella and Salmonella, assemble the type III secretion system (T3SS) to inject virulence proteins directly into eukaryotic cells to initiate infectious diseases. The needle apparatus of the T3SS consists of a base, an extracellular needle, a tip protein complex, and a translocon. The atomic structure of the assembled tip complex and the translocon is unknown. Here, we show by NMR paramagnetic relaxation enhancement (PRE) that the mixed alpha-beta domain at the distal region of the Shigella and Salmonella tip proteins interacts with the N-terminal ectodomain of their major translocon proteins. Our results reveal the binding surfaces involved in the tip-translocon protein-protein interaction and provide insights about the assembly of the needle apparatus of the T3SS. PMID- 26749043 TI - Association Between Ischemic Stroke and Tumor Necrosis Factor Inhibitor Therapy in Patients With Rheumatoid Arthritis. AB - OBJECTIVE: Patients with rheumatoid arthritis (RA) are at an increased risk of ischemic stroke. Tumor necrosis factor inhibitors (TNFi) may influence risk and mortality after ischemic stroke by reducing inflammation. This study was undertaken to examine the association of TNFi with the risk of incident ischemic stroke and with 30-day and 1-year mortality after ischemic stroke. METHODS: Patients with RA starting therapy with TNFi and a biologics-naive comparator group treated with synthetic disease-modifying antirheumatic drugs (DMARDs) only were recruited to the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis from 2001 to 2009. Patients were followed up via clinical and patient questionnaires as well as the national death register. Incident strokes were classified as ischemic if brain imaging reports suggested ischemia or if ischemic stroke was reported as the underlying cause of death on a death certificate. Patients with a previous stroke were excluded. Risk of ischemic stroke was compared between patients receiving synthetic DMARDs only and those ever-exposed to TNFi using a Cox proportional hazards regression model adjusted for potential confounders. Mortality after ischemic stroke was compared between synthetic DMARD-treated patients and TNFi-treated patients using logistic regression, adjusted for age and sex. RESULTS: To April 2010, 127 verified incident ischemic strokes (21 in 3,271 synthetic DMARD-treated patients and 106 in 11,642 TNFi-treated patients) occurred during 11,973 and 61,226 person-years of observation, respectively (incidence rate 175 versus 173 per 100,000 person years). After adjustment for confounders, there was no association between ever exposure to TNFi and ischemic stroke (hazard ratio 0.99 [95% confidence interval (95% CI) 0.54-1.81]). Mortality 30 days or 1 year after ischemic stroke was not associated with concurrent TNFi exposure (odds ratio 0.18 [95% CI 0.03-1.21] and 0.60 [95% CI 0.16-2.28], respectively). CONCLUSION: Exposure to TNFi does not appear to influence the occurrence of ischemic stroke in the medium term in patients with RA. The impact on mortality after ischemic stroke remains inconclusive. PMID- 26749044 TI - ERBB-2 overexpression as a risk factor for malignant phaeochromocytomas and paraganglinomas. AB - OBJECTIVE: There are currently no good histological or molecular markers to differentiate benign from malignant phaeochromocytomas and paraganglinomas (PPGLs). Our previous cross-sectional study observed that ERBB-2 overexpression was associated with malignant PPGLs. This study aimed to evaluate the predictive value of ERBB-2 overexpression for metastasis in PPGLs in a large population. METHODS: A total of 262 patients diagnosed as PPGLs in our institution between 2002 and 2012 were included. We analysed ERBB-2 protein expression in the primary PPGL tumours by immunohistochemistry (IHC) and ERBB-2 amplification by fluorescence in situ hybridization (FISH). Direct Sanger sequencing was performed to examine ERBB-2 exon 20 mutations. The occurrence of malignant PPGLs was documented in the follow-up period. Kaplan-Meier analysis and Cox proportional hazard models were used to evaluate the association between ERBB-2 overexpression and metastasis of PPGLs. RESULTS: Twenty-six (9.9%) patients had ERBB-2 overexpression in their primary PPGL tumours, which was significantly associated with ERBB-2 amplification (17/25, 68%). No ERBB-2 mutation was found. At a median follow-up of 4.5 years, a total of 23 malignant PPGLs were documented, including eight (30.8%) patients in the ERBB-2 overexpression group and 15 (6.4%) patients in the ERBB-2-negative group. The incidence rate of metastasis was 5.3 per 100 person-years vs 1.4 per 100 person-years in the ERBB-2 overexpression and ERBB-2 negative groups (P < 0.001), respectively. Kaplan-Meier analysis showed that ERBB 2 overexpression was associated with decreased metastasis-free survival (P = 0.001, log-rank test). After adjusting for primary tumour size and location, Cox regression analysis revealed that ERBB-2 overexpression was independently associated with risk of malignant PPGLs (HR = 2.78; 95% CI, 1.12-6.90; P = 0.028). CONCLUSION: Patients harbouring tumours with ERBB-2 overexpression have a significantly higher risk of developing malignant PPGLs. PMID- 26749045 TI - Instrumental variable analysis as a complementary analysis in studies of adverse effects: venous thromboembolism and second-generation versus third-generation oral contraceptives. AB - PURPOSE: A potentially useful role for instrumental variable (IV) analysis may be as a complementary analysis to assess the presence of confounding when studying adverse drug effects. There has been discussion on whether the observed increased risk of venous thromboembolism (VTE) for third-generation oral contraceptives versus second-generation oral contraceptives could be (partially) attributed to confounding. We investigated how prescribing preference IV estimates compare with conventional estimates. METHODS: Women in the Clinical Practice Research Database who started a second-generation or third-generation oral contraceptive from 1989 to 2013 were included. Ordinary least squares and two-stage least squares regression were used to estimate risk differences in VTE. Cox regression and IV for Cox proportional hazards regression were used to calculate hazard ratios (HR). The instrument used was the proportion of prescriptions for third generation oral contraceptives by the general practitioner in the year preceding the current prescription. RESULTS: All analyses pointed in the direction of an increased VTE risk for third-generation oral contraceptives. The adjusted HR from the conventional Cox regression was 1.62 (95% confidence interval 1.16-2.27) and the fully adjusted HR from the IV Cox regression was 3.45 (95% confidence interval; 0.97-11.7), showing a larger risk and wider confidence intervals in the IV analysis. CONCLUSIONS: The similarity in direction of results from the IV analyses and conventional analyses suggests that major confounding is unlikely. IV analysis can be a useful complementary analysis to assess the presence of confounding in studies of adverse drug effects in very large databases. PMID- 26749046 TI - Pediatric Aspects of Headache Classification in the International Classification of Headache Disorders-3 (ICHD-3 beta version). AB - This analysis looks at the applicability of the International Classification of Headache Disorders-3 beta (ICHD-3 beta) to various headache syndromes of children and adolescents. Areas of similarities and differences between adult and pediatric headaches are addressed as they relate to the ICHD-3 beta. PMID- 26749048 TI - Sinonasal complications of dental disease or treatment coming out of the c.l.o.s.e.t. PMID- 26749049 TI - Comment on: Comparison of steroid administration methods in patients with idiopathic sudden sensorineural hearing loss: a retrospective observational study. PMID- 26749050 TI - Recurrent laryngeal nerve identification in thyroidectomy by intra-operative staining with methylene blue in 46 patients. PMID- 26749051 TI - Re: A simple technique for minor salivary gland and oral biopsy in the clinic: our experience. PMID- 26749052 TI - Cardiac MR elastography of the mouse: Initial results. AB - PURPOSE: Many cardiovascular diseases are associated with abnormal function of myocardial contractility or dilatability, which is related to elasticity changes of the myocardium over the cardiac cycle. The mouse is a common animal model in studies of the progression of various cardiomyopathies. We introduce a novel noninvasive approach using microscopic scale MR elastography (MRE) to measure the myocardium stiffness change during the cardiac cycle on a mouse model. METHODS: A harmonic mechanical wave of 400 Hz was introduced into the mouse body. An electrocardiograph-gated and respiratory-gated fractional encoding cine-MRE pulse sequence was applied to encode the resulting oscillatory motion on a short-axis slice of the heart. Five healthy mice (age range, 3-13.5 mo) were examined. The weighted summation effective stiffness of the left ventricle wall during the cardiac cycle was estimated. RESULTS: The ratio of stiffness at end diastole and end systole was 0.5-0.67. Additionally, variation in shear wave amplitude in the left ventricle wall throughout the cardiac cycle was measured and found to correlate with estimates of stiffness variation. CONCLUSION: This study demonstrates the feasibility of implementing cardiac MRE on a mouse model. Magn Reson Med 76:1879-1886, 2016. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26749054 TI - Comparison of the gene encoding, and the predicted amino acid composition of, platelet membrane receptor subunit glycoprotein Ibalpha in members of the family Felidae. AB - BACKGROUND: There is minimal information regarding platelet receptors in the family Felidae. Comparative studies assist with identifying amino acids critical for protein structure and function. OBJECTIVE: The purpose of the study was to compare the gene encoding, and the predicted amino acid composition of, platelet membrane receptor subunit GPIbalpha in Felidae family members. METHODS: Genomic DNA samples isolated from whole blood of 13 domestic cats and 50 big cats representing 8 different species were subjected to PCR using primers designed to flank the coding region of GPIbalpha in overlapping fashion. PCR products were separated via electrophoresis on agarose gels, and extracted products were submitted for sequencing. DNA sequences were used to predict the length and amino acid composition of the protein. RESULTS: Varying protein lengths were predicted in Felidae family members which were primarily due to polymorphisms in the variable number of tandem repeats region encoding the macroglycopeptide region of GPIbalpha. Other areas of the gene and predicted amino acid compositions were fairly conserved when compared to human sequences and between Felidae family members. CONCLUSION: Various polymorphisms within GPIbalpha, including length variants encoding the macroglycopeptide region, were identified in members of the family Felidae. More studies are needed to determine if a correlation exists between various polymorphisms and predisposition for hemorrhage or thrombosis as suggested in people. PMID- 26749053 TI - Eliminating Size-Associated Diffusion Constraints for Rapid On-Surface Bioassays with Nanoparticle Probes. AB - Nanoparticle probes enable implementation of advanced on-surface assay formats, but impose often underappreciated size-associated constraints, in particular on assay kinetics and sensitivity. The present study highlights substantially slower diffusion-limited assay kinetics due to the rapid development of a nanoprobe depletion layer next to the surface, which static incubation and mixing of bulk solution employed in conventional assay setups often fail to disrupt. In contrast, cyclic solution draining and replenishing yields reaction-limited assay kinetics irrespective of the probe size. Using common surface bioassays, enzyme linked immunosorbent assays and immunofluorescence, this study shows that this conceptually distinct approach effectively "erases" size-dependent diffusion constraints, providing a straightforward route to rapid on-surface bioassays employing bulky probes and procedures involving multiple labeling cycles, such as multicycle single-cell molecular profiling. For proof-of-concept, the study demonstrates that the assay time can be shortened from hours to minutes with the same probe concentration and, at a typical incubation time, comparable target labeling can be achieved with up to eight times lower nanoprobe concentration. The findings are expected to enable realization of novel assay formats and stimulate development of rapid on-surface bioassays with nanoparticle probes. PMID- 26749056 TI - Tyramides in male alates of black imported fire ants Solenopsis richteri. PMID- 26749057 TI - An Alternative, Direct Approach for Arthroscopic Removal of Osteochondral Fragments in the Dorsal Pouch of the Proximal Intertarsal Joint of Horses. AB - OBJECTIVE: To describe an alternative technique and resulting outcomes for arthroscopic removal of osteochondral (OC) fragments from the proximal intertarsal joint (PIJ) using a direct approach without resection of the membrane between the tarsocrural joint (TCJ) and the PIJ. STUDY DESIGN: Retrospective case series. ANIMALS: Client owned horses (n = 11) with Category 1 OC fragments in the PIJ. METHODS: Arthroscopic examination of the dorsal pouch of the TCJ was performed with horses positioned in dorsal recumbency using routine portals. A hook probe placed through one of the standard portals was used to lift the edge of the communication between TCJ and PIJ to help pass the arthroscope into the PIJ from the opposite standard portal. A third direct portal into the PIJ was created under arthroscopic visualization, and loose OC fragments (Category 1) were removed using the direct portal. Medical records, race records, and owner surveys were reviewed for case details and outcome. RESULTS: The described technique allowed removal of all fragments in all 11 cases. No complications associated with the procedure were observed. Of the 9 horses with long term follow-up available, 7 were used as intended (4/4 riding horses, 3/5 racehorses). Two horses did not enter an athletic career because of reasons unrelated to fragment removal. CONCLUSION: A direct approach for arthroscopic removal of OC fragments of the PIJ using a third portal into this joint, without resection of the membrane between the TCJ and PIJ is a good alternative for removal of fragments at this site. PMID- 26749055 TI - The atypical IkappaB protein IkappaB(NS) is important for Toll-like receptor induced interleukin-10 production in B cells. AB - Although a major function of B cells is to mediate humoral immunity by producing antigen-specific antibodies, a specific subset of B cells is important for immune suppression, which is mainly mediated by the secretion of the anti-inflammatory cytokine interleukin-10 (IL-10). However, the mechanism by which IL-10 is induced in B cells has not been fully elucidated. Here, we report that IkappaBNS , an inducible nuclear IkappaB protein, is important for Toll-like receptor (TLR) mediated IL-10 production in B cells. Studies using IkappaB(NS) knockout mice revealed that the number of IL-10-producing B cells is reduced in IkappaB(NS)(-/ ) spleens and that the TLR-mediated induction of cytoplasmic IL-10-positive cells and IL-10 secretion in B cells are impaired in the absence of IkappaB(NS). The impairment of IL-10 production by a lack of IkappaB(NS) was not observed in TLR triggered macrophages or T-cell-receptor-stimulated CD4(+) CD25(+) T cells. In addition, IkappaB(NS)-deficient B cells showed reduced expression of Prdm1 and Irf4 and failed to generate IL-10(+) CD138(+) plasmablasts. These results suggest that IkappaB(NS) is selectively required for IL-10 production in B cells responding to TLR signals, so defining an additional role for IkappaB(NS) in the control of the B-cell-mediated immune responses. PMID- 26749058 TI - What interventions can improve the mental health nursing practice environment? AB - The nursing practice environment is an important factor for services to consider in the attraction and retention of a skilled workforce during future nursing shortages. Despite the significant number of international studies undertaken to understand the influence of the practice environment on nurse satisfaction and retention, few have been undertaken within the mental health setting. This paper reports on results from a survey conducted in a large Australian public mental health hospital to examine nurses' perceptions of their practice environment, and identifies interventions that could be implemented to improve the practice environment. The hospital is the only remaining, standalone public mental health hospital in Western Australia. PMID- 26749060 TI - The 2011 flood event in the Mekong Delta: preparedness, response, damage and recovery of private households and small businesses. AB - Floods frequently cause substantial economic and human losses, particularly in developing countries. For the development of sound flood risk management schemes that reduce flood consequences, detailed insights into the different components of the flood risk management cycle, such as preparedness, response, flood impact analyses and recovery, are needed. However, such detailed insights are often lacking: commonly, only (aggregated) data on direct flood damage are available. Other damage categories such as losses owing to the disruption of production processes are usually not considered, resulting in incomplete risk assessments and possibly inappropriate recommendations for risk management. In this paper, data from 858 face-to-face interviews among flood-prone households and small businesses in Can Tho city in the Vietnamese Mekong Delta are presented to gain better insights into the damage caused by the 2011 flood event and its management by households and businesses. PMID- 26749059 TI - Participation of B-cell-activating factor receptors in the pathogenesis of immune thrombocytopenia. AB - ESSENTIALS: Dysfunctional B-cell-activating factor (BAFF) system is related to many autoimmune diseases. The regulatory functions of BAFF/BAFF receptors were investigated in an in vitro coculture system. Different regulatory roles of BAFF were investigated via different receptors in immune thrombocytopenia. The upregulated BAFF receptors on autoreactive lymphocytes lead to their hypersensitivity to BAFF. SUMMARY: BACKGROUND: The pathogenesis of immune thrombocytopenia (ITP) remains enigmatic. B-cell-activating factor (BAFF) and its receptors (BAFF receptor [BAFF-R], transmembrane activator and calcium modulator and cyclophilin ligand interactor [TACI], and B-cell maturation antigen) play central roles in the integrated homeostatic regulation of lymphocytes. OBJECTIVES: To investigate the pathologic roles of BAFF receptors in regulating the bioactivities of lymphocytes in ITP. METHODS: An in vitro culture system was established by stimulating CD14(-) peripheral lymphocytes with platelet-preloaded dendritic cells in the presence of recombinant human BAFF (rhBAFF; 20 ng mL(-1)). The functions of BAFF receptors were specifically blocked with blocking antibodies. RESULTS: BAFF-R, besides prolonging the survival of B cells in both patients and healthy controls, prominently promoted the survival of CD8(+) T cells and the proliferation of B cells in patients with ITP. TACI, as a positive regulator, not only promoted the proliferation of CD4(+) and CD8(+) T cells, but also significantly enhanced the secretion of interleukin-4 in patients with ITP, but not in controls. Besides revealing the pathologic roles of BAFF receptors, these results also indicate that lymphocytes of patients with ITP have enhanced antiapoptotic or proliferative capacity as compared with those from healthy controls when exposed under similar stimulation of rhBAFF. Further study demonstrated that activated autoreactive B cells and CD4(+) T cells from patients with ITP showed significantly higher expression of BAFF-R or TACI than those from healthy controls. CONCLUSIONS: Both BAFF-R and TACI are pathogenic participants in ITP. Their dysregulated expression in patients with ITP may lead to hyperreactivity of activated autoreactive lymphocytes in response to rhBAFF, and thus is highly significant in the pathogenesis of ITP. PMID- 26749062 TI - Enzymatic recycling of ascorbic acid from dehydroascorbic acid by glutathione like peptides in the extracellular loops of aminergic G-protein coupled receptors. AB - The intracellular recycling of ascorbic acid from dehydroascorbic acid by the glutathione-glutathione reductase system has been well-characterized. We propose that extracellular recycling of ascorbic acid is performed in a similar manner by cysteine-rich, glutathione-like regions of the first and second extracellular loops of some aminergic receptors including adrenergic, histaminergic, and dopaminergic receptors. Previous research in our laboratory demonstrated that ascorbic acid binds to these receptors at a site on their first or second extracellular loops, significantly enhancing ligand activity, and apparently recycling hundreds of times their own concentration of ascorbate in an enzymatic fashion. In this study, we have synthesized 25 peptides from the first and second extracellular loops of aminergic and insulin receptors and compared them directly to glutathione for their ability to prevent the oxidation of ascorbate and to regenerate ascorbate from dehydroascorbic acid. Peptide sequences that mimic glutathione in containing a cysteine and a glutamic acid-like amino acid also mimic glutathione activity in effects and in kinetics. Some (but not all) peptide sequences that contain one or more methionines instead of cysteine can significantly retard the oxidation of ascorbic acid but do not recycle it from dehydroascorbate into ascorbate. Peptides lacking both cysteines and methionines uniformly failed to alter significantly ascorbate or dehydroascorbate oxidation or reduction. We believe that this is the first proof that receptors may carry out both ligand binding and enzymatic activity extracellularly. Our results suggest the existence of a previously unknown extracellular system for recycling ascorbate. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26749061 TI - Does robotics improve minimally invasive rectal surgery? Functional and oncological implications. AB - OBJECTIVE: Robot-assisted surgery has been reported to be a safe and effective alternative to conventional laparoscopy for the treatment of rectal cancer in a minimally invasive manner. Nevertheless, substantial data concerning functional outcomes and long-term oncological adequacy is still lacking. We aimed to assess the current role of robotics in rectal surgery focusing on patients' functional and oncological outcomes. METHODS: A comprehensive review was conducted to search articles published in English up to 11 September 2015 concerning functional and/or oncological outcomes of patients who received robot-assisted rectal surgery. All relevant papers were evaluated on functional implications such as postoperative sexual and urinary dysfunction and oncological outcomes. RESULTS: Robotics showed a general trend towards lower rates of sexual and urinary postoperative dysfunction and earlier recovery compared with laparoscopy. The rates of 3-year local recurrence, disease-free survival and overall survival of robotic-assisted rectal surgery compared favourably with those of laparoscopy. CONCLUSIONS: This study fails to provide solid evidence to draw definitive conclusions on whether robotic systems could be useful in ameliorating the outcomes of minimally invasive surgery for rectal cancer. However, the available data suggest potential advantages over conventional laparoscopy with reference to functional outcomes. PMID- 26749063 TI - Electrically Conductive Porous Metal-Organic Frameworks. AB - Owing to their outstanding structural, chemical, and functional diversity, metal organic frameworks (MOFs) have attracted considerable attention over the last two decades in a variety of energy-related applications. Notably missing among these, until recently, were applications that required good charge transport coexisting with porosity and high surface area. Although most MOFs are electrical insulators, several materials in this class have recently demonstrated excellent electrical conductivity and high charge mobility. Herein we review the synthetic and electronic design strategies that have been employed thus far for producing frameworks with permanent porosity and long-range charge transport properties. In addition, key experiments that have been employed to demonstrate electrical transport, as well as selected applications for this subclass of MOFs, will be discussed. PMID- 26749065 TI - H-classic: a new method to identify classic articles in Implant Dentistry, Periodontics, and Oral Surgery. AB - INTRODUCTION: The study of classic papers permits analysis of the past, present, and future of a specific area of knowledge. This type of analysis is becoming more frequent and more sophisticated. Our objective was to use the H-classics method, based on the h-index, to analyze classic papers in Implant Dentistry, Periodontics, and Oral Surgery (ID, P, and OS). MATERIAL AND METHODS: First, an electronic search of documents related to ID, P, and OS was conducted in journals indexed in Journal Citation Reports (JCR) 2014 within the category 'Dentistry, Oral Surgery & Medicine'. Second, Web of Knowledge databases were searched using Mesh terms related to ID, P, and OS. Finally, the H-classics method was applied to select the classic articles in these disciplines, collecting data on associated research areas, document type, country, institutions, and authors. RESULTS: Of 267,611 documents related to ID, P, and OS retrieved from JCR journals (2014), 248 were selected as H-classics. They were published in 35 journals between 1953 and 2009, most frequently in the Journal of Clinical Periodontology (18.95%), the Journal of Periodontology (18.54%), International Journal of Oral and Maxillofacial Implants (9.27%), and Clinical Oral Implant Research (6.04%). These classic articles derived from the USA in 49.59% of cases and from Europe in 47.58%, while the most frequent host institution was the University of Gothenburg (17.74%) and the most frequent authors were J. Lindhe (10.48%) and S. Socransky (8.06%). CONCLUSION: The H-classics approach offers an objective method to identify core knowledge in clinical disciplines such as ID, P, and OS. PMID- 26749064 TI - Association of Systemic Sclerosis With a Unique Colonic Microbial Consortium. AB - OBJECTIVE: To compare colonic microbial composition in systemic sclerosis (SSc) patients and healthy controls and to determine whether certain microbial genera are associated with gastrointestinal (GI) tract symptoms in patients with SSc. METHODS: Healthy controls were age- and sex-matched (1:1) with adult SSc patients. Cecum and sigmoid mucosal lavage samples were obtained during colonoscopy. The microbiota in these samples were determined by Illumina HiSeq 2000 16S sequencing, and operational taxonomic units were selected. Linear discriminant analysis effect size was used to identify the genera that showed differential expression in SSc patients versus controls. Differential expression analysis for sequence count data was used to identify specific genera associated with GI tract symptoms. RESULTS: Among 17 patients with SSc (88% female; median age 52.1 years), the mean +/- SD total GI Tract 2.0 score was 0.7 +/- 0.6. Principal coordinate analysis illustrated significant differences in microbial communities in the cecum and sigmoid regions in SSc patients versus healthy controls (both P = 0.001). Similar to the findings in inflammatory disease states, SSc patients had decreased levels of commensal bacteria, such as Faecalibacterium and Clostridium, and increased levels of pathobiont bacteria, such as Fusobacterium and gamma-Proteobacteria, compared with healthy controls. Bifidobacterium and Lactobacillus, which are typically reduced under conditions of inflammation, were also increased in abundance in patients with SSc. In SSc patients with moderate/severe GI tract symptoms, the abundance of Bacteroides fragilis was decreased, and that of Fusobacterium was increased, compared with patients who had no or mild symptoms. CONCLUSION: This study demonstrates a distinct colonic microbial signature in SSc patients compared with healthy controls. This unique ecologic change may perpetuate immunologic aberrations and contribute to clinical manifestations of SSc. PMID- 26749067 TI - Precision mixology challenge. PMID- 26749068 TI - Solution to rubbery egg challenge. PMID- 26749066 TI - Productivity outcomes following endoscopic sinus surgery for recurrent acute rhinosinusitis. AB - OBJECTIVES/HYPOTHESIS: We sought to evaluate preoperative and postoperative productivity losses and quality of life (QOL) impairment reported by patients with recurrent acute rhinosinusitis (RARS) as compared to patients with chronic rhinosinusitis without nasal polyposis (CRSsNP). STUDY DESIGN: Prospective, multi institutional, nested case-control. METHODS: Participants with RARS (n = 20) and CRSsNP (n = 20) undergoing endoscopic sinus surgery (ESS) were enrolled as part of a prospective cohort study. For comparison, participants diagnosed with RARS cases were age/gender-matched to control participants diagnosed with CRSsNP using a 1:1 ratio. RESULTS: RARS and CRSsNP participants were followed for ~14 months postoperatively. Productivity losses were reported as the number of days missed from normal productive activities out of the previous 90 days. RARS participants reported similar baseline productivity losses (12.6 +/- 27.1 [standard deviation]) as participants with CRSsNP (11.7 +/- 20.9; P = .314). Postoperatively, improvement in productivity losses was similar between RARS participants and CRSsNP controls (-6.7 +/- 20.0 vs. -9.8 +/- 19.1; P = .253). Preoperative and postoperative disease-specific QOL measures (Sino-Nasal Outcomes Test-22 and Rhinosinusitis Disability Index) were similar between the two groups. RARS participants reported a significant decrease in days of previous antibiotic (P = .009) and nasal decongestant (P = .004) use following ESS, whereas participants with CRSsNP reported a significant decrease in antibiotic (P = .002) and oral corticosteroid use (P = .002). CONCLUSIONS: RARS patients report baseline productivity losses and disease-specific QOL impairment to levels that parallel those with CRSsNP. Patients with RARS report improvement in QOL following ESS in all disease-specific QOL measures and in several medication measures. Productivity losses and postoperative improvements are similar between patients with RARS and CRSsNP. LEVEL OF EVIDENCE: 3b Laryngoscope, 126:1046-1053, 2016. PMID- 26749070 TI - Telemetry-derived heart rate variability responses to a physical stressor. AB - : Analysis of heart rate variability (HRV) responses to an orthostatic challenge can be used to investigate autonomic control of heart rate, an index of cardiovascular function. HRV is typically assessed using the electrocardiogram (ECG), which can be impractical for use with large population-based studies. PURPOSE: To assess the validity and reliability of telemetry-derived HRV responses to an orthostatic challenge. METHODS: Twenty healthy adults (26 + 5 years, 45% male) were tested on three separate mornings. Following 20-min supine rest, R-R intervals were recorded using a telemetric device during three conditions: BASE, TILT and RECOVERY. ECG was simultaneously used on 1 day for validity comparison. Measures of HRV included the following: standard deviation of normal-to-normal intervals (SDNN), the root-mean-square of successive differences (RMSSD) and the low-frequency (LF) and high-frequency (HF) spectral power. RESULTS: For all parameters, there was excellent agreement between devices for BASE (r = 0.96-0.99), TILT (r = 0.89-1.00) and RECOVERY (r = 0.96-1.00). For the telemetric device, between-day intraclass coefficient values for RMSDD, SDNN and HF were all above the 0.75 criterion for each condition, indicating excellent between-day reliability. For each condition, the reliability coefficient, expressed as a percentage of the mean (RC%), was marginally lower (greater reliability) for RMSDD (RC% 11-13) and SDNN (RC% 10-12) compared to HF (RC% 12 17). However, SDNN did not significantly respond to the orthostatic challenge. CONCLUSION: Telemetric HRV, particularly RMSDD and HF, can be used to provide a sensitive, valid and reliable assessment of autonomic control of heart rate. PMID- 26749071 TI - Cognitive Modeling at ICCM: State of the Art and Future Directions. AB - The goal of cognitive modeling is to build faithful simulations of human cognition. One of the challenges is that multiple models can often explain the same phenomena. Another challenge is that models are often very hard to understand, explore, and reuse by others. We discuss some of the solutions that were discussed during the 2015 International Conference on Cognitive Modeling. PMID- 26749069 TI - Axl, Ferritin, Insulin-Like Growth Factor Binding Protein 2, and Tumor Necrosis Factor Receptor Type II as Biomarkers in Systemic Lupus Erythematosus. AB - OBJECTIVE: To evaluate the performance of 4 serum protein markers for detecting concurrent clinical activity in patients with systemic lupus erythematosus (SLE). METHODS: Consecutive patients who fulfilled >=4 American College of Rheumatology classification criteria for SLE and healthy controls were recruited for serologic testing of 4 protein markers identified by antibody-coated microarray screen, namely Axl, ferritin, insulin-like growth factor binding protein 2 (IGFBP-2), and tumor necrosis factor receptor type II (TNFRII). SLE disease activity was assessed by the Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and physician's global assessment (PGA). Levels of these markers were correlated with SLEDAI scores, and their sensitivity and specificity for clinical SLE activity were determined. RESULTS: A total of 94 SLE patients (98% women, mean +/- SD age 28.7 +/- 9.4 years, mean +/- SD disease duration 5.4 +/- 5.0 years) and 49 healthy controls were studied. Fifty-two patients had clinically active SLE (defined as SLEDAI score >=6 or having a flare). The serum concentrations of Axl, ferritin, IGFBP-2, and TNFRII were significantly higher in patients with active SLE than in those with inactive SLE or in controls. The levels of these markers correlated strongly and significantly with anti-double stranded DNA (anti-dsDNA), C3, and clinical SLEDAI and PGA scores. These markers were more specific, but less sensitive, in detecting concurrent SLE activity than elevated anti-dsDNA or depressed C3. Levels of Axl, TNFRII, and IGFBP-2, but not ferritin, could differentiate active renal from active nonrenal or inactive SLE. The specificity of Axl and IGFBP-2 for concurrent active lupus nephritis was higher than anti dsDNA or C3. CONCLUSION: Serum proteomic markers are potentially useful for diagnosing SLE and monitoring disease activity. The performance of Axl and IGFBP 2 in lupus nephritis should be further explored in a longitudinal cohort of SLE patients. PMID- 26749072 TI - High Performance Particle/Polymer Nanofiber Anodes for Li-ion Batteries using Electrospinning. AB - Electrospun nanofiber mats containing carbon nanoparticles in a poly(vinylidene fluoride) binder were prepared and characterized as Li-ion battery anodes. The mats exhibited an initial capacity of 161 mAh g(-1) with 91.7% capacity retention after 510 cycles at 0.1 C (1 C=372 mA gcarbon (-1)). Whereas many nanoscale electrodes are limited to low areal and/or volumetric capacities, the particle/polymer nanofiber anodes can be made thick with a high fiber volume fraction while maintaining good rate capabilities. Thus, a nanofiber anode with a fiber volume fraction of 0.79 exhibits a volumetric capacity of 55 mAh cm(-3) at 2 C, which is twice that of a typical graphite anode. Similarly, thick nanofiber mats with a high areal capacity of 4.3 mAh cm(-2) were prepared and characterized. The excellent performance of electrospun anodes is attributed to electrolyte intrusion throughout the interfiber void space and efficient Li(+) transport between the electrolyte and carbon nanoparticles in the radial fiber direction. PMID- 26749074 TI - Investigation on the Interaction of Hydroxyethyl Starch 130/0.4 (Voluven) and Serum Albumin for Pharmacokinetic and Toxicological Implications. AB - The interaction of hydroxyethyl starch 130/0.4 (Voluven) with human serum albumin (HSA) has been investigated by fluorescence (steady state and synchronous), Fourier transforms infrared (FT-IR), and circular dichroism (CD) spectroscopies. Analysis of the fluorescence quenching data of HSA by Voluven using the Stern Volmer method revealed the formation of 1:1 ground-state complex. Evaluation of binding parameters and binding energy indicated that the binding reaction was exothermic. On the basis of fluorescence measurements, it was concluded that electrostatic forces play a crucial role in stabilizing the complex. The binding distance was calculated by using Forster resonance energy transfer (FRET) theory. The conformational changes of HSA were obtained qualitatively as well as quantitatively using synchronous fluorescence, FT-IR, and CD. The HSA underwent partial unfolding in the presence of Voluven. PMID- 26749073 TI - Effect of fish oil on monoepoxides derived from fatty acids during cardiac surgery. AB - Our objective was to assess the dynamics of monoepoxides derived from polyunsaturated fatty acids (MEFAs), and their response to n-3 PUFA supplementation, in the setting of acute tissue injury and inflammation (cardiac surgery) in humans. Patients (479) undergoing cardiac surgery in three countries were randomized to perioperative fish oil (EPA + DHA; 8-10 g over 2-5 days preoperatively, then 2 g/day postoperatively) or placebo (olive oil). Plasma MEFAs derived from n-3 and n-6 PUFAs were measured 2 days postoperatively. Based on serial measures in a subset of the placebo group, levels of all MEFAs declined substantially following surgery (at postoperative day 2), with declines ranging from 37% to 63% (P < 0.05 each). Compared with placebo at postoperative day 2, levels of EPA- and DHA-derived MEFAs were 40% and 18% higher, respectively (P <= 0.004). The n-3 PUFA supplementation did not significantly alter the decline in n 6 PUFA-derived MEFAs. Both enrollment level and changes in plasma phospholipid EPA and DHA were associated with their respective MEFAs at postoperative day 2 (P < 0.001). Under the acute stress of cardiac surgery, n-3 PUFA supplementation significantly ameliorated the reduction in postoperative n-3 MEFAs, but not n-6 MEFAs, and the degree of increase in n-3 MEFAs related positively to the circulating level of their n-3 PUFA precursors. PMID- 26749075 TI - RNA synthesis and turnover in the molluscan nervous system studied by Click-iT method. AB - RNA synthesis can be detected by means of the in vivo incorporation of 5 ethynyluridine (EU) in newly-synthesized RNA with the relatively simple Click-iT method. We used this method to study the RNA synthesis in the CNS tissue of adult and juvenile terrestrial snails Helix lucorum L. Temporally, first labeled neurons were detected in the adult CNS after 4-h of isolated CNS incubation in EU solution, while 12-h of incubation led to extensive labeling of most CNS neurons. The EU labeling was present as the nuclear and nucleolar staining. The cytoplasm staining was observed after 2-3 days of CNS washout following the EU exposure for 16 h. In juvenile CNS, the first staining reaction was apparent as the staining of apical region in the procerebral lobe of cerebral ganglia after 1h of CNS incubation in EU, while the maximum pattern of staining was obtained after 4h of CNS incubation. Thus, age-related differences in RNA synthesis are present. Activation of neurons elicited by serotonin and caffeine applications noticeably increased the intensity of staining. EU readily penetrates into the bodies of juvenile snails immersed in the EU solution. When the intact juvenile animals were immersed in the EU solution for 1h, the procerebrum staining, similar to the one detected in the incubated juvenile CNS, was observed. PMID- 26749077 TI - Synchrotron radiation X-ray micro-fluorescence: Protocol to study mesenchymal stem cells. AB - The micro-X-ray fluorescence by synchrotron radiation (MU-XRF) is a method to determine the composition of tissues without destroying the samples. However, this technique has never been used for the analysis of mesenchymal stem cells (MSC). This study compared different protocols for fixing, storing, preserving, and establishing the correct numbers of dental derived MSC submitted to MU-XRF analysis. Stem cells were obtained from human dental tissue. After cell expansion, and MACS isolation, the samples were fixed and the following quantities of cells 1 * 10(4) to 1 * 10(7) were divided in two groups: G1: fixed in 4% paraformaldehyde diluted in phosphate-buffered saline solution, and G2: fixed in 4% paraformaldehyde diluted in MilliQ water. The G1 cells showed precipitation of chemical components from the solution resulting in the formation of salt crystals while G2 cells were clear and almost transparent in the sample holder. With regards to cells concentration, the best results occurred when four droplets of 1 * 10(7) cells were analyzed. This work shows that to identify and study the distribution of trace elements in MSC by MU-XRF, the best protocol is fixation in 4% paraformaldehyde diluted with MilliQ water at 4 degrees C and a concentration of four incremental droplets of 1 * 10(7) cells. PMID- 26749078 TI - Retrospective comparison of thromboelastography results to postmortem evidence of thrombosis in critically ill dogs: 39 cases (2005-2010). AB - OBJECTIVE: To determine whether there is an association between thromboelastography (TEG) data and necropsy evidence of thrombosis in a cohort of critically ill dogs. DESIGN: Retrospective study (2005-2010). SETTING: University teaching hospital. ANIMALS: Thirty-nine client-owned critically ill dogs for which TEG was performed within 7 days of complete necropsy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thrombi were found in 26 (67%) dogs. Spayed females (n = 20) were significantly more likely to have thrombosis (P = 0.0127). No significant association was found between presence of thrombosis and any TEG parameter, the calculated coagulation index, results of coagulation testing, type of vascular access, or clinical diagnosis. D-dimers were significantly higher in dogs with thrombosis (P = 0.0207) and a weak positive correlation was found between D-dimer value and number of sites of thrombosis (rho = 0.18, P = 0.0045). Dogs with WBC > 16 * 10(3) /MUL were more likely to have thrombosis compared to others (odds ratio 5.56, 95% confidence interval 1.2-25.7, P = 0.025). CONCLUSIONS: This study found no association between any TEG parameter and the presence of thrombosis on postmortem examination. PMID- 26749079 TI - Efficacy of intravitreal ranibizumab combined with Ahmed glaucoma valve implantation for the treatment of neovascular glaucoma. AB - BACKGROUND: Neovascular glaucoma is a refractive glaucoma. Recently, anti-VEGF factors have been used alone or in combination for the treatment of neovascular glaucoma. However, the medium- and long-term efficacy of such drugs remains to be evaluated. This study was to determine the efficacy of intravitreal ranibizumab combined with Ahmed glaucoma valve implantation for the treatment of neovascular glaucoma. METHODS: In this prospective non-randomized study, 43 neovascular glaucoma patients (43 eyes) were assigned to receive either 0.5 mg intravitreal ranibizumab for three to 14 days before Ahmed glaucoma valve implantation (injection group, n = 21) or Ahmed glaucoma valve implantation alone (control group, n = 22). The patients were followed up for six to 12 months. Differences in surgical success rate, intraocular pressure, best corrected visual acuity, anti-glaucoma medications and postoperative complications were compared between the two groups. Surgical success was defined as IOP > = 6 mm Hg and < = 21 mm Hg, with or without the use of anti-glaucoma medications, and without severe complications or reoperation. RESULTS: Of the 43 patients, 40 completed the 6 month follow-up and 37 completed the 1-year follow-up. Success rate was 73.7% vs. 71.4% at six months and 72.2% vs. 68.4% at 12 months in the injection group and the control group respectively. No significant difference was noted between the two groups (six months: P = 0.87, 12 months: P = 1.00). There were no significant differences in the two groups with respect to intraocular pressure, best corrected visual acuity, anti-glaucoma medications or postoperative complications at six months or 12 months. CONCLUSIONS: Single intravitreal ranibizumab (0.5 mg) before surgery has no significant effect on the medium- or long-term outcomes of neovascular glaucoma treated with Ahmed glaucoma valve implantation. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( ChiCTR-OOC-14005709, Trial registration date: 2014-12-01). PMID- 26749080 TI - [Cholestatic hepatitis in immunoglobulin-resistant Kawasaki disease]. PMID- 26749076 TI - Conclusions about interventions, programs, and approaches for improving executive functions that appear justified and those that, despite much hype, do not. AB - The 'Executive Functions' (EFs) of inhibitory control, working memory, and cognitive flexibility enable us to think before we act, resist temptations or impulsive reactions, stay focused, reason, problem-solve, flexibly adjust to changed demands or priorities, and see things from new and different perspectives. These skills are critical for success in all life's aspects and are sometimes more predictive than even IQ or socioeconomic status. Understandably, there is great interest in improving EFs. It's now clear they can be improved at any age through training and practice, much as physical exercise hones physical fitness. However, despite claims to the contrary, wide transfer does not seem to occur and 'mindless' aerobic exercise does little to improve EFs. Important questions remain: How much can EFs be improved (are benefits only superficial) and how long can benefits be sustained? What are the best methods for improving EFs? What about an approach accounts for its success? Do the answers to these differ by individual characteristics such as age or gender? Since stress, sadness, loneliness, or poor health impair EFs, and the reverse enhances EFs, we predict that besides directly train EFs, the most successful approaches for improving EFs will also address emotional, social, and physical needs. PMID- 26749081 TI - Whole-body MRI with diffusion-weighted imaging: a valuable alternative to contrast-enhanced CT for initial staging of aggressive lymphoma. AB - AIM: To compare the accuracy of whole-body magnetic resonance imaging (Wb-MRI) with diffusion-weighted imaging (DWI) to that of contrast-enhanced computed tomography (CE-CT) and 2-[(18)F]-fluoro-2-deoxy-d-glucose ((18)F-FDG) positron emission tomography co-registered with low dose-CT (PET-CT) in defining lymphoma disease stage. MATERIALS AND METHODS: From February 2010 to May 2014, 41 lymphoma patients underwent Wb-MRI-DWI, CE-CT, and (18)F-FDG PET-CT. Histological subtypes included aggressive B-cell (n=11), follicular (n=13), mantle cell (n=3), and Hodgkin's (n=14) lymphoma. To compare the procedures, the reference standard (RS) assessment was defined by combining the results from (18)F-FDG PET-CT, CE-CT, and bone marrow (BM) histology, modifications after therapy, and histological re assessments of uncertain lesions. RESULTS: Among 1025 nodal sites, 217 had disease involvement according to the RS. CE-CT yielded 23 false-negative and 11 false-positive errors. Wb-MRI-DWI failed to recognise 17 localisations and had six false-positive errors; (18)F-FDG PET-CT had no errors. Among 458 extranodal sites, 37 were positive according to the RS. (18)F-FDG PET-CT yielded four false negative and two false-positive results. CE-CT yielded 17 false-negative errors. Wb-MRI-DWI yielded a single false-negative error. Wb-MRI-DWI was the most reliable imaging technique for BM evaluation. Considering each procedure alone, the final stage would have been missed in four cases using (18)F-FDG PET-CT, 12 cases using CE-CT, and none using Wb-MRI-DWI. CONCLUSION: The present data support Wb-MRI-DWI as a sensitive and specific imaging technique for lymphoma evaluation, supporting its use in place of CE-CT for staging. PMID- 26749082 TI - Dual energy can accurately differentiate uric acid-containing urinary calculi from calcium stones. AB - PURPOSE: To retrospectively evaluate the accuracy of dual-energy CT (DECT) in the detection of the chemical composition of urinary calculi in correlation with infrared spectroscopic stone analysis. METHODS: We reviewed the CT scans of 255 patients who underwent DECT due to a clinical suspicion of urolithiasis. Out of this group, we included 64 patients with clinically symptomatic urolithiasis requiring stone removal. After surgical removal of the stone by ureterorenoscopy, chemical composition was analyzed with infrared spectroscopy. We correlated DECT stone characterization results with chemical stone composition based on dual energy indices (DEI). A total of 213 renal and ureteral stones could be removed and chemically analyzed. RESULTS: A total of 213 calculi were evaluated. Thirty eight out of sixty four (59 %) patients had >1 stone. DECT was used to differentiate stones by using DEI. Stones harboring calcium (CA) were color-coded in blue, while stones containing uric acid (UA) were colored red. Median DEI in UA-containing stones were 0.001. Non-UA-containing stones had a DEI between 0.073 for pure CA stones and 0.077 containing CA and other substances (p = 0.001; p = 0.03, respectively). Sensitivity of DECT was 98.4 % for differentiation of UA from non-UA-containing calculi. Specificity was 98.1 %. Mean effective radiation dose of DECT was 4.18 mSv (0.44-14.27 mSv), thus comparable to conventional CT scans of the abdomen. Conventional measurement of Hounsfield units did not correlate with stone composition. CONCLUSION: DECT with image post-processing reliably discriminates UA-containing calculi from all other stones, but the study offered limitations. Discrimination within the non-UA stones cannot be reliably achieved but is clinically insignificant. PMID- 26749083 TI - Intermolecular Peptide Cross-Linking by Using Diaminodicarboxylic Acids. AB - Synthetic methods aimed at preparing peptides cross-linked by diaminodiacids remain an important chemical challenge. These cross-links are known to play a crucial role on the activity, structural stability, and folding of the host peptides and proteins. Recent developments in the syntheses of such systems have led to intriguing advances in the understanding of intermolecular side-chain cross-linking and the role that these structural motifs play in the biochemistry of proteins. Herein we provide an overview of the existing synthetic methodology that has been developed to effect protein cross-linking using diaminodiacids. PMID- 26749085 TI - Identification With Terrorist Victims of the Washington, DC Sniper Attacks: Posttraumatic Stress and Depression. AB - In October 2002, a series of sniper attacks in the Washington, DC area left 10 people dead and 3 wounded. We examined the association between identification with terrorist victims and psychological and behavioral outcomes. Participants were 1,238 residents of the Washington, DC area (ages 18-90 years; M = 41.73, SD = 12.56) who completed the Impact of Event Scale-Revised, Patient Health Questionnaire-9, and items pertaining to identification with attack victims approximately 3 weeks following the first sniper shooting. We examined 3 types of identification with the victims: (a) as like oneself, (b) as like a friend, and (c) as like a family member. The relationships of identification to posttraumatic stress and depressive symptoms were examined using linear regression analyses. Greater total identification was associated with more posttraumatic stress and depressive symptoms (B = 0.27, p < .001, and B = 0.44, p < .001, respectively), after adjusting for demographics. Those who specifically identified with the victims as either self (B = 0.24, p < .001), friend (B = 0.30, p < .001), or family member (B = 0.27, p < .001) reported more PTSD symptoms (n = 1,101). Identifying with victims as like a friend or family member, but not as like oneself, was associated with increased depressive symptoms (B = 0.61, p < .001, and B = 0.45, p = .01, respectively; n = 1,222). Presence and type of identification play a differential role in psychological and behavioral responses during traumatic events. PMID- 26749084 TI - Three-dimensional reconstruction of Haversian systems in human cortical bone using synchrotron radiation-based micro-CT: morphology and quantification of branching and transverse connections across age. AB - This study uses synchrotron radiation-based micro-computed tomography (CT) scans to reconstruct three-dimensional networks of Haversian systems in human cortical bone in order to observe and analyse interconnectivity of Haversian systems and the development of total Haversian networks across different ages. A better knowledge of how Haversian systems interact with each other is essential to improve understanding of remodeling mechanisms and bone maintenance; however, previous methodological approaches (e.g. serial sections) did not reveal enough detail to follow the specific morphology of Haversian branching, for example. Accordingly, the aim of the present study was to identify the morphological diversity of branching patterns and transverse connections, and to understand how they change with age. Two types of branching morphologies were identified: lateral branching, resulting in small osteon branches bifurcating off of larger Haversian canals; and dichotomous branching, the formation of two new osteonal branches from one. The reconstructions in this study also suggest that Haversian systems frequently target previously existing systems as a path for their course, resulting in a cross-sectional morphology frequently referred to as 'type II osteons'. Transverse connections were diverse in their course from linear to oblique to curvy. Quantitative assessment of age-related trends indicates that while in younger human individuals transverse connections were most common, in older individuals more evidence of connections resulting from Haversian systems growing inside previously existing systems was found. Despite these changes in morphological characteristics, a relatively constant degree of overall interconnectivity is maintained throughout life. Altogether, the present study reveals important details about Haversian systems and their relation to each other that can be used towards a better understanding of cortical bone remodeling as well as a more accurate interpretation of morphological variants of osteons in cross-sectional microscopy. Permitting visibility of reversal lines, synchrotron radiation-based micro-CT is a valuable tool for the reconstruction of Haversian systems, and future analyses have the potential to further improve understanding of various important aspects of bone growth, maintenance and health. PMID- 26749086 TI - Collagen structural alterations contribute to stiffening of tissue after split thickness skin grafting. AB - The gold standard treatment for full thickness injuries of the skin is autologous split-thickness skin grafting. This involves harvesting the epidermis and superficial dermis from healthy skin and transplanting it onto the prepared wound bed. The donor site regenerates spontaneously, but the appendages and cellular components from the dermal layer are excluded from the graft. As a result, the new tissue is inferior; the healed graft site is dry/itchy, has decreased elasticity, increased fragility, and altered sensory function. Because this dermal layer is composed of collagen and other extracellular matrix proteins, the aim was to characterize the changes in the dermal collagen after split thickness grafting that could contribute to a deficit in functionality. This will serve as a baseline for future studies designed to improve skin function using pharmacological or cell-based therapies for skin repair. A xenograft model whereby human split-thickness grafts were implanted into full-thickness defects on immunocompromised (athymic Nu/Nu) mice was used. The grafts were harvested 4 and 8 weeks later. The collagen microstructure was assessed with second harmonic generation with dual-photon microscopy and light polarization analysis. Collagen fiber stiffness and engagement stretch were estimated by fitting the results of biaxial mechanical tensile tests to a histo-mechanical constitutive model. The stiffness of the collagen fibril-proteoglycan complex increased from 682 +/- 226 kPa/sr to 1016 +/- 324 kPa/sr between 4 and 8 weeks postgrafting. At the microstructural level there were significant decreases in both thickness of collagen fibers (3.60 +/- 0.34 MUm vs. 2.10 +/- 0.27 MUm) and waviness ratio (2.04 +/- 0.17 vs. 1.43 +/- 0.08) of the collagen fibers postgrafting. The decrease of the macroscopic engagement stretch from 1.19 +/- 0.11 to 1.09 +/- 0.08 over time postgrafting mirrored the decrease in waviness measured at the microscopic level. This suggested that the integrity of the collagen fibers was compromised and contributed to the functional deficit of the skin postgrafting. PMID- 26749087 TI - Assessment of Functional Fibrinolysis in Cord Blood Using Modified Thromboelastography. AB - BACKGROUND: The fibrinolytic system in newborns is immature and probably impaired. The aim of this study was to prospectively evaluate functional fibrinolytic capacity of newborn's cord blood using a new thromboelastometry (rotational thromboelastogram, ROTEM(r)) test. METHODS: Infants born at Sheba Medical Center were studied prospectively. Cord blood was obtained immediately after clumping, and ROTEM parameters were assessed applying non-activated TEM (NATEM) assay with increasing concentration of tissue plasminogen activator (tPA, 0-200 U/ml). Baseline clotting time (CT), clot formation time (CFT), alpha angle, and maximum clot firmness (MCF) were compared among infants versus adults. Each infant's demographic information was prospectively followed up until discharge. RESULTS: One hundred one newborns were tested. CT and CFT values were lower and alpha angles were higher among neonate's cord blood compared to adults (n = 23; P = 0.001, 0.03, and 0.02, respectively). The addition of tPA significantly shortened CT and CFT, and reduced alpha angles and MCF in both groups. The lysis index at 30 min (LI30) and lysis onset time (LOT) decreased significantly, and fibrinolysis was more rapid in the newborns. Hematocrit and platelet counts in neonates correlated with LI30 (P = 0.035 and 0.037, respectively) and LOT (P = 0.02) when higher tPA concentrations were used. ROTEM values were unrelated to the occurrence of postnatal complications. CONCLUSIONS: This first report of functional fibrinolysis in cord blood demonstrated that neonatal fibrinolysis may be augmented as compared to adult values. Further studies are required to validate this test and assess its predictive value and clinical relevance. PMID- 26749088 TI - Systematic review of literature: functional outcomes of implant-prosthetic treatment in patients with surgical resection for oral cavity tumors. AB - The current systematic review was performed to assess the functional outcomes of implant-prosthetic treatment on patients who have had surgical resection of oral cavity tumors. The assessment of function, satisfaction, or quality of life (QoL) were the major outcomes that evaluated preoperative and/or before and after implant-prosthetic treatment. Only eight published studies fulfilled the inclusion criteria. Three publications evaluated chewing ability, masticatory performance, and neuromuscular function, and the other five publications used questionnaire as a method of assessment. These publications mainly reported on implant-prosthetic treatment in mandibulectomy patients. It was found that implant-retained prosthesis had a beneficial effect on masticatory performance and masseter muscle activity on the defect side, but not on the non-defect side. Swallowing threshold performance and jaw movement parameters showed no significant differences between non-implant-retained prosthesis and implant retained prosthesis. Significant improvement in prosthesis and patients' satisfaction with implant-retained prosthesis compared to non-implant-retained prosthesis was observed. However, general improvement in patients' QoL was not observed after implant-prosthetic treatment. Patients with intraoral resection might benefit from implant-retained prosthesis with regard to masticatory function and satisfaction. However, future clinical trials with an adequate sample size are needed to identify the group of patients who are likely to benefit from the implant-prosthetic treatment modality. PMID- 26749089 TI - Evolution of Transporters: The Relationship of SWEETs, PQ-loop, and PnuC Transporters. PMID- 26749091 TI - Utility of DN4 questionnaire in assessment of neuropathic pain and its clinical correlations in Turkish patients with diabetes mellitus. AB - AIM: We aimed to assess the utility of DN4 questionnaire (Douleur Neuropathique en 4 questions) to define the frequency and severity of neuropathic pain (NP) and also its clinical correlation to daily clinical practice. METHODS: We included 1357 patients with diabetes (56.5% women, 90.4% type 2 diabetes) who were followed up in our diabetes outpatient clinic. Presence of NP was evaluated by performing simultaneous DN4 questionnaires and physical examination. Those who had a DN4 score >=4 were considered to have NP. RESULTS: The mean age was 58.2+/ 12.1 years, mean duration was 12.5+/-7.5; (min-max: 1-45) years, mean HbA1c level was 7.8+/-1.6% (min-max: 5-16.2%), (61.7+/-6.0mmol/mol; min-max: 31.1 153.6mmol/mol). Three hundred thirteen patients (23%) were diagnosed with NP using the DN4 tool. Male gender (p=0.01), receiving antihypertensive treatment (p=0.01), presence of retinopathy (p<0.001), cardiovascular disease (CVD) (p=0.01) and previously diagnosed neuropathy (p<0.001) were significantly associated with higher NP scores. Those who had increased DN4 scores were more likely to be on oral hypoglycemic agents (OHA)+insulin combinations (p<0.001), had longer diabetes duration (p<0.001) and higher HbA1c levels (p=0.001). Logistic regression model revealed that diabetes duration (OR: 1.02, 95% CI: 1.00 1.04, p=0.007), elevated HbA1c levels (1.11, 1.02-1.21, 0.015), presence of retinopathy (1.41, 1.20-1.64, <0.001), management with at least one OHA (1.47; 1.12-1.92; 0.004) or any insulin regimen (1.62; 1.16-2.27; 0.005) (compared with diet only-regimens) were significantly associated with NP. CONCLUSION: Utilization of DN4 questionnaire in daily clinical practice is an effective tool in the identification of pain related with peripheral diabetic polyneuropathy. PMID- 26749090 TI - 5-Hydroxytryptamine 1A receptors in the dorsomedial hypothalamus connected to dorsal raphe nucleus inputs modulate defensive behaviours and mediate innate fear induced antinociception. AB - The dorsal raphe nucleus (DRN) is an important brainstem source of 5 hydroxytryptamine (5-HT), and 5-HT plays a key role in the regulation of panic attacks. The aim of the present study was to determine whether 5-HT1A receptor containing neurons in the medial hypothalamus (MH) receive neural projections from DRN and to then determine the role of this neural substrate in defensive responses. The neurotracer biotinylated dextran amine (BDA) was iontophoretically microinjected into the DRN, and immunohistochemical approaches were then used to identify 5HT1A receptor-labelled neurons in the MH. Moreover, the effects of pre treatment of the dorsomedial hypothalamus (DMH) with 8-OH-DPAT and WAY-100635, a 5-HT1A receptor agonist and antagonist, respectively, followed by local microinjections of bicuculline, a GABAA receptor antagonist, were investigated. We found that there are many projections from the DRN to the perifornical lateral hypothalamus (PeFLH) but also to DMH and ventromedial (VMH) nuclei, reaching 5HT1A receptor-labelled perikarya. DMH GABAA receptor blockade elicited defensive responses that were followed by antinociception. DMH treatment with 8-OH-DPAT decreased escape responses, which strongly suggests that the 5-HT1A receptor modulates the defensive responses. However, DMH treatment with WAY-100635 failed to alter bicuculline-induced defensive responses, suggesting that 5-HT exerts a phasic influence on 5-HT1A DMH neurons. The activation of the inhibitory 5-HT1A receptor had no effect on antinociception. However, blockade of the 5-HT1A receptor decreased fear-induced antinociception. The present data suggest that the ascending pathways from the DRN to the DMH modulate panic-like defensive behaviours and mediate antinociceptive phenomenon by recruiting 5-HT1A receptor in the MH. PMID- 26749092 TI - Current Pharmacological Management of Premature Ejaculation: A Systematic Review and Meta-analysis. AB - CONTEXT: Premature ejaculation (PE) is the most prevalent male sexual dysfunction. In the last few years, several pharmacologic approaches for oral or topical treatment of PE have been studied. OBJECTIVE: To systematically review the literature on the outcome of pharmacologic interventions for PE on intravaginal ejaculation latency time (IELT) in comparison to placebo. EVIDENCE ACQUISITION: A systematic literature search of PubMed and Scopus using the term "premature ejaculation" was performed on 10 April 2015. Full-text articles on prospective randomized controlled trials (RCTs) investigating pharmacotherapy were included. The main outcome measure was IELT. EVIDENCE SYNTHESIS: Out of 266 unique records, a total of 22 were reviewed. The majority of RCTs were of unclear methodological quality because of limited reporting of methods. Pooled evidence suggests that selective serotonin reuptake inhibitors (SSRIs), topical anesthetic creams (TAs), tramadol, and phosphodiesterase type 5 inhibitors (PDE5is) are more effective than placebo at increasing IELT (all p<0.05). However, interpretation of the current meta-analyses may be impaired as a result of frequent heterogeneity in the pooled analyses (all I(2) > 70%). Only pooled analyses for dapoxetine 30mg and 60mg were characterized by homogeneous data (both I(2)<30%) while showing a modest but statistically significant improvement in IELT compared with placebo (mean difference 1.39min, 95% confidence interval 1.23-1.54min; p<0.00001). CONCLUSIONS: Meta-analysis revealed that treatment with dapoxetine significantly improves IELT in patients with PE but with modest efficacy. The efficacy of SSRIs, TAs, tramadol, and PDE5is remains unclear owing to high heterogeneity of the available RCT data. There is a persisting need for drug research and development in the field. PATIENT SUMMARY: Premature ejaculation is a condition for which the cause is not well understood. Several types of treatment with medium to low efficacy are available. More research is necessary to identify the ideal treatment. PMID- 26749094 TI - Osteoporosis and Fracture Risk in Men with Prostate Cancer. PMID- 26749093 TI - The Role of Prostate-specific Antigen Persistence After Radical Prostatectomy for the Prediction of Clinical Progression and Cancer-specific Mortality in Node positive Prostate Cancer Patients. AB - BACKGROUND: A complete biochemical response (BR) immediately after surgery could be considered an indicator of optimal cancer control after radical prostatectomy (RP). OBJECTIVE: To evaluate the prognostic value of early postoperative prostate specific antigen (PSA) levels after RP in patients with lymph node invasion (LNI). DESIGN, SETTING, AND PARTICIPANTS: The study included 319 prostate cancer patients with LNI who were treated with RP and extended pelvic lymph node dissection (ePLND) at a single institution between 1998 and 2013. All men had complete clinical, pathologic, and follow-up data, including PSA value at 6 wk after surgery. Patients were divided into two groups according to PSA value at 6 wk after surgery: complete BR (PSA <0.1 ng/ml) and PSA persistence (PSA >=0.1 ng/ml). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier analyses were used to assess 8-yr clinical recurrence (CR) and cancer-specific mortality (CSM) rates according to PSA persistence after RP. Multivariable Cox regression analysis was used to test the association between PSA persistence and CR. Covariates consisted of pathologic Gleason score (<=7 vs >=8), number of positive nodes, surgical margins status (negative vs positive), and adjuvant therapies (none vs androgen deprivation therapy (ADT) vs adjuvant radiotherapy plus ADT). When we performed multivariable analyses assessing the association between PSA persistence and CSM pathologic Gleason score represented the only covariate due to the low number of events (n=13). RESULTS AND LIMITATIONS: Overall, 83 patients (26%) had PSA persistence. Men with PSA persistence had higher 8-yr CR and CSM rates than those with complete BR (69% vs 12% and 16% vs 4.2%, respectively; all p<=0.002). This was confirmed in multivariable analyses, where PSA persistence at 6 wk after surgery was an independent predictor of both CR (hazard ratio [HR]: 8.3; 95% confidence interval [CI], 4.73-14.7; p<=0.001) and CSM (HR: 2.16; 95% CI, 1.63-2.86; p<=0.001). Pathologic stage lower than pT3a, biopsy and pathologic Gleason score >=8, positive surgical margins, and three or more positive lymph nodes were significantly associated with PSA persistence (all p<=0.04). Our study is limited by its retrospective design. CONCLUSIONS: Early BR can be achieved in approximately 75% of men with LNI submitted to RP and ePLND. PSA assessment early after surgery has an important prognostic role in the prediction of CR and CSM in node-positive patients. A risk stratification of these patients based on PSA persistence could guide physicians to properly select patients who may benefit the most from timely multimodal treatments. PATIENT SUMMARY: The risk of clinical recurrence and cancer-specific mortality is heterogeneous in patients with prostate cancer with lymph node invasion. Node-positive patients with complete biochemical response early after surgery share more favorable oncologic outcomes than those with PSA persistence. These results are important to plan the optimal postoperative patient management. PMID- 26749095 TI - Visual multiple recognition of protein biomarkers based on an array of aptamer modified gold nanoparticles in biocomputing to strip biosensor logic operations. AB - We developed a strip biosensors array based on aptamer-modified gold nanoparticles as receptors and combined the protein-aptamer binding reaction with the streptavidin-biotin interaction as well as the sandwich format. We found that a series of protein receptors obtained a distinct response pattern to each target protein. Three proteins have been well distinguished with the naked eyes and a portable reader without mutual interference, accompanying with lower limit of detection and wider linear range. A complete set of four elementary logic gates (AND, OR, INH, and NAND) and eight combinative logic gates (AND-OR; AND-INH; OR INH; INH-NAND; AND-OR-INH; AND-INH-NAND; OR-INH-NAND; AND-OR-INH-NAND) are thoroughly realized using this array, which could eventually be applicable to the keypad-lock system with enhanced complexity in the near future. Moreover, this array shows excellent linear relationships, anti-interference capability, real human serum samples applicability, long-term storage stability and reproducibility. All indicate that this design has very good prospects for development. PMID- 26749096 TI - Protein-templated cobaltous phosphate nanocomposites for the highly sensitive and selective detection of platelet-derived growth factor-BB. AB - We synthesized novel Co3(PO4)2-based nanocomposites with 3D porous architectures via self-assembly; here, bovine serum albumin (BSA) and aptamer were used as organic phases to produce Co3(PO4)2@BSA and Co3(PO4)2@Apt nanocomposites, respectively. The formation mechanism of Co3(PO4)2-based nanocomposites was described based on characterizations of their physio-chemical performance, and the developed nanocomposites were applied as scaffold materials to construct a novel electrochemical aptasensor and detect platelet-derived growth factor-BB (PDGF-BB). The PDGF-BB targeting aptamer must be immobilized onto the Co3(PO4)2@BSA-modified electrode to detect PDGF-BB, whereas Co3(PO4)2@Apt-based aptasensor may be directly used to determine the target protein. Electrochemical impedance spectroscopy results showed that the developed Co3(PO4)2@BSA- and Co3(PO4)2@Apt-based aptasensors present highly sensitive detection ability toward PDGF-BB. Due to the special nanoflower structure, the Co3(PO4)2@BSA-based aptasensor features a detection limit of 3.7 pg mL(-1); while the limit of detection of the Co3(PO4)2@Apt-based aptasensor is 61.5 pg mL(-1), which is the possible bioactivity loss of the aptamer in Co3(PO4)2@Apt nanocomposite. The two detection limits obtained are still much lower than or comparable with those of previously reported aptasensors. The Co3(PO4)2@BSA- and Co3(PO4)2@Apt-based aptasensors showed high selectivity, stability, and applicability for detecting the desired protein. This finding indicates that the Co3(PO4)2-based nanocomposites could be used as an electrochemical biosensor for various detection procedures in the biomedical field. PMID- 26749097 TI - Enhanced electrochemiluminescence of RuSi nanoparticles for ultrasensitive detection of ochratoxin A by energy transfer with CdTe quantum dots. AB - This paper develops a new approach to enhance the electrochemiluminescence (ECL) emission of the Ru(bpy)3(2+)-tripropyl amine (TPrA) system for ultrasensitive determination of ochratoxin A (OTA). Ru(bpy)3(2+)-doped silica nanoparticles (RuSi NPs) act as ECL materials, which are immobilized on the surface of electrode by chitosan to fabricate a solid-state ECL sensor. CdTe quantum dots (QDs) can enhance the ECL emission of the Ru(bpy)3(2+)-TPrA ECL system by energy transfer. This strategy can improve the sensitivity of the sensor. In this assay, we combine the ECL with molecular imprinting technique to improve the selectivity of this sensor. The template molecule could be eluted from the molecularly imprinted polymer (MIP), and the formed cavities could then selectively recognize the target. The cavities could also work as the tunnel for the transfer of coreactant TPrA to produce responsive signal. With the increase of the concentration of OTA in samples, more cavities were filled because of the rebinding of OTA to the MIP surface, resulting in a gradual decrease in ECL intensity. The results showed that the ECL decrease value depended linearly on the logarithm of the OTA concentration in the range from 1.00*10(-5) to 11.13 ng mL(-1) with lower detection limit of 3.0 fg mL(-1) (S/N=3). This ECL sensor has also been applied to detect OTA concentration in the real samples with satisfied results, and the recoveries range from 85.1% to 107.9%. PMID- 26749098 TI - Development of a lab-on-chip electrochemical biosensor for water quality analysis based on microalgal photosynthesis. AB - The present work was dedicated to the development of a lab-on-chip device for water toxicity analysis and more particularly herbicide detection in water. It consists in a portable system for on-site detection composed of three-electrode electrochemical microcells, integrated on a fluidic platform constructed on a glass substrate. The final goal is to yield a system that gives the possibility of conducting double, complementary detection: electrochemical and optical and therefore all materials used for the fabrication of the lab-on-chip platform were selected in order to obtain a device compatible with optical technology. The basic detection principle consisted in electrochemically monitoring disturbances in metabolic photosynthetic activities of algae induced by the presence of Diuron herbicide. Algal response, evaluated through oxygen (O2) monitoring through photosynthesis was different for each herbicide concentration in the examined sample. A concentration-dependent inhibition effect of the herbicide on photosynthesis was demonstrated. Herbicide detection was achieved through a range (blank - 1 uM Diuron herbicide solution) covering the limit of maximum acceptable concentration imposed by Canadian government (0.64 uM), using a halogen white light source for the stimulation of algal photosynthetic apparatus. Superior sensitivity results (limit of detection of around 0.1 uM) were obtained with an organic light emitting diode (OLED), having an emission spectrum adapted to algal absorption spectrum and assembled on the final system. PMID- 26749100 TI - Plasma treatment of paper for protein immobilization on paper-based chemiluminescence immunodevice. AB - A novel protein immobilization method based on plasma treatment of paper on the low-cost paper-based immunodevice was established in this work. By using a benchtop plasma cleaner, the paper microzone was treated by oxygen plasma treatment for 4 min and then the antibody can be directly immobilized on the paper surface. Aldehyde group was produced after the plasma treatment, which can be verified from the fourier transform infrared spectroscopy (FT-IR) spectra and x-ray photoelectron spectroscopy (XPS) spectra. By linked to aldehyde group, the antibody can be immobilized on the paper surface without any other pretreatment. A paper-based immunodevice was introduced here through this antibody immobilization method. With sandwich chemiluminescence (CL) immunoassay method, the paper-based immunodevice was successfully performed for carcinoembryonic antigen (CEA) detection in human serum with a linear range of 0.1-80.0 ng/mL. The detection limit was 0.03 ng/mL, which was 30 times lower than the clinical CEA level. Comparing to the other protein immobilization methods on paper-based device, this strategy was faster and simpler and had potential applications in point-of-care testing, public health and environmental monitoring. PMID- 26749099 TI - Fe3O4@Ag magnetic nanoparticles for microRNA capture and duplex-specific nuclease signal amplification based SERS detection in cancer cells. AB - A functionalized Fe3O4@Ag magnetic nanoparticle (NP) biosensor for microRNA (miRNA) capture and ultrasensitive detection in total RNA extract from cancer cells was reported in this paper. Herein, Raman tags-DNA probes modified Fe3O4@Ag NPs were designed both as surface-enhanced Raman scattering (SERS) SERS and duplex-specific nuclease signal amplification (DSNSA) platform. Firstly, target miRNAs were captured to the surface of Fe3O4@Ag NPs through DNA/RNA hybridization. In the presence of endonuclease duplex specific nuclease (DSN), one target miRNA molecule could rehybrid thousands of DNA probes to trigger the signal-amplifying recycling. Base on the superparamagnetic of Fe3O4@Ag NPs, target miRNA let-7b can be captured, concentrated and direct quantified within a PE tube without any PCR preamplification treatment. The detection limit was 0.3fM (15 zeptomole, 50MUL), nearly 3 orders of magnitude lower than conventional fluorescence based DSN biosensors for miRNA(~100fM), even single-base difference between the let-7 family members can be discriminated. The result provides a novel proposal to combine the perfect single-base recognition and signal amplifying ability of the endonuclease DSN with cost-effective SERS strategy for miRNA point-of-care (POC) clinical diagnostics. PMID- 26749101 TI - Quick, non-invasive and quantitative assessment of small fiber neuropathy in patients receiving chemotherapy. AB - Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common, potentially severe and dose-limiting adverse effect; however, it is poorly investigated at an early stage due to the lack of a simple assessment tool. As sweat glands are innervated by small autonomic C-fibers, sudomotor function testing has been suggested for early screening of peripheral neuropathy. This study aimed to evaluate Sudoscan, a non-invasive and quantitative method to assess sudomotor function, in the detection and follow-up of CIPN. Eighty-eight patients receiving at least two infusions of Oxaliplatin only (45.4%), Paclitaxel only (14.8%), another drug only (28.4%) or two drugs (11.4%) were enrolled in the study. At each chemotherapy infusion the accumulated dose of chemotherapy was calculated and the Total Neuropathy Score clinical version (TNSc) was carried out. Small fiber neuropathy was assessed using Sudoscan (a 3-min test). The device measures the Electrochemical Skin Conductance (ESC) of the hands and feet expressed in microSiemens (uS). For patients receiving Oxaliplatin mean hands ESC changed from 73 +/- 2 to 63 +/- 2 and feet ESC from 77 +/- 2 to 66 +/- 3 uS (p < 0.001) while TNSc changed from 2.9 +/- 0.5 to 4.3 +/- 0.4. Similar results were observed in patients receiving Paclitaxel or another neurotoxic chemotherapy. During the follow-up, ESC values of both hands and feet with a corresponding TNSc < 2 were 70 +/- 2 and 73 +/- 2 uS respectively while they were 59 +/- 1.4 and 64 +/- 1.5 uS with a corresponding TNSc >= 6 (p < 0.0001 and p = 0.0003 respectively). This preliminary study suggests that small fiber neuropathy could be screened and followed using Sudoscan in patients receiving chemotherapy. PMID- 26749102 TI - A Population Pharmacokinetic/Pharmacodynamic Model Predicts Favorable HDL Cholesterol Changes Over the First 5 Years in Children Treated With Current Efavirenz-Based Regimens. AB - Efavirenz use is associated with changes in cholesterol concentrations, but it is unclear whether this effect is related to drug concentrations. Using efavirenz and cholesterol plasma concentrations measured in 87 antiretroviral-naive children in Thailand, we assessed indirect response models to describe the evolution of high- and low-density lipoprotein (HDL, LDL) cholesterol concentrations in relation to efavirenz plasma concentrations over time where efavirenz was assumed to either stimulate cholesterol production or inhibit its elimination. Simulations of cholesterol evolution for children with different average efavirenz concentrations (Cav ) according to their assumed status of "fast" or "slow" metabolizers of efavirenz were performed. At treatment initiation, children's median (interquartile range, IQR) age was 8 years (5 to 10), body mass index z-score 0.01 (-1.05 to 1.44), HDL 31 mg/dL (24 to 44), and LDL 83 mg/dL (69 to 100). Median (IQR) efavirenz Cav was 1.7 mg/L (1.3 to 2.1) during the period of observation. The best model describing the evolution of HDL and LDL cholesterol concentrations over time assumed that efavirenz inhibited their elimination. HDL concentrations increase over 5 years, whereas LDL concentrations increased only during the first 4 months and then returned to baseline levels afterward. Simulations predicted that, after 3 years, HDL would increase to 63 mg/dL in "fast" metabolizers and 97 mg/dL in "slow" metabolizers of efavirenz. The population pharmacokinetic-pharmacodynamic (PK-PD) model shows that favorable HDL cholesterol changes can be expected in children with current efavirenz dosing guidelines over 5 years of treatment. PMID- 26749103 TI - Patterns of differentially expressed genes in oral mucosal lesions visualised under autofluorescence (VELscope(TM) ). AB - OBJECTIVES: We aimed to elucidate the molecular pathways associated with fluorescence properties of oral potentially malignant disorders (OPMD) visualised under direct tissue autofluorescence (VELscope(TM)). MATERIALS AND METHODS: Forty two oral mucosal biopsies correlated with clinical fluorescence characteristics were categorised based on histopathological diagnosis. Four oral squamous cell carcinoma (OSCC), 15 oral epithelial dysplasia (OED), nine oral lichen planus (OLP) and 14 oral epithelial hyperplasia (OEH) presenting with three fluorescence patterns including retained fluorescence (RF), loss of fluorescence (LAF) with blanching (LB) and LAF with no blanching (LNB) were assessed. Relative gene expression was measured through RNA sequencing. RESULTS: Although each lesion type had a specific set of histology-related differentially expressed genes (DEGs), all tested samples shared a number of DEGs, and we could not identify a discriminatory component between histological groups. Gene ontology enrichment revealed LAF in OEH was mostly due to changes in inflammation, cell cycle regulation and apoptosis, while in OED was due to inflammation, angiogenesis and extracellular matrix remodelling. Inflammatory reactions were associated with diascopic fluorescence (DF) for both OEH and OED. CONCLUSION: Uncovering the molecular mechanisms underlying LAF and DF may lead to reduction in the number of false-positive and false-negative findings and improve the efficacy and utility of VELscope(TM). PMID- 26749105 TI - [Perception and attitudes of health professionals from a health area regarding influenza vaccination]. AB - OBJECTIVE: Influenza is an infectious, acute and highly contagious disease, and vaccination remains the most effective prevention measure. Health professionals are considered at risk because of their daily exposure with patients. Vaccine coverage among health professionals in Spain is relatively low. The aim of this paper is to describe and analyse the perception and attitudes about influenza vaccination among health professionals from a health care area. METHOD: A descriptive cross-sectional study was conducted using a web application method (EUSurvey). Data were analysed using descriptive, bivariate, and multivariate (logistic regression) analysis using R-project statistical software. RESULTS: A total of 161 professionals (17.9%) responded to the online survey, 54.0% women (n=87) and 45.9% men (n=74). Influenza vaccination rate coverage among health professionals was 34.7%. The main reason reported by health professionals for getting vaccinated was to protect themselves (98.1%), to protect their family (72.6%), and to protect their patients (65.4%). On the other hand, the reasons for health professionals that reported not getting vaccinated was because of the lack of information about it (37.4%), fear of adverse reactions (22.2%), not having had time (14.1%), and considering that the vaccine does not work (14.1%). Multivariate analysis showed that the main factors for not getting vaccinated was to be female, type of service (administrative, medical-surgical and surgical), lack of information, and not been vaccinated before. CONCLUSIONS: In order to increase vaccine uptake among health care personnel, information on the benefits of influenza vaccinations must be increased. Vaccination strategies should be targeted at those groups with lower coverage and are at high risk. PMID- 26749106 TI - Virtual Issue celebrating the 100th volume of the Journal of Animal Physiology and Animal Nutrition. PMID- 26749108 TI - "And the Survey Says!". PMID- 26749104 TI - Signalling mucin Msb2 Regulates adaptation to thermal stress in Candida albicans. AB - Temperature is a potent inducer of fungal dimorphism. Multiple signalling pathways control the response to growth at high temperature, but the sensors that regulate these pathways are poorly defined. We show here that the signalling mucin Msb2 is a global regulator of temperature stress in the fungal pathogen Candida albicans. Msb2 was required for survival and hyphae formation at 42 degrees C. The cytoplasmic signalling domain of Msb2 regulated temperature dependent activation of the CEK mitogen activated proteins kinase (MAPK) pathway. The extracellular glycosylated domain of Msb2 (100-900 amino acid residues) had a new and unexpected role in regulating the protein kinase C (PKC) pathway. Msb2 also regulated temperature-dependent induction of genes encoding regulators and targets of the unfolded protein response (UPR), which is a protein quality control (QC) pathway in the endoplasmic reticulum that controls protein folding/degradation in response to high temperature and other stresses. The heat shock protein and cell wall component Ssa1 was also required for hyphae formation and survival at 42 degrees C and regulated the CEK and PKC pathways. PMID- 26749111 TI - Integrating global health with medical education. AB - BACKGROUND: Globalisation has implications for the next generation of doctors, and thus for medical education. Increasingly, global health is being taught in medical schools, although its incorporation into an already full curriculum presents challenges. Global health was introduced into the MBChB curriculum at the University of Aberdeen through a student-selected component (SSC) as part of an existing medical humanities block. The Global Health and Humanities (GHH) module was first delivered in the autumn of 2013 and will shortly enter its third year. METHODS: This student-led study used quantitative and qualitative methods to assess the module's appropriateness and effectiveness for strengthening learning on global health, consisting of online surveys for course participants and semi-structured interviews with faculty members. RESULTS: Integrating global health into the undergraduate medical curriculum by way of an SSC was regarded by teaching staff as an effective and realistic approach. A recognised strength of delivering global health as part of the medical humanities block was the opportunity to expose students to the social determinants of health through interdisciplinary teaching. Participating students all agreed that the learning approach strengthened both their knowledge of global health and a range of generic skills. DISCUSSION: SSCs are, by definition, self-selecting, and will have a tendency to attract students already with an interest in a topic - here global health. A wide range of learning opportunities is needed to integrate global health throughout medical curricula, and to reach all students. PMID- 26749107 TI - The pathological effects of connexin 26 variants related to hearing loss by in silico and in vitro analysis. AB - Gap junctions (GJs) are intercellular channels associated with cell-cell communication. Connexin 26 (Cx26) encoded by the GJB2 gene forms GJs of the inner ear, and mutations of GJB2 cause congenital hearing loss that can be syndromic or non-syndromic. It is difficult to predict pathogenic effects using only genetic analysis. Using ionic and biochemical coupling tests, we evaluated the pathogenic effects of Cx26 variants using computational analyses to predict structural abnormalities. For seven out of ten variants, we predicted the variation would result in a loss of GJ function, whereas the others would completely fail to form GJs. Functional studies demonstrated that, although all variants were able to function normally as hetero-oligomeric GJ channels, six variants (p.E47K, p.E47Q, p.H100L, p.H100Y, p.R127L, and p.M195L) did not function normally as homo oligomeric GJ channels. Interestingly, GJs composed of the Cx26 variant p.R127H were able to function normally, even as homo-oligomeric GJ channels. This study demonstrates the particular location and property of an amino acid are more important mainly than the domain where they belong in the formation and function of GJ, and will provide information that is useful for the accurate diagnosis of hearing loss. PMID- 26749112 TI - Pediatric Nonalcoholic Fatty Liver Disease: A Report from the Expert Committee on Nonalcoholic Fatty Liver Disease (ECON). PMID- 26749113 TI - Neurodevelopmental Outcome and Treatment Efficacy of Benzoate and Dextromethorphan in Siblings with Attenuated Nonketotic Hyperglycinemia. AB - OBJECTIVE: To evaluate the impact of sodium benzoate and dextromethorphan treatment on patients with the attenuated form of nonketotic hyperglycinemia. STUDY DESIGN: Families were recruited with 2 siblings both affected with attenuated nonketotic hyperglycinemia. Genetic mutations were expressed to identify residual activity. The outcome on developmental progress and seizures was compared between the first child diagnosed and treated late with the second child diagnosed at birth and treated aggressively from the newborn period using dextromethorphan and benzoate at dosing sufficient to normalize plasma glycine levels. Both siblings were evaluated with similar standardized neurodevelopmental measures. RESULTS: In each sibling set, the second sibling treated from the neonatal period achieved earlier and more developmental milestones, and had a higher developmental quotient. In 3 of the 4 sibling pairs, the younger sibling had no seizures whereas the first child had a seizure disorder. The adaptive behavior subdomains of socialization and daily living skills improved more than motor skills and communication. CONCLUSIONS: Early treatment with dextromethorphan and sodium benzoate sufficient to normalize plasma glycine levels is effective at improving outcome if used in children with attenuated disease with mutations providing residual activity and when started from the neonatal period. PMID- 26749115 TI - Halorhabdus rudnickae sp. nov., a halophilic archaeon isolated from a salt mine borehole in Poland. AB - Two halophilic archaea, designated strains WSM-64(T) and WSM-66, were isolated from a sample taken from a borehole in the currently unexploited Barycz mining area belonging to the "Wieliczka" Salt Mine Company, in Poland. Strains are red pigmented and form non-motile cocci that stain Gram-negative. Strains WSM-64(T) and WSM-66 showed optimum growth at 40 degrees C, in 20% NaCl and at pH 6.5-7.5. The strains were facultative anaerobes. The major polar lipids of the two strains were phosphatidylglycerol (PG2), phosphatidylglycerol phosphate methyl ester (PGP Me) and sulfated diglycosyl diether (S-DGD). Menaquinone MK-8 was the major respiratory quinone. The DNA G+C content of strain WSM-64(T) was 61.2 mol% by HPLC method; 61.0 mol% by genome sequencing. Analysis of the almost complete 16S rRNA gene sequence indicated that the strains WSM-64(T) and WSM-66 (99.7% identity) represented a member of the genus Halorhabdus in the family Halobacteriaceae. Both strains formed a distinct cluster and were most closely related to Halorhabdus tiamatea SARL4B(T) and Halorhabdus utahensis AX-2(T) (DSM 12940(T)) (95.4% and 95.6%, respectively). ANI values of WSM-64(T) with the closest relative type strains were <78.5%. Based on 16S rRNA gene sequence and whole genome analyses, physiological and biochemical characteristics we describe a new species represented by strain WSM-64(T) (=DSM 29498(T) =CECT 8673(T)) for which we propose the name Halorhabdus rudnickae sp. nov. PMID- 26749114 TI - Cell Therapy for Parkinson's Disease: A Translational Approach to Assess the Role of Local and Systemic Immunosuppression. AB - Neural transplantation is a promising therapeutic approach for neurodegenerative diseases; however, many patients receiving intracerebral fetal allografts exhibit signs of immunization to donor antigens that could compromise the graft. In this context, we intracerebrally transplanted mesencephalic pig xenografts into primates to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Parkinsonian primates received WT or CTLA4-Ig transgenic porcine xenografts and different durations of peripheral immunosuppression to test whether systemic plus graft-mediated local immunosuppression might avoid rejection. A striking recovery of spontaneous locomotion was observed in primates receiving systemic plus local immunosuppression for 6 mo. Recovery was associated with restoration of dopaminergic activity detected both by positron emission tomography imaging and histological examination. Local infiltration by T cells and CD80/86+ microglial cells expressing indoleamine 2,3-dioxigenase were observed only in CTLA4-Ig recipients. Results suggest that in this primate neurotransplantation model, peripheral immunosuppression is indispensable to achieve the long-term survival of porcine neuronal xenografts that is required to study the beneficial immunomodulatory effect of local blockade of T cell costimulation. PMID- 26749116 TI - Successful treatment of two pediatric port wine stains in darker skin types using 595 nm laser. AB - BACKGROUND AND OBJECTIVE: Port wine stain (PWS) is a congenital vascular malformation of skin involving post-capillary venules, which commonly occurs on the face. While successful treatment has been reported with Caucasian, Hispanic, and Asian skin, physicians have battled treating these progressive lesions in patients of darker skin color, as the targeted chromophore (hemoglobin) shares a similar absorption coefficient as melanin. There are no reports of favorable outcomes in African-American children or adults. Although treatment in darker skin types has been previously discouraged we present a case series of patients of African descent with port wine stains treated using a pulsed-dye laser (Vbeam Perfecta, Candela Laser,Wayland, Mass) with significant improvement and no complications. STUDY DESIGN/MATERIAL AND METHODS: Presentation of two pediatric patients of African descent (skin types 4 and 5) ages 1 month and 4 years old seen and treated in our office using a pulsed-dye laser until resolution. Laser parameters were spot size 10 mm; fluence 7-8.25 J/cm2; wavelength 595 nm; pulse duration 1.5 Millisecond with dynamic cooling. RESULTS: Resolution of the port wine stain without complication. CONCLUSION: This early approach represents a new and safe therapeutic option for treating port wine stains in this patient population. To our knowledge, the successful use of pulsed dye laser for the treatment of port wine stain in patients of African descent without complications has not yet been reported. PMID- 26749117 TI - The association between impaired glucose tolerance and soluble CD40 ligand: a 15 year prospective cohort study. AB - BACKGROUND AND AIMS: The aim of the present study was to assess soluble CD40 Ligand (sCD40L) levels in relation to impaired glucose tolerance (IGT) at population level. METHODS: This study is part of a prospective, population-based cohort study, carried out from 1990 to 2008 in northern Finland. Study members, born in 1935 and living in the City of Oulu, underwent oral glucose tolerance test (OGTT) and measurement of plasma sCD40L at three different time points during the 15-year follow-up. The total number of study members who underwent OGTT was 768 at the baseline, 557 at the first and 467 at the second follow-up. SCD40L levels in patients with IGT were compared with those in subjects with normal glucose tolerance or impaired fasting glucose (non-IGT). RESULTS: Geometric mean level of sCD40L was significantly higher in the IGT group compared with the non-IGT group at the baseline (0.42 vs. 0.27 ng/mL) and at the first follow-up (1.50 vs. 0.36 ng/mL) (repeated measures mixed models ANOVA, p < 0.05). At the second follow-up (age 72-73 years), however, the difference was not statistically significant (9.44 vs. 7.24 ng/mL). During the entire follow-up, the levels of sCD40L increased significantly both in IGT and non-IGT groups. CONCLUSION: We found that plasma sCD40L level increases with age as well as there are elevated levels of plasma sCD40L in subjects with IGT compared with non-IGT. This may indicate an increased cardiovascular risk in older age and in subjects with IGT. PMID- 26749119 TI - Structural Characteristics and Properties of a New Graphitic-Based Material. AB - The hydrogenation of commercial graphite using lithium/ammonia as the reducing agent and tert-butyl alcohol as a proton source was investigated. Characterization of the products after successive reductions of the same material by high-resolution transmission electron microscopy revealed a new material that was replete with edge and circular dislocations. Analysis by solid-state (13)C NMR spectroscopy indicates that after three reductions, the remaining aromatic rings appear to be interior benzene rings. NMR spectroscopy also offers strong evidence for the presence of small amounts of tert-butyl alcohol and ethanol (workup solvent) that could not be removed in vacuo from the samples. These compounds could be observed to move freely between the layers of the hydrographene. PMID- 26749120 TI - Dopaminergic treatment modulates sensory attenuation at the onset of the movement in Parkinson's disease: A test of a new framework for bradykinesia. AB - BACKGROUND: The primary motor sign of Parkinson's disease is bradykinesia. It has been surprisingly difficult to provide a clear neurobiological mechanism for this fundamental movement deficit in Parkinson's disease. It has been proposed that in healthy individuals the gating of sensory afferents prior to and during movement is an essential step in initiating movement. This down-weighting has been proposed to account for the attenuation of the somatosensory evoked potential following median nerve stimulation at the onset of and during hand movements. The objective of this study was to test whether this sensory attenuation present at movement onset in healthy controls is present in patients with Parkinson's disease. METHODS: Eighteen right-handed patients with idiopathic Parkinson's disease and 16 right-handed age-matched healthy participants were studied. Somatosensory evoked potentials were elicited after electrical stimulation of the median nerve at the wrist. Electroencephalograms were recorded over the scalp at 3 sites on according to the International 10-20 System (F3, C3, and P3). Somatosensory evoked potentials were recorded in 2 conditions: at rest and at the onset of movement (a self-paced abduction movement of the right thumb). RESULTS: Off medication, Parkinson's disease patients had no sensory attenuation at movement onset. On medication, sensory attenuation at movement onset was present. CONCLUSIONS: We suggest that this preliminary result is consistent with the hypothesis that, a failure in sensory attenuation contributes to the difficulties in movement initiation in Parkinson's disease. PMID- 26749121 TI - Nasal rhinosporidiosis: a report of two cases. PMID- 26749118 TI - Liraglutide and obesity in elderly: efficacy in fat loss and safety in order to prevent sarcopenia. A perspective case series study. AB - BACKGROUND: For the growing numbers of obese elderly with diabetes, the glucagon like peptide-1 (GLP-1) receptor analogue (liraglutide) appears a safe way to promote and maintain substantial weight loss. Given this background, the aim of this study was to assess the effect of the liraglutide treatment, at doses up to 3.0 mg per day, on the body composition, focusing on sarcopenia, in overweight and obese elderly with type 2 diabetes mellitus (T2DM). METHODS: A perspective study was carried out in overweight and obese T2DM patients with HbA1c equal to 7.0 % (53 mmol/mol) ~10.0 % (86), under 3-month treatment (at least) of maximal dose of metformin at stable regime, and additional liraglutide at doses up to 3.0 mg per day. Body composition markers such as skeletal muscle index (SMI), android and gynoid fat mass, and arms and legs fat free mass, was measured by dual-energy X-ray densitometry (DXA) at baseline and after 24 weeks of liraglutide treatment. Glucose control was also carried out by glucose and HbA1c. RESULTS: Nine subjects (male/female 6/3, mean age 68.22 +/- 3.86 years, BMI 32.34 +/- 4.89 kg/m2) were evaluated. We noted a median decrease in BMI (-0.78 kg/m2), weight (-2000 g), fat mass (-1498 g) and android fat (-0.9 %), and a increase in SMI (+0.03 kg/m2) from baseline. Glycemic control also improved, with a median change HbA1c of -0.80 %. CONCLUSIONS: Twenty-four weeks of liraglutide treatment was associated with reductions in fat mass and android fat. In addition, in order to prevent sarcopenia, it preserved the muscular tropism. PMID- 26749123 TI - The enduring role and relevance of cytology in the diagnosis of infectious diseases. PMID- 26749122 TI - Does cataract surgery reduce the long-term risk of glaucoma in eyes with pseudoexfoliation syndrome? AB - PURPOSE: To compare glaucoma development and intraocular pressure (IOP) in the longer term following phacoemulsification cataract surgery in eyes with and without pseudoexfoliation syndrome (PEX). METHODS: Fifty-one patients with PEX were compared with 102 age- and gender-matched controls without PEX. Patients were re-examined a mean of 76 (SD 5.4) months after cataract surgery, recording IOP, glaucoma diagnosis, glaucoma treatment and LogMAR. Data from the preoperative visit (baseline) and IOP on the first postoperative day were obtained from medical records. A glaucoma parameter was predefined as patients developing glaucoma or needing increased glaucoma treatment during the postoperative time period. RESULTS: One new glaucoma case in each group was diagnosed postoperatively, yielding glaucoma incidences of 0.47 cases per 100 person-years [95% confidence interval (CI) 0.006-2.61] and 0.17 cases per 100 person-years (CI 0.002-0.95) in the PEX and control groups respectively (p = 0.53). IOP declined by 2.6 (SD 4.0) mmHg in the PEX group (p < 0.001) and 1.9 (SD 3.5) mmHg in the control group (p < 0.001) from baseline to the re-examination, with a non-significant group difference (p = 0.310). IOP spike (>=6 mmHg increase) was significantly associated with the glaucoma parameter, both within the PEX (p = 0.034) and the control group (p = 0.044). CONCLUSION: The number of newly diagnosed glaucoma cases was lower than expected 6-7 years following cataract extraction, especially in the PEX group, which indicates that PEX eyes benefit particularly from cataract surgery in terms of IOP and glaucoma development. PMID- 26749124 TI - Nursing workload: a concept analysis. AB - AIM: The aim of the present study was to develop a comprehensive understanding of the concept 'workload' within the nursing profession in order to arrive at a clear definition of nursing workload based on the evidence in existing literature. BACKGROUND: Nursing workload is a common term used in the health literature, but often without specification of its exact meaning. Concept clarification is needed to delineate the meaning of the term 'nursing workload'. METHOD: A concept analysis was conducted using Walker and Avant's method to clarify the defining attributes of nursing workload. As the subject matter was nursing focused, only one database was searched, the Cumulative Index for Nursing and Allied Health Literature (CINAHL). Articles that did not use 'workload' in the title or abstract were excluded. A model case, contrary case, related case and empirical referents were constructed to clarify the concept and to demonstrate how the workload is captured by the main attributes. RESULTS: The attributes of nursing workload found in the literature fall into five main categories: the amount of nursing time; the level of nursing competency; the weight of direct patient care; the amount of physical exertion; and complexity of care. The attributes were organised according to the leading antecedents, which were identified as the patient, nurse and health institution. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers need to address the workload issues with regard to the real nature of nursing work; this could increase nurses' productivity, nurses' satisfaction, turnover, work stress and provide sufficient staffing to patient care needs. CONCLUSION: The concept analysis demonstrated clearly the complexity of the concept and its implications for practice and research. It is believed that the current concept analysis will help to provide a better understanding of nursing workload and contribute towards the standardisation of the nursing workload and the development of a valid and reliable measurement system. PMID- 26749129 TI - FHHS NEWS. PMID- 26749127 TI - SPECIAL SECTION CELEBRATING FRANZ SAMELSON'S CONTRIBUTIONS TO THE HISTORY OF PSYCHOLOGY. PMID- 26749130 TI - NEWS AND NOTES-WINTER 2016. PMID- 26749125 TI - Analysis of amino acid substitutions in AraC variants that respond to triacetic acid lactone. AB - The Escherichia coli regulatory protein AraC regulates expression of ara genes in response to l-arabinose. In efforts to develop genetically encoded molecular reporters, we previously engineered an AraC variant that responds to the compound triacetic acid lactone (TAL). This variant (named "AraC-TAL1") was isolated by screening a library of AraC variants, in which five amino acid positions in the ligand-binding pocket were simultaneously randomized. Screening was carried out through multiple rounds of alternating positive and negative fluorescence activated cell sorting. Here we show that changing the screening protocol results in the identification of different TAL-responsive variants (nine new variants). Individual substituted residues within these variants were found to primarily act cooperatively toward the gene expression response. Finally, X-ray diffraction was used to solve the crystal structure of the apo AraC-TAL1 ligand-binding domain. The resolved crystal structure confirms that this variant takes on a structure nearly identical to the apo wild-type AraC ligand-binding domain (root-mean square deviation 0.93 A), suggesting that AraC-TAL1 behaves similar to wild-type with regard to ligand recognition and gene regulation. Our results provide amino acid sequence-function data sets for training and validating AraC modeling studies, and contribute to our understanding of how to design new biosensors based on AraC. PMID- 26749132 TI - Novel missense mutations in a conserved loop between ERCC6 (CSB) helicase motifs V and VI: Insights into Cockayne syndrome. AB - Cockayne syndrome is caused by biallelic ERCC8 (CSA) or ERCC6 (CSB) mutations and is characterized by growth restriction, microcephaly, developmental delay, and premature pathological aging. Typically affected patients also have dermal photosensitivity. Although Cockayne syndrome is considered a DNA repair disorder, patients with UV-sensitive syndrome, with ERCC8 (CSA) or ERCC6 (CSB) mutations have indistinguishable DNA repair defects, but none of the extradermal features of Cockayne syndrome. We report novel missense mutations affecting a conserved loop in the ERCC6 (CSB) protein, associated with the Cockayne syndrome phenotype. Indeed, the amino acid sequence of this loop is more highly conserved than the adjacent helicase motifs V and VI, suggesting that this is a crucial structural component of the SWI/SNF family of proteins, to which ERCC6 (CSB) belongs. These comprise two RecA-like domains, separated by an interdomain linker, which interact through helicase motif VI. As the observed mutations are likely to act through destabilizing the tertiary protein structure, this prompted us to re evaluate ERCC6 (CSB) mutation data in relation to the structure of SWI/SNF proteins. Our analysis suggests that antimorphic mutations cause Cockayne syndrome and that biallelic interdomain linker deletions produce more severe phenotypes. Based on our observations, we propose that further investigation of the pathogenic mechanisms underlying Cockayne syndrome should focus on the effect of antimorphic rather than null ERCC6 (CSB) mutations. PMID- 26749135 TI - Has provoking microbiota aggression driven the obesity epidemic? AB - Alterations in the gut microbiome have increasingly been implicated in driving obesity and its associated diseases, but underlying mechanisms remain poorly defined. Herein, in addition to reviewing the field, we hypothesize that a highly significant causative factor of such inflammatory disease-associated microbiome alterations is a more aggressive microbiota that encroaches upon its host, with components having high potential to activate host pro-inflammatory gene expression in a manner that drives metabolic disease. We further hypothesize that a range of societal changes, including use of antibiotics and increasing consumption of food additives, have provoked such microbiota aggression and, consequently, may be contributing factors to the increased incidence of obesity and its associated diseases. PMID- 26749133 TI - Celecoxib and fish oil: a combination strategy for decreased inflammatory mediators in early stages of experimental mammary cancer. AB - Chronic inflammation has been directly linked to cancer progression. Therefore, current study was designed to understand the mechanism of action of chemo preventive effect of celecoxib and fish oil on inflammatory mediators in experimental mammary carcinoma. Female Wistar rats were distributed into control and DMBA treated groups and further subdivided based on pretreatment with celecoxib and/or fish oil. Inflammation was measured by assessing expression of NF-kappaB, COX-2 and cytokines. The results indicated an elevation in expression of NF-kappaB, COX-2 and cytokines' levels (IFN-gamma, IL-4 and IL-10) in DMBA group as compared to controls. On pretreatment with celecoxib and/or fish oil in DMBA treated animals, a significant reduction in expression of NF-kappaB, COX-2 and cytokines' levels was observed. The decrease was more pronounced with combinatorial regimen than either celecoxib or fish oil alone. To conclude, a combinatorial strategy of celecoxib and fish oil may generate an immune response against the tumor cell by altering cytokine repertoire and decrease the tendency of tumor cells to escape immune surveillance. PMID- 26749134 TI - 50 Hz hippocampal stimulation in refractory epilepsy: Higher level of basal glutamate predicts greater release of glutamate. AB - OBJECTIVE: The effect of electrical stimulation on brain glutamate release in humans is unknown. Glutamate is elevated at baseline in the epileptogenic hippocampus of patients with refractory epilepsy, and increases during spontaneous seizures. We examined the effect of 50 Hz stimulation on glutamate release and its relationship to interictal levels in the hippocampus of patients with epilepsy. In addition, we measured basal and stimulated glutamate levels in a subset of these patients where stimulation elicited a seizure. METHODS: Subjects (n = 10) were patients with medically refractory epilepsy who were undergoing intracranial electroencephalography (EEG) evaluation in an epilepsy monitoring unit. Electrical stimulation (50 Hz) was delivered through implanted hippocampal electrodes (n = 11), and microdialysate samples were collected every 2 min. Basal glutamate, changes in glutamate efflux with stimulation, and the relationships between peak stimulation-associated glutamate concentrations, basal zero-flow levels, and stimulated seizures were examined. RESULTS: Stimulation of epileptic hippocampi in patients with refractory epilepsy caused increases in glutamate efflux (p = 0.005, n = 10), and 4 of ten patients experienced brief stimulated seizures. Stimulation-induced increases in glutamate were not observed during the evoked seizures, but rather were related to the elevation in interictal basal glutamate (R(2) = 0.81, p = 0.001). The evoked-seizure group had lower basal glutamate levels than the no-seizure group (p = 0.04), with no stimulation-induced change in glutamate efflux (p = 0.47, n = 4). Conversely, increased glutamate was observed following stimulation in the no-seizure group (p = 0.005, n = 7). Subjects with an atrophic hippocampus had higher basal glutamate levels (p = 0.03, n = 7) and higher stimulation-induced glutamate efflux. SIGNIFICANCE: Electrical stimulation of the epileptic hippocampus either increased extracellular glutamate efflux or induced seizures. The magnitude of stimulated glutamate increase was related to elevation in basal interictal glutamate, suggesting a common mechanism, possibly impaired glutamate metabolism. Divergent mechanisms may exist for seizure induction and increased glutamate in patients with epilepsy. These data highlight the potential risk of 50 Hz stimulation in patients with epilepsy. PMID- 26749136 TI - Serum deprivation response inhibits breast cancer progression by blocking transforming growth factor-beta signaling. AB - Serum deprivation response (SDPR), a key substrate for protein kinase C, play a critical role in inducing membrane curvature and participate in the formation of caveolae. However, the function of SDPR in cancer development and progression is still not clear. Here, we found that SDPR is downregulated in human breast cancer. Overexpression of SDPR suppresses cell proliferation and invasion in MDA MB-231 cells, while depletion of SDPR promotes cell proliferation and invasion in MCF10A cells. Subsequently, SDPR depletion induces epithelial-mesenchymal transition (EMT)-like phenotype. Finally, knockdown of SDPR activates transforming growth factor-beta (TGF-beta) signaling by upregulation of TGF-beta1 expression. In conclusion, our results showed that SDPR inhibits breast cancer progression by blocking TGF-beta signaling. Serum deprivation response suppresses cell proliferation and invasion in breast cancer cells. SDPR depletion induces epithelial-mesenchymal transition by activation of TGF-beta signaling. PMID- 26749137 TI - Cisplatin Binding to Biological Ligands Revealed at the Encounter Complex Level by IR Action Spectroscopy. AB - Cisplatin [cis-diamminedichloroplatinum(II)] was the first platinum-based antineoplastic agent and is still a cornerstone for the treatment of various solid tumors. Reactive events responsible for cisplatin activity are unveiled here at the molecular level. Simple ligands (L) representing ubiquitous functional groups in the biological environment likely to be encountered by administered cisplatin have been allowed to react with cis-[PtCl(NH3)2 (H2O)](+), the primary intermediate from cisplatin hydrolysis. The substitution reactions have been examined by a combined experimental and computational approach and the structural features of the substitution product, cis-[PtCl(NH3)2(L)](+), have been probed by IR multiple-photon dissociation (IRMPD) spectroscopy. Furthermore, IRMPD spectroscopy has been exploited to elucidate the structure of [PtCl(NH3)2(L)(H2O)](+) clusters, also obtained by electrospray ionization (ESI) from the aqueous solution and representing the major focus of this investigation. These ions conform to the encounter complex of cis-[PtCl(NH3)2 (H2O)](+) with the incoming ligand and represent the first direct evidence of a prototypical Eigen Wilkins encounter complex in solution, lying on the reaction coordinate for ligand substitution and extracted by ESI for mass spectrometric analysis. Activated [PtCl(NH3)2(L)(H2O)](+) ions dissociate by the loss of either H2O or L, the former process implying a ligand substitution event. IRMPD spectroscopy has thus revealed both structural details and reaction dynamics at the level of the isolated encounter complex. PMID- 26749138 TI - Ventricular Septal Dissection/Perforation and Takotsubo Syndrome. PMID- 26749139 TI - Using the knowns to discover the unknowns: MS-based dereplication uncovers structural diversity in 17-hydroxygeranyllinalool diterpene glycoside production in the Solanaceae. AB - Exploring the diversity of plant secondary metabolism requires efficient methods to obtain sufficient structural insights to discriminate previously known from unknown metabolites. De novo structure elucidation and confirmation of known metabolites (dereplication) remain a major bottleneck for mass spectrometry-based metabolomic workflows, and few systematic dereplication strategies have been developed for the analysis of entire compound classes across plant families, partly due to the complexity of plant metabolic profiles that complicates cross species comparisons. 17-hydroxygeranyllinalool diterpene glycosides (HGL-DTGs) are abundant defensive secondary metabolites whose malonyl and glycosyl decorations are induced by jasmonate signaling in the ecological model plant Nicotiana attenuata. The multiple labile glycosidic bonds of HGL-DTGs result in extensive in-source fragmentation (IS-CID) during ionization. To reconstruct these IS-CID clusters from profiling data and identify precursor ions, we applied a deconvolution algorithm and created an MS/MS library from positive-ion spectra of purified HGL-DTGs. From this library, 251 non-redundant fragments were annotated, and a workflow to characterize leaf, flower and fruit extracts of 35 solanaceous species was established. These analyses predicted 105 novel HGL-DTGs that were restricted to Nicotiana, Capsicum and Lycium species. Interestingly, malonylation is a highly conserved step in HGL-DTG metabolism, but is differentially affected by jasmonate signaling among Nicotiana species. This MS based workflow is readily applicable for cross-species re identification/annotation of other compound classes with sufficient fragmentation knowledge, and therefore has the potential to support hypotheses regarding secondary metabolism diversification. PMID- 26749140 TI - Disruptive selection without genome-wide evolution across a migratory divide. AB - Transcontinental migration is a fascinating example of how animals can respond to climatic oscillation. Yet, quantitative data on fitness components are scarce, and the resulting population genetic consequences are poorly understood. Migratory divides, hybrid zones with a transition in migratory behaviour, provide a natural setting to investigate the micro-evolutionary dynamics induced by migration under sympatric conditions. Here, we studied the effects of migratory programme on survival, trait evolution and genome-wide patterns of population differentiation in a migratory divide of European barn swallows. We sampled a total of 824 individuals from both allopatric European populations wintering in central and southern Africa, respectively, along with two mixed populations from within the migratory divide. While most morphological characters varied by latitude consistent with Bergmann's rule, wing length co-varied with distance to wintering grounds. Survival data collected during a 5-year period provided strong evidence that this covariance is repeatedly generated by disruptive selection against intermediate phenotypes. Yet, selection-induced divergence did not translate into genome-wide genetic differentiation as assessed by microsatellites, mtDNA and >20 000 genome-wide SNP markers; nor did we find evidence of local genomic selection between migratory types. Among breeding populations, a single outlier locus mapped to the BUB1 gene with a role in mitotic and meiotic organization. Overall, this study provides evidence for an adaptive response to variation in migration behaviour continuously eroded by gene flow under current conditions of nonassortative mating. It supports the theoretical prediction that population differentiation is difficult to achieve under conditions of gene flow despite measurable disruptive selection. PMID- 26749141 TI - Prostate cancer detection with magnetic resonance-ultrasound fusion biopsy: The role of systematic and targeted biopsies. AB - BACKGROUND: The current study was conducted to evaluate the performance of magnetic resonance (MR)-ultrasound-guided fusion biopsy in diagnosing clinically significant prostate cancer (csCaP). METHODS: A total of 1042 men underwent multiparametric MR imaging (mpMRI) and fusion biopsy consecutively in a prospective trial (2009-2014). An expert reader graded mpMRI regions of interest (ROIs) as 1 to 5 using published protocols. The fusion biopsy device was used to obtain targeted cores from ROIs (when present) followed by a fusion image-guided, 12-core systematic biopsy in all men, even if no suspicious ROI was noted. The primary endpoint of the study was the detection of csCaP (ie, Gleason score >= 7). RESULTS: Among 825 men with >= 1 suspicious ROI of >= grade 3, 289 (35%) were found to have csCaP. Powerful predictors of csCaP were ROI grade (grade 5 vs grade 3: odds ratio, 6.5 [P<.01]) and prostate-specific antigen density (each increase of 0.05 ng/mL/cc: odds ratio, 1.4 [P<.01]). Combining systematic and targeted biopsies resulted in the detection of more patients with csCaP (289 patients) than targeting (229 patients) or systematic (199 patients) biopsy alone. Among patients with no suspicious ROI, 35 (16%) were found to have csCaP on systematic biopsy. CONCLUSIONS: In this prospective trial, MR-ultrasound fusion biopsy allowed for the detection of csCaP, with a direct relationship noted with ROI grade and prostate-specific antigen density. The combination of targeted and systematic biopsy detected more csCaP than either modality alone; systematic biopsies revealed csCaP in 16% of men with no suspicious MRI target. The advantages of this new biopsy method are apparent, but issues of cost, training, and reliability await resolution before its widespread adoption. PMID- 26749142 TI - Bone marrow infiltration by multiple myeloma causes anemia by reversible disruption of erythropoiesis. AB - Multiple myeloma (MM) infiltrates bone marrow and causes anemia by disrupting erythropoiesis, but the effects of marrow infiltration on anemia are difficult to quantify. Marrow biopsies of newly diagnosed MM patients were analyzed before and after four 28-day cycles of non-erythrotoxic remission induction chemotherapy. Complete blood cell counts and serum paraprotein concentrations were measured at diagnosis and before each chemotherapy cycle. At diagnosis, marrow area infiltrated by myeloma correlated negatively with hemoglobin, erythrocytes, and marrow erythroid cells. After successful chemotherapy, patients with less than 30% myeloma infiltration at diagnosis had no change in these parameters, whereas patients with more than 30% myeloma infiltration at diagnosis increased all three parameters. Clinical data were used to develop mathematical models of the effects of myeloma infiltration on the marrow niches of terminal erythropoiesis, the erythroblastic islands (EBIs). A hybrid discrete-continuous model of erythropoiesis based on EBI structure/function was extended to sections of marrow containing multiple EBIs. In the model, myeloma cells can kill erythroid cells by physically destroying EBIs and by producing proapoptotic cytokines. Following chemotherapy, changes in serum paraproteins as measures of myeloma cells and changes in erythrocyte numbers as measures of marrow erythroid cells allowed modeling of myeloma cell death and erythroid cell recovery, respectively. Simulations of marrow infiltration by myeloma and treatment with non-erythrotoxic chemotherapy demonstrate that myeloma-mediated destruction and subsequent reestablishment of EBIs and expansion of erythroid cell populations in EBIs following chemotherapy provide explanations for anemia development and its therapy-mediated recovery in MM patients. PMID- 26749144 TI - Calculating sample size. Alpha, Beta, Mu and Sigma--it's all Greek. PMID- 26749143 TI - Geographic variation in human papillomavirus-related oropharyngeal cancer: Data from 4 multinational randomized trials. AB - BACKGROUND: There are variations in the proportions of head and neck cancers caused by the human papillomavirus (HPV) between countries and regions. It is unclear if these are true variations or due to different study designs and assays. METHODS: We tested formalin-fixed paraffin-embedded diagnostic biopsies for p16 immunohistochemistry and HPV-DNA (by polymerase chain reaction [PCR] and in situ hybridization [ISH]) using validated protocols on samples from 801 patients with head and neck cancer recruited prospectively between 2006 and 2011 in 4 randomized controlled trials (RCTs). RESULTS: Twenty-one percent of patients (170 of 801) showed both HPV-DNA and p16-positivity, detected almost exclusively in oropharyngeal cancer (55%; 15 of 302); and only 1% of the patients (5 of 499) with nonoropharyngeal cancer were HPV positive. HPV-positive oropharyngeal cancer differed between Western and Eastern Europe (37%, 155 of 422 vs 6%, 8 of 144; p < .0001) and between Western Europe and Asia (37% vs 2%; 4 of 217; p < .0001). Other independent determinants of HPV positivity were tumor site and smoking. CONCLUSION: This is the first study to establish geographic variability as an independent risk factor in HPV-positive oropharyngeal cancer prevalence, with higher prevalence in Western Europe. (c) 2016 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: E1863-E1869, 2016. PMID- 26749146 TI - Continuing the Celebration. AB - Ten years and counting: Theresa Kueckmann, Editor-in-Chief, reflects on how far the journal has come since its launch in December, 2005. PMID- 26749148 TI - Transanal total mesorectal excision for rectal cancer: early outcomes in 50 consecutive patients. AB - AIM: Minimally invasive approaches to proctectomy for rectal cancer have not been widely adopted due to inherent technical challenges. A modification of traditional transabdominal mobilization, termed transanal total mesorectal excision (TaTME), has the potential to improve access to the distal rectum. The aim of the current study is to assess outcomes following TaTME for rectal cancer. METHOD: This is a retrospective analysis of a prospectively maintained database of consecutive patients who underwent TaTME for rectal cancer at a single institution. The study period was from 1 March 2012 to 31 July 2015. RESULTS: During the study period 50 patients underwent TaTME. The median tumour distance from the anal verge was 4.4 (3.0-5.5) cm. The rate of conversion from a planned minimally invasive approach was 2.2%. The median operative time was 267.0 (227.0 331.0) min. The median lymph node yield was 18.0 (12.0-23.8), the macroscopic quality assessment of the resected specimen was incomplete in 2% and the circumferential resection margin positivity rate was 4%. Intra-operative morbidity occurred in 6% and the 30 day morbidity rate was 36%. The median length of stay was 4.5 (4.0-8.0) days. The median follow-up was 15.1 (7.0-23.2) months; two patients have developed a local recurrence and eight patients have developed distant recurrence. CONCLUSION: These data suggest that TaTME for rectal cancer is feasible with an acceptable pathological outcome and morbidity profile. Further data on functional and long-term survival outcomes are required. PMID- 26749145 TI - Heart valve surgery in hemodialysis-dependent patients: nutrition status impact on surgical outcome. AB - Valve surgery in hemodialysis-dependent patients is associated with postoperative complications and a high mortality rate, and such patients frequently suffer cachexia. This study aimed to determine pre- and intraoperative risk factors associated with in-hospital mortality and long-term survival in hemodialysis dependent patients undergoing heart valve surgery from the viewpoint of nutrition status. Eighty-seven hemodialysis-dependent patients who underwent valve surgery between January 1998 and October 2015 were retrospectively reviewed. Thirty-seven potential perioperative risk factors were evaluated. The in-hospital mortality rate was 12.6 % (11 patients). Univariate analysis identified New York Heart Association Functional Classification III or IV, emaciation (body mass index <17.6 kg/m(2)), total cholesterol <120 mg/dl, serum albumin <3.0 mg/dl, emergent/urgent surgery, and intraoperative blood transfusion >3000 ml as predictors of in-hospital death. Multivariate logistic regression analysis confirmed low serum albumin <3.0 mg/dl (hazard ratio 7.22; p = 0.032) and emergent/urgent operation (hazard ratio 43.57; p = 0.035) as independent predictors of in-hospital death. The 1- and 3-year actuarial survival rates were 64.9 +/- 5.4 and 51.8 +/- 5.8 %, respectively. Long-term survival estimated by log-rank test was negatively impacted by anemia (hemoglobin <10 mg/dl), low serum albumin, emergent/urgent operation, and infective endocarditis. Multivariate analysis using Cox proportional hazards modeling indicated low serum albumin (hazard ratio 2.12; p = 0.047) and emergent/urgent operation (hazard ratio 8.97; p = 0.0002) as independent predictors of remote death. Hypoalbuminemia and emergent/urgent operation are strong predictors of in-hospital and remote death. Malnutrition before surgery should be considered for operative risk estimation, and adequate preoperative nutrition management may improve surgical outcomes for hemodialysis-dependent patients. PMID- 26749149 TI - A Potent Glucose-Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells. AB - Three rationally designed glucose-platinum conjugates (Glc-Pts) were synthesized and their biological activities evaluated. The Glc-Pts, 1-3, exhibit high levels of cytotoxicity toward a panel of cancer cells. The subcellular target and cellular uptake mechanism of the Glc-Pts were elucidated. For uptake into cells, Glc-Pt 1 exploits both glucose and organic cation transporters, both widely overexpressed in cancer. Compound 1 preferentially accumulates in and annihilates cancer, compared to normal epithelial, cells in vitro. PMID- 26749151 TI - Chronic effects of non-weathered and weathered crude oil and dispersant associated with the Deepwater Horizon incident on development of larvae of the eastern oyster, Crassostrea virginica. AB - The present study examined the effects of chronic exposure of eastern oyster (Crassostrea virginica) larvae to the water-accommodated fractions of fresh and weathered oils collected from the Deepwater Horizon incident, with and without additions of the dispersant Corexit 9500A, as well as to solutions of Corexit alone. Both shell growth of larvae exposed to test materials for a period of 10 d and larval settlement after 28 d of exposure were the most sensitive endpoints, with the 10-d growth endpoint being less variable among replicates. Growth and settlement endpoints were more sensitive than larval survival and normal development after 10 d and 28 d. Acute-to-chronic ratios calculated in the present study suggest that acute toxicities of oils and dispersant for oysters are not predictive of chronic effect levels for growth and settlement; therefore, chronic bioassays are necessary to assess these sublethal effects, in addition to standard 48-h acute toxicity tests. Comparison of 10% effective concentration (EC10) values for chronic 10-d growth and 28-d settlement endpoints with concentrations of total polycyclic aromatic hydrocarbons and dipropylene glycol n butyl ether (a marker for Corexit) in seawater samples, collected during and after the Deepwater Horizon incident, indicated it was unlikely that elevated concentrations of water-soluble fractions of oil and dispersant in the nearshore environment had significant adverse effects on the growth and settlement of eastern oyster larvae. Environ Toxicol Chem 2016;35:2029-2040. (c) 2016 SETAC. PMID- 26749152 TI - Therapeutic angiogenesis using tumor cell-conditioned medium. AB - Stem cell-conditioned medium (CM), which contains angiogenic factors that are secreted by stem cells, represents a potential therapy for ischemic diseases. Along with stem cells, tumor cells also secrete various angiogenic factors. Here, tumor cells as a cell source of CM for therapeutic angiogenesis was evaluated and the therapeutic efficacy of tumor cell CM in mouse hindlimb ischemia models was demonstrated. CM obtained from a human fibrosarcoma HT1080 cell line culture was compared with CM obtained from a human bone marrow-derived mesenchymal stem cell (MSC) culture. HT1080 CM contained higher concentrations of angiogenic factors compared with MSC CM, which was attributable to the higher cell density that resulted from a much faster growth rate of HT1080 cells compared with MSCs. For use in in vitro and in vivo angiogenesis studies, HT1080 CM was diluted such that HT1080 CM and MSC CM would have the same cell number basis. The two types of CMs induced the same extent of human umbilical vein endothelial cell (HUVEC) proliferation in vitro. The injection of HT1080 CM into mouse ischemic limbs significantly improved capillary density and blood perfusion compared with the injection of fresh medium. Although the therapeutic outcome of HT1080 CM was similar to that of MSC CM, the preparation of CM by tumor cell line culture would be much more efficient due to the faster growth and unlimited life-time of the tumor cell line. These data suggest the potential application of tumor cell CM as a therapeutic modality for angiogenesis and ischemic diseases. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:456-464, 2016. PMID- 26749150 TI - Therapeutic approaches in Parkinson's disease and related disorders. AB - The lack of effective therapies for neurodegenerative disorders is one of the most relevant challenges of this century, considering that, as the global population ages, the incidence of these type of diseases is quickly on the rise. Among these disorders, synucleinopathies, which are characterized by the abnormal accumulation and spreading of the synaptic protein alpha-synuclein in the brain, already constitute the second leading cause of parkinsonism and dementia in the elderly population. Disorders with alpha-synuclein accumulation include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Numerous therapeutic alternatives for synucleinopathies are being tested in pre clinical models and in the clinic; however, only palliative treatments addressing the dopaminergic deficits are approved to date, and no disease-modifying options are available yet. In this article, we provide a brief overview of therapeutic approaches currently being explored for synucleinopathies, and suggest possible explanations to the clinical trials outcomes. Finally, we propose that a deeper understanding of the pathophysiology of synucleinopathies, together with a combination of therapies tailored to each disease stage, may lead to better therapeutic outcomes in synucleinopathy patients. Synucleinopathies, neurodegenerative disorders characterized by the abnormal accumulation of the protein alpha-synuclein, constitute the second leading cause of parkinsonism and dementia in the elderly population, however, no disease-modifying options are available yet. In this review, we summarize the therapeutic approaches currently being explored for synucleinopathies, suggest possible explanations to the clinical outcomes, and propose areas of further therapeutic improvement. This article is part of a special issue on Parkinson disease. PMID- 26749154 TI - Lower extremity reticulated hyperpigmentation with bullae. PMID- 26749153 TI - Retro-rectus repair of complex incisional hernia leads to low recurrence rate. AB - BACKGROUND: To assess the outcome of retro-rectus repair of complex abdominal wall repair (CAWR) in a single institution in relation to the use of biologic and synthetic mesh. METHOD: A retrospective review was undertaken of complex abdominal wall repairs performed by a single surgical team, assessing the outcome of the retro-rectus repair and factors affecting the outcome. RESULTS: Between 2007 and 2013, 57 (33 male) patients underwent CAWR retro-rectus repair. The material used was assessed as either synthetic or biologic (cross-linked porcine dermal collagen). The Ventral Hernia Working Group grades were similar between groups of patients having a repair with synthetic and biologic mesh. Median follow-up in the synthetic group was 18 months (1-80.5) and 18.4 months (0.5 70.7) in the biologic group. There was no statistical difference in seroma, wound infection or haematoma rates. No fistulae occurred in either group. Overall recurrence was 3.4% and there was no statistical difference between groups. CONCLUSION: The retro-rectus repair technique is associated with a low rate of recurrence and is now the technique of choice. The choice of material, biologic or synthetic, in Ventral Hernia Working Group grades 1-3 remains controversial. PMID- 26749155 TI - A Bis(guanidinium)alcohol Attached to a Hairpin Polyamide: Synthesis, DNA Binding, and Plasmid Cleavage. AB - Bis(guanidinium)alcohols have been designed to react with phosphodiester substrates in a fast transphosphorylation step, a quasi-intramolecular process taking place in contact ion pairs. Here the attachment of such compounds to Dervan-type hairpin polyamides is described. The resulting conjugate 1 binds to AT-rich DNA duplexes with affinity similar to that of the parent polyamide as shown by UV melting experiments and CD titrations. Conjugate 1 nicks plasmid DNA at concentrations ranging from micromolar to high nanomolar. PMID- 26749156 TI - Perceptions about eating experiences of low-literate older adults with heart disease: a qualitative study. AB - AIMS: To explore perceptions of low-literate older adults with heart disease about their eating experiences. BACKGROUND: Heart disease has been closely linked with nutrition, and nutritional status is poor in patients with limited education, but no studies have explored the eating experiences of low-literate adults with heart disease. DESIGN: Qualitative descriptive study. METHODS: Data were collected in tape-recorded semi-structured interviews from March-June 2012. A convenience sample of 13 low-literate older adults with heart disease was recruited from a cardiovascular ward of a medical centre in northern Taiwan. Participants were recruited until findings reached saturation and data were analysed using qualitative content analysis. FINDINGS: Analysis of participants' interview data on eating experiences identified three main categories: (1) eating related hardships because of low literacy; (2) eating adjustments due to low literacy; and (3) misinformation about dietary modifications for heart disease. CONCLUSION: Because of their low literacy, these older adults had difficult life experiences, gained inappropriate or inadequate eating information and held a passive, fatalistic perspective about eating with heart disease. Healthcare practitioners caring for this population need to appreciate their unique eating challenges and respect their eating customs. Nurses could play a greater role in educating and supporting low-literate older adults in selecting appropriate foods and preparing meals. Strategies to help this population learn to select, prepare and cook their food should be easy and practical, using specific symbols, concrete signs and simple labels. PMID- 26749157 TI - A Meta-Analysis to Estimate the Placebo Effect in Randomized Controlled Trials in Juvenile Idiopathic Arthritis. AB - OBJECTIVE: To estimate the placebo effect in juvenile idiopathic arthritis (JIA) through a meta-analysis of phase III clinical trials with placebo comparator. METHODS: A systematic literature search was carried out up to December 2014. For parallel design studies the outcome was evaluated as a single 1-dimensional (1-D) variable or as a composite score; outcomes of withdrawal studies were evaluated only as composite scores. RESULTS: We included 26 of 224 trials (12%). In trials with parallel study design and a 1-D outcome, the placebo effect was 0.35 (95% confidence interval [95% CI] 0.27-0.43). Among trials with parallel study design and a composite score outcome, the placebo rate response was higher in trials that included patients with nonsystemic JIA (0.35 [95% CI 0.29-0.42]) than in trials that included only patients with systemic JIA (0.17 [95% CI 0.10-0.30]). In the withdrawal design trials, the percentages of patients receiving placebo who had disease flares during the double-blind phase were lower in trials that included patients with nonsystemic JIA (0.55 [95% CI 0.47-0.64]) than in trials that included only patients with systemic JIA (0.68 [95% CI 0.33-0.90]). CONCLUSION: In trials with a parallel study design a sizable number of patients seem to benefit from a placebo effect, although this effect is smaller in patients with systemic JIA. In trials with a withdrawal design the inverse placebo effect is similar among the different JIA categories. This placebo effect should be considered when evaluating the effectiveness of proposed interventions and for future calculations of sample size. PMID- 26749158 TI - Factors associated with non-adherence to Buprenorphine-naloxone among opioid dependent African-Americans: A retrospective chart review. AB - BACKGROUND AND OBJECTIVES: Opioid use disorders are common, chronic relapsing disorders. Buprenorphine (BUP) is an FDA approved medication in the treatment of opioid use disorders, but patient adherence to this medication remains a challenge. To identify risk factors for non-adherence, this chart review study examined the association between DSM-IV Axis I psychiatric disorders, substance use, demographics, and adherence to BUP-naloxone in African-American patients. METHODS: Charts were selected of patients who had >=5 visits and completed psychometric screens (Patient Health Questionnaire, Mood Disorder Questionnaire, and a posttraumatic stress disorder questionnaire) at the time of the initial visit (N = 50). Urine drug screens (UDS) were also obtained. Treatment adherence was defined as BUP presence in UDS for >=80% of the visits. RESULTS: A total of 48% of patients were adherent to treatment. Non-adherent patients had higher rates of use for not only opioids, but also cocaine, and alcohol. Cocaine use was associated with BUP-naloxone non-adherence even after controlling for opioid use. Attendance in cognitive behavioral group therapy sessions (CBT) was significantly associated with adherence. Patients endorsing PTSD symptoms showed higher adherence to treatment compared to those who did not endorse these symptoms. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Our results indicate that alcohol and illicit substance use is associated with non-adherence to BUP-naloxone treatment, and suggests that CBT and efforts to promote abstinence from non-opioid substance use may improve adherence among African-Americans. These findings contribute to growing literature on understanding adherence to BUP-naloxone, which is critical to reduce morbidity and mortality. PMID- 26749160 TI - Implication of metabolomic profiles to wide thermoneutral zone in Mongolian gerbils (Meriones unguiculatus). AB - Mongolian gerbils (Meriones unguiculatus) have evolved a wide thermoneutral zone (26.5-38.9 degrees C) and high upper critical temperature, and appear to have a high tolerance for heat exposure. Here, we use a metabolomic approach to measure global metabolite profiles for gerbils between lower (27 degrees C) and upper critical temperatures (38 degrees C) to investigate the role of metabolomic characterization in maintaining basal metabolic rates within a wide thermoneutral zone. We found that in serum and liver, 14 and 19 metabolites were significantly altered, respectively. In the aerobic respiration-related tricarboxylic cycle (TCA), 5 intermediates (isocitric acid, cis-aconitic acid, alpha-ketoglutaric acid, fumaric acid and malic acid) were increased in serum in 38 degrees C animals; however, no such increase was found in the liver. A stable level of hepatic TCA cycle intermediates may be related to the steady state of aerobic respiration at 38 degrees C. Metabolomic results also revealed that acute heat exposure caused increased oxidative stress and low molecular weight antioxidants in Mongolian gerbils. Increased methionine and 2-hydroxybutyrate suggest an accelerated synthesis of glutathione. Increased urate and its precursors, inosine and hypoxanthine, were detected at 38 degrees C. Glucuronate, threonate and oxalate involved in ascorbate synthesis and degradation were increased in serum at 38 degrees C. In conclusion, although dramatic metabolomic variation was found, a stable hepatic TCA cycle may contribute to maintaining a constant basal metabolic rate within a wide thermoneutral zone in Mongolian gerbils. PMID- 26749161 TI - Effect of temporal resolution and serial autocorrelations in event-related functional MRI. AB - PURPOSE: To assess the impact of colored noise on statistics in event-related functional MRI (fMRI) (visual stimulation using checkerboards) acquired by simultaneous multislice imaging enabling repetition times (TRs) between 2.64 to 0.26 s. METHODS: T-values within the visual cortex obtained with analysis tools that assume a first-order autoregressive plus white noise process (AR(1)+w) with a fixed AR coefficient versus higher-order AR models with spatially varying AR coefficients were compared. In addition, dependency of T-values on correction of physiological noise (respiration, heart rate) was evaluated. RESULTS: Optimal statistical power was obtained for a TR of 0.33 s, but T-values as obtained by AR(1)+w models were strongly dependent on the predefined AR coefficients in fMRI with short TRs which required higher-order AR models to achieve stable statistics. Direct estimation of AR coefficients revealed the highest values within the default mode network while physiological noise had little influence on statistics in cortical structures. CONCLUSION: Colored noise in event-related fMRI obtained at short TRs originates mainly from neural sources and calls for more sophisticated correction of serial autocorrelations which cannot be achieved with standard methods relying on AR(1)+w models with globally fixed AR coefficients. Magn Reson Med 76:1805-1813, 2016. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26749162 TI - Comparison of microwave-assisted and heat reflux extraction techniques for the extraction of ten major compounds from Zibu Piyin Recipe using ultra high performance liquid chromatography with tandem mass spectrometry. AB - Microwave-assisted extraction and efficient ultra-high performance liquid chromatography with triple quadrupole mass spectrometry were previously used to quickly extract and simultaneously quantify ginsenoside Rf, Ro, and Rd, 20(S) ginsenoside-Rg2 , 20(R)-ginsenoside-Rg2 , tanshinone IIA, cryptotanshinone, dihydrotanshinone I, lithospermic acid, and osthole from Zibu Piyin Recipe. We here showed that heat reflux extraction provides higher extraction efficiency of these target compounds but is more time consuming. Chromatographic separation was achieved on an Agilent ZORBAX RRHD Eclipse Plus C18 column with a gradient mobile phase consisting of water/0.5% formic acid and acetonitrile at a flow rate of 0.2 mL/min, and detection was performed by positive and negative ion multiple reaction monitoring mode. All analytes showed good linearity (r, 0.9989-0.9999) within the test range, with a limit of detection of 0.002-0.180 MUg/mL. The overall intra- and interday variations of the ten compounds were <=2.9%, and the accuracy was evaluated using a recovery test at three concentrations and was in the range 97.61-103.18% (RSD <= 4.25%). The analytical results showed remarkable differences in the concentrations of the ten compounds extracted from Zibu Piyin Recipe by microwave-assisted extraction and heat reflux extraction. These findings provide important information for determining the quality of Zibu Piyin Recipe. PMID- 26749163 TI - Confident body, confident child: A randomized controlled trial evaluation of a parenting resource for promoting healthy body image and eating patterns in 2- to 6-year old children. AB - OBJECTIVE: Body image and eating patterns develop in early childhood and are influenced by the family environment. This research evaluated Confident Body, Confident Child (CBCC), an intervention for parents of 2- to 6-year-old children, designed to promote body satisfaction, healthy eating, and weight management in early childhood. METHOD: A randomized controlled trial compared four groups: (A) received the CBCC resource pack and a workshop, (B) received the CBCC resource pack only, (C) received a nutrition-only resource and (D) received no interventions until all questionnaires were completed (i.e., functioned as waitlist control). Measures of parenting variables relevant to child body image and eating patterns, parent-report of child weight, and evaluation questions about the resource, were implemented pre- and post-intervention. RESULTS: At 6 weeks post-intervention, the CBCC resource was associated with significant reductions in parents' intentions to use behaviors that increase the risk of negative body attitudes or unhealthy eating in their children, in parents' use of feeding practices associated with childhood overweight, and in television watching during family meals. Significant increases in parents' intentions to use positive behaviors and knowledge of child body image and healthy eating patterns were also found. Superior results were found for the CBCC resource + workshop condition, suggesting it is the preferred delivery method. DISCUSSION: CBCC positively impacts parenting variables associated with childhood risk for body dissatisfaction, unhealthy eating and weight. (c) 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:458-472). PMID- 26749164 TI - Responses of Authors Accused of Plagiarism by Journal Editors. PMID- 26749166 TI - Evaluation of the reference genes for expression analysis using quantitative real time polymerase chain reaction in the green peach aphid, Myzus persicae. AB - The green peach aphid, Myzus persicae Sulzer (Hemiptera, Aphididae), is an important cosmopolitan pest. Real time qRT-PCR has been used for target gene expression analysis on M. persicae. Using real time qRT-PCR, the expression levels are normalized on the basis of the reliable reference genes. However, to date, the stability of available reference genes has been insufficient. In this study, we evaluated nine candidate reference genes from M. persicae under diverse experimental conditions. The tested candidate genes were comprehensively ranked based on five alternative methods (RefFinder, geNorm, Normfinder, BestKeeper and the comparative DeltaCt method). 18s, Actin and ribosomal protein L27 (L27) were recommended as the most stable reference genes for M. persicae, whereas ribosomal protein L27 (L27) was found to be the least stable reference genes for abiotic studies (photoperiod, temperature and insecticide susceptibility). Our finding not only sheds light on establishing an accurate and reliable normalization of real time qRT-PCR data in M. persicae but also lays a solid foundation for further studies of M. persicae involving RNA interference and functional gene research. PMID- 26749167 TI - Long Term Outcome of Conservative Management or Surgical Treatment of Bovine Spastic Paresis: 79 Cases. AB - OBJECTIVE: To report the long term clinical outcome of calves treated surgically or managed conservatively for bovine spastic paresis of the gastrocnemius (BSP G), quadriceps femoris muscle (BSP-Q), or mixed muscle involvement (BSP-M). STUDY DESIGN: Retrospective case study. ANIMALS: Calves (n = 79) with bovine spastic paresis. METHODS: Medical records of calves treated by partial tibial neurectomy or managed conservatively for bovine spastic paresis were analyzed for sex, breed, lineage history, and the onset, duration, and severity of clinical signs. Cases were classified as unilateral or bilateral BSP-G, BSP-Q, or BSP-M. Long term follow-up information was obtained by telephone questionnaire. RESULTS: The study group included 26 BSP-G (33%), 16 BSP-Q (20%), and 37 BSP-M (47%) calves. BSP-M and BSP-Q calves were significantly more bilaterally affected compared to BSP-G calves. Twenty-five of 26 BSP-G calves were treated surgically; 86% had complete resolution of clinical signs. Twenty-nine of 37 BSP-M calves were treated surgically; 81.5% improved, but none completely recovered. In all of the conservatively managed BSP-M calves, clinical signs gradually worsened. None of the BSP-Q calves were treated surgically; in 66.7%, clinical signs gradually worsened and 33.3% of calves spontaneously improved. CONCLUSION: Partial tibial neurectomy is advocated for the treatment of BSP-G and in selected cases of BSP M. However, only partial resolution of clinical signs should be expected for BSP M. No surgical treatment exists for BSP-Q calves, although spontaneous improvement is possible. PMID- 26749165 TI - Presentation of high antigen-dose by splenic B220(lo) B cells fosters a feedback loop between T helper type 2 memory and antibody isotype switching. AB - Effective humoral immunity ensues when antigen presentation by B cells culminates in productive cooperation with T lymphocytes. This collaboration, however, remains ill-defined because naive antigen-specific B cells are rare and difficult to track in vivo. Herein, we used a defined transfer model to examine how B lymphocytes, as antigen-presenting cells, shape the development of T-cell memory suitable for generation of relevant antibody responses. Specifically, we examined how B cells presenting different doses of antigen during the initial priming phase shape the development of CD4 T-cell memory and its influence on humoral immunity. The findings indicate that B cells presenting low dose of antigen favour the development of T helper type 1 (Th1) type memory, while those presenting a high antigen dose yielded better Th2 memory cells. The memory Th2 cells supported the production of antibodies by effector B cells and promoted isotype switching to IgG1. Moreover, among the B-cell subsets tested for induction of Th2 memory, the splenic but not peritoneal B220(lo) cells were most effective in sustaining Th2 memory development as well as immunoglobulin isotype switching, and this function involved a tight control by programmed death 1 programmed death ligand 2 interactions. PMID- 26749168 TI - Subtilase cytotoxin produced by locus of enterocyte effacement-negative Shiga toxigenic Escherichia coli induces stress granule formation. AB - Subtilase cytotoxin (SubAB) is mainly produced by locus of enterocyte effacement (LEE)-negative strains of Shiga-toxigenic Escherichia coli (STEC). SubAB cleaves an endoplasmic reticulum (ER) chaperone, BiP/Grp78, leading to induction of ER stress. This stress causes activation of ER stress sensor proteins and induction of caspase-dependent apoptosis. We found that SubAB induces stress granules (SG) in various cells. Aim of this study was to explore the mechanism by which SubAB induced SG formation. Here, we show that SubAB-induced SG formation is regulated by activation of double-stranded RNA-activated protein kinase (PKR)-like endoplasmic reticulum kinase (PERK). The culture supernatant of STEC O113:H21 dramatically induced SG in Caco2 cells, although subAB knockout STEC O113:H21 culture supernatant did not. Treatment with phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, and lysosomal inhibitors, NH4 Cl and chloroquine, suppressed SubAB-induced SG formation, which was enhanced by PKC and PKD inhibitors. SubAB attenuated the level of PKD1 phosphorylation. Depletion of PKCdelta and PKD1 by siRNA promoted SG formation in response to SubAB. Furthermore, death-associated protein 1 (DAP1) knockdown increased basal phospho PKD1(S916) and suppressed SG formation by SubAB. However, SG formation by an ER stress inducer, Thapsigargin, was not inhibited in PMA-treated cells. Our findings show that SubAB-induced SG formation is regulated by the PERK/DAP1 signalling pathway, which may be modulated by PKCdelta/PKD1, and different from the signal transduction pathway that results in Thapsigargin-induced SG formation. PMID- 26749169 TI - ATP-binding cassette transporter 1 (ABCA1) deficiency decreases platelet reactivity and reduces thromboxane A2 production independently of hematopoietic ABCA1. AB - ESSENTIALS: The role of ATP-binding cassette transporter 1 (ABCA1) in platelet functions is poorly characterized. We studied the impact of ABCA1 deficiency on platelet responses in a mouse model and two Tangier patients. ABCA1-deficient platelets exhibit reduced positive feedback loop mechanisms. This reduced reactivity is dependent on external environment and independent of hematopoietic ABCA1. SUMMARY: BACKGROUND: The ATP-binding cassette transporter ABCA1 is required for the conversion of apolipoprotein A-1 to high-density lipoprotein (HDL), and its defect causes Tangier disease, a rare disorder characterized by an absence of HDL and accumulation of cholesterol in peripheral tissues. The role of ABCA1 in platelet functions remains poorly characterized. OBJECTIVE: To determine the role of ABCA1 in platelet functions and to clarify controversies concerning its implication in processes as fundamental as platelet phosphatidylserine exposure and control of platelet membrane lipid composition. METHODS AND RESULTS: We studied the impact of ABCA1 deficiency on platelet responses in a mouse model and in two Tangier patients. We show that platelets in ABCA1-deficient mice are slightly larger in size and exhibit aggregation and secretion defects in response to low concentrations of thrombin and collagen. These platelets have normal cholesterol and major phospholipid composition, granule morphology, or calcium induced phosphatidylserine exposure. Interestingly, ABCA1-deficient platelets display a reduction in positive feedback loop mechanisms, particularly in thromboxane A2 (TXA2) production. Hematopoietic chimera mice demonstrated that defective eicosanoids production, particularly TXA2, was primarily dependent on external environment and not on the hematopoietic ABCA1. Decreased aggregation and production of TXA2 and eicosanoids were also observed in platelets from Tangier patients. CONCLUSIONS: Absence of ABCA1 and low HDL level induce reduction of platelet reactivity by decreasing positive feedback loops, particularly TXA2 production through a hematopoietic ABCA1-independent mechanism. PMID- 26749170 TI - Cultural issues in post-disaster reconstruction: the case of Typhoon Morakot in Taiwan. AB - Most members of Taiwan's indigenous communities live in areas that are prone to natural disasters. Yet, due to their marginalised cultural, economic and political status, each time such calamities strike, any assistance they receive is usually provided without considering their actual needs. The areas hardest hit by Typhoon Morakot in August 2009 were the indigenous villages in the southern and eastern parts of the island. After the initial emergency relief efforts had been completed, there remained the highly challenging task of reconstruction and the resettlement of those who lost their homes and livelihoods. This paper examines the cultural conflicts that arose during the reconstruction process, with special emphasis on the participation of Taiwan's indigenous communities and their capacity for resilience. It was found that community participation and identification are key issues in effective disaster governance. PMID- 26749171 TI - Adverse events associated with ribavirin in sofosbuvir-based therapies for patients with chronic hepatitis C: A community practice experience. AB - OBJECTIVE: Due to high sustained virological response (SVR) rates, sofosbuvir based regimens are currently a mainstay for hepatitis C virus (HCV) therapies. The addition of pegylated interferon (PEG-IFN) and ribavirin impacts patients' quality of life during treatment. This study aimed to compare severe adverse events (SAEs) amongst therapeutic combinations for HCV in a community clinic setting. METHODS: From December 2013 to July 2014, 128 chronic HCV-infected patients were treated with sofosbuvir, ribavirin and weekly PEG-IFN for 12 weeks (cohort 1), 12 or 24 weeks of sofosbuvir and ribavirin (cohorts 2 and 3) or sofosbuvir plus simeprevir for 12 weeks (cohort 4). Adverse events were recorded from baseline to 12 or 24 weeks of treatment. RESULTS: SAEs appeared in 15.6 53.8% of ribavirin-inclusive treated patients compared to 4.8% of the ribavirin free regimen. PEG-IFN, sofosbuvir plus ribavirin had the highest frequencies of fatigue, headache and rash compared to either 12 or 24 weeks of ribavirin and sofosbuvir. However, sofosbuvir and ribavirin regimens led to significant increases in dyspnea, need for ribavirin dose reductions and withdrawal from treatment due to SAEs. Anemia was also more frequent in ribavirin-inclusive combinations (P < 0.001). Conversely, sofosbuvir plus simeprevir reached similar SVR rates at week 12 post-treatment compared to all ribavirin-containing regimens, but with significantly fewer adverse events (P = 0.006). At week 12 post-treatment, cirrhotic patients experienced a higher virological relapse rate than non-cirrhotic patients (P = 0.019). CONCLUSIONS: Ribavirin-inclusive HCV therapies increased the frequencies of SAEs, had higher dropout rates and increased patient morbidity. PMID- 26749172 TI - Mechanisms of Stress-Induced Visceral Pain: Implications in Irritable Bowel Syndrome. AB - Visceral pain is a term describing pain originating from the internal organs of the body and is a common feature of many disorders, including irritable bowel syndrome (IBS). Stress is implicated in the development and exacerbation of many visceral pain disorders. Recent evidence suggests that stress and the gut microbiota can interact through complementary or opposing factors to influence visceral nociceptive behaviours. The Young Investigator Forum at the International Society of Psychoneuroendocrinology (ISPNE) annual meeting reported experimental evidence suggesting the gut microbiota can affect the stress response to affect visceral pain. Building upon human imaging data showing abnormalities in the central processing of visceral stimuli in patients with IBS and knowledge that the amygdala plays a pivotal role in facilitating the stress axis, the latest experimental evidence supporting amygdala-mediated mechanisms in stress-induced visceral pain was reviewed. The final part of the session at ISPNE reviewed experimental evidence suggesting that visceral pain in IBS may be a result, at least in part, of afferent nerve sensitisation following increases in epithelial permeability and mucosal immune activation. PMID- 26749173 TI - Hypercrosslinked Additives for Ageless Gas-Separation Membranes. AB - The loss of internal pores, a process known as physical aging, inhibits the long term use of the most promising gas-separation polymers. Previously we reported that a porous aromatic framework (PAF-1) could form a remarkable nanocomposite with gas-separation polymers to stop aging. However, PAF-1 synthesis is very onerous both from a reagent and reaction-condition perspective, making it difficult to scale-up. We now reveal a highly dispersible and scalable additive based on alpha,alpha'-dichloro-p-xylene (p-DCX), that inhibits aging more effectively, and crucially almost doubles gas-transport selectivity. These synergistic effects are related to the intimately mixed nanocomposite that is formed though the high dispersibility of p-DCX in the gas-separation polymer. This reduces particle-size effects and the internal free volume is almost unchanged over time. This study shows this inexpensive and scalable polymer additive delivers exceptional gas-transport performance and selectivity. PMID- 26749175 TI - Bacterial influence on consolidation of bone grafts in maxillary sinus elevation. AB - OBJECTIVES: The aim of this study was to identify microorganisms present on the maxillary sinus floor at the moment of sinus elevation surgery and, using tomography, to investigate the repercussions these might have for regenerated bone 9 months after the procedure. MATERIALS AND METHODS: 174 patients (90 women and 84 men) with a mean age of 55.92 years underwent 227 sinus elevations (120 left sinus, 107 right sinus). As the membrane was lifted, a sample of the maxillary sinus floor was collected with a cotton swab, and placed on a blood agar and chocolate agar culture to incubate for 48 h at 37 degrees C; the samples then underwent microbiological analysis. Orthopantomographs and computerized tomographs were made immediately after the sinus grafting and after 9 months to measure the amount of remaining and regenerated bone in vertical and transversal direction. RESULTS: 18.1% of 227 cultures were bacteria-positive. 45% of the germs were of the Streptococcus genus, most of which belonged to the S. viridans group (61.1%). Patients presenting negative cultures had 5% more regenerated bone than patients with bacteria-positive cultures, which represents an additional 2.28 mmof vertical bone (with a confidence interval between 0.83 mm and 3.73 mm). CONCLUSIONS: Patients with bacteria-positive cultures obtained previously to the sinus grafting procedure have greater risk of bone height loss after 9 months, which indicates that bacterial contamination may influence bone graft regeneration. PMID- 26749174 TI - Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 Treatment Recommendations for Psoriatic Arthritis. AB - OBJECTIVE: To update the 2009 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for the spectrum of manifestations affecting patients with psoriatic arthritis (PsA). METHODS: GRAPPA rheumatologists, dermatologists, and PsA patients drafted overarching principles for the management of PsA, based on consensus achieved at face-to-face meetings and via online surveys. We conducted literature reviews regarding treatment for the key domains of PsA (arthritis, spondylitis, enthesitis, dactylitis, skin disease, and nail disease) and convened a new group to identify pertinent comorbidities and their effect on treatment. Finally, we drafted treatment recommendations for each of the clinical manifestations and assessed the level of agreement for the overarching principles and treatment recommendations among GRAPPA members, using an online questionnaire. RESULTS: Six overarching principles had >=80% agreement among both health care professionals (n = 135) and patient research partners (n = 10). We developed treatment recommendations and a schema incorporating these principles for arthritis, spondylitis, enthesitis, dactylitis, skin disease, nail disease, and comorbidities in the setting of PsA, using the Grading of Recommendations, Assessment, Development and Evaluation process. Agreement of >80% was reached for approval of the individual recommendations and the overall schema. CONCLUSION: We present overarching principles and updated treatment recommendations for the key manifestations of PsA, including related comorbidities, based on a literature review and consensus of GRAPPA members (rheumatologists, dermatologists, other health care providers, and patient research partners). Further updates are anticipated as the therapeutic landscape in PsA evolves. PMID- 26749176 TI - Neck abscess: An unusual clinical presentation of immunoglobulin G4 related disease. AB - : Immunoglobulin G4 related disease (IgG4-RD) is a systemic fibroinflammatory disease that can affect almost any organ. Only a few cases of IgG4-RD have been reported to present with cervical lymphadenopathy and none with neck abscesses. We report a case in a patient with bilateral neck mass and bilateral neck abscesses. The patient underwent bilateral neck incision for drainage of the abscesses on two occasions, followed by a neck dissection after a third recurrence. Immunohistochemistry of the specimen revealed IgG4-RD. Although surgery is not the recommended first-line approach for IgG4-RD, only a neck dissection enabled clinical resolution of the lesions in our patient. LEVEL OF EVIDENCE: NA Laryngoscope, 126:1114-1116, 2016. PMID- 26749177 TI - Can We Predict Those With Osteoarthritis Who Will Worsen Following a Chronic Disease Management Program? AB - OBJECTIVE: To identify predictors of worsening symptoms and overall health of the treated hip or knee joint following 26 weeks of a nonsurgical chronic disease management program for hip and knee osteoarthritis (OA) and to examine the consistency of these predictors across 3 definitions of worsening. METHODS: This prospective cohort study followed 539 participants of the program for 26 weeks. The 3 definitions of worsening included symptomatic worsening based on change in the Western Ontario and McMaster Universities Osteoarthritis Index Global score (WOMAC-G) measuring pain, stiffness, and function; a transition scale that asked about overall health of the treated hip or knee joint; and a composite outcome including both. Multivariate logistic regression models were constructed for the 3 definitions of worsening. RESULTS: Complete data were available for 386 participants: mean age was 66.3 years, 69% were female, 85% reported knee joint pain as primary symptom (signal joint), 46% were waitlisted for total joint arthroplasty (TJA). TJA waitlist status, signal joint, 6-Minute Walk Test (6MWT), depressive symptoms, pain, and age were independently associated with at least 1 definition of worsening. TJA waitlist status and 6MWT remained in the multivariate models for the transition and composite definitions of worsening. CONCLUSION: Participants reporting worsening on the transition scale did not consistently meet the WOMAC-G definition of worsening symptoms. TJA waitlist status was predictive of the composite definition of worsening, a trend apparent for the transition definition. However, variables that predict worsening remain largely unknown. Further research is required to direct comprehensive and targeted management of patients with hip and knee OA. PMID- 26749178 TI - The lactate and ventilatory thresholds in resistance training. AB - PURPOSE: This study was designed to identify the lactate threshold (LT) and first ventilatory threshold (VT1 ) in a graded resistance half-squat test and determine whether both thresholds are produced at the same workload. A further goal was to compare the visual inspection and algorithm adjustment methods of detecting both thresholds during graded resistance exercise. METHODS: Twenty-four young men completed two test sessions 48 h apart; (i) the one-repetition maximum (1RM) was determined, (ii) an incremental load test was performed to locate LT and VT1 . VT1 was calculated in three different ways based on pulmonary ventilation, the ventilatory equivalent of oxygen or the end-tidal oxygen pressure (as VT1 -VE, VT1 -VE.VO2-1 or VT1 -PetO2, respectively). RESULTS: LT and VT1 were located at the same intensity of exercise during the incremental load test. Using the algorithm method, the LT and VT1 -VE were estimated at 24.8 +/- 4.8% 1RM (50.6 +/ 10.5 kg) and 23.7 +/- 4.8% 1RM (48.4 +/- 10.0 kg), respectively; the difference between the two values being non-significant (P = 0.127). In addition, positive correlation was observed between the two thresholds (r = 0.761; P<0.001; intraclass correlation coefficient (ICC) (0.864). The visual inspection and algorithm adjustment methods provided similar LT and VT1 values (r > 0.796; ICC > 0.885). CONCLUSIONS: The LT and VT1 were readily located during the incremental load half-squat test at similar workloads using both the visual inspection and algorithm adjustment methods. Both thresholds served to define two physiological stages (I, II) corresponding to the zones described for endurance exercise. Thus, both LT and VT1 could be used to prescribe the same intensity of resistance half squat exercise. PMID- 26749179 TI - Rational Irrationality: Modeling Climate Change Belief Polarization Using Bayesian Networks. AB - Belief polarization is said to occur when two people respond to the same evidence by updating their beliefs in opposite directions. This response is considered to be "irrational" because it involves contrary updating, a form of belief updating that appears to violate normatively optimal responding, as for example dictated by Bayes' theorem. In light of much evidence that people are capable of normatively optimal behavior, belief polarization presents a puzzling exception. We show that Bayesian networks, or Bayes nets, can simulate rational belief updating. When fit to experimental data, Bayes nets can help identify the factors that contribute to polarization. We present a study into belief updating concerning the reality of climate change in response to information about the scientific consensus on anthropogenic global warming (AGW). The study used representative samples of Australian and U.S. PARTICIPANTS: Among Australians, consensus information partially neutralized the influence of worldview, with free market supporters showing a greater increase in acceptance of human-caused global warming relative to free-market opponents. In contrast, while consensus information overall had a positive effect on perceived consensus among U.S. participants, there was a reduction in perceived consensus and acceptance of human-caused global warming for strong supporters of unregulated free markets. Fitting a Bayes net model to the data indicated that under a Bayesian framework, free-market support is a significant driver of beliefs about climate change and trust in climate scientists. Further, active distrust of climate scientists among a small number of U.S. conservatives drives contrary updating in response to consensus information among this particular group. PMID- 26749180 TI - Emotion and hypervigilance: negative affect predicts increased P1 responses to non-negative pictorial stimuli. AB - Previous research has demonstrated that negative affect influences attentional processes. Here, we investigate whether pre-experimental negative affect predicts a hypervigilant neural response as indicated by increased event-related potential amplitudes in response to neutral and positive visual stimuli. In our study, seventeen male participants filled out the German version of the positive and negative affect schedule (Watson et al. in J Pers Soc Psychol 54:1063-1070, 1988; Krohne et al. in Diagnostica 42:139-156, 1996) and subsequently watched positive (erotica, extreme sports, beautiful women) and neutral (daily activities) photographs while electroencephalogram was recorded. In line with our hypothesis, low state negative affect but not (reduced) positive affect predicted an increase in the first positive event-related potential amplitude P1 as a typical marker of increased selective attention. As this effect occurred in response to non threatening picture conditions, negative affect may foster an individual's general hypervigilance, a state that has formerly been associated with psychopathology only. PMID- 26749183 TI - Direct Hydrogenation of Biobased Carboxylic Acids Mediated by a Nitrogen-centered Tridentate Phosphine Ligand. AB - A novel nitrogen-centered tridentate ligand was identified from a series of multidentate ligands and applied for the direct hydrogenation of 9 biogenic acids into alcohols, lactones and esters with high yields. Comparison of substrates and ruthenium precursors suggested that the Ru(II) hydride cationic species was more active to transform acids than the corresponding lactone or esters. PMID- 26749181 TI - Rhythmic arm movements are less affected than discrete ones after a stroke. AB - Recent reports indicate that rhythmic and discrete upper-limb movements are two different motor primitives which recruit, at least partially, distinct neural circuitries. In particular, rhythmic movements recruit a smaller cortical network than discrete movements. The goal of this paper is to compare the levels of disability in performing rhythmic and discrete movements after a stroke. More precisely, we tested the hypothesis that rhythmic movements should be less affected than discrete ones, because they recruit neural circuitries that are less likely to be damaged by the stroke. Eleven stroke patients and eleven age matched control subjects performed discrete and rhythmic movements using an end effector robot (REAplan). The rhythmic movement condition was performed with and without visual targets to further decrease cortical recruitment. Movement kinematics was analyzed through specific metrics, capturing the degree of smoothness and harmonicity. We reported three main observations: (1) the movement smoothness of the paretic arm was more severely degraded for discrete movements than rhythmic movements; (2) most of the patients performed rhythmic movements with a lower harmonicity than controls; and (3) visually guided rhythmic movements were more altered than non-visually guided rhythmic movements. These results suggest a hierarchy in the levels of impairment: Discrete movements are more affected than rhythmic ones, which are more affected if they are visually guided. These results are a new illustration that discrete and rhythmic movements are two fundamental primitives in upper-limb movements. Moreover, this hierarchy of impairment opens new post-stroke rehabilitation perspectives. PMID- 26749184 TI - Asymptomatic Severe Aortic Stenosis and Noncardiac Surgery. PMID- 26749182 TI - Neurophysiological and behavioural effects of dual-hemisphere transcranial direct current stimulation on the proximal upper limb. AB - Dual-hemisphere transcranial direct current stimulation over the primary motor cortex (M1-M1 tDCS) is assumed to modulate neural excitability in a polarity dependent manner and improve motor performance of the hand. In the proximal upper limb, the neurophysiological and behavioural after-effects of M1-M1 tDCS are not well known. This study investigated the after-effects of M1-M1 tDCS on contralateral, ipsilateral and transcallosal excitability to the proximal upper limb muscle biceps brachii (BB). Circle tracing was used to assess motor performance before and after tDCS as this task requires coordination of proximal and distal musculature. Sixteen healthy right-handed adults participated in the study, each receiving M1-M1 tDCS (1 mA, 15 min) or sham tDCS in separate sessions. The anode was positioned over right M1 and cathode over left M1. M1-M1 tDCS suppressed transcallosal inhibition from the M1 under the cathode (P < 0.045). No other neurophysiologic or behavioural effects were observed (P > 0.6). The study provides important information regarding inconsistent neurophysiological and behavioural changes following tDCS that have implications for future tDCS research on the motor system. PMID- 26749185 TI - Proliferation of Online Medical Journals. PMID- 26749186 TI - Use of the data system for field management of a clinical study conducted in Kolkata, India. AB - BACKGROUND: Designing an appropriate data system is important to the success of a clinical study. However, little information is available on this topic. We share our experiences on designing, developing, and implementation of a data system for management of data and field activities of a complex clinical study. METHODS: The data system was implemented aiming at determining the biological basis for the underperformance of oral vaccines, such as polio and rotavirus vaccines in children at a site in Kolkata, India. The system included several functionalities to control data and field activities. It was restricted to authorized users based on their access privileges. A relational database platform was chosen, and Microsoft Visual FoxPro 7.0 (Microsoft Corporation, Seattle, WA, USA) was used to develop the system. The system was installed at the clinic and data office to facilitate both the field and data management activities. RESULTS: Data were doubly entered by two different data operators to identify keypunching errors in the data. Outliers, duplication, inconsistencies, missing entries, and linkage were also checked. Every modification and users log-in/log-out information was auto-recorded in an audit trail. The system offered tools for preparation of visit schedule of the participants. A visit considered as protocol deviation was documented by the system. The system alerted field staff to every upcoming visit date to organize the field activities and to inform participants which day to come. The system also produced a growth chart for evaluating nutritional status and referring the child to a specialized clinic if found to be severely malnourished. CONCLUSION: The data system offered unique features for controlling for both data and field activities, which led to minimize drop-out rates as well as protocol deviations. Such system is warranted for a successful clinical study. PMID- 26749187 TI - Effect of 90 degrees counterclockwise rotation of the endotracheal tube on its advancement through the larynx during nasal fiberoptic intubation in children: a randomized and blinded study. AB - BACKGROUND: Resistance to the passage of the endotracheal tube (ETT) is frequently encountered in children as it is advanced over the fiberoptic scope for placement into the trachea because it gets hung up at the laryngeal inlet. Literature in adults indicates that a 90 degrees counterclockwise rotation (CCR) of the ETT before advancing results in smooth passage. We found no literature in children. OBJECTIVES: Our aim was to study if a 90 degrees counterclockwise rotation (CCR) of the ETT before advancement leads to smooth passage of the ETT into the larynx in children. METHODS: Following IRB approval, we performed this study in two parts: Part 1: An unblinded, observational, pilot study on 20 children scheduled for oral rehabilitation where we concurrently used a fiberoptic scope nasally and GlideScope orally. We visualized the ETT path and observed that 90 degrees CCR allowed smooth passage without hang up. Part 2: A blinded and randomized study on 40 children to confirm if 90 degrees CCR from the outset would improve passage of the ETT during nasal intubation with a fiberoptic scope in children. All children were divided into two groups: group S, ETT bevel facing left; group R, ETT bevel facing down. RESULTS: In Part 1, we observed that the ETT got hung up in 57% of children with standard bevel direction (facing left) and in 0% of children when prerotated. In Part 2, efficacy of prerotation was confirmed; the ETT got hung up in 50% of children in group S but in only 10.5% of children in group R. CONCLUSION: A change in ETT tip orientation from bevel facing left to facing down by 90 degrees CCR, leads to a significantly higher first-attempt success rate by nasal approach in children. We believe the ETT should be rotated before insertion into the nostril to ensure that full 90 degrees CCR of the tip has been accomplished. PMID- 26749188 TI - Effect of defocus on response time in different age groups: A pilot study. AB - PURPOSE: To assess the response time associated with visual performance (VP) tasks in the presence of defocus in different presbyopic populations. METHODS: 58 eyes between the ages of 35 and 50 years were studied. Subjects were categorized as pre-presbyopic (35-39 years), early-presbyopic (40-45 years), and mid presbyopic (46-50 years). VP measurements obtained monocularly included distance and near high contrast (HC) and low contrast (LC) optotype recognition, and contrast threshold at 12cpd for different defocus magnitudes between 0D and 3D in 1D steps. Response time defined as the time taken to recognize and verbalize an optotype, was compared among different presbyopic age groups. RESULTS: From 58 eyes, mean (SD) response time for high contrast distance visual acuity for 0D through 3D ranged between 1.48 (0.23) and 1.87 (0.31)s, whereas low contrast distance visual acuity ranged between 1.5 (0.22) and 2.09 (0.49)s. Mean response time for high contrast near visual acuity for 0D through 3D ranged between 1.56 (0.19) and 2.23 (0.45)s. However, for low contrast near visual acuity it ranged between 1.75 (0.32) and 2.71 (0.94)s. Mean (SD) response time for 12cpd ranged between 2.11 (0.50) and 5.72 (1.09)s. ANOVA revealed a significant difference in response time for distance, near visual acuity and contrast sensitivity as a function of defocus for different age groups. CONCLUSIONS: Response time is increased in the presence of increasing defocus for both distance and near visual acuity and could impact on performance for critical tasks. Full correction of visual acuity at distance and near in presbyopes is warranted always. PMID- 26749190 TI - Audit of the use of anticoagulation for atrial fibrillation in hemodialysis patients. PMID- 26749189 TI - Modality-independent representations of small quantities based on brain activation patterns. AB - Machine learning or MVPA (Multi Voxel Pattern Analysis) studies have shown that the neural representation of quantities of objects can be decoded from fMRI patterns, in cases where the quantities were visually displayed. Here we apply these techniques to investigate whether neural representations of quantities depicted in one modality (say, visual) can be decoded from brain activation patterns evoked by quantities depicted in the other modality (say, auditory). The main finding demonstrated, for the first time, that quantities of dots were decodable by a classifier that was trained on the neural patterns evoked by quantities of auditory tones, and vice-versa. The representations that were common across modalities were mainly right-lateralized in frontal and parietal regions. A second finding was that the neural patterns in parietal cortex that represent quantities were common across participants. These findings demonstrate a common neuronal foundation for the representation of quantities across sensory modalities and participants and provide insight into the role of parietal cortex in the representation of quantity information. PMID- 26749192 TI - Current diagnosis and treatment of Castleman's disease. AB - Castleman's disease is not just a single disease but rather an uncommon, heterogeneous group of nonclonal lymphoproliferative disorders, which have a broad spectrum of clinical expression. Three histological types have been reported, along with several clinical forms according to clinical presentation, histological substrate and associated diseases. Interleukin-6, its receptor polymorphisms, the human immunodeficiency virus and the human herpes virus 8 are involved in the etiopathogenesis of Castleman's disease. The study of this disease has shed light on a syndrome whose incidence is unknown. Despite recent significant advances in our understanding of this disease and the increasing therapeutic experience with rituximab, tocilizumab and siltuximab, there are still difficult questions concerning its aetiology, prognosis and optimal treatment. PMID- 26749191 TI - Long-term outcomes of adult chronic idiopathic hydrocephalus treated with a ventriculo-peritoneal shunt. AB - INTRODUCTION: Adult chronic idiopathic hydrocephalus (ACIH) is a cause of dementia that can be treated by implanting a ventriculo-peritoneal shunt (VPS). We aim to study clinical and functional outcomes in patients with ACIH corrected with a VPS. SUBJECTS AND METHODS: Observational cohort study of patients diagnosed with probable ACIH (Japan Neurosurgical Society guidelines) and undergoing shunt placement between 2008 and 2013 in a centre of reference for neurosurgery in Spain. Clinical improvement was classified in 4 categories (resolution, partial improvement, equivocal improvement, and no improvement); functional outcome was assessed on the modified Rankin scale (mRS). RESULTS: The study included 29 patients with a mean age of 73.9 years; 62.1% were male and 65.5% had hypertension. Clinical improvement (complete or partial) was observed in 58% after one year and in 48% by the end of the follow-up period (mean follow up time was 37.8 months). Older age, presence of hypertension, and surgery related complications were more prevalent in the group responding poorly to treatment. One patient died, 20.7% experienced severe complications, and 69% were dependent (mRS >= 3) by the end of the follow-up period. Age at diagnosis was independently associated with poorer clinical response at one year and a higher degree of dependency by the end of follow-up. CONCLUSION: Symptomatic benefits offered by VPS were partial and transient; treatment was associated with a high complication rate and poor functional outcomes in the long term, especially in the oldest patients. PMID- 26749193 TI - (CH3 NH3 )2 PdCl4 : A Compound with Two-Dimensional Organic-Inorganic Layered Perovskite Structure. AB - The synthesis of previously unknown perovskite (CH3 NH3 )2 PdCl4 is reported. Despite using an organic cation with the smallest possible alkyl group, a 2D organic-inorganic layered Pd-based perovskites was still formed. This demonstrates that Pd-based 2D perovskites can be obtained even if the size of the organic cation is below the size limit predicted by the Goldschmidt tolerance factor formula. The (CH3 NH3 )2 PdCl4 phase has a bulk resistivity of 1.4 Omega cm, a direct optical gap of 2.22 eV, and an absorption coefficient on the order of 104 cm-1 . XRD measurements suggest that the compound is moderately stable in air, an important advantage over several existing organic-inorganic perovskites that are prone to phase degradation problems when exposed to the atmosphere. Given the recent interest in organic-inorganic perovskites, the synthesis of this new Pd-based organic-inorganic perovskite may be helpful in the preparation and understanding of other organic-inorganic perovskites. PMID- 26749194 TI - Global deletion of Panx3 produces multiple phenotypic effects in mouse humeri and femora. AB - Pannexins form single-membrane channels that allow passage of small molecules between the intracellular and extracellular compartments. Of the three pannexin family members, Pannexin3 (Panx3) is the least studied but is highly expressed in skeletal tissues and is thought to play a role in the regulation of chondrocyte and osteoblast proliferation and differentiation. The purpose of our study is to closely examine the in vivo effects of Panx3 ablation on long bone morphology using micro-computed tomography. Using Panx3 knockout (KO) and wildtype (WT) adult mice, we measured and compared aspects of phenotypic shape, bone mineral density (BMD), cross-sectional geometric properties of right femora and humeri, and lean mass. We found that KO mice have absolutely and relatively shorter diaphyseal shafts compared with WT mice, and relatively larger areas of muscle attachment sites. No differences in BMD or lean mass were found between WT and KO mice. Interestingly, KO mice had more robust femora and humeri compared with WT mice when assessed in cross-section at the midshaft. Our results clearly show that Panx3 ablation produces phenotypic effects in mouse femora and humeri, and support the premise that Panx3 has a role in regulating long bone growth and development. PMID- 26749195 TI - The association of dairy intake of children and adolescents with different food and nutrient intakes in the Netherlands. AB - BACKGROUND: Dairy products are nutrient-rich foods that may contribute to adequate nutrient intakes. However, dairy intake might also be associated with other food sources that influence nutrient intakes. Therefore, we studied the association of dairy, milk and cheese intake with intake of foods and nutrients from (non)dairy sources. METHODS: Dietary intake was assessed from 2007 to 2010 through two non-consecutive 24-h dietary recalls in 1007 children (7-13 years) and 706 adolescents (14-18 years). Participants were divided into non-consumers of a particular dairy product and tertiles according to their dairy intake (lowest, medium and highest intake). P for trend was calculated by linear regression over the median intakes of non-consumers and the tertiles for dairy, milk and cheese. RESULTS: In children, higher dairy consumption was associated with higher intakes of fruits (54.8 g +/- 22.3; p < 0.0001), vegetables (25.0 g +/- 14.6; p = 0.001) and cereals (18.5 g +/- 20.7; p = 0.01) and with lower consumption of non-alcoholic beverages (-281 g +/- 101; p = 0.01): soft drinks ( 159 g +/- 28.2; p < 0.0001) and fruit juices (-40.5 +/- 14.8; p = 0.01). Results were comparable for milk consumption. In adolescents, similar results were found for milk and dairy consumption, except for the associations with higher fruits and vegetable intake. In children and adolescents, higher cheese consumption was associated with higher vegetable and non-alcoholic beverages consumption; and lower meat consumption (-7.8 g +/- 4.8; p = 0.05) in children. Higher cheese consumption was also associated with higher intakes of saturated fat (8.5 g +/- 0.9), trans-fatty acids (0.48 g +/- 0.06), sodium (614 mg +/- 59.3) and several vitamins and minerals . CONCLUSIONS: Higher milk and dairy consumption were associated with lower non-alcoholic beverages consumption, and higher cereal, fruit and vegetable consumption in children, which was also reflected in the nutrient intakes. These findings confirm that the consumption of milk and dairy products might be a marker for healthier eating habits. PMID- 26749196 TI - Efficacy of Fifteen Emerging Interventions for the Treatment of Posttraumatic Stress Disorder: A Systematic Review. AB - Although there is an abundance of novel interventions for the treatment of posttraumatic stress disorder (PTSD), often their efficacy remains unknown. This systematic review assessed the evidence for 15 new or novel interventions for the treatment of PTSD. Studies that investigated changes to PTSD symptoms following the delivery of any 1 of the 15 interventions of interest were identified through systematic literature searches. There were 19 studies that met the inclusion criteria for this study. Eligible studies were assessed against methodological quality criteria and data were extracted. The majority of the 19 studies were of poor quality, hampered by methodological limitations, such as small sample sizes and lack of control group. There were 4 interventions, however, stemming from a mind-body philosophy (acupuncture, emotional freedom technique, mantra-based meditation, and yoga) that had moderate quality evidence from mostly small- to moderate-sized randomized controlled trials. The active components, however, of these promising emerging interventions and how they related to or were distinct from established treatments remain unclear. The majority of emerging interventions for the treatment of PTSD currently have an insufficient level of evidence supporting their efficacy, despite their increasing popularity. Further well-designed controlled trials of emerging interventions for PTSD are required. PMID- 26749197 TI - Substance P enhances EPC mobilization for accelerated wound healing. AB - Wound healing is essential for the survival and tissue homeostasis of unicellular and multicellular organisms. The current study demonstrated that the neuropeptide substance P (SP) accelerated the wound healing process, particularly in the skin. Subcutaneous treatment of SP accelerated wound closing, increased the population of alpha-smooth muscle actin positive myofibroblasts, and increased extracellular matrix deposition at the wound site. Moreover, SP treatment enhances angiogenesis without a local increase in the expression levels of vascular endothelial growth factor and stromal cell-derived factor-1. Importantly, SP treatment increased both the population of circulating endothelial progenitor cells in the peripheral blood and in CD31 positive cells in Matrigel plugs. The tube forming potential of endothelial cells was also enhanced by SP treatment. The results suggested that the subcutaneous injection of SP accelerated the wound healing in the skin via better reconstitution of blood vessels, which possibly followed an increase in the systemic mobilization of endothelial progenitor cells and a more effective assembly of endothelial cells into tubes. PMID- 26749198 TI - Professor Matti Weckstrom (1959-2015). PMID- 26749199 TI - Four photoreceptor classes in the open rhabdom eye of the red palm weevil, Rynchophorus ferrugineus Olivier. AB - The red palm weevil (RPW) is a severe palm pest with high dispersal capability. Its visual sense allows it to navigate long distances and to discriminate among differently colored traps. We investigated the RPW compound eyes with anatomical and electrophysiological methods. The ommatidia are composed of eight photoreceptor cells in an open rhabdom arrangement with six peripheral and two central photoreceptors. The photoreceptor signals are relatively slow and noisy. The majority of recorded photoreceptors have broad spectral sensitivity with a peak in the green, at 536 nm. Three minor classes of photoreceptors have narrower spectral sensitivities with maxima in the UV (366 nm), green (520 nm) and yellow (564 nm). Sensitivity below 350 nm is very low due to filtering by the UV absorbing cornea. The set of photoreceptors represents the retinal substrate for putative trichromatic color vision. PMID- 26749201 TI - EDITORIAL. PMID- 26749200 TI - Influence of internal pore architecture on biological and mechanical properties of three-dimensional fiber deposited scaffolds for bone regeneration. AB - Fused deposition modeling has been used to fabricate three-dimensional (3D) scaffolds for tissue engineering applications, because it allows to tailor their pore network. Despite the proven flexibility in doing so, a limited amount of studies have been performed to evaluate whether specific pore shapes have an influence on cell activity and tissue formation. Our study aimed at investigating the influence of internal pore architecture on the biological and mechanical properties of 3D scaffolds seeded with mesenchymal stromal cells. Polycaprolactone scaffolds with six different geometries were fabricated. The 3D samples were manufactured with different lay-down pattern of the fibers by varying the layer deposition angle from 0 degrees /15 degrees /30 degrees , to 0 degrees /30 degrees /60 degrees , 0 degrees /45 degrees /90 degrees , 0 degrees /60 degrees /120 degrees , 0 degrees /75 degrees /150 degrees , and 0 degrees /90 degrees /180 degrees . The scaffolds were investigated by scanning electron microscopy and micro computed tomographical analysis and displayed a fully interconnected pore network. Cell proliferation and differentiation toward the osteogenic lineage were evaluated by DNA, alkaline phosphatase activity, and polymerase chain reaction. The obtained scaffolds had structures with open porosity (50%-60%) and interconnected pores ranging from 380 to 400 um. Changing the angle deposition affected significantly the mechanical properties of the scaffolds. With increasing the angle deposition between successive layers, the elastic modulus increased as well. Cellular studies also showed influence of the internal architecture on cell adhesion and proliferation within the 3D construct, yet limited influence on cell differentiation was observed. PMID- 26749202 TI - Criteria used when deciding on eligibility for total knee arthroplasty--Between thinking and doing. AB - BACKGROUND: Clinical decision-making in total knee arthroplasty (TKA) is a complex process needing further clarification. The aim of this study was to compare TKA eligibility criteria considered most important by orthopedic surgeons (OSs) to characteristics of patients with knee osteoarthritis (OA) eventually found eligible for TKA. METHODS: Nine OSs chose the five criteria most important when deciding on TKA eligibility. Cross-sectional data from 200 patients found either eligible (n=100) or not eligible (n=100) for TKA by one of the nine OS, were analyzed in a regression analyses with TKA eligibility as the dependent variable. RESULTS: Radiographic severity (n=8), pain (n=9), functional disability (n=8) and not responding to the recommended non-surgical treatment (n=7) were considered most important by OSs. Associations (P<0.25) between TKA eligibility and criteria found important by the OS were demonstrated for worse radiographic severity and more functional limitations, but not for pain and not responding to the recommended non-surgical treatment. Furthermore, more comorbidities and higher Body Mass Index (BMI) were associated with TKA-eligibility, but not found important for TKA eligibility by the OS. CONCLUSION: Radiographic severity and functional limitations were confirmed as drivers for TKA eligibility, while pain was not. Not responding to non-surgical treatment was not included in the decision-making, suggesting low uptake of clinical guidelines in clinical practice. This study highlights the complexity of the decision-making with some overlap between the criteria that OSs think they apply and what is actually applied in clinical practice. PMID- 26749203 TI - The anterolateral ligament of the knee: A dissection study. AB - BACKGROUND: Recent studies have described the presence of the anterolateral ligament (ALL). However, there is still no consensus regarding the anatomy of this structure with the topic controversially discussed. The aim of this study was to provide an anatomical description of the ligamentous structures on the anterolateral side of the knee with special emphasis on the ALL. METHODS: Forty four human cadaveric knees were dissected to reveal the ALL and other significant structures in the anterolateral compartment of the knee joint. The ALL was defined as a firm structure running in an oblique direction from the lateral femoral epicondyle to a bony insertion at the anterolateral tibia. RESULTS: The ALL was identified in 45.5% (n=20) of the dissected knee joints. The structure originates together with the fibular collateral ligament (45%) or just posterior and proximal to it (55%). The ligament has an extra-capsular, anteroinferior, oblique course to the anterolateral tibia with a bony insertion between Gerdy's tubercle and the fibular head. The ALL had its greatest extend at 60 degrees of knee flexion and maximal internal rotation. CONCLUSION: The ALL is a firm ligamentous structure in the anterolateral part of the knee present in 45.5% of the cases. Given the course and characteristics of this structure, a function in providing rotational stability by preventing internal rotation of the knee is likely. CLINICAL RELEVANCE: The ALL might be an important stabilizer in the knee and may play a significant role in preventing excessive internal tibial rotation and subluxation of the knee joint. PMID- 26749204 TI - Epidemiological characteristics of patellofemoral osteoarthritis in elderly Koreans and its symptomatic contribution in knee osteoarthritis. AB - BACKGROUND: Many studies have reported the prevalence of knee osteoarthritis (OA) but have invariably focused on the tibiofemoral (TF) joint and overlooked the patellofemoral (PF) joint. Accordingly, little epidemiological information is available regarding the PF OA. The purpose of the current study was to document the epidemiological characteristics of PF OA in elderly Koreans. METHODS: Radiographic assessment was performed for 681 elderly (>=65 years old) Koreans recruited from a community, and symptom severity was evaluated using Western Ontario and McMaster Universities Index (WOMAC) and Short Form-36 (SF-36) scales. Prevalence of different categories of knee OA (isolated PF OA, isolated TF OA and combined PF and TF OA) was calculated. The symptoms of isolated PF OA group and non-OA group were compared. RESULTS: The overall prevalence of OA was 22.0% in the PF compartment and 34.1% in the TF compartment. The prevalence of isolated PF OA, isolated TF OA, and combined PF and TF OA was 3.8%, 17.8%, and 19.2%, respectively. Female sex, aging, and obesity were not associated with isolated PF OA. No significant differences were found in any clinical outcome scales between the isolated PF and non-OA groups. CONCLUSION: This study documents that OA in the PF joint is common in elderly Koreans, but isolated PF OA is rare. Demographic risk factors are not associated with isolated PF OA, suggesting that isolated PF OA may have a different pathophysiology from other types of knee OA. Our study also indicates that the presence of isolated PF OA should not be construed to be responsible for clinical symptoms. PMID- 26749205 TI - The innate alarm circuit in post-traumatic stress disorder: Conscious and subconscious processing of fear- and trauma-related cues. AB - Fast defensive responses to salient threatening stimuli are an important clinical feature of post-traumatic stress disorder (PTSD). We investigated the neural correlates of subliminal and supraliminal processing of fearful faces and individualized trauma-related words in individuals with PTSD (n=26) compared with healthy controls (n=20) using functional magnetic resonance imaging. Increased activity in the right cerebellum and the posterior cingulum was observed in individuals with PTSD during subliminal processing of trauma-related words, whereas increased activity of the basal forebrain was found within the PTSD group when processing supraliminal trauma-related words. Moreover, significant positive correlations were found between re-experiencing symptoms and response within the amygdala, and between hyper-arousal symptoms and response within the periaqueductal gray matter, during subliminal processing of trauma-related words and during supraliminal processing of fearful faces, respectively. These findings further our understanding of rapid threat processing and defensive responses, highlighting the role of the cerebellum and periaqueductal gray matter as part of an 'innate alarm system' in PTSD. PMID- 26749206 TI - Turkish health care providers' views on inappropriate use of emergency department: Who, when and why? AB - OBJECTIVE: Inappropriate use of emergency departments is recognized globally as a widespread problem. The study was undertaken to determine the perceptions of emergency department personnel regarding inappropriate use of this department. METHODS: The study was undertaken with 124 emergency department employees from six emergency departments in a province of the Eastern Black Sea region of Turkey. Using a questionnaire form designed by the researcher, the data were gathered and analyzed with the chi-square test, numerical and percentage calculations. RESULTS: According to the emergency department employees, more than half of emergency department visits were inappropriate with most visits occurring between the hours of 19:01 and 01:00. In order of occurrence, employees also indicated that most inappropriate use concerned requests for prescription renewals, treatment for pain, and upper respiratory tract infections (URTI). According to the employees, patients made inappropriate use of emergency departments in the belief that these provide services for every kind of health problem. Unfortunately, according to the health care workers this misperception of emergency services results in less effective patient care and a decrease in employee motivation. CONCLUSION: Health team members thought that inappropriate use of emergency services led to negative outcomes in the quality of care and motivation of the workers. Solutions to minimize inappropriate use of emergency departments need to be developed and put into place. PMID- 26749207 TI - Concussion management in the ED: Beyond GCS. PMID- 26749208 TI - Incorporating Health Literacy Screening Into Patients' Health Assessment. AB - Low health literacy (HL) has been associated with several negative health outcomes, yet routine HL screening is not commonplace. This study's purpose was to determine the feasibility of incorporating HL screening into the electronic health record (EHR) of patients admitted to a large Mid-Atlantic teaching hospital. After Registered Nurse (RN) training, the HL screening was implemented for all adult patients upon admission. After implementation, RNs were surveyed about the feasibility of HL screening, and patient EHRs were reviewed for HL status. Results indicated that RNs were receptive to HL screening. Approximately 20% of all patients screened were at risk for low HL, with HL scores decreasing as age increased. Patients with low HL had significantly higher hospital readmissions, even when controlling for age and number of health conditions. Further research is needed to determine how healthcare providers alter their patient interactions if they have knowledge that patients are at risk for having low HL. PMID- 26749209 TI - Effect of Precede-Proceed Model on Preventive Behaviors for Type 2 Diabetes Mellitus in High-Risk Individuals. AB - This study sought to assess the effect of precede-proceed model on preventive behaviors for type 2 diabetes mellitus (DM) in high-risk individuals. In this semi-experimental study, 164 high-risk individuals for type 2 DM were selected and were randomly divided into two groups of intervention and control ( n = 85). Educational intervention was performed as a single session face-to-face instruction for 1.5 hr for the intervention group participants. Data were collected before (baseline) and immediately and 1 month after the intervention in the two groups. The mean score of predisposing (knowledge) factors ( p = .001), reinforcing factors ( p = .001), and enabling factors ( p = .02) were significantly different at baseline and 1 month after the intervention in the intervention group compared with the control group ( p < .05). A significant improvement occurred in the nutritional habits of high-risk participants in the intervention group at 1 month after the intervention compared with controls ( p = .001). The precede-proceed model can be effective for promoting the preventive behaviors for type 2 DM in high-risk individuals. PMID- 26749210 TI - Through-thickness stress relaxation in bacterial cellulose hydrogel. AB - Biological hydrogels, e.g. bacterial cellulose (BC) hydrogel, attracted increasing interest in recent decades since they show a good potential for biomedical engineering as replacements of real tissues thanks mainly to their good biocompatibility and fibrous structure. To select potential candidates for such applications, a comprehensive understanding of their performance under application-relevant conditions is needed. Most hydrogels demonstrate time dependent behaviour due to the contribution of their liquid phase and reorientation of fibres in a process of their deformation. To quantify such time dependent behaviour is crucial due to their exposure to complicated loading conditions in body environment. Some hydrogel-based biomaterials with a multi layered fibrous structure demonstrate a promise as artificial skin and blood vessels. To characterise and model time-dependent behaviour of these multi layered hydrogels along their through-thickness direction is thereby of vital importance. Hence, a holistic study combining mechanical testing and micro morphological observations of BC hydrogel with analytical modelling of its relaxation behaviour based on fraction-exponential operators was performed. The results show a good potential to use a fraction-exponential model to describe such behaviour of multi-layered hydrogels, especially at stages of stress decay at low forces and of stress equilibrium at high forces. PMID- 26749211 TI - Neighborhood disadvantage and physical aggression in children and adolescents: A systematic review and meta-analysis of multilevel studies. AB - Child and adolescent physical aggression are influenced by multiple contexts, such as peers, family, school, and neighborhood. However, the effect of neighborhoods on youth physical aggression remains unclear. The objective of this study was to quantitatively synthesize studies that have examined the effect of neighborhood disadvantage on physical aggression in children and adolescents and to identify potential moderators. We searched seven databases for articles published before April 25, 2015. Studies were considered eligible if they were published in peer-reviewed journals, used multilevel data, controlled for neighborhood clustering, used physical aggression as the study outcome, and considered children or adolescents as the study population. Of the 152 eligible studies, we included 43 in the meta-analysis. The results from the random-effects model revealed that neighborhood disadvantage was positively and significantly associated with physical aggression (P < .001). Metaregression and moderator analyses further indicated a stronger association between neighborhood disadvantage and physical aggression among studies with younger participants, a higher percentage of female participants, and a longer follow-up period (P < .05). Current findings, however, may not be generalized to other types of aggression. The observed neighborhood effects may also be limited because of the omission of studies that did not provide sufficient information for calculating the pooled effect. In summary, the results provide supporting evidence for the adverse effect of living in disadvantaged neighborhoods on physical aggression after adjusting for the individual-level characteristics of children and adolescents. Interventions targeting structural contexts in neighborhoods are required to assist in reducing physical aggression in young people. Aggr. Behav. 42:441-454, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26749212 TI - Eomesodermin promotes interferon-gamma expression and binds to multiple conserved noncoding sequences across the Ifng locus in mouse thymoma cell lines. AB - The T-box transcription factors T-bet and eomesodermin (Eomes) have been shown to regulate the lineage-specific expression of interferon-gamma (IFN-gamma). However, in contrast to T-bet, the role of Eomes in the expression of IFN-gamma remains unclear. In this study, we investigated the Eomes-dependent expression of IFN-gamma in the mouse thymoma BW5147 and EL4 cells, which do not express T-bet or Eomes. The ectopic expression of Eomes induced BW5147 and EL4 cells to produce IFN-gamma in response to phorbol 12-myristate 13-acetate (PMA) and ionomycin (IM). In BW5147 cells, Eomes augmented luciferase activity driven by the Ifng promoter encoding from -2500 to +113 bp; however, it was not increased by a stimulation with PMA and IM. A chromatin immunoprecipitation assay showed that Eomes bound to the Ifng promoter and conserved noncoding sequence (CNS) -22 kb across the Ifng locus with high efficacy in BW5147 cells. Moreover, Eomes increased permissive histone modifications in the Ifng promoter and multiple CNSs. The stimulation with PMA and IM greatly augmented Eomes binding to CNS-54, CNS-34, CNS+19 and CNS+30, which was inhibited by FK506. These results indicated that Eomes bound to the Ifng promoter and multiple CNSs in stimulation-dependent and stimulation-independent manners. PMID- 26749213 TI - The AP-2 complex is required for proper temporal and spatial dynamics of endocytic patches in fission yeast. AB - In metazoans the AP-2 complex has a well-defined role in clathrin-mediated endocytosis. By contrast, its direct role in endocytosis in unicellular eukaryotes has been questioned. Here, we report co- immunoprecipitation between the fission yeast AP-2 component Apl3p and clathrin, as well as the genetic interactions between apl3Delta and clc1 and sla2Delta/end4Delta mutants. Furthermore, a double clc1 apl3Delta mutant was found to be defective in FM4-64 uptake. In an otherwise wild-type strain, apl3Delta cells exhibit altered dynamics of the endocytic sites, with a heterogeneous and extended lifetime of early and late markers at the patches. Additionally, around 50% of the endocytic patches exhibit abnormal spatial dynamics, with immobile patches and patches that bounce backwards to the cell surface, showing a pervasive effect of the absence of AP-2. These alterations in the endocytic machinery result in abnormal cell wall synthesis and morphogenesis. Our results complement those found in budding yeast and confirm that a direct role of AP-2 in endocytosis has been conserved throughout evolution. PMID- 26749214 TI - [Value of neck dissection before definitive radiation therapy for locoregionally advanced squamous cell carcinoma of the head and neck]. AB - PURPOSE: Optimal timing of neck dissection remains debated in the conservative management of patients with locoregionally advanced squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: The files of 63 patients with radiographic evidence of bulky or necrotic nodal metastases treated by up-front neck dissection and definitive radiotherapy between 2000 and 2012 at two institutions were retrospectively reviewed. RESULTS: The primary site was oropharyngeal, hypopharyngeal or laryngeal in 63%, 21% and 13% cases, respectively. Overall, 83% of the tumours were staged pN2b or more. Extracapsular spread was found in 48 cases (77%). After a 48-month median follow-up, the 3-year locoregional control and overall survival were 88% and 68%, respectively. Only one isolated failure occurred in the dissected neck. CONCLUSION: This combination therapy provides a good locoregional tumour control. It should be considered as an option in laryngeal, hypopharyngeal or oropharyngeal squamous cell carcinomas with bulky or necrotic nodal metastases at presentation. PMID- 26749215 TI - Trial design and endpoints in clinical transplant research. AB - The number of clinical trials in solid organ transplantation is progressively increasing year on year, but the quality of design and reporting still varies considerably. The constraints on organ availability, improving short-term outcomes, ethics and timescales involved in organ transplantation present unique challenges for trials in this field. An understanding of the methodology and potential pitfalls in clinical research is essential both to interpret trial results and to design robust studies. This review summarizes the scope and quality of reporting in existing transplant clinical trials and details aspects of clinical trial methodology with particular relevance to transplantation. We highlight initiatives designed to improve the quality of this process to ensure that the results of clinical trials are robust, well reported and of use in everyday clinical practice. PMID- 26749217 TI - Differentiating the Effect of an Opioid Agonist on Cardiac Repolarization From u Receptor-mediated, Indirect Effects on the QT Interval: A Randomized, 3-way Crossover Study in Healthy Subjects. AB - PURPOSE: A thorough QT study was conducted in healthy subjects to evaluate the effect of buprenorphine hydrochloride administered through a buccal soluble film under coverage of naltrexone to block confounding, secondary QT effects. METHODS: Healthy subjects were enrolled in a randomized, partially blinded, 4-way crossover designed study. Subjects received buprenorphine 3 mg with naltrexone, naltrexone alone (with placebo films), placebo (placebo films and placebo naltrexone), and open-label moxifloxacin 400 mg with placebo naltrexone in separate in-house treatment periods. Naltrexone treatment (50 mg) was initiated 12 hours before buprenorphine and was given every 12 hours for a total of 4 doses. ECG data were extracted from a continuous recording predose and serially after dosing on the treatment day. ECG intervals were measured at a central ECG laboratory by using the high-precision QT technique. The QT interval was corrected for heart rate with Fridericia's formula (QTcF), and change-from predose baseline QTcF (?QTcF) was analyzed by using a mixed effect model. FINDINGS: Fifty-eight subjects (35 males) with a mean age of 32 were enrolled into the study. Treatment with buprenorphine 3 mg resulted in a small QT effect with the largest mean naltrexone-corrected ?QTcF reaching 5.8 msec at 8 hours' postdosing (upper bound of the 90% CI below 10 msec). Exposure response analysis with a linear model demonstrated a significant linear relationship between plasma levels and naltrexone-corrected ?QTcF, with an estimated mean slope of 0.65 msec per nanogram/milliliter (90% CI, 0.22 to 1.08). Using the exposure response model, an effect on ?QTcF of 4.5 msec (2.80 to 6.12) can be predicted at the observed geometric peak plasma level after administration of the 3-mg buprenorphine dose in this study (3.6 ng/mL [3.33 to 3.98]). Naltrexone alone did not have a relevant effect on the QTcF interval. IMPLICATIONS: The present study showed that buprenorphine plasma levels up to 5 ng/mL had no effect on the QTc above the level of clinical concern. PMID- 26749216 TI - Antimicrobial Efficacy of an Array of Essential Oils Against Lactic Acid Bacteria. AB - The essential oils of clove bud, cinnamon bark and thyme, and their individual compounds including allyl isothiocyanate (AIT), carvacrol, cinnamaldehyde, cinnamic acid, eugenol, and thymol were initially assessed for antimicrobial activity against 9 lactic acid bacteria (LAB) species. Carvacrol and thymol were the most inhibitory with MICs of 0.1% (v/v and w/v, respectively). Cinnamaldehyde, cinnamon bark oil, clove bud oil, eugenol, and thyme oil were moderately inhibitive (MICs = 0.2% v/v), while cinnamic acid required a concentration of 0.5% (w/v). AIT was not effective with MICs in excess of concentrations tested (0.75% v/v). The bactericidal capability of the oil components carvacrol, cinnamaldehyde, eugenol, and thymol were further examined against Pediococcus acidilactici, Lactobacillus buchneri, and Leuconostoc citrovorum. Thymol at 0.1% (w/v) was bactericidal against L. citrovorum (>4-log reduction), but resulted in a 2-log CFU/mL reduction against L. buchneri and P. acidilactici. Cinnamaldehyde at 0.2% to 0.25% (v/v) was effective against L. citrovorum, L. buchneri, and P. acidilactici, resulting in a >2-log reduction. All 3 organisms were susceptible to 0.2% carvacrol with >3-log reduction observed after exposure for 6 h. Eugenol was the least effective. Concentrations of 0.2% and 0.25% (v/v) were needed to achieve an initial reduction in population, >3-log CFU/mL after 6 h exposure. However, at 0.2%, P. acidilactici and L. buchneri recovered to initial populations in 48 to 72 h. Results indicate essential oils have the capacity to inactivate LAB that are commonly associated with spoilage of shelf stable low-acid foods. PMID- 26749219 TI - Pharmacokinetic Profile and Sustained 24-hour Analgesia of a Once-daily Hydrocodone Bitartrate Extended-release Tablet with Abuse-deterrent Properties. AB - PURPOSE: The purpose of this study was to evaluate the pharmacokinetics (PK) and 24-hour analgesic effectiveness of once-daily, single-entity, extended-release hydrocodone (HYD) with abuse-deterrent properties. METHODS: Four studies were included. Three open-label PK studies had the following designs: single-dose, 5 treatment, 4-period, crossover, dose-proportionality study; HYD 120 mg for 5 days (steady-state study 1); 2-treatment, 2-period, multiple-dose crossover study assessing the relative bioavailability of HYD 30 mg and hydrocodone 7.5 mg/ibuprofen 200 mg administered every 6 hours (steady-state study 2). A long term, open-label study assessed the safety and effectiveness of HYD 20 to 120 mg in patients during a 52-week maintenance period. FINDINGS: Thirty-one, 25, and 22 healthy subjects completed the dose-proportionality study, steady-state study 1, and steady-state study 2, respectively, while 410 patients with moderate to severe chronic nonmalignant and non-neuropathic pain completed the long-term effectiveness study. Mean systemic exposure and peak plasma concentration were dose proportional after administration of single doses of HYD 20 to 120 mg. Pharmacokinetic profiles were comparable at day 1 and day 5 after administration of HYD 120 mg once daily. Once-daily HYD 30 mg was associated with lower fluctuating plasma hydrocodone concentrations compared with immediate-release hydrocodone 7.5 mg/ibuprofen 200 mg administered every 6 hours. In the long-term study, pain control was consistent over the 24-hour dosing interval. IMPLICATIONS: Once-daily HYD exhibits linear, dose-proportional PK properties and is associated with a lower variability in plasma hydrocodone concentrations when compared with an immediate-release hydrocodone combination product. Notably, analgesia provided by HYD is sustained during the 24-hour dosing interval. ClinicalTrials.gov identifier: NCT01400139 (Study 4). PMID- 26749218 TI - Association of Lower Socioeconomic Position in Pregnancy with Lower Diurnal Cortisol Production and Lower Birthweight in Male Infants. AB - PURPOSE: Low maternal socioeconomic position (SEP) has been associated with adverse neonatal outcomes, including preterm birth, low birthweight, intrauterine growth restriction, and infant mortality. A key biological mechanism that has been proposed to explain this association is hypothalamic-pituitary-adrenal (HPA) activity, yet the association between SEP and HPA activity in pregnancy has received little attention. In this study we aimed to examine the associations between SEP and 2 forms of maternal cortisol regulation-diurnal slope and wakening response-across pregnancy. Furthermore, we aimed to assess whether these associations differed by the sex of the fetus. METHODS: A total of 217 pregnant women aged 18 to 40 years with singleton pregnancies participated. Women were excluded from participating if they were aged <18 or >40 years and if they were at risk for maternal or obstetric complications. Women provided information on socioeconomic characteristics of adults contributing to the participants' household to compute a Hollingshead Four Factor Index of Social Status score of SEP. Women provided salivary cortisol samples on awakening, 30 minutes after wakeup, and at bedtime, at 3 times over pregnancy and once 30 days postpartum to calculate the diurnal slope and cortisol awakening response (CAR). Using linear regression analyses, we examined the relationships between maternal SEP and maternal diurnal slope and CAR. We explored the relationships between maternal SEP and cortisol by fetal sex using linear regression analyses. We also explored links between maternal SEP, maternal cortisol, and infant birth outcomes. FINDINGS: Women of lower SEP displayed smaller awakening responses and less change over the day compared with women of higher SEP. SEP was significantly associated with attenuated diurnal slope only among women carrying female fetuses, whereas for CAR, the association between SEP and attenuated CAR was significant only for women carrying male fetuses. Lower SEP was associated with decreased birthweight, and this association was partially explained by maternal HPA activity in pregnancy. IMPLICATIONS: Women of low SEP displayed attenuated HPA activity across the perinatal period, and patterns varied by fetal sex and cortisol metric. Findings are in need of replication. More research is needed to understand the links between SEP, HPA activity, and neonatal health. PMID- 26749220 TI - Pharmacokinetics, Safety, and Tolerability of Amygdalin and Paeoniflorin After Single and Multiple Intravenous Infusions of Huoxue-Tongluo Lyophilized Powder for Injection in Healthy Chinese Volunteers. AB - PURPOSE: Huoxue-Tongluo lyophilized powder for injection (HTLPI), a traditional Chinese medicine preparation, is a compound of Persicae semen and Paeoniae Radix Rubra that is used mainly for treating blood-stasis obstruction syndrome in the acute stage of cerebral ischemic stroke. Amygdalin (AD) and paeoniflorin (PF) are 2 typical bioactive components in HTLPI and were selected as indicators for this pharmacokinetic study of HTLPI. The objective of this study was to investigate the safety profile, tolerability, and pharmacokinetic properties of AD and PF after single and multiple intravenous infusions of HTLPI in healthy Chinese volunteers. METHODS: Twenty-one healthy Chinese subjects were recruited for this open-label, single ascending-dose (3, 6, and 9 g) and multiple-dose (6 g, once daily) study. Safety profile was assessed by adverse events and physical examination throughout the study. Serial plasma and urine samples were analyzed by HPLC-MS/MS. Pharmacokinetic parameters of AD and PF were calculated using noncompartmental analysis. FINDINGS: In the single-dose phase of the study, the mean maximum plasma concentration and the mean area under the plasma concentration-time curve of AD and PF increased proportionally with each dose escalation. In the multiple-dose phase, the steady state was achieved by day 4 after multiple-dose administration of 6 g HTLPI. Mean pharmacokinetic parameters achieved on day 1 were similar to those on day 7. No significant accumulation was observed after repeat doses of 6 g HTLPI. Approximately 79.6% of the administered AD and 48.4% of the administered PF were excreted unchanged in urine within 24 hours. No serious adverse events were observed during the entire study. IMPLICATIONS: The pharmacokinetic properties of AD and PF were linear after a single intravenous infusion of HTLPI in the dose range of 3-9 g. No systemic accumulation was observed with repeat doses of HTLPI. Sex had no significant effect on the pharmacokinetic properties of AD and PF. Intravenous infusion of HTLPI was well tolerated in healthy Chinese subjects. PMID- 26749221 TI - The impact of medical student surgical conferences. AB - BACKGROUND: Recent reports have shown that in the UK there has been a decrease in interest towards pursuing a surgical career, whereas early exposure to surgery may increase interest. We aimed to assess the effect of a 1-day medical school surgical conference in encouraging attendees to pursue a surgical career. METHODS: All attendees of the 2014 Barts and The London National Undergraduate Surgical conference were invited to participate in an online survey. Data were collected and analysed to evaluate students' reasons for attending the conference, and attitudes to careers in surgery before and after the conference. RESULTS: Of 229 students, 130 (56.8%) completed the survey. Year-12 high-school and preclinical medical students showed a statistically significant difference in interest in pursuing a surgical career after the conference than before it (p = 0.0002 and p = 0.0027, respectively), but clinical medical students demonstrated no such change. CONCLUSION: Attendance at surgical conferences designed for medical students can significantly increase the desire of high-school students and preclinical medical students to pursue a surgical career, but may not have the same effect for clinical medical students. Surgical conferences may act as an effective means of recruiting students towards choosing a surgical career for a certain subset of students. PMID- 26749222 TI - Multi-substrate biodegradation interaction of 1, 4-dioxane and BTEX mixtures by Acinetobacter baumannii DD1. AB - This study evaluated substrate interactions during the aerobic biodegradation of 1, 4-dioxane and BTEX mixtures by a pure culture, Acinetobacter baumannii DD1, which is capable of utilizing 1, 4-dioxane for growth. A. baumannii DD1 could utilize BTEX as a sole carbon source, but could not utilize m-xylene and p xylene. In binary mixtures, there was a lag of about 14 h before the degradation of BTE, and 1, 4-dioxane only started to be utilized when BTE was completely degraded by 1, 4-dioxane-grown DD1. Furthermore, the biodegradation rate of 1, 4 dioxane decreased from 73.33 to 40.74 mg/(h g dry weight) after the biodegradation of benzene. 1, 4-dioxane could not be degraded after the biodegradation of o-xylene in 80 h. DD1 could also not degrade m-xylene and p xylene coexisting with 1, 4-dioxane. The ability of DD1 to degrade BTEX occurred in the following order: benzene > ethylbenzene > toluene > o-xylene > m-xylene = p-xylene. The biodegradation of 1, 4-dioxane was not activated in the mixture with o-xylene, primarily because of the accumulation of the specific toxic intermediate, 2, 3-dimethylphenol. The lag in BTE degradation was presumably because of the induction of enzymes necessary for BTE degradation. Additionally, SDS-PAGE analysis demonstrated that there were different proteins during the degradation of benzene and 1, 4-dioxane. PMID- 26749223 TI - Impact of heat waves on nonaccidental deaths in Jinan, China, and associated risk factors. AB - An ecological study and a case-crossover analysis were conducted to evaluate the impact of heat waves on nonaccidental deaths, and to identify contributing factors of population vulnerability to heat-related deaths in Jinan, China. Daily death data and meteorological data were collected for summer months (June to August) of 2012-2013. Excess mortality was calculated and multivariate linear regression models were used to assess the increased risk of heat waves on deaths. Univariate and multivariate logistic regression models were performed to estimate the odd ratios (ORs) of risk factors and their 95 % confidence intervals (CIs). Overall, heat waves were related to 24.88 % excess deaths of total nonaccidental deaths and 31.33 % excess deaths of circulatory diseases, with an OR of 16.07 (95 % CI 8.80-23.33) for total nonaccidental deaths and 12.46 (95 % CI 7.39-17.53) for deaths of circulatory diseases. The case-crossover analysis indicated that older people were more likely to die during heat waves (OR = 1.233, 95 % CI 1.076 1.413) and more deaths occurred outside a hospital during heat waves (OR = 1.142, 95 % CI 1.006-1.296). In conclusion, heat waves have caused excess deaths and significantly increased the risk of circulatory deaths. The risk factors identified in our study have implications for public health interventions to reduce heat-related mortality during extreme heat events. PMID- 26749224 TI - Sediment characteristics and benthic ecological status in contrasting marine environments of subtropical Hong Kong. AB - Sediment characteristics and benthic communities on a finer sampling scale in four contrasting environments in subtropical Hong Kong were analyzed in summer and winter 2012. In two harbour habitats which suffered from historic sewage pollution or hypoxic events, organic carbon, nutrient and trace metal content in the sediment were significantly higher than that in an offshore area and a marine reserve. The relatively low organic and nutrient content in the offshore habitat could be resulted from enhanced resuspension of such materials from the seabed owing to intense water mixing and disturbance caused by bottom trawling. The biotic indices AMBI and M-AMBI were shown to be useful in assessing the benthic ecological status of these habitats. Such indices can also be more sensitive than sediment physico-chemical parameters in differentiating the response of macrofauna to seasonal changes in the benthic environment. PMID- 26749225 TI - Effect of enhanced reactive nitrogen availability on plant-sediment mediated degradation of polycyclic aromatic hydrocarbons in contaminated mangrove sediment. AB - As land-ocean interaction zones, mangrove systems receive substantial polycyclic aromatic hydrocarbons (PAHs) from sewage and combustion of fossil fuel. In this study, we investigated the relationship between dissolved inorganic nitrogen (DIN) availability and degradation rate of phenanthrene, a typical PAH compound, in mangrove plant-sediment systems, using Avicennia marina as a model plant. After 50 day incubation, phenanthrene removal ratios in sediments ranged from 53.8% to 97.2%. In non-rhizosphere sediment, increasing DIN accessibility increased microbial biomass and total microbial activity, while enhancements in population size of phenanthrene degradation bacteria (PDB) and phenanthrene degradation rates were insignificant. In contrast, the presence of excessive DIN in rhizosphere sediment resulted in a significantly large number of PDB, leading to a rapid dissipation rate of phenanthrene. The differences in degradation rates and abundances of degrader in sediment may be explained by the enhanced root activity due to the elevation in DIN accessibility. PMID- 26749227 TI - The antibacterial effect of sinoporphyrin sodium photodynamic therapy on Staphylococcus aureus planktonic and biofilm cultures. AB - BACKGROUND AND OBJECTIVES: Staphylococcus aureus (S. aureus) are important causes of nosocomial and medical-device-related infections. Photodynamic treatment (PDT) has been proposed as an alternative approach for the inactivation of bacteria. Sinoporphyrin sodium (DVDMS) is a newly identified photosensitizer and has high photo-sensitivity when used in PDT. This study aims to evaluate the antibacterial effect of DVDMS mediated PDT on S. aureus planktonic and biofilm cultures. STUDY DESIGN/MATERIALS AND METHODS: The uptake of DVDMS in S. aureus was evaluated according to photometry after alkali lysis. Then bacteria were incubated with DVDMS and exposed to light treatment. After PDT treatment, counting colony forming units (CFU) was applied to estimate the bactericidal effect. Intracellular reactive oxygen species (ROS) production was detected by flow cytometry. Scanning electron microscope (SEM) was performed to assess the disruption of biofilm. RESULTS: With the incubation time increased, the relative fluorescence intensity of DVDMS in bacteria increased and reached peak at 75 minutes. DVDMS alone did not produce significant toxicity compared with the untreated group, while, remarkable survival decrease was observed in PDT groups in a dose-dependent manner. More than 90% of the bacteria were effectively killed by the combined treatment of 2 uM DVDMS with 10 J/cm2 light irradiation, and 4 log reduction in CFU was observed after 5 uM DVDMS treatment followed by 100 J/cm2 light irradiation. Intracellular ROS level was significantly enhanced after PDT treatment. The disruption of biofilm was confirmed by SEM, suggesting DVDMS PDT effectively damaged the biofilm. CONCLUSION: These results indicate DVDMS-PDT presents significant bactericidal activity. PMID- 26749229 TI - GlideScope Video Laryngoscope for Difficult Intubation in Emergency Patients: a Quasi-Randomized Controlled Trial. AB - Macintosh direct laryngoscope has been the most widely used device for tracheal intubation. GlideScope video laryngoscope (GVL) has been recently introduced as an alternative device for performing intubation; however, its validity in emergency settings has not been thoroughly evaluated. The aim of this study was to compare Macintosh direct laryngoscope versus GVL for emergency endotracheal intubation. This quasi-randomized clinical trial was performed on 97 patients referred to Imam Reza Hospital whom all needed emergency intubation in 2011. Patients were divided into two groups of the easy airway and difficult airway; intubation was performed for patients with direct laryngoscopy or GVL. Then, the patients were evaluated in terms of demographic characteristics, successful intubation rate and intubation time. Data was analyzed by SPSS software 16. There was no significant difference in demographic characteristics of the patients in both easy airway and difficult airway groups who intubated with direct laryngoscopy and GVL methods (P>0.05). In difficult airway group, a significant difference was found in successful intubation at the first attempt (60.9% vs. 87.5%; P=0.036), overall intubation time (32.7 +/- 14.58 vs. 22.5+/-7.88; P<0.001) and first attempt intubation time (28.43 +/- 12.51 vs. 21.48+/-7.8; P=0.001) between direct laryngoscopy and GVL. These variables were not significantly different between two methods in easy airway group. According to the results, GVL can be a useful alternative to direct laryngoscopy in emergency situations and especially in cases with a difficult airway. PMID- 26749230 TI - Association of Metabolic Syndrome and Its Components with Knee Osteoarthritis. AB - The association of obesity and other metabolic conditions with osteoarthritis is under debate; however, a strong link between metabolic disturbances is suggested to contribute to increased incidences and progression of osteoarthritis. We examined the association of metabolic syndrome and its components with the incidence of knee osteoarthritis in Iranian population. A community-based study was conducted on a total of 625 Iranian volunteers with the complaint of knee pain. Weight-bearing and anteroposterior plain radiographs of both knees were taken on the day of admission. Metabolic syndrome was diagnosed using the modified Adult Treatment Panel III of the National Cholesterol Education Program criteria. Prevalence rates of metabolic syndrome were 22.5% in males and 11.6% in females (P=0.002). The prevalence rate of knee osteoarthritis was 20.0% in males and 43.8% of females (P<0.001). In both genders, osteoarthritis group had higher serum levels of triglyceride and systolic blood pressure in comparison with non osteoarthritis group. Women with osteoarthritis had higher Body Mass Index (BMI), however, this association was not observed in men. In females, the presence of osteoarthritis was significantly associated with the presence of metabolic syndrome, with the risk of metabolic syndrome in the osteoarthritis group at 2.187 fold the risk in the non-osteoarthritis group. But, the presence of osteoarthritis was not associated with metabolic syndrome in males. Metabolic syndrome mainly through high BMI is associated with knee osteoarthritis in the Iranian women, but neither metabolic syndrome nor any related components are associated with knee osteoarthritis in men. PMID- 26749228 TI - Attenuation of Hemodynamic Responses to Intubation by Gabapentin in Coronary Artery Bypass Surgery: a Randomized Clinical Trial. AB - A varieties of medications have been suggested to prevent hemodynamic instabilities following laryngoscopy and endotracheal intubation. This study was conducted to determine the beneficial effects of gabapentin on preventing hemodynamic instabilities associated with intubation in patients who were a candidate for coronary artery bypass surgery (CABG). This double blinded randomized, parallel group clinical trial was carried out on 58 normotensive patients scheduled for elective CABG under general anesthesia with endotracheal intubation in Shariati Hospital. Patients were randomly allocated to two groups of 29 patients that received 1200 mg of gabapentin in two dosages (600 mg, 8 hours before anesthesia induction and 600 mg, 2 hours before anesthesia induction) as gabapentin group or received talc powder as placebo (placebo group). Heart rate, mean arterial pressure, systolic and diastolic blood pressure were measured immediately before intubation, during intubation, immediately after intubation, 1 and 2 minutes after tracheal intubation. Inter-group comparisons significantly showed higher systolic and diastolic blood pressure, mean arterial pressure and heart rate immediately before intubation, during intubation, immediately after intubation, 1 and 2 minutes after tracheal intubation in the placebo group in comparison to gabapentin group. The median of anxiety verbal analog scale (VAS) at the pre-induction room in gabapentin and placebo groups were 2 and 4, respectively that was significantly lower in the former group (P. value =0.04 ); however, regarding median of pain score no difference was observed between them (P. value =0.07). Gabapentin (1200 mg) given preoperatively can effectively attenuate the hemodynamic response to laryngoscopy, intubation and also reduce preoperative related anxiety in patients who were a candidate for CABG. PMID- 26749226 TI - Codominant Role of Interferon-gamma- and Interleukin-17-Producing T Cells During Rejection in Full Facial Transplant Recipients. AB - Facial transplantation is a life-changing procedure for patients with severe composite facial defects. However, skin is the most immunogenic of all transplants, and better understanding of the immunological processes after facial transplantation is of paramount importance. Here, we describe six patients who underwent full facial transplantation at our institution, with a mean follow-up of 2.7 years. Seum, peripheral blood mononuclear cells, and skin biopsy specimens were collected prospectively, and a detailed characterization of their immune response (51 time points) was performed, defining 47 immune cell subsets, 24 serum cytokines, anti-HLA antibodies, and donor alloreactivity on each sample, producing 4269 data points. In a nonrejecting state, patients had a predominant T helper 2 cell phenotype in the blood. All patients developed at least one episode of acute cellular rejection, which was characterized by increases in interferon gamma/interleukin-17-producing cells in peripheral blood and in the allograft's skin. Serum monocyte chemotactic protein-1 level was significantly increased during rejection compared with prerejection time points. None of the patients developed de novo donor-specific antibodies, despite a fourfold expansion in T follicular helper cells at 1 year posttransplantation. In sum, facial transplantation is frequently complicated by a codominant interferon gamma/interleukin-17-mediated acute cellular rejection process. Despite that, medium-term outcomes are promising with no evidence of de novo donor-specific antibody development. PMID- 26749231 TI - Features of Childhood Acute Myeloid Leukemia in Iran: a Report from Double Center Study. AB - Acute Myeloblastic Leukemia is one of the important malignancies in children. For better managing the prognosis of this disease, there should be enough information about common features of this malignancy. The aim of this study was to evaluate these common features in children with Acute Myeloblastic Leukemia. A total of 104 eligible children less than 15-year-old have been referred from 2007-2011 to two referral centers for childhood malignancies. Basic epidemiological information recorded in checklists for each individual. Analyzes have been done by SPSS version 22. Out of patients, 57 cases were males (54.8%). The male/female ratio was 1.2. The mean age of patients was 6.5 +/- 4.3 years. The majority subtypes of patients were M3, M4, non-M3, and M2, respectively. The common molecular abnormalities were t (15;17) and inv (16). Of patients, 19.2% had an early relapse. The mean age of relapse in patients was 6.7 +/- 3.9 years. Sixty patients (57.7%) were alive, and 44 cases (42.3%) died during or after therapy. The three years overall survival rate of patients was 42% in this study. According to our data, AML has the same frequency as compared with data from developing countries. But different epidemiological characteristic was a lower rate of three years overall survival in patients. These data may serve the health authorities for more effective environmental and preventive measurements, purposeful allocation of resources for facilitating up-to-date diagnostic and treatment modalities, psychological support programs for respective family members and educational purposes. PMID- 26749232 TI - Dimensions of Quality of Life in Spinal Cord Injured Veterans of Iran: a Qualitative Study. AB - The purpose of this study was to shed light on the identification of themes and sub-themes of the quality of life (QOL) in Iranian veterans with spinal cord injury (SCI). Studies have reported decreased QOL in SCI patients which encompass all aspects of their life. Little is known about QOL in SCI veterans from Iran. The aim of this qualitative study was to identify related aspects of such patients through in-depth patient interviews. The present study was a qualitative study of content analysis. Sampling took place in the Veterans Department of Khatam-Al-Anbia Hospital and was objective focused in accordance with qualitative studies. The participants were 11 SCI veterans and 4 veteran spouses. The data was collected by means of in-depth interviews and the use of the constant comparison method. The five themes of QOL included social, economic, cultural, medical, and environmental resulted from 7530 primary codes. We noted 29 QOL sub themes. This article addresses different dimensions of QOL for SCI veterans. The current study suggests that the main aspects that should be evaluated in SCI veterans are the social, economic, cultural, medical, and environmental issues which affect their QOL. Moreover, participants put the most weight on their financial situation. PMID- 26749233 TI - Trans-Cutaneous Bilirubinometery versus Serum Bilirubin in Neonatal Jaundice. AB - Hyperbilirubinemia is a common problem in neonates and causes serious complications. Thus, serial measurements of bilirubin should be done. This assessment is done through two methods of laboratory measurement in serum sample and transcutaneous bilirubinometer. This descriptive study compared transcutaneous bilirubin assessment and laboratory serum bilirubin. Bilirubin level was assessed among 256 neonates admitted to the Qods Children's Hospital in Qazvin- Iran, because of neonatal indirect jaundice, through two methods of transcutaneous bilirubinometery from two sites of forehead and sternum and laboratory measurement of bilirubin in serum. The cases were non-hemolytic icteric term neonates weighing 2500 gram or more and had not received phototherapy or other treatments. Neonates with hemolytic forms of jaundice, sepsis and suspicious to metabolic disorders were excluded. Assessments by means of KJ-8000 transcutaneous bilirubinometer from two sites of forehead and sternum and through laboratory measurement of serum bilirubin were registered and analyzed. The results of the current study showed that there was a correlation of 0.82 between serum bilirubin and transcutaneous forehead bilirubin assessment and for the used device sensitivity of 0.844; specificity of 0.842, Youden Index of 0.709 and Shortest of 0.042 for a cut-off of 12.4 in bilirubin of participants. Furthermore, Likelihood Ratio positive and negative (LR) were 5.665 and 0.164, respectively and diagnostic Odds Ratio (LR+/LR-) was 34.56. Transcutaneous bilirubinometery can be considered as a reliable tool to assess bilirubin for the screening of neonatal jaundice in term neonates. PMID- 26749234 TI - The Intricate Expression of CC Chemokines in Glial Tumors: Evidence for Involvement of CCL2 and CCL5 but Not CCL11. AB - Chemokines are biologically active peptides involved in the pathogenesis of various pathologies including brain malignancies. They are amongst primitive regulators of the development of immune responses against malignant glial tumors. The present study aimed to examine the expression of CC chemokines in anaplastic astrocytoma and glioblastoma multiform patients at both mRNA and protein levels. Blood specimens in parallel with stereotactic biopsy specimens were obtained from 123 patients suffering from glial tumors and 100 healthy participants as a control. The serum levels of CCL2, CCL5, and CCL11 were measured by ELISA and stereotactic samples subjected to western and northern blotting methods for protein and mRNA, respectively. Demographic characteristics were also collected by a researcher-designed questionnaire. Results of the present study indicated that, however,CCL2 and CCL5 are elevated in serum and tumor tissues of patients suffering from a glial tumor at both mRNA and protein levels, the CCL11 was almost undetectable. According to the findings of the present investigation, it could presumably be reasonable to conclude that chemokines are good predictive molecules for expecting disease severity, metastasis, and response to treatment. PMID- 26749236 TI - Proptosis, Micrognathia, Low Set Ear and Chest Deformity in a Patient with Extra Marker Chromosome 22. AB - There is a number of syndromes, associated with proptosis, micrognathia, low-set ear and chest deformity. Herein, we report a 9-year-old female with such phenotype who was presented with a vaginal neuroma. The result of karyotype showed 47XX, with extra marker chromosome 22. Although such a manifestation had not been reported in the literature, it should be considered as a very rare manifestation of the disease. PMID- 26749235 TI - Evaluation of Magnesium Levels in Serum and Cerebrospinal Fluid of Patients with Febrile Convulsion Hospitalized in Bahrami Hospital in Tehran in 2010-2011. AB - Evaluation of magnesium levels in serum and cerebrospinal fluid of patients with febrile convulsion (FC) hospitalized in Bahrami hospital in Tehran in 2010-2011. In the past, decreased levels of magnesium in serum and CSF of patients with FC were reported. The purpose of this study was to identify the possible role of magnesium in febrile seizures in children. Identifying this condition, we may control seizures and also prevent subsequent convulsion. In this cross-sectional study, inclusion criteria were the existence of convulsion due to fever and exclusion criteria were having a known neurological disease which could induce a seizure, and children younger than one month. In each group (cases include children with febrile convulsion and controls include febrile children without convulsion), Mg was measured in blood, and cerebrospinal fluid of 90 children and then they were compared. The data were analyzed by SPSS (alpha=0.05). The mean serum and CSF levels of Mg in case and control groups were equal (P<0.87 and P<0.22 respectively). There was no difference between two groups in terms of sex, but mean age was significantly different (P<0.003). There was not an association between serum and CSF levels of magnesium and the presence of FC. Therefore, it's not suggested to measure the level of magnesium in serum or CSF in children with fever routinely. PMID- 26749237 TI - Primary Cutaneous Lymphoma-Associated Pseudoepitheliomatous Hyperplasia Masquerading as Squamous Cell Carcinoma in a Young Adult. AB - Primary cutaneous anaplastic large cell lymphoma is a T-cell malignancy with atypical CD30 positive lymphocytes. Pseudoepitheliomatous hyperplasia is an uncommon finding in primary cutaneous anaplastic large cell lymphoma, and may mimic squamous cell carcinoma as pseudomalignancy. Careful attention of a pathologist to correct diagnosis of pseudoepitheliomatous hyperplasia and its underlying causes will help physicians to avoid inappropriate management. Here, we present a 22-year-old man referred to our hospital with a solitary nodule persistent on his forearm which was diagnosed as squamous cell carcinoma in the first biopsy. The lesion recurred after two months and histopathologic and immunohistochemistry examination revealed anaplastic large cell lymphoma with florid pseudoepitheliomatous hyperplasia which masquerading as well differentiated squamous cell carcinoma. Diagnosis of pseudoepitheliomatous hyperplasia must guide the pathologist to search for underlying causes, such as primary cutaneous lymphoma. Pseudoepitheliomatous hyperplasia may mimic squamous cell carcinoma and this can result in inappropriate diagnosis and management. PMID- 26749238 TI - Yellow Nail Syndrome Associated with Pericarditis and Pericardial Effusion: a Case Report. AB - Yellow nail syndrome (YNS) is an uncommon condition characterized by nail changes, lymphedema, in addition to pulmonary disorders and pleural effusion. Pericarditis and non-cardiac disorders can evolve with pericardial effusions including autoimmune conditions, hypothyroidism, malignancies, tuberculosis, and uremia. A 72-year-old Brazilian woman under treatment for arterial hypertension and hypothyroidism was admitted with pericarditis and pericardial effusion concomitant with yellow nail syndrome. She denied tobacco smoking, alcohol abuse, and similar disorders in her family. Clinical and complementary evaluation ruled out infectious diseases, malignancies, and autoimmune disorders as etiologic factors in this case. Hypothyroidism is a well-known cause of pericardial effusion, the vast majority in the absence of pericarditis, and has been described as an associated condition in some individuals with YNS. Case studies might contribute to better understanding of these causal or casual relationships. PMID- 26749239 TI - Scar Endometriosis: a Case Report with Literature Review. AB - Endometriosis is defined as the presence of functioning endometrial tissue outside the uterine cavity. Endometriosis can sometimes occur in a previous surgical scar. Scar endometriosis is rare and difficult to diagnose. It mostly follows obstetrical and gynecological surgeries. This condition is often confused with other surgical conditions. We are reporting one case of scar endometriosis involving rectus sheath following cesarean section. The patient required wide surgical excision of the lesion. The pathogenesis, diagnosis, and treatment of this rare condition are being discussed. PMID- 26749240 TI - Microwave-Assisted Solvothermal Synthesis of VO2 Hollow Spheres and Their Conversion into V2O5 Hollow Spheres with Improved Lithium Storage Capability. AB - Monodispersed hierarchically structured V2O5 hollow spheres were successfully obtained from orthorhombic VO2 hollow spheres, which are in turn synthesized by a simple template-free microwave-assisted solvothermal method. The structural evolution of VO2 hollow spheres has been studied and explained by a chemically induced self-transformation process. The reaction time and water content in the reaction solution have a great influence on the morphology and phase structure of the resulting products in the solvothermal reaction. The diameter of the VO2 hollow spheres can be regulated simply by changing vanadium ion content in the reaction solution. The VO2 hollow spheres can be transformed into V2O5 hollow spheres with nearly no morphological change by annealing in air. The nanorods composed of V2O5 hollow spheres have an average length of about 70 nm and width of about 19 nm. When used as a cathode material for lithium-ion batteries, the V2O5 hollow spheres display a diameter-dependent electrochemical performance, and the 440 nm hollow spheres show the highest specific discharge capacity of 377.5 mAhg(-1) at a current density of 50 mAg(-1) , and are better than the corresponding solid spheres and nanorod assemblies. PMID- 26749243 TI - The Movement Disorders journal 2016 and onward. PMID- 26749242 TI - Spectrum of mucocutaneous manifestations in an Asian cohort of patients with leukemia. AB - BACKGROUND: Literature on cutaneous manifestations of leukemia is limited. OBJECTIVE: To determine the pattern of mucocutaneous manifestations in adult Asian patients with leukemia and to establish their relation with the leukemia type. SUBJECTS AND METHODS: After previous consent, 196 consecutively registered patients with leukemia aged >=18 years were recruited. All patients were prospectively followed for 3 months to evaluate the patterns of mucocutaneous involvement. The mucocutaneous manifestations were categorized into specific lesions with leukemic infiltration and non-specific lesions. RESULTS: Seventy nine (40.3%) of 196 (males 128 and females 68) recruited patients showed one or more mucocutaneous manifestations. The total number of complaints observed was 87 with mean number of dermatoses per patient being 0.44. Specific manifestations (leukemia cutis) were present in six (3.06%) and nonspecific mucocutaneous manifestations in 73 (37.2%, reactive dermatoses n = 21 and infections n = 52). Cutaneous viral infections were significantly associated with acute lymphoblastic leukemia (P < 0.005). Antiviral prophylaxis with acyclovir significantly reduced the incidence of varicella-zoster infection (P = 0.016). CONCLUSION: Cutaneous manifestations are common in Asian patients with leukemia, and a thorough cutaneous examination will aid in their management. PMID- 26749241 TI - Disease-Causing SDHAF1 Mutations Impair Transfer of Fe-S Clusters to SDHB. AB - SDHAF1 mutations cause a rare mitochondrial complex II (CII) deficiency, which manifests as infantile leukoencephalopathy with elevated levels of serum and white matter succinate and lactate. Here, we demonstrate that SDHAF1 contributes to iron-sulfur (Fe-S) cluster incorporation into the Fe-S subunit of CII, SDHB. SDHAF1 transiently binds to aromatic peptides of SDHB through an arginine-rich region in its C terminus and specifically engages a Fe-S donor complex, consisting of the scaffold, holo-ISCU, and the co-chaperone-chaperone pair, HSC20 HSPA9, through an LYR motif near its N-terminal domain. Pathogenic mutations of SDHAF1 abrogate binding to SDHB, which impairs biogenesis of holo-SDHB and results in LONP1-mediated degradation of SDHB. Riboflavin treatment was found to ameliorate the neurologic condition of patients. We demonstrate that riboflavin enhances flavinylation of SDHA and reduces levels of succinate and Hypoxia Inducible Factor (HIF)-1alpha and -2alpha, explaining the favorable response of patients to riboflavin. PMID- 26749244 TI - Effect of selective laser trabeculoplasty on corneal biomechanics. AB - PURPOSE: To evaluate the effect of selective laser trabeculoplasty (SLT) on ocular biomechanics as measured with the ocular response analyzer (ORA, AMETEK Inc. and Reichert Inc.). METHODS: In a prospective case series, 52 eyes of 52 patients (aged 66.6 +/- 9.6 years) with insufficient intraocular pressure (IOP) control despite maximum tolerated medical therapy underwent SLT (Solo(TM) SLT, Ellex Inc.) for further IOP reduction. Goldmann-correlated IOP (IOPg), corneal compensated IOP (IOPcc), corneal hysteresis (CH) and the corneal resistance factor (CRF) were measured with the ORA prior to and at least 4 weeks following SLT. RESULTS: IOPg decreased statistically significantly from 18.0 +/- 6.4 to 14.8 +/- 3.8 mmHg and IOPcc from 20.2 +/- 6.5 to 16.7 +/- 3.4 mmHg (p < 0.001). CH increased from 8.53 +/- 2.03 to 9.12 +/- 1.83 mmHg (p = 0.028) and CRF decreased from 9.58 +/- 2.18 to 9.1 +/- 2.1 mmHg (p = 0.037), which was statistically significant. Correcting the CH and CRF data for the influence of IOP reduction with a covariance analysis, however, resulted in an unchanged CH (IOPg adjusted: p = 0.318; IOPcc adjusted: p = 0.468) and CRF (IOPg adjusted: p = 0.320; IOPcc adjusted: p = 0.464) after SLT. CONCLUSION: Selective laser trabeculoplasty does not change corneal biomechanical properties as measured with the ORA in already pretreated patients with glaucoma. The measured increase in CH and decrease in CRF can be solely explained by IOP reduction. PMID- 26749245 TI - A practical hybrid model of application, integration, and competencies at interactive table conferences in histology (ITCH). AB - Significant changes have been implemented in the way undergraduate medical education is structured. One of the challenges for component courses such as histology in medical and dental curricula is to restructure and deliver training within new frameworks. This article describes the process of aligning the purpose and experience in histology laboratory to the goal of applying knowledge gained to team-based medical practice at Tulane University School of Medicine. Between 2011 and 2015, 711 medical students took either a traditional laboratory-based histology course (353 students) or a team-based hybrid histology course with active learning in laboratory (358 students). The key difference was in the laboratory component of the hybrid course - interactive table conferences in histology-during which students developed new competencies by working in teams, reviewing images, solving problems by applying histology concepts, and sharing learning. Content, faculty and online resources for microscopy were the same in both courses. More student-student and student-faculty interactions were evident during the hybrid course but student evaluation ratings and grades showed reductions following introduction of table conferences when compared to previous ratings. However, outcomes at National Board of Medical Examiners((r)) (NBME((r)) ) Subject Examination in Histology and Cell Biology showed significant improvement (72.4 +/- 9.04 and 76.44 +/- 9.36 for percent correct answers, traditional and hybrid courses, respectively, P < 0.0001). This model of table conferences to augment the traditional histology laboratory experience exemplifies the extent that restructuring enhancements can be used in currently taught courses in the undergraduate medical curriculum. Anat Sci Educ 9: 286-294. (c) 2016 American Association of Anatomists. PMID- 26749246 TI - The work engagement of nurses in multiple hospital sectors in Saudi Arabia: a comparative study. AB - AIM: To examine the differences in work engagement among nurses in Saudi Arabia and its relationship with personal characteristics across different hospital affiliations. BACKGROUND: Quality care requires an adequate supply of engaged nurses who are dedicated, energised and absorbed in their work. In the nursing profession, work engagement is of considerable importance, owing to the shortage of nurses and the continuing reduction in healthcare costs. METHOD: An analytic comparative cross-sectional design was used. Eight hospitals from three provinces and different affiliation types participated in the study. The Utrecht work engagement scale (UWES) was used to measure 980 nurses' work engagement. RESULTS: The findings indicate that nurses' total engagement scores were closer to the higher end of the Likert scale. The findings indicate generally high levels of work engagement, particularly regarding the element of dedication. Furthermore, the study shows significant differences in nurses' engagement among the various work settings and in nurses' age and experience. CONCLUSIONS: A number of nurses' personal characteristics have independent influences on their work engagement. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse leaders should acknowledge that a statement of professional nursing scope of practice is a necessity to encourage and fulfil engagement. PMID- 26749247 TI - The diversity of H3 loops determines the antigen-binding tendencies of antibody CDR loops. AB - Of the complementarity-determining regions (CDRs) of antibodies, H3 loops, with varying amino acid sequences and loop lengths, adopt particularly diverse loop conformations. The diversity of H3 conformations produces an array of antigen recognition patterns involving all the CDRs, in which the residue positions actually in contact with the antigen vary considerably. Therefore, for a deeper understanding of antigen recognition, it is necessary to relate the sequence and structural properties of each residue position in each CDR loop to its ability to bind antigens. In this study, we proposed a new method for characterizing the structural features of the CDR loops and obtained the antigen-binding ability of each residue position in each CDR loop. This analysis led to a simple set of rules for identifying probable antigen-binding residues. We also found that the diversity of H3 loop lengths and conformations affects the antigen-binding tendencies of all the CDR loops. PMID- 26749248 TI - In vitro and in vivo evaluation of the prebiotic effect of raw and roasted almonds (Prunus amygdalus). AB - BACKGROUND: Almonds contain considerable amounts of potential prebiotic components, and the roasting process may alter these components. The aim of this study was to compare the in vitro fermentation properties and in vivo prebiotic effect of raw and roasted almonds. RESULTS: In vitro, predigested raw and roasted almonds promoted the growth of Lactobacillus acidophilus (La-14) and Bifidobacterium breve (JCM 1192), and no significant differences were found between these two nuts. In a 4-week animal trial, daily intake of raw or roasted almonds promoted the population of Bifidobacterium spp. and Lactobacillus spp. and inhibited the growth of Enterococcus spp. in faeces and caecal contains of rats. Compared with roasted almonds, raw almonds had a greater bifidobacteria promotion effect. Besides, significantly higher beta-galactosidase activity and lower beta-glucuronidase and azoreductase activities in faeces or caecal contents of rats were observed with raw almonds than with roasted almonds. While, in terms of metabolic effects, the ingestion of roasted almonds resulted in significantly greater intestinal lipase activities. CONCLUSION: Both raw and roasted almonds exhibit potential prebiotic effects, including regulation of intestinal bacteria and improved metabolic activities. The roasting process may slightly reduce the prebiotic effects of almonds but significantly improve the metabolic effects PMID- 26749249 TI - Genotype/phenotype correlation in a female patient with 21q22.3 and 12p13.33 duplications. AB - Many chromosomal rearrangements that lead to copy-number gains or losses have been shown to cause distinctive and recognizable clinical phenotypes. Conventional cytogenetic analysis can detect many, but not all, rearrangements depending on its power of resolution. The wide use of whole-genome array-based comparative genomic hybridization (array-CGH) techniques has allowed the detection of novel syndromes and to establish genotype-phenotype correlations by delineating at high resolution the regions involved in specific chromosomal aberrations. We report on a two and half-year-old female patient with intellectual disability and distinctive phenotypic features resulting from a de novo duplication of about 0.3 Mb in 21q22.3 associated with duplication of about 0.3 Mb in 12p13.33. The patient's chromosomal abnormalities were identified at the cytogenetic molecular level, using SNP array analysis, while GTG banding technique revealed a normal karyotype. Clinical findings of the patient were compared with Down syndrome and 12p duplication syndrome. This study suggests that an area of contiguous genes on the distal part of chromosome 21 (21q22.3) contribute to the Down syndrome phenotype and indicates that genes in the distal region of 12p (12p13.33) account for many facial characteristics and hypotonia of trisomy 12p syndrome. PMID- 26749250 TI - Technical aspects of pediatric epilepsy surgery: Report of a multicenter, multinational web-based survey by the ILAE Task Force on Pediatric Epilepsy Surgery. AB - Surgical techniques may vary extensively between centers. We report on a web based survey aimed at evaluating the current technical approaches in different centers around the world performing epilepsy surgery in children. The intention of the survey was to establish technical standards. A request was made to 88 centers to complete a web-based survey comprising 51 questions. There were 14 questions related to general issues, 13 questions investigating the different technical aspects for children undergoing epilepsy surgery, and 24 questions investigating surgical strategies in pediatric epilepsy surgery. Fifty-two centers covering a wide geographic representation completed the questionnaire. The median number of resective procedures per center per year was 47. Some important technical practices appeared (>80% of the responses) such as the use of prophylactic antibiotics (98%), the use of high-speed drills for bone opening (88%), nonresorbable material for bone flap closure (85%), head fixation (90%), use of the surgical microscope (100%), and of free bone flaps. Other questions, such as the use of drains, electrocorticography (ECoG) and preoperative withdrawal of valproate, led to mixed, inconclusive results. Complications were noted in 3.8% of the patients submitted to cortical resection, 9.9% hemispheric surgery, 5% callosotomy, 1.8% depth electrode implantation, 5.9% subdural grids implantation, 11.9% hypothalamic hamartoma resection, 0.9% vagus nerve stimulation (VNS), and 0.5% deep brain stimulation. There were no major differences across regions or countries in any of the subitems above. The present data offer the first overview of the technical aspects of pediatric epilepsy surgery worldwide. Surprisingly, there seem to be more similarities than differences. That aside many of the evaluated issues should be examined by adequately designed multicenter randomized controlled trials (RCTs). Further knowledge on these technical issues might lead to increased standardization and lower costs in the future, as well as definitive practice guidelines. PMID- 26749251 TI - Getting fat from an inflamed relationship? The revenge of the holobiont. PMID- 26749253 TI - Binary Zinc Azides. AB - Pure, solvent-free Zn(N3 )2 was prepared by reaction of diethyl zinc and hydrazoic acid in aprotic solvents. The single-crystal structure determination, along with the comprehensive characterization of alpha-Zn(N3 )2 and two metastable polymorphs, could be achieved for the first time. Since these data disagree in large parts with the known, previously reported values, all previous syntheses of Zn(N3 )2 , and for comparison Zn(N3 )2 ?2.5 H2 O and Zn(OH)N3 were reinvestigated, indicating that some of the earlier work has to be revised. PMID- 26749254 TI - Left Ventricular Assist Device and Bariatric Surgery: A Bridge to Heart Transplant by Weight and Waiting Time Reduction. AB - Obesity poses significant challenges in advanced heart failure patients who otherwise meet criteria for listing for heart transplant. We present a patient who underwent bariatric surgery while on LVAD support that subsequently lost weight and was successfully bridged to heart transplantation. PMID- 26749252 TI - Novel combination of serum microRNA for detecting breast cancer in the early stage. AB - MicroRNA (miRNA), which are stably present in serum, have been reported to be potentially useful for detecting cancer. In the present study, we examined the expression profiles of serum miRNA in several large cohorts to identify novel miRNA that can be used to detect early stage breast cancer. We comprehensively evaluated the serum miRNA expression profiles using highly sensitive microarray analysis. A total of 1280 serum samples of breast cancer patients stored in the National Cancer Center Biobank were used. In addition, 2836 serum samples were obtained from non-cancer controls, 451 from patients with other types of cancers, and 63 from patients with non-breast benign diseases. The samples were divided into a training cohort including non-cancer controls, other cancers and breast cancer, and a test cohort including non-cancer controls and breast cancer. The training cohort was used to identify a combination of miRNA that could detect breast cancer, and the test cohort was used to validate that combination. miRNA expressions were compared between patients with breast cancer and non-breast cancer, and a combination of five miRNA (miR-1246, miR-1307-3p, miR-4634, miR 6861-5p and miR-6875-5p) was found to be able to detect breast cancer. This combination had a sensitivity of 97.3%, specificity of 82.9% and accuracy of 89.7% for breast cancer in the test cohort. In addition, this combination could detect early stage breast cancer (sensitivity of 98.0% for Tis). PMID- 26749255 TI - Orchestration of hydrogen peroxide and nitric oxide in brassinosteroid-mediated systemic virus resistance in Nicotiana benthamiana. AB - Brassinosteroids (BRs) play essential roles in modulating plant growth, development and stress responses. Here, involvement of BRs in plant systemic resistance to virus was studied. Treatment of local leaves in Nicotiana benthamiana with BRs induced virus resistance in upper untreated leaves, accompanied by accumulations of H2O2 and NO. Scavenging of H2O2 or NO in upper leaves blocked BR-induced systemic virus resistance. BR-induced systemic H2O2 accumulation was blocked by local pharmacological inhibition of NADPH oxidase or silencing of respiratory burst oxidase homolog gene NbRBOHB, but not by systemic NADPH oxidase inhibition or NbRBOHA silencing. Silencing of the nitrite-dependent nitrate reductase gene NbNR or systemic pharmacological inhibition of NR compromised BR-triggered systemic NO accumulation, while local inhibition of NR, silencing of NbNOA1 and inhibition of NOS had little effect. Moreover, we provide evidence that BR-activated H2O2 is required for NO synthesis. Pharmacological scavenging or genetic inhibiting of H2O2 generation blocked BR-induced systemic NO production, but BR-induced H2O2 production was not sensitive to NO scavengers or silencing of NbNR. Systemically applied sodium nitroprusside rescued BR induced systemic virus defense in NbRBOHB-silenced plants, but H2O2 did not reverse the effect of NbNR silencing on BR-induced systemic virus resistance. Finally, we demonstrate that the receptor kinase BRI1(BR insensitive 1) is an upstream component in BR-mediated systemic defense signaling, as silencing of NbBRI1 compromised the BR-induced H2O2 and NO production associated with systemic virus resistance. Together, our pharmacological and genetic data suggest the existence of a signaling pathway leading to BR-mediated systemic virus resistance that involves local Respiratory Burst Oxidase Homolog B (RBOHB)-dependent H2O2 production and subsequent systemic NR-dependent NO generation. PMID- 26749257 TI - Reduced evoked motor and sensory potential amplitudes in obstructive sleep apnea patients. AB - It is unknown to what extent chronic intermittent hypoxaemia in obstructive sleep apnea causes damage to the motor and sensory peripheral nerves. It was hypothesized that patients with obstructive sleep apnea would have bilaterally significantly impaired amplitudes of both motor and sensory peripheral nerve evoked potentials of both lower and upper limbs. An observational study was conducted on 43 patients with obstructive sleep apnea confirmed by the whole night polysomnography, and 40 controls to assess the relationship between obstructive sleep apnea and peripheral neuropathy. All obstructive sleep apnea subjects underwent standardized electroneurographic testing, with full assessment of amplitudes of evoked compound muscle action potentials, sensory neural action potentials, motor and sensory nerve conduction velocities, and distal motor and sensory latencies of the median, ulnar, peroneal and sural nerves, bilaterally. All nerve measurements were compared with reference values, as well as between the untreated patients with obstructive sleep apnea and control subjects. Averaged compound muscle action potential and sensory nerve action potential amplitudes were significantly reduced in the nerves of both upper and lower limbs in patients with obstructive sleep apnea compared with controls (P < 0.001). These results confirmed that patients with obstructive sleep apnea had significantly lower amplitudes of evoked action potentials of both motor and sensory peripheral nerves. Clinical/subclinical axonal damage exists in patients with obstructive sleep apnea to a greater extent than previously thought. PMID- 26749256 TI - Hoarding in Youth with Autism Spectrum Disorders and Anxiety: Incidence, Clinical Correlates, and Behavioral Treatment Response. AB - This study examined the nature and correlates of hoarding among youth with autism spectrum disorders (ASD). Forty children with ASD and a comorbid anxiety disorder were administered a battery of clinician-administered measures assessing presence of psychiatric disorders and anxiety severity. Parents completed questionnaires related to child hoarding behaviors, social responsiveness, internalizing and externalizing behaviors, and functional impairment. We examined the impact of hoarding behaviors on treatment response in a subsample of twenty-six youth who completed a course of personalized cognitive-behavioral therapy targeting anxiety symptoms. Hoarding symptoms were common and occurred in a clinically significant manner in approximately 25 % of cases. Overall hoarding severity was associated with increased internalizing and anxiety/depressive symptoms, externalizing behavior, and attention problems. Discarding items was associated with internalizing and anxious/depressive symptoms, but acquisition was not. Hoarding decreased following cognitive-behavioral therapy but did not differ between treatment responders and non-responders. These data are among the first to examine hoarding among youth with ASD; implications of study findings and future directions are highlighted. PMID- 26749259 TI - Response to correspondence: Flow cytometric quantification of neutrophil extracellular traps: Limitations of the methodological approach by Ciepiela et al. PMID- 26749258 TI - Helicobacter pylori infection in patients with selective immunoglobulin a deficiency. AB - Selective immunoglobulin A (IgA) deficiency (IgAD) is the most common primary immunodeficiency in the western world. The aim of the study was to investigate the prevalence and clinical characteristics of Helicobacter pylori-infected dyspeptic patients with IgAD. Case samples were drawn from all subjects >= 12 years of age (n = 104729) who had undergone serum total IgA measurements during 2004-14 for any reason at Leumit Healthcare Services (Israel) and had serum total IgA < 0.07 g/l. The control group was comprised of a random sample of remaining patients with a case-control ratio of 10 controls for each case. The dyspeptic diseases were identified and retrieved from Leumit Health Care Services electronic database using specific ICD-9-CM diagnostic codes. The case group included 347 subjects and the control group 3470 subjects. There were no significant differences in the prevalence of patients with dyspepsia [84 (24.2%) versus 821 (23.6%) for cases and controls, respectively]. Additionally, there was no difference in a proportion of dyspeptic H. pylori-positive subjects [59 (17.1%) versus 524 (15.1%)] between the case and control groups. Only 59 (17%) among the 347 IgAD patients underwent gastroscopy. A significantly larger proportion of case subjects experienced several forms of gastritis [13 (61.9%) versus 38 (21.6%), P < 0.001), duodenal ulcers [seven (33.3%) versus 19 (10.8%); P = 0.01] and nodular lymphoid hyperplasia (NLH) [two (9.5%) versus none; P = 0.011]. IgAD is not associated with increased prevalence of H. pylori-associated dyspepsia; nevertheless, H. pylori-infected dyspeptic IgAD subjects experience more EGD-proved gastritis, duodenal ulcers and NLH. PMID- 26749260 TI - Bileaflet Mitral Valve Prolapse and Risk of Ventricular Dysrhythmias and Death. AB - INTRODUCTION: Bileaflet mitral valve prolapse (BiMVP) is common among survivors of otherwise unexplained sudden cardiac death, but prognostic implications of BiMVP are unknown. This study evaluated whether patients with BiMVP are at higher risk for ventricular dysrhythmias, ICD placement, or death compared to controls with either single-leaflet mitral valve prolapse (SiMVP) or no mitral valve prolapse (MVP). METHODS AND RESULTS: This retrospective, matched cohort study included 18,786 patients who underwent echocardiography at Mayo Clinic between June 1990 and September 2014. The study included three cohorts: BiMVP, SiMVP, and controls without MVP. We assessed rates of ventricular dysrhythmias, ICD placement, and all-cause mortality between groups. BiMVP was associated with higher rates of ventricular tachycardia compared to SiMVP and controls (adjusted HR 1.48 [1.14-1.92], P = 0.003 and 1.40 [1.04-1.88], P = 0.026, respectively); however, there were no statistically significant differences in rates of ventricular fibrillation/cardiac arrest or ICD placement between groups. BiMVP was associated with a lower rate of all-cause mortality compared to SiMVP and controls (adjusted HR 0.86 [0.79-0.94], P = 0.0008, and 0.55 [0.50-0.60], P < 0.0001, respectively). CONCLUSION: Although BiMVP is associated with ventricular tachycardia, it is not associated with an increased risk of cardiac arrest/ventricular fibrillation or ICD implantation and is, paradoxically, associated with a better survival compared to SiMVP or matched controls. The findings suggest that, despite its association with ventricular tachycardia, BiMVP in the absence of other risk factors does not seem to portend a poor prognosis at the population level. PMID- 26749262 TI - An Approach for the Selective Detection of Nitric Oxide in Biological Systems: An in vitro and in vivo Perspective. AB - A naphthalimide-based fluorescent probe, LyNP-NO, was designed and synthesized for the selective detection of exogenously and endogenously generated nitric oxide (NO) in C6 glial cells. In addition, LyNP-NO was also explored for monitoring endogenous NO levels in rat hippocampus at various tissue depths by stimulating the brain with N-methyl-d-aspartate (NMDA). PMID- 26749263 TI - Emergency laparoscopic repair of an incarcerated obturator hernia--a video vignette. PMID- 26749261 TI - First trimester screening cut-offs for noninvasive prenatal testing as a contingent screen: Balancing detection and screen-positive rates for trisomy 21. AB - OBJECTIVE: To provide data on how screen-positive and detection rates of first trimester prenatal screening for fetal Down syndrome vary with changes in the risk cut-off and maternal age to inform contingency criteria for publicly funded noninvasive prenatal testing. MATERIALS AND METHODS: First trimester screening and diagnostic data were collected for all women attending for first trimester fetal aneuploidy screening in Western Australia between 2005 and 2009. Prenatal screening and diagnostic data were linked to pregnancy outcomes, including data from the Midwives' Notification System and the Western Australian Registry of Developmental Anomalies. The prevalence of Down syndrome and performance of screening by risk cut-off and/or for women >35 years were analysed. RESULTS: The current screening risk cut-off of 1:300 has screen-positive and detection rates of 3.5% and 82%. The screen-positive rate increases by 0.7-0.8% for each 100 point change in risk, up to 19.2% at 1:2500 (96% detection rate). Including all women >35 years as screen positive would increase the screen-positive rate and detection rates to 30.2% and 97.2%. CONCLUSION: Variation in screening risk cut off and the use of maternal age to assess eligibility for noninvasive testing could significantly impact the demand for, and cost of, the test. A contingent first trimester screening approach for risk assessment is superior to the use of a combination of screening and maternal age alone. These data will inform decisions regarding the criteria used to determine eligibility for publicly funded noninvasive prenatal testing. PMID- 26749264 TI - Expanding the Landscape of Diterpene Structural Diversity through Stereochemically Controlled Combinatorial Biosynthesis. AB - Plant-derived diterpenoids serve as important pharmaceuticals, food additives, and fragrances, yet their low natural abundance and high structural complexity limits their broader industrial utilization. By mimicking the modularity of diterpene biosynthesis in plants, we constructed 51 functional combinations of class I and II diterpene synthases, 41 of which are "new-to-nature". Stereoselective biosynthesis of over 50 diterpene skeletons was demonstrated, including natural variants and novel enantiomeric or diastereomeric counterparts. Scalable biotechnological production for four industrially relevant targets was accomplished in engineered strains of Saccharomyces cerevisiae. PMID- 26749265 TI - Cell adhesion and polarity in squamous cell carcinoma of the lung. AB - Lung cancer is a deadly disease that can roughly be classified into three histopathological groups: lung adenocarcinomas, lung squamous cell carcinomas (LSCCs), and small cell carcinomas. These types of lung cancer are molecularly, phenotypically, and regionally diverse neoplasms, reflecting differences in their cells of origin. LSCCs commonly arise in the airway epithelium of a main or lobar bronchus, which is an important line of defence against the external environment. Furthermore, most LSCCs are characterized histopathologically by the presence of keratinization and/or intercellular bridges, consistent with the molecular features of these tumours, characterized by high levels of transcripts encoding keratins and proteins relevant to intercellular junctions and cell polarity. In this review, the relationships between the molecular features of LSCCs and the types of cell and epithelia of origin are discussed. Recurrent alterations in genes involved in intercellular adhesion and cell polarity in LSCCs are also reviewed, emphasizing the importance of the disruption of PAR3 and the PAR complex. Finally, the possible functional effects of these alterations on epithelial homeostasis, and how they contribute to the development of LSCC, are discussed. PMID- 26749266 TI - Acute effects of non-weathered and weathered crude oil and dispersant associated with the Deepwater Horizon incident on the development of marine bivalve and echinoderm larvae. AB - Acute toxicity tests (48-96-h duration) were conducted with larvae of 2 echinoderm species (Strongylocentrotus purpuratus and Dendraster excentricus) and 4 bivalve mollusk species (Crassostrea virginica, Crassostrea gigas, Mytilus galloprovincialis, and Mercenaria mercenaria). Developing larvae were exposed to water-accommodated fractions (WAFs) and chemically enhanced water-accommodated fractions (CEWAFs) of fresh and weathered oils collected from the Gulf of Mexico during the Deepwater Horizon incident. The WAFs (oils alone), CEWAFs (oils plus Corexit 9500A dispersant), and WAFs of Corexit alone were prepared using low energy mixing. The WAFs of weathered oils had no effect on survival and development of echinoderm and bivalve larvae, whereas WAFs of fresh oils showed adverse effects on larval development. Similar toxicities were observed for weathered oil CEWAFs and WAFs prepared with Corexit alone for oyster (C. gigas and C. virginica) larvae, which were the most sensitive of the tested invertebrate species to Corexit. Mean 10% effective concentration values for total polycyclic aromatic hydrocarbons and dipropylene glycol n-butyl ether (a marker for Corexit) in the present study were higher than all concentrations reported in nearshore field samples collected during and after the Deepwater Horizon incident. The results suggest that water-soluble fractions of weathered oils and Corexit dispersant associated with the Deepwater Horizon incident had limited, if any, acute impacts on nearshore larvae of eastern oysters and clams, as well as other organisms with similar sensitivities to those of test species in the present study; however, exposure to sediments and long-term effects were not evaluated. Environ Toxicol Chem 2016;35:2016-2028. (c) 2016 SETAC. PMID- 26749267 TI - Synthetic chimeras with orthogonal ribosomal proteins increase translation yields by recruiting mRNA for translation as measured by profiling active ribosomes. AB - In addition to their roles in protein biosynthesis, components of cellular ribosomes perform roles that contribute to a number of important cellular processes. Exploitation of processes has led to the use of ribosomal parts as solubility enhancer partners and purification matrices in protein expression. In this work, an engineered version of the E. coli ribosomal protein L29 (L4H2) as a fusion partner for enhancing cellular expression of proteins that are poorly expressed in bacteria was exploited. It was demonstrated that a chimeric fusion of L4H2 with various Fcgamma receptors increases total expression up to 3.2-fold, relative to Fcgamma receptors expressed without the fusion. Mechanistic insights using a novel application of in vivo ribosome display suggested that, although total cellular mRNA levels of L4H2-Fcgamma receptor remained unchanged relative to wild-type Fcgamma receptors, mRNA levels of actively translated L4H2-Fcgamma transcript increased about 3.8-fold relative to actively translated levels of wild-type Fcgamma transcript. Similar increases in protein expression in the context of the other proteins tested, showing the generality of this approach for proteins beyond human receptors was observed. These results extended the number of potential schemes by which orthogonal ribosomal parts can be used to enhance complex protein expression in bacterial platforms. Within a larger scope, this study features the possibility of engineering 5' tags that enhance mRNA affinity to ribosomes as strategies to augment translation. It was envisioned that the successful application of profiling active ribosomes in a highly targeted manner could be beneficial for mechanistic translation studies concerning synthesis of target proteins. (c) 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:285-293, 2016. PMID- 26749269 TI - Colonic adenocarcinoma encasing the femoral nerve: complete surgical excision with preservation of function. PMID- 26749270 TI - Ulcerated draining plaque below stoma. PMID- 26749268 TI - Review on clinical update of essential tremor. AB - Essential tremor (ET) is considered a benign disease without any pathological changes. Nevertheless, this point of view has recently been challenged. In recent years, studies have shown that ET occurs with other non-motor symptoms, such as cognitive deficits, depression, anxiety, balance disorder, hearing impairment, olfactory dysfunction and sleep problems. Advancements in neuroimaging have revealed widespread alterations in the brain, and cerebellar involvement was the most consistent finding. In addition, studies have also shown that ET patients might experience poor quality of life, reflecting motor or non-motor symptoms. Both pharmacotherapy and non-pharmacotherapy have recently been suggested for the treatment of ET. This review briefly describes the current information on ET, including the non-movement symptoms, neuroimaging findings, the impact on daily life and ET therapy. PMID- 26749271 TI - Juxta-terminal Helix Unwinding as a Stabilizing Factor to Modulate the Dynamics of Transmembrane Helices. AB - Transmembrane helices of integral membrane proteins often are flanked by interfacial aromatic residues that can serve as anchors to aid the stabilization of a tilted transmembrane orientation. Yet, physical factors that govern the orientation or dynamic averaging of individual transmembrane helices are not well understood and have not been adequately explained. Using solid-state (2) H NMR spectroscopy to examine lipid bilayer-incorporated model peptides of the GWALP23 (acetyl-GGALW(LA)6 LWLAGA-amide) family, we observed substantial unwinding at the terminals of several tilted helices spanning the membranes of DLPC, DMPC, or DOPC lipid bilayers. The fraying of helix ends might be vital for defining the dynamics and orientations of transmembrane helices in lipid bilayer membranes. PMID- 26749272 TI - Investigating the use of Barrows Cards to improve self-management and reduce healthcare costs in adolescents with blood cancer: a pilot study. AB - AIM: To test if the Barrows Cards method improves adherence to immunosuppressive therapy self-management following hematopoietic stem-cell transplantation in adolescents affected by blood cancer and reduce costs. BACKGROUND: Chronically ill adolescents need to be helped to improve self-management, make sure they can confidently and safely manage therapy at home and reduce readmissions and costs. We identified the Barrows Cards method, originally used to test decision-making skills and critical thinking in medical students. In this pilot study, we tested the efficacy of the Barrows Cards Method in improving adhesion to immunosuppressive therapy in a group of adolescents following hematopoietic stem cell transplantation and analysed its cost-effectiveness. DESIGN: A mixed-method study. METHODS: The Barrows Cards method is an educational intervention based on the theory of problem-based learning that uses at least 15 cards specially designed to teach participants how to manage a specific problem. We piloted the Barrows cards method in terms of adherence to immunosuppressive therapy and self management in a group of 17 adolescents affected by blood cancer before being discharged. Participants were enrolled between 2013-2015. Activity Based Costing was used to analyse the cost-effectiveness. RESULTS: The Barrows Cards method significantly improved adherence to immunosuppressive therapy in blood cancer adolescents and reduced readmissions. We also showed how this method could significantly reduce healthcare costs. CONCLUSIONS: Further research is required, but the Barrows Cards method could be effectively used by nurses to improve self management in chronic patients and reduce health costs. PMID- 26749273 TI - Reply. PMID- 26749274 TI - The association between chronic periodontitis and vasculogenic erectile dysfunction: a systematic review and meta-analysis. AB - AIM: The purpose of this systematic review and meta-analysis was to explore the association between erectile dysfunction (ED) and chronic periodontitis (CP) in observational studies. MATERIALS AND METHODS: A literature search of PubMed, EMBASE and Cochrane up to and including May 22, 2015, was conducted by two independent reviewers. Statistical analysis was performed using Review Manager 5.3, and the results are expressed as odds ratios (ORs) together with 95% confidence intervals (CIs), as determined using a random effects model. Subgroup analysis was performed by age. RESULTS: Of the 250 potentially eligible articles, four studies, involving 38,111 cases and 174,807 controls, were included. Based on random effects meta-analysis, a significant association between CP and ED was identified (OR = 3.07, 95% CI: 1.87-5.05, p < 0.001). Sensitivity analysis was performed due to the presence of statistically extensive heterogeneity (I(2) = 98%). CONCLUSIONS: The results of this systematic review revealed a positive association between CP and ED; however, because the presence and extent of statistical heterogeneity limits the conclusiveness of our findings, larger and better-controlled studies of socially homogeneous populations as well as pathophysiological studies are required to confirm the relationship between CP and ED and to explore the biological mechanisms involved. PMID- 26749275 TI - The Effects of Smoking Bans on Self-Assessed Health: Evidence from Germany. AB - We examine the effects of smoking bans on self-assessed health in Germany taking into account heterogeneities by smoking status, gender and age. We exploit regional variation in the dates of enactment and dates of enforcement across German federal states. Using data from the German Socio-Economic Panel, our difference-in-differences estimates show that non-smokers' health improves, whereas smokers report no or even adverse health effects in response to bans. We find statistically significant health improvements especially for non-smokers living in households with at least one smoker. Non smokers' health improvements materialise largely with the enactment of smoking bans. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26749276 TI - Review of mammalogical research in the Guianas of northern South America. AB - Research on mammals in the Guianas of northern South America has had a checkered history. In this review, I summarize the notable contributions to mammalogical study in Guyana, Suriname and French Guiana. These studies began in the mid-18th century with the binomial nomenclature system of scientific classification created by the Swedish naturalist Carl Linnaeus, who described 23 species new to science based on holotype specimens from the Guianas. Notwithstanding popular accounts by amateur naturalists visiting this region, over the next 7 decades there was only sporadic taxonomic work done on Guianan mammals primarily by researchers at European museums. The first comprehensive biological exploration took place in the 1840s during a geographic survey of the boundaries of British Guiana. However, it was not until almost half a century later that scientific publications began to regularly document the increasing species diversity in the region, including the prodigious work of Oldfield Thomas at the British Museum of Natural History in London. Another lull in the study of mammals occurred in the mid-1910s to the early 1960s after which foreign researchers began to rediscover the Guianas and their pristine habitats. This biological renaissance is still ongoing and I give a prospectus on the direction of future research in one of the last frontiers of tropical rainforest. An initiative that would be greatly beneficial is the establishment of a university network in the Guianas with graduate-based research to develop a cadre of professional experts on biodiversity and evolution as seen in other countries of South America. PMID- 26749277 TI - Efficient gradient calibration based on diffusion MRI. AB - PURPOSE: To propose a method for calibrating gradient systems and correcting gradient nonlinearities based on diffusion MRI measurements. METHODS: The gradient scaling in x, y, and z were first offset by up to 5% from precalibrated values to simulate a poorly calibrated system. Diffusion MRI data were acquired in a phantom filled with cyclooctane, and corrections for gradient scaling errors and nonlinearity were determined. The calibration was assessed with diffusion tensor imaging and independently validated with high resolution anatomical MRI of a second structured phantom. RESULTS: The errors in apparent diffusion coefficients along orthogonal axes ranged from -9.2% +/- 0.4% to + 8.8% +/- 0.7% before calibration and -0.5% +/- 0.4% to + 0.8% +/- 0.3% after calibration. Concurrently, fractional anisotropy decreased from 0.14 +/- 0.03 to 0.03 +/- 0.01. Errors in geometric measurements in x, y and z ranged from -5.5% to + 4.5% precalibration and were likewise reduced to -0.97% to + 0.23% postcalibration. Image distortions from gradient nonlinearity were markedly reduced. CONCLUSION: Periodic gradient calibration is an integral part of quality assurance in MRI. The proposed approach is both accurate and efficient, can be setup with readily available materials, and improves accuracy in both anatomical and diffusion MRI to within +/-1%. Magn Reson Med 77:170-179, 2017. (c) 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. PMID- 26749279 TI - Erratum to: Promyelocytic leukemia protein enhances apoptosis of gastric cancer cells through Yes-associated protein. PMID- 26749278 TI - alpha-1-Antitrypsin detected by MALDI imaging in the study of glomerulonephritis: Its relevance in chronic kidney disease progression. AB - Idiopathic glomerulonephritis (GN), such as membranous glomerulonephritis, focal segmental glomerulosclerosis (FSGS), and IgA nephropathy (IgAN), represent the most frequent primary glomerular kidney diseases (GKDs) worldwide. Although the renal biopsy currently remains the gold standard for the routine diagnosis of idiopathic GN, the invasiveness and diagnostic difficulty related with this procedure highlight the strong need for new diagnostic and prognostic biomarkers to be translated into less invasive diagnostic tools. MALDI-MS imaging MALDI-MSI was applied to fresh-frozen bioptic renal tissue from patients with a histological diagnosis of FSGS (n = 6), IgAN, (n = 6) and membranous glomerulonephritis (n = 7), and from controls (n = 4) in order to detect specific molecular signatures of primary glomerulonephritis. MALDI-MSI was able to generate molecular signatures capable to distinguish between normal kidney and pathological GN, with specific signals (m/z 4025, 4048, and 4963) representing potential indicators of chronic kidney disease development. Moreover, specific disease-related signatures (m/z 4025 and 4048 for FSGS, m/z 4963 and 5072 for IgAN) were detected. Of these signals, m/z 4048 was identified as alpha-1 antitrypsin and was shown to be localized to the podocytes within sclerotic glomeruli by immunohistochemistry. alpha-1-Antitrypsin could be one of the markers of podocyte stress that is correlated with the development of FSGS due to both an excessive loss and a hypertrophy of podocytes. PMID- 26749281 TI - Investigation of FIH-1 and SOCS3 expression in KRAS mutant and wild-type patients with colorectal cancer. AB - Colorectal cancer (CRC) is a multistep process based on the accumulation of somatic mutations in genes such as APC and KRAS. Data on the presence of mutations in KRAS gene in CRC and its relationship with clinicopathological parameters and expression of genes involved in tumor progression are scarce. We unbiasedly examined the KRAS status in samples from 99 patients and its correlation with clinicopathological parameters such as age, sex, tumor location, lymph node metastasis, tumor stage, tumor grade, and vascular invasion. Consistent with reports of other researchers, 38.4 % of our samples harbored KRAS mutation in their genomes with preferential mutation in codon 12 (89.4 %). Nevertheless, unlike previous reports, we were not able to correlate KRAS status with clinicopathological parameters (P > 0.05) except for vascular invasion. Patients with KRAS mutation have more vascular invasion compared with patient having wild-type KRAS. Next, we investigated the expression of two tumor suppressor genes, factor-inhibiting hypoxia-inducible factor 1 (FIH-1) and suppressor of cytokine signaling (SOCS3), in both KRAS mutant and wild-type groups and looked for any correlation between their expression and clinicopathological parameters. Although the expression of both genes was not regular, none of the clinicopathological parameters were associated with the expressions of FIH-1 and SOCS3 at mRNA level (P > 0.05). However, decline in FIH 1 expression at protein level in KRAS mutant group was correlated with stage IV and grade 2 of tumor (P <= 0.05). Our results demonstrated that there is no or low correlation between KRAS status, FIH-1, and SOCS3 expression with epidemiologic and clinicpathological characteristics in CRC. PMID- 26749280 TI - MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells. AB - The Runx1 transcription factor, known for its essential role in normal hematopoiesis, was reported in limited studies to be mutated or associated with human breast tumor tissues. Runx1 increases concomitantly with disease progression in the MMTV-PyMT transgenic mouse model of breast cancer. Compelling questions relate to mechanisms that regulate Runx1 expression in breast cancer. Here, we tested the hypothesis that dysregulation of Runx1-targeting microRNAs (miRNAs) allows for pathologic increase of Runx1 during breast cancer progression. Microarray profiling of the MMTV-PyMT model revealed significant downregulation of numerous miRNAs predicted to target Runx1. One of these, miR 378, was inversely correlated with Runx1 expression during breast cancer progression in mice and in human breast cancer cell lines MCF7 and triple negative MDA-MB-231 that represent early- and late-stage diseases, respectively. MiR-378 is nearly absent in MDA-MB-231 cells. Luciferase reporter assays revealed that miR-378 binds the Runx1 3' untranslated region (3'UTR) and inhibits Runx1 expression. Functionally, we demonstrated that ectopic expression of miR-378 in MDA-MB-231 cells inhibited Runx1 and suppressed migration and invasion, while inhibition of miR-378 in MCF7 cells increased Runx1 levels and cell migration. Depletion of Runx1 in late-stage breast cancer cells resulted in increased expression of both the miR-378 host gene PPARGC1B and pre-miR-378, suggesting a feedback loop. Taken together, our study identifies a novel and clinically relevant mechanism for regulation of Runx1 in breast cancer that is mediated by a PPARGC1B-miR-378-Runx1 regulatory pathway. Our results highlight the translational potential of miRNA replacement therapy for inhibiting Runx1 in breast cancer. PMID- 26749282 TI - Evaluation of RIP1K and RIP3K expressions in the malignant and benign breast tumors. AB - Receptor-interacting protein kinase 1 (RIP1K) and RIP3K belong to RIPK family, which regulate cell survival and cell death. In the present investigation, the expression levels of RIP1K and RIP3K were evaluated in the 30 malignant, 15 benign, and 20 normal breast tissues, and their correlation with clinicopathological characteristics was also studied. The expression levels of RIP1K and RIP3K were determined, by western blot analysis. The relative RIP1K expression was significantly higher in the malignant and benign tumors when compared to those of normal tissues (P < 0.0001 and P < 0.001, respectively). However, the expression level of RIP3K was significantly lower in the malignant tumors than those of normal and benign values (P < 0.001 and P < 0.01, respectively). Positive significant correlation was found for RIP1K expression with tumor size (P < 0.001), grades (P < 0.0001), and c-erbB2 (P < 0.001), but negative significant correlation was detected with patient's age (P < 0.001), estrogen receptor (ER) (P < 0.001), progesterone receptor (PR) (P < 0.01), and P53 (P<0.01) status. RIP3K expression was significantly lower in the pre menopauses (P < 0.01), grade III (P < 0.05), ER-negative (P < 0.05), and c-erbB2 negative malignant tumors, but no correlation was detected with tumor size, PR, and P53 status. No significant correlation was observed for RIP1K and RIP3K expressions with Ki67 and Her2. Based on the present results, it is concluded that reduction of RIP3K expression in the malignant breast tumor might be an important evidence to support the antitumor activity of this enzyme in vivo. However, RIP1K expression was shown to be higher in the malignant breast tumors than those of normal and benign breast tissues, which probably designates as a poor prognostic factor. PMID- 26749283 TI - TIMP3 regulates osteosarcoma cell migration, invasion, and chemotherapeutic resistances. AB - Tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs) to limit degradation of the extracellular matrix. Low levels of TIMP3 have been demonstrated in cancer tissues at advanced clinical stages, with positive distant metastasis and chemotherapeutic resistance. We examined the role of TIMP3 in osteosarcoma (OS) cell invasiveness and chemoresistance. TIMP3 was overexpressed or knocked down in the human OS cell lines Saos2 and MG63. Cell migration and invasion capacities were then evaluated using Transwell assays, and resistance to cisplatin was assessed by CCK-8 assay and flow cytometry. Real-time PCR and western blotting were used to investigate activation of signaling pathways downstream of TIMP3. Overexpression of TIMP3 inhibited the migration and invasion of Saos2 and MG63 cells, while knockdown of TIMP3 had the opposite effect. Cell survival after exposure to cisplatin was inhibited by TIMP3 overexpression in both Saos2 and MG63 cells. Consistently, downregulation of TIMP3 gene expression significantly decreased the sensitivity of OS cells to cisplatin treatment. MMP1, MMP2, Bcl-2, and Akt1 were all downregulated following TIMP3 overexpression, while Bax and cleaved caspase-3 were upregulated. TIMP3 knockdown had opposite effects on the regulation of these genes. Taken together, our findings suggest TIMP3 as a new target for inhibition of OS progression and chemotherapeutic resistance. PMID- 26749285 TI - Effects of Medical Marijuana on Migraine Headache Frequency in an Adult Population. AB - STUDY OBJECTIVE: No clinical trials are currently available that demonstrate the effects of marijuana on patients with migraine headache; however, the potential effects of cannabinoids on serotonin in the central nervous system indicate that marijuana may be a therapeutic alternative. Thus, the objective of this study was to describe the effects of medical marijuana on the monthly frequency of migraine headache. DESIGN: Retrospective chart review. SETTING: Two medical marijuana specialty clinics in Colorado. PATIENTS: One hundred twenty-one adults with the primary diagnosis of migraine headache who were recommended migraine treatment or prophylaxis with medical marijuana by a physician, between January 2010 and September 2014, and had at least one follow-up visit. MEASUREMENTS AND RESULTS: The primary outcome was number of migraine headaches per month with medical marijuana use. Secondary outcomes were the type and dose of medical marijuana used, previous and adjunctive migraine therapies, and patient-reported effects. Migraine headache frequency decreased from 10.4 to 4.6 headaches per month (p<0.0001) with the use of medical marijuana. Most patients used more than one form of marijuana and used it daily for prevention of migraine headache. Positive effects were reported in 48 patients (39.7%), with the most common effects reported being prevention of migraine headache with decreased frequency of migraine headache (24 patients [19.8%]) and aborted migraine headache (14 patients [11.6%]). Inhaled forms of marijuana were commonly used for acute migraine treatment and were reported to abort migraine headache. Negative effects were reported in 14 patients (11.6%); the most common effects were somnolence (2 patients [1.7%]) and difficulty controlling the effects of marijuana related to timing and intensity of the dose (2 patients [1.7%]), which were experienced only in patients using edible marijuana. Edible marijuana was also reported to cause more negative effects compared with other forms. CONCLUSION: The frequency of migraine headache was decreased with medical marijuana use. Prospective studies should be conducted to explore a cause-and-effect relationship and the use of different strains, formulations, and doses of marijuana to better understand the effects of medical marijuana on migraine headache treatment and prophylaxis. PMID- 26749284 TI - E2F1: a promising regulator in ovarian carcinoma. AB - E2F is a family of transcription factors that recognized to regulate the expression of genes essential for a wide range of cellular functions, including cell cycle progression, DNA repair, DNA replication, differentiation, proliferation, and apoptosis. E2F1, the most classic member of the E2F family, exhibits a complex role in tumor development regulation. In recent years, a growing body of data suggested an intimate relationship between E2F1 and ovarian carcinoma. And E2F1 was well identified to play dual functions and serve as a useful prognostic indicator in ovarian carcinoma. However, the mechanism underlying E2F1 associated with ovarian carcinoma remains elusive. It is necessary to clarify the fundamental role of E2F1 in ovarian carcinoma. In this review, we tried to sum up the knowledge of E2F1, including its structure and related mechanism. We also attempt to absorb the research achievements and collect the mechanism of E2F1 in ovarian carcinoma. PMID- 26749287 TI - Surgical Management of Omphalophlebitis and Long Term Outcome in Calves: 39 Cases (2008-2013). AB - OBJECTIVE: To describe and evaluate the surgical management of omphalophlebitis and to report the short and long term outcomes in calves. STUDY DESIGN: Retrospective case series. ANIMALS: Calves (n = 39). METHODS: Medical records (2008-2013) of calves diagnosed with omphalophlebitis and that underwent surgical correction were reviewed. Short term (hospital discharge) and long term (>=6 months after surgery) survival rates were obtained. Descriptive statistics were used to describe the population and a Fisher's exact test was used to evaluate the relationship between clinical signs, surgical management, and outcome. RESULTS: Thirty-nine calves (median age 30 days) were included in the study. Eleven calves had septic arthritis associated with omphalophlebitis and 18 had evidence of liver abscesses on ultrasound. Complete surgical en bloc resection was achieved in 18 calves and umbilical vein marsupialization was performed on the other 21 calves. Thirty-five calves were discharged from the hospital and long term followup was obtained for 30 of them. Twenty-nine animals were performing according to the owner's expectation at least 6 months after surgery (14 for marsupialization and 15 for en bloc resection). A better prognosis was detected when en bloc resection was performed (100% survival); however, when marsupialization was performed, the prognosis was good (74%; P = .05). Septic arthritis had a significant negative effect on overall survival (P < .001). CONCLUSION: The overall survival is good with both surgical options, and even calves with liver involvement and septic arthritis associated can be successfully treated with a combination of long term antibiotics and umbilical vein marsupialization. PMID- 26749288 TI - Tetraspanin CD151 and integrin alpha6beta1 mediate platelet-enhanced endothelial colony forming cell angiogenesis. AB - ESSENTIALS: Platelet releasates (PRs) enhance endothelial colony forming cell (ECFC) angiogenesis. The impact of platelet membrane components on ECFC angiogenesis was studied by a tube formation assay. Platelets enhanced ECFC angiogenesis more potently than PR, via tetraspanin CD151 and integrin alpha6beta1. Optimal enhancement of ECFC angiogenesis by platelets requires both membrane proteins and PR. SUMMARY: BACKGROUND: Platelets promote angiogenesis of endothelial colony forming cells (ECFCs), with the underlying mechanisms not being fully understood. OBJECTIVE: To investigate if platelets regulate the angiogenic property of ECFCs via mechanisms beyond platelet-released angiogenic regulators. METHODS AND RESULTS: Endothelial colony forming cells were generated by ECFC-directed cell culture of peripheral blood mononuclear cells. Capillary like tube formation of ECFCs was assessed using a Matrigel assay. Platelets promoted ECFC tube formation in both basic and complete ECFC medium. Importantly, the ECFC angiogenic responses induced by platelets were stronger than those induced by platelet releasates. Thus, the branching points of ECFC tube formation (30.5 +/- 9.0/field, ECFC alone) were increased by platelet releasates (58.2 +/- 8.3/field) and even more profoundly by platelets (95.5 +/- 17.6/field), indicating that platelet membrane components also promoted ECFC tube formation. The latter was further supported by evidence that fixed platelets did enhance ECFC tube formation. Subsequent experiments revealed that the promotion was dependent on platelet-surface glycoproteins, as removal of sialic acid from platelet glycoproteins by neuraminidase abolished the enhancement. Furthermore, platelet-expressed, but not ECFC-expressed, CD151 was important for the enhancement, as pretreatment of platelets, but not ECFCs, with a CD151-blocking antibody attenuated the effect. Integrin alpha6beta1 on both ECFCs and platelets also participated in platelet-promoted tube formation, as integrin alpha6 or beta1 blockade of either cell type markedly or totally inhibited the phenomenon. Moreover, platelets exerted the enhancement via the Src-PI3K signaling pathway of ECFCs. CONCLUSION: Platelet-enhanced ECFC angiogenesis requires platelet tetraspanin CD151 and alpha6beta1 integrin, as well as ECFC alpha6beta1 integrin and Src-PI3K signaling. PMID- 26749286 TI - Gfi1, a transcriptional repressor, inhibits the induction of the T helper type 1 programme in activated CD4 T cells. AB - A transcriptional repressor Gfi1 promotes T helper type 2 (Th2) cell development and inhibits Th17 and inducible regulatory T-cell differentiation. However, the role of Gfi1 in regulating Th1 cell differentiation and the Th1-type immune response remains to be investigated. We herein demonstrate that Gfi1 inhibits the induction of the Th1 programme in activated CD4 T cells. The activated Gfi1 deficient CD4 T cells spontaneously develop into Th1 cells in an interleukin-12- and interferon-gamma-independent manner. The increase of Th1-type immune responses was confirmed in vivo in Gfi1-deficient mice using a murine model of nickel allergy and delayed-type hypersensitivity (DTH). The expression levels of Th1-related transcription factors were found to increase in Gfi1-deficient activated CD4 T cells. Tbx21, Eomes and Runx2 were identified as possible direct targets of Gfi1. Gfi1 binds to the Tbx21, Eomes and Runx2 gene loci and reduces the histone H3K4 methylation levels in part by modulating Lsd1 recruitment. Together, these findings demonstrate a novel regulatory role of Gfi1 in the regulation of the Th1-type immune response. PMID- 26749289 TI - Efficacy and safety of LY2963016 insulin glargine in patients with type 1 and type 2 diabetes previously treated with insulin glargine. AB - The safety and efficacy of LY2963016 insulin glargine (LY IGlar) and Lantus insulin glargine (IGlar), products with identical primary amino acid sequences, were assessed in subgroups of patients with type 1 (T1D, n = 452) or type 2 diabetes (T2D, n = 299) reporting prestudy IGlar treatment in 52-week open-label (ELEMENT-1) and 24-week double-blind (ELEMENT-2) studies. At randomization, patients transitioned from their prestudy IGlar to equivalent doses of LY IGlar or IGlar. Primary efficacy (change in glycated haemoglobin from baseline to 24 weeks), other efficacy and select safety outcomes of LY IGlar were compared with those of IGlar. Continuous data were analysed using analysis of covariance, categorical data by Fisher's exact test, and treatment comparisons for hypoglycaemia by Wilcoxon test. No statistically significant treatment differences were identified for efficacy and safety outcomes except for weight change (T1D), overall incidence of detectable insulin antibodies (T2D), and serious adverse events (T2D). These differences were neither consistently observed across both studies nor observed in the total study populations, and their magnitude suggests they were not clinically meaningful. LY IGlar and IGlar show similar efficacy and safety profiles in patients reporting prestudy IGlar treatment. PMID- 26749290 TI - Expression and modulation of neuroligin and neurexin in the olfactory organ of the cotton leaf worm Spodoptera littoralis. AB - Carboxylesterases are enzymes widely distributed within living organisms. In insects, they have been mainly involved in dietary metabolism and detoxification function. Interestingly, several members of this family called carboxylesterase like adhesion molecules (CLAMs) have lost their catalytic properties and are mainly involved in neuro/developmental functions. CLAMs include gliotactins, neurotactins, glutactins, and neuroligins. The latter have for binding partner the neurexin. In insects, the function of these proteins has been mainly studied in Drosophila central nervous system or neuromuscular junction. Some studies suggested a role of neuroligins and neurexin in sensory processing but CLAM expression within sensory systems has not been investigated. Here, we reported the identification of 5 putative CLAMs expressed in the olfactory system of the model pest insect Spodoptera littoralis. One neuroligin, Slnlg4-yll and its putative binding partner neurexin SlnrxI were the most expressed in the antennae and were surprisingly associated with olfactory sensilla. In addition, both transcripts were upregulated in male antennae after mating, known to modulate the sensitivity of the peripheral olfactory system in S. littoralis, suggesting that these molecules could be involved in sensory plasticity. PMID- 26749291 TI - The Four Cs of disaster partnering: communication, cooperation, coordination and collaboration. AB - Public, nonprofit and private organisations respond to large-scale disasters domestically and overseas. Critics of these assistance efforts, as well as those involved, often cite poor interorganisational partnering as an obstacle to successful disaster response. Observers frequently call for 'more' and 'better' partnering. We found important qualitative distinctions existed within partnering behaviours. We identified four different types of interorganisational partnering activities often referred to interchangeably: communication, cooperation, coordination and collaboration-the Four Cs. We derived definitions of the Four Cs from the partnering literature. We then tested them in a case study of the response to the 2010 Haiti earthquake. We suggest that the Four Cs are distinct activities, that organisations are typically strong or weak in one or more for various reasons, and that the four terms represent a continuum of increased interorganisational embeddedness in partnering activities. PMID- 26749292 TI - Salsolinol Up-Regulates Oxytocin Expression and Release During Lactation in Sheep. AB - Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) is a dopamine derived compound present in the central nervous system and pituitary gland. Several previous studies on lactating sheep and rats have reported that salsolinol plays a crucial role in the regulation of prolactin secretion. The present study investigated the effects of salsolinol, which was infused into the third ventricle of the brain, on oxytocin expression and release in lactating sheep, 48 h after weaning of 8-week-old lambs. Serial 30-min infusions of salsolinol and vehicle were performed at 30-min intervals from 10.00 to 15.00 h. Blood samples were collected every 10 min. The supraoptic nucleus (SON), paraventricular nucleus (PVN) and posterior pituitary were collected immediately after the experiment. Expression levels of mRNAs for oxytocin and peptidylglycine alpha-amidating monooxygenase (PAM), the terminal enzyme in the oxytocin synthesis pathway, were measured using a real-time polymerase chain reaction. Oxytocin peptide content in the posterior pituitary was measured by an enzyme linked immunosorbent assay, and plasma oxytocin concentration was measured by radioimmunoassay. Salsolinol treatment significantly up-regulated oxytocin and PAM gene expression in the SON (P < 0.01 and P < 0.05, respectively), PVN (P < 0.01 and P < 0.05, respectively) and posterior pituitary (P < 0.05 and P < 0.05, respectively). Oxytocin peptide content in the posterior pituitary and the area under the response curve of plasma oxytocin were significantly (P < 0.05 and P < 0.01, respectively) higher in salsolinol-treated sheep than in control animals. The present study shows for the first time that salsolinol stimulates oxytocin secretion during lactation in sheep. PMID- 26749293 TI - Zinc Oxide Nanoparticles Supported Lipase Immobilization for Biotransformation in Organic Solvents: A Facile Synthesis of Geranyl Acetate, Effect of Operative Variables and Kinetic Study. AB - The present study describes grafting of zinc oxide (ZnO) nanoparticles with polyethyleneimine (PEI) followed by modification with glutraldehyde used as the bridge for binding the enzyme to support. The prepared nanocomposites were then characterized using Fourier transform infrared spectroscopy, thermogravimetric analysis, and transmission electron microscopy, utilized for synthesis of geranyl acetate in n-hexane. Among all the three prepared nanocomposites (ZnO + PEI, ZnO + PEI + SAA, ZnO + PEI + GLU), Candida rugosa lipase immobilized on ZnO-PEI-GLU was found to be best for higher ester synthesis. The operating conditions that maximized geranyl acetate resulted in the highest yield of 94 % in 6 h, molar ratio of 0.1:0.4 M (geraniol/vinyl acetate) in the presence of n-hexane as reaction medium. Various kinetic parameters such as V max, K i(G), K m(G), and K m(VA) were determined using nonlinear regression analysis for order bi-bi mechanism. The kinetic study showed that reaction followed order bi-bi mechanism with inhibition by geraniol. Activation energy (E a ) was found to be lower for immobilized lipase (12.31 kJ mol(-1)) than crude lipase (19.04 kJ mol(-1)) indicating better catalytic efficiency of immobilized lipase. Immobilized biocatalyst demonstrated 2.23-fold increased catalytic activity than crude lipase and recycled 20 times. The studies revealed in this work showed a promising perspective of using low-cost nanobiocatalysts to overcome the well-known drawbacks of the chemical-catalyzed route. PMID- 26749294 TI - Effects of Chromosomal Integration of the Vitreoscilla Hemoglobin Gene (vgb) and S-Adenosylmethionine Synthetase Gene (metK) on epsilon-Poly-L-Lysine Synthesis in Streptomyces albulus NK660. AB - epsilon-Poly-L-lysine (epsilon-PL) is a widely used natural food preservative. To test the effects of the Vitreoscilla hemoglobin (VHb) and S-adenosylmethionine (SAM) on epsilon-PL synthesis in Streptomyces albulus NK660, the heterologous VHb gene (vgb) and SAM synthetase gene (metK) were inserted into the S. albulus NK660 chromosome under the control of the constitutive ermE* promoter. CO-difference spectrum analysis showed S. albulus NK660-VHb strain could express functional VHb. S. albulus NK660-VHb produced 26.67 % higher epsilon-PL and 14.57 % higher biomass than the wild-type control, respectively. Reversed-phase high-pressure liquid chromatography (RP-HPLC) results showed the overexpression of the metK gene resulted in increased intracellular SAM synthesis in S. albulus NK660-SAM, which caused increases of biomass as well as the transcription level of epsilon PL synthetase gene (pls). Results indicated that the expression of vgb and metK gene improved on epsilon-PL synthesis and biomass for S. albulus NK660, respectively. PMID- 26749296 TI - Production, Purification, and Biochemical Characterization of Thermostable Metallo-Protease from Novel Bacillus alkalitelluris TWI3 Isolated from Tannery Waste. AB - Protease enzymes in tannery industries have enormous applications. Seeking a potential candidate for efficient protease production has emerged in recent years. In our study, we sought to isolate proteolytic bacteria from tannery waste dumping site in Tamilnadu, India. Novel proteolytic Bacillus alkalitelluris TWI3 was isolated and tested for protease production. Maximum protease production was achieved using lactose and skim milk as a carbon and nitrogen source, respectively, and optimum growth temperature was found to be 40 degrees C at pH 8. Protease enzyme was purified using ammonium sulfate precipitation method and anion exchange chromatography. Diethylaminoethanol (DEAE) column chromatography and Sephadex G-100 chromatography yielded an overall 4.92-fold and 7.19-fold purification, respectively. The 42.6-kDa TWI3 protease was characterized as alkaline metallo-protease and stable up to 60 degrees C and pH 10. Ca(2+), Mn(2+), and Mg(2+) ions activated the protease, while Hg(2+), Cu(2+), Zn(2+), and Fe(2+) greatly inhibited it. Ethylenediaminetetraacetic acid (EDTA) inhibited TWI3 protease and was activated by Ca(2+), which confirmed that TWI3 protease is a metallo-protease. Moreover, this protease is capable of dehairing goat skin and also removed several cloth stains, which makes it more suitable for various biotechnological applications. PMID- 26749295 TI - Soluble Expression and Characterization of a New scFv Directed to Human CD123. AB - Leukemic cancer stem cells (LSCs), as a unique cell population in acute myeloid leukemia (AML) marked by CD123 overexpression, are thought to play a key role in relapsed AML after chemotherapy. Thus, CD123 is considered as a particularly important target candidate for antibody-derived diagnosis and therapy. In the present work, we constructed an immunized murine antibody phage display library and isolated the functional anti-CD123 Single-chain fragment variable (scFv) clones. We also introduced fusing variable light (VL) and heavy (VH) chains with a new 18-amino acid residue linker as an alternative to conventional linkers. CD123-specific phage clones were progressively enriched through 4 rounds of biopanning, validated by phage ELISA, and anti-CD123 scFv clones with highest affinity were produced in Escherichia coli. The expression and purification of soluble scFv were verified by Western blot, and the results were indicative of the functionality of our proposed linker. The purified scFv specifically recognized CD123 by ELISA and flow cytometry, without any cross-reactivity with other related cell markers. Affinity of anti-CD123 scFv was measured to be 6.9 * 10(-7) M, using the competitive ELISA. Our work, therefore, provides a framework for future studies involving biological functions and applications of our anti CD123 scFv. It also reveals the feasibility of high throughput methods to isolate biomarker-specific scFvs. PMID- 26749297 TI - Elucidating the Beneficial Effect of Corncob Acid Hydrolysate Environment on Lipid Fermentation of Trichosporon dermatis by Method of Cell Biology. AB - In present study, the beneficial effect of corncob acid hydrolysate environment on lipid fermentation of Trichosporon dermatis was elucidated by method of cell biology (mainly using flow cytometry and microscope) for the first time. Propidium iodide (PI) and rhodamine 123 (Rh123) staining showed that corncob acid hydrolysate environment was favorable for the cell membrane integrity and mitochondrial membrane potential of T. dermatis and thus made its lipid fermentation more efficient. Nile red (NR) staining showed that corncob acid hydrolysate environment made the lipid accumulation of T. dermatis slower, but this influence was not serious. Moreover, the cell morphology of T. dermatis elongated in the corncob acid hydrolysate, but the cell morphology changed as elliptical-like during fermentation. Overall, this work offers one simple and effective method to evaluate the influence of lignocellulosic hydrolysates environment on lipid fermentation. PMID- 26749298 TI - Mesoporous Manganese Oxide Catalyzed Aerobic Oxidative Coupling of Anilines To Aromatic Azo Compounds. AB - Herein we introduce an environmentally friendly approach to the synthesis of symmetrical and asymmetrical aromatic azo compounds by using air as the sole oxidant under mild reaction conditions in the presence of cost-effective and reusable mesoporous manganese oxide materials. PMID- 26749299 TI - Hydroxychloroquine Serum Concentrations and Flares of Systemic Lupus Erythematosus: A Longitudinal Cohort Analysis. AB - OBJECTIVE: To study the relationship between serum hydroxychloroquine (HCQ) concentrations and flares of systemic lupus erythematosus (SLE) in a longitudinal cohort of patients. METHODS: Patients who fulfilled >=4 American College of Rheumatology classification criteria for SLE and had been treated with HCQ for >6 months were studied. Blood was assayed for HCQ levels by tandem mass spectrometry. Patients were serially assessed for disease activity, using the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and flares (SELENA flares instrument). Comparison of the mean summated SLEDAI scores over time and rates of flares in groups with different HCQ levels was performed by the Kruskal-Wallis test. RESULTS: A total of 276 SLE patients were studied (93% women, mean +/- SD age 41.0 +/- 13.8 years). The proportion of patients with HCQ levels <10 (total noncompliance), 10-500 (subtherapeutic), and >500 ng/ml (therapeutic) was 11%, 77%, and 12%, respectively. HCQ levels correlated significantly with the prescribed dose but not with body weight or renal function. The prescribed HCQ dose also correlated significantly with baseline SLEDAI scores, indicating that higher doses were used for more active manifestations. After a mean +/- SD observation period of 32.5 +/- 5.5 months, the mean summated SLEDAI score and the incidence of SLE flares was not statistically different among patients with different baseline HCQ levels. In a subgroup of 73 patients with serologic and clinical remission and having therapeutic HCQ levels, a trend of lower disease activity and fewer incidences of flares was observed. CONCLUSION: Noncompliance and subtherapeutic serum HCQ levels were seen frequently in these SLE patients, which was partly due to the low prescribed dose. In patients in remission, higher HCQ concentrations were associated with a trend showing fewer flares over time. PMID- 26749300 TI - Sequential healing of onlay bone grafts using combining biomaterials with cross linked collagen in dogs. AB - OBJECTIVES: The aim of this study was to observe the sequential healing of onlay grafts in terms of the volumetric and histologic changes using different bone substances and absorbable membranes according to the presence of collagen cross linking. MATERIAL AND METHODS: Four groups involving onlay grafting with different materials were randomly assigned to both sides of the maxillae of 15 beagle dogs: (i) control group without any treatment; (ii) group NN, bovine hydroxyapatite incorporated into a non-cross-linked collagen matrix (BHC) + non cross-linked collagen membrane (NCCM); (iii) group NC, BHC + cross-linked collagen membrane (CCM); and (iv) group CC, porcine hydroxyapatite incorporated into a cross-linked collagen matrix + CCM. Radiographic and histological analyses were performed after three different healing periods: 4, 8 and 12 weeks. RESULTS: At week 4, the bone substances were well localized under the barrier membrane in groups NC and CC, while the bone substances became spread out and flattened in group NN. Similarly, the augmented height was significantly greater in groups NC and CC (2.55 and 2.51 mm, respectively; median) than in group NN (1.96 mm, P < 0.001, both). The percentages of newly formed bone were significantly higher at week 12 than at weeks 4 and 8 in all of the groups. The NCCM showed an earlier angiogenesis pattern than the CCM; however, earlier degradation was observed at week 12. CONCLUSION: Combining biomaterials with cross-linked collagen might contribute to maintaining its initial morphology with excellent biocompatibility in early healing period of lateral onlay grafts. PMID- 26749301 TI - Measurement of maximal isometric torque and muscle quality of the knee extensors and flexors in healthy 50- to 70-year-old women. AB - Muscle quality is defined as strength per unit muscle mass. The aim of this study was to measure the maximal voluntary isometric torque of the knee extensor and flexor muscle groups in healthy older women and to develop an index of muscle quality based on the combined knee extensor and flexor torque per unit lean tissue mass (LTM) of the upper leg. One hundred and thirty-six healthy 50- to 70 year-old women completed an initial measurement of isometric peak torque of the knee extensors and flexors (Con-Trex MJ; CMV AG, Dubendorf, Switzerland) that was repeated 7 days later. Subsequently, 131 women returned for whole- and regional body composition analysis (iDXATM ; GE Healthcare, Chalfont St Giles, Buckinghamshire, UK). Isometric peak torque demonstrated excellent within assessment reliability for both the knee extensors and flexors (ICC range: 0.991 1.000). Test-retest reliability was lower (ICC range: 0.777-0.828) with an observed mean increase of 5% in peak torque [6.2 (17.2) N m] on the second day of assessment (P<0.001). The relative mean decrease in combined isometric peak torque (-12.2%; P = 0.001) was double that of the relative, non-significant, median difference in upper leg LTM (-5.3%; P = 0.102) between those in the 5th and 6th decade. The majority of difference in peak isometric torque came from the knee extensors (15.1 N m, P<0.001 versus 2.4 N m, P = 0.234). Isometric peak torque normalized for upper leg LTM (muscle quality) was 8% lower between decades (P = 0.029). These findings suggest strength per unit tissue may provide a better indication of age-related differences in muscle quality prior to change in LTM. PMID- 26749302 TI - Plant community controls on short-term ecosystem nitrogen retention. AB - Retention of nitrogen (N) is a critical ecosystem function, especially in the face of widespread anthropogenic N enrichment; however, our understanding of the mechanisms involved is limited. Here, we tested under glasshouse conditions how plant community attributes, including variations in the dominance, diversity and range of plant functional traits, influence N uptake and retention in temperate grassland. We added a pulse of (15) N to grassland plant communities assembled to represent a range of community-weighted mean plant traits, trait functional diversity and divergence, and species richness, and measured plant and microbial uptake of (15) N, and leaching losses of (15) N, as a short-term test of N retention in the plant-soil system. Root biomass, herb abundance and dominant plant traits were the main determinants of N retention in the plant-soil system: greater root biomass and herb abundance, and lower root tissue density, increased plant (15) N uptake, while higher specific leaf area and root tissue density increased microbial (15) N uptake. Our results provide novel, mechanistic insight into the short-term fate of N in the plant-soil system, and show that dominant plant traits, rather than trait functional diversity, control the fate of added N in the plant-soil system. PMID- 26749304 TI - Future Global Change and Cognition. AB - The 11 articles in this issue explore how people respond to climate change and other global challenges. The articles pursue three broad strands of enquiry that relate (1) to the effects and causes of "skepticism" about climate change, (2) the purely cognitive challenges that are posed by a complex scientific issue, and (3) the ways in which climate change can be communicated to a wider audience. Cognitive science can contribute to understanding people's responses to global challenges in many ways, and it may also contribute to implementing solutions to those problems. PMID- 26749303 TI - Brief Report: Proatherogenic Cytokine Microenvironment in the Aortic Adventitia of Patients With Rheumatoid Arthritis. AB - OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk of developing cardiovascular disease (CVD) via mechanisms that have not yet been defined. Inflammatory pathways, in particular within the vascular adventitia, are implicated in the pathogenesis of primary CVD but could be amplified in RA at the local tissue level. The aim of this study was to examine the aortic adventitia of coronary artery disease (CAD) patients with or without RA to determine the cytokine profile contained therein. METHODS: Aortic adventitia and internal thoracic artery biopsy specimens obtained from 19 RA patients and 20 non-RA patients undergoing coronary artery bypass graft surgery were examined by immunohistochemistry. RESULTS: Interleukin-18 (IL-18), IL-33, and tumor necrosis factor (TNF) were expressed in aortic adventitia biopsy specimens from both groups, and expression of these cytokines was significantly higher in RA patients. In RA patients, IL-33 expression in endothelial cells correlated positively with the number of swollen joints, suggesting a link between the systemic disease state and the local vascular tissue microlesion. CONCLUSION: The presence of the proinflammatory cytokines IL-18, IL-33, and TNF may play a role in the inflammatory process within the adventitia that contributes to plaque formation and destabilization. In theory, the amplified expression of these cytokines may contribute to the known increased occurrence and severity of CAD in patients with RA. PMID- 26749305 TI - Correlations between Synaptic Initiation and Meiotic Recombination: A Study of Humans and Mice. AB - Meiotic recombination is initiated by programmed double strand breaks (DSBs), only a small subset of which are resolved into crossovers (COs). The mechanism determining the location of these COs is not well understood. Studies in plants, fungi, and insects indicate that the same genomic regions are involved in synaptic initiation and COs, suggesting that early homolog alignment is correlated with the eventual resolution of DSBs as COs. It is generally assumed that this relationship extends to mammals, but little effort has been made to test this idea. Accordingly, we conducted an analysis of synaptic initiation sites (SISs) and COs in human and mouse spermatocytes and oocytes. In contrast to our expectation, we observed remarkable sex- and species-specific differences, including pronounced differences between human males and females in both the number and chromosomal location of SISs. Further, the combined data from our studies in mice and humans suggest that the relationship between SISs and COs in mammals is a complex one that is not dictated by the sites of synaptic initiation as reported in other organisms, although it is clearly influenced by them. PMID- 26749306 TI - An Efficient Multiple-Testing Adjustment for eQTL Studies that Accounts for Linkage Disequilibrium between Variants. AB - Methods for multiple-testing correction in local expression quantitative trait locus (cis-eQTL) studies are a trade-off between statistical power and computational efficiency. Bonferroni correction, though computationally trivial, is overly conservative and fails to account for linkage disequilibrium between variants. Permutation-based methods are more powerful, though computationally far more intensive. We present an alternative correction method called eigenMT, which runs over 500 times faster than permutations and has adjusted p values that closely approximate empirical ones. To achieve this speed while also maintaining the accuracy of permutation-based methods, we estimate the effective number of independent variants tested for association with a particular gene, termed Meff, by using the eigenvalue decomposition of the genotype correlation matrix. We employ a regularized estimator of the correlation matrix to ensure Meff is robust and yields adjusted p values that closely approximate p values from permutations. Finally, using a common genotype matrix, we show that eigenMT can be applied with even greater efficiency to studies across tissues or conditions. Our method provides a simpler, more efficient approach to multiple-testing correction than existing methods and fits within existing pipelines for eQTL discovery. PMID- 26749307 TI - Maternal Modifiers and Parent-of-Origin Bias of the Autism-Associated 16p11.2 CNV. AB - Recurrent deletions and duplications at chromosomal region 16p11.2 are a major genetic contributor to autism but also associate with a wider range of pediatric diagnoses, including intellectual disability, coordination disorder, and language disorder. In order to investigate the potential genetic basis for phenotype variability, we assessed the parent of origin of the 16p11.2 copy-number variant (CNV) and the presence of additional CNVs in 126 families for which detailed phenotype data were available. Among de novo cases, we found a strong maternal bias for the origin of deletions (59/66, 89.4% of cases, p = 2.38 * 10(-11)), the strongest such effect so far observed for a CNV associated with a microdeletion syndrome. In contrast to de novo events, we observed no transmission bias for inherited 16p11.2 CNVs, consistent with a female meiotic hotspot of unequal crossover driving this maternal bias. We analyzed this 16p11.2 CNV cohort for the presence of secondary CNVs and found a significant maternal transmission bias for secondary deletions (32 maternal versus 14 paternal, p = 1.14 * 10(-2)). Of the secondary deletions that disrupted a gene, 82% were either maternally inherited or de novo (p = 4.3 * 10(-3)). Nine probands carry secondary CNVs that disrupt genes associated with autism and/or intellectual disability risk variants. Our findings demonstrate a strong bias toward maternal origin of 16p11.2 de novo deletions as well as a maternal transmission bias for secondary deletions that contribute to the clinical outcome on a background sensitized by the 16p11.2 CNV. PMID- 26749310 TI - Usefulness of stroke volume variation to assess blood volume during blood removal for autologous blood transfusion in pediatric patients. AB - BACKGROUND: Dynamic variables based on the heart-lung interaction induced by positive pressure ventilation have not been shown to be useful in assessing cardiac preload in pediatric patients. OBJECTIVE: To evaluate whether stroke volume variation (SVV) obtained from the FloTrac/Vigileo(TM) monitoring system can reflect a change in blood volume during the blood removal and fluid replacement protocol in acute normovolemic hemodilution (ANH). METHODS: Sixteen pediatric patients scheduled for elective cranioplasty were recruited. In the ANH protocol, 10 ml . kg(-1) blood removal and fluid replacement were performed. SVV, heart rate, mean blood pressure, and femoral venous pressure were recorded. Differences at four time points (T0: baseline, T1: 5 ml . kg(-1) blood loss, T2: 10 ml . kg(-1) blood loss, and T3: after fluid replacement) during ANH were compared. The blood volume (EBV) was estimated as 70 ml . kg(-1) at T0 and decreased to 60 ml . kg(-1) at T2. RESULTS: Of the 16 patients, four were excluded and 12 were analyzed. Significant differences in all of the parameters were observed between each time point. The SVV significantly increased after the blood removal and decreased after the fluid replacement (P < 0.01, Bonferroni adjustment). In addition, the increases in SVV during the blood removal, T0-T1 and T0-T2, were 70% +/- 40% and 159% +/- 91%, respectively. SVV showed a significant correlation with EBV during the blood removal in ANH (rs = -0.68, 95% confidence interval -0.73 to -0.63, P < 0.001). CONCLUSION: Stroke volume variation obtained from the FloTrac/Vigileo(TM) monitoring system revealed a strong correlation with EBV during ANH without surgical stimulation. The usefulness of this device as an indicator of cardiac preload under hypovolemic or normovolemic conditions in children during surgery remains to be determined. PMID- 26749308 TI - Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA. AB - We performed whole-genome sequencing (WGS) of 208 genomes from 53 families affected by simplex autism. For the majority of these families, no copy-number variant (CNV) or candidate de novo gene-disruptive single-nucleotide variant (SNV) had been detected by microarray or whole-exome sequencing (WES). We integrated multiple CNV and SNV analyses and extensive experimental validation to identify additional candidate mutations in eight families. We report that compared to control individuals, probands showed a significant (p = 0.03) enrichment of de novo and private disruptive mutations within fetal CNS DNase I hypersensitive sites (i.e., putative regulatory regions). This effect was only observed within 50 kb of genes that have been previously associated with autism risk, including genes where dosage sensitivity has already been established by recurrent disruptive de novo protein-coding mutations (ARID1B, SCN2A, NR3C2, PRKCA, and DSCAM). In addition, we provide evidence of gene-disruptive CNVs (in DISC1, WNT7A, RBFOX1, and MBD5), as well as smaller de novo CNVs and exon specific SNVs missed by exome sequencing in neurodevelopmental genes (e.g., CANX, SAE1, and PIK3CA). Our results suggest that the detection of smaller, often multiple CNVs affecting putative regulatory elements might help explain additional risk of simplex autism. PMID- 26749309 TI - Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2. AB - Congenital hereditary endothelial dystrophy 1 (CHED1) and posterior polymorphous corneal dystrophy 1 (PPCD1) are autosomal-dominant corneal endothelial dystrophies that have been genetically mapped to overlapping loci on the short arm of chromosome 20. We combined genetic and genomic approaches to identify the cause of disease in extensive pedigrees comprising over 100 affected individuals. After exclusion of pathogenic coding, splice-site, and copy-number variations, a parallel approach using targeted and whole-genome sequencing facilitated the identification of pathogenic variants in a conserved region of the OVOL2 proximal promoter sequence in the index families (c.-339_361dup for CHED1 and c.-370T>C for PPCD1). Direct sequencing of the OVOL2 promoter in other unrelated affected individuals identified two additional mutations within the conserved proximal promoter sequence (c.-274T>G and c.-307T>C). OVOL2 encodes ovo-like zinc finger 2, a C2H2 zinc-finger transcription factor that regulates mesenchymal-to epithelial transition and acts as a direct transcriptional repressor of the established PPCD-associated gene ZEB1. Interestingly, we did not detect OVOL2 expression in the normal corneal endothelium. Our in vitro data demonstrate that all four mutated OVOL2 promoters exhibited more transcriptional activity than the corresponding wild-type promoter, and we postulate that the mutations identified create cryptic cis-acting regulatory sequence binding sites that drive aberrant OVOL2 expression during endothelial cell development. Our data establish CHED1 and PPCD1 as allelic conditions and show that CHED1 represents the extreme of what can be considered a disease spectrum. They also implicate transcriptional dysregulation of OVOL2 as a common cause of dominantly inherited corneal endothelial dystrophies. PMID- 26749311 TI - [Nutritional therapy in the obese patient with insulin resistance and cardiovascular risk]. AB - Currently, each of the different scientific societies advocate one kind or another nutritional recommendations for patients with vascular risk. This variety of diets on the one hand enrich the nutritional therapeutic possibilities, but on the other can lead to some confusion, both for the patient and for the professional that advises. Furthermore, most studies assessing vascular risk mention a "diet" without defining or specifying to which kind of diet they refer, thereby introducing an important bias in the results of those studies. In fact, some of them bear a degree of contradiction. This review aims to shed some light on such a controversial topic. PMID- 26749312 TI - How Accurate is Your Sclerostin Measurement? Comparison Between Three Commercially Available Sclerostin ELISA Kits. AB - Sclerostin, bone formation antagonist is in the spotlight as a potential biomarker for diseases presenting with associated bone disorders such as chronic kidney disease (CDK-MBD). Accurate measurement of sclerostin is therefore important. Several immunoassays are available to measure sclerostin in serum and plasma. We compared the performance of three commercial ELISA kits. We measured sclerostin concentrations in serum and EDTA plasma obtained from healthy young (18-26 years) human subjects using kits from Biomedica, TECOmedical and from R&D Systems. The circulating sclerostin concentrations were systematically higher when measured with the Biomedica assay (serum: 35.5 +/- 1.1 pmol/L; EDTA: 39.4 +/ 2.0 pmol/L; mean +/- SD) as compared with TECOmedical (serum: 21.8 +/- 0.7 pmol/L; EDTA: 27.2 +/- 1.3 pmol/L) and R&D Systems (serum: 7.6 +/- 0.3 pmol/L; EDTA: 30.9 +/- 1.5 pmol/L). We found a good correlation between the assay for EDTA plasma (r > 0.6; p < 0.001) while in serum, only measurements obtained using TECOmedical and R&D Systems assays correlated significantly (r = 0.78; p < 0.001). There was no correlation between matrices results when using the Biomedica kit (r = 0.20). The variability in values generated from Biomedica, R&D Systems and TECOmedical assays raises questions regarding the accuracy and specificity of the assays. Direct comparison of studies using different kits is not possible and great care should be given to measurement of sclerostin, with traceability of reagents. Standardization with appropriate material is required before different sclerostin assays can be introduced in clinical practice. PMID- 26749314 TI - Contemporary strategies for risk stratification and prevention of sudden death with the implantable defibrillator in hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is regarded as the most common nontraumatic cause of sudden death (SD) in young people (including trained athletes). Introduction of implantable cardioverter-defibrillators (ICD) to HCM 15 years ago represented a new paradigm for clinical practice and probably the most significant advance in management of this disease. ICDs offer protection against SD by terminating potentially lethal ventricular tachyarrhythmias (11%/year secondary and 4%/year primary prevention), although implant decisions are weighed against the possibility of device-related complications (5%/year). ICDs have altered the natural history of HCM, creating the opportunity for extended or normal longevity for many patients. However, assessing SD risk and targeting appropriate candidates for prophylactic device therapy can be compounded by unpredictability of the underlying arrhythmogenic substrate, evident by delays >=10 years between implant and first ICD intervention. Multiple or a single strong risk marker within the clinical profile of an individual HCM patient can justify consideration for a primary-prevention ICD when combined with physician judgment and shared decision making. The role of the mathematical SD risk score proposed by the European Society of Cardiology to identify patients who benefit from ICD therapy is incompletely resolved. Contemporary treatment interventions and advanced risk stratification using >=1 conventional markers have served the HCM patient population well, with reduced disease-related mortality rates across all age groups to <1%/year, due largely to the penetration of ICDs into HCM practice. Prevention of SD has now become an integral, albeit challenging, component of HCM management, contributing importantly to its emergence as a contemporary treatable cardiac disease. PMID- 26749313 TI - Impact of early complications on outcomes in patients with implantable cardioverter-defibrillator for primary prevention. AB - BACKGROUND: The lifesaving benefit of implantable cardioverter-defibrillators (ICDs) has been demonstrated. Their use has increased considerably in the past decade, but related complications have become a major concern. OBJECTIVE: The purpose of this study was to assess the incidence and effect on outcomes of early (<=30 days) complications after ICD implantation for primary prevention in a large French population. METHODS: We analyzed data from 5539 patients from the multicenter French DAI-PP (Defibrillateur Automatique Implantable-Prevention Primaire) registry (2002-2012) who had coronary artery disease or dilated cardiomyopathy and were implanted with an ICD for primary prevention. RESULTS: Overall, early complications occurred in 707 patients (13.5%), mainly related to lead dislodgment or hematoma (57%). Independent factors associated with occurrence of early complications were severe renal impairment (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.17-2.37, P = .02), age >=75 years (OR 1.01, 95% CI 1.00-1.02, P = .03), cardiac resynchronization therapy (OR 1.58, 95% CI 1.16-2.17, P = .01), and anticoagulant therapy (OR 1.28, 95% CI 1.02-1.61, P = .03). During a mean +/- SD follow-up of 3.1 +/- 2.3 years, 824 (15.8%) patients experienced >=1 late complication (>30 days), and 782 (14.9%) patients died. After adjustment, early complications remained associated with occurrence of late complications (OR 2.15, 95% CI 1.73-2.66, P < .0001) and mortality (OR 1.70, 95% CI 1.34-2.17, P = .003). CONCLUSION: Early complications are common after ICD implantation for primary prevention, occurring in 1 in 7 patients, and are associated with an increased risk of late complications and overall mortality. Further studies are needed to investigate the underlying mechanisms of such associations. PMID- 26749316 TI - Diagnosis of pheochromocytoma in a hemodialysis patient through measurement of plasma catecholamines. AB - We report the case of a patient on chronic hemodialysis treatment with paroxysms of severe arterial hypertension accompanied by tachycardia, pallor, sweating and tremor. Measurement of plasma catecholamines revealed norepinephrine level of 4625 pg/mL (reference range 191-225 pg/mL), epinephrine level of 1035 pg/mL (58 76 pg/mL) and dopamine level of 148 pg/mL (50-100 pg/mL). MRI showed a left adrenal mass of 2 cm. After the patient was started on an alpha-1 adrenergic receptor blocker, she underwent a left adrenalectomy. Anatomopathological examination confirmed the diagnosis of pheochromocytoma. Although urinary testing is not possible in anuric hemodialysis patients, diagnosis of pheochromocytoma can be made through measurement of plasma free metanephrines and/or plasma catecholamines. PMID- 26749315 TI - FMRI of spinal and supra-spinal correlates of temporal pain summation in fibromyalgia patients. AB - Fibromyalgia syndrome (FM) is a debilitating chronic pain condition, which afflicts primarily females. Although the etiology of this illness is not completely understood, FM pain is thought to rely on enhanced pain sensitivity maintained by central mechanisms. One of these mechanisms is central pain amplification, which is characterized by altered temporal summation of second pain (TSSP). Here we use a TSSP paradigm and functional MRI (fMRI) of the spinal cord, brainstem, and brain to noninvasively examine the central nervous system contributions to TSSP in FM patients and normal controls (NC). Functional MRI of pain-free female adults (N = 15) and FM patients (N = 14) was conducted while brief, repetitive heat pain stimuli (0.33 Hz) were applied to the thenar eminence of the hand (C6 dermatome). The stimulus intensity was adjusted to each participant's heat pain sensitivity to achieve moderate pain. Data were analyzed by means of a General Linear Model and region-of-interest analyses. All participants demonstrated significant pain summation in the TSSP condition. FM subjects, however, required significantly lower stimulus intensities than NC to achieve similar TSSP. fMRI analyses of perceptually equal TSSP identified similar brain activity in NC and FM subjects; however, multiple areas in the brainstem (rostral ventromedial medulla and periaqueductal grey region) and spinal cord (dorsal horn) exhibited greater activity in NC subjects. Finally, increased after sensations and enhanced dorsal horn activity was demonstrated in FM patients. In conclusion, the spinal and brainstem BOLD responses to TSSP are different between NC and FM patients, which may indicate alterations to descending pain control mechanisms suggesting contributions of these mechanisms to central sensitization and pain of FM patients. PMID- 26749317 TI - Solitary Langerhans cell histiocytosis in an adult: case report and literature review. AB - BACKGROUND: Langerhans cell histiocytosis (LCH) is a disease that often affects children, but can also occur in adults and smokers. Oral manifestations are unusual and are characterized by bone pain, tooth mobility, necrotic ulcers and local edema. The aim of this paper is to describe a clinical case of LCH in an oral cavity that mimicked oral squamous cell carcinoma. CASE PRESENTATION: A male, 63 years old, complaining about a "wound in the mouth" for 6 months, without any pain or spontaneous bleeding. His medical history was free of disease. The patient was a smoker for 33 years. Intraoral examination revealed a destructive ulcerative lesion around the upper left first and second molars that resembled an oral squamous cell carcinoma. Biopsy of the ulcerative lesion was performed and the microscopic features showed an inflammatory infiltrate rich in plasma cells. Based on this microscopical finding, the final diagnosis was periodontal disease associated with a proliferative non-neoplastic lesion. The patient was referred to a specialized dental surgeon and underwent periodontal therapy including surgical procedures. After that, according to follow-up with the patient, there were no signs of disease remission. The lesion increased in size, although the patient did not complain of any symptoms. A second biopsy was performed and the microscopic features again showed a rich inflammatory infiltrate with mononuclear cells and histiocytic cells, characterized by pale histiocytes with lobed nuclei, resembling a bean. A varying number of eosinophils also were observed, without any evidence of atypical cells present in this infiltrate. An immunohistochemical staining panel was done to determine the nature of this inflammatory infiltrate by using antibodies S-100, CD1a, CD-68 and CD45RO that were positive. These immunohistochemical findings were fundamental for the final diagnosis of LCH. The treatment included surgical extraction of all superior teeth, radiation and systemic corticoid therapies. After 8 years of treatment, the patient is free of disease. CONCLUSION: Although LCH is an unusual lesion in an oral cavity, it can be present. Biopsy and a histological exam are essential to establish the diagnosis. Immunohistochemicals were fundamental to exclude malignant lesion and to confirm the diagnosis of LCH. PMID- 26749318 TI - [Gut microbiota: Description, role and pathophysiologic implications]. AB - The human gut contains 10(14) bacteria and many other micro-organisms such as Archaea, viruses and fungi. Studying the gut microbiota showed how this entity participates to gut physiology and beyond this to human health, as a real "hidden organ". In this review, we aimed to bring information about gut microbiota, its structure, its roles and its implication in human pathology. After bacterial colonization in infant, intestinal microbial composition is unique for each individual although more than 95% can be assigned to four major phyla. The use of culture independent methods and more recently the development of high throughput sequencing allowed to depict precisely gut microbiota structure and diversity as well as its alteration in diseases. Gut microbiota is implicated in the maturation of the host immune system and in many fundamental metabolic pathways including sugars and proteins fermentation and metabolism of bile acids and xenobiotics. Imbalance of gut microbial populations or dysbiosis has important functional consequences and is implicated in many digestive diseases (inflammatory bowel diseases, colorectal cancer, etc.) but also in obesity and autism. These observations have led to a surge of studies exploring therapeutics which aims to restore gut microbiota equilibrium such as probiotics or fecal microbiota transplantation. But recent research also investigates biological activity of microbial products which could lead to interesting therapeutics leads. PMID- 26749319 TI - A Study on the Photoreaction of 2(5H)-Furanones with Substituted Acetylenes: Evidence for a Mechanistic Reformulation. AB - The photoreaction of 2(5H)-furanones with alkynes has been investigated. The complexity of this process is evidenced by the variety of isolated products, which have allowed disclosing interesting mechanistic aspects. When the reaction is performed in acetonitrile under direct excitation, in addition to the primary [2+2] cycloadducts, products derived from an 1,3-acyl shift rearrangement are also formed. For unsymmetrical alkynes, the rearrangement of the head-to-tail primary adducts produces new regioisomers and, when the starting furanone is chiral, this rearrangement inverts the relative anti/syn geometry of the primary cycloadducts. In the reactions performed in acetone under photosensitized conditions, rearranged products were never detected, supporting that the 1,3-acyl shift takes place from the singlet excited state S1 of the beta,gamma-unsaturated lactone. When bis(trimethylsilyl)acetylene is used as the alkyne partner, the major photoproducts are monocyclic bis(trimethylsilyl)lactones. PMID- 26749320 TI - Linking structure and function in food webs: maximization of different ecological functions generates distinct food web structures. AB - Trophic interactions are central to ecosystem functioning, but the link between food web structure and ecosystem functioning remains obscure. Regularities (i.e. consistent patterns) in food web structure suggest the possibility of regularities in ecosystem functioning, which might be used to relate structure to function. We introduce a novel, genetic algorithm approach to simulate food webs with maximized throughput (a proxy for ecosystem functioning) and compare the structure of these simulated food webs to real empirical food webs using common metrics of food web structure. We repeat this analysis using robustness to secondary extinctions (a proxy for ecosystem resilience) instead of throughput to determine the relative contributions of ecosystem functioning and ecosystem resilience to food web structure. Simulated food webs that maximized robustness were similar to real food webs when connectance (i.e. levels of interaction across the food web) was high, but this result did not extend to food webs with low connectance. Simulated food webs that maximized throughput or a combination of throughput and robustness were not similar to any real food webs. Simulated maximum-throughput food webs differed markedly from maximum-robustness food webs, which suggests that maximizing different ecological functions can generate distinct food web structures. Based on our results, food web structure would appear to have a stronger relationship with ecosystem resilience than with ecosystem throughput. Our genetic algorithm approach is general and is well suited to large, realistically complex food webs. Genetic algorithms can incorporate constraints on structure and can generate outputs that can be compared directly to empirical data. Our method can be used to explore a range of maximization or minimization hypotheses, providing new perspectives on the links between structure and function in ecological systems. PMID- 26749321 TI - Mental Health Following Separation in a Disaster: The Role of Attachment. AB - Short-term separation from close family members during a disaster is a highly salient event for those involved. Yet, its subsequent impact on mental health has received little empirical attention. One relevant factor may be attachment style, which influences patterns of support-seeking under threatening conditions. Individuals (N = 914) affected by the 2009 Victorian bushfires in southeastern Australia were assessed for disaster experiences, depression, posttraumatic stress disorder (PTSD) symptoms, and attachment style 3-4 years after the fires. Using multigroup structural equation modelling, individuals who reported separation from close family members during the bushfires (n = 471) were compared to those who reported no separation (n = 443). Cross-sectional results indicated that separated individuals had higher levels of PTSD symptoms. Furthermore, attachment anxiety was more strongly positively associated with depression among separated (b = 0.62) versus not separated individuals (b = 0.32). Unexpectedly, among separated individuals, attachment avoidance had a statistically weaker association with depression (b = 0.17 vs. b = 0.35) and with PTSD symptoms (b = 0.06 vs. b = 0.22). These results suggest that attachment anxiety amplifies a negative reaction to separation; meanwhile, for avoidant individuals, separation in times of danger may facilitate defensive cognitive processes. PMID- 26749322 TI - PLGA based drug delivery systems: Promising carriers for wound healing activity. AB - Wound treatment remains one of the most prevalent and economically burdensome healthcare issues in the world. Current treatment options are limited and require repeated administrations which led to the development of new therapeutics to satisfy the unmet clinical needs. Many potent wound healing agents were discovered but most of them are fragile and/or sensitive to in vivo conditions. Poly(lactic-co-glycolic acid) (PLGA) is a widely used biodegradable polymer approved by food and drug administration and European medicines agency as an excipient for parenteral administrations. It is a well-established drug delivery system in various medical applications. The aim of the current review is to elaborate the applications of PLGA based drug delivery systems carrying different wound healing agents and also present PLGA itself as a wound healing promoter. PLGA carriers encapsulating drugs such as antibiotics, anti-inflammatory drugs, proteins/peptides, and nucleic acids targeting various phases/signaling cycles of wound healing, are discussed with examples. The combined therapeutic effects of PLGA and a loaded drug on wound healing are also mentioned. PMID- 26749323 TI - High-resolution synchrotron X-ray analysis of bioglass-enriched hydrogels. AB - Enrichment of hydrogels with inorganic particles improves their suitability for bone regeneration by enhancing their mechanical properties, mineralizability, and bioactivity as well as adhesion, proliferation, and differentiation of bone forming cells, while maintaining injectability. Low aggregation and homogeneous distribution maximize particle surface area, promoting mineralization, cell particle interactions, and homogenous tissue regeneration. Hence, determination of the size and distribution of particles/particle agglomerates in the hydrogel is desirable. Commonly used techniques have drawbacks. High-resolution techniques (e.g., SEM) require drying. Distribution in the dry state is not representative of the wet state. Techniques in the wet state (histology, uCT) are of lower resolution. Here, self-gelling, injectable composites of Gellan Gum (GG) hydrogel and two different types of sol-gel-derived bioactive glass (bioglass) particles were analyzed in the wet state using Synchrotron X-ray radiation, enabling high resolution determination of particle size and spatial distribution. The lower detection limit volume was 9 * 10(-5) mm(3) . Bioglass particle suspensions were also studied using zeta potential measurements and Coulter analysis. Aggregation of bioglass particles in the GG hydrogels occurred and aggregate distribution was inhomogeneous. Bioglass promoted attachment of rat mesenchymal stem cells (rMSC) and mineralization. PMID- 26749326 TI - Phytochemical meanings of tetrahydro-beta-carboline moiety in strictosidine derivatives. AB - Synthesis of 13 different tetrahydro-beta-carbolines (THBC) was accomplished by applying the Pictet-Spengler reaction with seven aldehydes, which have been coupled with tryptamine (6) and l-tryptophan methyl ester (7), respectively. The resulting products represent analogues of strictosidine (1) and carboxystrictosidine (5). They were investigated with respect to possible effects on herbivores in feeding bioassays upon the generalist Spodoptera littoralis. Maximum inhibition averages were 42% after four and 46% after six days for the most effective product (19) at 1000ppm. Additionally, the frass of this particular bioassay was investigated via HPLC-UV for THBC digestion. All synthesized THBCs were also tested for their radical scavenger activity by monitoring their interaction with 2,2-diphenyl-1-picrylhydrazyl (DPPH). Compounds 16-20, 24 and 25 exhibited radical scavenging activity, ranging from 50% to 74% compared to that of alpha-tocopherol. All results were discussed with respect to possible contributions of tetrahydro-beta-carboline moieties in bioactivities of strictosidine (1) and its biodegradation products. PMID- 26749324 TI - Anticancer efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in osteolytic breast cancer murine models. AB - Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, hypoxia offers treatment opportunities, exemplified by the development of compounds that target hypoxic regions within tumors. Evofosfamide (TH-302) is a prodrug created by the conjugation of 2-nitroimidazole to bromo isophosphoramide mustard (Br-IPM). When evofosfamide is delivered to hypoxic regions, the DNA cross-linking effector, Br-IPM, is released. This study assessed the cytotoxic activity of evofosfamide in vitro and its antitumor activity against osteolytic breast cancer either alone or in combination with paclitaxel in vivo. A panel of human breast cancer cell lines were treated with evofosfamide under hypoxia and assessed for cell viability. Osteolytic MDA-MB-231-TXSA cells were transplanted into the mammary fat pad, or into tibiae of mice, allowed to establish and treated with evofosfamide, paclitaxel, or both. Tumor burden was monitored using bioluminescence, and cancer-induced bone destruction was measured using micro-CT. In vitro, evofosfamide was selectively cytotoxic under hypoxic conditions. In vivo evofosfamide was tumor suppressive as a single agent and cooperated with paclitaxel to reduce mammary tumor growth. Breast cancer cells transplanted into the tibiae of mice developed osteolytic lesions. In contrast, treatment with evofosfamide or paclitaxel resulted in a significant delay in tumor growth and an overall reduction in tumor burden in bone, whereas combined treatment resulted in a significantly greater reduction in tumor burden in the tibia of mice. Evofosfamide cooperates with paclitaxel and exhibits potent tumor suppressive activity against breast cancer growth in the mammary gland and in bone. PMID- 26749325 TI - The usefulness of school-based syndromic surveillance for detecting malaria epidemics: experiences from a pilot project in Ethiopia. AB - BACKGROUND: Syndromic surveillance is a supplementary approach to routine surveillance, using pre-diagnostic and non-clinical surrogate data to identify possible infectious disease outbreaks. To date, syndromic surveillance has primarily been used in high-income countries for diseases such as influenza- however, the approach may also be relevant to resource-poor settings. This study investigated the potential for monitoring school absenteeism and febrile illness, as part of a school-based surveillance system to identify localised malaria epidemics in Ethiopia. METHODS: Repeated cross-sectional school- and community based surveys were conducted in six epidemic-prone districts in southern Ethiopia during the 2012 minor malaria transmission season to characterise prospective surrogate and syndromic indicators of malaria burden. Changes in these indicators over the transmission season were compared to standard indicators of malaria (clinical and confirmed cases) at proximal health facilities. Subsequently, two pilot surveillance systems were implemented, each at ten sites throughout the peak transmission season. Indicators piloted were school attendance recorded by teachers, or child-reported recent absenteeism from school and reported febrile illness. RESULTS: Lack of seasonal increase in malaria burden limited the ability to evaluate sensitivity of the piloted syndromic surveillance systems compared to existing surveillance at health facilities. Weekly absenteeism was easily calculated by school staff using existing attendance registers, while syndromic indicators were more challenging to collect weekly from schoolchildren. In this setting, enrolment of school-aged children was found to be low, at 54%. Non enrolment was associated with low household wealth, lack of parental education, household size, and distance from school. CONCLUSIONS: School absenteeism is a plausible simple indicator of unusual health events within a community, such as malaria epidemics, but the sensitivity of an absenteeism-based surveillance system to detect epidemics could not be rigorously evaluated in this study. Further piloting during a demonstrated increase in malaria transmission within a community is recommended. PMID- 26749327 TI - Dual-Energy CT in Patients with Suspected Gouty Arthritis: Effects on Treatment Regimen and Clinical Outcome. AB - RATIONALE AND OBJECTIVES: This investigation aimed to evaluate the impact on treatment regimen and clinical outcome of dual-energy computed tomography (DECT) in patients with suspected gouty arthritis. MATERIALS AND METHODS: We retrospectively analyzed electronic medical records (EMR) of 39 patients (36 male, 3 female; age range, 36-85 years) who underwent DECT of peripheral joints because of suspected gouty arthritis. We assessed the prior medical history, lab results, treatment regimen, and medications before and after DECT, and changes in subjective severity of symptoms as stated by patients in the EMR. The presence of monosodium urate (MSU) crystals in the index joint was verified with DECT. RESULTS: Several patients had a prior diagnosis of gout (n = 9), hyperuricemia (n = 6), rheumatoid arthritis (n = 3), or psoriatic arthritis (n = 3). Elevated uric acid blood levels were detected in 32 patients (82%) before DECT. On DECT, MSU crystals were detected in 23 patients (59%). Of the 36 cases, the current treatment regimen was modified after DECT to gout-specific therapy in 22 cases and other rheumatic diseases were targeted in 14 cases. Several medications were prescribed more frequently based after DECT compared to before DECT imaging, including steroids (n = 20 vs. n = 12, respectively), colchicine (n = 13 vs. n = 4, respectively), and urate-lowering medication (n = 18 vs. n = 11, respectively). A subjective reduction of clinical symptoms during cumulative follow-up was reported by 34 patients (87.2%). CONCLUSIONS: Both positive and negative findings of MSU crystals on DECT have a significant impact on the treatment regimen and clinical outcome of patients with suspected gouty arthritis and facilitate differentiation from other rheumatic diseases. PMID- 26749329 TI - Botulinum toxin uses in strabismus: A review of the injections performed during one year in a general hospital. AB - OBJECTIVE: To analyse the indications, dosage and efficacy of botulinum toxin A injection performed in patients in a Strabismus Department. METHODS: In this prospective study, botulinum toxin A was injected into 28 patients diagnosed with strabismus. Data was obtained from the records of patients that were evaluated during 2013 in the Strabismus Unit of Rey Juan Carlos Hospital (Mostoles, Madrid, Spain) in order to assess the indications and dosage of botulinum toxin A use in strabismus, as well as its clinical effect and differences in paediatric and adult patients. The outcomes in the last visit, at least 14 months after the injections, were analysed. RESULTS: An analysis was performed on the data from 11 children, 6 females (54.5%), and 17 adults, 11 males (64%). The mean age was 4.42+/-3.48 years and 58.71+/-18.07 years in the children and adult groups, respectively. The majority of cases in both groups were esotropia (81.8% in children and 47.1% in adults). However the pathologies in the adult group were quite heterogeneous, including 4 patients with exotropia (26.5%), 4 with hypertropia (26.5%), and one with isolated nystagmus (5.9%). The mean number of the botulinum toxin injections in children was 1.45+/-0.93, although 72.7% received a single injection. In the adult group, the mean number of injections was 3.27+/-1.41. There was a statistically significant difference between pre- and post-injection in the tropia and phoria measurements in children and adults group (P<.05). In both groups there was a statistically significant improvement in post-injection torticollis when compared with the pre-injection measurement (P<.05). An improvement in the stereoacuity could be detected in 4 children. Two children (18.2%) and 5 adults (29.4%) required subsequent surgical intervention. Eight adult patients (49.1%) complained of diplopia in the primary position, which was resolved in 6 cases with toxin injection, whereas 2 needed surgery for diplopia correction. CONCLUSIONS: Botulinum toxin is a very useful tool in the management of strabismus, obtaining better sensory and motor results in children, but it is also effective as a symptomatic treatment in some types of strabismus in adults. PMID- 26749330 TI - Antonio Vena's sign. PMID- 26749331 TI - Scleral patch graft in the management of necrotising scleritis with inflammation. A case report. PMID- 26749328 TI - Automated Assessment of Left Ventricular Function and Mass Using Heart Deformation Analysis: Initial Experience in 160 Older Adults. AB - RATIONALE AND OBJECTIVES: To assess the performance of automated quantification of left ventricular function and mass based on heart deformation analysis (HDA) in asymptomatic older adults. MATERIALS AND METHODS: This study complied with Health Insurance Portability and Accountability Act regulations. Following the approval of the institutional review board, 160 asymptomatic older participants were recruited for cardiac magnetic resonance imaging including two-dimensional cine images covering the entire left ventricle in short-axis view. Data analysis included the calculation of left ventricular ejection fraction (LVEF), left ventricular mass (LVM), and cardiac output (CO) using HDA and standard global cardiac function analysis (delineation of end-systolic and end-diastolic left ventricle epi- and endocardial borders). The agreement between methods was evaluated using intraclass correlation coefficient (ICC) and coefficient of variation (CoV). RESULTS: HDA had a shorter processing time than the standard method (1.5 +/- 0.3 min/case vs. 5.8 +/- 1.4 min/case, P < 0.001). There was good agreement for LVEF (ICC = 0.552, CoV = 10.5%), CO (ICC = 0.773, CoV = 13.5%), and LVM (ICC = 0.859, CoV = 14.5%) acquired with the standard method and HDA. There was a systemic bias toward lower LVEF (62.8% +/- 8.3% vs. 69.3% +/- 6.7%, P < 0.001) and CO (4.4 +/- 1.0 L/min vs. 4.8 +/- 1.3 L/min, P < 0.001) by HDA compared to the standard technique. Conversely, HDA overestimated LVM (114.8 +/- 30.1 g vs. 100.2 +/- 29.0 g, P < 0.001) as compared to the reference method. CONCLUSIONS: HDA has the potential to measure LVEF, CO, and LVM without the need for user interaction based on standard cardiac two-dimensional cine images. PMID- 26749332 TI - Prophylactic augmentation of the proximal femur: an investigation of two techniques. AB - INTRODUCTION: Osteoporotic hip fractures are an increasing problem in an ageing population. They result in high morbidity, mortality and high socioeconomic costs. For patients with poor bone quality, prophylactic augmentation of the proximal femur might be an option for fracture prevention. METHODS: In two groups of paired human femora the potential of limited polymethyl-methacrylate (PMMA) augmentation (11-15 ml) in a V-shape pattern and the insertion of a proximal femur nail antirotation (PFNA) blade were investigated. The testing was carried out pair wise simulating the single leg stand. The untreated femur in each pair served as control. An axial load was applied until failure. Load displacement parameters and temperature increase during the augmentation process were recorded. RESULTS: In the PMMA group no significant difference was found between the augmented and non-augmented specimen concerning load to failure (p = 0.35) and energy to failure (p = 0.9). A median temperature increase of 9.5 degrees C was observed in the augmented specimen. A significant correlation was found between the amount of applied PMMA and the temperature increase (Cor. Coef. = 0.82, p = 0.042). In the PFNA group, a significant decrease of load to failure and a non-significant decrease of energy to failure were observed (p = 0.037 and p = 0.075). CONCLUSION: Limited V-shaped PMMA augmentation and PFNA blade insertion did not show any improvement in failure load or energy to failure. Volumes of up to 15 ml PMMA did not cause a critical surface temperature increase. PMID- 26749333 TI - Musculoskeletal Ultrasound: A Novel Approach for Luschka's Joint and Vertebral Artery. AB - BACKGROUND: Cervical vertigo has been a controversial diagnosis for several years, and the lack of a diagnostic test is a critical problem. Musculoskeletal ultrasound (MSUS) is a real-time dynamic approach that is used to investigate the musculoskeletal and vascular systems. MATERIAL/METHODS: In this study, MSUS was used to examine whether there is a relationship among vertigo, the vertebral artery (VA), and Luschka's joint proliferation in patients with cervical vertigo. RESULTS: MSUS clearly revealed the size, shape, and characteristics of the Luschka's joint, the VA, and the surrounding structures. The Luschka's joint proliferation was not distributed uniformly, but the predilection sites were C4/5 (50.5%) and C5/6 (32.3%). The proliferation from C4/5 and C5/6 Luschka's joints was the major cause of the grade 2/3 VA tortuosity. Moreover, there was a significant correlation between VA compression from Luschka's joint proliferation and the symptoms of cervical vertigo. CONCLUSIONS: MSUS is a real-time and noninvasive technique that can be used to locate and observe Luschka's joint and the VA during research and clinical applications. In future practice MSUS could be used as a diagnostic approach for patients with suspected cervical vertigo. PMID- 26749334 TI - Hospitalizations due to allergic reactions in Finnish and Swedish children during 1999-2011. AB - BACKGROUND: Several authors have reported on allergic reactions that resulted in presentation to the emergency department. However, studies of the secular trend of hospitalizations for paediatric allergic reactions, including anaphylaxis, are scarce. The aim of this study was to describe the secular trends of hospitalizations for allergic reactions, including anaphylaxis, among children aged 0-19 years in Finland and Sweden, and to establish the trend of prescribed epinephrine auto-injectors (EAI) among paediatric populations. METHODS: Using national databases, we identified hospitalizations between 1999 and 2011 with the primary diagnosis of allergic reaction per International Classification of Diseases, 10th Revision. RESULTS: Hospitalizations for allergic reactions totalled 1987 in Finland and 5433 in Sweden. Incidence rates increased in both countries. In Finland, the incidence of admission was 7.8 per 100 000 person years at the start of the study period and 15.8 at the end of the study period. The corresponding numbers among Swedish children were 13.7 and 31.8 per 100 000 person-years. In Finland, 60% of children hospitalized were aged under 10 years. In Sweden, this proportion was somewhat lower, at 48%. Most hospitalizations occurred between May and September. The prevalence of EAI prescriptions in Finland increased by fourfold during the study period. In Sweden, such an increase was not identified. CONCLUSIONS: The incidence of allergic reactions leading to hospitalizations between 1999 and 2011 increased in Finland and Sweden among children aged 0 to 19 years. In Finland, the incidence was lower throughout the study period compared to Sweden. Younger children constituted the majority of hospitalized children. PMID- 26749336 TI - The Significance of Tinospora crispa in Treatment of Diabetes Mellitus. AB - Tinospora crispa is a medicinal plant belonging to the botanical family Menispermiaceae. The plant is widely distributed in Southeast Asia and the northeastern region of India. A related species Tinospora cordifolia is used in Ayurveda for treating a large spectrum of diseases. Traditional healers of Thailand, Malaysia, Guyana, Bangladesh and the southern Indian province of Kerala use this plant in the treatment of diabetes. Many diterpenes, triterpenes, phytosteroids, alkaloids and their glycosides have been isolated from T. crispa. Cell culture and animal studies suggest that the herb stimulates secretion of insulin from beta-cells. It also causes dose-dependent and time-dependent enhancement of glucose uptake in muscles. However, in view of the reported hepatotoxicity, this herb may be used with caution. This article reviews the animal studies and human clinical trials carried out using this herb. Areas of future research are also identified. PMID- 26749337 TI - Post-transplant lymphoproliferative disorder following kidney transplantation: a population-based cohort study. AB - Post-transplant lymphoproliferative disorder (PTLD) incidence is difficult to determine, mainly because both early and other lesions may go unrecognized and unregistered. Few studies have included systematic pathology review to maximize case identification and decide more accurately PTLD frequency after long-term post-transplantation follow-up. A retrospective population-based cohort study including all kidney transplant recipients at two Danish centres (1990-2011; population covered 3.1 million; 2175 transplantations in 1906 patients). Pathology reports were reviewed for all patient biopsies to identify possible PTLDs. Candidate PTLDs underwent histopathological review and classification. Seventy PTLD cases were identified in 2175 transplantations (3.2%). The incidence rate (IR) after first transplantation was 5.4 cases per 1000 patient-years (95% CI: 4.0-7.3). Most PTLDs were monomorphic (58.5%), or early lesions (21.5%). Excluding early lesions and patients <18 years, IR was 3.7 (95% CI: 2.9-5.5). Ten patients with PTLD were retransplanted, 2 developing further PTLDs. Post transplant patient survival was inferior in patients with PTLD, while death censored graft survival was not. Using registry data together with extensive pathological review and long follow-up, a rather high incidence of PTLD was found. PMID- 26749338 TI - Investigating cerebral oedema using poroelasticity. AB - Cerebral oedema can be classified as the tangible swelling produced by expansion of the interstitial fluid volume. Hydrocephalus can be succinctly described as the abnormal accumulation of cerebrospinal fluid (CSF) within the brain which ultimately leads to oedema within specific sites of parenchymal tissue. Using hydrocephalus as a test bed, one is able to account for the necessary mechanisms involved in the interaction between oedema formation and cerebral fluid production, transport and drainage. The current state of knowledge about integrative cerebral dynamics and transport phenomena indicates that poroelastic theory may provide a suitable framework to better understand various diseases. In this work, Multiple-Network Poroelastic Theory (MPET) is used to develop a novel spatio-temporal model of fluid regulation and tissue displacement within the various scales of the cerebral environment. The model is applied through two formats, a one-dimensional finite difference - Computational Fluid Dynamics (CFD) coupling framework, as well as a two-dimensional Finite Element Method (FEM) formulation. These are used to investigate the role of endoscopic fourth ventriculostomy in alleviating oedema formation due to fourth ventricle outlet obstruction (1D coupled model) in addition to observing the capability of the FEM template in capturing important characteristics allied to oedema formation, like for instance in the periventricular region (2D model). PMID- 26749339 TI - Gelling Properties of Fish/Pork Mince Mixtures. AB - The gel properties of silver carp/pork mince mixtures were investigated as well as the protein structural changes and interactions during gelling using rheology, SEM, and FT-Raman spectroscopy. The breaking force values for gels containing 0% to 40% pork was significantly lower (P < 0.05) compared with gels containing 50% to 100% pork. Gels containing 70% to 100% pork had significantly higher (P < 0.05) breaking force values compared with gels containing 50% to 60% pork. Deformation values were more mixed. Dynamic rheological data suggested that mixing fish and pork at 3:7 could strengthen the gel network. The addition of 40% pork or above, significantly decreased (P < 0.05) the water retention of the gels compared with the 100% fish gels. The dimensional ordering of gels was also reduced by addition of pork. The reduced ordering was one of the reasons for the low water retention for fish/pork mixed gels. Raman spectral analysis confirmed that mixing fish and pork in 7:3 and 3:7 ratios could promote hydrophobic interactions such as bringing tyrosine residues into the intermolecular interface. The interactions in the 3:7 fish/pork mixed gels were favorable for forming a stronger gel. However, the interactions in the 7:3 fish/pork mixed gels were adverse. The water retention of gels was related to both molecular interactions and secondary structures of protein as well as the microstructure of the gels. PMID- 26749340 TI - Demystifying aged care for medical students. AB - BACKGROUND: Residential aged care environments can provide valuable learning opportunities for health professional education. An aged care community university partnership developed the Beyond the Teaching Nursing Home: Community Partnership of Learning and Care (BTTNH: CPLC) programme, where older adults volunteer in learning activities with health professional students. This article describes medical students' experience of participating in a clinical learning activity as part of the broader programme. METHOD: Fourth-year medical students (enrolled in a 6-year medical degree) on geriatric medicine rotation participated in a half-day clinical visit as part of the BTTNH: CPLC programme. Medical students participated in an interview activity with an older adult from the aged care facility. A survey was administered to evaluate medical students' experience of the structured clinical visit to a residential aged care facility. Residential aged care environments can provide valuable learning opportunities for health professional education RESULTS: Medical students valued the learning experience of interacting with older adults, observation of the residential aged care environment and learning about the needs of older adults living in residential aged care. CONCLUSIONS: Providing meaningful learning opportunities for medical students in residential aged care environments may contribute to a better understanding of residents, aged care environments, development of communication skills, professional role and clinical decision-making skills that are relevant for the care of older adults not only in aged care but also in other care settings. PMID- 26749341 TI - Exploring the relationship between fall risk-increasing drugs and fall-related fractures. AB - BACKGROUND: Hospital admissions due to fall-related fractures are a major problem in the aging population. Several risk factors have been identified, including drug use. Most studies often retrieved prescription-only drugs from national databases. These are associated with some limitations as they do not always reliably reproduce the complete patient's active drug list. OBJECTIVE: To evaluate the association between the number of FRIDs intake identified by a standardised medication reconciliation process and a fall-related fracture leading to a hospital admission in older adults. SETTING: The first cohort has been recruited from one traumatology ward of a tertiary teaching hospital in Belgium and the second cohort has been recruited from 11 community pharmacies in Belgium. METHOD: A prospective study with two individually matched cohorts was performed. Adult patients (>=75 years) admitted with an injury due to a fall were included in the first cohort (faller group). The second cohort consisted of patients who did not suffer from a fall within the last 6 months (non-faller group). Matching was performed for age, gender, place of residence and use of a walking aid. In both groups, clinical pharmacists and undergraduate pharmacy students obtained the medication history, using a standardised approach. A list of drugs considered to increase the risk of falling was created. It included cardiovascular drugs and drugs acting on the nervous system. A linear mixed model was used to compare the number of fall risk-increasing drugs between fallers and non-fallers. MAIN OUTCOME MEASURE: The number of fall risk-increasing drugs in a faller versus a non-faller group. RESULTS: Sixty-one patients were matched with 121 non-fallers. Patients received on average 3.1 +/- 2.1 and 3.2 +/- 1.8 fall risk-increasing drugs in the faller and in the non-faller group, respectively. The mean number of fall risk-increasing drugs was comparable in both groups (p = 0.844), even after adjusting for alcohol consumption, fear of falling, vision and foot problems (p = 0.721). CONCLUSION: In a sample of hospitalised patients admitted for a fall-related injury, no significant difference in the number of fall risk-increasing drugs versus that of an outpatient group of non-fallers was found. PMID- 26749343 TI - Proton pump inhibitor co-prescription with dual antiplatelet therapy among patients with acute coronary syndrome in Qatar. AB - BACKGROUND: There are increasing concerns about clinically significant interactions between proton pump inhibitors (PPIs) and clopidogrel, resulting in adverse cardiovascular outcomes in patients with acute coronary syndromes (ACS). However, published evidence on the prevalence and predictors of PPI use with dual antiplatelet therapy (DAPT) is scarce. OBJECTIVE: This study investigated the prevalence of PPI use among patients with ACS receiving DAPT and possible predictors of co-prescribing the PPIs with the DAPT. SETTING: Heart Hospital, a specialized tertiary care center in Qatar. METHODOLOGY: A retrospective observational study of a prescription database was conducted. Subjects included 626 patients admitted between January and December 2012 with the diagnosis of ACS who received DAPT and discharged with or without a PPI. Univariate analysis and multivariate binary logistic regression analysis were performed to determine the predictors of PPI-DAPT co-prescription. MAIN OUTCOME MEASURES: Prevalence of PPI co-prescribing with DAPT in proportions and percentages and odd ratios for the predictors of PPI-DAPT co-prescribing. RESULTS: A total of 626 patients were analyzed for PPI prevalence, with 200 patients (32 %) being prescribed PPI with DAPT upon discharge. After controlling for confounders, PPI use on admission (aOR 14.5; 95 % CI 7.6-27.6, p < 0.001), nationality (aOR 3.2; 95 % CI 1.1-9.9, p = 0.041), and having a history of diabetes (aOR 0.5; 95 % CI 0.24-0.99, p = 0.046) significantly influenced PPI-DAPT co-prescribing. Users of PPI on admission compared to nonusers were about 15 times more likely to be prescribed PPI with DAPT upon discharge; likewise, having Qatari nationality increased the likelihood of co-prescribing PPI with DAPT upon discharge by three folds. Lastly, patients with a history of diabetes were 50 % less likely to be prescribed PPIs upon discharge compared to those with no history of diabetes. CONCLUSION: The rate of PPI co-prescribing with DAPT in the population studied was relatively high. The strongest predictor of PPI co-prescription with DAPT upon discharge was PPI use on admission. Furthermore, PPI prescribing was significantly predicted by nationality and not having diabetes. Further studies are warranted to better predict the factors associated with PPI-DAPT co-prescription and to investigate rational prescribing of PPIs among ACS patients. PMID- 26749342 TI - Risk management of QTc-prolongation in patients receiving haloperidol: an epidemiological study in a University hospital in Belgium. AB - BACKGROUND: Many drugs, including haloperidol, are linked with a risk of QTc prolongation, which can lead to Torsade de Pointes and sudden cardiac death. OBJECTIVE: To investigate the prevalence of concomitant risk factors for QTc prolongation in patients treated with haloperidol, and the use of safety measures to minimize this risk. SETTING: University Hospitals of Leuven, Belgium. Methods A retrospective epidemiological study was performed. On 15 consecutive Mondays, all patients with a prescription for haloperidol were included. A risk score for QTc-prolongation, inspired by the pro-QTc score of Haugaa et al., was calculated based on gender, comorbidities, lab results and concomitant QTc-prolonging drugs (each factor counting for one point). Available electrocardiograms before and during the treatment of haloperidol were registered. MAIN OUTCOME MEASURE: Management of the risk of QTc-prolongation. RESULTS: Two hundred twenty-two patients were included (59.0 % men, median age 77 years) of whom 26.6 % had a risk score of >=4 (known to significantly increase the mortality). Overall, 24.3 % received haloperidol in combination with other drugs with a known risk of Torsade de Pointes. Half of the patients had an electrocardiogram in the week before the start of haloperidol; only in one-third a follow-up electrocardiogram during haloperidol treatment was performed. Of the patients with a moderately (n = 41) or severely (n = 14) prolonged QTc-interval before haloperidol, 48.8 % and 42.9 % respectively had a follow-up electrocardiogram. In patients with a risk score >=4, significantly more electrocardiograms were taken before starting haloperidol (p = 0.020). CONCLUSIONS: Although many patients had risk factors for QTc-prolongation (including the use of other QTc-prolonging drugs) or had a prolonged QTc on a baseline electrocardiogram, follow-up safety measures were limited. Persistent efforts should be taken to develop decision support systems to manage this risk. PMID- 26749345 TI - [Limbic encephalitis: a poorly known disease]. PMID- 26749346 TI - [Ventilator-associated pneumonia by Chryseobacterium indologenes]. PMID- 26749344 TI - Chimeric Allografts Induced by Short-Term Treatment With Stem Cell-Mobilizing Agents Result in Long-Term Kidney Transplant Survival Without Immunosuppression: A Study in Rats. AB - Transplant tolerance allowing the elimination of lifelong immunosuppression has been the goal of research for 60 years. The induction of mixed chimerism has shown promise and has been extended successfully to large animals and to the clinic; however, it remains cumbersome and requires heavy early immunosuppression. In this study, we reported that four injections of AMD3100, a CXCR4 antagonist, plus eight injections of low-dose FK506 (0.05 mg/kg per day) in the first week after kidney transplantation extended survival, but death from renal failure occurred at 30-90 days. Repeating the same course of AMD3100 and FK506 at 1, 2 and 3 mo after transplant resulted in 92% allograft acceptance (n = 12) at 7 mo, normal kidney function and histology with no further treatment. Transplant acceptance was associated with the influx of host stem cells, resulting in a hybrid kidney and a modulated host immune response. Confirmation of these results could initiate a paradigm shift in posttransplant therapy. PMID- 26749347 TI - [Charles Bonnet syndrome secondary to intravitreal ranibizumab in a patient with exudative age-related macular degeneration]. PMID- 26749348 TI - [Cyanoacrylate-related pulmonary embolism following transhepatic embolization of esophageal varices]. PMID- 26749349 TI - [Proctitis in an HIV-infected male who have sex with men]. PMID- 26749351 TI - [Reply]. PMID- 26749350 TI - [Iatrogenic rhabdomyolysis in a patient with ischemic heart disease]. PMID- 26749352 TI - [Cholethorax: An unusual delayed complication of recurrent cholangitis]. PMID- 26749353 TI - [Chronic bilateral panuveitis as first manifestation of Whipple's disease]. PMID- 26749354 TI - [Hepatitis E infections in Zaragoza, Spain (2011-2015)]. PMID- 26749355 TI - [Peripartum septic shock by Streptococcus pyogenes in a young mother]. PMID- 26749356 TI - Visual presentations of efficacy data in direct-to-consumer prescription drug print and television advertisements: A randomized study. AB - OBJECTIVE: To determine whether visual aids help people recall quantitative efficacy information in direct-to-consumer (DTC) prescription drug advertisements, and if so, which types of visual aids are most helpful. METHODS: Individuals diagnosed with high cholesterol (n=2504) were randomized to view a fictional DTC print or television advertisement with no visual aid or one of four visual aids (pie chart, bar chart, table, or pictograph) depicting drug efficacy. We measured drug efficacy and risk recall, drug perceptions and attitudes, and behavioral intentions. RESULTS: For print advertisements, a bar chart or table, compared with no visual aid, elicited more accurate drug efficacy recall. The bar chart was better at this than the pictograph and the table was better than the pie chart. For television advertisements, any visual aid, compared with no visual aid, elicited more accurate drug efficacy recall. The bar chart was better at this than the pictograph or the table. CONCLUSION: Visual aids depicting quantitative efficacy information in DTC print and television advertisements increased drug efficacy recall, which may help people make informed decisions about prescription drugs. PRACTICE IMPLICATIONS: Adding visual aids to DTC advertising may increase the public's knowledge of how well prescription drugs work. PMID- 26749357 TI - Automated alerts and reminders targeting patients: A review of the literature. AB - OBJECTIVE: Information technology supporting patient self-management has the potential to foster shared accountability for healthcare outcomes by improving patient adherence. There is growing interest in providing alerts and reminders to patients to improve healthcare self-management. This paper describes a literature review of automated alerts and reminders directed to patients, the technology used, and their efficacy. METHODS: An electronic literature search was conducted in PubMed to identify relevant studies. The search produced 2418 abstracts; 175 articles underwent full-text review, of which 124 were rejected. 51 publications were included in the final analysis and coding. RESULTS: The articles are partitioned into alerts and reminders. A summary of the analysis for the 51 included articles is provided. CONCLUSION: Reminders and alerts are advantageous in many ways; they can be used to reach patients outside of regular clinic settings, be personalized, and there is a minimal age barrier in the efficacy of automated reminders sent to patients. As technologies and patients' proficiencies evolve, the use and dissemination of patient reminders and alerts will also change. PRACTICE IMPLICATIONS: Automated technology may reliably assist patients to adhere to their health regimen, increase attendance rates, supplement discharge instructions, decrease readmission rates, and potentially reduce clinic costs. PMID- 26749358 TI - 3D printing-assisted fabrication of double-layered optical tissue phantoms for laser tattoo treatments. AB - BACKGROUND AND OBJECTIVE: Artificial skin phantoms have been developed as an alternative tissue for human skin experiments due to convenient use and easy storage. However, fabricating both thin (~100 MUm) epidermis and relatively thick dermis is often cumbersome, and most developed phantoms have hardly reflected specific human skin types. The objective of this study was to fabricate skin phantoms with 3D printing technique to emulate various human skin types (I-VI) along with the corresponding optical and mechanical properties for laser tattoo removal. STUDY DESIGN/MATERIALS AND METHODS: Both gelatin and agar powders were mixed with coffee and TiO2 particles to fabricate skin phantoms with materials properties for various skin types (I-VI). A 3D printer was employed to precisely control the thickness of each phantom for epidermis and dermis layers. A number of concentrations of the coffee and TiO2 particles were used to determine the degree of absorption and scattering effects in various skin types. The optical properties between 500 and 1,000 nm for the fabricated phantoms were measured by double-integrating spheres with an inverse adding-doubling (IAD) algorithm. Optical coherence tomography (OCT) and rheometer were also utilized to evaluate optical (absorption and reduced scattering coefficients) and mechanical properties (compression modulus) of the fabricated phantoms, respectively. RESULTS: Visible color inspections presented that the skin phantoms for types I, III, and VI similarly emulated the color space of the human skin types. The optical property measurements demonstrated that the absorption (MUa) and reduced scattering (MU(s')) coefficients decreased with wavelengths. Compared to the human skin type VI, a dermis phantom represented quite equivalent values of MUa and MU(s') whereas an epidermis phantom showed up to 30% lower MUa but almost identical MU(s') over the wavelengths. The OCT measurements confirmed that the thicknesses of the epidermis and the dermis phantoms were measured to be 138.50 +/- 0.01 MUm and 0.81 +/- 0.04 mm, respectively. The mechanical properties of the phantoms mixed with the agar volume of 40% yielded a compression modulus of 83.7 +/- 14.8 kPa, which well corresponded to that of human forearm skin (50-95 kPa). CONCLUSION: The 3D printing technique was able to reliably fabricate the double layered phantoms emulating a variety of skin types (I-VI) along with the comparable optical and mechanical properties. Further investigations will incorporate artificial chromophores into the fabricated skin phantoms to reliably evaluate the new therapeutic wavelengths for laser tattoo removal. PMID- 26749359 TI - Cardiac function in BRCA1/2 mutation carriers with history of breast cancer treated with anthracyclines. AB - Animal data suggest that defects in BRCA1/2 genes significantly increase the risk of heart failure and mortality in mice exposed to doxorubicine. Women with BRCA1/2 mutations who develop breast cancer (BC) may receive anthracyclines but their risk of cardiac dysfunction has not been investigated. Our study tested the hypothesis that women with history of BRCA1/2 mutation-associated BC treated with anthracyclines have impaired parameters of cardiac function compared to similarly treated women with history of sporadic BC. Women with history of BC and anthracycline treatment underwent an echocardiographic exam for assessment of primary outcomes, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). The sample size of 81 provided 79 % power with two sided two-sample t test and alpha of 0.05 to detect a clinically meaningful difference in cardiac function of absolute 5 % points difference for LVEF and 2 % points difference for GLS. Of 81 normotensive participants, 39 were BRCA1/2 mutation carriers and 42 in the sporadic group. Mean age was 50 +/- 9 years in both groups (P = 0.99) but BRCA1/2 mutation carriers had longer anthracycline treatment-to-enrollment time (7.5 +/- 5.3 vs. 4.2 +/- 3.3 years, P = 0.001). There were no significant differences in LVEF (P = 0.227) or GLS (P = 0.53) between the groups. LVEF was normal in 91 % of women and subclinical cardiac dysfunction defined as absolute GLS value <18.9 % was seen in 4 (10 %) BRCA1/2 mutation carriers and 7 (17 %) sporadic participants. In this first prospective examination of cardiac function in BRCA1/2 mutation carriers, we found no significant differences in sensitive echocardiographic parameters of cardiac function between BRCA1/2 mutation carriers and women with history of sporadic BC who received anthracycline treatment. In contrast to laboratory animal data, our findings indicate lack of elevated cardiac risk with the use of standard-doses of adjuvant anthracyclines in treatment of BRCA1/2 mutation carriers with early stage BC. PMID- 26749361 TI - A phase II trial of trabectedin in triple-negative and HER2-overexpressing metastatic breast cancer. AB - Trabectedin is an alkylating agent that binds to the minor groove of DNA. Early studies with trabectedin suggested efficacy in triple-negative and HER2 overexpressing metastatic breast cancer (MBC). The efficacy and safety of trabectedin in pretreated patients with these tumors were evaluated in this parallel-cohort phase II trial. Patients received a 3-h infusion of trabectedin 1.3 mg/m(2) intravenously every 3 weeks until progression or unmanageable/unacceptable toxicity. The primary objective was to evaluate the efficacy using the objective response rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST). Secondary objectives comprised time-to-event endpoints and safety assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.3.0. Patients with heavily pretreated triple-negative (n = 50) or HER2-overexpressing (n = 37) MBC were enrolled. No confirmed responses were found in triple-negative MBC patients, with median progression-free survival (PFS) of 2.2 months (95 % CI 1.3-2.7 months). Confirmed partial responses occurred in 4 of 34 evaluable HER2-overexpressing MBC patients (ORR = 12 %; 95 % CI 3-27 %) and lasted a median of 12.5 months (95 % CI, 6.2-14.7 months); median PFS was 3.8 months (95 % CI, 1.8-5.5 months). Most trabectedin-related adverse events were mild or moderate, and the most frequent were fatigue, nausea, vomiting, constipation, and anorexia. Severe neutropenia and transaminase increases were non-cumulative and transient and were mostly managed by infusion delays or dose reductions. Single-agent trabectedin is well tolerated in aggressive MBC and has moderate activity in HER2-overexpressing tumors. Further studies are warranted to evaluate trabectedin combined with HER2 targeted treatments in this subtype. PMID- 26749364 TI - Association of diet with acne vulgaris among adolescents in Ibadan, southwest Nigeria. AB - BACKGROUND: Acne vulgaris is a chronic inflammatory disease of the pilosebaceous units that affects 85% of the world's population aged 11-30 years. Diet is believed to affect the severity of acne vulgaris. OBJECTIVES: This study was designed to identify possible associations of diet with acne vulgaris in Nigeria. METHODS: A cross-sectional study was conducted among adolescents in Ibadan in 2011. Students were interviewed for demographic data, history of acne, and frequency of intake of specific foods in the previous 12 months. Each participant was examined for facial acne. Body mass index (BMI) was calculated for each participant. RESULTS: Data for 464 students were analyzed. The mean +/- standard deviation age of all subjects was 13.6 +/- 3.6 years, and the mean BMI was 17.8 kg/m(2) . A total of 299 (64.4%) students were found to have acne vulgaris. Frequencies of intake of various foods varied widely. Prevalences of acne were higher among those who reported an at least daily intake of milk as beverage (72.6% vs. 62.0%; P = 0.035), corn (76.6% vs. 62.3%; P = 0.016), fried beef (75.0% vs. 62.1%; P = 0.042), and cake (77.8% vs. 62.3%; P = 0.012), and less common among those students who reported an at least daily intake of bananas (55.3% vs. 67.6%; P = 0.032). CONCLUSIONS: The present findings suggest associations between some foods and acne in the Nigerian context. An interventional dietary study will be required to further ascertain the effects of these foods on acne vulgaris. PMID- 26749360 TI - Assessing cost-utility of predictive biomarkers in oncology: a streamlined approach. AB - Evaluation of cost-utility is critical in assessing the medical utility of predictive or prognostic biomarkers. Current methods involve complex state transition models, requiring comprehensive data inputs. We propose a simplified decision-analytic tool to explore the relative effect of factors contributing to the cost-utility of a biomarker. We derived a cost-utility metric, the "test incremental cost-effectiveness ratio" (TICER) for biomarker-guided treatment compared to no biomarker use. This method uses data inputs readily accessible through clinical literature. We compared our results with traditional cost effectiveness analysis of predictive biomarkers for established (HER2-guided trastuzumab, ALK-guided crizotinib, OncotypeDX-guided adjuvant chemotherapy) and emerging (ROS1-guided crizotinib) targeted treatments. We conducted sensitivity analysis to determine which factors had the greatest impact on TICER estimates. Base case TICER for HER2 was $149,600/quality-adjusted life year (QALY), for ALK was $22,200/QALY, and for OncotypeDX was $11,600/QALY, consistent with literature reported estimates ($180,000/QALY, $202,800/QALY, $8900/QALY, respectively). Base case TICER for ROS1-guided crizotinib was $205,900/QALY. Generally, when treatment cost is considerably greater than biomarker testing costs, TICER is driven by clinical outcomes and health-related quality of life, while biomarker prevalence and treatment cost have a lesser effect. Our simplified decision analytic approach produces values consistent with existing cost-effectiveness analyses. Our results suggest that biomarker value is mostly driven by the clinical efficacy of the targeted agent. A user-friendly web tool for complete TICER analysis has been made available for open use at http://medicine.yale.edu/lab/pusztai/ticer/ . PMID- 26749362 TI - Lactobacillus casei BL23 regulates Treg and Th17 T-cell populations and reduces DMH-associated colorectal cancer. AB - BACKGROUND: Chronic intestinal inflammation alters host physiology and could lead to colorectal cancer (CRC). We have previously reported beneficial effects of the probiotic strain of Lactobacillus casei BL23 in different murine models of intestinal inflammation. In addition, there is an emerging interest on the potential beneficial effects of probiotics to treat CRC. We thus explored whether L. casei BL23 displays protective effects on CRC. METHODS: Mice were subcutaneously injected with 1,2-dimethylhydrazine (DMH) weekly during 10 weeks and orally administered with L. casei BL23 in the drinking water until the 10th week. Multiple plaque lesions in the large intestine were observed macroscopically and counted and intestinal tissues were also histologically analyzed. Finally, T-cell populations and cytokine production were evaluated after co-incubation of L. casei BL23 with spleen cells from non-treated mice to determine the immuno-modulatory effects of this bacterium. RESULTS: Our results show that oral treatment with this probiotic bacterium modulates host immune responses and significantly protect mice against DMH-induced CRC. This protection may be associated with the modulation of regulatory T-cells towards a Th17-biased immune response accompanied by the expression of regulatory cytokines (IL-6, IL 17, IL-10 and TGF-beta), as demonstrated in L. casei BL23-treated splenocytes, but also with the colonic expression of IL-22 observed in vivo on L. casei BL23 treated mice; suggesting the induction of a fine-tune Th17-biased response. CONCLUSIONS: Altogether our results reveal the high potential of L. casei BL23 to treat CRC and opens new frontiers for the study of immunomodulatory functions of probiotics. PMID- 26749366 TI - On the Effect of Eltoprazine in Dyskinetic Hemiparkinsonian Rats. PMID- 26749365 TI - Metal-Cation Recognition in Water by a Tetrapyrazinoporphyrazine-Based Tweezer Receptor. AB - A series of zinc azaphthalocyanines with two azacrowns in a rigid tweezer arrangement were prepared and the fluorescence sensing properties were investigated. The size-driven recognition of alkali and alkaline earth metal cations was significantly enhanced by the close cooperation of the two azacrown units, in which both donor nitrogen atoms need to be involved in analyte binding to switch the sensor on. The mono- or biphasic character of the binding isotherms, together with the binding stoichiometry and magnitude of association constants (KA ), indicated specific complexation of particular analytes. Water solvation was shown to play an important role and resulted in a strong quenching of sensor fluorescence in the ON state. The lead compound was embedded into silica nanoparticles and advantageous sensing properties towards K(+) were demonstrated in water (lambdaF =671 nm, apparent KA =82 m(-1) , increase of 17*), even in the presence of (supra)physiological concentrations of Na(+) and Ca(2+) . PMID- 26749367 TI - Renal involvement in patients with mucolipidosis IIIalpha/beta: Causal relation or co-occurrence? AB - Mucolipidosis IIIalpha/beta (MLIIIalpha/beta) is a rare lysosomal storage disorder characterized by childhood onset of flexion contractures of fingers, joint stiffness in the shoulders, hips, and knees, and mild short stature. Recessive mutations in the GNPTAB gene have been associated with MLIIIalpha/beta. We present five children aged 9-16 years from a large kindred family whose serum activities of several lysosomal enzymes were significantly elevated. Whole exome sequencing followed by confirmation by Sanger sequencing identified a novel homozygous missense mutation (c.22 A > G; p.R8G) in the GNPTAB gene in all affected subjects. The five patients initially presented with flexion contractures of fingers followed by stiffnes of large joints. Only two affected boys also had a nephrotic-range proteinuria. Renal biopsy showed focal segmental glomerulosclerosis and foamy appearance of glomerular visceral epithelial cells which were compatible with storage disease. No other known causes of proteinuria could be detected by both laboratory and biopsy findings. There was no known family history of hereditary kidney disease, and healthy siblings and parents had normal renal function and urinalysis. These findings suggest that the renal involvement probably due to MLIIIalpha/beta, although it can still be present by coincidence in the two affected patients. PMID- 26749368 TI - Influence of an ultrasonic nozzle in spray-drying and storage on the properties of blueberry powder and microcapsules. AB - BACKGROUND: Recently, ultrasonic nozzle technology has been applied in spray drying because of its numerous advantages, including providing more uniform droplets and reducing damage observed in bioactive compounds. In this study, the production of blueberry powders and microcapsules by using an ultrasonic spray nozzle was investigated. Firstly, the important ultrasonic nozzle parameters were optimised by using response surface methodology and compared with a conventional nozzle (control). Secondly, powder and microcapsules obtained at the optimum point were stored at 22 degrees C and 35 degrees C at 0.32 water activity (aw ). RESULTS: The optimum conditions were estimated as 125 degrees C inlet air temperature, 9 W ultrasonic power and 8% feed pump rate. There was significantly difference (P < 0.05) in the total phenolic content and antioxidant power of microcapsules produced by an ultrasonic nozzle and a conventional nozzle. Because the temperature affected the stability of powders negatively, the blueberry powder showed higher losses than microcapsules in the content of bioactive compounds. In addition, the ultrasonic nozzle showed a significantly greater protective effect on physico-chemical properties than did the conventional nozzle. CONCLUSION: Results of the study point that the production of ultrasonic nozzle powders and microcapsules is feasible to use as a functional ingredient in food industry. (c) 2016 Society of Chemical Industry. PMID- 26749369 TI - Crystal structure of the FK506 binding domain of human FKBP25 in complex with FK506. AB - Human FKBP25 (hFKBP25) is a nuclear immunophilin and interacts with several nuclear proteins, hence involving in many nuclear events. Similar to other FKBPs, FK506 binding domain (FKBD) of hFKBP25 also binds to immunosuppressive drugs such as rapamycin and FK506, albeit with a lower affinity for the latter. The molecular basis underlying this difference in affinity could not be addressed due to the lack of the crystal structure of hFKBD25 in complex with FK506. Here, we report the crystal structure of hFKBD25 in complex with FK506 determined at 1.8 A resolution and its comparison with the hFKBD25-rapamycin complex, bringing out the microheterogeneity in the mode of interaction of these drugs, which could possibly explain the lower affinity for FK506. PMID- 26749370 TI - Distinct white matter integrity in glutamic acid decarboxylase and voltage-gated potassium channel-complex antibody-associated limbic encephalitis. AB - OBJECTIVE: Autoantibodies against glutamic acid decarboxylase (GAD) and the voltage-gated potassium channel (VGKC) complex are associated with distinct subtypes of limbic encephalitis regarding clinical presentation, response to therapy, and outcome. The aim of this study was to investigate white matter changes in these two limbic encephalitis subtypes by means of diffusion tensor imaging (DTI). METHODS: Diffusion data were obtained in 14 patients with GAD antibodies and 16 patients with VGKC-complex antibodies and compared with age- and gender-matched control groups. Voxelwise statistical analysis was carried out using tract-based spatial statistics. The results were furthermore compared with those of 15 patients with unilateral histologically confirmed hippocampal sclerosis and correlated with verbal and figural memory performance. RESULTS: We found widespread changes of fractional anisotropy and all diffusivity parameters in GAD-associated limbic encephalitis, whereas no changes were found in VGKC complex-associated limbic encephalitis. The changes observed in the GAD group were even more extensive when compared against those of the hippocampal sclerosis group, although the disease duration was markedly shorter in patients with GAD antibodies. Correlation analysis revealed areas with a trend toward a negative correlation of diffusivity parameters with figural memory performance located mainly in the right temporal lobe in the GAD group as well. SIGNIFICANCE: The present study provides further evidence that, depending on the associated antibody, limbic encephalitis features clearly distinct imaging characteristics by showing widespread white matter changes in GAD-associated limbic encephalitis and preserved white matter integrity in VGKC-complex-associated limbic encephalitis. Furthermore, our results contribute to a better understanding of the specific pathophysiologic properties in these two subforms of limbic encephalitis by revealing that patients with GAD antibodies show widespread affections of white matter across various regions of the brain. In contrast to this, the inflammatory process seems to be more localized in VGKC-complex associated limbic encephalitis, primarily affecting mesiotemporal gray matter. PMID- 26749371 TI - Systematic review with meta-analysis: the adverse effects of tobacco smoking on the natural history of Crohn's disease. AB - BACKGROUND: Tobacco smoking is a well-established risk factor for the development of Crohn's disease, and this may lead to a more complicated disease course. However, recent evidence suggests that many patients with Crohn's disease are unaware of this fact. AIM: To perform a systematic review and meta-analysis of the effects of smoking on disease course in Crohn's disease. METHODS: A search of MEDLINE, EMBASE and EMBASE classic was carried out (up to July 2015) to identify observational studies reporting data on smoking and rates of surgery or flares of disease activity in patients with Crohn's disease. Dichotomous data were pooled to obtain odds ratios (ORs) for flares of disease activity or need for surgery, with 95% confidence intervals (CIs). RESULTS: The search identified 33 eligible studies. Compared with nonsmokers, smokers had increased odds of flare of disease activity (OR, 1.56; 95% CI, 1.21-2.01), flare after surgery (OR, 1.97; 95% CI, 1.36-2.85), need for first surgery (OR, 1.68; 95% CI, 1.33-2.12) and need for second surgery (OR, 2.17; 95% CI, 1.63-2.89). The odds of these outcomes among ex smokers diminished upon smoking cessation, with ORs comparable to those among nonsmokers and, in the case of flare or second surgery, significantly lower than smokers. CONCLUSIONS: Smokers with Crohn's disease have a more complicated disease course than nonsmokers, and quitting smoking may ameliorate this. Patients should be reminded of the detrimental effects of smoking on the course of their disease, and smoking cessation advice should be provided to reduce disease burden and costs in these patients. PMID- 26749372 TI - The effect of size and sex ratio experiences on reproductive competition in Nicrophorus vespilloides burying beetles in the wild. AB - Male parents face a choice: should they invest more in caring for offspring or in attempting to mate with other females? The most profitable course depends on the intensity of competition for mates, which is likely to vary with the population sex ratio. However, the balance of pay-offs may vary among individual males depending on their competitive prowess or attractiveness. We tested the prediction that sex ratio and size of the resource holding male provide cues regarding the level of mating competition prior to breeding and therefore influence the duration of a male's biparental caring in association with a female. Male burying beetles, Nicrophorus vespilloides were reared, post eclosion, in groups that differed in sex ratio. Experimental males were subsequently translocated to the wild, provided with a breeding resource (carcass) and filmed. We found no evidence that sex ratio cues prior to breeding affected future parental care behaviour but males that experienced male-biased sex ratios took longer to attract wild mating partners. Smaller males attracted a higher proportion of females than did larger males, securing significantly more monogamous breeding associations as a result. Smaller males thus avoided competitive male-male encounters more often than larger males. This has potential benefits for their female partners who avoid both intrasexual competition and direct costs of higher mating frequency associated with competing males. PMID- 26749373 TI - Functioning and disability in autism spectrum disorder: A worldwide survey of experts. AB - OBJECTIVE: This study is the second of four to prepare International Classification of Functioning, Disability and Health (ICF; and Children and Youth version, ICF(-CY)) Core Sets for Autism Spectrum Disorder (ASD).The objective of this study was to survey the opinions and experiences of international experts on functioning and disability in ASD. METHODS: Using a protocol stipulated by the World Health Organization (WHO) and monitored by the ICF Research Branch, an email-based questionnaire was circulated worldwide among ASD experts, and meaningful functional ability and disability concepts were extracted from their responses. These concepts were then linked to the ICF(-CY) by two independent researchers using a standardized linking procedure. RESULTS: N = 225 experts from 10 different disciplines and all six WHO-regions completed the survey. Meaningful concepts from the responses were linked to 210 ICF(-CY) categories. Of these, 103 categories were considered most relevant to ASD (i.e., identified by at least 5% of the experts), of which 37 were related to Activities and Participation, 35 to Body functions, 22 to Environmental factors, and 9 to Body structures. A variety of personal characteristics and ASD-related functioning skills were provided by experts, including honesty, loyalty, attention to detail and creative talents. Reported gender differences in ASD comprised more externalizing behaviors among males and more internalizing behaviors in females. CONCLUSION: The ICF(-CY) categories derived from international expert opinions indicate that the impact of ASD on functioning extends far beyond core symptom domains. Autism Res 2016, 9: 959-969. (c) 2016 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research. PMID- 26749375 TI - Interpreting DTBZ binding data in rodent: Inherent variability and compensation. AB - [11C]-dihydrotetrabenazine (DTBZ) Positron Emission Tomography was used to evaluate the vesicular monoamine transporter type 2 as an index of dopaminergic function in the striatum of adult Sprague-Dawley rats obtained from two different animal sources (Charles River Laboratories [CR] or UBC's Animal Care Centre [ACC]) and later submitted to two different unilateral lesions of the nigro striatal pathway. The results showed a significant difference in the striatal binding potential (BP(ND)) at baseline (before lesioning) between the CR and ACC groups providing evidence that the origin of the animals, possibly due to differences in early environmental factors or breeding conditions associated with different animal vendors plays a role in the development of the adult dopaminergic system. Further, in both animal models, an increase in DTBZ BP(ND) was observed, after unilateral intervention, in the striatum contralateral to the lesion, likely reflecting compensatory effects. Based on these findings, we conclude that in unilateral models, the unlesioned side/hemisphere may not be an appropriate control and that care should be taken to control for the origin of the animals in any given study, especially in longitudinal and replication studies. PMID- 26749376 TI - One-Step Pyro-Synthesis of a Nanostructured Mn3 O4 /C Electrode with Long Cycle Stability for Rechargeable Lithium-Ion Batteries. AB - A nanostructured Mn3 O4 /C electrode was prepared by a one-step polyol-assisted pyro-synthesis without any post-heat treatments. The as-prepared Mn3 O4 /C revealed nanostructured morphology comprised of secondary aggregates formed from carbon-coated primary particles of average diameters ranging between 20 and 40 nm, as evidenced from the electron microscopy studies. The N2 adsorption studies reveal a hierarchical porous feature in the nanostructured electrode. The nanostructured morphology appears to be related to the present rapid combustion strategy. The nanostructured porous Mn3 O4 /C electrode demonstrated impressive electrode properties with reversible capacities of 666 mAh g-1 at a current density of 33 mA g-1 , good capacity retentions (1141 mAh g-1 with 100 % Coulombic efficiencies at the 100th cycle), and rate capabilities (307 and 202 mAh g-1 at 528 and 1056 mA g-1 , respectively) when tested as an anode for lithium-ion battery applications. PMID- 26749374 TI - Antibody-dependent cellular cytotoxicity toward neuroblastoma enhanced by activated invariant natural killer T cells. AB - Anti-ganglioside GD2 antibodies mainly work through antibody-dependent cellular cytotoxicity (ADCC) and have demonstrated clinical benefit for children with neuroblastoma. However, high-risk neuroblastoma still has a high recurrence rate. For further improvement in patient outcomes, ways to maximize the cytotoxic effects of anti-GD2 therapies with minimal toxicity are required. Activated invariant natural killer T (iNKT) cells enhance both innate and type I acquired anti-tumor immunity by producing several kinds of cytokines. In this report, we investigated the feasibility of combination therapy using iNKT cells and an anti GD2 antibody. Although some of the expanded iNKT cells expressed natural killer (NK) cell markers, including FcgammaR, iNKT cells were not directly associated with ADCC. When co-cultured with activated iNKT cells, granzyme A, granzyme B and interferon gamma (IFNgamma) production from NK cells were upregulated, and the cytotoxicity of NK cells treated with anti-GD2 antibodies was increased. Not only cytokines produced by activated iNKT cells, but also NK-NKT cell contact or NK cell-dendritic cell contact contributed to the increase in NK cell cytotoxicity and further IFNgamma production by iNKT cells and NK cells. In conclusion, iNKT cell-based immunotherapy could be an appropriate candidate for anti-GD2 antibody therapy for neuroblastoma. PMID- 26749377 TI - Prenatal counseling for neurodevelopmental delay in congenital heart disease: results of a worldwide survey of experts' attitudes advise caution. PMID- 26749378 TI - How many hours do people sleep in Bangladesh? A country-representative survey. AB - This study investigated total sleep time in the Bangladeshi population and identified the proportion of the population at greater risk of developing chronic diseases due to inadequate sleep. Using a cross-sectional survey, total sleep time was captured and analysed in 3968 respondents aged between 6 and 106 years in 24 (of 64) districts in Bangladesh. Total sleep time was defined as the hours of total sleep in the previous 24 h. We used National Sleep Foundation (2015) guidelines to determine the recommended sleep hours in different age categories. Less or more than the recommended total sleep time (in hours) was considered 'shorter' and 'longer' sleep time, respectively. Linear and multinomial logistic regression models were used to determine the relationship between demographic variables and estimated risk of shorter and longer total sleep time. The mean (+/ standard deviation) total sleep time of children (6-13 years), teenagers (14-17 years), young adults and adults (18-64 years) and older adults (>=65 years) were 8.6 (+/-1.1), 8.1 (+/-1.0), 7.7 (+/-0.9) and 7.8 (+/-1.4) h, respectively, which were significantly different (P < 0.01). More than half of school-age children (55%) slept less than, and 28.2% of older adults slept longer than, recommended. Residents in all divisions (except Chittagong) in Bangladesh were less likely to sleep longer than in the Dhaka division. Rural populations had a 3.96* greater chance of sleeping for a shorter time than urban residents. The Bangladeshi population tends to sleep for longer and/or shorter times than their respective recommended sleep hours, which is detrimental to health. PMID- 26749380 TI - Percutaneous Epicardial Access as an Alternative Approach for Catheter Ablation of a Posteroseptal Accessory Pathway Related to the Coronary Venous System. PMID- 26749381 TI - Comparison of Suicide Attempters and Decedents in the U.S. Army: A Latent Class Analysis. AB - A clearer understanding of risk factors for suicidal behavior among soldiers is of principal importance to military suicide prevention. It is unclear whether soldiers who attempt suicide and those who die by suicide have different patterns of risk factors. As such, preventive efforts aimed toward reducing suicide attempts and suicides, respectively, may require different strategies. We conducted a latent class analysis (LCA) to examine classes of risk factors among suicide attempters (n = 1,433) and decedents (n = 424). Both groups were represented by three classes: (1) External/Antisocial Risk Factors, (2) Mental Health Risk Factors, and (3) No Pattern. These findings support the conceptualization that military suicide attempters and decedents represent a single population. PMID- 26749382 TI - Ultraviolet exposure from indoor tanning devices: a systematic review. AB - Use of indoor tanning devices increases the risk of cutaneous melanoma and nonmelanoma skin cancer. Indoor tanning devices have become important sources of ultraviolet (UV) exposure, both UVB and UVA. This systematic review assessed UV measurements performed in indoor tanning devices related to irradiance level, wavelength distribution and similarities to natural sun. The study was performed in accordance with the MOOSE and PRISMA guidelines. We searched PubMed, Embase and Web of Science from inception to May 2015, and also examined the reference lists of the retrieved studies. Eighteen studies were included. Twelve studies examined the erythema-weighted UV irradiances of indoor tanning devices, 11 studies examined UVB and 13 studies studied UVA. Compliance with irradiance limits was reported in nine studies. Erythema-weighted irradiances were highest in the most recent studies. Most studies had mean values higher than from natural sun and with large variations between devices. All studies except two had mean unweighted UVB irradiances lower than from natural summer sun (at latitudes from 37 degrees S to 35 degrees N), while mean unweighted UVA irradiances were, with one exception, substantially higher than from natural sun. The high values of UVA exposure from modern tanning devices are alarming in light of the increased focus on UVA irradiance as a carcinogen, and as UVA exposure confers little protection against subsequent UV exposure. PMID- 26749379 TI - Pneumolysin activates neutrophil extracellular trap formation. AB - The primary objective of the current study was to investigate the potential of the pneumococcal toxin, pneumolysin (Ply), to activate neutrophil extracellular trap (NET) formation in vitro. Isolated human blood neutrophils were exposed to recombinant Ply (5-20 ng ml(-1) ) for 30-90 min at 37 degrees C and NET formation measured using the following procedures to detect extracellular DNA: (i) flow cytometry using Vybrant(r) DyeCycleTM Ruby; (ii) spectrofluorimetry using the fluorophore, Sytox((r)) Orange (5 MUM); and (iii) NanoDrop((r)) technology. These procedures were complemented by fluorescence microscopy using 4', 6-diamino-2 phenylindole (DAPI) (nuclear stain) in combination with anti-citrullinated histone monoclonal antibodies to visualize nets. Exposure of neutrophils to Ply resulted in relatively rapid (detected within 30-60 min), statistically significant (P < 0.05) dose- and time-related increases in the release of cellular DNA impregnated with both citrullinated histone and myeloperoxidase. Microscopy revealed that NETosis appeared to be restricted to a subpopulation of neutrophils, the numbers of NET-forming cells in the control and Ply-treated systems (10 and 20 ng ml(-1) ) were 4.3 (4.2), 14.3 (9.9) and 16.5 (7.5), respectively (n = 4, P < 0.0001 for comparison of the control with both Ply treated systems). Ply-induced NETosis occurred in the setting of retention of cell viability, and apparent lack of involvement of reactive oxygen species and Toll-like receptor 4. In conclusion, Ply induces vital NETosis in human neutrophils, a process which may either contribute to host defence or worsen disease severity, depending on the intensity of the inflammatory response during pneumococcal infection. PMID- 26749383 TI - Anion-Exchange Properties of Trifluoroacetate and Triflate Salts of N Alkylammonium Resorcinarenes. AB - The synthesis of N-benzyl- and N-cyclohexylammonium resorcinarene trifluoroacetate (TFA) and triflate (OTf) salt receptors was investigated. Solid state analysis by single-crystal X-ray diffraction revealed that the N alkylammonium resorcinarene salts (NARSs) with different upper substituents had different cavity sizes and different affinities for anions. Anion-exchange experiments by mixing equimolar amounts of N-benzylammonium resorcinarene trifluoroacetate and N-cyclohexylammonium resorcinarene triflate, as well as N benzylammonium resorcinarene triflate and N-cyclohexylammonium resorcinarene trifluoroacetate showed that the NARS with flexible benzyl groups preferred the larger OTf anion, whereas the rigid cyclohexyl groups preferred the smaller TFA anions. The anion-exchange processes were confirmed in the solid state by single crystal and powder X-ray diffraction experiments and in the gas phase by electrospray ionization mass spectrometry. PMID- 26749384 TI - Redox-Switchable 20pi-, 19pi-, and 18pi-Electron 5,10,15,20-Tetraaryl-5,15 diazaporphyrinoid Nickel(II) Complexes. AB - The first examples of air-stable 20pi-electron 5,10,15,20-tetraaryl-5,15-diaza 5,15-dihydroporphyrins, their 18pi-electron dications, and the 19pi-electron radical cation were prepared through metal-templated annulation of nickel(II) bis(5-arylamino-3-chloro-8-mesityldipyrrin) complexes followed by oxidation. The neutral 20pi-electron derivatives are antiaromatic and the cationic 18pi-electron derivatives are aromatic in terms of the magnetic criterion of aromaticity. The meso N atoms in these diazaporphyrinoids give rise to characteristic redox and optical properties for the compounds that are not typical of isoelectronic 5,10,15,20-tetraarylporphyrins. PMID- 26749385 TI - The anal fistula plug in Crohn's disease patients with fistula-in-ano: a systematic review. AB - AIM: This study aimed to review, consolidate and analyse the findings of studies investigating the efficacy of anal fistula plugs (AFPs) in treating fistula-in ano in patients with Crohn's disease. METHOD: A literature review was conducted via Pubmed, Embase, Medline, Scopus and the Cochrane Library for the period 1995 2015. Articles were selected and reviewed based on specific inclusion and exclusion criteria. RESULTS: A total of 16 studies were extracted, of which 12 were included in the systematic review. In total, 84 patients (n = 1-20 per study) with a median age of 45 (18-72) years and a median follow-up time of 9 (3 24) months were analysed. The total success rate, defined as closure of the fistula tract, was 49/84 (58.3%, 95% CI 47-69). Success in patients with recurrent anal fistulae was 2/5 (40%, 95% CI 5-85). Overall, the success rates of Surgisis and GORE BIO-A brand plugs were 48/80 (60%, 95% CI 48-71) and 1/4 (25%, 95% CI 1-81). The recurrence rate of fistula-in-ano in the five studies that reported recurrence was 3/22 (13.6%). In two comparative studies, inferior overall success rates were found in patients who received preoperative immunomodulators vs. those who did not [3/11 (27.3%) vs. 17/23 (73.9%)]. CONCLUSION: The studies suggest that the use of an AFP in patients with Crohn's disease is a safe procedure with reasonable success, little morbidity and a low risk of incontinence. The current literature is limited by a number of factors, including small study cohorts, grouping of fistulae in Crohn's disease with other types of anal fistula, short and highly variable follow-up times and multiple confounding factors such as number of fistula tracts, use of preoperative steroids or immunosuppressants, previous use of setons and variation in surgical technique. PMID- 26749386 TI - Mitochondrial DNA copy number in cumulus cells is a strong predictor of obtaining good-quality embryos after IVF. AB - PURPOSE: The aim of this study was to establish a simple tool to predict good quality embryos in in vitro fertilization (IVF) by using cumulus cells (CCs) or peripheral blood cells (PBCs). METHODS: Mitochondrial DNA was extracted from CCs and PBCs in patients undergoing IVF. Using real-time polymerase chain reaction, mtDNA copy number in a single cell was calculated. Embryo quality was assessed when it was transferred or frozen. RESULTS: CCs were obtained from 60 oocyte cumulus-cell complexes (OCCCs) in 30 women, and PBCs were collected from 18 women. For the 30 women in the study, the median age was 37 years old (range, 24 43), and the mean body mass index was 21.4 (standard error, 2.0). mtDNA content of CCs and PBCs was highly correlated (Pearson's r = 0.900, p < 0.0001). The median mtDNA content of CCs for good- and poor-quality embryos was 140 and 57, respectively (p < 0.0001). The median mtDNA content of PBCs for good- and poor quality embryos was 36 and 13, respectively (p = 0.604). The logistic regression model indicated that mtDNA content in CCs was the only parameter that predicted good-quality embryos (p = 0.020). The receiver operating characteristic curve for obtaining good-quality embryos by mtDNA copy number in CCs had an area under the curve of 0.823, and using a threshold of 86, positive and negative predictive values were 84.4 and 82.1 %, respectively. CONCLUSIONS: The determination of mtDNA content in CCs can be used to predict good-quality embryos. PMID- 26749387 TI - Abnormally cleaving embryos are able to produce live births: a time-lapse study. AB - PURPOSE: This study investigated the prevalence of abnormally cleaved embryos and determined which types of abnormally cleaved embryos (1-3c, 2-4c, 3-5c, 4-6c), might be suitable for transfer based on live birth data. METHODS: One hundred seventy-one women (whose transferred embryos were confirmed to be either fully implanted or fully unimplanted) provided 1256 embryos, which were analyzed. RESULTS: Of these embryos, 320 embryos were transferred, of these transferred embryos, 291 embryos were normal and 29 embryos were abnormal, which five embryos were not analyzed because each one was presented one abnormal cleavage type. These 24 embryos were divided into four groups. Inclusion criteria were as follows: women under 37 years of age undergoing first fresh in vitro fertilization (IVF) treatment with a basal antral follicle count of 5-15, body mass index (BMI) of 18-25 kg/m(2), number of retrieved oocytes between 5 and 20, and tubal factors as the cause of infertility. Time-lapse imaging analysis software was used to compare temporal parameters of normal cleavage and abnormal cleavage groups (there were four abnormal groups, based on the prevalence of abnormal cleavage embryos). Cleavage times were analyzed before the abnormal cleavage occurred, and time intervals were analyzed after the abnormal cleavage based upon the types of abnormal cleavage. In addition, the time intervals of t4 t3 and t8-t5 were also analyzed; corresponding time parameters were measured in the normal group as well. Implantation rate, clinical pregnancy rate, ongoing pregnancy rate, and live birth rate were also measured in the normally cleaved and abnormally cleaved embryos. The prevalence of abnormal cleavage was 15.92% (200/1256). T8-t5 was the most important parameter in the prediction of potential development (production of a live-born baby) of abnormally cleaving embryos. CONCLUSIONS: Abnormally cleaving embryos were able to produced live births with T8-t5 the best parameter to predict the developmental potential of abnormally cleaving embryos. PMID- 26749388 TI - The freezing method of cleavage stage embryos has no impact on the weight of the newborns. AB - PURPOSE: The aim of this study was to study the effect of the embryo freezing method on the birth weight of newborns from frozen embryo transfer (FET) cycles, and the pregnancy results of cleavage stage embryos cryopreserved by slow freezing or vitrification. METHODS: This is a retrospective cohort study undertaken in a University Hospital IVF unit using concurrently both the slow freezing and the vitrification techniques. All frozen-thawed and vitrified-warmed day 2 and day 3 embryo transfers during the time period from 1 April 2009 to 31 November 2013 were included in the study. RESULTS: There was no statistically significant weight difference between newborns from vitrified or slow-frozen embryos (3588 vs 3670 g). A higher post-thaw viability rate was achieved after cryopreservation by the vitrification technique compared to the slow-freezing protocol (83.4 vs 61.4%). The miscarriage rate was lower in the vitrification group (15.7 vs 29.0%). The live birth rates were similar (19.5 vs 19.1%) in the slow-freezing and vitrification groups, respectively. Among vitrified embryos, 7.4 embryos needed to be thawed to produce one delivery; in the slow-freezing group, that number was 11.9. CONCLUSIONS: The freezing method has no impact on the weight of the newborn. With lower post-thaw survival rates and higher miscarriage rates, the slow-freezing cryopreservation protocol is inferior to the vitrification technique. PMID- 26749389 TI - Live births resulting from 0PN-derived embryos in conventional IVF cycles. AB - PURPOSE: The aim of this study was to (1) investigate the incidence of embryos derived from "unfertilized oocytes" i.e., oocytes not displaying pronuclei (0PN) at the time of the fertilization check and (2) determine the clinical pregnancy rates when transferring 0PN-derived embryos. METHODS: In this retrospective study, 4424 IVF-ET cycles were reviewed. RESULTS: In total, 11.3% (4966/43,949) 0PN-derived embryos were observed. It was found that female age, number of oocytes, and the top-quality embryo rate were significantly correlated with 0PN derived embryo occurrence. The source of embryos transferred did not impact significantly on clinical pregnancy and live-birth rates. Of the 183 cycles included in this study where 275 0PN-derived embryos were transferred in total, only 0PN-derived embryos were available in 70 of those cycles. It was noteworthy that 13 healthy infants resulted from 0PN-derived embryos with an implantation rate of 17.0%. CONCLUSION: These results indicate that the traditional method of excluding embryos because of those oocytes originally lacking any sign of a pronucleus at the fertilization check should be re-considered as transferring 0PN derived embryos with subsequent expected developmental performance may be considered as an option for those patients where no other embryos are available. PMID- 26749390 TI - Lay Conceptions of Volitional Personality Change: From Strategies Pursued to Stories Told. AB - Recent research suggests that individuals play an active role in their own personality development. Here, we investigated lay conceptions of this volitional personality change process. In Study 1, participants (N = 602) provided open ended descriptions of their desired personality changes as well as the strategies they were using to achieve these changes. In Study 2, participants (N = 578) completed these same measures and provided narrative descriptions of the emergence of their desires for (and previous) personality changes. Desired changes were quantified in a manner consistent with the Five-Factor Model (though desires pertinent to Openness to Experience were rare), whereas reported strategies were distinguished on the basis of cognitive and behavioral content. Desires to increase in Extraversion corresponded negatively with the use of cognitive strategies and positively with the use of behavioral strategies, whereas desires to increase in Agreeableness exhibited the opposite pattern. Finally, desires for change were typically construed as stimulated by specific events, whereas previous personality changes were attributed to shifts in social roles. Laypersons hold a diverse range of desired changes and strategies. In addition, different categories of events are recognized as catalysts of desires for (and previous) changes. PMID- 26749392 TI - Surgical ward round checklist: does it improve medical documentation? A clinical review of Christchurch general surgical notes. AB - BACKGROUND: Poor documentation of medical notes and plans not only adversely affects patient management but also has medico-legal implications. A standardized ward round checklist (adhesive proforma sticker, PFS) was introduced at our institution in 2013 to improve documentation by junior doctors. We aimed to examine the current pattern of PFS documentation (2 years after its introduction) and to identify which fields, if any, have been the most problematic to complete. METHODS: Notes of all current general surgical inpatients admitted to Christchurch Public Hospital on or before the two study days were reviewed. All information written in the PFS, regardless of accuracy, authorship or completeness, was recorded. Documentation of the various PFS fields was classified as well documented (completed in >80% of PFS), inadequate (40-80%) or minimal (<40%). RESULTS: Four hundred and seventy-nine PFS were reviewed. Most fields in the PFS were documented to an adequate level (i.e. >80%). Problematic fields identified were dietary plans, diagnosis, national health index number, estimated date of discharge and the patient's first name. Notes of patients on outlying ward contained significantly fewer PFS compared with home-ward patients' notes (0.71 PFS/day versus 1.21 PFS/day, respectively, P < 0.001). CONCLUSION: Our study has shown generally adequate patterns of medical note documentation in the General Surgery service. Certain fields remain challenging to document accurately. The proposed modified PFS was designed to help rectify this; electronic data record may be the step forward, however. It is hoped that other institutions in Australasia would benefit from our experience. PMID- 26749391 TI - An International Urogynecological Association (IUGA) / International Continence Society (ICS) Joint Report on the Terminology for Female Pelvic Organ Prolapse (POP). AB - INTRODUCTION: The terminology for female pelvic floor prolapse (POP) should be defined and organized in a clinically-based consensus Report. METHODS: This Report combines the input of members of two International Organizations, the International Urogynecological Association (IUGA) and the International Continence Society (ICS), assisted at intervals by external referees. Appropriate core clinical categories and a sub-classification were developed to give a coding to definitions. An extensive process of fourteen rounds of internal and external review was involved to exhaustively examine each definition, with decision-making by collective opinion (consensus). RESULTS: A Terminology Report for female POP, encompassing over 230 separate definitions, has been developed. It is clinically based with the most common diagnoses defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in female pelvic floor dysfunction and POP. Female-specific imaging (ultrasound, radiology and MRI) and conservative and surgical managements are major additions and appropriate figures have been included to supplement and clarify the text. Emerging concepts and measurements, in use in the literature and offering further research potential, but requiring further validation, have been included as an appendix. Interval (5-10 year) review is anticipated to keep the document updated and as widely acceptable as possible. CONCLUSION: A consensus-based Terminology Report for female POP has been produced to aid clinical practice and research. PMID- 26749393 TI - Spectacular response of metastatic vulval Crohn's disease to infliximab treatment. PMID- 26749394 TI - Aliphatic Halogenase Enables Late-Stage C-H Functionalization: Selective Synthesis of a Brominated Fischerindole Alkaloid with Enhanced Antibacterial Activity. AB - The anion promiscuity of a newly discovered standalone aliphatic halogenase WelO5 was probed and enabled the selective synthesis of 13R-bromo-12-epi-fischerindole U via late-stage enzymatic functionalization of an unactivated sp(3) C-H bond. Pre-saturating the WelO5 active site with a non-native bromide anion was found to be critical to the highly selective in vitro transfer of bromine, instead of chlorine, to the target carbon center and also allowed the relative binding affinity of bromide and chloride towards the WelO5 enzyme to be assessed. This study further revealed the critical importance of halogen substitution on modulating the antibiotic activity of fischerindole alkaloids and highlights the promise of WelO5-type aliphatic halogenases as enzymatic tools to fine-tune the bioactivity of complex natural products. PMID- 26749395 TI - A short note on measuring subjective life expectancy: survival probabilities versus point estimates. AB - Understanding subjective longevity expectations is important, but measurement is not straightforward. Two common elicitation formats are the direct measurement of a subjective point estimate of life expectancy and the assessment of survival probabilities to a range of target ages. This study presents one of the few direct comparisons of these two methods. Results from a representative sample of the Dutch population indicate that respondents on average gave higher estimates of longevity using survival probabilities (83.6 years) compared to point estimates (80.2 years). Individual differences between elicitation methods were smaller for younger respondents and for respondents with a higher socioeconomic status. The correlation between the subjective longevity estimations was moderate, but their associations with respondents' characteristics were similar. Our results are in line with existing literature and suggest that findings from both elicitation methods may not be directly comparable, especially in certain subgroups of the population. Implications of inconsistent and focal point answers, rounding and anchoring require further attention. More research on the measurement of subjective expectations is required. PMID- 26749396 TI - The enablers and barriers to continue breast milk feeding in women returning to work. AB - AIM: To describe the enablers and barriers working women experience in continuing breast milk feeding after they return to work postpartum in urban Malaysia. BACKGROUND: In Malaysia, urban working women have low rates of breastfeeding and struggle to achieve the recommended 6 months exclusive breastfeeding. DESIGN: A qualitative enquiry based on a phenomenological framework and multiple methods were used to explore women's experiences in depth. METHODS: Multiple qualitative methods using face-to-face interview and participant diary were used. Data collection took place in urban suburbs around Penang and Klang Valley, Malaysia from March-September 2011. Participants were 40 employed women with infants less than 24 months. FINDINGS: Only 11 of the participants worked from home. Based on the women's experiences, we categorized them into three groups: 'Passionate' women with a strong determination and exclusively breastfed for 6 months, 'Ambivalent' women who initiated breastfeeding, but were unable to sustain exclusive breastfeeding after returning to work and 'Equivalent' women who introduced infant formula prior to returning to work. CONCLUSION: Passion and to a lesser extent intention, influenced women's choice. Women's characteristics played a greater role in their infant feeding outcomes than their work environment. PMID- 26749397 TI - The Need to Target Mucosa-Associated Lymphoid Tissue for Preventing Lymphoma in Rheumatoid Factor-Positive Patients With Sjogren's Syndrome: Comment on the Article by Nocturne et al. PMID- 26749398 TI - Diagnostic value of eccrine glands and hair follicles in direct immunofluorescent analysis of pemphigus vulgaris and bullous pemphigoid. AB - The immunofluorescence pattern in adnexal structures may be of value, especially when the epidermis is not well represented in diagnostic sections. We studied a total of 88 cases of pemphigus vulgaris (PV) and bullous pemphigoid (BP) accessioned between 2010 and 2015 (40 cases of PV and 48 cases of BP). Immunofluorescence patterns and sensitivity in adnexal structures were similar to those observed in the epidermis. One case of PV and three cases of BP showed weak or absent fluorescence in the epidermis, while the eccrine glands were strongly positive, suggesting that careful examination of adnexal structures can be of value. PMID- 26749399 TI - Anticipatory Behavior in Response to Medicare Part D's Coverage Gap. AB - Under the standard Medicare Part D benefit structure, copayments for medications change discontinuously at certain levels of accumulative drug spending. Beneficiaries pay 25% of the cost of medications in the initial phase, 100% in the coverage gap, and 5% in the catastrophic phase. We examine whether individuals anticipate these copayment changes and adjust their consumption in advance. We use variation in birth-months of beneficiaries who enroll in Part D plans when they first turn 65. Birth-months generate exogenous variation in the end-of-year price because those who enroll earlier in the year are more likely to reach the coverage gap than those who enroll later. We study the impact of variation in end-of-year price on the first three months of medication use immediately following enrollment. We use difference-in-differences to adjust for seasonal trends in use, by comparing our main study group with those who receive low-income subsidies, and therefore do not face a coverage gap. We find strong evidence of anticipatory behavior, with an implied elasticity with respect to future prices ranging from -0.2 to -0.5. In addition, we find that beneficiaries modify their consumption by changing the quantity of prescriptions filled, instead of switching between brand-name and generic drugs. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26749400 TI - Does kinship affect spatial organization in a small and isolated population of a solitary felid: The Eurasian lynx? AB - Social organization in wild carnivores is mostly determined by patterns of family bonds, which may shape the degree of relatedness among individuals in the population. We studied kinship in a small and isolated population of a solitary carnivore, the Eurasian lynx (Lynx lynx) to evaluate its effect on spatial distribution of individuals. We investigated the relationship between spatial location and pair-wise kinship among 28 lynx individuals identified in 2004-2011 by telemetry, non-invasive sampling and genotyping with the use of 12 autosomal microsatellites in the Bialowieza Primeval Forest, Poland. The average relatedness of the lynx population was relatively low (Lynch and Ritland's R = 0.03). Females were significantly more related to each other than males with other males. The inferred pedigree showed that the population was dominated by only 2 familial groups. We did not find significant correlations between the relatedness and the extent of home range overlap or the straight-line distances between the home ranges' central points. These results suggest that the dynamics of kinship in this solitary felid may not differ from the random mating processes described in social carnivores. Although the chances of random mating could be limited to a few resident males and females, the presence of unrelated floaters may provide a "breeding buffer" that may prevent an increase of relatedness and likely inbreeding in the population. This system is likely to fail in preserving genetic diversity in small, highly isolated populations; therefore, restoring habitat connectivity is crucial to ensure sufficient immigration from neighboring populations. PMID- 26749401 TI - Conformation analysis of d-glucaric acid in deuterium oxide by NMR based on its JHH and JCH coupling constants. AB - d-Glucaric acid (GA) is an aldaric acid and consists of an asymmetric acyclic sugar backbone with a carboxyl group positioned at either end of its structure (i.e., the C1 and C6 positions). The purpose of this study was to conduct a conformation analysis of flexible GA as a solution in deuterium oxide by NMR spectroscopy, based on J-resolved conformation analysis using proton-proton ((3) JHH ) and proton-carbon ((2) JCH and (3) JCH ) coupling constants, as well as nuclear overhauser effect spectroscopy (NOESY). The (2) JCH and (3) JCH coupling constants were measured using the J-resolved heteronuclear multiple bond correlation (HMBC) NMR technique. NOESY correlation experiments indicated that H2 and H5 were in close proximity, despite the fact that these protons were separated by too large distance in the fully extended form of the chain structure to provide a NOESY correlation. The validities of the three possible conformers along the three different bonds (i.e., C2?C3, C3?C4, and C4?C5) were evaluated sequentially based on the J-coupling values and the NOESY correlations. The results of these analyses suggested that there were three dominant conformers of GA, including conformer 1, which was H2H3:gauche, H3H4:anti, and H4H5:gauche; conformer 2, which was H2H3:gauche, H3H4:anti, and H4H5:anti; and conformer 3, which was H2H3:gauche, H3H4: gauche, and H4H5:anti. These results also suggested that all three of these conformers exist in equilibrium with each other. Lastly, the results of the current study suggested that the conformational structures of GA in solution were 'bent' rather than being fully extended. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26749402 TI - Advancing translational research with next-generation protein microarrays. AB - Protein microarrays are a high-throughput technology used increasingly in translational research, seeking to apply basic science findings to enhance human health. In addition to assessing protein levels, posttranslational modifications, and signaling pathways in patient samples, protein microarrays have aided in the identification of potential protein biomarkers of disease and infection. In this perspective, the different types of full-length protein microarrays that are used in translational research are reviewed. Specific studies employing these microarrays are presented to highlight their potential in finding solutions to real clinical problems. Finally, the criteria that should be considered when developing next-generation protein microarrays are provided. PMID- 26749403 TI - Anakinra-Induced Acute Liver Failure in an Adolescent Patient with Still's Disease. AB - The interleukin-1 (IL-1) family consists of 11 cytokines that play key regulatory roles in many immune and inflammatory processes. Anakinra (Kineret, Amgen, Inc.) is an IL-1 receptor antagonist (IL-1ra). Increased levels of IL-1 are found in several disease states suggesting that anakinra may be beneficial in disorders associated with elevated IL-1 levels. Anakinra has been effectively used in the treatment of systemic juvenile idiopathic arthritis and adult-onset Still's disease (AOSD). Despite its therapeutic benefits, anakinra also has potential side effects, including hepatotoxicity. We present a case of AOSD in an adolescent male that was treated with anakinra. During treatment, the patient developed acute liver failure that resolved upon withdrawal of anakinra. Although anakinra-induced liver injury has been reported in adults, including one case of subacute liver failure, we believe our case is the first to show severe acute liver failure in an adolescent treated with anakinra. This case provides significant insight into a potentially serious complication associated with anakinra. It is important to further delineate these complications as the treatment indications for this drug expand. PMID- 26749405 TI - Diagnostic Accuracy of Ultrasound to Predict the Location of Solitary Hepatic Masses in Dogs. AB - OBJECTIVE: To determine the sensitivity, specificity, and predictive value of ultrasonography for localizing hepatic masses in dogs and to identify patient factors associated with diagnostic accuracy. STUDY DESIGN: Retrospective cross sectional study. ANIMALS: Client-owned dogs (n = 137). METHODS: Medical records of dogs diagnosed with a solitary hepatic mass on abdominal ultrasound and confirmed by laparotomy or laparoscopy were reviewed. Location of the mass predicted by ultrasound was compared to mass location identified at surgery. Ultrasound exams were performed by or under the supervision of a board certified radiologist. Sensitivity, specificity, and positive predictive values were calculated. Patient factors associated with accurate localization were identified using logistic regression. RESULTS: Ultrasound correctly localized liver masses in 71/137 dogs (51.8%). The sensitivity of ultrasound localization was 55% for left and right division masses and 29% for central division masses. The specificity was 98% for left division masses, 87% for central division masses, and 89% for right division masses. Correct localization was 3.2 times more likely when the mass arose from the right or left division compared to the central division (odds ratio [OR] 3.2; 95% confidence intervals [CI] 1.1, 9.0; P = .030). Correct localization was significantly less likely when diffuse or multifocal hepatic disease was present (OR 0.32; 95% CI 0.15, 0.70; P = .004). CONCLUSION: Ultrasound was specific but not sensitive for localizing hepatic masses, and localization accuracy was influenced by mass location and the presence of concurrent liver pathology. These findings should be taken into consideration by veterinary surgeons using ultrasound examination to guide patient treatment and surgical planning. PMID- 26749406 TI - Collagen-mediated hemostasis. AB - Collagens mediate essential hemostasis by maintaining the integrity and stability of the vascular wall. Imbalanced turnover of collagens by uncontrolled formation and/or degradation may result in pathologic conditions such as fibrosis. Thickening of the vessel wall because of accumulation of collagens may lead to arterial occlusion or thrombosis. Thinning of the wall because of collagen degradation or deficiency may lead to rupture of the vessel wall or aneurysm. Preventing excessive hemorrhage or thrombosis relies on collagen-mediated actions. Von Willebrand factor, integrins and glycoprotein VI, as well as clotting factors, can bind collagen to restore normal hemostasis after trauma. This review outlines the essential roles of collagens in mediating hemostasis, with a focus on collagens types I, III, IV, VI, XV, and XVIII. PMID- 26749407 TI - Effect of ranolazine on glycaemic control in patients with type 2 diabetes treated with either glimepiride or metformin. AB - AIM: To report the results of two phase III trials assessing the efficacy of ranolazine for glycaemic control in patients with type 2 diabetes on metformin or glimepiride background therapy. METHODS: In two double-blind trials we randomized 431 and 442 patients with type 2 diabetes to ranolazine 1000 mg twice daily versus placebo added to either glimepiride (glimepiride add-on study) or metformin background therapy (metformin add-on study). Patients receiving ranolazine added to metformin had their metformin dose halved (with the addition of a metformin-matched placebo) relative to the placebo group to correct for a metformin-ranolazine pharmacokinetic interaction. The primary endpoint of the trials was the change from baseline in glycated haemoglobin (HbA1c) at week 24. RESULTS: When added to glimepiride, ranolazine caused a 0.51% least squares mean [95% confidence interval (CI) 0.71, 0.32] decrease from baseline in HbA1c at 24 weeks relative to placebo and roughly doubled the proportion of patients achieving an HbA1c of <7% (27.1 vs 14.1%; p = 0.001). When added to metformin background therapy, there was no significant difference in the 24-week HbA1c change from baseline [placebo-corrected LS mean difference -0.11% (95% CI -0.31, 0.1)]. CONCLUSIONS: Compared with placebo, addition of ranolazine in patients with type 2 diabetes treated with glimepiride, but not metformin, significantly reduced HbA1c over 24 weeks. The decreased dose of metformin used in the metformin add-on study complicates the interpretation of this trial. Whether an effective regimen of ranolazine added to metformin for glycaemic control can be identified remains unclear. PMID- 26749408 TI - Effect of Rifampin on the Pharmacokinetics of Apixaban, an Oral Direct Inhibitor of Factor Xa. AB - OBJECTIVE: Apixaban is a substrate of cytochrome P450 3A4 (CYP3A4) and P glycoprotein. The effects of rifampin, a strong inducer of CYP3A4 and P glycoprotein, on the pharmacokinetics of oral and intravenous apixaban were evaluated in an open-label, randomized, sequential crossover study. METHODS: Twenty healthy participants received single doses of apixaban 5 mg intravenously on day 1 and 10 mg orally on day 3, followed by rifampin 600 mg once daily on days 5-15. Finally, participants received single doses of apixaban 5 mg intravenously and 10 mg orally separately on days 12 and 14 in one of two randomized sequences. RESULTS: Apixaban, given intravenously and orally, was safe and well tolerated when administered in the presence and absence of rifampin. Apixaban absolute oral bioavailability was 49 % when administered alone and 39 % following induction by rifampin. Rifampin reduced apixaban area under the plasma concentration-time curve from time zero to infinity (AUCinfinity) by 39 % after intravenous administration and by 54 % after oral administration. Rifampin induction increased mean clearance by 1.6-fold for intravenous apixaban and mean apparent clearance by 2.1-fold for oral apixaban, indicating rifampin affected both pre-systemic and systemic apixaban elimination pathways. CONCLUSION: Co administration of apixaban with rifampin reduced apixaban exposure via both decreased bioavailability and increased systemic clearance. PMID- 26749404 TI - Mechanisms of autoimmunity in the non-obese diabetic mouse: effector/regulatory cell equilibrium during peak inflammation. AB - Immune imbalance in autoimmune disorders such as type 1 diabetes may originate from aberrant activities of effector cells or dysfunction of suppressor cells. All possible defective mechanisms have been proposed for diabetes-prone species: (i) quantitative dominance of diabetogenic cells and decreased numbers of regulatory T cells, (ii) excessive aggression of effectors and defective function of suppressors, (iii) perturbed interaction between effector and suppressor cells, and (iv) variations in sensitivity to negative regulation. The experimental evidence available to date presents conflicting information on these mechanisms, with identification of perturbed equilibrium on the one hand and negation of critical role of each mechanism in propagation of diabetic autoimmunity on the other hand. In our analysis, there is no evidence that inherent abnormalities in numbers and function of effector and suppressor T cells are responsible for the immune imbalance responsible for propagation of type 1 diabetes as a chronic inflammatory process. Possibly, the experimental tools for investigation of these features of immune activity are still underdeveloped and lack sufficient resolution, in the presence of the extensive biological viability and functional versatility of effector and suppressor elements. PMID- 26749409 TI - Prolonged Clopidogrel Use is Associated with Improved Clinical Outcomes Following Drug-Eluting But Not Bare Metal Stent Implantation. AB - BACKGROUND: Guidelines recommend clopidogrel use for 6-12 months following drug eluting stent (DES) implantation and 1-12 months following bare metal stent (BMS) implantation. The role of clopidogrel beyond 12 months is unclear. METHODS: We linked hospital administrative, community pharmacy and cardiac revascularization data to determine clopidogrel use and outcomes for all patients (those with acute presentations and those with stable angina) receiving a coronary stent in British Columbia 2004-2006, with follow-up until the end of 2008. Cox proportional hazard regression was performed to evaluate the effect of clopidogrel duration (<=12 vs. >12 months) on outcomes following BMS or DES implantation. Patients who died <=12 months from index stent placement were excluded. RESULTS: A total of 15,629 patients were included in the study. Of 3599 patients who received at least one DES and 12,030 patients who received only BMS, 1326 (37 %) and 2121 (18 %), respectively, filled a prescription for clopidogrel >12 months from the index procedure. The mean duration of clopidogrel was 406 +/- 35 days and 407 +/- 37 days in the prolonged use (>12 months) DES and BMS cohorts, respectively, compared with 224 +/- 112 days (p < 0.001) and 122 +/- 117 days (p < 0.001), respectively, for patients receiving clopidogrel <=12 months. Clopidogrel use beyond 12 months was associated with a reduction in mortality [hazard ratio (HR) 0.66, 95 % confidence interval (CI) 0.45-0.97] and the composite of mortality and readmission for myocardial infarction (HR 0.72, 95 % CI 0.55-0.94) in patients treated with DES, but not BMS alone. Prolonged clopidogrel use was not associated with bleeding-related mortality. CONCLUSIONS: Clopidogrel use beyond 12 months was associated with a reduction in death and hospitalization for myocardial infarction following DES, but not BMS, implantation. Our findings support a longer duration of clopidogrel therapy for patients treated with DES. PMID- 26749411 TI - Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass for Type 2 Diabetes Mellitus. AB - BACKGROUND: Laparoscopic sleeve gastrectomy with duodenojejunal bypass (LSG-DJB), which has been positioned as a novel bariatric procedure, is the combination of vertical sleeve gastrectomy and proximal intestinal bypass and is theoretically expected to have strong anti-diabetic effect. Also, preserving the pylorus, a physiological valve, leads to less occurrence of dumping syndrome and anastomotic stenosis which are often problematic after laparoscopic Roux-en-Y gastric bypass (LRYGB), a gold standard. The purpose of this study was to investigate the clinical effects of LSG-DJB on obese patients with type 2 diabetes mellitus (T2DM). METHODS: Consecutive 75 obese patients (female 44/male 31) associated with T2DM who underwent LSG-DJB and were followed up for at least 1 year were analyzed. The mean age was 45.5 +/- 8.6 years, and the mean preoperative body weight (BW) and body mass index (BMI) were 108.4 +/- 21.4 kg and 39.6 +/- 7.3 kg/m(2), respectively. The mean hemoglobin A1c (HbA1c) at the first visit was 9.0 +/- 1.9 %, and the duration of T2DM from diagnosis was 7.2 +/- 6.2 years. Thirty six out of the 75 patients (48 %) were treated with insulin preoperatively. All patients were evaluated and managed under a strict multidisciplinary team approach. The follow-up rate at 1 year was 89 %. RESULTS: At 1 year, the mean BW and BMI significantly dropped to 74.6 +/- 16.9 kg and 27.5 +/- 5.7 kg/m(2), respectively. The mean percent of excess weight loss (%EWL) and percent of total body weight loss (%TWL) were 99.4 +/- 42.4 and 31.6 +/- 8.8 %, respectively. Consequently, 68.7 % of the patients achieved HbA1c less than 6 %, and 82.1 % of them achieved HbA1c less than 6.5 % without diabetes medications. Glycemic control of HbA1c less than 7 % was achieved in 91.0 % of the patients. The percentage of patients who satisfied the American Diabetes Association (ADA) defined composite endpoints for cardiovascular disease (CVD) risk factor control increased from 0 % (at baseline) to 31 % (at 1 year). A meal tolerance test revealed significant reduction of glucose area under the curve (AUC) and increase of insulin AUC postoperatively. CONCLUSIONS: LSG-DJB for obese patients with T2DM has strong anti-diabetic effect in the short-term; however, a larger number of patients with a longer follow-up period are needed for definitive conclusions. PMID- 26749410 TI - Small Bowel Limb Lengths and Roux-en-Y Gastric Bypass: a Systematic Review. AB - There is currently no consensus on the combined length of small bowel that should be bypassed as biliopancreatic or alimentary limb for optimum results with Roux en-Y gastric bypass. A number of different limb lengths exist, and there is significant variation in practice amongst surgeons. Inevitably, this means that some patients have too much small bowel bypassed and end up with malnutrition and others end up with a less effective operation. Lack of standardisation poses further problems with interpretation and comparison of scientific literature. This systematic review concludes that a range of 100-200 cm for combined length of biliopancreatic or alimentary limb gives optimum results with Roux-en-Y gastric bypass in most patients. PMID- 26749412 TI - Formation and removal of poly-ubiquitin chains in the regulation of tumor necrosis factor-induced gene activation and cell death. AB - Tumor necrosis factor (TNF) is a potent cytokine known for its involvement in inflammation, repression of tumorigenesis and activation of immune cells. Consequently, accurate regulation of the TNF signaling pathway is crucial for preventing the potent noxious effects of TNF. These pathological conditions include chronic inflammation, septic shock, cachexia and cancer. The TNF signaling cascade utilizes a complex network of post-translational modifications to control the cellular response following its activation. Next to phosphorylation, the ubiquitination of signaling complex components is probably the most important modification. This process is mediated by a specialist class of enzymes, the ubiquitin ligases. Equally important is the class of dedicated ubiquitin-specific proteases, the deubiquitinases. Together with ubiquitin binding proteins, this ubiquitination-deubiquitination system enables the dynamics of signaling complexes. In TNF signaling, these dynamics translate into the precise regulation of the induction of gene activation or cell death. Here, we review and discuss current knowledge of TNF signaling regulation by the ubiquitin system. PMID- 26749413 TI - Effects of Dietary Copper-Methionine on Matrix Metalloproteinase-2 in the Lungs of Cold-Stressed Broilers as an Animal Model for Pulmonary Hypertension. AB - The objective of the present study was to investigate the effects of different levels of copper (as supplemental copper-methionine) on ascites incidence and matrix metalloproteinase-2 (MMP-2) changes in the lungs of cold-stressed broilers. For this purpose, 480 1-day-old Ross 308 broiler chickens were randomly assigned to six treatments. Treatments consisted of two ambient temperatures (thermoneutral and cold stress) each combined with 0, 100, and 200 mg supplemental copper/kg as copper-methionine in a 2 * 3 factorial arrangement in a completely randomized design with four replicates. Ascites was diagnosed based on abdominal and pericardial fluid accumulation at 45 days of age. Fourty-eight broilers were killed at 38 and 45 days of age, and their lungs were collected for biological analysis. Results showed that MMP-2 increased in the lungs of ascitic broilers and that copper-methionine supplementation significantly reduced MMP-2 in cold-stressed broiler chickens. Treatments did not affect tissue inhibitor of metalloproteinase-2 (TIMP-2) at 38 and 45 days of age, and no difference was observed between 100 and 200 mg/kg copper-methionine treatments. In conclusion, copper-methionine at higher than conventional levels of supplementation decreased ascites incidence in low temperature through reduced MMP-2 concentration. Further research is warranted to investigate the effect of copper on MMP-2 concentrations in other tissues with high oxygen demand. PMID- 26749414 TI - Zinc Carnosine Inhibits Lipopolysaccharide-Induced Inflammatory Mediators by Suppressing NF-kappab Activation in Raw 264.7 Macrophages, Independent of the MAPKs Signaling Pathway. AB - This study aimed to investigate the role of the mitogen-activated protein kinases (MAPKs) signaling pathway in the anti-inflammatory effects of zinc carnosine (ZnC) in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Cells were pretreated with ZnC (0-100 MUM) for 2 h prior to the addition of LPS (1 MUg/ml). Following 24 h of treatment, ZnC was found not to be cytotoxic to RAW 264.7 cells up to the concentration of 100 MUM. Our current findings showed that ZnC did not protect RAW 264.7 cells from LPS-induced "respiratory burst". Significant increment in intracellular glutathione (GSH) level and reduction in thiobarbituric acid reactive substances (TBARS) concentration can only be observed in cell pretreated with high doses of ZnC only (50 and 100 MUM for GSH and 100 MUM only for TBARS). On the other hand, pretreatment of cells with ZnC was able to inhibit LPS-induced inducible nitric oxide synthase and cyclooxygenase-2 expression significantly. Furthermore, results from immunoblotting showed that ZnC was able to suppress nuclear factor-kappaB (NF-kappaB) activation, and highest suppression can be observed at 100 MUM of ZnC pretreatment. However, pretreatment of ZnC did not inhibit the early activation of MAPKs. In conclusion, pretreatment with ZnC was able to inhibit the expression of inflammatory mediators in LPS-induced RAW 264.7 cells, mainly via suppression of NF-kappaB activation, and is independent of the MAPKs signaling pathway. PMID- 26749415 TI - Clinical characteristics of type 2 diabetic patients on basal insulin therapy with adequate fasting glucose control who do not achieve HbA1c targets. AB - BACKGROUND: The aim of the present study was to determine the clinical characteristics of patients with type 2 diabetes mellitus (T2DM) treated with basal insulin who achieved an adequate fasting plasma glucose (FPG) level (<130 mg/dL), but were unable to achieve the HbA1c target (<7%; <53 mmol/mol). METHODS: A cross-sectional study was performed on T2DM patients aged 31-90 years treated with basal insulin registered in the SIDIAPQ primary healthcare electronic database during 2010. RESULTS: In 2010, of a population of 126 811 T2DM subjects, 9899 were treated with basal insulin (neutral protamine Hagedorn [NPH], detemir, or glargine). Of these, 23.5% (n = 2322) achieved optimal FPG control levels (<130 mg/dL) but an inadequate HbA1c target (>7%). Mean HbA1c values in the contolled and uncontrolled groups were 8.15% (65.6 mmol/mol) and 6.31% (45.5 mmol/mol), respectively. Patients with controlled FPG but uncontrolled HbA1c had longer T2DM duration (11.6 vs 9.9 years), higher systolic blood pressure (138.2 vs 136.3 mmHg) and low-density lipoprotein cholesterol (104 vs 99 mg /dL), and a higher prevalence of retinopathy (24.8% vs 18.2%) than patients (17.8%) with optimal control of both glycemic targets (P < 0.05). Multivariate analysis showed that inadequate glycemic control was positively related only to younger age. CONCLUSION: One-quarter of T2DM patients treated with basal insulin have difficulties attaining the recommended HbA1c goal despite adequate FPG levels. As some guidelines state, healthcare professionals should focus on PPG to identify and intensify treatment to control prandial glucose excursions in these patients. PMID- 26749416 TI - Vulnerability to typhoon hazards in the coastal informal settlements of Metro Manila, the Philippines. AB - In many low- and middle-income countries informal communities-also termed slum and squatter areas-have become a dominant and distinct form of urban settlement, with ever increasing populations. Such communities are often located in areas of high hazard exposure and frequently affected by disasters. While often recognised as one of the highest 'at risk' populations, this paper will argue that informal settlers have been directly and indirectly excluded from many formal mechanisms, thereby increasing their vulnerability to disaster events. Household surveys were conducted across several frequently flooded informal coastal communities in Metro Manila, the Philippines, following a major typhoon and storm surge disaster. The study revealed a large level of diversity in socio-economic vulnerability, although all households faced similar levels of physical exposure and physical vulnerability. Disaster risk reduction policies and responses need to better integrate informal settlement areas and recognise the diversity within these communities. PMID- 26749417 TI - The fate of buccal bone around dental implants. A 12-month postloading follow-up study. AB - INTRODUCTION AND AIM: Buccal bone thickness is considered to be an important factor during implant surgery. Its resorption might have an effect on the soft tissue stability and eventually on implant survival. This study aimed to investigate the resorption of the buccal bone over the first 12 months after implant loading. MATERIALS AND METHODS: Twenty-four subjects (47 implants) were included. The buccal bone thickness was measured during implant surgery at several distances from the implant shoulder using a specifically designed device which allows buccal bone thickness measurements without the elevation of a muco periostal flap. These measurements were repeated after 12 months of loading. Sixteen implants were placed flapless and 31 with the elevation of a flap. Of the latter, 19 were placed following a one-stage protocol and 12 following a two stage protocol. RESULTS: The mean reduction in buccal bone thickness, when all groups pooled, was 0.26, 0.36, 0.35 and 0.27 mm at the shoulder and 2, 4 and 6 mm apically. Implants with initial bone thickness <1mm (thin buccal plate) did not lose significantly more bone than those with an initial thickness >=1mm (thick bone plate) except in the 'open-flap, one-stage' group (P = 0.009). A flapless procedure leads to less bone resorption compared to an open-flap procedure (P = 0.03). However, the number of surgeries (one stage vs. two stages) did not influence the rate of bone resorption (P = 0.23). CONCLUSION: Within the limitations of this study, one might question the necessity of having a thick bone plate at the vestibular site of the implant. PMID- 26749418 TI - Flexible Electronics: Theoretical and Experimental Studies of Epidermal Heat Flux Sensors for Measurements of Core Body Temperature (Adv. Healthcare Mater. 1/2016). AB - On page 119, J. A. Rogers and co-workers present theoretical approaches, modeling algorithms, materials, and device designs for the noninvasive measurement of core body temperature by using multiple differential temperature sensors that attach softly and intimately onto the surface of the skin. The image shows the construction of differential temperature sensors using thermally insulating foam as the separation material. PMID- 26749420 TI - A Tribute to Professor Kahp-Yang Suh (1972-2013). PMID- 26749423 TI - Circulating calcium concentrations, vascular disease and mortality: a systematic review. AB - Associations between serum calcium and vascular disease have been reported, but the consistency of these findings is unknown. We conducted a systematic review to determine whether circulating calcium concentrations are associated with risks of cardiovascular disease and death in normocalcaemic populations. We conducted PubMed searches up to 18 December 2014 and scrutinized reference lists of papers. Eligible studies related serum calcium to mortality or cardiovascular events in humans. A follow-up of at least one year was required for longitudinal studies. Studies in populations selected on the basis of renal disease or abnormal serum calcium were excluded. Two investigators performed independent data extraction. The results were tabulated and, where possible, meta-analysed. Five of 11 studies reported a statistically significant positive association between serum calcium and mortality. Meta-analysis of eight of these studies showed a hazard ratio of death of 1.13 (1.09, 1.18) per standard deviation of serum calcium. Eight of 13 studies reported a statistically significant positive association between serum calcium and cardiovascular disease. Meta-analysis of eight studies showed a hazard ratio of cardiovascular disease of 1.08 (1.04, 1.13) per standard deviation of serum calcium. For two studies reporting odds ratios, the pooled odds ratio per standard deviation was 1.22 (1.11, 1.32). When hazard ratios adjusted for cardiovascular risk factors were meta-analysed, the pooled hazard ratio was 1.04 (1.01, 1.08). Other studies demonstrated associations between serum calcium and stroke and between serum calcium and direct measurements of arterial disease and calcification. These observational data indicate that serum calcium is associated with vascular disease and death, but they cannot determine causality. PMID- 26749425 TI - Integrating Multiple Biomarkers of Fish Health: A Case Study of Fish Health in Ports. AB - Biomarkers of fish health are recognised as valuable biomonitoring tools that inform on the impact of pollution on biota. The integration of a suite of biomarkers in a statistical analysis that better illustrates the effects of exposure to xenobiotics on living organisms is most informative; however, most published ecotoxicological studies base the interpretation of results on individual biomarkers rather than on the information they carry as a set. To compare the interpretation of results from individual biomarkers with an interpretation based on multivariate analysis, a case study was selected where fish health was examined in two species of fish captured in two ports located in Western Australia. The suite of variables selected included chemical analysis of white muscle, body condition index, liver somatic index (LSI), hepatic ethoxyresorufin-O-deethylase activity, serum sorbitol dehydrogenase activity, biliary polycyclic aromatic hydrocarbon metabolites, oxidative DNA damage as measured by serum 8-oxo-dG, and stress protein HSP70 measured on gill tissue. Statistical analysis of individual biomarkers suggested little consistent evidence of the effects of contaminants on fish health. However, when biomarkers were integrated as a set by principal component analysis, there was evidence that the health status of fish in Fremantle port was compromised mainly due to increased LSI and greater oxidative DNA damage in fish captured within the port area relative to fish captured at a remote site. The conclusions achieved using the integrated set of biomarkers show the importance of viewing biomarkers of fish health as a set of variables rather than as isolated biomarkers of fish health. PMID- 26749426 TI - A Primitive Growth Factor, NME7AB , Is Sufficient to Induce Stable Naive State Human Pluripotency; Reprogramming in This Novel Growth Factor Confers Superior Differentiation. AB - Scientists have generated human stem cells that in some respects mimic mouse naive cells, but their dependence on the addition of several extrinsic agents, and their propensity to develop abnormal karyotype calls into question their resemblance to a naturally occurring "naive" state in humans. Here, we report that a recombinant, truncated human NME7, referred to as NME7AB here, induces a stable naive-like state in human embryonic stem cells and induced pluripotent stem cells without the use of inhibitors, transgenes, leukemia inhibitory factor (LIF), fibroblast growth factor 2 (FGF2), feeder cells, or their conditioned media. Evidence of a naive state includes reactivation of the second X chromosome in female source cells, increased expression of naive markers and decreased expression of primed state markers, ability to be clonally expanded and increased differentiation potential. RNA-seq analysis shows vast differences between the parent FGF2 grown, primed state cells, and NME7AB converted cells, but similarities to altered gene expression patterns reported by others generating naive-like stem cells via the use of biochemical inhibitors. Experiments presented here, in combination with our previous work, suggest a mechanistic model of how human stem cells regulate self-replication: an early naive state driven by NME7, which cannot itself limit self-replication and a later naive state regulated by NME1, which limits self-replication when its multimerization state shifts from the active dimer to the inactive hexamer. PMID- 26749424 TI - Netrin-1 Regulates Fibrocyte Accumulation in the Decellularized Fibrotic Sclerodermatous Lung Microenvironment and in Bleomycin-Induced Pulmonary Fibrosis. AB - OBJECTIVE: Fibrocytes are collagen-producing leukocytes that accumulate in patients with systemic sclerosis (SSc; scleroderma)-related interstitial lung disease (ILD) via unknown mechanisms that have been associated with altered expression of neuroimmune proteins. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in SSc has not been explored. The aim of this study was to use a novel translational platform based on decellularized human lungs to determine whether the lung ECM of patients with scleroderma controls the development of fibrocytes from peripheral blood mononuclear cells. METHODS: We performed biomechanical evaluation of decellularized scaffolds prepared from lung explants from healthy control subjects and patients with scleroderma, using tensile testing and biochemical and proteomic analysis. Cells obtained from healthy controls and patients with SSc-related ILD were cultured on these scaffolds, and CD45+pro ColIalpha1+ cells meeting the criteria for fibrocytes were quantified. The contribution of the neuromolecule netrin-1 to fibrosis was assessed using neutralizing antibodies in this system and by administering bleomycin via inhalation to netrin-1(+/-) mice. RESULTS: Compared with control lung scaffolds, lung scaffolds from patients with SSc-related ILD showed aberrant anatomy, enhanced stiffness, and abnormal ECM composition. Culture of control cells in lung scaffolds from patients with SSc-related ILD increased production of pro ColIalpha1+ cells, which was stimulated by enhanced stiffness and abnormal ECM composition. Cells from patients with SSc-related ILD demonstrated increased pro ColIalpha1 responsiveness to lung scaffolds from scleroderma patients but not enhanced stiffness. Enhanced detection of netrin-1-expressing CD14(low) cells in patients with SSc-related ILD was observed, and antibody-mediated netrin-1 neutralization attenuated detection of CD45+pro-ColIalpha1+ cells in all settings. Netrin-1(+/-) mice were protected against bleomycin-induced lung fibrosis and fibrocyte accumulation. CONCLUSION: Factors present in the lung matrices of patients with scleroderma regulate fibrocyte accumulation via a netrin-1-dependent pathway. Netrin-1 regulates bleomycin-induced pulmonary fibrosis in mice. Netrin-1 might be a novel therapeutic target in SSc-related ILD. PMID- 26749427 TI - iBodies: Modular Synthetic Antibody Mimetics Based on Hydrophilic Polymers Decorated with Functional Moieties. AB - Antibodies are indispensable tools for biomedicine and anticancer therapy. Nevertheless, their use is compromised by high production costs, limited stability, and difficulty of chemical modification. The design and preparation of synthetic polymer conjugates capable of replacing antibodies in biomedical applications such as ELISA, flow cytometry, immunocytochemistry, and immunoprecipitation is reported. The conjugates, named "iBodies", consist of an HPMA copolymer decorated with low-molecular-weight compounds that function as targeting ligands, affinity anchors, and imaging probes. We prepared specific conjugates targeting several proteins with known ligands and used these iBodies for enzyme inhibition, protein isolation, immobilization, quantification, and live-cell imaging. Our data indicate that this highly modular and versatile polymer system can be used to produce inexpensive and stable antibody substitutes directed toward virtually any protein of interest with a known ligand. PMID- 26749428 TI - Postoperative pain control with paravertebral catheters after pediatric total pancreatectomy and islet autotransplantation: a retrospective cohort study. AB - BACKGROUND: Total pancreatectomy and islet autotransplantation (TPIAT) has been used to treat pediatric patients with chronic pancreatitis. The primary symptom of this disease is extreme poorly controlled pain. This results in significant alterations in the quality of life of the patient. We sought to determine if the addition of bilateral thoracic paravertebral catheters with continuous ropivacaine infusion would improve postoperative opioid use and pain control. METHODS: The medical records of 32 patients who underwent TPIAT from March 2011 to July 2014 were analyzed retrospectively (15 without paravertebral catheters and 17 with paravertebral catheters). Maximum and minimum pain scores, opioid use (mg . kg(-1) . day(-1)), percent opioid use above baseline, length of stay, and complications were recorded. RESULTS: Those patients who had bilateral thoracic paravertebral catheters had decreased total opioid use in the first 7 days postoperatively when compared to those who did not (612 (95% CI: 432-792) vs 943.7 (95% CI: 650-1237) mg of morphine equivalents; P = 0.043). The total opioid use remained significantly decreased when corrected for weight (12.53 (95% CI: 9.19-15.44) vs 18.85 (95% CI: 13.69-24.03) mg . kg(-1) of morphine equivalents; P = 0.03). In addition, those on preoperative opioids had less percent opioid use above baseline on postoperative days 1, 2, and 7 as well as decreased opioid use (mg . kg(-1) . day(-1)) on postoperative days 1, 2, 3, and 7. There were no differences in complications or length of stay. CONCLUSIONS: Bilateral paravertebral catheters may provide decreased opioid use and improved postoperative pain control after TPIAT. PMID- 26749429 TI - Attention Modulates Spatial Precision in Multiple-Object Tracking. AB - We present a computational model of multiple-object tracking that makes trial level predictions about the allocation of visual attention and the effect of this allocation on observers' ability to track multiple objects simultaneously. This model follows the intuition that increased attention to a location increases the spatial resolution of its internal representation. Using a combination of empirical and computational experiments, we demonstrate the existence of a tight coupling between cognitive and perceptual resources in this task: Low-level tracking of objects generates bottom-up predictions of error likelihood, and high level attention allocation selectively reduces error probabilities in attended locations while increasing it at non-attended locations. Whereas earlier models of multiple-object tracking have predicted the big picture relationship between stimulus complexity and response accuracy, our approach makes accurate predictions of both the macro-scale effect of target number and velocity on tracking difficulty and micro-scale variations in difficulty across individual trials and targets arising from the idiosyncratic within-trial interactions of targets and distractors. PMID- 26749432 TI - Gold-Catalyzed Tandem Cycloisomerization-Halogenation of Chiral Homopropargyl Sulfonamides. AB - Two new gold-catalyzed tandem cycloisomerization-halogenation reactions of chiral homopropargyl sulfonamides have been developed. Various enantioenriched 3,3 diiodopyrrolidin-2-ols and 3-fluoropyrrolidin-2-ols were obtained in moderate-to good yields with excellent enantio- and diastereoselectivity. PMID- 26749430 TI - Focal colorectal uptake in (18)FDG-PET/CT: maximum standard uptake value as a trigger in a semi-automated screening setting. AB - BACKGROUND: Focal colorectal uptake in (18)FDG-PET/CT may be associated with a malignancy and can be quantified. This provides the basis for an automatic trigger threshold above which cases are flagged for colonoscopic evaluation and below which for individual assessment. PURPOSE: To determine the lowest maximum standard uptake (SUVmax) in colorectal cancer that could be used as a threshold to trigger endoscopic evaluation and to evaluate whether the SUVmax needs to be further normalised to a priori known extrinsic factors. METHODS: The SUVmax was measured in 54 colorectal carcinomas and correlated with gender, age, blood glucose level, injected activity, body mass index and time to scan using t test or correlation coefficients (Pearson or Spearman, according to distribution). RESULTS: There was no correlation between SUVmax and any of the extrinsic factors mentioned above. The lowest SUVmax value was 5 [mean +/- SD (range): 11.1 +/- 4.8 (5.0-24.6)]. CONCLUSION: In contrast to most other screening techniques, semi automation in colorectal screening seems possible with PET/CT. This opens the door for further study into the feasibility of automated screening. Independent from extrinsic factors, an SUVmax >=5.0 in a focal colorectal uptake in (18)FDG PET/CT should automatically trigger for endoscopic evaluation, if not contraindicated. Cases with SUVmax <5 should be assessed individually before referral for endoscopy. Thus, more interpretation time could be spent on those cases with a lower uptake and more ambiguous diagnosis. PMID- 26749431 TI - National evaluation of strategies to reduce safety violations for working from heights in construction companies: results from a randomized controlled trial. AB - BACKGROUND: The objective of this study is to evaluate the effectiveness of a face-to-face strategy and a direct mail strategy on safety violations while working from heights among construction companies compared to a control condition. METHODS: Construction companies with workers at risk for fall injuries were eligible for this three-armed randomized controlled trial. In total, 27 cities were randomly assigned to intervention groups-where eligible companies were given either a face-to-face guidance strategy or a direct mailing strategy with access to internet facilities-or to a control group. The primary outcomes were the number and type of safety violations recorded by labor inspectors after three months. A process evaluation for both strategies was performed to determine reach, program implementation, satisfaction, knowledge and perceived safety behavior. A cost analysis was performed to establish the financial costs for each intervention strategy. Analyses were done by intention to treat. RESULTS: In total, 41% (n = 88) of the companies eligible for the face-to-face intervention participated and 73% (n = 69) for direct mail. Intervention materials were delivered to 69 % (face-to-face group) and 100 % (direct mail group); completion of intervention activities within companies was low. Satisfaction, increase in knowledge, and safety behavior did not differ between the intervention groups. Costs for personal advice were 28% higher than for direct mail. Ultimately, nine intervention companies were captured in the 288 worksite measurements performed by the labor inspectorate. No statistical differences in mean number of safety violations (1.8-2.4) or penalties (72%-100%) were found between the intervention and control groups based on all worksite inspections. CONCLUSIONS: No conclusions about the effect of face-to-face and direct mail strategies on safety violations could be drawn due to the limited number of intervention companies captured in the primary outcome measurements. The costs for a face-to-face strategy are higher compared with a direct mail strategy. No difference in awareness and attitude for safe working was found between employers and workers between both strategies. TRIAL REGISTRATION: NTR 4298 on 29-Nov-2013. PMID- 26749433 TI - Description of common musculoskeletal findings in Williams Syndrome and implications for therapies. AB - Williams syndrome (WS), also referred to as Williams-Beuren syndrome (WBS), is a relatively rare genetic disorder affecting ~1/10,000 persons. Since the disorder is caused by a micro-deletion of ~1.5 Mb, it is not surprising that the manifestations of WS are extremely broad, involving most body systems. In this paper, we primarily focus on the musculoskeletal aspects of WS as these findings have not been the subject of a comprehensive review. We review the MSK features commonly seen in individuals with WS, along with related sensory and neurological issues interacting with and compounding underlying MSK abnormalities. We end by providing perspective, particularly from the vantage point of a physical therapist, on therapeutic interventions to address the most common MSK and related features seen in WS. Clin. Anat. 29:578-589, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26749434 TI - Identified metabolic signature for assessing red blood cell unit quality is associated with endothelial damage markers and clinical outcomes. AB - BACKGROUND: There has been interest in determining whether older red blood cell (RBC) units have negative clinical effects. Numerous observational studies have shown that older RBC units are an independent factor for patient mortality. However, recently published randomized clinical trials have shown no difference of clinical outcome for patients receiving old or fresh RBCs. An overlooked but essential issue in assessing RBC unit quality and ultimately designing the necessary clinical trials is a metric for what constitutes an old or fresh RBC unit. STUDY DESIGN AND METHODS: Twenty RBC units were profiled using quantitative metabolomics over 42 days of storage in SAGM with 3- to 4-day time intervals. Metabolic pathway usage during storage was assessed using systems biology methods. The detected time intervals of the metabolic states were compared to clinical outcomes. RESULTS: Using multivariate statistics, we identified a nonlinear decay process exhibiting three distinct metabolic states (Days 0-10, 10 17, and 17-42). Hematologic variables traditionally measured in the transfusion setting (e.g., pH, hemolysis, RBC indices) did not distinguish these three states. Systemic changes in pathway usage occurred between the three states, with key pathways changing in both magnitude and direction. Finally, an association was found between the time periods of the metabolic states with the clinical outcomes of more than 280,000 patients in the country of Denmark transfused over the past 15 years and endothelial damage markers in healthy volunteers undergoing autologous transfusions. CONCLUSION: The state of RBC metabolism may be a better indicator of cellular quality than traditional hematologic variables. PMID- 26749435 TI - Isolation, Characterization and Virulence Potential of Tenacibaculum dicentrarchi in Salmonid Cultures in Chile. AB - In this study, we isolated, identified and characterized isolates of Tenacibaculum dicentrarchi in Atlantic salmon (Salmo salar) farmed in Chile for the first time. In 2010 and 2014, mortalities were observed in Atlantic salmon (average weight 25-30 and 480-520 g, respectively) at an aquaculture centre in Puerto Montt, Chile. Severe tail rots, frayed fins and, in some cases, damaged gills were detected. Wet smear analyses of these lesions revealed a high occurrence of Gram-negative, filamentous bacteria. Microbiological analysis of infected gill and tail tissues yielded six bacterial isolates. All were identified as T. dicentrarchi through polyphasic taxonomy, which included phenotypic characterization, 16S rRNA sequencing and multilocus sequence typing. The latter method revealed a close relationship of the Chilean genotype with the T. dicentrarchi type strain and two Norwegian Atlantic cod (Gadus morhua) isolates. The pathogenic potential of the TdChD05 isolate was assessed by challenging Atlantic salmon and rainbow trout (Oncorhynchus mykiss) for one hour, which resulted in mean cumulative mortality rates of 65% and 93%, respectively, as well as clinical signs 14 days post-challenge. However, challenged Coho salmon (Oncorhynchus kisutch) presented no mortalities or clinical signs of infection. These findings indicate that the geographical and host distribution of T. dicentrarchi is wider than previously established and that this bacterium may have negative impacts on salmonid cultures. PMID- 26749436 TI - Physical activity using wrist-worn accelerometers: comparison of dominant and non dominant wrist. AB - The purpose of this study was to determine whether there is a difference in physical activity assessment between a wrist-worn accelerometer at the dominant or non-dominant arm. The secondary purpose was to assess the concurrent validity of measures of physical activity from the wrist-worn accelerometer and the waist worn accelerometer. Forty adults wore three accelerometers simultaneously, one on the waist and one each on the non-dominant wrist and dominant wrist, respectively, for 24 consecutive hours of free-living conditions. Data were uploaded from the monitor to a computer following a 1-day test period. There were no significant differences in physical activity when comparing the dominant versus the non-dominant wrist, regardless of axis (P>0.05). Mean daily accelerometer output data from both wrists were strongly correlated with average counts per minute from the ActiGraph worn around the waist (r = 0.88, P<0.001). Findings suggest that the choice to wear the accelerometer on the non-dominant or dominant wrist has no impact on results. Data from this study contribute to the knowledge of how to best assess physical activity habits. PMID- 26749437 TI - The association between codon72 polymorphism of p53 gene and the risk of endometrial cancer: an updating meta-analysis. AB - OBJECTIVE: Controversy still exists in the relationship between p53 codon72 polymorphism and the risk of endometrial cancer. MATERIALS AND METHODS: In order to figure out this inconsistency, database on HuGE Navigator, PubMed and Web of Science about the case-control studies were compiled in the present work. Statistic analysis was performed by STATA 12.0. RESULTS: Total 11 eligible publications were selected in this meta-analysis including 1086 endometrial cancer and 1403 controls. There was no significant relationship between codon72 polymorphism of p53 gene and the risk of endometrial cancer under allele model [Pro versus Arg: OR 0.99, 95 % CI (0.87, 1.15)], dominant model [ArgPro + ProPro versus ArgArg: OR 0.88, 95 % CI (0.67, 1.15)], recessive model [ProPro versus ArgArg + ArgPro: OR 1.09, 95 % CI (0.84, 1.42)] and addictive model [ProPro versus ArgArg: OR 0.97, 95 % CI (0.72, 1.29)]. Samples from endometrial tissue with homozygous ArgArg have the increased risk of EC [allele model: OR 0.71, 95 % CI (0.53, 0.96); addictive model: OR 0.46, 95 % CI (0.24, 0.87)]. CONCLUSION: This meta-analysis revealed a weak association between the codon72 polymorphism of p53 gene and the risk of endometrial cancer. Women with homozygous Arg72 may be more susceptible to endometrial cancer than others with heterozygotes and homozygous Pro72. PMID- 26749439 TI - Prenatal and familial factors of caries in first permanent molars in schoolchildren living in urban area of Lodz, Poland. AB - The objective of the present work is to identify the set of prenatal and familial factors that contribute to dental caries of first permanent molars in preschool and young schoolchildren, which will make it possible to determine a high-risk group that should be considered for special preventive measures. This study contributes to the evidence for the multifactorial nature of dental caries. Material was collected during a 2009-2010 study conducted in randomly selected schools and kindergartens in the city of Lodz (Poland). Only children with first permanent molars present were considered for the analysis, which limited the database to 1131 children. Dental examinations were accompanied by a questionnaire completed by the parents, covering items pertaining to prenatal and familial determinants. The present study shows that there are significant differences in the prevalence of caries in first molars between children of different ages (5-13 lat) and that no such differences exist between boys and girls. The prenatal and familial factors conducive to caries include maternal education level (OR=0.55), mode of delivery (OR=0.63) and birth order (OR=0.63). Mothers' smoking habit is also associated with increased caries prevalence in children. Caries prevention should already begin during the prenatal period primarily in respect of mothers with lower educational attainment who are pregnant with a second or subsequent child. PMID- 26749438 TI - Attention-deficit/hyperactivity disorder and sluggish cognitive tempo throughout childhood: temporal invariance and stability from preschool through ninth grade. AB - BACKGROUND: Although multiple cross-sectional studies have shown symptoms of sluggish cognitive tempo (SCT) and attention-deficit/hyperactivity disorder (ADHD) to be statistically distinct, studies have yet to examine the temporal stability and measurement invariance of SCT in a longitudinal sample. To date, only six studies have assessed SCT longitudinally, with the longest study examining SCT over a 2-year period. The overall goals of this study were to assess the 10-year longitudinal stability and interfactor relationships of ADHD and SCT symptoms among a community sample of children. METHODS: Confirmatory factor analysis was used to assess the temporal invariance of ADHD and SCT symptoms in a large population-based longitudinal sample (International Longitudinal Twin Study of Early Reading Development) that included children assessed at preschool and after kindergarten, first, second, fourth, and ninth grades (n = 489). Latent autoregressive models were then estimated to assess the stability of these constructs. RESULTS: Results demonstrated invariance of item loadings and intercepts from preschool through ninth grades, as well as invariance of interfactor correlations. Results further indicated that both ADHD and SCT are highly stable across these years of development, that these symptom dimensions are related but also separable, and that hyperactivity/impulsivity and SCT are both more strongly correlated with inattention than with each other and show differential developmental trajectories. Specifically, even in the presence of latent simplex analyses providing support for the developmental stability of these dimensions, linear comparisons indicated that that mean levels of hyperactivity/impulsivity decreased with time, inattentive ratings were generally stable, and SCT tended to increase slightly across development. CONCLUSIONS: This study adds to the current literature by being the first to systematically assess and demonstrate the temporal invariance and stability of ADHD and SCT across a span of 10 years. PMID- 26749440 TI - Increased prevalence of eosinophilia in a hemodialysis population: Longitudinal and case control studies. AB - Eosinophilia is commonly found in patients with clinical reactions to the hemodialysis circuit. With modern membranes, such reactions have become less common, but they may be under diagnosed in patients with subtle symptoms, in whom the presence of eosinophilia is an important diagnostic feature. Two case reports are presented, along with a hemodialysis study of the frequency and clinical associations of eosinophilia. In three hemodialysis facilities, all current hemodialysis patients with persistent eosinophilia (greater than 1 * 10(9) /L for 3 months) were identified. Control patients without eosinophilia (less than 0.5 * 10(9) /L for 3 months) matched for age, gender, and ethnicity were identified from the same facilities. A historical cohort of patients, dialyzing at the same facilities 5 years ago, was screened for the presence of persistent eosinophilia. From 510 patients, 24 cases of persistent eosinophilia were identified (4.7%). The median eosinophil count was 1.75 * 10(9) /L (range 1.1-7.5 * 10(9) /L). The prevalence in a historical cohort 5 years previously was significantly less at 1.5% (P = 0.046). Compared to controls, patients with eosinophilia were more likely to be on an angiotensin converting enzyme inhibitor (41.7% vs. 12.5%, P = 0.049), had a lower C-reactive protein (10 vs. 24 mg/L, P = 0.02) and were more likely to be using a fistula for access (P = 0.049). Over the following 12 months, there was no difference in the mean number of hospital admission days between cases and controls (7.6 vs. 11.5 days, P = 0.54), and no difference in mortality over 29 months (25.0% vs. 29.2%, P = 1.00). Eosinophilia remains not uncommon in hemodialysis patients, and in most cases reflects allergy to components of the dialysis circuit, which is usually subclinical. The overall prognosis for asymptomatic patients appears to be favourable. PMID- 26749442 TI - Aspergillus Cell Wall Melanin Blocks LC3-Associated Phagocytosis to Promote Pathogenicity. AB - Concealing pathogen-associated molecular patterns (PAMPs) is a principal strategy used by fungi to avoid immune recognition. Surface exposure of PAMPs during germination can leave the pathogen vulnerable. Accordingly, beta-glucan surface exposure during Aspergillus fumigatus germination activates an Atg5-dependent autophagy pathway termed LC3-associated phagocytosis (LAP), which promotes fungal killing. We found that LAP activation also requires the genetic, biochemical or biological (germination) removal of A. fumigatus cell wall melanin. The attenuated virulence of melanin-deficient A. fumigatus is restored in Atg5 deficient macrophages and in mice upon conditional inactivation of Atg5 in hematopoietic cells. Mechanistically, Aspergillus melanin inhibits NADPH oxidase dependent activation of LAP by excluding the p22phox subunit from the phagosome. Thus, two events that occur concomitantly during germination of airborne fungi, surface exposure of PAMPs and melanin removal, are necessary for LAP activation and fungal killing. LAP blockade is a general property of melanin pigments, a finding with broad physiological implications. PMID- 26749441 TI - High-Throughput Assay and Discovery of Small Molecules that Interrupt Malaria Transmission. AB - Preventing transmission is an important element of malaria control. However, most of the current available methods to assay for malaria transmission blocking are relatively low throughput and cannot be applied to large chemical libraries. We have developed a high-throughput and cost-effective assay, the Saponin-lysis Sexual Stage Assay (SaLSSA), for identifying small molecules with transmission blocking capacity. SaLSSA analysis of 13,983 unique compounds uncovered that >90% of well-characterized antimalarials, including endoperoxides and 4 aminoquinolines, as well as compounds active against asexual blood stages, lost most of their killing activity when parasites developed into metabolically quiescent stage V gametocytes. On the other hand, we identified compounds with consistent low nanomolar transmission-blocking activity, some of which showed cross-reactivity against asexual blood and liver stages. The data clearly emphasize substantial physiological differences between sexual and asexual parasites and provide a tool and starting points for the discovery and development of transmission-blocking drugs. PMID- 26749443 TI - The programming effects of nutrition-induced catch-up growth on gut microbiota and metabolic diseases in adult mice. AB - Substantial evidence indicated that catch-up growth could increase the susceptibility to obesity, insulin resistance, and type 2 diabetes mellitus in adulthood. However, investigations into the "programming" effects of catch-up growth on gut microbiota in the offspring are limited. C57/BL6 mice were fed on either low protein (LP) or normal chow (NC) diet throughout gestation and lactation. Then, the offspring were randomly weaned to either NC or high fat (HF) diet until 32 weeks of age, generating four experimental groups: NC-NC, NC-HF, LP NC, and LP-HF. Metabolic parameters and gut microbiota were examined in the offspring. It showed that the NC-HF and LP-HF offspring displayed higher body weight (P < 0.05), impaired glucose tolerance (P < 0.001), and elevated serum lipids (P < 0.05) at 32 weeks of age. Both the operational taxonomic units (OTUs) and the Shannon indexes (P < 0.05) showed significantly lower microbial diversity in NC-HF and LP-HF offspring. There were significant variations in the compositions of gut microbiota in the NC-HF and LP-HF offspring, compared with NC NC offspring (P < 0.05). Furthermore, it indicated Lactobacillus percentage was negatively associated with blood glucose concentrations of intraperitoneal glucose tolerance test (r = -0.886, P = 0.019). In conclusion, catch-up growth predisposes the offspring to gut microbiota perturbation, obesity, impaired glucose tolerance, insulin resistance, and dyslipidemia. Our study is novel in showing the "programming" effects of nutrition-induced catch-up growth on gut microbiota and metabolic diseases in later life. PMID- 26749444 TI - Determinants of plasma PCB, brominated flame retardants, and organochlorine pesticides in pregnant women and 3 year old children in The Norwegian Mother and Child Cohort Study. AB - BACKGROUND: Exposure to persistent organic pollutants (POPs) during prenatal and postnatal life has been extensively studied in relation to adverse health effects in children. OBJECTIVES: The aim was to identify determinants of the concentrations of polychlorinated biphenyls (PCBs), brominated flame retardants (polybrominated diphenyl ethers, PBDEs; polybrominated biphenyl, PBB), and organochlorine pesticides (OCPs) in blood samples from pregnant women and children in The Norwegian Mother and Child Cohort Study (MoBa). METHODS: Blood samples were collected from two independent subsamples within MoBa; a group of women (n=96) enrolled in mid-pregnancy during the years 2002-2008 and a group of 3 year old children (n=99) participating during 2010-2011. PCB congeners (74, 99, 138, 153, 180, 170, 194, 209, 105, 114, 118, 156, 157, 167, and 189), brominated flame retardants (PBDE-28, 47, 99, 100, 153, 154, and PBB-153), as well as the OCPs hexachlorobenzene (HCB), oxychlordane, 4,4'dichlorodiphenyltrichloroethane (DDT), and 4,4'dichlorodiphenyldichloroethylene (DDE) were measured in both pregnant women and children. RESULTS: Age, low parity, and low pre-pregnant BMI were the most important determinants of increased plasma concentrations of POPs in pregnant women. In 3 year old children, prolonged breastfeeding duration was a major determinant of increased POP concentrations. Estimated dietary exposure to PCBs during pregnancy was positively associated with plasma concentrations in 3 year old children, but not in pregnant women. Plasma concentrations were approximately 40% higher in children compared to pregnant women. CONCLUSIONS: Several factors associated with exposure and toxicokinetics, i.e. accumulation, excretion and transfer via breastmilk of POPs were the main predictors of POP levels in pregnant women and children. Diet, which is the main exposure source for these compounds in the general population, was found to predict PCB levels only among children. For the PBDEs, for which non-dietary sources are more important, toxicokinetic factors appeared to have less predictive impact. PMID- 26749446 TI - The Structure of the Toxin and Type Six Secretion System Substrate Tse2 in Complex with Its Immunity Protein. AB - Tse2 is a cytoactive toxin secreted by a type six secretion apparatus of Pseudomonas aeruginosa. The Tse2 toxin naturally attacks a target in the cytoplasm of bacterial cells, and can cause toxicity if artificially introduced into eukaryotic cells. The X-ray crystal structure of the complex of Tse2 and its cognate immunity protein Tsi2 revealed a heterotetrameric structure with an extensive binding interface. Structural identity was found between Tse2 and NAD dependent enzymes, especially ADP-ribosylating toxins, which facilitated the identification of the Tse2 active site and revealed it to be occluded upon binding the inhibitor Tsi2. The structural identity shared with NAD-dependent enzymes, including conserved catalytic residues, suggests that the mechanism of Tse2 toxicity may be NAD dependent. PMID- 26749445 TI - Conformational Chaperones for Structural Studies of Membrane Proteins Using Antibody Phage Display with Nanodiscs. AB - A major challenge in membrane biophysics is to define the mechanistic linkages between a protein's conformational transitions and its function. We describe a novel approach to stabilize transient functional states of membrane proteins in native-like lipid environments allowing for their structural and biochemical characterization. This is accomplished by combining the power of antibody Fab based phage display selection with the benefits of embedding membrane protein targets in lipid-filled nanodiscs. In addition to providing a stabilizing lipid environment, nanodiscs afford significant technical advantages over detergent based formats. This enables the production of a rich pool of high-performance Fab binders that can be used as crystallization chaperones, as fiducial markers for single-particle cryoelectron microscopy, and as probes of different conformational states. Moreover, nanodisc-generated Fabs can be used to identify detergents that best mimic native membrane environments for use in biophysical studies. PMID- 26749447 TI - Probing the Binding Interfaces of Protein Complexes Using Gas-Phase H/D Exchange Mass Spectrometry. AB - Fast gas-phase hydrogen/deuterium exchange mediated by ND3 gas and measured by mass spectrometry (gas-phase HDX-MS) is a largely unharnessed, fast, and sensitive method for probing primary- and higher-order polypeptide structure. Labeling of heteroatom-bound non-amide hydrogens in a sub-millisecond time span after electrospray ionization by ND3 gas can provide structural insights into protein conformers present in solution. Here, we have explored the use of gas phase HDX-MS for probing the higher-order structure and binding interfaces of protein complexes originating from native solution conditions. Lysozyme ions bound by an oligosaccharide incorporated less deuterium than the unbound ion. Similarly, trypsin ions showed reduced deuterium uptake when bound by the peptide ligand vasopressin. Our results are in good agreement with crystal structures of the native protein complexes, and illustrate that gas-phase HDX-MS can provide a sensitive and simple approach to measure the number of heteroatom-bound non-amide side-chain hydrogens involved in the binding interface of biologically relevant protein complexes. PMID- 26749449 TI - Molecular Interactions in the Voltage Sensor Controlling Gating Properties of CaV Calcium Channels. AB - Voltage-gated calcium channels (CaV) regulate numerous vital functions in nerve and muscle cells. To fulfill their diverse functions, the multiple members of the CaV channel family are activated over a wide range of voltages. Voltage sensing in potassium and sodium channels involves the sequential transition of positively charged amino acids across a ring of residues comprising the charge transfer center. In CaV channels, the precise molecular mechanism underlying voltage sensing remains elusive. Here we combined Rosetta structural modeling with site directed mutagenesis to identify the molecular mechanism responsible for the specific gating properties of two CaV1.1 splice variants. Our data reveal previously unnoticed interactions of S4 arginines with an aspartate (D1196) outside the charge transfer center of the fourth voltage-sensing domain that are regulated by alternative splicing of the S3-S4 linker. These interactions facilitate the final transition into the activated state and critically determine the voltage sensitivity and current amplitude of these CaV channels. PMID- 26749450 TI - Structure of an Actinobacterial-Type [NiFe]-Hydrogenase Reveals Insight into O2 Tolerant H2 Oxidation. AB - A novel group of bacterial [NiFe]-hydrogenases is responsible for high-affinity H2 uptake from the troposphere, and is therefore thought to play an important role in the global H2 cycle. Here we present the first crystal structure at 2.85 A resolution of such an actinobacterial-type hydrogenase (AH), which was isolated from the dihydrogen oxidizing bacterium, Ralstonia eutropha. The enzyme has a dimeric structure carrying two active [NiFe] sites that are interconnected by six [4Fe4S] clusters over a range of approximately 90 A. Unlike most other [NiFe] hydrogenases, the [4Fe4S] cluster proximal to the [NiFe] site is coordinated by three cysteines and one aspartate. Mutagenesis experiments revealed that this aspartate residue is related to the apparent O2 insensitivity of the AH. Our data provide first structural insight into specialized hydrogenases that are supposed to consume atmospheric H2 under challenging conditions, i.e. at high O2 concentration and wide temperature and pH ranges. PMID- 26749451 TI - Effects of 1alpha-Calcidol (Alfacalcidol) on Microvascular Endothelial Function, Arterial Stiffness, and Blood Pressure in Type II Diabetic Nephropathy Patients. AB - OBJECTIVES: To determine the effects of six months alfacalcidol on microvascular endothelial function, arterial stiffness, and BP in DN patients. METHODS: Twenty eight DN patients on alfacalcidol, 0.25 MUg daily for six months were compared to 32 controls on conventional treatment. Measurements of microvascular endothelial function, arterial stiffness [AIx and PWV], hsCRP, and BP were performed; differences between baseline and six months treatment were evaluated. RESULTS: No difference was seen in microvascular endothelial function for both groups after six months. Improvement in CSBP (p = 0.027) with trends of improvement in AIx (p = 0.063), PWV (p = 0.075), and systolic BP (p = 0.088) were seen in the alfacalcidol group with no changes observed in controls. Subgroup analysis of alfacalcidol group showed that vitamin D-deficient patients had better response to treatment. hsCRP level remained unchanged in alfacalcidol group; significant increase was however seen in controls. CONCLUSION: Alfacalcidol did not have an effect on microvascular endothelial function in DN patients. Alfacalcidol significantly improved CSBP with trends of improvement in arterial stiffness and peripheral BP. Alfacalcidol appears to be more beneficial in vitamin D-deficient patients. PMID- 26749452 TI - Medical care and treatment of allergic rhinitis: a population-based cohort study based on routine healthcare utilization data. AB - BACKGROUND: Health services research on medical care and treatment of allergic rhinitis (AR) is scarce. OBJECTIVES: To investigate the prevalence, incidence, comorbidities, and treatment of AR in a realistic setting. METHODS: A cohort of 1 811 094 German National Health Insurance beneficiaries in 2005 was followed until 2011. To avoid misclassification, the ICD-10 code for AR (J30) had to be documented at least twice to classify patients as having AR. Descriptive statistics and logistic regression models were used to describe the burden, comorbidities, and treatment of AR. RESULTS: A total of 111 394 patients (6.2%) had prevalent AR in 2005/2006. In another 60 145 individuals (3.3%), AR was newly diagnosed in 2007 to 2011 (incident cases). Patients with prevalent AR were three times more likely to develop asthma compared to patients without AR (age and sex adjusted risk ratio (RR) 3.04; 95% confidence interval (95%CI) 2.98-3.10). Newly diagnosed recurrent depressive disorder (RR 1.61; 95%CI 1.55-1.68), anxiety disorder (RR 1.52; 95%CI 1.48-1.56), and ADHD (RR 1.21; 95%CI 1.13-1.29) were also related to prevalent AR. Approximately 20% of children and 36% of adults with AR were exclusively treated by general practitioners. Allergy immunotherapy (AIT) was prescribed for 16.4% of patients with AR. Subcutaneous immunotherapy was most frequently used (80% of AIT). CONCLUSIONS: This study highlights the significant burden of AR. Despite the established benefits of AIT to treat AR and prevent asthma, this study suggests significant undertreatment. Future research is necessary to develop and implement adequate measures to increase guideline adherence. PMID- 26749448 TI - The Structure of a BamA-BamD Fusion Illuminates the Architecture of the beta Barrel Assembly Machine Core. AB - The beta-barrel assembly machine (BAM) mediates folding and insertion of integral beta-barrel outer membrane proteins (OMPs) in Gram-negative bacteria. Of the five BAM subunits, only BamA and BamD are essential for cell viability. Here we present the crystal structure of a fusion between BamA POTRA4-5 and BamD from Rhodothermus marinus. The POTRA5 domain binds BamD between its tetratricopeptide repeats 3 and 4. The interface structural elements are conserved in the Escherichia coli proteins, which allowed structure validation by mutagenesis and disulfide crosslinking in E. coli. Furthermore, the interface is consistent with previously reported mutations that impair BamA-BamD binding. The structure serves as a linchpin to generate a BAM model where POTRA domains and BamD form an elongated periplasmic ring adjacent to the membrane with a central cavity approximately 30 * 60 A wide. We propose that nascent OMPs bind this periplasmic ring prior to insertion and folding by BAM. PMID- 26749453 TI - Providing sustained transgene induction through affinity-based drug delivery. AB - Small molecule drug activators of gene expression have been used in applications ranging from gene therapy, to tissue engineering and regenerative medicine. One concern is that for sustained gene expression, a long-term, controlled delivery system is needed. Insoluble polymers containing a high proportion of cyclodextrin (CD) affinity groups have been shown to prolong drug delivery far beyond that capable of polymers relying on diffusion alone. In this study we evaluate the capacity of such polymers to deliver the transgene inducer doxycycline. Our results show that initial drug loading is proportional to affinity, with ~8% loading in high-affinity gamma-CD polymers; ~7% loading in moderate-affinity beta CD polymers; and only ~4.5% loading in the non-affinity control polymer made from linear dextran. When release aliquots from these polymers were incubated with cells genetically modified for inducible transgene expression we observed activation of transgene expression for up to three weeks from samples released by affinity-based polymers. We showed that drug stability is maintained over the course of the study using a bacterial zone of inhibition assay where again affinity-based polymers show sustained availability of drug, weeks longer than non-affinity controls. Lastly we provide theoretical calculations of strength of binding interactions between cyclodextrins and many additional transgene inducers demonstrating the broad utility of this delivery platform. PMID- 26749454 TI - Maxillary sinus hemangioma: usefulness of embolization according to classification. PMID- 26749455 TI - Imbalance in the diurnal salivary testosterone/cortisol ratio in men with severe obstructive sleep apnea: an observational study. AB - INTRODUCTION: The complex relationship between sleep disorders and hormones could lead to alterations in the production of cortisol and testosterone in obstructive sleep apnea (OSA) patients. OBJECTIVE: The purpose of this study was to determine the diurnal trajectories of salivary free-testosterone, free-cortisol and their ratio (T/C). METHODS: Ten subjects newly diagnosed with OSA, based on nocturnal polysomnography evaluation and excessive daytime sleepiness, and seven matched controls were consecutively recruited. Cortisol and testosterone were measured in salivary samples collected upon awakening, at noon and in the evening. The psychometric evaluation of anxiety/depression and referred sexual function disturbances was performed to evaluate the presence of neuropsychological comorbidities. RESULTS AND CONCLUSION: The main finding was that OSA subjects displayed hypocortisolism upon awakening and a significant reduction in testosterone concentration in the evening in comparison with the control group, which has maintained the physiological testosterone and cortisol diurnal fluctuation, with higher hormone concentrations in the morning and lower concentrations in the evening. The use of data from multiple diurnal measurements rather than a single point allowed the detection of T/C ratio changes of opposite signs at the beginning and end of the day: the OSA subjects had a higher T/C ratio than the controls in the morning, while their T/C ratio was significantly lower than that of the controls in the evening. The imbalances in the anabolic catabolic diurnal equilibrium suggest that OSA is associated with a dysregulation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, potentially an underlying cause of some of the neuropsychological comorbidities observed in OSA patients. PMID- 26749456 TI - Polymorphisms in methylenetetrahydrofolate reductase and cystathionine beta synthase in oral cancer - a case-control study in southeastern Brazilians. AB - INTRODUCTION: Oral squamous cell carcinoma (OSCC) is a serious public health problem, due to its high mortality rate and worldwide rising incidence. OSCC susceptibility is mediated by interactions between genetic and environmental factors. Studies suggest that genetic variants encoding enzymes involved in folate metabolism may modulate OSCC risk by altering DNA synthesis/repair and methylation process. OBJECTIVE: The goals of this study were to evaluate the association of three genotypic polymorphism (MTHFR C677T, MTHFR A1298C and CBS 844ins68) and oral cancer risk in southeastern Brazilians and evaluate the interactions between polymorphisms and clinical histopathological parameters. METHODS: This case-control study included 101 cases and 102 controls in the state of Espirito Santo, Brazil. MTHFR genotyping was done by PCR-RFLP (polymerase chain reaction - restriction fragment length polymorphism) and CBS genotyping by PCR (polymerase chain reaction) analysis. RESULTS: MTHFR C677T polymorphism was associated with lymph node involvement. Genotype CT+TT acted as a protective factor. MTHFR A1298C AC+CC genotype was associated with tumor differentiation, and possibly with a better prognosis. In risk analysis, no correlation was observed between genotypes and OSCC. CONCLUSION: We concluded that MTHFR C677T, MTHFR A1298C and CBS 844ins68 polymorphisms were not associated with OSCC risk in southeastern Brazilians; however, we suggest a prognosis effect associated with MTHFR C677T and A1298C polymorphisms in OSCC. PMID- 26749457 TI - Predictive factors of occult neck metastasis in patients with oral squamous cell carcinoma. AB - INTRODUCTION: It is well established that cervical lymph node metastasis is the most important prognostic factor in patients with oral squamous cell carcinoma of the upper aerodigestive tract. The definition of parameters and classifications that could separate patients in groups of low, intermediate and high-risk is being attempted for several years. OBJECTIVE: The objective of this study was to determine possible predictive factors related to the occurrence of occult cervical lymph node metastasis through the analysis of histopathological reports of surgical specimens obtained after oral squamous cell carcinoma resection and selective neck dissections of patients initially classified as N0. METHODS: This was a primary, retrospective, observational, case-control study. Histopathological reports were reviewed to determine if some findings were related to the occurrence of occult lymph node metastasis. The events analyzed were oral cavity subsites, pT-stage, muscular infiltration, desmoplasia, vascular emboli, perineural infiltration, tumor thickness and compromised margins. RESULTS: Occult cervical metastasis accounted for 19.10 percent of the cases. Desmoplasia, perineural infiltration, tumor thickness and pT4a stage are predictive factors of occult neck metastasis (p-value=0.0488, 0.0326, 0.0395, 0.0488, respectively). CONCLUSION: The accurate definition of predictive factors of occult cervical metastasis may guide the selection of patients that should be referred to radiotherapy, avoiding the unnecessary exposure of low-risk patients to radiation and allowing a better regional control of the disease in those of moderate or high risk. PMID- 26749458 TI - Testing nursing students' clinical judgment in a patient deterioration simulation scenario: Development of a situation awareness instrument. AB - BACKGROUND: Situation awareness may be used to operationalize nursing students' clinical judgment of patient deterioration simulation scenarios. OBJECTIVES: To develop and test an instrument to measure bachelor-level nursing students' situation awareness in a patient deterioration simulation scenario, using the Situation Awareness Global Assessment Technique (SAGAT). DESIGN: Instrument development and validation. SETTINGS: A faculty of nursing of a French-Canadian university. PARTICIPANTS: 15 critical care experts and 234 bachelor-level nursing students from a critical care course. METHODS: The queries were developed from evidence and guidelines regarding nurses' assessment and response to patient deterioration and an inventory of nursing diagnosis. After expert content validation, the instrument was administered to three cohorts of nursing students in a high-fidelity simulation with a scenario of hypovolemic hemorrhagic shock. Difficulty, discrimination, and fidelity indices were computed. The impact of the instrument on student's performance was assessed with a post-simulation survey. RESULTS: The instrument comprised 31 queries, which obtained high content validity indices. Most showed satisfying difficulty, discrimination, and fidelity properties. Inadequate properties of the queries may be explained by the content of the simulation scenario, the assessment practices of nursing students, and their reliance on medical assistance. Students perceived that completing the instrument helped them realize what they forgot to assess in the simulation. CONCLUSIONS: This instrument appears as a promising research tool, although it still needs to be tested with other populations and in other patient deterioration simulation scenarios. PMID- 26749459 TI - Serratus anterior or pectoralis minor: Which muscle has the upper hand during protraction exercises? AB - BACKGROUND: The Serratus Anterior (SA) has a critical role in stabilizing the scapula against the thorax. Research has linked shoulder and neck disorders to impairments in the SA activation. Exercises that target the SA are included in the rehabilitation of shoulder or neck pain and mostly include a protraction component. The Pectoralis Minor (PM) functions as a synergist of the SA. From the literature it is unclear to what extent PM is activated during SA exercises. OBJECTIVES: To determine the activity of SA and PM during different protraction exercises. DESIGN: Controlled laboratory study. METHOD: 26 subjects performed 3 exercises: Modified Push-Up Plus (Wall Version), Modified Knee Push-Up Plus (Floor version) and Serratus Punch. Electromyographic (EMG) data was collected from the SA (surface) and PM (fine-wire EMG). RESULTS: During the Serratus Punch the SA activity was significantly higher than the PM activity. During the Modified Push-Up Plus exercises (both Wall and Floor version), the SA and PM activity were comparable. The PM showed the highest activity during the Serratus Punch and the Modified Push-Up Plus (Floor), which was significantly higher than during the Modified Push-Up Plus (Wall). The SA showed the highest activity during the Serratus Punch, which was significantly higher than during the Modified Push-Up Plus (Floor) which was in turn significantly higher than the activity during the Modified Push-Up Plus (Wall). CONCLUSIONS: All exercises activated the PM between 15 and 29% Maximum Voluntary Isometric Contraction and the SA between 15 and 43%. The Modified Push-Up Plus exercise against the wall and the floor activated the SA and PM to a similar degree. When maximum activation of the SA with minimal activation of the PM is desired in healthy subjects, the "Serratus punch" seems to be the optimal exercise. PMID- 26749460 TI - Cervicogenic somatosensory tinnitus: An indication for manual therapy? Part 1: Theoretical concept. AB - Tinnitus can be evoked or modulated by input from the somatosensory and somatomotor systems. This means that the loudness or intensity of tinnitus can be changed by sensory or motor stimuli such as muscle contractions, mechanical pressure on myofascial trigger points, transcutaneous electrical stimulation or joint movements. The neural connections and integration of the auditory and somatosensory systems of the upper cervical region and head have been confirmed by many studies. These connections can give rise to a form of tinnitus known as somatosensory tinnitus. To date only a handful of publications have focussed on (cervicogenic) somatosensory tinnitus and manual therapy. Broadening the current understanding of somatosensory tinnitus would represent a first step towards providing therapeutic approaches relevant to manual therapists. Treatment modalities involving the somatosensory systems, and particularly manual therapy, should now be re-assessed in the subgroup of patients with cervicogenic somatosensory tinnitus. The conceptual phase of this study aims to uncover underlying mechanisms linking the auditory and somatosensory systems in relation to subjective tinnitus through (i) review of the literature (part 1) and (ii) through design of a pilot study that will explore characteristics of the study population and identify relevant components and outcomes of manual therapy in patients with cervicogenic somatosensory tinnitus (part 2). This manuscript focusses the theoretical concept of (cervicogenic) somatosensory tinnitus, either with or without secondary central tinnitus or tinnitus sensitization. PMID- 26749461 TI - The victims of unethical human experiments and coerced research under National Socialism. AB - There has been no full evaluation of the numbers of victims of Nazi research, who the victims were, and of the frequency and types of experiments and research. This paper gives the first results of a comprehensive evidence-based evaluation of the different categories of victims. Human experiments were more extensive than often assumed with a minimum of 15,754 documented victims. Experiments rapidly increased from 1942, reaching a high point in 1943. The experiments remained at a high level of intensity despite imminent German defeat in 1945. There were more victims who survived than were killed as part of or as a result of the experiments, and the survivors often had severe injuries. PMID- 26749462 TI - 6-Gingerol Mediates its Anti Tumor Activities in Human Oral and Cervical Cancer Cell Lines through Apoptosis and Cell Cycle Arrest. AB - 6-Gingerol, a potent nutraceutical, has been shown to have antitumor activity in different tumors, although its mechanism of action is not well understood. In this study, we evaluated antitumor activities of 6-gingerol on human oral (SCC4, KB) and cervical cancer (HeLa) cell lines with or without wortmannin, rapamycin, and cisplatin. Tumor cell proliferation was observed using 3-(4,5-dimethylthiazol 2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium, inner salt assay, cell cycle analysis by propidium iodide labeling and flow cytometry, apoptosis by Annexin-V binding assay, and caspase activity by chemiluminescence assay. 6-Gingerol showed dose-dependent cytotoxicity in all three cell lines. Combinations of 6-gingerol with wortmannin and cisplatin showed additive effects, while with rapamycin, it showed 50% cytotoxicity that was equivalent to IC50 of 6 gingerol alone. Treatment with 6-gingerol resulted in G2-phase arrest in KB and HeLa cells and S-phase arrest in SCC4 cells. 6-Gingerol, wortmannin, and rapamycin treatment showed almost two-fold higher expression of caspase 3 in all cell lines. The results imply that 6-gingerol either alone or in combination with PI-3 K inhibitor and cisplatin may provide better therapeutic effects in oral and cervical carcinoma. Thus, 6-gingerol appears to be a safe and potent chemotherapeutic/chemopreventive compound acting through cell cycle arrest and induction of apoptosis in human oral and cervical tumor cells. PMID- 26749463 TI - High expression of chemokine CCL2 is associated with recurrence after surgery in clear-cell renal cell carcinoma. AB - PURPOSE: Chemokine (C-C motif) ligand 2 (CCL2) is known to recruit monocytes and macrophages to sites of inflammation. Recent studies suggest CCL2 is overexpressed in multiple cancer types and may play a role in the tumor progression. The aim of this study was to assess the association between CCL2 expression and the risk of recurrence after surgery in patients with clear-cell renal cell carcinoma (ccRCC). METHODS: This study included 268 ccRCC patients who underwent nephrectomy at a single institute between 2001 and 2004. Clinicopathologic variables and recurrence-free survival (RFS) were recorded. CCL2 expression levels were evaluated by immunohistochemical staining in tumor tissues. Kaplan-Meier method was applied to compare survival curves. Cox regression models were fitted to analyze the effect of prognostic factors on recurrence-free survival (RFS). Harrell's concordance index was calculated to assess predictive accuracy. RESULTS: High CCL2 expression was associated with a greater risk of recurrence in ccRCC patients (P<0.001). Multivariate analysis confirmed that CCL2 expression was an independent prognostic factor for RFS (P = 0.045). The predictive accuracy of the Leibovich prognostic score was improved when CCL2 expression was added (0.76 vs. 0.71, P<0.001). Notably, the improvement in prediction was more pronounced in patients with low-risk disease. A nomogram integrating CCL2 expression and pathologic factors was then constructed, which predicted 5- and 10-year RFS well for ccRCC patients. CONCLUSIONS: High chemokine CCL2 expression is an independent predictor of recurrence in ccRCC patients. Evaluation of CCL2 could help guide postsurgical management for ccRCC patients. PMID- 26749464 TI - Patient-centered risk stratification of disposition outcomes following radical cystectomy. AB - PURPOSE: Patient-centered care involves providing understandable information to facilitate individualized health decisions among patients. We sought to determine the effect of age and comorbidity status on clinically meaningful outcomes following radical cystectomy (RC), in an effort the help optimize patient selection and enhance discussions among those considering surgery. MATERIALS AND METHODS: In a retrospective review, 6,460 patients were treated with RC for bladder cancer from the U.S. Premier Perspectives Database between 2007 and 2013. The influence of age and comorbidity count on the rates of inpatient mortality, prolonged length of stay (LOS), disposition to other than home and hospital readmission within the month of surgery or month after, were assessed. Comorbidity was calculated using the Elixhauser method. Prolonged LOS was defined as >10 days. Multivariable logistic regression models were used. RESULTS: Following RC, 16% of patients were discharged to somewhere other than home, 37% had a prolonged LOS and 2% died during the index admission. Among those discharged home after surgery, 27% of patients were readmitted. Prolonged LOS was associated with increasing comorbidities and age >70 years (P < 0.001). The adjusted likelihood of readmission increased with increasing burden of comorbid conditions (P < 0.001), however, not with age. The likelihood of being discharged to other than home increased with age and comorbidity count (P < 0.001). Mortality was associated with >=3 comorbidities and age >70 years. CONCLUSIONS: Increasing age and comorbidity are associated with poorer outcomes following RC, with comorbidity being the predominant factor. Our findings may improve surgical selection and better align patient expectations following surgery by providing estimated rates of postoperative events for patients considering RC. PMID- 26749466 TI - Antimicrobial, Rheological, and Thermal Properties of Plasticized Polylactide Films Incorporated with Essential Oils to Inhibit Staphylococcus aureus and Campylobacter jejuni. AB - Polylactide (PLA) is the most mature biobased and biodegradable polymer. Due to its inherent brittleness, the polymer cannot be used as a packaging material without plasticizer. An attempt was made to develop antimicrobial plasticized PLA film by incorporating polyethylene glycol (PEG) and 3 essential oils (EO), namely cinnamon, garlic, and clove by solvent casting method. Physical, thermal, and rheological properties of those films were evaluated for practical applications whereas the antimicrobial properties were tested against Staphylococcus aureus and Campylobacter jejuni-pathogens related to poultry industry. Both PEG and EOs led to the formation of flexible PLA/PEG/EO films with significant drop in the glass transition temperature (Tg ), and mechanical property. Time-temperature superposition (TTS) principle was employed to melt rheology of EO-based films at selected temperature, and rheological moduli superimposed well in an extended frequency range. Among EOs, cinnamon and clove oil-based films (PLA/PEG/CIN and PLA/PEG/CLO) exhibited a complete zone of inhibition against C. jejuni at the maximum concentration (1.6 mL per 2 g PLA/PEG blend) whereas the garlic oil-based film (PLA/PEG/GAR) had the lowest activity. PMID- 26749469 TI - Fluorescent Organic Planar pn Heterojunction Light-Emitting Diodes with Simplified Structure, Extremely Low Driving Voltage, and High Efficiency. AB - Fluorescent organic light-emitting diodes capable of radiative utilization of both singlet and triplet excitons are achieved via a simple double-layer planar pn hetero-junction configuration without a conventional emission layer, leading to high external quantum efficiency above 10% and extremely low driving voltages close to the theoretical minima. PMID- 26749470 TI - Light-Emitting Diodes: Phosphorescent Nanocluster Light-Emitting Diodes (Adv. Mater. 2/2016). AB - On page 320, R. R. Lunt and co-workers demonstrate electroluminescence from earth abundant phosphorescent metal halide nanoclusters. These inorganic emitters, which exhibit rich photophysics combined with a high phosphorescence quantum yield, are employed in red and near-infrared light-emitting diodes, providing a new platform of phosphorescent emitters for low-cost and high-performance light emission applications. PMID- 26749474 TI - Power of the patient voice in medical education. PMID- 26749465 TI - A specifically designed nanoconstruct associates, internalizes, traffics in cardiovascular cells, and accumulates in failing myocardium: a new strategy for heart failure diagnostics and therapeutics. AB - AIMS: Ongoing inflammation and endothelial dysfunction occurs within the local microenvironment of heart failure, creating an appropriate scenario for successful use and delivery of nanovectors. This study sought to investigate whether cardiovascular cells associate, internalize, and traffic a nanoplatform called mesoporous silicon vector (MSV), and determine its intravenous accumulation in cardiac tissue in a murine model of heart failure. METHODS AND RESULTS: In vitro cellular uptake and intracellular trafficking of MSVs was examined by scanning electron microscopy, confocal microscopy, time-lapse microscopy, and flow cytometry in cardiac myocytes, fibroblasts, smooth muscle cells, and endothelial cells. The MSVs were internalized within the first hours, and trafficked to perinuclear regions in all the cell lines. Cytotoxicity was investigated by annexin V and cell cycle assays. No significant evidence of toxicity was found. In vivo intravenous cardiac accumulation of MSVs was examined by high content fluorescence and confocal microscopy, with results showing increased accumulation of particles in failing hearts compared with normal hearts. Similar to observations in vitro, MSVs were able to associate, internalize, and traffic to the perinuclear region of cardiomyocytes in vivo. CONCLUSIONS: Results show that MSVs associate, internalize, and traffic in cardiovascular cells without any significant toxicity. Furthermore, MSVs accumulate in failing myocardium after intravenous administration, reaching intracellular regions of the cardiomyocytes. These findings represent a novel avenue to develop nanotechnology-based therapeutics and diagnostics in heart failure. PMID- 26749475 TI - The D1 family dopamine receptor, DopR, potentiates hind leg grooming behavior in Drosophila. AB - Drosophila groom away debris and pathogens from the body using their legs in a stereotyped sequence of innate motor behaviors. Here, we investigated one aspect of the grooming repertoire by characterizing the D1 family dopamine receptor, DopR. Removal of DopR results in decreased hind leg grooming, as substantiated by quantitation of dye remaining on mutant and RNAi animals vs. controls and direct scoring of behavioral events. These data are also supported by pharmacological results that D1 receptor agonists fail to potentiate grooming behaviors in headless DopR flies. DopR protein is broadly expressed in the neuropil of the thoracic ganglion and overlaps with TH-positive dopaminergic neurons. Broad neuronal expression of dopamine receptor in mutant animals restored normal grooming behaviors. These data provide evidence for the role of DopR in potentiating hind leg grooming behaviors in the thoracic ganglion of adult Drosophila. This is a remarkable juxtaposition to the considerable role of D1 family dopamine receptors in rodent grooming, and future investigations of evolutionary relationships of circuitry may be warranted. PMID- 26749476 TI - Compositional changes in (iso)flavonoids and estrogenic activity of three edible Lupinus species by germination and Rhizopus-elicitation. AB - The effects of germination and elicitation on (iso)flavonoid composition of extracts from three edible lupine species (Lupinus luteus, Lupinus albus, Lupinus angustifolius) were determined by RP-UHPLC-MS(n). The total (iso)flavonoid content of lupine increased over 10-fold upon germination, with the total content and composition of isoflavonoids more affected than those of flavonoids. Glycosylated isoflavones were the most predominant compounds found in lupine seedlings. Lesser amounts of isoflavone aglycones, including prenylated ones, were also accumulated. Elicitation with Rhizopus oryzae, in addition to germination, raised the content of isoflavonoids further: the total content of 2' hydroxygenistein derivatives was increased considerably, without increasing that of genistein derivatives. Elicitation by fungus triggered prenylation of isoflavonoids, especially of the 2'-hydroxygenistein derivatives. The preferred positions of prenylation differed among the three lupine species. The change in isoflavone composition increased the agonistic activity of the extracts towards the human estrogen receptors, whereas no antagonistic activity was observed. PMID- 26749477 TI - Renal duplex ultrasound findings in fenestrated endovascular aortic repair for juxtarenal aortic aneurysms. AB - OBJECTIVE: This study characterized duplex ultrasound (DUS) findings and clinical outcomes associated with covered stent placement in renal arteries during fenestrated endovascular aortic repair (FEVAR) to determine if velocity criteria for native renal artery stenosis can be applied. METHODS: Data from a prospectively maintained database of patients who underwent FEVAR between January 2010 and August 2014 were obtained before FEVAR (preoperative or baseline) and at follow-up assessments at 30 days, 6 months, and 1, 2, and 3 years. The established DUS threshold criteria for >=60% stenosis in native renal arteries were applied at baseline and all follow-up intervals: renal artery peak systolic velocity (PSV) >=200 cm/s or renal-aortic velocity ratio (RAR) >=3.5. RESULTS: Forty-nine patients underwent placement of 88 covered renal artery stents during FEVAR. At least 30-day follow-up was available for 43 patients with 80 stents. A >=60% stenosis was identified in seven renal arteries of six patients on baseline DUS, and these patients were analyzed separately. The remaining 73 renal arteries were classified as normal or <60% stenosis at baseline, with a median PSV of 121 cm/s (interquartile range, 96-143) and median RAR of 1.4 (interquartile range, 1.1-1.7). No significant differences were found between the baseline and follow up PSV measurements at any time point. The RAR differed significantly at some time points, although median values remained below the >=60% stenosis threshold. Some increased RAR values were attributed to low aortic velocities after repair. In the 13 patients with 17 covered renal artery stents found to have PSV or RAR exceeding a DUS threshold for >=60% native renal artery stenosis, there was no evidence of stenosis by computed tomography angiography, of renal dysfunction by estimated glomerular filtration rate, or of renal volume decrease by three dimensional analysis. None of the seven renal arteries with >=60% stenosis at baseline showed evidence of restenosis at 1, 2, or 3 years. CONCLUSIONS: Covered stent placement in nonstenotic renal arteries during FEVAR is safe and durable, with PSV and RAR remaining in the normal or <60% stenosis range in most patients. Increases in PSV or RAR that occur are not associated with clinically significant sequelae or in-stent stenosis on computed tomography angiography. DUS velocity criteria for stenosis in native renal arteries appear to overestimate the severity of stenosis in covered stents after FEVAR. PMID- 26749478 TI - Percutaneous embolization of arteriovenous malformations at the plantar aspect of the foot. AB - Peripheral arteriovenous malformations (AVM) remain most challenging among various congenital vascular malformations to be treated. Here we present three illustrative patients with Yakes type IIIb and type IV AVM at the plantar aspect of the foot who were successfully treated by minimally invasive embolization. The value of the Yakes AVM classification system to guide the therapeutic decision making by directing specific therapeutic procedures to specific AVM types defined by their angioarchitecture is demonstrated. Direct percutaneous AVM puncture with coiling of aneurysmal outflow vein and subsequent ethanol embolization is shown. Finally, the report illustrates that several AVM types can coexist. PMID- 26749479 TI - Increased blood flow in keloids and adjacent skin revealed by laser speckle contrast imaging. AB - BACKGROUND AND OBJECTIVES: Keloids are fibroproliferative lesions of unknown origin that are characterized by increased collagen deposition. Vascularization may play a role in the pathogenesis of keloids, but existing reports are contradictory. Thus, we assessed perfusion within keloids and surrounding skin using laser speckle contrast imaging (LSCI). STUDY DESIGN/MATERIALS AND METHODS: Twenty-one patients with 61 untreated keloids were enrolled into this study. LSCI was used to evaluate blood flow in the keloids and surrounding skin. Three regions of interest were manually defined: keloids (K), skin adjacent to keloids (A), and nonadjacent skin separated by at least 0.3 cm from the edge of the keloids (N). Mean perfusion in each of these regions was determined and ratios (K/N, A/N) were calculated. RESULTS: Significantly higher perfusion was noted in keloids and adjacent skin compared with nonadjacent skin (P < 0.05). The mean values (95% confidence intervals) of the ratios were: K/N = 2.41 (2.28-2.54) and A/N = 1.33 (1.28-1.37). A heterogeneous perfusion map was frequently observed. Mean perfusion in keloids and nonadjacent skin in the chest region was significantly higher than that on the back (P < 0.05). There was no statistical signficant difference in K/N at different locations (P > 0.05). CONCLUSIONS: Perfusion values in keloids and adjacent skin were significantly higher than those in nonadjacent skin. LSCI may be a suitable and useful way of assessing perfusion in keloids. PMID- 26749481 TI - Force and location between direct and indirect laryngoscopes. PMID- 26749480 TI - Isolation of novel PSII-LHCII megacomplexes from pea plants characterized by a combination of proteomics and electron microscopy. AB - In higher plants, photosystem II (PSII) is a multi-subunit pigment-protein complex embedded in the thylakoid membranes of chloroplasts, where it is present mostly in dimeric form within the grana. Its light-harvesting antenna system, LHCII, is composed of trimeric and monomeric complexes, which can associate in variable number with the dimeric PSII core complex in order to form different types of PSII-LHCII supercomplexes. Moreover, PSII-LHCII supercomplexes can laterally associate within the thylakoid membrane plane, thus forming higher molecular mass complexes, termed PSII-LHCII megacomplexes (Boekema et al. 1999a, in Biochemistry 38:2233-2239; Boekema et al. 1999b, in Eur J Biochem 266:444 452). In this study, pure PSII-LHCII megacomplexes were directly isolated from stacked pea thylakoid membranes by a rapid single-step solubilization, using the detergent n-dodecyl-alpha-D-maltoside, followed by sucrose gradient ultracentrifugation. The megacomplexes were subjected to biochemical and structural analyses. Transmission electron microscopy on negatively stained samples, followed by single-particle analyses, revealed a novel form of PSII LHCII megacomplexes, as compared to previous studies (Boekema et al.1999a, in Biochemistry 38:2233-2239; Boekema et al. 1999b, in Eur J Biochem 266:444-452), consisting of two PSII-LHCII supercomplexes sitting side-by-side in the membrane plane, sandwiched together with a second copy. This second copy of the megacomplex is most likely derived from the opposite membrane of a granal stack. Two predominant forms of intact sandwiched megacomplexes were observed and termed, according to (Dekker and Boekema 2005 Biochim Biophys Acta 1706:12-39), as (C2S2)4 and (C2S2 + C2S2M2)2 megacomplexes. By applying a gel-based proteomic approach, the protein composition of the isolated megacomplexes was fully characterized. In summary, the new structural forms of isolated megacomplexes and the related modeling performed provide novel insights into how PSII-LHCII supercomplexes may bind to each other, not only in the membrane plane, but also between granal stacks within the chloroplast. PMID- 26749483 TI - NURSES' BEREAVEMENT NEEDS AND ATTITUDES TOWARDS PATIENT DEATH: A QUALITATIVE DESCRIPTIVE STUDY OF NURSES IN A DIALYSIS UNIT. AB - BACKGROUND: Dialysis nurses have a unique relationship with their patients and often require bereavement support should a patient death occur. This study was conducted in 2014 and aimed to explore the attitudes of dialysis nurses to death and dying and to identify suitable bereavement strategies following a death of a patient. METHODS: A purposeful, convenience sample of all nurses employed in the dialysis service completed a demographic profile and The Death Attitudes Profile Revisited (DAP_R) survey. RESULTS: There were 52 responses to the survey (98% response rate). The mean age of the participants was 45 years +/- 8.0 years; 87% had >10 years nursing experience. Nurses suggest that debriefing and the use of a counsellor would support them in their grieving process while new graduate nurses appear to require extra support following a patient death. Analysis of the death attitude profile-revised (DAP-R) showed significant relationships between fear of death/death avoidance as well as fear of death/neutral acceptance. Spirituality and religion correlate strongly with 'Approach Acceptance' in this study group. Forty-four percent people who 'approach acceptance' of death can be explained by the strength of religious beliefs. CONCLUSIONS: Many dialysis nurses appear to have strong religious or spiritual belief systems and this contributes to their acceptance of death, although there also appears to be a degree of death avoidance. The study has highlighted the need to provide adequate bereavement support for dialysis nurses. PMID- 26749482 TI - Computational simulation and comparison of prothrombin complex concentrate dosing schemes for warfarin reversal in cardiac surgery. AB - BACKGROUND: Prothrombin complex concentrate (PCC) is increasingly used for acute warfarin reversal. We hypothesized that computational modeling of thrombin generation (TG) could be used to optimize the timing and dose of PCC during hemodilution induced by cardiopulmonary bypass (CPB). METHODS: Thrombin generation patterns were modeled in anticoagulated patients (n = 59) using a published computational model. Four dosing schemes were evaluated including single full dose (median, 41.2 IU/kg) of PCC before or after CPB, 1/2-dose before and after CPB, or 1/3-dose before CPB plus 2/3-dose after CPB. Hemodilution was modeled as 40 or 60 % dilution of factors from baseline. The lag time (s) of TG, and peak thrombin level (nM) were evaluated. RESULTS: Prolonged lag time, and reduced peak TG were due to low vitamin K-dependent (VKD) factors, and pre-CPB PCC dose-dependently restored TG to near-normal or normal range. After 40 % dilution, TG parameters were similar among 4 regimens at the end of therapy. The recovery of VKD factors was less when PCC was given before CPB after 60 % dilution, but TG parameters were considered hemostatically effective (>200 nM) with any regimen. Withholding the full dose of PCC until post-CPB resulted in severely depressed TG peak (median, 47 nM) after 60 % dilution, and some supra normal TG peaks after treatment. CONCLUSIONS: Pre-CPB administration of full or divided doses of PCC prevents extremely low TG peak during surgery, and maintains hemostatic TG peaks in both 40 and 60 % hemodilution models. Although PCC's hemostatic activity appears to be highest using the full dose after CPB, hypercoagulability may develop in some cases. PMID- 26749484 TI - Relocation of patients after cardiac surgery: is it worth the effort? AB - BACKGROUND: Fast-track protocols may facilitate early patient discharge from the site of surgery through the implementation of more expedient pathways. However, costs may merely be shifted towards other parts of the health care system. We aimed to investigate the consequence of patient transfers on overall hospitalisation, follow-up and readmission rate after cardiac surgery. METHODS: A single-centre descriptive cohort study using prospectively entered registry data. The study included 4,515 patients who underwent cardiac surgery at Aarhus University Hospital during the period 1 April 2006 to 31 December 2012. Patients were grouped and analysed based on type of discharge: Directly from site of surgery or after transfer to a regional hospital. The cohort was obtained from the Western Denmark Heart Registry and matched to the Danish National Hospital Register. RESULTS: Median overall length of stay was 9 days (7.0;14.4). Transferred patients had longer length of stay, median difference of 2.0 days, p < 0.001. Time to first outpatient consultation was 41(30;58) days in transferred patients vs. 45(29;74) days, p < 0.001. 18.6% was readmitted within 30 days. Mean time to readmission was 18.4 +/- 6.4 days. Median length of readmission was 3(1,6) days. There was no difference in readmissions between groups. Leading cause of readmission was cardiovascular disease with 48%. CONCLUSION: Transfer of patients does not overtly reduce health care costs, but overall LOS and time to first outpatient consultation are substantially longer in patients transferred to secondary hospitals than in patients discharged directly. Readmission rate is high during the month after surgery, but with no difference between groups. PMID- 26749485 TI - Novel copy number variants and major limb reduction malformation: Report of three cases. AB - Limb reduction malformations are highly heterogeneous in their clinical presentation and so, predicting the underlying mutation on a clinical basis can be challenging. Molecular karyotyping is a powerful genomic tool that has quickly become the mainstay for the study of children with malformation syndromes. We describe three patients with major limb reduction anomalies in whom pathogenic copy number variants were identified on molecular karyotyping. These include a patient with hypoplastic phalanges and absent hallux bilaterally with de novo deletion of 11.9 Mb on 7p21.1-22.1 spanning 63 genes including RAC1, another patient with severe Holt-Oram syndrome and a large de novo deletion 2.2 Mb on 12q24.13-24.21 spanning 20 genes including TBX3 and TBX5, and a third patient with acheiropodia who had a nullizygous deletion of 102 kb on 7q36.3 spanning LMBR1. We discuss the potential of these novel genomic rearrangements to improve our understanding of limb development in humans. PMID- 26749486 TI - Survival after Sublobar Resection for Early-Stage Lung Cancer: Methodological Obstacles in Comparing the Efficacy to Lobectomy. AB - INTRODUCTION: Surgery is the treatment of choice for early-stage lung cancer (LC). Although lobectomy (L) is the historic standard treatment, the issue of whether long-term outcomes of sublobar resection (SL) are comparable is still under debate. The objective of this study was to perform a review of the literature on 5-year survival rates after SL compared to L for patients with early-stage LC. METHODS: A priori inclusion criteria were as follows: (1) observational studies, (2) L compared to SL for early-stage LC, (3) radiographic staging by computed tomography scan, and (4) 5-year survival reported. A Medline search through January 2015 resulted in 31 studies representing 23 distinct datasets. The absolute difference in 5-year survival was calculated and plotted for each study. RESULTS: L was performed in 4564 patients and SL in 2287 patients. Of 19 studies reporting the reason for SL, 11 indicated that SL was performed because of comorbidities or impaired cardiopulmonary function. Four studies showed no difference in 5-year survival, 13 favored L, and six favored SL. One propensity score study favored L and the other favored SL. Of 20 studies reporting recurrence rate, 11 favored L and nine favored SL. CONCLUSIONS: Studies comparing 5-year survival rates of SL to L are sufficiently heterogeneous to prevent carrying out traditional meta-analysis. SL survival is often similar to L when adjustments are made for age, comorbidities, or impaired cardiopulmonary function. New approaches are needed for the comparison of L to SL. PMID- 26749487 TI - Pooled Analysis of the Prognostic and Predictive Value of KRAS Mutation Status and Mutation Subtype in Patients with Non-Small Cell Lung Cancer Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors. AB - OBJECTIVES: This pooled analysis of four trials of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) versus placebo was conducted to clarify the prognostic and predictive roles of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations (MUTs) and to explore the importance of MUT subtype. METHODS: Data were pooled from four trials of EGFR TKIs versus placebo (National Cancer Institute of Canada Clinical Trials Group [NCIC CTG] trial BR.21, TOPICAL, NCIC CTG trial BR.26, and NCIC CTG trial BR.19). Analyses of the combined data were performed to determine relationships of MUT status/subtype to response and survival end points. RESULTS: KRAS status was known for 1362 of 2624 patients (785 receiving EGFR TKIs and 577 receiving placebo); 275 (20%) had KRAS MUTs (248 at codon 12; 15 at codon 13; 12 at other codons). In the placebo arms there was no difference in overall survival (OS) for patients with KRAS MUTs or wild-type tumors (hazard ratio [HR] = 1.04, confidence interval [CI]: 0.81-1.33 for univariable analysis and HR = 1.09, CI: 0.85-1.41 for multivariable analysis). Patients with guanine-to-thymidine transversion MUTs had longer OS than did those with guanine-to-adenine transition MUTs or guanine-to-cytosine transversion MUTs (median OS 6.3, 1.8, and 3.9 months, respectively, p = 0.01). Patients with KRAS MUT tumors derived no benefit from EGFR TKIs (OS HR = 1.13, CI: 0.85-1.51; progression-free survival HR = 1.02, CI: 0.76-1.36). The interaction between KRAS status and EGFR TKI effect was significant for progression-free survival (p = 0.04) but not for OS (p = 0.17). For patients with G12V MUTs, EGFR TKI treatment was harmful (OS HR = 1.96, CI: 1.03-3.70, p = 0.04), whereas guanine-to-adenine transition MUTs were associated with an OS benefit from EGFR TKIs (HR = 0.49, CI: 0.24-1.00, p = 0.05). CONCLUSIONS: Overall, KRAS MUT is neither prognostic nor predictive of benefit from EGFR TKIs. However, it appears that KRAS MUT subtypes are not homogeneous in terms of their prognostic and predictive effects. These observations require prospective validation. PMID- 26749489 TI - Muon-Substituted Malonaldehyde: Transforming a Transition State into a Stable Structure by Isotope Substitution. AB - Isotope substitutions are usually conceived to play a marginal role on the structure and bonding pattern of molecules. However, a recent study [Angew. Chem. Int. Ed. 2014, 53, 13706-13709; Angew. Chem. 2014, 126, 13925-13929] further demonstrates that upon replacing a proton with a positively charged muon, as the lightest radioisotope of hydrogen, radical changes in the nature of the structure and bonding of certain species may take place. The present report is a primary attempt to introduce another example of structural transformation on the basis of the malonaldehyde system. Accordingly, upon replacing the proton between the two oxygen atoms of malonaldehyde with the positively charged muon a serious structural transformation is observed. By using the ab initio nuclear-electronic orbital non-Born-Oppenheimer procedure, the nuclear configuration of the muon substituted species is derived. The resulting nuclear configuration is much more similar to the transition state of the proton transfer in malonaldehyde rather than to the stable configuration of malonaldehyde. The comparison of the "atoms in molecules" (AIM) structure of the muon-substituted malonaldehyde and the AIM structure of the stable and the transition-state configurations of malonaldehyde also unequivocally demonstrates substantial similarities of the muon-substituted malonaldehyde to the transition state. PMID- 26749488 TI - Acquired C797S Mutation upon Treatment with a T790M-Specific Third-Generation EGFR Inhibitor (HM61713) in Non-Small Cell Lung Cancer. AB - T790M mutation is most common resistant mechanism to epidermal growth factor receptor gene (EGFR) tyrosin kinase inhibitor (TKI). Several third-generation EGFR-mutant selective TKI, such as AZD9291 (AstraZeneca), Rociletinib (Clovis), or HM61713 (Hanmi) have been developed. Acquired resistant C797S mutation was known to be one of the resistance mechanisms of AZD9291, which has not been reported for HM61713 yet. This is the first case report of C797S mutation as resistance mechanism of HM61713. PMID- 26749490 TI - Feed additive production by fermentation of herb Polygonum hydropiper L. and cassava pulp with simultaneous flavonoid dissolution. AB - Fermentation of herb Polygonum hydropiper L. (PHL) and cassava pulp (CP) for feed additive production with simultaneous flavonoid dissolution was investigated, and a two-stage response surface methodology (RSM) based on Plackett-Burman factorial design (PB design) was used to optimize the flavonoid dissolution and protein content. Using the screening function of PB design, four different significant factors for the two response variables were acquired: factors A (CP) and B (PHL) for the flavonoid dissolution versus factors G (inoculum size) and H (fermentation time) for protein content. Then, two RSMs were used sequentially to improve the values of the two response variables separately. The mutual corroboration of the experimental results in the present study confirmed the validity of the associated experimental design. The validation experiment showed a flavonoid dissolution rate of 94.00%, and a protein content of 18.20%, gaining an increase in 21.20% and 199.10% over the control, respectively. The present study confirms the feasibility of feed additive production by Saccharomyces cerevisiae with CP and PHL and simultaneous optimization of flavonoid dissolution and protein content using a two-stage RSM. PMID- 26749491 TI - Intralesional cryosurgery for the treatment of basal cell carcinoma of the lower extremities in elderly subjects: a feasibility study. AB - BACKGROUND: Incidences of basal cell carcinoma (BCC) on the lower extremities in elderly patients are rising. Surgical approaches to the treatment of BCC are subject to possible difficulties in healing, failure of skin grafts, and wound infection. This study assessed the efficacy of intralesional cryosurgery in the treatment of BCC of the lower limbs in elderly patients. METHODS: This study included eight patients aged >60 years in whom a total of 10 nodular or superficial BCCs of the lower limbs were confirmed by biopsy. The patients' medical histories revealed comorbidities including hypertension, diabetes, hypercholesterolemia, venous insufficiency, and deep vein thrombosis of the legs, congestive heart failure, chronic renal failure, and ischemic heart disease. Using liquid nitrogen, an intralesional cryosurgery needle (CryoShape) was inserted into the tumor to facilitate its complete freezing. Treatment success was confirmed by biopsy taken approximately 3 months after complete healing of the cryo-wound. RESULTS: The average size of the lesions treated was 2.49 cm(2) (16.4 * 15.2 mm). Mean recovery time was 79.9 days. Biopsies were obtained at a mean of 85.3 days after the wound had healed. All 10 biopsies verified the complete destruction of the tumor. There was no evidence of wound infection or tumor recurrence over a follow-up period of 28 months. CONCLUSIONS: This study demonstrates that a single intralesional cryosurgery session can completely eradicate BCC on the lower extremities in elderly patients. This technique is associated with relatively minor complications, is well tolerated, and represents a safe and effective therapeutic modality for BCC of the lower limbs. PMID- 26749492 TI - Dietary burden calculations relating to fish metabolism studies. AB - Fish farming is increasingly dependent on plant commodities as a source of feed leading to an increased risk for pesticide residues in aquaculture diets and consequently their transfer into aquaculture food products. The European pesticide regulation requires fish metabolism and fish feeding studies where residues in fish feed exceed 0.1 mg kg(-1) of the total diet (dry weight basis) to enable the setting of appropriate maximum residue levels in fish commodities. Fish dietary burden calculation is therefore an important prerequisite to decide on further experimental testing as part of the consumer risk assessment. In this review, the different aquaculture production systems are compared with regard to their specific feeding practices and the principles of dietary burden calculation are described. PMID- 26749493 TI - Males adjust their signalling behaviour according to experience of male signals and male-female signal duets. AB - Sexual signals are conspicuous sources of information about neighbouring competitors, and species in which males and females signal during pair formation provide various sources of public information to which individuals can adjust their behaviour. We performed two experiments with a duetting vibrational insect, Enchenopa binotata treehoppers (Hemiptera: Membracidae), to ask whether males adjust their signalling behaviour according to (1a) their own experience of competitors' signals, (1b) how females adjust their mate preferences on the basis of their experience of male signals (described in prior work), and/or (2) their own experience of female response signals to competitors' signals. We presented males with synthetic male signals of different frequencies and combinations thereof for 2 weeks. We recorded males a day after their last signal exposure, finding that (1a) male signal rate increased in response to experience of attractive competitors, but that (1b) male signal frequency did not shift in a manner consistent with how females adjust their mate preferences in those experience treatments. Second, we presented males with different male-female duets for 2 weeks, finding that (2) male signal length increased from experience of female duets with attractive competitors. Males thus make two types of adjustment according to two sources of public information: one provided by experience of male signals and another by experience of female responses to male signals. Signalling plasticity can generate feedback loops between the adjustments that males and females make, and we discuss the potential consequences of such feedback loops for the evolution of communication systems. PMID- 26749494 TI - Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME) in a unique south Indian community. AB - Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME)/familial adult onset myoclonic epilepsy (FAME) is a nonprogressive disorder characterized by (1) distal tremors that are usually precipitated by posture and action; (2) stimulus-sensitive myoclonus that is predominantly seen in the upper limb and is precipitated by photic stimuli, fatigue, emotional stress, and sleep deprivation; (3) seizures that were predominantly of the generalized tonic-clonic type that showed significant response to antiepileptic drugs (AEDs). ADCME has been reported worldwide with different genetic loci in Japanese families (8q23.3 q24.1), Italian families (2p11.1-q12.2), a French family (5p15.3.1-p15.1), and a Thai family (3q26.32-q28). ADCME has not been reported in South India and is still not recognized as an independent entity under the International League Against Epilepsy (ILAE). We report 241 patients with ADCME identified belonging to 48 families. The 48 families are domiciled in two southern districts of Tamilnadu in India, belonging to a community called "Nadar" whose nativity is confined to these southern districts, with reported unique genetic characteristics. This study is reported for the presentation of this rare disease in a unique ethnic group, and is the largest single report on ADCME worldwide. PMID- 26749495 TI - GANP protein encoded on human chromosome 21/mouse chromosome 10 is associated with resistance to mammary tumor development. AB - Human chromosome 21 is known to be associated with the high risk of hematological malignancy but with resistance to breast cancer in the study of Down syndrome. In human cancers, we previously observed the significant alterations of the protein expression encoded by the ganp/MCM3AP gene on human chromosome 21q22.3. Here, we investigated GANP protein alterations in human breast cancer samples (416 cases) at various stages by immunohistochemical analysis. This cohort study clearly showed that expression of GANP is significantly decreased in human breast cancer cases with poor prognosis as an independent risk factor (relapse-free survival, hazard ratio = 2.37, 95% confidence interval, 1.27-4.42, P = 0.007 [univariate analysis]; hazard ratio = 2.70, 95% confidence interval, 1.42-5.13, P = 0.002 [multivariate analysis]). To investigate whether the altered GANP expression is associated with mammary tumorigenesis, we created mutant mice that were conditionally deficient in the ganp/MCM3AP gene using wap-cre recombinase transgenic mice. Mammary gland tumors occurred at a very high incidence in female mammary gland-specific GANP-deficient mice after severe impairment of mammary gland development during pregnancy. Moreover, tumor development also occurred in female post parous GANP-heterodeficient mice. GANP has a significant role in the suppression of DNA damage caused by estrogen in human breast cancer cell lines. These results indicated that the GANP protein is associated with breast cancer resistance. PMID- 26749498 TI - Delivering Better Quality of Care: Relentless Focus and Starting with the End in Mind at DaVita. AB - The care of patients with end-stage renal disease has been evolving since the implementation of the Medicare entitlement for ESRD in 1973. Over the past 43 years, patients with ESRD have become increasingly complex with multiple comorbid conditions and the average age of new ESRD patients has continued to climb. Despite these challenges, progress has been made in improving mortality and morbidity, but the pace has generally been slow. The consolidation of the US dialysis industry has afforded large providers to achieve economies of scale and efficiencies. By reinvesting resources in innovative programs, the improvements in outcomes have accelerated. At DaVita, we have reimagined care for our ESRD patients by creating a Patient-Focused Quality Pyramid, an approach to holistic, patient-centered care that builds on the foundation of well-known dialysis metrics like adequacy and anemia management to drive more complex programs like fluid, medication, diabetes, and infection management. The ultimate goal is to improve survival, keep patients healthy and out of the hospital, enhance the patient experience of care, and thereby achieve optimal health-related quality of life. For two consecutive years, DaVita facilities, using this approach, have achieved superior performance in the CMS 5-Star rating program, most recently with 46% of facilities achieving 4 or 5 stars compared with only 23% of facilities outside of DaVita receiving 4 or 5 stars. This rating system has components of fundamentals, and more complex outcomes and our results are an external validation of the success of our approach in improving the lives of patients. PMID- 26749496 TI - Structural and functional features of the NAD(P) dependent Gfo/Idh/MocA protein family oxidoreductases. AB - The Gfo/Idh/MocA protein family contains a number of different proteins, which almost exclusively consist of NAD(P)-dependent oxidoreductases that have a diverse set of substrates, typically pyranoses. In this study, to clarify common structural features that would contribute to their function, the available crystal structures of the members of this family have been analyzed. Despite a very low sequence identity, the central features of the three-dimensional structures of the proteins are surprisingly similar. The members of the protein family have a two-domain structure consisting of a N-terminal nucleotide-binding domain and a C-terminal alpha/beta-domain. The C-terminal domain contributes to the substrate binding and catalysis, and contains a betaalpha-motif with a central alpha-helix carrying common essential amino acid residues. The beta-sheet of the alpha/beta-domain contributes to the oligomerization in most of the proteins in the family. PMID- 26749500 TI - Synthesis of Optically Active, X-Shaped, Conjugated Compounds and Dendrimers Based on Planar Chiral [2.2]Paracyclophane, Leading to Highly Emissive Circularly Polarized Luminescence. AB - Invited for the cover of this issue is Yasuhiro Morisaki at Kwansei Gakuin University together with the group of Yoshiki Chujo at Kyoto University. The image depicts the circularly polarized luminescence of the dendrimer films described in their Full Paper. Read the full text of the article at 10.1002/chem.201504270. PMID- 26749499 TI - Prevalence, symptom patterns and management of episodic diarrhoea in the community: a population-based survey in 11 countries. AB - BACKGROUND: The extent of episodic diarrhoea in the community is relatively unknown. AIM: To ascertain the prevalence, symptoms and management behaviours associated with self-reported diarrhoea across 11 countries. METHODS: Community screening surveys were conducted using quota sampling of respondents to identify a nationally representative sample of individuals suffering from 'episodic' diarrhoea (occurring once a month or more often). Second-phase in-depth surveys provided data on epidemiology, symptoms, attributed causes and management of episodic diarrhoea. RESULTS: A total of 11 508 phase 1 and 6613 phase 2 surveys were completed. The prevalence of self-reported episodic diarrhoea ranged from 16% to 23% across the 11 countries. The majority of episodic diarrhoea sufferers were female (57%) and were not diagnosed with pre-existing irritable bowel syndrome (IBS); IBS diagnosis ranged from 9% in Mexico to 44% in Italy. Diarrhoea was frequently attributed to anxiety/stress, food-related causes, gastrointestinal 'sensitivity' and menstruation. Accompanying symptoms included 'stomach pain/cramping' (35-62%), 'stomach grumbling' (29-68%) and 'wind' (18 74%). The proportion of episodic sufferers who reported treating their symptoms with remedies or medications ranged between 46% in Belgium and Canada and 90% in Mexico. CONCLUSIONS: A substantial proportion of the population in middle- to high-income countries report episodic diarrhoea in the absence of a pre-existing diagnosis. These symptoms are likely to be associated with substantial social and economic costs, and have implications on how best to configure and guide self led, pharmacist-led and primary care management. PMID- 26749501 TI - Virtual hysteroscopy with HDlive. PMID- 26749497 TI - Crossing the barrier: treatment of brain tumors using nanochain particles. AB - Despite advancements in surgery and radiotherapy, the aggressive forms of brain tumors, such as gliomas, are still uniformly lethal with current therapies offering only palliation complicated by significant toxicities. Gliomas are characteristically diffuse with infiltrating edges, resistant to drugs and nearly inaccessible to systemic therapies due to the brain-tumor barrier. Currently, aggressive efforts are underway to further understand brain-tumor's microenvironment and identify brain tumor cell-specific regulators amenable to pharmacologic interventions. While new potent agents are continuously becoming available, efficient drug delivery to brain tumors remains a limiting factor. To tackle the drug delivery issues, a multicomponent chain-like nanoparticle has been developed. These nanochains are comprised of iron oxide nanospheres and a drug-loaded liposome chemically linked into a 100-nm linear, chain-like assembly with high precision. The nanochain possesses a unique ability to scavenge the tumor endothelium. By utilizing effective vascular targeting, the nanochains achieve rapid deposition on the vascular bed of glioma sites establishing well distributed drug reservoirs on the endothelium of brain tumors. After reaching the target sites, an on-command, external low-power radiofrequency field can remotely trigger rapid drug release, due to mechanical disruption of the liposome, facilitating widespread and effective drug delivery into regions harboring brain tumor cells. Integration of the nanochain delivery system with the appropriate combination of complementary drugs has the potential to unfold the field and allow significant expansion of therapies for the disease where success is currently very limited. WIREs Nanomed Nanobiotechnol 2016, 8:678-695. doi: 10.1002/wnan.1387 For further resources related to this article, please visit the WIREs website. PMID- 26749502 TI - Polysomnographic measures of sleep in cocaine dependence and alcohol dependence: Implications for age-related loss of slow wave, stage 3 sleep. AB - BACKGROUND AND AIMS: Sleep disturbance is a prominent complaint in cocaine and alcohol dependence. This controlled study evaluated differences of polysomnographic (PSG) sleep in cocaine- and alcohol-dependent subjects, and examined whether substance dependence interacts with age to alter slow wave sleep and rapid eye movement (REM) sleep. DESIGN: Cross-sectional comparison. SETTING: Los Angeles and San Diego, CA, USA. PARTICIPANTS: Abstinent cocaine-dependent subjects (n = 32), abstinent alcohol-dependent subjects (n = 73) and controls (n = 108); mean age 40.3 years recruited 2005-12. MEASUREMENTS: PSG measures of sleep continuity and sleep architecture primary outcomes of Stage 3 sleep and REM sleep. Covariates included age, ethnicity, education, smoking, body mass index and depressive symptoms. FINDINGS: Compared with controls, both groups of substance dependent subjects showed loss of Stage 3 sleep (P < 0.001). A substance dependence * age interaction was found in which both cocaine- and alcohol-dependent groups showed loss of Stage 3 sleep at an earlier age than controls (P < 0.05 for all), and cocaine-dependent subjects showed loss of Stage 3 sleep at an earlier age than alcoholics (P < 0.05). Compared with controls, REM sleep was increased in both substance-dependent groups (P < 0.001), and cocaine and alcohol dependence were associated with earlier age-related increase in REM sleep (P < 0.05 for all). CONCLUSIONS: Cocaine and alcohol dependence appear to be associated with marked disturbances of sleep architecture, including increased rapid eye movement sleep and accelerated age-related loss of slow wave, Stage 3 sleep. PMID- 26749504 TI - Wireless Ultrasound-Guided Axillary Vein Cannulation for the Implantation of Cardiovascular Implantable Electric Devices. AB - INTRODUCTION: Ultrasound guidance for vascular cannulation seems safer and more effective than an anatomical landmark approach, though it has not gained widespread support partly due to workflow interference of wired probes. A wireless ultrasound transducer (WUST) may overcome this issue. We report the effectiveness, time consumption, and safety of the first-in-human experience in axillary vein cannulation guided with a novel WUST for the implantation of cardiovascular implantable electric devices (CIEDs). METHODS AND RESULTS: After a one-month training period, we routinely performed WUST-guided puncture to all first implants, prospectively registering data from the first 50 patients. We analyzed the time needed for preparing the WUST and for achieving each vein cannulation, and the rate of unsuccessful or accidental arterial punctures and complications. WUST-guided axillary vein access was successful in 49 out of 50 patients, totaling 86 cannulated veins. Median WUST preparation time was 55 [44 62] seconds and median time needed for each venous cannulation was 56 [36-71] seconds. A total of 84.9% of the veins were cannulated at the first attempt. There were 7 unsuccessful puncture attempts and 1 accidental arterial puncture. No pneumothorax, hemothorax, or nervous injury occurred in the 49 successfully cannulated patients. The unsuccessful one (distal subclavian occlusion) developed a minor local subcutaneous emphysema with no confirmed radiologic pneumothorax, not requiring intervention. During a follow-up of 2.5 +/- 1.1 months, a patient developed a pocket infection, with no other significant complications. CONCLUSION: Ultrasound-guided axillary vein cannulation using a wireless transducer for the implantation of CIEDs is a feasible, fast, and safe method. PMID- 26749503 TI - Complement activation in leprosy: a retrospective study shows elevated circulating terminal complement complex in reactional leprosy. AB - Mycobacterium leprae infection gives rise to the immunologically and histopathologically classified spectrum of leprosy. At present, several tools for the stratification of patients are based on acquired immunity markers. However, the role of innate immunity, particularly the complement system, is largely unexplored. The present retrospective study was undertaken to explore whether the systemic levels of complement activation components and regulators can stratify leprosy patients, particularly in reference to the reactional state of the disease. Serum samples from two cohorts were analysed. The cohort from Bangladesh included multi-bacillary (MB) patients with (n = 12) or without (n = 46) reaction (R) at intake and endemic controls (n = 20). The cohort from Ethiopia included pauci-bacillary (PB) (n = 7) and MB (n = 23) patients without reaction and MB (n = 15) patients with reaction. The results showed that the activation products terminal complement complex (TCC) (P <= 0.01), C4d (P <= 0.05) and iC3b (P <= 0.05) were specifically elevated in Bangladeshi patients with reaction at intake compared to endemic controls. In addition, levels of the regulator clusterin (P <= 0.001 without R; P < 0.05 with R) were also elevated in MB patients, irrespective of a reaction. Similar analysis of the Ethiopian cohort confirmed that, irrespective of a reaction, serum TCC levels were increased significantly in patients with reactions compared to patients without reactions (P <= 0.05). Our findings suggests that serum TCC levels may prove to be a valuable tool in diagnosing patients at risk of developing reactions. PMID- 26749505 TI - Reply. PMID- 26749507 TI - New insights on the mitochondrial proteome plasticity in Parkinson's disease. AB - Parkinson's disease (PD) is one of the most common neurodegenerative diseases whose relentless progression results in severe disability. Although PD aetiology is unknown, growing evidences point to the mitochondrial involvement in the pathobiology of this disorder. So, it seems imperative to understand the means by which the molecular pathways harboured in this organelle are regulated. With the advances in MS-based proteomics, there is a substantial expectation in the increased knowledge of mitochondrial protein dynamics. Still, few studies have been performed on mitochondrial protein profiling in the context of PD. In order to integrate data from these studies, network analyses were performed taking into consideration variables such as model of PD, cell line, or tissue origin. Overall, data retrieved from these analyses highlighted the modulation of the biological processes related with "generation of energy," "cellular metabolism," and "mitochondrial transport" in PD. However, it was noted that the impact of sample type and/or PD model on the biological processes was modulated by the disease. Moreover, technical considerations related to protein characterization using gel-based or gel-free MS approaches should be considered in data comparison among different studies. Data from the present review will help to envisage future studies targeting these mechanisms. PMID- 26749508 TI - Hierarchical Self-Assembly for Nanomedicine. AB - Function at all scales: Hierarchical assemblies of nanoparticles provide routes to multifunctional materials, in which structures at different scales impart different functions. Plasmonic vesicles formed by nanoparticle "strings" are useful both as contrast agents for photoacoustic imaging and as light-activated drug-delivery vehicles. PMID- 26749506 TI - Continuous usage of a hair dye product containing 2-methoxymethyl-para phenylenediamine by hair-dye-allergic individuals. AB - BACKGROUND: Despite a positive patch test reaction to para-phenylenediamine (PPD) and/or toluene-2,5-diamine (PTD), many people attempt to continue dyeing their hair with products containing PPD or its derivatives. OBJECTIVES: Investigation of elicitation reactions among PPD/PTD-allergic individuals to hair dye products containing the less sensitizing PPD derivative 2-methoxymethyl (ME)-PPD. METHODS: Elicitation reactions were studied in 43 PPD/PTD-allergic individuals by a 45-min pretest with an ME-PPD-containing hair dye on their forearm. Upon a negative result this was followed by exposure to subsequent hair colour treatment(s). RESULTS: Overall, 38 of 43 PPD/PTD-allergic individuals did not develop an elicitation reaction during the pretest with ME-PPD-containing hair dye products, and were eligible for subsequent hair colour treatments. Of these 38 PPD/PTD allergic individuals, 29 tolerated subsequent hair dyeing with ME-PPD-containing hair dye products, while seven showed mild and two showed moderate/marked allergic reactions upon the first hair colour treatment. CONCLUSIONS: Hair dye products with the less sensitizing ME-PPD were tolerated by 29 of 43 (67%) PPD/PTD-allergic individuals throughout continued hair dyeing with an average of nine treatments per year. Five individuals reacted upon pretesting, while only mild-to-moderate/marked skin reactions occurred upon hair dyeing in nine individuals who were not identified by the pretest. To our knowledge this is the first study among PPD/PTD-allergic individuals indicating that a negative 45-min pretest with a hair dye product helps to avoid severe allergic reactions. PMID- 26749509 TI - Laparoscopic extralevator abdominoperineal excision for low rectal cancer--a video vignette. PMID- 26749510 TI - Acute lung injury induced by lipopolysaccharide is inhibited by wogonin in mice via reduction of Akt phosphorylation and RhoA activation. AB - OBJECTIVES: Neutrophil infiltration into the lung is the critical characteristic of acute lung injury (ALI), which is a clinical state with acute inflammatory syndrome. Up to now, there is no effective medicine for ALI. Wogonin has been shown to posses serval biological activities including anti-inflammation, anti oxidant and anti-carcinoma. METHODS: Acute lung injury was induced by intratracheal injection of LPS, and wogonin at various concentrations was injected intraperitoneally 30 min prior to LPS. Contents of myeloperoxidase (MPO) and expression of chemokines and adhesion molecules were determined by commercially and ELISA assay kits, respectively. Akt phosphorylation and RhoA activation were measured by western blot and RhoA pull-down activation assay, respectively. KEY FINDING: Neutrophil infiltration was reduced by wogonin in a concentration-dependent manner in the LPS-induced ALI mice model. LPS-induced proinflammatory cytokines and adhesion molecules were inhibited by wogonin in bronchoalveolar lavage fluid (BALF) with LPS-induced ALI. Furthermore, wogonin suppressed Akt phosphorylation and RhoA activation in lungs in LPS-induced ALI. The similar parallel trend was observed as wogonin reduced LPS-induced neutrophils infiltration, proinflammatory cytokines generation, adhesion molecules expression, Akt phosphorylation, and RhoA activation. SUMMARY: These results suggested that the effects of wogonin in LPS-induced ALI were induced by inhibition of Akt phosphorylation and RhoA activation. PMID- 26749511 TI - Music for the birds: effects of auditory enrichment on captive bird species. AB - With the increase of mixed species exhibits in zoos, targeting enrichment for individual species may be problematic. Often, mammals may be the primary targets of enrichment, yet other species that share their environment (such as birds) will unavoidably be exposed to the enrichment as well. The purpose of this study was to determine if (1) auditory stimuli designed for enrichment of primates influenced the behavior of captive birds in the zoo setting, and (2) if the specific type of auditory enrichment impacted bird behavior. Three different African bird species were observed at the Buffalo Zoo during exposure to natural sounds, classical music and rock music. The results revealed that the average frequency of flying in all three bird species increased with naturalistic sounds and decreased with rock music (F = 7.63, df = 3,6, P = 0.018); vocalizations for two of the three species (Superb Starlings and Mousebirds) increased (F = 18.61, df = 2,6, P = 0.0027) in response to all auditory stimuli, however one species (Lady Ross's Turacos) increased frequency of duetting only in response to rock music (X(2) = 18.5, df = 2, P < 0.0001). Auditory enrichment implemented for large mammals may influence behavior in non-target species as well, in this case leading to increased activity by birds. PMID- 26749512 TI - Risk factors for new vertebral compression fractures after vertebroplasty: a meta analysis. AB - BACKGROUND: The risk factors for new vertebral compression fractures (VCFs) after vertebroplasty are unclear. The aim of this meta-analysis was to identify potential risk factors. METHODS: A systematic electronic literature search was performed using the following databases: PubMed, Embase and Cochrane Library; the databases were searched from the earliest available records in 1966 to May 2015. Pooled odds ratios (ORs) or standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using random- or fixed-effects models. The Newcastle-Ottawa scale was used to evaluate the methodological quality of the studies, and Stata 11.0 was used to analyse the data. RESULTS: The primary factors that were associated with new fractures after vertebroplasty were low bone mineral density (SMD -0.375; 95% CI -0.579 to -0.171), steroid usage (OR 2.632; 95% CI 1.399 to 4.950) and the presence of multiple treated vertebrae (OR 2.027; 95% CI 1.442 to 2.851). The data did not support that age, sex, body mass index, non-steroidal anti-inflammatory drug usage, vacuum cleft, thoracolumbar junction, cement volume, kyphosis correction, or intradiscal cement leakage could lead to infection after vertebroplasty. CONCLUSIONS: The present analysis demonstrated that low bone mineral density, the presence of multiple treated vertebrae and a history of steroid usage were associated with the new VCFs after vertebroplasty. Patients with these factors should be informed of the potential increased risk. PMID- 26749513 TI - Importance of appropriate location and frequency of biopsy for cutaneous manifestations in eosinophilic granulomatosis with polyangiitis. PMID- 26749514 TI - Contribution of intracellular negative ion capacity to Donnan effect across the membrane in alkaliphilic Bacillus spp. AB - To elucidate the energy production mechanism of alkaliphiles, the relationship between the H(+) extrusion rate by the respiratory chain and the corresponding ATP synthesis rate was determined in the facultative alkaliphile Bacillus cohnii YN-2000 and compared with those in the obligate alkaliphile Bacillus clarkii DSM 8720(T) and the neutralophile Bacillus subtilis IAM 1026. Under high aeration condition, much higher ATP synthesis rates and larger Deltapsi in the alkaliphilic Bacillus spp. grown at pH 10 than those in the neutralophilic B. subtilis grown at pH 7 were observed. This high ATP productivity could be attributed to the larger Deltapsi in alkaliphiles than in B. subtilis because the H(+) extrusion rate in alkaliphiles cannot account for the high ATP productivity. However, the large Deltapsi in the alkaliphiles could not be explained only by the H(+) translocation rate in the respiratory chain in alkaliphiles. There is a possibility that the Donnan effect across the membrane has the potential to contribute to the large Deltapsi. To estimate the contribution of the Donnan effect to the large Deltapsi in alkaliphilic Bacillus spp. grown at pH 10, intracellular negative ion capacity was examined. The intracellular negative ion capacities in alkaliphiles grown at pH 10 under high aeration condition corresponding to their intracellular pH (pH 8.1) were much higher than those in alkaliphiles grown under low aeration condition. A proportional relationship is revealed between the negative ion capacity and Deltapsi in alkaliphiles grown under different aeration conditions. This relationship strongly suggests that the intracellular negative ion capacity contributes to the formation of Deltapsi through the Donnan effect in alkaliphilic Bacillus spp. grown at pH 10. PMID- 26749515 TI - Hydrogen Bonding in Liquid Water and in the Hydration Shell of Salts. AB - A near-IR spectral study on pure water and aqueous salt solutions is used to investigate stoichiometric concentrations of different types of hydrogen-bonded water species in liquid water and in water comprising the hydration shell of salts. Analysis of the thermodynamics of hydrogen-bond formation signifies that hydrogen-bond making and breaking processes are dominated by enthalpy with non negligible heat capacity effects, as revealed by the temperature dependence of standard molar enthalpies of hydrogen-bond formation and from analysis of the linear enthalpy-entropy compensation effects. A generalized method is proposed for the simultaneous calculation of the spectrum of water in the hydration shell and hydration number of solutes. Resolved spectra of water in the hydration shell of different salts clearly differentiate hydrogen bonding of water in the hydration shell around cations and anions. A comparison of resolved liquid water spectra and resolved hydration-shell spectra of ions highlights that the ordering of absorption frequencies of different kinds of hydrogen-bonded water species is also preserved in the bound state with significant changes in band position, band width, and band intensity because of the polarization of water molecules in the vicinity of ions. PMID- 26749516 TI - Effect of temporomandibular disorder therapy on otologic signs and symptoms: a systematic review. AB - The most common temporomandibular disorders (TMD) signs and symptoms are related to muscle sensitivity through palpation, restricted mouth opening, asymmetric mandibular movements, joint sounds, pain and otologic signs and symptoms. To date, counselling, occlusal splints, exercises, biofeedback and acupuncture are examples of conservative modalities proposed for TMD therapy. The aim of this systematic review was to investigate the effect of these conservative therapies for TMD on otologic signs and symptoms. The authors searched the following electronic databases published up to 1st May 2015: PubMed, LILACS, Scopus, Web of Science and Science Direct with no time or language limitations. Using a two phase selection process, the authors identified 08 articles and used them to conduct a qualitative analysis. Methodological quality of each article was performed with the aid of 'Quality Assessment of a Cohort Study' and 'Quality Assessment of a Randomized Clinical Trial', developed by the Dutch Cochrane Centre, a centre of the Cochrane Collaboration. This systematic review showed in seven of the eight studies included that a total or partial resolution of otologic complains occurred after counselling, exercise therapies and occlusal splint therapy. Upon the limitations of the studies included in this systematic review, the present outcomes suggested that there is insufficient evidence in favour or against the conservative therapies for TMD on changes in otologic signs and symptoms. Thus, further studies with a higher level of evidence and more representative samples should be conducted to better understand the relationship of TMD therapy changes on otologic complains. PMID- 26749517 TI - Editorial: Insulin Resistance: Releasing the Brakes on Synovial Inflammation and Osteoarthritis? PMID- 26749518 TI - Narrative in nursing research: an overview of three approaches. AB - AIM: The aim of this paper is to present and discuss three popular narrative research approaches which have been successfully used by the authors in nursing research. Examples of each approach are offered to illustrate potential application in healthcare contexts. BACKGROUND: The creation, function and interpretation of narratives are of increasing interest to nurse researchers worldwide. Currently a variety of narrative research approaches are used to explore how people make sense of experience. While this diversity adds to the richness and scope of the methodology, practitioners new to narrative research may struggle in determining which approach best suits their research purposes and contexts. DESIGN: This discussion paper presents the philosophical basis, methodology, strengths and challenges of the following three commonly used narrative approaches: Murray's Narrative Framework, the Biographical Narrative Interpretive Method and Arts-Based Narrative Methods. DATA SOURCES: Data sources dating from 1934-2014 were used. These included seminal texts and articles from nursing and social science journals on narrative and narrative research found in the CINAHL, Medline and PsycInfo databases. IMPLICATIONS FOR NURSING: This discussion offers clarity and guidance to nurse researchers who are considering/ using narrative research methods to enquire into the storied nature of human experience and sense making processes. CONCLUSIONS: Employing a specific narrative research approach requires close attention to the 'fit' of the research question/context with the particular method under consideration. While sharing some narrative commonalities, each of these three methods enables the emergence of unique analytic and interpretive perspectives about stories relevant to nursing practice. PMID- 26749520 TI - Ecology and local knowledge of the Baird's tapir (Tapirella bairdii) in the Sierra Madre de Oaxaca, Mexico. AB - As well as being of global cultural importance (from local tribal folklore to being an iconic species for conservation), the tapir plays an important role in its ecosystem as a herbivore and seed disperser. However, the ecology and ethnozoology of the endangered Baird's tapir in the north of Oaxaca, Mexico is poorly understood. We used camera traps to estimate its relative abundance and density and to describe the activity patterns of the northernmost population of Baird's tapir in the Sierra Madre de Oaxaca. Local knowledge concerning the tapir was also documented, along with the conservation strategies undertaken by the 2 indigenous communities that own the land where the study site is located. Only adult tapirs were photographed, and these were active 14 h per day, but were mainly nocturnal and crepuscular. The estimated relative abundance (12.99 +/- 2.24 events/1000 camera days) and density values (0.07-0.24 individuals/km(2) ) were both similar to those found in another site in Mexico located within a protected area. Semi-structured interviews revealed that people have a basic understanding of the eating habits, activity and main predators of the tapir. There were reports of hunting, although not among those respondents who regularly consume bush meat. Thus, the relative abundance and density estimates of tapir at the study site could be related to the favorable condition of the forest and the absence of hunting and consumption of tapir meat. Fortunately, the local people are conducting initiatives promoting the conservation of this ungulate and its habitat that combine to constitute a regional trend of habitat and wildlife protection. PMID- 26749519 TI - Post-diagnosis social networks, and lifestyle and treatment factors in the After Breast Cancer Pooling Project. AB - OBJECTIVE: Larger social networks have been associated with better breast cancer survival. To investigate potential mediators, we evaluated associations of social network size and diversity with lifestyle and treatment factors associated with prognosis. METHODS: We included 9331 women from the After Breast Cancer Pooling Project who provided data on social networks within approximately two years following diagnosis. A social network index was derived from information about the presence of a spouse or intimate partner, religious ties, community participation, friendship ties, and numbers of living relatives. Diversity was assessed as variety of ties, independent of size. We used logistic regression to evaluate associations with outcomes and evaluated whether effect estimates differed using meta-analytic techniques. RESULTS: Associations were similar across cohorts though analyses of smoking and alcohol included US cohorts only because of low prevalence of these behaviors in the Shanghai cohort. Socially isolated women were more likely to be obese (OR = 1.21, 95% CI:1.03-1.42), have low physical activity (<10 MET-hours/week, OR = 1.55, 95% CI:1.36-1.78), be current smokers (OR = 2.77, 95% CI:2.09-3.68), and have high alcohol intake (>=15 g/d, OR = 1.23, 95% CI:1.00-1.51), compared with socially integrated women. Among node positive cases from three cohorts, socially isolated women were more likely not to receive chemotherapy (OR = 2.10, 95% CI:1.30-3.39); associations differed in a fourth cohort. Other associations (nonsignificant) were consistent with less intensive treatment in socially isolated women. Low social network diversity was independently associated with more adverse lifestyle, but not clinical, factors. CONCLUSIONS: Small, less diverse social networks measured post-diagnosis were associated with more adverse lifestyle factors and less intensive cancer treatment. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26749522 TI - A Retrospective Study on the Protective Effects of Topical Vancomycin in Patients Undergoing Multilevel Spinal Fusion. AB - BACKGROUND: Topical vancomycin may be an effective intervention to decrease the risk of postoperative surgical site infections (SSIs). The primary objective of this study was to evaluate the impact of topical vancomycin with intravenous (IV) cefazolin compared with IV cefazolin alone on the incidence of SSI in instrumented multilevel spinal fusion (MLSF) surgery. METHODS: This was a retrospective cohort study of patients 18 years and older who underwent instrumented MLSF surgery between January 1, 2010, and July 31, 2014. Patients who underwent anterior cervical diskectomy and fusion, had spine surgery within 3 months prior to index case, received antibiotics other than IV cefazolin prior to surgery, or had preoperative length of stay longer than 5 days were excluded. SSIs were identified using Centers for Disease Control and Prevention National Healthcare Safety Network definitions. Summary statistics were computed. Variables found to be associated with increased risk of SSI through univariate analysis were included in a multivariate analysis. RESULTS: Among 326 patients, 29 (8.9%) developed an SSI. Univariate analysis showed a trend toward decreased SSI incidence in the cohort receiving topical vancomycin with IV cefazolin compared with IV cefazolin alone, although this was not statistically significant ([6/116] 5.2% vs [23/210] 11.0%, p = 0.08). Topical vancomycin was associated with a protective effect against SSI in the multivariate analysis (odds ratio [OR] 0.26, p = 0.02). Significant risk factors for the development of SSI included female sex (OR 3.3, p = 0.01), increasing invasiveness score (p < 0.01), and diabetes mellitus (OR 5.1, p < 0.01). CONCLUSION: Topical vancomycin administered in addition to IV cefazolin was associated with a decreased risk of SSI in high-risk MLSF patients. Female patients and those with diabetes mellitus were at higher risk of developing postsurgical infection. Further prospective studies are needed to confirm these results and to define the most clinically effective dose of topical vancomycin in this patient population. PMID- 26749521 TI - Trends in esophageal cancer survival in United States adults from 1973 to 2009: A SEER database analysis. AB - BACKGROUND AND AIM: The rise in incidence of esophageal cancer (EC) in the USA over the last four decades has been well documented; however, data on trends in long-term survival and impact on modern therapies associated with survival are lacking. METHODS: The Surveillance, Epidemiology, and End Results database was queried to identify patients with confirmed EC. Cox proportional hazard regression was used to determine independent mortality factors. RESULTS: Of 93 167 patients diagnosed with EC between 1973 and 2009, 49% had a histologic diagnosis of esophageal adenocarcinoma (EAC). There was an increase (almost double) in the proportion of patients with adenocarcinoma from the 1970s to 2000s (n = 2,350; 35% to n = 32,212; 61%, P < 0.001). Surgery was performed for localized disease in a majority of EC regardless of type (n = 46 683; 89%). Use of surgical treatment increased significantly over the study period (49% to 64%, P < 0.001). There was also an increase in overall median survival (6 months versus 10 months, P < 0.001) and 5-year survival rate (9% to 22%, P < 0.001). Median survival increased consistently for EAC and squamous cell carcinoma (SCC) until the 1990s. After this period, median survival of EAC continued to increase more rapidly while SCC remained relatively stable. CONCLUSION: A significant survival improvement in esophageal cancer was seen from 1973 to 2009, largely because of earlier detection at a curative stage and greater utilization of treatment modalities (especially surgery). Despite the rising prevalence, patients with EAC have better long-term survival outcomes than those SCC. PMID- 26749523 TI - Integration of transcriptomic and proteomic analysis towards understanding the systems biology of root hairs. AB - Plants and other multicellular organisms consist of many types of specialized cells. Systems-wide exploration of large-scale information from singe cell level is essential to understand how cell works. Root hairs, tubular-shaped outgrowths from root epidermal cells, play important roles in the acquisition of nutrients and water, in the interaction with microbe, and in plant anchorage, and represent an ideal model to study the biology of a single cell type. Single cell sampling combined with omics approaches has been applied to study plant root hairs. This review emphasizes the integration of omics approaches towards understanding the systems biology of root hairs, unraveling the common and plant species-specific properties of root hairs, as well as the concordance of protein and transcript abundance. Understanding plant root hair biology by mining the integrated omics data will provide a way to know how a single cell differentiates, elongates, and functions, which might help molecularly modify crops for developing sustainable agriculture practices. PMID- 26749524 TI - Decreased fluidity of cell membranes causes a metal ion deficiency in recombinant Saccharomyces cerevisiae producing carotenoids. AB - The genome-wide transcriptional responses of S. cerevisiae to heterologous carotenoid biosynthesis were investigated using DNA microarray analysis. The results show that the genes involved in metal ion transport were specifically up regulated in the recombinant strain, and metal ions, including Cu(2+), Fe(2+), Mn(2+), and Mg(2+), were deficient in the recombinant strain compared to the ion content of the parent strain. The decrease in metal ions was ascribed to a decrease in cell membrane (CM) fluidity caused by lower levels of unsaturated fatty acids and ergosterol. This was confirmed by the observation that metal ion levels were restored when CM fluidity was increased by supplying linoleic acid. In addition, a 24.3 % increase in the beta-carotene concentration was observed. Collectively, our results suggest that heterologous production of carotenoids in S. cerevisiae can induce cellular stress by rigidifying the CM, which can lead to a deficiency in metal ions. Due to the importance of CM fluidity in cellular physiology, maintaining normal CM fluidity might be a potential approach to improving carotenoid production in genetically engineered S. cerevisiae. PMID- 26749525 TI - Engineering of Saccharomyces cerevisiae to utilize xylan as a sole carbohydrate source by co-expression of an endoxylanase, xylosidase and a bacterial xylose isomerase. AB - Xylan represents a major component of lignocellulosic biomass, and its utilization by Saccharomyces cerevisiae is crucial for the cost effective production of ethanol from plant biomass. A recombinant xylan-degrading and xylose-assimilating Saccharomyces cerevisiae strain was engineered by co expression of the xylanase (xyn2) of Trichoderma reesei, the xylosidase (xlnD) of Aspergillus niger, the Scheffersomyces stipitis xylulose kinase (xyl3) together with the codon-optimized xylose isomerase (xylA) from Bacteroides thetaiotaomicron. Under aerobic conditions, the recombinant strain displayed a complete respiratory mode, resulting in higher yeast biomass production and consequently higher enzyme production during growth on xylose as carbohydrate source. Under oxygen limitation, the strain produced ethanol from xylose at a maximum theoretical yield of ~90 %. This study is one of only a few that demonstrates the construction of a S. cerevisiae strain capable of growth on xylan as sole carbohydrate source by means of recombinant enzymes. PMID- 26749526 TI - Use of dental clinics and oral hygiene practices in the Kingdom of Saudi Arabia, 2013. AB - OBJECTIVES: We conducted a large household survey in 2013 to determine the current status of oral health practices and use of oral health services in the Kingdom of Saudi Arabia (KSA). METHODS: The Saudi Health Information Survey is a national multistage survey of individuals >= 15 years of age. We used a backward elimination multivariate logistic regression model to measure the association between having been to a dental clinic during the last year, and sex, age, marital status, education, time since last routine medical examination, history of diagnosis with a cardiovascular chronic condition, brushing or flossing teeth and use of Miswak (a chewing stick). RESULTS: Between April and June 2013, 10,735 participants completed the survey (89.4% of the households contacted). An estimated 1.5 million (11.5%) and 6.3 million (48.6%) Saudi Arabian people, >= 15 years of age, had visited a dental clinic for a routine check-up and for a complaint during the last year, respectively. In total, 16.3%, 85.0% and 52% of Saudi Arabian people never brush their teeth, never floss their teeth or never use Miswak, respectively. The probability of visiting a dental clinic increased with education, among individuals who brushed or flossed their teeth and who used Miswak. CONCLUSIONS: Oral hygiene practices are not common among Saudi Arabian people, and use of health care for prevention of oral disease is limited. Hence, the need for oral health promotion is pressing. The KSA Ministry of Health should develop and implement programmes, through its primary health clinics, to increase the awareness of the importance of good oral health. PMID- 26749528 TI - Platelet immunoreceptor tyrosine-based activation motif (ITAM) and hemITAM signaling and vascular integrity in inflammation and development. AB - Platelets are essential for maintaining hemostasis following mechanical injury to the vasculature. Besides this established function, novel roles of platelets are becoming increasingly recognized, which are critical in non-injury settings to maintain vascular barrier integrity. For example, during embryogenesis platelets act to support the proper separation of blood and lymphatic vessels. This role continues beyond birth, where platelets prevent leakage of blood into the lymphatic vessel network. During the course of inflammation, platelets are necessary to prevent local hemorrhage due to neutrophil diapedesis and disruption of endothelial cell-cell junctions. Surprisingly, platelets also work to secure tumor-associated blood vessels, inhibiting excessive vessel permeability and intra-tumor hemorrhaging. Interestingly, many of these novel platelet functions depend on immunoreceptor tyrosine-based activation motif (ITAM) signaling but not on signaling via G protein-coupled receptors, which plays a crucial role in platelet plug formation at sites of mechanical injury. Murine platelets express two ITAM-containing receptors: the Fc receptor gamma-chain (FcRgamma), which functionally associates with the collagen receptor GPVI, and the C-type lectin like 2 (CLEC-2) receptor, a hemITAM receptor for the mucin-type glycoprotein podoplanin. Human platelets express an additional ITAM receptor, FcgammaRIIA. These receptors share common downstream effectors, including Syk, SLP-76 and PLCgamma2. Here we will review the recent literature that highlights a critical role for platelet GPVI/FcRgamma and CLEC-2 in vascular integrity during development and inflammation in mice and discuss the relevance to human disease. PMID- 26749530 TI - RANK as a therapeutic target in cancer. AB - The RANK signaling pathway has emerged as a new target in breast cancer as receptor activator of nuclear factor kappaB ligand (RANKL) and its receptor RANK mediate the pro-tumorigenic role of progesterone in the mammary gland. Thousands of cancer patients worldwide are already taking RANKL inhibitors for the management of bone metastasis, given the relevance of this pathway in osteoclastogenesis and bone resorption. RANK signaling also has multiple divergent effects in immunity and inflammation, both in the generation of active immune responses and in the induction of tolerance: it is required for lymph node organogenesis, thymic medullary epithelial development and self-tolerance, and regulates activation of several immune cells and inflammatory processes. The RANK pathway interferes with mammary epithelial differentiation and mediates the major proliferative response of mammary epithelium to progesterone and progesterone driven expansion of mammary stem cells; it also controls hair follicle and epidermal stem cell homeostasis, pointing to RANK as a key regulator of epithelial stemness. Here we revisit the main functions of RANK signaling in bone remodeling, immune cells and epithelial differentiation. We also discuss the mechanistic evidence that supports its pleiotropic effects on cancer: from bone metastasis to immune and cancer-cell-dependent effects. PMID- 26749531 TI - CT angiography of the aorta using 80 kVp in combination with sinogram-affirmed iterative reconstruction and automated tube current modulation: Effects on image quality and radiation dose. AB - INTRODUCTION: The objective of this study was to evaluate image quality and radiation dose of a CT angiography (CTA) protocol using 80 kVp in combination with iterative reconstruction and automated tube current modulation. METHODS: Ninety-five aortic CTA examinations were included in this study. A novel 80 kVp aortic CTA-protocol with iterative reconstruction was introduced in our department in March 2012 for patients with a body mass index (BMI) below 32 kg/m(2). The first 72 consecutive examinations were retrospectively assigned to group A (56 patients, 42 men, 14 women, mean age 69.6 +/- 10.7 years, BMI range 19.7-31.1 kg/m(2)). For comparison, the last 23 consecutive examinations performed with the old protocol (100 kVp) were assigned to group B (21 patients, 13 men, 8 women, mean age 67.4 +/- 11.1 years, BMI range 19.7-31.9 kg/m(2)). Thoracic and abdominal contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR) and aortic attenuation were assessed. Subjective image quality was rated on a 5 point scale (1 = non diagnostic; 5 = excellent). Furthermore, dose length product (DLP) and volumetric computed tomography dose index (CTDIvol) were analysed. RESULTS: All examinations achieved diagnostic image quality. Attenuation of the aorta was significantly higher in group A compared with B (thoracic: 443.5 +/- 90.5 Hounsfield units (HU) vs. 296.0 +/- 61.0 HU; abdominal: 426.3 +/- 94.2 HU vs. 283.6 +/- 60.5 HU; P < 0.05, respectively). CNR, SNR and subjective image quality were comparable between both groups (CNR: 12.8 +/- 3.7 vs. 13.0 +/- 7.4; SNR 14.4 +/- 3.9 vs. 14.9 +/- 8.2; subjective image quality: 4.3 +/- 0.6 vs. 4.5 +/- 0.6; P > 0.05, respectively). CTDIvol and DLP were significantly lower in group A (1.9 +/- 0.5 mGy; 139.2 +/- 41.1 mGy * cm) as compared with group B (4.2 +/- 1.4 mGy; 292.1 +/- 91.5 mGy * cm; P < 0.001, respectively). CONCLUSION: Low dose CTA of the aorta using 80 kVp with iterative reconstruction enables a significant dose reduction of up to 50% compared with a 100 kVp protocol in patients with a BMI below 32 kg/m(2) while diagnostic image quality is maintained. PMID- 26749529 TI - Efficacy and safety of teneligliptin, a novel dipeptidyl peptidase-4 inhibitor, in Korean patients with type 2 diabetes mellitus: a 24-week multicentre, randomized, double-blind, placebo-controlled phase III trial. AB - We assessed the 24-week efficacy and safety of teneligliptin, a novel dipeptidyl peptidase-4 inhibitor, in Korean patients with type 2 diabetes mellitus (T2DM) that was inadequately controlled with diet and exercise. The present study was designed as a multicentre, randomized, double-blind, placebo-controlled, parallel group, phase III study. Patients (n = 142) were randomized 2 : 1 into two different treatment groups as follows: 99 received teneligliptin (20 mg) and 43 received placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) level from baseline to week 24. Teneligliptin significantly reduced the HbA1c level from baseline compared with placebo after 24 weeks. At week 24, the differences between changes in HbA1c and fasting plasma glucose (FBG) in the teneligliptin and placebo groups were -0.94% [least-squares (LS) mean -1.22, 0.65] and -1.21 mmol/l (-1.72, -0.70), respectively (all p < 0.001). The incidence of hypoglycaemia and adverse events were not significantly different between the two groups. This phase III, randomized, placebo-controlled study provides evidence of the safety and efficacy of 24 weeks of treatment with teneligliptin as a monotherapy in Korean patients with T2DM. PMID- 26749532 TI - 'Are you prepared?' Representations and management of floods in Lomanikoro, Rewa (Fiji). AB - The islands of Fiji, in the Western Pacific, are exposed to a wide range of natural hazards. Tropical storms and associated floods are recurring natural phenomena, but it has been regularly alleged that Fijians lack preparation, over rely on state assistance in post-disaster situations or engage in risky behaviours that aggravate the negative impact of floods. Risk reduction strategies, which are now implemented by government authorities and international organisations, heavily promote the principle of 'community preparedness'. Both community awareness programmes and capacity-building programmes are conducted throughout the country in the most vulnerable communities. This paper analyses how the inhabitants of Lomanikoro village, in the low areas of the Rewa Delta, perceive and manage existing flood risks. It examines social and cultural factors that contribute to shape risk response locally-in particular, why villagers may be reluctant to adopt some recommended preparedness measures and resettle in higher, safer zones. PMID- 26749534 TI - Massive ascites mimicking acute urinary retention. PMID- 26749533 TI - Effect of continuous smoking reduction and abstinence on blood pressure and heart rate in smokers switching to electronic cigarettes. AB - We present prospective blood pressure (BP) and hear rate (HR) changes in smokers invited to switch to e-cigarettes in the ECLAT study. BP and HR changes were compared among (1) different study groups (users of high, low, and zero nicotine products) and (2) pooled continuous smoking phenotype classification (same phenotype from week 12 to -52), with participants classified as quitters (completely quit smoking), reducers (>=50% reduction in smoking consumption) and failures (<50% or no reduction in smoking consumption). Additionally, the latter comparison was repeated in a subgroup of participants with elevated BP at baseline. No significant changes were observed among study groups for systolic BP, diastolic BP, and HR. In 145 subjects with a continuous smoking phenotype, we observed lower systolic BP at week 52 compared to baseline but no effect of smoking phenotype classification. When the same analysis was repeated in 66 subjects with elevated BP at baseline, a substantial reduction in systolic BP was observed at week 52 compared to baseline (132.4 +/- 12.0 vs. 141.2 +/- 10.5 mmHg, p < 0.001), with a significant effect found for smoking phenotype classification. After adjusting for weight change, gender and age, reduction in systolic BP from baseline at week 52 remains associated significantly with both smoking reduction and smoking abstinence. In conclusion, smokers who reduce or quit smoking by switching to e-cigarettes may lower their systolic BP in the long term, and this reduction is apparent in smokers with elevated BP. The current study adds to the evidence that quitting smoking with the use of e-cigarettes does not lead to higher BP values, and this is independently observed whether e-cigarettes are regularly used or not. PMID- 26749535 TI - Patient-reported outcomes of implant placement performed concomitantly with transcrestal sinus floor elevation or entirely in native bone. AB - AIM: Based on the hypothesis that maxillary sinus floor elevation with a transcrestal approach (tSFE) does not increase the morbidity of implant surgery, the study evaluated the patient-reported outcomes as well as the type and incidence of complications when implants are placed either concomitantly with tSFE (performed according to Trombelli et al. 2008, 2010a,b) or entirely in native bone. METHODS: Data from the record charts of patients undergone implant placement for single-tooth rehabilitation in the posterior maxilla were retrospectively obtained from four clinical centers. Cases for tSFE group were included if they showed an extent of sinus lift >=4 mm concomitantly to implant placement. Cases for N group were included when implant placement was performed entirely in native bone. Patient-reported outcomes had been assessed using 100-mm visual analog scales (postoperative pain, VASpain ) and visual rating scales (level of discomfort, VRSdiscomfort ; willingness to undergo the same surgery, VRSwillingness ). The dose of analgesics had been self-recorded. RESULTS: A convenience sample of 14 patients and 17 patients (contributing with one implant site each) treated with tSFE and N, respectively, was obtained for this study. Membrane perforation occurred in 1 tSFE case, without compromising the completion of the procedure. VASpain remained low (<12) in both groups. A tendency of VASpain to decrease with time was observed in both groups. The area under the curve for VASpain (AUCpain ), indicating the level of pain experience through the first week following surgery, was 18.0 (IR: 8.5-85.0) and 11.5 (IR: 4.5-18.5) in tSFE and N groups, respectively, with no significant inter-group differences (P = 0.084). The dose of analgesics was similarly low between groups. No significant inter-group difference in VRSdiscomfort and VRSwillingness was observed. CONCLUSIONS: Implant placement performed either concomitantly with tSFE (according to Trombelli et al. 2008, 2010a,b) or entirely in native bone is associated with limited incidence of complications, low postoperative pain and medication and are both well tolerated. PMID- 26749536 TI - Editorial: HLA-B27: The Story Continues to Unfold. PMID- 26749537 TI - The glycocalyx and its significance in human medicine. AB - Cells are covered by a surface layer of glycans that is referred to as the 'glycocalyx'. In this review, we focus on the role of the glycocalyx in vascular diseases (atherosclerosis, stroke, hypertension, kidney disease and sepsis) and cancer. The glycocalyx and its principal glycosaminoglycans [heparan sulphate (HS) and hyaluronic acid (HA)] and core proteins (syndecans and glypicans) are degraded in vascular diseases, leading to a breakdown of the vascular permeability barrier, enhanced access of leucocytes to the arterial intima that propagate inflammation and alteration of endothelial mechanotransduction mechanisms that protect against disease. By contrast, the glycocalyx on cancer cells is generally robust, promoting integrin clustering and growth factor signalling, and mechanotransduction of interstitial flow shear stress that is elevated in tumours to upregulate matrix metalloproteinase release which enhances cell motility and metastasis. HS and HA are consistently elevated on cancer cells and are associated with tumour growth and metastasis. Later, we will review the agents that might be used to enhance or protect the glycocalyx to combat vascular disease, as well as a different set of compounds that can degrade the cancer cell glycocalyx to suppress cell growth and metastasis. It is clear that what is beneficial for either vascular disease or cancer will not be so for the other. The overarching conclusions are that (i) the importance of the glycocalyx in human medicine is only beginning to be recognized, and (ii) more detailed studies of glycocalyx involvement in vascular diseases and cancer will lead to novel treatment modalities. PMID- 26749538 TI - Low-Density Granulocytes Are Increased in Antiphospholipid Syndrome and Are Associated With Anti-beta2 -Glycoprotein I Antibodies: Comment on the Article by Yalavarthi et al. PMID- 26749539 TI - A Simple Graphical Method to Determine the Order in Catalyst. AB - A graphical analysis to elucidate the order in catalyst is presented. This analysis uses a normalized time scale, t [cat]T (n) , to adjust entire reaction profiles constructed with concentration data. The method is fast and simple to perform because it directly uses the concentration data, therefore avoiding the data handling that is usually required to extract rates. Compared to methods that use rates, the normalized time scale analysis requires fewer experiments and minimizes the effects of experimental errors by using information on the entire reaction profile. PMID- 26749540 TI - Preoperative evaluation and comprehensive risk assessment for children with Down syndrome. AB - Down syndrome is a common chromosome disorder affecting all body systems. This creates unique physiologic concerns that can affect safety during anesthesia and surgery. Little consensus exists, however, on the best way to evaluate children with Down syndrome in preparation for surgery. We review a number of salient topics affecting these children in the perioperative period, including cervical spine instability, cardiovascular abnormalities, pulmonary hypertension, upper airway obstruction, hematologic disturbances, prematurity, low birth weight, and the use of supplements and alternative therapies. Recommendations include obtaining a complete blood count to detect an increased risk for bleeding or stroke, and cardiology evaluation to identify patients with pulmonary hypertension, as well as undiagnosed or residual heart disease. Pediatric cardiac anesthesiologists and intensivists should be involved as needed. The potential for cervical spine instability should be considered, and the anesthesiologist may wish to have several options available both for the medications and equipment used. The child's family should always be asked if he or she is on any nutritional supplements, as some products marketed to families may have secondary effects such as inhibition of platelet function. Using this evaluation in presurgical planning will allow physicians to better consider the individual circumstances for their patients with Down syndrome. Our goal was to optimize patient safety by choosing the most appropriate setting and perioperative personnel, and to mitigate those risk factors amenable to intervention. PMID- 26749542 TI - [Editorial]. PMID- 26749543 TI - [Editorial]. PMID- 26749541 TI - Nucleocapsid proteins: roles beyond viral RNA packaging. AB - Viral nucleocapsid proteins (NCs) enwrap the RNA genomes of viruses to form NC RNA complexes, which act as a template and are essential for viral replication and transcription. Beyond packaging viral RNA, NCs also play important roles in virus replication, transcription, assembly, and budding by interacting with viral and host cellular proteins. Additionally, NCs can inhibit interferon signaling response and function in cell stress response, such as inducing apoptosis. Finally, NCs can be the target of vaccines, benefiting from their conserved gene sequences. Here, we summarize important findings regarding the additional functions of NCs as much more than structural RNA-binding proteins, with specific emphasis on (1) their association with the viral life cycle, (2) their association with host cells, and (3) as ideal candidates for vaccine development. PMID- 26749544 TI - [The concept of Health Literacy and its importance for nursing]. AB - INTRODUCTION: Individuals and population's health is influenced by environmental, social economical and cultural aspects which in turn connect individuals to society. In order to decide autonomously, independently and consciously individuals should have several competences. The aim of this study is to identify, analyse and emphasise health literacy concept relevance per se,its relationship with nursing through a narrative revision focused on: Health literacy definition recognition and analysis; evaluation of connection between nursing and health literacy. METHODS: A narrative review was carried out through PUBMED and CINHAL, using 'health literacy' and nursing related terms, in English or Italian between 2010 and 2015. RESULTS: Results show that 'health literacy' is fully appraised, while attention paid by nurses on the topic is poor due both to a lack of awareness of its relevance on individuals' health and of appraisal. Twenty-height definition emerged from the revision; concepts expressed by scholars are mainly focused on very few individuals' abilities and competences applied to the health context (reading, writing, calculation, comprehension, listening and so on). CONCLUSIONS: According to the results it is difficult to define health literacy due to its multidimensional nature. Notwithstanding the above an attempt to develop a unique new definition of health literacy has been carried out although its multidimensional nature and its strong connection to several variables constantly under development. Nevertheless it is imperative that educational modules would be developed and stably integrated in health care education, at the same time a strong effort is due from professional and policy makers to provide population of the necessary tools in order to improve their health. PMID- 26749545 TI - [Structural empowerment and job satisfaction among nurses coordinators: a pilot study]. AB - INTRODUCTION: In literature, the structural empowerment and the job satisfaction have been studied in many different work settings but more need to be done in the setting of Head Nurses. OBJECTIVE: The goal of the study is to evaluate the structural empowerment level of head nurses and if it impacts on the job satisfaction. METHODS: A cross sectional design study was used. We enrolled 125 head nurses from three different hospitals of Rome. To collect the data we used a questionnaire that included both a part of the collection of sociopersonal data and the two scales (job satisfaction and structural empowerment). We used the SPSS19.0 statistical Software for data analysis to detect significant results. RESULTS: Head Nurse declared to be not enough satisfied at work (mean=3.43) and their structural empowerment level resulted moderate (mean=3.16). The structural empowerment of head nurses impacts their job satisfaction especially concerning opportunities for social and professional interactions, praises, awards, audit and responsibilities. CONCLUSIONS: Results underline structural empowerment relevance in head nurses job satisfaction. Healthcare organizations need to address job satisfaction to improve quality of care and more specifically that of head nurses since they directly impact on nurses job satisfaction. PMID- 26749546 TI - [Nursing role in prevention of Ventilator Associated Pneumonia: Spanish project "Neumonia Zero"]. AB - The incidence of Ventilator Associated Pneumonia (VAP) varies between 8 and 28% on patients with invasive mechanical ventilation, and it is associated with high mortality rates. The international literature indicates that the VAP has some risk factors that cannot be changed and some other that are closely related to nursing care procedures. The aim of this study is to analyze compliance level to the protocol of nursing prevention of the VAP in the ICU of "General Hospital" in Castellon de la Plana (Spain) within the project "Neumonia Zero". The data were collected during the months of May and June 2012 through direct observation which lasted 33 days. 5 check lists based on international recommendations were used for the objective evaluation on the adoption of preventive treatments. 58 patients in invasive mechanical ventilation and 43 ICU nurses were enrolled. Compliance procedure showed no significant differences among each other with an average adhesion of 78% of the observations. The observations trend shows a tendency of improvement in accordance with the checklists of cuff pressure and of the inclination of the bed head. An incidence rate of VAP 13,37/1000 was observed. In conclusion, direct observation showed good compliance to the protocols used in the ward. The obtained data allows to re-direct educational choices and assume a systematic application of this methodology with an important contribution to nursing. PMID- 26749547 TI - [Study of the application of the guidelines for the handling of citotoxic drugs in some health facilities]. AB - AIM: A survey in 5 Roman hospital was carried out to have a deep understanding of guidelines application and existing regulations regarding health professionals' protection in handling antiblastic drugs. METHODS: A questionnaire was administered to 122 nurses, working in oncology units, about the main points required by guidelines for safe handling of antiblastic drugs. RESULTS: Results show that attention to collective protection equipment and working practices is evident, nevertheless other elements are still partly applied, first the lack of staff training, which not involved all health professionals and the frequency which does not fit guidelines. The use of Personal Protective equipment, where provided, is sometimes ignored, a situation which can be connected to the lack of specific training of personnel. CONCLUSIONS: Greater attention must be taken to ensure that required training for nurses involved in the preparation and administration of antiblastic drugs, this is the starting point for the proper use of Personal Protective equipment and of appropriate procedures in each work phase. Increased control by the institutional bodies to confirm compliance with the rules and regulations for the protection of workers' health is desiderable. PMID- 26749548 TI - [Planning With Nanda, Noc, Nic Taxonomies In Neurologic Rehabilitation. A clinical study]. AB - INTRODUCTION: Nursing classifications identify a specific professional responsibility, increase nursing visibility, according with nursing evolution of these last years. OBJECTIVE: To evaluate care planning with NANDA taxonomy in neurologic rehabilitation context. METHOD: Care plan managing with NANDA taxonomy, regarding diagnosis of constipation and impaired skin integrity, using a computerized tool for systematically observation, organized in check list. RESULTS: Registered data with taxonomy planning are higher in quantitative and qualitative terms. For most of patients (87%) one diagnosis has been opened, both diagnosis for 60% of them. CONCLUSION: Nursing care plan with NANDA taxonomy can be considered a valid methodology of care for neurologic patient, this since it requests a deep and complete registration of first assessment a systematically registration of each monitoring, it increases visibility of nursing job, and it underlines specific autonomy and responsibility in prevention and management of problems. PMID- 26749549 TI - [Identification of Nursing Diagnosis "Non compliance (00079)" and "Ineffective Self-Health Management (00078)": Pilot study]. AB - OBJECTIVES: Survey on a sample of second and third years nursing students, data concerning skills in identifying nursing diagnosis "Ineffective Self-Health management (00078)" and "Non compliance (00079)". The main objectives were to determine differences and similarities between the two diagnosis detected by students, to recognize which elements taken into account to identify them and to determine possible causes of misidentification. METHODS: Semi structured interview with analisys of a clinical case. RESULTS: Lacking knowledge was found regarding both diagnosis. Students stated to have some difficulties to understand and identify diagnosis; most of the them interviewed tend to confuse these two diagnosis precisely because they do not discern the differences. Despite that, most of them succeded in identifying the correct diagnosis in reference to the proposed clinical case, and were able to justify properly the choices made. CONCLUSIONS: The study highlights the need to develop students' skills for the identification of the two diagnoses. There is a overall confusion in describing patient's health conditions, this leads to an innapropriate identification of nursing goals and interventions and to an not efficient delivery of care. Improving actions should be addressed to the causes of a difficult differential identification. Educator therefore should be focus on learning development in order to change knowledge, attitudes and beliefs, perception of self-efficacy, but also in clinical practice in order to improve cognitive skills on nursing diagnosis. PMID- 26749551 TI - Ring Opening of a meso-Triaryl 25-Oxasmaragdyrin Macrocycle by m Chloroperoxybenzoic Acid. AB - Smaragdyrin, a class of expanded porphyrin macrocycles, upon treatment with meta chloroperoxybenzoic acid (mCPBA) underwent oxidative ring opening to form an unprecedented linear pentaheterocyclic compound. The linear pentaheterocyclic compound was freely soluble in common organic solvents and characterized in detail by HRMS, 1D and 2D NMR spectroscopy, and X-ray crystallography. Our preliminary studies indicated that the linear pentaheterocyclic compound can specifically sense anions such as H2 PO4- and CN- ions, which was corroborated by absorption and fluorescence studies. PMID- 26749550 TI - Nurses as seen by patients: a phenomenological study. AB - OBJECTIVE: during the various periods of the history of the nursing profession, many differing representations of nurses have emerged in the collective imagination. The main purpose of this study, based on a qualitative approach, has been to discover the images of the nurse that patients retain in their minds when receiving care. METHODS: 6 sound-recorded focus groups were created, made up of patients and caregivers. These persons were members of 6 associations. The recordings and observations made were then analysed by adopting a hermeneutic phenomenological approach. RESULTS: 6 themes characterising nurses emerged: Training; Between flexibility and personalisation; Organisation and nursing; Continuity in caregiving; Professional maturity; and Relations. While these themes do not provide a uniform definition for the figure of the nurse they do present the profiles that had the greatest impact on persons receiving care. CONCLUSIONS: From the experiences collected among the participants in the focus groups, no pre-defined "image" of nurses emerged, and the stereotypes and prejudices described in the literature were also not to be found. Important indications did, in any case, emerge as to the type of nurse these people want, and concerning areas which must be worked on. These indications provide valuable information that, if acted upon, might contribute to the profession's growth and improvement. In brief, there are various planes of activity upon which nurses should concentrate their efforts: training (greater specialisation), organisation (greater flexibility), and the profession (consideration of professional identity in the light of the task of meeting patients' needs). PMID- 26749552 TI - Prader-Willi Syndrome: A spectrum of anatomical and clinical features. AB - Prader-Willi Syndrome (PWS) is estimated to affect 400,000 people worldwide. First described clinically in 1956, PWS is now known to be a result of a genetic mutation, involving Chromosome 15. The phenotypical appearance of individuals with the syndrome follows a similar developmental course. During infancy, universal hypotonia accompanied by feeding problems, hypogonadism, and dolichocephaly are evident. Characteristic facial features such as narrow bifrontal diameter, almond-shaped eyes, and small mouth (with downturned corners and thin upper lip) may also be evident at this stage. In early childhood, the craniofacial features become more obvious and a global developmental delay is observed. Simultaneously, individuals develop hyperphagia that leads to excessive or rapid weight gain, which, if untreated, exists throughout their lifespan and may predispose them to numerous, serious health issues. The standard tool for differential diagnosis of PWS is genetic screening; however, clinicians also need to be aware of the characteristic features of this disorder, including differences between the genetic subtypes. As the clinical manifestations of the syndrome vary between individuals and become evident at different developmental time points, early assessment is hindered. This article focuses on the clinical and anatomical manifestations of the syndrome and highlights the areas of discrepancy and limitations within the existing literature. Clin. Anat. 29:590 605, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26749553 TI - Antibodies to human neutrophil antigen HNA-4b implicated in a case of neonatal alloimmune neutropenia. AB - BACKGROUND: Maternal alloantibodies directed against human neutrophil antigens (HNAs) can cause moderate-severe neutropenia in the newborn in a condition known as neonatal alloimmune neutropenia (NAIN). Neonates with NAIN can present with sepsis or be asymptomatic. NAIN has previously been reported as caused by antibodies against HNA-1a, -1b, and -1c; CD16b, -2, -3a, -4a, and -5a; and HLA, but not by antibodies against HNA-4b. We report a case of NAIN due to anti- HNA 4b alloimmunization in a term neonate. CASE REPORT: An infant with persistent and marked neutropenia was suspected of having neonatal alloimmune neutropenia. Blood samples from both parents were investigated for HNA and HLA incompatibilities by molecular typing techniques and the mother for the presence of HNA and HLA antibodies by serologic techniques. RESULTS: Initial results indicated the presence of granulocyte antibodies in the maternal serum, the specificity of which were shown to be anti-HNA-4b. Subsequently, the mother was genotyped as HNA 4b negative and the father as heterozygous HNA-4ab. The child was shown to have inherited the incompatible HNA-4b allele. CONCLUSION: We have demonstrated the first case of NAIN due to maternal alloimmunization against HNA-4b, pending ratification by the International Granulocyte Immunobiology Workshop. PMID- 26749554 TI - Q Fever Serological Survey and Associated Risk Factors in Veterinarians, Southern Belgium, 2013. AB - A sero-epidemiological survey was organized among veterinarians working in Southern Belgium to estimate the seroprevalence of Q fever and the risk factors associated with exposure. A total of 108 veterinarians took part to this cross sectional study, with a majority practicing with livestock animals. The overall seroprevalence was 45.4%, but it increased to 58.3% among veterinarians having contact with livestock. Three main serological profiles were detected (relatively recent, past and potentially chronic infections). The contact with manure during the prior month was the risk factor associated with seropositivity after multivariate logistic regression analysis. Classification and regression tree analysis identified the age as the most predictive variable to exclude potentially chronic infection in apparently healthy seropositive veterinarians. In conclusion, livestock veterinarians practicing in Southern Belgium are highly exposed to Q fever, a neglected zoonosis for which serological and medical examinations should be envisaged in at risk groups. PMID- 26749555 TI - Progression of fibrosis in patients with chronic viral hepatitis is associated with IL-17(+) neutrophils. AB - BACKGROUND & AIMS: The pro-inflammatory cytokine IL-17 plays a crucial role in liver diseases associated with hepatic fibrosis and increased risk of cancer development. Nevertheless, the cellular source of this cytokine has never been characterized in patients with liver fibrosis. METHODS: In this study, we investigated liver biopsies from 49 patients with chronic viral hepatitis at different stages of liver fibrosis. We monitored IL-17 production by intracellular flow cytometry, immunofluorescence and immunohistochemical in situ stainings, allowing a precise quantification, characterization and localization of IL-17(+) cells. RESULTS: Density of IL-17(+) cells increased with the stage of liver fibrosis specifically in fibrotic septa and portal areas (correlation coefficient r = 0.7373; P < 0.0001). Data clearly show that the frequency of intrahepatic IL-17(+) lymphocytes (including T, NKT and NK cells) was independent on stage of liver fibrosis, and we observed no statistical differences in number of IL-17(+) macrophages during progression of fibrosis. On the other hand, the number of IL-17(+) neutrophils in fibrotic septa and portal areas strongly correlated with the stages of fibrosis (correlation coefficient r = 0.6986; P < 0.0001), contributing significantly to total IL-17 production in liver tissue. CONCLUSIONS: Our data indicate that neutrophils represent an important source of IL-17 in the human liver, especially in late fibrosis stages. Inhibition of this specific harmful subset of neutrophils may offer therapeutic opportunities in fibrotic liver. PMID- 26749556 TI - Smart greenhouse fuzzy logic based control system enhanced with wireless data monitoring. AB - Greenhouse climate control is complicated procedure since the number of variables involved on it and which are dependent on each other. This paper presents a contribution to integrate greenhouse inside climate key's parameters, leading to promote a comfortable micro-climate for the plants growth while saving energy and water resources. A smart fuzzy logic based control system was introduced and improved through specific measure to the temperature and humidity correlation. As well, the system control was enhanced with wireless data monitoring platform for data routing and logging, which provides real time data access. The proposed control system was experimentally validated. The efficiency of the system was evaluated showing important energy and water saving. PMID- 26749559 TI - Modified facelift incision for partial parotidectomy versus bayonet-shaped incision: a comparison using visual analog scale. AB - The aim of this study is to show differences between a modified facelift incision (MFI) for partial parotidectomy versus a bayonet-shaped incision (BSI). 24 patients presenting with a parotid tumor were surgically treated with a partial parotidectomy using a MFI. We generated a "matched pair control group" regarding age, tumor size and gender, who received a BSI. A questionnaire was sent to all patients and relevant data reviewed. The cosmetic satisfaction on a VAS with a MFI was 9.74 (+/-0.47) compared to BSI with 7.63 (+/-2.44, p = 0.004). The scoring in the two subgroups "visible scar" and "people noticed my surgery" was significantly better in the MFI group The postoperative skin numbness, skin depression, facial nerve function postoperatively showed no statistical differences. The MFI for parotid tumors has a better outcome than the BSI regarding cosmetic satisfaction and visible scarring. PMID- 26749560 TI - Management of CSF leakage after microsurgery for vestibular schwannoma via the middle cranial fossa approach. AB - Microsurgery is one of the primary current standard options for the treatment of vestibular schwannoma (VS). Especially the middle cranial fossa (MCF) approach is a safe and efficacious technique for the preservation of hearing and facial nerve function in small VS. Postoperative complications are rare, although a leakage of cerebrospinal fluid (CSF) is common. The aim of this study was to analyze postoperative CSF leaks and to describe strategies for postoperative treatment. Between October 2005 and May 2012, 148 patients suffering from VS and selected for microsurgery via the MCF approach were treated in our department. Postoperative CSF leakage occurred in 19 patients. We found a leakage via the Eustachian tube into the nasopharynx in 18 patients and one case of incisional leakage. In 13 cases leaking stopped within 5 days by conservative management including bed rest and intravenous (i.v) antibiotics. Five patients needed lumbar drainage (LD) and only two patients had to undergo revision surgery to seal and pack the mastoid. Analyzed risk factors were age, gender, tumor size and pneumatization of the mastoid. Only the latter showed a significant influence on CSF leakage. We could demonstrate that a stepwise strategy is needed for successful treatment of CSF leaks. PMID- 26749562 TI - Radioisotopes produced by neutron irradiation of food. AB - The use of neutrons for cargo interrogation has the potential to drastically improve threat detection. Previous research has focussed on the production of (24)Na, based on the isotopes produced in pharmaceuticals and medical devices. For both the total activity and the ingestion dose we show that a variety of isotopes contribute and that (24)Na is only dominant under certain conditions. The composition of the foods has a strong influence on the resulting activity and ingestion dose suggesting that the pharmaceuticals and medical devices considered initially are not a viable analogue for foodstuffs. There is an energy dependence to the isotopes produced due to the cross-sections of different reactions varying with neutron energy. We show that this results in different isotopes dominating the ingestion dose at different energies, which has not been considered in the previous literature. PMID- 26749561 TI - Microvirga massiliensis sp. nov., the human commensal with the largest genome. AB - Microvirga massiliensis sp. nov. strain JC119(T) is a bacteria isolated in Marseille from a stool sample collected in Senegal. The 16S rRNA (JF824802) of M. massiliensis JC119(T) revealed 95% sequence identity with Microvirga lotononidis WSM3557(T) (HM362432). This bacterium is aerobic, gram negative, catalase positive, and oxidase negative. The draft genome of M. massiliensis JC119(T) comprises a 9,207,211-bp-long genome that is the largest bacterial genome of an isolate in humans. The genome exhibits a G+C content of 63.28% and contains 8685 protein-coding genes and 77 RNA genes, including 21 rRNA genes. Here, we describe the features of M. massiliensis JC119(T), together with the genome sequence information and its annotation. PMID- 26749563 TI - ? PMID- 26749565 TI - Tissue distribution of teneligliptin in rats and comparisons with data reported for other dipeptidyl peptidase-4 inhibitors. AB - We investigated the tissue distribution of teneligliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, in rats, and compared it with tissue distributions previously reported for other DPP-4 inhibitors. Following the oral administration of [14 C]teneligliptin to Sprague-Dawley rats, it was predominantly distributed to the kidney and liver, followed by the lung, spleen, and pituitary gland. The elimination half-life (t1/2 ) of [14 C]teneligliptin was 68.3 and 69.0 h in the kidney and liver, respectively; these values were about 10 times greater than the plasma t1/2 . Of note, the elimination of [14 C]teneligliptin from tissues with high DPP-4 activity (kidney, liver, and lung) was slower in wild-type rats than in DPP-4-deficient rats, especially in the kidney. By contrast, in the heart and pancreas, which weakly express DPP-4, we observed no difference in [14 C]teneligliptin concentrations between the two animal strains. In the kidney, most radioactivity was attributable to unchanged teneligliptin from 0.5 to 72 h after administration. The marked difference in the distribution of [14 C]teneligliptin between the two strains suggests that the high binding affinity of teneligliptin for DPP-4 is involved in its tissue distribution. The currently marketed DPP-4 inhibitors are highly distributed to the liver, kidney, and lung, but the extent of tissue distribution varies greatly among the drugs. The differences in the tissue distributions of DPP-4 inhibitors might be related to differences in their pleiotropic effects. This article is protected by copyright. All rights reserved. PMID- 26749564 TI - Hyperglycemia-Mediated Oxidative Stress Increases Pulmonary Vascular Permeability. AB - OBJECTIVE: Hyperglycemia in diabetes mellitus is associated with endothelial dysfunction as evidenced by increased oxidative stress and vascular permeability. Whether impaired glucose control in metabolic syndrome impacts pulmonary vascular permeability is unknown. We hypothesized that in metabolic syndrome, hyperglycemia increases lung vascular permeability through superoxide. METHODS: Lung capillary Kf and vascular superoxide were measured in the isolated lungs of LZ and OZ rats. OZ were subjected to 4 weeks of metformin treatment (300 mg/kg/day orally) to improve insulin sensitivity. In a separate experiment, lung vascular permeability and vascular superoxide were measured in LZ exposed to acute hyperglycemia (30 mM). RESULTS: As compared to LZ, OZ had impaired glucose and insulin tolerance and elevated vascular superoxide which was associated with an elevated lung Kf. Chronic metformin treatment in OZ improved glucose control and insulin sensitivity which was associated with decreased vascular oxidative stress and lung Kf. Acute hyperglycemia in isolated lungs from LZ increased lung Kf, which was blocked with the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin (3 mM). Apocynin also decreased baseline Kf in OZ. CONCLUSIONS: These data suggest that hyperglycemia in metabolic syndrome exacerbates lung vascular permeability through increases in vascular superoxide, possibly through NADPH oxidase. PMID- 26749566 TI - Cell-secreted extracellular matrix formation and differentiation of adipose derived stem cells in 3D alginate scaffolds with tunable properties. AB - Three dimensional (3D) alginate scaffolds with tunable mechanical and structural properties are explored for investigating the effect of the scaffold properties on stem cell behavior and extracellular matrix (ECM) formation. Varying concentrations of crosslinker (20 - 60%) are used to tune the stiffness, porosity, and the pore sizes of the scaffolds post-fabrication. Enhanced cell proliferation and adipogenesis occur in scaffolds with 3.52 +/- 0.59 kPa stiffness, 87.54 +/- 18.33% porosity and 68.33 +/- 0.88 MUm pore size. On the other hand, cells in scaffolds with stiffness greater than 11.61 +/- 1.74 kPa, porosity less than 71.98 +/- 6.25%, and pore size less than 64.15 +/- 4.34 MUm preferentially undergo osteogenesis. When cultured in differentiation media, adipose-derived stem cells (ASCs) undergoing terminal adipogenesis in 20% firming buffer (FB) scaffolds and osteogenesis in 40% and 60% FB scaffolds show the highest secretion of collagen as compared to other groups of scaffolds. Overall, this study demonstrates the three-way relationship between 3D scaffolds, ECM composition, and stem cell differentiation. PMID- 26749567 TI - Rewarming affects EEG background in term newborns with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia. AB - OBJECTIVE: To investigate how rewarming impacts the evolution of EEG background in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). METHODS: We recruited a retrospective cohort of 15 consecutive newborns with moderate (9) and severe (6) HIE monitored with a continuous EEG during TH and at least 12h after its end. EEG background was analyzed using conventional visual and quantitative EEG analysis methods including EEG discontinuity, absolute and relative spectral magnitudes. One patient with seizures on rewarming was excluded from analyses. RESULTS: Visual and quantitative analyses demonstrated significant changes in EEG background from pre to post-rewarming, characterized by an increased EEG discontinuity, more pronounced in newborns with severe compared to moderate HIE. Neonates with moderate HIE also had an increase in the relative magnitude of slower delta and a decrease in higher frequency theta and alpha waves with rewarming. CONCLUSIONS: Rewarming affects EEG background in HIE newborns undergoing TH, which may represent a transient adaptive response or reflect an evolving brain injury. SIGNIFICANCE: EEG background impairment induced by rewarming may represent a biomarker of evolving encephalopathy in HIE newborns undergoing TH and underscores the importance of continuously monitoring the brain health in critically ill neonates. PMID- 26749568 TI - The 2015 ESPEN Arvid Wretlind lecture. Evolving concepts on perioperative metabolism and support. AB - The aim of the present lecture is to review the changes in perioperative nutritional policy throughout years. Many advances on both knowledge and clinical practice occurred with time, particularly on preoperative patient assessment and preparation, modulation of surgical stress, identification of the gut as regulator of postoperative inflammatory response, and perioperative fasting policy. Improvement of patient's condition should be obtained by recognizing and treating undernutrition, optimizing body composition, and encouraging physical activity perioperatively. The use of specific nutrients with metabolic effects as well as reducing both preoperative and postoperative fasting within an enhanced recovery pathway can help to modulate postsurgical stress. PMID- 26749570 TI - LCZ696, an angiotensin receptor-neprilysin inhibitor, improves cardiac function with the attenuation of fibrosis in heart failure with reduced ejection fraction in streptozotocin-induced diabetic mice. AB - AIMS: Angiotensin receptor-neprilysin inhibitors (ARNis) acts an ARB and neprilysin inhibitor. Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure (HF). Therefore, we evaluated the effects and mechanisms of ARNi in HF with reduced ejection fraction (HFrEF) in streptozotocin-induced diabetic mice. METHODS AND RESULTS: Male C57BL/6J mice were injected with streptozotocin to produce diabetic mice. After myocardial reperfusion injury, diabetic mice were randomized to treatment for 4 weeks with LCZ696 (60 mg/kg), valsartan (30 mg/kg), or no treatment (n = 26-28 in each group). Cardiac function was assessed by a pressure-volume Millar catheter. The ratios of heart weight to body weight in the valsartan (P = 0.02) and LCZ696 (P = 0.005) groups were significantly less than that in the control group. Treatment with LCZ696 improved LVEF (43 +/- 3.4%) with a significantly reduction of atrial natriuretic peptide mRNA in the left ventricle compared with that in the control group (29 +/- 3.2%) (P = 0.006). The fibrotic area in the LCZ696 group was significantly suppressed compared with those in the control (P = 0.003) and valsartan (P = 0.04) groups. Moreover, the mRNA level of transforming growth factor-beta (TGF-beta) in the left ventricle was suppressed in the LCZ696 group compared with that in the control (P = 0.002) group. CONCLUSION: The ARNi LCZ696 improved cardiac function with the reduction of fibrosis in an HF-rEF model in diabetic mice, by suppressing TGF-beta. This effect may be due to the specific inhibition of neprilysin, beyond the ARB effect of LCZ696. PMID- 26749571 TI - Strategies for Inorganic Incorporation using Neat Block Copolymer Thin Films for Etch Mask Function and Nanotechnological Application. AB - Block copolymers (BCPs) and their directed self-assembly (DSA) has emerged as a realizable complementary tool to aid optical patterning of device elements for future integrated circuit advancements. Methods to enhance BCP etch contrast for DSA application and further potential applications of inorganic nanomaterial features (e.g., semiconductor, dielectric, metal and metal oxide) are examined. Strategies to modify, infiltrate and controllably deposit inorganic materials by utilizing neat self-assembled BCP thin films open a rich design space to fabricate functional features in the nanoscale regime. An understanding and overview on innovative ways for the selective inclusion/infiltration or deposition of inorganic moieties in microphase separated BCP nanopatterns is provided. Early initial inclusion methods in the field and exciting contemporary reports to further augment etch contrast in BCPs for pattern transfer application are described. Specifically, the use of evaporation and sputtering methods, atomic layer deposition, sequential infiltration synthesis, metal-salt inclusion and aqueous metal reduction methodologies forming isolated nanofeatures are highlighted in di-BCP systems. Functionalities and newly reported uses for electronic and non-electronic technologies based on the inherent properties of incorporated inorganic nanostructures using di-BCP templates are highlighted. We outline the potential for extension of incorporation methods to triblock copolymer features for more diverse applications. Challenges and emerging areas of interest for inorganic infiltration of BCPs are also discussed. PMID- 26749569 TI - Longer-term increased cortisol levels in young people with mental health problems. AB - Disturbance of hypothalamus-pituitary-adrenal axis activity is commonly reported in a range of mental disorders in blood, saliva and urine samples. This study aimed to look at longer-term cortisol levels and their association with clinical symptoms. Hair strands of 30 young people (16-25 years) presenting with mental health problems (Mage+/-SD=21+/-2.4, 26 females) and 28 healthy controls (HC, Mage+/-SD=20+/-2.9, 26 females) were analyzed for cortisol concentrations, representing the past 6 months prior to hair sampling. Clinical participants completed an assessment on psychiatric symptoms, functioning and lifestyle factors. All participants completed the Perceived Stress Scale. Hair cortisol concentrations representing the past 3 (but not 3-6) months were significantly increased in clinical participants compared to HC. Perceived stress in the past month was significantly higher in clinical participants compared to HC, but not significantly correlated with hair cortisol. Hair cortisol levels were not significantly associated with any other measures. Hair segment analyses revealed longer-term increased levels of cortisol in the past 3 months in early mental health problems. Further insight into the role of cortisol on the pathogenesis of mental illnesses requires longitudinal studies relating cortisol to psychopathology and progression of illness. PMID- 26749573 TI - TGF-beta1-induced Fascin1 promotes cell invasion and metastasis of human 786-0 renal carcinoma cells. AB - OBJECTIVE: To investigate the effect of transforming growth factor-beta1 (TGF beta1) on the expression of Fascin1 protein and its impact on cell invasion and metastasis in human renal carcinoma. METHODS: Renal tissue slices of 52 cases when undergoing radical nephrectomy were collected to be the observation group, and the normal renal tissues of 23 cases when undergoing nephrectomy due to trauma were collected to be the control group. The expressions of TGF-beta1 and Fascin1 were measured by immunohistochemical staining. Human renal carcinoma 786 0 cell line was selected as the study subject. The cells were divided into six groups including NT (no transfection), si-NC (transfection with pGenesil-1-con) si-Fascin1 (transfection with pGen-1-FSCN1) groups, and three corresponding groups: NT, si-NC and si-Fascin1 groups treated with TGF-beta1. RT-qPCR, Western Blot, Transwell, and flow cytometry method were used in this study. RESULTS: The expressions of TGF-beta1 and Fascin1 in the observation group were significantly higher than those in the control group. The expression of TGF-beta1 was positively correlated with that of Fascin1. After 24 and 48h of treatment with TGF-beta1 (10ng/mL), the invasive and metastatic abilities of the 786-0 cells in the NT and si-NC groups were higher than those before the treatment (P<0.05). Comparing the three groups before TGF-beta1 treatment, the invasive and metastatic ability of 786-0 cells in the si-Fascin1 were significantly lower than those in the NT group and si-NC group (P<0.05). CONCLUSION: TGF-beta1 could induce the expressions of 786-0 Fascin1 mRNA and protein and thus improve the invasive and metastatic ability of human 786-0 renal carcinoma cell. PMID- 26749574 TI - Change in the editorial team of the Portuguese Journal of Cardiology. PMID- 26749572 TI - GSK3beta isoform-selective regulation of depression, memory and hippocampal cell proliferation. AB - Abnormally active glycogen synthase kinase-3 (GSK3) contributes to pathological processes in multiple psychiatric and neurological disorders. Modeled in mice, this includes increasing susceptibility to dysregulation of mood-relevant behaviors, impairing performance in several cognitive tasks and impairing adult hippocampal neural precursor cell (NPC) proliferation. These deficits are all evident in GSK3alpha/beta knockin mice, in which serine-to-alanine mutations block the inhibitory serine phosphorylation regulation of both GSK3 isoforms, leaving GSK3 hyperactive. It was unknown if both GSK3 isoforms perform redundant actions in these processes, or if hyperactivity of one GSK3 isoform has a predominant effect. To test this, we examined GSK3alpha or GSK3beta knockin mice in which only one isoform was mutated to a hyperactive form. Only GSK3beta, not GSK3alpha, knockin mice displayed heightened vulnerability to the learned helplessness model of depression-like behavior. Three cognitive measures impaired in GSK3alpha/beta knockin mice showed differential regulation by GSK3 isoforms. Novel object recognition was impaired in GSK3beta, not in GSK3alpha, knockin mice, whereas temporal order memory was not impaired in GSK3alpha or GSK3beta knockin mice, and co-ordinate spatial processing was impaired in both GSK3alpha and GSK3beta knockin mice. Adult hippocampal NPC proliferation was severely impaired in GSK3beta knockin mice, but not impaired in GSK3alpha knockin mice. Increased activity of GSK3beta, in the absence of overexpression or disease pathology, is sufficient to impair mood regulation, novel object recognition and hippocampal NPC proliferation, whereas hyperactive GSK3alpha individually does not impair these processes. These results show that hyperactivity of the two GSK3 isoforms execute non-redundant effects on these processes. PMID- 26749575 TI - Permanent junctional reciprocating tachycardia in a patient with an atypically located accessory pathway in the left lateral mitral annulus. AB - Permanent junctional reciprocating tachycardia (PJRT) is an uncommon form of atrioventricular reentrant tachycardia due to an accessory pathway characterized by slow and decremental retrograde conduction. The majority of accessory pathways in PJRT are located in the posteroseptal zone. Few cases of atypical location have been described. We report a case of PJRT in a 72-year-old woman in whom the accessory pathway was located in the left lateral region and treated by radiofrequency catheter ablation. PMID- 26749576 TI - Cell-free DNA testing in the maternal blood in high-risk pregnancies after first trimester combined screening. AB - OBJECTIVE: The objective of this study was to investigate a strategy for clinical implementation of cell-free DNA (cfDNA) testing in high-risk pregnancies after first-trimester combined screening. METHODS: In 259 singleton pregnancies undergoing invasive testing after first-trimester combined screening, a maternal blood sample was sent to the laboratory Natera for cfDNA testing using a single nucleotide polymorphism-based methodology. RESULTS: The cfDNA test provided a result in 249 (96.1%) pregnancies and, among these, identified as being at high risk 35 of 36 cases of trisomy 21, 13 of 13 with trisomy 18, five of five with trisomy 13 and three of four with sex chromosome aneuploidies. A policy of performing an invasive test in women with a combined risk of >=1 in 10 or NT >=4 mm and offering cfDNA testing to the remaining cases would detect all cases of trisomy 21, 18 or 13, 80% of sex aneuploidies and 62.5% of other defects and would avoid an invasive procedure in 82.4% of euploid fetuses. CONCLUSION: In high-risk pregnancies after combined screening, a policy of selecting a subgroup for invasive testing and another for cfDNA testing would substantially reduce the number of invasive procedures and retain the ability to diagnose most of the observed aneuploidies. PMID- 26749578 TI - How Do School-Based Prevention Programs Impact Teachers? Findings from a Randomized Trial of an Integrated Classroom Management and Social-Emotional Program. AB - A number of classroom-based interventions have been developed to improve social and behavioral outcomes for students, yet few studies have examined how these programs impact the teachers who are implementing them. Impacts on teachers may affect students and therefore also serve as an important proximal outcome to examine. The current study draws upon data from a school-based randomized controlled trial testing the impact of two prevention programs. In one intervention condition, teachers were trained in the classroom behavior management program, PAX Good Behavior Game (PAX GBG). In a second intervention condition, teachers were trained to use an integrated program, referred to as PATHS to PAX, of the PAX GBG and a social and emotional learning curriculum called Promoting Alternative Thinking Strategies (PATHS(c)). This study aimed to determine whether both interventions positively impacted teachers, with a particular interest in the teachers' own beliefs and perceptions regarding self efficacy, burnout, and social-emotional competence. The sample included 350 K-5 teachers across 27 schools (18 schools randomized to intervention, 9 to control). Multilevel latent growth curve analyses indicated that the PATHS to PAX condition generally demonstrated the most benefits to teachers, relative to both the control and PAX GBG conditions. These findings suggest that school-based preventive interventions can have a positive impact on teachers' beliefs and perceptions, particularly when the program includes a social-emotional component. Several possible mechanisms might account for the added benefit to teachers. Additional research is needed to better understand how these programs impact teachers, as well as students. PMID- 26749579 TI - Synthesis of pH-responsive beta-CD-based star polymer and impact of its self assembly behavior on pectinase activity. AB - A novel type of pH-responsive star polymer based on beta-cyclodextrin (beta-CD) was synthesized and further covalently conjugated with enzyme. The impact of its self-assembly behavior on enzyme activity was investigated. In our design, azide containing the polymer (N3 )7 -beta-CD-(PtBA)14 was synthesized via atom transfer radical polymerization of tert-butyl acrylate using (N3 )7 -beta-CD-(Br)14 as the multifunctional initiator. The final product (N3 )7 -beta-CD-(PAA)14 was obtained via hydrolysis and covalently conjugating pectinase onto pH-responsive polyacrylic acid (PAA) arms. PAA can change its conformation with the self assembly by altered pH, leading its nanostructure into micellar nanoparticles in aqueous solution and further affecting the activity of immobilized pectinase. The results were proved by fluorescence spectroscopy and dynamic light scattering. This system proves that the activity of immobilized enzyme can be tailored predictably, and this pH-responsive polymer holds great potential for controllable delivery of enzymes. PMID- 26749580 TI - Do we need research on reporting on diabetes research? PMID- 26749577 TI - Fatal injuries in rural and urban areas in northern Finland: a 5-year retrospective study. AB - BACKGROUND: Finland has the fourth highest injury mortality rate in the European Union. To better understand the causes of the high injury rate, and prevent these fatal injuries, studies are needed. Therefore, we set out to complete an analysis of the epidemiology of fatal trauma, and any contributory role for alcohol, long suspected to promote fatal injuries. As a study area, we chose the four northernmost counties of Finland; their mix of remote rural areas and urban centres allowed us to correlate mortality rates with 'rurality'. METHODS: The Causes of Death Register was consulted to identify deaths from external causes over a 5-year time period. Data were retrieved from death certificates, autopsy reports and medical records. The municipalities studied were classified as either rural or urban. RESULTS: Of 2915 deaths categorized as occurring from external causes during our study period, 1959 were eligible for inclusion in our study. The annual crude mortality rate was 54 per 100,000 inhabitants; this rate was higher in rural vs. urban municipalities (65 vs. 45 per 100,000 inhabitants/year). Additionally, a greater number of pre-hospital deaths from accidental high-energy trauma occurred in rural areas (78 vs. 69%). 42% of all pre-hospital deaths occurred under the influence of alcohol. CONCLUSION: The crude mortality rate for fatal injuries was high overall as compared to other studies, and elevated in rural areas, where pre-hospital deaths were more common. Almost half of pre-hospital deaths occurred under the influence of alcohol. PMID- 26749582 TI - Aspirin use is associated with lower indices of liver fibrosis among adults in the United States. AB - BACKGROUND: Recent animal studies have shown that platelets directly activate hepatic stellate cells to promote liver fibrosis, whereas anti-platelet agents decrease liver fibrosis. It is unknown whether platelet inhibition by aspirin prevents liver fibrosis in humans. AIM: To examine the association between aspirin use and liver fibrosis among adults with suspected chronic liver disease. METHODS: We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey III. We identified 1856 individuals with suspected chronic liver disease (CLD). The degree of liver fibrosis was determined using four validated fibrosis indices and a composite index. RESULTS: The use of aspirin was associated with a significantly lower composite liver fibrosis index calculated from FIB4, APRI, Forns and NFS [0.24 standard deviation (s.d.) units lower; 95% CI -0.42 to -0.06, P = 0.009]. The association of aspirin with lower fibrosis scores was significantly larger among those with suspected CLD compared to those without (-0.23 vs. -0.03 s.d. units; P interaction = 0.05). The negative association between aspirin use and lower fibrosis index was consistent across all four fibrosis indices (P = 0.002-0.08) in individuals with chronic viral hepatitis, suspected alcoholic liver disease and NASH. In comparison, no negative associations with liver fibrosis were seen with ibuprofen in parallel analyses. CONCLUSIONS: The use of aspirin was associated with significantly lower indices of liver fibrosis among US adults with suspected chronic liver diseases. Aspirin and other anti-platelet drugs warrant further investigation for the prevention and treatment of liver fibrosis. PMID- 26749581 TI - Modulation of Brain Glutathione Reductase and Peroxiredoxin 2 by alpha-Tocopheryl Phosphate. AB - alpha-Tocopheryl phosphate (alphaTP) is a phosphorylated form of alpha tocopherol. Since it is phosphorylated in the hydroxyl group that is essential for the antioxidant property of alpha-tocopherol, we hypothesized that alphaTP would modulate the antioxidant system, rather than being an antioxidant agent per se. alpha-TP demonstrated antioxidant activity in vitro against iron-induced oxidative stress in a mitochondria-enriched fraction preparation treated with 30 or 100 uM alpha-TP. However, this effect was not observed ex vivo with mitochondrial-enriched fraction from mice treated with an intracerebroventricular injection of 0.1 or 1 nmol/site of alphaTP. Two days after treatment (1 nmol/site alphaTP), peroxiredoxin 2 (Prx2) and glutathione reductase (GR) expression and GR activity were decreased in cerebral cortex and hippocampus. Glutathione content, glutathione peroxidase, and thioredoxin reductase activities were not affected by alphaTP. In conclusion, the persistent decrease in GR and Prx2 protein content is the first report of an in vivo effect of alphaTP on protein expression in the mouse brain, potentially associated to a novel and biologically relevant function of this naturally occurring compound. PMID- 26749583 TI - Intergenerational Childhood Maltreatment in Persons with DSM-IV Pathological Gambling and Their First-Degree Relatives. AB - This study investigates the characteristics of individuals with DSM-IV pathological gambling (PG) who experienced childhood maltreatment and rates of maltreatment occurring in their first-degree relatives (FDRs). 94 subjects with DSM-IV PG, 91 controls, and 312 FDRs were assessed for childhood maltreatment as part of a family study of PG. Maltreatment was evaluated using the Revised Childhood Experiences Questionnaire. The Family Assessment Device was used to evaluate the functionality of the PG subject's (or control's) family of origin. Data were analyzed using logistic regression by the method of generalized estimating equations. Rates of maltreatment were significantly higher in subjects with PG than controls (61 vs. 25 %, P < 0.001). Subjects with PG who experienced maltreatment were more likely to be female, had more severe PG symptoms, had co occurring mood and anxiety disorders, and reported greater early family life dysfunction than those with PG who did not experience maltreatment. Rates of maltreatment were higher in FDRs of PG subjects than controls (41 vs. 24 %, P = .002). Rates in FDRs of individuals with PG who experienced maltreatment themselves were still higher that in FDRs of those with PG who did not experience maltreatment (50 vs. 28 %, P = .009). The former were also more likely to have anxiety disorders, substance use disorders, and suicide attempts. The results suggest that childhood maltreatment in persons with PG is common and intergenerational. Rates of maltreatment in FDRs of PG subjects are high, particularly among those who experienced abuse. The implications of the findings are discussed. PMID- 26749585 TI - Short-Term Stability of Whole Blood Polyunsaturated Fatty Acid Content on Filter Paper During Storage at -28 degrees C. AB - Finger or heel-pricked blood sampling for fatty acid analysis is suitable especially in newborn infants where blood sampling is difficult and phlebotomy for research can be unethical. The aim of this study was to evaluate dried blood long chain polyunsaturated fatty acids (LC-PUFA) stability during storage at -28 degrees C. We collected 12 blood cord samples that were analyzed immediately after blood drawing, with and without drying the blood on filter paper. Dried samples were then analyzed 7 days and 1, 3, and 6 months after collection. Butylated hydroxytoluene was added to all samples. Fatty acid composition and (13)C enrichment were measured by gas chromatography and by gas chromatography isotope ratio mass spectrometry, respectively. The fatty acid composition, expressed in mol%, of the major LC-PUFA at day 7 was not statistically different from time 0, however lower values were found by the first month of storage. The (13)C enrichment of 20:4n-6 and 22:6n-3 did not differ during the whole study period. LC-PUFA analysis from dried umbilical cord blood in neonates should be performed within a week, major losses of LC-PUFA occur afterwards. However, fatty acids obtained from dried blood maintain their (13)C enrichment value for up to 6 months and thus these samples are suitable for natural abundance isotopic studies. PMID- 26749584 TI - The Chronicity of HIV Infection Should Drive the Research Strategy of NeuroHIV Treatment Studies: A Critical Review. AB - HIV infection has become a chronic illness when successfully treated with combined antiretroviral therapy (cART). The long-term health prognosis of aging with controlled HIV infection and HIV-associated neurocognitive disorder (HAND) remains unclear. In this review, we propose that, almost 20 years after the introduction of cART, a change in research focus is needed, with a greater emphasis on chronicity effects driving our research strategy. We argue that pre emptive documentation of episodes of mild neurocognitive dysfunction is needed to determine their long-term prognosis. This strategy would also seek to optimally represent the entire HAND spectrum in therapeutic trials to assess positive and/or negative treatment effects on brain functions. In the first part of the paper, to improve the standard implementation of the Frascati HAND diagnostic criteria, we provide a brief review of relevant quantitative neuropsychology concepts to clarify their appropriate application for a non-neuropsychological audience working in HIV research and wanting to conduct randomized clinical trials on brain functions. The second part comprises a review of various antiretroviral drug classes and individual agents with respect to their effects on HAND, while also addressing the question of when cART should be initiated to potentially reduce HAND incidence. In each section, we use recent observational studies and randomized controlled trials to illustrate our perspective while also providing relevant statistical comments. We conclude with a discussion of the neuroimaging methods that could be combined with neuropsychological approaches to enhance the validity of HIV neurology (neuroHIV) treatment effect studies. PMID- 26749586 TI - Treatment of recurrent and platinum-refractory stage IV non-small cell lung cancer with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as a single agent. AB - The role of single-agent nab-paclitaxel in relapsed or platinum-refractory advanced non-small cell lung cancer (NSCLC) has not been well reported in Western populations. We reviewed our own institution's experience using nab-paclitaxel in these settings. We analyzed the records of stage IV NSCLC patients with relapsed or platinum-refractory disease treated with single-agent nab-paclitaxel at Weill Cornell Medical College between October 2008 and December 2013. The primary endpoint of the study was treatment failure-free survival (TFFS), defined as the time from the start of nab-paclitaxel therapy to discontinuation of the drug for any reason. The best overall response was recorded for each patient, and overall response and disease control rates were calculated. Thirty-one stage IV NSCLC patients received a median of 4 cycles (range 1-40) of nab-paclitaxel. Dose reduction or drug discontinuation due to toxicity occurred in 10 patients, mainly because of grade 2/3 fatigue or peripheral neuropathy. The overall response rate was 16.1 %, and the disease control rate was 64.5 %. Median TFFS was 3.5 months (95 % CI 1.3-5.3 months). No statistically significant difference in TFFS based on line of therapy or prior taxane exposure was identified. There was a statistically significant decrease in TFFS for patients with non-adenocarcinoma histology, although there were only five patients in this group. There was a trend toward reduction in the risk of treatment failure with increasing age. One patient remained on nab-paclitaxel therapy for over 3 years. Single-agent nab paclitaxel was well tolerated and demonstrated efficacy in advanced NSCLC patients with relapsed or platinum-refractory disease. Further prospective clinical trials with nab-paclitaxel in these settings are warranted. PMID- 26749587 TI - Gene expression classifier for the diagnosis of indeterminate thyroid nodules: a meta-analysis. AB - Prior studies demonstrate that a novel genomic test, the gene expression classifier (GEC), could identify a benign gene expression signature in those nodules with indeterminate cytology with a negative predictive value of greater than 95 %. Examine the performance of the AFIRMA gene expression classifier in predicting benign and malignant nodules in patients with cytologically indeterminate nodules. MEDLINE and EMBASE search for studies meeting eligibility criteria between January 1, 2005, and August 30, 2015. A total of 58 studies identified. After excluding duplicates, case reports, reviews, commentary, insufficient data, a total of seven studies selected for analysis. We combined individual patient data from seven studies that examined the GEC test for indeterminate thyroid nodules. The reference standard for determination of benign or malignant nodules was the histopathology of the thyroidectomy specimen. A QUADAS-2 report for all studies included in the final analysis was tabulated for risk of bias and applicability. The pooled sensitivity of the GEC was 95.7 % (95 % CI 92.2-97.9, I (2) value 45.4 %, p = 0.09), and the pooled specificity was 30.5 % (95 % CI 26.0-35.3, I (2) value 92.1 %, p < 0.01). Overall, the diagnostic odds ratio was 7.9 (95 % CI 4.1-15.1). Patients with benign GEC were not followed long enough to ascertain the actual false-negative rates of the index test. Our meta-analysis revealed a high pooled sensitivity and a low specificity for the AFIRMA-GEC test for indeterminate thyroid nodules. This makes it an excellent tool to rule out malignancy. PMID- 26749588 TI - Hypoxia promotes the invasion and metastasis of laryngeal cancer cells via EMT. AB - The purpose of this study is to explore the role of hypoxia on the invasion and metastasis of laryngeal carcinoma. The invasion and migration ability of laryngeal cancer SCC10A cell was detected by transwell assay. Western blot was applied to analyze the expression of EMT-related proteins. Fifty-seven samples from postoperative patients with laryngeal cancer were collected to study. Immunohistochemistry was used to examine the expression of GLUT-1 and EMT-related proteins (Vim, E-cad, N-cad) in normal laryngeal squamous epithelial tissue, laryngeal cancer adjacent tissues and laryngeal squamous cell carcinoma tissues. Hypoxia promoted laryngeal cancer cell invasion and migration. Hypoxia also enhanced the expression of GLUT-1, vimentin and N-cad, which exist statistically significant correlation with the clinical staging and lymph node metastases (P < 0.05). The expression of GLUT-1 is positively correlated with Vim and N-cad expression in laryngeal squamous cell carcinoma tissues, but negatively correlated with E-cad expression. The patient survival rate with the positive expression of GLUT-1, Vim and N-cad becomes much shorter compared with those with negative expression of GLUT-1, Vim and N-cad (P < 0.05). Hypoxia promoted laryngeal cancer cell invasion and migration via EMT. PMID- 26749589 TI - The mean and variability of a floral trait have opposing effects on fitness traits. AB - BACKGROUND AND AIMS: Floral traits are essential for ensuring successful pollination and reproduction in flowering plants. In particular, style and anther positions are key for pollination accuracy and efficiency. Variation in these traits among individuals has been well studied, but less is known about variation within flowers and plants and its effect on pollination and reproductive success. METHODS: Style deflexion is responsible for herkogamy and important for pollen deposition in Passiflora incarnata. The degree of deflexion may vary among stigmas within flowers as well as among flowers. We measured the variability of style deflexion at both the flower and the plant level. The fitness consequences of the mean and variation of style deflexion were then evaluated under natural pollination by determining their relationship to pollen deposition, seed production and average seed weight using structural equation modelling. In addition, the relationship between style deflexion and self-pollen deposition was estimated in a greenhouse experiment. KEY RESULTS: We found greater variation in style deflexion within flowers and plants than among plants. Variation of style deflexion at the flower and plant level was positively correlated, suggesting that variability in style deflexion may be a distinct trait in P. incarnata. Lower deflexion and reduced variation in that deflexion increased pollen deposition, which in turn increased seed number. However, lower styles also increased self-pollen deposition. In contrast, higher deflexion and greater variability of that deflexion increased variation in pollen deposition, which resulted in heavier seeds. CONCLUSIONS: Variability of style deflexion and therefore stigma placement, independent from the mean, appears to be a property of individual P. incarnata plants. The mean and variability of style deflexion in P. incarnata affected seed number and seed weight in contrasting ways, through the quantity and potentially quality of pollen deposition. This antagonistic selection via different fitness components may maintain diverse style phenotypes. PMID- 26749593 TI - 'Rent seeking' is coming from all angles. PMID- 26749590 TI - Crop acquisition of phosphorus, iron and zinc from soil in cereal/legume intercropping systems: a critical review. AB - BACKGROUND: Phosphorus (P), iron (Fe) and zinc (Zn) are essential elements for plant growth and development, but their availability in soil is often limited. Intercropping contributes to increased P, Fe and Zn uptake and thereby increases yield and improves grain nutritional quality and ultimately human health. A better understanding of how intercropping leads to increased plant P, Fe and Zn availability will help to improve P-fertilizer-use efficiency and agronomic Fe and Zn biofortification. SCOPE: This review synthesizes the literature on how intercropping of legumes with cereals increases acquisition of P, Fe and Zn from soil and recapitulates what is known about root-to-shoot nutrient translocation, plant-internal nutrient remobilization and allocation to grains. CONCLUSIONS: Direct interspecific facilitation in intercropping involves below-ground processes in which cereals increase Fe and Zn bioavailability while companion legumes benefit. This has been demonstrated and verified using isotopic nutrient tracing and molecular analysis. The same methodological approaches and field studies should be used to explore direct interspecific P facilitation. Both niche complementarity and interspecific facilitation contribute to increased P acquisition in intercropping. Niche complementarity may also contribute to increased Fe and Zn acquisition, an aspect poorly understood. Interspecific mobilization and uptake facilitation of sparingly soluble P, Fe and Zn from soil, however, are not the only determinants of the concentrations of P, Fe and Zn in grains. Grain yield and nutrient translocation from roots to shoots further influence the concentrations of these nutrients in grains. PMID- 26749594 TI - REGULATE-OR NEVER EVENTS WILL KEEP HAPPENING. PMID- 26749595 TI - EVERY TRUST NEEDS A CHIEF QUALITY OFFICER. PMID- 26749592 TI - Prevalence and Antimicrobial Resistance of Campylobacterjejuni and Campylobacter coli from Adult Hospitalized Patients with Diarrhea in Thailand. AB - BACKGROUND: Infection with Campylobacter jejuni and C. coli are recognized as the major cause of bacterial gastroenteritis in humans. METHODS: A total of 310 fecal samples collected from Thai adult patients with diarrhea in 2008 were screened for the presence of Campylobacter by PCR. Resistance to fluoroquinolone and macrolides of the detected Campylobacter strains were analyzed by studying the mutations in the gyrA and 23S rRNA genes, respectively. RESULTS: Campylobacter species were detected in 4/310 (1.3%) of diarrheal patients, and C. jejuni was found in 3 of the 4 cases (75%). Fluoroquinolone resistance was noted in 2 cases (50%); however, no resistance to macrolides was observed. CONCLUSIONS: Campylobacter was detected in a low prevalence in adult Thai patients hospitalized with diarrhea, and the resistance to fluoroquinolones is still a matter of concern in case antibiotic therapy is required. PMID- 26749596 TI - SERVICE REDESIGN. WIN THE A&E BATTLE. PMID- 26749597 TI - LONG-TERM CONDITIONS. THE BEST SHOT. PMID- 26749598 TI - External versus endoscopic approach in the management of 131 sinonasal inverted papillomas. AB - BACKGROUND: Incidence of inverted Papilloma (IP) is around 0.5% to 4% of all nasal tumours. It is characterised by its propensy for local invasiveness, recurrence and malignant transformation. The treatment of reference is surgery. The aim of our study was to compare our oncologic outcome and morbidity between the open and the endoscopic approach to remove inverted papillomas. MATERIAL AND METHOD: This retrospective study includes all primary and benign cases operated between 1985 and 2012. We assessed epidemiologic data, medical history, tumour location, morbidity of treatment, pathological outcomes, patient's follow-up and rate of recurrence. The mean time of surgery, of follow-up and recurrence delay were compared. RESULTS: 131 patients were included: 77 operated by lateral rhinotomy or mid-facial degloving and 54 by endoscopic approach (+/- associated with a limited Caldwell-Luc or a frontal incision). The mean time of surgery for the endoscopic approach was 76 +/- 46 min (10-240 min) vs 163 +/- 46 min (60-300 min) for the open approach (p< 10(-5)). The uncinate process was included in most of the IP (97/131; 74%), including its horizontal and/or vertical parts. The mean follow-up in endoscopic group was 43 +/- 32 months (12-177 months) vs 73 +/- 48 months (12-221 months) for the open approach group (p< 10(-4)). The recurrence rates are not significantly different for both groups: 9% (7/77) after open approach vs 7.4% (4/54) after endoscopic approach (p> 0.05). Also, the mean delay of recurrence was not different between both group (p> 0.05) and the propensy of recurrence didn't depend on the degree of dysplasia. There were fewer complications in the endoscopic group (13%) than in the open approach group (57%). CONCLUSION: According to several authors we found no statistical difference on the oncological outcome between surgery via open versus endoscopic approach to remove IP. Endoscopic surgery offers less complications and morbidity than external approach. PMID- 26749599 TI - [Covering of parotid and cervical lymph nodes metastasis of cutaneous squamous cell carcinoma of the head, about 18 cases]. AB - AIM: To describe 18 cases of patients treated for advanced cutaneous squamous cell carcinoma (CSCC) of the head metastasing to cervical lymph nodes and parotid gland. To estimate their survival and the risk factors of metastases. PATIENTS AND METHODS: 18 cases of patients affected by CSCC of the head, metastatic to parotid and cervical lymph nodes were afterward analyzed. Two populations were differentiated: the patients already treated for their CSCC, with secondary appearance of metastases in the Population A, the patients by whom the metastase is concomitantly discovered to the CSCC in the Population B. RESULTS: The treatment consisted of a parotidectomy and neck dissection, possibly associated with excision of the primary tumour. Adjuvant radiotherapy was systematic. Metastatic progression was on lungs most of the time (57%), in patients of the population B (80%), or of whom primitive CSCC was of bad forecast (group 2) (78%). The mortality was bound to the complications induced by distant metastases (63%), at 5 years it was superior in the population B (100%) than in the population A (77%). CONCLUSION: CSCC of the head, metastatic to parotid and cervical lymph nodes have a severe prognosis for survival in spite of an optimal curative treatment applied to fragile old patients. PMID- 26749600 TI - [Functional comparison of the voice quality after either open conservative surgery or only radiotherapy for early glottic carcinoma]. AB - OBJECTIVES: The aim of this article is to compare the functional results after open conservative surgery versus radiotherapy alone in the management of early glottic carcinoma using the Voice Handicap Index questionnaire (VHI). METHODS: Retrospective study was done using VHI for evaluation of 37 patients treated either by open conservative surgery or radiotherapy in T1-T2N0M0 glottic laryngeal carcinoma. RESULTS: 19 patients were treated with radiotherapy. The overall survival rate and disease free after 5 years were 91.3%. The functional result was mild in 89%. 18 patients were treated surgically. The overall survival rate and disease free after 5 years were 93.1% and 95.4% respectively. The functional result was mild in 61% after surgery. CONCLUSION: Radiotherapy alone seems to provide better functional results than partial surgery in T1-T2 glottic tumors. PMID- 26749601 TI - Vestibular neuritis: Evaluation and effect of vestibular rehabilitation. AB - Vestibular neuritis (VN) is a caloric vestibular areflexia that occurs suddenly, and whose compensation can take several weeks, sometimes several months. Usually these patients are rehabilitated, but the most affected patients (cervical vestibular evoked myogenic potential (cVEMP) absent) have a worse prognosis of vestibulo-ocular compensation. Thanks to symptomatic, videographic and posturographic evaluation tools, we objectify and quantify which factors influence the recovery or more accurately the compensation of this type of disorder. EQUIPMENT AND METHOD: We have colligated 34 observations of VN whose beginning could be precisely dated. These 34 unilateral caloric areflexic patients had a symptomatic evaluation (SE) with scales (vertigo symptom scale, dizziness handicap inventory, short form 36), an evaluation of the vestibulo ocular reflex (VOR) (spontaneous nystagmus, head shaking test, mastoid bone skull vibration test, and finally an evaluation of the vestibulo-spinal function (VSF) on a dynamic posturography platform (DPY). On the other hand were evaluated eight elements supposed to influence (influence factors FI) the care and/or the outcome of the treatment (age, cVEMP absent, duration of deficiency, sports and walk practice, rehabilitation of VOR, rehabilitation of VSF, waiting period before application of rehabilitation, vertigo medications treatment). RESULTS: By comparing averages and with a Fischer's exact test, we can show here that the medical treatment, the waiting period before the application of the rehabilitation, the number of rehabilitation sessions or the type of rehabilitation influence only partially the state of health of neuritis. The age of the patients and absent cVEMP don't have a major influence either. However, patients with the most important physical activity feel better from a symptomatic point of view, over a long period after the episode. The effect of rehabilitation might be temporary if daily activity is minimal. CONCLUSION: The evaluation of the vestibulo-ocular reflex has long remained the main element for the evaluation of the state of health of vestibular neuritis. But if you use in addition posturography and symptomatic scales to assess the state of health, the neuritis considered to be compensated with the VOR will not always be symptomatically compensated. Estimating the functional recovery of neuritis can't be limited to estimating or quantifying the VOR. Rehabilitating neuritis can't be limited to rehabilitating the VOR. Finally we show here that physical activity is probably more necessary than any type of rehabilitation. PMID- 26749602 TI - Vestibular disorders in Bell's palsy: A prospective study. AB - OBJECTIVES: To ascertain the prevalence of vestibular abnormalities in individuals with Bell's palsy (BP) compared with a normal population and to correlate these findings with clinical evolution. METHOD: A prospective study involving 120 individuals submitted to computerized vector-electronystagmography (VENG) was conducted. The sample included 60 BP patients and 60 control subjects, matched for gender and age. RESULTS: Twenty-five percent of the Bell's palsy patients had results consistent with deficient peripheral vestibular syndrome. All exams were normal in the control group (p< 0.001). No relationship between vestibular abnormalities and degree of palsy improvement was observed. CONCLUSION: Patients with Bell's palsy exhibited 25% vestibular abnormalities on vector- electronystagmography exams. Vestibular abnormalities were more frequent in patients with BP compared to normal control individuals. No relationship between vestibular abnormalities and degree of palsy improvement was observed. PMID- 26749603 TI - Audiological comparison between two different clips prostheses in stapes surgery. AB - OBJECTIVES: To compare audiometric results and complications of stapes surgery with two different types of piston prosthesis, the Portmann Clip Piston (Medtronic) (PCP) and the Soft Clip Piston (Kurz) (SCP). MATERIAL AND METHODS: Study conducted on 64 patients who underwent primary stapedotomy from 2008 to 2011. We matched for each case of stapedotomy with the PCP (Medtronic Xomed Inc. Portmann Clip Piston Stainless Steel/Fluoroplastic) a case with the SCP (Heinz Kurz GmbH Medizintechnik Soft Piston Clip Titanium). Each group consisted of 32 patients, and patients in both groups were matched with respect to gender, age, bilateral or unilateral otosclerosis, otological symptoms (tinnitus, vertigo or dizziness), family history, operated side and the Portmann grading for otosclerosis. The length of the prosthesis used was reported. Post-operative complications such as tinnitus, vertigo, hearing loss and altered taste were documented. Each patient was subjected to a preoperative and postoperative audiogram (follow-up at the second month after the surgery). We used the Student test for statistical analysis. Statistical significance was set at < 0.01. RESULTS: None of the patients experienced a post-operative hearing loss and none required a later revision surgery. No statistically significant difference was found between the two populations regarding demographic data (age, sex, side, bilaterality, family history, stage and lenght of piston) and hearing level (> 0.01) in the air, bone conduction and air-bone gap (ABG). Postoperative complications did not result to be significantly different between the two groups. Also, both groups showed a significant improvement (< 0.01) in the post operative air, bone conduction and air-bone gap. There was no statistically significant difference (> 0.01) between the post-operative hearing results (bone conduction, air conduction, air-bone gap) using the two pistons. The mean ABG improvement was respectively 16.63 dB in the SCP group and 20.59 dB in the PCP group. CONCLUSION: The titanium Soft clip piston (SCP) is a good alternative to the Portmann clip piston (PCP). Nevertheless there are some differences in the surgical fixing of these two pistons in the correct position. PMID- 26749604 TI - [The silent sinus syndrome: A reconstruction of the orbital floor with Medpor implant]. AB - INTRODUCTION: The silent sinus syndrome (SSS) is a rare clinical entity in both ENT and ophthalmology. It is characterized by enophthalmos and ptosis associated with a reduction in pressure in the maxillary sinus caused by chronic hypoventilation. The objective of this study was to demonstrate the importance of maxillary hypoplasia whether congenital or acquired in this disease, and the use of Medpor implant for reconstruction of the orbital floor. MATERIAL AND METHODS: We report 3 cases of silent sinus syndrome proved clinically and radiologically. The first is a 45 year old male patient complaining of enophthalmos which occurred gradually, without any medical history; the second case is that of a woman of 39 years with a gradual onset enophthalmos, with a history of sinusitis; the third case, a man of 25 years who had a history of nasal trauma and consults for enophthalmos and diplopia. RESULTS: Endoscopic surgery is performed quickly allowing a disappearance of enophthalmos and diplopia. All patients underwent a reconstruction of the orbital floor with a Medpor implant fixed by miniplates without complications. PMID- 26749605 TI - Recurrent mandibular ameloblastoma with anterior skull base invasion: Case report. AB - Recurrent ameloblastoma with skull base invasion is a rare clinical entity with poor prognosis. We report a case of a mandibular ameloblastoma recurrence involving the anterior skull base. The diagnostic and therapeutic processes are presented with emphasis on the radiologic features of ameloblastoma. Another aim of this case report is to underline the importance of close and long-term follow up after resection. Ameloblastoma recurrences are frequent and mainly occur after incomplete surgical resection. These recurrences may be diagnosed late because of lack of symptoms in the mandibular area. PMID- 26749606 TI - [Surgical treatement by intracapsular enucleation of cervical peripheral neural sheath tumors]. AB - Schwannomas and neurofibromas are benign tumors of the peripheral neural sheath tumors (PNST), representing 5% of soft tissue tumors. Cervical PNST are mainly located on the vagus nerve or in the sympathetic nervous system. The treatment is based on a tumor resection with preservation of nerve function. Classical surgery consists in total tumor removal after dissection of the nerve and is frequently complicated by nerve paralysis. The authors describe a simpler surgical technique consisting in a resection of the intracapsular enucleation of PNST that can limit the risk of nerve injury without increasing recidivism. The description of this surgical technique is illustrated by its use in a type I neurofibromatosis patient with a large vagal nerve neurofibroma. PMID- 26749607 TI - Day in the life... Michelle Thomas, senior lecturer, University of South Wales. PMID- 26749608 TI - Research reflections. PMID- 26749609 TI - CPD CONFIDENCE. PMID- 26749610 TI - Domestic abuse ongoing after separation. PMID- 26749611 TI - Academic performance of poor children in London is improving. PMID- 26749612 TI - World AIDs day. PMID- 26749614 TI - Preventing paediatric continence services going down the pan. PMID- 26749615 TI - Child neglect identification: The health visitor's role. AB - Child neglect is a significant public health issue, with impact often persisting into adulthood. However, neglect is not easily identifiable and may go undetected for many years. This library-based literature review critically analyses the research to uncover effective practices to aid neglect identification. The literature identifies that professionals may observe particular risk factors in a child's life that make neglect more probable. Additionally, children who suffer neglect, and parents who neglect their children, may display signs that practitioners can be alert to. However, a number of barriers exist that make identification difficult. The literature highlights that health visitors have a significant role to play in identifying neglect. Final conclusions relate to the need for professional supervision, use of assessment tools and frameworks, multi agency training, and timely interventions to safeguard children. PMID- 26749613 TI - New meningococcal vaccines in the UK. PMID- 26749616 TI - Initial analysis of a community-based bereavement programme. AB - It is well evidenced that childhood bereavement has a negative impact upon a range of psychological and educational outcomes. This article describes a service evaluation of the national child bereavement charity, Winston's Wish SWITCH programme. SWITCH is a community outreach bereavement programme targeted at children that are at risk of antisocial and self-destructive behaviour. A preliminary evaluation of baseline to follow up of parent (n=31) and young person (n=96) Strength and Difficulties (SDQ) data suggests that the programme contributes to a positive impact upon emotional distress, relationships, and concentration. Further, more robust evaluation needs to be conducted to understand the long-term implications of the programme on vulnerable young people. PMID- 26749617 TI - Capacity building deconstructed. AB - Community engagement and seeking out health needs are core principles of the Specialist Community Public Health Nurse's (SCPHN) role. In view of the changes to health service provision, the ability to work with the community in a positive manner and facilitate a Community to help themselves, and enable good health outcomes, is the essence of Building Community Capacity (BCC). However, the challenges faced by SCPHNs in the often long and complex processes involved with BCC projects highlights the intensive nature of this work and how disparity in provision of BCC remains an issue. This article strives to define and discuss BCC, the positives to staff, communities and individuals involved and debates the role of BCC in the future of Health Visiting. PMID- 26749618 TI - Last word with... PROFESSOR JANE APPLETON. PMID- 26749619 TI - Reducing wait times is an election mirage. PMID- 26749620 TI - PATIENT CHOICE GOES HAND IN HAND WITH COMPETITION LAW. PMID- 26749621 TI - Clinical innovation. Shot in the arm for diabetes care management. PMID- 26749622 TI - Clinical innovation: case studies. Glucose gamers. PMID- 26749623 TI - PROCUREMENT. GET HIP, PAY LESS. PMID- 26749625 TI - PRIMARY CARE. Rise to the restructure for better care delivery. PMID- 26749624 TI - THE PATIENT EXPERIENCE DEBATE GOES GLOBAL. PMID- 26749626 TI - INNOVATION. Networks nurture great NHS ideas. PMID- 26749627 TI - Private sector with public spirit. PMID- 26749629 TI - [Tardive dyskinesia and second generation antipsychotics: a review of four cases]. AB - We report four cases of tardive dyskinesia (TD) with second generation antipsychotics (SGA). All of those cases where women, three of them had affective psychosis. The presentation of TD where choreo athetosis in one case, respiratory dyskinesia in another and a tardive dystonia in a third. The fourth one had a very precocious form after just a few weeks of treatment. All of them, except one, had a major form of the disorder, with a major impact on their quality of live. We discuss the necessity to remain aware of this dangerous side effect and to keep it in mind while prescribing SGA for bipolar disorders. PMID- 26749628 TI - [Predatory journals and editors: a menace for quality scientific information]. PMID- 26749630 TI - [Profile and trends of pediatric hospital morbidity in the region of Monastir (Tunisia) for a decade]. AB - INTRODUCTION: Hospital morbidity studies allow us to draw the hospital pathological profile of a region and to follow its evolution. This study aims to describe the profile and the main trends of pediatric diseases within public structures in the region of Monastir between 2000 and 2010. MATERIEL AND METHODS: A descriptive study which concerns all pediatric hospitalizations of public structures in the region of Monastir between 2000 and 2010. Informations were collected from the regional register of hospital morbidity implanted at the Department of Preventive Medicine and Epidemiology of the University Hospital of Monastir. RESULTS: A total of 52.443 hospitalizations were collected between 2000 and 2010 with a means annual hospitalization rate of 3,9 %. The mean age was 7,2 +/- 5,4 years and 15,3 % had not exceeded the first year of life. Major diagnostic categories (MDC) were dominated by diseases of the digestive and respiratory systems with 14,4 and 14 % respectively. Main chronological trends have shown that the rate of childhood asthma rise significantly from 0,2 %. in 2000 to 2,5 %. in 2010 and Hydatid Cyst whose rate increased also from 0,2 %. in 2000 to 1,8 %. in 2010 (P < 0,05). CONCLUSION: This morbidity profile incites managers to focus their efforts to improve the management of most important diseases. PMID- 26749631 TI - [Loneliness and adolescence: clinical implications and outlook. Literature review]. AB - Loneliness is particularly prevalent during adolescence, a time also associated with the appearance of psychiatric illnesses. Loneliness has been linked to a number of mental health indicators such as depressive symptoms, self-esteem, anxiety, and perceived stress. During adolescence, the individual undergoes major social and personal transformations through redefining their social network thus making them more susceptible to developing mental health problems. Some studies suggest that the risk of mental health problems arises when an adolescent is repeatedly faced with loneliness. Mental health workers should therefore focus on any given adolescent's inability to establish satisfactory interpersonal relationships as a predictive element of loneliness. Thus, it would seem that the development of loneliness prevention and intervention programs aimed at adolescents who are unable to establish satisfactory interpersonal relationships could be of benefit to many. PMID- 26749632 TI - [Are antidepressants really effective?]. AB - Antidepressants are widely used for a long time and it is estimated that about 10 % of the belgian population is taking some of them each year. However, there are important controversies about their real efficacy. We review successively arguments for and against their efficacy. On the one hand, meta-analysis have shown no big efficacy differences between antidepressants and placebo. On the other hand, those meta-analysis have been criticized for their methodology. Animal models show a real effect of antidepressants on the brain and clinical observations, such as an impact on suicide prevention, the possibility of induced manic switch, and an efficacy on anxiety disorders are in favour of a real efficacy. Given our current state of knowledge about them it seems appropriate to continue to use anti-depressants in the treatment of depressive patients. PMID- 26749633 TI - [Supraorbital approach to treat a fronto-orbital fracture with pneumocephaly, a minimal invasive technique]. AB - We describe a supraorbital approach through an upper eyebrow skin incision to treat a fronto-orbital fracture with pneumocephaly in a 84-year-old cardiac patient. The clinical and cosmetic results are excellent. This case is illustrated by pre- and postoperative CT-scan and MRI as well as pictures showing the minimal invasive technique. PMID- 26749634 TI - [Pre-hospital treatment of an anterior shoulder dislocation: medico-legal concerns]. AB - A man of 23 years, diabetic of type 1, shows a functional handicap of the right upper limb following a convulsion in the context of hypoglycemia. On arrival of the "S.A.M.U.", the physician diagnoses an anterior shoulder dislocation that he decides to reduce on the spot after analgesic treatment. The X-ray examination at the emergency shows a reduction of the dislocation as well as a fracture of the greater tuberosity. Has the fracture followed the convulsion or the reduction movement ? The absence of an X-ray examination before the reduction movement presents a forensic medical problem. Certain criteria mentioned in several studies would allow the reduction without X-ray before. However, these studies remain controversial. PMID- 26749635 TI - [Hemolytic anemia and dysenteric syndrome: a case of ulcerative colitis]. AB - A 53-years-old man has a dysentery since two weeks. The blood test shows Coombs positive hemolytic anemia and inflammation. Autoimmune hemolytic anemia (AIHA) is treated with corticosteroid. A colonoscopy reveals an ulcerative colitis. The evolution of the patient is complicated by a spontaneous digestive perforation treated by total proctocolectomy. After this intervention, there is a resolution of the AIHA and the patient is gradually weaned from corticosteroids. AIHA is a rare extra-intestinal manifestation of inflammatory bowel disease essentially ulcerative colitis. Identification of this cause of secondary AIHA is important for the therapeutic strategy. However treatment is nonspecific and based on low levels of evidence. PMID- 26749638 TI - TRANSFORMATION. SUPPORTING CHANCE. PMID- 26749636 TI - [Orf nodules and immunosuppression: a case report and review of therapeutics]. AB - In immunocompromised patient, parapoxvirus infection can be extensively necrotic and recurrent evolution. We describe a case of Orf nodule in a liver transplanted woman. We will consider the therapeutic options in case of infections by parapox in immunosuppressive patients, as described in the medical literature. In our specific case, local application of cidofovir (concentration of 1 %) together with local antiseptic solution, povidone iodine, led to complete remission of the lesion without any sign of toxicity. Finally, we will consider the therapeutic use of local cidofovir. PMID- 26749639 TI - TRANSFORMATION: CASE STUDIES. POINT AND CLICK. PMID- 26749637 TI - [Hermann Joris (1875-1910), a forgotten histologist]. AB - Hermann Joris (1875-1910) was professor of histology at the Medical college of the Universite libre de Bruxelles between 1908 and 1910. At the time of its nomination, its work relating to the pituitary gland and the neurons was the object of critical sharp by Albert Brachet. The author analyzes in what these criticisms rested certainly on sometimes debatable interpretations scientific, but betray also a quarrel between two generations of teachers of the University. PMID- 26749640 TI - HEALTH INEQUALITIES. A TALE OF NEGLECT. PMID- 26749641 TI - EXTERNAL PROVIDERS. LEND A HAND OPERATION. PMID- 26749642 TI - OVERVIEW. 'EVERYBODY'S TALKING ABOUT IT'. PMID- 26749643 TI - PARTNERSHIPS. IT'S A HOME RUN. PMID- 26749644 TI - EMPOWERMENT. FOCAL POINT. PMID- 26749645 TI - EMPOWERMENT: CASE STUDIES. AMBITIOUS MOVES. PMID- 26749646 TI - WORKFORCE. SEAMLESS SYNERGY. PMID- 26749647 TI - TECHNOLOGY. INSTANT ACCESS. PMID- 26749649 TI - DATA PROTECTION. IT'S A BREACH OF TRUST. PMID- 26749648 TI - TECHNOLOGY: CASE STUDIES. 'THIS TRULY LIBERATES'. PMID- 26749650 TI - EFFICIENCY. OUT OF THE BOX. PMID- 26749651 TI - SERVICE IMPROVEMENT. BRINGING PATIENTS INTO FOCUS. PMID- 26749652 TI - SERVICE REDESIGN. VISIBLE RESULTS. PMID- 26749653 TI - EDUCATION. BROADER BASE. PMID- 26749654 TI - ESTATES MANAGEMENT. FIRM FOUNDATION. PMID- 26749655 TI - WORKFORCE. WE ARE ALL LEADERS. PMID- 26749656 TI - OVERVIEW. DISPENSING WISDOM. PMID- 26749657 TI - PUBLIC HEALTH. AT THE HURT OF THE COMMUNITY. PMID- 26749659 TI - DEMAND MANAGEMENT. BREATHING ROOM. PMID- 26749658 TI - COMMUNITY SERVICES. HOME FOR GOOD. PMID- 26749660 TI - OVERVIEW. THE ERA OF PREVENTION. PMID- 26749661 TI - SERVICE IMPROVEMENT. COMPLETE MAKEOVER. PMID- 26749662 TI - EDUCATION. THE RIGHT TIME. PMID- 26749663 TI - PATIENT ENGAGEMENT. GREAT ON PAPER. PMID- 26749664 TI - SERVICE REDESIGN. OUTSIDER CHANCE. PMID- 26749665 TI - PATIENT INVOLVEMENT. HELPING EACH OTHER. PMID- 26749666 TI - SELF-CARE. FULL PARTNERS. PMID- 26749667 TI - OVERVIEW. TO ERR IS HUMAN.... PMID- 26749668 TI - TECHNOLOGY. RAISE THE BAR. PMID- 26749670 TI - STAFF ENGAGEMENT: CASE STUDIES. THE WHOLE JOURNEY. PMID- 26749669 TI - STAFF ENGAGEMENT. DO IT YOUR WAY. PMID- 26749671 TI - PARTNERSHIP. BRING OUT THE BEST. PMID- 26749672 TI - WORKFORCE. OUTSIDE CHANCE. PMID- 26749673 TI - WORKFORCE: CASE STUDIES. TRAINING GROUND. PMID- 26749674 TI - PARTNERSHIPS. LOWER THE PRESSURE. PMID- 26749675 TI - Pattern of variations in superficial palmar arch in 134 Negro cadaveric hands. AB - OBJECTIVE: To investigate the incidence of anatomical variations of superficial palmar arch in Negro population. MATERIALS AND METHOD: A total of 134 upper limbs comprising 74 right and 60 left specimens embalmed with formaldehyde were used for the investigation. The hand was dissected with palmar aponeurosis identified and removed to expose the ulnar and radial arteries. RESULTS: A complete superficial arch was observed in 73.9% specimens. In 70.1% cases the superficial branch of the ulnar artery communicated with its radial arterial counterpart. In 3.0% cases the arch was formed entirely by the ulnar artery while in a single case (0.8%), a rare pattern was observed in which the superficial palmar branch of the ulnar artery gave rise to the princeps pollicis artery as its terminal branch with the exclusion of radialis indicis that had its origin from deep palmar branch of radial artery. The incomplete arch constituted 26.1% of the entire palmar arch formation. CONCLUSION: In our Negro population study, deviation from normal anatomical pattern was common. Therefore, a review of vascular pattern prior to invasive or intervention surgery is strongly recommended to be able to detect anomalies likely to necessitate modification of surgical procedures. PMID- 26749676 TI - Position of the mandibular foramen in adult male Tanzania mandibles. AB - Failure of the inferior alveolar nerve block anesthesia is common in various dental operations. Anatomical variations of the location of the inferior alveolar nerve as it enters the mandibular foramen have been implicated as a main cause of these anesthesia failures. The aim of this work was to determine the location of the mandibular foramen in relation to the occlusal plane at the level of mandibular first molar and second premolar--often used as landmarks during the blocking procedure--and to different landmarks on the ramus of the mandible. The study was performed using mandibles from adult black male Tanzanians aged 30-45 years. Measurements were accomplished using two-digit electronic Vernier calipers. The distances were determined from the center of the mandibular foramen to the different reference points. The mandibular foramen was above the occlusal plane at the M1 and PM2 reference points in all the mandibles studied. It was also located about 20 mm and 12 mm from the anterior and posterior borders of the ramus respectively. There was no significant difference between the left and right side in any of the measurements. These results indicate that during anesthetic or other clinical procedures, the clinician can precisely determine the position of neurovascular bundle of the inferior alveolar nerve above the occlusal plane. PMID- 26749677 TI - Review of the nomenclature of the liver anatomical and functional areas by three dimensional volume rendering 64-multislice computed tomography. Proposal for an update of the terminology. AB - In the last centuries, the anatomy of the liver has been the object of increasing interest. The International Anatomical Terminology tries to unify the terminology of liver anatomy, making it a living language. A single, worldwide-accepted classification of the liver still does not exist. In fact, definition of segments according to Couinaud's nomenclature is different from that of Goldsmith and Woodburne. The aim of this paper was to revise the liver topography by 64 Multislice Computed Tomography, in patients who had undergone repair of cholelithiasis, starting from classifications based on the efferent venous system or on the Glissonian system. This technique allows to remove virtually the liver parenchyma, and, together with the subsequent three-dimensional reconstruction of images, represents the best tool to visualise the hepatic ducts and segments. Through this approach, we propose a new terminology, which considers the liver divided into five lobes and seven segments plus one caudate lobe. In conclusion, this paper can represent a working hypothesis for a possible and future revision of the nomenclature of the hepatic functional territories and can be useful for clinical and didactic aims. PMID- 26749678 TI - Multi-detector computed tomography in the evaluation of variants and anomalies of aortic arch and its branching pattern. AB - OBJECTIVE: Evaluate the prevalence of aortic arch anatomy and branching pattern variants and anomalies in 1359 patients by Multi-Detector Computed Tomography Angiography. METHODS: Retrospective multi-centric study including exams performed for various clinical issues with the same acquisition and injection protocols on 64-slices scanners. Multi-Planar reformations and Volume Rendering Images were available in all cases. RESULTS: A total of 965 patients (71%) had normal aortic arch anatomy and branching pattern. Anatomical variations and anomalies were present in the remaining 394 patients (29%). The most common variation was the common origin of the brachiocephalic and the left common carotid arteries (302/1359 cases, about 22%). The most common anomaly were aberrant right subclavian artery (4/1359, about 0.5%) and right aortic arch (4/1359 cases, about 0.5%). CONCLUSIONS: Our multicentric series is, as far as we know, the largest reported to date for the definition of the prevalence of variation and anomalies of aortic arch anatomy and branching pattern. Knowledge of such findings may avoid both in the immediate and in the long term an injury to the patient, decreasing the rate of complications during surgery and interventional radiology procedures in the head and neck district. PMID- 26749680 TI - Facial soft-tissue volumes in adult Northern Sudanese individuals with Down syndrome. AB - OBJECTIVE: To investigate dimensions and ratios of soft-tissue facial volumes of adult Northern Sudanese subjects with Down syndrome by using computerized anthropometric measurements. DESIGN, SETTING, AND PATIENTS: The 3D coordinates of soft-tissue facial landmarks were obtained by a computerized digitizer in 26 Northern Sudanese adult subjects with Down syndrome (18 men, 8 women, aged 17-34 years), and in 99 healthy Northern Sudanese controls (48 women, 51 men) of the same age range. From the landmarks, several facial volumes and volume ratios were calculated. Data were compared to those collected in healthy individuals by computing z-scores. RESULTS: In subjects with Down syndrome, facial volumes were significantly smaller than in control subjects (Student's t, p < 0.05). The patterns of deviation from the norm were similar in men and women. When compared to controls, subjects with Down syndrome had no differences in nose volume as a fraction of total facial volume and a larger total lip volume as a fraction of total facial volume; within the facial middle third, they had relatively larger upper lip volumes and relatively smaller nose volumes. CONCLUSIONS: The facial soft-tissue structures of subjects with Down syndrome differed from those of normal controls of the same age, sex and ethnic group: a reduced facial size was coupled with specific variations in the nasal and labial regions. PMID- 26749679 TI - Contrast radiographic study of venous drainage of the corpus cavernosum and the corpus spongiosum of the cat penis. AB - The aim of this study was to determine the drainage routes of the corpus cvernosum penis and the corpus spongiosum penis in the cat using contrast cavernosography. Five male cats, 1.5-2.5 years old, weighing between 4.5 and 5.5 kg were investigated. The cats were anesthetized and the root and the proximal part of the penis were exposed by an incision on the perineum reaching the scrotum. Each cat was radiographed in lateral and dorsal recumbency before and during injection of contrast medium into the erectile bodies. The corpus spongiosum penis was injected at the bulb of the penis and the corpus cavernosum penis at the root. Injection of contrast media into the cavernous bodies showed that both the external and internal iliac veins drain the erectile bodies into the caudal vena cava. Drainage from the corpus spongiosum penis was from the bulb for the proximal part and from the glans for the distal part. The corpus cavernosum penis was drained only proximally, from the crura. There was a network of veins above the pelvic symphysis and the drainage of erectile bodies where through various routes into the internal and external iliac veins. PMID- 26749681 TI - Multimodal imaging in the diagnosis and evaluation of intestinal malrotations in adults: a case report. AB - Midgut malrotation is a congenital anomaly referring to either lack of or incomplete rotation of the fetal intestines around the axis of the superior mesenteric artery during fetal development. It is rare in adulthood and the true incidence is difficult to estimate because most patients are asymptomatic. The diagnosis is usually performed with several radiological and surgical methods. We report a case of a woman who presented with cramp-like abdominal pain localized to the right iliac fossa. The patient underwent abdominal ultrasound, radiological examination without and with contrast, and computed tomography with three-dimensional volume rendering reconstruction. Although small bowel followthrough is often enough to recognize the type of malrotation, using multimodal imaging may offer a better definition of this abnormality with a better definition of the kind of malrotation, by adding additional anatomical information. In our case, the imaging clearly showed malrotation of the small bowel with reverse rotation of the colon. Hence a multimodal imaging strategy proved useful for the diagnosis of intestinal malrotation in an adult afflicted by chronic cramp-like abdominal pain. PMID- 26749682 TI - Climate related histological changes in the stomach papillae of Cephalophus Niger (Gray 1846). Implications of climate dynamics and prolonged drought. AB - This study surveyed selected tissue samples obtained from the stomach compartments of the Cephalophus niger including, rumen, reticulum, omasum and abomasum. We utilized 40 antelope's stomach compartments, comprising of 20 males and females respectively; half of the total samples were taken during the peak period of wet seasons and the other half in dry seasons. The relative dimensions of the papillae at various locations within the fore and glandular stomach, observed under a light microscope at magnifications of x100 and x400, revealed significant variations in heights (h), curved surface area (pi rs), base area (pi r2) being a factor which determines the size of other dimensions, total surface area (pi r2 + pi rs) and cross sectional diameters between the seasons. Because prolonged drought may force the species to migrate further hinterland with risks of exposure to predators and reduced survivability of the young, the observed morphological reductive changes may be ecoadaptation for survival in the habitat in prolonged drought since they predispose the compartments to reduce fermentation capability and production and bioutilization of volatile fatty acids. They may also contribute to the occurrence of dental abnormalities and influence disease epidemiology. The results may be used as a model for the assessment and determination of optimal season food bioutilization index, a parameter relevant to remedial interventions for the conservation of less adaptive feeders. PMID- 26749683 TI - Median ulnar nerves communication in the forearm: a study with autopsy material. AB - The incidence of median-ulnar communication in the forearm presents variability in different population groups. The aim of this study was to determine the incidence and morphologic expression of the median-ulnar communication in a sample of the Colombian population. One hundred and eight forearms of autopsy material at the National Institute of Forensic Medicine of Bucaramanga, Colombia were studied. Using an approach of the flexor compartment of forearm the median and ulnar nerves were dissected and the communications between these two structures were characterized. The communicating branch occurred in 28 (25.9%) forearms. It occurred unilaterally in 12 specimens and bilaterally in 8, with statistically significant difference (P=0.01). The communication between the anterior interosseous and ulnar nerves was most frequent, observed in 13 (46.4%) forearms. The length of the communicating branch was 56.9 +/- 8.3 mm. The distance of the proximal and distal points of the communicating branch to the bi- epicondylar line was 59.6 +/- 15.4 mm and 102.7 +/- 23.5 mm respectively. The length of the forearm was 269.8 +/- 15.9 mm. A projection of the communicating branch from the upper third to the midthird of the forearm was observed. The incidence of the median-ulnar communication in the present study is in the high rank reported in the literature; there is an agreement with prior studies in finding more numerous communicating branches in the right forearm. The median ulnar communication should be taken into account for surgical approach of the forearm. PMID- 26749684 TI - A photographic method for multi-plane assessment of adolescent posture. AB - To date there have been no photographic methods reported for assessing the standing postural alignment in a manner that can be used in large scale populations. The purpose of this study was to describe a photographic, multi plane postural measurement method in a pilot group of subjects in a school setting. A total of 83 healthy male adolescents, volunteered for the study, were photographed. The mean age was 14.5 +/- 0.7 years (range 14-16). The mean height was 170.7 +/- 3.5 cm, (range 155-187), and the mean weight was 63.2 +/- 13.9 kg (range 37-110). During procedure, subjects stood on a platform, with specific markers placed on landmarks that could be identified photographically. Photography was accomplished from above, below, each side, and front and back. These six photographs permit views to be projected onto the six sides of an ideal parallelepiped enclosing the body. Five angles were calculated and reported to describe the alignments of the head, shoulders, torso, and pelvis. As expected the means of each of the five angles were small, the absolute value varying from 0 to 7 degrees. This paper describes the results of a simple, practical, and effective way to gather data concerning standing postural alignment in adolescents using a photographic technique. This technique will be used to form a normative database by large-scale studies. Using this approach, a number of angles can be calculated and eventually models can be developed, relating these angles to sitting posture measurements and to symptoms. PMID- 26749685 TI - Andre Latarjet (1877-1947). Anatomist and surgeon specialized in sports medicine. AB - Andre Latarjet (1877-1947), physician and surgeon, outstanding professor of anatomy, made important contributions to the study of human anatomy. He was the disciple and successor of Dr. Leo Testut and continued the diffusion of his work. He was a member of the French Academy of Medicine and President of the International Federation of Sports Medicine. PMID- 26749686 TI - How does Adamkiewicz artery influence blood supply to the fetal spinal cord? AB - Adamkiewicz artery became important in clinical practice since it was noticed that its damage during aorta aneurysm repair surgery can sometimes lead to distal spinal cord ischemia. The complexity of anatomical variations can be related to the development of spinal cord arteries. The aim was to describe topography of Adamkiewicz artery and its relations to the anterior spinal artery in fetuses. The study was carried on 4 Batson's resin corrosion casts and 24 formalin-fixed fetuses injected with dyed gelatin or latex aged 15-24 weeks gestational age. In fixed specimens vertebral canals were dissected, the anterior spinal artery was traced and Adamkiewicz artery localized. Arteries were photographed and digitally measured. Data were afterwards statistically analyzed. Anterior spinal artery was duplicated in 3/28 cases. There were from 1 to 3 Adamkiewicz arteries per specimen, mean 1.71. No relation was found between the number of Adamkiewicz artery and age. In 37/48 cases Adamkiewicz artery emptied into the anterior spinal artery on the left side. Mean degree of narrowing in anterior spinal artery (diameter of the anterior spinal artery above junction with Adamkiewicz artery divided by its diameter under that junction) was 76.74%. The diameter of Adamkiewicz artery was also correlated linearly with the degree of narrowing of anterior spinal artery (r=0.68; p<0.05). The arteries of the anterior aspect of thoracolumbar spinal cord in the 2nd trimester of pregnancy represent the adult pattern. A potentially great impact of Adamkiewicz artery on the distal spinal cord circulation may be postulated on the basis of these morphological data. PMID- 26749687 TI - Bathrocephaly: a case report of a head shape associated with a persistent mendosal suture. AB - Bathrocephaly is a posterior cranial deformity associated with failure of fusion of the mendosal suture. Infants are born with a prominent occipital bone. Here we discuss a case report of bathrocephaly in a newborn discussing management, imaging finding, differential diagnosis and relevant bony anatomy and development. PMID- 26749688 TI - Inspiring Tanzanian medical students into the profession: appraisal of cadaveric dissection stress and coping strategies. AB - Learning experiences and environments greatly influence mastery of competencies during training and in future career. From its nature, cadaveric dissection early in the medical training has the potential to daunt the student's interest in the medical profession during training and in the future clinical practice. This study aimed at appraising the Tanzanian first year medical students at Muhimbili University of Health and Allied Sciences on emotional and physical stress during practice in cadaver dissection room, coping strategies and attitude on dissection. 169 students completed a self administered questionnaire that assessed emotional and physical symptoms encountered during cadaver dissection. The questionnaire also asked for the coping strategies. The frequency distributions were used to summarize demographic variables, reaction and coping strategies. The commonest symptoms were disgust, fear and nausea. Curiosity, prior mental preparedness, pressure and help from the staff were the major coping strategies. About four in five students were fearful and anxious at the beginning, but the figure dropped towards the end of the dissection course. Females reported significantly higher rates of symptoms than males. Prior exposure to a dead body significantly lowered the levels of stress. Close to 95% positively favored dissection over other methods. About 90% would go through the dissection course given another chance. Almost all students would recommend the medical profession to their younger relatives. Anatomy staff and mentors should devise appropriate coping strategies including gradual introduction to dissection room, proper cadaver preparations, proper counselling and complementing dissection with videos and radiographic pictures. PMID- 26749689 TI - Immunopathogenesis of psoriasis: a possible role of TGFbeta/Smads pathway. AB - Psoriasis is a chronic immune-mediated inflammatory skin disease with both genetic and environmental factors contributing to its pathogenesis. Transforming Growth Factor beta (TGFbeta) is a member of a large family of pleiotropic cytokines with three different isoforms (TGFbeta1,2,3). Smads are a family of eight-related proteins that function as intracellular signaling intermediates for TGFbeta once the latter is bound to its receptors (TGFbRI, II and III). The involvement of Smads in TGFbeta signaling has been studied intensively in the skin in the process of wound healing. Few studies, and with controversial results, have investigated at the immunohistochemical and molecular level the role of TGFbeta/Smads signaling in psoriasis. PMID- 26749690 TI - Features of intestinal lesions in the clinical course of inflammatory bowel diseases. AB - Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic, progressive and relapsing inflammatory disorders of unknown etiology. UC is characterized by inflammation of the large bowel mucosa and submucosa, whereas in CD inflammation is transmural and may involve various sites of the gastrointestinal tract. Superficial mucosal lesions are most prone to heal, whereas deep ulcers or transmural fissures may heal with more difficulty and may be followed by the development of fibrosis and strictures requiring surgery. Inflammation appears to be necessary to trigger the onset of the fibrotic process, but subsequently plays a minor role in its progression. In IBD, anti-inflammatory treatment does not prevent evolution of fibrosis once the process has started. Therefore, the mechanisms that regulate fibrosis appear to be distinct from those regulating inflammation. Intestinal fibrosis is due to an abnormal accumulation of extracellular matrix proteins producted by activated intestinal myofibroblasts. Increased evidence indicate that a number of molecules are involved in the development of the disease and a crosstalk between TGFbeta/Smads pathway and alphavbeta6 integrin, mTOR and PPARgamma could play a crucial role in the development of intestinal fibrosis. Animal models represent a useful tool to investigate the molecular and cellular mechanisms of intestinal inflammation and fibrosis and to test the effectiveness of novel therapeutic strategies for the prevention and treatment of intestinal fibrosis that still remain the major cause of surgical intervention. PMID- 26749691 TI - Dendritic cells: phenotypic and functional heterogeneity. AB - Dendritic cells are specialized to capture antigens, process them and present them to T cells to initiate, regulate and fine tune immune responses towards pathogens and tumours. The story of these cells began more than forty years ago and the interest for them is ever growing because of their central role in immunobiology. Dendritic cells are heterogeneous for origin, anatomical localization, phenotype and function: several subsets of myeloid dendritic cells and plasmacytoid dendritic cells have been recognized until now. Dendritic cells differentiate from haematopoietic stem cells-derived precursors, migrate from sites of antigen uptake to lymphoid organs and during this process mature to antigen presenting cells capable of interacting with lymphocytes and stimulate both immune response and peripheral tolerance to self. Since dendritic cells play crucial roles in infection, cancer, allergy, autoimmunity and graft rejection, thorough knowledge of their subsets and behaviour will open the path to tools allowing better control of many clinical conditions. PMID- 26749692 TI - [French health: senators, one effort more!]. PMID- 26749693 TI - [Drugs and alcohol: a bad mix]. PMID- 26749694 TI - [Vaccination against yellow fever: lifetime protection?]. PMID- 26749695 TI - [Is tobacco plain packaging effective in tobacco control?]. PMID- 26749696 TI - [Immigration, a phenomenon with no name]. PMID- 26749697 TI - [EMPATHY IN MEDICINE, NECESSARY BUT NOT FREE FROM RISKS]. AB - Empathy may be defined as the ability to understand or even share others' emotional state. It is a multi-faceted construct that relies on discrete psychological processes with specific neural correlates. In the context of doctor patient relationships, clinical empathy also encompasses the physician's ability to communicate his or her understanding of the emotional state of the patient. However, sharing the emotional states may elicit compassion fatigue and burnout symptoms among physicians and medical students and eventually reduce their empathic capacities. A decline of these capacities is indeed observed during medical training. Perspective-taking may protect physicians from such detrimental effects while allowing them to show sustained empathic concern. Interventions to promote empathy among medical students should target both communication skills and humanist values, as the former may depend on the later to grow. PMID- 26749698 TI - [Treatment of type 2 diabetes]. PMID- 26749699 TI - [COMMENTS ON FRENCH RECOMMENDATIONS ON GLYCEMIC CONTROL IN TYPE 2 DIABETES]. AB - The French guidelines recently changed after that several studies highlighted that normoglycemia was not an acceptable target for everyone. Normoglycemia can be only recommended at the beginning of diabetes, using metformin as treatment. But later, targeting an HbA1c < 7% is a good objective, except in patients with a severe cardiovascular disease: in that case, an HbAlc <8% without hypoglycemia is reasonable. In old patients with severe comorbidities, a comfortable objective is an HbA1c <9%. After melformine use, sulfoaylurea may he used as the second line treatment DPP-4 inhibitors are the third line treatment GLP-1 analogs have to be kept for patients with complicated overweight and an HbA1c above 1% over target PMID- 26749700 TI - [GLP-1 receptor agonists: current state]. PMID- 26749701 TI - [DPP4 inhibitors: what is the cardiovascular risk?]. PMID- 26749703 TI - [Treatment of frail or dependent elderly patients with type 2 diabetes]. AB - In elderly type 2 diabetes, treatment of hyperglycemia has to be integrated into global and individualized care, driven by geriatric assessment In addition to avoiding lethal complications of diabetes, the prevention of decrease in the level of functional independence is the most important goal of this care, and must be implemented by taking into account the type of patient, vigourous or frail. For the dependent patient, maintaining comfort becomes the priority goal. From this assessment ensue the therapeutic and glycemic goals. The choice of therapeutic tools is a function of fixed goals, of comorbidities, of the organization of care at home or in nursing homes, and of the atrogenic risk, in particular the undernutrition and the hypoglycemia. PMID- 26749702 TI - [When and why start insulin in type 2 diabetes?]. AB - Insulin initiation is a major step in medical management and life of patients with type 2 diabetes. Insulin is necessary if combination of 2 or 3 oral antidiabetic agents fail to achieve target glycemic goals, especially if HbA1c are superior to 1% from target or weight loss. Insulin will be started with bedtime intermediate-acting insulin. Insulin can be initiated with 10 units or 0.2 units/kg then increase by 2 units every 3 days until fasting levels are consistantly in targets range. If hypoglycemia occurs, insulin dose will be reduced by 4 units. Insulin initiation requires specific educational program for the acceptation of injection and to learn insulin injection, capillary blood glucose test and adjustment of insulin regimens. PMID- 26749704 TI - [TREATMENT OF TYPE 2 DIABETES IN PATIENTS WITH HISTORY OF CARDIOVASCULAR DISEASE]. AB - Cardiovascular risk events are frequent in patients with type 2 diabetes. The way to treat type 2 diabetes with history of cardiovascular disease is not really different from the one used in a patient without this history with a pathophysiologic approach designed according to the importance of each therapeutic target: insulin-resistance and insulin deficiency. However, it is recommended to use antidiabetic drugs without detrimental cardiovascular effects. Metformin can be used in patients with history of cardiovascular disease (in the exception of renal failure or severe heart failure) since its use has been shown to be associated with a reduction of cardiovascular events in several clinical trials. Among sulfonylureas, first generation sulfonylureas and glibenclamide are not recommended because they impair ischemic preconditioning. Glinides, acarbose, GLP-1 agonists and DPP-4 inhibitors can be used in type 2 diabetic patients with history of cardiovascular disease. DPP-4 inhibitors have been shown to he safe in recent cardiovascular outcome trials. In addition, data from the ORIGIN trial indicate that insulin itself is not likely to increase cardiovascular risk. Most importantly, the risk of hypoglycaemia must be an important concern in patients with history of cardiovascular disease and the use of antidiabetic agents that may induce hypoglycaemic events should he limited. PMID- 26749705 TI - [What type of physical activity to recommend for patients with type 2 diabetes?]. PMID- 26749706 TI - [Kasabach-Merritt syndrome]. PMID- 26749707 TI - [Secondary staphylococcus aureus psoas abscess with anti-tumor necrosis factor therapy]. PMID- 26749708 TI - [A YOUNG MAN WHOSE LDL-CHOLESTEROL IS GREATER THAN 1.9 G/L]. AB - Familial hypercholosterolemia (FH) is both a frequent (estimated prevalence of heterozygous FH: 1/200 to 1/500) and underdiagnosed (< 5 V of diagnosed FH in most countries) genetic disease. Non-treated FH is associated with an increased risk of coronary heart disease (CHD) linked to premature atherosclerosis. The diagnosis of FH should be considered when a subject presents with plasma LDL cholesterol (LDL-C) level > 190 mg/dl (4.9 mmol/l), premature CHO, tendon xanthomas, familial history of hyperGholesterolemia, premature CHD or cardiac death. Cascade screening and genetic analysis help to identify affected relatives. The therapeutic objective is to obtain LDL-C target < 130 mg/dL in young adults without additional cardiovascular risk factors, < 100 mg/dL in the majority of FH patients and < 70 mg/dL in adults with known CHD. Therapeutic management is based on the combination on lifestyle and dietary counselling and pharmacological approaches with maximal potent statin dose, ezetimibe and bile acid sequestrants. In a near future, PCSK9 inhibitors should be a valuable option in FH patients not at LDL-C goal. PMID- 26749709 TI - [Living with HIV]. PMID- 26749710 TI - [What's new in neurology]. PMID- 26749711 TI - [INFECTIONS IN THE TRANSPLANT PATIENT]. AB - Infections in the transplant patient are common. There are infections related to the host (recipient), those related to the graft and the related donor. Infectious risk factors depend on the history of the underlying disease of the transplanted organ, the donor, the immunosuppressive treatment. All pathogens, bacteria, viruses, fungi and parasites are possible but their frequency varies according to the transplanted organ, the selected immunosuppressive therapy and prophylaxis. Indeed, it is important to detect and treat latent infections in pro transplant and prevent post-transplant infections by lifestyle and dietary measures, vaccinations, intraoperative antibiotic, antiviral, antifugal, antiparasitic treatments according graft and a variable length depending on the immunosuppression and donor-recipient status. PMID- 26749712 TI - [THROMBOANGIITIS OBLITERANS (BUERGER'S DISEASE)]. AB - To day there appears to be a consensus to recognize thromboangiftis obliterans (Buerger's disease) as a distinct clinical and pathological entity, characterized by an inflammatory occlusive vasculitis of the small and medium-sized arteries and veins that affects young adult smokers. The strong link with smoking is one of the unique features of thromboangiitis obliterans. Once the disease has became established stepping smoking is the only effective way to prevent evolution of the disease and to reduce the risk of major amputations. Ischaemia of the lower and upper limbs and superficial thrombophlabitis are the essential features of the clinical presentation. However the diagnosis of thromboangiitis is rendered difficult by the lack of specific clinical, radiological, biological and histapathological features. Thus the diagnosis is funded on a probabilistic approach. Discontinuation of tobacco use and to day cannabis are the cornerstone of therapeutic management of patients with thromboangiitis. In patients with ischaemic lesions local care is the other main component of therapeutic management, infusion of iloprost had demonstrated some efficacy. PMID- 26749714 TI - [Cystic fibrosis]. PMID- 26749713 TI - [OVERUSE INJURIES IN THE YOUNG ATHLETE]. AB - Sport injuries are common in children and teenaggers, especially overuse injuries. Typical musculoskelotal disorders include apophyseal pains or avulsion, stess fractures, and also epiphyseal ostoochondritis. Some lesions are specific according the practice, such spine or wrist lesions. Prevention of sport injury should be the main priority as well for the parents than the coaches and children themselves. Proper education and preparation, specific training and streching are essential for all sports activities. PMID- 26749715 TI - [FRENCH CYSTIC FIBROSIS EPIDEMIOLOGY AFTER A DECADE OF NEONATAL SCREENING]. AB - Since its description in 1938, the life expectancy of cystic fibrosis patients has increased from a few months to nearly 50 years in most Western countries. This significant improvement was related to new symptomatic treatments, for nutritional and respiratory cares in specialized multidisciplinary teams. Systematic neonatal screening for the disease avoides the diagnostic delays that have very deleterious impact on the prognosis of the disease. It allows early optimal management; their nutritional benefit has been demonstrated. The French registry of cystic fibrosis shows that adult patients outnumber children. The median age of death remains under thirty years and the prognosis is very closely linked to the progression chronic respiratory insufficiency. About one hundred patients were annually treated by lung transplant PMID- 26749716 TI - [CYSTIC FIBROSIS: CARE OF THE LUNG DISEASE]. AB - (Rh-DNase) and/or hydration (hypertonic saline) nebulisations, Moreover, treatment with inhaled antibiotics is indicated (tobramycin, colistine or aztreonam lysine) for chronic lung infection with Pseudomonas aeruginosa (PA). The treatment regimen also includes bronchodilators for bronchospasms and azithromycin. Regular physical activity is recommended. A treatment potentiating the CFTR protein, ivacaftor, is now indicated for patients with a class 3 mutation. Initial bronchial infection with PA must be treated as soon as possible in order to eradicate the pathogen. Pulmonary exacerbations require antibiotic courses, either orally or intravenously for PA infection. Complications require hospitalisation, with thoracic chest tube placement for a pneumothorax or bronchial artery embolisation for massive hemoptysis. Oxygen therapy and non invasive ventilation with a nasal mask become necessary when respiratory insufficiency progresses, justifying the initiation of the lung transplant process. Lung disease affects the prognosis of cystic fibrosis, therefore its management in cystic fibrosis centres is of utmost importance. Maintenance treatment mainly relies on daily chest physiotherapy, which can be facilitated by mucolytic PMID- 26749717 TI - [NUTRITIONAL STATUS ASSESSMENT IN PATIENTS WITH CYSTIC FIBROSIS]. AB - Prognosis of cystic fibrosis has been largely modified over the past 30 years. Optimization of nutrition is one of the most important contributing factors of this improvement. Nutritional defect result from the conjunction of loss of calories, maldigestion, hypercatabolism and insufficient intake. Pancreatic opotherapy and ADEK vitamin administration is mandatory in pancreatic insufficient patients. Nutritional status must be evaluated at each clinics to detect nutritional defect as early as possible. Nutritional intake must be hypercaloric, normalipidic and adapted to the tastes of the patient. The clinician must be aware of at risk nutritional period: first year of life, puberty, infectious exacerbation, respiratory worsening and diabetes, In neonatal screened babies, recovery of birth weight percentile must be targeted at 6 months, and for the height must be in accordance to genetic height at 2 years. In all cases it is mandatory to treat denutrition by oral supplementation and if necessay enteral nutrition. PMID- 26749718 TI - [Cystic fibrosis: many comorbidities including diabetes, the most common]. PMID- 26749719 TI - [FUTURE THERAPIES FOR CYSTIC FIBROSIS]. AB - Current cystic fibrosis treatment is symptomatic and has greatly increased life expectancy over the last decades. However, mean age of death is still 29-years old. Innovative therapeutic molecules aiming at restoring CFTR function are developed. Ivacaftor is the first medicine approved in 2012 for the 3% of patients worldwide carrying the rare CFTR mutation called G5510. Ivacafter is associated with a sustained improvement in respiratory function and a decreased frequency of pulmonary exacerbations. Other pharmacotherapies are being developed that aim at correcting other CFTR defects due to other CFTR mutations, especially the most frequent F508del mutation. PMID- 26749720 TI - [History of acute promyelocytic leukemia]. PMID- 26749721 TI - [ALLOTRANSPLANTATION OF CRYOPRESERVATED VASCULARIZED BONE IN LIMB SALVAGE SURGERY FOR CHILDREN AND ADOLESCENTS WITH OSTEOSARCOMA]. AB - OBJECTIVE: To investigate the effectiveness and technical key points of limb salvage surgery by allotransplantation of cryopreservated vascularized bone in children and adolescents with osteosarcoma. METHODS: A retrospective analysis was made on the clinical data of 21 children and adolescents with osteosarcoma receiving limb salvage surgery by allotransplantation of cryopreservated vascularized bone from their relatives between February 2004 and April 2012. There were 13 males and 8 females, aged from 7 to 16 years (mean, 12.6 years). According to Enneking stage system, 15 cases were rated as stage IIA and 6 cases as stage IIB. The tumors located at the distal femur in 10 cases, at the proximal femur in 1 case, at the proximal tibia in 8 cases, at the proximal humerus in 1 case, and at the distal radius in 1 case. Imaging examination showed that epiphyseal extension of malignant bone tumors in 7 cases. The iliac bone allograft with deep iliac vessels was obtained from their lineal consanguinity. After preservation by a two-step freezing schedule, the iliac bone allograft with deep iliac vessels was implanted into the bone defect area after tumor resection. The size of iliac bone flap was 8.0 cm x 3.0 cm x 2.0 cm-14.0 cm x 5.0 cm x 2.5 cm. Reserved joint surgery was performed on 16 cases and joint fusion surgery on 5 cases, and external fixation was used in all cases. The chemotherapy was given according to sequential high-dose methotraxate, adriamycin, and cisplatine before and after operation. RESULTS: All 21 cases were followed up from 5 months to 11 years (mean, 6.4 years). At 2 weeks after operation, the erythrocyte rosette forming cells accounted for 56.7% +/- 3.9%, showing no significant difference when compared with that of normal control (58.3% +/- 4.3%) (t = 1.56, P = 0.13), which suggested no acute rejection. At 4 weeks after operation, single photon emission computerized tomography bone scan indicated that the blood supply of bone graft was rich, and the metabolism was active. At 12 weeks after operation, the digital subtraction angiography showed the artery of iliac bone flap kept patency. X-ray films showed that malunion and non-union occurred at 5 and 6 months after operation in 1 case, respectively. The bone graft healed in the other patients, and the healing time was 3.2-6.0 months (mean, 4.4 months). At last follow-up, American Musculoskeletal Tumor Society (MSTS) score was significantly improved to 26.80 +/- 2.14 from preoperative value (17.15 +/- 1.86) (t = -4.15, P = 0.00). The survival rate was 85.7% (18/21) and the recurrence rate was 9.5% (2/21). CONCLUSION: Allotransplantation of cryopreservated vascularized bone from the relatives provides a new method for the treatment of osteosarcoma in children and adolescents. A combination of allotransplantation and chemotherapy can achieve the ideal treatment effect. The correct cutting, preservation, and transplantation of the donor bone, and indication are the key to improve the effectiveness. PMID- 26749722 TI - [ANALYSIS OF PROSTHESIS-RELATED COMPLICATIONS AFTER EXTENSIBLE SEMI-JOINT PROSTHESIS REPLACEMENT FOR LOWER LIMBS OSTEOSARCOMA IN CHILDREN]. AB - OBJECTIVE: To investigate the causes of the complications and prevention strategy by analyzing occurrence of prosthesis-related complications after extensible semi joint prosthesis replacement for lower limbs osteosarcoma in children. METHODS: Eleven children with lower limbs osteosarcoma underwent resection of tumor and replacement of the extensible semi-joint prosthesis between May 2006 and October 2012. There were 6 boys and 5 girls, with an average age of 9.3 years (range, 7 12 years). The lesions located at the distal femur in 6 cases, at the proximal femur in 2 cases, and at the proximal tibia in 3 cases. The disease duration was 2-8 months (mean, 3.6 months). According to the Enneking stage, 3 cases were rated as stage II A and 8 cases as stage II B. The pulmonary CT and ECT results showed no pulmonary metastasis or multi spots before operation. All patients received preoperative chemotherapy treatment for 4 times. RESULTS: Primary healing of incision was obtained in 10 cases. Infection occurred in 1 case at 1 week after operation, and was cured after symptomatic treatment. Nine patients received postoperative chemotherapy for 12 times, 2 patients for 2 times and 4 times respectively. One case died of multiple metastasis; in 3 cases of pulmonary metastasis, 2 cases died and 1 case survived after resection of metastatic lesion. Eight survival cases received a follow-up of 25-89 months (mean, 42.5 months). Loosening and dislocation of the proximal femoral prosthesis occurred in 1 case, loosening and subsidence of the distal femoral prosthesis in 1 case, subluxation in 1 case, and retraction in 1 case. The incidence of prosthesis related complications was 50%. Lengthening operation was performed on 3 cases for 1 time, and on 1 case for 2 times. And 4 cases did not undergo lengthening operation. According to Enneking function evaluation standard after malignant tumor limb-salvage surgery, the results were excellent in 1 case, good in 3, fair in 3, and poor in 1 at last follow-up with an excellent and good rate of 50%. CONCLUSION: The prosthesis-related complications include loosening and subsidence, dislocation, knee instability, and retraction after extensible semi joint prosthesis replacement for lower limbs osteosarcoma. The prosthesis-related complications can be reduced by the improvement of prosthesis design and manufacture, and the use of intraoperative bone cement, artificial mesh, and postoperative restrictive brace. PMID- 26749723 TI - [COMPARISON OF PERIOPERATIVE INFLAMMATORY MARKERS BETWEEN PATIENTS WITH ANKYLOSING SPONDYLITIS AND NON-INFLAMMATORY DISEASES UNDERGOING TOTAL HIP ARTHROPLASTY]. AB - OBJECTIVE: To evaluate the inflammatory markers in patients with ankylosing spondylitis (AS) or non-inflammatory diseases undergoing total hip arthroplasty (THA) and to ascertain the variation trend of perioperative inflammatory markers and the influence of inflammation markers after THA. METHODS: Between January 2013 and December 2014, 153 consecutive patients with AS were included. According to the range of motion (ROM), the patients were divided into ankylosis group (ROM: 0 degrees; group A, n = 92) and stiff group (ROM: 3-46 degrees; group B, n = 61); 120 non-inflammatory diseases patients having no bacterial infection and undergoing primary THA served as non-inflammatory group (group C). The inflammatory markers including C-reactive protein (CRP), interleukin-6 (IL-6), and erythrocyte sedimentation rate (ESR) concentrations were measured before operation and at 1, 3, 5, and 7 days after operation, and the complication was observed. RESULTS: Perioperative serum CRP, IL-6, and ESR increased at first after operation, and then decreased in 3 groups. There were significant differences in CRP and ESR between at pre- and post-operation (P < 0.05); the IL 6 at 1, 3, and 5 days after operation were significantly higher than that at preoperation (P<0.05), but no significant difference was found between at 7 days and at preoperation (P > 0.05). CRP, IL-6, and ESR of group B were significantly higher than those of group A at preoperation (P < 0.05); CRP and IL-6 of groups A and B were significantly higher than those of group C at preoperation and at 1 day after operation (P < 0.05); ESR of groups A and B was significantly higher than that of group C at preoperation, and at 1 day and 3 days after operation (P < 0.05); and no significant difference was shown among 3 groups at the other time points (P > 0.05). No inflammatory activity or increased complication was observed. CONCLUSION: AS and non-inflammatory diseases show similar change trend of inflammatory markers at pre- and post-operation. The inflammatory activity of AS has no significant effect on the changes of inflammation markers and does not increase the incidence of postoperative complications. PMID- 26749724 TI - [EFFECTIVENESS OF KNEE EXTENSOR MECHANISM RECONSTRUCTION FOR RECURRENT PATELLAR SUBLUXATION WITH BONE ANCHOR IN ADOLESCENTS]. AB - OBJECTIVE: To explore the effectiveness of knee extensor mechanism reconstruction in the treatment of recurrent patellar subluxation with bone anchor in adolescents. METHODS: Between January 2010 and December 2013, 20 patients with patellar subluxation were treated by knee extensor mechanism reconstruction with bone anchor. There were 11 males and 9 females, aged from 12 to 17 years (mean, 15.3 years). The left knee was involved in 12 cases and the right knee in 8 cases. The disease duration was 5-10 years (mean, 7 years). All the patients had knee pain and lateral subluxation of the patella. Preoperative Lysholm knee score was 71.4 +/- 4.7. All the patients received the MRI examination to exclude menisci or ligaments lesion. CT examination showed the tibial tuberosity trochlear groove spacing ranged from 15 to 20 mm (mean, 17 mm). X-ray film examination indicated that no varus or valgus was observed, and bony structure was normal. RESULTS: All the incisions healed at first stage. The patients received follow-up of 12-24 months (mean, 13 months). Knee pain occurred in 2 cases and were cured after symptomatic treatment. The axial X-ray films showed good position of the patella and normal anatomic relationship of the patellofemoral joint. No anchor loosening and pulling out, internal fixation failure, pseudoarthrosis formation, and postoperative recurrent patellar subluxation occurred during follow-up. At 1 year, the Lysholm knee score was significantly improved to 94.2 +/- 3.4 (t = 22.705, P = 0.000). According to Insall criterion, the results were excellent in 9 cases, good in 9 cases, and fair in 2 cases, with an excellent and good rate of 90%. CONCLUSION: The bone anchor for extensor mechanism reconstruction is a convenient and reliable way to treat the recurrent patellar subluxation, with a satisfactory early effectiveness and less complications; however, its long-term effectiveness is required a further follow-up. PMID- 26749725 TI - [EFFECTIVENESSES OF SINGLE-BUNDLE AND DOUBLE-BUNDLE ANTERIOR CRUCIATE LIGAMENT RECONSTRUCTION BY TWO METHODS]. AB - OBJECTIVE: To compare the effectiveness of single-bundle and double-bundle anterior cruciate ligament (ACL) reconstruction by two methods. METHODS: Qualified for the selective standard, 120 patients with ACL injury between May 2010 and April 2013 were divided into 4 groups: double-bundle reconstruction was performed by the conventional procedure in 30 cases (group A); anatomic double bundle reconstruction was performed in the original ACL residual footprints in 30 cases (group B); single-bundle reconstruction was performed by the conventional procedure in 30 cases (group C); and anatomic single-bundle reconstruction was performed in the original ACL residual footprints in 30 cases (group D). There was no significant difference in gender, age, disease duration, pathogenesis, injury side, Lysholm scores, International Knee Documentation Committee (IKDC) ratings, Lachman test, anterior drawer test, and pivot shift test among groups (P > 0.05). The impingement between the ACL implants and intercondylar notch was evaluated with postoperative immediate MRI scan and the three-dimensional digital model. Lachman test, anterior drawer test, and pivot shift test results, Lysholm scores, and IKDC ratings were used to compare the effectiveness among groups after operation. RESULTS: Three-dimensional digital model after operation showed impingement in 11 cases (36.7%) of group A, 1 case (3.3%) of group B, 9 cases (30.0%) of group C, and no impingement in group D. The impingement rates of groups A and C were significantly higher than that of groups B and D (P < 0.05), but no significant difference was found between groups A and C, and between groups B and D (P > 0.05. All incisions healed by first intention, and no early complication was found. The patients were followed up 24-30 months (mean, 26 months). Lysholm scores, Lachman test, anterior drawer test, and pivot shift test results at 24 months after operation were significantly better than preoperative ones in 4 groups (P < 0.05), but no significant difference was shown among groups (P > 0.05). The IKDC ratings of groups B and D were significantly better than that of groups A and C (P < 0.05); but there was no significant difference between groups A and C, and between groups B and D (P > 0.05). CONCLUSION: Compared with the conventional procedure, the individual anatomic single- and double-bundle reconstruction in the original ACL residual footprints has decreased impingement rate and increased IKDC rating. PMID- 26749726 TI - [EFFECTIVENESS COMPARISON BETWEEN MODIFIED Brostrom METHOD REPAIR AND ANATOMICAL RECONSTRUCTION WITH SINGLE FIBULAR TUNNEL IN TREATMENT OF CHRONIC LATERAL ANKLE INSTABILITY]. AB - OBJECTIVE: To compare the effectiveness between modified Brostrom method repair and anatomical reconstruction anterior talofibular ligament (ATFL) and calcaneofibular ligament (CFL) with single fibular tunnel for chronic lateral ankle instability. METHODS: Twenty ankle specimens of fresh cadaver were dissected to provide the anatomic data of ATFL and CFL and to observe the neurovascular distribution. Between January 2008 and December 2011, 48 patients (48 ankles) with chronic lateral ankle instability were randomly divided to groups A and B (n = 24). The direct repair of ATFL and CFL by modified Brostrom method was performed in group A, and anatomic double-bundle reconstruction of ATFL and CFL with free semitendinosus tendon autograft in group B. There was no significant difference in sex, age, body mass index, injury side, the causes of injury, interval of injury and operation, talar tilt angle, talus forward shift, ankle plantar flexion, dorsiflexion, valgus, varus, American Orthopaedic Foot and Ankle Society (AOFAS) score, and visual analogue score (VAS) between 2 groups (P > 0.05). The image parameters and range of motion were compared between 2 groups after operation; AOFAS and VAS scores were used to evaluate the effectiveness. RESULTS: All the incisions healed by first intention in 2 groups; no complication of nerve injury, infection, or skin necrosis was observed. All the patients were followed up 2-5 years (mean, 3.4 years); no subtalar stiffness or recurrent instability occurred during follow-up. The talar tilt angle, talus forward shift, AOFAS score, and VAS score were significantly improved at 2 years after operation when compared with preoperative ones in 2 groups (P < 0.05). There was no significant difference in range of motion of ankle plantar flexion, dorsiflexion, and ankle valgus, and VAS score between 2 groups (P > 0.05), but group B was significantly better than group A in the range of motion of ankle varus, talar tilt angle, talus forward shift, and AOFAS score (P < 0.05). In the each item of AOFAS score, there was no significant difference in pain, 2 groups (P > 0.05), but group B was significantly better than group A in walking, maximum walking distance, and ankle stability (P < 0.05). CONCLUSION: The described technique, which involves anatomic double-bundle reconstruction of the ATFL and CFL with single fibular tunnel and modified incision, is a viable option for treating lateral ankle instability, especially for young patients who need high stability and revision. PMID- 26749727 TI - [TIBIAL PERIOSTEAL FLAP PEDICLED WITH INTERMUSCULAR BRANCH OF POSTERIOR TIBIAL VESSELS COMBINED WITH AUTOLOGOUS BONE GRAFT FOR TIBIAL BONE DEFECT]. AB - OBJECTIVE: To investigate the effectiveness of tibial periosteal flap pedicled with intermuscular branch of posterior tibial vessels combined with autologous bone graft in the treatment of tibial bone defects. METHODS: Between January 2007 and December 2013, 19 cases of traumatic tibia bone and soft tissue defects were treated. There were 14 males and 5 females, aged from 18 to 49 years (mean, 28 years). The tibial fracture site located at the middle tibia in 6 cases and at the distal tibia in 13 cases. According to Gustilo type, 4 cases were rated as type III A, 14 cases as type III B, and 1 case as type III C (injury of anterior tibial artery). The length of bone defect ranged from 4.3 to 8.5 cm (mean, 6.3 cm). The soft tissue defects ranged from 8 cm x 5 cm to 17 cm x 9 cm. The time from injury to operation was 3 to 8 hours (mean, 4 hours). One-stage operation included debridement, external fixation, and vacuum sealing drainage. After formation of granulation tissue, the fresh wound was repaired with sural neurovascular flap or posterior tibial artery perforator flap. The flap size ranged from 10 cmx6 cm to 19 cm x 11 cm. In two-stage operation, tibial periosteal flap pedicled with intermuscular branch of posterior tibial vessels combined with autologous bone graft was used to repair tibial defect. The periosteal flap ranged from 6.5 cm x 4.0 cm to 9.0 cm x 5.0 cm; bone graft ranged from 4.5 to 9.0 cm in length. External fixation was changed to internal fixation. RESULTS: All flaps survived with soft texture, and no ulcer and infection occurred. All incisions healed by the first intention. All patients were followed up 18-40 months (mean, between normal and affected sides.The function of the knee an ankle joint was good without infection, malunion, and equinus. According to the Johner standard at last follow-up, the results were excellent in 15 cases, good in 3 cases, and fair in 1 case, with an excellent and good rate of 94.7%. CONCLUSION: Tibial periosteal flap pedicled with intermuscular branch of posterior tibial vessels combined with autologous bone graft is an effective method to treat bone defect of the tibia. PMID- 26749728 TI - [360 degrees INTERNAL FIXATION BY DOUBLE APPROACHES FOR HIGH-ENERGY CLOSED Pilon FRACTURES]. AB - OBJECTIVE: To observe the effectiveness of 360 degrees internal fixation by anteromedial and posterior-lateral approaches for high-energy closed Pilon fractures. METHODS: Between February 2013 and February 2015, 18 cases of high energy closed Pilon fractures were treated. There were 11 males and 7 females with an average age of 40.5 years (range, 20-65 years). The causes were falling injury in 10 cases and traffic accident injury in 8 cases. All fractures were Ruedi-Allgower type III Pilon fracture combined with ipsilateral fibula fracture. The average interval from injury to operation was 8 days (range, 5-13 days). Reduction of fracture was performed by anteromedial and posterior-lateral approaches and the fracture fragments were fixed by 360 degrees internal fixation. The effectiveness was assessed by ankle X-ray film and Mazur score at last follow-up. RESULTS: Two cases had skin necrosis and received flap surgery, the other cases obtained primary healing of incision. All the cases were followed up 11.2 months on average (range, 3-27 months). X-ray film showed that all fractures healed at 3-4 months after operation (mean, 3.6 months). No deep infection or plate exposure occurred. According to Mazur score, the results were excellent in 8 cases, good in 7 cases, fair in 2 cases, and poor in 1 case, and the excellent and good rate was 83.3%. CONCLUSION: The effectiveness of the 360 degrees internal fixation for treatment of high-energy closed Pilon fractures has the advantages of reliable fixation, early functional exercise, and good functional recovery of the ankle joint. PMID- 26749729 TI - [EFFECTIVENESS OF LOCKING COMPRESS PLATE FOR TREATMENT OF ASEPTIC DIAPHYSEAL HUMERAL NONUNIONS]. AB - OBJECTIVE: To evaluate the effectiveness of locking compress plate (LCP) for the treatment of aseptic diaphyseal humeral nonunions. METHODS: Between January 2006 and January 2012, 23 patients with aseptic diaphyseal humeral nonuninons were treated with LCP and autologous iliac crest bone graft, and the clinical data were retrospectively analyzed. There were 15 males and 8 females with the average age of 42.5 years (range, 28-60 years). The fracture located at left side in 11 cases and right side in 12 cases. The mechanism of the injury was traffic accident in 15 patients, and falling from height in 8 patients. Fracture was treated by internal fixation in 20 cases and external fixation in 3 cases. And 6 patients had open fractures and other 17 had close fractures. Based on the Weber Cech classification, 6 cases were rated as atrophic nonunions, and 17 cases as hypertrophic nonuninons. Shoulder function was evaluated by Constant-Murley score and elbow function was evaluated by Mayo score. RESULTS: After operation, 2 patients had transient radial nerve symptoms of numbness and 1 patient had superficial infection. Primary healing of incision was obtained in the other patients. All patients were followed up 22.22 months on average (range, 16-30 months). Normal range of motion of the shoulder was found in 11 cases; and limited movements of abduction, elevation, and posterior extension were observed in 12 cases. And osseous union was observed clinically and radiographically in all patients. The average union time was 16.95 weeks (range, 12-24 weeks). The average Constant-Murley score was 81.87 (range, 50-98); and shoulder function was excellent in 14 cases, good in 6, and fair in 3. And the average Mayo score was 87.78 (range, 70-96); and the result was excellent in 14 cases, good in 7, and fair in 2. CONCLUSION: Aseptic diaphyseal humeral nonunions can be successfully treated with LCP, coupled with the use of autologous iliac crest bone graft. PMID- 26749730 TI - [BIOMECHANICAL COMPARATIVE STUDY ON FOUR INTERNAL FIXATIONS FOR ACETABULAR FRACTURES IN QUADRILATERAL AREA]. AB - OBJECTIVE: To compare the biomechanical difference of 4 kinds of internal fixations for acetabular fracture in quadrilateral area. METHODS: The transverse fracture models were created in 16 hemipelves specimens from 8 adult males, and were randomly divided into 4 groups according to different internal fixation methods (n = 4): infrapectineal buttress reconstruction plate (group A), infrapectineal buttress locking reconstruction plate (group B), reconstruction plate combined with trans-plate quadrilateral screws (group C), and anterior reconstruction plate-lag screw (group D). Then the horizontal displacement, longitudinal displacement of fractures, and axial stiffness were measured and counted to compare the stability after continuous vertical loading. RESULTS: Under the same loading, the horizontal and longitudinal displacements of groups A, B, C, and D were decreased gradually; when the loading reached 1 800 N, the longitudinal displacement of group A was more than 3.00 mm, indicating the failure criterion, while the axial stiffness increased gradually. Under 200 N loading, there was no significant difference (P > 0.05) in horizontal displacement, longitudinal displacement, and axial stiffness among 4 groups. When the loading reached 600-1 800 N, significant differences were found in horizontal displacement, longitudinal displacement, and axial stiffness among 4 groups (P < 0.05) except the horizontal displacement between groups C and D (P > 0.05). CONCLUSION: For acetabular fracture in the quadrilateral area, anterior reconstruction plate-lag screw for internal fixation has highest stability, followed by reconstruction plate combined with trans-plate quadrilateral screws, and they are better than infrapectineal buttress reconstruction plate and infrapectineal buttress locking reconstruction plate. PMID- 26749731 TI - [MODEL ESTABLISHMENT, MRI AND PATHOLOGICAL FEATURES OF EARLY STEROID-INDUCED AVASCULAR NECROSIS OF FEMORAL HEAD IN RABBIT]. AB - OBJECTIVE: To establish an rabbit model of early steroid-induced avascular necrosis of the femoral head (SANFH) and evaluate its validity with MRI and pathological examination. METHODS: Twenty 6-month-old rabbits (weighing, 2-3 kg) were randomly divided into 2 groups (control group and model group), 10 rabbits in each group. Dexamethasone sodium phosphate solution (10 mg/kg) was injected into bilateral gluteus in model group, and the same amount of saline was injected in control group, every 3 days for 14 times. General observation was done after modelling. Osteonecrosis was verified by pathological observation and MRI findings at 6 weeks. RESULTS: After 6 weeks, rabbits did not show obvious changes in control group; increased hair removal, decreased food intake, and slight limp were observed in model group. The MRI results showed normal shape of the bilateral femoral head and no abnormal signals in control group; irregular shape of the bilateral femoral head and a slice of irregular abnormal signals were observed, and necrosis and cystolization of the subchondral bone and sparse changes of trabecular bone were shown in model group. General observation from coronal section of femoral head showed smooth red cartilage surface in control group; on the contrary, the cartilage surface of the femoral head became dull, thin even visible hemorrhage under articular cartilage and necrosis of the femoral head were observed. The histopathological examination indicated that trabecular bone of the femoral head in control group was massive, thick, and close and osteocytes in the bone lacunae had normal shapes. The osseous trabecular became thinner and broken; karyopyknosis of osteocytes and bone empty lacunae could be obviously seen in model. group. The rates of empty lacunae were 8.0% +/- 0.5% in control group and 49.0% +/- 0.3% in model group, showing significant difference (t = 21.940, P = 0.000). CONCLUSION: Establishing a model of early SANFH through injecting short-term, shock, and high dose of dexamethasone, and it can been evaluated effectively with MRI and pathological examination. PMID- 26749732 TI - [MINIMALLY INVASIVE SURGERY FOR DIRECT REPAIR OF LUMBAR SPONDYLOLYSIS BY UTILIZING INTRAOPERATIVE NAVIGATION AND MICROENDOSCOPIC TECHNIQUES]. AB - OBJECTIVE: To analyze the effectiveness of direct screw repair for lumbar spondylolysis by using intraoperative O-arm based navigation and microendoscopic techniques. METHODS: Between February 2012 and May 2014, 11 consecutive patients with lumbar spondylolysis were treated with Buck's procedure by the aid of intraoperative O-arm based navigation and minimally invasive approach. The debridement and autograft of pars interarticularis defects was performed under microendoscopy. There were 7 males and 4 females, with an average age of 28.4 years (range, 19 - 47 years) and an average disease duration of 10.5 months (range, 8-23 months); no nerve symptoms or signs of lower limb was observed. The radiological examinations showed single level bilateral lumbar spondylolysis without obvious disc degeneration, lumbar instability, or spondylolisthesis. Isthmic injury located at L4 in 2 cases and at L5 in 9 cases. Of 11 patients, 7 were rated as grade 2 disc degeneration, and 4 as grade 3 disc degeneration according to the modified Pfirrmann classification system. The operation time, intraoperative blood loss, and complications were recorded. The fluoroscopic examinations were performed to assess defect repair and screw position. Visual analogue scale (VAS) score was used to evaluate the improvement of low back pain. RESULTS: The average operation time was 147.6 minutes (range, 126-183 minutes). The average blood loss was 54.9 mL (range, 40-85 mL). Primary healing of incision was obtained. There was no complication of nerve root injury, dural tear, or infection. Three patients had pain at donor site postoperatively, and pain disappeared within 3 weeks. The average follow-up duration was 15.7 months (range, 10-23 months). VAS score of low back pain was significantly decreased from preoperative 7.1 +/- 2.3 to 1.8 +/- 0.4 at last follow-up (t = 13.42, P = 0.01). Of 22 isthmic bone grafting, bilateral isthmic bony fusion was achieved in 7 patients and unilateral isthmic bony fusion in 3 patients at 6-10 months (mean, 7.9 months). One patient failed bilateral isthmic bony fusion, and had bony resorption. CONCLUSION: Debridement, autograft, and percutaneous intralaminar screw fixation by microendoscopy and O-arm based navigation may provide safe and effective treatment for spondylolysis. Minimally invasive direct repair can obtain satisfactory effectiveness. PMID- 26749733 TI - [VALUE OF SMART PHONE Scoliometer SOFTWARE IN OBTAINING OPTIMAL LUMBAR LORDOSIS DURING L4-S1 FUSION SURGERY]. AB - OBJECTIVE: To investigate the value of smart phone Scoliometer software in obtaining optimal lumbar lordosis (LL) during L4-S1 fusion surgery. METHODS: Between November 2014 and February 2015, 20 patients scheduled for L4-S1 fusion surgery were prospectively enrolled the study. There were 8 males and 12 females, aged 41-65 years (mean, 52.3 years). The disease duration ranged from 6 months to 6 years (mean, 3.4 years). Before operation, the pelvic incidence (PI) and Cobb angle of L4-S1 (CobbL4-S1) were measured on lateral X-ray film of lumbosacral spine by PACS system; and the ideal CobbL4-S1 was then calculated according to previously published methods [(PI+9 degrees) x 70%]. Subsequently, intraoperative CobbL4-S1 was monitored by the Scoliometer software and was defined as optimal while it was less than 5 degrees difference compared with ideal CobbL4-S1. Finally, the CobbL4-S1 was measured by the PACS system after operation and the consistency was compared between Scoliometer software and PACS system to evaluate the accuracy of this software. In addition, value of this method in obtaining optimal LL was validated by comparing the difference between ideal CobbL4-S1 and preoperative one with that between ideal CobbL4-S1 and postoperative one. RESULTS: The CobbL4-S1 was (36.17 +/- 1.53)degrees for ideal one, (22.57 +/- 5.50)degrees for preoperative one, (32.25 +/- 1.46)degrees for intraoperative one measured by Scoliometer software, and (34.43 +/- 1.72)degrees for postoperative one, respectively. The observed intraclass correlation coefficient (ICC) was excellent [ICC = 0.96, 95% confidence interval (0.93, 0.97)] and the mean absolute difference (MAD) was low (MAD = 1.23) between Scoliometer software and PACS system. The deviation between ideal CobbL4-S1 and postoperative CobbL4-S1 was (2.31 +/- 0.23)degrees, which was significantly lower than the deviation between ideal CobbL4-S1 and preoperative CobbL4-S1 (13.60 +/- 1.85)degrees (t = 6.065, P = 0.001). CONCLUSION: Scoliometer software can help surgeon obtain the optimal LL and deserve further dissemination. PMID- 26749734 TI - [COMPARISON OF EFFECTIVENESS BETWEEN PARA-MEDIAN INCISION MINIMALLY INVASIVE AND OPEN TRANSFORAMINAL LUMBAR INTERBODY FUSION FOR SINGLE SEGMENTAL LUMBAR DEGENERATIVE DISEASE]. AB - OBJECTIVE: To investigate the advantage and short- and medium-term effectivenesses of paramedian incision minimally invasive transforaminal lumbar interbody fusion (mini-TLIF) by comparing with open TLIF. METHODS: A retrospective analysis was made on the clinical data of 54 patients with single segmental lumbar degenerative disease who accorded with the inclusion criteria between January 2012 and March 2014. Open TLIF was performed in 26 patients (open group), mini-TLIF in 28 cases (minimally invasive group). There was no significant difference in gender, age, disease duration, etiology, and affected segments between 2 groups (P > 0.05). The indexes of surgical trauma, systemic inflammatory response, clinical outcome, and interbody fusion rate were compared between 2 groups. RESULTS: Dural rupture occurred in 1 case of open group, L5 nerve root injury in 1 case of minimally invasive group. All patients obtained primary healing of incision. The operation time, intraoperative blood loss, and postoperative drainage of minimally invasive group were significantly lower than those of open group (P < 0.05). C-reactive protein, leucocyte count, and creatine kinase-MM (CK-MM) of open group were significantly higher than those of minimally invasive group at 24 hours after operation (P < 0.05). At 7 days after operation, the CK-MM of minimally invasive group was significantly lower than that of open group (P < 0.05), but no significant difference was found in C-reactive protein and leucocyte count between 2 groups (P > 0.05). The follow-up time was 1.2-3.1 years in open group and 1.4-2.9 years in minimally invasive group. At 1 year after operation, the Oswestry disability index (ODI) and visual analogue scale (VAS) scores were significantly improved in 2 groups (P < 0.05). Minimally invasive group was better than open group in ODI and VAS score of back pain (P < 0.05), but VAS score of leg pain showed no significant difference (P > 0.05). According to the Suk interbody fusion standard, solid fusion was obtained in 18 cases, probable fusion in 4 cases, and nonunion in 4 cases, and the fusion rate was 84.61% in open group; solid fusion was obtained in 21 cases, probable fusion in 3 cases, and nonunion in 4 cases, and the fusion rate was 85.71% in minimally invasive group; and the interbody fusion rates showed no significant difference between 2 groups (Chi2 = 0.072, P = 0.821). CONCLUSION: Compared with open TLIF, paramedian incision mini-TLIF has advantages of minimal surgical trauma and little blood loss for single-level lumbar degenerative disease. The short- and medium-term effectivenesses are satisfactory. PMID- 26749735 TI - [EFFECTIVENESS OF POSTERIOR UNILATERAL TRANSPEDICULAR DEBRIDEMENT, BONE GRAFT FUSION, AND PEDICLE SCREW FIXATION FOR THORACOLUMBAL TUBERCULOSIS]. AB - OBJECTIVE: To explore the effectiveness of posterior unilateral transpedicular debridement, bone graft fusion, and pedicle screw fixation for thoracolumbar tuberculosis. METHODS: Between January 2009 and January 2013, 97 patients with thoracolumbar tuberculosis were treated with posterior unilateral transpedicular debridement, bone graft fusion, and pedicle screw fixation in 53 cases (group A), and with traditional posterior operation in 44 cases (group B). There was no significant difference in age, sex, disease duration, affected segments, Frankel grade, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), sagittal Cobb angle, visual analogue scale (VAS), and Oswestry disability index (ODI) between 2 groups (P > 0.05). The surgery and follow-up results were compared between 2 groups. RESULTS: The patients were followed up 24-60 months. All patients achieved intervertebral bone fusion after operation. The bone graft fusion time of groups A and B was (6.79 +/- 1.68) months and (6.89 +/- 2.00) months respectively, showing no significant difference (t = -0.251, P = 0.802). There was no significant difference in operation time, intraoperation blood loss, and postoperative hospitalization time between 2 groups (P > 0.05); the postoperative drainage volume of group A was significantly less than that of group B (P < 0.05). The CRP and ESR at 1 year and the VAS score at last follow-up were significantly decreased when compared with preoperative values in 2 groups (P < 0.05), but no significant difference was found between 2 groups (P > 0.05). The Cobb angle at 1 week and at last follow-up and ODI at 3 months and at last follow-up were significantly improved in 2 groups (P < 0.05), but there was no significant difference between the time points after operation (P > 0.05). At 3 months after operation, the ODI of group A was significantly lower than that of group B (t = -2.185, P = 0.027), but no significant difference was found in Cobb angle, Cobb angle loss, and ODI at other time points between 2 groups (P > 0.05). At last follow-up, the Frankel classification of nerve function was improved 1-2 grades in 2 groups, showing no significant difference between 2 groups (Z = 0.180, P = 0.857). No complication of internal fixation breakage or loosening was observed. CONCLUSION: The effectiveness of posterior unilateral transpedicular debridement, bone graft fusion, and pedicle screw fixation in the treatment of thoracolumbar tuberculosis is satisfactory, with the advantages of less trauma, strong spinal stability, and fast function recovery. PMID- 26749736 TI - [GRADED INFUSION OF BONE CEMENT IN PERCUTANEOUS VERTEBROPLASTY FOR Kummell's DISEASE]. AB - OBJECTIVE: To explore the safety and effectiveness of graded infusion of bone cement in the unipedicular percutaneous vertebroplasty (PVP) for Kummell's disease. METHODS: Eighteen patients with Kummell's disease were treated by unipedicular PVP with graded infusion of bone cement between January 2012 and January 2014. Of 18 cases, 6 were male and 12 were female, aged from 65 to 88 years (mean, 75 years), with a disease duration from 3 to 32 months (mean, 11.6 months). The bone mineral density was measured by dual-energy X-ray absorptiometry; the T value ranged from -4.0 to -2.8 (mean, -3.4). Affected segments included T11 in 3 cases, T12 in 10 cases, L1 in 3 cases, and L2 in 2 cases. X-ray films were taken after operation to observe bone cement leakage and anterior height changes of affected vertebrae. Visual analogue scale (VAS) and Oswestry disability index (ODI) were used to assess pain status and functional activity. RESULTS: All cases underwent smoothly unipedicular PVP and were followed up 12-26 months (mean, 14 months). Cement leakage occurred in 4 patients, including 1 case of anterior paravertebral soft tissue leakage, 2 cases of intervertebral disc leakage, and 1 case of canal venous leakage, but there was no other complications. The anterior height of affected vertebrae were significantly improved (P < 0.05) from 29.1% +/- 6.7% at preoperation to 68.1% +/ 7.3% at 3 days after operation and 67.8% +/- 5.9% at last follow-up; the VAS scores were significantly decreased (P < 0.05) from 8.11 +/- 1.32 at preoperation to 2.14 +/- 0.78 at 3 days and 1.97 +/- 0.50 at last follow-up; and ODI were significantly decreased (P < 0.05) from 84.6% +/- 8.5% to 24.1% +/- 9.7% and 23.8% +/- 10.2%; but no significant difference was found between at 3 days and at last follow-up (P > 0.05). CONCLUSION: Graded infusion of bone cement in unipedicular PVP is a safe and effective procedure for Kummell's disease and this technique could decrease the incidence of bone cement leakage. PMID- 26749737 TI - [CORRELATION ANALYSIS OF CHANGES OF SPINE-PELVIC SAGITTAL PARAMETERS BEFORE AND AFTER OPERATION AND EFFECTIVENESS IN PATIENTS WITH LUMBAR SPONDYLOLISTHESIS]. AB - OBJECTIVE: To investigate the correlation between the effectiveness and the changes of spine-pelvic sagittal parameters for patients with spondylolisthesis before and after operation. METHODS: A retrospective analysis was made on the clinical data of 32 patients with single segmental degenerative lumbar spondylolisthesis at L4 who accorded with the inclusion criteria between June 2011 and January 2014 (trial group). There were 13 males and 19 females, aged 51 67 years (mean, 59 years). According to Meyerding degree, there were 21 cases of degree I, 10 cases of degree II, and 1 case of degree III. All patients were treated with transforaminal lumbar interbody fusion (TLIF) surgery. Thirty-five healthy adults at the age of 46-67 years (mean, 57 years) were enrolled as normal controls (control group). The standing position lumbar lateral X-ray films (T12 S1, bilateral femoral head) were taken at pre- and post-operation to measure the pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), lumbar lordosis (LL), disc height (DH), and slip percentage (SP); the visual analogue scale (VAS) and Oswestry disability index (ODI) were recorded. Pearson correlation analysis was used to analyze the correlation between the preoperative various spine-pelvic sagittal parameters and the VAS score and the ODI. After operation, Pearson correlation analysis was used to evaluate the correlation between the changes of these parameters and the improve rates of VAS score and ODI. RESULTS: All patients of trial group were followed up 15 - 22 months (mean, 18 months). At last follow-up, the VAS score, ODI, PT, SS, LL, SP, and DH were significantly improved when compared with preoperative values (P < 0.05), except for PI (t = 1.445, P = 0.158). There was no significant difference in PT, SS, LL, and DH between trial and control groups at last follow-up (P > 0.05); PI was slightly bigger than that of control group (t = 8.531, P = 0.043). Pearson correlation analysis showed that there was a correlation between spine-pelvic sagittal parameters of PI, PT, SS, and LL (P < 0.05); preoperative parameters (except for LL and DH) had correlation with ODI and VAS scores (P < 0.05). Postoperative parameters (except for PI) had correlation with the improve rates of ODI and VAS scores (P < 0.05), especially for the changes of PT and the improvements of ODI and VAS scores. CONCLUSION: There is a correlation between the changes of spine pelvic sagittal parameters at pre- and post-operation and effectiveness in patients with lumbar spondylolisthesis. The correlation between the changes of PT and the improvement rates of ODI and VAS scores is more marked. The good effectiveness is closely related with the improved PT. PMID- 26749738 TI - [EFFECTS OF ANTERIOR SINGLE SEGMENT FIXATION ON SPINAL STABILITY IN TREATMENT OF THORACOLUMBAR BURST FRACTURE OF Denis TYPE B WITH PEDICLE INJURY]. AB - OBJECTIVE: To investigate the effects of anterior single segment fixation on the spinal biomechanical stabilization in the treatment of thoracolumbar burst fracture of Denis type B with pedicle injury. METHODS: Six fresh human cadaveric spine specimens (T11-L3) were harvested as normal control (group A). Then the L1 Denis type B fracture model was created by the hemi-corpectomy method. Each specimen was tested in 3 different scenarios: anterior single segment (T12, L1) fixation with the integrity of the pedicle (group B), anterior single segment fixation with the resection of the unilateral pedicle (group C), and anterior single segment fixation with the resection of the bilateral pedicles (group D). Range of motion (ROM) in flexion/extension, bilateral bending, and bilateral axial rotation was measured by spinal three-dimensional measuring system under pure moments of 8.0 N x m. RESULTS: The ROM values of T12, L1 in flexion, extension, and right/left lateral bending of groups B, C, and D were significantly lower than those of group A (P < 0.05); group D was significantly higher than groups B and C (P < 0.05); but groups B and C showed no significant difference (P > 0.05). The ROM values of T12, L1 in right/left axial rotation of groups B and C were significantly lower than those of groups A and D (P < 0.05), but there was no significant difference (P > 0.05) between groups B and C and between groups A and D. The ROM values of L1,2 in flexion, extension, right/left lateral bending, and right/left axial rotation showed no significant difference between groups (P > 0.05). CONCLUSION: Resection of the unilateral pedicle has litter effects on the spine biomechanical stabilization of the anterior single segment fixation in the 6 degrees of freedom. However, the bilateral resection results show significant decrease in flexion, extension, lateral bending, and rotation motion stability by the single segment fixation devices, especially in the axial rotation aspect. PMID- 26749739 TI - [MODIFIED Politano-Leadbetter REIMPLANTATION FOR TREATMENT OF CONGENITAL MALFORMATION OF VESICOURETERAL JUNCTION IN CHILDREN]. AB - Corresponding author: HUANG Lugang, E-mail: lugang992001@aliyun.com OBJECTIVE: To explore the effectiveness of modified Politano-Leadbetter reimplantation for the treatment of congenital malformation of the vesicoureteral junction in children. METHODS: A retrospective analysis was made on the clinical data of 53 patients with congenital malformation of the vesicoureteral junction treated with modified Politano-Leadbetter reimplantation between June 2000 and October 2014. Of 53 cases, there were 24 boys and 29 girls, aged from 8 months to 7 years (mean, 2.1 years); 23 had congenital vesicoureteral junction obstruction (14 left, 5 right, and 4 bilateral), and 30 had vesicoureteral reflux (12 unilateral, 18 bilateral), which were verified by voiding cystourethrography. The disease duration was from 1 month to 1 year (mean, 5 months). RESULTS: All of the patients underwent modified Politano-Leadbetter reimplantation successfully. The mean operation time was 74 minutes (range, 65-85 minutes) for unilateral cases and 105 minutes (range, 98-130 minutes) for bilateral cases. There was no dysuria, infection of incision, or incision dehiscence after urinary catheter removal. The follow-up time was 6 months to 14 years (median, 28 months); all patients were free from complications of fistula, vesicoureteral reflux, vesicoureteral junction obstruction, or hypertension. The new ureteral orifices had good appearance at 1 month after operation. Urologic ultrasound showed that hydronephrosis relieved at 3 months after operation. Urinary tract infection rate was 13.2% (7/53) during 6 months after operation, which was cured by antibiotics. Voiding cystourethrography showed no vesicoureteral reflux in 32 cases at 6 months after operation. CONCLUSION: The modified Politano-Leadbetter reimplantation simplifies he operation course, which has the longitudinal ureter after operation and is similar to physiological state. It is a safe and effective option for congenital malformation of vesicoureteral junction in children with few complications, especially for patients with unilateral megaloureter. PMID- 26749740 TI - [CLINICAL APPLICATION OF FREE DESCENDING BRANCH OF LATERAL CIRCUMFLEX FEMORAL ARTERY PERFORATOR TISSUE FLAP AND ITS IMPACT ON DONOR SITE]. AB - OBJECTIVE: To investigate the feasibility of the free descending branch of lateral circumflex femoral artery perforator tissue flap (fascia flap plus skin flap) to repair large soft tissue defects of the extremities and its impact on the donor site. METHODS: Between January 2013 and February 2015, 9 cases of large tissue defects of the extremities were repaired with the free descending branch of lateral circumflex femoral artery perforator tissue flap. There were 8 males and 1 female, aged from 13 to 56 years (median, 36 years). The causes included traffic accident injury in 6 cases and crushing injury by heavy object in 3 cases. Soft tissue defect located at the lower limbs in 7 cases and at the upper limbs in 2 cases, including 2 cases of simple tendon exposure, 2 cases of simple bone exposure, and 5 cases of tendon and bone exposure. After debridement, the soft tissue defect area ranged from 13 cm x 7 cm to 20 cm x 18 cm. The tissue flaps ranged from 14 cm x 8 cm to 23 cm x 19 cm. The donor site was directly sutured, scalp graft was used to cover the fascia flap. RESULTS: After operation, partial necrosis of the skin grafting on the fascia flap occurred in 2 cases and healed after dressing change. Arterial crisis occurred in 1 case and the flap survived after anastomosis. The other tissue flaps survived and wounds healed by first intention. The skin grafting healed by first intention in 7 cases, by second intention in 2 cases. The patients were followed up 4-24 months (mean, 10 months). The appearance and function of the tissue flaps were satisfactory, only linear scar was observed at the donor site, which had less damage and no effect on walking. CONCLUSION: Free descending branch of lateral circumflex femoral artery perforator tissue flap can repair large soft tissue defect of the extremities. The donor site can be sutured directly, which reduces damage to donor site and is accord with the principle of plastic surgery. PMID- 26749741 TI - [miR-93-5P SUPPRESSES OSTEOGENIC DIFFERENTIATION OF MOUSE C3H10T1/2 CELLS BY TARGETING Smad5]. AB - OBJECTIVE: To investigate whether miR-93-5p suppresses osteogenic differentiation of mouse mesenchymal stem cells (C3H10T1/2) by targeting Smad5, a predicted target in silicon. METHODS: Smad5 3'-UTR-luciferase vector (pmiR-RB-REPORT) was constructed and dual-luciferase reporter gene assay was employed to examine the effect of miR-93-5p on Smad5 3'-UTR-luciferase activity to identify whether Smad5 was the target gene of miR-93-5p. miR-93-5p mimics (group M), miR-93-5p inhibitor (group In), miR-93-5p mimics negative control (group MC), and miR-93-5p inhibitor negative control (group InC) were transfected into the C3H10T1/2 cells, respectively, and followed by induction of osteogenic differentiation. After 48 hours, the real-time fluorescent quantitative PCR (qRT-PCR) and Western blot assays were performed to detect the relative expressions of Smad5 mRNA and protein. At 14 days, to realize the regulation role of miR-93-5p in osteogenic differentiation, the extracellular calcium deposition during the osteogenesis of C3H10T1/2 cells was tested by Alizarin red staining. RESULTS: Dual-luciferase reporter gene assay showed that miR-93-5p could combine with Smad5 mRNA 3'-UTR specificity, and inhibited its luciferase activity (P < 0.05). After 48 hours, no significant difference was shown in the relative expression of Smad5 mRNA between group M and group MC as well as between group In and group InC by qRT-PCR assay (P > 0.05); however, the results of Western blot assay showed that the relative expression of Smad5 protein was significantly decreased in group M and increased in group In when compared with groups MC and InC (P < 0.05). At 14 days after osteogenic induction, Alizarin red staining showed that the extracellular calcium deposition of group M was obviously less than that of group MC, and it was obviously more in group In than in group InC. CONCLUSION: Smad5 may be the target gene of miR-93-5p. And miR-93-5p can suppress osteogenic differentiation of C3H10T1/2 cells by directly targeting Smad5. PMID- 26749742 TI - [ISOLATION AND IDENTIFICATION OF RAT INTERVERTEBRAL DISC NUCLEUS PULPOSUS CELLS AT DIFFERENT SEGMENTS AND COMPARATIVE STUDY ON BIOLOGICAL CHARACTERISTICS]. AB - Corresponding author: WANG Yuntao, E-mail: wangyttod@seu.edu.cn OBJECTIVE: To isolate nucleus pulposus cells (NPCs) from the caudal and lumbar intervertebral disc of rat, and to identify the morphology and to compare the characteristics. METHODS: The whole spine was separated from 8-week-old Sprague Dawley rats under the sterile conditions. NPCs of different segments (lumbar group: L1, 2-L6, S1; caudal group: C1, 2-C17, 18) were cultured by adherent cultivation approach. Cellular morphologic change was noted by HE staining and continuous observation under inverted phase contrast microscope. Besides, the aggrecan and collagen type II expression were examined by toluidine blue and immunocytochemistry staining respectively. The total protein contents, senescence level, and the cell viability of passage 1-5 (P1-5) were detected. The growth curves of the P1 cells in lumbar and caudal groups were determined by cell counting kit 8. RESULTS: The NPCs were isolated and identified successfully. The adherence time of the primary cells (the cell fusion reached 90%) in lumbar group was significantly longer than that in caudal group in primary generation (P < 0.05). HE staining showed that cytoplasm was pink with the blue nucleus. Lumbar disc NPCs were spindle. The larger caudal disc NPCs were polygonal or irregular. Toluidine blue staining showed that the proteoglycan was stained as blue. In the cytoplasm of cells, collagen type II was stained as brown surround the blue-black nucleus. The cell viability had no significant difference between lumbar and caudal groups and between different passages in the same group (P > 0.05). The caudal disc NPCs reached their logarithmic growth phase after 3 days of culture, while the cells in lumbar segments did after 4-5 days of culture. The cell proliferation in caudal segments was more than that in lumbar segments at 3-9 days (P < 0.05). The difference in the total protein contents was not significant between cells at P1 5 in 2 groups (P > 0.05), and the caudal disc NPCs had higher protein contents than lumbar disc NPCs (P < 0.05). There was no significant difference in cell senescence rate between cells at P1, P2, and P3 in 2 groups (P > 0.05), but significant difference was shown in senescence rate between 2 groups in cells at P4 and P5 (P < 0.05). CONCLUSION: Caudal disc NPCs have a better status, which is more suitable for experiment as a seed cell than the lumbar disc NPCs in the same generation. PMID- 26749743 TI - [STUDY ON MODIFICATION OF BIOMATERIALS OF ACELLULAR BOVINE PERICARDIUM WITH DIFFERENT CROSSLINKING REAGENTS]. AB - OBJECTIVE: To investigate the effects of modification of acellular bovine pericardium with 1-ethyl-3-(3- dinethylami-nopropyl) carbodimide (EDC)/N hydroxysuccininide (NHS) or genipin and find out the best crosslinking reagent. METHODS: The cellular components of the bovine pericardiums were removed. The effects of decellularization were tested by HE staining. The acellular bovine pericardiums were crosslinked with EDC/NHS (EDC/NHS group) or genipin (genipin group). The properties of the crosslinked acellular matrix were evaluated by scanning electron microscope (SEM), matrix thickness, crosslinking index, mechanical property, denaturation temperature, enzymatic degradation, and cytotoxicity test before and after the crosslinking. Acellular bovine pericardium (ABP group) or normal bovine pericardium (control group) were harvested as controls. RESULTS: SEM showed that collagen fibers were reticulated in bovine pericardial tissues after crosslinked by EDC/NHS or genipin, and relative aperture of the collagen fiber was from 10 to 20 MUm. The thickness and denaturation temperature of the scaffolds were increased significantly after crosslinking with EDC/NHS or genipin (P < 0.05), while there was no significant difference between EDC/NHS group and genipin group (P > 0.05). The difference had no statistical significance in crosslinking index between EDC/NHS group and genipin group (t = 0.205, P = 0.218). The degradation rate in EDC/NHS group and genipin group was significantly lower than that in ABP group and control group (P < 0.05). Elastic modulus and fracture stress in EDC/NHS group and genipin group were significantly lower than those in ABP group (P < 0.05), but there was no significant difference among EDC/NHS group, genipin group, and control group (P > 0.05). The break elongation in EDC/NHS group and genipin group were significantly increased than those in ABP group and control group (P < 0.05). The difference had no statistical significance in stability and mechanical properties between EDC/NHS group and genipin group (P > 0.05). Cytotoxicity of genipin crosslinked tissue (grade 1) were much lower than that of EDC/NHS (grade 2) at 5 days. CONCLUSION: Acellular bovine pericardium crosslinked with genipin has better biocompatibility than EDC/NHS. PMID- 26749744 TI - [RESEARCH PROGRESS OF MINIMALLY INVASIVE SURGERY FOR UNICOMPARTMENTAL KNEE ARTHROPLASTY]. AB - OBJECTIVE: To summarize the priority and indications of the unicompartmental knee arthroplasty (UKA) and the evolution of minimally invasive surgery-UKA (MIS-UKA), and to discuss the effectiveness. METHODS: The related literature on UKA was extensively reviewed, summarized, and analyzed. RESULTS: Recently, satisfactory results has been achieved in UKA for the treatment of single room knee osteoarthritis. Both the design of the single condyle prosthesis and the surgical technique are becoming more advanced, which make the MIS-UKA possible. Especially the application of navigation computer and robot assisted system on UKA improves the accuracy of unicompartmental prosthesis implantation greatly. CONCLUSION: The superiority and indications of MIS-UKA are gradually expanding with the progress of surgical technique and the design of the single condyle prosthesis. However, whether the application of navigation computer and robot assisted system can improve the effectiveness needs to be further confirmed. PMID- 26749746 TI - Conference delivers insights, innovation, and inspiration. PMID- 26749747 TI - Specific care bundles successfully cut surgical site infection rates. PMID- 26749745 TI - [RESEARCH PROGRESS OF microRNA IN INTERVERTEBRAL DISC DEGENERATION]. AB - OBJECTIVE: To comprehensively analyze the relationship between microRNAs and intervertebral disc degeneration at home and abroad. METHODS: The literature about the relationship between microRNAs and intervertebral disc degeneration was reviewed and analyzed. RESULTS: MicroRNA can lead to intervertebral disc degeneration by regulating the gene expression, thus influencing the cell's apoptosis and proliferation, increasing of the production of inflammatory mediator and protease, which play important roles in intervertebral disc degeneration. CONCLUSION: MicroRNA is a research focus in the field of intervertebral disc degeneration. Further research of the relationship between microRNAs and intervertebral disc degeneration will help to identify the pathogenesis of intervertebral disc degeneration and furnish the new ideal for the diagnosis and treatment of intervertebral disc degeneration. PMID- 26749748 TI - Build a strong anesthesia quality program to boost patient safety and the bottom line. PMID- 26749749 TI - Vanderbilt's anesthesia QI program reduces adverse postoperative events. PMID- 26749751 TI - Disaster planning exercises prepare ASCs to care for patients and assist communities. PMID- 26749750 TI - Infection control noncompliance cited in high percentage of Joint Commission surveys. PMID- 26749752 TI - [Overcoming resistance to digital change]. PMID- 26749753 TI - [PERIPHERALLY INSERTED CENTRAL VENOUS CATHETER THROUGH DRUM SYSTEM]. AB - It described a one lumen central venous catheter peripherally inserted drum system whose insertion into the vein is performed through a plastic splittable cannula by braunula technique. The braunula technique is particularly important in certain urgent or emergency situations, where speed and aseptic conditions of which the procedure is performed represent a further improvement over other insertion techniques. The catheter mantains the advantages, in terms of easy placement, that all devices equipped with a drum system have but at the same time eliminates the complications presented by other similar catheters whose insertion to the venous circulation used to be performed through a needle. These catheters allow quick, simple and safe access to the central venous circulation and reduce risks associated with the procedure, improving patient safety. PMID- 26749754 TI - [HEALTH INCIDENT MANAGEMENT MATERIAL]. AB - INTRODUCTION: The problems encountered with medical device increase patient morbidity, affect safety professionals and in crease health spending. The Material Resources Committee a the Hospital Clinic of Barcelona decided to understand the im plications associated with these products through a system o incident reporting from October2011 to June2013. METHODOLOGY: A descriptive retrospective study. No probabi listic statements consecutive occurrences sampling. Variable studied: type of material, type and time resolution and degre, of impact. For statistical analysis SPSS version 20 software wa used. RESULTS: 103 incident statements of 68 items, of which 83.8% were medical supplies and 16.2% for non-health were collected. The medical supplies impacted more frequently and severely in patients compared to non-health (p = 0.026). According to the family of the material, the incidents were related: 30.9%, to "infusion"; 17.6 %, to "cover material"; 13.2 %, to "cures" and 11.8 %, to "ventilation". Families of infusion and ventilation items got more serious problems in patients (p = 0.001). Incidences sanitary items were resolved in an average of 18.0 +/- 28.0 days and non-health at an average of 8 4 +/- 6.6 days (p = 0.03). CONCLUSIONS: The medical equipment is the one with most incidents, severely impacting on patient safety. These incidents ar resolved over a long period of time that could be imoroved. PMID- 26749755 TI - [CHALLENGES OF THE NURSING PROFESSION AT EUROPEAN LEVEL]. AB - Professional nurses are internationally sought after, a fact reinforced under the frames of exchange and cooperation promoted by the European Union. Given the high percentage of mobility shown by health professionals, nurses need a thorough preparation to facilitate their integration in the countries where they are likely to develop their professional careers. In order to promote exchange and facilitate discussion between nurses from different European countries, the Health School of the Polytechnic Institute of Portalegre (Portugal), organized on the 2nd and 3rd of September the International Health Sciences Meeting ESS 2015 ("Promoting bonds - A newchallenge for the future ofhealth professions in Europe"). The diverse working conditions that nurses are faced with in different countries highlight the need to foster awareness of the profession at European level, facilitating ties, exchange and scientific platforms to address the current reality of the labor market. PMID- 26749756 TI - [LIMB SHAKING: DESCRIPTION OF A CASE FROM A NURSING PERSPECTIVE]. AB - INTRODUCTION: Limb shaking, which was described by MillerFisher in 1962, is characterized by involuntary, irregular, stereotyped a hemibody triggered by the contralateral hemisphere hypoperfusion. It is associated with an occlusion or stenosis preoclusive of the extracranial internal carotid artery (ICA) contralateral to the movements, and poor circulation contralateral. This causes ischemia resulting in typical clinical manifestations of stroke and these abnormal movements. OBJECTIVE: To describe a case of limb shaking. MATERIALS AND METHODS: 59 years old man, with cardiovascular risk factors, who go to the Emergency room with symptoms and motor dysphasia and sudden loss of strength in right limbs, with distal brachial predominance. Admitted to Stroke Unit for neurological and hemodynamic monitoring, which coincides with the beginning of the sitting have an episode of these involuntary movements. RESULTS: Diagnostic tests confirm a left frontal cortical ischemic stroke. The EEG shows a normal background bioelectric activity. The angio-MRI and angiography showed a left ICA pseudoocclusion. DISCUSSON: A diagnosis of limb shaking based in the clinical examination and additional tests, which confirm the finding of a left ICA pseudo occlusion and refractory to antiepileptic treatment. CONCLUSION: The limb shaking is a rare syndrome, which must be recognized and differentiated early from other processes to treat it properly. Treatment is aimed at restoring cerebral blood flow through the ischemic hemisphere revascularization. PMID- 26749757 TI - [PATIENT SAFETY IN FRONT OF THE USE OF BANDAGES]. AB - The safety of the patient is one of the main priorities in healthcare environment. One of the most commonly used products are bandages and their effectiveness and safety depends on many factors: the quality of the materials used, their manufacturing process and the main purpose of use. All sanitary products need to comply with the Royal Decree 1591/2009, October 16, that describes the characteristics and functions of each type of these products. Bandages are classified as a Sanitary Products Class l and, hence, they do not require any microbiological control in order to sell them. Therefore, it is fair to ask whether the bandages that are used in healthcare are totally safe for patients. PMID- 26749758 TI - [EPIDEMIOLOGY OF FALLS IN THE NON-INSTITUTIONALIZED SPANISH ELDERLY POPULATION, SYSTEMATIC REVIEW 2014]. AB - OBJECTIVE To identify scientific publications about falls among non institutionalized Spanish elderly population and to summarize the study findings which analysed the incidence, the risk factors and the consequences of the falls in the geriatric spanish population aged 65 years and over who lives institutionalized in our country. MATERIAL AND METHOD: Systematic review of the epidemiological observational studies in Spain, with recording of falls, with temporary retrospective and published as scientific articles between the years 2003 and 2014 included. The articles search took place in July 2014, with the limit of language and publication year, in the electronic databases PubMed, Dialnet, RedALyC, SciELO, Enfispo and Google Scholar. RESULTS: The percentage of people who suffered falls depending on the publication year. The frequency of falls recorded varied from 14.9 % to 66.2 %. The mean intake of daily drugs was between 2.7 to 4.5 drugs per day. The fear of falling that had the elderly population non-institutionalized was between 44.7 % and 49.4 %. The vast majority of falls occurred at home, with percentages between 55.1 % and 61 %. Between 30 % and 55.1 % of people who suffered falls maintained health care contact immediately and the fractures prevalence was between 0 % and 26.1 %. CONCLUSTON: It can be confirmed that the falls prevalence in the spanish elderly population is high, so the need ofnew researches are appreciated. PMID- 26749759 TI - [THE NEW FAMILY TYPES IN THE HEALTH SYSTEM]. AB - Changes in the Spanish families are critical in the planning of health services, in the evolution oftheirdemands, and in their relationships with healthcare staff We describe the characteristics of the new family structures (single-parent families, LGBT families, older families, multiple birth families, stepfamilies, adoptive families and families that resort to assisted reproductive techniques), what are their concerns, their needs and their requirements, and what are the implications for the health system. PMID- 26749760 TI - [EFFECTIVENESS OF NOBECUTAN(r) PLASTIC DRESSING SPRAY IN REDUCING PAIN ASSOCIATED WITH PERINEAL TRAUMA AFTER VAGINAL DELIVERY]. AB - OBJECTIVE: The aim of this study was to compare the difference in perineal pain between women with dressing spray versus no dressing spray applied after perineal repair. DESIGN: Randomized controlled trial. SETTING: The Hospital Universitario Fundacion Alcorcon, a state hospital belonging to the Community of Madrid. SAMPLE: The study involved eighty-two nulliparous women, who had undergone vaginal delivery with episiotomy or second-degree perineal laceration. METHOD: They were randomized. One group was applied the dressing spray directly on the wound (experimental group). The other group was applied the dressing spray on the skin around the wound (control group). MAIN OUTCOME MEASURES: The participants were questioned regarding the sensation of pain (0-100 scale) in repose and during different activities (such as sitting, walking, urinating and during defecation), and the use of painkillers at 24 and 48 hours postpartum. RESULTS: Women treated with plastic dressing spray on the wound had less pain at repose, sitting, walking, urinating and during defecation at 24 hours and 48 hours postpartum. Only reached statistical significance the pain in urination at 48 hours. The difference was 9.5 mm (95 %; 1.2 to 17.4) and the effect size (Cohen's d): d = 0.51). The need for analgesia was higher in the control group than in the experimental, but not significant differences being observed. CONCLUSIONS. Findings suggest that Nobecutan(r) plastic dressing spray can decrease perineal pain in nulliparous women in the first 48 hours after birth. PMID- 26749761 TI - [THE VALUE OF INFORMATION AND COMMUNICATIONS TECHNOLOGY IN AGING]. AB - Nowadays, acquiring, managing, disseminating and understanding information through new technologies is an important aspect of our daily life. We can search for and store information, but we can also spread it. The proper handling of information and communications technology (TICs) is beneficial, but does not reach all alike. The difficulties posed by the elderly when adapting to TICs are increased by the fact that they are unknown and unfamiliar to them, resulting in rejection from the elderly and thus an increased risk of inequality and social exclusion. TICs value in aging lies in the improvement of self-learning and personal development as well as in promoting participation, social integration and healthy aging. PMID- 26749763 TI - Creating a strong data security program. Support strategic initiatives with the right mix of technology. PMID- 26749762 TI - Too much Big Data may not be enough. Providers are aiming for multimedia healthcare. PMID- 26749764 TI - Paper-era security in the digital age. Does hospital data security start with you? PMID- 26749765 TI - Google Glass: Seeing too much of your patients? PMID- 26749766 TI - Change the 'hoarding' culture. Utilize RTLS for lean, efficient practice management. PMID- 26749767 TI - Achieving and sustaining ICD-10 success. PMID- 26749768 TI - Everything's different; nothing has changed. ICD-10 disruptions don't have to be scary. PMID- 26749769 TI - MU Stage 3: Can we get there from here? PMID- 26749770 TI - Facing a deluge with a leaky roof. Robust integration capabilities can shield you from the storm. PMID- 26749771 TI - Connecting what matters. Patient-centered interoperability leads to better care. PMID- 26749772 TI - Systems Integration. Top 10 imaging interoperability concerns. PMID- 26749773 TI - Medication management: A cure for the common payment reform. PMID- 26749774 TI - Roadblocks to Licensure. PMID- 26749775 TI - The Care and Feeding of Employees. PMID- 26749776 TI - Honesty is Best Policy. PMID- 26749777 TI - Could We Be Doing More? PMID- 26749778 TI - Robert J Herzog, D.D.S., CIP, chair of the NYSDA Committee on Chemical Dependency, provided the following response to Dr. Buccigrossi. PMID- 26749779 TI - What Mentorship Means to Me. PMID- 26749780 TI - Contrasting Perspectives of Dental Faculty and Their Students Concerning Dental Academia. AB - Attitudes of dental students and faculty towards research, faculty recruitment, new school openings, and academic career rewards and disadvantages were evaluated. Both groups believe that research should be discretionary. Faculty had significantly higher support for supervising and encouraging students to conduct research. Students favored recruitment of better quality (not more) faculty, and some displayed concerns about a tuition increase if additional faculty members were recruited. Both groups said there is no significant need for new dental schools. Faculty displayed a more favorable view toward an academic career and a significantly more favorable view of faculty recruitment. PMID- 26749781 TI - Risk Factors in the Development of Oral Bisphosphonate-induced Osteonecrosis. AB - Bisphosphonates (BPs) are routinely prescribed to prevent pathologic fractures in osteoporotic patients. Bisphosphonate-associated osteonecrosis of the jaw (BRONJ) is a rare, but serious complication, most often following extraction in patients treated with intravenous BPs. We report a case of BRONJ in a patient following six years of oral BP administration for the management of osteoporosis, complicated by four years of prednisone therapy for pulmonary fibrosis. This rare presentation led us to investigate other causative factors, in particular, glucocorticoids. This report aims to construct a clinically relevant predictive model of the disease through better understanding of concomitant risk factors. PMID- 26749782 TI - Occlusal Characteristics of the Primary Dentition Revisited. AB - The occlusal characteristics of the primary dentition of 130 children 3 to 6 years old were examined. Variables were the terminal plane relationship, primary canine occlusion, spacing, overjet and overbite relationships. The flush terminal plane was the most common finding. A Class I relationship of the primary canine occurred in 85% of the subjects. Spaced dentitions occurred 81% of the time, while the presence of primate spaces occurred in at least one of the four quadrants. The overjet relationship varied from +1 mm to 4 mm in all subjects, and the majority of children were considered to have a normal overbite. PMID- 26749783 TI - Multiple Radiolucencies of the Jaws in a 6 Year Old. AB - Radiolucencies of the jaws are a common finding. Mostly, they are isolated findings associated with inflammatory processes and consistent with inflammatory periapical disease, such as periapical cysts and periapical granulomas. If associated with the crowns of unerupted teeth, they may represent dentigerous cysts. However, occasionally, larger lytic/radiolucent lesions are identified; even more infrequently, these radiographic findings may be multiple and concurrent. The purpose of this report is to present the case of a 6-year-old female patient with no known concomitant syndrome who presented with multiple intraoral swellings and to discuss the treatment of multiple, bilateral mandibular and maxillary radiolucencies. PMID- 26749784 TI - The Evolution and Fabrication of Implant-supported Full-arch Hybrid Prostheses. From Conventional Casted Metal to an All-Ceramic Zirconia. AB - Implant-supported, full-arch hybrid prostheses have developed from cast-metal frameworks with acrylic or porcelain to all-ceramic zirconia frameworks. CAD/CAM manufacturing removed the inaccuracies seen with casting and made use of zirconia possible. The materials and processes for prosthodontic fabrication are explained. Zirconia is highly opaque and versatile. However, porcelain-veneered zirconia frameworks have shown higher enamel wear, among other problems. Lithium disilicate has been shown to be more translucent than zirconia. Improved stained and more translucent zirconia frameworks have been produced as well. These promising new methods have gained popularity, but long-term studies are scarce and, thus, more research is required. PMID- 26749786 TI - You Might be having a Bad Day, When... . We've all been there: a perfectly good day marred by a difficult patient or office catastrophe. PMID- 26749785 TI - Herpes Zoster of the Third Division of the Trigeminal Nerve. A Clinical Pathologic Conference. AB - Herpes zoster of the trigeminal nerve is a disease that often challenges dentists and dental specialists trying to make the proper diagnosis, as many ulcerative and vesiculobullous diseases of the mouth have a similar clinical appearance. We report a clinical case in which a 27-year-old patient sought care for this vesicular lesion. Included are the differential diagnosis and treatment modalities that we used to diagnose the disease. A clinical pathologic conference is provided to highlight the appropriate courses of action in the management of herpes zoster. PMID- 26749787 TI - Minamata: two years on. PMID- 26749788 TI - Infected Dentine Revisited. AB - Dentine becomes infected as a result of caries lesion formation on root surfaces and when lesions progress following cavitation of enamel lesions. However, this infection is unimportant because the driving force for lesion formation and progression is the overlying biofilm. This explains why root surface caries can be controlled by mechanical plaque control and fluoride, and restorations are not needed to arrest these lesions. Similarly, the infected dentine in cavitated coronal lesions does not have to be removed to arrest the lesion. If the lesion is either accessible or opened for cleaning by the patient or parent, the lesion can be arrested. Sealing of infected dentine within the tooth, either by a Hall crown in the primary dentition or by partial caries removal prior to placing a well-sealed filling, will also arrest the lesion. When restoring deep lesions in symptomless, vital teeth, vigorous excavation of infected dentine is likely to expose the pulp and make root canal treatment necessary. Thus complete excavation'is not needed and should be avoided. CPD/CLINICAL RELEVANCE: Root surface caries can be arrested by cleaning and fluoride application. Restorations are not essential. Vigorous excavation of softened dentine in deep cavities of symptomless, vital teeth is contra-indicated. It is not needed and increases the risk of pulp exposure. PMID- 26749789 TI - Modern Endodontic Principles Part 3: Preparation. AB - The purpose of instrumentation is to facilitate irrigation and allow controlled obturation. This article will revisit methods of instrumentation of the root canal system with consideration given to length determination, apical preparation and the concept of patency filing. It will discuss hand instrumentation and rotary preparation looking at emerging technology such as reciprocating systems and the self-adjusting file. CPD/CLINICAL RELEVANCE: Mechanical preparation of the root canal system is of fundamental importance in achieving success, creating a more easily managed environment from a biological perspective. PMID- 26749790 TI - Coronectomy; Good or Bad? AB - The removal of mandibular third molars can be complicated by injury to the inferior alveolar nerve (IAN). Coronectomy retains the tooth root; this method has been found to be preferable to extraction in the context of mandibular third molars. A failed coronectomy may cause mobilization of these roots, thereby requiring a subsequent extraction. Having undergone a previous coronectomy, extraction is then safer as the roots usually migrate away from the IAN. Computed tomography is more accurate than radiography when imaging mandibular third molars pre-operatively owing to its three-dimensional nature. Longer studies need to be conducted to evaluate the long term benefits of coronectomy. CPD/CLINICAL RELEVANCE: The removal of mandibular third molars can be complicated by the presence of the close lying inferior alveolar nerve. Coronectomy can be useful in this setting and therefore it is important to be aware of the pros and cons of this technique. PMID- 26749791 TI - Dental Materials: What Goes Where? Class V Restorations. AB - A large number of Class V restorations are placed per annum to restore cervical lesions. This paper evaluates the pathogenesis of these lesions, with particular reference to the role of occlusal factors, and reviews the literature in order to provide advice on the material(s) which are most likely to produce optimal longevity of a Class V restoration. CPD/CLINICAL RELEVANCE: Resin-modified glass ionomer materials appear to provide optimal survival for a Class V restoration, but a (flowable) comDosite miaht Droduce a better aesthetic result. PMID- 26749792 TI - A New Generation of Antiplatelet, and Anticoagulant Medication and the Implications for the Dental Surgeon. AB - The management of dental patients taking either antiplatelet medication, anticoagulant medication or both has been well established in the previous literature. Recently, new generations of drugs have emerged which are becoming increasingly common, including direct thrombin inhibitors, factor X inhibitors and a new class of oral thienopyridines. The implications of these drugs for the dental surgeon are not yet fully known. Awareness remains low and there is very little information available within the literature on safe use during surgery. This review paper aims to provide some guidance for dental practitioners performing invasive procedures. CPD/CLINICAL RELEVANCE: A new generation of anticoagulant and antiplatelet drugs have serious implications for patients undergoing surgery and their use is increasing. PMID- 26749793 TI - Pain Part 5b: Non-Odontogenic Dysfunctional Pain. AB - Orofacial chronic pain provides a significant challenge to all clinicians and the patients seeking treatment for it. Due to the anatomical and regional complexities, diagnosis can be extremely difficult, and due to the lack of cross specialty training, patients will undergo a variety of treatment under different disciplines. Dysfunctional pain provides a unique challenge for patient management and requires a multidisciplinary team. CLINICAL RELEVANCE: Lack of recognition of dysfunctional chronic pain can result in inappropriate dental treatment and further damage. to the patient. Appropriate patient reassurance and referral to an orofacial pain multidisciplinary team is recommended as most of these conditions require medical management. PMID- 26749794 TI - Mouth Cancer for Clinicians Part 6: Potentially Malignant Disorders. AB - A MEDLINE search early in 2015 revealed more than 250,000 papers on head and neck cancer; over 100,000 on oral cancer; and over 60,000 on mouth cancer. Not all publications contain robust evidence. We endeavour to encapsulate the most important of the latest information and advances now employed in practice, in a form comprehensible to healthcare workers, patients and their carers. This series offers the primary care dental team, in particular, an overview of the aetiopathogenesis, prevention, diagnosis and multidisciplinary care of mouth cancer, the functional and psychosocial implications, and minimization of the impact on the quality of life of patient and family. CLINICAL RELEVANCE: This article offers the dental team an overview of oral potentially malignant disorders. PMID- 26749795 TI - Periodontal Disease, Dental Implants, Extractions and Medications Related to Osteonecrosis of the Jaws. AB - Patients taking bisphosphonates and other anti-resorptive drugs are likely to attend general dental practice. The term 'bisphosphonate'is often immediately associated with osteonecrosis of the jaws (ONJ). Risk assessment and subsequent management of these patients should be carried out taking into account all the risk factors associated with ONJ. The introduction of newer drugs, also shown to be associated with ONJ, demands increased awareness of general dental practitioners about these medications. CPD/CLINICAL RELEVANCE: This paper provides an update on medication-related ONJ and considers the effects of anti resorptive drugs on the management of patients needing exodontia, treatment for periodontal disease and dental implant placement. PMID- 26749796 TI - Clinical Challenges Q&A 15. Brown Discoloration of Permanent Dentition. PMID- 26749797 TI - Technique Tips - A Direct Wax-up Technique for an Immediate Provisional Crown. PMID- 26749798 TI - Re-Discovery of the Plant Kingdom as a Valuable Source of Novel Drugs. Preface. PMID- 26749799 TI - Antimicrobial Activity of neo-Clerodane Diterpenoids isolated from Lamiaceae Species against Pathogenic and Food Spoilage Microorganisms. AB - Antimicrobial activity of nineteen neo-clerodane diterpenoids, isolated from the acetone extracts of the aerial parts of Scutellaria and Salvia species (Lamiaceae) were tested against thirteen strains belonging to nine different species of pathogenic and food spoilage bacteria Aeromonas hydrophila, Bacillus cereus, Escherichia coli, Listeria monocytogenes, Proteus vulgaris, Pseudomonas aeruginosa, Pseudomonas fluorescens, Salmonella abony and Staphylococcus aureus as well as against two yeast strains belonging to species Candida albicans. Seven of the evaluated compounds scutalpin A, scutalpin E, scutalpin F, salviarin, splenolide A, splenolide B and splendidin demonstrated antimicrobial activity against used test microbial strains, the rest of the compounds were inactive within the studied concentration range. Among all of the tested compounds the highest antimicrobial activity was detected for scutalpin A against Staphylococcus aureus (MIC 25 ug/mL). PMID- 26749800 TI - Study of an Acid-Free Technique for the Preparation of Glycyrrhetinic Acid from Ammonium Glycyrrhizinate in Subcritical Water. AB - The aim of this work was to study an application of a previously developed expedient acid-free technique for the preparation of glycyrrhetinic acid from ammonium glycyrrhizinate that requires no use of acids and toxic organic solvents. Subcritical water that serves as a reactant and a solvent was used in order to obtain glycyrrhetinic acid in good yields starting from ammonium glycyrrhizinate. It has been shown that variation of only one parameter of the process (temperature) allows alteration to thecomposition of the hydrolysis products. A new method was used for the synthesis of glycyrrhetinic acid (glycyrrhizic acid aglycone) and its monoglycoside. HPLC combined with mass spectrometry and NMR spectroscopy were used to determine the quantitative and qualitative compositions of the obtained products. The method developed for the production of glycyrrhetinic acid in subcritical water is environmentally friendly and faster than conventional hydrolysis methods that use acids and expensive and toxic organic solvents. The proposed technique has a potential for the future development of inexpensive and environmentally friendly technologies for production of new pharmaceutical plant-based substances. PMID- 26749801 TI - New Flavonol Glycoside from the Leaves of Ventilago africana. AB - A new flavonol diglycoside, rhamnocitrin-3-O-alpha-L-rhamnopyranosyl-(1-->6)-beta D-galactopyranoside, was isolated from the leaves of Ventilago Africana, in addition to 11 known flavonoids. Their structures were determined by spectroscopic methods including 1D- and 2D-NMR, and HR-ESI-MS analysis. The isolated compounds were evaluated for their antioxidant activity by using DPPH radical-scavenging assay. Compounds 4, 7-9 have discrete to good antioxidant potential with EC50 values ranging from 20.9 to 40.4 uM, compared with ascorbic acid (EC50 60 uM) used as positive control. PMID- 26749802 TI - Change in the Chemical Profile of Mangifera indica Leaves after their Metabolism in the Tropidacris collaris Grasshopper. AB - This present work addresses research on the discovery of new compounds from natural sources. It is based on a study of Mangifera indica leaf metabolism by the Tropidacris collaris grasshopper. We found that the grasshopper hydrolyzed the flavonoid isoquercitrin to quercetin when the O-glycosidic bond was broken and sugar released as a probable energy source for the insect. There was not, however, hydrolysis of the major compound in the leaves, mangiferin, which contains the C-glycosidic bond. All compounds were isolated and their chemical structure determined by UV, IR, MS, 1H and 13C NMR. PMID- 26749803 TI - Complexes of Lapachol and Lawsone with Lanthanides. AB - Naturally occurring 2-hydroxy-1,4-naphthoquinones are well known to form readily stable complexes with transition metals. In this short communication we describe for the first time the synthesis and preliminary data about structural characterization of complexes between two naturally widespread 2-hydroxy-1,4 naphthoquinones, namely lapachol (1) and lawsone (2), with selected lanthanides like lanthanum, gadolinium, and ytterbium. When tested as cytotoxic compounds, such complexes exhibited an activity that was either higher or equal to that of the parent naphthoquinone. PMID- 26749804 TI - Synthesis of the Furan Nucleus Promoted by Ytterbium Triflate. AB - An efficient synthesis of differently substituted furans from acetylene dicarboxylates and beta-dicarbonyl compounds is described. The furan nucleus was built by means of an Yb(OTf)3 catalyzed cycloaddition reaction yielding desired adducts in 91%-98% yield. PMID- 26749805 TI - Analysis of Organic Acids, Deacetyl Asperulosidic Acid and Polyphenolic Compounds as a Potential Tool for Characterization of Noni (Morinda citrifolia) Products. AB - Organic acids, deacetyl asperulosidic acid (DAA) and polyphenolic compounds in various noni (Morinda citrifolia L.) products (4 juices, 4 dry fruit powders and 2 capsules with dry fruit powder) were analyzed. Reversed-phase high-performance liquid chromatography (RP-HPLC) coupled with a variable wavelength detector (VWD) and electrospray ionization time-of-flight mass spectrometer (ESI-TOF MS) was applied for simultaneous analysis of organic acids (malic, lactic, citric and succinic acid) and DAA. An RP-HPLC method with diode-array detector (DAD) was developed for the analysis of polyphenolic compound content (rutin, catechin, quercitrin, kaempferol, gallic acid, caffeic acid and p-coumaric acid). The developed methods can contribute to better characterization of available noni products that is required from the consumers. In our study, we discovered significant dissimilarities in the content of DAA, citric acid and several phenolic compounds in some samples. PMID- 26749806 TI - Antioxidant Activity and Polyphenol Content of Some Brazilian Medicinal Plants Exploiting the Formation of the Fe(II)/2,2'-bipyridine Complexes. AB - Aqueous plant extracts contain polyphenols that reduce Fe3+ to Fe2+, which in the presence of excess 2,2'-bipyridine (bipy) yield the Fe(bipy)3(2+) complex (lambdamax = 521 nm). This reaction was used to quantify the total polyphenol content (TPC) of nineteen Brazilian medicinal species using pyrogallic acid (PA) as a standard. A calibration curve of absorbance values at 521 nm values vs. PA was linear from 0.378 to 3.03 mg L(-1) (r = 0.998; n = 8) with a limit of detection 0.16 mg L(-1). The TPC quantification using the proposed reaction was compared with values obtained with the Folin-Ciocalteu reagent, yielding good agreement (r = 0.965). For the same species the TPC obtained with the proposed method also resulted in good correlation (r = 0.773) with the antioxidant capacity values quantified using the 2,2-diphenyl-lI-picrylhydrazyl method. It was also found that Fe(bipy)3(2+) complexes can be used to calculate the reducing capability of polyphenols. The polyphenol structure, and the number and position of the hydroxyl group attached to the benzene ring modify this reductive capacity. PMID- 26749807 TI - Reactive Nitrogen Species Scavenging Capacity of Aqueous and Ethanolic Extracts from Galinsoga parviflora and G. quadriradiata Herbs. AB - The aim of the study was to determine the scavenging capacity of aqueous and ethanolic extracts derived from the herb of two species of Galinsoga against NO and ONOO-. In both tests the aqueous extracts of both Galinsoga species were more active than the ethanolic extracts. The highest scavenging activity against NO, and also against ONOO- was shown by G. quadriradiata aqueous extract (SC50 +/- SD = 1.54 +/- 0.32, and 2.10 +/- 1.98, respectively). The study showed that the activity of the extracts from both Galinsoga species is related not only to the presence of flavonoids but also to caffeic acid derivatives and caffeic acid. The results of this study partly explain the beneficial effects of Galinsoga herb extracts in the treatment of skin diseases. PMID- 26749809 TI - Lipid Metabolites from the Mushroom Meripilus giganteus. AB - The phytochemical investigation of the methanolic extract of the white rot fungus Meripilus giganteus resulted in the isolation and identification of complex mixtures of free fatty acids (1), monoacylglycerols (2), cerebrosides (3), ergosterol (4) and ergosterol peroxide (5). The structures of the isolated lipid metabolites (1-5) were determined by chemical and spectroscopic methods. The antioxidant activity of the whole MeOH extract of the fungus was evaluated through in vitro model systems, such as 2,2-diphenyl-l-picrylhydrazyl (DPPH) and superoxide anion. In all two systems, the results indicated that the extract of the fungus showed the same free-radical-scavenging activity with SC50 data of 47.70 ug/mL, compared with the positive control quercetin (DPPH assay). None of the isolated compounds (1-5) showed a significant activity. Compounds 2-4 were isolated from Meripilus giganteus for the first time. PMID- 26749808 TI - Combination of Antioxidants from Different Sources Could Offer Synergistic Benefits: A Case Study of Tea and Ginger Blend. AB - Tea and ginger are plants with high antioxidant potential. Combinations of antioxidants from different sources could also produce synergistic antioxidant effects. This study investigated the influence of solvent on antioxidant content of tea, ginger, and tea + ginger blends. Under the investigated extraction conditions, water was the most effective extraction solvent to maximise peroxide scavenging and iron chelating activity of tea, ginger, and their blends. Aqueous ethanol was the most effective solvent to maximise ABTS radical scavenging activity and ethanol was the best solvent to maximise DPPH radical scavenging activity. A good multivariate regression model that explains the relationship between the total flavonoid content of the extracts and their antioxidant activities was obtained (R2 and Q2 of 0.93 and 0.83, respectively). Extracts of tea-ginger blends exhibited synergistic effects in their ABTS and DPPH radical scavenging activity. PMID- 26749810 TI - HPLC Analysis, Antioxidant, Anti-inflammatory and Xanthine Oxidase Inhibitory Activity of Cudrania tricuspidata. AB - Cudrania tricuspidata is a plant used in folk medicine in Korea for treatment of diseases related to oxidative stress and inflammation. In this study the leaf and shoot extract was studied for its antioxidant, anti-inflammatory, and xanthine oxidase (XO) inhibitory activities. The extract with predominant phenolics was quantified using HPLC-DAD. Antioxidant activity was measured using ABTS [2,2' azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) and FRAP (ferric ion reducing antioxidant power), and anti-inflammatory activity by diene-conjugate and beta glucuronidase assays. The average antioxidant effects of C. tricuspidata extracts (1-2 mg/mL) revealed significant activity of 32.5% to 50.2% (ABTS) and 24.2 to 40.5% (FRAP) compared with Trolox, having 55.1% (ABTS) and 42.6% (FRAP) activity, respectively. The anti-inflammatory activities showed as 26.5% to 40.5% (DC) and 40.2% to 70.2% (betaG) inhibition compared with the control {phenylbutazone; 42.1% (DC) and 80.2% (betaG) inhibition, respectively}. The XO inhibitory activity of the plant extract revealed 90.5% inhibition of that of the control (allopurinol) (97% inhibition at 100 ug/mL concentration). The kinetic parameters of XO inhibition revealed a noncompetitive type of inhibition, where, Km and Vmax of C. tricuspidata extracts (25 to 100 ug/mL) were 0.25 mM/mL and 0.040, 0.036, 0.032, and 0.030 (ug/min), while for the positive control Km and Vmax the values were 0.30 mM/mL and 0.045 (ug/min), respectively. Results suggest that C. tricuspidata can be exploited against diseases associated with free radical formation and xanthine oxidase activity. PMID- 26749811 TI - Renoprotective Effects, Protein Thiols and Liver Glycogen Content of Alloxan induced Diabetic Rats Treated with Different Fractions of Heartwood of Pterocarpus marsupium. AB - Oxidative stress is believed to be a pathogenic factor in the development of diabetic complications. In the present study, we aimed to evaluate the effects of different fractions of heart wood of Pterocarpus marsupium on antioxidant enzyme like protein thiols and also check the efficacy of the extract for the protection of the renal function in alloxan induced diabetic rats. The present study also investigates the levels of liver glycogen which are considered as the best biomarker for assaying the hypoglycemic activity of any drug. Diabetes was induced by administering alloxan dissolved in saline, while the normal control group was given propylene glycol. Diabetes induced animals were randomly assigned into different groups. Blood samples were collected from all the experimental and control groups. Estimation of urea, uric acid and creatinine along with protein thiols was made on day 30 only. At the end, all the animals were sacrificed to collect liver tissue to analyze glycogen content. The 30 days treatment with various extracts (75 mg/kg body wt) significantly lowered protein thiol levels, which probably represents increased utilization for neutralizing free radicals. There was no significant increase in the levels of renal parameters in the extract treated groups which revealed that the employed dose of the extract is nontoxic to the kidney. There was also a significant decrease in the glycogen content in insulin and alcohol-extract treated groups and should be encouraging for the treatment of diabetes mellitus. The extract showed a promising antioxidant effect, as well as hypoglycemic activity, and should be encouraged for the treatment of diabetes. PMID- 26749812 TI - Medicinal Plants Used by a Mbya-Guarani Tribe Against Infections: Activity on KPC Producing Isolates and Biofilm-Forming Bacteria. AB - The traditional use of medicinal plants for treatment of infectious diseases by an indigenous Mbya-Guarani tribe from South Brazil was assessed by evaluating the antibiotic and antibiofilm activities against relevant bacterial pathogens. Aqueous extracts from 10 medicinal plants were prepared according to indigenous Mbya-Guarani traditional uses. To evaluate antibiotic (OD600) and antibiofilm (crystal violet method) activities, Pseudomonas aeruginosa ATCC 27853, Staphylococcus epidermidis ATCC 35984 and seven multi-drug resistant Klebsiella pneumoniae carbapenemase (KPC)-producing bacterial clinical isolates were challenged with the extracts. Furthermore, the susceptibility profile of KPC producing bacteria and the ability of these isolates to form biofilm were evaluated. The plants Campomanesia xanthocarpa, Maytenus ilicifolia, Bidens pilosa and Verbena sp. showed the best activity against bacterial growth and biofilm formation. The majority of KPC-producing isolates, which showed strong ability to form biofilm and a multidrug resistance profile, was inhibited by more than 50% by some extracts. The Enterobacter cloacae (KPC 05) clinical isolate was the only one resistant to all extracts. This study confirms the importance of indigenous traditional medicinal knowledge and describes for the first time the ability of these plants to inhibit biofilm formation and/or bacterial growth of multi-drug resistant KPC-producing isolates. PMID- 26749813 TI - Chemistry and Pharmacognosy of the Genus Durio. AB - Durio is well known as one of the sources of seasonal fruit production in Southeast Asia with its center of diversity in Borneo. Thailand, Indonesia, and Malaysia are the main Durio producers in the world. Besides having much information about the utilization and benefit from its timber and fruits as a food substance, traditionally some parts of this plant, such as leaves, bark and root, can also be used for medical purposes. This review deals with chemical constituents and the biological activities of Durio plants. PMID- 26749814 TI - General Characteristics, Phytochemistry and Pharmacognosy of Lippia sidoides. AB - Lippia sidoides Cham. is a plant that belongs to the family Verbenaceac and is commonly known as "alecrim-pimenta". It was first found in northeastern Brazil, where it is extensively used in traditional medicine. Many studies have been made with the essential oil of L. sidoides, which has a high content of the isomeric compounds thymol and carvacrol. L. sidoides extracts, and particularly the essential oil extracted from its aerial parts, have shown many biological activities such as antifungal, antibacterial, and insecticidal. Given the great biological potentialities of L. sidoides and the amount of recent studies about this plant, the present study aimed to make a survey of its general attributes, cultivation methods, chemical characterization of its extracts and essential oil, as well as its different biological activities. PMID- 26749815 TI - Poplar-type Propolis: Chemical Composition, Botanical Origin and Biological Activity. AB - Propolis is one of the most used natural products known for centuries for its beneficial effects. Due to significant differences in chemical composition of samples originating from different geographic and climatic zones it is crucial to characterize reliably each type of propolis. This article comprises the latest findings concerning the poplar type propolis, i.e. it gives a cross section of chemical composition, botanical origin and biological activity of poplar type propolis in order to encourage further investigations that would indicate its beneficial effects. PMID- 26749816 TI - Activities of Tannins--From In Vitro Studies to Clinical Trials. AB - Tannins are considered as valuable plant secondary metabolites providing many benefits for human health. In this review information was gathered about bioactivity in vitro and in vivo, as well as about conducted clinical trials. The literature research was based on ScienceDirect, Scopus, and Cochrane databases and presents a wide range of tested activities of tannins. The described clinical trials verify laboratory tests and show the effective health benefits taken from supplementation with tannins. PMID- 26749817 TI - Organoselenium Compounds as Phytochemicals from the Natural Kingdom. AB - Selenium is naturally present in soils but it is also produced by pollution from human activities into the environment. Its incorporation into plants affords organoselenium metabolites that, depending on the nature of the molecules and the plant species, can be incorporated into proteins, stored or eliminated by volatilization. The possibility to use the selenium metabolism of some plants as a method for bioremediation and, at the main time, as a source of selenated phytochemicals is here discussed taking into consideration the growing interest in organic selenium derivatives as new potential therapeutic agents. PMID- 26749818 TI - Spasmolytic Activity of Carvone and Limonene Enantiomers. AB - Aromatic plants produce volatile substances with high therapeutic potential. In view of the need for new respiratory and cardiovascular system pharmacological agents, the present study reports on the spasmolytic activity of two enantiomers of carvone and limonene, constituents of essential oils. The enantiomers tested showed pharmacological activity in Guinea pig trachea and rat aorta smooth muscle. No differences were observed in the pharmacological profiles of the enantiomer pairs. The oxygenated monoterpenes (+)-carvone and (-)-carvone were pharmacologically more effective than the hydrocarbon monoterpenes (+)-limonene and (-)-limonene. The results of this study show the therapeutic potential of these compounds found in many aromatic plants for the treatment of respiratory and cardiovascular system diseases. PMID- 26749820 TI - Constituents of the Stem of Nauclea orientalis. AB - A new alpha-pinene derivative (1) was isolated from the stem of Nauclea orientalis (L.) L. (Rubiaceae), together with twelve known compounds, including four terpenoids, loganetin (2), loganin (3), sweroside (4), grandifloroside (5), four simple phenols, methyl protocatechuate (6), trans-p-coumaric acid (7), 3 (2,4- dihydroxylphenyl)propanoic acid (8), methyl 3-(2,4 dihydroxylphenyl)propanoate (9), two coumarin glucosides, skimmin (10), adicardin (11), an anthraquinone, aloe emodin (12), and a lignan, (+)-pinoresinol (13). Their structures were elucidated on the basis of spectroscopic data. All compounds were tested for DPPH free radical scavenging and lipid peroxidation inhibitory activities. Among them, compounds 5 and 6 displayed strong antioxidant activity with IC50 values of 6.6 and 67.9 uM, 12.4 and 813.0 uM, respectively. PMID- 26749819 TI - New Glycosides and Trypanocidal Metabolites from Vangueria edulis. AB - A new iridoid glucoside, 10-methoxy apodanthoside (1), and a new monoterpene glycoside, (3S,6S)-cis linalool-3,7-oxide O-beta-D-glucopyranosyl-(1"-->5')-beta D- xylofuranoside (2), were isolated from V. edulis (Rubiaceae), along with eighteen known compounds (3-20), including monoterpenes, iridoid glycosides, and a lignin, which were encountered for the first time in the genus Vangueria,. The structural elucidation of the isolates was based on the analysis of spectroscopic (1D and 2D NMR) and HR-ESI-MS data. Detailed stereochemical studies of 1 and related iridoid glucosides (compounds 3, 4 and 8) were made by matching the calculated ECD peaks with the experimental ones. All isolates were tested for their antiprotozoal, antifungal, and antiplasmodial activities. Compounds 9, 15 and 16 showed good trypanocidal activities against Trypanosoma brucei brucei with IC50 values of 8.18, 9.02 and 7.80 ug/mL, respectively and IC90 values of > 10, > 10 and 9.76 ug/mL, respectively. Compound 16 showed a moderate activity against Candida glabrata with an IC50 value of 8.66 ug/mL. Compound 20 showed a weak antiplasmodial activity against chloroquine-sensitive (D6) and resistant (W2) Plasmodium falciparum with IC50 values of 3.29 (SI, > 1.4) and 4.53 (SI, > 1) ug/mL, respectively. PMID- 26749821 TI - Deodarone Isomers in Cedrus atlantica Essential Oils and Tar Oils. AB - Deodarone [2,2,6-trimethyl-6-(4-methylcyclohex-3-enyl)-tetrahydro-4-pyrone] is a sesquiterpene tetrahydro-gamma-pyrone related to bisabolene and atlantone, first isolated from Cedrus deodora essential oil. With respect to the stereochemistry of the asymmetric carbons C4 and C8, two diastereoisomers may be distinguished. Identification and quantification of both diastereoisomers in wood and tar oils from C. atlantica has been achieved using 13C NMR spectroscopy, in combination with GC (polar column). The contents of (4R,8R)- and (4R,8S)-deodarone varied between 1.1-2.8% and 1.0-3.0%, respectively. PMID- 26749822 TI - A New Trinor-guaiane Sesquiterpene from an Indonesian Soft Coral Anthelia sp. AB - A new trinor-guaiane sesquiterpene has been isolated from an Indonesian soft coral Anthelia sp. The planar structure, possessing an octahydroazulene skeleton, and relative stereochemistry were established by analyzing 1D and 2D NMR data, including NOE experiments. Its absolute stereochemistry was elucidated to be 1S, 4S, 7R, and 10R by comparing observed and calculated optical rotation values. The new compound showed weak cytotoxicity against NBT-T2 cells. PMID- 26749824 TI - A New Isocyanosesquiterpene from the Nudibranch Phyllidiella pustulosa. AB - In the course of our study on the chemical and genetic diversity of the nudibranch Phylidiella pustulosa, we identified a series of isocyanosesquiterpenes. In addition to known sesquiterpenes, we isolated a new molecule 1, the structure of which was elucidated by analyzing NMR and other spectral data. We report the structure and cytotoxicity of compound 1 herein. PMID- 26749823 TI - A New Cytotoxic Gymnomitrane Sesquiterpene from Ganoderma lucidum Fruiting Bodies. AB - A new gymnomitrane-type sesquiterpenoid, gymnomitrane-3alpha,5alpha,9beta,15 tetrol (1), was isolated from the fruiting body of Ganoderma lucidum. Its structure was elucidated using spectroscopic methods. This compound significantly inhibited the growth of epidermal growth factor receptor-tyrosine kinase inhibitor EGFR-TKI-resistant human lung cancer A549 and human prostate cancer PC3 cell lines. PMID- 26749825 TI - Antimicrobial Diterpenes from Azorella Species Against Gram-Positive Bacteria. AB - The present study was aimed at evaluating the antibacterial activity of mulinane and azorellane diterpenes isolated from the Andean plants Azorella compacta and A. trifoliolata and semisynthetic derivatives against reference and multidrug resistant strains. The results revealed that the semisynthetic compound 7-acetoxy mulin-9,12-diene (5) exhibited antibacterial activity against reference and multidrug-resistant strains of Staphylococcus aureus and moderate antimycobacterial activity against Mycobacterium smegmatis ATCC 14468. PMID- 26749826 TI - A Novel Norclerodane Diterpenoid from the Roots of Croton crassifolius. AB - A chemical investigation of Croton crassifolius afforded a novel norclerodane diterpenoid (1) with an unprecedented six-membered oxygen ring between C-1 and C 12, together with three known compounds. The structure of the new compound was elucidated based on spectroscopic (IR, 1D, and 2D NMR) and HR-ESI-MS techniques. This report describes the first example of a natural norclerodane with a 4H chromene ring system. PMID- 26749827 TI - Production of Triterpenoid Sapogenins in Hairy Root Cultures of Silene vulgaris. AB - Silene vulgaris (Moench) Garcke (Caryophyllaceae) is widely distributed in North America and contains bioactive oleanane-type saponins. In order to investigate in vitro production of triterpenoid saponins, hairy root cultures of S. vulgaris were established by infecting leaf explants with five strains of Agrobacterium rhizogenes (LBA9402, R1000, A4, 13333, and 15834). The A. rhizogenes strain LBA9402 had an infection of 100% frequency and induced the most hairy roots per plant. Methyl jasmonate (MeJA)-induced changes in triterpenoid saponins in S. vulgaris hairy roots were analyzed. Accumulation of segetalic acid and gypsogenic acid after MeJA treatment was 5-and 2-fold higher, respectively, than that of control root. We suggest that hairy root cultures of S. vulgaris could be an important alternative approach to the production of saponins. PMID- 26749828 TI - Extraction and Isolation of Antineoplastic Pristimerin from Mortonia greggii (Celastraceae). AB - The aim of this research was to identify, extract and isolate pristimerin in leaves, stems and roots of the Mexican plant Mortonia greggii (Celastraceae). The principal objective was to determine the best laboratory experimental conditions for the extraction and isolation of this powerful natural anticancer agent from the root tissue. Six experimental factors in solid-liquid pristimerin extraction were analyzed: solvent systems, number of extractions, ratio of plant weight (g)/solvent volume (mL) used, time of extraction, temperature and agitation. A mathematical model was generated for pristimerin purity and yield. Ethanol, first extraction, 0.5 ratio of plant weight/solvent volume (g/mL), 0.5 h, 200 rpm and 49.7 degrees C were optimal conditions for the extraction of this phytochemical. The degree of purification of pristimerin root extract was studied by size exclusion chromatography (SEC) using Sephadex LH-20 reaching fractions with purification indexes (PI) greater than 2 and recoveries of 28.3%. When fractions with purification indices higher than 1 and less than 2 were accumulated, the recovery of pristimerin increased by about 73.6%. By combining the optimum extracts and SEC purification protocols, an enriched fraction containing 245.6 mg pristimerin was obtained from 100 g of root bark, representing about 14.4%, w/w, pristimerin from the total solids presented in the fraction. PMID- 26749829 TI - Bioassay-guided Isolation of Antiproliferative Triterpenoids from Euonymus alatus Twigs. AB - Euonymus alatus (Celastraceae) has been used as an anticancer agent in Korean traditional medicine. However, the potential bioactive contributors to the anticancer effects have not been thoroughly studied. Our screening test revealed that the MeOH extract of E. alatus twigs exhibited significant cytotoxicity against A549, SK-OV-3, and SK-MEL-2 cell lines. A bioassay-guided separation of the MeOH extract of E. alatus twigs resulted in the isolation and identification of 14 triterpenes as main phytochemicals. The structures of the compounds were elucidated on the basis of spectroscopic evidence as lupeol (1), betulin (2), 3beta,28,30-lup-20(29)-ene triol (3), lupenone (4), betulone (5), 28,30-dihydroxy 3-oxolup-20(29)-ene (6), messagenin (7), glut-5-en-3beta-ol (8), maslinic acid (9), hederagenin (10), 3-oxo-11alpha-methoxyolean-12-ene (11), 3beta-hydroxy-1 oxo-olean-12-en-28-oic acid (12), ursolic acid (13), and 2a-hydroxy- ursolic acid (14). Of these compounds, 3, 6-8, and 10-14 were isolated for the first time from this plant. All isolated triterpenoids had consistent antiproliferative activities against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines. Compounds 2, 5, and 7 showed significant cytotoxicity against all four cell lines tested, with IC50 values of 3.26-8.61 uM. PMID- 26749830 TI - Two New Triterpenoidal Saponins from Roots of Pachystela msolo. AB - Two new triterpenoidal saponins, pachystelanosides A (1) and B (2), and six known compounds have been isolated from the roots of Pachystela msolo. Their structures were elucidated on the basis of extensive ID and 2D NMR studies ('H, "C, DEPT, COSY, TOCSY, NOESY, HSQC, HMBC), and ESI-MS as 3-O-(beta-D-glucopyranosyl-(1-->2) beta-D-apiofuranosyl-(1-->6)-beta-D-glucopyranosyl)-28-O-(beta-D-xylopyranosyl-(1 -4)[alpha-L-rhamnopyranosyl-(1-->2)}-alpha-L-arabino- pyranosyl) hydroxyprotobassic acid (1) and 3-O-(beta-D-glucopyranosyl-(1-->2)-beta-D apiofuranosyl-(1-->6)-beta-D-glucopyranosyl)-28-O-(beta-D-xylopyranosyl- (1- >4)[alpha-L-rhamnopyranosyl-(1-->2)]-alpha-L-arabinopyranosyl)-7alpha hydroxyprotobassic acid (2). PMID- 26749831 TI - The Influence on LPS-Induced ROS Formation in Macrophages of Capelloside A, a New Steroid Glycoside from the Starfish Ogmaster capella. AB - A new steroid glycoside, capelloside A (1), was isolated from the ethanolic extract of the startish Ugmaster capella along with the previously known coscinasteroside B (2). The structures of 1 was elucidated by extensive NMR and ESI-MS techniques as (24S)-24-O-(3-O-methyl-beta-D-xylopyranosyl)-5a- cholestane 3beta,6beta,8,15alpha,24-pentoI 15-O-sulfate (1). Compounds 1 and 2 decreased intracellular ROS (reactive oxygen species) levels in murine macrophages of the RAW 264.7 cell line at induction by endotoxic lipopolysaccharide (LPS) from E. coli by 60% and 41%, correspondingly. PMID- 26749832 TI - Steroidal Saponins from the Mesocarp of the Fruits of Raphia farinifera (Arecaceae) and their Cytotoxic Activity. AB - Eight steroidal saponins (1-8), including one previously unreported derivative (1), have been isolated from the mesocarp of Raphia farinifera fruits by combined column chromatography and RP-HPLC methods. They were characterized by spectroscopic (1D and 2D NMR experiments) and spectrometric (ESIMS) methods, as well as by comparison of their spectral data with those of reported compounds in the literature. All the isolated compounds were tested for cytotoxicity against urinary bladder carcinoma cells (ECV-304). Our results revealed that, for a high cytotoxicity, a sugar chain of at least three sugar moieties attached to C-3 of the steroidal saponin is necessary. PMID- 26749833 TI - Bromotyrosine Alkaloids with Acetylcholinesterase Inhibitory Activity from the Thai Sponge Acanthodendrilla sp. AB - Twenty bromotyrosine alkaloids, including a new compound, 13-oxosubereamolline D (5), were isolated from the Thai sponge Acanthodendrilla sp. Their structures were determined by analyses of 1D- and 2D-NMR, high-resolution mass, and circular dichroism data. The complete 1H and 13C NMR assignments of 5,7beta dichlorocavernicolin (19) and 5,7alpha-dichlorocavernicolin (20) are described herein for the first time. The acetylcholinesterase (AChE) inhibitory activity of all isolated compounds was evaluated. Only homoaerothionin (7) and fistularin 1 (10) exhibited inhibitory activity against human recombinant AChE (hrAChE) with IC50s of 4.5 and 47.5 uM, respectively. The hrAChE inhibition kinetics of 7, the most potent alkaloid, showed increased Km and unchanged Vmaxvalues, suggesting its competitive mode of inhibition. The spirocyclohexadienylisoxazole and the length of the alkyl diamine linkage were proposed as the crucial parts for its strong inhibitory activity. This finding indicates a therapeutic potential for 7 in acetylcholine-related diseases, most importantly Alzheimer's disease. PMID- 26749834 TI - Ircinal E, a New Manzamine Derivative from the Indonesian Marine Sponge Acanthostrongylophora ingens. AB - Chemical investigation of the MeOH extract of the sponge Acanthostrongylophora ingens afforded the new manzamine derivative ircinal E (1), in addition to six known metabolites (2-7). The structure of the new compound was unequivocally elucidated using one- and two-dimensional NMR spectroscopy, as well as high resolution mass spectrometry. Compounds 1-6 exhibited strong to moderate cytotoxicity against the murine lymphoma L5178Y cell line with IC50 values ranging from 2.8 to 21.7 uM. PMID- 26749835 TI - Ruta graveolens Extracts and Metabolites against Spodoptera frugiperda. AB - The biological activity of Ruta graveolens leaf tissue extracts obtained with different solvents (ethyl acetate, ethanol, and water) and metabolites (psoralen, 2- undecanone and rutin) against Spodoptera frugiperda was evaluated. Metabolites levels in extracts were quantified by HPLC and GC. Ethyl acetate and ethanol extracts showed 94% and 78% mortality, respectively. Additionally, psoralen metabolite showed a high mortality as cypermethrin. Metabolite quantification in extracts shows the presence of 2-undecanone (87.9 umoles mg(-1) DW), psoralen (3.6 umoles mg(-1) DW) and rutin (0.001 pmoles mg(-1) DW). We suggest that these concentrations of 2-undecanone and psoralen in R. graveolens leaf tissue extracts could be responsible for S. frugiperda mortality. PMID- 26749836 TI - A New Isoflavone Apioglucoside from the Roots of Dalbergia spinosa. AB - Targeting the discovery of novel natural products, the roots of Dalbergia spinosa Roxb has yielded a new isoflavone apioglycoside, 5-hydroxy-6-methoxy- 3',4' methylenedioxy-7-[(6-O-beta-D-apiofuranosyl-beta-D-glucopyranosyl) oxy]isoflavone (dalspinin-7-O-beta-D-[apiofuranosy (1-->6)] glucopyranoside) (1), together with the known isoflavones, dalspinin (2), dalspinosin (3) and caviunin (4). Their structures were elucidated on the basis of extensive spectral and chemical evidence. To the best of our knowledge, this is the first report of the occurrence of an apioglucoside of dalspinin in Nature. PMID- 26749837 TI - Antioxidant and alpha-Glucosidase Inhibitory Properties and Chemical Profiles of Moroccan Propolis. AB - The chemical profiles of propolis hydroalcoholic extracts from different regions of Morocco were studied by gas chromatography coupled to mass spectrometry after silylation. Samples from Khamissat and Imouzzer belong to the poplar type, as typical poplar flavonoids predominated. Propolis from Rabat also contained high percentage of flavonoids, but had significantly lower amount of phenolic acid esters and contained no pinobanksin-3-O-acetate. Propolis from Bhalil demonstrated a profile rich in diterpenes (74.3%), and is a typical Mediterranean propolis sample. All samples had the capacity for inhibiting glucosidase and amylase enzymes, as well as the capacity for scavenging free radicals and preventing lipid peroxidation. Both activities were significantly higher in the flavonoids-rich samples. PMID- 26749838 TI - A Novel Acylated Anthocyanin with a Linear Trisaccharide from Flowers of Convolvulus althaeoides. AB - An acylated anthocyanin trioside was isolated from pink flowers of Convolvulus althaeoides using a combination of chromatographic techniques. On the basis of MS (MALDI-TOF) and NMR (1H NMR, 1H-1H COSY, 1D TOCSY, HSQC, HMBC, 13C CAPT) its structure was determined as cyanidin 3-O-[6-O-(4-O- (6-O-(E-caffeoyl)-beta-D glucopyranosyl)-beta-L-rhamnopyranosyl)-beta-D-glucopyranoside]-5-O-beta-D glucopyranoside. The absolute configuration of the aldose enantiomer moieties was determined from the separation of the corresponding thiazolidine diastereoisomer derivatives by HPLC-DAD. This is a novel trisaccharide within the flavonoids, and the first complete characterization of a linear glucosyl-rhamnosyl-glucoside (4' glucosylrutinoside) within the anthocyanins. Whilst acylation of rhamnose moieties in position 4 is quite common, the occurrence in anthocyanins of a glycosylated rhamnose is a unique trait. Although many complex anthocyanins have been found amongst the Convolvulaceae, the genus Convolvulus had not yet been surveyed for anthocyanins and thus this account could be of significance within the current chemotaxonomy of this family. PMID- 26749839 TI - Bioactive Xanthones from Cratoxylum cochinchinense. AB - Chemical investigation of Cratoxylum cochinchinense stem bark has led to the isolation and identification of a new xanthone, cochinchinone M (1), together with 12 known compounds. Their structures were elucidated on the basis of spectroscopic methods, including UV, IR, NMR and MS. Some compounds were evaluated for their antibacterial and acetylcholinesterase inhibitory activities. PMID- 26749840 TI - A New 3'-Prenyloxypsoralen from the Raw Fruits of Aegle marmelos and its Cytotoxic Activity. AB - One new furanocoumarin, 3'-prenyloxypsoralen (1), and two known furanocoumarins, imperatorin (2) and xanthotoxin (3) were isolated from the raw fruits of Aegle marmelos. The structures of the isolated coumarins were confirmed by spectroscopic evidence. Compound 1 exhibited moderate cytotoxic activity against HEK293, HeLa, MCF7, and HT29 cell lines with IC50 values of 31.2, 44.8, 36.3, and > 50.0 ug/mL, respectively. PMID- 26749842 TI - Three New Chlorinated Cyclopentenols, Palmaenols A and B and Palmaetriol, from the Discomycete Lachnum palmae. AB - The new chlorinated cyclopentenols, palmaenol A (1) and palmaetriol (3), were isolated from the culture broth of the discomycete Lachnum palmae (NBRC- 106495). In addition, a new chlorinated cyclopentenol, palmaenol B (2), a geometric isomer of 1, was also obtained from the culture broth containing KCl. The structures of 1-3 were elucidated from spectroscopic data. Compounds 1-3 are cyclopentenols containing three or two chlorines; 1 and 2 are also reduced forms of palmaenones A (4) and B (5), which have been isolated from the same discomycete, respectively. Compounds 4 and 5 had potent antimicrobial activity, while compounds 1-3 showed no such activity. Thus, it is suggested that the unsaturated carbonyl group at C-6 has an important role for the antimicrobial activity. PMID- 26749841 TI - New Gallotannin and other Phytochemicals from Sycamore Maple (Acer pseudoplatanus) Leaves. AB - The maple (Acer) genus is a reported source of bioactive (poly)phenols, including gallotannins, but several of its members, such as the sycamore maple (A. pseudoplatanus), remain uninvestigated. Herein, thirty-nine compounds, including a new gallotannin, 1,2,3-tri-O-galloyl-6-O-(p-hydroxybenzoyl)-beta-D- glucopyranoside (1), and thirty-eight (2-39) known compounds, consisting of four gallotannins, one ellagitannin, thirteen flavonoids, eight hydroxycinnamic acids, ten benzoic acid derivatives, and two sesquiterpenoids, were isolated from sycamore maple leaves. Their structures were determined based on NMR and mass spectral analyses. The isolates were evaluated for alpha-glucosidase inhibitory and antioxidant activities. Among the isolates, the gallotannins were the most potent alpha-glucosidase inhibitors with thirteen-fold more potent activity compared with the clinical drug, acarbose (IC50 = 16-31 vs. 218 uM). Similarly, the gallotannins showed the highest antioxidant activities, followed by the other phenolic sub-classes, while the sesquiterpenoids were inactive. PMID- 26749843 TI - Prebiotic Effects of Agave salmiana Fructans in Lactobacillus acidophilus and Bifidobacterium lactis Cultures. AB - Agave salmiana is a fructan rich species that is widely distributed in Mexico. The aim of this investigation was to extract the fructans of A. salmiana and evaluate their prebiotic effect in 48 hours in vitro cultures of Bifidobacterium lactis and Lactobacillus acidophilus and to compare this effect with other available fructan sources. A significant difference in pH, optical density and biomass was found in the cultures depending on the source of fructans and the type of bacteria. It was possible to determine a dose-response effect of the A. salmiana fructans and the growth of the studied strains. PMID- 26749844 TI - Synergy Effects of Three Plant Extracts on Protection of Gastric Mucosa. AB - The gastric mucosa protection effect of three natural plant extracts, Hericium erinaceus (HE), Centella asiatica (CA) and Amomum villosum (AV), were evaluated using the indomethacin damage model. Compared with a single extract, a combination of HE/CA/AV, especially with the ratios of 80:10:10, 45:45:10 and 45:10:45, showed significant synergistic effects for protection of the gastric mucosa with gastric ulcer inhibition rates of 97.8 +/- 0.7%, 86.5 +/- 2.8% and 86.1 +/- 3.6%, respectively. Microscopic appearances of the gastric mucosa were carried out to help confirm the results. PMID- 26749845 TI - Aloe arborescens Extract Protects IMR-32 Cells against Alzheimer Amyloid Beta Peptide via Inhibition of Radical Peroxide Production. AB - Aloe arborescens is commonly used as a pharmaceutical ingredient for its effect in burn treatment and ability to increase skin wound healing properties. Besides, it is well known to have beneficial phytotherapeutic, anticancer, and radio protective properties. In this study, we first provided evidence that A. arborescens extract protects IMR32, a neuroblastoma human cellular line, from toxicity induced by beta amyloid, the peptide responsible for Alzheimer's disease. In particular, pretreatment with A. arborescens maintains an elevated cell viability and exerts a protective effect on mitochondrial functionality, as evidenced by oxygen consumption experiments. The protective mechanism exerted by A. arborescens seems be related to lowering of oxidative potential of the cells, as demonstrated by the ROS measurement compared with the results obtained in the presence of amyloid beta (1-42) peptide alone. Based on these preliminary observations we suggest that use ofA. arborescens extract could be developed as agents for the management of AD. PMID- 26749846 TI - Volatile Constituents of Three Piper Species from Vietnam. AB - The chemical compositions of the essential oils obtained by hydrodistillation of three Piper plants grown in Vietnam are reported. The analysis was achieved by means of gas chromatography with flame ionization detection (GC-FID) and gas chromatography coupled with mass spectrometry (GC-MS). The main constituents of the leaf oil of Piper majusculum Blume were beta-caryophyllene (20.7%), germacrene D (18.6%) and beta-elemene (11.3%). The quantitatively significant compounds of the volatile oils of P. harmandii C. DC were sabinene (leaves, 14.5%; stems, 16.2%), benzyl benzoate (leaves, 20.0%; stems, 29.40%) and benzyl salicylate (leaves, 14.1%; stems, 24.3%). Also, alpha-cadinol (17.0%) was identified in large proportion in the leaf oil. However, sabinene (leaves, 17.9%; stems, 13.5%), benzyl benzoate (leaves, 20.5%; stems, 32.5%) and beta-eudesmol (leaves, 13.8%; stems, 8.4%) were the main constituents of P. brevicaule C. DC. This is the first report on the volatile constituents of both P. harmandii and P. brevicaule. PMID- 26749847 TI - Volatile Constituents from the Flowers of Spathodea campanulata from the Venezuelan Andes. AB - The chemical composition is reported of the essential oil obtained by hydrodistillation of Spathodea campanulata P. Beauv. (Bignoniaceae) flowers collected in the Andes region of Venezuela. Thirty compounds were characterized, representing 96.5% of the total oil composition; benzyl benzoate (17.5%) was the major constituent. Others major components were a mixture of geranyl acetone with a-humulene (12.7%), beta-caryophyllene (9.5%), farnesyl acetone (6.0%), aromadendrene (4.3%), alpha-gurjunene (3.9%) and tricosane (3.7%). This is the first report related to the chemical composition of the essential oil of S. campanulata flowers. PMID- 26749848 TI - Composition and Variability of the Essential Oil of the Flowers of Lavandula stoechas from Various Geographical Sources. AB - Samples of flowers of wild Lavandula stoechas L. spp. stoechas populations were collected in three areas of Sicily (Italy) and were characterized in agronomic and chemical terms. Essential oil (EO) was extracted by hydrodistillation and analyzed by GC-FID and GC-MS. GC-FID and GC-MS analyses permitted identification of 89 compounds from the EO. The samples were separated into 3 groups using PCA (Principal Component Analysis) statistical method, with reference to the chemical composition of the EO. All three Sicilian populations of lavender were identified as the fenchone chemotype with percentage content ranged between 52.8-71.1%. The population of Partinico showed the highest dry weight of flowers per plant (221.3 g), but the lowest EO yield (0.37%). The essential oils of the three wild Sicilian populations of L. stoechas L. spp. stoechas showed a greater chemical differentiation than those obtained from other Mediterranean areas. PMID- 26749849 TI - Antioxidant and Anti-inflammatory Activities of Essential Oil and Extracts of Piper miniatum. AB - The chemical composition of the essential oil and antioxidant and anti inflammatory activities of the extracts from Piper miniatum were determined. GC and GC-MS analysis of the essential oil resulted in the identification of 64 components, accounting for 89.2% of the total. The major components were caryophyllene oxide (20.3%) and alpha-cubebene (10.4%). The antioxidant activity was evaluated by beta-carotene/linoleic acid bleaching, DPPH radical scavenging and total phenolic content. In the beta-carotene assay, the n-hexane extract showed the highest inhibition activity with 42.7%, while the oil gave 91.3%. The essential oil and extracts were tested for anti-inflammatory activity by using the TPA-induced mouse ear edema model and lipoxygenase assays. The essential oil exhibited significant activity in both models as an anti-inflammatory agent. The n-hexane extract showed strong activity with inhibition of 85.9% in the TPA induced mouse ear edema model, while the chloroform extract showed the highest activity with 94.2% in the lipoxygenase assay. PMID- 26749850 TI - Potential Skin Regeneration Activity and Chemical Composition of Absolute from Pueraria thunbergiana Flower. AB - The flower of Pueraria thunbergiana BENTH (PTBF) contains isoflavonoids and essential oil components. It has many biological and pharmacological activities, including anti-diabetes, anti-oxidant, and weight loss. However, its effect on skin regeneration remains unknown. In the present study, we isolated the absolute from PTBF through solvent extraction and determined the role of the absolute on skin regeneration-associated responses in human epidermal-keratinocytes (HaCats). The PTBF absolute, which contained 10 compounds, stimulated migration and proliferation and increased the phosphorylation of serine/threonine-specific protein kinase and extracellular signal-regulated kinasel/2 in HaCats. It induced type I and IV collagen synthesis in HaCats. In addition, treatment with PTBF absolute resulted in increased sprout outgrowth in HaCats. These findings suggest that PTBF absolute may participate in skin regeneration, probably through promotion of migration, proliferation, and collagen synthesis. PMID- 26749851 TI - Composition, in vitro Cytotoxicity, and Anti-mildew Activities of the Leaf Essential Oil of Machilus thunbergii from Taiwan. AB - This study investigated the chemical composition, in-vitro cytotoxicity, and anti mildew fungal activities of the essential oil isolated from the leaf of Machilus thunbergii from Taiwan. The essential oil was isolated using hydrodistillation in a Clevenger-type apparatus, and characterized by GC-FID and GC-MS. Eighty-three compounds were identified, representing 99.8% of the oil. The main components identified were n-decanal (26.6%), beta-caryophyllene (15.8%), alpha-humulene (10.8%), and beta-eudesmol (10.5%). The oil exhibited cytotoxic activity against human oral, liver, lung, colon, melanoma, and leukemic cancer cells. The active source compounds were beta-caryophyllene, a-humulene, and beta-eudesmol. The anti mildew activity of the leaf oil was also evaluated. Results showed that the leaf oil had excellent anti-mildew activity. For the anti-mildew activity of the leaf oil, the active source compound was determined to be beta-eudesmol. PMID- 26749852 TI - [Recent advances in the analysis of gibberellins plant hormones]. AB - Gibberellins (GAs) are a class of phytohormones that exert profound and diverse effects on plant growth and development, such as seed germination and leaf expansion. Up to now, 136 members of GAs have been identified and recognized. All known GAs are diterpenoid acids with similar chemical structures, only double bonds, hydroxyl numbers and locations on gibberellin alkane skeleton are different. However, the content of GAs in plants is of ultra trace levels (usually at ng/g and even pg/g levels) with little ultraviolet (UV) absorption, no fluorescence and no distinguishing chemical characteristics. Moreover, the matrix of plant samples is complicated. Thus, quantification of GAs is always extremely difficult. Nowadays, the bottle necks for the study of GAs in plants are due to the lack of efficient sample preparation and sensitive detection techniques. This article reviews the analytical methods for determination of GAs in recent years, hoping to provide some references to develop new methods and techniques. PMID- 26749853 TI - Molecularly imprinted polymers combination with deep eutectic solvents for solid phase extraction of caffeic acid from hawthorn. AB - Molecularly imprinted polymers (MIPs) with caffeic acid as template and non imprinted polymers (NIPs) materials were prepared in the same procedure. Field emission scanning electron microscopy (FE-SEM) and adsorption capacity test were used to evaluate characteristic of the new materials. MIPs, NIPs and C18 were used for rapid purification of caffeic acid from hawthorn with solid-phase extraction ( SPE) , and extract yields of caffeic acid with the proposed materials were 3.46 ug/g, 1.01 ug/g and 1.17 ug/g, respectively. To optimize the MIPs-SPE procedures, different kinds of elution solutions were studied. Deep eutectic solvents (DESs) were prepared by choline chloride (ChCl)-glycerol (1/2, n/n) and choline chloride-urea (1/ 2, n/n). Methanol was mixed with the two kinds of DESs (glycerol-based DESs, urea-based DESs) in different ratios (0.5:1, 1:1, 2:1, 3:1, 4:1, 5:1, v/v), and they were used to investigated as elution solutions in the above MIPs-SPE procedures. The results showed that MIPs were potential SPE materials, and methanol/ glycerol-based DESs (3 :1, v/v) had the best elution capability with the recovery of 82.32%. PMID- 26749854 TI - [Simultaneous determination of fifteen ultraviolet filters in sunscreen cosmetics by high performance liquid chromatography]. AB - An analytical method for the simultaneous determination of fifteen ultraviolet (UV) filters in sunscreen cosmetics was developed by high performance liquid chromatography (HPLC). Various cosmetic samples including lotions, emulsions, creams and waxes were firstly mixed thoroughly by adding tetrahydrofuran containing 2 g/L ammonium hydroxide followed by vortex and oscillation. If the wax samples were still homogenized incompletely, a ultrasonic oscillation protocol with heating to 50 degrees C was adopted. The homogeneous samples were then ultrasonically extracted by 80% aqueous methanol solution. After centrifugation and micropore filtration, the extracted components were separated on an XTerra MS C18 column with gradient elution by water containing 0. 1% (v/v) formic acid and methanol containing 0. 1% (v/v) formic acid, determined by a diode array detector (DAD) at 280 nm and 311 nm, and quantified using external standard method. Optimization for the pretreatment conditions of different matrices of cosmetics including sample dispersion solvents, extraction solvents and time were carried out. This developed method showed good linearity (r2 >= 0.999 1) and the limits of quantification (LOQs) were between 1.2 and 5.1 ug/g. The recoveries of the fifteen compounds ranged from 84.2% to 100.7% at three spiked levels with the relative standard deviations (RSDs) between 0.9% and 9.5%. The analytes were well separated and this analytical method proved to be sensitive and accurate, so it can be used in the practical determination of the fifteen UV filters in commercial sunscreen cosmetics. PMID- 26749855 TI - [Determination of sugars, organic acids and alcohols in microbial consortium fermentation broth from cellulose using high performance liquid chromatography]. AB - A high performance liquid chromatographic method was established for the determination of metabolites (sugars, organic acids and alcohols) in microbial consortium fermentation broth from cellulose. Sulfate was first added in the samples to precipitate calcium ions in microbial consortium culture medium and lower the pH of the solution to avoid the dissociation of organic acids, then the filtrates were effectively separated using high performance liquid chromatography. Cellobiose, glucose, ethanol, butanol, glycerol, acetic acid and butyric acid were quantitatively analyzed. The detection limits were in the range of 0.10-2.00 mg/L. The linear correlation coefficients were greater than 0.999 6 in the range of 0.020 to 1.000 g/L. The recoveries were in the range of 85.41% 115.60% with the relative standard deviations of 0.22% -4.62% (n = 6). This method is accurate for the quantitative analysis of the alcohols, organic acids and saccharides in microbial consortium fermentation broth from cellulose. PMID- 26749856 TI - [Fingerprint of Solanum nigrum L. from different habitats using high performance liquid chromatography with evaporative light-scattering detection]. AB - Solanum nigrum L. contains a variety of active ingredients. It has been applied broadly in clinical practice. However, the compositions of Solanum nigrum L. from different cultivated areas are quite different. Therefore, it is necessary to set up a standard fingerprint. In this work, a series of Solanum nigrum L. samples were collected from different habitats. A high performance liquid chromatography with evaporative light-scattering detection (HPLC-ELSD) method was developed to study the differences in quality of these samples. The method was optimized by comparing different columns, gradient or isocratic elution and temperatures of evaporating tube. A Phenomenex C18 column was finally selected for separation with gradient elution. The mobile phases were acetonitrile-20% (v/v) methanol aqueous solution containing 0. 03% (v/v) triethylamine. The temperature of evaporating tube was set at 40 degrees C. The validation was performed and the results showed that the method had good precision, repeatability and stability. The validated method was applied to detect Solanum nigrum L. from different habitats. The similarities of the acquired chromatograms were analyzed by using the similarity evaluation system for chromatographic fingerprint of traditional Chinese medicine (TCM). The chromatograms with a similarity between 0. 9 and 1. 0 were normalized and fitted to form a standard fingerprint of Solanum nigrum L. Thirteen common peaks were found and eleven peaks were identified with authentic standards. The results showed that remarkable differences were found among Solanum nigrum L. from different habitats. These herbs could be distinguished based on the compositions detected by HPLC-ELSD. This method provided a technology to evaluate the homogeneity and stability of Solanum nigrum L with wide application prospects and practical value. PMID- 26749857 TI - [Rapid determination of lactose, sucrose, glucose and fructose in foods by capillary zone electrophoresis with indirect ultraviolet detection]. AB - A new and rapid method for the simultaneous determination of lactose, sucrose, glucose and fructose by capillary zone electrophoresis ( CZE) with indirect ultraviolet detection was developed. The separation was completed with an uncoated fused-silica capillary with 30.2 cm of total length (effective length of 20 cm) x 50 um. The separation buffer consisted of 4 mmol/L potassium sorbate, 10 mmol/L sodium phosphate, 30 mmol/L NaOH (pH 12. 56) and 0. 5 mmol/L hexadecytrimethylammonium bromide (CTAB). The separation was performed at a voltage of -8 kV with the ultraviolet detection at 254 nm. The analysis of the four carbohydrates was completed within 10 min. The limits of detection (S/N= 3) for lactose, sucrose, glucose and fructose were 50, 75, 25 and 25 mg/L, and the limits of quantification (S/N = 10) were 150, 225, 75 and 75 mg/L, respectively. The average recoveries for the four carbohydrates were in the range of 87.0% 107.0% with the relative standard deviations of 1.2%-4.7%. No organic solvent was consumed throughout the whole process of the analysis. The method was used for the analysis of nine food samples and a quality control sample. The results demonstrated that the method is simple, rapid, accurate, and suitable for the routine analysis of the four carbohydrates in food samples. PMID- 26749858 TI - [Rapid screening of 28 acidic artificial dyes in fishery products by ultra performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry]. AB - An analytical method was established for the simultaneous determination of 28 acidic artificial dyes in fishery products by ultra performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UPLC-Q TOF MS). The analytes in fishery products were extracted with ethyl alcohol containing 20% (v/v) ammonia water and 10% (v/v) water. Then the extract solution was purified according to amination adsorbent matrix dispersion method. The compounds were separated by an Eclipse Plus-C18 column with acetonitrile and 0.1% (v/v) formic acid-5 mmol/L ammonium acetate solution as the mobile phases, and measured by UPLC-Q-TOF MS with electrospray ionization in negative mode. As a result, the limits of quantification ( LOQs, S/N = 10) of the target compounds were 20-100 ug/kg in fishery products. The 28 analytes behaved linearly in wide range with the correlation coefficients more than 0. 991 as well as the relative standard deviations (RSDs) of the peak areas less than 5.61% (n = 6). The average recoveries of the 28 analytes spiked at three levels were ranged from 70. 24% to 106. 47% with RSDs of 5.62%-9.65% (n = 6). This method can be applied to the analysis of the 28 acidic artificial dyes in fishery products due to its fastness, simplicity and relatively high sensitivity. PMID- 26749859 TI - [Determination of 30 carbamate pesticide residues in vegetative foods by QuEChERS liquid chromatography-tandem mass spectrometry]. AB - Via the classification of vegetative foods in British Standard EN 15662, six representative food matrices were chosen in the current study. The QuEChERS method for each matrix was optimized. The 30 carbamate pesticide residues in the samples after pretreatment were determined by liquid chromatography-tandem mass spectrometry in positive ionization mode. According to the experimental results, the linear ranges were 1-100 ug/kg for aldicarb sulfone and 2-100 ug/kg for the others. The recoveries at three spiked levels of 5, 20 and 100 ug/kg in the six representative matrices were between 56.13% and 127.6%, with the RSDs between 0.47% and 16%. The limits of quantification (S/N-10) were in the range of 0.041 1.9 kg/kg. In conclusion, this method provides a sensitive and efficient way suitable for the analysis of the 30 carbamate pesticide residues in vegetative foods. PMID- 26749860 TI - [Determination of five beta2-agonist residues in pork by ultra-high performanc liquid chromatography-tandem mass spectrometry with molecularly imprinted solid phase extraction]. AB - An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC MS/MS) method with molecularly imprinted solid phase extraction for the determination of five beta2-gonists residues in pork has been developed. After the sample preparation, the ammonium acetate/acetic acid buffer was added, followed by the internal standard and beta-glucuronidase/arylsulfatase enzyme. The solution was incubated at 55 degrees C for 2 h. After adjusting the pH of the solution, it was purified by a molecularly imprinted solid phase extraction column, then analyzed on a BEH C18 column with methanol-0.1% (v/v) formic acid aqueous solution as the mobile phases in gradient elution mode. The MS/MS analysis was in positive ion mode and multiple reaction monitoring mode. The analytes were quantified by the internal standard method. The limits of detection (LODs, S/N = 3) and the limits of quantification (LOQs, S/N = 10) were 0.005 0.009 ug/kg and 0.015-0.025 ug/kg, respectively. In the range of 0-10 ug/kg, the correlation coefficients of linear calibration curves were not less than 0.993 3. At the spiked levels of 0.25, 1.0 and 5.0 ug/kg, the recoveries were 80.4%-92.9% with the relative standard deviations of 1.3%-6.3%. The method is of high sensitivity, good reproducibility, high recovery, and is useful for the simultaneous determination of multiple beta2-agonists residues. PMID- 26749861 TI - [Simultaneous determination of 22 typical pharmaceuticals and personal care products in environmental water using ultra performance liquid chromatography- triple quadrupole mass spectrometry]. AB - An analytical method for simultaneous determination of 22 typical pharmaceuticals and personal care products (PPCPs) in environmental water samples was developed by ultra performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-MS/MS). An Oasis HLB solid phase extraction cartridge, methanol as washing solution, water containing 0. 1% formic acid-methanol (7:3, v/v) as the mobile phases were selected for sample pretreatment and chromatographic separation. Based on the optimized sample pretreatment procedures and separation condition, the target recoveries ranged from 73% to 125% in water with the relative standard deviations ( RSDs) from 8.8% to 17.5%, and the linear ranges were from 2 to 2 000 ug/L with correlation coefficients (R2) not less than 0.997. The method can be applied to simultaneous determination of the 22 typical PPCPs in environmental water samples because of its low detection limits and high recoveries. It can provide support and help for the related research on water environmental risk assessment and control of the micro-organic pollutants. PMID- 26749862 TI - [Synchronous extraction and determination of phenoxy acid herbicides in water by on-line monolithic solid phase microextraction-high performance liquid chromatography]. AB - A C18 monolithic capillary column was utilized as the solid phase microextraction column to construct an in-tube SPME-HPLC system which was used to simultaneously extract and detect five phenoxy acid herbicides, including 2,4 dichlorophenoxyacetic acid (2,4-D), 2- (2-chloro)-phenoxy propionic acid (2,2 CPPA), 2-(3-chloro)-phenoxy propionic acid (2,3- CPPA), phenoxy propionic acid (PPA) and 2-(2,4-dichlorophenoxy) propionic acid (2,4-DP). The operating parameters of the in-tube SPME-HPLC system, including the length of the monolithic column, the sampling flow rate, the sampling time, the elution flow rate and the elution time, had been investigated in detail. The optimized operating parameters of the in-tube SPME-HPLC system were as follow: the length of the monolithic column was 20 cm, the sampling flow rate was 0. 04 mL/min, sampling time was 13 min; the elution flow rate was 0.02 mL/min, elution time was 5 min. Under the optimized conditions, the detection limits of the five phenoxy acid herbicides were as follows: 9 ug/L for PPA, 4 ug/L for 2,2-CPPA, 4 ug/L for 2,3-CPPA, 5 ug/L for 2,4-D, 5 ug/L for 2,4-DP. Compared with the HPLC method with direct injection, the combined system showed a good enrichment factors to the analytes. The recoveries of the five phenoxy acid herbicides were between 79.0% and 98.0% (RSD <= 3.9%). This method was successfully used to detect the five phenoxy acid herbicides in water samples with satisfactory results. PMID- 26749864 TI - [Development of an automatic vacuum liquid chromatographic device and its application in the separation of the components from Schisandra chinensis (Turz) Baill]. AB - In order to meet the needs of efficient purification of products from natural resources, this paper developed an automatic vacuum liquid chromatographic device (AUTO-VLC) and applied it to the component separation of petroleum ether extracts of Schisandra chinensis (Turcz) Baill. The device was comprised of a solvent system, a 10-position distribution valve, a 3-position changes valve, dynamic axis compress chromatographic columns with three diameters, and a 10-position fraction valve. The programmable logic controller (PLC) S7- 200 was adopted to realize the automatic control and monitoring of the mobile phase changing, column selection, separation time setting and fraction collection. The separation results showed that six fractions (S1-S6) of different chemical components from 100 g Schisandra chinensis (Turcz) Baill. petroleum ether phase were obtained by the AUTO-VLC with 150 mm diameter dynamic axis compress chromatographic column. A new method used for the VLC separation parameters screened by using multiple development TLC was developed and confirmed. The initial mobile phase of AUTO-VLC was selected by taking Rf of all the target compounds ranging from 0 to 0.45 for fist development on the TLC; gradient elution ratio was selected according to k value (the slope of the linear function of Rf value and development times on the TLC) and the resolution of target compounds; elution times (n) were calculated by the formula n ~ DeltaRf/k. A total of four compounds with the purity more than 85% and 13 other components were separated from S5 under the selected conditions for only 17 h. Therefore, the development of the automatic VLC and its method are significant to the automatic and systematic separation of traditional Chinese medicines. PMID- 26749863 TI - [Simultaneous determination of total specific migration limit of seven benzene polycarbonic acids and their derivatives in food simulants by high performance liquid chromatography-ultraviolet detection]. AB - A novel method for simultaneous determination of total specific migration limits (SML (T)) of trimellitic, isophthalic, terephthalic, phthalic acid and their derivatives (1, 2, 4-benzenetricarboxylic anhydride, isophthaloyl chloride and terephthaloyl chloride) in food simulants (10% (v/v) ethanol, 20% (v/v) ethanol, 50% (v/v) ethanol, 3% (w/v) acetic acid and olive oil) was developed by high performance liquid chromatography-ultraviolet detection (HPLC-UV). After the migration test, the soaking solution was cooled down and vortexed. After the extraction of olive oil food simulants with 0. 1% (w/v) ammonium acetate aqueous solution, the clear aqueous solution or other aqueous food simulants was filtered through a hydrophilic polytetrafluoroethylene filter with a disposable syringe before injection. The Synergi Polar-RP column (250 mm x 4.6 mm, 4 um) and gradient elution mode were selected. The variable wavelength detector was set at 232 nm. The limits of quantification were 0.1-0.2 mg/kg; the linearity of the method was good with r2 > 0.999 91 over the range from 0.5 to 12 mg/L for aqueous food simulants or 0.5 to 12 mg/kg for olive oil food simulants. The recoveries of them were between 94. 3% and 105% with the relative standard deviations between 0.1% and 2.3% at the levels of 1.25, 2.50, 6.25 mg/kg. The method shows the low limits of detection, good recoveries and accuracies, and meets the requirement of ( EU) No 10/2011 regulation for the total specific migration limits of trimellitic, isophthalic, terephthalic, phthalic acids and their derivatives. The method has been applied to the analysis of food contact material samples. PMID- 26749865 TI - [Determination of 99 pesticide residues in Paeoniae Radix Alba by gas chromatography-triple quadrupole tandem mass spectrometry]. AB - A method was established for the simultaneous determination of 99 pesticide residues with combination of solid-phase extraction technique ( SPE) and gas chromatography-triple quadrupole tandem mass spectrometry (GC-QqQ-MS). The sample was extracted with ethyl acetate, and cleaned-up by an amino SPE column. The extract was determined by GC-MS/MS in multi-reaction monitoring (MRM) mode, and matrix-matched internal standard method was applied to quantify the pesticides. The results of all the 99 pesticides showed good linearity in the range of 0.001 0.25 mg/L, with correlation coefficients (r2) > 0.99. The limits of quantification (LOQs) were between 0.001-0.050 mg/kg. The recoveries were between 66.7% and 128.0% with RSD values typically lower than 18.3% at three spiked levels of 0.05, 0.10 and 0.20 mg/kg. This method has been applied to determine thirteen batches of commercially available samples, chlorpyriphos-ethyl and p,p' DDE were detected in four batches of Paeoniae Radix Alba. The method is highly accurate, reliable and sensitive for monitoring the 99 pesticide residues in Paeoniae Radix Alba. PMID- 26749866 TI - [Determination of 16 polychlorinated biphenyls in fish oil by gas chromatography negative ion chemical ionization-mass spectrometry]. AB - An analytical method for the simultaneous determination of 16 polychlorinated biphenyls (PCBs) in fish oil was developed. PCBs were extracted from fish oil with n-hexane, purified by sulfuric acid and determined by using gas chromatography-negative ion chemical ionization-mass spectrometry (GC-NCI-MS) in selected ion-monitoring (SIM) mode. A good linear relationship (r > 0.99) was observed with the PCBs concentrations from 0.01 ug/L to 10 ug/L, and the limits of quantification (LOQ, S/N = 10) were between 3 pg/g and 67 pg/g for different kinds of PCBs. The average recoveries ranged from 62.3% to 121.8% with the relative standard deviations ( RSDs, n = 3) smaller than 12%. Compared with the traditional pre-treatment of multiple material solid phase extraction, this new method is simple, rapid and less organic solvent usage. Meanwhile the method has good selectivity and sensitivity, and it is suitable for the determination of multiple trace PCBs in fish oil. PMID- 26749867 TI - [Determination of eight polybrominated diphenyl ethers in marine sediments by ultrasonically assisted alkaline degradation extraction and gas chromatography electron capture detection]. AB - For determination of the eight polybrominated diphenyl ethers (PBDEs) in marine sediments based on gas chromatography-electron capture detection (GC-ECD), a rapid and effective method for simultaneous sample extraction and purification was developed, in which ultrasonically assisted alkaline hydrolysis was combined with solvent extraction. The sediment sample was processed in an ultrasonic bath in 2. 00 mol/L NaOH-methanol solution for 30 min, and subsequently extracted by n hexane. The organic phase was then separated and purified by silica column and concentrated to 100 uL for GC-ECD analysis. Under the optimized conditions, the recoveries and relative standard deviations (RSDs) for eight PBDE congeners ranged from 63.6% to 110.3% and from 1.7% to 10.5% (n = 5), respectively. The limits of detection (LODs, S/N = 3) ranged from 0.002 to 0.011 ng/g except for deca-brominated diphenyl ether (BDE-209), which was 0.097 ng/g. With high accuracy, good stability and adequate recovery, the established method was successfully applied to the analysis of PBDEs in the surface sediments from Bohai Sea. The concentrations of ?8PBDEs (sum of 2,4,4'-tribromodiphenyl ether (BDE 28), 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), 2, 2', 4, 4', 5 pentabromodiphenyl ether (BDE-99), 2, 2', 4, 4', 6-pentabromodiphenyl ether (BDE100), 2, 2', 4, 4', 5, 5'- 1.566 to 6.760 ng/g and from 1.461 to 6.438 ng/g, respectively. A decreasing gradient of concentration was basically observed with increasing distance off the shore, indicating that anthropogenic activities, surface runoff and river inputs may be the sources of PBDEs in the sediments from Bohai Sea. PMID- 26749868 TI - [Simultaneous determination of three sulfonamide residues in modified milk by ultra performance liquid chromatography-tandem mass spectrometry]. AB - An ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/ MS) method for the residue determination of sulfadiazine, sulfamerazine and sulfamethazine in modified milk was established. The modified milk samples were extracted and their protein precipitated with water (containing 1% (v/v) acetic acid) and methanol. Then they were purified with an HLB solid phase extraction cartridge. The separation was performed on an ACQUITY UPLC HSS T3 column (100 mm x 2.1 mm, 1.8 um) with a gradient system of water (containing 0.1% (v/v) formic acid) and acetonitrile as mobile phases at a flow rate of 0.3 mL/min, and detected by the MS in ESI+ mode. Standard curves were drawn by using matrix standard addition method, and the external standard method was used for quantitative analysis. The limits of quantification were 1 ug/kg. The calibration curves for the three sulfa drugs were linear in the mass concentration range of 1 100 ug/L with R2 >= 0.998. The recoveries at the levels of 1, 2, 10 ug/kg fortified samples ranged from 76.5% to 101.9% with the relative standard deviations of 1.2%-12.4%. The method is simple, rapid, accurate, and its performance can meet the requirements of the domestic and international legislations. It is suitable for the detection of sulfonamide residues in modified milk. PMID- 26749870 TI - Honoring Dentistry Today's Leaders in CE. PMID- 26749869 TI - [Rapid screening and confirmation of illegally added anti- impotence preparations in health care products by high performance liquid chromatography-high resolution mass spectrometry]. AB - A method was established for rapid screening and quantifying 11 illegally added anti-impotence preparations (yohimbine, acetildenafil, nor-acetildenafil, homosildenafil, hydroxy-homosildenafil, sildenafil, vardenafil, thioaildenafil, tadalafil, pseudovardenafil, dapoxetine) in health care products by high performance liquid chromatography-high resolution mass spectrometry. The samples were extracted with methanol and analyzed by positive mode in the MS detection. The results showed that the limits of detection were 25.0 ng/mLexcept for nor acetildenafil (5.0 ng/mL), the linear ranges were 5.0-200.0 ng/mL except for nor acetildenafil (25.0-500.0 ng/mL) with the correlation coefficients not less than 0.999 0. The recoveries were in the range of 82.0%-105.9% with the relative standard deviations of 4.7%-16.5%. This method is accurate, simple and rapid, and can be used in rapid screening and quantitative analysis of the 11 illegally added anti-impotence in health care products. PMID- 26749871 TI - Occlusion Fails. PMID- 26749872 TI - FOCUS ON: Endodontics. PMID- 26749873 TI - A Contemporary Approach to Intraoral Optical Scanning and In-Office 3-D Printing. PMID- 26749875 TI - Full-Arch Zirconia Screw-Retained Bridges: The Advantages of a Guided Surgical Approach. PMID- 26749874 TI - Guided Implant Surgical Applications. PMID- 26749876 TI - Quality Aesthetics in the Digital Age of Crown and Bridge. PMID- 26749877 TI - Interdisciplinary Treatment Planning: The Restorative Quarterback. PMID- 26749878 TI - Tooth Resorption: The "Black Hole" of Dentistry. PMID- 26749879 TI - Where Are All The Dentists Going? PMID- 26749880 TI - A Conversation with Endodontic Experts. PMID- 26749882 TI - Changes in aged care. PMID- 26749881 TI - FLOOR OF THE MOUTH LESION. PMID- 26749883 TI - The Age of REASON. SHINING THE SPOTLIGHT ON AGED CARE. PMID- 26749884 TI - The loss of common decency. PMID- 26749885 TI - The value of male faculty from the perspective of newly graduated male registered nurses. PMID- 26749886 TI - Patient and carer information: Can they read and understand it? An example from palliative care. PMID- 26749887 TI - Taking it from excellence and making it exceptional. PMID- 26749888 TI - Are there warning signs for suicide? PMID- 26749889 TI - Sexual diversity and social stigma on HIV prevention for Thai gay men. PMID- 26749890 TI - Has the Practice Nurse Incentive Program improved health promotion and illness prevention education access for men? PMID- 26749891 TI - Men's mental health. PMID- 26749892 TI - Men's health--the man with breast cancer. PMID- 26749893 TI - Getting men to talk about suicide. PMID- 26749894 TI - Perinatal mental health and men. PMID- 26749895 TI - An attitude of adventure. PMID- 26749896 TI - Men's health in Australia. PMID- 26749897 TI - Men's health--it should be a feminist issue. PMID- 26749898 TI - Chlamydia in men--are you thinking about it? PMID- 26749899 TI - Staffing in aged care. PMID- 26749900 TI - [Human brown adipose tissue]. AB - Adult humans have heat-producing and energy-consuming brown adipose tissue in the clavicular region of the neck. There are two types of brown adipose cells, the so called classic and beige adipose cells. Brown adipose cells produce heat by means of uncoupler protein 1 (UCP1) from fatty acids and sugar. By applying positron emission tomography (PET) measuring the utilization of sugar, the metabolism of brown fat has been shown to multiply in the cold, presumably influencing energy consumption. Active brown fat is most likely present in young adults, persons of normal weight and women, least likely in obese persons. PMID- 26749902 TI - [Structure and function of intestinal microbiota in health and disease--130 years after Theodor Escherich]. AB - Since early life we are colonized by developing communities of microbes that dominate our body in great numbers. In the intestinal tract they constitute the largest microbial ecosystem close to our heart: our microbes inside. Recent studies have shown that these microbes, collectively termed microbiota, are essential for our health through interacting with our gut, gut-liver and gut brain axis, and our immune system. Hence this contribution deals with these aspects and provides an overview of the structure and function of the microbiota as well as the impact on future therapies ranging from fecal transplantations to the use of a synthetic microbiome. PMID- 26749901 TI - [Fetal diagnosis from the mother's blood--noninvasive screening of chromosomal aberrations]. AB - In Finland, the screening of fetal chromosome aberrations is currently based on combined screening in the first trimester. Non-invasive prenatal testing (NIPT) is a new method enabling a more accurate screening than combined screening of fetal chromosome aberrations from the mother's blood sample by analyzing cell free fetal DNA (cffDNA). In addition, it is possible to determine the gender of the fetus or assess the number of sex chromosomes. Although NIPT is an accurate screening method, an aberrant result should always be confirmed by an invasive fetal diagnostic test. PMID- 26749903 TI - [Early microbial contact and child health]. AB - Contact with the microbial environment and the developing intestinal microbiota in early childhood is essential for the normal maturation of the immune system. Microbial programming of the immune and metabolic phenotype may begin already before birth. In prospective clinical studies, perturbations in early gut microbiota composition have been associated with the development of chronic conditions including atopic diseases as well as obesity. Birth by caesarean section and early exposure to antibiotic agents may disturb the development of the intestinal microbiota and increase the risk of chronic diseases in later childhood. PMID- 26749904 TI - [Limits and possibilities of pediatric surgery]. AB - Organ damage in some congenital defects can be so grave that not even the best postnatal treatment is able to guarantee survival. Treatment can also result in an unsatisfactory outcome. The defect can also become worse during fetal development. Today, fetal imaging is able to produce accurate anatomic and pathophysiologic information about the developing organ system already starting from weeks 18 to 20 of pregnancy. This has enabled corrective procedures for the fetus. For the time being, conclusive scientific evidence of the efficacy of invasive fetal therapies is available only for the twin-to-twin transfusion syndrome and fetal meningomyelocele. PMID- 26749905 TI - [Research has changed our view about psychoses]. AB - Psychoses are associated with problems in the development and maturation of the central nervous system and disturbances of brain connectivity. In all likelihood, their etiology is heterogenous. The susceptibility to and onset of psychosis result from the combined effect of the genome, biological and social risk factors of the early environment and the negative social experiences in childhood and adolescence. Among the neurobiological factors of psychoses, the best characterized is sensitization of the dopamine system in patients affected with schizophrenia, leading to misinterpretation of external stimuli. Psychoses are also associated with alterations in the immune system and metabolism the significance of which in the etiology of the disease is under vigorous research. PMID- 26749906 TI - [Inflammatory heart diseases--cardiac sarcoidosis and giant cell myocarditis]. AB - The most common symptoms of cardiac sarcoidosis and giant cell myocarditis are atrioventricular block, ventricular tachycardia and cardiac insufficiency. Magnetic resonance imaging of the heart or positron emission tomography are utilized to evaluate the possibility of inflammatory heart disease. The diagnosis is based on histologic examination of a cardiac muscle tissue specimen. For both diseases, the increase in the number of diagnoses is likely to be due to improved diagnostics. The cause of cardiac sarcoidosis is not known, but granulomatous inflammation can be suppressed with corticosteroids. In giant cell myocarditis, more powerful immunosuppression is utilized than in sarcoidosis, but one third of the patients still require heart transplantation within one year from the diagnosis. PMID- 26749908 TI - [Incidental finding as a diagnostic and therapeutic challenge]. AB - Incidental findings have increased with imaging studies. On the average, an incidental finding is made for one out of four patients in connection with an imaging study. The finding may be a harmless change without any significance for the patient's prognosis or treatment. Most incidental findings are indeed benign. On the other hand, an incidental finding may necessitate further investigations, follow-up or even immediate treatment in case of a malignant or other life threatening change. Ideally, collaboration between a radiologist and a clinician leads to the correct decisions. PMID- 26749907 TI - [Vitamin signaling underlying degenerative diseases]. AB - Our knowledge of the significance of nutrients in the treatment of degenerative diseases of tne nervous system and muscle is poor. In addition to scarcity of vitamins in the diet, a tissue-specific vitamin deficiency may underlie these diseases. Gene defects of folate or thiamine transport proteins cause severe pediatric encephalopathies that can partly or completely be prevented with early vitamin therapy. In other words, a vitamin deficiency restricted to an individual tissue develops in degenerative diseases despite a well-balanced diet. The focus is especially on B vitamins, the effects of which as regulators of cell growth and energy metabolism are only beginning to be understood. PMID- 26749909 TI - [Succinate dehydrogenase-deficient tumors--a novel mechanism of tumor formation]. AB - Succinate dehydrogenase (SDH) is a heterotetrameric enzyme complex participating in the Krebs cycle and electron transfer of oxidative phosphorylation. These tumors, discovered during the past 15 years, often occur in young patients and include 15% of paragangliomas, 7% of gastric gastrointestinal stromal tumors (GISTs), and <1% of renal cell carcinomas and pituitary adenomas. SDH-deficient tumors have lost SDH complex activity via bi-allelic genomic losses or epigenetic silencing. This deficiency is oncogenic, activating pseudohypoxia signaling. SDH deficiency has to be suspected in the above-cited tumor types presenting at a young age. Immunohistochemical testing of tumor tissue for SDHB loss is diagnostic. PMID- 26749911 TI - [Big data in the promotion of public health]. AB - Big data (very large data sets) are increasing in an accelerating speed. More and more data is also becoming freely available. This article is an overview of this progress and data sources related to molecular biology and public health especially from the Finnish perspective. Finland has several excellent data sources that are currently not used effectively. Big data has already produced major benefits especially in molecular biology, but benefits in public health and individual choice are only now being materialised. The paradigm in research may change dramatically, if the effort switches from article production to the production of knowledge crystals, i.e. collaborative data-based answers to research questions. Also the role of a clinician is becoming more like that of a coach. PMID- 26749910 TI - [Triumphal march of cancer therapy goes on]. AB - Therapeutic results for cancer have gradually improved. The relative five-year survival rate of those affected with the disease already exceeds 65% in Finland. New cancer therapies play an indisputable role in the improvement of the prognosis. Besides therapy and its availability, many other causes may also have a considerable effect on the survival of affected persons, making comparison of regional survival rates unreliable as a measure of cancer treatment. The review deals with factors affecting the survival of persons having cancer and includes descriptions of some of the most recent cancer treatments and a discussion about the challenges of developing cancer therapies. PMID- 26749912 TI - Bronchial Anthracofibrosis: A Perilous Consequence of Exposure to Biomass Fuel Smoke. PMID- 26749913 TI - Quantification of Emphysema in Chronic Obstructive Pulmonary Disease by Volumetric Computed Tomography of Lung. AB - BACKGROUND AND OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with small airway inflammation and emphysema. Emphysema is permanent enlargement of air spaces distal to terminal bronchioles accompanied by destruction of alveolar walls. These morphological changes can be studied on quantitative computed tomography (CT). METHODS: Thirty-four patients diagnosed to have COPD as per Global Initiative for Chronic Obstructive Lung Disease guidelines underwent chest CT using full inspiration with low dose radiation protocol. Pulmo-CT software was used to analyse the scans. The primary aim was to quantify emphysema and emphysema clusters and secondary aim was to assess correlation between percentage emphysema and lung function. RESULTS: Their mean [standard deviation (SD)] age was 66.4 (7.0) years; 11 (32.4%) were current smokers (median pack years 45.5). Their mean (SD) forced expiratory volume in the first second (FEV1%) was 55.6 (17.6), mean (SD) %emphysema was 26.8 (11.1), mean (SD) lung density was -848.35 (29.5) Hounsfield units (HU), median (interquartile range) %cluster class 4 emphysema was 22.4 (13.5-32.6). There was no significant difference in %low attenuation volume (%LAV) in current and exsmokers (p=0.4); across various severity grades of COPD (p=0.15). Further, no significant correlation was observed between %emphysema and post-bronchodilator FEV1%. CONCLUSIONS: Volumetric CT can detect and quantify emphysema. Majority of emphysema clusters in COPD are >25mm. The %emphysema does not correlate to the severity of the disease. Quantitative CT is a good objective method to study emphysema and can be used to phenotype COPD radiologically. PMID- 26749914 TI - Clinico-pathological Profile of Bronchogenic Carcinoma Among Females in North India. AB - OBJECTIVE: The present study was undertaken to explore the clinico-pathological profile of bronchogenic carcinoma among females. METHODS: One hundred and twenty four female patients with histopathologically proven bronchogenic carcinoma who were hospitalised in the Department of Pulmonary Medicine, King George's Medical University, Lucknow from July 1985 to February 2007 were retrospectively studied. RESULTS: Their mean age was 61 years; 12.9% of these were less than 40 years of age. Of these, 79% of female patients of lung cancer were first regarded as pulmonary tuberculosis; 76% belonged to rural area. Use of biomass fuel and kerosene oil exposure was the predominant risk factors evident among the 116 non smoker women. Adenocarcinoma was observed in 43.5%, followed by squamous cell carcinoma in 33.1% and the remaining 23.4% cases were small cell carcinoma. The majority (77.4%) of non-small cell lung cancer (NSCLC) patients had advanced stage disease (I]Ib and IV) and 58% of small cell lung cancer (SCLC) patients had limited disease and 42% of SCLC patients had extensive disease at the time of diagnosis. CONCLUSION: Adenocarcinoma was found to be the most common histopathological type of bronchogenic carcinoma among these females. PMID- 26749915 TI - Rapidly Fatal Silicosis Among Jewellery Workers Attending a District Medical College of West Bengal, India. AB - BACKGROUND: Silicosis is a slowly progressive chronic occupational lung disease, developed after a prolong period of exposure to high concentration of silica dust. METHODS: In this longitudinal study, we enrolled old and new silicosis patients (n=19; 8 jewellery polishers, 11 from other occupations) seen at our Pulmonary Medicine Department from June 2009 to December 2012 to document the course of illness as per their occupational exposure. RESULTS: Six of the eight jewellery polishing workers had developed silicosis within five years of exposure, while six of the 11 other workers with other occupational exposure had developed silicosis after exposure of 10 years or more. Mean duration of exposure was significantly less among jewellery polishing workers compared to other workers (3.4 +/- 1.7 versus 9.3 +/- 4.1; p=0.001). Mean duration of illness (months) (14.9 +/- 5.8 versus 28.5 +/- 16.5; p=0.040) were significantly less among the jewellery polishing workers compared to other workers. At the end of the study period, all eight jewellery polishing workers with silicosis had died while four of the 11 patients with other occupational exposure had died. CONCLUSION: Silicosis among jewellery polishing workers was found to be more severe and progressive compared to silicosis due to other occupational exposures, in our study. PMID- 26749917 TI - An Unusual Cause of a Pulmonary Mass: Actinomycosis. AB - We present the case of a 62-year-old male with chronic obstructive pulmonary disease and poorly controlled diabetes mellitus who presented with haemoptysis. A radiograph of the chest showed a right lower parahilar opacity which on the contrast enhanced computed tomography was seen to be an irregular, spiculated mass localised to the middle lobe. Considering malignancy as the most probable diagnosis, a bronchoscopic endobronchial biopsy was performed which surprisingly established pulmonary actinomycosis as the diagnosis. The patient was successfully managed with amoxicillin and clavulanic acid and glycaemic control. PMID- 26749916 TI - An Unusual Cause of Calcific Thoracic Metastases. PMID- 26749918 TI - Primary Malignant Melanoma of the Lung: Case Report and Literature Review. AB - Primary malignant melanoma of the lung (PMML) is an extremely rare tumour with only sporadic case reports. We report the occurrence of PMML in a 58-year-old female. Although extremely rare, it must be considered in the differential diagnosis of bronchogenic carcinoma and a detailed systemic examination must be done to rule out any primary skin or eye involvement. PMID- 26749919 TI - Co-existence of Carcinoma Tongue with Pulmonary Tuberculosis. AB - We present the case of a 45-year-old male diagnosed to have carcinoma base of tongue, whose chest radiograph showed bilateral lung infiltrates and was referred for evaluation of suspected pulmonary metastases. Diagnostic evaluation confirmed the diagnosis of smear-positive pulmonary tuberculosis. PMID- 26749920 TI - Rare Mediastinal Hydatid Cyst. AB - Hydatid disease is a parasitic disease caused by the larval form of Echinococcus granulosus. Most common sites are liver, lungs, and brain. The disease is rarely present in the mediastinum. We report the rare instance of a 52-year-old female who presented with hydatid disease in the uncommon location of posterior mediastinum. PMID- 26749921 TI - Hydatid Cyst Presenting With Endobronchial Rupture. AB - Diagnosis of lung hydatidosis becomes difficult with unusual radiographic findings especially with rupture of hydatid cyst. Here we present the case of a patient who presented with hydatid cyst with endobronchial rupture. A 40-year-old woman presented with a 3-year history of cough with mucoid expectoration, breathlessness on exertion, intermittent fever and left-sided chest pain. Chest radiograph and computed tomography of chest showed a mass obstructing the left main bronchus and post-obstructive cavity formation. Fluorodeoxyglucose positron emission tomography (FDG-PET) showed uptake [maximum standardised uptake value (SUVmax) 2.5 G/mL) in left lower lobe cavity. Fibreoptic bronchoscopy showed obstruction of the left main bronchus with white gelatinous material. After the bronchoscope was withdrawn, the patient expectorated large quantifies of this material. Histopathological examination of the aspirated membrane showed laminated acellular layer and focal inner germinal layer suggestive of hydatid cyst. PMID- 26749922 TI - Poncet's Arthritis in a Patient with Multidrug-Resistant Tuberculosis. AB - A 17-year-old female diagnosed to have multidrug-resistant pulmonary tuberculosis (MDR-TB), presented with Poncet's arthritis which responded to second-line anti TB treatment. Poncet's disease is more commonly present in association with extra pulmonary TB and involves large and small joints. However, our patient had pulmonary MDR-TB and small joint involvement. PMID- 26749923 TI - Chest Sonography in the Diagnosis of Pneumothorax. PMID- 26749924 TI - The Author's Reply. PMID- 26749926 TI - Dare to bare? PMID- 26749925 TI - Voice of the child. PMID- 26749927 TI - Rights for grandparents. PMID- 26749928 TI - Mandatory duty to report FGM to police. PMID- 26749929 TI - Sugar at the heart of the obesity debate. PMID- 26749930 TI - RCM calls for more specialist maternal mental health midwives. PMID- 26749931 TI - Record numbers of children now in care. PMID- 26749932 TI - Realising the potential: early help for neglect. PMID- 26749933 TI - Can responsive feeding help to encourage healthy growth? PMID- 26749934 TI - Immunisation update: Meningococcal B and ACWY vaccines. PMID- 26749935 TI - Encephalitis: a brief overview. PMID- 26749936 TI - Childhood obesity--the eleventh hour. PMID- 26749937 TI - Is it eczema? PMID- 26749938 TI - 'Lives are being put at risk'. PMID- 26749939 TI - 'Our global community has changed the way I view school nursing'. PMID- 26749941 TI - Operation smile! PMID- 26749942 TI - Is it "The View," or Our Vision? PMID- 26749940 TI - Still small voice? PMID- 26749943 TI - Pre-Exposure Prophylaxis (PrEP): Can HIV be Prevented? PMID- 26749944 TI - Suicide Assessment and Prevention. PMID- 26749945 TI - 5 Considerations for RNs Facing Ethical Challenges on the Job. PMID- 26749946 TI - American Nurses Association Makes New Recommendation that All Nurses Should be Immunized Against Vaccine-Preventable Diseases. PMID- 26749947 TI - ANA Sets 'Zero Tolerance' Policy for Workplace Violence, Bullying. Position Statement Calls on Health Care Employers to Implement Violence Prevention Programs. PMID- 26749948 TI - [BICUSPID AORTIC VALVE AND LEFT VENTRICULAR OUTFLOW TRACT DEFECTS IN CIIILDREN - SYNDROME OF BICUSPID AORTOPATHY?]. AB - Although bicuspid aortic valve (BAV) is considered the most common congenital heart defect (CHD) in adult age, with the 0.5-2% prevalence, BAV is not part of epidemiological studies of congenital heart defects (CHD) in children. Aortic valvulogenesis disorder is part of the left ventricular outflow tract (LVOT) genetic disorders which include: hypoplastic left heart syndrome (HLHS), aortic stenosis (AS) and insufficiency (AI), dilatation of the ascending aorta (DAA), coaretation of the aorta (CoA), Shone's syndrome (SS), and probably some other disorders. Our observations indicate that BAV related significant pathologic and hemodynamic changes occur in children already. In an 11-year long retrospective study (2000-2011) we have found 229 BAV patients, predominantly males (1.7). The most common BAV associated disorder was CoA (75 patients, 32.6%). Of all the children with BAV, 62.4% (143:229) had hemodynamic alterations on the aortic valve which manifested themselves as aortic stenosis and/or insufficiency. AS is mostly progressive and becomes hemodynamically relevant in childhood age already, while AI is mostly mild and rarely hemodynamically relevant. A large proportion of patients had isolated AS with DAA (21 or 14.7%), while most patients had combined AS and AI (29 or 20.3%). Due to morphological changes on the valve itself and on the adjoining defects, numerous interventional and cardiosurgical procedures have been performed. Their number has been growing with age, in accordance with the expected progression of pathological changes on the valve (AS, AI) or on the aorta (DAA). DAA in children with BAV was found in 76 (33.2%) patients, in various combinations with other associated LVOT anomalies. Already in childhood have the following surgical procedures on children with primary BAV diagnosis been performed : resection of CoA with T-T anastomosis was performed in 56 patients (24.5%); balloon aortic valvuloplasty in 28 patients (12.3%); commissurotomy in 19 patients (8.3%); balloon dilatation of CoA in 15 patients (6.5%); subaortic membrane resection in 11 patients (4.8%); Ross procedure in 8 patients (3.5%); resection of CoA with reconstruction in 8 patients (3.5%); valvuloplasty in 6 patients (2.6%); ascending aortoplasty in 5 patients (2.2%); mechanical valve replacement in 3 patients (1.3%); "subclavian flap" in 3 patients (1.3%); biological aortic valve replacement in 2 patients (0.9%); Bentall procedure in 1 patient (0.4%); David procedure in 1 patient (0.4%). CONTRIBUTION OFTHE STUDY: A BAV finding in children is a predictive factor for a progressive development of morphological changes in various LVOT parts, requiring that in some patients hemodynamic repercussions be removed already in childhood. CONCLUSION: The term valvular aortopathy, that is bicuspid aortic valve syndrome, should be in use already for children, and the anomaly should be included in epidemiological CHD research. PMID- 26749949 TI - [AUTOLOGOUS STEM CELL TRANSPLANTATION IN REFRACTORY OR RELAPSED DIFFUSE LARGE B CELL LYMPHOMA - A SINGLE CENTRE EXPERIENCE]. AB - Autologous stem cell transplantation represents the gold standard in chemosensitive diffuse B large cell lymphoma in relapse or in refractory setting. The aim of this study was to present the outcome of peripheral autologous stem cell transplantation in patients with refractory or relapsed diffuse large B cell lymphoma. We retrospectively analysed the data of 62 patients, who underwent this procedure for the period 2000-2013. The majority of patients (71%) were treated with miniBEAM salvage chemotherapy and all received BEAM myeloablative protocol followed by the stem cell reinfusion. The overall response rate for autologous transplantation was 75.8%. Median overall survival was 37.2 months. Median event free survival was 16.9 months. Factors associated with overall survival were state of disease prior to salvage chemotherapy, chemosensitivity of disease, International prognostic index, disease activity at the relapse, response to autologous transplantation and post-transplantation radiotherapy. The use of rituximab was not significantly correlated to the outcome. In this patient group autologous stem cell transplantation was found to be effective in achieving remission and survival showing the adequate role of this procedure in this clinical setting. We stress out that autologous stem cell transplantation was effective in 32.5% patients with chemorefractory disease after salvage therapy. PMID- 26749950 TI - [C1Q NEPHROPATHY: CASE REPORTS AND LITERATURE REVIEW]. AB - C1q nephropathy is considered a form of glomerulonephritis, defined by histological findings of dominant Clq immune deposits in renal biopsy. It is a rare disease, most often manifested in children and young adults. The most common clinical manifestation of the disease is nephrotic syndrome, but other renal syndromes could also be found. The cause of the disease is not known, but the immune pathogenesis could be assumed. Often, resistance to glucocorticoid or other immunosuppressive therapy is present, potentially leading to chronic renal insufficiency. We present ten patients with renal biopsy and clinical findings of Clq nephropathy. None of the patients had clinical or serological manifestations of systemic lupus. All patients had normal findings of C3 and C4 components of complement, as well as normal ANF, anti-dsD-NA and ANCA antibodies. PMID- 26749951 TI - [ACCIDENTAL POISONING WITH A PLANT COLCHICUM AUTUMNALE: REPORT OF TWO CASES]. AB - Colchicine poisonings are serious and highly fatal conditions that occur as a result of food poisoning from plants that contain this alkaloid or overdose with drug containing colchicine. The leaves of edible wild garlic because of their similarity are often replaced with highly poisonous leaves of autumn crocus, causing poisoning. Described are two cases of food poisoning with Colchicum autumnale, who had similar symptoms in the initial stage, but different clinical course and outcome. Signs of poisoning require early identification and intensive supportive therapy, which increases the chances of survival. PMID- 26749952 TI - [HEMOGLOBIN A1c AND THE QUALITY OF DIABETES CARE]. AB - Global diabetes epidemics is currently representing one of the most prominent medical and societal challenges. Hemoglobin A1c (HbA1c), a biochemical marker of an average blood glucose concentration has been used for more than 30 years as a clinical indicator of both diabetes treatment efficacy and the risk for development of complications. Recently, HbA1C was proposed as a diabetes diagnostic test as well. Regular monitoring of glycemic control and adjustment of therapy towards the recommended HbA1c-based treatment-goals is a pivotal request of contemporary diabetes care guidelines, as well as a quality indicator proclaimed by numerous national health-care-delivery systems. Standardized and attainable analytical methodology of high-quality and a good knowledge on determinants of biological variability, able to influence test results, are crucial elements for the confident clinical use of HbA1c. In this review, essential analytical and clinical aspects necessary for the reliable use of HbA1c results in diabetes care are concisely presented, together with the degree of Croatian laboratory and clinical practice harmonization with the relevant international standards. PMID- 26749953 TI - [COMPLEX REGIONAL PAIN SYNDROME]. AB - Complex regional pain syndrome (CRPS) represents a state of constant and often disabling pain, affecting one region (usually hand) and often occurs after a trauma whose severity does not correlate with the level of pain. The older term for this condition of chronic pain associated with motor and autonomic symptoms is reflex sympathetic dystrophy or causalgia. The aim of this review, based on contemporary literature, is to show the epidemiology and etiology, proposed pathophysiological mechanisms, method of diagnosis and treatment options, prevention and mitigation of this under-recognized disease. CRPS I occurs without known neurological damage, unlike CRPS II, where the history of trauma is present and in some cases damage to the peripheral nervous system can be objectively assessed using electromyoneurography. New diagnostic methods, such as quantitative sensory testing (CST), challenge this division because the CST findings in patients with CRPS I can suggest damage to Adelta peripheral nerve fibers. Except for distinguishing type I and type II disease, it is important to bear in mind the diversity of clinical presentation of CRPS in acute and chronic phase of the disease. This regional pain syndrome typically includes the autonomic and motor signs and thus differs from other peripheral neuropathic pain syndromes. The complexity of the clinical presentation indicates the likely presence of different pathophysiological mechanisms underlying this disease. Previous studies have demonstrated the autonomic dysfunction, neurogenic inflammation and neuroplastic changes. The diagnosis of CRPS is based on anamnesis and clinical examination on the basis of which the disease can be graded according to the Budapest Criteria. A valuable aid in differentiating subtypes of the disease is electromyoneurography. The treatment of CRPS is as complex as the clinical picture and the pathophysiology of the disease and requires interdisciplinary cooperation and individual approach. The pharmacological approach is mainly symptomatic, including analgesics, glucocorticoids, baclofen, bisphosphonates and prophylactic administration of vitamin C. Physical therapy besides preventing atrophy and contractures reduces the use of analgesic therapy. Invasive approach includes stimulation of the spinal cord, peripheral nerve catheters with anesthetic and amputation that patients in severe condition gladly accept. Further research is needed to better understand the disease and more effective therapies. PMID- 26749954 TI - [HAND FRACTURES IN CHILDREN - CAUSES AND MECHANISMS OF INJURY]. AB - Hand is extremely exposed to various loads and traumas of everyday tasks and activities, resulting in fist fractures being fairly common injuries. The most common mechanism of injury is a direct blow. This retrospective study analyzed the data on 274 children admitted for hand fractures at Clinical Hospital Center Zagreb in the period from 2006 to 2014. The study included 76 girls (28%) and 198 boys (72%). The average patient age was 11.9 years and most were between 10 and 13 years of age. Phalangeal fractures accounted for 80%, metacarpal fractures for 17%, and carpal fractures for 3% of all injuries. Most commonly injuries occurred during recreation (4 1%), at home (37%), at school (18%) and in the street (4%). Direct blow was the major cause of injury (76%), and 24% were caused by fall. Injuries during sport activities are the most common cause of the hand fractures in pediatric population and direct blow is the main mechanism of injury. The peak incidence is at the age of 10-13 years in boys and girls, so prevention should be aimed at this age group. Preventive actions should be focused on injuries that tend to occur in parks, schools and during sport activities. PMID- 26749955 TI - [MIDDLE EAR INFECTION]. AB - Middle ear infection is one of the most common childhood infections and the leading reason for antibiotic prescriptions. Although the etiological diagnosis is rarely discovered, successful identification of pathogens depends on properly collected sample, chosen method and microbiological analysis made on time. The most common bacterial pathogen is Streptococcus pneumoniae. Others include Haemophilus influenzae, Moraxella catarrhalis and Pseudomonas aeruginosa, known as the most common bacterial pathogen of chronic inflamations. Viral or polimicrobial upper respiratory tract infections often precede this infection. Pneumococcal conjugate vaccines given during infancy decrease rates of acute middle ear inflammation. It is a self-limited disease with rare complications. The best treatment is watchful waiting for two days followed by amoxicillin during 7 days, only if it is necessary. If there is resistance, then combination of amoxicillin and beta lactamase inhibitor is second line. The best choice for patients allergic to penicillin are macrolides. Antibiotic treatment has contributed to frequent relapses and increase of multi-drug resistant pathogens by permitting their colonization, which eliminates protective nasopharyngeal flora. PMID- 26749957 TI - [Magdalena Kadrnka Lovrencic (8.8.1935 - 8.7.2014)]. PMID- 26749958 TI - [Mirko Dubravcic (23.5.1929 - 21.5.2015)]. PMID- 26749956 TI - [LEFT VENTRICULAR NON-COMPACTION]. AB - Left ventricular non-compaction (LVNC) is a rare cardiomyopathy, which is today, due to modern ultrasound technology more frequently detected in clinical practice. It is caused by the failure of normal embryonic development of the myocardium from loosely arranged muscle fibers to the mature compacted form of myocardium. Morphologic presentation consists of unique two-layered structure, a thick noncompacted endocardial and a thin compact epicardial layer, in infero lateral and apical segments. The endocardial layer contains loosely arranged muscle fibers, prominent trabeculations and deep perfused intertrabecular recesses. It could be diagnosed both as an infantile or adult type, appearing sporadically or among families where it is transferred x-linked or autosomal dominant. The recognition of the disease is mandatory because of its high mortality and morbidity due to the progressive heart failure, thromboembolic events and lethal arrhythmias. Echocardiography is the procedure of choice to confirm the diagnosis and in the follow-up of patients with LVNC. A literature review about LVNC pathogenesis, diagnostis, and treatment was discussed. PMID- 26749959 TI - A Look to the Future. As Attack One hangs it up, its crew imagines what the system to come might look like. PMID- 26749960 TI - Embracing Mistakes. If you can acknowledge your shortcomings, you have matured as a manager. PMID- 26749961 TI - How To Hire Right the First Time. What are the keys to maximizing the employee interview? PMID- 26749962 TI - The Godfather's Rules for EMS. A film classic yields wisdom surprisingly applicable to prehospital care. PMID- 26749963 TI - Looking forward. PMID- 26749964 TI - Presidential Address: Challenges for the second Century. PMID- 26749965 TI - When silicone medical devices were under attack: A regulatory leviathan. PMID- 26749966 TI - Bariatric surgery, liability, and trauma: Key issues debated in state legislatures. PMID- 26749967 TI - Dr. Timothy Miller: A career in service to military, patients, veterans. PMID- 26749968 TI - Executive Director's annual report. PMID- 26749969 TI - Successfully navigating the transition to ICD-10 terminology. PMID- 26749970 TI - CMS creates new place of service code for outpatient care at hospitals. PMID- 26749971 TI - Prospective comparative effectiveness trial for malignant bowel obstruction: SWOG S1316. PMID- 26749972 TI - The high reliability journey: A look in the mirror with Oro 2.0. PMID- 26749973 TI - NTBA DATA POINTS: "Holiday Road". PMID- 26749974 TI - Case-Based Management of Neuromuscular Block, Reversal, and Recovery: Ensuring Optimal Outcomes. PMID- 26749975 TI - [Ultrafine particle emissions from laser printers]. AB - In recent years there has been growing attention to the importance of indoor air quality on which scientist and experts have no doubts since in modern society we tend to spend most of the time in various types of indoor environments (office, private homes, etc.). Laser printers, in particular, release an aerosol into the environment including solid and liquid particles and gaseous compounds. The measurement of all these components is not practically feasible. Therefore, it is necessary to identify a marker which, when measured, shows accurately the frequency, duration and magnitude of the exposure. The measure with an optical particle counter (OPC) and a condensation particle counter (CPC) is an indicator with high sensitivity and representativeness. The major advantage of using these tools is the ability to detect the presence of ultrafine particles and also detect the particles in the liquid phase. The continuous recording of submicron particulate matter emitted during the printing activity allows to measure the exposure of personnel, while the ratio between the peak values and the values without printing activity can be used to classify the printers according to their emissivity. The particulate generated during the processes of printing has size less than 0.3 micron and therefore extends in the size range of nanoparticles (ultrafine particles less than 100 nm). These activities lead to high concentrations of ultrafine particles with a variability related to factors such as type of printer, toner, paper type, frequency of maintenance and air exchange. The concentrations of ultrafine particles in office environments can be reduced by proper choice of the printers, with the use of appropriate filtration techniques and placing the equipment away from workstations. PMID- 26749976 TI - [Considerations on the use of meta-analyses in the orientation of knowledge and decisions in Occupational Medicine]. AB - In recent years, due to the need to elaborate the amount of information available from the scientific literature, the meta-analyses and systematic reviews have become very numerous. The meta-analyses are carried out to evaluate the association between two events when single researches haven't provided comprehensive data. On the other hand, a good meta-analysis must satisfy certain criteria, from the selection of the studies until the evaluation of the outcomes; to this purpose, the application of methods for quality assessment is a crucial point to obtain data of adequate reliability. The aim of this review is to give some introductory tools for a critical approach to meta-analyses and systematic reviews, which have become useful instruments also in occupational medicine. PMID- 26749977 TI - [The occupational medicine specialist advice in support of the competent physician in the elaboration of the judgement of suitability to the job specification: evaluation method and analysis of case studies]. AB - INTRODUCTION: Still today, one of the most problematic, qualified and awkward assignments for the occupational physician, also for its ethical and socio economic involvements, is to provide for each worker a fitness judgment to a specific work task. AIM: The aim of this study is to describe and to support results and effectiveness of a "second level" expert advice in occupational medicine, among workers with a "problematic" judgment of fitness to work. MATERIALS AND METHODS: We considered 80 requests for a "second level" advice. They were all requested, during 6 years, to the same Occupational Medicine Unit (UOOML) of a single hospital in north of Italy by a single large metalwork company, following the art. 39 of the 81/2008 legislative decree. RESULTS: The study underlined the effectiveness of "second level" advices in evaluating the adequacy of worker's health conditions related to the specific occupational task. Moreover, this study contributed to develop all operative protocol to carry out a systematic and effective process when "second level" advices are addressed to an Occupational Medicine Unit (UOOML). In particular, our operative proposal suggests, as a key point in the assessment process, a careful visit to the occupational environment, to directly study each single task and to deepen the needs of each single occupational emplacement. PMID- 26749978 TI - [CO detector: a tool for the early diagnosis of carbon monoxide intoxication and a personal protective equipment. The experience of the Emergency Medical Sevice (118) in the Province of Cuneo]. AB - BACKGROUND: Many people are poisoned by carbon monoxide (CO) each year, either intentionally (e.g. suicide attempts) or by accident. In the prehospital care the early diagnosis is primary for a correct treatment with high flow of oxygen and for the appropriate hospitalization of the patient. The aim of this study is to detect the main factors associated with CO poisoning in our area and to evaluate the role of CO detector in the prehospital setting. METHODS: From 1 January 2012 to 1 May 2013, all cases of carbon monoxide poisoning, recorded by the Emergency Medical Service (118) in the Province of Cuneo, were analyzed. RESULTS: Seventy clinical cases were collected, 68.5% of poisonings occurred in the months of December, January and February. Boilers were found to be the main source of indoor CO poisoning (average CO concentration of 66.78 versus 32.92 ppm generated by other heating systems, p = 0.004). CO detector was used in 77.4% of cases. The prehospital diagnosis was properly made in 96% (48/50) of cases in which CO detector was used, versus 70% (14/20) of correct clinical assessment without its use (p = 0.005). CONCLUSIONS: The CO detector is not only a personal protective equipment for Emergency Medical Service operators, but it contributes significantly to increase prehospital diagnosis of CO poisoning, thus suggesting its use in all emergency services in the national territory. PMID- 26749979 TI - Functional assessment and quality of life before and after pulmonary endoarterectomy. AB - PURPOSE: The study investigates Quality of Life (QOL) and correlation with functional status of patients affected by Chronic Thromboembolic Pulmonary Hypertension who undergo Pulmonary Endoarterectomy. METHODS: We investigated with an observational design (before surgery, three and twelve months afterwards) the hemodynamic data (NYHA class, mean pulmonary arterial pressure, cardiac output and pulmonary vascular resistance), the functional status (using the 6-Minute Walk Test) and the QOL, using three questionnaires: Medical Outcome Study Short Form-36 (SF-36), Minnesota Living with Heart Failure Questionnaire (MLHFQ), Saint George Respiratory Questionnaire (SGRQ). We report the results of forty-nine patients. RESULTS: After surgery there was an improvement on functional and hemodynamic parameters and on QOL. The physical domain (PCS) of SF-36 was weakly but significantly associated with all functional parameters. There was no association between functional parameters and mental domain (MCS) of SF-36 or SGRQ. The improvement in 6-Minute Walk Distance was associated with an increase in MLHFQ. CONCLUSIONS: Both QOL and submaximal exercise tolerance improve after surgery. However only the physical domains of SF-36 appear to be significantly associated to the functional data. PMID- 26749980 TI - [Economic performance and well being in call center operators]. AB - INTRODUCTION: Many studies highlight that workers showing high well-being prove high job performance, but it is unknown whether economic performance affects psychological well-being. This study is aimed to analyze the relationships between economic performance and well-being in call center operators. METHOD: Forty-nine telephone operators, engaged in the sale of credit cards, were required to fill in questionnaires assessing the following dimensions: Well being, Alexithymia, Coping, Psychopathological symptoms, and Self-declared Economic performance. RESULTS: Results show that workers with low Economic performance have moderate levels of Self-Acceptance and Positive Interpersonal Relationships and high levels of Psychopathological Symptoms. CONCLUSIONS: Though these results are preliminary, given the limited number of participants, they indicate that a low economic performance is associated with a reduced psychological well-being of operators, which is reflected in poor self acceptance, in lower positive interpersonal relationships, in the presence of distress and psychological symptoms. PMID- 26749981 TI - Team-building through sailing: effects on health status, job satisfaction and work performance of health care professionals involved in organ and tissue donation. AB - The aim of this study was to evaluate the effects of a team-building learning project on job satisfaction, psychological wellbeing, and performance of health care workers involved in the process of organ and tissue donation. The project was conducted between June and September 2011 and consisted of two one-day meetings and a one week sailing, involving 20 staff members. GHQ-12, MBI-HSS, and 25 items taken from the Multidimensional Organizational Health Questionnaire (MOHQ) were used to assess health status, burnout, and job satisfaction. Results of the descriptive analyses were expressed as mean +/- SD and as counts and percentages; Chi-square test was used to evaluate statistical significance of differences before and after the initiative. 6 (30,0%) participants showed the likelihood to suffering from anxiety and depression (i.e. recognized as 'cases' by the GHQ-12), 3 (15.0%) of them at baseline and 3 (15.0%), different from the previous ones, in the post-intervention. The presence of stress was revealed in 9 (45.0%) and 12 subjects (60.0%) before and after the experience, respectively (6 subjects showed the presence of stress in both circumstances). We documented 4 burnout cases, 3 (15.0%) at baseline and 1 (5.0%) after the experience. Nevertheless, about 80% of the participants showed a high degree ofjob satisfaction, in terms of positive influence of job in the professional satisfaction and of clear satisfaction for the organization, during both evaluation. In respect to 2010, the number of organ donors and that of ocular tissue donors improved of about 16% and 10%, respectively, during the year of the project and in the following year (mean value). We recognize that our team building project for personnel involved in the stressful and demanding setting of organ and tissue donation, worthwhile and recompensing at the same time, possibly influenced the personal commitment and the quality of job provided. The high level of stress showed by participants should be appropriately targeted in order to prevent burnout. PMID- 26749982 TI - [The Human Model, a tool for assessing preventive ergonomic postural appearance]. AB - D.Lgs. 81/08 requires the employer to design work systems, methods and tools in accordance to the ergonomic principles. In order to check the compliance of the design with current regulation, it is appropriate and effective to make use of simulation tools since the design phase. The paper describes a tool based on multi body approach. Once the gender and the anthropometric percentile of the worker have been specified, the tool simulates the postures that the worker is likely to assume during the execution of the work task. The tool can be used in the design as well as in the re-design phase, taking into account the different percentile of workers for a proper accommodation of the same. PMID- 26749983 TI - WHAT'S THE MATTER WITH ILLINOIS? PMID- 26749984 TI - Trending Up The Center's OM Five-Star Rating. PMID- 26749985 TI - Labor Board Makes Joint Employer Status More Likely. PMID- 26749986 TI - Managing Chronic Conditions In Older Adults. PMID- 26749987 TI - Career Planning: A Process of Discovery. Three elements are key to success. PMID- 26749988 TI - Putting Patients at the Center of Care. PMID- 26749989 TI - Diagnosing the Patient Experience. PMID- 26749990 TI - BEYOND EBOLA: Lessons Learned in Infectious Disease Outbreak. PMID- 26749991 TI - Making Ethical Decisions. A six-step process should guide ethical decision making in healthcare. PMID- 26749992 TI - When Culture and Strategy Collide. Develop a strategy for moving from a culture of "sometimes" to a culture of "always". PMID- 26749993 TI - The Importance of Collaboration. One hospital's work with the community improves both. PMID- 26749994 TI - Value-Based Purchasing Turns the Corner. The move away from fee for service holds some consequences for management strategy. PMID- 26749995 TI - Know Yourself First. To find the career that is satisfying, you must first look introspectively. PMID- 26749996 TI - After the Merger: To Combine Medical Staffs--Or Not? The benefits and challenges of merging medical staffs require serious discussion. PMID- 26749997 TI - Preventing Breaches in Disinfection. One culprit for superbugs is within hospitals' power to eradicate. PMID- 26749998 TI - Philanthropy as a Change Agent. The CEO's role is vital for a strong return on investment. PMID- 26749999 TI - [MID- AND LONG-TERM EFFECTIVENESS OF THIRD-GENERATION CERAMIC-ON-CERAMIC TOTAL HIP ARTHROPLASTY IN YOUNGER PATIENTS]. AB - OBJECTIVE: To analyze the mid- and long-term effectiveness of the 3rd-generation ceramic-on-ceramic (CoC) total hip arthroplasty (THA) in the younger patients. METHODS: A retrospective analysis was made on the clinical data of 68 younger patients (73 hips) who accepted the 3rd-generation CoC THA between March 2001 and May 2009. Of 68 cases, 39 was male and 29 was female with the average age of 38.6 years (range, 18-50 years); there were 15 cases (15 hips) of osteonecrosis of the femoral head, 9 cases (9 hips) congenital dysplasia of the hip, 5 cases (8 hips) of ankylosing spondylitis, 10 cases (10 hips) of osteoarthritis of the hip joint, 12 cases (12 hips) of traumatic hip arthritis, 12 cases (12 hips) of femoral neck fracture, 4 cases (6 hips) of rheumatoid hip arthritis, and 1 case (1 hip) of tumor of the femoral neck. The Harris score and University of California Los Angeles (UCLA) score were used to evaluate the hip joint function and activity level respectively. The visual analogue scale (VAS) was used to assess postoperative thigh pain. Radiological signs of osteolysis, loosening, and alumina ceramic related complications were evaluated continuously. And the Kaplan Meier survival analysis was used to assess the prosthesis survival. RESULTS: The average duration of follow-up was 9.7 years (range, 6-14 years). Sandwich ceramic liners fracture was observed in 3 cases (3 hips), and revision was performed; 1 case had "squeaking" hip because of physical activity. At last follow-up, Harris score and UCLA score were significantly improved when compared with preoperative scores (P<0.05). Bony healing was obtained in all patients, without osteolysis, loosening, and thigh pain. The VAS score was 0. The 5-year and 10-year cumulative survival rates for ceramic fracture revision were 98.6% and 95.9%, and the 5-year and 10-year cumulative survival rates for osteolysis and loosening revision both were 100%. CONCLUSION: The 3rd-generation CoC prosthesis offer an excellent option for younger patients in THA and the mid- and long-term effectiveness are satisfactory. PMID- 26750000 TI - [EFFECT OF MEDIAL 1/3 ANATOMICAL ORIENTATION OF TIBIAL TUBERCLE ON ROTATIONAL ALIGNMENT OF Gemini MK-II TIBIAL COMPONENTS IN TOTAL KNEE ARTHROPLASTY]. AB - OBJECTIVE: To investigate the effect of medial 1/3 anatomical orientation of the tibial tubercie on tne rotational alignment of Gemini MK-II tibial components in total knee arthroplasty (TKA). METHODS: Between March 2011 and December 2012, 61 cases (67 knees) of varus knee osteoarthritis underwent Gemini MK-II knee arthroplasty, and the clinical data were retrospectively analyzed. There were 12 males and 49 females, with an average age of 67.6 years (range, 50-82 years). The body mass index ranged from 20.9 to 33.7 kg/m2 (mean, 28.2 kg/m2). Unilateral TKA was performed in 55 cases and bilatepal TKA in 6 cases. The duration of knee osteoarthritis ranged from 2 to 30 years (mean, 12.1 years). According to radiographic changes, 56 knees were rated as Kellgren-Lawrence grade III and 11 knees as grade IV. During TKA, the tibial rotational alignment was determined by medial 1/3 anatomical orientation of the tibial tubercle. The anteroposterior and lateral X-ray films and CT scan were taken to measure the tibial rotational angle (TRA) at pre- and post-operation and to analyze the relative factors for TRA by Pearson correlation analysis. RESULTS: All the patients were followed up 18-41 months (mean, 20.5 months). The range of motion (ROM) significantly increased from (98.806+/-16.969) degrees preoperatively to (116.806+/-11.458) at last follow-up (t= -11.760, P=0.000). The knee society score (KSS) significantly increased from 111.239+/-20.344 to 160.522+/-17.872 at last follow-up (t= 27.271, P=0.000). The anatomical tibiofemoral angle (ATFA), posterior condylar angle (PCA), and TRA were all improved after TKA, showing significant differences when compared with preoperative ones (P<0.05). Rotational malalignment was observed in 11 knees (16.42%). before TKA, and in 14 knees (20.90%) at 1 week after TKA, showing no significant difference (chi2=0.443, P=0.506). There were 8 knees (11.94%) of internal rotation (>8 degrees ) and 6 knees (8.96%) of external rotation (>8 degrees ). The postoperative tibial prosthesis TRA had no correlation with the preoperative ATFA and tibial plateau TRA, the postoperative PCA and ATFA (r= -0.174, P=0.159; r=0.220, P=0.074; r=0.237, P=0.053; r= -0.095, P=0.442). CONCLUSION: In patients with varus knee osteoarthritis, medial 1/3 anatomical orientation of the tibial tubercle will contribute to the development of tibial rotational malalignment when TKA is performed by using Gemini MK-II tibial components. PMID- 26750001 TI - [TREATMENT OF POSTEROLATERAL TIBIAL PLATEAU COLLAPSED AND SPLITED FRACTURES BY POSTEROMEDIAL AND ANTEROLATERAL APPROACHES]. AB - OBJECTIVE: To explore the effectiveness of posteromedial and anterolateral approaches in the treatment of posterolateral tibial plateau collapsed and splited fractures. METHODS: Nineteen consecutive patients with posterolateral tibial plateau collapsed and splited fractures were treated between August 2010 and August 2013, and the clinical data were retrospectively analyzed. There were 13 males and 6 females, with an average age of 36.9 years (range, 25-75 years). All cases had closed fractures, involving 8 left sides and 11 right sides. Fractures involved posterior column according to the three-column classification based on CT scans; according to the Schatzker classification, all fractures were type II; according to the AO/Association for the Study of Internal Fixation classification (AO/OTA), all fractures were type 41-B3.1.2. The interval between injury and operation was 7-14 days (mean, 9 days). The reduction of collapsed fractures and implantation of artificial bone allograft were supported by T shaped distal radius plate via the posteromedial approach. The splited fractures was fixed by less invasive stabilization system (LISS) plate via the anterolateral approach. RESULTS: The mean operation time was 69.0 minutes (range, 50-105 minutes). All incisions healed by first intention without neurovascular complications or wound infection. All patients were followed up 14-20 months (mean, 18.2 months). X-ray and CT examinations showed that collapsed tibial plateau and joint surface were completely corrected; bony union was obtained at 12 weeks on average (range, 10-16 weeks). No secondary collapsed fracture and knee varus or valgus occurred. The results were excellent in 12 cases, good in 5 cases, and fair in 2 cases with an excellent and good rate of 89.5% according to the Rasmussen's scoring system for knee function. CONCLUSION: The posteromedial approach combined with anterolateral approach for posterolateral tibial plateau fractures can fully expose the posterolateral aspects of the tibial plateau, and thus collapsed and splited fractures can be treated at the same time, which will lead to less operative time and good outcomes in the treatment of posterolateral tibial plateau collapsed and splited fractures. PMID- 26750002 TI - [EFFECTIVENESS OF SURGICAL TREATMENT FOR SENILE CHRONIC SHOULDER DISLOCATION]. AB - OBJECTIVE: To investigate the surgical treatment and effectiveness of senile chronic shoulder dislocation. METHODS: Between October 2011 and April 2014, 7 elderly patients with chronic shoulder dislocation were treated. There were 2 males and 5 females with an average age of 74 years (range, 61-83 years). The causes of injuries were falling injury in 6 patients and traffic accident injury in 1 patient. The interval between injury and confirmed diagnosis was 4-12 weeks (mean, 6.7 weeks). Preoperative apprehension test and Dugas sign of the shoulder joint were positive. Before operation, the forward elevation, abduction, and external rotation were (50.7+/-8.4), (44.5+/-3.3), and (35.8+/-4.8), respectively; and internal rotation reached T6, T11, L4 in 1 case and reached T10, T12 in 2 cases separately. The Constant-Murley score and Neer score were 51.2+/-8.3 and 45.4+/-7.3, respectively. RESULTS: All the incisions healed by first intention, and no complication of fracture or neurovascular injuries occurred. Seven patients were followed up 12-18 months (mean, 16 months), and no re-dislocation happened. At last follow-up, apprehension test and Dugas sign of the shoulder joint were negative. The forward elevation, abduction, and external rotation were significantly improved to (117.5+/-13.1), (72.0+/-4.6), and (39.0+/ 3.4) degrees (t= -33.746, P=0.000; t= -30.614, P=0.000; t= -2.802, P=0.031); and internal rotation reached T6, T10, T12, and L3 in 1 case respectively, and L3 in 3 cases, showing no significant difference when compared with preoperative values (Z= -1.732, P=0.083). The Constant-Murley score and Neer score were significantly improved to 85.4+/-4.3 and 84.0+/-4.8 when compared with preoperative score (t= 21.016, P=0.000; t= -29.518, P=0.000). CONCLUSION: Surgical treatment of senile chronic shoulder dislocation can improve the range of motion and function of the shoulder joint obviously. PMID- 26750003 TI - [BIOMECHANICAL STUDY ON SUTURE WITH NECKWEAR-KNOT-LOOP-LIGATURE FOR TIBIAL EMINENCE AVULSION FRACTURES]. AB - OBJECTIVE: To study the biomechanical stability of neckwear-knot-loop-ligature fixation for tibial eminence avulsion fractures by comparing with cannulated screw fixation and suture anchor fixation. METHODS: Twenty-four fresh porcine knee joints were selected. After the model of tibial eminence avulsion fracture (type III) was made, 24 samples were randomly divided into 3 groups: neckwear knot-loop-ligature group (group A), cannulated screw group (group B), and suture anchor group (group C), 8 samples in each group. The Universal electromagnetic and mechanical testing machines were used for the biomechanical tests. After 200 cyclic tests, pull-out test was done until fixation failure. The maximum failure load, yield load, stiffness, and displacement were measured. RESULTS: Failure mode: the displacement was beyond limit in 8 samples of group A; screws extraction (5 samples) and bone fragment re-fracture (3 samples) were observed in group B; and suture anchor extraction (4 samples), suture rupture (3 samples), and suture thread cutting (1 sample) were found in group C. Biomechanical test: From groups A to C, the maximum failure load and yield load showed significant decreasing tendency (P<0.05), but the displacements showed significant increasing tendency (P<0.05). The stiffness also gradually decreased, but differences was not significant (P>0.05). CONCLUSION: Compared with cannulated screw and suture anchor, neckwear-knot-loop-ligature fixation for tibial eminence avulsion fracture has good biomechanical performance and the advantages of firm fixation and simple operation. PMID- 26750004 TI - [BIOMECHANICAL RESEARCH OF DIFFERENT INTERNAL FIXATIONS USING LOCKING RECONSTRUCTION PLATE FOR ACETABULAR TRANSVERSE FRACTURE]. AB - OBJECTIVE: To compare the biomechanical stability of acetabular transverse fracture fixed with single column locking reconstruction plate, locking reconstruction plate combined with lag screw, and double columns lag screws. METHODS: Acetabular transverse fractures were established in 20 adult fresh semi pelvis specimens, and divided into 5 groups randomly (n=4). The anterior columns were fixed with locking reconstruction plates in group A; the posterior columns were fixed with locking reconstruction plates in group B; the anterior columns were fixed with locking reconstruction plates and the posterior columns with lag screws in group C; the anterior columns were fixed with lag screws and the posterior columns with locking reconstruction plates in group D; the double columns were fixed with lag screws in group E. When loading three times weight, the longitudinal displacement of fracture fragment was measured, and the shear rigidity was calculated to compare the stability among groups. RESULTS: The longitudinal displacement of groups A and B were significantly greater than that of groups C, D, and E (P<0.05), and the shear rigidity of groups A and B were significantly lower than that of groups C, D, and E (P< 0.05). The longitudinal displacement of group B was significantly greater than that of group A (P< 0.05), but no significant difference was found in the shear rigidity between groups A and B (P>0.05). There was no significant difference in the longitudinal displacement and shear rigiditramong groups C, D, and E (P>0.05). CONCLUSION: Locking reconstruction plate combined with lag screw and double columns lag screws have similar stability, they have stronger stability than the single column locking reconstruction plate. The stability of anterior column locking reconstruction plate is better than that of the posterior column locking reconstruction plate. PMID- 26750005 TI - [COMPUTER ASSISTED DESIGN AND ELECTRON BEAMMELTING RAPID PROTOTYPING METAL THREE DIMENSIONAL PRINTING TECHNOLOGY FOR PREPARATION OF INDIVIDUALIZED FEMORAL PROSTHESIS]. AB - OBJECTIVE: To study the feasibility of preparation of the individualized femoral prosthesis through computer assisted design and electron beammelting rapid prototyping (EBM-RP) metal three-dimensional (3D) printing technology. METHODS: One adult male left femur specimen was used for scanning with 64-slice spiral CT; tomographic image data were imported into Mimics15.0 software to reconstruct femoral 3D model, then the 3D model of individualized femoral prosthesis was designed through UG8.0 software. Finally the 3D model data were imported into EBM RP metal 3D printer to print the individualized sleeve. RESULTS: According to the 3D model of individualized prosthesis, customized sleeve was successfully prepared through the EBM-RP metal 3D printing technology, assembled with the standard handle component of SR modular femoral prosthesis to make the individualized femoral prosthesis. CONCLUSION: Customized femoral prosthesis accurately matching with metaphyseal cavity can be designed through the thin slice CT scanning and computer assisted design technology. Titanium alloy personalized prosthesis with complex 3D shape, pore surface, and good matching with metaphyseal cavity can be manufactured by the technology of EBM-RP metal 3D printing, and the technology has convenient, rapid, and accurate advantages. PMID- 26750006 TI - [MEDIUM-TERM EFFECTIVENESS OF ANTERIOR RELEASE INTERNAL DISTRACTION FOR SEVERE AND RIGID SCOLIOSIS]. AB - OBJECTIVE: To observe the medium-term clinical and radiological outcomes of anterior release internal distraction in treatment of severe and rigid scoliosis. METHODS: Between March 2009 and March 2012, 26 patients with severe and rigid scoliosis were treated with anterior release, posterior internal distraction, and two stage posterior spinal fusion. There were 11 males and 15 females with an average age of 19.6 years (range, 14-25 years). The average disease duration was 13.6 years (range, 3-2:4 years). All cases were idiopathic scoliosis. Of 26 cases, 2 cases were rated as Lenke type I, 8 as type II, 13 as type IV, 1 as type V, and 2 as type VI. The apical vertebrae located at T6 in 1 case, at T7 in 3 cases, at T8 in 7 cases, at T9 in 13 cases, and at T10 in 2 cases. The average 4 vertebral bodies were released by anterior approach, and average 14 vertebral bodies were fused after posterior surgery. Fourteen patients received 2 times distraction. Scoliosis Research Society-22 (SRS-22) questionnaire was used to access health-related quality of life. The radiological parameters were measured, including coronal plane Cobb angel of major curve, apical vertebral translation (AVT), C7 plumb line-center sacral vertical line (C7PL-CSVL), sagittal vertical axis (SVA), and thoracic kyphosis (TK) at pre- and post-operation. Results The average total operation time was 592.7 minutes; the average total blood loss volume was 1 311.2 mL; and total hospitalization cost was (14.7+/-1.4)x10(4) yuan RMB. The coronal plane Cobb angle of major curve was (55.7+/-16.5) degrees , and the TK was (43.2+/-16.2) degrees after first distraction. The patients were followed up 2-5 years (mean, 3.8 years). Temporary dyspnea and pleural effusion occurred in 1 case respectively after distraction, and symptoms disappeared after symptomatic treatment. Screw loosening and pseudoarthrosis formation was observed in 1 case at 6 months after fusion, good recovery was achieved after revision. No infection or neurological complication was found. The coronal plane Cobb angel of major curve, TK, and AVT after fusion and at last follow-up were significantly lower than preoperative ones (P<0.05), but no significant difference was found between at post-fusion and last follow-up (P>0.05). There was no significant difference in C,PL-CSVL and SVA between at pre- and post-operation (P>0.05). At last follow-up, SRS-22 questionnaire scores were 4.32+/-0.42 for active degree, 4.54+/-0.58 for mental health, 3.97+/-0.76 for self-image, 4.09+/-0.64 for pain, and 4.03+/-0.83 for satisfaction degree. CONCLUSION: Anterior release internal distraction can provide satisfactory correction results for severe and rigid scoliosis with higher safety and lower incidence of complication. PMID- 26750007 TI - [EFFECT OF ANTERIOR CERVICAL SPINAL CORD COMPRESSION FACTOR IN TREATMENT OF CERVICAL SPONDYLOTIC MYELOPATHY]. AB - OBJECTIVE: To observe the effectiveness of posterior cervical laminoplasty, and to determine the significance of the classification of spinal cord compression of multi-level cervical spondylotic myelopathy (CSM). METHODS: The clinical data were analyzed from 1 216 cases of multi-level CSM undergoing posterior cervical laminoplasty between February 1998 and February 2013. The patients were divided into 4 groups: soft anterior spinal cord compression and light canal occupation (<50%) in 569 cases (46.8%, group A), soft anterior spinal cord compression and heavy canal occupation (>= 50%) in 365 cases (30.0%, group B), bony anterior spinal cord compression and light canal occupation in 210 cases (17.3%, group C), and bony anterior spinal cord compression and heavy canal occupation in 72 cases (5.9%, group D). There was no significant difference in gender, age, disease duration, lesion level, and complications among 4 groups (P>0.05). Because of different levels of spinal cord compression, there were significant differences in visual analogue scale (VAS) and Japanese Orthopaedic Association (JOA) score among 4 groups (P<0.05). RESULTS: Cerebrospinal fluid leakage occurred in 9 cases (2 cases in group A, 1 case in group B, 3 cases in group C, and 3 cases in group D), and was cured after symptomatical treatment. There was no postoperative complication of wound infection, lamina re-closing, or C5 nerve root paralysis in 4 groups. The follow-up time ranged from 24 to 74 months (mean, 35 months). In group D, 17 patients (23.6%) had deteriorated symptom at 6-12 months after operation, and good recovery was achieved in the patients of the other 3 groups. At last follow-up, the JOA score and VAS score were significantly improved when compared with the preoperative scores in 4 groups (P<0.05); the JOA score, improvement rate, and VAS score of group D were significantly lower than those of groups A, B, and C (P<0.05), but there was no significant difference among groups A, B, and C (P>0.05). CONCLUSION: In the multi-level CSM, the anterior compression of the spinal cord should be classified, this has a guiding significance for the prognosis of CSM and the choice of surgical method. PMID- 26750008 TI - [MEDIUM-TERM EFFECTIVENESS OF Waveflex SYSTEM IN TREATMENT OF MULTIPLE LUMBAR DEGENERATIVE DISEASES]. AB - OBJECTIVE: To evaluate the medium-term effectiveness of Waveflex system in the treatment of multiple lumbar degenerative diseases. METHODS: Between May 2010 and July 2012, 26 patients with multiple lumbar degenerative diseases underwent posterior decompression, transforaminal lumbar interbody fusion (TLIF), and internal fixation with Waveflex system. There were 15 males and 11 females, aged 23-65 years (mean, 34.2 years). The disease duration was 9 months to 8 years (median, 3 years and 3 months). The lesion located at L3-S1. The visual analogue scale (VAS), Oswestry disability index (ODI), and the short-form 36 health survey scale (SF-36) were used to evaluate the status of clinical recovery, meanwhile the Stauffer-Coventry evaluation standard was used to access the satisfaction at last follow-up; the disc space height (DSH), intervertebral angle (IVA), and range of motion (ROM) were measured on X-ray film or three-dimensional CT, and the adjacent segment degeneration was classified by Pfirrmann score based on MRI findings. RESULTS: All patients obtained primary incision healing without nerve injury, cerebrospinal fluid leakage, or internal fixation failure. All patients were followed up 31-50 months (mean, 40.6 months). The VAS, ODI, and SF-36 scores were significantly improved at 6 months after operation and last follow-up when compared with preoperative ones (P<0.05), but no significant difference was found between at 6 months and last follow-up (P>0.05). According to the Stauffer Coventry evaluation standard, the results were excellent in 21 cases, good in 2 cases, moderate in 2 cases, and poor in 1 case, with an excellent and good rate of 88.5% at last follow-up. X-ray films showed that there was no complication of screws pulling-out or fixed rod rupture and displacement. At 7 days, 6 months, and last follow-up, the DSH of adjacent segment was significantly increased (P<0.05), and the ROM of adjacent segment was significantly decreased (P<0.05) when compared with preoperative ones; there was no significant difference in IVA between at pre- and post-operation (P>0.05). According to Brantigan grade for fusion, 19 cases were rated as grade E, 6 cases as grade D, and 1 case as grade C, and the fusion rate was 96%. There was no significant difference in Pfirrmann score between at pre-operation and last follow-up (Z=0.000, P=1.000). CONCLUSION: The Waveflex system combined with TLIF is effective and safe to treat multiple lumbar degenerative diseases during medium-term follow-up. PMID- 26750009 TI - [APPLICATION VALUE OF DIGITAL SUBTRACTION ANGIOGRAPHY IN REPAIR OF FOOT AND ANKLE WOUNDS WITH POSTERIOR TIBIAL ARTERIAL PERFORATOR FLAP]. AB - OBJECTIVE: To explore the application value of digital subtraction angiography (DSA) in repairing foot and ankle wounds with posterior tibial arterial perforator flaps. METHODS: Between January 2010 and May 2014, 12 cases of foot and ankle wounds were repaired using posterior tibial arterial perforator flaps. There were 7 males and 5 females with an average age of 36 years (range, 22-54 years). The causes were machine injury in 2 cases, falling injury in 3 cases, and traffic accident injury in 7 cases. The disease duration ranged from 7 to 45 days (mean, 16 days). The size of wound ranged from 6 cm x 4 cm to 10 cm x 5 cm. Preoperative DSA was performed to observe the orientation and distribution of the posterior tibial arterial perforator and the relationship between perforator vessels. Correspondently, the flaps were designed and harvested. The size of flap ranged from 7 cm x 5 cm to 11 cm x 6 cm. The donor sites were repaired with skin grafts. RESULTS: Posterior tibial arterial perforator vessels send out ascending branches and descending branches while going down in the superficial layer. All branches were connected to form vertical chain-form anastamosis, and its orientation was consistent with limb vertical axis. According to DSA results, the flaps were designed and harvested easily. All flaps survived after operation. Meanwhile, wounds healed by first intention. All skin grafts at donor site survived. All patients were followed up 6 months. The flaps had good appearance, color, and texture. No ulcer was found. Affected feet had normal walking function. CONCLUSION: The size, distribution, and chain-form anastamosis condition of the posterior tibial arterial perforator vessels can be accurately observed by DSA, which provides imaging evidence for harvesting posterior tibial arterial perforator flaps and improves the success rate for repairing foot and ankle wounds. PMID- 26750010 TI - [APPLICATION VALUE OF INDOCYANINE GREEN ANGIOGRAPHY IN FLAP RECONSTRUCTIVE SURGERY]. AB - OBJECTIVE: To investigate the utility of indocyanine green angiography in flap reconstructive surgery and possibility of decrease the complications. METHODS: Indocyanine green angiography was performed on 14 patients undergoing flap reconstructive surgery between February and December 2014 to evaluate the blood perfusion of the flap and to adjust the operation plan. Of 14 cases, 2 were male and 12 were female, aged 23-58 years (mean, 35.5 years); 11 flaps were used for breast reconstruction [including 3 free deep inferior epigastric antery perforator (DIEP) flaps, 4 pedicled transverse rectus abdominis myocutaneous flaps (TRAM), 2 pedicled TRAM and free TRAM, and 2 pedicled latissimus dorsi myocutaneous flaps and prosthesis], 1 pedicled latissimus dorsi myocutaneous flap for repairing chest wall defect, 1 pedicled profunda artery perforator (PAP) flap for upper leg defect, and 1 pedicled descending genicular artery perforator flap for knee defect. The size of the flaps ranged from 9 cm x 6 cm to 26 cm x 12 cm. RESULTS: A total of 32 indocyanine green angiography were performed. There was no adverse reactions to the infusion of indocyanine green. The surgery management was adjusted according to results of indocyanine green angiography findings in 5 of 14 cases. The distal part of flap were discarded because of poor perfusion in 3 cases (1 DIEP flap, 1 TRAM, and 1 PAP flap) and the other 2 cases (pedicled TRAM) needed additional free anastomosis to ensure sufficient blood supply (pedicled TRAM and free TRAM); the other flaps were harvested according to preoperative plan and repaired defect successfully. The mean follow-up was 5 months (range, 1-9 months). The other flaps survived without infection or fat necrosis except 1 PAP flap with distal necrosis. CONCLUSION: Intraoperative indocyanine green angiography can provide real-time information of flap perfusion and then the operation plan can be adjusted in time to ensure the flap survival. PMID- 26750011 TI - [EFFECTIVENESS OF DORSAL PENTAGONAL FLAP FOR RECONSTRUCTION OF THE WEB SPACE IN CONGENITAL TOE SYNDACTYLY]. AB - OBJECTIVE: To investigate the effectiveness of dorsal pentagonal flap for reconstruction of the web space in congenital toe syndactyly. METHODS: Between January 2009 and June 2014, 10 patients with congenital toe syndactyly were treated for web space reconstruction with dorsal pentagonal flap. There were 6 boys and 4 girls with the average age of 42 months (range, 8 months to 9 years). The congenital toe syndactyly located at the left foot in 5 cases, the right foot in 4 cases, and both feet in 1 case; 7 patients had polydactyly and 1 patient had brachydactylia. During follow-up, the toe function and web space appearance, web space depth, and web space gradient were observed to evaluate the effectiveness. RESULTS: All 13 flaps survived and incisions healed by first intention. Ten patients were followed up 6-50 months (mean, 26 months). The skin color and texture in 13 reconstructed web spaces were close to normal web space. in 9 patients undergoing web spaces reconstruction of single foot, the abduction angle of toes was (42.879+/-3.703) at the injured side, showing no significant difference when compared with the normal side [(45.922+/-2.657) degrees ] (t= 2.004, P=0.062); the web space depth was (1.881+/-0.266) cm at the injured side and was (1.631+/-0.202) cm at the normal side, showing significant difference (t=2.248, P=0.039); and the web space gradient was (42.733+/-3.421) degrees at the injured side and was (41.189+/-5.593) degrees at the normal side, showing no significant difference (t=0.707, P=0.490). The web space appearance, web space depth, and web space gradient were close to those of the normal web space in 1 patient undergoing bilateral web spaces reconstruction. CONCLUSION: Web space reconstruction with dorsal pentagonal flap is easy to perform with reliable blood supply and low re-operated rate. The cosmetic and functional results are satisfactory. PMID- 26750012 TI - [EFFECTIVENESS OF ADVANCED SKIN FLAP AND V-SHAPED VENTRAL INCISION ALONG THE ROOT OF PENILE SHAFT FOR CONCEALED PENIS]. AB - OBJECTIVE: To investigate effectiveness of advanced skin flap and V-shaped ventral incision along the root of penile shaft for concealed penis in children. METHODS: Between July 2007 and January 2015, 121 boys with concealed penis were treated with advanced skin flap and V-shaped ventral incision along the root of penile shaft. The age varied from 18 months to 13 years (mean, 7.2 years). Repair was based on a vertical incision in median raphe, complete degloving of penis and tacking its base to the dermis of the skin. Advanced skin flap and a V-shaped ventral incision along the root of penile shaft were used to cover the penile shaft. RESULTS: The operation time ranged from 60 to 100 minutes (mean, 75 minutes). Disruption of wound occurred in 1 case, and was cured after dressing change; and primary healing of incision was obtained in the others. The follow-up period ranged from 3 months to 7 years (median, 24 months). All patients achieved good to excellent cosmetic results with a low incidence of complications. The results were satisfactory in exposure of penis and prepuce appearance. No obvious scar was observed. The penis had similar appearance to that after prepuce circumcision. CONCLUSION: A combination of advanced skin flap and V-shaped ventral incision along the root of penile shaft is a simple, safe, and effective procedure for concealed penis with a similar appearance result to the prepuce circumcision. PMID- 26750013 TI - [A COMPARATIVE STUDY ON TREATMENT OF SCAR CONTRACTURE ON FACE, NECK, AND JOINTS WITH PRE-EXPANDED FLAPS AND SKIN GRAFTS]. AB - OBJECTIVE: To study the treatment results of the pre-expanded flaps for scar contracture on face, neck, and joints by comparing with the skin grafts. METHODS: A total of 240 cases of scar contracture between July 2004 and June 2014 were included in the study by random sampling; skin grafts were used in 120 cases (skin graft group), and pre-expanded flaps in 120 cases (pre-expanded flap group). There was no significant difference in age, sex, injury sites, and disease duration between 2 groups (P>0.05). Re-operation rate and A&F 0-6 quantization score were used to evaluate the treatment results. RESULTS: The patients were followed up 12 to 75 months (mean, 23.47 months) in the skin graft group, and 12 to 61 months (mean, 19.62 months) in the pre-expanded flap group. The re-operation rate of the skin graft group was 72.5% (87/120), and was significantly higher than that of the pre-expanded flap group (19.2%, 23/120) (P=0.000). The re-operation rate of the neck contracture in teenagers was the highest. It was 93.9% in the skin graft group and 35.0% in the pre-expanded flap group. In the patients who did not undergo re-operations, A&F 0-6 quantization score of the skin graft group was 2.85+/-1.12, and was significantly lower than that of the pre-expanded flap group (5.22+/-0.74) (t=13.830, P=0.000). CONCLUSION: Pre-expanded flap for scar contracture on face, neck, and joints has lower re-operation rate and better aesthetic and functional restoration than skin graft. It should be regarded as the preferred method for teenagers. PMID- 26750014 TI - [MID-TERM RESULTS OF ARTERIOVENOUS AXILLARY LOOP GRAFT ON CHEST FOR ESTABLISHING HEMODIALYSIS ACCESS]. AB - OBJECTIVE: To explore the role of arteriovenous axillary loop graft (AVALG) on chest for establishing hemodialysis access in patients with chronic renal failure. METHODS: A retrospective analysis was made on the clinical data of 12 patients with chronic renal failure who underwent an AVALG on chest for hemodialysis access between December 2010 and May 2014. There were 2 males and 10 females with an average age of 65.25 years (range, 46-75 years). The main causes were chronic glomerulonephritis in 6 cases, diabetic nephropathy in 4 cases, and both kidney resection because of urinary tract tumors in 2 cases. The disease duration was 2-12 years (mean, 6 years). The 12 patients all underwent 5-14 times (mean, 7 times) failed prior vascular accesses [arteriovenous fistula (AVF) and arteriovenous graft (AVG)] leading to exhaustion of venous access sites on the upper extremities. RESULTS: The AVALG on chest were functionally useful for hemodialysis access, 2-3 times per week, and the blood flow was 250-350 mL/minute; the average time for the first dialysis was 48 days (range, 42-93 days). All patients were followed up 12-54 months (mean, 20.92 months). There was no death during perioperative period. The primary patency rates at 6 and 12 months were 91.7% and 83.3% respectively, and the secondary patency rates at 6 and 12 months were both 100%. After operation, infection (1 case), thrombosis (2 cases), bleeding (2 cases), and swollen (1 case) occurred, which were all cured after corresponding treatment. CONCLUSION: AVALG on chest is a supplementary option for chronic renal failure patients with inadequate upper extremity venous access sites after repeat occlusion. PMID- 26750015 TI - [EFFECTIVENESS OF MODIFIED Park METHOD OF BLEPHAROPLASTY FOR CORRECTION OF MILD BLEPHAROPTOSIS]. AB - OBJECTIVE: To explore the effectiveness of the modified Park method of blepharoplasty for correction of mild blepharoptosis. METHODS: Between October 2012 and January 2015, a new modified Park method of blepharoplasty was performed on 23 patients with foldless eyelid combined mild blepharoptosis. There were 14 males and 9 females, aged 16 to 35 years (mean, 25 years). Unilateral eyelid was involved in 16 cases, bilateral eyelids in 7 cases. The upper eyelid was located at the edge of the pupil, and the drop was 1-2 mm (mean, 1.5 mm). RESULTS: All incisions healed at the first stage; no obvious blood stasis and swelling occurred. The patients were followed up 4 to 26 months, with an average of 15 months. The double eyelid fold was natural and smooth, and ptosis was completely corrected; the eyelid shape and position were symmetry when in situ fixation and movement. According to "double eyelid operation effect evaluation standard discussion" method by Chinese Medical Cosmetology Association, the results were excellent in all patients. CONCLUSION: The modified Park method of blepharoplasty can achieve blepharoplasty and correcting blepharoptosis at the same time for correction of foldless eyelid combined mild blepharoptosis during operation without separated and amputated levator aponeurosis, with small surgical trauma, good controllability, and maneuverability in correction amplitude. PMID- 26750016 TI - [EXPERIMENTAL STUDY ON HUMAN UMBILICAL CORD MESENCHYMAL STEM CELLS-ALGINATE WOUND DRESSING]. AB - OBJECTIVE: To observe the growth characteristics of human umbilical cord mesenchymal stem cells (hUCMSCs) cultured on the alginate gel scaffolds and to explore the feasibility of hUCMSCs-alginate dressing for wound healing. METHODS: hUCMSCs were separated from human umbilical cords and cultured in vitro. After the 4th passage cells were co-cultured with alginate gel (experimental group), the cell growth characteristics were observed under the inverted phase contrast microscope. Vascular endothelial growth factor (VEGF) content was measured and the number of cells was counted at 0, 3, 6, and 9 days after culture; and the cell migration capacity was observed. The hUCMSCs were cultured without alginated gel as control. The model of full-thickness skin defects was established in 32 8 week-old Balb/c male mice and they were randomly divided into 4 groups (n=8): wounds were covered with hUCMSCs-alginate gel compound (MSC-gel group), cell supernatants-alginate gel compound (CS-gel group), 10% FBS-alginate gel compound (FBS-gel group), and 0.01 mol/L PBS-alginate compound (PBS-gel group), respectively. Wound healing rates at 5, 10, and 15 days were observed and calculated; and the wound tissues were harvested for histological and immunohistochemical staining to assess new skin conditions at 15 days after operation. RESULTS: hUCMSCs grew well with grape-like proliferation on the alginate gel, but no cell migration was observed at 7 days after cultivation. VEGF expression and cell number in experimental group were significantly less than those in control group at 3 days (P<0.05); then they gradually increased, and VEGF expression and cell number were significantly more than those in control group at 9 days (P<0.05). The wound healing rates of MSC-gel and CS-gel groups were significantly higher than those of FBS-gel and PBS-gel groups at 5, 10, and 15 days (P<0.05). The squamous epithelium, fibroblasts, sebaceous glands, capillaries and VEGF expression of the new skin in MSC-gel and CS-gel groups were significantly more than FBS-gel and PBS-gel groups (P<0.05). But there was no significance between MSC-gel and CS-gel groups (P>0.05). CONCLUSION: hUCMSCs can continuously express VEGF in alginate gel, which is necessary for wound healing. The hUCMSCs-alginate compound is probably a good wound dressing. PMID- 26750017 TI - [BIOCOMPATIBILITY OF POLY-LACTIDE-CO-GLYCOLIDE/COLLAGEN TYPE I SCAFFOLD WITH RAT VAGINAL EPITHELIAL CELLS]. AB - OBJECTIVE: To explore the biocompatibility of the poly-lactide-co-glycolide (PLGA)/collagen type I scaffold with rat vaginal epithelial cells, and the feasibility of using PLGA/collagen type I as scaffold to reconstruct vagina by the tissue engineering. METHODS: PLGA/collagen type I scaffold was prepared with PLGA covered polylysine and collagen type I. The vaginal epithelial cells of Sprague Dawley rat of 10-12 weeks old were cultured by enzyme digestion method. The vaginal epithelial cells of passage 2 were cultured in the leaching liquor of scaffold for 48 hours to detect its cytotoxicity by MTT. The vaginal epithelial cells were inoculated on the PLGA/collagen type I scaffold (experimental group) and PLGA scaffold (control group) to calculate the cell adhesion rate. Epithelial cells-scaffold complexes were implanted subcutaneously on the rat back. At 2, 4, and 8 weeks after implantation, the epithelial cells-scaffold complexes were harvested to observe the cell growth by HE staining and immunohistochemical analysis. The epithelial cells-scaffold complexes were transplanted to reconstruct vagina in 6 rats with vaginal defect. After 3 and 6 months, the vaginal length was measured and the appearance was observed. The neovagina tissues were harvested for histological evaluation after 6 months. RESULTS: The epithelial cells grew and proliferated well in the leaching liquor of PLGA/collagen type I scaffold, and the cytotoxicity was at grade 1. The cell adhesion rate on the PLGA/collagen type I scaffold was 71.8%+/-9.2%, which significantly higher than that on the PLGA scaffold (63.4%+/-5.7%) (t=2.195, P=0.005). The epithelial cells could grow and adhere to the PLGA/collagen type I scaffolds. At 2 weeks after implanted subcutaneously, the epithelial cells grew and proliferated in the pores of scaffolds, and the fibroblasts were observed. At 4 weeks, 1-3 layers epithelium formed on the surface of scaffold. At 8 weeks, the epithelial cells increased and arranged regularly, which formed the membrane-like layer on the scaffold. The keratin expression of the epithelium was positive. At 3 months after transplantation in situ, the vaginal mucosa showed pink and lustrous epithelialization, and the majority of scaffold degraded. After 6 months, the neovagina length was 1.2 cm, without obvious stenosis; the vaginal mucosa had similar appearance and epithelial layer to normal vagina, but it had less duplicature; there were nail-like processes in the basal layer, but the number was less than that of normal vagina. The immunohistochemistry staining for keratin was positive. CONCLUSION: The PLGA/collagen type I scaffolds have good cytocompatibility with the epithelial cells, and can be used as the biodegradable polymer scaffold of the vaginal tissue engineering. PMID- 26750018 TI - [RESEARCH PROGRESS OF ENDOTHELIAL PROGENITOR CELLS DERIVED EXTRACELLULAR VESICLES]. AB - OBJECTIVE: To review the current progresses in purification strategies, biological characters, and functions of endothelial progenitor cells (EPCs) derived extracellular vesicles (EVs) (EPC-EVs). METHODS: Recent relevant publications on the EPC-EVs were extensively reviewed, analyzed, and summarized. RESULTS: EPC-EVs are usually isolated by differential centrifugation and exhibit a homogenous pattern of spheroid particles with a diameter ranging from 60 to 160 nm under transmission electron microscopy. EPC-EVs are positive for cell-surface markers of EPCs (CD31, CD34, and CD133), and negative for markers of platelets (P selectin and CD42b) and monocytes (CD14). Recent studies have shown the effectiveness of EPC-EVs in ischemic injuries, anti-Thyl glomerulonephritis, and cardiomyocyte hypertrophy, and also shown their predictive role in cardio cerebral-vascular diseases. CONCLUSION: An alluring prospect exists on the EPC EVs-related research. Further studies are required to decipher the composition of EPC-EVs and their precise role in pathophysiological processes, and to investigate the molecular mechanisms for their targeting and function. PMID- 26750019 TI - [RESEARCH PROGRESS OF TISSUE ENGINEERED SCAFFOLDS AND STROMAL-DERIVED FACTOR 1 COMPOSITE GRAFT]. AB - OBJECTIVE: To review the research progress of tissue engineered scaffolds and stromal-derived factor 1 (SDF-1) composite graft. METHODS: The recent papers about SDF-1 with different kinds of tissue engineered scaffolds were reviewed and analyzed. The primary mechanism of SDF-1 homing function for stem cells was retrospected. The results of different kinds of tissue engineered scaffolds carrying SDF-1 for repairing the injured tissues and organs were reviewed. RESULTS: It is shown that SDF-1 combined with tissue engineered scaffolds will play a role of multipotent stem cells chemotaxis, however, the exact chemotaxis mechanism has not been fully understood. It still needs more researches of SDF-1 effects in vivo. CONCLUSION: Although some research progress has been made in regeneration in situ of tissue engineered scaffolds combined with SDF-1, it will need to further study on the mechanism of chemotactic functions of SDF-1 and its influence on proliferation and differentiation of cells. PMID- 26750020 TI - [RESEARCH PROGRESS OF TISSUE ENGINEERED LIGAMENT]. AB - OBJECTIVE: To review the research progress of tissue engineered ligament. METHODS: The literature in recent years on tissue engineered ligament in repair of anterior cruciate ligament (ACL) injury was extensively reviewed, including cell sources, scaffold materials, growth factors, and mechanical stimulation in tissue engineered ligament. RESULTS: Tissue engineered ligament constructed by mesenchymal stem cells and ACL fibroblasts has been successfully used in animal experiments. It is crucial for qualified tissue engineered ligament to choose appropriate seed cells, scaffold, mechanical stimulation, and essential cytokines. To further optimize culture condition and how to realize the tissue engineered ligament in vivo better survival and prognosis need to be further studied. CONCLUSION: Enormous progress has been made in tissue engineered ligament for repair and regeneration of ACL. With the development of biochemistry and scaffold materials, tissue engineered ligament will be used in clinic in the near future. PMID- 26750022 TI - [RESEARCH PROGRESS IN COMPLICATIONS OF RETROGRADE INTRAMEDULLARY NAIL FIXATION FOR TIBIOTALOCALCANEAL ARTHRODESIS]. AB - OBJECTIVE: To review the cause, treatment, and prevention of complications of retrograde intramedullary nail fixation for tibiotalocalcaneal arthrodesis and enhance the recognition on the complications of tibiotalocalcaneal arthrodesis. METHODS: The recent literature concerning intramedullary nail fixation for tibiotalocalcaneal arthrodesis was consulted and reviewed. RESULTS: There are intraoperative and postoperative complications of intramedullary nail fixation for tibiotalocalcaneal arthrodesis, and the causes, treatment, and prevention of complications are various. CONCLUSION: Progress of retrograde intramedullary nail fixation increases the successful rate of tibiotalocalcaneal arthrodesis. However, there is still a high complication rate, so strict preoperative assessment and skilled surgical technique are necessary to prevent complications. PMID- 26750021 TI - [RESEARCH PROGRESS OF MICROENVIRONMENT FOR TREATMENT OF PERIPHERAL NERVOUS INJURIES]. AB - OBJECTIVE: To review the research progress of microenvironment for the treatment of peripheral nervous injuries. METHODS: The recent literature concerning the treatment mechanism of peripheral nervous injuries was extensively consulted, and the microenvironment response involved in the treatment of peripheral nervous injuries was reviewed. RESULTS: The complex microenvironment for treatment of peripheral nervous injuries is dependent on nerve regeneration chamber, the formation of neurotrophic factors, inflammation response, regulation of hormones, signaling pathways, and related enzymes in regulation. In-depth study will help us have a clearer understanding on the distal and proximal neurons axons at the cellular and molecular levels after peripheral nervous injuries. CONCLUSION: In recent years, the researches of microenvironment for the treatment of peripheral nervous injuries have achieved obvious progress. With the current nanotechnology, materials science, genetic engineering, and stem cell transplantation technology, it will provide new ideas and corresponding basis for clinical treatment. PMID- 26750023 TI - [CURRENT PROGRESS OF CLINICAL THERAPY FOR HEMIFACIAL MICROSOMIA]. AB - OBJECTIVE: To summarize the current progress of clinical therapy for hemifacial microsomia (HFM). METHODS: The domestic and overseas articles concerning the treatment of HFM were reviewed and analyzed. RESULTS: The unified therapeutic schedule of HFM has not yet been determined due to its variable clinical manifestation. Therapies mainly include: correction of bone deformity, which attain high effectiveness by adopting distraction osteogenesis or the improvement approach based on it; repair of the hypoplasia of facial soft tissue using graft of free tissue or autologous fat, augmentation of prosthesis materials. Autologous fat is becoming a hot research area and is widely used in recent years. For the aspect of treatment of microtia, different methods are adopted according to the severity of the malformation. CONCLUSION: The uniform clinical diagnosis and therapy of HFM are not determined for its complicated classification and unknown etiology. The research of etiology and tissue engineering may provide the therapy of HFM. PMID- 26750024 TI - Vigilance vital to ensure high standards. PMID- 26750025 TI - Be aware of the Adjusted Treatment Index. AB - The authors of the interim report relating to the Review of Operational Productivity in NHS providers, published in June of this year, are, as many will know, developing a set of Adjusted Treatment Index (ATI) metrics, and are also to publish a model of their interpretation of what an estates department should look like in terms of its operational productivity and cost. This article argues that the underlying reason for the past failures was the creation of static 'point value' metrics similar to the ATIs proposed, and that this can only be overcome by designing and populating a series of non-linear dynamic simulation models with feedback control of an organisation's estate in relation to its asset base and condition with respect to time, together with the resultant financial capital and revenue consequences. It concludes by calling on IHEEM's Council to urgently make representation to the authors of the June 2015 report, and suggests that the Institute's members be fully involved in the design, testing, and interpretation, of the estates model and ATIs. IHEEM's Technology Platforms are ideally placed to play a central role in this. PMID- 26750027 TI - Six thousand lessons 'learned the hard way'. PMID- 26750026 TI - Getting water safety planning right. PMID- 26750028 TI - Delivering change--from vision to reality. PMID- 26750029 TI - Complete wing decanted in L3 m renovation. PMID- 26750030 TI - Hospital 'assets' more quickly located. PMID- 26750031 TI - Using EPCs to deliver energy savings. PMID- 26750032 TI - Reducing water leaks at Castle Hill Hospital. PMID- 26750033 TI - A good showcase for repeatable design. PMID- 26750035 TI - Being aware of the threats from listeriosis. PMID- 26750034 TI - A valuable tool for optimising design. PMID- 26750036 TI - Aiming for a quieter environment. PMID- 26750037 TI - Water wastage reduced and costs cut. PMID- 26750039 TI - Addressing Ghana's rising healthcare demand. PMID- 26750038 TI - Avoiding a slip-up when choosing safety flooring. PMID- 26750040 TI - 'Intelligent load optimisation' in focus. PMID- 26750041 TI - Pipework must be tough and resilient. PMID- 26750042 TI - Planning for the optimal sluice room. PMID- 26750043 TI - Severe malnutrition in children in Papua New Guinea: effect of a multi-faceted intervention to improve quality of care and nutritional outcomes. AB - BACKGROUND AND AIMS: Severe malnutrition remains a major problem in Papua New Guinea; it is associated with 11% of paediatric hospital admissions and 33% of all child deaths, with a case fatality rate around 20%. This article aims to evaluate the effectiveness of a multi-faceted intervention for improving care for children with severe malnutrition. METHODS: Severe malnutrition was defined as weight-for-age (WFA) <-3 Z-scores with severe wasting or mid upper arm circumference <115 mm or generalised oedema owing to malnutrition. The intervention included training for health-care workers on WHO guidelines for severe malnutrition, ward-round checklists, posters and support for nurses to provide better patient nutrition. Three point prevalence surveys were conducted; one before the intervention and two afterwards at 3-month intervals. The main outcomes were weight change since admission, energy intake and the proportion of the calculated required energy intake in the previous 24 hours. Each stage of the WHO guidelines for severe malnutrition management was assessed for adherence. RESULTS: There were significant improvements in the WHO steps for the management of severe malnutrition. At pre-intervention baseline, children received a median of 356 ml/day (IQR 178-450): 31% (95% CI 21-48) of their estimated daily energy requirements for weight. In the first follow-up survey, children received a median of 820 (IQR 600-1110) ml/day: 98% (95% CI 67-100) of daily energy requirements; and in the second follow-up survey they received 780 (IQR 480-900) ml/day: 86% (95% CI 46-100%) of daily requirement (P<0.001 both for volume received and percentage of energy requirements). Median weight gain prior to the intervention was 1.55 g/kg/day (IQR -4.3-6.0) which increased to 5.56 g/kg/day (IQR -3.7-12.0) and 10.19 g/kg/day (IQR 0-16.0) in the first and second follow-up surveys, respectively (P=0.013). CONCLUSION: Implementation of a multi-faceted intervention to improve the management of children with severe malnutrition was associated with improved quality of care and improved weight gain. PMID- 26750046 TI - What's in a Name? Confusing Agitated Saline Contrast with Ultrasound Contrast Agents. PMID- 26750047 TI - Transient Ischemic Attack Caused by Contrast Echocardiography in a Patient with Platypnea-Orthodeoxia. PMID- 26750048 TI - Obscurum Per Obscurius. Which Contrast Agent Should Be Contraindicated for Cardiac Shunt Detection (Agitated Saline Agent vs. Ultrasound Contrast Agent)?: Reply to two Letters. PMID- 26750081 TI - Bioinspired surfaces and materials. PMID- 26750082 TI - Aggregation of alpha-crystallins in kynurenic acid-sensitized UVA photolysis under anaerobic conditions. AB - The reactions of photoexcited kynurenic acid (KNA) with bovine alpha-crystallins under anaerobic conditions proceed via the electron transfer from tryptophan (Trp) and tyrosine (Tyr) residues to the triplet KNA molecules. The subsequent radical reactions lead to the protein aggregation and insolubilization. The absorption of the photolyzed proteins at 335 nm as well as their total fluorescence significantly increases, while the tryptophan-related fluorescence decreases. It has been established that the alterations of the protein optical properties are related to the modifications of Trp residues. Intrinsic lens antioxidants ascorbate (Asc) and glutathione (GSH) that are present in the human lens at the millimolar level effectively block the formation of the observed light-induced protein modifications. The protective effect of Asc was attributed to its ability to quench highly reactive triplet states, while the role of GSH, most likely, corresponds to the reduction of photochemically formed radicals into a diamagnetic state. The results obtained disclose the possible mechanism of UVA induced modifications of the lens crystallins, leading to the formation of cataract, and the role of major lens antioxidants Asc and GSH in the protection of the lens proteins. PMID- 26750086 TI - Ethics teaching in rehabilitation: results of a pan-Canadian workshop with occupational and physical therapy educators. AB - PURPOSE: Ethical practice is an essential competency for occupational and physical therapists. However, rehabilitation educators have few points of reference for choosing appropriate pedagogical and evaluation methods related to ethics. The objectives of this study were to: (1) identify priority content to cover in ethics teaching in occupational therapy (OT) and physical therapy (PT) programmes and (2) explore useful and innovative teaching and evaluation methods. METHOD: Data for this qualitative descriptive study were collected during a 1-d knowledge exchange workshop focused on ethics teaching in rehabilitation. RESULTS: Twenty-three educators from 11 OT and 11 PT Canadian programmes participated in the workshop. They highlighted the importance of teaching foundational theoretical/philosophical approaches and grounding this teaching in concrete examples drawn from rehabilitation practice. A wide range of teaching methods was identified, such as videos, blogs, game-based simulations and role play. For evaluation, participants used written assignments, exams, objective structured clinical examinations and reflective journals. The inclusion of opportunities for student self-evaluation was viewed as important. CONCLUSION: The CREW Day provided ethics educators the opportunity to share knowledge and begin creating a community of practice. This space for dialogue could be expanded to international rehabilitation ethics educators, to facilitate a broader network for sharing of tacit and experiential knowledge. Implications for Rehabilitation According to the study participants, rehabilitation ethics education should include learning about foundational knowledge related to ethical theory; be grounded in examples and cases drawn from clinical rehabilitation practice; and contribute to building professional competencies such as self-knowledge and critical thinking in students. Regardless of the methods used by occupational therapy (OT) and physical therapy (PT) educators for teaching and evaluation, the value of creating spaces that support open discussion for students (e.g. protected discussion time in class, peer-discussions with the help of a facilitator, use of a web discussion forum) was consistently identified as an important facet. Educators from OT and PT programmes should work with various professionals involved in OT and PT student training across the curricula (e.g. clinical preceptors, other educators) to extend discussions of how ethics can be better integrated into the curriculum outside of sessions specifically focused on ethics. The CREW Day workshop was the first opportunity for Canadian rehabilitation ethics educators to meet and discuss their approaches to teaching and evaluating ethics for OT and PT students. Including international rehabilitation ethics educators in this dialogue could positively expand on this initial dialogue by facilitating the sharing of tacit and experiential knowledge amongst a larger and more diverse group of ethics educators. PMID- 26750085 TI - Comparison of Follicular and Luteal Phase Mucosal Markers of HIV Susceptibility in Healthy Women. AB - The purpose of this study was to evaluate differences in vaginal immune cell populations, vaginal tissue gene expression, antimicrobial activity of the cervicovaginal (CV) lavage (CVL), vaginal flora, and p24 antigen production from CV tissues after ex vivo human immunodeficiency virus (HIV) infection between follicular (FOL) and luteal (LUT) phases of the menstrual cycle. CV tissue biopsies, CV secretions, and blood samples were obtained as part of two longitudinal clinical trials of healthy women (CONRAD D11-119 and A12-124 studies). Participants (n = 39) were HIV-seronegative women not using exogenous hormone supplementation, with normal menstrual cycles, who were screened to exclude sexually transmitted and reproductive tract infections. Serum levels of estradiol and progesterone were significantly higher in the LUT versus the FOL phase of the menstrual cycle. Controlling for race, reported contraceptive use/sexual practices, and clinical trial, we found no differences in vaginal tissue immune cell populations and activation status, transcriptomes, inhibition of HIV, herpes simplex virus type 2 and Escherichia coli by the CVL, vaginal pH or Nugent score, or production of p24 antigen after ex vivo infection by HIV-1BaL between CV samples obtained in the FOL phase versus the LUT phase of the menstrual cycle. There were no significant correlations between serum estradiol and progesterone levels and CV endpoints. The hypothesis that the LUT phase of the menstrual cycle represents a more vulnerable stage for mucosal infection with HIV was not supported by data from samples obtained from the lower genital tract (ectocervix and vagina) from these two clinical trials. PMID- 26750087 TI - Discontinuation of Systematic Surveillance and Contact Precautions for Vancomycin Resistant Enterococcus (VRE) and Its Impact on the Incidence of VRE faecium Bacteremia in Patients with Hematologic Malignancies. AB - OBJECTIVE To study the effect of discontinuation of systematic surveillance for vancomycin-resistant Enterococcus (VRE) and contact isolation of colonized patients on the incidence of VRE bacteremia SETTING A hematology-oncology unit with high prevalence of VRE colonization characterized by predominantly sporadic molecular epidemiology PARTICIPANTS Inpatients with hematologic malignancies and recipients of hematopoietic stem cell transplantation METHODS The incidence of VRE bacteremia was measured prospectively during 2 different 3-year time periods; the first during active VRE surveillance and contact precautions and the second after discontinuation of these policies. We assessed the collateral impact of this policy change on the incidence of bacteremia due to methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile infection even though we maintained contact precautions for these organisms. Incidence of infectious events was measured as number of events per 1,000 patients days per month. Time series analysis was used to evaluate trends. RESULTS The incidence of VRE bacteremia remained stable after discontinuation of VRE surveillance and contact precautions. The incidence of MRSA bacteremia and Clostridium difficile infection for which we continued contact precautions also remained stable. Aggregated antibiotic utilization and nursing hours per patient days were similar between the 2 study periods. CONCLUSION Active surveillance and contact precautions for VRE colonization did not appear to prevent VRE bacteremia in patients with hematologic malignancies and recipients of hematopoietic stem cell transplantation with high prevalence of VRE characterized by predominantly sporadic molecular epidemiology. PMID- 26750088 TI - Effectiveness of Community Participation in Earthquake Preparedness: A Community Based Participatory Intervention Study of Tehran. AB - OBJECTIVE: The aim of this study was to evaluate the effectiveness of a community based participatory intervention on earthquake preparedness in Tehran. METHODS: This community-engaged research was conducted during 2011 to 2013. An intervention and a control neighborhood were chosen through systematic cluster sampling. In the intervention group 305 households and in the control group 314 households were sampled for pre- and post-assessment surveys. A participatory intervention was designed on the basis of consultation with the community advisory board and was implemented by trained volunteers. Changes in outcome variables in the intervention and control groups were detected in terms of knowledge, attitude, and practice. Pearson chi-square tests and covariance regression were used to evaluate the effectiveness of the intervention. RESULTS: The results showed that the frequency of earthquake experience in the intervention and control groups was 69.2% and 79.0%, respectively. Moreover, the mean difference scores in knowledge, attitude, and practice in the intervention and control groups before and after the intervention were significant (P<0.001). CONCLUSIONS: A participatory intervention effectively improved disaster preparedness at a community level. To ensure sustainability, the participatory approach should be integrated into public health disaster planning. PMID- 26750089 TI - The Role of Decidual Macrophages During Normal and Pathological Pregnancy. AB - Macrophages perform many specific functions including host defense, homeostasis, angiogenesis, and tissue development. Macrophages are the second most abundant leukocyte population in the non-pregnant endometrium and pregnant decidua and likely play a central role in the establishment and maintenance of normal pregnancy. Importantly, aberrantly activated uterine macrophages can affect trophoblast function and placental development, which may result in various adverse pregnancy outcomes ranging from pre-eclampsia to fetal growth restriction or demise. Only by fully understanding the roles of macrophage in pregnancy will we be able to develop interventions for the treatment of these various pregnancy complications. This review discusses the general origin and classification of monocytes and macrophages and focuses on the phenotype and functional roles of decidual macrophage at the maternal-fetal interface in normal pregnancy, as well as discussing the potential contribution of the abnormal state of these cells to various aspects of pregnancy pathologies. PMID- 26750090 TI - Enhanced Sensitivity for Electrochemical Detection Using Screen-Printed Diamond Electrodes via the Random Microelectrode Array Effect. AB - The electrochemical properties of screen-printed diamond electrodes with various insulating polyester (PES) resin binder/boron-doped diamond powder (BDDP) ratios were investigated for high sensitivity electrochemical detection. For PES/BDDP weight ratios in the range of 0.3-0.5, the BDDP-printed electrodes exhibited cyclic voltammetry (CV) characteristics for Fe(CN)6(3-/4-) that are typical of a planar electrode, whereas microelectrode-like characteristics with sigmoidal CV curves were observed for PES/BDDP ratios of 1.0-2.0. Cu elemental mapping images of copper-electrodeposited BDDP-printed electrodes indicated the formation of island structures with conductive BDDP domains surrounded by an insulating PES matrix for large PES/BDDP ratios. The electrochemical detection of ascorbic acid (AA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) was also investigated using polycrystalline BDD thin-film and BDDP-printed electrodes (PES/BDDP ratio = 0.3 and 1.0). As a result, the signal-to-background (S/B) ratios for the voltammetric detection of AA and 8-OHdG were in the order BDDP-printed electrode (PES/BDDP = 1.0) > BDDP-printed electrode (PES/BDDP = 0.3) > polycrystalline BDD thin film electrode, based on the large faradaic current with respect to the background current. Therefore, the BDDP-printed electrode with a large insulating binder/BDDP ratio has the potential for use as a disposable electrode for electrochemical detection. The electrode is cheaper, lighter and more sensitive than conventional BDD electrodes. PMID- 26750091 TI - Immediate hypersensitivity to iodinated contrast media: diagnostic accuracy of skin tests and intravenous provocation test with low dose. AB - BACKGROUND: The diagnosis of HSR to iodinated contrast media (ICM) is challenging based on clinical history and skin tests. OBJECTIVE: This study evaluates the negative predictive value (NPV) of skin tests and intravenous provocation test (IPT) with low-dose ICM in patients with suspected immediate hypersensitivity reaction (HSR) to ICM. METHODS: Thirty-seven patients with suspected immediate hypersensitivity reaction to ICM were included retrospectively. Skin tests and a single-blind placebo-controlled intravenous provocation test (IPT) with low-dose iodinated contrast media (ICM) were performed. RESULTS: Skin tests with ICM were positive in five cases (one skin prick test and five intradermal test). Thirty six patients were challenged successfully by IPT, and only one patient had a positive challenge result, with a grade I reaction by the Ring and Messmer classification. Ten of 23 patients followed up by telephone were re-exposed to a negative tested ICM during radiologic examination; two experienced a grade I immediate reaction. CONCLUSIONS & CLINICAL RELEVANCE: For immediate hypersensitivity reaction to ICM, the NPV for skin tests and IPT with low dose was 80% (95% CI 44-97%). PMID- 26750093 TI - Docosahexaenoic acid attenuates adipose tissue angiogenesis and insulin resistance in high fat diet-fed middle-aged mice via a sirt1-dependent mechanism. AB - SCOPE: Docosahexaenoic acid (DHA; C22: 6, n-3), one of PUFAs, exerts beneficial effects on inflammatory diseases, obesity and diabetes. Angiogenesis in adipose tissue has a major role in the development of obesity and its related metabolic complications. Inhibition of angiogenesis is an emerging strategy for the novel treatment for obesity. Thus, we examined the effect of DHA on angiogenesis in adipose tissues and investigated the underlying mechanisms. METHODS AND RESULTS: In high-fat diet (HFD) fed middle-aged mice, DHA inhibited the macrophage-derived inflammation and angiogenesis in adipose tissues, reduced adipocyte size and body fat composition and improved insulin sensitivity. Moreover, DHA reversed the HFD induced reduction of Sirt1 in adipose tissues. Interestingly, the effects of DHA were attenuated by lentivirus-mediated Sirt1 knockdown with increasing expression of markers of macrophage-derived inflammation and angiogenesis, associated with impaired insulin sensitivity. CONCLUSION: Overall, our findings demonstrated that DHA reduced angiogenesis of adipose tissues and attenuated insulin resistance in HFD-induced obese mice via the activation of Sirt1. PMID- 26750092 TI - Neonicotinoid concentrations in UK honey from 2013. AB - BACKGROUND: Concentrations of the neonicotinoid insecticides clothianidin, thiamethoxam and imidacloprid were determined in honey collected in Spring 2013 from a variety of locations in England. The honey was produced before the moratorium in the EU on the use of neonicotinoids in pollinator-attractive crops became effective. RESULTS: Neither imidacloprid nor its metabolites were detected in any honey samples. Concentrations of clothianidin ranged from <0.02 to 0.82 ug kg(-1) , and thiamethoxam concentrations were between <0.01 and 0.79 ug kg(-1) . CONCLUSION: Neonicotinoid concentrations were below those likely to cause any chronic mortality. The concentrations detected should provide a useful baseline against which the effectiveness of the moratorium in reducing exposure of honeybees can be measured. (c) 2016 Society of Chemical Industry. PMID- 26750094 TI - Large Omnivore Movements in Response to Surface Mining and Mine Reclamation. AB - Increasing global demands have resulted in widespread proliferation of resource extraction. Scientists are challenged to develop environmental mitigation strategies that meet societal expectations of resource supply, while achieving minimal disruption to sensitive "wilderness" species. We used GPS collar data from a 9-year study on grizzly bears (Ursus arctos) (n = 18) in Alberta, Canada to assess movements and associated space use during versus after mining. Grizzly bear home range overlap with mined areas was lower during active mining except for females with cubs, that also had shortest movements on active mines. However, both females with cubs and males made shorter steps when on/close to mines following mine closure and reclamation. Our results show differences in bear movement and space-use strategies, with individuals from a key population segment (females with cubs) appearing most adaptable to mining disturbance. Preserving patches of original habitat, reclaiming the landscape and minimizing the risk of direct human-induced mortality during and after development can help conserve bears and other wildlife on industrially modified landscapes. PMID- 26750095 TI - Coordinative Modulation of Chlorothricin Biosynthesis by Binding of the Glycosylated Intermediates and End Product to a Responsive Regulator ChlF1. AB - Chlorothricin, isolated from Streptomyces antibioticus, is a parent member of spirotetronate family of antibiotics that have long been appreciated for their remarkable biological activities. ChlF1 plays bifunctional roles in chlorothricin biosynthesis by binding to its target genes (chlJ, chlF1, chlG, and chlK). The dissociation constants of ChlF1 to these genes are ~ 102-140 nm. A consensus sequence, 5'-GTAANNATTTAC-3', was found in these binding sites. ChlF1 represses the transcription of chlF1, chlG, and chlK but activates chlJ, which encodes a key enzyme acyl-CoA carboxyl transferase involved in the chlorothricin biosynthesis. We demonstrate that the end product chlorothricin and likewise its biosynthetic intermediates (demethylsalicycloyl chlorothricin and deschloro chlorothricin) can act as signaling molecules to modulate the binding of ChlF1 to its target genes. Intriguingly, a correlation between the antibacterial activity and binding ability of signaling molecules to the regulator ChlF1 is clearly observed. These features of the signaling molecules are associated with the glycosylation of spirotetronate macrolide aglycone. The findings provide new insights into the TetR family regulators responding to special structure of signaling molecules, and we reveal the regulatory mini-network mediated by ChlF1 in chlorothricin biosynthesis for the first time. PMID- 26750097 TI - The macular findings on spectral-domain optical coherence tomography in premature infants with or without retinopathy of prematurity. AB - The purpose of the study was to present spectral-domain optical coherence tomography (OCT) findings in premature infants with or without mild-to-severe retinopathy of prematurity (ROP). Seventy-two infants born <37 weeks of gestation were analyzed, prospectively. Group 1 (n = 18) included infants without ROP. Infants with stage 1, 2, or 3 ROP without indication for treatment formed the second group (n = 15). Group 3 (n = 21) included threshold cases, who would receive laser photocoagulation (LPC) after OCT examinations. Group 4 (n = 18) had already received LPC. The mean central foveal thickness (CFT) (MUm) in right eyes was 194.27 +/- 19.93, 207.67 +/- 25.44, 224.29 +/- 21.42, and 222.00 +/- 37.80, for groups 1, 2, 3, and 4, respectively (p = 0.01). The presence of a well-formed foveal pit was documented in 60 % of right and 67 % of left eyes in group 1, while a well-formed foveal pit was observed in 14 % of right and 16 % of left eyes in group 3 (p < 0.05). Cystoid macular edema (CME) was shown in 29 % of right and 21 % of left eyes in group 3 (p < 0.05 for right eyes). CME was observed in two of right and left eyes in group 4. Epiretinal membrane (ERM) was shown in one right eye in group 3, two right and four left eyes in group 4 (p < 0.05 for left eyes). Thicker CFT, CME, and failure of a well-formed foveal pit could be related to the severity of ROP. The development of ERM could be the consequence of LPC. PMID- 26750098 TI - The tumor suppressive role of RASSF1A in osteosarcoma through the Wnt signaling pathway. AB - Ras-association domain family 1 isoform A (RASSF1A) is a tumor suppressor gene and its expression is lost in numerous types of cancer cells, including primary osteosarcoma cells. However, its functional significance in osteosarcoma has not been well defined. The messenger RNA (mRNA) expression of RASSF1A in osteosarcoma tissues and corresponding non-tumoral tissues was measured by real-time PCR. Overexpression of RASSF1A was established by an adenoviral vector expressing RASSF1A. Cell migration and invasion were analyzed in transwells. Apoptosis and cell cycle were analyzed using flow cytometry. Wnt/beta-catenin activity was measured by TCF reporter dual-luciferase assay. Cell viability was measured by MTT assay. Protein expression was detected by Western blot. RASSF1A mRNA expression was significantly lower in osteosarcoma tissues than that in the corresponding non-tumoral tissues. The lowered RASSF1A expression correlated with the clinical severity of osteosarcoma. rAd-RASSF1A injection significantly inhibited the growth of xenograft MNNG/HOS tumors in mice. Overexpression of RASSF1A resulted in significant inhibition of the proliferation, migration, and invasion; induced apoptosis; and arrested cell cycle at G0/G1 phase in both the MNNG/HOS and SaOS2 cells. Overexpression of RASSF1A inhibited the Wnt/beta catenin activity, decreased phosphorylation of Akt/glycogen synthase kinase-3 beta (GSK3-beta), and increased phosphorylation of mammalian sterile 20-like kinase 1 (MST1). Overexpression of RASSF1A downregulated the cyclin D1, c-Myc, and matrix metalloproteinase-7 (MMP-7) protein levels. RASSF1A functions as a tumor suppressor in osteosarcoma and exerts anti-cancer roles through regulating Akt/GSK-3-Wnt/beta-catenin signaling. PMID- 26750096 TI - Quantitative Profiling of the Activity of Protein Lysine Methyltransferase SMYD2 Using SILAC-Based Proteomics. AB - The significance of non-histone lysine methylation in cell biology and human disease is an emerging area of research exploration. The development of small molecule inhibitors that selectively and potently target enzymes that catalyze the addition of methyl-groups to lysine residues, such as the protein lysine mono methyltransferase SMYD2, is an active area of drug discovery. Critical to the accurate assessment of biological function is the ability to identify target enzyme substrates and to define enzyme substrate specificity within the context of the cell. Here, using stable isotopic labeling with amino acids in cell culture (SILAC) coupled with immunoaffinity enrichment of mono-methyl-lysine (Kme1) peptides and mass spectrometry, we report a comprehensive, large-scale proteomic study of lysine mono-methylation, comprising a total of 1032 Kme1 sites in esophageal squamous cell carcinoma (ESCC) cells and 1861 Kme1 sites in ESCC cells overexpressing SMYD2. Among these Kme1 sites is a subset of 35 found to be potently down-regulated by both shRNA-mediated knockdown of SMYD2 and LLY-507, a selective small molecule inhibitor of SMYD2. In addition, we report specific protein sequence motifs enriched in Kme1 sites that are directly regulated by endogenous SMYD2 activity, revealing that SMYD2 substrate specificity is more diverse than expected. We further show direct activity of SMYD2 toward BTF3-K2, PDAP1-K126 as well as numerous sites within the repetitive units of two unique and exceptionally large proteins, AHNAK and AHNAK2. Collectively, our findings provide quantitative insights into the cellular activity and substrate recognition of SMYD2 as well as the global landscape and regulation of protein mono-methylation. PMID- 26750099 TI - Influence of PEG Molecular Weight on the Drug Release and In vitro Cytotoxicity of Single-Walled Carbon Nanotubes-PEG-Gemcitabine Conjugates. AB - BACKGROUND: Gemcitabine (GEM) is a highly hydrophil anticancer drug which extensively used in the clinic for the treatment of a range of solid tumors, including pancreatic and lung cancers. We have designed a drug delivery system based on single-walled carbon nanotubes (SWCNTs) for the anticancer drug GEM, which has limitations under biological conditions, by using polyethylene glycol (PEG) to obtain nanoconjugates with high loading capacity, controlled drug release and effective cytotoxicity. METHODS: Raw SWCNTs were functionalized through carboxylation, acylation, PEGylation and finally GEM conjugation via a cleavable ester bond. Different characterization techniques such as Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectrometer (NMR) and differential scanning calorimetry analysis (DSC) were performed to confirm the successful functionalization. Next, the influence of molecular weight (MW) of PEG on the drug loading capacity, drug release and cytotoxicity was studied. RESULTS: Experimental results showed that the drug loading capacity was dependent on the MW of PEG, but the drug release was independent. Also, the results revealed that the nanoconjugates with lower PEG MW caused higher cytotoxicity in A549 and MIA PaCa-2 cancer cells. CONCLUSION: Our studies indicated which of PEG MWs could be useful for this drug delivery system. PMID- 26750100 TI - The Anticancer Activity of Complex [Cu2(MU-(C6H5)2CHCOO)3(bipy)2)] (ClO4) -Solid Lipid Nanoparticles on MCF-7 Cells. AB - Recent studies have focused on the potential use of metal-based complexes for the treatment of cancer. However, there are some limitations of metal-based ligands for the treatment of cancer due to their toxic effects. In the present study, a novel bimetallic Cu(II) complex, [Cu2(MU-(C6H5)2CHCOO)3 (bipy)2)](ClO4), has firstly been synthesized and characterized by FT-IR, and X-ray crystallography. Furthermore, Cu(II) complex-loaded solid lipid nanoparticles (SLNs) were initially prepared by hot homogenization method to overcome their toxic effects. After characterization, comparative cytotoxic and apoptotic activities of the complex and Cu(II) complex-SLNs on human breast cancer cells (MCF-7) and human umbilical vein endothelial cells (HUVEC) were determined. Cu(II) complex demonstrated considerable in vitro cytotoxic effects on MCF-7 (p<0.05) and induced apoptotic cell death (88.02 +/- 3.95%) of MCF-7 cells. But, the complex has also toxic effects (69.5%) on HUVEC control cells. For this purpose, Cu(II) complex-loaded solid lipid nanoparticles (SLN) were firstly produced, with a distrubution range of 190+/-1.45 nm to 350+/-1.72 nm and zeta potentials of 27.4+/-1.98 mV and -18.2+/-1.07 mV, respectively. The scanning electron microscopy (SEM) images of SLNs were also obtained. In vitro studies have shown that Cu(II) complex-SLNs help in reducing the side effect of Cu(II) complex (29.9%) on HUVEC control cells. Therefore, metal based complex might potentially be used for cancer treatment through nanoparticle based drug delivery systems. PMID- 26750101 TI - Solution-based routes to ammine metal borohydrides: formation of ammonia-borane. AB - Ammine metal borohydrides (AMBs) have recently commanded attention as low temperature hydrogen sources. As an alternative to widely used mechanochemical synthesis that affords mixtures with salt co-products, we have been investigating solution synthesis routes to obtain pure AMBs. Here we show that reactions of MCln + nNaBH4 with ammonia in thf afford ammonia-borane (AB) via borane abstraction from M-coordinated borohydride. The amount of AB formed correlates roughly with the metal ion electronegativity and AMB thermal stability, except for reducible metals such as Ti, which affords nearly 3 equiv. of AB per Ti. PMID- 26750104 TI - Functionalization of P4 in the coordination sphere of coinage metal cations. AB - Selective functionalization of white phosphorus is achieved by addition of ArLi to unique cationic coinage metal eta(2)-P4 complexes. This novel approach allows controlled P-C bond formation using the bulky DmpLi (Dmp = 2,6-Mes2C6H3) and the unencumbered MesLi, giving sterically diverse doubly complexed RP4 butterfly derivatives in a single step. PMID- 26750102 TI - Adverse birth outcomes and childhood caries: a cohort study. AB - OBJECTIVES: To examine the association between adverse birth outcomes and dental caries in primary teeth. METHODS: This study included children in Khon Kaen, Thailand, who participated in the Prospective Cohort Study of Thai Children. Preterm was defined as a birth at <37 weeks gestation, low birthweight (LBW) as birthweight <2500 g, and small-for-gestational age (SGA) as birthweight <10th percentile of expected weight for gestational age. Two calibrated dentists measured dental caries in primary teeth when the children were 3-4 years old using decayed, missing and filled surfaces (dmfs) index following the World Health Organization criteria. We used negative binomial regression with generalize linear models to estimate relative risks (RRs) and their 95% confidence intervals (CIs), adjusted for confounding factors. Of 758 children with gestational age data and 833 with birthweight data, the 544 (follow-up rate of 71.8% in preterm and 65.3% in LBW) who had dental data available were included in the analysis. RESULTS: Dental caries was observed in 480 children (88.2%), with a mean dmfs of 14.3 (standard deviation 12.8). The adjusted RR for dental caries was 0.61 (95% CI 0.43, 0.85) for preterm, 0.89 (95% CI 0.67, 1.21) for LBW, and 0.96 (95% CI 0.74, 1.26) for SGA. CONCLUSIONS: There was an inverse association between preterm and childhood caries. LBW and SGA were not associated with dental caries in this population. PMID- 26750105 TI - A burrowing frog from the late Paleocene of Mongolia uncovers a deep history of spadefoot toads (Pelobatoidea) in East Asia. AB - Fossils are indispensible in understanding the evolutionary origins of the modern fauna. Crown-group spadefoot toads (Anura: Pelobatoidea) are the best-known fossorial frog clade to inhabit arid environments, with species utilizing a characteristic bony spade on their foot for burrowing. Endemic to the Northern Hemisphere, they are distributed across the Holarctic except East Asia. Here we report a rare fossil of a crown-group spadefoot toad from the late Paleocene of Mongolia. The phylogenetic analysis using both morphological and molecular information recovered this Asian fossil inside the modern North American pelobatoid clade Scaphiopodidae. The presence of a spade and the phylogenetic position of the new fossil frog strongly support its burrowing behavior. The late Paleocene age and other information suggestive of a mild climate cast doubt on the conventional assertion that burrowing evolved as an adaptation to aridity in spadefoot toads. Temporally and geographically, the new fossil provides the earliest record of Scaphiopodidae worldwide, and the only member of the group in Asia. Quantitative biogeographic analysis suggests that Scaphiopodidae, despite originating in North America, dispersed into East Asia via Beringia in the Early Cenozoic. The absence of spadefoot toads in East Asia today is a result of extinction. PMID- 26750106 TI - Comparison of curved root canals preparation using reciprocating, continuous and an association of motions. AB - The aim of this study was to compare the rotary ProTaper Universal system, the single-file reciprocating WaveOne system and an association of motions assessing shaping ability, cleanliness, preparation time and instrument failures after preparation of curved root canals. Sixty root canals of extracted human molar teeth, with curvatures ranging between 20 degrees and 40 degrees , were divided into three groups, according with preparation system. Canals were prepared until apical size 25 using the ProTaper Universal system (G1), WaveOne (G2), or a hybrid technique (G3) associating reciprocating preparation with rotary glide path and cervical pre-enlargement. Teeth were scanned pre and post-operatively using computed tomography. Direction of transportation and centering ability of canals were measured using a computer image analysis program, and the results were analyzed statistically using one-way ANOVA. Preparation time was analyzed by one-way ANOVA and the Tukey post hoc test. Instrument failures were recorded. The amounts of debris and smear layer were quantified based on a numerical evaluation scale by scanning electron microscopy and were analyzed statistically using the Kruskal-Wallis test. No difference in transportation and centering ratio was found between the systems. Instrumentation with WaveOne was significantly faster than with other instruments (p < 0.05). During preparation, no instruments fractured and three suffered deformations. For debris removal and remaining smear layer, the results for the three groups were similar. The single-file reciprocating instrument was capable of providing faster root canal preparation with similar transporting, centralization and cleaning ability when compared with continuous and an association of motions in curved canals. SCANNING 38:462-468, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26750107 TI - Expression of tropomyosins in lung cancer - a potential role in carcinogenesis and its utility in a histopathological diagnosis. AB - We herein analyzed the relationships between tropomyosin protein expression levels and clinicopathological factors in order to determine the significance of tropomyosins in lung cancers. Although neoplastic cells expressed different isoforms of tropomyosin, overall expression levels were lower than those in bronchial and alveolar epithelial cells. In adenocarcinomas, tropomyosin levels were markedly reduced in poorly differentiated or solid subtype carcinomas, suggesting that a loss in the expression of tropomyosins is involved in the progression of lung adenocarcinomas. The potential utility of the immunohistochemical expression of tropomyosins for a histopathological diagnosis was also investigated. The sensitivity and specificity of a loss in the expression of tropomyosins were 100% and 50%, respectively, which were superior to those for the strong expression of p53 (sensitivity 100% and specificity 44%), a conventional biomarker. An immunohistochemical examination of tropomyosins may assist in the histopathological detection of lung cancer cells in small biopsy specimens. PMID- 26750103 TI - The roles of macrophage autophagy in atherosclerosis. AB - Although various types of drugs and therapies are available to treat atherosclerosis, it remains a major cause of mortality throughout the world. Macrophages are the major source of foam cells, which are hallmarks of atherosclerotic lesions. Consequently, the roles of macrophages in the pathophysiology of atherosclerosis are increasingly investigated. Autophagy is a self-protecting cellular catabolic pathway. Since its discovery, autophagy has been found to be associated with a variety of diseases, including cardiovascular diseases, malignant tumors, neurodegenerative diseases, and immune system disorders. Accumulating evidence demonstrates that autophagy plays an important role in inhibiting inflammation and apoptosis, and in promoting efferocytosis and cholesterol efflux. These facts suggest the induction of autophagy may be exploited as a potential strategy for the treatment of atherosclerosis. In this review we mainly discuss the relationship between macrophage autophagy and atherosclerosis and the molecular mechanisms, as well as the recent advances in targeting the process of autophagy to treat atherosclerosis. PMID- 26750108 TI - Academic and Social Functioning Associated with Attention-Deficit/Hyperactivity Disorder: Latent Class Analyses of Trajectories from Kindergarten to Fifth Grade. AB - Children with attention-deficit/hyperactivity disorder (ADHD) are known to exhibit significantly lower academic and social functioning than other children. Yet the field currently lacks knowledge about specific impairment trajectories experienced by children with ADHD, which may constrain early screening and intervention effectiveness. Data were analyzed from a nationally representative U.S. cohort in the Early Childhood Longitudinal Study, Kindergarten Class of 1998 1999 (ECLS-K) for 590 children (72.7 % male) whose parents reported a formal diagnosis of ADHD. Children's math, reading, and interpersonal skills were assessed at 5 time points between kindergarten and fifth grade. Growth mixture model analyses indicated 4 latent trajectory classes for reading, 8 classes for math, and 4 classes for interpersonal skills. Membership in reading and math trajectory classes was strongly related; overlaps with interpersonal skills classes were weaker. Trajectory class membership was correlated with demographic characteristics and behavioral functioning. Children with ADHD display substantial heterogeneity in their reading, math, and interpersonal growth trajectories, with some groups of children especially likely to display relatively severe levels of academic and social impairment over time. Early screening and intervention to address impairment, particularly reading difficulties, among kindergarten students with ADHD is warranted. PMID- 26750109 TI - Amylin receptor components and the leptin receptor are co-expressed in single rat area postrema neurons. AB - Amylin is a pancreatic beta-cell hormone that acts as a satiating signal to inhibit food intake by binding to amylin receptors (AMYs) and activating a specific neuronal population in the area postrema (AP). AMYs are heterodimers that include a calcitonin receptor (CTR) subunit [CTR isoform a or b (CTRa or CTRb)] and a member of the receptor activity-modifying proteins (RAMPs). Here, we used single-cell quantitative polymerase chain reaction to assess co-expression of AMY subunits in AP neurons from rats that were injected with amylin or vehicle. Because amylin interacts synergistically with the adipokine leptin to reduce body weight, we also assessed the co-expression of AMY and the leptin receptor isoform b (LepRb) in amylin-activated AP neurons. Single cells were collected from Wistar rats and from transgenic Fos-GFP rats that express green fluorescent protein (GFP) under the control of the Fos promoter. We found that the mRNAs of CTRa, RAMP1, RAMP2 and RAMP3 were all co-expressed in single AP neurons. Moreover, most of the CTRa+ cells co-expressed more than one of the RAMPs. Amylin down-regulated RAMP1 and RAMP3 but not CTR mRNAs in AMY+ neurons, suggesting a possible negative feedback mechanism of amylin at its own primary receptors. Interestingly, amylin up-regulated RAMP2 mRNA. We also found that a high percentage of single cells that co-expressed all components of a functional AMY expressed LepRb mRNA. Thus, single AP cells expressed both AMY and LepRb, which formed a population of first-order neurons that presumably can be directly activated by amylin and, at least in part, also by leptin. PMID- 26750112 TI - Application of Model-Based Approaches to Evaluate Hepatic Transporter-Mediated Drug Clearance: In vitro, In vivo, and In vitro-In vivo Extrapolation. AB - BACKGROUND: Hepatic transporters, including efflux transporters and uptake transporters, have been recognized to play an important role in the disposition of various drugs. These membrane transporters show extensive substrate specificity with an abundance of overlap, implying the probability of transporter involved in the drug-drug interactions with other drugs. Thus reliable techniques are taken into consideration to evaluate the role of transporter-mediated drug disposition and possible effects on pharmacokinetics in the research. METHODS: An electronic search of PubMed database from inception to December, 2015 was conducted. In addition, we searched the reference lists of included studies and carried out a citation search for the included studies via Web of Science to find other potentially relevant studies. RESULTS AND CONCLUSION: The function of membrane transporters could be evaluated in vitro, in situ and in vivo, employing models spanning from cell-based assay to transgenic mouse. Each technique has its own application with specific advantages and limitations. The readers will gain insight into techniques applied to evaluate the drug clearance mediated by hepatic transporters. In addition, this review focuses particularly on the in vitro-in vivo extrapolation of hepatic transporter-mediated drug clearance. The challenges and gaps of the extrapolation are further discussed. The increased understanding of this knowledge would improve the capability to predict the in vivo situation. PMID- 26750110 TI - Direct and Absolute Quantification of over 1800 Yeast Proteins via Selected Reaction Monitoring. AB - Defining intracellular protein concentration is critical in molecular systems biology. Although strategies for determining relative protein changes are available, defining robust absolute values in copies per cell has proven significantly more challenging. Here we present a reference data set quantifying over 1800Saccharomyces cerevisiaeproteins by direct means using protein-specific stable-isotope labeled internal standards and selected reaction monitoring (SRM) mass spectrometry, far exceeding any previous study. This was achieved by careful design of over 100 QconCAT recombinant proteins as standards, defining 1167 proteins in terms of copies per cell and upper limits on a further 668, with robust CVs routinely less than 20%. The selected reaction monitoring-derived proteome is compared with existing quantitative data sets, highlighting the disparities between methodologies. Coupled with a quantification of the transcriptome by RNA-seq taken from the same cells, these data support revised estimates of several fundamental molecular parameters: a total protein count of ~100 million molecules-per-cell, a median of ~1000 proteins-per-transcript, and a linear model of protein translation explaining 70% of the variance in translation rate. This work contributes a "gold-standard" reference yeast proteome (including 532 values based on high quality, dual peptide quantification) that can be widely used in systems models and for other comparative studies. PMID- 26750114 TI - Progress in neuroscience in Africa: editorial. PMID- 26750113 TI - Botulinum toxin for treatment of Harlequin syndrome. AB - We described a patient with Harlequin syndrome, a rare neurological condition, characterized by unilateral facial sweating and flushing, who had a good response to botulinum toxin application. She had been submitted to sympathectomy a few years, however she still complained of excessive sweating in the regions mentioned and intense flushing. PMID- 26750111 TI - Molecular Targets for Small-Molecule Modulators of Circadian Clocks. AB - BACKGROUND: Circadian clocks are endogenous timing systems that regulate various aspects of mammalian metabolism, physiology and behavior. Traditional chronotherapy refers to the administration of drugs in a defined circadian time window to achieve optimal pharmacokinetic and therapeutic efficacies. In recent years, substantial efforts have been dedicated to developing novel small-molecule modulators of circadian clocks. METHODS: Here, we review the recent progress in the identification of molecular targets of small-molecule clock modulators and their efficacies in clock-related disorders. Specifically, we examine the clock components and regulatory factors as possible molecular targets of small molecules, and we review several key clock-related disorders as promising venues for testing the preventive/therapeutic efficacies of these small molecules. Finally, we also discuss circadian regulation of drug metabolism. RESULTS: Small molecules can modulate the period, phase and/or amplitude of the circadian cycle. Core clock proteins, nuclear hormone receptors, and clock-related kinases and other epigenetic regulators are promising molecular targets for small molecules. Through these targets small molecules exert protective effects against clock related disorders including the metabolic syndrome, immune disorders, sleep disorders and cancer. Small molecules can also modulate circadian drug metabolism and response to existing therapeutics. CONCLUSION: Small-molecule clock modulators target clock components or diverse cellular pathways that functionally impinge upon the clock. Target identification of new small-molecule modulators will deepen our understanding of key regulatory nodes in the circadian network. Studies of clock modulators will facilitate their therapeutic applications, alone or in combination, for clock-related diseases. PMID- 26750115 TI - Editorial: Targeting Defective DNA Damage Response Signaling. PMID- 26750118 TI - Pharmacoterrorism: the potential role of psychoactive drugs in the Paris and Tunisian attacks. PMID- 26750117 TI - The Role of Routine Upper Gastrointestinal Endoscopy Before Bariatric Surgery. AB - BACKGROUND: Obesity remains a major health concern for which surgery has proven to be the most effective treatment in the long term. Routine upper gastrointestinal endoscopy (UGE) is recommended before surgery, but few studies have evaluated its impact on postoperative complications. METHODS: We studied a cohort of 613 patients submitted to UGE before being listed for bariatric surgery between May 2004 and May 2015. A logistic regression analysis was performed to evaluate potential predictors of postoperative complications. RESULTS: Three hundred forty-five patients (56.3 %) presented abnormal endoscopic findings. Helicobacter pylori (Hp) was the strongest predictor of an abnormal endoscopy (OR 10.343, 95 % CI [3.970-26.943], p < 0.001). Of the 342 patients who underwent surgery, 43 (12.6%) developed a postsurgical complication and 2 (0.6%) patients died. In regression analysis, endoscopic ulceration was the only predictor of postoperative complications (OR 11.10, 95 % CI [1.80-68.467], p = 0.01). All patients with gastroduodenal ulcers were infected with Hp. CONCLUSIONS: UGE before bariatric surgery can identify a wide range of abnormal findings. Gastric and duodenal ulcers appear to be the major findings associated with postoperative complications. Routine Hp eradication may potentially reduce the risk of postoperative complications and should be attempted in all patients before surgery. PMID- 26750116 TI - Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding. AB - AIMS/HYPOTHESIS: Individuals who had a low birthweight (LBW) are at an increased risk of insulin resistance and type 2 diabetes when exposed to high-fat overfeeding (HFO). We studied genome-wide mRNA expression and DNA methylation in subcutaneous adipose tissue (SAT) after 5 days of HFO and after a control diet in 40 young men, of whom 16 had LBW. METHODS: mRNA expression was analysed using Affymetrix Human Gene 1.0 ST arrays and DNA methylation using Illumina 450K BeadChip arrays. RESULTS: We found differential DNA methylation at 53 sites in SAT from LBW vs normal birthweight (NBW) men (false discovery rate <5%), including sites in the FADS2 and CPLX1 genes previously associated with type 2 diabetes. When we used reference-free cell mixture adjustments to potentially adjust for cell composition, 4,323 sites had differential methylation in LBW vs NBW men. However, no differences in SAT gene expression levels were identified between LBW and NBW men. In the combined group of all 40 participants, 3,276 genes (16.5%) were differentially expressed in SAT after HFO (false discovery rate <5%) and there was no difference between LBW men and controls. The most strongly upregulated genes were ELOVL6, FADS2 and NNAT; in contrast, INSR, IRS2 and the SLC27A2 fatty acid transporter showed decreased expression after HFO. Interestingly, SLC27A2 expression correlated negatively with diabetes- and obesity-related traits in a replication cohort of 142 individuals. DNA methylation at 652 CpG sites (including in CDK5, IGFBP5 and SLC2A4) was altered in SAT after overfeeding in this and in another cohort. CONCLUSIONS/INTERPRETATION: Young men who had a LBW exhibit epigenetic alterations in their adipose tissue that potentially influence insulin resistance and risk of type 2 diabetes. Short-term overfeeding influences gene transcription and, to some extent, DNA methylation in adipose tissue; there was no major difference in this response between LBW and control participants. PMID- 26750119 TI - Myelodysplastic syndrome with del (5q) and JAK2(V617F) mutation transformed to acute myeloid leukaemia with complex karyotype. PMID- 26750120 TI - Cloning, Expression, Purification, Regulation, and Subcellular Localization of a Mini-protein from Campylobacter jejuni. AB - The Cj1169c-encoded putative protein of Campylobacter was expressed and purified from E. coli after sequence optimization. The purified protein allowed the production of a specific rabbit antiserum that was used to study the protein expression in vitro and its subcellular localization in the bacterial cell and putative interactions with other proteins. This protein is produced in Campylobacter and it clearly localizes into the periplasmic space. The level of protein production depends on factors, including pH, temperature, osmolarity, and growth phase suggesting a role in the Campylobacter environmental adaptation. The cysteine residues present in the sequence are probably involved in disulfide bridges, which may promote covalent interactions with other proteins of the Campylobacter envelope. PMID- 26750121 TI - Conservation of the Essential Genome Among Caulobacter and Brevundimonas Species. AB - When the genomes of Caulobacter isolates NA1000 and K31 were compared, numerous genome rearrangements were observed. In contrast, similar comparisons of closely related species of other bacterial genera revealed nominal rearrangements. A phylogenetic analysis of the 16S rRNA indicated that K31 is more closely related to Caulobacter henricii CB4 than to other known Caulobacters. Therefore, we sequenced the CB4 genome and compared it to all of the available Caulobacter genomes to study genome rearrangements, discern the conservation of the NA1000 essential genome, and address concerns about using 16S rRNA to group Caulobacter species. We also sequenced the novel bacteria, Brevundimonas DS20, a representative of the genus most closely related to Caulobacter and used it as part of an outgroup for phylogenetic comparisons. We expected to find that there would be fewer rearrangements when comparing more closely related Caulobacters. However, we found that relatedness was not correlated with the amount of observed "genome scrambling." We also discovered that nearly all of the essential genes previously identified for C. crescentus are present in the other Caulobacter genomes and in the Brevundimonas genomes as well. However, a few of these essential genes were only found in NA1000, and some were missing in a combination of one or more species, while other proteins were 100 % identical across species. Also, phylogenetic comparisons of highly conserved genomic regions revealed clades similar to those identified by 16S rRNA-based phylogenies, verifying that 16S rRNA sequence comparisons are a valid method for grouping Caulobacters. PMID- 26750122 TI - In Vitro Antibiofilm Activity of an Exopolysaccharide from the Marine Thermophilic Bacillus licheniformis T14. AB - The development of antibiofilm strategies is of major interest in contrasting bacterial pathogenic biofilms. A novel fructose and fucose rich exopolysaccharide (EPS1-T14) produced by the recently described thermophilic Bacillus licheniformis T14, isolated from a shallow hydrothermal vent of Panarea Island (Eolian Island, Italy), was evaluated for its effects on biofilm formation by multiresistant clinical strains of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. The antibiofilm activity of EPS1-T14 was assessed by microtiter plate assays and visualized by confocal laser scanning microscopic images. EPS1-T14, with molecular weight of 1000 kDa, reduced biofilm formation on abiotic surfaces without affecting bacterial vitality. The novel EPS1-T14 is a water-soluble, noncytotoxic exopolymer able to prevent biofilm formation and its use may represent a promising therapeutic strategy for combating bacterial biofilm-associated infections. EPS1-T14 as antiadhesive biomolecule could be useful for novel prospective in medical and nonmedical applications. PMID- 26750123 TI - Carotenoid Production by Halophilic Archaea Under Different Culture Conditions. AB - Carotenoids are pigments that may be used as colorants and antioxidants in food, pharmaceutical, and cosmetic industries. Since they also benefit human health, great efforts have been undertaken to search for natural sources of carotenoids, including microbial ones. The optimization of culture conditions to increase carotenoid yield is one of the strategies used to minimize the high cost of carotenoid production by microorganisms. Halophilic archaea are capable of producing carotenoids according to culture conditions. Their main carotenoid is bacterioruberin with 50 carbon atoms. In fact, the carotenoid has important biological functions since it acts as cell membrane reinforcement and it protects the microorganism against DNA damaging agents. Moreover, carotenoid extracts from halophilic archaea have shown high antioxidant capacity. Therefore, current review summarizes the effect of different culture conditions such as salt and carbon source concentrations in the medium, light incidence, and oxygen tension on carotenoid production by halophilic archaea and the strategies such as optimization methodology and two-stage cultivation already used to increase the carotenoid yield of these microorganisms. PMID- 26750124 TI - BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. PMID- 26750125 TI - BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part II: analgesics and other drugs used in rheumatology practice. PMID- 26750126 TI - Non-Invasive Neuromodulation for Headache Disorders. AB - Migraine and other chronic headache disorders are common and if inadequately treated, can lead to significant disability. The effectiveness of medications can be limited by side effects, drug interactions, and comorbid diseases necessitating alternative methods. Technological developments in the past 5 years have made it possible to use non-invasive methods of neuromodulation to treat primary headache disorders. This field includes technologies such as supraorbital transcutaneous stimulation (STS), transcranial magnetic stimulation (TMS), and non-invasive vagal nerve stimulation (nVNS). Existing trials show these modalities are safe and well tolerated and can be combined with standard pharmacotherapy. We review the technologies, biological rationales, and trials involving non-invasive neuromodulation for the treatment of primary headache disorders. PMID- 26750127 TI - Developments in Varicella Zoster Virus Vasculopathy. AB - Varicella zoster virus (VZV) is a highly neurotropic human herpesvirus. Primary infection usually causes varicella (chicken pox), after which virus becomes latent in ganglionic neurons along the entire neuraxis. VZV reactivation results in zoster (shingles) which is frequently complicated by chronic pain (postherpetic neuralgia). VZV reactivation also causes meningoencephalitis, myelitis, ocular disorders, and vasculopathy, all of which can occur in the absence of rash. This review focuses on the association of VZV and stroke, and on the widening spectrum of disorders produced by VZV vasculopathy in immunocompetent and immunocompromised individuals, including recipients of varicella vaccine. Aside from ischemic stroke, VZV infection of cerebral arteries may lead to development of intracerebral aneurysms, with or without hemorrhage. Moreover, recent clinical-virological case reports and retrospective pathological virological analyses of temporal arteries positive or negative for giant cell arteritis (GCA) indicate that extracranial VZV vasculopathy triggers the immunopathology of GCA. While many patients with GCA improve after corticosteroid treatment, prolonged corticosteroid use may potentiate VZV infection, leading to fatal vasculopathy in the brain and other organs. PMID- 26750128 TI - Nitrosoureas in the Management of Malignant Gliomas. AB - Nitrosoureas represent one of the most active classes of agents in the treatment of high-grade gliomas and glioblastoma. In clinical practice, the most commonly used compounds are lomustine (either alone or in combination with procarbazine and vincristine), carmustine, and fotemustine. Given their toxicity profile and subsequent to the introduction of temozolomide in clinical practice, most of these agents were moved to the recurrent setting. This review focuses on the role of the nitrosoureas currently used in clinical practice for the treatment of malignant gliomas. PMID- 26750129 TI - Non-pharmacological Management of Behavioral Symptoms in Frontotemporal and Other Dementias. AB - Worldwide prevalence of dementia is predicted to double every 20 years. The most common cause in individuals over 65 is Alzheimer's disease (AD), but in those under 65, frontotemporal dementia (FTD) is as frequent. The physical and cognitive decline that characterizes these diseases is commonly accompanied by troublesome behavioral symptoms. These behavioral symptoms contribute to significant morbidity and mortality among both patients and caregivers. Medications have been largely ineffective in managing these symptoms and carry significant adverse effects. Non-pharmacological interventions have been recommended to precede the utilization of pharmacological treatments. This article reviews the research about these interventions with special attention to the variations by etiology, especially FTD. The authors offer recommendations for improving utilization of these strategies and future research recommendations. PMID- 26750133 TI - Editorial: Look for Changes in 2016. PMID- 26750130 TI - Current Management of Adult Diffuse Infiltrative Low Grade Gliomas. AB - Diffuse infiltrative low grade gliomas (LGG) account for approximately 15 % of all gliomas. The prognosis of LGG differs between high-risk and low-risk patients notwithstanding varying definitions of what constitutes a high-risk patient. Maximal safe resection optimally is the initial treatment. Surgery that achieves a large volume resection improves both progression-free and overall survival. Based on results of three randomized clinical trials (RCT), radiotherapy (RT) may be deferred in patients with low-risk LGG (defined as age <40 years and having undergone a complete resection), although combined chemoradiotherapy has never been prospectively evaluated in the low-risk population. The recent RTOG 9802 RCT established a new standard of care in high-risk patients (defined as age >40 years or incomplete resection) by demonstrating a nearly twofold improvement in overall survival with the addition of PCV (procarbazine, CCNU, vincristine) chemotherapy following RT as compared to RT alone. Chemotherapy alone as a treatment of LGG may result in less toxicity than RT; however, this has only been prospectively studied once (EORTC 22033) in high-risk patients. A challenge remains to define when an aggressive treatment improves survival without impacting quality of life (QoL) or neurocognitive function and when an effective treatment can be delayed in order to preserve QoL without impacting survival. Current WHO histopathological classification is poorly predictive of outcome in patients with LGG. The integration of molecular biomarkers with histology will lead to an improved classification that more accurately reflects underlying tumor biology, prognosis, and hopefully best therapy. PMID- 26750131 TI - Molecular identification and phylogenetic analysis of Dipetalonema evansi (LEWIS, 1882) in camels (Camelus dromedarius) of Iran. AB - Despite the economic importance of camels, the parasites that affect them have not received adequate attention so far and molecular studies are scarce compared to other livestock. In this study, we characterized peripheral blood microfilariae in 200 healthy one-humped camels (Camelus dromedarius) from south east Iran by microscopy and molecular tools to receive a more detailed insight into prevalence and species that affect them. Moreover, adult specimens of the filarial nematode Dipetalonema evansi were collected from the carcass of an infected animal. Microscopic examination was performed on Giemsa-stained blood smears, and blood was also spotted on Whatman FTA((r)) cards for DNA analysis. Genomic DNA was extracted, and PCR was carried out for the detection of filaroid helminths, followed by sequence analysis of positive samples. Four samples were positive for microfilariae by microscopy, while 16 animals (8 %) were positive by PCR. Sequence analysis revealed D. evansi in all cases. Phylogenetic analysis of a cytochrome C oxidase subunit I (COI) sequence of filaroid nematodes showed that most species in a single genus cluster in the same clade; however, D. evansi and D. gracile are not monophyletic and branch rather at the base of the tree. Further studies on the life cycle of D. evansi, specifically the identification of intermediate host(s), have become feasible with the provision of the first specific COI sequences in this study. PMID- 26750132 TI - Age-Related Expression of a Repeat-Rich Intergenic Long Noncoding RNA in the Rat Brain. AB - Genome-wide transcriptome analysis has shown that ~90 % of the mammalian genome undergoes pervasive transcription into various small and long noncoding RNAs with diverse biological functions and only ~1.5 % is protein coding. Recent literature suggests that various structurally diverse sense and antisense long noncoding RNAs (lncRNAs) (>200 nt) are expressed from the intronic, intergenic and repeat rich regions in the mammalian central nervous system (CNS). Till date, many of them have been found to be regulated in developmental, spatio-temporal and cell type-specific manners and are involved in various neurological processes. However, still much is left to be understood regarding their functional relevance in mammalian brain development, maturation and ageing. Furthermore, various signalling factors and metabolites such as all-trans retinoic acid (atRA) have been known to regulate brain functions during development, though their role in adult brain function is much less known. Here, we report differential and age related expression of a novel repeat sequence-rich, long intergenic nonprotein coding RNA (lincRNA), named as LINC-RSAS (repeat-rich sense-antisense transcript) in different neuroanatomical regions of the rat brain. The LINC-RSAS was found to be moderately conserved and contained regulatory elements of various cell growth- and development-specific transcriptional factors in its up/downstream flanking sequences in the genome. Through RNA expression by reverse transcription polymerase chain reaction (RT-PCR) and localization by in situ RNA hybridization, we found that both sense and antisense transcripts of LINC-RSAS were expressed in the cortex, hippocampus and cerebellum regions of the rat brain in cell type specific and age-related manner. Furthermore, both the expression level and subcellular localization of the antisense LINC-RSAS transcript were significantly induced in the cultured primary hippocampal neurons after treatment with atRA. Overall, our study provides insights into the possible involvement of an atRA inducible, intergenic lncRNA in different functional regions of mammalian brain and its association with brain maturation and ageing. PMID- 26750134 TI - Is personality relevant in the choice of bleaching? AB - OBJECTIVES: The purpose was to administer the NEO-FFI personality test to patients who did and did not want to have their teeth bleached and before and after bleaching to the participants who accepted the treatment. The research question is to correlate styles and personality factors with bleaching. MATERIALS AND METHODS: There were 128 patients eligible for bleaching; 58 accepted (AB) while 70 refused (RB). The test was administered to both groups (AB-RB). The group AB was administered before and 1 week after the end of the bleaching. For each personality domain comparison, the Mann-Whitney test was used. For the group AB, the results for each domain before and after bleaching were compared using the Wilcoxon test. RESULTS: There was a significant difference between the groups (AB-RB) in the extraversion factor (p = 0.01). There was no significant difference between any of the personality items before and after bleaching (p > 0.1). The comparison between groups by sex revealed significant differences in extraversion and neuroticism factors. Males who AB scored higher in extraversion than males who RB (p < 0.05). Females scored higher in neuroticism than males who AB (p < 0.05). CONCLUSIONS: There were personality differences between people who decided to bleach compared with those who did not want the bleaching, which was mainly in the extroversion factor. This stereotypes the patients, who could be described as more sociable, extroverted, and concerned about esthetics and cleanliness. The bleaching protocol, however, cannot modify any of the personality factors. CLINICAL SIGNIFICANCE: It is important to understand a patient's behavior to meet their needs and to determine the type of patients who would like to have their teeth bleached. PMID- 26750136 TI - Vitamin D Deficiency in Critically Ill Children: Bystander or Culprit? PMID- 26750135 TI - Salivary function impairment in type 2 Diabetes patients associated with concentration and genetic polymorphisms of chromogranin A. AB - OBJECTIVES: The purpose of this study was to evaluate the effect of type 2 diabetes mellitus (T2DM) on salivary function impairments according to glycemic control status and subsequently compare the concentration of chromogranin A (CHGA) with its genetic profile. MATERIALS AND METHODS: Thirty-six patients with controlled T2DM, 36 with poorly controlled T2DM, and 38 nondiabetic subjects underwent salivary flow rate measurements by means of unstimulated labial (ULS), unstimulated whole (UWS), and stimulated whole saliva (SWS) collections. CHGA concentrations were determined in saliva and plasma with ELISA, and two CHGA polymorphisms (T-415C and Glu264Asp) were analyzed by polymerase chain reaction restriction fragment length polymorphism. RESULTS: T2DM patients presented significantly lower ULS and UWS flow rates regardless of glycemic control status compared to controls (P = 0.002 and P = 0.027, respectively). The SWS flow rate in the poorly controlled T2DM was the lowest among the groups (P = 0.026). Significantly higher plasma and salivary CHGA levels were found in T2DM groups (P = 0.019 and P < 0.001, respectively). CHGA gene variants (T-415C and Glu264Asp) revealed significant differences between diabetics and control subjects when associated with lower salivary flow and higher salivary CHGA production (P < 0.05). CONCLUSIONS: T2DM causes abnormalities in the function of salivary glands. However, poorly controlled T2DM has the most influence on SWS flow rates. Our findings indicate an association between plasma and salivary CHGA levels and T2DM patients. Furthermore, the results suggest that CGHA polymorphisms might be associated with salivary gland hypofunction and higher salivary CHGA production in T2DM patients. Nevertheless, further epidemiological studies are required to elucidate this clinical implication. CLINICAL RELEVANCE: Salivary impairments and high levels of CHGA are associated with T2DM patients. In addition, CGHA polymorphisms might be associated with salivary gland hypofunction and higher salivary CHGA production in T2DM patients. This could be a significant insight to establish a role for salivary CHGA as a potential clinical biomarker to T2DM. PMID- 26750137 TI - Patterns and surgical significance of facial nerve branching within the parotid gland in 43 cases. AB - PURPOSE: Different patterns of facial nerve branching within the parotid gland were detected, and these anatomical variations may affect the treatment approaches and outcomes of surgery. The aim of this study was to identify the patterns of facial nerve branching with the parotid gland and their importance in surgical procedures. MATERIALS AND METHODS: A total of 43 patients undergoing surgical treatments of parotid lesions were included in this study. Each patient's demographic data and type of operation were recorded. In addition, the courses of the facial nerve within the gland were classified into six types according to their branching patterns and communication. RESULTS: In all of the patients, the facial nerve consisted of one trunk separated into two divisions. Branching type III was the most common variety found (30.2 %) followed by type II (23.2 %), while type V represented the least frequent pattern (4.6 %). CONCLUSION: It is essential for surgeons to become familiar with the different types of nerve morphologies in order to avoid morbidity and preserve the facial nerve during surgery. Variations and anastomosis can explain the different consequences of facial nerve injury that may occur after parotid surgery. PMID- 26750140 TI - Advances in Exploring the Role of Micrornas in Inflammatory Bowel Disease. AB - Inflammatory bowel diseases, including Crohn's Disease and Ulcerative Colitis, result from a dysregulated inflammatory response to environmental factors in genetically predisposed individuals. The list of genetic factors involved in the development of these diseases has considerably increased in last years. However, recently, new promising insights on inflammatory bowel diseases have been produced by studies on microRNAs. MicroRNAs are small non coding RNA molecules, that play a pivotal role in gene expression and regulation. They are involved in many biological processes, such as cellular proliferation and differentiation, signal transduction and, more recently, they have been recognized as also having a role in the innate and adaptative response. In this review we give an overview on the role of microRNAs in the pathogenesis of inflammatory bowel diseases. PMID- 26750138 TI - The Role of Lymphocyte to Monocyte Ratio, Microvessel Density and HiGH CD44 Tumor Cell Expression in Non Hodgkin Lymphomas. AB - Prognostic significance of immune microenvironment has been emphasized using the most advanced analysis, with consecutive attempts to reveal prognostic impact of this findings. The aim of this study was to compare and define prognostic significance of clinical parameters, microvessel density (MVD) in tumour tissue and expression of CD44s as adhesive molecule on tumour cells in diffuse large B cell lymphoma-DLBCL, primary central nervous system DLBCL-CNS DLBCL and follicular lymphoma-FL. A total of 202 histopathological samples (115 DLBCL/65 FL/22 CNS DLBCL) were evaluated. Overall response (complete/partial remission) was achieved in 81.3 % DLBCL patients, 81.8 % primary CNS DLBCL and 92.3 % FL. Absolute lymphocyte count-ALC/Absolute monocyte count-AMC >2.6 in DLBCL and ALC/AMC >= 4.7 in FL were associated with better event-free survival (EFS) and overall survival (OS) (p < 0.05). In DLBCL, MVD > 42 blood vessels/0.36 mm(2) correlated with primary resistant disease (p < 0.0001), poorer EFS and OS (p = 0.014). High CD44s expression in FL correlated with inferior EFS and OS (p < 0.01). In DLBCL, multivariate Cox regression analysis showed that ALC/AMC was independent parameter that affected OS (HR 3.27, 95 % CI 1.51-7.09, p = 0.003) along with the NCCN-IPI (HR 1.39, 95 % CI 1.08-1.79, p = 0.01). Furthermore, in FL, ALC/AMC mostly influenced OS (HR 5.21, 95 % CI 1.17-23.21, p = 0.03), followed with the FLIPI (HR 3.98, 95 % CI 1.06-14.95, p = 0.041). In DLBCL and FL, ALC/AMC is simple and robust tool that is, with current prognostic scores, able to define long-term survival and identify patients with inferior outcome. The introduction of immunochemotherapy might altered the prognostic significance of microenvionmental biomarkers (MVD and CD44s). PMID- 26750139 TI - Historical Hallmarks of Anticoagulation and Antiplatelet Agents. AB - Thrombosis is a well known phenomenon among physicians since antiquity. A variety of peculiar agents, such as leeches and bark, were used to prevent it. Hirudin was used during the 19th century. The next eon, heparin, strepokinase, urokinase, TPA, dicumarol, warfarin, aspirin, ticlopidine, Clopidogrel, SSHA and SP54 provoked huge advances in anticoagulation. During 21st century with the use of fondaparinux, dabigatran, rivaroxaban and Ticagrelor antithrombotic prevention and therapeutic interaction entered an era of medical challenges. Although the risk after a thrombotic episode is now highly reduced, blood clots still present damaging or even lethal consequences in human organisms and further research is strongly recommended. PMID- 26750141 TI - Induced phosphorescence from Pt -> Ag and Ag(i)...Ag(i) metallophilic interactions in benzenedithiolatodiimine-Pt2/Ag2 clusters: a combined experimental and theoretical investigation. AB - We report the synthesis and luminescence properties of a novel platinum(ii) silver(i) cluster exhibiting supramolecular donor-acceptor dative Pt -> Ag bonds as well as d(10)...d(10) argentophilic interactions. This compound was obtained by a self-assembly process upon mixing silver triflate with the [Pt(bdt)(bpy)] (1) building block. The new compound was characterized by infrared, NMR ((1)H, (13)C) and UV-vis spectroscopy. In addition, the molecular structure was unequivocally ascertained by a single-crystal X-ray diffraction study and shows that the assembly is identified as [(Pt2Ag2(o-bdt)2(bpy)2](CF3SO3)2 (2). Remarkably, the structure shows that complex 2 exists as two isomers I and II displaying different types of argentophilic interactions Ag...Ag as well as Pt -> Ag dative bonds. These interactions are highly important and turn on phosphorescent emissions at low temperature depending on the nature of the isomer. The photophysical properties of both isomers were investigated and rationalized through TD-DFT calculations. This work paves the way to the synthesis of novel supramolecular assemblies displaying peculiar properties imparted from metallophilic as well as donor-acceptor metal-metal interactions. PMID- 26750142 TI - The precision and torque production of common hip adductor squeeze tests used in elite football. AB - OBJECTIVES: Decreased hip adductor strength is a known risk factor for groin injury in footballers, with clinicians testing adductor strength in various positions and using different protocols. Understanding how reliable and how much torque different adductor squeeze tests produce will facilitate choosing the most appropriate method for future testing. In this study, the reliability and torque production of three common adductor squeeze tests were investigated. DESIGN: Test retest reliability and cross-sectional comparison. METHODS: Twenty elite level footballers (16-33 years) without previous or current groin pain were recruited. Relative and absolute test-retest reliability, and torque production of three adductor squeeze tests (long-lever in abduction, short-lever in adduction and short-lever in abduction/external rotation) were investigated. Each participant performed a series of isometric strength tests measured by hand-held dynamometry in each position, on two test days separated by two weeks. RESULTS: No systematic variation was seen for any of the tests when using the mean of three measures (ICC=0.84-0.97, MDC%=6.6-19.5). The smallest variation was observed when taking the mean of three repetitions in the long-lever position (ICC=0.97, MDC%=6.6). The long-lever test also yielded the highest mean torque values, which were 69% and 11% higher than the short-lever in adduction test and short-lever in abduction/external rotation test respectively (p<0.001). CONCLUSIONS: All three tests described in this study are reliable methods of measuring adductor squeeze strength. However, the test performed in the long-lever position seems the most promising as it displays high test-retest precision and the highest adductor torque production. PMID- 26750144 TI - New perspectives: the President's update on the International Society for Laboratory Hematology. PMID- 26750143 TI - Long-term fertilization alters chemically-separated soil organic carbon pools: Based on stable C isotope analyses. AB - Quantification of dynamics of soil organic carbon (SOC) pools under the influence of long-term fertilization is essential for predicting carbon (C) sequestration. We combined soil chemical fractionation with stable C isotope analyses to investigate the C dynamics of the various SOC pools after 25 years of fertilization. Five types of soil samples (0-20, 20-40 cm) including the initial level (CK) and four fertilization treatments (inorganic nitrogen fertilizer, IN; balanced inorganic fertilizer, NPK; inorganic fertilizer plus farmyard manure, MNPK; inorganic fertilizer plus corn straw residue, SNPK) were separated into recalcitrant and labile fractions, and the fractions were analysed for C content, C:N ratios, delta(13)C values, soil C and N recalcitrance indexes (RIC and RIN). Chemical fractionation showed long-term MNPK fertilization strongly increased the SOC storage in both soil layers (0-20 cm = 1492.4 gC m(2) and 20-40 cm = 1770.6 gC m(2)) because of enhanced recalcitrant C (RC) and labile C (LC). The 25 years of inorganic fertilizer treatment did not increase the SOC storage mainly because of the offsetting effects of enhanced RC and decreased LC, whereas no clear SOC increases under the SNPK fertilization resulted from the fast decay rates of soil C. PMID- 26750146 TI - Structural, electrochemical and spectroelectrochemical study on the geometric and electronic structures of [(corrolato)Au(III)](n) (n = 0, +1, -1) complexes. AB - Synthesis of two new Au(III) corrole complexes with unsymmetrically substituted corrole ligands is presented here. The newly synthesized Au-compounds have been characterized by various spectroscopic techniques. The structural characterization of a representative Au(III) corrole has also been possible. Electrochemical, UV-vis-NIR/EPR spectroelectrochemical and DFT studies have been used to decipher the electronic structures of various electro-generated species. These are the first UV-vis-NIR/EPR spectroelectrochemical investigations on Au(III) corroles. Assignment of redox states of electro-generated Au(III) corroles is supported by DFT analysis. In contrast to the metal centered reduction reported in Au(III) porphyrins, one electron reduction in Au(III) corroles has been assigned to corrole centered on the basis of experimental and theoretical studies. Thus, the Au(III) corroles (not the analogous Au(III) porphyrin derivatives!) bear a truly redox inactive Au(III) center. Additionally, these Au-corrole complexes display NIR electrochromism, the origin of which is all on corrole-centered processes. PMID- 26750149 TI - Modified protocol including topical minocycline in orabase to manage medication related osteonecrosis of the jaw cases. AB - OBJECTIVE: Management of medication-related osteone-crosis of the jaw (MRONJ) with active infection can be a serious challenge for clinicians. Based on Association of Oral and Maxillofacial Surgeons (AAOMS) recommendations, we have tested a modified treatment protocol using topical minocycline. STUDY DESIGN: Five patients diagnosed with stage II or III MRONJ lesions were willing to consent to our protocol. In addition to conventional treatment as suggested by the AAOMS, such as, surgical debridement, chlorhexidine irrigation, and systemic antibiotics, we applied 10% minocycline to the lesions once a week for sustained local antibiotic delivery. RESULTS: All five patients reported pain relief after the first minocycline application. Complete healing occurred in three patients; case three healed completely after the third application, one case continues to improve toward resolution and one withdraws due to other non-relevant medical problem. CONCLUSIONS: In this study, we are reporting favorable results using a modified protocol with topical minocycline to treat MRONJ lesions. PMID- 26750147 TI - Selective pressure against horizontally acquired prokaryotic genes as a driving force of plastid evolution. AB - The plastid organelle comprises a high proportion of nucleus-encoded proteins that were acquired from different prokaryotic donors via independent horizontal gene transfers following its primary endosymbiotic origin. What forces drove the targeting of these alien proteins to the plastid remains an unresolved evolutionary question. To better understand this process we screened for suitable candidate proteins to recapitulate their prokaryote-to-eukaryote transition. Here we identify the ancient horizontal transfer of a bacterial polyphenol oxidase (PPO) gene to the nuclear genome of an early land plant ancestor and infer the possible mechanism behind the plastidial localization of the encoded enzyme. Arabidopsis plants expressing PPO versions either lacking or harbouring a plastid targeting signal allowed examining fitness consequences associated with its subcellular localization. Markedly, a deleterious effect on plant growth was highly correlated with PPO activity only when producing the non-targeted enzyme, suggesting that selection favoured the fixation of plastid-targeted protein versions. Our results reveal a possible evolutionary mechanism of how selection against heterologous genes encoding cytosolic proteins contributed in incrementing plastid proteome complexity from non-endosymbiotic gene sources, a process that may also impact mitochondrial evolution. PMID- 26750148 TI - Contribution of adrenomedullin to the switch of G protein-coupled MU-opioid receptors from Gi to Gs in the spinal dorsal horn following chronic morphine exposure in rats. AB - BACKGROUND AND PURPOSE: Chronic exposure to morphine increases spinal adrenomedullin (AM) bioactivity resulting in the development and maintenance of morphine tolerance. This study investigated the possible involvement of AM in morphine-evoked alteration in MU-opioid receptor-coupled G proteins. EXPERIMENTAL APPROACH: Agents were administered intrathecally (i.t.) in rats. Nociceptive behaviours and cumulative dose-response of morphine analgesia were assessed. Neurochemicals in the spinal dorsal horn were assayed by immunoprecipitation, Western blot analysis and ELISA. KEY RESULTS: Intrathecal injection of AM (8 MUg) for 9 days decreased and increased the levels of MU receptor-coupled Gi and Gs proteins respectively. Morphine stimulation (5 MUg) after chronic treatment with AM also induced an increase in cAMP production in the spinal dorsal horn. Co administration of the selective AM receptor antagonist AM22-52 inhibited chronic morphine-evoked switch of G protein-coupled MU receptor from Gi to Gs. Chronic exposure to AM increased the phosphorylation of cAMP-responsive element-binding protein (CREB) and ERK. Co-administration of the PKA inhibitor H-89 (5 MUg) or MEK1 inhibitor PD98059 (1 MUg) reversed the AM-induced thermal/mechanical hypersensitivity, decline in morphine analgesic potency, switch of G protein coupled MU receptor and increase in cAMP. CONCLUSIONS AND IMPLICATIONS: The present study supports the hypothesis that an increase in AM activity in the spinal dorsal horn contributes to the switch of the MU receptor-coupled G protein from Gi to Gs protein via the activation of cAMP/PKA/CREB and ERK signalling pathways in chronic morphine use. PMID- 26750150 TI - Factors associated with failure of free gracilis flap in reconstruction of acute traumatic leg defects. AB - BACKGROUND: Possible factors associated with failure of free gracilis flaps were studied. MATERIALS AND METHODS: All gracilis free flaps used to reconstruct acute traumatic leg defects in a 5 year period were collected. This included open fractures of the tibia and/or fibula in which a gracilis free flap was used for reconstruction. Pre-op factors included age, ethnicity, gender, presence of diabetes, ischaemic heart disease, peripheral vascular disease, or coagulation disorders; days from trauma to flap surgery, Gustilo class, presence of a concurrent ipsilateral femur fracture, and use of CT angiogram to determine adequacy of blood supply. Intra-op factors included type of arterial anastomosis (end to side or end to end), presence of arterial transection, initial arterial anastomotic failure, initial venous anastomotic failure, use of systemic vasoconstrictors by anaesthetists for correction of hypotension, and use of modulators of the coagulation mechanism (dextran/heparin). Post-op factors included post-op day when flap was removed and use of modulators of the coagulation mechanism. RESULTS: Patients with a concurrent ipsilateral femur fracture had a 9.67 (95% CI of OR = 1.32-70.96) times increased risk of flap failure compared to patients without an associated femur fracture. CONCLUSION: The finding of increased risk of free gracilis flap failure for coverage of leg defects in patients with ipsilateral femur fractures has implications on flap selection and pre-operative counselling. In such a situation, a non-microvascular option could be safer if it is available as an alternative. PMID- 26750151 TI - Activation of medullary dorsal horn gamma isoform of protein kinase C interneurons is essential to the development of both static and dynamic facial mechanical allodynia. AB - The gamma isoform of protein kinase C (PKCgamma), which is concentrated in a specific class of interneurons within inner lamina II (IIi ) of the spinal dorsal horn and medullary dorsal horn (MDH), is known to be involved in the development of mechanical allodynia, a widespread and intractable symptom of inflammatory or neuropathic pain. However, although genetic and pharmacological impairment of PKCgamma were shown to prevent mechanical allodynia in animal models of pain, after nerve injury or reduced inhibition, the functional consequences of PKCgamma activation alone on mechanical sensitivity are still unknown. Using behavioural and anatomical approaches in the rat MDH, we tested whether PKCgamma activation in naive animals is sufficient for the establishment of mechanical allodynia. Intracisternal injection of the phorbol ester, 12,13-dibutyrate concomitantly induced static as well as dynamic facial mechanical allodynia. Monitoring neuronal activity within the MDH with phospho-extracellular signal-regulated kinases 1 and 2 immunoreactivity revealed that activation of both lamina I-outer lamina II and IIi -outer lamina III neurons, including lamina IIi PKCgamma expressing interneurons, was associated with the manifestation of mechanical allodynia. Phorbol ester, 12,13-dibutyrate-induced mechanical allodynia and associated neuronal activations were all prevented by inhibiting selectively segmental PKCgamma with KIG31-1. Our findings suggest that PKCgamma activation, without any other experimental manipulation, is sufficient for the development of static and dynamic mechanical allodynia. Lamina IIi PKCgamma interneurons have been shown to be directly activated by low-threshold mechanical inputs carried by myelinated afferents. Thus, the level of PKCgamma activation within PKCgamma interneurons might gate the transmission of innocuous mechanical inputs to lamina I, nociceptive output neurons, thus turning touch into pain. PMID- 26750152 TI - Giardiasis outbreaks in the United States, 1971-2011. AB - Giardia intestinalis is the leading parasitic aetiology of human enteric infections in the United States, with an estimated 1.2 million cases occurring annually. To better understand transmission, we analysed data on all giardiasis outbreaks reported to the Centers for Disease Control and Prevention for 1971 2011. The 242 outbreaks, affecting ~41 000 persons, resulted from waterborne (74.8%), foodborne (15.7%), person-to-person (2.5%), and animal contact (1.2%) transmission. Most (74.6%) waterborne outbreaks were associated with drinking water, followed by recreational water (18.2%). Problems with water treatment, untreated groundwater, and distribution systems were identified most often during drinking water-associated outbreak investigations; problems with water treatment declined after the 1980s. Most recreational water-associated outbreaks were linked to treated swimming venues, with pools and wading pools implicated most often. Produce was implicated most often in foodborne outbreaks. Additionally, foods were most commonly prepared in a restaurant and contaminated by a food handler. Lessons learned from examining patterns in outbreaks over time can help prevent future disease. Groundwater and distribution system vulnerabilities, inadequate pool disinfection, fruit and vegetable contamination, and poor food handler hygiene are promising targets for giardiasis prevention measures. PMID- 26750155 TI - The practice manager role and relevance to general practice-based research: a review of the literature. AB - Research based in Australian general practice is essential to ensure that health care provided in this setting is evidenced-based and delivered effectively. Research designed for general practice must be feasible and acceptable to general practitioners (GPs) and practice managers (PMs), who are responsible for coordinating practice activities. However, little is known about the PM role and their contribution to research undertaken in general practice. The aim of this systematic review is to examine this role and its relevance to the conduct of general practice-based research. Databases searched (Medline, PubMed, CINAHL and Scopus) identified six relevant studies. One study investigated the role of the PM in general practice-based research and five examined aspects of the PM role. Data about study design, number and type of participants and findings was extracted and managed using a matrix framework. The limited findings suggested PMs are interested in managing research at the practice level. The PM is central to practice communication and coordination but the role varies depending on qualifications, size of practice and expectations of the GPs. This paper highlights the paucity of evidence about the PM role and their contribution to the conduct of research undertaken in general practice. Further investigation is required to gain insights into establishing and managing future research in Australian general practice. PMID- 26750153 TI - Human Heat shock protein 40 (Hsp40/DnaJB1) promotes influenza A virus replication by assisting nuclear import of viral ribonucleoproteins. AB - A unique feature of influenza A virus (IAV) life cycle is replication of the viral genome in the host cell nucleus. The nuclear import of IAV genome is an indispensable step in establishing virus infection. IAV nucleoprotein (NP) is known to mediate the nuclear import of viral genome via its nuclear localization signals. Here, we demonstrate that cellular heat shock protein 40 (Hsp40/DnaJB1) facilitates the nuclear import of incoming IAV viral ribonucleoproteins (vRNPs) and is important for efficient IAV replication. Hsp40 was found to interact with NP component of IAV RNPs during early stages of infection. This interaction is mediated by the J domain of Hsp40 and N-terminal region of NP. Drug or RNAi mediated inhibition of Hsp40 resulted in reduced nuclear import of IAV RNPs, diminished viral polymerase function and attenuates overall viral replication. Hsp40 was also found to be required for efficient association between NP and importin alpha, which is crucial for IAV RNP nuclear translocation. These studies demonstrate an important role for cellular chaperone Hsp40/DnaJB1 in influenza A virus life cycle by assisting nuclear trafficking of viral ribonucleoproteins. PMID- 26750154 TI - Madecassoside ameliorates bleomycin-induced pulmonary fibrosis in mice through promoting the generation of hepatocyte growth factor via PPAR-gamma in colon. AB - BACKGROUND AND PURPOSE: Madecassoside has potent anti-pulmonary fibrosis (PF) effects when administered p.o., despite having extremely low oral bioavailability. Herein, we explored the mechanism of this anti-PF effect with regard to gut hormones. EXPERIMENTAL APPROACH: A PF model was established in mice by intratracheal instillation of bleomycin. Haematoxylin and eosin stain and Masson's trichrome stain were used to assess histological changes in the lung. Quantitative-PCR and Western blot detected mRNA and protein levels, respectively, and cytokines were measured by ELISA. Small interfering RNA was used for gene silencing. EMSA was applied to detect DNA-binding activity. KEY RESULTS: Administration of madecassoside, p.o., but not its main metabolite madecassic acid, exhibited a direct anti-PF effect in mice. However, i.p. madecassoside had no anti-PF effect. Madecassoside increased the expression of hepatocyte growth factor (HGF) in colon tissues, and HGF receptor antagonists attenuated its anti PF effect. Madecassoside facilitated the secretion of HGF from colonic epithelial cells by activating the PPAR-gamma pathway, as shown by an up-regulation of PPAR gamma mRNA expression, nuclear translocation and DNA-binding activity both in vitro and in vivo. Also GW9662, a selective PPAR-gamma antagonist, almost completely prevented the madecassoside-induced increased expression of HGF and amelioration of PF. CONCLUSIONS AND IMPLICATIONS: The potent anti-PF effects induced by p.o. madecassoside in mice are not mediated by its metabolites or itself after absorption into blood. Instead, madecassoside increases the activity of PPAR-gamma, which subsequently increases HGF expression in colonic epithelial cells. HGF then enters into the circulation and lung tissue to exert an anti-PF effect. PMID- 26750156 TI - Liquid crystal phases of two-dimensional dipolar gases and Berezinskii-Kosterlitz Thouless melting. AB - Liquid crystals are phases of matter intermediate between crystals and liquids. Whereas classical liquid crystals have been known for a long time and are used in electro-optical displays, much less is known about their quantum counterparts. There is growing evidence that quantum liquid crystals play a central role in many electron systems including high temperature superconductors, but a quantitative understanding is lacking due to disorder and other complications. Here, we analyse the quantum phase diagram of a two-dimensional dipolar gas, which exhibits stripe, nematic and supersolid phases. We calculate the stiffness constants determining the stability of the nematic and stripe phases, and the melting of the stripes set by the proliferation of topological defects is analysed microscopically. Our results for the critical temperatures of these phases demonstrate that a controlled study of the interplay between quantum liquid and superfluid phases is within experimental reach for the first time, using dipolar gases. PMID- 26750157 TI - The synthetic progesterone Norgestrel is neuroprotective in stressed photoreceptor-like cells and retinal explants, mediating its effects via basic fibroblast growth factor, protein kinase A and glycogen synthase kinase 3beta signalling. AB - The synthetic progesterone Norgestrel has been shown to have proven neuroprotective efficacy in two distinct models of retinitis pigmentosa: the rd10/rd10 (B6.CXBI-Pde6b(rd10)/J) mouse model and the Balb/c light-damage model. However, the cellular mechanism underlying this neuroprotection is still largely unknown. Therefore, this study aimed to examine the downstream signalling pathways associated with Norgestrel both in vitro and ex vivo. In this work, we identify the potential of Norgestrel to rescue stressed 661W photoreceptor-like cells and ex vivo retinal explants from cell death over 24 h. Norgestel is thought to work through an upregulation of neuroprotective basic fibroblast growth factor (bFGF). Analysis of 661W cells in vitro by real-time polymerase chain reaction (rt-PCR), enzyme-linked immunosorbent assay (ELISA) and Western blotting revealed an upregulation of bFGF in response to Norgestrel over 6 h. Specific siRNA knockdown of bFGF abrogated the protective properties of Norgestrel on damaged photoreceptors, thus highlighting the crucial importance of bFGF in Norgestrel-mediated protection. Furthermore, Norgestrel initiated a bFGF dependent inactivation of glycogen synthase kinase 3beta (GSK3beta) through phosphorylation at serine 9. The effects of Norgestrel on GSK3beta were dependent on protein kinase A (PKA) pathway activation. Specific inhibition of both the PKA and GSK3beta pathways prevented Norgestrel-mediated neuroprotection of stressed photoreceptor cells in vitro. Involvement of the PKA pathway following Norgestrel treatment was also confirmed ex vivo. Therefore, these results indicate that the protective efficacy of Norgestrel is, at least in part, due to the bFGF-mediated activation of the PKA pathway, with subsequent inactivation of GSK3beta. PMID- 26750158 TI - Athlete: a working definition for medical and health sciences research. PMID- 26750159 TI - Erratum. PMID- 26750160 TI - Health MDG's: what was been achieved in improving maternal and child health. PMID- 26750161 TI - Health-care providers' perception of knowledge, skills and preparedness for disaster management in primary health-care centres in Jordan. AB - This survey in primary health-care centres in north Jordan aimed to assess health care providers' perceptions of their knowledge, skills and preparedness for disaster management. A multistage random sample was used to recruit nurses and physicians from 57 health centres. A total of 207 participants completed the Arabic version of the Disaster Preparedness Evaluation Tool. Participants perceived themselves as having moderate preparation for disaster management [mean score 74.9 (SD 21.6)], moderate knowledge [mean 49.9 (SD 12.3)] and moderate to weak skills in disaster management [mean 35.3 (SD 12.7)]. Significant differences were revealed in participants' perceptions of their disaster preparedness, knowledge and skills according to their sex, specialty and exposure to a real disaster situation. Further education and training courses are needed to enhance providers' preparedness for disaster management in Jordan. PMID- 26750162 TI - Reliability and known-group validity of the Arabic version of the 8-item Morisky Medication Adherence Scale among type 2 diabetes mellitus patients. AB - No validation study has previously been made for the Arabic version of the 8-item Morisky Medication Adherence Scale (MMAS-8((c))) as a measure for medication adherence in diabetes. This study in 2013 tested the reliability and validity of the Arabic MMAS-8 for type 2 diabetes mellitus patients attending a referral centre in Tripoli, Libya. A convenience sample of 103 patients self-completed the questionnaire. Reliability was tested using Cronbach alpha, average inter-item correlation and Spearman-Brown coefficient. Known-group validity was tested by comparing MMAS-8 scores of patients grouped by glycaemic control. The Arabic version showed adequate internal consistency (alpha = 0.70) and moderate split half reliability (r = 0.65). Known-group validity was supported as a significant association was found between medication adherence and glycaemic control, with a moderate effect size (phic = 0.34). The Arabic version displayed good psychometric properties and could support diabetes research and practice in Arab countries. PMID- 26750163 TI - Are insulin analogues an unavoidable necessity for the treatment of type 2 diabetes in developing countries? The case of Jordan. AB - Despite their reported benefits in terms of glycaemic control, insulin analogues are expensive for patients in developing countries. This study in Jordan aimed to compare the effectiveness and adverse events of premixed human insulin (BHI30) versus premixed insulin analogue (BIAsp30) in patients with type 2 diabetes. In a retrospective cohort study from October 2012 to March 2013, outcomes (HbA1c, weight, hypoglycaemia and lipohypertrophy) were compared at baseline and 6 months after treatment in 628 patients. BHI30 produced a significantly greater reduction in HbA1c than did BIAsp30. This difference in HbA1c remained significant after controlling for the effects of age, sex, duration of diabetes, body mass index and hypoglycaemia (beta-coefficient was -0.18 in favour of BHI30). Weight gain and mild hypoglycaemia was significantly higher with BHI30 than with BIAsp30. BHI30 achieved better reduction in HbA1c compared with BIAsp30, with less cost, slightly more weight gain and greater reported mild hypoglycaemia. PMID- 26750165 TI - Social capital of Iranian patients living with acquired immune deficiency syndrome and associated factors. AB - This study investigated the social capital of Iranian patients living with acquired immune deficiency syndrome (AIDS) and the associated factors. In a cross sectional study the Integrated Social Capital Questionnaire was filled by a sequential sample of 300 patients visiting a referral counselling centre in Tehran. The patients' social capital scores were around 50% in the trust, social cohesion, collective action and cooperation and political empowerment domains. The groups and networks membership domain scored the lowest (27.1%). In regression analysis, employment status was significantly associated with groups and networks membership; age, marital status and financial status were associated with collective action and cooperation; period of disease awareness and marital status affected social cohesion and inclusion; and having risky behaviour affected empowerment and political action. Efforts are needed to enhance the social capital of those patients living with AIDS who are younger, unemployed, divorced/widowed, with risky behaviours and shorter disease awareness. PMID- 26750164 TI - Epidemiological status of leishmaniasis in the Islamic Republic of Iran, 1983 2012. AB - Leishmaniasis has a long history in the Islamic Republic of Iran. This study aimed to show the trend in leishmaniasis incidence from 1983 to 2012 and to describe the epidemiological characteristics in 2012. In a retrospective cross sectional study, data were extracted from th%e national leishmaniasis surveillance system for the 3 clinical types-cutaneous (zoonotic and anthroponotic) and visceral (zoonotic). The average annual number of cutaneous leishmaniasis cases was 18 884 (average annual incidence 32 cases per 100 000 inhabitants). In 2012 the highest incidences were in age groups 1-4 and 5-9-years (43 and 40 per 100 000), and more males (57%) than females (43%) were infected. The annual average number of zoonotic visceral leishmaniasis cases was 175 (average annual incidence 0.18 per 100 000). The incidences of cutaneous and zoonotic visceral leishmaniasis have decreased in recent years, which coincides with national leishmaniasis control efforts. PMID- 26750166 TI - Assessment of the nutritional status of residents in homes for the elderly in Lattakia, Syrian Arab Republic. AB - Malnutrition is common among residents of homes for the elderly. This study aimed to identify the nutritional status of people in residential homes for the elderly in Lattakia, Syrian Arab Republic, and to determine the factors that affected nutritional status in these homes. A total of 103 elderly people in 3 residential homes were interviewed individually using an Arabic version of the Mini Nutritional Assessment (MNA) scale, and anthropometric measurements were carried out to assess nutritional status. The mean age was 70.9 (SD 6.4) years. Two thirds of residents were either at risk of malnutrition (39.8%; score 17-23 on the MNA) or malnourished (19.4%; score < 17 on the MNA). Mean body mass index was 22.0 (SD 4.7) kg/m(2). Nutritional status was significantly affected by age, level of education, source of income, duration of stay in the home, number of diseases, number of medicines taken, anthropometric data and teeth and vision problems. PMID- 26750167 TI - Functional and prognostic relevance of -173 G/C gene polymorphism of macrophage migration inhibitory factor in sepsis patients in Egyptian intensive care units. AB - This study aimed to evaluate the association of plasma MIF level and -173 G/C single nucleotide polymorphism of the MIF gene with the occurrence, severity and mortality of sepsis patients. A study was conducted in adult surgical intensive care units of Zagazig University Hospitals, Egypt on 25 patients with sepsis, 27 with severe sepsis and 28 controls. Gram-negative bacilli were the most common isolates in both severe sepsis (63.0%) and sepsis (56.0%) patients. A highly statistically significant difference was found in MIF levels between sepsis cases and controls and a statistically significant difference as regards MIF level in different genotypes of the studied groups. MIF level was significantly associated with mortality in sepsis cases. High MIF levels and MIF -173G/C gene polymorphism are powerful predictors of the severity of sepsis and its outcome. PMID- 26750168 TI - WHO events addressing public health priorities. PMID- 26750169 TI - Regional Committee papers. PMID- 26750170 TI - The persistence of long-term potentiation in the projection from ventral hippocampus to medial prefrontal cortex in awake rats. AB - A potentially vital pathway in the processing of spatial memory is the pathway from ventral hippocampus to medial prefrontal cortex (vHPC-mPFC). To assess long term potentiation (LTP) induction and maintenance across days in this pathway, the effects of several induction paradigms were compared in awake, freely moving rats. Two different high-frequency stimulation (HFS) protocols generated LTP lasting no longer than 1 week. However, after delivering HFS on three consecutive days, LTP lasted an average of 20 days, due mainly to the greater initial induction. Thus the pathway does not require extensive multi-day stimulation to induce LTP, as for other intra-neocortical pathways, but also it does not exhibit the extremely long-lasting and stable LTP previously observed in area CA1 and the dentate gyrus. By using bilaterally placed stimulating and recording electrodes, we found that HFS in one vHPC generated responses and LTP in the contralateral mPFC, even when the ipsilateral mPFC was inactivated by CNQX. We attribute this crossed response to a polysynaptic pathway from the vHPC to the contralateral mPFC. Finally, we found that repeated overnight exposure to an enriched environment also potentiated the vHPC-mPFC response, but this too was a transient effect lasting < 9 days, declining to baseline even before the enriched environment treatment was completed. Overall, these findings are consistent with the view that potentiation of vHPC-mPFC pathway may play a key role in promoting the hippocampus-mPFC interplay that, over days, leads to long-term storage in the frontal cortex of memories that are independent of the hippocampus. PMID- 26750171 TI - What researchers think of involving consumers in health research. AB - Involving consumers in research enhances its quality and appropriateness, and is required within many research funding schemes. While the rationale for consumer involvement is understood, its implementation is unclear. The researcher investigated views of a group of Australia's leading researchers (n=38) about the role of consumers in their research using a brief survey administered at the Australia National Health and Medical Research (NHMRC) Translation Conference in 2014. Interpretive content analysis was used for data analysis. Respondents noted the importance of consumer involvement in the planning and design of research, to ensure its relevance to the community as end-users of research outcomes. Therefore, consumers were seen as central to research translation by the respondents. Many respondents perceived empathy for the experiences of others as a fundamental researcher skill. Despite strong acknowledgement of the benefits of consumer involvement in research, gaps exist between the rhetoric and practice of consumer involvement beyond consultative roles. Power over decisions made about research processes and ownership of research are continuing barriers to greater consumer involvement in research. Structural changes to how research is funded, evaluated and reported provide a means of addressing these gaps. NHMRC leadership is needed to promote these changes. PMID- 26750174 TI - Tanzanian midwives' perception of their professional role and implications for continuing professional development education. AB - This study explored Tanzanian midwives' perceptions of their professional role within their local context. Findings were to inform recommendations for continuing professional development education programs by Western midwifery educators. Using focus group interviews with sixteen Tanzanian midwives, the findings revealed that the midwives' overwhelming focus was on saving lives of women and newborns. The fundamental elements of saving lives involved prioritising care through receiving handover and undertaking physical assessment. Midwives were challenged by the poor working conditions, perceived lack of knowledge and associated low status within the local community. Based upon these findings, recommendations for continuing professional development education for Tanzanian midwives must ensure that saving lives is a major focus and that strategies taught must be relevant to the low-resource context of this developing country. In recognition of the high-risk women being cared for, there needs to be a focus on the prevention and management of maternity emergencies, in collaboration with medical practitioners. PMID- 26750175 TI - One more time: The importance of student-faculty connection. PMID- 26750176 TI - Clinical education and training of student nurses in four moderately new European Union countries: Assessment of students' satisfaction with the learning environment. AB - Nurses underwent different models of education during various historical periods. The recent decade in Europe has been marked with educational transitions for the nursing profession related to Bologna Declaration and enlargement of the European Union. This paper aims to explore the situation of clinical placements for student nurses and assess students' satisfaction with the learning environment in four relatively new member states of European Union: the Czech Republic, Hungary, Lithuania and Romania. The data for cross-sectional quantitative study were collected during the exploratory phase of EmpNURS Project via a web based questionnaire which utilized a part of Clinical Learning Environment scale (CLES + T). The students evaluated their clinical learning environment mainly positively. The students' utter satisfaction with their clinical placements reached a high level and strongly correlated with the supervisory model. Although the commonest model for supervision was traditional group supervision, the most satisfied students had the experience of individualised supervision. The study gives a picture of the satisfaction of students with the learning environment and, moreover, with clinical placement education of student nurses in four EU countries. The results highlight the individualized supervision model as a crucial factor of students' total satisfaction during their clinical training periods. PMID- 26750177 TI - The timing of worm exclusion in dogs repeatedly infected with the cestode Echinococcus multilocularis. AB - Experimental Echinococcus multilocularis infection and deworming was repeated three or five times in nine dogs at various re-infection schedules. The mean number of worms decreased more than 91% in dogs with repeated infection, compared to first infection controls (n= 6). The copro-antigen assay and the egg count in the faeces suggested that the worm burden gradually decreased each time the dogs were re-infected. To examine whether such worm exclusion was a non-specific response, five dogs were sequentially infected with the parasite four times and subsequently fed freely for 6 months. Even after the 6-month interval, the five dogs that were infected five times with the parasite were still able largely to exclude the adult worms. The results suggested that the ability of worm exclusion in dogs that developed a resistance did not become rapidly extinct. Observation of the condition of faeces and the excretion of hooks in the faeces of repeatedly infected dogs revealed that the exclusion of worms started at the first week after the re-infection, and it continued during the patent period. Serum antibodies specific to the parasite antigen increased gradually until the third infection and significantly decreased during the 6-month interval. There was little enhancement of serum antibodies after the fifth infection in most dogs, although no clear correlation was observed between the antibody response and the worm burden. These findings suggested the possibility of developing a vaccine. PMID- 26750178 TI - Regulation and functions of bacterial PNPase. AB - Polynucleotide phosphorylase (PNPase) is an exoribonuclease that catalyzes the processive phosphorolytic degradation of RNA from the 3'-end. The enzyme catalyzes also the reverse reaction of polymerization of nucleoside diphosphates that has been implicated in the generation of heteropolymeric tails at the RNA 3' end. The enzyme is widely conserved and plays a major role in RNA decay in both Gram-negative and Gram-positive bacteria. Moreover, it participates in maturation and quality control of stable RNA. PNPase autoregulates its own expression at post-transcriptional level through a complex mechanism that involves the endoribonuclease RNase III and translation control. The activity of PNPase is modulated in an intricate and still unclear manner by interactions with small molecules and recruitment in different multiprotein complexes. Not surprisingly, given the wide spectrum of PNPase substrates, PNPase-defective mutations in different bacterial species have pleiotropic effects and perturb the execution of genetic programs involving drastic changes in global gene expression such as biofilm formation, growth at suboptimal temperatures, and virulence. PMID- 26750179 TI - Mandatory Rest Stops Improve Athlete Safety during Event Medical Coverage for Ultramarathons. AB - INTRODUCTION: Provisions of medical direction and clinical services for ultramarathons require specific attention to heat illness. Heat stress can affect athlete performance negatively, and heat accumulation without acclimatization is associated with the development of exertional heat stroke (EHS). In order to potentially mitigate the risk of this safety concern, the Jungle Marathon (Para, Brazil) instituted mandatory rest periods during the first two days of this 7 day, staged, Brazilian ultramarathon. METHODS: Race records were reviewed retrospectively to determine the number of runners that suffered an emergency medical complication related to heat stress and did not finish (DNF) the race. Review of records included three years before and three years after the institution of these mandatory rest periods. RESULTS: A total of 326 runners competed in the Jungle Marathon during the 2008-2013 period of study. During the pre-intervention years, a total of 46 athletes (21%) DNF the full race with 25 (54.3%) cases attributed to heat-related factors. During the post-intervention years, a total of 26 athletes (24.3%) DNF the full race with four (15.4%) cases attributed to heat-related factors. CONCLUSION: Mandatory rest stops during extreme running events in hot or tropical environments, like the Jungle Marathon, are likely to improve athlete safety and improve the heat acclimatization process. PMID- 26750180 TI - KLRG1 and PD-1 expression are increased on T-cells following tuberculosis treatment and identify cells with different proliferative capacities in BCG vaccinated adults. AB - In cancer and chronic infectious diseases, immune checkpoint-blockade of inhibitory receptors can enhance T-cell immunity. In tuberculosis (TB), a chronic infectious disease, prolonged antigen exposure can potentially drive terminal T cell differentiation towards functional 'exhaustion': in human TB T-cells express PD-1 (programmed cell death protein-1) and CTLA-4 (cytotoxic T-lymphocyte associated protein-4). However, in murine TB not PD-1 but rather killer cell lectin-like receptor subfamily-G1 (KLRG1) was a superior indicator of terminal T cell differentiation. We therefore compared expression of KLRG1, PD-1 and CTLA-4 on T-cells in different stages of human TB, and also analysed their induction following BCG-vaccination. KLRG1, PD-1 and CTLA-4-expression were highest on in vitro BCG-stimulated CD4(+) T-cells following recent TB-treatment; KLRG1 and PD-1 expression on CD4(+) T-cells in active--but not latent--TB were only slightly increased compared to healthy donors. BCG-vaccination induced KLRG1-expression on BCG-stimulated CD8(+) but not CD4(+) T-cells, while neither PD-1 nor CTLA-4 expression increased. KLRG1-expressing CD8(+) T-cells exhibited markedly decreased proliferation, whereas PD-1(+) T-cells proliferated after in vitro BCG stimulation. Thus, we demonstrate the presence of increased KLRG1-expressing T cells in TB-treated individuals, and present KLRG1 as a marker of decreased human T-cell proliferation following BCG-vaccination. These results expand our understanding of cell-mediated immune control of mycobacterial infections. PMID- 26750182 TI - Neutrophilic dermatosis of the hands (localized Sweet's syndrome). PMID- 26750181 TI - Atherosclerotic cardiovascular disease: a review of initiators and protective factors. AB - Atherosclerotic cardiovascular disease (CVD) is a collective term comprising of a group of disorders of the heart and blood vessels. These diseases are the largest cause of morbidity and premature death worldwide. Coronary heart disease and cerebrovascular disease (stroke) are the most frequently occurring diseases. The two major initiators involved in the development of atherosclerotic CVD are vascular production of reactive oxygen species (ROS) and lipid oxidation. In atherosclerosis development, ROS is associated with rapid loss of anti inflammatory and anti-atherogenic activities of the endothelium-derived nitric oxide (NO(.)) resulting in endothelial dysfunction. In part involving activation of the transcription factor NF-kappaB, ROS have been involved in signaling cascades leading to vascular pro-inflammatory and pro-thrombotic gene expression. ROS is also a potent activator of matrix metalloproteinases (MMPs), which indicate plaque destabilization and rupture. The second initiator involved in atherosclerotic CVD is the oxidation of low-density lipoproteins (LDL). Oxidation of LDL in vessel wall leads to an inflammatory cascade that activates atherogenic pathway leading to foam cell formation. The accumulation of foam cells leads to fatty streak formation, which is the earliest visible atherosclerotic lesion. In contrast, the cardiac sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a) and hepatic apolipoprotein E (apoE) expression can improve cardiovascular function. SERCA2a regulates the cardiac contractile function by lowering cytoplasmic calcium levels during relaxation, and affecting NO(.) action in vascular cells, while apoE is a critical ligand in the plasma clearance of triglyceride- and cholesterol-rich lipoproteins. PMID- 26750183 TI - Target sign in woman with abdominal pain and systemic lupus erythematosus treated with plasma exchange. PMID- 26750184 TI - Use of human acellular dermal matrix during classic bladder exstrophy repair. AB - INTRODUCTION: The extent of the abdominal wall defect in people with classic bladder exstrophy (CBE) varies, and can be extensive. In this study, human acellular dermis (HAD) was used to bridge the fascial gap, as an alternative to osteotomy, to support a fascial repair of the abdominal wall, and as a filler in selected cases of CBE. OBJECTIVE: To demonstrate the efficacy of the employed techniques of using HAD within the bladder exstrophy population. MATERIALS AND METHODS: The medical records of six males, born with CBE, and who had abdominal wall defects were reviewed. Two children, aged 6 and 8 years old, were referred from overseas with unrepaired bladder exstrophy plates and large abdominal wall defects (8 cm and 12 cm wide). Both had their bladders reconstructed, placed within the pelvis, and HAD was used to replace the absent abdominal wall (bridged repair) without the use of pelvic osteotomy. In three other patients, HAD reinforced the native fascial repair (bolster repair). In three patients, HAD also served as a filler for the abdominal depression that was present following initial staged repair. Where HAD was used for bridged or bolster repair, the edges of the allograft were extended 2-3 cm circumferentially beyond the perimeter of the abdominal wall defect. RESULTS: All six patients healed well, without evidence of abdominal wall hernias at 1-3 years postoperatively. Functionally, each patient regained an appropriate level of abdominal wall strength. Two children successfully underwent a secondary procedure through the bridged allograft repair, as each required bladder neck reconstruction and bilateral ureteral reimplantation through the reconstructed abdominal wall. Continence was achieved in these two patients, with one child voiding at 2-hourly intervals and the second at 3-hourly intervals. One patient developed a urethral cutaneous fistula, distant to location of the allograft. There were no associated wound complications. CONCLUSIONS: In this series of patients born with classic bladder exstrophy, HAD acted as a biologic scaffold and allowed native cellular ingrowth and tissue remodeling. It served as an alternative to pelvic osteotomy in older patients with unrepaired CBE. The material reinforced a weak or potentially suboptimal fascial repair and filled a tissue gap, resulting in improved aesthetics. Given its ease of preparation and the lack of significant morbidity associated with its use, combined with the functional and esthetic results in the present series, HAD may be considered during delayed reconstruction of abdominopelvic tissues in people born with CBE. PMID- 26750185 TI - Initial experiences of laparoscopic intravesical detrusorraphy using the Politano Leadbetter technique. AB - INTRODUCTION: Minimally invasive laparoscopic surgical procedures are increasingly being used for the management of vesicoureteral reflux. OBJECTIVE: We present our experience of the laparoscopic Politano-Leadbetter technique performed under pneumovesicum conditions, which allows an orthotopic ureteral location after vesicoureteral reflux correction. Our procedure recreates the new ureteric orifice in a normal anatomical position with potential less morbidity and better cosmesis. STUDY DESIGN: Our series comprises ten cases. The three 5 mm ports were introduced through bladder wall under cystoscopic vision. A 5-0 monofilament traction suture was used and dissection was carried out. After the ureteral mobilization, the location of the new hiatus was selected in a straight line superior to the original orifice. Dissection of the submucosal tunnel was started from the new hiatus and advanced to the original hiatus and the ureter was gently drawn passed through the tunnel. The ureter was rolled up and muscle fibers were incised until ureter could freely move from the base of the new hiatus. Finally, after spatulation of the terminal part of the ureter, ureterovesical anastomosis was performed with intracorporeal suturing using 5-0 monofilament sutures. RESULTS: The average operative time was 125 min, with an average of 93 min for unilateral and 133 min for bilateral reimplantation. Blood loss was minimal and drains were used selectively. Removal of urethral catheter was decided empirically after hematuria stopped. Mean catheterization time was 5.1 days. The mean postoperative hospital stay was 6.2 days. DISCUSSION: This study had limitations: the small number of cases, follow-up period is relatively short and data on the pre-operative bladder capacity, catheter-related morbidity, pain control and cosmesis are lacking. But most cases showed positive clinical results including acceptable operating time and good resolution rate with minimal complication. Our Politano-Leadbetter transvesicoscopic ureteric reimplantation is safe and useful in the resolution of VUR, even though the laparoscopic ureteric reimplantation is technically demanding even for experienced pediatric surgeons. Considering the main advantages of endoscopic surgery, our new vesicoscopic technique could be an optional treatment to the open reimplantation and has merits because whole the procedure are performed within the bladder, so there is no risk of intraperitoneal organ injury. CONCLUSION: Though the role of this new technique in the treatment of VUR remains to be determined, the technique could be an optional treatment to replace other surgical methods as a less invasive and effective therapeutic method. PMID- 26750187 TI - Pedicled distal phalanx fillet flap for finger length preservation in trauma. AB - Lawnmower injuries to the digits are becoming increasingly common and are often complex in nature with multiple levels of injury. The management of these injuries as with that of other hand injuries is often tailored to the individual patient considering factors such as occupation and hobbies with the ultimate goal of restoration of function and a sensate fingertip. The concept of using amputated, mangled or non-salvageable parts in a form of fillet flap has become more common in the recent years. We report a complex case of a multi-level injury to the dominant index finger of a professional typist from a lawnmower where finger length was maximised using a pedicled distal phalanx fillet flap which ultimately allowed the patient to return to work. PMID- 26750186 TI - Is there a risk of filarial infection during long-term missions in Haiti? AB - BACKGROUND: Haiti has the highest prevalence of lymphatic filariasis (Wuchereria bancrofti) in the Western Hemisphere. Still, the risk of filarial infection for long-term visitors such as humanitarian aid workers or military personnel is uncertain. The presented study analyzed the exposure to W. bancrofti in Chilean participants of the UN Stabilization Mission in Haiti (MINUSTAH) in 2011. METHODS: Blood samples collected from 531 participants were screened for antifilarial antibodies by IgG ELISA, and, if positive, analyzed by immunofluorescence assay (IFA), IgG4 ELISA, Real-Time PCR, and circulating filarial antigen (CFA) card test. RESULTS: ELISA screening was positive in 10 cases. Seroconversion occurred in only two cases (0.38%) based on ELISA values determined in samples taken before and after deployment. Positive IgG ELISA values could not be confirmed by IFA and IgG4 ELISA. Real-Time PCR and CFA testing did not reveal the presence of filaria. CONCLUSIONS: Our data indicate that in the examined cohort of MINUSTAH participants in 2011, the risk of filarial exposure or infection was low. PMID- 26750188 TI - Role of computed tomography urography in the clinical evaluation of upper tract urothelial carcinoma. AB - Intravenous urography has been widely used for the evaluation of upper tract urothelial carcinoma. However, computed tomography urography presently has a higher diagnostic accuracy for upper tract urothelial carcinoma (94.2-99.6%) than intravenous urography (80.8-84.9%), and has replaced intravenous urography as the first-line imaging test for investigating patients with a high risk of upper tract urothelial carcinoma. Although the detection rate for bladder tumors using standard computed tomography urography is not yet high enough to replace cystoscopy, the addition of a 60- to 80-s delayed scan after the administration of contrast material for the whole pelvis improves the detection rate. A drawback to computed tomography urography is the higher radiation dose of 15-35 mSv, compared with a mean effective dose of 5-10 mSv for intravenous urography. Among several approaches to reducing the radiation dose, the use of an iterative reconstruction algorithm is most likely to become an effective solution because of its simplicity. One advantage of computed tomography urography over intravenous urography is its ability to reliably differentiate between upper tract urothelial carcinoma and calculi or blood clots. Computed tomography urography also shows characteristic findings of other benign conditions. These findings, in combination with negative cytology, are very important diagnostic clues for avoiding an unnecessary nephroureterectomy. For the clinical staging, a recent study has reported the high diagnostic accuracy of computed tomography urography with respect to >=pT3 tumors. The present review shows the current status of computed tomography urography for the evaluation of upper tract urothelial carcinoma. PMID- 26750190 TI - [Spontaneous mediastinal emphysema]. AB - Spontaneous mediastinal emphysema, also known as spontaneous pneumomediastinum, is defined as radiologically detected free air in the mediastinum, without preceding trauma. It is a rare condition, mainly affecting young adults. It can be caused by coughing, strenuous sports or cocaine inhalation, however, 40% are idiopatic. Common symptoms are chest pain and dyspnoea. 75-90% can be diagnosed with a chest X-ray, and 100% with a computed tomography. Treatment is symptomatic and complications are rare, however, pneumothorax and pneumorrachis have been reported. PMID- 26750189 TI - [Low-carbohydrate diet for patients with Type 2 diabetes]. AB - Recently, low-carbohydrate diets have increased in popularity as a method to achieve glycaemic control and weight loss in Type 2 diabetes patients. However, there is a lack of consistency and long-term results in existing studies on patients with Type 2 diabetes. In this review, we address current knowledge of low-carbohydrate diets and how they affect glycaemic control, diabetic dyslipidaemia, weight and markers of cardiovascular risk, and our aim is to aid medical practitioners in guiding patients with Type 2 diabetes who wish to try a low-carbohydrate diet in order to take control of their disease. PMID- 26750191 TI - [Vegetarians are at high risk of vitamin B12 deficiency]. AB - Since vegetarians have a lower intake of vitamin B12 (B12) than non-vegetarians, they are at increased risk of developing B12 deficiency. The less animal products the food contains the worse the B12 status. However, even lacto-ovo-vegetarians run the risk of becoming deficient in B12. Vegetarians are recommended regularly to take supplements of B12, and they should be informed of the lacking content of B12 of plant products and the hazards of B12 deficiency. Furthermore, vegetarians should routinely be checked for possible B12 deficiency. PMID- 26750192 TI - [The first case of Hypoderma tarandi-associated human myiasis in Greenland]. AB - We present the first case of human myiasis in Greenland caused by the warble fly Hypoderma tarandi. Noticing a persisting, migrating, stinging facial sensation, a female patient eventually extirpated a larva from her upper eyelid, and the larva was confirmed to species level using DNA-based methods. A high prevalence of H. tarandi in reindeer, the main reservoir host, and increasing populations of musk ox may imply an increased risk of zoonotic transmission. Although diagnosis is challenging, rapid intervention is crucial to reduce the risk of ophthalmomyiasis. PMID- 26750193 TI - [In Process Citation]. PMID- 26750194 TI - [In Process Citation]. PMID- 26750195 TI - [In Process Citation]. PMID- 26750196 TI - [Catatonia is often overlooked in child and adolescent psychiatry]. AB - Catatonia is a common but often overlooked motor syndrome in child and adolescent psychiatry. It is characterized by a variety of symptoms, most often excitement, immobility, stupor, catalepsy, grimacing, echolalia, echopraxia, stereotypies, mannerisms, logorrhoea, verbigeration, negativism, staring and withdrawal. This case report illustrates how a 17-year-old man was diagnosed with catatonia after one year of repeating psychiatric care. The catatonic symptoms decreased significantly after a short period of lorazepam administration. PMID- 26750197 TI - [Positive results with haematology webcasting for junior doctors]. AB - Webcasting is an educational activity where the teacher and the participants are separated in space and time when using modern information technology. It is widely used for all learning levels and in all educational forms of haematology training in Europe. A working group in the Education Council of internal medicine, haematology in the eastern part of Denmark initiated a project with webcasting from local haematological departments. The aim of the education project was to contribute to spreading knowledge and support the training of specialist in haematology. Our experience is hereby reported. PMID- 26750198 TI - [Good social function in a child with severe visual loss due to colobomas]. AB - A child born with bilateral colobomas was referred to the department of ophthalmology. At birth the child was assumed to be blind. During the follow-up period of seven years his visual acuity improved to 0.08 and he became a socially and intellectually well-functioning child. He attended a normal school, and in his spare time he was able to ride his bike, swim and play football. This example illustrates how difficult it is to predict the visual and social function of a newborn with poor vision. PMID- 26750199 TI - [Limited evidence for best treatment of uncomplicated gallbladder stones]. AB - Gallbladder stones will rarely lead to colic pain attacks and even more seldom to complications. A conservative watchful waiting strategy may be an alternative to cholecystectomy for uncomplicated symptomatic gallbladder stone disease. Evidence for whether the optimal treatment should be cholecystectomy or watchful waiting is weak. This narrative-condensed review critically analyses current evidence with special focus on epidemiological risk factors of developing symptoms or complications related to gallbladder stones. The evidence for treatment is discussed. PMID- 26750201 TI - Hollow-structured Si/SiC@C nanospheres as highly active catalysts for cycloaddition of epoxides with CO2 under mild conditions. AB - Hollow-structured Si/SiC@C nanospheres were prepared through a magnesiothermic reduction of resin-coated SiO2 spheres. These nanostructured materials with high surface area not only show high adsorption capacities of industrial dyes from wastewater, but also exhibit excellent catalytic activities for chemical fixation of CO2 under mild, solvent-free conditions. PMID- 26750200 TI - Neurogenesis and anxiety-like behavior in male California mice during the mate's postpartum period. AB - Our understanding of postpartum anxiety (PPA) in fathers is limited, despite the negative consequences of anxiety on the father and child. Offspring contact reduces PPA in mothers; however, parallel investigations in fathers has gone unaddressed. Adult neurogenesis in the dentate gyrus (DG) contributes to anxiety regulation and is altered during the postpartum period, yet the effects of fatherhood on the production, or survival, of newborn cells in the DG, and the role of adult neurogenesis in PPA regulation, have not been examined. Using the biparental California mouse (Peromyscus californicus), we examined the relationships among postnatal day, anxiety-like behavior and adult neurogenesis in fathers. We hypothesized that attenuated anxiety-like behavior and enhanced adult neurogenesis would be observed when father-offspring contact was increased. We observed a reduction in anxiety-like behavior on the elevated plus-maze, but only at PND 16, a time of peak pup retrieval. Fatherhood reduced 1-week survival of newborn cells; however, surviving cells were maintained until 2 weeks postpartum. In contrast, non-fathers experienced a significant reduction in the survival of newborn cells between 1 and 2 weeks postpartum. Fatherhood also increased the numbers of newborn cells that expressed a neuronal phenotype. Collectively, these findings suggest that offspring interaction contributes to reductions in anxiety-like behavior and the maintenance of newborn neurons in the DG of fathers. These data contribute to our knowledge of the postpartum affective state in fathers, findings that may contribute to improved health of both the father and offspring. PMID- 26750202 TI - Reactivation from the Ni-B state in [NiFe] hydrogenase of Ralstonia eutropha is controlled by reduction of the superoxidised proximal cluster. AB - The tolerance towards oxic conditions of O2-tolerant [NiFe] hydrogenases has been attributed to an unusual [4Fe-3S] cluster that lies proximal to the [NiFe] active site. Upon exposure to oxygen, this cluster converts to a superoxidised (5+) state, which is believed to secure the formation of the so-called Ni-B state that is rapidly reactivated under reducing conditions. Here, the reductive reactivation of the membrane-bound [NiFe]-hydrogenase (MBH) from Ralstonia eutropha in a native-like lipid membrane was characterised and compared to a variant that instead carries a typical [4Fe-4S] proximal cluster. Reactivation from the Ni-B state was faster in the [4Fe-4S] variant, suggesting that the reactivation rate in MBH is limited by the reduction of the superoxidised [4Fe 3S] cluster. We propose that the [4Fe-3S] cluster plays a major role in protecting MBH by blocking the reversal of electron transfer to the [NiFe] active site, which would produce damaging radical oxygen species. PMID- 26750204 TI - Prevalence of Influenza A Virus in Exhibition Swine during Arrival at Agricultural Fairs. AB - The exhibition swine at agricultural fairs provides a critical human-swine interface that allows for the bidirectional transmission of influenza A virus (IAV). Previous IAV surveillance at the end of fairs has resulted in frequent detection of IAV-infected swine; little is known, however, about the frequency with which swine arrive at fairs already infected with IAV. We investigated the IAV prevalence among exhibition swine entering fairs to better understand the epidemiology of IAV in this unique human-swine interface. In 2014, snout wipes were collected from 3547 swine during the first day of nine agricultural exhibitions in Indiana and Ohio. Samples were screened for IAV using rRT-PCR and positive samples were inoculated into cultured cells for virus isolation. The overall IAV prevalence detected among swine arriving at exhibitions was 5.3% (188/3547) via rRT-PCR and 1.5% (53/3547) via virus isolation, with IAV being detected and recovered from swine at 5 of the 9 exhibitions. Within the fairs with IAV-positive swine, the individual exhibition IAV prevalence ranged from 0.2% (1/523) to 34.4% (144/419) using rRT-PCR and 0.2% (1/523) to 10.3% (43/419) with virus isolation. Single IAV subtypes were detected at three of the fairs but subtype diversity was detected among the pigs at two fairs as both H1N1 and H3N2 were recovered from incoming swine. At two of the exhibitions, a temporal relationship was observed between the order of the individual swine in sampling and the associated IAV rRT-PCR results, indicating the fomite transmission of IAV through common contact surfaces may occur. With the knowledge that a small proportion of swine arrive at fairs shedding IAV, resources should be directed towards preventive strategies focused on limiting transmission during fairs to protect swine and humans during exhibitions. PMID- 26750205 TI - Anomalous Raman scattering and lattice dynamics in mono- and few-layer WTe2. AB - Tungsten ditelluride (WTe2) is a layered material that exhibits excellent magnetoresistance and thermoelectric behaviors, which are deeply related with its distorted orthorhombic phase that may critically affect the lattice dynamics of this material. Here, we report comprehensive characterization of Raman spectra of WTe2 from bulk to monolayer using experimental and computational methods. We find that mono and bi-layer WTe2 are easily identified by Raman spectroscopy since two or one Raman modes that are observed in higher-layer WTe2 are greatly suppressed below the noise level in the mono- and bi-layer WTe2, respectively. In addition, the frequency of in-plane A1(7) mode of WTe2 remains almost constant as the layer number decreases, while all the other Raman modes consistently blueshift, which is completely different from the vibrational behavior of hexagonal metal dichalcogenides. First-principles calculation validates experimental results and reveals that anomalous lattice vibrations in WTe2 are attributed to the formation of tungsten chains that make WTe2 structurally one-dimensional. PMID- 26750206 TI - The road to independence: how to get funding in neuroscience. PMID- 26750247 TI - Theory of Andreev reflection spectroscopy for tetrahedral and non-unitary superconductors. AB - A general formula for point contact conductance from a normal metal tip into a superconductor is derived using the Blonder-Tinkham-Klapwijk theory of Andreev reflection, with special emphasis on non-unitary superconductors. The results of a comprehensive set of conductance spectrum calculations are presented: all symmetry-allowed gap functions for superconductors with tetrahedral symmetry, such as PrOs4Sb12, are considered, including several non-unitary cases. PMID- 26750244 TI - Distribution, congruence, and hotspots of higher plants in China. AB - Identifying biodiversity hotspots has become a central issue in setting up priority protection areas, especially as financial resources for biological diversity conservation are limited. Taking China's Higher Plants Red List (CHPRL), including Bryophytes, Ferns, Gymnosperms, Angiosperms, as the data source, we analyzed the geographic patterns of species richness, endemism, and endangerment via data processing at a fine grid-scale with an average edge length of 30 km based on three aspects of richness information: species richness, endemic species richness, and threatened species richness. We sought to test the accuracy of hotspots used in identifying conservation priorities with regard to higher plants. Next, we tested the congruence of the three aspects and made a comparison of the similarities and differences between the hotspots described in this paper and those in previous studies. We found that over 90% of threatened species in China are concentrated. While a high spatial congruence is observed among the three measures, there is a low congruence between two different sets of hotspots. Our results suggest that biodiversity information should be considered when identifying biological hotspots. Other factors, such as scales, should be included as well to develop biodiversity conservation plans in accordance with the region's specific conditions. PMID- 26750249 TI - Targeting cancer cells with oleanolic and ursolic acid derived hydroxamates. AB - Oleanolic and ursolic acid derived hydroxamates were easily obtained from their parent compounds; they were screened for their cytotoxicity applying SRB assays employing several human tumor cell lines. Low EC50 values were determined for compounds in which the nitrogen as well as the oxygen in the hydroxamic acid part still holds acidic hydrogens. Thus, ursolic acid derived compounds having at least an OH and/or NH moiety in the hydroxamate part of the molecule showed good cytotoxicity but they are significantly less selective for the tumor cells than oleanolic acid derived compounds. Good results were determined for oleanolic acid derived 7 for tumor cell lines 518A2 (melanoma, EC50=3.3 MUM), A2780 (ovarian carcinoma, EC50=3.4 MUM) and HT29 (colon adenocarcinoma, EC50=5.6 MUM) while being significantly less cytotoxic for fibroblasts (EC50=20.4 MUM). PMID- 26750203 TI - NADPH oxidases in oxidant production by microglia: activating receptors, pharmacology and association with disease. AB - : Microglia are the resident immune cells of the CNS and constitute a self sustaining population of CNS-adapted tissue macrophages. As mononuclear phagocytic cells, they express high levels of superoxide-producing NADPH oxidases (NOX). The sole function of the members of the NOX family is to generate reactive oxygen species (ROS) that are believed to be important in CNS host defence and in the redox signalling circuits that shape the different activation phenotypes of microglia. NOX are also important in pathological conditions, where over generation of ROS contributes to neuronal loss via direct oxidative tissue damage or disruption of redox signalling circuits. In this review, we assess the evidence for involvement of NOX in CNS physiopathology, with particular emphasis on the most important surface receptors that lead to generation of NOX-derived ROS. We evaluate the potential significance of the subcellular distribution of NOX isoforms for redox signalling or release of ROS to the extracellular medium. Inhibitory mechanisms that have been reported to restrain NOX activity in microglia and macrophages in vivo are also discussed. We provide a critical appraisal of frequently used and recently developed NOX inhibitors. Finally, we review the recent literature on NOX and other sources of ROS that are involved in activation of the inflammasome and discuss the potential influence of microglia derived oxidants on neurogenesis, neural differentiation and culling of surplus progenitor cells. The degree to which excessive, badly timed or misplaced NOX activation in microglia may affect neuronal homeostasis in physiological or pathological conditions certainly merits further investigation. LINKED ARTICLES: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc. PMID- 26750250 TI - Enantiomeric 3-deaza-1',6'-isoneplanocin and its 3-bromo analogue: Synthesis by the Ullmann reaction and their antiviral properties. AB - The 1',6'-isomer of neplanocin A possesses biological properties that have not been optimised through rationally conceived analogues. In that direction, this Letter reports the use of the Ullmann reaction to achieve enantiomeric 3-deaza 1',6'-isoneplanocin and 3-bromo-3-deaza-1',6'-isoneplanocin. These four compounds showed significant Ebola activity that is not specifically due to their inhibition of S-adenonosylhomocysteine hydrolase, as might have been expected for 3-deazaadenine carbocyclic nucleosides. For some members of this group, antiviral activity was also found against human cytomegalovirus, hepatitis B, norovirus, and measles. PMID- 26750243 TI - A human monoclonal antibody against HPV16 recognizes an immunodominant and neutralizing epitope partially overlapping with that of H16.V5. AB - The presence of neutralizing epitopes in human papillomavirus (HPV) L1 virus-like particles (VLPs) is the structural basis of prophylactic vaccines. An anti-HPV16 neutralizing monoclonal antibody (N-mAb) 26D1 was isolated from a memory B cell of a human vaccinee. The pre-binding of heparan sulfate to VLPs inhibited the binding of both N-mAbs to the antigen, indicating that the epitopes are critical for viral cell attachment/entry. Hybrid VLP binding with surface loop swapping between types indicated the essential roles of the DE and FG loops for both 26D1 (DEa in particular) and H16.V5 binding. Specifically, Tyr(135) and Val(141) on the DEa loop were shown to be critical residues for 26D1 binding via site directed mutagenesis. Partially overlap between the epitopes between 26D1 and H16.V5 was shown using pairwise epitope mapping, and their binding difference is demonstrated to be predominantly in DE loop region. In addition, 26D1 epitope is immunodominant epitope recognized by both antibodies elicited by the authentic virus from infected individuals and polyclonal antibodies from vaccinees. Overall, a partially overlapping but distinct neutralizing epitope from that of H16.V5 was identified using a human N-mAb, shedding lights to the antibody arrays as part of human immune response to vaccination and infection. PMID- 26750251 TI - 2-Amino-4-bis(aryloxybenzyl)aminobutanoic acids: A novel scaffold for inhibition of ASCT2-mediated glutamine transport. AB - Herein, we report the discovery of 2-amino-4-bis(aryloxybenzyl)aminobutanoic acids as novel inhibitors of ASCT2(SLC1A5)-mediated glutamine accumulation in mammalian cells. Focused library development led to two novel ASCT2 inhibitors that exhibit significantly improved potency compared with prior art in C6 (rat) and HEK293 (human) cells. The potency of leads reported here represents a 40-fold improvement over our most potent, previously reported inhibitor and represents, to our knowledge, the most potent pharmacological inhibitors of ASCT2-mediated glutamine accumulation in live cells. These and other compounds in this novel series exhibit tractable chemical properties for further development as potential therapeutic leads. PMID- 26750253 TI - Amides of non-steroidal anti-inflammatory drugs with thiomorpholine can yield hypolipidemic agents with improved anti-inflammatory activity. AB - Novel amides of non steroidal anti-inflammatory drugs (NSAIDs), alpha-lipoic acid and indole-3-acetic acid with thiomorpholine were synthesised by a simple method and at high yields (60-92%). All the NSAID derivatives highly decreased lipidemic indices in the plasma of Triton treated hyperlipidemic rats. The most potent compound was the indomethacin derivative, which decreased total cholesterol, triglycerides and LDL cholesterol by 73%, 80% and 83%, respectively. They reduced acute inflammation equally or more than most parent acids. Hence, it could be concluded that amides of common NSAIDs with thiomorpholine acquire considerable hypolipidemic potency, while they preserve or augment their anti-inflammatory activity, thus addressing significant risk factors for atherogenesis. PMID- 26750252 TI - Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors. AB - Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Expression of ALK in normal human tissues is only found in a subset of neural cells, however it is involved in the genesis of several cancers through genetic aberrations involving translocation of the kinase domain with multiple fusion partners (e.g., NPM-ALK in anaplastic large cell lymphoma ALCL or EML4-ALK in non-small cell lung cancer) or activating mutations in the full-length receptor resulting in ligand-independent constitutive activation (e.g., neuroblastoma). Here we are reporting the discovery of novel and selective anaplastic lymphoma kinase inhibitors from specific modifications of the 2,4-diaminopyridine core present in TAE684 and LDK378. Synthesis, structure activity relationships (SAR), absorption, distribution, metabolism, and excretion (ADME) profile, and in vivo efficacy in a mouse xenograft model of anaplastic large cell lymphoma are described. PMID- 26750254 TI - Role of the phenolic OH moiety of GluN2B-selective NMDA antagonists with 3 benzazepine scaffold. AB - In order to analyze the role of the phenolic OH moiety of ifenprodil (1) and 3 benzazepin-1,7-diol 2 for the affinity and selectivity at GluN2B subunit containing NMDA receptors, the 3-benzazepin-1-ols 3 were designed, synthesized and pharmacologically evaluated and furthermore, the molecular interactions of the phenylbutyl derivative 3c with the GluN2B receptor were investigated. In order to avoid decarbonylation during the intramolecular Friedel-Crafts acylation of 11, the N-atom has to be protected with a trifluoromethylsulfonyl group. The second key step of the synthesis was the removal of the N-triflyl group, which was realized by K2CO3 induced elimination of trifluoromethanelsulfinate (F3CSO2( )). In receptor binding studies with the radioligand [(3)H]ifenprodil the 3 benzazepin-1-ol 3c revealed a GluN2B affinity of 73 nM indicating that the phenolic OH moiety of 1 and 2 is not essential but favorable for high GluN2B affinity. In docking studies 3-benzazepin-1-ol 3c shows the same binding pose as ifenprodil-keto 1A in the X-ray crystal structure. H-bond interactions and lipophilic interactions of 3c and 1A are very similar. PMID- 26750255 TI - Synthesis and biological evaluation of quinoxaline di-N-oxide derivatives with in vitro trypanocidal activity. AB - We report the synthesis and in vitro activity against Trypanosoma cruzi epimastigotes of 15 novel quinoxaline derivatives. Ten of the derivatives presented IC50 values lower than the reference drugs Nfx and Bzn; four of them standed out with IC50 values lower than 1.5 MUM. Moreover, unspecific cytotoxicity and genotoxicity studies are also reported. Compound 14 showed a SI higher than 24, whereas compound 10 was the only one that was negative in the genotoxicity screening. PMID- 26750256 TI - Synthesis and evaluation of atorvastatin esters as prodrugs metabolically activated by human carboxylesterases. AB - We synthesized 11 kinds of prodrug with an esterified carboxylic acid moiety of atorvastatin in moderate to high yields. We discovered that they underwent metabolic activation specifically by the human carboxylesterase 1 (CES1) isozyme. The results suggested that these ester compounds of atorvastatin have the potential to act as prodrugs in vivo. PMID- 26750257 TI - In vitro efficacy of 2,N-bisarylated 2-ethoxyacetamides against Plasmodium falciparum. AB - Investigation of a series of 2,N-bisarylated 2-ethoxyacetamides resulted in the identification of four inhibitors 5, 20, 24, 29 with single-digit micromolar in vitro efficacy against two drug-resistant Plasmodium falciparum strains. These compounds are analogs of structurally-related 1,3-bisaryl-2-propen-1-ones (chalcones), the latter showing efficacy in vitro but not in a malaria-infected mouse. The 2,N-bisarylated 2-ethoxyacetamides (e.g., 2, 5, 20) were shown to possess significantly greater stability in the presence of metabolizing enzymes than the corresponding 1,3-bisaryl-2-propen-1-ones (e.g., 1, 3, 18). PMID- 26750258 TI - TRPA1 channels as targets for resveratrol and related stilbenoids. AB - A series of twenty resveratrol analogues was synthesized and tested on TRPA1 and TRPV1 channels. None was able to significantly modulate TRPV1 channels. Conversely, most of them exhibited remarkably higher TRPA1 modulating activity than resveratrol. Optimal potency was observed with ortho monoxygenated stilbenes 6 and 17. PMID- 26750259 TI - Multimodal formyl peptide receptor 1 targeted inflammation imaging probe: cFLFLF MHI-DOTA. AB - Formyl peptide receptor 1 (FPR1) targeting multimodal probe cFLFLFK-MHI-DOTA for leukocyte based inflammation imaging is described. The compound consists of three domains, (a) cFLFLF peptide for FPR1 recognition and binding for activated leukocyte, (b) heptamethine cyanine dye (MHI) for near infrared fluorescence (NIRF) detection and imaging, and (c) metal chelator DOTA ligand that could form complex with a radiometal for nuclear (PET/SPECT) imaging or with a paramagnetic metal for MRI imaging. Detailed synthesis, characterization and in vitro evaluation are reported. The availability of dual mode inflammation imaging probe would allow in vivo gross level imaging of inflammation foci as well as ex vivo microscopic level cellular imaging for role played by innate immune cells in inflamed tissue. PMID- 26750260 TI - High Dynamic Range Pixel Array Detector for Scanning Transmission Electron Microscopy. AB - We describe a hybrid pixel array detector (electron microscope pixel array detector, or EMPAD) adapted for use in electron microscope applications, especially as a universal detector for scanning transmission electron microscopy. The 128*128 pixel detector consists of a 500 um thick silicon diode array bump bonded pixel-by-pixel to an application-specific integrated circuit. The in-pixel circuitry provides a 1,000,000:1 dynamic range within a single frame, allowing the direct electron beam to be imaged while still maintaining single electron sensitivity. A 1.1 kHz framing rate enables rapid data collection and minimizes sample drift distortions while scanning. By capturing the entire unsaturated diffraction pattern in scanning mode, one can simultaneously capture bright field, dark field, and phase contrast information, as well as being able to analyze the full scattering distribution, allowing true center of mass imaging. The scattering is recorded on an absolute scale, so that information such as local sample thickness can be directly determined. This paper describes the detector architecture, data acquisition system, and preliminary results from experiments with 80-200 keV electron beams. PMID- 26750261 TI - Dual nucleophilic substitution at a W(ii) eta(2)-coordinated diiodo acetylene leading to an amidinium carbyne complex. AB - The synthesis and reactivity of a W(ii) C2I2 complex towards various nucleophiles are described. Soft, aprotic nucleophiles like 4-dimethylaminopyridine (DMAP) lead to substitution of one CO at tungsten, whereas reaction with an excess of benzylamine results in a dual nucleophilic substitution at the alkyne moiety involving the rearrangement to a novel cationic amidinium carbyne complex. PMID- 26750262 TI - Competing ferro- and antiferromagnetic interactions in a hexagonal bipyramidal nickel thiolate cluster. AB - A new hexagonal bipyramidal Ni8 cluster is reported and its magnetic behaviour is analyzed. The molecular structure consists of a hexagonal wheel capped by two additional apical Ni(2+) ions. This structure supports ferromagnetic superexchange interactions between adjacent Ni(2+) ions in the wheel and an antiferromagnetic superexchange interaction between the wheel and apical Ni(2+) ions. PMID- 26750263 TI - REPLACR-mutagenesis, a one-step method for site-directed mutagenesis by recombineering. AB - Mutagenesis is an important tool to study gene regulation, model disease-causing mutations and for functional characterisation of proteins. Most of the current methods for mutagenesis involve multiple step procedures. One of the most accurate methods for genetically altering DNA is recombineering, which uses bacteria expressing viral recombination proteins. Recently, the use of in vitro seamless assembly systems using purified enzymes for multiple-fragment cloning as well as mutagenesis is gaining ground. Although these in vitro isothermal reactions are useful when cloning multiple fragments, for site-directed mutagenesis it is unnecessary. Moreover, the use of purified enzymes in vitro is not only expensive but also more inaccurate than the high-fidelity recombination inside bacteria. Here we present a single-step method, named REPLACR-mutagenesis (Recombineering of Ends of linearised PLAsmids after PCR), for creating mutations (deletions, substitutions and additions) in plasmids by in vivo recombineering. REPLACR-mutagenesis only involves transformation of PCR products in bacteria expressing Red/ET recombineering proteins. Modifications in a variety of plasmids up to bacterial artificial chromosomes (BACs; 144 kb deletion) have been achieved by this method. The presented method is more robust, involves fewer steps and is cost-efficient. PMID- 26750300 TI - Mapping two measures to the International Classification Of Functioning, Disability and Health and the brief ICF core set for spinal cord injury in the post-acute context. AB - OBJECTIVE: To evaluate the extent to which the rehabilitation outcome levels (ROL) and the spinal cord independence measure (SCIM) III could be mapped to the International Classification of Functioning, Disability and Health (ICF) and the brief core set for spinal cord injury (SCI) in the post-acute context. METHODS: Two professionals used the published protocol to map the concepts derived from both measures to the ICF categories. Further, the endorsed categories at the second level of the ICF were used to determine the coverage of the Brief ICF Core Set for SCI. RESULTS: Three items of the ROL could not be conceptualised within the ICF, while the rest were mapped to 42 second-level categories, mainly to the activity and participation domain. All the items of the SCIM III were mapped, yielding 52 ICF categories, mostly at the third level (32). For the mapping to the Core Set for SCI, the ROL covered five and the SCIM III all nine categories of 'activities and participation' included as the candidate categories of the brief version. CONCLUSION: In terms of content, the ROL appears to be a more global measure of functioning, compared with the SCIM III that covers specific 'activity' aspects as proposed in the Brief Core Set for SCI. It is thus recommended that standardised measures, such as the SCIM III, be used due to its conceptual underpinnings and coverage of important aspects. Implications for Rehabilitation Rehabilitation professionals should select appropriately validated outcome measures specific to the health condition in order to evaluate the effectiveness of rehabilitation. Rehabilitation professional working with outcome measures should be aware of the limitations of measures, in terms of content, and supplement the evaluation with appropriate standardised measures or the use of the Core Sets. To enhance evidence-based practise in routine clinical practise, standardised outcome measures should be used. PMID- 26750301 TI - Synthesis of substituted benzo[ij]imidazo[2,1,5-de]quinolizine by rhodium(III) catalyzed multiple C-H activation and annulations. AB - The cascade oxidative annulation reactions of aryl imidazoles with two molecules of alkynes via multiple C-H activation proceed efficiently in the presence of [Cp*RhCl2]2 and Cu(OAc)2.H2O to give substituted benzo[ij]imidazo[2,1,5 de]quinolizine-based polyheteroaromatic compounds. This method is compatible with various functional groups, which are very useful for further synthetic transformations. PMID- 26750264 TI - Orexin/hypocretin neuron activation is correlated with alcohol seeking and preference in a topographically specific manner. AB - Orexin (ORX) (also known as hypocretin) neurons are located exclusively in the posterior hypothalamus, and are involved in a wide range of behaviours, including motivation for drugs of abuse such as alcohol. Hypothalamic subregions contain functionally distinct populations of ORX neurons that may play different roles in regulating drug-motivated and alcohol-motivated behaviours. To investigate the role of ORX neurons in ethanol (EtOH) seeking, we measured Fos activation of ORX neurons in rats following three different measures of EtOH seeking and preference: (i) context-induced reinstatement, or ABA renewal; (ii) cue-induced reinstatement of extinguished responding for EtOH; and (iii) a home cage task in which preference for EtOH (vs. water) was measured in the absence of either reinforcer. We found significant activation of ORX neurons in multiple subregions across all three behavioural tests. Notably, ORX neuron activation in the lateral hypothalamus correlated with the degree of seeking in context reinstatement and the degree of preference in home cage preference testing. In addition, Fos activation in ORX neurons in the dorsomedial hypothalamic and perifornical areas was correlated with context and home cage seeking/preference, respectively. Surprisingly, we found no relationship between the degree of cue-induced reinstatement and ORX neuron activation in any region, despite robust activation overall during reinstatement. These results demonstrate a strong relationship between ORX neuron activation and EtOH seeking/preference, but one that is differentially expressed across ORX field subregions, depending on reinstatement modality. PMID- 26750303 TI - Developing Emotion-Based Case Formulations: A Research-Informed Method. AB - OBJECTIVES: New research-informed methods for case conceptualization that cut across traditional therapy approaches are increasingly popular. This paper presents a trans-theoretical approach to case formulation based on the research observations of emotion. METHODS: The sequential model of emotional processing (Pascual-Leone & Greenberg, 2007) is a process research model that provides concrete markers for therapists to observe the emerging emotional development of their clients. We illustrate how this model can be used by clinicians to track change and provides a 'clinical map,' by which therapist may orient themselves in session and plan treatment interventions. RESULTS: Emotional processing offers as a trans-theoretical framework for therapists who wish to conduct emotion-based case formulations. First, we present criteria for why this research model translates well into practice. Second, two contrasting case studies are presented to demonstrate the method. CONCLUSIONS: The model bridges research with practice by using client emotion as an axis of integration. Key Practitioner Message Process research on emotion can offer a template for therapists to make case formulations while using a range of treatment approaches. The sequential model of emotional processing provides a 'process map' of concrete markers for therapists to (1) observe the emerging emotional development of their clients, and (2) help therapists develop a treatment plan. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26750302 TI - Construction of a 3D rGO-collagen hybrid scaffold for enhancement of the neural differentiation of mesenchymal stem cells. AB - The cell-material interface is one of the most important considerations in designing a high-performance tissue engineering scaffold because the surface of the scaffold can determine the fate of stem cells. A conductive surface is required for a scaffold to direct stem cells toward neural differentiation. However, most conductive polymers are toxic and not amenable to biological degradation, which restricts the design of neural tissue engineering scaffolds. In this study, we used a bioactive three-dimensional (3D) porcine acellular dermal matrix (PADM), which is mainly composed of type I collagen, as a basic material and successfully assembled a layer of reduced graphene oxide (rGO) nanosheets on the surface of the PADM channels to obtain a porous 3D, biodegradable, conductive and biocompatible PADM-rGO hybrid neural tissue engineering scaffold. Compared with the PADM scaffold, assembling the rGO into the scaffold did not induce a significant change in the microstructure but endowed the PADM-rGO hybrid scaffold with good conductivity. A comparison of the neural differentiation of rat bone-marrow-derived mesenchymal stem cells (MSCs) was performed by culturing the MSCs on PADM and PADM-rGO scaffolds in neuronal culture medium, followed by the determination of gene expression and immunofluorescence staining. The results of both the gene expression and protein level assessments suggest that the rGO-assembled PADM scaffold may promote the differentiation of MSCs into neuronal cells with higher protein and gene expression levels after 7 days under neural differentiation conditions. This study demonstrated that the PADM-rGO hybrid scaffold is a promising scaffold for neural tissue engineering; this scaffold can not only support the growth of MSCs at a high proliferation rate but also enhance the differentiation of MSCs into neural cells. PMID- 26750304 TI - Changes in pathogenicity and immunogenicity of Mycoplasma mycoides subsp. mycoides strains revealed by comparative genomics analysis. AB - Mycoplasma mycoides subsp. mycoides is the causative agent of contagious bovine pleuropneumonia. A pathogenic strain BEN-1 was isolated from bovine lung and underwent continuous passages in rabbits for 468 generations. During this process, the strain's strong virulence became weak and, gradually, it lost the ability to confer protective immunity in cattle but developed virulence in rabbits. In order to gain insight into the mechanisms behind the reduction in virulence and the loss of immunogenicity, we sequenced five representative strains of the BEN series, including the original strain (BEN-1), the strain generation that first acquired virulence in rabbits (BEN-50), the two vaccine strain generations (BEN-181 and BEN-326), and the strain generation showing the greatest loss of immunogenicity (BEN-468). The gene mutation rate in the four different propagation stages varied greatly, and over half of variations observed in each generation were removed during the propagation process. However, the variation maintained in the BEN-468 generation might contribute to its changes in virulence and immunogenicity. We thus identified 18 genes associated with host adaptation, six genes contributing to virulence in cattle, and 35 genes participating in conferring immunity in cattle. These findings might help us optimize the vaccine to obtain more effective immunization results. PMID- 26750305 TI - Open Source Bayesian Models. 3. Composite Models for Prediction of Binned Responses. AB - Bayesian models constructed from structure-derived fingerprints have been a popular and useful method for drug discovery research when applied to bioactivity measurements that can be effectively classified as active or inactive. The results can be used to rank candidate structures according to their probability of activity, and this ranking benefits from the high degree of interpretability when structure-based fingerprints are used, making the results chemically intuitive. Besides selecting an activity threshold, building a Bayesian model is fast and requires few or no parameters or user intervention. The method also does not suffer from such acute overtraining problems as quantitative structure activity relationships or quantitative structure-property relationships (QSAR/QSPR). This makes it an approach highly suitable for automated workflows that are independent of user expertise or prior knowledge of the training data. We now describe a new method for creating a composite group of Bayesian models to extend the method to work with multiple states, rather than just binary. Incoming activities are divided into bins, each covering a mutually exclusive range of activities. For each of these bins, a Bayesian model is created to model whether or not the compound belongs in the bin. Analyzing putative molecules using the composite model involves making a prediction for each bin and examining the relative likelihood for each assignment, for example, highest value wins. The method has been evaluated on a collection of hundreds of data sets extracted from ChEMBL v20 and validated data sets for ADME/Tox and bioactivity. PMID- 26750306 TI - Frontal sinus surgery and sinus distribution of nasal irrigation. AB - BACKGROUND: Effective mucus lavage and delivery of topical pharmaceuticals are central to successful management of chronic rhinosinusitis (CRS). The frontal sinus remains difficult to penetrate with topical therapies. This study evaluates the benefit of Draf III frontal dissection compared to traditional Draf IIa for distribution of topical therapies. METHODS: Fresh human cadaver heads were dissected sequentially with Draf IIa frontal sinusotomy and then Draf III procedures. Each cavity was irrigated with pediatric (120 mL) and adult (240 mL) irrigation bottles with 1/1000 10% fluorescein-labeled free water in 2 fixed positions (vertex and Frankfort horizontal). An endoscope at a fixed position within the frontal sinus recorded frontal sinus and frontal recess penetration. The images then underwent blinded evaluation of fluid distribution scored as 0 to 4 (nasal cavity only, frontal recess, medial one-half, lateral one-half, and lavage). Ordinal distribution score was analyzed with Kendall's tau-b. RESULTS: Eight specimens (age 76 +/- 11.2 years; 50% female) were assessed. Draf III was superior to Draf IIa in ability to achieve frontal sinus distribution of irrigation (90.6% vs 50.1%, p < 0.001). Vertex head position improved distribution (90.6% vs 50.1%, p < 0.001), was synergistic with Draf III (100% with 87.5% lavage, p < 0.001), but was unable to overcome Draf IIa (81.2% with 25% lavage, p < 0.001). Irrigation volume trended toward improved distribution with larger volume irrigations. CONCLUSION: Successful treatment of sinonasal disease may require postoperative delivery of topical therapies. Draf III frontal sinusotomy achieves superior topical access, and access to the frontal sinus with Draf IIa appears limited, despite large volumes and positioning. PMID- 26750307 TI - Co-utilization of glycerol and lignocellulosic hydrolysates enhances anaerobic 1,3-propanediol production by Clostridium diolis. AB - Anaerobic fermentation using lignocellulosic hydrolysates as co-substrates is an economically attractive method to enhance 1,3-propanediol (1,3-PD) production by increasing the conversion yield from glycerol. Lignocellulosic hydrolysates contain the mixed sugars that are primarily glucose, xylose, and arabinose. Therefore, these three individual sugars were used, separately, as co-substrates with glycerol, in 1,3-PD production by a Clostridium diolis strain DSM 15410, resulting in an 18%-28% increase in the 1,3-PD yield. Co-fermentation of the mixed sugars and glycerol obtained a higher intracellular NADH/NAD(+) ratio and increased the 1,3-PD yield by 22% relative to fermentation of glycerol alone. Thereafter, two kinds of lignocellulosic hydrolysates, corn stover hydrolysate and corncob molasses, were individually co-fermented with glycerol. The maximum 1,3-PD yield from glycerol reached 0.85 mol/mol. Fed-batch co-fermentation was also performed, improving the 1,3-PD yield (from 0.62 mol/mol to 0.82 mol/mol). These results demonstrate that the co-fermentation strategy is an efficient and economical way to produce 1,3-PD from glycerol. PMID- 26750308 TI - Altered trafficking of abnormal prion protein in atypical scrapie: prion protein accumulation in oligodendroglial inner mesaxons. AB - AIMS: Prion diseases exist in classical and atypical disease forms. Both forms are characterized by disease-associated accumulation of a host membrane sialoglycoprotein known as prion protein (PrPd ). In classical forms of prion diseases, PrPd can accumulate in the extracellular space as fibrillar amyloid, intracellularly within lysosomes, but mainly on membranes in association with unique and characteristic membrane pathology. These membrane changes are found in all species and strains of classical prion diseases and consist of spiral, branched and clathrin-coated membrane invaginations on dendrites. Atypical prion diseases have been described in ruminants and man and have distinct biological, biochemical and pathological properties when compared to classical disease. The purpose of this study was to determine whether the subcellular pattern of PrPd accumulation and membrane changes in atypical scrapie were the same as those found in classical prion diseases. METHODS: Immunogold electron microscopy was used to examine brains of atypical scrapie-affected sheep and Tg338 mice. RESULTS: Classical prion disease-associated membrane lesions were not found in atypical scrapie-affected sheep, however, white matter PrPd accumulation was localized mainly to the inner mesaxon and paranodal cytoplasm of oligodendroglia. Similar lesions were found in myelinated axons of atypical scrapie Tg338-infected mice. However, Tg338 mice also showed the unique grey matter membrane changes seen in classical forms of disease. CONCLUSIONS: These data show that atypical scrapie infection directs a change in trafficking of abnormal PrP to axons and oligodendroglia and that the resulting pathology is an interaction between the agent strain and host genotype. PMID- 26750309 TI - Impact of adenotonsillectomy on vocal emission in children. AB - INTRODUCTION: Adenotonsillectomy is the most common surgery performed by otolaryngologists in pediatric age, and one of the most frequently asked questions about the postoperative period is whether there is a potential for change in vocal pattern of these children. OBJECTIVE: To evaluate the impact of adenotonsillectomy in the voice emission pattern of children with hypertrophy of palatine and pharyngeal tonsils. METHODS: This is a prospective study in which we carried out perceptual auditory assessments and acoustic analysis of 26 children with adenotonsillar hypertrophy at three time points: before surgery, one month and three months after surgery. The following acoustic parameters were estimated using the Praat software: fundamental frequency, jitter, shimmer, and harmonic noise ratio. RESULTS: A statistically significant change was found between shimmer and harmonic-noise ratio during vowel /u/ production between the preoperative and 1st month postoperative time points. No significant differences were detected for acoustic parameters between preoperative analysis and that of the 3rd month post-operation. CONCLUSION: Transient changes in acoustic parameters occur in children with adenotonsillar hypertrophy submitted to adenotonsillectomy, progressing to normalization in the 3rd postoperative month. PMID- 26750310 TI - The impact of laronidase treatment in otolaryngological manifestations of patients with mucopolysaccharidosis. AB - INTRODUCTION: Mucopolysaccharidosis (MPS) is a lysosomal storage disease caused by deficiency of alpha-l-iduronidase. The otolaryngological findings include hearing loss, otorrhea, recurrent otitis, hypertrophy of tonsils and adenoid, recurrent rhinosinusitis, speech disorders, snoring, oral breathing and nasal obstruction. OBJECTIVE: To evaluate the impact of enzymatic replacement therapy with laronidase (Aldurazyme((r))) in patients with mucopolysaccharidosis (MPS I), regarding sleep and hearing disorders, and clinical manifestations in the upper respiratory tract (URT). METHODS: Nine patients with MPS I (8 Hurler-Scheie, and 1 Scheie phenotypes) of both sexes, ages ranging between 3 and 20 years, were included in this study. Patients were evaluated between seven and 11 months before the treatment and between 16 and 22 months after the onset of the enzymatic replacement. They were all submitted to a clinical and otolaryngological evaluation, including nasofibroscopical, polysomnographic and audiologic exams. RESULTS: The results' data showed decreasing of the frequency of ear, nose and throat infections, with improvement of the rhinorrhea and respiratory quality. No remarkable changes were observed regarding macroglossia and tonsil and adenoid hypertrophy. Audiometric and polysomnographic evaluations did not show statistical significance. CONCLUSION: Enzymatic replacement therapy in patients with mucopolysaccharidosis I provides control of recurrent URT infections, rhinorrhea and respiratory quality, however it is does not seem to improve audiologic and polisomnographic parameters, with no effect on adenoid and tonsils hypertrophy and macroglossia. PMID- 26750311 TI - Interleukin-23-Induced Transcription Factor Blimp-1 Promotes Pathogenicity of T Helper 17 Cells. AB - Interleukin-23 (IL-23) is a pro-inflammatory cytokine required for the pathogenicity of T helper 17 (Th17) cells but the molecular mechanisms governing this process remain unclear. We identified the transcription factor Blimp-1 (Prdm1) as a key IL-23-induced factor that drove the inflammatory function of Th17 cells. In contrast to thymic deletion of Blimp-1, which causes T cell development defects and spontaneous autoimmunity, peripheral deletion of this transcription factor resulted in reduced Th17 activation and reduced severity of autoimmune encephalomyelitis. Furthermore, genome-wide occupancy and overexpression studies in Th17 cells revealed that Blimp-1 co-localized with transcription factors RORgammat, STAT-3, and p300 at the Il23r, Il17a/f, and Csf2 cytokine loci to enhance their expression. Blimp-1 also directly bound to and repressed cytokine loci Il2 and Bcl6. Taken together, our results demonstrate that Blimp-1 is an essential transcription factor downstream of IL-23 that acts in concert with RORgammat to activate the Th17 inflammatory program. PMID- 26750314 TI - Click Chemistry in Biomaterials, Nanomedicine, and Drug Delivery. PMID- 26750313 TI - Getting back on the beat: links between auditory-motor integration and precise auditory processing at fast time scales. AB - The auditory system is unique in its ability to precisely detect the timing of perceptual events and use this information to update motor plans, a skill that is crucial for language. However, the characteristics of the auditory system that enable this temporal precision are only beginning to be understood. Previous work has shown that participants who can tap consistently to a metronome have neural responses to sound with greater phase coherence from trial to trial. We hypothesized that this relationship is driven by a link between the updating of motor output by auditory feedback and neural precision. Moreover, we hypothesized that neural phase coherence at both fast time scales (reflecting subcortical processing) and slow time scales (reflecting cortical processing) would be linked to auditory-motor timing integration. To test these hypotheses, we asked participants to synchronize to a pacing stimulus, and then changed either the tempo or the timing of the stimulus to assess whether they could rapidly adapt. Participants who could rapidly and accurately resume synchronization had neural responses to sound with greater phase coherence. However, this precise timing was limited to the time scale of 10 ms (100 Hz) or faster; neural phase coherence at slower time scales was unrelated to performance on this task. Auditory-motor adaptation therefore specifically depends upon consistent auditory processing at fast, but not slow, time scales. PMID- 26750315 TI - Higher Order Factor Convergence and Divergence of Two Distinct Personality Systems: Cattell's HSPQ And Jackson's PRF. AB - The 14 scales of the HSPQ and 20 scales of the PRF were administered to 1,862 adolescents. Scales were intercorrelated, factored, and the factors rotated to simple structure solutions, separately for each instrument. Cross-instrument relationships were subsequently examined by: (a) Dwyer extension analysis procedure, and (b) estimating correlations of "true" factor scores between the two sets of factors. Results indicated both cross-instrument commonalities and specificities. Higher stratum dimensions (HSPQ-PRF) of Exvia-Ascendance, Superego Strength-Impulse Control, Cortertia-Aesthetic Intellectual Orientation, and Dependence-Social Contact were found to be closely related in the two instruments. Dimensions such as Aggression (PRF), Achievement (PRF), and Anxiety (HSPQ) were found to be instrument-specific. It was concluded that neither instrument provides for a comprehensive mapping of the personality domain, broadly defined. Implications of the levels of factor convergence and divergence obtained in relation to theory building and prediction are discussed. PMID- 26750312 TI - Interleukin-2-Dependent Allergen-Specific Tissue-Resident Memory Cells Drive Asthma. AB - Exposure to inhaled allergens generates T helper 2 (Th2) CD4(+) T cells that contribute to episodes of inflammation associated with asthma. Little is known about allergen-specific Th2 memory cells and their contribution to airway inflammation. We generated reagents to understand how endogenous CD4(+) T cells specific for a house dust mite (HDM) allergen form and function. After allergen exposure, HDM-specific memory cells persisted as central memory cells in the lymphoid organs and tissue-resident memory cells in the lung. Experimental blockade of lymphocyte migration demonstrated that lung-resident cells were sufficient to induce airway hyper-responsiveness, which depended upon CD4(+) T cells. Investigation into the differentiation of pathogenic Trm cells revealed that interleukin-2 (IL-2) signaling was required for residency and directed a program of tissue homing migrational cues. These studies thus identify IL-2 dependent resident Th2 memory cells as drivers of lung allergic responses. PMID- 26750316 TI - Dissimilarity Measures For Unconstrained Sorting Data. AB - In this article, three dissimilarity measures for the unconstrained sorting task are investigated. All three measures are metrics, but they differ in the kind of compensation which they make for differences in the sizes of cells within sortings. Empirical tests of the three measures are done with sorting data for occupations names and the names of behaviors, using the multidimensional scaling method. PMID- 26750317 TI - Multivariable-Multimethod Convergence in the Domain of Interpersonal Behavior. AB - While empirical studies of the domain of interpersonal behavior indicate a great deal of conceptual convergence, there are few data bearing on the convergent validity of indices of interpersonal behavior across modes of measurement within the same population of subjects. As part of a larger study of the assessment of interpersonal behavior, 64 Ss participated in a multivariable-multimethod investigation, and completed a variety of self-report assessment devices, direct self ratings, and peer ratings. Substantial convergence for three dimensions of interpersonal behavior, Aggressive Dominance, Affiliation-Sociability, and Autonomy, was obtained across all modes of measurement. The results have implications for the assessment of interpersonal behavior, the individual differences versus situational variance controversy, and associated theoretical and methodological problems in multivariable-multimethod-multisituational designs. PMID- 26750318 TI - The Utility of Homogeneous Subgroups and Individual Information in Prediction. AB - A number of behavioral research studies have employed subgroups of subjects for prediction. In using subgroups for predictive purposes, a key assumption is often overlooked, i.e., at least one of the grouping or predictor dimensions affects the relationships between the other grouping dimensions and the criteria. The purposes of the present study were (a) to emphasize this commonly overlooked assumption and (b) to examine empirically the utility of subgroup versus individual information in prediction. Data collected on 509 freshmen in 32 life history subgroups (19 male and 13 female subgroups) were used to evaluate the utility of subgroup information in prediction. Of 24 criteria (college experience data, e.g., academic achievement) predicted by subgroup information, predictive efficiency of four criterion measures was enhanced when subgroup information was added to individual information. However, for the vast majority of the criterion measures, predictive efficiency would have been lost had only subgroup information been used in prediction. It is recommended that researchers carefully evaluate the effects on predictive efficiency when using subgroups rather than individual information in prediction. PMID- 26750319 TI - Conjoint Psychotherapeutic Experience: Some Dimensions and Determinants. AB - In our previous reports we have specified the empirical structure of patients' and therapists' experiences in psychotherapeutic sessions. The present report explores the structure of experience within the therapeutic dyad -- conjoint experience. Seven factors were derived from the reports of 28 patient-therapist pairs. One factor reflected the therapist's approach to his role as a help-giver, and another reflected the patient's approach to her role. Other patterns showed convergent perceptions, while still others showed conjoint experiential processes -- inter-experience. Determinants of these experiences were sought among the personal and social characteristics of the participants. Several clinically suggestive patterns of determinants emerged. PMID- 26750320 TI - Invariance of Factors of Mouse Emotionality With Changed Experimental Conditions. AB - Six factors of mouse emotionality (autonomic balance, motor discharge, acrophobia, territoriality, tunneling-1, and tunneling-2) were compared across three separate studies. Each study included 19 measures from five tests of emotionality: open field, straightaway, pole, cell, and hole-in-wall. However, conditions of testing differed significantly in each study. In the first study, the measures taken were part of a large test battery. In the second study, a reduced test battery included only the 19 measures. In the third study, this reduced battery was used again, but subjects were injected with psychoactive drugs prior to testing. In addition to these changes, different genotypes were used across studies. Subjects in the first study were tested as part of a 6 * 6 diallel table. In the second and third studies, two emotionally contrasted strains (SWR and SJL) were tested. Each population was refactored by alpha factoring with varimax, followed by promax rotations. Factors obtained were compared by quantitative means using S-index and r[SUBc] coefficients of factor matching. Although support was obtained for the invariance of all six factors, the results indicate invariance as being strongest for motor discharge and acrophobia and weakest for tunneling-1 and tunneling-2 factors. PMID- 26750321 TI - The Method of Sorting as a Data-Gathering Procedure in Multivariate Research. AB - This study compares two basic variants of the sorting method: single-sort in which each respondent is given only one opportunity to sort the items; and multiple-sort in which the respondent is given several opportunities to sort, each time on a different basis. Kinship terms serve as stimulus materials. Multidimensional scaling solutions show large differences between the two methods with respect to the degree to which the kinship dimensions are used as a basis for sorting. In particular, most respondents ignore the most obvious dimension (sex of the terms) when they believe they have only one opportunity to indicate the dimensions in the set. Similar observations of pairwise judgments in another stimulus domain (consonant phonemes) suggest the same bias may be present in such judgments. Moreover, in both instances hierarchical clustering completely fails to represent the minority of judges who do not ignore the given dimension. These results indicate that a multiple set of judgments from each set of respondents may be superior to a single set of judgments for certain stimulus domains. Finally, the kinship data also indicate that male and female respondents emphasize different kinship dimensions but that aggregated multiple-sort data do appear to reflect the cognitive dimensions present in any given individual. PMID- 26750322 TI - Brief Report: Second-Order Cluster Analysis of Personal Orientation Inventory Items in a Prison Sample. AB - The responses of 500 male prisoners to the 150 items of the Personal Orientation Inventory were clustered, using hierarchical linkage analysis. Six second-order clusters accounted for all the items. K-R 20 reliabilities of these clusters were comparable to those of the first-order clusters. The relative validity of cluster scores and scale scores remains to be determined. PMID- 26750323 TI - Brief Report: On the Proportionate Contributions of Transformed Factors to Common Variance. AB - A generalized matrix procedure is developed for computing the proportionate contribution of a factor, either orthogonal or oblique, to the total common variance of a factor solution. PMID- 26750325 TI - Reply. PMID- 26750326 TI - Synthesis of polyhydroxylated pyrrolidines from sugar-derived bromonitriles through a cascade addition of allylmagnesium bromide/cyclization/reduction. AB - The synthesis of polyhydroxylated 2-allylpyrrolidines from sugar-derived bromonitriles in a cascade addition of allylmagnesium bromide/SN2 cyclization/reduction with Zn(BH4)2 is described. The stereochemical course of the reduction step is rationalized. Two of the obtained compounds are transformed into stereoisomers of naturally-occurring iminosugar (+)-lentiginosine. In an alternative approach, 2,2-diallylpyrrolidines are obtained from bromonitriles in a cascade addition of allylmagnesium bromide/SN2 cyclization/addition of another equivalent of allylmagnesium bromide. PMID- 26750324 TI - Bright and photostable push-pull pyrene dye visualizes lipid order variation between plasma and intracellular membranes. AB - Imaging lipid organization in cell membranes requires advanced fluorescent probes. Here, we show that a recently synthesized push-pull pyrene (PA), similarly to popular probe Laurdan, changes the emission maximum as a function of lipid order, but outperforms it by spectroscopic properties. In addition to red shifted absorption compatible with common 405 nm diode laser, PA shows higher brightness and much higher photostability than Laurdan in apolar membrane environments. Moreover, PA is compatible with two-photon excitation at wavelengths >800 nm, which was successfully used for ratiometric imaging of coexisting liquid ordered and disordered phases in giant unilamellar vesicles. Fluorescence confocal microscopy in Hela cells revealed that PA efficiently stains the plasma membrane and the intracellular membranes at >20-fold lower concentrations, as compared to Laurdan. Finally, ratiometric imaging using PA reveals variation of lipid order within different cellular compartments: plasma membranes are close to liquid ordered phase of model membranes composed of sphingomyelin and cholesterol, while intracellular membranes are much less ordered, matching well membranes composed of unsaturated phospholipids without cholesterol. These differences in the lipid order were confirmed by fluorescence lifetime imaging (FLIM) at the blue edge of PA emission band. PA probe constitutes thus a new powerful tool for biomembrane research. PMID- 26750327 TI - Asymmetric synthesis of cyclopentanes bearing four contiguous stereocenters via an NHC-catalyzed Michael/Michael/esterification domino reaction. AB - An NHC-catalyzed Michael/Michael/esterification domino reaction via homoenolate/enolate intermediates for the asymmetric synthesis of tetrasubstituted cyclopentanes bearing four contiguous stereocenters is described. A variety of alpha,beta-unsaturated aldehydes and 2-nitroallylic acetates react well with good domino yields and high stereoselectivities. PMID- 26750331 TI - Determination of the hyperfine coupling tensor in organic conductors kappa-(BEDT TTF)2X (X=Cu[N(CN)2]Br, Cu(NCS)2) on central 13C sites. AB - Although the organic superconductors kappa-(BEDT-TTF)2X (X=Cu[N(CN)2]Br and Cu(NCS)2) have been studied by NMR spectroscopy, hyperfine coupling tensors are required to quantify NMR spectra. Angle dependences of NMR spectra were measured to determine hyperfine coupling tensors applicable to further NMR assessments of attractive physical phenomena on kappa-salts. The tensors of kappa-(BEDT-TTF)2X and beta(')-(BEDT-TTF)2ICl2 salts were compared to determine the hyperfine coupling mechanism in organic metals, with the results indicating that off-site dimer contribution should be considered. We also report the electron correlation of these salts and further application of the tensors. PMID- 26750333 TI - The fabrication of a novel Ag3VO4/WO3 heterojunction with enhanced visible light efficiency in the photocatalytic degradation of TC. AB - The construction of efficient photocatalysts for environmental remediation has attracted a great deal of attention in recent years. In this study, a novel Ag3VO4/WO3 heterojunction photocatalyst has been successfully prepared via a hydrothermal process and a facile precipitation reaction. Under visible light irradiation, the hybrid materials could significantly enhance photocatalytic activity for the degradation of tetracycline (TC) in comparison with single Ag3VO4 and WO3. Within 30 min, 71.2% TC could be photodegraded by the optimum sample (10% A/W), which was about 3.1 times and 4.6 times higher than that of the individual Ag3VO4 and WO3, respectively. Based on the active species trapping experiments and ESR, the photocatalytic oxidation mechanism of the Ag3VO4/WO3 composite was also discussed. It can be assumed that the enhancement of the photocatalytic activity was attributed to the heterojunction which could widely accelerate the separation of photogenerated electron-hole pairs. In general, WO3 hybridized with Ag3VO4 will also efficiently address the problem of low photocatalytic activity. PMID- 26750332 TI - Local recurrence of small cell lung cancer following radiofrequency ablation is induced by HIF-1alpha expression in the transition zone. AB - Local recurrence of lung cancer following radiofrequency ablation (RFA) treatment is common. The aims of the present study were to assess how RFA treatment affects the growth of small cell lung cancer (SCLC) micrometastases in the transition zone (TZ) surrounding the ablated region and in the reference zones (RZs) of the ablated or unablated lobes and to identify the molecular mechanism(s) of lung cancer recurrence following RFA treatment. After lung micrometastases of human SCLCs had formed, RFA treatment was applied to the right upper lobe (RUL) of the lung in nude mice. Hypoxia inducible factor (HIF)-1alpha expression, proliferation and angiogenesis potential both in the TZ and RZ were evaluated over time. Separately, at day 1, 7 and 14 following RFA treatment, the growth of micrometastases showed an ~2-fold increase in the TZ compared to the RZ of the unablated lobe, as the right lower lobe (RLL) and the growth of micrometastases in the RZ of the RUL was also induced by RFA. In addition, accelerated tumor growth in the TZ was induced by HIF-1alpha, but was not associated with tissue angiogenesis potential. We concluded that local recurrences of SCLCs caused by overproliferation of micrometastases following RFA treatment were driven by HIF 1alpha, although angiogenesis was not the driving force in the TZ. PMID- 26750334 TI - Control of YAP/TAZ Activity by Metabolic and Nutrient-Sensing Pathways. AB - Metabolism is a fundamental cellular function that can be reprogrammed by signaling pathways and oncogenes to meet cellular requirements. An emerging paradigm is that signaling and transcriptional networks can be in turn regulated by metabolism, allowing cells to coordinate their metabolism and behavior in an integrated manner. The activity of the YAP/TAZ transcriptional coactivators, downstream transducers of the Hippo cascade and powerful pro-oncogenic factors, was recently found to be regulated by metabolic pathways, such as aerobic glycolysis and mevalonate synthesis, and by the nutrient-sensing LKB1-AMPK and TSC-mTOR pathways. We discuss here current data linking YAP/TAZ to metabolism and suggest how this coupling might coordinate nutrient availability with genetic programs that sustain tissue growth, neoplastic cell proliferation, and tumor malignancy. PMID- 26750336 TI - Quantifying Parsimony in Structural Equation Modeling. AB - Fitting propensity (FP) is defined as a model's average ability to fit diverse data patterns, all else being equal. The relevance of FP to model selection is examined in the context of structural equation modeling (SEM). In SEM it is well known that the number of free model parameters influences FP, but other facets of FP are routinely excluded from consideration. It is shown that models possessing the same number of free parameters but different structures may exhibit different FPs. The consequences of this fact are demonstrated using illustrative examples and models culled from published research. The case is made that further attention should be given to quantifying FP in SEM and considering it in model selection. Practical approaches are suggested. PMID- 26750335 TI - Simulation-based otolaryngology - head and neck surgery boot camp: 'how I do it'. AB - BACKGROUND: In otolaryngology, surgical emergencies can occur at any time. An annual surgical training camp (or 'boot camp') offers junior residents from across North America the opportunity to learn and practice these skills in a safe environment. The goals of this study were to describe the set-up and execution of a simulation-based otolaryngology boot camp and to determine participants' confidence in performing routine and emergency on-call procedures in stressful situations before and after the boot camp. METHODS: There were three main components of the boot camp: task trainers, simulations and an interactive panel discussion. Surveys were given to participants before and after the boot camp, and their confidence in performing the different tasks was assessed via multiple t-tests. RESULTS: Participants comprised 22 residents from 12 different universities; 10 of these completed both boot camp surveys. Of the nine tasks, the residents reported a significant improvement in confidence levels for six, including surgical airway and orbital haematoma management. CONCLUSION: An otolaryngology boot camp gives residents the chance to learn and practice emergency skills before encountering the emergencies in everyday practice. Their confidence in multiple skillsets was significantly improved after the boot camp. Given the shift towards competency-based learning in medical training, this study has implications for all surgical and procedural specialties. PMID- 26750337 TI - Separating "Rotators" From "Nonrotators" in the Mental Rotations Test: A Multigroup Latent Class Analysis. AB - Items of mental rotation tests can not only be solved by mental rotation but also by other solution strategies. A multigroup latent class analysis of 24 items of the Mental Rotations Test (MRT) was conducted in a sample of 1,695 German pupils and students to find out how many solution strategies can be identified for the items of this test. The results showed that five subgroups (latent classes) can be distinguished. Although three of the subgroups differ mainly in the number of items reached, one class shows are very low performance. In another class, a special solution strategy is used. This strategy seems to involve analytic rather than mental rotation processes and is efficient only for a special MRT item type, indicating that not all MRT items require a mental rotation approach. In addition, the multigroup analysis revealed significant sex differences with respect to the class assignment, confirming prior findings that on average male participants perform mental rotation tasks faster and better than female participants. Females were also overrepresented in the analytic strategy class. The results are discussed with respect to psychometric and substantive implications, and suggestions for the optimization of the MRT items are provided. PMID- 26750338 TI - The Performance of Cross-Validation Indices Used to Select Among Competing Covariance Structure Models Under Multivariate Nonnormality Conditions. AB - Cudeck and Browne (1983) proposed using cross-validation as a model selection technique in structural equation modeling. The purpose of this study is to examine the performance of eight cross-validation indices under conditions not yet examined in the relevant literature, such as nonnormality and cross validation design. The performance of each cross-validation index was measured in terms of true model selection rate as well as consistency of model selection. The performance of the cross-validation indices tended to improve as factor loading and sample size increased but performed less well as nonnormality increased. The double cross-validated indices outperformed their simple cross-validated counterparts in certain conditions. Recommendations are provided as to which cross-validation methods would optimally perform in a given condition. PMID- 26750339 TI - Bayesian Analysis of Structural Equation Models With Nonlinear Covariates and Latent Variables. AB - In this article, we formulate a nonlinear structural equation model (SEM) that can accommodate covariates in the measurement equation and nonlinear terms of covariates and exogenous latent variables in the structural equation. The covariates can come from continuous or discrete distributions. A Bayesian approach is developed to analyze the proposed model. Markov chain Monte Carlo methods for obtaining Bayesian estimates and their standard error estimates, highest posterior density intervals, and a PP p value are developed. Results obtained from two simulation studies are reported to respectively reveal the empirical performance of the proposed Bayesian estimation in analyzing complex nonlinear SEMs, and in analyzing nonlinear SEMs with the normal assumption of the exogenous latent variables violated. The proposed methodology is further illustrated by a real example. Detailed interpretation about the interaction terms is presented. PMID- 26750340 TI - A Comparison of Single Sample and Bootstrap Methods to Assess Mediation in Cluster Randomized Trials. AB - A Monte Carlo study examined the statistical performance of single sample and bootstrap methods that can be used to test and form confidence interval estimates of indirect effects in two cluster randomized experimental designs. The designs were similar in that they featured random assignment of clusters to one of two treatment conditions and included a single intervening variable and outcome, but they differed in whether the mediator was measured at the participant or site level. A bias-corrected bootstrap had the best statistical performance for each design and was closely followed by the empirical-Mtest, either of which is recommended for testing and estimating indirect effects in multilevel designs. In addition, consistent with previous research, the commonly used z test had relatively poor performance. PMID- 26750341 TI - Examining Temporal Stability of Scale Validity in Longitudinal Studies. AB - A method for examining invariance in validity of multiple-component instruments in repeated measure designs is outlined. The approach is developed within the framework of covariance structure modeling and is applicable for purposes of ascertaining temporal stability in scale validity. In addition, the procedure provides a range of plausible values in a population under investigation for the change in composite validity across longitudinal assessment occasions. The proposed method can also be used to examine possible sources of lack of validity invariance, and is illustrated with a pair of examples. PMID- 26750342 TI - Length of intact plasma membrane determines the diffusion properties of cellular water. AB - Molecular diffusion in a boundary-free medium depends only on the molecular size, the temperature, and medium viscosity. However, the critical determinant of the molecular diffusion property in inhomogeneous biological tissues has not been identified. Here, using an in vitro system and a high-resolution MR imaging technique, we show that the length of the intact plasma membrane is a major determinant of water diffusion in a controlled cellular environment and that the cell perimeter length (CPL) is sufficient to estimate the apparent diffusion coefficient (ADC) of water in any cellular environment in our experimental system (ADC = -0.21 * CPL + 1.10). We used this finding to further explain the different diffusion kinetics of cells that are dying via apoptotic or non-apoptotic cell death pathways exhibiting characteristic changes in size, nuclear and cytoplasmic architectures, and membrane integrity. These results suggest that the ADC value can be used as a potential biomarker for cell death. PMID- 26750377 TI - A quantitative investigation of linker histone interactions with nucleosomes and chromatin. AB - Linker histones such as H1 are abundant basic proteins that bind tightly to nucleosomes, thereby acting as key organizers of chromatin structure. The molecular details of linker histone interactions with the nucleosome, and in particular the contributions of linker DNA and of the basic C-terminal tail of H1, are controversial. Here we combine rigorous solution-state binding assays with native gel electrophoresis and Atomic Force Microscopy, to quantify the interaction of H1 with chromatin. We find that H1 binds nucleosomes and nucleosomal arrays with very tight affinity by recognizing a specific DNA geometry minimally consisting of a solitary nucleosome with a single ~18 base pair DNA linker arm. The association of H1 alters the conformation of trinucleosomes so that only one H1 can bind to the two available linker DNA regions. Neither incorporation of the histone variant H2A.Z, nor the presence of neighboring nucleosomes affects H1 affinity. Our data provide a comprehensive thermodynamic framework for this ubiquitous chromatin architectural protein. PMID- 26750378 TI - Acute increase in blood pressure during inhalation of coarse particulate matter air pollution from an urban location. AB - Particulate matter (PM) air pollution is a leading global risk factor for cardiovascular mortality. Although exposure to fine PM <2.5 MUm raises arterial blood pressure (BP), few studies have evaluated the impact of coarse PM which differs in size (2.5-10 MUm), sources, and chemistry. Twenty-nine healthy adults (30.4 +/- 8.2 years) underwent a randomized double-blind crossover study involving 2-hour exposures to concentrated ambient coarse PM (164.2 +/- 80.4 MUg/m(3)) at an urban location (Dearborn, Michigan) versus filtered air. Cardiovascular outcomes were measured during, immediately, and 2 hours after exposures. Both systolic (1.9 mm Hg; 95% confidence interval: 0.96, 2.8; P < .001) and diastolic (1.9 mm Hg; 95% confidence interval: 1.1, 2.7; P < .001) BP levels were higher throughout coarse PM compared with filtered air exposures by mixed-model analyses. Heart rate variability, endothelial function, and arterial compliance were not significantly affected. Brief exposure to coarse PM in an urban environment raises arterial BP. These findings add mechanistic support to the contention that coarse PM may be capable of promoting cardiovascular events. PMID- 26750380 TI - Electronic structure of the para-benzoquinone radical anion revisited. AB - Photoinduced dynamics of the para-benzoquinone anion features a subtle interplay between autodetachment and non-adiabatic transitions involving a dense manifold of resonances. We report the results of a multistate multireference perturbation theory study of the electronic structure of the para-benzoquinone anion in the ground, several low-lying excited electronic states, and in the lowest electron detached state (the ground state of the neutral molecule). The electronic structure calculations revealed non-planar equilibrium geometry of the (2)Au excited state of the anion, but the effects of non-planarity on the shape of the absorption spectrum are found to be minor. Despite the large differences in the vertical excitation energies for the two lowest bright excited states, (2)Au (2.55 eV) and (2)B3u (2.93 eV), the simulated absorption spectra significantly overlap for the photon energies below 2.7 eV. Relevant minimum energy crossing points have been located using the CASSCF method. Excited-state deactivation channels are discussed in the context of accurate energetics and recent spectroscopic studies of the para-benzoquinone anion. PMID- 26750382 TI - Translational immunology: The new EJI challenge. PMID- 26750384 TI - EFIS elects its new Board. PMID- 26750389 TI - Air Force Pilot Personality: Hard Data on the "Right Stuff". AB - Three-hundred and fifty Air Force pilots undergoing Undergraduate Pilot Training were administered the Personality Research Form (PRF) and the Millon Clinical Multiaxial Inventory (MCMI) within the first four weeks of training. Pilots were significantly different from non-flying college students on several PRF scales. Cluster analyses indicated that three very distinct personality types exist in the data. These types were supported through multiple cross-validations. Descriptions of pilot personality types are given in terms of PRF and MCMI personality variables. The accuracy of prevailing stereotypes is examined in light of the data. Implications for future research and pilot selection criteria are discussed. PMID- 26750390 TI - Millon MCMI Scales Factor Analyzed and Correlated with MMPI and CPS Scales. AB - The Millon MCMI was administered in translation to 527 applicants for drivers' licenses in Israel who were required to undergo psychological screening. Three hundred of these subjects also took the Comrey Personality Scales (CPS) and the other 227 also took the MMPI. A factor analysis of the 20 MCMI scales was carried out and these scales were also correlated with the CPS and MMPI scales. A meaningful five-factor solution was obtained and canonical correlations were computed between the MCMI scales and those from the other two tests. Evidence from this and previous studies suggests that the MCMI scales overlap each other more than they should for purposes of optimum differential diagnosis. PMID- 26750391 TI - Self-Report Methods of Assessing Health Status and Health Service Utilization: A Hierarchical Confirmatory Analysis. AB - Self reports are often used to determine health status and extent of health service utilization. These assessments are frequently used as indicators of health quality. Using a sample of 739 young adults, this study examines gender differences and the factor structure of 15 self-reported measures of health and health seeking behavior. Women consistently reported more physical problems, less physical hardiness, more physical symptoms, and more utilization of medical services than men. These mean differences were apparent both on the individual variables and on the latent-factor means. However, the factor structure of the 15 variables was found to vary only slightly between men and women. Four primary order factors were confirmed using latent-variable models. These factors included Physical Hardiness, Subjective Health Problems, Physical Symptomatology, and Health Service Utilization. The three health status factors were highly intercorrelated and were found to be generated by a second-order factor of Poor Physical Health. This general factor was correlated moderately with the Health Service Utilization construct, suggesting that seeking medical services is not an excellent indicator of health status: It probably grossly underestimates the extent of illness in a given population and measures attitudes toward help seeking and availability of medical services. PMID- 26750392 TI - Test Construction and Targeted Factor Solutions Derived by Multiple Group and Procrustes Methods. AB - An hypothesized multidimensional structure for items comprising a psychological measure generally requires empirical verification. Least-squares confirmatory factor strategies have involved (a) multiple group factor analysis and (b) targeted (Procrustean) rotations of arbitrary factor solutions. Alternatively, inferences of structure have been based simply on (c) product-moment correlations of item responses with total scale scores. All three methods were used in this study to verify empirically the assumed structures of data from four published psychological test batteries. Confirmatory maximum likelihood factor analysis was similarly evaluated in supplementary analyses. Because, among other reasons, solutions derived by multiple group analysis and item-total correlation analysis were generally most interpretable from a psychological perspective, it was concluded that their application to test construction is to be preferred over Procrustean or confirmatory maximum likelihood approaches. PMID- 26750388 TI - Short-Term Cognitive-Behavioural Group Treatment for Hoarding Disorder: A Naturalistic Treatment Outcome Study. AB - : The study aim was to test whether a 12-week publically rebated group programme, based upon Steketee and Frost's Cognitive Behavioural Therapy-based hoarding treatment, would be efficacious in a community-based setting. Over a 3-year period, 77 participants with clinically significant hoarding were recruited into 12 group programmes. All completed treatment; however, as this was a community based naturalistic study, only 41 completed the post-treatment assessment. Treatment included psychoeducation about hoarding, skills training for organization and decision making, direct in-session exposure to sorting and discarding, and cognitive and behavioural techniques to support out-of-session sorting and discarding, and nonacquiring. Self-report measures used to assess treatment effect were the Savings Inventory-Revised (SI-R), Savings Cognition Inventory, and the Depression, Anxiety and Stress Scales. Pre-post analyses indicated that after 12 weeks of treatment, hoarding symptoms as measured on the SI-R had reduced significantly, with large effect sizes reported in total and across all subscales. Moderate effect sizes were also reported for hoarding related beliefs (emotional attachment and responsibility) and depressive symptoms. Of the 41 participants who completed post-treatment questionnaires, 14 (34%) were conservatively calculated to have clinically significant change, which is considerable given the brevity of the programme judged against the typical length of the disorder. The main limitation of the study was the moderate assessment completion rate, given its naturalistic setting. This study demonstrated that a 12-week group treatment for hoarding disorders was effective in reducing hoarding and depressive symptoms in an Australian clinical cohort and provides evidence for use of this treatment approach in a community setting. Copyright (c) 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: A 12-week group programme delivered in a community setting was effective for helping with hoarding symptoms with a large effect size. Hoarding beliefs (emotional attachment and responsibility) and depression were reduced, with moderate effect sizes. A third of all participants who completed post-treatment questionnaires experienced clinically significant change. Suggests that hoarding CBT treatment can be effectively translated into real-world settings and into a brief 12 session format, albeit the study had a moderate assessment completion rate. PMID- 26750393 TI - The Factorial Invariance of Responses by Males and Females to a Multidimensional Self-Concept Instrument: Substantive and Methodological Issues. AB - The factorial invariance of responses by preadolescent males and females to a multidimensional self-concept instrument was examined for responses to the Self Description Questionnaire (SDQ). Sets of responses by 500 males and by 500 females were each randomly divided in half to form four groups (M1, M2, Fl, and F2). The factorial invariance of an a priori structure demonstrated the replicability of the structure across cross-validation groups (M1 and M2, F1 and F2) and the generality of the structure across sex (M1 and Fl, M2 and F2). Additional a posteriori structures that better fit the data were derived on the basis of the initial analyses, but the estimated values of the new parameters were not invariant across cross-validation groups or across sex. This suggests that some of the improved fit was illusory and due to capitalizing on chance. However, factor loadings and factor correlations were invariant across sex for a priori and a posteriori structures. Hence the results support the replicability of SDQ factor structure across cross-validation samples and its generality across responses by preadolescent males and females. PMID- 26750395 TI - A Note on the Orthogonal Rotation of "Harris Factors". AB - In response to a suggestion by Harris (1962) concerning the need for a particular method for orthogonal rotation, it is demonstrated that no such method is possible. PMID- 26750394 TI - A Comparison of Two Noncentral F Approximations, with Applications to Power Analysis in Set Correlation. AB - The preparation of tables for power analysis for set correlation requires the use of the noncentral F distribution for which sufficiently detailed tables are not available. Laubscher (1960) provides approximations based on the square and cube roots. As a basis for a choice between them, we undertook a Monte Carlo investigation of the empirical power of Rao's approximate F test that employed 97 correlation matrices of three sizes and resulted in 521 power determinations, each based on 1000 samples, to which the two approximations could be compared. In addition, a subsample of 205 determinations could be compared with exact power values. Both approximations proved quite adequate, but the square root approximation had a slight edge and was chosen for the computation of the set correlation power tables. PMID- 26750396 TI - The association between the serotonin and dopamine neurotransmitters and personality traits. AB - Evidence from previous studies has reported that complex traits, including psychiatric disorders, are moderately to highly heritable. Moreover, it has also been shown that specific personality traits may increase the risk to develop mental illnesses. Therefore the focus of the research shifted towards the identification of the biological mechanisms underpinning these traits by exploring the effects of a constellation of genetic polymorphisms in healthy subjects. Indeed, studying the effect of genetic variants in normal personality provides a unique means for identifying candidate genes which may increase the risk for psychiatric disorders. In this review, we discuss the impact of two of the most frequently studied genetic polymorphisms on personality in healthy subjects, the 5-HTT polymorphism of the serotonin transporter and the DRD2/DRD4 polymorphisms of the D2/D4 dopamine's receptors. The main aims are: (a) to highlight that the study of candidate genes provides a fruitful ground for the identification of the biological underpinnings of personality without, though, reaching a general consensus about the strength of this relationship; and (b) to outline that the research in personality genetics should be expanded to provide a clearer picture of the heritability of personality traits. PMID- 26750398 TI - Hip external rotator exercise contributes to improving physical functions in the early stage after total hip arthroplasty using an anterolateral approach: a randomized controlled trial. AB - PURPOSE: The purpose of this study was to investigate the effects of an exercise program focusing on hip external rotator muscle on physical recovery in the early post-operative period of total hip arthroplasty (THA). METHODS: Patients who underwent THA were randomized to an exercise group (n = 14) or a control group (n = 14). In exercise group, the hip external rotator exercise program was performed 5 times per week for four weeks. Outcome measures were hip pain, hip range of motion, muscle strength of lower extremity and Timed Up and Go (TUG) test. RESULTS: Both the hip abductor strength (effect size = 0.60) and TUG test (effect size= -0.53) in the exercise group improved significantly after the intervention. CONCLUSIONS: The results of the present study demonstrated that exercise program focusing on hip external rotator muscle was an effective intervention, especially in improving both hip abductor strength and walking ability in the acute post-THA stage. Implication for Rehabilitation After THA, in order to safely progress patients back to their desired activity level, there is a need to develop rehabilitation strategies to expedite and promote the recovery during the acute postoperative period. Exercise program focusing on hip external rotator muscle may lead to significant improvement of hip abductor muscle strength and gait ability in the acute post-THA stage. PMID- 26750397 TI - Nuclease Target Site Selection for Maximizing On-target Activity and Minimizing Off-target Effects in Genome Editing. AB - The rapid advancement in targeted genome editing using engineered nucleases such as ZFNs, TALENs, and CRISPR/Cas9 systems has resulted in a suite of powerful methods that allows researchers to target any genomic locus of interest. A complementary set of design tools has been developed to aid researchers with nuclease design, target site selection, and experimental validation. Here, we review the various tools available for target selection in designing engineered nucleases, and for quantifying nuclease activity and specificity, including web based search tools and experimental methods. We also elucidate challenges in target selection, especially in predicting off-target effects, and discuss future directions in precision genome editing and its applications. PMID- 26750399 TI - A diagnostic dilemma: chronic sinusitis diagnosed by non-otolaryngologists. AB - BACKGROUND: Ambulatory care visits for chronic sinusitis outnumber visits for acute sinusitis. The majority of these visits are with non-otolaryngologists. In order to better understand patients diagnosed with chronic sinusitis by non otolaryngologists, we sought to determine if incident cases of chronic sinusitis diagnosed by primary care (PC) or emergency medicine (EM) providers meet diagnostic criteria. METHODS: This was a retrospective cohort study. Patients were identified using administrative data from 2005 to 2006. The dataset was then clinically annotated based on chart review. We excluded prevalent cases. RESULTS: We identified 114 patients with newly diagnosed chronic sinusitis in EM (75) or PC settings (39). Rhinorrhea (EM 61%, PC 59%) and nasal obstruction (EM 67%, PC 64%) were common in both settings but facial fullness (EM 80%, PC 39%) and pain (EM 40%, PC 18%) were more common in the EM setting. Few patients reported symptoms of 90 days or longer (EM 6.0%, PC 24%) and no patient had evidence of inflammation on physical examination. A minority of patients received a sinus computed tomography (CT) scan (22.8%) or nasal endoscopy (1.8%). In total, only 1 patient diagnosed with chronic sinusitis met the diagnostic criteria. CONCLUSION: Most patients diagnosed with chronic sinusitis by non-otolaryngologists do not have the condition. Caution should be used in studying chronic sinusitis using administrative data from non-otolaryngology providers because a large proportion of the patients may not actually have the disease. PMID- 26750379 TI - Sexual risk behaviour among people living with HIV according to the biomedical risk of transmission: results from the ANRS-VESPA2 survey. AB - INTRODUCTION: People living with HIV (PLHIV) on antiretroviral therapy (ART), with sustained undetectable viral load (sUVL) and no history of sexually transmitted infections for at least six months, are considered to have a low risk of HIV transmission (LRT). We aimed to characterize, in a representative sample of French PLHIV, the sexual behaviour of LRT PLHIV compared with non-LRT PLHIV. METHODS: The cross-sectional ANRS-VESPA2 survey was conducted on adult PLHIV attending French hospitals in 2011. The LRT PLHIV group included participants with sUVL and no sexually transmitted infection for at least 12 months. Socio behavioural and medical data were collected. Chi-square tests helped compare sexual risk indicators between LRT and non-LRT PLHIV. The survey's retrospective nature allowed us to perform complementary category-based analyses of LRT PLHIV according to whether they had sUVL for at least 18, 24 or 36 months in three socio-epidemiological groups: men who have sex with men (MSM), other men and women. RESULTS: Analysis included 2638 PLHIV diagnosed > 12 months with available viral load data. The proportion of LRT PLHIV varied from 58% (>= 12 months sUVL) to 38% (>= 36 months sUVL). Irrespective of sUVL duration, we found the following: 1) LRT men (MSM and other men) were more likely to report having no sexual partner than their non-LRT counterparts. Among men having sexual partners in the previous 12 months, no significant difference was seen between LRT and non LRT men in the number of sexual partners. LRT women were less likely to report having more than one sexual partner than non-LRT women; 2) LRT MSM were more likely to report being in sexually inactive couples than their non-LRT counterparts; 3) among sexually active participants, no difference was observed between LRT and non-LRT PLHIV concerning condom use with their serodiscordant steady partner or with their most recent casual sexual partners. CONCLUSIONS: LRT PLHIV with sUVL >= 12 months did not report more sexual risk behaviours than their non-LRT counterparts. Because the same result was obtained for those having a sUVL >= 36 months, the hypothesis of increased sexual risk behaviour over time in PLHIV meeting non-transmission biomedical criteria is not supported. PMID- 26750401 TI - Design, Synthesis, and Biological Evaluation of Novel Selenium (Se-NSAID) Molecules as Anticancer Agents. AB - The synthesis and anticancer evaluation of novel selenium-nonsteroidal anti inflammatory drug (Se-NSAID) hybrid molecules are reported. The Se-aspirin analogue 8 was identified as the most effective agent in reducing the viability of different cancer cell lines, particularly colorectal cancer (CRC) cells, was more selective toward cancer cells than normal cells, and was >10 times more potent than 5-FU, the current therapy for CRC. Compound 8 inhibits CRC growth via the inhibition of the cell cycle in G1 and G2/M phases and reduces the cell cycle markers like cyclin E1 and B1 in a dose dependent manner; the inhibition of the cell cycle may be dependent on the ability of 8 to induce p21 expression. Furthermore, 8 induces apoptosis by activating caspase 3/7 and PARP cleavage, and its longer exposure causes increase in intracellular ROS levels in CRC cells. Taken together, 8 has the potential to be developed further as a chemotherapeutic agent for CRC. PMID- 26750400 TI - Apigenin-7-O-beta-D-glucuronide inhibits LPS-induced inflammation through the inactivation of AP-1 and MAPK signaling pathways in RAW 264.7 macrophages and protects mice against endotoxin shock. AB - Apigenin-7-O-beta-D-glucuronide (AG), an active flavonoid derivative isolated from the agricultural residue of Juglans sigillata fruit husks, possesses multiple pharmacological activities, including anti-oxidant, anti-complement, and aldose reductase inhibitory activities. To date, no report has identified the anti-inflammatory mechanisms of AG. This study was therefore designed to characterize the molecular mechanisms of AG on lipopolysaccharide (LPS)-induced inflammatory cytokines in RAW 264.7 cells and on endotoxin-induced shock in mice. AG suppressed the release of nitric oxide (NO), prostaglandin E2 (PGE2), and tumour necrosis factor-alpha (TNF-alpha) in LPS-stimulated RAW 264.7 macrophages in a dose-dependent manner without affecting cell viability. Additionally, AG suppressed LPS-induced mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and TNF-alpha. AG treatment decreased the translocation of c-Jun into the nucleus, and decreased activator protein-1 (AP-1)-mediated luciferase activity through the inhibition of both p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) phosphorylation. Consistent with the in vitro observations, AG protected mice from LPS-induced endotoxin shock by inhibiting proinflammatory cytokine production. Taken together, these results suggest that AG may be used as a source of anti inflammatory agents as well as a dietary complement for health promotion. PMID- 26750402 TI - Sensing the quantum behaviour of magnetic nanoparticles by electron magnetic resonance. AB - We have investigated Magnetic Nanoparticles (MNPs) of spinel type iron oxide (of approximately 8 nm) mineralized in the internal cavity of the bioreactor ferritin nanocage. In particular, we have used Electron Magnetic Resonance, EMR, spectroscopy and taken advantage of the capacity of the protein shells to control the size of the MNPs. EMR measurements in perpendicular and parallel configurations have been recorded at various temperatures. A model based on the giant spin is used to interpret the experimental results. The analysis indicates that the observed quantum behaviour has to be ascribed to the whole MNP and that the thermal population of excited spin states has a strong influence in the EMR behaviour of MNPs. PMID- 26750404 TI - Predictors of Booster Response to Hepatitis B Vaccine at 15 years of age: A Cross Sectional School-Based Study. AB - BACKGROUND: The current consensus does not support the use of booster dose because of its anamnestic response in almost all children 15 years after universal infant hepatitis B virus (HBV) vaccination. However, in our clinical setting, numerous concerned parents request a booster administration for their children. We aimed to provide the possible predictors of booster response in adolescents before this booster administration. METHODS: This study comprised a series of cross-sectional serological surveys of HBV markers in 15-year-old individuals between 2008 and 2012. Data on serum hepatitis B surface antigen, hepatitis B surface antibody (anti-HBs), and liver-function biomarkers in a total of 887 senior high-school students were collected. There were two parts to this study: HBV seroepidemiology and booster-response analysis to identify the possible response predictors and decay factors after the HBV booster administration. RESULTS: The overall anti-HBs and hepatitis B surface antigen seropositivity rates were 34.7% and 0.7%, respectively, and the median anti-HBs titer was 3.3 mIU/mL. Six weeks after one dose of recombinant HBV vaccine, the overall booster-response rate in the double-seronegative recipients was 94% (471/501). Among the participants whose initial anti-HBs titers were undetectable or low, 72.4% (247/341) and 95.6% (153/160), respectively, reactivated their anti HBs titers >= 100 mIU/mL about 6 weeks after the booster administration. The likelihood of postbooster anti-HBs titer reaching an adequate protective level increased with the prebooster titer. The female participants had stronger anamnestic responses compared to the male participants. CONCLUSION: We found that the female participants and prebooster anti-HBs titers above the detection limit of the immunoassay were good predictors of HBV booster response. PMID- 26750403 TI - An integrated chinmedomics strategy for discovery of effective constituents from traditional herbal medicine. AB - Traditional natural product discovery affords no information about compound structure or pharmacological activities until late in the discovery process, and leads to low probabilities of finding compounds with unique biological properties. By integrating serum pharmacochemistry-based screening with high resolution metabolomics analysis, we have developed a new platform, termed chinmedomics which is capable of directly discovering the bioactive constituents. In this work, the focus is on ShenQiWan (SQW) treatment of ShenYangXu (SYX, kidney-yang deficiency syndrome) as a case study, as determined by chinmedomics. With serum pharmacochemistry, a total of 34 peaks were tentatively characterised in vivo, 24 of which were parent components and 10 metabolites were detected. The metabolic profiling and potential biomarkers of SYX were also investigated and 23 differential metabolites were found. 20 highly correlated components were screened by the plotting of correlation between marker metabolites and serum constituents and considered as the main active components of SQW. These compounds are imported into a database to predict the action targets: 14 importantly potential targets were found and related to aldosterone-regulated sodium reabsorption and adrenergic signaling pathways. Our study showed that integrated chinmedomics is a powerful strategy for discovery and screening of effective constituents from herbal medicines. PMID- 26750405 TI - Microstructural Changes in Absence Seizure Children: A Diffusion Tensor Magnetic Resonance Imaging Study. AB - BACKGROUND: Absence seizures are a subtype of epileptic seizures clinically characterized by transient alterations in states of consciousness and by electroencephalography indicating diffuse spike-wave discharges (SWD). Conventional brain magnetic resonance imaging (MRI) is not routinely used to establish the diagnosis, but rather to rule out other diseases. The present study investigated tissue integrity in children with SWD epilepsy using diffusion tensor imaging (DTI). METHODS: Magnetic resonance imaging (MRI)-DTI was conducted in 18 patients with absence seizures and 10 control participants. Brain areas were evaluated using diffusion maps, and fractional anisotropy (FA), mean diffusivity (MD), parallel diffusivity (lambda||), and perpendicular diffusivity (lambda?) values were extracted and analyzed. Tractography at the regions of abnormal diffusion indices was then reconstructed in each group, and tract symmetry was evaluated by an index of asymmetry (AI). Statistical analyses were performed using nonparametric Mann-Whitney U tests, with p values < 0.05 indicating statistical significance. RESULTS: Compared to the control group, patients with SWD epilepsy had lower FA values and higher MD values at the genu of the corpus callosum. There was also a stronger negative correlation between MD and FA values at the genu of the corpus callosum in patients than in control participants. The AI for the fiber tracts through the genu of the corpus callosum in the SWD group was significantly higher than that of the control group, indicating that tract distribution was more asymmetric in patients with epilepsy. There were no significant differences between groups in diffusion indices for other brain areas. CONCLUSION: We observed microstructural changes in the genu of the corpus callosum, as well as reduced FA values, increased lambda? values, increased MD values, and asymmetric distribution of fiber tracts, indicating that DTI is more sensitive than conventional MRI to detect brain abnormalities in children with absence seizures. PMID- 26750406 TI - Early and Late Infections in Newborns: Where Do We Stand? A Review. AB - Neonatal sepsis still represents an important cause of mortality and morbidity among infants. According to the onset, we can distinguish "early onset sepsis" when microbiological cultures positive for external pathogens come from newborns during the first 7 days of life (maternal intrapartum transmission); "late onset sepsis" when microbiological cultures positive for external pathogens come from newborns after the first 7 days from delivery (postnatal acquisition). In this review we synthesize the incidence, risk factors, clinical manifestations, and methods of diagnosis and treatment of each type of neonatal infection, in order to better define such a pathological condition which is of great importance in common clinical practice. PMID- 26750407 TI - Effects of Complementary DNA and Salt on the Thermoresponsiveness of Poly(N isopropylacrylamide)-b-DNA. AB - The thermoresponsive structural transition of poly(N-isopropylacrylamide) (PNIPAAm)-b-DNA copolymers was explored. Molecular assembly of the block copolymers was facilitated by adding salt, and this assembly was not nucleated by the association between DNA strands but by the coil-globule transition of PNIPAAm blocks. Below the lower critical solution temperature (LCST) of PNIPAAm, the copolymer solution remained transparent even at high salt concentrations, regardless of whether DNA was hybridized with its complementary partner to form a double-strand (or single-strand) structure. At the LCST, the hybridized copolymer assembled in spherical nanoparticles, surrounded by double-stranded DNA; subsequently, the non-cross-linking aggregation occurred, while the nanoparticles were dispersed if the salt concentration was low or DNA blocks were unhybridized. When the DNA duplex was denatured to a single-stranded state by heating, the aggregated nanoparticles redispersed owing to the recovery of the steric repulsion of the DNA strands. The changes in the steric and electrostatic effects by hybridization and the addition of salt did not result in any specific attraction between DNA strands but merely decreased the repulsive interactions. The van der Waals attraction between the nanoparticles overcame such repulsive interactions so that the non-cross-linking aggregation of the micellar particles was mediated. PMID- 26750408 TI - Diagnosing brain death. PMID- 26750409 TI - Diagnosing brain death - a reply. PMID- 26750410 TI - Universal neuromuscular blockade monitoring. PMID- 26750411 TI - Universal neuromuscular blockade monitoring - a reply. PMID- 26750412 TI - iPhone accelerometry for monitoring quantitative neuromuscular function. PMID- 26750413 TI - Sugammadex in anaphylaxis. A case-control study? PMID- 26750414 TI - Sugammadex in anaphylaxis - a case-control study? A reply. PMID- 26750415 TI - TAP blocks for laparoscopic appendicectomy. PMID- 26750416 TI - TAP blocks for laparoscopic appendicectomy - a reply. PMID- 26750417 TI - Videolaryngoscopy in real patients - a welcome change. PMID- 26750418 TI - Quadratus lumborum block with paramedian sagittal oblique (subcostal) approach. PMID- 26750419 TI - Chlorhexidine anaphylaxis: implications for post-resuscitation management. PMID- 26750420 TI - A painful (mis)connection. PMID- 26750421 TI - Time series analysis of the association between ambient temperature and cerebrovascular morbidity in the elderly in Shanghai, China. AB - Research on the association between ambient temperature and cerebrovascular morbidity is scarce in China. In this study, we applied mixed generalized additive model (MGAM) to daily counts of cerebrovascular disease of Shanghai residents aged 65 years or older from 2007-2011, stratified by gender. Weighted daily mean temperature up to lags of one week was smoothed by natural cubic spline, and was added into the model to assess both linear and nonlinear effects of temperature. We found that when the mean temperature increased by 1 degrees C, the male cases of cerebrovascular disease reduced by 0.95% (95% Confidence Interval (CI): 0.80%, 1.10%) or reduced by 0.34% (95% CI: -0.68, 1.36%) in conditions of temperature was below or above 27 degrees C. However, for every 1 degrees C increase in temperature, the female cases of cerebrovascular disease increased by 0.34% (95% CI: -0.26%, 0.94%) or decreased by 0.92% (95% CI: 0.72, 1.11%) in conditions of temperature was below or above 8 degrees C, respectively. Temperature and cerebrovascular morbidity is negatively associated in Shanghai. MGAM is recommended in assessing the association between environmental hazards and health outcomes in time series studies. PMID- 26750422 TI - Experiences relating to adverse drug reactions in the community: a cross sectional survey among patients and the general public in Thailand. AB - OBJECTIVE: To determine the frequency and characteristics of adverse drug reactions (ADRs), experiences of receiving and desire for information about medicines, and attitudes toward ADR knowledge and reporting among the community dwelling Thai population. METHODS: A cross-sectional self-administered survey conducted during October 2013 to December 2014 by convenience sampling. The study was conducted in three settings in the second-largest city, North-eastern Thailand: primary care units, community pharmacies and public areas. RESULTS: Of 2400 respondents, 414 (17.3%) reported experiencing an ADR; two-thirds of which involved mild symptoms (66.7%) and 55.6% occurred within the last year. Self reported ADR knowledge was low (4.1 +/- 2.5 on a scale of 0 to 10). Pharmacists and physicians were the most common sources of information about medicines, but only 28.5% had received information about ADRs. Over 40% wanted information about ADRs and drug interactions, with healthcare professionals and information leaflets being desirable sources. The majority of individuals had positive views towards both receiving information and reporting their ADR experiences. CONCLUSIONS: To enable the Thai public to report their experiences of ADRs more effectively, they require more medicines information. Information leaflets should be more widely available, while healthcare professionals should provide more detailed information of ADRs. PMID- 26750423 TI - The CO oxidation mechanism on the W(111) surface and the W helical nanowire investigated by the density functional theory calculation. AB - Two CO oxidation reactions (CO + O2 -> CO2 + O and CO + O -> CO2) were considered in the Eley-Rideal (ER) reaction mechanism. These oxidation processes on the W(111) surface and the W helical nanowire were investigated by the density functional theory (DFT) calculation. The stable adsorption sites of O2 and O as well as their adsorption energies were obtained first. In order to understand the catalytic properties of the W helical nanowire, the Fukui function and local density of state (LDOS) profiles were determined. The nudged elastic band (NEB) method was applied to locate transition states and minimum energy pathways (MEPs) of CO oxidation processes on the W helical nanowire and on the W(111) surface. In this study, we have demonstrated that the catalytic ability of the W helical nanowire is superior to that of the W(111) surface for CO oxidation. PMID- 26750425 TI - The US Supreme Court and the Future of Reproductive Health. PMID- 26750424 TI - The variation in the eating quality of beef from different sexes and breed classes cannot be completely explained by carcass measurements. AB - Delivering beef of consistent quality to the consumer is vital for consumer satisfaction and will help to ensure demand and therefore profitability within the beef industry. In Australia, this is being tackled with Meat Standards Australia (MSA), which uses carcass traits and processing factors to deliver an individual eating quality guarantee to the consumer for 135 different 'cut by cooking methods' from each carcass. The carcass traits used in the MSA model, such as ossification score, carcass weight and marbling explain the majority of the differences between breeds and sexes. Therefore, it was expected that the model would predict with eating quality of bulls and dairy breeds with good accuracy. In total, 8128 muscle samples from 482 carcasses from France, Poland, Ireland and Northern Ireland were MSA graded at slaughter then evaluated for tenderness, juiciness, flavour liking and overall liking by untrained consumers, according to MSA protocols. The scores were weighted (0.3, 0.1, 0.3, 0.3) and combined to form a global eating quality (meat quality (MQ4)) score. The carcasses were grouped into one of the three breed categories: beef breeds, dairy breeds and crosses. The difference between the actual and the MSA-predicted MQ4 scores were analysed using a linear mixed effects model including fixed effects for carcass hang method, cook type, muscle type, sex, country, breed category and postmortem ageing period, and random terms for animal identification, consumer country and kill group. Bulls had lower MQ4 scores than steers and females and were predicted less accurately by the MSA model. Beef breeds had lower eating quality scores than dairy breeds and crosses for five out of the 16 muscles tested. Beef breeds were also over predicted in comparison with the cross and dairy breeds for six out of the 16 muscles tested. Therefore, even after accounting for differences in carcass traits, bulls still differ in eating quality when compared with females and steers. Breed also influenced eating quality beyond differences in carcass traits. However, in this case, it was only for certain muscles. This should be taken into account when estimating the eating quality of meat. In addition, the coefficients used by the Australian MSA model for some muscles, marbling score and ultimate pH do not exactly reflect the influence of these factors on eating quality in this data set, and if this system was to be applied to Europe then the coefficients for these muscles and covariates would need further investigation. PMID- 26750426 TI - The interplay of thermally activated delayed fluorescence (TADF) and room temperature organic phosphorescence in sterically-constrained donor-acceptor charge-transfer molecules. AB - A series of phenothiazine-dibenzothiophene-S,S-dioxide charge-transfer molecules have been synthesized. Increasing steric restriction around the donor-acceptor bond significantly alters contributions from TADF and phosphorescence. Bulky substituents on the 1-(and 9) position(s) of the phenothiazine result in no TADF in the solid state; instead strong phosphorescence is observed at ambient temperature. PMID- 26750427 TI - Integration of inorganic nanostructures with polydopamine-derived carbon: tunable morphologies and versatile applications. AB - Polydopamine (PDA), a mussel adhesive-inspired biomimetic polymer, has attracted tremendous attention owing to its extremely versatile adhesion properties, facile aqueous coating process, capability of self-assembly to form nanostructures, and abundant surface functional groups for secondary modification. PDA is also a fantastic carbon source because it gives nitrogen (N)-doped graphite-like carbon in high yield, and the carbonized PDA (C-PDA) thin coatings have similar properties to those of N-doped multilayered graphene, i.e., they exhibit high electrical conductivity, and good electrochemical and mechanical properties. In comparison with other carbon sources, an outstanding feature of PDA lies in its ease of integration with inorganic nanostructures and capability for easy tailoring the structure and morphology of the resultant composite nanostructures. In this article, different routes for the preparation of C-PDA-based composite nanostructures, such as carbon/metal oxide and carbon/Si hollow, mesoporous, core shell, yolk-shell nanostructures, are introduced with typical examples. The structures, morphologies and properties of the C-PDA-based composite nanostructures are also reviewed, and their potential applications in various engineering fields, such as energy storage, solar water splitting, flexible electronics, catalysis, sensing and environmental engineering, are highlighted. Finally a future outlook for this fascinating composite-nanostructure enabler is also presented. PMID- 26750428 TI - Differences in the associations of anthropometric measures with insulin resistance and type 2 diabetes mellitus between Korean and US populations: Comparisons of representative nationwide sample data. AB - BACKGROUNDS: Variation among ethnic groups in the association between obesity and insulin resistance (IR)/diabetes has been suggested, but studies reported inconsistent results. We evaluated ethnic differences in the association between obesity and insulin resistance (IR)/diabetes. METHODS: We conducted a cross sectional analysis using Korea (n=18,845) and the USA (n=4657) National Health and Nutrition Examination Survey(NHANES) 2007-2010. We performed statistical comparisons of AUC-ROC (area under the curve in a receiver operating characteristic curve) values for body mass index (BMI), waist circumference (WC) and homeostasis model assessment of insulin resistance (HOMA-IR) to predict IR or diabetes among different ethnic groups. RESULTS: AUC-ROC values for BMI and WC for predicting IR were highest in Whites (0.8324 and 0.8468) and lowest in Koreans (0.7422 and 0.7367). Whites showed the highest AUC-ROC values for BMI (0.6869) and WC (0.7421) for predicting diabetes, while the AUC-ROC for HOMA-IR was highest in Koreans (0.8861). Linear regression showed significant interactions between ethnicity and the main effects (all P<0.0001). Increases in BMI were associated with a larger increase in HOMA-IR in Whites (beta=0.0719) and WC in Hispanics (beta=0.0324), while BMI was associated with a larger increase in fasting glucose in Koreans (beta=0.8279) and WC in Blacks (beta=0.4037). In addition, the slope for fasting glucose with increasing HOMA-IR was steeper in Koreans (beta=16.5952, P<0.001) than in other groups. CONCLUSION: The ability of BMI and WC to predict IR and diabetes was highest in Whites, while the ability of HOMA-IR to predict diabetes was highest in Koreans. PMID- 26750430 TI - Anomalous Size Dependence of Optical Properties in Black Phosphorus Quantum Dots. AB - Understanding electron transitions in black phosphorus nanostructures plays a crucial role in applications in electronics and optoelectronics. In this work, by employing time-dependent density functional theory calculations, we systematically study the size-dependent electronic, optical absorption, and emission properties of black phosphorus quantum dots (BPQDs). Both the electronic gap and the absorption gap follow an inversely proportional law to the diameter of BPQDs in conformity to the quantum confinement effect. In contrast, the emission gap exhibits anomalous size dependence in the range of 0.8-1.8 nm, which is blue-shifted with the increase of size. The anomaly in fact arises from the structure distortion induced by the excited-state relaxation, and it leads to a huge Stokes shift in small BPQDs. PMID- 26750431 TI - Review: The spectrum of clinical features seen with alpha synuclein pathology. AB - It has been recognized for many years that a number of chronic neurodegenerative diseases of the CNS are characterized by the development of intracellular inclusion bodies, but it is only relatively recently that the core proteins defining these pathologies have been defined. One such protein is alpha synuclein, that was found to be the main component of Lewy bodies in the late 1990s, and this discovery reinforced the emerging view that alpha synuclein was intimately linked to diseases characterized by this type of pathology--namely Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Furthermore at around this time, this same protein was also found within the glial inclusion bodies of patients dying with multiple system atrophy (MSA). These three disorders constitute the majority of patients with an 'alpha synucleinopathy', although there are a number of rarer conditions that can also cause this pathology including inherited metabolic disorders such as Gaucher's disease (GD). In this review, we will concentrate on PD, the commonest alpha synucleinopathy, and its associated dementia (PDD), as well as discussing DLB and MSA and will highlight how the clinical features of these conditions vary as a function of pathology. PMID- 26750432 TI - In vitro comparison of contemporary radiographic imaging techniques for the measurement of inter-radicular width. AB - OBJECTIVE: To assess the reliability of inter-radicular measurements taken using dental pantomograms (DPT), long cone periapical radiographs (LCPA) and cone bean computed tomography (CBCT). MATERIALS/METHODS: A typodont simulating a hypodontia patient undergoing fixed appliance treatment was used. LCPAs, DPT, I-CAT and Accuitomo CBCT images were taken and the distances between the edentulous spans were measured at the midpoint of the roots and the cemento-enamel junctions (CEJ) of adjacent teeth. The results of each modality were compared to each other to the actual inter-radicular space. RESULTS: The DPT overestimated inter-radicular widths by 2 mm or more [mean: 2.48; 95% confidence interval (CI): -1.09 to 6.05 mm]. The LCPA overestimated the inter-radicular widths by 1.5 mm with a 95% CI of -0.095 to 4.03 mm. The mean differences between gold standard (model) and Accuitomo was 0.57 mm (95% CI: -0.37 to 1.51 mm) for the root mean and 0.22 mm (95% CI: -0.52 to 0.96 mm) for the CEJ. This was similar to the differences between the model and I-CAT where the inter-radicular root mean difference was 0.38 mm (95% CI: -0.38 to 1.14 mm) and the CEJ mean difference was 0.21 mm (95% CI: -0.50 to 0.92 mm). CONCLUSION: The CBCT overestimated the root distance by 0.48 mm and the CEJ width by 0.22 mm, which is clinically irrelevant for implant placement. The DPT overestimated inter-radicular width by 2 mm and the LCPA by 1.5 mm and this difference may put roots of adjacent teeth at risk during implant placement. PMID- 26750429 TI - Global Transcriptomic Analysis of Interactions between Pseudomonas aeruginosa and Bacteriophage PaP3. AB - The interactions between Bacteriophage (phage) and host bacteria are widespread in nature and influences of phage replication on the host cells are complex and extensive. Here, we investigate genome-wide interactions of Pseudomonas aeruginosa (P. aeruginosa) and its temperate phage PaP3 at five time points during phage infection. Compared to the uninfected host, 38% (2160/5633) genes of phage-infected host were identified as differentially expressed genes (DEGs). Functional analysis of the repressed DEGs revealed infection-stage-dependent pathway communications. Based on gene co-expression analysis, most PaP3 middle genes were predicted to have negative impact on host transcriptional regulators. Sub-network enrichment analysis revealed that adjacent genes of PaP3 interacted with the same host genes and might possess similar functions. Finally, our results suggested that during the whole infection stage, the early genes of PaP3 had stronger regulatory role in host gene expression than middle and late genes, while the host genes involved amino acid metabolism were the most "vulnerable" targets of these phage genes. This work provides the basis for understanding survival mechanisms of parasites and host, and seeking phage gene products that could potentially be used in anti-bacterial infection. PMID- 26750433 TI - Elevated prevalence of malnutrition and malaria among school-aged children and adolescents in war-ravaged South Sudan. AB - Emerging as a sovereign state from decades of civil war, the Republic of South Sudan now faces poverty, a lack of health care infrastructure, a high burden of infectious diseases and a widespread food insecurity. School-aged children and youth, in particular, represent a high-risk demographic for malnutrition and infectious diseases. We screened 109 school-aged children and youth for nutritional status and malaria antigenaemia in Akuak Rak, South Sudan, and found a large proportion of underweight (77/109 = 73%) and prevalent malaria (44/109 = 40%). There was no significant association between malnutrition and malaria. This study represents one of the few published reports on child and youth nutritional status and malaria prevalence in South Sudan since its independence. The implementation of nutrition and malaria screening combined with evidence-based interventions in schools could help target this high burden vulnerable group. PMID- 26750434 TI - Spatial neglect in stroke patients after discharge from rehabilitation to own home: a mixed method study. AB - PURPOSE: To explore the usefulness of conventional tests for assessing spatial neglect and contrast these tests with daily challenges encountered by patients after discharge from rehabilitation to home. METHODS: A mixed method prospective study of 15 patients with neglect after a right hemisphere stroke, <1 month after discharge to home. Data were obtained from: (1) Catherine Bergego Scale (CBS), (2) star cancellation and figure copying and (3) observations and interviews. Qualitative data were analysed with content analysis and quantitative data with non-parametric statistics. The data were presented in a 'mixing matrix' and integrated by 'following threads'. Finally, a synthesis was written into a vignette. RESULTS: The CBS significantly underestimated fluctuations and did not capture important items of neglect. The star cancellation and figure copying did not identify neglect in mildly affected participants. Left starting point in the star cancellation and a characteristic process of drawing in figure copying were observed in all participants. CONCLUSION: Traditional numerical interpretations of paper-pencil tests inadequately confirmed mild neglect. Starting points of the star cancellation and observation of drawing should be incorporated into screening procedures. Assessment strategies need improvement to identify patients with subtle forms of neglect. Implications for Rehabilitation Findings demonstrate that identification of spatial neglect and the way symptoms of neglect impact on daily life functioning of stroke patients must be carefully pursued by health-care professionals working in stroke rehabilitation. Areas that should receive professional attention in the rehabilitation process include: preparing patients and their family for fluctuations related to neglect in the patient's own home, locating issues that might impact safety, and identifying unique factors that either enhance or diminish neglect within each patient's daily life context. The results of this study could be used to develop more wide ranging assessment strategies to assist health-care professionals in identifying neglect after hospital discharge, for instance by expanding existing ecological assessment tools and including qualitative evaluation of test performance in paper-pencil tests, such as the star cancellation and figure copying. PMID- 26750435 TI - Radiation and breast reconstruction: Algorithmic approach and evidence-based outcomes. AB - Postmastectomy radiation (PMRT) in the setting of immediate breast reconstruction has been associated with increased complications and poorer aesthetic outcomes for both autologous and implant reconstructions. Many centers have attempted to mitigate the deleterious effects associated with radiation by implementing an algorithmic approach to breast reconstruction. Although the literature regarding the optimal timing of radiotherapy and breast reconstruction remains controversial, reported outcomes following various algorithms have been encouraging and warrant further consideration. J. Surg. Oncol. 2016;113:906-912. (c) 2016 Wiley Periodicals, Inc. PMID- 26750436 TI - Solvation dynamics and rotational relaxation of coumarin 153 in mixed micelles of Triton X-100 and cationic gemini surfactants: effect of composition and spacer chain length of gemini surfactants. AB - Solvation dynamics and rotational relaxation of coumarin 153 (C-153) in mixed micelles of non-ionic surfactant, Triton X-100 and a series of cationic gemini surfactants, 12-s-12, 2Br with varying polymethylene spacer chain length (s = 3, 6, 8, 12) at different bulk mole fractions of a surfactant were studied. Studies were carried out by means of UV-Vis absorption, steady-state fluorescence and fluorescence anisotropy, time-resolved fluorescence and fluorescence anisotropy, and dynamic light scattering measurements. While micropolarity of the environment around C-153 in mixed micelles increased, the microviscosity decreased with increasing amount of a gemini surfactant. This is because the thickness of the Stern layer of micelles increases as a result of greater extent of penetration of water molecules. Solvation dynamics and rotational relaxation of C-153 become faster with increasing mole fraction of a gemini surfactant in the mixed micelles. Increasing the thickness of the Stern layer leads to an increase in the number of water molecules hydrogen bonded among themselves, resulting in an increase in polarity and microfluidity of the environment. At a given bulk mole fraction of a surfactant, the microviscosity of micelles decreases with increasing the spacer chain length of the gemini surfactant resulting in an increase in the rate of the rotational relaxation process. However, at a given bulk mole fraction of a surfactant, solvation dynamics becomes slower with increasing spacer chain length from s = 3 to 8 because of the increasing degree of counter ion dissociation. The slow rotational relaxation process is mainly due to the lateral diffusion of C-153 along the surface of the micelles. Rotationalmotion of the micelle as a whole is much slower than the lateral diffusion of C-153. PMID- 26750437 TI - Correction to "Glycoluril Dimer Isomerization under Aqueous Acidic Conditions Related to Cucurbituril Formation". PMID- 26750438 TI - Quantitative analysis of the cell-surface roughness and viscoelasticity for breast cancer cells discrimination using atomic force microscopy. AB - Breast cancer has been one of the most common malignant tumors threatening female health with high incidence. Cell mechanics is becoming an important issue and could serves as a potential indicator for early cancer diagnosis. In this study, atomic force microscopy (AFM) was applied to characterize and compare the surface nanostructure and viscoelasticity of different breast cell lines. Our results show that breast cancerous cells MCF-7 exhibit more disorganized filamentous cytoskeleton structure with increased membrane roughness compared to benign breast cells MCF-10A (P < 0.05). The viscoelastic properties, including elasticity and viscosity, are significantly different between the two cell lines. MCF-7 displays reduced elasticity and viscosity, indicating that breast cancer cells are softer and more fluid than benign counterpart. Our findings provide new insights into the biophysical changes of cells during tumor transformation and suggest it could be used for early cancer detection at single cell level. SCANNING 38:558-563, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26750439 TI - Caspase Allostery and Conformational Selection. AB - The role of caspase proteases in regulated processes such as apoptosis and inflammation has been studied for more than two decades, and the activation cascades are known in detail. Apoptotic caspases also are utilized in critical developmental processes, although it is not known how cells maintain the exquisite control over caspase activity in order to retain subthreshold levels required for a particular adaptive response while preventing entry into apoptosis. In addition to active site-directed inhibitors, caspase activity is modulated by post-translational modifications or metal binding to allosteric sites on the enzyme, which stabilize inactive states in the conformational ensemble. This review provides a comprehensive global view of the complex conformational landscape of caspases and mechanisms used to select states in the ensemble. The caspase structural database provides considerable detail on the active and inactive conformations in the ensemble, which provide the cell multiple opportunities to fine tune caspase activity. In contrast, the current database on caspase modifications is largely incomplete and thus provides only a low-resolution picture of global allosteric communications and their effects on the conformational landscape. In recent years, allosteric control has been utilized in the design of small drug compounds or other allosteric effectors to modulate caspase activity. PMID- 26750440 TI - Endoplasmic reticulum stress-mediated upregulation of miR-29a enhances sensitivity to neuronal apoptosis. AB - Disturbance of homeostasis within the endoplasmic reticulum (ER) lumen leads to the accumulation of unfolded and misfolded proteins. This results in the activation of an evolutionary conserved stress response termed ER stress that, if unresolved, induces apoptosis. Previously the Bcl-2 homology domain 3-Only Protein Puma was identified as a mediator of ER stress-induced apoptosis in neurons. In the search of alternative contributors to ER stress-induced apoptosis, a downregulation of the anti-apoptotic Bcl-2 family protein Mcl-1 was noted during ER stress in both mouse cortical neurons and human SH-SY5Y neuroblastoma cells. Downregulation of Mcl-1 was associated with an upregulation of microRNA-29a (miR-29a) expression, and subsequent experiments showed that miR 29a targeted the 3'-untranslated region of the anti-apoptotic Bcl-2 family protein, Mcl-1. Inhibition of miR-29a expression using sequence-specific antagomirs or the overexpression of Mcl-1 decreased cell death following tunicamycin treatment, while gene silencing of Mcl-1 increased cell death. miR 29a did not alter the signalling branches of the ER stress response, rather its expression was controlled by the ER stress-induced transcription factor activating-transcription-factor-4 (ATF4). The current data demonstrate that the ATF4-mediated upregulation of miR-29a enhances the sensitivity of neurons to ER stress-induced apoptosis. PMID- 26750445 TI - Differential efficacy of cognitive behavioral therapy and psychodynamic therapy for major depression: a study of prescriptive factors. AB - BACKGROUND: Minimal efficacy differences have been found between cognitive behavioral therapy (CBT) and psychodynamic therapies for depression, but little is known about patient characteristics that might moderate differential treatment effects. We aimed to generate hypotheses regarding such potential prescriptive factors. METHOD: We conducted post-hoc model-based recursive partitioning analyses alongside a randomized clinical trial comparing the efficacy of CBT and short-term psychodynamic supportive psychotherapy (SPSP). Severely depressed patients received additional antidepressant medication. We included 233 adults seeking treatment for a major depressive episode in psychiatric outpatient clinics, who completed post-treatment assessment. Post-treatment mean Hamilton Depression Rating Scale scores constituted the main outcome measure. RESULTS: While treatment differences (CBT v. SPSP) were minimal in the total sample of patients (d = 0.04), model-based recursive partitioning indicated differential treatment efficacy in certain subgroups of patients. SPSP was found more efficacious among moderately depressed patients receiving psychotherapy only who showed low baseline co-morbid anxiety levels (d = -0.40) and among severely depressed patients receiving psychotherapy and antidepressant medication who reported a duration of the depressive episode of ?1 year (d = -0.31), while CBT was found more efficacious for such patients reporting a duration <1 year (d = 0.83). CONCLUSIONS: Our findings are observational and need validation before they can be used to guide treatment selection, but suggest that knowledge of prescriptive factors can help improve the efficacy of psychotherapy for depression. Depressive episode duration and co-morbid anxiety level should be included as stratification variables in future randomized clinical trials comparing CBT and psychodynamic therapy. PMID- 26750446 TI - Impaired sleep and recovery after night matches in elite football players. AB - Despite the perceived importance of sleep for elite footballers, descriptions of the duration and quality of sleep, especially following match play, are limited. Moreover, recovery responses following sleep loss remain unclear. Accordingly, the present study examined the subjective sleep and recovery responses of elite footballers across training days (TD) and both day and night matches (DM and NM). Sixteen top division European players from three clubs completed a subjective online questionnaire twice a day for 21 days during the season. Subjective recall of sleep variables (duration, onset latency, time of wake/sleep, wake episode duration), a range of perceptual variables related to recovery, mood, performance and internal training loads and non-exercise stressors were collected. Players reported significantly reduced sleep durations for NM compared to DM (-157 min) and TD (-181 min). In addition, sleep restfulness (SR; arbitrary scale 1 = very restful, 5 = not at all restful) and perceived recovery (PR; acute recovery and stress scale 0 = not recovered at all, 6 = fully recovered) were significantly poorer following NM than both TD (SR: +2.0, PR: -2.6), and DM (SR: +1.5; PR: 1.5). These results suggest that reduced sleep quantity and quality and reduced PR are mainly evident following NM in elite players. PMID- 26750447 TI - Functional connectivity of brain regions for self- and other-evaluation in children, adolescents and adults with autism. AB - Developing strong ties between oneself and others lays the foundation for developing social competence. Neuroimaging studies have consistently identified specific cortical midline regions activated during evaluative judgments about the self and others. Individuals with autism spectrum disorder (ASD) process self relevant information differently from their peers, both behaviorally and at the neural level. We compared resting-state functional connectivity (rsFC) of regions involved in self-referential (e.g. medial prefrontal cortex; mPFC) and other referential (e.g. posterior cingulate cortex; PCC) processing between neurotypical individuals and individuals with ASD in three age cohorts using regions of interest (ROIs) identified through an activation likelihood estimation meta-analysis. Typically developing children demonstrated greater connectivity within the midline self- and other-referential networks compared with age-matched children with ASD. No group differences in rsFC of mPFC or PCC emerged between typically developing adolescents and adolescents with ASD. Neurotypical adults exhibited stronger rsFC of the PCC with orbitofrontal cortex compared with adults with ASD. Developmental differences in functional connectivity between areas underlying self- and other-referential thought may explain altered developmental trajectories in the understanding of self and others in individuals with ASD. PMID- 26750449 TI - Abstracts of the AAGBI WSM London, 13-15 January 2016, London, UK. PMID- 26750450 TI - Development of a stable phosphoarginine analog for producing phosphoarginine antibodies. AB - Protein phosphorylation is one of the most common and extensively studied post translational modifications (PTMs). Compared to the O-phosphorylation on Ser, Thr and Tyr residues, our understanding of arginine phosphorylation is relatively limited, both in prokaryotes and eukaryotes, due to the intrinsic instability of phosphoarginine (pArg) and the lack of a feasible method to produce anti-pArg antibodies. We report the design and synthesis of a stable pArg analog, in which the labile N-P bond is replaced with a non-hydrolyzable C-P bond. Significantly, this analog was successfully used as a hapten to raise an immune response and the first mouse polyclonal antibody that specifically recognizes pArg-containing peptides and proteins was produced using analog-KLH conjugated as the immunogen. The generated antibody shows excellent specificity towards pArg-containing peptides and proteins, and could be used for a variety of biological detection methods. This provides us an invaluable tool to unravel the mystery of the biological function of pArg. PMID- 26750448 TI - LEGO: a novel method for gene set over-representation analysis by incorporating network-based gene weights. AB - Pathway or gene set over-representation analysis (ORA) has become a routine task in functional genomics studies. However, currently widely used ORA tools employ statistical methods such as Fisher's exact test that reduce a pathway into a list of genes, ignoring the constitutive functional non-equivalent roles of genes and the complex gene-gene interactions. Here, we develop a novel method named LEGO (functional Link Enrichment of Gene Ontology or gene sets) that takes into consideration these two types of information by incorporating network-based gene weights in ORA analysis. In three benchmarks, LEGO achieves better performance than Fisher and three other network-based methods. To further evaluate LEGO's usefulness, we compare LEGO with five gene expression-based and three pathway topology-based methods using a benchmark of 34 disease gene expression datasets compiled by a recent publication, and show that LEGO is among the top-ranked methods in terms of both sensitivity and prioritization for detecting target KEGG pathways. In addition, we develop a cluster-and-filter approach to reduce the redundancy among the enriched gene sets, making the results more interpretable to biologists. Finally, we apply LEGO to two lists of autism genes, and identify relevant gene sets to autism that could not be found by Fisher. PMID- 26750451 TI - Low diversity of planktonic bacteria in the tropical ocean. AB - The diversity of macro-organisms increases towards the equator, with almost no exceptions. It is the most conserved biogeographical pattern on earth and is thought to be related to the increase of temperature and productivity in the tropics. The extent and orientation of a latitudinal gradient of marine bacterioplankton diversity is controversial. Here we studied the euphotic zone of the Atlantic Ocean based on a transect covering ~12.000 km from 51 degrees S to 47 degrees N. Water samples were collected at 26 stations at five depths between 20 and 200 m and sequentially filtered through 8 MUm, 3 MUm and 0,22 MUm filters, resulting in a total of 359 samples. Illumina sequencing of the V5-V6 region of the 16S rRNA gene revealed a clear biogeographic pattern with a double inverted latitudinal gradient. Diversity was higher in mid-latitudinal regions of the Atlantic Ocean and decreased towards the equator. This pattern was conserved for bacteria from all three planktonic size fractions. Diversity showed a non-linear relationship with temperature and was negatively correlated with bacterial cell numbers in the upper depth layers (<100 m). The latitudinal gradients of marine bacterial diversity and the mechanisms that govern them are distinct from those found in macro-organisms. PMID- 26750452 TI - Tissue loads applied by a novel medical device for closing large wounds. AB - Closure of large soft tissue defects following surgery or trauma as well as closure of large chronic wounds constitutes substantial but common reconstructive challenges. In such cases, an attempt to use conventional suturing will result in high-tension closure, therefore alternative external skin stretching systems were developed. These types of devices were meant to reduce local mechanical loads in the skin and the underlying tissues, taking advantage of the viscoelastic properties of the skin, especially mechanical creep, for primary wound closure. Studies have shown the clinical advantages of skin stretching systems, however, quantitative bioengineering models, demonstrating closure of large wounds, are lacking. Here we present finite element (FE) modeling of the TopClosure((r)) tension relief system (TRS) and its biomechanical efficacy in three (real) wound cases, compared with the alternative of a conventional surgical suturing closure technique. Our simulations showed that peak effective stresses on the skin were at least an order of magnitude greater (and sometimes nearly 2 orders-of magnitude greater) when tension sutures were used with respect to the corresponding TRS data. For the tension suture simulations, the tensile stress was in the range of 415-648 MPa and in the TRS simulations, it was 16-30 MPa. Based on the present computational FE modeling, the TRS reduces localized tissue deformations and stress concentrations in skin and underlying tissues while closing large wounds, compared to the deformations and stresses that are inflicted during the process of suturing. This substantial reduction of loads allows surgeons to better employ the viscoelastic properties of the skin for primary wound closure. PMID- 26750454 TI - Pregnancy after liver transplantation. How safe? A retrospective case-series study in a large tertiary hospital. AB - OBJECTIVE: To study pregnancies achieved after liver transplantation in terms of obstetric complications, maternal, neonatal outcomes and post-pregnancy allograft function. METHODS: A retrospective study of prospectively collected data was conducted, enrolling women with a history of liver transplantation performed in the Transplantation Unit of our hospital that delivered in our department. Obstetric characteristics and antenatal complications were reviewed. Apgar score, admission to Neonatal Intensive Care Unit (NICU) and need for emergency intubation were analyzed. Outcomes of regular follow-up concerning all complications of allograft function observed after pregnancy were also studied. RESULTS: There were five cases of allograft recipients delivering their pregnancies during the study period. Mean maternal age was 32.2 +/- 5 years. Interval from transplantation to delivery ranged from 40 to 219 months. Mean gestational week at delivery was 34.4 +/- 2.5 weeks. Antenatal complications observed were pre-eclampsia (3 of 5 cases) and vaginal bleeding (1 of 5 cases). All preterm neonates were admitted to NICU, but no emergency intubation was demanded. One patient died a month after delivery, while three others were complicated by implant dysfunction up to 5 years after the delivery. CONCLUSION: Pregnancy in a liver transplant recipient is associated with complications for mother and infant. PMID- 26750455 TI - Strong interband Faraday rotation in 3D topological insulator Bi2Se3. AB - The Faraday effect is a representative magneto-optical phenomenon, resulting from the transfer of angular momentum between interacting light and matter in which time-reversal symmetry has been broken by an externally applied magnetic field. Here we report on the Faraday rotation induced in the prominent 3D topological insulator Bi2Se3 due to bulk interband excitations. The origin of this non resonant effect, extraordinarily strong among other non-magnetic materials, is traced back to the specific Dirac-type Hamiltonian for Bi2Se3, which implies that electrons and holes in this material closely resemble relativistic particles with a non-zero rest mass. PMID- 26750459 TI - ON THE INTERNAL STRUCTURE OF THE MMPI. AB - This article contains 2 principal parts: (1) a detailed criticism of the MMPI and the methods used to construct it; and (2) a report on studies of the factor structure in the behavior represented by responses to MMPI items. The criticisms are intended to banish the MMPI in its present form from the domain of psychological assessments. PMID- 26750453 TI - Exploring the genetic basis of early-onset chronic kidney disease. AB - The primary causes of chronic kidney disease (CKD) in children differ from those of CKD in adults. In the USA the most common diagnostic groups of renal disease that manifest before the age of 25 years are congenital anomalies of the kidneys and urinary tract, steroid-resistant nephrotic syndrome, chronic glomerulonephritis and renal cystic ciliopathies, which together encompass >70% of early-onset CKD diagnoses. Findings from the past decade suggest that early onset CKD is caused by mutations in any one of over 200 different monogenic genes. Developments in high-throughput sequencing in the past few years has rendered identification of causative mutations in this high number of genes feasible. Use of genetic analyses in patients with early onset-CKD will provide patients and their families with a molecular genetic diagnosis, generate new insights into disease mechanisms, facilitate aetiology-based classifications of patient cohorts for clinical studies, and might have consequences for personalized approaches to the prevention and treatment of CKD. In this Review, we discuss the implications of next-generation sequencing in clinical genetic diagnostics and the discovery of novel genes in early-onset CKD. We also delineate the resulting opportunities for deciphering disease mechanisms and the therapeutic implications of these findings. PMID- 26750456 TI - Nutritional conditions regulate transcriptional activity of SF-1 by controlling sumoylation and ubiquitination. AB - Steroidogenic factor 1 (SF-1) is a transcription factor expressed in the ventral medial nucleus of the hypothalamus that regulates energy homeostasis. However, the molecular mechanisms of SF-1 in the control of energy balance are largely unknown. Here, we show that nutritional conditions, such as the presence or absence of serum, affect SF-1 action. Serum starvation significantly decreased hypothalamic SF-1 levels by promoting ubiquitin-dependent degradation, and sumoylation was required for this process. SF-1 transcriptional activity was also differentially regulated by nutritional status. Under normal conditions, the transcriptional activity of hypothalamic SF-1 was activated by SUMO, but this was attenuated during starvation. Taken together, these results indicate that sumoylation and ubiquitination play crucial roles in the regulation of SF-1 function and that these effects are dependent on nutritional conditions, further supporting the importance of SF-1 in the control of energy homeostasis. PMID- 26750461 TI - INFORMATION LEVEL AND DIMENSIONALITY OF LIBERALISM-CONSERVATISM. AB - This study explores, again, the question of the magnitude of relationships between different aspects of political-economic liberalism-conservatism. The question has not been resolved by numerous investigations. This study, urtilizing extensive indices of political stance, is designed to shed light on several alternative hypotheses regarding the structure of this important attitude-belief system. PMID- 26750460 TI - SEVEN MISSING NORMAL PERSONALITY FACTORS IN THE QUESTIONNAIRE PRIMARIES. AB - Rather more than 16 primary factors, by factor-number tests, have regularly been found from the personality sphere in Q-data. PMID- 26750458 TI - Rotigaptide protects the myocardium and arterial vasculature from ischaemia reperfusion injury. AB - AIM: Ischaemia-reperfusion injury (IRI) causes impaired endothelial function and is a major component of the adverse effects of reperfusion following myocardial infarction. Rotigaptide increases gap junction conductance via connexin-43. We tested the hypothesis that rotigaptide reduces experimental myocardial infarction size and ameliorates endothelial IRI in humans. METHODS: Myocardial infarction study: porcine myocardial infarction was achieved by catheter-induced occlusion of the left anterior descending artery. In a randomized double-blind study, rotigaptide (n = 9) or placebo (n = 10) was administered intravenously as a 10 min bolus prior to reperfusion and continuously during 2 h of reperfusion. Myocardial infarction size (IS) was assessed as proportion of the area at risk (AAR). Human translational study: forearm IRI was induced in the presence or absence of intra-arterial rotigaptide. In a randomized double-blind study, forearm arterial blood flow was measured at rest and during intra-arterial infusion of acetylcholine (5-20 MUg min(-1) ; n = 11) or sodium nitroprusside (2 8 mg min(-1) ; n = 10) before and after intra-arterial infusion of placebo or rotigaptide, and again following IRI. RESULTS: Myocardial infarction study: Rotigaptide treatment was associated with a reduction of infarct size (IS/AAR[%]: 18.7 +/- 4.1 [rotigaptide] vs. 43.6 +/- 4.2 [placebo], P = 0.006). Human translational study: Endothelium-dependent vasodilatation to acetylcholine was attenuated after ischaemia-reperfusion in the presence of placebo (P = 0.007), but not in the presence of rotigaptide (P = NS). Endothelium-independent vasodilatation evoked by sodium nitroprusside was unaffected by IRI or rotigaptide (P = NS). CONCLUSIONS: Rotigaptide reduces myocardial infarction size in a porcine model and protects from IRI-related endothelial dysfunction in man. Rotigaptide may have therapeutic potential in the treatment of myocardial infarction. PMID- 26750462 TI - VARIABLES ASSOCIATED WITH SOCIAL CLASS DIFFERENCES IN THE INTELLIGENCE OF YOUNG CHILDREN. AB - Although disagreement still exists over the relative contribu- tions to intelligence of heredity and environment, must authors agree that the mode of action of the latter and the interaction be- tween them are more important research issues than the question of which predominates. It is scarcely disputed that the influence of the physical and social environment is important. The means by which its influence is accomplished needs considerable clarifica- tion if remedial efforts, short of the complete abolition of social inequality, are to be effective. Hunt (1961) and Anashsi (1965) have bobh argued persuasively that efforts to resolve the nature- nurture conflict are less useful than are efforts to determine the mediators of the effect of the child's environment upon his intel- lectual development. PMID- 26750464 TI - A MULTIVARIATE INVESTIGATION OF PREFERENCES. AB - The concept of preference is of primary importance in psychology. It has had an implicit role in almost every psychological theory, but no major efforts have been directed toward the explication of preference as a psychological concept. Why is one object preferred to another? is a question which has remained unan- swered, at least to the extent that the psychological nature of pref- erence has remained subservient to the other purposes of investigators. PMID- 26750463 TI - MEASURING THE DYNAMIC PATTERNS OF DEVELOPMENT: THE CASE OF ASIA 1949-1968. AB - The research reported here is a first step toward the building of a general theory of development in Asia. The specific goals involved are: (1) to delineate major patterns of development in Asia; (2) to examine the fluctuation of each nation's pattern scores; and (3) to evaluate trends in Asia as a system. PMID- 26750473 TI - Saos-2 cell-mediated mineralization on collagen gels: Effect of densification and bioglass incorporation. AB - Plastic compression is a collagen densification process that has been widely used for the development of mechanically robust collagen-based materials. Incorporation of bioglass within plastically compressed collagen gels has been shown to mimic the microstructural properties of native bone and enhance in vitro cell-mediated mineralization. The current study seeks to decouple the effects of collagen densification and bioglass incorporation to understand the interplay between collagen packing density and presence of bioglass on cell-mediated mineralization. Saos-2 cell-mediated mineralization was assessed as a measure of the osteoconductivity of four different collagen gels: (1) uncompressed collagen gel (UC), (2) bioglass incorporated uncompressed collagen gel (UC + BG), (3) plastically compressed collagen gel (PC), and (4) bioglass incorporated plastically compressed collagen gel (PC + BG). The results indicated that collagen densification enhanced mineralization as shown by SEM, increased alkaline phosphatase activity and produced significantly higher amounts of mineralized nodules on PC gels compared to UC gels. Further, the amount of nodule formation on PC gels was significantly higher compared to UC + BG gels indicating that increase in matrix stiffness due to collagen densification had a greater effect on cell-mediated mineralization compared to bioglass incorporation into loosely packed UC gels. Incorporation of bioglass into PC gels further enhanced mineralization as evidenced by significantly larger nodule size and higher amount of mineralization on PC + BG gels compared to PC gels. In conclusion, collagen densification via plastic compression improves the osteoconductivity of collagen gels. Further, incorporation of bioglass within PC gels has an additive effect and further enhances the osteoconductivity of collagen gels. PMID- 26750474 TI - Mild activation of CeO2-supported gold nanoclusters and insight into the catalytic behavior in CO oxidation. AB - We report a new activation method and insight into the catalytic behavior of a CeO2-supported, atomically precise Au144(SR)60 nanocluster catalyst (where thiolate -SR = -SCH2CH2Ph) for CO oxidation. An important finding is that the activation of the catalyst is closely related to the production of active oxygen species on CeO2, rather than ligand removal of the Au144(SR)60 clusters. A mild O2 pretreatment (at 80 degrees C) can activate the catalyst, and the addition of reductive gases (CO or H2) can enhance the activation effects of O2 pretreatment via a redox cycle in which CO could reduce the surface of CeO2 to produce oxygen vacancies-which then adsorb and activate O2 to produce more active oxygen species. The CO/O2 pulse experiments confirm that CO is adsorbed on the cluster catalyst even with ligands on, and active oxygen species present on the surface of the pretreated catalyst reacts with CO pulses to generate CO2. The Au144(SR)60/CeO2 exhibits high CO oxidation activity at 80 degrees C without the removal of thiolate ligands. The surface lattice-oxygen of the support CeO2 possibly participates in the oxidation of CO over the Au144(SR)60/CeO2 catalyst. PMID- 26750475 TI - Correlation between diffusion barriers and alloying energy in binary alloys. AB - In this paper, we explore the notion that a negative alloying energy may act as a descriptor for long term stability of Pt-alloys as cathode catalysts in low temperature fuel cells. Using density functional theory calculations, we show that there is a correlation between the alloying energy of an alloy, and the diffusion barriers of the minority component. Alloys with a negative alloying energy may show improved long term stability, despite the fact that there is typically a greater thermodynamic driving force towards dissolution of the solute metal over alloying. In addition to Pt, we find that this trend also appears to hold for alloys based on Al and Pd. PMID- 26750476 TI - The state-of-the art in macromolecular crystallization: the IYCr series concludes. PMID- 26750477 TI - Cloning, expression, purification, crystallization and X-ray diffraction analysis of dihydrodipicolinate synthase from the human pathogenic bacterium Bartonella henselae strain Houston-1 at 2.1 A resolution. AB - The enzyme dihydrodipicolinate synthase catalyzes the committed step in the synthesis of diaminopimelate and lysine to facilitate peptidoglycan and protein synthesis. Dihydrodipicolinate synthase catalyzes the condensation of L-aspartate 4-semialdehyde and pyruvate to synthesize L-2,3-dihydrodipicolinate. Here, the cloning, expression, purification, crystallization and X-ray diffraction analysis of dihydrodipicolinate synthase from the pathogenic bacterium Bartonella henselae, the causative bacterium of cat-scratch disease, are presented. Protein crystals were grown in conditions consisting of 20%(w/v) PEG 4000, 100 mM sodium citrate tribasic pH 5.5 and were shown to diffract to ~2.10 A resolution. They belonged to space group P212121, with unit-cell parameters a = 79.96, b = 106.33, c = 136.25 A. The final R values were Rr.i.m. = 0.098, Rwork = 0.183, Rfree = 0.233. PMID- 26750478 TI - Structure of a thermostable serralysin from Serratia sp. FS14 at 1.1 A resolution. AB - Serralysin is a well studied metalloprotease, and typical serralysins are not thermostable. The serralysin isolated from Serratia sp. FS14 was found to be thermostable, and in order to reveal the mechanism responsible for its thermostability, the crystal structure of serralysin from Serratia sp. FS14 was solved to a crystallographic R factor of 0.1619 at 1.10 A resolution. Similar to its homologues, it mainly consists of two domains: an N-terminal catalytic domain and a 'parallel beta-roll' C-terminal domain. Comparative studies show that the shape of the catalytic active-site cavity is more open owing to the 189-198 loop, with a short 310-helix protruding further from the molecular surface, and that the beta-sheets comprising the 'parallel beta-roll' are longer than those in its homologues. The formation of hydrogen bonds from one of the nonconserved residues (Asn200) to Lys27 may contribute to the thermostability. PMID- 26750480 TI - Crystallization of nepenthesin I using a low-pH crystallization screen. AB - Nepenthesins are aspartic proteases secreted by carnivorous pitcher plants of the genus Nepenthes. They significantly differ in sequence from other plant aspartic proteases. This difference, which provides more cysteine residues in the structure of nepenthesins, may contribute to their unique stability profile. Recombinantly produced nepenthesin 1 (rNep1) from N. gracilis in complex with pepstatin A was crystallized under two different crystallization conditions using a newly formulated low-pH crystallization screen. The diffraction data were processed to 2.9 and 2.8 A resolution, respectively. The crystals belonged to space group P212121, with unit-cell parameters a = 86.63, b = 95.90, c = 105.40 A, alpha = beta = gamma = 90 degrees and a = 86.28, b = 97.22, c = 103.78 A, alpha = beta = gamma = 90 degrees , respectively. Matthews coefficient and solvent-content calculations suggest the presence of two molecules of rNep1 in the asymmetric unit. Here, the details of the crystallization experiment and analysis of the X-ray data are reported. PMID- 26750479 TI - Expression, crystallization and structure elucidation of gamma-terpinene synthase from Thymus vulgaris. AB - The biosynthesis of gamma-terpinene, a precursor of the phenolic isomers thymol and carvacrol found in the essential oil from Thymus sp., is attributed to the activitiy of gamma-terpinene synthase (TPS). Purified gamma-terpinene synthase from T. vulgaris (TvTPS), the Thymus species that is the most widely spread and of the greatest economical importance, is able to catalyze the enzymatic conversion of geranyl diphosphate (GPP) to gamma-terpinene. The crystal structure of recombinantly expressed and purified TvTPS is reported at 1.65 A resolution, confirming the dimeric structure of the enzyme. The putative active site of TvTPS is deduced from its pronounced structural similarity to enzymes from other species of the Lamiaceae family involved in terpenoid biosynthesis: to (+)-bornyl diphosphate synthase and 1,8-cineole synthase from Salvia sp. and to (4S) limonene synthase from Mentha spicata. PMID- 26750481 TI - New crystal form of human ubiquitin in the presence of magnesium. AB - Ubiquitin is a small globular protein that has a considerable number of lysine residues on its surface. This results in a high surface entropy that precludes the formation of crystal-packing interactions. To date, only a few structures of the native form of ubiquitin have been solved, and most of the crystals that led to these structures were obtained in the presence of different divalent metal cations. In this work, a new crystallographic structure of human ubiquitin solved from crystals grown in the presence of magnesium is presented. The crystals belonged to a triclinic space group, with unit-cell parameters a = 29.96, b = 30.18, c = 41.41 A, alpha = 88.52, beta = 79.12, gamma = 67.37 degrees . The crystal lattice is composed of stacked layers of human ubiquitin molecules with a large hydrophobic interface and a smaller polar interface in which the magnesium ion lies at the junction between adjacent layers in the crystal. The metal ion appears in a hexa-aquo coordination, which is key to facilitating the crystallization of the protein. PMID- 26750482 TI - Purification, crystallization and structural elucidation of D-galactaro-1,4 lactone cycloisomerase from Agrobacterium tumefaciens involved in pectin degradation. AB - Pectin is found in the cell wall of plants and is often discarded as waste. A number of research groups are interested in redirecting this biomass waste stream for the production of fuel and bulk chemicals. The primary monomeric subunit of this polysaccharide is D-galacturonate, a six-carbon acid sugar that is degraded in a five-step pathway to central metabolic intermediates by some bacteria, including Agrobacterium tumefaciens. In the third step of the pathway, D galactaro-1,4-lactone is converted to 2-keto-3-deoxy-L-threo-hexarate by a member of the mandelate racemase subgroup of the enolase superfamily with a novel activity for the superfamily. The 1.6 A resolution structure of this enzyme was determined, revealing an overall modified (beta/alpha)7beta TIM-barrel domain, a hallmark of the superfamily. D-Galactaro-1,4-lactone was manually docked into the active site located at the interface between the N-terminal lid domain and the C terminal barrel domain. On the basis of the position of the lactone in the active site, Lys166 is predicted to be the active-site base responsible for abstraction of the alpha proton. His296 on the opposite side of the active site is predicted to be the general acid that donates a proton to the beta carbon as the lactone ring opens. The lactone ring appears to be oriented within the active site by stacking interactions with Trp298. PMID- 26750483 TI - Crystal structure of HINT from Helicobacter pylori. AB - Proteins belonging to the histidine triad (HIT) superfamily bind nucleotides and use the histidine triad motif to carry out dinucleotidyl hydrolase, nucleotidyltransferase and phosphoramidite hydrolase activities. Five different branches of this superfamily are known to exist. Defects in these proteins in humans are linked to many diseases such as ataxia, diseases of RNA metabolism and cell-cycle regulation, and various types of cancer. The histidine triad nucleotide protein (HINT) is nearly identical to proteins that have been classified as protein kinase C-interacting proteins (PKCIs), which also have the ability to bind and inhibit protein kinase C. The structure of HINT, which exists as a homodimer, is highly conserved from humans to bacteria and shares homology with the product of fragile histidine triad protein (FHit), a tumour suppressor gene of this superfamily. Here, the structure of HINT from Helicobacter pylori (HpHINT) in complex with AMP is reported at a resolution of 3 A. The final model has R and Rfree values of 26 and 28%, respectively, with good electron density. Structural comparison with previously reported homologues and phylogenetic analysis shows H. pylori HINT to be the smallest among them, and suggests that it branched out separately during the course of evolution. Overall, this structure has contributed to a better understanding of this protein across the animal kingdom. PMID- 26750485 TI - Improved purification, crystallization and crystallographic study of Hyd-2-type [NiFe]-hydrogenase from Citrobacter sp. S-77. AB - The purification procedure of Hyd-2-type [NiFe]-hydrogenase from Citrobacter sp. S-77 was improved by applying treatment with trypsin before chromatography. Purified protein samples both with and without trypsin treatment were successfully crystallized using the sitting-drop vapour-diffusion method with polyethylene glycol as a precipitant. Both crystals belonged to space group P21, with unit-cell parameters a = 63.90, b = 118.89, c = 96.70 A, beta = 100.61 degrees for the protein subjected to trypsin treatment and a = 65.38, b = 121.45, c = 98.63 A, beta = 102.29 degrees for the sample not treated with trypsin. The crystal obtained from the trypsin-treated protein diffracted to 1.60 A resolution, which is considerably better than the 2.00 A resolution obtained without trypsin treatment. The [NiFe]-hydrogenase from Citrobacter sp. S-77 retained catalytic activity with some amount of O2, indicating that it has clear O2 tolerance. PMID- 26750484 TI - Expression, purification, crystallization and crystallographic analysis of the N terminal domain of translocated intimin receptor. AB - Translocated intimin receptor (Tir) is an Escherichia coli-encoded protein that is transported into the host cell through a sophisticated bacterial type III secretion system (T3SS). Tir anchors the infected cell membrane twice using both its N- and C-termini from inside the host cytoplasm for signalling. It plays a key role in enterohemorrhagic Escherichia coli (EHEC) infection, attaching and effacing (A/E) lesions and intracellular signal transduction. Here, the overexpression, purification and crystallization of its N-terminal intracellular domain are reported. The crystal belonged to the orthorhombic space group I4122, with unit-cell parameters a = b = 59.79, c = 183.11 A. The asymmetric unit contained one molecule, with a solvent content of 51% and a VM of 2.55 A(3) Da( 1). PMID- 26750486 TI - Sqt1p is an eight-bladed WD40 protein. AB - Ribosome biogenesis in eukaryotes is a complex and highly orchestrated process involving more than 200 accessory factors in addition to ribosomal RNAs and ribosomal proteins. Among the many factors involved, Sqt1p has been reported to specifically bind to uL16 and to act as a chaperone. The crystal structure of full-length Sqt1p from the yeast Saccharomyces cerevisiae has been solved at 3.35 A resolution. A SAD experiment at the Se K edge and an S-SAD experiment on the same selenomethionine-substituted protein crystal allowed unambiguous positioning of the selenomethionine and Cys residues. On the basis of the atomic structure of Sqt1p, the potential residues involved in uL16 interaction were identified and tested. PMID- 26750487 TI - Structure of methionine gamma-lyase from Clostridium sporogenes. AB - Methionine gamma-lyase (MGL) is a pyridoxal 5'-phosphate-dependent enzyme that catalyzes the gamma-elimination reaction of L-methionine. The enzyme is a promising target for therapeutic intervention in some anaerobic pathogens and has attracted interest as a potential cancer treatment. The crystal structure of MGL from Clostridium sporogenes has been determined at 2.37 A resolution. The fold of the protein is similar to those of homologous enzymes from Citrobacter freundii, Entamoeba histolytica, Pseudomonas putida and Trichomonas vaginalis. A comparison of these structures revealed differences in the conformation of two flexible regions of the N- and C-terminal domains involved in the active-site architecture. PMID- 26750489 TI - Forests as a natural seismic metamaterial: Rayleigh wave bandgaps induced by local resonances. AB - We explore the thesis that resonances in trees result in forests acting as locally resonant metamaterials for Rayleigh surface waves in the geophysics context. A geophysical experiment demonstrates that a Rayleigh wave, propagating in soft sedimentary soil at frequencies lower than 150 Hz, experiences strong attenuation, when interacting with a forest, over two separate large frequency bands. This experiment is interpreted using finite element simulations that demonstrate the observed attenuation is due to bandgaps when the trees are arranged at the sub-wavelength scale with respect to the incident Rayleigh wave. The repetitive bandgaps are generated by the coupling of the successive longitudinal resonances of trees with the vertical component of the Rayleigh wave. For wavelengths down to 5 meters, the resulting bandgaps are remarkably large and strongly attenuating when the acoustic impedance of the trees matches the impedance of the soil. Since longitudinal resonances of a vertical resonator are inversely proportional to its length, a man-made engineered array of resonators that attenuates Rayleigh waves at frequency <=10 Hz could be designed starting from vertical pillars coupled to the ground with longitudinal resonance <=10 Hz. PMID- 26750488 TI - Upregulation and axonal transport of synaptotagmin-IV in the direct-pathway medium spiny neurons in hemi-parkinsonian rats induced by dopamine D1 receptor stimulation. AB - Synaptotagmin-IV (Syt-IV) may function as a regulator of Ca(2+) -dependent synaptic transmission. In the hemi-parkinsonian rats with unilateral lesions of dopaminergic nigrostriatal neurons Syt-IV and substance-P (SP) mRNAs could be upregulated within the dopaminergically hypersensitive striatum of the lesioned brain hemisphere via the stimulation of striatal dopamine D1 (D1-R), but not D2 receptors. The hypersensitive D1-R-mediated transmission may be the culprit for the undesired expression of levodopa-induced dyskinesia, implying the involvement of Syt-IV and SP in the process. First, striatal cellular phenotypes expressing Syt-IV were determined. It was found to be expressed in all striatal neurons and a small population of astrocytes. Then it was examined, if the D1-R-mediated upregulation of Syt-IV mRNA may result in the upregulation of the translated protein. It was found that, after acute stimulation with a selective D1 agonist, (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-82958), Syt-IV was elevated within the SP-expressing striatal neurons of the lesioned side. This was followed by the upregulation of Syt-IV, but not of its mRNA, within the ipsilateral target nuclei of the direct-pathway medium spiny neurons, indicating axonal transport of de novo synthesized protein to their SP-positive synaptic terminals. However, despite the striatal upregulation of SP and Syt-IV following a similar time-course, their subcellular co-localization within the axonal terminals was not found. It was therefore suggested that Syt-IV may regulate the hypersensitive striatal synaptic transmission, although via a SP-independent mechanism. PMID- 26750490 TI - miR-17-5p promotes the growth of osteosarcoma in a BRCC2-dependent mechanism. AB - MicroRNA-17-5p has been proven upregulated in many human malignancies and correlated with tumor progression. However, its expression and clinical significance in osteosarcoma is still unclear. Thus, the aim of the present study was to explore the effects of miR-17-5p in osteosarcoma tumorigenesis and development. The expression level of miR-17-5p was quantified by quantitative real-time reverse-transcriptase-polymerase chain reaction in primary osteosarcoma tissues and osteosarcoma cell lines. MTT, Transwell and matrigel assays were used to test the proliferation, migration and invasion of miR-17-5p transfection osteosarcoma cells, and a mouse model was used to investigate tumorigenesis. The expression levels of miR-17-5p in osteosarcoma tissues were significantly higher than those in corresponding non-cancerous bone tissues. In addition, miR-17-5p upregulation more frequently occurred in osteosarcoma specimens with advanced clinical stage, positive distant metastasis and poor response to neo-adjuvant chemotherapy. After miR-17-5p transfection, cell proliferation, migration, invasion and tumorigenesis in the osteosarcoma cells were significantly promoted. We further demonstrated that BRCC2 is a direct target of miR-17-5p. These findings indicate that miR-17-5p may act not only as a novel diagnostic and prognostic marker, but also as a potential target for molecular therapy of osteosarcoma. PMID- 26750491 TI - Predicting future uncertainty constraints on global warming projections. AB - Projections of global mean temperature changes (DeltaT) in the future are associated with intrinsic uncertainties. Much climate policy discourse has been guided by "current knowledge" of the DeltaTs uncertainty, ignoring the likely future reductions of the uncertainty, because a mechanism for predicting these reductions is lacking. By using simulations of Global Climate Models from the Coupled Model Intercomparison Project Phase 5 ensemble as pseudo past and future observations, we estimate how fast and in what way the uncertainties of DeltaT can decline when the current observation network of surface air temperature is maintained. At least in the world of pseudo observations under the Representative Concentration Pathways (RCPs), we can drastically reduce more than 50% of the DeltaTs uncertainty in the 2040 s by 2029, and more than 60% of the DeltaTs uncertainty in the 2090 s by 2049. Under the highest forcing scenario of RCPs, we can predict the true timing of passing the 2 degrees C (3 degrees C) warming threshold 20 (30) years in advance with errors less than 10 years. These results demonstrate potential for sequential decision-making strategies to take advantage of future progress in understanding of anthropogenic climate change. PMID- 26750492 TI - Importance of fundamental science as the cornerstone for translational research. PMID- 26750493 TI - Penis cancer management: insight into the future. PMID- 26750494 TI - Should we worry about positive surgical margins in prostate cancer? PMID- 26750495 TI - Should we start with low-dose anti-cholinergics when alpha-blockers alone fail to control mixed lower urinary tract symptoms in men? PMID- 26750496 TI - When two and two don't make four. PMID- 26750497 TI - Current evidence for the diagnostic value of gadoxetic acid-enhanced magnetic resonance imaging for liver metastasis. AB - A variety of imaging techniques, including ultrasonography (US), multidetector computed tomography (MDCT), magnetic resonance imaging (MRI) and positron emission tomography combined with CT scan (PET/CT), are available for diagnosis and treatment planning in liver metastasis. Contrast-enhanced MDCT is a relatively non-invasive, widely available and standardized method for hepatic work-up. Gadoxetic acid (gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid; EOB Primovist(r)]) is a recently developed liver-specific hepatobiliary MR contrast agent that offers both dynamic imaging as well as liver-specific static hepatocyte imaging, referred to as the hepatobiliary phase. Following contrast injection, this technique reveals dynamic vascular phases (arterial, portal venous and delayed phases), in addition to the hepatobiliary phase upon uptake by functional hepatocytes. The overall sensitivity of gadoxetic acid-enhanced MRI was significantly higher than that of contrast-enhanced CT. Specifically, the higher sensitivity of gadoxetic acid-enhanced MRI was observed in lesions smaller than 1 cm in diameter. Gadoxetic acid-enhanced MRI is considered an extremely useful tool for the diagnosis of liver metastases. Future studies will focus on diagnostic algorithms involving combinations of modalities such as MRI, MDCT and/or (18) F-fluorodeoxyglucose PET/CT, which may impact the treatment plan for these patients. PMID- 26750498 TI - Individual Differences in Assimilation Resistance and Affective Responses in Problem Solving. AB - Data on problem solving collected within the framework of Eckblad's (198lb) cognitive theory of affect are analyzed with three-mode principal component analysis. Eckblad's theory contends that affect is mediated by cognitive schemes. When schemes are inadequate for input assimilation, the resistances call forth affects with respect to the events. In this study, the task information load was varied to provide different levels of resistance. Data comprised 6 judgment scales (Pleasant-Unpleasant, Interesting-Boring, Comfortable-Uncomfortable, ComplexSimple, Varied-Monotone, and Confused-Clear) by 8 problem solving tasks (ordered a priori by information load) by 32 thirteen-year-old boys. The general results were consistent with the hypotheses of curvex scale relationships and joint scale-task fan-shaped vector configurations, but the fit was modest and vulnerable to other interpretations. Although many of the problems were accommodated by Eckblad's general scheme theory, it is suggested that assimilation resistance must be more rigorously operationalized to afford greater insight into the correspondence between cognition and affect. In general, this study illustrates the effectiveness of the threemode principal component analysis (TUCKALS) method for the assessment of the nomothetic validity of a theoretical framework as it pertains to within and across person variation. PMID- 26750499 TI - Model Modification in Covariance Structure Analysis: Application of the Expected Parameter Change Statistic. AB - This paper examines the problem of model modification in covariance structure analysis. Two methods of model modification are studied: the Modification Index (MI) which suggests modifications based on the largest drop in the overall value of the test statistic, and the Expected Parameter Change Statistic (EPC) which suggests modifications based on the removal of large and interesting specifications errors. Following a detailed discussion of the theory behind the MI and EPC, these methods are studied and applied to two specifications of the Wisconsin status attainment model. Additionally, a standardized version of the EPC statistic (SEPC) is proposed and applied to one of these models. Results indicate that the MI tends to suggest freeing substantively implausible parameters. The EPC and SEPC, by contrast, suggest freeing substantively interesting parameters. Results are discussed in terms of the practice of covariance structure modeling. PMID- 26750500 TI - Approximate Confidence Intervals for Estimates of Redundancy Between Sets of Variables. AB - Use of redundancy analysis would be enhanced by having available a procedure that (a) evaluates the statistical significance of the estimated proportion of variance in the criterion variable set extracted by a given predictor variate, Ry i (2), as well as by all predictor variates combined, R(y 2), and (b) is lenient with respect to assumptions about the distributions of redundancy estimates. A previous testing method leaves in doubt the assessment of redundancy attributed individually to each predictor variate, and it requires parametric assumptions about the distributions of the estimators. This paper describes and demonstrates the bootstrap methodology which yields approximations of the sampling variation of redundancy estimates while assuming little a priori knowledge about the distributions of these statistics. The procedure is applicable for evaluating the estimated proportions of criterion set variance explained solely by a given predictor variate and cumulatively by all predictor variates. PMID- 26750501 TI - Replication Problems of Substance Abuser MMPI Cluster Types. AB - Cluster analysis solutions of drug abuser (primarily heroin addict) Minnesota Multiphasic Personality Inventory (MMPI) profiles are critically reviewed. We followed the procedures in five published research studies, using 183 heroin addict MMPI profiles. The published claim that cluster analytic results have been replicated is not supported, primarily because of methodological differences in previous research. In particular, methods using measures of shape as input (primarily Pearson correlation) did not yield classifications that agreed with methods using Euclidean distance when all methods were used on the same data. A preferred solution using complete linkage with Pearson correlation is presented and recommendations for future cluster analysis research are made. Of the four heroin addict clusters identified, the "schizoid psychopath" (8-4) cluster was associated with a significantly greater number of arrests before first drug use than was the "hypomanic psychopath" (9-4) cluster. PMID- 26750502 TI - Evaluating the Internal Structure of the Eysenck Personality Questionnaire: Objective Criteria. AB - Controversy over the internal structure of personality inventories has centered on appropriate methodology and has often been based on differing criteria among researchers. Much of this controversy has revolved in particular around the Eysenck Personality Questionnaire (EPQ) or other Eysenck tests. An approach based on targeted rotations and the test's scoring key is proposed as a means of providing common criteria. These are based on the number of items having their highest loading on their keyed scale, the mean loading of keyed items and the number of items having their highest loading on non-keyed scales. Several data sets from earlier studies are analyzed, together with a new set based on the responses to the EPQ of 195 undergraduates, using the proposed criteria. Results were very similar across samples and suggested specific weaknesses with two EPQ scales. This provided support for the utility of the three criteria. PMID- 26750503 TI - A Comparison of Alternatives to Conducting Monte Carlo Analyses for Determining Parallel Analysis Criteria. AB - The parallel analysis method for determining the number of components to retain in a principal components analysis has received a recent resurgence of support and interest. However, researchers and practitioners desiring to use this criterion have been hampered by the required Monte Carlo analyses needed to develop the criteria. Two recent attempts at presenting regression estimation methods to determine eigenvalues were found to be deficient in several respects, and less accurate in general, than a simple linear interpolation of tabled random data eigenvalues generated through Monte Carlo simulation. Other methods for determining the parallel analysis criteria are discussed. PMID- 26750504 TI - Turning conductive carbon nanospheres into nanosheets for high-performance supercapacitors of MnO2 nanorods. AB - Oxidized carbon nanosheets (OCNs), produced from black carbon nanospheres and used as a conductive additive in the supercapacitor electrodes of MnO2 nanorods, can significantly improve the charge-storage performance of the symmetric MnO2 nanorod supercapacitors with a maximum specific energy of 64 W h kg(-1) and power of 3870 W kg(-1). An optimum material composition of the supercapacitor electrode finely tuned is 60 : 30 : 10 wt% of MnO2 : OCN : PVDF, respectively. Interestingly, after 5000 charge/discharge cycles, the oxidation numbers of Mn at the positive and negative electrodes of the as-fabricated supercapacitor are +3.22 and +3.04, respectively. PMID- 26750505 TI - Multi-decadal trends in global terrestrial evapotranspiration and its components. AB - Evapotranspiration (ET) is the process by which liquid water becomes water vapor and energetically this accounts for much of incoming solar radiation. If this ET did not occur temperatures would be higher, so understanding ET trends is crucial to predict future temperatures. Recent studies have reported prolonged declines in ET in recent decades, although these declines may relate to climate variability. Here, we used a well-validated diagnostic model to estimate daily ET during 1981-2012, and its three components: transpiration from vegetation (Et), direct evaporation from the soil (Es) and vaporization of intercepted rainfall from vegetation (Ei). During this period, ET over land has increased significantly (p < 0.01), caused by increases in Et and Ei, which are partially counteracted by Es decreasing. These contrasting trends are primarily driven by increases in vegetation leaf area index, dominated by greening. The overall increase in Et over land is about twofold of the decrease in Es. These opposing trends are not simulated by most Coupled Model Intercomparison Project phase 5 (CMIP5) models, and highlight the importance of realistically representing vegetation changes in earth system models for predicting future changes in the energy and water cycle. PMID- 26750507 TI - Influence of a Rotational Speed Modulation System Used With an Implantable Continuous-Flow Left Ventricular Assist Device on von Willebrand Factor Dynamics. AB - We have developed a rotational speed (RS) modulation system for a continuous-flow left ventricular assist device (EVAHEART) that can change RS in synchronization with a patient's electrocardiogram. Although EVAHEART is considered not to cause significant acquired von Willebrand syndrome, there remains a concern that the repeated acceleration and deceleration of the impeller may degrade von Willebrand factor (vWF) multimers. Accordingly, we evaluated the influence of our RS modulation system on vWF dynamics. A simple mock circulation was used. The circulation was filled with whole bovine blood (650 mL), and the temperature was maintained at 37 +/- 1 degrees C. EVAHEART was operated using the electrocardiogram-synchronized RS modulation system with an RS variance of 500 rpm and a pulse frequency of 60 bpm (EVA-RSM; n = 4). The pumps were operated at a mean flow rate of 5.0 +/- 0.2 L/min against a mean pressure head of 100 +/- 3 mm Hg. The continuous-flow mode of EVAHEART (EVA-C; n = 4) and ROTAFLOW (ROTA; n = 4) was used as controls. Whole blood samples were collected at baseline and every 60 min for 6 h. Complete blood counts (CBCs), normalized indexes of hemolysis (NIH), vWF antigen (vWF:Ag), vWF ristocetin cofactor (vWF:Rco), the ratio of vWF:Rco to vWF:Ag (Rco/Ag), and high molecular weight multimers (HMWM) of vWF were evaluated. There were no significant changes in CBCs throughout the 6 h test period in any group. NIH levels of EVA-RSM, EVA-C, and ROTA were 0.0035 +/ 0.0018, 0.0031 +/- 0.0007, and 0.0022 +/- 0.0011 g/100 L, respectively. Levels of vWF:Ag, vWF:Rco, and Rco/Ag did not change significantly during the test. Immunoblotting analysis of vWF multimers showed slight degradation of HMWM in all groups, but there were no significant differences between groups in the ratios of HMWM to low molecular weight multimers, calculated by densitometry. This study suggests that our RS modulation system used with EVAHEART does not have marked adverse influences on vWF dynamics. The low NIH and the absence of significant decreases in CBCs indicate that EVAHEART is hemocompatible, regardless of whether it is operated with the RS modulation system. PMID- 26750506 TI - Amrubicin for relapsed small-cell lung cancer: a systematic review and meta analysis of 803 patients. AB - Currently, amrubicin is permitted for relapsed small-cell lung carcinoma (SCLC) only in Japan. The efficacy and adverse effects of amrubicin as reported by previous studies varied greatly. The inclusion criterion was a prospective study that was able to provide data for efficacy and safety by the AMR single agent regimen as second-line chemotherapy for a patient with SCLC. Binary data were meta-analyzed with the random-model generic inverse variance method. We included nine articles consisted of 803 patients. The pooled three-, six-, and nine-month progression-free survival were 63% (95% CI 57-69%, I(2) = 53%), 28% (95% CI 21 35%, I(2) = 71%), and 10% (95% CI 6-14%, I(2) = 41%), respectively. The pooled six-, 12-, and 18-month overall survival were 69% (95% CI 61-78%, I(2) = 83%), 36% (95% CI 28-44%, I(2) = 80%), and 15% (95% CI 8-21%, I(2) = 81%), respectively. Amrubicin seemed much more beneficial for Japanese patients. However, compared to the efficacy of topotecan presented in a previous meta analysis, amrubicin may be a better treatment option than topotecan for both Japanese and Euro-American. Adverse effects by amrubicin were almost exclusively observed to be hematological. Notably, grade III/IV neutropenia incidence was 70% and febrile neutropenia incidence was 12%. PMID- 26750508 TI - The use of the analyst as an autistic shape. AB - In this paper I describe through detailed clinical material the challenges posed by patients who employ entangled autistic defenses. I discuss the complicated nature of treating a patient who employed entangled autistic defenses and utilized my voice in an effort to preserve an undifferentiated state of dual unity. My patient's pursuit of dual unity took a very concrete form in her attempt to mitigate the terror of separateness. This concreteness was expressed via the patient's urgent request that I read letters she wrote to me between sessions. This type of autistic defense placed great strain on my ability to think analytically and I also became increasingly concrete in my response to the patient. Crucial to the analyst's regaining a space in which to think and a sense of separateness is the ability to contact the ground floor of her separate bodily experience. This is just the beginning step in the analyst separating herself from the powerful press to join the patient in a state of dual unity. Interpretation in action (Ogden, 1994) was an effective way to convey the importance of creating and tolerating internal space in myself and begin to create internal space in the patient. Previously such space had been closed down in order to manage primitive fears of annihilation. When a patient is absorbed in an entangling autistic retreat words do not reach the patient on a symbolic level but rather are experienced primarily as an assault on the need for dual unity with the analyst. The patient's need to be wrapped in a sensation based world of dual unity is preferable to a world of spoken words that carry the danger of delineating psychic separateness. In essence there is no self to speak words, only a whirl of an amorphous sensation self lacking definition. I believe with certain kinds of patients it may be necessary to first lose and then work to regain one's analytic mind, as I have powerfully described in the case of Linda. Linda's profound loss of connection to the ground floor of her experience could only begin to be addressed when I worked to extricate myself from 'our magic carpet ride' of dual unity, contacting the reality of my bodily experience, and begin to tolerate the terror I felt regarding my separateness from Linda. I also describe the confusing vacillation between entangled and encapsulated defenses in patients like Linda as previously identified by Cohen and Jay (1996). Ultimately, this kind of slow difficult analytic work began to help Linda develop a capacity to think and provided an alternative to the deadened world of her autistic protections. PMID- 26750509 TI - Safety of long-term high-volume sinonasal budesonide irrigations for chronic rhinosinusitis. AB - BACKGROUND: Off-label high-volume sinonasal budesonide irrigations are commonly used during the management of chronic rhinosinusitis (CRS). Although short-term use (4 to 8 weeks) has been demonstrated to be safe, the long-term effects on the hypothalamic-pituitary-adrenal (HPA) axis remain unclear. The objective of this study is to determine whether CRS patients using long-term (minimum greater than 12 months) budesonide sinonasal irrigations have evidence of HPA axis suppression. METHODS: Patients with CRS being managed with high-volume sinonasal budesonide irrigations were recruited from 2 tertiary level rhinology clinics between March 2014 and July 2015. Inclusion criteria were as follows: (1) adult (age greater than 18 years); (2) guideline-based diagnosis of CRS; (3) previous endoscopic sinus surgery; (4) minimum of twice daily high-volume sinonasal budesonide irrigation (concentration of 1 mg per irrigation; total daily dose of 2 mg); and (5) a minimum of 12-month duration. Exclusion criteria included systemic corticosteroid use within 3 months of HPA axis testing. The primary outcomes were morning (am) serum cortisol levels and, when indicated, cosyntropin stimulation levels. RESULTS: A total of 35 patients fulfilled eligibility criteria and underwent HPA axis testing. Mean duration of budesonide sinonasal irrigation therapy use was 38.2 months (2.9 years). The mean +/- standard deviation (SD) am serum cortisol was 431.2 +/- 146.9 nmol/L (normal, 200 to 650 nmol/L). Subsequent cosyntropin stimulation tests, in indicated patients (n = 19), demonstrated no evidence of HPA axis suppression. CONCLUSION: Outcomes from this study suggest that daily high-volume sinonasal budesonide irrigations fail to produce evidence of HPA axis suppression with prolonged courses lasting longer than 2 years. PMID- 26750510 TI - A single-group pilot feasibility study of cognitive behavioural therapy in people with multiple sclerosis with depressive symptoms. AB - PURPOSE: The aims were to evaluate (a) the feasibility of face-to-face cognitive behavioural therapy (CBT) in people with MS (PwMS) with depressive symptoms; (b) the feasibility of methods and measurements used; and (c) the outcome of the intervention before the conducting of an equivalence study of comparative methods of face-to-face CBT. DESIGN: A single-group pilot feasibility study. PATIENTS: PwMS (n = 15) with sub-threshold to moderate depressive symptoms, recruited at the Karolinska University Hospital, Stockholm, Sweden. METHODS: The intervention consisted of 15-20 sessions of face-to-face CBT. Feasibility outcomes included recruitment rate, recruitment procedure and adverse events. Primary clinical outcome was the Beck Depression Inventory-II (BDI-II). Follow-ups were conducted after 3 weeks and 3 months. An estimated sample size calculation was conducted. RESULTS: The face-to-face CBT intervention, methods and measurements used were feasible. The outcome on BDI-II indicated that face-to-face CBT is an effective method for alleviating sub-threshold to moderate depressive symptoms in PwMS. CONCLUSION: Face-to-face CBT is feasible for use in PwMS aiming at decrease depressive symptoms. For an equivalence study, a screening process for depressive symptoms and two comparative intervention arms including traditional face-to-face CBT and low-intensity face-to-face CBT is recommended. Primary outcomes should include the BDI-II and also assessment of anxiety symptoms. Implications for Rehabilitation Depression is common among people with MS (PwMS), however, depressed PwMS do not always receive adequate treatment for depression which may lead to increased disability and worse health-related quality of life (HRQL). Cognitive behavioural therapy (CBT) is a psychological treatment method that might be beneficial for PwMS with depressive symptoms, but the evidence is still weak and further research is needed. The results from our pilot feasibility study demonstrate that for an effectiveness study of face-to-face CBT for PwMS with sub threshold to moderate depressive symptoms the following points should be acknowledged. The design of an effectiveness study should be a randomized controlled trial including two treatment arms: traditional face-to-face CBT and a low-intensity face-to-face CBT. To increase the inclusion rate a screening process for depressive symptoms is recommended. Primary outcomes besides the Beck Depression Inventory-II should include the Hospital Anxiety and Depression Scale in order to capture anxiety symptoms and the Multiple Sclerosis Impact Scale-29 to capture HRQL. PMID- 26750511 TI - The use of social media to supplement resident medical education - the SMART-ME initiative. AB - BACKGROUND: Residents work at variable times and are often unable to attend all scheduled educational sessions. Therefore, new asynchronistic approaches to learning are essential in ensuring exposure to a comprehensive education. Social media tools may be especially useful, because they are accessed at times convenient for the learner. OBJECTIVE: Assess if the use of Twitter for medical education impacts the attitude and behavior of residents toward using social media for medical education. DESIGN: Preintervention and postintervention surveys. Internal medicine resident physicians were surveyed before the launch of a residency-specific Twitter webpage on August 1, 2013, and again 135 days later, to determine their use of the Twitter application and web page, as well as other social media for medical education. PARTICIPANTS: Residents at an internal medicine urban academic training program. MAIN MEASURES: All residents within our training program were administered web-based surveys. The surveys assessed resident views and their frequency of use of social media for medical education purposes, and consisted of 10 Likert scale questions. Each answer consisted of a datapoint on a 1-5 scale (1=not useful, 3=useful, 5=very useful). The final survey question was open-ended and asked for general comments. KEY RESULTS: Thirty-five of 50 residents (70%) completed the presurvey and 40 (80%) participated in the postsurvey. At baseline, 34 out of 35 residents used social media and nine specifically used Twitter. Twenty-seven (77%) used social media for medical education; however, only three used Twitter for educational purposes. After the establishment of the Twitter page, the percentage of residents using social media for educational purposes increased (34 of 40 residents, 85%), and 22 used Twitter for this purpose (p<0.001 for the change). The percentage of residents using the application at least once a week also increased from 11.4 to 60.0% (p<0.001). Almost all residents (38 of 40) felt that social media could be useful as a medical education tool, which slightly increased from 30 out of 35 in the preintervention survey (p=0.01). CONCLUSION: Residents believe social media could be used for medical education. After we launched a Twitter page for medical education, there was a significant increase in the use and frequency of Twitter for resident medical education over the ensuing 6 months. Further research should be performed to see if social media can impact overall medical knowledge and patient care, and whether longer term use is maintained. PMID- 26750512 TI - Cognetics: Robotic Interfaces for the Conscious Mind. AB - Cognetics joins the cognitive neuroscience of bodily awareness with robotics to study, control, and enhance perception, cognition, and consciousness. We highlight robot-controlled bodily perception, conscious states, and social interactions and sketch how future cognetic interfaces will impact cognitive neuroscience and human enhancement. PMID- 26750513 TI - Survival effects of adjuvant gemcitabine plus S-1 chemotherapy on pancreatic carcinoma stratified by preoperative resectability status. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the efficacy of adjuvant gemcitabine plus S-1(GS) chemotherapy for pancreatic carcinoma patients, stratified by the National Comprehensive Cancer Network (NCCN) preoperative resectability definition. METHODS: A total of 141 consecutive patients with resected pancreatic carcinoma who received adjuvant GS chemotherapy were evaluated retrospectively. According to the NCCN preoperative resectability definition, tumors were divided into resectable tumors (R group), borderline resectable tumors with portal vein contact (BR-PV group), and borderline resectable tumors with arterial contact (BR-A group). Overall survival and prognostic factors were analyzed. RESULTS: Overall 1-, 2-, and 5-year survival rates for the 141 patients were 89.6%, 69.9%, and 41.1%, respectively. Overall survival of the R group was significantly better than that of the BR-PV group and the BR-A group (P < 0.05). Overall 5-year survival rates of the R group, the BR PV group, and the BR-A group were 49.0%, 25.0%, and 11.3%, respectively. Arterial contact (P = 0.020), preoperative CA 19-9 level >=150 U/ml (P < 0.001), and positive nodal involvement (P = 0.025) were independent prognostic factors for poor overall survival. CONCLUSIONS: Adjuvant GS chemotherapy may provide a survival benefit especially for patients with resectable pancreatic carcinoma. J. Surg. Oncol. 2016;113:405-412. (c) 2016 Wiley Periodicals, Inc. PMID- 26750515 TI - Time trend in depression diagnoses among acute coronary syndrome patients and a reference population from 2001 to 2009 in Denmark. AB - Introduction In the last decade a range of recommendations to increase awareness of depression in acute coronary syndrome patients have been published. To test the impact of those recommendations we examine and compare recent time trends in depression among acute coronary syndrome patients and a reference population. Methods 87 218 patients registered with acute coronary syndrome from 2001-2009 in Denmark and a match reference population were followed through hospital registries and medication prescriptions for early (<=30 days), intermediate (31 days to 6 months) and later (6 months to 2 years) depression in the acute coronary syndrome population and overall depression in the reference population. Cox regression models were used to compare hazard ratios (HRs) for depression over calendar years. Results During the study period, 11.0% and 6.2% were diagnosed with depression in the acute coronary syndrome population and in the reference population, respectively. For the acute coronary syndrome population, the adjusted HRs increased for early (HR (95% CI) 1.04 (1.01-1.06)) and intermediate depression (HR (95% CI) 1.01 (1.00-1.03)), whereas the adjusted HRs did not change for later depression (HR (95% CI) 0.99 (0.98-1.00)). For the reference population the adjusted HRs for depression increased through the study period (HR (95% CI) 1.01 (1.01-1.03)). Conclusion Increase in diagnoses of depressions within 6 months of acute coronary syndrome may be explained by increased focus on depression in this patient group in combination with increased awareness of depression in the general population. PMID- 26750514 TI - Microbial Fe(III) oxide reduction potential in Chocolate Pots hot spring, Yellowstone National Park. AB - Chocolate Pots hot springs (CP) is a unique, circumneutral pH, iron-rich, geothermal feature in Yellowstone National Park. Prior research at CP has focused on photosynthetically driven Fe(II) oxidation as a model for mineralization of microbial mats and deposition of Archean banded iron formations. However, geochemical and stable Fe isotopic data have suggested that dissimilatory microbial iron reduction (DIR) may be active within CP deposits. In this study, the potential for microbial reduction of native CP Fe(III) oxides was investigated, using a combination of cultivation dependent and independent approaches, to assess the potential involvement of DIR in Fe redox cycling and associated stable Fe isotope fractionation in the CP hot springs. Endogenous microbial communities were able to reduce native CP Fe(III) oxides, as documented by most probable number enumerations and enrichment culture studies. Enrichment cultures demonstrated sustained DIR driven by oxidation of acetate, lactate, and H2 . Inhibitor studies and molecular analyses indicate that sulfate reduction did not contribute to observed rates of DIR in the enrichment cultures through abiotic reaction pathways. Enrichment cultures produced isotopically light Fe(II) during DIR relative to the bulk solid-phase Fe(III) oxides. Pyrosequencing of 16S rRNA genes from enrichment cultures showed dominant sequences closely affiliated with Geobacter metallireducens, a mesophilic Fe(III) oxide reducer. Shotgun metagenomic analysis of enrichment cultures confirmed the presence of a dominant G. metallireducens-like population and other less dominant populations from the phylum Ignavibacteriae, which appear to be capable of DIR. Gene (protein) searches revealed the presence of heat-shock proteins that may be involved in increased thermotolerance in the organisms present in the enrichments as well as porin-cytochrome complexes previously shown to be involved in extracellular electron transport. This analysis offers the first detailed insight into how DIR may impact the Fe geochemistry and isotope composition of a Fe-rich, circumneutral pH geothermal environment. PMID- 26750516 TI - Analysis and prediction of drug-drug interaction by minimum redundancy maximum relevance and incremental feature selection. AB - Drug-drug interaction (DDI) defines a situation in which one drug affects the activity of another when both are administered together. DDI is a common cause of adverse drug reactions and sometimes also leads to improved therapeutic effects. Therefore, it is of great interest to discover novel DDIs according to their molecular properties and mechanisms in a robust and rigorous way. This paper attempts to predict effective DDIs using the following properties: (1) chemical interaction between drugs; (2) protein interactions between the targets of drugs; and (3) target enrichment of KEGG pathways. The data consisted of 7323 pairs of DDIs collected from the DrugBank and 36,615 pairs of drugs constructed by randomly combining two drugs. Each drug pair was represented by 465 features derived from the aforementioned three categories of properties. The random forest algorithm was adopted to train the prediction model. Some feature selection techniques, including minimum redundancy maximum relevance and incremental feature selection, were used to extract key features as the optimal input for the prediction model. The extracted key features may help to gain insights into the mechanisms of DDIs and provide some guidelines for the relevant clinical medication developments, and the prediction model can give new clues for identification of novel DDIs. PMID- 26750517 TI - Trypanosoma cruzi Proline Transport Presents a Cell Density-dependent Regulation. AB - Trypanosoma cruzi, the etiological agent of Chagas disease, uses proline as its main carbon source, essential for parasite growth and stage differentiation in epimastigotes and amastigotes. Since proline is mainly obtained from extracellular medium by transport proteins, in this work we studied the regulation of the T. cruzi proline transporter TcAAAP069. Proline uptake and intracellular concentration presented oscillations during epimastigote growth phases, increasing during the early exponential phase (322 pmol/min) and decreasing to undetectable levels during the late exponential phase. Transporter expression rate correlated with proline uptake, and its subcellular localization alternated from both, the plasma membrane and close to the flagellar pocket, when the transport is higher, to only the flagellar pocket region, when the transport decreased until proline uptake and TcAAAP069 protein became undetectable at the end of the growth curve. Interestingly, when parasites were treated with conditioned medium or were concentrated to artificially increase the culture density, the proline transport was completely abolished resembling the effects observed in late exponential phase. These data highlight for the first time the existence of a density-associated regulation of relevant physiological processes such as proline metabolism. PMID- 26750519 TI - Nanomaterial size distribution analysis via liquid nebulization coupled with ion mobility spectrometry (LN-IMS). AB - We apply liquid nebulization (LN) in series with ion mobility spectrometry (IMS, using a differential mobility analyzer coupled to a condensation particle counter) to measure the size distribution functions (the number concentration per unit log diameter) of gold nanospheres in the 5-30 nm range, 70 nm * 11.7 nm gold nanorods, and albumin proteins originally in aqueous suspensions. In prior studies, IMS measurements have only been carried out for colloidal nanoparticles in this size range using electrosprays for aerosolization, as traditional nebulizers produce supermicrometer droplets which leave residue particles from non-volatile species. Residue particles mask the size distribution of the particles of interest. Uniquely, the LN employed in this study uses both online dilution (with dilution factors of up to 10(4)) with ultra-high purity water and a ball-impactor to remove droplets larger than 500 nm in diameter. This combination enables hydrosol-to-aerosol conversion preserving the size and morphology of particles, and also enables higher non-volatile residue tolerance than electrospray based aerosolization. Through LN-IMS measurements we show that the size distribution functions of narrowly distributed but similarly sized particles can be distinguished from one another, which is not possible with Nanoparticle Tracking Analysis in the sub-30 nm size range. Through comparison to electron microscopy measurements, we find that the size distribution functions inferred via LN-IMS measurements correspond to the particle sizes coated by surfactants, i.e. as they persist in colloidal suspensions. Finally, we show that the gas phase particle concentrations inferred from IMS size distribution functions are functions of only of the liquid phase particle concentration, and are independent of particle size, shape, and chemical composition. Therefore LN IMS enables characterization of the size, yield, and polydispersity of sub-30 nm particles. PMID- 26750518 TI - Q-learning residual analysis: application to the effectiveness of sequences of antipsychotic medications for patients with schizophrenia. AB - Q-learning is a regression-based approach that uses longitudinal data to construct dynamic treatment regimes, which are sequences of decision rules that use patient information to inform future treatment decisions. An optimal dynamic treatment regime is composed of a sequence of decision rules that indicate how to optimally individualize treatment using the patients' baseline and time-varying characteristics to optimize the final outcome. Constructing optimal dynamic regimes using Q-learning depends heavily on the assumption that regression models at each decision point are correctly specified; yet model checking in the context of Q-learning has been largely overlooked in the current literature. In this article, we show that residual plots obtained from standard Q-learning models may fail to adequately check the quality of the model fit. We present a modified Q learning procedure that accommodates residual analyses using standard tools. We present simulation studies showing the advantage of the proposed modification over standard Q-learning. We illustrate this new Q-learning approach using data collected from a sequential multiple assignment randomized trial of patients with schizophrenia. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26750532 TI - Patient satisfaction after acute admission for psychosis. AB - Background Measuring patient satisfaction in mental health care potentially provides valuable information, but studies in acutely admitted psychosis patients are scarce. Aims The aims were to assess satisfaction among patients acutely admitted with psychosis, to compare satisfaction in voluntarily versus involuntarily admitted patients, and to assess the influence of symptom load and insight. Methods The UKU Consumer Satisfaction Rating Scale (UKU-ConSat) was used. A total of 104 patients completed the UKU-ConSat at discharge/follow-up (between 6-11 weeks after admittance if not discharged earlier) (mean duration of stay 4 weeks), thus corresponding to the end of the acute treatment phase. Results A total of 88.4% had total scores above zero (satisfied). Only three of the eight single items were statistically significantly different among patients admitted voluntarily versus involuntarily, and only the information item score remained significantly different in adjusted analyses. Insight level at admittance, and an increasing level of insight during the acute phase were positively associated with patient satisfaction, whereas levels and changes in positive and negative psychosis symptoms were indirectly related to satisfaction via this process of insight. Conclusions The vast majority of the acutely admitted patients were satisfied with treatment. There were few differences between the involuntarily and voluntarily admitted patient groups, except that the involuntary care group was clearly less satisfied with the information provided. Poor insight had a major negative impact on treatment satisfaction in psychosis. The provision of sufficient and adequate information is an important target for mental health care service improvement. PMID- 26750534 TI - An extended DFTB-CI model for charge-transfer excited states in cationic molecular clusters: model studies versus ab initio calculations in small PAH clusters. AB - We present an extension of the constrained density functional tight binding scheme combined with configuration interaction (DFTB-CI) to efficiently compute excited states of molecular cluster cations and their oscillator strengths from the ground state. The present extension consists of generalizing the initial model, relying on configurations with holes in the monomer HOMOs only, to configurations involving sub-HOMO holes, allowing for the description of higher excited states. The extended scheme is benchmarked on selected energy pathways with respect to available ab initio and new CASPT2 reference calculations on the benzene, naphthalene and pyrene dimer cations. The ability of the model to describe the potential energy surfaces and the transition dipole moments is discussed. The vertical electronic absorption spectra of the three dimer cations are calculated and compared with the theoretical litterature and available experimental data. Finally, the electronic absorption spectra of low energy isomers of the trimer and tetramer pyrene cluster cations are also predicted. PMID- 26750533 TI - Stomatin-like protein 2 overexpression in papillary thyroid carcinoma is significantly associated with high-risk clinicopathological parameters and BRAFV600E mutation. AB - Stomatin-like protein 2 (SLP-2), a member of the stomatin protein family, has emerged as a potential molecular hallmark of tumor progression in several human malignancies. The aim of this study was to analyze SLP-2 expression pattern in benign and malignant thyroid tumors (n = 210) and to examine its relationship with clinicopathological parameters and BRAFV600E mutation in thyroid cancer. SLP 2 immunohistochemical expression was not detected in benign adenomas and was absent/weak in follicular and anaplastic carcinomas. High expression levels of SLP-2, found only in papillary thyroid carcinoma (PTC), particularly in the classical variant, were significantly associated with adverse clinicopathological parameters: lymph node metastasis (p = 0.002), extrathyroid invasion (p < 0.001), pT status (p < 0.001), and advanced tumor stage (p = 0.001). Additional genotyping of PTC cases for the BRAFV600E mutation revealed for the first time a close relation between SLP-2 overexpression and the presence of BRAF mutation (p = 0.02) with high positive rates of lymph node metastasis (70%) and extrathyroid invasion (80%) in these cases. The significant association of SLP-2 overexpression with unfavorable clinicopathological characteristics and BRAFV600E mutation indicates that SLP-2 may have a role in aggressiveness of BRAF-mutated PTC and that SLP-2 evaluation could be clinically useful in identification of high-risk PTC patients. PMID- 26750535 TI - Integrating Si nanoscale building blocks into micro-sized materials to enable practical applications in lithium-ion batteries. AB - This article highlights recent advances in micro-sized silicon anode materials composed of silicon nanoscale building blocks for lithium-ion batteries. These materials show great potential in practical applications since they combine good cycling stability, high rate performance, and high volumetric capacity. Different preparation methods are introduced and the features and performance of the resulting materials are discussed. Key take-away points are interspersed through the discussion, including comments on the roles of the nanoscale building blocks. Finally, we discuss current challenges and provide an outlook for future development of micro-sized silicon-based anode materials. PMID- 26750536 TI - IL-6 mediates the signal pathway of JAK-STAT3-VEGF-C promoting growth, invasion and lymphangiogenesis in gastric cancer. AB - Gastric cancer shows the highest invasive and metastasis features, especially lymph metastasis, which is closely associated with poor prognosis of gastric cancer. Although there is evidence that interleukin-6 (IL-6) can promote gastric cancer progression, the underlying specific mechanisms and the mechanisms of gastric cancer lymphangiogenesis are largely unknown. In the present study, we explore whether IL-6 could promote the proliferation and invasion activity of gastric cancer cells, and whether IL-6 mediating VEGF-C production affected the lymphangiogenesis in gastric cancer cells. Our results revealed that IL-6 and its receptors (IL-6 and gp130) are broadly expressed in various gastric cancer cell lines including SGC-7901, MGC, MKN-28 and AGS. Exogenous IL-6 increased the ability of gastric cancer cell proliferation and invasion, which could be weakened by AG490. in addition, exogenous IL-6 promoted the VEGF-C production of gastric cancer cells and the lymphangiogenesis of HDLECs. As we expected, AG490 was able to reduce these effects. Western blot analysis showed that IL-6 increased JKA, STAT3, p-STAT3 and VEGF-C protein levels in the gastric cancer cells. However, the JKA, STAT3, p-STAT3 and VEGF-C protein expression levels were inhibited by AG490. Our data suggested that IL-6 mediates the singnal pathway of JAK-STAT3-VEGF-C promoting the growth, invasion and lymphangiogenesis in gastric cancer. Thus, IL-6 and its related signal pathways may be a promising target for treatment of gastric cancer growth and lymphangiogenesis. PMID- 26750537 TI - Forced desorption of semiflexible polymers, adsorbed and driven by molecular motors. AB - We formulate and characterize a model to describe the dynamics of semiflexible polymers in the presence of activity due to motor proteins attached irreversibly to a substrate, and a transverse pulling force acting on one end of the filament. The stochastic binding-unbinding of the motor proteins and their ability to move along the polymer generate active forces. As the pulling force reaches a threshold value, the polymer eventually desorbs from the substrate. Performing underdamped Langevin dynamics simulation of the polymer, and with stochastic motor activity, we obtain desorption phase diagrams. The correlation time for fluctuations in the desorbed fraction increases as one approaches complete desorption, captured quantitatively by a power law spectral density. We present theoretical analysis of the phase diagram using mean field approximations in the weakly bending limit of the polymer and performing linear stability analysis. This predicts an increase in the desorption force with the polymer bending rigidity, active velocity and processivity of the motor proteins to capture the main features of the simulation results. PMID- 26750539 TI - CdSe/ZnS quantum dots as sensors for the local refractive index. AB - We explore the potential of CdSe/ZnS colloidal quantum dots (QDs) as probes for their immediate dielectric environment, based on the influence of the local refractive index on the fluorescence dynamics of these nanoemitters. We first compare ensembles of quantum dots in homogeneous solutions with single quantum dots dispersed on various dielectric substrates, which allows us to test the viability of a conceptual framework based on a hard-sphere region-of-influence and the Bruggeman effective-medium approach. We find that all our measurements can be integrated into a coherent description, provided that the conceptualized point-dipole emitter is positioned at a distance from the substrate that corresponds to the geometry of the QD. Three theoretical models for the evolution of the fluorescence decay rate as a function of the local refractive index are compared, showing that the classical Lorentz approach (virtual cavity) is the most appropriate for describing the data. Finally, we use the observed sensitivity of the QDs to their environment to estimate the detection limit, expressed as the minimum number of traceable streptavidin molecules, of a potential QD-nanosensor based on fluorescence lifetime. PMID- 26750540 TI - Electrochemical comportment of Ni-Ti alloys immersed in two types of artificial saliva. AB - The main objective of this work was to study the electrochemical behavior of Ni Ti alloy immersed in two types of artificial saliva: neutral saliva (Ringer's solution, pH = 7.4) and acidic saliva (Fusayama solution pH ~ 2.3). This study was conducted by the application of various electrochemical methods [monitoring of the corrosion potential over time; E = f(t), polarization curves; j = f(E), and electrochemical impedance spectroscopy EIS]. The overall results showed that the acidification of the saliva and/or the increase of its temperature causes the ignition of the corrosion phenomena of the Ni-Ti alloy. Indeed, the corrosion rate increases significantly with increasing temperature and the decreasing of the pH medium. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 778-784, 2017. PMID- 26750538 TI - Diagnosis and Management of Childhood Headache. AB - Headache is one of the most common chief complaints seen in the pediatrician's office. Oftentimes, identifying the etiology of headache and differentiating primary and secondary causes can present a diagnostic conundrum. Understanding the most common causes of primary and secondary headache is vital to making a correct diagnosis. Here we review the typical presentations of the most common primary headache disorders and the approach to evaluation of the pediatric patient presenting with headache. Diagnostic workup, including the key features to elicit on physical examination, when to order head imaging, and the use of other ancillary tests, is discussed. Current treatment modalities and their indications are reviewed. We will also describe some of the new, emerging therapies that may alter the way we manage headache in the pediatric population. Headache can, at times, be a frustrating symptom seen in the pediatrician's office, but here we hope to better elucidate the approach to evaluation, management, and treatment as well as provide some hope in regards to more effective upcoming therapies. PMID- 26750541 TI - Evaluation of the internal and external responsiveness of the Pressure Ulcer Scale for Healing (PUSH) tool for assessing acute and chronic wounds. AB - AIM: To examine the internal and external responsiveness of the Pressure Ulcer Scale for Healing (PUSH) tool for assessing the healing progress in acute and chronic wounds. BACKGROUND: It is important to establish the responsiveness of instruments used in conducting wound care assessments to ensure that they are able to capture changes in wound healing accurately over time. DESIGN: Prospective longitudinal observational study. METHOD: The key study instrument was the PUSH tool. Internal responsiveness was assessed using paired t-testing and effect size statistics. External responsiveness was assessed using multiple linear regression. All new patients with at least one eligible acute or chronic wound, enrolled in the Nurse and Allied Health Clinic-Wound Care programme between 1 December 2012 - 31 March 2013 were included for analysis (N = 541). RESULTS: Overall, the PUSH tool was able to detect statistically significant changes in wound healing between baseline and discharge. The effect size statistics were large. The internal responsiveness of the PUSH tool was confirmed in patients with a variety of different wound types including venous ulcers, pressure ulcers, neuropathic ulcers, burns and scalds, skin tears, surgical wounds and traumatic wounds. After controlling for age, gender and wound type, subjects in the 'wound improved but not healed' group had a smaller change in PUSH scores than those in the 'wound healed' group. Subjects in the 'wound static or worsened' group had the smallest change in PUSH scores. The external responsiveness was confirmed. CONCLUSION: The internal and external responsiveness of the PUSH tool confirmed that it can be used to track the healing progress of both acute and chronic wounds. PMID- 26750542 TI - Phosphorescence quenching of fac-tris(2-phenylpyridyl)iridium(iii) complexes in thin films on dielectric surfaces. AB - We study the influence of the film thickness on the time-resolved phosphorescence and the luminescence quantum yield of fac-tris(2-phenylpyridyl)iridium(iii) [Ir(ppy)3]-cored dendrimers deposited on dielectric substrates. A correlation is observed between the surface quenching velocity and the quenching rate by intermolecular interactions in the bulk film, which suggests that both processes are controlled by dipole-dipole interactions between Ir(ppy)3 complexes at the core of the dendrimers. It is also found that the surface quenching velocity decreases as the refractive index of the substrate is increased. This can be explained by partial screening of dipole-dipole interactions by the dielectric environment. PMID- 26750543 TI - Comparison of pi-hole tetrel bonding with sigma-hole halogen bonds in complexes of XCN (X = F, Cl, Br, I) and NH3. AB - In addition to the standard halogen bond formed when NH3 approaches XCN (X = F, Cl, Br, I) along its molecular axis, a perpendicular approach is also possible, toward a pi-hole that is present above the X-C bond. MP2/aug-cc-pVDZ calculations indicate the latter geometry is favored for X = F, and the sigma-hole structure is preferred for the heavier halogens. The pi-hole structure is stabilized by charge transfer from the NH3 lone pair into the pi*(CN) antibonding orbital, and is characterized by a bond path from the N of NH3 to the C atom of XCN, a form of tetrel bond. The most stable 2 : 1 NH3/XCN heterotrimer for X = F and Cl is cyclic and contains a tetrel bond augmented by a pair of NHN H-bonds. For X = Br and I, the favored trimer is noncyclic, stabilized by a tetrel and a halogen bond. PMID- 26750552 TI - Radiation dose produced by patients during radiopharmaceutical incorporation in nuclear medicine diagnostic procedures. AB - OBJECTIVES: The aim of this study was to assess the dose received by members of the public due to close contact with patients undergoing nuclear medicine procedures during radiopharmaceutical incorporation, and comparing it with the emitted radiation dose when the test was complete, in order to establish recommendations. MATERIAL AND METHODS: A prospective study was conducted on 194 patients. H*(10) dose rates were measured at 0.1, 0.5, and 1.0m after the radiopharmaceutical administration, before the image acquisition, and at the end of the nuclear medicine procedure. Effective dose for different close contact scenarios were calculated, according to 95th percentile value (bone scans) and the maximum value (remaining tests). RESULTS: During the radiopharmaceutical incorporation, a person who stays with another injected patient in the same waiting room may receive up to 0.59 mSv. If the patient had a medical appointment, or went to a restaurant or a coffee shop, members of the public could receive 23, 43, and 22 MUSv, respectively. After finishing the procedure, these doses are reduced by a factor 3. In most of the studies, the use of private instead of public transport may reduce the dose by more than a factor 6. CONCLUSION: It is recommended to increase the distance between the patients during the radiopharmaceutical incorporation and to distribute them according to the diagnostic procedure. Patients should be encouraged to use private instead of public transport. Depending on the number of nuclear medicine outpatients per year attended by a physician, it could be necessary to apply restrictions. PMID- 26750554 TI - Ultrasound-accelerated organogel: application for visual discrimination of Hg(2+) from Ag(+). AB - A new kind of naphthalimide-based organogelator, TN, was designed and synthesized. The intramolecular guanylation of TN promoted by Hg(2+) or Ag(+) in both solution and gel state was studied through several approaches including FL, UV-visible, NMR, FT-IR and SEM experiments. TN could selectively sense Hg(2+) and Ag(+) ions with obvious fluorescence quenching and color changes from yellow to colorless among test ions in the solution state. Interestingly, the S-gel of TN could be used to selectively discriminate Hg(2+) from Ag(+)via phase and morphology changes. Hg(2+) ions triggered the gel-to-gel transition with morphology changes of the TN S-gel from nanofibrils to porous sheet structure, together with fluorescence quenching. In contrast, the gel collapsed in the presence of Ag(+) ions, which was comprised of short and disordered fiber structure. To the best of the authors' knowledge, this is the first example of gels selectively sensing Hg(2+) or Ag(+)via a reaction approach. PMID- 26750553 TI - Bone scintigraphy as cornerstone in the diagnosis of Erdheim-Chester disease. AB - The Erdheim-Chester disease (ECD) is an extremely rare form of non-Langerhans cell histiocytosis. The main difficulty for its diagnosis lies in the wide variety of non-specific symptoms and signs that can occur in the disease process, leading, therefore, to there being no clear-cut algorithm as a guide for an optimal biopsy to confirm the diagnosis. An 81-year-old male with history of diabetes insipidus was admitted due to non-specific respiratory signs. Imaging techniques revealed osteoblastic lesions in the lumbar spine. Whole-body bone scintigraphy (BS) was performed, in which lesions involving the axial and appendicular skeleton, with different rates of osteoblastic activity, were observed. This highlighted a symmetrical severely intense uptake in the knees, leading to an accurate biopsy specimen that enabled making the definitive diagnosis. BS is a widely available, safe, and inexpensive technique that shows a characteristic pattern of uptake for ECD, thus its use is highly recommended for screening and guiding biopsy if clinical suspicion exists. Furthermore, when the scintigraphy pattern is incidentally observed, biopsy of increased uptake areas (tibia preferably) is mandatory in order to rule out the disease. PMID- 26750555 TI - Facile Peptides Functionalization of Lanthanide-Based Nanocrystals through Phosphorylation Tethering for Efficient in Vivo NIR-to-NIR Bioimaging. AB - Peptide modification of nanoparticles is a challenging task for bioapplications. Here, we show that noncovalent surface engineering based on ligand exchange of peptides for lanthanide based upconversion and downconversion near-infrared (NIR) luminescent nanoparticles can be efficiently realized by modifying the hydroxyl functional group of a side grafted serine of peptides into a phosphate group (phosphorylation). By using the phosphorylated peptide with the arginine-glycine aspartic acid (RGD) targeting motifs as typical examples, the modification allows improving the selectivity, sensitivity, and signal-to-noise ratio for the cancer targeting and bioimaging and reducing the toxicity derived from nonspecific interactions of nanoparticles with cells. The in vivo NIR bioimaging signal could even be detected at low injection amounts down to 20 MUg per animal. PMID- 26750557 TI - Low-photon-number optical switch and AND/OR logic gates based on quantum dot bimodal cavity coupling system. AB - We propose a new scheme based on quantum dot-bimodal cavity coupling system to realize all-optical switch and logic gates in low-photon-number regime. Suppression of mode transmission due to the destructive interference effect is theoretically demonstrated by driving the cavity with two orthogonally polarized pulsed lasers at certain pulse delay. The transmitted mode can be selected by designing laser pulse sequence. The optical switch with high on-off ratio emerges when considering one driving laser as the control. Moreover, the AND/OR logic gates based on photon polarization are achieved by cascading the coupling system. Both proposed optical switch and logic gates work well in ultra-low energy magnitude. Our work may enable various applications of all-optical computing and quantum information processing. PMID- 26750558 TI - CHANGING FACE OF MEDICARE'S NATIONAL COVERAGE DETERMINATIONS FOR TECHNOLOGY. AB - OBJECTIVES: The Centers for Medicare and Medicaid Services (CMS) issues National Coverage Determinations (NCDs) for medical interventions expected to have a significant impact on Medicare, the health insurance program for US citizens aged 65 years and older and certain people with disabilities under the age of 65 years. The objective of this study was to evaluate NCDs issued from 1999 to 2013 to identify key trends, and to discuss implications for future CMS policy. METHODS: We used the Tufts Medical Center Medicare National Coverage Determination Database to examine characteristics of NCDs from 1999 through 2013. We examined various characteristics of NCDs, including: whether the intervention under review is used for prevention or treatment of disease, the type of intervention considered, evidence limitations cited by CMS, and coverage determination outcome. We evaluated longitudinal trends in categorical and continuous variables in the database, using Cochran-Armitage trend tests and linear regression, respectively. RESULTS: We found that NCDs increasingly focus on preventive care (p = 0.072), pertain to diagnostic imaging (p = 0.033), and evaluate health education/behavioral therapy interventions (p = 0.051). CMS increasingly cites the lack of relevant outcomes (p = 0.019) and the lack of applicability of study results to the Medicare population (p < 0.001) as evidence limitations. CMS less often restricts coverage to certain population subgroups in NCDs (p < 0.001), but increasingly applies coverage with evidence development policies (p < 0.001). CONCLUSIONS: Identified trends reflect broader changes in Medicare as CMS shifts its focus from treatment to prevention of disease, addresses potentially overutilized technologies, and attempts to issue flexible coverage policies. PMID- 26750559 TI - Evidence for contact calls in fish: conspecific vocalisations and ambient soundscape influence group cohesion in a nocturnal species. AB - Soundscapes provide a new tool for the study of fish communities. Bigeyes (Pempheris adspersa) are nocturnal planktivorous reef fish, feed in loose shoals and are soniferous. These vocalisations have been suggested to be contact calls to maintain group cohesion, however direct evidence for this is absent, despite the fact that contact calls are well documented for many other vertebrates, including marine mammals. For fish, direct evidence for group cohesion signals is restricted to the use of visual and hydrodynamic cues. In support of adding vocalisation as a contributing cue, our laboratory experiments show that bigeyes significantly increased group cohesion when exposed to recordings of ambient reef sound at higher sound levels while also decreasing vocalisations. These patterns of behaviour are consistent with acoustic masking. When exposed to playback of conspecific vocalisations, the group cohesion and vocalisation rates of bigeyes both significantly increased. These results provide the first direct experimental support for the hypotheses that vocalisations are used as contact calls to maintain group cohesion in fishes, making fish the evolutionarily oldest vertebrate group in which this phenomenon has been observed, and adding a new dimension to the interpretation of nocturnal reef soundscapes. PMID- 26750560 TI - Do Rheumatoid Arthritis Patients Rate their Health Status Different than their Caregivers? AB - OBJECTIVE: To compare the ratings given by the caregivers regarding the health status of their rheumatoid arthritis (RA) patients to those recorded by the patients themselves and to assess the effect of caring for a patient with RA on the mental health of the caregiver. METHODS: This is a non-interventional, cross sectional, multi-center epidemiological study conducted at the outpatient clinics of two hospitals in Saudi Arabia. The patients included were diagnosed with RA, over 18 years of age with 1-5 years of disease duration, and all had an identifiable single caregiver who was willing to participate in the study. RESULTS: 40 patients of whom 92.5% were women and the mean age of 44.6 years. The mean visual analogue scale (VAS) score was 4.98 for general health. The mean Health Assessment Questionnaire (HAQ) for the patients according to themselves was 1.31 (+/-0.68), while that stated by caregivers was 1.40 (+/-0.69); thus, the mean scores given by the caregivers was 0.091 points higher than that provided by the patients themselves (95% confidence interval [CI], 0.167-0.014) (p=0.0214). Further, 43% of the caregivers gave higher HAQ scores to their related patients than the patients themselves, while 30% gave similar HAQ scores. The caregivers scored a mean of 21 points in the Zarit Burden Interview (+/-12.1), with 47.5% reporting mild to moderate burden, and 5% reporting moderate to severe burden. CONCLUSION: RA patients showed a tendency to understate their disease burden and as compared to that observed by caregivers who suffer from considerable level of burden. PMID- 26750556 TI - Comprehensive maternal serum proteomics identifies the cytoskeletal proteins as non-invasive biomarkers in prenatal diagnosis of congenital heart defects. AB - Congenital heart defects (CHDs) are the most common group of major birth defects. Presently there are no clinically used biomarkers for prenatally detecting CHDs. Here, we performed a comprehensive maternal serum proteomics assessment, combined with immunoassays, for the discovery of non-invasive biomarkers for prenatal diagnosis of CHDs. A total of 370 women were included in this study. An isobaric tagging for relative and absolute quantification (iTRAQ) proteomic approach was used first to compare protein profiles in pooled serum collected from women who had CHD-possessing or normal fetuses, and 47 proteins displayed significant differential expressions. Targeted verifications were performed on 11 proteins using multiple reaction monitoring mass spectrometry (MRM-MS), and the resultant candidate biomarkers were then further validated using ELISA analysis. Finally, we identified a biomarker panel composed of 4 cytoskeletal proteins capable of differentiating CHD-pregnancies from normal ones [with an area under the receiver operating characteristic curve (AUC) of 0.938, P < 0.0001]. The discovery of cytoskeletal protein changes in maternal serum not only could help us in prenatal diagnosis of CHDs, but also may shed new light on CHD embryogenesis studies. PMID- 26750562 TI - Response to Comment on "Neonicotinoid Residues in Wildflowers, A Potential Route of Chronic Exposure for Bees". PMID- 26750561 TI - Network-Based Comparative Analysis of Arabidopsis Immune Responses to Golovinomyces orontii and Botrytis cinerea Infections. AB - A comprehensive exploration of common and specific plant responses to biotrophs and necrotrophs is necessary for a better understanding of plant immunity. Here, we compared the Arabidopsis defense responses evoked by the biotrophic fungus Golovinomyces orontii and the necrotrophic fungus Botrytis cinerea through integrative network analysis. Two time-course transcriptional datasets were integrated with an Arabidopsis protein-protein interaction (PPI) network to construct a G. orontii conditional PPI sub-network (gCPIN) and a B. cinerea conditional PPI sub-network (bCPIN). We found that hubs in gCPIN and bCPIN played important roles in disease resistance. Hubs in bCPIN evolved faster than hubs in gCPIN, indicating the different selection pressures imposed on plants by different pathogens. By analyzing the common network from gCPIN and bCPIN, we identified two network components in which the genes were heavily involved in defense and development, respectively. The co-expression relationships between interacting proteins connecting the two components were different under G. orontii and B. cinerea infection conditions. Closer inspection revealed that auxin-related genes were overrepresented in the interactions connecting these two components, suggesting a critical role of auxin signaling in regulating the different co-expression relationships. Our work may provide new insights into plant defense responses against pathogens with different lifestyles. PMID- 26750563 TI - Thermal and Electrical Conduction of Single-crystal Bi2Te3 Nanostructures grown using a one step process. AB - Single-crystal Bi2Te3 nanowires (NWs) and nanoribbons (NRs) were synthesized by a vapor-liquid-solid (VLS) method from Bi2Te3 powder. To investigate the thermal properties of the Bi2Te3 nanostructure, a nondestructive technique based on temperature dependent Raman mapping was carried out. The Raman peaks were red shifted with increasing temperature. In addition, the fraction of the laser power absorbed inside the Bi2Te3 nanostructures was estimated by optical simulation and used to calculate the thermal conductivity value (kappa). The thermal conductivity value obtained for the Bi2Te3 NW and NR was 1.47 Wm(-1)K(-1) and 1.81 Wm(-1)K(-1) at 300 K, respectively. The electrical conductivity of the Bi2Te3 nanostructure was also measured. In particular, an excellent electrical conductivity value of 1.22 * 10(3 )Omega(-1) cm(-1) was obtained for the Bi2Te3 NW at 300 K. This result can be attributed to topological insulator surface states. As a result of our study, the figure of merit (ZT) for the Bi2Te3 NW and NR can be significantly improved. PMID- 26750565 TI - Magnetic Phase Formation in Self-Assembled Epitaxial BiFeO3-MgO and BiFeO3 MgAl2O4 Nanocomposite Films Grown by Combinatorial Pulsed Laser Deposition. AB - Self-assembled epitaxial BiFeO3-MgO and BiFeO3-MgAl2O4 nanocomposite thin films were grown on SrTiO3 substrates by pulsed laser deposition. A two-phase columnar structure was observed for BiFeO3-MgO codeposition within a small window of growth parameters, in which the pillars consisted of a magnetic spinel phase (Mg,Fe)3O4 within a BiFeO3 matrix, similar to the growth of BiFeO3-MgFe2O4 nanocomposites reported elsewhere. Further, growth of a nanocomposite with BiFeO3 (CoFe2O4/MgO/MgFe2O4), in which the minority phase was grown from three different targets, gave spinel pillars with a uniform (Mg,Fe,Co)3O4 composition due to interdiffusion during growth, with a bifurcated shape from the merger of neighboring pillars. BiFeO3-MgAl2O4 did not form a well-defined vertical nanocomposite in spite of having lower lattice mismatch, but instead formed a two phase film with in which the spinel phase contained Fe. These results illustrate the redistribution of Fe between the oxide phases during oxide codeposition to form a ferrimagnetic phase from antiferromagnetic or nonmagnetic targets. PMID- 26750567 TI - Topological Model for the Search of New Antibacterial Drugs. 158 Theoretical Candidates. AB - In this paper, molecular topology was used to develop a mathematical model capable of classifying compounds according to their antibacterial activity. Topological indices were used as structural descriptors and their relation to antibacterial activity was determined by applying linear discriminant analysis (LDA) on a group of quinolones, widely used nowadays because of their broad spectrum of activity, well tolerance profile and advantageous pharmacokinetic properties. The topological model of activity obtained included two discriminant functions, selected by a combination of various statistical paremeters such as Fisher-Snedecor F and Wilk's lambda, and allows the reliable prediction of antibacterial activity in any organic compound. After a virtual pharmacological screening on a library of 6375 compounds, the model has selected 263 as active compounds, from which 40% have proven antibacterial activity. The results obtained clearly reveal the high efficiency of molecular topology for the prediction of pharmacological activities. These models are very helpful in the discovery of new applications of natural and synthetic molecules with different chemical or biological properties. Therefore, we finally present 158 strong candidates to be developed as novel antibacterials. PMID- 26750564 TI - Downregulation of Organic Anion Transporting Polypeptide (OATP) 1B1 Transport Function by Lysosomotropic Drug Chloroquine: Implication in OATP-Mediated Drug Drug Interactions. AB - Organic anion transporting polypeptide (OATP) 1B1 mediates the hepatic uptake of many drugs including lipid-lowering statins. Decreased OATP1B1 transport activity is often associated with increased systemic exposure of statins and statin induced myopathy. Antimalarial drug chloroquine (CQ) is also used for long-term treatment of rheumatoid arthritis and systemic lupus erythematosus. CQ is lysosomotropic and inhibits protein degradation in lysosomes. The current studies were designed to determine the effects of CQ on OATP1B1 protein degradation, OATP1B1-mediated transport in OATP1B1-overexpressing cell line, and statin uptake in human sandwich-cultured hepatocytes (SCH). Treatment with lysosome inhibitor CQ increased OATP1B1 total protein levels in HEK293-OATP1B1 cells and in human SCH as determined by OATP1B1 immunoblot. In HEK293-FLAG-tagged OATP1B1 stable cell line, co-immunofluorescence staining indicated that intracellular FLAG OATP1B1 is colocalized with lysosomal associated membrane glycoprotein (LAMP)-2, a marker protein of late endosome/lysosome. Enlarged LAMP-2-positive vacuoles with FLAG-OATP1B1 protein retained inside were readily detected in CQ-treated cells, consistent with blocking lysosomal degradation of OATP1B1 by CQ. In HEK293 OATP1B1 cells, without pre-incubation, CQ concentrations up to 100 MUM did not affect OATP1B1-mediated [(3)H]E217G accumulation. However, pre-incubation with CQ at clinically relevant concentration(s) significantly decreased [(3)H]E217G and [(3)H]pitavastatin accumulation in HEK293-OATP1B1 cells and [(3)H]pitavastatin accumulation in human SCH. CQ pretreatment (25 MUM, 2 h) resulted in ~1.9-fold decrease in Vmax without affecting Km of OATP1B1-mediated [(3)H]E217G transport in HEK293-OATP1B1 cells. Pretreatment with monensin and bafilomycin A1, which also have lysosome inhibition activity, significantly decreased OATP1B1-mediated transport in HEK293-OATP1B1 cells. Pharmacoepidemiologic studies using data from the U.S. Food and Drug Administration Adverse Event Reporting System indicated that CQ plus pitavastatin, rosuvastatin, and pravastatin, which are minimally metabolized by the cytochrome P450 enzymes, led to higher myopathy risk than these statins alone. In summary, the present studies report novel findings that lysosome is involved in degradation of OATP1B1 protein and that pre-incubation with lysosomotropic drug CQ downregulates OATP1B1 transport activity. Our in vitro data in combination with pharmacoepidemiologic studies support that CQ has potential to cause OATP-mediated drug-drug interactions. PMID- 26750566 TI - Vitamin D deficiency is associated with increased human sinonasal fibroblast proliferation in chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: Vitamin D3 (VD3) is a steroid hormone with known antiproliferative properties. Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have been shown to be VD3-deficient. Moreover, VD3 deficiency is associated with worse disease in patients with CRSwNP. One cell type thought to play a role in chronic rhinosinusitis (CRS) is the human sinonasal fibroblast (HSNF). The aim of this study was to investigate VD3 deficiency and HSNF proliferation in CRSwNP. METHODS: Blood and sinus tissue explants were collected at the time of surgery from patients with CRSwNP (n = 15). Control subjects (n = 12) were undergoing surgery for cerebrospinal fluid leak repair or to remove non-hormone-secreting pituitary tumors. Ex vivo HSNF proliferation was analyzed with flow cytometry using expression of fibroblast-specific protein (FSP) and the proliferation marker Ki67. Plasma levels of 25-hydroxyvitamin D3 (25VD3) were measured by enzyme-linked immunosorbent assay. In vitro analysis of HSNF proliferation after treatment with calcitriol (1,25VD3) was performed using carboxyfluorescein succinimidyl ester (CFSE) and analyzed with flow cytometry. RESULTS: In CRSwNP patients there was an inverse correlation between 25VD3 and proliferating HSNFs (p = 0.0135). This correlation was not seen for control patients (p = 0.3869). In vitro analysis showed that HSNFs from patients with CRSwNP had a higher proliferation index at baseline than HSNFs from control patients (p < 0.01). When treated with 1,25VD3, there was a significant decrease in HSNF proliferation index in patients with CRSwNP (p < 0.01), but not control patients. CONCLUSION: VD3 deficiency is associated with increased HSNF proliferation in CRSwNP. Further investigation into how HSNFs and VD3 impact CRSwNP pathophysiology is warranted. PMID- 26750570 TI - Histological verification of the prehypogastric and ovarian ganglia confirms a bilaterally symmetrical organization of the ganglia comprising the aortic plexus in female human cadavers. AB - The aortic plexus is a network of sympathetic nerves positioned along the infrarenal abdominal aorta. Recently, we characterized the aortic plexus and its ganglia (inferior mesenteric, left/right spermatic, and prehypogastric ganglion) in males; however, the literature minimally describes its anatomy in females. In the present study, we conducted the first histological examination of the left and right ovarian ganglia, while also investigating whether females, like males, exhibit a prehypogastric ganglion. The ganglia were dissected from embalmed (n = 32) and fresh (n = 1) human cadavers, and H&E staining was used to confirm the presence of a left ovarian ganglion in 31/31 specimens, a right ovarian ganglion in 29/29 specimens and a prehypogastric ganglion in 25/28 specimens. Comparable to the topographic arrangement in males, there is a bilateral organization of the ganglia comprising the aortic plexus in females. More specifically, the left and right ovarian ganglia were positioned in close relation to their respective ovarian artery, whereas the prehypogastric ganglion was positioned within the right cord of the aortic plexus, contralateral to the inferior mesenteric ganglion. Using immunohistochemistry, it was shown that all ganglia from the fresh cadaver stained positive for tyrosine hydroxylase, thereby confirming their sympathetic nature. Having provided the first topographical and histological characterization of the ovarian and prehypogastric ganglia in females, future studies should seek to determine their specific function. PMID- 26750569 TI - Associations between smoking and caffeine consumption in two European cohorts. AB - AIMS: To estimate associations between smoking initiation, smoking persistence and smoking heaviness and caffeine consumption in two population-based samples from the Netherlands and the United Kingdom. DESIGN: Observational study employing data on self-reported smoking behaviour and caffeine consumption. SETTING: Adults from the general population in the Netherlands and the United Kingdom. PARTICIPANTS: Participants from the Netherlands Twin Register [NTR: n = 21 939, mean age 40.8, standard deviation (SD) = 16.9, 62.6% female] and the Avon Longitudinal Study of Parents and Children (ALSPAC: n = 9086, mean age 33.2, SD = 4.7, 100% female). MEASUREMENTS: Smoking initiation (ever versus never smoking), smoking persistence (current versus former smoking), smoking heaviness (number of cigarettes smoked) and caffeine consumption in mg per day through coffee, tea, cola and energy drinks. FINDINGS: After correction for age, gender (NTR), education and social class (ALSPAC), smoking initiation was associated with consuming on average 52.8 [95% confidence interval (CI) = 45.6-60.0; NTR] and 59.5 (95% CI = 51.8-67.2; ALSPAC) mg more caffeine per day. Smoking persistence was also associated with consuming more caffeine [+57.9 (95% CI = 45.2-70.5) and +83.2 (95% CI = 70.2-96.3) mg, respectively]. Each additional cigarette smoked per day was associated with 3.7 (95% CI = 1.9-5.5; NTR) and 8.4 (95% CI = 6.9 10.0; ALSPAC) mg higher daily caffeine consumption in current smokers. Smoking was associated positively with coffee consumption and less strongly with cola and energy drinks. For tea, associations were positive in ALSPAC and negative in NTR. CONCLUSIONS: There appears to be a positive association between smoking and caffeine consumption in the Netherlands and the United Kingdom. PMID- 26750571 TI - Prevalence of Borrelia miyamotoi in Ixodes persulcatus in Irkutsk City and its neighboring territories, Russia. AB - Adult Ixodes persulcatus were collected in highly populated districts in Irkutsk city, Russia, and in popular recreational and professional areas in its neighboring territories. Borrelia miyamotoi infection in I. persulcatus was examined using multiplex Taqman-PCR targeting 16S rDNA, and nested PCR and sequencing analyses targeting flaB and 16S rDNA. B. miyamotoi and Lyme disease Borrelia species were detected in 13 (infection rate, 2.9%) and 77 (17.3%) out of 445 I. persulcatus ticks, respectively, collected from 4 sites around the Baikal Lake. The 16S rDNA and flaB sequences of these amplicons were closely related to those of B. miyamotoi detected and/or isolated from I. persulcatus in Japan and Far Eastern Russia, and clustered separately from those of Europe and North America. These results indicate that additional surveillance for B. miyamotoi infection is needed in order to determine how it affects human health in Irkutsk City and its neighboring territories. PMID- 26750572 TI - Antidepressants and, suicide and self-injury: Causal or casual association? AB - OBJECTIVE: The causal relationship between antidepressants and the increase of self-injury and suicide in the paediatric age is highly debated. The black-box warnings about increased risks of suicidal thinking and behaviour in children and young adults, led to a reduction in both treatment and diagnosis of depression also in adults, in the face of an increasing need for therapies. The debate originates also from contrasting reports in the literature. METHODS: We carried out an interpretative review of the most recent reports (2012-2014), from which three topics emerged. RESULTS: First, the presence of populations with different baseline risks of self-injury among published works introduced bias in the results. Second, the application of inappropriate or excessively variegated outcome measures for self-injury introduced confounding factors that prevent the successful conduction of meta-analyses. This hinders constructive debate involving different groups, as shown in the correspondence by senior authors in the field. Third, the regulatory actions that limited the prescription of antidepressants were taken in perspective of scientific advances, not yet due. This turned temporary cautions into long-lasting limitations. CONCLUSIONS: While some clinical improvements can already be suggested, only the fulfilment of this debate will allow to revise the black-box warnings and to improve the antidepressant therapies. PMID- 26750573 TI - Recent advances in multifunctional silica-based hybrid nanocarriers for bioimaging and cancer therapy. AB - In recent years, there has been a considerable research focus on integrating cancer cell imaging and therapeutic functions into single nanoscale platforms for better treatment of cancer. This task could often be achieved by incorporating multiple components into a hybrid nanosystem. In this minireview, we highlight different types of silica-based hybrid nanosystems and their recent applications as integrated multifunctional platforms for cancer imaging and treatment. The discussions are divided into several sections focusing on various types of materials employed to integrate with silica, which include silica-metallic nanoparticle based hybrid nanocarriers, silica-gold nanoparticle based hybrid nanocarriers, silica-quantum dot based hybrid nanocarriers, silica-upconversion nanoparticle based hybrid nanocarriers, silica-carbon based hybrid nanocarriers, and organosilica nanocarriers. Therapeutic agents loaded in such hybrids include chemodrugs, proteins, DNA/RNA and photosensitizers. For targeted delivery into tumor sites, targeting ligands such as antibodies, peptides, aptamers, and other small molecules are grafted on the surface of the nanocarriers. At the end of the review, a brief summary and research outlook are presented. This minireview aims to provide a quick update of recent research achievements in the field. PMID- 26750574 TI - Correlation between cardio-ankle vascular index and biomarkers of oxidative stress. AB - Arterial stiffness is a pathological event related to arteriosclerosis that is also closely related to oxidative stress. The cardio-ankle vascular index (CAVI) is a novel arteriosclerotic index that has been used to detect arterial stiffness. However, the association between CAVI and oxidative stress has not yet been elucidated, especially in patients with risk of metabolic disorders. The aim of this study was to investigate the correlation between arterial stiffness by CAVI and biomarkers of oxidative stress. A total of 83 participants were enrolled in this study. Venous blood samples were collected for measurement of plasma oxidative biomarkers. All participants were examined for CAVI score. The univariate analysis showed that age (p < 0.001), systolic blood pressure (SBP) (p = < 0.001), plasma triglyceride (p = 0.02), plasma glucose (p = 0.003) are related to CAVI value. However, the multivariate analysis showed that age was the only significant independent factor related to the CAVI value. In addition, the CAVI and plasma malondialdehyde (MDA) levels showed a positive correlation (r = 0.29, p < 0.01) while, the CAVI was negatively correlated with catalase (CAT) (r = -0.4, p < 0.001) and GPx (r = -0.60, p < 0.001). In conclusion, this study demonstrated that age is the most influential factor for assessing arterial stiffness by the CAVI method, which is possibly due to the increase in oxidative stress. PMID- 26750576 TI - Is better preservation of eccentric strength after stroke due to altered prefrontal function? AB - Ventrolateral prefrontal cortex (VLPFC) is part of a network that exerts inhibitory control over the motor cortex (MC). Recently, we demonstrated that VLPFC was more activated during imagined maximum eccentric than during imagined concentric contractions in healthy participants. This was accompanied with lower activation levels within motor regions during imagined eccentric contractions. The aim was to test a novel hypothesis of an involvement of VLPFC in contraction mode-specific modulation of force. Functional magnetic resonance imaging was used to examine differences in VLPFC and motor regions during the concentric and the eccentric phases of imagined maximum contractions in a selected sample of subjects with stroke (n = 4). The subjects were included as they exhibited disturbed modulation of force. The previously demonstrated pattern within VLPFC was evident only on the contralesional hemisphere. On the ipsilesional hemisphere, the recruitment in VLPFC was similar for both modes of contractions. The findings support a hypothesis of the involvement of VLPFC in contraction mode specific modulation of maximum force production. A disturbance of this system might underlie the lack of contraction mode-specific modulation commonly found among stroke subjects, often expressed as an increased ratio between eccentric and concentric strength. PMID- 26750575 TI - Recurrent Stroke, Myocardial Infarction, and Major Vascular Events during the First Year after Acute Ischemic Stroke: The Multicenter Prospective Observational Study about Recurrence and Its Determinants after Acute Ischemic Stroke I. AB - BACKGROUND: Patients with acute ischemic stroke (AIS) are at high risk of subsequent vascular events. The aim of this study was to estimate rates of recurrent stroke, myocardial infarction (MI), and major vascular events during the first year after AIS in Korea. METHODS: Through a multicenter stroke registry in Korea, 12,227 consecutive cases of AIS were identified between November 2010 and May 2013 and were followed up for recurrent stroke, MI, and major vascular events up to 1 year after stroke. RESULTS: Cumulative 30-day, 90-day and 1-year rates were 2.7%, 3.9%, and 5.7% for recurrent stroke; .1%, .3%, and .5% for MI; and 8.1%, 10.6%, and 13.7% for major vascular events, indicating that the early period is at high risk of recurrent stroke and major vascular events. The risk of recurrent stroke was substantially higher than the risk of MI: 13.0 times at 90 days and 11.4 times at 1 year. Compared to those with small-vessel occlusion (SVO), those with ischemic stroke subtypes other than SVO had a higher risk of recurrent stroke as well as major vascular events. Other common independent predictors for recurrent stroke and major vascular events were diabetes and prior stroke history. CONCLUSIONS: During the first year after AIS, one in 18 had recurrent stroke and one in 7 major vascular events. More than two thirds of recurrent stroke and three quarters of major vascular events developed within 90 days in a Korean cohort of stroke patients. Better prevention strategies are required for high-risk patients during this high-risk period. PMID- 26750577 TI - Evidence of small fiber neuropathy in a patient with Ehlers-Danlos syndrome, hypermobility-type. PMID- 26750578 TI - (Non-) invasive mapping of cortical language areas. PMID- 26750580 TI - Motor unit number index (MUNIX): Is it relevant in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)? AB - OBJECTIVE: To determine the test-retest reliability of motor unit number index (MUNIX) technique and to explore if the MUNIX sumscore could be related with disability in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: The MUNIX technique was unilaterally assessed in the abductor digiti mini (ADM), the abductor pollicis brevi (APB) and the tibialis anterior (TA) muscles two different times by two blinded examiners. The MUNIX sumscore was calculated by adding the results of the ADM, APB and TA muscles. RESULTS: 14 CIDP patients were enrolled. The intraclass correlation coefficient (ICC) was great for inter and intra variability for ADM muscles (0.8 and 0.81), TA muscles (0.86 and 0.89) and MUNIX sumscore (0.76 and 0.83). The MUNIX sumscores from the first and second evaluations were strongly correlated (r=0.83, p<0.001). The MUNIX sumscore was significantly correlated with MRC testing (r=0.71, p<0.01), overall neuropathy limitation scale (ONLS) (r=-0.70, p<0.001), rasch-built overall disability scale (R-ODS) (r=0.71, p<0.001). CONCLUSIONS: The MUNIX technique has a good reproducibility and the MUNIX sumscore is related to the disability. SIGNIFICANCE: The MUNIX technique estimates the axonal loss and the number of functional motor units. The MUNIX sumscore may be a good instrument to evaluate the CIDP patients during their follow-up. PMID- 26750579 TI - Tongue electrical impedance in amyotrophic lateral sclerosis modeled using the finite element method. AB - OBJECTIVE: Electrical impedance myography (EIM) of the tongue has demonstrated alterations in patients with amyotrophic lateral sclerosis (ALS) compared to normal subjects. Whether these differences are due to reduced tongue size or diseased-associated alterations in the electrical characteristics of intrinsic tongue muscles is uncertain. METHODS: We employed computer simulations using the finite element method, inputting data from healthy and ALS mouse muscle, to help answer that question, comparing our modeled results to human data. RESULTS: The models revealed that much of the electrical current flows superficially in the tongue and that tongue thickness only begins to have a major impact on the measured impedance when substantial atrophy is present. Modeled values paralleled the human tongue data. CONCLUSIONS: These findings suggest that the observed changes in tongue impedance in ALS are mainly due to alterations in the electrical properties of the tongue and are not a mere consequence of tongue volume loss. SIGNIFICANCE: Further development of EIM for evaluation of bulbar dysfunction in ALS may provide useful information on drug efficacy and could serve as a biomarker in future clinical trials. PMID- 26750581 TI - The additional lateralizing and localizing value of the postictal EEG in frontal lobe epilepsy. AB - OBJECTIVE: The aim of this study was to describe the additional lateralizing and localizing value of the postictal EEG in frontal lobe epilepsy (FLE). The ictal EEG in FLE is frequently challenging to localize. METHODS: We identified patients investigated for epilepsy surgery with unilateral FLE based on consistent semiology, a clear lesion and/or with frontal onset on intracranial EEG. A one hour section of postictal EEG was analyzed by two raters for new or activated EEG features and it was assessed whether these features offered additional information when compared to the ictal EEG. Postictal features assessed included asymmetrical return of the posterior dominant rhythm and potentiated lateralized or regional frontal slowing, spikes or sharp waves. RESULTS: Thirty-eight patients were included who had a combined total of ninety-six seizures. 47/96 (49%) postictal periods contained correctly lateralizing or localizing information. The sensitivity for asymmetrical return of the posterior dominant rhythm was 24%. The sensitivity for regional frontal slow and frontal spikes was 23% and 20% respectively. Further analysis showed that in 14/38 (39%) patients, at least one seizure with an unhelpful ictal EEG was followed by postictal EEG features that added new localizing or lateralizing information. A subgroup of 11 patients who were ?1 year seizure-free (ILAE class 1) and thus classified as having a 'gold-standard' FLE diagnosis were analyzed separately and it was found that 14/30 of their seizures (47%) had extra postictal information. CONCLUSIONS: The new postictal information was always concordant with the ultimate diagnosis, except for asymmetric postictal return of background activity ipsilateral to the epileptogenic zone in three patients. SIGNIFICANCE: This study shows that a close examination of the postictal EEG can offer additional information which can contribute to the identification of a potentially resectable epileptogenic zone. PMID- 26750583 TI - Histone modifying enzymes: novel disease biomarkers and assay development. AB - Histones are the chief components of chromatin. When being catalyzed by a series of histone modifying enzymes, histones may undergo various post-translational modifications such as acetylation, methylation, phosphorylation, ubiquitylation and SUMOylation. The dysregulation of histone modifying enzymes will alter the histone post-modification patterns and cause diverse diseases including cancers. Consequently, the histone modifying enzymes have emerged as the promising biomarkers for disease diagnosis and prognosis. In this review, we summarize the recent researches about the histone modifying enzymes as the disease biomarkers, and highlight the development of methods for histone modifying enzyme assays. PMID- 26750582 TI - Quantifying risk over the life course - latency, age-related susceptibility, and other time-varying exposure metrics. AB - Identification of the latency period and age-related susceptibility, if any, is an important aspect of assessing risks of environmental, nutritional, and occupational exposures. We consider estimation and inference for latency and age related susceptibility in relative risk and excess risk models. We focus on likelihood-based methods for point and interval estimation of the latency period and age-related windows of susceptibility coupled with several commonly considered exposure metrics. The method is illustrated in a study of the timing of the effects of constituents of air pollution on mortality in the Nurses' Health Study. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26750584 TI - How do language-specific characteristics affect the acquisition of different relative clause types? Evidence from Finnish. AB - We report three studies (one corpus, two experimental) that investigated the acquisition of relative clauses (RCs) in Finnish-speaking children. Study 1 found that Finnish children's naturalistic exposure to RCs predominantly consists of non-subject relatives (i.e. oblique, object) which typically have inanimate head nouns. Study 2 tested children's comprehension of subject, object, and two types of oblique relatives. No difference was found in the children's performance on different structures, including a lack of previously widely reported asymmetry between subject and object relatives. However, children's comprehension was modulated by animacy of the head referent. Study 3 tested children's production of the same RC structures using sentence repetition. Again we found no subject object asymmetry. The pattern of results suggested that distributional frequency patterns and the relative complexity of the relativizer contribute to the difficulty associated with particular RC structures. PMID- 26750585 TI - A review of the nationwide proficiency test on natural radioactivity measurements by gamma spectrometry. AB - This study is the review of the first proficiency test on radioactivity measurement organized in Turkey by Saraykoy Nuclear Research and Training Center (SANAEM) of Turkish Atomic Energy Authority (TAEK) in 2013. The objective of the test was to determine (226)Ra, (232)Th and (40)K activity concentrations in natural soil samples using gamma-ray spectrometry. The bulk material consisting of uranium- and thorium-rich soil and sand was milled, mixed thoroughly and sieved. Homogeneity of the final mix was tested with 6 randomly taken samples. 16 proficiency test samples were distributed to 16 participating laboratories. 12 laboratories reported results. The results were evaluated on the accuracy and precision criteria adopted by the IAEA Proficiency Testing Group. The percentage of acceptable scores was 49%. Some recommendations have been provided to the laboratories to improve the quality of their results. It is planned to extend these proficiency tests periodically for various radionuclides in various matrices. PMID- 26750586 TI - Reconstruction of atmospheric soot history in inland regions from lake sediments over the past 150 years. AB - Historical reconstruction of atmospheric black carbon (BC, in the form of char and soot) is still constrained for inland areas. Here we determined and compared the past 150-yr records of BC and polycyclic aromatic compounds (PACs) in sediments from two representative lakes, Huguangyan (HGY) and Chaohu (CH), in eastern China. HGY only receives atmospheric deposition while CH is influenced by riverine input. BC, char, and soot have similar vertical concentration profiles as PACs in both lakes. Abrupt increases in concentrations and mass accumulation rates (MARs) of soot have mainly occurred since ~1950, the establishment of the People's Republic of China, when energy usage changed to more fossil fuel contributions reflected by the variations in the concentration ratios of char/soot and individual PACs. In HGY, soot MARs increased by ~7.7 times in the period 1980-2012 relative to the period 1850-1950. Similar increases (~6.7 times) were observed in CH. The increase in soot MARs is also in line with the emission inventory records in the literature and the fact that the submicrometer-sized soot particles can be dispersed regionally. The study provides an alternative method to reconstruct the atmospheric soot history in populated inland areas. PMID- 26750589 TI - A comparison of the abilities of natural rubber (NR) and synthetic polyisoprene cis-1,4 rubber (IR) to crystallize under strain at high strain rates. AB - Strain induced crystallization (SIC) of a natural rubber (NR) and a synthetic rubber (IR) with a high amount of cis-1,4 units (98.6%) is studied, thanks to in situ wide angle X-ray (WAXS) experiments at room temperature performed in a large range of strain rates. During stretching at a low strain rate (4.2 * 10(-3) s( 1)), SIC in IR occurs at a larger stretching ratio than in NR. As a result, the crystallinity index at a given stretching ratio is lower in IR than in NR, in spite of the similar crosslink densities of the chains involved in the crystallization in both materials. This lower ability for crystallization in IR is attributed to the presence of branching along its backbone and its lower stereoregularity. Conversely, dynamic experiments performed at high strain rates (10(1)/10(2) s(-1)) show for both materials a similar ability to crystallize. This unexpected result is confirmed by monotonic tensile tests performed in a large range of strain rates. The reason is thermodynamic: the chain extension plays a predominant role compared to the role of the microstructure defects when the strain rate is high, i.e. when the kinetics of the crystallite nucleation forces the crystallization to occur at a large stretching ratio. A thermodynamic model enables qualitative reproduction of the experimental results. PMID- 26750587 TI - Characterization of age-associated exhausted CD8+ T cells defined by increased expression of Tim-3 and PD-1. AB - Aging is accompanied by altered T-cell responses that result in susceptibility to various diseases. Previous findings on the increased expression of inhibitory receptors, such as programmed cell death protein 1 (PD-1), in the T cells of aged mice emphasize the importance of investigations into the relationship between T cell exhaustion and aging-associated immune dysfunction. In this study, we demonstrate that T-cell immunoglobulin mucin domain-3 (Tim-3), another exhaustion marker, is up-regulated on aged T cells, especially CD8(+) T cells. Tim-3 expressing cells also produced PD-1, but Tim-3(+) PD-1(+) CD8(+) T cells had a distinct phenotype that included the expression of CD44 and CD62L, from Tim-3(-) PD-1(+) cells. Tim-3(+) PD-1(+) CD8(+) T cells showed more evident properties associated with exhaustion than Tim-3(-) PD-1(+) CD8(+) T cells: an exhaustion related marker expression profile, proliferative defects following homeostatic or TCR stimulation, and altered production of cytokines. Interestingly, these cells produced a high level of IL-10 and induced normal CD8(+) T cells to produce IL 10, which might contribute to immune dysregulation in aged mice. The generation of Tim-3-expressing CD8(+) T cells in aged mice seems to be mediated by encounters with antigens but not by specific infection, based on their high expression of CD49d and their unbiased TCR Vbeta usage. In conclusion, we found that a CD8(+) T-cell population with age-associated exhaustion was distinguishable by its expression of Tim-3. These results provide clues for understanding the alterations that occur in T-cell populations with age and for improving dysfunctions related to the aging of the immune system. PMID- 26750590 TI - Breaking Nano-Spaghetti: Bending and Fracture Tests of Nanofibers. AB - Nanofibers composed of silica nanoparticles, used as structural building blocks, and polystyrene nanoparticles introduced as sacrificial material are fabricated by bicolloidal electrospinning. During fiber calcination, sacrificial particles are combusted leaving voids with controlled average sizes. The mechanical properties of the sintered silica fibers with voids are investigated by suspending the nanofiber over a gap and performing three-point bending experiments with atomic force microscopy. We investigate three different cases: fibers without voids and with 60 or 260 nm voids. For each case, we study how the introduction of the voids can be used to control the mechanical stiffness and fracture properties of the fibers. Fibers with no voids break in their majority at a single fracture point (70% of cases), segmenting the fiber into two pieces, while the remaining cases (30%) fracture at multiple points, leaving a gap in the suspended fiber. On the other hand, fibers with 60 nm voids fracture in only 25% of the cases at a single point, breaking predominantly at multiple points (75%). Finally, fibers with 260 nm voids fracture roughly in equal proportions leaving two and multiple pieces (46% vs 54%, respectively). The present study is a prerequisite for processes involving the controlled sectioning of nanofibers to yield anisometric particles. PMID- 26750588 TI - ACT-PRESTO: Rapid and consistent tissue clearing and labeling method for 3 dimensional (3D) imaging. AB - Understanding the structural organization of organs and organisms at the cellular level is a fundamental challenge in biology. This task has been approached by reconstructing three-dimensional structure from images taken from serially sectioned tissues, which is not only labor-intensive and time-consuming but also error-prone. Recent advances in tissue clearing techniques allow visualization of cellular structures and neural networks inside of unsectioned whole tissues or the entire body. However, currently available protocols require long process times. Here, we present the rapid and highly reproducible ACT-PRESTO (active clarity technique-pressure related efficient and stable transfer of macromolecules into organs) method that clears tissues or the whole body within 1 day while preserving tissue architecture and protein-based signals derived from endogenous fluorescent proteins. Moreover, ACT-PRESTO is compatible with conventional immunolabeling methods and expedites antibody penetration into thick specimens by applying pressure. The speed and consistency of this method will allow high-content mapping and analysis of normal and pathological features in intact organs and bodies. PMID- 26750591 TI - Decongestion: more than meets the eye! PMID- 26750592 TI - Engineering Signaling Aptamers That Rely on Kinetic Rather Than Equilibrium Competition. AB - During the past decade, aptasensors have largely been designed on the basis of the notion that ligand-modulated equilibration between aptamer conformations could be exploited for sensing. One implementation of this strategy has been to denature the aptamer with an antisense oligonucleotide, wait for dissociation of the antisense oligonucleotide, and stabilize the folded, signaling conformer with a ligand. However, there is a large kinetic barrier associated with releasing the oligonucleotide from the aptamer to again obtain an active, binding conformation. If the length of the antisense oligonucleotide is decreased to make dissociation from the aptamer more favorable, higher background signals are observed. To improve the general methodology for developing aptasensors, we have developed a novel and robust strategy for aptasensor design in which an oligonucleotide kinetically competes with the ligand for binding rather than having to be released from a stable duplex. While the oligonucleotide can induce conformational change, it initially chooses between the aptamer and a molecular beacon (MB), a process that does not require a lengthy pre-equilibration. Using an anti-ricin aptamer as a starting point, we developed a "competitive" aptasensor with a measured limit of detection (LOD) of 30 nM with an optical readout and as low as 3 nM for ricin toxin A-chain (RTA) detection on an electrochemical platform. PMID- 26750594 TI - Prognostic significance of cytoplasmic p27 in oral squamous cell carcinoma. AB - OBJECTIVE: p27 is a cell cycle-dependent kinase inhibitor whose presence in nucleus is associated with good prognosis. Recent studies propose that when localized to cytoplasm, it functions as an oncogene and confers a poorer prognosis. This study aimed at analysing the subcellular localization of p27 and its prognostic significance in oral squamous cell carcinomas (OSCCs). METHODS: Immunohistochemistry for p27 was carried out on 60 cases of OSCC (30 cases each of those with lymph node metastasis [LN+ve SCC] and without lymph node metastasis [LN-ve SCC]) and 30 normal mucosa. The relationship between p27 localization and prognosis was analysed statistically. RESULTS: Nuclear immunopositivity was seen in 15%, 23%, 7% and 60%, while cytoplasmic immunopositivity was seen in 80%, 63%, 97% and 43% of all SCC, LN+ve OSCC, LN-ve SCC cases and normal mucosa, respectively. There was a significant inverse correlation between nuclear and cytoplasmic p27 immunopositivity (P = 0.001). Nodal status and tumour stage were the only two parameters that correlated with disease-free survival (DFS) in OSCC cases. However, in LN+ve SCC, a significantly shortened DFS was seen in cases with cytoplasmic p27 expression compared to those without (P = 0.02). Conversely, LN+ve SCC with nuclear p27 had longer DFS on comparison with those without (P = 0.04). CONCLUSIONS: To the best of our knowledge, this is the first study to analyse cytoplasmic localization of p27 in OSCC and correlate with prognosis. Cytoplasmic localization is associated with poor prognosis in OSCC with lymph node metastasis allowing the consideration of cytoplasmic p27 in predicting prognosis and targeted therapeutic approaches. PMID- 26750595 TI - In Memoriam Kurt G. Hofer (1939-2015). PMID- 26750593 TI - Bilaminar Device of Poly(Lactic-co-Glycolic Acid)/Collagen Cultured With Adipose Derived Stem Cells for Dermal Regeneration. AB - Several materials are commercially available as substitutes for skin. However, new strategies are needed to improve the treatment of skin wounds. In this study, we developed and characterized a new device consisting of poly(lactic-co-glycolic acid) (PLGA) and collagen associated with mesenchymal stem cells derived from human adipose tissue. To develop the bilaminar device, we initially obtained a membrane of PLGA by dissolving the copolymer in chloroform and then produced a collagen type I scaffold by freeze-drying. The materials were characterized physically by gel permeation chromatography, scanning electron microscopy, and mass loss. Biological activity was assessed by cell proliferation assay. A preliminary study in vivo was performed with a pig model in which tissue regeneration was assessed macroscopically and histologically, the commercial device Integra being used as a control. The PLGA/collagen bilaminar material was porous, hydrolytically degradable, and compatible with skin growth. The polymer complex allowed cell adhesion and proliferation, making it a potentially useful cell carrier. In addition, the transparency of the material allowed monitoring of the lesion when the dressings were changed. Xenogeneic mesenchymal cells cultured on the device (PLGA/collagen/ASC) showed a reduced granulomatous reaction to bovine collagen, down-regulation of alpha-SMA, enhancement in the number of neoformed blood vessels, and collagen organization as compared with normal skin; the device was superior to other materials tested (PLGA/collagen and Integra) in its ability to stimulate the formation of new cutaneous tissue. PMID- 26750597 TI - General Introduction. PMID- 26750596 TI - 1,25D3 prevents CD8(+)Tc2 skewing and asthma development through VDR binding changes to the Cyp11a1 promoter. AB - Effector CD8(+) T cells convert from IFN-gamma(+) (Tc1) to IL-13(+) (Tc2) cells in the presence of IL-4. Underlying regulatory mechanisms are not fully defined. Here, we show that addition of 1,25D3, the active form of vitamin D3, during CD8(+) T-cell differentiation prevents IL-4-induced conversion to IL-13 producers. Transfer of 1,25D3-treated CD8(+) T cells into sensitized and challenged CD8(+)-deficient recipients fails to restore development of lung allergic responses. 1,25D3 alters vitamin D receptor (VDR) recruitment to the Cyp11a1 promoter in vitro and in vivo in the presence of IL-4. As a result, protein levels and enzymatic activity of CYP11A1, a steroidogenic enzyme regulating CD8(+) T-cell conversion, are decreased. An epistatic effect between CYP11A1 and VDR polymorphisms may contribute to the predisposition to childhood asthma. These data identify a role for 1,25D3 in the molecular programming of CD8(+) T-cell conversion to an IL-13-secreting phenotype through regulation of steroidogenesis, potentially governing asthma susceptibility. PMID- 26750599 TI - Chromatin: Its history, current research, and the seminal researchers and their philosophy. AB - The concept of chromatin as a complex of nucleic acid and proteins in the cell nucleus was developed by cytologists and biochemists in the late 19th century. It was the starting point for biochemical research on DNA and nuclear proteins. Although interest in chromatin declined rapidly at the beginning of the 20th century, a few decades later a new focus on chromatin emerged, which was not only related to its structure, but also to its function in gene regulatory processes in the development of higher organisms. Since the late 20th century, research on chromatin modifications has also been conducted under the label of epigenetics. This article highlights the major phases of chromatin research until the present time and introduces major investigators and their scientific and philosophical outlooks. PMID- 26750600 TI - Genomics, "Discovery Science," Systems Biology, and Causal Explanation: What Really Works? AB - Diverse and non-coherent sets of epistemological principles currently inform research in the general area of functional genomics. Here, from the personal point of view of a scientist with over half a century of immersion in hypothesis driven scientific discovery, I compare and deconstruct the ideological bases of prominent recent alternatives, such as "discovery science," some productions of the ENCODE project, and aspects of large data set systems biology. The outputs of these types of scientific enterprise qualitatively reflect their radical definitions of scientific knowledge, and of its logical requirements. Their properties emerge in high relief when contrasted (as an example) to a recent, system-wide, predictive analysis of a developmental regulatory apparatus that was instead based directly on hypothesis-driven experimental tests of mechanism. PMID- 26750601 TI - Dual Function of DNA Sequences: Protein-Coding Sequences Function as Transcriptional Enhancers. AB - Most of our genome comprises noncoding sequences that include diverse transcriptional regulatory elements, such as enhancers, while only ~1.5% of the genome codes for proteins. Nevertheless, DNA sequences that code for protein (exons) can also function as enhancers (eExons) that regulate transcription. Mutations in eExons can lead to multiple phenotypes due to their dual function. The prevalence of protein-coding sequences that possess transcriptional regulatory function (such as eExons) and the consequences of their mutations are not well described. Using advanced sequencing technologies, protein-coding sequences were analyzed for their potential regulatory function in mammalian cells and found to be overrepresented in the genome (>6%). Dissection of the enhancer activity of eExons at single nucleotide resolution in liver cells has demonstrated that: (1) most nucleotide changes with high impact effect are deleterious; (2) deleterious enhancer mutations are correlated with the location of transcription factor-binding sites; (3) synonymous and non-synonymous mutations have similar effects on enhancer activity; and (4) the transcription factor repertoire that controls the activity of enhancers differs across cell types, indicating differences in deleterious mutation profiles. Thus, eExon mutations can disrupt both protein structure and enhancer activity with differential effect across cell types, suggesting that a mutation in a gene could cause a phenotype that has nothing to do with its protein-coding function but is due to its additional hidden regulatory function. PMID- 26750602 TI - Pseudoalleles and Gene Complexes: The Search for the Elusive Link Between Genome Structure and Gene Function. AB - After their discovery in the first decades of the 20th century, pseudo-alleles generated much interest among geneticists, because they apparently violated the conception of the genome as a collection of independent genes, a view elaborated by Thomas Morgan's group. This article focuses on two issues: the way the phenomenon of pseudoallelism suggests that the genome is more than a simple addition of independent genes, and the connection established between the formation of pseudoalleles during evolution and their functional roles. The article discusses the first explanations for the origin of pseudoalleles elaborated in the mid-1930s, the metabolic/developmental sequential model proposed by Ed Lewis in the 1950s, the disappointments encountered with the T complex in the 1970s, and the fading of the previous models after the molecular characterization of the pseudoallelic gene complexes in the 1980s. Genomes are more than collections of genes, but their structures are the result of a complex evolutionary history that leaves no place for simplistic models. PMID- 26750604 TI - Reprogramming and Stemness. AB - Reprogramming technologies show that cellular identity can be reprogrammed, challenging the classical conception of cell differentiation as an irreversible process. If non-stem cells can be reprogrammed into stem cells, then what is it to be a stem cell, and what kind of property is stemness? This article addresses this question both philosophically and biologically, states the different possibilities, and illustrates their potential consequences for science with the example of anti-cancer therapies. PMID- 26750603 TI - Immune Cell Identity: Perspective from a Palimpsest. AB - The immune system in mammals is composed of multiple different immune cell types that migrate through the body and are made continuously throughout life. Lymphocytes and myeloid cells interact with each other and depend upon each other, but each are highly diverse and specialized for different roles. Lymphocytes uniquely require developmentally programmed mutational changes in the genome itself for their maturation. Despite profound differences between their mechanisms of threat recognition and threat response, however, the developmental origins of lymphocytes and myeloid cells are interlinked, and important aspects of their response mechanisms remain shared. It is notable that the chain of logic toward our current understanding of the immune defense system over the past 50 years has been driven by strongly posited models that have led to crucial discoveries, even though these models ended up being partly wrong. The predictive strength of these models and their success as guides to incisive experimental research have illuminated the limits of each model's explanatory scope, beyond which another model needed to assume the lead. This brief review describes how a succession of distinct paradigms has helped to clarify a sophisticated picture of immune cell generation and control. PMID- 26750606 TI - Synthesis and anti-mycobacterial activity of glycosyl sulfamides of arabinofuranose. AB - A series of arabino N-glycosyl sulfamides, forced to adopt the furanose form by removal of the 5-hydroxyl group, were synthesised as putative isosteric mimics of decaprenolphosphoarabinose, the donor processed by arabinosyltransferases during mycobacterial cell wall assembly. Compounds showed moderate anti-mycobacterial activity, which was maximal for a C10 sulfamide side chain. PMID- 26750605 TI - DNA methylation dynamics in mouse preimplantation embryos revealed by mass spectrometry. AB - Following fertilization in mammals, paternal genomic 5-methyl-2'-deoxycytidine (5 mC) content is thought to decrease via oxidation to 5-hydroxymethyl-2' deoxycytidine (5 hmC). This reciprocal model of demethylation and hydroxymethylation is inferred from indirect, non-quantitative methods. We here report direct quantification of genomic 5 mC and 5 hmC in mouse embryos by small scale liquid chromatographic tandem mass spectrometry (SMM). Profiles of absolute 5 mC levels in embryos produced by in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) were almost identical. By 10 h after fertilization, 5 mC levels had declined by ~40%, consistent with active genomic DNA demethylation. Levels of 5 mC in androgenotes (containing only a paternal genome) and parthenogenotes (containing only a maternal genome) underwent active 5 mC loss in the first 6 h, showing that both parental genomes can undergo demethylation independently. We found no evidence for net loss of 5 mC 10-48 h after fertilization, implying that any passive 'demethylation' following DNA replication was balanced by active 5 mC maintenance methylation. However, levels of 5 mC declined during development after 48 h, to 1% (measured as a fraction of G-residues) in blastocysts (~96 h). 5 hmC levels were consistently low (<0.2% of G-residues) throughout development in normal diploid embryos. This work directly quantifies the dynamics of global genomic DNA modification in mouse preimplantation embryos, suggesting that SMM will be applicable to other biomedical situations with limiting sample sizes. PMID- 26750607 TI - Development and validation of a checklist for assessing recorded performance of laparoscopic inguinal hernia repair. AB - BACKGROUND: Despite a need for video assessment for the performance transabdominal preperitoneal procedure (TAPP), the present assessment tools have not been validated for the use of evaluation of the recorded performance. We aimed to develop a checklist for the evaluation of the recorded performance of TAPP. METHODS: The TAPP checklist was developed by hernia experts from multiple institutes. Thirty unedited TAPP videos were rated by 3-blinded hernia experts. Inter-rater reliability and construct and concurrent validities were evaluated. RESULTS: The inter-rater reliability for 3 raters was .75 (95% confidence interval .60 to .86). The median total score of each group demonstrated a significant difference among experienced (>50 TAPP), intermediate (>=10 TAPP, <50), and novice (<10 TAPP) surgeons (P < .001). The checklist score showed a high correlation with TAPP experience and previously validated global scale for laparoscopic inguinal hernia repair. CONCLUSIONS: The TAPP checklist is a valid metrics for the assessment of the recorded TAPP performance. PMID- 26750609 TI - Editorial: Oxidative Stress and Alzheimer Disease: Where Do We Stand? PMID- 26750610 TI - Distinct structural and dynamical difference between supercooled and normal liquids of hydrogen molecules. AB - Supercooled hydrogen liquid as well as superfluid have continued to elude experimental observation due to rapid crystallization. We computationally realized and investigated supercooled hydrogen liquid by a recently developed non empirical real-time molecular dynamics method, which describes non-spherical hydrogen molecules with the nuclear quantum effects. We demonstrated that the hydrogen supercooled liquid is not a simply cooled liquid but rather exhibits intrinsic structural and dynamical characters including a precursor of tunneling and superfluidity which neither normal hydrogen liquid nor solid possesses. All of the insights provide a milestone for planning experiments of metastable hydrogen systems like glassy and superfluid states and for identifying various unknown hydrogen phases. PMID- 26750611 TI - Label-free mapping of single bacterial cells using surface-enhanced Raman spectroscopy. AB - Here we presented a simple, rapid and label-free surface-enhanced Raman spectroscopy (SERS) based mapping method for the detection and discrimination of Salmonella enterica and Escherichia coli on silver dendrites. The sample preparation was first optimized to maximize sensitivity. The mapping method was then used to scan through the bacterial cells adsorbed on the surface of silver dendrites. The intrinsic and distinct SERS signals of bacterial cells were used as the basis for label-free detection and discrimination. The results show the developed method is able to detect single bacterial cells adsorbed on the silver dendrites with a limit of detection as low as 10(4) CFU mL(-1), which is two orders of magnitude lower than the traditional SERS method under the same experimental condition. The time needed for collecting a 225 points map was approximately 24 minutes. Moreover, the developed SERS mapping method can realize simultaneous detection and identification of Salmonella enterica subsp. enterica BAA1045 and Escherichia coli BL21 from a mixture sample using principle component analysis. Our results demonstrate the great potential of the label-free SERS mapping method to detect, identify and quantify bacteria and bacterial mixtures simultaneously. PMID- 26750608 TI - DPSC colonization of functionalized 3D textiles. AB - Fiber scaffolds are attractive materials for mimicking, within a 3D in vitro system, any living environment in which animal cells can adhere and proliferate. In three dimensions, cells have the ability to communicate and organize into complex architectures similar to those found in their natural environments. The aim of this study was to evaluate, in terms of cell reactivity, a new in vitro cell model: dental pulp stem cells (DPSCs) in a 3D polymeric textile. Scaffolds were knitted from polyglycolic acid (PGA) or polydioxanone (PDO) fibers differing in surface roughness. To promote cell adhesion, these hydrophobic fabrics were also functionalized with either chitosan or the peptide arginine-glycine-aspartic acid (RGD). Cell behavior was examined 1, 10, and 21 days post-seeding with a LIVE/DEAD(r) Kit. Confocal laser scanning microscopy (CLSM) highlighted the biocompatibility of these materials (cell survival rate: 94% to 100%). Fiber roughness was found to influence cell adhesion and viability significantly and favorably. A clear benefit of polymeric textile functionalization with chitosan or RGD was demonstrated in terms of cell adhesion and viability. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 785-794, 2017. PMID- 26750612 TI - Weak reversible cross links may decrease the strength of aligned fiber bundles. AB - Reversible cross-linking is an effective strategy to specifically tailor the mechanical properties of polymeric materials that can be found in a variety of biological as well as man-made materials. Using a simple model in this paper the influence of weak, reversible cross-links on the mechanical properties of aligned fiber bundles is investigated. Special emphasis in this analysis is put on the strength of the investigated structures. Using Monte Carlo methods two topologies of cross-links exceeding the strength of the covalent backbone are studied. Most surprisingly only two cross-links are sufficient to break the backbone of a multi chain system, resulting in a reduced strength of the material. The found effect crucially depends on the ratio of inter- to intra-chain cross-links and, thus, on the grafting density that determines this ratio. PMID- 26750613 TI - Evaluation of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in a community setting: A cost-utility analysis of a hospital's initial experience and reflections on the health care system. AB - BACKGROUND: The combination of Cytoreductive Surgery (CRS) plus Hyperthermic Intraperitoneal Chemotherapy (HIPEC) has been gaining a considerable interest by surgeons throughout the United States due to the significant survival improvement it provides for peritoneal surface malignancies and the ability to reproduce comparable clinical results in numerous health care centers. However, CRS plus HIPEC has not been sufficiently investigated from the economic standpoint in the United States where a wide variety of health care insurers exists. This study was conducted to analyze hospital/surgeon cost and reimbursement data at a community hospital offering a new peritoneal surface malignancy program, and expand the discussion to analyze future healthcare implementation on this procedure in the United States. METHODS: This is a retrospective economic analysis of an initial CRS plus HIPEC experience at a community non-teaching medical center. This study was conducted using hospital/surgeon cost and reimbursement based on the Office of Finance data at Edward Hospital Cancer Center (Naperville, IL). All patients who underwent CRS and HIPEC between June 2013 and August 2014 were included in this analysis. We aimed to assess CRS plus HIPEC purely from the financial perspective on the initial admission regardless of the patients' advancement of the disease or postoperative adverse events. RESULTS: Twenty-five patients underwent 26 CRS plus HIPEC procedures. Twelve patients had private insurance plans (PRV) whereas 13 were covered by public insurers (PUB). Median overall length of stay (LOS) was 10 days (PRV 10 days vs. PUB 11 days; P = 0.76.) Average hospital cost was $38,369 (PRV $37,093 vs. PUB $39,463; P = 0.67), and average reimbursement for our patient population was $45,243 (PRV $48,954 vs. PUB $42,062; P = 0.53). It was noted that CRS plus HIPEC generated more net profit in patients with private insurance than in those with public plans, however, not statistically significant ($11,861 vs. $2,599 per patient, respectively; P = 0.38). Evaluating surgeon's data, average surgeon's charge was $29,139 (PRV $28,440 vs. PUB $29,737; P = 0.80), and average patients' payment was $8,126 (PRV 9,234 vs. PUB 7,176; P = 0.47). CONCLUSION: CRS plus HIPEC is profitable in the community setting for both the hospital and surgeon. Both private and public insurers reimbursed profitably, though with a greater profit margin from private insurers. As CRS plus HIPEC is becoming more widely recognized as a standard of care for patients with peritoneal surface malignancy, it is increasingly important to understand and report its associated costs and variability in insurance coverage, especially in light of the current healthcare structure changes in the United States. It is strongly encouraged to report and present a wider scope of CRS plus HIPEC economic experiences in a variety of hospital settings to provide further evidence for future healthcare implementations in the United States. J. Surg. Oncol. 2016;113:544-547. (c) 2016 Wiley Periodicals, Inc. PMID- 26750614 TI - SALL4 is a marker of poor prognosis in serous ovarian carcinoma promoting invasion and metastasis. AB - Spalt-like transcription factor 4 (SALL4) is a transcription factor which is able to regulate development and embryonic stem cell pluripotency, and it is also involved in some tumor progression. However, the role of SALL4 in serous ovarian carcinoma (SOC) is still controversial. In this study, we determined the SALL4 expression in ovarian carcinoma (OC) cell lines and SOC tissues, and explored the clinical value of SALL4 in SOC. The SALL4 mRNA and protein expression in OC cell lines were examined by real-time PCR and western blotting. The SALL4 protein expression of 91 SOC tissue samples were examined by immunohistochemistry, and the correlation with clinicopathologic features as well as the survivals of SOC patients were analyzed. The invasion potential of OC cells were determined by cytoskeleton immunofluorescence, wound-healing, Transwell and colony formation assays. Our study found SALL4 mRNA and protein were highly expressed in OC cell lines, especially in HO-8910PM. SALL4 protein was highly expressed in SOC tissues, and positively associated with advanced FIGO stage, high histological grade, lymph node involvement, distant metastasis, recurrence and death of SOC (all P<0.05). Survival analysis showed that high expression of SALL4 indicated poorer overall and progression-free survival (P<0.05). Univariate and multivariate analysis showed that SALL4 is an independent marker for prognosis prediction (P<0.05). SALL4 ectopic expression significantly increased the migration, invasion and proliferation capacity of OC cells. In contrast, inhibition of SALL4 markedly decreased these capacities in vitro. In addition, SALL4-interference changed critical signaling involved in cancer progression. In conclusion, SALL4 was highly expressed and correlated with poor prognosis in SOC patients, promoting invasion and metastasis of OC cells. SALL4 could be a novel molecular target and prognostic marker for SOC. PMID- 26750616 TI - Value of multiplex PCR to determine the bacterial and viral aetiology of pneumonia in school-age children. AB - BACKGROUND: Conventional methods for the aetiological diagnosis of community acquired pneumonia (CAP) are often insufficient owing to low sensitivity and the long wait for the results of culture and particularly serology, and it often these methods establish a diagnosis in only half of cases. AIM: To evaluate the most common bacterial and viral agents in CAP using a fast responsive PCR method and investigate the relationship between clinical/laboratory features and aetiology, thereby contributing to empirical antibiotic selection and reduction of treatment failure. METHODS: In children aged 4-15 years consecutively admitted with a diagnosis of CAP, the 10 most commonly detected bacterial and 12 most commonly detected viral agents were investigated by induced sputum using bacterial culture and multiplex PCR methods. Clinical and laboratory features were compared between bacterial and viral pneumonia. RESULTS: In 78 patients, at least one virus was detected in 38 (48.7%) and at least one bacterium in 32 (41%). In addition, both bacteria and viruses were detected in 16 (20.5%) patients. Overall, the agent detection rate was 69.2%. The most common viruses were respiratory syncytial virus and influenza and the most frequently detected bacteria were S. pneumoniae and H. influenzae. PCR was superior to culture for bacterial isolation (41% vs 13%, respectively). Fever, wheezing and radiological features were not helpful in differentiating between bacterial and viral CAP. White blood cell count, CRP and ESR values were significantly higher in the bacterial/mixed aetiology group than in the viral aetiology group. CONCLUSION: In CAP, multiplex PCR is highly reliable, superior in detecting multiple pathogens and rapidly identifies aetiological agents. Clinical features are poor for differentiation between bacterial and viral infections. The use of PCR methods allow physicians to provide more appropriate antimicrobial therapy, resulting in a better response to treatment, and it may be possible for use as a routine service if costs can be reduced. PMID- 26750617 TI - Additive manufacturing of biologically-inspired materials. AB - Additive manufacturing (AM) technologies offer an attractive pathway towards the fabrication of functional materials featuring complex heterogeneous architectures inspired by biological systems. In this paper, recent research on the use of AM approaches to program the local chemical composition, structure and properties of biologically-inspired materials is reviewed. A variety of structural motifs found in biological composites have been successfully emulated in synthetic systems using inkjet-based, direct-writing, stereolithography and slip casting technologies. The replication in synthetic systems of design principles underlying such structural motifs has enabled the fabrication of lightweight cellular materials, strong and tough composites, soft robots and autonomously shaping structures with unprecedented properties and functionalities. Pushing the current limits of AM technologies in future research should bring us closer to the manufacturing capabilities of living organisms, opening the way for the digital fabrication of advanced materials with superior performance, lower environmental impact and new functionalities. PMID- 26750618 TI - Functionalized Coumarine Fragment to Obtain Fluorescent and Selective P Glycoprotein Ligands. AB - Starting from our lead compound MC70 displaying high P-glycoprotein (P-gp) inhibition activity but low selectivity, a new class of coumarine derivatives was studied to develop selective and fluorescent P-gp ligands. In this series, the biphenyl moiety of MC70 was replaced with the coumarine fluorophore as a bioisostere of the biphenyl nucleus in order to improve the selectivity toward P gp and the fluorescent properties for in vitro studies. Moreover, the presence and position of substituents on the coumarine nucleus were probed to develop suitable fluorescent probes to study the expression and activity of P-gp in living cells. The best result was found for compound 4c, which exerts a good P-gp activity profile (EC50 = 13 MUM) as substrate and a high selectivity toward the pump since it is inactive toward MRP1. PMID- 26750615 TI - Tumor necrosis factor-alpha G-308A (rs1800629) polymorphism and aggressive periodontitis susceptibility: a meta-analysis of 16 case-control studies. AB - Association between tumor necrosis factor-alpha (TNF-alpha) G-308A (rs1800629) polymorphism and susceptibility to aggressive periodontitis (AgP) were inconsistent, hence we performed this meta-analysis to clarify the association between them using Comprehensive Meta-Analysis v2.2 software. 16 case-control studies were searched from the PubMed, Embase and CNKI databases up to February 2, 2015. The meta-analysis showed a significantly increased risk in A vs. G (OR = 1.23, 95%CI = 1.04-1.44), AA vs. GG (OR = 2.07, 95%CI = 1.11-3.87), and AA vs. AG+GG genetic models (OR = 2.09, 95%CI = 1.13-3.86); however, the non significantly increased risk was shown in AG vs. GG (OR = 1.06, 95%CI = 0.85 1.32) and AA+AG vs. GG genetic models (OR = 1.06, 95%CI = 0.85-1.31). Cumulative analysis showed that the association changed from non-significant to significant with new studies accumulated and the CIs became more and more narrow, sensitivity analysis indicated results were statistically robust. Stratified analyses of confirmed of HWE, Asians, Caucasians, and population-based controls obtained results similar to that of overall analysis. There was no evidence of publication bias. In summary, current evidence demonstrates that TNF-a G-308A polymorphism might be associated with AgP susceptibility, especially in Asians and Caucasians. PMID- 26750619 TI - How do people with dementia utilise primary care physicians and specialists within dementia networks? Results of the Dementia Networks in Germany (DemNet-D) study. AB - Outpatient dementia healthcare is predominantly fragmented, and dementia networks (DNs) represent an integrated care concept to overcome this problem. Little is known about the patients of these networks with regard to utilisation of physicians and associated factors. We interviewed 560 caregivers of people with dementia in 13 different DNs in Germany in 2013 and assessed socio-demographics, clinical data and physician utilisation. Networks were categorised in predominantly medical DNs and community-oriented DNs. Descriptive and multivariate statistical models were used to identify associated factors between DNs and users' data. Overall, the users of networks received high rates of physician care; 93% of the sample stated at least one contact with a primary care physician within the last 6 months, and 74% had been treated by a specialist (neurology/psychiatry physician). Only 5% of the sample had no contact with a physician in the 6 months preceding the interview. Females showed a lower odds for physician specialist consultations (OR = 0.641). Users of medical DNs receive greater specialist consultations overall (OR = 8.370). Compared to the German general population and people with dementia in other settings, users of DNs receive physician care more regularly, especially with regard to the consultations of neurologist/psychiatrists. Therefore, DNs seem to perform a supportive role within the integration of physician healthcare. More research is needed on the appropriate relationship between the needs of the people with dementia and utilisation behaviour. PMID- 26750621 TI - [Chronic heart failure]. AB - Incidence of chronic heart failure (HF) is increasing steadily in all developed countries, predominantly due to population ageing. The prevalence of HF in population is 1-2%, reaching up to 10% in higher age categories. At present HF is classified according to left ventricular ejection fraction (EF) value to HF with reduced EF (formerly systolic HF) and HF with preserved EF (formerly diastolic HF). Coronary artery disease dominates in the aetiology of HF with reduced EF (about 70%), especially status post myocardial infarction. Pathophysiology of HF with preserved EF is very complex and still not fully understood. Multiple comorbidities play an important role, especially hypertension and diabetes mellitus. HF with preserved EF represents about half of all HF cases and its rate is slowly increasing. Morbidity expressed as hospitalization rate is comparable in patients with both types of HF, whereas mortality is a little bit lower in patients with HF with preserved EF. But in patients with HF and preserved EF the prevailing causes of both, the hospitalizations and the deaths are non cardiovascular.Diagnosis of HF is relatively simple in fully manifested cases, but it could be a problem in milder forms especially of the HF with preserved EF in elderly patients with multiple comorbidities. For the definite diagnosis of HF the patient has to have typical symptoms and clinical signs as well as objectively documented left ventricular dysfunction, usually by echocardiography. According to the EF value the type of HF is determined. In HF with preserved EF an evidence of a structural heart impairment and/or left ventricular diastolic dysfunction is also necessary. Plasma levels of natriuretic peptides could be helpful for determination of correct diagnosis, particularly in untreated patients. Basic examination of patients with suspected HF is completed by ECG and some laboratory parameters (e.g. renal function, ions, red blood count).Treatment of HF with reduced EF is based on evidence from many clinical trials. It is complex and consists on non-pharmacological interventions, pharmacotherapy (ACE inhibitors, sartans, betablockers, mineralocortikoid receptor blockers, in specific situations also ivabradine and digoxin), surgery and devices. There is no evidence-based treatment for HF with preserved EF, therefore it still remains empiric. PMID- 26750622 TI - [Study PARADIGM-HF - a paradigm shift in the treatment of chronic heart failure]. AB - Chronic heart failure is a crucial problem of current cardiology. Despite that, no major development has occurred in the therapy in recent years. In this regard, first results of studies with ARNI inhibitors (angiotensin-receptor neprilysin inhibitors) may be considered hopeful. Dual inhibition of AT1 receptors and neprilysin blocks renin-angiotensin-aldosteron (RAS) axis and concurrently supports natural vasodilatory and diuretic effect of natriuretic peptides. Large scale prospective randomized multicenter trial PARADIGM-HF with more than 8000 individuals with stabilized chronic heart failure with systolic dysfunction (LV EF 40%, later 35%), mostly in functional class NYHA II-III with elevated BNP/NT pro BNP has shown 20% decrease in primary endpoint (cardiovascular death or hospitalization for heart failure) in a group treated by ARNI (LCZ696; sacubiltril - valsartan). Beneficial effect of ARNI was consistent also for total and cardiovascular mortality, for hospitalization for heart failure and in other pre-specified subgroup analyses, including quality of life. The treatment was safe, typical adverse event was hypotension, however without a need to interrupt the treatment. Dual RAS and neprilysin inhibition might thus after long time become a change in stable chronic heart failure with systolic dysfunction treatment "paradigm". Czech Republic significantly contributed to this study and all study sites should be congratulated and thanked for their high-quality work provided. PMID- 26750623 TI - [Non-cardiogenic pulmonary edema, acute respiratory distress syndrome]. AB - Non-cardiogenic pulmonary edema is a clinical syndrome manifested by rapidly progressive respiratory distress leading, without therapy, to severe respiratory insufficiency and subsequent multiorgan failure. The pathophysiological causes are: the change in the pressure gradients in the pulmonary capillaries, the impaired membrane permeability of the alveolocapillary in the lungs, and impaired lymphatic drainage. Unlike in cardiogenic pulmonary edema, cardiac disease is not a cause, and there is no increase in wedge pressure (< 18 mm Hg). The aetiological base is diverse and includes more clinical pathological factors. The diagnosis and evaluation are usually very difficult due to the rapidly deteriorating clinical condition of the patients. A decisive, quick and comprehensive approach, using all available invasive and non-invasive methods is necessary. The basic steps of treatment are: the use of different types of ventilatory support in order to achieve adequate oxygenation, dealing with possible hemodynamic instability, and, when needed, other specific procedures. It is always important to keep in mind that this is a very serious condition with a high mortality rate. And there is a need for fast and efficient access to the best specialized clinic. PMID- 26750624 TI - [Mountain sickness]. AB - Mountaineering brings many health risks, one of which is mountain sickness. Its mildest form - acute mountain sickness - is mainly characterized by subjective symptoms (headache, loss of appetite, insomnia, weakness, nausea and rarely also vomiting). Advanced and life-threatening forms are characterized by tissue edema cerebral or pulmonary high altitude edema. The common denominator of these acute forms is the low oxygen tension leading to hypoxemia and tissue ischemia. Sum of maladaptive or adaptive processes can modify the clinical picture. Underlying mechanisms of the chronic forms of pulmonary disease are the adaptation processes - pulmonary hypertension and polycythemia leading to heart failure.The only causal therapeutic intervention is to restore adequate oxygen tension, descend to lower altitudes or oxygen therapy. Pharmacotherapy has only a supportive effect. The prophylaxis includes stimulation of the respiratory center by carbonic anhydrase inhibitors (acetazolamide) antiedematous treatment with glucocorticoids (dexamethasone), increase lymphatic drainage of the lungs and brain by beta2 agonists (salmeterol) or mitigation of pulmonary hypertension by calcium channel blockers or phosphodiesterase-5 inhibitors (sildenafil or tadalafil). PMID- 26750620 TI - An interneuron progenitor maintains neurogenic potential in vivo and differentiates into GABAergic interneurons after transplantation in the postnatal rat brain. AB - Dysfunction of cortical GABAergic interneurons are involved in numerous neurological disorders including epilepsy, schizophrenia and autism; and replenishment of these cells by transplantation strategy has proven to be a feasible and effective method to help revert the symptoms in several animal models. To develop methodology of generating transplantable GABAergic interneurons for therapy, we previously reported the isolation of a v-myc-induced GABAergic interneuron progenitor clone GE6 from embryonic ganglionic eminence (GE). These cells can proliferate and form functional inhibitory synapses in culture. Here, we tested their differentiation behavior in vivo by transplanting them into the postnatal rat forebrain. We found that GE6 cells migrate extensively in the neonatal forebrain and differentiate into both neurons and glia, but preferentially into neurons when compared with a sister progenitor clone CTX8. The neurogenic potential of GE6 cells is also maintained after transplantation into a non-permissive environment such as adult cortex or when treated with inflammatory cytokine in culture. The GE6-derived neurons were able to mature in vivo as GABAergic interneurons expressing GABAergic, not glutamatergic, presynaptic puncta. Finally, we propose that v-myc-induced human interneuron progenitor clones could be an alternative cell source of transplantable GABAergic interneurons for treating related neurological diseases in future clinic. PMID- 26750625 TI - Medical Consequences of Chernobyl with Focus on the Endocrine System - Part 2. AB - In the last 70 years, atomic disasters have occurred several times. The nuclear power plant accident at Chernobyl in 1986 in North-Central Ukraine was a unique experience in population exposures to radiation by all ages, and ongoing studies have brought a large amount of information effects of radiation on human organism. Concerning the deteriorating global security situation and the strong rhetoric of some of the world leaders, the knowledge on the biological effects of ionizing radiation and the preventive measures designed to decrease the detrimental effects of radiation gains a new dimension, and involves all of us. This review focuses on the long-term effects of Chernobyl catastrophe especially on the endocrine system in children and in adults, and includes a summary of preventive measures in case of an atomic disaster. PMID- 26750626 TI - [Analysis of the relationship of heavy/light chain pairs of immunoglobulin (Hevylite) to the results of gel electrophoresis and nefelometric examination of serum proteins at the time of multiple myeloma diagnosis]. AB - BACKGROUND: The diagnostics and treatment of multiple myeloma (MM) requires precise analysis of serum immunoglobulins, which might be limited by the sensitivity of standard examination methods. Hevylite method enables quantitative analysis of heavy/light chain pairs (HLC) of normal and tumor IgG and IgA immunoglobulin and their ratio (HLC-r). The aim of the study was to assess the contribution of Hevylite method in the diagnostics of MM in comparison with nephelometry (NEF), standard protein electrophoresis (SPE), immunofixation electrophoresis (IFE) and the examination of serum free light chains (FLC) of immunoglobulin using Freelite test and heavy/light chain pairs of immunoglobulin (HLC) using Hevylite. METHODS: Using the methods Hevylite, NEF, SPE, IFE and Freelite, we examined a cohort of 134 individuals fulfilling the International Myeloma Working Group (IMWG) criteria. 96 patients were of IgG and 38 of IgA type. RESULTS: The levels of HLC-kappa (K) and HLC-lambda (L), as well as HLC-r were independent of age and gender. Abnormal HLC levels were present in 84-100%, pathological HLC-r was in 92-100% cases based on MIg isotype. We found strong positive correlation between IgG and IgA (NEF) and the sum of HLC IgG-K + IgG-L (Hevylite) (r = 0.80, p < 0.0001) and HLC IgA-K + IgA-L (r = 0.75, p < 0.0001). Very strong positive correlation was between the concentration of MIg (SPE) and the levels of HLC (Hevylite) in IgG-K (r = 0.73), IgG-L (r = 0.76), IgA-K (r = 0.70) and IgA-L (r = 0.89), p < 0,0001. Systematic difference between Hevylite vs. MIg (SPE) was confirmed by Bland-Altmann test in the case of HLC IgA-K and IgA-L (not HLC IgG-K and IgG-L), and in the correlation of HLC with IgG and IgA (NEF). The most significant correlation between SPE (patients with < 15 g/L) vs. Hevylite was found within the analysis of HLC IgG-K+ IgA-K (r = 0.85, p < 0.0001), and in the whole cohort of MM patients, i.e. IgG + IgA-kappa and lambda (r = 0.76, p < 0.0001), confirmed by Bland-Altmann test. Tight positive correlation was between HLC-r and index of monoclonality FLC-K/L in MM of IgG and IgA type MM (p < 0.0001). CONCLUSION: Hevylite method, especially the assessment of HLC-r of IgA type MM is more sensitive in comparison with SPE evaluated by NEF, and increases the diagnostic sensitivity and the extent of tumor mass examination. Despite its limitation in the case of high levels of IgG type MIg, Hevylite technique has a promising potential to enrich the standard analytic tools as it enables to assess the concentration and ratio of the levels of both tumor and physiological immunoglobulins e.g. depth of immunoparesis, valid especially in MM with low levels of MIg. PMID- 26750628 TI - Comparative sequence analyses of rhodopsin and RPE65 reveal patterns of selective constraint across hereditary retinal disease mutations. AB - Retinitis pigmentosa (RP) comprises several heritable diseases that involve photoreceptor, and ultimately retinal, degeneration. Currently, mutations in over 50 genes have known links to RP. Despite advances in clinical characterization, molecular characterization of RP remains challenging due to the heterogeneous nature of causal genes, mutations, and clinical phenotypes. In this study, we compiled large datasets of two important visual genes associated with RP: rhodopsin, which initiates the phototransduction cascade, and the retinoid isomerase RPE65, which regenerates the visual cycle. We used a comparative evolutionary approach to investigate the relationship between interspecific sequence variation and pathogenic mutations that lead to degenerative retinal disease. Using codon-based likelihood methods, we estimated evolutionary rates (d N/d S) across both genes in a phylogenetic context to investigate differences between pathogenic and nonpathogenic amino acid sites. In both genes, disease associated sites showed significantly lower evolutionary rates compared to nondisease sites, and were more likely to occur in functionally critical areas of the proteins. The nature of the dataset (e.g., vertebrate or mammalian sequences), as well as selection of pathogenic sites, affected the differences observed between pathogenic and nonpathogenic sites. Our results illustrate that these methods can serve as an intermediate step in understanding protein structure and function in a clinical context, particularly in predicting the relative pathogenicity (i.e., functional impact) of point mutations and their downstream phenotypic effects. Extensions of this approach may also contribute to current methods for predicting the deleterious effects of candidate mutations and to the identification of protein regions under strong constraint where we expect pathogenic mutations to occur. PMID- 26750627 TI - Effects of experimental fuel additions on fire intensity and severity: unexpected carbon resilience of a neotropical forest. AB - Global changes and associated droughts, heat waves, logging activities, and forest fragmentation may intensify fires in Amazonia by altering forest microclimate and fuel dynamics. To isolate the effects of fuel loads on fire behavior and fire-induced changes in forest carbon cycling, we manipulated fine fuel loads in a fire experiment located in southeast Amazonia. We predicted that a 50% increase in fine fuel loads would disproportionally increase fire intensity and severity (i.e., tree mortality and losses in carbon stocks) due to multiplicative effects of fine fuel loads on the rate of fire spread, fuel consumption, and burned area. The experiment followed a fully replicated randomized block design (N = 6) comprised of unburned control plots and burned plots that were treated with and without fine fuel additions. The fuel addition treatment significantly increased burned area (+22%) and consequently canopy openness (+10%), fine fuel combustion (+5%), and mortality of individuals >=5 cm in diameter at breast height (dbh; +37%). Surprisingly, we observed nonsignificant effects of the fuel addition treatment on fireline intensity, and no significant differences among the three treatments for (i) mortality of large trees (>=30 cm dbh), (ii) aboveground forest carbon stocks, and (iii) soil respiration. It was also surprising that postfire tree growth and wood increment were higher in the burned plots treated with fuels than in the unburned control. These results suggest that (i) fine fuel load accumulation increases the likelihood of larger understory fires and (ii) single, low-intensity fires weakly influence carbon cycling of this primary neotropical forest, although delayed postfire mortality of large trees may lower carbon stocks over the long term. Overall, our findings indicate that increased fine fuel loads alone are unlikely to create threshold conditions for high-intensity, catastrophic fires during nondrought years. PMID- 26750629 TI - Synthesis, Structure, White-Light Emission, and Temperature Recognition Properties of Eu/Tb Mixed Coordination Polymers. AB - Two series of Eu(III)/Tb(III) coordination polymers, [LnL(glu)]n.2nH2O (Ln = Eu (1), Tb (2)) and [LnL(glu)(H2O)]n (Ln = Eu (3), Tb (4)) [HL = (2-(2 sulfophenyl)imidazo(4,5-f)(1,10)-phenanthroline, H2glu = glutaric acid] have been hydrothermally synthesized by controlling the pH values and characterized by elemental analysis, infrared spectra, and single-crystal X-ray diffraction. Isomorphic compounds 1 and 2 exhibit 6-connected 3D network with the pcu topological net, containing left- and right-handed helical chains. Isomorphic compounds 3 and 4 show 3,4-connected 2D new topology with the point symbol of (4(2).6(3).8)(4(2).6). Multicolor luminescence can be tailored from red to green regions by singly varying the mixing molar ratio of Eu(III)/Tb(III) cations. The mixing component of 1Eu/2Tb = 4:6 not only achieves white-light emission with the CIE coordinate of (0.323, 0.339) upon excitation at 405 nm but also presents a temperature recognition property with the significantly high sensitivity of 0.68% per K in the 50-225 K temperature range upon excitation at 370 nm. PMID- 26750630 TI - Precision-cut intestinal slices: alternative model for drug transport, metabolism, and toxicology research. AB - INTRODUCTION: The absorption, distribution, metabolism, excretion and toxicity (ADME-tox) processes of drugs are of importance and require preclinical investigation intestine in addition to the liver. Various models have been developed for prediction of ADME-tox in the intestine. In this review, precision cut intestinal slices (PCIS) are discussed and highlighted as model for ADME-tox studies. AREAS COVERED: This review provides an overview of the applications and an update of the most recent research on PCIS as an ex vivo model to study the transport, metabolism and toxicology of drugs and other xenobiotics. The unique features of PCIS and the differences with other models as well as the translational aspects are also discussed. EXPERT OPINION: PCIS are a simple, fast, and reliable ex vivo model for drug ADME-tox research. Therefore, PCIS are expected to become an indispensable link in the in vitro-ex vivo-in vivo extrapolation, and a bridge in translation of animal data to the human situation. In the future, this model may be helpful to study the effects of interorgan interactions, intestinal bacteria, excipients and drug formulations on the ADME tox properties of drugs. The optimization of culture medium and the development of a (cryo)preservation technique require more research. PMID- 26750631 TI - Use of a self-adherent parietal traction mesh to close laparostomy (with video). PMID- 26750637 TI - Social variables exert selective pressures in the evolution and form of primate mimetic musculature. AB - Mammals use their faces in social interactions more so than any other vertebrates. Primates are an extreme among most mammals in their complex, direct, lifelong social interactions and their frequent use of facial displays is a means of proximate visual communication with conspecifics. The available repertoire of facial displays is primarily controlled by mimetic musculature, the muscles that move the face. The form of these muscles is, in turn, limited by and influenced by phylogenetic inertia but here we use examples, both morphological and physiological, to illustrate the influence that social variables may exert on the evolution and form of mimetic musculature among primates. Ecomorphology is concerned with the adaptive responses of morphology to various ecological variables such as diet, foliage density, predation pressures, and time of day activity. We present evidence that social variables also exert selective pressures on morphology, specifically using mimetic muscles among primates as an example. Social variables include group size, dominance 'style', and mating systems. We present two case studies to illustrate the potential influence of social behavior on adaptive morphology of mimetic musculature in primates: (1) gross morphology of the mimetic muscles around the external ear in closely related species of macaque (Macaca mulatta and Macaca nigra) characterized by varying dominance styles and (2) comparative physiology of the orbicularis oris muscle among select ape species. This muscle is used in both facial displays/expressions and in vocalizations/human speech. We present qualitative observations of myosin fiber-type distribution in this muscle of siamang (Symphalangus syndactylus), chimpanzee (Pan troglodytes), and human to demonstrate the potential influence of visual and auditory communication on muscle physiology. In sum, ecomorphologists should be aware of social selective pressures as well as ecological ones, and that observed morphology might reflect a compromise between the demands of the physical and the social environments. PMID- 26750641 TI - A cost-effectiveness model for the use of a cannabis-derived oromucosal spray for the treatment of spasticity in multiple sclerosis. AB - BACKGROUND: Severity of spasticity in multiple sclerosis (MS) directly correlates with the level and cost of care required. This study assessed whether a tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray for treatment of moderate-severe MS spasticity is a cost-effective use of healthcare resources in Wales. METHODS: A Markov model was developed to compare THC/CBD plus standard of care (SoC) treatments with SoC alone. RESULTS: At 30 years, total incremental cost for THC/CBD plus SoC treatment was estimated at L3,836/patient (ICER: L10,891/quality-adjusted life year [QALY]). Hospital admission costs had the greatest effect on the base case ICER. Inclusion of carer cost led to incremental cost of -L33,609/patient (ICER: -L95,423/QALY). CONCLUSIONS: The THC/CBD spray was found to be cost-effective for the treatment of spasticity in MS, and dominant, if home carer costs were included. Use of THC/CBD has the potential to generate cost savings by significantly improving the symptoms of moderate to severe MS spasticity. PMID- 26750640 TI - In situ probing of microbial activity within anammox granular biomass with microelectrodes. AB - An anaerobic rotating biological contactor was fed with inorganic synthetic wastewater for anammox. Besides biofilm, granular biomass with average diameter of approximately 5 mm formed. NH4(+), NO2(-), NO3(-) and pH microelectrodes were used to probe microbial activity in situ within the granules. At a sufficient substrate concentration, the anammox reaction was observed in the upper layer of granules, and the most active zone was found to be in the surface of 200-400 MUm. The in situ anammox activity increased with increasing substrate concentration, and a maximum ammonium consumption rate of 83.3 MUmol cm(-3) h(-1) was obtained at an ammonium concentration of 1000 MUmol L(-1). Under an ammonium-limited condition, denitrification activity was observed in the inner layer, and the most active zone was limited to 700-1000 MUm. This study revealed that denitrification bacteria coexisted with anammox bacteria within inorganic anammox granules. PMID- 26750639 TI - Comparison of Medicaid spending in schizoaffective patients treated with once monthly paliperidone palmitate or oral atypical antipsychotics. AB - BACKGROUND: Compared to oral atypical antipsychotics (OAAs), long-acting injectable antipsychotics require less frequent administration, and thus may improve adherence and reduce risk of relapse in schizoaffective disorder (SAD) patients. OBJECTIVE: To evaluate the impact of once monthly paliperidone palmitate (PP) versus OAAs on healthcare resource utilization, Medicaid spending, and hospital readmission among SAD patients. METHODS: Using FL, IA, KS, MS, MO, and NJ Medicaid data (January 2009-December 2013), adults with >=2 SAD diagnoses initiated on PP or OAA (index date) were identified. Baseline characteristics and outcomes were assessed during the 12month pre- and post-index periods, respectively. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to reduce confounding and compare the estimated treatment effect for PP versus OAA. RESULTS: A total of 10,778 OAA treated patients and 876 PP-treated patients were selected. Compared to OAAs, PP was associated with significantly lower medical costs (PSM: mean monthly cost difference [MMCD] = -$383, p < 0.001; IPTW: MMCD = -$403, p = 0.016), which offset the higher pharmacy costs associated with PP (PSM: MMCD = $270, p < 0.001; IPTW: MMCD = $350, p < 0.001) and resulted in similar total healthcare cost (PSM: MMCD = -$113, p = 0.414; IPTW: MMCD = -$53, p = 0.697) for PP versus OAA. Reduced risk of hospitalization (PSM: incidence rate ratio [IRR] = 0.85, p = 0.128; IPTW: IRR = 0.96, p = 0.004) and fewer hospitalization days (PSM: IRR = 0.74, p = 0.008; IPTW: IRR = 0.85, p < 0.001) were observed in PP versus OAA patients. Among hospitalized patients, PP was associated with a lower risk of 30 day hospital readmission compared to OAA (IPTW: odds ratio = 0.89, p = 0.041). Limitations The Medicaid data may not be representative of the nation or other states, and includes pre-rebate pharmacy costs (potentially over-estimated). Also changes in treatment over time were possible. CONCLUSIONS: Total healthcare costs associated with the use of once monthly PP versus OAAs appeared comparable; higher pharmacy costs for PP users were offset by lower medical costs related to fewer and shorter inpatients visits. PMID- 26750642 TI - Light and cucurbit[7]uril complexation dual-responsiveness of a cyanostilbene based self-assembled system. AB - A cyanostilbene-based amphiphile (CS) was synthesized, which could self-assemble into non-emissive bilayer vesicles and ultra-thin ribbons. Cucurbit[7]uril (CB[7]) could form an inclusion complex with CS with a significant hypochrome effect, giving a strong blue emission from non-emissive species. CS underwent photoisomerization induced by light irradiation, which allowed the membrane contraction into smaller vesicles. PMID- 26750638 TI - BRAF V600E inhibition stimulates AMP-activated protein kinase-mediated autophagy in colorectal cancer cells. AB - Although BRAF(V600E) mutation is associated with adverse clinical outcomes in patients with colorectal cancer (CRC), response and resistance mechanisms for therapeutic BRAF(V600E) inhibitors remains poorly understood. In the present study, we demonstrate that selective BRAF(V600E) inhibition activates AMP activated protein kinase (AMPK), which induces autophagy as a mechanism of therapeutic resistance in human cancers. The present data show AMPK-dependent cytoprotective roles of autophagy under conditions of therapeutic BRAF(V600E) inhibition, and AMPK was negatively correlated with BRAF(V600E)-dependent activation of MEK-ERK-RSK signaling and positively correlated with unc-51-like kinase 1 (ULK1), a key initiator of autophagy. Furthermore, selective BRAF(V600E) inhibition and concomitant suppression of autophagy led to the induction of apoptosis. Taken together, present experiments indicate that AMPK plays a role in the survival of BRAF(V600E) CRC cells by selective inhibition and suggest that the control of autophagy contributes to overcome the chemoresistance of BRAF(V600E) CRC cells. PMID- 26750643 TI - Consolidation therapy with mitoxantrone, ifosfamide and etoposide with or without rituximab before stem cell transplantation in relapsed diffuse large B-cell lymphoma patients failing second-line treatment. PMID- 26750644 TI - Co-existence of m.10663T>C Mutation with Haplogroup L3f1b Background in a Patient with LHON. PMID- 26750645 TI - Endocarditis is not an Independent Predictor of Blood Transfusion in Aortic Valve Replacement Patients With Severe Aortic Regurgitation. AB - OBJECTIVE: This study sought to evaluate if the presence of endocarditis was independently associated with increased perioperative blood transfusion in patients undergoing aortic valve replacements (AVR) with aortic regurgitation. DESIGN: This was a retrospective study. SETTING: Large Canadian tertiary care hospital. PARTICIPANTS: Six hundred sixty-two consecutive patients with aortic regurgitation score of 3 or higher undergoing AVR from 1995 to 2012. INTERVENTIONS: No interventions were performed in this retrospective study. MEASUREMENTS AND MAIN RESULTS: After REB approval, data were obtained from a center-specific database. Univariate analysis was performed to identify variables that may be associated with transfusion of any allogeneic blood product perioperatively. A multivariate logistic regression was generated to identify independent predictors of perioperative transfusion. Unadjusted transfusion rates in patients with no endocarditis and with endocarditis were 32% and 70% (p<0.001), respectively. Independent predictors of any transfusion were moderate to-severe preoperative anemia, preoperative renal failure, non-isolated AVR, age>70, urgent/emergent surgery, BMI<25, and female sex. Endocarditis was not an independent predictor of transfusion (OR = 0.748; 95% CI = 0.35-1.601). CONCLUSIONS: In patients undergoing AVR, unadjusted perioperative transfusion rates were higher when endocarditis was present. However, after adjustment, aortic valve endocarditis was not independently associated with blood transfusion. The authors' observation could be explained by the higher prevalence of many independent predictors of transfusion, such as comorbidities or more complex surgery, within the endocarditis group. Thus, AV endocarditis, in the absence of other risk factors, was not associated with increased perioperative transfusion risk. PMID- 26750646 TI - Calculating the Protamine Dose Necessary to Neutralize Heparin in All Patients Under All Circumstances. PMID- 26750647 TI - Extraluminal Placement of an Arndt Bronchial Blocker Through a Tracheal Stoma. PMID- 26750648 TI - Scale Lines to Facilitate Out-Plane Ultrasound Guidance for Vascular Access. PMID- 26750649 TI - Anesthetic Management of Patients Undergoing Right Lung Surgery After Left Upper Lobectomy: Selection of Tubes for One-Lung Ventilation (OLV) and Oxygenation During OLV. AB - OBJECTIVE: To investigate anesthesia management in patients undergoing right lung surgery after a previous left upper lobectomy (LUL) that may require special precautions since angulation of the left bronchus can hamper correct placement of a left-sided double-lumen tube (DLT), and one-lung ventilation (OLV) depending solely on the left lower lobe may lead to inadequate oxygenation. DESIGN: A retrospective data analysis. SETTING: Single university hospital. PARTICIPANTS: Patients underwent right lung surgery after previous LUL. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Anesthesia management was investigated in 18 patients who underwent right lung surgery following LUL. All intubation procedures were performed under bronchoscopic guidance to prevent airway trauma. OLV could be achieved with a left-sided DLT in 12 patients, while tubes other than this were required in 6 patients, including a right-sided DLT (n = 3) and a bronchial blocker (n = 3). The presence or absence of remarkable bronchial angulation, characterized by a combination of a wide (>140 degrees ) angle between the trachea and left main bronchus and a narrow (<100 degrees ) angle between the left main and lower bronchi critically affected tube selections. The minimum SpO2 during OLV was 90.9+/-4.1%. In 2 patients, intermittent bilateral ventilation was required to treat desaturation. In all the patients, the scheduled surgery could be completed. CONCLUSIONS: Extent of left bronchial angulations had a critical impact on whether or not a left-sided DLT could be used in patients undergoing right lung surgery after LUL. PMID- 26750650 TI - Comparison of Cuff Pressure Increases by Transesophageal Echocardiography: A Simulation Analysis Using a Porcine Pharyngeal Model. PMID- 26750651 TI - Effect of Ultrafiltration on Pulmonary Function and Interleukins in Patients Undergoing Cardiopulmonary Bypass. AB - OBJECTIVE: To evaluate the effect of ultrafiltration on interleukins, TNF-alpha levels, and pulmonary function in patients undergoing coronary artery bypass grafting (CABG). DESIGN: Prospective, randomized, controlled trial. SETTING: University hospital. PARTICIPANTS: Forty patients undergoing CABG were randomized into a group assigned to receive ultrafiltration (UF) during cardiopulmonary bypass (CPB) or into another group (control) that underwent the same procedure but without ultrafiltration. METHODS: Interleukins and TNF-alpha levels, pulmonary gas exchange, and ventilatory mechanics were measured in the preoperative, intraoperative, and postoperative periods. Interleukins and TNF alpha also were analyzed in the perfusate of the test group. MEASUREMENTS AND MAIN RESULTS: There were increases in IL-6 and IL-8 at 30 minutes after CPB and 6, 12, 24, and 36 hours after surgery, along with an increase in TNF-alpha at 30 minutes after CPB and 24, 36, and 48 hours after surgery in both groups. IL-1 increased at 30 minutes after CPB and 12 hours after surgery, while IL-6 increased 24 and 36 hours after surgery in the UF group. The analysis of the ultrafiltrate showed the presence of TNF-alpha and traces of IL-1beta, IL-6, and IL-8. There were alterations in the oxygen index, alveolar-arterial oxygen difference, deadspace, pulmonary static compliance and airway resistance after anesthesia and sternotomy, as well as in airway resistance at 6 hours after surgery in both groups, with no difference between them. CONCLUSIONS: Ultrafiltration increased the serum level of IL-1 and IL-6, while it did not interfere with gas exchange and pulmonary mechanics in CABG. PMID- 26750652 TI - High Left Ventricular Filling Pressure on Doppler Echocardiography Is Associated With Graft Failure and Overall Mortality Following Kidney Transplantation. AB - OBJECTIVE: Although E/e' is prognostic of mortality in patients with end-stage renal disease (ESED), little is known about the prognostic implications of E/e' following kidney transplant (KT). The objective of this study was to evaluate whether an elevated E/e' is associated with graft function, postoperative hemodialysis, and overall mortality in end-stage renal disease patients following KT. DESIGN: A retrospective observational study. SETTING: Tertiary teaching hospital. PARTICIPANTS: In total, 1,045 patients underwent KT at the authors' hospital between January 2006 and December 2013. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Patients were divided into groups with an E/e'<15 or>=15, as assessed by preoperative echocardiography (median time from preoperative assessment of echocardiography to surgery: 37 days [IQR: 16-68 days]). Of 1,045 patients, 821 patients (78.6%) had an E/e'<15, and 224 patients (21.4%) had an E/e'>=15. Multivariate analysis indicated that age (odds ratio [OR]: 1.03; 95% confidence interval [CI]: 1.01-1.04, p = 0.001), diabetes mellitus (OR: 2.7; CI: 1.94-3.83, p<0.001), beta-blocker (OR: 1.4; CI: 1.03-1.95, p = 0.034), left atrial dimension (OR: 1.07; CI: 1.04-1.11, p<0.001), and left ventricular mass index (OR: 1.02; CI: 1.01-1.03, p<0.001) are predictive of E/e'>=15. After adjustment using inverse probability of treatment weighting, E/e'>=15 also was associated independently with postoperative hemodialysis (OR: 2.0; 95% CI: 1.5 2.6, p<0.001), graft failure (OR: 1.7; 95% CI: 1.4-2.2; p<0.001), and overall mortality (hazard ratio [HR]: 3.2; 95% CI: 2.1-4.8, p<0.001). CONCLUSIONS: Preoperative E/e' is a prognostic indicator of overall mortality in ESRD patients undergoing KT. PMID- 26750653 TI - Knowing the Thebesian Valve by the Perioperative Echocardiographer. PMID- 26750655 TI - Outcomes of Gleason score 3 + 4 = 7 prostate cancer with minimal amounts (<6%) vs >=6% of Gleason pattern 4 tissue in needle biopsy specimens. AB - OBJECTIVE: The International Society of Urological Pathology Gleason grading system was modified in 2005. Since the modified system was introduced, many cancers that previously would have been categorized as Gleason score (GS) 6 are now categorized as GS 7 based on biopsy specimens that only contain minimal amounts (<6%) of Gleason pattern (GP) 4 tissue. However, the clinical significance of observing <6% of GP 4 tissue in biopsies of GS 7 prostate cancer has not been studied. MATERIAL AND METHODS: This study was based on needle biopsy specimens that were categorized as GS 6 or GS 7 and were obtained from patients who underwent radical prostatectomy (RP) with available follow-up data. We assessed the quantity of GP 4 tissue in biopsy specimens of GS 7 prostate cancer. Further, we evaluated the correlation between the quantity of GP 4 tissue and disease progression after RP. RESULTS: GP 4 comprising 26-49% of the specimen, GS 4+3 and percentage of total core tissue scored as positive were significant and independent predictors of prostate-specific antigen (PSA) failure after RP, as assessed using a multivariate Cox regression model that included the quantity of GP 4 in the prostate biopsy specimen, preoperative PSA, perineural invasion, clinical stage, number of positive cores, and percentage of core tissue scored as positive. Cases with GS 3+3 and cases in which the observed GP 4 area was <6% did not differ significantly in terms of biochemical PSA recurrence (BPR) status. In contrast, cases with 6-25% GP 4 tissue, 26-49% GP 4 tissue, and GS 4+3 showed more frequent BPR than cases with GS 3+3. CONCLUSIONS: Our data suggest that the quantity of GP 4 tissue in GS 7 cancer has clinical significance. However, there is a need for larger studies of the clinical significance of biopsy specimens that include <6% GP 4 tissue. We should reconsider whether the amount of GP 4 should be included in standart pathology reports. PMID- 26750654 TI - Defects in MAP1S-mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed. AB - Autophagy is a cellular process that executes the turnover of dysfunctional organelles and misfolded or abnormally aggregated proteins. Microtubule associated protein MAP1S interacts with autophagy marker LC3 and positively regulates autophagy flux. LC3 binds with fibronectinmRNA and facilitates its translation. The synthesized fibronectin protein is exported to cell surface to initiate the assembly of fibronectin extracellular matrix. Fibronectin is degraded in lysosomes after it is engulfed into cytosol via endocytosis. Here, we show that defects in MAP1S-mediated autophagy trigger oxidative stress, sinusoidal dilation, and lifespan reduction. Overexpression of LC3 in wild-type mice increases the levels of fibronectin and gamma-H2 AX, a marker of DNA double strand breakage. LC3-induced fibronectin is efficiently degraded in lysosomes to maintain a balance of fibronectin levels in wild-type mice so that the mice live a normal term of lifespan. In the LC3 transgenic mice with MAP1S deleted, LC3 enhances the synthesis of fibronectin but the MAP1S depletion causes an impairment of the lysosomal degradation of fibronectin. The accumulation of fibronectin protein promotes liver fibrosis, induces an accumulation of cell population at the G0/G1 stage, and further intensifies oxidative stress and sinusoidal dilatation. The LC3-induced overexpression of fibronectin imposes stresses on MAP1S-deficient mice and dramatically reduces their lifespans. Therefore, MAP1S-mediated autophagy plays an important role in maintaining mouse lifespan especially in the presence of extra amount of fibronectin. PMID- 26750660 TI - Molecular dynamics study on the nucleation of methane + tetrahydrofuran mixed guest hydrate. AB - The nucleation of methane (CH4), tetrahydrofuran (THF), and CH4 + THF hydrates are investigated by microsecond MD simulations. These three systems exhibit distinct structural developments in the aqueous phase quantified by the formation of cage structures of hydrogen bonded water molecules. The development of a cluster of cages in the CH4 system is limited by the scarce CH4 molecules in the solution, while in the THF system it is limited by the short lifetime of cages. In the CH4 + THF mixed guest system, a small cluster of caged CH4 molecules can be rapidly stabilized by abundant neighboring cages of THF molecules. Therefore, the induction time of the CH4 + THF mixed guest system is found to be significantly shorter than that of the pure CH4 and pure THF systems. Furthermore, the structure of cages found in the initially formed cage clusters are often different from the typical 5(12)6(n) (n = 0, 2, 3, 4) cages observed in clathrate hydrate systems. The cluster of cages may grow or transform into structure I or II clathrate hydrate in the later stages. PMID- 26750659 TI - Control of Surface Segregation in Bimetallic NiCr Nanoalloys Immersed in Ag Matrix. AB - Cr-surface segregation is a main roadblock encumbering many magneto-biomedical applications of bimetallic M-Cr nanoalloys (where M = Fe, Co and Ni). To overcome this problem, we developed Ni95Cr5:Ag nanocomposite as a model system, consisting of non-interacting Ni95Cr5 nanoalloys (5 +/- 1 nm) immersed in non-magnetic Ag matrix by controlled simultaneous co-sputtering of Ni95Cr5 and Ag. We employed Curie temperature (TC) as an indicator of phase purity check of these nanocomposites, which is estimated to be around the bulk Ni95Cr5 value of 320 K. This confirms prevention of Cr-segregation and also entails effective control of surface oxidation. Compared to Cr-segregated Ni95Cr5 nanoalloy films and nanoclusters, we did not observe any unwanted magnetic effects such as presence Cr-antiferromagnetic transition, large non-saturation, exchange bias behavior (if any) or uncompensated higher TC values. These nanocomposites films also lose their unique magnetic properties only at elevated temperatures beyond application requirements (>=800 K), either by showing Ni-type behavior or by a complete conversion into Ni/Cr-oxides in vacuum and air environment, respectively. PMID- 26750656 TI - TSPO ligand residence time: a new parameter to predict compound neurosteroidogenic efficacy. AB - The pharmacological activation of the cholesterol-binding Translocator Protein (TSPO) leads to an increase of endogenous steroids and neurosteroids determining benefic pleiotropic effects in several pathological conditions, including anxiety disorders. The relatively poor relationship between TSPO ligand binding affinities and steroidogenic efficacies prompted us to investigate the time (Residence Time, RT) that a number of compounds with phenylindolylglyoxylamide structure (PIGAs) spends in contact with the target. Here, given the poor availability of TSPO ligand kinetic parameters, a kinetic radioligand binding assay was set up and validated for RT determination using a theoretical mathematical model successfully applied to other ligand-target systems. TSPO ligand RT was quantified and the obtained results showed a positive correlation between the period for which a drug interacts with TSPO and the compound ability to stimulate steroidogenesis. Specifically, the TSPO ligand RT significantly fitted both with steroidogenic efficacy (Emax) and with area under the dose response curve, a parameter combining drug potency and efficacy. A positive relation between RT and anxiolytic activity of three compounds was evidenced. In conclusion, RT could be a relevant parameter to predict the steroidogenic efficacy and the in vivo anxiolytic action of new TSPO ligands. PMID- 26750661 TI - Performance of sludge settling property under nitrite existing conditions. AB - Performance of sludge settling property and filamentous bacteria growth under nitrite existing conditions were studied. Biomass was cultivated in three anoxic/aerobic sequencing batch reactors (SBRs). Two of them were dosed with nitrite to the anoxic and aerobic phases, respectively, leaving the remaining one without nitrite added as control. The results showed that nitrite had a significant negative effect on sludge settling property, a serious bulking (sludge volumn index (SVI)>350 mL/g) and a limited bulking (SVI about 220 mL/g) were observed in the anoxic- and aerobic-nitrite-dosed systems, respectively. Filamentous bulking more easily happened when nitrite existed in the anoxic conditions than in the aerobic conditions. There was almost no differences in terms of filamentous species between the nitrite-dosed and non-nitrite-dosed systems, which indicated that nitrite did not play a key role in determining the filamentous species. The nitrite existing under both anoxic and aerobic conditions showed a negative effect on microbiological intracellular storage capability, the maximum polyhydroxyalkanoates (PHA) production and the maximum specific PHA production rate in nitrite-dosed systems were both significantly lower than that in the control system. PMID- 26750662 TI - Flux Control at the Malonyl-CoA Node through Hierarchical Dynamic Pathway Regulation in Saccharomyces cerevisiae. AB - The establishment of a heterologous pathway in a microbial host for the production of industrially relevant chemicals at high titers and yields requires efficient adjustment of the central carbon metabolism to ensure that flux is directed toward the product of interest. This can be achieved through regulation at key branch points in the metabolic networks, and here we present a novel approach for dynamic modulation of pathway flux and enzyme expression levels. The approach is based on a hierarchical dynamic control system around the key pathway intermediate malonyl-CoA. The upper level of the control system ensures downregulation of endogenous use of malonyl-CoA for fatty acid biosynthesis, which results in accumulation of this pathway intermediate. The lower level of the control system is based on use of a novel biosensor for malonyl-CoA to activate expression of a heterologous pathway using this metabolite for production of 3-hydroxypropionic acid (3-HP). The malonyl-CoA sensor was developed based on the FapR transcription factor of Bacillus subtilis, and it demonstrates one of the first applications of a bacterial metabolite sensor in yeast. Introduction of the dual pathway control increased the production of 3-HP by 10-fold and can also be applied for production of other malonyl-CoA-derived products. PMID- 26750663 TI - Effect of different parameters of Er:YAG laser irradiations on class V composite restorations: A scanning electron microscopy study. AB - The purpose of this study was to compare different parameters of Er:YAG laser irradiations on the marginal microleakage of Class V resin composite restorations. A total of 45 extracted premolars were selected for the study. Class V cavities prepared on both buccal and lingual surfaces of teeth by Er:YAG laser or bur and divided into nine groups. The occlusal margins were in enamel and the cervical margins were in cementum. Group-1: bur preparation; Group-2: laser preparation (lp) (600 mJ/5 Hz); Group-3: lp (300 mJ/10 Hz); Group-4: lp (200 mJ/15 Hz); Group-5: lp (150 mJ/20 Hz); Group-6: lp (200 mJ/20 Hz); Group-7: lp (300 mJ/14 Hz); Group-8: lp (400 mJ/10 Hz); Group-9: lp (700 mJ/5 Hz). All teeth were stored in distilled water at 37 degrees C for 24 h, then thermocycled 1,000 times (5-55 degrees C). Five teeth from each group were chosen for the microleakage investigation and two teeth for the scanning electron microscope (SEM) evaluation. Teeth, which were prepared for the microleakage test were immersed in 0.5% methylene blue dye for 24 h. After immersing, the teeth were sectioned and observed under a stereomicroscope for dye penetration. Data were analyzed by Kruskal-Wallis and Mann-Whitney U tests (p < 0.05). More microleakage was observed in cervical regions compared to occlusal regions in all groups (p < 0.05) except for Group 6 (p > 0.05). No significant difference was observed among groups in terms of occlusal and cervical surfaces, separately (p > 0.05). It may be concluded that the cavities prepared by Er:YAG laser showed higher degree of microleakage than bur prepared at cervical regions. Different parameters of Er:YAG laser irradiations affected microleakage. SCANNING 38:434-441, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26750664 TI - High-efficiency robust perovskite solar cells on ultrathin flexible substrates. AB - Wide applications of personal consumer electronics have triggered tremendous need for portable power sources featuring light-weight and mechanical flexibility. Perovskite solar cells offer a compelling combination of low-cost and high device performance. Here we demonstrate high-performance planar heterojunction perovskite solar cells constructed on highly flexible and ultrathin silver mesh/conducting polymer substrates. The device performance is comparable to that of their counterparts on rigid glass/indium tin oxide substrates, reaching a power conversion efficiency of 14.0%, while the specific power (the ratio of power to device weight) reaches 1.96 kW kg(-1), given the fact that the device is constructed on a 57-MUm-thick polyethylene terephthalate based substrate. The flexible device also demonstrates excellent robustness against mechanical deformation, retaining >95% of its original efficiency after 5,000 times fully bending. Our results confirmed that perovskite thin films are fully compatible with our flexible substrates, and are thus promising for future applications in flexible and bendable solar cells. PMID- 26750665 TI - Gambogic acid potentiates clopidogrel-induced apoptosis and attenuates irinotecan induced apoptosis through down-regulating human carboxylesterase 1 and -2. AB - 1. In this study, we report that gambogic acid (GA), a promising anticancer agent, potentiates clopidogrel-induced apoptosis and attenuates CPT-11-induced apoptosis by down-regulating human carboxylesterase (CES) 1 and -2 via ERK and p38 MAPK pathway activation, which provides a molecular explanation linking the effect of drug combination directly to the decreased capacity of hydrolytic biotransformation. 2. The expression levels of CES1 and CES2 decreased significantly in a concentration- and time-dependent manner in response to GA in Huh7 and HepG2 cells; hydrolytic activity was also reduced. 3. The results showed that pretreatment with GA potentiated clopidogrel-induced apoptosis by down regulating CES1. Moreover, the GA-mediated repression of CES2 attenuated CPT-11 induced apoptosis. 4. Furthermore, the ERK and p38 MAPK pathways were involved in the GA-mediated down-regulation of CES1 and CES2. 5. Taken together, our data suggest that GA is a potent repressor of CES1 and CES2 and that combination with GA will affect the metabolism of drugs containing ester bonds. PMID- 26750666 TI - Editor's importunate role towards medical journalism in 2016-way to go! PMID- 26750667 TI - Mild therapeutic hypothermia in patients resuscitated from out-of-hospital cardiac arrest: A meta-analysis of randomized controlled trials. AB - AIMS: Guidelines recommend mild therapeutic hypothermia (MTH) for survivors of out-of-hospital cardiac arrest (OHCA). However, there is little literature demonstrating a survival benefit. We performed a meta-analysis of randomized controlled trials (RCTs) assessing the efficacy of MTH in patients successfully resuscitated from OHCA. MATERIALS AND METHODS: Electronic databases were searched for RCT involving MTH in survivors of OHCA, and the results were put through a meta-analysis. The primary endpoint was all-cause mortality, and the secondary endpoint was favorable neurological function. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using the Mantel-Haenszel method. A fixed-effect model was used and, if heterogeneity (I2 ) was >40, effects were analyzed using a random model. RESULTS: Six RCT (n = 1400 patients) were included. Overall survival was 50.7%, and favorable neurological recovery was 45.5%. Pooled data demonstrated no significant all-cause mortality (OR, 0.81; 95% CI 0.55-1.21) or neurological recovery (OR, 0.77; 95% CI 0.47-1.24). No evidence of publication bias was observed. CONCLUSION: This meta-analysis demonstrated that MTH did not confer benefit on overall survival rate and neurological recovery in patients resuscitated from OHCA. PMID- 26750669 TI - Comparative study between the effects of dexmedetomidine and propofol on cerebral oxygenation during sedation at pediatric cardiac catheterization. AB - INTRODUCTION: Nowadays, assessment of brain oxygen saturation, which is simply appliable and noninvasive method, can provide the anesthesia plans to be optimized according to the needs of the brain, which is the main target organ. Brain may be exposed to hypoxia due to supply-demand imbalance of oxygen not only in general anesthesia procedures but also in sedation practices. The aim of the study is to compare the effects of dexmedetomidine and propofol which are widely used agents for pediatric catheterization procedures on brain oxygen saturation using Fore-Sight. MATERIAL AND METHODS: A total of 44 patients undergoing diagnostic cardiac catheterization between 1 and 18 years old were included in the study. All patients, who were randomly divided into two groups, had ASA physical status I-II. In Group Propofol (Group P, n = 22),induction of sedation was made by midazolam (0.5 mg,iv) + propofol (1m/kg,iv), and in Group Dexmedetomidine (Group D, n = 22), induction of sedation was made by midazolam (0.5 mg,iv) +dexmedetomidine (1mcg/kg, iv). Throughout the sedation, cerebral tissue oxygen saturation (SctO 2 ) was recorded by Fore-Sight in addition to routine monitoring. RESULTS: There were no statistically significant differences between the groups in terms of demographic data, hemodynamic data and sedation scores. On other hand, statistically significant decreases in cerebral tissue oxygen saturation were detected especially at 5th and 10th minutes, in Group D, while cerebral oxygenation level did not decrease in Group P. Though, statistically significant difference was determined between two groups in terms of cerebral oxygen saturation, the obtained data was not interpreted as cerebral desaturation. CONCLUSION: As a conclusion, there was a statistically significant but clinically insignificant decrease in cerebral tissue oxygen saturation in dexmedetomidine group compared to propofol group. Although it does not seem to be important in hemodynamic stabilization, we assume that may cause problems for clinically unstable patients. PMID- 26750668 TI - Dynamic changes in the ischemic mitral annulus: Implications for ring sizing. AB - OBJECTIVES: Contrary to the rest of the mitral annulus, inter-trigonal distance is known to be relatively less dynamic during the cardiac cycle. Therefore, intertrigonal distance is considered a suitable benchmark for annuloplasty ring sizing during mitral valve (MV) surgery. The entire mitral annulus dilates and flattens in patients with ischemic mitral regurgitation (IMR). It is assumed that the fibrous trigone of the heart and the intertrigonal distance does not dilate. In this study, we sought to demonstrate the changes in mitral annular geometry in patients with IMR and specifically analyze the changes in intertrigonal distance during the cardiac cycle. METHODS: Intraoperative three-dimensional transesophageal echocardiographic data obtained from 26 patients with normal MVs undergoing nonvalvular cardiac surgery and 36 patients with IMR undergoing valve repair were dynamically analyzed using Philips Qlab (r) software. RESULTS: Overall, regurgitant valves were larger in area and less dynamic than normal valves. Both normal and regurgitant groups displayed a significant change in annular area (AA) during the cardiac cycle (P < 0.01 and P < 0.05, respectively). Anteroposterior and anterolateral-posteromedial diameters and inter-trigonal distance increased through systole (P < 0.05 for all) in accordance with the AAs in both groups. However, inter-trigonal distance showed the least percentage change across the cardiac cycle and its reduced dynamism was validated in both cohorts (P > 0.05). CONCLUSIONS: Annular dimensions in regurgitant valves are dynamic and can be measured feasibly and accurately using echocardiography. The echocardiographically identified inter-trigonal distance does not change significantly during the cardiac cycle. PMID- 26750670 TI - Postoperative metabolic acidosis following the minimally invasive radiofrequency maze procedure. AB - PURPOSE: Atrial fibrillation (AF) is the most common arrhythmia treated in the world. While medical treatment with antiarrhythmic drugs remains the primary treatment modality, symptomatic refractory AF often requires treatment with a catheter or surgical ablation. One minimally invasive therapy is the Mini-Maze procedure, which utilizes epicardial radiofrequency ablation via a subxiphoid approach to rid the heart of arrhythmogenic atrial foci without a median sternotomy or cardiopulmonary bypass. The goal of this retrospective cohort study was to identify clinical factors associated with metabolic acidosis following the Mini-Maze procedure. MATERIALS AND METHODS: After Institutional Review Board approval, we studied patients undergoing the Mini-Maze procedure, off-pump coronary artery bypass grafting or patients conventional Cox-Maze on cardiopulmonary bypass. The first base deficit value obtained in the Intensive Care Unit was used as a measure of metabolic acidosis. Using logistic regression with Akaike information criteria, we analyzed preoperative, intraoperative, and postoperative data to determine the factors associated with changes in base deficit. RESULTS: A multivariable model using stepwise selection demonstrated that diabetes mellitus and weight were associated with a decrease in the base deficit by 2.87 mEq/L (95% CI: -5.55--0.19) and 0.04 mEq/L (95%CI: -0.08, 0.004), respectively. Furthermore, creatinine was associated with a 1.57 mEq/L (95% CI: 0.14, 2.99) increase in the base deficit. CONCLUSION: The Mini-Maze procedure was not associated with postoperative metabolic acidosis. Instead, nondiabetic patients and patients with higher creatinine were associated with greater base deficits after undergoing cardiac surgery. PMID- 26750671 TI - Coronary computed tomography angiography for risk stratification before noncardiac surgery. AB - BACKGROUND: Currently, there are limited available data for coronary computed tomography angiography (CCTA) in the setting of the risk stratification before noncardiac surgery. The main purpose of this study is to investigate the role of CCTA in cardiac risk stratification before noncardiac surgery. MATERIALS AND METHODS: Ninety-three patients underwent CCTA in the assessment of cardiac risk before noncardiac surgery. Patients with normal or mildly abnormal CCTA (<50% stenosis) underwent surgery without any further testing (Group 1). Patients with abnormal CCTA (17 patients) (more than 50% stenosis) and nondiagnostic CCTA (5%) underwent either stress myocardial perfusion scintigraphy or conventional coronary angiography, Group 2. RESULTS: Group one consists of 71 patients who went for surgery without any further testing. 59 of 71 (83%) patients had no complications in the postoperative period, 9 patients had noncardiac complications, 1 had a cardiac complication (new onset atrial fibrillation), and 2 patients died in the postoperative period due to noncardiac complications. Group 2 comprises 22 (26%) patients, 16 patients had no postoperative complications, 5 patients had noncardiac complications, and one patient developed postoperative acute heart failure. CONCLUSIONS: CCTA is diagnostic in up to 95% in the preoperative setting, and it provides a comprehensive cardiac examination in the risk stratification before intermediate and high-risk noncardiac surgery. Therefore, CCTA may be considered as an alternative test for already established imaging techniques for preoperative cardiac risk stratification before noncardiac surgery. PMID- 26750672 TI - Effect of preoperative statin therapy on early postoperative memory impairment after off-pump coronary artery bypass surgery. AB - CONTEXT: Frequent incidence of early postoperative memory impairment (POMI) after cardiac surgery remains a concern because of associated morbidity, impaired quality of life, and increased health care cost. AIM: To assess the effect of preoperative statin therapy on POMI in patients undergoing off-pump coronary artery bypass (OPCAB) surgery. SETTING AND DESIGN: Prospective observational study in a tertiary level hospital. METHODS: Sixty patients aged 45-65 years undergoing OPCAB surgery were allocated into two groups of 30 each. Group A patients were receiving statin and Group B patients were not receiving statins. All patients underwent memory function assessment preoperatively after admission to hospital and on the 6 th postoperative day using postgraduate institute memory scale. STATISTICAL ANALYSIS: Appropriate tests were applied with SPSS 20 to compare both groups. The value P < 0.05 was considered statistically significant. Multiple regression analysis was performed with confounding factors to determine the effect on memory impairment. RESULTS: Patients in Group A showed significant postoperative deterioration in 6 of the 10 functions and in Group B showed deterioration in 9 of 10 functions tested compared to preoperative scores. Intergroup comparison detected less POMI in Group A compared to Group B and was statistically significant in 8 memory functions. Multiple regression analysis detected statin as an independent factor in preventing memory impairment. CONCLUSIONS: Preoperative statin therapy attenuates the early POMI in patients undergoing OPCAB. Future long-term studies will define the efficacy of statin on POMI. PMID- 26750673 TI - Conventional hemofiltration during cardiopulmonary bypass increases the serum lactate level in adult cardiac surgery. AB - OBJECTIVE: To evaluate the effect of hemofiltration during cardiopulmonary bypass on lactate level in adult patients who underwent cardiac surgery. DESIGN: An observational study. SETTING: Prince Sultan cardiac center, Riyadh, Saudi Arabia. PARTICIPANTS: The study included 283 patients classified into two groups: Hemofiltration group (n=138), hemofiltration was done during CPB. Control group (n = 145), patients without hemofiltration. INTERVENTIONS: Hemofiltration during cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: Monitors included hematocrit, lactate levels, mixed venous oxygen saturation, amount of fluid removal during hemofiltration and urine output. The lactate elevated in group H than group C (P < 0.05), and the PH showed metabolic acidosis in group H (P < 0.05). The mixed venous oxygen saturation decreased in group H than group C (P < 0.05). The number of transfused packed red blood cells was lower in group H than group C (P < 0.05). The hematocrit was higher in group H than group C (P < 0.05). The urine output was lower in group H than group C (P < 0.05). CONCLUSIONS: Hemofiltration during cardiopulmonary bypass leads to hemoconcentration, elevated lactate level and increased inotropic support. There are some recommendations for hemofiltration: First; Hemofiltration should be limited for patients with impaired renal function, positive fluid balance, reduced response to diuretics or prolonged bypass time more than 2 hours. Second; Minimal amount of fluids should be administered to maintain adequate cardiac output and reduction of priming volumes is preferable to maintain controlled hemodilution. Third; it should be done before weaning of or after cardiopulmonary bypass and not during the whole time of cardiopulmonary bypass. PMID- 26750674 TI - Comparison of levosimendan and nitroglycerine in patients undergoing coronary artery bypass graft surgery. AB - BACKGROUND: Levosimendan a calcium ion sensitizer improves both systolic and diastolic functions. This novel lusitropic drug has predictable antiischemic properties which are mediated via the opening of mitochondrial adenosine triphosphate-sensitive potassium channels. This action of levosimendan is beneficial in cardiac surgical patients as it improves myocardial contractility, decreases systemic vascular resistance (SVR), and increases cardiac index (CI) and is thought to be cardioprotective. We decided to study whether levosimendan has any impact on the outcomes such as the duration of ventilation, the length of Intensive Care Unit (ICU) stay, and the hospital stay when compared with the nitroglycerine (NTG), which is the current standard of care at our center. MATERIALS AND METHODS: Forty-seven patients undergoing elective coronary artery bypass surgery were randomly assigned to two groups receiving either levosimendan or NTG. The medications were started before starting surgery and continued until 24 h in the postoperative period. Baseline hemodynamic parameters were evaluated before beginning of the operation and then postoperatively at 3 different time intervals. N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) levels were also measured in both groups. RESULTS: In comparison to the NTG group, the duration of ventilation and length of ICU stay were significantly less in levosimendan group (P < 0.05, P = 0.02). NT-proBNP level analysis showed a slow rising pattern in both groups and a statistically significant rise in the levels was observed in NTG group (P = 0.03, P = 0.02) in postoperative period when compared to levosimendan group of patients. CONCLUSION: Levosimendan treatment in patients undergoing surgical revascularization resulted in improved CI, decreased SVR and lower heart rate. And, thereby the duration of ventilation and length of ICU stay were significantly less in this group of patients when compared with NTG group. PMID- 26750675 TI - Cerebral oxygenation monitoring in patients with bilateral carotid stenosis undergoing urgent cardiac surgery: Observational case series. AB - BACKGROUND: Patients with significant bilateral carotid artery stenosis requiring urgent cardiac surgery have an increased risk of stroke and death. The optimal management strategy remains inconclusive, and the available evidence does not support the superiority of one strategy over another. MATERIALS AND METHODS: A number of noninvasive strategies have been developed for minimizing perioperative stroke including continuous real-time monitoring of cerebral oxygenation with near-infrared spectroscopy (NIRS). The number of patients presenting with this combination (bilateral significant carotid stenosis requiring urgent cardiac surgery) in any single institution will be small and hence there is a lack of large randomized studies. RESULTS: This case series describes our early experience with NIRS in a select group of patients with significant bilateral carotid stenosis undergoing urgent cardiac surgery (n = 8). In contrast to other studies, this series is a single surgeon, single center study, where the entire surgery (both distal ends and proximal ends) was performed during single aortic clamp technique, which effectively removes several confounding variables. NIRS monitoring led to the early recognition of decreased cerebral oxygenation, and corrective steps (increased cardiopulmonary bypass flow, increased pCO 2 , etc.,) were taken. CONCLUSION: The study shows good clinical outcome with the use of NIRS. This is our "work in progress," and we aim to conduct a larger study. PMID- 26750676 TI - Ultrasound evaluation of effect of different degree of wrist extension on radial artery dimension at the wrist joint. AB - CONTEXT: Successful arterial cannulation requires wide and patent arterial lumen. A recent study has shown that success rate of radial arterial cannulation at first attempt is more at 45 degrees angle of wrist extension in both young and elderly patients. No study has reasoned whether these high success rates at 45 degrees is because of less compression of the radial artery at this particular angle of wrist extension. Hence, we attempted to study whether the radial artery dimensions changes with increasing angles of wrist extension in young, healthy female volunteers using ultrasound examination. AIM: To investigate the effect of increasing angle of wrist extension of 0, 15, 30, 45, 60, and 75 degrees on radial artery dimensions at the level of the wrist joint using ultrasound examination. SETTINGS AND DESIGN: A prospective single blinded study in volunteers. SUBJECTS AND METHODS: Sonographic measurements of radial artery dimension at the wrist level were performed in 48 young, healthy female subjects. Height (anteroposterior in mm), width (mediolateral in mm) and depth (skin to artery) were measured at wrist extension of 0, 15, 30, 45, 60, and 75 degrees . The dimensions at each angle are compared with 0 degrees as the control and statistical analysis done. STATISTICAL ANALYSIS: One-way analysis of variance test. RESULTS: No statistically significant change in dimension of the radial artery is observed with increasing angle of wrist extension. CONCLUSION: Ultrasound evaluation showed that increasing angle of wrist extension does not significantly change the dimensions of radial artery at the wrist joint level in young healthy female volunteers. PMID- 26750677 TI - Comparison of hemodynamic responses to laryngoscopy and intubation with Truview PCDTM, McGrath(r) and Macintosh laryngoscope in patients undergoing coronary artery bypass grafting: A randomized prospective study. AB - CONTEXT: We hypothesized that reduced oropharyngolaryngeal stimulation with video laryngoscopes would attenuate hemodynamic response to laryngoscopy and intubation. AIM: Comparison of hemodynamic response to laryngoscopy and intubation with video laryngoscopes and Macintosh (MC) laryngoscope. SETTING AND DESIGN: Superspecialty tertiary care public hospital; prospective, randomized control study. METHODS: Sixty adult patients undergoing elective coronary artery bypass grafting (CABG) were randomly allocated to three groups of 20 each: MC, McGrath (MG), and TruviewTM. Hemodynamic parameters were serially recorded before and after intubation. Laryngoscopic grade, laryngoscopy, and tracheal intubation time, ST segment changes, and intra-/post-operative complications were also recorded and compared between groups. STATISTICAL ANALYSIS: SPSS version 17 was used, and appropriate tests applied. P < 0.05 was considered significant. RESULTS: Heart rate and diastolic arterial pressure increased at 0 and 1 min of intubation in all the three groups (P < 0.05) while mean arterial pressure increased at 0 min in the MG and TV groups and at 1 min in all three groups (P < 0.05). A significant increase in systolic arterial pressure was only observed in TV group at 1 min (P < 0.05). These hemodynamic parameters returned to baseline by 3 min of intubation in all the groups. The intergroup comparisons of all hemodynamic parameters were not significant at any time of observation. Highest intubation difficulty score was observed with MC (2.16 +/- 1.86) as compared with MG (0.55 +/- 0.88) and TV (0.42 +/- 0.83) groups (P = 0.003 and P = 0.001, respectively). However, duration of laryngoscopy and intubation was significantly less in MC (36.68 +/- 16.15 s) as compared with MG (75.25 +/- 30.94 s) and TV (60.47 +/- 27.45 s) groups (P = 0.000 and 0.003, respectively). CONCLUSIONS: Video laryngoscopes did not demonstrate any advantage in terms of hemodynamic response in patients with normal airway undergoing CABG. PMID- 26750678 TI - Prevalence of carotid artery stenosis in neurologically asymptomatic patients undergoing coronary artery bypass grafting for coronary artery disease: Role of anesthesiologist in preoperative assessment and intraoperative management. AB - OBJECTIVE(S): This study aimed to determine the prevalence of carotid artery stenosis (CAS) due to atherosclerosis in neurologically asymptomatic patients undergoing coronary artery bypass grafting (CABG) for coronary artery disease (CAD). It contemplated a greater role for the cardiac anesthesiologist in the perioperative management of such patients with either previously undiagnosed carotid artery disease or towards re-assessment of severity of CAS. DESIGN: Prospective, observational clinical study. SETTING: Operation room of a cardiac surgery centre of a tertiary teaching hospital. PARTICIPANTS: A hundred adult patients with New York Heart Association (NYHA) classification I to III presenting electively for CABG. INTERVENTIONS: All patients included in this study were subjected to ultrasonic examination by means of acarotid doppler scan to access for presence of CAS just prior to induction of general anesthesia. MEASUREMENTS AND MAIN RESULTS: Based on parameters measured using carotid doppler, the presence of CAS was defined using standard criteria. The prevalence of CAS was found to be as high as 38% amongst the patients included in our study. The risk factors for CAS were identified to be advanced age, history of smoking, diabetes mellitus, dyslipidaemia and presence of a carotid bruit. CONCLUSION: This study points towards the relatively wide prevalence of carotid artery disease in neurologically asymptomatic patients undergoing CABG for CAD in the elective setting. It highlights the need to routinely incorporate carotid ultrasonography in the armamentarium of the cardiac anesthesiologist as standard of care for all patients presenting for CABG. PMID- 26750679 TI - Patient prosthesis mismatch after aortic valve replacement: An Indian perspective. AB - CONTEXT: Perioperative period. AIMS: Occurrence of PPM after AVR, factors associated with PPM, impact on mortality. SETTINGS AND DESIGN: Teritary Care Referral Cardiac Centre. MATERIALS AND METHODS: A retrospective analysis of AVR procedures at a single centre over 4 years was conducted. Demographic, echocardiographic and outcome data were collected from institute database. Rahimtoola criteria of indexed effective orifice area (iEOA) were used to stratify patients into PPM categories. Patients with and without PPM were compared for associated factors. STATISTICAL ANALYSIS USED: Independent t-test, chi-square test, logistic regression analysis, ROC-AUC, Youden index. RESULTS: 606 patients with complete data were analysed for PPM. The incidence of mild, moderate and severe PPM was 6.1% (37), 2.5% (15) and 0.5% (3) respectively. There was no impact of PPM on all-cause in-hospital mortality. PPM was observed more with Aortic Stenosis (AS) compared to Aortic Regurgitation (AR) as etiology. Aortic annulus indexed to BSA (iAA) had a very good predictive ability for PPM at <16mm/m 2 BSA. CONCLUSIONS: PPM has lower incidence after AVR in this Indian population and does not increase early mortality. Patients with AS and iAA<16mm/m2BSA should be cautiously dealt with to prevent PPM. PMID- 26750680 TI - Management of refractory hypoxemia. AB - Mechanical ventilation remains the cornerstone in the management of severe acute respiratory failure. Acute respiratory distress syndrome (ARDS) is the most common cause of respiratory failure. It is associated with substantial mortality, and unmanageable refractory hypoxemia remains the most feared clinical possibility. If hypoxemia persists despite application of lung protective ventilation, additional therapies including inhaled vasodilators, prone positioning, recruitment maneuvers, high-frequency oscillatory ventilation, neuromuscular blockade (NMB), and extracorporeal membrane oxygenation may be needed. NMB and prone ventilation are modalities that have been clearly linked to reduced mortality in ARDS. Rescue therapies pose a clinical challenge requiring a precarious balance of risks and benefits, as well as, in-depth knowledge of therapeutic limitations. PMID- 26750682 TI - Strain and strain rate: An emerging technology in the perioperative period. AB - Newer noninvasive parameters are being used for perioperative detection of myocardial ischaemia. TDI and global strain rate are some of these parameters. TDI signal is a modification of the routine Doppler flow signal. It is obtained by using thresholding and filtering algorithms that reject echoes originating from the blood pool (by-passing the high pass filter). Set-Up of the machine by activating the TDI function allows decreasing the system gain using a low pass filter and eliminates the signal produced by blood flow. Doppler shift obtained from myocardial tissue motion are of higher amplitudes (reflectivity 40 dB higher) and move about 10 times slower than blood (velocity range: 0.06 to 0.24 m/s). Speckle tracking echocardiography (tissue tracking, 2D strain) utilizes routine gray-scale 2D echo images to calculate myocardial strain. Interactions of ultrasound with myocardium result in reflection and scattering. These interactions generate a finely gray-shaded, speckled pattern (acoustic marker). This speckled pattern is unique for each myocardial region and relatively stable throughout the cardiac cycle. Spatial and temporal image processing of acoustic speckles in both 2D and 3D allows for the calculation of myocardial velocity, strain, and Strain rate. PMID- 26750681 TI - Adult venovenous extracorporeal membrane oxygenation for severe respiratory failure: Current status and future perspectives. AB - Extracorporeal membrane oxygenation (ECMO) for severe acute respiratory failure was proposed more than 40 years ago. Despite the publication of the ARDSNet study and adoption of lung protective ventilation, the mortality for acute respiratory failure due to acute respiratory distress syndrome has continued to remain high. This technology has evolved over the past couple of decades and has been noted to be safe and successful, especially during the worldwide H1N1 influenza pandemic with good survival rates. The primary indications for ECMO in acute respiratory failure include severe refractory hypoxemic and hypercarbic respiratory failure in spite of maximum lung protective ventilatory support. Various triage criteria have been described and published. Contraindications exist when application of ECMO may be futile or technically impossible. Knowledge and appreciation of the circuit, cannulae, and the physiology of gas exchange with ECMO are necessary to ensure lung rest, efficiency of oxygenation, and ventilation as well as troubleshooting problems. Anticoagulation is a major concern with ECMO, and the evidence is evolving with respect to diagnostic testing and use of anticoagulants. Clinical management of the patient includes comprehensive critical care addressing sedation and neurologic issues, ensuring lung recruitment, diuresis, early enteral nutrition, treatment and surveillance of infections, and multisystem organ support. Newer technology that delinks oxygenation and ventilation by extracorporeal carbon dioxide removal may lead to ultra-lung protective ventilation, avoidance of endotracheal intubation in some situations, and ambulatory therapies as a bridge to lung transplantation. Risks, complications, and long-term outcomes and resources need to be considered and weighed in before widespread application. Ethical challenges are a reality and a multidisciplinary approach that should be adopted for every case in consideration. PMID- 26750685 TI - Approaches to internal jugular and subclavian vein. PMID- 26750683 TI - Perioperative management of patient with intracoronary stent presenting for noncardiac surgery. AB - As the number of percutaneous coronary interventions increase annually, patients with intracoronary stents (ICS) who present for noncardiac surgery (NCS) are also on the rise. ICS is associated with stent thrombosis (STH) and requires mandatory antiplatelet therapy to prevent major adverse cardiac events. The risks of bleeding and ischemia remain significant and the management of these patients, especially in the initial year of ICS is challenging. The American College of Cardiologists guidelines on the management of patients with ICS recommend dual antiplatelet therapy (DAT) for minimal 14 days after balloon angioplasty, 30 days for bare metal stents, and 365 days for drug-eluting stents. Postponement of elective surgery is advocated during this period, but guidelines concerning emergency NCS are ambiguous. The risk of STH and surgical bleeding needs to be assessed carefully and many factors which are implicated in STH, apart from the type of stent and the duration of DAT, need to be considered when decision to discontinue DAT is made. DAT management should be a multidisciplinary exercise and bridging therapy with shorter acting intravenous antiplatelet drugs should be contemplated whenever possible. Well conducted clinical trials are needed to establish guidelines as regards to the appropriate tests for platelet function monitoring in patients undergoing NCS while on DAT. PMID- 26750684 TI - Anesthetic considerations for endovascular abdominal aortic aneurysm repair. AB - Aneurysm is defined as a localized and permanent dilatation with an increase in normal diameter by more than 50%. It is more common in males and can affect up to 8% of elderly men. Smoking is the greatest risk factor for abdominal aortic aneurysm (AAA) and other risk factors include hypertension, hyperlipidemia, family history of aneurysms, inflammatory vasculitis, and trauma. Endovascular Aneurysm Repair [EVAR] is a common procedure performed for AAA, because of its minimal invasiveness as compared with open surgical repair. Patients undergoing EVAR have a greater incidence of major co-morbidities and should undergo comprehensive preoperative assessment and optimization within the multidisciplinary settings. In majority of cases, EVAR is extremely well tolerated. The aim of this article is to outline the Anesthetic considerations related to EVAR. PMID- 26750686 TI - Transesophageal echocardiography for dextro-transposition of great arteries. PMID- 26750687 TI - Some clarifications regarding multiple comparisons. PMID- 26750688 TI - Large aortic root hematoma mimicking left atrial mass in a cardiac postoperative patient. PMID- 26750689 TI - Conversion of a single lumen tube to double lumen tube in an anticipated difficult airway: Flexible fiberoptic bronchoscope assisted with intubating introducer-guided technique. PMID- 26750690 TI - Case report of aortopulmonary window with undiagnosed interrupted aortic arch: Role of transesophageal echocardiography. PMID- 26750691 TI - Life-threatening ruptured femoral artery pseudoaneurysm: A delayed complication of endovascular aortic repair of abdominal aortic aneurysm. PMID- 26750692 TI - Late Sir A. P. J. Abdul Kalam no more: Still he alive in our heart. PMID- 26750693 TI - Endovascular repair of expanding thoracic aortic aneurysms in high surgical risk patients. PMID- 26750694 TI - Cardiac papillary fibroelastoma; when, how, why? AB - We would like to present an interesting case operated on in our department and discuss the international bibliography about this issue. We also present some interesting images of this case. Our material is composed from a 68-year-old woman treated by the authors. She presented with a small murmur in the auscultation while she was asymptomatic and then she diagnosed with a tumor on of the left coronary cusp of the aortic valve with the characteristics of papillary fibroelastoma. On the basis of the potential embolic risk either of the mass itself or of associated thrombus and the possibility of further enlargement, the patient although asymptomatic at the time of diagnosis was referred for elective surgical excision of the mass. She underwent on median sternotomy and through extracorporeal circulation the mass has been excised with the preservation of the well-functioning valve. Through this case, we would like to discuss the bibliography for the decision making in these cases. Hence, the aim of our study is that we have to keep in mind that this kind of friable mass may be the cause of embolism, stroke or coronary artery occlusion and must be excided in a conservative setting, sparing the aortic valve. PMID- 26750695 TI - Perceval S aortic valve implantation in an achondroplastic Dwarf. AB - Despite cardiovascular disease in patients with dwarfism is not rare; there is a lack of reports referring to cardiac interventions in such patients. Dwarfism may be due to achondroplasia or hormonal growth disorders. We present a 58-year-old woman with episodes of dyspnea for several months. She underwent on transthoracic echocardiography, and she diagnosed with severe aortic valve stenosis. She referred to our department for surgical treatment of this finding. In accordance of her anthropometric characteristics and her very small aortic annulus, we had the dilemma of prosthesis selection. We decided to implant a stentless valve to optimize her effective orifice area. Our aim is to present the successful Perceval S valve implantation and the descriptions of the problems coming across in operating on these special patients. To our knowledge, this is the first case patient in which a Perceval S valve is implanted according to the international bibliography. PMID- 26750696 TI - Left ventricular pseudoaneurysm versus aneurysm a diagnosis dilemma. AB - Free wall rupture of the left ventricle (LV) is a rare but life-threatening complication of acute myocardial infaction. Very rarely such rupture may be contained by the adhering pericardium creating a pseudoaneurysm. This condition warrants for an emergency surgery. Left ventricular aneurysm is the discrete thinning of the ventricular wall (<5 mm) with akinetic or dyskinetic wall motion causing an out-pouching of the ventricle. Given the propensity for pseudoaneurysms to rupture leading to cardiac tamponade, shock, and death, compared with a more benign natural history for true aneurysms, accurate diagnosis of these conditions is important. True aneurysm, usually, calls for an elective surgery. Clinically differentiating the two conditions remains a challenge. We report the case of a patient with LV pseudoaneurysm, initially diagnosed as true aneurysm at our institution. We have attempted to review the existing literature and discussed the characteristic findings of each entity. PMID- 26750697 TI - Right ventricular thrombus in case of atrial septal defect with massive pulmonary embolism: A diagnostic dilemma. PMID- 26750698 TI - Fontan's circulation with dextrocardia, recent pulmonary embolism, and inferior vena cava filter: Anesthetic challenges for urgent hysterectomy. AB - Fontan's circulation is a unique challenge for the anesthesiologist. Venous pressure is the only source of blood flow for the pulmonary circulation. Patients with such circulation are extremely sensitive to progression of cyanosis (decreased pulmonary blood flow) or circulatory failure. Any major venous compression can compromise the pulmonary blood flow worsening cyanosis; simultaneously, an increased afterload can precipitate circulatory failure. We present a rare patient of surgically corrected Ivemark syndrome with Fontan's physiology with dextrocardia who developed a large uterine fibroid compressing inferior vena cava (IVC). As a result of compression, not only the pulmonary circulation was compromised but she also developed stasis-induced venous thrombosis in the lower limbs that lead to pulmonary embolism (PE) (increased afterload). In addition to oral anticoagulation an IVC filter was inserted to prevent ongoing recurrent PE. Further, to prevent both circulatory compromise and deep venous thrombosis an urgent myomectomy/hysterectomy was planned. In the present case, we discuss the issues involved in the anesthetic management of such patients and highlight the lacunae in the present guidelines for managing perioperative anticoagulation these situations. PMID- 26750699 TI - Simultaneous "traumatic Gerbode" and aortic rupture due to blunt chest trauma. AB - The Gerbode defect is characterized by a perimembranous ventricular septal defect between the left ventricle and the right atrium. This intracardiac shunt is a congenital defect but may be iatrogenic after valve surgery or atrioventricular node ablation, may be the result of endocarditis or may be traumatic. It is really rarely encountered as sequelae of non-penetrating heart trauma, and their clinical manifestations may often be unrecognized in the multi-injured patient. However, they are serious complications, and their diagnostic approach is not always feasible. We hereby present a case of a young man with the left ventricle to the right atrium communication after blunt thoracic trauma due to a car accident and concomitant rupture of the thoracic aorta. We present also the case and the ways of treatment according to the international bibliography. PMID- 26750700 TI - Lactate clearance for initiating and weaning off extracorporeal membrane oxygenation in a child with regressed left ventricle after arterial switch operation. AB - We hereby report a child with transposition of great arteries and regressed ventricle who underwent arterial switch operation (ASO) with the aid of cardiopulmonary bypass and "integrated" extracorporeal membrane oxygenation (ECMO) circuit. The significance of lactate clearance as a guide to initiate and terminate veno-arterial ECMO in a post ASO child with regressed left ventricle is discussed. PMID- 26750702 TI - The role of side stream dark field microvasculature imaging in a rare case of vancomycin-resistant enterococcal endocarditis complicated by heparin-induced thrombocytopenia. AB - Sidestream dark field (SDF) imaging allows direct visualization of microvascular architecture and function. We examine the role of an SDF imaging device in visualizing the sub-lingual microvasculature as a surrogate for splanchnic microperfusion. We demonstrate good correlation between current monitoring techniques and the SDF imaging device in a rare case of vancomycin-resistant enterococcal (VRE) sepsis along with heparin-induced thrombocytopenia (HIT). To the best of our knowledge, VRE endocarditis with concurrent HIT has not been described in literature. The role of SDF imaging may predict the earlier need for escalation of care, improving morbidity and mortality. PMID- 26750701 TI - Intravenous thrombolytic therapy for patients with ventricular assist device thrombosis: An attempt to avoid reoperation. AB - A growing number of patients are undergoing prolonged management of advanced heart failure with the use of continuous flow left ventricular assist devices (LVADs). Subsequently, an increasing number of patients are presenting with complications associated with these devices. Based on an analysis of three major LVAD institutions, the number of patients developing LVAD pump thrombosis may be much higher than originally projected. [1],[2] The management of this highly feared complication continues to be challenging, as the population of LVAD patients is very heterogeneous and heavily burdened with comorbidities. The standard protocol of increasing anticoagulation may fail to achieve successful resolution of thrombus. Difficulty and poor prognosis may make reoperation less than desirable. Here, we present a case of successful thrombolysis following intravenous administration of tissue plasminogen activator in the Intensive Care Unit setting. PMID- 26750703 TI - Thoracic aorta aneurysm open repair in heart transplant recipient; the anesthesiologist's perspective. AB - Many years following transplantation, heart transplant recipients may require noncardiac major surgeries. Anesthesia in such patients may be challenging due to physiological and pharmacological problems regarding allograft denervation and difficult immunosuppressive management. Massive hemorrhage, hypoperfusion, renal, respiratory failure, and infections are some of the most frequent complications related to thoracic aorta aneurysm repair. Understanding how to optimize hemodynamic and infectious risks may have a substantial impact on the outcome. This case report aims at discussing risk stratification and anesthetic management of a 54-year-old heart transplant female recipient, affected by Marfan syndrome, undergoing thoracic aorta aneurysm repair. PMID- 26750704 TI - Erratum: Brugada syndrome and its relevance in the perioperative period. PMID- 26750706 TI - The Kaiser, Hunka and Bianchini Factor Similarity Coefficients: A Cautionary Note. AB - Kaiser, Hunka and Bianchini (1971) have given a method to compare two matrices of factor loadings based on the same variables, but different groups of individuals. They suggest expressing the factor similarity by the elements of the rotation matrix that optimizes the sum of inner products between corresponding columns or rows of the matrices. The optimal rotation involved in this method is examined from a mathematical point of view and, on the basis of this, the method is shown to be invalid. PMID- 26750707 TI - Correcting for Nonresponse in Latent Class Analysis. AB - Monte Carlo methods were used to evaluate an EM algorithm for correction for missing data in latent class analysis. Bias in parameter estimates was assessed under various assumptions concerning the mechanism for missingness including cases where missingness was not at random. Findings suggest practical limits for the utility of the EM algorithm in terms of sample size and nonresponse rate. PMID- 26750709 TI - Multidimensional Scaling of Binary Dissimilarities: Direct and Derived Approaches. AB - Given a matrix of dissimilarities, it has been debated whether researchers should perform multidimensional scaling on this original matrix or on a new one derived by comparing rows in the original matrix. Careful comparison studies (Drasgow & Jones, 1979; Van der Kloot & Van Herk, 1991) in the context of sorting data indicated that most of the initial enthusiasm for the derivative approach was unfounded. The current work, a Monte Carlo study of structured binary data derived from known two-dimensional configurations using ALSCAL, complements and extends the previous studies. We discuss a weakness in the squared difference (delta) row-comparison rule used previously and propose an alternative row comparison measure based on the Jaccard coefficient. Scaling the binary data directly gave better performance, as gauged by Procrustes statistics, than did scaling A data across a range of noise levels. The quality of solutions obtained by scaling Jaccard data was always better or essentially equal to that from scaling delta data, and in certain parameter regions improved upon that of direct scaling. Another alternative approach, applying the delta rule after first row centering the binary data, was found to be generally ineffective. These findings are pertinent to the analysis not just of stimulus sorting data but of coarse dissimilarities generally, for example from direct pairwise judgment tasks and in fields outside statistical psychology. PMID- 26750708 TI - Robustness is Not Dimensionality: On the Sensitivity of Component Comparability Coefficients to Sample Size. AB - Everett (1983) has proposed that, under certain conditions, replicability provides an answer to the question of the number of dimensions to retain in component analysis. But replicability must logically be a function of sample size as well as dimensionality. In the present study, the effects of sample size and sample composition are systematically examined on the replicability of principal components. Using observer ratings of personality from the California Adult Q Set, comparability coefficients are examined in 192 series of principal components analyses. Results indicate that (a) once one has 20 or more subjects per item, the most comparable solution typically has as many components as items; (b) if these full solutions are ignored, there is still a substantial relationship between prescribed number of components and sample size when one uses either the .90 or .85 threshold decision rules and (c) other criteria for determining the number of components to retain, such as the Minimum Average Partial (MAP) rule, do not show the same relationship with sample size. These results indicate that dimensionality cannot be inferred from component robustness, as these are empirically as well as logically separate matters. PMID- 26750705 TI - Astragaloside IV inhibits microglia activation via glucocorticoid receptor mediated signaling pathway. AB - Inhibition of microglia activation may provide therapeutic treatment for many neurodegenerative diseases. Astragaloside IV (ASI) with anti-inflammatory properties has been tested as a therapeutic drug in clinical trials of China. However, the mechanism of ASI inhibiting neuroinflammation is unknown. In this study, we showed that ASI inhibited microglia activation both in vivo and in vitro. It could enhance glucocorticoid receptor (GR)-luciferase activity and facilitate GR nuclear translocation in microglial cells. Molecular docking and TR FRET GR competitive binding experiments demonstrated that ASI could bind to GR in spite of relative low affinity. Meanwhile, ASI modulated GR-mediated signaling pathway, including dephosphorylation of PI3K, Akt, I kappaB and NF kappaB, therefore, decreased downstream production of proinflammatory mediators. Suppression of microglial BV-2 activation by ASI was abrogated by GR inhibitor, RU486 or GR siRNA. Similarly, RU486 counteracted the alleviative effect of ASI on microgliosis and neuronal injury in vivo. Our findings demonstrated that ASI inhibited microglia activation at least partially by activating the glucocorticoid pathway, suggesting its possible therapeutic potential for neuroinflammation in neurological diseases. PMID- 26750710 TI - A Comparison of Bias and Mean Squared Error in Parameter Estimates of Interaction Effects: Moderated Multiple Regression versus Error-in-Variables Regression. AB - The results of moderated multiple regression (MMR) are highly affected by the unreliability of the predictor variables (regressors). Errors-in-variables regression (EIVR) may remedy this problem as it corrects for measurement error in the regressors, and thus provides less biased parameter estimates. However, little is known about the properties of the EIVR estimators in the moderator variable context. The present study used simulation methods to compare the moderator variable detection capabilities of MMR and EIVR. Specifically, the study examined the bias and mean squared error of the MMR and EIVR estimates under varying conditions of sample size, reliability of the predictor variables, and intercorrelations among the predictor variables. Findings showed that EIVR estimates are superior to MMR estimates when sample size is high (i.e., at least 250) and the reliabilities of the predictors are high (i.e., rij >= .65). However, MMR appears to be the better strategy when reliabilities or sample size are low. PMID- 26750711 TI - Latent Variable Regression: A Technique for Estimating Interaction and Quadratic Coefficients. AB - The article proposes a technique to estimate regression coefficients for interaction and quadratic latent variables that combines regression analysis with the measurement model portion of structural equation analysis (e.g., analysis involving CALLS, EQS or LISREL). The measurement model provides parameter estimates that can be combined to correct the variance-covariance matrix used in regression, as Heise (1986) and others recommend. The proposed technique will provide coefficient estimates for regression models involving existing measures, or new measures for which a priori error estimates are not available. PMID- 26750712 TI - Childhood Risks for Young Adult Symptoms of Personality Disorder: Method and Substance. AB - This article employs data gathered prospectively over a 17 year period to assess 36 childhood risk factors for personality disorder in young adults. Measurement issues are discussed, and the overall extent of prediction is assessed in younger and older boys and girls. Prediction is shown to be better for girls than for boys and, among girls, better over a younger age span than over an older age span covering an equivalent time. Risks are shown to predict independently of the continuity of symptoms over time. The effects of individual risks are examined by means of a) correlation coefficients, b) standardized mean differences, c) odds ratios for scaled measures, and d) attributable fractions. PMID- 26750713 TI - Stereoselective synthesis of spirooxindole derivatives using an organocatalyzed tandem Michael-Michael reaction. AB - A highly efficient stereoselective method for the synthesis of functionalized spirooxindole derivatives with three stereogenic centers was realized through an organocatalytic tandem Michael-Michael reaction. By employing (S)-alpha,alpha diphenylprolinol trimethylsilyl ether as the catalyst and N,N'-bis[3,5 bis(trifluoromethyl)phenyl]thiourea as the cocatalyst, the reaction between N tritylisatylidenemalononitriles and (E)-7-alkyl-7-oxohept-5-enals yields the desired spirooxindole products in good yields (76-95%) and with excellent diastereoselectivities (up to 97 : 3 dr) and enantioselectivities (up to 98% ee), which can be stereoselectively converted into the spiro[indoline-3,8' isoquinoline] derivative through an intramolecular reductive amination reaction. PMID- 26750714 TI - The influence of smoking on radiation-induced bystander signal production in esophageal cancer patients. AB - The relevance of radiation-induced bystander effects in humans is unclear. Much of the existing data relate to cell lines but the effect of bystander signals in complex human tissues is unclear. A phase II clinical study was untaken, where blood sera from 60 patients along with 15 cancer-free volunteers were used to detect whether measurable bystander factor(s) could be found in the blood following high dose rate (HDR) brachytherapy. Overall, there was no significant change in bystander signal production (measured in a human keratinocyte reporter system) before and after one treatment fraction of HDR brachytherapy (p>0.05). Further assessment of patient characteristics and environmental modifiable factors including smoking were also analyzed. Similar to previously published data, samples taken from smokers produced weaker signals compared to non-smokers (p<0.05). Although the number of non-smoking subjects was low, there was a clear decrease in cloning efficiency observed in keratinocyte cultures for these patients that requires further study. This study found that samples taken from smokers do not produce bystander signals, whereas samples taken from non-smokers can produce such signals following HDR brachytherapy. These findings highlight the importance of studying the interactions of multiple stressors including environmental modifiers with radiation, since some factors such as smoking may elicit protection in tumor cells which could counteract the effectiveness of radiation therapy. PMID- 26750715 TI - MRI monitoring of nanocarrier accumulation and release using Gadolinium-SPIO co labelled thermosensitive liposomes. AB - Encapsulation of anticancer drugs in triggerable nanocarriers can beneficially modify pharmacokinetics and biodistribution of chemotherapeutic drugs, and consequently increase tumor drug concentration and efficacy, while reducing side effects. Thermosensitive liposomes release their contents triggered by hyperthermia, which can be, for example, precisely delivered using an MR Imaging guided focused ultrasound procedure. In such a scenario, it is attractive to demonstrate the accumulation of liposomes before applying hyperthermia, as well as to document the release of liposome content using MRI. To address this need, thermosensitive liposomes were developed and characterized, which were doubly loaded by iron oxide nanoparticles and Gd-chelate, as opposed to loading with a single contrast agent. When intact, the transverse relaxivity of the liposomes is high allowing detection of carriers in tissue. After heating the longitudinal relaxivity steeply increases indicating release of the small molecular contents. By choosing the appropriate MR sequences, availability and release can be evaluated without interference of one contrast agent with the other. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26750716 TI - Oligonucleotide-stabilized fluorescent silver nanoclusters for the specific and sensitive detection of biotin. AB - A novel biotin fluorescent probe based on oligonucleotide-stabilized silver nanoclusters (DNA-AgNCs) was synthesized by employing a biotinylated cytosine rich sequence as a synthesized template. The fluorescence properties of the DNA AgNCs are related to the modified position of the DNA. When biotin is linked to the middle thymine base of the DNA sequence, the DNA-AgNCs emit the strongest fluorescence. Moreover, the stability of the DNA-AgNCs was affected by avidin through biotin-avidin binding, quenching the fluorescence of the DNA-AgNCs. In contrast, if free biotin is further introduced into this system, the quenching is apparently weakened by competition, leading to the restoration of fluorescence. This phenomenon can be utilized for the detection of biotin. Under the optimal conditions, the fluorescence recovery is linearly proportional to the concentration of biotin in the range of 10 nM-1.0 MUM with a detection limit of 6.0 nM. This DNA-AgNCs probe with excellent fluorescent properties is sensitive and selective for the detection of biotin and has been applied for the determination of biotin in wheat flour. PMID- 26750718 TI - Enhanced cation recognition by a macrocyclic ionophore at the air-solution interface probed by mass spectrometry. AB - Interfacial environments have the potential to drive unexpected events of supramolecular recognition, leading to advances in the development of novel functional materials and molecular sensing techniques. We present experimental evidence for a noticeable enhancement of the cation binding specificity of a prototype calixarene macrocycle (cesium ionophore II) at the air-solution interface, in comparison to bulk solution and to isolated solvent-less conditions. A rationalization of this intriguing finding is outlined, with the support of quantum calculations, in terms of the 'half-solvation' conditions provided by the interface and of conformational effects posed by the backbone structure and the side chains of the macrocyclic ionophore. The investigation involves the introduction of a mass spectrometry method to determine the relative abundances of interfacial complexes that should be of general application in the field and guide future advances in analytical techniques based on molecular recognition. PMID- 26750717 TI - Disclosure of positron emission tomography amyloid imaging results: A preliminary study of safety and tolerability. AB - INTRODUCTION: Three (18)F-labeled radiopharmaceuticals have been Food and Drug Administration-approved for the identification of cortical amyloidosis in clinical settings. Although there has been strong debate among professionals as to the ethical and social consequences of disclosing such information, increasing numbers of participants are being recruited into secondary prevention trials for which they are likely to, and/or desire to, receive their positron emission tomography (PET) imaging results. METHODS: Healthy older adults (n = 63, mean age = 62 years) enrolled in a preclinical Alzheimer's disease (AD) biomarkers trial, and 11 requested disclosure of PET amyloid imaging results to their treating neurologist, per institutional review board-approved study protocol. These individuals completed a follow-up psychoeducational program and structured interviews to assess impact of disclosure on several key psychological factors. RESULTS: Four of 11 subjects demonstrated increased amyloid aggregation and reported that they were not surprised, particularly given their family histories and subjective memory concerns. All indicated that they had shared this information with pertinent significant others; they were satisfied with their level of social support, and the imaging results had motivated them to change their lifestyle by exercising more, changing their diet, and planning ahead. Amyloid-positive participants showed little change in levels of depressive, anxiety, and stress symptoms, subjective sense of memory impairment, or on measures of intrusion, avoidance, and hyperarousal, and reported risk of self harm. DISCUSSION: Disclosure of PET amyloid status did not significantly impact mood, subjective sense of memory impairment, or perceived risk of developing AD; nor was this associated with significant emotional impact, irrespective of actual amyloid burden status. Those subjects with increased amyloid burden were more likely than those without significant amyloidosis to make positive changes to their lifestyle (e.g., engaging in more exercise and changing their diet). PMID- 26750719 TI - Characterization of the crosslinking kinetics of multi-arm poly(ethylene glycol) hydrogels formed via Michael-type addition. AB - Tunable properties of multi-arm poly(ethylene glycol) (PEG) hydrogel, crosslinked by Michael-type addition, support diverse applications in tissue engineering. Bioactive modification of PEG is achieved by incorporating integrin binding sequences, like RGD, and crosslinking with tri-functional protease sensitive crosslinking peptide (GCYKNRGCYKNRCG), which compete for the same reactive groups in PEG. This competition leads to a narrow range of conditions that support sufficient crosslinking density to provide structural control. Kinetics of hydrogel formation plays an important role in defining the conditions to form hydrogels with desired mechanical and biological properties, which have not been fully characterized. In this study, we explored how increasing PEG functionality from 4 to 8-arms and the concentration of biological moieties, ranging from 0.5 mM to 3.75 mM, affected the kinetics of hydrogel formation, storage modulus, and swelling after the hydrogels were allowed to form for 15 or 60 minutes. Next, human bone marrow stromal cells were encapsulated and cultured in these modified hydrogels to investigate the combined effect of mechano-biological properties on phenotypes of encapsulated cells. While the molar concentration of the reactive functional groups (-vinyl sulfone) was identical in the conditions comparing 4 and 8-arm PEG, the 8-arm PEG formed faster, allowed a greater degree of modification, and was superior in three-dimensional culture. The degrees of swelling and storage modulus of 8-arm PEG were less affected by the modification compared to 4-arm PEG. These findings suggest that 8-arm PEG allows a more precise control of mechanical properties that could lead to a larger spectrum of tissue engineering applications. PMID- 26750721 TI - Corrigendum: IL-1alpha is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity. PMID- 26750720 TI - Expression and mechanism of microRNA-181A on incidence and survival in late liver metastases of colorectal cancer. AB - The emerging role of microRNA-181A (miR-181A) in CRC patients with late liver metastases was studied. In the present study we investigated the association between expression and mechanism of miRNA-181A, liver metastasis and prognosis of colorectal cancer (CRC). The expression of miR-181A and PTEN in CRC patients with late liver metastases was higher than that of the normal (control) group, whereas the expression of miR-181A and PTEN was lower in all pathological groups (TNM I TNM IV). Overall survival (OS) of lower expression miR-181A CRC patients with late liver metastases was higher than that of higher expression miR-181A CRC patients with late liver metastases. The expression of miR-181A and PTEN in the colon cell line NCM460 was lower than that of the colon cancer SW620 cell line. Upregulation of miR-181A promoted cell viability and inhibited apoptosis of SW620 cells, suppressed PTEN expression and activated phosphorylation of AKT (p-AKT) in SW620 cells. Additionally, downregulation of miR-181A inhibited cell viability of SW620 cells through promotion of PTEN and inhibition of p-AKT. Together, our results indicate that miR-181A expression is associated with CRC patients with late liver metastases through PTEN/AKT signaling. PMID- 26750722 TI - GDF 15--A Novel Biomarker in the Offing for Heart Failure. AB - BACKGROUND: Several diagnostic and prognostic biomarkers are being explored in heart failure. GDF-15 belongs to the transforming growth factor beta (TGF-beta) cytokine family that is highly up regulated in inflammatory conditions. We undertook this systematic review to summarize the current evidence on the utility of GDF-15 as a biomarker in heart failure. DESIGN AND METHODS: Multiple electronic databases for studies that reported the association between GDF- 15 and heart failure were searched using different electronic databases such as MEDLINE, Science Direct, Springer Link, Scopus, Cochrane Reviews, and Google Scholar using pre-defined inclusion- exclusion criteria. RESULTS: Twenty one original studies were identified that included data from 20,920 study participants. GDF 15 was found to be a strong prognosticator of all-cause mortality in heart failure patients. Several studies found the benefit of using GDF-15 as a component of a multi-biomarker strategy in prognosticating patients with heart failure. CONCLUSION: More studies are warranted to elucidate the molecular pathways involving GDF-15 and to see how knowledge about GDF-15 can be used to make therapeutic decisions in the clinic. PMID- 26750724 TI - Simulations of inorganic-bioorganic interfaces to discover new materials: insights, comparisons to experiment, challenges, and opportunities. AB - Natural and man-made materials often rely on functional interfaces between inorganic and organic compounds. Examples include skeletal tissues and biominerals, drug delivery systems, catalysts, sensors, separation media, energy conversion devices, and polymer nanocomposites. Current laboratory techniques are limited to monitor and manipulate assembly on the 1 to 100 nm scale, time consuming, and costly. Computational methods have become increasingly reliable to understand materials assembly and performance. This review explores the merit of simulations in comparison to experiment at the 1 to 100 nm scale, including connections to smaller length scales of quantum mechanics and larger length scales of coarse-grain models. First, current simulation methods, advances in the understanding of chemical bonding, in the development of force fields, and in the development of chemically realistic models are described. Then, the recognition mechanisms of biomolecules on nanostructured metals, semimetals, oxides, phosphates, carbonates, sulfides, and other inorganic materials are explained, including extensive comparisons between modeling and laboratory measurements. Depending on the substrate, the role of soft epitaxial binding mechanisms, ion pairing, hydrogen bonds, hydrophobic interactions, and conformation effects is described. Applications of the knowledge from simulation to predict binding of ligands and drug molecules to the inorganic surfaces, crystal growth and shape development, catalyst performance, as well as electrical properties at interfaces are examined. The quality of estimates from molecular dynamics and Monte Carlo simulations is validated in comparison to measurements and design rules described where available. The review further describes applications of simulation methods to polymer composite materials, surface modification of nanofillers, and interfacial interactions in building materials. The complexity of functional multiphase materials creates opportunities to further develop accurate force fields, including reactive force fields, and chemically realistic surface models, to enable materials discovery at a million times lower computational cost compared to quantum mechanical methods. The impact of modeling and simulation could further be increased by the advancement of a uniform simulation platform for organic and inorganic compounds across the periodic table and new simulation methods to evaluate system performance in silico. PMID- 26750725 TI - Editorial. PMID- 26750723 TI - Adenosine A3 Receptor: A promising therapeutic target in cardiovascular disease. AB - Cardiovascular complications are one of the major factors for early mortality in the present worldwide scenario and have become a major challenge in both developing and developed nations. It has thus become of immense importance to look for different therapeutic possibilities and treatments for the growing burden of cardiovascular diseases. Recent advancements in research have opened various means for better understanding of the complication and treatment of the disease. Adenosine receptors have become tool of choice in understanding the signaling mechanism which might lead to the cardiovascular complications. Adenosine A3 receptor is one of the important receptor which is extensively studied as a therapeutic target in cardiovascular disorder. Recent studies have shown that A3AR is involved in the amelioration of cardiovascular complications by altering the expression of A3R. This review focuses towards the therapeutic potential of A3AR involved in cardiovascular disease and it might help in better understanding of mechanism by which this receptor may prove useful in improving the complications arising due to various cardiovascular diseases. Understanding of A3AR signaling may also help to develop newer agonists and antagonists which might be prove helpful in the treatment of cardiovascular disorder. PMID- 26750727 TI - Knock-down of ZBED6 in insulin-producing cells promotes N-cadherin junctions between beta-cells and neural crest stem cells in vitro. AB - The role of the novel transcription factor ZBED6 for the adhesion/clustering of insulin-producing mouse MIN6 and betaTC6 cells was investigated. Zbed6-silencing in the insulin producing cells resulted in increased three-dimensional cell-cell clustering and decreased adhesion to mouse laminin and human laminin 511. This was paralleled by a weaker focal adhesion kinase phosphorylation at laminin binding sites. Zbed6-silenced cells expressed less E-cadherin and more N-cadherin at cell-to-cell junctions. A strong ZBED6-binding site close to the N-cadherin gene transcription start site was observed. Three-dimensional clustering in Zbed6 silenced cells was prevented by an N-cadherin neutralizing antibody and by N cadherin knockdown. Co-culture of neural crest stem cells (NCSCs) with Zbed6 silenced cells, but not with control cells, stimulated the outgrowth of NCSC processes. The cell-to-cell junctions between NCSCs and betaTC6 cells stained more intensely for N-cadherin when Zbed6-silenced cells were co-cultured with NCSCs. We conclude that ZBED6 decreases the ratio between N- and E-cadherin. A lower N- to E-cadherin ratio may hamper the formation of three-dimensional beta cell clusters and cell-to-cell junctions with NCSC, and instead promote efficient attachment to a laminin support and monolayer growth. Thus, by controlling beta cell adhesion and cell-to-cell junctions, ZBED6 might play an important role in beta-cell differentiation, proliferation and survival. PMID- 26750729 TI - [Treatment of patients with myocardial infarction in Hungary on the basis of available health data]. AB - The authors review data sources related to death arising from myocardial infarction, as well as the major elements of the Hungarian data collection of the Central Statistical Office, the National Health Insurance Fund and the National Registry of Myocardial Infarction. They also discuss conclusions which can be drawn from the data. It was found that the financial database - in accordance with its purpose - is suitable for monitoring the costs arising during the treatment of patient, but the quality and efficiency of treatment cannot be judged on the basis of this database. The Central Statistical Office compiles mortality data on the basis of international conventions, the basis of which is the autopsy report. However, the validity of statistical data depends on the correct completion of this report. Therefore. it is not possible to judge treatment of patients with myocardial infarction simply on the basis of mortality statistics. Considering national databases, only patient registries are suitable for monitoring the quality and efficiency of treatment currently. It is recommended that data of the National Registry of Myocardial Infarction should be used when the quality of treatment of patients with myocardial infarction is evaluated. PMID- 26750728 TI - [Changes in radioiodine therapy for thyroid disorders]. AB - Radioiodine therapy for benign and malignant thyroid diseases was introduced about 70 years ago, however, there is still a lack of consensus regarding indications, doses and procedure. This review covers treatment results in immunogenic hyperthyroidism including the problem of orbitopathy. Radioiodine therapy for toxic and non-toxic multinodular goiter is also discussed with striking possibility of enhanching the radioiodine uptake. In this respect the recombinant human thyrotropin should be mentioned. Thyroid cancer treatment protocol has changed, too, due to ineffectivity in low-risk patients. More attention is needed to the carcinogenecity of radioiodine. The numerous problems mentioned above require large and well-designed prospective trials to resolve the fundamental questions. The author emphasizes that radioiodine dose should be administered in doses as low as reasonably achievable. PMID- 26750730 TI - [Most common skin disorders caused by excessive exposure to sunlight]. AB - The healing properties of sunlight has been known for millennia, however the gradual deterioration of the ozone layer and the increased use of sun tanning beds in recent decades are causing an increase in skin damaging ultraviolet exposure. In this article the most common photodermatoses and the principles of their treatments are reviewed. PMID- 26750731 TI - [Development of the registry for Philadelphia-negative chronic myeloproliferative neoplasia in Hungary]. AB - INTRODUCTION: The establishment and operation of disease registry can be used to collect data on epidemiology cases. In addition, the registry can help to work out medical and health economical and political decisions for longer term. AIM: The aim of the authors was to collect and analyse data of patients with Philadelphia negative neoplasia in Hungary and draw conclusions about the basic types and features of the relevant disease. METHOD: An online electronic data collection system has been established, based on the permission of the Regional and Institutional Committee of Science and Research Ethics obtained in April 8, 2013. Data collection has been initiated by hematology centres in Hungary. In addition to collection of the epidemiologic data, blood and bone marrow analysis data have been collected, as well. Also, based on cardiovascular factors, risk stratification has been established. Finally, the authors have investigated the method and practice of patient treatment in Hungary. RESULTS: Data of 901 patients from 15 Hungarian haematology centres have been recorded up to the date of June 30, 2015. After clarification of the data, 426 polycythaemia vera, 350 essential thrombocythaemia and 82 myelofibrosis cases were used for analysis. CONCLUSIONS: An online registry has been established which helps to clarify and analyse the basic features of certain medical cases and their treatment in Hungary. Including additional medical centres could help to improve the accuracy of medical analysis. PMID- 26750732 TI - [Long-term follow-up of patients with transposition of the great arteries following Senning or Mustard operations. Results from the CSONGRAD Registry]. AB - INTRODUCTION: Transposition of the great arteries is one of the most common cyanotic congenital heart diseases. AIM: The present study aimed to examine and compare long-term survival, functional grading, arrhytmologic and quality of life control in patients with transposition of the great arteries following Senning- and Mustard-operations. METHODS: The present study comprised 85 patients with transposition of the great arteries, of whom Senning-operation was performed in 37 cases and Mustard-operation in 48 subjects. Follow-up study was performed in all cases. RESULTS: The success rate of long-term follow-up proved to be 74%. Twelve out of the 31 Senning-operated and 16 out of 32 Mustard-operated patients died during the follow-up (39% vs. 50%, p = 0.45). Neither features of heart failure, nor those of arrhythmias showed differences between the groups, but parameters of quality of life and functional capacity proved to be favourable in Senning-operated patients. CONCLUSIONS: There is no significant difference in mortality and morbidity of patients with transposition of the great arteries following Mustard- and Senning-operations. Regarding to long-term follow-up quality of life and functional capacity of Senning-operated patients were more favourable. PMID- 26750734 TI - Design of chimeric antigen receptors with integrated controllable transient functions. AB - The ability to control T cells engineered to permanently express chimeric antigen receptors (CARs) is a key feature to improve safety. Here, we describe the development of a new CAR architecture with an integrated switch-on system that permits to control the CAR T-cell function. This system offers the advantage of a transient CAR T-cell for safety while letting open the possibility of multiple cytotoxicity cycles using a small molecule drug. PMID- 26750735 TI - Modulation of oxidative stress, inflammation, autophagy and expression of Nrf2 in hippocampus and frontal cortex of rats fed with acai-enriched diets. AB - OBJECTIVE: Acai (Euterpe spp.), an exotic palm fruit, has recently emerged as a promising source of natural antioxidants with wide pharmacological and nutritional value. In this study, two different species of acai pulp extracts, naturally grown in two distinct regions of the Amazon, namely, Euterpe oleracea Mart. (habitat: Brazilian floodplains of the Amazon) and Euterpe precatoria Mart. (habitat: Bolivian Amazon), were studied for their effects on brain health and cognition. METHODS: Neurochemical analyses were performed in critical brain regions associated with memory and cognition of 19-month-old acai-fed rats, in whom the cognitive benefits of acai had been established. RESULTS: Results indicated significant reductions (P< 0.05) in prooxidant NADPH-oxidoreductase-2 (NOX2) and proinflammatory transcription factor NF-kappaB in acai-fed rats. Measurement of Nrf2 expression, a transcription factor for antioxidant enzymes, and a possible link between oxidative stress, neuroinflammation and autophagy mechanisms, indicated significant overexpression (P<0.005) in the hippocampus and frontal cortex of the acai-fed rats. Furthermore, significant activation of endogenous antioxidant enzymes GST and SOD were also observed in the acai-fed animals when compared to control. Analysis of autophagy markers such as p62, phospho-mTOR, beclin1 and MAP1B-LC3 revealed differential expression in frontal cortex and hippocampus, mostly indicating an upregulation in the acai-fed rats. DISCUSSION: In general, results were more profound for EP than EO in hippocampus as well as frontal cortex. Therefore, an acai-enriched diet could possibly modulate Nrf2, which is known to modulate the intracellular redox status, thereby regulating the ubiquitin-proteosomal pathway, ultimately affecting cognitive function in the aging brain. PMID- 26750737 TI - Diameter-selective non-covalent functionalization of carbon nanotubes with porphyrin monomers. AB - We report on the spontaneous non-covalent functionalization of carbon nanotubes with hydrophobic porphyrin molecules in micellar aqueous solution. By monitoring the species concentrations with optical spectroscopies, we can follow the kinetics of the reaction and study its thermodynamical equilibrium as a function of the reagent concentrations. We show that the reaction is well accounted for by a cooperative Hill equation, reaching a molecular coverage close to a compact monolayer for a porphyrin concentration larger than a diameter-specific threshold concentration. The equilibrium constant is measured for 16 nanotube chiral species. The Gibbs energy of the reaction (of the order of -40 kJ mol(-1)) and its evolution with the nanotube diameter is consistent with theoretical calculations of the binding energy. This thermodynamical study shows a strong preferential binding of TPP molecules to larger diameter nanotubes. This original curvature selectivity can be used to induce diameter selective species enrichment. PMID- 26750738 TI - Many faces of REM sleep behavior disorder: an editorial. PMID- 26750736 TI - The Communication Supports Inventory-Children & Youth (CSI-CY), a new instrument based on the ICF-CY. AB - PURPOSE: Two studies are presented that evaluated the Communication Supports Inventory-Children & Youth (CSI-CY), an instrument designed to facilitate the development of communication-related educational goals for students with complex communication needs (CCN). The CSI-CY incorporates a code set based on the ICF CY. The studies were designed to determine the effect of using the CSI-CY on IEP goals for students with CCN and to evaluate consumer satisfaction. METHOD: In Study 1, sixty-one educators and speech-language pathologists were randomly assigned to either (a) provide a student's current IEP (control group) or (b) complete the CSI-CY prior to preparing a student's next IEP and to submit the new IEP (experimental group). Study 2 was a field test to generate consumer satisfaction data. RESULTS: Study 1 showed that IEP goals submitted by participants in the experimental group referenced CSI-CY-related content significantly more frequently than did those submitted by control participants. Study 2 revealed high satisfaction with the instrument. CONCLUSIONS: The code set basis of the CSI-CY extends the common language of the ICF-CY to practical educational use for children with CCN across diagnostic groups. The CSI-CY is well regarded as an instrument to inform the content of communication goals related to CCN. Implications for Rehabilitation The CSI-CY will guide rehabilitation professionals to develop goals for children with complex communication impairments. The CSI-CY is a new instrument that is based on the ICF-CY for documentation of communication goals. PMID- 26750739 TI - Effect of low-level laser therapy as an adjuvant in the treatment of periodontitis induced in rats subjected to 5-fluorouracil chemotherapy. AB - BACKGROUND AND OBJECTIVE: This study aimed to assess the effect of multiple sessions of a low-level laser therapy (LLLT) adjuvant to scaling and root planing (SRP) on the treatment of experimental periodontitis (EP) in rats treated with 5 fluorouracil (5-FU). MATERIAL AND METHODS: A total of 120 rats were divided into five groups: no treatment (NT); treatment with 5-FU (60 and 40 mg/kg) and no local periodontal treatment (5FU); treatment with 5-FU and SRP (5FU-SRP); treatment with 5-FU, SRP and one LLLT session (660 nm; 0.035 W; 4.2 J; 120 s) (5FU-SRP-1LLLT); and treatment with 5-FU, SRP and four LLLT sessions (0, 24, 48 and 72 h) (5FU-SRP-4LLLT). EP was induced in the mandibular molars through ligature placement. The alveolar bone loss (ABL) area in the furcation region was analysed histometrically. TRAP, proliferating cell nuclear antigen, RANKL, osteoprotegerin and activated caspase-3 patterns were analysed by immunolabeling. Prostaglandin E2 was quantified using an ELISA, and tumour necrosis factor alpha and interleukin-6 were assessed using the multiplex method. The prevalence rates of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella nigrescens, Prevotella intermedia and Fusobacterium nucleatum were assessed using the PCR method. The data were subjected to statistical analysis (alpha = 5%). RESULTS: 5FU, 5FU-SRP and 5FU-SRP-1LLLT treatment groups showed higher ABL compared with the NT group (p < 0.05), whereas the 5FU-SRP-4LLLT group showed lower ABL compared with the 5FU group on day 7 and decreased RANKL immunolabeling (p < 0.05). CONCLUSION: Treatment with 5-FU worsened EP, and multiple LLLT sessions adjuvant to SRP seemed to improve periodontitis in rats subjected to 5 FU chemotherapy. PMID- 26750740 TI - Histone deacetylase inhibitor abexinostat (S78454/PCI-24781) as a successful approach in a case of refractory peripheral angio-immunoblastic T-cell lymphoma, as a bridge to reduced intensity conditioning haplo-identical allogenic stem cell transplant. PMID- 26750741 TI - Predictors of Persistent Carbapenem-Resistant Enterobacteriaceae Carriage upon Readmission and Score Development. AB - BACKGROUND: Carriers of carbapenem-resistant Enterobacteriaceae (CRE) are often readmitted, exposing patients to CRE cross-transmission. OBJECTIVE To identify predictors of persistent CRE carriage upon readmission, directing a risk prediction score. DESIGN: Retrospective cohort study. SETTING: University affiliated general hospital. PATIENTS: A cohort of 168 CRE carriers with 474 readmissions. METHODS: The primary and secondary outcomes were CRE carriage status at readmission and length of CRE carriage. Predictors of persistent CRE carriage upon readmission were analyzed using a generalized estimating equations (GEE) multivariable model. Readmissions were randomly divided into derivation and validation sets. A CRE readmission score was derived to predict persistent CRE carriage in 3 risk groups: high, intermediate, and low. The discriminatory ability of the model and the score were expressed as C statistics. RESULTS: CRE carrier status persisted for 1 year in 33% of CRE carriers. Positive CRE status was detected in 202 of 474 readmissions (42.6%). The following 4 variables were associated with persistent CRE carriage at readmission: readmission within 1 month (odds ratio [OR], 6.95; 95% confidence interval [CI], 2.79-17.30), positive CRE status on preceding admission (OR, 5.46; 95% CI, 3.06-9.75), low Norton score (OR, 3.07; 95% CI, 1.26-7.47), and diabetes mellitus (OR, 1.84; 95% CI, 0.98 3.44). The C statistics were 0.791 and 0.789 for the derivation set (n=322) model and score, respectively, and the C statistic was 0.861 for the validation set of the score (n=152). The rates of CRE carriage at readmissions (validation set) for the groups with low, intermediate, and high scores were 8.6%, 38.9%, and 77.6%, respectively. CONCLUSIONS: CRE carrier state commonly persists upon readmission, and this risk can be estimated to guide screening policy and infection control measures. PMID- 26750742 TI - Altered serum levels of FGF-23 and magnesium are independent risk factors for an increased albumin-to-creatinine ratio in type 2 diabetics with chronic kidney disease. AB - AIMS: To investigate the role of FGF-23 and magnesium in relation to the albumin to-creatinine ratio in type 2 diabetics with chronic kidney disease (CKD) stages 2-4. METHODS: In a cross-sectional study we included all eligible type 2 diabetic patients with CKD stages 2-4, followed in our outpatient Diabetic Kidney clinic. We used descriptive statistics, the Student'st-test, ANOVA and the chi-square tests. Our population was divided according to the UACR (G1 30-300 mg/g and G2>=300 mg/g), and compared these groups regarding several biological and laboratorial parameters. We employed a multiple regression model to identify risk factors of increased UACR. RESULTS: The patients in G2 displayed a lower eGFR (p=0.0001) and, had lower levels of magnesium (p=0.004) as well as higher levels of FGF-23 (p=0.043) compared to patients in G1. FGF-23 (beta=0.562, P=0.0001) and the magnesium (beta=- 8.916, p=0.0001) were associated with increased UACR. CONCLUSIONS: A dysregulation of mineral metabolism, reflected by altered levels of magnesium and FGF-23, correlates with an increased UACR in type 2 diabetic patients with CKD stages 2-4. PMID- 26750744 TI - Treatment of spontaneous bacterial peritonitis: beyond the current international guidelines. PMID- 26750743 TI - Costs and effects of a telephonic diabetes self-management support intervention using health educators. AB - BACKGROUND: Self-management is crucial to successful glycemic control in patients with diabetes, yet it requires patients to initiate and sustain complicated behavioral changes. Support programs can improve glycemic control, but may be expensive to implement. We report here an analysis of the costs of a successful telephone-based self-management support program delivered by lay health educators utilizing a municipal health department A1c registry, and relate them to near term effectiveness. METHODS: Costs of implementation were assessed by micro costing of all resources used. Per-capita costs and cost-effectiveness ratios from the perspective of the service provider are estimated for net A1c reduction, and percentages of patients achieving A1c reductions of 0.5 and 1.0 percentage points. One-way sensitivity analyses of key cost elements, and a Monte Carlo sensitivity analysis are reported. RESULTS: The telephone intervention was provided to 443 people at a net cost of $187.61 each. Each percentage point of net A1c reduction was achieved at a cost of $464.41. Labor costs were the largest component of costs, and cost-effectiveness was most sensitive to the wages paid to the health educators. CONCLUSIONS: Effective telephone-based self-management support for people in poor diabetes control can be delivered by health educators at moderate cost relative to the gains achieved. The costs of doing so are most sensitive to the prevailing wage for the health educators. PMID- 26750745 TI - Lipid profile and cardiovascular risk factors in pediatric liver transplant recipients. AB - Cardiovascular diseases induce long-term morbidity and mortality of adult LT recipients. The aim of this retrospective study was to assess CVRF, lipid abnormalities, and atherosclerosis (appraised by c-IMT), more than 10 yr after pediatric LT. Thirty-one children who underwent LT between December 1990 and December 2000 were included. Median age at LT was 14 months (range 4-64), and median follow-up after LT was 11.9 yr (range 9.0-17.3). In our cohort, obesity (9.7%) and treated hypertension (9.7%) were rare. None of the patients was smoker or diabetic. High TC and TG were both observed in 6.5% of the patients. The mean c-IMT for male patients was 1.22 +/- 1.55 and 1.58 +/- 1.23 mm in female patients. Seven patients (22%) had a mean c-IMT above +2 s.d. Values below the 5th percentile were noted for LDL-cholesterol (58.1%), HDL-cholesterol (25.8%), apolipoprotein B (40%), and apolipoprotein A1 (20%). LDL-cholesterol and apolipoprotein B levels were significantly lower in patients treated by tacrolimus in comparison with CsA (p < 0.05). In conclusion, our results suggest that pediatric LT patients do not present significant CVRF; moreover, instead of hyperlipidemia, hypocholesterolemia (LDL-C) is frequent and immunosuppressive therapy is probably the cause. PMID- 26750746 TI - Proceedings of the 2015 Santa Fe Bone Symposium: Clinical Applications of Scientific Advances in Osteoporosis and Metabolic Bone Disease. AB - The 2015 Santa Fe Bone Symposium was a venue for healthcare professionals and clinical researchers to present and discuss the clinical relevance of recent advances in the science of skeletal disorders, with a focus on osteoporosis and metabolic bone disease. Symposium topics included new developments in the translation of basic bone science to improved patient care, osteoporosis treatment duration, pediatric bone disease, update of fracture risk assessment, cancer treatment-related bone loss, fracture liaison services, a review of the most significant studies of the past year, and the use of telementoring with Bone Health Extension for Community Healthcare Outcomes, a force multiplier to improve the care of osteoporosis in underserved communities. PMID- 26750747 TI - Ranking of Molecular Biomarker Interaction with Targeted DNA Nucleobases via Full Atomistic Molecular Dynamics. AB - DNA-based sensors can detect disease biomarkers, including acetone and ethanol for diabetes and H2S for cardiovascular diseases. Before experimenting on thousands of potential DNA segments, we conduct full atomistic steered molecular dynamics (SMD) simulations to screen the interactions between different DNA sequences with targeted molecules to rank the nucleobase sensing performance. We study and rank the strength of interaction between four single DNA nucleotides (Adenine (A), Guanine (G), Cytosine (C), and Thymine (T)) on single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with acetone, ethanol, H2S and HCl. By sampling forward and reverse interaction paths, we compute the free-energy profiles of eight systems for the four targeted molecules. We find that dsDNA react differently than ssDNA to the targeted molecules, requiring more energy to move the molecule close to DNA as indicated by the potential of mean force (PMF). Comparing the PMF values of different systems, we obtain a relative ranking of DNA base for the detection of each molecule. Via the same procedure, we could generate a library of DNA sequences for the detection of a wide range of chemicals. A DNA sensor array built with selected sequences differentiating many disease biomarkers can be used in disease diagnosis and monitoring. PMID- 26750749 TI - Molecular and biochemical investigations of patients with intermediate or severe hyperhomocysteinemia. AB - A discrepancy has been identified between numbers of expected and identified patients with homocystinuria due to cystathionine beta-synthase (CBS) deficiency. Patients homozygous for the frequent c.833T>C (p.I278T) are most often responsive to vitamin B6, and can present with a total-homocysteine (tHcy) <100 MUM on a normal diet. In Denmark, patients with tHcy <100 MUM are not routinely sequenced for CBS(2) mutations. This study investigated the prevalence of CBS mutations and the common methylenetetrahydrofolate reductase (MTHFR) c.677C>T polymorphism in patients with tHcy >= 50 MUM and the association with clinical manifestations. We studied a cohort of patients with intermediate and severe hyperhomocysteinemia (tHcy >= 50 MUM) determined between 1996 and 2011. Among the 413 eligible patients, 184 (45%) patients agreed to participate in the present follow-up study. A MTHFR(3)c.677TT genotype was found in 49% of the patients. Eight patients were found to have mutations in CBS(2). Of those, two were homozygous for c.833T>C (p.I278T), and four were compound heterozygous for c.833T>C. One c.833T>C (p.I278T) compound heterozygote was identified by lowering the threshold for sequencing from tHcy at 100 MUM to 50 MUM. The most prominent clinical presentation among patients with a CBS(2) mutation was thrombosis presenting at a median age of 25 years. In case of arterial or venous thrombosis without any explanation in individuals below 40 years, tHcy should be part of the thrombophilia screening. When tHcy is between 50 and 100 MUM genotyping for the MTHFR(3) c.677TT is relevant, and when tHcy >100 MUM CBS should be genotyped. PMID- 26750750 TI - Lyso-glycosphingolipid abnormalities in different murine models of lysosomal storage disorders. AB - In lysosomal glycosphingolipid storage disorders, marked elevations in corresponding glycosphingoid bases (lyso-glycosphingolipids) have been reported, such as galactosylsphingosine in Krabbe disease, glucosylsphingosine in Gaucher disease and globotriaosylsphingosine in Fabry disease. Using LC-MS/MS, we comparatively investigated the occurrence of abnormal lyso-glycosphingolipids in tissues and plasma of mice with deficiencies in lysosomal alpha-galactosidase A, glucocerebrosidase and galactocerebrosidase. The nature and specificity of lyso glycosphingolipid abnormalities are reported and compared to that in correspondingly more abundant N-acylated glycosphingolipids. Specific elevations in tissue and plasma globotriaosylsphingosine were detected in alpha galactosidase A-deficient mice; glucosylsphingosine in glucocerebrosidase deficient mice and galactosylsphingosine in galactocerebrosidase-deficient animals. A similar investigation was conducted for two mouse models of Niemann Pick type C (Npc1nih and Npc1nmf164), revealing significant tissue elevation of several neutral glycosphingolipids and concomitant increased plasma glucosylsphingosine. This latter finding was recapitulated by analysis of plasma of NPC patients. The value of plasma glucosylsphingosine in biochemical confirmation of the diagnosis of NPC is discussed. PMID- 26750748 TI - Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. AB - Peroxisome biogenesis disorders in the Zellweger spectrum (PBD-ZSD) are a heterogeneous group of genetic disorders caused by mutations in PEX genes responsible for normal peroxisome assembly and functions. As a result of impaired peroxisomal activities, individuals with PBD-ZSD can manifest a complex spectrum of clinical phenotypes that typically result in shortened life spans. The extreme variability in disease manifestation ranging from onset of profound neurologic symptoms in newborns to progressive degenerative disease in adults presents practical challenges in disease diagnosis and medical management. Recent advances in biochemical methods for newborn screening and genetic testing have provided unprecedented opportunities for identifying patients at the earliest possible time and defining the molecular bases for their diseases. Here, we provide an overview of current clinical approaches for the diagnosis of PBD-ZSD and provide broad guidelines for the treatment of disease in its wide variety of forms. Although we anticipate future progress in the development of more effective targeted interventions, the current guidelines are meant to provide a starting point for the management of these complex conditions in the context of personalized health care. PMID- 26750751 TI - Leucine zipper motif in RRS1 is crucial for the regulation of Arabidopsis dual resistance protein complex RPS4/RRS1. AB - Arabidopsis thaliana leucine-rich repeat-containing (NLR) proteins RPS4 and RRS1, known as dual resistance proteins, confer resistance to multiple pathogen isolates, such as the bacterial pathogens Pseudomonas syringae and Ralstonia solanacearum and the fungal pathogen Colletotrichum higginsianum. RPS4 is a typical Toll/interleukin 1 Receptor (TIR)-type NLR, whereas RRS1 is an atypical TIR-NLR that contains a leucine zipper (LZ) motif and a C-terminal WRKY domain. RPS4 and RRS1 are localised near each other in a head-to-head orientation. In this study, direct mutagenesis of the C-terminal LZ motif in RRS1 caused an autoimmune response and stunting in the mutant. Co-immunoprecipitation analysis indicated that full-length RPS4 and RRS1 are physically associated with one another. Furthermore, virus-induced gene silencing experiments showed that hypersensitive-like cell death triggered by RPS4/LZ motif-mutated RRS1 depends on EDS1. In conclusion, we suggest that the RRS1-LZ motif is crucial for the regulation of the RPS4/RRS1 complex. PMID- 26750752 TI - Intracoronary Transplantation of Mesenchymal Stem Cells with Overexpressed Integrin-Linked Kinase Improves Cardiac Function in Porcine Myocardial Infarction. AB - The effect of mesenchymal stem cell (MSCs)-based therapy on treating acute myocardial infarction (MI) is limited due to poor engraftment and limited regenerative potential. Here we engineered MSCs with integrin-linked kinase (ILK), a pleiotropic protein critically regulating cell survival, proliferation, differentiation, and angiogenesis. We firstly combined ferumoxytol with poly-L lysine (PLL), and found this combination promisingly enabled MRI visualization of MSCs in vitro and in vivo with good safety. We provided visually direct evidence that intracoronary ILK-MSCs had substantially enhanced homing capacity to infarct myocardium in porcine following cardiac catheterization induced MI. Intracoronary transplantation of allogeneic ILK-MSCs, but not vector-MSCs, significantly enhanced global left ventricular ejection fraction (LVEF) by 7.8% compared with baseline, by 10.3% compared with vehicles, and inhibited myocardial remodeling compared with vehicles at 15-day follow-up. Compared with vector-MSCs, ILK-MSCs significantly improved regional LV contractile function, reduced scar size, fibrosis, cell apoptosis, and increased regional myocardial perfusion and cell proliferation. This preclinical study indicates that ILK-engineered MSCs might promote the clinical translation of MSC-based therapy in post-MI patients, and provides evidence that ferumoxytol labeling of cells combined with PLL is feasible in in vivo cell tracking. PMID- 26750753 TI - Role of the Proximal Cysteine Hydrogen Bonding Interaction in Cytochrome P450 2B4 Studied by Cryoreduction, Electron Paramagnetic Resonance, and Electron-Nuclear Double Resonance Spectroscopy. AB - Crystallographic studies have shown that the F429H mutation of cytochrome P450 2B4 introduces an H-bond between His429 and the proximal thiolate ligand, Cys436, without altering the protein fold but sharply decreases the enzymatic activity and stabilizes the oxyferrous P450 2B4 complex. To characterize the influence of this hydrogen bond on the states of the catalytic cycle, we have used radiolytic cryoreduction combined with electron paramagnetic resonance (EPR) and (electron nuclear double resonance (ENDOR) spectroscopy to study and compare their characteristics for wild-type (WT) P450 2B4 and the F429H mutant. (i) The addition of an H-bond to the axial Cys436 thiolate significantly changes the EPR signals of both low-spin and high-spin heme-iron(III) and the hyperfine couplings of the heme-pyrrole (14)N but has relatively little effect on the (1)H ENDOR spectra of the water ligand in the six-coordinate low-spin ferriheme state. These changes indicate that the H-bond introduced between His and the proximal cysteine decreases the extent of S -> Fe electron donation and weakens the Fe(III)-S bond. (ii) The added H-bond changes the primary product of cryoreduction of the Fe(II) enzyme, which is trapped in the conformation of the parent Fe(II) state. In the wild-type enzyme, the added electron localizes on the porphyrin, generating an S = (3)/2 state with the anion radical exchange-coupled to the Fe(II). In the mutant, it localizes on the iron, generating an S = (1)/2 Fe(I) state. (iii) The additional H-bond has little effect on g values and (1)H-(14)N hyperfine couplings of the cryogenerated, ferric hydroperoxo intermediate but noticeably slows its decay during cryoannealing. (iv) In both the WT and the mutant enzyme, this decay shows a significant solvent kinetic isotope effect, indicating that the decay reflects a proton-assisted conversion to Compound I (Cpd I). (v) We confirm that Cpd I formed during the annealing of the cryogenerated hydroperoxy intermediate and that it is the active hydroxylating species in both WT P450 2B4 and the F429H mutant. (vi) Our data also indicate that the added H-bond of the mutation diminishes the reactivity of Cpd I. PMID- 26750755 TI - Total synthesis of (+/-)-epithuriferic acid methyl ester via Diels-Alder reaction. AB - In this paper, we have described the first total synthesis of (+/-)-epithuriferic acid methyl ester from non-natural sources, in four steps (20% overall yield). The key step involves the Diels-Alder reaction of isobenzofuran with methyl 3 (dimethoxyphosphoryl)acrylate which is controlled by "ortho" regio- and endo stereoselectivities due to the COOMe group. PMID- 26750757 TI - Direct oxidative amidation of aldehydes with amines catalyzed by heteropolyanion based ionic liquids under solvent-free conditions via a dual-catalysis process. AB - A simple and efficient procedure for the synthesis of amides directly from aldehydes and amines catalyzed by heteropolyanion-based ionic liquids under solvent-free conditions has been reported. The practical protocol was found to tolerate a wide range of substrates with different functional groups. Moderate to excellent yields, solvent-free media, and operational simplicity are the main highlights. The proposed dual-catalysis mechanistic pathway was briefly investigated. Furthermore, the heteropolyanion-based ionic liquids were easily reusable for this oxidative amidation. PMID- 26750754 TI - A novel cell-penetrating peptide suppresses breast tumorigenesis by inhibiting beta-catenin/LEF-1 signaling. AB - The inhibition of beta-catenin/LEF-1 signaling is an emerging strategy in cancer therapy. However, clinical targeted treatment of the beta-catenin/LEF-1 complex remains relatively ineffective. Therefore, development of specific molecular targets is a key approach for identifying new cancer therapeutics. Thus, we attempted to synthesize a peptide (TAT-NLS-BLBD-6) that could interfere with the interaction of beta-catenin and LEF-1 at nuclei in human breast cancer cells. TAT NLS-BLBD-6 directly interacted with beta-catenin and inhibited breast cancer cell growth, invasion, migration, and colony formation as well as increased arrest of sub-G1 phase and apoptosis; it also suppressed breast tumor growth in nude mouse and zebrafish xenotransplantation models, showed no signs of toxicity, and did not affect body weight. Furthermore, the human global gene expression profiles and Ingenuity Pathway Analysis software showed that the TAT-NLS-BLBD-6 downstream target genes were associated with the HER-2 and IL-9 signaling pathways. TAT-NLS BLBD-6 commonly down-regulated 27 candidate genes in MCF-7 and MDA-MB-231 cells, which are concurrent with Wnt downstream target genes in human breast cancer. Our study suggests that TAT-NLS-BLBD-6 is a promising drug candidate for the development of effective therapeutics specific for Wnt/beta-catenin signaling inhibition. PMID- 26750756 TI - Th17 cells and IL-17 promote the skin and lung inflammation and fibrosis process in a bleomycin-induced murine model of systemic sclerosis. AB - OBJECTIVES: Systemic sclerosis (SSc) is characterised by fibrosis of the skin and internal organs, such as the lungs. Enhanced Th17 responses are associated with skin fibrosis in patients with SSc, however, whether they are associated with lung fibrosis has not been clarified. This study aimed to investigate the potential association of Th17 responses with the skin and pulmonary fibrosis as well as the potential mechanisms in a mouse bleomycin (BLM) model of SSc. METHODS: BALB/c mice were injected subcutaneously with phosphate buffered saline (PBS) (control) or BLM for 28 days and the skin and pulmonary inflammation and fibrosis were characterized by histology. The percentages of circulating, skin and pulmonary infiltrating Th17 cells and the contents of collagen in mice were analysed. The levels of RORgammat, IL-17A, IL-6 and TGF-beta1 mRNA transcripts in the skin and lungs were determined by quantitative RTPCR and the levels of serum IL-17A, IL-6 and TGF-beta1 were determined by ELISA. Furthermore, the effect of rIL-17A on the proliferation of pulmonary fibroblasts and their cytokine expression was analysed. The potential association of Th17 responses with the severity of skin and lung fibrosis was analysed. RESULTS: In comparison with the control mice, significantly increased skin and pulmonary inflammation and fibrosis and higher levels of hydroxyproline were detected in the BLM mice. Significantly higher frequency of circulating, skin and lung infiltrating Th17 cells and higher levels of serum, skin and lung IL-17A, TGF-beta1, IL-6 and RORgammat were detected in the BLM mice. The concentrations of serum IL-17A were correlated positively with the percentages of Th17 cells and the contents of skin hydroxyproline in the BLM mice. The levels of IL-17A expression were positively correlated with the skin and lung inflammatory scores as well as the skin fibrosis in the BLM mice. In addition, IL-17A significantly enhanced pulmonary fibroblast proliferation and their type I collagen, TGF-beta and IL-6 expression in vitro, which were attenuated by treatment with anti-IL-17A. CONCLUSIONS: Our results indicate that Th17 cells participate in the pathogenesis of skin and lung fibrosis by enhancing fibroblast proliferation and cytokine production in a mouse BLM model of SSc. PMID- 26750759 TI - Future Warming Patterns Linked to Today's Climate Variability. AB - The reliability of model projections of greenhouse gas (GHG)-induced future climate change is often assessed based on models' ability to simulate the current climate, but there has been little evidence that connects the two. In fact, this practice has been questioned because the GHG-induced future climate change may involve additional physical processes that are not important for the current climate. Here I show that the spatial patterns of the GHG-induced future warming in the 21(st) century is highly correlated with the patterns of the year-to-year variations of surface air temperature for today's climate, with areas of larger variations during 1950-1979 having more GHG-induced warming in the 21(st) century in all climate models. Such a relationship also exists in other climate fields such as atmospheric water vapor, and it is evident in observed temperatures from 1950-2010. The results suggest that many physical processes may work similarly in producing the year-to-year climate variations in the current climate and the GHG induced long-term changes in the 21(st) century in models and in the real world. They support the notion that models that simulate present-day climate variability better are likely to make more reliable predictions of future climate change. PMID- 26750758 TI - Fully Enzymatic Membraneless Glucose|Oxygen Fuel Cell That Provides 0.275 mA cm( 2) in 5 mM Glucose, Operates in Human Physiological Solutions, and Powers Transmission of Sensing Data. AB - Coimmobilization of pyranose dehydrogenase as an enzyme catalyst, osmium redox polymers [Os(4,4'-dimethoxy-2,2'-bipyridine)2(poly(vinylimidazole))10Cl](+) or [Os(4,4'-dimethyl-2,2'-bipyridine)2(poly(vinylimidazole))10Cl](+) as mediators, and carbon nanotube conductive scaffolds in films on graphite electrodes provides enzyme electrodes for glucose oxidation. The recombinant enzyme and a deglycosylated form, both expressed in Pichia pastoris, are investigated and compared as biocatalysts for glucose oxidation using flow injection amperometry and voltammetry. In the presence of 5 mM glucose in phosphate-buffered saline (PBS) (50 mM phosphate buffer solution, pH 7.4, with 150 mM NaCl), higher glucose oxidation current densities, 0.41 mA cm(-2), are obtained from enzyme electrodes containing the deglycosylated form of the enzyme. The optimized glucose-oxidizing anode, prepared using deglycosylated enzyme coimmobilized with [Os(4,4'-dimethyl 2,2'-bipyridine)2(poly(vinylimidazole))10Cl](+) and carbon nanotubes, was coupled with an oxygen-reducing bilirubin oxidase on gold nanoparticle dispersed on gold electrode as a biocathode to provide a membraneless fully enzymatic fuel cell. A maximum power density of 275 MUW cm(-2) is obtained in 5 mM glucose in PBS, the highest to date under these conditions, providing sufficient power to enable wireless transmission of a signal to a data logger. When tested in whole human blood and unstimulated human saliva maximum power densities of 73 and 6 MUW cm( 2) are obtained for the same fuel cell configuration, respectively. PMID- 26750761 TI - Age at disease onset may help to further characterize the disease phenotype in psoriatic arthritis. AB - OBJECTIVE: To evaluate whether the age of disease presentation helps to better characterize the disease phenotype in PsA. METHODS: Retrospective cohort study that included 205 consecutive patients fulfilling the CASPAR criteria for PsA. Study outcomes were assessed using univariate and multivariate analyses according to the age of onset of both skin and joint disease (cut off at 40years). RESULTS: Early onset psoriasis (EOP) showed more extensive skin involvement (OR 2.3, P=0.011), axial pattern as disease onset (OR 4.6, P=0.009) and mixed pattern during evolution (OR 2.4, P=0.019), family history of both psoriasis (OR 3.1, P=0.003) and PsA (OR 4.0, P=0.021), higher prevalence of HLA-C*06 (OR 2.03, P=0.03) and HLA-B*27 (OR 2.7, P=0.02). Early onset arthritis (EOA) had more family history of PsA (OR 2.9, P=0.007), and HLA-B*27 positivity (OR 5.9, P<0.0001). Patients with late onset arthritis (LOA) were more likely to have DM (OR 4.0, P=0.009), hypertension (OR 2.5, P=0.004), dyslipidemia (OR 2.3, P=0.011), and obesity (OR 1.7, P=0.012). Late onset psoriasis (LOP) tended to have more obesity (OR 1.9, P=0.035), DM (OR 9.4, P<0.0001), hypertension (OR 4.1, P<0.0001), and ischemic heart disease during follow-up (OR 5.9, P=0.021). In multivariate analysis, LOP predicted DM development (OR 12.1, P=0.006). LOA was shown to be an independent risk factor for hypertension (OR 5.2, P=0.039). CONCLUSION: Age at disease onset exerts a strong influence on several domains of disease phenotype in PsA. Therefore, this descriptor should be considered a good stratification option for epidemiological and genetic studies in PsA. PMID- 26750760 TI - Spatial Abundance and Distribution of Potential Microbes and Functional Genes Associated with Anaerobic Mineralization of Pentachlorophenol in a Cylindrical Reactor. AB - Functional interplays of microbial activity, genetic diversity and contaminant transformation are poorly understood in reactors for mineralizing halogenated aromatics anaerobically. Here, we investigated abundance and distribution of potential microbes and functional genes associated with pentachlorophenol (PCP) anaerobic mineralization in a continuous-flow cylindrical reactor (15 cm in length). PCP dechlorination and the metabolite (phenol) were observed at segments 0-8 cm from inlet, where key microbes, including potential reductive dechlorinators (Dehalobacter, Sulfurospirillum, Desulfitobacterium and Desulfovibrio spp.) and phenol degraders (Cryptanaerobacter and Syntrophus spp.), as well as putative functional genes, including putative chlorophenol reductive dehalogenase (cprA) and benzoyl-CoA reductase (bamB), were highly enriched simultaneously. Five types of putative cprAs, three types of putative bamBs and seven types of putative nitrogenase reductase (nifHs) were determined, with their copy numbers decreased gradually from inlet to outlet. Distribution of chemicals, bacteria and putative genes confirmed PCP dechlorination and phenol degradation accomplished in segments 0-5 cm and 0-8 cm, respectively, contributing to a high PCP mineralization rate of 3.86 MUM d(-1). Through long-term incubation, dechlorination, phenol degradation and nitrogen fixation bacteria coexisted and functioned simultaneously near inlet (0-8 cm), verified the feasibility of anaerobic mineralization of halogenated aromatics in the compact reactor containing multiple functional microbes. PMID- 26750763 TI - Tocilizumab for refractory relapsing polychondritis-long-term response monitoring by magnetic resonance imaging. PMID- 26750762 TI - The clinical relevance of early anti-adalimumab antibodies detection in rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis: A prospective multicentre study. AB - OBJECTIVES: To evaluate the relevance of anti-adalimumab (anti-ADA) antibodies (Abs) and their relationship with clinical/laboratory features in rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). METHODS: Fifty-eight patients affected with RA, AS and PsA were prospectively enrolled. Clinical/laboratory characteristics, disease activity, anti-ADA, anti nuclear (ANA), anti-double strand (ds)DNA, anti-extractable nuclear antigens (anti-ENA) and anti-phospholipid Abs (aPL) were evaluated at baseline, 4, 12 and 24 weeks of adalimumab treatment. RESULTS: Anti-ADA Abs were observed in 11/58 (19%) patients; they were detected within the 4th week of therapy in 90.9% of the positive subjects. Anti-ADA positivity was associated with significantly lower mean adalimumab serum levels (P<0.05). Treatment failure was observed in 20/58 (34.5%) patients and was significantly associated with anti-ADA Abs (P<0.05). Mean adalimumab serum levels were significantly lower in patients with treatment failure than in the responders one, both in the whole cohort (P<0.01) and in the group of anti-ADA positive patients (P<0.01). Adverse events happened more often in anti-ADA positive then in anti-ADA negative patients (27.3% vs 14.9%). CONCLUSIONS: Anti-ADA abs could be considered an early marker associated to a poor clinical response to adalimumab treatment. Routine ANA/anti-ENA/aPL monitoring did not reveal as useful tools to predict the development of anti-ADA abs. PMID- 26750764 TI - Small, medium but not large arteries are involved in digital ulcers associated with systemic sclerosis. AB - OBJECTIVE: Digital ulcers (DU) are a burden in systemic sclerosis (SSc). Microangiopathy is a cardinal feature of SSc that plays a critical role in the development of DU. However, whether injury of medium or large vessels also contributes to DU in SSc remains controversial. METHODS: To measure concomitantly in SSc patients with and without active DU: (i) the Augmentation Index of the reflected wave (Aix_75) by radial applanation tonometry, an index of small and medium arterial function; (II) the aortic pulse wave velocity (PWV), a marker of large vessel injury (aortic stiffness). RESULTS: Sixty-three consecutive SSc patients were included (49 females, aged 60 [49-65] years, disease duration of 8.5 [5-13] years), including 10 (15.9%) with active DU. Patients with active DU versus those without had increased Aix_75 (35% [28-38] versus 28% [20-34], P=0.041) whereas no difference existed in PWV (7.0m/s [6.7-10.1] versus 7.6m/s [6.8-8.7], P=0.887), in systolic, diastolic, as well as aortic pulse pressure (P=0.126, 0.592, and 0.161, respectively). When compared to patients in the low tertile, patients having Aix_75 in the highest tertile had 10-fold more DU (OR=10.23; 95% CI 1.12 to 93.34, P=0.039). CONCLUSION: The presence of DU is associated with increased Aix_75 whereas there is no relation with PWV. These data suggest that small and medium arteries are involved in the occurrence of DU whether large vessel stiffness does not contribute. Whether Aix_75 is predictive of further DU remained to be studied. PMID- 26750766 TI - Initial classification of pediatric hearing impairment using behavioral measures of early prelingual auditory development. AB - OBJECTIVE: Determine the sensitivity, specificity, and accuracy of pediatric hearing loss classification using behavioral evidence of early prelingual auditory development (EPLAD). Validate behavioral measures of EPLAD. DESIGN: EPLAD was assessed in a prospective sample of hearing-impaired children using the infant-toddler meaningful auditory integration scale (ITMAIS/MAIS). Hearing losses were classified using tone-burst auditory brainstem response (ABR) and ITMAIS/MAIS scores. This process was repeated in a second retrospective sample. STUDY SAMPLE: The prospective sample was comprised of 139 hearing-impaired children under five years of age. Approximately equal proportions of mild moderate, severe, and profound losses were included. The second retrospective sample was comprised of case records for 144 hearing-impaired children meeting the same selection criteria. This sample contained more than 80% profound losses. RESULTS: EPLAD trajectories reached different asymptotes after two years of age, depending on the severity of hearing loss, allowing children over this age to be classified. The sensitivity of EPLAD classifications was over 90%; specificity was over 82%; and accuracy was over 88%. CONCLUSIONS: Behavioral evidence of EPLAD provides an initial means of classifying pediatric hearing losses which can facilitate initial treatment options prior to diagnostic evaluation with tone burst ABR. PMID- 26750767 TI - Catalytic asymmetric hetero-Diels-Alder reactions of enones with isatins to access functionalized spirooxindole tetrahydropyrans: scope, derivatization, and discovery of bioactives. AB - The development of concise methods for the synthesis of functionalized small molecules is important in the search for new bioactive molecules. To contribute to this, we have developed oxa-hetero-Diels-Alder reactions of enones with isatins catalyzed by amine-based catalyst systems. Various spirooxindole tetrahydropyranones were synthesized either in enantiomerically enriched forms or as racemic forms depending on the catalyst system. The reaction products were further transformed at the ketone carbonyl group and the indole nitrogen. Using these reactions, functionalized spirooxindole tetrahydropyran derivatives with functional groups in four directions in a three-dimensional space were concisely obtained. From these synthesized compounds, an inhibitor of human ion channel Nav1.7 with MUM-level activity was identified, indicating that the developed reaction methods are useful for providing molecules for the discovery of new biofunctional molecules. PMID- 26750765 TI - Multimodal Detection of a Small Molecule Target Using Stimuli-Responsive Liposome Triggered by Aptamer-Enzyme Conjugate. AB - Nanomaterials which can respond to external stimuli have attracted considerable attention due to their potential applications in sensing and biomedicine. One of the most promising classes of such materials is the stimuli-responsive liposome that can release its contents in response to a specific target. Despite recent progress, development of liposomes responsive to small molecular targets remains a challenge, due to the difficulty in designing the transduction process to link between target binding and triggered release, even though small molecular metabolites play important roles in many biological processes. Herein, we demonstrate a combination of an aptamer (apt) for target recognition and enzyme phosphatidylcholine 2-acetylhydrolase (PLA2) for rupture of liposome. As a proof of-concept, cocaine molecules were used to trigger the release of the enzyme. The exposure to DNA-PLA2 conjugates induced the rupture of liposome containing uranin and gadopentetic acid (Gd-DTPA), allowing multimodal fluorescent and MRI detection of cocaine. The strategy demonstrated in this work can be generally applied to other imaging modalities by loading different imaging agents, as well as other targets by using different functional DNAs. PMID- 26750768 TI - MicroRNA-Let-7f reduces the vasculogenic mimicry of human glioma cells by regulating periostin-dependent migration. AB - The present study was the first to examine the effect of microRNA-Let-7f (miR-Let 7f) inhibiting vasculogenic mimicry (VM) of human glioma cells. The postoperative survival time was significantly poor in VM-positive glioma patients compared with those without VM. Thus, it is reasonable to postulate that miR-Let-7f functions as a potent tumor suppressor by inhibiting glioma VM. However, the molecular mechanisms involved remain poorly clarified. Our preliminary studies revealed that miR-Let-7f suppressed VM by disturbing periostin (POSTN)-induced migration of glioma cells. Our results clearly demonstrated that inhibiting the pro migratory function of POSTN by the overexpression of miR-Let-7f significantly reduced the formation of VM. Our findings suggest that miR-Let-7f may serve as a potential complementary therapeutic target in the anti-angiogenesis treatment of gliomas via suppressing VM. PMID- 26750769 TI - Ratiometric Fluorescent Pattern for Sensing Proteins Using Aqueous Polymer Pyrene/gamma-Cyclodextrin Inclusion Complexes. AB - A ratiometric, versatile, and selective fluorescent pattern to sense and distinguish proteins on the basis of dissociation of aqueous polymer-pyrene/gamma cyclodextrin (gamma-CD) inclusion complexes was developed. First, two kinds of aqueous polymer-pyrene were prepared via atom transfer radical polymerization using pyrene functionalized initiator. Then, the pyrene molecules could be accumulated into gamma-CD cavity and form polymer-pyrene/gamma-CD complexes, resulting in appearance of excimer emissions. The resultant complexes responded to proteins in two ways: nonmetalloproteins binding to polymer component triggered dissociation of the inclusion complexes, accompanied by alteration of pyrene excimer/monomer emission and ratiometric fluorescent intensity changes; the presence of metalloproteins could quench pyrene excimer/monomer emission because of energy transfer. Moreover, the fluorescent responses of the inclusion complexes to different proteins could be modulated by changing polymer type and chain length, resulting in a tunable selectivity and sensitivity. The proposed fluorescent inclusion complexes could provide a promising platform for sensing proteins. PMID- 26750770 TI - Decision-making and outcomes of hearing help-seekers: A self-determination theory perspective. AB - OBJECTIVE: To explore the explanatory power of a self-determination theory (SDT) model of health behaviour change for hearing aid adoption decisions and fitting outcomes. DESIGN: A quantitative approach was taken for this longitudinal cohort study. Participants completed questionnaires adapted from SDT that measured autonomous motivation, autonomy support, and perceived competence for hearing aids. Hearing aid fitting outcomes were obtained with the international outcomes inventory for hearing aids (IOI-HA). Sociodemographic and audiometric information was collected. STUDY SAMPLE: Participants were 216 adult first-time hearing help seekers (125 hearing aid adopters, 91 non-adopters). RESULTS: Regression models assessed the impact of autonomous motivation and autonomy support on hearing aid adoption and hearing aid fitting outcomes. Sociodemographic and audiometric factors were also taken into account. Autonomous motivation, but not autonomy support, was associated with increased hearing aid adoption. Autonomy support was associated with increased perceived competence for hearing aids, reduced activity limitation and increased hearing aid satisfaction. Autonomous motivation was positively associated with hearing aid satisfaction. CONCLUSION: The SDT model is potentially useful in understanding how hearing aid adoption decisions are made, and how hearing health behaviour is internalized and maintained over time. Autonomy supportive practitioners may improve outcomes by helping hearing aid adopters maintain internalized change. PMID- 26750772 TI - Comparison of two cognitive interventions for adults experiencing executive dysfunction post-stroke: a pilot study. AB - Purpose This pilot partially randomised controlled trial compared the feasibility and preliminary efficacy of two promising interventions for persons with executive dysfunction post-stroke: (1) occupation-based strategy training using an adapted version of the Cognitive Orientation to daily Occupational Performance (CO-OP) approach; and (2) Computer-based EF training (COMPUTER training). Method Participants received 16 h of either CO-OP or COMPUTER training. We assessed feasibility and acceptability of each intervention, and change in intervention outcomes at baseline, post-intervention and one-month follow-up. Performance and satisfaction with performance in self-selected everyday life goals were measured by the participant and the significant other-rated Canadian Occupational Performance Measure (COPM). Other intervention outcomes included changes in EF impairment, participation in daily life and self-efficacy. Results Six participants received CO-OP and five received COMPUTER training: one in each group discontinued the intervention for medical reasons unrelated to the intervention. The remaining nine participants completed all 16 sessions. Participants expressed high levels of satisfaction with both interventions. Both treatment groups showed large improvements in self and significant other-rated performance and satisfaction with performance on their goals immediately post intervention and at follow-up (CO-OP: effect sizes (ES) = 1.6-3.5; COMPUTER: ES = 0.9-4.0), with statistically significant within-group differences in CO-OP (p < 0.05). The COMPUTER group also showed large improvements in some areas of EF impairment targeted by the computerised tasks (ES = 0.9-1.6); the CO-OP group demonstrated large improvements in self-efficacy for performing everyday activities (ES = 1.5). Conclusions Our findings provide preliminary evidence supporting the feasibility of using both CO-OP and COMPUTER training with patients with executive dysfunction post-stroke. Implications for Rehabilitation Computerised executive function training and occupation-based strategy training are feasible to deliver and acceptable to persons with executive dysfunction post stroke. Preliminary evidence suggests that both interventions have a positive impact on real-world outcomes; and, that CO-OP might have a greater impact on improving self-efficacy for performing everyday activities. PMID- 26750771 TI - Intraabdominal candidiasis in surgical ICU patients treated with anidulafungin: A multicenter retrospective study. AB - OBJECTIVE: Patients with recent intraabdominal events are at uniquely risk for intraabdominal candidiasis (IAC). Candida peritonitis is a frequent and life threatening complication in surgically ill patients. International guidelines do not specifically address IAC. This study describes clinical features of IAC in critical patients treated with anidulafungin in Surgical ICUs (SICUs). METHODS: A practice-based retrospective study was performed including all adults with IAC admitted to 19 SICUs for >=24h treated with anidulafungin. IAC was documented (Candida isolation from blood/peritoneal fluid/abscess fluid and/or histopathological confirmation) or presumptive (host factors plus clinical criteria without mycological support). Total population and the subgroup of septic shock patients were analyzed. RESULTS: One hundred and thirty nine patients were included, 94 (67.6%) with septic shock, 112 (86.2%) after urgent surgery. Of them, 77.7% presented peritonitis and 21.6% only intraabdominal abscesses. Among 56.8% cases with documented IAC, C. albicans (52.8%) followed by C. glabrata (27.8%) were the most frequent species. Anidulafungin was primarily used as empirical therapy (59.7%), microbiologically directed (20.9%) and anticipated therapy (15.8%). Favourable response was 79.1% (76.6% among patients with septic shock). Intra-SICU mortality was 25.9% (28.7% among patients with septic shock). CONCLUSIONS: Among IACs managed at SICUs, peritonitis was the main presentation, with high percentage of patients presenting septic shock. C. albicans followed by C. glabrata were the main responsible species. Anidulafungin treatment was mostly empirical followed by microbiologically directed therapy, with a favourable safety profile, even among patients with septic shock. PMID- 26750773 TI - Inverted hybrid CdSe-polymer solar cells adopting PEDOT:PSS/MoO3 as dual hole transport layers. AB - Inverted CdSe quantum dots (QDs):poly (3-hexylthiophene) (P3HT) organic/inorganic hybrid solar cells (OIHSCs) with the PEDOT: PSS/MoO3 dual hole transport layers (HTLs) showed superior performance over those with a single HTL of PEDOT: PSS or MoO3. The enhanced electron blocking at the active layer/anode interface as well as the prevention of leakage current accounted for the enhancement in the efficiency of the solar cells with the dual HTLs. By adopting the inverted structure and using the dual HTLs, the resistive losses of the CdSe QDs:P3HT hybrid system at high illumination power were effectively prevented. Further study showed the structure of dual HTLs was applicable to the solar cells with CdSe QDs and nanorods (NRs) blended with poly(thienothiophene-co benzodithiophenes)7-F20 (PTB7-F20). PMID- 26750775 TI - Pyridine-copper(ii) formates for the generation of high conductivity copper films at low temperatures. AB - Pyridine derivatives coordinated to copper(ii) formates are shown to have lower decomposition temperatures than the alkylamine analogues. Using heating profiles compatible with low temperature substrates, deposited inks made from these compounds are transformed into copper traces with a resistivity value of 14 MUOmega cm when sintered at 135 degrees C in <5 minutes. PMID- 26750774 TI - Comparative Analysis of Real-Time Polymerase Chain Reaction Methods to Typing HLA B*57:01 in HIV-1-Positive Patients. AB - The HLA-B*57:01 allele is strongly associated with the hypersensitivity reaction to Abacavir (ABC). Therefore, treatment guidelines recommend that patients initiating ABC are preventively tested for the presence of this allele. To date, four different commercial assays based on the real-time quantitative polymerase chain reaction (Q-PCR) technique are available for the detection of HLA-B*57:01: Duplicalpha-RealTime Reagent Set HLA-B*57:01 by Euroclone, HLA-B*57:01 Real-TM by Sacace Biotechnologies, COBAS AmpliPrep/COBAS TaqMan HLA-B*57:01 Screening Test by Roche Diagnostic, and HLA-B*57:01 by Nuclear Laser Medicine. The study was carried out to compare the performance of the first three commercially available Q-PCR kits in a routine clinical setting. A total of 98 samples from Policlinico Umberto I Hospital were tested. Results obtained by the Duplicalpha-RealTime Genotyping kit and AmpliPrep/TaqMan system were 100% concordant. In contrast, genotyping by the HLA-B*57:01 Real-TM kit showed poor agreement with the other systems, that is, 12 out of 33 positive samples were detected as HLA-B*57:01 negative. To confirm the correct genotype of these discordant samples, two additional methods with rapid turnaround times and already implemented into routine clinical practice were used, that is, a PCR-based microsequence-specific primer DNA typing test and a laboratory-developed screening test in Q-PCR. All 12 discordant samples were genotyped as HLA-B*57:01-positive samples using these two additional methods in a single-blinded manner, thus confirming the low sensitivity of HLA-B*57:01 Real-TM test. These findings underline the need to compare results obtained with commercial assays before choosing a test suitable for use in a routine clinical laboratory. PMID- 26750777 TI - CO2 activation through silylimido and silylamido zirconium hydrides supported on N-donor chelating SBA15 surface ligands. AB - Density functional theory calculations and 2D 1H-13C HETCOR solid state NMR spectroscopy prove that CO2 can be used to probe, by its own reactivity, different types of N-donor surface ligands on SBA15-supported Zr(IV) hydrides: [=(Si-O-)(=Si-N=)[Zr]H] and [=(Si-NH-)(=Si-X-)[Zr]H2] (X=O or NH). Moreover, [=(Si-O-)(=Si-N=)[Zr]H] activates CO2 more efficiently than the other complexes and leads to the formation of a carbimato Zr formate. PMID- 26750776 TI - Encapsulation of alkyldiammonium ions within two different cavities of twisted cucurbit[14]uril. AB - Binding interactions between twisted cucurbit[14]uril (tQ[14]) and a series of alkyldiammonium ions both in aqueous solution and DMSO media were investigated by NMR spectroscopy and ITC. Experimental data indicate that tQ[14] possesses two kinds of cavities with different space environments, which can encapsulate two or even three guest molecules with suitable shape and size. PMID- 26750778 TI - Should parasitic disease be investigated in immigrant children with relative eosinophilia from tropical and sub-tropical regions? AB - BACKGROUND: Immigrants to Spain are mainly from low- and middle-income countries, and around 20% are children. Absolute eosinophilia is defined as >0.45*109 eosinophilic leucocytes/L of peripheral blood. Absolute eosinophilia in travelers and immigrants from tropical and sub-tropical areas is frequently associated with parasitic diseases. However, the significance of relative eosinophilia in immigrant children, defined as >5% eosinophilic leucocytes in those with <0.45*109 eosinophils/L, is unresolved. OBJECTIVES: To describe the importance of relative eosinophilia in a cohort of immigrant children (<18 years) from sub Saharan Africa, North Africa and Latin America. METHODS: 176 immigrant children without absolute eosinophilia were prospectively evaluated. RESULTS: 25 of them (14.2%) had relative eosinophilia. 10 patients with relative eosinophilia had no diagnosis. 15 with relative eosinophilia (60%) were diagnosed with a parasitic disease, 7 (46.7%) of whom had only one parasite, while co-infection accounted for 8 of the 15 cases (53.3%). Of the parasitic infections, the most frequent causes of relative eosinophilia were filariasis spp. (7/15, 46.7%), strongyloides spp. (5/15, 33.3%), schistosoma spp. (4/15, 26.6%) and Ascaris lumbricoides (2/15, 13.3%). CONCLUSION: The findings suggest that relative eosinophilia is frequently associated with helminthic infection in immigrant children from tropical and sub-tropical areas, so a thorough parasitological study is highly advisable in this group of patients. PMID- 26750779 TI - Creating religiously compliant milk banks in the Muslim world: a commentary. AB - Human milk banks are vital for providing donor milk to infants for whom there are maternal or postnatal barriers to the mother's own milk. Although more than 35 countries have active milk banks, not one of those is a Muslim country.(1) Despite widespread support for breastfeeding across the Muslim world, religious constraints surrounding milk-sharing have created challenging barriers to the creation of milk banks. The religious objection centres around the Islamic tenet that consuming human milk builds a kinship bond between individuals who have consumed the same woman's milk which prohibits future marriage between the 'milk brothers and sisters.' While a small-scale, experimental 'milk exchange' programme has been attempted in two Muslim countries (Kuwait and Malaysia), the only proposed milk bank in the Muslim world was a pilot programme in Turkey that was halted because of religious concerns. The problem with milk banking is the step in the process during which the milk from individual donors is pooled and de identified, making it impossible to trace its origins and acknowledge the newly formed kinship relationship. To meet the need for Muslim children to be able to access human milk while remaining compliant with the prevalent understanding of Islamic doctrine on milk-sharing, we propose a new approach to milk banking that we term the Conditional Identified Milk Banking System (CIMBS). In this new system, both the donor's and recipient's identities are accessible to all parties through a voluntary registry, and the milk-pooling is limited to three milk donors. Based on recent survey data, we believe that there would be receptivity among practicing Muslims and religious leaders to this alternative approach. PMID- 26750780 TI - 1,25-Dihydroxyvitamin D3 and its analogues increase catalase at the mRNA, protein and activity level in a canine transitional carcinoma cell line. AB - Antioxidant enzymes, such as catalase, superoxide dismutases (SOD), MnSOD and Cu/ZnSOD, protect cells by scavenging reactive oxygen species (ROS). Numerous studies have reported the anti-cancer effects of 1,25-dihydroxyvitamin D3 (calcitriol) and its related analogues, seocalcitol and analogue V. In this study, canine bladder transitional cell carcinoma (cbTCC) cells were used to determine effects of calcitriol and its related analogues on antioxidant enzyme gene expression, protein expression and activity. Catalase mRNA was increased in response to calcitriol (10(-7) M), and seocalcitol (10(-7) and 10(-9) M). MnSOD mRNA was decreased in response to calcitriol at 10(-7) M. Catalase was significantly increased in response to calcitriol (10(-7) and 10(-9) M), and seocalcitol (10(-9) M). Catalase enzymatic activity increased in response to calcitriol, seocalcitol and analogue V (10(-9) M). In addition, global gene expression analysis identified the involvement of mitogen-activated protein kinase (MAPK) signalling in cbTCC's response to calcitriol and seocalcitol treatment. PMID- 26750781 TI - The authors' reply. PMID- 26750782 TI - Author's response. Regression to the mean does not explain everything, every time. PMID- 26750783 TI - All I Want for Christmas.... PMID- 26750784 TI - Chronic Maternal Stress Linked to Higher Prevalence of Pediatric Cavities. PMID- 26750785 TI - ADHA White Paper Highlights Changes Occurring in Dental Hygiene Education. PMID- 26750786 TI - Mandated ratios--Victorian nurses and midwives celebrate ratios win. PMID- 26750787 TI - ANMF delivers sonic boom at Fair Work Commission. PMID- 26750788 TI - Revamped electronic health records. PMID- 26750790 TI - CRANAplus conference utilises power of sharing stories. PMID- 26750789 TI - Prominent Aboriginal leaders tie for major award. PMID- 26750791 TI - Ban on over the counter codeine products. PMID- 26750792 TI - Review into tragic infant deaths at Victorian health service. PMID- 26750794 TI - Men at work: study probing fathers' work-life balance. PMID- 26750793 TI - Post-Traumatic Stress Disorder. PMID- 26750795 TI - Nindee Men's Shed a place to reconnect. PMID- 26750796 TI - New funding to raise men's health awareness. PMID- 26750797 TI - A NEW DAY DAWNS. PMID- 26750798 TI - Hospital CEO Survey on Senior Leadership Teams in Freestanding Hospitals. PMID- 26750799 TI - Ethics Self-Assessment. PMID- 26750800 TI - Responsibility for Mentoring. PMID- 26750801 TI - Combination immune checkpoint blockade with ipilimumab and nivolumab in the management of advanced melanoma. AB - INTRODUCTION: The use of immune checkpoint inhibitors for the treatment of advanced melanoma has evolved beyond monotherapies such as ipilimumab and nivolumab to combination strategies involving both. This combination approach results in response rates around 60% and superior progression-free survival compared with ipilimumab monotherapy (median 11.5 versus 2.9 months). AREAS COVERED: A comprehensive literature search was undertaken including search terms of 'ipilimumab and nivolumab' and 'combination immune checkpoint therapy'. Relevant information contained in abstracts and conference presentations was included. This article summarizes the mechanism of action, efficacy and safety of combination ipilimumab and nivolumab across Phase I, II and III clinical trials. It also describes the place of combination therapy in the current market of advanced melanoma treatment options. EXPERT OPINION: Efficacy for the combination approach is seen across a wide array of subgroups and occurs regardless of BRAF mutation status. Counterbalancing the apparent advantages, combination ipilimumab with nivolumab is associated with a high rate (55%) of grade 3/4 adverse events leading to discontinuation in a third of those treated. Most of these are manageable and do not appear to compromise durability of response. Overall survival information is currently immature but appears promising. PMID- 26750803 TI - Can particle beam therapy be improved using helium ions? - a planning study focusing on pediatric patients. AB - Aim To explore the potential of scanned helium ion beam therapy ((4)He) compared to proton therapy in a comparative planning study focusing on pediatric patients. This was motivated by the superior biological and physical characteristics of (4)He. Material and methods For eleven neuroblastoma (NB), nine Hodgkin lymphoma (HL), five Wilms tumor (WT), five ependymoma (EP) and four Ewing sarcoma (EW) patients, treatment plans were created for protons and (4)He. Dose prescription to the planning target volume (PTV) was 21 Gy [relative biological effectiveness (RBE)] (NB), 19.8 Gy (RBE) (HL), 25.2 Gy (RBE) for the WT boost volume and 54 Gy (RBE) for EP and EW patients. A pencil beam algorithm for protons (constant RBE = 1.1) and (4)He was implemented in the treatment planning system Hyperion. For (4)He the relative biological effectiveness (RBE) was calculated with a 'zonal' model based on different linear energy transfer regions. Results Target constraints were fulfilled for all indications. For NB patients differences for kidneys and liver were observed for all dose-volume areas, except the high-dose volume. The body volume receiving up to 12.6 Gy (RBE) was reduced by up to 10% with (4)He. For WT patients the mean and high-dose volume for the liver was improved when using (4)He. For EP normal tissue dose was reduced using (4)He with 12.7% of the voxels receiving higher doses using protons. For HL and EW sarcoma patients the combination of large PTV volumes with the position of the organs at risk (OARs) obliterated the differences between the two particle species, while patients with the heart close to the PTV could benefit from (4)He. Conclusion Treatment plan quality improved with (4)He compared to proton plans, but advantages in OAR sparing were depending on indication and tumor geometries. These first results of scanned (4)He therapy motivate comprehensive research on (4)He, including acquisition of experimental data to improve modeling of (4)He. PMID- 26750802 TI - OASL1 deficiency promotes antiviral protection against genital herpes simplex virus type 2 infection by enhancing type I interferon production. AB - Type I interferon (IFN) interferes with virus replication, promotes antiviral responses, and controls innate and adaptive immune responses to certain viruses. Recently, we reported that 2'-5' oligoadenylate synthetase-like 1 (OASL1) negatively regulates type I IFN production by inhibiting the translation of the type I IFN-regulating master transcription factor, IRF7. Notably, while OASL1 deficient mice induce robust production of type I IFN and are resistant to systemic viral infection, the effects of OASL1 during localized viral infection has not been studied. To this end, we investigated the role of OASL1 during mucosal HSV-2 infection of the genital tract. Oasl1(-/-) mice exhibited better survival rates than wild type (WT) mice following intravaginal HSV-2 infection, and suppressed virus replication more efficiently despite comparable recruitment of effector immune cells. Moreover, Ly6C(high) monocytes, and not pDCs or other cell types, displayed enhanced production of type I IFNs in Oasl1(-/-) mice in response to HSV-2 infection. Furthermore, cytotoxic T cell responses including IFN-gamma production were accelerated in Oasl1(-/-) mice after mucosal HSV-2 infection. Collectively, these results demonstrate that OASL1 deficiency promotes antiviral immunity against local mucosal viral infection and suggest that OASL1 could be a therapeutic target for treatment of HSV-2 infection of the genital mucosa. PMID- 26750804 TI - Vergence anomalies in a sample of high school students in South Africa. AB - AIM: To study the prevalence of nearpoint vergence anomalies (convergence insufficiency, convergence excess and fusional vergence dysfunction) and association with gender, age groups, grade level and study site (suburban and rural). METHODS: The study design was cross sectional and data was analyzed for 1201 high school students aged 13-19 years who were randomly selected from 13 high schools in uMhlathuze municipality. Of the total sample, 476 (39.5%) were males and 725 (60.5%) were females. The visual functions evaluated included refractive errors, heterophoria, near point of convergence, accommodative functions and fusional vergences. Possible associations between vergence anomalies and demographic variables (gender, age groups, school grade levels and study site) were explored. RESULTS: Prevalence estimates were 11.8%, 6% and 4.3% for low suspect, high suspect and definite convergence insufficiency, and 1.9% for the pseudo convergence insufficiency. Convergence excess prevalence was 5.6%, and fusional vergence dysfunction was 3.3%. The prevalence of low suspect CI was significantly higher in suburban than in rural participants (p=0.01), the reverse was the case for pseudoconvergence insufficiency while the prevalence of convergence excess was significantly higher in the younger than in the older age group (p=0.02). No other category showed any statistically significant associations with vergence anomalies. CONCLUSION: The prevalence estimates for vergence anomalies in a sample of black high school students in South Africa were relatively low. Only study location and age influenced some vergence anomalies. Identification and referrals are important steps toward diagnosis and treatment for vergence anomalies. Further studies to compare vergence anomalies in various racial populations will be relevant. PMID- 26750805 TI - Sustained viral response and treatment-induced cytopenia correlate with SLCs and KLF12 genotypes in interferon/ribavirin-treated Chinese chronic hepatitis C patients. AB - BACKGROUND AND AIM: Genetic variations in solute carrier (SLC) genes are associated with liver diseases, and Kruppel-like factor 12 (KLF12) affects the b chain of hemoglobin. We investigated possible correlations of SLC and KLF12 polymorphisms with viral clearance (spontaneous and treatment-induced) and adverse effects in Chinese chronic hepatitis C (CHC) patients. METHODS: We genotyped the single nucleotide polymorphisms in 525 CHC patients, 137 patients with spontaneous clearance, and 207 healthy controls. Three hundred fifty-seven CHC patients received recombinant interferon-alpha2b/ribavirin (IFN-alpha2b/RBV) treatment, and 175 patients were chosen for analysis of drug-induced cytopenia. All raw P-values were corrected by the Bonferroni method. RESULTS: A higher rate of sustained viral response was detected in patients with SLC4A11 rs3810560 CC variant versus TT/TC variant (76.9% vs 59.2%; OR, 2.42; 95% CI, 1.06-5.56, P = 0.037 after adjustment), but there was no significant difference among different hepatitis C virus genotypes. RBV-induced anemia was independently correlated with SLC29A1 rs760370 AA genotype (OR, 2.90; 95% CI, 1.29-6.54, P = 0.010), and the severity of IFN-induced thrombocytopenia was related to GG genotype (OR, 4.98; 95% CI, 1.27-19.61; P = 0.021); the detected effects held true for HCV-2a patients but weakened in HCV-1b patients. A reactive increase in platelet count was closely associated with KLF12 rs9543524 TT variant. CONCLUSION: SLC4A11 rs3810560 polymorphism independently affected the sustained viral response rates in CHC patients, whereas SLC29A1 rs760370 and KLF12 rs9543524 single nucleotide polymorphisms correlated with treatment-induced adverse events. Clearly, the predictive power varied with HCV genotypes and the reason for genotype-dependent discrepancy was not fully understood. PMID- 26750806 TI - Rapid detection of proteins in transgenic crops without protein reference standards by targeted proteomic mass spectrometry. AB - BACKGROUND: Liquid chromatography coupled with tandem mass spectrometry is increasingly used for protein detection for transgenic crops research. Currently this is achieved with protein reference standards which may take a significant time or efforts to obtain and there is a need for rapid protein detection without protein reference standards. RESULTS: A sensitive and specific method was developed to detect target proteins in transgenic maize leaf crude extract at concentrations as low as ~30 ng mg(-1) dry leaf without the need of reference standards or any sample enrichment. A hybrid Q-TRAP mass spectrometer was used to monitor all potential tryptic peptides of the target proteins in both transgenic and non-transgenic samples. The multiple reaction monitoring-initiated detection and sequencing (MIDAS) approach was used for initial peptide/protein identification via Mascot database search. Further confirmation was achieved by direct comparison between transgenic and non-transgenic samples. Definitive confirmation was provided by running the same experiments of synthetic peptides or protein standards, if available. CONCLUSION: A targeted proteomic mass spectrometry method using MIDAS approach is an ideal methodology for detection of new proteins in early stages of transgenic crop research and development when neither protein reference standards nor antibodies are available. (c) 2016 Society of Chemical Industry. PMID- 26750808 TI - alpha1B -Adrenoceptor signalling regulates bone formation through the up regulation of CCAAT/enhancer-binding protein delta expression in osteoblasts. AB - BACKGROUND AND PURPOSE: The sympathetic nervous system regulates bone remodelling, in part, through beta2 -adrenoceptor signalling. However, the physiological role of alpha1 -adrenoceptor signalling in bone in vivo remains unclear. Therefore, to obtain a deeper understanding of bone remodelling by the sympathetic nervous system, we investigated the role of alpha1B -adrenoceptor signalling in bone metabolism. EXPERIMENTAL APPROACH: Prazosin, a nonspecific alpha1 -adrenoceptor antagonist, was administered for 2 weeks in C57BL6 mice, and efficacy was evaluated by bone microarchitecture using microcomputed tomography and determination of bone formation by fluorescent labelling of bone. We also compared the bone phenotype of alpha1B -adrenoceptor null mice (alpha1B (-/-) ) with that of wild-type littermates. KEY RESULTS: We demonstrated that the systemic administration of prazosin decreased bone formation. In addition, alpha1B -adrenoceptor-deficient mice had a lower bone mass due to decreased bone formation but did not exhibit any changes in bone-resorbing activity. Furthermore, stimulation with phenylephrine, a non-specific alpha1 -adrenoceptor agonist, increased the expression of the transcriptional factor CCAAT/enhancer binding protein delta (Cebpd) in MC3T3-E1 osteoblastic cells. The overexpression of Cebpd induced cellular proliferation in MC3T3-E1 cells, whereas the silencing of Cebpd suppressed it. CONCLUSIONS AND IMPLICATIONS: Taken together, these results suggested that alpha1B -adrenoceptor signalling is required for bone formation and regulated cellular proliferation through a mechanism relevant to the up-regulation of Cebpd in osteoblasts and, thus, provide new evidence for the physiological importance of alpha1B -adrenoceptor signalling in bone homeostasis. PMID- 26750812 TI - The use of exercises to enhance and assess interlocal collaboration in preparedness: A qualitative analysis. AB - INTRODUCTION: Interlocal collaboration, or collaboration among neighboring independent municipalities, has been generally accepted as an emergency preparedness strategy. In the absence of large-scale disasters, emergency preparedness exercises may serve to test the effectiveness of interlocal collaboration on emergency preparedness. However, the use of emergency preparedness exercises to enhance or assess interlocal collaboration, or its impact on preparedness, requires additional empirical exploration. HYPOTHESIS/PROBLEM: This exploratory study aims to understand the perspectives of key informants (KIs) with broad knowledge of the history, goals, and implementation of the Urban Area Security Initiative (UASI) program, as well as knowledge of interlocal collaboration exercises conducted as part of the UASI program, about the role of exercises in improving and assessing interlocal collaboration for emergency preparedness. METHOD: In early 2014, 28 KIs were interviewed during 24 semistructured interviews. Interviews were recorded and analyzed to identify key themes related to emergency preparedness exercises and the enhancement and assessment of interlocal collaboration. RESULTS: KIs perceived exercises to enhance interlocal collaboration in preparedness by promoting regional, interlocal: risk assessment; emergency plan testing and operationalization; relationship development; support for regional plans and operational structures; capability delivery practice; best practice sharing across interlocal collaborations; and engagement of elected or senior leadership in interlocal preparedness endeavors. Exercise participants, scenarios, administration, formats, and assessment strategies to promote interlocal collaboration were identified. CONCLUSIONS: Seven distinct mechanisms by which exercises can enhance interlocal collaboration that can be used to guide future research and policy development were identified. The format, scenario, participation, and administration of emergency preparedness exercises can be tailored to enhance collaboration. PMID- 26750807 TI - Anti-oxidative effect of AST-120 on kidney injury after myocardial infarction. AB - BACKGROUND AND PURPOSE: Chronic kidney disease (CKD) is a crucial risk factor for cardiovascular disease (CVD), and combined CKD and CVD further increases morbidity and mortality. Here, we investigated effects of AST-120 on oxidative stress and kidney injury using a model of myocardial infarction (MI) in rats. EXPERIMENTAL APPROACH: At 10 weeks, male spontaneously hypertensive rats (SHR) were divided into three groups: SHR (n = 6), MI (n = 8) and MI + AST-120 (n = 8). AST-120 administration was started at 11 weeks after MI. At 18 weeks, the rats were killed, and blood and urine, mRNA expression and renal histological analyses were performed. Echocardiography was performed before and after MI. KEY RESULTS: At 18 weeks, the BP was significantly lower in the MI and MI+AST-120 groups than in the SHR group. Elevated levels of indoxyl sulfate (IS), one of the uremic toxins, in serum and urine were reduced by AST-120 treatment, compared with the MI group. Markers of oxidative stress in urine and serum biomarkers of kidney injury were decreased in the MI+AST-120 group compared with the other two groups. Renal expression of mRNAs for kidney injury related-markers were decreased in the MI+AST-120 group, compared with the MI group. In vitro data also supported the influence of IS on kidney injury. Immunohistological analysis showed that intrarenal oxidative stress was reduced by AST-120 administration. CONCLUSIONS AND IMPLICATIONS: Serum IS was increased after MI and treatment with AST-120 may have protective effects on kidney injury after MI by suppressing oxidative stress. PMID- 26750811 TI - Emergency management and homeland security: Exploring the relationship. AB - In the years after the 9/11 tragedy, the United States continues to face risks from all forms of major disasters, from potentially dangerous terrorist attacks to catastrophic acts of nature. Professionals in the fields of emergency management and homeland security have responsibilities for ensuring that all levels of government, urban areas and communities, nongovernmental organizations, businesses, and individual citizens are prepared to deal with such hazards though actions that reduce risks to lives and property. Regrettably, the overall efficiency and effectiveness of the nation's ability to deal with disasters is unnecessarily challenged by the absence of a common understanding on how these fields are related in the workforce and educational arenas. Complicating matters further is the fact that neither of these fields has developed agreed definitions. In many ways, homeland security and emergency management have come to represent two different worlds and cultures. These conditions can have a deleterious effect on preparedness planning for public and private stakeholders across the nation when coordinated responses among federal, state, and local activities are essential for dealing with consequential hazards. This article demonstrates that the fields of emergency management and homeland security share many responsibilities but are not identical in scope or skills. It argues that emergency management should be considered a critical subset of the far broader and more strategic field of homeland security. From analytically based conclusions, it recommends five steps that be taken to bring these fields closer together to benefit more from their synergist relationship as well as from their individual contributions. PMID- 26750814 TI - Framework for crisis preparedness planning: Four required areas for developing a learning process. AB - OBJECTIVE: To outline a framework for preparedness planning at the organizational level. DESIGN: The study is based on a content analysis of research literature as well as an analysis of interviews with six preparedness planners working in Swedish local authorities. SETTING: The study setting included Swedish local authorities of different sizes. SUBJECTS, PARTICIPANTS: The participants are preparedness planners responsible for coordinating crisis management work in Swedish local authorities. The study includes preparedness planners with different backgrounds, education, experiences, and gender. INTERVENTIONS: A presentation of 19 factors of preparedness planning identified in the literature and a discussion around how preparedness planners perceive those factors. MAIN OUTCOME MEASURE(S): The main outcome measures are knowledge about how both researcher and practitioner understand and argue around different factors of preparedness planning. RESULTS: The result of this study is a framework for preparedness planning. As preparedness planning ought to be a learning process, the presented framework builds on four areas connected to learning: prerequisites for preparedness planning, who should be involved, what is to be learned, and how should the work be shaped. CONCLUSIONS: The analysis of factors identified in the literature and also in the interviews with preparedness planners illustrates that the four areas connected to learning are required for developing a preparedness planning process. PMID- 26750813 TI - The evolution of shortcomings in Incident Command System: Revisions have allowed critical management functions to atrophy. AB - The original Incident Command System (ICS) was created through the federally funded Firefighting Resources of Southern California Organized for Potential Emergencies (FIRESCOPE) program. Initially developed as one element of multiagency coordination for managing severe wildfires, the FIRESCOPE ICS guidance was adopted and evolved through increasingly routine wildl and firefighting. It then was modified for all hazards for the fire service. Only later, through the National Incident Management System (NIMS), was ICS officially adopted for all hazards and all responders. Over this multidecade evolution, the current NIMS ICS version became simplified in several key areas compared to the original, robust FIRESCOPE ICS. NIMS ICS is now promulgated as guidance for managing today's novel, complex, and lengthy disasters involving multidisciplinary response but experiences recurrent problems in key functions. This article examines the history of the subtle, yet critical differences in current ICS compared to the original system design, and focuses on information dissemination and intermediate, long-range and contingency planning. ICS transitions resulted in simplification and consolidation of positions and functions, without recognizing and maintaining critical position tasks necessary for managing complex, extended incidents. PMID- 26750815 TI - Religious congregations in disaster response. AB - Knowledge of whether or not religious congregations are indeed involved in disaster response and-if involved-in what tasks and activities they are engaged is important for the planning and management of disaster response. Although limited in generalizability of findings based on methodologies used, a review of the academic literature demonstrates a fairly clear role for religious congregations in disaster recovery activities but does not delineate a distinct role for congregations in response functions. However, anecdotal evidence and limited empirical evidence exists that suggests that religious congregations might and could play a role in pre-impact response activities, including warning, precautionary action, and evacuation, as well as in post impact response activities associated with providing for the welfare of survivors. The research literature also provides predictors of congregational involvement, as well as a number of barriers and limitations to involvement. This involvement-or lack thereof-has implications for both the discipline and practice of emergency management. PMID- 26750816 TI - What influences the acceptance of emergency management decision-support software? A study of county emergency management officials. AB - OBJECTIVE: While the benefits of emergency management decision-support software (EMDSS) have been touted for helping reduce time in decision making, increasing interoperability, and real-time data management for effective disaster response, little is understood regarding the factors that influence the acceptance of these technologies by emergency management officials. This study aims to fill this gap and contribute to theory on user acceptance of EMDSS in the public sector and highlight practical constraints and solutions for emergency managers. DESIGN: This research uses secondary data available from the 2006 survey of county emergency management agencies conducted by the National Center for the Study of Counties. RESULTS: Having a lead county emergency management official with higher qualifications and an in-house geographic information system division, both have a positive influence on the acceptance of EMDSS by that agency. CONCLUSIONS: Contrary to expectations, the level of local collaborative planning efforts, the perceived level of threat, and number of disaster declarations for the county did not influence the use of these sophisticated EMDSS. To ensure use of such technology for effective emergency management, more funding to offer specialized training in the use of DSS is required in those agencies that do not have in house GIS specialists. PMID- 26750817 TI - Risk management and disaster recovery planning for online libraries. AB - This article presents an overview of risk management and disaster recovery planning for online libraries. It is suitable for a broad audience interested in online libraries and research centers in universities and colleges. It outlines risk mitigation strategies, and disaster recover planning for online resource centered information systems. PMID- 26750818 TI - Planning for partnerships: Maximizing surge capacity resources through service learning. AB - Infectious disease outbreaks and natural or human-caused disasters can strain the community's surge capacity through sudden demand on healthcare activities. Collaborative partnerships between communities and schools of nursing have the potential to maximize resource availability to meet community needs following a disaster. This article explores how communities can work with schools of nursing to enhance surge capacity through systems thinking, integrated planning, and cooperative efforts. PMID- 26750819 TI - MnO2-promoted carboesterification of alkenes with anhydrides: a facile approach to gamma-lactones. AB - An efficient carboesterification of alkenes with anhydrides promoted by MnO2 has been developed to afford functionalized gamma-lactones in good to excellent yields. This method shows a broad substrate scope and provides a valuable and convenient synthetic tool for constructing gamma-lactones. PMID- 26750820 TI - On Wiener polarity index of bicyclic networks. AB - Complex networks are ubiquitous in biological, physical and social sciences. Network robustness research aims at finding a measure to quantify network robustness. A number of Wiener type indices have recently been incorporated as distance-based descriptors of complex networks. Wiener type indices are known to depend both on the network's number of nodes and topology. The Wiener polarity index is also related to the cluster coefficient of networks. In this paper, based on some graph transformations, we determine the sharp upper bound of the Wiener polarity index among all bicyclic networks. These bounds help to understand the underlying quantitative graph measures in depth. PMID- 26750861 TI - Temperature-induced 1D lanthanide polymeric frameworks based on Ln(n) (n = 2, 2, 4, 6) cores: synthesis, crystal structures and luminescence properties. AB - The hydrothermal reaction of the same reactive system containing Ln(NO3)3.6H2O, tetrafluorophthalic acid (H2TFPht), and 1,10-phenanthroline (phen) at different temperatures yielded coordination polymers, [Ln2(TFPht)3(phen)2(H2O)2].H2O (Ln = Sm 1, Eu 2, Gd 3, Tb 4, Dy 5; at 120 degrees C), La(TFPht)(TFBA)(phen)(H2O) (6; at 160 degrees C), Ln3(TFPht)4(TFBA)(phen)3(H2O)3 (Ln = Dy 7, Tb 8, Yb 9; at 160 degrees C), and Ln2(TFBA)6(phen)2 (Ln = Eu 10, Tb 11; at 180 degrees C). 2,3,4,5-Tetrafluorobenzoic acid (TFBA) was produced from the decarboxylation of TFPht. X-ray structural analysis reveals that these compounds contain different structural motifs. Complexes 1-5 exhibit zigzag chain structures based on the center-related tetranuclear [Ln4] as SBUs (Secondary Building Units) with two crystallographically independent Ln(3+) ions. Complex 6 contains a double chain structure with center-related binuclear [La2] as SBUs. Complexes 7-9 show single chain structures involving center-related hexanuclear [Ln6] as SBUs with three crystallographically independent Ln(3+) ions. Complexes 10 and 11 have ribbon chain structures involving binuclear [Ln2] as SBUs with two crystallographically independent Ln(3+) ions. The photoluminescence properties of complexes 1-5 were studied. The Eu(3+) and Tb(3+) complexes exhibit bright red and green emissions with quantum yields of 15.87% for 2 and 23.82% for 4. The two-component Dy:Eu- and three-component Gd:Dy,Eu-doped complexes provided white light emission. Moreover, 2 could be a potential luminescent probe for detecting nitrobenzene and Ni(2+) ion through significant fluorescence decrease of Eu(3+). PMID- 26750862 TI - Spouses' experience of living with a partner diagnosed with a dementia: a synthesis of the qualitative research. AB - BACKGROUND: The majority of people diagnosed with a dementia live at home with the support of their spouse. While this situation has advantages, it brings many challenges for the spouse, particularly dealing with the emotional impact of the behavioral changes associated with the dementia. A growing body of qualitative research has focused on understanding the spousal caregiver perspective of living with a partner diagnosed with dementia. The aim of this study was to complete a synthesis of the results of published qualitative studies that have explored the spousal experience. METHOD: An electronic database search of Ovid Medline, CINAHL, EMBASE, and PsychINFO from January 1980 to September 2014 was conducted. Sixteen studies met the inclusion criteria. Verbatim quotes of the participant interview data derived from these studies were collated and a thematic analysis was conducted. RESULTS: Synthesis of the published data revealed five major themes. The theme of "loss of partner" was central, and around this central experience spouses described various processes: acknowledging change, being in crisis, adapting and adjusting, accepting and moving forward. CONCLUSIONS: These findings provide insights into the day-to-day adjustments and experiences of spousal caregivers whilst highlighting the importance of considering the impact of cognitive decline and dementia in a social-relational context. PMID- 26750863 TI - ASC provides a potential link between depression and inflammatory disorders: A clinical study of depressed Iranian medical students. AB - Background and aims AIM2 is a component of inflammasomes which can activate caspase-1 via an adaptor protein (ASC) after pathogen-associated molecular pattern (PAMP) or danger-associated molecular pattern (DAMP) recognition. Activation of caspase-1 is a trigger for the induction of IL-1 and IL-18 which are important pro-inflammatory cytokines. Furthermore, IL-1beta, which can regulate inflammatory responses, has also been associated with depression. Previous studies revealed that patients suffering from depression may also have altered immune responses, but the mechanisms underlying this correlation are unclear. Thus, the aim of this study was to determine the mRNA levels of AIM2 and ASC in the peripheral blood mononuclear cells (PBMCs) isolated from Iranian medical students suffering from depression. Materials and methods The participants used for the study included 38 Iranian medical students diagnosed with depression and 43 non-depressed students as a control group. The mRNA levels of AIM2 and ASC were evaluated by quantitative real-time polymerase chain reaction (PCR) using beta-actin as a housekeeping gene for the normalization of expression. Results The results showed that mRNA levels of AIM2 were similar in both groups. However, ASC levels were significantly increased in PBMCs isolated from individuals with elevated depressive symptoms when compared to non-depressed participants. Conclusions Based on the current results, it appears that ASC transcript expression may be a surrogate marker for depression and may represent a link between depression and the altered immune responses observed in these categories of individuals with elevated depressive symptoms. PMID- 26750866 TI - Bromomethyllithium-mediated chemoselective homologation of disulfides to dithioacetals. AB - An efficient, chemoselective homologation of disulfides and diselenides to the corresponding dithio- and diselenoacetals has been developed via the addition of bromomethyllithium. Chemoselectivity is fully preserved in the presence of concomitant electrophilic sites decorating the substrates. The synthetic potential of selected dithioacetals has been evaluated in Feringa-Fananas-Mastral type Pd-catalyzed coupling with an organolithium and in the unusual 1,4-addition to a Weinreb amide. PMID- 26750864 TI - Identification, Validation, and Application of Molecular Diagnostics for Insecticide Resistance in Malaria Vectors. AB - Insecticide resistance is a major obstacle to control of Anopheles malaria mosquitoes in sub-Saharan Africa and requires an improved understanding of the underlying mechanisms. Efforts to discover resistance genes and DNA markers have been dominated by candidate gene and quantitative trait locus studies of laboratory strains, but with greater availability of genome sequences a shift toward field-based agnostic discovery is anticipated. Mechanisms evolve continually to produce elevated resistance yielding multiplicative diagnostic markers, co-screening of which can give high predictive value. With a shift toward prospective analyses, identification and screening of resistance marker panels will boost monitoring and programmatic decision making. PMID- 26750865 TI - The Warburg effect and drug resistance. AB - : The Warburg effect describes the increased utilization of glycolysis rather than oxidative phosphorylation by tumour cells for their energy requirements under physiological oxygen conditions. This effect has been the basis for much speculation on the survival advantage of tumour cells, tumourigenesis and the microenvironment of tumours. More recently, studies have begun to reveal how the Warburg effect could influence drug efficacy and how our understanding of tumour energetics could be exploited to improve drug development. In particular, evidence is emerging demonstrating how better modelling of the tumour metabolic microenvironment could lead to a better prediction of drug efficacy and the identification of new combination strategies. This review will provide details of the current understanding of the complex interplay between glucose metabolism and pharmacology and discuss opportunities for utilizing the Warburg effect in future drug development. PMID- 26750867 TI - The Role of Electrostatic Interactions in Folding of beta-Proteins. AB - Atomic-level molecular dynamic simulations are capable of fully folding structurally diverse proteins; however, they are limited in their ability to accurately represent electrostatic interactions. Here we have experimentally tested the role of charged residues on stability and folding kinetics of one of the most widely simulated beta-proteins, the WW domain. The folding of wild type Pin1 WW domain, which has two positively charged residues in the first turn, was compared to the fast folding mutant FiP35 Pin1, which introduces a negative charge into the first turn. A combination of FTIR spectroscopy and laser-induced temperature-jump coupled with infrared spectroscopy was used to probe changes in the amide I region. The relaxation dynamics of the peptide backbone, beta-sheets and beta-turns, and negatively charged aspartic acid side chain of FiP35 were measured independently by probing the corresponding bands assigned in the amide I region. Folding is initiated in the turns and the beta-sheets form last. While the global folding mechanism is in good agreement with simulation predictions, we observe changes in the protonation state of aspartic acid during folding that have not been captured by simulation methods. The protonation state of aspartic acid is coupled to protein folding; the apparent pKa of aspartic acid in the folded protein is 6.4. The dynamics of the aspartic acid follow the dynamics of the intermediate phase, supporting assignment of this phase to formation of the first hairpin. These results demonstrate the importance of electrostatic interactions in turn stability and formation of extended beta-sheet structures. PMID- 26750870 TI - Influence of simulated MSW sizes on the combustion process in a fixed bed: CFD and experimental approaches. AB - This work presents the effect of the simulated sizes of Municipal Solid Waste (MSW) on the combustion process in a fixed bed experimentally and numerically. The effect of temperature, gas emissions, flame front velocity and process rate are discussed for three different sizes of MSW: 10, 30, and 50 mm. The study found that for the operating conditions of the current model, when the diameter of particles is decreased, the bulk density of the material is increased, resulting in a decrease of convective heat transfer as well as combustion speed. As the diameter size of the material particles increase, the height of the post combustion zone is increased, while the temperature in a high temperature area is decreased, due to the decrease in the material's bulk density and the excessive increase in porosity. Results also show that the average emission concentration of CO and CO2 decreases gradually with an increase in the particle diameter size. PMID- 26750871 TI - Chlorine and temperature directed self-assembly of Mg-Ru2(ii,iii) carbonates and particle size dependent magnetic properties. AB - A series of heterometallic magnesium diruthenium(ii,iii) carbonates, namely K{Mg(H2O)6}2[Ru2(CO3)4Cl2].4H2O (1), K2[{Mg(H2O)4}2Ru2(CO3)4(H2O)Cl]Cl2.2H2O (2), K[Mg(H2O)5Ru2(CO3)4].5H2O (3) and K[Mg(H2O)4Ru2(CO3)4].H2O (4), were synthesized from the reaction of Ru2(CO3)4(3-) and Mg(2+) in aqueous solution. Compound 1 is composed of ionic crystals with the Ru2(CO3)4Cl2(5-) : Mg(H2O)6(2+) : K(+) ratio of 1 : 2 : 1. Compound 2 consists of two dimensional layer structures, in which each octahedral environment Mg(H2O)4(2+) bonds to two [Ru2(CO3)4(H2O)Cl](4-) units in a cis manner forming a neutral square-grid layer {Mg(H2O)4Ru2(CO3)4(H2O)Cl}n. For compound 3, one water molecule of each Mg(H2O)6(2+) is substituted by an oxygen atom of Ru2(CO3)4(3-) forming [Mg(H2O)5Ru2(CO3)4](-), and then the neighboring Ru2 dimers are linked together by the rest of the two oxygen atoms of carbonates to form a layer structure {Mg(H2O)5Ru2(CO3)4}n(n-). In compound 4, the neighboring squared-grid layers {Ru2(CO3)4}n(3n-), similar to those in compound 3, are linked by each octahedral environment Mg(H2O)4(2+) in a cis manner forming the three-dimensional network {Mg(H2O)4Ru2(CO3)4}n(n-). Compound 3 shows ferromagnetic coupling between Ru2 dimers, and a long-range ordering is observed below 3.8 K. Compound 4 displays a magnetic ordering below 3.5 K, and a systematic study of the size-dependent magnetic properties of compound 4 reveals that the coercivity of 4 has been improved with reduced sample particle size from the micrometer to the nanometer scale. PMID- 26750868 TI - Single administration of recombinant IL-6 restores the gene expression of lipogenic enzymes in liver of fasting IL-6-deficient mice. AB - BACKGROUND AND PURPOSE: Lipogenesis is intimately controlled by hormones and cytokines as well as nutritional conditions. IL-6 participates in the regulation of fatty acid metabolism in the liver. We investigated the role of IL-6 in mediating fasting/re-feeding changes in the expression of hepatic lipogenic enzymes. EXPERIMENTAL APPROACH: Gene and protein expression of lipogenic enzymes were examined in livers of wild-type (WT) and IL-6-deficient (IL-6(-/-) ) mice during fasting and re-feeding conditions. Effects of exogenous IL-6 administration on gene expression of these enzymes were evaluated in vivo. The involvement of STAT3 in mediating these IL-6 responses was investigated by using siRNA in human HepG2 cells. KEY RESULTS: During feeding, the up-regulation in the hepatic expression of lipogenic genes presented similar time kinetics in WT and IL-6(-/-) mice. During fasting, expression of lipogenic genes decreased gradually over time in both strains, although the initial drop was more marked in IL-6(-/-) mice. Protein levels of hepatic lipogenic enzymes were lower in IL-6(-/-) than in WT mice at the end of the fasting period. In WT, circulating IL-6 levels paralleled gene expression of hepatic lipogenic enzymes. IL-6 administration in vivo and in vitro showed that IL-6-mediated signalling was associated with the up regulation of hepatic lipogenic enzyme genes. Moreover, silencing STAT3 in HepG2 cells attenuated IL-6 mediated up-regulation of lipogenic gene transcription levels. CONCLUSIONS AND IMPLICATIONS: IL-6 sustains levels of hepatic lipogenic enzymes during fasting through activation of STAT3. Our findings indicate that clinical use of STAT3-associated signalling cytokines, particularly against steatosis, should be undertaken with caution. PMID- 26750869 TI - Evidence for redox sensing by a human cardiac calcium channel. AB - Ion channels are critical to life and respond rapidly to stimuli to evoke physiological responses. Calcium influx into heart muscle occurs through the ion conducting alpha1C subunit (Cav1.2) of the L-type Ca(2+) channel. Glutathionylation of Cav1.2 results in increased calcium influx and is evident in ischemic human heart. However controversy exists as to whether direct modification of Cav1.2 is responsible for altered function. We directly assessed the function of purified human Cav1.2 in proteoliposomes. Truncation of the C terminus and mutation of cysteines in the N terminal region and cytoplasmic loop III-IV linker did not alter the effects of thiol modifying agents on open probability of the channel. However mutation of cysteines in cytoplasmic loop I II linker altered open probability and protein folding assessed by thermal shift assay. We find that C543 confers sensitivity of Cav1.2 to oxidative stress and is sufficient to modify channel function and posttranslational folding. Our data provide direct evidence for the calcium channel as a redox sensor that facilitates rapid physiological responses. PMID- 26750920 TI - GTA: a game theoretic approach to identifying cancer subnetwork markers. AB - The identification of genetic markers (e.g. genes, pathways and subnetworks) for cancer has been one of the most challenging research areas in recent years. A subset of these studies attempt to analyze genome-wide expression profiles to identify markers with high reliability and reusability across independent whole transcriptome microarray datasets. Therefore, the functional relationships of genes are integrated with their expression data. However, for a more accurate representation of the functional relationships among genes, utilization of the protein-protein interaction network (PPIN) seems to be necessary. Herein, a novel game theoretic approach (GTA) is proposed for the identification of cancer subnetwork markers by integrating genome-wide expression profiles and PPIN. The GTA method was applied to three distinct whole-transcriptome breast cancer datasets to identify the subnetwork markers associated with metastasis. To evaluate the performance of our approach, the identified subnetwork markers were compared with gene-based, pathway-based and network-based markers. We show that GTA is not only capable of identifying robust metastatic markers, it also provides a higher classification performance. In addition, based on these GTA based subnetworks, we identified a new bonafide candidate gene for breast cancer susceptibility. PMID- 26750873 TI - Betulinic Acid Increases eNOS Phosphorylation and NO Synthesis via the Calcium Signaling Pathway. AB - Betulinic acid (BA) is a naturally occurring pentacyclic triterpene that attenuates vascular diseases and atherosclerosis, but the mechanism by which it stimulates endothelial nitric oxide synthase (eNOS) is unclear. eNOS is the key regulatory enzyme in the vascular endothelium. This study examined the intracellular pathways underlying the effects of BA on eNOS activity and endothelial nitric oxide (NO) production in endothelial cells. BA treatment induced both eNOS phosphorylation at Ser1177 and NO production. It also increased the level of intracellular Ca(2+) and phosphorylation of Ca(2+)/calmodulin dependent kinase IIalpha (CaMKIIalpha) and Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta). Inhibition of the L-type Ca(2+) channel (LTCC) and the ryanodine receptor (RyR) abolished BA-induced intracellular levels of Ca(2+) and eNOS phosphorylation. Treatment with W7 (a CaM antagonist), KN-93 (a selective inhibitor of CaMKII), and STO 609 (a selective inhibitor of CaMKK) suppressed eNOS phosphorylation and NO production. Moreover, AMP-activated protein kinase (AMPK) was induced by BA, and BA-induced eNOS phosphorylation was inhibited by compound C, an AMPK inhibitor. Taken together, these results indicate that BA activates eNOS phosphorylation and NO synthesis via the Ca(2+)/CaMKII and Ca(2+)/CaMKK/AMPK pathways. These findings provide further insight into the eNOS signaling pathways involved in the antiatherosclerosis effects of BA. PMID- 26750872 TI - Metacommunity analysis of amoeboid protists in grassland soils. AB - This study reveals the diversity and distribution of two major ubiquitous groups of soil amoebae, the genus Acanthamoeba and the Myxomycetes (plasmodial slime moulds) that are rarely, if ever, recovered in environmental sampling studies. We analyzed 150 grassland soil samples from three Biodiversity Exploratories study regions in Germany. We developed specific primers targeting the V2 variable region in the first part of the small subunit of the ribosomal RNA gene for high throughput pyrotag sequencing. From ca. 1 million reads, applying very stringent filtering and clustering parameters to avoid overestimation of the diversity, we obtained 273 acanthamoebal and 338 myxomycete operational taxonomic units (OTUs, 96% similarity threshold). This number is consistent with the genetic diversity known in the two investigated lineages, but unequalled to date by any environmental sampling study. Only very few OTUs were identical to already known sequences. Strikingly different OTUs assemblages were found between the three German regions (PerMANOVA p.value = 0.001) and even between sites of the same region (multiple-site Simpson-based similarity indices <0.4), showing steep biogeographical gradients. PMID- 26750921 TI - Fluorescent supramolecular nanoparticles signal the loading of electrostatically charged cargo. AB - Fluorescently labeled supramolecular nanoparticles (SNPs) were used to study the effects of their loading with oppositely charged cargo. SNPs shrank until neutralization, upon which they destabilized and aggregated. Using a dye-labelled guest, FRET occurred between the SNPs and a dye-labeled cargo. This effect may allow the development of responsive imaging and drug delivery vehicles. PMID- 26750923 TI - Erratum to: Clinical metagenomic identification of Balamuthia mandrillaris encephalitis and assembly of the draft genome: the continuing case for reference genome sequencing. PMID- 26750922 TI - Resveratrol ameliorates myocardial fibrosis by inhibiting ROS/ERK/TGF beta/periostin pathway in STZ-induced diabetic mice. AB - BACKGROUND: Myocardial fibrosis is an essential hallmark of diabetic cardiomyopathy (DCM) contributing to cardiac dysfunctions. Resveratrol, an antioxidant, exerts its anti-fibrotic effect via inhibition of oxidative stress, while the underlying molecular mechanism remains largely elusive. Periostin, a fibrogenesis matricellular protein, has been shown to be associated with oxidative stress. In the present study, we investigated the role of periostin in anti-fibrotic effect of resveratrol in streptozocin (STZ)-induced diabetic heart and the underlying mechanisms. METHODS: Diabetic mice were induced by STZ injection. After treatment with resveratrol (5 or 25 mg/kg/day i.g) or Saline containing 0.5% carboxymethyl cellulose (CMC) for 2 months, the hearts were detected for oxidative stress and cardiac fibrosis using western blot, Masson's trichrome staining and Dihydroethidium (DHE) staining. In in vitro experiments, proliferation and differentiation of fibroblasts under different conditions were investigated through western blot, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di phenytetrazoliumromide (MTT) assay and immunofluorescence staining. RESULTS: Administration of resveratrol significantly mitigated oxidative level, interstitial fibrosis and expressions of related proteins in STZ-induced diabetic hearts. In in vitro experiments, resveratrol exhibited anti-proliferative effect on primary mouse cardiac fibroblasts via inhibiting reactive oxygen species (ROS)/extracellular regulated kinase (ERK) pathway and ameliorated myofibroblast differentiation via suppressing ROS/ERK/ transforming growth factor beta (TGF beta)/periostin pathway. CONCLUSION: Increased ROS production, activation of ERK/TGF-beta/periostin pathway and myocardial fibrosis are important events in DCM. Alleviated ROS genesis by resveratrol prevents myocardial fibrosis by regulating periostin related signaling pathway. Thus, inhibition of ROS/periostin may represent a novel approach for resveratrol to reverse fibrosis in DCM. PMID- 26750924 TI - An Approach for Identification of Novel Drug Targets in Streptococcus pyogenes SF370 Through Pathway Analysis. AB - Streptococcus pyogenes is one of the most important pathogens as it is involved in various infections affecting upper respiratory tract and skin. Due to the emergence of multidrug resistance and cross-resistance, S. Pyogenes is becoming more pathogenic and dangerous. In the present study, an in silico comparative analysis of total 65 metabolic pathways of the host (Homo sapiens) and the pathogen was performed. Initially, 486 paralogous enzymes were identified so that they can be removed from possible drug target list. The 105 enzymes of the biochemical pathways of S. pyogenes from the KEGG metabolic pathway database were compared with the proteins from the Homo sapiens by performing a BLASTP search against the non-redundant database restricted to the Homo sapiens subset. Out of these, 83 enzymes were identified as non-human homologous while 30 enzymes of inadequate amino acid length were removed for further processing. Essential enzymes were finally mined from remaining 53 enzymes. Finally, 28 essential enzymes were identified in S. pyogenes SF370 (serotype M1). In subcellular localization study, 18 enzymes were predicted with cytoplasmic localization and ten enzymes with the membrane localization. These ten enzymes with putative membrane localization should be of particular interest. Acyl-carrier-protein S malonyltransferase, DNA polymerase III subunit beta and dihydropteroate synthase are novel drug targets and thus can be used to design potential inhibitors against S. pyogenes infection. 3D structure of dihydropteroate synthase was modeled and validated that can be used for virtual screening and interaction study of potential inhibitors with the target enzyme. PMID- 26750925 TI - Addition of Hyperoxic Component to Adaptation to Hypoxia Prevents Impairments Induced by Low Doses of Toxicants (Free Radical Oxidation and Proteins of HSP Family). AB - We studied the possibility of preventing disturbances caused by administration of low doses of toxicants by adaptation to interval hypoxia and hyperoxia. The preventive protective effect of adaptation to hypoxia-hyperoxia manifested in suppression of free radical oxidation, decrease in the levels of HIF-1alpha and inducible HOx-1, and improvement of tolerance to physical exercises. PMID- 26750926 TI - Stabilization of Homeostasis in Rats during Cold Exposure with Ethanol. AB - The role of ethanol metabolism system in adaptation of laboratory animals to cold temperatures was shown. Cold stress (1-2 degrees C) modeled in male Wistar rats over 7 weeks significantly modulated endogenous ethanol metabolism and led to reorganization of many physiological systems, which resulted in activation of metabolic processes. Under these conditions, endogenous ethanol was utilized as the most easily and fast metabolized energy substrate, due to which its blood concentration decreased and was replenished at the expense of exogenous ethanol. Normalization of blood ethanol concentration led to better adaptation to cold. PMID- 26750927 TI - Role of Ebola Virus vp24 Protein in Inhibition of Interferonogenesis. AB - The effects of recombinant analog of natural Ebola virus protein vp24 in configurations virulent (vp24-ad) and avirulent (vp24-w) for guinea pigs on interferonogenesis were studied in vivo and in vitro. Amino acid differences were determined by His186 substitution in avirulent (nonlethal) configuration for Tyr in the virulent (lethal) one. Recombinant analogs vp24-w and vp24-ad inhibited interferonogenesis in vivo and in vitro. Inhibition by the two protein configurations was virtually the same. PMID- 26750928 TI - Role of Collagen Gene Polymorphisms in the Structure of Early Gestation Loss. AB - Studies of collagen gene polymorphisms associated with predisposition to early recurrent miscarriages revealed significant differences in the distribution of COL1A1 C-1997A C>A (rs1107946) genotypes and alleles in the group of pregnant patients with early miscarriages in comparison with controls (normal pregnancy). Identification of COL1A1 C-1997A C>A (rs1107946) collagen gene polymorphisms at the stage of pregnancy planning will make it possible to form early miscarriage risk groups for more thorough preparation to gestation and optimization of follow up of this patient population. PMID- 26750929 TI - Role of Glutathione System Redox Potential in Apoptosis Dysregulation in MCF-7 Breast Adenocarcinoma. AB - MCF-7 breast cancer cells and HBL-100 breast epithelial cells were cultured with N-ethylmaleimide, a blocker of SH groups. Changes in redox potential of the glutathione system, activities of glutathione reductase, glutathione peroxidase, and intensity of apoptotic cell death were evaluated. The results indicate that incubation with N-ethylmaleimide led to glutathione system imbalance, reduced tumor cell redox potential, and induced their programmed death, which seemed useful for prospective target therapy of tumor diseases. PMID- 26750930 TI - Analysis of Antiviral Properties of Hexoral In Vitro against Some Viruses that Cause Acute Respiratory Infections and Herpes. AB - Antiviral properties of Hexoral (0.1% solution and 0.2% aerosol for local application) and its constituent hexetidine against viruses causing human respiratory tract infections and herpes virus were studied in vitro. It was found that non-cytotoxic concentrations of hexetidine (alone and as a component of Hexoral) attenuated infectious properties of highly virulent influenza virus A/H5N1, pandemic influenza virus A/H1N1pdm, respiratory syncytial virus, and herpes simplex virus type 1 after a short-term exposure (30 sec) by 100 or more times. It was found that hexidine mostly contributes to the virucidal effect of Hexoral. PMID- 26750931 TI - Simulation of Viral Hepatitis E in Marmosets. AB - We developed a model of hepatitis E virus infection in common marmosets (Callithrix jacchus) and determined optimal route of infection, duration, clinical and virological characteristics of infection in laboratory animals. Using this model, we demonstrated that replication of hepatitis E virus primarily occurs in the liver, while virus replication presumed to take place in the intestine was not confirmed in this experiment. PMID- 26750933 TI - Temperature Evolution of Methylammonium Trihalide Vibrations at the Atomic Scale. AB - The temperature evolution of vibrations of CH3NH3PbI3 (MAPI) is studied by combining first principles and classical molecular dynamics and compared to available experimental data. The work has a fundamental character showing that it is possible to reproduce the key features of the vibrational spectrum by the simple physical quantities included in the classical model, namely the ionic dispersive hybrid interactions and the mass difference between organic and inorganic components. The dynamics reveals a sizable temperature evolution of the MAPI spectrum along with the orthorhombic-to-tetragonal-to-cubic transformation and a strong dependence on molecular confinement and order. The thermally induced weakening of the H-I interactions and the anharmonic mixing of modes give two vibrational peaks at 200-250 cm(-1) that are not present at zero temperature and are expected to have detectable infrared activity. The infrared inactive vibrational peak at ~140 cm(-1) due to molecular spinning disappears abruptly at the orthorhombic-to-tetragonal transition and forms a broad molecular band red shifting progressively with temperature. This trend is correlated to the reduced confinement of the rotating cations due to thermal expansion of the lattice. PMID- 26750932 TI - Development of Endoplasmic Reticulum Stress during Experimental Oxalate Nephrolithiasis. AB - Morphological and ultrastructural study of the kidney was performed in rats with oxalate nephrolithiasis. Specific features of endoplasmic reticulum stress were evaluated during nephrolithiasis and treatment with alpha-tocopherol. We observed the signs of endoplasmic reticulum stress with activation of proapoptotic pathways and injury to the cell lining in nephron tubules and collecting ducts. Ultrastructural changes were found in the organelles, nuclei, and cell membranes of epitheliocytes. A relationship was revealed between endoplasmic reticulum stress and oxidative damage, which developed at the early state of lithogenesis. PMID- 26750934 TI - Predictors of citation rate. PMID- 26750935 TI - Significance of amyloid A immunoexpression in the prognosis of renal cell carcinoma. AB - The study investigated immunoexpression of amyloid A (AA) in clear cell renal cell carcinoma (CCRCC) and evaluated its clinicopathologic correlation, particularly in disease progression. Expression of AA protein was evaluated in patients with CCRCC by immunohistochemistry. 146 cancerous tissue samples from 86 male and 60 female patients were studied. The relationship between AA protein expression and TNM stage, nuclear grade, renal capsule invasion, perirenal invasion, and survival of the patients were assessed. Thirty four percent of CCRCC cases were AA positive. The positive AA immunoexpression was related to higher Fuhrman nuclear grade, presence of perirenal invasion of the tumor, and poor survival of patients with CCRCC. There was not any statistically significant difference between patients' gender, status of capsule invasion, and stages of the tumor in terms of AA immunoexpression. Tumor stage (Hazard ratio (HR) = 7.76 (95% CI: 2.43-24.8) for stage 3 and HR = 29.9 (95% CI: 6.97-128.32) for stage 4) and AA immunoexpression (HR = 2.16 (95% CI: 1.01-4.64) were found to be associated with survival of the patients with CCRCC in Cox regression analysis. Immunoexpression of AA was increased in high grade CCRCCs. Immunoexpression of AA was associated with poor survival in patients with CCRCC. Thus, AA staining might be used as a useful immunohistological marker for the prediction of poor prognosis in renal cell cancer. PMID- 26750936 TI - The first step in ensuring patient-centred quality of care: ask the patient. AB - Health providers may not be aware of their patients' needs or preferences, and patients reluctant to raise their concerns. Consequently, the first step in ensuring quality of care is to ask the patient about the care that they would like. A cross-sectional sample of 244 medical oncology outpatients were surveyed about provider-asking behaviours across six dimensions of patient-centred care defined by the Institute of Medicine. Specifically, were patients asked by clinic staff at the treatment centre about their physical and emotional symptoms, information needs to enable decision-making, preferences for involvement in decision-making, involvement of family and friends, and appointment scheduling. Patients were significantly (Cochran's chi2 (9) = 122.541, P < 0.001) less likely to be asked about emotional symptoms (35% infrequently asked), preferences for the involvement of family and friends (25% infrequently asked), and preferences for involvement in medical decision-making (23% infrequently asked). Only a minority of patients were infrequently asked about their treatment-related information needs (8%), physical symptoms (13% pain, 14% fatigue) and preferences for appointment scheduling (13%). Younger age, not Australian born and greater educational qualifications were associated with being infrequently asked. Improvements to care delivery can be made if clinic staff were to more regularly elicit patient's emotional symptoms, and their preferences for the involvement of family/friends and participation in medical decision-making. PMID- 26750973 TI - Sequence dependent proton conduction in self-assembled peptide nanostructures. AB - The advancement of diverse electrochemistry technologies depends on the development of novel proton conducting polymers. Inspired by the efficacy of proton transport through proteins, we show in this work that self-assembling peptide nanostructures may be a promising alternative for such organic proton conducting materials. We demonstrate that aromatic amino acids, which participate in charge transport in nature, unprecedentedly promote proton conduction under both high and low relative humidity conditions for d,l alpha-cyclic peptide nanotubes. For dehydrated networks long-range order of the assemblies, induced by the aromatic side chains, is shown to be a dominating factor for promoting conductivity. However, for hydrated networks this order of effect is less significant and conductivity can be improved by the introduction of proton donating carboxylic acid peptide side chains in addition to the aromatic side chains despite the lower order of the assemblies. Based on these observations, a novel cyclic peptide that incorporates non-natural naphthyl side chains was designed. Self-assembled nanotubes of this peptide show greatly improved dehydrated conductivity, while maintaining high conductivity under hydrated conditions. We envision that the demonstrated modularity and versatility of these bio inspired nanostructures will make them extremely attractive building blocks for the fabrication of devices for energy conversion and storage applications, as well as other applications that involve proton transport, whether dry or wet conductivity is desired. PMID- 26750974 TI - Molecular mechanism investigation of the neutralization of cadmium toxicity by transferrin. AB - Cadmium adversely affects the biological function of the liver. Transferrin might be involved in the detoxification system of cadmium. However, owing to the lack of investigation of the molecular mechanism of cadmium conjugating to transferrin, the role of transferrin in cadmium detoxification in the liver and how transferrin undergoes conformational and functional changes upon cadmium binding are not clear. In this article, we demonstrated the potential role of transferrin in the protection of the mouse primary hepatocytes against cadmium toxicity. After the incubation of hepatocytes with 10 and 100 MUM CdCl2, pretreatment with transferrin significantly attenuated the reduction of cell viability in comparison with the samples treated with CdCl2 alone. Furthermore, a detailed molecular mechanism investigation of the interaction of CdCl2 with transferrin was reported using biophysical methods. Multi-spectroscopic measurements showed that CdCl2 formed complexes with transferrin and caused structural and conformational changes of transferrin. Isothermal titration calorimetry measurements revealed that transferrin has two classes of binding sites with different binding constants for CdCl2 binding. Hydrophobic forces and electrostatic forces are the major driving forces of the interaction. Preferred specific binding sites on transferrin were identified by dialysis experiments, molecular docking studies and molecular dynamics simulations. Upon low CdCl2 concentration exposure, no content of iron was released from transferrin because CdCl2 preferentially binds to the surface of transferrin molecules. Upon higher CdCl2 concentration exposure, the release of iron content from transferrin was observed due to the interaction of CdCl2 with the key residues around iron binding sites. PMID- 26750975 TI - The Dynamic contribution of chronic conditions to temporal trends in disability among U.S. adults. AB - BACKGROUND: Although evidence has shown that U.S. late-life disability has been declining, studies have also suggested that there has been an increase in chronic diseases between 1984 and 2007. OBJECTIVES: To further illuminate these potentially contradictory trends, we explicate how the contribution of chronic conditions changes across four common types of disability (ADL, IADL, mobility disability, and functional limitations) by age (A), period (P), and birth cohorts (C) among adults aged 20 and above. METHODS: Our data came from seven cross sectional waves of the National Health and Nutrition Examination Survey (NHANES). We utilize a cross-classified random effect model (CCREM) to simultaneously estimate age, period, and cohort trends for each disability. Each chronic condition was sequentially then simultaneously added to our base models (sociodemographics only). Reductions in predicted probability from the base model were then calculated for each chronic condition by each temporal dimension (A/P/C) to assess the contribution of each chronic condition. RESULTS: There was increasing age-based contribution of chronic conditions to all disabilities. The period-based contribution remained quite stagnant across years while cohort-based contributions showed a continual decline for recent cohorts. Arthritis showed the greatest contribution to disability of all types which was followed by obesity. Cancer was the least important contributor to disabilities. CONCLUSION: Although chronic conditions are becoming less disabling across recent cohorts, other competing risk factors might suggest prevailing causes of disability. PMID- 26750976 TI - Why stay home? Temporal association of pain, fatigue and depression with being at home. AB - BACKGROUND: Community participation is important to most people with disabilities despite the fact that common secondary conditions like pain, fatigue and depression may increase the difficulty of leaving home. Despite decades of research on these secondary conditions, little is known about how they are associated with being at home. OBJECTIVE: We used Ecological Momentary Assessment data to examine within subject fluctuation in these secondary conditions to examine their effect on the likelihood that participants remain at or return home. METHODS: Participants (n = 139) were recruited from a population based sampling frame to complete an Ecological Momentary Assessment that queried their location and experience with secondary conditions six times a day for two weeks. RESULTS: Between subjects secondary condition ratings averaged across time periods indicated that pain and depression were associated with the share of measurement periods that respondents reported being at home. Within subject results indicated that a standard unit increase in pain, fatigue and depression was associated with being home one to two days later. Within day results indicated that increases in pain and fatigue were associated with increased likelihood of being home later, but increases in depression were associated with lower likelihood of being home later. CONCLUSION: These results suggest there may be a complicated relationship among these secondary conditions and community participation with effects observed both across and within days. One interpretation suggests that secondary condition severity is tempered by adjusting participation. These results may have implications for intervening on these secondary conditions. PMID- 26750979 TI - Introduction of carbon nano-tubes into the phosphor to restrain the saturation behavior in low voltage cathodoluminescence. AB - To restrain the saturation behavior in low voltage cathodoluminescence, a small amount of carbon nano-tubes (CNT) was introduced into the phosphor to form CNT introduced phosphor material. In the specific working conditions in low voltage cathodoluminescence, the field enhancement effect is initiated in the CNT introduced phosphor material, and the local electric fields surrounding the top of each CNT is much stronger than the background electric field. The CNTs, with enhanced local electric fields surrounding their tops, play a key role in removing the electrons in the phosphor material, in which the CNTs act as convenient channels for electrons to be removed in cathodoluminescence. By introducing a small amount of CNTs into the phosphor, the saturation behavior in low voltage cathodoluminescence is effectively restrained, which has a similar effect as improving the conductivity of the phosphor material. The field enhancement effect in the CNT-introduced phosphor material may be activated and become more effective when the applied current density in cathodoluminescence is increased, thus the dynamic performance of the CNT-introduced phosphor material is favorable in low voltage cathodoluminescence. PMID- 26750980 TI - Critical Casimir forces for colloidal assembly. AB - Critical Casimir forces attract increasing interest due to their opportunities for reversible particle assembly in soft matter and nano science. These forces provide a thermodynamic analogue of the celebrated quantum mechanical Casimir force that arises from the confinement of vacuum fluctuations of the electromagnetic field. In its thermodynamic analogue, solvent fluctuations, confined between suspended particles, give rise to an attractive or repulsive force between the particles. Due to its unique temperature dependence, this effect allows in situ control of reversible assembly. Both the force magnitude and range vary with the solvent correlation length in a universal manner, adjusting with temperature from fractions of the thermal energy, k B T, and nanometre range to several ten kT and micrometer length scale. Combined with recent breakthroughs in the synthesis of complex particles, critical Casimir forces promise the design and assembly of complex colloidal structures, for fundamental studies of equilibrium and out-of-equilibrium phase behaviour. This review highlights recent developments in this evolving field, with special emphasis on the dynamic interaction control to assemble colloidal structures, in and out of equilibrium. PMID- 26750978 TI - Temperature-Induced Aggregate Transitions in Mixtures of Cationic Ammonium Gemini Surfactant with Anionic Glutamic Acid Surfactant in Aqueous Solution. AB - The aggregation behaviors of the mixtures of cationic gemini surfactant 1,4 bis(dodecyl-N,N-dimethylammonium bromide)-2,3-butanediol (C12C4(OH)2C12Br2) and anionic amino acid surfactant N-dodecanoylglutamic acid (C12Glu) in aqueous solution of pH = 10.0 have been studied. The mixture forms spherical micelles, vesicles, and wormlike micelles at 25 degrees C by changing mixing ratios and/or total surfactant concentration. Then these aggregates undergo a series of transitions upon increasing the temperature. Smaller spherical micelles transfer into larger vesicles, vesicles transfer into solid spherical aggregates and then into larger irregular aggregates, and entangled wormlike micelles transfer into branched wormlike micelles. Moreover, the larger irregular aggregates and branched micelles finally lead to precipitation and clouding phenomenon, respectively. All these transitions are thermally reversible, and the transition temperatures can be tuned by varying the mixing ratios and/or total concentration. These temperature-dependent aggregate transitions can be elucidated on the basis of the temperature-induced variations in the dehydration, electrostatic interaction, and hydrogen bonds of the headgroup area and in the hydrophobic interaction between the hydrocarbon chains. The results suggest that the surfactants carrying multiple binding sites will greatly improve the regulation ability and temperature sensitivity. PMID- 26750982 TI - 2D Cocrystallization from H-Bonded Organic Ferroelectrics. AB - The synthesis of 2D H-bonded cocrystals from the room-temperature ferroelectric organics croconic acid (CA) and 3-hydroxyphenalenone (3-HPLN) is demonstrated through self-assembly on a substrate under ultrahigh vacuum. 2D cocrystal polymorphs of varied stoichiometry were identified with scanning tunneling microscopy, and one of the observed structural building blocks consists of two CA and two 3-HPLN molecules. Computational analysis with density functional theory confirmed that the experimental (CA)2(3-HPLN)2 tetramers are lower in energy than single-component structures due to the ability of the tetramers to pack efficiently in two dimensions, the promotion of favorable electrostatic interactions between tetramers, and the optimal number of intermolecular hydrogen bonds. The structures investigated, especially the experimentally found tetrameric building blocks, are not polar. However, it is demonstrated computationally that cocrystallization can, in principle, result in heterogeneous structures with dipole moments that exceed those of homogeneous structures and that 2D structures with select stoichiometries could favor metastable polar structures. PMID- 26750983 TI - Covalent Labeling Denaturation Mass Spectrometry for Sensitive Localized Higher Order Structure Comparisons. AB - Protein higher order structure (HOS) describes the three-dimensional folding arrangement of a given protein and plays critical roles in structure/function relationships. As such, it is a key product quality attribute that is monitored during biopharmaceutical development. Covalent labeling of surface residues, combined with mass spectrometry analysis, has increasingly played an important role in characterizing localized protein HOS. Since the label can potentially induce conformation changes, protocols generally use a small amount of label to ensure that the integrity of the protein HOS is not disturbed. The present study, however, describes a method that purposely uses high amounts of isobaric label (levels that induce denaturation) to enhance the sensitivity and resolution for detecting localized structural differences between two or more biological products. The method proved to be highly discriminative, detecting differences in HOS affecting as little as 2.5-5% of the molecular population, levels at which circular dichroism and nuclear magnetic resonance spectroscopy fingerprinting, both gold standard HOS techniques, were unable to adequately differentiate. The methodology was shown to have comparable sensitivity to differential scanning calorimetry for detecting HOS differences. In addition, the workflow presented herein can also quantify other product attributes such as post-translational modifications and site-specific glycosylation, using a single liquid chromatography-tandem mass spectrometry (LC-MS/MS) run with automated data analysis. We applied this technique to characterize a large (>90 kDa), multiply glycosylated therapeutic protein under different heat stress conditions and aggregation states. PMID- 26750984 TI - Investigation of selective inhibitory effects of glycyrol on human CYP 1A1 and 2C9. AB - 1. Glycyrol is a coumarin derivative isolated from the roots of Glycyrrhiza uralensis called Gamcho in Korea and commonly used as a sweetener in oriental medicine. Glycyrol shows several biological activities, including anti-oxidative, anti-inflammatory, antibacterial, anti-angiogenic, and anti-allergenic properties. Although there have been studies on the biological effects of glycyrol, the inhibitory effects of glycyrol on cytochrome P450 (CYP) activities have not been investigated. 2. We investigated the inhibitory effects of glycyrol on the activities of CYP isoforms using a cocktail of probe substrates in pooled human liver microsome (HLM) and human recombinant cDNA-expressed CYPs. Glycyrol strongly inhibited CYP1A-mediated phenacetin O-deethylation and CYP2C9-mediated diclofenac 4'-hydroxylation in HLMs, which were the result of competitive inhibition as revealed by a Dixon plot. In addition, glycyrol showed selective inhibition of CYP1A1- and CYP1A2-catalyzed phenacetin O-deethylase activity with a half-maximal inhibitory concentration of (IC50) 1.3 and 16.1 MUM in human recombinant cDNA-expressed CYP1A1 and CYP1A2, respectively. 3. Glycyrol decreased CYP2C9-catalyzed diclofenac 4'-hydroxylation activity with IC50 values of 0.67 MUM in human recombinant cDNA-expressed CYP2C9. This is the first investigation of competitive inhibitory effects on CYP1A1 and CYP2C9 in HLMs. PMID- 26750985 TI - Phase I study of idarubicin dose escalation for remission induction therapy in acute myeloid leukemia. AB - The maximum tolerated dose (MTD) of idarubicin should be reevaluated in the treatment of acute myeloid leukemia (AML) in the era of granulocyte colony stimulating factor and better supportive care. We conducted a phase I study to investigate the safety of escalating doses of idarubicin in combination with cytarabine 100 mg/m(2)/day for seven days for previously untreated AML. The starting dose of idarubicin was 12 mg/m(2)/day for three days with dose escalations by 3 mg/m(2)/day up to 18 mg/m(2)/day. The study design was adopted from traditional 3 + 3 design for phase I cancer clinical trials. The grade 4 hematologic toxicities were observed at all dose levels; however, these toxicities did not meet the criteria of the hematologic dose-limiting toxicities as defined in this study. There were no instances of grade 4 non-hematologic toxicities at any dose levels. The MTD of idarubicin was not reached in this trial. PMID- 26750986 TI - Factors Affecting Peptide Interactions with Surface-Bound Microgels. AB - Effects of electrostatics and peptide size on peptide interactions with surface bound microgels were investigated with ellipsometry, confocal microscopy, and atomic force microscopy (AFM). Results show that binding of cationic poly-L lysine (pLys) to anionic, covalently immobilized, poly(ethyl acrylate-co methacrylic acid) microgels increased with increasing peptide net charge and microgel charge density. Furthermore, peptide release was facilitated by decreasing either microgel or peptide charge density. Analogously, increasing ionic strength facilitated peptide release for short peptides. As a result of peptide binding, the surface-bound microgels displayed pronounced deswelling and increased mechanical rigidity, the latter quantified by quantitative nanomechanical mapping. While short pLys was found to penetrate the entire microgel network and to result in almost complete charge neutralization, larger peptides were partially excluded from the microgel network, forming an outer peptide layer on the microgels. As a result of this difference, microgel flattening was more influenced by the lower Mw peptide than the higher. Peptide induced deswelling was found to be lower for higher Mw pLys, the latter effect not observed for the corresponding microgels in the dispersed state. While the effects of electrostatics on peptide loading and release were similar to those observed for dispersed microgels, there were thus considerable effects of the underlying surface on peptide-induced microgel deswelling, which need to be considered in the design of surface-bound microgels as carriers of peptide loads, for example, in drug delivery or in functionalized biomaterials. PMID- 26750988 TI - HPLC and HPLC/MS analysis of red ink on counterfeit 100-yuan notes. AB - Counterfeiting is a significant problem for most major currencies and has high social and economic costs. Chemical and physical identifiers that are unique to counterfeit currency are critical to forensic analysis. The 100-yuan Chinese note is mostly red. Here, we analyzed the red ink used in 100-yuan Chinese notes and developed a method to extract and analyze these dyes via high performance liquid chromatography (HPLC) and HPLC/mass spectrometry (MS). We used this approach to analyze the chemical structures of the adulterated colorants from 46 counterfeit 100-yuan notes seized from different locations. The results showed that a variety of inks were found among the seized counterfeit notes from different sources. The chromatographic data signature could be used to clearly discriminate authentic from counterfeit notes, but could also potentially be used to trace the notes to the counterfeiter. To the best of our knowledge, this is the first report to use HPLC/MS to profile red dyes in Chinese currency with important implications for the forensics and law enforcement communities. PMID- 26750987 TI - Rhabdomyolysis induced by antiepileptic drugs: characteristics, treatment and prognosis. AB - INTRODUCTION: Rhabdomyolysis syndrome refers to a variety of factors that affect the striated muscle cell membrane, the membrane channels and its energy supply. Most cases of rhabdomyolysis are due to direct trauma. However, infection, toxins, drugs, muscle ischemia, electrolyte imbalance, metabolic diseases, genetic diseases and abnormal body temperature can also lead to rhabdomyolysis. Epilepsy is one of the most common chronic neurological diseases. The primary long-term treatment is antiepileptic drugs (AEDs), which may cause rhabdomyolysis. This article summarizes the characteristics, treatment methods and prognosis of patients with rhabdomyolysis that is induced by antiepileptic drugs. AREAS COVERED: This review is based on PubMed, EMBASE and MEDLINE searches of the literature using the keywords "epilepsy", "antiepileptic drugs","status epilepticus","rhabdomyolysis", and "antiepileptic drugs and rhabdomyolysis syndrome" as well as extensive personal clinical experience with various antiepileptic drugs. Potential relationships between antiepileptic drugs and rhabdomyolysis are discussed. EXPERT OPINION: Worldwide, there are approximately 50 million epilepsy patients, most of whom are treated with drugs. Reports have indicated that the majority of antiepileptic drugs on the market can cause rhabdomyolysis. Although rhabdomyolysis induced by antiepileptic drugs is a rare condition with a low incidence, this condition has serious consequences and merits attention from clinicians. PMID- 26750989 TI - Determination of hair ketamine cut-off value from Hong Kong ketamine users by LC MS/MS analysis. AB - Ketamine is one of the most frequent abused drugs in Hong Kong and South-East Asia, and the cases of ketamine abused have been reported worldwide. Hair has been commonly used as a specimen for the proof of chronic drug abused because of its non-invasiveness and long detection windows. The determinations of ketamine in hair with varieties of state-of-the-art instruments and detection methods have been developed in the past decade; however, the cut-off value for ketamine abuser has not been developed according to the international guidelines. The aim of this study is to propose a cut-off value for ketamine in hair by analyzing ketamine and its metabolite norketamine by LC-MS/MS method in a population of ketamine users in Hong Kong. The limit of detection (LOD) and limit of quantification (LOQ) for ketamine and norketamine were 20pg/mg and 100pg/mg, respectively. From 977 ketamine abusers, the cut-off value for ketamine in hair was proposed to be 400pg/mg of hair. This proposed cut-off value is the concentration of hair ketamine when over 90% of samples are being detected with the presence of norketamine, which is a proof of ketamine abuse. This value could be applied as a screening or occupational cut-off for reference. PMID- 26750990 TI - An alternative approach for estimating stature from long bones that is not population- or group-specific. AB - An accurate and precise estimate of stature can be very useful in the analysis of human remains in forensic cases. A problem with many stature estimation methods is that an unknown individual must first be assigned to a specific group before a method can be applied. Group membership has been defined by sex, age, year of birth, race, ancestry, continental origin, nationality or a combination of these criteria. Univariate and multivariate sex-specific and generic equations are presented here that do not require an unknown individual to be assigned to a group before stature is estimated. The equations were developed using linear regression with a sample (n=244) from the Terry Collection and tested using independent samples from the Forensic Anthropology Databank (n=136) and the Lisbon Collection (n=85). Tests with these independent samples show that (1) the femur provides the best univariate results; (2) the best multivariate equation includes the humerus, femur and tibia lengths; (3) a generic equation that does not require an unknown to first be assigned to a given category provides the best results most often; (4) a population-specific equation does not provide better results for estimating stature; (5) sex-specific equations can provide slightly better results in some cases; however, estimating the wrong sex can have a negative impact on precision and accuracy. With these equations, stature can be estimated independently of age at death, sex or group membership. PMID- 26750991 TI - Ensemble-Based Virtual Screening Led to the Discovery of New Classes of Potent Tyrosinase Inhibitors. AB - In this study, we report new classes of potent tyrosinase inhibitors identified by enhanced structure-based virtual screening prediction; the enzyme and melanin content assays were also confirmed. Tyrosinase, a type-3 copper protein, participates in two distinct reactions, hydroxylation of tyrosine to DOPA and conversion of DOPA to dopaquinone, in melanin biosynthesis. Although numerous inhibitors of this reaction have been reported, there is a lag in the discovery of the new functional moieties. In order to improve the performance of virtual screening, we first produced an ensemble of 10,000 structures using molecular dynamics simulation. Quantum mechanical calculation was used to determine the partial charges of catalytic copper ions based on the met and deoxy states. Second, we selected a structure showing an optimal receiver operating characteristic (ROC) curve with known direct binders and their physicochemically matched decoys. The structure revealed more than 10-fold higher enrichment at 1% of the ROC curve than those observed in X-ray structures. Third, high-throughput virtual screening with DOCK 3.6 was performed using a library consisting of approximately 400,000 small molecules derived from the ZINC database. Fourth, we obtained the top 60 molecules and tested their inhibition of mushroom tyrosinase. The extended assays included 21 analogs of the 21 initial hits to test their inhibition properties. Here, the moieties of tetrazole and triazole were identified as new binding cores interacting with the dicopper catalytic center. All 42 inhibitors showed inhibitory constant, Ki, values ranging from 11.1 nM and 33.4 MUM, with a tetrazole compound exhibiting the strongest activity. Among the 42 molecules, five displayed more than 30% reduction in melanin production when treated in B16F10 melanoma cells; cell viability was >90% at 20 MUM. Particularly, a thiosemicarbazone-containing compound reduced melanin content by 55%. PMID- 26750992 TI - No longer a deadly encounter? AB - A careful analysis shows that the mortality rates associated with epidemics following the contact between Amazonian indigenous communities and the external word have decreased in recent years. However, whether isolated indigenous populations can be contacted safely is still open to debate; many will argue that these populations should remain uncontacted in order to survive. PMID- 26750993 TI - High-Resolution Kelvin Probe Force Microscopy Imaging of Interface Dipoles and Photogenerated Charges in Organic Donor-Acceptor Photovoltaic Blends. AB - We present noncontact atomic force microscopy and Kelvin probe force microscopy studies of nanophase segregated photovoltaic blends based on an oligothiophene fluorenone oligomer and [6,6]-phenyl C70 butyric acid methyl ester. We carried out a complete analysis of the influence of the tip-surface interaction regime on the topographic, in-dark contact potential and surface photovoltage contrasts. It is demonstrated that an optimal lateral resolution is achieved for all channels below the onset of a contrast in the damping images. With the support of electrostatic simulations, it is shown that in-dark contact potential difference contrasts above subsurface acceptor clusters are consistent with an uneven distribution of permanent charges at the donor-acceptor interfaces. A remarkable dependence of the surface photovoltage magnitude with respect to the tip-surface distance is evidenced and attributed to a local enhancement of the electromagnetic field at the tip apex. PMID- 26750994 TI - The mediating role of internalized racism in the relationship between racist experiences and anxiety symptoms in a Black American sample. AB - OBJECTIVES: The current study explores the potential mediating role of internalized racism in the relationship between racist experiences and anxiety symptomology in a Black American sample. METHOD: One hundred and 73 Black American participants, between 18 and 62 years of age, completed a questionnaire packet containing measures of anxious arousal and stress symptoms, internalized racism, and experiences of racist events. RESULTS: Results indicated that internalized racism mediated the relationship between past-year frequency of racist events and anxious arousal as well as past-year frequency of racist events and stress symptoms. CONCLUSIONS: Internalized racism may be 1 mechanism that underlies the relationship between racism and anxious symptomology for Black Americans. These preliminary findings suggest that internalized racism may be an avenue through which clinicians can target the anxiety elicited by racist experiences. The clinical implications of these findings and future research directions are discussed. (PsycINFO Database Record PMID- 26750995 TI - Examining the Panic Attack Specifier in Social Anxiety Disorder. AB - Panic attacks (PAs) are characterized by overwhelming surges of fear and discomfort and are one of the most frequently occurring symptoms in psychiatric populations. The most recent version of the Diagnostic and Statistical Manual of Mental Disorders (i.e. DSM-5) allows for a panic attack (PA) specifier for all disorders, including social anxiety disorder (SAD). However, there is little research examining differences between individuals diagnosed with SAD with the PA specifier versus individuals diagnosed with SAD without the PA specifier. The current study examined social anxiety, mood, anxiety, and anxiety sensitivity social concerns, a risk factor for social anxiety in SAD-diagnosed individuals without (N = 52) and with (N = 14) the PA specifier. The groups differed only in somatic symptoms of anxiety. Result of the current study provides preliminary evidence that the presence of the PA specifier in social anxiety does not result in elevated levels of comorbidity or a more severe presentation of social anxiety. PMID- 26750998 TI - Chiral Frustrated Lewis Pairs Catalyzed Highly Enantioselective Hydrosilylations of 1,2-Dicarbonyl Compounds. AB - A highly enantioselective hydrosilylation of 1,2-dicarbonyl compounds was successfully realized for the first time utilizing the combination of tricyclohexylphosphine and chiral alkenylborane derived in situ from diyne as a frustrated Lewis pair catalyst. A variety of optically active alpha-hydroxy ketones and esters were obtained in 52-98% yields with 86-99% ee's. PMID- 26750997 TI - Incomplete target neutralization by the anti-cancer antibody rilotumumab. AB - The antibody rilotumumab, which has been tested in multiple Phase 2 and Phase 3 trials, has been reported to neutralize hepatocyte growth factor (HGF), the ligand for the oncogene MET. However, we report that rilotumumab does not prevent HGF from directly binding to MET on conventional and primary patient-derived human gliomasphere lines, a trait driven by the HGF alpha-chain, which remains free to engage cell-surface glycosaminoglycans and the receptor MET. This binding induces MET phosphorylation, initiates robust AKT and ERK signaling and potentiates biological effects such as cell scattering. This partial antagonism was highly exacerbated in the presence of activated epidermal growth factor receptor, which is common in several cancers. Hence, we confirm that rilotumumab is only a partial antagonist of HGF activity, a finding that has considerable implications for the therapeutic use of rilotumumab. PMID- 26750999 TI - Agouti signalling protein (ASIP) gene: molecular cloning, sequence characterisation and tissue distribution in domestic goose. AB - Agouti signalling protein (ASIP) is an endogenous antagonist of melanocortin-1 receptor (MC1R) and is involved in the regulation of pigmentation in mammals. The objective of this study was to identify and characterise the ASIP gene in domestic goose. The goose ASIP cDNA consisted of a 44-nucleotide 5'-terminal untranslated region (UTR), a 390-nucleotide open-reading frame (ORF) and a 45 nucleotide 3'-UTR. The length of goose ASIP genomic DNA was 6176 bp, including three coding exons and two introns. Bioinformatic analysis indicated that the ORF encodes a protein of 130 amino-acid residues with a molecular weight of 14.88 kDa and an isoelectric point of 9.73. Multiple sequence alignments and phylogenetic analysis showed that the amino-acid sequence of ASIP was conserved in vertebrates, especially in the avian species. RT-qPCR showed that the goose ASIP mRNA was differentially expressed in the pigment deposition tissues, including eye, foot, feather follicle, skin of the back, as well as in skin of the abdomen. The expression level of the ASIP gene in skin of the abdomen was higher than that in skin of the back. Those findings will contribute to further understanding the functions of the ASIP gene in geese plumage colouring. PMID- 26751000 TI - Synergistic Effects of a Combination of Cr2O3-Functionalization and UV Irradiation Techniques on the Ethanol Gas Sensing Performance of ZnO Nanorod Gas Sensors. AB - There have been very few studies on the effects of combining two or more techniques on the sensing performance of nanostructured sensors. Cr2O3 functionalized ZnO nanorods were synthesized using carbothermal synthesis involving the thermal evaporation of a mixture of ZnO and graphite powders followed by a solvothermal process for Cr2O3-functionalization. The ethanol gas sensing properties of multinetworked pristine and Cr2O3-functionalized ZnO nanorod sensors under UV illumination were examined to determine the effects of combining Cr2O3-ZnO heterostructure formation and UV irradiation on the gas sensing properties of ZnO nanorods. The responses of the pristine and Cr2O3 functionalized ZnO nanorod sensors to 200 ppm of ethanol at room temperature by UV illumination at 2.2 mW/cm(2) were increased by 3.8 and 7.7 times, respectively. The Cr2O3-functionalized ZnO nanorod sensor also showed faster response/recovery and better selectivity than those of the pristine ZnO nanorod sensor at the same ethanol concentration. This result suggests that a combination heterostructure formation and UV irradiation had a synergistic effect on the gas sensing properties of the sensor. The synergistic effect might be attributed to the catalytic activity of Cr2O3 for ethanol oxidation as well as to the increased change in conduction channel width accompanying adsorption and desorption of ethanol under UV illumination due to the presence of Cr2O3 nanoparticles in the Cr2O3-functionalized ZnO nanorod sensor. PMID- 26750996 TI - Vaccine-preventable infections in Systemic Lupus Erythematosus. AB - Systemic Lupus Erythematosus (SLE) is characterized by abnormal autoantibody production and clearance. Infections are among the most important causes of morbidity and mortality in SLE patients; they have an increased frequency of severe bacterial and viral infections possibly due to inherited genetic and immunologic defects and to immunosuppressive therapies. In addition, infectious agents can switch on lupus disease expression and activity. Among the strategies to reduce the risk of infection, vaccination can be considered the most reliable option. Most vaccines are effective and safe in SLE patients, although in certain cases immunogenicity may be sub-optimal and vaccination can trigger a flare. Although these issues are currently unresolved, the risk benefit balance is in favor for vaccination to reduce the risk of infection in SLE patients. In the present review we discuss the preventive strategies currently recommended to reduce bacterial and viral infections in SLE. PMID- 26751001 TI - Effective Biological DeNOx of Industrial Flue Gas by the Mixotrophic Cultivation of an Oil-Producing Green Alga Chlorella sp. C2. AB - Nitrogen oxides (NOx) are the components of fossil flue gas that result in the most serious environmental concerns. We previously showed that the biological removal of NOx by microalgae appears superior to traditional treatments. This study optimizes the strategy for the microalgal-based DeNOx of flue gas by fed batch mixotrophic cultivation. By using actual flue gas fixed salts (FGFS) as the nitrogen supply, the mixotrophical cultivation of the green alga Chlorella sp. C2 with high NOx absorption efficiency was optimized in a stepwise manner in a 5 L bioreactor and resulted in a maximum biomass productivity of 9.87 g L(-1) d(-1). The optimized strategy was further scaled up to 50 L, and a biomass productivity of 7.93 g L(-1) d(-1) was achieved, with an overall DeNOx efficiency of 96%, along with an average nitrogen CR of 0.45 g L(-1) d(-1) and lipid productivity of 1.83 g L(-1) d(-1). With an optimized mixotrophical cultivation, this study further proved the feasibility of using Chlorella for the combination of efficient biological DeNOx of flue gas and microalgae-based products production. Thus, this study shows a promising industrial strategy for flue gas biotreatment in plants with limited land area. PMID- 26751002 TI - Role of Chain Morphology and Stiffness in Thermal Conductivity of Amorphous Polymers. AB - Designing thermally conductive polymer is of scientific interest and practical importance for applications like thermal interface materials, electronics packing, and plastic heat exchangers. In this work, we study the fundamental relationship between the molecular morphology and thermal conductivity in bulk amorphous polymers. We use polyethylene as a model system and performed systematic parametric study in molecular dynamics simulations. We find that the thermal conductivity is a strong function of the radius of gyration of the molecular chains, which is further correlated to persistence length, an intrinsic property of the molecule that characterizes molecular stiffness. Larger persistence length can lead to more extended chain morphology and thus higher thermal conductivity. Further thermal conductivity decomposition analysis shows that thermal transport through covalent bonds dominates the effective thermal conductivity over other contributions from nonbonded interactions (van der Waals) and translation of molecules disregarding the morphology. As a result, the more extended chains due to larger persistence length provide longer spatial paths for heat to transfer efficiently and thus lead to higher thermal conductivity. In addition, rigid rod-like polymers with very large persistence length tend to spontaneously crystallize and form orientated chains, leading to a thermal conductivity increase by more than 1 order of magnitude. Our results will provide important insights into the design of thermally conductive amorphous polymers. PMID- 26751004 TI - National Survey of Infectious Diseases Physicians on Prevention Practices for Multidrug-Resistant Acinetobacter baumannii in Thailand. PMID- 26751003 TI - Content Validity of the Lee Chronic Graft-versus-Host Disease Symptom Scale as Assessed by Cognitive Interviews. AB - The Lee Chronic Graft-versus-Host Disease (cGVHD) Symptom Scale has been recommended for use by the 2005 and 2014 National Institutes of Health (NIH) Consensus Conferences to capture cGVHD symptoms. Although the cGVHD Symptom Scale was previously validated, this study aims to reexamine the instrument's content validity by exploring the clarity, comprehensibility, relevance, and ease of use in a contemporary cGVHD sample, toward Food and Drug Administration (FDA) qualification of this patient-reported outcomes (PRO) instrument as a drug development tool. Attaining FDA qualification means that an instrument has been judged to be a reliable and valid measure of clinical benefit. Twenty adult patients with a median age of 58 year (range, 31 to 79 years) participated. The median duration of cGVHD was 33 months (range, 0 to 134.4 months), and current NIH severity score was mild in 1 patient, moderate in 10 patients, and severe in 9 patients, with a median of 5.5 treatments (range, 0 to 14) ever used for cGVHD. The median summary score was 23 (range, 8 to 51), and the median time to complete the scale was 2 minutes, 7 seconds (range, 1 minute, 8 seconds to 4 minutes). Symptoms of cGVHD were well captured on the Lee cGVHD Symptom Scale, although 4 additional symptoms/signs were mentioned by 15% of the participants. Participants mostly reported that item wording was clear and provided accurate definitions of specific terminologies; however, 7 participants (35%) reported finding 1 or more items in the skin domain unclear, reporting, for example, that rashes and itchy skin seemed synonymous. Two of 19 participants (10.5%) described how their answers would have changed had they been asked about their symptoms within the past month instead of within the past week, owing to recently resolved symptoms. All participants were able to accurately explain the concept of "bother" in their own words and distinguish it from symptom severity or other related symptom attributes. In summary, participants found the Lee GVHD Symptom Scale to be a comprehensive and understandable way to report their cGVHD symptom experience. Future work will focus on options for the recall period, the phrasing of skin items, and whether some very rare symptoms (eg, feeding tube, use of oxygen) should continue to be a part of the scale. PMID- 26751007 TI - A picture is worth a thousand words? Not when it comes to associative memory of older adults. AB - Properties of the binding mechanism in associative recognition were studied by examining the influence of the pictorial superiority effect on the age-related associative deficit. The informative aspect of associative recognition is the recollection of the pairing. Previous findings indicate that recollection is susceptible to aging and that pictorial presentation can enhance recollection and facilitate associative recognition. Pictorial presentation was found to facilitate item recognition by both young and older adults, associative recognition by young adults, but not associative recognition by older adults. Our findings support the hypothesis that the binding mechanism in associative recognition is content independent. Theoretical implications are discussed. PMID- 26751005 TI - Story asides as a useful construct in examining adults' story recall. AB - Older adults sometimes exhibit higher levels of off-target verbosity during story recall than do young adults. This appears as the inclusion of extraneous information not directly relevant to the topic. Some production of such material has been clearly related to cognitive decline, particularly older adults' inability to inhibit production of irrelevant information. In tandem, however, research also suggests that some extraneous information is indirectly related to the topic and may reflect age differences in communicative styles. To further elucidate the social-cognitive aspect of this issue, the question of import is: What is the content of the additional information provided by participants during story recall? The present study answers this question. Grounded in the autobiographical memory and life story literatures, we introduce the construct, story asides, and a reliable content-analytic scheme for its assessment. Young and older adults (N = 129) recalled 1 of 2 types of stories: a personal autobiographical memory or an experimenter-generated fictional story. Narratives were reliably coded for story asides. As expected, older adults produced more story asides than young adults only for autobiographical stories. The discussion focuses on the role of story asides in everyday communication including the possibility that they may be a sign of communicative expertise. PMID- 26751008 TI - Evidence for Germanene growth on epitaxial hexagonal (h)-AlN on Ag(1 1 1). AB - In this work, a structural analysis of Ge layers deposited by molecular beam epitaxy (MBE) on Ag(1 1 1) surfaces with and without an AlN buffer layer have been investigated by x-ray Absorption Spectroscopy (XAS) at the Ge-K edge. For the Ge layers deposited on h-AlN buffer layer on Ag(1 1 1) an interatomic Ge-Ge distance [Formula: see text] A is found, typical of 2-Dimensional Ge layers and in agreement with the theoretical predictions for free standing low-buckled Germanene presented in literature. First principles calculations, performed in the density functional theory (DFT) framework, supported the experimental RHEED and XAS findings, providing evidence for the epitaxial 2-D Ge layer formation on h-AlN/Ag(1 1 1) template. PMID- 26751006 TI - Anxiety trajectories in the second half of life: Genetic and environmental contributions over age. AB - Clinically significant anxiety symptoms are prevalent among the elderly, yet knowledge about the longitudinal course of anxiety symptoms in later life remains scarce. The goals of this study were to (a) characterize age trajectories of state anxiety symptoms in the second half of life, and (b) estimate genetic and environmental contributions to individual differences in the age trajectory of state anxiety. This study was based on data from 1,482 participants in the Swedish Adoption/Twin Study of Aging who were aged 50 and older at their first occasion (512 complete twin pairs, 458 singletons) and had up to 6 measurement occasions spanning 11 years. Consistent with life span developmental theories of age-related emotional change, anxiety symptom levels declined during the transition from midlife to the mid-60s, followed by a mild increase that gradually plateaued in the 80s. There were substantial individual differences in the age trajectory of anxiety. After accounting for effects of sex, cohort, mode of testing, and proximity to death, this longitudinal variation was partitioned into biometric sources. Nonshared environmental variance was highest in the late 60s and declined thereafter, whereas genetic variance increased at an accelerated pace from approximately age 60 onward. There was no evidence for effects of rearing or other shared environment on anxiety symptoms in later life. These findings highlight how the etiology of anxiety symptoms changes from midlife to old age. PMID- 26751009 TI - Nitrogen-Doped Hollow Amorphous Carbon Spheres@Graphitic Shells Derived from Pitch: New Structure Leads to Robust Lithium Storage. AB - Nitrogen-doped mesoporous hollow carbon spheres (NHCS) consisting of hybridized amorphous and graphitic carbon were synthesized by chemical vapor deposition with pitch as raw material. Treatment with HNO3 vapor was performed to incorporate oxygen-containing groups on NHCS, and the resulting NHCS-O showed excellent rate capacity, high reversible capacity, and excellent cycling stability when tested as the anode material in lithium-ion batteries. The NHCS-O electrode maintained a reversible specific capacity of 616 mAh g(-1) after 250 cycles at a current rate of 500 mA g(-1) , which is an increase of 113 % compared to the pristine hollow carbon spheres. In addition, the NHCS-O electrode exhibited a reversible capacity of 503 mAh g(-1) at a high current density of 1.5 A g(-1) . The superior electrochemical performance of NHCS-O can be attributed to the hybrid structure, high N and O contents, and rich surface defects. PMID- 26751010 TI - Wrongness in different relationships: Relational context effects on moral judgment. AB - Morality primarily serves social-relational functions. However, little research in moral psychology investigates how relational factors impact moral judgment, and a theoretically grounded approach to such investigations is lacking. We used Relational Models Theory and Moral Foundations Theory to explore how varying actor-victim relationships impacts judgment of different types of moral violations. Across three studies, using a diverse range of moral violations and varying the experimental design, relational context substantially influenced third-party judgment of moral violations, and typically independent of several factors strongly associated with moral judgment. Results lend novel but mixed support to Relationship Regulation Theory and provide some novel implications for Moral Foundations Theory. These studies highlight the importance of relational factors in moral psychology and provide guidelines for exploring how relational factors might shape moral judgment. PMID- 26751011 TI - Qualitative and quantitative diffusion-weighted imaging of the breast at 3T - A useful adjunct to contrast-enhanced MRI in characterization of breast lesions. AB - OBJECTIVE: To distinguish between benign and malignant breast lesions on the basis of their signal intensity on diffusion-weighted imaging and their apparent diffusion coefficient (ADC) values at 3 T MRI, along with histopathological correlation. MATERIALS AND METHODS: A retrospective analysis of 500 patients who underwent 3 T MRI between August 2011 and May 2013 was done. Of these, 226 patients with 232 lesions that were proved by histopathology were included in the study. ADC values were calculated at b values of 0, 1000, and 1500 s/mm(2) after identification on contrast-enhanced images and appropriate ROI(Region of interest) placement. ADC value and histopathology correlation was analyzed. RESULTS: Out of 232 lesions, 168 lesions were histologically malignant and 64 were histologically benign. With an ADC cut-off value of 1.1 *10(-3) mm(2)/s for malignant lesions, a sensitivity of 92.80% and specificity of 80.23% was obtained. Out of 12/232 false-negative lesions, 6 were mucinous carcinoma in which a high ADC value of 1.8-1.9 *10(-3) mm(2)/s was obtained. Purely DCIS (Ductal carcinoma in situ) lesions presenting as non-mass-like enhancement had a high ADC value of 1.2-1.5 *10(-3) mm(2)/s, thereby reducing specificity. CONCLUSION: Diffusion-weighted Imaging and quantitative assessment by ADC values may act as an effective parameter in increasing the diagnostic accuracy and specificity of contrast-enhanced breast MRI in characterization of breast lesions. PMID- 26751013 TI - Modeling valuations from experience: A comment on Ashby and Rakow (2014). AB - What are the cognitive mechanisms underlying subjective valuations formed on the basis of sequential experiences of an option's possible outcomes? Ashby and Rakow (2014) have proposed a sliding window model (SWIM), according to which people's valuations represent the average of a limited sample of recent experiences (the size of which is estimated by the model) formed after sampling has been terminated (i.e., an end-of-sequence process). Ashby and Rakow presented results from which they concluded, on the basis of model-selection criteria, that the SWIM performs well compared with alternative models (e.g., value-updating model, summary model). Further, they reported that the individual window sizes estimated by the SWIM correlated with a measure of working-memory capacity. In a reanalysis of the Ashby and Rakow data, we find no clear evidence in support of any of the models tested, and a slight advantage for the summary model. Further, we demonstrate that individual differences in the window-size estimated by the SWIM can reflect differences in noise. In computer simulations, we examine the more general question of how well the models tested by Ashby and Rakow can actually be discriminated. The results reveal that the models' ability to fit data depends on a complex interplay of noise and the sample size of outcomes on which a valuation response is based. This can critically influence model performance and conclusions regarding the underlying cognitive mechanisms. We discuss the implications of these findings and suggest ways of improving model comparisons in valuations from experience. (PsycINFO Database Record PMID- 26751014 TI - "A violation of the conditional independence assumption in the two-high-threshold Model of recognition memory": Correction to Chen, Starns, and Rotello (2015). AB - Reports an error in "A violation of the conditional independence assumption in the two-high-threshold model of recognition memory" by Tina Chen, Jeffrey J. Starns and Caren M. Rotello (Journal of Experimental Psychology: Learning, Memory, and Cognition, 2015[Jul], Vol 41[4], 1215-1222). In the article, Chen et al. compared three models: a continuous signal detection model (SDT), a standard two-high-threshold discrete-state model in which detect states always led to correct responses (2HT), and a full-mapping version of the 2HT model in which detect states could lead to either correct or incorrect responses. After publication, Rani Moran (personal communication, April 21, 2015) identified two errors that impact the reported fit statistics for the Bayesian information criterion (BIC) metric of all models as well as the Akaike information criterion (AIC) results for the full-mapping model. The errors are described in the erratum. (The following abstract of the original article appeared in record 2014 56216-001.) The 2-high-threshold (2HT) model of recognition memory assumes that test items result in distinct internal states: they are either detected or not, and the probability of responding at a particular confidence level that an item is "old" or "new" depends on the state-response mapping parameters. The mapping parameters are independent of the probability that an item yields a particular state (e.g., both strong and weak items that are detected as old have the same probability of producing a highest-confidence "old" response). We tested this conditional independence assumption by presenting nouns 1, 2, or 4 times. To maximize the strength of some items, "superstrong" items were repeated 4 times and encoded in conjunction with pleasantness, imageability, anagram, and survival processing tasks. The 2HT model failed to simultaneously capture the response rate data for all item classes, demonstrating that the data violated the conditional independence assumption. In contrast, a Gaussian signal detection model, which posits that the level of confidence that an item is "old" or "new" is a function of its continuous strength value, provided a good account of the data. (PsycINFO Database Record PMID- 26751012 TI - IL-9, a local growth factor for synovial T cells in inflammatory arthritis. AB - OBJECTIVE: The regulatory role of the Th9 cells along with its signature cytokine IL-9 in human immune system and its aberrant activation in autoimmune diseases is currently under investigation. We are reporting the functional significance of IL 9 in the pathogenesis of autoimmune inflammatory arthritis. METHODS: CD3(+) T cells were obtained from peripheral blood (PB) and synovial fluid (SF) of psoriatic arthritis (PsA), rheumatoid arthritis (RA), and osteoarthritis (OA) patients. MTT, FACS based CFSE dilution assay and apoptosis assay (Annexin-V) were performed to determine the pro-growth/survival effect of human recombinant IL-9 on activated CD3(+) T cells. Immunoblots were performed to determine the signaling proteins responsible for the progrowth/survival effect of IL-9. RESULTS: SF of PsA and RA was enriched with IL-9 producing CD3(+) T cells compared to the SF in OA. IL-9 level measured by ELISA was significantly elevated in PsA and RA patients compared to SF in OA (<.001). Activated T cells of PsA and RA had higher levels of IL-9 receptors. IL-9 promoted proliferation and survival of the CD3(+) T cells of PB and SF of PsA and RA and compared to untreated (media) controls (p<.005, t-test). IL-9 induced proliferation of T cells was dependent on PI3K/Akt/mTOR signaling pathway. CONCLUSION: IL-9 is functionally active, and is a pro-growth/survival factor for the localized pathologic T cells in the synovium of inflammatory arthritis. The pro-growth/survival effect is mediated by the activation of mTOR kinase cascade. To our knowledge, this is the first report of a functional role of IL-9 in human autoimmune arthritis. PMID- 26751015 TI - Scanning electron microscopic examination of resected root apices obtained from endodontic microsurgery. AB - This study was designed to examine the morphological features of the resected root apices obtained from endodontic microsurgery using a scanning electron microscope (SEM) as well as their anatomical effect on the clinical outcome of the surgical treatment. One-hundred-six resected root apices from 91 patients/surgeries were obtained by endodontic microsurgery, and fixed immediately for storage. The resected apices were prepared for SEM to examine their morphological features, such as the number and size of the apical foramina. The patients were periodically checked up at least 1 year and the clinical outcome of the microsurgery was judged as a success or failure according to the Molven's criteria. The SEM findings and the clinical outcome of apical surgery were evaluated to see any potential correlation between them. The SEM examination revealed that 60.4% of specimens had more than two portals of exit on the resected root apices and the size of the major foramen was at least 386 micrometer and 334 micrometer from maxillary and mandibular molar, respectively. With a recall rate of 72.9%, 91.9% of the surgical cases were decided to have successful outcomes. Based on this SEM study, a relatively high frequency of multiple portals of exit was existed and the sizes of major foramina were bigger than that were reported in previous reports. The clinical outcomes of endodontic microsurgery were not correlated with the anatomical features of resected apical root apices. SCANNING 38:455-461, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26751017 TI - Nanoclay migration from food packaging materials. AB - A recent trend is to use nanocomposites materials for food-packaging applications. Different kinds of nanoparticles are incorporated into the polymers to improve their characteristics, and, among them, nanoclay is used to improve their barrier properties to gases. In this work, the results of migration studies with different food simulants (ethanol 10% and acetic acid 3%), temperatures and times (40 oC for 10 days and 70 oC for 2 h) from two commercialised LDPE nanocomposite bags are presented. The migration solutions thus obtained were analysed by ICP-MS to evaluate the amount of aluminium which migrated into the solutions both in dissolved form and as a part of nanoparticles. Aluminium migration was observed for both samples with a maximum migration value of 51.65 ng cm(-)(2) for the Aisaika bags and 24.14 ng cm(-)(2) for the Debbie Meyer bags. The presence of spikes working in single-particle mode using ICP-MS indicated that part of this aluminium was present as nanoparticles. The size and morphology of the nanoclay, in both the original material and the migration solutions, was studied by scanning electron microscopy coupled to energy-dispersive X-ray diffraction (SEM-EDX). In this manner, nanoparticles of different morphologies and sizes were found to migrate into the food simulants. PMID- 26751016 TI - Dendritic Cell Immunotherapy for HIV-1 Infection Using Autologous HIV-1 RNA: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. AB - BACKGROUND: The genomic heterogeneity of HIV-1 impedes the ability of consensus sequences in vaccines to elicit effective antiviral immune responses. AGS-004 amplifies translation-competent RNA molecules encoding for Gag, Rev, Vpr, and Nef from the patient's autologous virus and loads them into dendritic cells. METHODS: This phase IIB, multicenter, 2:1 randomized, double-blind, placebo-controlled study enrolled 54 HIV-1-infected patients on antiretroviral therapy with viral loads (VLs) <50 copies per milliliter, current CD4 T-cell counts >450 cells per cubic millimeter, and nadir counts >200 cells per cubic millimeter, to receive intradermal injections of study product into the axillary lymph node region every 4 weeks. At week 16, a 12-week analytical treatment interruption (ATI) was undertaken. RESULTS: There was no difference in the end-of-ATI VL (average of values from weeks 11 and 12) between the 2 arms of the study [4.39 (4.17, 4.69) vs. 4.47 (3.76, 4.64) log10 HIV-1 RNA; P = 0.73]. Between arms, no change between pre-antiretroviral therapy VL and the end-of-ATI VL [-0.06 (0.24, -0.32) vs. 0.17 (0.17, -0.32) log10 HIV-1 RNA; P = 0.43] was observed. When interferon gamma, interleukin-2, tumor necrosis factor alpha, CD107a, and granzyme b expressions were measured by multicolor flow cytometry, a greater percentage of AGS-004 than of placebo recipients had multifunctional cytotoxic T-lymphocyte responses induced in the CD28+/CD45RA-CD8 effector/memory T-cell population to dendritic cells electroporated with autologous antigens. Adverse events consisted of transient, mild (grade 1) local injection site reactions. CONCLUSIONS: Despite the induction of HIV-specific effector/memory CD8 T-cell responses, no antiviral effect was seen after the administration of AGS-004 when compared with placebo. PMID- 26751018 TI - 25-Hydroxyvitamin D in Patients With Cognitive Decline. PMID- 26751019 TI - Genome-wide analysis of sperm DNA methylation from monozygotic twin bulls. AB - Monozygotic (MZ) twins are of great interest to elucidate the contributions of pre- and postnatal environmental factors on epigenetics in the expression of complex traits and diseases. Progeny testing recently revealed that MZ twin bulls do not necessarily lead to identical genetic merit estimates (i.e. breeding values). Therefore, to explain differences in offspring productivity of MZ twin bulls despite their identical genetic backgrounds, we hypothesised that paternal sperm epigenomes vary between MZ twin bulls. In the present study, semen characteristics and global sperm DNA methylome were profiled for four pairs of MZ twin bulls. Some MZ twin pairs had divergent semen quality (sperm morphology, motility and viability). Comparative genome-wide DNA methylome surveys were performed using methyl-sensitive enrichment and microarray identification. Between 2% and 10% of all probes (400000) were differentially methylated between MZ twin pairs. In addition, there were 580 loci differentially methylated across all pairs of MZ twins. Furthermore, enrichment analysis indicated a significant enrichment for fertility associated quantitative trait loci (P=0.033). In conclusion, differences in the sperm epigenome may contribute to incongruous diverging performances of daughters sired by bulls that are MZ twins. PMID- 26751020 TI - Assembly of polyaniline nanotubes by interfacial polymerization for corrosion protection. AB - Polyaniline (PANI) was synthesized by the oxidation of aniline with ammonium peroxydisulfate as an oxidant in an immiscible organic/aqueous biphasic system and with decylphosphonic acid (DPA) or benzylphosphonic acid (BPA) in the aqueous phase. Nanofibers of aniline oligomers were produced using BPA in the aqueous phase while high quality polyaniline nanotubes were produced using DPA in the aqueous phase. PANI nanotubes have a outer diameter 160-240 nm, an inner diameter of 50-100 nm and a length of the order of several MUm. The understanding of the formation of PANI nanotubes was examined by isolation of reaction intermediates and their ex situ characterization by atomic force microscopy. The roles of BPA and DPA on the morphology formation of the PANI nanostructures were discussed. A nanofibrillar template produced by aniline oligomers was found to guide the growth of PANI to nanotubular morphology. PANI nanotubes are thus not derived from DPA vesicles. Preliminary corrosion tests exhibit high corrosion protection efficiency of PANI nanotubes because of their high surface area and corrosion inhibitive properties of DPA dopant. PMID- 26751022 TI - Multidimensional Scaling of Sorting Data: A Comparison of Three Procedures. AB - Dissimilarity measures (D) derived from sortings of stimuli can be submitted to multidimensional scaling (MDS) either directly, or after transforming them to profile distances (Delta) computed on the rows of the D matrix. The latter procedure was criticized by Drasgow and Jones (1979) who performed two simulation studies, which are criticized here in turn. In the present article two sets of real sorting data were used for comparing the results of MDS on D and Delta, both with each other and with the results of two other procedures: multiple correspondence analysis (by means of HOMALS) on the raw sorting data, and MDS on the pairwise similarity ratings of the same stimuli by the same subjects. The three procedures were compared both with respect to the final configurations and with regard to the fit of the corresponding distances to the data. These comparisons suggested that MDS on D is slightly superior to MDS on Delta. The latter analysis, however, yields results that are similar to those of the much more efficient HOMALS program. The differences, however, are on the average very small. PMID- 26751021 TI - German students' current choice of profession in the field of psychotherapy: Reasons for or against engaging in psychoanalytic training. AB - The psychoanalytic societies in Germany as in many other countries are concerned by a decline in the number of candidates for full psychoanalytic training. While this situation is partly attributable to changes both in society and in educational and healthcare systems, it is questionable whether psychoanalytic training institutions have yet found adequate responses to it. Under the banner of 'evidence-based treatment', behaviour therapy has come to be widely disseminated, with major implications for the teaching of different psychotherapy paradigms at universities. To investigate the determinants of this trend in the specific German situation, a large-scale, multi-method exploratory study supported by IPA's DPPT programme was undertaken, focusing on the reasons given by a population (N = 679) of German psychology, medical, and education students for embarking on training in psychoanalysis or behaviour therapy. The results suggest that behaviour therapy is more compatible with the prevailing scientific understanding and with current societal and cultural trends, owing in part to inadequacies or bias in university teaching of the various paradigms of psychotherapy. While most of the psychology students expressed a preference for behavioural training, the psychotherapy option proved less attractive for their counterparts in the fields of medicine and education. Semi-standardized qualitative interviews were used to gain a deeper understanding of the students' decisions for or against training in a specific paradigm, and led to the identification of seven decision-making prototypes. Possible reasons for the students' decisions are discussed, and concrete proposals and recommendations are presented. PMID- 26751023 TI - The Maslach Burnout Inventory: Validating Factorial Structure and Invariance Across Intermediate, Secondary, and University Educators. AB - The purposes of the study were: (a) to test for the factorial validity of the Maslach Burnout Inventory (MBI), for 543 teachers at the intermediate (n = 163), secondary (n = 162), and university (n = 218) levels, and (b) to test for the equivalence of factorial measurements and structure across groups. Initial confirmatory factor analysis of the hypothesized 3-factor structure yielded a malfitting model for each group of educators. With a view to improving the MBI for use with educators, subsequent exploratory and confirmatory factor analyses resulted in the deletion of four scale items. Tests for invariance revealed the equivalency of remaining items across intermediate and secondary teachers, and items measuring Emotional Exhaustion and Depersonalization across all three groups; the structure of burnout was only partially invariant across educators. The study has important implications for substantive studies focusing on multigroup comparisons across teaching panels. PMID- 26751024 TI - Controlling Correlational Bias via Confirmatory Factor Analysis of MTMM Data. AB - Confirmatory factor analysis of multitrait-multimethod (MTMM) data has proven to be a useful tool for assessing convergent and discriminant validity. However, researchers have not made full use of the results of MTMM analyses in examining the relationship between MTMM factors and variables outside the MTMM. Often, researchers simply average the various measures of each trait. Alternatively, they estimate LISREL MTMM models, but estimate only relationships between MTMM traits and the outside variables. In the present article, we show that these two approaches to analyzing data outside the MTMM produce equally highly biased parameter estimates when the actual correlations between MTMM method factors and the outside variables are substantial. An algebraic explanation and a simulated data illustration are given for the bias due to misspecification. Also, the problem is illustrated with a brief empirical example. Implications for applied research are discussed. PMID- 26751025 TI - Age, Cohort and Period in Life-Span Research: A Three-Way Analysis with Logically Missing Cells. AB - A solution is shown for addressing the age x cohort x period issue in life-span research. Previous solutions have utilized only portions of the data in a given two-way layout. The proposed solution uses all data, which for at least two of the three two-way layouts involves missing cells. The method can be used for repeated measure designs, or designs in which new subjects are measured at each period. The design allows the assessment of each main effect and each two-way interaction. The hypotheses tested are explicitly shown, together with the linear models that accomplish this testing. PMID- 26751026 TI - Testing Behavioral Consistency and Coherence with the Situation-Response Measure of Achievement Motivation. AB - The Situation-Response (S-R) Measure of Achievement Motivation was developed to analyze the cross-situational consistency of achievement-related behavior. This measure was based on a conceptualization of achievement motivation that included the following three components: need to achieve, need to avoid failure, and perceived self-efficacy. Data obtained from 246 college students provided evidence for the validity of the new instrument. However, exploratory factor analyses performed on the items in the instrument indicated the presence of only two factors, namely Striving and Apprehensiveness. Regression analyses further indicated the possible inappropriateness of a theoretically-based difference score, which combined the striving and apprehensiveness composites into a resultant tendency. Confirmatory factor analysis was used to test behavioral consistency of the responses to the S-R measure. Although all of the models tested had relatively poor fits with the data, the results (a) provided evidence for item-specific covariation that inflated the cross-situational correlations among the achievement-related composites of the S-R measure, and (b) indicated, after this item-specific covariation had been partialled out, a lack of support for second-order factors representing general achieving tendencies across situations. A final set of analyses indicated the presence of three distinct types of response patterns. These types were tentatively called socially anxious, cynically motivated, and anxiously striving. It was found that membership in one of these subgroups was more informative of an individual's pattern of achievement motivation than conventionally used personality tests. PMID- 26751027 TI - Variances and Covariances of Kendall's Tau and Their Estimation. AB - We generalize the formulas derived by Daniels and Kendall (1947) for the variance of the sample tau correlation. It is assumed that multivariate data are sampled from a population, and sample taus between pairs of variables are being used to estimate their population counterparts. Expressions for the variance of tau-a are generalized to allow for ties on either variable, and we further provide an expression for the covariance between two taus, including the special case where there is a variable in common. Unbiased estimators of the variance and the covariances are also derived for use in small samples. The variances and covariances of tau-a are used to provide asymptotic variances for tau-b and Somers' d. PMID- 26751028 TI - The Structure of Student Interest in Computers and Information Technology: An Application of Facet Theory and Multidimensional Scaling. AB - The present study addressed the question of whether computers and information technology constitute a uniform attitude object which can influence the study interests of students. Based on a facet design, an interest questionnaire with 72 university course descriptions was constructed in which computers and information technology was embedded as one of four item-design facets (Weinsier & Leutner, 1988). One hundred students from each of two universities responded to the questionnaire. The multidimensional interest structures of the two samples were nearly identical. The design facets constituted uniform attitude objects and the multidimensional scaling solution of the inter-item correlation matrix could be partitioned almost perfectly according to regional hypotheses derived from the facet design. Next to the discipline facet (i.e., academic discipline), computers and information technology constituted the most relevant facet of student interest. An analysis of variance supported the conclusions drawn from the multidimensional scalings. PMID- 26751029 TI - Resampling Approaches to Complex Psychological Experiments. AB - The bootstrap is a relatively new technique. In using it, the analyst intensively examines the data actually gathered to estimate the precision of the sample statistic, rather than relying on a parametric theory. While this makes little sense when parametric theories are available (such as is the case with the correlation coefficient, the mean and most other common statistics), it is a useful adjunct to traditional statistical methods when these elegant methods cannot be used. An application of the bootstrap to a complex psychological analysis approach is demonstrated. The method provides variance estimates and allows the testing of nested competing models. Most importantly, it gives a preliminary idea about the variability of quite complex parameters. PMID- 26751030 TI - The Assessment of Dimensionality for Use in Item Response Theory. AB - The application of item response theory (IRT) models requires the identification of the data's dimensionality. A popular method for determining the number of latent dimensions is the factor analysis of a correlation matrix. Unlike factor analysis, which is based on a linear model, IRT assumes a nonlinear relationship between item performance and ability. Because multidimensional scaling (MDS) assumes a monotonic relationship this method may be useful for the assessment of a data set's dimensionality for use with IRT models. This study compared MDS, exploratory and confirmatory factor analysis (EFA and CFA, respectively) in the assessment of the dimensionality of data sets which had been generated to be either one- or two-dimensional. In addition, the data sets differed in the degree of interdimensional correlation and in the number of items defining a dimension. Results showed that MDS and CFA were able to correctly identify the number of latent dimensions for all data sets. In general, EFA was able to correctly identify the data's dimensionality, except for data whose interdimensional correlation was high. PMID- 26751031 TI - Identification of Invasive Salmonella Enterica Serovar Typhimurium ST313 in Ambulatory HIV-Infected Adults in Mozambique. AB - INTRODUCTION: Despite evidence describing the burden of invasive non-typhoidal salmonella (iNTS) disease in sub-Saharan Africa, iNTS is not recognized as a priority within global health policy institutions. Recently, Salmonella enterica serovar Typhimurium, sequence type (ST) 313, has been identified as the predominant cause of iNTS disease in multiple sub-Saharan African countries. MATERIALS AND METHODS: We conducted multilocus sequence typing (MLST) to determine the prevalence of the ST313 genotype in a sample of blood isolates from ambulatory HIV-infected Mozambican adults with iNTS disease. RESULTS: Of the 29 samples of NTS obtained and analyzed by MLST, all (29/29) were assigned the ST313 sequence type based on the set of allele types derived from each of the seven loci. For quality control, five randomly selected strains taken from the original cultures were confirmed as ST313, and the positive control strain SL3261 (taken from the original culture) was categorized as S. Typhimurium ST19. CONCLUSION: S. Typhimurium ST313 is an important example of a widely distributed pathogen that lacks a coordinated strategy for control. The highly vulnerable populations at risk for ST313 infection in Mozambique, and within the region, would benefit greatly from the development of new policy and on-the-ground capacity to support increased surveillance, prevention, and treatment initiatives. PMID- 26751032 TI - Measuring adherence with medications: time is of the essence. PMID- 26751033 TI - Citizen Science: The First Peninsular Malaysia Butterfly Count. AB - BACKGROUND: Over the past 50 years, Southeast Asia has suffered the greatest losses of biodiversity of any tropical region in the world. Malaysia is a biodiversity hotspot in the heart of Southeast Asia with roughly the same number of mammal species, three times the number of butterfly species, but only 4% of the land area of Australia. Consequently, in Malaysia, there is an urgent need for biodiversity monitoring and also public engagement with wildlife to raise awareness of biodiversity loss. Citizen science is "on the rise" globally and can make valuable contributions to long-term biodiversity monitoring, but perhaps more importantly, involving the general public in science projects can raise public awareness and promote engagement. Butterflies are often the focus of citizen science projects due to their charisma and familiarity and are particularly valuable "ambassadors" of biodiversity conservation for public outreach. NEW INFORMATION: Here we present the data from our citizen science project, the first "Peninsular Malaysia Butterfly Count". Participants were asked to go outdoors on June 6, 2015, and (non-lethally) sample butterfly legs for species identification through DNA barcoding. Fifty-seven citizens responded to our adverts and registered to take part in the butterfly count with many registering on behalf of groups. Collectively the participants sampled 220 butterfly legs from 26 mostly urban and suburban sampling localities. These included our university campus, a highschool, several public parks and private residences. On the basis of 192 usable DNA barcodes, 43 species were sampled by the participants. The most sampled species was Appias olferna, followed by Junonia orithya and Zizina otis. Twenty-two species were only sampled once, five were only sampled twice, and four were only sampled three times. Three DNA barcodes could not be assigned species names. The sampled butterflies revealed that widely distributed, cosmopolitan species, often those recently arrived to the peninsula or with documented "invasive" potential, dominated the habitat types sampled by the participants. Data from this first Butterfly Count helps establish a baseline from which we can monitor the patterns and changes in butterfly communities in Peninsular Malaysia. PMID- 26751034 TI - Major Bleeding and Case Fatality Rate with the Direct Oral Anticoagulants in Orthopedic Surgery: A Systematic Review and Meta-Analysis. AB - The novel direct oral anticoagulants (DOACs) have been proposed as alternatives to low-molecular-weight heparins (LMWHs) for the prevention of venous thromboembolism in orthopedic surgery. However, the clinical impact of postsurgical bleeding with the DOACs has not been extensively evaluated. MEDLINE and EMBASE databases, supplemented with conference abstract books and www.clinicaltrial.gov, were searched up to the first week of March 2015. We included phase II and phase III randomized controlled trials comparing the DOACs with LMWHs in patients undergoing major orthopedic surgery. Data regarding major, fatal, and intracranial bleeding were collected, to calculate the pooled relative risk (RR) and the case-fatality rate (CFR), with 95% confidence interval (CI). We retrieved 25 studies (5 evaluating dabigatran, 4 apixaban, 6 edoxaban, and 10 rivaroxaban), enrolling 42,170 patients. There was no significant difference between the DOACs and LMWHs in the risk of major (1.23 vs. 1.16%; RR: 1.07, 95% CI: 0.89-1.29), fatal (0.02 vs. 0.01%; RR: 1.63, 95% CI: 0.39-6.77), and intracranial bleeding (0 vs. 0.01%; RR: 0.33, 95% CI: 0.03-3.18). The weighted mean CFR of major bleeding was 3.3% (95% CI, 1.5-5.7) and 2.3% (95% CI, 0.7-4.6), respectively. Bleeding complications and the associated CFR during prophylactic anticoagulation in orthopedic surgery were very low and not significantly different between the DOACs and LMWHs. PMID- 26751036 TI - Keep on growing: building and patterning leaves in the grasses. AB - Monocot leaves have unique features that arise early in their development. Maturing leaves protectively enclose younger leaves and the meristem, the pool of founder cells from which a leaf emerges. Through the maturation process, proximal sheath and distal blade tissues differentiate and are separated by the ligule and auricle structures. Here we review current research focusing on the contribution of gene regulatory factors and phytohormones on the patterning and differentiation of monocot leaves primarily focusing on research in the grasses (Poaceae). The 10000 members of the grasses include the true grain cereals (wheat, rice, maize, etc.), biofuel crops such as sugarcane, pasture grasses, and bamboo. They are the most studied of the monocots due to their tremendous agricultural and agronomic importance. PMID- 26751035 TI - Health concerns and management of select veterinary drug residues. AB - The aim of this manuscript is to review the potential adverse health effects in humans if exposed to residues of selected veterinary drugs used in food-producing animals. Our other objectives are to briefly inform the reader of why many of these drugs are or were approved for use in livestock production and how drug residues can be mitigated for these drugs. The selected drugs include several antimicrobials, beta agonists, and phenylbutazone. The antimicrobials continue to be of regulatory concern not only because of their acute adverse effects but also because their use as growth promoters have been linked to antimicrobial resistance. Furthermore, nitroimidazoles and arsenicals are no longer approved for use in food animals in most jurisdictions. In recent years, the risk assessment and risk management of beta agonists, have been the focus of national and international agencies and this manuscript attempts to review the pharmacology of these drugs and regulatory challenges. Several of the drugs selected for this review can cause noncancer effects (e.g., penicillins) and others are potential carcinogens (e.g., nitroimidazoles). This review also focuses on how regulatory and independent organizations manage the risk of these veterinary drugs based on data from human health risk assessments. PMID- 26751037 TI - Semiautomatic Evaluation of Tricuspid Annular Plane Systolic Excursion from Two Dimensional Echocardiographic Images. AB - BACKGROUND: Tricuspid annular plane systolic excursion (TAPSE) has emerged as a reliable marker of right ventricular (RV) systolic function. Recently, TAPSE derived using 2D images (2D-TAPSE) was shown to correlate with M-mode TAPSE (MM TAPSE). We have developed a novel technique for semiautomatic evaluation of TAPSE (SA-TAPSE). The purpose of this study was to determine the accuracy of this novel technique and validate it on normal hearts and pulmonary hypertension (PH). METHODS: A total of 110 patients (56 with normal heart and 54 with PH) were retrospectively identified for analysis. The semiautomatic algorithm tracked the lateral tricuspid valve hinge point (TVHP) and the apex in the apical 4-chamber view. SA-TAPSE was calculated as displacement of the TVHP in end-diastole (ED) and end-systole (ES). The same points were manually identified to derive 2D TAPSE. RESULTS: The system was able to accurately identify ED and ES in 304/330 heartbeats within three cardiac frames. The automatically identified TVHP points were within 1.2 +/- 0.7 mm from the manually identified points. Intra-class correlation between SA-TAPSE and 2D-TAPSE was 0.96 (95% CI 0.93-0.98) for normal hearts and 0.92 (95% CI 0.87-0.96) for those with PH. Bland-Altman analysis showed a strong agreement between SA-TAPSE and 2D-TAPSE for normal hearts and those with PH. CONCLUSION: Using the novel custom-made software, SA-TAPSE could be measured in majority of our patients and was accurate when applied to normal hearts and those with PH. Future work will focus on fully automating the system for a rapid retrospective analysis of TAPSE. PMID- 26751039 TI - Parenting Practices and Perceived Social Support: Longitudinal Relations with the Social Competence of Mexican-origin Children. AB - Social bonds and supportive relationships are widely recognized as being indispensable to healthy psychological functioning and well-being. Social support is a psychological resource that is expected to also contribute positively to parenting practices. The present study longitudinally examined the relations between mothers' (N = 674) and fathers' (N = 430) perceived social support and parenting behaviors, and their relations with children's social competence during early adolescence in Mexican-origin single and two-parent families. Our constructs of interest (warm parenting, monitoring, perceived social support, and children's social competence) were significantly correlated at T1, and demonstrated significant stability across time for both parental models. Parental warmth (as reported by the child, and opposite parent) and parental monitoring (self-reported by mothers and fathers) were correlated and also showed bidirectional associations across time. Parental monitoring at T2 positively predicted change in children's social competence at T3 (controlling for T1 social competence) for mothers. Parental warmth at T2 positively predicted change in children's social competence at T3 (controlling for T1 social competence) for fathers. For mothers, the indirect effect of social support at T1 on children's social competence at T3 via parental monitoring at T2 (and controlling for prior levels) was significant. Findings suggest that maternal perceived social support contributes to children's social competence due to its positive relation to maternal monitoring. Results may also suggest that mothers' and fathers' parenting behaviors differentially relate to children's social competence in Latino families, although additional work focused on comparing parenting behaviors in two-parent families is needed. PMID- 26751038 TI - Risk of liver injury after alpha-glucosidase inhibitor therapy in advanced chronic kidney disease patients. AB - Although alpha-glucosidase inhibitors (AGIs) are commonly used for controlling postprandial blood glucose, AGIs-induced liver injuries have been reported. However, the relationship between AGIs and liver injuries in advanced chronic kidney disease (CKD) patients remains unexplored. In this nationwide case-control study, we recruited 1765 advanced diabetic CKD patients, who received AGIs therapy from January 1, 2000 to December 31, 2010 as the study sample and 5295 matched controls. Recent and former AGIs users were defined as patients who received the AGIs prescription for 30-60 d and 30-210 d before the event of liver injury. The risk of AGIs-induced liver injury was examined using time-dependent Cox proportional hazards model. Liver injury occurred in 3.9% of patients in the study group and 3.3% of patients in the control group. AGIs use did not increase the risk of liver injury in advanced CKD patients (P = 0.19). The stratified analysis indicated no increased risk of liver injury in all AGIs-using subgroups (all P > 0.05). The available evidence supports extending the use of AGIs without increasing the risk of liver injury in patients with advanced CKD. Additional randomized controlled trials are warranted to confirm our results. PMID- 26751040 TI - Effect of age and latent CMV infection on CD8+ CD56+ T cells (NKT-like) frequency and functionality. AB - Changes in the T cell pool caused by CMV infection have been proposed to contribute to immunosenescence, but it has been postulated that CMV can also have some beneficial effects in young individuals improving the immune response to other pathogens. T cells expressing CD56 (NKT-like cells) are cytotoxic effector cells with a significant role in the immune response against cancer. We have studied how age and latent CMV infection affect the frequency of NKT-like cells (CD8+ CD56+ T cells) and their response to Staphylococcal Enterotoxin B (SEB) in the context of CMV and ageing. NKT-like cell percentage increases with the combination of both CMV and age. The response to SEB and the polyfunctional index of NKT-like cells also increase with age in CMV-seropositive individuals. In young individuals, CMV infection induces a shift on the polyfunctional profile of CD8+ CD56- T cells not observed on the NKT-like cells response. NKT-like cells expressing CD57 are expanded in CMV-seropositive individuals and are more polyfunctional than their CD57- counterpart. In addition CD57- NKT-like cells are more polyfunctional than CD8+ CD56- CD57- T cells. The results support that the expansion of polyfunctional NKT-cells may have a beneficial effect on the immune response against pathogens. PMID- 26751041 TI - A Death in the Family: Lessons From a Tragedy. PMID- 26751042 TI - Regional Variations in the Public Delivery of Bariatric Surgery: An Evaluation of the Center of Excellence Model. AB - OBJECTIVE: We evaluated regional access to bariatric surgery within the high volume, center of excellence (COE) model of Ontario, Canada. BACKGROUND: In 2009, Ontario implemented Canada's first regionalized bariatric surgical care system based on a COE. Because of this, a small number of COEs service a large population and geographic area. METHODS: This study identified all patients older than 18 years, who received bariatric surgery from April 2009 to March 2012. Morbid obesity-adjusted rates of surgery were then calculated for each neighborhood, and a cluster analysis was performed to determine aggregation of neighborhoods with significantly higher (hot spots) or lower (cold spots) rates of surgery. Ordinal logistic regression was used to identify independent predictors of neighborhood access. RESULTS: The cluster analysis identified 49 cold spot neighborhoods, representing 1.7 million people. Forty of these neighborhoods lie within a relatively small area that contains 3 of the 4 COEs. In the multivariate analysis, for every 100 km from the nearest COE, neighborhoods were 0.88 times as likely to live in a hot spot [95% CI (confidence interval): 0.80-0.97; P = 0.012]. In addition, having a bariatric facility within the same administrative health region as the neighborhood made it almost twice as likely to be a hot spot, odds ratio = 1.75 (95% CI: 1.10-2.79; P = 0.018). Low neighborhood socioeconomic status was not associated with decreased delivery of care. CONCLUSIONS: This study identified an unequal delivery of bariatric surgery within Ontario. Both longer distances and not having a bariatric facility within the same health region had significant negative effects. Further research into patient attitudes and referral patterns is required to better characterize these disparities. PMID- 26751043 TI - A Randomized Prospective Multicenter Trial of Pancreaticoduodenectomy With and Without Routine Intraperitoneal Drainage? PMID- 26751044 TI - Exploration of multiphoton entangled states by using weak nonlinearities. AB - We propose a fruitful scheme for exploring multiphoton entangled states based on linear optics and weak nonlinearities. Compared with the previous schemes the present method is more feasible because there are only small phase shifts instead of a series of related functions of photon numbers in the process of interaction with Kerr nonlinearities. In the absence of decoherence we analyze the error probabilities induced by homodyne measurement and show that the maximal error probability can be made small enough even when the number of photons is large. This implies that the present scheme is quite tractable and it is possible to produce entangled states involving a large number of photons. PMID- 26751045 TI - Efficient collection of viable virus aerosol through laminar-flow, water-based condensational particle growth. AB - AIMS: State-of-the-art bioaerosol samplers have poor collection efficiencies for ultrafine virus aerosols. This work evaluated the performance of a novel growth tube collector (GTC), which utilizes laminar-flow water-based condensation to facilitate particle growth, for the collection of airborne MS2 viruses. METHODS AND RESULTS: Fine aerosols (<500 nm) containing MS2 coliphage were generated from a Collison nebulizer, conditioned by a dilution dryer and collected by a GTC and a BioSampler. The GTC effectively condensed water vapour onto the virus particles, creating droplets 2-5 MUm in diameter, which facilitated collection. Comparison of particle counts upstream and downstream revealed that the GTC collected >93% of the inlet virus particles, whereas the BioSampler's efficiency was about 10%. Viable counts of the GTC-collected viruses were also one order of magnitude higher than those of the BioSampler (P = 0.003). CONCLUSION: The efficiency of the GTC for the viable collection of MS2 viruses exceeds that of industry standard instrument, the BioSampler, by a factor of 10-100. SIGNIFICANCE AND IMPACT OF THE STUDY: This study reveals that the GTC is an effective collector of viable MS2 aerosols, and concludes the instrument will be an effective tool for studying viable virus aerosols and the inhalation risks posed by airborne viruses. PMID- 26751046 TI - High level of persistent liver injury is one of clinical characteristics in treatment-naive acute onset autoimmune hepatitis: experience in a community hospital. AB - BACKGROUND: There is, as yet, no gold standard for making the diagnosis of acute onset autoimmune hepatitis (A-AIH). Novel histological characteristics have been reported, but etiologies other than AIH could show similar histological pattern. We attempted to determine what clinical characteristics we should consider as A AIH different from other etiologies, and to whom histological characteristics should be applied for the diagnosis. METHODS: Clinical, biochemical, immunological and pathological features of 46 patients (35 women, mean age 55.9 +/- 14.2 years) with non-severe A-AIH admitted to a community hospital between 2001 and 2015 were analyzed. RESULTS: Immunoglobulin G level was normal in 28%, and anti-nuclear antibody titer was < * 80 in 28%. Liver histology of 49% showed acute form and 51% chronic one. Centrilobular necrosis/collapse and/or plasma cell accumulation, rosette formation were characteristic for A-AIH. High levels of alanine aminotransferase persisted in 21 patients who could be observed for equal to or more than 4 weeks before the start of treatment. CONCLUSIONS: Long persistence of high levels of alanine aminotransferase would be one of clinical features for considering A-AIH along with conventional features. Histological diagnostic features should be applied for such patients. Guidelines for diagnosing A-AIH should be urgently drawn up. PMID- 26751047 TI - An undergraduate laboratory activity on molecular dynamics simulations. AB - Vision and Change [AAAS, 2011] outlines a blueprint for modernizing biology education by addressing conceptual understanding of key concepts, such as the relationship between structure and function. The document also highlights skills necessary for student success in 21st century Biology, such as the use of modeling and simulation. Here we describe a laboratory activity that allows students to investigate the dynamic nature of protein structure and function through the use of a modeling technique known as molecular dynamics (MD). The activity takes place over two lab periods that are 3 hr each. The first lab period unpacks the basic approach behind MD simulations, beginning with the kinematic equations that all bioscience students learn in an introductory physics course. During this period students are taught rudimentary programming skills in Python while guided through simple modeling exercises that lead up to the simulation of the motion of a single atom. In the second lab period students extend concepts learned in the first period to develop skills in the use of expert MD software. Here students simulate and analyze changes in protein conformation resulting from temperature change, solvation, and phosphorylation. The article will describe how these activities can be carried out using free software packages, including Abalone and VMD/NAMD. PMID- 26751049 TI - Facile fabrication of freestanding three-dimensional composites for supercapacitors. AB - A facile and highly efficient method for the fabrication of free-standing three dimensional (3D) composites with different morphologies was designed by the combination of the electrospinning method and hydrothermal reaction. The controlled hierarchical nanoarrays showed excellent electrochemical performance for their potential use as supercapacitor electrodes. PMID- 26751050 TI - First coordination compounds based on a bis(imino nitroxide) biradical and 4f metal ions: synthesis, crystal structures and magnetic properties. AB - The synthesis, crystal structures and magnetic properties of two families of heterospin complexes containing lanthanide ions and a bis(imino nitroxide) biradical (IPhIN = 1-iodo-3,5-bis(4',4',5',5'-tetramethyl-4',5'-dihydro-1H imidazole-1'-oxyl)benzene) are reported: in [Ln2(hfac)6(IPhIN)(H2O)2] compounds, two lanthanide ions [Ln = Gd(III) (1) and Dy(III) (2)] are coordinated to the biradical, and in [Ln(hfac)3(IPhIN)(H2O)] compounds, one lanthanide ion (Ln = Tb(III) (3), Gd(III) (4) or Dy(III) (5)) is coordinated to the biradical. Ferromagnetic intramolecular magnetic interactions between Gd(III) and the biradical were found for 1 and 4, while intramolecular magnetic interactions between the radicals were ferro- and antiferromagnetic, respectively. Compound 2 shows a field induced slow relaxation of magnetization, which (under an external applied field of 2 kOe) exhibits an activation energy barrier of DeltaE/kB = 27 K and a pre-exponential factor of 1.4 * 10(-8) s. To support the magnetic characterization of compound 3ab initio calculations were also performed. PMID- 26751048 TI - Shear stress activates monovalent cation channel transient receptor potential melastatin subfamily 4 in rat atrial myocytes via type 2 inositol 1,4,5 trisphosphate receptors and Ca(2+) release. AB - KEY POINTS: During each contraction and haemodynamic disturbance, cardiac myocytes are subjected to fluid shear stress as a result of blood flow and the relative movement of sheets of myocytes. The present study aimed to characterize the shear stress-sensitive membrane current in atrial myocytes using the whole cell patch clamp technique, combined with pressurized fluid flow, as well as pharmacological and genetic interventions of specific proteins. The data obtained suggest that shear stress indirectly activates the monovalent cation current carried by transient receptor potential melastatin subfamily 4 channels via type 2 inositol 1,4,5-trisphosphate receptor-mediated Ca(2+) release in subsarcolemmal domains of atrial myocytes. Ca(2+) -mediated interactions between these two proteins under shear stress may be an important mechanism by which atrial cells measure mechanical stress and translate it to alter their excitability. ABSTRACT: Atrial myocytes are subjected to shear stress during the cardiac cycle under physiological or pathological conditions. The ionic currents regulated by shear stress remain poorly understood. We report the characteristics, molecular identity and activation mechanism of the shear stress-sensitive current (Ishear ) in rat atrial myocytes. A shear stress of ~16 dyn cm(-2) was applied to single myocytes using a pressurized microflow system, and the current was measured by whole-cell patch clamp. In symmetrical CsCl solutions with minimal concentrations of internal EGTA, Ishear showed an outwardly rectifying current-voltage relationship (reversal at -2 mV). The current was conducted primarily (~80%) by monovalent cations but not Ca(2+) . It was suppressed by intracellular Ca(2+) buffering at a fixed physiological level, inhibitors of transient receptor potential melastatin subfamily 4 (TRPM4), intracellular introduction of TRPM4 antibodies or knockdown of TRPM4 expression, suggesting that TRPM4 carries most of this current. A notable reduction in Ishear occurred upon inhibition of Ca(2+) release through the ryanodine receptors or inositol 1,4,5-trisphosphate receptors (IP3 R) and upon depletion of sarcoplasmic reticulum Ca(2+) . In type 2 IP3 R (IP3 R2) knockout atrial myocytes, Ishear was 10-20% of that in wild-type myocytes. Immunocytochemistry and proximity ligation assays revealed that TRPM4 and IP3 R2 were expressed at peripheral sites with co-localization, although they are not localized within 40 nm. Peripheral localization of TRPM4 was intact in IP3 R2 knockout cells. The data obtained in the present study suggest that shear stress activates TRPM4 current by triggering Ca(2+) release from the IP3 R2 in the peripheral domains of atrial myocytes. PMID- 26751051 TI - Undersampled linogram trajectory for fast imaging (ULTI): experiments at 3 T and 7 T. AB - In this study, the performance of linogram acquisition was investigated for the reconstruction of images from undersampled data using parallel imaging methods. The point spread function (PSF) of linogram sampling was analyzed for image sharpness and artifacts. Generalized auto-calibrating partially parallel acquisition was implemented for this new sampling scheme, and images were reconstructed with high acceleration rates. The results were compared with conventional radial sampling methods using simulations and phantom experiments at 3 T. Additionally, a human volunteer was scanned at 7 T. The results demonstrated that the PSF was sharper and the mean artifact power was lower for linogram sampling compared with radial sampling. Results of simulations and phantom experiments were in accord with the findings of the PSF analysis. In simulations, errors in the reconstructed images were lower for linogram sampling. In phantom experiments, fine details and sharp edges were preserved for linogram sampling, while details were blurred for radial sampling. The in vivo human study demonstrated that linogram sampling could provide high quality images of anatomy, even at high acceleration rates. Linogram sampling not only possesses the advantages of radial sampling, such as reduced sensitivity to motion and higher acceleration rates, but it also provides sharper images with fewer artifacts. Moreover, it is less prone to off-resonance artifacts compared with radial sampling. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26751052 TI - The ups and downs of exercise and insulin sensitivity: a role for the myokine myostatin in glucose metabolism? PMID- 26751053 TI - Phosphocholine-decorated superparamagnetic iron oxide nanoparticles: defining the structure and probing in vivo applications. AB - Superparamagnetic Iron Oxide Nanoparticles (SPIONs) are performing contrast agents for Magnetic Resonance Imaging (MRI). A functionalization strategy for SPIONs based on hydrophobic interactions is a versatile approach easily extendable to several kinds of inorganic nanoparticles and suitable for obtaining stable and biocompatible systems. Here we report on the original preparation of functionalized SPIONs with an 8 nm radius exploiting the hydrophobic interaction between a phosphocholine and an inner amphiphilic. With respect to other similarly functionalized SPIONs, characterized by the typical nanoparticle clustering that leads to large aggregates, our phosphocholine-decorated SPIONs are demonstrated to be monodisperse. We report the in vitro and in vivo study that proves the effective applicability of phosphocholine-decorated SPIONs as MRI contrast agents. The versatility of this functionalization approach is highlighted by introducing on the SPION surface a ruthenium-based potential antitumoral drug, named ToThyCholRu. Even if in this case we observed the formation of SPION clusters, ascribable to the presence of the amphiphilic ruthenium complex, interesting and promising antiproliferative activity points at the ToThyCholRu-decorated SPIONs as potential theranostic agents. PMID- 26751054 TI - Metabolic Syndrome Components After Pediatric Liver Transplantation: Prevalence and the Impact of Obesity and Immunosuppression. AB - Metabolic syndrome is associated with long-term morbidity and mortality after adult liver transplantation (LT). Whether pediatric LT recipients have a higher prevalence of metabolic syndrome remains controversial. In a cross-sectional study, we evaluated pediatric LT recipients aged 8-30 years using National Health and Nutrition Examination Survey (NHANES) protocols. LT recipients were matched by gender, race/ethnicity, and age with controls from NHANES. Pediatric LT recipients (n = 83), after adjusting for overweight/obesity and glucocorticoid use, had increased prevalence of prehypertension and hypertension, impaired glucose tolerance (IGT; 2-h glucose after oral glucose tolerance test >=140 mg/dL), and low high-density lipoprotein compared to matched NHANES controls (n = 235) despite a lower prevalence of overweight/obesity. Among LT recipients, the adjusted odds of IGT doubled for every 7.5 years taking calcineurin inhibitors (odds ratio = 2.10, 95% confidence interval 1.06-4.17 per 7.5 years taking calcineurin inhibitors, p = 0.03). Among all subjects with IGT, LT recipients had a lower prevalence of overweight/obesity and less insulin resistance (homeostatic model assessment of insulin resistance) than did controls with IGT. Among normal weight subjects, LT recipients were significantly more likely than controls to have prehypertension/hypertension, IGT, low high-density lipoprotein, and metabolic syndrome. Pediatric LT recipients have unique metabolic syndrome profiles and risk factors and will require tailored screening and management protocols. PMID- 26751056 TI - Measurement noise 100 times lower than the quantum-projection limit using entangled atoms. AB - Quantum metrology uses quantum entanglement--correlations in the properties of microscopic systems--to improve the statistical precision of physical measurements. When measuring a signal, such as the phase shift of a light beam or an atomic state, a prominent limitation to achievable precision arises from the noise associated with the counting of uncorrelated probe particles. This noise, commonly referred to as shot noise or projection noise, gives rise to the standard quantum limit (SQL) to phase resolution. However, it can be mitigated down to the fundamental Heisenberg limit by entangling the probe particles. Despite considerable experimental progress in a variety of physical systems, a question that persists is whether these methods can achieve performance levels that compare favourably with optimized conventional (non-entangled) systems. Here we demonstrate an approach that achieves unprecedented levels of metrological improvement using half a million (87)Rb atoms in their 'clock' states. The ensemble is 20.1 +/- 0.3 decibels (100-fold) spin-squeezed via an optical-cavity based measurement. We directly resolve small microwave-induced rotations 18.5 +/- 0.3 decibels (70-fold) beyond the SQL. The single-shot phase resolution of 147 microradians achieved by the apparatus is better than that achieved by the best engineered cold atom sensors despite lower atom numbers. We infer entanglement of more than 680 +/- 35 particles in the atomic ensemble. Applications include atomic clocks, inertial sensors, and fundamental physics experiments such as tests of general relativity or searches for electron electric dipole moment. To this end, we demonstrate an atomic clock measurement with a quantum enhancement of 10.5 +/- 0.3 decibels (11-fold), limited by the phase noise of our microwave source. PMID- 26751055 TI - NANOG alone induces germ cells in primed epiblast in vitro by activation of enhancers. AB - Nanog, a core pluripotency factor in the inner cell mass of blastocysts, is also expressed in unipotent primordial germ cells (PGCs) in mice, where its precise role is yet unclear. We investigated this in an in vitro model, in which naive pluripotent embryonic stem (ES) cells cultured in basic fibroblast growth factor (bFGF) and activin A develop as epiblast-like cells (EpiLCs) and gain competence for a PGC-like fate. Consequently, bone morphogenetic protein 4 (BMP4), or ectopic expression of key germline transcription factors Prdm1, Prdm14 and Tfap2c, directly induce PGC-like cells (PGCLCs) in EpiLCs, but not in ES cells. Here we report an unexpected discovery that Nanog alone can induce PGCLCs in EpiLCs, independently of BMP4. We propose that after the dissolution of the naive ES-cell pluripotency network during establishment of EpiLCs, the epigenome is reset for cell fate determination. Indeed, we found genome-wide changes in NANOG binding patterns between ES cells and EpiLCs, indicating epigenetic resetting of regulatory elements. Accordingly, we show that NANOG can bind and activate enhancers of Prdm1 and Prdm14 in EpiLCs in vitro; BLIMP1 (encoded by Prdm1) then directly induces Tfap2c. Furthermore, while SOX2 and NANOG promote the pluripotent state in ES cells, they show contrasting roles in EpiLCs, as Sox2 specifically represses PGCLC induction by Nanog. This study demonstrates a broadly applicable mechanistic principle for how cells acquire competence for cell fate determination, resulting in the context-dependent roles of key transcription factors during development. PMID- 26751057 TI - A lithium-oxygen battery based on lithium superoxide. AB - Batteries based on sodium superoxide and on potassium superoxide have recently been reported. However, there have been no reports of a battery based on lithium superoxide (LiO2), despite much research into the lithium-oxygen (Li-O2) battery because of its potential high energy density. Several studies of Li-O2 batteries have found evidence of LiO2 being formed as one component of the discharge product along with lithium peroxide (Li2O2). In addition, theoretical calculations have indicated that some forms of LiO2 may have a long lifetime. These studies also suggest that it might be possible to form LiO2 alone for use in a battery. However, solid LiO2 has been difficult to synthesize in pure form because it is thermodynamically unstable with respect to disproportionation, giving Li2O2 (refs 19, 20). Here we show that crystalline LiO2 can be stabilized in a Li-O2 battery by using a suitable graphene-based cathode. Various characterization techniques reveal no evidence for the presence of Li2O2. A novel templating growth mechanism involving the use of iridium nanoparticles on the cathode surface may be responsible for the growth of crystalline LiO2. Our results demonstrate that the LiO2 formed in the Li-O2 battery is stable enough for the battery to be repeatedly charged and discharged with a very low charge potential (about 3.2 volts). We anticipate that this discovery will lead to methods of synthesizing and stabilizing LiO2, which could open the way to high energy-density batteries based on LiO2 as well as to other possible uses of this compound, such as oxygen storage. PMID- 26751058 TI - Application of Cervical Arthroplasty With Bryan Cervical Disc: 10-Year Follow-up Results in China. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: The aims of this study were to evaluate the radiographic and clinical outcomes of Bryan cervical disc arthroplasty at 10-year follow-up. SUMMARY OF BACKGROUND DATA: Cervical arthroplasty is a new technique for treating degenerative cervical disease. Previous reports have shown that cervical arthroplasty with Bryan disc gained good clinical outcomes at 4- to 6-year follow-up. METHODS: Clinical outcomes and dynamic x-ray examination were evaluated at baseline and at final follow-up. RESULTS: Thirty-three patients with complete clinical and radiographic data were included in this study. The mean follow-up period was 120.5 months (116-130 months). Twenty-five patients underwent single-level arthroplasty and 7 underwent arthroplasty at 2 levels. One patient underwent arthroplasty at 3 levels. Eight of the 33 patients presented with radiculopathy and 25 patients with myelopathy. The 42 levels of surgery included C3/4 (3 levels), C4/5 (7 levels), C5/6 (26 levels) and C6/7 (6 level). The mJOA score of the 25 patients with myelopathy was 11.8 at the baseline and 15.9 at the final follow-up. No patient suffered from adjacent segment disease. Two patients received revision surgeries at the index level for recurrent radiculopathy caused by osteophyte formation and heterotopic ossification. On x-ray examination, the range of motion at the operated level was 7.8 degree at the baseline and 4.7 degree at the final follow-up. Heterotopic ossification was observed in 29 (69.0%) levels and heterotopic ossification of Grade 4 was observed in 14 levels. Adjacent segment degeneration was observed in 30 (47.6%) levels. CONCLUSION: Cervical arthroplasty using Bryan cervical disc prosthesis resulted in fine clinical outcomes in this study. Heterotopic ossification was common after Bryan disc arthroplasty, which decreased the range of motion. LEVEL OF EVIDENCE: 4. PMID- 26751059 TI - Are S1 Screws a Useful Adjunct to Iliac Screws in Long Fusions to the Sacrum in Cerebral Palsy? AB - STUDY DESIGN: Multicenter prospective database review of patients with cerebral palsy (CP) and spinal deformity. OBJECTIVE: To determine if the type of distal fixation is associated with improved correction of coronal deformity or pelvic obliquity (PO) at 2 years in long posterior fusions to the sacrum. SUMMARY OF BACKGROUND DATA: Multiple techniques are utilized for distal fixation in patients with CP. Although there is emerging evidence that the augmentation of iliac screws with S1 screws may be beneficial, this remains controversial. METHODS: A prospective, multicenter database was used to identify patients with CP who underwent long posterior fusions to the sacrum. Eighty-eight patients were included, 52 with iliac screws (I) and 36 with iliac and S1 screws (IS) for distal fixation. Preoperative, first erect, and 2-year follow-up radiographs and complications were analyzed. Statistical analysis was performed using ANOVA and repeated measures ANOVA with significance set at P < 0.05. RESULTS: Scoliosis was the primary deformity in greater than 90% of patients in both groups (P=0.84). Preoperative coronal deformity was similar (I = 83 degrees , IS = 87 degrees , P = 0.49), but correction was better with the use of S1 screws on the first erect radiograph and at 2 years (I = 35 degrees , IS = 22 degrees , P = 0.001), reflecting correction of 58% and 74% for iliac and iliac-S1 screws, respectively (P < 0.001). Preoperative PO was similar (I = 29 degrees , IS = 30 degrees , P = 0.71) and was noted to improve more in the iliac-S1 group by 2 years (I = 11 degrees , IS = 5 degrees , P = 0.004), representing correction of 60% and 77% for the iliac and iliac-S1 groups, respectively (P = 0.018). There was no difference in the rate of major (P = 0.27) or minor (P = 0.65) complications in either group. CONCLUSION: Bilateral S1 and iliac screws are associated with improved spinal deformity and PO correction at 2 years in the CP population. Two points of distal fixation, S1, and ilium should be considered for this population. LEVEL OF EVIDENCE: 3. PMID- 26751060 TI - Mechanism of Action of Spinal Mobilizations: A Systematic Review. AB - STUDY DESIGN: Systematic review. OBJECTIVE: To review the evidence regarding the mechanism of action of mobilizations. SUMMARY OF BACKGROUND DATA: Spinal mobilizations-low velocity passive oscillatory movements-reduce spinal pain in some patient subgroups. Identifying patients likely to respond remains a challenge since mobilizations' mechanism(s) of action are unclear. METHODS: Medline, Web of Science, Cinahl, Embase, and Scopus databases were searched for relevant studies. Reference lists of included studies were hand searched. Studies were included if the intervention was passive spinal mobilizations, participants were symptomatic, and outcomes evaluated possible mechanisms of action. Methodological quality was independently assessed by two assessors using a modified Cochrane Back Review Group tool. RESULTS: Twenty-four studies were included in the review. Four were classified high risk, 14 moderate risk, and four low risk of bias. Commonest methodological limitations were lack of participant blinding, adequate randomization and allocation concealment, and sample size calculation. Evidence suggests that spinal mobilizations cause neurophysiological effects resulting in hypoalgesia (local and/or distal to mobilization site), sympathoexcitation, and improved muscle function. Mobilizations have no effect on temperature pain threshold. Three of four studies reported reduction in spinal stiffness, heterogeneous in location and timing. There is limited evidence (one study in each case) to suggest that mobilizations produce increased nociceptive flexion reflex threshold, improved posture, decreased concentration of substance P in saliva, and improved sway index measured in cervical extension. Evidence does not support an effect on segmental vertebral movement. Two studies investigated correlations between hypoalgesia and mechanism: one found a correlation with sympathoexcitatory changes, whereas the other found no correlation with change in stiffness. CONCLUSION: These findings suggest involvement of an endogenous pain inhibition system mediated by the central nervous system, although this is yet to be investigated directly. There is limited evidence regarding other possible mechanisms. LEVEL OF EVIDENCE: 3. PMID- 26751062 TI - Letter. PMID- 26751061 TI - Complications and Rates of Subsequent Lumbar Surgery Following Lumbar Total Disc Arthroplasty and Lumbar Fusion. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE: To examine complications and rates of subsequent surgery following lumbar spinal fusion (LF) and lumbar total disc arthroplasty (TDA) at up to 5-year follow-up. SUMMARY OF BACKGROUND DATA: LF is commonly used in the management of degenerative disc disease causing pain refractory to nonoperative management. Lumbar TDA was developed as an alternative to fusion with the theoretical advantage of reducing rates of adjacent segment pathology and reoperation. Most prior reports comparing these 2 interventions have come from industry-sponsored investigational device exemption trials and no large-scale administrative database comparisons exist. METHODS: The California Office of Statewide Health Planning and Development discharge database was queried for patients aged 18 to 65 years undergoing lumbar TDA and LF for degenerative disc disease from 2004 to 2010. Patient characteristics were collected, and rates of complications and readmission were identified. Rates of repeat lumbar surgery were calculated at 90-day and 1-, 3-, and 5-year follow-up intervals. RESULTS: A total of 52,877 patients met the inclusion criteria (LF = 50,462, TDA = 2415). Wound infections were more common following LF than TDA (1.03% vs. 0.25%, P < 0.001). Rates of subsequent lumbar surgery at 90-day and 1 year follow-up were lower with lumbar TDA than LF (90-day-TDA: 2.94% vs. LF: 4.01%, P = 0.007; 1-yr-TDA: 3.46% vs. LF: 4.78%, P = 0.009). However, there were no differences in rates of subsequent lumbar surgery between the 2 groups at 3 year and 5-year follow-up. CONCLUSION: Lumbar TDA was associated with fewer early reoperations, though beyond 1 year, rates of reoperation were similar. Lumbar TDA may be associated with fewer acute infections, though this may be approach related and unrelated to the device itself. LEVEL OF EVIDENCE: 3. PMID- 26751064 TI - Ecological Assessment of Two Species of Potamonautid Freshwater Crabs from the Eastern Highlands of Zimbabwe, with Implications for Their Conservation. AB - The spatial ecology of freshwater crabs and their conservation status is largely understudied in Africa. An ecological assessment was conducted at 104 localities in 51 rivers and/or streams in the Eastern Highlands of Zimbabwe whereby the distribution and abundances of freshwater crab species were mapped and the possible drivers of the observed trends in population structure explored. In addition, information on crab utilisation as a food resource by local communities was assessed via face to face interviews across the region. Finally, the conservation status of each species was assessed using the IUCN Red List criteria. Only two crab species Potamonautes mutareensis and Potamonautes unispinus were recorded within the region of study. Potamonautes mutareensis was largely restricted to less impacted environments in the high mountainous river system, whereas P. unispinus was found in low laying areas. In stretches of river where both species were found to co-occur, the species were never sampled from the same site, with P. mutareensis occurring in shallower, faster flowing environments and P. unispinus in deeper, slow flowing sites. Interview results revealed that the local communities, particularly in the southern part of the Eastern Highlands around the Chipinge area, had a considerable level of utilisation (55% of households) on the harvesting of crabs for household consumption during the non-agricultural season (May to September). Results from the IUCN Red List assessment indicate that both species should be considered as "Least Concern". Threats to freshwater crabs in the Eastern Highlands, however, include widespread anthropogenic impacts such as habitat destruction associated with gold and diamond mining, inorganic and organic pollution and possibly exploitation for human consumption. The current study provides important information and insight towards the possible development of a freshwater crab conservation action plan within the region. PMID- 26751065 TI - Serum Trimethylamine-N-Oxide Is Strongly Related to Renal Function and Predicts Outcome in Chronic Kidney Disease. AB - BACKGROUND: The microbial metabolite Trimethylamine-N-oxide (TMAO) has been linked to adverse cardiovascular outcome and mortality in the general population. OBJECTIVE: To assess the contribution of TMAO to inflammation and mortality in chronic kidney disease (CKD) patients ranging from mild-moderate to end-stage disease and 1) associations with glomerular filtration rate (GFR) 2) effect of dialysis and renal transplantation (Rtx) 3) association with inflammatory biomarkers and 4) its predictive value for all-cause mortality. METHODS: Levels of metabolites were quantified by a novel liquid chromatography/tandem mass spectrometry-based method in fasting plasma samples from 80 controls and 179 CKD 3-5 patients. Comorbidities, nutritional status, biomarkers of inflammation and GFR were assessed. RESULTS: GFR was the dominant variable affecting TMAO (beta = 0.41; p<0.001), choline (beta = -0.38; p<0.001), and betaine (beta = 0.45; p<0.001) levels. A longitudinal study of 74 CKD 5 patients starting renal replacement therapy demonstrated that whereas dialysis treatment did not affect TMAO, Rtx reduced levels of TMAO to that of controls (p<0.001). Following Rtx choline and betaine levels continued to increase. In CKD 3-5, TMAO levels were associated with IL-6 (Rho = 0.42; p<0.0001), fibrinogen (Rho = 0.43; p<0.0001) and hsCRP (Rho = 0.17; p = 0.022). Higher TMAO levels were associated with an increased risk for all-cause mortality that remained significant after multivariate adjustment (HR 4.32, 95% CI 1.32-14.2; p = 0.016). CONCLUSION: Elevated TMAO levels are strongly associated with degree of renal function in CKD and normalize after renal transplantation. TMAO levels correlates with increased systemic inflammation and is an independent predictor of mortality in CKD 3-5 patients. PMID- 26751067 TI - Correction: Methylation Profiles Reveal Distinct Subgroup of Hepatocellular Carcinoma Patients with Poor Prognosis. PMID- 26751066 TI - Gender-Specific Differences in Low-Dose Haloperidol Response for Prevention of Postoperative Nausea and Vomiting: A Register-Based Cohort Study. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is one of the most common and distressing complications after general anesthesia and surgery, with young non-smoking females receiving postoperative opioids being high-risk patients. This register-based study aims to evaluate the effect of low-dose haloperidol (0.5 mg intravenously) directly after induction of general anesthesia to reduce the incidence of PONV in the postoperative anesthesiological care unit (PACU). METHODS: Multivariable regression models were used to investigate the association between low-dose haloperidol and the occurrence of PONV using a patient registry containing 2,617 surgical procedures carried out at an university hospital. RESULTS: Haloperidol 0.5 mg is associated with a reduced risk of PONV in the total collective (adjusted odds ratio = 0.75, 95% confidence interval: [0.56, 0.99], p = 0.05). The results indicate that there is a reduced risk in male patients (adjusted odds ratio = 0.45, 95% confidence interval: [0.28, 0.73], p = 0.001) if a dose of 0.5 mg haloperidol was administered while there seems to be no effect in females (adjusted odds ratio = 1.02, 95% confidence interval: [0.71, 1.46], p = 0.93). Currently known risk factors for PONV such as female gender, duration of anesthesia and the use of opioids were confirmed in our analysis. CONCLUSION: This study suggests that low-dose haloperidol has an antiemetic effect in male patients but has no effect in female patients. A confirmation of the gender-specific effects we have observed in this register-based cohort study might have major implications on clinical daily routine. PMID- 26751068 TI - The Ratio of Docosahexaenoic Acid and Arachidonic Acid in Infant Formula Influences the Fatty Acid Composition of the Erythrocyte Membrane in Low-Birth Weight Infants. AB - OBJECTIVE: The arachidonic acid (ARA) and docosahexaenoic acid (DHA) contents in the infant formula influence on the growth and development of low-birth-weight infants (LBWI). In Japan, many infant formulas are fortified only with DHA. We investigated the safety and efficacy of an infant formula (H2025A) fortified with DHA and ARA (DHA/ARA ratio of 2:1, the same as that in Japanese breast milk). METHODS: In this randomized double-blind trial, 35 LBWI were randomly allocated to 2 groups fed with H2025A or an infant formula fortified only with DHA (control formula) after discharge from the NICU. The duration of this study was one month, and the growth and fatty acid composition of the erythrocyte membrane were compared between the 2 groups. RESULTS: No difference was found in the body weight gain, height gain and head circumstance gain development between the 2 groups, and no adverse event occurred in both groups. The ARA content of the erythrocyte membrane after feeding for 1 month was significantly higher in the H2025A group than in the control group. On analysis adjusted with the breast-fed ratio, the ARA and DHA contents were significantly higher in the H2025A group. CONCLUSION: It was suggested that H2025A significantly increased the ARA and DHA contents of the erythrocyte membrane of LBWI compared to the contents of the control formula. PMID- 26751069 TI - Wuho Is a New Member in Maintaining Genome Stability through its Interaction with Flap Endonuclease 1. AB - Replication forks are vulnerable to wayward nuclease activities. We report here our discovery of a new member in guarding genome stability at replication forks. We previously isolated a Drosophila mutation, wuho (wh, no progeny), characterized by a severe fertility defect and affecting expression of a protein (WH) in a family of conserved proteins with multiple WD40 repeats. Knockdown of WH by siRNA in Drosophila, mouse, and human cultured cells results in DNA damage with strand breaks and apoptosis through ATM/Chk2/p53 signaling pathway. Mice with mWh knockout are early embryonic lethal and display DNA damage. We identify that the flap endonuclease 1 (FEN1) is one of the interacting proteins. Fluorescence microscopy showed the localization of WH at the site of nascent DNA synthesis along with other replication proteins, including FEN1 and PCNA. We show that WH is able to modulate FEN1's endonucleolytic activities depending on the substrate DNA structure. The stimulatory or inhibitory effects of WH on FEN1's flap versus gap endonuclease activities are consistent with the proposed WH's functions in protecting the integrity of replication fork. These results suggest that wh is a new member of the guardians of genome stability because it regulates FEN1's potential DNA cleavage threat near the site of replication. PMID- 26751070 TI - Association between Carotid Artery Stenosis and Cognitive Impairment in Stroke Patients: A Cross-Sectional Study. AB - To investigate potential associations between carotid artery stenosis and cognitive impairment among patients with acute ischemic stroke and to provide important clinical implications. We measured the degree of carotid artery stenosis and recorded the Mini-Mental State Examination score (MMSE) at admission in 3116 acute ischemic stroke patients. The association between carotid stenosis and cognitive impairment assessed by MMSE was tested using multivariate regression analysis. Other clinical variables of interest were also studied. After adjusting for age, gender, education level, marriage, alcohol use, tobacco use, physical activity, hypertension, diabetes, hypercholesterolemia, atrial fibrillation, myocardial infarction and NIHSS (National Institutes of Health Stroke Scale) score, we found that participants with high-grade stenosis of the carotid artery had a higher likelihood of cognitive impairment compared to those without carotid artery stenosis (OR = 1.49, 95%CI: 1.05-2.11, p<0.001). Left common carotid artery stenosis was associated with cognitive impairment in the univariate analysis, although this effect did not persist after adjustment for the NIHSS score. Cognitive impairment was associated with high-grade stenosis of the right carotid artery. PMID- 26751071 TI - Mycobacterial Metabolic Syndrome: LprG and Rv1410 Regulate Triacylglyceride Levels, Growth Rate and Virulence in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (Mtb) mutants lacking rv1411c, which encodes the lipoprotein LprG, and rv1410c, which encodes a putative efflux pump, are dramatically attenuated for growth in mice. Here we show that loss of LprG-Rv1410 in Mtb leads to intracellular triacylglyceride (TAG) accumulation, and overexpression of the locus increases the levels of TAG in the culture medium, demonstrating a role of this locus in TAG transport. LprG binds TAG within a large hydrophobic cleft and is sufficient to transfer TAG from donor to acceptor membranes. Further, LprG-Rv1410 is critical for broadly regulating bacterial growth and metabolism in vitro during carbon restriction and in vivo during infection of mice. The growth defect in mice is due to disrupted bacterial metabolism and occurs independently of key immune regulators. The in vivo essentiality of this locus suggests that this export system and other regulators of metabolism should be considered as targets for novel therapeutics. PMID- 26751072 TI - Targeting of Proteoglycan Synthesis Pathway: A New Strategy to Counteract Excessive Matrix Proteoglycan Deposition and Transforming Growth Factor-beta1 Induced Fibrotic Phenotype in Lung Fibroblasts. AB - Stimulation of proteoglycan (PG) synthesis and deposition plays an important role in the pathophysiology of fibrosis and is an early and dominant feature of pulmonary fibrosis. Transforming growth factor-beta1 (TGF-beta1) is a major cytokine associated with fibrosis that induces excessive synthesis of matrix proteins, particularly PGs. Owing to the importance of PGs in matrix assembly and in mediating cytokine and growth factor signaling, a strategy based on the inhibition of PG synthesis may prevent excessive matrix PG deposition and attenuates profibrotic effects of TGF-beta1 in lung fibroblasts. Here, we showed that 4-MU4-deoxy-beta-D-xylopyranoside, a competitive inhibitor of beta4 galactosyltransferase7, inhibited PG synthesis and secretion in a dose-dependent manner by decreasing the level of both chondroitin/dermatan- and heparin-sulfate PG in primary lung fibroblasts. Importantly, 4-MU4-deoxy-xyloside was able to counteract TGF-beta1-induced synthesis of PGs, activation of fibroblast proliferation and fibroblast-myofibroblast differentiation. Mechanistically, 4 MU4-deoxy-xyloside treatment inhibited TGF-beta1-induced activation of canonical Smads2/3 signaling pathway in lung primary fibroblasts. The knockdown of beta4 galactosyltransferase7 mimicked 4-MU4-deoxy-xyloside effects, indicating selective inhibition of beta4-galactosyltransferase7 by this compound. Collectively, this study reveals the anti-fibrotic activity of 4-MU4-deoxy xyloside and indicates that inhibition of PG synthesis represents a novel strategy for the treatment of lung fibrosis. PMID- 26751074 TI - Patient Characteristics and Comorbidities Influence Walking Distances in Symptomatic Peripheral Arterial Disease: A Large One-Year Physiotherapy Cohort Study. AB - OBJECTIVES: The aim of this study is to investigate the association between age, gender, body-mass index, smoking behavior, orthopedic comorbidity, neurologic comorbidity, cardiac comorbidity, vascular comorbidity, pulmonic comorbidity, internal comorbidity and Initial Claudication Distance during and after Supervised Exercise Therapy at 1, 3, 6 and 12 months in a large sample of patients with Intermittent Claudication. METHODS: Data was prospectively collected in standard physiotherapy care. Patients received Supervised Exercise Therapy according to the guideline Intermittent Claudication of the Royal Dutch Society for Physiotherapy. Three-level mixed linear regression analysis was carried out to analyze the association between patient characteristics, comorbidities and Initial Claudication Distance at 1, 3, 6 and 12 months. RESULTS: Data from 2995 patients was analyzed. Results showed that being female, advanced age and a high body-mass index were associated with lower Initial Claudication Distance at all-time points (p = 0.000). Besides, a negative association between cardiac comorbidity and Initial Claudication Distance was revealed (p = 0.011). The interaction time by age, time by body-mass index and time by vascular comorbidity were significantly associated with Initial Claudication Distance (p<= 0.05). Per year increase in age (range: 33-93 years), the reduction in Initial Claudication Distance was 8m after 12 months of Supervised Exercise Therapy. One unit increase in body-mass index (range: 16-44 kg/m2) led to 10 m less improvement in Initial Claudication Distance after 12 months and for vascular comorbidity the reduction in improvement was 85 m after 12 months. CONCLUSIONS: This study reveals that females, patients at advanced age, patients with a high body-mass index and cardiac comorbidity are more likely to show less improvement in Initial Claudication Distances (ICD) after 1, 3, 6 and 12 months of Supervised Exercise Therapy. Further research should elucidate treatment adaptations that optimize treatment outcomes for these subgroups. PMID- 26751073 TI - Decreased Interleukin-10 Responses in Children with Severe Mycoplasma pneumoniae Pneumonia. AB - Several cytokines may play roles in the immunological pathogenesis of mycoplasmal pneumonia caused by Mycoplasma pneumoniae. In this study, we investigated serum cytokine profiles in children with mycoplasmal pneumonia. The serum levels of interleukin (IL)-8, IL-10, and IL-18 were examined using ELISA kits in 34 patients with M. pneumoniae infection (Group 1, 11 with severe mycoplasmal pneumonia; Group 2, 13 with mild mycoplasmal pneumonia; Group 3, 10 with asthma) and 32 age-matched, non-infected controls. The serum levels of IL-8, IL-10, and IL-18 increased significantly in patients with mycoplasmal pneumonia compared with those in controls (P<0.01). The serum levels of IL-10 decreased significantly in Group 1 compared with those in Group 2 (P<0.01). The serum levels of IL-18 increased significantly in Group 1 compared with those in Group 2 (P<0.01). The serum levels of IL-10 and IL-18 decreased significantly in 10 M. pneumoniae-infected patients with asthma compared with those in 24 M. pneumoniae infected patients without asthma (P<0.01). We examined the level of interleukins (IL-8, IL-10 and IL-18) after the patients started therapy. The data showed that IL-18 were lower after therapy (P<0.01). Collectively, our data suggested that these cytokines may be involved in the pathogenesis of mycoplasmal pneumonia. PMID- 26751075 TI - Clinical and Virological Characteristics of Chronic Hepatitis B Patients with Coexistence of HBsAg and Anti-HBs. AB - Coexistence of hepatitis B surface antigen (HBsAg) and antibody against HBsAg (anti-HBs) comprises an atypical serological profile in patients with chronic hepatitis B virus (HBV) infection. In this study, in total 94 patients with coexisting HBsAg and anti-HBs and 94 age- and sex-matched patients with positive HBsAg were characterized by quantitatively measuring HBsAg and HBV DNA, sequencing large S genes, and observing clinical features. Compared with common hepatitis B patients, the patients with coexisting HBsAg and anti-HBs had lower HBsAg and HBV DNA levels. These two groups had similar rate of pre-S deletion mutations. However, in patients with coexisting HBsAg and anti-HBs, more amino acid substitutions in the a determinant of S gene were observed in HBV genotype C, but not in genotype B. Fourteen patients with coexisting HBsAg and anti-HBs were followed up for an average of 15.5 months. There were no significant changes in the levels of HBsAg, anti-HBs, HBV DNA and ALT over the follow-up period. Compared with the baseline sequences, amino acid substitutions in the MHR of HBsAg occurred in 14.3% (2/14) patients. In conclusion, coexistence of HBsAg and anti-HBs may be associated with higher frequency of mutations in the a determinant of HBV genotype C. PMID- 26751076 TI - The Mechanisms of Water Exchange: The Regulatory Roles of Multiple Interactions in Social Wasps. AB - Evolutionary benefits of task fidelity and improving information acquisition via multiple transfers of materials between individuals in a task partitioned system have been shown before, but in this paper we provide a mechanistic explanation of these phenomena. Using a simple mathematical model describing the individual interactions of the wasps, we explain the functioning of the common stomach, an information center, which governs construction behavior and task change. Our central hypothesis is a symmetry between foragers who deposit water and foragers who withdraw water into and out of the common stomach. We combine this with a trade-off between acceptance and resistance to water transfer. We ultimately derive a mathematical function that relates the number of interactions that foragers complete with common stomach wasps during a foraging cycle. We use field data and additional model assumptions to calculate values of our model parameters, and we use these to explain why the fullness of the common stomach stabilizes just below 50 percent, why the average number of successful interactions between foragers and the wasps forming the common stomach is between 5 and 7, and why there is a variation in this number of interactions over time. Our explanation is that our proposed water exchange mechanism places natural bounds on the number of successful interactions possible, water exchange is set to optimize mediation of water through the common stomach, and the chance that foragers abort their task prematurely is very low. PMID- 26751077 TI - A Spectroscopic Approach to Investigate the Molecular Interactions between the Newly Approved Irreversible ErbB blocker "Afatinib" and Bovine Serum Albumin. AB - The interaction of afatinib (AFB) with bovine serum albumin (BSA) was examined via fluorescence and UV-Vis spectroscopy. Spectrofluorimetric measurements revealed that AFB can strongly quench the BSA intrinsic fluorescence through producing a non-fluorescent complex. This quenching mechanism was thoroughly investigated with regard to the type of quenching, binding constant, number of binding locations and the fundamental thermodynamic parameters. Subsequently, the association constant of AFB with BSA was computed at three different temperatures and was found to range from 7.34 to 13.19 x10(5) L mol(-1). Thermodynamic parameters calculations demonstrated a positive DeltaSO value with both negative DeltaHTheta and DeltaGTheta values for AFB-BSA complex, which in turn infers that a spontaneous binding is taking place with both electrostatic bonding and hydrophobic interactions participating in the binding of AFB and BSA. Similarly, the UV absorption spectra of AFB-BSA system were studied and confirmed the interaction. Conformational alteration of the protein upon binding to AFB was elaborated with the aid of three dimensional fluorescence measurements as well as synchronous fluorescence spectra. PMID- 26751082 TI - Cluttered environments: Differential effects of obstacle position on grasp and gaze locations. AB - Previous research has investigated the effects of nontarget objects (NTOs) on reach trajectories, but their effects on eye-hand coordination remain to be determined. The current investigation utilized an eye-hand coordination paradigm, where a reaching and grasping task was performed in the presence of an NTO positioned exclusively in the right or left workspace of each right-handed participant. NTOs varied in their closeness to the subject and reach-path, between the starting location of the hand and the target-object of the reach. A control condition, where only the target was present, was also included. When an NTO was presented on the right (ipsilateral to the reaching hand), it pushed the final grasp and gaze locations on the target, shifting them to the left-away from the "obstacle." The impact of the ipsilateral NTO was increased as it was moved into positions closer to the participant that were of greater obstruction to the hand and arm. In contrast, when the NTO was contralateral, the risk of collision was low and participants developed a set reach plan that was repeated nearly identically for each contralateral NTO position. Our findings also indicate that the "invasiveness" of the NTO positions had a greater effect on grasp than it did on gaze position-demonstrating how the arrangement of clutter in an environment can differentially affect gaze and grasp when reaching for an object. (PsycINFO Database Record PMID- 26751080 TI - Up-Regulation of Human Inducible Nitric Oxide Synthase by p300 Transcriptional Complex. AB - p300, a ubiquitous transcription coactivator, plays an important role in gene activation. Our previous work demonstrated that human inducible nitric oxide synthase (hiNOS) expression can be highly induced with the cytokine mixture (CM) of TNF-alpha + IL-1beta + IFN-gamma. In this study, we investigated the functional role of p300 in the regulation of hiNOS gene expression. Our initial data showed that overexpression of p300 significantly increased the basal and cytokine-induced hiNOS promoter activities in A549 cells. Interestingly, p300 activated cytokine-induced hiNOS transcriptional activity was completely abrogated by deleting the upstream hiNOS enhancer at -5 kb to -6 kb in the promoter. Furthermore, p300 over-expression increased cytokine-induced transcriptional activity on a heterologous minimal TK promoter with the same hiNOS enhancer. Site-directed mutagenesis of the hiNOS AP-1 motifs revealed that an intact upstream (-5.3 kb) AP-1 binding site was critical for p300 mediated cytokine-induced hiNOS transcription. Furthermore, our ChIP analysis demonstrated that p300 was binding to Jun D and Fra-2 proteins at -5.3 kb AP-1 binding site in vivo. Lastly, our 3C assay was able to detect a long DNA loop between the hiNOS enhancer and core promoter site, and ChIP loop assay confirmed that p300 binds to AP-1 and RNA pol II proteins. Overall, our results suggest that coactivator p300 mediates cytokine-induced hiNOS transactivation by forming a distant DNA loop between its enhancer and core promoter region. PMID- 26751081 TI - Inhibitory Activity of (+)-Usnic Acid against Non-Small Cell Lung Cancer Cell Motility. AB - Lichens are symbiotic organisms that produce various unique chemicals that can be used for pharmaceutical purposes. With the aim of screening new anti-cancer agents that inhibit cancer cell motility, we tested the inhibitory activity of seven lichen species collected from the Romanian Carpathian Mountains against migration and invasion of human lung cancer cells and further investigated the molecular mechanisms underlying their anti-metastatic activity. Among them, Alectoria samentosa, Flavocetraria nivalis, Alectoria ochroleuca, and Usnea florida showed significant inhibitory activity against motility of human lung cancer cells. HPLC results showed that usnic acid is the main compound in these lichens, and (+)-usnic acid showed similar inhibitory activity that crude extract have. Mechanistically, beta-catenin-mediated TOPFLASH activity and KITENIN mediated AP-1 activity were decreased by (+)-usnic acid treatment in a dose dependent manner. The quantitative real-time PCR data showed that (+)-usnic acid decreased the mRNA level of CD44, Cyclin D1 and c-myc, which are the downstream target genes of both beta-catenin/LEF and c-jun/AP-1. Also, Rac1 and RhoA activities were decreased by treatment with (+)-usnic acid. Interestingly, higher inhibitory activity for cell invasion was observed when cells were treated with (+)-usnic acid and cetuximab. These results implied that (+)-usnic acid might have potential activity in inhibition of cancer cell metastasis, and (+)-usnic acid could be used for anti-cancer therapy with a distinct mechanisms of action. PMID- 26751079 TI - Iron and Oxidative Stress in Parkinson's Disease: An Observational Study of Injury Biomarkers. AB - Parkinson's disease (PD) is characterized by progressive motor impairment attributed to progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta. In addition to an accumulation of iron, there is also an increased production of reactive oxygen/nitrogen species (ROS/RNS) and inflammatory markers. These observations suggest that iron dyshomeostasis may be playing a key role in neurodegeneration. However, the mechanisms underlying this metal-associated oxidative stress and neuronal damage have not been fully elucidated. To determine peripheral levels of iron, ferritin, and transferrin in PD patients and its possible relation with oxidative/nitrosative parameters, whilst attempting to identify a profile of peripheral biomarkers in this neurological condition. Forty PD patients and 46 controls were recruited to compare serum levels of iron, ferritin, transferrin, oxidative stress markers (superoxide dismutase (SOD), catalase (CAT), nitrosative stress marker (NOx), thiobarbituric acid reactive substances (TBARS), non-protein thiols (NPSH), advanced oxidation protein products (AOPP), ferric reducing ability of plasma (FRAP) and vitamin C) as well as inflammatory markers (NTPDases, ecto-5' nucleotidase, adenosine deaminase (ADA), ischemic-modified albumin (IMA) and myeloperoxidase). Iron levels were lower in PD patients, whereas there was no difference in ferritin and transferrin. Oxidative stress (TBARS and AOPP) and inflammatory markers (NTPDases, IMA, and myeloperoxidase) were significantly higher in PD, while antioxidants FRAP, vitamin C, and non-protein thiols were significantly lower in PD. The enzymes SOD, CAT, and ecto-5'-nucleotidase were not different among the groups, although NOx and ADA levels were significantly higher in the controls. Our data corroborate the idea that ROS/RNS production and neuroinflammation may dysregulate iron homeostasis and collaborate to reduce the periphery levels of this ion, contributing to alterations observed in the pathophysiology of PD. PMID- 26751083 TI - Deciphering How Pore Formation Causes Strain-Induced Membrane Lysis of Lipid Vesicles. AB - Pore formation by membrane-active antimicrobial peptides is a classic strategy of pathogen inactivation through disruption of membrane biochemical gradients. It remains unknown why some membrane-active peptides also inhibit enveloped viruses, which do not depend on biochemical gradients. Here, we employ a label-free biosensing approach based on simultaneous quartz crystal microbalance-dissipation and ellipsometry measurements in order to investigate how a pore-forming, virucidal peptide destabilizes lipid vesicles in a surface-based experimental configuration. A key advantage of the approach is that it enables direct kinetic measurement of the surface-bound peptide-to-lipid (P:L) ratio. Comprehensive experiments involving different bulk peptide concentrations and biologically relevant membrane compositions support a unified model that membrane lysis occurs at or above a critical P:L ratio, which is at least several-fold greater than the value corresponding to the onset of pore formation. That is consistent with peptide-induced pores causing additional membrane strain that leads to lysis of highly curved membranes. Collectively, the work presents a new model that describes how peptide-induced pores may destabilize lipid membranes through a membrane strain-related lytic process, and this knowledge has important implications for the design and application of membrane-active peptides. PMID- 26751078 TI - Ixodes scapularis Tick Saliva Proteins Sequentially Secreted Every 24 h during Blood Feeding. AB - Ixodes scapularis is the most medically important tick species and transmits five of the 14 reportable human tick borne disease (TBD) agents in the USA. This study describes LC-MS/MS identification of 582 tick- and 83 rabbit proteins in saliva of I. scapularis ticks that fed for 24, 48, 72, 96, and 120 h, as well as engorged but not detached (BD), and spontaneously detached (SD). The 582 tick proteins include proteases (5.7%), protease inhibitors (7.4%), unknown function proteins (22%), immunity/antimicrobial (2.6%), lipocalin (3.1%), heme/iron binding (2.6%), extracellular matrix/ cell adhesion (2.2%), oxidant metabolism/ detoxification (6%), transporter/ receptor related (3.2%), cytoskeletal (5.5%), and housekeeping-like (39.7%). Notable observations include: (i) tick saliva proteins of unknown function accounting for >33% of total protein content, (ii) 79% of proteases are metalloproteases, (iii) 13% (76/582) of proteins in this study were found in saliva of other tick species and, (iv) ticks apparently selectively inject functionally similar but unique proteins every 24 h, which we speculate is the tick's antigenic variation equivalent strategy to protect important tick feeding functions from host immune system. The host immune responses to proteins present in 24 h I. scapularis saliva will not be effective at later feeding stages. Rabbit proteins identified in our study suggest the tick's strategic use of host proteins to modulate the feeding site. Notably fibrinogen, which is central to blood clotting and wound healing, was detected in high abundance in BD and SD saliva, when the tick is preparing to terminate feeding and detach from the host. A remarkable tick adaptation is that the feeding lesion is completely healed when the tick detaches from the host. Does the tick concentrate fibrinogen at the feeding site to aide in promoting healing of the feeding lesion? Overall, these data provide broad insight into molecular mechanisms regulating different tick feeding phases. These data set the foundation for in depth I. scapularis tick feeding physiology and TBD transmission studies. PMID- 26751086 TI - Perceived barriers to seeking mental health care among United States Marine Corps noncommissioned officers serving as gatekeepers for suicide prevention. AB - Reducing mental health stigma and perceived barriers to care is a necessary strategy for addressing the public health problem of suicide among the United States Armed Forces. The purpose of this study was threefold: (a) to empirically evaluate the principal component structure of the Perceived Barriers to Care (PBTC) measure; (b) to gain an understanding of the perceived barriers to seeking mental health services among Marine Corps noncommissioned officers (NCOs) selected to participate in a primary suicide prevention training program, Never Leave a Marine Behind (NLMB); and (c) to explore the relationship among sex, education, prior exposure to suicide within one's military unit, and perceived barriers to seeking mental health services. The data for the PBTC (N = 1,758) were drawn from a previously performed pretest/posttest program evaluation study of the Marine Corp's NLMB program, which took place over 6 months in 2009 (April October). The three highest perceptions of barriers to care reported by NCOs for their Marines were related to being embarrassed, having members of one's unit have less confidence in the Marine, and concerns about being treated differently by military unit leadership. Three principal components for PBTC were identified, accounting for approximately 59% of the total variance. Higher education and prior exposure to suicide within one's military unit significantly correlated with greater perceived barriers to care; sex was not significantly correlated with greater perceived barriers to care. Implications of these findings, in relation to future research, are further discussed. (PsycINFO Database Record PMID- 26751085 TI - The impact of failing to identify suspect effort in patients undergoing adult attention-deficit/hyperactivity disorder (ADHD) assessment. AB - [Correction Notice: An Erratum for this article was reported in Vol 28(10) of Psychological Assessment (see record 2016-22725-001). In the article, the penultimate sentence of the abstract should read "These results suggest that a significant percentage of those making a suspect effort will be diagnosed with ADHD using the most commonly employed assessment methods: an interview alone (71%); an interview and ADHD behavior rating scales combined (65%); and an interview, behavior rating scales, and most continuous performance tests combined (62%)." All versions of this article have been corrected.] This retrospective study examines how many adult patients would plausibly receive a diagnosis of attention-deficit/hyperactivity disorder (ADHD) if performance and symptom validity measures were not administered during neuropsychological evaluations. Five hundred fifty-four patients were extracted from an archival clinical dataset. A total of 102 were diagnosed with ADHD based on cognitive testing, behavior rating scales, effort testing, and clinical interview; 115 were identified as putting forth suspect effort in accordance with the Slick, Sherman, and Iverson (1999) criteria. From a clinical decision-making perspective, suspect effort and ADHD groups were nearly indistinguishable on ADHD behavior, executive function, and functional impairment rating scales, as well as on cognitive testing and key clinical interview questions. These results suggest that a significant percentage of those making a suspect effort will be diagnosed with ADHD using the most commonly employed assessment methods: an interview alone (71%); an interview and ADHD behavior rating scales combined (65%); and an interview, behavior rating scales, and most continuous performance tests combined (62%) [corrected]. This research makes clear that it is essential to evaluate task engagement and possible symptom amplification during clinical evaluations. PMID- 26751084 TI - Liposome-Cross-Linked Hybrid Hydrogels for Glutathione-Triggered Delivery of Multiple Cargo Molecules. AB - Novel, liposome-cross-linked hybrid hydrogels cross-linked by the Michael-type addition of thiols with maleimides were prepared via the use of maleimide functionalized liposome cross-linkers and thiolated polyethylene glycol (PEG) polymers. Gelation of the materials was confirmed by oscillatory rheology experiments. These hybrid hydrogels are rendered degradable upon exposure to thiol-containing molecules such as glutathione (GSH), via the incorporation of selected thioether succinimide cross-links between the PEG polymers and liposome nanoparticles. Dynamic light scattering (DLS) characterization confirmed that intact liposomes were released upon network degradation. Owing to the hierarchical structure of the network, multiple cargo molecules relevant for chemotherapies, namely doxorubicin (DOX) and cytochrome c, were encapsulated and simultaneously released from the hybrid hydrogels, with differential release profiles that were driven by degradation-mediated release and Fickian diffusion, respectively. This work introduces a facile approach for the development of advanced, hybrid drug delivery vehicles that exhibit novel chemical degradation. PMID- 26751087 TI - Psychometric analysis of the PTSD Checklist-5 (PCL-5) among treatment-seeking military service members. AB - The Posttraumatic Stress Disorder Checklist (PCL-5; Weathers et al., 2013) was recently revised to reflect the changed diagnostic criteria for posttraumatic stress disorder (PTSD) in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric Association, 2013). We investigated the psychometric properties of PCL-5 scores in a large cohort (N = 912) of military service members seeking PTSD treatment while stationed in garrison. We examined the internal consistency, convergent and discriminant validity, and DSM-5 factor structure of PCL-5 scores, their sensitivity to clinical change relative to PTSD Symptom Scale-Interview (PSS-I; Foa, Riggs, Dancu, & Rothbaum, 1993) scores, and their diagnostic utility for predicting a PTSD diagnosis based on various measures and scoring rules. PCL-5 scores exhibited high internal consistency. There was strong agreement between the order of hypothesized and observed correlations among PCL-5 and criterion measure scores. The best-fitting structural model was a 7-factor hybrid model (Armour et al., 2015), which demonstrated closer fit than all other models evaluated, including the DSM-5 model. The PCL-5's sensitivity to clinical change, pre- to posttreatment, was comparable with that of the PSS-I. Optimally efficient cut scores for predicting PTSD diagnosis were consistent with prior research with service members (Hoge, Riviere, Wilk, Herrell, & Weathers, 2014). The results indicate that the PCL-5 is a psychometrically sound measure of DSM-5 PTSD symptoms that is useful for identifying provisional PTSD diagnostic status, quantifying PTSD symptom severity, and detecting clinical change over time in PTSD symptoms among service members seeking treatment. (PsycINFO Database Record PMID- 26751088 TI - The factor structure and psychometric properties of the Spanish version of the Mayer-Salovey-Caruso Emotional Intelligence Test. AB - This research examined evidence regarding the reliability and validity of scores on the Spanish version of the Mayer-Salovey-Caruso Emotional Intelligence Test, Version 2.0 (MSCEIT; Mayer, Salovey, & Caruso, 2002). In Study 1, we found a close convergence of the Spanish consensus scores and the general and expert consensus scores determined with Mayer, Salovey, Caruso, and Sitarenios (2003) data. The MSCEIT also demonstrated adequate evidence of reliability of test scores as estimated by internal consistency and test-retest correlation after 12 weeks. Confirmatory factor analysis supported a 3-level higher factor model with 8 manifest variables (task scores), 4 first-level factors (corresponding to the 4 branch model of Mayer & Salovey [1997], with 2 tasks for each branch), 2 second level factors (experiential and strategic areas, with 2 branches for each area), and 1 third-level factor (overall emotional intelligence [EI]), and multigroup analyses supported MSCEIT cross-gender invariance. Study 2 found evidence for the discriminant validity of scores on the MSCEIT subscales, which were differentially related to personality and self-reported EI. Study 3 provided evidence of the incremental validity of scores on the MSCEIT, which added significant variance to the prospective prediction of psychological well-being after controlling for personality traits. The psychometric properties of the Spanish MSCEIT are similar to those of the original English version, supporting its use for assessing emotional abilities in the Spanish population. (PsycINFO Database Record PMID- 26751091 TI - Quantum Mechanical Wave Packet Dynamics at a Conical Intersection with Strong Vibrational Dissipation. AB - We derive a reduced model for the nonadiabatic quantum dynamics of an electronic wave packet moving through a conical intersection in the presence of strong vibrational damping. Starting from the dissipative two-state two-model model, we transform the tuning and the coupling mode to the bath. The resulting quantum two state model with two highly structured environments is solved numerically exactly in the regime of strong vibrational damping. We find negative cross peaks in the ultrafast optical 2D spectra as clear signatures of the conical intersection. They arise from secondary excitations of the wave packet after having passed through the photophysical energy funnel. This feature is in agreement with recent transient absorption measurements of rhodopsin. PMID- 26751089 TI - General inattentiveness is a long-term reliable trait independently predictive of psychological health: Danish validation studies of the Mindful Attention Awareness Scale. AB - The Mindful Attention Awareness Scale (MAAS) measures perceived degree of inattentiveness in different contexts and is often used as a reversed indicator of mindfulness. MAAS is hypothesized to reflect a psychological trait or disposition when used outside attentional training contexts, but the long-term test-retest reliability of MAAS scores is virtually untested. It is unknown whether MAAS predicts psychological health after controlling for standardized socioeconomic status classifications. First, MAAS translated to Danish was validated psychometrically within a randomly invited healthy adult community sample (N = 490). Factor analysis confirmed that MAAS scores quantified a unifactorial construct of excellent composite reliability and consistent convergent validity. Structural equation modeling revealed that MAAS scores contributed independently to predicting psychological distress and mental health, after controlling for age, gender, income, socioeconomic occupational class, stressful life events, and social desirability (beta = 0.32-.42, ps < .001). Second, MAAS scores showed satisfactory short-term test-retest reliability in 100 retested healthy university students. Finally, MAAS sample mean scores as well as individuals' scores demonstrated satisfactory test-retest reliability across a 6 months interval in the adult community (retested N = 407), intraclass correlations >= .74. MAAS scores displayed significantly stronger long-term test retest reliability than scores measuring psychological distress (z = 2.78, p = .005). Test-retest reliability estimates did not differ within demographic and socioeconomic strata. Scores on the Danish MAAS were psychometrically validated in healthy adults. MAAS's inattentiveness scores reflected a unidimensional construct, long-term reliable disposition, and a factor of independent significance for predicting psychological health. (PsycINFO Database Record PMID- 26751092 TI - Clickable Periodic Mesoporous Organosilica Monolith for Highly Efficient Capillary Chromatographic Separation. AB - A novel clickable periodic mesoporous organosilica monolith with the surface area up to 1707 m(2) g(-1) was in situ synthesized in the capillary by the one-step condensation of the organobridged-bonded alkoxysilane precursor bis(triethoxysilyl)ethylene. With Si-C bonds in the skeleton, the monolith possesses excellent chemical and mechanical stability. With vinyl groups highly loaded and homogeneously distributed throughout the structure, the monolith can be readily functionalized with functional groups by effective thiol-ene "click" chemistry reaction. Herein, with "click" modification of C18, the obtained monolith was successfully applied for capillary liquid chromatographic separation of small molecules and proteins. The column efficiency could reach 148,000 N/m, higher than most reported hybrid monoliths. Moreover, intact proteins could be separated well with good reproducibility, even after the monolithic column was exposed by basic mobile phase (pH 10.0) overnight, demonstrating the great promising of such monolith for capillary chromatographic separation. PMID- 26751093 TI - Kinetics of CO2 Absorption into Aqueous Basic Amino Acid Salt: Potassium Salt of Lysine Solution. AB - Aqueous amino acid salts are considered as an attractive alternative to alkanolamine solvents (e.g., MEA) for carbon dioxide (CO2) absorption. The kinetics of CO2 into unloaded aqueous solutions of potassium lysinate (LysK) was studied using a wetted wall column at concentrations ranging from 0.25 to 2.0 M and temperatures from 298 to 333 K. Physicochemical properties of aqueous LysK solutions such as density, viscosity, and physical solubility of CO2 were measured to evaluate the reaction rate constants. The reaction pathway is described using zwitterion mechanism taking into account the effect of ionic strength on the reaction rate. Under the fast pseudo-first-order regime, the reaction rate parameters were obtained and correlated in a power-law reaction rate expression. LysK shows higher chemical reactivity toward CO2 than the industrial standard MEA and most of amino acid salts. Its reaction rate constants increase considerably with concentration and temperature. The reaction order is found to be an average value of 1.58 with respect to LysK. The forward second order kinetic rate constant, k2 0 , are obtained as 31615 and 84822 m3 kmol-1 s-1 at 298 and 313 K, respectively with activation energy of 51.0 kJ mol-1. The contribution of water to the zwitterion deprotonation seems to be more significant than that of LysK for the above-mentioned kinetic conditions PMID- 26751095 TI - Controlled Veiling of Silver Nanocubes with Graphene Oxide for Improved Surface Enhanced Raman Scattering Detection. AB - Hybrid graphene oxide (GO)/metal nanocomposites have been recently proposed as novel surface-enhanced Raman scattering (SERS) substrates. Despite an increasing interest in these systems, standardization in their fabrication process is still lacking but urgently required to support their use for real-life applications. In this work we investigate how the assembly of GO should be conducted to control adsorption geometry and optical properties at the interface with plasmonic nanostructures as monolayer assemblies of silver nanocubes, by tuning main experimental parameters including GO concentration and self-assembly time. We finally identified the experimental conditions for building up a close-fitting soft dressing of the plasmonic surface, which shows optimal characteristics for flexible and reliable SERS detection. PMID- 26751096 TI - Geometrical spin manipulation in Dirac flakes. AB - We investigate numerically the spin properties of electrons in flakes made of materials described by the Dirac equation, in the presence of intrinsic spin orbit coupling (SOC). We show that electrons flowing along the borders of flakes via edge states become helically spin-polarized for strong SOC, for materials with and without a gap at the Fermi energy, corresponding to the massive and massless Dirac equation respectively. The helically spin-polarized electrons create spin-resolved transport, controlled by the flake's geometry in a multi terminal device setup. A simple analytical model containing the basic ingredients of the problem is introduced to get an insight into the helical mechanism, along with our numerical results which are based on an effective tight-binding model. PMID- 26751097 TI - Traumatic brain injury and the post-concussion syndrome: A diffusion tensor tractography study. AB - AIM: The aim of the present study is to evaluate diffusion tensor tractography (DTT) as a tool for detecting diffuse axonal injury in patients of acute, mild, and moderate traumatic brain injury (TBI), using two diffusion variables: Fractional anisotropy (FA) and mean diffusivity (MD). The correlation of these indices with the severity of post-concussive symptoms was also assessed. MATERIALS AND METHODS: Nineteen patients with acute, mild, or moderate TBI and twelve age- and sex-matched healthy controls were recruited. Following Magnetic Resonance Imaging (MRI) on a 3.0-T scanner, DTT was performed using the 'fiber assignment by continuous tracking' (FACT) algorithm for fiber reconstruction. Appropriate statistical tools were used to see the difference in FA and MD values between the control and patient groups. In the latter group, the severity of post concussive symptoms was assessed six months following trauma, using the Rivermead Postconcussion Symptoms Questionnaire (RPSQ). RESULTS: The patients displayed significant reduction in FA compared to the controls (P < 0.05) in several tracts, notably the corpus callosum, fornix, bilateral uncinate fasciculus, and bilateral superior thalamic radiations. Changes in MD were statistically significant in the left uncinate, inferior longitudinal fasciculus, and left posterior thalamic radiation. A strong correlation between these indices and the RPSQ scores was observed in several white matter tracts. CONCLUSION: Diffusion tensor imaging (DTI)-based quantitative analysis in acute, mild, and moderate TBI can identify axonal injury neuropathology, over and above that visualized on conventional MRI scans. Furthermore, the significant correlation observed between FA and MD indices and the severity of post-concussive symptoms could make it a useful predictor of the long-term outcome. PMID- 26751098 TI - Molecular cloning, characterisation and functional analysis of the duck Forkhead box O3 (FOXO3) gene. AB - 1. The Forkhead box O3 (FOXO3) transcription factor is a crucial regulator of cell fate that controls proliferation, apoptosis and differentiation. However, the role of FOXO3 regulation in duck myoblasts is not fully understood. 2. The aim of this study was to clone and determine the complete coding sequence (CDS) of the duck FOXO3 gene and to assess its function in myoblasts. 3. Primers specific for the predicted duck FOXO3 gene were designed using the public mallard duck reference sequence in GenBank. The CDS was cloned by RT-PCR and double digested to generate the expression vector pEGFP-N1-FOXO3. 4. Sequence analysis showed that the full-length FOXO3 CDS is 1467 bp, encoding 488 amino acids and is highly conserved across many bird species. Amino acid sequence analysis revealed a DNA-binding domain (aa 1-77). 5. Myoblast transfection with pEGFP-N1-FOXO3 showed that FOXO3 mRNA expression at 24 h was elevated in pEGFP-N1-FOXO3 transfected myoblasts compared to pEGFP-N1-transfected cells or controls. MRF4, MyoD, MyoG, Myf5 and PAX7 mRNA expression in the pEGFP-N1-FOXO3 group was lowest. However, myostatin (MSTN) and PAX3 mRNA expression did not differ. 6. These results suggest that FOXO3 plays a critical role in the proliferation and differentiation of duck myoblasts. PMID- 26751094 TI - Adsorption and Unfolding of a Single Protein Triggers Nanoparticle Aggregation. AB - The response of living systems to nanoparticles is thought to depend on the protein corona, which forms shortly after exposure to physiological fluids and which is linked to a wide array of pathophysiologies. A mechanistic understanding of the dynamic interaction between proteins and nanoparticles and thus the biological fate of nanoparticles and associated proteins is, however, often missing mainly due to the inadequacies in current ensemble experimental approaches. Through the application of a variety of single molecule and single particle spectroscopic techniques in combination with ensemble level characterization tools, we identified different interaction pathways between gold nanorods and bovine serum albumin depending on the protein concentration. Overall, we found that local changes in protein concentration influence everything from cancer cell uptake to nanoparticle stability and even protein secondary structure. We envision that our findings and methods will lead to strategies to control the associated pathophysiology of nanoparticle exposure in vivo. PMID- 26751099 TI - Recombinant immune complexes as versatile and potent vaccines. AB - Immune complexes (IC) used as vaccines have the potential to enhance both antibody and cell-mediated immune responses over those obtained with antigen alone. However, difficulty of manufacture represents a significant hurdle to the widespread use of IC as vaccines. Recombinant IC (RIC) and their expression in plants enable manufacturing by the coordinate expression of immunoglobulin and antigen as a fusion protein. The use of a modular RIC system facilitates insertion of antigen genes and provides a broadly applicable platform that can be adapted for a wide variety of antigens. PMID- 26751100 TI - Older anti-TNF-alpha agents: why not group them for common indications in the EU? PMID- 26751101 TI - Corrigendum. Two zebrafish hsd3b genes are distinct in function, expression and evolution. PMID- 26751103 TI - Testing the Bivalent Fear of Evaluation Model of Social Anxiety: The Relationship between Fear of Positive Evaluation, Social Anxiety, and Perfectionism. AB - The Bivalent Fear of Evaluation (BFOE) model of social anxiety proposes that fear of negative evaluation (FNE) and fear of positive evaluation (FPE) play distinct roles in social anxiety. Research is however lacking in terms of how FPE is related to perfectionism and how these constructs interact to predict social anxiety. Participants were 382 individuals from the general community and included an oversampling of individuals with social anxiety. Measures of FPE, FNE, perfectionism, and social anxiety were administered. Results were mostly consistent with the predictions made by the BFOE model and showed that accounting for confounding variables, FPE correlated negatively with high standards but positively with maladaptive perfectionism. FNE was also positively correlated with maladaptive perfectionism, but there was no significant relationship between FNE and high standards. Also consistent with BFOE model, both FNE and FPE significantly moderated the relationship between maladaptive perfectionism and social anxiety with the relationship strengthened at high levels of FPE and FNE. These findings provide additional support for the BFOE model and implications are discussed. PMID- 26751104 TI - Haldane's Lungs: A Case Study in Path Analysis. AB - Using a data set on lung ventilation, a number of alternative assumptions governing nondirected paths in structural equation models without latent variables are examined and compared. Some problems with the conventional procedures in path analysis are pointed out, and alternative possibilities are suggested. PMID- 26751102 TI - Roux-en-Y gastrojejunal bypass using a hybrid NOTES-12 mm trocar technique in a porcine model. AB - AIMS: To evaluate the feasibility and safety of Roux-en-Y gastrojejunal bypass procedure using a hybrid NOTES-12 mm trocar technique in a survival porcine model. MATERIAL AND METHODS: The procedure was carried out on ten pigs. Two gastroscopes were introduced through the mouth and through a 12 mm trocar, respectively. A mechanical circular gastro-jejunal anastomosis was created by introducing a stapler after the trocar incision was enlarged. A 21 mm EEA OrVil circular stapler was utilized in the first six pigs and a 25 mm one was used in the other four. All pigs were fed beginning 24 hours after the procedure and were euthanized three weeks later. RESULTS: The procedure was successfully completed in all ten animals. The mean length of the skin incision was 2.5 cm. All pigs survived without complications. Endoscopic inspection detected anastomotic strictures in 5/6 of the 21 mm-stapler and in 0/4 of the 25 mm-stapler anastomoses (p < 0.05). CONCLUSION: Roux-en-Y gastrojejunal bypass using a hybrid NOTES-single 12 mm trocar access technique is a simple and safe procedure in a survival porcine model. Functional results need to be evaluated by further studies. PMID- 26751105 TI - Control of Type I Errors with Multiple Tests of Constraints in Structural Equation Modeling. AB - Two contrasting views toward the evaluation of multiple tests of constraints and control of Type 1 errors in structural equation modeling are presented. (a) Exploring; data helps researchers make decisions about inclusion of relevant model parameters and control of Type 1 errors hinders this process. (b) Exploring data is not likely to yield meaningful models unless we can limit the process on the basis of methods and theory, and controlling Type I errors is a useful device: to force us to limit our searches. Also, in evaluating multiple tests of constraints for applications other than exploratory analyses, we should control for Type I errors as we do in testing multiple comparisons in analysis of variance. We argue for the second perspective and present examples to illustrate methods for controlling Type 1 errors when making model comparisons. PMID- 26751106 TI - Mean and Covariance Structures (MACS) Analyses of Cross-Cultural Data: Practical and Theoretical Issues. AB - Practical and theoretical issues are discussed for testing (a) the comparability, or measurement equivalence, of psychological constructs and (b) detecting possible sociocultural difference on the constructs in cross-cultural research designs. Specifically, strong factorial invariance (Meredith, 1993) of each variable's loading and intercept (mean-level) parameters implies that constructs are fundamentally the same in each sociocultural group, and thus comparable. Under this condition, hypotheses about the nature of sociocultural differences and similarities can be confidently and meaningfully tested among the constructs' moments in each sociocultural sample. Some of the issues involved in making such tests are reviewed and explicated within the framework of multiple-group mean and covariance structures analyses. PMID- 26751107 TI - Using a Regression Approach to Study the Influence of Male Fetuses on the Genital Morphology of Neonatal Female Rats. AB - Among newborn female rats considerable variability is found in genital morphology (e.g., anogenital distance, AGD). Presumably, such differences are related to prenatal androgen exposure, with greater exposure resulting in larger AGD's and thus in a trend toward masculinization. The source of prenatal androgen in female fetuses is unclear, but a role for male uterine mates has been implicated. The present study investigated the effect of a number of prenatal factors related to number and position of males in utero on female AGD in two strains of rats. Because such prenatal factors often show systematic covariance, a methodology was used that enabled statistical control over variables that could not be /experimentally controlled. Results confirmed the importance of caudal males to Female AGD,and identified two additional intra-uterine variables salient to female genital masculinization, namely the distance of the female fetus from the nearest caudal male, and the overall number of males sharing the same uterine horn. An increase in number of adjacent males was, contrary to previous reports, associated with a decrease in AGD, but this effect was limited to one strain. There was considerable variation in AGD across the two strains, and, more importantly, across litters, suggesting the importance of factors impacting the litter as a whole rather than specific individuals within the litter. PMID- 26751108 TI - Metabolic profile of Fructus Gardeniae in human plasma and urine using ultra high performance liquid chromatography coupled with high-resolution LTQ-orbitrap mass spectrometry. AB - 1. In China, Fructus Gardeniae was used as a traditional Chinese medicine (TCM) with a wide array of biological activities. The bioactive components identified in Fructus Gardeniae mainly included iridoids, flavonids, pigments, and so on. Among them, iridoids were regarded as important compounds in Fructus Gardeniae. Though analyses of the constituents in biological samples after oral administration of Fructus Gardeniae effective fraction or its active compounds have been reported, few efforts have been made to investigate the metabolic profile of Fructus Gardeniae in humans. In this study, the constituents and metabolites of Fructus Gardeniae in human blood and urine after oral administration of Fructus Gardeniae were investigated using ultra high performance liquid chromatography (UHPLC) coupled with high-resolution LTQ Orbitrap mass spectrometery. 2. Totally, 14 constituents (two parent compounds and 12 metabolites) of Fructus Gardeniae were identified in human plasma and urine either by comparing the retention time and mass spectrometry data with that of reference compounds or by the accurate high-resolution MS/MS data of the chemicals. The compounds identified were mainly iridoid glycosides such as geniposide and the derivatives of genipin-O-glucuronide. Among them, 11 metabolites were detected in human plasma and urine while the other three metabolites including geniposidic acid (M1), demethylation derivative of genipin O-glucuronide (M2), and dehydration product of mono-hydroxylated genipin-O glucuronide (M9) were only discovered in human urine. Further, the possible metabolic pathways of Fructus Gardeniae in vivo were proposed and the peak area time curve of the most abundant metabolite genipin-O-glucuronide (M13) in human plasma after oral administration of Fructus Gardeniae was depicted. The results suggested that a metabolic difference existed between rats and humans. 3. The results obtained in the present research would provide basic information to understand the metabolic profile of Fructus Gardeniae in humans and explore the chemicals responsible for the hepatotoxicity of Fructus Gardeniae in vivo. Moreover, it would be beneficial for us to further study the pharmacokinetic behavior of Fructus Gardeniae in humans systematically. PMID- 26751109 TI - Emerging drugs for the treatment of mucopolysaccharidoses. AB - INTRODUCTION: Despite being reported for the first time almost one century ago, only in the last few decades effective have treatments become available for the mucopolysaccharidoses (MPSs), a group of 11 inherited metabolic diseases that affect lysosomal function. These diseases are progressive, usually severe, and, in a significant number of cases, involve cognitive impairment. AREAS COVERED: This review will not cover established treatments such as bone marrow/hematopoietic stem cell transplantation and classic intravenous enzyme replacement therapy (ERT), whose long-term outcomes have already been published (MPS I, MPS II, and MPS VI), but it instead focuses on emerging therapies for MPSs. That includes intravenous ERT for MPS IVA and VII, intrathecal ERT, ERT with fusion proteins, substrate reduction therapy, gene therapy, and other novel approaches. EXPERT OPINION: The available treatments have resulted in improvements for several disease manifestations, but they still do not represent a cure for these diseases; thus, it is important to develop alternative methods to approach the unmet needs (i.e. bone disease, heart valve disease, corneal opacity, and central nervous system (CNS) involvement). The work in progress with novel approaches makes us confident that in 2017, when MPS will commemorate 100 years of its first report, we will be much closer to an effective cure for these challenging conditions. PMID- 26751110 TI - Regulation of plants' phosphate uptake in common mycorrhizal networks: Role of intraradical fungal phosphate transporters. AB - We have recently identified two genes coding for inorganic phosphate transporters (Pht) in sorghum (Sorghum bicolor) and flax (Linum usitatissimum) that were induced in roots colonized by arbuscular mycorrhizal (AM) fungi. Mycorrhizal acquisition of inorganic phosphorus (Pi) was strongly affected by the combination of plant and AM fungal species, but the expression level of these genes coding for AM-inducible Pi transporters did not explain differences in plant phosphorus acquisition where flax and sorghum are sharing a common mycorrhizal network. In the present study, we investigated the possible role of fungal Pi transporters in the regulation of mycorrhizal Pi acquisition by measuring their expression in roots of flax and sorghum. One Pi transporter of Rhizophagus irregularis (RiPT5) showed a positive correlation with mycorrhizal Pi acquisition of sorghum. This indicates that a possible involvement in the regulation of mycorrhizal Pi acquisition. In general, expression of AMF Pi transporters was more related to mycorrhizal Pi acquisition of sorghum than of flax, indicating plant species specific differences in the regulation of mycorrhizal Pi acquisition. PMID- 26751111 TI - Analytical method for fast screening and confirmation of multi-class veterinary drug residues in fish and shrimp by LC-MS/MS. AB - A multi-class, multi-residue analytical method based on LC-MS/MS detection was developed for the screening and confirmation of 28 veterinary drug and metabolite residues in flatfish, shrimp and eel. The chosen veterinary drugs are prohibited or unauthorised compounds in Korea, which were categorised into various chemical classes including nitroimidazoles, benzimidazoles, sulfones, quinolones, macrolides, phenothiazines, pyrethroids and others. To achieve fast and simultaneous extraction of various analytes, a simple and generic liquid extraction procedure using EDTA-ammonium acetate buffer and acetonitrile, without further clean-up steps, was applied to sample preparation. The final extracts were analysed by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). The method was validated for each compound in each matrix at three different concentrations (5, 10 and 20 ng g(-1)) in accordance with Codex guidelines (CAC/GL 71-2009). For most compounds, the recoveries were in the range of 60-110%, and precision, expressed as the relative standard deviation (RSD), was in the range of 5-15%. The detection capabilities (CCbetas) were below or equal to 5 ng g(-1), which indicates that the developed method is sufficient to detect illegal fishery products containing the target compounds above the residue limit (10 ng g(-1)) of the new regulatory system (Positive List System - PLS). PMID- 26751112 TI - Temperature rise during polymerization of different cavity liners and composite resins. AB - OBJECTIVE: The purpose of this study was to evaluate the thermal insulating properties of different light curing cavity liners and composite resins during light emitting diode (LED) curing. MATERIALS AND METHODS: Sixty-four dentin discs, 1 mm thick and 8 mm in diameter, were prepared. Specimens were divided into four groups. Calcium hydroxide (Ca[OH]2), resin-modified glass ionomer cement, flowable composite and adhesive systems were applied to dentin discs according to the manufacturers' instructions. The rise in temperature during polymerization with a LED curing unit (LCU) was measured using a K-type thermocouple connected to a data logger. Subsequently, all specimens were randomly divided into one of two groups. A silorane-based composite resin and a methacrylate-based composite resin were applied to the specimens. Temperature rise during polymerization of composite resins with LCU were then measured again. Data were analyzed using one-way ANOVA and post hoc Tukey analyses. RESULTS: There were significant differences in temperature rise among the liners, adhesives, and composite resins (P < 0.05). Silorane-based composite resin exhibited significantly greater temperature rises than methacrylate-based resin (P < 0.05). The smallest temperature rises were observed in Ca(OH)2 specimens. CONCLUSION: Thermal insulating properties of different restorative materials are important factors in pulp health. Bonding agents alone are not sufficient to protect pulp from thermal stimuli throughout curing. PMID- 26751113 TI - Observational multicentric study to evaluate efficacy, adverse effects and acceptance of bowel cleansing prior to colonoscopy with sodium picosulfate / magnesium citrate formulation CitraFleet(r). AB - The various efficient methods available for bowel preparation prior to colonoscopy differ in patient acceptance. Combining the laxative sodium picosulfate with hyperosmotic magnesium citrate, used in this study in the formulation CitraFleet((r)), allows the uptake of the purgative substances as a solution of low volume. This observational study with 737 patients evaluated efficacy of bowel preparation, potential side or adverse effects and patient acceptance of this medicinal product when used by resident physicians in Germany.Colon cleansing with CitraFleet((r)) was considered very good to sufficient in 95.2 % of the patients and inadequate in only 4.8 %. In 75 % of the colonoscopies, bowel preparation was rated very good or good. Compared to the standard regimen of two portions taken the day before endoscopy, cleaning efficacy was better when patients received one of the doses on the morning of the day of colonoscopy. The quality of bowel preparation was rated lower by gastroenterologists without any prior experience with sodium picosulfate/magnesium citrate. The overall assessment of the colon cleansing procedure by the 76 participating physicians was very positive and patient acceptance was also very high which can be considered a clear advantage over alternative methods. Efficacy of colon cleansing with CitraFleet((r)) was not substantially affected by typical deviations from the recommended standard procedure, emphasizing the robustness of the method. Only one of the patients reported a mild adverse effect potentially caused by the cleansing agents. PMID- 26751114 TI - Endoscopic therapy for infected pancreatic necrosis using fully covered self expandable metal stents: combination of transluminal necrosectomy, transluminal and percutaneous drainage. AB - BACKGROUND/AIMS: Endoscopic transluminal therapy has become the standard of care as a less invasive alternative to surgery. In a retrospective case series of two tertiary referral centers we report on an individualized concept combining EUS guided drainage with self-expanding metal stents, direct transluminal debridement und percutaneous drainage. METHODS: We treated 13 patients with infected pancreatic necrosis. Initially in all patients an EUS-guided drainage with plastic stents was performed under antibiotic protection (transduodenal: 2, transgastral: 11). After clinical consolidation (after 9.6 +/- 9.4 days) a covered self-expanding metal stent (Niti-S, Taewoong medical Co., Seoul, Korea) was inserted by performing direct endoscopic necrosectomy in 2.9 +/- 1.7 sessions through the stent. In cases of disrupted duct syndromes a pancreatic plastic stent was inserted (5 of 13 patients). In 5 of 13 cases additional percutaneous drainage was applied because of extended necrosis. In one patient percutaneous endoscopic drainage using the percutaneous access was needed. RESULTS: A sustained clinical success was achieved in 12 of 13 cases (CRP before therapy 23.5 +/- 14.4 mg/L, after 3.1 +/- 2.6 mg/lL). Discharge occurred after 2.5 +/- 22.4 days. The self-expanding metal stent was extracted after 82.5 +/- 56.6 days. Mean follow up was 8.5 +/- 5.9 months. CONCLUSION: Our concept of combining transluminal drainage, direct endoscopic necrosectomy and percutaneuos drainage offers a safe and reliable alternative to surgery, even in case of extended necrosis. PMID- 26751115 TI - [Computer-assisted 3D-navigated laparoscopic resection of a vanished colorectal liver metastasis after chemotherapy]. AB - BACKGROUND: Modern chemotherapy regimen for colorectal cancer results in complete radiologic remission in a substantial number of cases. However, these "vanished liver metastases" (VLM) often contain vital tumor cells, which mandates the resection of such lesions. In these cases, intraoperative identification of VLM can be challenging, in particular in laparoscopic approaches. We describe the first laparoscopic computer-assisted 3D-navigated resection of a VLM. CASE REPORT: A 60-year-old patient with a synchronous liver metastasis (segment IVb) of sigmoid colon cancer (T4 N1 M1) was referred to our center for elective liver resection after laparoscopic sigmoid resection and systemic chemotherapy (FOLFIRI/Panitumumab). The metastasis was not visible anymore on preoperative CT or sonography. Thus, a 3 D reconstruction of the liver was performed. The size of the initial metastasis (before chemotherapy) was transferred into the current CT. A computer-assisted 3D-navigated laparoscopic resection of the metastasis was performed on these fused images. The metastasis was also not clearly visible upon intraoperative ultrasound. Histology of the resected specimen revealed a 0.5 cm metastasis with predominantly vital tumor cells (regression degree 4 of Rubbia Brandt) and a sufficient resection margin of at least 7 mm. The postoperative course was uneventful. CONCLUSION: Computer-assisted 3D-navigation enabled a safe oncologic resection of a vanished liver metastasis after chemotherapy. This technique was particularly helpful due to the limited haptic feedback of laparoscopic surgery. Further studies are necessary to verify the clinical benefit of computer assisted 3D-navigated liver surgery. PMID- 26751116 TI - Ischemic colitis following uncomplicated colonoscopy. AB - BACKGROUND/OBJECTIVE: Ischemic colitis is a disorder of the intestine arising from a multitude of reasons thus representing a challenge for causal research. Our aim was to shed further light on the course, etiology and triggers of non occlusive ischemic colitis by presenting an atypical complication after colonoscopy. DESIGN: We present the case report of a 77-year-old male patient presenting with ischemic colitis after an uneventful outpatient colonoscopy two days prior to onset of symptoms. RESULTS: So far only few cases of post colonoscopy ischemic colitis have been reported. In the present case no single reason was identified. It remains to be assumed that a combination of predisposing conditions with a modest decrease of blood pressure and short-term increased intraluminal pressure during colonoscopy may have led to ischemic colitis. CONCLUSION: Awareness of ischemic colitis as a complication in comparable settings is favorable. So far, early countermeasures against even modest hypotension in patients with comparable past history may be considered on an individual basis depending on the entirety of risk factors. However, prospective studies are necessary to evaluate potential risk profiles for ischemic colitis in terms of colonoscopy. PMID- 26751117 TI - Ultrasonography in acute diverticulitis - credit where credit is due. AB - Diagnosing diverticulitis implies physical and laboratory examination, cross sectional imaging (computed tomography [CT] or ultrasonography [US]), and a classification of the type of diverticular disease. This article illustrates the role of ultrasonography in view of the recently published Guidelines on diverticular disease of the Consensus Conference of the German Societies of Gastroenterology (DGVS) and Visceral Surgery (DGAV). The focus is to foster both sensitivity for pictorial analysis and improving practical accomplishments of US in diverticulitis. Based on the German classification of diverticular disease (CDD), characteristic features of each type of diverticulitis are presented and commented along with possible differential diagnoses. In the literature qualified US is equipotent to qualified CT. US is frequently effective for the diagnosis and unsurpassed resolution enables detailed imaging thereby allowing one to differentiate and stratify the relevant types of diverticular disease according to the new classification. This educational review is a guided tour through the different facettes of diverticulitis on ultrasonography thereby expanding and multiplying individual competence to more users. With expert performance, US is in the pole position for diagnosing diverticulitis, however, this does come with the price of responsibility and requires transfer of advanced standards and performance in the broad. PMID- 26751118 TI - Update S3-guideline: "sedation for gastrointestinal endoscopy" 2014 (AWMF register-no. 021/014). PMID- 26751120 TI - Rational design of Raman-labeled nanoparticles for a dual-modality, light scattering immunoassay on a polystyrene substrate. AB - BACKGROUND: Surface-enhanced Raman scattering (SERS) is a powerful light scattering technique that can be used for sensitive immunoassay development and cell labeling. A major obstacle to using SERS is the complexity of fabricating SERS probes since they require nanoscale characterization and optical uniformity. The light scattering response of SERS probes may also be modulated by the substrate used for SERS analysis. A typical SERS substrate such as quartz can be expensive. Polystyrene is a cheaper substrate option but can decrease the SERS response due to interfering Raman emission peaks and high background fluorescence. The goal of this research is to develop an optimized process for fabricating Raman-labeled nanoparticles for a SERS-based immunoassay on a polystyrene substrate. RESULTS: We have developed a method for fabricating SERS nanoparticle probes for use in a light scattering immunoassay on a polystyrene substrate. The light scattering profile of both spherical gold nanoparticle and gold nanorod SERS probes were characterized using Raman spectroscopy and optical absorbance spectroscopy. The effects of substrate interference and autofluorescence were reduced by selecting a Raman reporter with a strong light scattering response in a spectral region where interfering substrate emission peaks are minimized. Both spherical gold nanoparticles and gold nanorods SERS probes used in the immunoassay were detected at labeling concentrations in the low pM range. This analytical sensitivity falls within the typical dynamic range for direct labeling of cell-surface biomarkers using SERS probes. CONCLUSION: SERS nanoparticle probes were fabricated to produce a strong light scattering signal despite substrate interference. The optical extinction and inelastic light scattering of these probes was detected by optical absorbance spectroscopy and Raman spectroscopy, respectively. This immunoassay demonstrates the feasibility of analyzing strongly enhanced Raman signals on polystyrene, which is an inexpensive yet non-ideal Raman substrate. The assay sensitivity, which is in the low pM range, suggests that these SERS probe particles could be used for Raman labeling of cell or tissue samples in a polystyrene tissue culture plate. With continued development, this approach could be used for direct labeling of multiple cell surface biomarkers on strongly interfering substrate platforms. PMID- 26751119 TI - Early life stress elicits visceral hyperalgesia and functional reorganization of pain circuits in adult rats. AB - Early life stress (ELS) is a risk factor for developing functional gastrointestinal disorders, and has been proposed to be related to a central amplification of sensory input and resultant visceral hyperalgesia. We sought to characterize ELS-related changes in functional brain responses during acute noxious visceral stimulation. Neonatal rats (males/females) were exposed to limited bedding (ELS) or standard bedding (controls) on postnatal days 2-9. Age 10-11 weeks, animals were implanted with venous cannulas and transmitters for abdominal electromyography (EMG). Cerebral blood flow (rCBF) was mapped during colorectal distension (CRD) using [14C]-iodoantipyrine autoradiography, and analyzed in three-dimensionally reconstructed brains by statistical parametric mapping and functional connectivity. EMG responses to CRD were increased after ELS, with no evidence of a sex difference. ELS rats compared to controls showed a greater significant positive correlation of EMG with amygdalar rCBF. Factorial analysis revealed a significant main effect of 'ELS' on functional activation of nodes within the pain pathway (somatosensory, insular, cingulate and prefrontal cortices, locus coeruleus/lateral parabrachial n. [LC/LPB], periaqueductal gray, sensory thalamus), as well as in the amygdala, hippocampus and hypothalamus. In addition, ELS resulted in an increase in the number of significant functional connections (i.e. degree centrality) between regions within the pain circuit, including the amygdala, LC/LPB, insula, anterior ventral cingulate, posterior cingulate (retrosplenium), and stria terminalis, with decreases noted in the sensory thalamus and the hippocampus. Sex differences in rCBF were less broadly expressed, with significant differences noted at the level of the cortex, amygdala, dorsal hippocampus, raphe, sensory thalamus, and caudate-putamen. ELS showed a sexually dimorphic effect ('Sex x ELS' interaction) at the LC/LPB complex, globus pallidus, hypothalamus, raphe, septum, caudate-putamen and cerebellum. Our results suggest that ELS alters functional activation of the thalamo-cortico-amydala pathway, as well as the emotional-arousal network (amygdala, locus coeruleus), with evidence that ELS may additionally show sexually dimorphic effects on brain function. PMID- 26751121 TI - Increased number of cases of Chikungunya virus (CHIKV) infection imported from the Caribbean and Central America to northern Italy, 2014. AB - This report describes an increased number of cases of Chikungunya virus (CHIKV) infection imported in northern Italy (Emilia-Romagna region) during the period May-September 2014, indicating that the recent spread of CHIKV and its establishment in the Caribbean and in central America, resulted in a high number of imported cases in Europe, thus representing a threat to public health. From May to September 2014, 14 imported cases of CHIKV infection were diagnosed; the patients were returning to Italy from Dominican Republic (n = 6), Haiti (n = 3), Guadeloupe (n = 2), Martinique (n = 1), Puerto Rico (n = 1) and Venezuela (n = 1). Phylogenetic analysis performed on the envelope protein (E1) gene sequences, obtained from plasma samples from two patients, indicated that the virus strain belongs to the Caribbean clade of the Asian genotype currently circulating in the Caribbean and Americas. The rise in the number of imported cases of CHIKV infection should increase healthcare professionals' awareness of the epidemiological situation and clinical presentation of CHIKV infection in order to enhance surveillance and early diagnosis in the forthcoming season of vector activity in Europe and North America. PMID- 26751122 TI - Altered gene expression of the innate immune, neuroendocrine, and nuclear factor kappa B (NF-kappaB) systems is associated with posttraumatic stress disorder in military personnel. AB - Whole transcriptome analysis provides an unbiased examination of biological activity, and likely, unique insight into the mechanisms underlying posttraumatic stress disorder (PTSD) and comorbid depression and traumatic brain injury. This study compared gene-expression profiles in military personnel with PTSD (n=28) and matched controls without PTSD (n=27) using HG-U133 Plus 2.0 microarrays (Affymetrix), which contain 54,675 probe sets representing more than 38,500 genes. Analysis of expression profiles revealed 203 differentially expressed genes in PTSD, of which 72% were upregulated. Using Partek Genomics Suite 6.6, differentially expressed transcription clusters were filtered based on a selection criterion of >=1.5 relative fold change at a false discovery rate of <=5%. Ingenuity Pathway Analysis (Qiagen) of the differentially expressed genes indicated a dysregulation of genes associated with the innate immune, neuroendocrine, and NF-kappaB systems. These findings provide novel insights that may lead to new pharmaceutical agents for PTSD treatments and help mitigate mental and physical comorbidity risk. PMID- 26751123 TI - Gradients, waves and timers, an overview of limb patterning models. AB - The vertebrate limb represents one of the oldest and most studied models in developmental and regenerative biology. Starting with classical experimental embryology and regenerative studies, its relevance in understanding biological mechanisms has expanded through the molecular biology era and now leads systems biology approaches in organogenesis. Limb patterning is organized along three main orthogonal axes; proximo-distal (P-D), antero-posterior (A-P) and dorso ventral (D-V). Considerable heterogeneity has been found for the mechanisms involved in patterning these three axes, including signal gradients, cell intrinsic timers and Turing-type signalling wave formation. Here we concentrate on reviewing patterning mechanisms along the P-D and A-P axes, in which different mechanisms converge and interact to pattern segmented structures. PMID- 26751125 TI - To three sections and shorter reviewing times. PMID- 26751124 TI - Avoidance of cancer communication, perceived social support, and anxiety and depression among patients with cancer. AB - PURPOSE: Patients with cancer are reported to experience high anxiety and depression related to their medical status. The current study aimed to investigate the effects of avoidance of cancer communication and of social support from family and medical professionals on the patients' anxiety and depression. METHODS: A national survey was conducted through regional branches of the National Cancer Center of South Korea, which yielded 296 patient-caregiver dyads. Patients' medical records complemented their self-report survey data. RESULTS: Patients' anxiety was predicted by the family's avoidance of cancer communication and the level of emotional support from family. Patients' depression was predicted by the stage of cancer (Surveillance, Epidemiology, and End Results), the family's avoidance of cancer communication, the emotional support from family, and the medical professionals' respect. Interaction effects were not statistically significant. CONCLUSION: The implications of the findings are discussed in terms of the psycho-oncological and psycho-social interventions. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26751126 TI - Tubular and glomerular kidney effects in the Chinese general population with low environmental cadmium exposure. AB - Cadmium (Cd), a well-known nephrotoxic agent, has received a great deal of attention from the Chinese public because of reports of its presence in rice. But very few studies have assessed the renal risk of Cd exposure in children. In this cross-sectional study, we aimed to determine whether biologic measures of Cd exposure were associated with biomarkers of early kidney damage in children, adolescents and adults. A total of 1235 subjects (2-86.8 years old) participated in this study and provided samples of blood and urine. As a result, the median urinary Cd level was 0.38 MUg g(-1) creatinine in adult men and 0.42 MUg g(-1) creatinine in adult women, similar to reference values observed in the United States (median: 0.32-0.40 MUg L(-1) in adults). Multiple linear regressions showed Cd in urine to be significantly positively associated with effects on renal tubule biomarkers (as indicated by increased levels of N-acetyl-beta-D glucosaminidase and beta2-microglobulin) after adjusting for age, body mass index, blood lead, and urinary density, in all age groups including children. We also found positive associations between blood Cd and renal tubule biomarkers in children. In conclusion, adverse tubular renal effects might have occurred at the current low Cd levels in the study population, including children. These findings are particularly relevant assessing health risks associated with low environmental exposures to Cd. PMID- 26751127 TI - Effects of bisphenol analogues on steroidogenic gene expression and hormone synthesis in H295R cells. AB - The use of Bisphenol A (BPA) has been regulated in many countries because of its potential adverse effects on human health. As a result of the restriction, structural anologues such as bisphenol S (BPS) and bisphenol F (BPF) have already been used for industrial applications as alternatives to BPA. Bisphenol AF (BPAF) is mainly used as a crosslinker in the synthesis of specialty fluoroelastomers. These compounds have been detected in various environmental matrices and human samples. Previous studies have shown that these compounds have potential endocrine disrupting effects on wildlife and mammals in general. However, the effects on adrenocortical function and the underlying mechanisms are not fully understood. In the present study, the H295R cell line was used as a model to compare the cell toxicity and to investigate the potential endocrine disrupting action of four BPs (including BPA, BPS, BPF, and BPAF). The half lethal concentration (LC50) values at 72 h exposure indicated that the rank order of toxicities of the chemicals was BPAF > BPA > BPS > BPF. The hormone results demonstrated that BPA analogues, such as BPF, BPS and BPAF were capable of altering steroidogenesis in H295R cells. BPA and BPS exhibited inhibition of hormone production, BPF predominantly led to increased progesterone and 17beta estradiol levels and BPAF showed induction of progesterone and reduction of testosterone. Inhibition effects of BPA and BPAF on hormone production were probably mediated by down-regulation of steroidogenic genes in H295R cells. However, the mechanisms of the endocrine interrupting action of BPF and BPS are still unclear, which may have additional mechanisms that have not been detected with BPA. PMID- 26751128 TI - Bioreduction and reoxidation of uranium enhanced by thiol functional groups in natural organic matter. AB - Although natural organic matter (NOM) is known to affect biological reduction of U(VI) and subsequent reoxidation of U(IV), the underlying mechanisms remain unclear. This study investigated the redox reactions of sulfide with NOM to form thiol functional groups, which can greatly enhance U(VI) bioreduction and U(IV) reoxidation. Results showed that humic acid (HA) was found to be more effective than fulvic acid (FA) in producing thiol groups, both U(VI) bioreduction and U(IV) reoxidation rates increased with the increase of thiols content in HA and FA. These findings suggested that among other redox sites, thiol groups in NOM may play an important role in the electron transport between uranium and microbial cells, and are of great environmental implications because they provided direct proof that thiol groups are responsible for bioremediation and immobilization of uranium when it enters into the natural environments such as soil and groundwater. PMID- 26751129 TI - Challenges in developing drugs for primary headaches. AB - This review considers the history of drug development in primary headaches and discusses challenges to the discovery of innovative headache therapeutics. Advances in headache genetics have yet to translate to new classes of therapeutics and there are currently no clear predictive human biomarkers for any of the primary headaches that can guide preventative drug discovery and development. Primary headache disorder subtypes despite common phenotypic presentation are undoubtedly heterogeneous in their pathophysiology as judged by the variability of response to headache medicines. Sub-classification of headache subtypes into more homogenous and specific phenotypes groups may facilitate genotyping and provide sentinel patient groups that can be used in a mechanism specific manner to test new and more personalized treatment strategies in headache medicine. The development of the triptan class of serotonin 5-HT1B/1D/1F receptor agonists has advanced our understanding of the neurobiology of migraine pain, which subsequently resulted in the development of calcitonin gene-related peptide (CGRP) modulators that are now showing promise as acute and preventative anti-migraine agents. Despite these successes, there have been many near misses and failures in the discovery and development of headache therapeutics. Glutamate receptor antagonism whilst efficacious has central side effects and some approaches such as nitric oxide synthase inhibition, substance P antagonism and cortical spreading depression blockade, despite having promising effects in basic pain models, have not delivered efficacy in the clinic. Future efforts may triage novel physiological mediators using human experimental models of headache pain to support drug discovery strategies that target active pathways pharmacologically. PMID- 26751130 TI - Nanostructured materials in electroanalysis of pharmaceuticals. AB - Basic strategies and recent developments for the enhancement of the sensory performance of nanostructures in the electroanalysis of pharmaceuticals are reviewed. A discussion of the properties of nanostructures and their application as modified electrodes for drug assays is presented. The electrocatalytic effect of nanostructured materials and their application in determining low levels of drugs in pharmaceutical forms and biofluids are discussed. PMID- 26751131 TI - LIN-28B/let-7a/IGF-II axis molecular subtypes are associated with epithelial ovarian cancer prognosis. AB - OBJECTIVES: Aberrant expressions of LIN-28B, let-7a and IGF-II occur in epithelial ovarian cancer, and the LIN-28B/let-7a/IGF-II axis is associated with human disease. The purpose of this study was to investigate the associations between LIN-28B/let-7a/IGF-II axis molecular subtypes and epithelial ovarian cancer prognosis. METHODS: Using quantitative reverse transcription PCR, we analyzed LIN-28B, let-7a and IGF-II mRNA in 211 primary epithelial ovarian cancer tissues, and also performed Classification and Regression Tree (CART) and survival analyses. RESULTS: Four terminal subtypes were identified in the CART analysis in combination with survival analysis. Kaplan-Meier survival curves showed that subtypes LIN-28B(low)let-7a(low) and LIN-28B(low)let-7a(high)IGF II(low) had significantly better survival than subtypes LIN-28B(high) or LIN 28B(low)let-7a(high)IGF-II(high) (p<0.0001 for overall, p=0.017 for progression free survival, respectively). Multivariate Cox regression models showed that compared to subtype LIN-28B(high), subtypes LIN-28B(low)let-7a(low) and LIN 28B(low)let-7a(high)IGF-II(low) had significantly reduced mortality and reduced relapse risks. Moreover, subtype LIN-28B(low)let-7a(low) had better response to chemotherapy than subtype LIN-28B(high). CONCLUSIONS: These results suggest that molecular subtypes of the LIN-28B/let-7a/IGF-II axis associate with heterogeneous progression and may have clinical implications in predicting epithelial ovarian cancer prognosis. PMID- 26751132 TI - Newborn screening for cystic fibrosis - The parent perspective. AB - BACKGROUND: Newborn screening for CF started 01/2011 in Switzerland. We investigated the parents' opinions about the information received, their feelings, and overall approval of the screening. METHODS: This is a prospective questionnaire survey of all parents of positively screened children. Parents were phoned by CF-centres and invited for diagnostic investigations. They completed a questionnaire after the visit to the CF-centre. RESULTS: From 2011-2013, 246 families received the questionnaire and 138 (56%) replied. Of these 77 (60%) found the information received at birth satisfactory; 124 (91%) found the information provided in the CF-centre satisfactory. Most parents (n=98, 78%) felt troubled or anxious when the CF-centre called, 51 (38%) remained anxious after the visit. Most parents (n=122; 88%) were satisfied with the screening, 4 (3%) were not, and 12 (9%) were unsure. CONCLUSIONS: The smooth organisation of the screening process, with personal information by a CF specialist and short delays between this information and the final diagnostic testing, might have contributed to reduce anxiety among parents. Most families were grateful that their child had been screened, and are happy with the process. PMID- 26751133 TI - Effects of ultrasound, CaCl2 and STPP on the ultrastructure of the milk goat longissimus muscle fiber observed with atomic force microscopy. AB - The aim of this study was to analyze the effects of ultrasound bath intensity, CaCl2 and sodium tripolyphosphate (STPP) concentration on the ultrastructure of longissimus muscle fiber from milk goats. The sarcomere length was measured by atomic force microscopy. According to the results of AFM images, the sarcomere length is longest when the conditions were an intensity of 100 W ultrasound bath (42.77% increment), a concentration of 300 mM CaCl2 injection (44.68% increment) or 90 mM STPP injection (19.41% increment). Apart from the sarcomere length, the study put forward a potential index (roughness) to represent tenderness of meat which was treated by ultrasound bath. Among different methods, ultrasound bath was chosen as the preferred tenderization method. SCANNING 38:545-553, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26751134 TI - Metal-Free Dehydrogenation of Amine-Boranes by Tunable N-Heterocyclic Iminoboranes. AB - We report the synthesis of structurally tunable boron complexes supported by N heterocyclic imine ligands IPr=N-BR2 (IPr=[(HCNDipp)2 C], Dipp=2,6-iPr2 C6 H3 , R=Cl and/or Ph) that have the ability to abstract dihydrogen from amine-boranes, and instigate their dehydrocoupling. In one instance, mild heating of the hydrogen addition product IPr=NH-B(Ph)HCl releases H2 to regenerate the starting N-heterocyclic iminoborane; accordingly IPr=N-B(Ph)Cl can be used as a metal-free catalyst to promote the dehydrocoupling of MeNH2 ?BH3 to yield N methylaminoborane oligomers [MeNH-BH2 ]x . PMID- 26751135 TI - Use of pulsed dye laser treatments in patients with vocal fold mucosal bridges with sulcus vocalis - our experience of five cases. PMID- 26751136 TI - Adult cortical plasticity: a murine model? (Commentary on Smolders et al.). PMID- 26751137 TI - Accelerating the use of molecular modeling in the high school classroom with VMD Lite. AB - It is often difficult for students to develop an intuition about molecular processes, which occur in a realm far different from day-to-day life. For example, thermal fluctuations take on hurricane-like proportions at the molecular scale. Students need a way to visualize realistic depictions of molecular processes to appreciate them. To this end, we have developed a simplified graphical interface to the widely used molecular visualization and analysis tool Visual Molecular Dynamics (VMD) called VMD lite. We demonstrate the use of VMD lite through a module on diffusion and the hydrophobic effect as they relate to membrane formation. Trajectories from molecular dynamics simulations, which students can interact with freely, illustrate the dynamical behavior of lipid molecules and water. VMD lite was tested by ~70 students with overall positive reception. Remaining deficiencies in conceptual understanding were noted, however, and the module has been revised in response. PMID- 26751138 TI - Short-term complications of intra-operative radiotherapy for early breast cancer. AB - INTRODUCTION: IORT is becoming an accepted radiotherapy technique for treatment of early breast cancer. Data regarding the early complications of breast IORT are lacking. OBJECTIVES: Assess the nature and risk factors for early complications of breast conserving surgery (BCS) and intraoperative radiotherapy (IORT) with INTRABEAM(r). METHODS: IORT with INTRABEAM(r) was administered to breast cancer patients in Carmel Medical Center as part of an institutional clinical registry project. Three hundred and ninety five patients treated during 2006-2013 were included. Clinical and treatment data and data regarding complications documented within 1 year of surgery were collected. The association between clinical and treatment variables and risk of complications was assessed. RESULTS: Complications were documented in 108 (27.3%) of patients. Grade III or IV complications were found in 5% of patients. Infections were diagnosed in 43 (10.8%) patients, seroma in 40 (10.1%), wound dehiscence in 32 (8.1%), and bleeding and hematomas in 11(2.8%). Two patients had a small size skin necrosis. Sixteen patients with a seroma had a secondary complication. All complications resolved. Diabetes mellitus and use of anticoagulants were associated with an increased risk of wound dehiscence and bleeding, respectively. CONCLUSIONS: IORT for breast cancer is safe in appropriately selected patients. Careful surgical technique and postoperative care is prudent. J. Surg. Oncol. 2016;113:370-373. (c) 2016 Wiley Periodicals, Inc. PMID- 26751139 TI - Productivity changes in OECD healthcare systems: bias-corrected Malmquist productivity approach. AB - This study evaluates productivity changes in the healthcare systems of 30 Organization for Economic Co-operation and Development (OECD) countries over the 2002-2012 periods. The bootstrapped Malmquist approach is used to estimate bias corrected indices of healthcare performance in productivity, efficiency and technology by modifying the original distance functions. Two inputs (health expenditure and school life expectancy) and two outputs (life expectancy at birth and infant mortality rate) are used to calculate productivity growth. There are no perceptible trends in productivity changes over the 2002-2012 periods, but positive productivity improvement has been noticed for most OECD countries. The result also informs considerable variations in annual productivity scores across the countries. Average annual productivity growth is evenly yielded by efficiency and technical changes, but both changes run somewhat differently across the years. The results of this study assert that policy reforms in OECD countries have improved productivity growth in healthcare systems over the past decade. Countries that lag behind in productivity growth should benchmark peer countries' practices to increase performance by prioritizing an achievable trajectory based on socioeconomic conditions. For example, relatively inefficient countries in this study indicate higher income inequality, corresponding to inequality and health outcomes studies. Although income inequality and globalization are not direct measures to estimate healthcare productivity in this study, these issues could be latent factors to explain cross-country healthcare productivity for future research. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26751140 TI - Severe Epidermal Nerve Fiber Loss in Diabetic Neuropathy Is Not Reversed by Long Term Normoglycemia After Simultaneous Pancreas and Kidney Transplantation. AB - Whether nerve fiber loss, a prominent feature of advanced diabetic neuropathy, can be reversed by reestablishment of normal glucose control remains questionable. We present 8-year follow-up data on epidermal nerve fiber (ENF) density and neurological function in patients with type 1 diabetes after simultaneous pancreas and kidney transplantation (SPK) with long-term normoglycemia. Distal thigh skin biopsies with ENF counts, vibration perception thresholds (VPTs), autonomic function testing (AFT) and electrophysiological examinations were performed at time of SPK and 2.5 and 8 years after SPK in 12 patients with type 1 diabetes. In comparison to controls, baseline ENF density, VPT and AFT results of patients indicated severe neuropathy. At follow-up, all SPK recipients were insulin independent with excellent glycemic control and kidney graft function; however, the severe ENF depletion present at baseline had not improved, with total ENF absence in 11 patients at 8-year follow-up. Similarly, no amelioration occurred in the VPT and AFT results. Numerical improvement was seen in some electrophysiological parameters; however, statistical significance was achieved only in median motor nerve conduction velocity. ENF loss and functional deficits in advanced diabetic peripheral neuropathy are rarely reversible, even by long-term normoglycemia, which underscores the importance of neuropathy prevention by early optimal glycemic control. PMID- 26751141 TI - Hemispheric differences in language processing in autism spectrum disorders: A meta-analysis of neuroimaging studies. AB - Language impairments, a hallmark feature of autism spectrum disorders (ASD), have been related to neuroanatomical and functional abnormalities. Abnormal lateralization of the functional language network, increased reliance on visual processing areas, and increased posterior brain activation have all been reported in ASD and proposed as explanatory models of language difficulties. Nevertheless, inconsistent findings across studies have prevented a comprehensive characterization of the functional language network in ASD. The aim of this study was to quantify common and consistent patterns of brain activation during language processing in ASD and typically developing control (TD) participants using a meta-analytic approach. Activation likelihood estimation (ALE) meta analysis was used to examine 22 previously published functional Magnetic Resonance Imaging (fMRI)/positron emission tomography studies of language processing (ASD: N = 328; TD: N = 324). Tasks included in this study addressed semantic processing, sentence comprehension, processing figurative language, and speech production. Within-group analysis showed largely overlapping patterns of language-related activation in ASD and TD groups. However, the ASD participants, relative to TD participants, showed: (1) more right hemisphere activity in core language areas (i.e., superior temporal gyrus and inferior frontal gyrus), particularly in tasks where they had poorer performance accuracy; (2) bilateral MTG hypo-activation across many different paradigms; and (3) increased activation of the left lingual gyrus in tasks where they had intact performance. These findings show that the hypotheses reviewed here address the neural and cognitive aspects of language difficulties in ASD across all tasks only in a limited way. Instead, our findings suggest the nuances of language and brain in ASD in terms of its context-dependency. Autism Res 2016, 9: 1046-1057. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26751144 TI - TO THE EDITOR. Re: Kim HS, Suk KS, Moon SH, et al. Safety evaluation of freehand lateral mass screw fixation in the sub axial cervical spine: evaluation of 1256 screws. Spine (Phila Pa 1976) 2015;40:2-5. PMID- 26751143 TI - Treatment of Slow Transit Constipation With Fecal Microbiota Transplantation: A Pilot Study. AB - BACKGROUND: Fecal microbiota transplantation (FMT) has been proposed as a therapeutic approach for functional gastrointestinal disease. We launched a clinical study to examine the safety and efficacy of FMT for slow transit constipation (STC). MATERIALS AND METHODS: Twenty-four patients with STC, aged from 20 to 74 were enrolled in this prospective open-label study. Patients received FMT on 3 consecutive days through nasojejunal tubes and followed up for 12 weeks after treatment. Rate of clinical improvement and remission, Wexner constipation scale, Bowel movement per week, and gastrointestinal quality-of-life index were evaluated. RESULTS: The rate of clinical improvement and remission based on clinical activity at week 12 was 50% (12/24) and 37.5% (9/24), respectively. The patient's stool frequency increased from a mean of 1.8 (SD 1.3) per week pre-FMT to 4.1 (SD 2.6) at week 12 post-FMT without laxative usage (P<0.01). The stool consistency showed a tendency to improve after FMT administration. Comparison of pre-FMT and post-FMT Wexner constipation scores demonstrated a significant reduction between baseline (14.1+/-3.3) and the first week (9.8+/-4.9), which was maintained up to the following 12 weeks (7.5+/-3.2; P<0.01). Compared with baseline, significant overall improvements were also seen in gastrointestinal quality-of-life index score at week 1, week 2, week 4, week 8, and week 12 of follow-up (P<0.01). The improvements were accompanied by the decline of colonic transit time. No severe adverse events during the whole FMT procedure follow-up except for venting (6/24), abdominal pain (3/24), bloating (2/24), and diarrhea (7/24). CONCLUSION: This is a pilot study demonstrating that FMT was safe and may have the potential to improve symptoms in patients with STC. PMID- 26751145 TI - TO THE EDITOR. In Response to Letter to The Editor: Re: Kim HS, Suk KS, Moon SH, et al. Safety Evaluation of freehand Lateral Mass Screw Fixation in the Sub Axial Cervical Spine: Evaluation of 1256 Screws. Spine (Phila Pa 1976)2015;40:2-5. PMID- 26751146 TI - Response to the Letter to the Editor. PMID- 26751147 TI - Heptanickel(ii) double-cubane core in wells-dawson heteropolytungstate, [Ni7(OH)6(H2O)6(P2W15O56)2](16-). AB - The hepta-Ni(2+)-containing 30-tungsto-4-phosphate(v) [Ni7(OH)6(H2O)6(P2W15O56)2](16-) (1) has been synthesized in aqueous, slightly basic medium under conventional reaction conditions, and charactarized via different physical methods. Single-crystal XRD showed that 1 consists of a corner fused double-cubane {Ni7(OH)6(H2O)6}(8+) fragment sandwiched by two trilacunary [P2W15O56](12-) units. Polyanion 1 is solution-stable as shown by (31)P NMR. Ferromagnetic coupling interaction between the 7 paramagnetic centers of the double-cubane core in 1 with a S = 7 ground state was demonstrated. Electrochemical studies were also performed on 1. PMID- 26751148 TI - Dependence of cobaltocenium diffusion in ionic liquids on the alkyl chain length of 1-alkyl-3-methylimidazolium cations. AB - The electrochemical behavior of cobaltocenium (Cc(+)) on a Au(111) electrode was investigated in five 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide ([Cnmim][Tf2N], n = 2, 4, 6, 8, or 10) ionic liquids (ILs) in the temperature range from 293.15 to 343.15 K by cyclic voltammetry and chronoamperometry. The redox couple of Cc(+) exhibited a clear reversible one-electron reaction in all the [Cnmim][Tf2N] ILs. The diffusion coefficients of Cc(+) increased with an increase in the alkyl chain length of [Cnmim](+) and a decrease in the viscosity of the IL upon elevating the temperature. The viscosity of the IL plays an important role in determining the activation energy for the diffusion of Cc(+). The obtained results suggested that the alkyl chain length of [Cnmim](+) affects the strength of the interaction between Cc(+) and the surrounding ion species. The results also clarified that the equation proposed by Sutherland adequately describes the diffusion of Cc(+) in ILs when the effect of the type of IL and the temperature on the product of the Stokes radius of Cc(+) and the Sutherland coefficient is considered. PMID- 26751149 TI - CPh3 as a functional group in P-heterocyclic chemistry: elimination of HCPh3 in the reaction of P-CPh3 substituted Li/Cl phosphinidenoid complexes with Ph2C=O. AB - P-CPh3 substituted oxaphosphirane complexes 3 were prepared using Li/Cl phosphinidenoid complexes 2 (M = Cr, Mo, W) and benzaldehyde. Employing 2 and benzophenone resulted in the formation of oxaphospholane complexes 4 and 5, the former bearing a benzo[c]-1,2-oxaphospholane and the latter a novel pentacyclic P ligand. According to DFT studies the latter P-heterocycle arises from formal dimerization of a transient benzofused 2-phosphafurane complex 8, one of the fragments undergoing water-catalyzed [1,3]H shift (4) and the other (11) formed via elimination of HCPh3. PMID- 26751150 TI - Structure-based design of 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines as inhibitors of myeloid cell leukemia-1 (Mcl-1). AB - Mcl-1 has recently emerged as an attractive target to expand the armamentarium in the war on cancer. Using structure-based design, 3-carboxy-substituted 1,2,3,4 tetrahydroquinolines were developed as a new chemotype to inhibit the Mcl-1 oncoprotein. The most potent compound inhibited Mcl-1 with a Ki of 120 nM, as determined by a fluorescence polarization competition assay. Direct binding was confirmed by 2D (1)H-(15)N HSQC NMR spectroscopy with (15)N-Mcl-1, which indicated that interactions with R263 and T266, and occupation of the p2 pocket are likely responsible for the potent binding affinity. The short and facile synthetic chemistry to access target molecules is expected to mediate lead optimization. PMID- 26751151 TI - Preadoption adversity and long-term clinical-range behavior problems in adopted Chinese girls. AB - In this study, we report findings on the role of preadoption adversity on long term clinical-range problems in adopted Chinese girls. Four waves (2005, 2007, 2009 and 2011) of problem behavior data on 1,223 adopted Chinese girls (M = 4.86 years, SD = 2.82 in 2005) were collected from the adoptive mothers with the Child Behavior Checklist (CBCL). At Wave 1 (2005), data on the following indicators of preadoption adversity was collected: age at adoption, physical signs/symptoms (e.g., sores) of preadoption adversity, developmental delays at arrival, refusal/avoidance behaviors and crying/clinging behaviors toward adoptive parents during the first 3 weeks of adoption. We found that the percentage of clinical range internalizing problems was 11.1%, 16.5%, 11.3%, and 16.1% at Wave 1, Wave 2, Wave 3, and Wave 4, respectively; the corresponding percentage of clinical range externalizing problems was 8.4%, 10.5%, 8.4% and 9.9% respectively; and the corresponding percentage of clinical-range total CBCL problems was 9.3%, 13.0%, 9.8% and 12.6% respectively. Analyses with Mplus showed that controlling for demographic variables, indicators of preadoption adversity, except age at adoption, increased the odds for clinical-range behavior problems. Longitudinal path models revealed that controlling for demographic variables and the children's adjustment status in the previous wave, refusal/avoidance remained significant in predicting clinical-range internalizing, externalizing and total CBCL problems at Wave 2, delays at arrival and signs/symptoms were significant in predicting clinical-range internalizing problems at Wave 3. Overall, adoptees with clinical-range CBCL problems in earlier waves were 9-28 times as likely to show clinical-range CBCL problems in subsequent waves. PMID- 26751152 TI - Do psychotherapists improve with time and experience? A longitudinal analysis of outcomes in a clinical setting. AB - OBJECTIVE: Psychotherapy researchers have long questioned whether increased therapist experience is linked to improved outcomes. Despite numerous cross sectional studies examining this question, no large-scale longitudinal study has assessed within-therapist changes in outcomes over time. METHOD: The present study examined changes in psychotherapists' outcomes over time using a large, longitudinal, naturalistic psychotherapy data set. The sample included 6,591 patients seen in individual psychotherapy by 170 therapists who had on average 4.73 years of data in the data set (range = 0.44 to 17.93 years). Patient-level outcomes were examined using the Outcome Questionnaire-45 and a standardized metric of change (prepost d). Two-level multilevel models (patients nested within therapist) were used to examine the relationship between therapist experience and patient prepost d and early termination. Experience was examined both as chronological time and cumulative patients seen. RESULTS: Therapists achieved outcomes comparable with benchmarks from clinical trials. However, a very small but statistically significant change in outcome was detected indicating that on the whole, therapists' patient prepost d tended to diminish as experience (time or cases) increases. This small reduction remained when controlling for several patient-level, caseload-level, and therapist-level characteristics, as well as when excluding several types of outliers. Further, therapists were shown to vary significantly across time, with some therapists showing improvement despite the overall tendency for outcomes to decline. In contrast, therapists showed lower rates of early termination as experience increased. CONCLUSIONS: Implications of these findings for the development of expertise in psychotherapy are explored. (PsycINFO Database Record PMID- 26751153 TI - As good as it gets? Therapy outcomes of trainees over time. AB - There is a paucity of empirical studies that demonstrate psychotherapy trainees improve at assisting their clients' therapy outcomes over time. We examined whether trainees (i.e., practicum, predoctoral interns, and postdoctoral fellows) improved in their clients' therapy outcomes over time. We examined 114 trainees (i.e., who were trainees for the first client in the database) and had over 12 months of client outcome data (M = 45.31 months). At the start of their time in our database, about half of the participants (48.2%) were predoctoral interns, 42.1% were practicum students, and 9.6% were postdoctoral fellows. Collectively, they treated 2,991 clients (M = 26 clients per trainee). Clients completed the Behavioral Health Measure, which assesses general psychological functioning (i.e., well-being, symptom distress, and life functioning), as a measure of therapy outcomes. Trainees demonstrated small-sized growth in their clients' outcomes over time (d = 0.04 per year); however, this growth was moderated by client severity. That is, trainees demonstrated growth over time in working with clients who were less distressed (d = -0.13 to 0.10 over time), but there was no change over time for trainees when working with more distressed clients (d = 0.67 to .65 over time). The results were consistent across trainee level (i.e., practicum, predoctoral intern, postdoctoral fellow), yet trainees varied in their patterns of growth. Psychotherapy training has a small, but positive, effect on trainees' ability to foster positive outcomes with their clients over time. (PsycINFO Database Record PMID- 26751154 TI - "The efficacy of empathy training: A meta-analysis of randomized controlled trials": Correction to Teding van Berkhout and Malouff (2015). AB - Reports an error in "The Efficacy of Empathy Training: A Meta-Analysis of Randomized Controlled Trials" by Emily Teding van Berkhout and John M. Malouff (Journal of Counseling Psychology, Advanced Online Publication, Jul 20, 2015, np). In the article, the last name of author Emily Teding van Berkhout was incorrectly set in the running head as van Berkhout. It should be Teding van Berkhout. All versions of this article have been corrected. (The following abstract of the original article appeared in record 2015-32537-001.) High levels of empathy are associated with healthy relationships and prosocial behavior; in health professionals, high levels of empathy are associated with better therapeutic outcomes. To determine whether empathy can be taught, researchers have evaluated empathy training programs. After excluding 1 outlier study that showed a very large effect with few participants, the meta-analysis included 18 randomized controlled trials of empathy training with a total of 1,018 participants. The findings suggest that empathy training programs are effective overall, with a medium effect (g = 0.63), adjusted to 0.51 after trim-and-fill evaluation for estimated publication bias. Moderator analyses indicated that 4 factors were statistically significantly associated with higher effect sizes: (a) training health professionals and university students rather than other types of individuals, (b) compensating trainees for their participation, (c) using empathy measures that focus exclusively on assessing understanding the emotions of others, feeling those emotions, or commenting accurately on the emotions, and (d) using objective measures rather than self-report measures. Number of hours of training and time between preintervention assessment and postintervention assessment were not statistically significantly associated with effect size, with 6 months the longest time period for assessment. The findings indicate that (a) empathy training tends to be effective and (b) experimental research is warranted on the impact of different types of trainees, training conditions, and types of assessment. (PsycINFO Database Record PMID- 26751155 TI - Social representation of therapeutic relationship among cognitive-behavioral psychotherapists. AB - The present study investigates the content and structure of the social representation (SR) that cognitive-behavioral (CBT) psychotherapists have of the therapeutic relationship (TR), through a discovery-oriented, mixed-methods approach. For this purpose, our reference point was social representation theory, in particular, the theory of the central nucleus (Abric, 2003; Moscovici, 1961). Data came from a sample of 63 CBT therapists. The results enabled us to identify a series of contents marking CBTs SR of the TR that overlap with the current pan theoretical conceptualization of this construct. The results also allowed us to identify the complex, clear, and stratified organization of these contents, which are characteristics of a majority and of a minority of the sample studied. These results are discussed with regard of their theoretical, methodological, and practical implications. (PsycINFO Database Record PMID- 26751156 TI - "Self-critical perfectionism, daily stress, and disclosure of daily emotional events": Correction to Richardson and Rice (2015). AB - Reports an error in "Self-critical perfectionism, daily stress, and disclosure of daily emotional events" by Clarissa M. E. Richardson and Kenneth G. Rice (Journal of Counseling Psychology, 2015[Oct], Vol 62[4], 694-702). In the article, the labels of the two lines in Figure 1 were inadvertently transposed. The dotted line should be labeled High SCP and the solid line should be labeled Low SCP. The correct version is present in the erratum. (The following abstract of the original article appeared in record 2015-30890-001.) Although disclosure of stressful events can alleviate distress, self-critical perfectionism may pose an especially strong impediment to disclosure during stress, likely contributing to poorer psychological well-being. In the current study, after completing a measure of self-critical perfectionism (the Discrepancy subscale of the Almost Perfect Scale-Revised; Slaney, Rice, Mobley, Trippi, & Ashby, 2001), 396 undergraduates completed measures of stress and disclosure at the end of each day for 1 week. Consistent with hypotheses and previous research, multilevel modeling results indicated significant intraindividual coupling of daily stress and daily disclosure where disclosure was more likely when experiencing high stress than low stress. As hypothesized, Discrepancy moderated the relationship between daily stress and daily disclosure. Individuals higher in self-critical perfectionism (Discrepancy) were less likely to engage in disclosure under high stress, when disclosure is often most beneficial, than those with lower Discrepancy scores. These results have implications for understanding the role of stress and coping in the daily lives of self-critical perfectionists. (PsycINFO Database Record PMID- 26751157 TI - Transgender community belongingness as a mediator between strength of transgender identity and well-being. AB - This study examined transgender community belongingness as a mediator between strength of transgender identity and well-being. A total of 571 transgender adults (n = 209 transgender women, n = 217 transgender men, and n = 145 nonbinary identified individuals) completed an online survey assessing transgender community belongingness, strength of transgender identity (operationalized as the extent to which a person self-categorizes their identity as transgender and the extent to which they believe their gender transition to be important to their self-definition), and well-being (using measures of self-esteem, satisfaction with life, and psychological well-being). Structural equation modeling was used to analyze the data. When controlling for participants' income, age, and stage of gender transition, transgender community belongingness fully mediated the relationship between strength of transgender identity and well-being. Strength of transgender identity was indirectly and positively related to well-being through community belongingness, but was not directly related to well-being. Results suggest that transgender community belongingness is an important construct in the mental health of transgender people. The strength of a person's transgender identity also appears to be a significant construct in transgender people's well being via its relationship with transgender community belongingness. Implications of the findings are discussed. (PsycINFO Database Record PMID- 26751158 TI - Discrimination, mental health, and suicidal ideation among LGBTQ people of color. AB - Discrimination based on race/ethnicity, sexual orientation, and gender identity has been linked to many negative psychological and physical health outcomes in previous research, including increased suicidal ideation. Two hundred lesbian, gay, bisexual, transgender, and queer (LGBTQ) people of color (POC) were surveyed on their experiences of LGBTQ-based discrimination, racism, mental health (depression, anxiety, satisfaction with life), and suicidal ideation in a national online study based in the United States. A structural equation model (SEM) was created and found that LGBTQ-based discrimination exerted an indirect effect on suicidal ideation through mental health. Racism exerted a direct effect on mental health but was not associated with suicidal ideation in the SEM. The effects of LGBTQ-based discrimination on mental health may be a key area for interventions to reduce suicidal ideation in LGBTQ POC. (PsycINFO Database Record PMID- 26751159 TI - Global Adoption of Genetically Modified (GM) Crops: Challenges for the Public Sector. AB - Advances in biotechnology continue to drive the development of a wide range of insect-protected, herbicide-tolerant, stress-tolerant, and nutritionally enhanced genetically modified (GM) crops, yet societal and public policy considerations may slow their commercialization. Such restrictions may disproportionately affect developing countries, as well as smaller entrepreneurial and public sector initiatives. The 2014 IUPAC International Congress of Pesticide Chemistry (San Francisco, CA, USA; August 2014) included a symposium on "Challenges Associated with Global Adoption of Agricultural Biotechnology" to review current obstacles in promoting GM crops. Challenges identified by symposium presenters included (i) poor public understanding of GM technology and the need for enhanced communication strategies, (ii) nonharmonized and prescriptive regulatory requirements, and (iii) limited experience with regulations and product development within some public sector programs. The need for holistic resistance management programs to enable the most effective use of insect-protected crops was also a point of emphasis. This paper provides details on the symposium discussion and provides background information that can be used in support of further adoption of beneficial GM crops. Overall, it emphasizes that global adoption of modern agricultural biotechnology has not only provided benefits to growers and consumers but has great potential to provide solutions to an increasing global population and diminishing agricultural land. This potential will be realized by continued scientific innovation, harmonized regulatory systems, and broader communication of the benefits of the high-yielding, disease resistant, and nutritionally enhanced crops attainable through modern biotechnology. PMID- 26751160 TI - Primary Cutaneous Cryptococcus in a Patient With Multiple Sclerosis Treated With Fingolimod. PMID- 26751162 TI - Noninvasive Experimental Evidence of the Linear Pore Size Dependence of Water Diffusion in Nanoconfinement. AB - We show that nuclear magnetic relaxation experiments at variable magnetic fields (NMRD) provide noninvasive means for probing the spatial dependence of liquid diffusion close to solid interfaces. These experiments performed on samples of cylindrical and spherical nanopore geometries demonstrate that the average diffusion coefficient parallel to the interface is proportional to the pore radii in different dynamics regimes. A master curve method allows extraction of gradients of diffusion coefficients in proximity of the pore surfaces, indicative of the efficiency of coupling between liquid layers. Due to their selectivity in frequency, NMRD experiments are able to differentiate the different water dynamical events induced by heterogeneous surfaces or composed dynamical processes. This analysis relevant in physical and biological confinements highlights the interplay between the molecular and continuous description of fluid dynamics near interfaces. PMID- 26751161 TI - Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors. AB - GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer's disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics. PMID- 26751163 TI - Raman Spectroscopy of Isotopic Water Diffusion in Ultraviscous, Glassy, and Gel States in Aerosol by Use of Optical Tweezers. AB - The formation of ultraviscous, glassy, and amorphous gel states in aqueous aerosol following the loss of water results in nonequilibrium dynamics due to the extended time scales for diffusive mixing. Existing techniques for measuring water diffusion by isotopic exchange are limited by contact of samples with the substrate, and methods applied to infer diffusion coefficients from mass transport in levitated droplets requires analysis by complex coupled differential equations to derive diffusion coefficients. We present a new technique that combines contactless levitation with aerosol optical tweezers with isotopic exchange (D2O/H2O) to measure the water diffusion coefficient over a broad range (Dw ~ 10(-12)-10(-17) m(2).s(-1)) in viscous organic liquids (citric acid, sucrose, and shikimic acid) and inorganic gels (magnesium sulfate, MgSO4). For the organic liquids in binary and ternary mixtures, Dw depends on relative humidity and follows a simple compositional Vignes relationship. In MgSO4 droplets, water diffusivity decreases sharply with water activity and is consistent with predictions from percolation theory. These measurements show that, by combining micrometer-sized particle levitation (a contactless measurement with rapid mixing times) with an established probe of water diffusion, Dw can be simply and directly quantified for amorphous and glassy states that are inaccessible to existing methods. PMID- 26751164 TI - (1)H NMR and GC-MS Based Metabolomics Reveal Defense and Detoxification Mechanism of Cucumber Plant under Nano-Cu Stress. AB - Because copper nanoparticles are being increasingly used in agriculture as pesticides, it is important to assess their potential implications for agriculture. Concerns have been raised about the bioaccumulation of nano-Cu and their toxicity to crop plants. Here, the response of cucumber plants in hydroponic culture at early development stages to two concentrations of nano-Cu (10 and 20 mg/L) was evaluated by proton nuclear magnetic resonance spectroscopy ((1)H NMR) and gas chromatography-mass spectrometry (GC-MS) based metabolomics. Changes in mineral nutrient metabolism induced by nano-Cu were determined by inductively coupled plasma-mass spectrometry (ICP-MS). Results showed that nano Cu at both concentrations interferes with the uptake of a number of micro- and macro-nutrients, such as Na, P, S, Mo, Zn, and Fe. Metabolomics data revealed that nano-Cu at both levels triggered significant metabolic changes in cucumber leaves and root exudates. The root exudate metabolic changes revealed an active defense mechanism against nano-Cu stress: up-regulation of amino acids to sequester/exclude Cu/nano-Cu; down-regulation of citric acid to reduce the mobilization of Cu ions; ascorbic acid up-regulation to combat reactive oxygen species; and up-regulation of phenolic compounds to improve antioxidant system. Thus, we demonstrate that nontargeted (1)H NMR and GC-MS based metabolomics can successfully identify physiological responses induced by nanoparticles. Root exudates metabolomics revealed important detoxification mechanisms. PMID- 26751165 TI - P-Doped Porous Carbon as Metal Free Catalysts for Selective Aerobic Oxidation with an Unexpected Mechanism. AB - An extremely simple and rapid (seconds) approach is reported to directly synthesize gram quantities of P-doped graphitic porous carbon materials with controlled P bond configuration. For the first time, it is demonstrated that the P-doped carbon materials can be used as a selective metal free catalyst for aerobic oxidation reactions. The work function of P-doped carbon materials, its connectivity to the P bond configuration, and the correlation with its catalytic efficiency are studied and established. In direct contrast to N-doped graphene, the P-doped carbon materials with higher work function show high activity in catalytic aerobic oxidation. The selectivity trend for the electron donating and withdrawing properties of the functional groups attached to the aromatic ring of benzyl alcohols is also different from other metal free carbon based catalysts. A unique catalytic mechanism is demonstrated, which differs from both GO and N doped graphene obtained by high temperature nitrification. The unique and unexpected catalytic pathway endows the P-doped materials with not only good catalytic efficiency but also recyclability. This, combined with a rapid, energy saving approach that permits fabrication on a large scale, suggests that the P doped porous materials are promising materials for "green catalysis" due to their higher theoretical surface area, sustainability, environmental friendliness, and low cost. PMID- 26751166 TI - Seasonal divergence in the interannual responses of Northern Hemisphere vegetation activity to variations in diurnal climate. AB - Seasonal asymmetry in the interannual variations in the daytime and nighttime climate in the Northern Hemisphere (NH) is well documented, but its consequences for vegetation activity remain poorly understood. Here, we investigate the interannual responses of vegetation activity to variations of seasonal mean daytime and nighttime climate in NH (>30 degrees N) during the past decades using remote sensing retrievals, FLUXNET and tree ring data. Despite a generally significant and positive response of vegetation activity to seasonal mean maximum temperature (Tmax) in ~22-25% of the boreal (>50 degrees N) NH between spring and autumn, spring-summer progressive water limitations appear to decouple vegetation activity from the mean summer Tmax, particularly in climate zones with dry summers. Drought alleviation during autumn results in vegetation recovery from the marked warming-induced drought limitations observed in spring and summer across 24-26% of the temperate NH. Vegetation activity exhibits a pervasively negative correlation with the autumn mean minimum temperature, which is in contrast to the ambiguous patterns observed in spring and summer. Our findings provide new insights into how seasonal asymmetry in the interannual variations in the mean daytime and nighttime climate interacts with water limitations to produce spatiotemporally variable responses of vegetation growth. PMID- 26751168 TI - Peptide nanostructures: Aromatic dipeptides light up. PMID- 26751167 TI - CUL2-mediated clearance of misfolded TDP-43 is paradoxically affected by VHL in oligodendrocytes in ALS. AB - The molecular machinery responsible for cytosolic accumulation of misfolded TDP 43 in amyotrophic lateral sclerosis (ALS) remains elusive. Here we identified a cullin-2 (CUL2) RING complex as a novel ubiquitin ligase for fragmented forms of TDP-43. The von Hippel Lindau protein (VHL), a substrate binding component of the complex, preferentially recognized misfolded TDP-43 at Glu246 in RNA-recognition motif 2. Recombinant full-length TDP-43 was structurally fragile and readily cleaved, suggesting that misfolded TDP-43 is cleared by VHL/CUL2 in a step-wise manner via fragmentation. Surprisingly, excess VHL stabilized and led to inclusion formation of TDP-43, as well as mutant SOD1, at the juxtanuclear protein quality control center. Moreover, TDP-43 knockdown elevated VHL expression in cultured cells, implying an aberrant interaction between VHL and mislocalized TDP-43 in ALS. Finally, cytoplasmic inclusions especially in oligodendrocytes in ALS spinal cords were immunoreactive to both phosphorylated TDP-43 and VHL. Thus, our results suggest that an imbalance in VHL and CUL2 may underlie oligodendrocyte dysfunction in ALS, and highlight CUL2 E3 ligase emerges as a novel therapeutic potential for ALS. PMID- 26751170 TI - A biomimetic DNA-based channel for the ligand-controlled transport of charged molecular cargo across a biological membrane. AB - Biological ion channels are molecular gatekeepers that control transport across cell membranes. Recreating the functional principle of such systems and extending it beyond physiological ionic cargo is both scientifically exciting and technologically relevant to sensing or drug release. However, fabricating synthetic channels with a predictable structure remains a significant challenge. Here, we use DNA as a building material to create an atomistically determined molecular valve that can control when and which cargo is transported across a bilayer. The valve, which is made from seven concatenated DNA strands, can bind a specific ligand and, in response, undergo a nanomechanical change to open up the membrane-spanning channel. It is also able to distinguish with high selectivity the transport of small organic molecules that differ by the presence of a positively or negatively charged group. The DNA device could be used for controlled drug release and the building of synthetic cell-like or logic ionic networks. PMID- 26751171 TI - Gate-induced superconductivity in atomically thin MoS2 crystals. AB - When thinned down to the atomic scale, many layered van der Waals materials exhibit an interesting evolution of their electronic properties, whose main aspects can be accounted for by changes in the single-particle bandstructure. Phenomena driven by interactions are also observed, but identifying experimentally systematic trends in their thickness dependence is challenging. Here, we explore the evolution of gate-induced superconductivity in exfoliated MoS2 multilayers ranging from bulk-like to individual monolayers. We observe a clear transition for all thicknesses down to the ultimate atomic limit, providing the first demonstration of gate-induced superconductivity in atomically thin exfoliated crystals. Additionally, we characterize the superconducting state by measuring the critical temperature TC and magnetic field BC in a large number of multilayer devices while decreasing their thickness. We find that the superconducting properties exhibit a pronounced reduction in TC and BC when going from bilayers to monolayers, for which we discuss possible microscopic mechanisms. PMID- 26751169 TI - Bioinspired fluorescent dipeptide nanoparticles for targeted cancer cell imaging and real-time monitoring of drug release. AB - Peptide nanostructures are biodegradable and are suitable for many biomedical applications. However, to be useful imaging probes, the limited intrinsic optical properties of peptides must be overcome. Here we show the formation of tryptophan phenylalanine dipeptide nanoparticles (DNPs) that can shift the peptide's intrinsic fluorescent signal from the ultraviolet to the visible range. The visible emission signal allows the DNPs to act as imaging and sensing probes. The peptide design is inspired by the red shift seen in the yellow fluorescent protein that results from pi-pi stacking and by the enhanced fluorescence intensity seen in the green fluorescent protein mutant, BFPms1, which results from the structure rigidification by Zn(II). We show that DNPs are photostable, biocompatible and have a narrow emission bandwidth and visible fluorescence properties. DNPs functionalized with the MUC1 aptamer and doxorubicin can target cancer cells and can be used to image and monitor drug release in real time. PMID- 26751172 TI - Tailoring high-temperature radiation and the resurrection of the incandescent source. AB - In solar cells, the mismatch between the Sun's emission spectrum and the cells' absorption profile limits the efficiency of such devices, while in incandescent light bulbs, most of the energy is lost as heat. One way to avoid the waste of a large fraction of the radiation emitted from hot objects is to tailor the thermal emission spectrum according to the desired application. This strategy has been successfully applied to photonic-crystal emitters at moderate temperatures, but is exceedingly difficult for hot emitters (>1,000 K). Here, we show that a plain incandescent tungsten filament (3,000 K) surrounded by a cold-side nanophotonic interference system optimized to reflect infrared light and transmit visible light for a wide range of angles could become a light source that reaches luminous efficiencies (~40%) surpassing existing lighting technologies, and nearing a limit for lighting applications. We experimentally demonstrate a proof of-principle incandescent emitter with efficiency approaching that of commercial fluorescent or light-emitting diode bulbs, but with exceptional reproduction of colours and scalable power. The ability to tailor the emission spectrum of high temperature sources may find applications in thermophotovoltaic energy conversion and lighting. PMID- 26751174 TI - Large-Scale Self-Assembly of 3D Flower-like Hierarchical Ni/Co-LDHs Microspheres for High-Performance Flexible Asymmetric Supercapacitors. AB - In this study, a facile and inexpensive and self-assembled strategy to massively fabricate Ni/Co layered double hydroxides (LDHs) is developed under mild reaction conditions (55 degrees C). The resulting composite material displays a special three-dimensional hierarchical microsphere structure with well-defined flower like configuration. The fabrication mechanism can be ascribed to stepwise and regular reaction process of nanoparticles and nanosheets gradually growing to nanopetals and then assembling into flower-like microspheres, based on the systematically investigation of various reaction factors including the Ni:Co feeding ratio, the reaction time and the initial pH-value. Because of its large surface, ultrathin feature and synergetic results of this Ni/Co LDHs nanosheets (20 nm), these Ni/Co-LDHs microspheres deliver an excellent capacitance value about 2228 F.g(-1) (1 A.g(-1)). An all-solid-state flexible asymmetric supercapacitor is designed and assembled by exploiting this Ni/Co-LDHs as the positive materials, which exhibits energy density of 165.51 Wh.kg(1-) at 1.53 KW.kg(1-). It may have vast potential significance in personal wearable equipment. Moreover, this monolithic design provides a promising approach for large scale fabrication of other LDHs materials. PMID- 26751173 TI - Functional genetic screens for enhancer elements in the human genome using CRISPR Cas9. AB - Systematic identification of noncoding regulatory elements has, to date, mainly relied on large-scale reporter assays that do not reproduce endogenous conditions. We present two distinct CRISPR-Cas9 genetic screens to identify and characterize functional enhancers in their native context. Our strategy is to target Cas9 to transcription factor binding sites in enhancer regions. We identified several functional enhancer elements and characterized the role of two of them in mediating p53 (TP53) and ERalpha (ESR1) gene regulation. Moreover, we show that a genomic CRISPR-Cas9 tiling screen can precisely map functional domains within enhancer elements. Our approach expands the utility of CRISPR-Cas9 to elucidate the functions of the noncoding genome. PMID- 26751175 TI - New insights into the compressibility and high-pressure stability of Ni(CN)2: a combined study of neutron diffraction, Raman spectroscopy, and inelastic neutron scattering. AB - Nickel cyanide is a layered material showing markedly anisotropic behaviour. High pressure neutron diffraction measurements show that at pressures up to 20.1 kbar, compressibility is much higher in the direction perpendicular to the layers, c, than in the plane of the strongly chemically bonded metal-cyanide sheets. Detailed examination of the behaviour of the tetragonal lattice parameters, a and c, as a function of pressure reveal regions in which large changes in slope occur, for example, in c(P) at 1 kbar. The experimental pressure dependence of the volume data is fitted to a bulk modulus, B0, of 1050 (20) kbar over the pressure range 0-1 kbar, and to 124 (2) kbar over the range 1-20.1 kbar. Raman spectroscopy measurements yield additional information on how the structure and bonding in the Ni(CN)2 layers change with pressure and show that a phase change occurs at about 1 kbar. The new high-pressure phase, (Phase PII), has ordered cyanide groups with sheets of D4h symmetry containing Ni(CN)4 and Ni(NC)4 groups. The Raman spectrum of phase PII closely resembles that of the related layered compound, Cu1/2Ni1/2(CN)2, which has previously been shown to contain ordered C=N groups. The phase change, PI to PII, is also observed in inelastic neutron scattering studies which show significant changes occurring in the phonon spectra as the pressure is raised from 0.3 to 1.5 kbar. These changes reflect the large reduction in the interlayer spacing which occurs as Phase PI transforms to Phase PII and the consequent increase in difficulty for out-of-plane atomic motions. Unlike other cyanide materials e.g. Zn(CN)2 and Ag3Co(CN)6, which show an amorphization and/or a decomposition at much lower pressures (~100 kbar), Ni(CN)2 can be recovered after pressurising to 200 kbar, albeit in a more ordered form. PMID- 26751176 TI - Cytokine and Chemokine Signature in Elite Versus Viremic Controllers Infected with HIV. AB - HIV long-term nonprogressors (LTNPs) maintaining high CD4(+) T-cell counts without antiretroviral therapy (ART) are divided into elite controllers (ECs) with undetectable and viremic controllers (VCs) with low viral loads. Little is known about the long-term changes of T-cell subsets and inflammation patterns in ECs versus VCs. The aim of the study was to explore the long-term evolution of CD4(+) T-cell levels in LTNPs and to analyze cytokine profiles in ECs versus VCs. Nineteen ECs and 15 VCs were enrolled from the natural virus controller cohort (NaViC). T-cell counts were monitored over years, the mean annual change was calculated, and plasma concentrations of 25 cytokines were evaluated using a multiplex bead array. While absolute numbers of T cells did not differ between ECs and VCs over time, we observed a significant decrease of CD4(+) T-cell percentages in VCs, but not in ECs (median [interquartile range]: ECs: 37% [28 41] vs. VCs: 29% [25-34]; p = .02). ECs had lower levels of macrophage inflammatory protein-1beta (MIP-1beta, p = .003), interferon gamma-induced protein-10 (IP-10, p = .03), and monokine induced by interferon-gamma (MIG, p = .02). CD4(+) T-cell percentages inversely correlated with MIP 1-beta (r = -0.42, p = .017) and IP-10 (r = -0.77, p < .0001). A subtle decline of CD4(+) T-cell percentages could be observed in VCs, but not in ECs, which was associated with higher plasma levels of proinflammatory cytokines. Hence, even low levels of HIV replication might go along with a progressive decline in CD4(+) T-cell counts in LTNPs. PMID- 26751178 TI - Rapid detection of Cronobacter sakazakii by real-time PCR based on the cgcA gene and TaqMan probe with internal amplification control. AB - Cronobacter sakazakii is a severe virulent strain that is frequently detected in powdered infant formula (PIF). Therefore, it is necessary to develop a fast and specific detection method. The specificity of our newly developed quantitative real-time PCR (qRT-PCR) was validated with DNA from 46 strains. Among them, 12 C. sakazakii strains were correctly amplified, whereas no positive florescent signal was observed from 34 nontarget controls. The detection limit of C. sakazakii was about 110 CFU/mL in broth and 1100 CFU/g in PIF. After enrichment in buffered peptone water for 6 h, our developed qRT-PCR assay could reliably detect C. sakazakii when the inoculation level was as low as 2 CFU/25 g (0.08 CFU/g) in PIF. The growth of C. sakazakii could be inhibited by the presence of Lactobacillus pentosus and Bacillus cereus, which used a longer enrichment period before the isolation was accomplished. However, at 5 and 50 CFU/25 g inoculation levels of C. sakazakii in the presence of 4 * 10(6) CFU L. pentosus/25 g or of 2 * 10(4) CFU B. cereus/25 g, the qRT-PCR assay could detect the presence of Cronobacter even though these artificially spiked samples were negative in culture. Therefore, our results indicated that the qRT-PCR assay could detect samples containing inhibitors and could avoid false negatives by using an internal amplification control. PMID- 26751179 TI - Investigating Group Differences on Cognitive Tests Using Spearman's Hypothesis: An Evaluation of Jensen's Method. AB - Jensen has posited a research method to investigate group differences in cognitive tests. This method consists of first extracting a general intelligence factor by means of exploratory factor analysis. Secondly, similarity of factor loadings across groups is evaluated in an attempt to ensure that the same constructs are measured. Finally, the correlation is computed between the loadings of the tests on the general intelligence factor and the mean differences between groups on the tests. This part is referred to as a test of "Spearman's Hypothesis", which essentially states that differences in g account for the main part of differences in observed scores. Based on the correlation, inferences are made with respect to group differences in general intelligence. The validity of these inferences is investigated and compared to the validity of inferences based on multi-group confirmatory factor analysis. For this comparison, population covariance matrices are constructed which incorporate violations of the central assumption underlying Jensen's method concerning the existence of g and/or violations of Spearman's Hypothesis. It is demonstrated that Jensen's method is quite insensitive to the violations. This lack of specificity is observed consistently for all types of violations introduced in the present study. Multi group confirmatory factor analysis emerges as clearly superior to Jensen's method. PMID- 26751177 TI - Reproductive factors, tumor estrogen receptor status and contralateral breast cancer risk: results from the WECARE study. AB - Several reproductive factors are known to be associated with risk of breast cancer; however, relationships between these factors with risk of second primary asynchronous contralateral breast cancer (CBC) have not been widely studied. The Women's Environmental, Cancer, and Radiation Epidemiology (WECARE) Study is a population-based case-control study of 1521 CBC cases and 2212 individually matched controls with unilateral breast cancer. Using multivariable conditional logistic regression models, we examined associations between reproductive factors and CBC risk, and whether associations differed by estrogen receptor (ER) status and menopausal status of the first breast cancer. Older age at menarche was inversely associated with CBC risk (>=14 vs. <=11 years risk ratio (RR) = 0.82, 95 % confidence interval (CI) 0.65-1.03, P trend = 0.02). Among parous women, an increasing number of full-term pregnancies (FTP) was inversely associated with risk (>=4 vs. 1 FTP RR = 0.60, 95 % CI 0.41-0.88, P trend = 0.005). Ever breast feeding was inversely associated with CBC risk only among women with ER-negative first tumors (ever vs. never breast-fed RR = 0.69, 95 % CI 0.48-1.00, P heterogeneity = 0.05). Older age at first FTP was inversely associated with CBC risk among women with ER-negative first tumors (>=30 vs. <20 years old RR = 0.66, 95 % CI 0.35-1.27, P trend = 0.03), but suggestively positively associated with risk among women with ER-positive first tumors (P heterogeneity = 0.03). Young age at menarche and low parity, both risk factors for first primary breast cancer, were also associated with overall CBC risk. Reductions in risk associated with breast-feeding were limited to women with ER-negative first tumors, who are at higher CBC risk than women with ER-positive primaries. PMID- 26751181 TI - Factor Analysis of Ordinal Variables: A Comparison of Three Approaches. AB - Theory and methodology for exploratory factor analysis have been well developed for continuous variables. In practice, observed or measured variables are often ordinal. However, ordinality is most often ignored and numbers such as 1, 2, 3, 4, representing ordered categories, are treated as numbers having metric properties, a procedure which is incorrect in several ways. In this article we describe four approaches to factor analysis of ordinal variables which take proper account of ordinality and compare three of them with respect to parameter estimates and fit. The comparison is made both in terms of their relative methodological advantages and in terms of an empirical data example and two generated data examples. In particular, we discuss the issue of how to test the model and to measure model fit. PMID- 26751180 TI - Estimating Success in Predicting a Variable with Nominal Measurement Using Other Variables with Nominal Measurements. AB - In this article we are concerned with the situation where one is estimating the outcome of a variable Y, with nominal measurement, on the basis of the outcomes of several predictor variables, X 1, X 2, ..., X r, each with nominal measurement. We assume that we have a random sample from the population. Here we are interested in estimating p, the probability of successfully predicting a new Y from the population, given the X measurements for this new observation. We begin by proposing an estimator, pa, which is the success rate in predicting Y from the current sample. We show that this estimator is always biased upwards. We then propose a second estimator, pb, which divides the original sample into two groups, a holdout group and a training group, in order to estimate p. We show that procedures such as these are always biased downwards, no matter how we divide the original sample into the two groups. Because one of these estimators tends to overestimate p while the other tends to underestimate p, we propose as a heuristic solution to use the mean of these two estimators, pc, as an estimator for p. We then perform several simulation studies to compare the three estimators with respect to both bias and MSE. These simulations seem to confirm that $ p c is a better estimator than either of the other two. PMID- 26751182 TI - An Extension of the Internal/External Frame of Reference Model: A Response to Bong (1998). AB - Bong (1998) extended the internal/external frame of reference (I/E) model by attempting to operationalize the internal and external comparison processes that are central to the model and expanding the range of academic self-concept domains. Bong concluded that the "I/E model failed to receive clear support" (p. 102) in relation to predictions that she derived from her extension of the original model. Our critical evaluation and reanalysis, however, reveals problems in the operationalization of the internal and external comparisons, the rationale for post hoc confirmatory factor analysis models and, thus, the original conclusions. Our reanalysis, however, provide strong support for the original I/E model, some support for the separation of the internal and external comparison processes, and good support for a new extension to incorporate a wider range of academic domains. In particular, for these largely Hispanic-American students, Spanish achievement and self-concept were very distinct from achievements and self-concepts in all other school subjects. Accomplishments in Spanish provided one basis for evaluating accomplishments in other school subjects. In contrast, achievements and self-concepts in these other school subjects could be explained in terms of higher-order Verbal achievement and self-concept factors and higher order Math achievement and self-concept factors. PMID- 26751183 TI - Using Trimmed Means to Compare K Measures Corresponding to Two Independent Groups. AB - Consider two independent groups with K measures for each subject. For the j(th) group and k(th) measure, let MU(tjk) be the population trimmed mean, j = 1, 2; k = 1, ..., K. This article compares several methods for testing H 0 : u1k = t2k such that the probability of at least one Type I error is, and simultaneous probability coverage is 1 - alpha when computing confidence intervals for MU(t1k) - MU(t2k) . The emphasis is on K = 4 and alpha = .05. For zero trimming the problem reduces to comparing means, but it is well known that when comparing means, arbitrarily small departures from normality can result in extremely low power relative to using say 20% trimming. Moreover, when skewed distributions are being compared, conventional methods for comparing means can be biased for reasons reviewed in the article. A consequence is that in some realistic situations, the probability of rejecting can be higher when the null hypothesis is true versus a situation where the means differ by a half standard deviation. Switching to robust measures of location is known to reduce this problem, and combining robust measures of location with some type of bootstrap method reduces the problem even more. Published articles suggest that for the problem at hand, the percentile t bootstrap, combined with a 20% trimmed mean, will perform relatively well, but there are known situations where it does not eliminate all problems. In this article we consider an extension of the percentile bootstrap approach that is found to give better results. PMID- 26751184 TI - Fitting the Normal-Ogive Factor Analytic Model to Scores on Tests. AB - This article (a) describes how McDonald's nonlinear factor analytic approach to the normal ogive curve can be used to factor analyse total test scores, (b) discusses the conditions in which this model is more appropriate than the widely used linear model, and (c) illustrates the applicability of both models using an empirical example. The rationale for the described procedure is that the test scores are simple sums of binary item responses whose item characteristic curves are adequately represented by normal ogives. The results obtained in the empirical example are meaningful and informative, and agree with the results obtained at the item level. PMID- 26751185 TI - From personal to global: Understandings of social accountability from stakeholders at four medical schools. AB - AIM: This paper addresses the question of how social accountability is conceptualised by staff, students and community members associated with four medical schools aspiring to be socially accountable in two countries. METHODS: Using a multiple case study approach this research explored how contextual issues have influenced social accountability at four medical schools: two in Australia and two in the Philippines. This paper reports on how research participants understood social accountability. Seventy-five participants were interviewed including staff, students, health sector representatives and community members. Field notes were taken and a documentary analysis was completed. RESULTS: Overall there were three common understandings. Socially accountable medical education was about meeting workforce, community and health needs. Social accountability was also determined by the nature and content of programs the school implemented or how it operated. Finally, social accountability was deemed a personal responsibility. The broad consensus masked the divergent perspectives people held within each school. CONCLUSION: The assumption that social accountability is universally understood could not be confirmed from these data. To strengthen social accountability it is useful to learn from these institutions' experiences to contribute to the development of the theory and practice of activities within socially accountable medical schools. PMID- 26751186 TI - The resurgence of mumps and pertussis. AB - Vaccines and extended vaccination programs have had an extensive impact on morbidity and mortality rates due to infectious diseases. Because of the continuous and extensive use of vaccines in industrialized countries, many infectious diseases such as poliomyelitis, diphtheria and measles have been reduced to near-extinction. However, in recent years, many countries including the United States of America, the United Kingdom and Belgium, have been confronted with a resurgence of mumps and pertussis, despite high vaccination coverage for both vaccines. In this commentary, possible causes of this resurgence will be discussed, such as the occurrence of adapted microbes, failure to vaccinate and primary and secondary vaccine failure. Additional research of the immunological mechanisms is clearly needed to support the development of possible new and more immunogenic vaccines against mumps and pertussis. Meanwhile, extensive vaccination campaigns with both vaccines remain necessary. PMID- 26751187 TI - Polio endgame: the global switch from tOPV to bOPV. AB - Globally, polio cases have reached an all-time low, and type 2 poliovirus (one of three) is eradicated. Oral polio vaccine (OPV) has been the primary tool, however, in rare cases, OPV induces paralysis. In 2013, the World Health Assembly endorsed the phased withdrawal of OPV and introduction of inactivated poliovirus vaccine (IPV) into childhood routine immunization schedules. Type 2 OPV will be withdrawn through a globally synchronized "switch" from trivalent OPV (all three types) to bivalent OPV (types 1 and 3). The switch will happen in 155 OPV-using countries between April 17(th) and May 1(st), 2016. Planned activities to reduce type 2 outbreak risks post-switch include the following: tOPV campaigns to increase type 2 immunity prior to the switch, monovalent OPV2 stockpiling to respond to outbreaks should they occur, containment of both wild and vaccine type 2 viruses, enhanced acute flaccid paralysis (AFP) and environmental surveillance, outbreak response protocols, and ensured access to IPV and bivalent OPV. PMID- 26751188 TI - Effects of silencing 14-3-3 protein in Paracoccidiodes brasiliensis infection. PMID- 26751189 TI - Androgen-Induced Relaxation of Uterine Myocytes Is Mediated by Blockade of Both Ca(2+) Flux and MLC Phosphorylation. AB - CONTEXT: Uterine quiescence must be maintained until pregnancy reaches term. Premature activation of myometrial contractility leads to preterm labor and delivery. OBJECTIVE: To scrutinize the potential of androgens to relax the myometrium and the mechanism of their action. SAMPLES: A pregnancy-derived myometrial smooth muscle cell line (PHM1-41) and myometrial strips prepared from tissues obtained from pregnant women (lean, n = 9; obese, n = 6) undergoing elective cesarean section at term and from nonpregnant C57BL/6 mice (n=5) were each utilized. DESIGN: The contraction of collagen-embedded PHM1-41s and the stretch-induced contraction of human and murine myometrial strips were assessed after incubation with Testosterone (T), dihydrotestosterone (DHT), and T conjugated to BSA. Intracellular calcium ([Ca(2+)]) and phosphorylated myosin light chain concentrations were quantified in PHM1-41s using a Fluo-4 Ca(2+) assay and in-cell Westerns, respectively. SETTING: University research institute. RESULTS: DHT and T, but not T conjugated to BSA, impaired the contractile function of PHM1-41s and of human and murine myometrial strips. The response was rapid (observed within minutes), was sustainable for up to 48 hours, and was not abolished on knockdown of the androgen receptor. DHT (100 MUm) reduced the amplitude of lean strip contraction to 2 +/- 2% of the pretreatment value and T (100 MUm) to 3.3 +/- 1%. These values for obese strips were 15 +/- 6.7% and 11 +/ 6.7%, respectively. At the same doses, in murine strips, DHT reduced the amplitude to 4.8 +/- 3% and T to 4.9 +/- 3%. DHT (50 MUm) pretreatment reduced the oxytocin-stimulated increase in [Ca(2+)] (P < .0001; n = 6) and phosphorylated myosin light chain (P < .05; n = 5) in PHM1-41s. CONCLUSION: Lipid soluble androgens could be developed as tocolytic agents for the treatment of preterm labor. PMID- 26751190 TI - Robust Thyroid Gene Expression and Radioiodine Uptake Induced by Simultaneous Suppression of BRAF V600E and Histone Deacetylase in Thyroid Cancer Cells. AB - CONTEXT: Use of BRAF V600E inhibitors to restore thyroid iodide-handling gene expression and radioactive iodine (RAI) avidity is an attractive therapeutic strategy for RAI-refractory thyroid cancer, but recent initial clinical responses were modest. Given histone deacetylation at the sodium/iodide symporter promoter by histone deacetylase (HDAC) as a mechanism, simultaneously targeting BRAF V600E and HDAC could be a more effective strategy. OBJECTIVES: The objective of the study was to test whether suppressing both BRAF V600E and HDAC could more effectively induce thyroid gene expression and RAI uptake in thyroid cancer cells. RESEARCH DESIGN: We tested the BRAF V600E inhibitor PLX4032 (vemurafenib) and the HDAC inhibitor SAHA (vorinostat), two major anticancer drugs currently approved for clinical use, in inducing thyroid gene expression and RAI uptake in thyroid cancer cells. RESULTS: PLX4032 alone induced a modest expression of thyroid genes and RAI uptake preferentially in thyroid cancer cells harboring BRAF V600E. SAHA showed an effect in a genetic-independent manner in all the cells. A robust synergistic effect on thyroid gene expression and RAI uptake was observed in BRAF V600E-positive thyroid cancer cells when the two inhibitors were simultaneously used. This was dramatically enhanced further by TSH; triple combination of PLX4032, SAHA, and TSH showed the most robust effect on thyroid gene expression and RAI uptake in cells harboring BRAF V600E. Abundant sodium/iodide symporter protein expression in thyroid cancer cells under these conditions was confirmed by immunofluorescent microscopy. CONCLUSIONS: Simultaneously suppressing BRAF V600E and HDAC, particularly when cotreated with TSH, induced a far more robust expression of thyroid genes and RAI uptake in thyroid cancer cells than suppressing BRAF V600E alone. Triple combination of PLX4032, SAHA, and TSH is a specific robust regimen to restore RAI avidity in RAI refractory BRAF V600E-positive thyroid cancer, which warrants clinical trials to confirm. PMID- 26751191 TI - Single-Dose Study of a Corticotropin-Releasing Factor Receptor-1 Antagonist in Women With 21-Hydroxylase Deficiency. AB - CONTEXT: Treatment of 21-hydroxylase deficiency (21OHD) is difficult to optimize. Normalization of excessive ACTH and adrenal steroid production commonly requires supraphysiologic doses of glucocorticoids. OBJECTIVES: We evaluated the safety and tolerability of the selective corticotropin releasing factor type 1 (CRF1) receptor antagonist NBI-77860 in women with classic 21OHD and tested the hypothesis that CRF1 receptor blockade decreases early-morning ACTH and 17alpha hydroxyprogesterone (17OHP) in these patients. PARTICIPANTS: The study enrolled eight classic 21OHD females, ages 18-58 years, seen at a single tertiary referral university setting. DESIGN: This was a phase Ib, single-blind, placebo controlled, fixed-sequence, single-dose trial. During three treatment periods separated by 3-week washout intervals, patients sequentially received placebo, NBI-77860 300 mg, and NBI-77860 600 mg at 10 pm; glucocorticoid therapy was withheld for 20 hours. We evaluated ACTH, 17OHP, androstenedione, and testosterone as well as NBI-77860 pharmacokinetics over 24 hours. RESULTS: Dose dependent reductions of ACTH and/or 17OHP were observed in six of eight subjects. Relative to placebo, NBI-77860 led to an ACTH and 17OHP reduction by a mean of 43% and 0.7% for the 300 mg dose, respectively, and by 41% and 27% for the 600 mg dose, respectively. Both NBI-77860 doses were well tolerated. CONCLUSION: The meaningful reductions in ACTH and 17OHP following NBI-77860 dosing in 21OHD patients demonstrate target engagement and proof of principle in this disorder. These promising data provide a rationale for additional investigations of CRF1 receptor antagonists added to physiologic doses of hydrocortisone and fludrocortisone acetate for the treatment of classic 21OHD. PMID- 26751192 TI - Impact of Delay in Diagnosis in Outcomes in MEN1: Results From the Dutch MEN1 Study Group. AB - OBJECTIVE: Identifying a germline mutation in the multiple endocrine neoplasia type 1 (MEN1) gene in an index case has consequences for a whole family. Eligible family members should be offered genetic counseling and MEN1 mutation testing. Subsequently, clinical screening of mutation carriers according to the guidelines should be initiated. We assessed whether there is a lag time from MEN1 diagnosis of the index case to MEN1 diagnosis of family members. In addition, we determined whether this lag time was associated with an increased morbidity and mortality risk. DESIGN: A cohort study was performed using the Dutch MEN1 database, including >90% of the Dutch MEN1 population >16 years of age (n = 393). RESULTS: Fifty-eight MEN1 families were identified, of whom 57 were index cases and 247 were non-index cases (n = 304). The median lag time in MEN1 diagnosis of family members was 3.5 (range, 0-30) years. At the time of MEN1 diagnosis, 30 (12.1%) non-index cases had a duodenopancreatic neuroendocrine tumor, of whom 20% had metastases with a mean lag time of 10.9 years, in comparison with 7.1 years without metastases. Twenty-five (10.1%) non-index cases had a pituitary tumor, of whom 80% had a microadenoma and 20% had a macroadenoma, with mean lag times of 7.2 and 10.6 years, respectively. Ninety-five (38.4%) non-index cases had a primary hyperparathyroidism with a mean lag time of 9.5 years in comparison with seven patients without a primary hyperparathyroidism with a mean lag time of 3 years (P = .005). Ten non-index cases died because of a MEN1-related cause that developed during or before the lag time. CONCLUSION: There is a clinically relevant delay in MEN1 diagnosis in families because of a lag time between the diagnosis of an index case and the rest of the family. More emphasis should be placed on the conduct of proper counseling and genetic testing in all eligible family members. PMID- 26751193 TI - Effect of Hesperidin With and Without a Calcium (Calcilock) Supplement on Bone Health in Postmenopausal Women. AB - CONTEXT: Citrus fruits contain unique flavanones. One of the most abundant of the flavanones, hesperidin, has been shown to prevent bone loss in ovariectomized rats. OBJECTIVE: The objective of the study was to measure the effect of hesperidin with or without calcium supplementation on bone calcium retention in postmenopausal women. DESIGN: The study was a double-blind, placebo-controlled, randomized-order crossover design of 500 g hesperidin with or without 500 mg calcium supplement in 12 healthy postmenopausal women. Bone calcium retention was determined from urinary excretion of the rare isotope, (41)Ca, from bone. RESULTS: Calcium plus hesperidin, but not hesperidin alone, improved bone calcium retention by 5.5% (P < .04). CONCLUSION: Calcium supplementation (Calcilock), in combination with hesperidin, is effective at preserving bone in postmenopausal women. PMID- 26751194 TI - Long-Term Safety of Letrozole and Gonadotropin Stimulation for Fertility Preservation in Women With Breast Cancer. AB - CONTEXT AND OBJECTIVE: There has been increased attention to the issue of fertility preservation (FP). We aimed to investigate the long-term safety of FP via controlled ovarian stimulation with letrozole supplementation (COSTLES) prior to breast cancer treatment. DESIGN, SETTING, AND PARTICIPANTS: This is a prospective, nonrandomized, controlled study conducted between the years 2002 and 2014. A total of 337 women diagnosed with stage 3 or less invasive breast cancer were enrolled during a FP consultation before chemotherapy. Of those, 120 elected to undergo COSTLES for FP prior to chemotherapy (FP group). The remaining 217 patients did not undergo any FP procedure and served as the controls. MAIN OUTCOME MEASURE: The primary end point was cancer recurrence defined as the detection of locoregional tumor (chest wall, regional nodal disease), distant metastases, or contralateral invasive breast cancer. RESULTS: The baseline characteristics at enrollment were similar between the FP and control groups except for the less frequent lymph node involvement (P = .02) in the former. The mean follow-up after diagnosis was 5.0 years in the FP group and 6.9 years in the control group. In the FP group, the hazard ratio for recurrence after ovarian stimulation was 0.77 (95% confidence interval 0.28-2.13), and the survival was not compromised compared with controls (P = .61). Neither BRCA gene mutation status (P = .57) nor undergoing FP before or after breast surgery (P = .44) affected survival outcomes in the FP group. Likewise, none of the tumor characteristics including the estrogen receptor status affected the survival rates after the COSTLES. CONCLUSIONS: COSTLES is unlikely to cause a substantially increased recurrence risk in breast cancer during the 5 years after diagnosis. PMID- 26751195 TI - Musculoskeletal and Endocrine Health in Adults With Cerebral Palsy: New Opportunities for Intervention. AB - CONTEXT: Cerebral palsy (CP) increases fracture risk through diminished ambulation, nutritional deficiencies, and anticonvulsant medication use. Studies examining bone mineral density (BMD) in adults with CP are limited. OBJECTIVE: To examine the relationship between body composition, BMD, and fractures in adults with CP. The effect of functional, nutritional, and endocrine factors on BMD and body composition is also explored. DESIGN: Retrospective cross-sectional study. SETTING AND PARTICIPANTS: Forty-five adults with CP (mean age, 28.3 +/- 11.0 years) who had dual-energy x-ray absorptiometry imaging at a single tertiary hospital between 2005 and 2015. RESULTS: Seventeen (38%) had a past history of fragility fracture; 43% had a Z-score of <= -2.0 at the lumbar spine (LS) and 41% at the femoral neck (FN). In nonambulatory patients, every one unit decrease in FN Z-score increased the risk of fracture 3.2-fold (95% confidence interval, 1.07 9.70; P = .044). Stepwise linear regression revealed that the Gross Motor Function Classification System was the best predictor of LS Z-score (R(2) = 0.550; beta = -0.582; P = .002) and FN Z-score (R(2) = 0.428; beta = -0.494; P = .004); 35.7% of the variance in BMD was accounted for by lean tissue mass. Hypogonadism, present in 20% of patients, was associated with reduced lean tissue mass and reduced LS BMD. Lean tissue mass positively correlated with BMD in eugonadal patients, but not in hypogonadal patients. CONCLUSIONS: Low BMD and fractures are common in adults with CP. This is the first study to document hypogonadism in adults with CP with detrimental changes in body composition and BMD. PMID- 26751197 TI - Randomized controlled trials: how to describe your study population. PMID- 26751198 TI - Emerging drugs for the treatment of sepsis. AB - INTRODUCTION: The incidence of sepsis, the systemic inflammatory response of the host to an infectious insult, has steadily increased over past decades. This trend is expected to continue. Sepsis is a leading cause of death and disability worldwide. Treatment relies on antibiotics associated to source control and supportive care. Major progress has been made in the understanding and overall management of sepsis. However, there is no specific treatment for sepsis. AREAS COVERED: We searched PubMed and the ClinicalTrials.gov site for English language reports of phase II and III clinical trials pertaining to the field of sepsis. The current review provides a summary of promising candidate treatments for sepsis. We broadly separated candidate drugs into three distinct categories: Blood purification techniques, immunomodulatory drugs and treatments targeting other systems including the heart, the endothelium or coagulation. EXPERT OPINION: Efforts to identify an efficient treatment for sepsis are hampered by the broad definition of the syndrome associated with major heterogeneity between patients affected by sepsis. The characterization of homogeneous groups of patients, through biological or clinical markers is unfortunately lacking. Current research remains active. Candidate drugs for sepsis include hemoperfusion with polymyxin B coated fibre devices, modulation of the immune system with treatments such as hydrocortisone, intravenous immunoglobulins, mesenchymal stem cells, GM-CSF or interferon gamma. Candidate drugs acting on the cardiovascular system include short acting beta 1 blockers, levosimendan or selepressin. Finally, promising strategies, involving monoclonal antibodies or protein antagonists, which selectively inhibit bacterial virulence factors are being assessed at the bedside. A much awaited and needed specific treatment for sepsis will hopefully soon emerge. PMID- 26751196 TI - Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades. AB - CONTEXT: Thiazide diuretics, the antihypertensive agent prescribed most frequently worldwide, are commonly associated with hypercalcemia. However, the epidemiology and clinical features are poorly understood. OBJECTIVE: To update the incidence of thiazide-associated hypercalcemia and clarify its clinical features. PATIENTS AND METHODS: In a population-based descriptive study, Olmsted County, Minnesota, residents with thiazide-associated hypercalcemia were identified through the Rochester Epidemiology Project and the Mayo Clinic Laboratory Information System from 2002-2010 and were added to the historical cohort beginning in 1992. MAIN OUTCOME: Incidence rates were adjusted to the 2010 United States white population. RESULTS: Overall, 221 Olmsted County residents were identified with thiazide-associated hypercalcemia an average of 5.2 years after initiation of treatment. Subjects were older (mean age, 67 years) and primarily women (86.4%). The incidence of thiazide-associated hypercalcemia increased after 1997 and peaked in 2006 with an annual incidence of 20 per 100,000, compared to an overall rate of 12 per 100,000 in 1992-2010. Severe hypercalcemia was not observed in the cohort despite continuation of thiazide treatment in 62.4%. Of patients discontinuing thiazides, 71% continued to have hypercalcemia. Primary hyperparathyroidism was diagnosed in 53 patients (24%), including five patients who underwent parathyroidectomy without thiazide discontinuation. CONCLUSIONS: Many patients with thiazide-associated hypercalcemia have underlying primary hyperparathyroidism. Additionally, a sharp rise in thiazide-associated hypercalcemia incidence began in 1998, paralleling the increase observed in primary hyperparathyroidism in this community. Case ascertainment bias from targeted osteoporosis screening is the most likely explanation. PMID- 26751199 TI - Restoring integrity--A grounded theory of coping with a fast track surgery programme. AB - AIMS AND OBJECTIVES: The aim of this study was to generate a theory conceptualizing and explaining behavioural processes involved in coping in order to identify the predominant coping types and coping type-specific features. BACKGROUND: Patients undergoing fast track procedures do not experience a higher risk of complications, readmission, or mortality. However, such programmes presuppose an increasing degree of patient involvement, placing high educational, physical, and mental demands on the patients. There is a lack of knowledge about how patients understand and cope with fast track programmes. DESIGN: The study design used classical grounded theory. METHODS: The study used a multimodal approach with qualitative and quantitative data sets from 14 patients. RESULTS: Four predominant types of coping, with distinct physiological, cognitive, affective, and psychosocial features, existed among patients going through a fast track total hip replacement programme. These patients' main concern was to restore their physical and psychosocial integrity, which had been compromised by reduced function and mobility in daily life. To restore integrity they economized their mental resources, while striving to fulfil the expectations of the fast track programme. This goal was achieved by being mentally proactive and physically active. Three out of the four predominant types of coping matched the expectations expressed in the fast track programme. The non-matching behaviour was seen among the most nervous patients, who claimed the right to diverge from the programme. CONCLUSION: In theory, four predominant types of coping with distinct physiological, cognitive, affective, and psychosocial features occur among patients going through a fast track total hip arthroplasty programme. PMID- 26751201 TI - Diastolic Dysfunction and Outcome in Acute Ischemic Stroke. AB - BACKGROUND: Left ventricular diastolic dysfunction (DD) is associated with an increased mortality in general population and patients with myocardial infarct. In the present study, we investigated whether DD is associated with outcomes after ischemic stroke. METHODS: Five hundred and three acute ischemic stroke patients with normal left ventricular ejection fraction (>=50%) were retrospectively included. Echocardiography and tissue Doppler imaging were used to evaluate and grade diastolic function. Ordinal logistic and Cox regression analyses were used to examine relations between DD and modified Rankin Scale (mRS) score at 3 months and mortality after stroke, respectively. RESULTS: Mean age was 67.2 +/- 11.8 years and 63% were men. Among parameters of diastolic function, early mitral inflow velocity/early diastolic mitral annulus velocity (E/e') was independently related with higher mRS score at 3 months and mortality after ischemic stroke. The highest quartile of E/e' (>14) was independently associated with higher mRS score (adjusted OR 3.86, 95% CI 2.27-6.54) as well as with mortality (hazards ratio [HR] 2.87, 95% CI 1.17-7.04) as compared to the lowest quartile of E/e' (<8.8). In addition, moderate-to-severe DD grade was related to higher mRS score (adjusted OR 2.41, 95% CI 1.15-5.06) and mortality (HR 6.63, 95% CI 1.80-24.43) compared to the normal diastolic function. CONCLUSION: In patients with ischemic stroke, DD is associated with functional outcome at 3 months and mortality. Our data suggest that more attention should be given to DD in patients with ischemic stroke. PMID- 26751200 TI - Distributed Function Mining for Gene Expression Programming Based on Fast Reduction. AB - For high-dimensional and massive data sets, traditional centralized gene expression programming (GEP) or improved algorithms lead to increased run-time and decreased prediction accuracy. To solve this problem, this paper proposes a new improved algorithm called distributed function mining for gene expression programming based on fast reduction (DFMGEP-FR). In DFMGEP-FR, fast attribution reduction in binary search algorithms (FAR-BSA) is proposed to quickly find the optimal attribution set, and the function consistency replacement algorithm is given to solve integration of the local function model. Thorough comparative experiments for DFMGEP-FR, centralized GEP and the parallel gene expression programming algorithm based on simulated annealing (parallel GEPSA) are included in this paper. For the waveform, mushroom, connect-4 and musk datasets, the comparative results show that the average time-consumption of DFMGEP-FR drops by 89.09%%, 88.85%, 85.79% and 93.06%, respectively, in contrast to centralized GEP and by 12.5%, 8.42%, 9.62% and 13.75%, respectively, compared with parallel GEPSA. Six well-studied UCI test data sets demonstrate the efficiency and capability of our proposed DFMGEP-FR algorithm for distributed function mining. PMID- 26751202 TI - Increased Risk of Herpes Zoster in Diabetic Patients Comorbid with Coronary Artery Disease and Microvascular Disorders: A Population-Based Study in Taiwan. AB - We investigated the association between the risk of herpes zoster (HZ) and diabetes-related macrovascular comorbidities and microvascular disorders in diabetic patients. This retrospective study included 25,345 patients with newly identified HZ and age- and gender-matched controls retrieved from the National Health Insurance Research Database in Taiwan during the period of 2005 to 2011. Multivariate logistic regression analyses were used to calculate the odds ratios (OR) and to assess the risk factors for HZ in diabetic patients with associated macrovascular or microvascular disorders. Risk factors for HZ were significantly increased in cases of diabetes mellitus (DM) compared with those in cases of non DM controls (20.2% vs. 17.0%, OR = 1.24, p<0.001). Results of age- and gender adjusted analyses demonstrated a significantly higher risk of HZ in DM patients with accompanying coronary artery disease (CAD) (adjusted OR = 1.21, p<0.001) and microvascular disorders (aOR = 1.32, p<0.001) than in DM patients with other comorbidities but no microvascular disorders. Patients who took thiazolidinedione, alpha-glucosidase inhibitors and insulin had a higher HZ risk than those taking metformin or sulphonylureas alone (aOR = 1.11, 1.14 and 1.18, p<0.001, respectively). Patients who took insulin alone or in combination with other antidiabetic agents had a significantly higher risk of HZ (aOR = 1.25, p<0.001) than those who received monotherapy. Diabetic patients comorbid with coronary artery disease and associated microvascular disorders had an increased risk of HZ occurrence. PMID- 26751203 TI - Intergroup Contact Effects via Ingroup Distancing among Majority and Minority Groups: Moderation by Social Dominance Orientation. AB - Five studies tested whether intergroup contact reduces negative outgroup attitudes through a process of ingroup distancing. Based on the deprovincialization hypothesis and Social Dominance Theory, we hypothesized that the indirect effect of cross-group friendship on outgroup attitudes via reduced ingroup identification is moderated by individuals' Social Dominance Orientation (SDO), and occurs only for members of high status majority groups. We tested these predictions in three different intergroup contexts, involving conflictual relations between social groups in Germany (Study 1; N = 150; longitudinal Study 2: N = 753), Northern Ireland (Study 3: N = 160; Study 4: N = 1,948), and England (Study 5; N = 594). Cross-group friendship was associated with reduced ingroup identification and the link between reduced ingroup identification and improved outgroup attitudes was moderated by SDO (the indirect effect of cross-group friendship on outgroup attitudes via reduced ingroup only occurred for individuals scoring high, but not low, in SDO). Although there was a consistent moderating effect of SDO in high-status majority groups (Studies 1-5), but not low-status minority groups (Studies 3, 4, and 5), the interaction by SDO was not reliably stronger in high- than low-status groups. Findings are discussed in terms of better understanding deprovincialization effects of contact. PMID- 26751204 TI - Correction: Pigment Epithelium-Derived Factor (PEDF) Expression Induced by EGFRvIII Promotes Self-renewal and Tumor Progression of Glioma Stem Cells. AB - [This corrects the article DOI: 10.1371/journal.pbio.1002152.]. PMID- 26751206 TI - Nonsurgical endodontic management of dens invaginatus with open apex: A case report. AB - Dens invaginatus is a rare malformation with a widely varied morphology. It typically affects permanent maxillary lateral incisors, central incisors, and premolars. This article demonstrates rapid management of type II dens invagination with open apex and large periradicular lesion using calcium hydroxide as intracanal medicament for 1-week followed by apical plug formation with mineral trioxide aggregate Plus and lateral condensation of Gutta-percha. At 24-month follow-up, the patient was asymptomatic and lesion was entirely resolved. PMID- 26751205 TI - Dnajb8, a Member of the Heat Shock Protein 40 Family Has a Role in the Tumor Initiation and Resistance to Docetaxel but Is Dispensable for Stress Response. AB - Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined by their abilities of tumor initiation, self-renewal and differentiation. In a previous study, we showed by gene knockdown using siRNA and gene overexpression experiments that Dnaj (Hsp40) homolog, subfamily B, member 8 (DNAJB8), a role in the maintenance, of renal cell carcinoma CSCs/CICs. In the present study, we established Dnajb8 knockout (KO) renal cell carcinoma (RCC) line cells (RenCa cells) and analyzed the cells to confirm the function of Dnajb8 in RCC CSCs/CICs. Dnajb8 KO cells showed reduced ratios of side population cells and reduced sphere forming ability. An in vivo single cell tumor initiation assay revealed that the numbers of CSCs/CICs were 3 in 4 wild-type RenCa cells and 1 in 4 Dnajb8 KO cells. Dnajb8 KO cells showed sensitivity to Docetaxel. On the other hand, Dnajb8 KO cells did not show any sensitivities to stresses including low pH, low glucose, heat shock and sensitivity to cisplatin. The results indicate that Dnajb8 has a role in tumor initiation, side population ratio and sphere formation but it is dispensable for stress responses. PMID- 26751208 TI - Effects of Photo and Genotype-Based Misidentification Error on Estimates of Survival, Detection and State Transition using Multistate Survival Models. AB - We simulated multistate capture histories (CHs) by varying state survival (phi), detection (p) and transition (psi), number of total capture occasions and releases per capture occasion and then modified these scenarios to mimic false rejection error (FRE), a common misidentification error, resulting from the failure to match samples of the same individual. We then fit a multistate model and estimated accuracy, bias and precision of state-specific phi, p and psi to better understand the effects of FRE on different simulation scenarios. As expected, phi, and p, decreased in accuracy with FRE, with lower accuracy when CHs were simulated under a shorter-term study and a lower number of releases per capture occasion (lower sample size). Accuracy of psi estimates were robust to FRE except in those CH scenarios simulated using low sample size. The effect of FRE on bias was not consistent among parameters and differed by CH scenario. As expected, phi was negatively biased with increased FRE (except for the low phi low p CH scenario simulated with a low sample size), but we found that the magnitude of bias differed by scenario (high p CH scenarios were more negatively biased). State transition was relatively unbiased, except for the low p CH scenarios simulated with a low sample size, which were positively biased with FRE, and high p CH scenarios simulated with a low sample size. The effect of FRE on precision was not consistent among parameters and differed by scenario and sample size. Precision of phi decreased with FRE and was lowest with the low phi low p CH scenarios. Precision of p estimates also decreased with FRE under all scenarios, except the low phi high p CH scenarios. However, precision of psi increased with FRE, except for those CH scenarios simulated with a low sample size. Our results demonstrate how FRE leads to loss of accuracy in parameter estimates in a multistate model with the exception of psi when estimated using an adequate sample size. PMID- 26751207 TI - Simplified Paper Format for Detecting HIV Drug Resistance in Clinical Specimens by Oligonucleotide Ligation. AB - Human immunodeficiency virus (HIV) is a chronic infection that can be managed by antiretroviral treatment (ART). However, periods of suboptimal viral suppression during lifelong ART can select for HIV drug resistant (DR) variants. Transmission of drug resistant virus can lessen or abrogate ART efficacy. Therefore, testing of individuals for drug resistance prior to initiation of treatment is recommended to ensure effective ART. Sensitive and inexpensive HIV genotyping methods are needed in low-resource settings where most HIV infections occur. The oligonucleotide ligation assay (OLA) is a sensitive point mutation assay for detection of drug resistance mutations in HIV pol. The current OLA involves four main steps from sample to analysis: (1) lysis and/or nucleic acid extraction, (2) amplification of HIV RNA or DNA, (3) ligation of oligonucleotide probes designed to detect single nucleotide mutations that confer HIV drug resistance, and (4) analysis via oligonucleotide surface capture, denaturation, and detection (CDD). The relative complexity of these steps has limited its adoption in resource limited laboratories. Here we describe a simplification of the 2.5-hour plate format CDD to a 45-minute paper-format CDD that eliminates the need for a plate reader. Analysis of mutations at four HIV-1 DR codons (K103N, Y181C, M184V, and G190A) in 26 blood specimens showed a strong correlation of the ratios of mutant signal to total signal between the paper CDD and the plate CDD. The assay described makes the OLA easier to perform in low resource laboratories. PMID- 26751209 TI - Brugia malayi Asparaginyl-tRNA Synthetase Stimulates Endothelial Cell Proliferation, Vasodilation and Angiogenesis. AB - A hallmark of chronic infection with lymphatic filarial parasites is the development of lymphatic disease which often results in permanent vasodilation and lymphedema, but all of the mechanisms by which filarial parasites induce pathology are not known. Prior work showed that the asparaginyl-tRNA synthetase (BmAsnRS) of Brugia malayi, an etiological agent of lymphatic filariasis, acts as a physiocrine that binds specifically to interleukin-8 (IL-8) chemokine receptors. Endothelial cells are one of the many cell types that express IL-8 receptors. IL-8 also has been reported previously to induce angiogenesis and vasodilation, however, the effect of BmAsnRS on endothelial cells has not been reported. Therefore, we tested the hypothesis that BmAsnRS might produce physiological changes in endothelial by studying the in vitro effects of BmAsnRS using a human umbilical vein cell line EA.hy926 and six different endothelial cell assays. Our results demonstrated that BmAsnRS produces consistent and statistically significant effects on endothelial cells that are identical to the effects of VEGF, vascular endothelial growth factor. This study supports the idea that new drugs or immunotherapies that counteract the adverse effects of parasite derived physiocrines may prevent or ameliorate the vascular pathology observed in patients with lymphatic filariasis. PMID- 26751210 TI - Use of a Probabilistic Motif Search to Identify Histidine Phosphotransfer Domain Containing Proteins. AB - The wealth of newly obtained proteomic information affords researchers the possibility of searching for proteins of a given structure or function. Here we describe a general method for the detection of a protein domain of interest in any species for which a complete proteome exists. In particular, we apply this approach to identify histidine phosphotransfer (HPt) domain-containing proteins across a range of eukaryotic species. From the sequences of known HPt domains, we created an amino acid occurrence matrix which we then used to define a conserved, probabilistic motif. Examination of various organisms either known to contain (plant and fungal species) or believed to lack (mammals) HPt domains established criteria by which new HPt candidates were identified and ranked. Search results using a probabilistic motif matrix compare favorably with data to be found in several commonly used protein structure/function databases: our method identified all known HPt proteins in the Arabidopsis thaliana proteome, confirmed the absence of such motifs in mice and humans, and suggests new candidate HPts in several organisms. Moreover, probabilistic motif searching can be applied more generally, in a manner both readily customized and computationally compact, to other protein domains; this utility is demonstrated by our identification of histones in a range of eukaryotic organisms. PMID- 26751211 TI - Heterologous Immunity between Adenoviruses and Hepatitis C Virus: A New Paradigm in HCV Immunity and Vaccines. AB - Adenoviruses (Ad) are commonly used as vectors for gene therapy and/or vaccine delivery. Recombinant Ad vectors are being tested as vaccines for many pathogens. We have made a surprising observation that peptides derived from various hepatitis C virus (HCV) antigens contain extensive regions of homology with multiple adenovirus proteins, and conclusively demonstrate that adenovirus vector can induce robust, heterologous cellular and humoral immune responses against multiple HCV antigens. Intriguingly, the induction of this cross-reactive immunity leads to significant reduction of viral loads in a recombinant vaccinia HCV virus infected mouse model, supporting their role in antiviral immunity against HCV. Healthy human subjects with Ad-specific pre-existing immunity demonstrated cross-reactive cellular and humoral immune responses against multiple HCV antigens. These findings reveal the potential of a previously uncharacterized property of natural human adenovirus infection to dictate, modulate and/or alter the course of HCV infection upon exposure. This intrinsic property of adenovirus vectors to cross-prime HCV immunity can also be exploited to develop a prophylactic and/or therapeutic vaccine against HCV. PMID- 26751212 TI - Involving a Citizens' Jury in Decisions on Individual Screening for Prostate Cancer. AB - AIMS: Most public health agencies and learned societies agree that the prostate specific antigen (PSA) test in asymptomatic men should not be recommended, on account of its potential for harm. Yet PSA is still widely used as a screening test and is not being abandoned. This remains a significant public health issue, and citizens' engagement is needed. This study was designed to produce a deliberation on the PSA screening test by a citizens' jury. METHODS: Fifteen citizens were selected and balanced for sex, age, and education. They received an information booklet and participated in a two-day meeting with experts to reach a deliberation on the question "Should the National Health Service discourage or recommend PSA as an individual screening test for prostate cancer in men 55-69 years old?". A facilitator ran the jurors' discussion. RESULTS: All except three of the jurors decided that the National Health Service should discourage the use of PSA as an individual screening test for prostate cancer in 55-69 year-old men. The jury was particularly convinced by the uncertainty of the test outcomes, the utility of the test, and its cost/benefit ratio. Before the meeting 60% of jurors would have recommended the test to a relative, and all the male jurors would have done so. After the meeting these percentages fell to 15% and 12%. CONCLUSIONS: This experience confirms the feasibility and effectiveness of delegating to a group of citizens the responsibility to decide on public health issues on behalf of the community. Public health authorities should invest in information campaigns aimed at the public and in educational initiatives for physicians. This also provided an opportunity to disseminate information on screening, over diagnosis, and over-treatment. PMID- 26751213 TI - Ischemic Stroke in Critically Ill Patients with Malignancy. AB - BACKGROUND: Cerebrovascular diseases are a frequent cause of neurological symptoms in patients with cancer. The clinical characteristics of ischemic stroke (IS) in patients with cancer have been reported in several studies; however, limited data are available regarding critically ill patients with cancer who develop IS during their stay in the intensive care unit (ICU). METHODS: All consecutive patients who underwent brain magnetic resonance imaging (MRI) for suspicion of IS with acute abnormal neurologic symptoms or who developed signs of IS while in the ICU were retrospectively evaluated. We compared the clinical characteristics and diffusion-weighted imaging (DWI) lesion patterns between patients finally diagnosed as having or not having IS. RESULTS: Over the study period, a total of 88 patients underwent brain MRI for suspicion of IS, with altered mental status in 55 (63%), hemiparesis in 28 (32%), and seizure in 20 (23%). A total of 43 (49%) patients were ultimately diagnosed with IS. Multiple DWI lesions (41%) were more common than single lesions (8%). The etiologies of IS were not determined in the majority of patients (n = 27, 63%). In the remaining 16 (37%) patients, the most common aetiology of IS was cardioembolism (n = 8), followed by large-vessel atherosclerosis (n = 3) and small-vessel occlusion (n = 2). However, brain metastases were newly diagnosed in only 7 (8%) patients. Univariate comparison of the baseline characteristics between patients with or without IS did not reveal any significant differences in sex, malignancy type, recent chemotherapy, vascular risk factors, or serum D-dimer levels at the time of suspicion of IS. Thrombotic events were more common in the IS group than in the non-IS group (P = 0.028). However, patients who were ultimately diagnosed with IS had more hemiparesis symptoms at the time of suspicion of IS (P = 0.001). This association was significant even after adjusting for potentially confounding factors (adjusted odds ratio 5.339; 95% confidence interval, 1.521-19.163). CONCLUSIONS: IS developed during ICU stays in critically ill patients with cancer have particular features that may be associated with cancer-related mechanism. PMID- 26751214 TI - EBNA3C Directs Recruitment of RBPJ (CBF1) to Chromatin during the Process of Gene Repression in EBV Infected B Cells. AB - It is well established that Epstein-Barr virus nuclear antigen 3C (EBNA3C) can act as a potent repressor of gene expression, but little is known about the sequence of events occurring during the repression process. To explore further the role of EBNA3C in gene repression-particularly in relation to histone modifications and cell factors involved-the three host genes previously reported as most robustly repressed by EBNA3C were investigated. COBLL1, a gene of unknown function, is regulated by EBNA3C alone and the two co-regulated disintegrin/metalloproteases, ADAM28 and ADAMDEC1 have been described previously as targets of both EBNA3A and EBNA3C. For the first time, EBNA3C was here shown to be the main regulator of all three genes early after infection of primary B cells. Using various EBV-recombinants, repression over orders of magnitude was seen only when EBNA3C was expressed. Unexpectedly, full repression was not achieved until 30 days after infection. This was accurately reproduced in established LCLs carrying EBV-recombinants conditional for EBNA3C function, demonstrating the utility of the conditional system to replicate events early after infection. Using this system, detailed chromatin immunoprecipitation analysis revealed that the initial repression was associated with loss of activation-associated histone modifications (H3K9ac, H3K27ac and H3K4me3) and was independent of recruitment of polycomb proteins and deposition of the repressive H3K27me3 modification, which were only observed later in repression. Most remarkable, and in contrast to current models of RBPJ in repression, was the observation that this DNA-binding factor accumulated at the EBNA3C-binding sites only when EBNA3C was functional. Transient reporter assays indicated that repression of these genes was dependent on the interaction between EBNA3C and RBPJ. This was confirmed with a novel EBV-recombinant encoding a mutant of EBNA3C unable to bind RBPJ, by showing this virus was incapable of repressing COBLL1 or ADAM28/ADAMDEC1 in newly infected primary B cells. PMID- 26751215 TI - Cadmium Activates Multiple Signaling Pathways That Coordinately Stimulate Akt Activity to Enhance c-Myc mRNA Stability. AB - Cadmium is a known environmental carcinogen. Exposure of Cd leads to the activation of several proto-oncogenes in cells. We investigated here the mechanism of c-Myc expression in hepatic cells under Cd treatment. The c-Myc protein and mRNA levels increased in dose- and time-dependent manners in HepG2 cells with Cd treatment. This increase was due to an increase in c-Myc mRNA stability. To explore the mechanism involved in enhancing the mRNA stability, several cellular signaling factors that evoked by Cd treatment were analyzed. PI3K, p38, ERK and JNK were activated by Cd. However, ERK did not participate in the Cd-induced c-Myc expression. Further analysis revealed that mTORC2 was a downstream factor of p38. PI3K, JNK and mTORC2 coordinately activated Akt. Akt was phosphorylated at Thr450 in the untreated cells. Cd treatment led to additional phosphorylation at Thr308 and Ser473. Blocking any of the three signaling factors resulted in the reduction of phosphorylation level at all three Akt sites. The activated Akt phosphorylated Foxo1 and allowed the modified protein to translocate into the cytoplasm. We conclude that Cd-induced accumulation of c-Myc requires the activation of several signaling pathways. The signals act coordinately for Akt activation and drive the Foxo1 from the nucleus to the cytoplasm. Reduction of Foxo1 in the nucleus reduces the transcription of its target genes that may affect c-Myc mRNA stability, resulting in a higher accumulation of the c-Myc proteins. PMID- 26751216 TI - Isolation and Characterization of Pepper Genes Interacting with the CMV-P1 Helicase Domain. AB - Cucumber mosaic virus (CMV) is a destructive pathogen affecting Capsicum annuum (pepper) production. The pepper Cmr1 gene confers resistance to most CMV strains, but is overcome by CMV-P1 in a process dependent on the CMV-P1 RNA1 helicase domain (P1 helicase). Here, to identify host factors involved in CMV-P1 infection in pepper, a yeast two-hybrid library derived from a C. annuum 'Bukang' cDNA library was screened, producing a total of 76 potential clones interacting with the P1 helicase. Beta-galactosidase filter lift assay, PCR screening, and sequencing analysis narrowed the candidates to 10 genes putatively involved in virus infection. The candidate host genes were silenced in Nicotiana benthamiana plants that were then inoculated with CMV-P1 tagged with the green fluorescent protein (GFP). Plants silenced for seven of the genes showed development comparable to N. benthamiana wild type, whereas plants silenced for the other three genes showed developmental defects including stunting and severe distortion. Silencing formate dehydrogenase and calreticulin-3 precursor led to reduced virus accumulation. Formate dehydrogenase-silenced plants showed local infection in inoculated leaves, but not in upper (systemic) leaves. In the calreticulin-3 precursor-silenced plants, infection was not observed in either the inoculated or the upper leaves. Our results demonstrate that formate dehydrogenase and calreticulin-3 precursor are required for CMV-P1 infection. PMID- 26751219 TI - Observed temperament from ages 6 to 36 months predicts parent- and teacher reported attention-deficit/hyperactivity disorder symptoms in first grade. AB - This study tested the prospective association between observational indicators of temperament, which were obtained across multiple assessments when children were 6 36 months of age, and parent and teacher reports of children's attention deficit/hyperactivity disorder (ADHD) behaviors, when children were in first grade. Data were drawn from the Family Life Project and included 1,074 children for whom temperament and either parent- or teacher-reported ADHD behavioral data were available. The results of variable-centered regression models indicated that individual differences in temperament regulation, but not temperamental reactivity, was uniquely predictive of parent- and teacher-reported ADHD behaviors. Latent profile analyses were used to characterize configurations of temperamental reactivity and regulation. Person-centered regression models were subsequently estimated in which temperamental profile membership replaced continuous indicators of temperamental reactivity and regulation as predictors. The results of person-centered regression models indicated that temperamental reactivity and regulation both contributed (both alone and in combination) to the prediction of subsequent ADHD behaviors. In general, the predictive associations from early temperament to later ADHD were of modest magnitude (R 2 = .10-.17). Results are discussed with respect to interest in the early identification of children who are at elevated risk for later ADHD. PMID- 26751217 TI - Whole Genome Sequencing of Mycobacterium africanum Strains from Mali Provides Insights into the Mechanisms of Geographic Restriction. AB - BACKGROUND: Mycobacterium africanum, made up of lineages 5 and 6 within the Mycobacterium tuberculosis complex (MTC), causes up to half of all tuberculosis cases in West Africa, but is rarely found outside of this region. The reasons for this geographical restriction remain unknown. Possible reasons include a geographically restricted animal reservoir, a unique preference for hosts of West African ethnicity, and an inability to compete with other lineages outside of West Africa. These latter two hypotheses could be caused by loss of fitness or altered interactions with the host immune system. METHODOLOGY/PRINCIPAL FINDINGS: We sequenced 92 MTC clinical isolates from Mali, including two lineage 5 and 24 lineage 6 strains. Our genome sequencing assembly, alignment, phylogeny and average nucleotide identity analyses enabled us to identify features that typify lineages 5 and 6 and made clear that these lineages do not constitute a distinct species within the MTC. We found that in Mali, lineage 6 and lineage 4 strains have similar levels of diversity and evolve drug resistance through similar mechanisms. In the process, we identified a putative novel streptomycin resistance mutation. In addition, we found evidence of person-to-person transmission of lineage 6 isolates and showed that lineage 6 is not enriched for mutations in virulence-associated genes. CONCLUSIONS: This is the largest collection of lineage 5 and 6 whole genome sequences to date, and our assembly and alignment data provide valuable insights into what distinguishes these lineages from other MTC lineages. Lineages 5 and 6 do not appear to be geographically restricted due to an inability to transmit between West African hosts or to an elevated number of mutations in virulence-associated genes. However, lineage-specific mutations, such as mutations in cell wall structure, secretion systems and cofactor biosynthesis, provide alternative mechanisms that may lead to host specificity. PMID- 26751221 TI - Biomarkers of bacterial translocation in advanced chronic liver disease: the key to individualizing prognosis. PMID- 26751218 TI - The Synergistic Roles of Cholecystokinin B and Dopamine D5 Receptors on the Regulation of Renal Sodium Excretion. AB - Renal dopamine D1-like receptors (D1R and D5R) and the gastrin receptor (CCKBR) are involved in the maintenance of sodium homeostasis. The D1R has been found to interact synergistically with CCKBR in renal proximal tubule (RPT) cells to promote natriuresis and diuresis. D5R, which has a higher affinity for dopamine than D1R, has some constitutive activity. Hence, we sought to investigate the interaction between D5R and CCKBR in the regulation of renal sodium excretion. In present study, we found D5R and CCKBR increase each other's expression in a concentration- and time-dependent manner in the HK-2 cell, the specificity of which was verified in HEK293 cells heterologously expressing both human D5R and CCKBR and in RPT cells from a male normotensive human. The specificity of D5R in the D5R and CCKBR interaction was verified further using a selective D5R antagonist, LE-PM436. Also, D5R and CCKBR colocalize and co-immunoprecipitate in BALB/c mouse RPTs and human RPT cells. CCKBR protein expression in plasma membrane-enriched fractions of renal cortex (PMFs) is greater in D5R-/- mice than D5R+/+ littermates and D5R protein expression in PMFs is also greater in CCKBR-/- mice than CCKBR+/+ littermates. High salt diet, relative to normal salt diet, increased the expression of CCKBR and D5R proteins in PMFs. Disruption of CCKBR in mice caused hypertension and decreased sodium excretion. The natriuresis in salt-loaded BALB/c mice was decreased by YF476, a CCKBR antagonist and Sch23390, a D1R/D5R antagonist. Furthermore, the natriuresis caused by gastrin was blocked by Sch23390 while the natriuresis caused by fenoldopam, a D1R/D5R agonist, was blocked by YF476. Taken together, our findings indicate that CCKBR and D5R synergistically interact in the kidney, which may contribute to the maintenance of normal sodium balance following an increase in sodium intake. PMID- 26751220 TI - Advances in mass spectrometry-based clinical biomarker discovery. AB - The greatest unmet needs in biomarker discovery are those discoveries that lead to the development of clinical diagnostic tests. These clinical diagnostic tests can provide early intervention when a patient would present otherwise healthy (e.g., cancer or cardiovascular disease) and aid clinical decision making with improved clinical outcomes. The past two decades have seen significant technological improvements in the analytical capabilities of mass spectrometers. Mass spectrometers are unique in that they can directly analyze any biological molecule susceptible to ionization. The biological studies of human metabolites and proteins using contemporary mass spectrometry technology (metabolomics and proteomics, respectively) has been ongoing for over a decade. Some of these studies have resulted in exciting insights into human biology. However, relatively few biomarkers have been translated into clinical tests. This review will discuss some key technological developments that have occurred over this time with an emphasis on technologies that will create new avenues for biomarker discovery. PMID- 26751236 TI - Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial. AB - BACKGROUND: First-line treatment of isolated resectable colorectal peritoneal metastases remains unclear. This study (the Swedish peritoneal study) compares cytoreductive surgery and intraperitoneal chemotherapy (surgery arm) with systemic chemotherapy (chemotherapy arm). METHODS: Patients deemed resectable preoperatively were randomised to surgery and intraperitoneal 5-fluorouracil 550 mg/m(2)/d for 6 d with repeated courses every month or to systemic oxaliplatin and 5-fluorouracil regimen every second week. Both treatments continued for 6 months. Primary end-point was overall survival (OS) and secondary end-points were progression-free survival (PFS), and morbidity. RESULTS: The study terminated prematurely when 48 eligible patients (24/arm) were included due to recruitment difficulties. Two-year OS was 54% in the surgery arm and 38% in the chemotherapy arm (p = 0.04). After 5 years, 8 versus 1 patient were alive, respectively (p = 0.02). Median OS was 25 months versus 18 months, respectively, hazard ratio 0.51 (95% confidence interval: 0.27-0.96, p = 0.04). PFS in the surgery arm was 12 months versus 11 months in the chemotherapy arm (p = 0.16) with 17% versus 0% 5 year PFS. Grade III-IV morbidity was seen in 42% and 50% of the patients, respectively. No mortalities. CONCLUSIONS: Cytoreductive surgery with intraperitoneal chemotherapy may be superior to systemic oxaliplatin-based treatment of colorectal cancer with resectable isolated peritoneal metastases.(ClinicalTrials.gov nr:NCT01524094). PMID- 26751237 TI - Patient isolation precautions and 30-day risk of readmission or death after hospital discharge: a prospective cohort study. AB - OBJECTIVES: Concerns have been raised that isolation precautions may have unintended consequences. The relationship between patient isolation and the 30 day risk of readmission or death among patients discharged from a general medicine ward was examined. METHODS: A prospective cohort study of adult patients discharged to the community from seven general internal medicine wards in Edmonton, Alberta, Canada, from October 2013 to November 2014, was performed. Patients under contact, respiratory, or droplet precautions were considered isolated. Covariates measured at discharge included the Charlson comorbidity score, LACE index, clinical frailty, depression, anxiety, health-related quality of life, and patient satisfaction. Outcomes were measured at 30 days by telephone follow-up and provincial electronic health record query. RESULTS: Of 495 patients (mean age 62 years, 51% female), 75 (18%) were isolated during their admission. Isolated and non-isolated patients had similar lengths of stay (6.2 vs. 6.2 days), depression, anxiety, health-related quality of life, and satisfaction scores at discharge (all p-values non-significant). At 30 days, 85 (17.2%) patients had been readmitted or had died (20.0% of isolated patients vs. 16.7% of non-isolated patients; adjusted odds ratio 1.11, 95% confidence interval 0.57 2.18). CONCLUSIONS: In-hospital isolation does not appear to have an adverse impact on outcomes once patients are discharged from hospital. PMID- 26751238 TI - Health literacy and infectious diseases: why does it matter? AB - OBJECTIVES: Multifactorial interventions are crucial to arrest the threat posed by infectious diseases. Public involvement requires adequate information, but determinants such as health literacy can impact on the effective use of such knowledge. The influence of health literacy on infectious diseases is examined in this paper. METHODS: Databases were searched from January 1999 through July 2015 seeking studies reporting on health literacy and infections such tuberculosis, malaria, and influenza, and infection-related behaviours such as vaccination and hand hygiene. HIV was excluded, as comprehensive reviews have already been published. RESULTS: Studies were found on antibiotic knowledge and use, the adoption of influenza and MMR immunizations, and screening for sexually transmitted and viral hepatitis infections. There was a lack of investigations on areas such as tuberculosis, malaria, hand hygiene, and diarrhoeal diseases. CONCLUSIONS: Limited or insufficient health literacy was associated with reduced adoption of protective behaviours such as immunization, and an inadequate understanding of antibiotics, although the relationship was not consistent. Large gaps remain in relation to infectious diseases with a high clinical and societal impact, such as tuberculosis and malaria. PMID- 26751239 TI - Adding a psychological dimension to mass gatherings medicine. AB - Mass gatherings pose distinctive challenges for medicine. One neglected aspect of this is that the behaviour of people participating in such events is different from the behaviour they exhibit in their everyday lives. This paper seeks to describe a social psychological perspective on the processes shaping people's behaviour at mass gatherings and to explore how these are relevant for an understanding of the processes impacting on the transmission of infection. It is inadequate to conceptualize mass gatherings as simply an aggregate of a large number of individuals. Rather, those present may conceptualize themselves in terms of a collective with a shared group identity. Thinking of oneself and others as members of a collective changes one's behaviour. First, one behaves in terms of one's understanding of the norms associated with the group. Second, the relationships between group members become more trusting and supportive. Understanding these two behavioural changes is key to understanding how and why mass gathering participants may behave in ways that make them more or less vulnerable to infection transmission. Implications for health education interventions are discussed. PMID- 26751241 TI - Ictal dancing associated with hippocampal sclerosis. PMID- 26751240 TI - Syphilis screening practices in blood transfusion facilities in Ghana. AB - OBJECTIVES: The primary objective of this study was to compare laboratory practices for screening blood donors for syphilis at blood transfusion facilities in Ghana with the recommendations of the World Health Organization and the National Blood Service, Ghana (NBSG). The prevalence of syphilis antibodies in blood donors in Ghana was also estimated. METHODS: Over an 11-month period, from February 2014 to January 2015, a semi-structured questionnaire was administered to 122 laboratory technical heads out of a total of 149 transfusion facilities in Ghana. The response rate was 81.9%. RESULTS: A total of 58 (48%) transfusion facilities tested donors for syphilis, with an estimated 3.7% seroprevalence (95% confidence interval 3.6-3.8%). A total of 62782 out of 91386 (68.7%) donations were tested with assays that are not recommended. The estimated syphilis seroprevalence in voluntary donations was 2.9%, compared to 4.0% in family donations (p=0.001). Only 6.9% of the health facilities were using standard operating procedures (SOPs). CONCLUSIONS: Despite international and national recommendations, more than half of the studied health facilities that provide blood transfusions in Ghana are not screening blood donations for syphilis. These data show a considerable mismatch between recommendations and practice, with serious consequences for blood safety and public health. PMID- 26751243 TI - Rational search for genes in familial cortical myoclonic tremor with epilepsy, clues from recent advances. AB - Familial cortical myoclonic tremor with epilepsy (FCMTE) is an autosomal dominant epilepsy syndrome with considerable clinical and genetic heterogeneity. The most important clinical manifestations include adult onset, cortical myoclonic tremor, with or without epileptic seizures. Of the four loci reported, which included 8q24 (FCMTE1), 2p11.1-q12.2 (FCMTE2), 5p15.31-p15.1 (FCMTE3), and 3q26.32-3q28 (FCMTE4), only one probably causative mutation was found co-segregated in two FCMTE2 pedigrees in the alpha2-adrenergic receptor subtype B (ADRA2B) gene. In this review we discuss studies that focused on the molecular genetics of FCMTE, its neuropathology, clinical, neurophysiological and neuroimaging features, which may offer useful clues for the search for causative FCMTE genes. Next-generation sequencing has identified many causative genes in monogenic diseases. However, most next-generation sequencing applications focus on detecting single nucleotide variants or small insertions/deletions, which do not completely resolve the challenge of identifying causative genes in FCMTE. Recent progress in exploring FCMTE has revealed that special mutations such as copy number variants, exon rearrangements and large trinucleotide repeat expansion (or polynucleotide repeat expansion) should be considered. Clues from neuropathological, clinical, neurophysiological and neuroimaging studies indicate that the candidate causative genes should be expressed in the cerebellum, especially in Purkinje cells, and be associated with calcium signaling and GABA receptors. We propose that the developing novel algorithms of next-generation sequencing data, which could detect structure variants and candidate causative gene selection when combined with special mutations detection analysis represent possible future direction of a rational search for causative genes in FCMTE. PMID- 26751242 TI - Patients with psychogenic nonepileptic seizures report more severe migraine than patients with epilepsy. AB - PURPOSE: Clinical observations suggest that psychogenic non-epileptic seizure (PNES) patients often have severe migraine, more severe than epilepsy patients. Investigations into migraine characteristics in patients with PNES are lacking. In this study we tested the hypothesis that, compared to epilepsy patients, PNES patients have more severe migraine, with more frequent and longer duration attacks that cause greater disability. METHOD: In this observational study, 633 patients with video-EEG proven epilepsy or PNES were identified from the Mayo Clinic Epilepsy Monitoring Unit database. Contacted patients were screened for migraine via a validated questionnaire, and when present, data regarding migraine characteristics were collected. Two-sample t-tests, chi square analyses, and Mann Whitney U tests were used to compare migraine characteristics in PNES patients to those of epilepsy patients. RESULTS: Data from 43 PNES patients with migraine and 29 epilepsy patients with migraine were available. Compared to epilepsy patients, PNES patients reported having more frequent headaches (mean 15.1 +/- 9.8 vs. 8.1 +/- 6.6 headache days/month, p<.001), more frequent migraine attacks (mean 6.5 +/ 6.3 vs. 3.8. +/- 4.1 migraines/month, p=.028), longer duration migraines (mean 39.5 +/- 28.3 vs. 27.3 +/- 20.1h, p=.035), and more frequently had non-visual migraine auras (78.6% vs. 46.7% of patients with migraine auras, p=.033). Migraine-related disability scores were not different between PNES and epilepsy patients (median 39, interquartile range 89 vs. 25, interquartile range 60.6, p=.15). CONCLUSION: Compared to epilepsy patients with migraine, PNES patients with migraine report having a more severe form of migraine with more frequent and longer duration attacks that are more commonly associated with non-visual migraine auras. PMID- 26751244 TI - Hypoxia alters steroidogenesis in female marine medaka through miRNAs regulation. AB - Hypoxia is a worldwide environmental problem in marine ecosystems, leading to serious declines in fishery production over large areas. Our previous studies demonstrated that hypoxia is an endocrine disruptor which can cause reproductive impairment through the regulation of miRNAs, suggesting the functional role of miRNAs in reproductive systems in response to hypoxia. In this study, we used small RNA sequencing to determine the change in miRNA profile in ovary of marine medaka Oryzias melastigma under hypoxic stress. A total of 509 miRNAs were found in the ovary of marine medaka, in which, 33 and 10 miRNAs were found to be statistically significant upregulated and downregulated under hypoxia, respectively. Bioinformatics analysis highlighted that a large number of hypoxia suppressed miRNAs that target a variety of steroidogenic enzymes including steroidogenic acute regulatory protein, aromatase, and 17-alpha-monooxygenase. Also, estrogen receptor 2 and androgen receptor were found to be targeted by hypoxia-responsive miRNAs. For the first time, our results showed that hypoxia may upregulate specific steroidogenic enzymes and hormone receptors through actions of miRNA, and hence provide a novel mechanism for the observed female reproductive impairment caused by hypoxia. PMID- 26751246 TI - A dual role of Erk signaling in embryonic stem cells. AB - Erk signaling plays a critical role in maintaining the pluripotency of mouse embryonic stem cells (ESCs). Inhibition of Mek/Erk signaling by pharmacologic Mek inhibitor promotes self-renewal and pluripotency of mouse ESCs. However, knockout of Erk1/2 genes compromises the self-renewal and genomic stability of mouse ESCs. In this review, we summarize recent progress in understanding the role of Erk signaling in pluripotency maintenance, discuss the dual role of Erk in mouse ESCs, and provide explanations for the conflicting data regarding Mek inhibition and Erk knockout. Remaining questions and the prospects of Erk signaling in pluripotency maintenance are also discussed. PMID- 26751245 TI - Toxicity assessment and comparison between two types of iron oxide nanoparticles in Mytilus galloprovincialis. AB - Nanoparticles (NPs), due to their increased application and production, are being released into the environment with unpredictable impact on the physiology of marine organisms, as well as on entire ecosystems and upcoming effects on human health. The aim of the present study was to evaluate and compare the oxidative responses of the mussel Mytilus galloprovincialis after exposure to iron oxide NPs and to iron oxide NPs incorporated into zeolite for 1, 3 and 7 days. Our results showed that both effectors induced changes on animal physiology by causing oxidative stress in hemocytes of exposed mussels compared to control animals. This was shown by the significant increase in reactive oxygen species (ROS) production, protein carbonylation, lipid peroxidation, ubiquitin conjugates and DNA damage. In addition an increase in prooxidant levels as measured by the prooxidant-antioxidant balance (PAB) assay was observed in exposed mussels' hemolymph. The results show that ROS, DNA damage, protein and lipid oxidation, ubiquitin conjugates and PAB could constitute, after further investigation, reliable biomarkers for the evaluation of pollution or other environmental stressors. In addition, more studies are needed in order to ensure the safety of these NPs on various biomedical applications, since it is critical to design NPs that they meet the demands of application without causing cellular toxicity. PMID- 26751247 TI - Systematic Review of Correlates and Determinants of Physical Activity in Persons With Multiple Sclerosis. AB - OBJECTIVE: To review the current evidence regarding correlates and determinants of physical activity (PA) in persons with multiple sclerosis (pwMS). DATA SOURCES: PubMed and Scopus (1980 to January 2015) and reference lists of eligible studies. STUDY SELECTION: Eligible studies include adults with multiple sclerosis; have a cross-sectional or prospective observational design; or examine the effect of a theory-based intervention trial on PA, including a mediation analysis. Eligible studies also apply a quantitative assessment of PA and correlates or proposed mediators and are published in English or German language. DATA EXTRACTION: Two reviewers independently evaluated the risk of bias, extracted data, and categorized variables according to the International Classification of Functioning, Disability and Health. DATA SYNTHESIS: Consistency and the direction of associations were evaluated with a semiquantitative approach. Fifty-six publications with data from observational studies and 2 interventional studies provided evidence for 86 different variables. Consistent correlates of PA were the disability level, walking limitations in particular, PA related self-efficacy, self-regulation constructs, employment status, and educational level. One interventional study provided evidence for a causal relation between self-regulation and PA. However, 59 of the 86 investigated variables in observational studies are based on 1 or 2 study findings, and most results stem from cross-sectional designs. CONCLUSIONS: Beside the importance of the general disability level and walking limitations, the results highlight the importance of personal factors (eg, PA-related self-efficacy, self-regulatory constructs, sociodemographic factors). Limitations and implications of the current review are discussed. Research that is more rigorous is needed to better understand what affects PA in pwMS. PMID- 26751248 TI - A novel method to induce nicotine dependence by intermittent drug delivery using osmotic minipumps. AB - Although osmotic minipumps are a reliable method for inducing nicotine dependence in rodents, continuous nicotine administration does not accurately model the intermittent pattern of nicotine intake in cigarette smokers. Our objectives, therefore, were to investigate whether intermittent nicotine delivery via osmotic minipumps could induce dependence in rats, and to compare the magnitude and duration of withdrawal following forced abstinence from intermittent nicotine to that induced by continuous nicotine administration. In order to administer nicotine intermittently, rats were surgically implanted with saline-filled osmotic minipumps attached to polyethylene tubing that contained hourly unit doses of nicotine alternating with mineral oil to mimic "injections". Three doses of nicotine (1.2, 2.4, and 4.8mg/kg/day) and saline were administered for 14days using this method. In order to compare our intermittent delivery method with the more traditional continuous nicotine delivery, a second group of rats was implanted with minipumps attached to tubing that delivered continuous nicotine for 14days. Rats were administered a 1.5mg/kg subcutaneous (SC) mecamylamine challenge and observed for somatic signs of withdrawal on days 7, 14, 21, and 28 following minipump implantation. Fifteen somatic withdrawal signs were summed within a 50-minute observation period to obtain a composite Dependence Score. A generalized linear mixed-effects model revealed a significant Day*Dose*Method interaction. Amongst continuously-treated rats, only 4.8mg/kg/d nicotine resulted in dependence scores significantly greater than those of controls at 14days of exposure. In contrast, all intermittent nicotine groups showed significantly higher scores beginning at 7days of exposure and persisting beyond 7days of abstinence. In general, intermittent delivery produced a more robust withdrawal syndrome than continuous delivery, and did so at a lower dose threshold and with greater persistence after forced abstinence. PMID- 26751249 TI - Seven root canals in a deciduous maxillary molar detected by the dental operating microscope and micro-computed tomography. AB - The root and root canal morphology of deciduous molars shows considerable variations. Consequently, a comprehensive understanding of the normal and unusual root and root canal configuration types in deciduous teeth is of prime importance. The purpose of this report is to describe a rare anatomical variation in a double-rooted maxillary deciduous molar examined by the dental operating microscope and micro-computed tomography. SCANNING 38:554-557, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26751251 TI - Review and future prospects for DNA barcoding methods in forensic palynology. AB - Pollen can be a critical forensic marker in cases where determining geographic origin is important, including investigative leads, missing persons cases, and intelligence applications. However, its use has previously been limited by the need for a high level of specialization by expert palynologists, slow speeds of identification, and relatively poor taxonomic resolution (typically to the plant family or genus level). By contrast, identification of pollen through DNA barcoding has the potential to overcome all three of these limitations, and it may seem surprising that the method has not been widely implemented. Despite what might seem a straightforward application of DNA barcoding to pollen, there are technical issues that have delayed progress. However, recent developments of standard methods for DNA barcoding of pollen, along with improvements in high throughput sequencing technology, have overcome most of these technical issues. Based on these recent methodological developments in pollen DNA barcoding, we believe that now is the time to start applying these techniques in forensic palynology. In this article, we discuss the potential for these methods, and outline directions for future research to further improve on the technology and increase its applicability to a broader range of situations. PMID- 26751250 TI - More about the geographical pattern of distribution of the genus Pseudouroplectes Lourenco, 1995 (Scorpiones: Buthidae) from Madagascar. AB - The genus Pseudouroplectes Lourenco, 1995 (Buthidae) remains among the less speciose Malagasy genera and all the known species are extremely rare. A new species is described from the dry forests in the Tsingy formations of the National Park Bemaraha, extending the distribution of the genus further north. Once again, the single holotype specimen was obtained by extraction with the use of Berlese system. With the description of the new species, the distributional pattern of this genus is confirmed for dry forest formations from the south to the middle of the island; however, for the first time the group's distribution overlaps that of another micro-scorpion genus, Microcharmus Lourenco, 1995. The distribution patterns of the humicolous micro-scorpions endemic to Madagascar are considered to further explore the "Neogrosphus rule" as a possible explanation of global species distribution patterns in changing environments. PMID- 26751252 TI - Detailed Investigation of the Structural, Thermal, and Electronic Properties of Gold Isocyanide Complexes with Mechano-Triggered Single-Crystal-to-Single-Crystal Phase Transitions. AB - Mechano-induced phase transitions in organic crystalline materials, which can alter their properties, have received much attention. However, most mechano responsive molecular crystals exhibit crystal-to-amorphous phase transitions, and the intermolecular interaction patterns in the daughter phase are difficult to characterize. We have investigated phenyl(phenylisocyanide)gold(I) (1) and phenyl(3,5-dimethylphenylisocyanide)gold(I) (2) complexes, which exhibit a mechano-triggered single-crystal-to-single-crystal phase transition. Previous reports of complexes 1 and 2 have focused on the relationships between the crystalline structures and photoluminescence properties; in this work we have focused on other aspects. The face index measurements of complexes 1 and 2 before and after the mechano-induced phase transitions have indicated that they undergo non-epitaxial phase transitions without a rigorous orientational relationship between the mother and daughter phases. Differential scanning calorimetry analyses revealed the phase transition of complex 1 to be enthalpically driven by the formation of new aurophilic interactions. In contrast, the phase transition of complex 2 was found to be entropically driven, with the closure of an empty void in the mother phase. Scanning electron microscopy observation showed that the degree of the charging effect of both complexes 1 and 2 was changed by the phase transitions, which suggests that the formation of the aurophilic interactions affords more effective conductive pathways. Moreover, flash photolysis time-resolved microwave conductivity measurements revealed that complex 1 increased in conductivity after the phase change, whereas the conductivity of complex 2 decreased. These contrasting results were explained by the different patterns in the aurophilic interactions. Finally, an intriguing disappearing polymorphism of complex 2 has been reported, in which a polymorph form could not be obtained again after some period of time, even with repeated trials. The present studies provide us with a variety of hitherto unknown insights into mechano-responsive molecular crystals, which help us to understand the phase transition behaviors upon mechanical stimulation and establish rational design principles. PMID- 26751254 TI - Current status of palliative care services in Indonesia: a literature review. AB - AIM: To review healthcare literature in relation to the provision of palliative care in Indonesia and to identify factors that may impact on palliative care development. BACKGROUND: People living with life-limiting illness benefit from access to palliative care services to optimize quality of life. Palliative care services are being expanded in developing countries but in Indonesia such services are in their infancy with many patients with life-limiting illnesses having access to appropriate health care compromised. METHODS: Relevant healthcare databases including CINAHL, PubMed, Science Direct and Scopus were searched using the combinations of search terms: palliative care, terminal care, end-of-life care, Indonesia and nursing. A search of grey literature including Internet sites was also carried out. RESULTS: Nine articles were included in the review. Facilitating factors supporting the provision of palliative care included: a culture of strong familial support, government policy support, volunteering and support from regional organizations. Identified barriers to palliative care provision were a limited understanding of palliative care among healthcare professionals, the challenging geography of Indonesia and limited access to opioid medications. CONCLUSIONS: There are facilitators and barriers that currently impact on the development of palliative care in Indonesia. Strategies that can be implemented to improve palliative care include training of nurses and doctors in the primary care sector, integrating palliative care in undergraduate medical and nursing curriculum and educating family and community about basic care. Nurses and doctors who work in primary care can potentially play a role in supporting and educating family members providing direct care to patients with palliative needs. PMID- 26751253 TI - Dynamics of bacterial populations during bench-scale bioremediation of oily seawater and desert soil bioaugmented with coastal microbial mats. AB - This study describes a bench-scale attempt to bioremediate Kuwaiti, oily water and soil samples through bioaugmentation with coastal microbial mats rich in hydrocarbonoclastic bacterioflora. Seawater and desert soil samples were artificially polluted with 1% weathered oil, and bioaugmented with microbial mat suspensions. Oil removal and microbial community dynamics were monitored. In batch cultures, oil removal was more effective in soil than in seawater. Hydrocarbonoclastic bacteria associated with mat samples colonized soil more readily than seawater. The predominant oil degrading bacterium in seawater batches was the autochthonous seawater species Marinobacter hydrocarbonoclasticus. The main oil degraders in the inoculated soil samples, on the other hand, were a mixture of the autochthonous mat and desert soil bacteria; Xanthobacter tagetidis, Pseudomonas geniculata, Olivibacter ginsengisoli and others. More bacterial diversity prevailed in seawater during continuous than batch bioremediation. Out of seven hydrocarbonoclastic bacterial species isolated from those cultures, only one, Mycobacterium chlorophenolicum, was of mat origin. This result too confirms that most of the autochthonous mat bacteria failed to colonize seawater. Also culture-independent analysis of seawater from continuous cultures revealed high-bacterial diversity. Many of the bacteria belonged to the Alphaproteobacteria, Flavobacteria and Gammaproteobacteria, and were hydrocarbonoclastic. Optimal biostimulation practices for continuous culture bioremediation of seawater via mat bioaugmentation were adding the highest possible oil concentration as one lot in the beginning of bioremediation, addition of vitamins, and slowing down the seawater flow rate. PMID- 26751255 TI - Increased white matter connectivity in traumatized children with attention deficit hyperactivity disorder. AB - To distinguish between the consequences of trauma exposure and those of attention deficit hyperactivity disorder (ADHD), we compared brain diffusion tensor imaging (DTI) of children according to the diagnosis and the presence of a potentially traumatic event (PTE). The Early Trauma Inventory Self Report-Short Form (ETISR SF) was used for the assessment of PTEs. Subjects who experienced any traumatic event were placed in the PTE group, and subjects who did not experience such a traumatic event were placed in the non-PTE group. We examined the interactions between ADHD and PTEs in brain [fractional anisotropy (FA) values and mean diffusivity (MD) values] in 54 children with ADHD (29 with PTEs and 25 without PTEs) and 41 controls (18 with PTEs and 23 without PTEs). Analysis of covariance (ANCOVA) revealed main effects of ADHD for FA and MD values in several white matter tracts in the absence of main effects for PTEs. In addition, there was a significant ADHD-PTEs interaction in relation to FA and MD values in several white matter tracts. Further longitudinal studies in a larger sample are warranted to evaluate the neurobiological sequelae related to childhood trauma, ADHD, and interaction between the two. PMID- 26751256 TI - Deciphering phonemes from syllables in blood oxygenation level-dependent signals in human superior temporal gyrus. AB - Linguistic units such as phonemes and syllables are important for speech perception. How the brain encodes these units is not well understood. Many neuroimaging studies have found distinct representations of consonant-vowel syllables that shared one phoneme and differed in the other phoneme (e.g. /ba/ and /da/), but it is unclear whether this discrimination ability is due to the neural coding of phonemes or syllables. We combined functional magnetic resonance imaging with multivariate pattern analysis to explore this question. Subjects listened to nine Mandarin syllables in a consonant-vowel form. We successfully decoded phonemes from the syllables based on the blood oxygenation level dependent signals in the superior temporal gyrus (STG). Specifically, a classifier trained on the cortical patterns elicited by a set of syllables, which contained two phonemes, could distinguish the cortical patterns elicited by other syllables that contained the two phonemes. The results indicated that phonemes have unique representations in the STG. In addition, there was a categorical effect, i.e. the cortical patterns of consonants were similar, and so were the cortical patterns of vowels. Further analysis showed that phonemes exhibited stronger encoding specificity in the mid-STG than in the anterior STG. PMID- 26751257 TI - Molecular dynamics characterization of the conformational landscape of small peptides: A series of hands-on collaborative practical sessions for undergraduate students. AB - Molecular modelling and simulations are nowadays an integral part of research in areas ranging from physics to chemistry to structural biology, as well as pharmaceutical drug design. This popularity is due to the development of high performance hardware and of accurate and efficient molecular mechanics algorithms by the scientific community. These improvements are also benefitting scientific education. Molecular simulations, their underlying theory, and their applications are particularly difficult to grasp for undergraduate students. Having hands-on experience with the methods contributes to a better understanding and solidification of the concepts taught during the lectures. To this end, we have created a computer practical class, which has been running for the past five years, composed of several sessions where students characterize the conformational landscape of small peptides using molecular dynamics simulations in order to gain insights on their binding to protein receptors. In this report, we detail the ingredients and recipe necessary to establish and carry out this practical, as well as some of the questions posed to the students and their expected results. Further, we cite some examples of the students' written reports, provide statistics, and share their feedbacks on the structure and execution of the sessions. These sessions were implemented alongside a theoretical molecular modelling course but have also been used successfully as a standalone tutorial during specialized workshops. The availability of the material on our web page also facilitates this integration and dissemination and lends strength to the thesis of open-source science and education. PMID- 26751258 TI - Platelet count is more useful for predicting posthepatectomy liver failure at surgery for hepatocellular carcinoma than indocyanine green clearance test. AB - BACKGROUND AND OBJECTIVES: Preoperatively evaluating reserved liver function is critical in preventing posthepatectomy liver failure (PHLF) in patients undergoing liver resection. The commonly used indocyanine green (ICG) clearance test has several drawbacks. Patients would benefit from a more reliable and straightforward means of assessing the risk of PHLF. METHODS: This study included 277 patients with hepatocellular carcinoma (HCC) undergoing liver resection. The predictive value of known risk factors for PHLF was compared to that of ICG. RESULTS: PHLF was identified in 25 out of 277 patients (9.0%). Multivariate logistic regression analysis for identifying predictors for the PHLF development revealed platelet count and resected liver volume as significant independent predictors. In a subgroup analysis based on resected liver volume, platelet count was significantly correlated with PHLF in both larger volume (>=100 g) and smaller volume resection groups (<100 g), although ICG R15 level was associated with PHLF only in larger volume group. CONCLUSIONS: Platelet count is superior to ICG R15 level in predicting PHLF development in HCC patients. J. Surg. Oncol. 2016;113:565-569. (c) 2016 Wiley Periodicals, Inc. PMID- 26751259 TI - Topiramate for the management of methamphetamine dependence: a pilot randomized, double-blind, placebo-controlled trial. AB - To date, no medication has been approved as an effective treatment for methamphetamine dependence. Topiramate has attracted considerable attention as a treatment for the dependence on alcohol and stimulants. Therefore, this study aimed to evaluate the effect of topiramate for methamphetamine dependence. This study was a double-blind, randomized, placebo-controlled trial. In the present investigation, 62 methamphetamine-dependent adults were enrolled and randomized into two groups, and received topiramate or a placebo for 10 weeks in escalating doses from 50 mg/day to the target maintenance dose of 200 mg/day. Addiction severity index (ASI) and craving scores were registered every week. The Beck questionnaire was also given to each participant at baseline and every 2 weeks during the treatment. Urine samples were collected at baseline and every 2 weeks during the treatment. Fifty-seven patients completed 10 weeks of the trial. There was no significant difference between both groups in the mean percentage of prescribed capsules taken by the participants. At week six, the topiramate group showed a significantly lower proportion of methamphetamine-positive urine tests in comparison with the placebo group (P = 0.01). In addition, there were significantly lower scores in the topiramate group in comparison with the placebo group in two domains of ASI: drug use severity (P < 0.001) and drug need (P < 0.001). Furthermore, the craving score (duration) significantly declined in the topiramate patients compared to those receiving the placebo. In conclusion, the results of this trial suggest that topiramate may be beneficial for the treatment of methamphetamine dependence. PMID- 26751260 TI - Incidence of cancer in patients with chronic heart failure: a long-term follow-up study. AB - AIMS: With improvement in survival of chronic heart failure (HF), the clinical importance of co-morbidity is increasing. The aim of this study was to assess the incidence and risk of cancer and all-cause mortality in a large Danish HF cohort. METHODS AND RESULTS: A total of 9307 outpatients with verified HF without a prior diagnosis of cancer (27% female, mean age 68 years, 89% with LVEF <45%) were included in the study. A diagnosis of any cancer and all-cause mortality was obtained from Danish national registries. Outcome was compared with the general Danish population. Overall and type-specific risk of cancer was analysed in an adjusted Poisson and Cox regression analysis. The 975 diagnoses of cancer in the HF cohort and 330 843 in the background population corresponded to incidence rates per 10 000 patient-years of 188.9 [95% confidence interval (CI) 177.2 200.6] and 63.0 (95% CI 63.0-63.4), respectively. When stratified by age, incidence rates were increased in all age groups in the HF cohort. Risk of any type of cancer was increased, with an incidence rate ratio of 1.24 (95% CI 1.15 1.33, c < 0.0001). Type-specific analysis demonstrated an increased hazard ratio for all major types of cancer except for prostate cancer. All-cause mortality was higher in HF patients with cancer compared with cancer patients from the background population. CONCLUSIONS: Patients with HF have an increased risk of cancer, which persists after the first year after the diagnosis of HF, and their prognosis is worse compared with that of cancer patients without HF. PMID- 26751261 TI - Aryl Hydrocarbon Receptor-Dependent Pathways in Immune Regulation. AB - The idea of possible involvement of the aryl hydrocarbon receptor (AhR) in transplant tolerance can be traced back >30 years, when very low doses of dioxin the most potent AhR ligand-were found to markedly reduce the generation of cytotoxic T lymphocytes in response to alloantigen challenge in vivo. AhR is a ligand-activated transcription factor that is activated by dioxins and other environmental pollutants. We now know that AhR can bind a broad variety of activating ligands that are disparate in nature, including endogenous molecules and those formed in the gut from food and bacterial products. Consequently, in addition to its classical role as a toxicological signal mediator, AhR is emerging as a transcription factor involved in the regulation of both innate and adaptive immune responses in various immune cell types, including lymphocytes and antigen-presenting cells (APCs). Allograft rejection is mostly a T cell-mediated alloimmune response initiated by the recognition of alloantigens presented by donor and recipient APCs to recipient CD4(+) and CD8(+) T cells. Based on those findings, AhR may function as a critical sensor of outside and inside environments, leading to changes in the immune system that may have relevance in transplantation. PMID- 26751263 TI - New Invasive Assessment Measures of Coronary Artery Disease Severity. AB - Ischemic heart disease is the leading cause of mortality worldwide. The assessment and treatment of patients with ischemic heart disease have advanced greatly over the past decade. Particular attention has been given recently to the recognition of lesions that cause ischemia or that are prone to plaque rupture. New invasive measures of coronary artery disease have been developed, including fractional flow reserve, intravascular ultrasound, optical coherence tomography, and most recently, near-infrared spectroscopy. These technologies have helped to guide the assessment of hemodynamically significant lesions and have shown particular promise in guiding percutaneous coronary interventions. However, mortality and the rate of revascularization have shown mixed results to date. This review seeks to investigate the use and potential benefit of these technologies, with particular attention to clinical end points. PMID- 26751262 TI - A novel treatment adjunct for aspirin exacerbated respiratory disease: the low salicylate diet: a multicenter randomized control crossover trial. AB - BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a clinical triad consisting of aspirin/acetylsalicylic acid (ASA) sensitivity, bronchial asthma, and nasal polyposis. Although respiratory reactions following ingestion of ASA and other nonsteroidal anti-inflammatory drugs (NSAIDs) are considered a hallmark of the condition, respiratory inflammation persists despite patients' avoidance of NSAIDs. Treatment of this condition remains challenging and includes both medical and surgical options. METHODS: A prospective crossover single-blind multicenter study involving 4 tertiary rhinology care centers (n = 30) was conducted in which patients were randomized to start with either 6 weeks of a regular diet or 6 weeks of a low-salicylate diet and then crossed-over for a total study duration of 12 weeks. Patients were evaluated at baseline, 6 weeks (at crossover) and 12 weeks using subjective measures (22-item Sino-Nasal Outcome Test-22 [SNOT-22], Nasal Sinus Symptom Scale [NSSS], and 7-item Asthma Control Questionnaire [ACQ-7]) and objective outcome instruments (Perioperative Sinus Evaluation [POSE] and Lund-Kennedy Endoscopic Score [LKES]). RESULTS: Data was analyzed for 30 patients. Wilcoxon rank sum tests determined that patients had improvement in their median difference in scores, which were all statistically significant, when they followed the low-salicylate diet compared to their regular diet: SNOT-22: 15 (95% confidence interval [CI], 10 to 23.25), p < 0.001; NSSS: 3 (95% CI, 1.75 to 4), p < 0.001; ACQ-7: 4.5 (95% CI, 1.5 to 8.5), p < 0.001; POSE 6 (95% CI, 2.5 to 10), p < 0.001; and LKES: 2.5 (95% CI, 1.5 to 4), p < 0.001). CONCLUSION: The low-salicylate diet may offer a novel treatment adjunct to the current management of AERD. Clinically and statistically significant improvements on both subjective and objective outcome measures were noted for the upper and lower respiratory tracts. PMID- 26751264 TI - Revascularization for Left Anterior Descending Artery Stenosis: A Review of the Evidence That Supports Practice. AB - Disease of the proximal left anterior descending (LAD) artery is a common pathological finding often combined with disease in other coronary arteries. In this article, we review specifically the evidence (and the guidelines arising from the data) for lesions isolated to the proximal LAD only. Critical review of the data reveals limitations with few trials that reflect contemporary practice. Much of the data are observational rather than from randomized trials, and therefore subject to bias. We identified 2 randomized trials of drug-eluting stents versus left internal mammary artery grafting for isolated lesions of the proximal LAD. One reported no difference in major adverse cardiovascular events, but at an early timepoint (6 months), which is likely to be too early to reveal treatment differences. In the second trial, target lesion revascularization excess was noted in the drug-eluting stent arm. Therefore, at the current time, there are little data available to inform interventional cardiologists as to the best revascularization strategy for isolated lesions of the proximal LAD. Further randomized, controlled trials are needed. PMID- 26751265 TI - Identification of New Small Molecules as Apoptosis Inhibitors in Vascular Endothelial Cells. AB - Vascular endothelial cell (VEC) apoptosis is involved in the development of atherosclerosis and other cardiovascular diseases. We previously found that ethyl 1-(2-hydroxy-3-aroxypropyl)-3-aryl-1H-pyrazole -5-carboxylate derivatives (3a-o) play important roles in cell fate control. In this study, among the 15 compounds, we further screened 2 compounds, 3d and 3k, that suppressed VEC apoptosis induced by deprivation of serum and fibroblast growth factor 2. To clarify which chiral enantiomers of 3d and 3k functioned, we synthesized 3d-S and its enantiomer 3d-R, 3k-S, and its enantiomer 3k-R. Then, we investigated the apoptosis-inhibiting activity of the chiral compounds in VECs. Four small molecules, 3d-S, 3d-R, 3k-S, 3k-R, significantly elevated VEC viability and inhibited apoptosis. Furthermore, these small molecules could obviously decrease the level of integrin beta4 that plays a key role in the regulation of VEC apoptosis. 3k-S and 3k-R increased Bcl 2/Bax ratio and reduced reactive oxygen species levels dramatically. Therefore, we provide new VEC apoptosis inhibitors. These compounds may be potential agents in the prevention of vascular diseases associated with VEC apoptosis. PMID- 26751267 TI - Therapeutic Drug Monitoring of Clobazam and Its Metabolite-Impact of Age and Comedication on Pharmacokinetic Variability. AB - BACKGROUND: Clobazam (CLB) has been used as an antiepileptic drug for several decades. There is still insufficient data regarding its pharmacokinetic variability in clinical practice. The purpose of this study was to investigate pharmacokinetic variability of CLB with emphasis on the impact of age and comedication in patients with epilepsy. METHODS: Serum concentration measurements of CLB and its metabolite N-desmethylclobazam (NCLB), as well as demographic and clinical data were retrieved from the routine therapeutic drug monitoring service at the National Center for Epilepsy, Norway, 2009-2013. NCLB/CLB and total (CLB + NCLB), CLB and NCLB concentration/dose (C/D) ratios were calculated. RESULTS: 550 patients (296 women/254 men), average age 27 years (range 1-86), were included. The interindividual pharmacokinetic variability was extensive, as illustrated by a 100-fold variability in serum concentration compared with dose (total C/D ratio 0.03-3.29 umol.L.mg). The CLB C/D ratio was 36% lower in young children (2-9 years) than in adults (18-64 years), reflecting a higher clearance. In patients receiving phenytoin, felbamate, stiripentol, oxcarbazepine or eslicarbazepine acetate, valproate, phenobarbital, zonisamide or carbamazepine one or more of the calculated ratios were significantly different from that in patients receiving no or neutral comedications. The mean values for the different groups were in the order of 20%-230% of C/D ratios in the neutral group and 200%-950% of the NCLB/CLB ratio. CONCLUSIONS: The pharmacokinetic variability of CLB and its metabolite NCLB in clinical practice is extensive, and is influenced by drug-drug interactions, age, and pharmacogenetics. Therapeutic drug monitoring of CLB and NCLB is therefore valuable in patient management. PMID- 26751268 TI - Molecular dynamics of the Bacillus subtilis expansin EXLX1: interaction with substrates and structural basis of the lack of activity of mutants. AB - Expansins are disruptive proteins that loosen growing plant cell walls and can enhance the enzymatic hydrolysis of cellulose. The canonical expansin structure consists of one domain responsible for substrate binding (D2) and another domain (D1) of unknown function, but essential for activity. Although the effects of expansins on cell walls and cellulose fibrils are known, the molecular mechanism underlying their biophysical function is poorly understood. Here, we use molecular dynamics simulations to gain insights into the mechanism of action of the Bacillus subtilis expansin BsEXLX1. We show that BsEXLX1 can slide on the hydrophobic surface of crystalline cellulose via the flat aromatic surface of its binding domain D2, comprised mainly of residues Trp125 and Trp126. Also, we observe that BsEXLX1 can hydrogen bond a free glucan chain in a twisted conformation and that the twisting is chiefly induced by means of residue Asp82 located on D1, which has been shown to be essential for expansin activity. These results suggest that BsEXLX1 could move on the surface of cellulose and disrupt hydrogen bonds by twisting glucan chains. Simulations of the inactive BsEXLX1 mutants Asp82Asn and Tyr73Ala indicate structural alterations around the twisting center in the domain D1, which suggest a molecular basis for the lack of activity of these mutants and corroborate the idea that BsEXLX1 works by inducing twists on glucan chains. Moreover, simulations of the double mutant Asp82Asn/Tyr73Leu predict the recovery of the lost activity of BsEXLX1-Asp82Asn. Our results provide a dynamical view of the expansin-substrate interactions at the molecular scale and help shed light on the expansin mechanism. PMID- 26751269 TI - Capturing the missing [AgF2](-) anion within an Ru2(III/III) dimeric dumbbell complex. AB - The complex {[Ru2(ap)4]2[AgF2]}[BF4]3 ({2}[BF4]3, ap = 2-anilinopyridine), containing the [AgF2](-) anion ligated to two [Ru2](6+) cores, is prepared, characterized, and compared to dimeric dumbbell-type structures, monomeric Ru2 structures, as well as the known set of dihalo coinage-metalate anions. X-ray crystallography indicates that the Ru-Ru and Ru-F distances are rather short, 2.2835(3) A and 2.054(1) A, respectively, while the Ag-F distance of 2.274(1) A is longer than that calculated for the free/un-ligated anion. Cyclic voltammetry in dichloromethane indicates that, while some of {2}(3+) breaks apart into an [Ru2(ap)4F](+) ([3](+)) monomer in solution, the remaining dimer has a single reversible two-electron redox feature for the Ru2(6/5+) couple that is at a lower potential than that of [3](+). This is one of the few examples of a ligated dihalo coinage-metalate, and it is the first example of a coinage metal difluoride anion, either free or ligated. PMID- 26751270 TI - Palladium-catalyzed direct C-H arylation of 3-aryl-2H-benzo[1,2,4]thiadiazine 1,1 dioxides: an efficient strategy to the synthesis of benzothiadiazine-1,1-dioxide derivatives. AB - A new palladium-catalyzed benzothiadiazine-1,1-dioxide direct arylation of C(sp(2))-H bonds is described. 3-Aryl-2H-benzo[1,2,4]thiadiazine 1,1-dioxides react with various aryl iodides to give the corresponding mono-arylation products 3-(biphenyl-2-yl)-2H-benzo[1,2,4]thiadiazine 1,1-dioxides with high reactivity and regioselectivity in the presence of AgOAc. Remarkedly, the addition of TFA is crucial to improve the arylation yield. PMID- 26751271 TI - Enhanced Ultraviolet Stability of Air-Processed Polymer Solar Cells by Al Doping of the ZnO Interlayer. AB - Photostability of organic photovoltaic devices represents a key requirement for the commercialization of this technology. In this field, ZnO is one of the most attractive materials employed as an electron transport layer, and the investigation of its photostability is of particular interest. Indeed, oxygen is known to chemisorb on ZnO and can be released upon UV illumination. Therefore, a deep analysis of the UV/oxygen effects on working devices is relevant for the industrial production where the coating processes take place in air and oxygen/ZnO contact cannot be avoided. Here we investigate the light-soaking stability of inverted organic solar cells in which four different solution processed ZnO-based nanoparticles were used as electron transport layers: (i) pristine ZnO, (ii) 0.03 at %, (iii) 0.37 at %, and (iv) 0.8 at % aluminum-doped AZO nanoparticles. The degradation of solar cells under prolonged illumination (40 h under 1 sun), in which the ZnO/AZO layers were processed in air or inert atmosphere, is studied. We demonstrate that the presence of oxygen during the ZnO/AZO processing is crucial for the photostability of the resulting solar cell. While devices based on undoped ZnO were particularly affected by degradation, we found that using AZO nanoparticles the losses in performance, due to the presence of oxygen, were partially or totally prevented depending on the Al doping level. PMID- 26751272 TI - 25-Hydroxyvitamin D in Patients With Cognitive Decline-Reply. PMID- 26751266 TI - G Protein-coupled Receptor Biased Agonism. AB - G protein-coupled receptors are the largest family of targets for current therapeutics. The classic model of their activation was binary, where agonist binding induced an active conformation and subsequent downstream signaling. Subsequently, the revised concept of biased agonism emerged, where different ligands at the same G protein-coupled receptor selectively activate one downstream pathway versus another. Advances in understanding the mechanism of biased agonism have led to the development of novel ligands, which have the potential for improved therapeutic and safety profiles. In this review, we summarize the theory and most recent breakthroughs in understanding biased signaling, examine recent laboratory investigations concerning biased ligands across different organ systems, and discuss the promising clinical applications of biased agonism. PMID- 26751274 TI - (18)F-Labeling of Arenes and Heteroarenes for Applications in Positron Emission Tomography. AB - Diverse radiochemistry is an essential component of nuclear medicine; this includes imaging techniques such as positron emission tomography (PET). As such, PET can track diseases at an early stage of development, help patient care planning through personalized medicine and support drug discovery programs. Fluorine-18 is the most frequently used radioisotope in PET radiopharmaceuticals for both clinical and preclinical research. Its physical and nuclear characteristics (97% beta(+) decay, 109.8 min half-life, 635 keV positron energy) and high specific activity make it an attractive nuclide for labeling and molecular imaging. Arenes and heteroarenes are privileged candidates for (18)F incorporation as they are metabolically robust and therefore widely used by medicinal chemists and radiochemists alike. For many years, the range of (hetero)arenes amenable to (18)F-fluorination was limited by the lack of chemically diverse precursors, and of radiochemical methods allowing (18)F incorporation in high selectivity and efficiency (radiochemical yield and purity, specific activity, and radio-scalability). The appearance of late-stage fluorination reactions catalyzed by transition metal or small organic molecules (organocatalysis) has encouraged much research on the use of these activation manifolds for (18)F-fluorination. In this piece, we review all of the reactions known to date to install the (18)F substituent and other key (18)F-motifs (e.g., CF3, CHF2, OCF3, SCF3, OCHF2) of medicinal relevance onto (hetero)arenes. The field has changed significantly in the past five years, and the current trend suggests that the radiochemical space available for PET applications will expand rapidly in the near future. PMID- 26751273 TI - Discovery of Tetrahydropyrazolopyridine as Sphingosine 1-Phosphate Receptor 3 (S1P3)-Sparing S1P1 Agonists Active at Low Oral Doses. AB - FTY720 is the first oral small molecule approved for the treatment of people suffering from relapsing-remitting multiple sclerosis. It is a potent agonist of the S1P1 receptor, but its lack of selectivity against the S1P3 receptor has been linked to most of the cardiovascular side effects observed in the clinic. These findings have triggered intensive efforts toward the identification of a second generation of S1P3-sparing S1P1 agonists. We have recently disclosed a series of orally active tetrahydroisoquinoline (THIQ) compounds matching these criteria. In this paper we describe how we defined and implemented a strategy aiming at the discovery of selective structurally distinct follow-up agonists. This effort culminated with the identification of a series of orally active tetrahydropyrazolopyridines. PMID- 26751275 TI - Quantitative Profiling Identifies Potential Regulatory Proteins Involved in Development from Dauer Stage to L4 Stage in Caenorhabditis elegans. AB - When Caenorhabditis elegans encounters unfavorable growth conditions, it enters the dauer stage, an alternative L3 developmental period. A dauer larva resumes larval development to the normal L4 stage by uncharacterized postdauer reprogramming (PDR) when growth conditions become more favorable. During this transition period, certain heterochronic genes involved in controlling the proper sequence of developmental events are known to act, with their mutations suppressing the Muv (multivulva) phenotype in C. elegans. To identify the specific proteins in which the Muv phenotype is highly suppressed, quantitative proteomic analysis with iTRAQ labeling of samples obtained from worms at L1 + 30 h (for continuous development [CD]) and dauer recovery +3 h (for postdauer development [PD]) was carried out to detect changes in protein abundance in the CD and PD states of both N2 and lin-28(n719). Of the 1661 unique proteins identified with a < 1% false discovery rate at the peptide level, we selected 58 proteins exhibiting >=2-fold up-regulation or >=2-fold down-regulation in the PD state and analyzed the Gene Ontology terms. RNAi assays against 15 selected up regulated genes showed that seven genes were predicted to be involved in higher Muv phenotype (p < 0.05) in lin-28(n791), which is not seen in N2. Specifically, two genes, K08H10.1 and W05H9.1, displayed not only the highest rate (%) of Muv phenotype in the RNAi assay but also the dauer-specific mRNA expression, indicating that these genes may be required for PDR, leading to the very early onset of dauer recovery. Thus, our proteomic approach identifies and quantitates the regulatory proteins potentially involved in PDR in C. elegans, which safeguards the overall lifecycle in response to environmental changes. PMID- 26751276 TI - Evaluating Digital PCR for the Quantification of Human Genomic DNA: Accessible Amplifiable Targets. AB - Polymerase chain reaction (PCR) multiplexed assays perform best when the input quantity of template DNA is controlled to within about a factor of ?2. To help ensure that PCR assays yield consistent results over time and place, results from methods used to determine DNA quantity need to be metrologically traceable to a common reference. Many DNA quantitation systems can be accurately calibrated with solutions of DNA in aqueous buffer. Since they do not require external calibration, end-point limiting dilution technologies, collectively termed "digital PCR (dPCR)", have been proposed as suitable for value assigning such DNA calibrants. The performance characteristics of several commercially available dPCR systems have recently been documented using plasmid, viral, or fragmented genomic DNA; dPCR performance with more complex materials, such as human genomic DNA, has been less studied. With the goal of providing a human genomic reference material traceably certified for mass concentration, we are investigating the measurement characteristics of several dPCR systems. We here report results of measurements from multiple PCR assays, on four human genomic DNAs treated with four endonuclease restriction enzymes using both chamber and droplet dPCR platforms. We conclude that dPCR does not estimate the absolute number of PCR targets in a given volume but rather the number of accessible and amplifiable targets. While enzymatic restriction of human genomic DNA increases accessibility for some assays, in well-optimized PCR assays it can reduce the number of amplifiable targets and increase assay variability relative to uncut sample. PMID- 26751277 TI - Five-year prospective investigation of self-harm/suicide-related behaviors in the development of borderline personality disorder. AB - Although borderline personality disorder (BPD) is frequently characterized by nonsuicidal self-injurious behavior (NSSI), suicide attempts (SA), suicidal ideation (SI), and/or suicide threats (ST), it is unclear whether these behaviors are precursors of BPD in adolescence. This study examined self-harm/suicide related behaviors in the development of BPD from adolescence to adulthood in psychiatrically hospitalized adolescents. Participants were 116 adolescents consecutively admitted for a psychiatric hospitalization for self-harm/suicide related behaviors. Adolescents completed self-report questionnaires assessing self-harm/suicide-related behaviors, maladaptive familial behavior, and peer victimization upon admission. Admission diagnoses and history of sexual/physical abuse were abstracted from medical/psychiatric records. Five years after index hospitalization, medical/psychiatric records were systematically reviewed and information on diagnoses was collected. Using multivariable logistic regression analyses, ST predicted BPD above and beyond NSSI, SA, and SI 5 years later (odds ratio = 1.31, 95% confidence interval [1.06, 1.62], p > .01). Traditional risk factors of BPD were not predictive of BPD at 5-year follow-up. Suicidal threats are an important risk factor in adolescents who engage in self-harm/suicide related behaviors that may differentiate those adolescents who go on to develop BPD as adults. Implications for research and treatment are discussed. (PsycINFO Database Record PMID- 26751279 TI - Editorial for personality disorders: Theory, research, and treatment. PMID- 26751278 TI - The impact of psychopathology, race, and environmental context on violent offending in a male adolescent sample. AB - Research has identified a multitude of demographic, psychological, and contextual factors that are associated with violent offending among youth. However, much of the previous research has focused on single factors, and little is known about the effects of these various factors in tandem. The present study examines whether certain community factors impact the effects of race and psychopathology on violent crime. Multivariate analyses were used to investigate race psychopathology combinations and the moderating influence of exposure to community violence in a sample of youth (N = 1,116). Youth without antisocial personality disorder (APD) or psychopathy were less violent than the other diagnostic groups, and Black youth were less likely to have psychopathy compared with Whites and Hispanics. However, Black youth with APD and psychopathy were twice as likely to exhibit violent crime versatility. Furthermore, Black and Hispanic youth demonstrating aggressive conduct problems committed a greater number of violent crime types than Whites. This relationship was further qualified, such that Black and Hispanic youth with APD and psychopathy, who were more exposed to community violence, committed a greater number of violent crime types compared with Whites. These results suggest that prevention and intervention strategies should consider individual and community-level factors. (PsycINFO Database Record PMID- 26751280 TI - Organization of Endothelial Cells, Pericytes, and Astrocytes into a 3D Microfluidic in Vitro Model of the Blood-Brain Barrier. AB - The endothelial cells lining the capillaries supplying the brain with oxygen and nutrients form a formidable barrier known as the blood-brain barrier (BBB), which exhibits selective permeability to small drug molecules and virtually impermeable to macromolecular therapeutics. Current in vitro BBB models fail to replicate this restrictive behavior due to poor integration of the endothelial cells with supporting cells (pericytes and astrocytes) following the correct anatomical organization observed in vivo. We report the coculture of mouse brain microvascular endothelial cells (b.End3), pericytes, with/without C8-D1A astrocytes in layered microfluidic channels forming three-dimensional (3D) bi- and triculture models of the BBB. The live/dead assay indicated high viability of all cultured cells up to 21 days. Trans-endothelial electrical resistance (TEER) values confirmed the formation of intact monolayers after 3 days in culture and showed statistically higher values for the triculture model compared to the single and biculture models. Screening the permeability of [(14)C]-mannitol and [(14)C]-urea showed the ability of bi- and triculture models to discriminate between different markers based on their size. Further, permeability of [(14)C] mannitol across the triculture model after 18 days in culture matched its reported permeability across the BBB in vivo. Mathematical calculations also showed that the radius of the tight junctions pores (R) in the triculture model is similar to the reported diameter of the BBB in vivo. Finally, both the bi- and triculture models exhibited functional expression of the P-glycoprotein efflux pump, which increased with the increase in the number of days in culture. These results collectively indicate that the triculture model is a robust in vitro model of the BBB. PMID- 26751281 TI - Imaging Ferroelectric Domains and Domain Walls Using Charge Gradient Microscopy: Role of Screening Charges. AB - Advanced scanning probe microscopies (SPMs) open up the possibilities of the next generation ferroic devices that utilize both domains and domain walls as active elements. However, current SPMs lack the capability of dynamically monitoring the motion of domains and domain walls in conjunction with the transport of the screening charges that lower the total electrostatic energy of both domains and domain walls. Charge gradient microscopy (CGM) is a strong candidate to overcome these shortcomings because it can map domains and domain walls at high speed and mechanically remove the screening charges. Yet the underlying mechanism of the CGM signals is not fully understood due to the complexity of the electrostatic interactions. Here, we designed a semiconductor-metal CGM tip, which can separate and quantify the ferroelectric domain and domain wall signals by simply changing its scanning direction. Our investigation reveals that the domain wall signals are due to the spatial change of polarization charges, while the domain signals are due to continuous removal and supply of screening charges at the CGM tip. In addition, we observed asymmetric CGM domain currents from the up and down domains, which are originated from the different debonding energies and the amount of the screening charges on positive and negative bound charges. We believe that our findings can help design CGM with high spatial resolution and lead to breakthroughs in information storage and energy-harvesting devices. PMID- 26751282 TI - Spatial potential ripples of azimuthal surface modes in topological insulator Bi2Te3 nanowires. AB - Topological insulators (TI) nanowires (NW) are an emerging class of structures, promising both novel quantum effects and potential applications in low-power electronics, thermoelectrics and spintronics. However, investigating the electronic states of TI NWs is complicated, due to their small lateral size, especially at room temperature. Here, we perform scanning probe based nanoscale imaging to resolve the local surface potential landscapes of Bi2Te3 nanowires (NWs) at 300 K. We found equipotential rings around the NWs perimeter that we attribute to azimuthal 1D modes. Along the NW axis, these modes are altered, forming potential ripples in the local density of states, due to intrinsic disturbances. Potential mapping of electrically biased NWs enabled us to accurately determine their conductivity which was found to increase with the decrease of NW diameter, consistent with surface dominated transport. Our results demonstrate that TI NWs can pave the way to both exotic quantum states and novel electronic devices. PMID- 26751283 TI - Investigation of the Thermal Stability of Nd(x)Sc(y)Zr(1-x-y)O(2-delta) Materials Proposed for Inert Matrix Fuel Applications. AB - Inert matrix fuels (IMF) consist of transuranic elements (i.e., Pu, Am, Np, Cm) embedded in a neutron transparent (inert) matrix and can be used to "burn up" (transmute) these elements in current or Generation IV nuclear reactors. Yttria stabilized zirconia has been extensively studied for IMF applications, but the low thermal conductivity of this material limits its usefulness. Other elements can be used to stabilize the cubic zirconia structure, and the thermal conductivity of the fuel can be increased through the use of a lighter stabilizing element. To this end, a series of Nd(x)Sc(y)Zr(1-x-y)O(2-delta) materials has been synthesized via a co-precipitation reaction and characterized by multiple techniques (Nd was used as a surrogate for Am). The long-range and local structures of these materials were studied using powder X-ray diffraction, scanning electron microscopy, and X-ray absorption spectroscopy. Additionally, the stability of these materials over a range of temperatures has been studied by annealing the materials at 1100 and 1400 degrees C. It was shown that the Nd(x)Sc(y)Zr(1-x-y)O(2-delta) materials maintained a single cubic phase upon annealing at high temperatures only when both Nd and Sc were present with y >= 0.10 and x + y > 0.15. PMID- 26751285 TI - Overlapping illusions by transformation optics without any negative refraction material. AB - A novel method to achieve an overlapping illusion without any negative refraction index material is introduced with the help of the optic-null medium (ONM) designed by an extremely stretching spatial transformation. Unlike the previous methods to achieve such an optical illusion by transformation optics (TO), our method can achieve a power combination and reshape the radiation pattern at the same time. Unlike the overlapping illusion with some negative refraction index material, our method is not sensitive to the loss of the materials. Other advantages over existing methods are discussed. Numerical simulations are given to verify the performance of the proposed devices. PMID- 26751284 TI - Ketamine and MAG Lipase Inhibitor-Dependent Reversal of Evolving Depressive-Like Behavior During Forced Abstinence From Alcohol Drinking. AB - Although alcoholism and depression are highly comorbid, treatment options that take this into account are lacking, and mouse models of alcohol (ethanol (EtOH)) intake-induced depressive-like behavior have not been well established. Recent studies utilizing contingent EtOH administration through prolonged two-bottle choice access have demonstrated depression-like behavior following EtOH abstinence in singly housed female C57BL/6J mice. In the present study, we found that depression-like behavior in the forced swim test (FST) is revealed only after a protracted (2 weeks), but not acute (24 h), abstinence period. No effect on anxiety-like behavior in the EPM was observed. Further, we found that, once established, the affective disturbance is long-lasting, as we observed significantly enhanced latencies to approach food even 35 days after ethanol withdrawal in the novelty-suppressed feeding test (NSFT). We were able to reverse affective disturbances measured in the NSFT following EtOH abstinence utilizing the N-methyl D-aspartate receptor (NMDAR) antagonist and antidepressant ketamine but not memantine, another NMDAR antagonist. Pretreatment with the monoacylglycerol (MAG) lipase inhibitor JZL-184 also reduced affective disturbances in the NSFT in ethanol withdrawn mice, and this effect was prevented by co-administration of the CB1 inverse agonist rimonabant. Endocannabinoid levels were decreased within the BLA during abstinence compared with during drinking. Finally, we demonstrate that the depressive behaviors observed do not require a sucrose fade and that this drinking paradigm may favor the development of habit-like EtOH consumption. These data could set the stage for developing novel treatment approaches for alcohol-withdrawal-induced mood and anxiety disorders. PMID- 26751288 TI - One-Step Coating toward Multifunctional Applications: Oil/Water Mixtures and Emulsions Separation and Contaminants Adsorption. AB - Here, a method that can simultaneously separate oil/water mixtures and remove water-soluble contaminants has been developed. Various substrates with different pore size were coated by polydopamine and polyethylenepolyamine codeposition films. The as-prepared materials were superhydrophilic and under-water superoleophobic. The materials can separate a range of different oil/water mixtures (including immiscible oil/water mixtures and surfactant-stabilized emulsions) in a single unit operation, with >99.6% separation efficiency and high fluxes. Copper ion and methyl blue can be effectively absorbed from water when it permeates through the materials. This method can be applied on organic and inorganic substrates and used in preparing large-scale product. Therefore, the simple and facile method has excellent potential in practical application and creates a new field for oil/water separation materials with multifunctional applications. PMID- 26751291 TI - Estimating Multi-Level Discrete-Time Hazard Models Using Cross-Sectional Data: Neighborhood Effects on the Onset of Adolescent Cigarette Use. AB - Investigating the effects of social context (e.g., neighborhood or school context) on the timing of behaviors (such as cigarette use initiation) requires both multi-level modeling and eventhistory analysis, and often requires the construction of a retrospective person-period data set from cross-sectional data. In this article we describe procedures for constructing such a data set and discuss modeling strategies for estimating multi-level discrete-time event history models. We show that the estimation of two-level discrete-time models involves three distinct modeling assumptions (the assumptions that individual- and neighborhood-level covariates have the same effect at all time points and the assumption that the baseline logithazard curves in each neighborhood are parallel) and discuss methods of relaxing and empirically testing each of these assumptions. Estimation can be simplified in some cases if we additionally assume that the shape of the baseline logit-hazard curve in each neighborhood can be approximated by a simple functional form. The methods described here are applicable to a wide variety of questions where the dependent variable of interest is either onset or cessation. Here we apply these methods to the analysis of cigarette use initiation in a sample of 1,979 11- to 18-year-olds drawn from 79 neighborhoods of Chicago. We find that the racial composition of a neighborhood accounts for roughly half of the difference in age of smoking initiation between Black and White teenagers. Specifically, we find that living in a neighborhood with a large percentage of Black residents is associated with a lower hazard of adolescent cigarette use initiation than is living in neighborhoods with few Black residents. PMID- 26751286 TI - De novo DNA methylation drives 5hmC accumulation in mouse zygotes. AB - Zygotic epigenetic reprogramming entails genome-wide DNA demethylation that is accompanied by Tet methylcytosine dioxygenase 3 (Tet3)-driven oxidation of 5 methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC; refs 1-4). Here we demonstrate using detailed immunofluorescence analysis and ultrasensitive LC-MS based quantitative measurements that the initial loss of paternal 5mC does not require 5hmC formation. Small-molecule inhibition of Tet3 activity, as well as genetic ablation, impedes 5hmC accumulation in zygotes without affecting the early loss of paternal 5mC. Instead, 5hmC accumulation is dependent on the activity of zygotic Dnmt3a and Dnmt1, documenting a role for Tet3-driven hydroxylation in targeting de novo methylation activities present in the early embryo. Our data thus provide further insights into the dynamics of zygotic reprogramming, revealing an intricate interplay between DNA demethylation, de novo methylation and Tet3-driven hydroxylation. PMID- 26751292 TI - A Comparison of Data Analysis Strategies for Testing Omnibus Effects in Higher Order Repeated Measures Designs. AB - Methods for analyzing repeated measures data, in addition to the conventional and corrected degrees of freedom univariate and multivariate solutions, are presented in this review. These "newer" methods offer researchers either improved control over Type I errors and/or greater power to detect treatment effects when (a) certain assumptions are violated, and/or (b) missing data exists. In particular, Huynh's (1978) Improved General Approximate method, a multivariate Welch (1951)/James (1951)-type test, the mixedmodel approach (Littell, Milliken, Stroup, & Wolfinger, 1996) and Boik's (1997) empirical Bayes method are discussed. We review the literature regarding these procedures with respect to their robustness, ability to handle missing data, and availability of software to obtain numerical results. PMID- 26751290 TI - Concurrent Validity of activPAL and activPAL3 Accelerometers in Older Adults. AB - The aim of this study was to assess concurrent validity between activPAL and activPAL3 accelerometers in a sample of 53 community-dwelling older adults >= 65 years. Physical activity (PA) was measured simultaneously with activPAL and activPAL3 while performing scripted activities. The level of agreement between both devices was calculated for sitting/lying, standing, and walking. In addition, PA was measured over one week using activPAL to estimate the expected agreement with activPAL3 in real life. Overall agreement between activPAL and activPAL3 was 97%. Compared with activPAL, the largest disagreement was seen for standing, with 5% categorized as walking by activPAL3. For walking and sitting/lying, the disagreement was 2%, respectively. The expected daily differences between activPAL3 and activPAL were +15.0 min (95% CI: 11.3-18.8) for walking and +29.5 min (95% CI: 6.2-52.7) for standing. ActivPAL and activPAL3 showed good agreement in older adults. However, if using these devices interchangeably, observed differences might still bias results. PMID- 26751293 TI - Applying the Bollen-Stine Bootstrap for Goodness-of-Fit Measures to Structural Equation Models with Missing Data. AB - The study proposed a method for extending the Bollen-Stine bootstrap of model fit to structural equation models with missing data. Matrix algebra difficulties associated with an incomplete data matrix are circumvented by applying the Bollen Stine transformation to each case (or group of cases sharing a common pattern of missing data) using reduced arrays that contain elements corresponding to the observed variables. A SAS macro program is provided for the purposes of implementing this procedure, and its' performance was assessed in a simulation that varied distribution shape, sample size, and the missing data rate. Compared to the unadjusted fit statistic, which produced dramatically inflated Type I error rates, the bootstrap yielded model rejection rates quite close to the nominal 5% level, although rejection rates were conservative under small sample conditions. PMID- 26751294 TI - Effects of Misspecifying the First-Level Error Structure in Two-Level Models of Change. AB - Computer simulation methods were used to examine the sensitivity of model fit criteria to misspecification of the first-level error structure in two-level models of change, and then to examine the impact of misspecification on estimates of the variance parameters, estimates of the fixed effects, and tests of the fixed effects. Fit criteria frequently failed to identify the correct model when series lengths were short. Misspecification led to substantially biased estimates of variance parameters. The estimates of the fixed effects, however, remained unbiased for most conditions, and the tests of fixed effects were robust to misspecification for most conditions. The problems in the fixed effects occurred when nonlinear growth trajectories were coupled with data that were unequally spaced by different amounts for different individuals. PMID- 26751295 TI - Consequences of Continuity: The Hunt for Intrinsic Properties within Parameters of Dynamics in Psychological Processes. AB - A little over three hundred years ago Sir Isaac Newton wrote of a simple set of relations that could be used to predict the motions of objects relative to one another. The main advantage of this insight was that the relationship between the movements of the planets and stars could be predicted much more simply than with the accurate, but cumbersome Ptolemaic calculations. But perhaps the most important consequence of the acceptance of Newton's insight was that intrinsic properties such as mass could be distinguished from measurements such as weight. The success of Newtonian mechanics led directly to the widespread use of parameters such as force, relative speed, and momentum as a way of understanding the dynamics of moving objects. A similar revolution in thinking appears to be underway in the behavioral sciences. It is likely that intensive longitudinal measurement coupled with dynamical systems analyses will lead to simplified but powerful models of the evolution of psychological processes. In this case, it is reasonable to expect that a set of intrinsic psychological properties may be able to be extracted from the parameters of successful dynamical systems models. The purpose of this article is to issue an invitation to the hunt, to provide a tentative map as to where the game might likely be found, and blow a call on the hunting horn. PMID- 26751287 TI - The LINK-A lncRNA activates normoxic HIF1alpha signalling in triple-negative breast cancer. AB - Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1alpha phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1alpha stabilization, HIF1alpha-p300 interaction, and activation of HIF1alpha transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to the EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1alpha Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1alpha stabilization. Both LINK-A expression and LINK-A-dependent signalling pathway activation correlate with triple-negative breast cancer (TNBC), promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer. PMID- 26751337 TI - High-pressure phase transition makes B4.3C boron carbide a wide-gap semiconductor. AB - Single-crystal B4.3C boron carbide is investigated through the pressure dependence and inter-relation of atomic distances, optical properties and Raman active phonons up to ~70 GPa. The anomalous pressure evolution of the gap width to higher energies is striking. This is obtained from observations of transparency, which most rapidly increases around 55 GPa. Full visible optical transparency is approached at pressures of >60 GPa indicating that the band gap reaches ~3.5 eV; at high pressure, boron carbide is a wide-gap semiconductor. The reason is that the high concentration of structural defects controlling the electronic properties of boron carbide at ambient conditions initially decreases and finally vanishes at high pressures. The structural parameters and Raman active phonons indicate a pressure-dependent phase transition in single-crystal (nat)B4.3C boron carbide near 40 GPa, likely related to structural changes in the C-B-C chains, while the basic icosahedral structure appears to be less affected. PMID- 26751338 TI - Damage to Trichothecium roseum caused by sodium silicate is independent from pH. AB - Trichothecium roseum is one of the most important postharvest pathogens in arid and semiarid regions. Sodium silicate (NaSi) and environmental pH have significant inhibitory effects on fungal growth. However, no study has addressed the relationship of NaSi and pH in combination and the effects on T. roseum. In this work, we showed that spore germination, germ tube elongation, and mycelial growth of T. roseum were significantly inhibited by various NaSi concentrations, which had corresponding increasing pHs. Furthermore, these NaSi solutions showed a much greater impact than did pH treatments alone. The pathogenicity of NaSi treated conidia on a model assay (conidia-inoculated apple fruit) was dramatically reduced, whereas no changes of pathogenicity were evident for the corresponding pH (various sodium hydroxide (NaOH) solutions) treatments. Fluorescent microscopy, using propidium iodide staining, showed damage of the plasma membranes of T. roseum conidia treated with both NaSi and NaOH, although the damage was more severe with NaSi. Leakage of proteins and sugars was significantly higher in NaSi-treated and NaOH-treated conidia than in untreated controls. In addition, serious damage was observed in the conidia exposed to NaSi for longer periods of time. Ultrastructural observations showed that treatment with either NaSi or NaOH caused a plasmolysis state and disorganized organelles. Taken together the results show that NaSi has inhibitory effects on T. roseum and that the inherent higher pH of NaSi solutions of higher concentrations simply acts as an enhancer of the inhibitory effects of NaSi. PMID- 26751341 TI - Virulence profile: W. Conrad Liles. PMID- 26751340 TI - Improvement in imaging diagnosis technique and modalities for solitary pulmonary nodules: from ground-glass opacity nodules to part-solid and solid nodules. AB - With advances in CT technology and the popularity of low-dose CT as a device for lung cancer screening, the detection rate of sub-solid pulmonary nodules as well as solid nodules has been increased. Distinguishing solid from sub-solid features is an essential step in the CT evaluation of solitary pulmonary nodules (SPNs) because strategies for nodule characterization and guidelines for management are different for each category. In addition to conventional CT parameters, numerous novel concepts and modalities have been developed. Although there is currently no single effective method for differentiating malignant from benign nodules, growth rate measurement using volumetry, evaluation of tumor vascularity on dynamic helical CT, dual-energy CT and MRI and physiologic evaluation with PET/CT can all be useful for nodule characterization. New techniques such as tomosynthesis can improve detection over radiography alone. The purpose of this article is to enhance our understanding of the evidence-based strategies involved in diagnosing SPNs. PMID- 26751339 TI - Vaccinology: The art of putting together the right ingredients. AB - Historically vaccines were produced using whole attenuated or killed pathogens and still a large proportion of current vaccines utilizes such procedure. However, for safety and quality reasons the development of novel vaccines is preferentially based on the selection and use of specific pathogen components which alone are capable of eliciting protective immune responses against the pathogens they derived from. The big challenge for vaccinologists is how to select the right antigens and to combine them with proper immune stimulatory components (adjuvants) in order to induce protective immunity. This Commentary outlines the authors' view on the current and future strategies for the efficient and rapid identification of the most effective protective antigens and adjuvants. Since efficacious subunit-based vaccines against recalcitrant pathogens are likely to require more than one antigen and/or immune stimulator, this poses the problem of how to make such vaccines economically acceptable. In this regard, the authors also present their view of how bacterial Outer Membrane Vesicles (OMVs) could become a promising platform for the development of future vaccines. The unique properties of OMVs might be exploited in the field of infectious diseases and oncology. PMID- 26751342 TI - Is a Cholestrol-Enriched Diet a Risk Factor for Alveolar Bone Loss? AB - BACKGROUND: This study aims to investigate the effects of a 2% cholesterol enriched diet on alveolar bone loss (ABL) and serum levels of pro-oxidants and antioxidant enzymes in rats with experimental periodontitis. METHODS: Rats were randomized into the four groups: 1) group C (standard diet/periodontally healthy); 2) group Hc (high-cholesterol diet); 3) group HcP (high-cholesterol diet/periodontitis); and 4) group P (standard diet/periodontitis). All rats were fed for 8 weeks. At 6 weeks, experimental periodontitis was induced. At the end of week 8, the rats were sacrificed. Histomorphometric and histopathologic analyses were performed. Malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase, and glutathione peroxidase (GPX) levels in serum were measured with enzyme-linked immunosorbent assay. RESULTS: Experimental groups exhibited increases in: 1) total cholesterol, 2) low-density lipoprotein, and 3) high density lipoprotein compared to group C. The cholesterol-enriched diet induced ABL in group Hc; groups HcP and P had more extensive ABL. The most polymorphonuclear leukocyte infiltration in periodontal tissues was found in group HcP. MDA levels were higher in all experimental groups than in group C, but significant in the HcP group. A high-cholesterol diet, with or without periodontitis, resulted in more decreases in GPX and more increases in NO compared to group P. CONCLUSION: Although any additive effect of cholesterol enriched diet to ABL was not found in rats with ligature-induced experimental periodontitis, these findings revealed that a cholesterol-enriched diet could lead to ABL and an increase in periodontal inflammation and serum pro-oxidants. PMID- 26751344 TI - Commentary: Statistical Significance Versus Clinical Relevance in Periodontal Research: Implications for Clinical Practice. PMID- 26751343 TI - Dexamethasone Delivery by an Implant-Mediated Drug Delivery System in the Canine Mandible. AB - BACKGROUND: A newly introduced implant-mediated drug delivery system (IMDDS) showed promising results in a rabbit tibia model. The aim of the present study is to evaluate whether dexamethasone administered by the IMDDS has sustained effects in the canine mandible - a different anatomic location, in a different species. METHODS: IMDDS was installed at the mesial root of the second premolar site in the mandibles of six beagle dogs. After complete healing, 10 mg dexamethasone was administered through the IMDDS. The same amount of drug was administered to five control animals by intramuscular injection. The release pattern was monitored for 2 weeks by measuring plasma drug concentrations. RESULTS: A sustained plasma dexamethasone concentration was detected after a peak at 6 hours until the end of the observation period, despite individual variations. The concentration was lower than reported in the rabbit tibia model. In contrast, plasma concentration of the control group showed an early peak at 2 hours and decreased rapidly. CONCLUSION: Dexamethasone was effectively released from the IMDDS for a prolonged time in the canine mandible model. PMID- 26751345 TI - Recombinant Human Bone Morphogenetic Protein 9 (rhBMP9) Induced Osteoblastic Behavior on a Collagen Membrane Compared With rhBMP2. AB - BACKGROUND: Bone morphogenetic protein 9 (BMP9) has previously been characterized as one of the most osteogenic growth factors of the BMP family. To the best of the authors' knowledge, previous experiments have only used adenovirus transfection (gene therapy). With the recent development of recombinant human BMP9 (rhBMP9), the present study investigates the osteopromotive potential of BMP9 versus rhBMP2 when loaded onto collagen membranes. METHODS: ST2 stromal bone marrow cells were seeded onto: 1) control; 2) low-dose rhBMP2 (10 ng/mL); 3) high dose rhBMP2 (100 ng/mL); 4) low-dose rhBMP9 (10 ng/mL); and 5) high-dose rhBMP9 (100 ng/mL) porcine collagen membranes. The following parameters were compared among groups: 1) cell adhesion (at 8 hours); 2) cell proliferation (at 1, 3, and 5 days); 3) real-time polymerase chain reaction for genes encoding runt-related transcription factor 2; 4) alkaline phosphatase (ALP); 5) bone sialoprotein ([BSP] at 3 and 14 days); and 6) alizarin red staining (at 14 days). RESULTS: rhBMP2 and rhBMP9 demonstrated little effect on cell attachment and proliferation; however, pronounced increases were observed in osteoblast differentiation. All groups significantly induced ALP messenger RNA (mRNA) levels at 3 days and BSP levels at 14 days; however, high-dose rhBMP9 showed significantly higher values compared with all other groups for ALP levels (five fold increase at 3 days and two-fold increase at 14 days). Alizarin red staining further revealed both concentrations of rhBMP9 induced up to three-fold more staining compared with rhBMP2. CONCLUSIONS: Results indicate that the combination of collagen membranes with rhBMP9 induced significantly higher ALP mRNA expression and alizarin red staining compared with rhBMP2. These findings suggest that rhBMP9 may be a suitable growth factor for future regenerative procedures in bone biology. PMID- 26751346 TI - The relationship between catatonia and dissociation: A preliminary investigation. AB - Unlike the relationship between dissociation and Schneiderian first-rank symptoms, the relationship between dissociation and catatonia has not been investigated empirically. In order to gather some initial data about catatonia, dissociation, and childhood adverse experiences, we administered the Bush-Francis Catatonia Scale (BFCS), the Dissociative Experiences Scale (DES), the Adverse Childhood Experiences Questionnaire, and the Dissociative Disorders Interview Schedule to 100 inpatients in a hospital trauma program. The average DES score was 44.1 (SD = 22.4), and 86 participants were in the DES-Taxon. The average score on the BFCS was 7.7 (SD = 10.3); 81 participants scored 2 or higher, and 67 scored 5 or higher. The results showed that, in this sample, catatonic symptoms are frequent and related to adverse childhood experiences but seem to be a separate symptom category from both dissociation and psychosis. PMID- 26751347 TI - Terpenoids with neurite outgrowth-promoting activity from the branches and leaves of Illicium merrillianum. AB - Eighteen terpenoids (1-18) were isolated from Illicium merrillianum. Compound 1 was identified as new compound, and its structure was established by comprehensive spectroscopic analysis and single-crystal X-ray diffraction. All compounds were evaluated for nerve growth factor (NGF)-mediated neurite outgrowth activity using rat pheochromocytoma (PC12) cells as a model system of neuronal differentiation. Compounds 1, 3, 18 showed significant neurite outgrowth promoting activity in the presence of 20 ng/ml NGF in a dose-dependent manner at concentrations of 1-100 MUM after 24-h treatment. Subtle difference of functional groups at C-2 position in hopane-type triterpene resulted in enormous bioactivity difference, compound 1 was neurotrophic but 2 was cytotoxic. PMID- 26751348 TI - Predicting and preventing antimicrobial resistance utilizing pharmacodynamics: Part I gram positive bacteria. AB - INTRODUCTION: Antimicrobial resistance is a potentially inevitable consequence of widespread use of antibiotics in the healthcare system. An enhanced understanding of pharmacodynamic (PD) targets that prevent antimicrobial resistance development will improve currently availably therapies and help to guide future drug development strategies. Current in vitro methods to predict bacterial resistance to antimicrobials consist of serial dilution experiments, determination of the mutant prevention concentration (MPC), mutant selection window (MSW), and human simulated pharmacodynamics studies. Clinical trial data and real -world surveillance studies can help validate or disprove in vitro modeling. AREAS COVERED: This review will discuss methods of predicting development of resistance and how the use of pharmacodynamics can reduce or eliminate the emergence of resistance among Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus species. EXPERT OPINION: Pharmacodynamic targets can be used successfully to guide antimicrobial therapy to prevent resistance development. Currently, PD targets do not take into consideration horizontal resistance gene transfer and various factors may lead to different PD targets based on sites of infection. Further research is necessary to guide future drug development strategies and optimize new drug therapies. PMID- 26751349 TI - Editor's Corner: The Role of Public Health Surveillance in Protecting Young People From Alcohol Marketing. PMID- 26751350 TI - The Potential Impact of a "No-Buy" List on Youth Exposure to Alcohol Advertising on Cable Television. AB - OBJECTIVE: The purpose of this study was to outline a method to improve alcohol industry compliance with its self-regulatory advertising placement guidelines on television with the goal of reducing youth exposure to noncompliant advertisements. METHOD: Data were sourced from Nielsen (The Nielsen Company, New York, NY) for all alcohol advertisements on television in the United States for 2005-2012. A "no-buy" list, that is a list of cable television programs and networks to be avoided when purchasing alcohol advertising, was devised using three criteria: avoid placements on programs that were noncompliant in the past (serially noncompliant), avoid placements on networks at times of day when youth make up a high proportion of the audience (high-risk network dayparts), and use a "guardbanded" (or more restrictive) composition guideline when placing ads on low rated programs (low rated). RESULTS: Youth were exposed to 15.1 billion noncompliant advertising impressions from 2005 to 2012, mostly on cable television. Together, the three no-buy list criteria accounted for 99% of 12.9 billion noncompliant advertising exposures on cable television for youth ages 2 20 years. When we evaluated the no-buy list criteria sequentially and mutually exclusively, serially noncompliant ads accounted for 67% of noncompliant exposure, high-risk network-daypart ads accounted for 26%, and low-rated ads accounted for 7%. CONCLUSIONS: These findings suggest that the prospective use of the no-buy list criteria when purchasing alcohol advertising could eliminate most noncompliant advertising exposures and could be incorporated into standard post audit procedures that are widely used by the alcohol industry in assessing exposure to television advertising. PMID- 26751351 TI - Not in My Back Yard: A Comparative Analysis of Crime Around Publicly Funded Drug Treatment Centers, Liquor Stores, Convenience Stores, and Corner Stores in One Mid-Atlantic City. AB - OBJECTIVE: This research examined whether publicly funded drug treatment centers (DTCs) were associated with violent crime in excess of the violence happening around other commercial businesses. METHOD: Violent crime data and locations of community entities were geocoded and mapped. DTCs and other retail outlets were matched based on a Neighborhood Disadvantage score at the census tract level. Street network buffers ranging from 100 to 1,400 feet were placed around each location. Negative binomial regression models were used to estimate the relationship between the count of violent crimes and the distance from each business type. RESULTS: Compared with the mean count of violent crime around drug treatment centers, the mean count of violent crime (M = 2.87) was significantly higher around liquor stores (M = 3.98; t test; p < .01) and corner stores (M = 3.78; t test; p < .01), and there was no statistically significant difference between the count around convenience stores (M = 2.65; t test; p = .32). In the adjusted negative binomial regression models, there was a negative and significant relationship between the count of violent crime and the distance from drug treatment centers (beta = -.069, p < .01), liquor stores (beta = -.081, p < .01), corner stores (beta = -.116, p < .01), and convenience stores (beta = .154, p < .01). CONCLUSIONS: Violent crime associated with drug treatment centers is similar to that associated with liquor stores and is less frequent than that associated with convenience stores and corner stores. PMID- 26751352 TI - The Low Level of Response to Alcohol-Based Heavy Drinking Prevention Program: One Year Follow-Up. AB - OBJECTIVE: Heavy drinking is common on college campuses, with a marked increase from high school to freshman year. Programs addressing heavy campus drinking often personalize prevention protocols to fit a student's demography and prior drinking characteristics. Few efforts have individualized approaches to address a person's vulnerability through his or her low level of response (low LR) to alcohol. METHOD: This article describes the recently completed 55-week outcome in drinking quantities and problems for the >90% of 500 participants in a prevention program at a U.S. university (62% female, mean age = 18 years) who completed a 4 week series of 50-minute videos delivered via the Internet. We evaluated whether, for low LRs, participation in an educational approach that focused on a low LR (the LR-based [LRB] condition) was associated with better outcomes than a state of-the-art (SOTA) general education or with a no-intervention control condition. RESULTS: Using a mixed-design analysis of variance and focusing on the most closely ethnically matched high and low LR pairs, students with low LRs in the LRB condition demonstrated the greatest decreases in usual and maximum drinks over the 55 weeks, especially when compared with closely ethnically matched students with high LRs. Low LR controls showed the highest drinking values over time. CONCLUSIONS: This study underscores the potential importance of targeting a person's specific preexisting vulnerability toward heavy drinking when he or she enters college. The approach can be used in a relatively inexpensive protocol of video education sessions delivered via the Internet. PMID- 26751353 TI - Profiles of College Drinkers Defined by Alcohol Behaviors at the Week Level: Replication Across Semesters and Prospective Associations With Hazardous Drinking and Dependence-Related Symptoms. AB - OBJECTIVE: Types of college drinkers have been identified using traditional measures (e.g., 12-month drinking frequency). We used an alternative multidimensional approach based on daily reports of alcohol behaviors to identify college drinker statuses, each with a unique behavioral profile. The current study aimed to (a) identify drinker statuses at the week level across four semesters, (b) examine the predictive utility of drinker status by testing associations with senior-year hazardous drinking and dependence symptoms, and (c) identify concurrent predictors (gender, drinking motivations, hazardous drinking, any dependence symptoms) of senior-year drinker status. We also compared the week level drinker statuses with drinker statuses identified using traditional measures. METHOD: A multi-ethnic sample of U.S. college students completed 14-day bursts of daily web surveys across college (91%-96% completed >=6 daily reports of the sampled week). Analyses focus on nine alcohol-related behaviors (including estimated blood alcohol concentration, pregaming, and drinking games) assessed daily in spring/sophomore year to fall/senior year and drinking motivations, hazardous drinking, and dependence symptoms assessed fall/senior year (n = 569; 56% women). RESULTS: Four week-level drinker statuses were replicated across semesters: Nondrinker, Light Weekend, Heavy Weekend, and Heavy Frequent. Across semesters, drinker status was associated with senior-year hazardous drinking and any dependence symptoms. Senior-year fun/social motivations were also associated with senior-year drinker status. Differences in behavioral profiles between week level drinker statuses and those identified using traditional measures were found. CONCLUSIONS: Replicable week-level drinker statuses were identified, suggesting consistency in possible types of drinking weeks. Drinker statuses were predictive of senior-year hazardous drinking and dependence symptoms. PMID- 26751354 TI - Summer Versus School-Year Alcohol Use Among Mandated College Students. AB - OBJECTIVE: Longitudinal research examining college students' alcohol use during the summer months, especially in at-risk individuals, is limited. The current study evaluated changes in mandated college students' alcohol use and related consequences over the summer. METHOD: Participants (n = 305, 67% male) who had violated campus alcohol policy and were subsequently mandated to treatment completed follow-up assessments at 3, 6, and 9 months. For the majority of students, one of these follow-up assessments occurred over the summer. Hierarchical linear modeling was used to examine changes in alcohol use and related consequences during the school year and summer. RESULTS: Participants reported consuming significantly fewer drinks per occasion, reaching lower peak blood alcohol concentrations, and experiencing fewer alcohol-related consequences during the summer months. All outcomes were mediated by summer housing, indicating that summer influenced alcohol use indirectly through participants' tendency to live at home. CONCLUSIONS: Despite small but significant decreases in alcohol consumption and related consequences when living with a parent/guardian, mandated college students continue to exhibit risky drinking and consequences during the summer months. Given these findings, summer may be an appropriate time to implement prevention and intervention strategies with mandated and other at risk populations. PMID- 26751355 TI - Relationship of Usual Volume and Heavy Consumption to Risk of Alcohol-Related Injury: Racial/Ethnic Disparities in Four U.S. National Alcohol Surveys. AB - OBJECTIVE: National population data on racial/ethnic disparities and risk of alcohol-related injury are scarce. Alcohol-related injury and drinking patterns are examined in a sample of respondents from four (1995, 2000, 2005, 2010) U.S. National Alcohol Surveys using risk function analysis. METHOD: Self-reported consumption of 15,476 current drinkers was assessed as the average number of drinks consumed monthly and, separately, the frequency of consuming five or more drinks in a day (5+ days) in the last year. Alcohol-related injury was defined as drinking within 6 hours before the event. Risk curves were defined, separately for Whites, Blacks, and Hispanics, using fractional polynomial regression. RESULTS: Risk was greatest for Hispanics to 110 drinks per month (3-4 drinks per day) and above 240 drinks per month, whereas risk was greatest for Whites between these levels. Blacks were at lower risk at all monthly volume levels when demographic and socioeconomic status characteristics were controlled for. Whites had the highest risk of an alcohol-related injury based on 5+ drinking days at all levels up to nearly daily 5+ drinking, whereas Blacks had the lowest risk at all levels of 5+ drinking. CONCLUSIONS: A disparity in alcohol-related injury was found for Hispanics compared with Whites at the same average monthly volume of consumption at lower and higher volume levels, but not at the same number of 5+ drinking days, and a lower risk of alcohol-related injury was found for Blacks for both consumption measures when demographic and socioeconomic status characteristics were taken into account. Although exposure to hazards other than alcohol, which could account for some of the racial/ethnic disparity observed, was not taken into account, these mixed findings suggest this is an important area deserving future research attention. PMID- 26751356 TI - Race, Ethnicity, and Exposure to Alcohol Outlets. AB - OBJECTIVE: Prior studies suggest that Black and Hispanic minority populations are exposed to greater concentrations of alcohol outlets, potentially contributing to health disparities between these populations and the White majority. We tested the alternative hypothesis that urban economic systems cause outlets to concentrate in low-income areas and, controlling for these effects, lower demand among minority populations leads to fewer outlets. METHOD: Market potential for alcohol sales, a surrogate for demand, was estimated from survey and census data across census block groups for 50 California cities. Hierarchical Bayesian conditional autoregressive Poisson models then estimated relationships between observed geographic distributions of outlets and the market potential for alcohol, income, population size, and racial and ethnic composition. RESULTS: Market potentials were significantly smaller among lower income Black, Hispanic, and Asian populations. Block groups with greater market potential and lower income had greater concentrations of outlets. When we controlled for these effects, the racial and ethnic group composition of block groups was mostly unrelated to outlet concentrations. CONCLUSIONS: Health disparities related to exposure to alcohol outlets are primarily driven by distributions of income and population density across neighborhoods. PMID- 26751357 TI - Transitions in Riding With an Alcohol/Drug-Impaired Driver From Adolescence to Emerging Adulthood in the United States. AB - OBJECTIVE: The purpose of this study was to examine changes and predictors of changes in riding with an alcohol/drug-impaired driver (RWI) from 10th grade through the first post-high school year. METHOD: Transition models were used to estimate the association of four waves (W1-W4) of RWI with W4 environmental status variables and time-varying covariates in the NEXT Generation Health Study, a nationally representative cohort of U.S. 10th graders (N = 2,785). RESULTS: Overall, 33% (weighted) of adolescents reported RWI in the past 12 months in W1, and slightly declined in W2 (24%), W3 (27%), and W4 (26%). Across time, transition models with generalized estimating equations showed that RWI was more likely among those who previously reported RWI (ORs from 3.62 to 3.66, p < .001), substance use (ORs from 1.81 to 1.82, p < .001), and heavy episodic drinking (ORs from 1.85 to 1.86, p < .001). Those living on college campuses were somewhat more likely to engage in RWI (OR = 1.38, .05 < p <.10) than those living at home. The effects of parental monitoring knowledge and peer alcohol/substance use on RWI were suppressed when individual substance use and heavy episodic drinking were taken into consideration. CONCLUSIONS: Substance use and heavy episodic drinking in previous waves and the history of RWI were persistent factors of RWI in a dynamic pattern. The setting in which emerging adults live during their first post-high school year could affect their engagement in RWI. The findings suggest that harm-reduction strategies should focus on the identification of early RWI coupled with reduction of substance use and heavy episodic drinking. PMID- 26751358 TI - Acute Effects of Alcohol on Encoding and Consolidation of Memory for Emotional Stimuli. AB - OBJECTIVE: Acute doses of alcohol impair memory when administered before encoding of emotionally neutral stimuli but enhance memory when administered immediately after encoding, potentially by affecting memory consolidation. Here, we examined whether alcohol produces similar biphasic effects on memory for positive or negative emotional stimuli. METHOD: The current study examined memory for emotional stimuli after alcohol (0.8 g/kg) was administered either before stimulus viewing (encoding group; n = 20) or immediately following stimulus viewing (consolidation group; n = 20). A third group received placebo both before and after stimulus viewing (control group; n = 19). Participants viewed the stimuli on one day, and their retrieval was assessed exactly 48 hours later, when they performed a surprise cued recollection and recognition test of the stimuli in a drug-free state. RESULTS: As in previous studies, alcohol administered before encoding impaired memory accuracy, whereas alcohol administered after encoding enhanced memory accuracy. Critically, alcohol effects on cued recollection depended on the valence of the emotional stimuli: Its memory impairing effects during encoding were greatest for emotional stimuli, whereas its memory-enhancing effects during consolidation were greatest for emotionally neutral stimuli. Effects of alcohol on recognition were not related to stimulus valence. CONCLUSIONS: This study extends previous findings with memory for neutral stimuli, showing that alcohol differentially affects the encoding and consolidation of memory for emotional stimuli. These effects of alcohol on memory for emotionally salient material may contribute to the development of alcohol related problems, perhaps by dampening memory for adverse consequences of alcohol consumption. PMID- 26751359 TI - The Relationships of Parental Alcohol Versus Tobacco and Marijuana Use With Early Adolescent Onset of Alcohol Use. AB - OBJECTIVE: This study examined whether the use of tobacco and marijuana by fathers or mothers predicted onset of alcohol use in their offspring over and above effects of parental alcohol use. METHOD: The present study included 146 children of 93 parents (90 fathers and 85 mothers). The fathers were originally recruited as boys to the Oregon Youth Study, a study of community, familial, and individual risk factors for delinquency. RESULTS: Only mothers' but not fathers' alcohol use was associated with children's age at onset. Children's age at onset was predicted by mothers' tobacco use and by the interaction of fathers' marijuana use and alcohol use. These effects were observed when controlling for parental education, child's gender, and also child's antisocial behavior-a general developmental risk factor for substance use onset in adolescence. CONCLUSIONS: Mothers' substance use played a major role in childhood onset of alcohol use, yet the role of maternal substance use as a risk factor for their children has previously received less attention than the role of paternal substance use. Also, findings imply that it may be important to identify children of polysubstance-using parents for targeted prevention programs. PMID- 26751361 TI - The Relationships of Cigarette and Alcohol Use With the Initiation, Reinitiation, and Persistence of Cannabis Use. AB - OBJECTIVE: This study used a prospective survey to examine (a) the relationships of early onset and prior consumption of cannabis, cigarette, and alcohol use with later cannabis use initiation, reinitiation, and persistence; and (b) whether the quantity or frequency of alcohol or cigarette use was more predictive of cannabis use initiation, reinitiation, or persistence. METHOD: This study used data from the National Epidemiologic Survey of Alcohol and Related Conditions, Wave 1 (2001 2002) and Wave 2 (2004-2005), including 27,741 nonusers, 5,623 prior users, and 1,279 current cannabis users at baseline who were at risk of cannabis use initiation, reinitiation, and persistence, respectively, between baseline and follow-up assessments. We employed logistic regression to examine the effects of prior substance use on cannabis use initiation, reinitiation, and persistence, controlling for sociodemographics. RESULTS: Frequency and early-onset status of cigarette use (<=14 years) and alcohol use (<=17 years) predicted cannabis use initiation and reinitiation but not persistence. While considering the potential effects of early onset and consumption levels of cannabis use, baseline alcohol and cigarette use quantity and frequency did not predict persistent cannabis use. Frequency, compared with quantity, of alcohol and cigarette use was more predictive of cannabis use initiation and reinitiation. CONCLUSIONS: Early onset and prior experience with cannabis, cigarettes, and alcohol could have effects on later cannabis use, varying among the three at-risk populations. Different strategies are needed for preventing cannabis use initiation, reinitiation, and persistence, based on targeting early use of alcohol and cigarettes. PMID- 26751360 TI - Sexual Risk Behavior and Heavy Drinking Among Weekly Marijuana Users. AB - OBJECTIVE: Sexual behavior that incurs increased risk for sexually transmitted infections and HIV incidence is associated with both heavy alcohol and marijuana use. Whereas detrimental effects of alcohol on increased sexual risk have been documented in event-level and laboratory studies, less is known about the combined use of alcohol and marijuana and their relative impact on sexual risk behavior. We examined the degree to which both heavy drinking and marijuana use were associated with condomless sexual intercourse with casual versus main partners in a sample of weekly marijuana smokers. METHOD: Participants reported substance use and sexual activity using a 60-day Timeline Followback interview method (n = 112). RESULTS: Results of generalized estimating equations indicated that both alcohol and marijuana use were independently associated with greater odds of having sexual intercourse but were not associated with greater odds of unprotected sex with a casual partner. Heavy drinking on a given day was associated with increased odds of having casual protected sex. Using both substances synergistically increased the likelihood of unprotected sex with a main partner. CONCLUSIONS: Findings suggest that behaviors posing higher sexual risk (condomless intercourse or sex with casual partners) occur on days when alcohol use exceeds moderate drinking guidelines. Interventions designed to reduce sexual risk behaviors may need to specifically target heavy drinking alone or when used with marijuana. PMID- 26751363 TI - School Investment, Drinking Motives, and High-Risk, High-Reward Partying Decisions Mediate the Relationship Between Trait Self-Control and Alcohol Consumption Among College Drinkers. AB - OBJECTIVE: Research has shown trait self-control, neuroticism, and coping and enhancement drinking motives to be predictors of alcohol consumption among college students. Recent research also provides evidence for the effects of role investment and role-based alcohol consumption-decision making (i.e., partying decisions). The goal of the present study was to clarify the organization and contributions of these multifarious influences on college student drinking. METHOD: College students (N = 355; 51.8% female) with a heterogeneous prevalence of alcohol dependence completed measures of trait self-control; neuroticism; coping and enhancement drinking motives; subjective college student role investment, satisfaction, and stress; role-based partying scenarios; and a typical weekly alcohol consumption interview. Internal and comparative fit indices for alternative path models were evaluated and bootstrapping procedures were used to examine indirect effects. RESULTS: Modeling results favored a more stratified organization, where (a) the association between trait self-control and consumption was mediated by drinking motives and partying decisions, (b) the association between neuroticism and consumption was mediated by coping motives, and (c) the association between role investment and consumption was mediated by partying decisions. The associations between motives and consumption were not mediated by partying decisions. CONCLUSIONS: The results provide support for disinhibitory and distress pathways to college student drinking, where impulsive and anxious students are more likely to drink excessively because of more frequent mood-affecting drinking goals, less academic involvement, and/or more frequent decisions to attend parties where negative academic consequences are likely but where perceived rewarding alcohol-related and social features are present. PMID- 26751364 TI - Group Membership and Adolescents' Alcohol Intake: The Role of Drinking Motives. AB - OBJECTIVE: Group norms and drinking motives are crucial predictors of adolescents' alcohol intake. The current study examined the role of drinking motives in the association between descriptive group norms and alcohol intake. METHOD: A sample of 525 Italian adolescents (56% men) was surveyed. Participants completed measures of group norms, drinking motives, and personal drinking. RESULTS: Hierarchical multiple regression analysis revealed that stronger group norms were positively related to increased alcohol intake. Drinking for enhancement and social motives also were related to increased alcohol intake. Mediation analysis showed that group norms were related to alcohol intake through social and enhancement drinking motives. CONCLUSIONS: Drinking motives provide fruitful insights into the relationship between descriptive group norms and excessive alcohol use among adolescents. Implications for future research are discussed. PMID- 26751362 TI - The Effect of Residence, School Status, Work Status, and Social Influence on the Prevalence of Alcohol Use Among Emerging Adults. AB - OBJECTIVE: The first year after high school is a transitional year, with increased independence from parental supervision, contact with other independent youth, and exposure to new environments, all of which may influence substance use. This article reports longitudinal predictors of change in the prevalence of alcohol use and heavy episodic drinking among adolescents and environmental correlates (i.e., residence, college attendance, and work status) with drinking the year after high school. METHOD: A national sample of study participants (N = 2,659; 55% female) in the NEXT Generation Health Study were followed annually from 10th grade (Wave 1) to the year after high school (Wave 4). Longitudinal binary outcomes, including recent (30-day) drinking and two measures of heavy episodic drinking, were examined. Transition models with generalized estimating equations estimated the effect of previous drinking behaviors, social influences, and current residential status and activity (school and/or work) on drinking prevalence. RESULTS: Drinking increased from 40.5% among high school seniors (Wave 3) to 53.5% in Wave 4 for 30-day use, and from 29.0% to 41.2% for heavy episodic drinking. Significant predictors of 30-day drinking included previous drinking status (odds ratio [OR] = 5.48), peer drinking often (OR = 3.25), parental expectations (OR = 0.91), and current year living on campus (OR = 2.10). The same significant predictors with similar magnitudes were found for both measures of heavy episodic drinking. Peer use did not interact with college attendance or residence. CONCLUSIONS: Predictors of drinking and heavy episodic drinking during the first year after high school included being White, living on campus, previous drinking, lower parental expectations, and having peers who drink. PMID- 26751367 TI - Sports Participation and Alcohol Use: Associations With Sports-Related Identities and Well-Being. AB - OBJECTIVE: Studies indicate that those participating in sports are a high-risk population for hazardous alcohol use. Previous research identifies psychosocial drivers underpinning this link between sports participation and risky drinking behavior; however, the evidence is restricted to cross-sectional prevalence studies. Theoretical evaluations suggest that psychologically constructed identities are a defining factor for behaviors in this context. Therefore, the present study sought to examine longitudinally the relationships among sports related identities, well-being, and alcohol behaviors in those participating in sports. METHOD: Respondents completed self-report questionnaires on their alcohol consumption, drinking motives, athlete identity (personal identity), sports group identification (social identity), and general well-being. A sample of 475 participants (male = 55.6%; mean age = 20.2 years) provided data at Time 1 for cross-sectional analysis. Longitudinal associations were conducted with 92 participants (male = 42.4%; mean age = 20.8 years) who provided follow-up data (Time 1 and 6 months later). RESULTS: Cross-sectional results revealed an association between social identity and alcohol consumption, which was fully mediated by positive reinforcement drinking motives. Correlation analysis found a significant positive relationship between Time 1 alcohol consumption and social identity 6 months later. Furthermore, social identity was positively associated with consumption, whereas athlete identity was negatively associated therewith. Finally, well-being was positively associated only with sports group identification over time. CONCLUSIONS: Our findings suggest that sport-related drinking may be an avenue for building group identification, and this identification is linked to well-being. PMID- 26751365 TI - Daily Associations Between Alcohol Consumption and Dating Violence Perpetration Among Men and Women: Effects of Self-Regulation. AB - OBJECTIVE: Alcohol intoxication has been associated with dating violence perpetration, defined here as psychological and/or physical violence occurring between young adult dating partners. However, little is known about how the individual variability in the level of alcohol intoxication would influence dating violence perpetration and how sex and self-regulation might influence this association. METHOD: College-aged men and women (N = 146) from a large southwestern U.S. university completed background questionnaires, including the Brief Self-Control Scale, to assess self-regulation and then reported their dating violence perpetration and alcohol consumption using a 90-day Timeline Followback assessment. Their average estimated blood alcohol concentration (eBAC) and their daily deviation from this average were calculated for each of the 90 days to examine the between- and within-person effects of alcohol consumption, respectively. RESULTS: Results of a two-level generalized estimating equation suggest that increases in daily eBAC were associated with an increased likelihood of perpetrating dating violence; however, this association was stronger for those who had a low average eBAC compared with those who had a high average eBAC. For those who had a low average eBAC, higher self-regulation was associated with a lower probability of perpetrating dating violence, whereas among those with a high average eBAC, self-regulation was not associated with dating violence perpetration. Sex did not moderate the association between eBAC and dating violence perpetration. CONCLUSIONS: Findings highlight the importance of self regulation in dating violence perpetration-particularly for those with low average eBACs-and the need for varied intervention strategies, depending on one's typical drinking pattern. PMID- 26751366 TI - The Relationship Between Client Characteristics and Wraparound Services in Substance Use Disorder Treatment Centers. AB - OBJECTIVE: The National Institute on Drug Abuse (NIDA) recommends a comprehensive treatment program for individuals with substance use disorder (SUD) in order to treat needs they often have in addition to their SUD. Specifically, NIDA suggests providing services related to the following issues: medical care, mental health care, HIV/AIDS, child care, educational, vocational, family counseling, housing, transportation, financial, and legal. By providing a comprehensive model that combines core and wraparound services, treatment centers can deliver a higher quality of treatment. In this article, we assessed the relationship between client characteristics and the availability of wraparound services in SUD treatment centers. METHOD: We combined two nationally representative samples of treatment centers and used a negative binomial regression and a series of logistic regressions to analyze the relationship between client characteristics and wraparound services. RESULTS: On average, centers offered fewer than half of the wraparound services endorsed by NIDA. Our results indicated that client characteristics were significantly related to the provision of wraparound services. Most notably, the proportion of adolescent clients was positively related to educational services, the proportion of female clients was positively related to child care, but the proportion of clients referred from the criminal justice system was negatively associated with the provision of multiple wraparound services. CONCLUSIONS: Our findings have important implications for SUD clients and suggest that, although centers are somewhat responsive to their clients' ancillary needs, most centers do not offer the majority of wraparound services. PMID- 26751368 TI - Genetic Diversity Affects the Daily Transcriptional Oscillations of Marine Microbial Populations. AB - Marine microbial communities are genetically diverse but have robust synchronized daily transcriptional patterns at the genus level that are similar across a wide variety of oceanic regions. We developed a microarray-inspired gene-centric approach to resolve transcription of closely-related but distinct strains/ecotypes in high-throughput sequence data. Applying this approach to the existing metatranscriptomics datasets collected from two different oceanic regions, we found unique and variable patterns of transcription by individual taxa within the abundant picocyanobacteria Prochlorococcus and Synechococcus, the alpha Proteobacterium Pelagibacter and the eukaryotic picophytoplankton Ostreococcus. The results demonstrate that marine microbial taxa respond differentially to variability in space and time in the ocean. These intra-genus individual transcriptional patterns underlie whole microbial community responses, and the approach developed here facilitates deeper insights into microbial population dynamics. PMID- 26751370 TI - Dynamics of Soil Organic Carbon and Aggregate Stability with Grazing Exclusion in the Inner Mongolian Grasslands. AB - Grazing exclusion (GE) has been deemed as an important approach to enhance the soil carbon storage of semiarid grasslands in China; however, it remains unclear how different organic carbon (OC) components in soils vary with the duration of GE. Here, we observed the changing trends of different OC components in soils with increased GE duration in five grassland succession series plots, ranging from free grazing to 31-year GE. Specifically, we measured microbial biomass carbon (MBC), easily oxidizable OC (EOC), water-soluble OC (WSOC), and OC in water stable aggregates (macroaggregates [250-2000 MUm], microaggregates [53-250 MUm], and mineral fraction [< 53 MUm]) at 0-20 cm soil depths. The results showed that GE significantly enhanced EOC and WSOC contents in soils, but caused a decline of MBC at the three decade scale. Macroaggregate content (F = 425.8, P < 0.001), OC stored in macroaggregates (F = 84.1, P < 0.001), and the mean weight diameter (MWD) of soil aggregates (F = 371.3, P < 0.001) increased linearly with increasing GE duration. These findings indicate that OC stored in soil increases under three-decade GE with soil organic matter (SOM) stability improving to some extent. Long-term GE practices enhance the formation of soil aggregates through higher SOM input and an exclusion of animal trampling. Therefore, the practice of GE may be further encouraged to realize the soil carbon sequestration potential of semi-arid grasslands, China. PMID- 26751371 TI - Topological Vulnerability Evaluation Model Based on Fractal Dimension of Complex Networks. AB - With an increasing emphasis on network security, much more attentions have been attracted to the vulnerability of complex networks. In this paper, the fractal dimension, which can reflect space-filling capacity of networks, is redefined as the origin moment of the edge betweenness to obtain a more reasonable evaluation of vulnerability. The proposed model combining multiple evaluation indexes not only overcomes the shortage of average edge betweenness's failing to evaluate vulnerability of some special networks, but also characterizes the topological structure and highlights the space-filling capacity of networks. The applications to six US airline networks illustrate the practicality and effectiveness of our proposed method, and the comparisons with three other commonly used methods further validate the superiority of our proposed method. PMID- 26751369 TI - Cortical Superficial Siderosis in Memory Clinic Patients: Further Evidence for Underlying Cerebral Amyloid Angiopathy. AB - BACKGROUND: Cerebral amyloid angiopathy (CAA) is associated with many cases of spontaneous symptomatic lobar intracerebral haemorrhage in older individuals and is emerging as an important contributor to cognitive impairment. Cortical superficial siderosis (cSS) is an increasingly recognized haemorrhagic neuroimaging manifestation of CAA. We sought to investigate its prevalence and its association with underlying CAA among memory clinic patients. METHODS: We included consecutive eligible patients who presented to the out-patient memory clinic at the Massachusetts General Hospital from 2007 to 2010 and had appropriate MRI, including blood-sensitive sequences. We analyzed the prevalence and topography of cSS according to demographic, clinical, APOE and MRI data. RESULTS: Our cohort consisted of 339 memory clinic patients: Alzheimer's disease (n = 86); mild cognitive impairment (n = 162); vascular dementia/mixed dementia (n = 18); other dementia/undetermined (n = 42); and subjective cognitive complains (n = 31). cSS was detected in 10 patients (3%; 95% CI 1.4-5.4): in 7 cases cSS was focal and in 3 cases, it was disseminated. In multivariable logistic regression analysis, the presence of cSS was associated with lobar microbleeds (OR 1.08; 95% CI 1.03-1.13; p = 0.001, per each additional microbleed) and severe white matter hyperintensities (Fazekas score 5-6, OR 4.43; 95% CI 1.21-26.28; p = 0.028) after adjusting for age. These associations were not influenced by the clinical diagnosis. In patients with APOE data, the APOE epsilon4/epsilon4 genotype was overrepresented among subjects with vs. without cSS. In the subgroup of patients with probable CAA (n = 68; 9 with cSS) based on the presence of strictly lobar microbleeds, cSS was also associated with a higher prevalence of severe white matter hyperintensities (66.7 vs. 10.2%; p = 0.001), high centrum semiovale perivascular spaces burden (88.9 vs. 52.4%; p = 0.041) and higher counts of lobar microbleeds (median 13; IQR 10-36 vs. median 1; IQR 1-2; p < 0.00001), compared to patients without cSS. CONCLUSIONS: Our data provide further evidence supporting the hypothesis that cSS is a manifestation of advanced CAA in memory clinic populations. Future longitudinal studies should explore any direct effect of cSS on cognition or haemorrhage risk and disease progression. PMID- 26751372 TI - Cluster-Randomized Non-Inferiority Trial to Compare Supplement Consumption and Adherence to Different Dosing Regimens for Antenatal Calcium and Iron-Folic Acid Supplementation to Prevent Preeclampsia and Anaemia: Rationale and Design of the Micronutrient Initiative Study. AB - BACKGROUND: To prevent pre-eclampsia in populations with insufficient dietary calcium (Ca) intake, the World Health Organisation (WHO) recommends routine Ca supplementation during antenatal care (ANC). WHO guidelines suggest a complex dosing regimen, requiring as many as 5 pill-taking events per day when combined with iron and folic acid (IFA) supplements. Poor adherence may undermine public health effectiveness, so simpler regimens may be preferable. This trial will compare the effect of the WHO-recommended (higher-dose) regimen vs. a simpler, lower-dose regimen on supplement consumption and pill-taking behaviours in Kenyan ANC clients. DESIGN AND METHODS: This is a parallel, non-inferiority, cluster randomized trial; we examined 16 primary care health facilities in Kenya, 1047 pregnant women between 16-30 weeks gestational age. Higher-dose regimen: 1.5 g elemental calcium in 3 separate doses (500 mg Ca/pill) and IFA (60 mg Fe + 400 ug folic acid) taken with evening dose. Lower-dose regimen: 1.0 g calcium in 2 separate doses (500 mg Ca/pill) with IFA taken as above. MEASUREMENTS: Primary outcome is Ca pills consumed per day, measured by pill counts. Secondary outcomes include IFA pills consumed per day, client knowledge, motivation, social support, and satisfaction, measured at 4 to 10 weeks post-enrolment. STATISTICAL ANALYSES: Unit of randomization is the healthcare facility; unit of analysis is individual client. Intent-to-treat analysis will be implemented with multi-level models to account for clustering. EXPECTED PUBLIC HEALTH IMPACT: If pregnant women prescribed lower doses of Ca ingest as many pills as women prescribed the WHO recommended regimen, developing a lower-dose recommendation for antenatal Ca and IFA supplementation programs could save resources. Significance for public healthPre-eclampsia is a leading cause of maternal mortality. Based on clinical evidence of significant reduction in risk of pre-eclampsia, the WHO recommends including calcium (Ca) supplementation in antenatal care services in settings with inadequate dietary Ca intakes. A high daily amount of Ca administered in a complex dosing regimen is recommended to maximize efficacy and bioavailability. Factors such as client adherence, motivation, cost and logistical complexities may undermine effectiveness when implemented in public health programs. This cluster-randomized trial will compare Ca supplement consumption between higher and lower-dose regimens delivered through antenatal care in Kenya, integrated with iron-folic acid supplementation. If a lower-dose regimen improves adherence, women's Ca supplement consumption may be comparable to that achieved under a complex, higher-dose regimen. Evidence gained from this trial will guide public health planning for antenatal calcium supplementation programs to maximize benefits through reducing logistical, cost and adherence barriers. PMID- 26751373 TI - Consistency of VDJ Rearrangement and Substitution Parameters Enables Accurate B Cell Receptor Sequence Annotation. AB - VDJ rearrangement and somatic hypermutation work together to produce antibody coding B cell receptor (BCR) sequences for a remarkable diversity of antigens. It is now possible to sequence these BCRs in high throughput; analysis of these sequences is bringing new insight into how antibodies develop, in particular for broadly-neutralizing antibodies against HIV and influenza. A fundamental step in such sequence analysis is to annotate each base as coming from a specific one of the V, D, or J genes, or from an N-addition (a.k.a. non-templated insertion). Previous work has used simple parametric distributions to model transitions from state to state in a hidden Markov model (HMM) of VDJ recombination, and assumed that mutations occur via the same process across sites. However, codon frame and other effects have been observed to violate these parametric assumptions for such coding sequences, suggesting that a non-parametric approach to modeling the recombination process could be useful. In our paper, we find that indeed large modern data sets suggest a model using parameter-rich per-allele categorical distributions for HMM transition probabilities and per-allele-per-position mutation probabilities, and that using such a model for inference leads to significantly improved results. We present an accurate and efficient BCR sequence annotation software package using a novel HMM "factorization" strategy. This package, called partis (https://github.com/psathyrella/partis/), is built on a new general-purpose HMM compiler that can perform efficient inference given a simple text description of an HMM. PMID- 26751374 TI - Gardnerella vaginalis Subgroups Defined by cpn60 Sequencing and Sialidase Activity in Isolates from Canada, Belgium and Kenya. AB - Increased abundance of Gardnerella vaginalis and sialidase activity in vaginal fluid is associated with bacterial vaginosis (BV), a common but poorly understood clinical entity associated with poor reproductive health outcomes. Since most women are colonized with G. vaginalis, its status as a normal member of the vaginal microbiota or pathogen causing BV remains controversial, and numerous classification schemes have been described. Since 2005, sequencing of the chaperonin-60 universal target (cpn60 UT) has distinguished four subgroups in isolate collections, clone libraries and deep sequencing datasets. To clarify potential clinical and diagnostic significance of cpn60 subgroups, we undertook phenotypic and molecular characterization of 112 G. vaginalis isolates from three continents. A total of 36 subgroup A, 33 B, 35 C and 8 D isolates were identified through phylogenetic analysis of cpn60 sequences as corresponding to four "clades" identified in a recently published study, based on sequencing 473 genes across 17 isolates. cpn60 subgroups were compared with other previously described molecular methods for classification of Gardnerella subgroups, including amplified ribosomal DNA restriction analysis (ARDRA) and real-time PCR assays designed to quantify subgroups in vaginal samples. Although two ARDRA patterns were observed in isolates, each was observed in three cpn60 subgroups (A/B/D and B/C/D). Real-time PCR assays corroborated cpn60 subgroups overall, but 13 isolates from subgroups A, B and D were negative in all assays. A putative sialidase gene was detected in all subgroup B, C and D isolates, but only in a single subgroup A isolate. In contrast, sialidase activity was observed in all subgroup B isolates, 3 (9%) subgroup C isolates and no subgroup A or D isolates. These observations suggest distinct roles for G. vaginalis subgroups in BV pathogenesis. We conclude that cpn60 UT sequencing is a robust approach for defining G. vaginalis subgroups within the vaginal microbiome. PMID- 26751375 TI - Public Health Impact of Complete and Incomplete Rotavirus Vaccination among Commercially and Medicaid Insured Children in the United States. AB - BACKGROUND: This study (NCT01682005) aims to assess clinical and cost impacts of complete and incomplete rotavirus (RV) vaccination. METHODS: Beneficiaries who continuously received medical and pharmacy benefits since birth were identified separately in Truven Commercial Claims and Encounters (2000-2011) and Truven Medicaid Claims (2002-2010) and observed until the first of end of insurance eligibility or five years. Infants with >=1 RV vaccine within the vaccination window (6 weeks-8 months) were divided into completely and incompletely vaccinated cohorts. Historically unvaccinated (before 2007) and contemporarily unvaccinated (2007 and after) cohorts included children without RV vaccine. Claims with International Classification of Disease 9th edition (ICD-9) codes for diarrhea and RV were identified. First RV episode incidence, RV-related and diarrhea-related healthcare resource utilization after 8 months old were calculated and compared across groups. Poisson regressions were used to generate incidence rates with 95% confidence intervals (CIs). Mean total, inpatient, outpatient and emergency room costs for first RV and diarrhea episodes were calculated; bootstrapping was used to construct 95% CIs to evaluate cost differences. RESULTS: 1,069,485 Commercial and 515,557 Medicaid patients met inclusion criteria. Among commercially insured, RV incidence per 10,000 person years was 3.3 (95% CI 2.8-3.9) for completely, 4.0 (95% CI 3.3-5.0) for incompletely vaccinated, and 20.9 (95% CI 19.5-22.4) for contemporarily and 40.3 (95% CI 38.6-42.1) for historically unvaccinated. Rates in Medicaid were 7.5 (95% CI 4.8-11.8) for completely, 9.0 (95% CI 6.5-12.3) for incompletely vaccinated, and 14.6 (95% CI 12.8-16.7) for contemporarily and 52.0 (95% CI 50.2-53.8) for historically unvaccinated. Mean cost for first RV episode per cohort member was $15.33 (95% CI $12.99-$18.03) and $4.26 ($95% CI $2.34-$6.35) lower for completely vaccinated versus contemporarily unvaccinated in Commercial and Medicaid, respectively. CONCLUSIONS: RV vaccination results in significant reduction in RV infection. There is evidence of indirect benefit to unvaccinated individuals. PMID- 26751376 TI - Characterization of MTAP Gene Expression in Breast Cancer Patients and Cell Lines. AB - MTAP is a ubiquitously expressed gene important for adenine and methionine salvage. The gene is located at 9p21, a chromosome region often deleted in breast carcinomas, similar to CDKN2A, a recognized tumor suppressor gene. Several research groups have shown that MTAP acts as a tumor suppressor, and some therapeutic approaches were proposed based on a tumors' MTAP status. We analyzed MTAP and CDKN2A gene (RT-qPCR) and protein (western-blotting) expression in seven breast cancer cell lines and evaluated their promoter methylation patterns to better characterize the contribution of these genes to breast cancer. Cytotoxicity assays with inhibitors of de novo adenine synthesis (5-FU, AZA and MTX) after MTAP gene knockdown showed an increased sensitivity, mainly to 5-FU. MTAP expression was also evaluated in two groups of samples from breast cancer patients, fresh tumors and paired normal breast tissue, and from formalin-fixed paraffin embedded (FFPE) core breast cancer samples diagnosed as Luminal-A tumors and triple negative breast tumors (TNBC). The difference of MTAP expression between fresh tumors and normal tissues was not statistically significant. However, MTAP expression was significantly higher in Luminal-A breast tumors than in TNBC, suggesting the lack of expression in more aggressive breast tumors and the possibility of using the new approaches based on MTAP status in TNBC. PMID- 26751377 TI - Impact of Urate Level on Cardiovascular Risk in Allopurinol Treated Patients. A Nested Case-Control Study. AB - BACKGROUND: Gout gives rise to increased risk of cardiovascular events. Gout attacks can be effectively prevented with urate lowering drugs, and allopurinol potentially reduces cardiovascular risk. What target level of urate is required to reduce cardiovascular risk is not known. OBJECTIVES: To investigate the effect of achieving target plasma urate with allopurinol on cardiovascular outcomes in a case-control study nested within long-term users of allopurinol. METHODS: We identified long-term users of allopurinol in Funen County, Denmark. Among these, we identified all cases of cardiovascular events and sampled 4 controls to each case from the same population. The cases and controls were compared with respect to whether they reached a urate target below 0.36 mmol/l on allopurinol. The derived odds ratios were controlled for potential confounders available from data on prescriptions, laboratory values and in- and outpatient contacts. RESULTS: No association between treatment-to-target urate level and cardiovascular events were found (adjusted odds ratio of 1.01, 95% confidence interval 0.79-1.28). No significant effect was seen in any subgroup defined by age, gender, renal function, allopurinol dose or the achieved urate level. Overall, the doses of allopurinol used in this study were low (mean ~ 140 mg/day). CONCLUSION: We were unable to demonstrate a link between achieved urate level in patients treated with allopurinol and risk of cardiovascular events. Possible explanations include that allopurinol doses higher than those used in this study are required to achieve cardiovascular risk reduction or that the cardiovascular effect of allopurinol is not mediated through low urate levels. It remains to be seen whether allopurinol has a dose-response relationship with cardiovascular events at higher doses. PMID- 26751378 TI - Neurokernel: An Open Source Platform for Emulating the Fruit Fly Brain. AB - We have developed an open software platform called Neurokernel for collaborative development of comprehensive models of the brain of the fruit fly Drosophila melanogaster and their execution and testing on multiple Graphics Processing Units (GPUs). Neurokernel provides a programming model that capitalizes upon the structural organization of the fly brain into a fixed number of functional modules to distinguish between these modules' local information processing capabilities and the connectivity patterns that link them. By defining mandatory communication interfaces that specify how data is transmitted between models of each of these modules regardless of their internal design, Neurokernel explicitly enables multiple researchers to collaboratively model the fruit fly's entire brain by integration of their independently developed models of its constituent processing units. We demonstrate the power of Neurokernel's model integration by combining independently developed models of the retina and lamina neuropils in the fly's visual system and by demonstrating their neuroinformation processing capability. We also illustrate Neurokernel's ability to take advantage of direct GPU-to-GPU data transfers with benchmarks that demonstrate scaling of Neurokernel's communication performance both over the number of interface ports exposed by an emulation's constituent modules and the total number of modules comprised by an emulation. PMID- 26751379 TI - Development and evaluation of a Smartphone-enabled, caregiver-supported educational intervention for management of physical disabilities following stroke in India: protocol for a formative research study. AB - The incidence and prevalence of stroke in India has reached epidemic proportions. The growing magnitude of disability in patients with stroke in India poses a major public health challenge. Given the nature of the condition, affected individuals often become disabled with profound effects on their quality of life. The availability of rehabilitation services for people with disabilities is inadequate in India. Rehabilitation services are usually offered by private hospitals located in urban areas and many stroke survivors, especially those who are poor or live in rural areas, cannot afford to pay for, or do not have access to, such services. Thus, identification of cost-effective ways to rehabilitate people with stroke-related disability is an important challenge. Educational interventions in stroke rehabilitation can assist stroke survivors to make informed decisions regarding their on-going treatment and to self-manage their condition with support from their caregivers. Although educational interventions have been shown to improve patient knowledge for self-management of stroke, an optimal format for the intervention has not as yet been established, particularly in low- and middle-income countries. This formative research study aims to systematically develop an educational intervention for management of post-stroke disability for stroke survivors in India, and evaluate the feasibility and acceptability of delivering the intervention using Smartphones and with caregiver support. The research study will be conducted in Chennai, India, and will be organised in three different phases. Phase 1: Development of the intervention. Phase 2: Field testing and finalising the intervention. Phase 3: Piloting of the intervention and assessment of feasibility and acceptability. A mixed-methods approach will be used to develop and evaluate the intervention. If successful, it will help realise the potential of using Smartphone-enabled, carer-supported educational intervention to bridge the gaps in service access for rehabilitation of individuals with stroke-related disability in India. The proposed research will also provide valuable information for clinicians and policymakers. PMID- 26751380 TI - A Retrospective Study of Preferable Alternative Route to Right Internal Jugular Vein for Placing Tunneled Dialysis Catheters: Right External Jugular Vein versus Left Internal Jugular Vein. AB - BACKGROUND: Right internal jugular vein (IJV) is a preferred access route for tunneled (cuffed) dialysis catheters (TDCs), and both right external jugular vein (EJV) and left IJV are alternative routes for patients in case the right IJV isn't available for TDC placement. This retrospective study aimed to determine if a disparity exists between the two alternative routes in hemodialysis patients in terms of outcomes of TDCs. METHODS: 49 hemodialysis patients who required TDCs through right EJV (n = 21) or left IJV (n = 28) as long-term vascular access were included in this study. The primary end point was cumulative catheter patency. Secondary end points include primary catheter patency, proportion of patients that never required urokinase and incidence of catheter-related bloodstream infections (CRBSI). RESULTS: A total of 20,870 catheter-days were evaluated and the median was 384 (interquartile range, 262-605) catheter-days. Fewer catheters were removed in the right EJV group than in the left IJV group (P = 0.007). Mean cumulative catheter patency was higher in the right EJV group compared with the left IJV group (P = 0.031). There was no significant difference between the two groups in the incidence of CRBSI, primary catheter patency or proportion of patients that never required urokinase use. Total indwell time of antecedent catheters was identified as an independent risk factor for cumulative catheter patency by Cox regression hazards test with an HR of 2.212 (95% CI, 1.363-3.588; p = 0.001). CONCLUSIONS: Right EJV might be superior to left IJV as an alternative insertion route for TDC placement in hemodialysis patients whose right IJVs are unavailable. PMID- 26751382 TI - The Genotypic and Phenotypic Stability of Plasmodium falciparum Field Isolates in Continuous In Vitro Culture. AB - The Plasmodium falciparum in vitro culture system is critical for genotypic and phenotypic analyses of the parasites. For genotypic analysis, the genomic DNA can be obtained directly from the patient blood sample or from culture adapted parasites whereas for phenotypic analysis, immediate ex vivo or in vitro culture adapted parasites are used. However, parasite biology studies have not investigated whether culture adaptation process affects genotypic and/or phenotypic characteristics of the parasites in short- or long-term cultures. Here, we set out to study the dynamics and stability of parasite genetic and phenotypic profiles as field isolate parasites were adapted in continuous cultures. Parasites collected from three different patients presenting with uncomplicated malaria were adapted and maintained in drug-free continuous cultures. Aliquots from the continuous cultures were collected every 24-48 hours for analyses. Each aliquot was treated as a separate parasite sample. For genetic analysis, microsatellite (MS) typing and single nucleotide polymorphism (SNP) analyses of 23 drug resistance markers were done. The 50% inhibitory concentrations (IC50) for some of the samples were also established for four antimalarial drugs. Samples from each patient (parasite-line) were compared as they were passed through the continuous culture. Data revealed genotypic and phenotypic profiles for the three parasite-lines fluctuated from one generation to the next with no specific pattern or periodicity. With few exceptions, multilocus analysis revealed samples from each parasite-line had high genetic diversity with unique haplotypes. Interestingly, changes in MS and SNP profiles occurred simultaneously. The difference in the IC50s of samples in each parasite line reached statistical significance. However, phenotypic changes did not correspond or correlate to genotypic changes. Our study revealed parasite genetic and phenotypic characteristics fluctuates in short- and long-term cultures, which indicates parasite genetic information obtained even in short cultures is likely to be different from the natural infection parasites. PMID- 26751383 TI - Mono-(2-Ethylhexyl) Phthalate Promotes Pro-Labor Gene Expression in the Human Placenta. AB - Women exposed to phthalates during pregnancy are at increased risk for delivering preterm, but the mechanism behind this relationship is unknown. Placental corticotropin-releasing hormone (CRH) and cyclooxygenase-2 (COX-2) are key mediators of parturition and are regulated by the non-canonical NF-kB (RelB/p52) signaling pathway. In this study, we demonstrate that one of the major phthalate metabolites, mono-(2-ethylhexyl)-phthalate (MEHP), increased CRH and COX-2 mRNA and protein abundance in a dose-dependent manner in primary cultures of cytotrophoblast. This was coupled with an increase in nuclear import of RelB/p52 and its association with the CRH and COX-2 promoters. Silencing of NF-kB inducing kinase, a central signaling component of the non-canonical NF-kB pathway, blocked MEHP-induced upregulation of CRH and COX-2. These results suggest a potential mechanism mediated by RelB/p52 by which phthalates could prematurely induce pro labor gene activity and lead to preterm birth. PMID- 26751381 TI - LPS-Enhanced Glucose-Stimulated Insulin Secretion Is Normalized by Resveratrol. AB - Low-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS) resulting in endotoxemia could be a candidate. Here we test the effect of LPS and the anti-inflammatory compound resveratrol on glucose homeostasis, insulin levels and inflammation. Mice were subcutaneously implanted with osmotic mini pumps infusing either low-dose LPS or saline for 28 days. Half of the mice were treated with resveratrol delivered through the diet. LPS caused increased inflammation of the liver and adipose tissue (epididymal and subcutaneous) together with enlarged spleens and increased number of leukocytes in the blood. Resveratrol specifically reduced the inflammatory status in epididymal fat (reduced expression of TNFa and Il1b, whereas the increased macrophage infiltration was unaltered) without affecting the other tissues investigated. By LC-MS, we were able to quantitate resveratrol metabolites in epididymal but not subcutaneous adipose tissue. LPS induced insulin resistance as the glucose-stimulated insulin secretion during an oral glucose tolerance test was increased despite similar plasma glucose level resulting in an increase in the insulinogenic index (IGI; delta0-15insulin/delta0 15glucose) from 13.73 to 22.40 pmol/mmol (P < 0.001). This aberration in insulin and glucose homeostasis was normalized by resveratrol. IN CONCLUSION: Low-dose LPS enhanced the glucose-stimulated insulin secretion without affecting the blood glucose suggesting increased insulin resistance. Resveratrol restored LPS-induced alteration of the insulin secretion and demonstrated anti-inflammatory effects specifically in epididymal adipose tissue possibly due to preferential accumulation of resveratrol metabolites pointing towards a possible important involvement of this tissue for the effects on insulin resistance and insulin secretion. PMID- 26751384 TI - A Course on Terror Medicine: Content and Evaluations. AB - INTRODUCTION: The development of medical school courses on medical responses for disaster victims has been deemed largely inadequate. To address this gap, a 2 week elective course on Terror Medicine (a field related to Disaster and Emergency Medicine) has been designed for fourth year students at Rutgers New Jersey Medical School in Newark, New Jersey (USA). This elective is part of an overall curricular plan to broaden exposure to topics related to Terror Medicine throughout the undergraduate medical education. RATIONALE: A course on Terror Medicine necessarily includes key aspects of Disaster and Emergency Medicine, though the converse is not the case. Courses on Disaster Medicine may not address features distinctively associated with a terror attack. Thus, a terror-related focus not only assures attention to this important subject but to accidental or naturally occurring incidents as well. METHODS: The course, implemented in 2014, uses a variety of teaching modalities including lectures, videos, and tabletop and hands-on simulation exercises. The subject matter includes biological and chemical terrorism, disaster management, mechanisms of injury, and psychiatry. This report outlines the elective's goals and objectives, describes the course syllabus, and presents outcomes based on student evaluations of the initial iterations of the elective offering. RESULTS: All students rated the course as "excellent" or "very good." Evaluations included enthusiastic comments about the content, methods of instruction, and especially the value of the simulation exercises. Students also reported finding the course novel and engaging. CONCLUSION: An elective course on Terror Medicine, as described, is shown to be feasible and successful. The student participants found the content relevant to their education and the manner of instruction effective. This course may serve as a model for other medical schools contemplating the expansion or inclusion of Terror Medicine-related topics in their curriculum. PMID- 26751385 TI - Validity and reliability of Nike + Fuelband for estimating physical activity energy expenditure. AB - BACKGROUND: The Nike + Fuelband is a commercially available, wrist-worn accelerometer used to track physical activity energy expenditure (PAEE) during exercise. However, validation studies assessing the accuracy of this device for estimating PAEE are lacking. Therefore, this study examined the validity and reliability of the Nike + Fuelband for estimating PAEE during physical activity in young adults. Secondarily, we compared PAEE estimation of the Nike + Fuelband with the previously validated SenseWear Armband (SWA). METHODS: Twenty-four participants (n = 24) completed two, 60-min semi-structured routines consisting of sedentary/light-intensity, moderate-intensity, and vigorous-intensity physical activity. Participants wore a Nike + Fuelband and SWA, while oxygen uptake was measured continuously with an Oxycon Mobile (OM) metabolic measurement system (criterion). RESULTS: The Nike + Fuelband (ICC = 0.77) and SWA (ICC = 0.61) both demonstrated moderate to good validity. PAEE estimates provided by the Nike + Fuelband (246 +/- 67 kcal) and SWA (238 +/- 57 kcal) were not statistically different than OM (243 +/- 67 kcal). Both devices also displayed similar mean absolute percent errors for PAEE estimates (Nike + Fuelband = 16 +/- 13 %; SWA = 18 +/- 18 %). Test-retest reliability for PAEE indicated good stability for Nike + Fuelband (ICC = 0.96) and SWA (ICC = 0.90). CONCLUSION: The Nike + Fuelband provided valid and reliable estimates of PAEE, that are similar to the previously validated SWA, during a routine that included approximately equal amounts of sedentary/light-, moderate- and vigorous-intensity physical activity. PMID- 26751386 TI - Adjuvant chemotherapy for colon cancer: a consensus statement of the Hellenic and Cypriot Colorectal Cancer Study Group by the HeSMO. AB - Colorectal cancer remains a major cause of cancer mortality in the Western world both in men and women. In this manuscript a concise overview and recommendations on adjuvant chemotherapy in colon cancer are presented. An executive team from the Hellenic Society of Medical Oncology was assigned to develop a consensus statement and guidelines on the adjuvant treatment of colon cancer. Fourteen statements on adjuvant treatment were subjected to the Delphi methodology. Voting experts were 68. All statements achieved a rate of consensus above than 80% (>87%) and none revised and entered to a second round of voting. Three and 8 of them achieved a 100 and an over than 90% consensus, respectively. These statements describe evaluations of therapies in clinical practice. They could be considered as general guidelines based on best available evidence for assistance in treatment decision-making. Furthermore, they serve to identify questions and targets for further research and the settings in which investigational therapy could be considered. PMID- 26751388 TI - Mycobacterium leprae-Infected Macrophages Preferentially Primed Regulatory T Cell Responses and Was Associated with Lepromatous Leprosy. AB - BACKGROUND: The persistence of Mycobacterium leprae (M. leprae) infection is largely dependent on the types of host immune responses being induced. Macrophage, a crucial modulator of innate and adaptive immune responses, could be directly infected by M. leprae. We therefore postulated that M. leprae-infected macrophages might have altered immune functions. METHODOLOGY/PRINCIPAL FINDINGS: Here, we treated monocyte-derived macrophages with live or killed M. leprae, and examined their activation status and antigen presentation. We found that macrophages treated with live M. leprae showed committed M2-like function, with decreased interleukin 1 beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNF alpha) and MHC class II molecule expression and elevated IL-10 and CD163 expression. When incubating with naive T cells, macrophages treated with live M. leprae preferentially primed regulatory T (Treg) cell responses with elevated FoxP3 and IL-10 expression, while interferon gamma (IFN-gamma) expression and CD8+ T cell cytotoxicity were reduced. Chromium release assay also found that live M. leprae-treated macrophages were more resistant to CD8+ T cell-mediated cytotoxicity than sonicated M. leprae-treated monocytes. Ex vivo studies showed that the phenotype and function of monocytes and macrophages had clear differences between L-lep and T-lep patients, consistent with the in vitro findings. CONCLUSIONS/SIGNIFICANCE: Together, our data demonstrate that M. leprae could utilize infected macrophages by two mechanisms: firstly, M. leprae-infected macrophages preferentially primed Treg but not Th1 or cytotoxic T cell responses; secondly, M. leprae-infected macrophages were more effective at evading CD8+ T cell-mediated cytotoxicity. PMID- 26751387 TI - Proinflammatory Stimulation of Toll-Like Receptor 9 with High Dose CpG ODN 1826 Impairs Endothelial Regeneration and Promotes Atherosclerosis in Mice. AB - BACKGROUND: Toll-like receptors (TLR) of the innate immune system have been closely linked with the development of atherosclerotic lesions. TLR9 is activated by unmethylated CpG motifs within ssDNA, but also by CpG motifs in nucleic acids released during vascular apoptosis and necrosis. The role of TLR9 in vascular disease remains controversial and we sought to investigate the effects of a proinflammatory TLR9 stimulation in mice. METHODS AND FINDINGS: TLR9-stimulation with high dose CpG ODN at concentrations between 6.25 nM to 30 nM induced a significant proinflammatory cytokine response in mice. This was associated with impaired reendothelialization upon acute denudation of the carotid and increased numbers of circulating endothelial microparticles, as a marker for amplified endothelial damage. Chronic TLR9 agonism in apolipoprotein E-deficient (ApoE-/-) mice fed a cholesterol-rich diet increased aortic production of reactive oxygen species, the number of circulating endothelial microparticles, circulating sca 1/flk-1 positive cells, and most importantly augmented atherosclerotic plaque formation when compared to vehicle treated animals. Importantly, high concentrations of CpG ODN are required for these proatherogenic effects. CONCLUSIONS: Systemic stimulation of TLR9 with high dose CpG ODN impaired reendothelialization upon acute vascular injury and increased atherosclerotic plaque development in ApoE-/- mice. Further studies are necessary to fully decipher the contradictory finding of TLR9 agonism in vascular biology. PMID- 26751389 TI - Human Gut Bacteria Are Sensitive to Melatonin and Express Endogenous Circadian Rhythmicity. AB - Circadian rhythms are fundamental properties of most eukaryotes, but evidence of biological clocks that drive these rhythms in prokaryotes has been restricted to Cyanobacteria. In vertebrates, the gastrointestinal system expresses circadian patterns of gene expression, motility and secretion in vivo and in vitro, and recent studies suggest that the enteric microbiome is regulated by the host's circadian clock. However, it is not clear how the host's clock regulates the microbiome. Here, we demonstrate at least one species of commensal bacterium from the human gastrointestinal system, Enterobacter aerogenes, is sensitive to the neurohormone melatonin, which is secreted into the gastrointestinal lumen, and expresses circadian patterns of swarming and motility. Melatonin specifically increases the magnitude of swarming in cultures of E. aerogenes, but not in Escherichia coli or Klebsiella pneumoniae. The swarming appears to occur daily, and transformation of E. aerogenes with a flagellar motor-protein driven lux plasmid confirms a temperature-compensated circadian rhythm of luciferase activity, which is synchronized in the presence of melatonin. Altogether, these data demonstrate a circadian clock in a non-cyanobacterial prokaryote and suggest the human circadian system may regulate its microbiome through the entrainment of bacterial clocks. PMID- 26751390 TI - [Bickerstaff encephalitis: A case report]. PMID- 26751391 TI - [Is perioperative bridging anticoagulation necessary in patients with non valvular atrial fibrillation?]. PMID- 26751392 TI - Single-nucleotide polymorphism in the 5-alpha-reductase gene (SRD5A2) is associated with increased prevalence of metabolic syndrome in chemotherapy treated testicular cancer survivors. AB - PURPOSE: Chemotherapy-treated testicular cancer survivors are at risk for development of the metabolic syndrome, especially in case of decreased androgen levels. Polymorphisms in the gene encoding steroid 5-alpha-reductase type II (SRD5A2) are involved in altered androgen metabolism. We investigated whether single-nucleotide polymorphisms (SNPs) rs523349 (V89L) and rs9282858 (A49T) in SRD5A2 are associated with cardiometabolic status in testicular cancer survivors. METHODS: In 173 chemotherapy-treated testicular cancer survivors, hormone levels and cardiometabolic status were evaluated cross-sectionally (median 5 years [range 3-20] after chemotherapy) and correlated with SNPs in SRD5A2. RESULTS: The metabolic syndrome was more prevalent in survivors who were homozygous or heterozygous variant for SRD5A2 rs523349 compared to wild type (33% versus 19%, P = 0.032). In particular, patients with lower testosterone levels (<15 nmol/l) and a variant genotype showed a high prevalence of the metabolic syndrome (66.7%). Mean intima-media thickness of the carotid artery and urinary albumin excretion, both markers of vascular damage, were higher in the group of survivors homozygous or heterozygous variant for rs523349 (0.62 versus 0.57 mm, P = 0.026; 5.6 versus 3.1 mg/24 h, P = 0.017, respectively). No association was found between cardiometabolic status and SNP rs9282858 in SRD5A2. CONCLUSION: Metabolic syndrome develops more frequently in testicular cancer survivors homozygous or heterozygous variant for SNP rs523349 in SRD5A2. Altered androgen sensitivity appears to be involved in the development of adverse metabolic and vascular changes in testicular cancer survivors and is a target for intervention. PMID- 26751393 TI - Rationale for anti-CD137 cancer immunotherapy. AB - The consideration of the complex interplay between the tumour microenvironment (TME) and the immune response is the key for designing effective immunotherapies. Therapeutic strategies that harness co-stimulatory receptors have recently gained momentum in the clinic. One such strategy with promising clinical applications is the targeting of CD137, a member of the tumour necrosis factor receptor superfamily. Its expression on both innate and adaptive immune cells, coupled with its unique ability to potentiate antitumour responses through modulating the TME and to ameliorate autoimmune responses, has established it as an appealing target. In this review, we will discuss the various CD137-targeted immunotherapeutics that have reached clinical development, with a focus on recent advances and novel modalities such as CD137 chimeric antigen receptors and CD137 bispecific antibodies. We will also highlight the effect of CD137 targeting on the TME and discuss the importance of probing TME changes for predicting and testing the efficacy of CD137-mediated immunotherapy. PMID- 26751394 TI - Structural characterization of a Vatairea macrocarpa lectin in complex with a tumor-associated antigen: A new tool for cancer research. AB - Legume lectins are the most thoroughly studied group of lectins and have been widely linked to many pathological processes. Their use as immunohistochemistry markers for cell profiling and cancer diagnosis have made these molecules important tools for immunological studies and have stimulated the prospection and characterization of new lectins. The crystal structures of a recombinant seed lectin from Vatairea macrocarpa (rVML) and its complexes with GalNAcalpha1-O-Ser, GalNAc and alpha-lactose, have been determined at 1.90, 1.97, 2.70 and 1.83A resolution, respectively. Small angle X-ray scattering and calorimetry assays have confirmed the same pH stable oligomerization pattern and binding profiles proposed for its wild-type counterpart. In silico analyzes have explored the potential of this recombinant lectin as new tool for cancer research through a comparative profile with other legume lectins widely used for cancer diagnosis and prognosis. The results suggest the recognition of specific epitopes exhibited on different cancer cells as a process that relies on the disposition of hydrophobic clusters and charged regions around the lectin carbohydrate-binding site, favouring the anchorage of different groups in the antigen boundaries, highlighting the different potential of each analyzed lectin. In conclusion, the experimental results and comparative analysis show that rVML is as a promising tool for cancer research, able to bind with high affinity specific tumor associated antigens, highly stable and easily produced. PMID- 26751396 TI - Quaternionic representation of the genetic code. AB - A heuristic diagram of the evolution of the standard genetic code is presented. It incorporates, in a way that resembles the energy levels of an atom, the physical notion of broken symmetry and it is consistent with original ideas by Crick on the origin and evolution of the code as well as with the chronological order of appearance of the amino acids along the evolution as inferred from work that mixtures known experimental results with theoretical speculations. Suggested by the diagram we propose a Hamilton quaternions based mathematical representation of the code as it stands now-a-days. The central object in the description is a codon function that assigns to each amino acid an integer quaternion in such a way that the observed code degeneration is preserved. We emphasize the advantages of a quaternionic representation of amino acids taking as an example the folding of proteins. With this aim we propose an algorithm to go from the quaternions sequence to the protein three dimensional structure which can be compared with the corresponding experimental one stored at the Protein Data Bank. In our criterion the mathematical representation of the genetic code in terms of quaternions merits to be taken into account because it describes not only most of the known properties of the genetic code but also opens new perspectives that are mainly derived from the close relationship between quaternions and rotations. PMID- 26751395 TI - De Novo Truncating Mutations in the Kinetochore-Microtubules Attachment Gene CHAMP1 Cause Syndromic Intellectual Disability. AB - A rare syndromic form of intellectual disability with impaired speech was recently found associated with mutations in CHAMP1 (chromosome alignment maintaining phosphoprotein 1), the protein product of which is directly involved in microtubule-kinetochore attachment. Through whole-exome sequencing in six unrelated nonconsanguineous families having a sporadic case of intellectual disability, we identified six novel de novo truncating mutations in CHAMP1: c.1880C>G p.(Ser627*), c.1489C>T; p.(Arg497*), c.1876_1877delAG; p.(Ser626Leufs*4), c.1043G>A; p.(Trp348*), c.1002G>A; p.(Trp334*), and c.958_959delCC; p.(Pro320*). Our clinical observations confirm the phenotypic homogeneity of the syndrome, which represents therefore a distinct clinical entity. Besides, our functional studies show that CHAMP1 protein variants are delocalized from chromatin and are unable to bind to two of its direct partners, POGZ and HP1. These data suggest a pathogenic mechanism of the CHAMP1-associated intellectual disability syndrome mediated by direct interacting partners of CHAMP1, several of which are involved in chromo/kinetochore-related disorders. PMID- 26751397 TI - Functional interfaces for biomimetic energy harvesting: CNTs-DNA matrix for enzyme assembly. AB - The development of 3D structures exploring the properties of nano-materials and biological molecules has been shown through the years as an effective path forward for the design of advanced bio-nano architectures for enzymatic fuel cells, photo-bio energy harvesting devices, nano-biosensors and bio-actuators and other bio-nano-interfacial architectures. In this study we demonstrate a scaffold design utilizing carbon nanotubes, deoxyribose nucleic acid (DNA) and a specific DNA binding transcription factor that allows for directed immobilization of a single enzyme. Functionalized carbon nanotubes were covalently bonded to a diazonium salt modified gold surface through carbodiimide chemistry creating a brush-type nanotube alignment. The aligned nanotubes created a highly ordered structure with high surface area that allowed for the attachment of a protein assembly through a designed DNA scaffold. The enzyme immobilization was controlled by a zinc finger (ZNF) protein domain that binds to a specific dsDNA sequence. ZNF 268 was genetically fused to the small laccase (SLAC) from Streptomyces coelicolor, an enzyme belonging to the family of multi-copper oxidases, and used to demonstrate the applicability of the developed approach. Analytical techniques such as X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and enzymatic activity analysis, allowed characterization at each stage of development of the bio-nano architecture. This article is part of a Special Issue entitled Biodesign for Bioenergetics--the design and engineering of electronic transfer cofactors, proteins and protein networks, edited by Ronald L. Koder and J.L. Ross Anderson. PMID- 26751398 TI - Kinetics and mass spectrometric measurements of myoglobin unfolding in aqueous ionic liquid solutions. AB - Recent studies have characterized the effects of aqueous ionic liquids on myoglobin unfolding for the broader purposes of understanding their effects on protein structures, stabilities, and ultimately biocompatibilities for future applications. Here, we investigated the effects of four different ionic liquids (ILs) on the thermal stability, unfolding kinetics, and tertiary shape of myoglobin. We compared results for four different ILs: 1-butyl-3-methyl imidazolium tetrafluoroborate (BMIBF4); 1-butyl-3-methyl pyrrolidinium tetrafluoroborate (PyrrBF4); 1-ethyl-3-methyl imidazolium acetate (EMIAc); and tetramethylguanidinium acetate (TMGAc). Results showed that ILs accelerate myoglobin unfolding kinetics both through aqueous solution ionic strength effects and ionic liquid-specific effects. Arrhenius plots of observed rate constants reveal that some ILs lower the energy barrier to unfolding, possibly by destabilizing the native protein state. The magnitude of these ionic liquid effects correlates with their effects on protein thermodynamic stabilities. Hydrogen-deuterium exchange (HDX) experiments using ESI-MS showed that myoglobin exhibits a more open, and presumably less stable, tertiary shape in aqueous IL solutions. Overall, BMIBF4 and TMGAc exhibit the strongest effect on the myoglobin stability, unfolding rate, and tertiary structure while PyrrBF4 and EMIAc have weaker effects under our experimental conditions. PMID- 26751399 TI - Role of the durum wheat dehydrin in the function of proteases conferring salinity tolerance in Arabidopsis thaliana transgenic lines. AB - Dehydrins are claimed to stabilize macromolecules against freezing damage, dehydration, ionic or osmotic stresses, thermal stress and re-folding yield. However, their precise function remains unknown. In this context, we report the behavior of protease activities in dehydrin transgenic Arabidopsis lines against the wild type plant under salt stress (100mM NaCl). Indeed, proteases play key roles in plants, maintaining strict protein quality control and degrading specific sets of proteins in response to diverse environmental and developmental stimuli. We proved that durum wheat DHN-5 modulates the activity of some proteases, summarized on the promotion of the Cysteinyl protease and the decrease of the Aspartyl protease activity. This fact is also upgraded in salt stress conditions. We conclude that the dehydrin transgenic context encodes salinity tolerance in transgenic lines through the modulation of the interaction not only at transcriptional level but also at protein level and also with the impact of salt stress as an endogenous and exogenous effector on some biocatalysts like proteases. PMID- 26751400 TI - Biochemical, immunological and kinetic characterization and partial sequence analysis of a thiol proteinase inhibitor from Bubalus bubalis kidney: An attempt targeting kidney disorders. AB - In the present study a thiol proteinase inhibitor was isolated from buffalo kidney making use of ammonium sulphate precipitation and gel filtration chromatography on Sephacryl S-100HR column. Purified inhibitor is homogeneous as it displayed a single band in gel electrophoresis both under reducing and non reducing environment and is of 65KDa as revealed by gel filtration and SDS PAGE. Kinetic studies revealed the presence of reversible accompanied with competitive mode of inhibition; showing maximum efficacy against papain (Ki=2.90*10-4). It was maximally active at pH 8.0 and was stable for a period of 30, 60 and 90 days at 37, 4 and -20 degrees C respectively. Immunological studies confirmed its purity of epitopes as a single precipitin line is obtained in immunodiffusion. N terminal analysis revealed that it shared a good homology with mouse kidney cystatin as well as with Human Cys C and Cys E thereby advocating its use as a model for various human oriented studies which targets how the kidney cystatin level varies in accordance with various drugs that are currently being used as a target for variety of diseases. PMID- 26751401 TI - The status of glycation in protein aggregation. AB - Protein crucial function and flexibility directly depend on its whole structure which is determined by the native distribution of structural elements. Any disturbances in a protein architecture leads to many kind of abnormalities and intra- or extracellular accumulation of misfolded proteins which are the basis of conformational diseases. Glycation is one of the most important unwanted post translational modifications (PTM) which modifies protein three dimensional decoration and triggers its abnormalities. In current review, we take a look at the brief history of protein glycation, its mechanism and kinetics, glycation consequences and toxic products and its involvement in protein chemical modification, aggregation amyloids and fibril formation and different mechanisms induced by such alterations. PMID- 26751402 TI - A Combinatorial effect of carboxymethyl cellulose based scaffold and microRNA-15b on osteoblast differentiation. AB - The present study was aimed to synthesize and characterize a bio-composite scaffold containing carboxymethyl cellulose (CMC), zinc doped nano-hydroxyapatite (Zn-nHAp) and ascorbic acid (AC) for bone tissue engineering applications. The fabricated bio-composite scaffold was characterized by SEM, FT-IR and XRD analyses. The ability of scaffold along with a bioactive molecule, microRNA-15b (miR-15b) for osteo-differentiation at cellular and molecular levels was determined using mouse mesenchymal stem cells (mMSCs). miR-15b acts as posttranscriptional gene regulator and regulates osteoblast differentiation. The scaffold and miR-15b were able to promote osteoblast differentiation; when these treatments were combined together on mMSCs, there was an additive effect on promotion of osteoblast differentiation. Thus, it appears that the combination of CMC/Zn-nHAp/AC scaffold with miR-15b would provide more efficient strategy for treating bone related defects and bone regeneration. PMID- 26751403 TI - Scan-rescan precision of subchondral bone curvature maps from routine 3D DESS water excitation sequences: Data from the Osteoarthritis Initiative. AB - BACKGROUND: Subchondral bone (SCB) undergoes changes in the shape of the articulating bone surfaces and is currently recognized as a key target in osteoarthritis (OA) treatment. The aim of this study was to present an automated system that determines the curvature of the SCB regions of the knee and to evaluate its cross-sectional and longitudinal scan-rescan precision METHODS: Six subjects with OA and six control subjects were selected from the Osteoarthritis Initiative (OAI) pilot study database. As per OAI protocol, these subjects underwent 3T MRI at baseline and every twelve months thereafter, including a 3D DESS WE sequence. We analyzed the baseline and twenty-four month images. Each subject was scanned twice at these visits, thus generating scan-rescan information. Images were segmented with an automated multi-atlas framework platform and then 3D renderings of the bone structure were created from the segmentations. Curvature maps were extracted from the 3D renderings and morphed into a reference atlas to determine precision, to generate population statistics, and to visualize cross-sectional and longitudinal curvature changes. RESULTS: The baseline scan-rescan root mean square error values ranged from 0.006mm(-1) to 0.013mm(-1), and from 0.007mm(-1) to 0.018mm(-1) for the SCB of the femur and the tibia, respectively. The standardized response of the mean of the longitudinal changes in curvature in these regions ranged from -0.09 to 0.02 and from -0.016 to 0.015, respectively. CONCLUSION: The fully automated system produces accurate and precise curvature maps of femoral and tibial SCB, and will provide a valuable tool for the analysis of the curvature changes of articulating bone surfaces during the course of knee OA. PMID- 26751404 TI - An experimental evaluation of electrical skin conductivity changes in postmortem interval and its assessment for time of death estimation. AB - In forensic medicine, estimation of the time of death (ToD) is one of the most important and challenging medico-legal problems. Despite the partial accomplishments in ToD estimations to date, the error margin of ToD estimation is still too large. In this study, electrical conductivity changes were experimentally investigated in the postmortem interval in human cases. Electrical conductivity measurements give some promising clues about the postmortem interval. A living human has a natural electrical conductivity; in the postmortem interval, intracellular fluids gradually leak out of cells. These leaked fluids combine with extra-cellular fluids in tissues and since both fluids are electrolytic, intracellular fluids help increase conductivity. Thus, the level of electrical conductivity is expected to increase with increased time after death. In this study, electrical conductivity tests were applied for six hours. The electrical conductivity of the cases exponentially increased during the tested time period, indicating a positive relationship between electrical conductivity and the postmortem interval. PMID- 26751405 TI - The Nature of Activated Non-classical Hydrogen Bonds: A Case Study on Acetylcholinesterase-Ligand Complexes. AB - Molecular recognition events in biological systems are driven by non-covalent interactions between interacting species. Here, we have studied hydrogen bonds of the CH???Y type involving electron-deficient CH donors using dispersion-corrected density functional theory (DFT) calculations applied to acetylcholinesterase ligand complexes. The strengths of CH???Y interactions activated by a proximal cation were considerably strong; comparable to or greater than those of classical hydrogen bonds. Significant differences in the energetic components compared to classical hydrogen bonds and non-activated CH???Y interactions were observed. Comparison between DFT and molecular mechanics calculations showed that common force fields could not reproduce the interaction energy values of the studied hydrogen bonds. The presented results highlight the importance of considering CH???Y interactions when analysing protein-ligand complexes, call for a review of current force fields, and opens up possibilities for the development of improved design tools for drug discovery. PMID- 26751407 TI - Are generalist parasites being lost from their hosts? AB - Co-extinctions should be regarded as fundamental co-evolutionary events promoting species turnover, prior than a consequence of human induced biodiversity loss. Focusing on current scenarios is key to biodiversity conservation, but predicting future trends could be harder and less fruitful than trying to get a better grasp on the past. PMID- 26751408 TI - A retrospective study of endotracheal intubation skill acquired by medical students in the operating theater. PMID- 26751406 TI - Impact of GGCX, STX1B and FPGS Polymorphisms on Warfarin Dose Requirements in European-Americans and Egyptians. AB - Genotype-based algorithms that include VKORC1 and CYP2C9 genotypes are less predictive of warfarin dose variability in Africans as opposed to Europeans. Polymorphisms in GGCX, FPGS, or STX1B are associated with warfarin dose requirements in African-Americans. We sought to determine if they influenced warfarin dose in European-Americans, and another African population, specifically Egyptians. We genotyped 529 adults (n = 325 European-Americans, 204 Egyptians) on a stable warfarin dose for GGCX rs12714145 and rs10654848, FPGS rs7856096, and STX1B rs4889606. Rs12714145, rs10654848, and rs7856096 were not associated with warfarin dose, whereas STX1B rs4889606 was a significant determinant in univariate analysis (P < 0.0001) in both cohorts. However, STX1B rs4889606 was in high linkage disequilibrium with VKORC1-1639 G>A, and was no longer significant after including VKORC1-1639 G>A in the regression model. Based on these data, the polymorphisms do not appear to influence, in a clinically important way, warfarin dose requirements in European-Americans and Egyptians. PMID- 26751409 TI - Survival Analysis in the Presence of Competing Risks: The Example of Waitlisted Kidney Transplant Candidates. AB - Competing events (or risks) preclude the observation of an event of interest or alter the probability of the event's occurrence and are commonly encountered in transplant outcomes research. Transplantation, for example, is a competing event for death on the waiting list because receiving a transplant may significantly decrease the risk of long-term mortality. In a typical analysis of time-to-event data, competing events may be censored or incorporated into composite end points; however, the presence of competing events violates the assumption of "independent censoring," which is the basis of standard survival analysis techniques. The use of composite end points disregards the possibility that competing events may be related to the exposure in a way that is different from the other components of the composite. Using data from the Scientific Registry of Transplant Recipients, this paper reviews the principles of competing risks analysis; outlines approaches for analyzing data with competing events (cause-specific and subdistribution hazards models); compares the estimates obtained from standard survival analysis, which handle competing events as censoring events; discusses the appropriate settings in which each of the two approaches could be used; and contrasts their interpretation. PMID- 26751410 TI - Carbetocin is a Functional Selective Gq Agonist That Does Not Promote Oxytocin Receptor Recycling After Inducing beta-Arrestin-Independent Internalisation. AB - Carbetocin, a long-acting oxytocin analogue, has been reported to elicit interesting and peculiar behavioural effects. The present study investigated the molecular pharmacology of carbetocin, aiming to better understand the molecular basis of its action in the brain. Using bioluminescence resonance energy transfer biosensors, we characterised the effects of carbetocin on the three human oxytocin/vasopressin receptors expressed in the nervous system: the oxytocin receptor (OXTR) and the vasopressin V1a (V1aR) and V1b (V1bR) receptors. Our results indicate that (i) carbetocin activates the OXTR but not the V1aR and V1bR at which it may act as an antagonist; (ii) carbetocin selectively activates only the OXTR/Gq pathway displaying a strong functional selectivity; (iii) carbetocin is a partial agonist at the OXTR/Gq coupling; (iv) carbetocin promotes OXTR internalisation via a previously unreported beta-arrestin-independent pathway; and (v) carbetocin does not induce OXTR recycling to the plasma membrane. Altogether, these molecular pharmacology features identify carbetocin as a substantially different analogue compared to the endogenous oxytocin and, consequently, carbetocin is not expected to mimic oxytocin in the brain. Whether these unique features of carbetocin could be exploited therapeutically remains to be established. PMID- 26751413 TI - Spectroscopic evidence for the formation of pentalene(+) in the dissociative ionization of naphthalene. AB - Although acetylene loss is well known to constitute the main breakdown pathway of polycyclic aromatic hydrocarbon (PAH) species, the molecular structure of the dissociation products remains only poorly characterized. For instance, the structure of the C8H6 product ion formed upon acetylene loss from the smallest PAH naphthalene (C10H8) has not been experimentally established. Several C8H6(+) isomers are conceivable, including phenylacetylene, benzocyclobutadiene, pentalene as well as a number of a-cyclic products. Here we present infrared (IR) spectroscopic evidence for the formation of the (anti-aromatic) pentalene structure using a combination of tandem mass spectrometry and IR laser spectroscopy. The formation of pentalene is suggestive of facile 6- to 5-membered ring conversion, which possibly has implications for the PAH/fullerene interrelationship in energetic settings such as the interstellar medium and combustion environments. PMID- 26751412 TI - Prognostic factors in patients with malignant pleural effusion: Is it possible to predict mortality in patients with good performance status? AB - BACKGROUND AND OBJECTIVES: The aim of this study was to identify predictors of mortality only in patients with malignant pleural effusion (MPE) showing good performance status which required pleural palliative procedures. METHODS: All patients with MPE submitted to pleural palliative procedure were enrolled in a prospective study between 2013 and 2014. Patients with Eastern cooperative oncology group (ECOG) score zero, one, and two were considered with good performance status. The possible prognostic factors were tested for significance using the log-rank test (Kaplan-Meier method) and those with significance on univariate analysis were entered into a multivariable Cox model. RESULTS: A total of 64 patients were included in the analysis. Median follow-up time for surviving patients was 263 days. Median survival for the entire cohort was not reached yet. In the multivariate analysis, gastrointestinal primary site (P = 0.006), low albumin concentration in the pleural fluid (P = 0.017), and high serum NLR (P = 0.007) were associated with mortality. CONCLUSION: In our cohort of ECOG 0-2 patients with MPE submitted to pleural palliative procedures, gastrointestinal malignancy compared to other sites, low pleural fluid albumin and high NLR were significantly associated with mortality. The identification of these prognostic factors may assist the choice of the optimal palliative technique. J. Surg. Oncol. 2016;113:570-574. (c) 2016 Wiley Periodicals, Inc. PMID- 26751411 TI - Spontaneous cleavage of proteins at serine and threonine is facilitated by zinc. AB - Old proteins are widely distributed in the body. Over time, they deteriorate and many spontaneous reactions, for example isomerisation of Asp and Asn, can be replicated by incubation of peptides under physiological conditions. One of the signatures of long-lived proteins that has proven to be difficult to replicate in vitro is cleavage on the N-terminal side of Ser residues, and this is important since cleavage at Ser, and also Thr, has been observed in a number of human proteins. In this study, the autolysis of Ser- and Thr-containing peptides was investigated with particular reference to discovering factors that promote cleavage adjacent to Ser/Thr at neutral pH. It was found that zinc catalyses cleavage of the peptide bond on the N-terminal side of Ser residues and further that this process is markedly accelerated if a His residue is adjacent to the Ser. NMR analysis indicated that the imidazole group co-ordinates zinc and that once zinc is co-ordinated, it can polarize the carbonyl group of the peptide bond in a manner analogous to that observed in the active site of the metalloexopeptidase, carboxypeptidase A. The hydroxyl side chain of Ser/Thr is then able to cleave the adjacent peptide bond. These observations enable an understanding of the origin of common truncations observed in long-lived proteins, for example truncation on the N-terminal side of Ser 8 in Abeta, Ser 19 in alpha B crystallin and Ser 66 in alpha A crystallin. The presence of zinc may therefore significantly affect the long-term stability of cellular proteins. PMID- 26751414 TI - Late aspergilloma of a renal allograft without need for operative management: a case report and review of the literature. AB - Aspergillus infection localized to the renal allograft is a rare and potentially life-threatening infection and typically requires a combination of operative and medical management. We report the case of a renal allograft aspergilloma in a renal transplant patient presenting 2 years post transplant, successfully managed non-surgically. To our knowledge, this is the first report of a patient presenting with an allograft aspergilloma so long after transplantation and being successfully managed with antifungal therapy alone. PMID- 26751417 TI - Towards rational use of inhaled Nitric Oxide in preterm babies. PMID- 26751416 TI - 'First, do no harm'--the use of analgesia or placebo as control for babies in painful clinical trials. PMID- 26751418 TI - Can teaching hospitals provide superior care? PMID- 26751419 TI - Child health in times of austerity as a result of the economic crisis that started in 2008. PMID- 26751420 TI - Children with anorectal malformations and Hirschsprung disease need special education or remedial support at school. PMID- 26751421 TI - Evaluating bulk Nb2O2F3 for Li-battery electrode applications. AB - This investigation has the primary objective of elucidating the lithium intercalation process in the crystal structure of a new niobium oxyfluoride compound Nb2O2F3. The framework of the density functional theory was applied in a generalized gradient approximation together with the hybrid functional method. It is revealed that lithium atoms intercalate in this material in a maximum concentration of one Li atom per formula unit forming LiNb2O2F3. Moreover, octahedral positions in between the layers of Nb-O-F appear as the Li preferred occupancy resulting in a structural volume expansion of only 5%. Electronic structure evolution with the insertion of lithium displays a transformation from semi-conductor to metal when half of the lithium atoms are added. This transformation occurs due to a symmetry break induced by the transition from the +8 to +7 oxidation state of half of the Nb2 dimers. Then, after full lithiation the symmetry is recovered and the material becomes a semiconductor again with a band gap amounting to 1 eV. The evaluated average deintercalation potential reaches 1.29 V vs. Li/Li(+) with activation energy for lithium ion migration of 0.79 eV. The computed low potential of the redox reaction Nb2(8+) to Nb2(7+) includes niobium oxyfluoride in the map of possible materials for the anode application of Li-ion batteries. PMID- 26751422 TI - Restenosis after coronary spasm in a bioresorbable vascular scaffold. PMID- 26751423 TI - The relationship between admission monocyte HDL-C ratio with short-term and long term mortality among STEMI patients treated with successful primary PCI. AB - BACKGROUND: Monocyte to HDL-C ratio (MHR) represents a simple assessment method for inflammatory status. The aim of the present study was to investigate whether MHR may be of short-term and long-term prognostic value in ST-elevation myocardial infarction (STEMI) patients who have undergone a primary percutaneous coronary intervention (PCI). MATERIALS AND METHODS: A total of 682 consecutive STEMI patients who underwent successful primary PCI between March 2013 and September 2015 were included in this study. Patients were divided into groups according to their admission MHR values. Clinical follow-up data of participating patients were obtained through an outpatient examination 30 months after PCI. RESULTS: The study population included 172 patients with an MHR less than 1.16 (Q1), 169 patients with an MHR 1.16-1.59 (Q2), 161 patients with an MHR 1.60-2.21 (Q3), and 180 patients with an MHR greater than 2.21 (Q4). Rates of in-hospital mortality, major adverse cardiovascular events, cardiopulmonary resuscitation, dialysis, use of inotropic agents, shock, late mortality, target vessel revascularization, stroke, and reinfarct were higher in the Q4 group compared with the other MHR quartile groups. CONCLUSION: The results of this study have indicated that admission MHR is associated independently and significantly with short-term and long-term mortality in STEMI patients who undergo successful primary PCI. PMID- 26751424 TI - Thrombus aspiration in acute myocardial infarction: concepts, clinical trials, and current guidelines. AB - The pathogenesis that underlies acute myocardial infarction is complex and multifactorial. One of the most important components, however, is the role of thrombus formation following atherosclerotic plaque rupture, leading to sudden coronary occlusion and subsequent ischemia and infarction. Thrombus aspiration provides the opportunity of intracoronary clot extraction with the aim to improve coronary and myocardial perfusion, by reducing the risk of no-reflow secondary to distal embolization of thrombus. The utility of thrombus aspiration during primary percutaneous coronary intervention has been assessed in an increasing number of observational and randomized studies. This article reviews the contemporary data and provides insights into the validity of thrombus aspiration in the setting of acute myocardial infarction. PMID- 26751425 TI - Time course of intramyocardial hematoma secondary to Ellis type III coronary rupture during chronic total occlusion intervention. PMID- 26751426 TI - Factors influencing platelet reactivity in patients undergoing coronary artery bypass surgery. AB - OBJECTIVE: Because coronary artery bypass graft (CABG) surgery is associated with a high turnover of platelets, assessment of platelet function should enable assessment of the effect of young (RNA-containing) platelets on platelet reactivity. This study was designed to assess platelet reactivity 1 day after CABG in patients treated previously with clopidogrel or ticagrelor. METHODS: Patients (n=18) with acute coronary syndrome who required urgent CABG and had been treated for up to 2 days before surgery with aspirin plus clopidogrel (n=13) or aspirin plus ticagrelor (n=5) were enrolled. Care was not altered by participation, which entailed review of medical records and taking one sample of blood 1 day after surgery. The percentage of RNA-containing platelets was quantified using thiazole orange, and platelet function was assessed by flow cytometry. RESULTS: Young platelets constituted, on average, 24% of platelets (range 4-54%) and were more likely to be activated in the absence or presence of an agonist (P<0.001). Differences between RNA-containing (young) and non-RNA containing platelets were evident in patients treated previously with clopidogrel (P<0.001), whereas a nonsignificant trend was apparent in patients treated previously with ticagrelor. A high but variable prevalence of young platelets was seen 1 day after CABG. CONCLUSION: Young platelets were more reactive and, consistent with the irreversible binding of clopidogrel to P2Y12, this effect was more pronounced after treatment with clopidogrel. The reversible binding of ticagrelor to the platelet P2Y12 receptor may be advantageous in patients with a high platelet turnover. PMID- 26751428 TI - Catalytic asymmetric [3 + 2]-cycloaddition for stereodivergent synthesis of chiral indolyl-pyrrolidines. AB - The stereochemical divergent synthesis of indolyl-pyrrolidines was accomplished using an imidazoline-aminophenol (IAP)-Ni(OAc)2 complex and a bis(imidazolidine)pyridine (PyBidine)-Cu(OTf)2 complex. The former catalyzed exo' selective asymmetric [3 + 2] cyclization of iminoesters with indolyl nitroalkenes, and the latter catalyzed the reaction in an endo-selective manner. These catalysts are tolerant toward highly functional substrates that supply chiral indolyl-pyrrolidine hybrids. PMID- 26751427 TI - The Impact of Age Upon Healing: Absolute Quantification of Osteogenic Genes in Calvarial Critical-Sized Defects. AB - BACKGROUND: The current study was performed to elucidate changes in growth factor expression over time in critical-sized calvarial defects in rats from infancy to skeletal maturity. MATERIALS AND METHODS: Critical-sized parietal defects of 5, 6, and 8 mm were created in postnatal day 6 (P6), postnatal day (P20), and postnatal day (P84) adult rats, respectively. Dura was harvested at 3, 7, or 14 days after surgery, and serial micro-computed tomography imaging was performed through 12 weeks postoperatively. Absolute quantitative polymerase chain reaction was performed for Bone Morphogenic Protein-2 (BMP-2), Fibroblast Growth Factor-2 (FGF-2), Insulin-like Growth Factor-1 (IGF-1), and Transforming Growth Factor beta1 (TGF-beta). RESULTS: The P6 (6-d-old) rats showed the greatest difference in gene expression between the dura derived from the defect side and the dura derived from the control side, demonstrating significant differences in TGF beta1, BMP-2, IGF-1, and FGF-2 at various time intervals. Absolute gene expression in the defect dura was highest in the P6 rats and declined with age. Significant differences were noted at limited time points in the P20 rats for TGF beta1 and BMP-2 as well as in the P84 rats for TGF-beta1. TGF-beta1 was the only gene studied that showed significant differences at postoperative days 3, 7, and 14 in varying age groups. CONCLUSIONS: The P6 rats have a higher osteogenic potential accompanied by a more vigorous alteration in growth factor expression compared with the P20 or P84 rats. Decrease in BMP-2 and FGF-2 as well as relative increase in TGFbeta-1 messenger RNA were observed in healing defects. These data provide valuable insight into the mechanism of healing of critical sized defects and may be of use to engineer factor-releasing implants to correct skull defects. PMID- 26751429 TI - Reformulated meat products protect against ischemia-induced cardiac damage. AB - The protective effects of the antioxidants present in food are of great relevance for cardiovascular health. This study evaluates whether the extracts from reformulated meat products with a reduction in fat and/or sodium content exert a cardioprotective effect against ischemia-induced oxidative stress in cardiomyocytes, compared with non-meat foods. Ischemic damage caused loss of cell viability, increased reactive oxygen species and lipid peroxidation and decreased the antioxidant activity. Pretreatment for 24 h with digested or non-digested extracts from reformulated meat products led to protection against ischemia induced oxidative damage: increased cell viability, reduced oxidative stress and restored the antioxidant activity. Similar results were obtained using extracts from tuna fish, but not with the extracts of green peas, salad or white beans. These results suggest that reformulated meat products have a beneficial impact in protecting cardiac cells against ischemia, and they may represent a source of natural antioxidants with benefits for cardiovascular health. PMID- 26751434 TI - Unimolecular Solvolyses in Ionic Liquid: Alcohol Dual Solvent Systems. AB - A study was undertaken of the solvolysis of pivaloyl triflate in a variety of ionic liquid:alcohol solvent mixtures. The solvolysis is a kDelta process (i.e., a process in which ionization occurs with rearrangement), and the resulting rearranged carbocation intermediate reacts with the alcohol cosolvent via two competing pathways: nucleophilic attack or elimination of a proton. Five different ionic liquids and three different alcohol cosolvents were investigated to give a total of fifteen dual solvent systems. 1H-NMR analysis was used to determine relative amounts of elimination and substitution products. It was found, not surprisingly, that increasing the bulkiness of alcohol cosolvent led to increased elimination product. The change in the amount of elimination product with increasing ionic liquid concentration, however, varied greatly between ionic liquids. These differences correlate strongly, though not completely, to the Kamlet-Taft solvatochromic parameters of the hydrogen bond donating and accepting ability of the solvent systems. An additional factor playing into these differences is the bulkiness of the ionic liquid anion. PMID- 26751435 TI - Isolation and Biosynthetic Analysis of Haliamide, a New PKS-NRPS Hybrid Metabolite from the Marine Myxobacterium Haliangium ochraceum. AB - Myxobacteria of marine origin are rare and hard-to-culture microorganisms, but they genetically harbor high potential to produce novel antibiotics. An extensive investigation on the secondary metabolome of the unique marine myxobacterium Haliangium ochraceum SMP-2 led to the isolation of a new polyketide-nonribosomal peptide hybrid product, haliamide (1). Its structure was elucidated by spectroscopic analyses including NMR and HR-MS. Haliamide (1) showed cytotoxicity against HeLa-S3 cells with IC50 of 12 MUM. Feeding experiments were performed to identify the biosynthetic building blocks of 1, revealing one benzoate, one alanine, two propionates, one acetate and one acetate-derived terminal methylene. The biosynthetic gene cluster of haliamide (hla, 21.7 kbp) was characterized through the genome mining of the producer, allowing us to establish a model for the haliamide biosynthesis. The sulfotransferase (ST)-thioesterase (TE) domains encoded in hlaB appears to be responsible for the terminal alkene formation via decarboxylation. PMID- 26751436 TI - Antibacterial Properties of Tebipenem Pivoxil Tablet, a New Oral Carbapenem Preparation against a Variety of Pathogenic Bacteria in Vitro and in Vivo. AB - AIMS: To systemically investigate the in vitro and in vivo antibacterial properties of tebipenem pivoxil tablet. In addition, acute toxicity of this preparation was also studied. METHODS: In vitro, minimum inhibitory concentration (MIC) or minimal inhibitory concentration (MBC) were determined by using the serial 2-fold broth or agar dilution methods. Further, cumulative MIC inhibition curves were then made to assess the antibacterial effects of the drug at various concentrations. In vivo, minimum lethal dose (MLD) in combination with maximum tolerance dose (MTD) was used to measure the acute toxicity of the tebipenem pivoxil tablet in mice. After that, sepsis mouse models challenged with Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, respectively, were established to evaluate the anti-infective effect of this preparation. RESULTS: The MIC90 values of tebipenem pivoxil against Gram positive bacteria such as methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive Staphylococcus epidermidis (MSSE), methicillin-resistant Staphylococcus epidermidis (MRSE), Pyogenic streptococcus, and Enterococcus faecalis were <= 0.125, 16, 0.5, 8, <= 0.125, and 32 MUg/mL, respectively. Correspondingly, the MIC90 values of tebipenem pivoxil against Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Haemophilus influenzae, Pseudomonas aeruginosa, and Acinetobacter baumannii were 1, 0.5, <= 0.125, 0.25, 64, 64 MUg/mL, respectively. The MBC values of tebipenem pivoxil against Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae were 0.016-2, 0.063-32, 0.031 32 MUg/mL, respectively. The acute toxicity study showed that the MLD of the tebipenem pivoxil tablet was 4.00 g/kg and the MTD was 3.40 g/kg in mice. In all the sepsis mouse models, the simultaneous administration of the tebipenem pivoxil tablets significantly reduced mortality of the sepsis-model mice as compared with the control. Furthermore, the survival rate in the tebipenem pivoxil tablet group was remarkably higher than that in the meropenem group in all the sepsis mouse models tested. In the sepsis model challenged with Staphylococcus aureus ATCC29213, Escherichia coli ATCC25922, Pseudomonas aeruginosa ATCC27853, and Pseudomonas aeruginosa clinical strain, respectively, tebipenem pivoxil tablet (100 mg/kg) displayed a better protective effect than tebipenem pivoxil granules (100 mg/kg). CONCLUSIONS: In summary, tebipenem pivoxil displays an excellent antibacterial activity against a variety of pathogenic bacteria in vitro. Importantly, tebipenem pivoxil tablet significantly protects the sepsis mice challenged with various pathogenic bacteria, which may provide a potential approach to treating bacterial sepsis in clinic. PMID- 26751437 TI - Functionalised Oximes: Emergent Precursors for Carbon-, Nitrogen- and Oxygen Centred Radicals. AB - Oxime derivatives are easily made, are non-hazardous and have long shelf lives. They contain weak N-O bonds that undergo homolytic scission, on appropriate thermal or photochemical stimulus, to initially release a pair of N- and O centred radicals. This article reviews the use of these precursors for studying the structures, reactions and kinetics of the released radicals. Two classes have been exploited for radical generation; one comprises carbonyl oximes, principally oxime esters and amides, and the second comprises oxime ethers. Both classes release an iminyl radical together with an equal amount of a second oxygen centred radical. The O-centred radicals derived from carbonyl oximes decarboxylate giving access to a variety of carbon-centred and nitrogen-centred species. Methods developed for homolytically dissociating the oxime derivatives include UV irradiation, conventional thermal and microwave heating. Photoredox catalytic methods succeed well with specially functionalised oximes and this aspect is also reviewed. Attention is also drawn to the key contributions made by EPR spectroscopy, aided by DFT computations, in elucidating the structures and dynamics of the transient intermediates. PMID- 26751438 TI - Natural Products for the Prevention and Treatment of Hangover and Alcohol Use Disorder. AB - Alcoholic beverages such as beer, wine and spirits are widely consumed around the world. However, alcohol and its metabolite acetaldehyde are toxic and harmful to human beings. Chronic alcohol use disorder or occasional binge drinking can cause a wide range of health problems, such as hangover, liver damage and cancer. Some natural products such as traditional herbs, fruits, and vegetables might be potential dietary supplements or medicinal products for the prevention and treatment of the problems caused by excessive alcohol consumption. The aim of this review is to provide an overview of effective natural products for the prevention and treatment of hangover and alcohol use disorder, and special emphasis is paid to the possible functional component(s) and related mechanism(s) of action. PMID- 26751439 TI - Cross-Species, Amplifiable EST-SSR Markers for Amentotaxus Species Obtained by Next-Generation Sequencing. AB - Amentotaxus, a genus of Taxaceae, is an ancient lineage with six relic and endangered species. Four Amentotaxus species, namely A. argotaenia, A. formosana, A. yunnanensis, and A. poilanei, are considered a species complex because of their morphological similarities. Small populations of these species are allopatrically distributed in Asian forests. However, only a few codominant markers have been developed and applied to study population genetic structure of these endangered species. In this study, we developed and characterized polymorphic expressed sequence tag-simple sequence repeats (EST-SSRs) from the transcriptome of A. formosana. We identified 4955 putative EST-SSRs from 68,281 unigenes as potential molecular markers. Twenty-six EST-SSRs were selected for estimating polymorphism and transferability among Amentotaxus species, of which 23 EST-SSRs were polymorphic within Amentotaxus species. Among these, the number of alleles ranged from 1-4, the polymorphism information content ranged from 0.000-0.692, and the observed and expected heterozygosity were 0.000-1.000 and 0.080-0.740, respectively. Population genetic structure analyses confirmed that A. argotaenia and A. formosana were separate species and A. yunnanensis and A. poilanei were the same species. These novel EST-SSRs can facilitate further population genetic structure research of Amentotaxus species. PMID- 26751440 TI - Comparative Transcriptome Profile of the Cytoplasmic Male Sterile and Fertile Floral Buds of Radish (Raphanus sativus L.). AB - Radish cytoplasmic male sterility (CMS) has been widely used for breeding in Raphanus and Brassica genera. However, the detailed regulation network of the male sterility remains to be determined. Our previous work has shown that the abnormalities in a CMS radish appeared shortly after the tetrad stage when microspores were malformed and the tapetal cells grew abnormally large. In this work, histological analysis shows that anthers are at the tetrad stage when the radish buds are about 1.5 mm in length. Furthermore, a high throughput RNA sequencing technology was employed to characterize the transcriptome of radish buds with length about 1.5 mm from two CMS lines possessing the CMS-inducing orf138 gene and corresponding near-isogenic maintainer lines. A total of 67,140 unigenes were functionally annotated. Functional terms for these genes are significantly enriched in 55 Gene Ontology (GO) groups and 323 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The transcriptome detected transcripts for 72 out of a total of 79 protein genes encoded in the chloroplast genome from radish. In contrast, the radish mitochondrial genome contains 34 protein genes, but only 16 protein transcripts were detected from the transcriptome. The transcriptome comparison between CMS and near-isogenic maintainer lines revealed 539 differentially expressed genes (DEGs), indicating that the false positive rate for comparative transcriptome profiling was clearly decreased using two groups of CMS/maintainer lines with different nuclear background. The level of 127 transcripts was increased and 412 transcripts were decreased in the CMS lines. No change in levels of transcripts except CMS-inducing orf138 was identified from the mitochondrial and chloroplast genomes. Some DEGs which would be associated with the CMS, encoding MYB and bHLH transcription factors, pentatricopeptide repeat (PPR) proteins, heat shock transcription factors (HSFs) and heat shock proteins (HSPs), are discussed. The transcriptome dataset and comparative analysis will provide an important resource for further understanding anther development, the CMS mechanism and to improve molecular breeding in radish. PMID- 26751441 TI - Neuropeptide Substance-P-Conjugated Chitosan Nanofibers as an Active Modulator of Stem Cell Recruiting. AB - The goal to successful wound healing is essentially to immobilize and recruit appropriate numbers of host stem or progenitor cells to the wound area. In this study, we developed a chitosan nanofiber-immobilized neuropeptide substance-P (SP), which mediates stem cell mobilization and migration, onto the surfaces of nanofibers using a peptide-coupling agent, and evaluated its biological effects on stem cells. The amount of immobilized SP on chitosan nanofibers was modulated over the range of 5.89 +/- 3.27 to 75.29 +/- 24.31 ng when reacted with 10 to 500 ng SP. In vitro migration assays showed that SP-incorporated nanofibers induced more rapid migration of human mesenchymal stem cells on nanofibers compared to pristine samples. Finally, the conjugated SP evoked a minimal foreign body reaction and recruited a larger number of CD29- and CD44-positive stem cells into nanofibers in a mouse subcutaneous pocket model. PMID- 26751443 TI - Design and Development of Layered Security: Future Enhancements and Directions in Transmission. AB - Today, security is a prominent issue when any type of communication is being undertaken. Like traditional networks, supervisory control and data acquisition (SCADA) systems suffer from a number of vulnerabilities. Numerous end-to-end security mechanisms have been proposed for the resolution of SCADA-system security issues, but due to insecure real-time protocol use and the reliance upon open protocols during Internet-based communication, these SCADA systems can still be compromised by security challenges. This study reviews the security challenges and issues that are commonly raised during SCADA/protocol transmissions and proposes a secure distributed-network protocol version 3 (DNP3) design, and the implementation of the security solution using a cryptography mechanism. Due to the insecurities found within SCADA protocols, the new development consists of a DNP3 protocol that has been designed as a part of the SCADA system, and the cryptographically derived security is deployed within the application layer as a part of the DNP3 stack. PMID- 26751444 TI - Contactless Inductive Bubble Detection in a Liquid Metal Flow. AB - The detection of bubbles in liquid metals is important for many technical applications. The opaqueness and the high temperature of liquid metals set high demands on the measurement system. The high electrical conductivity of the liquid metal can be exploited for contactless methods based on electromagnetic induction. We will present a measurement system which consists of one excitation coil and a pickup coil system on the opposite sides of the pipe. With this sensor we were able to detect bubbles in a sodium flow inside a stainless steel pipe and bubbles in a column filled with a liquid Gallium alloy. PMID- 26751442 TI - Enzymatic Kinetic Properties of the Lactate Dehydrogenase Isoenzyme C4 of the Plateau Pika (Ochotona curzoniae). AB - Testis-specific lactate dehydrogenase (LDH-C4) is one of the lactate dehydrogenase (LDH) isozymes that catalyze the terminal reaction of pyruvate to lactate in the glycolytic pathway. LDH-C4 in mammals was previously thought to be expressed only in spermatozoa and testis and not in other tissues. Plateau pika (Ochotona curzoniae) belongs to the genus Ochotona of the Ochotonidea family. It is a hypoxia-tolerant species living in remote mountain areas at altitudes of 3000-5000 m above sea level on the Qinghai-Tibet Plateau. Surprisingly, Ldh-c is expressed not only in its testis and sperm, but also in somatic tissues of plateau pika. To shed light on the function of LDH-C4 in somatic cells, Ldh-a, Ldh-b, and Ldh-c of plateau pika were subcloned into bacterial expression vectors. The pure enzymes of Lactate Dehydrogenase A4 (LDH-A4), Lactate Dehydrogenase B4 (LDH-B4), and LDH-C4 were prepared by a series of expression and purification processes, and the three enzymes were identified by the method of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and native polyacrylamide gel electrophoresis (PAGE). The enzymatic kinetics properties of these enzymes were studied by Lineweaver-Burk double-reciprocal plots. The results showed the Michaelis constant (Km) of LDH-C4 for pyruvate and lactate was 0.052 and 4.934 mmol/L, respectively, with an approximate 90 times higher affinity of LDH-C4 for pyruvate than for lactate. At relatively high concentrations of lactate, the inhibition constant (Ki) of the LDH isoenzymes varied: LDH-A4 (Ki = 26.900 mmol/L), LDH-B4 (Ki = 23.800 mmol/L), and LDH-C4 (Ki = 65.500 mmol/L). These data suggest that inhibition of lactate by LDH-A4 and LDH B4 were stronger than LDH-C4. In light of the enzymatic kinetics properties, we suggest that the plateau pika can reduce reliance on oxygen supply and enhance its adaptation to the hypoxic environments due to increased anaerobic glycolysis by LDH-C4. PMID- 26751445 TI - Performance Evaluation of Target Detection with a Near-Space Vehicle-Borne Radar in Blackout Condition. AB - Radar is a very important sensor in surveillance applications. Near-space vehicle borne radar (NSVBR) is a novel installation of a radar system, which offers many benefits, like being highly suited to the remote sensing of extremely large areas, having a rapidly deployable capability and having low vulnerability to electronic countermeasures. Unfortunately, a target detection challenge arises because of complicated scenarios, such as nuclear blackout, rain attenuation, etc. In these cases, extra care is needed to evaluate the detection performance in blackout situations, since this a classical problem along with the application of an NSVBR. However, the existing evaluation measures are the probability of detection and the receiver operating curve (ROC), which cannot offer detailed information in such a complicated application. This work focuses on such requirements. We first investigate the effect of blackout on an electromagnetic wave. Performance evaluation indexes are then built: three evaluation indexes on the detection capability and two evaluation indexes on the robustness of the detection process. Simulation results show that the proposed measure will offer information on the detailed performance of detection. These measures are therefore very useful in detecting the target of interest in a remote sensing system and are helpful for both the NSVBR designers and users. PMID- 26751446 TI - Integrated Amorphous Silicon p-i-n Temperature Sensor for CMOS Photonics. AB - Hydrogenated amorphous silicon (a-Si:H) shows interesting optoelectronic and technological properties that make it suitable for the fabrication of passive and active micro-photonic devices, compatible moreover with standard microelectronic devices on a microchip. A temperature sensor based on a hydrogenated amorphous silicon p-i-n diode integrated in an optical waveguide for silicon photonics applications is presented here. The linear dependence of the voltage drop across the forward-biased diode on temperature, in a range from 30 degrees C up to 170 degrees C, has been used for thermal sensing. A high sensitivity of 11.9 mV/ degrees C in the bias current range of 34-40 nA has been measured. The proposed device is particularly suitable for the continuous temperature monitoring of CMOS compatible photonic integrated circuits, where the behavior of the on-chip active and passive devices are strongly dependent on their operating temperature. PMID- 26751447 TI - A Comparison of Alternative Distributed Dynamic Cluster Formation Techniques for Industrial Wireless Sensor Networks. AB - In this paper, we investigate alternative distributed clustering techniques for wireless sensor node tracking in an industrial environment. The research builds on extant work on wireless sensor node clustering by reporting on: (1) the development of a novel distributed management approach for tracking mobile nodes in an industrial wireless sensor network; and (2) an objective comparison of alternative cluster management approaches for wireless sensor networks. To perform this comparison, we focus on two main clustering approaches proposed in the literature: pre-defined clusters and ad hoc clusters. These approaches are compared in the context of their reconfigurability: more specifically, we investigate the trade-off between the cost and the effectiveness of competing strategies aimed at adapting to changes in the sensing environment. To support this work, we introduce three new metrics: a cost/efficiency measure, a performance measure, and a resource consumption measure. The results of our experiments show that ad hoc clusters adapt more readily to changes in the sensing environment, but this higher level of adaptability is at the cost of overall efficiency. PMID- 26751448 TI - A Novel Hybrid Error Criterion-Based Active Control Method for on-Line Milling Vibration Suppression with Piezoelectric Actuators and Sensors. AB - Milling vibration is one of the most serious factors affecting machining quality and precision. In this paper a novel hybrid error criterion-based frequency domain LMS active control method is constructed and used for vibration suppression of milling processes by piezoelectric actuators and sensors, in which only one Fast Fourier Transform (FFT) is used and no Inverse Fast Fourier Transform (IFFT) is involved. The correction formulas are derived by a steepest descent procedure and the control parameters are analyzed and optimized. Then, a novel hybrid error criterion is constructed to improve the adaptability, reliability and anti-interference ability of the constructed control algorithm. Finally, based on piezoelectric actuators and acceleration sensors, a simulation of a spindle and a milling process experiment are presented to verify the proposed method. Besides, a protection program is added in the control flow to enhance the reliability of the control method in applications. The simulation and experiment results indicate that the proposed method is an effective and reliable way for on-line vibration suppression, and the machining quality can be obviously improved. PMID- 26751450 TI - Development of a Room Temperature SAW Methane Gas Sensor Incorporating a Supramolecular Cryptophane A Coating. AB - A new room temperature supra-molecular cryptophane A (CrypA)-coated surface acoustic wave (SAW) sensor for sensing methane gas is presented. The sensor is composed of differential resonator-oscillators, a supra-molecular CrypA coated along the acoustic propagation path, and a frequency signal acquisition module (FSAM). A two-port SAW resonator configuration with low insertion loss, single resonation mode, and high quality factor was designed on a temperature compensated ST-X quartz substrate, and as the feedback of the differntial oscillators. Prior to development, the coupling of modes (COM) simulation was conducted to predict the device performance. The supramolecular CrypA was synthesized from vanillyl alcohol using a double trimerisation method and deposited onto the SAW propagation path of the sensing resonators via different film deposition methods. Experiential results indicate the CrypA-coated sensor made using a dropping method exhibits higher sensor response compared to the unit prepared by the spinning approach because of the obviously larger surface roughness. Fast response and excellent repeatability were observed in gas sensing experiments, and the estimated detection limit and measured sensitivity are ~0.05% and ~204 Hz/%, respectively. PMID- 26751451 TI - Design and Analysis of a Sensor System for Cutting Force Measurement in Machining Processes. AB - Multi-component force sensors have infiltrated a wide variety of automation products since the 1970s. However, one seldom finds full-component sensor systems available in the market for cutting force measurement in machine processes. In this paper, a new six-component sensor system with a compact monolithic elastic element (EE) is designed and developed to detect the tangential cutting forces Fx, Fy and Fz (i.e., forces along x-, y-, and z-axis) as well as the cutting moments Mx, My and Mz (i.e., moments about x-, y-, and z-axis) simultaneously. Optimal structural parameters of the EE are carefully designed via simulation driven optimization. Moreover, a prototype sensor system is fabricated, which is applied to a 5-axis parallel kinematic machining center. Calibration experimental results demonstrate that the system is capable of measuring cutting forces and moments with good linearity while minimizing coupling error. Both the Finite Element Analysis (FEA) and calibration experimental studies validate the high performance of the proposed sensor system that is expected to be adopted into machining processes. PMID- 26751449 TI - Gait Partitioning Methods: A Systematic Review. AB - In the last years, gait phase partitioning has come to be a challenging research topic due to its impact on several applications related to gait technologies. A variety of sensors can be used to feed algorithms for gait phase partitioning, mainly classifiable as wearable or non-wearable. Among wearable sensors, footswitches or foot pressure insoles are generally considered as the gold standard; however, to overcome some inherent limitations of the former, inertial measurement units have become popular in recent decades. Valuable results have been achieved also though electromyography, electroneurography, and ultrasonic sensors. Non-wearable sensors, such as opto-electronic systems along with force platforms, remain the most accurate system to perform gait analysis in an indoor environment. In the present paper we identify, select, and categorize the available methodologies for gait phase detection, analyzing advantages and disadvantages of each solution. Finally, we comparatively examine the obtainable gait phase granularities, the usable computational methodologies and the optimal sensor placements on the targeted body segments. PMID- 26751452 TI - Recognition of Activities of Daily Living with Egocentric Vision: A Review. AB - Video-based recognition of activities of daily living (ADLs) is being used in ambient assisted living systems in order to support the independent living of older people. However, current systems based on cameras located in the environment present a number of problems, such as occlusions and a limited field of view. Recently, wearable cameras have begun to be exploited. This paper presents a review of the state of the art of egocentric vision systems for the recognition of ADLs following a hierarchical structure: motion, action and activity levels, where each level provides higher semantic information and involves a longer time frame. The current egocentric vision literature suggests that ADLs recognition is mainly driven by the objects present in the scene, especially those associated with specific tasks. However, although object-based approaches have proven popular, object recognition remains a challenge due to the intra-class variations found in unconstrained scenarios. As a consequence, the performance of current systems is far from satisfactory. PMID- 26751453 TI - Low Dark-Current, High Current-Gain of PVK/ZnO Nanoparticles Composite-Based UV Photodetector by PN-Heterojunction Control. AB - We propose a solution-processable ultraviolet (UV) photodetector with a pn heterojunction hybrid photoactive layer (HPL) that is composed of poly-n vinylcarbazole (PVK) as a p-type polymer and ZnO nanoparticles (NPs) as an n-type metal oxide. To observe the effective photo-inducing ability of the UV photodetector, we analyzed the optical and electrical properties of HPL which is controlled by the doping concentration of n-type ZnO NPs in PVK matrix. Additionally, we confirmed that the optical properties of HPL dominantly depend on the ZnO NPs from the UV-vis absorption and the photoluminescence (PL) spectral measurements. This HPL can induce efficient charge transfer in the localized narrow pn-heterojunction domain and increases the photocurrent gain. It is essential that proper doping concentration of n-type ZnO NPs in polymer matrix is obtained to improve the performance of the UV photodetector. When the ZnO NPs are doped with the optimized concentration of 3.4 wt.%, the electrical properties of the photocurrent are significantly increased. The ratio of the photocurrent was approximately 103 higher than that of the dark current. PMID- 26751454 TI - Authentication Based on Non-Interactive Zero-Knowledge Proofs for the Internet of Things. AB - This paper describes the design and analysis of a new scheme for the authenticated exchange of confidential information in insecure environments within the Internet of Things, which allows a receiver of a message to authenticate the sender and compute a secret key shared with it. The proposal is based on the concept of a non-interactive zero-knowledge proof, so that in a single communication, relevant data may be inferred to verify the legitimacy of the sender. Besides, the new scheme uses the idea under the Diffie-Hellman protocol for the establishment of a shared secret key. The proposal has been fully developed for platforms built on the Android Open Source Project, so it can be used in any device or sensor with this operating system. This work provides a performance study of the implementation and a comparison between its promising results and others obtained with similar schemes. PMID- 26751455 TI - Optimization and Experimentation of Dual-Mass MEMS Gyroscope Quadrature Error Correction Methods. AB - This paper focuses on an optimal quadrature error correction method for the dual mass MEMS gyroscope, in order to reduce the long term bias drift. It is known that the coupling stiffness and demodulation error are important elements causing bias drift. The coupling stiffness in dual-mass structures is analyzed. The experiment proves that the left and right masses' quadrature errors are different, and the quadrature correction system should be arranged independently. The process leading to quadrature error is proposed, and the Charge Injecting Correction (CIC), Quadrature Force Correction (QFC) and Coupling Stiffness Correction (CSC) methods are introduced. The correction objects of these three methods are the quadrature error signal, force and the coupling stiffness, respectively. The three methods are investigated through control theory analysis, model simulation and circuit experiments, and the results support the theoretical analysis. The bias stability results based on CIC, QFC and CSC are 48 degrees /h, 9.9 degrees /h and 3.7 degrees /h, respectively, and this value is 38 degrees /h before quadrature error correction. The CSC method is proved to be the better method for quadrature correction, and it improves the Angle Random Walking (ARW) value, increasing it from 0.66 degrees /?h to 0.21 degrees /?h. The CSC system general test results show that it works well across the full temperature range, and the bias stabilities of the six groups' output data are 3.8 degrees /h, 3.6 degrees /h, 3.4 degrees /h, 3.1 degrees /h, 3.0 degrees /h and 4.2 degrees /h, respectively, which proves the system has excellent repeatability. PMID- 26751456 TI - Bioactive Polycyclic Quinones from Marine Streptomyces sp. 182SMLY. AB - Chemical investigation of the cultures of marine Streptomyces sp. 182SMLY led to the discovery of two new polycyclic anthraquinones, which were elucidated as N acetyl-N-demethylmayamycin (1) and streptoanthraquinone A (2) based on the extensive spectroscopic analysis including 2D NMR, HRESIMS, and an electronic circular dichroism (ECD) calculation. Both anthraquinones remarkably suppressed the proliferation of four different glioma cell lines with IC50 values in a range from 0.5 to 7.3 MUM and induced apoptosis in the glioma cells. The ratios of IC50 for normal human astrocytes to IC50 for glioma cells were 6.4-53 for 1 and >14-31 for 2. N-acetyl-N-demethylmayamycin (1) also inhibited the growth of methicillin resistant Staphylococcus aureus with MIC 20.0 MUM. PMID- 26751457 TI - Pinnisterols A-C, New 9,11-Secosterols from a Gorgonian Pinnigorgia sp. AB - Three new 9,11-secosterols, pinnisterols A-C (1-3), were isolated from a gorgonian coral Pinnigorgia sp., collected off the waters of Taiwan. The structures of these compounds were elucidated on the basis of spectroscopic methods. The new sterols 1 and 3 displayed significant inhibitory effects on the generation of superoxide anions and the release of elastase by human neutrophils, and sterol 1 was found to show moderate cytotoxicity in hepatic stellate cells (HSCs). PMID- 26751458 TI - Inhibition of Ultraviolet B-Induced Expression of the Proinflammatory Cytokines TNF-alpha and VEGF in the Cornea by Fucoxanthin Treatment in a Rat Model. AB - Ultraviolet B (UVB) irradiation is the most common cause of radiation damage to the eyeball and is a risk factor for human corneal damage. We determined the protective effect of fucoxanthin, which is a carotenoid found in common edible seaweed, on ocular tissues against oxidative UVB-induced corneal injury. The experimental rats were intravenously injected with fucoxanthin at doses of 0.5, 5 mg/kg body weight/day or with a vehicle before UVB irradiation. Lissamine green for corneal surface staining showed that UVB irradiation caused serious damage on the corneal surface, including severe epithelial exfoliation and deteriorated epithelial smoothness. Histopathological lesion examination revealed that levels of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor (VEGF), significantly increased. However, pretreatment with fucoxanthin inhibited UVB radiation-induced corneal disorders including evident preservation of corneal surface smoothness, downregulation of proinflammatory cytokine expression, and decrease of infiltrated polymorphonuclear leukocytes from UVB-induced damage. Moreover, significant preservation of the epithelial integrity and inhibition of stromal swelling were also observed after UVB irradiation in fucoxanthin-treated groups. Pretreatment with fucoxanthin may protect against UVB radiation-induced corneal disorders by inhibiting expression of proinflammatory factors, TNF-alpha, and VEGF and by blocking polymorphonuclear leukocyte infiltration. PMID- 26751459 TI - Association between CRP and TNF-alpha genes Variants and Cardiovascular Heart Disease in a Mexican Population: Protocol for a Case-Control Study. AB - BACKGROUND: The C-reactive protein (CRP) and the tumor necrosis factor-alpha (TNF alpha) are considered markers of inflammation and have been shown to predict the risk of incident cardiovascular events. However, few studies have undertaken a comprehensive examination of SNPs (single nucleotide polymorphisms) of the CRP and TNF-alpha genes; due to this, we will present a protocol study to evaluate the role of the CRP and TNF-alpha genes in Mexican individuals. METHODS/DESIGN: we will perform a case-control study to explore the CRP and TNF-alpha genotype distribution as well as the serum influence of rs1800947, rs1130864, rs2794521 and rs1205 (polymorphisms of the CRP gene) and rs361525, rs1800629, rs1799724, rs1800630, rs1799964 (of the TNF-alpha gene) in Mexican individuals who present coronary artery disease. ETHICS AND DISSEMINATION: a written informed consent will be obtained from all the participating subjects. An article detailing the results of the study will be submitted for publication in an international peer reviewed journal, in accordance with STROBE criteria. PMID- 26751462 TI - Comments on Scheffler et al. Cytotoxic Evaluation of E-Liquid Aerosol using Different Lung Derived Cell Models. Int. J. Environ. Res. Public Health, 2015, 12, 12466-12474. AB - There is merit in considering a simple toxicological screening method that evaluates the total cytotoxic potential of e-liquids or electronic cigarettes (ECs) aerosol emissions in one single testing. However, there is growing confusion, with several researchers endorsing their personal solution to the problem. Here, we discuss as an example the recent paper by Scheffler and colleagues, in which the authors suggest that more relevant and well differentiated cell lines from human airways could be the most suitable candidates for toxicological evaluation of ECs aerosol emissions. We advance recommendations for validated protocols and advocate for an international coordinated effort aimed at establishing consensus on methodology. PMID- 26751461 TI - Beyond Smoking Prevalence: Exploring the Variability of Associations between Neighborhood Exposures across Two Nested Spatial Units and Two-Year Smoking Trajectory among Young Adults. AB - Young adults have the highest prevalence of smoking amongst all age groups. Significant uptake occurs after high school age. Although neighborhood exposures have been found to be associated with smoking behavior, research on neighborhood exposures and the smoking trajectories among young adults, and on the role of geographic scale in shaping findings, is scarce. We examined associations between neighborhood exposures across two nested, increasingly large spatial units and smoking trajectory over two years among young adults living in Montreal, Canada. A sample of 2093 participants aged 18-25 years from the Interdisciplinary Study of Inequalities in Smoking (ISIS) was surveyed. The dependent variable was self reported smoking trajectory over the course of two years. Residential addresses, data on presence of tobacco retail outlets, and the presence of smoking accommodation facilities were coded and linked to spatial units. Three-level multinomial models were used to examine associations. The likelihood of being a smoker for 2+ years was significantly greater among those living in larger spatial unit neighborhoods that had a greater presence of smoking accommodation. This association was not statistically significant at the smaller spatial units. Our findings highlight the importance of studying young adults' smoking trajectories in addition to static smoking outcomes, and point to the relevance of considering spatial scale in studies of neighborhoods and smoking. PMID- 26751460 TI - Personal Care Product Use in Pregnancy and the Postpartum Period: Implications for Exposure Assessment. AB - Concern regarding the potential for developmental health risks associated with certain chemicals (e.g., phthalates, antibacterials) used in personal care products is well documented; however, current exposure data for pregnant women are limited. The objective of this study was to describe the pattern of personal care product use in pregnancy and the post-partum period. Usage patterns of personal care products were collected at six different time points during pregnancy and once in the postpartum period for a cohort of 80 pregnant women in Ottawa, Canada. The pattern of use was then described and groups of personal care product groups commonly used together were identified using hierarchical cluster analysis. The results showed that product use varied by income and country of birth. General hygiene products were the most commonly used products and were consistently used over time while cosmetic product use declined with advancing pregnancy and post-delivery. Hand soaps and baby products were reported as used more frequently after birth. This study is the first to track personal care product use across pregnancy and into the postpartum period, and suggests that pregnant populations may be a unique group of personal care product users. This information will be useful for exposure assessments. PMID- 26751463 TI - Response to Polosa et al. Comments on Scheffler et al. Cytotoxic Evaluation of E Liquid Aerosol Using Different Lung Derived Cell Models. Int. J. Environ. Res. Public Health, 2015, 12, 12466-12474. PMID- 26751465 TI - Housing Stakeholder Preferences for the "Soft" Features of Sustainable and Healthy Housing Design in the UK. AB - It is widely recognised that the quantity and sustainability of new homes in the UK need to increase. However, it is important that sustainable housing is regarded holistically, and not merely in environmental terms, and incorporates elements that enhance the quality of life, health and well-being of its users. This paper focuses on the "soft" features of sustainable housing, that is, the non-technological components of sustainable housing and neighbourhood design that can impact occupants' health and well-being. Aims of the study are to ascertain the relative level of importance that key housing stakeholders attach to these features and to investigate whether the opinions of housing users and housing providers are aligned with regards to their importance. An online survey was carried out to gauge the level of importance that the key stakeholders, such as housing users, local authorities, housing associations, and developers (n = 235), attach to these features. Results revealed that while suitable indoor space was the feature regarded as most important by all stakeholders, there were also a number of disparities in opinion between housing users and housing providers (and among the different types of providers). This implies a scope for initiatives to achieve a better alignment between housing users and providers. PMID- 26751464 TI - Water-Food-Nutrition-Health Nexus: Linking Water to Improving Food, Nutrition and Health in Sub-Saharan Africa. AB - Whereas sub-Saharan Africa's (SSA) water scarcity, food, nutrition and health challenges are well-documented, efforts to address them have often been disconnected. Given that the region continues to be affected by poverty and food and nutrition insecurity at national and household levels, there is a need for a paradigm shift in order to effectively deliver on the twin challenges of food and nutrition security under conditions of water scarcity. There is a need to link water use in agriculture to achieve food and nutrition security outcomes for improved human health and well-being. Currently, there are no explicit linkages between water, agriculture, nutrition and health owing to uncoordinated efforts between agricultural and nutrition scientists. There is also a need to develop and promote the use of metrics that capture aspects of water, agriculture, food and nutrition. This review identified nutritional water productivity as a suitable index for measuring the impact of a water-food-nutrition-health nexus. Socio-economic factors are also considered as they influence food choices in rural communities. An argument for the need to utilise the region's agrobiodiversity for addressing dietary quality and diversity was established. It is concluded that a model for improving nutrition and health of poor rural communities based on the water-food-nutrition-health nexus is possible. PMID- 26751466 TI - Association between UGT1A1 Polymorphism and Risk of Laryngeal Squamous Cell Carcinoma. AB - Laryngeal cancer is one of the largest subgroups of head and neck cancers. In addition to smoking and alcohol consumption, genetic polymorphisms are also risk factors for the development of laryngeal cancer. However, the exact relation between genetic variants and pathogenesis of laryngeal cancer has remained elusive. The aim of this study was to examine UGT1A1*6 (rs4148323 A/G) polymorphisms in 103 patients with laryngeal cancer and 220 controls using the high resolution melting curve (HRM) technique and to explore the association between UGT1A1*6 (rs4148323 A/G) polymorphisms and laryngeal cancer. The results showed an association between the rs4148323 G allele and increased risk of laryngeal cancer. While there was no statistically significant difference between rs4148323 genotype frequencies and different histological grades or different clinical stages of laryngeal cancer, stratification analysis indicated smoking or alcohol consumption and rs4148323 G allele combined to increase the risk of laryngeal cancer. In conclusion, the rs4148323 G allele is associated with the high UGT1A1 enzyme activity, and might increase the risk of laryngeal cancer. Furthermore, smoking or alcohol consumption and the rs4148323 G allele act synergistically to increase the risk of laryngeal cancer. PMID- 26751467 TI - A Longitudinal Study of Association between Heavy Metals and Itchy Eyes, Coughing in Chronic Cough Patients: Related with Non-Immunoglobulin E Mediated Mechanism. AB - The association between heavy metals exposure and respiratory diseases or allergic sensitization showing high serum immunoglobulin E (IgE) has been suggested. However, previous findings have been inconsistent and the mechanisms responsible remain unclear. We evaluated heavy metal exposure and its association with coughing, itchy eyes in chronic cough patients with different IgE levels. Ninety outpatients in Kanazawa University Hospital were recruited between January June 2011. Subjects whose total IgE measured by radioimmunosorbent test were asked to record their daily symptoms. We collected daily total suspended particles (TSP) from which concentrations of calcium (Ca), cadmium (Cd), chromium (Cr), iron (Fe), manganese (Mn), nickel (Ni), and lead (Pb) were determined then divided into high and low level groups. Generalized estimating equations were applied to compute the relationship between concentrations of these metals and symptoms. All metals at high levels were significantly associated with itchy eyes compared with low levels, with exception of Ca, the six others were significant in patients with IgE < 250 IU/mL. Cd, Fe, Mn had association with coughing (odds ratio-OR (95% confidence interval-CI): 1.13 (1.03, 1.24), 1.22 (1.05, 1.42), and 1.13 (1.01, 1.27), respectively), this relationship remained significant for Cd (OR (95% CI): 1.14 (1.03, 1.27)) and Mn (OR (95% CI): 1.15 (1.00, 1.31)) in patients with lower IgE. Our findings demonstrate the relationship between aerial heavy metals and itchy eyes, coughing in chronic cough patients, suggesting these symptoms may be due to a non-IgE mediated mechanism. PMID- 26751468 TI - MicroRNA and Pathogenesis of Enterovirus Infection. AB - There are no currently available specific antiviral therapies for non-polio Enterovirus infections. Although several vaccines have entered clinical trials, the efficacy requires further evaluation, particularly for cross-strain protective activity. Curing patients with viral infections is a public health problem due to antigen alterations and drug resistance caused by the high genomic mutation rate. To conquer these limits in the development of anti-Enterovirus treatments, a comprehensive understanding of the interactions between Enterovirus and host cells is urgently needed. MicroRNA (miRNA) constitutes the biggest family of gene regulators in mammalian cells and regulates almost a half of all human genes. The roles of miRNAs in Enterovirus pathogenesis have recently begun to be noted. In this review, we shed light on recent advances in the understanding of Enterovirus infection-modulated miRNAs. The impacts of altered host miRNAs on cellular processes, including immune escape, apoptosis, signal transduction, shutdown of host protein synthesis and viral replication, are discussed. Finally, miRNA-based medication provides a promising strategy for the development of antiviral therapy. PMID- 26751470 TI - Direct Identification of Enteroviruses in Cerebrospinal Fluid of Patients with Suspected Meningitis by Nested PCR Amplification. AB - Enteroviruses, the most common human viral pathogens worldwide, have been associated with serous meningitis, encephalitis, syndrome of acute flaccid paralysis, myocarditis and the onset of diabetes type 1. In the future, the rapid identification of the etiological agent would allow to adjust the therapy promptly and thereby improve the course of the disease and prognosis. We developed RT-nested PCR amplification of the genomic region coding viral structural protein VP1 for direct identification of enteroviruses in clinical specimens and compared it with the existing analogs. One-hundred-fifty-nine cerebrospinal fluids (CSF) from patients with suspected meningitis were studied. The amplification of VP1 genomic region using the new method was achieved for 86 (54.1%) patients compared with 75 (47.2%), 53 (33.3%) and 31 (19.5%) achieved with previously published methods. We identified 11 serotypes of the Enterovirus species B in 2012, including relatively rare echovirus 14 (E-14), E-15 and E-32, and eight serotypes of species B and 5 enteroviruses A71 (EV-A71) in 2013. The developed method can be useful for direct identification of enteroviruses in clinical material with the low virus loads such as CSF. PMID- 26751469 TI - Overcoming Barriers in Oncolytic Virotherapy with HDAC Inhibitors and Immune Checkpoint Blockade. AB - Oncolytic viruses (OVs) target and destroy cancer cells while sparing their normal counterparts. These viruses have been evaluated in numerous studies at both pre-clinical and clinical levels and the recent Food and Drug Administration (FDA) approval of an oncolytic herpesvirus-based treatment raises optimism that OVs will become a therapeutic option for cancer patients. However, to improve clinical outcome, there is a need to increase OV efficacy. In addition to killing cancer cells directly through lysis, OVs can stimulate the induction of anti tumour immune responses. The host immune system thus represents a "double-edged sword" for oncolytic virotherapy: on the one hand, a robust anti-viral response will limit OV replication and spread; on the other hand, the immune-mediated component of OV therapy may be its most important anti-cancer mechanism. Although the relative contribution of direct viral oncolysis and indirect, immune-mediated oncosuppression to overall OV efficacy is unclear, it is likely that an initial period of vigorous OV multiplication and lytic activity will most optimally set the stage for subsequent adaptive anti-tumour immunity. In this review, we consider the use of histone deacetylase (HDAC) inhibitors as a means of boosting virus replication and lessening the negative impact of innate immunity on the direct oncolytic effect. We also discuss an alternative approach, aimed at potentiating OV-elicited anti-tumour immunity through the blockade of immune checkpoints. We conclude by proposing a two-phase combinatorial strategy in which initial OV replication and spread is maximised through transient HDAC inhibition, with anti-tumour immune responses subsequently enhanced by immune checkpoint blockade. PMID- 26751472 TI - Dissolution of Intact, Divided and Crushed Circadin Tablets: Prolonged vs. Immediate Release of Melatonin. AB - Circadin 2 mg prolonged-release tablet is the only licensed melatonin product available in the UK. Circadin is indicated for patients with primary insomnia aged 55 and over, but is more widely used "off-label" to treat sleep disorders especially in the paediatric population. Children and older people often have difficulty swallowing tablets and dividing the tablet is sometimes required to ease administration. The aim of this study was to measure the release profile of melatonin from Circadin tablets when divided or crushed, and compare this with release from intact tablets. Dissolution testing was also performed for unlicensed melatonin products for comparison. Dissolution tests were performed using the pharmacopoeial paddle apparatus, with melatonin release analyzed by high performance liquid chromatography. Melatonin content, hardness, friability, and disintegration of the products were also evaluated. The prolonged release of melatonin from Circadin tablets was unlike that of any other product tested. When divided into halves, Circadin preserved most of the prolonged-release characteristic (f2 = 58), whereas quarter-cut and crushed tablet had a more immediate melatonin release profile. Circadin is significantly less expensive and should be preferred to unlicensed medicines which are not pharmaceutically equivalent and offer less quality assurance. PMID- 26751471 TI - Quantifying Next Generation Sequencing Sample Pre-Processing Bias in HIV-1 Complete Genome Sequencing. AB - Genetic analyses play a central role in infectious disease research. Massively parallelized "mechanical cloning" and sequencing technologies were quickly adopted by HIV researchers in order to broaden the understanding of the clinical importance of minor drug-resistant variants. These efforts have, however, remained largely limited to small genomic regions. The growing need to monitor multiple genome regions for drug resistance testing, as well as the obvious benefit for studying evolutionary and epidemic processes makes complete genome sequencing an important goal in viral research. In addition, a major drawback for NGS applications to RNA viruses is the need for large quantities of input DNA. Here, we use a generic overlapping amplicon-based near full-genome amplification protocol to compare low-input enzymatic fragmentation (NexteraTM) with conventional mechanical shearing for Roche 454 sequencing. We find that the fragmentation method has only a modest impact on the characterization of the population composition and that for reliable results, the variation introduced at all steps of the procedure--from nucleic acid extraction to sequencing--should be taken into account, a finding that is also relevant for NGS technologies that are now more commonly used. Furthermore, by applying our protocol to deep sequence a number of pre-therapy plasma and PBMC samples, we illustrate the potential benefits of a near complete genome sequencing approach in routine genotyping. PMID- 26751473 TI - Impact of Multi-Micronutrient Fortified Rice on Hemoglobin, Iron and Vitamin A Status of Cambodian Schoolchildren: a Double-Blind Cluster-Randomized Controlled Trial. AB - In Cambodia, micronutrient deficiencies remain a critical public health problem. Our objective was to evaluate the impact of multi-micronutrient fortified rice (MMFR) formulations, distributed through a World Food Program school-meals program (WFP-SMP), on the hemoglobin concentrations and iron and vitamin A (VA) status of Cambodian schoolchildren. The FORISCA-UltraRice+NutriRice study was a double-blind, cluster-randomized, placebo-controlled trial. Sixteen schools participating in WFP-SMP were randomly assigned to receive extrusion-fortified rice (UltraRice Original, UltraRice New (URN), or NutriRice) or unfortified rice (placebo) six days a week for six months. Four additional schools not participating in WFP-SMP were randomly selected as controls. A total of 2440 schoolchildren (6-16 years old) participated in the biochemical study. Hemoglobin, iron status, estimated using inflammation-adjusted ferritin and transferrin receptors concentrations, and VA status, assessed using inflammation adjusted retinol-binding protein concentration, were measured at the baseline, as well as at three and six months. Baseline prevalence of anemia, depleted iron stores, tissue iron deficiency, marginal VA status and VA deficiency were 15.6%, 1.4%, 51.0%, 7.9%, and 0.7%, respectively. The strongest risk factors for anemia were hemoglobinopathy, VA deficiency, and depleted iron stores (all p < 0.01). After six months, children receiving NutriRice and URN had 4 and 5 times less risk of low VA status, respectively, in comparison to the placebo group. Hemoglobin significantly increased (+0.8 g/L) after three months for the URN group in comparison to the placebo group; however, this difference was no longer significant after six months, except for children without inflammation. MMFR containing VA effectively improved the VA status of schoolchildren. The impact on hemoglobin and iron status was limited, partly by sub-clinical inflammation. MMFR combined with non-nutritional approaches addressing anemia and inflammation should be further investigated. PMID- 26751474 TI - Changes in Expression of Genes Regulating Airway Inflammation Following a High Fat Mixed Meal in Asthmatics. AB - Consumption of a high fat meal can increase neutrophilic airway inflammation in asthma subjects. This study investigates the molecular mechanisms driving airway neutrophilia following a high fat meal in asthmatics. Subjects with asthma (n = 11) and healthy controls (n = 8) consumed a high-fat/energy meal, containing total energy (TE) of 3846 kJ and 48 g of total fat (20.5 g saturated). Sputum was induced at 0 and 4 h, and gene expression was examined by microarray and quantitative real-time PCR (qPCR). Following the high fat dietary challenge, 168 entities were significantly differentially expressed greater than >1.5 fold in subjects with asthma, whereas, in healthy controls, only 14 entities were differentially expressed. Of the 168 genes that were changed in asthma, several biological processes were overrepresented, with 25 genes involved in "immune system processes". qPCR confirmed that S100P, S100A16, MAL and MUC1 were significantly increased in the asthma group post-meal. We also observed a strong correlation and a moderate correlation between the change in NLRP12 and S100A16 gene expression at 4 h compared to baseline, and the change in total and saturated non-esterified plasma fatty acid levels at 2 h compared to baseline. In summary, our data identifies differences in inflammatory gene expression that may contribute to increased airway neutrophilia following a high fat meal in subjects with asthma and may provide useful therapeutic targets for immunomodulation. This may be particularly relevant to obese asthmatics, who are habitually consuming diets with a high fat content. PMID- 26751477 TI - Development of a Novel Enzyme-Targeting Radiosensitizer (New KORTUC) Using a Gelatin-Based Hydrogel Instead of a Sodium Hyaluronate. AB - We recently developed Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas (KORTUC) as a strategy to increase intratumoral oxygen concentrations and degrade antioxidant enzymes such as peroxidase and catalase. We then developed KORTUC II, which uses sodium hyaluronate containing hydrogen peroxide as a radiosensitizer. KORTUC II requires twice-weekly administration to sustain its effects, but decreasing the frequency of radiosensitizer injections to once-weekly would reduce the burden on the patients and the physicians. The goal of this study was thus to develop a new formulation of KORTUC (New KORTUC) that only requires once weekly administration. We performed experimental studies using a mouse tumor model and biodegradable hydrogel. C3H/He mice were allocated to control, KORTUC, or hydrogel groups. At 72 h after injection, each tumor was irradiated with a 6 MeV electron beam to a total dose of 30 Gy. During a 62-day observation period, changes in tumor volume and survival rates were assessed in each group. Tumor growth rate was slowest in the hydrogel groups. These data suggest that hydrogel could represent a useful adjunct as a long-acting radiosensitizer in place of sodium hyaluronate. New KORTUC, which contains hydrogen peroxide and hydrogel, exerted a radiosensitizing effect that persisted beyond 72 h following injection of the agent. Use of this new formulation allows radiosensitizer injections to be performed once-weekly with good effect. PMID- 26751475 TI - Ageing Is Associated with Decreases in Appetite and Energy Intake--A Meta Analysis in Healthy Adults. AB - It is not well recognized that in the elderly weight loss is more common than weight gain. The aim of this analysis was to determine the effect of ageing on appetite (hunger/fullness) and energy intake, after overnight fasting and in a postprandial state, by meta-analyses of trials that included at least two age groups (>18 years). We hypothesized that appetite and energy intake would be less in healthy older compared with younger adults. Following a PubMed-database systematic search up to 30 June 2015, 59 studies were included in the random effects-model meta-analyses. Energy intake was 16%-20% lower in older (n = 3574/~70 years/~71 kg/~25 kg/m2) than younger (n = 4111/~26 years/~69 kg/~23 kg/m2) adults (standardized mean difference: -0.77 (95% confidence interval -0.90 to -0.64)). Hunger was 25% (after overnight fasting; weighted mean difference (WMD): -17 (-22 to -13) mm) to 39% (in a postprandial state; WMD: -14 (-19 to -9) mm) lower, and fullness 37% (after overnight fasting; WMD: 6 mm (95% CI: 1 to 11 mm)) greater in older than younger adults. In conclusion, appetite and energy intake are less in healthy older than younger adults, suggesting that ageing per se affects food intake. PMID- 26751479 TI - Training the Future Leaders in Personalized Medicine. AB - The era of personalized medicine has arrived, and with it a need for leaders in this discipline. This generation of trainees requires a cadre of new skill sets to lead the implementation of personalized medicine into mainstream healthcare. Traditional training programs no longer provide trainees with all the skills they will need to optimize implementation of this revolution now underway in medicine. Today's trainees must manage clinical teams, act as clinical and molecular diagnostic consultants, train other healthcare professionals, teach future generations, and be knowledgeable about clinical trials to facilitate genomic based therapies. To prepare trainees for the transition to junior faculty positions, contemporary genomic training programs must emphasize the development of these management, teaching, and clinical skills. PMID- 26751476 TI - Hepatic Transcriptome Responses of Domesticated and Wild Turkey Embryos to Aflatoxin B1. AB - The mycotoxin, aflatoxin B1 (AFB1) is a hepatotoxic, immunotoxic, and mutagenic contaminant of food and animal feeds. In poultry, AFB1 can be maternally transferred to embryonated eggs, affecting development, viability and performance after hatch. Domesticated turkeys (Meleagris gallopavo) are especially sensitive to aflatoxicosis, while Eastern wild turkeys (M. g. silvestris) are likely more resistant. In ovo exposure provided a controlled AFB1 challenge and comparison of domesticated and wild turkeys. Gene expression responses to AFB1 in the embryonic hepatic transcriptome were examined using RNA-sequencing (RNA-seq). Eggs were injected with AFB1 (1 MUg) or sham control and dissected for liver tissue after 1 day or 5 days of exposure. Libraries from domesticated turkey (n = 24) and wild turkey (n = 15) produced 89.2 Gb of sequence. Approximately 670 M reads were mapped to a turkey gene set. Differential expression analysis identified 1535 significant genes with |log2 fold change| >= 1.0 in at least one pair-wise comparison. AFB1 effects were dependent on exposure time and turkey type, occurred more rapidly in domesticated turkeys, and led to notable up-regulation in cell cycle regulators, NRF2-mediated response genes and coagulation factors. Further investigation of NRF2-response genes may identify targets to improve poultry resistance. PMID- 26751478 TI - Preclinical Activity of the Vascular Disrupting Agent OXi4503 against Head and Neck Cancer. AB - Vascular disrupting agents (VDAs) represent a relatively distinct class of agents that target established blood vessels in tumors. In this study, we examined the preclinical activity of the second-generation VDA OXi4503 against human head and neck squamous cell carcinoma (HNSCC). Studies were performed in subcutaneous and orthotopic FaDu-luc HNSCC xenografts established in immunodeficient mice. In the subcutaneous model, bioluminescence imaging (BLI) along with tumor growth measurements was performed to assess tumor response to therapy. In mice bearing orthotopic tumors, a dual modality imaging approach based on BLI and magnetic resonance imaging (MRI) was utilized. Correlative histologic assessment of tumors was performed to validate imaging data. Dynamic BLI revealed a marked reduction in radiance within a few hours of OXi4503 administration compared to baseline levels. However, this reduction was transient with vascular recovery observed at 24 h post treatment. A single injection of OXi4503 (40 mg/kg) resulted in a significant (p < 0.01) tumor growth inhibition of subcutaneous FaDu-luc xenografts. MRI revealed a significant reduction (p < 0.05) in volume of orthotopic tumors at 10 days post two doses of OXi4503 treatment. Corresponding histologic (H&E) sections of Oxi4503 treated tumors showed extensive areas of necrosis and hemorrhaging compared to untreated controls. To the best of our knowledge, this is the first report, on the activity of Oxi4503 against HNSCC. These results demonstrate the potential of tumor-VDAs in head and neck cancer. Further examination of the antivascular and antitumor activity of Oxi4503 against HNSCC alone and in combination with chemotherapy and radiation is warranted. PMID- 26751482 TI - Effects of Dark Brooders on Behavior and Fearfulness in Layers. AB - Chicks require heat to maintain body temperature during the first weeks after hatch. This may be provided by dark brooders; i.e. , horizontal heating elements equipped with curtains. The objective was to test effects of rearing layer chicks with dark brooders on time budget and fearfulness. Behavioral observations were performed during the first six weeks of age. Three different fear tests were conducted when the birds were age 3-6, 14-15 and 26-28 weeks. During the first four days, brooder chicks rested more than control chicks whereas they spent less time drinking, feather pecking and on locomotion ( p <= 0.009). On days 16, 23, 30 and 42, brooder chicks spent less time on feather pecking, locomotion and fleeing ( p <= 0.01) whereas foraging and dust bathing occurred more often on day 42 ( p <= 0.032). Brooder birds had shorter durations of tonic immobility at all ages ( p = 0.0032), moved closer to the novel object at age 15 weeks ( p < 0.0001), and had shorter latencies to initiate locomotion in the open-field test at age 28 weeks ( p < 0.0001). Results support the suggestion that dark brooders can be a successful method of reducing or preventing fear and feather pecking in layers. PMID- 26751481 TI - Food Deprivation, Body Weight Loss and Anxiety-Related Behavior in Rats. AB - In behavioral studies, food deprivation protocols are routinely used to initiate or maintain motivational states that are required in a particular test situation. However, there is limited evidence as to when food deprivation compromises animal welfare. This study investigated the effects of different lengths of food deprivation periods and restricted (fixed-time) feeding on body weight loss as well as anxiety-related and motivated behavior in 5-6 month old male and female Wistar rats. The observed body weight loss was not influenced by sex and ranged between 4% (16 h deprivation) to approximately 9% (fixed-time feeding). Despite significant body weight loss in all groups, the motivation to eat under the aversive test conditions of the modified open field test increased only after 48 h of food deprivation. Long-lasting effects on anxiety as measured in the elevated plus maze test 24 h after refeeding have not been observed, although fixed-time feeding could possibly lead to a lasting anxiogenic effect in female rats. Overall, female rats showed a more anxiolytic profile in both tests when compared to male rats. Despite these sex differences, results suggest that food deprivation is not always paralleled by an increased motivation to feed in a conflict situation. This is an important finding as it highlights the need for tailored pilot experiments to evaluate the impact of food deprivation protocols on animals in regard to the principles of the 3Rs introduced by Russell and Burch. PMID- 26751480 TI - Insecticide Resistance and Management Strategies in Urban Ecosystems. AB - The increased urbanization of a growing global population makes imperative the development of sustainable integrated pest management (IPM) strategies for urban pest control. This emphasizes pests that are closely associated with the health and wellbeing of humans and domesticated animals. Concurrently there are regulatory requirements enforced to minimize inadvertent exposures to insecticides in the urban environment. Development of insecticide resistance management (IRM) strategies in urban ecosystems involves understanding the status and mechanisms of insecticide resistance and reducing insecticide selection pressure by combining multiple chemical and non-chemical approaches. In this review, we will focus on the commonly used insecticides and molecular and physiological mechanisms underlying insecticide resistance in six major urban insect pests: house fly, German cockroach, mosquitoes, red flour beetle, bed bugs and head louse. We will also discuss several strategies that may prove promising for future urban IPM programs. PMID- 26751483 TI - Individual Differences in Anticipatory Somatosensory Cortex Activity for Shock is Positively Related with Trait Anxiety and Multisensory Integration. AB - Anxiety is associated with an exaggerated expectancy of harm, including overestimation of how likely a conditioned stimulus (CS+) predicts a harmful unconditioned stimulus (US). In the current study we tested whether anxiety associated expectancy of harm increases primary sensory cortex (S1) activity on non-reinforced (i.e., no shock) CS+ trials. Twenty healthy volunteers completed a differential-tone trace conditioning task while undergoing fMRI, with shock delivered to the left hand. We found a positive correlation between trait anxiety and activity in right, but not left, S1 during CS+ versus CS- conditions. Right S1 activity also correlated with individual differences in both primary auditory cortices (A1) and amygdala activity. Lastly, a seed-based functional connectivity analysis demonstrated that trial-wise S1 activity was positively correlated with regions of dorsolateral prefrontal cortex (dlPFC), suggesting that higher-order cognitive processes contribute to the anticipatory sensory reactivity. Our findings indicate that individual differences in trait anxiety relate to anticipatory reactivity for the US during associative learning. This anticipatory reactivity is also integrated along with emotion-related sensory signals into a brain network implicated in fear-conditioned responding. PMID- 26751485 TI - Osseointegration of Titanium Implants in Onlay of CeramentTM, a New Ceramic Bone Substitute. AB - The purpose was to investigate whether a new biphasic and injectable ceramic bone substitute CeramentTM that rapidly remodels to bone, may contribute to the retention of titanium implant screws during the healing period, and to analyze the pattern of bone formation around titanium implants.Titanium screws were implanted in rat tibiae and embedded with or without CeramentTM on the cortical surface. Torsional resistance was measured after 1 day, and after 6 and 12 weeks. Implant areas without bone substitute were analyzed histologically for comparison. The torsional resistance increased over time as the screws were osseointegrated. There was no difference in resistance between screws embedded in the bone substitute and control screws. The bone apposition was more pronounced on the proximal side of the screw than on the distal side. CeramentTM is capable of conducting bone growth from a cortical bone surface. The newly formed bone in this application does not significantly add to the osseointegrative strength of the implant screw, as measured by torque resistance, during the first 12 weeks. PMID- 26751484 TI - Tissue-Mimicking Geometrical Constraints Stimulate Tissue-Like Constitution and Activity of Mouse Neonatal and Human-Induced Pluripotent Stem Cell-Derived Cardiac Myocytes. AB - The present work addresses the question of to what extent a geometrical support acts as a physiological determining template in the setup of artificial cardiac tissue. Surface patterns with alternating concave to convex transitions of cell size dimensions were used to organize and orientate human-induced pluripotent stem cell (hIPSC)-derived cardiac myocytes and mouse neonatal cardiac myocytes. The shape of the cells, as well as the organization of the contractile apparatus recapitulates the anisotropic line pattern geometry being derived from tissue geometry motives. The intracellular organization of the contractile apparatus and the cell coupling via gap junctions of cell assemblies growing in a random or organized pattern were examined. Cell spatial and temporal coordinated excitation and contraction has been compared on plain and patterned substrates. While the alpha-actinin cytoskeletal organization is comparable to terminally-developed native ventricular tissue, connexin-43 expression does not recapitulate gap junction distribution of heart muscle tissue. However, coordinated contractions could be observed. The results of tissue-like cell ensemble organization open new insights into geometry-dependent cell organization, the cultivation of artificial heart tissue from stem cells and the anisotropy-dependent activity of therapeutic compounds. PMID- 26751486 TI - Asymmetric Mach-Zehnder Interferometer Based Biosensors for Aflatoxin M1 Detection. AB - In this work, we present a study of Aflatoxin M1 detection by photonic biosensors based on Si3N4 Asymmetric Mach-Zehnder Interferometer (aMZI) functionalized with antibodies fragments (Fab'). We measured a best volumetric sensitivity of 104 rad/RIU, leading to a Limit of Detection below 5 * 10(-7) RIU. On sensors functionalized with Fab', we performed specific and non-specific sensing measurements at various toxin concentrations. Reproducibility of the measurements and re-usability of the sensor were also investigated. PMID- 26751487 TI - DNA Methylation Analysis: Choosing the Right Method. AB - In the burgeoning field of epigenetics, there are several methods available to determine the methylation status of DNA samples. However, choosing the method that is best suited to answering a particular biological question still proves to be a difficult task. This review aims to provide biologists, particularly those new to the field of epigenetics, with a simple algorithm to help guide them in the selection of the most appropriate assay to meet their research needs. First of all, we have separated all methods into two categories: those that are used for: (1) the discovery of unknown epigenetic changes; and (2) the assessment of DNA methylation within particular regulatory regions/genes of interest. The techniques are then scrutinized and ranked according to their robustness, high throughput capabilities and cost. This review includes the majority of methods available to date, but with a particular focus on commercially available kits or other simple and straightforward solutions that have proven to be useful. PMID- 26751488 TI - Alcoholic Liver Disease: Update on the Role of Dietary Fat. AB - Alcoholic liver disease (ALD) spans a spectrum of liver pathology, including fatty liver, alcoholic steatohepatitis, and cirrhosis. Accumulating evidence suggests that dietary factors, including dietary fat, as well as alcohol, play critical roles in the pathogenesis of ALD. The protective effects of dietary saturated fat (SF) and deleterious effects of dietary unsaturated fat (USF) on alcohol-induced liver pathology are well recognized and documented in experimental animal models of ALD. Moreover, it has been demonstrated in an epidemiological study of alcoholic cirrhosis that dietary intake of SF was associated with a lower mortality rates, whereas dietary intake of USF was associated with a higher mortality. In addition, oxidized lipids (dietary and in vivo generated) may play a role in liver pathology. The understanding of how dietary fat contributes to the ALD pathogenesis will enhance our knowledge regarding the molecular mechanisms of ALD development and progression, and may result in the development of novel diet-based therapeutic strategies for ALD management. This review explores the relevant scientific literature and provides a current understanding of recent advances regarding the role of dietary lipids in ALD pathogenesis. PMID- 26751489 TI - Activation of the DNA Damage Response by RNA Viruses. AB - RNA viruses are a genetically diverse group of pathogens that are responsible for some of the most prevalent and lethal human diseases. Numerous viruses introduce DNA damage and genetic instability in host cells during their lifecycles and some species also manipulate components of the DNA damage response (DDR), a complex and sophisticated series of cellular pathways that have evolved to detect and repair DNA lesions. Activation and manipulation of the DDR by DNA viruses has been extensively studied. It is apparent, however, that many RNA viruses can also induce significant DNA damage, even in cases where viral replication takes place exclusively in the cytoplasm. DNA damage can contribute to the pathogenesis of RNA viruses through the triggering of apoptosis, stimulation of inflammatory immune responses and the introduction of deleterious mutations that can increase the risk of tumorigenesis. In addition, activation of DDR pathways can contribute positively to replication of viral RNA genomes. Elucidation of the interactions between RNA viruses and the DDR has provided important insights into modulation of host cell functions by these pathogens. This review summarises the current literature regarding activation and manipulation of the DDR by several medically important RNA viruses. PMID- 26751490 TI - Targeting Stromal-Cancer Cell Crosstalk Networks in Ovarian Cancer Treatment. AB - Ovarian cancer is a histologically, clinically, and molecularly diverse disease with a five-year survival rate of less than 30%. It has been estimated that approximately 21,980 new cases of epithelial ovarian cancer will be diagnosed and 14,270 deaths will occur in the United States in 2015, making it the most lethal gynecologic malignancy. Ovarian tumor tissue is composed of cancer cells and a collection of different stromal cells. There is increasing evidence that demonstrates that stromal involvement is important in ovarian cancer pathogenesis. Therefore, stroma-specific signaling pathways, stroma-derived factors, and genetic changes in the tumor stroma present unique opportunities for improving the diagnosis and treatment of ovarian cancer. Cancer-associated fibroblasts (CAFs) are one of the major components of the tumor stroma that have demonstrated supportive roles in tumor progression. In this review, we highlight various types of signaling crosstalk between ovarian cancer cells and stromal cells, particularly with CAFs. In addition to evaluating the importance of signaling crosstalk in ovarian cancer progression, we discuss approaches that can be used to target tumor-promoting signaling crosstalk and how these approaches can be translated into potential ovarian cancer treatment. PMID- 26751491 TI - Guardian of Genetic Messenger-RNA-Binding Proteins. AB - RNA in cells is always associated with RNA-binding proteins that regulate all aspects of RNA metabolism including RNA splicing, export from the nucleus, RNA localization, mRNA turn-over as well as translation. Given their diverse functions, cells express a variety of RNA-binding proteins, which play important roles in the pathologies of a number of diseases. In this review we focus on the effect of alcohol on different RNA-binding proteins and their possible contribution to alcohol-related disorders, and discuss the role of these proteins in the development of neurological diseases and cancer. We further discuss the conventional methods and newer techniques that are employed to identify RNA binding proteins. PMID- 26751492 TI - Moderate (2%, v/v) Ethanol Feeding Alters Hepatic Wound Healing after Acute Carbon Tetrachloride Exposure in Mice. AB - Wound healing consists of three overlapping phases: inflammation, proliferation, and matrix synthesis and remodeling. Prolonged alcohol abuse can cause liver fibrosis due to deregulated matrix remodeling. Previous studies demonstrated that moderate ethanol feeding enhances liver fibrogenic markers and frank fibrosis independent of differences in CCl4-induced liver injury. Our objective was to determine whether or not other phases of the hepatic wound healing response were affected by moderate ethanol after CCl4 exposure. Mice were fed moderate ethanol (2% v/v) for two days and then were exposed to CCl4 and euthanized 24-96 h later. Liver injury was not different between pair- and ethanol-fed mice; however, removal of necrotic tissue was delayed after CCl4-induced liver injury in ethanol fed mice. Inflammation, measured by TNFalpha mRNA and protein and hepatic Ly6c transcript accumulation, was reduced and associated with enhanced hepatocyte apoptosis after ethanol feeding. Hepatocytes entered the cell cycle equivalently in pair- and ethanol-fed mice after CCl4 exposure, but hepatocyte proliferation was prolonged in livers from ethanol-fed mice. CCl4-induced hepatic stellate cell activation was increased and matrix remodeling was prolonged in ethanol-fed mice compared to controls. Taken together, moderate ethanol affected each phase of the wound healing response to CCl4. These data highlight previously unknown effects of moderate ethanol exposure on hepatic wound healing after acute hepatotoxicant exposure. PMID- 26751495 TI - Functional Analysis of the Glucuronyltransferases GlcAT-P and GlcAT-S of Drosophila melanogaster: Distinct Activities towards the O-linked T-antigen. AB - The Drosophila melanogaster glucuronyltransferases dGlcAT-S and dGlcAT-P were reported to be expressed ubiquitously and results of in vitro activity assays indicate a functional redundancy. We analyzed both transferases in vivo and in vitro and could show significant differences in their activity towards N-and O glycoproteins in vivo. While GlcAT-P is able to use N-linked N-acetyllactosamine chains and the O-linked T-antigen as a substrate to form non-sulfated HNK1- (GlcAbeta1-3Galbeta1-4GlcNAcbeta1-) and glucuronyl-T-antigens in vivo, GlcAT-S adds glucuronic acid only to N-linked chains, thereby synthesizing only the non sulfated HNK1-antigen. PMID- 26751497 TI - Liposomal Coencapsulation of Doxorubicin with Listeriolysin O Increases Potency via Subcellular Targeting. AB - Liposomal doxorubicin is a clinically important drug formulation indicated for the treatment of several different forms of cancer. For doxorubicin to exert a therapeutic effect, it must gain access to the nucleus. However, a large proportion of the liposomal doxorubicin dose fails to work because it is sequestered within endolysosomal organelles following endocytosis of the liposomes due to the phenomenon of ion trapping. Listeriolysin O (LLO) is a pore forming protein that can provide a mechanism for endosomal escape. The present study demonstrates that liposomal coencapsulation of doxorubicin with LLO enables a significantly larger percentage of the dose to colocalize with the nucleus compared to liposomes containing doxorubicin alone. The change in intracellular distribution resulted in a significantly more potent formulation of liposomal doxorubicin as demonstrated in both the ovarian carcinoma cell line A2780 and its doxorubicin-resistant derivative A2780ADR. PMID- 26751493 TI - Tau Protein Hyperphosphorylation and Aggregation in Alzheimer's Disease and Other Tauopathies, and Possible Neuroprotective Strategies. AB - Abnormal deposition of misprocessed and aggregated proteins is a common final pathway of most neurodegenerative diseases, including Alzheimer's disease (AD). AD is characterized by the extraneuronal deposition of the amyloid beta (Abeta) protein in the form of plaques and the intraneuronal aggregation of the microtubule-associated protein tau in the form of filaments. Based on the biochemically diverse range of pathological tau proteins, a number of approaches have been proposed to develop new potential therapeutics. Here we discuss some of the most promising ones: inhibition of tau phosphorylation, proteolysis and aggregation, promotion of intra- and extracellular tau clearance, and stabilization of microtubules. We also emphasize the need to achieve a full understanding of the biological roles and post-translational modifications of normal tau, as well as the molecular events responsible for selective neuronal vulnerability to tau pathology and its propagation. It is concluded that answering key questions on the relationship between Abeta and tau pathology should lead to a better understanding of the nature of secondary tauopathies, especially AD, and open new therapeutic targets and strategies. PMID- 26751498 TI - Compact Layer Free Perovskite Solar Cells with a High-Mobility Hole-Transporting Layer. AB - A high-mobility diketopyrrolopyrrole-based copolymer (P) was employed in compact layer free CH3NH3PbI3 perovskite solar cells as a hole-transporting layer (HTL). By using the P-HTL, the 6.62% device efficiency with conventional poly-3 hexylthiophene was increased to 10.80% in the simple device configuration (ITO/CH3NH3PbI3/HTL/MoO3/Ag). With improved short circuit current density, open circuit voltage, and fill factor, the higher power conversion efficiency of P-HTL device is ascribed to the higher carrier mobility, more suitable energy level, and lower interfacial charge recombination. Advantages of applying P-HTL to perovskite solar cells, such as low cost, low-temperature processing, and excellent performance with simple cell structure, exhibit a possibility for commercial applications. PMID- 26751494 TI - Characteristics of Tau and Its Ligands in PET Imaging. AB - Tau deposition is one of the neuropathological hallmarks in Alzheimer's disease as well as in other neurodegenerative disorders called tauopathies. Recent efforts to develop selective tau radiopharmaceuticals have allowed the visualization of tau deposits in vivo. In vivo tau imaging allows the assessment of the regional distribution of tau deposits in a single human subject over time for determining the pathophysiology of tau accumulation in aging and neurodegenerative conditions as well as for application in drug discovery of anti dementia drugs as surrogate markers. However, tau deposits show complicated characteristics because of different isoform composition, histopathology, and ultrastructure in various neurodegenerative conditions. In addition, since tau radiopharmaceuticals possess different chemotype classes, they may show different binding characteristics with heterogeneous tau deposits. In this review, we describe the characteristics of tau deposits and their ligands that have beta sheet binding properties, and the status of tau imaging in clinical studies. PMID- 26751496 TI - Nuclear Tau and Its Potential Role in Alzheimer's Disease. AB - Tau protein, found in both neuronal and non-neuronal cells, forms aggregates in neurons that constitutes one of the hallmarks of Alzheimer's disease (AD). For nearly four decades, research efforts have focused more on tau's role in physiology and pathology in the context of the microtubules, even though, for over three decades, tau has been localised in the nucleus and the nucleolus. Its nuclear and nucleolar localisation had stimulated many questions regarding its role in these compartments. Data from cell culture, mouse brain, and the human brain suggests that nuclear tau could be essential for genome defense against cellular distress. However, its nature of translocation to the nucleus, its nuclear conformation and interaction with the DNA and other nuclear proteins highly suggest it could play multiple roles in the nucleus. To find efficient tau based therapies, there is a need to understand more about the functional relevance of the varied cellular distribution of tau, identify whether specific tau transcripts or isoforms could predict tau's localisation and function and how they are altered in diseases like AD. Here, we explore the cellular distribution of tau, its nuclear localisation and function and its possible involvement in neurodegeneration. PMID- 26751499 TI - High performance broadband photodetector using fabricated nanowires of bismuth selenide. AB - Recently, very exciting optoelectronic properties of Topological insulators (TIs) such as strong light absorption, photocurrent sensitivity to the polarization of light, layer thickness and size dependent band gap tuning have been demonstrated experimentally. Strong interaction of light with TIs has been shown theoretically along with a proposal for a TIs based broad spectral photodetector having potential to perform at the same level as that of a graphene based photodetector. Here we demonstrate that focused ion beam (FIB) fabricated nanowires of TIs could be used as ultrasensitive visible-NIR nanowire photodetector based on TIs. We have observed efficient electron hole pair generation in the studied Bi2Se3 nanowire under the illumination of visible (532 nm) and IR light (1064 nm). The observed photo-responsivity of ~300 A/W is four orders of magnitude larger than the earlier reported results on this material. Even though the role of 2D surface states responsible for high reponsivity is unclear, the novel and simple micromechanical cleavage (exfoliation) technique for the deposition of Bi2Se3 flakes followed by nanowire fabrication using FIB milling enables the construction and designing of ultrasensitive broad spectral TIs based nanowire photodetector which can be exploited further as a promising material for optoelectronic devices. PMID- 26751503 TI - Modulated Hydrothermal Synthesis of UiO-66(Hf)-Type Metal-Organic Frameworks for Optimal Carbon Dioxide Separation. AB - Recently, there has been growing interest in hafnium (Hf) metal-organic frameworks (MOFs). These MOFs may perform better as gas adsorbents than zirconium (Zr) MOFs due to the presence of Bronsted acid sites with high affinity toward adsorbates, together with the outstanding chemical and hydrothermal stabilities similar to their Zr analogues. However, Hf-MOFs have been rarely reported due to the lack of effective synthetic methods. We herein report a modulated hydrothermal synthesis of UiO-66(Hf)-type MOFs. Among these MOFs, UiO-66(Hf) (OH)2 possesses a very high CO2 gravimetric uptake of 1.81 mmol g(-1) at 0.15 bar and 298 K, which is 400% higher than that of UiO-66(Hf) (0.36 mmol g(-1)). It also exhibits a record-high volumetric CO2 uptake of 167 v/v at 1 bar and 298 K. Ideal adsorbed solution theory calculations showed a CO2/N2 (molar ratio 15:85) selectivity of 93 and CO2/H2 (molar ratio 30:70) selectivity above 1700. Breakthrough simulations also confirmed its optimal CO2 separation attribute. Our results have demonstrated for the first time the strong potential of Hf-MOFs for advanced adsorbents for high-performance CO2-related separations. PMID- 26751502 TI - Gold Aerogels: Three-Dimensional Assembly of Nanoparticles and Their Use as Electrocatalytic Interfaces. AB - Three-dimensional (3D) porous metal nanostructures have been a long sought-after class of materials due to their collective properties and widespread applications. In this study, we report on a facile and versatile strategy for the formation of Au hydrogel networks involving the dopamine-induced 3D assembly of Au nanoparticles. Following supercritical drying, the resulting Au aerogels exhibit high surface areas and porosity. They are all composed of porous nanowire networks reflecting in their diameters those of the original particles (5-6 nm) via electron microscopy. Furthermore, electrocatalytic tests were carried out in the oxidation of some small molecules with Au aerogels tailored by different functional groups. The beta-cyclodextrin-modified Au aerogel, with a host-guest effect, represents a unique class of porous metal materials of considerable interest and promising applications for electrocatalysis. PMID- 26751500 TI - Predictors of behavioral regulation in kindergarten: Household chaos, parenting, and early executive functions. AB - Behavioral regulation is an important school readiness skill that has been linked to early executive function (EF) and later success in learning and school achievement. Although poverty and related risks, as well as negative parenting, have been associated with poorer EF and behavioral regulation, chaotic home environments may also play a role in understanding both early EF and later behavioral regulation at school age. To explore these relationships, a unique longitudinal and representative sample was used of 1,292 children born to mothers who lived in low-wealth rural America who were followed from birth into early elementary school. This study examined whether household chaos, which was measured across the first 3 years of life, predicted behavioral regulation in kindergarten above and beyond poverty-related variables. In addition, this study tested whether parent responsivity and acceptance behaviors, measured during the first 3 years of life, as well as EF skills, which were measured when children were 3 to 5 years of age, mediated the relationship between early household chaos and kindergarten behavioral regulation. Results suggested that household chaos disorganization indirectly predicted kindergarten behavioral regulation through intermediate impacts on parenting behaviors and children's early EF skills. These findings suggest the importance of early household chaos disorganization, the parenting environment, and early EF skills in understanding behavioral regulation above and beyond poverty-related risks. PMID- 26751504 TI - Bootstrap Approach To Compare the Slopes of Two Calibrations When Few Standards Are Available. AB - Comparing the slopes of aqueous-based and standard addition calibration procedures is almost a daily task in analytical laboratories. As usual protocols imply very few standards, sound statistical inference and conclusions are hard to obtain for current classical tests (e.g., the t-test), which may greatly affect decision-making. Thus, there is a need for robust statistics that are not distorted by small samples of experimental values obtained from analytical studies. Several promising alternatives based on bootstrapping are studied in this paper under the typical constraints common in laboratory work. The impact of number of standards, homoscedasticity or heteroscedasticity, three variance patterns, and three error distributions on least-squares fits were considered (in total, 144 simulation scenarios). The Student's t-test is the most valuable procedure when the normality assumption is true and homoscedasticity is present, although it can be highly affected by outliers. A wild bootstrap method leads to average rejection percentages that are closer to the nominal level in almost every situation, and it is recommended for laboratories working with a small number of standards. Finally, it was seen that the Theil-Sen percentile bootstrap statistic is very robust but its rejection percentages depart from the nominal ones (<5%), so its use is not recommended when the number of standards is very small. Finally, a tutorial and free software are given to encourage analytical laboratories to apply bootstrap principles to compare the slopes of two calibration lines. PMID- 26751501 TI - Rsite2: an efficient computational method to predict the functional sites of noncoding RNAs. AB - Noncoding RNAs (ncRNAs) represent a big class of important RNA molecules. Given the large number of ncRNAs, identifying their functional sites is becoming one of the most important topics in the post-genomic era, but available computational methods are limited. For the above purpose, we previously presented a tertiary structure based method, Rsite, which first calculates the distance metrics defined in Methods with the tertiary structure of an ncRNA and then identifies the nucleotides located within the extreme points in the distance curve as the functional sites of the given ncRNA. However, the application of Rsite is largely limited because of limited RNA tertiary structures. Here we present a secondary structure based computational method, Rsite2, based on the observation that the secondary structure based nucleotide distance is strongly positively correlated with that derived from tertiary structure. This makes it reasonable to replace tertiary structure with secondary structure, which is much easier to obtain and process. Moreover, we applied Rsite2 to three ncRNAs (tRNA (Lys), Diels-Alder ribozyme, and RNase P) and a list of human mitochondria transcripts. The results show that Rsite2 works well with nearly equivalent accuracy as Rsite but is much more feasible and efficient. Finally, a web-server, the source codes, and the dataset of Rsite2 are available at http://www.cuialb.cn/rsite2. PMID- 26751505 TI - Comparison of ActiGraph GT3X+ and StepWatch Step Count Accuracy in Geriatric Rehabilitation Patients. AB - Activity monitors may not accurately detect steps in hospitalized older adults who walk slowly. We compared ActiGraph GT3X+ step counts (hip and ankle locations, default and low frequency extension [LFE] analyses) to the StepWatch monitor (ankle) during a hallway walk in 38 geriatric rehabilitation patients (83.2 +/- 7.1 years of age, 0.4 +/- 0.2 m/s gait speed). Absolute percent error values were low (<3%) and did not differ for the StepWatch and the GT3X+ (ankle, LFE); however, error values were high (19-97%) when the GT3X+ was worn at the hip and/ or analyzed with the default filter. Although these finding suggest the GT3X+ (ankle, LFE) functions as well as the StepWatch in detecting steps during walking in older adults with slow gait speeds, further research is needed to determine whether the GT3X+ is also able to disregard other body movements (e.g., fidgeting) that occur when full day monitoring is utilized. PMID- 26751506 TI - Association Between Change in Body Mass Index, Unified Parkinson's Disease Rating Scale Scores, and Survival Among Persons With Parkinson Disease: Secondary Analysis of Longitudinal Data From NINDS Exploratory Trials in Parkinson Disease Long-term Study 1. AB - IMPORTANCE: Greater body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) is associated with improved survival among persons with Huntington disease or amyotrophic lateral sclerosis. Weight loss is common among persons with Parkinson disease (PD) and is associated with worse quality of life. OBJECTIVE: To explore the association between change in BMI, Unified Parkinson's Disease Rating Scale (UPDRS) motor and total scores, and survival among persons with PD and to test whether there is a positive association between BMI at randomization and survival. DESIGN, SETTING, AND PARTICIPANTS: Secondary analysis (from May 27, 2014, to October 13, 2015) of longitudinal data (3-6 years) from 1673 participants who started the National Institute of Neurological Disorders and Stroke Exploratory Trials in PD Long-term Study-1 (NET-PD LS-1). This was a double-blind randomized placebo-controlled clinical trial of creatine monohydrate (10 g/d) that was performed at 45 sites throughout the United States and Canada. Participants with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) PD were enrolled from March 2007 to May 2010 and followed up until September 2013. MAIN OUTCOMES AND MEASURES: Change across time in motor UPDRS score, change across time in total UPDRS score, and time to death. Generalized linear mixed models were used to estimate the effect of BMI on the change in motor and total UPDRS scores after controlling for covariates. Survival was analyzed using Cox proportional hazards models of time to death. A participant's BMI was measured at randomization, and BMI trajectory groups were classified according to whether participants experienced weight loss ("decreasing BMI"), weight stability ("stable BMI"), or weight gain ("increasing BMI") during the study. RESULTS: Of the 1673 participants (mean [SD] age, 61.7 [9.6] years; 1074 [64.2%] were male), 158 (9.4%) experienced weight loss (decreasing BMI), whereas 233 (13.9%) experienced weight gain (increasing BMI). After adjusting for covariates, we found that the weight-loss group's mean (SE) motor UPDRS score increased by 1.48 (0.28) (P < .001) more points per visit than the weight-stable group's mean (SE) motor UPDRS score. The weight-gain group's mean (SE) motor UPDRS score decreased by -0.51 (0.24) (P = .03) points per visit, relative to the weight-stable group. While there was an unadjusted difference in survival between the 3 BMI trajectory groups (log-rank P < .001), this was not significant after adjusting for covariates. CONCLUSIONS AND RELEVANCE: Change in BMI was inversely associated with change in motor and total UPDRS scores in the NET-PD LS-1. Change in BMI was not associated with survival; however, these results were limited by the low number of deaths in the NET-PD LS-1. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00449865. PMID- 26751507 TI - Comparison of the Anti-Inflammatory Effects of Artificial Tears in a Rat Model of Corneal Scraping. AB - PURPOSE: Artificial tears (ATs) are used routinely to alleviate the symptoms of mild to moderate dry eye. Preservative-free cationic emulsions (eg, Cationorm((r))) are an innovative approach for the management of signs and symptoms of dry eye. The aim of the present exploratory experiment was to evaluate the efficacy of this cetalkonium chloride (CKC)-containing cationic emulsion on debrided cornea and to characterize its effects on scraping-induced inflammation. METHODS: Four ATs were assessed in a rat model of corneal scraping. The upper part of the corneal epithelium was scraped before a 5-day treatment, followed by clinical evaluations and fluorescein staining to evaluate cornea recovery. The anti-inflammatory efficacy of the ATs was assessed in vivo and in vitro. RESULTS: In vivo confocal microscopy (IVCM) revealed a trend toward better corneal clinical signs (lower IVCM scores) for the animals treated with the unpreserved ATs. Benzalkonium chloride treatment decreased goblet cell count by 37.5%. While the soft-preserved Systane Balance((r)) and Optive((r)) and the preservative-free Vismed((r)) had no effect on the goblet cell count, Cationorm increased this count by almost 40%. Interestingly, inflammatory cell infiltration in the stroma was at its lowest following treatment with the preservative-free Cationorm. Cationorm is also the only AT decreasing IL6- and IL8-stimulated secretion by 59% and 74%, respectively. CONCLUSION: By restoring an adequately hydrated ocular surface environment, the different ATs promote corneal epithelium healing. These data position Cationorm as a promising AT for the management of signs and symptoms of dry eye in patients with mild to moderate dry eye disease presenting chronic subclinical levels of ocular inflammation. PMID- 26751508 TI - Middle cerebellar peduncles: Magnetic resonance imaging and pathophysiologic correlate. AB - We describe common and less common diseases that can cause magnetic resonance signal abnormalities of middle cerebellar peduncles (MCP), offering a systematic approach correlating imaging findings with clinical clues and pathologic mechanisms. Myelin abnormalities, different types of edema or neurodegenerative processes, can cause areas of abnormal T2 signal, variable enhancement, and patterns of diffusivity of MCP. Pathologies such as demyelinating disorders or certain neurodegenerative entities (e.g., multiple system atrophy or fragile X associated tremor-ataxia syndrome) appear to have predilection for MCP. Careful evaluation of concomitant imaging findings in the brain or brainstem; and focused correlation with key clinical findings such as immunosuppression for progressive multifocal leukoencephalopahty; hypertension, post-transplant status or high dose chemotherapy for posterior reversible encephalopathy; electrolyte disorders for myelinolysis or suspected toxic-drug related encephalopathy; would yield an appropriate and accurate differential diagnosis in the majority of cases. PMID- 26751511 TI - Bacterial physiology: Pushing the envelope on protein repair. PMID- 26751509 TI - CRISPR-Cas adaptation: insights into the mechanism of action. AB - Since the first demonstration that CRISPR-Cas systems provide bacteria and archaea with adaptive immunity against phages and plasmids, numerous studies have yielded key insights into the molecular mechanisms governing how these systems attack and degrade foreign DNA. However, the molecular mechanisms underlying the adaptation stage, in which new immunological memory is formed, have until recently represented a major unresolved question. In this Progress article, we discuss recent discoveries that have shown both how foreign DNA is identified by the CRISPR-Cas adaptation machinery and the molecular basis for its integration into the chromosome to form an immunological memory. Furthermore, we describe the roles of each of the specific CRISPR-Cas components that are involved in memory formation, and consider current models for their evolutionary origin. PMID- 26751512 TI - A waterborn zoonotic helminthiase in an Italian diver: a case report of a cutaneous Sparganum infection and a review of European cases. AB - Many waterborne helminthes are opportunistic parasites that can travel directly from animals to man and may contain forms capable of penetrating the skin. Among these, Sparganum is the pseudophyllidean tapeworm that belongs to the genus Spirometra, which is responsible for parasitic zoonosis; it is rarely detected in Europe and is caused by the plerocercoid infective larva. Thus far, only six cases of cutaneous and ocular sparganosis have been reported in Europe; two and four cases have occurred in France and Italy, respectively. Herein, we describe a new case of sparganosis in Italy that affected a male diver who presented to the Bambino Gesu Children's Hospital of Rome. The patient's skin biopsy was submitted to the Parasitology department who, in consultation with Pathology, concluded that the morphologic and microscopic findings were those of Sparganum spp. larvae. The patient recovered following a single dose of 600 mg praziquantel. PMID- 26751514 TI - Trends in Acute Primary Angle-Closure Glaucoma, Peripheral Iridotomy and Cataract Surgery in Scotland, 1998-2012. AB - PURPOSE: We present rates of acute primary angle-closure glaucoma (APACG), peripheral iridotomy (PI) and cataract surgery in Scotland between 1998 and 2012. METHODS: The number of patients in Scotland with APACG in each of the years between 1998 and 2012 was obtained from Information Service Division (ISD) Scotland. Data was also obtained for patients who had undergone laser PI and cataract surgery. The annual rates of APACG, PI and cataract surgery were calculated using Scotland's population data during each of these years. RESULTS: Between 1998 and 2012 the rate of APACG in National Health Service patients decreased by 46.4% (from 46.7 to 25.0 per million, p < 0.005). The rate of PI increased overall by 116.3% (from 38.0 to 82.2 per million), but demonstrated a decrease of 48.2% (38.0 to 19.7 per million, p = 0.002) between 1998 and 2008, and an increase of 317.3% (19.7 to 82.2 per million, p = 0.005) between 2008 and 2012. Over the same 15-year period, cataract surgery increased by 73.4% (from 354.2 to 615.2 per 100,000, p < 0.005). In this timeframe, mid-year Scottish population estimates increased by 4.6%. CONCLUSION: Our results demonstrate a significant reduction in the rate of APACG in the Scottish population between 1998 and 2012, along with a rising rate of PI and cataract surgery. The trend of decreasing APACG may be due to the increasing rate of cataract surgery in the same time period. This parallels patterns seen in other European countries. We discuss these findings together with other related epidemiological factors. PMID- 26751513 TI - A systematic review of the efficacy of live attenuated influenza vaccine upon revaccination of children. AB - Four randomized, double-blind, placebo-controlled studies in 6090 children that investigated the efficacy of live attenuated influenza vaccine (LAIV) upon revaccination of children against laboratory-confirmed cases of influenza in consecutive seasons were reviewed. The efficacy in season 2 of LAIV administered over 2 consecutive seasons was 86.7% (95 % CI: 76.8%, 92.4%) against strains antigenically similar to those contained in the vaccine. The additional efficacy of LAIV administered in season 2 compared to LAIV recipients in season 1 only was 58.4% (28.3%, 75.9%). LAIV administered over 2 consecutive seasons also was more efficacious than was LAIV administered in season 2 only (relative efficacy: 53.9% [17.4%, 74.3%]). Residual efficacy of LAIV administered in season 1 only compared to placebo administered in two consecutive seasons was 56.4% (37.0%, 69.8%). This review did not find any evidence of decreasing efficacy of LAIV when administered during 2 consecutive seasons. PMID- 26751515 TI - Frequency and amplitude control of cortical oscillations by phosphoinositide waves. AB - Rhythmicity is prevalent in the cortical dynamics of diverse single and multicellular systems. Current models of cortical oscillations focus primarily on cytoskeleton-based feedbacks, but information on signals upstream of the actin cytoskeleton is limited. In addition, inhibitory mechanisms--especially local inhibitory mechanisms, which ensure proper spatial and kinetic controls of activation--are not well understood. Here, we identified two phosphoinositide phosphatases, synaptojanin 2 and SHIP1, that function in periodic traveling waves of rat basophilic leukemia (RBL) mast cells. The local, phase-shifted activation of lipid phosphatases generates sequential waves of phosphoinositides. By acutely perturbing phosphoinositide composition using optogenetic methods, we showed that pulses of PtdIns(4,5)P2 regulate the amplitude of cyclic membrane waves while PtdIns(3,4)P2 sets the frequency. Collectively, these data suggest that the spatiotemporal dynamics of lipid metabolism have a key role in governing cortical oscillations and reveal how phosphatidylinositol 3-kinases (PI3K) activity could be frequency-encoded by a phosphatase-dependent inhibitory reaction. PMID- 26751517 TI - The correlation of virulence, pathogenicity, and itraconazole resistance with SAP activity in Candida albicans strains. AB - The relationship between SAP2 activity and drug resistance in Candida albicans was investigated by using itraconazole-resistant and itraconazole-sensitive C. albicans isolates. The precipitation zones were measured to analyze SAP2 activity. Mice were classified into itraconazole-resistant and -sensitive C. albicans isolate groups, and a control group, with their survival and mortality rate being observed over 30 days. The relative expression levels of CDR1, CDR2, MDR1, and SAP2 were measured using RT-PCR. It was found that the secreted aspartyl proteinase activity of itraconazole-resistant C. albicans strains was significantly higher than that of itraconazole-sensitive C. albicans strains (P < 0.001). A significantly higher mortality rate was recorded for mice treated with itraconazole-resistant C. albicans than for mice treated with itraconazole sensitive C. albicans. In regards to the CDR1, CDR2, and MDR1 genes, there was no significant difference between the 2 groups of mice. Positive correlations between SAP2 and MDR1 and between CDR1 and CDR2 were found. The high expression level of SAP2 may relate to the virulence, pathogenicity, and resistance of C. albicans. PMID- 26751518 TI - Women's attitudes toward forming new partnerships in widowhood: The search for "your own someone" and for freedom. AB - This text is based on an analysis of 20 biographical interviews with women who are both retired and have been widowed. The text discusses women's attitudes toward beginning new intimate relationships and the kinds of partnerships some of them have formed in old age. The author discusses the role of gender and gendered behavior in the institution of marriage as an important factor influencing women's attitudes toward remarrying. The experience of being widowed is an important transition that, besides trauma and difficulties, also presents an opportunity to escape from the previous gender norms and expectations. The significance of these changes, which often open up opportunities for alternative forms of self-fulfillment, become part of the strategies that women select when entering future partnership arrangements. PMID- 26751516 TI - Protonation of a glutamate residue modulates the dynamics of the drug transporter EmrE. AB - Secondary active transport proteins play a central role in conferring bacterial multidrug resistance. In this work, we investigated the proton-coupled transport mechanism for the Escherichia coli drug efflux pump EmrE using NMR spectroscopy. Our results show that the global conformational motions necessary for transport are modulated in an allosteric fashion by the protonation state of a membrane embedded glutamate residue. These observations directly correlate with the resistance phenotype for wild-type EmrE and the E14D mutant as a function of pH. Furthermore, our results support a model in which the pH gradient across the inner membrane of E. coli may be used on a mechanistic level to shift the equilibrium of the transporter in favor of an inward-open resting conformation poised for drug binding. PMID- 26751520 TI - Can natural fibers be a silver bullet? Antibacterial cellulose fibers through the covalent bonding of silver nanoparticles to electrospun fibers. AB - Natural cotton was dissolved in a room-temperature ionic liquid 1-ethyl-3-methyl acetate and wet-jet electrospun to obtain nanoscale cotton fibers with a substantially reduced diameter-and therefore an increased surface area-relative to natural cotton fibers. The resulting nano-cotton fibers were esterified with trityl-3-mercaptopropionic acid, which after selective de-tritylation afforded nano-cotton fibers containing reactive thiol functionality. Silver nanoparticles that were covalently attached to these sulfhydryl groups were assembled next. The microstructure of the resulting nanocomposite was characterized, and the antibacterial activity of the resulting nano-cotton Ag-nanoparticle composite was also studied. This nanocomposite showed significant activity against both Gram negative and Gram-positive bacteria. PMID- 26751559 TI - Elevated nutrients change bacterial community composition and connectivity: high throughput sequencing of young marine biofilms. AB - Biofilms are integral to many marine processes but their formation and function may be affected by anthropogenic inputs that alter environmental conditions, including fertilisers that increase nutrients. Density composition and connectivity of biofilms developed in situ (under ambient and elevated nutrients) were compared using 454-pyrosequencing of the 16S gene. Elevated nutrients shifted community composition from bacteria involved in higher processes (eg Pseudoalteromonas spp. invertebrate recruitment) towards more nutrient-tolerant bacterial species (eg Terendinibacter sp.). This may enable the persistence of biofilm communities by increasing resistance to nutrient inputs. A core biofilm microbiome was identified (predominantly Alteromonadales and Oceanospirillales) and revealed shifts in abundances of core microbes that could indicate enrichment by fertilisers. Fertiliser decreased density and connectivity within biofilms indicating that associations were disrupted perhaps via changes to energetic allocations within the core microbiome. Density composition and connectivity changes suggest nutrients can affect the stability and function of these important marine communities. PMID- 26751558 TI - Regulation of drug-metabolizing enzymes by local and systemic liver injuries. AB - INTRODUCTION: Drug metabolism and disposition are critical in maintaining the chemical and functional homeostasis of xenobiotics/drugs and endobiotics. The liver plays an essential role in drug metabolism and disposition due to its abundant expression of drug-metabolizing enzymes (DMEs) and transporters. There is growing evidence to suggest that many hepatic and systemic diseases can affect drug metabolism and disposition by regulating the expression and/or activity of DMEs and transporters in the liver. AREAS COVERED: This review focuses on the recent progress on the regulation of DMEs by local and systemic liver injuries. Liver ischemia and reperfusion (I/R) and sepsis are used as examples of local and systemic injury, respectively. The reciprocal effect of the expression and activity of DMEs on animals' sensitivity to local and systemic liver injuries is also discussed. EXPERT OPINION: Local and systemic liver injuries have a major effect on the expression and activity of DMEs in the liver. Understanding the disease effect on DMEs is clinically important due to the concern of disease-drug interactions. Future studies are necessary to understand the mechanism by which liver injury regulates DMEs. Human studies are also urgently needed in order to determine whether the results in animals can be replicated in human patients. PMID- 26751561 TI - Diagnostic value of Tzanck smear in various erosive, vesicular, and bullous skin lesions. AB - BACKGROUND: Cutaneous cytology has long been shown to be useful in the diagnosis of several erosive, vesicular, and bullous skin lesions. The Tzanck smear although an old tool, still remains a simple, rapid, easily applied, and inexpensive test for these skin lesions. AIMS AND OBJECTIVES: The aim of this study was to evaluate the diagnostic value of Tzanck smear by determining its sensitivity and specificity in various erosive, vesicular, and bullous skin lesions. MATERIALS AND METHODS: One hundred and forty-two patients with erosive, vesicular, and/or bullous skin lesions were included in the study. Four groups of disorders were identified: infections, immunologic disorders, genodermatosis, and spongiotic dermatitis. All the study cases were evaluated by Tzanck smear. Definitive diagnosis was established by standard diagnostic techniques (including when appropriate, viral serology, bacterial culture, histopathology, direct immunoflourescence). RESULTS: The sensitivity and specificity of cytologic findings was respectively 86.36% and 91.30% for viral infections; for bacterial infections, it was 85.7% and 66.6%. The sensitivity and specificity of Tzanck smear was respectively 85.0% and 83.33% for pemphigus; for bullous pemhigoid it was 11.11% and 100.0%. Tzanck smear sensitivity in genodermatoses was 100%. The sensitivity and specificity of the test in spongiotic dermatitis could not be calculated due to an insufficient number of patients. CONCLUSION: The Tzanck smear is a quick and reliable tool for the evaluation of various erosive and vesiculobullous skin lesions. PMID- 26751519 TI - Let There Be Light: Gene and Cell Therapy for Blindness. AB - Retinal degenerative diseases are a leading cause of irreversible blindness. Retinal cell death is the main cause of vision loss in genetic disorders such as retinitis pigmentosa, Stargardt disease, and Leber congenital amaurosis, as well as in complex age-related diseases such as age-related macular degeneration. For these blinding conditions, gene and cell therapy approaches offer therapeutic intervention at various disease stages. The present review outlines advances in therapies for retinal degenerative disease, focusing on the progress and challenges in the development and clinical translation of gene and cell therapies. A significant body of preclinical evidence and initial clinical results pave the way for further development of these cutting edge treatments for patients with retinal degenerative disorders. PMID- 26751560 TI - Glutaminase 2 is a novel negative regulator of small GTPase Rac1 and mediates p53 function in suppressing metastasis. AB - Glutaminase (GLS) isoenzymes GLS1 and GLS2 are key enzymes for glutamine metabolism. Interestingly, GLS1 and GLS2 display contrasting functions in tumorigenesis with elusive mechanism; GLS1 promotes tumorigenesis, whereas GLS2 exhibits a tumor-suppressive function. In this study, we found that GLS2 but not GLS1 binds to small GTPase Rac1 and inhibits its interaction with Rac1 activators guanine-nucleotide exchange factors, which in turn inhibits Rac1 to suppress cancer metastasis. This function of GLS2 is independent of GLS2 glutaminase activity. Furthermore, decreased GLS2 expression is associated with enhanced metastasis in human cancer. As a p53 target, GLS2 mediates p53's function in metastasis suppression through inhibiting Rac1. In summary, our results reveal that GLS2 is a novel negative regulator of Rac1, and uncover a novel function and mechanism whereby GLS2 suppresses metastasis. Our results also elucidate a novel mechanism that contributes to the contrasting functions of GLS1 and GLS2 in tumorigenesis. PMID- 26751562 TI - Multi-Objective Ant Colony Optimization Based on the Physarum-Inspired Mathematical Model for Bi-Objective Traveling Salesman Problems. AB - Bi-objective Traveling Salesman Problem (bTSP) is an important field in the operations research, its solutions can be widely applied in the real world. Many researches of Multi-objective Ant Colony Optimization (MOACOs) have been proposed to solve bTSPs. However, most of MOACOs suffer premature convergence. This paper proposes an optimization strategy for MOACOs by optimizing the initialization of pheromone matrix with the prior knowledge of Physarum-inspired Mathematical Model (PMM). PMM can find the shortest route between two nodes based on the positive feedback mechanism. The optimized algorithms, named as iPM-MOACOs, can enhance the pheromone in the short paths and promote the search ability of ants. A series of experiments are conducted and experimental results show that the proposed strategy can achieve a better compromise solution than the original MOACOs for solving bTSPs. PMID- 26751563 TI - Universality of Citation Distributions for Academic Institutions and Journals. AB - Citations measure the importance of a publication, and may serve as a proxy for its popularity and quality of its contents. Here we study the distributions of citations to publications from individual academic institutions for a single year. The average number of citations have large variations between different institutions across the world, but the probability distributions of citations for individual institutions can be rescaled to a common form by scaling the citations by the average number of citations for that institution. We find this feature seems to be universal for a broad selection of institutions irrespective of the average number of citations per article. A similar analysis for citations to publications in a particular journal in a single year reveals similar results. We find high absolute inequality for both these sets, Gini coefficients being around 0.66 and 0.58 for institutions and journals respectively. We also find that the top 25% of the articles hold about 75% of the total citations for institutions and the top 29% of the articles hold about 71% of the total citations for journals. PMID- 26751564 TI - Thrombolysis in Stroke Patients with Isolated Aphasia. AB - BACKGROUND: Data about evolution of aphasia following stroke are rare and controversial especially following fibrinolysis. The aim of this study was to describe the early clinical patterns of isolated aphasia in consecutive stroke patients with or without thrombolysis. METHODS: Clinical and radiological data of consecutive stroke patients were routinely entered in prospective registry. Patients were considered aphasic when NIHSS (National Institutes of Health Stroke Scale) item 9 >0. 'Isolated aphasia' was defined by aphasic patients without motor limb deficit. We created a 'composite language score' obtained by summing the NIHSS items 1b, 1c and 9, which reflects language-processing ability. Recovery of functions was evaluated as measured by global NIHSS, composite language score and language screening test (LAST) at baseline, H24 and day 7 (D7). 'Mild deficit' was defined as global NIHSS <5. RESULTS: A total of 100 consecutive patients met study criteria for isolated aphasia. Twenty-five underwent thrombolysis and 75 did not. There was no difference between the 2 groups concerning demographic characteristics, involved territories and presence of arterial occlusion, initial median NIHSS, composite language and LAST scores at entrance. Evolution was significantly better in thrombolysed patient for the 3 testings: NIHSS, composite language score and LAST at D7 (respective p = 0.0002; p = 0.01 and p = 0.004). Similar results were found when we focused on the subgroups of patients with initial 'mild' deficits (p = 0.01; p = 0.0003 and p = 0.007). No symptomatic hemorrhagic transformation occurred following thrombolysis. CONCLUSION: These data strongly suggest that thrombolysis is safe and effective in patients with 'isolated aphasia,' even if the global NIHSS score is <5. PMID- 26751565 TI - Species Distribution 2.0: An Accurate Time- and Cost-Effective Method of Prospection Using Street View Imagery. AB - Species occurrence data provide crucial information for biodiversity studies in the current context of global environmental changes. Such studies often rely on a limited number of occurrence data collected in the field and on pseudo-absences arbitrarily chosen within the study area, which reduces the value of these studies. To overcome this issue, we propose an alternative method of prospection using geo-located street view imagery (SVI). Following a standardised protocol of virtual prospection using both vertical (aerial photographs) and horizontal (SVI) perceptions, we have surveyed 1097 randomly selected cells across Spain (0.1x0.1 degree, i.e. 20% of Spain) for the presence of Arundo donax L. (Poaceae). In total we have detected A. donax in 345 cells, thus substantially expanding beyond the now two-centuries-old field-derived record, which described A. donax only 216 cells. Among the field occurrence cells, 81.1% were confirmed by SVI prospection to be consistent with species presence. In addition, we recorded, by SVI prospection, 752 absences, i.e. cells where A. donax was considered absent. We have also compared the outcomes of climatic niche modeling based on SVI data against those based on field data. Using generalized linear models fitted with bioclimatic predictors, we have found SVI data to provide far more compelling results in terms of niche modeling than does field data as classically used in SDM. This original, cost- and time-effective method provides the means to accurately locate highly visible taxa, reinforce absence data, and predict species distribution without long and expensive in situ prospection. At this time, the majority of available SVI data is restricted to human-disturbed environments that have road networks. However, SVI is becoming increasingly available in natural areas, which means the technique has considerable potential to become an important factor in future biodiversity studies. PMID- 26751566 TI - A Network Model to Describe the Terminal Differentiation of B Cells. AB - Terminal differentiation of B cells is an essential process for the humoral immune response in vertebrates and is achieved by the concerted action of several transcription factors in response to antigen recognition and extracellular signals provided by T-helper cells. While there is a wealth of experimental data regarding the molecular and cellular signals involved in this process, there is no general consensus regarding the structure and dynamical properties of the underlying regulatory network controlling this process. We developed a dynamical model of the regulatory network controlling terminal differentiation of B cells. The structure of the network was inferred from experimental data available in the literature, and its dynamical behavior was analyzed by modeling the network both as a discrete and a continuous dynamical systems. The steady states of these models are consistent with the patterns of activation reported for the Naive, GC, Mem, and PC cell types. Moreover, the models are able to describe the patterns of differentiation from the precursor Naive to any of the GC, Mem, or PC cell types in response to a specific set of extracellular signals. We simulated all possible single loss- and gain-of-function mutants, corroborating the importance of Pax5, Bcl6, Bach2, Irf4, and Blimp1 as key regulators of B cell differentiation process. The model is able to represent the directional nature of terminal B cell differentiation and qualitatively describes key differentiation events from a precursor cell to terminally differentiated B cells. PMID- 26751568 TI - Comparing the Impact of Course-Based and Apprentice-Based Research Experiences in a Life Science Laboratory Curriculum. AB - This four-year study describes the assessment of a bifurcated laboratory curriculum designed to provide upper-division undergraduate majors in two life science departments meaningful exposure to authentic research. The timing is critical as it provides a pathway for both directly admitted and transfer students to enter research. To fulfill their degree requirements, all majors complete one of two paths in the laboratory program. One path immerses students in scientific discovery experienced through team research projects (course-based undergraduate research experiences, or CUREs) and the other path through a mentored, independent research project (apprentice-based research experiences, or AREs). The bifurcated laboratory curriculum was structured using backwards design to help all students, irrespective of path, achieve specific learning outcomes. Over 1,000 undergraduates enrolled in the curriculum. Self-report survey results indicate that there were no significant differences in affective gains by path. Students conveyed which aspects of the curriculum were critical to their learning and development of research-oriented skills. Students' interests in biology increased upon completion of the curriculum, inspiring a subset of CURE participants to subsequently pursue further research. A rubric-guided performance evaluation, employed to directly measure learning, revealed differences in learning gains for CURE versus ARE participants, with evidence suggesting a CURE can reduce the achievement gap between high-performing students and their peers. PMID- 26751570 TI - Impact of Monochorionicity and Twin to Twin Transfusion Syndrome on Prenatal Attachment, Post Traumatic Stress Disorder, Anxiety and Depressive Symptoms. AB - Monochronioric (MC) twin pregnancies are considered as high-risk pregnancies with potential complications requiring in-utero interventions. We aimed to assess prenatal attachment, anxiety, post-traumatic stress disorder (PTSD) and depressive symptoms in MC pregnancies complicated with Twin-To-Twin-transfusion syndrome (TTTS) in comparison to uncomplicated monochorionic (UMC) and dichorionic pregnancies (DC). Auto-questionnaires were filled out at diagnosis of TTTS and at successive milestones. Prenatal attachment, PTSD, anxiety and perinatal depression were evaluated respectively by the Prenatal Attachment Inventory (PAI) completed for each twin, the Post-traumatic Checklist Scale (PCLS), the State-Trait Anxiety Inventory (STAI) and the Edinburgh Perinatal Depression Scale (EPDS). There was no significant difference in the PAI scores between the two twins. In the DC and UMC groups, PAI scores increased throughout pregnancy, whilst it didn't for TTTS group. TTTS and DC had a similar prenatal attachment while MC mothers expressed a significantly higher attachment to their fetuses and expressed it earlier. At the announcement of TTTS, 72% of the patients present a score over the threshold at the EPDS Scale, with a higher score for TTTS than for DC (p = 0.005), and UMC (p = 0.007) at the same GA. 30% of mothers in TTTS group have PTSD during pregnancy. 50% of TTTS- patients present an anxiety score over the threshold (STAI-Scale), with a score significantly higher in TTTS than in UMC (p<0.001) or DC (p<0.001). The proportion of subject with a STAI-State over the threshold is also significantly higher in TTTS than in DC at 20 GW (p = 0.01) and at 26 GW (p<0.05). The STAI state scores in UMC and DC increase progressively during pregnancy while they decrease significantly in TTTS. TTTS announcement constitutes a traumatic event during a pregnancy with an important risk of PTSD, high level of anxiety and an alteration of the prenatal attachment. These results should guide the psychological support provided to these patients. PMID- 26751569 TI - Diagnostic Criteria for Problematic Internet Use among U.S. University Students: A Mixed-Methods Evaluation. AB - Empirical studies have identified increasing rates of problematic Internet use worldwide and a host of related negative consequences. However, researchers disagree as to whether problematic Internet use is a subtype of behavioral addiction. Thus, there are not yet widely accepted and validated diagnostic criteria for problematic Internet use. To address this gap, we used mixed-methods to examine the extent to which signs and symptoms of problematic Internet use mirror DSM-5 diagnostic criteria for substance use disorder, gambling disorder, and Internet gaming disorder. A total of 27 university students, who self identified as intensive Internet users and who reported Internet-use-associated health and/or psychosocial problems were recruited. Students completed two measures that assess problematic Internet use (Young's Diagnostic Questionnaire and the Compulsive Internet Use Scale) and participated in focus groups exploring their experiences with problematic Internet use. Results of standardized measures and focus group discussions indicated substantial overlap between students' experiences of problematic Internet use and the signs and symptoms reflected in the DSM-5 criteria for substance use disorder, gambling disorder, and Internet gaming disorder. These signs and symptoms included: a) use Internet longer than intended, b) preoccupation with the Internet, c) withdrawal symptoms when unable to access the Internet, d) unsuccessful attempts to stop or reduce Internet use, e) craving, f) loss of interest in hobbies or activities other than the Internet, g) excessive Internet use despite the knowledge of related problems, g) use of the Internet to escape or relieve a negative mood, and h) lying about Internet use. Tolerance, withdrawal symptoms, and recurrent Internet use in hazardous situations were uniquely manifested in the context of problematic Internet use. Implications for research and practice are discussed. PMID- 26751571 TI - Treating Sleep Problems in Patients with Schizophrenia. AB - BACKGROUND: Sleep disturbance is increasingly recognized as a major problem for patients with schizophrenia but it is rarely the direct focus of treatment. The main recommended treatment for insomnia is cognitive behavioural therapy, which we have been evaluating for patients with current delusions and hallucinations in the context of non-affective psychosis. AIMS: In this article we describe the lessons we have learned about clinical presentations of sleep problems in schizophrenia and the adaptations to intervention that we recommend for patients with current delusions and hallucinations. METHOD: Twelve factors that may particularly contribute to sleep problems in schizophrenia are identified. These include delusions and hallucinations interfering with sleep, attempts to use sleep as an escape from voices, circadian rhythm disruption, insufficient daytime activity, and fear of the bed, based upon past adverse experiences. Specific adaptations for psychological treatment related to each factor are described. CONCLUSIONS: Our experience is that patients want help to improve their sleep; sleep problems in schizophrenia should be treated with evidence-based interventions, and that the interventions may have the added benefit of lessening the psychotic experiences. A treatment technique hierarchy is proposed for ease of translation to clinical practice. PMID- 26751567 TI - Reduced Glucose Sensation Can Increase the Fitness of Saccharomyces cerevisiae Lacking Mitochondrial DNA. AB - Damage to the mitochondrial genome (mtDNA) can lead to diseases for which there are no clearly effective treatments. Since mitochondrial function and biogenesis are controlled by the nutrient environment of the cell, it is possible that perturbation of conserved, nutrient-sensing pathways may successfully treat mitochondrial disease. We found that restricting glucose or otherwise reducing the activity of the protein kinase A (PKA) pathway can lead to improved proliferation of Saccharomyces cerevisiae cells lacking mtDNA and that the transcriptional response to mtDNA loss is reduced in cells with diminished PKA activity. We have excluded many pathways and proteins from being individually responsible for the benefits provided to cells lacking mtDNA by PKA inhibition, and we found that robust import of mitochondrial polytopic membrane proteins may be required in order for cells without mtDNA to receive the full benefits of PKA reduction. Finally, we have discovered that the transcription of genes involved in arginine biosynthesis and aromatic amino acid catabolism is altered after mtDNA damage. Our results highlight the potential importance of nutrient detection and availability on the outcome of mitochondrial dysfunction. PMID- 26751572 TI - Maslinic Acid, a Natural Triterpene, Induces a Death Receptor-Mediated Apoptotic Mechanism in Caco-2 p53-Deficient Colon Adenocarcinoma Cells. AB - Maslinic acid (MA) is a natural triterpene present in high concentrations in the waxy skin of olives. We have previously reported that MA induces apoptotic cell death via the mitochondrial apoptotic pathway in HT29 colon cancer cells. Here, we show that MA induces apoptosis in Caco-2 colon cancer cells via the extrinsic apoptotic pathway in a dose-dependent manner. MA triggered a series of effects associated with apoptosis, including the cleavage of caspases -8 and -3, and increased the levels of t-Bid within a few hours of its addition to the culture medium. MA had no effect on the expression of the Bax protein, release of cytochrome-c or on the mitochondrial membrane potential. This suggests that MA triggered the extrinsic apoptotic pathway in this cell type, as opposed to the intrinsic pathway found in the HT29 colon-cancer cell line. Our results suggest that the apoptotic mechanism induced in Caco-2 may be different from that found in HT29 colon-cancer cells, and that in Caco-2 cells MA seems to work independently of p53. Natural antitumoral agents capable of activating both the extrinsic and intrinsic apoptotic pathways could be of great use in treating colon-cancer of whatever origin. PMID- 26751574 TI - Influence of Biological Factors on Connectivity Patterns for Concholepas concholepas (loco) in Chile. AB - In marine benthic ecosystems, larval connectivity is a major process influencing the maintenance and distribution of invertebrate populations. Larval connectivity is a complex process to study as it is determined by several interacting factors. Here we use an individual-based, biophysical model, to disentangle the effects of such factors, namely larval vertical migration, larval growth, larval mortality, adults fecundity, and habitat availability, for the marine gastropod Concholepas concholepas (loco) in Chile. Lower transport success and higher dispersal distances are observed including larval vertical migration in the model. We find an overall decrease in larval transport success to settlement areas from northern to southern Chile. This spatial gradient results from the combination of current direction and intensity, seawater temperature, and available habitat. From our simulated connectivity patterns we then identify subpopulations of loco along the Chilean coast, which could serve as a basis for spatial management of this resource in the future. PMID- 26751575 TI - Gene Silencing and Haploinsufficiency of Csk Increase Blood Pressure. AB - OBJECTIVE: Recent genome-wide association studies have identified 33 human genetic loci that influence blood pressure. The 15q24 locus is one such locus that has been confirmed in Asians and Europeans. There are 21 genes in the locus within a 1-Mb boundary, but a functional link of these genes to blood pressure has not been reported. We aimed to identify a causative gene for blood pressure change in the 15q24 locus. METHODS AND RESULTS: CSK and ULK3 were selected as candidate genes based on eQTL analysis studies that showed the association between gene transcript levels and the lead SNP (rs1378942). Injection of siRNAs for mouse homologs Csk, Ulk3, and Cyp1a2 (negative control) showed reduced target gene mRNA levels in vivo. However, Csk siRNA only increased blood pressure while Ulk3 and Cyp1a2 siRNA did not change it. Further, blood pressure in Csk+/- heterozygotes was higher than in wild-type, consistent with what we observed in Csk siRNA-injected mice. We confirmed that haploinsufficiency of Csk increased the active form of Src in Csk+/- mice aorta. We also showed that inhibition of Src by PP2, a Src inhibitor decreased high blood pressure in Csk+/- mice and the active Src in Csk+/- mice aorta and in Csk knock-down vascular smooth muscle cells, suggesting blood pressure regulation by Csk through Src. CONCLUSIONS: Our study demonstrates that Csk is a causative gene in the 15q24 locus and regulates blood pressure through Src, and these findings provide a novel therapeutic target for the treatment of hypertension. PMID- 26751576 TI - Increased bladder permeability in interstitial cystitis/painful bladder syndrome. AB - The definition of interstitial cystitis (IC) has evolved over the years from being a well-defined entity characterized by diagnostic lesion (Hunner's ulcer) in the urothelium to a clinical diagnosis by exclusion (painful bladder syndrome (PBS). Although the etiology is unknown, a central theme has been an association with increased permeability of the bladder. This article reviews the evidence for increased permeability being important to the symptoms of IC/PBS and in treating the disorder. Recent work showing cross-communication among visceral organs is also reviewed to provide a basis for understanding IC/PBS as a systemic disorder of a complex, interconnected system consisting of the bladder, bowel and other organs, nerves, cytokine-responding cells and the nervous system. PMID- 26751577 TI - A Probabilistic Atlas of Diffuse WHO Grade II Glioma Locations in the Brain. AB - Diffuse WHO grade II gliomas are diffusively infiltrative brain tumors characterized by an unavoidable anaplastic transformation. Their management is strongly dependent on their location in the brain due to interactions with functional regions and potential differences in molecular biology. In this paper, we present the construction of a probabilistic atlas mapping the preferential locations of diffuse WHO grade II gliomas in the brain. This is carried out through a sparse graph whose nodes correspond to clusters of tumors clustered together based on their spatial proximity. The interest of such an atlas is illustrated via two applications. The first one correlates tumor location with the patient's age via a statistical analysis, highlighting the interest of the atlas for studying the origins and behavior of the tumors. The second exploits the fact that the tumors have preferential locations for automatic segmentation. Through a coupled decomposed Markov Random Field model, the atlas guides the segmentation process, and characterizes which preferential location the tumor belongs to and consequently which behavior it could be associated to. Leave-one out cross validation experiments on a large database highlight the robustness of the graph, and yield promising segmentation results. PMID- 26751573 TI - Network Analysis of Human Genes Influencing Susceptibility to Mycobacterial Infections. AB - Tuberculosis and nontuberculous mycobacterial infections constitute a high burden of pulmonary disease in humans, resulting in over 1.5 million deaths per year. Building on the premise that genetic factors influence the instance, progression, and defense of infectious disease, we undertook a systems biology approach to investigate relationships among genetic factors that may play a role in increased susceptibility or control of mycobacterial infections. We combined literature and database mining with network analysis and pathway enrichment analysis to examine genes, pathways, and networks, involved in the human response to Mycobacterium tuberculosis and nontuberculous mycobacterial infections. This approach allowed us to examine functional relationships among reported genes, and to identify novel genes and enriched pathways that may play a role in mycobacterial susceptibility or control. Our findings suggest that the primary pathways and genes influencing mycobacterial infection control involve an interplay between innate and adaptive immune proteins and pathways. Signaling pathways involved in autoimmune disease were significantly enriched as revealed in our networks. Mycobacterial disease susceptibility networks were also examined within the context of gene-chemical relationships, in order to identify putative drugs and nutrients with potential beneficial immunomodulatory or anti-mycobacterial effects. PMID- 26751578 TI - Systemic levels of human beta-defensin 1 are elevated in patients with cirrhosis. AB - BACKGROUND: Bacterial translocation (BT) commonly occurs in cirrhosis. Reliable biomarkers for BT are currently lacking. Human beta defensin-1 (hBD-1) is a member of the family of natural antimicrobial peptides produced by epithelial cells and participates in the mucosal defensive mechanisms that prevent BT. The aim of the present study was to examine the local and systemic expression of hBD 1 in patients with cirrhosis. METHODS: Plasma concentrations of hBD-1 and of soluble CD14 (sCD14) proteins were measured by ELISA in patients with chronic viral hepatitis, cirrhosis, and healthy controls. Relative mRNA expression of various natural antimicrobial peptides was determined by real-time PCR in biopsies from the terminal ileum and colon. RESULTS: We found significant upregulation of hBD-1 and sCD14 in the peripheral blood of patients with cirrhosis compared to patients with chronic viral hepatitis and healthy controls. The etiology of cirrhosis did not affect the concentration of either protein. The levels of hBD-1 protein correlated significantly with the levels of sCD14 in blood collected from hepatic veins of cirrhotic patients. In contrast, no significant differences were observed in the intestinal mucosal mRNA expression of the Paneth cell specific defensin A5 or hBD-1 between patients with cirrhosis and healthy controls. CONCLUSIONS: hBD-1 is upregulated in patients with cirrhosis and highly correlates with the lipopolysaccharide-induced protein sCD14. hBD-1 may serve as a biomarker of BT in patients with cirrhosis. PMID- 26751579 TI - Identification and Functional Analysis of the Mycophenolic Acid Gene Cluster of Penicillium roqueforti. AB - The filamentous fungus Penicillium roqueforti is widely known as the ripening agent of blue-veined cheeses. Additionally, this fungus is able to produce several secondary metabolites, including the meroterpenoid compound mycophenolic acid (MPA). Cheeses ripened with P. roqueforti are usually contaminated with MPA. On the other hand, MPA is a commercially valuable immunosuppressant. However, to date the molecular basis of the production of MPA by P. roqueforti is still unknown. Using a bioinformatic approach, we have identified a genomic region of approximately 24.4 kbp containing a seven-gene cluster that may be involved in the MPA biosynthesis in P. roqueforti. Gene silencing of each of these seven genes (named mpaA, mpaB, mpaC, mpaDE, mpaF, mpaG and mpaH) resulted in dramatic reductions in MPA production, confirming that all of these genes are involved in the biosynthesis of the compound. Interestingly, the mpaF gene, originally described in P. brevicompactum as a MPA self-resistance gene, also exerts the same function in P. roqueforti, suggesting that this gene has a dual function in MPA metabolism. The knowledge of the biosynthetic pathway of MPA in P. roqueforti will be important for the future control of MPA contamination in cheeses and the improvement of MPA production for commercial purposes. PMID- 26751580 TI - Changes of Serum Total and Free Testosterone Concentrations in Male Chronic Hemodialysis Patients with Secondary Hyperparathyroidism in Response to Cinacalcet Treatment. AB - BACKGROUND/AIMS: Calcium sensing receptor (CaSR) is expressed, among others also in testis. Cinacalcet binds to the CaSR, increases sensitivity of CaSR to serum calcium and is used in the treatment of secondary hyperparathyroidism (sHPT) in chronic hemodialysis patients (HDP). In most of male HDP, serum testosterone concentration is lower than in healthy males. The aim of this study was to assess the influence of six-month treatment with cinacalcet on the serum total and free testosterone concentration in male HDP with sHPT. METHODS: 38 male, hemodialysed CKD patients with sHPT (PTH>300 pg/ml) were enrolled into the study. In each patient serum PTH, total testosterone (TT) and free testosterone (FT) concentrations were assessed before the first dose of cinacalcet and then after 3 and 6 months of treatment. The results are presented as means with 95% confidence interval. RESULTS: In 33 patients who completed the study cinacalcet treatment caused significant decrease of serum PTH from 1143 pg/ml (828 - 1458 pg/ml) at the baseline, to 809 pg/ml (487 - 1132 pg/ml) after 3 month of treatment (p = 0.002), and to 607 pg/ml (281 - 934 pg/ml; p < 0.0001) after 6 months of treatment. Serum TT concentration also decreased from 4.95 ng/ml (4.23 - 5.67 ng/ml) to 4.45 ng/ml (3.85 - 5.06 ng/ml) and to 4.39 ng/ml (3.75 - 5.03 ng/ml), respectively (p for trend = 0.009). Moreover, serum FT concentration decreased from 6.95 pg/ml (5.54 - 8.36 pg/ml) to 5.98 pg/ml (5.00-6.94 pg/ml); p = 0.14 and to 5.60 pg/ml (4.63 - 6.57 pg/ml); p = 0.034, respectively (p for trend = 0.012). CONCLUSION: Treatment with cinacalcet decreases serum total and free testosterone concentration in male hemodialysed patients with chronic kidney disease and secondary hyperparathyroidism. PMID- 26751581 TI - A review of virtual reality based training simulators for orthopaedic surgery. AB - This review presents current virtual reality based training simulators for hip, knee and other orthopaedic surgery, including elective and trauma surgical procedures. There have not been any reviews focussing on hip and knee orthopaedic simulators. A comparison of existing simulator features is provided to identify what is missing and what is required to improve upon current simulators. In total 11 hip replacements pre-operative planning tools were analysed, plus 9 hip trauma fracture training simulators. Additionally 9 knee arthroscopy simulators and 8 other orthopaedic simulators were included for comparison. The findings are that for orthopaedic surgery simulators in general, there is increasing use of patient specific virtual models which reduce the learning curve. Modelling is also being used for patient-specific implant design and manufacture. Simulators are being increasingly validated for assessment as well as training. There are very few training simulators available for hip replacement, yet more advanced virtual reality is being used for other procedures such as hip trauma and drilling. Training simulators for hip replacement and orthopaedic surgery in general lag behind other surgical procedures for which virtual reality has become more common. Further developments are required to bring hip replacement training simulation up to date with other procedures. This suggests there is a gap in the market for a new high fidelity hip replacement and resurfacing training simulator. PMID- 26751582 TI - Long-term response of femoral density to hip implant and bone fracture plate: Computational study using a mechano-biochemical model. AB - Although bone fracture plates can provide appropriate stability at the fracture site and lead to early patient mobilization, they significantly change the loading pattern in the bone after union (Stress shielding). This phenomenon results in a bone density decrease, which may cause premature failure of the implant. This paper presents the first study that quantifies the long-term response of femoral density to hip implantation and plating (lateral and anterior plating) using a mechano-biochemical model which considers the coupling effect between mechanical loading and biochemical affinities as stimuli for bone remodeling. The results showed that the regions directly beneath the plate experienced severe bone loss (i.e. up to ~ -70%). However, some level of bone formation was observed in the vicinity of the most proximal and distal screw holes in both lateral and anterior plated femurs (i.e. up to ~ +110%). The bone under the plate was divided into six zones. With respect to bone remodeling response, the findings revealed that anterior plating was not superior to lateral plating since the maximum and average bone losses among the zones in the anterior plated femur (i.e. -36% and -24%, respectively) were approximately the same as their corresponding values in the lateral plated femur (i.e. -38% and -24%, respectively). PMID- 26751583 TI - Access to Bacteriologic-Based Diagnosis in Smear Positive Retreatment Tuberculosis Patients in Rural China: A Cross-Sectional Study in Three Geographic Varied Provinces. AB - OBJECTIVE: To determine factors influencing the utilization and accessibility to bacteriologic-based tuberculosis (TB) diagnosis among sputum smear positive (SS+) retreatment TB patients, and to develop strategies for improving the case detection rate of MDR-TB in rural China. STUDY DESIGN AND SETTING: A cross sectional study of SS+ TB retreatment patients was conducted in eight counties from three provinces with different implementation period and strategy of MDR-TB program in China. Demographic and socioeconomic parameters were collected by self reporting questionnaires. Sputum samples were collected and cultured by the laboratory of county-designated TB clinics and delivered to prefectural Centers for Disease Prevention and Control (CDC) labs for DST with 4 first-line anti-TB drugs. RESULTS: Among the 196 SS+ retreatment patients, 61.22% received culture tests during current treatment. Patients from more developed regions (OR = 24.0 and 3.6, 95% CI: 8.6-67.3 and 1.1-11.6), with better socio-economic status (OR = 3. 8, 95% CI: 1.3-10.7), who had multiple previous anti-TB treatments (OR = 5.0, 95% CI: 1.6-15.9), and who failed in the most recent anti-TB treatment (OR = 2.6, 95% CI: 1.0-6.4) were more likely to receive culture tests. The percentage of isolates resistant to any of first-line anti-TB drugs and MDR-TB were 50.0% (95% CI: 39.8%-60.2%) and 30.4% (95% CI: 21.0%-39.8%) respectively. CONCLUSIONS: Retreatment SS+ TB patients, high risk MDR-TB population, had poor utilization of access to bacteriologic-based TB diagnosis, which is far from optimal. The next step of anti-TB strategy should be focused on how to make bacteriological-based diagnosis cheaper, safer and more maneuverable, and how to assure the DST-guided treatment for these high-risk TB patients. PMID- 26751585 TI - Needle aspiration versus intercostal tube drainage for pneumothorax in the newborn. AB - BACKGROUND: Pneumothorax occurs more frequently in the neonatal period than at any other time of life and is associated with increased mortality and morbidity. It may be treated with either needle aspiration or insertion of a chest tube. The former consists of aspiration of air with a syringe through a needle or an angiocatheter, usually through the second or third intercostal space in the midclavicular line. The chest tube is usually placed in the anterior pleural space passing through the sixth intercostal space into the pleural opening, turned anteriorly and directed to the location of the pneumothorax, and then connected to a Heimlich valve or an underwater seal with continuous suction. OBJECTIVES: To compare the efficacy and safety of needle aspiration and intercostal tube drainage in the management of neonatal pneumothorax. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 11), MEDLINE via PubMed (1966 to 30 November 2015), EMBASE (1980 to 30 November 2015), and CINAHL (1982 to 30 November 2015). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised controlled trials, quasi-randomised controlled trials and cluster trials comparing needle aspiration (either with the needle or angiocatheter left in situ or removed immediately after aspiration) to intercostal tube drainage in newborn infants with pneumothorax. DATA COLLECTION AND ANALYSIS: For each of the included trial, two authors independently extracted data (e.g. number of participants, birth weight, gestational age, kind of needle and chest tube, choice of intercostal space, pressure and device for drainage) and assessed the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow-up). The primary outcomes considered in this review are mortality during the neonatal period and during hospitalisation. MAIN RESULTS: One randomised controlled trial (72 infants) met the inclusion criteria of this review. We found no differences in the rates of mortality (risk ratio (RR) 1.50, 95% confidence interval (CI) 0.27 to 8.45) or complications related to the procedure. After needle aspiration, the angiocatheter was left in situ (mean 27.1 hours) and not removed immediately after the aspiration. The angiocatheter was in place for a shorter duration than the intercostal tube (mean difference (MD) 11.20 hours, 95% CI -15.51 to -6.89). None of the 36 newborns treated with needle aspiration with the angiocatheter left in situ required the placement of an intercostal tube drainage. Overall, the quality of the evidence supporting this finding is low. AUTHORS' CONCLUSIONS: At present there is insufficient evidence to determine the efficacy and safety of needle aspiration versus intercostal tube drainage in the management of neonatal pneumothorax. Randomised controlled trials comparing the two techniques are warranted. PMID- 26751584 TI - Reciprocity between Regulatory T Cells and Th17 Cells: Relevance to Polarized Immunity in Leprosy. AB - T cell defect is a common feature in lepromatous or borderline lepromatous leprosy (LL/BL) patients in contrast to tuberculoid or borderline tuberculoid type (TT/BT) patients. Tuberculoid leprosy is characterized by strong Th1-type cell response with localized lesions whereas lepromatous leprosy is hallmarked by its selective Mycobacterium leprae specific T cell anergy leading to disseminated and progressive disease. FoxP3+ Regulatory T cells (Treg) which are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases also dampen proinflammatory T cells that include T helper 17 (Th17) cells. This study is aimed at evaluating the role of Treg cells in influencing other effector T cells and its relationship with the cytokine polarized state in leprosy patients. Peripheral blood mononuclear cells from of BT/TT (n = 15) and BL/LL (n = 15) patients were stimulated with M. leprae antigen (WCL) in presence of golgi transport inhibitor monensin for FACS based intracellular cytokine estimation. The frequency of Treg cells showed >5-fold increase in BL/LL in comparison to BT/TT and healthy contacts. These cells produced suppressive cytokine, IL-10 in BL/LL as opposed to BT/TT (p = 0.0200) indicating their suppressive function. The frequency of Th17 cells (CD4, CD45RO, IL-17) was, however, higher in BT/TT. Significant negative correlation (r = 0.68, P = 0.03) was also found between IL-10 of Treg cells and IL-17+ T cells in BL/LL. Blocking IL-10/TGF-beta restored the IL-17+ T cells in BL/LL patients. Simultaneously, presence of Th17 related cytokines (TGF-beta, IL-6, IL-17 and IL 23) decreased the number of FoxP3+ Treg cells concomitantly increasing IL-17 producing CD4+ cells in lepromatous leprosy. Higher frequency of Programmed Death 1/PD-1+ Treg cells and its ligand, PDL-1 in antigen presenting cells (APCs) was found in BL/LL patients. Inhibition of this pathway led to rescue of IFN-gamma and IL-17 producing T cells. Results indicate that Treg cells are largely responsible for the kind of immunosuppression observed in BL/LL patients. This study also proves that Treg cells are profoundly affected by the cytokine milieu and this property may be utilized for benefit of the host. PMID- 26751586 TI - Transformation to SCLC after Treatment with the ALK Inhibitor Alectinib. AB - We report an anaplastic lymphoma receptor tyrosine kinase gene (ALK)-positive patient who showed a paradoxical response to the ALK inhibitor alectinib; the primary lesion increased in size, whereas other metastatic lesions decreased markedly. A biopsy of the primary lesion confirmed an ALK rearrangement; however, the tumor had transformed histologically into small cell lung cancer. The lack of reports of small cell lung cancer transformation in ALK-positive patients implies that this outcome was unusual; this patient was treated with alectinib, which is more selective and has a greater inhibitory effect than crizotinib. This case may reveal resistance mechanisms that differ according to the agent used for treatment. PMID- 26751587 TI - Enzymes Involved in Pyrophosphate and Calcium Metabolism as Targets for Anti scuticociliate Chemotherapy. AB - Inorganic pyrophosphate (PPi) is a key metabolite in cellular bioenergetics under chronic stress conditions in prokaryotes, protists and plants. Inorganic pyrophosphatases (PPases) are essential enzymes controlling the cellular concentration of PPi and mediating intracellular pH and Ca(2+) homeostasis. We report the effects of the antimalarial drugs chloroquine (CQ) and artemisinin (ART) on the in vitro growth of Philasterides dicentrarchi, a scuticociliate parasite of turbot; we also evaluated the action of these drugs on soluble (sPPases) and vacuolar H+-PPases (H+-PPases). CQ and ART inhibited the in vitro growth of ciliates with IC50 values of respectively 74 +/- 9 MUM and 80 +/- 8 MUM. CQ inhibits the H+ translocation (with an IC50 of 13.4 +/- 0.2 MUM), while ART increased translocation of H+ and acidification. However, both drugs caused a decrease in gene expression of H+-PPases. CQ significantly inhibited the enzymatic activity of sPPases, decreasing the consumption of intracellular PPi. ART inhibited intracellular accumulation of Ca(2+) induced by ATP, indicating an effect on the Ca(2+) -ATPase. The results suggest that CQ and ART deregulate enzymes associated with PPi and Ca(2+) metabolism, altering the intracellular pH homeostasis vital for parasite survival and providing a target for the development of new drugs against scuticociliatosis. PMID- 26751589 TI - A sensitive and efficient method for determination of N-acetylhexosamines and N acetylneuraminic acid in breast milk and milk-based products by high-performance liquid chromatography via UV detection and mass spectrometry identification. AB - A sensitive and efficient method of high performance liquid chromatography using 1-(2-naphthyl)-3-methyl-5-pyrazolone (NMP) as pre-column derivatization reagent coupled with UV detection (HPLC-UV) and online mass spectrometry identification was established for determination of the most common N-Acetylhexosamines (N acetyl-d-glucosamine (GlcNAc) and N-acetyl-d-galactosamine (GalNAc)) and N acetylneuraminic acid (Neu5Ac). In order to obtain the highest liberation level of the three monosaccharides without destruction of Neu5Ac or conversion of GlcNAc/GalNAc to GlcN/GalN in the hydrolysis procedure, the pivotal parameters affecting the liberation of N-acetylhexosamines/Neu5Ac from sample were investigated with response surface methodology (RSM). Under the optimized condition, maximum yield was obtained. The effects of key parameters on derivatization, separation and detection were also investigated. At optimized conditions, three monosaccharides were labeled fast and entirely, and all derivatives exhibited a good baseline resolution and high detection sensitivity. The developed method was linear over the calibration range 0.25-12MUM, with R(2)>0.9991. The detection limits of the method were between 0.48 and 2.01pmol. Intra- and inter-day precisions for the three monosaccharides (GlcNAc, GalNAc and Neu5Ac) were found to be in the range of 3.07-4.02% and 3.69-4.67%, respectively. Individual monosaccharide recovery from spiked milk was in the range of 81%-97%. The sensitivity of the method, the facility of the derivatization procedure and the reliability of the hydrolysis conditions suggest the proposed method has a high potential for utilization in routine trace N-acetylhexosamines and Neu5Ac analysis in biological samples. PMID- 26751591 TI - Preparation of Fe3O4@PPy magnetic nanoparticles as solid-phase extraction sorbents for preconcentration and separation of phthalic acid esters in water by gas chromatography-mass spectrometry. AB - The purpose of this paper is to introduce a solid-phase extraction method of separating and determining of phthalic acid esters (PAEs) by PPy-coated Fe3O4 magnetic nanoparticles (Fe3O4@PPy MNPs). In the process, nanoparticles were served as sorbents and the optimal conditions of the extraction have been explored. The composite was synthesized through the chemical oxidation method, combining pyrrole monomer with Fe3O4 magnetic ball in the form of aggregation state and the coated nanoparticles possessed core-shell construction. The PPy coated Fe3O4 magnetic microspheres have been extensively characterized by transmission electron microscopy, Fourier transform infrared spectroscopy and vibrating sample magnetometry. The optimum conditions were investigated by orthogonal experimental design, which was used to testing the influence of main factors and the interactions among them. The orthoplan is famous for the merit that it can study the whole experiments comprehensively through minimal tests. Under the optimal extraction conditions: 20mg of modified magnetite nanoparticles, eluting with acetic ester of 2mL, 40min of MSPE, eluting in 1h and 20mL of sample volume, good linearity (r(2)>0.9912) of all calibration curves was obtained in validation experiments. And the limits of detection (LODs) were from 0.006 to 0.021ng/mL. The recoveries in different sample matrices were in the range from 80.4% to 108.2% with relative standard deviations less than 12.8%. The present work demonstrates the applicability of the developed method for the determination of PAEs in water sample and the results justified that it can be applied successfully to the selective isolation and enrichment of PAEs in real water samples. PMID- 26751590 TI - Intact mass analysis of monoclonal antibodies by capillary electrophoresis-Mass spectrometry. AB - Characterization of monoclonal antibody (mAb) therapeutics by intact mass analysis provides important information on sequence integrity and post translational modifications. In order to obtain domain specific information, monoclonal antibodies are reduced to heavy and light chain components or enzymatically digested into smaller portions or peptides. Liquid chromatography (LC) is widely used for separation of the antibody fragments in line with mass spectrometry (MS) for characterization. Capillary electrophoresis (CE) is an analytical technique with high separation efficiency, high sensitivity, and minimal inter-run sample carryover. Combining the resolving power of CE with electrospray ionization (ESI) MS has great potential in regards to accurate mass characterization of protein therapeutics and has been a long sought-after approach. However, the intrinsic technical difficulty in coupling CE to MS has hindered the broad application of CE-MS across the biopharmaceutical industry. Recently, a CE-MS interface has been developed [1] and commercialized. Herein, we report implementation of this technology for coupling CE to an Agilent time-of flight (TOF) mass spectrometer. CE-MS provides an attractive complement to LC-MS for separation and intact mass determination of mAbs and antibody-based therapeutics. PMID- 26751588 TI - The Histone Demethylase PHF8 Is Essential for Endothelial Cell Migration. AB - Epigenetic marks critically control gene expression and thus the cellular activity state. The functions of many epigenetic modifiers in the vascular system have not yet been studied. We screened for histone modifiers in endothelial cells and observed a fairly high expression of the histone plant homeodomain finger protein 8 (PHF8). Given its high expression, we hypothesize that this histone demethylase is important for endothelial cell function. Overexpression of PHF8 catalyzed the removal of methyl-groups from histone 3 lysine 9 (H3K9) and H4K20, whereas knockdown of the enzyme increased H3K9 methylation. Knockdown of PHF8 by RNAi also attenuated endothelial proliferation and survival. As a functional readout endothelial migration and tube formation was studied. PHF8 siRNA attenuated the capacity for migration and developing of capillary-like structures. Given the impact of PHF8 on cell cycle genes, endothelial E2F transcription factors were screened, which led to the identification of the gene repressor E2F4 to be controlled by PHF8. Importantly, PHF8 maintains E2F4 but not E2F1 expression in endothelial cells. Consistently, chromatin immunoprecipitation revealed that PHF8 reduces the H3K9me2 level at the E2F4 transcriptional start site, demonstrating a direct function of PHF8 in endothelial E2F4 gene regulation. Conclusion: PHF8 by controlling E2F4 expression maintains endothelial function. PMID- 26751592 TI - Development and validation of an UFLC-MS/MS method for enantioselectivity determination of d,l-thero-methylphenidate, d,l-thero-ethylphenidate and d,l thero-ritalinic acid in rat plasma and its application to pharmacokinetic study. AB - A chiral UFLC-MS/MS method was established and validated for quantifying d-threo methylphenidate (d-threo-MPH), l-threo-methylphenidate (l-threo-MPH), d-threo ethylphenidate (d-threo-EPH), l-threo-ethylphenidate (l-threo-EPH) and d,l-threo ritalinic acid (d,l-threo-RA) in rat plasma over the linearity range of 1 500ng/mL. Chiral separation was performed on an Astec Chirobiotic V2 column (5MUm, 250*2.1mm) with isocratic elution using methanol containing 0.003% ammonium acetate (w/v) and 0.003% trifluoroacetic acid (v/v) at a flow of 0.3mL/min. All analytes and IS were extracted from rat plasma by a one-step liquid-liquid extraction (LLE) method. The intra- and inter-run accuracies were within 85-115%, and the intra- and inter-run precision were <10% for all analytes. Extraction recoveries were 55-62% for d-threo-MPH, 54-60% for l-threo MPH, 55-60% for d-threo-EPH, 53-57% for l-threo-EPH and 25-30% for d,l-threo-RA. The validated UFLC-MS/MS method successfully applied to the pharmacokinetic interaction study of oral d-threo-MPH and l-threo-MPH (alone or in combination) in female Sprague Dawley rats. The EPH was not detected in rat plasma following oral administrated MPH without EtOH. As far as it is known to the authors, this study is the first one step liquid-liquid extraction method to extract and UFLC MS/MS method to quantify d-threo-MPH, l-threo-MPH, d-threo-EPH, l-threo-EPH and d,l-threo-RA simultaneously. PMID- 26751593 TI - Synthesis and structure of new dicopper(II) complexes bridged by N-(2-hydroxy-5 methylphenyl)-N'-[3-(dimethylamino)propyl]oxamide with in vitro anticancer activity: A comparative study of reactivities towards DNA/protein by molecular docking and experimental assays. AB - Two new dicopper(II) complexes bridged by N-(2-hydroxy-5-methylphenyl)-N'-[3 (dimethyl-amino)propyl]oxamide (H3hmpoxd), and end-capped with 4,4'-dimethyl-2,2' bipyridine (Me2bpy) and 2,2'-bipyridine (bpy), were synthesized and structurally characterized, namely [Cu2(hmpoxd)(CH3OH)(Me2bpy)](ClO4) (1) and [Cu2(hmpoxd)(bpy)](ClO4)?CH3OH (2). The single-crystal X-ray diffraction analysis reveals that the endo- and exo-copper (II) ions bridged by the cis-hmpoxd(3-) ligand are located in square-planar and square-pyramidal geometries, respectively, for 1, and square-planar environments in 2. The DNA/protein-binding natures are studied theoretically and experimentally, indicating that both the two complexes can interact with the DNA in the mode of intercalation, and effectively quench the intrinsic fluorescence of protein BSA via the favored binding sites Trp213 for 1 and Trp134 for 2. In vitro anticancer activities showed that the two complexes are active against the selected tumor cell lines, and the anticancer activities are consistent with their DNA/BSA-binding affinities following the order of 1 > 2. The synergistic hydrophobicity of the bridging and terminal ligands in these complexes on DNA/BSA-binding events and in vitro anticancer activities is preliminarily discussed. PMID- 26751594 TI - Effectiveness of ketogenic diet in pentylenetetrazol-induced and kindling rats as well as its potential mechanisms. AB - The effects and mechanisms of ketogenic diets (KD) are unclear. In this study, we aimed to reveal electrographic and behavioral thresholds in responses to the KD in pentylenetetrazol (PTZ)-induced seizures, as well as its antiepileptogenic effects on PTZ-kindling rats. Additionally, we investigated the potential link between KD and expression levels of two cation chloride co-transporters: K(+)-Cl( ) co-transporter 2 (KCC2) and Na(+)-K(+)-Cl(-) co-transporter 1 (NKCC1). The KD group had significantly higher electrographic thresholds than the control (ND) group for the first spike-and-wave, subcontinuous spike-and-wave, high amplitude spike-and-wave, and polyspikes both in the cortex and hippocampus. Compared to the ND group, the KD group had higher behavioral thresholds for behavioral absence, first jerk, first overt myoclonia, and generalized seizures. In the PTZ kindling model, KD not only prolonged the latency of myoclonic and clonic convulsions, but shortened clonic and generalized duration. In addition, KD rats had higher KCC2 protein expression before kindling, during myoclonic jerks, and GTCS compared with ND rats. There were no significant differences in NKCC1 protein levels between both groups following the four-week dietary intervention without PTZ exposure (before kindling). Moreover, KD inhibited the upregulation of NKCC1 expression induced by kindling in myoclonic jerks and GTCS. Therefore, our findings demonstrated that KD had antiepileptic features in elevating thresholds to most electrographic and behavioral seizure patterns in PTZ-induced rats, as well as delaying the progression and alleviating the severity of seizure in PTZ-kindling model. The antiepileptogenic effects of KD may be attributed to its regulatory properties on KCC2 and NKCC1 protein expression. PMID- 26751595 TI - Using adjuvants and environmental factors to modulate the activity of antimicrobial peptides. AB - The increase in antibiotic resistant and multi-drug resistant bacterial infections has serious implications for the future of health care. The difficulty in finding both new microbial targets and new drugs against existing targets adds to the concern. The use of combination and adjuvant therapies are potential strategies to counter this threat. Antimicrobial peptides (AMPs) are a promising class of antibiotics (ABs), particularly for topical and surface applications. Efforts have been directed toward a number of strategies, including the use of conventional ABs combined with AMPs, and the use of potentiating agents to increase the performance of AMPs. This review focuses on combination strategies such as adjuvants and the manipulation of environmental variables to improve the efficacy of AMPs as potential therapeutic agents. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert. PMID- 26751596 TI - Avian dendritic cells: Phenotype and ontogeny in lymphoid organs. AB - Dendritic cells (DC) are critically important accessory cells in the innate and adaptive immune systems. Avian DCs were originally identified in primary and secondary lymphoid organs by their typical morphology, displaying long cell processes with cytoplasmic granules. Several subtypes are known. Bursal secretory dendritic cells (BSDC) are elongated cells which express vimentin intermediate filaments, MHC II molecules, macrophage colony-stimulating factor 1 receptor (CSF1R), and produce 74.3+ secretory granules. Avian follicular dendritic cells (FDC) highly resemble BSDC, express the CD83, 74.3 and CSF1R molecules, and present antigen in germinal centers. Thymic dendritic cells (TDC), which express 74.3 and CD83, are concentrated in thymic medulla while interdigitating DC are found in T cell-rich areas of secondary lymphoid organs. Avian Langerhans cells are a specialized 74.3-/MHC II+ cell population found in stratified squamous epithelium and are capable of differentiating into 74.3+ migratory DCs. During organogenesis hematopoietic precursors of DC colonize the developing lymphoid organ primordia prior to immigration of lymphoid precursor cells. This review summarizes our current understanding of the ontogeny, cytoarchitecture, and immunophenotype of avian DC, and offers an antibody panel for the in vitro and in vivo identification of these heterogeneous cell types. PMID- 26751597 TI - Executive functions predict conceptual learning of science. AB - We examined the relationship between executive functions and both factual and conceptual learning of science, specifically chemistry, in early adolescence. Sixty-three pupils in their second year of secondary school (aged 12-13 years) participated. Pupils completed tasks of working memory (Spatial Working Memory), inhibition (Stop-Signal), attention set-shifting (ID/ED), and planning (Stockings of Cambridge), from the CANTAB. They also participated in a chemistry teaching session, practical, and assessment on the topic of acids and alkalis designed specifically for this study. Executive function data were related to (1) the chemistry assessment which included aspects of factual and conceptual learning and (2) a recent school science exam. Correlational analyses between executive functions and both the chemistry assessment and science grades revealed that science achievements were significantly correlated with working memory. Linear regression analysis revealed that visuospatial working memory ability was predictive of chemistry performance. Interestingly, this relationship was observed solely in relation to the conceptual learning condition of the assessment highlighting the role of executive functions in understanding and applying knowledge about what is learned within science teaching. PMID- 26751598 TI - A Puckered Singlet Cyclopentane-1,3-diyl: Detection of the Third Isomer in Homolysis. AB - In the photochemical denitrogenation of 1,4-diaryl-2,3-diazabicyclo[2.2.1]heptane (AZ6) bearing sterically hindered substituents, a curious new absorption band at about 450 nm was observed under low-temperature matrix conditions, together with the previously well-characterized planar singlet diradical pl-(1) DR6 with lambdamax =~580 nm. The 450 nm species was electron paramagnetic resonance (EPR) silent. Instead of generating the planar diradical pl-(1) DR6 and the precursor azoalkane AZ6 upon warming, the ring-closed bicyclo[2.1.0]pentane derivative SB6, that is, the AZ6 denitrogenation product was identified. Based on product analysis, low-temperature spectroscopic observations, high-level quantum mechanical computations, viscosity effect, and laser-flash photolysis, the puckered singlet diradicaloid puc-(1) DR6 was assigned to the new 450 nm absorption. The latter was detected experimentally at the same time as the planar singlet diradical pl-(1) DR6. Sterically demanding substituents as well as viscosity impediments were essential for the detection of the experimentally hitherto unknown puckered singlet cyclopentane-1,3-diyl diradicaloid puc-(1) DR6, that is, the third isomer in homolysis. The present findings should stimulate future work on the mechanistically fascinating stereoselectivity documented in the formation of bicyclo[2.1.0]pentanes during the 2,3-diazabicyclo[2.2.1]heptane denitrogenation. PMID- 26751599 TI - Within-Person Link between Depressed Affect and Moderate-to-Vigorous Physical Activity in Adolescence: An Intensive Longitudinal Approach. AB - BACKGROUND: During adolescence, young women and men frequently show low physical activity and elevated depressed affect. This study aimed to examine the within person link between moderate-to-vigorous physical activity (MVPA) and depressed affect in everyday life. METHODS: Within an intensive longitudinal approach, adolescents (N = 72; 37% young women; M age = 17.36 years; age range: 12-26 years; mid-90% age range: 13-22 years) wore accelerometers to assess their daily MVPA and reported next-morning and same-evening depressed affect in diaries over eight consecutive days. The within-person link between MVPA and depressed affect on the next morning (time-lagged prediction) and the same evening (same-day link) was analyzed with mixed-effects models. RESULTS: More-than-usual MVPA significantly predicted less next-morning depressed affect on weekdays in young women, to the extent that a 60-min increase in MVPA over the person mean significantly predicted 50 per cent lower next-morning depressed affect. CONCLUSIONS: This study encourages the development of individually tailored physical activity interventions that could help adolescents enhance their daily amount of unstructured, self-initiated MVPA to reduce depressed affect. This approach may be particularly suitable for young women who have the highest risk for an inactive lifestyle and elevated depressed affect. PMID- 26751600 TI - Response to Strona & Fattorini: are generalist parasites being lost from their hosts? AB - We respond to criticism of our recent paper by examining assumptions about the structure of host-parasite networks, and discuss the implications of host extinction on our perception of parasite specificity. PMID- 26751602 TI - The effectiveness of conically shaped compared with cylindrically shaped interdental brushes - a randomized controlled clinical trial. AB - AIM: The purpose of this study was to compare the effectiveness of conically shaped versus cylindrically shaped interdental brushes (IDB) in patients receiving supportive periodontal therapy. MATERIALS AND METHODS: Periodontal maintenance patients volunteered to be enrolled into this randomized controlled examiner-blind parallel study. At baseline and after 3 months, plaque scores, bleeding upon pocket probing scores and probing pocket depth (PPD) were assessed. The type of IDB (conical or cylindrical) was randomly assigned to each patient and individual instruction was provided regarding the method of use and the appropriate size. Only those approximal sites that had sufficient space for the IDB were eligible, and for those sites the data were analysed separately. Analyses were performed for all eligible approximal surfaces and a sub-analysis was performed for vestibular and lingual surfaces. RESULTS: In total, 51 participants attended the baseline and the 3-month clinical appointments. Overall, there was no difference between conical and cylindrical IDBs. However, the conical IDB showed significantly higher plaque and bleeding scores at the lingual approximal sites. The cause of this difference was an increase in plaque and bleeding scores compared with baseline. With respect to the PPD, no difference between the IDBs was observed. CONCLUSION: Within the limitations of this experiment, the conical IDBs are less effective than cylindrical IDBs with respect to lingual approximal plaque removal. Thus, in patients receiving supportive periodontal therapy, the cylindrical shape should be the first choice of IDB to obtain and maintain gingival health around natural teeth. PMID- 26751601 TI - Influence of weight reduction on blood levels of C-reactive protein, tumor necrosis factor-alpha, interleukin-6, and oxylipins in obese subjects. AB - INTRODUCTION: Obesity is associated with inflammation and weight reduction has been shown to influence the inflammatory process. Besides classic inflammatory markers, oxidized polyunsaturated fatty acid (PUFA) metabolites (oxylipins) are potent mediators of inflammation. Little is known about endogenous levels of oxylipins, e.g. hydroxy, epoxy and dihydroxy FA in obese subjects with persistent low-grade inflammation. We aimed to evaluate levels of inflammatory markers and blood oxylipins in obese subjects before and after weight reduction. SUBJECTS AND METHODS: In the present study, 42 obese (BMI 32.7 +/- 0.22 kg/m(2)) men and women were classified in groups according to high-sensitivity C-reactive protein (hsCRP) levels (no inflammation<1mg/L; low-grade inflammation >= 3 mg/L). Subjects underwent an intervention for eight weeks, which consisted of two phases: (1) week 1 and 2: total replacement of three meals by a formula diet and (2) six week partial formula diet (replacement of 1-2 meals). Blood samples were taken prior and post intervention for analysis of plasma protein levels of hsCRP, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Plasma Levels of free (unesterified) hydroxy, epoxy, and dihydroxy FAs as well as several prostanoids were analyzed in plasma by means of LC-MS-based targeted metabolomics. RESULTS: At baseline subjects with low-grade inflammation (hsCRP 8.95 +/- 1.39 mg/L) showed significant higher levels of IL-6 (22.7 +/- 1.15 ng/L) and TNF-alpha (17.4 +/- 0.75 ng/L) compared to subjects with no inflammation (hsCRP: 0.69 +/- 0.05 mg/L; IL-6: 15.9 +/- 1.18 ng/L; TNF-alpha: 14.6 +/- 0.80 ng/L). In both group's body weight was significantly reduced (p<0.001) after intervention (no inflammation group: -7.19 +/- 0.86 kg, -7.3 +/- 0.89%, p<0.001; low-grade inflammation group: -6.78 +/- 0.87 kg, -6.7 +/- 0.81%, p<0.001). Moreover, we observed significant decreases in levels of hsCRP (4.66 +/- 0.64 mg/L; p=0.006), IL-6 (6.81 +/- 1.15 ng/L; p<0.001) and TNF-alpha (6.09 +/- 0.47 ng/L; p<0.001) in subjects with low-grade inflammation. Of 60 quantified oxylipins, 11 linoleic acid (LA)-, 1 dihomo-gamma-linolenic acid (DGLA)-, 7 alpha linolenic acid (ALA)-, 15 arachidonic acid (AA)-, 8 eicosapentaenoic acid (EPA)- and 18 docosahexaenoic acid (DHA)-metabolites could be detected in plasma. For most oxylipins no differences were found between the low and high hsCRP groups before and after weight reduction. Interestingly, in subjects with low- grade inflammation several AA-derived oxylipins (5-, 8-, 12-hydroxyeicosatetraenoic acids (HETE)) were significantly higher compared to subjects with no inflammation before weight reduction and significantly reduced after weight reduction. CONCLUSION: Even moderate weight loss in obese subjects correlates to a significant improvement in the inflammatory state, by reducing hsCRP, IL-6, TNF alpha and few oxylipins. The biological consequences of these changes remain to be further investigated. PMID- 26751604 TI - Proposing a new design for self-monitoring blood glucose logs. PMID- 26751603 TI - Flavonoids from the flowers of Impatiens glandulifera Royle isolated by high performance countercurrent chromatography. AB - INTRODUCTION: Impatiens glandulifera Royle (Balsaminaceae) is an annual herb from the Himalaya region, currently widespread along European river systems and one of the most important neophyte invading plants in Germany. Exploring the effects of allelopathic plant chemicals is important for the understanding of its ecological impacts in the process of suppression of indigenous plant species. OBJECTIVE: To investigate the chemical composition of Impatiens glandulifera flowers (IGFs) using high performance countercurrent chromatography (HPCCC). METHODS: The flowers of Impatiens glandulifera were manually separated and extracted with ethanol. LC-ESI-MS/MS was used to characterise the crude extract of IGF. The various flavonoids detected were isolated by HPCCC using of methyl tert-butyl ether-acetonitrile-water (2:2:3, v/v/v). The combination of the data provided by preparative ESI-MS/MS metabolite profiling, LC-ESI-MS/MS, UV-vis and 1D/2D-NMR spectroscopic analysis was used to elucidate the structures of the isolated compounds. RESULTS: HPCCC runs led to the direct isolation of pure dihydromyricetin (ampelopsin), eriodictyol-7-O-glucoside, kaempferol-3-O glucoside (astragalin) and kaempferol-3-O-6"-malonyl-glucoside, as well as the pre-purification of kaempferol-3-O-rhamno-rhamnosyldiglucoside, quercetin-3-O galactoside (hyperoside), quercetin and kaempferol in a single step. CONCLUSION: This is the first report on the flavonoid composition of the species Impatiens glandulifera. The developed protocol was successfully used to isolate the main flavonoids from the crude extract of IGFs. This combined HPCCC and HPLC procedure could be applied to the fast fractionation and recovery of flavonoid derivatives of other plant extracts. PMID- 26751605 TI - A preprocessing tool for removing artifact from cardiac RR interval recordings using three-dimensional spatial distribution mapping. AB - Artifact is common in cardiac RR interval data that is recorded for heart rate variability (HRV) analysis. A novel algorithm for artifact detection and interpolation in RR interval data is described. It is based on spatial distribution mapping of RR interval magnitude and relationships to adjacent values in three dimensions. The characteristics of normal physiological RR intervals and artifact intervals were established using 24-h recordings from 20 technician-assessed human cardiac recordings. The algorithm was incorporated into a preprocessing tool and validated using 30 artificial RR (ARR) interval data files, to which known quantities of artifact (0.5%, 1%, 2%, 3%, 5%, 7%, 10%) were added. The impact of preprocessing ARR files with 1% added artifact was also assessed using 10 time domain and frequency domain HRV metrics. The preprocessing tool was also used to preprocess 69 24-h human cardiac recordings. The tool was able to remove artifact from technician-assessed human cardiac recordings (sensitivity 0.84, SD = 0.09, specificity of 1.00, SD = 0.01) and artificial data files. The removal of artifact had a low impact on time domain and frequency domain HRV metrics (ranging from 0% to 2.5% change in values). This novel preprocessing tool can be used with human 24-h cardiac recordings to remove artifact while minimally affecting physiological data and therefore having a low impact on HRV measures of that data. PMID- 26751607 TI - Evaluation of iron-based electrocatalysts for water oxidation - an on-line mass spectrometry approach. AB - Using on-line mass spectrometry in combination with classical electroanalytical techniques makes it possible to reliably determine onset potentials and to distinguish between competing reactions such as oxygen evolution and carbon dioxide formation. Using these on-line MS methods, catalytic water oxidation activity was demonstrated for cis-[Fe(cyclam)Cl2]Cl (1) and [Fe(cyclamacetate)Cl] (2). PMID- 26751606 TI - Treatment of severe refractory epistaxis in hereditary hemorrhagic telangiectasia using a two-flap nasal closure method. AB - BACKGROUND: Nasal closure has been shown to effectively manage severe epistaxis refractory to other treatments in patients with hereditary hemorrhagic telangiectasia (HHT). The nasal closure procedure may be underutilized because of its surgical complexity and flap breakdown. METHODS: This work is a retrospective review of 13 HHT patients treated for severe epistaxis with nasal closure between 2005 and 2013. Operating room (OR) time, need for revision surgery, preprocedure, and postprocedure epistaxis severity score (ESS), complete blood count values, and Glasgow Benefit Inventory (GBI) questionnaire results were collected for each patient. The technique is described. We characterize a typical nasal closure patient and compare outcomes based on our experience with the traditional 3-flap closure and a simplified 2-flap nasal closure procedure. RESULTS: The average candidate for nasal closure in this series had an ESS of 7.88, hemoglobin (Hgb) of 8.3 g/dL, and received multiple transfusions, iron therapy, and cautery/coagulation procedures. Average ESS subsequent to nasal closure using the 2-flap method is 0.92 and mean GBI score is 56.3. Comparison of 5 patients who underwent the traditional 3-flap nasal closure procedure and 8 patients receiving the 2-flap nasal closure showed no significant difference in postoperative ESS or GBI metrics. Mean operating room times of the traditional and simplified methods were 3.12 hours and 1.44 hours (p = 0.0001). Mean time to first revision for 8 nasal closure patients was 21.5 months. CONCLUSION: In short-term follow-up, the 2-flap procedure showed comparable effectiveness with significantly reduced complexity and operative time compared to the traditional nasal closure method. PMID- 26751608 TI - Integration of albumin-bilirubin (ALBI) score into Barcelona Clinic Liver Cancer (BCLC) system for hepatocellular carcinoma. AB - BACKGROUND AND AIMS: The albumin-bilirubin (ALBI) grade is a recently reported, simpler, more objective, and evidence-based alternative to the Child-Pugh (CP) score for hepatocellular carcinoma (HCC). We aimed to study whether ALBI grade could substitute for CP score in Barcelona Clinic Liver Cancer (BCLC) for HCC. METHODS: An international multicentre cohort (n = 3696) was accrued to compare the prognostic performance of the CP-based and ALBI-based BCLC system, in terms of homogeneity, discriminatory ability, and monotonicity of gradients that were numerically reflected by homogeneity likelihood, linear trend chi-squares, and c indices, respectively. RESULTS: The ALBI grade performed as well as CP score when integrated into the BCLC staging system in terms of predicting clinical outcome of HCC regardless of regions, etiology, and treatment options. CP-based and ALBI based BCLC systems were highly concordant with weighted kappa value of 0.917. All restaged patients showed significantly different clinical outcomes compared with their original stage classification. In particular, ALBI-based BCLC upstaged 83 (2.2%) patients from lower CP-based BC LC stages to ALBI-based BCLC stage D, whose median overall survival was only 3 months. CONCLUSIONS: The overall prognostic performance of ALBI-based and CP-based BCLC systems was similar. It also potentially allows more precise patient selection for clinical trials on systemic agents. PMID- 26751609 TI - Optimization of second harmonic generation of gold nanospheres and nanorods in aqueous solution: the dominant role of surface area. AB - Size and shape of gold nanoparticles (AuNPs) have a strong influence on their second order nonlinear optical properties. In this work, we propose a systematic investigation of surface and shape effects in the case of small gold nanoparticles. Colloidal solutions on AuNPs with different sizes and shapes have been synthesized, i.e. nanospheres (diameters 3.0; 11.6; 15.8; 17.4; 20.0 and 43 nm) and nanorods (aspect ratios 1.47; 1.63 and 2.30). The first hyperpolarizability beta values of these AuNPs have been measured by harmonic light scattering (HLS) at 1064 nm. For nanospheres and nanorods, we found that their beta values are governed by a purely local, dipolar contribution, as confirmed by their surface area dependence. As an important consequence of these surface effects, we have revisited the previously reported aspect ratio dependence of beta values for gold nanorods, and evidenced the predominant influence of nanoparticle area over aspect ratio considerations. PMID- 26751610 TI - Online Pyrophosphate Assay for Analyzing Adenylation Domains of Nonribosomal Peptide Synthetases. AB - Nonribosomal peptide synthetases (NRPSs) produce many important and structurally complex natural products. Because of their architectures, reprogramming NRPSs has long been attempted to access new bioactive compounds. However, detailed characterization of NRPS catalysis and substrate selectivity by adenylation (A) domains is needed to support such efforts. We present a simple coupled NADH/pyrophosphate (PPi ) detection assay for analyzing A domain catalysis in vitro. PPi formation is coupled to the consumption of NADH by four enzymatic steps and is detected spectroscopically (lambda=340 nm) for simple analysis. We demonstrate the effectiveness of this assay with several adenylation domains, including a stand-alone A domain (DltA, cell wall biosynthesis) and an embedded A domain (Tcp10, teicoplanin biosynthesis). Substrate acceptance of the Tcp10 A domain was explored for the first time, thus demonstrating the applicability of the assay for complex, multi-domain NRPSs. PMID- 26751611 TI - Beneficial Properties of Argon After Experimental Subarachnoid Hemorrhage: Early Treatment Reduces Mortality and Influences Hippocampal Protein Expression. AB - OBJECTIVES: Until now, treatment ameliorating early brain injury following subarachnoid hemorrhage has been nonexistent. Here, we evaluate the neuroprotective properties of argon after experimental subarachnoid hemorrhage with mortality as the primary endpoint and functional outcome, as well as hippocampal cellular and molecular stress response as secondary endpoints. DESIGN: Randomized controlled animal study. SETTING: University research laboratory. SUBJECTS: Ninety-eight male Sprague-Dawley rats. INTERVENTIONS: One hour after subarachnoid hemorrhage induction via endovascular perforation technique or sham surgery, a breathing gas mixture containing 50 vol% argon/50 vol% oxygen (argon group) or 50 vol% nitrogen/50 vol% oxygen (control group) was applied for 1 hour. MEASUREMENTS AND MAIN RESULTS: The primary objective was mortality after subarachnoid hemorrhage. Additionally, outcome was assessed via 1) neurologic testing and 2) an open-field test 24 hours after subarachnoid hemorrhage, 3) protein analysis of hippocampal samples for hypoxia-inducible factor 1alpha and heme oxygenase 1, and 4) immunohistochemistry of hippocampal slices to quantify vital neurons. Animals were euthanized 6, 24, or 72 hours after subarachnoid hemorrhage or sham surgery. Occurrence of premature death (death prior to scheduled euthanasia) was assessed. Postconditioning with argon resulted in a reduction of risk with respect to premature death to 20.6% compared with the control group (95% CI, 4.39-96.7). Body weight was higher in the argon group over the entire observation period (p < 0.05). There was no difference in the neuroscore (p = 0.550). Expression of hypoxia-inducible factor 1alpha and heme oxygenase 1 in the hippocampus was increased in the argon group. Higher quantity of vital neurons in the hippocampal samples of the argon group was discovered 24 hours after subarachnoid hemorrhage. CONCLUSIONS: Argon application after experimental subarachnoid hemorrhage met the primary endpoint of reducing the risk of mortality. In addition, higher body weight indicating good overall condition was observed in the argon group over the entire observation period. Regarding the mechanism of action, hypoxia-inducible factor 1alpha-induced heme oxygenase 1 expression resulting in improved survival of neurons may contribute to the beneficial effect of argon application after subarachnoid hemorrhage. PMID- 26751612 TI - Early Circulating Lactate and Glucose Levels After Aneurysmal Subarachnoid Hemorrhage Correlate With Poor Outcome and Delayed Cerebral Ischemia: A Two Center Cohort Study. AB - OBJECTIVE: In critically ill patients, elevated blood lactate at admission is associated with poor outcome, but after aneurysmal subarachnoid hemorrhage, this has not been investigated. We studied the association between early circulating lactate and glucose with delayed cerebral ischemia and poor outcome. Lactate and glucose were both studied, hypothesizing that both may be increased due to sympathetic activation after subarachnoid hemorrhage similar to critically ill patients. DESIGN: Retrospective cohort study. SETTING: ICUs of two academic hospitals in the Netherlands. PATIENTS: Patients with aneurysmal subarachnoid hemorrhage admitted to the ICU within 24 hours after the bleed surviving beyond 48 hours after ICU admission and who had at least one lactate measurement within 24 hours after admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In 285 patients, maximal lactate and glucose levels within the first 24 hours after admission were determined. Early lactate and glucose were related with delayed cerebral ischemia-related infarction and poor outcome (a modified Rankin Scale score of 4, 5, or death at 3 mo). Delayed cerebral ischemia occurred in 84 patients (29%), and 106 patients (39%) had poor outcome. Multivariable analyses were performed with adjustment of established predictors for delayed cerebral ischemia and outcome: age, sex, World Federation of Neurological Surgeons grade at admission and Hijdra sum scores. Early lactate and glucose were strongly related (Spearman rho = 0.55; p < 0.001). Lactate and glucose were both independently associated with delayed cerebral ischemia and poor outcome in multivariable analyses with either lactate or glucose as covariates. When both lactate and glucose were included, only glucose showed an independent association with delayed cerebral ischemia (odds ratio, 1.14; 95% CI, 1.01-1.28) and only lactate showed an independent association with poor outcome (odds ratio, 1.42; 95% CI, 1.11-1.81). CONCLUSIONS: Early lactate and glucose levels after aneurysmal subarachnoid hemorrhage are associated with delayed cerebral ischemia and poor outcome, suggesting that they may be considered in conjunction with other parameters for future prognostic models. PMID- 26751614 TI - Triflate-functionalized calix[6]arenes as versatile building-blocks: application to the synthesis of an inherently chiral Zn(ii) complex. AB - Cavity-based metal complexes can find many applications notably in the fields of catalysis and biomimicry. In this context, it was shown that metal complexes of calix[6]arenes bearing three aza-coordinating arms at the small rim provide excellent structural models of the poly-imidazole sites found in the active site of many metallo-enzymes. All these N-donor ligands were synthesized from the 1,3,5-tris-methoxy-p-tBu-calix[6]arene platform, which presents some limitations in terms of functionalization. Therefore, there is a need for the development of new calix[6]arene-based building-blocks selectively protected at the small rim. Herein we describe the regioselective one step synthesis of two calix[6]arenes decorated with triflate groups, i.e. X6H4Tf2 and X6H3Tf3, from the parent calix[6]arene X6H6. It is shown that the triflate groups can either act as protecting or deactivating groups, allowing the elaboration of sophisticated calixarene-based systems selectively functionalized at the large and/or at the small rim. In addition, X6H3Tf3 is functionalized on the A, B, and D rings and thus gives access to inherently chiral compounds, as demonstrated by the synthesis of a rare example of inherently chiral cavity-based metal complex. PMID- 26751613 TI - Microvesicle Tissue Factor Activity and Interleukin-8 Levels are Associated with Mortality in Patients with Influenza A/H1N1 Infection. AB - OBJECTIVES: To identify plasma biomarkers that can be early predictors of mortality in critically ill patients with primary influenza A/H1N1. DESIGN: A prospective, multicenter, case-cohort pilot study. SETTING: Three academic ICUs. PATIENTS: Fifteen patients with primary influenza A/H1N1 that included seven survivors and eight nonsurvivors. For comparison, age- and gender-matched healthy controls (n = 27) were also studied. INTERVENTIONS: Plasma was prepared from whole blood drawn on ICU admission in patients with influenza (ICU day 1). Microvesicle tissue factor activity, thrombin-antithrombin complexes, and D dimers were measured as procoagulant markers and markers of activation of coagulation. Plasma cytokine levels were measured on the same blood samples in a subset of 12 patients with influenza using the Luminex Multi-Analyte Profiling system (Luminex Corporation, DeSoto, TX). Patients were followed up for the primary outcome of 28-day mortality. MEASUREMENTS AND MAIN RESULTS: The average admission Acute Physiology and Chronic Health Evaluation II score of the patients was 25.5 +/- 9.3, 60% of patients had shock, and the 28-day mortality rate was 53.3% (n = 8/15). Patients with influenza had dysregulated indices of coagulation and inflammation compared with controls. Among the markers of activation of coagulation measured on ICU day 1, only increased microvesicle tissue factor activity was significantly associated with subsequent influenza-related mortality (5.6 +/- 1.2 pg/mL in nonsurvivors vs 1.8 +/- 0.8 pg/mL in survivors; p < 0.05). Interleukin-8 was significantly higher in nonsurvivors compared with survivors (71.8 +/- 29.1 pg/mL, n = 5 vs 17.3 +/- 3.7 pg/mL, n = 7; p < 0.05). In addition, microvesicle tissue factor activity and interleukin-8 levels were significantly and positively correlated (r = 0.60; p = 0.003). Other cytokines, thrombin antithrombin complexes, and D-dimer were not different between nonsurvivors and survivors and did not correlate with illness severity or mortality. CONCLUSIONS: This study identifies an association between plasma interleukin-8 and microvesicle tissue factor activity measured on admission in patients with severe, primary influenza A/H1N1 infection and subsequent mortality. Thus, these biomarkers may serve as very early prognostic markers for patients with influenza A/H1N1. PMID- 26751615 TI - Milk with and without lactoferrin can influence intestinal damage in a pig model of malnutrition. AB - Malnutrition remains a leading contributor to the morbidity and mortality of children under the age of five worldwide. However, the underlying mechanisms are not well understood necessitating an appropriate animal model to answer fundamental questions and conduct translational research into optimal interventions. One potential intervention is milk from livestock that more closely mimics human milk by increased levels of bioactive components that can promote a healthy intestinal epithelium. We tested the ability of cow milk and milk from transgenic cows expressing human lactoferrin at levels found in human milk (hLF milk) to mitigate the effects of malnutrition at the level of the intestine in a pig model of malnutrition. Weaned pigs (3 weeks old) were fed a protein and calorie restricted diet for five weeks, receiving cow, hLF or no milk supplementation daily from weeks 3-5. After three weeks, the restricted diet induced changes in growth, blood chemistry and intestinal structure including villous atrophy, increased ex vivo permeability and decreased expression of tight junction proteins. Addition of both cow and hLF milk to the diet increased growth rate and calcium and glucose levels while promoting growth of the intestinal epithelium. In the jejunum hLF milk restored intestinal morphology, reduced permeability and increased expression of anti-inflammatory IL-10. Overall, this pig model of malnutrition mimics salient aspects of the human condition and demonstrates that cow milk can stimulate the repair of damage to the intestinal epithelium caused by protein and calorie restriction with hLF milk improving this recovery to a greater extent. PMID- 26751616 TI - Picosecond x-ray strain rosette reveals direct laser excitation of coherent transverse acoustic phonons. AB - Using a strain-rosette, we demonstrate the existence of transverse strain using time-resolved x-ray diffraction from multiple Bragg reflections in laser-excited bulk gallium arsenide. We find that anisotropic strain is responsible for a considerable fraction of the total lattice motion at early times before thermal equilibrium is achieved. Our measurements are described by a new model where the Poisson ratio drives transverse motion, resulting in the creation of shear waves without the need for an indirect process such as mode conversion at an interface. Using the same excitation geometry with the narrow-gap semiconductor indium antimonide, we detected coherent transverse acoustic oscillations at frequencies of several GHz. PMID- 26751617 TI - Combinatorial Evolution of Enzymes and Synthetic Pathways Using One-Step PCR. AB - DNA engineering is the fundamental motive driving the rapid development of modern biotechnology. Here, we present a versatile evolution method termed "rapidly efficient combinatorial oligonucleotides for directed evolution" (RECODE) for rapidly introducing multiple combinatorial mutations to the target DNA by combined action of a thermostable high-fidelity DNA polymerase and a thermostable DNA Ligase in one reaction system. By applying this method, we rapidly constructed a variant library of the rpoS promoters (with activity of 8-460%), generated a novel heparinase from the highly specific leech hyaluronidase (with more than 30 mutant residues) and optimized the heme biosynthetic pathway by combinatorial evolution of regulatory elements and pathway enzymes (2500 +/- 120 mg L(-1) with 20-fold increase). The simple RECODE method enabled researchers the unparalleled ability to efficiently create diverse mutant libraries for rapid evolution and optimization of enzymes and synthetic pathways. PMID- 26751619 TI - Effect of Different Mulches under Rainfall Concentration System on Corn Production in the Semi-arid Areas of the Loess Plateau. AB - The ridge and furrow farming system for rainfall concentration (RC) has gradually been popularized to improve the water availability for crops and to increase the water use efficiency (WUE), thereby stabilizing high yields. In the RC system, plastic-covered ridges are rainfall harvesting zones and furrows are planting zones. In this study, we optimized the mulching patterns for RC planting to mitigate the risks of drought during crop production in semi-arid agricultural areas. We conducted a four-year field study to determine the effects on corn production of mulching with 0.08-mm plastic film, maize straw, 8% biodegradable film, liquid film, bare furrow, and conventional flat (CF) farming. We found that RC significantly increased (P > 0.05) the soil moisture storage in the top 0-100 cm layer and the topsoil temperature (0-10 cm) during the corn-growing season. Combining RC with mulching further improved the rain-harvesting, moisture retaining, and yield-increasing effects in furrows. Compared with CF, the four year average yield increased by 1497.1 kg ha(-1) to 2937.3 kg ha(-1) using RC with mulch treatments and the WUE increased by 2.3 kg ha(-1) mm(-1) to 5.1 kg ha( 1) mm(-1). PMID- 26751618 TI - Oral Morphine Pharmacokinetic in Obesity: The Role of P-Glycoprotein, MRP2, MRP3, UGT2B7, and CYP3A4 Jejunal Contents and Obesity-Associated Biomarkers. AB - The objective of our work was to study the association between the jejunal expression levels of P-gp, MRP2, MRP3, UGT2B7, CYP3A4, the ABCB1 c.3435C > T polymorphism, and several obesity-associated biomarkers, as well as oral morphine and glucuronides pharmacokinetics in a population of morbidly obese subjects. The pharmacokinetics of oral morphine (30 mg) and its glucuronides was performed in obese patients candidate to bariatric surgery. A fragment of jejunal mucosa was preserved during surgery. Subjects were genotyped for the ABCB1 single nucleotide polymorphism (SNP) c.3435C > T. The subjects were 6 males and 23 females, with a mean body mass index of 44.8 (35.4-61.9) kg/m(2). The metabolic ratios AUC0-inf M3G/morphine and AUC0-inf M6G/morphine were highly correlated (rs = 0.8, p < 0.0001) and were 73.2 +/- 24.6 (34.7-137.7) and 10.9 +/- 4.1 (3.8-20.6). The pharmacokinetic parameters of morphine and its glucuronides were not associated with the jejunal contents of P-gp, CYP3A4, MRP2, and MRP3. The jejunal content of UGT2B7 was positively associated with morphine AUC0-inf (rs = 0.4, p = 0.03). Adiponectin was inversely correlated with morphine Cmax (rs = -0.44, p = 0.03). None of the factors studied was associated with morphine metabolic ratios. The interindividual variability in the jejunal content of drug transporters and metabolizing enzymes, the ABCB1 gene polymorphism, and the low-grade inflammation did not explain the variability in morphine and glucuronide exposure. High morphine metabolic ratio argued for an increased morphine glucuronidation in morbidly obese patients. PMID- 26751620 TI - Synthesis of Few-Atomic-Layer BN Hollow Nanospheres and Their Applications as Nanocontainers and Catalyst Support Materials. AB - In this work, few-atomic-layer boron nitride (BN) hollow nanospheres were directly synthesized via a modified CVD method followed by subsequent high temperature degassing treatment. The encapsulated impurities in the hollow nanospheres were effectively removed during the reaction process. The BN shells of most nanospheres consisted of 2-6 atomic layers. Because of the low thickness, the obtained BN hollow nanospheres presented excellent performance in many aspects. For instance, they were demonstrated as useful nanocontainers for controllable multistep release of iodine, which could diffuse and be encapsulated into the few-layer BN hollow nanospheres when heating. They were also promising support materials that could markedly increase the photocatalytic activity of TiO2 nanocrystals. PMID- 26751621 TI - The Forgotten One: Lemierre's Syndrome Due to Gram-Negative Rods Prevotella Bacteremia. AB - BACKGROUND: Lemierre's syndrome (LS) is a rare syndrome caused by an acute oropharyngeal infection with metastatic spreading. It was described in 1939 as jugular vein septic thrombophlebitis associated with retropharyngeal infection. Different organisms can cause LS, such as Fusobacterium species, Peptostreptococcus, group B and C, Streptococcus, Staphylococcus, and Enterococcus species, but the most commonly isolated pathogen is Fusobacterium necrophorum, a common oral flora. Management depends on the initial presentation, type of pathogen isolated, and proper selection of antibiotics. CASE REPORT: We report a case of a 22-year-old man with no past medical history, who presented with left jaw pain and progressive left facial area swelling associated with dyspnea. A final diagnosis of LS was made based on criteria of computed tomography (CT) of the neck and the clinical symptoms. The patient was started on broad-spectrum antibiotics. Subsequent imaging of the chest showed pleural effusion with septic emboli. He underwent thoracentesis and chest tube placement. Final blood cultures were remarkable for gram-negative rods - Prevotella anaerobes - which supported the diagnosis of LS. His condition improved, including the dyspnea, and he was discharged on the proper antibiotics coverage with outpatient follow-up. CONCLUSIONS: LS is a rare condition associated with metastatic infection spreading. This syndrome can be associated with further complications, such as pleural effusions and/or empyemas. Early recognition is important to prevent fatal complications and provide adequate antibiotics coverage. We report only the third case in the medical literature of Prevotella induced LS with a secondary complication of pleural effusion. PMID- 26751622 TI - Controlled Flexible Coordination in Tripodal Iron(II) Phosphane Complexes: Effects on Reactivity. AB - The possibility to alter properties of metal complexes without significant steric changes is a useful tool to tailor the reactivity of the complexes. Herein we present the synthesis of iron complexes with the tripodal phosphane ligands Triphos and Triphos(Si) and report on their different coordination properties. Whereas reaction of Triphos(Si) and FeX2 (X = Cl, Br) exclusively afforded (Triphos(Si))FeX2 with a kappa(2)-coordinated ligand, the homologous C-derived Fe complexes show rapid conversion in solution to afford [(Triphos)Fe(CH3CN)3][Fe2Cl6] or [(Triphos)Fe(CH3CN)3][FeBr4], respectively. The structural conversion was found to be temperature- and solvent-dependent and was accompanied by a linear change of the overall magnetization. The different ligand influence was shown to have a significant effect on the ability of (Triphos(Si))FeCl2 and (Triphos)FeCl2 to perform the Sonogashira cross-coupling reaction of 4-iodotoluene and phenyl acetylene as well as the hydrosilylation of acetophenone. The results presented herein show the different coordination properties of two structurally homologous tripodal ligands and demonstrate the importance of geometrically controlled ligand field splitting on the stability and reactivity of metal complexes. The C/Si exchange therefore provides a simple and straightforward tool to manipulate properties and reactivity of metal complexes. PMID- 26751624 TI - Palladium-Catalyzed Alkylarylation of Acrylamides with Unactivated Alkyl Halides. AB - An efficient palladium-catalyzed alkylarylation of acrylamides with unactivated alkyl halides has been developed. This method is highlighted by its broad substrate scope and excellent functional group tolerance. In addition to alkyl halides, fluoroalkyl halides and benzyl bromides also participated well in this transformation. A detailed mechanistic investigation suggests that a radical pathway is probably involved in the cyclization process. PMID- 26751625 TI - Atomic Scale Imaging of Nucleation and Growth Trajectories of an Interfacial Bismuth Nanodroplet. AB - Because of the lack of experimental evidence, much confusion still exists on the nucleation and growth dynamics of a nanostructure, particularly of metal. The situation is even worse for nanodroplets because it is more difficult to induce the formation of a nanodroplet while imaging the dynamic process with atomic resolution. Here, taking advantage of an electron beam to induce the growth of Bi nanodroplets on a SrBi2Ta2O9 platelet under a high resolution transmission electron microscope (HRTEM), we directly observed the detailed growth pathways of Bi nanodroplets from the earliest stage of nucleation that were previously inaccessible. Atomic scale imaging reveals that the dynamics of nucleation involves a much more complex trajectory than previously predicted based on classical nucleation theory (CNT). The monatomic Bi layer was first formed in the nucleation process, which induced the formation of the prenucleated clusters. Following that, critical nuclei for the nanodroplets formed both directly from the addition of atoms to the prenucleated clusters by the classical growth process and indirectly through transformation of an intermediate liquid film based on the Stranski-Krastanov growth mode, in which the liquid film was induced by the self-assembly of the prenucleated clusters. Finally, the growth of the Bi nanodroplets advanced through the classical pathway and sudden droplet coalescence. This study allows us to visualize the critical steps in the nucleation process of an interfacial nanodroplet, which suggests a revision of the perspective of CNT. PMID- 26751623 TI - Reliability and validity of measures of impulsive choice and impulsive action in smokers trying to quit. AB - Cross-sectional research suggests that smokers are more impulsive than are nonsmokers, but few studies have examined relations between impulsiveness and later success in quitting smoking. The purpose of this study was to investigate the reliability and predictive validity of facets of impulsiveness in adult smokers trying to quit. Baseline behavioral measures of impulsive choice (assessed with a delay discounting task) and impulsive action (assessed with a measure of behavioral disinhibition) were used as predictors of smoking cessation success over 12 weeks. The sample included 116 adult (18 years old or older) daily smokers from central New Jersey. Impulsive choice, impulsive action, and self-reported impulsiveness were not significantly related to one another at baseline. Impulsive choice had high test-retest reliability from pre- to postquit, whereas impulsive action was less stable. Test-retest reliability from prequit to 3 weeks' postquit was moderated by achievement of 7-day abstinence. Baseline impulsive action was significantly negatively related to quitting for at least 1 day in the first 2 weeks of a quit attempt and of prolonged abstinence (no relapse over the next 10 weeks). Baseline impulsive choice was robustly associated with biochemically verified 7-day point-prevalence abstinence 12 weeks' postquit, such that those with lower delay discounting were more likely to achieve abstinence. Facets of impulsiveness appear to function largely independently in adult smokers, as indicated by their lack of intercorrelation, differential stability, and differential relations with abstinence. Impulsive action may impede initial quitting, whereas impulsive choice may be an obstacle to maintaining lasting abstinence. PMID- 26751626 TI - Effects of Physical-Exercise-Based Rehabilitation Programs on the Quality of Life of Patients With Parkinson's Disease: A Systematic Review of Randomized Controlled Trials. AB - This study aimed to determine the effects of physical-exercise-based rehabilitation programs on quality of life of patients with Parkinson's disease through a systematic review of randomized clinical trials. For this purpose the following electronic databases were selected: Medline by PubMed, Cochrane, Web of Science, and PEDro. The search strategy included the proposed descriptors in the Medical Subject Headings (MeSH), associated with a sensitive list of terms to search for randomized controlled trials (RCTs), without year and language restrictions. Fourteen studies were potentially relevant, and these studies were included. Physical-exercise-based rehabilitation programs realized 2-4 times a week, 60 min each session, for 6-12 weeks, and follow-up of 3 months promotes significant positive effects on quality of life in Parkinson's disease patients at mild to moderate stages and disease duration around 6 years. PMID- 26751627 TI - Testosterone and estrogen impact social evaluations and vicarious emotions: A double-blind placebo-controlled study. AB - The abilities to "read" other peoples' intentions and emotions, and to learn from their experiences, are critical to survival. Previous studies have highlighted the role of sex hormones, notably testosterone and estrogen, in these processes. Yet it is unclear how these hormones affect social cognition and emotion using acute hormonal administration. In the present double-blind placebo-controlled study, we administered an acute exogenous dose of testosterone or estrogen to healthy female and male volunteers, respectively, with the aim of investigating the effects of these steroids on social-cognitive and emotional processes. Following hormonal and placebo treatment, participants made (a) facial dominance judgments, (b) mental state inferences (Reading the Mind in the Eyes Test), and (c) learned aversive associations through watching others' emotional responses (observational fear learning [OFL]). Our results showed that testosterone administration to females enhanced ratings of facial dominance but diminished their accuracy in inferring mental states. In men, estrogen administration resulted in an increase in emotional (vicarious) reactivity when watching a distressed other during the OFL task. Taken together, these results suggest that sex hormones affect social-cognitive and emotional functions at several levels, linking our results to neuropsychiatric disorders in which these functions are impaired. (PsycINFO Database Record PMID- 26751628 TI - Easy moves: Perceptual fluency facilitates approach-related action. AB - It is well established that processing fluency impacts preference judgments and physiological reactions indicative of affect. Yet, little is known about how fluency influences motivation-related action. Here, we offer a novel demonstration that fluency facilitates action-tendencies related to approach. Four experiments investigated this action effect, its boundary conditions, and concomitant affective responses. Experiment 1 found faster approach movements (reaction times [RTs] to initiate arm flexion) to perceptually fluent stimuli when participants acted to rapidly classify stimuli as either "good" or "bad." Experiment 2 eliminated this fluency effect on action when participants performed nonaffective classifications ("living" or "nonliving"), even though fluency robustly enhanced liking judgments. Experiment 3 demonstrated that fluency can also facilitate approach action that is not immediate, as long as the delayed action involves affective classification. This experiment also found that fluent stimuli elicit genuine hedonic responses, as reflected in facial electromyography (fEMG) activity over zygomaticus "smiling" muscle. Experiment 4 replicated the physiological (fEMG) evidence for hedonic responses to fluent stimuli, but similar to Experiment 2, we observed no fluency effects on actions involving nonaffective classification. The current studies offer the first evidence that perceptual fluency can facilitate approach-related movements, when such movements are embedded in the context of affective decisions. Generally, these results suggest that variations in processing dynamics can flexibly and implicitly shape action-tendencies. (PsycINFO Database Record PMID- 26751630 TI - Suffering and compassion: The links among adverse life experiences, empathy, compassion, and prosocial behavior. AB - Experiencing past adversity traditionally has been linked to negative life outcomes. However, emerging evidence suggests that heterogeneity exists with respect to links between adversity and resilience, with adversity often enhancing cooperation in the face of joint suffering. Here, the authors present 2 studies designed to examine if the severity of past adversity is associated with an enduring propensity for empathy-mediated compassion, and, if so, whether the resulting compassion directly is, in turn, linked to behavior meant to relieve the suffering of others. Using both MTurk and laboratory-based paradigms, the authors find that increasing severity of past adversity predicts increased empathy, which in turn, is linked to a stable tendency to feel compassion for others in need. In addition, they demonstrate that the resulting individual differences in compassion appear to engender behavioral responses meant to assist others (i.e., charitable giving, helping a stranger). PMID- 26751629 TI - Emotional expression in school context, social relationships, and academic adjustment in kindergarten. AB - This study evaluated direct relations of both kindergarteners' (N = 301) naturalistically observed emotion in 2 different school contexts and early kindergarten verbal competence to academic adjustment (i.e., standardized measures of academic achievement, teacher-reported academic skills, teacher reported and observed school engagement) and if these relations were mediated by teacher-reported conflict with students and by peer acceptance. When controlling for verbal competence, positive emotions expressed in the classroom context positively directly predicted academic skills, whereas positive emotions expressed outside class (lunch/recess) negatively predicted academic skills. Negative emotions observed in the classroom context and during lunch/recess negatively predicted academic achievement. Positive emotions observed in both contexts indirectly predicted higher school engagement through its positive relation to peer acceptance; positive emotions expressed in lunch and recess indirectly predicted higher school engagement via lower teacher-student conflict. Negative emotions observed in both contexts also indirectly predicted lower school engagement via higher teacher-student conflict. Furthermore, verbal competence indirectly predicted higher academic adjustment via lower teacher student conflict. Moreover, verbal competence moderated the association between peer acceptance (but not teacher-student conflict) and academic adjustment. Because verbal competence moderated the associations from peer competence, positive emotions in both contexts indirectly predicted higher academic adjustment via higher peer acceptance primarily for children with low, but not high, initial verbal competence. (PsycINFO Database Record PMID- 26751632 TI - Nostalgia fosters self-continuity: Uncovering the mechanism (social connectedness) and consequence (eudaimonic well-being). AB - Nostalgia, a sentimental longing for one's past, is an emotion that arises from self-relevant and social memories. Nostalgia functions, in part, to foster self continuity, that is, a sense of connection between one's past and one's present. This article examined, in 6 experiments, how nostalgia fosters self-continuity and the implications of that process for well-being. Nostalgia fosters self continuity by augmenting social connectedness, that is, a sense of belongingness and acceptance (Experiments 1-4). Nostalgia-induced self-continuity, in turn, confers eudaimonic well-being, operationalized as subjective vitality (i.e., a feeling of aliveness and energy; Experiments 5-6). The findings clarify and expand the benefits of nostalgia for both the self-system and psychological adjustment. (PsycINFO Database Record PMID- 26751631 TI - Leaders' smiles reflect cultural differences in ideal affect. AB - Cultures differ in the emotions they teach their members to value ("ideal affect"). We conducted 3 studies to examine whether leaders' smiles reflect these cultural differences in ideal affect. In Study 1, we compared the smiles of top ranked American and Chinese government leaders, chief executive officers, and university presidents in their official photos. Consistent with findings that Americans value excitement and other high-arousal positive states more than Chinese, American top-ranked leaders (N = 98) showed more excited smiles than Chinese top-ranked leaders (N = 91) across occupations. In Study 2, we compared the smiles of winning versus losing political candidates and higher versus lower ranking chief executive officers and university presidents in the United States and Taiwan/China. American leaders (N = 223) showed more excited smiles than Taiwanese/Chinese leaders (N = 266), regardless of election outcome or ranking. In Study 3, we administered self-report measures of ideal affect in college student samples from 10 different nations (N = 1,267) and then 8 years later, coded the smiles that legislators from those nations showed in their official photos (N = 3,372). The more nations valued excitement and other high arousal positive states, the more their leaders showed excited smiles; similarly, the more nations valued calm and other low-arousal positive states, the more their leaders showed calm smiles. These results held after controlling for national differences in democratization, human development, and gross domestic product per capita. Together, these findings suggest that leaders' smiles reflect the affective states valued by their cultures. PMID- 26751633 TI - Description of a species of Fabaeformiscandona (Ostracoda, Crustacea) from Kushiro Marsh, Hokkaido, Japan, with the nearly complete mitochondrial genomic sequence. AB - BACKGROUND: So far, 16 species of non-marine ostracods have been reported from Kushiro Marsh, Kushiro Shitsugen National Park, eastern Hokkaido, Japan (Hiruta and Smith 2001, Smith and Hiruta 2004). Nine of these species are in Candonidae, the second-most diverse family of non-marine ostracods. This family contains ca. 550 species, or around 25% of the total number of non-marine ostracod species (Martens et al. 2008). NEW INFORMATION: We sampled ostracods in Kushiro Marsh on 27 December 2012 and identified an undescribed species in the family Candonidae, herein described as Fabaeformiscandona kushiroensis sp. nov. This species belongs to the F. acuminata species group and is characterized by the shapes of the elongate, dorsally directed medial and outer lobes on the distal end of each hemipenis. We also determined for this species the sequence of the nearly complete mitochondrial genome, the first record from the order Podocopa. The genome (ca. 17 kbp) contains two ribosomal RNA, 22 transfer RNA, and 13 protein coding genes, as also found in other arthropods for which the mitochondrial genome has been sequenced. The gene arrangement is similar to the pancrustacean ground pattern, except that in the control region there is an approximately 2 kbp tandem repeat region composed of 220-bp motif sequences. We describe the genetic features of the mitochondrial genome, including nucleotide composition and the secondary structures of tRNAs and rRNAs, and compare them with the genome of Vargula hilgendorfii (Myodocopa, Ostracoda). PMID- 26751634 TI - Modeling the Interaction between AFM Tips and Pinned Surface Nanobubbles. AB - Although the morphology of surface nanobubbles has been studied widely with different AFM modes, AFM images may not reflect the real shapes of the nanobubbles due to AFM tip-nanobubble interactions. In addition, the interplay between surface nanobubble deformation and induced capillary force has not been well understood in this context. In our work we used constraint lattice density functional theory to investigate the interaction between AFM tips and pinned surface nanobubbles systematically, especially concentrating on the effects of tip hydrophilicity and shape. For a hydrophilic tip contacting a nanobubble, its hydrophilic nature facilitates its departure from the bubble surface, displaying a weak and intermediate-range attraction. However, when the tip squeezes the nanobubble during the approach process, the nanobubble shows an elastic effect that prevents the tip from penetrating the bubble, leading to a strong nanobubble deformation and repulsive interactions. On the contrary, a hydrophobic tip can easily pierce the vapor-liquid interface of the nanobubble during the approach process, leading to the disappearance of the repulsive force. In the retraction process, however, the adhesion between the tip and the nanobubble leads to a much stronger lengthening effect on nanobubble deformation and a strong long-range attractive force. The trends of force evolution from our simulations agree qualitatively well with recent experimental AFM observations. This favorable agreement demonstrates that our model catches the main intergradient of tip nanobubble interactions for pinned surface nanobubbles and may therefore provide important insight into how to design minimally invasive AFM experiments. PMID- 26751636 TI - Eyes on New Product Development. PMID- 26751635 TI - Safety and Clinical Effects of Mesenchymal Stem Cells Secreting Neurotrophic Factor Transplantation in Patients With Amyotrophic Lateral Sclerosis: Results of Phase 1/2 and 2a Clinical Trials. AB - IMPORTANCE: Preclinical studies have shown that neurotrophic growth factors (NTFs) extend the survival of motor neurons in amyotrophic lateral sclerosis (ALS) and that the combined delivery of these neurotrophic factors has a strong synergistic effect. We have developed a culture-based method for inducing mesenchymal stem cells (MSCs) to secrete neurotrophic factors. These MSC-NTF cells have been shown to be protective in several animal models of neurodegenerative diseases. OBJECTIVE: To determine the safety and possible clinical efficacy of autologous MSC-NTF cells transplantation in patients with ALS. DESIGN, SETTING, AND PARTICIPANTS: In these open-label proof-of-concept studies, patients with ALS were enrolled between June 2011 and October 2014 at the Hadassah Medical Center in Jerusalem, Israel. All patients were followed up for 3 months before transplantation and 6 months after transplantation. In the phase 1/2 part of the trial, 6 patients with early-stage ALS were injected intramuscularly (IM) and 6 patients with more advanced disease were transplanted intrathecally (IT). In the second stage, a phase 2a dose-escalating study, 14 patients with early-stage ALS received a combined IM and IT transplantation of autologous MSC-NTF cells. INTERVENTIONS: Patients were administered a single dose of MSC-NTF cells. MAIN OUTCOMES AND MEASURES: The primary end points of the studies were safety and tolerability of this cell therapy. Secondary end points included the effects of the treatment on various clinical parameters, such as the ALS Functional Rating Scale-Revised score and the respiratory function. RESULTS: Among the 12 patients in the phase 1/2 trial and the 14 patients in the phase 2a trial aged 20 and 75 years, the treatment was found to be safe and well tolerated over the study follow-up period. Most of the adverse effects were mild and transient, not including any treatment-related serious adverse event. The rate of progression of the forced vital capacity and of the ALS Functional Rating Scale Revised score in the IT (or IT+IM)-treated patients was reduced (from -5.1% to 1.2%/month percentage predicted forced vital capacity, P < .04 and from -1.2 to 0.6 ALS Functional Rating Scale-Revised points/month, P = .052) during the 6 months following MSC-NTF cell transplantation vs the pretreatment period. Of these patients, 13 (87%) were defined as responders to either ALS Functional Rating Scale-Revised or forced vital capacity, having at least 25% improvement at 6 months after treatment in the slope of progression. CONCLUSIONS AND RELEVANCE: The results suggest that IT and IM administration of MSC-NTF cells in patients with ALS is safe and provide indications of possible clinical benefits, to be confirmed in upcoming clinical trials. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT01051882 and NCT01777646. PMID- 26751637 TI - Retinal Vein Occlusion in a Multi-Ethnic Asian Population: The Singapore Epidemiology of Eye Disease Study. AB - PURPOSE: To describe the prevalence of retinal vein occlusion (RVO) and its risk factors in a multi-ethnic Asian population. METHODS: This population-based study of 10,033 participants (75.7% response rate) included Chinese, Indian and Malay persons aged 40 years and older. A comprehensive ophthalmic examination, standardized interviews and laboratory blood tests were performed. Digital fundus photographs were assessed for presence of RVO following the definitions used in the Blue Mountains Eye Study. Regression analysis models were constructed to study the relationship between ocular and systemic factors and RVO. Age-specific prevalence rates of RVO were applied to project the number of people affected in Asia from 2013 to 2040. RESULTS: The overall crude prevalence of RVO was 0.72% (n = 71; 95% confidence interval, CI, 0.54-0.87%). The crude prevalence of RVO was similar in Chinese, Indian and Malay participants (p = 0.865). In multivariable regression models, significant risk factors of RVO included increased age (odds ratio, OR, 1.03, 95% CI 1.01-1.06), hypertension (OR 3.65, 95% CI 1.61-8.31), increased serum creatinine (OR 1.04, 95% CI 1.01-1.06, per 10 mmol/L increase), history of heart attack (OR 2.25, 95% CI 1.11-4.54) and increased total cholesterol (OR 1.31, 95% CI 1.07-1.59, per 1 mmol/L increase). None of the ocular parameters were associated with RVO. RVO is estimated to affect up to 16 and 21 million people in Asia by 2020 and 2040, respectively. CONCLUSION: RVO was detected in 0.72% of a multi-ethnic Asian population aged 40-80 years in Singapore. The significant systemic risk factors of RVO are consistent with studies in white populations. PMID- 26751639 TI - Molecular and insecticidal characterization of Vip3A protein producing Bacillus thuringiensis strains toxic against Helicoverpa armigera (Lepidoptera: Noctuidae). AB - Vegetative insecticidal proteins (Vip) represent the second generation of insecticidal proteins produced by Bacillus thuringiensis (Bt) during the vegetative growth stage of growth. Bt-based biopesticides are recognized as viable alternatives to chemical insecticides; the latter cause environmental pollution and lead to the emergence of pest resistance. To perform a systematic study of vip genes encoding toxic proteins, a total of 30 soil samples were collected from diverse locations of Kashmir valley, India, and characterized by molecular and analytical methods. Eighty-six colonies showing Bacillus-like morphology were selected. Scanning electron microscopy observations confirmed the presence of different crystal shapes, and PCR analysis of insecticidal genes revealed a predominance of the lepidopteran-specific vip3 (43.18%) gene followed by coleopteran-specific vip1 (22.72%) and vip2 (15.90%) genes in the isolates tested. Multi-alignment of the deduced amino acid sequences revealed that vip3 sequences were highly conserved, whereas vip1 and vip2 showed adequate differences in amino acid sequences compared with already reported sequences. Screening for toxicity against Helicoverpa armigera larvae was performed using partially purified soluble fractions containing Vip3A protein. The mortality levels observed ranged between 70% and 96.6% in the isolates. The LC50 values of 2 of the native isolates, JK37 and JK88, against H. armigera were found to be on par with that of Bt subsp. kurstaki HD1, suggesting that these isolates could be developed as effective biopesticides against H. armigera. PMID- 26751638 TI - Association of CMV, HBV, or HCV co-infection with vaccine response in adults with well-controlled HIV infection. AB - Even after CD4 count recovery on antiretroviral therapy, HIV infection is associated with decreased response to most vaccines compared to the general population. Chronic infections with viruses such as cytomegalovirus (CMV), hepatitis B virus (HBV), and hepatitis C virus (HCV), which are more prevalent in HIV-infected populations, have been linked to immune dysfunction and decreased vaccine response in the general population. However, whether co-infection with these other viruses contributes to the decreased vaccine response seen in adults with well-controlled HIV infection is unknown. We conducted a secondary analysis of data and serum from adults with well-controlled HIV infection from an inactivated polio vaccine trial (224 subjects) and a pneumococcal conjugate vaccine study (128 subjects). We evaluated the association of CMV, HBV, or HCV co infection with post-vaccination antibody levels using both univariate and multivariate analyses, controlling for factors such as age, race, CD4 count, comorbidities, smoking status, and baseline antibody levels. Ninety-three percent, 7%, and 14% of subjects were co-infected with CMV, HBV, and HCV respectively. On both univariate and multivariate analysis, neither CMV nor HCV co-infection were significantly associated with post-vaccination antibody levels to either vaccine. HBV co-infection was significantly associated with post vaccination antibody concentrations for pneumococcal serotype 7F on univariate analysis and 6A on multivariate analysis, but the association was with higher antibody concentrations. In conclusion, co-infection with CMV, HBV, or HCV does not appear to contribute to the decreased vaccine response seen in adults with well-controlled HIV infection. PMID- 26751640 TI - A simple and versatile design concept for fluorophore derivatives with intramolecular photostabilization. AB - Intramolecular photostabilization via triple-state quenching was recently revived as a tool to impart synthetic organic fluorophores with 'self-healing' properties. To date, utilization of such fluorophore derivatives is rare due to their elaborate multi-step synthesis. Here we present a general strategy to covalently link a synthetic organic fluorophore simultaneously to a photostabilizer and biomolecular target via unnatural amino acids. The modular approach uses commercially available starting materials and simple chemical transformations. The resulting photostabilizer-dye conjugates are based on rhodamines, carbopyronines and cyanines with excellent photophysical properties, that is, high photostability and minimal signal fluctuations. Their versatile use is demonstrated by single-step labelling of DNA, antibodies and proteins, as well as applications in single-molecule and super-resolution fluorescence microscopy. We are convinced that the presented scaffolding strategy and the improved characteristics of the conjugates in applications will trigger the broader use of intramolecular photostabilization and help to emerge this approach as a new gold standard. PMID- 26751641 TI - Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation. AB - Prostate cancer evolution is driven by a combination of epigenetic and genetic alterations such as coordinated chromosomal rearrangements, termed chromoplexy. TMPRSS2-ERG gene fusions found in human prostate tumors are a hallmark of chromoplexy. TMPRSS2-ERG fusions have been linked to androgen signaling and depend on androgen receptor (AR)-coupled gene transcription. Here, we show that dimethylation of KDM1A at K114 (to form K114me2) by the histone methyltransferase EHMT2 is a key event controlling androgen-dependent gene transcription and TMPRSS2-ERG fusion. We identified CHD1 as a KDM1A K114me2 reader and characterized the KDM1A K114me2-CHD1 recognition mode by solving the cocrystal structure. Genome-wide analyses revealed chromatin colocalization of KDM1A K114me2, CHD1 and AR in prostate tumor cells. Together, our data link the assembly of methylated KDM1A and CHD1 with AR-dependent transcription and genomic translocations, thereby providing mechanistic insight into the formation of TMPRSS2-ERG gene fusions during prostate-tumor evolution. PMID- 26751642 TI - Concomitant binding of Afadin to LGN and F-actin directs planar spindle orientation. AB - Polarized epithelia form by oriented cell divisions in which the mitotic spindle aligns parallel to the epithelial plane. To orient the mitotic spindle, cortical cues trigger the recruitment of NuMA-dynein-based motors, which pull on astral microtubules via the protein LGN. We demonstrate that the junctional protein Afadin is required for spindle orientation and correct epithelial morphogenesis of Caco-2 cysts. Molecularly, Afadin binds directly and concomitantly to F-actin and to LGN. We determined the crystallographic structure of human Afadin in complex with LGN and show that it resembles the LGN-NuMA complex. In mitosis, Afadin is necessary for cortical accumulation of LGN and NuMA above the spindle poles, in an F-actin-dependent manner. Collectively, our results depict Afadin as a molecular hub governing the enrichment of LGN and NuMA at the cortex. To our knowledge, Afadin is the first-described mechanical anchor between dynein and cortical F-actin. PMID- 26751643 TI - N(6)-methyladenosine in mRNA disrupts tRNA selection and translation-elongation dynamics. AB - N(6)-methylation of adenosine (forming m(6)A) is the most abundant post transcriptional modification within the coding region of mRNA, but its role during translation remains unknown. Here, we used bulk kinetic and single molecule methods to probe the effect of m(6)A in mRNA decoding. Although m(6)A base-pairs with uridine during decoding, as shown by X-ray crystallographic analyses of Thermus thermophilus ribosomal complexes, our measurements in an Escherichia coli translation system revealed that m(6)A modification of mRNA acts as a barrier to tRNA accommodation and translation elongation. The interaction between an m(6)A-modified codon and cognate tRNA echoes the interaction between a near-cognate codon and tRNA, because delay in tRNA accommodation depends on the position and context of m(6)A within codons and on the accuracy level of translation. Overall, our results demonstrate that chemical modification of mRNA can change translational dynamics. PMID- 26751644 TI - Neil DNA glycosylases promote substrate turnover by Tdg during DNA demethylation. AB - DNA 5-methylcytosine is a dynamic epigenetic mark with important roles in development and disease. In the Tet-Tdg demethylation pathway, methylated cytosine is iteratively oxidized by Tet dioxygenases, and unmodified cytosine is restored via thymine DNA glycosylase (Tdg). Here we show that human NEIL1 and NEIL2 DNA glycosylases coordinate abasic-site processing during TET-TDG DNA demethylation. NEIL1 and NEIL2 cooperate with TDG during base excision: TDG occupies the abasic site and is displaced by NEILs, which further process the baseless sugar, thereby stimulating TDG-substrate turnover. In early Xenopus embryos, Neil2 cooperates with Tdg in removing oxidized methylcytosines and specifying neural-crest development together with Tet3. Thus, Neils function as AP lyases in the coordinated AP-site handover during oxidative DNA demethylation. PMID- 26751676 TI - Resonance control of mid-infrared metamaterials using arrays of split-ring resonator pairs. AB - We present our design, fabrication and characterization of resonance-controllable metamaterials operating at mid-infrared wavelengths. The metamaterials are composed of pairs of back-to-back or face-to-face U-shape split-ring resonators (SRRs). Transmission spectra of the metamaterials are measured using Fourier transform infrared spectroscopy. The results show that the transmission resonance is dependent on the distance between the two SRRs in each SRR pair. The dips in the transmission spectrum shift to shorter wavelengths with increasing distance between the two SRRs for both the back-to-back and face-to-face SRR pairs. The position of the resonance dips in the spectrum can hence be controlled by the relative position of the SRRs. This mechanism of resonance control offers a promising way of developing metamaterials with tunability for optical filters and bio/chemical sensing devices in integrated nano-optics. PMID- 26751646 TI - Identification of two novel ALS2 mutations in infantile-onset ascending hereditary spastic paraplegia. AB - Biallelic mutations of ALS2 cause a clinical spectrum of overlapping autosomal recessive neurodegenerative disorders: infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (ALS2). We report on eleven individuals affected with IAHSP from two consanguineous Pakistani families. A combination of linkage analysis with homozygosity mapping and targeted sequencing identified two novel ALS2 mutations, a c.194T > C (p.Phe65Ser) missense substitution located in the first RCC-like domain of ALS2/alsin and a c.2998delA (p.Ile1000*) nonsense mutation. This study of extended families including a total of eleven affected individuals suggests that a given ALS2 mutation may lead to a phenotype with remarkable intrafamilial clinical homogeneity. PMID- 26751645 TI - Genes involved in stress response and alcohol use among high-risk African American youth. AB - BACKGROUND: Genetic and environmental factors influence substance use behaviors in youth. One of the known environmental risk factors is exposure to life stressors. The aim of this project is to study the interaction between NR3C1 and CRHBP, genes thought to be involved in stress pathways, exposure to stressful life events, and adolescent alcohol use/misuse. METHODS: The sample included 541 African American individuals (ages 13-18) from the Genes, Environment, and Neighborhood Initiative, a subset of the Mobile Youth Survey sample from whom DNA and more extensive phenotypic data were collected. Participants were selected from high-poverty neighborhoods in Mobile, Alabama, with potential exposure to a variety of extreme life stressors. RESULTS: A measure of stressful life events was significantly predictive of alcohol use/misuse. In addition, this association was significantly dependent upon the number of putative risk variants at rs1715749, a single-nucleotide polymorphism (SNP) in CRHBP (P <= .006). There was no significant interaction between NR3C1 and stressful life events with respect to alcohol use/misuse, after taking into account multiple testing. CONCLUSIONS: These findings suggest that CRHBP variants are potentially relevant for adolescent alcohol use/misuse among African American youth populations being reared within the context of stressful life events and warrant replication. PMID- 26751677 TI - Gianotti-Crosti Syndrome following immunization in an 18 months old child. AB - Gianotti-Crosti syndrome (GCS) is an uncommon dermatological condition characterized by distinct, self-limiting, symmetrical, erythematous, papulovesicular eruptions distributed mainly on the extremities, buttocks and face in young children. Although GCS is commonly attributed to viral infections, vaccinations too can rarely precipitate this condition. We report a rare case of GCS following diptheria, pertussis, and tetanus (DPT) and oral polio immunisation in an 18-month-old child along with a review of similar vaccine-induced GCS cases reported in the literature. PMID- 26751679 TI - ApoE Polymorphisms and the Risk of Different Subtypes of Stroke in the Chinese Population: A Comprehensive Meta-Analysis. AB - BACKGROUND AND PURPOSE: Numerous studies have evaluated the association between apolipoprotein E (ApoE) gene polymorphisms and the risk of different subtypes of stroke. However, the results remain uncertain, and few sources of data specific to the Chinese ethnic population contribute to these outstanding questions. Therefore, we performed a meta-analysis to derive a more comprehensive estimate of the association between ApoE polymorphisms and stroke risk in the Chinese population. METHODS: Case-control studies in Chinese and English publications were identified by searching the PubMed, EMBASE, Web of Science, China Nation Knowledge Infrastructure Platform, Wanfang, and VIP databases and by hand searching relevant journals and the reference lists of the retrieved articles. ORs and 95% CIs were applied to assess the strength of the associations. Subgroup and sensitivity analyses were performed to explore between-study heterogeneity. RESULTS: Evidence of a significant association was found between the ApoE epsilon4 allele and different subtypes of stroke (for ischemic stroke (IS): OR 2.19, 95% CI 1.90-2.52, p < 0.001; for intracerebral hemorrhage (ICH): OR 2.08, 95% CI 1.57-2.75, p < 0.001; and for subarachnoid hemorrhage (SAH): OR 2.03, 95% CI 1.28-3.23, p = 0.003) among the Chinese population. In addition, a significant difference in the risk for different subtypes of stroke between epsilon4 carriers and epsilon3epsilon3 genotype carriers was found (for IS: OR 2.41, 95% CI 2.00 2.89, p < 0.001; for ICH: OR 2.41, 95% CI 1.68-3.47, p < 0.001; and for SAH: OR 2.04, 95% CI 1.21-3.45, p = 0.008). CONCLUSION: The ApoE epsilon4 allele may predict an increased risk for different subtypes of stroke, including IS, ICH and SAH, in the Chinese population, and the results of this genotypic analysis may help to identify populations at an increased risk for stroke. Further studies with larger sample sizes are needed to confirm our findings. PMID- 26751678 TI - Inhibition of Hepatitis C Virus in Mice by a Small Interfering RNA Targeting a Highly Conserved Sequence in Viral IRES Pseudoknot. AB - The hepatitis C virus (HCV) internal ribosome entry site (IRES) that directs cap independent viral translation is a primary target for small interfering RNA (siRNA)-based HCV antiviral therapy. However, identification of potent siRNAs against HCV IRES by bioinformatics-based siRNA design is a challenging task given the complexity of HCV IRES secondary and tertiary structures and association with multiple proteins, which can also dynamically change the structure of this cis acting RNA element. In this work, we utilized siRNA tiling approach whereby siRNAs were tiled with overlapping sequences that were shifted by one or two nucleotides over the HCV IRES stem-loop structures III and IV spanning nucleotides (nts) 277-343. Based on their antiviral activity, we mapped a druggable region (nts 313-343) where the targets of potent siRNAs were enriched. siIE22, which showed the greatest anti-HCV potency, targeted a highly conserved sequence across diverse HCV genotypes, locating within the IRES subdomain IIIf involved in pseudoknot formation. Stepwise target shifting toward the 5' or 3' direction by 1 or 2 nucleotides reduced the antiviral potency of siIE22, demonstrating the importance of siRNA accessibility to this highly structured and sequence-conserved region of HCV IRES for RNA interference. Nanoparticle-mediated systemic delivery of the stability-improved siIE22 derivative gs_PS1 siIE22, which contains a single phosphorothioate linkage on the guide strand, reduced the serum HCV genome titer by more than 4 log10 in a xenograft mouse model for HCV replication without generation of resistant variants. Our results provide a strategy for identifying potent siRNA species against a highly structured RNA target and offer a potential pan-HCV genotypic siRNA therapy that might be beneficial for patients resistant to current treatment regimens. PMID- 26751680 TI - Engineering Yarrowia lipolytica for Campesterol Overproduction. AB - Campesterol is an important precursor for many sterol drugs, e.g. progesterone and hydrocortisone. In order to produce campesterol in Yarrowia lipolytica, C-22 desaturase encoding gene ERG5 was disrupted and the heterologous 7 dehydrocholesterol reductase (DHCR7) encoding gene was constitutively expressed. The codon-optimized DHCR7 from Rallus norvegicus, Oryza saliva and Xenapus laevis were explored and the strain with the gene DHCR7 from X. laevis achieved the highest titer of campesterol due to D409 in substrate binding sites. In presence of glucose as the carbon source, higher biomass conversion yield and product yield were achieved in shake flask compared to that using glycerol and sunflower seed oil. Nevertheless, better cell growth rate was observed in medium with sunflower seed oil as the sole carbon source. Through high cell density fed-batch fermentation under carbon source restriction strategy, a titer of 453+/-24.7 mg/L campesterol was achieved with sunflower seed oil as the carbon source, which is the highest reported microbial titer known. Our study has greatly enhanced campesterol accumulation in Y. lipolytica, providing new insight into producing complex and desired molecules in microbes. PMID- 26751682 TI - Social and environmental adversities, neurobiological processes and mental disorders. PMID- 26751681 TI - Replication of the Shrimp Virus WSSV Depends on Glutamate-Driven Anaplerosis. AB - Infection with the white spot syndrome virus (WSSV) induces a metabolic shift in shrimp that resembles the "Warburg effect" in mammalian cells. This effect is triggered via activation of the PI3K-Akt-mTOR pathway, and it is usually accompanied by the activation of other metabolic pathways that provide energy and direct the flow of carbon and nitrogen. Here we show that unlike the glutamine metabolism (glutaminolysis) seen in most cancer cells to double deaminate glutamine to produce glutamate and the TCA cycle intermediate alpha-ketoglutarate (alpha-KG), at the WSSV genome replication stage (12 hpi), although glutaminase (GLS) expression was upregulated, only glutamate was taken up by the hemocytes of WSSV-infected shrimp. At the same time, we observed an increase in the activity of the two enzymes that convert glutamate to alpha-KG, glutamate dehydrogenase (GDH) and aspartate aminotransferase (ASAT). alpha-ketoglutarate concentration was also increased. A series of inhibition experiments suggested that the up regulation of GDH is regulated by mTORC2, and that the PI3K-mTORC1 pathway is not involved. Suppression of GDH and ASAT by dsRNA silencing showed that both of these enzymes are important for WSSV replication. In GDH-silenced shrimp, direct replenishment of alpha-KG rescued both ATP production and WSSV replication. From these results, we propose a model of glutamate-driven anaplerosis that fuels the TCA cycle via alpha-KG and ultimately supports WSSV replication. PMID- 26751684 TI - Superresolution and Fluorescence Dynamics Evidence Reveal That Intact Liposomes Do Not Cross the Human Skin Barrier. AB - In this study we use the combination of super resolution optical microscopy and raster image correlation spectroscopy (RICS) to study the mechanism of action of liposomes as transdermal drug delivery systems in human skin. Two different compositions of liposomes were applied to newly excised human skin, a POPC liposome and a more flexible liposome containing the surfactant sodium cholate. Stimulated emission depletion microscopy (STED) images of intact skin and cryo sections of skin treated with labeled liposomes were recorded displaying an optical resolution low enough to resolve the 100 nm liposomes in the skin. The images revealed that virtually none of the liposomes remained intact beneath the skin surface. RICS two color cross correlation diffusion measurements of double labeled liposomes confirmed these observations. Our results suggest that the liposomes do not act as carriers that transport their cargo directly through the skin barrier, but mainly burst and fuse with the outer lipid layers of the stratum corneum. It was also found that the flexible liposomes showed a greater delivery of the fluorophore into the stratum corneum, indicating that they functioned as chemical permeability enhancers. PMID- 26751683 TI - The Molecular Basis of Polyunsaturated Fatty Acid Interactions with the Shaker Voltage-Gated Potassium Channel. AB - Voltage-gated potassium (KV) channels are membrane proteins that respond to changes in membrane potential by enabling K+ ion flux across the membrane. Polyunsaturated fatty acids (PUFAs) induce channel opening by modulating the voltage-sensitivity, which can provide effective treatment against refractory epilepsy by means of a ketogenic diet. While PUFAs have been reported to influence the gating mechanism by electrostatic interactions to the voltage sensor domain (VSD), the exact PUFA-protein interactions are still elusive. In this study, we report on the interactions between the Shaker KV channel in open and closed states and a PUFA-enriched lipid bilayer using microsecond molecular dynamics simulations. We determined a putative PUFA binding site in the open state of the channel located at the protein-lipid interface in the vicinity of the extracellular halves of the S3 and S4 helices of the VSD. In particular, the lipophilic PUFA tail covered a wide range of non-specific hydrophobic interactions in the hydrophobic central core of the protein-lipid interface, while the carboxylic head group displayed more specific interactions to polar/charged residues at the extracellular regions of the S3 and S4 helices, encompassing the S3-S4 linker. Moreover, by studying the interactions between saturated fatty acids (SFA) and the Shaker KV channel, our study confirmed an increased conformational flexibility in the polyunsaturated carbon tails compared to saturated carbon chains, which may explain the specificity of PUFA action on channel proteins. PMID- 26751685 TI - Boolean Combinations of Implicit Functions for Model Clipping in Computer Assisted Surgical Planning. AB - This paper proposes an interactive method of model clipping for computer-assisted surgical planning. The model is separated by a data filter that is defined by the implicit function of the clipping path. Being interactive to surgeons, the clipping path that is composed of the plane widgets can be manually repositioned along the desirable presurgical path, which means that surgeons can produce any accurate shape of the clipped model. The implicit function is acquired through a recursive algorithm based on the Boolean combinations (including Boolean union and Boolean intersection) of a series of plane widgets' implicit functions. The algorithm is evaluated as highly efficient because the best time performance of the algorithm is linear, which applies to most of the cases in the computer assisted surgical planning. Based on the above stated algorithm, a user-friendly module named SmartModelClip is developed on the basis of Slicer platform and VTK. A number of arbitrary clipping paths have been tested. Experimental results of presurgical planning for three types of Le Fort fractures and for tumor removal demonstrate the high reliability and efficiency of our recursive algorithm and robustness of the module. PMID- 26751686 TI - Neurogenomics: Challenges and opportunities for Ghana. AB - The application of genomic tools and technologies has shown the potential to help improve healthcare and our understanding of disease mechanisms. While genomic tools are increasingly being applied to research on infectious diseases, malaria and neglected tropical diseases in Africa, an area that has seen little application of genomic approaches on this continent is neuroscience. In this article, we examined the prospects of developing neurogenomics research and its clinical use in Ghana, one of the African countries actively involved in genomics research. We noted that established international research funding sources and foundations in genomic research such as H3ABioNet nodes established at a couple of research centres in Ghana provide excellent platforms for extending the usage of genomic tools and techniques to neuroscience-related research areas. However, existing challenges such as the (i) lack of degree programmes in neuroscience, genomics and bioinformatics; (ii) low availability of infrastructure and appropriately-trained scientists; and (iii) lack of local research funding opportunities, need to be addressed. To promote and safeguard the long-term sustainability of neurogenomics research in the country, the impact of the existing challenges and possible ways of addressing them have been discussed. PMID- 26751687 TI - Assessment of Current Malaria Status in Light of the Ongoing Control Interventions, Socio-Demographic and Environmental Variables in Jiga Area, Northwest Ethiopia. AB - Following substantial decline in malaria burden in Ethiopia, the country is planning to eliminate malaria in certain low transmission settings by 2020. To evaluate the attainability of this goal in-depth examination of malaria parasite carriage at community level is necessary. This study was, therefore, aimed at assessing the current situation of malaria in relation to ongoing control interventions in Jiga area, Jabi Tehnan District in northwest Ethiopia. A cross sectional household (HH) survey was conducted in November-December 2013. Out of 2,574 HHs (11,815 people) in the entire Jabi Tehnan District, 392 (accommodating 1911 people) were randomly selected from three purposely selected villages. One randomly selected member from each selected HH was tested for malaria using rapid diagnostic test (mRDT). All participants tested for malaria (n = 392) were afebrile (axillary temperature <37.5 degrees C). Eleven individuals (2.8%, 95% confidence interval (CI):1.2-4.4%) were found to be mRDT positive. Most HHs (95.9%, 95% CI: 93.5-97.5%) had at least 1 long-lasting insecticidal net (LLIN). Insecticide residual spraying (IRS) coverage the last six months was 85.5% (95% CI: 82.0-88.9%). Malaria prevalence remains unexpectedly high despite high HH coverage of control interventions. PMID- 26751688 TI - Phylogenetic Relationships of Five Asian Schilbid Genera Including Clupisoma (Siluriformes: Schilbeidae). AB - The phylogenetic relationships of Asian schilbid catfishes of the genera Clupisoma, Ailia, Horabagrus, Laides and Pseudeutropius are poorly understood, especially those of Clupisoma. Herein, we reconstruct the phylogeny of 38 species of catfishes belonging to 28 genera and 14 families using the concatenated mitochondrial genes COI, cytb, and 16S rRNA, as well as the nuclear genes RAG1 and RAG2. The resulting phylogenetic trees consistently place Clupisoma as the sister taxon of Laides, and the five representative Asian schilbid genera form two monophyletic groups with the relationships (Ailia (Laides, Clupisoma)) and (Horabagrus, Pseudeutropius). The so-called "Big Asia" lineage relates distantly to African schilbids. Independent analyses of the mitochondrial and nuclear DNA data yield differing trees for the two Asian schilbid groups. Analyses of the mitochondrial gene data support a sister-group relationship for (Ailia (Laides, Clupisoma)) and the Sisoroidea and a sister-taxon association of (Horabagrus, Pseudeutropius) and the Bagridae. In contrast, analyses of the combined nuclear data indicate (Ailia (Laides, Clupisoma)) to be the sister group to (Horabagrus, Pseudeutropius). Our results indicate that the Horabagridae, recognized by some authors as consisting of Horabagrus, Pseudeutropius and Clupisoma does not include the latter genus. We formally erect a new family, Ailiidae fam. nov. for a monophyletic Asian group comprised of the genera Ailia, Laides and Clupisoma. PMID- 26751689 TI - First Direct Evidence for Natal Wintering Ground Fidelity and Estimate of Juvenile Survival in the New Zealand Southern Right Whale Eubalaena australis. AB - Juvenile survival and recruitment can be more sensitive to environmental, ecological and anthropogenic factors than adult survival, influencing population level processes like recruitment and growth rate in long-lived, iteroparous species such as southern right whales. Conventionally, Southern right whales are individually identified using callosity patterns, which do not stabilise until 6 12 months, by which time the whale has left its natal wintering grounds. Here we use DNA profiling of skin biopsy samples to identify individual Southern right whales from year of birth and document their return to the species' primary wintering ground in New Zealand waters, the Subantarctic Auckland Islands. We find evidence of natal fidelity to the New Zealand wintering ground by the recapture of 15 of 57 whales, first sampled in year of birth and available for subsequent recapture, during winter surveys to the Auckland Islands in 1995-1998 and 2006-2009. Four individuals were recaptured at the ages of 9 to 11, including two females first sampled as calves in 1998 and subsequently resampled as cows with calves in 2007. Using these capture-recapture records of known-age individuals, we estimate changes in survival with age using Cormack-Jolly-Seber models. Survival is modelled using discrete age classes and as a continuous function of age. Using a bootstrap method to account for uncertainty in model selection and fitting, we provide the first direct estimate of juvenile survival for this population. Our analyses indicate a high annual apparent survival for juveniles at between 0.87 (standard error (SE) 0.17, to age 1) and 0.95 (SE 0.05: ages 2-8). Individual identification by DNA profiling is an effective method for long-term demographic and genetic monitoring, particularly in animals that change identifiable features as they develop or experience tag loss over time. PMID- 26751690 TI - Effect of anti-tuberculosis drugs on hematological profiles of tuberculosis patients attending at University of Gondar Hospital, Northwest Ethiopia. AB - BACKGROUND: Tuberculosis (TB) treatment may present significant hematological disorder and some anti-TB drugs also have serious side effects. Although many other diseases may be reflected by the blood and its constituents, the abnormalities of red cells, white cells, platelets, and clotting factors are considered to be primary hematologic disorder as a result of tuberculosis treatment. The aim of this study was to determine hematological profiles of TB patients before and after intensive phase treatment. OBJECTIVE: The aim of this study was to determine hematological profiles of TB patients before and after intensive phase treatment. METHODS: Smear positive new TB patients were recruited successively and socio-demographic characteristics were collected using pre tested questionnaire. About 5 ml of venous blood was collected from each patient and the hematological profiles were determined using Mindry BC 3000 plus automated hematology analyzer. RESULT: The hematological profiles of TB patients showed statistically significant difference in hematocrit (38.5 % versus 35.7 %), hemoglobin (12.7 g/lversus11.8 g/l) and platelet (268 * 10(3)/MUlversus239 * 10(3)/MUl) values of patients before initiation of treatment and after completion of the intensive phase of tuberculosis treatment, respectively (P < 0.05). The red cell distribution width (RDW) of treatment naive TB patients was by far lower (17.6 +/- 7.09 %) than the corresponding RDW (31.9 +/- 5.19 %) of intensive phase treatment completed patients. Among TB patients that had high platelet distribution width (PDW) (n = 11) before initiation of TB treatment, 10 demonstrated lower PDW values after completion of the intensive phase. There was no significant difference on total white blood cell count among TB patients before and after completion of the 2 month treatment. CONCLUSION: The levels of hemoglobin, hematocrit and platelet count of the TB patients were significantly lowered after completion of the intensive phase of TB treatment. Significant variation of the RDW and PDW were also observed among treatment naive and treatment completed patients. Hematological abnormalities resulted from TB treatment should be assessed continuously throughout the course of tuberculosis therapy. PMID- 26751691 TI - ALDH3A1 Plays a Functional Role in Maintenance of Corneal Epithelial Homeostasis. AB - Aldehyde dehydrogenase 1A1 (ALDH1A1) and ALDH3A1 are corneal crystallins. They protect inner ocular tissues from ultraviolet radiation (UVR)-induced oxidative damage through catalytic and non-catalytic mechanisms. Additionally, ALDH3A1 has been postulated to play a regulatory role in the corneal epithelium based on several studies that report an inverse association between ALDH3A1 expression and corneal cell proliferation. The underlying molecular mechanisms and the physiological significance of such association remain poorly understood. In the current study, we established Tet-On human corneal epithelial cell (hTCEpi) lines, which express tetracycline-inducible wild-type (wt) or catalytically inactive (mu) ALDH3A1. Utilizing this cellular model system, we confirmed that human ALDH3A1 decreases corneal cell proliferation; importantly, this effect appears to be partially mediated by its enzymatic activity. Mechanistically, wt ALDH3A1, but not mu-ALDH3A1, promotes sequestering of tumor suppressor p53 in the nucleus. In the mouse cornea, however, augmented cell proliferation is noted only in Aldh1a1(-/-)/3a1(-/-) double knockout (DKO) mice, indicating in vivo the anti proliferation effect of ALDH3A1 can be rescued by the presence of ALDH1A1. Interestingly, the hyper-proliferative epithelium of the DKO corneas display nearly complete loss of p53 expression, implying that p53 may be involved in ALDH3A1/1A1-mediated effect. In hTCEpi cells grown in high calcium concentration, mRNA levels of a panel of corneal differentiation markers were altered by ALDH3A1 expression and modulated by its enzyme activity. In conclusion, we show for the first time that: (i) ALDH3A1 decreases corneal epithelial proliferation through both non-enzymatic and enzymatic properties; (ii) ALDH1A1 contributes to the regulation of corneal cellular proliferation in vivo; and (iii) ALDH3A1 modulates corneal epithelial differentiation. Collectively, our studies indicate a functional role of ALDH3A1 in the maintenance of corneal epithelial homeostasis by simultaneously modulating proliferation and differentiation through both enzymatic and non-enzymatic mechanisms. PMID- 26751692 TI - Black Ginseng Extract Counteracts Streptozotocin-Induced Diabetes in Mice. AB - Black ginseng, a new type of processed ginseng that has a unique ginsenoside profile, has been shown to display potent pharmacological activities in in vitro and in vivo models. Although red ginseng is considered beneficial for the prevention of diabetes, the relationship between black ginseng and diabetes is unknown. Therefore, this study was designed to evaluate the anti-diabetic potential of black ginseng extract (BGE) in streptozotocin (STZ)-induced insulin deficient diabetic mice, in comparison with red ginseng extract (RGE). HPLC analyses showed that BGE has a different ginsenoside composition to RGE; BGE contains Rg5 and compound k as the major ginsenosides. BGE at 200 mg/kg reduced hyperglycemia, increased the insulin/glucose ratio and improved islet architecture and beta-cell function in STZ-treated mice. The inhibition of beta cell apoptosis by BGE was associated with suppression of the cytokine-induced nuclear factor-kappaB-mediated signaling pathway in the pancreas. Moreover, these anti-diabetic effects of BGE were more potent than those of RGE. Collectively, our data indicate that BGE, in part by suppressing cytokine-induced apoptotic signaling, protects beta-cells from oxidative injury and counteracts diabetes in mice. PMID- 26751693 TI - Effects of static stretching of knee musculature on patellar alignment and knee functional disability in male patients diagnosed with knee extension syndrome: A single-group, pretest-posttest trial. AB - BACKGROUND: Knee extension (Kext) syndrome is based on movement system impairments and is described as knee pain associated with quadriceps stiffness. OBJECTIVE: To investigate the effects of 3 times per week for 4 weeks static stretching of knee musculature on patellar alignment and knee functional disability in male Kext syndrome patients. DESIGN: A single-group, pretest posttest clinical trial. SETTING: Hazrat-e-Rasoul Akram Hospital. PARTICIPANTS: Forty-six male Kext syndrome patients aged 18-35 years. METHODS: Knee functional disability was assessed by the Kujala questionnaire. Patellar tilt was assessed using the skyline view X-ray. In addition, patella alta was assessed by X-ray using the Insall-Salvati ratio. After intervention, changes in knee flexion extension range of motion (ROM) and hip adduction were assessed by goniometer and inclinometer. Changes in patellar tilt and patella alta were evaluated. Correlations between muscles length, patellar tilt and knee functional disability were also evaluated. RESULTS: The mean of patellar tilt in male Kext syndrome patients was 15.19 degrees . Only the correlation between rectus femoris shortness and patellar tilt (P = 0.002) and the correlation between rectus femoris shortness and knee functional disability (P = 0.037) were significant. Patella alta was not severe in male Kext syndrome patients (1.28 +/- 0.10). Knee flexion-extension ROM and femoral adduction increased significantly after a 12 session stretching programme (P < 0.0001). CONCLUSION: The results demonstrated that rectus femoris shortness had higher correlation with patellar tilt and knee functional disability than iliotibial band and hamstring shortness. Stretching was effective in reducing patellar tilt, patella alta, knee functional disability, increasing knee ROM and hip adduction in these patients. PMID- 26751694 TI - Multidetector computed tomography versus platelet/spleen diameter ratio as methods for the detection of gastroesophageal varices. AB - BACKGROUND: All patients with liver cirrhosis should undergo screening endoscopy, but there are limitations and this approach places a heavy burden upon endoscopy units. The aim of this study was to compare multidetector computed tomography (MDCT) and the platelet/spleen diameter ratio as non-invasive methods for the detection of gastroesophageal varices. METHODS: The study included 38 cirrhotics who underwent upper gastrointestinal (GI) endoscopy and MDCT within one month. Two radiologists reviewed the scans, in order to determine the presence and the size of varices. Blood tests and measurement of the spleen maximum diameter were also carried out and the platelet/spleen diameter ratio was calculated. Endoscopy was considered the gold standard and the results of the two methods were compared to it. RESULTS: Varices were detected by upper GI endoscopy in 24 of 38 patients. The mean sensitivity and specificity of MDCT for the two observers was 86.1% and 57.1% respectively. In patients with large varices (>5 mm), the sensitivity was 100% (4/4). Using 909 as a cut-off value of the platelet/spleen diameter ratio this method yielded a sensitivity of 56.5% and a specificity of 35.7%. The difference in sensitivity and specificity between the two methods was statistically significant P<0.05. CONCLUSION: MDCT was accurate for the detection of gastroesophageal varices, especially those with clinically significant size (>5 mm), and superior to platelet/spleen diameter ratio. MDCT could replace, in selected patients, upper GI endoscopy as a method for detecting gastroesophageal varices in cirrhotic patients. PMID- 26751697 TI - Pancreatic Kininogenase Ameliorates Renal Fibrosis in Streptozotocin Induced Diabetic Nephropathy Rat. AB - BACKGROUND/AIMS: We aimed to evaluate whether pancreatic kininogenase (PKase) can relieve renal fibrosis and investigate its mechanisms in diabetic nephropathy (DN) rats Methods: We established streptozotocin (STZ) induced-DN rats. After treatment with PKase for 4 weeks, urinary weight, urinary protein content and blood glucose concentration were detected, and then renal histopathological changes were examined using Hematoxylin and Eosin (H&E) and Masson's thrchrome staining. In addition, the expressions of miR-433, transforming growth factor beta1 (TGF-beta1) and antizyme inhibitor 1 (Azin1) were detected by qRT-PCR and/or western blotting. RESULTS: PKase reduced urinary weight, urinary protein contents and blood glucose concentrations. PKase treated DN rats exhibited less renal fibrosis than untreated DN rats (P < 0.05). Furthermore, the expression levels of TGF-beta and miR-433 were reduced (P < 0.05), while Azin1 expression was increased in renal tissues of PKase treated DN rats compared with untreated DN rats (P < 0.05). CONCLUSIONS: PKase might not only inhibit the development of DN by reducing urinary weight, urinary protein content and blood glucose concentration in DN rats, but also relieve renal fibrosis in DN rats through inhibiting the expression of TGF-beta1, and miR-433 and Azin1 might involve in this process. PMID- 26751695 TI - Protection against Experimental Stroke by Ganglioside GM1 Is Associated with the Inhibition of Autophagy. AB - Ganglioside GM1, which is particularly abundant in the central nervous system (CNS), is closely associated with the protection against several CNS disorders. However, controversial findings have been reported on the role of GM1 following ischemic stroke. In the present study, using a rat middle cerebral artery occlusion (MCAO) model, we investigated whether GM1 can protect against ischemic brain injury and whether it targets the autophagy pathway. GM1 was delivered to Sprague-Dawley male rats at 3 doses (25 mg/kg, 50 mg/kg, 100 mg/kg) by intraperitoneal injection soon after reperfusion and then once daily for 2 days. The same volume of saline was given as a control. Tat-Beclin-1, a specific autophagy inducer, was administered by intraperitoneal injection at 24 and 48 hours post-MCAO. Infarction volume, mortality and neurological function were assessed at 72 hours after ischemic insult. Immunofluorescence and Western blotting were performed to determine the expression of autophagy-related proteins P62, LC3 and Beclin-1 in the penumbra area. No significant changes in mortality and physiological variables (heart rate, blood glucose levels and arterial blood gases) were observed between the different groups. However, MCAO resulted in enhanced conversion of LC3-I into LC3-II, P62 degradation, high levels of Beclin 1, a large area infarction (26.3+/-3.6%) and serious neurobehavioral deficits. GM1 (50 mg/kg) treatment significantly reduced the autophagy activation, neurobehavioral dysfunctions, and infarction volume (from 26.3% to 19.5%) without causing significant adverse side effects. However, this biological function could be abolished by Tat-Beclin-1. IN CONCLUSION: GM1 demonstrated safe and robust neuroprotective effects that are associated with the inhibition of autophagy following experimental stroke. PMID- 26751698 TI - Improving patient safety: should we focus on implementing safety measures rather than searching for more evidence? PMID- 26751696 TI - Abnormal Skeletal Muscle Regeneration plus Mild Alterations in Mature Fiber Type Specification in Fktn-Deficient Dystroglycanopathy Muscular Dystrophy Mice. AB - Glycosylated alpha-dystroglycan provides an essential link between extracellular matrix proteins, like laminin, and the cellular cytoskeleton via the dystrophin glycoprotein complex. In secondary dystroglycanopathy muscular dystrophy, glycosylation abnormalities disrupt a complex O-mannose glycan necessary for muscle structural integrity and signaling. Fktn-deficient dystroglycanopathy mice develop moderate to severe muscular dystrophy with skeletal muscle developmental and/or regeneration defects. To gain insight into the role of glycosylated alpha dystroglycan in these processes, we performed muscle fiber typing in young (2, 4 and 8 week old) and regenerated muscle. In mice with Fktn disruption during skeletal muscle specification (Myf5/Fktn KO), newly regenerated fibers (embryonic myosin heavy chain positive) peaked at 4 weeks old, while total regenerated fibers (centrally nucleated) were highest at 8 weeks old in tibialis anterior (TA) and iliopsoas, indicating peak degeneration/regeneration activity around 4 weeks of age. In contrast, mature fiber type specification at 2, 4 and 8 weeks old was relatively unchanged. Fourteen days after necrotic toxin-induced injury, there was a divergence in muscle fiber types between Myf5/Fktn KO (skeletal muscle specific) and whole animal knockout induced with tamoxifen post development (Tam/Fktn KO) despite equivalent time after gene deletion. Notably, Tam/Fktn KO retained higher levels of embryonic myosin heavy chain expression after injury, suggesting a delay or abnormality in differentiation programs. In mature fiber type specification post-injury, there were significant interactions between genotype and toxin parameters for type 1, 2a, and 2x fibers, and a difference between Myf5/Fktn and Tam/Fktn study groups in type 2b fibers. These data suggest that functionally glycosylated alpha-dystroglycan has a unique role in muscle regeneration and may influence fiber type specification post-injury. PMID- 26751701 TI - Protoporphyrin IX-loaded magnetoliposomes as a potential drug delivery system for photodynamic therapy: Fabrication, characterization and in vitro study. AB - BACKGROUND: Protoporphyrin IX (PpIX) is a well-known photosensitizer that has great potential for use in photodynamic therapy (PDT). However, aggregation behavior of PpIX in neutral water makes it inappropriate for physiological studies. PpIX-loaded magnetoliposomes (MLs) were fabricated to increase PpIX biocompatibility. PpIX-loaded ML physical properties were characterized, and PpIX loaded ML drug release behavior was investigated under the influence of an external magnetic field and heat. Toxicity and photodynamic effects of the complex were also examined using in vitro experiments with MCF-7 human breast cancer cells. METHODS: The magnetoliposomes were prepared with DPPC, DSPE-PEG2000 lipids and Fe3O4 nanoparticles. The toxicity and in vitro photodynamic effects of the PpIX-loaded MLs at various concentrations were studied using the MCF-7 cell line. RESULTS: The produced PpIX-loaded MLs exhibited an average hydrodynamic diameter of 221nm; however, TEM measurements indicated that the diameter of the PpIX-loaded MLs varied between 166 and 720nm. The iron content of the MLs affected cell viability less than the content of the iron free liposomes. Cell viability was reduced to 66% when the concentration of the PpIX-loaded MLs was 350nM, but when white light was applied for 5min, all of the cells that were exposed to concentrations of 250nM and higher PpIX died within 24h. CONCLUSION: The results of this study demonstrated the effective application of PpIX-loaded MLs for in vitro photodynamic therapy at nanomolar concentrations. The results also indicated that an LED light source provided sufficient energy to stimulate the PpIX molecules. PMID- 26751700 TI - The clinical trial on the safety and effectiveness of the photodynamic diagnosis of non-muscle-invasive bladder cancer using fluorescent light-guided cystoscopy after oral administration of 5-aminolevulinic acid (5-ALA). AB - OBJECTIVE: To examine the utility and safety of photodynamic diagnosis (PDD) after oral administration of 5-aminolevulinic acid (5-ALA) (ALA-PDD) of non muscle-invasive bladder cancer (NMIBC) using fluorescent-light (FL)-cystoscopy. METHODS: The study was a single-arm, open-label, multi-center prospective study on ALA-PDD of NMIBC, with safety as the primary endpoint and efficacy as the secondary endpoint. Diagnostic potential was evaluated through comparisons with the conventional diagnostic method using a white-light (WL)-source. Clinically recommended doses were also examined. Oral administration of 5-ALA (1.0g/50mL) was performed 180-240min before FL-cystoscopy, and positive or negative results were judged using a WL-source and based on presence or absence of red fluorescence on exposure to a blue FL-source. RESULTS: Regarding safety, the adverse drug reactions were observed as grade 1 pruritus in 1 patient (0.6%). As for efficacy, specificity and positive predictability were lower than those of a WL-source, but sensitivity was higher with a FL-source than with a WL-source. The proportion of patients with tumors detected only by FL-cystoscopy was greater than the proportion of patients with tumors detected only by conventional WL cystoscopy. Moreover, not only sensitivity, but also the proportion of patients with tumors detected only by FL-cystoscopy, was highest among patients who received 5-ALA at ?20mg/kg/body. CONCLUSIONS: ALA-PDD was shown to be safe and effective. Furthermore, diagnostic accuracy of PDD increased with increased dose of 5-ALA, and the recommended dose was determined as ?20mg/kg/body in the present study. PMID- 26751703 TI - Preventing aspartimide formation in Fmoc SPPS of Asp-Gly containing peptides- practical aspects of new trialkylcarbinol based protecting groups. AB - In our efforts to develop a universal solution to the problem of aspartimide formation in Fmoc SPPS, we investigated the application of our new beta trialkylmethyl protected aspartic acid building blocks to the synthesis of peptides containing the Asp-Gly motif. The N(alpha)-Fmoc aspartic acid beta-tri (ethyl/propyl/butyl)methyl esters were used in the synthesis of the classic model peptide scorpion toxin II (VKDGYI), and their effectiveness in minimising aspartimide formation during extended piperidine treatments was evaluated. Furthermore, we compared their efficacy against that of the commonly used approach of adding acids to the Fmoc deprotection solution. Finally, we applied our aspartic acid building blocks to the stepwise Fmoc SPPS of teduglutide, a human GLP-2 analogue, whose synthesis is made challenging by extensive aspartimide formation. In all experiments, our approach led to almost complete reduction of aspartimide formation with accompanied suppression of aspartic acid epimerisation. PMID- 26751702 TI - Choroidal Vascularity Index (CVI)--A Novel Optical Coherence Tomography Parameter for Monitoring Patients with Panuveitis? AB - PURPOSE: To compute choroidal vascularity index (CVI) using an image binarization tool on enhanced depth imaging (EDI)-optical coherence tomography (OCT) scans as a non-invasive optical tool to monitor progression in panuveitis and to investigate the utility of volumetric data from EDI-OCT scans using custom image analysis software. MATERIALS AND METHODS: In this retrospective cohort study, segmented EDI-OCT scans of both eyes in 19 patients with panuveitis were taken at baseline and at 3-month follow-up and were compared with EDI-OCT scans of normal eyes. Subfoveal choroidal area was segmented into luminal (LA) and stromal interstitial area (SA). Choroidal vascularity index (CVI) was defined as the proportion of LA to the total circumscribed subfoveal choroidal area (TCA). RESULTS: The mean choroidal thickness was 265.5+/-100.1MUm at baseline and 278.4+/-102.6MUm at 3 months follow up (p = 0.06). There was no statistically significant difference in TCA between study and control eyes (p = 0.08). CVI in the control group was 66.9+/-1.5% at baseline and 66.4+/-1.5% at follow up. CVI was 74.1+/-4.7% at baseline and 69.4+/-4.8% at 3 months follow up for uveitic eyes (p<0.001). The % change in CVI was 6.2 +/-3.8 (4.3 to 8.0) for uveitic eyes, which was significantly higher from % change in CVI for control eyes (0.7+/-1.1, 0.2 to 1.3, p<0.001). CONCLUSION: The study reports composite OCT-derived parameters and CVI as a possible novel tool in monitoring progression in panuveitis. CVI may be further validated in larger studies as a novel optical tool to quantify choroidal vascular status. PMID- 26751705 TI - Comparison of 10-year clinical wear of annealed and remelted highly cross-linked polyethylene: A propensity-matched cohort study. AB - No previous studies comparing the clinical wear rates of the two different kinds of cross-linked ultra-high-molecular-weight polyethylene (XLPE), annealed and remelted, are available. We compared the creep and steady wear rates of 36 matched pairs (72 hips in total) adjusting for baseline characteristics with propensity score matching techniques. Zirconia femoral heads with 26-mm diameter were used in all cases. The femoral-head cup penetration was measured digitally on radiographs. Significantly greater creep (p=0.006) was detected in the remelted (0.234mm) than annealed (0.159mm) XLPE. However, no significant difference (p=0.19) was found between the steady wear rates (0.003 and 0.008mm/year, respectively) of the annealed and remelted XLPE. Multiple regression analyses showed that remelted XLPE is significant independent variable (p<0.001) that is positively associated with creep. However, the patient age and body weight, cup size, the liner thickness, cup inclination, follow-up periods, and postoperative Merle d'Aubigne hip score had no significant effects (p>0.05) on the steady wear rates. No patients exhibited above the osteolysis threshold of 0.1mm/year, progressive radiolucencies, osteolysis, or polyethylene fracture. This propensity-matched cohort study document no significant difference in wear resistant performances of annealed and remelted XLPE over an average period of 10 years. PMID- 26751706 TI - Bayesian calibration of hyperelastic constitutive models of soft tissue. AB - There is inherent variability in the experimental response used to characterize the hyperelastic mechanical response of soft tissues. This has to be accounted for while estimating the parameters in the constitutive models to obtain reliable estimates of the quantities of interest. The traditional least squares method of parameter estimation does not give due importance to this variability. We use a Bayesian calibration framework based on nested Monte Carlo sampling to account for the variability in the experimental data and its effect on the estimated parameters through a systematic probability-based treatment. We consider three different constitutive models to represent the hyperelastic nature of soft tissue: Mooney-Rivlin model, exponential model, and Ogden model. Three stress strain data sets corresponding to the deformation of agarose gel, bovine liver tissue, and porcine brain tissue are considered. Bayesian fits and parameter estimates are compared with the corresponding least squares values. Finally, we propagate the uncertainty in the parameters to a quantity of interest (QoI), namely the force-indentation response, to study the effect of model form on the values of the QoI. Our results show that the quality of the fit alone is insufficient to determine the adequacy of the model, and due importance has to be given to the maximum likelihood value, the landscape of the likelihood distribution, and model complexity. PMID- 26751704 TI - Dynamics of Vector-Host Interactions in Avian Communities in Four Eastern Equine Encephalitis Virus Foci in the Northeastern U.S. AB - BACKGROUND: Eastern equine encephalitis (EEE) virus (Togaviridae, Alphavirus) is a highly pathogenic mosquito-borne zoonosis that is responsible for occasional outbreaks of severe disease in humans and equines, resulting in high mortality and neurological impairment in most survivors. In the past, human disease outbreaks in the northeastern U.S. have occurred intermittently with no apparent pattern; however, during the last decade we have witnessed recurring annual emergence where EEE virus activity had been historically rare, and expansion into northern New England where the virus had been previously unknown. In the northeastern U.S., EEE virus is maintained in an enzootic cycle involving the ornithophagic mosquito, Culiseta melanura, and wild passerine (perching) birds in freshwater hardwood swamps. However, the identity of key avian species that serve as principal virus reservoir and amplification hosts has not been established. The efficiency with which pathogen transmission occurs within an avian community is largely determined by the relative reservoir competence of each species and by ecological factors that influence contact rates between these avian hosts and mosquito vectors. METHODOLOGY AND PRINCIPLE FINDINGS: Contacts between vector mosquitoes and potential avian hosts may be directly quantified by analyzing the blood meal contents of field-collected specimens. We used PCR-based molecular methods and direct sequencing of the mitochondrial cytochrome b gene for profiling of blood meals in Cs. melanura, in an effort to quantify its feeding behavior on specific vertebrate hosts, and to infer epidemiologic implications in four historic EEE virus foci in the northeastern U.S. Avian point count surveys were conducted to determine spatiotemporal host community composition. Of 1,127 blood meals successfully identified to species level, >99% of blood meals were from 65 avian hosts in 27 families and 11 orders, and only seven were from mammalian hosts representing three species. We developed an empirically informed mathematical model for EEE virus transmission using Cs. melanura abundance and preferred and non-preferred avian hosts. To our knowledge this is the first mathematical model for EEE virus, a pathogen with many potential hosts, in the northeastern U.S. We measured strong feeding preferences for a number of avian species based on the proportion of mosquito blood meals identified from these bird species in relation to their observed frequencies. These included: American Robin, Tufted Titmouse, Common Grackle, Wood Thrush, Chipping Sparrow, Black capped Chickadee, Northern Cardinal, and Warbling Vireo. We found that these bird species, most notably Wood Thrush, play a dominant role in supporting EEE virus amplification. It is also noteworthy that the competence of some of the aforementioned avian species for EEE virus has not been established. Our findings indicate that heterogeneity induced by mosquito host preference, is a key mediator of the epizootic transmission of vector-borne pathogens. CONCLUSION AND SIGNIFICANCE: Detailed knowledge of the vector-host interactions of mosquito populations in nature is essential for evaluating their vectorial capacity and for assessing the role of individual vertebrates as reservoir hosts involved in the maintenance and amplification of zoonotic agents of human diseases. Our study clarifies the host associations of Cs. melanura in four EEE virus foci in the northeastern U.S., identifies vector host preferences as the most important transmission parameter, and quantifies the contribution of preference-induced contact heterogeneity to enzootic transmission. Our study identifies Wood Thrush, American Robin and a few avian species that may serve as superspreaders of EEE virus. Our study elucidates spatiotemporal host species utilization by Cs. melanura in relation to avian host community. This research provides a basis to better understand the involvement of Cs. melanura and avian hosts in the transmission and ecology of EEE virus and the risk of human infection in virus foci. PMID- 26751707 TI - Comparison of four monolithic zirconia materials with conventional ones: Contrast ratio, grain size, four-point flexural strength and two-body wear. AB - OBJECTIVES: To test the mechanical and optical properties of monolithic zirconia in comparison to conventional zirconia. MATERIALS AND METHODS: Specimens were prepared from: monolithic zirconia: Zenostar (ZS), DD Bio ZX(2) hochtransluzent (DD), Ceramill Zolid (CZ), InCoris TZI (IC) and a conventional zirconia Ceramill ZI (CZI). Contrast ratio (N=75/n=15) was measured according to ISO 2471:2008. Grain sizes (N=75/n=15) were investigated with scanning electron microscope. Four point flexural strength (N=225/n=15/zirconia and aging regime) was measured initially, after aging in autoclave or chewing simulator (ISO 13356:2008). Two body wear of polished and glazed/veneered specimens (N=108/n=12) was analyzed in a chewing simulator using human teeth as antagonists. Data were analyzed using 2 /1-way ANOVA with post-hoc Scheffe, Kruskal-Wallis-H, Mann-Whitney-U, Spearman Rho, Weibull statistics and linear mixed models (p<0.05). RESULTS: The lowest contrast ratio values were found for ZS and IC and CZ. IC showed the largest grain size followed by DD and CZI. The smallest grain size was observed for ZS followed by CZ. There was no correlation between grain size and contrast ratio. The aging regime showed no impact on flexural strength. All non-aged and autoclave-aged specimens showed lower flexural strengths than the control group CZI. Within groups aged in chewing simulator, ZS showed significantly lower flexural strength than CZI. CZI showed higher material and antagonist wear than monolithic polished and glazed groups. Glazed specimens showed higher material and antagonist loss compared to polished ones. There was no correlation between roughness and wear. CONCLUSIONS: Monolithic zirconia showed higher optical, but lower mechanical properties than conventional zirconia. PMID- 26751708 TI - Carvedilol protects the kidneys of tumor-bearing mice without impairing the biodistribution or the genotoxicity of cisplatin. AB - Cisplatin (Cisp) is an effective antitumor drug; however, it causes severe nephrotoxicity. Minimization of renal toxicity is essential, but the interference of nephroprotective agents, particularly antioxidants, with the antitumor activity of cisplatin is a general concern. We have recently demonstrated that the anti-hypertensive and antioxidant drug carvedilol (CV) protects against the renal damage and increases the survival of tumor-bearing mice without impairing the tumor reduction by cisplatin. So far, reports on the antioxidant mechanism of CV are controversial and there are no data on the impact of CV on the antitumor mechanisms of cisplatin. Therefore, this study addresses the effect of CV on mechanisms underlying the tumor control by cisplatin. CV did not interfere with the biodistribution or the genotoxicity of cisplatin. We also addressed the antioxidant mechanisms of CV and demonstrated that it does not neutralize free radicals, but is an efficient chelator of ferrous ions that are relevant catalyzers in cisplatin nephrotoxicity. The present data suggest that oxidative damage and genotoxicity play different roles in the toxicity of cisplatin on kidneys and tumors and therefore, some antioxidants might be safe as chemoprotectors. Altogether, our studies provide consistent evidence of the beneficial effect of CV on animals treated with cisplatin and might encourage clinical trials. PMID- 26751710 TI - Deviance and resistance: Malaria elimination in the greater Mekong subregion. AB - Malaria elimination rather than control is increasingly globally endorsed, requiring new approaches wherein success is not measured by timely treatment of presenting cases but eradicating all presence of infection. This shift has gained urgency as resistance to artemisinin-combination therapies spreads in the Greater Mekong Sub-region (GMS) posing a threat to global health security. In the GMS, endemic malaria persists in forested border areas and elimination will require calibrated approaches to remove remaining pockets of residual infection. A new public health strategy called 'positive deviance' is being used to improve health promotion and community outreach in some of these zones. However, outbreaks sparked by alternative understandings of appropriate behaviour expose the unpredictable nature of 'border malaria' and difficulties eradication faces. Using a recent spike in infections allegedly linked to luxury timber trade in Thai borderlands, this article suggests that opportunities for market engagement can cause people to see 'deviance' as a means to material advancement in ways that increase disease vulnerability. A malaria outbreak in Ubon Ratchathani was investigated during two-week field-visit in November 2014 as part of longer project researching border malaria in Thai provinces. Qualitative data were collected in four villages in Ubon's three most-affected districts. Discussions with villagers focused primarily on changing livelihoods, experience with malaria, and rosewood cutting. Informants included ten men and two women who had recently overnighted in the nearby forest. Data from health officials and villagers are used to frame Ubon's rise in malaria transmission within moral and behavioural responses to expanding commodity supply-chains. The article argues that elimination strategies in the GMS must contend with volatile outbreaks among border populations wherein 'infectiousness' and 'resistance' are not simply pathogen characteristics but also behavioural dimensions born of insistent market aspirations. PMID- 26751709 TI - Serum Cytokines as Biomarkers in Islet Cell Transplantation for Type 1 Diabetes. AB - BACKGROUND: Islet cell transplantation holds a potential cure for type 1 diabetes, but many islet recipients do not reach long-lasting insulin independence. In this exploratory study, we investigated whether serum cytokines, chemokines and adipokines are associated with the clinical outcome of islet transplantation. METHODS: Thirteen islet transplant patients were selected on basis of good graft function (reaching insulin independence) or insufficient engraftment (insulin requiring) from our cohort receiving standardized grafts and immune suppressive therapy. Patients reaching insulin independence were divided in those with continued (>12 months) versus transient (<6 months) insulin independence. A panel of 94 proteins including cytokines and adipokines was measured in sera taken before and at one year after transplantation using a validated multiplex immunoassay platform. RESULTS: Ninety serum proteins were detectable in concentrations varying markedly among patients at either time point. Thirteen markers changed after transplantation, while another seven markers changed in a clinical subpopulation. All other markers remained unaffected after transplantation under generalized immunosuppression. Patterns of cytokines could distinguish good graft function from insufficient function including IFN-alpha, LIF, SCF and IL-1RII before and after transplantation, by IL 16, CCL3, BDNF and M-CSF only before and by IL-22, IL-33, KIM-1, S100A12 and sCD14 after transplantation. Three other proteins (Leptin, Cathepsin L and S100A12) associated with loss of temporary graft function before or after transplantation. CONCLUSIONS: Distinct cytokine signatures could be identified in serum that predict or associate with clinical outcome. These serum markers may help guiding patient selection and choice of immunotherapy, or act as novel drug targets in islet transplantation. PMID- 26751711 TI - Interventions for tic disorders: An overview of systematic reviews and meta analyses. AB - We conducted a comprehensive search and the overview included 22 systematic reviews (SRs) for treating tic disorders (TDs). Three SRs indicated typical antipsychotics (i.e., haloperidol, pimozide) were efficacious in the reduction of tic severity compared with placebo but with poor tolerability. Six SRs assessed the efficacy of atypical antipsychotics and indicated that atypical antipsychotics (i.e., risperidone, aripiprazole) could significantly improved tic symptoms compared with placebo or typical antipsychotics with less AEs. Four SRs indicated alpha adrenergic agonists (i.e., clonidine, guanfacine) could improve tic symptoms. Two SRs assessed the efficacy of antiepileptic drugs and indicated topiramate was a promising therapy. Six SRs evaluated the efficacy of behavior therapy and showed habit reversal therapy (HRT) and exposure and response prevention (ERP) were effective. One SR evaluated the efficacy deep brain stimulation (DBS) and indicated DBS is a promising treatment option for severe cases of TS. In conclusion, RCTs directly comparing different pharmacological treatment options are scarce. In practice, typical and atypical antipsychotics are often considered firstly while other pharmacological medications are suggested as alternatives in the case of treatment failure or contradictory outcomes. Behavioral therapies can be used either alone or in combination with medication. PMID- 26751712 TI - Cell type-specific bipolar cell input to ganglion cells in the mouse retina. AB - Many distinct ganglion cell types, which are the output elements of the retina, were found to encode for specific features of a visual scene such as contrast, color information or movement. The detailed composition of retinal circuits leading to this tuning of retinal ganglion cells, however, is apart from some prominent examples, largely unknown. Here we aimed to investigate if ganglion cell types in the mouse retina receive selective input from specific bipolar cell types or if they sample their synaptic input non-selectively from all bipolar cell types stratifying within their dendritic tree. To address this question we took an anatomical approach and immunolabeled retinae of two transgenic mouse lines (GFP-O and JAM-B) with markers for ribbon synapses and type 2 bipolar cells. We morphologically identified all green fluorescent protein (GFP) expressing ganglion cell types, which co-stratified with type 2 bipolar cells and assessed the total number of bipolar input synapses and the proportion of synapses deriving from type 2 bipolar cells. Only JAM-B ganglion cells received synaptic input preferentially from bipolar cell types other than type 2 bipolar cells whereas the other analyzed ganglion cell types sampled their bipolar input most likely from all bipolar cell terminals within their dendritic arbor. PMID- 26751713 TI - Cell-specific modulation of monocarboxylate transporter expression contributes to the metabolic reprograming taking place following cerebral ischemia. AB - Monocarboxylate transporters (MCTs) are involved in lactate trafficking and utilization by brain cells. As lactate is not only overproduced during ischemia but its utilization was shown to be essential upon recovery, we analyzed the expression of the main cerebral MCTs at 1 and 24h after an ischemic insult induced by a transient occlusion of the left middle cerebral artery (MCAO) in CD1 mice (n=5, 7 and 10 for control, 1 and 24h groups, respectively). After 1h of reperfusion, an upregulation of the three MCTs was observed in the striatum (MCT1 ipsilateral 2.73 +/- 0.2 and contralateral 2.01 +/- 0.4; MCT2 ipsilateral 2.1 +/- 0.1; MCT4 ipsilateral 1.65 +/- 0.1) and in the surrounding cortex of both the ipsilateral (MCT1 2.4 +/- 0.4; MCT2 1.62 +/- 0.2; MCT4 1.31 +/- 0.1) and contralateral (MCT1 2.78 +/- 0.4; MCT2 1.76 +/- 0.2) hemispheres, compared to the corresponding sham hemispheres. An increase of MCT1 (ipsilateral 2.1 +/- 0.2) and MCT2 (contralateral 1.9 +/- 0.1) expression was also observed in the hippocampus, while no effect was observed for MCT4. At 24h of reperfusion, total MCT2 and MCT4 expressions were decreased in the striatum (MCT2 ipsilateral 0.32 +/- 0.1 and contralateral 0.63 +/- 0.1; MCT4 ipsilateral 0.59 +/- 0.1) and the surrounding cortex (MCT4 ipsilateral 0.67 +/- 0.1), compared to the sham. At the cellular level, neurons which usually express only MCT2 strongly expressed MCT1 at both time points. Surprisingly, staining for MCT4 appeared on neurons and was strong at 24h post-insult, in the striatum and the cortex of both hemispheres. A similar expression pattern was observed also in the ipsilateral hemisphere of the sham operated animals at 24h. Overall, our study indicates that cell-specific changes in MCT expression induced by an ischemic insult may participate to the metabolic adaptations taking place in the brain after a transient ischemic episode. PMID- 26751714 TI - Analysis of recurrent events with an associated informative dropout time: Application of the joint frailty model. AB - This paper considers the analysis of a repeat event outcome in clinical trials of chronic diseases in the context of dependent censoring (e.g. mortality). It has particular application in the context of recurrent heart failure hospitalisations in trials of heart failure. Semi-parametric joint frailty models (JFMs) simultaneously analyse recurrent heart failure hospitalisations and time to cardiovascular death, estimating distinct hazard ratios whilst individual specific latent variables induce associations between the two processes. A simulation study was carried out to assess the suitability of the JFM versus marginal analyses of recurrent events and cardiovascular death using standard methods. Hazard ratios were consistently overestimated when marginal models were used, whilst the JFM produced good, well-estimated results. An application to the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity programme was considered. The JFM gave unbiased estimates of treatment effects in the presence of dependent censoring. We advocate the use of the JFM for future trials that consider recurrent events as the primary outcome. (c) 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. PMID- 26751715 TI - Allatostatin-type A, kisspeptin and galanin GPCRs and putative ligands as candidate regulatory factors of mantle function. AB - Allatostatin-type A (AST-A), kisspeptin (KISS) and galanin (GAL) G-protein coupled receptor (GPCR) systems share a common ancestral origin in arthropods and the vertebrates where they regulate metabolism and reproduction. The molluscs are the second most diverse phylum in the animal kingdom, they occupy an important phylogenetic position, and their genome is more similar to deuterostomes than the arthropods and nematodes and thus they are good models for studies of gene family evolution and function. This mini-review intends to extend the current knowledge about AST-A, KISS and GAL GPCR system evolution and their putative function in the mollusc mantle. Comparative evolutionary analysis of the target GPCR systems was established by identifying homologues in genomes and tissue transcriptome datasets available for molluscs and comparing them to those of other metazoan systems. Studies in arthropods have revealed the existence of the AST-A system but the loss of homologues of the KISS and GAL systems. Homologues of the insect AST-AR and vertebrate KISSR genes were found in molluscs but putative GALR genes were absent. Receptor gene number suggested that members of this family have suffered lineage specific evolution during the molluscan radiation. In molluscs, orthologues of the insect AST-A peptides were not identified but buccalin peptides that are structurally related were identified and are putative receptor agonists. The identification of AST-AR and KISSR genes in molluscs strengthens the hypotheses that in metazoans members of the AST-AR subfamily share evolutionary proximity with KISSRs. The variable number of receptors and large repertoire of buccalin peptides may be indicative of the functional diversity of the AST-AR/KISSR systems in molluscs. The identification of AST-A and KISS receptors and ligands in the mantle transcriptome indicates that in molluscs they may have acquired a novel function and may play a role in shell development or sensory detection in the mantle. PMID- 26751716 TI - Genome-wide analysis of RING finger proteins in the smallest free-living photosynthetic eukaryote Ostreococus tauri. AB - RING finger proteins and ubiquitination marks are widely involved in diverse aspects of growth and development, biological processes, and stress or environmental responses. As the smallest free-living photosynthetic eukaryote known so far, the green alga Ostreococus tauri has become an excellent model for investigating the origin of different gene families in the green lineage. Here, 65 RING domains in 65 predicted proteins were identified from O. tauri and on the basis of one or more substitutions at the metal ligand positions and spacing between them they were divided into eight canonical or modified types (RING-CH, H2, -v, -C2, -C3HCHC2, -C2HC5, -C3GC3S, and -C2SHC4), in which the latter four were newly identified and might represent the intermediate states between RING domain and other similar domains, respectively. RING finger proteins were classified into eight classes based on the presence of additional domains, including RING-Only, -Plus, -C3H1, -PHD, -WD40, -PEX, -TM, and -DEXDc classes. These RING family genes usually lack introns and are distributed over 17 chromosomes. In addition, 29 RING-finger proteins in O. tauri share different degrees of homology with those in the model flowering plant Arabidopsis, indicating they might be necessary for the basic survival of free-living eukaryotes. Therefore, our results provide new insight into the general classification and evolutionary conservation of RING domain-containing proteins in O. tauri. PMID- 26751717 TI - Unexpected Direct Hydride Transfer Mechanism for the Hydrogenation of Ethyl Acetate to Ethanol Catalyzed by SNS Pincer Ruthenium Complexes. AB - The hydrogenation of ethyl acetate to ethanol catalyzed by SNS pincer ruthenium complexes was computationally investigated by using DFT. Different from a previously proposed mechanism with fac-[(SNS)Ru(PPh3 )(H)2 ] (5') as the catalyst, an unexpected direct hydride transfer mechanism with a mer-SNS ruthenium complex as the catalyst, and two cascade catalytic cycles for hydrogenations of ethyl acetate to aldehyde and aldehyde to ethanol, is proposed base on our calculations. The new mechanism features ethanol-assisted proton transfer for H2 cleavage, direct hydride transfer from ruthenium to the carbonyl carbon, and C-OEt bond cleavage. Calculation results indicate that the rate determining step in the whole catalytic reaction is the transfer of a hydride from ruthenium to the carbonyl carbon of ethyl acetate, with a total free energy barrier of only 26.9 kcal mol-1 , which is consistent with experimental observations and significantly lower than the relative free energy of an intermediate in a previously postulated mechanism with 5' as the catalyst. PMID- 26751718 TI - Nitroarenes as Antitubercular Agents: Stereoelectronic Modulation to Mitigate Mutagenicity. AB - Nitroarenes are less preferred in drug discovery due to their potential to be mutagenic. However, several nitroarenes were shown to be promising antitubercular agents with specific modes of action, namely, nitroimidazoles and benzothiazinones. The nitro group in these compounds is activated through different mechanisms, both enzymatic and non-enzymatic, in mycobacteria prior to binding to the target of interest. From a whole-cell screening program, we identified a novel lead nitrobenzothiazole (BT) series that acts by inhibition of decaprenylphosphoryl-beta-d-ribose 2'-epimerase (DprE1) of Mycobacterium tuberculosis (Mtb). The lead was found to be mutagenic to start with. Our efforts to mitigate mutagenicity resulted in the identification of 6-methyl-7-nitro-5 (trifluoromethyl)-1,3-benzothiazoles (cBTs), a novel class of antitubercular agents that are non-mutagenic and exhibit an improved safety profile. The methyl group ortho to the nitro group decreases the electron affinity of the series, and is hence responsible for the non-mutagenic nature of these compounds. Additionally, the co-crystal structure of cBT in complex with Mtb DprE1 established the mode of binding. This investigation led to a new non-mutagenic antitubercular agent and demonstrates that the mutagenic nature of nitroarenes can be solved by modulation of stereoelectronic properties. PMID- 26751719 TI - Jagged1 inhibits osteoprotegerin expression by human periodontal ligament cells. AB - BACKGROUND AND OBJECTIVE: Notch signaling regulates bone homeostasis. The present study investigated the effect of Jagged1 on osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) expression in human periodontal ligament stromal (hPDL) cells. MATERIAL AND METHODS: hPDL cells were seeded on to indirect immobilized Jagged1 surfaces. OPG expression was determined using real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Lentiviral small hairpin RNA particles against NOTCH2 were employed to inhibit NOTCH2 expression. Osteoclast formation was evaluated using RAW264.7 cells. An influence of exogenous OPG on osteogenic differentiation was determined by real time polymerase chain reaction and Alizarin Red S staining. RESULTS: Jagged1 significantly enhanced HES1 and HEY1mRNA expression in a dose-dependent manner. Furthermore, OPG mRNA and protein levels dramatically decreased upon exposing hPDL cells to Jagged1. However, RANKL mRNA levels were not significantly different. There was also no difference in M-CSF and MCP-1mRNA expression. A gamma-secretase inhibitor and cycloheximide treatment rescued Jagged1-attenuated OPG expression. Furthermore, shNOTCH2 overexpressing hPDL cells did not exhibit a decrease in OPG expression upon exposure to Jagged1, implying the involvement of NOTCH2 in the regulatory mechanism. Culturing RAW264.7 cells with conditioned medium from Jagged1-treated hPDL cells enhanced osteoclast formation compared with those cultured with conditioned medium of the control group. Lastly, OPG treatment did not influence osteogenic differentiation by hPDL cells. CONCLUSION: These results suggest that Jagged1 activates Notch signaling in hPDL cells, leading to decreased OPG expression. This may imply an indirect role of Jagged1 on the regulation of osteoclast differentiation via hPDL cells. PMID- 26751720 TI - Bed-side inferior vena cava diameter and mean arterial pressure predict long-term mortality in hospitalized patients with heart failure: 36 months of follow-up. AB - BACKGROUND: In discharged patients with heart failure (HF), diverse conditions can intervene to worsen outcome. We would investigate whether such factors present on hospital admission can affect long-term mortality in subjects hospitalized for acute HF. METHODS: One hundred twenty-three consecutive patients hospitalized for acute HF (mean age 74.8 years; 57% female) were recruited and followed for 36 months after hospitalization. RESULTS: At multivariate Cox model, only inferior vena cava (IVC) diameter and mean arterial pressure (MAP) registered bed-side on admission, resulted, after correction for all confounders factors, the sole factors significantly associated with a higher risk of all cause mortality in long-term (HR 1.06, p=0.0057; HR 0.97, p=0.0218; respectively). Study population was subdivided according to median values of IVC diameter (23 mm) and MAP (93.3 mm Hg). The Kaplan-Meier curve showed that HF patients with both IVC >= 23 mm and MAP b93.3 mm Hg on admission had reduced probability of survival free from all-cause death (log rank p = 0.0070 and log rank p = 0.0028, respectively). CONCLUSIONS: In patients hospitalized for acute HF, IVC diameter, measured by hand-carried ultrasound (HCU), and MAP detected on admission are strong predictors of long-term all-cause mortality. The data suggest the need for a careful clinical-therapeutic surveillance on these patients during the post-discharge period. IVC diameter and MAP can be utilized as parameters to stratify prognosis on admission and to be supervised during follow-up. PMID- 26751723 TI - Choosing the best cropping systems to target pleiotropic effects when managing single-gene herbicide resistance in grass weeds. A blackgrass simulation study. AB - BACKGROUND: Managing herbicide-resistant weeds is becoming increasingly difficult. Here we adapted the weed dynamics model AlomySys to account for experimentally measured fitness costs linked to mutants of target-site resistance to acetyl-coenzyme A carboxylase (ACCase)-inhibiting herbicides in Alopecurus myosuroides. We ran simulations to test how effectively cultural practices manage resistance. RESULTS: Simulations of an oilseed rape/winter wheat/winter barley rotation showed that, when replacing one of the seven applied herbicides with an ACCase-inhibiting one, resistant mutants exceeded 1 plant m(-2) , with a probability of 40%, after an average of 18 years. This threshold was always exceeded when three or four ACCase-inhibiting herbicides were used, after an average of 8 and 6 years respectively. With reduced herbicide rates or suboptimal spraying conditions, resistance occurred 1-3 years earlier in 50% of simulations. Adding spring pea to the rotation or yearly mouldboard ploughing delayed resistance indefinitely in 90 and 60% of simulations respectively. Ploughing also modified the genetic composition of the resistant population by selecting a previously rare mutant that presented improved pre-emergent growth. The prevalence of the mutations was influenced more by their associated fitness cost or benefit than by the number of ACCase-inhibiting herbicides to which they conferred resistance. CONCLUSION: Simulations allowed us to rank weed management practices and suggest that pleiotropic effects are extremely important for understanding the frequency of herbicide resistance in the population. (c) 2016 Society of Chemical Industry. PMID- 26751726 TI - Recognizing peer reviewers and why that matters. PMID- 26751724 TI - Reduced severity of posttraumatic stress disorder associated with Val allele of Val66Met polymorphism at brain-derived neurotrophic factor gene among Chinese adolescents after Wenchuan earthquake. AB - The aim of the present study was to longitudinally investigate the association of BDNF Val66Met with PTSD symptoms in Chinese Han adolescents who experienced the 2008 Wenchuan earthquake. Variants of BDNF Val66Met were identified by polymerase chain reaction-restriction fragment length polymorphism analyses and verified by DNA sequencing. PTSD symptoms were assessed by the PTSD Checklist-Civilian Version (PCL-C) among high school students at 6, 12, and 18 months after the earthquake. No differences of PTSD prevalence and PCL-C scores were found between the Val/Val homozygotes and the Met allele carriers at 6, 12, and 18 months after the earthquake regardless of gender. Decreased PTSD prevalence was observed at 12 and 18 months when compared with that at 6 months after the earthquake regardless of gender and the genotype. Meanwhile, PCL-C scores were decreased consecutively in the female subjects regardless of the genotypes. However, the scores at 18 months were lower when compared with those at 12 months in the male Val/Val homozygotes, but not in the male Met allele carriers. In addition, differences were found for the predictors of PCL-C scores and PTSD prevalence between the Val/Val homozygotes and the Met allele carriers during follow-up. These findings suggest that the association of BDNF Val66Met with PTSD is longitudinally different in Chinese Han adolescents after the 2008 Wenchuan earthquake. The Val allele may be associated with reduced PTSD severity in male adolescents in the later stage of PTSD rehabilitation during follow-up. PMID- 26751727 TI - Construction of 1-pyrroline skeletons by Lewis acid-mediated conjugate addition of vinyl azides. AB - Lewis acid-mediated conjugate addition of vinyl azides to electron-deficient alkenes led to the efficient construction of 1-pyrroline skeletons. The reactions of vinyl azides with 3-alkylidene-2-oxoindolines afford 3',4' dihydrospiro[indoline-3,2'-pyrrol]-2-ones in a diastereoselective fashion, whereas those with dimethyl 2-alkylidenemalonates provide 4,5-dihydro-3H pyrroles. PMID- 26751721 TI - Tocopherols in cancer: An update. AB - Tocopherols exist in four forms designated as alpha, beta, delta, and gamma. Due to their strong antioxidant properties, tocopherols have been suggested to reduce the risk of cancer. Cancer prevention studies with tocopherols have mostly utilized alpha-tocopherol. Large-scale clinical trials with alpha-tocopherol provided inconsistent results regarding the cancer-preventive activities of tocopherols. This review summarizes our current understanding of the anticancer activities of different forms of tocopherols based on follow-up of the clinical trials, recent epidemiological evidences, and experimental studies using in vitro and in vivo models. The experimental data provide strong evidence in support of the anticancer activities of delta-tocopherol, gamma-tocopherol, and the natural tocopherol mixture rich in gamma-tocopherol, gamma-TmT, over alpha-tocopherol. Such outcomes emphasize the need for detailed investigation into the cancer preventive activities of different forms of tocopherols to provide a strong rationale for intervention studies in the future. PMID- 26751729 TI - A kinetic study on the reduction of CO2 by frustrated Lewis pairs: from understanding to rational design. AB - Carbon dioxide (CO2) is known as one of the major reasons for global warming. On the other hand, CO2 is considered as an abundant carbon source. Therefore, transformation of CO2 into target chemicals nowadays is of great interest. Recently, a concept of so-called "frustrated Lewis pairs" (FLPs) has been proposed. Such FLPs show unusual reactivity, such as hydrogen activation and the reduction of CO2. In this study, by means of density functional theory (DFT) and ab initio calculations, we conduct a kinetic survey on the reduction of CO2 by a series of FLPs. We investigate the relationship between the electronic structures and kinetic properties. The kinetic properties include: (1) reaction energy barriers, (2) the structural properties of the associated transition states (TSs), and (3) the natural charge population in these TSs. Our results indicate that there is a systematic relationship between the electronic structures and the kinetic properties, and, as a rule of thumb, similar activation barriers for both individual reactions are needed for best performance. The derived relationship can be used not only to rationalize the published experimental results, but also to assist the future design of more efficient Lewis acid-base pairs as metal-free catalysts for the reduction of CO2. PMID- 26751728 TI - A Novel Domain-Specific Mutation in a Sclerosteosis Patient Suggests a Role of LRP4 as an Anchor for Sclerostin in Human Bone. AB - Mutations in the LRP4 gene, coding for a Wnt signaling coreceptor, have been found to cause several allelic conditions. Among these, two are characterized by a strong skeletal involvement, namely sclerosteosis and Cenani-Lenz syndrome. In this work, we evaluated the role of LRP4 in the pathophysiology of these diseases. First, we report a novel LRP4 mutation, leading to the substitution of arginine at position 1170 in glutamine, identified in a patient with sclerosteosis. This mutation is located in the central cavity of the third beta propeller domain, which is in line with two other sclerosteosis mutations we previously described. Reporter assays demonstrate that this mutation leads to impaired sclerostin inhibition of Wnt signaling. Moreover, we compared the effect of this novel variant to mutations causing Cenani-Lenz syndrome and show that impaired membrane trafficking of the LRP4 protein is the likely mechanism underlying Cenani-Lenz syndrome. This is in contrast to sclerosteosis mutations, previously shown to impair the binding between LRP4 and sclerostin. In addition, to better understand the biology of LRP4, we investigated the circulating sclerostin levels in the serum of a patient suffering from sclerosteosis owing to a LRP4 mutation. We demonstrate that impaired sclerostin binding to the mutated LRP4 protein leads to dramatic increase in circulating sclerostin in this patient. With this study, we provide the first evidence suggesting that LRP4 is responsible for the retention of sclerostin in the bone environment in humans. These findings raise potential concerns about the utility of determining circulating sclerostin levels as a marker for other bone-related parameters. Although more studies are needed to fully understand the mechanism whereby LRP4 facilitates sclerostin action, it is clear that this protein represents a potent target for future osteoporosis therapies and an interesting alternative for the antisclerostin treatment currently under study. PMID- 26751731 TI - Psychological Distress Increases Perceived Stigma Toward Attempted Suicide Among Those With a History of Past Attempted Suicide. AB - People who suffer from mental illness have high self-stigmatizing attitudes. This study aims to test the effect of psychopathological distress on stigma toward attempted suicide in a population of suicide attempters. Data were collected through an interview and 2 questionnaires (90-item Symptom Checklist; Stigma of Suicide Attempt scale) administered to 67 patients hospitalized after an attempted suicide. Participants with a history of past attempted suicide had higher scores on the Stigma of Suicide Attempt scale (t58.9 = -2.51, p = 0.014). Higher levels of psychological distress were related to greater perceived stigma only in individuals with a history of past attempted suicide (standardized coefficient = 0.37; t = 2.36; p = 0.024; R2 = 14%; adjusted R2 = 11.5%). A previous experience of attempted suicide is related to greater self-stigmatizing attitudes toward suicidal behavior. Among those who have previously attempted suicide in particular, psychopathological distress may significantly contribute to increase the perception of stigma. PMID- 26751732 TI - Intensely Exposed Oklahoma City Terrorism Survivors: Long-term Mental Health and Health Needs and Posttraumatic Growth. AB - In this study, we explore directly exposed terrorism survivors' mental health and health status, healthcare utilization, alcohol and tobacco use, and posttraumatic growth 181/2 years postdisaster. Telephone surveys compared terrorism survivors and nonexposed community control subjects, using Hopkins Symptom Checklist, Breslau's PTSD screen, Posttraumatic Growth Inventory, and Health Status Questionnaire 12. Statistical analyses included multivariable logistic regression and linear modeling. Survivors, more than 80% injured, reported more anxiety and depression symptoms than did control subjects, with survivors' anxiety and depression associated with heavy drinking (>=5 drinks) and worse mental health and social functioning. While survivors had continued posttraumatic stress disorder symptoms (32 [23.2%] met probable posttraumatic stress disorder threshold), they also reported posttraumatic growth. Survivors had more care from physical, speech, respiratory, and occupational therapists. In this unprecedented long-term assessment, survivors' psychiatric symptoms, alcohol use, and ancillary health service utilization suggest unmet mental health and health needs. Extended recovery efforts might benefit from maximizing positive growth and coping. PMID- 26751733 TI - Synthesis, structure and pyrolysis of stabilised phosphonium ylides containing saturated oxygen heterocycles. AB - A range of twelve stabilised phosphonium ylides containing tetrahydrofuran, tetrahydropyran or 2,2-dimethyl-1,3-dioxolane rings have been prepared and fully characterised, including one X-ray structure determination of each type. The X ray structures confirm the P=C and C=O functions to be syn and all the compounds undergo thermal extrusion of Ph3PO to give the corresponding alkynes. In some cases there is also competing loss of Ph3P to give different carbene-derived products and evidence has been obtained for the generation of 2-phenyloxete in this way. Raising the pyrolysis temperature leads in several cases to new secondary reactions of the alkyne products involving a sequence of alkyne to vinylidene isomerisation, intramolecular CH insertion, and retro Diels Alder reaction. PMID- 26751730 TI - YedY: A Mononuclear Molybdenum Enzyme with a Redox-Active Ligand? AB - A recent electrochemical investigation suggests that the mononuclear molybdenum enzyme YdeY utilizes redox-active ligands during catalysis. PMID- 26751734 TI - Should there be a target level of docosahexaenoic acid in breast milk? AB - PURPOSE OF REVIEW: This article examines the evidence for and against establishing a target level of docosahexaenoic acid (DHA) in breast milk. RECENT FINDINGS: Two target levels for milk DHA have been recently proposed. One (~0.3% of milk fatty acids) was based on milk DHA levels achieved in women consuming the amount of DHA recommended by the American Academy of Pediatrics for pregnant and lactating women (at least 200 mg DHA/day). Another (~1.0%) was based on biomarker studies of populations with differing lifelong intakes of fish. Populations or research cohorts with milk DHA levels of 1.0% are associated with intakes that allow both the mother and infant to maintain relatively high DHA levels throughout lactation. Lower milk DHA levels may signal suboptimal maternal stores and possibly suboptimal infant intakes. SUMMARY: Based on the current data, a reasonable milk DHA target appears to be approximately 0.3%, which is about the worldwide average. Although this may not be the 'optimal' level (which remains to be defined), it is clearly an improvement over the currently low milk DHA levels (~0.2%) seen in many Western populations. PMID- 26751735 TI - From noise to synthetic nucleoli: can synthetic biology achieve new insights? AB - Synthetic biology aims to re-organise and control biological components to make functional devices. Along the way, the iterative process of designing and testing gene circuits has the potential to yield many insights into the functioning of the underlying chassis of cells. Thus, synthetic biology is converging with disciplines such as systems biology and even classical cell biology, to give a new level of predictability to gene expression, cell metabolism and cellular signalling networks. This review gives an overview of the contributions that synthetic biology has made in understanding gene expression, in terms of cell heterogeneity (noise), the coupling of growth and energy usage to expression, and spatiotemporal considerations. We mainly compare progress in bacterial and mammalian systems, which have some of the most-developed engineering frameworks. Overall, one view of synthetic biology can be neatly summarised as "creating in order to understand." PMID- 26751737 TI - BMP-6 inhibits the metastasis of MDA-MB-231 breast cancer cells by regulating MMP 1 expression. AB - Bone morphogenetic protein-6 (BMP-6) is a multifunctional molecule with distinct abilities in embryogenesis and organogenesis. In the present study, our results showed that the rate of BMP-6-negative expression was 30.56% in breast cancer tissues, but was 9.58% in normal tissues by immunohistochemical staining. This implied that BMP-6 expression is absent in breast cancer tissues and may suppress breast cancer metastasis. In addition, stable overexpression of BMP-6 in MDA-MB 231 cells was established to analyze the metastatic ability. The Boyden chamber assay showed that BMP-6 inhibited the migration and invasion of MDA-MB-231 cells. Moreover, real-time PCR analysis showed that BMP-6 markedly downregulated matrix metalloproteinase-1 (MMP-1) expression at both the mRNA and protein levels in the MDA-MB-231 cells. Importantly, the results of luciferase and CHIP assays revealed that BMP-6 inhibited MMP-1 promoter activity through the AP-1 response element. In MDA-MB-231 cells treated with BMP-6, a significant decrease in the recruitment of AP-1 components, c-Jun/c-Fos, to the endogenous MMP-1 promoter was noted. We also demonstrated that BMP-6 inhibited the invasion of MDA-MB-231 cells, and this effect was significantly attenuated by overexpression of MMP-1. In contrast, MMP 1 knockdown by RNA interference or MMP-1 inhibitor exhibited an opposite effect. These observations suggest a novel role of BMP-6 in the inhibition of breast cancer metastasis by regulating secretion of MMPs in the tumor microenvironment. PMID- 26751738 TI - Experimental distinction of Autler-Townes splitting from electromagnetically induced transparency using coupled mechanical oscillators system. AB - Here we experimentally demonstrated the electromagnetically induced transparency (EIT) and Autler-Townes splitting (ATS) effects in mechanical coupled pendulums. The analogue of EIT and ATS has been studied in mechanical systems and the intrinsic physics between these two phenomena are also been discussed. Exploiting the Akaike Information Criterion, we discern the ATS effect from EIT effect in our experimental results. PMID- 26751736 TI - Identification of a small molecule that simultaneously suppresses virulence and antibiotic resistance of Pseudomonas aeruginosa. AB - The rising antibiotic resistance of bacteria imposes a severe threat on human health. Inhibition of bacterial virulence is an alternative approach to develop new antimicrobials. Molecules targeting antibiotic resistant enzymes have been used in combination with cognate antibiotics. It might be ideal that a molecule can simultaneously suppress virulence factors and antibiotic resistance. Here we combined genetic and computer-aided inhibitor screening to search for such molecules against the bacterial pathogen Pseudomonas aeruginosa. To identify target proteins that control both virulence and antibiotic resistance, we screened for mutants with defective cytotoxicity and biofilm formation from 93 transposon insertion mutants previously reported with increased antibiotic susceptibility. A pyrD mutant displayed defects in cytotoxicity, biofilm formation, quorum sensing and virulence in an acute mouse pneumonia model. Next, we employed a computer-aided screening to identify potential inhibitors of the PyrD protein, a dihydroorotate dehydrogenase (DHODase) involved in pyrimidine biosynthesis. One of the predicted inhibitors was able to suppress the enzymatic activity of PyrD as well as bacterial cytotoxicity, biofilm formation and antibiotic resistance. A single administration of the compound reduced the bacterial colonization in the acute mouse pneumonia model. Therefore, we have developed a strategy to identify novel treatment targets and antimicrobial molecules. PMID- 26751739 TI - Cognition Regulated by Emotional Decision Making. AB - Cognitive ability did not appear de novo in humans. Despite our ability to recognize limited cognitive behavioral characteristics in animals, there has been no outcry to proclaim this phenomenon. The notion that humans are the only animals to possess cognition has taken advantage of the illusory potential in inter-subjectivity and placed him outside of reality. This deception, however, has positive survival value due to the fact that it is humankind's self proclaimed responsibility to excel beyond other simple animal species. However, at this point in evolution, we must allow our cognitive ability to reform itself and, in so doing, evolve with the benefit of the knowledge that this ability is itself creating. By recognizing that animals may have limited cognitive ability, we only enhance our self-esteem, not diminish it. Furthermore, cognition, given its limited brain controlling attributes, may mask another more diligent force for action and control, namely, emotion. Emotion provides the motivation for action, the mechanism to limit reason in a timely survival related manner and a coping strategy for dealing with other humans and animals while simultaneously modulating involuntary physiological functions in an appropriate manner. PMID- 26751741 TI - Comment on "Neonicotinoid Residues in Wildflowers, A Potential Route of Chronic Exposure for Bees". PMID- 26751740 TI - A 3D Heterometallic Coordination Polymer Constructed by Trimeric {NiDy2} Single Molecule Magnet Units. AB - The solvothermal reaction of DyCl3.6H2O, Ni(NO3)2.6H2O, and H4abtc ligands (H4abtc = 3,3',5,5'-azobenzene-tetracarboxylic acid) in the mixed DMF/H2O solvents (DMF = N,N-dimethylformamide) produced a three-dimensional (3D) Ni(II) Dy(III) heterometallic coordination polymer (HCP) formulated as {[NH2(CH3)2]2[NiDy2(HCOO)2(abtc)2]}n (1). In 1, Dy(III) and Ni(II) ions interconnect through carboxylic O donors of abtc(4-) ligands to generate a linear trimer "Hourglass"-type {NiDy2} cluster, and the adjacent trinuclear {NiDy2} units are bridged by HCOO(-) groups to give a 1D "ladder" chain, which is further bridged by abtc(4-) ligands to form a new topology and named as "zsw3". Alternating-current magnetic susceptibility results indicate that 1 exhibits frequency-dependent out-of-phase signals with two relaxation processes, which suggests that it shows single-molecule magnet (SMM) behavior and represents the first example by using an SMM cluster as the building block to create a 3D Ni-Ln HCP, to the best of our knowledge. The energy barriers for 1 under a 1000 Oe applied direct current magnetic field are estimated from Arrhenius plots to be 40 and 42 K at higher and lower frequencies, respectively. Additionally, the crystalline structure of 1 could be stable to at least 310 degrees C, supported by thermogravimetric analyses and in situ variable-temperature powder X-ray diffraction patterns. PMID- 26751742 TI - Magnetite/Polymer Brush Nanocomposites with Switchable Uptake Behavior Toward Methylene Blue. AB - The grafting from approach was used to prepare pH-responsive polyacid brushes using poly(itaconic acid) (PIA) and poly(acrylic acid) (PAA) at the amine functional groups of chitosan. Hybrid materials consisting of polymer brushes and magnetite nanoparticles (MNPs) were also prepared. The products were structurally characterized and displayed reversible pH-responsive behavior and controlled adsorption/desorption of methylene blue (MB). Switchable binding of MB involves cooperative effects due to conformational changes of brushes and swelling phenomena in solution which arise from response to changes in pH. Above the pKa, magnetic nanocomposites (MNCs) are deprotonated and display enhanced electrostatic interactions with high MB removal efficiency (>99%). Below the pKa, MNCs undergo self-assembly and release the cationic dye. The switchable binding of MB and the structure of the polymer brush between collapsed and extended forms relate to changes in osmotic pressure due to reversible ionization of acid groups at variable pH. Reversible adsorption-desorption with variable binding affinity and regeneration ability was demonstrated after five cycles. PMID- 26751743 TI - Moral expansiveness: Examining variability in the extension of the moral world. AB - The nature of our moral judgments-and the extent to which we treat others with care-depend in part on the distinctions we make between entities deemed worthy or unworthy of moral consideration-our moral boundaries. Philosophers, historians, and social scientists have noted that people's moral boundaries have expanded over the last few centuries, but the notion of moral expansiveness has received limited empirical attention in psychology. This research explores variations in the size of individuals' moral boundaries using the psychological construct of moral expansiveness and introduces the Moral Expansiveness Scale (MES), designed to capture this variation. Across 6 studies, we established the reliability, convergent validity, and predictive validity of the MES. Moral expansiveness was related (but not reducible) to existing moral constructs (moral foundations, moral identity, "moral" universalism values), predictors of moral standing (moral patiency and warmth), and other constructs associated with concern for others (empathy, identification with humanity, connectedness to nature, and social responsibility). Importantly, the MES uniquely predicted willingness to engage in prosocial intentions and behaviors at personal cost independently of these established constructs. Specifically, the MES uniquely predicted willingness to prioritize humanitarian and environmental concerns over personal and national self-interest, willingness to sacrifice one's life to save others (ranging from human out-groups to animals and plants), and volunteering behavior. Results demonstrate that moral expansiveness is a distinct and important factor in understanding moral judgments and their consequences. (PsycINFO Database Record PMID- 26751744 TI - Fracture Healing and its Disturbances. A Literature Review. AB - The healing of a bone fracture is a biological process depending on the activation of mesenchymal progenitors, their accumulation in the fracture gap, proliferation and differentiation into the osteoblastic cell lineage. Its aim is to form a callus in the fracture gap which is later remodelled into mature bone, restoring the mechanical properties lost in consequence of the fracture. Disturbances in fracture repair occur relatively often, causing therapeutic problems and increasing costs of treatment. They are caused by the lack of or damage to progenitor cells, disturbances in molecular regulation of their activation, homing, proliferation and differentiation into the osteoblastic cell lineage, or lack of appropriate environment for their optimal metabolism for fracture repair. This paper discusses the roles of individual factors crucial for the reparative process as well as the mechanisms responsible for their disturbances. PMID- 26751745 TI - Correlation between Hip Rotation Range-of-Motion Impairment and Low Back Pain. A Literature Review. AB - BACKGROUND: Hip rotation range-of-motion (ROM) impairment has been proposed as a contributing mechanical factor in the development of low back pain (LBP) symptoms. There is a hypothesis which suggests that a limited range of hip rotation results in compensatory lumbar spine rotation. Hence, LBP may develop as the result. This article reviews studies assessing hip rotation ROM impairment in the LBP population. MATERIAL AND METHODS: The MEDLINE and EMBASE databases were searched without time restriction. Two authors independently selected related articles using the same search strategy and key words. RESULTS: Among 124 articles 12 met the review inclusion criteria. The results of the studies are assessed in three sections, investigating the relationship between low back pain and 1) hip internal rotation ROM, 2) hip external rotation ROM and 3) hip total rotation ROM. Asymmetrical (right versus left, lead versus non-lead) and limited hip internal rotation ROM were common findings in patients with LBP. Reduced and asymmetrical total hip rotation was also observed in patients with LBP. However, none of the studies explicitly reported limited hip external rotation ROM. CONCLUSION: The precise assessment of hip rotation ROM, especially hip internal rotation ROM, must be included in the examination of patients with LBP symptoms. PMID- 26751746 TI - A Pre-fabricated Bracing System for the Management of Humeral Shaft Fractures: Experience of a Centre in the United Kingdom. AB - BACKGROUND: The aim of our study is to evaluate the ability of a pre- fabricated humeral bracing system in providing sufficient stability to fracture union and carry out a cost analysis comparing bracing versus surgical fixation for these fractures. MATERIAL AND METHODS: A review of humeral shaft fractures treated with a pre-fabricated humeral bracing system was undertaken. RESULTS: 20 humeral fractures (20 patients) were included. Mean patient age was 56.8 years (range 16- 89). There were 14 AO type A, 3 type B and 3 type C fractures. Median time interval from fracture to brace application was 8 days (range 0-41). Clinical and radiological union was achieved in 15 humeri (75%). Median time to clinical and radiological union was 80 days (range 32-434). The cost of treating humeral shaft fractures surgically by plating and by humeral bracing was estimated at L 2292.99 and L 1228 per case, respectively. CONCLUSIONS: 1. A pre-fabricated bracing system is an efficacious and cost-effective modality for humeral shaft fracture treatment. 2. It may, however, lead to a high non-union rate as well as shoulder and elbow stiffness. 3. A prospective randomized trial comparing bracing with internal fixation of humeral shaft fractures is needed. PMID- 26751747 TI - An Evaluation of Radiotherapy Effectiveness for Epicondylitis Humeri (EPH). AB - BACKGROUND: Humeral epicondylitis, a relatively common disease, is classified among inflammatory conditions of soft tissues and is frequently associated with elbow pain. The aim of the study was to assess the effectiveness of radiotherapy in patients with epicondylitis humeri. MATERIAL AND METHODS: The study was based on the observation of 50 cases. All patients were irradiated with 6-MV photons delivered in 1 Gy fraction doses, up to a total of 6 Gy, using two opposite coaxial fields. Follow-up examinations took place immediately after the treatment and at 1, 2-3, 4-6, 8-12, 19-24 and 26-30 months post-treatment. Pain relief, joint mobility, regional edema, joint temperature and the percentage of patients using analgesics were assessed. RESULTS: No adverse events were observed. The mean percentage of patients with pain relief was 22.8% directly after, compared to 70.2% at 8-12 months and 57.5% at 26-30 months post-treatment. A decrease in joint mobility was by 16% of the patients at one year after treatment and in 25% of the patients at 26-30 months after treatment. The percentages of patients with increased elbow temperature, elbow edema and analgesics uptake at the respective time points were 6% and 0%, 36% and 0%, and 0% and 37%. The percentage of patients reporting partial and complete pain relief was 41.7% and 45.8%, and 30% and 40%, respectively. CONCLUSION: Anti-inflammatory radiotherapy of patients with humeral epicondylitis is a safe and effective method of treatment. PMID- 26751748 TI - Reconstruction of Unstable Hips with Ilizarov Technique. Role of Pelvic Support and Distal Lengthening Realignment Osteotomy. AB - BACKGROUND: Hips can suffer severe damage due to untreated developmental dysplasia, septic arthritis, tuberculosis, a neglected fracture of the neck of femur and neglected hip dislocation. The Ilizarov technique offers an effective treatment by providing a stable hip with abolished Trendelenburg lurch and equalizing limb length discrepancy through distal lengthening realignment osteotomy. MATERIAL AND METHODS: 20 patients with hip instabilities due to various etiologies were treated with the Ilizarov technique of pelvic support osteotomy and distal lengthening realignment osteotomy. There were 12 females and 8 males in the study group and the age range was 13 to 30 years. Average limb length discrepancy was 5.95 cms (range 4-8.5 cms).The pre-operative and post operative range of motion and Harris hip score was collected and data analyzed by Student's paired t test. A p value of < 0.05 was taken to be statistically significant Results. The functional Harris hip score improved in all the patients at final follow-up. The mean Harris hip score was 56.95 (range 33-71) pre operatively, which improved to 83.25 (range 73-85) at final follow up and was statistically significant (P-value < 0.05). The mean length achieved was 5.53 cms (4-8 cms). The mean external fixation time was 8.6 months and the mean healing index was 1.54 months /cm. CONCLUSIONS: 1. Ilizarov hip reconstruction is an excellent method of salvage in patients with unstable hips diverse etiologies especially in this part of the world, where patients demand unrestricted range of motion at hip, and in the younger age group, where other procedures do not offer a long term solution. 2. It provides an excellent functional outcome in hips of different etiologies. 3. However, for an excellent outcome, surgical expertise, patient compliance and meticulous follow-up are mandatory. PMID- 26751750 TI - Assessment of Outcomes of Treatment of Fractures of Distal Femur with a Locking Plate Taking into Account Factors Influencing the Result. AB - BACKGROUND: The aim of this paper is to evaluate the results of treatment of distal femoral fractures (DFF) fixed with locking plates and analysis of factors that influence the final outcome. MATERIAL AND METHODS: The patients were treated at the Department of Traumatology and Orthopedics, Military Medical Institute in Warsaw, and the Department of Orthopedics and Traumatology, 4th Military Research Hospital in Wroclaw. We analysed 39 patients with 42 fractures of the distal femur. Treatment results were analysed using the KOOS and KSS scales. Factors influencing the outcome were also investigated. Statistical analysis was performed using STATISTICA v. 10. RESULTS: Mean KOOS scores indicate a predominance of poor outcomes, while mean KSS scores indicate good outcomes. Treatment outcomes were significantly influenced by pain and limited mobility. CONCLUSIONS: 1. Subjective evaluation of treatment of fractures of the distal femur using the KOOS scale per form edworse than a clinical evaluation using the KSS. 2. Post-operative management should emphasise pain relief and restoration of the performance of the treated lower limb to ensure good mobility without crutches. 3. Despite the use of modern operational methods of fracture fixation, treatment of distal femur fractures is still a challenge. PMID- 26751749 TI - Radiological Evaluation of Treatment of Periprosthetic Femoral Fractures. AB - BACKGROUND: Periprosthetic fracture of the femur is a common complication of total hip replacement surgery. There are several risk factors, including the female gender, an uncemented implant, the use of a straight or revision stem and secondary osteoarthritis. The aim of the study was a radiological evaluation of treatment of periprosthetic femoral fractures Material and methods. The study group consisted of patients who underwent hip replacement surgery at the Department of Orthopaedics and Traumatology, Medical University of Silesia, between 2002 and 2006. Radiologic evaluation of outcomes was based on the scheme developed by HIP Society, SICOT, AAOS and, additionally, on Beals and Tower's classification. RESULTS: The incidence of pathological findings, such as lucent zones along the stem-bone interface, crack of the cement and focal osteolysis of the greater trochanter and around the cement, did not exceed 10%. Lucent zones were most frequently seen in radiographs of cemented prostheses in Gruen's zones 2, 3 , 4 and 5. Cortical hypertrophy was seen medially in Gruen's zones 4, 5 and 6. Adams' arc osteolysis was found in 15.5% of patients with intraoperative fractures and almost 40% of patients with late fractures. Heterotopic ossification was noted only in 7 patients. CONCLUSIONS: 1. Radiological evaluation of treatment of periprosthetic femoral fractures after hip replacement surgery is one of the most difficult parts of patient status assessment in post surgical patients. 2. The most common pathological radiographic findings were stem subsidence and the presence of osteolytic foci around Adams' arc. 3. The occurrence of a periprosthetic fracture did not significantly affect Beals and Tower scores. PMID- 26751751 TI - Knee Function and Subjective Stability Following Total Condylar Arthroplasty in Joints with Preoperative Varus or Valgus Deformity. AB - BACKGROUND: Total knee arthroplasty in joints with valgus or varus deformity is technically demanding. Careful soft tissue balance as well as restitution of anatomical knee axis has a profound effect on postoperative function of the joint, however little is known about differences in subjective stability following surgery between preoperative valgus and varus knees. MATERIAL AND METHODS: Studied group consisted of 60 patients who underwent total condylar knee arthroplasty with one type of implant (Stryker Triathlon). Mean follow-up was 2,9 years (1-6 years). The group included 25 patients with valgus and 35 patients with varus preoperative deformity. All patients filled Knee Injury and Osteoarthritis Outcome Score (KOOS) forms. Detailed clinical and radiological assessment was performed. RESULTS: Mean KOOS score was slightly higher in patients with varus deformity, as compared to cases with valgus deformity. At physical examination higher LCL deficiency rate was observed in varus knees. Subjective instability was reported by eight patients (5 valgus and 3 varus). In all cases instability coexisted with decreased MCL tightness and implant position was correct in those patients. No subjective instability was reported by patients with clinical LCL deficiency. Furthermore KOOS scores in these patients were higher (85,8) as compared to cases with decreased MCL tension (79,1). CONCLUSIONS: 1. In patients with proper implant alignment subjective instability is related to postoperative MCL deficiency, regardless preoperative deformity in coronal plane. 2. The post-op LCL laxity does not compromise subjective stability, nor influence subjective outcome, as demonstrated with KOOS scores. PMID- 26751752 TI - Advantages and Complications Following Fassier-Duval Intramedullary Rodding in Children. Pilot Study. AB - BACKGROUND: The report presents the authors' experience with Fassier-Duval rods in children and an analysis of advantages and complications. MATERIAL AND METHODS: Over a period of 15 months, the authors operated on 10 children and 18 rod implantation procedures were performed. In five cases, the implantation was a primary procedure, while in the remaining 13 cases Fassier-Duval rods were used to replace short Rush rods. RESULTS: The mean follow-up was 18 months. Four children developed the following complications: lateral rod displacement within the distal epiphysis, male rod displacement outside the epiphysis ("negative telescoping"), retrograde displacement of the male rod from the distal epiphysis to the metaphysis and retrograde displacement of the female element beyond the greater trochanter. CONCLUSIONS: 1. FD rodding allows for decreasing the number of operations because the nails need not be replaced as the child grows older. 2. FD rod implantation is limited by the size of the medullary cavity of the bone, and thus the age of the patient. PMID- 26751753 TI - Assessment of the Therapeutic Effectiveness of Deep Electromagnetic Stimulation in Patients with Chronic Low Back Pain. AB - BACKGROUND: The study presents the results of the application of deep electromagnetic stimulation (DEMS) therapy in the treatment of low back pain. The study aimed to evaluate and compare pain severity before and after deep electromagnetic stimulation sessions and to assess persistence of the analgesic effect and identify factors which influenced it significantly. MATERIAL AND METHODS: The study enrolled a series of 105 consecutive patients with chronic low back pain who underwent a series of 10 sessions of deep electromagnetic stimulation. The effectiveness of the therapy was assessed according to VAS and Laitinen scores. Risk factors significantly affecting the stability of analgesic effect after DEMS therapy were identified using the Cox regression model. RESULTS: Statistically significant pain relief was observed after deep electromagnetic therapy. Both the Laitinen and VAS scales demonstrated the reduction in pain intensity by half (Me (IQR): 6 (5-9) before the therapy vs. 3 (24) afterwards, p<0.0001 for Laitinen scale and 7 (6-8) before vs. 3 (2-5) after the therapy, p<0.0001 for VAS). During 12-month follow up, pain recurred in 84 (80%) patients. Pain recurrence within a year after the therapy was stimulated in a statistically significant manner by pain duration (HR=1.032, 95% CI: 0.988 1.078; p=0.032) and the co-occurrence of degenerative joint disease (HR=5.521, 95%CI: 2.905-10.493; p=0.001). CONCLUSIONS: 1. Deep electromagnetic stimulation is an effective treatment in patients with chronic low back pain. 2. The degree of effectiveness of this modality in the longer term depends on the cause and duration of pain. PMID- 26751754 TI - High Pressure Injection Injury of the Thumb. Case Study. AB - High-pressure injection injury (HPII) is a rare severe hand trauma associated with high rates of complications and amputations of the peripheral parts of the fingers and permanent hand dysfunction. Early detection and treatment are crucial as any delay may result in a considerable functional deficit of the affected limb or amputation. The rate of amputation following HPII is 48%. This case report aims mainly to present the problem of HPII and general standards of management of such injuries. The routine use of supportive treatment in hyperbaric chambers, in the absence of contraindications, is also encouraged. PMID- 26751755 TI - Modular Approaches to Diversified Soft Lewis Basic Complexants through Suzuki Miyaura Cross-Coupling of Bromoheteroarenes with Organotrifluoroborates. AB - Remediation or transmutation of spent nuclear fuel obtained as a function of energy production and legacy waste remains a significant environmental concern. Substantive efforts over the last three decades have focused on the potential of soft-Lewis basic complexants for the chemoselective separation of trivalent actinides from lanthanides in biphasic solvent systems. Recent efforts in this laboratory have focused on the concept of modularity to rapidly prepare complexants and complexant scaffolds not easily accessible via traditional linear methods in a convergent manner to better understand solubility and complexation structure/activity function in process-relevant solvents. The current work describes an efficient method for the construction of diversified complexants through multi-Suzuki-Miyaura cross-coupling of bromoheteroarenes with organotrifluoroborates affording efficient access to 22 novel materials in 43-99% yield over two, three, or four cross-couplings on the same scaffold. Optimization of the catalyst/ligand system, application, and limitations are reported herein. PMID- 26751756 TI - Dielectrophoresis-Assisted Raman Spectroscopy of Intravesicular Analytes on Metallic Pyramids. AB - Chemical analysis of membrane-bound containers such as secretory vesicles, organelles, and exosomes can provide insights into subcellular biology. These containers are loaded with a range of important biomolecules, which further underscores the need for sensitive and selective analysis methods. Here we present a metallic pyramid array for intravesicular analysis by combining site selective dielectrophoresis (DEP) and Raman spectroscopy. Sharp pyramidal tips act as a gradient force generator to trap nanoparticles or vesicles from the solution, and the tips are illuminated by a monochromatic light source for concurrent spectroscopic detection of trapped analytes. The parameters suitable for DEP trapping were optimized by fluorescence microscopy, and the Raman spectroscopy setup was characterized by a nanoparticle based model system. Finally, vesicles loaded with 4-mercaptopyridine were concentrated at the tips and their Raman spectra were detected in real time. These pyramidal tips can perform large-area array-based trapping and spectroscopic analysis, opening up possibilities to detect molecules inside cells or cell-derived vesicles. PMID- 26751757 TI - Daily parental knowledge of youth activities is linked to youth physical symptoms and HPA functioning. AB - Considerable evidence documents linkages between parental knowledge of youth activities and youth risky behavior. We extended this research to determine whether parental knowledge was associated with youth physical health, including reports of physical symptoms (e.g., headaches, stomachaches) and a biomarker of hypothalamic pituitary adrenocortical (HPA) axis functioning (i.e., salivary cortisol levels). Participants were children of employees in the Information Technology division of a Fortune 500 company (N = 132, mean age youth = 13.39 years, 55% female) who participated in a daily diary study. Data were collected via telephone calls on 8 consecutive evenings. On 4 study days, cortisol samples were collected at 4 time points (waking, 30 min after waking, before dinner, bedtime). Multilevel models revealed that, at the between-person level, youth whose parents had higher average knowledge about their activities, exhibited lower bedtime cortisol levels. Furthermore, at the within-person level, on days when parents displayed more knowledge than usual (relative to their own 8-day average), youth had lower before-dinner cortisol than usual. Linkages between average parental knowledge and physical health symptoms were moderated by youth age: Younger but not older adolescents whose parents were more knowledgeable had fewer physical health symptoms, on average. A next step is to identify the processes that underlie these associations. PMID- 26751758 TI - Interplay between marital attributions and conflict behavior in predicting depressive symptoms. AB - Marital attributions-that is, causal inferences and explanations spouses make about their partners' behavior-have been implicated as predictors of relationship functioning. Extending previous work, we examined marital attributions as a moderator of the link between marital conflict and depressive symptoms 1 year later. Participants were 284 couples who reported on marital attributions and depressive symptoms. Couples also engaged in a videotaped marital conflict interaction, which was later coded for specific conflict behaviors. The results showed that husbands' and wives' marital attributions about their partner moderated relations between marital conflict behavior and later depressive symptoms, controlling for global marital sentiments. For husbands, positive behavior and affect during marital conflict predicted a decrease in depressive symptoms, but only for husbands' who made low levels of responsibility and causal attributions about their wives. Wives' causal attributions about their partner also moderated relations between positive behavior and affect during marital conflict and husbands' later depressive symptoms. Reflecting an unexpected finding, negative behavior and affect during marital conflict predicted increases in wives' depressive symptoms, but only for wives who made low levels of responsibility attributions about their partner. The findings suggest that, for husbands, low levels of negative marital attributions for spouses may be protective, strengthening the positive effect of constructive conflict behaviors for their mental health, whereas for wives low levels of responsibility attributions about their spouse may be a risk factor, exacerbating the negative effect of negative marital conflict behaviors on their later depressive symptoms. PMID- 26751759 TI - The roles of general and technology-related parenting in managing youth screen time. AB - This study examines the associations of 2 types of parenting practices-general adaptive parenting and technology-related strategies-with youth screen time. We hypothesized that technology-related parenting focused on behavioral control would relate directly to screen time and serve to link general parenting to screen time. Participants were 615 parents drawn from 3 community samples of families with children across 3 development stages: young childhood (3-7 years; n = 210), middle childhood (8-12 years; n = 200), and adolescents (13-17 years; n = 205). Using structural equation modeling, we found that general adaptive parenting was not related to child screen time but was positively related to technology-related parenting strategies for all 3 samples. For the young and, to some extent, middle childhood samples, but not for the adolescent sample, general adaptive parenting was positively linked to youth screen time through technology related parenting strategies. (PsycINFO Database Record PMID- 26751760 TI - Wenckebach-Second-Degree Heart Block and the Company It Keeps. PMID- 26751761 TI - Effect of Nanoclustering and Dipolar Interactions in Heat Generation for Magnetic Hyperthermia. AB - Biomedical magnetic colloids commonly used in magnetic hyperthermia experiments often display a bidisperse structure, i.e., are composed of stable nanoclusters coexisting with well-dispersed nanoparticles. However, the influence of nanoclusters in the optimization of colloids for heat dissipation is usually excluded. In this work, bidisperse colloids are used to analyze the effect of nanoclustering and long-range magnetic dipolar interaction on the magnetic hyperthermia efficiency. Two kinds of colloids, composed of magnetite cores with mean sizes of around 10 and 18 nm, coated with oleic acid and dispersed in hexane, and coated with meso-2,3-dimercaptosuccinic acid and dispersed in water, were analyzed. Small-angle X-ray scattering was applied to thoroughly characterize nanoparticle structuring. We proved that the magnetic hyperthermia performances of nanoclusters and single nanoparticles are distinctive. Nanoclustering acts to reduce the specific heating efficiency whereas a peak against concentration appears for the well-dispersed component. Our experiments show that the heating efficiency of a magnetic colloid can increase or decrease when dipolar interactions increase and that the colloid concentration, i.e., dipolar interaction, can be used to improve magnetic hyperthermia. We have proven that the power dissipated by an ensemble of dispersed magnetic nanoparticles becomes a nonextensive property as a direct consequence of the long-range nature of dipolar interactions. This knowledge is a key point in selecting the correct dose that has to be injected to achieve the desired outcome in intracellular magnetic hyperthermia therapy. PMID- 26751762 TI - USBombus, a database of contemporary survey data for North American Bumble Bees (Hymenoptera, Apidae, Bombus) distributed in the United States. AB - BACKGROUND: Bumble bees (Hymenoptera: Apidae, Bombus) are pollinators of wild and economically important flowering plants. However, at least four bumble bee species have declined significantly in population abundance and geographic range relative to historic estimates, and one species is possibly extinct. While a wealth of historic data is now available for many of the North American species found to be in decline in online databases, systematic survey data of stable species is still not publically available. The availability of contemporary survey data is critically important for the future monitoring of wild bumble bee populations. Without such data, the ability to ascertain the conservation status of bumble bees in the United States will remain challenging. NEW INFORMATION: This paper describes USBombus, a large database that represents the outcomes of one of the largest standardized surveys of bumble bee pollinators (Hymenoptera, Apidae, Bombus) globally. The motivation to collect live bumble bees across the United States was to examine the decline and conservation status of Bombus affinis, B. occidentalis, B. pensylvanicus, and B. terricola. Prior to our national survey of bumble bees in the United States from 2007 to 2010, there have only been regional accounts of bumble bee abundance and richness. In addition to surveying declining bumble bees, we also collected and documented a diversity of co-occuring bumble bees. However we have not yet completely reported their distribution and diversity onto a public online platform. Now, for the first time, we report the geographic distribution of bumble bees reported to be in decline (Cameron et al. 2011), as well as bumble bees that appeared to be stable on a large geographic scale in the United States (not in decline). In this database we report a total of 17,930 adult occurrence records across 397 locations and 39 species of Bombus detected in our national survey. We summarize their abundance and distribution across the United States and association to different ecoregions. The geospatial coverage of the dataset extends across 41 of the 50 US states, and from 0 to 3500 m a.s.l. Authors and respective field crews spent a total of 512 hours surveying bumble bees from 2007 to 2010. The dataset was developed using SQL server 2008 r2. For each specimen, the following information is generally provided: species, name, sex, caste, temporal and geospatial details, Cartesian coordinates, data collector(s), and when available, host plants. This database has already proven useful for a variety of studies on bumble bee ecology and conservation. However it is not publicly available. Considering the value of pollinators in agriculture and wild ecosystems, this large database of bumble bees will likely prove useful for investigations of the effects of anthropogenic activities on pollinator community composition and conservation status. PMID- 26751763 TI - The quality of information on the Internet on orthodontic retainer wear: a cross sectional study. AB - OBJECTIVES: The objectives of this study were to assess the accessibility, usability, reliability and quality of information on the Internet written for the lay public about orthodontic retainers, and to elucidate the different retention protocols encouraged. DESIGN: A cross-sectional, observational study. SETTING: Online, using a computer connected to the Internet in Australia. METHODS: Two search terms; 'orthodontic retainer' and 'how long should someone wear a retainer after their braces are removed?' were entered alternatively into five search engines. Twenty results for each search term per search engine that fulfilled the inclusion criteria were evaluated in terms of accessibility, usability, reliability and quality of information using the LIDA and DISCERN instruments, ensuring there were no internal or cross-search engine duplicates. Any information about frequency and duration of retainer wear was also collected. RESULTS: Two hundred different websites were identified and assessed. The median overall LIDA score was 72%, corresponding to a moderate quality level. The median total DISCERN score was 47%. Twenty-two websites recommended patients adhere to the specific protocol prescribed to them by their practitioner. There were 45 (22.5%) and 28 (14%) websites advising indefinite use of removable and bonded retainers respectively. CONCLUSIONS: Information about retainers on the Internet is easily accessible and usable, though the quality of the content is generally of a moderate level. However, the information is not always accurate and reliable. Both full-time and part-time wear of removable retainers was suggested over greatly varying time periods. Indefinite wear of removable and bonded retainers was also advocated. PMID- 26751764 TI - Mangiferin suppressed advanced glycation end products (AGEs) through NF-kappaB deactivation and displayed anti-inflammatory effects in streptozotocin and high fat diet-diabetic cardiomyopathy rats. AB - Given the importance of the aggregation of advanced glycation end products (AGEs) and cardiac inflammation in the onset and progression of diabetic cardiomyopathy (DCM), our objective in this study was to demonstrate the cardioprotective effect of mangiferin, an antidiabetic and anti-inflammatory agent, on diabetic rat model. The DCM model was established by a high-fat diet and a low dose of streptozotocin. DCM rats were treated orally with mangiferin (20 mg/kg) for 16 weeks. Serum and left ventricular myocardium were collected for determination of inflammatory cytokines. AGEs mRNA and protein expression of nuclear factor kappa B (NF-kappaB) and receptor for AGEs (RAGE) in myocardium were assayed by real time PCR and Western blot. ROS levels were measured by dihydroethidium fluorescence staining. NF-kappaB binding activity was assayed by TransAM NF kappaB p65 ELISA kit. Chronic treatment with mangiferin decreased the levels of myocardial enzymes (CK-MB, LDH) and inflammatory mediators (TNF-alpha, IL-1beta). Meanwhile, NF-kappaB is inhibited by the reduction of nuclear translocation of p65 subunit, and mangiferin reduced AGE production and decreased the mRNA and protein expression of RAGE in DCM rats. Our data indicated that mangiferin could significantly ameliorate DCM by preventing the release of inflammatory cytokines, and inhibiting ROS accumulation, AGE/RAGE production, and NF-kappaB nuclear translocation, suggesting that mangiferin treatment might be beneficial in DCM. PMID- 26751765 TI - Validation and evaluation of serological correlates of protection for inactivated enterovirus 71 vaccine in children aged 6-35 months. AB - BACKGROUND: A primary goal of this study was to establish the serological mechanistic correlate of protection (mCoP) for an inactivated Enterovirus 71 (EV71) vaccine. METHODS: We used the Prentice criterion framework and scaled logit model to explore the relationship between the neutralizing antibody (NTAb) and EV71-associated disease, and to build a protection curve for estimating the efficacy of EV71 vaccine. Data of NTAb at day 56 post-vaccination and the occurrence of EV71-associated disease during a 12-month follow-up period were collected from a phase 3 efficacy trial of EV71 vaccine in this study. RESULTS: NTAb at day 56 post-vaccination in participants met the Prentice criterion framework. According to the protection curve, the antibody levels of 14.7, 27.8, 55.7, 129.0 and 459.4 (U/mL) were associated with 50%, 60%, 70%, 80% and 90% clinical protection rate, respectively. Vaccine efficacy predicted by the model was 81.5%, which was very similar to the actual vaccine efficacy of 80.4% (95% CI, 58.2, 90.8) observed in the phase 3 trial. CONCLUSIONS: NTAb titers post vaccination can be validated as mCoP for evaluating the efficacy of an inactivated enterovirus 71 vaccine, with a titers of 14.7 (U/ml) as a surrogate associated with the protection of 50% against EV71-associated disease. PMID- 26751766 TI - Primary hip replacement stem taper fracture due to corrosion in 3 patients. PMID- 26751767 TI - Montelukast versus Dexamethasone Treatment in a Guinea Pig Model of Chronic Pulmonary Neutrophilic Inflammation. AB - Airway inflammation in chronic obstructive pulmonary disease (COPD) is refractory to corticosteroids and hence COPD treatment is hindered and insufficient. This study assessed the effects of oral treatment with Montelukast (10 and 30 mg/kg) or dexamethasone (20 mg/kg) for 20 days on COPD model induced by chronic exposure to lipopolysaccharide (LPS). Six groups of male guinea pigs were studied. Group 1: naive group, group 2: exposed to saline nebulization. Groups 3, 4, 5, and 6: exposed to 9 nebulizations of LPS (30 MUg/ml) for 1 hour, 48 hours apart with or without treatment with Montelukast or dexamethasone. Airway hyperreactivity (AHR) to methacholine (MCh), histopathological study and bronchoalveolar lavage fluid (BALF) as well as lung tissue analyses were performed 48 hours after the final exposure to LPS (day 20). LPS-induced pulmonary dysfunction was associated with increased neutrophil count, leukotriene (LT) B4, and tumor necrosis factor (TNF) alpha in BALF. Moreover, there was an increase in malondialdehyde (MDA) level and a decrease in histone deacetylases(HDAC) activity in the lung tissue. Both Montelukast (10 or 30 mg /kg) and dexamethasone significantly reduced neutrophil count in BALF and inflammatory cells in lung parenchyma as well as TNF-alpha, and MDA levels. However, dexamethasone was more effective (p < 0.05). Montelukast, at a dose of 30 mg /kg, significantly reduced specific airway resistance after the 9th LPS exposure, attenuated AHR to MCh, decreased LTB4 and increased HDAC activity in comparison to dexamethasone. These results suggest that treatment with Montelukast can be useful in chronic airway inflammatory diseases including COPD poorly responsive to glucocorticoids. PMID- 26751769 TI - Stochastic stick-slip nanoscale friction on oxide surfaces. AB - The force needed to move a nanometer-scale contact on various oxide surfaces has been studied using an atomic force microscope and theoretical modeling. Force distance traces unveil a stick-slip movement with erratic slip events separated by several nanometers. A linear scaling of friction force with normal load along with low pull-off forces reveals dispersive adhesive interactions at the interface. We model our findings by considering a variable Lennard-Jones-like interaction potential, which accounts for slip-induced variation of the effective contact area. The model explains the formation and fluctuation of stick-slip phases and provides guidelines for predicting transitions from stick-slip to continuous sliding on oxide surfaces. PMID- 26751768 TI - Replication landscape of the human genome. AB - Despite intense investigation, human replication origins and termini remain elusive. Existing data have shown strong discrepancies. Here we sequenced highly purified Okazaki fragments from two cell types and, for the first time, quantitated replication fork directionality and delineated initiation and termination zones genome-wide. Replication initiates stochastically, primarily within non-transcribed, broad (up to 150 kb) zones that often abut transcribed genes, and terminates dispersively between them. Replication fork progression is significantly co-oriented with the transcription. Initiation and termination zones are frequently contiguous, sometimes separated by regions of unidirectional replication. Initiation zones are enriched in open chromatin and enhancer marks, even when not flanked by genes, and often border 'topologically associating domains' (TADs). Initiation zones are enriched in origin recognition complex (ORC)-binding sites and better align to origins previously mapped using bubble trap than lambda-exonuclease. This novel panorama of replication reveals how chromatin and transcription modulate the initiation process to create cell-type specific replication programs. PMID- 26751770 TI - CHK2 stability is regulated by the E3 ubiquitin ligase SIAH2. AB - The serine threonine checkpoint kinase 2 (CHK2) is a critical protein involved in the DNA damage-response pathway, which is activated by phosphorylation inducing cellular response such as DNA repair, cell-cycle regulation or apoptosis. Although CHK2 activation mechanisms have been amply described, very little is known about degradation control processes. In the present study, we identify the ubiquitin E3 ligase SIAH2 as an interaction partner of CHK2, which mediates its ubiquitination and proteasomal degradation. CHK2 degradation is independent of both its activation and its kinase activity, but also of the phosphorylation in S456. We show that SIAH2-deficient cells present CHK2 accumulation together with lower ubiquitination levels. Accordingly, SIAH2 depletion by siRNA increases CHK2 levels. In response to DNA damage induced by etoposide, interaction between both proteins is disrupted, thus avoiding CHK2 degradation and promoting its stabilization. We also found that CHK2 phosphorylates SIAH2 at three residues (Thr26, Ser28 and Thr119), modifying its ability to regulate certain substrates. Cellular arrest in the G2/M phase induced by DNA damage is reverted by SIAH2 expression through the control of CHK2 levels. We observed that hypoxia decreases CHK2 levels in parallel to SIAH2 induction. Similarly, we provide evidence suggesting that resistance to apoptosis induced by genotoxic agents in cells subjected to hypoxia could be partly explained by the mutual regulation between both proteins. These results indicate that SIAH2 regulates CHK2 basal turnover, with important consequences on cell-cycle control and on the ability of hypoxia to alter the DNA damage-response pathway in cancer cells. PMID- 26751772 TI - FOXA1 acts upstream of GATA2 and AR in hormonal regulation of gene expression. AB - Hormonal regulation of gene expression by androgen receptor (AR) is tightly controlled by many transcriptional cofactors, including pioneer factors FOXA1 and GATA2, which, however, exhibit distinct expression patterns and functional roles in prostate cancer. Here, we examined how FOXA1, GATA2 and AR crosstalk and regulate hormone-dependent gene expression in prostate cancer cells. Chromatin immunoprecipitation sequencing analysis revealed that FOXA1 reprograms both AR and GATA2 cistrome by preferably recruiting them to FKHD-containing genomic sites. By contrast, GATA2 is unable to shift AR or FOXA1 to GATA motifs. Rather, GATA2 co-occupancy enhances AR and FOXA1 binding to nearby ARE and FKHD sites, respectively. Similarly, AR increases, but not reprograms, GATA2 and FOXA1 cistromes. Concordantly, GATA2 and AR strongly enhance the transcriptional program of each other, whereas FOXA1 regulates GATA2- and AR-mediated gene expression in a context-dependent manner due to its reprogramming effects. Taken together, our data delineated for the first time the distinct mechanisms by which GATA2 and FOXA1 regulate AR cistrome and suggest that FOXA1 acts upstream of GATA2 and AR in determining hormone-dependent gene expression in prostate cancer. PMID- 26751771 TI - CFTR is a tumor suppressor gene in murine and human intestinal cancer. AB - CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR promotes chloride and bicarbonate secretion, playing an essential role in ion and acid-base homeostasis. Cftr has been identified as a candidate driver gene for colorectal cancer (CRC) in several Sleeping Beauty DNA transposon-based forward genetic screens in mice. Further, recent epidemiological and clinical studies indicate that CF patients are at high risk for developing tumors in the colon. To investigate the effects of CFTR dysregulation on GI cancer, we generated Apc(Min) mice that carried an intestinal specific knockout of Cftr. Our results indicate that Cftr is a tumor suppressor gene in the intestinal tract as Cftr mutant mice developed significantly more tumors in the colon and the entire small intestine. In Apc(+/+) mice aged to ~1 year, Cftr deficiency alone caused the development of intestinal tumors in >60% of mice. Colon organoid formation was significantly increased in organoids created from Cftr mutant mice compared with wild-type controls, suggesting a potential role of Cftr in regulating the intestinal stem cell compartment. Microarray data from the Cftr-deficient colon and the small intestine identified dysregulated genes that belong to groups of immune response, ion channel, intestinal stem cell and other growth signaling regulators. These associated clusters of genes were confirmed by pathway analysis using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA). We also conducted RNA Seq analysis of tumors from Apc(+/+) Cftr knockout mice and identified sets of genes dysregulated in tumors including altered Wnt beta-catenin target genes. Finally we analyzed expression of CFTR in early stage human CRC patients stratified by risk of recurrence and found that loss of expression of CFTR was significantly associated with poor disease-free survival. PMID- 26751773 TI - Expression of a mutant prohibitin from the aP2 gene promoter leads to obesity linked tumor development in insulin resistance-dependent manner. AB - A critical unmet need for the study of obesity-linked cancer is the lack of preclinical models that spontaneously develop obesity and cancer sequentially. Prohibitin (PHB) is a pleiotropic protein that has a role in adipose and immune functions. We capitalized on this attribute of PHB to develop a mouse model for obesity-linked tumor. We achieved this by expressing Y114F-PHB (m-PHB) from the aP2 gene promoter for simultaneous manipulation of adipogenic and immune signaling functions. The m-PHB mice develop obesity in a sex-neutral manner, but only male mice develop impaired glucose homeostasis and hyperinsulinemia similar to transgenic mice expressing PHB. Interestingly, only male m-PHB mice develop histiocytosis with lymphadenopathy, suggesting that metabolic dysregulation or m PHB alone is not sufficient for the tumor development and that both are required for tumorigenesis. Moreover, ovariectomy in female m-PHB mice resulted in impaired glucose homeostasis, hyperinsulinemia and consequently tumor development similar to male m-PHB mice. These changes were not observed in sham-operated control m-Mito-Ob mice, further confirming the role of obesity-related metabolic dysregulation in tumor development in m-PHB mice. Our data provide a proof-of concept that obesity-associated hyperinsulinemia promotes tumor development by facilitating dormant mutant to manifest and reveals a sex-dimorphic role of PHB in adipose-immune interaction or immunometabolism. Targeting PHB may provide a unique opportunity for the modulation of immunometabolism in obesity, cancer and in immune diseases. PMID- 26751777 TI - The Dissociation Between Viral Load Suppression and Retention in Care. PMID- 26751774 TI - MUC5AC interactions with integrin beta4 enhances the migration of lung cancer cells through FAK signaling. AB - MUC5AC is a secretory mucin aberrantly expressed in various cancers. In lung cancer, MUC5AC is overexpressed in both primary and metastatic lesions; however, its functional role is not well understood. The present study was aimed at evaluating mechanistic role of MUC5AC on metastasis of lung cancer cells. Clinically, the overexpression of MUC5AC was observed in lung cancer patient tissues and was associated with poor survival. In addition, the overexpression of Muc5ac was also observed in genetically engineered mouse lung adenocarcinoma tissues (Kras(G12D); Trp53(R172H/+); AdCre) in comparison with normal lung tissues. Our functional studies showed that MUC5AC knockdown resulted in significantly decreased migration in two lung cancer cell lines (A549 and H1437) as compared with scramble cells. Expression of integrins (alpha5, beta1, beta3, beta4 and beta5) was decreased in MUC5AC knockdown cells. As both integrins and MUC5AC have a von Willebrand factor domain, we assessed for possible interaction of MUC5AC and integrins in lung cancer cells. MUC5AC strongly interacted only with integrin beta4. The co-localization of MUC5AC and integrin beta4 was observed both in A549 lung cancer cells as well as genetically engineered mouse adenocarcinoma tissues. Activated integrins recruit focal adhesion kinase (FAK) that mediates metastatic downstream signaling pathways. Phosphorylation of FAK (Y397) was decreased in MUC5AC knockdown cells. MUC5AC/integrin beta4/FAK mediated lung cancer cell migration was confirmed through experiments utilizing a phosphorylation (Y397)-specific FAK inhibitor. In conclusion, overexpression of MUC5AC is a poor prognostic marker in lung cancer. MUC5AC interacts with integrin beta4 that mediates phosphorylation of FAK at Y397 leading to lung cancer cell migration. PMID- 26751775 TI - SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment. AB - Most tumors initially respond to cytotoxic treatments, but acquired resistance often follows. The tumor microenvironment (TME) is a major barrier to clinical success by compromising therapeutic efficacy, and pathological relevance of multiple soluble factors released by a therapeutically remodeled TME remains largely unexplored. Here we show that the secreted frizzled-related protein 2 (SFRP2), a Wnt pathway modulator, is produced by human primary fibroblasts after genotoxic treatments. SFRP2 induction is remarkable in tumor stroma, with transcription mainly modulated by the nuclear factor-kappaB (NF-kappaB) complex, a property shared by several effectors of the DNA damage secretory program. Instead of directly altering canonical Wnt signaling, SFRP2 augments beta-catenin activities initiated by WNT16B, another soluble factor from DNA-damaged stroma. WNT16B recognizes cancer cell surface receptors including frizzled (FZD) 3/4/6, a process enhanced by SFRP2, coordinated by the co-receptor LRP6 but subject to abrogation by DKK1. Importantly, we found WNT16B plays a central role in promoting advanced malignancies particularly acquired resistance by counteracting cell death, an effect that can be minimized by a neutralizing antibody co administered with classical chemotherapy. Furthermore, DNA damage-triggered expression of WNT16B is systemic, imaged by significant induction among diverse solid organs and circulation in peripheral blood, thereby holding promise as not only a TME-derived anticancer target but also a novel biomarker for clinical evaluation of treatment efficacy. Overall, our study substantiates the biological complexity and pathological implication of a therapy-activated TME, and provides the proof of principle of co-targeting tumor and the TME to prevent acquired resistance, with the aim of improving intervention outcome in an era of precision medicine. PMID- 26751778 TI - Physical activity in chronic home-living and sub-acute hospitalized stroke patients using objective and self-reported measures. AB - BACKGROUND: Despite confirmed reduced physical activity (PA) after stroke in various stages of recovery, the type of activities stroke patients executed and the time spent at different activity levels have not been sufficiently verified with stroke-validated assessment tools. DESIGN: Observational study. OBJECTIVE: To determine PA of sub-acute stroke patients hospitalized in a rehabilitation centre (HOS) compared to chronic home-living stroke patients (HOM) using objective and self-reported measures during 2 weekdays and 1 weekend day. METHODS: Fifteen HOS and 15 HOM patients wore a Sense Wear Pro 2 accelerometer (METs*minutes/24 h) and a knee-worn pedometer Yamax Digi Walker SW 200 (steps) and filled in a coded activity diary (kcal/24 h; METs*minutes/24 h) during three consecutive days. RESULTS: In HOM significantly more steps (stepstotal HOM = 18722.6 +/- 10063.6; stepstotal HOS = 7097.8 +/- 5850.5) and higher energy expenditure (EE) levels (EEtotal HOM = 7759.34 +/- 2243.04; EEtotal HOS = 5860.15 +/- 1412.78) were measured. In this group less moderate activity (>=3-6 <= METs) was performed on a weekday (pday1 = 0.006; pday2 = 0.027) and in total (p = 0.037). Few therapy hours (physical, occupational and speech therapy, and psychological support) were provided in HOM compared to HOS (p < 0.001). Vigorous activities were only seen in HOM. In both groups few patients executed sport activities. CONCLUSIONS: In HOM significantly more steps were performed and higher EE values were measured. However, participation in moderate activities and time spent on therapy were less in HOM. Evaluating PA with quantitative measures is feasible in both chronic home-living and sub-acute hospitalized patients with stroke. PMID- 26751779 TI - Mandatory Nap Times and Group Napping Patterns in Child Care: An Observational Study. AB - Policy provision for naps is typical in child care settings, but there is variability in the practices employed. One practice that might modify children's early sleep patterns is the allocation of a mandatory nap time in which all children are required to lie on their beds without alternate activity permitted. There is currently limited evidence of the effects of such practices on children's napping patterns. This study examined the association between duration of mandatory nap times and group-level napping patterns in child care settings. Observations were undertaken in a community sample of 113 preschool rooms with a scheduled nap time (N = 2,114 children). Results showed that 83.5% of child care settings implemented a mandatory nap time (range = 15-145 min) while 14.2% provided alternate activities for children throughout the nap time period. Overall, 31% of children napped during nap times. Compared to rooms with <= 30 min of mandatory nap time, rooms with 31-60 min and > 60 min of mandatory nap time had a two-and-a-half and fourfold increase, respectively, in the proportion of children napping. Nap onset latency did not significantly differ across groups. Among preschool children, exposure to longer mandatory nap times in child care may increase incidence of napping. PMID- 26751776 TI - Distinct routes to metastasis: plasticity-dependent and plasticity-independent pathways. AB - The cascade that culminates in macrometastases is thought to be mediated by phenotypic plasticity, including epithelial-mesenchymal and mesenchymal epithelial transitions (EMT and MET). Although there is substantial support for the role of EMT in driving cancer cell invasion and dissemination, much less is known about the importance of MET in the later steps of metastatic colonization. We created novel reporters, which integrate transcriptional and post transcriptional regulation, to test whether MET is required for metastasis in multiple in vivo cancer models. In a model of carcinosarcoma, metastasis occurred via an MET-dependent pathway; however, in two prostate carcinoma models, metastatic colonization was MET independent. Our results provide evidence for both MET-dependent and MET-independent metastatic pathways. PMID- 26751781 TI - Dermatopathology quiz: Cerebriform papules of the scrotum. PMID- 26751780 TI - Rhythmic coordination of hippocampal neurons during associative memory processing. AB - Hippocampal oscillations are dynamic, with unique oscillatory frequencies present during different behavioral states. To examine the extent to which these oscillations reflect neuron engagement in distinct local circuit processes that are important for memory, we recorded single cell and local field potential activity from the CA1 region of the hippocampus as rats performed a context guided odor-reward association task. We found that theta (4-12 Hz), beta (15-35 Hz), low gamma (35-55 Hz), and high gamma (65-90 Hz) frequencies exhibited dynamic amplitude profiles as rats sampled odor cues. Interneurons and principal cells exhibited unique engagement in each of the four rhythmic circuits in a manner that related to successful performance of the task. Moreover, principal cells coherent to each rhythm differentially represented task dimensions. These results demonstrate that distinct processing states arise from the engagement of rhythmically identifiable circuits, which have unique roles in organizing task relevant processing in the hippocampus. PMID- 26751782 TI - Seasonal variation in major depressive episode prevalence in Canada. AB - BACKGROUND: The purpose of this paper is to describe variation, over the months of the year, in major depressive episode (MDE) prevalence. This is an important aspect of the epidemiological description of MDE, and one that has received surprisingly little attention in the literature. Evidence of seasonal variation in MDE prevalence has been weak and contradictory. Most studies have sought to estimate the prevalence of seasonal affective disorder using cut-points applied to scales assessing mood seasonality rather than MDE. This approach does not align with modern classification in which seasonal depression is a diagnostic subtype of major depression rather than a distinct category. Also, some studies may have lacked power to detect seasonal differences. We addressed these limitations by examining the month-specific occurrence of conventionally defined MDE and by pooling data from large epidemiological surveys to enhance precision in the analysis. METHOD: Data from two national survey programmes (the National Population Health Survey and the Canadian Community Health Survey) were used, providing ten datasets collected between 1996 and 2013, together including over 500,000. These studies assessed MDE using a short form version of the Composite International Diagnostic Interview (CIDI) for major depression, with one exception being a 2012 survey that used a non-abbreviated version of the CIDI. The proportion of episodes occurring in each month was evaluated using items from the diagnostic modules and statistical methods addressing complex design features of these trials. Overall month-specific pooled estimates and associated confidence intervals were estimated using random effects meta-analysis and a gradient was assessed using a meta-regression model that included a quadratic term. RESULTS: There was considerable sampling variability when the month specific proportions were estimated from individual survey datasets. However, across the various datasets, there was sufficient homogeneity to justify the pooling of these estimated proportions, producing large gains in precision. Seasonal variation was clearly evident in the pooled data. The highest proportion of episodes occurred in December, January and February and the lowest proportions occurred in June, July and August. The proportion of respondents reporting MDE in January was 70% higher than August, suggesting an association with implications for health policy. The pattern persisted with stratification for age group, sex and latitude. CONCLUSIONS: Seasonal effects in MDE may have been obscured by small sample sizes in prior studies. In Canada, MDE has clear seasonal variation, yet this is not addressed in the planning of services. These results suggest that availability of depression treatment should be higher in the winter than the summer months. PMID- 26751783 TI - Cell-Specific Cre Strains For Genetic Manipulation in Salivary Glands. AB - The secretory acinar cells of the salivary gland are essential for saliva secretion, but are also the cell type preferentially lost following radiation treatment for head and neck cancer. The source of replacement acinar cells is currently a matter of debate. There is evidence for the presence of adult stem cells located within specific ductal regions of the salivary glands, but our laboratory recently demonstrated that differentiated acinar cells are maintained without significant stem cell contribution. To enable further investigation of salivary gland cell lineages and their origins, we generated three cell-specific Cre driver mouse strains. For genetic manipulation in acinar cells, an inducible Cre recombinase (Cre-ER) was targeted to the prolactin-induced protein (Pip) gene locus. Targeting of the Dcpp1 gene, encoding demilune cell and parotid protein, labels intercalated duct cells, a putative site of salivary gland stem cells, and serous demilune cells of the sublingual gland. Duct cell-specific Cre expression was attempted by targeting the inducible Cre to the Tcfcp2l1 gene locus. Using the R26Tomato Red reporter mouse, we demonstrate that these strains direct inducible, cell-specific expression. Genetic tracing of acinar cells using PipGCE supports the recent finding that differentiated acinar cells clonally expand. Moreover, tracing of intercalated duct cells expressing DcppGCE confirms evidence of duct cell proliferation, but further analysis is required to establish that renewal of secretory acinar cells is dependent on stem cells within these ducts. PMID- 26751784 TI - Frequency and Risk Factors for Cerebral Arterial Disease in a HIV/AIDS Neuroimaging Cohort. AB - BACKGROUND: Infection with HIV predisposes patients to a myriad of neurologic disorders, including cerebrovascular disease. The pathophysiology is likely multifactorial, with proposed mechanisms including infectious vasculitis, HIV induced endothelial dysfunction and adverse effects of combination antiretroviral therapy (cART). Epidemiologic data on clinically evident cerebral vasculopathy in HIV-infected adults is scarce, even though stroke hospitalizations are rising in this patient population. METHODS: A total of 6,298 HIV-infected adults (San Francisco General Hospital, 2000-2013) were screened to generate a cohort of patients with dedicated neuroimaging of the intra- and extracranial cerebral vasculature. We extracted information regarding the extent of HIV disease (including serial viral load and CD4 counts), cardiovascular disease risk factors and exposure to cART (cross-referenced with pharmacy records) and performed multivariate logistic regression analysis to identify predictors of vasculopathy. RESULTS: Of 144 patients, 55 patients (38.2%) had radiographic evidence of cerebral vasculopathy. Twenty (13.9%) had a vasculopathy characterized by vessel dolichoectasia and intracranial aneurysm formation. Thirty-five patients (24.3%) had intra- and or extracranial stenosis/occlusion. cART use (OR 2.27, 95% CI 1.03 5) and tobacco abuse (OR 2.35, 95% CI 1.04-5.25) were independently associated with the development of any vasculopathy, whereas cART use was also an independent risk factor for the stenosis/occlusion subtype specifically (OR 2.87, 95% CI 1.11-7.45). CONCLUSIONS: There was a high frequency of cerebral arterial disease in this neuroimaging cohort of HIV/AIDS patients. A history of cART use and a history of tobacco abuse were independent risk factors for vasculopathy, though these findings should be confirmed with large-scale prospective studies. PMID- 26751785 TI - Urban Scaling of Cities in the Netherlands. AB - We investigated the socioeconomic scaling behavior of all cities with more than 50,000 inhabitants in the Netherlands and found significant superlinear scaling of the gross urban product with population size. Of these cities, 22 major cities have urban agglomerations and urban areas defined by the Netherlands Central Bureau of Statistics. For these major cities we investigated the superlinear scaling for three separate modalities: the cities defined as municipalities, their urban agglomerations and their urban areas. We find superlinearity with power-law exponents of around 1.15. But remarkably, both types of agglomerations underperform if we compare for the same size of population an agglomeration with a city as a municipality. In other words, an urban system as one formal municipality performs better as compared to an urban agglomeration with the same population size. This effect is larger for the second type of agglomerations, the urban areas. We think this finding has important implications for urban policy, in particular municipal reorganizations. A residual analysis suggests that cities with a municipal reorganization recently and in the past decades have a higher probability to perform better than cities without municipal restructuring. PMID- 26751786 TI - Rutin-Mediated Priming of Plant Resistance to Three Bacterial Pathogens Initiating the Early SA Signal Pathway. AB - Flavonoids are ubiquitous in the plant kingdom and have many diverse functions, including UV protection, auxin transport inhibition, allelopathy, flower coloring and insect resistance. Here we show that rutin, a proud member of the flavonoid family, could be functional as an activator to improve plant disease resistances. Three plant species pretreated with 2 mM rutin were found to enhance resistance to Xanthomonas oryzae pv. oryzae, Ralstonia solanacearum, and Pseudomonas syringae pv. tomato strain DC3000 in rice, tobacco and Arabidopsis thaliana respectively. While they were normally propagated on the cultural medium supplemented with 2 mM rutin for those pathogenic bacteria. The enhanced resistance was associated with primed expression of several pathogenesis-related genes. We also demonstrated that the rutin-mediated priming resistance was attenuated in npr1, eds1, eds5, pad4-1, ndr1 mutants, and NahG transgenic Arabidopsis plant, while not in either snc1-11, ein2-5 or jar1 mutants. We concluded that the rutin-priming defense signal was modulated by the salicylic acid (SA)-dependent pathway from an early stage upstream of NDR1 and EDS1. PMID- 26751787 TI - Follicular fluid dehydroepiandrosterone sulfate is a credible marker of oocyte maturity and pregnancy outcome in conventional in vitro fertilization cycles. AB - AIM: To investigate if the level of dehydroepiandrosterone sulfate (DHEA-s) in follicular fluid (FF) influences the competence of oocytes to fertilize, develop to the blastocyst stage, and produce a viable pregnancy in conventional in vitro fertilization (IVF) cycles. SETTINGS AND DESIGN: Prospective study of age matched, nonpolycystic ovary syndrome (PCOS) women undergoing antagonist stimulation protocol involving conventional insemination and day 5 blastocyst transfer. MATERIALS AND METHODS: FF levels of DHEA-s and E2 were measured by a radio-immuno-assay method using diagnostic kits. Fertilization rate, embryo development to the blastocyst stage and live birth rate were main outcome measures. Cycles were divided into pregnant/nonpregnant groups and also into low/medium/high FF DHEA-s groups. Statistical analysis was done by GraphPad Prism V software. RESULTS: FF DHEA-s levels were significantly higher in pregnant (n = 111) compared to nonpregnant (n = 381) group (1599 +/- 77.45 vs. 1372 +/- 40.47 ng/ml; P = 0.01). High (n = 134) FF DHEA-s group had significantly higher percentage of metaphase II (MII) oocytes (91.5 vs. 85.54 vs. 79.44%, P < 0.0001), fertilization rate (78.86 vs. 74.16 vs. 71.26%, P < 0.0001), cleavage rate (83.67 vs. 69.1 vs. 66.17%, P = 0.0002), blastocyst formation rate (37.15 vs. 33.01 vs. 26.95%, P < 0.0001), and live birth rate (29.85 vs. 22.22 vs. 14.78%, P = 0.017) compared to medium (n = 243) and low (n = 115) FF DHEA-s groups, respectively despite comparable number of oocytes retrieved and number of blastocysts transferred. FF DHEA-s levels correlated significantly with the attainment of MII oocytes (Pearson r = 0.41) and fertilization rates (Pearson r = 0.35). CONCLUSION: FF DHEA-s level influences the oocyte maturation process and is predictive of fertilization, embryo development to the blastocyst stage and live birth rates in non-PCOS women undergoing conventional IVF cycles. PMID- 26751788 TI - Genome-Wide Analysis Reveals Novel Regulators of Growth in Drosophila melanogaster. AB - Organismal size depends on the interplay between genetic and environmental factors. Genome-wide association (GWA) analyses in humans have implied many genes in the control of height but suffer from the inability to control the environment. Genetic analyses in Drosophila have identified conserved signaling pathways controlling size; however, how these pathways control phenotypic diversity is unclear. We performed GWA of size traits using the Drosophila Genetic Reference Panel of inbred, sequenced lines. We find that the top associated variants differ between traits and sexes; do not map to canonical growth pathway genes, but can be linked to these by epistasis analysis; and are enriched for genes and putative enhancers. Performing GWA on well-studied developmental traits under controlled conditions expands our understanding of developmental processes underlying phenotypic diversity. PMID- 26751789 TI - Adiposity Is Associated with Gender-Specific Reductions in Left Ventricular Myocardial Perfusion during Dobutamine Stress. AB - BACKGROUND: Obesity and visceral adiposity are increasingly recognized risk factors for cardiovascular disease. Visceral fat may reduce myocardial perfusion by impairing vascular endothelial function. Women experience more anginal symptoms compared to men despite less severe coronary artery stenosis, as assessed by angiography. Women and men have different fat storage patterns which may account for the observed differences in cardiovascular disease. Therefore, our objective was to evaluate the relationship between visceral adipose tissue distributions and myocardial perfusion in men and women. METHODS: Visceral and subcutaneous fat distributions and myocardial perfusion were measured in 69 men and women without coronary artery disease using magnetic resonance imaging techniques. Myocardial perfusion index was quantified after first-pass perfusion with gadolinium contrast at peak dose dobutamine stress. RESULTS: We observed inverse relationships between female gender (r = -0.35, p = 0.003), pericardial fat (r = -0.36, p = 0.03), intraperitoneal fat (r = -0.37, p = 0.001), and retroperitoneal fat (r = -0.36, p = 0.002) and myocardial perfusion index. Visceral fat depots were not associated with reduced myocardial perfusion at peak dose dobutamine in men. However, in women, BMI (r = -0.33, p = 0.04), pericardial fat (r = -0.53, p = 0.02), subcutaneous fat (r = -0.39, p = 0.01) and intraperitoneal fat (r = -0.30, p = 0.05) were associated with reduced myocardial perfusion during dobutamine stress. CONCLUSIONS: Higher visceral fat volumes are associated with reduced left ventricular myocardial perfusion at peak dose dobutamine stress in women but not in men. These findings suggest that visceral fat may contribute to abnormal microcirculatory coronary artery perfusion syndromes, explaining why some women exhibit more anginal symptoms despite typically lower grade epicardial coronary artery stenoses than men. PMID- 26751790 TI - Cost-Effectiveness of Bronchial Thermoplasty, Omalizumab, and Standard Therapy for Moderate-to-Severe Allergic Asthma. AB - BACKGROUND: Bronchial thermoplasty (BT) is a recently developed treatment for patients with moderate-to-severe asthma. A few studies have suggested the clinical efficacy of this intervention. However, no study has evaluated the cost effectiveness of BT compared to other alternative treatments for moderate-to severe allergic asthma, which currently include omalizumab and standard therapy. OBJECTIVE: To evaluate the cost-effectiveness of standard therapy, BT, and omalizumab for moderate-to-severe allergic asthma in the USA. METHODS: A probabilistic Markov model with weekly cycles was developed to reflect the course of asthma progression over a 5-year time horizon. The study population was adults with moderate-to-severe allergic asthma whose asthma remained uncontrolled despite using high-dose inhaled corticosteroids (ICS, with or without long-acting beta-agonists [LABA]). A perspective of the health-care system was adopted with asthma-related costs as well as quality-adjusted life years (QALYs) and exacerbations as the outcomes. RESULTS: For standard therapy, BT, and omalizumab, the discounted 5-year costs and QALYs were $15,400 and 3.08, $28,100 and 3.24, and $117,000 and 3.26, respectively. The incremental cost-effectiveness ratio (ICER) of BT versus standard therapy and omalizumab versus BT was $78,700/QALY and $3.86 million/QALY, respectively. At the willingness-to-pay (WTP) of $50,000/QALY and $100,000/QALY, the probability of BT being cost-effective was 9%, and 67%, respectively. The corresponding expected value of perfect information (EVPI) was $155 and $1,530 per individual at these thresholds. In sensitivity analyses, increasing the costs of BT from $14,900 to $30,000 increased its ICER relative to standard therapy to $178,000/QALY, and decreased the ICER of omalizumab relative to BT to $3.06 million/QALY. Reducing the costs of omalizumab by 25% decreased its ICER relative to BT by 29%. CONCLUSIONS: Based on the available evidence, our study suggests that there is more than 60% chance that BT becomes cost-effective relative to omalizumab and standard therapy at the WTP of $100,000/QALY in patients with moderate-to-severe allergic asthma. However, there is a substantial uncertainty in the underlying evidence, indicating the need for future research towards reducing such uncertainty. PMID- 26751793 TI - The spontaneous market order and evolution. AB - Darwin's theory of natural selection and the idea of a spontaneous order share a fundamental feature: the claim that apparent design or order do not necessarily imply a designer or rational planning. But they also present important differences, which touch upon central questions such as the evolution of morality, the role of human agency in social evolution, the existence (or not) of directionality in undesigned processes, and the presence (nor not) of a providential element in evolutionary accounts. In this article, I explore these themes and probe the relationship between the notion of a spontaneous order and the theory of evolution by natural selection. The reflections of Nobel laureate in economics, F.A. von Hayek, provide the beginning and endpoint in this voyage, for they constitute the most pronounced effort to develop a full-fledged theory combining evolution and economics in recent times. But along the way, I also investigate the influence of classical political economy on Darwin's thought, primarily that of Adam Smith, and consider the reasons for which Darwin did not refer to Smith when discussing the principle of natural selection in The Origin of Species. I conclude that the spontaneous order, as understood by Hayek, and evolution by natural selection constitute two disparate concepts. PMID- 26751792 TI - Diversity, Host Specialization, and Geographic Structure of Filarial Nematodes Infecting Malagasy Bats. AB - We investigated filarial infection in Malagasy bats to gain insights into the diversity of these parasites and explore the factors shaping their distribution. Samples were obtained from 947 individual bats collected from 52 sites on Madagascar and representing 31 of the 44 species currently recognized on the island. Samples were screened for the presence of micro- and macro-parasites through both molecular and morphological approaches. Phylogenetic analyses showed that filarial diversity in Malagasy bats formed three main groups, the most common represented by Litomosa spp. infecting Miniopterus spp. (Miniopteridae); a second group infecting Pipistrellus cf. hesperidus (Vespertilionidae) embedded within the Litomosoides cluster, which is recognized herein for the first time from Madagascar; and a third group composed of lineages with no clear genetic relationship to both previously described filarial nematodes and found in M. griveaudi, Myotis goudoti, Neoromicia matroka (Vespertilionidae), Otomops madagascariensis (Molossidae), and Paratriaenops furculus (Hipposideridae). We further analyzed the infection rates and distribution pattern of Litomosa spp., which was the most diverse and prevalent filarial taxon in our sample. Filarial infection was disproportionally more common in males than females in Miniopterus spp., which might be explained by some aspect of roosting behavior of these cave dwelling bats. We also found marked geographic structure in the three Litomosa clades, mainly linked to bioclimatic conditions rather than host-parasite associations. While this study demonstrates distinct patterns of filarial nematode infection in Malagasy bats and highlights potential drivers of associated geographic distributions, future work should focus on their alpha taxonomy and characterize arthropod vectors. PMID- 26751791 TI - Epidural Co-Administration of Dexmedetomidine and Levobupivacaine Improves the Gastrointestinal Motility Function after Colonic Resection in Comparison to Co Administration of Morphine and Levobupivacaine. AB - Gastrointestinal motility may be impaired after intestinal surgery. Epidural morphine is effective in controlling postoperative pain, but can further reduce gastrointestinal motility. Here, we aimed to investigate the effects of epidural dexmedetomidine on gastrointestinal motility in patients undergoing colonic resection. Seventy-four patients undergoing colonic resection were enrolled in this clinical trial and allocated randomly to treatment with dexmedetomidine (D group) or morphine (M group). The D group received a loading dose epidural administration of 3 ml dexmedetomidine (0.5 MUg kg(-1)) and then a continuous epidural administration of 80 MUg dexmedetomidine in 150 ml levobupivacaine (0.125%) at 3 ml h(-1) for two days. The M group received a loading dose epidural administration of 3 ml morphine (0.03 mg kg(-1)) and then a continuous epidural administration of 4.5 mg morphine in 150 ml levobupivacaine at 3 ml h(-1) for two days. Verbal rating score (VRS), postoperative analgesic requirements, side effects related to analgesia, the time to postoperative first flatus (FFL) and first feces (FFE) were recorded. VRS and postoperative analgesic requirements were not significantly different between treatment groups. In contrast, the time to FFL and time to FFE were significant longer in M group in comparison to D group (P < 0.05). Moreover, patients in M group had a significantly higher incidence of nausea, vomiting, and pruritus (P < 0.05). No patients showed neurologic deficits in either group. In comparison to morphine, epidural dexmedetomidine is safe and beneficial for the recovery of gastrointestinal motility after colonic resection when used as an adjunct with levobupivacaine for postoperative pain control. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TRC-14004644. PMID- 26751794 TI - The "History" of Victorian Scientific Naturalism: Huxley, Spencer and the "End" of natural history. AB - As part of their defence of evolutionary theory, T. H. Huxley and Herbert Spencer argued that natural history was no longer a legitimate scientific discipline. They outlined a secularized concept of life from biology to argue for the validity of naturalism. Despite their support for naturalism, they offered two different responses to the decline of natural history. Whereas Huxley emphasized the creation of a biological discipline, and all that that entailed, Spencer was more concerned with constructing an entire intellectual system based on the idea of evolution. In effect, Spencer wanted to create a new scientific worldview based on evolutionary theory. This had consequences for their understanding of human history, especially of how science had evolved through the ages. It affected their conceptions of human agency, contingency, and directionality in history. Examining Huxley's and Spencer's responses to the "end" of natural history reveals some of the deep divisions within scientific naturalism and the inherent problems of naturalism in general. Whereas Huxley chose to separate the natural and the historical, Spencer opted to fuse them into a single system. PMID- 26751796 TI - Endoscopic detection of a potentially dangerous large vessel coursing through a walled-off pancreatic necrosis. PMID- 26751795 TI - Src Family Tyrosine Kinase Signaling Regulates FilGAP through Association with RBM10. AB - FilGAP is a Rac-specific GTPase-activating protein (GAP) that suppresses lamellae formation. In this study, we have identified RBM10 (RNA Binding Motif domain protein 10) as a FilGAP-interacting protein. Although RBM10 is mostly localized in the nuclei in human melanoma A7 cells, forced expression of Src family tyrosine kinase Fyn induced translocation of RBM10 from nucleus into cell peripheries where RBM10 and FilGAP are co-localized. The translocation of RBM10 from nucleus appears to require catalytic activity of Fyn since kinase-negative Fyn mutant failed to induce translocation of RBM10 in A7 cells. When human breast carcinoma MDA-MB-231 cells are spreading on collagen-coated coverslips, endogenous FilGAP and RBM10 were localized at the cell periphery with tyrosine phosphorylated proteins. RBM10 appears to be responsible for targeting FilGAP at the cell periphery because depletion of RBM10 by siRNA abrogated peripheral localization of FilGAP during cell spreading. Association of RBM10 with FilGAP may stimulate RacGAP activity of FilGAP. First, forced expression of RBM10 suppressed FilGAP-mediated cell spreading on collagen. Conversely, depletion of endogenous RBM10 by siRNA abolished FilGAP-mediated suppression of cell spreading on collagen. Second, FilGAP suppressed formation of membrane ruffles induced by Fyn and instead produced spiky cell protrusions at the cell periphery. This protrusive structure was also induced by depletion of Rac, suggesting that the formation of protrusions may be due to suppression of Rac by FilGAP. We found that depletion of RBM10 markedly reduced the formation of protrusions in cells transfected with Fyn and FilGAP. Finally, depletion of RBM10 blocked FilGAP mediated suppression of ruffle formation induced by EGF. Taken together, these results suggest that Src family tyrosine kinase signaling may regulate FilGAP through association with RBM10. PMID- 26751797 TI - A Germline Variant on Chromosome 4q31.1 Associates with Susceptibility to Developing Colon Cancer Metastasis. AB - We tested for germline variants showing association to colon cancer metastasis using a genome-wide association study that compared Ashkenazi Jewish individuals with stage IV metastatic colon cancers versus those with stage I or II non metastatic colon cancers. In a two-stage study design, we demonstrated significant association to developing metastatic disease for rs60745952, that in Ashkenazi discovery and validation cohorts, respectively, showed an odds ratio (OR) = 2.3 (P = 2.73E-06) and OR = 1.89 (P = 8.05E-04) (exceeding validation threshold of 0.0044). Significant association to metastatic colon cancer was further confirmed by a meta-analysis of rs60745952 in these datasets plus an additional Ashkenazi validation cohort (OR = 1.92; 95% CI: 1.28-2.87), and by a permutation test that demonstrated a significantly longer haplotype surrounding rs60745952 in the stage IV samples. rs60745952, located in an intergenic region on chromosome 4q31.1, and not previously associated with cancer, is, thus, a germline genetic marker for susceptibility to developing colon cancer metastases among Ashkenazi Jews. PMID- 26751799 TI - Recognition of halides and Y-shaped oxoanions by carbonylchromium-based urea-like molecules: A theoretical analysis of hydrogen bonding modes. AB - One of the major challenges in anion recognition is to design hosts that can be used to distinguish between anions of different shapes. Urea-based molecules are widely used in anion recognition because the pair of -NH groups acts as an electron acceptor. Although these hosts can bind to both spherical anions (halides) and Y-shaped anions (oxoanions), experimental evidence to date does not provide a clear picture of what differences in the nature of the hydrogen bonding interactions could be used to distinguish between anions of different shapes. Here, we use several computational topology analyses to study the non-covalent interactions between Cr(CO)3-based organometallic urea-like hosts and halides and Y-shaped oxoanions. Our results suggest that the F(-) and AcO(-) anions are recognized experimentally due to a combination of strong interaction and large infrared (IR) shifts upon complexation, verifying the remarkable IR-reporting ability of the Cr(CO)3 moiety and its potential applications in anion recognition. The lone pairs of the oxygen atom in Y-shaped oxoanions directly interact with the -NH groups of the hosts, while all the shell electrons of the halides participate as a group in the interaction; however, the relative contributions of electrostatic and charge-transfer interactions are quite similar for the two types of anions. This insight into the nature of the anion-host interactions can be used to provide guidance for the design of hosts that differentiate between anions. PMID- 26751798 TI - Corneal Thickness Profile and Associations in Chinese Children Aged 7 to 15 Years Old. AB - Corneal thickness (CT) maps of the central (2-mm diameter), para-central (2 to 5 mm diameter), peripheral (5 to 6-mm diameter), and minimum (5-mm diameter) cornea were measured in normal Chinese school children aged 7 to 15 years old using Fourier-domain optical coherence tomography. Multiple regression analyses were performed to explore the effect of associated factors [age, gender, refraction, axial length and corneal curvature radius (CCR)] on CT and the relationship between central corneal thickness (CCT) and intraocular pressure (IOP). A total of 1228 eyes from 614 children were analyzed. The average CCT was 532.96 +/- 28.33 MUm for right eyes and 532.70 +/-28.45 MUm for left eyes. With a 10 MUm increase in CCT, the IOP was elevated by 0.37 mm Hg, as measured by noncontact tonometry. The CT increased gradually from the center to the periphery. The superior and superior nasal regions had the thickest CTs, while the thinnest points were primarily located in the inferior temporal cornea. The CCT was associated with CCR (p = 0.008) but not with gender (p = 0.075), age (p = 0.286), axial length (p = 0.405), or refraction (p = 0.985). In the para-central region and the peripheral cornea, increased CT was associated with younger age, male gender, and a flatter cornea. PMID- 26751800 TI - Evanescent Waves Nuclear Magnetic Resonance. AB - Nuclear Magnetic Resonance spectroscopy and imaging can be classified as inductive techniques working in the near- to far-field regimes. We investigate an alternative capacitive detection with the use of micrometer sized probes positioned at sub wavelength distances of the sample in order to characterize and model evanescent electromagnetic fields originating from NMR phenomenon. We report that in this experimental configuration the available NMR signal is one order of magnitude larger and follows an exponential decay inversely proportional to the size of the emitters. Those investigations open a new road to a better understanding of the evanescent waves component in NMR with the opportunity to perform localized spectroscopy and imaging. PMID- 26751801 TI - Construction and characterization of HIV type 1 CRF07_BC infectious molecular clone from men who have sex with men. AB - This study aimed to investigate the biological characterization of HIV type 1 (HIV-1) CRF07_BC infection among men who have sex with men (MSM). From November 2011 to November 2013, a total of 66 blood samples were collected from MSM with acute HIV-1 infection with CRF07_BC subgroup strains. Deletion in the gag p6 region was detected by sequence alignment and comparative analysis. Peripheral blood mononuclear cells (PBMCs) of HNXX1301-1307 samples were separated by density gradient centrifugation. Nested polymerase chain reaction (nPCR) was used to amplify the viral DNA. The near full-length HIV-1 DNA products were ligated to the long terminal repeat (LTR) vector plasmid (07BCLTR) to construct a full length HIV clone. The molecular clone was transfected into HEK-293T cells, TZM-b1 cells and patients' PBMCs. The pregenome of an infectious molecular clone of HIV 1 (pNL4-3) was amplified, and a subclone with CRF07_BC was developed to construct the full-length chimeric molecular clone pNL4-3/07BCLTR. Detection of p24 antigen and luciferase activity was used to measure the in vitro infectivity of pNL4 3/07BCLTR. Among the 66 MSM patients infected with CRF07_BC strains, deletion mutations of the Gag P6 proteins were found in 7 of 18CRF07_BC strains; deletion mutations of 2-13 amino acids in different regions were discovered in 6 strains; and the remaining 42 strains did not show deletions. Seven strains with amino acids deficiency in the P6 protein accounted for 27% of all strains and 75% of all deletion genotype strains. A total of 186 full-length molecular clones of CRF07_BC were constructed. There were 5, 9, 10 and 11 clones of HNXX1302, HNXX1304, HNXX1305 and HNXX1306 that resulted in p24-positive supernatant when transfected into HEK-293T cells. Full-length clones of HNXX1302, HNXX1304, HNXX1305 and HNXX1306 showed slight infection in the transfected TZM-b1 cells, as judged by the fluorescence values of TZM-b1 cells 48h post-transfection. However, we were unable to transfect the patients' PMBCs with the above four clones. The phylogenetic tree of the C2V3 segment of the Env gene showed that a significant gene cluster was formed by all of the chimeric full-length HNXX1306 clones, and the bootstrap value for this cluster was 97.5%. Patients' PBMCs could be infected by 1306N6, 1306N13 and 1306N22 chimeric full-length clones. The CRF07_BC subtype (6889-7407 nucleotide residues of HXB2) is one of the most prevalent epidemic HIV 1 virus strains among the MSM population. The full-length chimeric molecular clone pNL4-3/07BCLTR may significantly improve the in vitro infectivity of the CRF07_BC strain. PMID- 26751802 TI - Polymorphisms in the SLC12A3 Gene Encoding Sodium-Chloride Cotransporter are Associated with Hypertension: A Family-Based Study in the Mongolian Population. AB - BACKGROUND/AIMS: Hypertension or persistent high blood pressure (BP) is a leading cause of death worldwide. Extensive evidence indicates that the thiazide sensitive Na+-Cl- cotransporter (NCC) affects BP via regulation of renal sodium reabsorption. However, the relationship between genetic variants of the NCC encoding SLC12A3 gene and hypertension in the Mongolian population is still ambiguous. In this study, we aimed to genotype an extended cohort of hypertensive Mongolian families for polymorphisms in the SLC12A3 locus. METHODS: Eighty-eight families with a history of hypertension, including parents, offspring, and relatives underwent clinical testing. Family-based association tests and haplotype analysis were used to evaluate the association between hypertension and polymorphisms in the SLC12A3 locus. RESULTS: We identified three single nucleotide polymorphisms (SNPs), one in the SLC12A3 coding region (p = 0.05) and two in the intron (p = 0.02 and p = 0.07), which were significantly associated with the hypertension phenotype. Haplotype-specific association tests confirmed the correlation of these SNPs with hypertension (p < 0.05). CONCLUSION: These results suggest that SNPs in the SLC12A3 gene confer susceptibility to hypertension in the Mongolian population. Further research is needed to validate the functional role of SLC12A3 polymorphisms in hypertension. PMID- 26751803 TI - Fine-Scale Skeletal Banding Can Distinguish Symbiotic from Asymbiotic Species among Modern and Fossil Scleractinian Corals. AB - Understanding the evolution of scleractinian corals on geological timescales is key to predict how modern reef ecosystems will react to changing environmental conditions in the future. Important to such efforts has been the development of several skeleton-based criteria to distinguish between the two major ecological groups of scleractinians: zooxanthellates, which live in symbiosis with dinoflagellate algae, and azooxanthellates, which lack endosymbiotic dinoflagellates. Existing criteria are based on overall skeletal morphology and bio/geo-chemical indicators-none of them being particularly robust. Here we explore another skeletal feature, namely fine-scale growth banding, which differs between these two groups of corals. Using various ultra-structural imaging techniques (e.g., TEM, SEM, and NanoSIMS) we have characterized skeletal growth increments, composed of doublets of optically light and dark bands, in a broad selection of extant symbiotic and asymbiotic corals. Skeletons of zooxanthellate corals are characterized by regular growth banding, whereas in skeletons of azooxanthellate corals the growth banding is irregular. Importantly, the regularity of growth bands can be easily quantified with a coefficient of variation obtained by measuring bandwidths on SEM images of polished and etched skeletal surfaces of septa and/or walls. We find that this coefficient of variation (lower values indicate higher regularity) ranges from ~40 to ~90% in azooxanthellate corals and from ~5 to ~15% in symbiotic species. With more than 90% (28 out of 31) of the studied corals conforming to this microstructural criterion, it represents an easy and robust method to discriminate between zooxanthellate and azooxanthellate corals. This microstructural criterion has been applied to the exceptionally preserved skeleton of the Triassic (Norian, ca. 215 Ma) scleractinian Volzeia sp., which contains the first example of regular, fine-scale banding of thickening deposits in a fossil coral of this age. The regularity of its growth banding strongly suggests that the coral was symbiotic with zooxanthellates. PMID- 26751804 TI - Pertussis vaccination coverage among Australian women prior to childbirth in the cocooning era: a two-hospital, cross-sectional survey, 2010 to 2013. AB - BACKGROUND: Recent pertussis epidemics have triggered implementation of cocooning, involving caregiver vaccination to indirectly protecting susceptible infants. AIM: To determine patient, provider and setting factors associated with maternal pertussis booster vaccination (dTpa) within 5-10 years before childbirth. MATERIALS AND METHODS: Cross-sectional survey using Health Belief Model constructs among postpartum women in a tertiary referral centre and a private hospital in Sydney, Australia. RESULTS: Pertussis vaccination was current among 33.7% of the 2483 new mothers (0.5% vaccinated during pregnancy). Women were more likely to be vaccinated if they had heard of 'whooping cough' from a health professional (OR: 2.59, P < 0.001, 95% CI: 1.70-3.95), were recommended the vaccine (OR: 2.48, P < 0.00, 95% CI: 1.55-4.00), perceived pertussis as 'severe' for adults (OR: 1.21, p0.009, 95% CI: 1.05-1.39) and 'common' within their community (OR: 1.38, P < 0.001, 95% CI: 1.18-1.61). They more often agreed that it was their parental responsibility to be vaccinated (OR: 1.61, P = 0.002, 95% CI: 1.19-2.18), and this would help prevent their baby from contracting pertussis (OR: 1.22, P = 0.046, 95% CI: 1.00-1.47). Vaccinated women were less likely to report vaccination barriers: time constraints (OR: 0.75, P < 0.001, 95% CI: 0.66-0.85) and having safety concerns (OR: 0.80, P < 0.001, 95% CI: 0.69 0.92). Additionally, their partners reported three times higher uptake (76% vs 49%; P < 0.001; 95% CI: 2.66-3.85). CONCLUSIONS: Current pertussis vaccination in only one in every three postpartum participants may indicate insufficient coverage to protect newborns. Practitioners are instrumental in raising awareness and addressing vaccine concerns. Integrating vaccination into routine obstetric care, whether antenatally or postnatally, may minimise barriers. PMID- 26751806 TI - Effective lipid-detergent system for study of membrane active peptides in fluid liposomes. AB - The structure of peptide antibiotic gramicidin A (gA) was studied in phosphatidylcholin liposomes modified by nonionic detergent Triton X-100. First, the detergent : lipid ratio at which the saturation of lipid membrane by Triton X 100 occurs (Re (sat)), was determined by light scattering. Measurements of steady state fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene at sublytic concentrations of detergent showed that after saturation of the membrane by Triton X-100 microviscosity of lipid bilayer is reduced by 20%. The equilibrium conformational state of gA in phosphatidylcholine liposomes at Re (sat) was studied by CD spectroscopy. It was found that the conformational state of this channel-forming peptide changed crucially when Triton X-100 induced transition to more fluid membranes. The gA single-channel measurements were made with Triton X 100 containing bilayers. Tentative assignment of the channel type and gA structures was made by correlation of CD data with conductance histograms. Lipid detergent system with variable viscosity developed in this work can be used to study the structure and folding of other membrane-active peptides. PMID- 26751805 TI - Urinary Biomarkers of Brain Diseases. AB - Biomarkers are the measurable changes associated with a physiological or pathophysiological process. Unlike blood, urine is not subject to homeostatic mechanisms. Therefore, greater fluctuations could occur in urine than in blood, better reflecting the changes in human body. The roadmap of urine biomarker era was proposed. Although urine analysis has been attempted for clinical diagnosis, and urine has been monitored during the progression of many diseases, particularly urinary system diseases, whether urine can reflect brain disease status remains uncertain. As some biomarkers of brain diseases can be detected in the body fluids such as cerebrospinal fluid and blood, there is a possibility that urine also contain biomarkers of brain diseases. This review summarizes the clues of brain diseases reflected in the urine proteome and metabolome. PMID- 26751807 TI - Evaluation of serum granulysin as a potential biomarker for nasopharyngeal carcinoma. AB - BACKGROUND: Granulysin (GNLY) is excreted from cytotoxic T lymphocytes and natural killer cells, and plays an important role in antitumor immunity. However, few studies have estimated serum GNLY concentrations in patients with nasopharyngeal carcinoma (NPC). We evaluated GNLY as a potential biomarker for NPC. METHODS: Serum GNLY concentrations were measured in blood samples taken from 98 NPC patients, 56 nasopharyngitis (NPT) patients, and 99 healthy subjects. The clinical relevance of GNLY in NPC was also investigated. We also assessed the association between serum GNLY and serum immunoglobulin A antibodies against the Epstein-Barr virus (EBV) viral capsid antigen (VCA-IgA) and EBV DNA. RESULTS: Serum GNLY levels were significantly lower in NPC patients and significantly higher in nasopharyngitis patients compared to healthy controls. Thus, serum GNLY performs well as a biomarker for distinguishing between NPC and NPT. The serum GNLY concentration is elevated with corresponding increases in clinical stage and shows a significant correlation with VCA-IgA and EBV DNA concentration. CONCLUSIONS: Serum GNLY is closely associated with the clinical characteristics of NPC and may be a potential biomarker for NPC. PMID- 26751808 TI - HDL-sphingomyelin reduction after weight loss by an energy-restricted diet is associated with the improvement of lipid profile, blood pressure, and decrease of insulin resistance in overweight/obese patients. AB - BACKGROUND: Sphingomyelin (SM) diminishes the fluidity of the surface monolayer of high-density lipoproteins (HDL), affecting their intravascular metabolism and antiatherogenic properties. Since overweight is associated with an altered HDL structure, weight loss may result in changes in HDL subclasses, particularly in their SM content. Therefore, we determined the plasma SM concentrations associated to both total HDL and HDL subclasses after weight loss in obese patients. METHODS: Fifty overweight patients, 40 women and 10 men, aged 38.6+/ 6.4 y, were given an energy-restricted diet according to their sex, age, and height. No physical activity was prescribed. Plasma SM concentrations of HDL subclasses were determined by a gel surface method developed for this study. Cholesterol of HDL subclasses was also determined by enzymatic methods performed on a gel surface. RESULTS: Mean weight lost was 3.5+/-0.4 kg after 6 weeks of dietary intervention. As expected, insulin resistance and blood pressure decreased whereas lipid profile improved, except for HDL-cholesterol. SM in plasma and in all HDL subclasses significantly decreased after intervention. The magnitude of HDL-SM reduction was statistically associated with the amelioration of the components of the metabolic syndrome; the reduction of BMI explained the decrement of HDL-SM in a multivariate analysis. CONCLUSION: HDL-SM decreased after weight loss by an energy-restricted diet. Further, the association of this decrement with the improvement of blood pressure, lipid profile and the decrease of insulin resistance, was statistically significant; all HDL subclasses were similarly affected. Whether a reduction in HDL-SM contributes to the cardiovascular benefits of weight loss remains to be elucidated. PMID- 26751809 TI - Circulating epithelial cell enumeration facilitates the identification and follow up of a patient with early stage papillary thyroid microcarcinoma: A case report. AB - BACKGROUND: This study examines whether the measurement of circulating epithelial cells (CECs) facilitates the identification and follow-up of a patient with thyroid cancer. METHODS: A 29-y-old woman with no cancer history was enrolled as a healthy control in a CEC study. CECs were enriched from the peripheral blood by the negative selection system PowerMag. Various medical examinations were performed on the patient to establish the diagnosis and to follow-up her disease status during treatment. RESULTS: This patient had unexpectedly high CEC counts that were sustained for more than two weeks. Thyroid gland ultra-sonography revealed lesions in the left lobe that could not be confirmed as cancer by magnetic resonance imaging, (18)F-fludeoxyglucose-positron emission tomography computed tomography or cytopathological analysis, but were histologically confirmed after thyroidectomy as papillary thyroid microcarcinoma. Both the CEC count and serum thyroglobulin (Tg) concentration were significantly decreased after thyroidectomy, and they and the patient's disease status were correlated during remnant ablation therapy. The CEC count returned to normal when the patient was disease-free 10 months after thyroidectomy. CONCLUSIONS: CEC testing facilitates the identification of individuals at risk for cancer. Longitudinal follow-up of the CEC count may complement serum Tg testing for monitoring the status of patients with thyroid cancer. PMID- 26751810 TI - Quantification of the Blood Platelet Reactivity in the ADP-Induced Model of Non Lethal Pulmonary Thromboembolism in Mice with the Use of Laser Doppler Flowmetry. AB - INTRODUCTION: The paper describes an alternative method for quantification of in vivo ADP-induced thromboembolism. The aim of the studies was to develop a method of quantification which would not require either extravasation or labelling of platelets. Our proposed approach is based on the monitoring of changes of blood flow with the use of laser Doppler flowmetry. MATERIALS AND METHODS: Mice of C57Bl strain were used in the study. ADP was injected to the vena cava and blood flow was monitored with the use of a laser Doppler flowmeter in the mesentery. Measurements in platelet-depleted mice, mice pretreated with cangrelor, an ADP receptor antagonist, and eptifibatide, a blocker of fibrinogen binding to GPIIbIIIa, were conducted as the proof-of-concept in the performed experiments. Intravital microscopy and ex vivo imaging of organs was performed to identify the sites of aggregate formation resulting from ADP injection. RESULTS: The injection of ADP resulted in a dose-dependent reduction of the blood flow in the mesentery. These responses were fully attributable to blood platelet aggregation, as shown by the lack of the effect in platelet-depleted mice, and significantly reduced responses in mice pretreated with cangrelor and eptifibatide. No platelet aggregate formation in mesenteric vessels was revealed by intravital microscopy, while ex vivo imaging showed accumulation of fluorescent labelled platelets in the lung. CONCLUSIONS: Injection of ADP to the venous system results in the formation of platelet aggregates predominantly in the lung. This results in reversible blood flow cessation in peripheral blood vessels. The measurement of this blood flow cessation in the mesentery allows indirect measurement of ADP induced pulmonary thromboembolism. We suggest that this approach can be useful for in vivo screening for antiplatelet drug candidates. PMID- 26751812 TI - Field-scale fluorescence fingerprinting of biochar-borne dissolved organic carbon. AB - Biochar continues to receive worldwide enthusiasm as means of augmenting recalcitrant organic carbon in agricultural soils. Realistic biochar amendment rate (typically less than 1 wt%) in the field scale, and subsequent loss by sizing, rain, and other transport events demand reliable methods to quantify the remaining portions of amended biochar. This study employed fluorescence excitation-emission (EEM) spectrophotometry and parallel factor analysis (PARAFAC) to specifically target pyrogenic dissolved organic carbon (DOC) released by amended biochar during the course of a field trial at Bowling Green, KY experimental site. Toluene/methanol (1:6 v/v) extracts of surface (0-15 cm) soils amended with 21.28 t ha(-1) fast pyrolysis biochar afforded PARAFAC fingerprints representing different degrees of aromaticity. Compared to the control without treatments, biochar treatment (with and without poultry manure or chemical fertilizer) increased the relative contribution of PARAFAC fingerprint attributable to labile polyaromatic DOC structures. Poultry manure or chemical fertilizer alone (without biochar) did not influence the amounts of polyaromatic DOC structures. Existence of biochar could be further validated by the changes in %DOC (relative to the total carbon), fixed C content, and UV absorbance (360 nm), whereas FTIR, %O, and sorption of model agrochemical (deisopropylatrazine) did not reflect the presence of biochar in the soil samples. Developed toluene/methanol-based EEM-PARAFAC technique will provide a sensitive, rapid, and cost-competitive method to validate the long-term carbon sequestration by the biochar soil amendment. PMID- 26751811 TI - Multiplicity of Infection and Disease Severity in Plasmodium vivax. AB - BACKGROUND: Multiplicity of infection (MOI) refers to the average number of distinct parasite genotypes concurrently infecting a patient. Although several studies have reported on MOI and the frequency of multiclonal infections in Plasmodium falciparum, there is limited data on Plasmodium vivax. Here, MOI and the frequency of multiclonal infections were studied in areas from South America where P. vivax and P. falciparum can be compared. METHODOLOGY/PRINCIPAL FINDINGS: As part of a passive surveillance study, 1,328 positive malaria patients were recruited between 2011 and 2013 in low transmission areas from Colombia. Of those, there were only 38 P. vivax and 24 P. falciparum clinically complicated cases scattered throughout the time of the study. Samples from uncomplicated cases were matched in time and location with the complicated cases in order to compare the circulating genotypes for these two categories. A total of 92 P. vivax and 57 P. falciparum uncomplicated cases were randomly subsampled. All samples were genotyped by using neutral microsatellites. Plasmodium vivax showed more multiclonal infections (47.7%) than P. falciparum (14.8%). Population genetics and haplotype network analyses did not detect differences in the circulating genotypes between complicated and uncomplicated cases in each parasite. However, a Fisher exact test yielded a significant association between having multiclonal P. vivax infections and complicated malaria. No association was found for P. falciparum infections. CONCLUSION: The association between multiclonal infections and disease severity in P. vivax is consistent with previous observations made in rodent malaria. The contrasting pattern between P. vivax and P. falciparum could be explained, at least in part, by the fact that P. vivax infections have lineages that were more distantly related among them than in the case of the P. falciparum multiclonal infections. Future research should address the possible role that acquired immunity and exposure may have on multiclonal infections and their association with disease severity. PMID- 26751813 TI - Optimization performance of an AnSBBR applied to biohydrogen production treating whey. AB - The present study investigated the influence of the influent concentration of substrate, feeding time and temperature on the production of biohydrogen from cheese whey in an AnSBBR with liquid phase recirculation. The highest hydrogen yield (0.80 molH2.molLactose(-1)) and productivity (660 mLH2 L(-1) d(-1)) were achieved for influent concentrations of 5400 mgDQO L(-1). No significant difference was noted in the biological hydrogen production for the feeding time conditions analyzed. The lowest temperature tested (15 degrees C) promoted the highest hydrogen yield and productivity (1.12 molH2 molLactose(-1) and 1080 mLH2 L(-1) d(-1)), and for the highest temperature (45 degrees C), hydrogen production did not occur. The indicator values for the hydrogen production obtained with this configuration were higher than those obtained in other studies using traditional configurations such as UASBr and CSTR. A phylogenetic analysis showed that the majority of the analyzed clones were similar to Clostridium. In addition, clones phylogenetically similar to the Lactobacilaceae family, notably Lactobacillus rhamnosus, and clones with similar sequences to Acetobacter indonesiensis were observed in small proportion in the reactor. PMID- 26751815 TI - Galanin microinjection into the dorsal periaqueductal gray matter produces paradigm-dependent anxiolytic effects. AB - Galanin is a peptide that is present in the central nervous system in mammals, including rodents and humans. The actions of galanin are mediated by three types of metabotropic receptors: GAL1, GAL2, and GAL3. GAL1 and GAL3 increase K(+) efflux, and GAL2 increases intracellular Ca(2+) levels. The distribution of galanin and its receptors suggests its involvement in fear and/or anxiety. The periaqueductal gray matter (PAG) is a key mediator of defensive behaviors that is both targeted by galaninergic projections and supplied with GAL1 receptors and, less markedly, GAL2 receptors. We examined the effects of galanin microinjections in the dorsal PAG (dPAG) on the performance of rats in different models of anxiety. Male Wistar rats (n=7-12) were implanted with guide cannulae in the dPAG. They received microinjections of either galanin (0.3, 1.0, and 3.0 nmol) or vehicle and were tested in the Vogel conflict test (VCT), elevated plus maze (EPM), and elevated T-maze (ETM). Rats that were tested in the ETM were further evaluated for exploratory activity in the open field test (OFT). Galanin microinjections had no effects on anxiety-like behavior in the EPM or VCT or exploratory activity in the EPM or OFT. In the ETM, however, microinjections of 3 nmol galanin impaired learned anxiety (i.e., avoidance of the open arms) without changing unconditioned fear (i.e., escape from the open arms). The present data suggest that galanin transmission in the dPAG inhibits the acquisition of anxiety like responses in the ETM. PMID- 26751814 TI - Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning. AB - Intranasal delivery is an emerging method for bypassing the blood brain barrier (BBB) and targeting therapeutics to the CNS. Oximes are used to counteract the effects of organophosphate poisoning, but they do not readily cross the BBB. Therefore, they cannot effectively counteract the central neuropathologies caused by cholinergic over-activation when administered peripherally. For these reasons we examined intranasal administration of oximes in an animal model of severe organophosphate poisoning to determine their effectiveness in reducing mortality and seizure-induced neuronal degeneration. Using the paraoxon model of organophosphate poisoning, we administered the standard treatment (intramuscular pralidoxime plus atropine sulphate) to all animals and then compared the effectiveness of intranasal application of obidoxime (OBD) to saline in the control groups. Intranasally administered OBD was effective in partially reducing paraoxon-induced acetylcholinesterase inhibition in the brain and substantially reduced seizure severity and duration. Further, intranasal OBD completely prevented mortality, which was 41% in the animals given standard treatment plus intranasal saline. Fluoro-Jade-B staining revealed extensive neuronal degeneration in the surviving saline-treated animals 24h after paraoxon administration, whereas no detectable degenerating neurons were observed in any of the animals given intranasal OBD 30min before or 5min after paraoxon administration. These findings demonstrate that intranasally administered oximes bypass the BBB more effectively than those administered peripherally and provide an effective method for protecting the brain from organophosphates. The addition of intranasally administered oximes to the current treatment regimen for organophosphate poisoning would improve efficacy, reducing both brain damage and mortality. PMID- 26751817 TI - Tongue pressure production during swallowing in patients with mandibular prognathism. AB - Abnormalities of swallowing in patients with mandibular prognathism have not been evaluated quantitatively. The aim of this study was to compare tongue pressure production for bolus transfer between volunteers with normal occlusion and patients with mandibular prognathism. The control group had 10 female volunteers with normal occlusion, and the patient group had 10 women with mandibular prognathism. Tongue pressure was measured by a palatal sensor sheet at five sites on swallowing 4 mL of a tasteless and odourless jelly. RESULTS: The tongue pressure waveform differed between the control and patient groups. The incidence of a double-peak tongue pressure waveform was more frequent in the patient group. In both groups, the exertion of tongue pressure began at the anterior point of the sensor sheet, followed by the peripheral parts. Although the order of expression of tongue pressure was the same for the two groups, maximum tongue pressure at all parts of the sensor sheet was lower in the patient group than in the control group. Furthermore, swallowing time was longer in the patient group than in the control group at the peripheral parts of the palate. These results clearly show the difference in tongue pressure production during swallowing between patients with mandibular prognathism and volunteers with normal occlusion. The current findings suggest that maxillofacial morphology may affect tongue movement during swallowing. PMID- 26751816 TI - The Microbiome of Ehrlichia-Infected and Uninfected Lone Star Ticks (Amblyomma americanum). AB - The Lone Star tick, Amblyomma americanum, transmits several bacterial pathogens including species of Anaplasma and Ehrlichia. Amblyomma americanum also hosts a number of non-pathogenic bacterial endosymbionts. Recent studies of other arthropod and insect vectors have documented that commensal microflora can influence transmission of vector-borne pathogens; however, little is known about tick microbiomes and their possible influence on tick-borne diseases. Our objective was to compare bacterial communities associated with A. americanum, comparing Anaplasma/Ehrlichia -infected and uninfected ticks. Field-collected questing specimens (n = 50) were used in the analyses, of which 17 were identified as Anaplasma/Ehrlichia infected based on PCR amplification and sequencing of groEL genes. Bacterial communities from each specimen were characterized using Illumina sequencing of 16S rRNA gene amplicon libraries. There was a broad range in diversity between samples, with inverse Simpson's Diversity indices ranging from 1.28-89.5. There were no statistical differences in the overall microbial community structure between PCR diagnosed Anaplasma/Ehrlichia-positive and negative ticks, but there were differences based on collection method (P < 0.05), collection site (P < 0.05), and sex (P < 0.1) suggesting that environmental factors may structure A. americanum microbiomes. Interestingly, there was not always agreement between Illumina sequencing and PCR diagnostics: Ehrlichia was identified in 16S rRNA gene libraries from three PCR negative specimens; conversely, Ehrlichia was not found in libraries of six PCR positive ticks. Illumina sequencing also helped identify co-infections, for example, one specimen had both Ehrlichia and Anaplasma. Other taxa of interest in these specimens included Coxiella, Borrelia, and Rickettsia. Identification of bacterial community differences between specimens of a single tick species from a single geographical site indicates that intra-species differences in microbiomes were not due solely to pathogen presence/absence, but may be also driven by vector life history factors, including environment, life stage, population structure, and host choice. PMID- 26751819 TI - Promoting tumor penetration of nanoparticles for cancer stem cell therapy by TGF beta signaling pathway inhibition. AB - Cancer stem cells (CSCs), which hold a high capacity for self-renewal, play a central role in the development, metastasis, and recurrence of various malignancies. CSCs must be eradicated to cure instances of cancer; however, because they can reside far from tumor vessels, they are not easily targeted by drug agents carried by nanoparticle-based drug delivery systems. We herein demonstrate that promoting tumor penetration of nanoparticles by transforming growth factor beta (TGF-beta) signaling pathway inhibition facilitates CSC therapy. In our study, we observed that although nanoparticles carrying siRNA targeting the oncogene polo-like kinase 1 (Plk1) efficiently killed breast CSCs derived from MDA-MB-231 cells in vitro, this intervention enriched CSCs in the residual tumor tissue following systemic treatment. However, inhibition of the TGF-beta signaling pathway with LY364947, an inhibitor of TGF-beta type I receptor, promoted the penetration of nanoparticles in tumor tissue, significantly ameliorating the intratumoral distribution of nanoparticles in MDA MB-231 xenografts and further leading to enhanced internalization of nanoparticles by CSCs. As a result, synergistic treatment with a nanoparticle drug delivery system and LY364947 inhibited tumor growth and reduced the proportion of CSCs in vivo. This study suggests that enhanced tumor penetration of drug-carrying nanoparticles can enhance CSCs clearance in vivo and consequently provide superior anti-tumor effects. PMID- 26751818 TI - Pre-travel advice concerning vector-borne diseases received by travelers prior to visiting Cuzco, Peru. AB - Peru is an increasingly popular tourist destination that poses a risk to travelers due to endemic vector-borne diseases (VBDs). The objective of our study was to determine which factors are associated with receiving pre-travel advice (PTA) for VBDs among travelers visiting Cuzco, Peru. A cross-sectional secondary analysis based on data from a survey among travelers departing Cuzco at Alejandro Velazco Astete International Airport during the period January-March 2012 was conducted. From the 1819 travelers included in the original study, 1717 were included in secondary data analysis. Of these participants, 42.2% received PTA and 2.9% were informed about vector-borne diseases, including yellow fever (1.8%), malaria (1.6%) and dengue fever (0.1%). Receiving information on VBDs was associated with visiting areas endemic to yellow fever and dengue fever in Peru. The only disease travelers received specific recommendations for before visiting an endemic area for was yellow fever. Only 1 in 30 tourists received information on VBD prevention; few of those who traveled to an endemic area were warned about specific risks for infectious diseases prior to their trip. These important findings show that most tourists who travel to Peru do not receive PTA for the prevention of infectious and VBD, which can affect not only the travelers but their countries of origin as well. PMID- 26751820 TI - Synthesis and characterization of a new vertebroplasty cement based on gold containing PMMA microspheres. AB - There are a number of drawbacks to incorporating large concentrations of barium sulfate (BaSO4) as the radiopacifier in PMMA-based bone cements for percutaneous vertebroplasty. These include adverse effects on injectability, viscosity profile, setting time, mechanical properties of the cement and bone resorption. We have synthesized a novel cement that is designed to address some of these drawbacks. Its powder includes PMMA microspheres in which gold particles are embedded and its monomer is the same as that used in commercial cements for vertebroplasty. In comparison to one such commercial cement brand, VertaPlexTM, the new cement has longer doughing time, longer injection time, higher compressive strength, higher compressive modulus, and is superior in terms of cytotoxicity. For augmentation of fractured fresh-frozen cadaveric vertebral bodies (T6-L5) using simulated vertebroplasty, results for compressive strength and compressive stiffness of the construct and the percentage of the volume of the vertebral body filled by the cement were comparable for the two cements although the radiopacity of the new cement was significantly lower than that for VertaPlexTM. The present results indicate that the new cement warrants further study. PMID- 26751821 TI - Thermally reduced graphene is a permissive material for neurons and astrocytes and de novo neurogenesis in the adult olfactory bulb in vivo. AB - Graphene and graphene-based nanomaterials (GBNs) are being investigated as potential substrates for the growth of neural stem cells (NSCs), neurons and glia in cell culture models. In contrast, reports testing the effects of graphene directly with adult neural cells in vivo are missing. Here we studied the biocompatibility of thermally reduced graphene (TRG) with neurons and glia, as well as with the generation of new neurons in the adult brain in vivo. TRG injected in the brain together with a retroviral vector expressing GFP to label dividing progenitor cells in the core of the adult olfactory bulb (OB) did not alter de novo neurogenesis, neuronal and astrocyte survival nor did it produce a microglial response. These findings indicate that TRG may be a biocompatible material with neuronal and glial cells in vivo and support its use in studies of brain repair and function. PMID- 26751822 TI - Differential Expression Profile of Immunological Cytokines in Local Ovary in Patients with Polycystic Ovarian Syndrome: analysis by Flow Cytometry. AB - OBJECTIVE: Immune dysregulation may play an important role in the pathogenesis of polycystic ovary syndrome (PCOS). The purpose of this study was to investigate the Th1 and Th2-related cytokine profile in local ovary of women with PCOS. STUDY DESIGN: The T lymphocytes of follicular fluid (FF) were obtained at the time of oocyte retrieval before in-vitro fertilization (IVF) in woman with or without PCOS. After culturing with PMA, Ionomycin and Golgi stop agent, cells were detected for the intracellular cytokine production by flow cytometry. The profile of Th1 (IFN-gamma, IL-2) and Th2 (IL-4, IL-10) cytokines of CD3(+) CD4(+)T lymphocyte subsets were analyzed through invert gating. These cytokines in FF were also evaluated by ELISA. RESULTS: Flow cytometry analysis showed that the production of Th1 (IFN-gamma, IL-2) cytokines in FF lymphocytes in PCOS patients were significantly higher than those in controls; ELISA result also demonstrated that the concentration of Th1 cytokines (IFN-gamma, IL-2) in FF in PCOS patients is significantly increased compared with those in controls. CONCLUSION: It is concluded that the immune dominance of Th1 may be the immunological feature of the ovary in PCOS patients. It might participate in the immune pathogenesis in the ovary of PCOS patients. These results suggest that chronic inflammation maybe one of the underlying mechanism for the pathogenesis of PCOS. PMID- 26751823 TI - Type of gonadotropin during controlled ovarian stimulation affects the endocrine profile in follicular fluid and apoptosis rate in cumulus cells. AB - OBJECTIVE: To determine whether the type of gonadotropin affects the secretion of oocyte-specific factors, the endocrine pattern in follicular fluid, and the apoptosis rate in cumulus cells. STUDY DESIGN: Prospective and observational study into an university-affiliated private in vitro fertilization setting. Ninety women included in our oocyte donation program were stimulated with human menopausal gonadotropin (hMG), recombinant follicle-stimulating hormone (FSH) or urinary FSH. Main outcome measures were growth-differentiation factor 9 (GDF-9) and bone morphogenetic protein 15 (BMP-15) expression, hormonal profile and apoptosis rate. RESULTS: No statistically significant differences were observed for GDF-9 and BMP-15 among the three treatment groups. Estradiol concentrations in follicular fluid were significantly higher in women treated with hMG compared with recombinant FSH or urinary FSH. Testosterone levels were also higher in the group treated with hMG. A statistically significant association was found between the degree of apoptosis in cumulus cells and the type of gonadotropin. CONCLUSIONS: The type of gonadotropin used during controlled ovarian stimulation significantly affects endocrine profiles in follicular fluid and the apoptosis rate in cumulus cells. However, there were no significant differences in the levels of oocyte-secreted factors between treatments. PMID- 26751824 TI - The Synthesis of Organic Molecules of Intrinsic Microporosity Designed to Frustrate Efficient Molecular Packing. AB - Efficient reactions between fluorine-functionalised biphenyl and terphenyl derivatives with catechol-functionalised terminal groups provide a route to large, discrete organic molecules of intrinsic microporosity (OMIMs) that provide porous solids solely by their inefficient packing. By altering the size and substituent bulk of the terminal groups, a number of soluble compounds with apparent BET surface areas in excess of 600 m(2) g(-1) are produced. The efficiency of OMIM structural units for generating microporosity is in the order: propellane>triptycene>hexaphenylbenzene>spirobifluorene>naphthyl=phenyl. The introduction of bulky hydrocarbon substituents significantly enhances microporosity by further reducing packing efficiency. These results are consistent with findings from previously reported packing simulation studies. The introduction of methyl groups at the bridgehead position of triptycene units reduces intrinsic microporosity. This is presumably due to their internal position within the OMIM structure so that they occupy space, but unlike peripheral substituents they do not contribute to the generation of free volume by inefficient packing. PMID- 26751825 TI - Novel Insights into Structure-Activity Relationships of N-Terminally Modified PACE4 Inhibitors. AB - PACE4 plays important roles in prostate cancer cell proliferation. The inhibition of this enzyme has been shown to slow prostate cancer progression and is emerging as a promising therapeutic strategy. In previous work, we developed a highly potent and selective PACE4 inhibitor, the multi-Leu (ML) peptide, an octapeptide with the sequence Ac-LLLLRVKR-NH2 . Here, with the objective of developing a useful compound for in vivo administration, we investigate the effect of N terminal modifications. The inhibitory activity, toxicity, stability, and cell penetration properties of the resulting analogues were studied and compared to the unmodified inhibitor. Our results show that the incorporation of a polyethylene glycol (PEG) moiety leads to a loss of antiproliferative activity, whereas the attachment of a lipid chain preserves or improves it. However, the lipidated peptides are significantly more toxic when compared with their unmodified counterparts. Therefore, the best results were achieved not by the N terminal extension but by the protection of both ends with the d-Leu residue and 4-amidinobenzylamide, which yielded the most stable inhibitor, with an excellent activity and toxicity profile. PMID- 26751826 TI - Support vector regression to estimate the permeability enhancement of potential transdermal enhancers. AB - OBJECTIVES: Searching for chemicals that will safely enhance transdermal drug delivery is a significant challenge. This study applies support vector regression (SVR) for the first time to estimating the optimal formulation design of transdermal hydrocortisone formulations. METHODS: The aim of this study was to apply SVR methods with two different kernels in order to estimate the enhancement ratio of chemical enhancers of permeability. KEY FINDINGS: A statistically significant regression SVR model was developed. It was found that SVR with a nonlinear kernel provided the best estimate of the enhancement ratio for a chemical enhancer. CONCLUSIONS: Support vector regression is a viable method to develop predictive models of biological processes, demonstrating improvements over other methods. In addition, the results of this study suggest that a global approach to modelling a biological process may not necessarily be the best method and that a 'mixed-methods' approach may be best in optimising predictive models. PMID- 26751828 TI - Synthesis of N-Containing Heterocyclic Compounds Using Visible-light Photoredox Catalysis. AB - Nitrogen heterocycles represent a highly important class of compounds which are widely used in materials science, agrochemistry, and medicinal chemistry. Therefore, there is continuing interest in the development of convenient, efficient, and environmentally benign synthetic methods for the construction of nitrogen containing heterocycles. Due to its natural abundance, ease of use, and promising application in industry, the use of visible light as a driving force for chemical reactions has received considerable attention in the past few years. This account summarizes the synthesis of N-heterocycles using visible-light photoredox catalysis published in the last two years, according to the size and type of the formed N-heterocyclic rings. In the context of seminal works of others in this area, a concise summary of the contributions of the authors is also offered. PMID- 26751827 TI - A highly sensitive electrochemical biosensor for catechol using conducting polymer reduced graphene oxide-metal oxide enzyme modified electrode. AB - The fabrication, characterization and analytical performances were investigated for a catechol biosensor, based on the PEDOT-rGO-Fe2O3-PPO composite modified glassy carbon (GC) electrode. The graphene oxide (GO) doped conducting polymer poly (3,4-ethylenedioxythiophene) (PEDOT) was prepared through electrochemical polymerization by potential cycling. Reduction of PEDOT-GO was carried out by amperometric method. Fe2O3 nanoparticles were synthesized in ethanol by hydrothermal method. The mixture of Fe2O3, PPO and glutaraldehyde was casted on the PEDOT-rGO electrode. The surface morphology of the modified electrodes was studied by FE-SEM and AFM. Cyclic voltammetric studies of catechol on the enzyme modified electrode revealed higher reduction peak current. Determination of catechol was carried out successfully by Differential Pulse Voltammetry (DPV) technique. The fabricated biosensor investigated shows a maximum current response at pH 6.5. The catechol biosensor exhibited wide sensing linear range from 4*10( 8) to 6.20*10(-5)M, lower detection limit of 7*10(-9)M, current maxima (Imax) of 92.55uA and Michaelis-Menten (Km) constant of 30.48uM. The activation energy (Ea) of enzyme electrode is 35.93KJmol(-1) at 50 degrees C. There is no interference from d-glucose and l-glutamic acid, ascorbic acid and o-nitrophenol. The PEDOT rGO-Fe2O3-PPO biosensor was stable for at least 75 days when stored in a buffer at about 4 degrees C. PMID- 26751829 TI - Phenotyping Rh/Kell and risk of alloimmunization in haematological patients. AB - BACKGROUND: One of the biggest concerns in transfusion medicine is to avoid red blood cell alloimmunization. We evaluated the rate of alloimmunization in two groups of chronically transfused patients (A - not phenotyped and B - phenotyped for Rh/K antigens before the first transfusion) with primary haematological disorders and its distribution among the main haematological diseases, in order to adopt an efficient transfusional strategy. STUDY DESIGN AND METHODS: As methodology, we used the SIBAS and SAM databases for the retrospective study of all patients with primary haematological disorder between January 2011 and April 2013. RESULTS: A statistical difference in the rate of alloimmunization comparing groups A and B was found (P <0.0001). We also observed that alloimmunization was not homogeneously distributed in all primary haematological diseases. CONCLUSIONS: The Rh/K phenotype should be performed on all patients diagnosed with bone marrow failure, plasma cell dyscrasia and myelodysplastic syndrome in order to avoid alloimmunization. In patients with acute leukaemia and lymphoma it seems not necessary to perform it. In patients with haemoglobinopathy and myeloproliferative disorders, a larger group of patients is needed to decide its efficacy. PMID- 26751831 TI - Ablation dynamics of Co/ZnS targets under double pulse femtosecond laser irradiation. AB - Femtosecond lasers, used as tools to investigate the ablation dynamics of solids, can help to develop strategies to control the deposition of nanomaterials by pulsed laser ablation. In this work, Co/ZnS targets, potential candidates for the synthesis of diluted magnetic semiconductor materials, are irradiated by sequences of two femtosecond laser pulses delayed in the picosecond time scale. The ionic composition of the ablation plasma and the dependence of the ion signals on the interpulse delay and relative fluence are determined by time-of flight mass spectrometry. The results show that, when pulses of different fluence are used, highly asymmetric ion yields are obtained, with more intense ion signals detected when the lower fluence pulse is temporally ahead. The comparison between asymmetric and equal fluence double pulse ablation dynamics provides some understanding of the different processes that modify the properties of the layer irradiated by the first pulse and of the mechanisms affecting the coupling of the delayed pulse into the material. The final outcome of the double pulse irradiation is characterized through the analysis of the deposits produced upon ablation. PMID- 26751834 TI - Formation of Mgx Nby Ox+y through the Mechanochemical Reaction of MgH2 and Nb2O5, and Its Effect on the Hydrogen-Storage Behavior of MgH2. AB - The present study aims to understand the catalysis of the MgH2 -Nb2 O5 hydrogen storage system. To clarify the chemical interaction between MgH2 and Nb2 O5 , the mechanochemical reaction products of a composite mixture of MgH2 +0.167 Nb2 O5 was monitored at different time intervals (2, 5, 15, 30, and 45 min, as well as 1, 2, 5, 10, 15, 20, 25, and 30 h). The study confirms the formation of catalytically active Nb-doped MgO nanoparticles (typically Mgx Nby Ox+y , with a crystallite size of 4-8 nm) by transforming reactants through an intermediate phase typified by Mgm-x Nb2n-y O5n-(x+y) . The initially formed Mgx Nby Ox+y product is shown to be Nb rich, with the concentration of Mg increasing upon increasing milling time. The nanoscale end-product Mgx Nby Ox+y closely resembles the crystallographic features of MgO, but with at least a 1-4 % higher unit cell volume. Unlike MgO, which is known to passivate the surfaces in MgH2 system, the Nb-dissolved MgO effectively mediates the Mg-H2 sorption reaction in the system. We believe that this observation will lead to new developments in the area of catalysis for metal-gas interactions. PMID- 26751836 TI - Reasons for Drug Administration Problems and Perceived Needs for Assistance of Patients, Family Caregivers, and Nurses: A Qualitative Study. AB - OBJECTIVE: Investigation of drug administration problems, respective causes, and needs for assistance. METHODS: Focus group discussions with patients, family caregivers, and nurses were conducted using a semi-structured interview guideline for a focused exploration of the participants' drug administration experiences and perceived needs for assistance. All discussions were audio-recorded and video recorded, verbatim transcribed, and analyzed according to Mayring's qualitative content analysis. RESULTS: In total, 6 focus group discussions were conducted. The qualitative content analysis revealed that patients and family caregivers frequently trivialized drug administration, were unaware of errors, and primarily blamed the dosage form of causing administration problems. Nurses also considered health-care system-related conditions and patient factors as potential causes of administration problems. CONCLUSIONS: The administration problems and perceived causes were multifaceted and often directed toward inappropriate dosage forms or health-care system-related conditions rather than critically questioning the medicine user's administration skills. To increase medicine users' motivation to scrutinize wrong administration practices, health-care professionals should consider individual perspectives on administration problems and perceived causes, assist medicine users' to identify the true cause of a distinct problem, and provide individualized support. PMID- 26751830 TI - Stimulus sequence context differentially modulates inhibition-related theta and delta band activity in a go/no-go task. AB - Recent work suggests that dissociable activity in theta and delta frequency bands underlies several common ERP components, including the no-go N2/P3 complex, which can better index separable functional processes than traditional time-domain measures. Reports have also demonstrated that neural activity can be affected by stimulus sequence context information (i.e., the number and type of preceding stimuli). Stemming from prior work demonstrating that theta and delta index separable processes during response inhibition, the current study assessed sequence context in a go/no-go paradigm in which the number of go stimuli preceding each no-go was selectively manipulated. Principal component analysis of time-frequency representations revealed differential modulation of evoked theta and delta related to sequence context, where delta increased robustly with additional preceding go stimuli, while theta did not. Findings are consistent with the view that theta indexes simpler initial salience-related processes, while delta indexes more varied and complex processes related to a variety of task parameters. PMID- 26751837 TI - Dielectric depolarisation and concerted collective dynamics in AOT reverse micelles with and without ubiquitin. AB - In this computational study we present molecular dynamics (MD) simulations of reverse micelles, i.e. nano-scale water pools encapsulated by sodium bis(2 ethylhexyl) sulfosuccinate (AOT) and dissolved in isooctane. Although consisting of highly polar components, such micro-emulsions exhibit surprisingly low dielectric permittivity, both static and frequency-dependent. This finding is well supported by experimental dielectric measurements. Furthermore, the computational dielectric spectra of reverse micelles with and without the polar protein ubiquitin are almost identical. A detailed component analysis of our simulated systems reveals the underlying mechanism of the observed dielectric depolarisation. While each component by itself would make a remarkable contribution to the static dielectric permittivity, mutual compensation leads to the observed marginal net result. This compensatory behavior is maintained for all but the highest frequencies. Dielectric model theory adapted to the peculiarities of reverse micelles provides an explanation: embedding a system in a cavity engulfed by a low dielectric medium automatically leads to depolarization. In this sense experiment, simulation and theory are in accordance. PMID- 26751838 TI - A comparative study on the antibacterial photodynamic efficiency of a curcumin derivative and a formulation on a porcine skin model. AB - INTRODUCTION: The propagation of pathogens resistant to antibiotics around the globe has induced an urgent call for action: alternatives to conventional antibiotic therapy have to be developed to prevent a post-antibiotic catastrophe. This study focuses on the enhancement of Photodynamic Inactivation (PDI) of Gram(+) versus Gram(-) bacteria comparing a cationic derivative of curcumin (SACUR-3) to curcumin bound to polyvinylpyrrolidone (PVP-CUR) using an ex vivo porcine skin model to simulate an application on the human skin and foodstuff. EXPERIMENTAL: Porcine skin samples were inoculated with either Staphylococcus aureus or Escherichia coli and treated with either SACUR-3 or PVP-CUR at concentrations of 50 or 100 MUM, respectively. Subsequent to blue light illumination (435 nm, 33.8 J cm(-2)) quantitative analyses were performed by counting the colony forming units. Furthermore, the localization of both photoactive compounds in the porcine skin was determined by fluorescence microscopy. PDI of S. aureus resulted in a reduction of 2.2 log10 steps if employing 50 MUM of SACUR-3 and of 1.7 log10 steps with 50 MUM of PVP-CUR. Phototoxicity towards E. coli was 3.3 log10 steps using 100 MUM of SACUR-3 and 0.3 log10 steps for 100 MUM of PVP-CUR. Both compounds do not exceed the stratum corneum of the skin. CONCLUSION: A direct comparison of both approaches yields that the cationic curcumin derivative SACUR-3 is effective against Gram(+) and Gram(-) pathogens, whereas the formulation of PVP-CUR has a photokilling effect on the Gram(+) model strain only, but leaves the approval of curcumin as a food additive E100 unaffected. Our results suggest the applicability of SACUR-3-based PDI in dermatology, hand hygiene and food production. PMID- 26751835 TI - 1,25-Dihydroxyvitamin D Alone Improves Skeletal Growth, Microarchitecture, and Strength in a Murine Model of XLH, Despite Enhanced FGF23 Expression. AB - X-linked hypophosphatemia (XLH) is characterized by impaired renal tubular reabsorption of phosphate owing to increased circulating FGF23 levels, resulting in rickets in growing children and impaired bone mineralization. Increased FGF23 decreases renal brush border membrane sodium-dependent phosphate transporter IIa (Npt2a) causing renal phosphate wasting, impairs 1-alpha hydroxylation of 25 hydroxyvitamin D, and induces the vitamin D 24-hydroxylase, leading to inappropriately low circulating levels of 1,25-dihydroxyvitamin D (1,25D). The goal of therapy is prevention of rickets and improvement of growth in children by phosphate and 1,25D supplementation. However, this therapy is often complicated by hypercalcemia and nephrocalcinosis and does not always prevent hyperparathyroidism. To determine if 1,25D or blocking FGF23 action can improve the skeletal phenotype without phosphate supplementation, mice with XLH (Hyp) were treated with daily 1,25D repletion, FGF23 antibodies (FGF23Ab), or biweekly high-dose 1,25D from d2 to d75 without supplemental phosphate. All treatments maintained normocalcemia, increased serum phosphate, and normalized parathyroid hormone levels. They also prevented the loss of Npt2a, alpha-Klotho, and pERK1/2 immunoreactivity observed in the kidneys of untreated Hyp mice. Daily treatment with 1,25D decreased urine phosphate losses despite a marked increase in bone FGF23 mRNA and in circulating FGF23 levels. Daily 1,25D was more effective than other treatments in normalizing the growth plate and metaphyseal organization. In addition to being the only therapy that normalized lumbar vertebral height and body weight, daily 1,25D therapy normalized bone geometry and was more effective than FGF23Ab in improving trabecular bone structure. Daily 1,25D and FGF23Ab improved cortical microarchitecture and whole-bone biomechanical properties more so than biweekly 1,25D. Thus, monotherapy with 1,25D improves growth, skeletal microarchitecture, and bone strength in the absence of phosphate supplementation despite enhancing FGF23 expression, demonstrating that 1,25D has direct beneficial effects on the skeleton in XLH, independent of its role in phosphate homeostasis. (c) 2016 American Society for Bone and Mineral Research. PMID- 26751839 TI - Microtrauma: no longer to be ignored in spondyloarthritis? AB - PURPOSE OF REVIEW: Novel clinical and animal model data support that biomechanical factors play a role in the onset and progression of spondyloarthritis. Bringing together these insights with the progress made in our understanding of the immunopathogenesis and genetic susceptibility of spondyloarthritis may provide new opportunities for better management. RECENT FINDINGS: Tail suspension prevents arthritis in a tumor necrosis factor overexpression model. A similar approach also reduces new bone formation after acute arthritis in mice. Physical labor is associated with disease severity, including structural disease progression. Sentinel immune cells in the enthesis provide a link between local damage and the development of inflammation. Loss of stability likely triggers tissue remodeling, including the formation of syndesmophytes. Improving muscle strength and control while avoiding excessive strain or overuse should be considered in the approach toward patients. New regulators of tissue turnover and remodeling are emerging including microRNAs. SUMMARY: Local damage may provide a trigger for spondyloarthritis. For structural disease progression loss of stability may be an important factor. Control of inflammation will prevent stability issues and improve the long-term prognosis of disease. Physical therapy will continue to provide benefit for patients in the short and in long-term management of disease. PMID- 26751841 TI - The biology behind interleukin-6 targeted interventions. AB - PURPOSE OF REVIEW: Biological drugs that target the inflammatory cytokine interleukin-6 (IL-6) are increasingly considered as therapies for chronic disease and cancer. The purpose of this review is to place the biology of IL-6 in context. Here, we provide information on the biology behind IL-6 and consider mechanisms that are relevant to the application of IL-6 targeted therapies. RECENT FINDINGS: The clinical blockade of IL-6 activity with tocilizumab has fuelled considerable interest in the biology behind this inflammatory cytokine. Although IL-6 impacts both innate and adaptive immunity, and the control of tissue homeostasis, the signalling mechanisms that control IL-6 responsiveness are complex. Several alternative IL-6-directed interventions with unique modes of action are now approaching the clinic. However, various questions still remain about how and when to block IL-6. Owing to the complexity of IL-6 biology, this is not trivial. In this review, we introduce the immunobiology of IL-6 and explore the different therapeutic strategies in development that inhibit IL-6 activity. SUMMARY: Various inhibitors of IL-6 bioactivity are now in development of routine clinical practice. The key is to understand how best to apply these drugs. This review provides useful insight into the workings of IL-6 in health and disease. PMID- 26751842 TI - Computational identification and analysis of signaling subnetworks with distinct functional roles in the regulation of TNF production. AB - Inflammation is a complex process driven by the coordinated action of a vast number of pro- and anti-inflammatory molecular mediators. While experimental studies have provided an abundance of information about the properties and mechanisms of action of individual mediators, essential system-level regulatory patterns that determine the time-course of inflammation are not sufficiently understood. In particular, it is not known how the contributions from distinct signaling pathways involved in cytokine regulation combine to shape the overall inflammatory response over different time scales. We investigated the kinetics of the intra- and extracellular signaling network controlling the production of the essential pro-inflammatory cytokine, tumor necrosis factor (TNF), and its anti inflammatory counterpart, interleukin 10 (IL-10), in a macrophage culture. To tackle the intrinsic complexity of the network, we employed a computational modeling approach using the available literature data about specific molecular interactions. Our computational model successfully captured experimentally observed short- and long-term kinetics of key inflammatory mediators. Subsequent model analysis showed that distinct subnetworks regulate IL-10 production by impacting different temporal phases of the cAMP response element-binding protein (CREB) phosphorylation. Moreover, the model revealed that functionally similar inhibitory control circuits regulate the early and late activation phases of nuclear factor kappaB and CREB. Finally, we identified and investigated distinct signaling subnetworks that independently control the peak height and tail height of the TNF temporal trajectories. The knowledge of such subnetwork-specific regulatory effects may facilitate therapeutic interventions aimed at precise modulation of the inflammatory response. PMID- 26751840 TI - The thymus and rheumatology: should we care? AB - PURPOSE OF REVIEW: The purpose of this review is to discuss the mechanisms of central and peripheral tolerance in relation to T-cell mediated autoimmunity in rheumatoid arthritis (RA). RECENT FINDINGS: The well established association between major histocompatibility complex class II and RA has led us to understand that T cells, and the adaptive immune response, are important in the pathogenesis of disease. In order for autoimmune disease to develop, there is a breach of tolerance to self antigen and the mechanisms of both central and peripheral tolerance aim to prevent this. Here, we review evidence from mouse models indicating that alterations in T-cell receptor signalling thresholds during thymic selection may be linked to the escape of T cells that mediate autoimmune arthritis. In addition, we summarize the role of dendritic cells and Foxp3+ regulatory T cells in both peripheral and thymic tolerance, and highlight their relevance to what we know about the aetiology of RA. SUMMARY: Mechanisms of central tolerance in the thymus and peripheral tolerance are in place to control autoreactive T cells and to prevent the development of autoimmune disease. We anticipate that a better understanding of these mechanisms will lead to the development of better, antigen-specific therapeutics to restore tolerance. PMID- 26751843 TI - Cationic Peptide Conjugation Enhances the Activity of Peroxidase-Mimicking DNAzymes. AB - Peroxidase-mimicking DNAzymes containing G-quadruplex structures are widely applied in chemistry as catalysts and signal amplification for biosensing. Enhancing the catalytic activity of these DNAzymes can therefore improve the performance of many catalysts and biosensors using them. In this work, we synthesized cationic peptide conjugates of peroxidase-mimicking DNAzymes, which were found to exhibit both enhanced peroxidase and oxidase activities up to 4 fold and 3-fold compared with the original DNAzymes, respectively. Further investigation suggested that the enhanced activity was ascribed to the stabilization of parallel DNA G-quadruplex structures and hemin binding by the cationic peptide covalently attached to the DNAzyme. Such a mechanism of activity enhancement was successfully utilized for biosensing applications with improved sensitivity and broadened target range. Hydrogen peroxide (H2O2) detection in K(+)-free solutions by the DNAzyme-peptide conjugate showed 2-fold sensitivity enhancement over the unmodified DNAzyme under the same condition, and the activity switch by target-induced cleavage of the DNAzyme-peptide conjugate was also used for the detection of caspase 3 protease with enzymatic amplification in homogeneous solutions. PMID- 26751844 TI - Strong reproductive isolation despite occasional hybridization between a widely distributed and a narrow endemic Rhododendron species. AB - Reproductive isolation (RI) plays an important role for speciation, but assessing reproductive barriers at all life-cycle stages remains challenging. In plants, most studies addressing the topic have been focusing on herbs with short generation times. The present study attempted to quantify several reproductive barriers between a hybridizing species pair of long-lived woody rhododendrons. Consistent with findings of previous studies, pre-zygotic reproductive barriers contributed more to total RI than post-zygotic reproductive barriers. Especially in the more widespread species geographic isolation was an important barrier, and pollinator constancy contributed exceptionally to RI in both species. Additionally to strong pre-zygotic reproductive barriers, post-zygotic reproductive barriers were considerable, and had asymmetric tendencies favoring one of the species as maternal parent. Overall, despite occasional hybridization, the present study provides evidence for strong RI between R. cyanocarpum and R. delavayi. PMID- 26751846 TI - Structure of Brewer's Spent Grain Lignin and Its Interactions with Gut Microbiota in Vitro. AB - Lignin is part of dietary fiber, but its conversion in the gastrointestinal tract is not well understood. The aim of this work was to obtain structural information on brewer's spent grain (BSG) lignin and to understand the behavior of the polymeric part of lignin exposed to fecal microbiota. The original BSG and different lignin fractions were characterized by pyrolysis-GC/MS with and without methylation. Methylation pyrolysis proved that the ratio between guaiacyl and syringyl units was similar in all lignin samples, but the ratio between p coumaric and ferulic acids varied by the isolation method. Combined pyrolysis results indicated higher acylation of gamma-OH groups in syringyl than in guaiacyl lignin units. The polymeric lignin structure in the alkali-soluble fraction after enzymatic hydrolysis was slightly altered in the in vitro colon fermentation, whereas lignin in the insoluble residue after enzymatic treatments remained intact. PMID- 26751847 TI - Downregulation of human intercellular adhesion molecule-1 attenuates the metastatic ability in human breast cancer cell lines. AB - Intercellular adhesion molecule-1 (ICAM-1) is a cell surface glycoprotein that belongs to immunoglobulin superfamily and plays an important role in tumor cell expansion or metastasis. However, the detailed mechanisms of ICAM-1 in breast cancer remain unclear. In this study, we evaluated the expression level of ICAM-1 in breast cancer using tissue microarray and clinical tissue specimens by immunohistochemical method, and the results revealed that ICAM-1 is highly expressed in the breast cancer tissues. To investigate whether ICAM-1 can affect the metastasis ability in breast cancer, we knocked down ICAM-1 expression in breast cancer cell line MCF-7 by using lentivirus-mediated RNA interference (RNAi). As a result, we stably silenced ICAM-1 expression in MCF-7 cells by infection with lentivirus expressing green fluorescent protein (GFP), the change of metastatic ability of MCF-7 cells was assessed by wound-healing assay, Transwell assay or clone formation assay. Our results showed that silencing of ICAM-1 can inhibit the metastatic ability of MCF-7 cell lines in vitro significantly, and the decreased migration and invasion was accompanied by a reduction of MMP-14. These results implying that ICAM-1 might be involved in the progression of breast cancer metastasis and lentivirus-mediated silencing of ICAM 1 might be a potential therapeutic approach for the treatment of breast cancer. PMID- 26751845 TI - Evaluation of Color-Changing Effect and Complications After Nd: YAG Laser Application On Iris Surface. AB - BACKGROUND: The aim of this study was to evaluate the color-changing effect and adverse effects after Nd: YAG laser application on the iris surface of rabbit eyes. MATERIAL/METHODS: The study was performed on right eyes of 12 pigmented rabbits. A laser device that produces frequency doubled 532 nm wavelength Nd: YAG laser with 900 MUm spot diameter was used. The laser was applied in 3 sessions at 2-week intervals, at energy levels of 0.8 mJ in Group A and 1.5 mJ in Group B. Slit-lamp examinations and measurements of intraocular pressure (IOP) using a Tono-Pen were performed before and 1 day after each laser session. Iris thickness (IT) was measured at the beginning and the end using an ultrasonic biomicroscope. The eyes were enucleated for histopathologic examination on day 60. RESULTS: On the first day after each laser session, maximum grade 1 anterior chamber flare and cells were observed in both groups. In all eyes, flare and cells disappeared at the end of the first week. There was no significant difference in the IOP and IT values between measurements performed prior to and after laser sessions during the study (p>0.05). None of the eyes showed complications such as corneal edema, hypopyon, posterior synechia, transillumination defect, or pupillary defect. In histopathological examinations, reduction in pigment density was more profound in Group B compared to Group A, which was statistically significant (p<0.019). CONCLUSIONS: There were no serious complications apart from mild transient inflammatory signs. Change in iris color was more evident at the end of the second month. PMID- 26751848 TI - Plasmon-Assisted Nd(3+)-Based Solid-State Nanolaser. AB - Solid-state lasers constitute essential tools in a variety of scientific and technological areas, being available in many different designs. However, although nanolasing has been successfully achieved for dyes and semiconductor gain media associated with plasmonic structures, the operation of solid-state lasers beyond the diffraction limit has not been reported yet. Here, we demonstrate room temperature laser action with subwavelength confinement in a Nd(3+)-based solid state laser by means of the localized surface plasmon resonances supported by chains of metallic nanoparticles. We show a 50% reduction of the pump power at threshold and a remarkable 15-fold improvement of the slope efficiency with respect to the bulk laser operation. The results can be extended to the large diversity of solid-state lasers with the subsequent impact on their applications. PMID- 26751850 TI - Amido Ln(II) Complexes Coordinated by Bi- and Tridentate Amidinate Ligands: Nonconventional Coordination Modes of Amidinate Ligands and Catalytic Activity in Intermolecular Hydrophosphination of Styrenes and Tolane. AB - Heteroleptic Ln(II) and Ca(II) amides [tBuC(NC6H3-iPr2-2,6)2]MN(SiMe3)2(THF) (M = Yb (1Yb), Ca (1Ca)), [2-MeOC6H4NC(tBu)N(C6H3-iPr2-2,6)]LnN(SiMe3)2(THF) (Ln = Sm (2Sm), Yb (2Yb)), and [2-Ph2P(O)C6H4NC(tBu)N(C6H3-Me2-2,6)]YbN(SiMe3)2(THF) (3Yb) coordinated by bi- and tridentate amidinate ligands were obtained by the amine elimination reactions of M[N(SiMe3)2](THF)2 (M = Yb, Sm, Ca) with parent amidines in good yields. Complex [tBuC(NC6H3-iPr2-2,6)2]SmN(SiMe3)2 can be obtained only by a salt metathesis reaction of [tBuC(NC6H3-2,6-iPr2)2]SmI(THF)2 with NaN(SiMe3)2. Unlike 1Yb and 1Ca in 1Sm the amidinate ligand is coordinated to metal ion in kappa(1)-amido:eta(6)-arene fashion preventing THF coordination. The derivatives of tridentate amidinate ligands bearing pendant donor 2-MeOC6H4 or 2 Ph2P(O)C6H4N groups feature nonconventional kappa(1)-N,kappa(2)-O,eta(6)-arene coordination mode. Complexes 1Ca, 1Sm, 1Yb, 2Sm, 2Yb, and 3Yb proved to be efficient catalysts for styrene hydrophosphination with PhPH2 and Ph2PH. In styrene hydrophosphination with PhPH2 all the catalysts perform excellent chemoselectivity and afford a monoaddition product-secondary phosphine (PhCH2CH2)PhPH. Moreover, all the catalysts perform hydrophosphination reactions regioselectively with exclusive formation of the anti-Markovnikov addition product. Within the series of complexes coordinated by the same amidinate ligand catalytic activity decreases in the following order 1Ca >= 1Sm>1Yb. The turnover frequencies were in the range of TOF ~ 0.3-0.7 h(-1). However, application of tridentate amidinate ligand allowed one to increase catalytic activity significantly: for 2Sm TOF was found to be 8.3 h(-1). For the addition of PhPH2 to para-substituted styrenes catalyzed by 2Sm it was found that electron withdrawing substituents (Cl, F) do not affect the reaction rate while electron donating groups (tBu, OMe) noticeably slow down the reaction. PMID- 26751849 TI - Simple and effective exercise design for assessing in vivo mitochondrial function in clinical applications using (31)P magnetic resonance spectroscopy. AB - The growing recognition of diseases associated with dysfunction of mitochondria poses an urgent need for simple measures of mitochondrial function. Assessment of the kinetics of replenishment of the phosphocreatine pool after exercise using (31)P magnetic resonance spectroscopy can provide an in vivo measure of mitochondrial function; however, the wider application of this technique appears limited by complex or expensive MR-compatible exercise equipment and protocols not easily tolerated by frail participants or those with reduced mental capacity. Here we describe a novel in-scanner exercise method which is patient-focused, inexpensive, remarkably simple and highly portable. The device exploits an MR compatible high-density material (BaSO4) to form a weight which is attached directly to the ankle, and a one-minute dynamic knee extension protocol produced highly reproducible measurements of post-exercise PCr recovery kinetics in both healthy subjects and patients. As sophisticated exercise equipment is unnecessary for this measurement, our extremely simple design provides an effective and easy to-implement apparatus that is readily translatable across sites. Its design, being tailored to the needs of the patient, makes it particularly well suited to clinical applications, and we argue the potential of this method for investigating in vivo mitochondrial function in new cohorts of growing clinical interest. PMID- 26751851 TI - Waterproof Electronic-Bandage with Tunable Sensitivity for Wearable Strain Sensors. AB - We demonstrate high-performance wearable electronic-bandage (E-bandage) based on carbon nanotube (CNT)/silver nanoparticle (AgNP) composites covered with flexible media of fluoropolymer-coated polydimethylsiloxane (PDMS) films. The E-bandage can be used for motion-related sensors by directly attaching them to human skin, which achieves a fast and accurate electric response with high sensitivity according to the bending and stretching movements that induce changes in the conductivity. This advance in the E-bandage is realized as a result of the sensitivity that can be achieved by controlling the concentration of AgNPs in CNT pastes and by modifying the device architecture. The fluoropolymer encapsulation with hydrophobic surface characteristics allows for the E-bandage to operate in water and protects it from physical and chemical contact with the daily life conditions of the human skin. The reliability and scalability of the E-bandage as well as the compatibility with conventional microfabrication allow new possibilities to integrate flexible human-interactive nanoelectronics into mobile health-care monitoring systems combined with Internet of things (IoTs). PMID- 26751852 TI - An integrated utility-based model of conflict evaluation and resolution in the Stroop task. AB - Cognitive control allows humans to direct and coordinate their thoughts and actions in a flexible way, in order to reach internal goals regardless of interference and distraction. The hallmark test used to examine cognitive control is the Stroop task, which elicits both the weakly learned but goal-relevant and the strongly learned but goal-irrelevant response tendencies, and requires people to follow the former while ignoring the latter. After reviewing the existing computational models of cognitive control in the Stroop task, its novel, integrated utility-based model is proposed. The model uses 3 crucial control mechanisms: response utility reinforcement learning, utility-based conflict evaluation using the Festinger formula for assessing the conflict level, and top down adaptation of response utility in service of conflict resolution. Their complex, dynamic interaction led to replication of 18 experimental effects, being the largest data set explained to date by 1 Stroop model. The simulations cover the basic congruency effects (including the response latency distributions), performance dynamics and adaptation (including EEG indices of conflict), as well as the effects resulting from manipulations applied to stimulation and responding, which are yielded by the extant Stroop literature. PMID- 26751853 TI - Progress toward the Total Synthesis of Goniodomin A: Stereocontrolled, Convergent Synthesis of the C12-C36 Fragment. AB - Goniodomin A is a marine polyether macrolide natural product isolated from the dinoflagellate Alexandrium hiranoi. In this paper, we report stereocontrolled, convergent synthesis of a fully functionalized C12-C36 fragment of goniodomin A. The synthesis of the C12-C25 vinylstannane involved a Wittig reaction and a reductive cycloetherification for the construction of the dihydropyran ring. The C26-C36 thioester was synthesized via a Nozaki-Hiyama-Kishi reaction of an aldehyde and an iodoalkyne, the former of which was easily prepared from (R) malic acid as a chiral source by taking advantage of substrate-controlled diastereoselective reactions. Finally, a palladium-catalyzed coupling of the C12 C25 vinylstannane and the C26-C36 thioester completed the synthesis of the target compound. PMID- 26751854 TI - Modern analytical techniques in the assessment of the authenticity of Serbian honey. AB - Food authenticity in a broader sense means fulfilling chemical and physical criteria prescribed by the proposed legislation. In the case of honey authenticity, two aspects are of major concern: the manufacturing process and the labelling of final products in terms of their geographical and botanical origin. A reliable assessment of honey authenticity has been a longterm preoccupation of chemists-analysts and it usually involves the use of several criteria and chemical markers, as well as a combination of analytical and statistical (chemometric) methods. This paper provides an overview of different criteria and modern methods for the assessment of honey authenticity in the case of a statistically significant number of authentic honey samples of several botanical types from various regions of Serbia. PMID- 26751855 TI - Composition, labelling, and safety of food supplements based on bee products in the legislative framework of the European Union - Croatian experiences. AB - The European Union market is overflown by food supplements and an increasing number of consumers prefer those where bee products play an important part in their composition. This paper deals with complex European Union legislation concerning food supplements based on bee products, placing a special emphasis on their composition, labelling, and safety. Correct labelling of food supplements also represents a great challenge since, in spite of legal regulations in force, there are still open issues regarding the statements on the amount of propolis, which is not clearly defined by the legal framework. One of the key issues are the labels containing health claims from the EU positive list approved by the European Food Safety Authority. Emphasis will also be placed on informing consumers about food, as statements which imply the healing properties of food supplements and their capacity to cure diseases are forbidden. One of the key elements of product safety is HACCP based on the EU Regulations EC 178/02 and 852/2004. Health safety analyses of food supplements with bee products used as raw materials, which are standardised by legal regulations will also be discussed. In the future, attention should also be paid to establishing the European Union "nutrivigilance" system. Croatian experiences in addressing challenges faced by producers, supervisory entities, and regulatory and inspection bodies may serve as an example to countries aspiring to become part of the large European family. PMID- 26751856 TI - Mineral content of bee pollen from Serbia. AB - In this study we analysed mineral composition of bee pollen of different plant origin collected across Serbia using inductively coupled plasma - optical emission spectrometry. The most abundant elements were potassium, calcium, and magnesium. The samples were also exceptionally rich in iron and zinc, which are very important as nutrients. Judging by our findings, mineral composition of bee pollen much more depends on the type of pollen-producing plant than on its geographical origin. PMID- 26751857 TI - Major royal jelly proteins as markers of authenticity and quality of honey. AB - Until now, the properties of honey have been defined based exclusively on the content of plant components in the nectar of given plant. We showed that apalbumin1, the major royal jelly (RJ) protein, is an authentic and regular component of honey. Apalbumin1 and other RJ proteins and peptides are responsible for the immunostimulatory properties and antibiotic activity of honey. For the quantification of apalbumin1, an enzyme-linked immunosorbent assay (ELISA) was developed using polyclonal anti-apalbumin1 antibody. The method is suitable for honey authenticity determination; moreover it is useful for detection of the honey, honeybee pollen and RJ in products of medicine, pharmacy, cosmetics, and food industry, where presences of these honeybee products are declared. Results from the analysis for presence and amount of apalbumin1 in honeys will be used for high-throughput screening of honey samples over the world. On the basis of our experiments which show that royal jelly proteins are regular and physiologically active components of honey we propose to change the definition of honey (according to the EU Honey Directive 2001/110/EC) as follows: Honey is a natural sweet substance produced by honey bees from nectar of plants or from secretions of plants, or excretions of plant sucking insects, which honey bees collect, transform by combining with major royal jelly proteins and other specific substances of their own, deposit, dehydrate, store and leave in the honey comb to ripen and mature. PMID- 26751858 TI - The influence of royal jelly and human interferon-alpha (HuIFN-alphaN3) on proliferation, glutathione level and lipid peroxidation in human colorectal adenocarcinoma cells in vitro. AB - Among royal jelly's (RJ) various biological activities, its possible antitumour activity deserves particular attention. The purpose of this study was to investigate the influence of RJ, its bioactive component 10-hydroxy-2-decenoic acid (10- HDA), and human interferon-alpha (HuIFN-alphaN3) on the proliferation of human colorectal adenocarcinoma cells (CaCo- 2), and ascertain their effect on intracellular glutathione (GSH) level and lipid peroxidation. We studied the antiproliferative (AP) activity of RJ [(0.1 g/10 mL phosphate buffer saline (PBS)], HuIFN-alphaN3 (1000 I.U. mL-1), 10-HDA at 100.0 MUmol L-1, and their different combinations, in the ratio 1:1, 1:2, and 2:1 on CaCo-2 cells. The GSH level was measured by glutathione assay. The lipid peroxidation was measured by malondialdehyde (MDA) assay. Single RJ had a low AP activity: 2.0 (0.5 mg mL-1). HuIFN-alphaN3 had an AP activity of 2.5 (208.33 I.U. mL-1), while 10-HDA had an AP activity of 1.5 (37.5 MUmol mL-1). The highest AP activity of 3.8 was obtained when RJ and HuIFN-alphaN3 were applied at the ratio 2:1. In that combination the level of GSH was 24.9+/-2.4 nmol g-3 of proteins (vs. 70.2+/-3.2 nmol g-3 in the control) and the level of MDA was 72.3+/-3.1 nmol g-3 (vs. 23.6+/-9.1 nmol g-3 in the control). It is generally assumed that 10-HDA, an important constituent of RJ, together with HuIFN-alphaN3, is responsible for the inhibition of CaCo-2 cells proliferation in vitro. In our study, however, RJ and HuIFN-alphaN3 applied at 2:1 decreased the level of GSH the most and significantly increased lipid peroxidation via MDA in CaCo-2 cells. Future studies should show whether these GSH- and MDA-related activities of RJ, HuIFN-alphaN3, 10-HDA, and their combinations may decrease the tumorigenicity index and tumorigenic potential of various tumour cells in vitro. PMID- 26751859 TI - A suggestion for royal jelly specifications. AB - This article proposes guidelines for quality standards of royal jelly. The proposals are based on two sets of data; the first from our study of the factors that may affect the royal jelly's chemical composition (protein and sugar supplementation of beehives) and the second on the analysis of a great number of samples from across Greece to establish natural variability of this product. We compared our findings with the adopted national limits, the proposals of the working group of the International Honey Commission (IHC), and the draft proposal of the International Organization of Standardization (ISO). The studied parameters included moisture, total proteins, sugars (fructose, glucose, sucrose, total sugars), and 10-hydroxy- 2-decenoic acid (10-HDA). Our results indicate that the limits for royal jelly in some countries should be amended and the proposals of the IHC and the ISO reviewed in view of recent data on variability. We believe that our proposals could be considered for setting global standards for royal jelly, as they incorporate national legislations, proposals of scientific groups, experimental data, and updated information. PMID- 26751860 TI - Molecular basis of ALS and FTD: implications for translational studies. AB - Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The cause is unknown and no effective treatment currently exists. For ALS, there is only a drug Riluzole and a promising substance arimoclomol. The overlap between ALS and FTD occurs at clinical, genetic, and pathological levels. The majority of ALS cases are sporadic (SALS) and a subset of patients has an inherited form of the disease, familial ALS (FALS), with a common SOD1 mutation, also present in SALS. A few of the mutant genes identified in FALS have also been found in SALS. Recently, hexanucleotide repeat expansions in C9ORF72 gene were found to comprise the largest fraction of ALS- and FTD-causing mutations known to date. TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the pathological protein of FALS, SALS and, less frequently, FTD. The less frequent TDP-43 pathology in other forms of familial FTD has been linked to a range of mutations in GRN, FUS/TLS, rarely VCP, and other genes. TDP-43 and FUS/TLS have striking structural and functional similarities, most likely implicating altered RNA processing as a major event in ALS pathogenesis. The clinical overlap of the symptoms of FTD and ALS is complemented by overlapping neuropathology, with intracellular inclusions composed of microtubule-associated protein tau, TDP-43 and less frequently FUS, or unknown ubiquitinated proteins. Furthermore, new therapeutic approaches continue to emerge, by targeting SOD1, TDP-43 or GRN proteins. This review addresses new advances that are being made in our understanding of the molecular mechanisms of both diseases, which may eventually translate into new treatment options. PMID- 26751861 TI - Translation of in vitro to in vivo pyridinium oxime potential in tabun poisoning. AB - Even if organophosphorus (OP) nerve agents were banned entirely, their presence would remain a problem as weapons of terror (like in Syria). Oxime antidotes currently used in medical practice still fall short of their therapeutic purpose, as they fail to fully restore the activity of cholinesterases, the main target for OPs. As orphan drugs, these antidotes are tested too seldom for anybody's benefit. Over the last few decades, search for improved reactivators has reached new levels, but the translation of data obtained in vitro to in vivo application is still a problem that hinders efficient therapy. In this study, we tested the strengths and weaknesses of extrapolating pyridinium oxime antidotes reactivation efficiency from in vitro to in vivo application. Our results show that this extrapolation is possible with well-determined kinetic constants, but that it also largely depends on oxime circulation time and its tissue-specific distribution. This suggests that pharmacokinetic studies should be planned at the early stages of antidote development. Special attention should also be given to improving oxime distribution throughout the organism to overcome this major constraint in improving overall OP therapy. PMID- 26751862 TI - Chlorinated compounds in the muscle tissue of fish from the Croatian Adriatic: preliminary data on contamination and the associated health risks. AB - Levels of 17 polychlorinated biphenyl congeners (PCBs) and seven organochlorine pesticides (OCPs) were measured in the muscle tissue of 18 commercially important fish species from the eastern Adriatic Sea. PCBs [=18 month-old). A total number of 734 cows were enrolled in the study. The animals were screened with a commercial competitive ELISA (Bio-X Diagnostics, Belgium). To calculate true herd-level seroprevalence test sensitivity and specificity were adjusted from an individual- to a herd-level using FreeCalc method. The true overall herd-level seroprevalence of N. caninum infection was 56.7% (95% CI: 47.5%, 65.9%). The true herd-level seroprevalence in Podlaskie was 63.3% (95% CI: 43.0%, 83.6%) and 50.5% (95% CI: 32.8%, 68.2%) in Lodzkie province and these figures did not differ significantly between the two provinces (chi2 test p = 0.238). One hundred forty three of 734 cows (19.5%) were seropositive which gave the true overall individual-level seroprevalence of 20.1% (95% CI: 17.4%, 23.2%). Percentage of seropositive cows in each herd varied from 6% to 80%. This study is the first epidemiological investigation of herd-level seroprevalence of N. caninum infection in Polish dairy cattle population. In conclusion, the result of the study confirmed previous data that N. caninum infection is widespread in the Polish cattle population and thus should be considered as a potential cause of spontaneous abortions. PMID- 26751873 TI - Ultrastructure of Ascaridia galli (Schrank, 1788) (Nematoda: Ascaridida) from the endangered green peafowl Pavo muticus Linnaeus (Galliformes: Phasianidae). AB - Ascaridia galli (Schrank, 1788) is a common parasite of various galliform birds worldwide. Although A. galli has been extensively studied by many author, knowledge of the morphology of this species in detail is still insufficient. In the present paper, the detailed morphology of A. galli was further studied using light and scanning electron microscopy, based on specimens collected from the endangered green peafowl Pavo muticus Linnaeus (Galliformes: Phasianidae) in China. The results revealed some erroneous and previously unreported morphological features, including the lips lacking real denticles, the lateral alae beginning at some distance posterior to the base of the ventrolateral lips and the caudal papillae with 4 different morphotypes. The present morphological and morphometric data complement previous descriptions and enable us to recognize this species more precisely. PMID- 26751875 TI - Description of a new species of Chabaudus Inglis and Ogden, 1965 (Nematoda: Seuratoidea) from the frog Euphlyctis cyanophlyctis from Dehrandun, Uttarakhand, India. AB - Chabaudus dehradunensis sp. nov. (Nematoda: Seuratoidea) from the large intestine of the water skipper, Euphlyctis cyanophlyctis (Anura, Dicroglossidae), from Dehrandun, India is described and illustrated. Chabaudus dehradunensis sp. nov. is the 6th species assigned to the genus and 1st species reported from India. It is separated from its congeners based upon the number and arrangement of caudal papillae and the length of spicule. Euphlyctis cyanophlyctis is the new host record for the genus Chabaudus. PMID- 26751874 TI - Prevalence and risk factors associated to Eimeria spp. infection in unweaned alpacas (Vicugna pacos) from Southern Peru. AB - A total of 350 faecal samples from unweaned alpacas over 3 months of age were collected from 23 herds in order to determine the prevalence of Eimeria spp. in Southern Peru and to identify the risk factors associated to Eimeria infection in young alpacas. Samples were examined by a flotation technique and the identification of risk factors was assessed by a logistic regression analysis. Sixty four percent of the examined animals shed Eimeria oocysts; herd prevalence was 96%, with an intra-herd prevalence of 60% (range 5.9-100%). Five different Eimeria species were identified, being E. lamae (91%), E. alpacae (87%) and E. punoensis (78%) the most prevalent; E. macusaniensis (35%) and E. ivitaensis (13%) were less common. Mixed-species infections were more frequent (78%) than single infections (22%). E. lamae was the most common monospecific infection and E. lamae/E. alpacae the most frequent association. The geographical area has a significant effect on Eimeria infection rates (74.9% wet Puna vs 37.4% dry Puna) as well as the breeding system (65.1% traditional vs 63.8% modern). In contrast, the sex of the animals (64.6% males vs 64.0% females) showed no influence on the prevalence of infection by Eimeria. The high prevalence found at both individual and herd level and the common presence of highly pathogenic Eimeria species may lead to important economic losses for alpaca breeders and could require the implementation of suitable control measures. PMID- 26751876 TI - Fertilization in the cestode Echinococcus multilocularis (Cyclophyllidea, Taeniidae). AB - Fertilization in the taeniid cestode Echinococcus multilocularis with uniflagellate spermatozoa was examined by means of transmission electron microscopy (TEM). Fertilization in this species occurs in the oviduct lumen or in the fertilization canal proximal to the ootype, where the formation of the embryonic capsule precludes sperm contact with the oocytes. Cortical granules are not present in the cytoplasm of the oocytes of this species, however, several large bodies containing granular material where frequently observed. Spermatozoa coil spirally around the oocytes and syngamy occurs by lateral fusion of oocyte and sperm plasma membranes. In the ootype, one vitellocyte associates with fertilized oocyte, forming a membranous capsule which encloses both cell types. In this stage, the spirally coiled sperm body adheres partly to the external oocyte surface, and partially enters into the perinuclear cytoplasm. The electron dense sperm nucleus becomes progressively electron-lucent within the oocyte cytoplasm after penetration. Simultaneously with chromatin decondensation, the elongated sperm pronucleus changes shape, forming a spherical male pronucleus, which attains the size of the female pronucleus. Cleavage begins immediately after pronuclear fusion. PMID- 26751878 TI - Fourier transform infrared spectroscopy as a tool for identification of crude microbial extracts with anti-malarial potential. AB - Fourier transform infrared (FT-IR) spectroscopy is an indispensable tool for identifying biologically active functional groups in uncharacterized crude samples. Here, using FT-IR spectrum analysis, we identified crude extracts of Streptomyces that have anti-malarial activities and conducted a statistical analysis of their spectra. Among the three crude microbial extracts tested herein, an aromatic amine C-N stretching functional group was observed in the spectra of Streptomyces sp. BJSG1 and BJSG4 crude extracts. These extracts showed promising activity against Plasmodium falciparum in vitro cultures with IC50 values of 0.5 for BJSG1 and 0.4MUg/mL for BJSG4. The present results showed that FT-IR analysis is necessary for the primary analysis of unknown samples in anti malarial drug development. PMID- 26751877 TI - Expression analysis of viscerotropic leishmaniasis gene in Leishmania species by real-time RT-PCR. AB - Viscerotropic leishmaniasis (VTL) is a parasitic disease with non-specific manifestations caused by Leishmania tropica. Specific antigens produced by Viscerotropic leishmaniasis gene have been used for diagnosis of VTL. The aim of this study was to compare the expression level of VTL gene among the viscerotropic L. tropica isolates (n: 3) and visceral L. infantum isolates (n: 4). Also, the expression level was compared in L. tropica (n: 21) and L. major (n: 8) isolates, the main causes of cutaneous leishmaniasis in Iran by real time RT-PCR. Results showed viscerotropic leishmaniasis gene was expressed in all 3 species; L. tropica, L. major and L. infantum. The most expression rate was in L. tropica and L. major as the cutaneous species and the lowest in visceral isolates including L. infantum and viscerotropic L. tropica strains respectively. CONCLUSION: Results revealed that VTL gene can play an important role in visceralization process of L. tropica although there are other mechanisms to keep parasite visceralized. According to these primary results, increased the expression level of VTL gene probably could contribute to inhibit the invasive behavior of Leishmania parasites. However, more experimental researches are needed to confirm this idea. PMID- 26751879 TI - A 43 kDa recombinant plasmepsin elicits immune response in mice against Plasmodium berghei malaria. AB - Intraerythrocytic parasites degrade haemoglobin to make available nutrients for their growth and maturation. Plasmepsins, the aspartic proteases of Plasmodium play a significant role in haemoglobin degradation and are proposed as attractive drug targets. In the present study the gene which encodes plasmepsin in rodent malaria parasite, Plasmodium berghei, was cloned and expressed. The gene was sequenced and expressed in Escherichia coli BL21DE3 and a recombinant plasmepsin of molecular weight 43 kDa was obtained. The sequence obtained was analysed and compared with plasmepsins of other Plasmodium spp. Mice immunized with the recombinant plasmepsin induced a strong humoral immune response. ELISA and IFA performed on the serum of immunized mice showed high antibody titres. Along with this, in vivo study exhibited partial protection against P. berghei infection suggesting role of plasmepsin in malaria control. PMID- 26751880 TI - Effects of Echinostoma caproni miracidia dose on the amino acid contents of Biomphalaria glabrata as determined by high-performance thin-layer chromatography. AB - The effects of 5, 20, and 40 miracidia dose exposures of Echinostoma caproni on the amino acid contents of Biomphalaria glabrata were studied using high performance thin-layer chromatography-densitometry. Amino acids were identified and quantified in whole bodies of exposed snails and in the uninfected matched controls at 2 and 4 weeks post-exposure. Using cellulose layers with the mobile phase 2-butanol-pyridine-glacial acetic acid-deionized water (39:34:10:26) and ninhydrin detection reagent [2% ninhydrin in acetone-n-butanol (1:1)], five amino acids were identified, i.e., leucine/isoleucine, valine, alanine, glycine, and ornithine, by hRF value comparison and color differentiation. Quantitatively, there was a marked elevation in the amounts of four of these five amino acids (isoleucine/leucine, valine, alanine, and ornithine) across dose levels at 4 weeks post-infection (P<0.05). Elevation of the amino acid content in the high dose snail group suggested that some changes occurred in the amino acid metabolism of the snails in that group as a function of miracidia dose. PMID- 26751882 TI - Seasonal pattern in parasite infracommunities of Hoplerythrinus unitaeniatus and Hoplias malabaricus (Actinopterygii: Erythrinidae) from the Brazilian Amazon. AB - The present study investigated the effects of seasonal variation in parasites infracommunities of Hoplerythrinus unitaeniatus and Hoplias malabaricus from a tributary of Amazon River. For H. unitaeniatus and H. malabaricus, 11 parasite species were similar, and greatest parasite richness occurred during the rainy season. Ichthyophthirius multifiliis was the dominant parasite species for both hosts. In H. unitaeniatus, infection by Whittingtonocotyle caetei, Whittingtonocotyle jeju, Urocleidoides sp. and Anacanthorus sp. was higher during rainy season. Contracaecum sp., Procamallanus (Spirocamallanus) inopinatus, Nomimoscolex matogrossensis and Gorytocephalus spectabilis showed no seasonal pattern. For H. unitaeniatus, P. pillulare, Clinostomum marginatum and Argulus pestifer occurred only during dry season, while Trichodina sp., Dolops geayi, undetermined metacercariae and Posthodiplostomum sp. occurred only during the rainy season. In H. malabaricus, the prevalence of Urocleidoides eremitus was similar during the two seasons, but abundance was higher during the rainy season. Tetrahymena sp., C. marginatum, Dendrorchis neivai, undetermined metacercariae, Posthodiplostomum sp., Genarchella genarchella, Cystidicoloides sp., G. spectabilis, D. geayi, A. pestifer and Glossiphonidae gen. sp. occurred only during the dry season. However, Contracaecum sp. and P. (S.) inopinatus occurred during both seasons, but the prevalence of P. (S.) inopinatus was higher during the rainy season. Seasonal variation in this infection levels was due to the host's feeding behavior and habits and the availability of infectious forms of parasites with heteroxenic life cycles. The non-seasonal fluctuation detected are likely a result of the parasites biology, highly variable nature of this tributary of Amazon River and low abundance of parasites. PMID- 26751881 TI - In search of a potential diagnostic tool for molecular characterization of lymphatic filariasis. AB - Lymphatic filariasis (LF) is a chronic disease and is caused by the parasites Wuchereria bancrofti (W. bancrofti), Brugia malayi (B. malayi) and Brugia timori (B. timori). In the present study, Setaria cervi (S. cervi), a bovine filarial parasite has been used. Previously, it has been reported that the S. cervi shares some common proteins and antigenic determinants with that of human filarial parasite. The larval stages of filarial species usually cannot be identified by classical morphology. Hence, molecular characterization allows the identification of the parasites throughout all their developmental stages. The genomic DNA of S. cervi adult were isolated and estimated spectrophotometrically for the quantitative presence of DNA content. Screening of DNA sequences from filarial DNA GenBank and Expressed Sequence Tags (EST's) were performed for homologous sequences and then multiple sequence alignment was executed. The conserved sequences from multiple sequence alignment were used for In Silico primer designing. The successfully designed primers were used further in PCR amplifications. Therefore, in search of a promising diagnostic tool few genes were identified to be conserved in the human and bovine filariasis and these novel primers deigned may help to develop a promising diagnostic tool for identification of lymphatic filariasis. PMID- 26751883 TI - The first detection of the tick-borne encephalitis virus (TBEV) RNA in Dermacentor reticulatus ticks collected from the lowland European bison (Bison bonasus bonasus L.). AB - Tick borne encephalitis virus (TBEV) (Flaviviridae, Flavivirus) is the causative agent of tick-borne encephalitis (TBE), a potentially fatal neurological infection. The disease is endemic in a large region in Eurasia, where is transmitted mainly by hard ticks: Ixodes ricinus and I. persulcatus. It is known that also Dermacentor reticulatus is involved in a circulation of TBEV, but the knowledge of its importance in the TBE epidemiology is still insufficient. The Bialowieza Primeval Forest is located in eastern Poland and it is a well-known endemic focus of tick-borne encephalitis. The aim of this study was to identify the prevalence of tick-borne encephalitis virus (TBEV) in Dermacentor reticulatus ticks collected from European bison (Bison bonasus bonasus), an important host of hard ticks in the Bialowieza Primeval Forest. In the years 2008-2009, a total of 114 adult D. reticulatus ticks were collected from 7 European bison and examined individually for the presence of TBEV RNA using nested RT-PCR assay. Positive results were noted in 18.42% of ticks. This is the first record of TBEV infection in ticks collected from European bison. PMID- 26751884 TI - Assessing the influence of geographic distance in parasite communities of an exotic lizard. AB - The decay of similarity between biological communities with increasing geographical distance is a well-established pattern in ecology, but there are more complex factors acting on host population connections that influence this association for parasite communities, such as parasites' colonization ability and degree of connectivity between host populations. Here we aim to determine the helminth communities associated with different populations of the host lizard Hemidactylus mabouia, testing if the similarity of parasite communities decreases as the distance between them increases. For this, we collected samples of lizard populations in seven sites from Northeastern coast of Brazil and identified parasite species of helminths and pentastomids in each host, calculated the Sorensen indices of presence/absence and abundance of each pair of communities and related them to the geographical distance. We did not find a relationship of decaying similarity with increasing distance between the parasite communities of the host populations. This can be explained by factors such as the characteristics of the contact between the host populations, and by modes of transmission of most parasite species. Furthermore, it may be related to the exotic nature of the host in Brazil so that parasite communities have not reached equilibrium. PMID- 26751885 TI - Diagnostic value of semi-purified antigens of hydatid cyst fluid in human cystic echinococcosis. AB - Cystic Echinococcosis (CE) is an infection caused by the larval stage of Echinococcus granulosus. The diagnosis of this disease has been problematic. Serological tests detecting antibodies against E. granulosus are the most popular and mainly use the crude Hydatid Cyst Fluid (HCF) or its components, Ag 5 and B. However, the diagnostic value of these tests is limited by the problems of specificity and/or sensitivity. The use of purified HCF antigens could be more helpful in the serodiagnosis of CE compared to the whole HCF. In the present study, we have evaluated the diagnostic value of semi-purified antigens using ELISA tests. Our results have shown that the 53 KDa antigen gave the best specificity (97.5%) and sensitivity (80%). We have also used Western Blot technique to analyze the serological profile against HCF. The results have confirmed that the most immunogenic component of HCF is the Ag 5. PMID- 26751887 TI - Dactylogyrids (Monogenea) parasitic on cichlids from northern Brazil, with description of two new species of Sciadicleithrum and new host and geographical records. AB - Two new species of Sciadicleithrum Kritsky, Thatcher and Boeger, 1989 are described from two cichlids from the Araguari River, State of Amapa, northern Brazil. Sciadicleithrum edgari n. sp. from Satanoperca jurupari (Heckel, 1840) differs from all congeneric species in the morphology (hook-shaped, with middle process and distally bifurcate) of the accessory piece of the male copulatory organ (MCO). Sciadiclethrum araguariensis n. sp. from Crenicichla labrina (Spix and Agassiz, 1831) can be distinguished from all other species by a Y-shaped accessory piece of MCO. In addition to the description of two new species, new host and geographical records of six dactylogyrid monogeneans from cichlid fishes are presented. PMID- 26751886 TI - Occurrence and morphogenetic characteristics of Gyrodactylus (Monogenea: Gyrodactylidae) from a rainbow trout farm (Lake Ladoga, Russia). AB - Gyrodactylus parasite infected juveniles on rainbow trout Oncorhynchus mykiss (Walbaum, 1792) from a fish farm in Lake Ladoga were investigated. The observed cases of infection in fish featured a high prevalence, when almost all of the fish were infected. However, if an outbreak of the monogenean infection is observed in spring, the intensity of the infection may be low, and when the infection occurs in the ice-covered period (late autumn - winter), the number of parasites on the fins of a single fish may exceed 3000 specimens. Molecular identification of the parasite demonstrated that the infecting clone was identical with rainbow trout specific strain of Gyrodactylus salaris RBT widely spread in Northern Europe, but a small proportion of the parasites were the hybrid clone Gyrodactylus pomeraniae x G. lavareti. Morphological variations of hooks and other opisthaptor parts in the monogenean Gyrodactylus depending on the intensity of infection in rainbow trout were demonstrated. PMID- 26751888 TI - Molecular detection and prevalence of feline hemotropic mycoplasmas in Istanbul, Turkey. AB - The aim of this study was to investigate Mycoplasma spp. species in blood samples of the domestic cats from the province of Istanbul, Turkey. Three hundred eighty four blood samples of client-owned cats were used for the identification of Mycoplasma haemofelis (Mhf), Candidatus Mycoplasma haemominutum (CMhm) and Candidatus Mycoplasma turicensis (CMt) by Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) assays. Out of 384 blood samples, 74 (19.3%) were positive for one of Mycoplasma species. The total prevalence of Mhf, CMhm and CMt infections was 9.9%, 17.7% and 0.8% respectively. The most common species was CMhm. Co-infections were mostly with Mhf/CMhm and the frequency was 8.1%. Two cats were infected with three species. The current study was the first molecular prevalence study of hemotropic mycoplasmas in Istanbul, reporting the presence of CMt for the first time in Turkey. Prevalence of feline mycoplasma was notably high in Istanbul and PCR assay could be preferred rather than the microscopic examination for the diagnosis. PMID- 26751889 TI - First report of Cystoisospora belli parasitemia in a patient with acquired immunodeficiency syndrome. AB - Cystoisospora belli in patients with the acquired immunodeficiency syndrome (AIDS) has been described as cause of chronic diarrhea and disseminated cystoisosporosis. Diagnosis of intestinal cystoisosporosis can be achieved at the tissue level in the villus epithelium of the small bowel. Disseminated cystoisosporosis is diagnosed by microscopy identification of unizoite tissue cysts in the lamina propria of the intestine. We report a case of disseminated cystoisosporosis in a human immunodeficiency virus (HIV)-infected patient with detection of parasitemia. We studied a 39-year old patient with AIDS and chronic diarrhea by analysis of stool and duodenal biopsy samples. Blood samples were also collected and examined by light microscopy and molecular techniques for C. belli DNA detection. The unizoite tissue cyst stages were present in the lamina propria, with unsporulated oocysts in feces. Zoites were present in blood smears and DNA of C. belli was detected in blood samples. Our study identified a new stage in the life cycle of C. belli. Detection of parasitemia is a novel and noninvasive tool for diagnosis of disseminated cystoisosporosis. PMID- 26751890 TI - Cystic echinococcosis in Southern Israel. AB - The aim of this retrospective, population-based study was to characterize demographically and clinically cystic-echinococcosis (CE) in southern Israel, between 2005 and 2012. Newly-diagnosed (nd-CE) and past-diagnosed (pd-CE, diagnosed before the study) cases were defined. Two populations live in southern Israel, receiving medical treatment at a single hospital: the Jewish and the Bedouin populations (resembling resource-rich and resource-poor populations, respectively). 126 CE cases were identified; 55 nd-CE and 71 pd-CE. Mean annual nd-CE incidence per 100,000 in the Bedouin and Jewish populations were 2.7 +/- 1.2 and 0.4 +/- 0.3, respectively (P<0.001). None of the Bedouin and 86.5% of the Jewish patients were born outside Israel. Liver and lung involvement were recorded in 85.7% and 15.1% of overall-CE, respectively. Abdominal pain, cough, fever, eosinophilia and asymptomatic disease were documented in 63.6%, 32.7%, 27.3%, 41.5% and 12.7% of nd-CE, respectively. Serology sensitivity for first test and any positive test were 67.3% and 83.3%, respectively. Computed tomography, ultrasonography and X-ray diagnosis were documented in 79.2%, 58.4% and 17.0% of overall-CE, respectively, with ultrasonography mainly used in liver CE and X-ray in lung-CE. Treatment included surgery and albendazole in 50.0% and 55.3% of CE, respectively. We conclude that CE is endemic in southern-Israel among the Bedouin population, while disease is probably mainly imported in the Jewish population. Liver involvement and eosinophilia rates were high compared with those of other endemic regions, possibly due to differences in the timing of diagnosis. These findings may help developing treatment and prevention strategies. PMID- 26751891 TI - Toxocara canis glycans influence antigen recognition by mouse IgG1 and IgM antibodies. AB - The impact of sugar moieties of Toxocara canis glycoprotein antigens on their recognition by infected mouse antibodies was investigated in this study. Native TES and recombinant Toxocara mucins generated in Pichia pastoris yeast as well as their deglycosylated forms were used in ELISA. TES and recombinant mucins were equally recognized by T. canis infected mouse IgG1 antibodies. IgM immunoglobulins predominantly recognized TES antigens. Among mucins recognition of Tc-MUC-4 was the most significant. Deglycosylation of antigens resulted in significant loss of IgM and IgG1 reactivity to TES, mucins, Tc-MUC-3 and Tc-MUC 4. The presence of sugar moieties had no influence on IgE binding to native or recombinant T. canis antigens. Our results suggest that glycans are involved in epitope formation what should be taken into consideration in production of recombinant helminth antigens for diagnostic purposes. PMID- 26751892 TI - The transstadial persistence of tick-borne encephalitis virus in Dermacentor reticulatus ticks in natural conditions. AB - There are a number of reports regarding natural infection of Dermacentor reticulatus ticks with TBE virus; however, the transmission mode of TBE virus in this tick population has not been investigated. This study was conducted in Bialowieza Primeval Forest, east Poland. Forty fully engorged nymphs of D. reticulatus were sampled from root voles (Microtus oeconomus). Ticks were kept until molting. All ticks were screened for the presence of TBE virus by nested RT PCR. Three adult ticks were positive for infection with TBE virus. The present study for the first time demonstrates the possibility of transstadial mode of TBEV transmission in D. reticulatus ticks. PMID- 26751893 TI - The cloning, expression and purification of recombinant human neuritin from Escherichia coli and the partial analysis of its neurobiological activity. AB - Neuritin (Nrn1) is a neurotrophic factor that plays various roles in neural development and synaptic plasticity. In this study, the NRN1 gene was cloned and expressed in Escherichia coli and then recombinant neuritin protein was purified so that its neurobiological activity could be evaluated. The protein, which was obtained at a concentration of 0.45 mg/ml and > 90% purity, had the predicted molecular weight of 30 kDa, as determined via sodium dodecyl sulfate polyacrylamide gel electrophoresis. Western blot analysis confirmed that an anti neuritin antibody could recognize the fusion protein. Subsequent functional analyses revealed that recombinant neuritin promoted neurite outgrowth in embryonic chicken dorsal root ganglia and PC12 cells. These results suggest that recombinant neuritin protein could be a valuable tool for inducing neurite regeneration, for instance in cases of spinal cord injury or neurological diseases. PMID- 26751894 TI - Genetic analysis of hereditary angioedema in a Brazilian family by targeted next generation sequencing. AB - Hereditary angioedema (HAE) is accompanied by an overproduction of bradykinin (BK) as the primary mediator of swelling. Although many proteins may be involved in regulating the wide spectrum of HAE symptoms, most studies have only focused on C1-INH and FXII. For the first time, a next generation sequencing (NGS) method was applied to develop a robust, time- and cost-effective diagnostic and research tool to analyze selected genes related to HAE. The entire coding region and the exon-intron boundaries of 15 genes from 23 subjects of a Brazilian family, nine of whom were symptomatic, were analyzed by NGS. One new mutation found uniquely in the nine symptomatic patients, p.Ala457Pro in the SERPING1 gene, was estimated as likely to be pathogenic (PolyPhen-2 software analysis) and is the main candidate to be responsible for HAE in these patients. Alterations identified in a few asymptomatic individuals but also found in almost all symptomatic patients, such as p.Ile197Met (HMWK), p.Glu298Asp (NOS3) and p.Gly354Glu (B2R), may also be involved in modulating patient-specific symptoms. This NGS gene panel has proven to be a valuable tool for a quick and accurate molecular diagnosis of HAE and efficient to indicate modulators of HAE symptoms. PMID- 26751895 TI - Gestation specific reference intervals for thyroid function tests in pregnancy. AB - BACKGROUND: Thyroid function tests are frequently assessed during pregnancy to evaluate thyroid dysfunction or to monitor pre-existing thyroid disease. However, using non-pregnant reference intervals can lead to misclassification. International guidelines recommended that institutions should calculate their own pregnancy-specific reference intervals for free thyroxine (FT4), free triiodothyronine (FT3) and thyroid-stimulating hormone (TSH). The objective of this study is to establish gestation-specific reference intervals (GRIs) for thyroid function tests in pregnant Turkish women and to compare these with the age-matched non-pregnant women. METHODS: Serum samples were collected from 220 non-pregnant women (age: 18-48), and 2460 pregnant women (age: 18-45) with 945 (39%) in the first trimester, 1120 (45%) in the second trimester, and 395 (16%) in the third trimester. TSH, FT4 and FT3 were measured using the Abbott Architect i2000SR analyzer. RESULTS: GRIs of TSH, FT4 and FT3 for first trimester pregnancies were 0.49-2.33 mIU/L, 10.30-18.11 pmol/L and 3.80-5.81 pmol/L, respectively. GRIs for second trimester pregnancies were 0.51-3.44 mIU/L, 10.30 18.15 pmol/L and 3.69-5.90 pmol/L. GRIs for third trimester pregnancies were 0.58 4.31 mIU/L, 10.30-17.89 pmol/L and 3.67-5.81 pmol/L. GRIs for TSH, FT4 and FT3 were different from non-pregnant normal reference intervals. CONCLUSIONS: TSH levels showed an increasing trend from the first trimester to the third trimester, whereas both FT4 and FT3 levels were uniform throughout gestation. GRIs may help in the diagnosis and appropriate management of thyroid dysfunction during pregnancy which will prevent both maternal and fetal complications. PMID- 26751896 TI - Using the hazard ratio to evaluate allowable total error in predictive measurands. AB - BACKGROUND: Allowable total error is usually derived from data on biological variation or from state-of-the-art of measuring technology. Here we present a new principle for evaluating allowable total error when the concentration of the analyte (the measurand) is used for prediction: What are the predictive consequences of allowable total errors in terms of errors in the estimate of the hazard ratio (HR)? METHODS: We explored the effect of analytical measurement errors on Cox regression estimates of HR. Published data on Cox regression coefficients were used to illustrate the effect of measurement errors on predicting cardiovascular events or death based on serum concentration of cholesterol and on progression of chronic kidney disease to kidney failure based on serum concentrations of albumin, bicarbonate, calcium and phosphate, and urine albumin/creatinine-ratio. RESULTS: If the acceptable error in the estimate of the HR is 10%, allowable total errors in serum cholesterol, bicarbonate and phosphate are approximately the same as allowable total error based on biological variation, while allowable total error in serum albumin and calcium are a little larger than estimates based on biological variation. CONCLUSIONS: Evaluating allowable total error from its effect on the estimate of HR is universally applicable to measurands used for prediction. PMID- 26751897 TI - Preliminary probe of quality indicators and quality specification in total testing process in 5753 laboratories in China. AB - BACKGROUND: The aim of the study was to promote the establishment and implementation of quality indicators (QIs) in clinical laboratories, catch up with the state of art, and provide preliminary quality specifications for established QIs. METHODS: Clinical laboratories from different provinces in China were included in this QIs survey in 2015. All participants were asked to collect data related to QIs and complete QIs questionnaires. Defect percentages and sigma values were calculated for each QI. The 25th percentile, median, and the 75th percentile of defect percentages and TATs were calculated as optimum, desirable and minimum quality specifications. While 25th, median, and 75th of sigma values were calculated as minimum, desirable and optimum quality specifications, respectively. RESULTS: Five thousand seven hundred and fifty-three clinical laboratories from 28 provinces in China participated in this survey. Median defect percentages of pre-examination QIs varied largely from 0.01% (incorrect sample container) to 0.57% (blood culture contamination) with sigma values varied from 4.0sigma to 5.1sigma. Median defect percentages of examination phase QIs were all really high. The most common problem in examination phase was test uncovered by inter-laboratory comparison (86.67%). Defect percentages of critical values notification and timely critical values notification were all 0.00% (6.0sigma). While the median of defect percentages of incorrect laboratory reports was only 0.01% (5.4sigma). CONCLUSIONS: Improvements are needed in all phases of total testing process (TTP) in laboratories in China, especially in examination phase. More attention should be paid when microbiology specimens are collected and results are reported. Quality specifications can provide directions for laboratories to make effort for. PMID- 26751898 TI - Effect of Hb H on HbA1c measurements as measured by IFCC reference method and affinity HPLC. PMID- 26751900 TI - Cancer dynamics and the success of cancer screening programs. PMID- 26751899 TI - miRNAs as novel biomarkers in the management of prostate cancer. AB - microRNAs (miRNAs) are small non-coding RNAs that control gene expression posttranscriptionally and are part of the giant non codifying genoma. Cumulating data suggest that miRNAs are promising potential biomarkers for many diseases, including cancer. Prostate cancer (PCa) detection is currently based in the serum prostate-specific antigen biomarker and digital rectal examination. However, these methods are limited by a low predictive value and the adverse consequences associated with overdiagnosis and overtreatment. New biomarkers that could be used for PCa detection and prognosis are still needed. Recent studies have demonstrated that aberrant expressions of microRNAs are associated with the underlying mechanisms of PCa. This review attempts to extensively summarize the current knowledge of miRNA expression patterns, as well as their targets and involvement in PCa pathogenesis. We focused our review in the value of circulating and urine miRNAs as biomarkers in PCa patients, highlighting the existing discrepancies between different studies, probably associated with the important methodological issues related to their quantitation and normalization. The majority of studies have been performed in serum or plasma, but urine obtained after prostate massage appears as a new way to explore the usefulness of miRNAs. Large screening studies to select a miRNA profile have been completed, but bioinformatics tools appear as a new approach to select miRNAs that are relevant in PCa development. Promising preliminary results were published concerning miR-141, miR-375 and miR-21, but larger and prospective studies using standardized methodology are necessary to define the value of miRNAs in the detection and prognosis of PCa. PMID- 26751901 TI - Maternal obesity is associated with a low serum progesterone level in early pregnancy. AB - BACKGROUND: Progesterone is an important biomarker of early pregnancy failure. However, literature is limited regarding factors that influence progesterone levels in early pregnancy. Maternal obesity has been associated with adverse pregnancy outcomes such as miscarriages. MATERIALS AND METHODS: We investigated the association between maternal body mass index (BMI) and serum progesterone level in first trimester singleton pregnancies for 194 women at a tertiary maternity hospital in Singapore, from January 2012 to February 2014. Maternal characteristics and study outcomes were retrieved from clinical records. RESULTS: Multivariate analysis demonstrated an inverse relationship between first trimester maternal BMI category and serum progesterone level (p=0.012). Obesity (maternal BMI >=30 kg/m2), relative to normal weight (BMI 18.5-24.9 kg/m2), conferred an increased risk for serum progesterone <35 nmol/L (adjusted OR: 9.14; 95% CI: 2.12 - 39.5; p=0.003). The overall miscarriage rate in our study population was 13.9%. CONCLUSIONS: This study indicates that maternal obesity is associated with low first trimester serum progesterone. Pre-pregnancy weight optimization may be beneficial in regulation of serum progesterone level and maintenance of healthy pregnancy. PMID- 26751902 TI - Clinical implementation of pharmacogenetics. AB - In the last decade, pharmacogenetic research has been performed in different fields. However, the application of pharmacogenetic findings to clinical practice has not been as fast as desirable. The current situation of clinical implementation of pharmacogenetics is discussed. This review focuses on the advances of pharmacogenomics to individualize cancer treatments, the relationship between pharmacogenetics and pharmacodynamics in the clinical course of transplant patients receiving a combination of immunosuppressive therapy, the needs and barriers facing pharmacogenetic clinical application, and the situation of pharmacogenetic testing in Spain. It is based on lectures presented by speakers of the Clinical Implementation of Pharmacogenetics Symposium at the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society, held in April 20, 2015. PMID- 26751903 TI - High-Precision Tungsten Isotopic Analysis by Multicollection Negative Thermal Ionization Mass Spectrometry Based on Simultaneous Measurement of W and (18)O/(16)O Isotope Ratios for Accurate Fractionation Correction. AB - Determination of the (182)W/(184)W ratio to a precision of +/- 5 ppm (2sigma) is desirable for constraining the timing of core formation and other early planetary differentiation processes. However, WO3(-) analysis by negative thermal ionization mass spectrometry normally results in a residual correlation between the instrumental-mass-fractionation-corrected (182)W/(184)W and (183)W/(184)W ratios that is attributed to mass-dependent variability of O isotopes over the course of an analysis and between different analyses. A second-order correction using the (183)W/(184)W ratio relies on the assumption that this ratio is constant in nature. This may prove invalid, as has already been realized for other isotope systems. The present study utilizes simultaneous monitoring of the (18)O/(16)O and W isotope ratios to correct oxide interferences on a per integration basis and thus avoid the need for a double normalization of W isotopes. After normalization of W isotope ratios to a pair of W isotopes, following the exponential law, no residual W-O isotope correlation is observed. However, there is a nonideal mass bias residual correlation between (182)W/(i)W and (183)W/(i)W with time. Without double normalization of W isotopes and on the basis of three or four duplicate analyses, the external reproducibility per session of (182)W/(184)W and (183)W/(184)W normalized to (186)W/(183)W is 5-6 ppm (2sigma, 1-3 MUg loads). The combined uncertainty per session is less than 4 ppm for (183)W/(184)W and less than 6 ppm for (182)W/(184)W (2sigmam) for loads between 3000 and 50 ng. PMID- 26751904 TI - Adverse Effects Associated With Proton Pump Inhibitors. PMID- 26751905 TI - "Care that matters": Family-centered care, caregiving burden, and adaptation in parents of children with cancer. AB - INTRODUCTION: Family-centered care (FCC) is a health-care delivery approach endorsing the support and participation of families. To date, little research has addressed the associations between FCC and adaptation outcomes specifically in the context of pediatric cancer. The main objective of this research was to identify the direct and indirect associations, through caregiving burden, between parents' FCC and quality of life (QoL) and life satisfaction. METHOD: Participants were 204 parents of children diagnosed with cancer. Parents answered the Measure of Processes of Care questionnaire to evaluate their perceptions of FCC in 2 domains: family-centered services and provision of general information. Perceptions of caregiving burden (Revised Burden Measure), QoL (EUROHIS-QoL-8), and life satisfaction (Satisfaction with Life Scale) were also assessed. Pediatric oncologists provided information on the child's diagnosis and treatment status. RESULTS: Findings showed that when parents perceived their children's health care as more family-centered, they also reported lower caregiving burden. Family-centered services were indirectly linked to QoL and life satisfaction through caregiving burden. DISCUSSION: This research suggests that the way parents perceive formal care, namely as being more or less family-centered, may influence the burden they experience as caregivers of a child with cancer and, indirectly, their adaptation. These findings highlight the relevance of gaining greater understanding of the interaction between the family and the health-care systems in the context of pediatric cancer. PMID- 26751906 TI - Identification of Dewetting Stages and Preparation of Single Chain Gold Nanoparticle Rings by Colloidal Lithography. AB - Massively parallel nanoparticle assembly was carried out by means of colloidal lithographic experiments over a silicon substrate supported (sub)microparticle Langmuir-Blodgett monolayer, using high purity aqueous solution of PEGylated gold nanoparticles. The size of the polystyrene template particles in the monolayer was varied between 608 nm and 2.48 MUm, while gold nanoparticles with diameters between 18 and 65 nm were used. Thanks to the PEGylation of the gold nanoparticles, they could be used as tracer objects to follow the drying process. In this way, different dewetting stages could be identified in the confined space between and underneath the template polystyrene spheres. Depending on the concentration of the nanoparticles, the presented approach allows the preparation of single-particle width necklace structures composed of gold particles. At the same time, the high purity of the substrate as well as of the evolved particle rings is preserved and unwanted particle deposition on the substrate surface is minimized. PMID- 26751908 TI - Comment on Colbert and Mercer: Retraction of the Soft Palate During a Modified Hynes Pharyngoplasty: A Technical Note. PMID- 26751907 TI - Body Image and Quality of Life in Adolescents With Craniofacial Conditions. AB - OBJECTIVE: To evaluate body image in adolescents with and without craniofacial conditions and to examine relationships between body image and quality of life. DESIGN: Case-control design. SETTING: A pediatric hospital's craniofacial center and primary care practices. PARTICIPANTS: Seventy adolescents with visible craniofacial conditions and a demographically matched sample of 42 adolescents without craniofacial conditions. MAIN OUTCOME MEASURE: Adolescents completed measures of quality of life and body image including satisfaction with weight, facial and overall appearance, investment in appearance (importance of appearance to self-worth), and body image disturbance (appearance-related distress and impairment in functioning). RESULTS: Adolescents with craniofacial conditions reported lower appearance investment (P < .001) and were more likely to report concerns about facial features (P < .02) compared with nonaffected youth. Females in both groups reported greater investment in appearance, greater body image disturbance, and lower weight satisfaction compared with males (P < .01). Within both groups, greater body image disturbance was associated with lower quality of life (P < .01). The two groups did not differ significantly on measures of quality of life, body image disturbance, or satisfaction with appearance. CONCLUSIONS: Body image and quality of life in adolescents with craniofacial conditions are similar to nonaffected youth. Relationships between body image and quality of life emphasize that appearance perceptions are important to adolescents' well-being regardless of whether they have a facial disfigurement. Investment in one's appearance may explain variations in body image satisfaction and serve as an intervention target, particularly for females. PMID- 26751909 TI - Improving Dairy Organizational Communication from the Veterinarian's Perspective: Results of a Continuing Veterinary Medical Education Pilot Program. AB - The increasing size and complexity of US dairy farms could make it more difficult for a veterinary practitioner to effectively communicate protocol recommendations for prevention or treatment on the farm. A continuing education workshop was set up based on the results of research on dairy organizational communication on dairy farms, which resulted in a tool to assess dairy communication structure and flow. The workshop specifically focused on communication structure and whom to talk to when implementing health care changes in calf rearing. In addition, modern methods of veterinary-client communication knowledge and skills were provided. Primary outcomes of the workshops were to obtain feedback from participants about research findings and the communication model, to improve awareness about the complexity of communication structures on dairy farms, and to change participants' knowledge and skills associated with on-farm communication by providing communication theory and skills and an approach to evaluate and improve dairy organizational communication. Of the 37 participants completing the pre-program assessment, most recognized a need for themselves or their practice to improve communication with clients and farm employees. After the program, most participants were confident in their new communication skills and would consider using them. They highlighted specific new ideas they could apply in practice, such as conducting a "communication audit." The results from the assessment of this communication workshop, focused on dairy veterinarians, highlighted the need for communication training in this sector of the profession and practitioners' desire to engage in this type of training. PMID- 26751910 TI - Test Anxiety: Evaluation of a Low-Threshold Seminar-Based Intervention for Veterinary Students. AB - Veterinary students are confronted with a high workload and an extensive number of examinations. However, the skills students gained in high school cannot serve as satisfactory coping strategies during veterinary training. This disparity can lead to test anxiety, as frequently reported by international surveys. In response, a pilot study was carried out to evaluate the effects of a newly developed training seminar to prevent and/or reduce test anxiety. The seminar was offered on a voluntary basis as a low-threshold intervention to first- and second year veterinary students at three different veterinary schools in Germany. The intervention was offered in two different designs: in either a block or in a semester course containing cognitive and behavioral approaches as well as skill deficit methods. By conducting a survey and interviews among the participants it was determined whether the contents of the seminar were perceived as helpful for counteracting test anxiety. The potential of the intervention was evaluated using a German test anxiety questionnaire (PAF). The contents of the training seminar were all assessed as beneficial but evaluated slightly differently by first- and second-year students. The results indicate that the seminar prevents and reduces test anxiety significantly compared to the control group students. The greatest effects were achieved by offering the intervention to first-year students and as a block course. As the participants benefit from the intervention independent of the extent of test anxiety, these results suggest that it may be profitable to integrate a workshop on coping strategies in the veterinary curriculum. PMID- 26751911 TI - Massive Open Online Courses as a Tool for Global Animal Welfare Education. AB - Animal Behaviour and Welfare was a Massive Open Online Course (MOOC) hosted on Coursera as a free introductory animal welfare course. Through interrogating Coursera data and pre-/post-course student experience surveys, we investigated student retention, student experience, changes in attitudes, and changes in knowledge. The course ran for 5 weeks, and 33,501 students signed up, of which 16.4% (n=5,501) received a Certificate of Achievement, indicating they had completed all assessments within the course. This retention rate is above the industry standard of 10%; however, the value of retention rate as a metric to judge MOOC success is questionable. Instead, we focus on demographics, with Coursera data estimating that 41% of learners came from Europe, 35% from North America, 11% from Asia, 6% from Oceania, 5% from South America, and 2% from Africa. Most learners had completed an undergraduate degree. Despite this wide range of backgrounds, 57.2% of post-course respondents (n=2,399) strongly agreed that the information presented was at the right level and 64.9% strongly agreed that the course was interesting. After completion, more students (chi(2)[4]=132.40, p<.001) understood that animal welfare was based on the results of scientific study, and significantly fewer students (chi(2)[4]=361.32, p<.001) felt health was the most important part of animal welfare. Overall, learners agreed the course was enjoyable and informative, and 97.9% felt the course was a valuable use of their time. We conclude that MOOCs are an appropriate vehicle for providing animal welfare learning to a wide audience, but require a significant level of investment. PMID- 26751912 TI - Comparison of Two Clinical Teaching Models for Veterinary Emergency and Critical Care Instruction. AB - Standards to oversee the implementation and assessment of clinical teaching of emergency and critical care for veterinary students do not exist. The purpose of this study was to assess differences in the learning environment between two veterinary emergency and critical care clinical rotations (one required, one elective) with respect to caseload, technical/procedural opportunities, direct faculty contact time, client communication opportunities, and students' perception of practice readiness. The authors designed a 22-item survey to assess differences in the learning environment between the two rotations. It was sent electronically to 35 third- and fourth-year veterinary medicine students. Bivariate analysis, including the Wilcoxon signed-rank test and the t-test, were used to compare differences between pre-test and post-test scores among students. Twenty-six students' responses were included from the required rotation and nine from the elective rotation. Findings showed that students preferred the elective community emergency department setting to the required academic setting and that there were statistically significantly more positive experiences related to the variables of interest. Students saw significantly more cases at the community emergency department setting. Findings from this study offer guidance to assess students' emergency department rotations, suggest how teaching interactions can be modified for optimal learning experiences, and ensure that students receive maximal opportunities to treat patients that are representative of what they would encounter in practice. PMID- 26751913 TI - Tarsal tunnel syndrome after total ankle replacement--a report of 3 cases. PMID- 26751914 TI - Sommera cusucoana, a new species of Rubiaceae from Honduras. AB - Sommera cusucoana Lorence, D. Kelly & A. Dietzsch, sp. nov., (Rubiaceae), a new species from Honduras, differs from the other Mesoamerican Sommera species by the combination of large, obovate leaves with long red petioles, glabrous or glabrate intervenal areas, red stipules, lax, sparsely pubescent inflorescences with red axes, flowers with red hypanthium and calyx, long fruiting pedicels, and dark red mature fruits. It is known only from the type locality in Cusuco National Park. PMID- 26751917 TI - Chronology of the Use of the Laser Beam in Dentistry, and the State of Postgraduate University Education Programs in this Domain. PMID- 26751915 TI - Are plasma mineral levels related to antibody response to influenza vaccination in older adults? AB - INTRODUCTION: An effective immune response to vaccination may be related to nutritional status. This study examined the association of plasma mineral levels with hemagglutination inhibition (HI) titers produced in response to influenza vaccine in older adults. METHODS: Prior to (Day 0) and 21 (range = 19-28) days after receiving the 2013-14 influenza vaccine, 109 adults ages 51-81 years, provided blood samples. Serum samples were tested for HI activity against the A/H1N1 and A/H3N2 2013-2014 vaccine virus strains. Plasma minerals were collected in zinc-free tubes and assayed by inductively coupled plasma mass spectrometry. HI titers were reported as seroprotection (>=1:40) and seroconversion (>= 4-fold rise from Day 0 (minimum HI = 1:10) to Day 21). Both HI titers and mineral values were skewed and thus log2 transformed. Magnesium (Mg), phosphorus (P), zinc (Zn), copper (Cu), iron (Fe), potassium (K) and the Cu to Zn ratio were tested. Logistic regression analyses were used to determine the associations between mineral levels and seroconversion and seroprotection of HI titers for each influenza A strain. RESULTS: Participants were 61% white, 28% male, 39% diabetic, and 81% overweight/obese with a mean age of 62.6 y. In logistic regression, Day 21 A/H1N1 seroprotection was associated with P and Zn at Day 21(P < 0.05). Seroconversion of A/H1N1 was associated with Day 21 Cu, P, and Mg (P < 0.03). Day 21 A/H3N2 seroprotection and seroconversion were associated with Day 21 P (P < 0.05). CONCLUSIONS: Phosphorus was associated with seroprotection and seroconversion to influenza A after vaccination; these associations warrant additional studies with larger, more diverse population groups. PMID- 26751916 TI - CHRNA5/CHRNA3 Locus Associates with Increased Mortality among Smokers. AB - Polymorphisms in the nicotinic acetylcholine receptor gene (CHRNA5/CHRNA3 locus) have been associated with several smoking related traits such as nicotine dependence, cigarette consumption, smoking cessation, lung cancer, and COPD. The aim of this candidate gene study was to study the locus among the Finnish COPD patients and long-term smokers with regard to COPD risk, smoking behavior, cancer, and all-cause mortality. Genotyping of rs1051730, the locus tagging SNP was done in two longitudinal cohorts: Finnish COPD patients (N = 575, 74% men) and long-term smokers, all men (N = 1911). Finnish population sample (N = 1730) was used as controls. The analyses were done using logistic and Cox regression. The main findings were that the minor allele increased the risk of COPD when compared to the Finnish population at large (OR = 1.4, 95% CI 1.2-1.7, p = 3.2 * 10-5). Homozygosity for the risk allele was associated in both cohorts with all cause mortality (crude HR 2.2, 95% CI 1.2-3.8 and 1.3, 95% CI 1.1-1.5, respectively), with any type of cancer (crude OR 2.3, 95% CI 1.0-5.1) among the COPD patients and with the number of pack-years (crude OR 1.4, 95% CI 1.1-1.9) among the male smokers. CHRNA5/CHRNA3 locus tagged by rs1051730, which has been previously associated with several smoking related diseases was now shown to be associated also with increased all-cause mortality among long-term smokers with or without clinical COPD further emphasizing the clinical importance of the finding. PMID- 26751918 TI - The 975 nm Diode Laser in the Photothermal Treatment of the Aging and Sagging Face and Neck. AB - OBJECTIVE: The purpose of this study was to investigate the use of a 975 nm diode laser for skin tightening. BACKGROUND DATA: The photothermal effect of laser irradiation on the hypodermis causes retraction of superficial and deep skin layers by the heating of fibrous septa. New devices have been developed for repairing deformities in the cervicofacial region associated with aging and skin laxity. MATERIALS AND METHODS: This retrospective, cross-sectional study included the medical records of 17 patients who had undergone photothermal laser therapy to correct deformities in the cervicofacial region between June 2013 and February 2015. An energy dose of 3 kJ per 100 cm(2) skin area was used as a safety parameter to calculate the optimal cumulative energy for the treated areas. Four cervicofacial lines were measured preoperatively (baseline), immediately after treatment, and 3 months post-treatment with a caliper. Measurements were compared using the Wilcoxon test at a significance level of 0.05 (p < 0.05). RESULTS: A significant skin tightening was observed in all patients 3 months after the procedure. Mean length reductions found in the cervicofacial lines L1, L2, L3, and L4 at the 3-month follow-up were 0.9, 1.18, 1.32, and 1.27 cm, respectively. CONCLUSIONS: The use of a 975 nm diode laser resulted in skin tightening. PMID- 26751919 TI - Tellurium as a high-performance elemental thermoelectric. AB - High-efficiency thermoelectric materials require a high conductivity. It is known that a large number of degenerate band valleys offers many conducting channels for improving the conductivity without detrimental effects on the other properties explicitly, and therefore, increases thermoelectric performance. In addition to the strategy of converging different bands, many semiconductors provide an inherent band nestification, equally enabling a large number of effective band valley degeneracy. Here we show as an example that a simple elemental semiconductor, tellurium, exhibits a high thermoelectric figure of merit of unity, not only demonstrating the concept but also filling up the high performance gap from 300 to 700 K for elemental thermoelectrics. The concept used here should be applicable in general for thermoelectrics with similar band features. PMID- 26751920 TI - [Evin law: moderation in the addiction's age]. PMID- 26751921 TI - [impact of therapeutic education on lifestyles: perception of patients and their relatives]. AB - BACKGROUND: Therapeutic patient education, which advocates a change of behaviour, may affect the patient's and the patient's family's lifestyles. The aim of this survey was to describe the perception of heart failure patients and their families concerning the impact of TPE on their lifestyles. METHODS: A national self-administered questionnaire survey b was performed from january to May 2013 with patients and their relatives. A total of 2,153 questionnaires were sent to all patients registered in the Heart Failure Observatory registry (Odin), who forwarded them to a relative of their choice. Only relatives of educated patients were included. A total of 2,397 questionnaires were sent to patients. RESULTS: We obtained 149 responses from patient's families (7%). One half of them (50.3%) met our inclusion criteria. We obtained 257 responses from patients (11 %). Respondents noted a change in the patient's daily lifestyle after TPE (85.8% of the total population) and said that the patient had a more positive approach to his/her illness (70.7% of the total population). According to respondents, relatives had changed their lifestyle after their participation of TPE (67.8% of the total population). CONCLUSION: This study shows that patients and their relatives report a positive change in their lifestyle due to TPE. The patient's relatives appear to comply with the recommendations of health professionals, initially designed for the patient. PMID- 26751922 TI - [Effective interventions to prevent health damage related to ultraviolet exposure: a review of the literature]. AB - The purpose of this paper is to review the current scientific knowledge on health promotion interventions designed to prevent health damage caused by natural ultraviolet (UV) exposure. The current state of knowledge in this area was assessed using a specific method including a review of literature reviews and a classification of health promotion interventions identified using scientific databases. We found a large number of promising programmes. Briefly, some interventions based on environmental changes and provision of shade were considered to be promising. Health education programmes delivered at school have been proven to be effective in various settings, from nursery school to college. Some parentbased interventions designed to promote children's sun protection behaviours have been shown to be relevant. Appearance-based actions, using for instance photoaging information, may be effective. Finally, some multi-component interventions in community settings appear to be promising. These findings present a number of limitations due to the marked diversity of outcome measures and the general quality of the documents reviewed. Furthermore, most interventions are poorly described in the reviews. The present study should therefore be considered to be a first step that needs to be completed by a more detailed description of the promising interventions and of their transposition to the French context. PMID- 26751923 TI - [Effective interventions to prevent child injuries: a review of the literature]. AB - Child injuries represent an important public health problem. The aim of this paper is to review the current scientific knowledge on interventions designed to prevent child injuries. The current state of knowledge in this area was assessed by means of a specific method involving a review of literature reviews and a classification of health promotion interventions identified in these reviews (rapid reviews). We found a large number of effective or promising programmes devoted to the prevention of the most common child injuries: drowning, burns, falls, poisoning, electrocution, sports and leisure injuries. Some interventions are based on environmental measures, while others are educational or use law and regulatory processes. Some are primary prevention measures, others are secondary prevention measures, while others are multidimensional and can effectively reduce several types of injuries. For example, home safety education and provision of safety equipment, or home-based parenting interventions, can have an impact on injury rates. These findings present a number of limitations due to the marked diversity of the quality of the documents reviewed. It should also be stressed that interventions that are not listed in this article are not necessarily ineffective: they may simply lack a rigorous evaluation enabling them to be identified in our review. PMID- 26751924 TI - [Monitoring system on prison health: feasibility and recommendations]. AB - INTRODUCTION: This article presents the results of two studies designed to define the feasibility and framework of the future prison health monitoring system in France. The objective of the first study was to obtain the points of view of professionals involved in prison health and the second study was designed to assess the feasibility of using prisoner's medical files for epidemiological purposes. METHODS: The point of view of various professionals was collected by questionnaire sent to 43 randomly selected prison physicians and by 22 semi directive interviews. The feasibility study was based on analysis of the medical files of 330 randomly selected prisoners in eleven prisons chosen in order to reflect the diversity of correctional settings and prison populations. Additional interviews were conducted with the medical staff of these prison facilities. RESULTS: There is a consensus on the need to monitor prison health, but there are contrasting views on data collection methods (surveys or routinely collected data]. The feasibility study also showed that the implementation of a prison health monitoring system based on routinely collected data from prisoner's medical records was not feasible at the present time in France. CONCLUSIONS: In the light of these findings, it is recommended to initially develop a monitoring system based on regular nationwide surveys, while pursuing computerization and standardization of health data in prison. PMID- 26751925 TI - [Organizational impact of preparation for healthcare institution accreditation in Morocco]. AB - OBJECTIVE: This is the first study in Morocco to assess whether integration of the hospital accreditation programme generates organizational changes, based on the case of a health care institution in Morocco. METHODS: Quantitative and qualitative data were collected by means of questionnaires sent to professionals,focus groups, review of documentation and direct observation. RESULTS: The results indicate that the organization comprised components ensuring the success of the programme, as a shared vision was established with stakeholders in the programme with the development of skills, despite the lack of incentives and resources, centralizing the planning approach around the steering committee at the start of the project. As in many other countries, in which studies have shown the positive impact of accreditation on various domains of the health institution, we have also observed many changes. The most important changes concerned acquisition of management by quality, and new practices emerged following preparation for accreditation: planning, monitoring and evaluating the implementation of performance indicators and in-house quality audits, as well as risk management and development of writing skills. CONCLUSION: The institution has certainly made significant organizational changes, but the accreditation programme is not currently a sustainable strategic management technique, due to the constraints on the institution that interfere with the sustainability of the approach, the governing body must investigate the real reasons of dysfunctions and the best ways of addressing them PMID- 26751926 TI - [Regulators in access to anticancer drugs in Canada]. AB - Based exclusively on drugs approved by provincial public health insurance systems, many authors have reported significant variability in terms of access to anticancer drugs (ACD) among Canadian citizens, raising problems of equal access to these drugs.In this paper, we emphasize that the mere presence on the list of public drug plans cannot be considered to be a sufficient indicator to determine the real availability of anticancer drugs (ACD) for the patient. We describe and compare four sets of regulators defined in each province and determine their effects on the accessibility of ACD for patients in each province. The term regulator comprises the conditions which must be observed for access via the public health insurance system as well as the rules (strategies) decided by the third-party payer for the management of these conditions.The results of our analyses lead to the conclusion that there is indeed a variation between provinces in terms of access to drugs financed by public funds, but that this variability primarily impacts less important treatments. PMID- 26751928 TI - [Development and functioning of Multiprofessional Primary Care Practices in Rhone Aipes region]. AB - OBJECTIVE: The need to improve inter-professional cooperation encourages the grouping of primary care professionals in multi professional structures such as primary care practices. The objective of this study was to assess the implementation,organization and operation of primary care practices (PCP) in the French Rhone-Alpes region. METHODS: Cross-sectional survey by self-administered questionnaire of healthcare providers in charge of PCPs in RhOne-Alpes. RESULTS: The study included 35 PCPs across the 8 departments of the RhOne-Alpes region. Most (86%) had been operational since 2009. The number of professionals per PCP ranged from 6 to 30 with a median of 12. The most common~ represented occupations were nurses (125),general practitioners (105) and physical therapists(59). Inter professional cooperation was based on multidisciplinary consultation meetings in 68% of PCPs and 74% share delectronic patient records. The majority of PCPs (54%) were located in areas with insufficient access to healthcare. Most PCPs(91%) were accessible to people with reduced mobility, 49% had opening hours of more than 60 hours per week, and 54% reported frequent use of third-party payment. CONCLUSION: Dynamic of implementation of PCPs appeared to reflect an attraction of health professionals to collective practices.This trend is consistent with French health care strategy. PMID- 26751927 TI - [Cost accounting of a geriatric perioperative unit]. AB - AIM: Hip fracture management in a dedicated geriatric perioperative unit improves long-term mortality. In this "we report the" health economics evaluation of this geriatric perioperative care unit (UPOG). METHODS: This study was conducted in 2011. Direct expenditures were obtained from the Assistance Publique-Hopitaux de Paris database, indirect expenditures from the hospital cost accounting,and financial incomes from the PMSI Pilot programme. Emergency department incomes and expenditures were estimated together with additional incomes related to orthopaedic surgery. We estimated expenditures related to operating room (OR) activities in the framework of several models, one with an emergency OR open 24h/24, and one with a standard OR. Lastly, we compared incomes/expenditures according to regular paramedical staff or according to the paramedical staff that would appear to be necessary to ensure patient care. RESULTS: 253 patients were admitted to the UPOG during the study J215 (84%) of whom underwent surgery. The income statement was positive for both an emergency OR (+741,000 Euros) and a standard OR ( +490,000 Euros) and remained positive when paramedical staff was increased (+629,000 and +156,000 Euros, respectively). CONCLUSION: The UPOG income statement shows a positive result regardless of the model used, emergency 24h/24 OR or standard OR, and even when paramedical staff is increased PMID- 26751929 TI - [Does the National HIV /AIDS Control programme provide support for district hospitals in Cameroon?]. AB - The aim of this study was to investigate the effects of the national HIV/AIDS control programme on district hospitals in Cameroon. A multiple case study was conducted in two district hospitals- one public and one faith-based. Data were collected by document review, semi-structured interviews and observation of managerial processes and health care delivery. Programme interventions result in a series of positive and negative effects on the functioning of district hospitals and local health systems. High input and support of staff skills were observed for antiretroviral therapy and the management of opportunistic infections. However, the impact of the programme on the stewardship function is problematic. The low implication of district management teams in the implementation of HIV /AIDS activities reduces their structural capacity to run the local health systems. Programme and health system managers failed to take advantage of opportunities to develop synergies between the HIV/AIDS programme and local health systems. The HIV/AIDS programme weakens the systemic and structural capacity of local health systems. Managers of both programmes and general health systems should analyse and adapt their interventions in order to effective' strengthen health systems. One of the research questions is to understand why health system stakeholders do not seize opportunities to develop synergies between programmes and the general system and to strengthen health systems. PMID- 26751930 TI - [Local perceptions of community participation in health in Burkina Faso]. AB - OBJECTIVE: Burkina Faso has been implementing a strategy of community participation in the health system for several years.The main objective of this strategy is to involve people in the decision-making process in order to improve the use of health services and to encourage massive support of communities for health promotion activities. Empirical data indicate a low involvement of communities in activities designed to promote participation. This article aims to identify the perceptions of local people in relation to community participation in health. METHODS: The study was conducted in the Tenkodo go health district, located in the administrative region of East-Center, about 190 km from the capital. This exclusively qualitative study used two data collection methods: individual interviews and focus groups. Data were collected in two health areas. RESULTS: The results show that communities have negative perceptions on the community participation in health strategy,which is perceived by the majority as a mechanism of exploitation of the population by health workers and members of health center management committees. CONCLUSIONS: These negatives perceptions of the participation strategy have a negative impact on the behaviour of communities,reflected by the very low participation rate in community activities.Urgent action is needed to revitalize the existing participation mechanisms. PMID- 26751931 TI - [Formative research on community-based vital events registration in Mali]. AB - OBJECTIVES: The under-five mortality rate in Mali is high, with most deaths occurring in the community where there is no reliable vital events registration. The objective of this study was to collect data on community-based vital events registration in the Niono and Baroueli districts of the Segou region, in order to improve the community-based vital events registration system. METHODS: Data collection for this cross-sectional, descriptive, and qualitative study was conducted in May 2010. Participants included health and administrative workers, community members, women's associations, and non-governmental organizations. Data collection methods included individual interviews and focus groups, as well as document review. Data were entered and codified with Modalisa version 5.1. RESULTS: Pregnancy registration was performed exclusively by health workers in health facilities and was not performed before the third month of pregnancy due to concerns about losing the pregnancy (due to sorcery or spells). Birth registration was performed in administrative and health structures and at the community level, but after an interval of about 7 days. Childhood deaths were rarely registered because the community did not understand the importance of this registration, and because of problems accessing the structures in which deaths are registered. Community opinions were favourable to the implementation of an improved system involving relays (community-based volunteers). CONCLUSION: Improvements to vital events registration in this setting should make use of relays by increasing the awareness and involvement of the population. PMID- 26751932 TI - [Sociodemographic factors associated with incomplete immunization of children aged 12 to 59 months in six West African countries]. AB - Every year, thousands of children worldwide remain unimmunized or partially immunized, especially in developing countries. It therefore appears important to examine soda-demographic factors associated with incomplete immunization of children in West Africa. The present cross-sectional study examined factors associated with incomplete immunization of children aged 12 to 59 months in Cote d'lvoire, Ghana, Burkina Faso, Mali, Guinea, and Liberia, based on Demographic and Health Surveys data. The findings of the study showed that birth at home, absence of access of mothers to media, no religion, poverty, and illiteracy were associated with incomplete immunization of children. Health officials should take these immunization status predictors into account when making policies and immunization strategies in countries included in this study in order to achieve immunization coverage targets. PMID- 26751933 TI - [Smoking and related factors among college students in Dixinn, Guinea]. AB - INTRODUCTION: Very few published studies are available on smoking in schools In Guinea. This investigation was designed to determine the extent of smoking in Guinean urban schools. METHODS: This cross-sectional study was conducted from April to june 2012. Students from four public schools in the municipality of Dixinn were anonymously interviewed by self-administered questionnaire concerning their smoking habits. The questionnaires were then analysed by SPSS 20 software RESULTS: The prevalence of smoking, always in the form of cigarettes, was 13.4% (C/95%: 10.6-16.1) among college students. Early initiation of smoking was observed (13.9 years) and smokers frequently expressed the prospect of withdrawal. The most common predisposing factor was the imitation of the environment (32.9%). The influence of fashion and advertising (45.6%) and imitation of the per group (32.9%) were the factors most frequently cited to promote smoking. Male gender [odd ratio= 7.9 (95% confidence interval3.8 to 16.9)], having a close friend who smoked [1.7 (1.1-2.8)], and frequently seeing other students smoking {3 8 (2.3 to 6.2)] were associated with smoking. CONCLUSION: Smoking is common among college students in Conakry, Guinea. The authorities, including educational authorities, should be more actively involved in the fight against this growing scourge in developing countries. PMID- 26751935 TI - A light-trapping strategy for nanocrystalline silicon thin-film solar cells using three-dimensionally assembled nanoparticle structures. AB - We report three-dimensionally assembled nanoparticle structures inducing multiple plasmon resonances for broadband light harvesting in nanocrystalline silicon (nc Si:H) thin-film solar cells. A three-dimensional multiscale (3DM) assembly of nanoparticles generated using a multi-pin spark discharge method has been accomplished over a large area under atmospheric conditions via ion-assisted aerosol lithography. The multiscale features of the sophisticated 3DM structures exhibit surface plasmon resonances at multiple frequencies, which increase light scattering and absorption efficiency over a wide spectral range from 350-1100 nm. The multiple plasmon resonances, together with the antireflection functionality arising from the conformally deposited top surface of the 3D solar cell, lead to a 22% and an 11% improvement in power conversion efficiency of the nc-Si:H thin film solar cells compared to flat cells and cells employing nanoparticle clusters, respectively. Finite-difference time-domain simulations were also carried out to confirm that the improved device performance mainly originates from the multiple plasmon resonances generated from three-dimensionally assembled nanoparticle structures. PMID- 26751936 TI - The CaSm (LSm1) oncogene promotes transformation, chemoresistance and metastasis of pancreatic cancer cells. AB - The cancer-associated Sm-like (CaSm) oncogene is overexpressed in 87% of human pancreatic tumor samples and CaSm knockdown has demonstrated therapeutic efficacy in murine models of pancreatic cancer. Evidence indicates that CaSm modulates messenger RNA degradation; however, its target genes and the mechanisms by which CaSm promotes pancreatic cancer remain largely unknown. Here, we demonstrate that the CaSm overexpression alters several hallmarks of cancer-including transformation, proliferation, chemoresistance and metastasis. Doxycycline induced CaSm expression enhanced proliferation and both anchorage-dependent and independent growth of the human Panc-1 cells in vitro. CaSm induction decreased gemcitabine-induced cytotoxicity and altered the expression of apoptotic regulation genes, including Bad, E2F1 and Bcl-XL. CaSm-overexpressing Panc-1 cells were twofold more migratory and fourfold more invasive than the driver controls and demonstrated characteristics of epithelial-to-mesenchymal transition such as morphological changes and decreased E-cadherin expression. CaSm induction resulted in changes in RNA expression of metastasis-associated genes such as MMP1, SerpinB5, uPAR and Slug. Using a murine model of metastatic pancreatic cancer, injection of CaSm-induced Panc-1 cells resulted in a higher abundance of hepatic metastatic lesions. Overall, CaSm overexpression contributed to a more aggressive cancer phenotype in Panc-1 cells, further supporting the use of CaSm as a therapeutic target against pancreatic cancer. PMID- 26751937 TI - Effect of acute nitrate supplementation on neurovascular coupling and cognitive performance in hypoxia. AB - The matching of oxygen supply to neural demand (i.e., neurovascular coupling (NVC)) is an important determinant of cognitive performance. The impact of hypoxia on NVC remains poorly characterized. NVC is partially modulated by nitric oxide (NO), which may initially decrease in hypoxia. This study investigated the effect of acute NO-donor (nitrate) supplementation on NVC and cognitive function in hypoxia. Twenty healthy men participated in this randomized, double-blind, crossover design study. Following normoxic cognitive/NVC testing, participants consumed either nitrate (NIT) or a NIT-depleted placebo (PLA). Participants then underwent 120 min of hypoxia (11.6% +/- 0.1% O2) and all cognitive/NVC testing was repeated. NVC was assessed as change in middle cerebral artery (MCA) blood flow during a cognitive task (incongruent Stroop) using transcranial Doppler. Additional computerized cognitive testing was conducted separately to assess memory, executive function, attention, sensorimotor, and social cognition domains. Salivary nitrite significantly increased following supplementation in hypoxia for NIT (+2.6 +/- 1.0 arbitrary units (AU)) compared with PLA (+0.2 +/- 0.3 AU; p < 0.05). Memory performance (-6 +/- 13 correct) significantly decreased (p < 0.05) in hypoxia while all other cognitive domains were unchanged in hypoxia for both PLA and NIT conditions (p > 0.05). MCA flow increased during Stroop similarly in normoxia (PLA +5 +/- 6 cm.s(-1), NIT +7 +/- 7 cm.s(-1)) and hypoxia (PLA +5 +/- 9 cm.s(-1), NIT +6 +/- 7 cm.s(-1)) (p < 0.05) and this increase was not altered by PLA or NIT (p > 0.05). In conclusion, acute hypoxia resulted in significant reductions in memory concomitant with preservation of executive function, attention, and sensorimotor function. Hypoxia had no effect on NVC. Acute NIT supplementation had no effect on NVC or cognitive performance in hypoxia. PMID- 26751939 TI - A salute to Jacques Cohen. PMID- 26751938 TI - The Effect of Eye Drop Technique Education in Patients With Glaucoma. AB - Education about how to administer eye drops may improve a patient's ability to instill his or her eye drops correctly. Our objectives were to (a) document the methods providers use to educate glaucoma patients about eye drop technique; (b) determine whether eye drop technique education varies by provider and patient characteristics; and (c) evaluate whether education predicts improved patient technique. We conducted an 8-month longitudinal study of 279 glaucoma patients and 15 providers in which we recorded on videotape the content of glaucoma office visits at two time points (baseline and 4- to 6-week follow-up) and videotaped patient eye drop technique at three time points (baseline, 4- to 6-week follow up, and 8-month follow-up). Mann-Whitney rank sum tests were used to determine whether education was associated with improved patient eye drop technique over time. Ninety-four patients (34%) received technique education at either visit; 31% received verbal education and 10% received a technique demonstration. Only 24 patients (47%) who were new to eye drops received technique education at the baseline visit. Patients who were new to drops at baseline (p = .008) and patients who asked a question about drops (p < .001) were more likely to receive technique education. Education was not associated with improved technique. Eye drop technique education occurs infrequently during glaucoma office visits. Future studies should compare the effectiveness of different educational methods, such as patient demonstration versus provider verbal instruction, to determine which method is best at improving patient eye drop technique. PMID- 26751940 TI - Change and continuity. PMID- 26751941 TI - Baby factories in Nigeria: a new and challenging source of abuse. PMID- 26751942 TI - Hypersensitivity reactions during treatment with biological agents. AB - The recent development of biological agents, namely, anti-tumour necrosis factor alpha (TNF-alpha) agents (infliximab, adalimumab and etanercept), anti- CD20 monoclonal antibody (rituximab) and anti-interleukin 6 receptor (IL-6R) monoclonal antibody (tocilizumab), represents a major breakthrough for the treatment of immune-mediated disorders. Given their structural and functional differences, distinct safety profiles can be expected for each of these agents. Evidence in the literature indicates that patients treated with anti-TNF-alpha agents and tocilizumab are at increased risk for bacterial infections. However, an increased therapeutic use of these biological agents has disclosed other side effects, including immediate hypersensitivity reactions, such as anaphylaxis and urticaria. Both under-diagnosis and over-diagnosis of hypersensitivity reactions to biological agents are potential problems. Thus, it is important to identify these reactions and to adopt the right approach to manage them. This article reviews the general aspects of adverse events during biologic treatment, focusing on IgE-mediated hypersensitivity reactions to anti-TNF-alpha agents, rituximab and tocilizumab, and on the tools for the diagnosis of these life-threatening reactions. PMID- 26751943 TI - Acute generalized exanthematous pustulosis due to meropenem: An unusual side effect of a commonly used drug. PMID- 26751945 TI - Nonclassic congenital adrenal hyperplasia misdiagnosed as Turner syndrome. AB - We present a patient with nonclassic congenital adrenal hyperplasia (NCAH) misdiagnosed as mosaic Turner syndrome. She presented with complaints of primary infertility. Short stature, the presence of facial hair and hoarse voice was also noted. She had primary amenorrhea and was advised for karyotype at 16 years of age, which was reported as 45, X[20]/46, XX[80], stating her as a case of mosaic Turner syndrome. Clitoroplasty was done at 21 years of age for clitoromegaly, which was noticed during puberty. The diagnosis of mosaic Turner could not explain the virilization. Therefore, we repeated the karyotype, which revealed 46, XX in more than 100 metaphases and was sufficient to exclude mosaicism. Furthermore, the endocrinological evaluation revealed high testosterone level with a normal 17 alpha-hydroxyprogesterone (17-OHP). The presence of pubertal onset virilization with a karyotype of 46, XX and raised testosterone level with normal 17-OHP level, raised the suspicion of NCAH for which adrenocorticotropic hormone stimulation test was done which confirmed the diagnosis of NCAH. PMID- 26751946 TI - Real-Time Estimation of Core Infarct in Angiography Using Collateral Flow. AB - BACKGROUND AND PURPOSE: In order to attribute a diagnostic value to angiographic runs performed before revascularization, we aimed at developing a regional evaluation of leptomeningeal collateral flow that can be used to detect and predict infarction when performing stroke endovascular procedures. MATERIALS AND METHODS: We evaluated all consecutive patients treated for occlusions in the anterior circulation in our center between 2009 and 2013, with MRI imaging performed before the endovascular procedure. Two readers performed an evaluation of collateral circulation in 5 cortical regions based on the vascular anatomy. Regional scores were correlated with the presence of infarction in the same cortical sector on pretreatment and follow-up imaging. Global collateral scores for each patient were correlated with infarct volumes. RESULTS: In 89 patients with 408 cortical regions, we found a significant correlation between the degree of zonal collateral flow and the absence of infarction in the same zone on pretreatment imaging. In a subgroup of 37 recanalized patients (Thrombolysis in Cerebral Infarction scale 3) with 173 cortical zones, retrograde collateral flow to the proximal M4 segment predicted the absence of infarction within the same zone on follow-up imaging (positive predictive value 88.7%). We found good inter rater agreement for the presence of collateral flow to the M4 proximal segment or further - k = 0.77 (p = 0.05, 95% CI 0.66-0.88). Global collateral scores correlated with infarct volume on initial imaging; all patients with scores >=4 had infarct volumes <=70 ml, whereas all patients with global collateral scores <=1 had infarct volumes >=70 ml. CONCLUSION: Anatomic collateral flow evaluation using the angiographic runs performed during stroke endovascular procedures can provide a real-time estimation of the volume and location of core infarct. For each cortical region, good collateral flow is associated with the absence of infarct on pre-treatment imaging, and is predictive of the absence of infarct on follow-up imaging in recanalized patients. PMID- 26751944 TI - When Friends' and Society's Expectations Collide: A Longitudinal Study of Moral Decision-Making and Personality across College. AB - Early adulthood is a developmentally important time period, with many novel life events needing to be traversed for the first time. Despite this important transition period, few studies examine the development of moral decision-making processes during this critical life stage. In the present study, college students completed moral decision-making measures during their freshman and senior years of college. Results indicate that, across four years, moral decision-making demonstrates considerable rank-order stability as well as change, such that people become more likely to help a friend relative to following societal rules. To help understand the mechanisms driving changes in moral decision-making processes, we examined their joint development with personality traits, a known correlate that changes during early adulthood in the direction of greater maturity. We found little evidence that personality and moral decision-making developmental processes are related. In sum, findings indicate that while moral decision-making processes are relatively stable across a four-year period, changes do occur which are likely independent of developmental processes driving personality trait change. PMID- 26751947 TI - The Extratropical Northern Hemisphere Temperature Reconstruction during the Last Millennium Based on a Novel Method. AB - Large-scale climate history of the past millennium reconstructed solely from tree ring data is prone to underestimate the amplitude of low-frequency variability. In this paper, we aimed at solving this problem by utilizing a novel method termed "MDVM", which was a combination of the ensemble empirical mode decomposition (EEMD) and variance matching techniques. We compiled a set of 211 tree-ring records from the extratropical Northern Hemisphere (30-90 degrees N) in an effort to develop a new reconstruction of the annual mean temperature by the MDVM method. Among these dataset, a number of 126 records were screened out to reconstruct temperature variability longer than decadal scale for the period 850 2000 AD. The MDVM reconstruction depicted significant low-frequency variability in the past millennium with evident Medieval Warm Period (MWP) over the interval 950-1150 AD and pronounced Little Ice Age (LIA) cumulating in 1450-1850 AD. In the context of 1150-year reconstruction, the accelerating warming in 20th century was likely unprecedented, and the coldest decades appeared in the 1640s, 1600s and 1580s, whereas the warmest decades occurred in the 1990s, 1940s and 1930s. Additionally, the MDVM reconstruction covaried broadly with changes in natural radiative forcing, and especially showed distinct footprints of multiple volcanic eruptions in the last millennium. Comparisons of our results with previous reconstructions and model simulations showed the efficiency of the MDVM method on capturing low-frequency variability, particularly much colder signals of the LIA relative to the reference period. Our results demonstrated that the MDVM method has advantages in studying large-scale and low-frequency climate signals using pure tree-ring data. PMID- 26751948 TI - GLP-1 mimetic drugs and the risk of exocrine pancreatic disease: Cell and animal studies. AB - BACKGROUND: Glucagon Like Peptide 1 (GLP-1) mimetic drugs or degradation inhibitors mimic the action of native GLP-1 as a incretin hormone and have become a common second line of therapy for Type 2 diabetes. However, an important clinical issue is whether these drugs increase the incidence of pancreatitis and pancreatic cancer. OBJECTIVE: This paper reviews the physiology of GLP-1 including its synthesis, secretion and action of the peptide. Reported effects of the mimetic drugs on the exocrine pancreas in animal studies are also reviewed. RESULTS: GLP-1 is synthesized in a specific class of enteroendocrine cell, the L cell, by post-translational processing of proglucagon. It is released in response to the presence of nutrients in the small intestine and stimulates vagal afferent nerve endings as well as entering the blood where it is rapidly degraded by dipeptidyl peptidase IV. Its actions are mediated by specific G-protein coupled receptors. The major target tissues are the pancreatic islet beta cells, the brain and the heart but GLP-1 also affects gastrointestinal motility and secretion including the exocrine pancreas where its major systemic action is to inhibit secretion. In some animal, as well as human studies, the GLP-1 mimetic drugs are associated with pancreatitis or precursor lessions to pancreatic cancer but a mechanism is not clear. The most common occurrence of pathology in rodents is when the drugs are combined with a high fat diet. CONCLUSIONS: There is nothing in the physiology of GLP-1 or animal toxicology studies to support a mechanism of action or a major concern about the action of GLP-1 mimetic drugs on the exocrine pancreas. Further studies are warranted using animal models of disease and high fat diets. PMID- 26751949 TI - Sense of Coherence among Older Adult Residents of Long-Term Care Facilities in Taiwan: A Cross-Sectional Analysis. AB - BACKGROUND: Growing evidence shows that sense of coherence (SOC) is related to health promotion. Knowledge of SOC among older adults in Taiwan is limited. The present study aimed to investigate SOC status and its relationship to personal and environmental factors among older adult residents of long-term care facilities (LTCFs) in northeastern Taiwan. METHODS: This cross-sectional study was performed in Yilan, Taiwan. With face-to-face interviews, we obtained data from 104 LTCF residents (aged 65 years and older) using the Chinese version of Antonovsky's short 13-item SOC scale. We also collected the information on personal characteristics, physical and social environmental resources. Multiple linear regression was used to analyze factors potentially influencing SOC. RESULTS: Of the participants, the mean score (+/-standard deviation) of SOC was 58.3 (+/-8.8), while scores on SOC subscales (comprehensibility, manageability, and meaningfulness) were 23.4 +/-4.5, 17.9 +/-3.8, and 17.0 +/-3.2, respectively. Education level, activities of daily living and number of LTCF staff were found to be independently associated with SOC status after adjusting for demographic characteristics, health status, and environmental resources. In addition, interactions between personal and environmental factors had a crucial influence on SOC status. CONCLUSIONS: Participants in this study had relatively low SOC scores compared to their counterparts in Western countries. In addition to personal factors, environmental factors can play a significant role in SOC status among older adult LTCF residents. Comprehensive evaluation of SOC status should consider person-environment interaction effects. PMID- 26751952 TI - Aerobic Training in Patients with Congenital Myopathy. AB - INTRODUCTION: Congenital myopathies (CM) often affect contractile proteins of the sarcomere, which could render patients susceptible to exercise-induced muscle damage. We investigated if exercise is safe and beneficial in patients with CM. METHODS: Patients exercised on a stationary bike for 30 minutes, three times weekly, for 10 weeks at 70% of their maximal oxygen uptake (VO2max). Creatine kinase (CK) was monitored as a marker of muscle damage. VO2max, functional tests, and questionnaires evaluated efficacy. RESULTS: Sixteen patients with CM were included in a controlled study. VO2max increased by 14% (range, 6-25%; 95% CI 7 20; p < 0.001) in the seven patients who completed training, and tended to decrease in a non-intervention group (n = 7; change -3.5%; range, -11-3%, p = 0.083). CK levels were normal and remained stable during training. Baseline Fatigue Severity Scale scores were high, 4.9 (SE 1.9), and tended to decrease (to 4.4 (SE 1.7); p = 0.08) with training. Nine patients dropped out of the training program. Fatigue was the major single reason. CONCLUSIONS: Ten weeks of endurance training is safe and improves fitness in patients with congenital myopathies. The training did not cause sarcomeric injury, even though sarcomeric function is affected by the genetic abnormalities in most patients with CM. Severe fatigue, which characterizes patients with CM, is a limiting factor for initiating training in CM, but tends to improve in those who train. TRIAL REGISTRATION: The Regional Committee on Health Research Ethics of the Capital Region of Denmark H-2 2013-066 and ClinicalTrials.gov H2-2013-066. PMID- 26751950 TI - A trans-acting Variant within the Transcription Factor RIM101 Interacts with Genetic Background to Determine its Regulatory Capacity. AB - Most genetic variants associated with disease occur within regulatory regions of the genome, underscoring the importance of defining the mechanisms underlying differences in regulation of gene expression between individuals. We discovered a pair of co-regulated, divergently oriented transcripts, AQY2 and ncFRE6, that are expressed in one strain of Saccharomyces cerevisiae, ?1278b, but not in another, S288c. By combining classical genetics techniques with high-throughput sequencing, we identified a trans-acting single nucleotide polymorphism within the transcription factor RIM101 that causes the background-dependent expression of both transcripts. Subsequent RNA-seq experiments revealed that RIM101 regulates many more targets in S288c than in ?1278b and that deletion of RIM101 in both backgrounds abrogates the majority of differential expression between the strains. Strikingly, only three transcripts undergo a significant change in expression after swapping RIM101 alleles between backgrounds, implying that the differences in the RIM101 allele lead to a remarkably focused transcriptional response. However, hundreds of RIM101-dependent targets undergo a subtle but consistent shift in expression in the S288c RIM101-swapped strain, but not its ?1278b counterpart. We conclude that ?1278b may harbor a variant(s) that buffers against widespread transcriptional dysregulation upon introduction of a non native RIM101 allele, emphasizing the importance of accounting for genetic background when assessing the impact of a regulatory variant. PMID- 26751951 TI - Osteoprotegerin Regulates Pancreatic beta-Cell Homeostasis upon Microbial Invasion. AB - Osteoprotegerin (OPG), a decoy receptor for receptor activator of NF-kappaB ligand (RANKL), antagonizes RANKL's osteoclastogenic function in bone. We previously demonstrated that systemic administration of lipopolysaccharide (LPS) to mice elevates OPG levels and reduces RANKL levels in peripheral blood. Here, we show that mice infected with Salmonella, Staphylococcus, Mycobacteria or influenza virus also show elevated serum OPG levels. We then asked whether OPG upregulation following microbial invasion had an effect outside of bone. To do so, we treated mice with LPS and observed OPG production in pancreas, especially in beta-cells of pancreatic islets. Insulin release following LPS administration was enhanced in mice lacking OPG, suggesting that OPG inhibits insulin secretion under acute inflammatory conditions. Consistently, treatment of MIN6 pancreatic beta-cells with OPG decreased their insulin secretion following glucose stimulation in the presence of LPS. Finally, our findings suggest that LPS induced OPG upregulation is mediated in part by activator protein (AP)-1 family transcription factors, particularly Fos proteins. Overall, we report that acute microbial infection elevates serum OPG, which maintains beta-cell homeostasis by restricting glucose-stimulated insulin secretion, possibly preventing microbe induced exhaustion of beta-cell secretory capacity. PMID- 26751953 TI - Social-Biological Interactions in Oral Disease: A 'Cells to Society' View. AB - Oral diseases constitute a major worldwide public health problem, with their burden concentrating in socially disadvantaged and less affluent groups of the population, resulting in significant oral health inequalities. Biomedical and behavioural approaches have proven relatively ineffective in reducing these inequalities, and have potentially increased the health gap between social groups. Some suggest this stems from a lack of understanding of how the social and psychosocial contexts in which behavioural and biological changes occur influence oral disease. To unravel the pathways through which social factors affect oral health outcomes, a better understanding is thus needed of how the social 'gets under the skin,' or becomes embodied, to alter the biological. In this paper, we present the current knowledge on the interplay between social and biological factors in oral disease. We first provide an overview of the process of embodiment in chronic disease and then evaluate the evidence on embodiment in oral disease by reviewing published studies in this area. Results show that, in periodontal disease, income, education and perceived stress are correlated with elevated levels of stress hormones, disrupted immune biomarkers and increased allostatic load. Similarly, socioeconomic position and increased financial stress are related to increased stress hormones and cariogenic bacterial counts in dental caries. Based on these results, we propose a dynamic model depicting social-biological interactions that illustrates potential interdependencies between social and biological factors that lead to poor oral health. This work and the proposed model may aid in developing a better understanding of the causes of oral health inequalities and implicate the importance of addressing the social determinants of oral health in innovating public health interventions. PMID- 26751955 TI - Application of Ureteroscope in Emergency Treatment with Persistent Renal Colic Patients during Pregnancy. AB - BACKGROUND: Although the application of ureteroscopy in the treatment of ureteral calculi during pregnancy has been on the rise, for persistent renal colic patients without ultrasound-detected ureteral calculi, it may represent a clinical dilemma due to the potential risks for both mother and fetus. OBJECTIVE: The aim of the present study is to present our experience with the application of the ureteroscope in the emergency treatment of persistent renal colic patients during pregnancy. METHODS: From March 2009 to September 2014, a total of 117 pregnant women who received ureteroscopy for persistent renal colic were retrospectively analyzed. Patients were divided into three groups according to duration of the persistent renal colic: Group A (within 12 hours; 24 cases); Group B (12 to 24 hours; 76 cases); and Group C (more than 24 hours; 17 cases). The stone-free rate, complications, and other qualitative data were analyzed. RESULTS: Of the 117 patients, 31 patients who were found not to have renal or ureteral calculi received ureteroscopic double-J (DJ) stent insertion, whereas 86 patients who were found with ureteral calculi received ureteroscopic lithotripsy (URSL) and DJ stent insertion. Among them, 24 patients (27.9%) were found with ureteral calculi by ureteroscopy rather than ultrasound. In addition, 73 patients (84.9%) had complete fragmentation of calculi; 12 patients (10.3%) had a threatened abortion (the rates of threatened abortion in Groups A, B and C were 8.3% vs. 6.5% vs. 29.4%; Group C compared with Groups A and B, p<0.05), and one patient (1.2%) had urosepsis (in Group C). However, these complications were cured with conservative treatment, without postpartum infant and maternal complications. CONCLUSION: For pregnant patients with persistent renal colic/ureteral calculi and hydronephrosis, ureteroscopic DJ stent insertion and URSL are effective and safe options when conservative treatment fails, even if no urinary calculi were found by ultrasound. At the same time, for patients with persistent renal colic during pregnancy, early application of ureteroscopy may reduce the risk of preterm birth. PMID- 26751954 TI - Urinary Vitamin D Binding Protein and KIM-1 Are Potent New Biomarkers of Major Adverse Renal Events in Patients Undergoing Coronary Angiography. AB - BACKGROUND: Vitamin-D-binding protein (VDBP) is a low molecular weight protein that is filtered through the glomerulus as a 25-(OH) vitamin D 3/VDBP complex. In the normal kidney VDBP is reabsorbed and catabolized by proximal tubule epithelial cells reducing the urinary excretion to trace amounts. Acute tubular injury is expected to result in urinary VDBP loss. The purpose of our study was to explore the potential role of urinary VDBP as a biomarker of an acute renal damage. METHOD: We included 314 patients with diabetes mellitus or mild renal impairment undergoing coronary angiography and collected blood and urine before and 24 hours after the CM application. Patients were followed for 90 days for the composite endpoint major adverse renal events (MARE: need for dialysis, doubling of serum creatinine after 90 days, unplanned emergency rehospitalization or death). RESULTS: Increased urine VDBP concentration 24 hours after contrast media exposure was predictive for dialysis need (no dialysis: 113.06 +/- 299.61 ng/ml, n = 303; need for dialysis: 613.07 +/- 700.45 ng/ml, n = 11, Mean +/- SD, p<0.001), death (no death during follow-up: 121.41 +/- 324.45 ng/ml, n = 306; death during follow-up: 522.01 +/- 521.86 ng/ml, n = 8; Mean +/- SD, p<0.003) and MARE (no MARE: 112.08 +/- 302.00 ng/ml, n = 298; MARE: 506.16 +/- 624.61 ng/ml, n = 16, Mean +/- SD, p<0.001) during the follow-up of 90 days after contrast media exposure. Correction of urine VDBP concentrations for creatinine excretion confirmed its predictive value and was consistent with increased levels of urinary Kidney Injury Molecule-1 (KIM-1) and baseline plasma creatinine in patients with above mentioned complications. The impact of urinary VDBP and KIM-1 on MARE was independent of known CIN risk factors such as anemia, preexisting renal failure, preexisting heart failure, and diabetes. CONCLUSIONS: Urinary VDBP is a promising novel biomarker of major contrast induced nephropathy-associated events 90 days after contrast media exposure. PMID- 26751956 TI - Transcriptome Analysis of Honeybee (Apis Mellifera) Haploid and Diploid Embryos Reveals Early Zygotic Transcription during Cleavage. AB - In honeybees, the haplodiploid sex determination system promotes a unique embryogenesis process wherein females develop from fertilized eggs and males develop from unfertilized eggs. However, the developmental strategies of honeybees during early embryogenesis are virtually unknown. Similar to most animals, the honeybee oocytes are supplied with proteins and regulatory elements that support early embryogenesis. As the embryo develops, the zygotic genome is activated and zygotic products gradually replace the preloaded maternal material. The analysis of small RNA and mRNA libraries of mature oocytes and embryos originated from fertilized and unfertilized eggs has allowed us to explore the gene expression dynamics in the first steps of development and during the maternal-to-zygotic transition (MZT). We localized a short sequence motif identified as TAGteam motif and hypothesized to play a similar role in honeybees as in fruit flies, which includes the timing of early zygotic expression (MZT), a function sustained by the presence of the zelda ortholog, which is the main regulator of genome activation. Predicted microRNA (miRNA)-target interactions indicated that there were specific regulators of haploid and diploid embryonic development and an overlap of maternal and zygotic gene expression during the early steps of embryogenesis. Although a number of functions are highly conserved during the early steps of honeybee embryogenesis, the results showed that zygotic genome activation occurs earlier in honeybees than in Drosophila based on the presence of three primary miRNAs (pri-miRNAs) (ame-mir-375, ame-mir-34 and ame mir-263b) during the cleavage stage in haploid and diploid embryonic development. PMID- 26751957 TI - Classical and all-floating FETI methods for the simulation of arterial tissues. AB - High-resolution and anatomically realistic computer models of biological soft tissues play a significant role in the understanding of the function of cardiovascular components in health and disease. However, the computational effort to handle fine grids to resolve the geometries as well as sophisticated tissue models is very challenging. One possibility to derive a strongly scalable parallel solution algorithm is to consider finite element tearing and interconnecting (FETI) methods. In this study we propose and investigate the application of FETI methods to simulate the elastic behavior of biological soft tissues. As one particular example we choose the artery which is - as most other biological tissues - characterized by anisotropic and nonlinear material properties. We compare two specific approaches of FETI methods, classical and all floating, and investigate the numerical behavior of different preconditioning techniques. In comparison to classical FETI, the all-floating approach has not only advantages concerning the implementation but in many cases also concerning the convergence of the global iterative solution method. This behavior is illustrated with numerical examples. We present results of linear elastic simulations to show convergence rates, as expected from the theory, and results from the more sophisticated nonlinear case where we apply a well-known anisotropic model to the realistic geometry of an artery. Although the FETI methods have a great applicability on artery simulations we will also discuss some limitations concerning the dependence on material parameters. PMID- 26751960 TI - Ion Channels in Plant Bioenergetic Organelles, Chloroplasts and Mitochondria: From Molecular Identification to Function. AB - Recent technical advances in electrophysiological measurements, organelle targeted fluorescence imaging, and organelle proteomics have pushed the research of ion transport a step forward in the case of the plant bioenergetic organelles, chloroplasts and mitochondria, leading to the molecular identification and functional characterization of several ion transport systems in recent years. Here we focus on channels that mediate relatively high-rate ion and water flux and summarize the current knowledge in this field, focusing on targeting mechanisms, proteomics, electrophysiology, and physiological function. In addition, since chloroplasts evolved from a cyanobacterial ancestor, we give an overview of the information available about cyanobacterial ion channels and discuss the evolutionary origin of chloroplast channels. The recent molecular identification of some of these ion channels allowed their physiological functions to be studied using genetically modified Arabidopsis plants and cyanobacteria. The view is emerging that alteration of chloroplast and mitochondrial ion homeostasis leads to organelle dysfunction, which in turn significantly affects the energy metabolism of the whole organism. Clear-cut identification of genes encoding for channels in these organelles, however, remains a major challenge in this rapidly developing field. Multiple strategies including bioinformatics, cell biology, electrophysiology, use of organelle targeted ion-sensitive probes, genetics, and identification of signals eliciting specific ion fluxes across organelle membranes should provide a better understanding of the physiological role of organellar channels and their contribution to signaling pathways in plants in the future. PMID- 26751958 TI - Curiouser and Curiouser: The Macrocyclic Lactone, Abamectin, Is also a Potent Inhibitor of Pyrantel/Tribendimidine Nicotinic Acetylcholine Receptors of Gastro Intestinal Worms. AB - Nematode parasites may be controlled with drugs, but their regular application has given rise to concerns about the development of resistance. Drug combinations may be more effective than single drugs and delay the onset of resistance. A combination of the nicotinic antagonist, derquantel, and the macrocyclic lactone, abamectin, has been found to have synergistic anthelmintic effects against gastro intestinal nematode parasites. We have observed in previous contraction and electrophysiological experiments that derquantel is a potent selective antagonist of nematode parasite muscle nicotinic receptors; and that abamectin is an inhibitor of the same nicotinic receptors. To explore these inhibitory effects further, we expressed muscle nicotinic receptors of the nodular worm, Oesophagostomum dentatum (Ode-UNC-29:Ode-UNC-63:Ode-UNC-38), in Xenopus oocytes under voltage-clamp and tested effects of abamectin on pyrantel and acetylcholine responses. The receptors were antagonized by 0.03 MUM abamectin in a non competitive manner (reduced Rmax, no change in EC50). This antagonism increased when abamectin was increased to 0.1 MUM. However, when we increased the concentration of abamectin further to 0.3 MUM, 1 MUM or 10 MUM, we found that the antagonism decreased and was less than with 0.1 MUM abamectin. The bi-phasic effects of abamectin suggest that abamectin acts at two allosteric sites: one high affinity negative allosteric (NAM) site causing antagonism, and another lower affinity positive allosteric (PAM) site causing a reduction in antagonism. We also tested the effects of 0.1 MUM derquantel alone and in combination with 0.3 MUM abamectin. We found that derquantel on these receptors, like abamectin, acted as a non-competitive antagonist, and that the combination of derquantel and abamectin produced greater inhibition. These observations confirm the antagonistic effects of abamectin on nematode nicotinic receptors in addition to GluCl effects, and illustrate more complex effects of macrocyclic lactones that may be exploited in combinations with other anthelmintics. PMID- 26751961 TI - Catalytic Functions of the Isoprenyl Diphosphate Synthase Superfamily in Plants: A Growing Repertoire. PMID- 26751962 TI - Spectral Exploration of Calcium Accumulation in Organic Matter in Gray Desert Soil from Northwest China. AB - Little attention has been paid to the accumulation of soil organic matter (SOM) in the fringes of the mid-latitude desert. In this paper, soil samples from a long-term field experiment conducted from 1990 to 2013 at a research station in Urumqi, China by different fertilizer treatments, were used to determine soil properties and soil dissolved organic matter (DOM) by chemical analysis, fluorescence excitation emission matrix (EEM) spectroscopy, and high resolution transmission electron microscopy (HR-TEM). The binding features of DOM under the addition of Ca(2+) were analyzed using a two-dimensional (2D) Fourier transform infrared (FTIR) spectrometer further to explore the response of the DOM to increasing concentrations of Ca(2+). Long-term application of chemical fertilizers and goat manure increased soil organic carbon (SOC) by 1.34- and 1.86 fold, respectively, relative to the non-fertilized control (8.95 g.kg(-1)). Compared with the control, application of chemical fertilizers and manure significantly increased the concentrations of Ca, Mg, Si, humic and fulvic acid like substances in DOM but decreased the amounts of trivalent metals (Al and Fe) and protein-like substances. Although crystalline Al/Fe nanoparticles and amorphous or short-range-order Si/Al nanoparticles existed in all DOM samples, crystalline Ca/Si nanoparticles were predominant in the samples treated with goat manure. Although organic matter and Si-O-containing nanoparticles were involved in the binding of Ca(2+) to DOM, application of chemical fertilizers weakened Ca(2+) association with components of the amide II group (1510 cm(-1)) and Si-O linkage (1080 cm(-1)), whereas application of goat manure enhanced the affinity of Ca(2+) for Si-O linkage. Our results suggested that the enrichment of Ca in gray desert soil possibly helps accumulate SOM by forming crystalline Ca/Si nanoparticles in addition to Ca(2+) and organic matter complexes. PMID- 26751964 TI - Hypertensive/Microvascular Disease and COPD: a Case Control Study. AB - BACKGROUND/AIMS: This study tested the hypothesis that individuals with chronic obstructive pulmonary disease (COPD) have more small vessel disease and more severe disease than an age- and gender- matched hospital patient comparison group. METHODS: This was a single centre, case-control study of 151 individuals with COPD (FEV1/VC) < 0.7 recruited consecutively immediately after respiratory function tests at a Melbourne teaching hospital over a 4 month period in 2010. Controls were individuals with normal respiratory function tests recruited contemporaneously from the same centre. Retinal images were obtained with a nonmydriatic camera (KOWA or Canon CR5-45NM), deidentiifed and graded by two trained graders for microvascular retinopathy (Wong and Mitchell classification), and vessel calibre using a computer-assisted method and Knudtson's modification of the Parr-Hubbard formula. Differences in microvascular retinopathy and vessel calibre between COPD patients and the comparison group were examined using Fisher's exact test or the t test (StataCorp, Texas). RESULTS: Patients with COPD had more microvascular retinopathy (121, 80% and 76, 50%; OR 3.98, 95%CI 2.39 to 6.64) and more severe disease (42, 28% and 18, 12%; OR 2.85, 95% CI 1.55 to 5.23) than other hospital patients. COPD remained an independent determinant of microvascular retinopathy (OR 4.56, 95%CI 2.49 to 8.36) after adjusting for gender, hypertension, smoking, and diabetes duration. Retinal arterioles and venules were wider in patients with COPD than other hospital patients (mean difference +6.5 um, 95% confidence interval 1.4 to 11.6; and +17.4 um, 95%CI 9.4 to 25.5, respectively). Larger venules were more common in younger individuals (+0.6 um, 0.1 to 1.17) with more cigarette exposure (+0.3 um, 0.2 to 0.5) or a lower serum albumin (+23.0 um, 6.0 to 40.0). Venular calibre was not different in current and former smokers (p=0.77). There were trends for venules to be larger with more severe COPD (lower FEV1/VC, p=0.09) and with CT-demonstrated emphysema (p=0.06). CONCLUSIONS: Hypertensive/microvascular disease is more common and more severe in patients with COPD. This is likely to contribute to the associated increase in cardiac risk. PMID- 26751963 TI - Dysregulation of protein methyltransferases in human cancer: An emerging target class for anticancer therapy. AB - Protein methylation is one of the important post-translational modifications. Although its biological and physiological functions were unknown for a long time, we and others have characterized a number of protein methyltransferases, which have unveiled the critical functions of protein methylation in various cellular processes, in particular, in epigenetic regulation. In addition, it had been believed that protein methylation is an irreversible phenomenon, but through identification of a variety of protein demethylases, protein methylation is now considered to be dynamically regulated similar to protein phosphorylation. A large amount of evidence indicated that protein methylation has a pivotal role in post-translational modification of histone proteins as well as non-histone proteins and is involved in various processes of cancer development and progression. As dysregulation of this modification has been observed frequently in various types of cancer, small-molecule inhibitors targeting protein methyltransferases and demethylases have been actively developed as anticancer drugs; clinical trials for some of these drugs have already begun. In this review, we discuss the biological and physiological importance of protein methylation in human cancer, especially focusing on the significance of protein methyltransferases as emerging targets for anticancer therapy. PMID- 26751965 TI - Cost-Effective Marine Protection--A Pragmatic Approach. AB - This paper puts forward a framework for probabilistic and holistic cost effectiveness analysis to provide support in selecting the least-cost set of measures to reach a multidimensional environmental objective. Following the principles of ecosystem-based management, the framework includes a flexible methodology for deriving and populating criteria for effectiveness and costs and analyzing complex ecological-economic trade-offs under uncertainty. The framework is applied in the development of the Finnish Programme of Measures (PoM) for reaching the targets of the EU Marine Strategy Framework Directive (MSFD). The numerical results demonstrate that substantial cost savings can be realized from careful consideration of the costs and multiple effects of management measures. If adopted, the proposed PoM would yield improvements in the state of the Baltic Sea, but the overall objective of the MSFD would not be reached by the target year of 2020; for various environmental and administrative reasons, it would take longer for most measures to take full effect. PMID- 26751966 TI - Arginine starvation in colorectal carcinoma cells: Sensing, impact on translation control and cell cycle distribution. AB - Tumor cells rely on a continued exogenous nutrient supply in order to maintain a high proliferative activity. Although a strong dependence of some tumor types on exogenous arginine sources has been reported, the mechanisms of arginine sensing by tumor cells and the impact of changes in arginine availability on translation and cell cycle regulation are not fully understood. The results presented herein state that human colorectal carcinoma cells rapidly exhaust the internal arginine sources in the absence of exogenous arginine and repress global translation by activation of the GCN2-mediated pathway and inhibition of mTOR signaling. Tumor suppressor protein p53 activation and G1/G0 cell cycle arrest support cell survival upon prolonged arginine starvation. Cells with the mutant or deleted TP53 fail to stop cell cycle progression at defined cell cycle checkpoints which appears to be associated with reduced recovery after durable metabolic stress triggered by arginine withdrawal. PMID- 26751967 TI - Stress-induced upregulation of VLDL receptor alters Wnt-signaling in neurons. AB - Lipoprotein receptor family members hold multiple roles in the brain, and alterations in lipoprotein receptor expression and function are implicated in neuronal stress, developmental disorders and neurodegenerative diseases, such as Alzheimer's disease. Berberine (BBR), a nutraceutical shown to have both neuroprotective and neurotoxic properties, is suggested to regulate lipoprotein receptor expression. We show that subtoxic concentration of BBR regulates neuronal lipoprotein receptor expression in a receptor- and time-dependent fashion in cerebellar granule neurons (CGN). Similarly to BBR, subtoxic concentrations of neuronal stressors cobalt chloride, thapsigargin and rotenone increased very-low-density lipoprotein receptor (VLDLR) mRNA and protein expression in CGN suggesting a conserved pathway for stress-induced upregulation of VLDLR in neurons. We also show that VLDLR upregulation is accompanied by transiently increased stabilization of hypoxia-induced factor 1 alpha (HIF 1alpha) and decreased beta-catenin levels affecting the Wnt pathway through GSK3beta phosphorylation, a crucial player in neurodegenerative processes. Our results indicate that neuronal stress differentially regulates lipoprotein receptor expression in neurons, with VLDLR upregulation as a common element as a modulator of neuronal Wnt signaling. PMID- 26751970 TI - Viola plant cyclotide vigno 5 induces mitochondria-mediated apoptosis via cytochrome C release and caspases activation in cervical cancer cells. AB - Cyclotides describe a unique cyclic peptide family that displays a broad range of biological activities including uterotonic, anti-bacteria, anti-cancer and anti HIV. The vigno cyclotides consist of vigno 1-10 were reported recently from Viola ignobilis. In the present study, we examined the effects of vigno 5, a natural cyclopeptide from V. ignobilis, on cervical cancer cells and the underlying mechanisms. We found that vigno 5-treated Hela cells were killed off by apoptosis in a dose-dependent manner within 24h, and were characterized by the appearance of nuclear shrinkage, cleavage of poly (ADP-ribose) polymerase (PARP) and DNA fragmentation. The mitochondrial pathway of apoptosis revealed that cytochrome C is released from mitochondria to cytosol, associated with the activation of caspase-9 and -3, and the cleavage of poly (ADP-ribose) polymerase (PARP). Overall, the results indicate that vigno 5 induces apoptosis in part via the mitochondrial pathway, which is associated with a release of cytochrome C and elevated activity of caspase-9 and -3 in Hela cells. PMID- 26751969 TI - Serum Vitamin D Level and Rheumatoid Arthritis Disease Activity: Review and Meta Analysis. AB - BACKGROUND: The evidence from epidemiological studies concerning the relationship between serum vitamin D concentrations and rheumatoid arthritis (RA) is inconsistent. This meta-analysis is aimed at determining the magnitude of the correlation between this common autoimmune disease and vitamin D, an important nutrient known to dampen adaptive immune responses. METHODS: Through multiple search strategies, relevant literature was identified and evaluated for quality before May 16 2015. Data extracted from eligible studies was synthesized to calculate pooled correlation coefficient (r), mean difference (MD) and odds ratio (OR). The Venice criteria were applied to assess the credibility of the evidence for each statistically significant association. RESULTS: A total of 24 reports involving 3489 patients were selected for analysis. RA patients had lower vitamin D levels than healthy controls (MD:-16.52 nmol/L, 95% confidence intervals [CI]: 18.85 to -14.19 nmol/L). There existed a negative relationship between serum 25 hydroxyvitamin D (25OHD) level and disease activity index, e.g. 25OHD vs. Disease Activity Score in 28 joints (DAS28): r = -0.13, 95% CI -0.16 to -0.09; 25OHD vs. C-reactive protein: r = -0.12, 95% CI -0.23 to -0.00. Additionally, latitude stratified subgroup analysis yielded a relatively stronger negative correlation between 25OHD and DAS28 in low-latitude areas. This inverse relationship also appeared more significant in developing countries than in developed countries. No publication bias was detected. CONCLUSION: RA patients had lower vitamin D values than healthy controls. There was a negative association between serum vitamin D and RA disease activity. However, more strictly controlled studies are needed to validate these findings. PMID- 26751971 TI - Family-centred approaches to healthcare interventions in chronic diseases in adults: a quantitative systematic review. AB - BACKGROUND: Increasingly there is a focus on self-care strategies for both malignant and non-malignant conditions. Models of self-care interventions have focussed on the individual and less on the broader context of family and society. In many societies, decision-making and health seeking behaviours, involve family members. OBJECTIVE: To identify elements of effective family-centred self-care interventions that are likely to improve outcomes of adults living with chronic conditions. DESIGN: Review paper. DATA SOURCES: MEDLINE (Ovid), CINAHL, Academic Search Complete, PsychInfo and Scopus between 2000-2014. REVIEW METHODS: Quantitative studies targeting patient outcomes through family-centred interventions in adults were retrieved using systematic methods in January, 2015. Search terms used were: 'family', 'spouse', 'carer', 'caregiver', 'chronic', 'chronic disease', 'self-care', 'self-management' and 'self-efficacy'. Reference lists were reviewed. Risk of bias assessment was performed using the Cochrane Collaboration's tool. Data were reported using a narrative summary approach. RESULTS: Ten studies were identified. Improvements were noted in readmission rates, emergency department presentations, and anxiety levels using family centred interventions compared with controls. Elements of effective interventions used were a family-centred approach, active learning strategy and transitional care with appropriate follow-up. CONCLUSIONS: Involving the family in self-care has shown some positive results for patients with chronic conditions. The benefits of family-centred care may be more likely in specific socio-cultural contexts. LIMITATIONS: The review has year limits and further research needs to identify support for both the patients and family caregivers. PMID- 26751968 TI - Adolescent chronic stress causes hypothalamo-pituitary-adrenocortical hypo responsiveness and depression-like behavior in adult female rats. AB - Adolescence is a period of substantial neuroplasticity in stress regulatory neurocircuits. Chronic stress exposure during this period leads to long-lasting changes in neuroendocrine function and emotional behaviors, suggesting adolescence may be a critical period for development of stress vulnerability. This study investigated the effects of exposure to 14 days of chronic variable stress (CVS) in late-adolescent (pnd 45-58) female rats on neuroendocrine function, neuropeptide mRNA expression and depressive-like behavior in adolescence (pnd 59) and in adulthood (pnd 101). Adult females exposed to CVS in adolescence have a blunted hypothalamo-pituitary-adrenocortical (HPA) axis in response to a novel stressor and increased immobility in the forced swim test. Blunted HPA axis responses were accompanied by reduced vasopressin mRNA expression in the paraventricular nucleus of the hypothalamus (PVN), suggesting decreased central drive. Adolescent females tested immediately after CVS did not exhibit differences in stress reactivity or immobility in the forced swim test, despite evidence for enhanced central HPA axis drive (increased CRH mRNA expression in PVN). Overall, our study demonstrates that exposure to chronic stress in adolescence is sufficient to induce lasting changes in neuroendocrine drive and behavior, potentially altering the developmental trajectory of stress circuits as female rats age into adulthood. PMID- 26751973 TI - A new procedure for fractures of the medial epicondyle in children: Mitek((r)) bone suture anchor. AB - We present a new bone suture anchor technique for fractures of the medial epicondyle. The hypothesis was that the results would be similar to those with the divergent K-wire fixation. This retrospective study included 40 patients who presented with displaced fractures of the medial epicondyle: one group was treated with a Mitek((r)) non-resorbable bone suture anchor (group A: n=21), the other by K-wire fixation (group B: n=19). A medial approach was taken with an anchor placed above the olecranon fossa. The epicondyle was then repositioned by bone suture. After a mean follow-up of 18.6 months, union was obtained in all epicondyles. There was no difference in flexion-extension of the elbow. The rate of hypertrophy of the medial epicondyle was similar in both groups (57%). The bone suture anchor of the medial epicondyle is an effective technique that does not require hardware removal and is an alternative treatment option to divergent K-wire fixation. PMID- 26751974 TI - Effects of benthic organism Tubifex tubifex on hexachlorocyclohexane isomers transfer and distribution into freshwater sediment. AB - In this study, bioaccumulation and elimination of HCHs in tubifex, and the distribution of HCHs in overlying water and sediment, were studied during a 10-d experiment. A sensitive method was developed for the determination of HCHs in samples based on gas chromatograph (GC) equipped with a nickel-63 electron capture detector (MUECD). The limit of detection (LOD) was 0.35 ug/kg for alpha HCH and 0.82 ug/kg for beta-HCH. Tubifex accumulated HCHs rapidly, and the curves were approximately M-type. The highest level was reached on the 7th day, with 0.34 mg/kg(wwt) for alpha-HCH and 0.87 mg/kg(wwt) for beta-HCH in worms. The AFs of beta-HCH in tubifex were higher than those of alpha-HCH. Moreover, the existence of tubifex significantly reduced beta-HCH fluxes from the overlying water to sediment by uptake or degradation and decreased the concentrations of beta-HCH in the sediment, but it had little influence on alpha-HCH fluxes. Moreover, enantioselectivity of alpha-HCH enantiomers was not observed in tubifex, whether in the bioaccumulation or elimination experiments. At the end of the elimination experiment, approximately 80% and 70% of alpha-HCH and beta-HCH were eliminated, and the depuration half-lives were 4.43 and 5.39 days, respectively. PMID- 26751972 TI - Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni. AB - BACKGROUND: Schistosoma flatworm parasites cause schistosomiasis, a chronic and debilitating disease of poverty in developing countries. Praziquantel is employed for treatment and disease control. However, its efficacy spectrum is incomplete (less active or inactive against immature stages of the parasite) and there is a concern of drug resistance. Thus, there is a need to identify new drugs and drug targets. METHODOLOGY/PRINCIPAL FINDINGS: We show that RNA interference (RNAi) of the Schistosoma mansoni ortholog of human polo-like kinase (huPLK)1 elicits a deleterious phenotypic alteration in post-infective larvae (schistosomula or somules). Phenotypic screening and analysis of schistosomula and adult S. mansoni with small molecule inhibitors of huPLK1 identified a number of potent anti schistosomals. Among these was a GlaxoSmithKline (GSK) benzimidazole thiophene inhibitor that has completed Phase I clinical trials for treatment of solid tumor malignancies. We then obtained GSKs Published Kinase Inhibitor Sets (PKIS) 1 and 2, and phenotypically screened an expanded series of 38 benzimidazole thiophene PLK1 inhibitors. Computational analysis of controls and PLK1 inhibitor-treated populations of somules demonstrated a distinctive phenotype distribution. Using principal component analysis (PCA), the phenotypes exhibited by these populations were mapped, visualized and analyzed through projection to a low-dimensional space. The phenotype distribution was found to have a distinct shape and topology, which could be elicited using cluster analysis. A structure-activity relationship (SAR) was identified for the benzimidazole thiophenes that held for both somules and adult parasites. The most potent inhibitors produced marked phenotypic alterations at 1-2 MUM within 1 h. Among these were compounds previously characterized as potent inhibitors of huPLK1 in cell assays. CONCLUSIONS/SIGNIFICANCE: The reverse genetic and chemical SAR data support a continued investigation of SmPLK1 as a possible drug target and/or the prosecution of the benzimidazole thiophene chemotype as a source of novel anti schistosomals. PMID- 26751975 TI - Food Preference and Appetite after Switching between Sweet and Savoury Odours in Women. AB - BACKGROUND: Exposure to food odours increases the appetite for congruent foods and decreases the appetite for incongruent foods. However, the effect of exposure to a variety of food odours, as often occurs in daily life, is unknown. OBJECTIVE: Investigate how switching between sweet and savoury odours affects the appetite for sweet and savoury products. DESIGN: Thirty women (age: 18-45y; BMI: 18.5-25kg/m2) intensely smelled the contents of cups filled with banana, meat or water (no-odour) in a within-subject design with four combinations: no odour/banana, no-odour/meat, meat/banana and banana/meat. Participants received one combination per test day. In each combination, two cups with different fillings were smelled for five minutes after each other. Treatment order was balanced as much as possible. The effects of previous exposure and current odour on the appetite for (in)congruent sweet and savoury products, and odour pleasantness were analysed. A change from meat to banana odour or banana to meat odour was referred to as switch, whereas a change from no-odour to meat odour or no-odour to banana odour was no-switch. RESULTS: The current odour (P<0.001), as opposed to the previous exposure (P = 0.71), determined the appetite for (in)congruent sweet and savoury products, already one minute after a switch between sweet and savoury odours. The pleasantness of the odour decreased during odour exposure (P = 0.005). CONCLUSIONS: After a switch, the appetite for specific products quickly adjusted to the new odour and followed the typical pattern as found during odour exposure in previous studies. Interestingly, the appetite for the smelled food remained elevated during odour exposure, known as sensory-specific appetite, whereas the pleasantness of the odour decreased over time, previously termed olfactory sensory-specific satiety. This seeming contradiction may result from different mechanisms underlying the odour-induced anticipation of food intake versus the decrease in hedonic value during prolonged sensory stimulation. PMID- 26751977 TI - Synthesis of Optically Active, X-Shaped, Conjugated Compounds and Dendrimers Based on Planar Chiral [2.2]Paracyclophane, Leading to Highly Emissive Circularly Polarized Luminescence. AB - Optically active, Frechet-type dendrimers containing an emissive X-shaped pi electron system as the core unit were synthesized. Gram-scale optical resolution and transformations of 4,7,12,15-tetrasubstituted [2.2]paracyclophanes were also carried out. The high-generation dendrons effectively absorbed UV light and transferred energy to the core, resulting in high photoluminescence (PL) from the core. In addition, the dendrons sufficiently isolated the emissive X-shaped conjugated core and bright emission was observed from both thin films and solutions. Intense circularly polarized luminescence (CPL) was observed from the thin film. The dendrimer films exhibited excellent optical properties, such as large molar extinction coefficients, high fluorescence quantum efficiencies, intense PL and CPL, and large CPL dissymmetry factors. PMID- 26751978 TI - Co-extrusion as a processing technique to manufacture a dual sustained release fixed-dose combination product. AB - OBJECTIVES: This study aimed to design a fixed-dose combination dosage form which provides a sustained release profile for both the freely water-soluble metformin HCl and the poorly soluble gliclazide, two antidiabetic compounds used to treat diabetes mellitus. METHODS: Hot-melt co-extrusion was used as an innovative manufacturing technique for a pharmaceutical fixed-dose combination product. In this way, a matrix formulation that sustained metformin release could be developed, despite the high drug load in the formulation and the freely soluble nature of the drug. KEY FINDINGS: It was clear that co-extrusion was perfectly suited to produce a fixed-dose combination product with adequate properties for each of the incorporated APIs. A coat layer, containing at least 30% CAPA((r)) 6506 as a hydrophobic polymer, was necessary to adequately sustain the release of the highly dosed freely soluble drug from the 70% metformin HCl-loaded CAPA((r)) 6506 core of the co-extrudate. To obtain a complete gliclazide release over 24-h solubilization in Kollidon((r)) VA, added as a second polymer to the CAPA((r)) 6506 in the coat, was needed. CONCLUSIONS: Both active pharmaceutical ingredients (APIs), which have different physicochemical characteristics, were formulated in a single dosage form, using co-extrusion. PMID- 26751976 TI - Recent development of mass spectrometry and proteomics applications in identification and typing of bacteria. AB - Identification and typing of bacteria occupy a large fraction of time and work in clinical microbiology laboratories. With the certification of some MS platforms in recent years, more applications and tests of MS-based diagnosis methods for bacteria identification and typing have been created, not only on well-accepted MALDI-TOF-MS-based fingerprint matches, but also on solving the insufficiencies of MALDI-TOF-MS-based platforms and advancing the technology to areas such as targeted MS identification and typing of bacteria, bacterial toxin identification, antibiotics susceptibility/resistance tests, and MS-based diagnostic method development on unique bacteria such as Clostridium and Mycobacteria. This review summarizes the recent development in MS platforms and applications in bacteria identification and typing of common pathogenic bacteria. PMID- 26751980 TI - Long-term mortality and causes of death among patients with a total knee prosthesis in primary osteoarthritis. AB - BACKGROUND: Short and midterm mortality of patients with osteoarthritis (OA) who have undergone total knee arthroplasty (TKA) is generally lower than that of the general population. Due to an increasing number of young patients who undergo TKA the expected lifetime of these patients is increasing. The purpose of this study was to assess the causes of death and long-term mortality among Finnish TKA patients. METHODS: Standardized mortality ratios (SMRs) for total and site specific causes of death were calculated for 9443 TKA patients operated on in 1980 to 1996 for OA and followed until 2012. RESULTS: The mean follow-up time was 14 years (maximum 33 years). During follow-up, 77% of the patients had died. The all-cause SMR was 1.00. It was significantly lower than in the reference population (SMR 0.73) during the first 10 years after operation, but higher during the next 10 years (SMR 1.23), and even more after 20 years (SMR 1.95). The SMR for cardiovascular mortality was 1.03 and accounted for 52% of all deaths. Significant excess mortality was observed in diseases of the digestive tract (SMR 1.29). Deaths due to cardiovascular diseases, Alzheimer's disease and dementia comprised 68% of all deaths that took place 10 years or later after TKA. CONCLUSIONS: The mortality of TKA patients with OA is significantly reduced during the first 10 postoperative years but exceeds the mortality of the general population after that. This trend should be taken into account when young patients undergo a TKA. LEVEL OF EVIDENCE: Observational study, III. PMID- 26751979 TI - Investigating the relationship between internal tibial torsion and medial collateral ligament injury in patients undergoing knee arthroscopy due to tears in the posterior one third of the medial meniscus. AB - PURPOSE: To evaluate the relationship between medial collateral ligament (MCL) injury and degree of internal tibial torsion in patients who had undergone arthroscopic resection due to tears in the posterior one third of the medial meniscus. METHODS: Seventy-one patients were allocated into two groups with respect to foot femur angle (FFA) and transmalleolar angle (TMA) (Group 1 31 patients with FFA<8 degrees and Group 2 40 patients with FFA>=8 degrees ). The groups were compared in terms of valgus instability, Lysholm score, magnetic resonance view, FFA, and TMA, both before and after the operation. RESULTS: Lysholm scores were higher in Group 2 at both postoperative week 1 (p<0.001) and month 1 (p=0.045) relative to Group 1. Preoperative cartilage injury was encountered more frequently in Group 1 (p=0.037) than in Group 2. MCL injury was detected more frequently in Group 1 compared to Group 2 postoperatively at week 1 (p=0.001). CONCLUSION: We conclude that FFA and TFA, indicators of internal tibial torsion, may serve as markers for foreseeing clinical improvement and complications following arthroscopic surgery. LEVEL OF EVIDENCE: level III retrospective comparative study. PMID- 26751982 TI - BODIPY Dye, the Most Versatile Fluorophore Ever? AB - BODIPY laser dyes constitute a fascinating topic of research in modern photochemistry due to the large variety of options its chromophore offers, which is ready available for a multitude of synthetic routes. Indeed, in the literature one can find a huge battery of compounds based on the indacene core. The possibility of modulating the spectroscopic properties or inducing new photophysical processes by the substitution pattern of the BODIPY dyes has boosted the number of scientific and technological applications for these fluorophores. Along the following lines, I will overview the main results achieved in our laboratory with BODIPYs oriented to optoelectronic as well to biophotonic applications, stressing the more relevant photophysical issues to be considered in the design of a tailor-made BODIPY for a certain application and pointing out some of the remaining challenges. PMID- 26751981 TI - Self-initiated actions result in suppressed auditory but amplified visual evoked components in healthy participants. AB - Self-suppression refers to the phenomenon that sensations initiated by our own movements are typically less salient, and elicit an attenuated neural response, compared to sensations resulting from changes in the external world. Evidence for self-suppression is provided by previous ERP studies in the auditory modality, which have found that healthy participants typically exhibit a reduced auditory N1 component when auditory stimuli are self-initiated as opposed to externally initiated. However, the literature investigating self-suppression in the visual modality is sparse, with mixed findings and experimental protocols. An EEG study was conducted to expand our understanding of self-suppression across different sensory modalities. Healthy participants experienced either an auditory (tone) or visual (pattern-reversal) stimulus following a willed button press (self initiated), a random interval (externally initiated, unpredictable onset), or a visual countdown (externally initiated, predictable onset-to match the intrinsic predictability of self-initiated stimuli), while EEG was continuously recorded. Reduced N1 amplitudes for self- versus externally initiated tones indicated that self-suppression occurred in the auditory domain. In contrast, the visual N145 component was amplified for self- versus externally initiated pattern reversals. Externally initiated conditions did not differ as a function of their predictability. These findings highlight a difference in sensory processing of self-initiated stimuli across modalities, and may have implications for clinical disorders that are ostensibly associated with abnormal self-suppression. PMID- 26751983 TI - On the stability of manganese tris(beta-diketonate) complexes as redox mediators in DSSCs. AB - The photoelectrochemical properties and stability of dye sensitized solar cells containing Mn(beta-diketonato)3 complexes, [Mn(III)(acac)3] () (acac = acetylacetonate), [Mn(III)(CF2)3] () (CF2 = 4,4-difluoro-1-phenylbutanate-1,3 dione), [Mn(III)(DBM)3] () (DBM = dibenzoylmethanate), [Mn(II)(CF2)3]TBA (TBA = tetrabutylammonium) () and [Mn(II)(DBM)3]TBA (), have been evaluated. At room temperature, the complexes undergo ligand exchange with 4-tert-butyl-pyridine, an additive commonly used in the solar device to reduce charge recombination at the photoanode. An increased device stability was achieved by using the Z907 dye and passivating the photoanode with short chain siloxanes. It was also found that the Mn(ii)/(iii) couple is involved in the dye regeneration process, instead of Mn(iii)/(iv) (E1/2 > 1 V vs. SCE) previously indicated in the literature. PMID- 26751986 TI - Special nutritious solutions to enhance complementary feeding. PMID- 26751984 TI - Cost-Effectiveness of Osteoporosis Screening Strategies for Men. AB - Osteoporosis affects many men, with significant morbidity and mortality. However, the best osteoporosis screening strategies for men are unknown. We developed an individual-level state-transition cost-effectiveness model with a lifetime time horizon to identify the cost-effectiveness of different osteoporosis screening strategies for US men involving various screening tests (dual-energy X-ray absorptiometry [DXA]; the Osteoporosis Self-Assessment Tool [OST]; or a fracture risk assessment strategy using age, femoral neck bone mineral density [BMD], and Vertebral Fracture Assessment [VFA]); screening initiation ages (50, 60, 70, or 80 years); and repeat screening intervals (5 years or 10 years). In base-case analysis, no screening was a less effective option than all other strategies evaluated; furthermore, no screening was more expensive than all strategies that involved screening with DXA or the OST risk assessment instrument, and thus no screening was "dominated" by screening with DXA or OST at all evaluated screening initiation ages and repeat screening intervals. Screening strategies that most frequently appeared as most cost-effective in base-case analyses and one-way sensitivity analyses when assuming willingness-to-pay of $50,000/quality-adjusted life-year (QALY) or $100,000/QALY included screening initiation at age 50 years with the fracture risk assessment strategy and repeat screening every 10 years; screening initiation at age 50 years with fracture risk assessment and repeat screening every 5 years; and screening initiation at age 50 years with DXA and repeat screening every 5 years. In conclusion, expansion of osteoporosis screening for US men to initiate routine screening at age 50 or 60 years would be expected to be effective and of good value for improving health outcomes. A fracture risk assessment strategy using variables of age, femoral neck BMD, and VFA is likely to be the most effective of the evaluated strategies within accepted cost-effectiveness parameters. DXA and OST are also reasonable screening options, albeit likely slightly less effective than the evaluated fracture risk assessment strategy. (c) 2016 American Society for Bone and Mineral Research. PMID- 26751985 TI - The impact of physiological crowding on the diffusivity of membrane bound proteins. AB - Diffusion of transmembrane and peripheral membrane-bound proteins within the crowded cellular membrane environment is essential to diverse biological processes including cellular signaling, endocytosis, and motility. Nonetheless we presently lack a detailed understanding of the influence of physiological levels of crowding on membrane protein diffusion. Utilizing quantitative in vitro measurements, here we demonstrate that the diffusivities of membrane bound proteins follow a single linearly decreasing trend with increasing membrane coverage by proteins. This trend holds for homogenous protein populations across a range of protein sizes and for heterogeneous mixtures of proteins of different sizes, such that protein diffusivity is controlled by the total coverage of the surrounding membrane. These results demonstrate that steric exclusion within the crowded membrane environment can fundamentally limit the diffusive rate of proteins, regardless of their size. In cells this "speed limit" could be modulated by changes in local membrane coverage, providing a mechanism for tuning the rate of molecular interaction and assembly. PMID- 26751987 TI - Reproducibility and Daytime-Dependent Changes of Corneal Epithelial Thickness and Whole Corneal Thickness Measured With Fourier Domain Optical Coherence Tomography. AB - PURPOSE: To evaluate the reproducibility of Fourier domain anterior segment optical coherence tomography (RTVue) based on repeated measurements of corneal thickness (CT) and epithelial thickness (ET) and to test daytime-dependent changes of these parameters. METHODS: Twenty-three eyes from 23 healthy volunteers were included in this prospective study. Three clinical observers performed 3 consecutive measurements each of CT and ET in 3 sessions using RTVue, resulting in 9 measurements per session. Session 1 was performed at 9 AM +/- 1 hour, session 2 at 4 PM +/- 1 hour on the same day, and session 3 at 9 AM +/- 1 hour 2 days later. CT and ET were assessed in 9 areas: corneal vertex, 4 paracentral zones, and 4 peripheral zones. RESULTS: The mean intraclass correlations (ICCs) for intraobserver and interobserver reproducibility were almost perfect (0.81-0.99) for CT in all corneal zones and for ET in all but 2 peripheral zones. Intraobserver ICC was substantial (0.61-0.8) for superior peripheral area and interobserver ICC for superior and inferior peripheral positions. CT and ET decreased significantly from morning to afternoon sessions [ 3.15 MUm (P < 0.0001) and -0.52 MUm (P < 0.0001), respectively]. ET correlated weakly to moderately with CT. CONCLUSIONS: RTVue yields almost perfect reproducibility for CT and ET in central, paracentral, and peripheral lateral zones. Central CT and ET were significantly thinner in the afternoon compared with the morning. PMID- 26751988 TI - Accelerated Corneal Cross-Linking With a Hypoosmolar Riboflavin Solution in Keratoconic Thin Corneas: Short-Term Results. AB - PURPOSE: The aim of this study was to evaluate the early term topographic and aberration results of accelerated (9 mW/cm) corneal cross-linking (CXL) treatment in keratoconic thin corneas. METHODS: Forty-nine eyes from 43 patients (mean age of 21.2 +/- 7.1) with progressive keratoconic thin corneas (<400 MUm without epithelium) who had accelerated corneal CXL with hypoosmolar riboflavin solution throughout the procedure were enrolled. We measured the uncorrected and corrected distance visual acuity, refraction, slit-lamp examination, topographic values, and corneal higher-order aberrations (Pentacam HR, Oculus Optikgerate GmbH) preoperatively and 1, 3, and 6 months after surgery. RESULTS: Before surgery, the corneal thickness was 404 +/- 18 MUm, and the thickness was reduced to 360 +/- 24 MUm after removing the epithelium. After the application of hypoosmolar riboflavin solution, the thickness increased to 432 +/- 44 MUm. At month 6, there was a significant increase in uncorrected distance visual acuity (P = 0.043) and corrected distance visual acuity (P = 0.024), a decrease in spherical refraction (P = 0.041), maximum keratometry (Kmax, P = 0.003), anterior elevation values (P = 0.008), corneal thickness (P < 0.001), coma (P = 0.022), spherical aberration (P = 0.001), higher-order root mean square (P = 0.004), and total root mean square (P < 0.001), whereas the cylindrical refraction (P = 0.627), anterior (P = 0.665) and posterior astigmatism (P = 0.165) of the cornea, posterior elevation (P = 0.198), and trefoil (P = 0.141) remained unchanged. No patients showed any complications or scar formation during follow-up. CONCLUSIONS: Accelerated corneal CXL with hypoosmolar riboflavin solution throughout the procedure is effective in thin corneas. PMID- 26751989 TI - Differential Profiling of T-Cell Cytokines as Measured by Protein Microarray Across Dry Eye Subgroups. AB - PURPOSE: The purpose of this study is to explore the role of the adaptive immune system in patients with aqueous-deficient dry eye (ADDE) and lipid-deficient dry eye (LDDE). METHODS: Patients (n = 29) with moderate to severe dry eye (dry eye workshop [DEWS] severity grading scheme) were enrolled in a cross-sectional study and classified as ADDE (Schirmer < 10), LDDE (abnormal meibum), combined (meeting both criteria), or generic (meeting neither criterion). Tears were collected by Schirmer strips, and samples for both eyes were pooled for each subject. Thirty micrograms of total protein was used in a normalized volume for microarray analysis (Quantibody Human Inflammation Array 3; RayBiotech). Six markers of TH1 cells (interferon [IFN]gamma, interleukin [IL]-2), TH2 cells (IL-4, IL-5, IL-13), and TH17 cells (IL-17) were assessed. RESULTS: ADDE demonstrated the highest total cytokine concentration, followed by the LDDE, combined, and generic groups. IFNgamma and IL-2 were detectable in all subgroups. IL-4, -5, and -13 were detectable in ADDE and LDDE, but only IL-13 was detected in both the combined and generic groups. IL-17 was present in the ADDE, LDDE, and combined groups. CONCLUSIONS: TH1 cells seem to be involved in all forms of dry eye. ADDE and LDDE seem to be mediated by TH1, TH2, and TH17 cells. The combined-mechanism group is mediated by TH1 and TH17 cells, and generic dry eye seems to be mediated by TH1 cells only. ADDE has the greatest overall T-cell-mediated pathophysiology compared with the other subgroups, which is consistent with previous reports of improved efficacy with antiinflammatory therapy in these patients. PMID- 26751990 TI - Efficacy of Corneal Collagen Cross-Linking for the Treatment of Keratoconus: A Systematic Review and Meta-Analysis. AB - PURPOSE: To examine the efficacy of corneal collagen cross-linking (CXL) for the treatment of keratoconus (KCN). METHODS: A systemic literature review and meta analysis of ocular functional and structural parameters of patients with KCN undergoing cross-linking procedures were performed using PubMed and the web of science. A literature search was performed for relevant peer-reviewed publications on population-based studies. Data were analyzed with R software (Meta library), and heterogeneity was assessed with the Cochran Q and I. A random effects model was used for high heterogeneity; otherwise a fixed model was used. Sensitivity analysis of particular tested groups was used to explain high heterogeneity. The main outcome measures extracted from the articles were corrected distance visual acuity, uncorrected distance visual acuity, and maximum K. RESULTS: An improvement in visual acuity of 1 to 2 Snellen lines was found 3 months or more after undergoing CXL. Changes were more pronounced in uncorrected visual acuity. Some topography parameters were found to be improved (0.6-1 diopters) 12 to 24 months after CXL. The refractive cylinder improved by 0.4 to 0.7 diopters. Endothelial cell density decreased by 225 cells per square millimeter in the first 3 months and thereafter returned to normal. Corneal thickness was reduced by 10 to 20 MUm in the year following CXL but not after 24 months. No changes in intraocular pressure were noted. CONCLUSIONS: CXL is a safe and effective method for halting the deterioration of KCN, while slightly improving visual function. PMID- 26751991 TI - Correlation Between Corneal Button Size and Intraocular Pressure During Femtosecond Laser-Assisted Keratoplasty. AB - PURPOSE: To evaluate changes in intraocular pressure (IOP) in recipient and donor eyes during femtosecond laser-assisted keratoplasty (FLAK) and to assess for differences in the diameter of trephinated corneal buttons according to changes in pressure. MATERIALS AND METHODS: Twenty porcine whole eyes (recipient model) and 20 porcine-corneoscleral rims (donor model) were prepared, and anterior chamber pressures were measured using a fiberoptic sensing device (Opsens, Quebec, Canada) during the femtosecond laser corneal cutting process. To determine the diameter of corneal buttons, 10 porcine whole eyes (recipient model) and 12 corneoscleral rims (donor model) of each baseline IOP were cut with the femtosecond laser programmed to the following pattern: "vertical side cut"; 1200 MUm (depth), 8 mm (diameter). Digital photographs were obtained using microscopy and subsequently analyzed. RESULTS: The IOP (mean +/- SD) for the recipient model was 10.2 (+/-0.9) mm Hg at baseline and ranged from 96.6 (+/-4.5) to ~138.4 (+/-3.8) mm Hg during the corneal cutting process. This shows that the maximum IOP during FLAK increased 13.5 times compared with baseline. In the donor model, the mean pressure elevation from baseline artificial anterior chamber (AAC) pressure to corneal cutting was 15.8 (+/-5.4) mm Hg. This showed a positive correlation with baseline IOP [correlation coefficient (CC) = 0.827, P = 0.006]. As the baseline IOP in the recipient eye increased, trephinated corneal button size was reduced by up to 3.9% in diameter (CC = -0.945, P = 0.015). In addition, in donor eyes, the diameter was decreased by up to 11.7% as the baseline AAC pressure increased (CC = -0.934, P = 0.006). CONCLUSIONS: During the FLAK procedure, the IOP increases in both recipient and donor eyes. The diameter of the trephinated donor and recipient corneal buttons was decreased as the initial baseline IOP increased. Ophthalmic surgeons can determine the AAC pressure based on the baseline IOP in the recipient patient. PMID- 26751992 TI - Protein Oxidation Levels After Different Corneal Collagen Cross-Linking Methods. AB - PURPOSE: To evaluate advanced oxidation protein products (AOPP) levels, superoxide dismutase (SOD) enzyme activity, and total sulfhydryl (TSH) levels in rabbit corneas after different corneal collagen cross-linking (CXL) methods. METHODS: Eighteen eyes of 9 adult New Zealand rabbits were divided into 3 groups of 6 eyes. The standard CXL group was continuously exposed to UV-A at a power setting of 3 mW/cm for 30 minutes. The accelerated CXL (A-CXL) group was continuously exposed to UV-A at a power setting of 30 mW/cm for 3 minutes. The pulse light-accelerated CXL (PLA-CXL) group received UV-A at a power setting of 30 mW/cm for 6 minutes of pulsed exposure (1 second on, 1 second off). Corneas were obtained after 1 hour of UV-A exposure, and 360-degree keratotomy was performed. SOD enzyme activity, AOPP, and TSH levels were measured in the corneal tissues. RESULTS: Compared with the standard CXL and A-CXL groups (133.2 +/- 8.5 and 140.2 +/- 6.2 MUmol/mg, respectively), AOPP levels were found to be significantly increased in the PLA-CXL group (230.7 +/- 30.2 MUmol/mg) (P = 0.005 and 0.009, respectively). SOD enzyme activities and TSH levels did not differ between the groups (P = 0.167 and 0.187, respectively). CONCLUSIONS: CXL creates covalent bonds between collagen fibers because of reactive oxygen species. This means that more oxygen concentration during the CXL method will produce more reactive oxygen species and, thereby, AOPP. This means that in which CXL method occurs in more oxygen concentration that will produce more reactive oxygen species and thereby AOPP. This study demonstrated that PLA-CXL results in more AOPP formation than did standard CXL and A-CXL. PMID- 26751993 TI - Corneal Topographic Changes After Eyelid Ptosis Surgery. AB - PURPOSE: To evaluate the corneal topography and the topographic changes after ptosis surgery on patients affected by congenital and acquired blepharoptosis. METHODS: Twenty eyes of 17 patients affected by acquired and congenital ptosis underwent surgical correction through anterior levator complex tightening. Computerized tomography (Syrius Sistem; CSO) was used to analyze any change in corneal astigmatism (CYL), simulated keratometry, anterior corneal symmetry index front, apical keratometry front, and central corneal thickness. Visual acuity, margin reflex distance, and levator function were also measured. RESULTS: After surgical ptosis repair, corneal topography demonstrated a reduction in average keratometry of 0.15 +/- 0.47 diopters (D) and in corneal astigmatism of 0.26 +/- 1.12 D. Significant differences were found in apical keratometry front (-1.84 +/- 1.76 D) and in best-corrected visual acuity (-0.18 +/- 0.06 logMAR) in the postoperative examinations. Central corneal thickness did not show significant differences between preoperative and postoperative examinations. Postoperative topographic maps showed a reduction of symmetry index front (0.10 +/- 0.64 D). CONCLUSIONS: Eyelid ptosis modifies anterior corneal surface inducing refractive errors and modifying corneal astigmatism in patients, thus affecting the quality of vision. The surgical correction of blepharoptosis induces anterior corneal surface modification, restoring corneal symmetry and regular corneal astigmatism. Postoperative corneal topography showed normal corneal contours. PMID- 26751994 TI - Effect of Topically Applied Azithromycin on Corneal Epithelial and Endothelial Apoptosis in a Rat Model of Corneal Alkali Burn. AB - PURPOSE: To investigate the antiapoptotic effect of topically administered azithromycin (AZM) on corneal epithelial and endothelial cells in a rat model of corneal alkali burn. METHODS: Twenty-four Wistar albino rats were divided into 4 equal groups as pseudovehicle (group 1), control (group 2), alkali burned (group 3), and treatment (group 4) groups. Alkali injury was induced only in the right corneas of rats belonging to groups 3 and 4 using 1N NaOH. The rats in group 3 and the rats in group 4 were respectively treated either with an artificial tear gel or with 1.5% AZM eye drops for 5 days. At the fifth day of the experiment, the apoptosis in the corneal epithelium and endothelium of all rats was assessed using a terminal dUTP nick-end labeling (TUNEL) assay. In addition, tumor necrosis factor-alpha (TNF-alpha) density in the corneal epithelium was measured in all rats. RESULTS: The mean numbers of TUNEL+ cells in the corneal epithelium and endothelium of rats in group 3 were 117.1 +/- 23.8 and 34.6.+/- 11.3, respectively, whereas in group 4, they were 75.8 +/- 15.7 and 14.7 +/- 3.5, respectively. Also the mean TNF-alpha densities in the corneal epithelium in group 3 and group 4 were 2.65 +/- 1.3 and 1.65 +/- 1.1, respectively. There was a significant decrease in the mean number of TUNEL+ cells in the corneal epithelium and endothelium and in the mean TNF-alpha density in the corneal epithelium of rats in group 4, when compared with group 3. CONCLUSIONS: Topically applied AZM can decrease TNF-alpha-induced apoptosis in corneal alkali burn. PMID- 26751996 TI - Femtosecond Laser-Assisted Lamellar Keratectomy for Anterior Corneal Dystrophies. PMID- 26751995 TI - Intraoperative Fluorescein Staining of Cryopreserved Amniotic Membrane Grafts to Improve Visualization During and After Pterygium Surgery: A Novel Technique. AB - PURPOSE: To describe a new method of enhancing the visualization of amniotic membrane grafts with fluorescein staining during pterygium surgery. METHODS: Pterygium excision surgery using intraoperatively stained cryopreserved amniotic membranes was performed on 346 eyes. A sterile 0.6 mg sodium fluorescein strip was placed directly onto the amniotic membrane in the manufacturer's original packaging, and the stained allograft was then transplanted onto the planned site. Staining intensities, at 3, 5, and 10 minutes of dye immersion, were compared. Immediate postoperative pain rating (scale 0-10), visibility of the fluorescein stained amniotic membrane graft, and conjunctival autograft and amniotic membrane graft elevation, dehiscence, retraction, or displacement were recorded. The recurrence rate of the study population was compared with that of a previous cohort of 121 patients who underwent pterygium excision with conjunctival autograft without stained amniotic membrane. RESULTS: Direct contact of the fluorescein strip on the amniotic membrane at 3, 5, and 10 minutes showed no differences in subjective staining intensity. Fluorescein-stained amniotic membrane was easily detected on the ocular surface during and 24 hours after pterygium surgery. The average immediate postoperative pain rating was 0.8 +/- 1.8. No intraoperative complications or postoperative amniotic membrane graft dehiscence, retraction, or displacement occurred. The recurrence rate using fluorescein-stained amniotic membrane (3 patients, 0.9%, mean follow-up time 31.8 +/- 18.6 weeks) did not differ from that of the previous cohort without the stained amniotic membrane (2.5%; chi(1) = 1.837, P = 0.183). CONCLUSIONS: Fluorescein strip staining of the amniotic membrane is a novel and safe intraoperative method to enhance visualization and handling of the graft during and after ocular surgeries. PMID- 26751997 TI - Solid Lipid Nanoparticles for Image-Guided Therapy of Atherosclerosis. AB - Although the application of nanotechnologies to atherosclerosis remains a young field, novel strategies are needed to address this public health issue. In this context, the magnetic resonance imaging (MRI) approach has been gradually investigated in order to enable image-guided treatments. In this contribution, we report a new approach based on nucleoside-lipids allowing the synthesis of solid lipid nanoparticles (SLN) loaded with iron oxide particles and therapeutic agents. The insertion of nucleoside-lipids allows the formation of stable SLNs loaded with prostacycline (PGI2) able to inhibit platelet aggregation. The new SLNs feature better relaxivity properties in comparison to the clinically used contrast agent Feridex, indicating that SLNs are suitable for image-guided therapy. PMID- 26751998 TI - Excited-State Proton Transfer and Intramolecular Charge Transfer in 1,3-Diketone Molecules. AB - The photophysical signature of the tautomeric species of the asymmetric (N,N dimethylanilino)-1,3-diketone molecule are investigated using approaches rooted in density functional theory (DFT) and time-dependent DFT (TD-DFT). In particular, since this molecule, in the excited state, can undergo proton transfer reactions coupled to intramolecular charge transfer events, the different radiative and nonradiative channels are investigated by making use of different density-based indexes. The use of these tools, together with the analysis of both singlet and triplet potential energy surfaces, provide new insights into excited-state reactivity allowing one to rationalize the experimental findings including different behavior of the molecule as a function of solvent polarity. PMID- 26751999 TI - DUSP19, a downstream effector of leptin, inhibits chondrocyte apoptosis via dephosphorylating JNK during osteoarthritis pathogenesis. AB - Increased mitogen-activated protein kinase (MAPK) activity has been found in human osteoarthritis (OA). Dual specificity protein phosphatase 19 (DUSP19), a member of mitogen-activated protein kinase (MAPK) phosphatases (MKPs), controls the activity of various MAPKs. This study was aimed to explore the function of DUSP19 during OA pathogenesis. Here, OA and healthy control data were downloaded from the NCBI Gene Expression Omnibus database (GSE57218). Forty-five patients with OA and 25 healthy donors were enrolled in this study. A rat OA model was induced by anterior cruciate ligament transection. Primary cultured chondrocytes were treated with leptin (10 ng mL(-1)). Cell survival, cell apoptosis and reactive oxygen species (ROS) were identified by CCK-8 and flow cytometry, respectively. In the cartilage of OA patients, DUSP19 was expressed in a lower level than in the cartilage of healthy control. The DUSP19 level was negatively correlated with leptin, which was confirmed by experiments in the rat OA model. Moreover, cell apoptosis and JNK activation in the rat cartilage were increased with the increasing of leptin levels and the decreasing of DUSP19 mRNA levels. In primary culture chondrocytes, exogenous leptin suppressed DUSP19 expression. The ectopic expression of DUSP19 significantly ameliorated leptin-induced apoptosis in damaged chondrocytes, accompanied by the reduced production of ROS. Moreover, the activity of JNK stimulated by leptin was suppressed by DUSP19 overexpression. The present study indicated that DUSP19, a downstream of leptin, inhibited apoptosis of chondrocytes through dephosphorylating JNK. PMID- 26752002 TI - Gradual plasmon evolution and huge infrared near-field enhancement of metallic bridged nanoparticle dimers. AB - By three-dimensional (3D) finite element method (FEM) plasmon mapping, gradual plasmon evolutions of both bonding dipole plasmon (BDP) and charge transfer plasmon (CTP) modes are visualized. In particular, the evolved BDP mode provides a physical insight into the rapid degeneration of electromagnetic hot spots in practical applications, while the rising CTP mode enables a huge near-field enhancement for potential plasmonic devices at infrared wavelengths. PMID- 26752001 TI - Interplay between Steps and Oxygen Vacancies on Curved TiO2(110). AB - A vicinal rutile TiO2(110) crystal with a smooth variation of atomic steps parallel to the [1-10] direction was analyzed locally with STM and ARPES. The step edge morphology changes across the samples, from [1-11] zigzag faceting to straight [1-10] steps. A step-bunching phase is attributed to an optimal (110) terrace width, where all bridge-bonded O atom vacancies (Obr vacs) vanish. The [1 10] steps terminate with a pair of 2-fold coordinated O atoms, which give rise to bright, triangular protrusions (St) in STM. The intensity of the Ti 3d-derived gap state correlates with the sum of Obr vacs plus St protrusions at steps, suggesting that both Obr vacs and steps contribute a similar effective charge to sample doping. The binding energy of the gap state shifts when going from the flat (110) surface toward densely stepped planes, pointing to differences in the Ti(3+) polaron near steps and at terraces. PMID- 26752000 TI - A matrix metalloproteinase inhibitor enhances anti-cytotoxic T lymphocyte antigen 4 antibody immunotherapy in breast cancer by reprogramming the tumor microenvironment. AB - Anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) treatment is effective for the treatment of primary tumors, but not sufficient for the treatment of metastatic tumors, likely owing to the effects of the tumor microenvironment. In this study, we aimed to determine the therapeutic effects of combined treatment with a matrix metalloproteinase (MMP) inhibitor (MMPI) and anti-CTLA-4 antibody in a breast cancer model in mice. Interestingly, combined treatment with MMPI and anti-CTLA-4 antibody delayed tumor growth and reduced lung and liver metastases compared with anti-CTLA-4 alone or vehicle treatment. The functions of the liver and kidney in mice in the different groups did not differ significantly compared with that in normal mice. The CD8+/CD4+ ratio in T cells in the spleen and tumor were increased after monotherapy or combined anti-CTLA-4 antibody plus MMPI therapy compared with that in vehicle-treated mice. Anti-CTLA-4 antibody plus MMPI therapy reduced the percentage of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and decreased the Treg/Th17 cell ratio in the spleen compared with those in the vehicle-treated group. Additionally, anti-CTLA-4 antibody plus MMPI therapy reduced the percentages of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and Th17 cells in tumors compared with that in the vehicle-treated group. Moreover, combined treatment with MMPI and anti-CTLA-4 antibody reduced the microvessel density (MVD) in tumors compared with that in vehicle or MMPI-treated mice. There was a negative correlation between MVD and the CD8+ T cell percentage, CD4+ T cell percentage, and CD8+/CD4+ T cell ratio, but a positive correlation with Tregs, Th17 cells, Treg/Th17 cell ratio, and MDSCs. Thus, these data demonstrated that addition of MMPI enhanced the effects of anti-CTLA-4 antibody treatment in a mouse model of breast cancer by delaying tumor growth and reducing metastases. PMID- 26752004 TI - Differential Pigment Accumulation in Carrot Leaves and Roots during Two Growing Periods. AB - Carotenoids are important secondary metabolites involved in plant growth and nutritional quality of vegetable crops. These pigments are highly accumulated in carrot root, but knowledge about the impact of environmental factors on their accumulation is limited. The purpose of this work was to investigate the impact of environmental variations on carotenoid accumulation in carrot leaves and roots. In this work, carrots were grown during two contrasting periods to maximize bioclimatic differences. In leaves, carotenoid and chlorophyll contents were lower in the less favorable growing conditions, whereas relative contents were well conserved for all genotypes, suggesting a common regulatory mechanism. The down-regulation of all genes under environmental constraints demonstrates that carotenoid accumulation is regulated at the transcriptional level. In roots, the decrease in alpha-carotene and lutein contents was accompanied by an increase of beta-carotene relative content. At the transcriptional level, LCYB and ZEP expression increased, whereas LCYE expression decreased, in the less favorable conditions, suggesting that carotenoid biosynthesis is switched toward the beta branch. PMID- 26752007 TI - The Year 2015 in Inorganic Chemistry. PMID- 26752005 TI - Does oral exposure to cadmium and lead mediate susceptibility to colitis? The dark-and-bright sides of heavy metals in gut ecology. AB - Although the heavy metals cadmium (Cd) and lead (Pb) are known environmental health concerns, their long-term impacts on gut ecology and susceptibility to gastrointestinal autoimmune diseases have not been extensively investigated. We sought to determine whether subchronic oral exposure to Cd or Pb is a risk factor for the development and progression of inflammatory bowel disease (IBD). Mice were exposed to various doses of CdCl2 or PbCl2 in drinking water for 1, 4 or 6 weeks prior to infection with Salmonella, the induction of colitis with dextran sodium sulfate (DSS) or trinitrobenzene sulfonic acid (TNBS). In human cell-based models, exposure to Cd and Pb is associated with reduced transepithelial electric resistance and changes in bacteria-induced cytokine responses. Although 1- and 6 week exposures did not have clear effects on the response to Salmonella infectious challenges, 1-week short-term treatments with CdCl2 tended to enhance intestinal inflammation in mice. Unexpectedly, subchronic exposure to Cd and (to a lesser extent) Pb significantly mitigated some of the symptoms of DSS-induced colitis and reduced the severity of TNBS colitis in a dose-dependent manner. The possible adaptive and immunosuppressive mechanisms by which heavy metals might reduce intestinal inflammation are explored and discussed. PMID- 26752009 TI - Making Data Submitted to the Food and Drug Administration More Visible. PMID- 26752006 TI - Expression of Tumor-Related Macrophages and Cytokines After Surgery of Triple Negative Breast Cancer Patients and its Implications. AB - BACKGROUND: Triple-negative breast cancer (TNBC) has negative expression of progesterone receptor (PR) and estrogen receptor (ER), and low expression of human epithelial growth factor receptor-2 (HER-2). This study aimed to investigate the expressional profile of cytokines in TNBC patients with significant expression of macrophages. MATERIAL/METHODS: Immunohistochemical (IHC) S-P staining method was used to detect the tumor-associated macrophages (TAMs) marker CD68 expression in 48 cases of TNBC samples. The correlation between CD68 expression and prognosis was analyzed. Expressions of key cytokines- interleukin-6 (IL-6), IL-10, IL-12, IL-1beta, chemokine (C-C motif) ligand-5 (CCL 5), and macrophage inflammatory protein-2 (MIP-2)--were quantified by RT-PCR and enzyme-linked immunosorbent assay (ELISA). RESULTS: Thirty-four out of 48 TNBC samples (71.4%) had CD68-positive expression. IL-6 and CCL-5 were up-regulated in high-infiltrated tumors when compared to low-infiltrated samples. Other cytokines had no significant difference regarding the expression level across groups. CONCLUSIONS: TAMs were up-regulated in most TNBC patients after the surgery. Its expression suggested unfavorable prognosis, especially in the high-infiltrated group. Those tumors with more macrophage also had elevated expression of cytokine IL-6 and chemotactic factor CCL-5, both of which have potency to be clinical index and drug target for TNBC. PMID- 26752010 TI - The emergence and evolution of school psychology literature: A scientometric analysis from 1907 through 2014. AB - The objective of this current study is to identify the growth and development of scholarly literature that specifically references the term 'school psychology' in the Science Citation Index from 1907 through 2014. Documents from Web of Science were accessed and analyzed through the use of scientometric analyses, including HistCite and Pajek software, resulting in the identification of 4,806 scholars who contributed 3,260 articles in 311 journals. Whereas the database included journals from around the world, most articles were published by authors in the United States and in 20 journals, including the Journal of School Psychology, Psychology in the Schools, School Psychology Review, School Psychology International, and School Psychology Quarterly. Analyses of the database from the past century revealed that 20 of the most prolific scholars contributed 14% of all articles. Contributions from faculty and students at University of Minnesota Twin Cities, University of Nebraska-Lincoln, University of South Carolina, University of Wisconsin-Madison, and University of Texas-Austin represented 10% of all articles including the term school psychology in the Science Citation Index. Relationships among some of the most highly cited articles are also described. Collectively, the series of analyses reported herein contribute to our understanding of scholarship in school psychology. (PsycINFO Database Record PMID- 26752008 TI - Synthesis, characterization, and application of reversible PDLLA-PEG-PDLLA copolymer thermogels in vitro and in vivo. AB - In this study, a series of injectable thermoreversible and thermogelling PDLLA PEG-PDLLA copolymers were developed and a systematic evaluation of the thermogelling system both in vitro and in vivo was performed. The aqueous PDLLA PEG-PDLLA solutions above a critical gel concentration could transform into hydrogel spontaneously within 2 minutes around the body temperature in vitro or in vivo. Modulating the molecular weight, block length and polymer concentration could adjust the sol-gel transition behavior and the mechanical properties of the hydrogels. The gelation was thermally reversible due to the physical interaction of copolymer micelles and no crystallization formed during the gelation. Little cytotoxicity and hemolysis of this polymer was found, and the inflammatory response after injecting the hydrogel to small-animal was acceptable. In vitro and in vivo degradation experiments illustrated that the physical hydrogel could retain its integrity as long as several weeks and eventually be degraded by hydrolysis. A rat model of sidewall defect-bowel abrasion was employed, and a significant reduction of post-operative adhesion has been found in the group of PDLLA-PEG-PDLLA hydrogel-treated, compared with untreated control group and commercial hyaluronic acid (HA) anti-adhesion hydrogel group. As such, this PDLLA PEG-PDLLA hydrogel might be a promising candidate of injectable biomaterial for medical applications. PMID- 26752011 TI - Molecular Engineering of Thiazole Orange Dye: Change of Fluorescent Signaling from Universal to Specific upon Binding with Nucleic Acids in Bioassay. AB - The universal fluorescent staining property of thiazole orange (TO) dye was adapted in order to be specific for G-quadruplex DNA structures, through the introduction of a styrene-like substituent at the ortho-position of the TO scaffold. This extraordinary outcome was determined from experimental studies and further explored through molecular docking studies. The molecular docking studies help understand how such a small substituent leads to remarkable fluorescent signal discrimination between G-quadruplex DNA and other types of nucleic acids. The results reveal that the modified dyes bind to the G-quadruplex or duplex DNA in a similar fashion as TO, but exhibit either enhanced or quenched fluorescent signal, which is determined by the spatial length and orientation of the substituent and has never been known. The new fluorescent dye modified with a p (dimethylamino)styryl substituent offers 10-fold more selectivity toward telomeric G-quadruplexes than double-stranded DNA substrates. In addition, native PAGE experiments, FRET, CD analysis, and live cell imaging were also studied and demonstrated the potential applications of this class of thiazole-orange-based fluorescent probes in bioassays and cell imaging. PMID- 26752014 TI - Selecting CO2 Sources for CO2 Utilization by Environmental-Merit-Order Curves. AB - Capture and utilization of CO2 as alternative carbon feedstock for fuels, chemicals, and materials aims at reducing greenhouse gas emissions and fossil resource use. For capture of CO2, a large variety of CO2 sources exists. Since they emit much more CO2 than the expected demand for CO2 utilization, the environmentally most favorable CO2 sources should be selected. For this purpose, we introduce the environmental-merit-order (EMO) curve to rank CO2 sources according to their environmental impacts over the available CO2 supply. To determine the environmental impacts of CO2 capture, compression and transport, we conducted a comprehensive literature study for the energy demands of CO2 supply, and constructed a database for CO2 sources in Europe. Mapping these CO2 sources reveals that CO2 transport distances are usually small. Thus, neglecting transport in a first step, we find that environmental impacts are minimized by capturing CO2 first from chemical plants and natural gas processing, then from paper mills, power plants, and iron and steel plants. In a second step, we computed regional EMO curves considering transport and country-specific impacts for energy supply. Building upon regional EMO curves, we identify favorable locations for CO2 utilization with lowest environmental impacts of CO2 supply, so called CO2 oases. PMID- 26752012 TI - A pilot study of orthopaedic resident self-assessment using a milestones' survey just prior to milestones implementation. AB - OBJECTIVE: To pilot test if Orthopaedic Surgery residents could self-assess their performance using newly created milestones, as defined by the Accreditation Council on Graduate Medical Education. METHODS: In June 2012, an email was sent to Program Directors and administrative coordinators of the 154 accredited Orthopaedic Surgery Programs, asking them to send their residents a link to an online survey. The survey was adapted from the Orthopaedic Surgery Milestone Project. Completed surveys were aggregated in an anonymous, confidential database. SAS 9.3 was used to perform the analyses. RESULTS: Responses from 71 residents were analyzed. First and second year residents indicated through self assessment that they had substantially achieved Level 1 and Level 2 milestones. Third year residents reported they had substantially achieved 30/41, and fourth year residents, all Level 3 milestones. Fifth year, graduating residents, reported they had substantially achieved 17 Level 4 milestones, and were extremely close on another 15. No milestone was rated at Level 5, the maximum possible. Earlier in training, Patient Care and Medical Knowledge milestones were rated lower than the milestones reflecting the other four competencies of Practice Based Learning and Improvement, Systems Based Practice, Professionalism, and Interpersonal Communication. The gap was closed by the fourth year. CONCLUSIONS: Residents were able to successfully self-assess using the 41 Orthopaedic Surgery milestones. Respondents' rate improved proficiency over time. Graduating residents report they have substantially, or close to substantially, achieved all Level 4 milestones. Milestone self-assessment may be a useful tool as one component of a program's overall performance assessment strategy. PMID- 26752013 TI - Spectroscopic Method for Fast and Accurate Group A Streptococcus Bacteria Detection. AB - Rapid and accurate detection of pathogens is paramount to human health. Spectroscopic techniques have been shown to be viable methods for detecting various pathogens. Enhanced methods of Raman spectroscopy can discriminate unique bacterial signatures; however, many of these require precise conditions and do not have in vivo replicability. Common biological detection methods such as rapid antigen detection tests have high specificity but do not have high sensitivity. Here we developed a new method of bacteria detection that is both highly specific and highly sensitive by combining the specificity of antibody staining and the sensitivity of spectroscopic characterization. Bacteria samples, treated with a fluorescent antibody complex specific to Streptococcus pyogenes, were volumetrically normalized according to their Raman bacterial signal intensity and characterized for fluorescence, eliciting a positive result for samples containing Streptococcus pyogenes and a negative result for those without. The normalized fluorescence intensity of the Streptococcus pyogenes gave a signal that is up to 16.4 times higher than that of other bacteria samples for bacteria stained in solution and up to 12.7 times higher in solid state. This method can be very easily replicated for other bacteria species using suitable antibody-dye complexes. In addition, this method shows viability for in vivo detection as it requires minute amounts of bacteria, low laser excitation power, and short integration times in order to achieve high signal. PMID- 26752015 TI - Validity of the youth assessment and screening instrument: A juvenile justice tool incorporating risks, needs, and strengths. AB - The primary purpose of this study is to introduce the Youth Assessment and Screening Instrument (YASI; Orbis Partners, 2000), which is a comprehensive assessment protocol gauging a range of risks, needs, and strengths associated with criminal conduct in juvenile populations. Applied to a sample of 464 juvenile offenders bound by community supervision in Alberta, Canada, the Pre Screen version of the instrument achieved a high level of accuracy in predicting both general and violent offenses over an 18-month follow-up period (Area Under the Curve [AUC] = .79). No significant differences in overall predictive validity were found across demographic groups, save for the relatively lower level of accuracy achieved in predicting general reoffending across the subsample of girls (AUC = .68). With regard to strengths, a buffering effect was identified whereby high-risk cases with higher levels of strength had superior outcomes compared to their lower strength counterparts. Results suggest that it is advisable to consider the quantitative inclusion of strength-based items in the assessment of juvenile risk. PMID- 26752016 TI - Hydrogel Inverse Replicas of Breath Figures Exhibit Superoleophobicity Due to Patterned Surface Roughness. AB - The wetting behavior of a surface depends on both its surface chemistry and the characteristics of surface morphology and topography. Adding structure to a flat hydrophobic or oleophobic surface increases the effective contact angle and thus the hydrophobicity or oleophobicity of the surface, as exemplified by the lotus leaf analogy. We describe a simple strategy to introduce micropatterned roughness on surfaces of soft materials, utilizing the template of hexagonally packed pores of breath figures as molds. The generated inverse replicas represent micron scale patterned beadlike protrusions on hydrogel surfaces. This added roughness imparts superoleophobic properties (contact angle of the order of 150 degrees and greater) to an inherently oleophobic flat hydrogel surface, when submerged. The introduced pattern on the hydrogel surface changes morphology as it swells in water to resemble morphologies remarkably analogous to the compound eye. Analysis of the wetting behavior using the Cassie-Baxter approximation leads to estimation of the contact angle in the superoleophobic regime and in agreement with the experimental value. PMID- 26752017 TI - Heterogeneous Fenton oxidation of ofloxacin drug by iron alginate support. AB - A new catalytic wet peroxide oxidation of ofloxacin antibiotic is presented in this work. The removal was achieved using a biodegradable sodium alginate-iron material. Several parameters were studied such as iron content, drying duration of the catalytic support, temperature, solid amount and initial drug concentration. The process showed a strong oxidative ability; at optimum conditions, a nearly complete removal of the drug (around 98%) has been reached after three h of treatment. A relatively low decrease of support activity (around 10%) has been observed after three successive oxidation runs and a low iron leaching has been detected (1.2% of the incorporated quantity). The removal of the substrate has been also examined in the absence of hydrogen peroxide in order to discriminate between the contributions of simple adsorption and oxidation processes in the drug disappearance. We also discussed the influence of the studied experimental parameters on the removal kinetic. PMID- 26752018 TI - Relationship Between Mandibular Ramus Height and Masticatory Muscle Function in Patients With Unilateral Hemifacial Microsomia. AB - OBJECTIVE: To clarify the relationship between mandibular ramus height and function of masticatory muscles in patients with hemifacial microsomia. DESIGN: Retrospective study of imaging and physiological data. SETTING: Images and physiological data were obtained from the records of Sapporo Medical University Hospital. PATIENTS: A total of 29 patients with hemifacial microsomia who showed Pruzansky grades I, II deformity. MAIN OUTCOME MEASURES: Mandibular ramus height and masticatory muscle volume were evaluated with multi-detector row computed tomography. The electromyographic value was measured by the K7 Evaluation System. The hemifacial microsomia patients were classified into three groups based on the mandibular ramus height ratio of the affected and unaffected sides: group 0, >1.00; group 1, 1.00 to 0.85; group 2, <0.85. The Tukey-Kramer method and Games Howell method were used to determine correlations between parameters. RESULTS: Decreased mandibular ramus height was significantly correlated with both reduced electromyographic values of the masseter muscle (P < .05) and the amount of mandibular lateral deviation at the time of maximum opening (P < .05) on the affected side. These differences were prominent in unilateral hemifacial microsomia patients classified as group 2. CONCLUSIONS: Decreased mandibular ramus height may cause dysfunction of the masseter muscles but not the temporal muscle on the affected side in patients with hemifacial microsomia. PMID- 26752019 TI - Exploring the Teaching Motivations, Satisfaction, and Challenges of Veterinary Preceptors: A Qualitative Study. AB - Optimization of clinical veterinary education requires an understanding of what compels veterinary preceptors in their role as clinical educators, what satisfaction they receive from the teaching experience, and what struggles they encounter while supervising students in private practice. We explored veterinary preceptors' teaching motivations, enjoyment, and challenges by undertaking a thematic content analysis of 97 questionnaires and 17 semi-structured telephone interviews. Preceptor motivations included intrinsic factors (obligation to the profession, maintenance of competence, satisfaction) and extrinsic factors (promotion of the veterinary field, recruitment). Veterinarians enjoyed observing the learner (motivation and enthusiasm, skill development) and engaging with the learner (sharing their passion for the profession, developing professional relationships). Challenges for veterinary preceptors included variability in learner interest and engagement, time management, and lack of guidance from the veterinary medicine program. We found dynamic interactions among the teaching motivations, enjoyment, and challenges for preceptors. Our findings suggest that in order to sustain the veterinary preceptor, there is a need to recognize the interplay between the incentives and disincentives for teaching, to foster the motivations and enjoyment for teaching, and to mitigate the challenges of teaching in community private practice. PMID- 26752020 TI - Teaching Veterinary Histopathology: A Comparison of Microscopy and Digital Slides. AB - Virtual microscopy using digitized slides has become more widespread in teaching in recent years. There have been no direct comparisons of the use of virtual microscopy and the use of microscopes and glass slides. Third-year veterinary students from two different schools completed a simple objective test, covering aspects of histology and histopathology, before and after a practical class covering relevant material presented as either glass slides viewed with a microscope or as digital slides. There was an overall improvement in performance by students at both veterinary schools using both practical formats. Neither format was consistently better than the other, and neither school consistently outperformed the other. In a comparison of student appraisal of use of digital slides and microscopes, the digital technology was identified as having many advantages. PMID- 26752021 TI - Comparison of the Perceived Quality of Life between Medical and Veterinary Students in Tehran. AB - Medical and veterinary professional programs are demanding and may have an impact on a student's quality of life (QOL). The aim of this study was to compare the perceived QOL of these two groups. In this study, we used the SF-36 questionnaire in which higher scores mean a better perceived QOL. Only the students in the internship phase of their program were selected so that we could compare the two groups in a similar way. In total, 308 valid questionnaires were gathered. Apart from age and body mass index (BMI), the two groups were demographically similar. The scores of five domains (physical activity limitation due to health problems, usual role limitation due to emotional problems, vitality, general mental health, and general health perception) and also the total score were statistically higher in medical students. Only the score of one domain (social activity limitation due to physical or emotional problems) was statistically higher in veterinary students. BMI, physical activity limitation due to health problems, and vitality lost their significance after binomial logistic regression. We found that, in general, veterinary students have lower scores for the perceived QOL with social function being the only exception. It can be assumed that in medical students, interaction with human patients may have a negative impact in the score of this domain. Even though medical students have shown lower perceived QOL than the general population in previous studies, veterinary students appear to have slightly lower perceived QOL than medical students. PMID- 26752022 TI - Comparison between Training Models to Teach Veterinary Medical Students Basic Laparoscopic Surgery Skills. AB - The objective of this study was to compare the effectiveness of two different laparoscopic training models in preparing veterinary students to perform basic laparoscopic skills. Sixteen first- and second-year veterinary students were randomly assigned to a box trainer (Group B) or tablet trainer (Group T). Training and assessment for both groups included two tasks, "peg transfer" and "pattern cutting," derived from the well-validated McGill University Inanimate System for Training and Evaluation of Laparoscopic Skills. Confidence levels were compared by evaluating pre- and post-training questionnaires. Performance of laparoscopic tasks was scored pre- and post-training using a rubric for precision and speed. Results revealed a significant improvement in student confidence for basic laparoscopic skills (p<.05) and significantly higher scores for both groups in both laparoscopic tasks (p<.05). No significant differences were found between the groups regarding their assessment of the video quality, lighting, and simplicity of setup (p=.34, p=.15, and p=.43, respectively). In conclusion, the low-cost tablet trainer and the more expensive box trainer were similarly effective in preparing pre-clinical veterinary students to perform basic laparoscopic skills on a model. PMID- 26752024 TI - Early COPD Exacerbation Treatment with Combination of ICS and LABA for Patients Presenting with Mild-to-Moderate Worsening of Dyspnea. AB - This is a proof of concept study that aims to establish feasibility and safety of a new strategy that includes an action plan for early treatment of acute exacerbations of COPD (AECOPD) with doubling dose of a combination of a long acting beta2 agonist and an inhaled corticosteroid, and to explore its potential for avoiding the requirement of prednisone and its safety. Thirty-seven COPD outpatients with previous exacerbations were enrolled and followed-up for 12 months. The written action plan included a standing prescription to be used in the event of an AECOPD: Antibiotic, for 5 days (for purulent exacerbations) and doubling a combination of Salmeterol and Fluticasone Propionate for 10 days. The primary outcome was "treatment success" defined as "no need of prednisone within 30 days of the onset." Twenty-seven patients experienced an AECOPD and doubled their combination dose. Among the 27 patients, there were 21 patients (78%) who did not require prednisone, and none of those had cardiovascular events, pneumonia, ER and hospital admissions. We have assessed that an early treatment of AECOPD with doubling the dose of a combination of Salmeterol and Fluticasone Propionate appears to be safe, well-tolerated and adhered to, and results in no requirement of systemic corticosteroid in a large proportion of patients presenting with mild-to-moderate worsening of dyspnea. This trial has the potential to change the approach of treatment of AECOPD and reduce the use of oral corticosteroids. PMID- 26752025 TI - New combinations in Neotropical Thelypteridaceae. AB - 288 new combinations of Neotropical Thelypteridaceae taxa are proposed in order to recognize monophyletic genera, based on the results of the most recent molecular phylogeny of the family, as well as the morphological uniformity of characters for each genus. The new nomenclatural combinations correspond to 186 Amauropelta taxa, 77 species of Goniopteris, and 25 Steiropteris taxa. A key to all native Neotropical genera of the family is also presented. PMID- 26752026 TI - Corrigendum: Characterizing noise structure in single-cell RNA-seq distinguishes genuine from technical stochastic allelic expression. PMID- 26752023 TI - Induction of mucosal immunity through systemic immunization: Phantom or reality? AB - Generation of protective immunity at mucosal surfaces can greatly assist the host defense against pathogens which either cause disease at the mucosal epithelial barriers or enter the host through these surfaces. Although mucosal routes of immunization, such as intranasal and oral, are being intensely explored and appear promising for eliciting protective mucosal immunity in mammals, their application in clinical practice has been limited due to technical and safety related challenges. Most of the currently approved human vaccines are administered via systemic (such as intramuscular and subcutaneous) routes. Whereas these routes are acknowledged as being capable to elicit antigen-specific systemic humoral and cell-mediated immune responses, they are generally perceived as incapable of generating IgA responses or protective mucosal immunity. Nevertheless, currently licensed systemic vaccines do provide effective protection against mucosal pathogens such as influenza viruses and Streptococcus pneumoniae. However, whether systemic immunization induces protective mucosal immunity remains a controversial topic. Here we reviewed the current literature and discussed the potential of systemic routes of immunization for the induction of mucosal immunity. PMID- 26752027 TI - [Social determinants, health and public health policies: mobilization of all forms of knowledge]. PMID- 26752028 TI - [Free prescription practices at Ville-Evrard psychiatric hospital]. AB - Free access to medicines is an important element in the implementation of health care access policies. Paradoxically, this aspect is rarely addressed in the literature on this subject. The Ville-Evrard psychiatric hospital introduced so called "poverty prescriptions" allowing free drug dispensing, independently of specific PASS (Permanent Access to Health_ Care) systems. This paper presents the results of a study of all poverty prescriptions issued by the facility in 2011./t provides an analytical description of this system and shows that, despite the absence of strict controls, it was used relatively rarely. PMID- 26752029 TI - [Community-based screening: a motivating experience for drug users]. AB - OBJECTIVES: Hepatitis C virus infection (HCV) is a major public health problem among drug users. Screening for hepatitis C virus in this population is complicated. The aim of the study was to describe a community-based screening experience conducted by the Tours university hospital addiction medicine team. METHODS: Between 2008 and 2010, a free 14-day HCV, hepatitis B virus (HBV) and HIV community-based screening programme was conducted by the addiction medicine and prevention team. A questionnaire collected the main risk factors for transmission of these viruses and the subject's viral serology status. RESULTS: 76% of the 219 screened subjects reported being drug users. HCV prevalence was 20%. Risk factors for HCV infection were exclusive intravenous use and the use of several routes of administration. Among the 30 HCV patients with positive RNA, 83% were followed up. CONCLUSIONS: The prevalence of HCV infection was similar to that reported in the literature for drug users, whereas the number of patients treated and followed up was higher than in the literature. A community-based screening experience facilitated initiation and follow-up of medical care. PMID- 26752030 TI - [Determinants of the intention to abstain from or reduce alcohol, tobacco or cannabis use among 15-25 year-olds]. AB - OBJECTIVE: This study was designed to identify the sociodemographic and psychosocial factors (based on the theory of planned behaviour) associated with the intentions of young people to remain non-smokers and refrain from experimental cannabis use, and their intentions to reduce drinking during a party, quit smoking and reduce cannabis use among users. METHODS: 3,652 young people aged 15 to 25 years were interviewed by means of an on-line questionnaire. The sample was recruited from an internet access panel and constructed according to the quota method applied to the following variables: gender, age, region, habitat and head of family occupation. RESULTS: Each of the psychosocial determinants {attitudes, norms and control) helped to explain the subject's intention not to smoke and/or use cannabis. The presence of a prohibition norm in the family was also associated with a decreased intention to experiment with cannabis. Among substance users, attitude determined the intention to quit or reduce the use of the three substances {tobacco, alcohol and cannabis) and control was involved in the intention to reduce drinking and quit smoking. Finally, norms only influenced the intention to reduce drinking during parties. CONCLUSION: This study demonstrates the importance of considering psychosocial factors to explain health behaviours and to identify and propose interventions. These results support the priority given to smoking prevention, justify the value of early interventions and confirm the importance of considering social inequalities in health when developing prevention programmes. PMID- 26752031 TI - [Reflections on the evaluation and funding of complex public health interventions]. AB - In France, in a context of growing health inequalities, the need for action on life settings and, more broadly, on the social determinants of health (SDH), requires a contribution from health promotion research. Today's challenge is not only to design interventions tailored to contexts and actively targeting SDH, but also to develop innovative evaluation strategies of these complex interventions. A group of researchers and representatives from funding agencies met in Paris on june 2nd, 2014 to discuss current experiences conducted in France. The debates yielded five conclusions: (i) the context of the intervention must be considered as one of its active ingredients, (ii) evaluation must be guided by a sound intervention logic (iii) randomized controlled trials cannot capture the complexity of the environment and evaluation must be designed using alternative models, including process evaluation, (iv) interventional research should be collaborative, or co-constructed, (v) public health training should cover the diversity of evaluative methods. The conclusions described here, in the context of France, stress that to address these challenges, funding agencies, researchers and stakeholders should further engage in discussions concerning the conduct of interventional research, evaluation and implementation of complex public health interventions. PMID- 26752032 TI - [ASC-US Pap Smear follow-up in a French department in 2077]. AB - AIM: In the event of an ASC-US Pap smear, colposcopy, 6-month Pap smear or screening for oncogenic HPV are recommended as first-line testing options by the French National Authority for Health -HAS. The primary objective of this study was to determine the preferred option chosen by general practitioners and to assess their follow-up care. METHODS: The Maine-et-Loire cancer screening database was used to extract 283 files of women, aged 25 to 65, in whom ASC-US Pap smear was performed by their general practitioners (GPs) in 2011. RESULTS: 265 women (93.6%) underwent their first test (C1]. GPs performed 64.5% of tests: 93% of which were Pap smears, 5.3% were HPV tests and 1.7% were Pap smears combined with HPV tests. 164 patients (58%) received comprehensive follow-up, i.e 2 tests after the first ASC-US pap smear or a therapeutic intervention after an abnormal Cl. 14 patients were lost to follow-up. Follow-up rate was 57.6% in the case of a normal C1 and 83.3% in the case of an abnormal C1. 79.2% of first tests were normal and a total of 16 high-grade lesions were diagnosed (5.7%). CONCLUSION: The fact that liquid-based Pap smears were rarely used might explain why HPV testing is rarely prescribed. The rarity of ASC-US anomalies, the variable potential for progression and the possibility to choose between several follow-up options proved to be obstacles for GPs to apply guidelines. The poor coordination . between gynaecologists and GPs, the difficulties in planning follow-up and the lack of precision of test reports may limit the efficacy of monitoring. PMID- 26752033 TI - [Personalized medicine in radiotherapy: practitioners' perception]. AB - This exploratory study was designed to investigate the representations of radiotherapists in relation to personalized medicine. On the basis of current?>' available radiotherapy predictive tests, we tried to understand how these tests could be used in routine radiotherapy practice and in what way this possible change of practices could affect the role of radiotherapists in treatment protocols. In the absence of any available data allowing the construction of a quantitative tool, qualitative data were recorded by individual interviews with radiotherapists. Based on textual data analysis, a second national quantitative phase was conducted using a self-administered questionnaire. Crossover analysis of the two datasets highlighted the interest of radiotherapists in personalized medicine and the use of predictive tests, while indicating certain limitations and concerns in relation to ethical issues related to personalized medicine in oncology and the physician's position. PMID- 26752034 TI - [Difficulties in the management of precarious patients and precarious migrants]. AB - CONTEXT: General practitioners encounter difficulties in the management of patients in precarious situations. In order to identify and understand these difficulties, a survey combining both quantitative et qualitative approaches was conducted among general practitioners of the Meurthe-et-Moselle department. METHODS: Quantitative data were collected by self-administered questionnaires sent to all 856 general practitioners and 28 general practitioners grouped by geographic sector participated in 6 focus groups. RESULTS: Among the 46.5% of respondents, 92.5% doctors declared that they encountered difficulties in the management of precarious patients. 87.5% declared that they had an average or insufficient knowledge of the existing medical social organizations on their territory and two-thirds were interested in specific training. Analysis of the interviews showed that experience facilitates multidisciplinary networking, a good relationship with patients and ultimately their monitoring. Financial access to care is a major obstacle, which doctors consider to be a political issue. Ideas for improvement were proposed in response to the obstacles related to the characteristics of the medical consultation itself. Confirming the results of the questionnaire survey, training appeared to be essential to identify vulnerability and facilitate the doctor-patient relationship. CONCLUSION: We showed that the difficulties experienced by physicians contributes to socio-cultural inequalities in access to health care. Patient support, an enhanced self image and social ties were identified as major determinants of access to health. The development of training of physicians and multidisciplinary structures should be encouraged. PMID- 26752035 TI - [Haute Autorite de sante opinion on cost-effectiveness of health products : results and perspectives]. AB - Since 3rd October 2013 in France, drug companies applying for reimbursement of an innovative and expensive drug or medical device are required to provide the French National Authority for Health (HAS) with a cost-effectiveness assessment of their product. After a methodological audit of the economic evaluation submitted by the drug company, the Health Economics and Public Health Committee (CEESP) issues an opinion on the expected or observed cost-effectiveness. This opinion is sent to the Pricing Committee (CEPS) which determines the price of the product. After summarizing the French reimburse'!lent and pricing system, the objective of this article is to review the first 22 months of activity, in which HAS issued 30 cost-effectiveness opinions. The process, based on exchanges between drug companies and HAS, allowed the pricing committee to document the economic criterion in the majority of applications, while characterizing the degree of uncertainty of the results. For ten applications, major methodological concerns led the CEESP to reject the drug company's assessment. PMID- 26752036 TI - [Systematic review of hospital discharge summaries and general practitioners' wishes]. AB - BACKGROUND: Communication between general practitioners (GPs) and hospitals is one of the weak points of our health system. Unfortunately, hospital discharge summaries, the cornerstone of this communication, tend to be poorly defined. The purpose of this study was to identify the key elements of hospital discharges ummaries, with particular attention to GP expectations. METHOD: A systematic review of the international literature was conducted by searching Cochrane, Medline, Systeme universitaire de documentation (SUDoc) and Banque de donnees en sante publique (BDSP) databases as well as the French journals La Revue du Praticien, Prescrire and Exercer. RESULTS: This database and journal review identified 10,551 publications, 38 of which were finally included in this analysis. The preferred maximum time to reception of the discharge summary was one week. This summary should not exceed four half pages. The desired content did not differ between GPs and hospital practitioners. GPs expressed the desire for a brief liaison letter given to the patient at the time of discharge. GPs expected the discharge summary to contain the reason for admission, treatment on discharge, the main diagnosis and subsequent management. A standardized and structured form was preferred, but a narrative form was not recommended. Special attention had to be paid to treatment on discharge and outstanding results at the time of discharge. CONCLUSION: The elements identified from the literature will be used as a basis for a subsequent study designed to formalize discharge summaries for GPs. PMID- 26752037 TI - [Effect of reproductive health services restructuring on antenatal care at Marcory General Hospital, Ivory Coast]. AB - INTRODUCTION: Improvement of the work environment and staff training are health promotion strategies that can contribute to improving the supply of health care. This study evaluated the effects of reorganization of health services on antenatal care (ANC) activities. MATERIALS AND METHODS: A cross-sectional study was conducted over a period of 4 months in the ANC unit of Marcory General Hospital in Abidjan. The study population was health workers in charge of ANC and pregnant women attending the health facility. Self-administered questionnaires and observation sheets were used to collect data that were analysed with Epi Info 3.5.1 software. results: After reorganization, health workers said they were satisfied with the work environment and the care provided in 91% and 96.9% of cases, respectively. These results were confirmed by all pregnant respondents (100%) attending the centre, who said they were satisfied with the quality of care received. This could explain the ANC 4 coverage rate, which increased from 39.4% in 2010 to 56.7% in 2012 and tetanus vaccination coverage which increased from 59.4% to 87.5%, although the waiting time was still too long. CONCLUSION: This study showed an increase of ANC activity indicators, such as ANC 4 and tetanus vaccination coverage rate, after reorganization of health care services. This strategy could be an opportunity to strengthen ANC services. PMID- 26752038 TI - [Sociodemographic factors associated with incomplete immunization or children aged 12 to 59 months in six West African countries]. AB - INTRODUCTION: Every year, thousands of children in the world remain unimmunized or partially immunized, especially in developing countries. It therefore appears important to examine sociodemographic factors associated with incomplete immunization of children in West Africa. METHODS: This cross-sectional study examined factors associated with incomplete immunization of children aged 12 to 59 months in Cote d'Ivoire, Ghana, Burkina Faso, Mali, Guinea, and Liberia based on Demographic and Health Survey data. RESULTS: The findings of the study showed that birth at home, mothers with no access to media, no religion, poverty, and illiteracy were associated with incomplete immunization of children. DISCUSSION: Health officials should take these immunization status predictors into account when developing policies and immunization strategies in countries included in this study in order to achieve immunization coverage targets. PMID- 26752039 TI - [Pornography and sexual behaviour of schoolchildren in the Cocodydistrict of Abidjan]. AB - OBJECTIVE: The objective of this study was to document the influence of pornography on the sexual behaviour of school children in the Cocody district of Abidjan, Cote d'Ivoire. METHOD: This cross-sectional, descriptive and analytical study was conducted from October to November 2013 with pupils from four schools in Cocody, Abidjan. RESULTS: A total of 398 pupils (224 boys and 174 girls) were interviewed: 14.3% of them had access to pornography on internet or television. 52.8% (210) of the 398 pupils interviewed were sexually active at the time of the survey, 41.9% (88/210) of whom had at least two sexual partners. On bivariate analysis,access to pornography was statistically associated with being sexually active (OR= 2.61; 95%CI [1.41; 4.83]), early onset of sexual intercourse (OR= 2.38; 95%CI = [1.19; 4.76]) and multiples exual partners (OR== 6.09; 95%CI= [2.79; 13.3])Conclusion: The results of this study demonstrate that access to pornography had a negative influence on the sexual behaviour of school children in Abidjan (Cote d'Ivoire]. PMID- 26752040 TI - [Satisfaction of AIDS patients managed in Dafra district hospital: an overview]. AB - INTRODUCTION: Assessment of patient satisfaction is an essential tool for continuing improvement of health services. OBJECTIVE: In order to more clearly define what has been achieved and what remains to be achieved, from the patient's perspective, the level of satisfaction of AIDS patients managed at Dafra district hospital was assessed. METHODS: This cross-sectional study was based on data from Individual interviews conducted with patients on ARV therapy forat least six months on 1st April2014. Erin's multiattribute modelwas used to identify the content of the data collection. RESULTS: Patients were relatively satisfied with the comfort and the fact that some of their expectations were taken into account, such as nutritional support,free drug prescriptions and measurement of body temperature and blood pressure. However, they expressed complaints concerning the promptness of services, the courtesy of healthcare providers, confidentiality and questioned the skills ofhealthcare providers. CONCLUSION: The provision of good quality health care for AIDS patients in the Dafra health district requires permanent review of healthcare provider practices. Improvements are needed in terms of promptness of services, courtesy and confidentiality. Health care teams must take the sociocultural background of healthcare providers into account in order to develop, test and evaluate appropriate solutions. PMID- 26752041 TI - [Vulnerability of male prisoners to HIV /AIDS in Ouagadougou/ Burkina Faso]. AB - OBJECTIVE: To evaluate the vulnerability of male prisoners to HIV, risk behaviour and access to prevention. METHODS: This cross-sectional descriptive study was conducted in july and August 2012 in Ouagadougou Prison in Burkina Faso. Two trained investigators collected data by means of individual interviews in the prison visiting room using a questionnaire administered to male inmates 18 years and older, imprisoned for more than three months. Two focus groups were conducted with prison guards and healthcare personnel. RESULTS: A total of165 male prisoners were interviewed. The mean prison sentence was 19 months, the median age of the inmates was 28years and 45% of them were illiterate. About4% of male prisoners reported having had homosexual relations during their imprisonment. However, data indicate underreporting and denial of homosexual behaviour by prisoners. 49% of prisoners shared razors or razorblades in prison. None of the interviewees reported injected drug use or tattoos in prison. The majority (84%) of prisoners had a good knowledge of HIVjAIDS and 6% were aware of the risk of sexually transmitted infections. Only 5% of prisoners had had a screening test during their stay in prison. CONCLUSION: Prison conditions, homosexual behaviour and absence of condoms in prison accentuate the vulnerability of prisoners to HIV j AIDS. Implementation of a prevention programme and management HIV-positive prisoners would help to reduce significantly the risk of HIV transmission in prison. PMID- 26752043 TI - Enhancing pyridinic nitrogen level in graphene to promote electrocatalytic activity for oxygen reduction reaction. AB - We develop an efficient approach to fabricate nitrogen-doped graphene with tunable pyridinic nitrogen levels (from 1.1 to 1.8 at.%), abundant in-plane holes and high surface areas (623 m(2) g(-1)) via a hydrothermal treatment of graphene oxide with hydrogen peroxide and subsequent annealing under ammonia gas. It is found that the chemical etching is beneficial to the formation of pyridinic nitrogen in graphene during the nitrogen-doping process, which is crucial to enhancing the electrocatalytic properties of graphene for oxygen reduction reaction (ORR). Hence, the optimized NG exhibits good electrocatalytic activity, more positive onset potential than Pt-C (-0.08 V versus -0.09 V), good durability, and high selectivity when it is employed as a metal-free catalyst for ORR. This approach may uncover a mechanism in escalation of pyridinic N atoms doped on the graphene basal edge and provide an efficient platform for the synthesis of a series of heteroatom-doped graphene with tunable heteroatom content for broad applications. PMID- 26752044 TI - Low adherent cancer cell subpopulations are enriched in tumorigenic and metastatic epithelial-to-mesenchymal transition-induced cancer stem-like cells. AB - Cancer stem cells are responsible for tumor progression, metastasis, therapy resistance and cancer recurrence, doing their identification and isolation of special relevance. Here we show that low adherent breast and colon cancer cells subpopulations have stem-like properties. Our results demonstrate that trypsin sensitive (TS) breast and colon cancer cells subpopulations show increased ALDH activity, higher ability to exclude Hoechst 33342, enlarged proportion of cells with a cancer stem-like cell phenotype and are enriched in sphere- and colony forming cells in vitro. Further studies in MDA-MB-231 breast cancer cells reveal that TS subpopulation expresses higher levels of SLUG, SNAIL, VIMENTIN and N CADHERIN while show a lack of expression of E-CADHERIN and CLAUDIN, being this profile characteristic of the epithelial-to-mesenchymal transition (EMT). The TS subpopulation shows CXCL10, BMI-1 and OCT4 upregulation, differing also in the expression of several miRNAs involved in EMT and/or cell self-renewal such as miR 34a-5p, miR-34c-5p, miR-21-5p, miR-93-5p and miR-100-5p. Furthermore, in vivo studies in immunocompromised mice demonstrate that MDA-MB-231 TS cells form more and bigger xenograft tumors with shorter latency and have higher metastatic potential. In conclusion, this work presents a new, non-aggressive, easy, inexpensive and reproducible methodology to isolate prospectively cancer stem like cells for subsequent biological and preclinical studies. PMID- 26752045 TI - Formation of Mitochondrial Outer Membrane Derived Protrusions and Vesicles in Arabidopsis thaliana. AB - Mitochondria are dynamic organelles that have inner and outer membranes. In plants, the inner membrane has been well studied but relatively little is known about the outer membrane. Here we report that Arabidopsis cells have mitochondrial outer membrane-derived structures, some of which protrude from the main body of mitochondria (mitochondrial outer-membrane protrusions; MOPs), while others form vesicle-like structures without a matrix marker. The latter vesicle like structures are similar to some mammalian MDVs (mitochondrial-derived vesicles). Live imaging demonstrated that a plant MDV budded off from the tip of a MOP. MDVs were also observed in the drp3a drp3b double mutant, indicating that they could be formed without the mitochondrial fission factors DRP3A and DRP3B. Double staining studies showed that the MDVs were not peroxisomes, endosomes, Golgi apparatus or trans-Golgi network (TGN). The numbers of MDVs and MOPs increased in senescent leaves and after dark treatment. Together, these results suggest that MDVs and MOPs are related to leaf senescence. PMID- 26752046 TI - Which Aspects of Stroke Do Animal Models Capture? A Multitracer Micro-PET Study of Focal Ischemia with Endothelin-1. AB - BACKGROUND: Cortical injections of the vasoconstrictor endothelin-1 (ET1) have widely been used to induce focal circumscribed ischemic lesions in the motor cortex of rodents in the context of stroke recovery studies. In order to apply this model correctly, it is essential to understand the time course of regional flow changes and of the development of penumbra and infarction. METHODS: Multitracer micro-PET of ET1 focal ischemia in rats was performed using [11C] flumazenil ([11C]FMZ) as a flow- and viability tracer and [18F] fluoromisonidazole ([18F]FMISO) as hypoxia marker in order to characterize the physiological time-course of this model. Nine adult Sprague-Dawley rats received stereotaxic injections of ET1 into the right primary motor cortex, 3 served as controls. PET imaging was started 2, 3 and 20 h after the last ET1 injection. Histology was obtained at the end of the scans. Standardized uptake value ratios reflecting cerebral blood flow (CBF), [11C]FMZ-binding and [18F]FMISO-retention were calculated for the region of hypoperfusion and the normoperfused cortex. RESULTS: CBF in the hypoperfused cortex was significantly reduced (p < 0.01) at 5 h (0.58 +/- 0.025), 6 h (0.54 +/- 0.043) and 23 h (0.66 +/- 0.024) compared to controls (1.00 +/- 0.011) and moderately reduced (p < 0.05) in the remainder of the affected hemisphere at 5 h (0.93 +/- 0.036). [11C]FMZ-binding was within the control range at all time points. Significant [18F]FMISO-retention (1.16 +/- 0.091, p < 0.05) was observed only after 6 h in the ischemic core that later turned into infarct. CONCLUSION: ET1 injections yield reproducible, slowly developing ischemic lesions with constant levels of hypoperfusion. This multitracer micro-PET study suggests that the ET1 model is appropriate for inducing chronic circumscribed ischemic lesions but seems to be less suited for studying acute stroke pathophysiology. PMID- 26752048 TI - Semaphorin 7A Aggravates Pulmonary Inflammation during Lung Injury. AB - The extent of pulmonary inflammation during lung injury ultimately determines patient outcome. Pulmonary inflammation is initiated by the migration of neutrophils into the alveolar space. Recent work has demonstrated that the guidance protein semaphorin 7A (SEMA7A) influences the migration of neutrophils into hypoxic tissue sites, yet, its role during lung injury is not well understood. Here, we report that the expression of SEMA7A is induced in vitro through pro-inflammatory cytokines. SEMA7A itself induces the production of pro inflammatory cytokines in endothelial and epithelial cells, enhancing pulmonary inflammation. The induction of SEMA7A facilitates the transendothelial migration of neutrophils. In vivo, animals with deletion of SEMA7A expression showed reduced signs of pulmonary inflammatory changes following lipopolysaccharide challenge. We define here the role of SEMA7A in the development of lung injury and identify a potential pathway to interfere with these detrimental changes. Future anti-inflammatory strategies for the treatment of lung injury might be based on this finding. PMID- 26752047 TI - Rapamycin Inhibits Oxidized Low Density Lipoprotein Uptake in Human Umbilical Vein Endothelial Cells via mTOR/NF-kappaB/LOX-1 Pathway. AB - BACKGROUND: Lectin-like oxidized low-density lipoprotein-1 (LOX-1) is the major receptor for oxidized low density lipoprotein (ox-LDL) uptake in human umbilical vein endothelial cells (HUVECs). Previously, we found that rapamycin inhibited ox LDL accumulation in HUVECs, and this effect was related to its role in increasing the activity of autophagy-lysosome pathway. In this study, we determined whether rapamycin could also reduce ox-LDL uptake in HUVECs and investigated the underlying signaling mechanisms. RESULTS: Flow cytometry and live cell imaging showed that rapamycin reduced Dil-ox-LDL accumulation in HUVECs. Furthermore, rapamycin reduced the ox-LDL-induced increase in LOX-1 mRNA and protein levels. Western blotting showed that rapamycin inhibited mechanistic target of rapamycin (mTOR), p70s6k and IkappaBalpha phosphorylation triggered by ox-LDL. Flow cytometry implied that mTOR, NF-kappaB knockdown and NF-kappaB inhibitors significantly reduced Dil-ox-LDL uptake. Moreover, immunofluorescent staining showed that rapamycin reduced the accumulation of p65 in the nucleus after ox-LDL treatment for 30 h. mTOR knockdown decreased LOX-1 protein production and IkappaBalpha phosphorylation induced by ox-LDL. NF-kappaB knockdown and NF-kappaB inhibitors reduced LOX-1 protein production, but did not inhibit mTOR phosphorylation stimulated by ox-LDL. CONCLUSIONS: These findings demonstrate that rapamycin reduce mTOR phosphorylation and subsequently inhibit NF-kappaB activation and suppresses LOX-1, resulting in a reduction in ox-LDL uptake in HUVECs. PMID- 26752050 TI - Whole Blood Transcriptomics Is Relevant to Identify Molecular Changes in Response to Genetic Selection for Feed Efficiency and Nutritional Status in the Pig. AB - The molecular mechanisms underlying feed efficiency need to be better understood to improve animal efficiency, a research priority to support a competitive and sustainable livestock production. This study was undertaken to determine whether pig blood transcriptome was affected by differences in feed efficiency and by ingested nutrients. Growing pigs from two lines divergently selected for residual feed intake (RFI) and fed isoproteic and isocaloric diets contrasted in energy source and nutrients were considered. Between 74 and 132 days of age, pigs (n = 12 by diet and by line) received a regular diet rich in cereals and low in fat (LF) or a diet where cereals where partially substituted by lipids and fibers (HF). At the end of the feeding trial, the total number of white blood cells was not affected by the line or by the diet, whereas the red blood cell number was higher (P<0.001) in low RFI than in high RFI pigs. Analysis of the whole blood transcriptome using a porcine microarray reveals a higher number of probes differentially expressed (DE) between RFI lines than between diets (2,154 versus 92 probes DE, P<0.01). This corresponds to 528 overexpressed genes and 477 underexpressed genes in low RFI pigs compared with high RFI pigs, respectively. Overexpressed genes were predominantly associated with translational elongation. Underexpressed genes were mainly involved in the immune response, regulation of inflammatory response, anti-apoptosis process, and cell organization. These findings suggest that selection for RFI has affected the immune status and defense mechanisms of pigs. Genes DE between diets were mainly related to the immune system and lipid metabolism. Altogether, this study demonstrates the usefulness of the blood transcriptome to identify the main biological processes affected by genetic selection and feeding strategies. PMID- 26752049 TI - The Drosophila Helicase MLE Targets Hairpin Structures in Genomic Transcripts. AB - RNA hairpins are a common type of secondary structures that play a role in every aspect of RNA biochemistry including RNA editing, mRNA stability, localization and translation of transcripts, and in the activation of the RNA interference (RNAi) and microRNA (miRNA) pathways. Participation in these functions often requires restructuring the RNA molecules by the association of single-strand (ss) RNA-binding proteins or by the action of helicases. The Drosophila MLE helicase has long been identified as a member of the MSL complex responsible for dosage compensation. The complex includes one of two long non-coding RNAs and MLE was shown to remodel the roX RNA hairpin structures in order to initiate assembly of the complex. Here we report that this function of MLE may apply to the hairpins present in the primary RNA transcripts that generate the small molecules responsible for RNA interference. Using stocks from the Transgenic RNAi Project and the Vienna Drosophila Research Center, we show that MLE specifically targets hairpin RNAs at their site of transcription. The association of MLE at these sites is independent of sequence and chromosome location. We use two functional assays to test the biological relevance of this association and determine that MLE participates in the RNAi pathway. PMID- 26752051 TI - A New High-Throughput Approach to Genotype Ancient Human Gastrointestinal Parasites. AB - Human gastrointestinal parasites are good indicators for hygienic conditions and health status of past and present individuals and communities. While microscopic analysis of eggs in sediments of archeological sites often allows their taxonomic identification, this method is rarely effective at the species level, and requires both the survival of intact eggs and their proper identification. Genotyping via PCR-based approaches has the potential to achieve a precise species-level taxonomic determination. However, so far it has mostly been applied to individual eggs isolated from archeological samples. To increase the throughput and taxonomic accuracy, as well as reduce costs of genotyping methods, we adapted a PCR-based approach coupled with next-generation sequencing to perform precise taxonomic identification of parasitic helminths directly from archeological sediments. Our study of twenty-five 100 to 7,200 year-old archeological samples proved this to be a powerful, reliable and efficient approach for species determination even in the absence of preserved eggs, either as a stand-alone method or as a complement to microscopic studies. PMID- 26752053 TI - Abdominal Obesity and Insulin Resistance in People Exposed to Moderate-to-High Levels of Dioxin. AB - Obesity, a risk factor for developing metabolic complications, is a major public health problem. Abdominal obesity is strongly accompanied by a cluster of metabolic abnormalities characterized by insulin resistance. The link between persistent organic pollutants (POPs) and insulin resistance has been investigated in animal and epidemiological studies. We aimed to examine whether insulin resistance is greater in people with abdominal obesity (AO) and concomitant exposure to serum dioxins (PCDD/Fs). We conducted a cross-sectional descriptive study of 2876 participants living near a PCDD/Fs contaminated area. Seventeen 2,3,7,8-substituted PCDD/Fs congeners were measured, and then the associations between the main predictor variable, serum TEQDF-1998, abdominal obesity (AO), dependent variables, and insulin resistance were examined. Twelve of the 17 congeners, widely distributed among PCDDs, and PCDFs, had trends for associations with abdominal adiposity. In men, the highest quintiles of 1,2,3,7,8-PeCDF; 1,2,3,7,8-PeCDD; 2,3,7,8-TCDD; 2,3,7,8-TCDF; and 2,3,4,7,8-PeCDF had the top five adjusted odds ratios (AORs) + 95% confidence intervals (CIs):[4.2; 2.7-6.4], [3.6; 2.3-5.7], [3.2; 2.1-5.0], [3.0; 2.0-4.5], and [2.9; 1.9-4.7], respectively. In women, the highest quintiles of 1,2,3,4,7,8,9-HpCDF; 1,2,3,6,7,8-HxCDF; and 1,2,3,4,6,7,8-HpCDF had the top three AORs + 95% CIs:[3.0; 1.9-4.7], [2.0; 1.3 3.1], and [1.9; 1.3-2.9], respectively. After confounding factors had been adjusted for, men, but not women, with higher serum TEQDF-1998 levels or abdominal obesity had a significantly (Ptrend < 0.001) greater risk for abnormal insulin resistance. The groups with the highest joint serum TEQDF-1998 and abdominal obesity levels were associated with elevated insulin resistance at 5.0 times the odds of the groups with the lowest joint levels (AOR 5.23; 95% CI: 3.53 7.77). We hypothesize that serum TEQDF-1998 and abdominal obesity affect the association with insulin resistance in general populations. PMID- 26752052 TI - Chemiluminescence Imaging of Superoxide Anion Detects Beta-Cell Function and Mass. AB - Superoxide anion is produced during normal cellular respiration and plays key roles in cellular physiology with its dysregulation being associated with a variety of diseases. Superoxide anion is a short-lived molecule and, therefore, its homeostatic regulation and role in biology and disease requires dynamic quantification with fine temporal resolution. Here we validated coelenterazine as a reporter of intracellular superoxide anion concentration and used it as a dynamic measure both in vitro and in vivo. Chemiluminescence was dependent upon superoxide anion levels, including those produced during cellular respiration, and concentrations varied both kinetically and temporally in response to physiologically relevant fluctuations in glucose levels. In vivo imaging with coelenterazine revealed that beta cells of the pancreas have increased levels of superoxide anion, which acted as a measure of beta-cell function and mass and could predict the susceptibility of mice to diabetes mellitus. Glucose response and regulation are key elements of cellular physiology and organismal biology, and superoxide anion appears to play a fundamental and dynamic role in both of these processes. PMID- 26752054 TI - Aberrant Wound Healing in an Epidermal Interleukin-4 Transgenic Mouse Model of Atopic Dermatitis. AB - Wound healing in a pre-existing Th2-dominated skin milieu was assessed by using an epidermal specific interleukin-4 (IL-4) transgenic (Tg) mouse model, which develops a pruritic inflammatory skin condition resembling human atopic dermatitis. Our results demonstrated that IL-4 Tg mice had delayed wound closure and re-epithelialization even though these mice exhibited higher degrees of epithelial cell proliferation. Wounds in IL-4 Tg mice also showed a marked enhancement in expression of inflammatory cytokines/chemokines, elevated infiltration of inflammatory cells including neutrophils, macrophages, CD3+ lymphocytes, and epidermal dendritic T lymphocytes. In addition, these mice exhibited a significantly higher level of angiogenesis as compared to wild type mice. Furthermore, wounds in IL-4 Tg mice presented with larger amounts of granulation tissue, but had less expression and deposition of collagen. Taken together, an inflamed skin condition induced by IL-4 has a pronounced negative influence on the healing process. Understanding more about the pathogenesis of wound healing in a Th2- dominated environment may help investigators explore new potential therapeutic strategies. PMID- 26752058 TI - Return to Work and Normal Daily Life Activity after Open and Robot-Assisted Radical Prostatectomy--A Single Surgeon Analysis. AB - PURPOSE: To evaluate differences in health related quality of life and time to return to normal activities between patients treated with open radical prostatectomy (ORP) and robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: Three hundred and two patients treated with RARP or ORP were prospectively enrolled. One year after surgery, patients received a questionnaire to evaluate social life, duration of being limited in daily and sexual life as well as satisfaction with the treatment. RESULTS: Both cohorts showed no differences in age, prostate specific-antigen-levels, Gleason score, prostate volume or T-stage (p > 0.05). Median blood loss was significant lower and the surgical time was significant higher in the RARP group. There were no significant differences regarding the duration of being limited in social or daily life or regarding the satisfaction with the treatment. The median time patients felt affected in their work was 2 months. There were no significant differences in terms of subjective global health status and HrQoL 3 months (p = 0.60 and p = 0.40) and 6 months (p = 0.30 and p = 0.20) after surgery. CONCLUSION: The present study confirms significant perioperative benefits for patients undergoing RARP compared to ORP. However, there is no difference in HrQoL as well as in the time to return to normal activities between patients treated with RARP and ORP. PMID- 26752060 TI - Granuloma faciale. PMID- 26752059 TI - Precision (Repeatability and Reproducibility) and Agreement of Corneal Power Measurements Obtained by Topcon KR-1W and iTrace. AB - PURPOSE: To evaluate the repeatability and reproducibility of corneal power measurements obtained by Topcon KR-1W and iTrace, and assess the agreement with measurements obtained by Allegro Topolyzer and IOLMaster. METHODS: The right eyes of 100 normal subjects were prospectively scanned 3 times using all the 4 devices. Another observer performed additional 3 consecutive scans using the Topcon KR-1W and iTrace in the same session. About one week later, the first observer repeated the measurements using the Topcon KR-1W and iTrace. The steep keratometry (Ks), flat keratometry (Kf), mean keratometry (Km), J0 and J45 were analyzed. Repeatability and reproducibility of measurements were evaluated by the within-subject standard deviation (Sw), coefficient of variation (CoV), test retest repeatability (2.77Sw), and intraclass correlation coefficient (ICC). Agreements between devices were assessed using Bland-Altman analysis and 95% limits of agreement (LoA). RESULTS: Intraobserver repeatability and interobserver and intersession reproducibility of the Ks, Kf and Km showed a CoV of no more than 0.5%, a 2.77Sw of 0.70 D or less, and an ICC of no less than 0.99. However, J0 and J45 showed poor intraobserver repeatability and interobserver and intersession reproducibility (all ICCs not greater than 0.446). Statistically significant differences existed between Topcon KR-1W and IOLMaster, Topcon KR-1W and iTrace, Topcon KR-1W and Topolyzer, iTrace and Topolyzer, iTrace and IOLMaster for Ks, Kf and Km measurements (all P < 0.05). The mean differences between Topcon KR-1W, iTrace, and the other 2 devices were small. The 95% LoA were approximately 1.0 D to 1.5 D for all measurements. CONCLUSIONS: The Ks, Kf and Km obtained by Topcon KR-1W and iTrace showed excellent intraobserver repeatability and interobserver and intersession reproducibility in normal eyes. The agreement between Topcon KR-1W and Topolyzer, Topcon KR-1W and IOLMaster, iTrace and Topolyzer, iTrace and IOLMaster, Topcon KR-1W and iTrace were not so good, they should not be interchangeable in clinical application. Given that the intraobserver repeatability and interobserver and intersession reproducibility of corneal astigmatism measurements obtained by Topcon KR-1W and iTrace were poor, it should be cautious that Topcon KR-1W and iTrace were applied for the preparation of toric lens implantation. PMID- 26752057 TI - Tools for Single-Cell Kinetic Analysis of Virus-Host Interactions. AB - Measures of cellular gene expression or behavior, when performed on individual cells, inevitably reveal a diversity of behaviors and outcomes that can correlate with normal or diseased states. For virus infections, the potential diversity of outcomes are pushed to an extreme, where measures of infection reflect features of the specific infecting virus particle, the individual host cell, as well as interactions between viral and cellular components. Single-cell measures, while revealing, still often rely on specialized fluid handling capabilities, employ end-point measures, and remain labor-intensive to perform. To address these limitations, we consider a new microwell-based device that uses simple pipette based fluid handling to isolate individual cells. Our design allows different experimental conditions to be implemented in a single device, permitting easier and more standardized protocols. Further, we utilize a recently reported dual color fluorescent reporter system that provides dynamic readouts of viral and cellular gene expression during single-cell infections by vesicular stomatitis virus. In addition, we develop and show how free, open-source software can enable streamlined data management and batch image analysis. Here we validate the integration of the device and software using the reporter system to demonstrate unique single-cell dynamic measures of cellular responses to viral infection. PMID- 26752061 TI - Investigation of Content, Stoichiometry and Transfer of miRNA from Human Neural Stem Cell Line Derived Exosomes. AB - Exosomes are small (30-100 nm) membrane vesicles secreted by a variety of cell types and only recently have emerged as a new avenue for cell-to-cell communication. They are natural shuttles of RNA and protein cargo, making them attractive as potential therapeutic delivery vehicles. MicroRNAs (miRNAs) are short non-coding RNAs which regulate biological processes and can be found in exosomes. Here we characterized the miRNA contents of exosomes derived from human neural stem cells (hNSCs). Our investigated hNSC line is a clonal, conditionally immortalized cell line, compliant with good manufacturing practice (GMP), and in clinical trials for stroke and critical limb ischemia in the UK (clinicaltrials.gov: NCT01151124, NCT02117635, and NCT01916369). By using next generation sequencing (NGS) technology we identified the presence of a variety of miRNAs in both exosomal and cellular preparations. Many of these miRNAs were enriched in exosomes indicating that cells specifically sort them for extracellular release. Although exosomes have been proven to contain miRNAs, the copy number quantification per exosome of a given miRNA remains unclear. Herein we quantified by real-time PCR a highly shuttled exosomal miRNA subtype (hsa-miR 1246) in order to assess its stoichiometry per exosome. Furthermore, we utilized an in vitro system to confirm its functional transfer by measuring the reduction in luciferase expression using a 3' untranslated region dual luciferase reporter assay. In summary, NGS analysis allowed the identification of a unique set of hNSC derived exosomal miRNAs. Stoichiometry and functional transfer analysis of one of the most abundant identified miRNA, hsa-miR-1246, were measured to support biological relevance of exosomal miRNA delivery. PMID- 26752062 TI - HIV-1 A1 Subtype Epidemic in Italy Originated from Africa and Eastern Europe and Shows a High Frequency of Transmission Chains Involving Intravenous Drug Users. AB - BACKGROUND: Subtype A accounts for only 12% of HIV-1 infections worldwide but predominates in Russia and Former Soviet Union countries of Eastern Europe. After an early propagation via heterosexual contacts, this variant spread explosively among intravenous drug users. A distinct A1 variant predominates in Greece and Albania, which penetrated directly from Africa. Clade A1 accounts for 12.5% of non-B subtypes in Italy, being the most frequent after F1 subtype. AIM: Aim of this study was to investigate the circulation of A1 subtype in Italy and trace its origin and diffusion through phylogenetic and phylodynamic approaches. RESULTS: The phylogenetic analysis of 113 A1 pol sequences included in the Italian ARCA database, indicated that 71 patients (62.8%) clustered within 5 clades. A higher probability to be detected in clusters was found for patients from Eastern Europe and Italy (88.9% and 60.4%, respectively) compared to those from Africa (20%) (p < .001). Higher proportions of clustering sequences were found in intravenous drug users with respect to heterosexuals (85.7% vs. 59.3%, p = .056) and in women with respect to men (81.4% vs. 53.2%, p < .006). Subtype A1 dated phylogeny indicated an East African origin around 1961. Phylogeographical reconstruction highlighted 3 significant groups. One involved East European and some Italian variants, the second encompassed some Italian and African strains, the latter included the majority of viruses carried by African and Italian subjects and all viral sequences from Albania and Greece. CONCLUSIONS: Subtype A1 originated in Central Africa and spread among East European countries in 1982. It entered Italy through three introduction events: directly from East Africa, from Albania and Greece, and from the area encompassing Moldavia and Ukraine. As in previously documented A1 epidemics of East European countries, HIV-1 A1 subtype spread in Italy in part through intravenous drug users. However, Eastern European women contributed to the penetration of such variant, probably through sex work. PMID- 26752063 TI - General practitioners' attitudes and behaviors toward HPV vaccination: A French national survey. AB - OBJECTIVE: General practitioners (GPs) play a crucial role in human papillomavirus (HPV) vaccine acceptance in France. We sought to study: (1) GPs' perceptions of its risks and efficacy and their recommendation behavior; (2) the relative importance of factors associated with the frequency of their recommendations. METHODS: Cross-sectional observational study in 2014 nested in a national panel of 1712 randomly selected GPs in private practice in France (response rate: 92.4%). We used model averaging to analyze the associations of self-reported frequency of GPs' HPV vaccine recommendations with their perception of its risk-benefit balance and their opinions about the utility of vaccines in general. RESULTS: Overall, 72% of participants reported frequently recommending HPV vaccination; 60% considered that not enough is known about its risks. The model averaging showed that the factors most associated with infrequent recommendation of this vaccine by GPs were: unfavorable perceptions of its risk benefit balance (OR=0.13; 95%CI=0.09-0.21; partial R(2)=0.10), a decision not to vaccinate one's own daughter(s) with this vaccine (OR=0.13; 95%CI=0.07-0.24; partial R(2)=0.05), and doubts about vaccine utility in general (OR=0.78; 95%CI=0.71-0.86; partial R(2)=0.03). CONCLUSION: Although nearly three-quarters of French GPs frequently recommended the HPV vaccine, our findings indicate that a substantial percentage of them are hesitant about it. Doubts about its risks and efficacy strongly influence their recommendation behavior. More research is warranted to help design and evaluate tailored tools and multicomponent intervention strategies to address physician's hesitancy about this vaccine. PMID- 26752064 TI - Improving influenza vaccination in chronically ill children using a tertiary-care based vaccination clinic: Is there a role for the live-attenuated influenza vaccine (LAIV)? AB - BACKGROUND: Children with underlying medical conditions should receive influenza vaccine (IV) yearly; yet this remains sub-optimal. We aimed to describe our experience with a tertiary-care hospital-based influenza vaccination clinic for this at-risk population. METHODS: From October to December 2012, 2013, and 2014, we ran an influenza vaccination clinic at the Montreal Children's Hospital, where children with high-risk conditions come for their follow-up. Both injectable IV (IIV) and live-attenuated IV (LAIV) were offered free of charge to patients and their household contacts. Upon vaccination, parents were asked to fill a pre piloted questionnaire. RESULTS: We vaccinated a total of 2640 high-risk children and 1912 household members during the three influenza vaccination seasons. In 2012 and 2013, 631 and 630 patients with chronic illnesses were vaccinated, compared to 1379 in 2014. Caregivers preferred LAIV primarily because no needle was involved (49.0%) and because it was perceived as less painful (46.9%). LAIV was administered to 69% (2012), 55% (2013) and 47% (2014) of high-risk children. The main reason for not receiving LAIV was because it was contra-indicated. A small fraction of children previously vaccinated with LAIV who did not present any contraindication to LAIV opted for IIV: 12/101 (11.8%) in 2013 and 16/272 (5.9%) in 2014. In 2014, this was mainly due to a previous negative experience with LAIV (11/16). CONCLUSION: Having an influenza vaccination clinic on site at a tertiary care hospital, where children come for their scheduled visits, facilitates yearly influenza vaccination in children with chronic illnesses. LAIV is preferred by caregivers and patients, when not contraindicated. PMID- 26752065 TI - Burden of four vaccine preventable diseases in older adults. AB - BACKGROUND: Implementation of additional targeted vaccinations to prevent infectious diseases in the older adults is under discussion in different countries. When considering the added value of such preventive measures, insight into the current disease burden will assist in prioritization. The aim of this study was derive the first estimates of the disease burden in adults aged 50 years or over in the Netherlands for influenza, pertussis, pneumococcal disease and herpes zoster. METHODS: The average annual disease burden for these four diseases in the Netherlands was calculated for the period 2010-2013 using the disability-adjusted life years (DALY) measure. Disease models and parameters were obtained from previous research. Where possible we adapted these models specifically for older adults and applied age-specific parameters derived from literature. The disease burden based on these adapted models and parameters was compared with the disease burden based on the general population models. RESULTS: The estimated average annual disease burden was from high to low: pneumococcal disease (37,223 DALYs/year), influenza (7941 DALYs/year), herpes zoster (942 DALYs/year), and pertussis (812 DALYs/year). The adaptation of models and parameters specifically for the elderly resulted in a higher disease burden compared to the use of general population models. CONCLUSIONS: Among older adults, the disease burden in the period 2010-2013 was highest for pneumococcal disease, mostly because of high mortality, followed by influenza. Disease burden of herpes zoster and pertussis was relatively low and consisted mostly of years lived with disability. Better information on the course of infectious diseases and long-term consequences would enable more accurate estimation of disease burden in older adults. PMID- 26752069 TI - Human exposure to carbon-based fibrous nanomaterials: A review. AB - In an emerging field of nanotechnologies, assessment of exposure to carbon nanotubes (CNT) and carbon nanofibers (CNF) is an integral component of occupational and environmental epidemiology, risk assessment and management, as well as regulatory actions. The current state of knowledge on exposure to carbon based fibrous nanomaterials among workers, consumers and general population was studied in frame of the International Agency for Research on Cancer (IARC) Monographs-Volume 111 "Some Nanomaterials and Some Fibres". Completeness and reliability of available exposure data for use in epidemiology and risk assessment were assessed. Occupational exposure to CNT/CNF may be of concern at all stages of the material life-cycle from research through manufacture to use and disposal. Consumer and environmental exposures are only estimated by modeled data. The available information of the final steps of the life-cycle of these materials remains incomplete so far regarding amounts of handled materials and levels of exposure. The quality and amount of information available on the uses and applications of CNT/CNF should be improved to enable quantitative assessment of human exposure to these materials. For that, coordinated effort in producing surveys and exposure inventories based on harmonized strategy of material test, exposure measurement and reporting results is strongly encouraged. PMID- 26752066 TI - Post-Stroke Longitudinal Alterations of Inter-Hemispheric Correlation and Hemispheric Dominance in Mouse Pre-Motor Cortex. AB - PURPOSE: Limited restoration of function is known to occur spontaneously after an ischemic injury to the primary motor cortex. Evidence suggests that Pre-Motor Areas (PMAs) may "take over" control of the disrupted functions. However, little is known about functional reorganizations in PMAs. Forelimb movements in mice can be driven by two cortical regions, Caudal and Rostral Forelimb Areas (CFA and RFA), generally accepted as primary motor and pre-motor cortex, respectively. Here, we examined longitudinal changes in functional coupling between the two RFAs following unilateral photothrombotic stroke in CFA (mm from Bregma: +0.5 anterior, +1.25 lateral). METHODS: Local field potentials (LFPs) were recorded from the RFAs of both hemispheres in freely moving injured and naive mice. Neural signals were acquired at 9, 16 and 23 days after surgery (sub-acute period in stroke animals) through one bipolar electrode per hemisphere placed in the center of RFA, with a ground screw over the occipital bone. LFPs were pre-processed through an efficient method of artifact removal and analysed through: spectral,cross-correlation, mutual information and Granger causality analysis. RESULTS: Spectral analysis demonstrated an early decrease (day 9) in the alpha band power in both the RFAs. In the late sub-acute period (days 16 and 23), inter hemispheric functional coupling was reduced in ischemic animals, as shown by a decrease in the cross-correlation and mutual information measures. Within the gamma and delta bands, correlation measures were already reduced at day 9. Granger analysis, used as a measure of the symmetry of the inter-hemispheric causal connectivity, showed a less balanced activity in the two RFAs after stroke, with more frequent oscillations of hemispheric dominance. CONCLUSIONS: These results indicate robust electrophysiological changes in PMAs after stroke. Specifically, we found alterations in transcallosal connectivity, with reduced inter-hemispheric functional coupling and a fluctuating dominance pattern. These reorganizations may underlie vicariation of lost functions following stroke. PMID- 26752070 TI - An apparently untreatable ulcer of the face. PMID- 26752071 TI - Worry as an Uncertainty-Associated Emotion: Exploring the Role of Worry in Health Information Seeking. AB - This study was carried out to understand how and why worry motivates health related information seeking, and whether worry decreases after obtaining health related information. It was proposed that worry influences health-related information-seeking behavior indirectly through cancer patients' desire for obtaining additional information. It was further expected that perceived knowledge about cancer could be increased after 2 months of searching for health information over the Internet, which would subsequently affect levels of worry. Using panel data collected from 224 women diagnosed with breast cancer, worry was found to predict patients' health information seeking via the perceived need for additional information. The results further showed significant increases in patients' perceived knowledge about breast cancer and decreased levels of worry after the seeking of health information for 2 months. Theoretical and practical implications of the findings are discussed. PMID- 26752068 TI - Metformin inhibits the prometastatic effect of sorafenib in hepatocellular carcinoma by upregulating the expression of TIP30. AB - We previously found that a low dose of sorafenib had a prometastatic effect on hepatocellular carcinoma (HCC), which was caused by downregulation of TIP30 expression. More recently, metformin has been shown to have potential as a preventive and therapeutic agent for different cancers, including HCC. This study evaluated whether the combination of sorafenib and metformin is sufficient to revert the expression of TIP30, thereby simultaneously reducing lung metastasis and improving survival. Our data show that the combination of sorafenib and metformin inhibits proliferation and invasion in vitro, prolongs median survival, and reduces lung metastasis of HCC in vivo. This effect is closely associated with the upregulation of TIP30, partly through activating AMP-activated protein kinase. Thioredoxin, a prometastasis factor, is negatively regulated by TIP30 and plays an essential role during the process of HCC metastasis. Overall, our results suggest that metformin might be a potent enhancer for the treatment of HCC by using sorafenib. PMID- 26752074 TI - Basolateral but not corticomedial amygdala shows neuroarchitectural changes in schizophrenia. PMID- 26752072 TI - Inhibition of Aerobic Glycolysis Attenuates Disease Progression in Polycystic Kidney Disease. AB - Dysregulated signaling cascades alter energy metabolism and promote cell proliferation and cyst expansion in polycystic kidney disease (PKD). Here we tested whether metabolic reprogramming towards aerobic glycolysis ("Warburg effect") plays a pathogenic role in male heterozygous Han:SPRD rats (Cy/+), a chronic progressive model of PKD. Using microarray analysis and qPCR, we found an upregulation of genes involved in glycolysis (Hk1, Hk2, Ldha) and a downregulation of genes involved in gluconeogenesis (G6pc, Lbp1) in cystic kidneys of Cy/+ rats compared with wild-type (+/+) rats. We then tested the effect of inhibiting glycolysis with 2-deoxyglucose (2DG) on renal functional loss and cyst progression in 5-week-old male Cy/+ rats. Treatment with 2DG (500 mg/kg/day) for 5 weeks resulted in significantly lower kidney weights (-27%) and 2-kidney/total-body-weight ratios (-20%) and decreased renal cyst index (-48%) compared with vehicle treatment. Cy/+ rats treated with 2DG also showed higher clearances of creatinine (1.98+/-0.67 vs 1.41+/-0.37 ml/min), BUN (0.69+/-0.26 vs 0.40+/-0.10 ml/min) and uric acid (0.38+/-0.20 vs 0.21+/-0.10 ml/min), and reduced albuminuria. Immunoblotting analysis of kidney tissues harvested from 2DG treated Cy/+ rats showed increased phosphorylation of AMPK-alpha, a negative regulator of mTOR, and restoration of ERK signaling. Assessment of Ki-67 staining indicated that 2DG limits cyst progression through inhibition of epithelial cell proliferation. Taken together, our results show that targeting the glycolytic pathway may represent a promising therapeutic strategy to control cyst growth in PKD. PMID- 26752076 TI - State-Dependent Modulation of Locomotion by GABAergic Spinal Sensory Neurons. AB - The cerebrospinal fluid (CSF) constitutes an interface through which chemical cues can reach and modulate the activity of neurons located at the epithelial boundary within the entire nervous system. Here, we investigate the role and functional connectivity of a class of GABAergic sensory neurons contacting the CSF in the vertebrate spinal cord and referred to as CSF-cNs. The remote activation of CSF-cNs was shown to trigger delayed slow locomotion in the zebrafish larva, suggesting that these cells modulate components of locomotor central pattern generators (CPGs). Combining anatomy, electrophysiology, and optogenetics in vivo, we show that CSF-cNs form active GABAergic synapses onto V0 v glutamatergic interneurons, an essential component of locomotor CPGs. We confirmed that activating CSF-cNs at rest induced delayed slow locomotion in the fictive preparation. In contrast, the activation of CSF-cNs promptly inhibited ongoing slow locomotion. Moreover, selective activation of rostral CSF-cNs during ongoing activity disrupted rostrocaudal propagation of descending excitation along the spinal cord, indicating that CSF-cNs primarily act at the premotor level. Altogether, our results demonstrate how a spinal GABAergic sensory neuron can tune the excitability of locomotor CPGs in a state-dependent manner by projecting onto essential components of the excitatory premotor pool. PMID- 26752075 TI - Curve of Spee - from orthodontic perspective. AB - The presence of a curve of Spee (COS) of variable depth is common finding in the occlusal arrangement and is sixth key of occlusion The understanding of COS in the field of orthodontics is very important as orthodontists deal with it in virtually every patient they treat. An excessive COS is a common form of malocclusion that may be addressed in many ways, including posterior extrusion, anterior intrusion, and incisor proclination. The specific approach to leveling of COS should be selected based on each patient's needs. Soft tissue, crown gingival relations, occlusal plane, and skeletofacial concerns are among the special considerations for treatment planning for leveling of COS. PMID- 26752073 TI - Evaluation of the CCA Immuno-Chromatographic Test to Diagnose Schistosoma mansoni in Minas Gerais State, Brazil. AB - BACKGROUND: The Kato-Katz (KK) stool smear is the standard test for the diagnosis of Schistosoma mansoni infection, but suffers from low sensitivity when infections intensities are moderate to low. Thus, misdiagnosed individuals remain untreated and contribute to the disease transmission, thereby forestalling public health efforts to move from a modality of disease control to one of elimination. As an alternative, the urine-based diagnosis of schistosomiasis mansoni via the circulating cathodic antigen immuno-chromatographic test (CCA-ICT) has been extensively evaluated in Africa with the conclusion that it may replace the KK test in areas where prevalences are moderate or high. METHODS AND FINDINGS: The objective was to measure the performance of the CCA-ICT in a sample study population composed of residents from non-endemic and endemic areas for schistosomiasis mansoni in two municipalities of Minas Gerais state, Brazil. Volunteers (130) were classified into three infection status groups based on duplicate Kato-Katz thick smears from one stool sample (2KK test): 41 negative individuals from non-endemic areas, 41 negative individuals from endemic areas and 48 infected individuals from endemic areas. Infection status was also determined by the CCA-ICT and infection exposure by antibody ELISA (enzyme-linked immunosorbent assay) to S. mansoni soluble egg antigen (SEA) and soluble (adult) worm antigen preparation (SWAP). Sensitivity and specificity were influenced by whether the trace score visually adjudicated in the CCA-ICT was characterized as positive or negative for S. mansoni infection. An analysis of a two-graph receiver operating characteristic was performed to change the cutoff point. When the trace score was interpreted as a positive rather than as a negative result, the specificity decreased from 97.6% to 78.0% whereas sensitivity increased from 68.7% to 85.4%. A significantly positive correlation between the CCA-ICT scores and egg counts was identified (r = 0.6252, p = 0.0001). However, the CCA-ICT misdiagnosed as negative 14.6% of 2KK positive individuals, predominantly those with light infections (fewer than 100 eggs/g feces). Considering 2KK as reference test, the discriminating power of the CCA-ICT (the area under the curve [AUC] = 0.817) was greater than the SEA-ELISA (AUC = 0.744) and SWAP-ELISA (AUC = 0.704). CONCLUSION: Our data for the performance of the CCA-ICT in the Brazilian communities endemic for schistosomiasis mansoni support those from Africa, i.e., in areas with greater infection prevalence and intensities, the CCA-ICT may be useful as a tool to indicate community-based preventative chemotherapy without individual diagnosis. However, because of the Brazilian Ministry of Health's recommendation for individual diagnosis in areas where prevalence is less than 15%, i.e., those areas in which infection intensities are likely to be lowest, the CCA-ICT lacks the sensitivity to be used as standalone diagnostic tool. PMID- 26752077 TI - Early Social Experience Affects the Development of Eye Gaze Processing. AB - Eye gaze is a key channel of non-verbal communication in humans. Eye contact with others is present from birth, and eye gaze processing is crucial for social learning and adult-infant communication. However, little is known about the effect of selectively different experience of eye contact and gaze communication on early social and communicative development. To directly address this question, we assessed 14 sighted infants of blind parents (SIBPs) longitudinally at 6-10 and 12-16 months. Face scanning and gaze following were assessed using eye tracking. In addition, naturalistic observations were made when the infants were interacting with their blind parent and with an unfamiliar sighted adult. Established measures of emergent autistic-like behaviors and standardized tests of cognitive, motor, and linguistic development were also collected. These data were then compared with those obtained from a group of infants of sighted parents. Despite showing typical social skills development overall, infants of blind parents allocated less attention to adult eye movements and gaze direction, an effect that increased between 6-10 and 12-16 months of age. The results suggest that infants adjust their use of adults' eye gaze depending on gaze communication experience from early in life. The results highlight that human functional brain development shows selective experience-dependent plasticity adaptive to the individual's specific social environment. PMID- 26752078 TI - Consciousness and Complexity during Unresponsiveness Induced by Propofol, Xenon, and Ketamine. AB - A common endpoint of general anesthetics is behavioral unresponsiveness, which is commonly associated with loss of consciousness. However, subjects can become disconnected from the environment while still having conscious experiences, as demonstrated by sleep states associated with dreaming. Among anesthetics, ketamine is remarkable in that it induces profound unresponsiveness, but subjects often report "ketamine dreams" upon emergence from anesthesia. Here, we aimed at assessing consciousness during anesthesia with propofol, xenon, and ketamine, independent of behavioral responsiveness. To do so, in 18 healthy volunteers, we measured the complexity of the cortical response to transcranial magnetic stimulation (TMS)--an approach that has proven helpful in assessing objectively the level of consciousness irrespective of sensory processing and motor responses. In addition, upon emergence from anesthesia, we collected reports about conscious experiences during unresponsiveness. Both frontal and parietal TMS elicited a low-amplitude electroencephalographic (EEG) slow wave corresponding to a local pattern of cortical activation with low complexity during propofol anesthesia, a high-amplitude EEG slow wave corresponding to a global, stereotypical pattern of cortical activation with low complexity during xenon anesthesia, and a wakefulness-like, complex spatiotemporal activation pattern during ketamine anesthesia. Crucially, participants reported no conscious experience after emergence from propofol and xenon anesthesia, whereas after ketamine they reported long, vivid dreams unrelated to the external environment. These results are relevant because they suggest that brain complexity may be sensitive to the presence of disconnected consciousness in subjects who are considered unconscious based on behavioral responses. PMID- 26752079 TI - The Cyclic Nucleotide-Gated Channel CNGC14 Regulates Root Gravitropism in Arabidopsis thaliana. AB - In plant roots, auxin inhibits cell expansion, and an increase in cellular auxin levels on the lower flanks of gravistimulated roots suppresses growth and thereby causes downward bending. These fundamental features of root growth responses to auxin were first described over 80 years ago, but our understanding of the underlying molecular mechanisms has remained scant. Here, we report that CYCLIC NUCLEOTIDE-GATED CHANNEL 14 (CNGC14) is essential for the earliest phase of auxin induced ion signaling and growth inhibition in Arabidopsis roots. Using a fluorescence-imaging-based genetic screen, we found that cngc14 mutants exhibit a complete loss of rapid Ca(2+) and pH signaling in response to auxin treatment. Similarly impaired ion signaling was observed upon gravistimulation. We further developed a kinematic analysis approach to study dynamic root growth responses to auxin at high spatiotemporal resolution. These analyses revealed that auxin induced growth inhibition and gravitropic bending are significantly delayed in cngc14 compared to wild-type roots, where auxin suppresses cell expansion within 1 min of treatment. Finally, we demonstrate that auxin-induced cytosolic Ca(2+) changes are required for rapid growth inhibition. Our results support a direct role for CNGC14-dependent Ca(2+) signaling in regulating the early posttranscriptional phase of auxin growth responses in Arabidopsis roots. PMID- 26752081 TI - Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses. AB - Chikungunya virus (CHIKV) is an arthritogenic arbovirus of the Alphavirus genus, which has infected millions of people after its re-emergence in the last decade. In this study, a BHK cell line containing a stable CHIKV replicon with a luciferase reporter was used in a high-throughput platform to screen approximately 3000 compounds. Following initial validation, 25 compounds were chosen as primary hits for secondary validation with wild type and reporter CHIKV infection, which identified three promising compounds. Abamectin (EC50 = 1.5 MUM) and ivermectin (EC50 = 0.6 MUM) are fermentation products generated by a soil dwelling actinomycete, Streptomyces avermitilis, whereas berberine (EC50 = 1.8 MUM) is a plant-derived isoquinoline alkaloid. They inhibited CHIKV replication in a dose-dependent manner and had broad antiviral activity against other alphaviruses--Semliki Forest virus and Sindbis virus. Abamectin and ivermectin were also active against yellow fever virus, a flavivirus. These compounds caused reduced synthesis of CHIKV genomic and antigenomic viral RNA as well as downregulation of viral protein expression. Time of addition experiments also suggested that they act on the replication phase of the viral infectious cycle. PMID- 26752080 TI - Recurrent macrophage activation syndrome in spondyloarthritis and monoallelic missense mutations in PRF1: a description of one paediatric case. PMID- 26752082 TI - Tracing fetal and childhood exposure to lead using isotope analysis of deciduous teeth. AB - We report progress in using the isotopic composition and concentration of Pb in the dentine and enamel of deciduous teeth to provide a high resolution time frame of exposure to Pb during fetal development and early childhood. Isotope measurements (total Pb and (208)Pb/(206)Pb, (207)Pb/(206)Pb ratios) were acquired by laser ablation inductively coupled mass spectrometry at contiguous 100 micron intervals across thin sections of the teeth; from the outer enamel surface to the pulp cavity. Teeth samples (n=10) were selected from two cohorts of children, aged 5-8 years, living in NE England. By integrating the isotope data with histological analysis of the teeth, using the daily incremental lines in dentine, we were able to assign true estimated ages to each ablation point (first 2-3 years for molars, first 1-2 years for incisors+pre-natal growth). Significant differences were observed in the isotope composition and concentration of Pb between children, reflecting differences in the timing and sources of exposure during early childhood. Those born in 2000, after the withdrawal of leaded petrol in 1999, have the lowest dentine Pb levels (<0.2ugPb/g) with (208)Pb/(206)Pb (mean +/-2sigma: 2.126-2.079) (208)Pb/(206)Pb (mean +/-2sigma: 0.879-0.856) ratios that correlate very closely with modern day Western European industrial aerosols (PM10, PM2.5) suggesting that diffuse airborne pollution was probably the primary source and exposure pathway. Legacy lead, if present, is insignificant. For those born in 1997, dentine lead levels are typically higher (>0.4ugPb/g) with (208)Pb/(206)Pb (mean +/-2sigma: 2.145-2.117) (208)Pb/(206)Pb (mean +/-2sigma: 0.898-0.882) ratios that can be modelled as a binary mix between industrial aerosols and leaded petrol emissions. Short duration, high intensity exposure events (1-2 months) were readily identified, together with evidence that dentine provides a good proxy for childhood changes in the isotope composition of blood Pb. Our pilot study confirms that laser ablation Pb isotope analysis of deciduous teeth, when carried out in conjunction with histological analysis, permits a reconstruction of the timing, duration and source of exposure to Pb during early childhood. With further development, this approach has the potential to study larger cohorts and appraise environments where the levels of exposure to Pb are much higher. PMID- 26752083 TI - Forced degradation, LC-UV, MS(n) and LC-MS-TOF studies on azilsartan: Identification of a known and three new degradation impurities. AB - In the present study, Azilsartan (AZL) was subjected to ICH recommended forced degradation conditions of hydrolysis, oxidation, dry heat and photolysis. The drug degraded to four degradation products (I-IV) under acidic, alkaline and water hydrolysis and photolysis. All the four degradation products were resolved in a single run on a C-18 column (250mm*4.6mm; 5MU) with isocratic elution using mobile phase composed of ammonium formate (20mM, pH 3.0), methanol and acetonitrile (40:5:40% v/v), at a flow rate of 0.8mlmin(-1) at ambient temperature. The products were characterized through +ESI-MS(n) spectra of AZL and LC-MS-TOF studies as 2-ethoxy-3H-benzo-imidazole-4-carboxylic acid (I), 2 hydroxy-3-[2'-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-4-ylmethyl]-3H-benzoimidazole-4 carboxylic acid (II, deethylated AZL), 3-[2'-(1H-diazirin-3-yl)-biphenyl]-4 ylmethyl]-2-ethoxy-3H-benzoimidazole-4-carboxylic acid (III), and 3-[4'-(2-ethoxy benzo-imidazol-1-ylmethyl)-biphenyl-2-yl]-4H-[1,2,4]oxadiazol-5-one (IV, decarboxylated AZL). Product I was found to be a known process related impurity whereas the products II-IV were identified as new degradation impurities. The most probable mechanisms for formation of these degradation products were proposed. PMID- 26752084 TI - Covalent interlocking of glucose oxidase and peroxidase in the voids of paper: enzyme-polymer "spider webs". AB - A modular, general method for trapping enzymes within the voids of paper, without chemical activation of cellulose, is reported. Glucose oxidase and peroxidase were crosslinked with poly(acrylic acid) via carbodiimide chemistry, producing 3 dimensional networks interlocked in cellulose fibers. Interlocking prevented enzyme activity loss and enhanced the washability and stability. PMID- 26752085 TI - Three-Dimensional Macroassembly of Sandwich-Like, Hierarchical, Porous Carbon/Graphene Nanosheets towards Ultralight, Superhigh Surface Area, Multifunctional Aerogels. AB - A new, ultralight, superhigh surface area, multifunctional aerogel, which is macroassembled from sandwich-like, hierarchical, porous carbon/graphene nanosheets, is described. The multifunctional aerogel was characterized by means of XRD, SEM, TEM, Raman spectroscopy, and UV/Vis absorption spectroscopy. The multifunctional aerogel had an ultralow density of 8 mg cm(-3) and a superhigh surface area of 2650 m(2) g(-1) . The multifunctional aerogel was thermal stability and compressible. Meanwhile, the multifunctional aerogel exhibited high capacity for the adsorption of oils and organic solvents, unexpectedly high hydrogen adsorption and good electrochemical performance. PMID- 26752086 TI - Enhancing the circulating half-life and the antitumor effects of a tumor selective cytotoxic peptide by exploiting endogenous serum albumin as a drug carrier. AB - The elevated expression of bombesin receptors in many of the deadliest cancers has attracted special interest in developing bombesin-directed agents for tumor imaging and therapy. Previously, we constructed the chimeric peptide BB28 by fusing bombesin to a mitochondria-disrupting peptide. BB28 selectively induced the apoptosis of various tumor cells in vitro and showed promising in vivo antitumor effects. In general, a short circulating half-life limits the in vivo effect of peptides. To prolong the half-life of BB28, here, we generated the novel peptide ABB28 by fusing an albumin-binding domain (ABD) to the N-terminus of BB28. ABB28 exhibited much higher binding affinity for albumin than BB28, and this modification extended the peptide half-life from several minutes to 2 h. Optical imaging revealed that ABB28 accumulated in xenografted tumors within 1h post-injection and persisted at an evident level for up to 24 h. ABB28 exerted stronger tumor-suppressive effects than BB28. Significant differences in the tumor volumes (P<0.001) and the tumor weights (P=0.002) were observed between ABB28- and BB28-treated mice. Moreover, ABB28 exhibited tumor suppression comparable to that of PEGylated 5K-BB28 in vivo. These results suggest that half life extension via ABD fusion represents a useful strategy for optimizing bombesin-directed pharmaceuticals for cancer-targeted therapy. PMID- 26752087 TI - Multimodal approach to characterization of hydrophilic matrices manufactured by wet and dry granulation or direct compression methods. AB - PURPOSE OF THE RESEARCH: The purpose of the research was to investigate the effect of the manufacturing process of the controlled release hydrophilic matrix tablets on their hydration behavior, internal structure and drug release. Direct compression (DC) quetiapine hemifumarate matrices and matrices made of powders obtained by dry granulation (DG) and high shear wet granulation (HS) were prepared. They had the same quantitative composition and they were evaluated using X-ray microtomography, magnetic resonance imaging and biorelevant stress test dissolution. PRINCIPAL RESULTS: Principal results concerned matrices after 2 h of hydration: (i) layered structure of the DC and DG hydrated tablets with magnetic resonance image intensity decreasing towards the center of the matrix was observed, while in HS matrices layer of lower intensity appeared in the middle of hydrated part; (ii) the DC and DG tablets retained their core and consequently exhibited higher resistance to the physiological stresses during simulation of small intestinal passage than HS formulation. MAJOR CONCLUSIONS: Comparing to DC, HS granulation changed properties of the matrix in terms of hydration pattern and resistance to stress in biorelevant dissolution apparatus. Dry granulation did not change these properties-similar hydration pattern and dissolution in biorelevant conditions were observed for DC and DG matrices. PMID- 26752089 TI - Mandarin Tone and Vowel Recognition in Cochlear Implant Users: Effects of Talker Variability and Bimodal Hearing. AB - OBJECTIVES: For cochlear implant (CI) users with residual low-frequency acoustic hearing in the nonimplanted ear, bimodal hearing combining the use of a CI and a contralateral hearing aid (HA) may provide more salient talker voice cues than CI alone to handle the variability of talker identity across trials. This study tested the effects of talker variability, bimodal hearing, and their interaction on response accuracy and time of CI users' Mandarin tone, vowel, and syllable recognition (i.e., combined Mandarin tone and vowel recognition in this study). DESIGN: Fifteen prelingually deafened native Mandarin-speaking CI users (at age 20 or lower) participated in this study. Four talkers each produced six Mandarin single-vowel syllables in four lexical tones. The stimuli were presented in quiet via a single loudspeaker. To study the effects of talker variability, Mandarin tone, vowel, and syllable recognition was tested in two presentation conditions: with stimuli blocked according to talker (blocked-talker condition) or mixed across talkers from trial to trial (mixed-talker condition). To explore the effects of bimodal hearing, two processor conditions were tested: CI alone or CI + HA. The cumulative response time was recorded as an indirect indicator of the cognitive load or listening effort in each condition. The correlations were computed between demographic/hearing factors (e.g., hearing thresholds in the nonimplanted ear) and bimodal performance/benefits (where bimodal benefits refer to the performance differences between CI alone and CI + HA). RESULTS: Mandarin tone recognition with both CI alone and CI + HA was significantly poorer in the mixed-talker condition than in the blocked-talker condition, while vowel recognition was comparable in the two presentation conditions. Bimodal hearing significantly improved Mandarin tone recognition but not vowel recognition. Mandarin syllable recognition was significantly affected by both talker variability and bimodal hearing. The cumulative response time significantly reduced with CI + HA compared with CI alone, but remained invariant with respect to talker variability. There was no interaction between talker variability and bimodal hearing for any performance measure adopted in this study. Correlation analyses revealed that the bimodal performance and benefits in Mandarin tone, vowel, and syllable recognition could not be predicted by the hearing thresholds in the nonimplanted ear or by the demographic factors of the participants. CONCLUSIONS: Talker variability from trial to trial significantly degraded Mandarin tone and syllable recognition performance in both the CI alone and CI + HA conditions. While bimodal hearing did not reduce the talker variability effects on Mandarin tone and syllable recognition, generally better Mandarin tone and syllable recognition performance with shorter response time (an indicator of less listening effort) was observed when a contralateral HA was used in conjunction with the CI. On the other hand, vowel recognition was not significantly affected by either talker variability or bimodal hearing, because ceiling effects could not be counted out of the vowel recognition results. PMID- 26752090 TI - Providing Care Beyond the Hospital: Perspective of a Tertiary Care Hospital from a Developing Country. AB - BACKGROUND: Neurorehabilitation is an important aspect of continuing care for neurosurgical patients with functional disability. In developing countries, where formal home nursing frequently is unavailable, ensuring care after discharge is a difficult task. Training attendants to provide nursing care is an alternate option. In this study, we compared the outcomes of patients nursed by family members versus those looked after by a professional nurse. METHODS: This was a retrospective observational study conducted at the Aga Khan University Hospital Karachi. The study consisted of 2 groups. Group 1 (consisting of patients cared for by a professional nurse) included 94 patients and group 2 (patients cared for by family members) included 102. All these patients had activity of daily living score of >=3. Glasgow Outcomes Scale score, time to decannulation, development/worsening of bedsores, and mortality were recorded and compared between the groups at follow-up. RESULTS: The study included 196 patients. Traumatic brain injury was the most common diagnosis. Nursing requirements were similar between the 2 groups and included tracheostomy care, percutaneous endoscopic gastrostomy tube care, peripherally inserted central catheter line care, care of patients with no bone flap, and log-rolling. The outcomes of the 2 groups were comparable and included bedsore development/worsening of grade, Glasgow Outcomes Scale score at follow-up, time to decannulation, and 30-day mortality. CONCLUSIONS: There was no statistically significant difference in outcomes of patients nursed by family members compared with the patients looked after by professional nurses. PMID- 26752091 TI - Carotid Endarterectomy Is Safe, Effective, and Durable, but Can We Make It Better? PMID- 26752092 TI - Siglec-1 and -2 as potential biomarkers in autoimmune disease. AB - Autoimmune diseases (ADs) are currently treated with anti-inflammatory and immunosuppressive drugs, aimed at reducing symptoms of disease in order to improve quality of life for patients. However, for a significant number of patients these therapies are ineffective, leading to an increased risk of irreversible damage and eventual disability in certain cases. Growing evidence has implicated glycosylated proteins and their cognate receptors in modulation of the autoimmune response. This review will summarize these findings with particular focus on sialic acid-binding immunoglobulin-like lectin (Siglec)-1 and Siglec-2 involvement in AD. Fluctuations in these glycosylation-dependent pathways could act as sentinels of disease activity or drug responses. If validated, protein modification and cellular response markers could help clinicians achieve remission earlier. PMID- 26752093 TI - Smart Approach for In Situ One-Step Encapsulation and Controlled Delivery of a Chemotherapeutic Drug using Metal-Organic Framework-Drug Composites in Aqueous Media. AB - Controlled release of an anticancer drug, doxorubicin (dox), from metal-organic framework (MOF)-drug composites is demonstrated under different external stimuli. 1,3,5-Benzenetricarboxylic acid (H3 BTC) is used as an organic ligand, and iron acetate and zinc nitrate are used as metal sources to synthesize Fe-BTC and Zn BTC MOFs, which are known to be biocompatible. The in situ formation of MOF-drug composites demonstrates high drug loading capacity compared to conventional methods. The present methodology is devoid of any extra steps for loading the drug after synthesis. Moreover, the drug loading is also independent of pore size of the MOF as the drug molecules are embedded inside the MOF during their in situ formation. The drug release was monitored under external stimuli including change to acidic pH and the presence of biocompatible liposomes for a period of more than 72 h. Steady-state fluorescence spectroscopy is used to monitor the drug release as a function of time and confocal laser scanning microscopy is used to unravel the post-release fate of doxorubicin in the presence of liposomes. It is found that drug release rate is higher for the Zn-BTC-dox composite than for the Fe-BTC-dox composite. This is attributed to the stronger binding between dox and Fe-BTC than that between dox and Zn-BTC. This study highlights a novel approach for the preparation of MOF-drug composites in an aqueous medium for future biomedical applications. PMID- 26752094 TI - Design, synthesis and evaluation of novel 7-aminoalkyl-substituted flavonoid derivatives with improved cholinesterase inhibitory activities. AB - A novel series of 7-aminoalkyl-substituted flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential cholinesterase inhibitors. The results showed that most of the synthesized compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar range. Compound 2-(naphthalen-1-yl)-7-(8-(pyrrolidin 1-yl)octyloxy)-4H-chromen-4-one (5q) showed the best inhibitory activity (IC50, 0.64MUM for AChE and 0.42MUM for BChE) which were better than our previously reported compounds and the commercially available cholinergic agent Rivastigmine. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5q with AChE and BChE. Furthermore, molecular modeling study showed that 5q targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds (5a-5r) did not affect PC12 and HepG2 cell viability at the concentration of 10MUM. Consequently, these flavonoid derivatives should be further investigated as multipotent agents for the treatment of Alzheimer's disease. PMID- 26752095 TI - Design and synthesis of calindol derivatives as potent and selective calcium sensing receptor agonists. AB - We report the first comprehensive structure-activity study of calindol (4, (R)-N [(1H-indol-2-yl)methyl]-1-(1-naphthyl)ethanamine), a positive allosteric modulator, or calcimimetic, of the calcium sensing receptor (CaSR). While replacement of the naphthyl moiety of calindol by other aromatic groups (phenyl, biphenyl) was largely detrimental to calcimimetic activity, incorporation of substituents on the 4, 5 or 7 position of the indole portion of calindol was found to provide either equipotent derivatives compared to calindol (e.g., 4 phenyl, 4-hydroxy, 5-hydroxycalindol 44, 52, 53) or, in the case of 7 nitrocalindol (51), a 6-fold more active calcimimetic displaying an EC50 of 20nM. Unlike calindol, the more active CaSR calcimimetics were shown not to act as antagonists of the closely related GPRC6A receptor, suggesting a more selective profile for these new analogues. PMID- 26752096 TI - Reduced risk of prostate cancer in childless men as compared to fathers: a systematic review and meta-analysis. AB - The previously reported association between fatherhood status and prostate cancer risk was controversial. We carried out the present meta-analysis of all relevant studies to summarize evidence on this association. A comprehensive literature search of studies was performed in PubMed, Web of Science, and the Chinese National Knowledge Infrastructure (CNKI) databases, covering all the papers published from their inception to September 2015. The combined risk estimates with 95% confidence intervals (CIs) were calculated using a random effects model. Heterogeneity and publication bias were also evaluated. A total of 11 studies were finally included in this meta-analysis. We found a significantly reduced risk of prostate cancer associated with being childless (OR 0.91, 95% CI 0.87 0.96). There was statistically significant heterogeneity across the studies (P < 0.001, I(2) = 88.2%). In summary, this meta-analysis supports that being fatherless is associated with a lower risk of prostate cancer. Because of the substantial heterogeneity and residual confounding, using other study designs to further explore this association and the underling mechanism is warranted. PMID- 26752098 TI - Meditation programs for veterans with posttraumatic stress disorder: Aggregate findings from a multi-site evaluation. AB - OBJECTIVE: Interest in meditation to manage posttraumatic stress disorder (PTSD) symptoms is increasing. Few studies have examined the effectiveness of meditation programs offered to Veterans within Department of Veterans Affairs (VA) mental health services. The current study addresses this gap using data from a multisite VA demonstration project. METHOD: Evaluation data collected at 6 VA sites (N = 391 Veterans) before and after a meditation program, and a treatment-as-usual (TAU) program, were examined here using random effects meta-analyses. Site specific and aggregate between group effect sizes comparing meditation programs to TAU were determined for PTSD severity measured by clinical interview and self report. Additional outcomes included experiential avoidance and mindfulness. RESULTS: In aggregate, analyses showed medium effect sizes for meditation programs compared to TAU for PTSD severity (clinical interview: effect size (ES) = -0.32; self-report: ES = -0.39). Similarly sized effects of meditation programs were found for overall mindfulness (ES = 0.41) and 1 specific aspect of mindfulness, nonreactivity to inner experience (ES = .37). Additional findings suggested meditation type and program completion differences each moderated program effects. CONCLUSIONS: VA-sponsored meditation programs show promise for reducing PTSD severity in Veterans receiving mental health services. Where meditation training fits within mental health services, and for whom programs will be of interest and effective, require further clarification. (PsycINFO Database Record PMID- 26752099 TI - Cumulative trauma and current posttraumatic stress disorder status in general population and inmate samples. AB - OBJECTIVE: This research was undertaken to examine the role between cumulative exposure to different types of traumatic events and posttraumatic stress disorder (PTSD) status in general population and prison samples. METHODS: Two archival datasets were examined: the standardization sample for the Detailed Assessment of Posttraumatic States (DAPS; Briere, 2001), and data from a study on trauma and posttraumatic sequelae among inmates and others. RESULTS: PTSD was found in 4% of the general population sample and 48% of the prison sample. Trauma exposure was very common among prisoners, including a 70% rate of childhood sexual abuse for women and a 50% rate for men. Lifetime number of different types of trauma was associated with PTSD in both the general population and prison samples, even when controlling for the effects of sexual trauma. Cumulative interpersonal trauma predicted PTSD, whereas cumulative noninterpersonal trauma did not. In the general population sample, participants who had only 1 type of trauma exposure had a 0% likelihood of current PTSD, whereas those with 6 or more other trauma types had a 12% likelihood. In the prison sample, those with only 1 type of trauma exposure had a 17% percent likelihood of current PTSD, whereas those exposed to 6 or more other trauma types had a 64% chance of PTSD. CONCLUSION: Cumulative trauma predicts current PTSD in both general population and prison samples, even after controlling for sexual trauma. PTSD appears to develop generally as a function of exposure to multiple types of interpersonal trauma, as opposed to a single traumatic event. (PsycINFO Database Record PMID- 26752100 TI - Moments of joy and delight: the meaning of traditional food in dementia care. AB - AIMS AND OBJECTIVES: To learn about the meaning of traditional food to institutionalised patients with dementia. BACKGROUND: Traditional food strengthens the feelings of belonging, identity and heritage, which help persons with dementia to hold on to and reinforce their cultural identity and quality of life. Taste is more cultural than physiological. Dietary habits are established early in life and may be difficult to change. Being served unfamiliar dishes may lead to disappointment and a feeling of being betrayed and unloved. DESIGN AND METHOD: The three studies presented have a qualitative design. In-depth interviews of family members and nurses experienced in dementia care were conducted in South Africa and among ethnic Norwegians and the Sami in Norway. Content-focused analysis, hermeneutic in character, was used to enable the exploration of the thoughts, feelings and cultural meaning described. RESULTS: Traditional foods created a feeling of belonging and joy. Familiar tastes and smells awoke pleasant memories in patients and boosted their sense of well-being, identity and belonging, even producing words in those who usually did not speak. CONCLUSIONS: In persons with dementia, dishes remembered from their childhood may help maintain and strengthen cultural identity, create joy and increase patients' feeling of belonging, being respected and cared for. Traditional food furthermore improves patients' appetite, nutritional intake and quality of life. To serve traditional meals in nursing homes demands extra planning and resources, traditional knowledge, creativity and knowledge of patients' personal tastes. RELEVANCE FOR CLINICAL PRACTICE: This study provides insight into culture sensitive dietary needs of institutionalised patients with dementia. The cultural significance of food for feeling contentment and social and physical well-being is discussed. Besides helping to avoid undernutrition, being served traditional dishes may be very important to reminiscence, joy, thriving and quality of life. PMID- 26752097 TI - Single Cell "Glucose Nanosensor" Verifies Elevated Glucose Levels in Individual Cancer Cells. AB - Because the transition from oxidative phosphorylation to anaerobic glycolytic metabolism is a hallmark of cancer progression, approaches to identify single living cancer cells by their unique glucose metabolic signature would be useful. Here, we present nanopipettes specifically developed to measure glucose levels in single cells with temporal and spatial resolution, and we use this technology to verify the hypothesis that individual cancer cells can indeed display higher intracellular glucose levels. The nanopipettes were functionalized as glucose nanosensors by immobilizing glucose oxidase (GOx) covalently to the tip so that the interaction of glucose with GOx resulted in a catalytic oxidation of beta-d glucose to d-gluconic acid, which was measured as a change in impedance due to drop in pH of the medium at the nanopipette tip. Calibration studies showed a direct relationship between impedance changes at the tip and glucose concentration in solution. The glucose nanosensor quantified single cell intracellular glucose levels in human fibroblasts and the metastatic breast cancer lines MDA-MB-231 and MCF7 and revealed that the cancer cells expressed reproducible and reliable increases in glucose levels compared to the nonmalignant cells. Nanopipettes allow repeated sampling of the same cell, as cells remain viable during and after measurements. Therefore, nanopipette-based glucose sensors provide an approach to compare changes in glucose levels with changes in proliferative or metastatic state. The platform has great promise for mechanistic investigations, as a diagnostic tool to distinguish cancer cells from nonmalignant cells in heterogeneous tissue biopsies, as well as a tool for monitoring cancer progression in situ. PMID- 26752102 TI - Diarrheagenic Escherichia coli pathotypes investigation revealed atypical enteropathogenic E. coli as putative emerging diarrheal agents in children living in Botucatu, Sao Paulo State, Brazil. AB - The aim of the present study was to investigate the prevalence of Diarrheagenic Escherichia coli (DEC) pathotypes, a leading cause of diarrhea worldwide, among diarrheal and healthy children, up to 5 years of age, living in the city of Botucatu, Sao Paulo, Brazil. DEC, investigated by PCR detection of virulence factor-encoding genes associated with the distinct pathotypes, was isolated from 18.0% of the patients, and 19.0% of the controls, with enteroaggregative E. coli (EAEC), the most frequent pathotype, being detected in equal proportion between patients and controls (10.0%). Among the enteropathogenic E. coli (EPEC) isolates, only one isolate was able to produce the localized adherence pattern to HeLa cells, being thus the only typical EPEC identified. All the remaining EPEC were classified as atypical (aEPEC), and detected in 8.0% and 8.5% of the patients and controls, respectively. Regarding the serotypes, 26.5% of the analyzed EPEC isolates belonged to classical EPEC-serogroups, and the only two STEC found were serotyped as O26:H11 (patient) and O119:H7 (control). Antimicrobial susceptibility tests revealed that 43.6%, 29.5% and 2.6% of the DEC isolates were resistant to ampicillin, cotrimoxazole and gentamicin, respectively. Our data indicate that EAEC remains prevalent among children living in Botucatu, and revealed atypical EPEC as emerging putative diarrheal agents in this geographical region. PMID- 26752103 TI - The thickness-dependent band gap and defect features of ultrathin ZrO2 films studied by spectroscopic ellipsometry. AB - The band gap and defect features of ultrathin ZrO2 films with varying thicknesses have been investigated by spectroscopic ellipsometry through the point-by-point data inversion method. The epsilon2-sprectra in the 3-6 eV range are extracted based on an optical model consisting of a Si substrate/effective ZrO2 film/air ambient structure where the effective ZrO2 film is a combination of interfacial layers and ZrO2. Evident widening of the band gap with a reducing size is observed when the effective ZrO2 films are below a critical thickness, somewhere between 8.80 nm and 17.13 nm. This is due to quantum-confinement and amorphous effects. Moreover, the sub-band-gap defects at interfacial layers and in bulk ZrO2 are identified and present strong thickness dependence as well. The interfacial defects at 3.26, 4.13, 4.43, and 4.77 eV mainly exist below the critical thickness and exhibit a significant suppression with increasing film thickness. The bulk defects at 4.15 eV and 4.46 eV dominate in ZrO2 films once they are over the critical thickness. The evolution of the band gap and defects is closely related to variance in the electronic structure of amorphous ZrO2. Our results may be helpful in understanding controversial problems concerning the size effect on ultrathin high-k oxide films and exploring the further miniaturization of electronic devices based on them. PMID- 26752101 TI - Intralymphatic treatment of flagellin-ovalbumin mixture reduced allergic inflammation in murine model of allergic rhinitis. AB - BACKGROUND: Bacterial flagellin, a Toll-like receptor 5 agonist, is used as an adjuvant for immunomodulation. In this study, we aimed to evaluate the effect and its mechanism following intralymphatic administration of OVA-flagellin (FlaB) mixture in the mouse model of allergic rhinitis. MATERIALS AND METHODS: BALB/c mice were sensitized with OVA and treated with an OVA-FlaB mixture via intranasal, sublingual, and intralymphatic routes to evaluate the effect of each treatment. Several parameters for allergic inflammation and its underlying mechanisms were then evaluated. RESULTS: Intralymphatic injection of the OVA-FlaB mixture reduced symptom scores, eosinophil infiltration in the nasal mucosa, and total and OVA-specific IgE levels more significantly than intranasal and sublingual administration. Systemic cytokine (IL-4, IL-5, IL-6, IL-17, and IFN gamma) production and local cytokine (IL-4 and IL-5) production were also reduced significantly after intralymphatic injection with OVA-FlaB. Double intralymphatic injection of the mixture was more effective than single injection. Moreover, the expression of innate cytokines such as IL-25 and IL-33 in nasal epithelial cells was reduced, and the expression of chemokines such as CCL24 (eotaxin-2), CXCL1, and CXCL2 was decreased in the nasal mucosa, suggesting the underlying mechanism for intralymphatic administration of the OVA-FlaB mixture. CONCLUSION: Intralymphatic administration of an OVA-FlaB mixture was more effective in alleviating allergic inflammation than intranasal and sublingual administration in a mouse model of allergic rhinitis. This effect may be attributed to the reduced expression of innate cytokines and chemokines. This treatment modality can be considered as a new therapeutic method and agent. PMID- 26752106 TI - EMERGENCY DECLARATIONS AND TRIBES: MECHANISMS UNDER TRIBAL AND FEDERAL LAW. PMID- 26752105 TI - Electrical and mechanical switching of ferroelectric polarization in the 70 nm BiFeO3 film. AB - Ferroelectric polarization switching and its domain evolution play a key role on the macroscopic electric properties of ferroelectric or piezoelectric devices. Mechanical switching has been reported recently in ~5 nm BaTiO3 and PbZr0.2Ti0.8O3 epitaxial films; however it is still a challenge for a mechanical force to switch polarization of a slightly thicker film in the same way as an electric field. Here, we report that the polarization of a 70 nm BiFeO3 epitaxial film can be completely switched by a mechanical force, and its domain evolution is similar to that observed with electrical switching. With the gradual increase of the field/force, new domains nucleate preferentially at domain boundaries, the MUm-size domains commonly decompose to a mass of nm-size domains, and finally they may reorganize to MUm-size domains which undergo 180( degrees ) polarization switching through multi steps. Importantly, the complete mechanical switching of polarization was also established in the (0 0 1) film with a smooth surface. Furthermore, either upward or downward polarization can be read out nondestructively by a constant current. Our study sheds light on prospective applications of ferroelectrics in the absence of an electric field, such as memory devices and other micro-electromechanical systems. PMID- 26752104 TI - REV3L, the catalytic subunit of DNA polymerase zeta, is involved in the progression and chemoresistance of esophageal squamous cell carcinoma. AB - Protein reversionless 3-like (REV3L), the catalytic subunit of DNA polymerase (pol) zeta, is well known to participate in error-prone translesion synthesis (TLS) with less stringent and lower processivity. Recent evidence has demonstrated that REV3L is involved in carcinogenesis and tumor progression. However, the function of REV3L remains unclear in esophageal squamous cell carcinoma (ESCC). In the present study, we examined REV3L expression in ESCC tissues and its association with clinicopathological parameters. REV3L was found to be significantly upregulated and correlated with lymph node metastasis and clinical stage in the ESCC tissues. To further investigate the potential role of REV3L in esophageal cancer, stable ESCC cell lines with suppression of REV3L expression were established. Downregulation of REV3L expression led to a decrease in cell proliferation and invasive capacity partly through suppression of cyclin D1 and survivin expression, and an increase in cellular sensitivity to 5 fluorouracil (5-FU) by induction of G1 phase arrest and apoptosis. Therefore, REV3L plays an important role in ESCC progression and chemoresistance, and is a potential diagnostic marker and therapeutic target for ESCC. PMID- 26752107 TI - Surface Charge at the Oxide/Electrolyte Interface: Toward Optimization of Electrolyte Composition for Treatment of Aluminum and Magnesium by Plasma Electrolytic Oxidation. AB - Controlling microdischarges in plasma electrolytic oxidation is of great importance in order to optimize coating quality. The present study highlights the relationship between the polarity at which breakdown occurs and the electrolyte pH as compared with the isoelectric point (IEP). It is found that working at a pH higher than the IEP of the grown oxide prevents the buildup of detrimental cathodic discharges. The addition of phosphates results in a shift in the IEP to a lower value and therefore promotes anodic discharges at the expense of cathodic ones. PMID- 26752108 TI - Exercise and the Prevention of Low Back Pain: Ready for Implementation. PMID- 26752110 TI - Expanding the Boundaries of Endoscopic Resection: Circumferential Laterally Spreading Lesions of the Duodenum. PMID- 26752109 TI - Histamine Receptor H1-Mediated Sensitization of TRPV1 Mediates Visceral Hypersensitivity and Symptoms in Patients With Irritable Bowel Syndrome. AB - BACKGROUND & AIMS: Histamine sensitizes the nociceptor transient reporter potential channel V1 (TRPV1) and has been shown to contribute to visceral hypersensitivity in animals. We investigated the role of TRPV1 in irritable bowel syndrome (IBS) and evaluated if an antagonist of histamine receptor H1 (HRH1) could reduce symptoms of patients in a randomized placebo-controlled trial. METHODS: By using live calcium imaging, we compared activation of submucosal neurons by the TRPV1 agonist capsaicin in rectal biopsy specimens collected from 9 patients with IBS (ROME 3 criteria) and 15 healthy subjects. The sensitization of TRPV1 by histamine, its metabolite imidazole acetaldehyde, and supernatants from biopsy specimens was assessed by calcium imaging of mouse dorsal root ganglion neurons. We then performed a double-blind trial of patients with IBS (mean age, 31 y; range, 18-65 y; 34 female). After a 2-week run-in period, subjects were assigned randomly to groups given either the HRH1 antagonist ebastine (20 mg/day; n = 28) or placebo (n = 27) for 12 weeks. Rectal biopsy specimens were collected, barostat studies were performed, and symptoms were assessed (using the validated gastrointestinal symptom rating scale) before and after the 12-week period. Patients were followed up for an additional 2 weeks. Abdominal pain, symptom relief, and health-related quality of life were assessed on a weekly basis. The primary end point of the study was the effect of ebastine on the symptom score evoked by rectal distension. RESULTS: TRPV1 responses of submucosal neurons from patients with IBS were potentiated compared with those of healthy volunteers. Moreover, TRPV1 responses of submucosal neurons from healthy volunteers could be potentiated by their pre-incubation with histamine; this effect was blocked by the HRH1 antagonist pyrilamine. Supernatants from rectal biopsy specimens from patients with IBS, but not from the healthy volunteers, sensitized TRPV1 in mouse nociceptive dorsal root ganglion neurons via HRH1; this effect could be reproduced by histamine and imidazole acetaldehyde. Compared with subjects given placebo, those given ebastine had reduced visceral hypersensitivity, increased symptom relief (ebastine 46% vs placebo 13%; P = .024), and reduced abdominal pain scores (ebastine 39 +/- 23 vs placebo 62 +/- 22; P = .0004). CONCLUSIONS: In studies of rectal biopsy specimens from patients, we found that HRH1-mediated sensitization of TRPV1 is involved in IBS. Ebastine, an antagonist of HRH1, reduced visceral hypersensitivity, symptoms, and abdominal pain in patients with IBS. Inhibitors of this pathway might be developed as a new treatment approach for IBS. ClinicalTrials.gov no: NCT01144832. PMID- 26752113 TI - Novel Phenyl-Substituted 5,6-Dihydro-[1,2,4]triazolo[4,3-a]pyrazine P2X7 Antagonists with Robust Target Engagement in Rat Brain. AB - Novel 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine P2X7 antagonists were optimized to allow for good blood-brain barrier permeability and high P2X7 target engagement in the brain of rats. Compound 25 (huP2X7 IC50 = 9 nM; rat P2X7 IC50 = 42 nM) achieved 80% receptor occupancy for 6 h when dosed orally at 10 mg/kg in rats as measured by ex vivo radioligand binding autoradiography. Structure activity relationships within this series are described, as well as in vitro ADME results. In vivo pharmacokinetic data for key compounds is also included. PMID- 26752112 TI - Variable Intra-Tumor Genomic Heterogeneity of Multiple Lesions in Patients With Hepatocellular Carcinoma. AB - BACKGROUND & AIMS: Many patients with hepatocellular carcinoma (HCC) have multiple lesions (primary tumors, intrahepatic metastases, multiple occurrences, satellite nodules, and tumor thrombi); these have been associated with a poor prognosis and tumor recurrence after surgery. We investigated the clonal relationship among these lesions on the basis of genetic features. METHODS: We collected 43 lesions and 10 matched control samples (blood or nontumorous liver) from 10 patients with hepatitis B virus-associated HCC treated at Tianjin Cancer Hospital (China) from January 2013 through May 2014. We performed exome and low depth, whole-genome sequencing on these samples. Genomic aberrations, including somatic mutations and copy number variations, were identified using germline DNA as control. We compared the genetic features of different lesions from each patient and constructed phylogenetic trees to depict their evolutionary histories. RESULTS: In each patient, mutations shared by all the lesions were called ubiquitous mutations. The percentage of ubiquitous mutations varied from 8% to 97% among patients, indicating variation in the extent of intratumor heterogeneity. Branched evolution was evident, with somatic mutations, hepatitis B virus integrations, and copy number variations identified on both the trunks and branches of the phylogenetic trees. Intrahepatic metastases and tumor thrombi contained some, but not all, of the mutations detected in their matched primary lesions. By contrast, satellite nodules shared approximately 90% of mutations detected in primary lesions. In a patient with multicentric tumors, 6 lesions were assigned to 2 distinct groups, based on significant differences in genetic features. In another patient with combined hepatocellular and intrahepatic cholangiocarcinoma, the physically separate HCC and cholangiocarcinoma lesions shared 102 mutations. CONCLUSIONS: The extent of intratumor heterogeneity varies considerably among patients with HCC. Therefore, sequence analysis of a single lesion cannot completely characterize the genomic features of HCC in some patients. Genomic comparisons of multiple lesions associated with HCCs will provide important information on the genetic changes associated with tumor progression. PMID- 26752114 TI - Low-Volatility Model Demonstrates Humidity Affects Environmental Toxin Deposition on Plastics at a Molecular Level. AB - Despite the ever-increasing prevalence of plastic debris and endocrine disrupting toxins in aquatic ecosystems, few studies describe their interactions in freshwater environments. We present a model system to investigate the deposition/desorption behaviors of low-volatility lake ecosystem toxins on microplastics in situ and in real time. Molecular interactions of gas-phase nonylphenols (NPs) with the surfaces of two common plastics, poly(styrene) and poly(ethylene terephthalate), were studied using quartz crystal microbalance and sum frequency generation vibrational spectroscopy. NP point sources were generated under two model environments: plastic on land and plastic on a freshwater surface. We found the headspace above calm water provides an excellent environment for NP deposition and demonstrate significant NP deposition on plastic within minutes at relevant concentrations. Further, NP deposits and orders differently on both plastics under humid versus dry environments. We attributed the unique deposition behaviors to surface energy changes from increased water content during the humid deposition. Lastly, nanograms of NP remained on microplastic surfaces hours after initial NP introduction and agitating conditions, illustrating feasibility for plastic-bound NPs to interact with biota and surrounding matter. Our model studies reveal important interactions between low-volatility environmental toxins and microplastics and hold potential to correlate the environmental fate of endocrine disrupting toxins in the Great Lakes with molecular behaviors. PMID- 26752111 TI - Microsatellite Alterations With Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis. AB - BACKGROUND & AIMS: Molecular events that lead to recurrence and/or metastasis after curative treatment of patients with colorectal cancers (CRCs) are poorly understood. Patients with stage II or III primary CRC with elevated microsatellite alterations at selected tetranucleotide repeats and low levels of microsatellite instability (E/L) are more likely to have disease recurrence after treatment. Hypoxia and/or inflammation not only promote metastasis, but also induce elevated microsatellite alterations at selected tetranucleotide repeats by causing deficiency of MSH3 in the cancer cell nucleus. We aimed to identify genetic alterations associated with metastasis of primary colorectal tumors to liver and to determine their effects on survival. METHODS: We obtained 4 sets of primary colorectal tumors and matched liver metastases from hospitals in Korea and Japan. Intragenic microsatellites with large repeats at 141 loci were examined for frame-shift mutations and/or loss of heterozygosity (LOH) as possible consequences of MSH3 deficiency. Highly altered loci were examined for association with E/L in liver metastases. We analyzed data from 156 of the patients with stage II or III primary colorectal tumors to determine outcomes and whether altered loci were associated with E/L. RESULTS: LOH at several loci at chromosome 9p24.2 (9p24.2-LOH) was associated with E/L in liver metastases (odds ratio = 10.5; 95% confidence interval: 2.69-40.80; P = .0007). We found no significant difference in the frequency of E/L, 9p24.2-LOH, mutations in KRAS or BRAF, or the combination of E/L and 9p24.2-LOH, between primary colorectal tumors and their matched metastases. Patients with stage II or III colorectal tumors with E/L and 9p24.2-LOH had increased survival after CRC recurrence (hazard ratio = 0.25; 95% CI: 0.12-0.50; P = .0001), compared with patients without with E/L and 9p24.2-LOH. E/L with 9p24.2-LOH appeared to be an independent prognostic factor for overall survival of patients with stage III CRC (hazard ratio = 0.06; 95% CI: 0.01-0.57; P = .01). CONCLUSIONS: E/L with 9p24-LOH appears to be a biomarker for less aggressive metastasis from stage III primary colorectal tumors. PMID- 26752115 TI - Graphene Oxide Templated Growth and Superior Lithium Storage Performance of Novel Hierarchical Co2V2O7 Nanosheets. AB - Hierarchical Co2V2O7 nanosheets consisted of interconnected nanoparticles are synthesized by a facile method using graphene oxide as the template. The electrochemical reaction mechanism of the Co2V2O7 nanosheets is thoroughly investigated by in situ XRD and ex situ TEM. The initial Co2V2O7 transforms into CoO nanoparticles and vanadium oxides in the first cycle, and the following reversible conversion reaction mainly occurs between CoO and Co and lithiation/delithiation of the vanadium oxides. The Co2V2O7 nanosheet displays a high reversible capacity (962 mAh/g at 0.5 A/g) and remarkable high rate capability. When cycled at 5.0 A/g, a reversible capacity of 441 mAh/g can be retained after 900 cycles. The stable high capacity and excellent rate capability make the hierarchical Co2V2O7 nanosheets a promising anode material for lithium ion batteries. PMID- 26752116 TI - Photoinduced Electron Transfer between Anionic Corrole and DNA. AB - The interaction between a water-soluble anionic Ga(III) corrole [Ga(tpfc)(SO3Na)2] and calf thymus DNA (ct-DNA) has been investigated by using femtosecond transient absorption spectroscopy. A significant broadening from 570 to 585 nm of positive absorption band of the blend of Ga(tpfc)(SO3Na)2 and ct-DNA (Ga(tpfc)(SO3Na)2-ctDNA) has been observed from 0.15 to 0.50 ps after photoexcitation of Ga(tpfc)(SO3Na)2 into the Soret band. The control experiment has been performed on the model DNA ([poly(dG-dC)]2) rich in guanine bases, which exhibits a similar spectral broadening, whereas it is absent for [poly(dA-dT)]2 without guanine bases. The molecular orbital calculation shows that HOMO of Ga(tpfc)(SO3Na)2 is lower than that of guanine bases. The results of the electrochemical experiment show the reversible electron transfer (ET) between Ga(tpfc)(SO3Na)2 and guanine bases of ct-DNA is thermodynamically favorable. The dynamical analysis of the transient absorption spectra reveals that an ultrafast forward ET from the guanine bases to Ga(tpfc)(SO3Na)2 occurs within the pulse duration (156 fs), leading to the formation of an intermediate state. The following back ET to the ground state of Ga(tpfc)(SO3Na)2 may be accomplished in 520 fs. PMID- 26752117 TI - Development of Lipophilic Antioxidants and Chloroplasts during the Sprouting of Diverse Triticum spp. AB - The influence of sprouting times and illumination conditions on lipophilic antioxidants (carotenoids, tocochromanols, alkylresorcinols, and steryl ferulates), chlorophylls, and alpha-amylase activity was investigated using four varieties each of bread wheat (Triticum aestivum ssp. aestivum), spelt (T. aestivum ssp. spelta), durum (T. durum), emmer (T. dicoccum), and einkorn (T. monococcum). Carotenoid levels significantly increased during sprouting, particularly, under light exposure. In contrast, concentrations of other lipophilic antioxidants were affected to a lesser extent. Moreover, the quantitative development of lipophilic antioxidants was evidently determined by genotype. On the basis of the levels of carotenoids newly synthesized during sprouting, a chloroplast development index indicated that chloroplast ontogenesis during sprouting occurred at different species-dependent rates. Thermal degradation of carotenoids, tocochromanols, chlorophylls, and alpha-amylase activity was observed during the drying of sprouts at 40 and 90 degrees C, while alkylresorcinol and steryl ferulate levels remained unaffected. Wheat sprouts were shown to be potential functional ingredients to increase the nutritional value of cereal products. PMID- 26752118 TI - Using a structured questionnaire improves seizure description by medical students. AB - OBJECTIVE: The purpose of this study was to evaluate a structured questionnaire for improving a medical students' ability to identify, describe and interpret a witnessed seizure. METHODS: Ninety two 3rd year medical students, blinded to seizure diagnosis, viewed videos of a primary generalized seizure and a complex partial seizure. Students next completed an unstructured questionnaire that asked the students to describe the seizure video recordings. The students then completed a structured questionnaire that asked the student to respond to 17 questions regarding specific features occurring during the seizures. We determined the number and types of correct responses for each questionnaire. RESULTS: Overall, the structured questionnaire was more effective in eliciting an average of 9.25 correct responses compared to the unstructured questionnaire eliciting an average of 5.30 correct responses (p < 0.001). Additionally, 10 of the 17 seizure features were identified more effectively with the structured questionnaire. Potentially confounding factors, prior knowledge of someone with epilepsy or a prior experience of viewing a seizure, did not predict the student's ability to correctly identify any of the 17 features. CONCLUSIONS: A structured questionnaire significantly improves a medical student's ability to provide an accurate clinical description of primary generalized and complex partial witnessed seizures. Our analysis identified the 10 specific features improved by using the structured questionnaire. PMID- 26752119 TI - Effect of escitalopram versus placebo on GRalpha messenger RNA expression in peripheral blood cells of healthy individuals with a family history of depression - a secondary outcome analysis from the randomized AGENDA trial. AB - Background Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed as first-line drugs for the treatment of depression. However, the mechanisms of action for SSRIs are unclear and besides neurotransmitter modulation may depend on modulation of the hypothalamic-pituitary-adrenal (HPA) system. The glucocorticoid receptor (GR) isoform alpha plays an important role in the negative feedback regulation of the HPA axis and reduced GRalpha messenger RNA (mRNA) expression has been shown in mood disorder patients and first-degree relatives compared to healthy individuals with no family history of psychiatric disorders. Aim Based on the AGENDA trial dataset, we analysed whether an intervention with SSRI versus placebo decreases the GRalpha mRNA expression in peripheral blood cells in healthy first-degree relatives of patients with major depression. Methods The participants (N = 80) were randomly allocated to receive daily tablets of escitalopram 10 mg versus placebo for 4 weeks. GRalpha mRNA expression levels in peripheral blood were measured using reverse transcription polymerase chain reaction. Results Four weeks of intervention with escitalopram decreased the relative change from baseline in the expression of GRalpha mRNA compared with placebo (p = 0.002). Conclusion These findings from a randomized trial suggest that a 4-week escitalopram administration to healthy participants results in a decrease in GRalpha mRNA expression levels in peripheral blood compared with inert placebo. The decrease in GRalpha mRNA expression levels may reflect a decrease in the HPA axis activity. PMID- 26752121 TI - Theory of mind in children with Neurofibromatosis Type 1. AB - OBJECTIVE: Neurofibromatosis Type I (NF1) is a single gene disorder associated with cognitive and behavioral deficits. While there is clear evidence for poorer social outcomes in NF1, the factors underlying reduced social function are not well understood. This study examined theory of mind (ToM) in children with NF1 and unaffected controls. METHOD: ToM was assessed in children with NF1 (n = 26) and unaffected controls (n = 36) aged 4-12 years using a nonverbal picture sequencing task. The task assessed understanding of ToM (unrealized goals, false belief, pretence, intention), while controlling for social script knowledge and physical cause-and-effect reasoning. RESULTS: Children with NF1 made significantly more errors than unaffected controls on most ToM stories while demonstrating no difficulty sequencing physical cause-and-effect stories. Performance on the picture sequencing task was not related to lower intellectual function, symptoms of attention deficit-hyperactivity disorder (ADHD), or parent ratings of executive function. CONCLUSIONS: Results suggest a generalized ToM deficit in children with NF1 that appears to be independent of general cognitive abilities and ADHD symptoms. The study refines understanding of the clinical presentation of NF1 and identifies psychological constructs that may contribute to the higher prevalence of social dysfunction in children with NF1. (PsycINFO Database Record PMID- 26752120 TI - Gray matter integrity within regions of the dorsolateral prefrontal cortical subcortical network predicts executive function and fine motor dexterity in spina bifida. AB - OBJECTIVES: This study examined microstructural properties of cortical and subcortical gray matter components of the dorsolateral prefrontal (DLPFC) cortical-subcortical circuit in relation to parent-rated executive function and fine motor dexterity performance in youth with spina bifida myelomeningocele (SBM). Aberrant gray matter integrity of the DLPFC, basal ganglia nuclei, and thalamus were hypothesized to differentially relate to neurobehavioral outcomes. METHODS: Forty-nine youth between 8 and 18 years (M = 12.34) old with SBM underwent a 3T MRI including diffusion tensor imaging. Neurobehavioral measures of parent-rated executive function and fine motor dexterity were obtained from a standardized neuropsychological evaluation. Relations among indices of gray matter microstructural integrity (mean diffusivity [MD], fractional anisotropy [FA], cortical thickness) and neurobehavior were examined using 3 correlational methods to enhance reliability of brain-behavior relations. RESULTS: In SBM, higher FA values in the caudate were associated with poorer behavioral regulation. Higher FA values in the putamen and greater DLPFC thickness were both associated with poorer fine motor dexterity. CONCLUSION: Behavioral regulation and FA in the caudate related to behavioral inhibition in SBM. Similarly, associations between fine motor dexterity and indices of gray matter integrity in the putamen and DLPFC support fronto-striatal involvement in motor control in SBM. Examination of these neurobehavioral correlates revealed a pattern of attenuated behavioral impairments when gray matter structure was more similar to that of typically developing youth. (PsycINFO Database Record PMID- 26752123 TI - The Doors and People Test: The effect of frontal lobe lesions on recall and recognition memory performance. AB - OBJECTIVE: Memory deficits in patients with frontal lobe lesions are most apparent on free recall tasks that require the selection, initiation, and implementation of retrieval strategies. The effect of frontal lesions on recognition memory performance is less clear with some studies reporting recognition memory impairments but others not. The majority of these studies do not directly compare recall and recognition within the same group of frontal patients, assessing only recall or recognition memory performance. Other studies that do compare recall and recognition in the same frontal group do not consider recall or recognition tests that are comparable for difficulty. Recognition memory impairments may not be reported because recognition memory tasks are less demanding. METHOD: This study aimed to investigate recall and recognition impairments in the same group of 47 frontal patients and 78 healthy controls. The Doors and People Test was administered as a neuropsychological test of memory as it assesses both verbal and visual recall and recognition using subtests that are matched for difficulty. RESULTS: Significant verbal and visual recall and recognition impairments were found in the frontal patients. CONCLUSION: These results demonstrate that when frontal patients are assessed on recall and recognition memory tests of comparable difficulty, memory impairments are found on both types of episodic memory test. PMID- 26752124 TI - Impaired working memory for visual motion direction in schizophrenia: Absence of recency effects and association with psychopathology. AB - OBJECTIVE: Working memory (WM) impairments are a prominent neurocognitive symptom in schizophrenia (SZ) and include deficits in memory for serial order and abnormalities in serial position effects (i.e., primacy and recency effects). Former studies predominantly focused on investigating these deficits applying verbal or static visual stimuli, but little is known about WM processes that involve dynamic visual movements. We examined WM for visual motion directions, its susceptibility to distraction and the effect of serial positioning. METHOD: Twenty-three patients with paranoid SZ and 23 healthy control subjects (HC) took part in the study. We conducted an adapted Sternberg-type recognition paradigm: three random dot kinematograms (RDKs) that depicted coherent visual motion were used as stimuli and a distractor stimulus was incorporated into the task. RESULTS: SZ patients performed significantly worse in the WM visual motion task, when a distractor stimulus was presented. While HC showed a recency effect for later RDKs, the effect was absent in SZ patients. WM deficits were associated with more severe psychopathological symptoms, poor visual and verbal learning, and a longer duration of illness. Furthermore, SZ patients showed impairments in several other neurocognitive domains. CONCLUSIONS: Findings suggest that early WM processing of visual motion is susceptible to interruption and that WM impairments are associated with clinical symptoms in SZ. The absence of a recency effect is discussed in respect of 3 theoretical approaches-impaired WM for serial order information, abnormalities in early visual representations (i.e., masking effects), and deficits in later visual processing (i.e., attentional blink effect). (PsycINFO Database Record PMID- 26752126 TI - Multidisciplinary Treatment of Antley-Bixler Syndrome. AB - Antley-Bixler syndrome is a rare form of craniosynostosis characterized by unique clinical features that present particular challenges to long-term treatment. Typical craniofacial features include midface hypoplasia, trapezoidocephaly, frontal bossing, ocular proptosis, low-set protrusive ears, and choanal atresia. A staged surgical approach including fronto-orbital and midface advancements is required for intracranial pressure reduction, globe protection, airway patency, and malocclusion. In this case report, the combined, longitudinal surgical and orthodontic treatment strategies employed to correct severe facial deformity in a long-term 21-year survivor of Antley-Bixler syndrome are reviewed. PMID- 26752122 TI - Cognitive, emotion control, and motor performance of adolescents in the NCANDA study: Contributions from alcohol consumption, age, sex, ethnicity, and family history of addiction. AB - OBJECTIVE: To investigate development of cognitive and motor functions in healthy adolescents and to explore whether hazardous drinking affects the normal developmental course of those functions. METHOD: Participants were 831 adolescents recruited across 5 United States sites of the National Consortium on Alcohol and NeuroDevelopment in Adolescence 692 met criteria for no/low alcohol exposure, and 139 exceeded drinking thresholds. Cross-sectional, baseline data were collected with computerized and traditional neuropsychological tests assessing 8 functional domains expressed as composite scores. General additive modeling evaluated factors potentially modulating performance (age, sex, ethnicity, socioeconomic status, and pubertal developmental stage). RESULTS: Older no/low-drinking participants achieved better scores than younger ones on 5 accuracy composites (general ability, abstraction, attention, emotion, and balance). Speeded responses for attention, motor speed, and general ability were sensitive to age and pubertal development. The exceeds-threshold group (accounting for age, sex, and other demographic factors) performed significantly below the no/low-drinking group on balance accuracy and on general ability, attention, episodic memory, emotion, and motor speed scores and showed evidence for faster speed at the expense of accuracy. Delay Discounting performance was consistent with poor impulse control in the younger no/low drinkers and in exceeds-threshold drinkers regardless of age. CONCLUSIONS: Higher achievement with older age and pubertal stage in general ability, abstraction, attention, emotion, and balance suggests continued functional development through adolescence, possibly supported by concurrently maturing frontal, limbic, and cerebellar brain systems. Determination of whether low scores by the exceeds threshold group resulted from drinking or from other preexisting factors requires longitudinal study. (PsycINFO Database Record PMID- 26752125 TI - White matter and information processing speed following treatment with cranial spinal radiation for pediatric brain tumor. AB - OBJECTIVE: We compared the structure of specific white matter tracts and information processing speed between children treated for posterior fossa tumors with cranial-spinal radiation (n = 30), or with surgery +/- focal radiation (n = 29), and healthy children (n = 37). METHOD: Probabilistic diffusion tensor imaging (DTI) tractography was used to delineate the inferior longitudinal fasciculi, optic radiation, inferior frontal occipital fasciculi, and uncinate fasciculi bilaterally. Information processing speed was measured using the coding and symbol search subtests of the Wechsler Intelligence Scales, and visual matching, pair cancellation, and rapid picture naming subtests of the Woodcock Johnson Test of Cognitive Ability, 3rd revision. We examined group differences using repeated measures MANOVAs and path analyses were used to test the relations between treatment, white matter structure of the tracts, and information processing speed. RESULTS: DTI indices of the optic radiations, the inferior longitudinal fasciculi, and the inferior fronto-occipital fasciculi differed between children treated with cranial-spinal radiation and children treated with surgery +/- focal radiation, and healthy controls (p = .045). Children treated with cranial-spinal radiation also exhibited lower processing speed scores relative to healthy control subjects (p = .002). Notably, we observed that group differences in information processing speed were related to the structure of the right optic radiation (p = .002). CONCLUSION: We show that cranial-spinal radiation may have a negative impact on information processing speed via insult to the right optic radiations. (PsycINFO Database Record PMID- 26752127 TI - Measuring Symmetry in Children With Unrepaired Cleft Lip: Defining a Standard for the Three-Dimensional Midfacial Reference Plane. AB - OBJECTIVE: Quantitative measures of facial form to evaluate treatment outcomes for cleft lip (CL) are currently limited. Computer-based analysis of three dimensional (3D) images provides an opportunity for efficient and objective analysis. The purpose of this study was to define a computer-based standard of identifying the 3D midfacial reference plane of the face in children with unrepaired cleft lip for measurement of facial symmetry. PARTICIPANTS: The 3D images of 50 subjects (35 with unilateral CL, 10 with bilateral CL, five controls) were included in this study. INTERVENTIONS: Five methods of defining a midfacial plane were applied to each image, including two human-based (Direct Placement, Manual Landmark) and three computer-based (Mirror, Deformation, Learning) methods. MAIN OUTCOME MEASURE: Six blinded raters (three cleft surgeons, two craniofacial pediatricians, and one craniofacial researcher) independently ranked and rated the accuracy of the defined planes. RESULTS: Among computer-based methods, the Deformation method performed significantly better than the others. Although human-based methods performed best, there was no significant difference compared with the Deformation method. The average correlation coefficient among raters was .4; however, it was .7 and .9 when the angular difference between planes was greater than 6 degrees and 8 degrees , respectively. CONCLUSIONS: Raters can agree on the 3D midfacial reference plane in children with unrepaired CL using digital surface mesh. The Deformation method performed best among computer-based methods evaluated and can be considered a useful tool to carry out automated measurements of facial symmetry in children with unrepaired cleft lip. PMID- 26752128 TI - Structural Fat Grafting to Improve Reconstructive Outcomes in Secondary Cleft Lip Deformity. AB - OBJECTIVE: To describe the technique and results of structural fat grafting in cleft lip revision, including patient satisfaction and aesthetic outcome. DESIGN: Retrospective case series. SETTING: Multidisciplinary cleft care center. PATIENTS: All patients who underwent structural fat grafting between June 2006 and September 2012 for cleft lip revision, with appropriate photographic follow up included. Twenty-two cases were reviewed; 18 had sufficient data to be included. INTERVENTIONS: Patients underwent structural fat grafting for cleft lip revision, most commonly injecting fat under deficient philtral columns, the nostril base, and upper lip. MAIN OUTCOME MEASURES: Blinded observers rated outcomes using the Asher-McDade nasolabial appearance rating scale. Patients completed questionnaires assessing their satisfaction. A paired Student's t-test was used to test outcomes for significance (alpha = 0.05). RESULTS: Patients were an average of 16 years old (range: 6-43); average length of follow up was 11.7 months. Overall symmetry and aesthetics were improved based on the nasal form (P = 0.006) and vermillion border (P = 0.04) when rated using the Asher-McDade scale. No complications were recorded. Patients were significantly happier with their appearance after fat grafting (P < 0.001) and were uniformly positive when questioned about the ease of the surgery and rate of recovery. CONCLUSIONS: Structural fat grafting is a safe and effective way to improve symmetry and enhance facial proportions in patients with cleft lip. Given the high degree of patient satisfaction, few complications, and durable results, fat grafting offers many advantages in cleft lip revision. PMID- 26752129 TI - Concerning the Article Entitled "Judgment of Nasolabial Esthetics in Cleft Lip and Palate Is Not Influenced by Overall Facial Attractiveness". PMID- 26752130 TI - National Estimates of and Risk Factors for Inpatient Revision Surgeries for Orofacial Clefts. AB - OBJECTIVE: To provide national estimates of the number and cost of primary and revision cleft lip and palate surgeries in the U.S. and to determine patient and hospital characteristics associated with disproportionate use of revision surgery. DESIGN: Retrospective cross-sectional study using data obtained from the 2003, 2006, and 2009 Kids' Inpatient Database. SETTING: Inpatient. PATIENTS: Children with CL, CP, or CLP undergoing inpatient cleft lip and/or palate surgery. INTERVENTIONS: Inpatient cleft lip and/or palate surgery. MAIN OUTCOME MEASURES: Orofacial cleft surgery estimates, estimates of primary versus revision surgeries, and estimated inflation-adjusted hospitalization costs. RESULTS: In 2009, there were a total of 2824 and 5431 hospitalizations for cleft lip and palate surgeries, respectively. Revision surgery accounted for 24.2% of cleft lip surgeries and 36.8% of cleft palate surgeries. Children with CLP (OR 1.87, 95% CI: 1.48-2.38), a syndromic diagnosis (OR 1.47, 95% CI: 1.16-1.87), or private insurance (OR 1.71, 95% CI: 1.41-2.09) were more likely to undergo cleft lip revision surgery. Similar risk factors were found for children undergoing cleft palate revision. Mean cost per hospitalization ranged from $7564 to $8393 in 2009, depending on surgery type, and did not change significantly (in 2009 U.S. $) between 2003 and 2009. CONCLUSIONS: Interventions to reduce revision surgery by improving results of primary surgery should be targeted in the population of identified high-risk (e.g., syndromic) patients. In addition, the association of health insurance status with revision surgery highlights the need to understand and address the impact of economic disparities on cleft care delivery. PMID- 26752131 TI - Rapid Maxillary Expansion After Alveolar Bone Grafting With rhBMP-2 in UCLP Evaluated by Means of CBCT. AB - OBJECTIVE: To demonstrate the feasibility of rapid maxillary expansion (RME) after alveolar bone grafting (ABG) in complete unilateral cleft lip, alveolus and palate (UCLP) without damage to the grafted area. SETTING: Hospital for Rehabilitation of Craniofacial Anomalies (HRAC), University of Sao Paulo, Department of Orthodontics. PATIENT: A case report of a 10-year-old boy with a complete UCLP who was treated with RME after secondary ABG procedure. RME was performed 1.3 years after the bone grafting with rhBMP-2 in collagen membrane. RESULT: Postexpansion cone-beam computed tomography (CBCT) axial and coronal sections demonstrated the opening of the midpalatal suture in the premaxilla without damages to the alveolar bone grafting region. Postretention CBCT images showed bone formation at the split midsuture of the premaxilla. CONCLUSION: Rapid maxillary expansion performed after ABG with rH-BMP2 led to complete opening of the premaxillary midline suture without compromising the integrity of the grafted alveolar cleft. PMID- 26752133 TI - Do Pharyngeal Flaps Restrict Early Midface Growth in Patients With Clefts? AB - OBJECTIVE: To compare facial growth characteristics in patients with cleft palate who have undergone pharyngeal flap with those who had palatal lengthening or pharyngoplasty and to control subjects who have not had surgery for velopharyngeal insufficiency (VPI). DESIGN: Matched retrospective cohort study. SETTING: Multidisciplinary cleft care center. PATIENTS: All patients with cleft palate who had undergone pharyngeal flap or pharyngoplasty/palatal lengthening for VPI were included. Patients with craniofacial syndromes or those who had undergone maxillary protraction were excluded. A control group did not undergo surgery for VPI. The three groups were matched based on cleft type and ages at VPI surgery and cephalogram. MAIN OUTCOME MEASURES: Thirteen craniofacial measurements were evaluated on postoperative cephalograms using an analysis of variance with a Bonferroni adjustment for significant measures (alpha = 0.05). RESULTS: Seventy-two patients were included; mean ages at VPI surgery and postoperative cephalogram were 5 and 8 years, respectively. Twelve of thirteen craniofacial measures were not significantly different; notably, this included maxillary height and projection. Only gonial angle was found to differ significantly (P = .018) in that pharyngoplasty and pharyngeal flap yielded a smaller angle compared with that in control subjects. CONCLUSION: Facial growth, and in particular maxillary growth, was not altered as expected after pharyngeal flap surgery. Pharyngeal flap appears to be equivalent to pharyngoplasty and palatal lengthening in that no significant effects on early facial growth were detected after surgery for VPI in this cohort of children with cleft palate. PMID- 26752132 TI - Cone-Beam Computed Tomography Analysis of the Nasopharyngeal Airway in Nonsyndromic Cleft Lip and Palate Subjects. AB - OBJECTIVE: To assess the nasopharyngeal airway volume, cross-sectional area, and depth in previously repaired nonsyndromic unilateral cleft lip and palate versus bilateral cleft lip and palate patients compared with noncleft controls using cone-beam computed tomography with the ultimate goal of finding whether cleft lip and palate patients are more liable to nasopharyngeal airway obstruction. DESIGN: A retrospective analysis comparing bilateral cleft lip and palate, unilateral cleft lip and palate, and control subjects. Significance at P <= .05. SETTING: Cleft Care Center and the outpatient clinic that are both affiliated with our faculty. PARTICIPANTS: Cone-beam computed tomography data were selected of 58 individuals aged 9 to 12 years: 14 with bilateral cleft lip and palate and 20 with unilateral cleft lip and palate as well as 24 age- and gender-matched noncleft controls. VARIABLES: Volume, depth, and cross-sectional area of nasopharyngeal airway were measured. RESULTS: Patients with bilateral cleft lip and palate showed significantly larger nasopharyngeal airway volume than controls and patients with unilateral cleft lip and palate (P < .001). Patients with bilateral cleft lip and palate showed significantly larger cross-sectional area than those with unilateral cleft lip and palate (P < .001) and insignificant cross-sectional area compared with controls (P > .05). Patients with bilateral cleft lip and palate showed significantly larger depth than controls and those with unilateral cleft lip and palate (P < .001). Patients with unilateral cleft lip and palate showed insignificant nasopharyngeal airway volume, cross-sectional area, and depth compared with controls (P > .05). CONCLUSIONS: Unilateral and bilateral cleft lip and palate patients did not show significantly less volume, cross-sectional area, or depth of nasopharyngeal airway than controls. From the results of this study we conclude that unilateral and bilateral cleft lip and palate patients at the studied age and stage of repaired clefts are not more prone to nasopharyngeal airway obstruction than controls. PMID- 26752134 TI - Velopharyngeal Dysfunction and Sleep Apnea-A Survey to Ascertain Surgical Practice Patterns. AB - OBJECTIVE: To determine if all cleft surgeons uniformly and adequately evaluate patients with cleft for obstructive sleep apnea (OSA) and consider OSA in treatment of velopharyngeal dysfunction (VPD). DESIGN: A 22-question survey was administered via e-mail to 1117 surgeons who were members of the American Cleft Palate-Craniofacial Association. Logistic regression was used to determine if management was affected by years in practice, clinical volume, field of training, and region of practice. MAIN OUTCOME MEASURES: We sought to determine if years in practice, clinical volume, region of practice, and surgical specialty affected surgeons' evaluation of OSA and their approaches to VPD. RESULTS: A total of 231 surgeons responded (21% response rate), and 67% stated that they had trained in plastic surgery. With increasing years of practice, surgeons were less likely to refer patients for preoperative and postoperative sleep studies (P = .00 and P = .001, respectively), screen patients for sleep apnea (P = .008), or change their management based on a sleep study (P = .001). There were no significant differences in screening or testing for OSA based upon clinical volume. Among those surveyed, otolaryngologists were more likely to refer patients for postoperative sleep studies (P = .028). Surgeons in the Southeast were more likely to change their management based upon a sleep study (P = .038). CONCLUSIONS: Statistically significant trends in screening and testing for OSA in the setting of VPD were identified by this survey. Notably, older surgeons were less likely to investigate OSA in their patients, and not all specialties equally refer for postoperative sleep studies. PMID- 26752136 TI - Azoniaspiro salts: towards bridging the gap between room-temperature ionic liquids and molten salts. AB - In a continued effort to improve the suitability of ionic liquids in applications operating at raised temperatures, novel spirocyclic 'azoniaspiro' salts (with cations derived from five-, six-, seven- and eight-membered rings) are prepared and characterised. The structural and thermal properties of these salts are compared against those of established analogues. The stable geometries and ion pairing behaviour of these species are investigated via a combined experimental/computational approach, employing X-ray crystallography and Density Functional Theory (DFT) methods. Subsequently, the thermal stabilities of these organic salts are characterised and compared using a broad range of techniques. Hyphenated Thermogravimetry-Mass Spectrometry investigations enable complex mechanisms underlying thermal decomposition to be elucidated. Lastly, transition state structures are optimised, corresponding to plausible decomposition mechanisms of the azoniaspiro salt, 6-azoniaspiro[6.5]dodecanium chloride, and one prototypical monocyclic species 1-butyl-1-methylpiperidinium chloride, using DFT. The observed improved thermal stabilities of the azoniaspiro salts, and their potential higher-temperature stable-liquid ranges, render them promising candidates for future ionic liquid applications. PMID- 26752135 TI - Grommet Surgery in Children With Orofacial Clefts in England. AB - OBJECTIVE: To assess grommet insertion practice in the first 5 years of life among children with an orofacial cleft in England. DESIGN: Analysis of national administrative data of hospital admissions. SETTING: National Health Service hospitals, England. PATIENTS: Patients born between 1997 and 2005 who underwent surgical cleft repair. INTERVENTION: Children receiving grommets before the age of 5 years. OUTCOME MEASURES: The proportion of children receiving grommets before the age of 5 years, the timing of the first grommet insertion, and the proportion of children having repeat grommet insertions were examined according to cleft type, the absence or presence of additional anomalies, socioeconomic deprivation, and region of residence. RESULTS: The study included 8,269 children. Before the age of 5 years, 3,015 (36.5%) children received grommets. Of these, 33.2% received their first grommets at primary cleft repair and 33.3% underwent multiple grommet insertion procedures. The most common age for the first procedure was between 6 and 12 months. Children with a cleft affecting the palate were more likely to receive grommets than children with a cleft lip alone (45.5% versus 4.5%). Grommet insertion practice also varied according to year of birth, absence or presence of additional anomalies, socioeconomic deprivation, and region of residence. CONCLUSION: Grommets practice in children with a cleft appears to vary according to their clinical characteristics. The differences in practice observed according to deprivation and region of residence need to be further explored. PMID- 26752137 TI - Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation. AB - The outcome of patients with therapy-related myelodysplasia (t-MDS) or t-AML is very poor. The only curative treatment option implements allogeneic hematopoietic cell transplantation (aHCT); however, long-term follow-up data beyond 5 years are scarce. Here we report on a cohort of 79 consecutive patients with a median age of 58 years (range (r): 20-76) at transplantation and a median follow-up of 7.5 years (r: 0.07-19.0). Only 19 (24.1%) patients were in CR before aHCT. Non relapse mortality and relapse rates were 23% (95% confidence interval, 15-35%) and 42% (32-55%) at 5 years, and 32% (22-46%) and 44% (34-57%) at 10 years, respectively. Disease-free survival (DFS) and overall survival (OS) rates were 35% (24-46%) and 38% (27-49%) at 5 years, and 24% (14-36%) and 24% (13-36%) at 10 years, respectively. Although cytogenetic aberrations were associated with shorter DFS and higher relapse risk, persistent disease at the time of transplantation, an unrelated donor and patient age were not associated with shorter OS. In conclusion, long-term survival beyond 10 years of t-MDS/t-AML patients after aHCT is possible, even for refractory patients. Therefore, early donor search and rapid transplantation are warranted, also to decrease the risk of disease-related deterioration of patients' performance status. PMID- 26752138 TI - A comparison of lamivudine vs entecavir for prophylaxis of hepatitis B virus reactivation in allogeneic hematopoietic stem cell transplantation recipients: a single-institutional experience. AB - The aim of this study was to compare the efficacy of lamivudine vs entecavir in the prevention of hepatitis B virus (HBV) reactivation in HBV surface Ag (HBsAg) positive patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 216 consecutive patients were enrolled and retrospectively reviewed. Of these patients, 119 received lamivudine and 97 received entecavir. The median treatment duration to complete virological response in patients with baseline HBV-DNA levels >10(5) copies/mL was 2.0 months in the entecavir group, significantly shorter than that of the lamivudine group. After a median follow-up of 24 months post transplantation, the cumulative incidence rates of HBV reactivation at 6, 12 and 24 months following transplantation were 3.0%, 7.0% and 24.0% in the lamivudine group, and 0%, 0% and 2.0% in the entecavir group, respectively. In addition, entecavir treatment was associated with lower cumulative incidence rates of severe hepatitis caused by HBV reactivation. Mutations leading to drug resistance were detected in 25 patients in the lamivudine group and in only one patient in the entecavir group. Our data indicate that compared with lamivudine, entecavir has more potent antiviral efficacy and may be a better choice for prophylaxis of HBV reactivation in HBsAg-positive allo-HSCT recipients. PMID- 26752139 TI - Hemopoietic stem cell transplantation in thalassemia: a report from the European Society for Blood and Bone Marrow Transplantation Hemoglobinopathy Registry, 2000 2010. AB - Allogeneic hemopoietic stem cell transplantation (HSCT) is the only method currently available to cure transfusion-dependent thalassemia major that has been widely used worldwide. To verify transplantation distribution, demography, activity, policies and outcomes inside the European Group for Blood and Marrow Transplantation (EBMT), we performed a retrospective non-interventional study, extracting data from the EBMT hemoglobinopathy prospective registry database. We included 1493 consecutive patients with thalassemia major transplanted between 1 January 2000 and 31 December 2010. In total, 1359 (91%) transplants were performed on patients <18 years old, 1061 were from a human leukocyte Ag identical sibling donor. After a median observation time of 2 years, the 2-year overall survival (OS) and event-free survival (EFS; that is, thalassemia-free survival) were 88 +/- 1% and 81 +/- 1%, respectively. Transplantation from a human leukocyte Ag-identical sibling offered the best results, with OS and EFS of 91 +/- 1% and 83 +/- 1%, respectively. No significant differences in survival were reported between countries. The threshold age for optimal transplant outcomes was around 14 years, with an OS of 90-96% and an EFS of 83-93% when transplants were performed before this age. Allogeneic HSCT for thalassemia is a curative approach that is employed internationally and produces excellent results. PMID- 26752141 TI - Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation. AB - Ibrutinib, a recently approved inhibitor of Bruton's tyrosine kinase (BTK), has shown great efficacy in patients with high-risk CLL. Nevertheless, there are few data regarding its use in patients who relapsed after allogeneic stem cell transplantation (alloSCT). We report clinical data from five CLL patients treated with ibrutinib for relapse after first or even second allogeneic transplantation. Additionally, we performed analyses on cytokine levels and direct measuring of CD4 Th1 and CD4 Th2 cells to evaluate possible clinically relevant immunomodulatory effects of ibrutinib. All patients achieved partial responses including one minimal residual disease (MRD)-negative remission. Within 1 year of follow-up, no relapse was observed. One patient died of severe pneumonia while on ibrutinib treatment. Beside this, no unexpected adverse events were observed. Flow cytometry and analyses of T cell-mediated cytokine levels (IL10 and TNFalpha) did not reveal substantial changes in T-cell distribution in favor of a CD4 Th1 T-cell shift in our patients. No acute exacerbation of GvHD was reported. In conclusion, these results support further evaluation of ibrutinib in CLL patients relapsing after alloSCT. PMID- 26752140 TI - Low-dose irradiation prior to bone marrow transplantation results in ATM activation and increased lethality in Atm-deficient mice. AB - Ataxia telangiectasia is a genetic instability syndrome characterized by neurodegeneration, immunodeficiency, severe bronchial complications, hypersensitivity to radiotherapy and an elevated risk of malignancies. Repopulation with ATM-competent bone marrow-derived cells (BMDCs) significantly prolonged the lifespan and improved the phenotype of Atm-deficient mice. The aim of the present study was to promote BMDC engraftment after bone marrow transplantation using low-dose irradiation (IR) as a co-conditioning strategy. Atm-deficient mice were transplanted with green fluorescent protein-expressing, ATM-positive BMDCs using a clinically relevant non-myeloablative host conditioning regimen together with TBI (0.2-2.0 Gy). IR significantly improved the engraftment of BMDCs into the bone marrow, blood, spleen and lung in a dose dependent manner, but not into the cerebellum. However, with increasing doses, IR lethality increased even after low-dose IR. Analysis of the bronchoalveolar lavage fluid and lung histochemistry revealed a significant enhancement in the number of inflammatory cells and oxidative damage. A delay in the resolution of gamma-H2AX-expression points to an insufficient double-strand break repair capacity following IR with 0.5 Gy in Atm-deficient splenocytes. Our results demonstrate that even low-dose IR results in ATM activation. In the absence of ATM, low-dose IR leads to increased inflammation, oxidative stress and lethality in the Atm-deficient mouse model. PMID- 26752142 TI - Analysis of non-relapse mortality and causes of death over 15 years following allogeneic hematopoietic stem cell transplantation. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has curative potential against hematological malignancies. However, there are concerns about the associated risk of non-relapse mortality (NRM). We performed a retrospective single-center study to assess changes in outcomes after allo-HSCT and causes of NRM over three 5-year periods. The rates of 2-year NRM and overall survival (OS) were 16% and 59%, respectively. We found a significant decrease in NRM (P<0.001), with 2-year NRM of 26, 14 and 9%, and a significant increase in OS (P=0.005), with 2-year OS of 52%, 58% and 65%, over the three periods (1998-2002, 2003-2007 and 2008-2012), respectively. Of note, a steady improvement was observed in NRM, period by period, among patients aged 50 years or older, patients who underwent HSCT from an unrelated bone marrow donor and patients who underwent HSCT with a reduced-intensity conditioning regimen. Our data showed that the improved NRM can mainly be attributed to a decreased mortality related to infection after starting systemic steroid as GVHD treatment, and a decreased mortality related to organ failure. PMID- 26752143 TI - Rehabilitation need and referrals in hematopoietic stem cell transplantation: the experience of Quality of Life Working Party of the Rome Transplant Network. PMID- 26752145 TI - Treatment of hepatitis C in a pediatric patient using simeprevir and sofosbuvir immediately after an umbilical cord blood transplantation. PMID- 26752144 TI - Phosphorylated STAT3 expression in hematopoietic stem cell transplant-associated large granular lymphocytic leukemia. PMID- 26752146 TI - Early changes in bone mineral density and trabecular bone score following allogeneic stem cell transplant. PMID- 26752147 TI - Adverse reactions during stem cell infusion in children treated with autologous and allogeneic stem cell transplantation. AB - Adverse reactions (ARs) during the infusion of cellular therapy products (CTPs) are common in patients undergoing hematopoietic stem cell transplantation (HSCT). We retrospectively studied pediatric patients undergoing autologous and allogeneic HSCT to determine the incidence and grade of ARs during stem cell infusion and their predictors. We analyzed data from 213 patients (120 allogeneic and 93 autologous) who received at least 1 CTP, totaling 361 infusion episodes. Serious ARs, defined as grade 2 and 3, occurred in 25 and 11% of infusions, respectively. No grade 4 or 5 ARs were noted. Independent risk factors for developing a serious AR included stem cell source (PBSC vs marrow (odds ratio (OR) 1.8, 95% confidence interval (CI): 0.4-9); cord vs marrow (OR 7.3, 95% CI: 1.3-40), overall P=0.0001) but manipulated CTPs were protective (OR 0.4, 95% CI: 0.2-0.7, P=0.004). Unlike previous adult studies, WBC and granulocyte content were not found to be risk factors in this pediatric population. These data suggest that children tolerate higher WBC content during infusion of CTPs and support the use of manipulated CTP, as indicated, to reduce the risk of adverse infusion reactions. PMID- 26752149 TI - Sorption of water alkalinity and hardness from high-strength wastewater on bifunctional activated carbon: process optimization, kinetics and equilibrium studies. AB - Sorption optimization and mechanism of hardness and alkalinity on bifunctional empty fruit bunch-based powdered activation carbon (PAC) were studied. The PAC possessed both high surface area and ion-exchange properties, and it was utilized in the treatment of biotreated palm oil mill effluent. Batch adsorption experiments designed with Design Expert((r)) were conducted in correlating the singular and interactive effects of the three adsorption parameters: PAC dosage, agitation speed and contact time. The sorption trends of the two contaminants were sequentially assessed through a full factorial design with three factor interaction models and a central composite design with polynomial models of quadratic order. Analysis of variance revealed the significant factors on each design response with very high R(2) values indicating good agreement between model and experimental values. The optimum operating conditions of the two contaminants differed due to their different regions of operating interests, thus necessitating the utility of desirability factor to get consolidated optimum operation conditions. The equilibrium data for alkalinity and hardness sorption were better represented by the Langmuir isotherm, while the pseudo-second-order kinetic model described the adsorption rates and behavior better. It was concluded that chemisorption contributed majorly to the adsorption process. PMID- 26752148 TI - Distribution of human umbilical cord blood-derived mesenchymal stem cells in the Alzheimer's disease transgenic mouse after a single intravenous injection. AB - The aim of this study was to track the migration of human umbilical cord blood derived mesenchymal stem cells (hUCB-MSCs) administered through a single intravenous injection and to observe the consequential therapeutic effects in a transgenic Alzheimer's disease mouse model. Ten-month-old APP/PS1 mice received a total injection of 1*10 cells through the lateral tail vein and were killed 1, 4, and 7 days after administration. On the basis of immunohistochemical analysis, hUCB-MSCs were not detected in the brain at any of the time points. Instead, most of the injected mesenchymal stem cells were found to be distributed in the lung, heart, and liver. In terms of the molecular effects, statistically significant differences in the amyloid beta protein, neprilysin, and SOX2 levels were not observed among the groups. On the basis of the results from this study, we suggest that single intravenously administered hUCB-MSCs are not delivered to the brain and also do not have a significant influence on Alzheimer's disease pathology. PMID- 26752150 TI - Synthesis of antireflective silica coatings through the synergy of polypeptide layer-by-layer assemblies and biomineralization. AB - We report a versatile approach to synthesize silica coatings with antireflective (AR) characteristics through the combination of a layer-by-layer (LbL) assembly technique and biomineralization. LbL assembled decanoyl-modified poly(l lysine)/poly(l-glutamic acid) (PLL-g-Dec/PLGA) multilayer films were used as templates for silica mineralization, followed by calcination. The specific deposition of silica onto the LbL polypeptide assemblies through amine-catalyzed polycondensation resulted in silica coatings that exhibited the transcription of the nano-/microstructured polypeptide films and their film thickness and porosity can be tuned by varying the number of bilayers, degree of substitution, and PLL molecular weight. AR silica coatings exhibiting more than 6% increase in transmittance in the near UV/visible spectral range can be obtained at an optimized refractive index, thickness, and surface roughness. The abrasion test showed that the silica coatings exhibited sufficient structural durability due to continuous silica nanostructures and low surface roughness. This study demonstrated that nanostructured thin films can be synthesized for AR coatings using the synergy between the LbL assembly technique and biomineralization. PMID- 26752152 TI - Ratiometric Quantum Dot-Ligand System Made by Phase Transfer for Visual Detection of Double-Stranded DNA and Single-Nucleotide Polymorphism. AB - We have developed a proof-of-concept quantum dot-ligand (QD-L) system for visual selective detection of nucleic acids, in combination with a ratiometric fluorescence technique. This system comprises a dual-emission QDs nanohybrid formed by embedding a red-emission QD (rQD) in a silica nanoparticle and electrostatically assembling green-emission QDs (gQDs) onto the silica surface, as the signal displaying unit, and a hydrophobic compound, dipyrido[3,2-a:2',3' c]phenazine (dppz), attached onto the gQDs surface via phase transfer, as the ligand as well as fluorescence quencher of gQDs. This system is successfully used for quantification of double-stranded DNA (dsDNA). Because of its avid binding with dppz, dsDNA can break up the QD-L system, displacing the dppz ligand from the gQDs surface and restoring the gQDs emission. Since the red emission of embedded rQDs stays constant, variations of the dual-emission intensity ratios display continuous color changes from orange to bright green, which can be clearly observed by the naked eye. More importantly, this system is advantageous in terms of specificity over a QD ionic conjugate, because the electrical neutrality of dppz excludes its nonspecific electrostatic association with dsDNA. The QD-L system also is capable of detecting single-nucleotide polymorphism, exhibiting sequence-specific ratiometric fluorescence as a QD-bioconjugate does, but possessing the obvious advantage in terms of low cost, with the avoidance of modification, labeling, and purification processes. Therefore, the QD-L system provides an extremely simple but general strategy for detecting nucleic acids in a facile, sensitive, and specific manner. PMID- 26752151 TI - Perceptions of Human Papillomavirus (HPV) infection and acceptability of HPV vaccine among men attending a sexual health clinic differ according to sexual orientation. AB - Our aim was to gain a better understanding of the knowledge about Human Papillomavirus (HPV) infection and attitudes toward the HPV vaccine among men at risk for sexually transmitted infections (STI). A self-administered questionnaire was completed by attendees of the largest STI Center in Rome, Italy, from April to June 2013. Determinants of vaccine acceptability were investigated using a Structured Equation Model. A total of 423 males participated in the survey: 296 (70.0%) men who have sex with men (MSM) and 127 (30.0%) men who have sex with women (MSW). Only one half of the participants knew that HPV is the cause of genital warts (56.9% of MSM vs. 49.5% of MSW, p=0.28). Even less were aware that HPV causes cancer in men (37.2% vs. 27.3%, p=0.08). MSW were more likely to indicate HPV as a cause of cervical cancer (80.8% vs. 69.3%, p=0.03) and to have heard about the vaccine (58.3 vs. 43.6%, p=0.01). Moreover, 72.1% of MSM and 70.3% of MSW were willing to be vaccinated. A rise of one-unit in the HPV awareness score increased the OR of vaccine acceptability among MSM by 25% (OR 1.25, 95%CI: 1.05-1.49; p=0.013). Differently, only attitudes had a relevant effect on willingness to be vaccinated among MSW (OR 3.32, 95%CI: 1.53-7.17; p=0.002). Efforts should be made to maximize awareness of HPV, especially as a causative agent of genital warts and male cancers, and to reinforce positive attitudes toward vaccination among men visiting STI centers. PMID- 26752155 TI - Patient expectations for a multimodal pain rehabilitation programme: active participation and coping skills. A qualitative study. AB - PURPOSE: To describe what patients with chronic pain expect from a multimodal pain rehabilitation programme. MATERIAL AND METHOD: Qualitative interviews were used to uncover expectations about a multimodal rehabilitation programme offered at the Pain and Rehabilitations Centre, The University Hospital; Linkoping, Sweden. Sixteen women and two men (mean age 37 years; standard deviation 10 years) with chronic benign pain participated. The interviews were analysed using qualitative content analyses. RESULTS: To participate actively in the multimodal pain rehabilitation programme and to learn adequate coping strategies to improve daily life emerged as a main category. It was based on the following four categories comprising expectations about: participating actively in the programme, interacting with the professionals and fellow patients, cognitive effects of the programme and tools for coping, and explicit effects from the programme. CONCLUSIONS: Many patients expressed expectations which may reflect that the information before the programme had started rehabilitation process at the time point for this study. The results could be applied in rehabilitation programmes by acknowledging expectations to interact with professional team members and fellow patients, by early addressing of positive and negative expectations about the future pain and by incorporating and strengthen expectations of learning to cope with pain. Implications for Rehabilitation Patients' expectations to interact with professional team members and fellow patients by participating actively in the pain rehabilitation programme should be acknowledged in each rehabilitation situation. Patients expressed both positive and negative expectations about their future pain situation and these expectations should be addressed as early as possible in the rehabilitation screening process. Patients' expectations of learning to cope with pain should be incorporated and strengthened in multimodal pain rehabilitation programmes. PMID- 26752153 TI - Remission, Relapse, and Persistence of Vulvodynia: A Longitudinal Population Based Study. AB - BACKGROUND: Vulvodynia has been considered to be a chronic disorder. We sought to estimate the probability of and risk factors for remission, relapse, and persistence among women screening positive for vulvodynia. METHODS: Survey-based assessment in a longitudinal population-based study of women (the Woman to Woman Health Study) who screened positive for vulvodynia and completed at least four follow-up surveys. Outcome measures included remission without relapse, relapse (after remission), and persistence of a positive vulvodynia screen. Multinomial regression was used to assess factors associated with outcomes. RESULTS: Of 441 women screening positive for vulvodynia during the study, 239 completed 4 additional surveys. Of these, 23 (9.6%) had consistently positive vulvodynia screens, 121 (50.6%) remitted without relapse, and 95 (39.7%) relapsed following remission. Overall, factors associated with both relapse and persistence (compared with remission alone) included increased severity of pain ever (p < 0.001) or after intercourse (p = 0.03), longer duration of symptoms (p <= 0.001), and screening positive for fibromyalgia (p < 0.001). Factors associated with persistence (but not relapse) included more severe symptoms with intercourse (p = 0.001) and pain with oral sex (p = 0.003) or partner touch (p = 0.04). Factors associated with relapse (but not persistence) included having provoked pain (p = 0.001) or screening positive for interstitial cystitis (p = 0.05) at first positive vulvodynia screen. Demographic characteristics, age at pain onset, and whether vulvodynia was primary or secondary did not predict outcome. CONCLUSION: Remission of vulvodynia symptoms is common with approximately half of remitters experiencing a relapse within 6-30 months. Persistence without remission is the exception rather than the rule. Pain history and comorbid conditions were associated with the more severe outcomes of relapse and/or persistence compared with those who remitted only. These findings provide further support that vulvodynia is heterogeneous and often occurs in an episodic pattern. PMID- 26752157 TI - Neural stem cells sustain natural killer cells that dictate recovery from brain inflammation. AB - Recovery from organ-specific autoimmune diseases largely relies on the mobilization of endogenous repair mechanisms and local factors that control them. Natural killer (NK) cells are swiftly mobilized to organs targeted by autoimmunity and typically undergo numerical contraction when inflammation wanes. We report the unexpected finding that NK cells are retained in the brain subventricular zone (SVZ) during the chronic phase of multiple sclerosis in humans and its animal model in mice. These NK cells were found preferentially in close proximity to SVZ neural stem cells (NSCs) that produce interleukin-15 and sustain functionally competent NK cells. Moreover, NK cells limited the reparative capacity of NSCs following brain inflammation. These findings reveal that reciprocal interactions between NSCs and NK cells regulate neurorepair. PMID- 26752158 TI - Coherent neuronal ensembles are rapidly recruited when making a look-reach decision. AB - Selecting and planning actions recruits neurons across many areas of the brain, but how ensembles of neurons work together to make decisions is unknown. Temporally coherent neural activity may provide a mechanism by which neurons coordinate their activity to make decisions. If so, neurons that are part of coherent ensembles may predict movement choices before other ensembles of neurons. We recorded neuronal activity in the lateral and medial banks of the intraparietal sulcus (IPS) of the posterior parietal cortex while monkeys made choices about where to look and reach. We decoded the activity to predict the choices. Ensembles of neurons that displayed coherent patterns of spiking activity extending across the IPS--'dual-coherent' ensembles--predicted movement choices substantially earlier than other neuronal ensembles. We propose that dual coherent spike timing reflects interactions between groups of neurons that are important to decisions. PMID- 26752159 TI - Parallel specification of competing sensorimotor control policies for alternative action options. AB - Recent theory proposes that the brain, when confronted with several action possibilities, prepares multiple competing movements before deciding among them. Psychophysical supporting evidence for this idea comes from the observation that when reaching towards multiple potential targets, the initial movement is directed towards the average location of the targets, consistent with multiple prepared reaches being executed simultaneously. However, reach planning involves far more than specifying movement direction; it requires the specification of a sensorimotor control policy that sets feedback gains shaping how the motor system responds to errors induced by noise or external perturbations. Here we found that, when a subject is reaching towards multiple potential targets, the feedback gain corresponds to an average of the gains specified when reaching to each target presented alone. Our findings provide evidence that the brain, when presented with multiple action options, computes multiple competing sensorimotor control policies in parallel before implementing one of them. PMID- 26752156 TI - Repetitive sequences: the hidden diversity of heterochromatin in prochilodontid fish. AB - The structure and organization of repetitive elements in fish genomes are still relatively poorly understood, although most of these elements are believed to be located in heterochromatic regions. Repetitive elements are considered essential in evolutionary processes as hotspots for mutations and chromosomal rearrangements, among other functions - thus providing new genomic alternatives and regulatory sites for gene expression. The present study sought to characterize repetitive DNA sequences in the genomes of Semaprochilodus insignis (Jardine & Schomburgk, 1841) and Semaprochilodus taeniurus (Valenciennes, 1817) and identify regions of conserved syntenic blocks in this genome fraction of three species of Prochilodontidae (Semaprochilodus insignis, Semaprochilodus taeniurus, and Prochilodus lineatus (Valenciennes, 1836) by cross-FISH using Cot 1 DNA (renaturation kinetics) probes. We found that the repetitive fractions of the genomes of Semaprochilodus insignis and Semaprochilodus taeniurus have significant amounts of conserved syntenic blocks in hybridization sites, but with low degrees of similarity between them and the genome of Prochilodus lineatus, especially in relation to B chromosomes. The cloning and sequencing of the repetitive genomic elements of Semaprochilodus insignis and Semaprochilodus taeniurus using Cot-1 DNA identified 48 fragments that displayed high similarity with repetitive sequences deposited in public DNA databases and classified as microsatellites, transposons, and retrotransposons. The repetitive fractions of the Semaprochilodus insignis and Semaprochilodus taeniurus genomes exhibited high degrees of conserved syntenic blocks in terms of both the structures and locations of hybridization sites, but a low degree of similarity with the syntenic blocks of the Prochilodus lineatus genome. Future comparative analyses of other prochilodontidae species will be needed to advance our understanding of the organization and evolution of the genomes in this group of fish. PMID- 26752160 TI - KIF1A inhibition immortalizes brain stem cells but blocks BDNF-mediated neuronal migration. AB - Brain neural stem cells (radial glial progenitors, RGPs) undergo a mysterious form of cell cycle-entrained interkinetic nuclear migration (INM) that is driven apically by cytoplasmic dynein and basally by the kinesin KIF1A, which has recently been implicated in human brain developmental disease. To understand the consequences of altered basal INM and the roles of KIF1A in disease, we performed constitutive and conditional RNAi and expressed mutant KIF1A in E16 to P7 rat RGPs and neurons. RGPs inhibited in basal INM still showed normal cell cycle progression, although neurogenic divisions were severely reduced. Postmitotic neuronal migration was independently disrupted at the multipolar stage and accompanied by premature ectopic expression of neuronal differentiation markers. Similar effects were unexpectedly observed throughout the layer of surrounding control cells, mimicked by Bdnf (brain-derived neurotrophic factor) or Dcx RNAi, and rescued by BDNF application. These results identify sequential and independent roles for KIF1A and provide an important new approach for reversing the effects of human disease. PMID- 26752163 TI - Iodised salt contribution to iodine nutrition status of pregnant and lactating women--CORRIGENDUM. PMID- 26752162 TI - Bidirectional GABAergic control of action potential firing in newborn hippocampal granule cells. AB - Newly generated young neurons in the adult hippocampus receive GABAergic synaptic inputs, which are crucial for activity-dependent survival and functional maturation between 1-3 weeks after mitosis. We found synaptically driven action potential (AP) firing in these newborn young cells in adult mice. Although glutamatergic synaptic inputs remained subthreshold, activation of GABAergic synaptic inputs depolarized young neurons and reliably evoked APs. Furthermore, pairing of subthreshold excitatory postsynaptic potentials or somatic current injection with brief bursts of GABAergic inputs revealed efficient GABAergic excitation at conductances of ~ 1.5 nS, corresponding to the activity of only three or four interneurons. Stronger GABAergic inputs (>4 nS) effectively blocked AP firing via shunting inhibition, which might be important to dynamically control spiking output in both directions. Taken together, GABAergic interneurons differentially recruit newborn young granule cells by supporting either AP generation or shunting inhibition dependent on hippocampal network activity. PMID- 26752164 TI - Fetoplacental regional variations in the expression of angiopoietin-1, angiopoietin-2, and Tie2 in normal-term and near-term pregnancies. AB - BACKGROUND: Angiopoietin-1 (Ang1), angiopoietin-2 (Ang2), and the receptor tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (Tie2) are known to be involved in fetoplacental angiogenesis adequacy, which is a primary determinant of fetal growth. Regional variations in Ang1, Ang2, and Tie2 remain unknown, although fetoplacental vascularity and gene expressions differ between the placental center and the periphery. OBJECTIVE: The aim of this study was to test the hypothesis that there are regional variations in the expression of these angiopoietins in human placentas from uncomplicated term and near term pregnancies. STUDY DESIGN: In this prospective study, central and peripheral samples were collected from fresh placentas from normal-term and near-term pregnancies delivered by Cesarean section (n = 7, 36-41 week gestation) prior to the onset of labor. Regional differences in Ang1, Ang2, and Tie2 protein expressions were measured by Western blot and densitometric analyses with b-actin normalization, and their fetoplacental regional localization assessed by immunohistochemistry. The Ang1 and Ang2 ratios at central and peripheral sites were determined. Statistical analysis was performed using Student's t-test. RESULTS: Ang1 protein expression was higher in the placental periphery than in the center (2.48 +/- 0.42 versus 1.74 +/- 0.27, p = 0.01). In contrast, Ang2 protein expression was greater in the placental center than in the periphery (10.10 +/- 1.82 versus 7.15 +/- 1.12, respectively, p = 0.03). The Ang1-Ang2 ratio reflected these differential expressions. Tie2 protein expression was higher in the placental periphery than in the center (0.21 +/- 0.02 versus 0.16 +/- 0.02, p = 0.003). The immunoreactivity of Ang1 and Tie2 was stronger in the periphery than in the center, and that of Ang2 was stronger in the center than in the periphery. CONCLUSIONS: Ang1, Ang2, and Tie2 are differentially expressed in placental center and periphery. Ang1/Ang2 ratio reflects this regional variation in the angiogenic balance that has implications for fetoplacental villous angiogenesis. The results also demonstrate the importance of considering the location of placental sampling sites for any future investigations of fetoplacental villous angiogenesis. PMID- 26752165 TI - Thermal transport properties of MoS2 and MoSe2 monolayers. AB - The isolation of single- to few-layer transition metal dichalcogenides opens new directions in the application of two-dimensional materials to nanoelectronics. The characterization of thermal transport in these new low-dimensional materials is needed for their efficient implementation, either for general overheating issues or specific applications in thermoelectric devices. In this study, the lattice thermal conductivities of single-layer MoS2 and MoSe2 are evaluated using classical molecular dynamics methods. The interactions between atoms are defined by Stillinger-Weber-type empirical potentials that are developed to represent the structural, mechanical, and vibrational properties of the given materials. In the parameterization of the potentials, a stochastic optimization algorithm, namely particle swarm optimization, is utilized. The final parameter sets produce quite consistent results with density functional theory in terms of lattice parameters, bond distances, elastic constants, and vibrational properties of both single layer MoS2 and MoSe2. The predicted thermal properties of both materials are in very good agreement with earlier first-principles calculations. The discrepancies between the calculations and experimental measurements are most probably caused by the pristine nature of the structures in our simulations. PMID- 26752161 TI - Activation of raphe nuclei triggers rapid and distinct effects on parallel olfactory bulb output channels. AB - The serotonergic raphe nuclei are involved in regulating brain states over timescales of minutes and hours. We examined more rapid effects of raphe activation on two classes of principal neurons in the mouse olfactory bulb, mitral and tufted cells, which send olfactory information to distinct targets. Brief stimulation of the raphe nuclei led to excitation of tufted cells at rest and potentiation of their odor responses. While mitral cells at rest were also excited by raphe activation, their odor responses were bidirectionally modulated, leading to improved pattern separation of odors. In vitro whole-cell recordings revealed that specific optogenetic activation of raphe axons affected bulbar neurons through dual release of serotonin and glutamate. Therefore, the raphe nuclei, in addition to their role in neuromodulation of brain states, are also involved in fast, sub-second top-down modulation similar to cortical feedback. This modulation can selectively and differentially sensitize or decorrelate distinct output channels. PMID- 26752166 TI - An update on the strategies used for the treatment of chronic hepatitis B in children. AB - Chronic hepatitis B (CHB) in children shows a variety of clinical presentations, which influence its natural course and treatment options. This report provides an overview of the ongoing strategies in pediatric CHB management. Interferon-alpha represents the first choice of treatment in children showing HBV replication and hepatic inflammation (immune active CHB), while the recommendation is to monitor inactive/immune-tolerant children (normal transaminases and low/absent viral replication). When circumstances preclude the use of Interferon-alpha and in cases of compensated/decompensated cirrhosis, entecavir for children above 2 years of age or tenofovir for children above 12 years of age are the nucleos(t)ide analogues recommended by the most recent guidelines. PMID- 26752168 TI - Assessing Intentions to Eat a Healthful Diet Among National Collegiate Athletic Association Division II Collegiate Athletes. AB - CONTEXT: Many athletes fail to obtain the optimal levels of energy and nutrients to support health and performance. The constructs underlying the Theory of Planned Behavior (TPB) may help identify barriers to healthful eating that can be addressed in nutrition-education programs. OBJECTIVE: To use the TPB to examine factors regarding collegiate male and female student-athletes' intentions of eating a healthful diet. DESIGN: Cross-sectional study. SETTING: Online survey tool. PATIENTS OR OTHER PARTICIPANTS: The survey was taken by 244 male and female National Collegiate Athletic Association Division II athletes, and data from 201 were analyzed. Mean age of the athletes was 20 +/- 1.31 years (range, 18-24 years); most were white (86.1%) and female (78.6%). MAIN OUTCOME MEASURE(S): We assessed predictive strength of attitude, subjective norms, and perceived behavioral control on behavioral intentions. Regression analysis evaluated how the variables of TPB were valued and how they predict behavioral intentions. RESULTS: The combination of attitude, subjective norms, and perceived behavioral controls accounted for 73.4% (R 2) of the variance in behavioral intention (F = 180.82, P < .001). Attitude had the greatest influence on behavioral intentions (beta = .534, P < .001). CONCLUSIONS: Understanding both the intentions of collegiate athletes to eat healthfully and how highly they value nutrition is crucial for the development of effective nutrition education and counseling programs. PMID- 26752170 TI - Elevated Blood Pressure in Acute Ischemic Stroke--Treat or Leave? PMID- 26752169 TI - Incidence, risk factors and outcome of acute kidney injury in critically ill children - a developing country perspective. AB - BACKGROUND: Acute kidney injury (AKI) is common in critically ill children and is associated with poor outcome. OBJECTIVE: To study the incidence, risk factors and outcome of AKI in children admitted to paediatric intensive care unit (PICU) of a developing country. MATERIALS AND METHODS: This prospective observational study was conducted in a tertiary care PICU over one-year period. Critically ill children aged from 2 months to 18 years were included. RIFLE criteria based on GFR, and urine output was used for categorisation. RESULTS: Of 380 children, 53 children (14%) had AKI (met any of the RIFLE criteria). The most common diagnoses underlying AKI were acute lower respiratory tract infection, CNS illness and severe dehydration. Subjects with AKI had a higher PRISM score (>10) at admission, longer duration of stay and high mortality. Significant risk factors for AKI following multivariate analysis were: age 1-5, PRISM score (>10) at admission, shock, infection, thrombocytopenia, hypo-albuminaemia and multi-organ dysfunction. Twenty-six of 53 subjects fulfilled the maximum RIFLE criteria within 72 h after admission and the mean (SD) time to first RIFLE attend was 1.6 (1.2) day. Subjects with AKI (RIFLE criteria) had 4.5 times higher mortality than those without AKI (36 vs 8%, P< etc). CONCLUSION: A high incidence of AKI was noted in the PICU that was associated with high mortality. The RIFLE criterion is an effective tool which can be used not only for predicting the outcomes, but may help in the early identification of patients at risk for AKI. PMID- 26752167 TI - A Genome-wide study of blood pressure in African Americans accounting for gene smoking interaction. AB - Cigarette smoking has been shown to be a health hazard. In addition to being considered a negative lifestyle behavior, studies have shown that cigarette smoking has been linked to genetic underpinnings of hypertension. Because African Americans have the highest incidence and prevalence of hypertension, we examined the joint effect of genetics and cigarette smoking on health among this understudied population. The sample included African Americans from the genome wide association studies of HyperGEN (N = 1083, discovery sample) and GENOA (N = 1427, replication sample), both part of the FBPP. Results suggested that 2 SNPs located on chromosomes 14 (NEDD8; rs11158609; raw p = 9.80 * 10(-9), genomic control-adjusted p = 2.09 * 10(-7)) and 17 (TTYH2; rs8078051; raw p = 6.28 * 10( 8), genomic control-adjusted p = 9.65 * 10(-7)) were associated with SBP including the genetic interaction with cigarette smoking. These two SNPs were not associated with SBP in a main genetic effect only model. This study advances knowledge in the area of main and joint effects of genetics and cigarette smoking on hypertension among African Americans and offers a model to the reader for assessing these risks. More research is required to determine how these genes play a role in expression of hypertension. PMID- 26752171 TI - Phenotype and Hierarchy of Two Transgenic T Cell Lines Targeting the Respiratory Syncytial Virus KdM282-90 Epitope Is Transfer Dose-Dependent. AB - In this study, we compared two lines of transgenic CD8+ T cells specific for the same KdM282-90 epitope of respiratory syncytial virus in the CB6F1 hybrid mouse model. Here we found that these two transgenic lines had similar in vivo abilities to control viral load after respiratory syncytial virus infection using adoptive transfer. Transfer of the TRBV13-2 line resulted in higher levels of IL 6 and MIP1-alpha in the lung than TRBV13-1 transfer. Interestingly, when large numbers of cells were co-transferred, the lines formed a hierarchy, with TRBV13-2 being immunodominant over TRBV13-1 in the mediastinal lymph node despite no identifiable difference in proliferation or apoptosis between the lines. This hierarchy was not established when lower cell numbers were transferred. The phenotype and frequency of proliferating cells were also cell transfer dose dependent with higher percentages of CD127loCD62LloKLRG1lo and proliferating cells present when lower numbers of cells were transferred. These results illustrate the importance of cell number in adoptive transfer experiments and its influence on the phenotype and hierarchy of the subsequent T cell response. PMID- 26752178 TI - Simulation Manikin Modifications for High-Fidelity Training of Advanced Airway Procedures. AB - Thoracic anesthesia procedures are challenging to master during anesthesia training. A Laerdal ALS Simulator(r) manikin was modified by adding a bronchial tree module to create fidelity to the fourth generation. After modification, placement of endotracheal tubes up to 8.0 mm is possible by direct laryngoscopy, video laryngoscopy, and fiberoptically; in addition, it allows fiberoptically guided insertion of endobronchial blockers. Insertion of left and right 35-Fr double-lumen tubes permits double- and single-lung ventilation with continuous positive airway pressure and positive end-expiratory pressure. This anatomical modification created a high-fidelity training tool for thoracic anesthesia that has been incorporated into educational curricula for anesthesia. PMID- 26752177 TI - Circulatory Arrest due to Retrograde Embolization of a Transapically Implanted Aortic Valve Prosthesis with Subsequent Inversion and Left Ventricular Outflow Occlusion. AB - An 82-year-old man required aortic valve replacement because of aortic stenosis. A transapical approach was chosen to reduce surgical mortality. Initially, echocardiography and fluoroscopy confirmed correct valve positioning. Shortly thereafter, progressive paravalvular leakage, embolization of the valve prosthesis into the ventricle, and subsequent inversion of the prosthesis with complete left ventricular outflow occlusion were observed by echocardiography. Left ventricular outflow occlusion resulted in immediate circulatory arrest. We immediately converted to on-pump surgical aortic valve replacement. Cardiac output was restored once the valve was replaced. The patient fully recovered. This case report highlights the importance of periprocedural transesophageal echocardiography, which instantly detected the malpositioned valve and guided emergency management of this severe complication. PMID- 26752172 TI - In Vivo Differences between Two Optical Isomers of Radioiodinated o-iodo-trans decalinvesamicol for Use as a Radioligand for the Vesicular Acetylcholine Transporter. AB - PURPOSE: To develop a superior VAChT imaging probe for SPECT, radiolabeled (-) OIDV and (+)-OIDV were isolated and investigated for differences in their binding affinity and selectivity to VAChT, as well as their in vivo activities. PROCEDURES: Radioiodinated o-iodo-trans-decalinvesamicol ([125I]OIDV) has a high binding affinity for vesicular acetylcholine transporter (VAChT) both in vitro and in vivo. Racemic [125I]OIDV was separated into its two optical isomers (-) [125I]OIDV and (+)-[125I]OIDV by HPLC. To investigate VAChT binding affinity (Ki) of two OIDV isomers, in vitro binding assays were performed. In vivo biodistribution study of each [125I]OIDV isomer in blood, brain regions and major organs of rats was performed at 2,30 and 60 min post-injection. In vivo blocking study were performed to reveal the binding selectivity of two [125I]OIDV isomers to VAChT in vivo. Ex vivo autoradiography were performed to reveal the regional brain distribution of two [125I]OIDV isomers and (-)-[123I]OIDV for SPECT at 60 min postinjection. RESULTS: VAChT binding affinity (Ki) of (-)-[125I]OIDV and (+) [125I]OIDV was 22.1 nM and 79.0 nM, respectively. At 2 min post-injection, accumulation of (-)-[125I]OIDV was the same as that of (+)-[125I]OIDV. However, (+)-[125I]OIDV clearance from the brain was faster than (-)-[125I]OIDV. At 30 min post-injection, accumulation of (-)-[125I]OIDV (0.62 +/- 0.10%ID/g) was higher than (+)-[125I]OIDV (0.46 +/- 0.07%ID/g) in the cortex. Inhibition of OIDV binding showed that (-)-[125I]OIDV was selectively accumulated in regions known to express VAChT in the rat brain, and ex vivo autoradiography further confirmed these results showing similar accumulation of (-)-[125I]OIDV in these regions. Furthermore, (-)-[123I]OIDV for SPECT showed the same regional brain distribution as (-)-[125I]OIDV. CONCLUSION: These results suggest that radioiodinated (-)-OIDV may be a potentially useful tool for studying presynaptic cholinergic neurons in the brain. PMID- 26752179 TI - A Competitive Objective Structured Clinical Examination Event to Generate an Objective Assessment of Anesthesiology Resident Skills Development. AB - Residency programs are charged with teaching, assessing, and documenting resident competency for a multitude of skills throughout the course of residency training. An innovative, competition-based objective structured clinical examination event was designed in our department to objectively assess the skill level of anesthesiology residents. After conducting the identical event for 2 years in postgraduate year 1 (PGY1) and postgraduate year 2 (PGY2) residents, we tested the hypothesis that the event can provide adequate standardization to appropriately document progression in technical and nontechnical skills. Twenty one residents participated in both events during their PGY1 and PGY2 years: n = 10, 2012/2013, n = 11, 2013/2014. The PGY1 participants in 2012 were retested in 2013 (as PGY2 residents) during an identical event, and their performance was compared as a group and on an individual level. The PGY1 residents in 2013 did the same in 2014. Four workstations were analyzed to determine whether improvement in performance occurred between the PGY1 and the PGY2 years: (1) preoperative assessment, (2) operating room anesthesia station checkout, (3) peripheral IV and endotracheal tube placement, and (4) transfer of care in the postanesthesia care unit. The performances of PGY1 and PGY2 residents were compared. The assessments were performed by anesthesiology faculty using checklists, time to complete task, and Likert scale ratings. Data analysis showed improved technical anesthesia skills (operating room setup, peripheral IV, and endotracheal tube placement) and more complete anesthesia-related information management in the preoperative assessment and postoperative transition of care in the postanesthesia care unit in PGY2 residents compared with the PGY1 performance of the same residents. The described event is a valuable tool for objective assessment of multiple anesthesia skills and possible milestones during residency. PMID- 26752173 TI - Quercetin Feeding in Newborn Dairy Calves Cannot Compensate Colostrum Deprivation: Study on Metabolic, Antioxidative and Inflammatory Traits. AB - Immaturity of the neonatal immune system is causative for high morbidity in calves and colostrum intake is crucial for acquiring passive immunity. Pathogenesis is promoted by reactive oxygen species accumulating at birth if counter-regulation is inadequate. The flavonol quercetin exerts antioxidative and anti-inflammatory effects that may enhance neonatal health. The aim of this work was to study effects of quercetin feeding on metabolic, antioxidative and inflammatory parameters in neonatal calves to investigate whether quercetin could compensate for insufficient colostrum supply. Twenty-eight newborn calves were assigned to two dietary groups fed colostrum or milk-based formula on day 1 and 2 and milk replacer thereafter. From day 2 onwards, 7 calves per diet group were additionally fed quercetin aglycone (50 mg/(kg body weight * day)). Blood samples were taken repeatedly to measure plasma concentrations of flavonols, glucose, lactate, total protein, albumin, urea, non-esterified fatty acids, triglycerides, cholesterol, insulin, glucagon, cortisol, immunoglobulins, fibrinogen, haptoglobin and serum amyloid A. Trolox equivalent antioxidative capacity, ferric reducing ability of plasma, thiobarbituric acid reactive species and F2 isoprostanes were analyzed to evaluate plasma antioxidative status. Expression of tumor necrosis factor, interleukin-1alpha, interleukin-1beta, serum amyloid A, haptoglobin, fibrinogen, C-reactive protein, catalase, glutathione peroxidase and superoxide dismutase mRNA were measured in liver tissue on day 8. Plasma flavonol concentrations were detectable only after quercetin-feeding without differences between colostrum and formula feeding. Plasma glucose, lactate, total protein, immunoglobulins, triglycerides, cholesterol, trolox equivalent antioxidative capacity and thiobarbituric acid reactive species were higher after colostrum feeding. Body temperature, fecal fluidity and plasma concentrations of cortisol and haptoglobin were higher in formula- than in colostrum-fed groups. Hepatic mRNA expression of tumor necrosis factor was higher after quercetin feeding and expression of C-reactive protein was higher after formula feeding. Data confirm that colostrum improves neonatal health and indicate that quercetin feeding cannot compensate for insufficient colostrum supply. PMID- 26752180 TI - Adaptive Protein Evolution in Animals and the Effective Population Size Hypothesis. AB - The rate at which genomes adapt to environmental changes and the prevalence of adaptive processes in molecular evolution are two controversial issues in current evolutionary genetics. Previous attempts to quantify the genome-wide rate of adaptation through amino-acid substitution have revealed a surprising diversity of patterns, with some species (e.g. Drosophila) experiencing a very high adaptive rate, while other (e.g. humans) are dominated by nearly-neutral processes. It has been suggested that this discrepancy reflects between-species differences in effective population size. Published studies, however, were mainly focused on model organisms, and relied on disparate data sets and methodologies, so that an overview of the prevalence of adaptive protein evolution in nature is currently lacking. Here we extend existing estimators of the amino-acid adaptive rate by explicitly modelling the effect of favourable mutations on non-synonymous polymorphism patterns, and we apply these methods to a newly-built, homogeneous data set of 44 non-model animal species pairs. Data analysis uncovers a major contribution of adaptive evolution to the amino-acid substitution process across all major metazoan phyla-with the notable exception of humans and primates. The proportion of adaptive amino-acid substitution is found to be positively correlated to species effective population size. This relationship, however, appears to be primarily driven by a decreased rate of nearly-neutral amino-acid substitution because of more efficient purifying selection in large populations. Our results reveal that adaptive processes dominate the evolution of proteins in most animal species, but do not corroborate the hypothesis that adaptive substitutions accumulate at a faster rate in large populations. Implications regarding the factors influencing the rate of adaptive evolution and positive selection detection in humans vs. other organisms are discussed. PMID- 26752182 TI - Dextran Nanoparticle Synthesis and Properties. AB - Dextran is widely exploited in medical products and as a component of drug delivering nanoparticles (NPs). Here, we tested whether dextran can serve as the main substrate of NPs and form a stable backbone. We tested dextrans with several molecular masses under several synthesis conditions to optimize NP stability. The analysis of the obtained nanoparticles showed that dextran NPs that were synthesized from 70 kDa dextran with a 5% degree of oxidation of the polysaccharide chain and 50% substitution with dodecylamine formed a NP backbone composed of modified dextran subunits, the mean diameter of which in an aqueous environment was around 100 nm. Dextran NPs could be stored in a dry state and reassembled in water. Moreover, we found that different chemical moieties (e.g., drugs such as doxorubicin) can be attached to the dextran NPs via a pH-dependent bond that allows release of the drug with lowering pH. We conclude that dextran NPs are a promising nano drug carrier. PMID- 26752181 TI - Curcumin Suppresses Proliferation and Migration of MDA-MB-231 Breast Cancer Cells through Autophagy-Dependent Akt Degradation. AB - Previous studies have evidenced that the anticancer potential of curcumin (diferuloylmethane), a main yellow bioactive compound from plant turmeric was mediated by interfering with PI3K/Akt signaling. However, the underlying molecular mechanism is still poorly understood. This study experimentally revealed that curcumin treatment reduced Akt protein expression in a dose- and time-dependent manner in MDA-MB-231 breast cancer cells, along with an activation of autophagy and suppression of ubiquitin-proteasome system (UPS) function. The curcumin-reduced Akt expression, cell proliferation, and migration were prevented by genetic and pharmacological inhibition of autophagy but not by UPS inhibition. Additionally, inactivation of AMPK by its specific inhibitor compound C or by target shRNA-mediated silencing attenuated curcumin-activated autophagy. Thus, these results indicate that curcumin-stimulated AMPK activity induces activation of the autophagy-lysosomal protein degradation pathway leading to Akt degradation and the subsequent suppression of proliferation and migration in breast cancer cell. PMID- 26752184 TI - Circulating Adipocyte Fatty Acid Binding Protein (FABP4) Levels Are Associated with Irisin in the Middle-Aged General Chinese Population. AB - BACKGROUND: Adipocyte fatty acid binding protein (FABP4) has been recently characterized as an adipokine that is closely associated with obesity and metabolic syndrome. Irisin, a novel myokine, activates thermogenesis by increasing the transformation of white adipocytes to brown, and it has improved glucose homeostasis in animal models. In this study, we aimed to explore the relationship between serum FABP4 and irisin in middle-aged Chinese subjects. METHODS: A total of 111 normal residents (56 men and 55 women) of Fengxian District who were 40 to 60 years of age were recruited. Circulating FABP4 and irisin were determined by enzyme-linked immunosorbent assay. Anthropometric parameters, oral glucose tolerance test results, hemoglobin A1C (HbA1C), blood lipids, homeostasis model assessment of insulin resistance, homeostasis model assessment-beta and body fat composition were also determined. RESULTS: All participants were categorized by FABP4 tertiles. There were significant differences in blood pressure, body fat percentage, 2-h plasma glucose, and skeletal muscle mass among the three groups (P<0.05). Furthermore, FABP4 levels in the women were significantly higher than in the men (P<0.05). However, there was no sexual dimorphism in serum irisin (P>0.05). To exclude the effect of sex difference, partial correlations analysis showed that FABP4 was positively correlated with diastolic blood pressure (P<0.05) and body fat percentage (P<0.05) negatively correlated with skeletal muscle mass (P<0.05) and irisin (P<0.05), while irisin was positively correlated with HbA1c (P<0.05) and negatively correlated with creatinine (P<0.05). Multivariate regression analysis demonstrated that serum FABP4 was independently associated with skeletal muscle mass (P<0.001), diastolic blood pressure (P<0.05) and irisin (P<0.05) after adjustment for age, body mass index, body fat percentage, total cholesterol and HbA1C. CONCLUSIONS: Elevated FABP4 levels increase the risks of obesity-related metabolic disorders and hypertension. Serum irisin might exert antagonistic effects on FABP4 in the middle-aged Chinese population. PMID- 26752183 TI - Functions of Ceramide Synthase Paralogs YPR114w and YJR116w of Saccharomyces cerevisiae. AB - Ceramide is synthesized in yeast by two redundant acyl-CoA dependent synthases, Lag1 and Lac1. In lag1? lac1? cells, free fatty acids and sphingoid bases are elevated, and ceramides are produced through the redundant alkaline ceramidases Ypc1 and Ydc1, working backwards. Even with all four of these genes deleted, cells are surviving and continue to contain small amounts of complex sphingolipids. Here we show that these residual sphingolipids are not synthesized by YPR114w or YJR116w, proteins of unknown function showing a high degree of homology to Lag1 and Lac1. Indeed, the hextuple lag1? lac1? ypc1? ydc1? ypr114w? yjr116w? mutant still contains ceramides and complex sphingolipids. Yjr116w? exhibit an oxygen-dependent hypersensitivity to Cu2+ due to an increased mitochondrial production of reactive oxygen species (ROS) and a mitochondrially orchestrated programmed cell death in presence of copper, but also a general copper hypersensitivity that cannot be counteracted by the antioxidant N-acetyl cysteine (NAC). Myriocin efficiently represses the synthesis of sphingoid bases of ypr114w?, but not its growth. Both yjr116w? and ypr114w? have fragmented vacuoles and produce less ROS than wild type, before and after diauxic shift. Ypr114w?/ypr114w? have an increased chronological life span. Thus, Yjr116w and Ypr114w are related, but not functionally redundant. PMID- 26752186 TI - American Association of Oral and Maxillofacial Surgeons' Anesthesia and Third Molar Extraction Benchmark Study: Rationale, Methods, and Initial Findings. AB - PURPOSE: Benchmark statistics are used in quality assurance/quality improvement processes. The purposes of the present report are to 1) review the rationale for a new specialty-specific benchmark study, 2) summarize the methods to create a practice-based research collaborative (P-BRC) designed for collecting data to create benchmarks, and 3) describe the characteristics of the P-BRC surgeon participants. MATERIALS AND METHODS: The study was designed as a prospective cohort study. We created a P-BRC composed of randomly selected American Association of Oral and Maxillofacial Surgeons (AAOMS) members in private practice in the United States, who agreed to enroll patients scheduled to receive anesthesia of any type in the office-based ambulatory setting. The study variables included clinician demographics and their P-BRC status, grouped as 1) invited, active participants, 2) invited, inactive participants, and 3) uninvited AAOMS members. The P-BRC participants collected data for dozens of variables from their patients related to anesthesia. If the procedure was third molar (M3) surgery, additional M3 procedure-specific data were collected. Data analyses were composed of computing descriptive and bivariate statistics. Preliminary sample size estimates suggested that the P-BRC should include 300 surgeons to produce estimates with a +/-5% error. RESULTS: During the 1-year study interval, 642 surgeons (11.8%) were invited to join the P-BRC from a population of 5,455 eligible AAOMS members. The 124 active participants in the P-BRC contributed 6,344 subjects to the anesthesia data set and 2,978 subjects who had had 9,207 M3s removed to the M3 data set. The active participants in the P-BRC were younger and more likely to be board-certified than were the inactive participants (P < .05). Details of the anesthesia and M3 variables will follow in future reports. CONCLUSIONS: Despite vigorous efforts, we did not achieve our stated goal of creating a P-BRC composed of a random sample of 300 AAOMS members. With the current P-BRC sample, variables with very high (>93%) or very low (<7%) frequency estimates will produce estimates with the desired range of +/-5% error. The P-BRC includes a sample of self-selected, not random, participants and is well characterized in terms of age, gender, board-certification status, academic degrees, and geographic distribution. PMID- 26752187 TI - Early Arising Sarcoma After Adjuvant Radiotherapy for Oral Squamous Cell Carcinoma. AB - Radiation-induced sarcoma of the head and neck (RISHN) is a rare and long-term complication of radiation therapy (RT). This report describes a case of RISHN characterized by early and insidious onset. An 80-year-old man was surgically treated for advanced oral squamous cell carcinoma of the left retromolar trigone (pT4aN0). Sixteen months after completion of adjuvant RT, an exophytic sessile lesion arose in the left border of the soft palate. Histologic assessment showed a malignant neoplasm with spindle-shaped cells and areas of bone matrix without perivascular or perineural invasion; such features in addition to immunohistochemical assessment (negative for pan-cytokeratin; positive for vimentin; negative for epithelial membrane antigen; negative for p63; Ki-67, 30%) are consistent with poorly differentiated sarcoma (cT1aN0M0). Fifteen months after a wide surgical resection, the patient was free of disease. RISHN is usually an aggressive neoplasm with insidious onset. Nevertheless, early diagnosis followed by complete surgical excision could make the prognosis comparable to that of spontaneous sarcoma. PMID- 26752188 TI - Granuloma faciale: A master masquerader? PMID- 26752185 TI - Association between Time of Day of Sports-Related Physical Activity and the Onset of Acute Myocardial Infarction in a Chinese Population. AB - OBJECTIVE: To investigate the association between the time of day of sports related physical activity and the onset of acute myocardial infarction (AMI) in a coronary artery disease (CAD) population in China. METHODS: Between February 2014 and March 2015, a total of 696 patients from Nanjing, China, who had CAD were studied and divided into two groups (Non-AMI and AMI groups). The work-related activity and sports-related physical activity information were obtained from a self-reporting predesigned patient questionnaire. RESULTS: Sports-related physical activity was associated with a lower risk of the onset of AMI, after adjusting the established and potential confounders, with an adjusted odds ratio (OR) of 0.67 (95% CI, 0.47-0.94) compared with those who did not have any sports related physical activity. A dose-response relationship was observed for intensity, duration, and frequency of sports-related physical activity. Further stratification analysis revealed that the protective effects of sports-related physical activity were significant in the morning and evening groups, and patients who exercised in the evening were at a lower risk of AMI than those doing sports-related physical activity in the morning. The adjusted ORs for doing sports-related physical activity in the morning and evening groups were 0.60(0.36 0.98) and 0.56(0.37-0.87), respectively, compared with inactivity (all P<0.05). On the occurrence of AMI, doing sports-related physical activity in the evening had an adjusted OR of 0.93 (95% CI, 0.54-1.64, P = 0.824) compared with in the morning group. CONCLUSIONS: Sports-related physical activity is associated with a lower risk of onset of AMI than inactivity in Chinese people. For CAD patients, we suggest they participate in sports-related physical activity of high intensity, long duration, and high frequency. Doing sports-related physical activity in the evening and in the morning have similar benefits on the prevention of the onset of AMI. PMID- 26752190 TI - Correction: Psychotic-Like Experiences and Nonsuidical Self-Injury in England: Results from a National Survey. PMID- 26752189 TI - Mericitabine and Either Boceprevir or Telaprevir in Combination with Peginterferon Alfa-2a plus Ribavirin for Patients with Chronic Hepatitis C Genotype 1 Infection and Prior Null Response: The Randomized DYNAMO 1 and DYNAMO 2 Studies. AB - Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (<2-log10 reduction in HCV RNA by treatment week 12) to peginterferon/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA <25 IU/mL 12 weeks after the end of treatment (SVR12). Overall, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60-70% in DYNAMO 1 and of 71-96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-generation PI. TRIAL REGISTRATION: ClinicalTrials.gov NCT01482403 and ClinicalTrials.gov NCT01482390. PMID- 26752191 TI - Liver Transplantation After Ex Vivo Normothermic Machine Preservation: A Phase 1 (First-in-Man) Clinical Trial. AB - The number of donor organs suitable for liver transplantation is restricted by cold preservation and ischemia-reperfusion injury. We present the first patients transplanted using a normothermic machine perfusion (NMP) device that transports and stores an organ in a fully functioning state at 37 degrees C. In this Phase 1 trial, organs were retrieved using standard techniques, attached to the perfusion device at the donor hospital, and transported to the implanting center in a functioning state. NMP livers were matched 1:2 to cold-stored livers. Twenty patients underwent liver transplantation after NMP. Median NMP time was 9.3 (3.5 18.5) h versus median cold ischaemia time of 8.9 (4.2-11.4) h. Thirty-day graft survival was similar (100% NMP vs. 97.5% control, p = 1.00). Median peak aspartate aminotransferase in the first 7 days was significantly lower in the NMP group (417 IU [84-4681]) versus (902 IU [218-8786], p = 0.03). This first report of liver transplantation using NMP-preserved livers demonstrates the safety and feasibility of using this technology from retrieval to transplantation, including transportation. NMP may be valuable in increasing the number of donor livers and improving the function of transplantable organs. PMID- 26752192 TI - The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD. AB - INTRODUCTION: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensitive inflammatory disease is unclear, however. METHODS: Sputum, bronchoalveolar lavage (BAL) macrophages and serum were obtained from non-smokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR) and lung function were measured using whole body plethysmography. HIF-1alpha binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays. RESULTS: MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1alpha in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR. CONCLUSION: MIF and HIF-1alpha levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD. PMID- 26752193 TI - Endothelin-1 Predicts Hemodynamically Assessed Pulmonary Arterial Hypertension in HIV Infection. AB - BACKGROUND: HIV infection is an independent risk factor for PAH, but the underlying pathogenesis remains unclear. ET-1 is a robust vasoconstrictor and key mediator of pulmonary vascular homeostasis. Higher levels of ET-1 predict disease severity and mortality in other forms of PAH, and endothelin receptor antagonists are central to treatment, including in HIV-associated PAH. The direct relationship between ET-1 and PAH in HIV-infected individuals is not well described. METHODS: We measured ET-1 and estimated pulmonary artery systolic pressure (PASP) with transthoracic echocardiography (TTE) in 106 HIV-infected individuals. Participants with a PASP >= 30 mmHg (n = 65) underwent right heart catheterization (RHC) to definitively diagnose PAH. We conducted multivariable analysis to identify factors associated with PAH. RESULTS: Among 106 HIV-infected participants, 80% were male, the median age was 52 years and 77% were on antiretroviral therapy. ET-1 was significantly associated with higher values of PASP [14% per 0.1 pg/mL increase in ET-1, p = 0.05] and PASP >= 30 mmHg [PR (prevalence ratio) = 1.24, p = 0.012] on TTE after multivariable adjustment for PAH risk factors. Similarly, among the 65 individuals who underwent RHC, ET-1 was significantly associated with higher values of mean pulmonary artery pressure and PAH (34%, p = 0.003 and PR = 2.43, p = 0.032, respectively) in the multivariable analyses. CONCLUSIONS: Higher levels of ET-1 are independently associated with HIV-associated PAH as hemodynamically assessed by RHC. Our findings suggest that excessive ET-1 production in the setting of HIV infection impairs pulmonary endothelial function and contributes to the development of PAH. PMID- 26752194 TI - The Relationship between Diabetes and Mental Health Conditions in an Aging Population. PMID- 26752195 TI - Review of Hypoglycemia in the Older Adult: Clinical Implications and Management. AB - The aging of the population is a worldwide phenomenon. The prevalence of diabetes rises with increasing age, so the personal and financial costs of diabetes in the aging population have become significant burdens. In 2012, 104 billion (59%) of the estimated $176 billion in United States healthcare expenditures attributable to diabetes were utilized by patients older than 65 years of age [American Diabetes Association (1)]. With improvement in diabetes management and better glycemic control in the general population, there is an increase in the prevalence of hypoglycemia, which is the complication of the treatment of diabetes. Older adults with diabetes have a higher risk for hypoglycemia due to altered adaptive physiologic responses to low glucose levels. These patients also have comorbidities, such as cognitive and functional loss, that interfere with prompt identification and/or appropriate treatment of hypoglycemia. Older adults who suffer from hypoglycemia also have increased risk for falls, fall-related fractures, seizures and comas and exacerbation of chronic conditions, such as cognitive dysfunction and cardiac events. Thus, hypoglycemia in the older adult must be proactively avoided to decrease significant morbidity and mortality. Education of the patients and caregivers is important in prevention and treatment of hypoglycemia. In this article, we discuss the important aspects and unique challenges pertaining to hypoglycemia in older population. We also highlight the risks, consequences and prevention and management strategies for hypoglycemia that can be used by healthcare providers caring for older populations. PMID- 26752197 TI - Chest pain risk assessment in Indigenous and non-Indigenous Australians using HEART Score. AB - OBJECTIVE: The objectives of this study were to investigate factors that correlate to cardiac events within 30 days in Indigenous and non-Indigenous Australians who present to ED with chest pain and to describe the predictive ability of the HEART Score in these groups. METHODS: Patients who presented with chest pain between 1 January 2013 and 16 May 2013 in a university hospital were retrospectively enrolled in the study. HEART Scores were retrospectively assigned to participants. The study's end-point was Major Adverse Cardiac Events (MACE) within 30 days. RESULTS: Participants (678) were enrolled in the study, of which 148 were Indigenous Australian. Twenty-eight percent of Indigenous Australian participants and 19% of non-Indigenous Australian participants were diagnosed with MACE within 30 days. Within the Indigenous Australian participant cohort, 1.6% of those with HEART Scores 0-3, 29% of those with HEART Scores 4-6 and 96% of those with HEART Scores 7-10 were diagnosed with MACE within 30 days. Within the non-Indigenous Australian participant cohort, 0.58% of those with HEART Scores 0-3, 17% of those with HEART Scores 4-6 and 79% of those with HEART Scores 7-10 were diagnosed with MACE within 30 days. The negative predictive value of HEART Scores 0-3 for ruling out MACE within 30 days was 98% for Indigenous participants and 99% for non-Indigenous participants. CONCLUSION: The HEART Score is a reliable predictor of patient outcome in both Indigenous and non-Indigenous Australians. Modification of the HEART Score may not be required for use in the Indigenous Australian population who present to the ED with chest pain. PMID- 26752196 TI - Significant intratumoral heterogeneity of human epidermal growth factor receptor 2 status in gastric cancer: A comparative study of immunohistochemistry, FISH, and dual-color in situ hybridization. AB - The assessment of human epidermal growth factor receptor 2 (HER2) status is crucial for selecting patients with gastric cancer who may benefit from HER2 targeted therapy. Accurate assessment using biopsy specimens is important for patients with advanced-stage cancer. Intratumoral heterogeneity of HER2, however, is a major challenge in HER2 testing. Here, we aimed to examine whether assessment of HER2 status could be accurately carried out with currently used methods, namely, immunohistochemistry (IHC), FISH, and dual-color in situ hybridization (DISH). Human epidermal growth factor receptor 2 status was evaluated in 108 biopsy tissues from patients with gastric adenocarcinoma and 70 matched surgical specimens by IHC, FISH, and DISH; HER2 amplification was detected in 11 (10.2%) out of 108 biopsy specimens. The IHC and FISH results were well correlated, and FISH and DISH results were consistent for all cases. The overall concordance rate of HER2 status between biopsy tissues and surgical specimens was 91.4%. All six discordant cases were false negative on biopsy; of these cases, five showed HER2 heterogeneity on surgical resection. Assessment of the HER2 status of biopsy tissues could predict the status of the whole tumor; however, a proportion of these cases may be discordant because of intratumoral heterogeneity. PMID- 26752199 TI - A Lens Model Approach to the Communication of Pain. AB - Two studies examined the expression and detection of suppressed, genuine, and exaggerated pain. In Study 1, videotaped participants underwent an acute laboratory pain stressor and completed pain ratings. In Study 2, the lens model examined the cues encoders displayed while in pain (facial expressions of pain and viewers' global impressions), the cues decoders used to infer pain in the videotaped encoders, and decoders' accuracy in making judgments of pain. Results revealed expression differences between the suppressed, genuine, and exaggerated pain such that exaggerated expressions contained more tightened facial expressions while genuine expressions of pain contained more open facial expressions of pain. Decoders were accurate at detecting pain only in the exaggerated pain expressions. These results highlight the need for improving providers' accuracy in detecting pain intensity for suppressed, genuine, and exaggerated pain displays. Trainings should focus on teaching providers that patients who appear more agitated and less composed may be suppressing pain, while patients who appear more tense and determined may be exaggerating pain. Finally, patients who seem to not be in that much pain because they are not showing tightened facial expressions may actually be experiencing higher intensities of genuine pain. PMID- 26752198 TI - Enterococcal Infective Endocarditis following Periodontal Disease in Dogs. AB - In humans, one of the major factors associated with infective endocarditis (IE) is the concurrent presence of periodontal disease (PD). However, in veterinary medicine, the relevance of PD in the evolution of dogs' endocarditis remains poorly understood. In order to try to establish a correlation between mouth associated Enterococcus spp. and infective endocarditis in dogs, the present study evaluated the presence and diversity of enterococci in the gum and heart of dogs with PD. Samples were collected during necropsy of 32 dogs with PD and visually diagnosed with IE, which died of natural causes or euthanasia. Enterococci were isolated, identified and further characterized by Pulsed-Field Gel Electrophoresis (PFGE); susceptibility to antimicrobial agents and pathogenicity potential was also evaluated. In seven sampled animals, PFGE patterns, resistance and virulence profiles were found to be identical between mouth and heart enterococci obtained from the same dog, allowing the establishment of an association between enterococcal periodontal disease and endocarditis in dogs. These findings represent a crucial step towards understanding the pathogenesis of PD-driven IE, and constitute a major progress in veterinary medicine. PMID- 26752201 TI - TSC-22 Promotes Interleukin-2-Deprivation Induced Apoptosis in T-Lymphocytes. AB - Originally described as a TGF-beta-inducible gene, tsc-22 (Transforming growth factor-beta Stimulated Clone 22) encodes a transcriptional regulator affecting biological processes such as cell growth, differentiation, or apoptosis. Along with GILZ (Glucocorticoid-Induced Leucine Zipper), TSC-22 belongs to the evolutionary conserved TSC-22 Domain family. We previously showed that, in T lymphocytes, GILZ expression was induced upon IL-2 withdrawal, delaying apoptosis through down-regulation of the pro-apoptotic protein BIM expression. The aim of this work was then to elucidate the respective roles of GILZ and TSC-22 upon IL-2 deprivation-induced apoptosis. We report here that these two highly homologous genes are concomitantly expressed in most human tissues and in primary T lymphocytes and that expression of TSC-22 promotes T-lymphocytes apoptosis by inhibiting GILZ functions. Indeed, we demonstrated that TSC-22 expression in the murine lymphoid CTLL-2 cell line promoted IL-2 deprivation-induced apoptosis. BIM expression and caspases-9 and -3 activities were markedly increased in TSC-22 expressing clones compared to control clones. Analysis of GILZ expression revealed that TSC-22 prevented the induction of the GILZ protein upon IL-2 deprivation, by inhibiting gilz mRNA transcription. These results suggested that TSC-22 could counteract the protective effect of GILZ on IL-2-deprivation-induced apoptosis. Moreover, TSC-22-induced inhibition of GILZ expression was also found in CTLL-2 cells treated with glucocorticoids or TGF-beta. In the human NKL cell line deprived of IL-2, TSC-22 showed the same effect and thus may represent a potent repressor of GILZ expression in IL-2-dependent cells, independently of the cell type, or the stimulus, leading to an increase of IL-2-deprived T-cells apoptosis. J. Cell. Biochem. 117: 1855-1868, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26752200 TI - Allelic Variation of BnaC.TT2.a and Its Association with Seed Coat Color and Fatty Acids in Rapeseed (Brassica napus L.). AB - Efficient molecular markers for the selection of rapeseed genetic materials with high seed oil content and ideal fatty acid (FA) composition are preferred by rapeseed breeders. Recently, we reported the molecular mechanism of TRANSPARENT TESTA 2 (TT2) in inhibiting seed FA biosynthesis in Arabidopsis. However, evidence showing the association of rapeseed TT2 homologs and seed FA production are still insufficient. In this study, we collected 83 rapeseed (Brassica napus L.) landraces from different geographical backgrounds to conduct association mapping of BnaC.TT2.a in relation to seed coat color and FA biosynthesis. Population background was corrected by 84 pairs of SSR markers that were uniformly distributed among the linkage groups of the Tapidor-Ningyou-7 DH population. A single copy of BnaC.TT2.a for single nucleotide polymorphism (SNP) assay was cloned by a pair of previously reported specific primers. From the analysis of BnaC.TT2.a allelic variations using GLM+Q model, four SNPs on intron 1 of BnaC.TT2.a that were associated with seed FA were discovered. Moreover, an InDel at position 738 on exon 3 of BnaC.TT2.a indicated a change of protein function that was significantly associated with seed coat color, linoleic acid (C18:2), and total FA content. These findings revealed the role of BnaC.TT2.a in regulating the seed color formation and seed FA biosynthesis in rapeseed, thereby suggesting effective molecular markers for rapeseed breeding. PMID- 26752202 TI - The Spanish version of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for fibromyalgia: reliability and validity assessment. AB - OBJECTIVES: To investigate the reliability and validity of the Spanish version of the 2010 American College of Rheumatology (ACR) Preliminary Diagnostic Criteria for Fibromyalgia (FM) in patients with chronic pain. METHODS: The 2010 ACR Preliminary Diagnostic Criteria for FM were adapted to a Spanish version following the guidelines of the Rheumatology Spanish Society Study Group of FM. Based on the 1990 ACR classi cation criteria for FM, patients with chronic pain were initially divided into two groups: a FM group and another group of non-FM individuals. Patients from the FM group were evaluated by tender points (TP) examination, Fibromyalgia Impact Questionnaire (FIQ), Widespread Pain Index (WPI), and Symptom Severity Scale (SSS). The non-FM (control) group included patients with rheumatoid arthritis (RA) and osteoarthritis (OA). They were evaluated by WPI and SSS. RESULTS: We included 1,169 patients divided into two groups: FM group (n=803; 777 women and 26 men) and non-FM group (n= 366; 147 patients with RA, and 219 with OA). The median value of TP and FIQ in the FM group was 16 and 74 respectively. The preliminary 2010 ACR criteria were met by 665 (82.8%) FM patients and by 112 (30.6%) patients from the non-FM group (p<0.0001). Statistically signi cant differences in the number of TP (p<0.03), FIQ (p<0.0001), WPI (p<0.0001) and SSS (p<0.0001) were observed when FM patients fulfilling the 2010 ACR criteria were compared with the remaining FM patients who did not fulfill these criteria. Sensitivity of the Spanish version of the 2010 ACR criteria was 85.6% (95%CI: 83.1-88.1), speci city 73.2% (95%CI: 68.4-78), positive predictive value 87.7% (95%CI: 85.3-90.1) and negative predictive value 69.4% (95%CI: 64.5-74.2). CONCLUSIONS: Our results indicate that the 2010 ACR Preliminary Diagnostic Criteria for FM may be useful to establish a diagnosis of FM in Spanish individuals with chronic pain. PMID- 26752203 TI - Working Fast and Working Slow: The Benefits of Embedding Research in High Performance Sport. PMID- 26752204 TI - Placebo or Cost of Changing Speed? PMID- 26752205 TI - Neurocysticercosis: About 5 reported Thai cases. PMID- 26752207 TI - Comparison of physiological responses to affect eliciting pictures and music. AB - Recent investigations of the neural correlates of affect elicited from different modalities have found both modality-general and modality-specific representations (Chikazoe et al., 2014). The implications for how physiological responses to affect differ across stimulus modalities have not been fully investigated. This study examined similarities and differences between physiological signatures of affect derived from two different modes of presentation: visual pictures and auditory music sampled from an affective space defined by valence and arousal. Electromyography recordings for the zygomaticus major (EMGZ) and corrugator supercilii (EMGC) were measured along with heart rate and skin conductance level (SCL). Multidimensional scaling was used to visualize relationships from physiological and behavioral responses, and the observed relationships were statistically evaluated using multivariate and univariate analyses. Results for physiological measures demonstrated that valence was represented in the same general way across modalities, primarily reflected in EMGC responses. Arousal, however, was represented in a modality-specific manner, with SCL and EMGZ sensitive to music-based arousal but not picture-based arousal. Stimulus modality itself was predicted from EMGC. Thus, physiological responses to valence were similar across modalities but physiological responses to arousal differed across modalities. These results support the utility of testing for affective markers across modalities within the same experimental setting to reveal how physiological responses are linked to either affect, stimulus modality or both. PMID- 26752206 TI - The Trypanosoma cruzi Protein TcHTE Is Critical for Heme Uptake. AB - Trypanosoma cruzi, the etiological agent of Chagas' disease, presents nutritional requirements for several metabolites. It requires heme for the biosynthesis of several heme-proteins involved in essential metabolic pathways like mitochondrial cytochromes and respiratory complexes, as well as enzymes involved in the biosynthesis of sterols and unsaturated fatty acids. However, this parasite lacks a complete route for its synthesis. In view of these facts, T. cruzi has to incorporate heme from the environment during its life cycle. In other words, their hosts must supply the heme for heme-protein synthesis. Although the acquisition of heme is a fundamental issue for the parasite's replication and survival, how this cofactor is imported and distributed is poorly understood. In this work, we used different fluorescent heme analogs to explore heme uptake along the different life-cycle stages of T. cruzi, showing that this parasite imports it during its replicative stages: the epimastigote in the insect vector and the intracellular amastigote in the mammalian host. Also, we identified and characterized a T. cruzi protein (TcHTE) with 55% of sequence similarity to LHR1 (protein involved in L. amazonensis heme transport), which is located in the flagellar pocket, where the transport of nutrients proceeds in trypanosomatids. We postulate TcHTE as a protein involved in improving the efficiency of the heme uptake or trafficking in T. cruzi. PMID- 26752208 TI - Kinetics and mechanistic study of competitive inhibition of thymidine phosphorylase by 5-fluoruracil derivatives. AB - In a previous investigation, cationic liposomes formulated with new 5-FU derivatives, differing for the length of the polyoxyethylenic spacer that links the N(3) position of 5-FU to an alkyl chain of 12 carbon atoms, showed a higher cytotoxicity compared to free 5-FU, the cytotoxic effect being directly related to the length of the spacer. To better understand the correlation of the spacer length with toxicity, we carried out initial rate studies to determine inhibition, equilibrium and kinetic constants (KI, KM, kcat), and get inside inhibition activity of the 5-FU derivatives and their mechanism of action, a crucial information to design structural variations for improving the anticancer activity. The experimental investigation was supported by docking simulations based on the X-ray structure of thymidine phosphorylase (TP) from Escherichia coli complexed with 3'-azido-2'-fluoro-dideoxyuridin. Theoretical and experimental results showed that all the derivatives exert the same inhibition activity of 5-FU either as monomer and when embedded in lipid bilayer. PMID- 26752210 TI - Interaction of polyhedral oligomeric silsesquioxane containing epoxycyclohexyl groups with cholesterol at the air/water interface. AB - Binary mixtures of cholesterol and fully-condensed octakis[{2-(3,4 epoxycyclohexyl) etyl}dimethyl-silyloxy]octasilsesquioxane (OE-POSS) were characterized using Langmuir trough for obtaining surface pressure-area isotherms. The most characteristic feature of the mixed films is the presence of two collapse points on the isotherms. The first one is attributed to the collapse of less stable OE-POSS and it occurs at similar surface pressures for all compositions, while the second one corresponds to cholesterol collapse. Brewster angle microscopy observations confirmed the collapse behavior of the mixed film. Strong condensing effect was observed for the mean molecular areas dependence on cholesterol content in the film. Moreover, formation of microdomains of each component in the matrix of the other one was confirmed by BAM images. For the reasons of molecular structures and interactions a true mixed and homogenous film did not form in the systems considered. Phase separation was observed for all the compositions experimented. The lack of the interactions of OE-POSS with biomembrane components represented by cholesterol is beneficial for applications of OE-POSS in biomedical devices. PMID- 26752209 TI - Thiolated-2-methacryloyloxyethyl phosphorylcholine protected silver nanoparticles as novel photo-induced cell-killing agents. AB - Silver nanoparticles (AgNPs) have several medical applications as antimicrobial agents such as in drug delivery and cancer therapy. However, AgNPs are of limited use because of their toxicity, which may damage the surrounding healthy tissue. In this study, thiolated-2-methacryloyloxyethyl phosphorylcholine (MPC-SH) protected silver nanoparticles (MPC-AgNPs) are prepared as cell-killing agents under UV irradiation. MPC-AgNPs are characterized by X-ray diffraction (XRD), X ray photoelectron spectroscopy (XPS), and UV-visible spectrophotometry. The surface plasmon resonance (SPR) band of MPC-AgNPs is observed at 404 nm, and the average diameter of the particles is determined at 13.4 +/- 2.2 nm through transmission electron microscopy (TEM) and at 18.4 nm (PDI=0.18) through dynamic light scattering (DLS). Cell viability in contact with MPC-AgNPs is relatively high, and MPC-AgNPs also exhibit a cell-killing effect under UV irradiation. PMID- 26752211 TI - Controlled association and delivery of nanoparticles from jet-sprayed hybrid microfibrillar matrices. AB - To develop bioactive scaffolds of targeted properties for tissue repair or biomedical applications, hybrid microfiber-nanoparticle (MF-NP) matrices capable of controlled nanoparticle (NP) delivery were prepared through two novel approaches. In a first strategy, the suppleness of the jet-spraying method to produce polymer microfibers (MF) was used to deposit poly(d,l-lactide) (PLA) NP on poly(lactic-co-glycolic acid) (PLGA) MF by direct co-projection. The second approach relied on the post-incubation of PLA NP aqueous dispersion with MF preliminarily prepared by jet-spraying. NP coverage density onto MF and NP release was assessed by scanning electron microscopy and fluorescence measurements using coumarin-6 loaded NP. The first process was shown to allow high coverage density of NP onto MF (300 MUg/mg MF) and strong association, with no NP release observed over time. In the second approach, direct incubation of PLA NP with PLA MF led to lower NP coverage density (40 MUg/mg MF) with very fast release of NP from MF. The pre-coating of MF with poly-l-lysine (PLL) or the one of NP with lysozyme as a model protein drug afforded a higher coverage density and stronger association, coupled with a more sustained release of NP from MF over time. These results show the possibility to control the immobilization density and release of NP through appropriate preparation process and surface modification, and are of prime interest for the development of complex scaffolds with orchestrated bioactivity. PMID- 26752213 TI - Core-shell microcapsules of solid lipid nanoparticles and mesoporous silica for enhanced oral delivery of curcumin. AB - Newly designed microcapsules (MC) combining a core of solid lipid nanoparticle (SLN) and a mesoporous silica shell have been developed and explored as oral delivery system of curcumin (CU). CU-loaded MC (MC-CU) are 2 MUm sized and have a mesoporous silica shell of 0.3 MUm thickness with a wormlike structure as characterized by small angle X-ray scattering (SAXS), nitrogen adsorption/desorption and transmission electron microscopy (TEM) measurements. It was found that SLN acts as reservoir of curcumin while the mesoporous shell insures the protection and the controlled release of the drug. MC-CU displayed a pH-dependent in vitro release profile with marked drug retention at pH 2.8. Neutral red uptake assay together with confocal laser scanning microscopy (CLSM) showed a good cell tolerance to MC-CU at relatively high concentration of inert materials. Besides, the cell-uptake test revealed that fluorescent-MC were well internalized into Caco-2 cells, confirming the possibility to use MC for gut cells targeting. These findings suggest that organic core-silica shell microcapsules are promising drug delivery systems with enhanced bioavailability for poorly soluble drugs. PMID- 26752212 TI - A study of the synergistic effect of folate-decorated polymeric micelles incorporating Hydroxycamptothecin with radiotherapy on xenografted human cervical carcinoma. AB - In this study, Hydroxycamptothecin (HCPT)-loaded micelles were formed in water by the self-assembly of folate (FA)-decorated amphiphilic block copolymer, methoxy poly(ethylene glycol)-poly(epsilon-caprolactone) (MPEG-PCL), and achieved a hydrodynamic diameter about of 132 nm. HCPT release from the micelles exhibited no initial burst but showed a sustained release profile. The cytotoxicity and targeting ability of FA conjugated polymeric micelles was investigated by using methylthiazoletetrazolium (MTT) and fluorescence microscopy. We found that FA conjugated micelles had superior cytotoxicity against HeLa cells compared to non conjugated micelles, and that they exerted this effect by folate receptor (FR) mediated endocytosis. In addition, HeLa cells were xenografted into nude mice and subjected to radiotherapy (RT) and/or HCPT-loaded micelle treatment. The antitumor efficacy was detected by analysis of tumor growth delay (TGD) and median survival time. Micro fluorine-18-deoxyglucose PET/computed tomography ((18)F-FDG PET/CT) was performed to assess early tumor response to HCPT-loaded micelles in combination with RT. Analysis of cell cycle redistribution, apoptosis and expression of histone H2AX phosphorylation (lambda-H2AX) was used to evaluate the mechanism by which HCPT loaded micelles led to radiosensitization. Taken together, the results showed that HCPT-loaded FA decorated micelles efficiently sensitized xenografts in mice to RT, and induced G2/M phase arrest, apoptosis and expression of lambda-H2AX. PMID- 26752214 TI - Cell penetrating peptides from agglutinin protein of Abrus precatorius facilitate the uptake of Imatinib mesylate. AB - Targeted drug delivery is of paramount importance for cancer patients. Cell penetrating peptides (CPPs) have emerged as potent vehicles for this purpose. Herein, we demonstrate CPP- like properties of two peptides: NH2-SGASDDEEIAR-COOH (SR11) and NH2-ICSSHYEPTVRIGGR-COOH (IR15), derived from the tryptic digest of Abrus precatorius agglutinin. Both IR15 and SR11 were found to be non-toxic at lower doses (up to 50 MUg/ml). These two peptides entered into HeLa cells through lipid raft-mediated endocytosis within 15 min and penetrated the nuclear membrane in 60 min of incubation. Co-treatment of peptides (20 MUg/ml) and Imatinib (5 MUM) in HeLa cells increased uptake of the drug by ~ 55% and lowered the IC50 value to one-third in comparison to the drug added exclusively. However, co treatment of TAT peptide (standard CPP) did not alter the Imatinib uptake significantly. In summary, we have identified two novel CPPs from tryptic digest of Abrus agglutinin which increased the cellular uptake of Imatinib upon co administration. Further studies may result in deciphering a novel mode of drug delivery. PMID- 26752216 TI - Stereo- and Regioselective Synthesis of Tricyclic Spirolactones by Diastereoisomeric Differentiation of a Collective Key Precursor. AB - A general, parallel, and collective synthesis of 5/5/5- and 5/5/6-ring fusion topologies of tricyclic spiranoid lactones through the controlled cyclizations of easily accessible, common key precursors is described. The rapid composition of key cycloalkyl methylene precursors yielded an assembly of bicyclic diastereoisomeric iodolactones, which were individually converted into a wide range of tricyclic, angularly fused spiranoid lactones in a regioselective and stereodirected fashion through the diastereoisomeric differentiation of a collective key precursor. The critical stereochemical assignment of the bicyclic starting materials, as well as the tricyclic targets, was confirmed by X-ray crystal structure determination. PMID- 26752215 TI - Visualizing the Mechanism of Epoxide Hydrolysis by the Bacterial Virulence Enzyme Cif. AB - The CFTR inhibitory factor (Cif) is an epoxide hydrolase (EH) virulence factor secreted by the bacterium Pseudomonas aeruginosa. Sequence alignments reveal a pattern of Cif-like substitutions that proved to be characteristic of a new subfamily of bacterial EHs. At the same time, crystallographic and mutagenetic data suggest that EH activity is required for virulence and that Cif's active site remains generally compatible with a canonical two-step EH mechanism. A hallmark of this mechanism is the formation of a covalent hydroxyalkyl-enzyme intermediate by nucleophilic attack. In several well-studied EHs, this intermediate has been captured at near stoichiometric levels, presumably reflecting rate-limiting hydrolysis. Here we show by mass spectrometry that only minimal levels of the expected intermediate can be trapped with WT Cif. In contrast, substantial amounts of intermediate are recovered from an active-site mutant (Cif-E153Q) that selectively targets the second, hydrolytic release step. Utilizing Cif-E153Q and a previously reported nucleophile mutant (Cif-D129S), we then captured Cif in the substrate-bound, hydroxyalkyl-intermediate, and product bound states for 1,2-epoxyhexane, yielding the first crystallographic snapshots of an EH at these key stages along the reaction coordinate. Taken together, our data illuminate the proposed two-step hydrolytic mechanism of a new class of bacterial virulence factor. They also suggest that the failure of WT Cif to accumulate a covalent hydroxyalkyl-enzyme intermediate reflects an active-site chemistry in which hydrolysis is no longer the rate-limiting step, a noncanonical kinetic regime that may explain similar observations with a number of other EHs. PMID- 26752217 TI - Growth hormone actions during development influence adult phenotype and longevity. AB - There is considerable evidence that exposure to undernutrition, overnutrition, stress or endocrine disruptors during fetal development can increase the probability of obesity, hypertension, cardiovascular disease and other problems in adult life. In contrast to these findings, reducing early postnatal growth by altering maternal diet or number of pups in a litter can increase longevity. In hypopituitary Ames dwarf mice, which are remarkably long lived, a brief period of growth hormone therapy starting at 1 or 2weeks of age reduces longevity and normalizes ("rescues") multiple aging-related traits. Collectively, these findings indicate that nutritional and hormonal signals during development can have profound impact on the trajectory of aging. We suspect that altered "programming" of aging during development may represent one of the mechanisms of the Developmental Origins of Health and Disease (DOHaD) and the detrimental effects of "catch-up" growth. PMID- 26752219 TI - Cardiac Imaging 2015: A Selection of Topical Issues. PMID- 26752220 TI - Use of Complementary and Alternative Medicine and Quality of Life of Cancer Patients: Turkish Samples. AB - A large proportion of cancer patients use complementary and alternative medicine (CAM) to extend their quality of life. The purpose of this study was to determine the level of CAM use by patients undergoing cancer treatment. The study was conducted in Turkey at a large state university hospital and a government hospital between March and December 2013. The research sample consisted of a total of 147 cancer patients undergoing either chemotherapy or radiotherapy. Data collection was performed using a Patient Description Form and the EUROHIS (WHOQOL 8.Tr) quality-of-life scale through face-to-face interviews. The use of CAM, green tea (28.00 +/- 4.24), and garlic (29.00 +/- 0.00), as well as the use of a combination of plant products such as pomegranate juice, pollen, and herbal tea (31.25 +/- 5.96), not feeling the need to inform the physician of the use of CAM, regular use of CAM, finding CAM use effective, and suggesting CAM use to others were found to have a statistically significant relationship to average quality-of life scores (P < 0.05). This study could be used to develop holistic nursing interventions and CAM use by patients undergoing cancer treatment. PMID- 26752218 TI - Reduction of Cellular Expression Levels Is a Common Feature of Functionally Affected Pendrin (SLC26A4) Protein Variants. AB - Sequence alterations in the pendrin gene (SLC26A4) leading to functionally affected protein variants are frequently involved in the pathogenesis of syndromic and nonsyndromic deafness. Considering the high number of SLC26A4 sequence alterations reported to date, discriminating between functionally affected and unaffected pendrin protein variants is essential in contributing to determine the genetic cause of deafness in a given patient. In addition, identifying molecular features common to the functionally affected protein variants can be extremely useful to design future molecule-directed therapeutic approaches. Here we show the functional and molecular characterization of six previously uncharacterized pendrin protein variants found in a cohort of 58 Brazilian deaf patients. Two variants (p.T193I and p.L445W) were undetectable in the plasma membrane, completely retained in the endoplasmic reticulum and showed no transport function; four (p.P142L, p.G149R, p.C282Y and p.Q413R) showed reduced function and significant, although heterogeneous, expression levels in the plasma membrane. Importantly, total expression levels of all of the functionally affected protein variants were significantly reduced with respect to the wild-type and a fully functional variant (p.R776C), regardless of their subcellular localization. Interestingly, reduction of expression may also reduce the transport activity of variants with an intrinsic gain of function (p.Q413R). As reduction of overall cellular abundance was identified as a common molecular feature of pendrin variants with affected function, the identification of strategies to prevent reduction in expression levels may represent a crucial step of potential future therapeutic interventions aimed at restoring the transport activity of dysfunctional pendrin variants. PMID- 26752221 TI - Free flap reconstruction for patients with bisphosphonate related osteonecrosis of the jaws after mandibulectomy. AB - INTRODUCTION: Bisphosphonate related osteonecrosis of the jaws (BRONJ) is a recognised unwanted effect of these drugs which affect bone remodelling. Treatment options range from conservative approaches through local bone debridement to free flap reconstruction following segmental resection. This current study aims to evaluate clinical outcomes after microvascular tissue transfer in BRONJ patients. MATERIAL AND METHODS: A total of 212 BRONJ patients were included in this prospective investigation. Those who met defined inclusion criteria and received a surgical intervention were reviewed regularly during a follow-up period of at least 6 months. RESULTS: Twenty-five patients (11.8%) received free flap reconstructions. A mean of 2.12 local debridements were performed before microvascular tissue transfer. A mean of 29.25% showed BRONJ recurrence after minimalist surgical intervention, compared to significantly less in patients after resection and free flap reconstruction. The postoperative fistula rate was significantly higher in patients, who received mucoperiosteal flaps. DISCUSSION: This study underlines the importance and effectiveness radical resection and free flap reconstruction in the complex and challenging surgical treatment of BRONJ patients in a large patient cohort study. Nevertheless, all patients received radical intervention after failure of minimally invasive treatment. An individualized analysis and planning is necessary to identify appropriate patients for free flap reconstructions. PMID- 26752223 TI - The Effect of Exciton-Delocalizing Thiols on Intrinsic Dual Emitting Semiconductor Nanocrystals. AB - The emissive properties of thiol-capped CdSe nanocrystals (NCs) with intrinsic dual emission are investigated through temperature-dependent photoluminescence (PL) measurements. We demonstrate the influence of thiols on the relative PL intensities of the core and surface emissive states, as well as on the observed Stokes shifts. A redshift of both the core and surface PL in comparison with phosphonate-capped NCs is consistent with recent work exploring the effect of thiols as excitonic hole-delocalizing ligands. This observation is consistent with prior reports suggesting that surface excitons originate from electrons bound to cadmium trap states. PMID- 26752222 TI - Free flap transplantation using an extracorporeal perfusion device: First three cases. AB - BACKGROUND: Free flap transplantation may not be feasible in patients with inadequate or absent recipient vessels. We report successful mandibular composite reconstructions without anastomosis in three consecutive patients with vessel depleted neck. Based on clinical reports describing early neovascularisation, temporary extracorporeal perfusion of flaps was maintained until the flaps had become independent from the extracorporeal blood supply. METHODS: A blood transfusion bag filled with the patients' arterialised blood was connected to the flap artery and set under rhythmic compression to ensure continuous blood supply to the flap. The returning venous blood was collected but not reinfused. Extracorporeal circulation was sustained for 10-13 days until flaps had become independent from the external blood supply. Flap viability was assessed every 2 h using combined laser Doppler flowmetry and remission spectroscopy. RESULTS: Successful bony reconstructions were achieved in all three consecutive patients substantiated by MRI-, CT-scan or bone scintigraphy. Neovascularisation occurred within the soft tissues of all flaps with the exception of one skin paddle, which later developed necrosis. Systemic transfusion of 12-25 units of packed red cells was necessary to compensate for the blood loss. CONCLUSIONS: With this technique, transplantation of composite free flaps becomes feasible even in the absence of recipient vessels, opening up new treatment options to a broad range of complex surgical problems. Blood reinfusion should be pursued in the future to avoid excessive blood transfusions. The trial is registered with ClinicalTrials.gov, number NCT02449525. PMID- 26752224 TI - Synthesis of Pyrrole-Fused C,N-Cyclic Azomethine Imines and Pyrazolopyrrolopyrazines: Analysis of Their Aromaticity Using Nucleus-Independent Chemical Shifts Values. AB - The AgOTf-catalyzed reaction of C-2 substituted pyrrole hydrazones having an N propargyl group was studied. The selective 6-endo-dig mode of cyclization was observed, giving rise to the formation of pyrrole-fused C,N-cyclic azomethine imine derivatives. The reaction of one azomethine imine derivative with various dipolarophiles resulted in the formation of cycloadducts having a pyrazolopyrrolopyrazine skeleton. The aromaticity of C,N-cyclic azomethine imines as well as that of pyrazolopyrrolopyrazines was determined by calculating of nucleus-independent chemical shifts values. PMID- 26752225 TI - Combined effect of fluoride varnish to Er:YAG or Nd:YAG laser on permeability of eroded root dentine. AB - OBJECTIVE: This study evaluated the combined effect of fluoride varnish to Er:YAG or Nd:YAG laser on permeability of eroded root dentine. DESIGN: Sixty slabs of bovine root dentine (2*2*2mm) were eroded with citric acid 0.3% (pH 3.2) during 2h and then kept in artificial saliva during 24h. Specimens were randomly assigned in 6 groups (n=10), to receive the following treatments: fluoride varnish; fluoride varnish+Er:YAG laser; fluoride varnish+Nd:YAG laser; non fluoride varnish; non-fluoride varnish+Er:YAG laser; non-fluoride varnish+Nd:YAG laser. The Er:YAG (100mJ, 3Hz) and Nd:YAG (70mJ, 15Hz) were applied for 10s. Specimens were subjected to further erosive challenges with citric acid 0.3% 4*/day, during 1min, for 5 days, remaining in artificial saliva between cycles. Dentin permeability was then assessed. Two-way ANOVA demonstrated no significant interaction between laser and varnish (p=0.858). RESULTS: No effect was also detected for the main factor varnish (p=0.768), while permeability of eroded root dentin was significantly lower when such substrate was laser-irradiated, no matter the laser source (p<0.001). CONCLUSIONS: This study concluded that Er:YAG and Nd:YAG lasers can be employed to control the permeability of eroded root dentin, regardless of fluoride varnish application. PMID- 26752227 TI - Zoonotic Public Health Hazards in Backyard Chickens. AB - Backyard poultry has become increasingly popular in industrialized countries. In addition to keeping chickens for eggs and meat, owners often treat the birds as pets. However, several pathogenic enteric bacteria have the potential for zoonotic transmission from poultry to humans but very little is known about the occurrence of zoonotic pathogens in backyard flocks. The occurrence and the antimicrobial resistance of Salmonella enterica, Campylobacter spp., Listeria monocytogenes and enteropathogenic Yersinia spp. was studied in 51 voluntary backyard chicken farms in Finland during October 2012 and January 2013. Campylobacter isolates were further characterized by pulsed-field gel electrophoresis (PFGE), and the occurrence of ESBL/AmpC-producing E. coli was investigated. The findings from this study indicate that backyard chickens are a reservoir of Campylobacter jejuni strains and a potential source of C. jejuni infection for humans. Backyard chickens can also carry L. monocytogenes, although their role as a primary reservoir is questionable. Campylobacter coli, Yersinia pseudotuberculosis and Salmonella enterica were only found sporadically in the faecal and environmental samples of backyard poultry in Finland. No Yersinia enterocolitica carrying the virulence plasmid was isolated. All pathogens were highly susceptible to most of the antimicrobials studied. Only a few AmpC- and no ESBL-producing E. coli were found. PMID- 26752226 TI - Goniothalamin induces cell cycle arrest and apoptosis in H400 human oral squamous cell carcinoma: A caspase-dependent mitochondrial-mediated pathway with downregulation of NF-kappabeta. AB - Goniothalamin is a natural occurring styryl-lactone compound isolated from Goniothalamus macrophyllus. It had been demonstrated to process promising anticancer activity on various cancer cell lines. However, little study has been carried out on oral cancer. The aim of this study was to determine the cytotoxic effects of goniothalamin against H400 oral cancer cells and its underlying molecular pathways. Results from MTT assay demonstrated that goniothalamin exhibited selective cytotoxicity as well as inhibited cells growth of H400 in dose and time-dependent manner. This was achieved primarily via apoptosis where apoptotic bodies and membrane blebbing were observed using AO/PI and DAPI/Annexin V-FITC fluorescence double staining. In order to understand the apoptosis mechanisms induced by goniothalamin, apoptosis assessment based on mitochondrial membrane potential assay and cytochrome c enzyme-linked immunosorbent assay were carried out. Results demonstrated that the depolarization of mitochondrial transmembrane potential facilitated the release of mitochondrial cytochrome c into cytosol. Caspases assays revealed the activation of initiator caspase-9 and executioner caspase-3/7 in dose-dependent manners. This form of apoptosis was closely associated with the regulation on Bcl-2 family proteins, cell cycle arrest at S phase and inhibition of NF-kappabeta translocation from cytoplasm to nucleus. Conclusion, goniothalamin has the potential to act as an anticancer agent against human oral squamous cell carcinoma (H400 cells). PMID- 26752229 TI - A systematic review and content analysis of bullying and cyber-bullying measurement strategies. AB - Bullying has emerged as a behavior with deleterious effects on youth; however, prevalence estimates vary based on measurement strategies employed. We conducted a systematic review and content analysis of bullying measurement strategies to gain a better understanding of each strategy including behavioral content. Multiple online databases (i.e., PsychInfo, MedLine, ERIC) were searched to identify measurement strategies published between 1985 and 2012. Included measurement strategies assessed bullying behaviors, were administered to respondents with ages of 12 to 20, were administered in English, and included psychometric data. Each publication was coded independently by two study team members with a pre-set data extraction form, who subsequently met to discuss discrepancies. Forty-one measures were included in the review. A majority used differing terminology; student self-report as primary reporting method; and included verbal forms of bullying in item content. Eleven measures included a definition of bullying, and 13 used the term "bullying" in the measure. Very few definitions or measures captured components of bullying such as repetition, power imbalance, aggression, and intent to harm. Findings demonstrate general inconsistency in measurement strategies on a range of issues, thus, making comparing prevalence rates between measures difficult. PMID- 26752230 TI - Swiss national prospective surveillance of paediatric Mycoplasma pneumoniae associated encephalitis. AB - OBJECTIVE: To assess the presence of Mycoplasma pneumoniae-associated encephalitis in children in Switzerland and its likely pathogenesis. METHODS: M. pneumoniae-associated encephalitis cases seen at a single-centre during 2010-2013 were reviewed, and the Swiss Paediatric Surveillance Unit (SPSU) prospectively conducted a nationwide surveillance 2013-2015. Case definition included confirmed, probable and possible cases. RESULTS: Seven patients (median age 8.7 years, range 4.7-10.1 years) with confirmed or possible M. pneumoniae-associated encephalitis were observed. All patients manifested prodromal respiratory symptoms over at least 5 days and five out of the six who had a chest radiograph, showed pulmonary infiltrates. M. pneumoniae DNA in cerebrospinal fluid was negative in all patients. Intrathecally synthesised M. pneumoniae-specific immunoglobulin (IgM and IgG) were investigated and found positive in one patient (confirmed case). M. pneumoniae DNA in respiratory specimens and/or M. pneumoniae specific IgM and IgG in serum were detected in the other six patients (possible cases). One confirmed and two possible cases had neurological sequelae at 4-19 months follow-up. CONCLUSION: The lack of detectable M. pneumoniae DNA in cerebrospinal fluid of our encephalitis patients suggests a likely immune mediated pathogenesis ignited by a respiratory inflammatory process including pneumonia. PMID- 26752228 TI - In vivo articular cartilage deformation: noninvasive quantification of intratissue strain during joint contact in the human knee. AB - The in vivo measurement of articular cartilage deformation is essential to understand how mechanical forces distribute throughout the healthy tissue and change over time in the pathologic joint. Displacements or strain may serve as a functional imaging biomarker for healthy, diseased, and repaired tissues, but unfortunately intratissue cartilage deformation in vivo is largely unknown. Here, we directly quantified for the first time deformation patterns through the thickness of tibiofemoral articular cartilage in healthy human volunteers. Magnetic resonance imaging acquisitions were synchronized with physiologically relevant compressive loading and used to visualize and measure regional displacement and strain of tibiofemoral articular cartilage in a sagittal plane. We found that compression (of 1/2 body weight) applied at the foot produced a sliding, rigid-body displacement at the tibiofemoral cartilage interface, that loading generated subject- and gender-specific and regionally complex patterns of intratissue strains, and that dominant cartilage strains (approaching 12%) were in shear. Maximum principle and shear strain measures in the tibia were correlated with body mass index. Our MRI-based approach may accelerate the development of regenerative therapies for diseased or damaged cartilage, which is currently limited by the lack of reliable in vivo methods for noninvasive assessment of functional changes following treatment. PMID- 26752232 TI - Assessment of functional outcomes of temporalis muscle transfers for patients with longstanding facial paralysis. AB - BACKGROUND: Usually, clinical evaluation of facial reanimation provides accurate information about contraction of the mimetic muscles and phonation but fails to identify smile recovery and to quantify the motility of the lower third of the face during a smile. The purpose of this study was to verify that, in longstanding facial palsy, the modified temporalis muscle transfer (MTMT) can result in the ability to smile, not only voluntarily with chewing, but also spontaneously with a sudden emotional stimulus, and to confirm that a symmetric smile can be obtained. METHODS: Ten patients of the treated group (group T; 4 women and 6 men) were randomly selected from a population of 24 patients with longstanding facial palsy treated by MTMT. Five normal subjects of the control group (group C; 3 women and 2 men) were enrolled as the control population. Functional outcomes after transposed temporalis muscle were examined and measured through clinical assessment by using a scored smile symmetry grading system, video recording, and surface electromyography (sEMG). In addition, the voluntary smile test (VST) and the not-voluntary smile test (NVST) were performed to study voluntary and spontaneous smiling. RESULTS: Subjects in the VST group (group T) were able to smile voluntarily and the expression was characterized by symmetry. In the NVST group, they were able to smile spontaneously and the symmetry of the smile was maintained for 8 subjects and only partially for 2 subjects. During both tests, the temporalis muscle of the treated side and the orbicularis oris muscle of the not-treated side were activated during smiling, indicating spontaneous activity of the transposed temporalis muscle with an emotional stimulus. For the control group, smiles during VST and NVST were symmetric and the temporalis muscles were not activated during smiling, whereas the orbicularis oris muscles were. CONCLUSION: Our study shows that the Morrison MTMT is able to restore the voluntary smile ability. Particularly, this technique allows for recovery of the spontaneous smile with symmetry. This assessment would seem to suggest that the transposed temporalis muscle might adapt from a chewing to a mimetic muscle. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: E1535-E1543, 2016. PMID- 26752233 TI - Learning in the temporal bisection task: Relative or absolute? AB - We examined whether temporal learning in a bisection task is absolute or relational. Eight pigeons learned to choose a red key after a t-seconds sample and a green key after a 3t-seconds sample. To determine whether they had learned a relative mapping (short->Red, long->Green) or an absolute mapping (t-seconds >Red, 3t-seconds->Green), the pigeons then learned a series of new discriminations in which either the relative or the absolute mapping was maintained. Results showed that the generalization gradient obtained at the end of a discrimination predicted the pattern of choices made during the first session of a new discrimination. Moreover, most acquisition curves and generalization gradients were consistent with the predictions of the learning-to time model, a Spencean model that instantiates absolute learning with temporal generalization. In the bisection task, the basis of temporal discrimination seems to be absolute, not relational. PMID- 26752235 TI - Mediated overshadowing and potentiation of long-delay taste aversion learning: Two versus six cue-taste pairings. AB - Mediated overshadowing occurs when an evoked representation of one stimulus interferes with the formation of an association between two other stimuli. This study tested whether such an effect can be found in long-delay taste aversion learning. The general methodology was to pair a cue with a sour taste (hydrochloric acid [HCl]) and then introduce the cue during the delay between the target taste, sucrose, and injection with lithium chloride (LiCl). Either 2 or 6 cue-HCl pairings were given. In Experiment 1, introduction of the cue, an almond flavor, produced overshadowing of the sucrose aversion in the group given 2 cue HCl pairings (Paired-2), relative to an unpaired control, but potentiation of the sucrose aversion in the group given 6 cue-HCl pairings (Paired-6). This confirms that few pairings can be better than many in determining whether representation mediated effects occur (Holland, 1990). A possible explanation for the Paired-6 results is that almond evoked an aversive response rather than memory of the sour HCl and that this added to the aversion produced by the sucrose-lithium pairing. Experiment 2 obtained similar results when a context was used as the cue intended to evoke an HCl representation. PMID- 26752234 TI - Contexts control negative contrast and restrict the expression of flavor preference conditioning. AB - Consumption of a high concentration of sucrose can have either a detrimental, negative contrast effect or a facilitatory, preference conditioning effect on subsequent consumption of a low concentration of sucrose, depending on the cues that are present during consumption. The role of context and flavor cues in determining these effects were studied using analysis of the microstructure of licking in mice. Exposure to a high concentration followed by exposure to a low concentration resulted in a transient reduction in mean lick cluster size, which was context dependent (Experiment 1). However, there was no change in the total number of licks or overall consumption. When a flavor that had previously been paired with a high concentration was paired with a low concentration, there was an increase in the total number of licks, and overall consumption, but no change in the mean lick cluster size (Experiment 2). Pairing a high concentration with a flavor in a particular context before pairing the context and flavor compound with a low concentration resulted in abolishing the expression of the flavor preference conditioning effect on the total number of licks and consumption (Experiment 3). These results demonstrate that although context and flavor cues have dissociable effects on licking behavior, their interaction has an antagonistic effect on the behavioral expression of memory. PMID- 26752236 TI - Probing the early stages of solvation of cis-pinate dianions by water, acetonitrile, and methanol: a photoelectron spectroscopy and theoretical study. AB - cis-Pinic acid is one of the most important oxidation products of alpha-pinene--a key monoterpene compound in biogenic emission processes. Molecular level understanding of its interaction with water in cluster formation is an important and necessary prerequisite for ascertaining its role in the aerosol formation processes. In this work, we studied the structures and energetics of the solvated clusters of cis-pinate (cis-PA(2-)), the doubly deprotonated dicarboxylate of cis pinic acid, with H2O, CH3OH, and CH3CN by negative ion photoelectron spectroscopy and ab initio theoretical calculations. We found that cis-PA(2-) prefers being solvated alternately on the two -CO2(-) groups with increase of solvent coverage, a well-known solvation pattern that has been observed in microhydrated linear dicarboxylate dianion (DCn(2-)) clusters. Experiments and calculations further reveal an intriguing feature for the existence of the asymmetric type isomers for cis-PA(2-)(H2O)2 and cis-PA(2-)(CH3OH)2, in which both solvent molecules interact with only one of the -CO2(-) groups, a phenomenon that has not been observed in DCn(2-) water clusters and exhibits that the subtle effect of the rigid four membered carbon ring brought on the cis-PA(2-) solvation. The dominant interactions between cis-PA(2-) and solvent molecules form bidentate O(-)...H-O H bonds for H2O, O(-)...H-O and O(-)...H-C H-bonds for CH3OH, and tridentate O( )...H-C H-bonds for CH3CN. The formation of inter-solvent H-bonds between H2O and CH3CN is found to be favorable in mixed solvent clusters, different from that between H2O and CH3OH. These findings have important implications for understanding the mechanism of cluster growth and the formation of atmospheric organic aerosols, as well as for rationalizing the nature of structure-function relationship of proteins containing carboxylate groups in various solvent environments. PMID- 26752231 TI - BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis. AB - BACKGROUND: Glucocorticoid resistance has been associated with Th17-driven inflammation, the mechanisms of which are not clear. We determined whether human and mouse Th17 cells are resistant to glucocorticoid-induced apoptosis. METHODS: Freshly isolated human blood Th17 cells and in vitro differentiated Th17 cells from IL-17F red fluorescent protein reporter mice were treated with dexamethasone, a potent glucocorticoid. Apoptosis was measured using annexin V and DAPI staining. Screening of apoptosis genes was performed using the apoptosis PCR array. Levels of molecules involved in apoptosis were measured using quantitative RT-PCR, flow cytometry, and Western blotting. Knockdown of BCL-2 in murine Th17 cells was performed via retroviral transduction. Cytokines were measured using ELISA. A murine Th17-driven severe asthma model was examined for Th17 glucocorticoid sensitivity in vivo. RESULTS: Human and mouse Th17 cells and mouse Th2 cells were resistant to glucocorticoid-induced apoptosis. Th17 cells had glucocorticoid receptors levels comparable to those in other T effectors cells. Th17 cells had high levels of BCL-2, knockdown of which sensitized Th17 cells to dexamethasone-induced apoptosis. Production of IL-22, but not IL-17A and IL-17F, was suppressed by glucocorticoids. STAT3 phosphorylation in Th17 cells was insensitive to glucocorticoid inhibition. Lung Th17 cells in the murine severe asthma model were enhanced, rather than suppressed, by glucocorticoids. CONCLUSION: Th17 cells are resistant to glucocorticoid-induced apoptosis and cytokine suppression, at least in part due to high levels of BCL-2. These findings support a role of Th17 cells in glucocorticoid-resistant inflammatory conditions such as certain endotypes of asthma. PMID- 26752237 TI - Cost of illness of oral lichen planus in a U.K. population--a pilot study. AB - OBJECTIVE: To assess the economic burden of oral lichen planus (OLP) from the perspective of the healthcare provider in a U.K. population. METHODS: This prevalence-based cost-of-illness analysis was carried out via a cross-sectional study conducted in the Oral Medicine Unit of the Eastman Dental Hospital. This study was conducted in three phases - phase 1 involved framing of the cost-of illness analysis, development of the cost inventory and design of the patient questionnaire for ease of data collection. Data collected from patients were inputted during phase 2, and costings were determined. The final phase consisted of the calculation of the cost of illness of OLP. RESULTS: One hundred patients were enrolled in the study, 30 males and 70 females, with an average age of 59.9 years (+/-13.4 years). The average OLP patient, based on our cohort, attends the oral medicine unit 2.64 times per year, their general medical practitioner 1.13 times annually, their general dental practitioner 0.82 times in a year and fills on average 3.37 prescriptions annually. This leads to an average annual cost of L398.58 (?541.16) per patient per year from the perspective of the healthcare provider. CONCLUSION: The annual average cost of OLP to the healthcare provider in the U.K. is substantial. The prevalence-based cost-of-illness data generated in this study will facilitate comparison with other chronic oral mucosal diseases and with chronic diseases managed in allied medical specialties. PMID- 26752239 TI - Editorial. AB - This editorial discusses the history of the Journal of Occupational Health Psychology (JOHP), citing the various editors and the length of their editorships, as well as the support they received from the associate editors, editorial board members, reviewers, and the contributions of the authors' high quality articles. JOHP has become an international flagship journal, which plays an important role in advancing the field of occupational health psychology. The most recent impact factor and ranking reported by the American Psychological Association (2015) further supports the quality of this journal. PMID- 26752238 TI - Coming back to work in the morning: Psychological detachment and reattachment as predictors of work engagement. AB - Research has shown that recovery processes in general and psychological detachment in particular are important for work engagement. We argue that work engagement additionally benefits from reattachment to work in the morning (i.e., mentally reconnecting to work before actually starting to work) and that the gains derived from psychological detachment and reattachment are stronger in the morning than in the afternoon. We tested our hypotheses in a daily diary study with a sample of 167 employees who completed 2 surveys per day over the period of 2 workweeks. Hierarchical linear modeling showed that work engagement was higher in the morning than in the afternoon. Evening psychological detachment and morning reattachment positively predicted work engagement throughout the day. The association between reattachment and work engagement was stronger in the morning than in the afternoon. This study demonstrates that not only psychological detachment from work during leisure time, but also reattachment to work when coming back to work are crucial for daily engagement at work. (PsycINFO Database Record PMID- 26752240 TI - Time-Domain Simulations of Transient Species in Experimentally Relevant Environments. AB - Simulating the spectroscopic properties of short-lived thermal and photochemical reaction intermediates and products is a challenging task, as these species often feature atypical molecular and electronic structures. The complex environments in which such species typically reside in practice add further complexity to the problem. Herein, we tackle this problem in silico using ab initio molecular dynamics (AIMD) simulations, employing iso-CHBr3, namely H(Br)C-Br-Br, as a prototypical system. This species was chosen because it features both a nonconventional C-Br-Br bonding pattern, as well as a strong dependence of its spectral features on the local environment in which it resides, as illustrated in recent experimental reports. We simulate the UV-vis and IR spectra of iso-CHBr3 in the gas phase, as well as in a Ne cluster (64 atoms) and in a methylcyclohexane cage (14 solvent molecules) representative of the previously characterized matrix isolated and solvated iso-CHBr3 species. We exclusively perform fully quantum mechanical static and dynamic simulations. By comparing our condensed phase simulations to their experimental analogues, we stress the importance of (i) conformational sampling, even at cryogenic temperatures, and (ii) using a fully quantum mechanical description of both solute and bath to properly account for the experimental observables. PMID- 26752242 TI - Surface Complexation Modeling of Eu(III) and U(VI) Interactions with Graphene Oxide. AB - Graphene oxide (GO) has great potential for actinide removal due to its extremely high sorption capacity, but the mechanism of sorption remains unclear. In this study, the carboxylic functional group and an unexpected sulfonate functional group on GO were characterized as the reactive surface sites and quantified via diffuse layer modeling of the GO acid/base titrations. The presence of sulfonate functional group on GO was confirmed using elemental analysis and X-ray photoelectron spectroscopy. Batch experiments of Eu(III) and U(VI) sorption to GO as the function of pH (1-8) and as the function of analyte concentration (10-100, 000 ppb) at a constant pH ~ 5 were conducted; the batch sorption results were modeled simultaneously using surface complexation modeling (SCM). The SCM indicated that Eu(III) and U(VI) complexation to carboxylate functional group is the main mechanism for their sorption to GO; their complexation to the sulfonate site occurred at the lower pH range and the complexation of Eu(III) to sulfonate site are more significant than that of U(VI). Eu(III) and U(VI) facilitated GO aggregation was observed with high Eu(III) and U(VI) concentration and may be caused by surface charge neutralization of GO after sorption. PMID- 26752241 TI - Pharmacologic Interventions in Preventing Ovarian Hyperstimulation Syndrome: A Systematic Review and Network Meta-Analysis. AB - Ovarian hyperstimulation syndrome (OHSS) is a severe iatrogenic complication of controlled ovarian stimulation. Randomised controlled trials (RCTs) have proven several pharmacologic interventions to be effective in OHSS prevention, but these trials have seldom compared multiple drugs. We identified randomised controlled trials (RCTs) through June 2015 by searching databases and compared 11 intervention strategies in preventing OHSS (primary outcome) and their influence on pregnancy rate (secondary outcome). A network meta-analysis was used to evaluate the relative effectiveness among treatments and to create a rank probability table. Thirty-one RCTs were identified, including 7181 participants. Five pharmacologic interventions were superior to placebo in decreasing OHSS incidence: aspirin [relative risk (RR) 0.07, 95% credible interval (CrI) 0.01 0.30, p < 0.05], intravenous (IV) calcium [RR 0.11, 95% CrI 0.02-0.54, p < 0.05], cabergoline [RR 0.17, 95% CrI 0.06-0.43, p < 0.05], metformin [RR 0.20, 95% CrI 0.07-0.59, p < 0.05] and IV hydroxyethyl starch (HES) [RR 0.26, 95% CrI 0.05 0.99, p < 0.05]. The rank probability demonstrated aspirin (Rank 1: 36%) and IV calcium (Rank 1: 35%) to be the most efficacious. Additionally, albumin might decrease the pregnancy rate when compared with placebo [RR 0.85, 95% CI 0.74 0.97, p < 0.05]. This conclusion provides a relative standard and objective reference for choosing an OHSS prophylactic agent. PMID- 26752243 TI - Influence of Phenylethynylene of Push-Pull Zinc Porphyrins on the Photovoltaic Performance. AB - A series of zinc porphyrin dyes YD22-YD28 were synthesized and used for dye sensitized solar cells. Dyes YD26-YD28 consist of zinc porphyrin (ZnP) as core unit, arylamine (Am) as electron-donating group, and p-ethynylbenzoic acid (EBA) as an electron-withdrawing/-anchoring group. The dyes YD22-YD25 contain additional phenylethynylene group (PE) bridged between Am and ZnP units. The influence of the PE unit on molecular properties as well as photovoltaic performances were investigated via photophysical and electrochemical studies and density functional calculations. With the insertion of PE unit, the dyes YD22 YD25 possess better light-harvesting properties in terms of significantly red shifted Q-band absorption. The conversion efficiencies for dyes YD22-YD25 are better than those of dyes YD26-YD28 owing to larger J(SC) output. Natural transition orbitals and Mulliken charge analysis were used to analyze the electron injection efficiency for porphyrin dyes upon time-dependent DFT calculations. The results indicated that insertion of additional PE unit is beneficial to higher J(SC) by means of improved light-harvesting property due to broadened and red-shifted absorption. PMID- 26752244 TI - Age-dependent effects in fathead minnows from the anti-diabetic drug metformin. AB - The anti-diabetic drug metformin is thought to be the pharmaceutical most deposited into the aquatic environment by mass at up to 6tons per year from individual WWTPs in urban areas. Recent studies have shown that exposure to 40ug/L of metformin increased the relative expression of the egg yolk precursor protein vitellogenin in adult male fathead minnows (Pimephales promelas) (FHM). For this study, the expression of several other genes involved in estrogen biosynthesis, clearance and downstream effects were assessed in FHM after treatment to three concentrations of metformin, to better understand the estrogenic effects of metformin on FHM. In contrast to the previous study, although upward trends were observed, metformin failed to significantly alter the expression of VTG, ERalpha, GnRH3, and CYP3A126 in adult male FHM. However, a concentration-dependent response to metformin was observed in younger 80-90day juvenile FHM. A 17.7-, 22-, and 22-fold increase in the relative expression of VTG mRNA in juvenile FHM exposed to 1, 10, and 100MUg/L as compared to the control was observed. There was also a 3.3-, 4.7-, and 5.5-fold increase in GnRH3 in juvenile FHM exposed to 1, 10, and 100MUg/L as compared to the control. Similarly, a 14-, 16-, and 24-fold increase in the relative expression of CYP3A126 mRNA was measured in juvenile FHM exposed to 1, 10 and 100MUg/L metformin as compared to the control. These results indicate that juvenile FHM were more susceptible to the estrogenic effects of metformin during a 7-d exposure than older, sexually mature male FHM. PMID- 26752245 TI - Testosterone production in response to exogenous gonadotropin releasing hormone (GnRH challenge) depends on social environment and color polymorphism. AB - Testosterone is an important mediator of behavior, morphology and physiology. A cascade of signals regulates the amount of testosterone (T) circulating in the plasma; in response to stimulus the hypothalamus releases gonadotropin-releasing hormone (GnRH), which triggers secretion of gonadotropins from the pituitary, stimulating the synthesis and release of T from the gonads. Previous work has shown that changes to the social environment can alter circulating T-levels, which may have important fitness consequences, but it is currently unclear whether these changes are due to alterations in the signal from the brain, or changes in the ability of the pituitary and gonads to respond to this signal. Further, the strength and direction of response to a changing environment may differ according to life-history strategy. Species with genetically determined alternative strategies offer a pathway for examining these differences. Here we use a finch with a genetically determined polymorphism, the Gouldian finch (Erythrura gouldiae), to determine whether T-levels change in response to social environment. We also use injections of GnRH to determine whether these changes are due to alterations in the ability of the pituitary and gonads to respond to this signal. We found that social environment (presence of females) had a rapid effect on male circulating T-levels, and that this difference was reflected in responsiveness to GnRH. We observed no overall morph differences in T-levels, but we did observe morph differences in the pattern of T secretion across environments, and morph differences in the repeatability of T-levels across time and environment. PMID- 26752246 TI - Identifying the activation motif in the N-terminal of rainbow trout and zebrafish melanocortin-2 receptor accessory protein 1 (MRAP1) orthologs. AB - The activation of mammalian melanocortin-2 receptor (MC2R) orthologs is dependent on a four-amino acid activation motif (LDYL/I) located in the N-terminal of mammalian MRAP1 (melanocortin-2 receptor accessory protein). Previous alanine substitution analysis had shown that the Y residue in this motif appears to be the most important for mediating the activation of mammalian MC2R orthologs. Similar, but not identical amino acid motifs were detected in rainbow trout MRAP1 (YDYL) and zebrafish MRAP1 (YDYV). To determine the importance of these residues in the putative activation motifs, rainbow trout and zebrafish MRAP1 orthologs were individually co-expressed in CHO cells with rainbow trout MC2R, and the activation of this receptor with either the wild-type MRAP1 ortholog or alanine substituted analogs of the two teleost MRAP1s was analyzed. Alanine substitutions at all four amino acid positions in rainbow trout MRAP1 blocked activation of the rainbow trout MC2R. Single alanine substitutions of the D and Y residues in rainbow trout and zebrafish MRAP1 indicate that these two residues play a significant role in the activation of rainbow trout MC2R. These observations indicate that there are subtle differences in the way that teleost and mammalian MRAPs are involved in the activation of their corresponding MC2R orthologs. PMID- 26752247 TI - Drug Discontinuation and Follow-up Rates in Oral Antithrombotic Trials. PMID- 26752248 TI - Structure Characterization and Immunomodulating Effects of Polysaccharides Isolated from Dendrobium officinale. AB - A crude polysaccharide fraction (cDOP) has been determined to be the characteristic marker of Dendrobium officinale, an expensive tea material in Asia, but its chemistry and bioactivity have not been studied. In work reported here, cDOP was destarched (DOP, 90% yield) and separated into two subfraction polysaccharides, DOPa and DOPb, which were characterized by monosaccharide composition and methylation analyses and spectral analyses (FT-IR and (1)H and (13)C NMR). Both are composed of mannose and glucose at similar ratios and have a similar structure with a backbone of 1,4-linked beta-D-mannopyranosyl and beta-D glucopyranosyl residues. Significant differences were observed only in their molecular weights. Bioassay using mouse macrophage cell line RAW264.7 indicated that DOP and its two subfractions enhance cell proliferation, TNF-alpha secretion, and phagocytosis in a dose-dependent manner. They also induced the proliferation of lymphocytes alone and with mitogens. DOPa and DOPb are thus proven to be major, active polysaccharide markers of D. officinale. PMID- 26752250 TI - "A touch of physiotherapy" - the significance and meaning of touch in the practice of physiotherapy. AB - Touch, while ubiquitous and ever present in the practice of physiotherapy, is conspicuously absent from physiotherapy-related research. Based on a theoretical perspective inspired by phenomenology, this article explores and elaborates on the meaning and significance of touch in the practice of physiotherapy. The research data were generated through 16 close observations conducted in primary care clinics, and through interviews with 9 physiotherapists and with 9 patients suffering from chronic neck problems. The findings revealed how the use of touch in the practice of physiotherapy brings people into proximity in ways more complex than simple skin-to-skin contact. Through nontouch, touch, and movements, physiotherapists invite their patients to participate in the process of creating and performing therapy; dialogue through touch and movement is vital. Touch in physiotherapy depends on the physiotherapist's embodied skills; those they cultivate in order to respectfully listen to their patients and guide them to explore their own bodily capacity, limits and possibilities. The findings also suggest that observing therapy from outside and from participating in it offer significant different experiences, information, understanding, and meanings. The differences between physiotherapy as observed expression and as lived experience would seem to have important implications for understanding the practice of physiotherapy. PMID- 26752251 TI - Controlling the Supramolecular Architecture of Molecular Gels with Surfactants. AB - Manipulating molecular assembly is significant for achieving materials with desirable performances. In this paper, two nonionic surfactants, Span 20 and Triton X-100, are used to tune the nucleation and fiber growth of a molecular gelator 2,3-di-n-decyloxyanthracene (DDOA). Confocal microscopic images show that Span 20 induces elongation of DDOA spherulites, and promotes fiber side branching. In contrast, Triton X-100 enhances the primary nucleation of DDOA leading to the formation of smaller DDOA spherulites, and promotes fiber tip branching. (1)H NMR investigation demonstrates strong interactions between the hydrophobic tails of the surfactants and the alkyl chains of DDOA molecules.The interactions significantly reduce the diffusion of DDOA molecules. The different effects of the two surfactants could be attributable to their different alkyl hydrophobic tails. The hydrophobic tail of Span 20 is similar to the alkyl chain of DDOA, which could promote the adsorption of Span 20 on the fiber side surface rich in alkyl chains of DDOA.While the benzene ring in the hydrophobic tail of Triton X-100 could facilitate the primary nucleation of DDOA and the adsorpion of Triton X-100 on the fiber tip surface rich in aromatic structure of DDOA. The observations of this work will help the development of a convenient approach to tune the fiber network structure of molecular gels. PMID- 26752249 TI - Age-dependent impact of CaV 3.2 T-type calcium channel deletion on myogenic tone and flow-mediated vasodilatation in small arteries. AB - KEY POINTS: Blood pressure and flow exert mechanical forces on the walls of small arteries, which are detected by the endothelial and smooth muscle cells, and lead to regulation of the diameter (basal tone) of an artery. CaV 3.2 T-type calcium channels are expressed in the wall of small arteries, although their function remains poorly understood because of the low specificity of T-type blockers. We used mice deficient in CaV 3.2 channels to study their role in pressure- and flow dependent tone regulation and the possible impact of ageing on this role. In young mice, CaV 3.2 channels oppose pressure-induced vasoconstriction and participate in endothelium-dependent, flow-mediated dilatation. These effects were not seen in mature adult mice. The results of the present study demonstrate an age-dependent impact of CaV 3.2 T-type calcium channel deletion in rodents and suggest that the loss of CaV 3.2 channel function leads to more constricted arteries, which is a risk factor for cardiovascular disease. ABSTRACT: The myogenic response and flow-mediated vasodilatation are important regulators of local blood perfusion and total peripheral resistance, and are known to entail a calcium influx into vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), respectively. CaV 3.2 T-type calcium channels are expressed in both VSMCs and ECs of small arteries. The T-type channels are important drug targets but, as a result of the lack of specific antagonists, our understanding of the role of CaV 3.2 channels in vasomotor tone at various ages is scarce. We evaluated the myogenic response, flow-mediated vasodilatation, structural remodelling and mRNA + protein expression in small mesenteric arteries from CaV 3.2 knockout (CaV 3.2KO) vs. wild-type mice at a young vs. mature adult age. In young mice only, deletion of CaV 3.2 led to an enhanced myogenic response and a ~50% reduction of flow-mediated vasodilatation. Ni2+ had both CaV 3.2-dependent and independent effects. No changes in mRNA expression of several important K+ and Ca2+ channel genes were induced by CaV 3.2KO However, the expression of the other T-type channel isoform (CaV 3.1) was reduced at the mRNA and protein level in mature adult compared to young wild-type arteries. The results of the present study demonstrate the important roles of the CaV 3.2 T-type calcium channels in myogenic tone and flow-mediated vasodilatation that disappear with ageing. Because increased arterial tone is a risk factor for cardiovascular disease, we conclude that CaV 3.2 channels, by modulating pressure- and flow-mediated vasomotor responses to prevent excess arterial tone, protect against cardiovascular disease. PMID- 26752252 TI - Fetal Development of Human Oral Epithelial Pearls With Special Reference to Their Stage-Dependent Changes in Distribution. AB - OBJECTIVE: To access detailed distribution and age-dependent changes of oral epithelial pearls. DESIGN: Investigation and analysis with human fetal serial sections. SETTING: Institute of Embryology. METHODS: This study examined serial frontal sections of the upper and lower jaws of 19 human fetuses at 12 to 18 weeks and of the lower jaws of four late-stage fetuses. RESULTS: The upper jaw contained more than 20 midline and more than 60 lateral pearls greater than 20 MUm in diameter, whereas the lower jaw contained fewer than 30 pearls of the same size. Midline pearls in the upper jaw were often cylindrical or rugby-ball shaped, whereas all pearls in the lower jaw were small and spherical. Epithelial pearls in the upper jaw started developing along the upper midline until 12 weeks; lateral pearls and additional midline pearls (or strictly, paramedian pearls) developed until 15 weeks. In the lower jaw, however, pearl development started at 18 weeks and was almost always from the dental lamina. Some of the fetuses assessed had an open nasopalatine canal without a duct, but there was no fibrous connection between this canal and pearls. Similarly, the lip frenulum or incisive suture was not connected with these pearls. CONCLUSION: The timing and sequence of development suggest that postfusion rupture of the palate by midline pearls was unlikely. PMID- 26752253 TI - Electronic structure modification and Fermi level shifting in niobium-doped anatase titanium dioxide thin films: a comparative study of NEXAFS, work function and stiffening of phonons. AB - The electronic structure and tuning of work function (WF) by electronic excitations (EEs) induced by swift heavy ions (SHIs) in anatase niobium-doped titanium dioxide (NTO) thin films is reported. The densities of EEs were varied using 80 MeV O, 130 MeV Ni and 120 MeV Ag ions for irradiation. The EE-induced modifications in electronic structure were studied by O K-edge and Ti L3,2 edge absorption spectra using near edge X-ray absorption fine structure (NEXAFS) spectroscopy. The reduction of hybridized O 2p and Ti 3d unoccupied states in the conduction band with a decrease in energy of the crystal field strength of ~ 480 meV and the correlated effect on the decrease in the WF value of ~ 520 meV upon increasing the total energy deposition in the lattice are evident from the study of NEXAFS and scanning Kelvin probe microscopy (SKPM), respectively. The observed stiffening in the low frequency Raman mode (LFRM) of ~ 9 cm(-1) further validates the electronic structure modification under the influence of EE-induced strain in TiO6 octahedra. The reduction of hybridized valence states, stiffening behavior of LFRM and decrease in WF by nano-crystallization followed by amorphization and defects in NTO lattice are explained in terms of continuous, discontinuous amorphous ion tracks containing intestinally created defects and non stoichiometry in the lattice. These studies are very appropriate for better insights of electronic structure modification during phase transformation and controlled Fermi level shifting, which plays a crucial role in controlling the charge carrier injection efficiency in opto-electronic applications and also provides a deeper understanding of the involved physical processes. PMID- 26752254 TI - Identifying Factors Influencing Pancreatic Cancer Management to Inform Quality Improvement Efforts and Future Research: A Scoping Systematic Review. AB - Pancreatic cancer (PC) patients appear to receive suboptimal care. We conducted a systematic review to identify factors that influence PC management which are amenable to quality improvement. MEDLINE, EMBASE, and the references of eligible studies were searched from 1996 to July 2014. Two authors independently selected and reviewed eligible studies. Identified factors were mapped onto a framework of determinants of care delivery and outcomes. Methodological quality of studies was assessed using Downs and Black criteria. Most of the 33 eligible studies were population-based observational studies conducted in the United States. Patient (age, socioeconomic status, race) and institutional (case volume, academic status) factors influence care delivery and outcomes (complications, mortality, readmission, survival). Two studies implemented interventions to improve quality of care (centralization to high-volume hospitals, multidisciplinary care). One study examined system determinants (referral wait times). No studies examined the influence of guideline or provider characteristics. The overall lack of health services research in PC is striking. Factors and interventions identified here can be used to plan PC quality improvement programs. Further research is needed to explore the influence of guideline and provider factors on PC management and evaluate the impact of quality improvement interventions. PMID- 26752255 TI - Pancreatic Duct Changes in Patients With Chronic Pancreatitis Treated With Polyethylene and Sof-Flex Material Stents: A Blinded Comparison. AB - OBJECTIVES: Pancreatic stenting is used to improve painful, obstructive chronic pancreatitis. Data suggest that polyethylene stents (PESs) cause stent-associated changes (SACs). Whether a stent composed of more flexible material (Sof-Flex stent [SFS]) is associated with less SAC is unknown. METHODS: This study is a retrospective study of patients who underwent pancreatic duct stenting of at least 1 PES and 1 SFS on separate examinations and had a follow-up pancreatogram at the time of stent removal. The main outcome measurements were assessed for SAC on follow-up pancreatogram and interpreted by 2 radiologists blinded to the clinical data. RESULTS: Stent-associated changes were noted with 28% (13/47) of SFS and with 25% (13/52) of PES (P = 0.65). For 10F stent subgroups, SACs were seen with 25% (6/24) of the SFS compared with 50% (2/4) in the PES. Thirty percent (7/23) of the 8.5F SFS subgroup had SACs versus 29% (2/7) in the PES group (P = 0.887) for 8.5F + 10F combined comparison. CONCLUSIONS: In patients who have had polyethylene or SFSs of varying sizes, approximately 1 in 4 have SACs. Despite the use of a softer stent material for therapeutic stenting, the rate of SACs in the 8.5F and 10F subgroups seems similar between the 2 materials and design. PMID- 26752256 TI - An Unusual Presentation of Pediatric Autoimmune Pancreatitis. PMID- 26752257 TI - Hyperlipasemia in Pediatric Inflammatory Bowel Diseases. PMID- 26752258 TI - A Case of 36-Year-Old Woman With Recurrent Hypoglycemia Due to Insulinoma With Cytokeratin-19 Expression: A Marker of Poor Prognosis. PMID- 26752259 TI - Naturalistic study of the risky situations faced by novice riders. AB - This article sets out to identify the typical risky situations experienced by novice motorcyclists in the real world just after licensing. The procedure consists of a follow-up of six novices during their first two months of riding with their own motorbike instrumented with cameras. The novices completed logbooks on a daily basis in order to identify the risky situations they encountered, and were given face-to-face interviews to identify the context and their shortcomings during the reported events. Data show a large number of road configurations considered as risky by the riders (248 occurrences), especially during the first two weeks. The results revealed that a lack of hazard perception skills contributed to the majority of these incidents. These situations were grouped together to form clusters of typical incident scenarios on the basis of their similarities. The most frequent scenario corresponds to a lane change in dense traffic (15% of all incidents). The discussion shows how this has enhanced our understanding of novice riders' behaviour and how the findings can improve training and licensing. Lastly, the main methodological limitations of the study and some guidelines for improving future naturalistic riding studies are presented. Practitioner Summary: This article aims to identify the risky situations of novice motorcyclists in real roads. Two hundred forty-eight events were recorded and 13 incident scenarios identified. Results revealed that a lack of hazard perception contributed to the majority of these events. The most frequent scenario corresponds to a lane change in dense traffic. PMID- 26752260 TI - Carbon nanobuds based on carbon nanotube caps: a first-principles study. AB - Based on density functional theory calculations, we here show that the formation of a fullerene C60 carbon "nanobud" (CNB) on carbon nanotube (CNT) caps is energetically more favorable than that on CNT sidewalls. The dominant CNB formation mode for CNT caps is found to be the [2 + 2] cycloaddition reaction as in the conventional CNT sidewall case. However, it is identified to be exothermic in contrast to the endothermic reaction on CNT sidewalls. Computed reaction pathways further demonstrate that the formation (dissociation) barrier for the CNT cap-based CNB is slightly lower (significantly higher) than that of the CNT sidewall-based CNB, indicating an easier CNB formation as well as a higher structural stability. Additionally, performing matrix Green's function calculations, we study the charge transport properties of the CNB/metal electrode interfaces, and show that the C60 bonding to the CNT cap or open end induces resonant transmissions near the Fermi level. It is also found that the good electronic linkage in the CNT cap-C60 cycloaddition bonds results in the absence of quantum interference patterns, which contrasts with the case of the CNB formed on an open-ended CNT that shows a Fano resonance profile. PMID- 26752262 TI - Mobility-Selected Ion Trapping and Enrichment Using Structures for Lossless Ion Manipulations. AB - The integration of ion mobility spectrometry (IMS) with mass spectrometry (MS) and the ability to trap ions in IMS-MS measurements is of great importance for performing reactions, accumulating ions, and increasing analytical measurement sensitivity. The development of Structures for Lossless Ion Manipulations (SLIM) offers the potential for ion manipulations in an extended and more effective manner, while opening opportunities for many more complex sequences of manipulations. Here, we demonstrate an ion separation and trapping module and a method based upon SLIM that consists of a linear mobility ion drift region, a switch/tee and a trapping region that allows the isolation and accumulation of mobility-separated species. The operation and optimization of the SLIM switch/tee and trap are described and demonstrated for the enrichment of the low abundance ions. A linear improvement in ion intensity was observed with the number of trapping/accumulation events using the SLIM trap, illustrating its potential for enhancing the sensitivity of low abundance or targeted species. PMID- 26752261 TI - PLGA particulate delivery systems for subunit vaccines: Linking particle properties to immunogenicity. AB - Among the emerging subunit vaccines are recombinant protein- and synthetic peptide-based vaccine formulations. However, proteins and peptides have a low intrinsic immunogenicity. A common strategy to overcome this is to co-deliver (an) antigen(s) with (an) immune modulator(s) by co-encapsulating them in a particulate delivery system, such as poly(lactic-co-glycolic acid) (PLGA) particles. Particulate PLGA formulations offer many advantages for antigen delivery as they are biocompatible and biodegradable; can protect the antigens from degradation and clearance; allow for co-encapsulation of antigens and immune modulators; can be targeted to antigen presenting cells; and their particulate nature can increase uptake and cross-presentation by mimicking the size and shape of an invading pathogen. In this review we discuss the pros and cons of using PLGA particulate formulations for subunit vaccine delivery and provide an overview of formulation parameters that influence their adjuvanticity and the ensuing immune response. PMID- 26752264 TI - Child characteristics, caregiver characteristics, and environmental factors affecting the quality of life of caregivers of children with cerebral palsy. AB - PURPOSE: The study aimed to investigate comprehensively the determinants of the quality of life (QOL) of caregivers of children with cerebral palsy (CP) based on the International Classification of Functioning, Disability and Health for Children and Youth (ICF-CY). METHODS: A total of 167 children with CP (mean age 9.06 years, SD 2.61 years) and their caregivers (mean age 40.24 years, SD 5.43 years) participated in this study. The QOL of caregivers was measured with the World Health Organization Quality of Life-BREF-Taiwan version (WHOQOL-BREF-TW). The potential determinants of QOL were collected, including child characteristics, caregiver characteristics, and environmental factors from all dimensions of the ICF-CY and analysed using multiple regression models. RESULTS: Four multiple regression models revealed that determinants of the QOL of caregivers of children with CP was multidimensional, encompassing child characteristics (age, type of CP, fine motor impairment, other diseases, behaviour and emotions, visual impairment, hearing impairment), caregiver characteristics (general mental health, parenting stress, marital status, family coping patterns, and socio-economic status), and environmental factors (child's medication, school setting, and current rehabilitation service, caregiver's spouse's age, family life impacts, and domestic helper). CONCLUSIONS: Knowledge of the determinants of QOL could serve as a guide in a holistic approach to evaluation and intervention and help plan interventions targeted at these determinants to improve the QOL of caregivers of children with CP. Implications for Rehabilitation Caregivers of children with CP had lower QOL, except the environment QOL. The QOL determinants of caregivers of children with CP are multidimensional, including child characteristics, caregiver characteristics, and environmental factors. In addition to child characteristics of severity of fine motor impairments and emotional and behavioural problems, caregiver characteristics of general mental health, parenting stress, and coping patterns, and environmental factors of family life impacts, and school setting demonstrated important relationships with caregiver QOL. PMID- 26752263 TI - The spindle assembly checkpoint promotes chromosome bi-orientation: A novel Mad1 role in chromosome alignment. AB - Faithful chromosome segregation relies on dynamic interactions between spindle microtubules and chromosomes. Especially, all chromosomes must be aligned at the equator of the spindle to establish bi-orientation before they start to segregate. The spindle assembly checkpoint (SAC) monitors this process, inhibiting chromosome segregation until all chromosomes achieve bi-orientation. The original concept of 'checkpoints' was proposed as an external surveillance system that does not play an active role in the process it monitors. However, accumulating evidence from recent studies suggests that SAC components do play an active role in chromosome bi-orientation. In this review, we highlight a novel Mad1 role in chromosome alignment, which is the first conserved mechanism that links the SAC and kinesin-mediated chromosome gliding. PMID- 26752268 TI - Chromosome analysis of Endochironomus albipennis Meigen, 1830 and morphologically similar Endochironomus sp. (Diptera, Chironomidae) from water bodies of the Volga region, Russia. AB - Based upon the detailed chromosome map of polytene chromosomes of the eurybiont species Endochironomus albipennis Meigen, 1830, the localization of the centromere regions using a C-banding technique is defined. Chromosomal polymorphism in populations from two water bodies in the Volga region has been studied, 17 sequences are described. Polytene chromosomes of Endochironomus sp. (2n=6), having larvae morphologically similar to those of Endochironomus albipennis Meigen, 1830 (2n=6) are described for the first time. PMID- 26752267 TI - Hybridization of powdery mildew strains gives rise to pathogens on novel agricultural crop species. AB - Throughout the history of agriculture, many new crop species (polyploids or artificial hybrids) have been introduced to diversify products or to increase yield. However, little is known about how these new crops influence the evolution of new pathogens and diseases. Triticale is an artificial hybrid of wheat and rye, and it was resistant to the fungal pathogen powdery mildew (Blumeria graminis) until 2001 (refs. 1,2,3). We sequenced and compared the genomes of 46 powdery mildew isolates covering several formae speciales. We found that B. graminis f. sp. triticale, which grows on triticale and wheat, is a hybrid between wheat powdery mildew (B. graminis f. sp. tritici) and mildew specialized on rye (B. graminis f. sp. secalis). Our data show that the hybrid of the two mildews specialized on two different hosts can infect the hybrid plant species originating from those two hosts. We conclude that hybridization between mildews specialized on different species is a mechanism of adaptation to new crops introduced by agriculture. PMID- 26752266 TI - Genomic analysis of 38 Legionella species identifies large and diverse effector repertoires. AB - Infection by the human pathogen Legionella pneumophila relies on the translocation of ~ 300 virulence proteins, termed effectors, which manipulate host cell processes. However, almost no information exists regarding effectors in other Legionella pathogens. Here we sequenced, assembled and characterized the genomes of 38 Legionella species and predicted their effector repertoires using a previously validated machine learning approach. This analysis identified 5,885 predicted effectors. The effector repertoires of different Legionella species were found to be largely non-overlapping, and only seven core effectors were shared by all species studied. Species-specific effectors had atypically low GC content, suggesting exogenous acquisition, possibly from the natural protozoan hosts of these species. Furthermore, we detected numerous new conserved effector domains and discovered new domain combinations, which allowed the inference of as yet undescribed effector functions. The effector collection and network of domain architectures described here can serve as a roadmap for future studies of effector function and evolution. PMID- 26752270 TI - Investigation of the relationship between salivary cortisol, dehydroepiandrosterone sulfate, anxiety, and depression in patients with hyperemesis gravidarum. AB - BACKGROUND: The aim of this study was to determine the relationship of the salivary levels of dehydroepiandrosterone sulfate (DHEA-S) and cortisol with factors related to depression and anxiety in patients with hyperemesis gravidarum (HG). METHODS: Forty patients with a diagnosis of HG were selected for the study and matched with 40 control patients according to body mass index, parity, and age. Symptoms of depression and anxiety were investigated using the Beck Depression Inventory and Beck Anxiety Inventory for Adults, respectively. Saliva samples were collected in the morning and at night and subjected to enzyme-linked immunosorbent assay for the determination of DHEA-S and cortisol levels. RESULTS: We observed a positive correlation between increased levels of depression and anxiety and increased salivary levels of cortisol and DHEA-S in patients with HG. CONCLUSIONS: Salivary cortisol and DHEA-S levels, as well as mood disorders, should be monitored in patients with HG, although further large, prospective studies are needed to confirm our results. PMID- 26752269 TI - Molecular identification of Ancylostoma species from dogs and an assessment of zoonotic risk in low-income households, Sao Paulo State, Brazil. AB - Hookworm infection stands out for its worldwide distribution and for its veterinary and public health relevance. Based on copromicroscopic examinations and polymerase chain reaction (PCR) amplification of the ITS1-5.8S-ITS2 region, we assessed, respectively, the prevalence of intestinal parasites and the identification of canine hookworm species in faeces recovered from 278 dogs living in households of an inland municipality of Sao Paulo State, Brazil. Intestinal parasites were found in 67.3% of dogs and hookworm infection was found at the highest prevalence rate (56.6%), followed by Toxocara canis (11.9%), Isospora spp. (11.9%), Giardia spp. (5.8%), Sarcocystis spp. (4.0%), 'Hammondia like' (1.4%), Dipylidium caninum (1.1%) and Trichuris vulpis (0.7%). Of 158 samples positive for hookworm eggs, 106 (67.1%) were amplified by PCR and, of those, 88 (55.7%) were successfully sequenced for species identification. Single infections with Ancylostoma caninum and Ancylostoma braziliense were recorded in 61.4% and 12.5%, respectively, and mixed infections were found in 26.1%. The nucleotide sequences of both species showed high identity rates (98-100%) when compared with reference sequences. Although A. caninum was the most prevalent hookworm in the dogs assessed, the occurrence of both A. caninum and A. braziliense in single and/or mixed infections poses a potential risk for the local population in a low-income area, especially children, to acquire cutaneous larva migrans (CLM). PMID- 26752271 TI - Tuning band inversion symmetry of buckled III-Bi sheets by halogenation. AB - First-principles calculations are employed to investigate structural, electronic and topological insulating properties of XBi (X = B, Al, Ga, and In) monolayers upon halogenation. It is known that Y-XBi (X = Ga, In, Tl; Y = F, Cl, Br, I) can originate inversion-asymmetric topological insulators with large bulk band gaps. Our results suggest that Y-XBi (X = B, Al; Y = F, Cl, Br, I) may also result in nontrivial topological insulating phases. Despite the lower atomic number of B and Al, the spin-orbit coupling opens a band gap of about 400 meV in Y-XBi (X = B, Al), exhibiting an unusual electronic behavior for practical applications in spintronics. The nature of the bulk band gap and Dirac-cone edge states in their nanoribbons depends on the group-III elements and Y chemical species. They lead to a chemical tunability, giving rise to distinct band inversion symmetries and exhibiting Rashba-type spin splitting in the valence band of these systems. These findings indicate that a large family of Y-XBi sheets can exhibit nontrivial topological characteristics, by a proper tuning, and open a new possibility for viable applications at room temperature. PMID- 26752272 TI - Spatiotemporal dynamics of random stimuli account for trial-to-trial variability in perceptual decision making. AB - Decisions in everyday life are prone to error. Standard models typically assume that errors during perceptual decisions are due to noise. However, it is unclear how noise in the sensory input affects the decision. Here we show that there are experimental tasks for which one can analyse the exact spatio-temporal details of a dynamic sensory noise and better understand variability in human perceptual decisions. Using a new experimental visual tracking task and a novel Bayesian decision making model, we found that the spatio-temporal noise fluctuations in the input of single trials explain a significant part of the observed responses. Our results show that modelling the precise internal representations of human participants helps predict when perceptual decisions go wrong. Furthermore, by modelling precisely the stimuli at the single-trial level, we were able to identify the underlying mechanism of perceptual decision making in more detail than standard models. PMID- 26752273 TI - Extended use of Kinesiology Tape and Balance in Participants with Chronic Ankle Instability. AB - CONTEXT: Participants with chronic ankle instability (CAI) have been shown to have balance deficits related to decreased proprioception and neuromuscular control. Kinesiology tape (KT) has been proposed to have many benefits, including increased proprioception. OBJECTIVE: To determine if KT can help with balance deficits associated with CAI. DESIGN: Cohort study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty participants with CAI were recruited for this study. INTERVENTION(S): Balance was assessed using the Balance Error Scoring System (BESS). Participants were pretested and then randomly assigned to either the control or KT group. The participants in the KT group had 4 strips applied to the foot and lower leg and were instructed to leave the tape on until they returned for testing. All participants returned 48 hours later for another BESS assessment. The tape was then removed, and all participants returned 72 hours later to complete the final BESS assessment. MAIN OUTCOME MEASURE(S): Total BESS errors. RESULTS: Differences between the groups occurred at 48 hours post application of the tape (mean difference = 4.7 +/- 1.4 errors, P < .01; 95% confidence interval = 2.0, 7.5) and at 72 hours post-removal of the tape (mean difference = 2.3 +/- 1.1 errors, P = .04; 95% confidence interval = 0.1, 4.6). CONCLUSIONS: The KT improved balance after it had been applied for 48 hours when compared with the pretest and with the control group. One of the most clinically important findings is that balance improvements were retained even after the tape had been removed for 72 hours. PMID- 26752274 TI - Huge epiglottic cyst: a rare cause of airway obstruction in an adolescent. AB - A 15-year-old boy presented with airway obstruction and a history of sore throat and progressive dyspnoea for 1 month. A lateral neck radiograph showed an enlarged epiglottis, and a neck computed tomography (CT) demonstrated a cyst attached to the lingual surface of the epiglottis. A large epiglottic cyst, 4 cm in length, was removed surgically. Epiglottic cysts have been reported to cause airway obstruction in neonates, infants and adults, but, to the best of our knowledge, it has rarely been reported in adolescents. PMID- 26752265 TI - Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. AB - Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 * 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 * 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 * 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies. PMID- 26752276 TI - Elevated Blood Pressure in Acute Ischemic Stroke: Comment and Reply. PMID- 26752278 TI - Impact of HIV infection on treatment outcome of tuberculosis in Europe. AB - BACKGROUND: The effect of HIV on tuberculosis (TB) treatment outcomes has not been well established. We aimed to assess the impact of HIV infection on TB treatment outcomes by using data from notifiable disease surveillance in Europe. METHODS: We analyzed the treatment outcomes of TB cases reported from nine European countries during 2010-2012. We investigate the effect of HIV on TB treatment outcomes using a multilevel and a multinomial logistic model, and considering the interaction between HIV and multidrug-resistant (MDR) TB. RESULTS: A total of 61,138 TB cases including 5.5% HIV-positive were eligible for our analysis. In the multilevel model adjusted for age and an interaction with MDR TB, HIV was significantly associated with lower treatment success in all MDR strata [non-MDR TB: odds ratio (OR) 0.24 CI (confidence interval) 0.20-0.29; unknown MDR TB status: OR 0.26 CI 0.23-0.30; MDR TB: OR 0.57 CI 0.35-0.91]. In the multinomial regression model, HIV-positive cases had significantly higher relative risk ratio (RRR) for death (non-MDR TB: RRR 4.30 CI 2.31-7.99; unknown MDR TB status: 5.55 CI 3.10-9.92; MDR TB: 3.59 CI 1.56-8.28) and being 'still on treatment' (non-MDR TB: RRR 7.27 CI 3.00-17.6; unknown MDR TB status: 5.36 CI 2.44-11.8; MDR TB: 3.76 CI 2.48-5.71). We did not find any significant association between HIV and TB treatment failure (non-MDR TB: RRR 0.50 CI 0.15 1.67; unknown MDR TB status: 1.51 CI 0.86-2.64; MDR TB: 0.51 CI 0.13-1.87). CONCLUSION: This large study confirms that HIV is a strong risk factor for an adverse TB treatment outcome, which is mainly manifested by an increased risk of death and still being on TB treatment. PMID- 26752280 TI - Clinic-level factors influencing patient outcomes on antiretroviral therapy in primary health clinics in South Africa. AB - OBJECTIVES: To explore which clinic-level factors influence treatment outcomes in a multisite antiretroviral therapy (ART) programme in South Africa. DESIGN: Retrospective cohort study using 36 clinics. METHODS: We used random effects modelling to investigate clinic-level factors influencing ART outcomes, adjusting for patient-level factors and accounting for clustering at clinic level. Outcomes were unsuppressed viral load (>400 copies/ml) at 24 months after ART start and time to loss to follow-up. RESULTS: At clinic level, the mean proportion of patients with unsuppressed viral load at 24 months was 16% (range 8-33%). Loss to follow-up was also highly variable across clinics ranging from 3.5 to 23.4/100 person-years. Unsuppressed viral load was associated with a lower doctor-patient ratio [for every 500 patients, compared with >2.6 doctors: <0.7 doctors: adjusted odds ratio (OR) 1.52, 95% confidence interval (CI) 1.04-2.21; 0.7-2.6 doctors, OR 1.33, CI 0.91-1.93, P trend 0.04] after adjustment for patient factors. Combinations of psychosocial support interventions were weakly associated with reduced loss to follow-up [>6 interventions vs. <4 interventions: hazard ratio 0.39 (CI 0.15 - 1.04), P = 0.11]. Flexibility of services, integration of services, staff motivation, staff leadership and location of clinic were not consistently associated with improved outcomes. CONCLUSION: The dominant clinic level influences on patient outcomes were doctor : patient ratio, and combination interventions to reduce loss to follow-up. Further research is needed to define optimum staffing levels that are required to roll out ART and the combination intervention that is most effective to reduce loss to follow-up. PMID- 26752277 TI - Determinants of reduced cognitive performance in HIV-1-infected middle-aged men on combination antiretroviral therapy. AB - OBJECTIVE: The spectrum of risk factors for HIV-associated cognitive impairment is likely very broad and includes not only HIV/antiretroviral therapy-specific factors but also other comorbid conditions. The purpose of this current study was to explore possible determinants for decreased cognitive performance. DESIGN AND METHODS: Neuropsychological assessment was performed on 103 HIV-1-infected men with suppressed viraemia on combination antiretroviral therapy for at least 12 months and 74 HIV-uninfected highly similar male controls, all aged at least 45 years. Cognitive impairment and cognitive performance were determined by multivariate normative comparison (MNC). Determinants of decreased cognitive performance and cognitive impairment were investigated by linear and logistic regression analysis, respectively. RESULTS: Cognitive impairment as diagnosed by MNC was found in 17% of HIV-1-infected men. Determinants for decreased cognitive performance by MNC as a continuous variable included cannabis use, history of prior cardiovascular disease, impaired renal function, diabetes mellitus type 2, having an above normal waist-to-hip ratio, presence of depressive symptoms, and lower nadir CD4+ cell count. Determinants for cognitive impairment, as dichotomized by MNC, included cannabis use, prior cardiovascular disease, impaired renal function, and diabetes mellitus type 2. CONCLUSION: Decreased cognitive performance probably results from a multifactorial process, including not only HIV-associated factors, such as having experienced more severe immune deficiency, but also cardiovascular/metabolic factors, cannabis use, and depressive symptoms. PMID- 26752281 TI - No selection of CXCR4-using variants in cell reservoirs of dual-mixed HIV infected patients on suppressive maraviroc therapy. AB - We used ultradeep sequencing to investigate the evolution of the frequency of CXCR4-using viruses in the peripheral blood mononuclear cells of 22 patients infected with both CCR5 and CXCR4-using viruses treated with the CCR5 antagonist maraviroc for 24 weeks and a stable antiviral therapy. The mean CXCR4-using virus frequency in peripheral blood mononuclear cells was 59% before maraviroc intensification and 52% after 24 weeks of effective treatment, indicating no selection by maraviroc. PMID- 26752282 TI - Use of antiretroviral therapy and risk of end-stage liver disease and hepatocellular carcinoma in HIV-positive persons. AB - OBJECTIVES: Although several antiretroviral drugs, including the d-drugs stavudine (d4T) and didanosine (ddI), may cause biomarker-defined hepatotoxicity, their association with clinically defined end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC) remains unknown. DESIGN: Prospective cohort study. METHODS: Data collection on adverse events of anti-HIV drugs study (D:A:D) participants were followed until the first of ESLD (variceal bleeding, hepatic encephalopathy, hepatorenal syndrome or liver transplantation), HCC (histology or alpha-fetoprotein along with imaging), death, 6 months after last visit or 1 February 2014. Associations between ESLD/HCC and cumulative use of individual antiretrovirals were investigated using Poisson regression adjusting for potential confounders. RESULTS: During a median follow-up of 8.4 years, 319 ESLD/HCC cases occurred [incidence 1.01/1000 person-years (95% confidence interval 0.90-1.12)] with a 1-year mortality rate of 62.6%. After adjustment, cumulative (per 5 years) exposure to d4T [relative rate 1.46 (95% confidence interval 1.20-1.77)], ddI [1.32 (1.07-1.63)], tenofovir [TDF, 1.46 (1.11-1.93)] and (fos)amprenavir [APV; 1.47 (1.01-2.15)] was associated with increased ESLD/HCC rates. Longer exposure to emtricitabine [0.51 (0.32-0.83)] and nevirapine [0.76 (0.58-0.98)] were associated with lower ESLD/HCC rates. The ddI/d4T-associated increased ESLD/HCC rate only started to decline 6 years after cessation. CONCLUSION: Cumulative use of d4T, ddI, TDF and APV were independently associated with increased ESLD/HCC rates, and intensified monitoring of liver function should hence be considered among all individuals exposed for longer time periods. The use of d-drugs should furthermore be avoided, where there are alternatives available, and focus should be put on those with longer-term d-drugs exposure who remain at increased ESLD/HCC risk. The unexpected, and viral hepatitis-independent, TDF association calls for further investigations. PMID- 26752284 TI - Supragingival Microbial Profiles of Permanent and Deciduous Teeth in Children with Mixed Dentition. AB - OBJECTIVES: The present study was designed to investigate the microbial profiles of teeth in different locations in mixed-dentition-stage children, and to compare the microbiomes of permanent and deciduous teeth in the same healthy oral cavity. METHODS: Supragingival plaque samples of teeth in various locations-the first permanent molars, deciduous molars, deciduous canines and incisors and permanent incisors-were collected from 20 healthy mixed-dentition-stage children with 10-12 permanent teeth erupted. Plaque DNA was extracted, and the V3-V4 hypervariable region of the bacterial 16S rRNA gene was amplified and subjected to sequencing. RESULTS: On average, 18,051 high-quality sequences per sample were generated. Permanent tooth sites tended to host more diverse bacterial communities than those of deciduous tooth sites. A total of 12 phyla, 21 classes, 38 orders, 66 families, 74 genera were detected ultimately. Five predominant phyla (Proteobacteria, Firmicutes, Bacteroidetes, Fusobacteria and Actinobacteria) were highly variable among sites. Of 26 genera with a mean relative abundance of >0.1%, 16 showed significant differences in relative abundance among the groups. More than 20% of the total operational taxonomical units were detected only in permanent or deciduous teeth. The variation in the microbial community composition was due mainly to permanent teeth being enriched in Actinomyces and deciduous teeth in Treponema. The core microbiome of supragingival plaque in mixed dentition comprised 19 genera with complex correlationships. CONCLUSION: Our results suggest differences in microbial diversity and composition between permanent and deciduous teeth sites in mixed dentition. Moreover, the core microbiome of these sites was determined. These findings enhance our understanding of the development of the native oral microbiota with age. PMID- 26752283 TI - AdcAII of Streptococcus pneumoniae Affects Pneumococcal Invasiveness. AB - Across bacterial species, metal binding proteins can serve functions in pathogenesis in addition to regulating metal homeostasis. We have compared and contrasted the activities of zinc (Zn2+)-binding lipoproteins AdcA and AdcAII in the Streptococcus pneumoniae TIGR4 background. Exposure to Zn2+-limiting conditions resulted in delayed growth in a strain lacking AdcAII (DeltaAdcAII) when compared to wild type bacteria or a mutant lacking AdcA (DeltaAdcA). AdcAII failed to interact with the extracellular matrix protein laminin despite homology to laminin-binding proteins of related streptococci. Deletion of AdcA or AdcAII led to significantly increased invasion of A549 human lung epithelial cells and a trend toward increased invasion in vivo. Loss of AdcAII, but not AdcA, was shown to negatively impact early colonization of the nasopharynx. Our findings suggest that expression of AdcAII affects invasiveness of S. pneumoniae in response to available Zn2+ concentrations. PMID- 26752286 TI - Correction: Escape from Lethal Bacterial Competition through Coupled Activation of Antibiotic Resistance and a Mobilized Subpopulation. AB - [This corrects the article DOI: 10.1371/journal.pgen.1005722.]. PMID- 26752285 TI - Race, Ethnicity, Psychosocial Factors, and Telomere Length in a Multicenter Setting. AB - BACKGROUND: Leukocyte telomere length(LTL) has been associated with age, self reported race/ethnicity, gender, education, and psychosocial factors, including perceived stress, and depression. However, inconsistencies in associations of LTL with disease and other phenotypes exist across studies. Population characteristics, including race/ethnicity, laboratory methods, and statistical approaches in LTL have not been comprehensively studied and could explain inconsistent LTL associations. METHODS: LTL was measured using Southern Blot in 1510 participants from a multi-ethnic, multi-center study combining data from 3 centers with different population characteristics and laboratory processing methods. Main associations between LTL and psychosocial factors and LTL and race/ethnicity were evaluated and then compared across generalized estimating equations(GEE) and linear regression models. Statistical models were adjusted for factors typically associated with LTL(age, gender, cancer status) and also accounted for factors related to center differences, including laboratory methods(i.e., DNA extraction). Associations between LTL and psychosocial factors were also evaluated within race/ethnicity subgroups (Non-hispanic Whites, African Americans, and Hispanics). RESULTS: Beyond adjustment for age, gender, and cancer status, additional adjustments for DNA extraction and clustering by center were needed given their effects on LTL measurements. In adjusted GEE models, longer LTL was associated with African American race (Beta(beta)(standard error(SE)) = 0.09(0.04), p-value = 0.04) and Hispanic ethnicity (beta(SE) = 0.06(0.01), p value = 0.02) compared to Non-Hispanic Whites. Longer LTL was also associated with less than a high school education compared to having greater than a high school education (beta(SE) = 0.06(0.02), p-value = 0.04). LTL was inversely related to perceived stress (beta(SE) = -0.02(0.003), p<0.001). In subgroup analyses, there was a negative association with LTL in African Americans with a high school education versus those with greater than a high school education(beta(SE) = -0.11(0.03), p-value<0.001). CONCLUSIONS: Laboratory methods and population characteristics that differ by center can influence telomere length associations in multicenter settings, but these effects could be addressed through statistical adjustments. Proper evaluation of potential sources of bias can allow for combined multicenter analyses and may resolve some inconsistencies in reporting of LTL associations. Further, biologic effects on LTL may differ under certain psychosocial and racial/ethnic circumstances and could impact future health disparity studies. PMID- 26752287 TI - Using Linkage Analysis to Detect Gene-Gene Interactions. 2. Improved Reliability and Extension to More-Complex Models. AB - Detecting gene-gene interaction in complex diseases has become an important priority for common disease genetics, but most current approaches to detecting interaction start with disease-marker associations. These approaches are based on population allele frequency correlations, not genetic inheritance, and therefore cannot exploit the rich information about inheritance contained within families. They are also hampered by issues of rigorous phenotype definition, multiple test correction, and allelic and locus heterogeneity. We recently developed, tested, and published a powerful gene-gene interaction detection strategy based on conditioning family data on a known disease-causing allele or a disease associated marker allele4. We successfully applied the method to disease data and used computer simulation to exhaustively test the method for some epistatic models. We knew that the statistic we developed to indicate interaction was less reliable when applied to more-complex interaction models. Here, we improve the statistic and expand the testing procedure. We computer-simulated multipoint linkage data for a disease caused by two interacting loci. We examined epistatic as well as additive models and compared them with heterogeneity models. In all our models, the at-risk genotypes are "major" in the sense that among affected individuals, a substantial proportion has a disease-related genotype. One of the loci (A) has a known disease-related allele (as would have been determined from a previous analysis). We removed (pruned) family members who did not carry this allele; the resultant dataset is referred to as "stratified." This elimination step has the effect of raising the "penetrance" and detectability at the second locus (B). We used the lod scores for the stratified and unstratified data sets to calculate a statistic that either indicated the presence of interaction or indicated that no interaction was detectable. We show that the new method is robust and reliable for a wide range of parameters. Our statistic performs well both with the epistatic models (false negative rates, i.e., failing to detect interaction, ranging from 0 to 2.5%) and with the heterogeneity models (false positive rates, i.e., falsely detecting interaction, <=1%). It works well with the additive model except when allele frequencies at the two loci differ widely. We explore those features of the additive model that make detecting interaction more difficult. All testing of this method suggests that it provides a reliable approach to detecting gene-gene interaction. PMID- 26752288 TI - Role of Lung Function Genes in the Development of Asthma. AB - Although our previous GWAS failed to identify SNPs associated with pulmonary function at the level of genomewide significance, it did show that the heritability for FEV1/FVC was 41.6% in a Japanese population, suggesting that the heritability of pulmonary function traits can be explained by the additive effects of multiple common SNPs. In addition, our previous study indicated that pulmonary function genes identified in previous GWASs in non-Japanese populations accounted for 4.3% to 12.0% of the entire estimated heritability of FEV1/FVC in a Japanese population. Therefore, given that many loci with individual weak effects may contribute to asthma risk, in this study, we created a quantitative score of genetic load based on 16 SNPs implicated in lower lung function in both Japanese and non-Japanese populations. This genetic risk score (GRS) for lower FEV1/FVC was consistently associated with the onset of asthma (P = 9.6 * 10(-4)) in 2 independent Japanese populations as well as with the onset of COPD (P = 0.042). Clustering of asthma patients based on GRS levels indicated that an increased GRS may be responsible for the development of a particular phenotype of asthma characterized by early onset, atopy, and severer airflow obstruction. PMID- 26752290 TI - A Risk Index for Living Donor Kidney Transplantation. AB - Choosing between multiple living kidney donors, or evaluating offers in kidney paired donation, can be challenging because no metric currently exists for living donor quality. Furthermore, some deceased donor (DD) kidneys can result in better outcomes than some living donor kidneys, yet there is no way to compare them on the same scale. To better inform clinical decision-making, we created a living kidney donor profile index (LKDPI) on the same scale as the DD KDPI, using Cox regression and adjusting for recipient characteristics. Donor age over 50 (hazard ratio [HR] per 10 years = 1.15 1.241.33 ), elevated BMI (HR per 10 units = 1.01 1.091.16 ), African-American race (HR = 1.15 1.251.37 ), cigarette use (HR = 1.09 1.161.23 ), as well as ABO incompatibility (HR = 1.03 1.271.58 ), HLA B (HR = 1.03 1.081.14 ) mismatches, and DR (HR = 1.04 1.091.15 ) mismatches were associated with greater risk of graft loss after living donor transplantation (all p < 0.05). Median (interquartile range) LKDPI score was 13 (1-27); 24.2% of donors had LKDPI < 0 (less risk than any DD kidney), and 4.4% of donors had LKDPI > 50 (more risk than the median DD kidney). The LKDPI is a useful tool for comparing living donor kidneys to each other and to deceased donor kidneys. PMID- 26752289 TI - Calcium and Superoxide-Mediated Pathways Converge to Induce Nitric Oxide Dependent Apoptosis in Mycobacterium fortuitum-Infected Fish Macrophages. AB - Mycobacterium fortuitum causes 'mycobacteriosis' in wide range of hosts although the mechanisms remain largely unknown. Here we demonstrate the role of calcium (Ca+2)-signalling cascade on M. fortuitum-induced apoptosis in headkidney macrophages (HKM) of Clarias sp. M. fortuitum could trigger intracellular-Ca+2 influx leading to the activation of calmodulin (CaM), protein kinase C alpha (PKCalpha) and Calmodulin kinase II gamma (CaMKIIg). Gene silencing and inhibitor studies established the role of CaM in M. fortuitum pathogenesis. We noted that CaMKIIg activation is regulated by CaM as well as PKCalpha-dependent superoxide anions. This is altogether first report of oxidised CaMKIIg in mycobacterial infections. Our studies with targeted-siRNA and pharmacological inhibitors implicate CaMKIIg to be pro-apoptotic and critical for the activation of extra cellular signal regulated kinase 1/2 (ERK1/2). Inhibiting the ERK1/2 pathway attenuated nitric oxide synthase 2 (NOS2)-induced nitric oxide (NO) production. Conversely, inhibiting the NOS2-NO axis by specific-siRNA and inhibitors down regulated ERK1/2 activation suggesting the crosstalk between ERK1/2 and NO is essential for pathogenesis induced by the bacterium. Silencing the NOS2-NO axis enhanced intracellular bacterial survival and attenuated caspase-8 mediated activation of caspase-3 in the infected HKM. Our findings unveil hitherto unknown mechanism of M. fortuitum pathogenesis. We propose that M. fortuitum triggers intracellular Ca+2 elevations resulting in CaM activation and PKCalpha-mediated superoxide generation. The cascade converges in common pathway mediated by CaMKIIg resulting in the activation of ERK1/2-NOS2 axis. The crosstalk between ERK1/2 and NO shifts the balance in favour of caspase dependent apoptosis of M. fortuitum-infected HKM. PMID- 26752292 TI - Metabolic Analysis of Medicinal Dendrobium officinale and Dendrobium huoshanense during Different Growth Years. AB - Metabolomics technology has enabled an important method for the identification and quality control of Traditional Chinese Medical materials. In this study, we isolated metabolites from cultivated Dendrobium officinale and Dendrobium huoshanense stems of different growth years in the methanol/water phase and identified them using gas chromatography coupled with mass spectrometry (GC-MS). First, a metabolomics technology platform for Dendrobium was constructed. The metabolites in the Dendrobium methanol/water phase were mainly sugars and glycosides, amino acids, organic acids, alcohols. D. officinale and D. huoshanense and their growth years were distinguished by cluster analysis in combination with multivariate statistical analysis, including principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS DA). Eleven metabolites that contributed significantly to this differentiation were subjected to t-tests (P<0.05) to identify biomarkers that discriminate between D. officinale and D. huoshanense, including sucrose, glucose, galactose, succinate, fructose, hexadecanoate, oleanitrile, myo-inositol, and glycerol. Metabolic profiling of the chemical compositions of Dendrobium species revealed that the polysaccharide content of D. huoshanense was higher than that of D. officinale, indicating that the D. huoshanense was of higher quality. Based on the accumulation of Dendrobium metabolites, the optimal harvest time for Dendrobium was in the third year. This initial metabolic profiling platform for Dendrobium provides an important foundation for the further study of secondary metabolites (pharmaceutical active ingredients) and metabolic pathways. PMID- 26752291 TI - Development and Validation of a Prediction Model to Estimate Individual Risk of Pancreatic Cancer. AB - INTRODUCTION: There is no reliable screening tool to identify people with high risk of developing pancreatic cancer even though pancreatic cancer represents the fifth-leading cause of cancer-related death in Korea. The goal of this study was to develop an individualized risk prediction model that can be used to screen for asymptomatic pancreatic cancer in Korean men and women. MATERIALS AND METHODS: Gender-specific risk prediction models for pancreatic cancer were developed using the Cox proportional hazards model based on an 8-year follow-up of a cohort study of 1,289,933 men and 557,701 women in Korea who had biennial examinations in 1996 1997. The performance of the models was evaluated with respect to their discrimination and calibration ability based on the C-statistic and Hosmer Lemeshow type chi2 statistic. RESULTS: A total of 1,634 (0.13%) men and 561 (0.10%) women were newly diagnosed with pancreatic cancer. Age, height, BMI, fasting glucose, urine glucose, smoking, and age at smoking initiation were included in the risk prediction model for men. Height, BMI, fasting glucose, urine glucose, smoking, and drinking habit were included in the risk prediction model for women. Smoking was the most significant risk factor for developing pancreatic cancer in both men and women. The risk prediction model exhibited good discrimination and calibration ability, and in external validation it had excellent prediction ability. CONCLUSION: Gender-specific risk prediction models for pancreatic cancer were developed and validated for the first time. The prediction models will be a useful tool for detecting high-risk individuals who may benefit from increased surveillance for pancreatic cancer. PMID- 26752293 TI - Extensive terra firma forme dermatosis [TFFD]: A rare presentation. PMID- 26752294 TI - Processing of Scalar Inferences by Mandarin Learners of English: An Online Measure. AB - Scalar inferences represent the condition when a speaker uses a weaker expression such as some in a pragmatic scale like , and s/he has the intention to reject the stronger use of the other word like all in the utterance. Considerable disagreement has arisen concerning how interlocutors derive the inferences. The study presented here tries to address this issue by examining online scalar inferences among Mandarin learners of English. To date, Default Inference and Relevance Theory have made different predictions regarding how people process scalar inferences. Findings from recently emerging first language studies did not fully resolved the debate but led to even more heated debates. The current three online psycholinguistic experiments reported here tried to address the processing of scalar inferences from second language perspective. Results showed that Mandarin learners of English showed faster reaction times and a higher acceptance rate when interpreting some as some but not all and this was true even when subjects were under time pressure, which was manifested in Experiment 2. Overall, the results of the experiments supported Default Theory. In addition, Experiment 3 also found that working memory capacity plays a critical role during scalar inference processing. High span readers were faster in accepting the some but not all interpretation than low span readers. However, compared with low span readers, high span readers were more likely to accept the some and possibly all condition, possibly due to their working memory capacity to generate scenarios to fit the interpretation. PMID- 26752296 TI - Correction: Using Bayesian Population Viability Analysis to Define Relevant Conservation Objectives. PMID- 26752295 TI - Motility, digestive and nutritional problems in Esophageal Atresia. AB - Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) is a rare congenital malformation. Digestive and nutritional problems remain frequent in children with EA both in early infancy and at long-term follow-up. These patients are at major risk of presenting with gastroesophageal reflux and its complications, such as anastomotic strictures. Esophageal dysmotility is constant, and can have important consequences on feeding and nutritional status. Patients with EA need a systematic follow-up with a multidisciplinary team. PMID- 26752298 TI - Synthesizing Global and Local Datasets to Estimate Jurisdictional Forest Carbon Fluxes in Berau, Indonesia. AB - BACKGROUND: Forest conservation efforts are increasingly being implemented at the scale of sub-national jurisdictions in order to mitigate global climate change and provide other ecosystem services. We see an urgent need for robust estimates of historic forest carbon emissions at this scale, as the basis for credible measures of climate and other benefits achieved. Despite the arrival of a new generation of global datasets on forest area change and biomass, confusion remains about how to produce credible jurisdictional estimates of forest emissions. We demonstrate a method for estimating the relevant historic forest carbon fluxes within the Regency of Berau in eastern Borneo, Indonesia. Our method integrates best available global and local datasets, and includes a comprehensive analysis of uncertainty at the regency scale. PRINCIPAL FINDINGS AND SIGNIFICANCE: We find that Berau generated 8.91 +/- 1.99 million tonnes of net CO2 emissions per year during 2000-2010. Berau is an early frontier landscape where gross emissions are 12 times higher than gross sequestration. Yet most (85%) of Berau's original forests are still standing. The majority of net emissions were due to conversion of native forests to unspecified agriculture (43% of total), oil palm (28%), and fiber plantations (9%). Most of the remainder was due to legal commercial selective logging (17%). Our overall uncertainty estimate offers an independent basis for assessing three other estimates for Berau. Two other estimates were above the upper end of our uncertainty range. We emphasize the importance of including an uncertainty range for all parameters of the emissions equation to generate a comprehensive uncertainty estimate-which has not been done before. We believe comprehensive estimates of carbon flux uncertainty are increasingly important as national and international institutions are challenged with comparing alternative estimates and identifying a credible range of historic emissions values. PMID- 26752297 TI - A Novel Molecular Strategy for Surveillance of Multidrug Resistant Tuberculosis in High Burden Settings. AB - BACKGROUND: In South Africa and other high prevalence countries, transmission is a significant contributor to rising rates of multidrug resistant tuberculosis (MDR-TB). Thus, there is a need to develop an early detection system for transmission clusters suitable for high burden settings. We have evaluated the discriminatory power and clustering concordance of a novel and simple genotyping approach, combining spoligotyping with pncA sequencing (SpoNC), against two well established methods: IS6110-RFLP and 24-loci MIRU-VNTR. METHODS: A total of 216 MDR-TB isolates collected from January to June 2010 from the NHLS Central TB referral laboratory in Braamfontein, Johannesburg, representing a diversity of strains from South Africa, were included. The isolates were submitted for genotyping, pncA sequencing and analysis to the Centre for Tuberculosis in South Africa and the Public Health Research Institute Tuberculosis Center at Rutgers University in the United States. Clustering rates, Hunter-Gaston Discriminatory Indexes (HGI) and Wallace coefficients were compared between the methods. RESULTS: Overall clustering rates were high by both IS6110-RFLP (52.8%) and MIRU VNTR (45.8%), indicative of on-going transmission. Both 24-loci MIRU-VNTR and IS6110-RFLP had similar HGI (0.972 and 0.973, respectively), with close numbers of unique profiles (87 vs. 70), clustered isolates (129 vs. 146), and cluster sizes (2 to 26 vs. 2 to 25 isolates). Spoligotyping alone was the least discriminatory (80.1% clustering, HGI 0.903), with 28 unique types. However, the discriminatory power of spoligotyping was improved when combined with pncA sequencing using the SpoNC approach (61.8% clustering, HGI 0.958). A high proportion of MDR-TB isolates had mutations in pncA (68%, n = 145), and pncA mutations were significantly associated with clustering (p = 0.007 and p = 0.0013 by 24-loci MIRU-VNTR and IS6110-RFLP, respectively), suggesting high rates of resistance to pyrazinamide among all MDR-TB cases and particularly among clustered cases. CONCLUSION: We conclude that SpoNC provides good discrimination for MDR-TB surveillance and early identification of outbreaks in South Africa, with 24-loci MIRU-VNTR applied for pncA wild-type strains as needed. PMID- 26752300 TI - Trends toward an earlier peak of the growing season in Northern Hemisphere mid latitudes. AB - Changes in peak photosynthesis timing (PPT) could substantially change the seasonality of the terrestrial carbon cycle. Spring PPT in dry regions has been documented for some individual plant species on a stand scale, but both the spatio-temporal pattern of shifting PPT on a continental scale and its determinants remain unclear. Here, we use satellite measurements of vegetation greenness to find that the majority of Northern Hemisphere, mid-latitude vegetated area experienced a trend toward earlier PPT during 1982-2012, with significant trends of an average of 0.61 day yr(-1) across 19.4% of areas. These shifts correspond to increased annual accumulation of growing degree days (GDD) due to warming and are most highly concentrated in the eastern United States and Europe. Earlier mean PPT is generally a trait common among areas with summer temperatures higher than 27.6 +/- 2.9 degrees C, summer precipitation lower than 84.2 +/- 41.5 mm, and fraction of cold season precipitation greater than 89.2 +/- 1.5%. The trends toward earlier PPT discovered here have co-occurred with overall increases in vegetation greenness throughout the growing season, suggesting that summer drought is not a dominant driver of these trends. These results imply that continued warming may facilitate continued shifts toward earlier PPT and cause these trends to become more pervasive, with important implications for terrestrial carbon, water, nutrient, and energy budgets. PMID- 26752301 TI - The Acoustic Properties of Low Intensity Vocalizations Match Hearing Sensitivity in the Webbed-Toed Gecko, Gekko subpalmatus. AB - The design of acoustic signals and hearing sensitivity in socially communicating species would normally be expected to closely match in order to minimize signal degradation and attenuation during signal propagation. Nevertheless, other factors such as sensory biases as well as morphological and physiological constraints may affect strict correspondence between signal features and hearing sensitivity. Thus study of the relationships between sender and receiver characteristics in species utilizing acoustic communication can provide information about how acoustic communication systems evolve. The genus Gekko includes species emitting high-amplitude vocalizations for long-range communication (loud callers) as well as species producing only low-amplitude vocalizations when in close contact with conspecifics (quiet callers) which have rarely been investigated. In order to investigate relationships between auditory physiology and the frequency characteristics of acoustic signals in a quiet caller, Gekko subpalmatus we measured the subjects' vocal signal characteristics as well as auditory brainstem responses (ABRs) to assess auditory sensitivity. The results show that G. subpalmatus males emit low amplitude calls when encountering females, ranging in dominant frequency from 2.47 to 4.17 kHz with an average at 3.35 kHz. The auditory range with highest sensitivity closely matches the dominant frequency of the vocalizations. This correspondence is consistent with the notion that quiet and loud calling species are under similar selection pressures for matching auditory sensitivity with spectral characteristics of vocalizations. PMID- 26752299 TI - Anti-Tumor and Immune Enhancing Activities of Rice Bran Gramisterol on Acute Myelogenous Leukemia. AB - BACKGROUND: Acute myelogenous leukemia (AML) is a cancer of the blood that most commonly affects human adults. The specific cause of AML is unclear, but it induces abnormality of white blood cells that grow rapidly and accumulate in bone marrow interfering with the production and functions of the normal blood cells. AML patients face poor prognosis and low quality of life during chemotherapy or transplantation of hematopoietic stem cells due to the progressive impairment of their immune system. The goal of this study is to find natural products that have the potential to delay growth or eliminate the abnormal leukemic cells but cause less harmful effect to the body's immune system. METHODS AND FINDINGS: The unsaponified fraction of Riceberry rice bran (RBDS) and the main pure compound, gramisterol, were studied for cytotoxicity and biological activities in WEHI-3 cells and in the leukemic mouse model induced by transplantation of WEHI-3 cells intraperitoneally. In the in vitro assay, RBDS and gramisterol exerted sub-G1 phase cell cycle arrest with a potent induction of apoptosis. Both of them effectively decreased cell cycle controlling proteins (cyclin D1 and cyclin E), suppressed cellular DNA synthesis and mitotic division, and reduced anti apoptosis Bcl-2 protein, but increased apoptotic proteins (p53 and Bax) and activated caspase-3 enzyme in the intrinsic cell death stimulation pathway. In leukemic mice, daily feeding of RBDS significantly increased the amount of immune function-related cells including CD3+, CD19+, and CD11b+, and elevated the serum levels of IFN-gamma, TNF-alpha, IL-2, and IL-12beta cytokines, but suppressed IL 10 level. At the tumor sites, CD11b+ cells were polarized and became active phagocytotic cells. Treatment of mice normal immune cells with gramisterol alone or a combination of gramisterol with cytokines released from RBDS-treated leukemic mice splenocytes culture synergistically increased pSTAT1 transcriptional factor that up-regulated the genes controlling cell survival and function. Phosphorylation of STAT1 was absent in WEHI-3. Instead, similar treatments significantly decreased pSTAT3 signaling that regulates transcription of genes controlling tumor growth and proliferation. CONCLUSIONS: Rice bran gramisterol possesses a promising anti-cancer effect against a tumor of white blood cells and induces the production of anti-cancer immune-related cytokines. Gramisterol induces cell cycle arrest and apoptosis via suppression of pSTAT3 signaling control of tumor cells' growth and progression. Gramisterol increased IFN-gamma production and prevented the dysfunctional immune system of leukemic mice by enhancing pSTAT1 transcription signal controlling proliferation and functions of hematopoietic cells in the spleen. Together with IFN-gamma, gramisterol efficiently facilitates leukemic mice immune system modulation leading to improvement of the AML condition. Administration of RBDS containing gramisterol potentiates immune recovery of leukemic mice and extends their survival. This finding encourages the medicinal application of rice bran gramisterol as a palliative treatment or an alternative agent for future drug development against AML. PMID- 26752303 TI - Clinical features and risk factor analysis for lower extremity deep venous thrombosis in Chinese neurosurgical patients. AB - BACKGROUND: Deep venous thrombosis (DVT) contributes significantly to the morbidity and mortality of neurosurgical patients; however, no data regarding lower extremity DVT in postoperative Chinese neurosurgical patients have been reported. MATERIALS AND METHODS: From January 2012 to December 2013, 196 patients without preoperative DVT who underwent neurosurgical operations were evaluated by color Doppler ultrasonography and D-dimer level measurements on the 3(rd), 7(th), and 14(th) days after surgery. Follow-up clinical data were recorded to determine the incidence of lower extremity DVT in postoperative neurosurgical patients and to analyze related clinical features. First, a single factor analysis, Chi-square test, was used to select statistically significant factors. Then, a multivariate analysis, binary logistic regression analysis, was used to determine risk factors for lower extremity DVT in postoperative neurosurgical patients. RESULTS: Lower extremity DVT occurred in 61 patients, and the incidence of DVT was 31.1% in the enrolled Chinese neurosurgical patients. The common symptoms of DVT were limb swelling and lower extremity pain as well as increased soft tissue tension. The common sites of venous involvement were the calf muscle and peroneal and posterior tibial veins. The single factor analysis showed statistically significant differences in DVT risk factors, including age, hypertension, smoking status, operation time, a bedridden or paralyzed state, the presence of a tumor, postoperative dehydration, and glucocorticoid treatment, between the two groups (P < 0.05). The binary logistic regression analysis showed that an age greater than 50 years, hypertension, a bedridden or paralyzed state, the presence of a tumor, and postoperative dehydration were risk factors for lower extremity DVT in postoperative neurosurgical patients. CONCLUSIONS: Lower extremity DVT was a common complication following craniotomy in the enrolled Chinese neurosurgical patients. Multiple factors were identified as predictive of DVT in neurosurgical patients, including the presence of a tumor, an age greater than 50 years, hypertension, and immobility. PMID- 26752302 TI - A Rapid Screening Assay Identifies Monotherapy with Interferon-beta and Combination Therapies with Nucleoside Analogs as Effective Inhibitors of Ebola Virus. AB - To date there are no approved antiviral drugs for the treatment of Ebola virus disease (EVD). While a number of candidate drugs have shown limited efficacy in vitro and/or in non-human primate studies, differences in experimental methodologies make it difficult to compare their therapeutic effectiveness. Using an in vitro model of Ebola Zaire replication with transcription-competent virus like particles (trVLPs), requiring only level 2 biosafety containment, we compared the activities of the type I interferons (IFNs) IFN-alpha and IFN-beta, a panel of viral polymerase inhibitors (lamivudine (3TC), zidovudine (AZT) tenofovir (TFV), favipiravir (FPV), the active metabolite of brincidofovir, cidofovir (CDF)), and the estrogen receptor modulator, toremifene (TOR), in inhibiting viral replication in dose-response and time course studies. We also tested 28 two- and 56 three-drug combinations against Ebola replication. IFN alpha and IFN-beta inhibited viral replication 24 hours post-infection (IC50 0.038MUM and 0.016MUM, respectively). 3TC, AZT and TFV inhibited Ebola replication when used alone (50-62%) or in combination (87%). They exhibited lower IC50 (0.98-6.2MUM) compared with FPV (36.8MUM), when administered 24 hours post-infection. Unexpectedly, CDF had a narrow therapeutic window (6.25-25MUM). When dosed >50MUM, CDF treatment enhanced viral infection. IFN-beta exhibited strong synergy with 3TC (97.3% inhibition) or in triple combination with 3TC and AZT (95.8% inhibition). This study demonstrates that IFNs and viral polymerase inhibitors may have utility in EVD. We identified several 2 and 3 drug combinations with strong anti-Ebola activity, confirmed in studies using fully infectious ZEBOV, providing a rationale for testing combination therapies in animal models of lethal Ebola challenge. These studies open up new possibilities for novel therapeutic options, in particular combination therapies, which could prevent and treat Ebola infection and potentially reduce drug resistance. PMID- 26752304 TI - Identification of Combinatorial Genomic Abnormalities Associated with Prostate Cancer Early Recurrence. AB - Multiple biomarkers are needed to distinguish aggressive from indolent prostate cancer. We tested the prognostic utility of a three-marker fluorescent in situ hybridization (FISH) panel (TMPRSS2/ERG rearrangements, AR gain, and PTEN deletion) in a retrospective cohort (n = 210; median follow-up, 5.7 years). PTEN deletion was associated with an increased risk of biochemical recurrence (BcR; hazard ratio, 3.58; 95% CI, 1.39-9.22; P < 0.01) by multivariable Cox regression analyses and earlier BcR (P < 0.02) by Kaplan-Meier analysis. AR gain coexisted with X-chromosome gain and was associated with advanced tumor stage. When this panel was applied, two categories of combinatorial abnormalities proved clinically important. First, PTEN deletion without TMPRSS2/ERG rearrangement was enriched in pT3/4 tumors (70% versus 48%) and tumors with Gleason grades of 8 to 9 (60% versus 17%) compared with the entire cohort. These patients had earlier BcR than patients with normal FISH panel results (P < 0.01). In contrast, patients with PTEN deletion and ERG rearrangement had a BcR rate similar to patients who tested normal for all three markers (P > 0.1). Second, AR gain and concurrent trisomy 10 without TMPRSS2/ERG rearrangement were enriched in pT3/4 tumors and tumors with Gleason grades of 8 to 9. The three-marker FISH panel demonstrated prognostic utility and identified genomic aberrations associated with advanced disease state and early BcR in prostate cancer. PMID- 26752305 TI - Multiplex Preamplification of Serum DNA to Facilitate Reliable Detection of Extremely Rare Cancer Mutations in Circulating DNA by Digital PCR. AB - Tumor-specific mutations can be identified in circulating, cell-free DNA in plasma or serum and may serve as a clinically relevant alternative to biopsy. Detection of tumor-specific mutations in the plasma, however, is technically challenging. First, mutant allele fractions are typically low in a large background of wild-type circulating, cell-free DNA. Second, the amount of circulating, cell-free DNA acquired from plasma is also low. Even when using digital PCR (dPCR), rare mutation detection is challenging because there is not enough circulating, cell-free DNA to run technical replicates and assay or instrument noise does not easily allow for mutation detection <0.1%. This study was undertaken to improve on the robustness of dPCR for mutation detection. A multiplexed, preamplification step using a high-fidelity polymerase before dPCR was developed to increase total DNA and the number of targets and technical replicates that can be assayed from a single sample. We were able to detect multiple cancer-relevant mutations within tumor-derived samples down to 0.01%. Importantly, the signal/noise ratio was improved for all preamplified targets, allowing for easier discrimination of low-abundance mutations against false positive signal. Furthermore, we used this protocol on clinical samples to detect known, tumor-specific mutations in patient sera. This study provides a protocol for robust, sensitive detection of circulating tumor DNA for future clinical applications. PMID- 26752306 TI - Assessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy. AB - Charcot-Marie-Tooth disease is characterized by broad genetic heterogeneity with >50 known disease-associated genes. Mutations in some of these genes can cause a pure motor form of hereditary motor neuropathy, the genetics of which are poorly characterized. We designed a panel comprising 56 genes associated with Charcot Marie-Tooth disease/hereditary motor neuropathy. We validated this diagnostic tool by first testing 11 patients with pathological mutations. A cohort of 33 affected subjects was selected for this study. The DNAJB2 c.352+1G>A mutation was detected in two cases; novel changes and/or variants with low frequency (<1%) were found in 12 cases. There were no candidate variants in 18 cases, and amplification failed for one sample. The DNAJB2 c.352+1G>A mutation was also detected in three additional families. On haplotype analysis, all of the patients from these five families shared the same haplotype; therefore, the DNAJB2 c.352+1G>A mutation may be a founder event. Our gene panel allowed us to perform a very rapid and cost-effective screening of genes involved in Charcot-Marie Tooth disease/hereditary motor neuropathy. Our diagnostic strategy was robust in terms of both coverage and read depth for all of the genes and patient samples. These findings demonstrate the difficulty in achieving a definitive molecular diagnosis because of the complexity of interpreting new variants and the genetic heterogeneity that is associated with these neuropathies. PMID- 26752308 TI - Making a Long Journey Short: Alkyne Functionalization of Natural Product Scaffolds. AB - Biological selection makes natural products promising scaffolds for drug development and the ever growing number of newly identified, structurally diverse molecules helps to fill the gaps in chemical space. Elucidating the function of a small molecule, such as identifying its protein binding partners, its on- and off targets, is becoming increasingly important. Activity- and affinity-based protein profiling are modern strategies to acquire such molecular-level information. Introduction of a molecular handle (azide, alkyne, biotin) can shed light on the mode of action of small molecules. This Concept article covers central points on synthetic methodology for integrating a terminal alkyne into a molecule of interest. PMID- 26752307 TI - Three Rounds of External Quality Assessment in France to Evaluate the Performance of 28 Platforms for Multiparametric Molecular Testing in Metastatic Colorectal and Non-Small Cell Lung Cancer. AB - Personalized medicine has gained increasing importance in clinical oncology, and several clinically important biomarkers are implemented in routine practice. In an effort to guarantee high quality of molecular testing in France, three subsequent external quality assessment rounds were organized at the initiative of the National Cancer Institute between 2012 and 2014. The schemes included clinically relevant biomarkers for metastatic colorectal (KRAS, NRAS, BRAF, PIK3CA, microsatellite instability) and non-small cell lung cancer (EGFR, KRAS, BRAF, PIK3CA, ERBB2), and they represent the first multigene/multicancer studies throughout Europe. In total, 56 laboratories coordinated by 28 regional molecular centers participated in the schemes. Laboratories received formalin-fixed, paraffin-embedded samples and were asked to use routine methods for molecular testing to predict patient response to targeted therapies. They were encouraged to return results within 14 calendar days after sample receipt. Both genotyping and reporting were evaluated separately. During the three external quality assessment rounds, mean genotype scores were all above the preset standard of 90% for all biomarkers. Participants were mainly challenged in case of rare insertions or deletions. Assessment of the written reports showed substantial progress between the external quality assessment schemes on multiple criteria. Several essential elements such as the clinical interpretation of test results and the reason for testing still require improvement by continued external quality assessment education. PMID- 26752309 TI - Transfer of benzo[a]pyrene from microplastics to Artemia nauplii and further to zebrafish via a trophic food web experiment: CYP1A induction and visual tracking of persistent organic pollutants. AB - The uptake of microplastic particles and the transfer of potential harmful substances along with microplastics has been studied in a variety of organisms, especially invertebrates. However, the potential accumulation of very small microplastic particles along food webs ending with vertebrate models has not been investigated so far. Therefore, a simple artificial food chain with Artemia sp. nauplii and zebrafish (Danio rerio) was established to analyze the transfer of microplastic particles and associated persistent organic pollutants (POPs) between different trophic levels. Very small (1-20 MUm) microplastic particles accumulated in Artemia nauplii and were subsequently transferred to fish. Virgin particles not loaded with POPs did not cause any observable physical harm in the intestinal tracts of zebrafish, although parts of the particles were retained within the mucus of intestinal villi and might even have been taken up by epithelial cells. The transfer of associated POPs was tested with the polycyclic aromatic hydrocarbon benzo[a]pyrene and an ethoxyresorufin-O-deethylase (EROD) assay for CYP1A induction in zebrafish liver as well as via fluorescence analyses. Whereas a significant induction in the EROD assay could not be shown, because of high individual variation and low sensitivity regarding substance concentration, the fluorescence tracking of benzo[a]pyrene indicates that food borne microplastic-associated POPs may actually desorb in the intestine of fish and are thus transferred to the intestinal epithelium and liver. Environ Toxicol Chem 2016;35:1656-1666. (c) 2016 SETAC. PMID- 26752310 TI - [Relationship between nurse staffing and nursing outcomes: a narrative review of literature]. AB - INTRODUCTION: The measurement of nursing sensitive outcomes represents a fundamental element in "Health Management" in order to assess the suitability and quality of care given, particoulaly in hospitals for the acutely ill. OBJECTIVES: To highlight how some variables connected with nurse-staffing can determine the quality of processes and the care outcomes. METHODS: A narrative review of international literature has been carried out on investigating possible correlation between nurse-staffing characteristics and care outcomes regarding patients, taking into account primary and secondary sources, written either in English or Italian, without time limits. RESULTS: The bibliographical research strategies used, have brought about the restitution of no. 4244 articles were retrived, of these 56 were analyzed. Articles were categorized into 3 specific areas: 1) Which aspects determine the efficacy and quality of nursing care; 2) The direct effects of nursing care on care outcomes; 3) The indirect effects of nursing care on care outcomes. CONCLUSIONS: Results confirm the existence of a noticeable relationship between the main components of nurse-staffing and the direct and indirect outcomes on patients health. Longitudinal studies shound be carried out highlighting the results obtained up till now even more and assist in accurately measuring the importance of possible predictive variables on care outcomes correlated to nursing care. PMID- 26752311 TI - [Cross-sectional study on the determinants of work stress for nurses and intention of leaving the profession]. AB - INTRODUCTION: Occupational stress is one of the main causes of sick leaves among healthcare professionals and it determines high costs to health systems. Monitoring occupational related stress can be an important tool for policy makers. The Italian nursing research gave little attention to nurses' occupational stress. The aims of this study is to estimate the prevalence of occupational stress and evaluate risks factors among Italian nurses in order to evaluate health promotion intervention. METHODS: Cross-sectional study on a convenience sample of nurses from three Italian public hospitals was carried out. The Nursing Stress Scale was administrated together with socio-demographic data information(age, occupational age, family structure etc). The Nursing Stress Scale includes 34 items with a score from 0 to 3. Seven areas of job related stress are investigate in the scale: conflict with physicians, inadequate training, lack of support, conflict with other nurses, workload, uncertainty about treatments, death and suffering. Scores were calculated for each item and for each area. Associations between stress scores and socio-demographic data were analyzed. RESULTS: 231 nurses participated to the study. The two stress areas with the highest scores were "workload" (1.58) and "death and suffering" (1.39). Among the 13 items that exceed the overall mean stress score (i.e. 1.07), five belong to the "workload" area. "Watching a suffering patient" is the single item with the highest mean score. Demographic data associated to higher stress scores are, female gender (p=0.03) and working with night shifts (p=0.02). Intention to leave the nursing profession is associated to higher stress scores (p=0.002). Age, occupational age, time to commute to work, number of children, having disabled relatives at home, were not correlated to higher stress scores. CONCLUSIONS: Our study provides data regarding nurses' occupational stress that was not available before. This data may be useful for policy makers to plan preventive interventions for nurses' job related stress and to reduce nurses' intention to leave. PMID- 26752312 TI - [Generations of Italian nurses compared: an exploratory study]. AB - AIM: The influence that generations have on complex nursing work environment have not been investigated yet in Italy. The majority of studies realized on this topic up to now has a small sample size and is monocentric. None Italian study has directly investigated nursing multigenerational workforce. The study aimed to investigate the existence of generational differences in Italian nurses professional within the italian context and describe their characteristics. METHODS: A 33 items questionnaire devised for the purpose was administred to a sample of 317 nurses of two major Italian North-East hospital. Five dimensions were analyzed: professional space, professional role, professional culture, orientation to care, relationships among generations. RESULTS: Data showed statistically significant differences among nurses generations in 9 items. The dimensions with the greatest number of significant items were found to be relationship among generations (6 items), followed by orientation to care, professional space and professional role (1 item each). CONCLUSIONS: Results highlighted the existence of generational differences and give some information on perceptions and relationships between italian nurses generations. Being the first exploratory study on Italian nurses, it is currently impossible to compare these results with those of previous studies. Further investigation is needed to make more comparisons with international literature. PMID- 26752314 TI - [Utilization of Behavioral Pain Scale and Critical Care Pain Observation Tool for pain evaluation in Intensive Care Unit]. AB - AIM: To compare two evaluation pain scale the Behavioral Pain Scale (BPS) e Critical Care Pain Observation Tool (CPOT) in Intensive Care Unit in the Azienda Ospedaliera di Monza, and their correlation. To evaluate if consciousness level (evaluate through a third scale the Ritchmond Agitation Sedation Scale - RASS) influence the use of the pain scales. METHODS: 1083 data were collected from May 2012 and November 2012. The sample was made up by 36 patients, of these 20 men and 16 women, average age of 62,94+/-13,21 and hospital stay on average of 17+/ 12 days. RESULTS: BPS median is 3 (Q1: 3 - Q3:3 - range 3-12), CPOT median is (Q1 Quartile 25%: 0 - Q3- Quartile 75% : 1, range 0-8), RASS median is-1 (Q1: -4, Q3: 0 - range 0/- 5). Corellational coefficient is 0.784. There is a overall difficulty on use BPS and CPOT expecially with individuals with RASS -1. CONCLUSIONS: Results of this study suggest the need to carry out further research, expanding the validation of the pain scales for patients not able to speach to unexplored patients. PMID- 26752313 TI - [Nurses' attitudes towards nutritional care and malnutrition in hospitalised older people: A Survey in the Liguria Region]. AB - AIM: Evaluate nurses' attitudes towards nutritional assistance in elderly hospitalized individuals, using the scale "The Staff Attitudes To Nutritional Geriatric Nursing Care Scale (SANN-G Scale)", recently validated in Italian. METHODS: A descriptive survey was carried out, involving all head nurses and nurses of wards within University Hospital San Martino Hospital in Genoa and ASL3 Genovese Villa Scassi. A comparison was carried out using the Kruscall-Wallis test between wards, in order to determine whether there were significant differences in attitudes with respect to nutritional assistance. Results were compared between individuals who had follow a lecture on nutritional assistance and those who had not, using the test Mann Whitney. RESULTS: 110 questionnaires were delivered of these 103 were filled in (94%). Only 26% of the sample shows to have a strong positive attitude with respect nutritional assitance in elderly people. No significant differences were found either between wards and the other or between those who nurse had lecturer and those who have not. CONCLUSIONS: The study revealed a substantial negative attitude with respect to nutritional assitance and malnutrition in the elderly, confirming that aspects related to nutrition of the elderly are not properly taken into account in comparison to other nursing care activities. Our results are similar to those of the internationl literature. There is therefore a need also in Italy to increase awareness of professionals on these issues. PMID- 26752316 TI - Development of the Ethical Sensitivity Scale in Undergraduate Nursing Students. AB - AIMS: The objectives of this study were first to develop a valid and reliable instrument that measured the sensitivity of Italian nursing undergraduates, and, second, to conduct an observational study in second- and third-year Italian nursing students to provide new insight into the efficacy of nursing ethics education to develop ethical sensitivity. METHODS: A quantitative, descriptive, observational pilot study was conducted in two Italian universities. To investigate the students' sensitivity, a brand new scale entitled "Ethical sensitivity scale undergraduates nursing students" (ESS-UNS) was produced. Twenty items that referenced the principles of the Italian Nursing Code of Ethics were identified (2009). RESULTS: The measured exploratory factorial analysis outlined a two-factor solution. Based on the semantics of the items, the first dimension was named "Ethical sensitivity as a positive attitude" and it was created to detect the perceptions and opinions of the students regarding good behaviours in nursing. The second dimension was named "Ethics sensitivity as a negative attitude" in virtue of the perceptions of the students regarding the behaviours considered ethically negative. CONCLUSIONS: The added value of our study is in the verification that academic ethical education significantly increases students' awareness regarding the possible ethical violations observed and lived in during clinical training. This can help students understand and identify the ethical conflicts in relationship with their moral maturity. PMID- 26752315 TI - [Et d'allhora in poi, mai si senti piu bene: a historical survey to find nursing origins in post-tridentine whitchcraft lawsuits in County of Bormio (1596-1630)]. AB - INTRODUCTION: The phenomenon of witch-hunting in the post-tridentine period is a crucial moment for the history of nursing care. Modern historiography tells that women accused of witchcraft were custodian of female knowledge, both in domestic and small communities. PURPOSE: To investigate the witchcraft phenomenon in specific context of Bormio country- side, in order to identify proper nursing acts in gestures of women accused of witchcraft or sorcery. METHODS: Process for witchcraft - sorcery against 7 women in Bormio, between 1590 and 1631, were reviewed through a historical research methodology: sources retrieval, description and documentary analysis characterization, interpretation. RESULTS: In nearly all legal proceedings analyzed an indictment due to a healthcare expertise was found in terms of touch, feed, nearness, word. By multiple daily acts of women, intention to help and to express solidarity was clear, in a scenario of disease and suffering, solidarity is shown by acts of care. CONCLUSIONS: As a result of this study, we can resume that the period of the witches, so hard for women , was an age of repression for history of nursing itself. Mankind lifestyle, assistance, aid are ontological and anthropological foundations of nursing. Therefore, a past research of the traces of those foundations could mean rebuilding the own sense of nursing act: we tried to get an approach to that sense also "listening to" the gestures of women in Bormio. PMID- 26752317 TI - [Editorial]. PMID- 26752318 TI - Photoexcitation of the high-spin J=8 isomer in (176)Yb using 8.5MeV end-point energy Bremsstrahlung. AB - Excitation of the 1049.8keV isomeric state (t1/2=11.4s, spin difference between ground and isomeric states DeltaJ=8) in (176)Yb using Bremsstrahlung radiation is observed for the first time. In contrast to the photoexcitation of isomeric states in other nuclei with lower spin differences, where effective integrated cross-sections are of order tens to hundreds of barneV, an integrated cross section of just 0.0484+/-0.066barneV is observed for (176)Yb. PMID- 26752319 TI - Absence of Sema4D improves oligodendrocyte recovery after cerebral ischemia/reperfusion injury in mice. AB - Sema4D, originally identified as a negative regulator of axon guidance during development, is involved in various physiological and pathological responses. In this study, we evaluated the effect of Sema4D-deficiency on oligodendrocyte restoration after the cerebral ischemia/reperfusion using direct ligation of the middle cerebral artery followed by reperfusion. In both Sema4D(+/+) wild-type and Sema4D(-/-) null mutant mice, the peri-infarct area showed a decrease in the number of oligodendrocytes at 3 days post-reperfusion. Subsequently, the number of oligodendrocytes was observed to gradually recover in both groups. Sema4D deficient mice, however, showed an enhanced recovery of oligodendrocytes and an upregulation of oligodendrocyte progenitor cells at days 14 and 28 of reperfusion. Cell proliferation identified by incorporation of bromodeoxyuridine was enhanced in Sema4D(-/-) mice from days 3 to 14 post-reperfusion compared to the Sema4D(+/+) mice. Furthermore, apoptotic cell death of oligodendrocytes was reduced at days 7 post-reperfusion in Sema4D(-/-) mice compared to Sema4D(+/+) mice. These findings indicate that enhanced proliferation of progenitor cells and survival of oligodendrocytes resulted in improved oligodendrocyte recovery in Sema4D(-/-) mice. This may provide a new approach for neurorestorative treatment in patients with stroke, which aims to manipulate endogenous oligodendrogenesis and thereby to promote brain repair after stroke. PMID- 26752320 TI - Cell death is involved in sexual dimorphism during preimplantation development. AB - In bovine preimplantation development, female embryos progress at lower rates and originate smaller blastocysts than male counterparts. Although sex-specific gene expression patterns are reported, when and how sex dimorphism is established is not clear. Differences among female and male early development can be useful for human assisted reproductive medicine, when X-linked disorders risk is detected, and for genetic breeding programs, especially in dairy cattle, which requires female animals for milk production. The aim of this study was to characterize the development of female and male embryos, attempting to identify sex effects during preimplantation development and the role of cell death in this process. Using sex sorted semen from three different bulls for fertilization, we compared kinetics of bovine sex-specific embryos in six time points, and cell death was assessed in viable embryos. For kinetics analysis, we detected an increased population of female embryos arrested at 48 and 120h.p.i., suggesting this time points as delicate stages of development for female embryos that should be considered for testing improvement strategies for assisted reproductive technologies. Assessing viable embryos quality, we found 144h.p.i. is the first time point when viable embryos are phenotypically distinct: cell number is decreased, and apoptosis and cell fragmentation are increased in female embryos at this stage. These new results lead us to propose that sex dimorphism in viable embryos is established during morula-blastocyst transition, and cell death is involved in this process. PMID- 26752322 TI - Consumption of Pornography, Perceived Peer Norms, and Condomless Sex. AB - Sexual scripts in pornography rarely include condoms. Many U.S. college students consume pornography and have unprotected sex. Yet no study appears to have investigated whether pornography consumption is correlated with having unprotected sex among U.S. college students. This article reports results from two studies of pornography consumption and condomless sex among U.S. college students. Pornography consumption was directly associated with a higher likelihood of condomless sex in study 1. This finding was replicated in study 2. Study 2 also explored whether perceptions of peers' use of condoms partially mediates the association between pornography consumption and condomless sex. Pornography consumption was associated with lower estimations of peers' condom use, and lower estimations of peers' condom use were associated with personally engaging in condomless sex. PMID- 26752321 TI - Association of Cesarean Delivery and Formula Supplementation With the Intestinal Microbiome of 6-Week-Old Infants. AB - IMPORTANCE: The intestinal microbiome plays a critical role in infant development, and delivery mode and feeding method (breast milk vs formula) are determinants of its composition. However, the importance of delivery mode beyond the first days of life is unknown, and studies of associations between infant feeding and microbiome composition have been generally limited to comparisons between exclusively breastfed and formula-fed infants, with little consideration given to combination feeding of both breast milk and formula. OBJECTIVE: To examine the associations of delivery mode and feeding method with infant intestinal microbiome composition at approximately 6 weeks of life. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study of 102 infants followed up as part of a US pregnancy cohort study. EXPOSURES: Delivery mode was abstracted from delivery medical records, and feeding method prior to the time of stool collection was ascertained through detailed questionnaires. MAIN OUTCOMES AND MEASURES: Stool microbiome composition was characterized using next generation sequencing of the 16S rRNA gene. RESULTS: There were 102 infants (mean gestational age, 39.7 weeks; range, 37.1-41.9 weeks) included in this study, of whom 70 were delivered vaginally and 32 by cesarean delivery. In the first 6 weeks of life, 70 were exclusively breastfed, 26 received combination feeding, and 6 were exclusively formula fed. We identified independent associations between microbial community composition and both delivery mode (P< .001; Q < .001) and feeding method (P = .01; Q < .001). Differences in microbial community composition between vaginally delivered infants and infants delivered by cesarean birth were equivalent to or significantly larger than those between feeding groups (P = .003). Bacterial communities associated with combination feeding were more similar to those associated with exclusive formula feeding than exclusive breastfeeding (P = .002). We identified 6 individual bacterial genera that were differentially abundant between delivery mode and feeding groups. CONCLUSIONS AND RELEVANCE: The infant intestinal microbiome at approximately 6 weeks of age is significantly associated with both delivery mode and feeding method, and the supplementation of breast milk feeding with formula is associated with a microbiome composition that resembles that of infants who are exclusively formula fed. These results may inform feeding choices and shed light on the mechanisms behind the lifelong health consequences of delivery and infant feeding modalities. PMID- 26752323 TI - [Single intravenous tranexamic acid dose to reduce blood loss in primary total knee replacement]. AB - OBJECTIVE: To evaluate the effectiveness and safety of a single intravenous dose of tranexamic acid in order to reduce blood loss in total knee replacement. MATERIALS AND METHODS: Prospective observational study of the administration of tranexamic acid in patients undergoing primary total knee arthroplasty from November 2013 to February 2015, in which an autologous blood recovery system was used. The study included 98 patients, distributed into two groups of 49 patients according to whether or not they received intravenous tranexamic acid. The primary endpoint was the number of patients requiring autologous transfusion from the recovery system autologous blood recovery system. RESULTS: No drop-outs were recorded during follow-up. There were no significant differences between groups as regards the preoperative and hospital variables. The mean preoperative haemoglobin and haematocrit at 24 and 48 hours postoperatively were similar in both groups. The average volume of bleeding in the autologous blood recovery system and estimated average blood loss was lower in patients who had been administered tranexamic acid, with significant differences. No patients in the group that was administered tranexamic acid required blood autotransfusion. The transfusion rate was zero in the two groups. No adverse events related to the administration of tranexamic acid were recorded. CONCLUSIONS: Intravenous administration of tranexamic acid, according to the described protocol, has presented a non-autotransfusion or allo-transfusion rate of 100%, with no increased incidence of thrombotic events. Thus, its use in this group of patients is recommended. The indication should be individualized, its use justified in the patient medical records, and informed consent is mandatory. PMID- 26752325 TI - Copper-Catalyzed Intermolecular Chloro- and Bromotrifluoromethylation of Alkenes. AB - A highly practical copper-catalyzed intermolecular halotrifluoromethylation of alkenes has been developed under mild reaction conditions. A variety of Cl/Br containing trifluoromethyl derivatives were directly synthesized from a wide range of alkenes, including electron-deficient and unactivated alkenes. PMID- 26752324 TI - Quinones as Reversible Electron Relays in Artificial Photosynthesis. AB - We explore the potential of various hydroquinone/quinone redox couples as electron relays in a homogenous water reduction system between a Re-based photosensitizer and a sacrificial electron donor [tris-(2-carboxyethyl) phosphine, TCEP]. By using transient IR spectroscopy, flash photolysis as well as stopped-flow techniques covering timescales from picoseconds to 100 ms, we determine quenching rates and cage escape yields, the kinetics of the follow-up chemistry of the semiquinone, the recombination rates, as well as the re reduction rates by TCEP. The overall quantum yield of hydrogen production is low, and we show that the limiting factors are the small cage escape yields and, more importantly, the slow regeneration rate by TCEP in comparison to the undesired charge recombination with the reduced water reduction catalyst. PMID- 26752326 TI - Therapist drift redux: Why well-meaning clinicians fail to deliver evidence-based therapy, and how to get back on track. AB - Therapist drift occurs when clinicians fail to deliver the optimum evidence-based treatment despite having the necessary tools, and is an important factor in why those therapies are commonly less effective than they should be in routine clinical practice. The research into this phenomenon has increased substantially over the past five years. This review considers the growing evidence of therapist drift. The reasons that we fail to implement evidence-based psychotherapies are considered, including our personalities, knowledge, emotions, beliefs, behaviours and social milieus. Finally, ideas are offered regarding how therapist drift might be halted, including a cognitive-behavioural approach for therapists that addresses the cognitions, emotions and behaviours that drive and maintain our avoidance of evidence-based treatments. PMID- 26752328 TI - Exposure to virtual social interactions in the treatment of social anxiety disorder: A randomized controlled trial. AB - This randomized controlled trial investigated the efficacy of a stand-alone virtual reality exposure intervention comprising verbal interaction with virtual humans to target heterogeneous social fears in participants with social anxiety disorder. Sixty participants (Mage = 36.9 years; 63.3% women) diagnosed with social anxiety disorder were randomly assigned to individual virtual reality exposure therapy (VRET), individual in vivo exposure therapy (iVET), or waiting list. Multilevel regression analyses revealed that both treatment groups improved from pre-to postassessment on social anxiety symptoms, speech duration, perceived stress, and avoidant personality disorder related beliefs when compared to the waiting-list. Participants receiving iVET, but not VRET, improved on fear of negative evaluation, speech performance, general anxiety, depression, and quality of life relative to those on waiting-list. The iVET condition was further superior to the VRET condition regarding decreases in social anxiety symptoms at post- and follow-up assessments, and avoidant personality disorder related beliefs at follow-up. At follow-up, all improvements were significant for iVET. For VRET, only the effect for perceived stress was significant. VRET containing extensive verbal interaction without any cognitive components can effectively reduce complaints of generalized social anxiety disorder. Future technological and psychological improvements of virtual social interactions might further enhance the efficacy of VRET for social anxiety disorder. PMID- 26752327 TI - Anxiety sensitivity risk reduction in smokers: A randomized control trial examining effects on panic. AB - Empirical evidence has identified several risk factors for panic psychopathology, including smoking and anxiety sensitivity (AS; the fear of anxiety-related sensations). Smokers with elevated AS are therefore a particularly vulnerable population for panic. Yet, there is little knowledge about how to reduce risk of panic among high AS smokers. The present study prospectively evaluated panic outcomes within the context of a controlled randomized risk reduction program for smokers. Participants (N = 526) included current smokers who all received a state of-the-art smoking cessation intervention with approximately half randomized to the AS reduction intervention termed Panic-smoking Program (PSP). The primary hypotheses focus on examining the effects of a PSP on panic symptoms in the context of this vulnerable population. Consistent with prediction, there was a significant effect of treatment condition on AS, such that individuals in the PSP condition, compared to those in the control condition, demonstrated greater decreases in AS throughout treatment and the follow-up period. In addition, PSP treatment resulted in lower rates of panic-related symptomatology. Moreover, mediation analyses indicated that reductions in AS resulted in lower panic symptoms. The present study provides the first empirical evidence that brief, targeted psychoeducational interventions can mitigate panic risk among smokers. PMID- 26752329 TI - Public Knowledge and Attitudes Regarding the Use of Antibiotics and Resistance: Findings from a Cross-Sectional Study Among Palestinian Adults. AB - Antibiotics are considered to be among the most commonly sold drug classes in Palestine. Resistance to antibiotics has increased for reasons relating to the use and misuse of antibiotics. The aim of this study was to evaluate the knowledge, and attitudes regarding antibiotic use and awareness about resistance among adults visiting the emergency departments at hospitals in North Palestine. A self-administered cross-sectional questionnaire survey involving participants aged 18 or over was conducted from June 2012 to February 2013. Adults who visited the emergency departments at hospitals in North Palestine were included. Demographic characteristics, knowledge and attitudes towards antibiotic use were included in the questionnaire. Poor and good knowledge were defined as a total knowledge score of 0-7 and 8-15 of 15 questions, respectively. Attitude scores of 0-3 and 4-7 of 7 questions were considered poor and good, respectively. A total of 375 questionnaires were included in the study. A response rate of 83.3% was attained. About 55.0% of the participants had a good knowledge and 56.5% had a good attitude towards rational antibiotic use. A significant positive correlation was shown between participants' knowledge scores and participants' attitude scores towards antibiotic use (R = 0.344, P = 0.001. Participants with a high family income were more likely to be aware of appropriate antibiotic use than participants with a low family income (P-value <0.001). Participants with a higher educational level (university) had a good attitude towards rational antibiotic use than those with a lower education level (P-value <0.001). This study has documented important knowledge and attitude gaps in antibiotic use. These findings will help health policymakers in Palestine to implement intervention programmes to rationalize antibiotic use. Continuing medical education, professional development and training workshops for healthcare professionals regarding rational use of antibiotics and health risks associated with the spread of antibiotic resistance are needed. In addition, minimizing non prescription use of antibiotics and increasing the public awareness about the health and economic hazards of antibiotic resistance are also required. PMID- 26752330 TI - Polarization-sensitive optical projection tomography for muscle fiber imaging. AB - Optical projection tomography (OPT) is a tool used for three-dimensional imaging of millimeter-scale biological samples, with the advantage of exhibiting isotropic resolution typically in the micron range. OPT can be divided into two types: transmission OPT (tOPT) and emission OPT (eOPT). Compared with eOPT, tOPT discriminates different tissues based on their absorption coefficient, either intrinsic or after specific staining. However, it fails to distinguish muscle fibers whose absorption coefficients are similar to surrounding tissues. To circumvent this problem, in this article we demonstrate a polarization sensitive OPT system which improves the detection and 3D imaging of muscle fibers by using polarized light. We also developed image acquisition and processing protocols that, together with the system, enable the clear visualization of muscles. Experimental results show that the muscle fibers of diaphragm and stomach, difficult to be distinguished in regular tOPT, were clearly displayed in our system, proving its potential use. Moreover, polarization sensitive OPT was fused with tOPT to investigate the stomach tissue comprehensively. Future applications of polarization sensitive OPT could be imaging other fiber-like structures such as myocardium or other tissues presenting high optical anisotropy. PMID- 26752331 TI - De novo loss-of-function mutations in X-linked SMC1A cause severe ID and therapy resistant epilepsy in females: expanding the phenotypic spectrum. AB - De novo missense mutations and in-frame coding deletions in the X-linked gene SMC1A (structural maintenance of chromosomes 1A), encoding part of the cohesin complex, are known to cause Cornelia de Lange syndrome in both males and females. For a long time, loss-of-function (LoF) mutations in SMC1A were considered incompatible with life, as such mutations had not been reported in neither male nor female patients. However, recently, the authors and others reported LoF mutations in females with intellectual disability (ID) and epilepsy. Here we present the detailed phenotype of two females with de novo LoF mutations in SMC1A, including a de novo mutation of single base deletion [c.2364del, p.(Asn788Lysfs*10)], predicted to result in a frameshift, and a de novo deletion of exon 16, resulting in an out-of-frame mRNA splice product [p.(Leu808Argfs*6)]. By combining our patients with the other recently reported females carrying SMC1A LoF mutations, we ascertained a phenotypic spectrum of (severe) ID, therapy resistant epilepsy, absence/delay of speech, hypotonia and small hands and feet. Our data show the existence of a novel phenotypic entity - distinct from CdLS - and caused by de novo SMC1A LoF mutations. PMID- 26752332 TI - Human epidermal growth factor receptor 2/neu as a novel therapeutic target in sinonasal undifferentiated carcinoma. AB - BACKGROUND: Sinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive cancer. Despite multimodal therapy, the prognosis in SNUC remains poor, and new therapies are needed. Thus, the purpose of this study was to explore potential therapeutic targets in SNUC. METHODS: Using the human-derived SNUC MDA8788-6 cell line, we performed whole genome single nucleotide polymorphism (SNP) analysis to identify copy number changes in this line. Protein expression levels were evaluated by Western blotting. Cell growth inhibition was assessed by methylthiazol tetrazolium (MTT) and clonogenic assays. The mouse flank model was used to examine the effect of growth inhibition in vivo. RESULTS: The ERBB2 gene was highly amplified and cell extracts showed human epidermal growth factor receptor 2 (HER2) was overexpressed and phosphorylated in MDA8788-6. Lapatinib effectively inhibited the HER2 signaling pathway in our SNUC cell line. HER2 inhibition successfully suppressed the cell growth of MDA8788-6 cells both in vitro and in vivo. CONCLUSION: Targeting HER2 may be a promising avenue for the development of novel therapies for SNUC. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: E1926-E1934, 2016. PMID- 26752334 TI - How induced pluripotent stem cells are informing drug discovery in psychiatry. AB - Compared with other medical fields, psychiatry is particularly challenging for rational drug discovery. The therapeutic endpoints are abstract measures of cognitive and behavioral performance, for which we have a very limited understanding of the underlying biological mechanisms. Existing preclinical disease models are also limited in their translational fidelity. Recently, there have been active discussions on the use of human induced pluripotent stem cells (iPSCs) as a catalyzing research tool in psychiatry, but very few review articles in the field have given specific considerations to their use at the interface between psychiatric research and drug discovery. Here, we discuss recent perspectives emerging from this interface. For physicians and researchers on the clinical side, we explain how iPSC-based experimental approaches are placed at the crossroads with psychiatric genetics and how representative studies in the field are addressing biological mechanisms underlying psychiatric disorders. For researchers who directly work with iPSCs and aspire to develop new research techniques, we direct their attention to the utility of this approach for unmet needs in drug discovery workflows. PMID- 26752333 TI - Charge separation and charge recombination photophysical studies in a series of perylene-C60 linear and cyclic dyads. AB - A new donor-acceptor doubly bridged perylenediimide-fullerene dyad (PDI-C60, DB 3), where the perylenediimide (PDI) acts as a donor, has been synthesized and studied by time-resolved absorption spectroscopy. The DB-3 undergoes an electron transfer (ET) in both polar and non-polar media under photo-excitation. Structurally the DB-3 dyad resembles four other recently studied dyads (R. K. Dubey et al., Chem. Eur. J., 2013, 19, 6791-6806). Analysis of the ET reactions in this series of dyads was carried out in frame of both classic and semi-quantum ET theories. The result of the analysis for DB-3 suggests that the electronic coupling for the ET reaction is roughly 0.005 eV, internal reorganization energy is 0.16 eV, and outer sphere or solvent reorganization energy is 0.5 and 0.3 eV in benzonitrile and toluene, respectively. PMID- 26752335 TI - The SLMTA programme: Transforming the laboratory landscape in developing countries. AB - BACKGROUND: Efficient and reliable laboratory services are essential to effective and well-functioning health systems. Laboratory managers play a critical role in ensuring the quality and timeliness of these services. However, few laboratory management programmes focus on the competencies required for the daily operations of a laboratory in resource-limited settings. This report provides a detailed description of an innovative laboratory management training tool called Strengthening Laboratory Management Toward Accreditation (SLMTA) and highlights some challenges, achievements and lessons learned during the first five years of implementation (2009-2013) in developing countries. PROGRAMME: SLMTA is a competency-based programme that uses a series of short courses and work-based learning projects to effect immediate and measurable laboratory improvement, while empowering laboratory managers to implement practical quality management systems to ensure better patient care. A SLMTA training programme spans from 12 to 18 months; after each workshop, participants implement improvement projects supported by regular supervisory visits or on-site mentoring. In order to assess strengths, weaknesses and progress made by the laboratory, audits are conducted using the World Health Organization's Regional Office for Africa (WHO AFRO) Stepwise Laboratory Quality Improvement Process Towards Accreditation (SLIPTA) checklist, which is based on International Organization for Standardization (ISO) 15189 requirements. These internal audits are conducted at the beginning and end of the SLMTA training programme. CONCLUSION: Within five years, SLMTA had been implemented in 617 laboratories in 47 countries, transforming the laboratory landscape in developing countries. To our knowledge, SLMTA is the first programme that makes an explicit connection between the performance of specific management behaviours and routines and ISO 15189 requirements. Because of this close relationship, SLMTA is uniquely positioned to help laboratories seek accreditation to ISO 15189. PMID- 26752336 TI - Experiential avoidance and appraisals of voices as predictors of voice-related distress. AB - OBJECTIVES: Research has suggested that the extent to which voices (i.e., auditory verbal hallucinations) are experienced as distressing might be influenced by negative beliefs about voices as well as maladaptive metacognitive styles involving the negative appraisal and maladaptive control of mental experiences. This cross-sectional study examined the contribution of both specific appraisals of voices and a metacognitive factor (i.e., experiential avoidance) to voice-related distress. METHODS: Self-report measurers of voice characteristics (voice frequency, duration as well as amount and intensity of voice-related distress), experiential avoidance, and appraisals of voices were collected in a sample of 101 voice-hearers. RESULTS: Experiential avoidance and negative beliefs about voices were associated with higher levels of voice-related distress, but not to measures of voice frequency and duration. Experiential avoidance and negative 'metaphysical' beliefs about voices were significant predictors of voice-related distress even after accounting for the effect of frequency and duration of voices, and explained similar proportions of unique variance in distress. CONCLUSIONS: These findings suggest that the appraisals of voices and experiential avoidance are predictive of voice-related distress and that cognitive-behavioural interventions targeting both voice-specific appraisals and general maladaptive metacognitive processes could prove useful treatment approaches for clients with distressing voices. PRACTITIONER POINTS: Experiential avoidance (EA) and negative appraisals predict voice-related distress caused by voices, but not their frequency and duration. Interventions for voices should consider targeting EA and negative appraisals (e.g., cognitive-behavioural therapy, Acceptance and Commitment Therapy) to ameliorate distress. PMID- 26752338 TI - Ozone Promotes Chloropicrin Formation by Oxidizing Amines to Nitro Compounds. AB - Chloropicrin formation has been associated with ozonation followed by chlorination, but the reaction pathway and precursors have been poorly characterized. Experiments with methylamine demonstrated that ozonation converts methylamine to nitromethane at ~100% yield. Subsequent chlorination converts nitromethane to chloropicrin at ~50% yield under the conditions evaluated. Similarly high yields from other primary amines were limited to those with functional groups on the beta-carbon (e.g., the carboxylic acid in glycine) that facilitate carbon-carbon bond cleavage to release nitromethyl anion. Secondary amines featuring these reactive primary amines as functional groups (e.g., secondary N-methylamines) formed chloropicrin at high yields, likely by facile dealkylation to release the primary nitro compound. Chloropicrin yields from tertiary amines were low. Natural water experiments, including derivatization to transform primary and secondary amines to less reactive carbamate functional groups, indicated that primary and secondary amines were the dominant chloropicrin precursors during ozonation/chlorination. Ozonation followed by chlorination of the primary amine side chain of lysine demonstrated low yields (~0.2%) of chloropicrin, but high yields (~17%) of dichloronitrolysine, a halonitroalkane structural analogue to chloropicrin. However, chloropicrin yields increased and dichloronitrolysine yields decreased in the absence of hydroxyl radical scavengers, suggesting that future research should characterize the potential occurrence of such halonitroalkane analogues relative to natural radical scavenger (e.g., carbonate) concentrations. PMID- 26752339 TI - Strong association of the polymorphisms in PBEF1 and knee OA risk: a two-stage population-based study in China. AB - The association of Pre-B cell colony enhancing factor 1 (PBEF1) with obesity, together with its pro-inflammatory properties suggests that PBEF1 might be another crucial mediator that links inflammation with obesity and primary osteoarthritis (OA). We hypothesized that polymorphisms in PBEF1 may modify the risk of developing OA. Thus we systematically screened 4 tagging polymorphisms (rs4730153, rs2058540, rs3801267 and rs16872158) in PBEF1 and evaluated the association between the genetic variants and OA risk in a two-stage case-control study including 196 cases and 442 controls in the first stage and 143 cases and 238 controls in the second stage. In the first stage, two SNPs (rs4730153 and rs16872158) were found to be potentially associated with OA risk (P < 0.05), which were further confirmed in the second stage with similar effects. After combining the two stages, we found that rs4730153 was significantly associated with decreased risk of OA in an additive genetic model (P < 0.05), while rs16872158 showed increased risk of developing OA (P < 0.05). Combined analysis of these 2 SNPs showed a significant allele-dosage association between the number of risk alleles and OA risk (Ptrend = 5.25 * 10(-5)). These findings indicate that genetic variants in PBEF1 gene may modify individual susceptibility to OA in the Chinese population. PMID- 26752337 TI - Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. AB - IMPORTANCE: Proton pump inhibitors (PPIs) are among the most commonly used drugs worldwide and have been linked to acute interstitial nephritis. Less is known about the association between PPI use and chronic kidney disease (CKD). OBJECTIVE: To quantify the association between PPI use and incident CKD in a population-based cohort. DESIGN, SETTING, AND PARTICIPANTS: In total, 10,482 participants in the Atherosclerosis Risk in Communities study with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m(2) were followed from a baseline visit between February 1, 1996, and January 30, 1999, to December 31, 2011. The data was analyzed from May 2015 to October 2015. The findings were replicated in an administrative cohort of 248,751 patients with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m(2) from the Geisinger Health System. EXPOSURES: Self-reported PPI use in the Atherosclerosis Risk in Communities study or an outpatient PPI prescription in the Geisinger Health System replication cohort. Histamine2 (H2) receptor antagonist use was considered a negative control and active comparator. MAIN OUTCOMES AND MEASURES: Incident CKD was defined using diagnostic codes at hospital discharge or death in the Atherosclerosis Risk in Communities Study, and by a sustained outpatient estimated glomerular filtration rate of less than 60 mL/min/1.73 m(2) in the Geisinger Health System replication cohort. RESULTS: Among 10,482 participants in the Atherosclerosis Risk in Communities study, the mean (SD) age was 63.0 (5.6) years, and 43.9% were male. Compared with nonusers, PPI users were more often of white race, obese, and taking antihypertensive medication. Proton pump inhibitor use was associated with incident CKD in unadjusted analysis (hazard ratio [HR], 1.45; 95% CI, 1.11-1.90); in analysis adjusted for demographic, socioeconomic, and clinical variables (HR, 1.50; 95% CI, 1.14-1.96); and in analysis with PPI ever use modeled as a time-varying variable (adjusted HR, 1.35; 95% CI, 1.17 1.55). The association persisted when baseline PPI users were compared directly with H2 receptor antagonist users (adjusted HR, 1.39; 95% CI, 1.01-1.91) and with propensity score-matched nonusers (HR, 1.76; 95% CI, 1.13-2.74). In the Geisinger Health System replication cohort, PPI use was associated with CKD in all analyses, including a time-varying new-user design (adjusted HR, 1.24; 95% CI, 1.20-1.28). Twice-daily PPI dosing (adjusted HR, 1.46; 95% CI, 1.28-1.67) was associated with a higher risk than once-daily dosing (adjusted HR, 1.15; 95% CI, 1.09-1.21). CONCLUSIONS AND RELEVANCE: Proton pump inhibitor use is associated with a higher risk of incident CKD. Future research should evaluate whether limiting PPI use reduces the incidence of CKD. PMID- 26752343 TI - Measuring distress in South African children during burns dressing changes: A pilot study. AB - OBJECTIVES: To establish and trial a practical, evidence-based, sensitive, language-fair, and culture-fair test battery to measure South African children's distress during burns dressing change. METHODS: We previously identified a broad test battery for pediatric procedural distress from the literature. This comprised child and parent heart rate; three instruments for observed distress behaviors-(1) Face, Legs, Activity, Cry, Consolability (FLACC); (2) Pain Behavior Check List (PBCL); and (3) Children's Hospital Eastern Ontario Pain Scale (CHEOPS); and dressing change time, number of nurses required, and nurses' perspectives of child's distress. A consecutive cohort of South African inpatient children with burns was recruited. In the first study, three observers independently piloted the broad set of measures on four children. This set was subsequently modified to increase practicality of application and measurement sensitivity. In the second study, the modified battery was tested on 16 children for sensitivity to different children's distress levels during burns dressing change phases. RESULTS: The modified test battery was comprised of the CHEOPS, dressing change time, number of nurses required, and nurses' qualitative perspectives of child's distress. In combination, these tests were practical and sensitive to children's distress. DISCUSSION: South African children's distress during burn dressing changes manifests in different ways. Adequate capture of it requires a comprehensive set of objective, observational, and qualitative measures, which are independent of language and culture. PMID- 26752340 TI - Comparison between electronic cigarette refill liquid and nicotine on metabolic parameters in rats. AB - AIMS: Nicotine is known to promote body weight loss and to disturb glucose homeostasis and lipoprotein metabolism. Electronic cigarettes, as a substitute to nicotine, are becoming increasingly popular, although there is no evidence regarding their safety. Considering the dearth of information about e-cigarette toxicity, the present study was designed to compare nicotine alone to e-liquid with or without nicotine on metabolic parameters in Wistar rats. MAIN METHODS: For this purpose, e-liquid with or without nicotine and nicotine alone (0.5mg/kg of body weight) were administered intra-peritoneally during 28 days. KEY FINDINGS: Our results show a significant decrease in food and energy intake after nicotine or e-liquid with nicotine exposure, when compared to control or e-liquid without nicotine. Analysis of lipid status identified a significant decrease in cholesterol and LDL levels in e-cigarette groups, suggesting an improvement in lipid profile. Interestingly, e-liquid without nicotine induced hyperglycemia which is negatively correlated to hepatic glycogen level, acting like nicotine alone. Furthermore, an increase in liver biomarkers was observed in all treated groups. qRT-PCR analysis showed GSK3beta up-regulation in e-liquid with nicotine as well as, surprisingly, in e-liquid without nicotine exposure. In contrast, PEPCK genes were only up-regulated in e-liquid with nicotine. SIGNIFICANCE: While some features observed in rats may not be observed in human smokers, most of our data are consistent with, e-liquid per se i.e. without nicotine, not being neutral from a metabolic stand point since disrupting glucose homeostasis in rats. PMID- 26752342 TI - Breed and Lactation Stage Alter the Rumen Protozoal Fatty Acid Profiles and Community Structures in Primiparous Dairy Cattle. AB - The protozoal fatty acid (FA) composition and community structure are important to dairy cattle nutrition and their products. The purpose of the study was to observe if the rumen protozoal FA profiles and protozoal community structure differed by breed and lactation stage. At 93, 183, and 273 days in milk (DIM), whole rumen digesta samples were collected from seven co-housed Holstein (H), eight Jersey (J), and seven Holstein-Jersey crossbreed (C) cows. Rumen protozoal linoleic acid was higher at 183 DIM (8.1%) and 273 DIM (8.3%) than at 93 DIM (5.7%). Oleic acid was the most abundant protozoal unsaturated FA (10.1%). Protozoal rumenic acid and protozoa of the genus Metadinium were higher in J (9.9%) than in H (0.52%) and C (0.96%). Protozoa belonging to the genus Entodinium were more abundant in H (45.2%) than in J (23.4%) and C (30.2%). In conclusion, breed and DIM affected several protozoal FAs and genera. PMID- 26752341 TI - Invadopodia proteins, cortactin, N-WASP and WIP differentially promote local invasiveness in ameloblastoma. AB - BACKGROUND: Cell migration and invasion through interstitial tissues are dependent upon several specialized characteristics of the migratory cell notably generation of proteolytic membranous protrusions or invadopodia. Ameloblastoma is a benign odontogenic epithelial neoplasm with a locally infiltrative behaviour. Cortactin and MMT1-MMP are two invadopodia proteins implicated in its local invasiveness. Other invadopodia regulators, namely N-WASP, WIP and Src kinase remain unclarified. This study addresses their roles in ameloblastoma. MATERIALS AND METHOD: Eighty-seven paraffin-embedded ameloblastoma cases (20 unicystic, 47 solid/multicystic, 3 desmoplastic and 17 recurrent) were subjected to immunohistochemistry for expression of cortactin, N-WASP, WIP, Src kinase and F actin, and findings correlated with clinicopathological parameters. RESULTS: Invadopodia proteins (except Src kinase) and F-actin were widely detected in ameloblastoma (cortactin: n = 73/87, 83.9%; N-WASP: n = 59/87; 67.8%; WIP: n = 77/87; 88.5%; and F-actin: n = 87/87, 100%). Protein localization was mainly cytoplasmic and/or membranous, and occasionally nuclear for F-actin. Cortactin, which functions as an actin-scaffolding protein, demonstrated significantly higher expression levels within ameloblastoma tumoral epithelium than in stroma (P < 0.05). N-WASP, which coordinates actin polymerization and invadopodia mediated extracellular matrix degradation, was overexpressed in the solid/multicystic subtype (P < 0.05). WIP, an upstream regulator of N-WASP, and F actin were significantly upregulated along the tumour invasive front compared to tumour centres (P < 0.05). Except for males with cortactin overexpression, other clinical parameters (age, ethnicity and anatomical site) showed no significant correlations. CONCLUSIONS: Present results suggest that local invasiveness of ameloblastoma is dependent upon the migratory potential of its tumour cells as defined by their distribution of cortactin, N-WASP and WIP in correlation with F actin cytoskeletal dynamics. PMID- 26752344 TI - Biomass Vanillin-Derived Polymeric Microspheres Containing Functional Aldehyde Groups: Preparation, Characterization, and Application as Adsorbent. AB - The contribution reports the first polymeric microspheres derived from a biomass, vanillin. It reacted with methacryloyl chloride, providing monomer vanillin methacrylate (VMA), which underwent suspension polymerization in aqueous media and yielded microspheres in high yield (>90 wt %). By controlling the N2 bubbling mode and by optimizing the cosolvent for dissolving the solid monomer, the microspheres were endowed with surface pores, demonstrated by SEM images and mercury intrusion porosimetry measurement. Taking advantage of the reactive aldehyde groups, the microspheres further reacted with glycine, thereby leading to a novel type of Schiff-base chelating material. The functionalized microspheres demonstrated remarkable adsorption toward Cu(2+) (maximum, 135 mg/g) which was taken as representative for metal ions. The present study provides an unprecedented class of biobased polymeric microspheres showing large potentials as adsorbents in wastewater treatment. Also importantly, the reactive aldehyde groups may enable the microspheres to be used as novel materials for immobilizing biomacromolecules, e.g. enzymes. PMID- 26752345 TI - Effect of Water on Elastic and Creep Properties of Self-Standing Clay Films. AB - We characterized experimentally the elastic and creep properties of thin self standing clay films, and how their mechanical properties evolved with relative humidity and water content. The films were made of clay montmorillonite SWy-2, obtained by evaporation of a clay suspension. Three types of films were manufactured, which differed by their interlayer cation: sodium, calcium, or a mixture of sodium with calcium. The orientational order of the films was characterized by X-ray diffractometry. The films were mechanically solicited in tension, the resulting strains being measured by digital image correlation. We measured the Young's modulus and the creep over a variety of relative humidities, on a full cycle of adsorption-desorption for what concerns the Young's modulus. Increasing relative humidity made the films less stiff and made them creep more. Both the elastic and creep properties depended significantly on the interlayer cation. For the Young's modulus, this dependence must originate from a scale greater than the scale of the clay layer. Also, hysteresis disappeared when plotting the Young's modulus versus water content instead of relative humidity. Independent of interlayer cation and of relative humidity greater than 60%, after a transient period, the creep of the films was always a logarithmic function of time. The experimental data gathered on these mesoscale systems can be of value for modelers who aim at predicting the mechanical behavior of clay-based materials (e.g., shales) at the engineering macroscopic scale from the one at the atomistic scale, for them to validate the first steps of their upscaling scheme. They provide also valuable reference data for bioinspired clay-based hybrid materials. PMID- 26752348 TI - Can Diabetes Management Be Done Effectively Through the Cloud? PMID- 26752349 TI - Smart fluorescent probes for imaging macrophage activity. AB - Macrophages are multi-functional immune cells with key roles in host defense and tissue remodelling. The broad array of macrophage functions has prompted the development of very diverse smart fluorescent architectures, rationally designed to elicit a fluorescent signal only after target engagement. This tutorial review covers recent advances in the design, synthesis and application of smart fluorescent probes for imaging macrophage cellular activity, ranging from small fluorophores to peptide-based probes with internally quenched fluorescent pairs or activity-based reactive groups. PMID- 26752346 TI - Individual variability of cerebral autoregulation, posterior cerebral circulation and white matter hyperintensity. AB - KEY POINTS: Cerebral autoregulation (CA) is a key mechanism to protect brain perfusion in the face of changes in arterial blood pressure, but little is known about individual variability of CA and its relationship to the presence of brain white matter hyperintensity (WMH) in older adults, a type of white matter lesion related to cerebral small vessel disease (SVD). This study demonstrated the presence of large individual variability of CA in healthy older adults during vasoactive drug-induced changes in arterial pressure assessed at the internal carotid and vertebral arteries. We also observed, unexpectedly, that it was the 'over-' rather than the 'less-reactive' CA measured at the vertebral artery that was associated with WMH severity. These findings challenge the traditional concept of CA and suggest that the presence of cerebral SVD, manifested as WMH, is associated with posterior brain hypoperfusion during acute increase in arterial pressure. ABSTRACT: This study measured the individual variability of static cerebral autoregulation (CA) and determined its associations with brain white matter hyperintensity (WMH) in older adults. Twenty-seven healthy older adults (13 females, 66 +/- 6 years) underwent assessment of CA during steady state changes in mean arterial pressure (MAP) induced by intravenous infusion of sodium nitroprusside (SNP) and phenylephrine. Cerebral blood flow (CBF) was measured using colour-coded duplex ultrasonography at the internal carotid (ICA) and vertebral arteries (VA). CA was quantified by a linear regression slope (CA slope) between percentage changes in cerebrovascular resistance (CVR = MAP/CBF) and MAP relative to baseline values. Periventricular and deep WMH volumes were measured with T2-weighted magnetic resonance imaging. MAP was reduced by -11 +/- 7% during SNP, and increased by 21 +/- 8% during phenylephrine infusion. CA demonstrated large individual variability with the CA slopes ranging from 0.37 to 2.20 at the ICA and from 0.17 to 3.18 at the VA; no differences in CA were found between the ICA and VA. CA slopes measured at the VA had positive correlations with the total and periventricular WMH volume (r = 0.55 and 0.59, P < 0.01). Collectively, these findings demonstrated the presence of large individual variability of CA in older adults, and that, when measured in the posterior cerebral circulation, it is the higher rather than lower CA reactivity that is associated with WMH severity. PMID- 26752350 TI - A "copolymer-co-morphology" conception for shape-controlled synthesis of Prussian blue analogues and as-derived spinel oxides. AB - The morphologically and compositionally controlled synthesis of coordination polymers and spinel oxides is highly desirable for realizing new advanced nanomaterial functionalities. Here we develop a novel and scalable strategy, containing a "copolymer-co-morphology" conception, to shape-controlled synthesis of various types of Prussian blue analogues (PBAs). Three series of PBAs MyFe1 y[Co(CN)6]0.67.nH2O (MyFe1-y-Co, M = Co, Mn and Zn) with well-controlled morphology have been successfully prepared through this strategy. Using MnyFe1-y Co PBAs as the model, by increasing the relative content of Mn, flexible modulation of the morphology could be easily realized. In addition, a series of porous MnxFe1.8-xCo1.2O4 nano-dices with well-inherited morphologies and defined cation distribution could be obtained through a simple thermal treatment of the PBAs. All these results demonstrate the good universality of this novel strategy. When evaluated as an electrocatalyst, the octahedral-site Mn(III)/Mn(IV) content in MnxFe1.8-xCo1.2O4, mainly determined by sensitive (57)Fe Mossbauer in combination with X-ray photoelectron spectroscopic techniques, was discovered to be directly correlated with the oxygen reduction/evolution reaction (ORR/OER) activity. PMID- 26752347 TI - Vesicular Galectin-3 levels decrease with donor age and contribute to the reduced osteo-inductive potential of human plasma derived extracellular vesicles. AB - Aging results in a decline of physiological functions and in reduced repair capacities, in part due to impaired regenerative power of stem cells, influenced by the systemic environment. In particular osteogenic differentiation capacity (ODC) of mesenchymal stem cells (MSCs) has been shown to decrease with age, thereby contributing to reduced bone formation and an increased fracture risk. Searching for systemic factors that might contribute to this age related decline of regenerative capacity led us to investigate plasma-derived extracellular vesicles (EVs). EVs of the elderly were found to inhibit osteogenesis compared to those of young individuals. By analyzing the differences in the vesicular content Galectin-3 was shown to be reduced in elderly-derived vesicles. While overexpression of Galectin-3 resulted in an enhanced ODC of MSCs, siRNA against Galectin-3 reduced osteogenesis. Modulation of intravesicular Galectin-3 levels correlated with an altered osteo-inductive potential indicating that vesicular Galectin-3 contributes to the biological response of MSCs to EVs. By site directed mutagenesis we identified a phosphorylation-site on Galectin-3 mediating this effect. Finally, we showed that cell penetrating peptides comprising this phosphorylation-site are sufficient to increase ODC in MSCs. Therefore, we suggest that decrease of Galectin-3 in the plasma of elderly contributes to the age-related loss of ODC. PMID- 26752352 TI - Establishment of two quantitative nested qPCR assays targeting the human EPO transgene. AB - For ethical and safety reasons it is critical to develop easily implemented assays with high sensitivity and specificity for gene doping surveillance. Two nested quantitative real-time PCR (qPCR) assays were developed that target the human EPO (hEPO) cDNA sequence in a circular form, representative of recombinant adeno-associated viral (rAAV) vector genomes found in vivo. Through an interlaboratory evaluation, the assays were validated and utilized in an in vitro blinded study. These assays are specific and extremely sensitive with a limit of detection (LOD) of 1 copy of circular plasmid DNA and a limit of quantification (LOQ) of 10 to 20 copies in the presence of 500 ng of human genomic DNA (hgDNA) extracted from WBCs. Additionally, using the two nested qPCR assays in a non human primate study, where macaques were injected intramuscularly with a rAAV8 vector harboring a promoterless hEPO cDNA sequence, the viral vector was detected 8 to 14 weeks post-injection in macaque WBCs. The high sensitivity of the nested qPCR approach along with the capability of quantifying target DNA, make this approach a reliable tool for gene doping surveillance and the monitoring of exogenous DNA sequences. PMID- 26752353 TI - Overexpression of a glucokinase point mutant in the treatment of diabetes mellitus. AB - Glucokinase (GCK) is an important enzyme critical for glucose metabolism, and has been targeted as such in the pursuit of a cure for diabetes mellitus. We show that streptozotocin (STZ)-induced diabetic murine model exhibits low GCK expression with high blood glucose levels; moreover, aggravated glomerulonephritis is observed in the model when there is IL10 deficiency. Although T cells infiltrate into the liver and pancreas in STZ-induced diabetes mice, T helper 1 (Th1) and T helper 17 (Th17) cells decrease significantly with STZ addition in in vitro polarization. Using a mutant GCK gene (GCK 262) with a knocked out cytosine at position 2643 results in lower protein expression and more ubiquitination-led protein degradation compared with wild-type GCK (GCK 261). We further observed that hsa-mir-1302 can bind to 3'-untranslated region of mutant GCK, which can decrease GCK mRNA translation. Finally, delivery of mutant GCK by subcutaneous injection is more effective at decreasing blood glucose in the STZ-treated (STZ) murine diabetes model than insulin treatment alone. Similarly, mutant GCK consistently and moderately decreases blood glucose levels in GK rats over a period of 12 and 70 days without inducing hypoglycemia, whereas insulin is only effective over 12 h. These results suggest that mutant GCK may be a future cure for diabetes. PMID- 26752351 TI - HSV vector-mediated GAD67 suppresses neuropathic pain induced by perineural HIV gp120 in rats through inhibition of ROS and Wnt5a. AB - Human immunodeficiency virus (HIV)-related neuropathic pain is a debilitating chronic condition that is severe and unrelenting. Despite the extensive research, the exact neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments. Loss of GABAergic tone may have an important role in the neuropathic pain state. Glutamic acid decarboxylase 67 (GAD67) is one of the isoforms that catalyze GABA synthesis. Here, we used recombinant herpes simplex virus (HSV-1) vectors that encode gad1 gene to evaluate the therapeutic potential of GAD67 in peripheral HIV gp120-induced neuropathic pain in rats. We found that (1) subcutaneous inoculation of the HSV vectors expressing GAD67 attenuated mechanical allodynia in the model of HIV gp120-induced neuropathic pain, (2) the anti-allodynic effect of GAD67 was reduced by GABA-A and-B receptors antagonists, (3) HSV vectors expressing GAD67 reversed the lowered GABA IR expression and (4) the HSV vectors expressing GAD67 suppressed the upregulated mitochondrial superoxide and Wnt5a in the spinal dorsal horn. Taken together, our studies support the concept that recovering GABAergic tone by the HSV vectors may reverse HIV-associated neuropathic pain through suppressing mitochondrial superoxide and Wnt5a. Our studies provide validation of HSV-mediated GAD67 gene therapy in the treatment of HIV-related neuropathic pain. PMID- 26752356 TI - A Prospective Evaluation of Female External Genitalia Sensitivity to Pressure following Labia Minora Reduction and Clitoral Hood Reduction. PMID- 26752355 TI - Study of Small-Molecule-Membrane Protein Binding Kinetics with Nanodisc and Charge-Sensitive Optical Detection. AB - Nanodisc technology provides membrane proteins with a nativelike lipid bilayer and much-needed solubility and enables in vitro quantification of membrane protein binding with ligands. However, it has been a challenge to measure interaction between small-molecule ligands and nanodisc-encapsulated membrane proteins, because the responses of traditional mass-based detection methods scale with the mass of the ligands. We have developed a charge-sensitive optical detection (CSOD) method for label-free measurement of the binding kinetics of low molecular mass ligands with nanodisc-encapsulated membrane proteins. This microplate-compatible method is sensitive to the charge instead of the mass of a ligand and is able to measure both large and small molecules in a potentially high-throughput format. Using CSOD, we measured the binding kinetics between peptide and small-molecule ligands and a nanodisc-encapsulated potassium ion channel protein, KcsA-Kv1.3. Both association and dissociation rate constants for these ligands are obtained for the first time. The CSOD results were validated by the consistency of the values with reported binding affinities. In addition, we found that CSOD can tolerate up to 3.9% dimethyl sulfoxide (DMSO) and up to 10% serum, which shows its compatibility with realistic sample conditions. PMID- 26752354 TI - IL-15/sIL-15Ralpha gene transfer induces weight loss and improves glucose homeostasis in obese mice. AB - Obesity and its associated metabolic problems are a major public health issue. The objective of the current study is to investigate the therapeutic effects of interleukin 15/soluble interleukin 15 receptor-alpha (IL-15/sIL-15Ralpha) on high fat diet-induced obesity and obesity-associated metabolic disorders. We demonstrate that the multiple hydrodynamic delivery of 2 MUg IL-15/sIL-15Ralpha plasmid results in numerous beneficial effects, including a reduction of body weight and fat mass, an alleviation of fatty liver, an improvement in glucose homeostasis and insulin sensitivity in obese mice. These effects are accompanied by a suppressed expression of genes involved in lipid accumulation and lipogenesis, including Ppargamma, Cd36, Fabp4, Mgat1, Scd-1 and Fas, and elevated mRNA levels of genes involved in adaptive thermogenesis and fatty acid beta oxidation, such as Ucp1, Ucp3, Pgc-1alpha, Pgc-1beta, Pparalpha, Ppardelta, Cpt1 alpha and Cpt1-beta in obese animals. These results suggest that the overexpression of the Il-15/sIl-15Ralpha gene is an effective approach in treating diet-induced obesity and its associated metabolic complications. PMID- 26752357 TI - Reply: Is There a Safe Lipoaspirate Volume? A Risk Assessment Model of Liposuction Volume as a Function of Body Mass Index. PMID- 26752358 TI - Heat Shock Protein 90 Inhibitor Decreases Collagen Synthesis of Keloid Fibroblasts and Attenuates the Extracellular Matrix on the Keloid Spheroid Model. PMID- 26752359 TI - Reply: A Prospective Evaluation of Female External Genitalia Sensitivity to Pressure following Labia Minora Reduction and Clitoral Hood Reduction. PMID- 26752360 TI - Differences in insulin biosynthesis pathway between small and large islets do not correspond to insulin secretion. AB - In a variety of mammalian species, small islets secrete more insulin per volume than large islets. This difference may be due to diffusional limitations of large islets, or inherent differences in the insulin production pathways. The purpose of this study was to identify possible differences in the early phase of glucose stimulated insulin biosynthesis between large and small islets. Isolated small and large rat islets were challenged with 30 minutes of high glucose. The expression of insulin gene transcription factors (MafA, NeuroD/ Beta2, and PDX 1), preproinsulin mRNA, proinsulin and insulin were compared between large and small islets. Under basal (low glucose) conditions, MafA and NeuroD had higher mRNA levels and greater protein amounts in large islets compared to small when normalized to GAPDH levels. 30 minutes of high glucose stimulation failed to alter the mRNA or subsequent protein levels of either gene. However, 30 minutes of high glucose suppressed activated PDX-1 protein levels in both small and large islets. High glucose stimulation did not statistically alter the preproinsulin mRNA (insulin 1 and insulin 2) levels. At the translational level, high glucose increased the proinsulin levels, and large islets showed a higher proinsulin content per cell than small islets. Insulin content per cell was not significantly different between small and large islets under basal or high glucose levels. The results fail to explain the higher level of insulin secretion noted in small versus large islets and may suggest that possible differences lie downstream in the secretory pathway rather than insulin biosynthesis. PMID- 26752361 TI - The inclination for conscious motor control after stroke: validating the Movement Specific Reinvestment Scale for use in inpatient stroke patients. AB - PURPOSE: Stroke survivors are inclined to consciously control their movements, a phenomenon termed "reinvestment". Preliminary evidence suggests reinvestment to impair patients' motor recovery. To investigate this hypothesis, an instrument is needed that can reliably assess reinvestment post-stroke. Therefore, this study aimed to validate the Movement-Specific Reinvestment Scale (MSRS) within inpatient stroke patients. METHOD: One-hundred inpatient stroke patients (<1 year post-stroke) and 100 healthy peers completed the MSRS, which was translated to Dutch for the study purpose. To assess structural validity, confirmatory factor analysis determined whether the scale measures two latent constructs, as previously reported in healthy adults. Construct validity was determined by testing whether patients had higher reinvestment than controls. Reliability analyses entailed assessment of retest reliability (ICC), internal consistency (Cronbach's alpha), and minimal detectable change. RESULTS: Both structural and construct validity of the MSRS were supported. Retest reliability and internal consistency indices were acceptable to good. The minimal detectable change was adequate on group level, but considerable on individual level. CONCLUSIONS: The MSRS is a valid and reliable tool and suitable to assess the relationship between reinvestment and motor recovery in the first months post-stroke. Eventually, this may help therapists to individualize motor learning interventions based on patients' reinvestment preferences. IMPLICATIONS FOR REHABILITATION: This study showed that the Movement-Specific Reinvestment Scale (MSRS) is a valid and reliable tool to objectify stroke patients' inclination for conscious motor control. The MSRS may be used to identify stroke patients who are strongly inclined to consciously control their movements, as this disposition may hinder their motor recovery. Eventually, the MSRS may enable clinicians to tailor motor learning interventions to stroke patients' motor control preferences. PMID- 26752377 TI - COST ANALYSIS OF INTRA PROCEDURAL RAPID ON SITE EVALUATION OF CYTOPATHOLOGY WITH ENDOBRONCHIAL ULTRASOUND. AB - BACKGROUND: Rapid on site evaluation (ROSE) allows immediate processing and interpretation of the aspirate in the procedural suite. It improves diagnostic yield and lowers patient care costs. There are limited data on its cost effectiveness with endobronchial ultrasound (EBUS). METHODS: We developed an economic model with two arms, no ROSE (our current practice) and simulated ROSE. To simulate ROSE, a cytopathologist retrospectively identified the first diagnostic slide in each case. Using a decision analytic modeling technique under a hospital diagnostic unit perspective, the benefits of simulated ROSE were estimated as cost-savings. The model input was estimated from actual data, consulting experts, and the literature. The benefits were estimated as cost savings per patient and for the province of Alberta per year. Due to differences in the procedure, sarcoidosis and cancer patients were analyzed separately. The costs are shown in 2012 Canadian dollars, CAD. RESULTS: In our model without ROSE, the procedure cost/patient was CAD 646.00(USD 523.32) for cancer and CAD 1,170.00 (USD 947.73) for sarcoidosis. With simulated ROSE cost savings of CAD 63.00(37.00 to 89.00) [USD 51.04(29.97 to 72.10)], CAD 544.00(490.00 to 598.00) [USD 440.65(397.05 to 484.44)] for cancer and sarcoidosis, respectively. Extrapolating this to provincial data, our model estimates that EBUS with ROSE would lead to savings of CAD 50,000.00(30,000 to 71,000) [USD 40,501.24 (24,300.75 to 57,531.34)] for cancer and CAD 109,000.00 (87,000 to 130,000) [USD 88,337.07 (70,546.45 to 105,313.04) for sarcoidosis. CONCLUSION: The use of ROSE with EBUS is cost saving. The projected savings were CAD 50,000.00 (USD 40,501.24) and CAD 109,000.00(USD 88,337.07) in cancer and sarcoidosis, respectively, for the province of Alberta, Canada. PMID- 26752376 TI - Conditioning of naive CD4(+) T cells for enhanced peripheral Foxp3 induction by nonspecific bystander inflammation. AB - Inflammation induced during infection can both promote and suppress immunity. This contradiction suggests that inflammatory cytokines affect the immune system in a context-dependent manner. Here we show that nonspecific bystander inflammation conditions naive CD4(+) T cells for enhanced peripheral Foxp3 induction and reduced effector differentiation. This results in inhibition of immune responses in vivo via a Foxp3-dependent effect on antigen-specific naive CD4(+) T cell precursors. Such conditioning may have evolved to allow immunity to infection while limiting subsequent autoimmunity caused by release of self antigens in the wake of infection. Furthermore, this phenomenon suggests a mechanistic explanation for the idea that early tuning of the immune system by infection affects the long-term quality of immune regulation. PMID- 26752380 TI - Analysis of meiotic chromosome structure and behavior in Robertsonian heterozygotes of Ellobius tancrei (Rodentia, Cricetidae): a case of monobrachial homology. AB - Synaptonemal complex (SC) chains were revealed in semisterile intraspecific F1 hybrids of Ellobius tancrei Blasius, 1884 (2n = 49, NF=56 and 2n=50, NF=56), heterozygous for Robertsonian (Rb) translocations. Chains were formed by Rb submetacentrics with monobrachial homology. Chromosome synapsis in spermatocytes of these hybrids was disturbed, apparently because of the problematic release of the chromosomes from the SC chains. These hybrids suffer from low fertility, and our data support the opinion that this is because a formation of Rb metacentrics with monobrachial homology within different races of the same species might be an initial event for the divergence of chromosomal forms. PMID- 26752381 TI - Mediation Approaches at the Beginning or End of Life. AB - The approaches used in mediation may help ethics consultants, especially in difficult cases. In this piece, I primarily discuss these techniques. I also discuss how clinicians may be of the most help to parents of infants with severe genetic conditions, to research participants, and to patients who may be at risk for Alzheimer's disease and their surrogate decision makers. PMID- 26752378 TI - Lubricin/Proteoglycan 4 binds to and regulates the activity of Toll-Like Receptors In Vitro. AB - Proteoglycan 4 (PRG4/lubricin) is secreted by cells that reside in articular cartilage and line the synovial joint. Lubricin may play a role in modulating inflammatory responses through interaction with CD44. This led us to examine if lubricin could be playing a larger role in the modulation of inflammation/immunity through interaction with Toll-like receptors (TLRs). Human Embryonic Kidney (HEK) cells overexpressing TLRs 2, 4 or 5 and surface plasmon resonance were employed to determine if full length recombinant human lubricin was able to bind to and activate TLRs. Primary human synovial fibroblasts were also examined using flow cytometry and Luminex multiplex ELISA. A rat destabilization model of osteoarthritis (OA) was used to determine if lubricin injections were able to regulate pain and/or inflammation in vivo. Lubricin can bind to and regulate the activity of TLRs, leading to downstream changes in inflammatory signalling independent of HA. We confirmed these findings in vivo through intra-articular injections of lubricin in a rat OA model where the inhibition of systemic inflammatory signaling and reduction in pain were observed. Lubricin plays an important role in regulating the inflammatory environment under both homeostatic and tissue injury states. PMID- 26752382 TI - The "Commitment Model" for Clinical Ethics Consultations: Society's Involvement in the Solution of Individual Cases. AB - Several approaches to clinical ethics consultation (CEC) exist in medical practice and are widely discussed in the clinical ethics literature; different models of CECs are classified according to their methods, goals, and consultant's attitude. Although the "facilitation" model has been endorsed by the American Society for Bioethics and Humanities (ASBH) and is described in an influential manual, alternative approaches, such as advocacy, moral expertise, mediation, and engagement are practiced and defended in the clinical ethics field. Our Clinical Ethics Center in Paris was founded in 2002 in the wake of the Patients' Rights Act, and to date it is the largest center that provides consultation services in France. In this article we shall describe and defend our own approach to clinical ethics consultation, which we call the "Commitment Model," in comparison with other existing models. Indeed commitment implies, among other meanings, continuity through time, a series of coherent actions, and the realization of important social goals. By drawing on a recent consultation case, we shall describe the main steps of our consultation procedure: interviews with major stakeholders, including patients and proxies; case conferences; and follow up. We shall show why we have chosen the term "commitment" to represent our approach at three different but interrelated levels: commitment towards patients, within the case conference group, and towards society as a whole. PMID- 26752384 TI - Patient Decision Aids: A Case for Certification at the National Level in the United States. AB - Patient decision aids enable patients to be better informed about the potential benefits and harms of their healthcare options. Certification of patient decision aids at the national level in the United States is a critical step towards responsible governance-primarily as a quality measure that increases patients' safety, as mandated in the U.S. Patient Protection and Affordable Care Act (PPACA). Certification would provide a verification process to identify conflicts of interest that may otherwise bias the scientific evidence presented in decision aids. Certification also benefits clinicians who may otherwise face malpractice claims based on harm to patients caused by possible reliance on patient decision aids that are inaccurate, incomplete, or presented in a manner that biases the patient's decision. Existing work by the International Patient Decision Aid Standards Collaboration could guide the establishment of a certification process within the U.S. This article argues for national certification of patient decision aids and discusses how that may be achieved. PMID- 26752383 TI - Stakeholders' Perspectives on Preclinical Testing for Alzheimer's Disease. AB - BACKGROUND AND AIMS: Progress towards validating amyloid beta as an early indicator of Alzheimer's disease (AD) heightens the need for evaluation of stakeholders' perspectives of the benefits and harms of preclinical testing in asymptomatic individuals. METHODS: Investigators conducted and analyzed 14 semi structured interviews with family members of patients diagnosed with AD. RESULTS: Participants reported benefits, including the potential to seek treatment, make lifestyle changes, and prepare for cognitive impairment. Participants identified harms, including social harms, adverse life decisions, and psychological harms. Nine participants reported either a "positive global perspective" or a "positive global perspective (qualified)." CONCLUSION: Results from this study characterized stakeholders' perspectives on the potential benefits and harms of clinical use of preclinical testing for AD. Investigators used data from this study to develop a framework that contributes to ongoing discussions that will evaluate widespread adoption of preclinical testing and will inform future research. PMID- 26752385 TI - Teaching and Learning the Techniques of Conflict Resolution for Challenging Ethics Consultations. AB - Professional mediators have long possessed a skill set that is uniquely suited to facilitation of difficult conversations between and among individuals in emotionally charged situations. This skill set has increasingly been recognized as invaluable to the work of clinical ethics consultants as they navigate conflicts involving families, surrogates, and providers. Given widespread acknowledgment that communication difficulties lie at the root of many clinical ethics conflicts, mediation offers techniques to enhance communication between conflicting parties. This special section of The Journal of Clinical Ethics focuses on core aspects of the mediation process designed for effective management of clinical conflict emanating from communication breakdowns, highly charged value conflicts, and instances of perceived disrespect. PMID- 26752386 TI - Identifying Sources of Clinical Conflict: A Tool for Practice and Training in Bioethics Mediation. AB - Bioethics mediators manage a wide range of clinical conflict emanating from diverse sources. Parties to clinical conflict are often not fully aware of, nor willing to express, the true nature and scope of their conflict. As such, a significant task of the bioethics mediator is to help define that conflict. The ability to assess and apply the tools necessary for an effective mediation process can be facilitated by each mediator's creation of a personal compendium of sources that generate clinical conflict, to provide an orientation for the successful management of complex dilemmatic cases. PMID- 26752387 TI - Contentious Conversations: Using Mediation Techniques in Difficult Clinical Ethics Consultations. AB - Mediators utilize a wide range of skills in the process of facilitating dialogue and resolving conflicts. Among the most useful techniques for clinical ethics consultants (CECs)-and surely the least discussed-are those employed in acrimonious, hostile conversations between stakeholders. In the context of clinical ethics disputes or other bedside conflicts, good mediation skills can reverse the negative interactions that have prevented the creation of workable treatment plans or ethical consensus. This essay lays out the central framework mediators use in distinguishing positions from interests and describes a set of strategies for managing contentious ethics consultations or working with "difficult" patients, families, or patient-careprovider interactions. PMID- 26752388 TI - A Second Opinion: A Case Narrative on Clinical Ethics Mediation. AB - Contrasting traditional and common forms of ethics consultation with bioethics mediation, I describe the case of a "second opinion" consultation in the care of a patient with advanced cancer for whom treatment was futile. While the initial ethics consultation, performed by a colleague, led to a recommendation that some may deem ethical, the process failed to involve key stakeholders and failed to explore the underlying values and reasons for the opinions voiced by various stakeholders. The process of mediation ultimately led to creative solutions in which all stakeholders could reach consensus on a plan of care. PMID- 26752389 TI - Patient-Centered Care and the Mediator's Skills. AB - Bioethics mediation training offers knowledge and skills valuable for clinical ethics consultants who are engaged in high conflict situations. Furthermore, clinicians with this training can support organizational efforts to create a culture that is centered on the values, needs, and care preferences of patients and their families, rather than on those of the clinician or organization. Patient-centeredness is a hallmark of quality and an essential component for patients' safety. Clinicians with mediation training have the communication skills to address the myriad needs of patients and their loved ones, needs that are challenging to meet in inpatient hospital settings. The author illustrates principles of mediation such as validating patients' emotions, revealing the interests of all stakeholders, and shaping a shared solution to demonstrate how these skills have broad applicability in patient care settings. PMID- 26752390 TI - In the Ethos of the Safety Net: An Expanded Role for Clinical Ethics Mediation. AB - Clinical ethics mediation is invaluable for resolving intractable disputes in the hospital. But it is also a critical day-to-day skill for clinicians, especially those who serve a disproportionate number of vulnerable patients. While mediation is typically reserved for intractable cases, there are two important opportunities to expand its use. First is preventative mediation, in which clinicians incorporate clinical ethics mediation into their daily routine in order to address value-laden conflicts before they reach the point at which outside consultation becomes necessary. Second is guided mediation, in which clinical teams resolve conflicts with patients or surrogates with guidance from an ethics consultant, who operates at some distance from the conflict and, rather than recommending a single action, counsels clinicians on the process they can use to resolve the conflict on their own. These approaches build the capacity of all clinicians to use clinical ethics mediation to improve the care of vulnerable patients. PMID- 26752391 TI - Mediation Training for the Physician: Expanding the Communication Toolkit to Manage Conflict. AB - Good communication is critical to the practice of medicine. This is particularly true when outcomes are unpredictable and/or patients lack the capacity to participate in medical decision making. Disputes may develop that cannot be addressed using basic communication skills. Conflict of this nature can burden patients, families, and medical staff and may result in increased suffering for all parties. Many physicians lack the necessary communication tools to handle difficult conversations. Training in bioethics mediation provides physicians with skills that can promote healing by empowering participants to engage in effective discourse and break down barriers to find common ground. Mediation training for physicians can expand their capacity to connect with patients and enhance their ability to identify potential conflict early on, in order to collaborate more effectively. Competency in the processes of negotiation and conflict resolution should therefore be seen as essential elements of medical training. PMID- 26752392 TI - Preventing and De-Escalating Ethical Conflict: A Communication-Training Mediation Model. AB - While ethical conflicts in the provision of healthcare are common, the current third-party mediator model is limited by a lack of expert ethical mediators, who are often not on site when conflict escalates. In order to improve clinical outcomes in situations such as conflicts at the end of life, we suggest that clinicians-physicians, nurses and social workers-be trained to prevent and de escalate emerging conflicts. This can be achieved using a mediation model framed by a communication-training approach. A case example is presented and the model is discussed. The implication of this preventative/early intervention model for improving clinical outcomes, in particular end-of life conflict, is considered. PMID- 26752393 TI - Intensive Care, Intense Conflict: A Balanced Approach. AB - Caring for a child in a pediatric intensive care unit is emotionally and physically challenging and often leads to conflict. Skilled mediators may not always be available to aid in conflict resolution. Careproviders at all levels of training are responsible for managing difficult conversations with families and can often prevent escalation of conflict. Bioethics mediators have acknowledged the important contribution of mediation training in improving clinicians' skills in conflict management. Familiarizing careproviders with basic mediation techniques is an important step towards preventing escalation of conflict. While training in effective communication is crucial, a sense of fairness and justice that may only come with the introduction of a skilled, neutral third party is equally important. For intense conflict, we advocate for early recognition, comfort, and preparedness through training of clinicians in de-escalation and optimal communication, along with the use of more formally trained third-party mediators, as required. PMID- 26752395 TI - Medical Decision Making for Patients Without Proxies: The Effect of Personal Experience in the Deliberative Process. AB - The number of admissions to hospitals of patients without a proxy decision maker is rising. Very often these patients need fairly immediate medical intervention for which informed consent--or informed refusal--is required. Many have recommended that there be a process in place to make these decisions, and that it include a variety of perspectives. People are particularly wary of relying solely on medical staff to make these decisions. The University Hospitals Case Medical Center recruits community members from its Ethics Committee to serve on a subcommittee, the Patients Without Proxies (PWP) Committee, which works with medical staff during the decision-making process for these patients. Generally, the community members go to the bedside to observe patients. This article looks at how those unused to observing hospitalized patients who are sick and/or dying are affected, comparing them to mock jurors in a research study who are exposed to graphic photographs related to a fabricated crime scene. Judgments made by the mock jurors are affected by viewing such images. The personal experience of witnessing unfamiliar and shocking scenes affects their subsequent judgments. While it may be difficult to tease out whether observing patients causes PWP members to be benefited or harmed, they are affected by what they see. If a variety of perspectives is desirable to reduce possible bias or error, this article argues that at least one community member should refrain from seeing the patient in order to add a different and valuable voice to the decision-making process. Members of the subcommittee base their judgments on the various kinds of information available. Sometimes the things they see, hear, or feel may affect them particularly deeply, and affect their judgments as well. In this article I explore the idea that something like this may be happening in a particular kind of clinical ethics case consultation. PMID- 26752394 TI - "She Just Doesn't Know Him Like We Do": Illuminating Complexities in Surrogate Decision Making. AB - When patients are not able to speak for themselves, surrogate decision makers are asked to guide treatment decisions and formulate a plan of care in accordance with what the patients would have wanted. This necessitates an exploration into the patients' views about life and how it should be lived, how the patients constructed their identity or life story, and their attitudes towards sickness and suffering. When an individual appoints a surrogate, such as a healthcare power of attorney, a common presumption is that this designation evinces merit. This obscures the possibility of multiple other considerations that influence individual choice. This article presents a clinical case in which the claim to know someone best created a controversy that brought treatment decisions to a standstill. Further, it illuminates how the question, "Given the current medical condition, what would this person want?" risks presuming that a singular, unambiguous preference exists and that one person can provide the answer. Clinical ethicists can play a vital role in situations when there is a dispute among a designated surrogate and family members over a patient's preference. By embracing the complexity of the desire to synthesize seemingly irreconcilable perspectives about identity, uncovering the reasons that underlie disagreement, and guiding inquiry in such a way that allows stakeholders to move beyond the conflict, clinical ethicists can facilitate decision making that honors the patient and may mitigate moral distress. PMID- 26752396 TI - Legal Briefing: Medicare Coverage of Advance Care Planning. AB - This issue's "Legal Briefing" column covers the recent decision by the Centers for Medicare and Medicaid Services (CMS) to expand Medicare coverage of advance care planning, beginning 1 January 2016. Since 2009, most "Legal Briefings" in this journal have covered a wide gamut of judicial, legislative, and regulatory developments concerning a particular topic in clinical ethics. In contrast, this "Legal Briefing" is more narrowly focused on one single legal development. This concentration on Medicare coverage of advance care planning seems warranted. Advance care planning is a frequent subject of articles in JCE. After all, it has long been seen as an important, albeit only partial, solution to a significant range of big problems in clinical ethics. These problems range from medical futility disputes to decision making for incapacitated patients who have no available legally authorized surrogate. Consequently, expanded Medicare coverage of advance care planning is a potentially seismic development. It may materially reduce both the frequency and severity of key problems in clinical ethics. Since the sociological, medical, and ethical literature on advance care planning is voluminous, I will not even summarize it here. Instead, I focus on Medicare coverage. I proceed, chronologically, in six stages: 1. Prior Medicare Coverage of Advance Care Planning 2. Proposed Expanded Medicare Coverage in 2015 3. Proposed Expanded Medicare Coverage in 2016 4. The Final Rule Expanding Medicare Coverage in 2016 5. Remaining Issues for CMS to Address in 2017 6. Pending Federal Legislation. PMID- 26752397 TI - Current and emerging treatment options for interstitial lung disease in patients with rheumatic disease. AB - The management of connective tissue disease-associated interstitial lung disease (CTD-ILD) is complex and this arena offers many challenges to the practicing clinician. Unfortunately, treatment strategies and recommendations are often based on experience rather than evidence, and there are few effective therapeutic options. Pharmacologic intervention with immunosuppression is usually the mainstay of therapy and is reserved for those with clinically significant and/or progressive ILD. There is a desperate need for controlled trials across the spectrum of CTD-ILD and a number of potentially promising novel therapies warrant further study. It is important to address co-morbid conditions or aggravating factors (e.g., gastroesophageal reflux, aspiration, bone health, pulmonary hypertension, Pneumocystis jiroveci prophylaxis) and to institute non pharmacologic management strategies (e.g., supplemental oxygen and cardiopulmonary rehabilitation) as part of a comprehensive treatment plan in CTD ILD. PMID- 26752401 TI - Renal Neoplasms With Overlapping Features of Clear Cell Renal Cell Carcinoma and Clear Cell Papillary Renal Cell Carcinoma: A Clinicopathologic Study of 37 Cases From a Single Institution. AB - Clear cell papillary renal cell carcinoma (CCPRCC) was recently included in the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia as a subtype of RCC that is morphologically, immunohistochemically, and genetically distinct from both clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma. In our clinical practice we have observed tumors with overlapping histologic features of CCPRCC and CCRCC; therefore, our aim was to describe the morphologic, immunohistochemical, and clinical characteristics of these tumors. We examined a large series of consecutive nephrectomies diagnosed as CCRCC and found 37 tumors with morphologic overlap between CCRCC and CCPRCC, identifying 2 patterns. Pattern 1 tumors (N=19) had areas diagnosable as CCRCC admixed with foci having a prominent linear arrangement of nuclei away from the basement membrane imparting a resemblance to CCPRCC; however, other morphologic features commonly seen in CCPRCC (such as branching acini and cystic spaces with papillary tufts) were not typical and, when present, were focal or poorly developed. Pattern 2 (N=18) tumors had 2 discrete areas, one area with an appearance strongly resembling CCPRCC and the other with higher grade nuclei and features diagnosable as CCRCC, sometimes including rhabdoid differentiation, sarcomatoid differentiation, necrosis, and high-stage disease. Four (21%) of the pattern 1 tumors had grade 3 nuclei in the CCRCC-like areas, and 4 were high stage (pT3a). Of the 16 immunostained pattern 1 tumors, all expressed cytokeratin 7 (CK7) at least focally in the CCPRCC-like areas, strongly and diffusely in 9 (56%) cases; 12 (75%) showed negative to focal and/or weak CK7 expression in the CCRCC-like areas. CD10, alpha-methylacyl-CoA-racemase, high-molecular-weight cytokeratin, and carbonic anhydrase IX (CA IX) had no significant differential expression between these foci. No cup-like staining pattern was seen with CA IX. Two (11%) patients with pattern 1 tumors developed metastases, and 1 (5%) subsequently died of disease. Eleven (61%) pattern 2 cases had the International Society of Urological Pathology grade 3 nuclei in the CCRCC-like areas, and 7 (39%) were grade 4 (4 of these cases had rhabdoid features; 1 was also sarcomatoid). Of the 16 immunostained pattern 2 tumors, 8 (50%) showed strong diffuse CK7 expression in the CCPRCC-like areas, and 9 (56%) showed complete lack of CK7 expression in the CCRCC-like areas. CD10, alpha-methylacyl-CoA-racemase, and high-molecular-weight cytokeratin did not have significant differential expression. Membranous expression of CA IX, typically strong and diffuse, was identified in both the CCPRCC-like and CCRCC-like areas in all cases tested (with a cup-like pattern at least focally in the CCPRCC-like areas of 10 [63%] pattern 2 cases). Five (28%) patients with pattern 2 tumors had distant metastases, 3 (17%) of whom subsequently died of disease. Renal cell carcinomas with areas resembling both CCRCC and CCPRCC occur. Some can have high-grade and high-stage foci, and aggressive clinical outcomes are seen. Given this malignant potential, we would presently diagnose such cases as CCRCC. These 2 patterns of renal neoplasia underscore the need for caution in diagnosing CCPRCC on limited sampling, reserving the diagnosis for those tumors that strictly fulfill both morphologic and immunohistochemical criteria. PMID- 26752398 TI - Haemolytic uraemic syndrome with peripheral gangrene and Kawasaki disease in a 15 month-old child. AB - A 15-month-old boy presented with atypical haemolytic uraemic syndrome (HUS) (without antecedent diarrhoea or dysentery) following a gluteal abscess and subsequently developed digital gangrene. During plasma infusion therapy for HUS, the clinical features of Kawasaki disease (KD) evolved. Intravenous immunoglobulin and aspirin therapy led to resolution of the KD. The case is notable for development of digital gangrene, a rare phenomenon described with HUS, as well as the development of features of KD. This is the first report of atypical HUS in association with peripheral gangrene and KD. The possible pathophysiological mechanisms are discussed. PMID- 26752402 TI - Real-World Outcomes of Combination Chemotherapy with Trabectedin plus Pegylated Liposomal Doxorubicin in Patients with Recurrent Ovarian Cancer: A Single-Center Experience. AB - BACKGROUND: Trabectedin plus pegylated liposomal doxorubicin (PLD) proved efficacious as second-line treatment for patients with recurrent ovarian cancer (ROC). METHODS: We report a single-center retrospective analysis of the efficacy and tolerance of trabectedin 1.1 mg/m2 every 3 weeks in a cohort of real-life ROC patients. RESULTS: From February 2012 to January 2014, 17 patients were treated with trabectedin alone or combined with PLD. Median age was 61 years (range: 48 78). Performance status was 0-1 in 16 patients (94%). Disease response rate was 53% and disease control rate was 76%. At the end of the follow-up, 8 patients (47%) were alive. Median overall survival was 17.6 months (95% CI 13.6 to not reached). Median progression-free survival was 6.7 months (95% CI 5.4-10.0). The most frequent grade 3-4 toxicities were neutropenia (n = 4, 24%) and nausea/vomiting (n = 4, 24%). CONCLUSION: Trabectedin combined with PLD seems efficient in and well tolerated by real-life ROC patients. PMID- 26752403 TI - Differential Expression of Proteins Associated with the Hair Follicle Cycle - Proteomics and Bioinformatics Analyses. AB - Hair follicle cycling can be divided into the following three stages: anagen, catagen, and telogen. The molecular signals that orchestrate the follicular transition between phases are still unknown. To better understand the detailed protein networks controlling this process, proteomics and bioinformatics analyses were performed to construct comparative protein profiles of mouse skin at specific time points (0, 8, and 20 days). Ninety-five differentially expressed protein spots were identified by MALDI-TOF/TOF as 44 proteins, which were found to change during hair follicle cycle transition. Proteomics analysis revealed that these changes in protein expression are involved in Ca2+-regulated biological processes, migration, and regulation of signal transduction, among other processes. Subsequently, three proteins were selected to validate the reliability of expression patterns using western blotting. Cluster analysis revealed three expression patterns, and each pattern correlated with specific cell processes that occur during the hair cycle. Furthermore, bioinformatics analysis indicated that the differentially expressed proteins impacted multiple biological networks, after which detailed functional analyses were performed. Taken together, the above data may provide insight into the three stages of mouse hair follicle morphogenesis and provide a solid basis for potential therapeutic molecular targets for this hair disease. PMID- 26752404 TI - Systems Biology Approach to Model the Life Cycle of Trypanosoma cruzi. AB - Due to recent advances in reprogramming cell phenotypes, many efforts have been dedicated to developing reverse engineering procedures for the identification of gene regulatory networks that emulate dynamical properties associated with the cell fates of a given biological system. In this work, we propose a systems biology approach for the reconstruction of the gene regulatory network underlying the dynamics of the Trypanosoma cruzi's life cycle. By means of an optimisation procedure, we embedded the steady state maintenance, and the known phenotypic transitions between these steady states in response to environmental cues, into the dynamics of a gene network model. In the resulting network architecture we identified a small subnetwork, formed by seven interconnected nodes, that controls the parasite's life cycle. The present approach could be useful for better understanding other single cell organisms with multiple developmental stages. PMID- 26752405 TI - CD-Based Indices for Link Prediction in Complex Network. AB - Lots of similarity-based algorithms have been designed to deal with the problem of link prediction in the past decade. In order to improve prediction accuracy, a novel cosine similarity index CD based on distance between nodes and cosine value between vectors is proposed in this paper. Firstly, node coordinate matrix can be obtained by node distances which are different from distance matrix and row vectors of the matrix are regarded as coordinates of nodes. Then, cosine value between node coordinates is used as their similarity index. A local community density index LD is also proposed. Then, a series of CD-based indices include CD LD-k, CD*LD-k, CD-k and CDI are presented and applied in ten real networks. Experimental results demonstrate the effectiveness of CD-based indices. The effects of network clustering coefficient and assortative coefficient on prediction accuracy of indices are analyzed. CD-LD-k and CD*LD-k can improve prediction accuracy without considering the assortative coefficient of network is negative or positive. According to analysis of relative precision of each method on each network, CD-LD-k and CD*LD-k indices have excellent average performance and robustness. CD and CD-k indices perform better on positive assortative networks than on negative assortative networks. For negative assortative networks, we improve and refine CD index, referred as CDI index, combining the advantages of CD index and evolutionary mechanism of the network model BA. Experimental results reveal that CDI index can increase prediction accuracy of CD on negative assortative networks. PMID- 26752406 TI - Checkpoint Inhibitors in Kidney Transplant Recipients and the Potential Risk of Rejection. PMID- 26752407 TI - Correction: GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function. AB - [This corrects the article DOI: 10.1371/journal.pgen.1005710.]. PMID- 26752409 TI - Intestinal Microbiota in Patients with Spinal Cord Injury. AB - Human intestinal flora comprises thousands of bacterial species. Growth and composition of intestinal microbiota is dependent on various parameters, including immune mechanisms, dietary factors and intestinal motility. Patients with spinal cord injury (SCI) frequently display neurogenic bowel dysfunction due to the absence of central nervous system control over the gastrointestinal system. Considering the bowel dysfunction and altered colonic transit time in patients with SCI, we hypothesized the presence of a significant change in the composition of their gut microbiome. The objective of this study was to characterize the gut microbiota in adult SCI patients with different types of bowel dysfunction. We tested our hypothesis on 30 SCI patients (15 upper motor neuron [UMN] bowel syndrome, 15 lower motor neuron [LMN] bowel syndrome) and 10 healthy controls using the 16S rRNA sequencing. Gut microbial patterns were sampled from feces. Independent of study groups, gut microbiota of the participants were dominated by Blautia, Bifidobacterium, Faecalibacterium and Ruminococcus. When we compared all study groups, Roseburia, Pseudobutyrivibrio, Dialister, Marvinbryantia and Megamonas appeared as the genera that were statistically different between groups. In comparison to the healthy group, total bacterial counts of Pseudobutyrivibrio, Dialister and Megamonas genera were significantly lower in UMN bowel dysfunction group. The total bacterial count of Marvinbryantia genus was significantly lower in UMN bowel dysfunction group when compared to the LMN group. Total bacterial counts of Roseburia, Pseudobutyrivibrio and Megamonas genera were significantly lower in LMN bowel dysfunction group when compared to healthy groups. Our results demonstrate for the first time that butyrate-producing members are specifically reduced in SCI patients when compared to healthy subjects. The results of this study would be of interest since to our knowledge, microbiome-associated studies targeting SCI patients are non-existent and the results might help explain possible implications of gut microbiome in SCI. PMID- 26752410 TI - The Effect of Root Exudate 7,4'-Dihydroxyflavone and Naringenin on Soil Bacterial Community Structure. AB - Our goal was to investigate how root exudate flavonoids influence the soil bacterial community structure and to identify members of the community that change their relative abundance in response to flavonoid exudation. Using a model system that approximates flavonoid exudation of Medicago sativa roots, we treated a soil with 7,4'-dihydroxyflavone and naringenin in two separate experiments using three different rates: medium (equivalent to the exudation rate of 7,4' dihydroxyflavone from M. sativa seedlings), high (10* the medium rate), and low (0.1* the medium rate). Controls received no flavonoid. Soil samples were subjected to ATP assays and 16S rRNA gene amplicon sequencing. The flavonoid treatments caused no significant change in the soil ATP content. With the high 7,4'-dihydroxyflavone treatment rate, operational taxonomic units (OTUs) classified as Acidobacteria subdivision 4 increased in relative abundance compared with the control samples, whereas OTUs classified as Gaiellales, Nocardioidaceae, and Thermomonosporaceae were more prevalent in the control. The naringenin treatments did not cause significant changes in the soil bacterial community structure. Our results suggest that the root exudate flavonoid 7,4' dihydroxyflavone can interact with a diverse range of soil bacteria and may have other functions in the rhizosphere in addition to nod gene induction in legume rhizobia symbiosis. PMID- 26752411 TI - Acute and dramatic saxophone penis. AB - We present a case of intense genital swelling because of a hereditary angioedema. This rare disease should be included in the differential diagnosis of acute and asymptomatic genital edema, because it may prevent future potentially life threatening episodes of visceral angioedema. PMID- 26752412 TI - Eelgrass (Zostera marina) Food Web Structure in Different Environmental Settings. AB - This study compares the structure of eelgrass (Zostera marina L.) meadows and associated food webs in two eelgrass habitats in Denmark, differing in exposure, connection to the open sea, nutrient enrichment and water transparency. Meadow structure strongly reflected the environmental conditions in each habitat. The eutrophicated, protected site had higher biomass of filamentous algae, lower eelgrass biomass and shoot density, longer and narrower leaves, and higher above to below ground biomass ratio compared to the less nutrient-enriched and more exposed site. The faunal community composition and food web structure also differed markedly between sites with the eutrophicated, enclosed site having higher biomass of consumers and less complex food web. These relationships resulted in a column shaped biomass distribution of the consumers at the eutrophicated site whereas the less nutrient-rich site showed a pyramidal biomass distribution of consumers coupled with a more diverse consumer community. The differences in meadow and food web structure of the two seagrass habitats, suggest how physical setting may shape ecosystem response and resilience to anthropogenic pressure. We encourage larger, replicated studies to further disentangle the effects of different environmental variables on seagrass food web structure. PMID- 26752413 TI - Spatio-Temporal Dynamics of Foraging Networks in the Grass-Cutting Ant Atta bisphaerica Forel, 1908 (Formicidae, Attini). AB - Foraging networks are a key element for ant colonies because they facilitate the flow of resources from the environment to the nest and they allow the sharing of information among individuals. Here we report the results of an 8-month survey, extending from November 2009 to June 2010, of the foraging networks of four mature colonies of Atta bisphaerica, a species of grass-cutting ant which is considered as a pest in Brazil. We found that the distribution of foraging effort was strongly influenced by the landscape features around the nests, in particular by the permanently wet parts of the pasture in which the nests were located. The foraging networks consisted of underground tunnels which opened on average at 21.5m from the nests and of above-ground physical trails that reached on average 4.70m in length. The use of the foraging networks was highly dynamic, with few sections of the networks used for long periods of time. Three different phases, which could be linked to the seasonal change in the local rainfall regime, could be identified in the construction and use of the foraging networks. The first phase corresponded to the beginning of the rainy season and was characterized by a low foraging activity, as well as a low excavation and physical trail construction effort. The second phase, which began in February and extended up to the end of the humid season at the end of March, was characterized by an intense excavation and trail construction effort, resulting in an expansion of the foraging networks. Finally, in the third phase, which corresponded to the beginning of the dry season, the excavation and trail construction effort leveled off or decreased while foraging activity kept increasing. Our hypothesis is that ants could benefit from the underground tunnels and physical trails built during the humid season to maintain their foraging activity at a high level. PMID- 26752408 TI - Transcriptome Analysis of Salt Stress Responsiveness in the Seedlings of Dongxiang Wild Rice (Oryza rufipogon Griff.). AB - Dongxiang wild rice (Oryza rufipogon Griff.) is the progenitor of cultivated rice (Oryza sativa L.), and is well known for its superior level of tolerance against cold, drought and diseases. To date, however, little is known about the salt tolerant character of Dongxiang wild rice. To elucidate the molecular genetic mechanisms of salt-stress tolerance in Dongxiang wild rice, the Illumina HiSeq 2000 platform was used to analyze the transcriptome profiles of the leaves and roots at the seedling stage under salt stress compared with those under normal conditions. The analysis results for the sequencing data showed that 6,867 transcripts were differentially expressed in the leaves (2,216 up-regulated and 4,651 down-regulated) and 4,988 transcripts in the roots (3,105 up-regulated and 1,883 down-regulated). Among these differentially expressed genes, the detection of many transcription factor genes demonstrated that multiple regulatory pathways were involved in salt stress tolerance. In addition, the differentially expressed genes were compared with the previous RNA-Seq analysis of salt-stress responses in cultivated rice Nipponbare, indicating the possible specific molecular mechanisms of salt-stress responses for Dongxiang wild rice. A large number of the salt-inducible genes identified in this study were co-localized onto fine mapped salt-tolerance-related quantitative trait loci, providing candidates for gene cloning and elucidation of molecular mechanisms responsible for salt-stress tolerance in rice. PMID- 26752415 TI - Correction: Associations between Food Outlets around Schools and BMI among Primary Students in England: A Cross-Classified Multi-Level Analysis. PMID- 26752414 TI - Association of the HLA-G 3'UTR polymorphisms with colorectal cancer in Italy: a first insight. AB - This study aimed to explore functional and regulatory polymorphisms and haplotypes at the HLA-G 3'UTR region in colorectal cancer development. The presence of nonpolymorphic variants was also evaluated. Three-hundred and eight patients with colorectal cancer and 294 healthy controls were analysed at the germinal level. We found an association with increased risk of colorectal cancer for +2960 14-bp INDEL, +3196 C>G SNPs and UTR-2 haplotype, and a 'protective' role for +3003 T>C, +3010 C>G polymorphisms and UTR-4 haplotype. We detected in 3 distinct patients, a novel nucleotide change (+3037 C>A) and 2 already described rare variants, +3032 G/C (EUR MAF = 0.1%) and +3092 G/T (EUR MAF = 0%). This is the first study showing associations between different polymorphisms in the HLA-G 3'UTR and colorectal cancer susceptibility. PMID- 26752416 TI - Topiramate and motivational enhancement therapy for cannabis use among youth: a randomized placebo-controlled pilot study. AB - Cannabis misuse accounts for nearly all of the substance abuse treatment admissions among youth in the United States. Most youth do not experience sustained benefit from existing psychosocial treatments; however, medication development research for treating adolescent cannabis misuse is almost nonexistent. We conducted a double-blind, placebo-controlled, pilot study to test the potential efficacy of topiramate plus motivational enhancement therapy (MET) for treating cannabis use among adolescents. Sixty-six heavy cannabis users, ages 15 to 24 years, were randomized to one of two 6-week treatment conditions: topiramate plus MET or placebo plus MET. Topiramate was titrated over 4 weeks then stabilized at 200 mg/day for 2 weeks. MET was delivered biweekly for a total of three sessions. Only 48 percent of youths randomized to topiramate completed the 6-week trial (n = 19), compared with 77 percent of youths in the placebo condition (n = 20). Adverse medication side effects were the most common reason for withdrawal among participants in the topiramate group. Latent growth models showed that topiramate was superior to placebo for reducing the number of grams smoked per use day, but it did not improve abstinence rates. The same pattern of results was found when values for missing outcomes were imputed. We show that topiramate combined with MET demonstrated efficacy for reducing how much cannabis adolescents smoked when they used but did not affect abstinence rates. The magnitude of this effect was modest, however, and topiramate was poorly tolerated by youths, which calls into question the clinical importance of these findings. PMID- 26752417 TI - Comparison of Baseline versus Posttreatment Left Ventricular Ejection Fraction in Patients with Acute Decompensated Heart Failure for Predicting Cardiovascular Outcome: Implications from Single-Center Systolic Heart Failure Cohort. AB - AIMS: The prognostic values of left ventricular ejection fraction (LVEF) during heart failure (HF) with acute decompensation or after optimal treatment have not been extensively studied. We hypothesized that posttreatment LVEF has superior predictive value for long-term prognosis than LVEF at admission does. METHODS AND RESULTS: In Protocol 1, 428 acute decompensated HF (ADHF) patients with LVEF <=35% in a tertiary medical center were enrolled and followed for a mean period of 34.7 +/- 10.8 months. The primary and secondary end points were all-cause mortality and HF readmission, respectively. In total, 86 deaths and 240 HF readmissions were recorded. The predictive values of baseline LVEF at admission and LVEF 6 months posttreatment were analyzed and compared. The posttreatment LVEFs were predictive for future events (P = 0.01 for all-cause mortality, P < 0.001 for HF readmission), but the baseline LVEFs were not. In Protocol 2, the outcomes of patients with improved LVEF (change of LVEF: >=+10%), unchanged LVEF (change of LVEF: -10% to +10%), and reduced LVEF (change of LVEF: <=-10%) were analyzed and compared. Improved LVEF occurred in 171 patients and was associated with a superior long-term prognosis among all groups (P = 0.02 for all-cause mortality, P < 0.001 for HF readmission). In Protocol 3, independent predictors of improved LVEF were analyzed, and baseline LV end-diastolic dimension (LVEDD) was identified as a powerful predictor in ADHF patients (P < 0.001). CONCLUSIONS: In patients with ADHF, posttreatment LVEF but not baseline LVEF had prognostic power. Improved LVEF was associated with superior long-term prognosis, and baseline LVEDD identified patients who were more likely to have improved LVEF. Therefore, baseline LVEF should not be considered a relevant prognosis factor in clinical practice for patients with ADHF. PMID- 26752419 TI - Spectroscopic Evidence of the Improvement of Reactive Iron Mineral Content in Red Soil by Long-Term Application of Swine Manure. AB - Mineral elements in soil solutions are thought to be the precursor of the formation of reactive minerals, which play an important role in global carbon (C) cycling. However, information regarding the regulation of mineral elements release in soil is scarce. Here, we examined the long-term (i.e., 23 yrs) effects of fertilisation practices on Fe minerals in a red soil in Southern China. The results from chemical analysis and Fourier-transform infrared spectroscopy showed that long-term swine manure (M) treatment released greater amounts of minerals into soil solutions than chemical fertilisers (NPK) treatment, and Fe played a dominant role in the preservation of dissolved organic C. Furthermore, Fe K-edge X-ray absorption near-edge fine structure spectroscopy demonstrated that reactive Fe minerals were mainly composed of less crystalline ferrihydrite in the M treated soil and more crystalline goethite in the NPK-treated soil. In conclusion, this study reported spectroscopic evidence of the improvement of reactive Femineral content in the M-treated soil colloids when compared to NPK treated soil colloids. PMID- 26752418 TI - The Therapeutic Potential of AN-7, a Novel Histone Deacetylase Inhibitor, for Treatment of Mycosis Fungoides/Sezary Syndrome Alone or with Doxorubicin. AB - The 2 histone deacetylase inhibitors (HDACIs) approved for the treatment of cutaneous T-cell lymphoma (CTCL) including mycosis fungoides/sezary syndrome (MF/SS), suberoylanilide hydroxamic acid (SAHA) and romidepsin, are associated with low rates of overall response and high rates of adverse effects. Data regarding combination treatments with HDACIs is sparse. Butyroyloxymethyl diethylphosphate (AN-7) is a novel HDACI, which was found to have selective anticancer activity in several cell lines and animal models. The aim of this study was to compare the anticancer effects of AN-7 and SAHA, either alone or combined with doxorubicin, on MF/SS cell lines and peripheral blood lymphocytes (PBL) from patients with Sezary syndrome (SPBL). MyLa cells, Hut78 cells, SPBL, and PBL from healthy normal individuals (NPBL) were exposed to the test drugs, and the findings were analyzed by a viability assay, an apoptosis assay, and Western blot. AN-7 was more selectively toxic to MyLa cells, Hut78 cells, and SPBL (relative to NPBL) than SAHA and also acted more rapidly. Both drugs induced apoptosis in MF/SS cell lines, SAHA had a greater effect on MyLa cell line, while AN-7 induced greater apoptosis in SPBL; both caused an accumulation of acetylated histone H3, but AN-7 was associated with earlier kinetics; and both caused a downregulation of the HDAC1 protein in MF/SS cell lines. AN-7 acted synergistically with doxorubicin in both MF/SS cell lines and SPBL, and antagonistically with doxorubicin in NPBL. By contrast, SAHA acted antagonistically with doxorubicin on MF/SS cell lines, SPBL, and NPBL, leaving <50% viable cells. In conclusion, AN-7 holds promise as a therapeutic agent in MF/SS and has several advantages over SAHA. Our data provide a rationale for combining AN-7, but not SAHA, with doxorubicin to induce the cell death in MF/SS. PMID- 26752421 TI - Functional Improvement after Photothrombotic Stroke in Rats Is Associated with Different Patterns of Dendritic Plasticity after G-CSF Treatment and G-CSF Treatment Combined with Concomitant or Sequential Constraint-Induced Movement Therapy. AB - We have previously shown that granulocyte-colony stimulating factor (G-CSF) treatment alone, or in combination with constraint movement therapy (CIMT) either sequentially or concomitantly, results in significantly improved sensorimotor recovery after photothrombotic stroke in rats in comparison to untreated control animals. CIMT alone did not result in any significant differences compared to the control group (Diederich et al., Stroke, 2012;43:185-192). Using a subset of rat brains from this former experiment the present study was designed to evaluate whether dendritic plasticity would parallel improved functional outcomes. Five treatment groups were analyzed (n = 6 each) (i) ischemic control (saline); (ii) CIMT (CIMT between post-stroke days 2 and 11); (iii) G-CSF (10 MUg/kg G-CSF daily between post-stroke days 2 and 11); (iv) combined concurrent group (CIMT plus G CSF) and (v) combined sequential group (CIMT between post-stroke days 2 and 11; 10 MUg/kg G-CSF daily between post-stroke days 12 and 21, respectively). After impregnation of rat brains with a modified Golgi-Cox protocol layer V pyramidal neurons in the peri-infarct cortex as well as the corresponding contralateral cortex were analyzed. Surprisingly, animals with a similar degree of behavioral recovery exhibited quite different patterns of dendritic plasticity in both peri lesional and contralesional areas. The cause for these patterns is not easily to explain but puts the simple assumption that increased dendritic complexity after stroke necessarily results in increased functional outcome into perspective. PMID- 26752420 TI - Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model. AB - The pathogenesis of renal impairment in chronic liver diseases (CLDs) has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3,5-diethoxycarbonyl-1,4 dihydrocollidine (DDC) shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy), autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet-fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the pathophysiological mechanisms of sublethal tubular cell injury. PMID- 26752423 TI - Syntheses of Platinum-Sulindac Complexes and Their Nanoparticles as Targeted Anticancer Drugs. AB - Platinum(II)-sulindac complexes [{eta2 -C5 H4 SN(O)}Pt(DMSO){O(C=O)Sulindac}], [{eta2 -C5 H4 SN(O)}PtCl{(S=O)Sulindac}], [{eta2 -C5 H4 SN(O)}PtCl{(S=O)Sulindac succinimide}], and [{eta2 -C5 H4 SN(O)}PtCl{(S=O)Sulindac-thymidine}] were synthesized that exhibited IC50 values of 2.9-4.8 MUm against human oral cancer cells OECM1. The poly(lactic-co-glycolic acid) (PLGA) encapsulated [{eta2 -C5 H4 SN(O)}PtCl{(S=O)Sulindac}] also showed cytotoxic activity although less potent than the pristine species. PMID- 26752422 TI - Number of Players and Relative Pitch Area per Player: Comparing Their Influence on Heart Rate and Physical Demands in Under-12 and Under-13 Football Players. AB - The aim of the present study is to analyse the influence of different large-sided games (LSGs) on the physical and physiological variables in under-12s (U12) and 13s (U13) soccer players. The effects of the combination of different number of players per team, 7, 9, and 11 (P7, P9, and P11, respectively) with three relative pitch areas, 100, 200, and 300 m(2) (A100, A200, and A300, respectively), were analysed in this study. The variables analysed were: 1) global indicator such as total distance (TD); work:rest ratio (W:R); player-load (PL) and maximal speed (Vmax); 2) heart rate (HR) mean and time spent in different intensity zones of HR (<75%, 75-84%, 84-90% and >90%), and; 3) five absolute (<8, 8-13, 13-16 and >16 Km h(-1)) and three relative speed categories (<40%, 40-60% and >60% Vmax). The results support the theory that a change in format (player number and pitch dimensions) affects no similarly in the two players categories. Although it can seem that U13 players are more demanded in this kind of LSG, when the work load is assessed from a relative point of view, great pitch dimensions and/or high number of player per team are involved in the training task to the U12 players. The results of this study could alert to the coaches to avoid some types of LSGs for the U12 players such as: P11 played in A100, A200 or A300, P9 played in A200 or A300 and P7 played in A300 due to that U13>U12 in several physical and physiological variables (W:R, time spent in 84 90%HRmax, distance in 8-13 and 13-16 Km h(-1) and time spent in 40-60%Vmax). These results may help youth soccer coaches to plan the progressive introduction of LSGs so that task demands are adapted to the physiological and physical development of participants. PMID- 26752424 TI - Generation of mt:egfp transgenic zebrafish biosensor for the detection of aquatic zinc and cadmium. AB - Zebrafish embryo toxicity testing has become a popular method for detecting environmental pollutions. However, the present research showed that zebrafish embryos exhibited no visible paramorphia, malformation, or mortality when exposed to heavy metals in a range above environmental standard limits, indicating that zebrafish embryos are an imprecise model for monitoring environmental heavy metals concentrations above regulatory limits. Aiming to obtain a biosensor for aquatic heavy metals, a metal-sensitive vector including zebrafish metallothionein (MT) promoter and enhanced green fluorescent protein (EGFP) was reconstructed and microinjected into 1-cell stage zebrafish embryos. The authors obtained an mt:egfp transgenic zebrafish line sensitive to aquatic zinc and cadmium. A quantitative experiment showed that zinc and cadmium treatment significantly induced the expression of EGFP in a dose- and time-dependent manner. In particular, EGFP messenger RNA levels increased remarkably when exposed to heavy metals above the standard limits. The results suggest that the transgenic zebrafish is a highly sensitive biosensor for detecting environmental levels of zinc and cadmium. Environ Toxicol Chem 2016;35:2066-2073. (c) 2016 SETAC. PMID- 26752425 TI - Friendship in school-age boys with autism spectrum disorders: A meta-analytic summary and developmental, process-based model. AB - Friendship-making is considered a well-established domain of deficit for children with autism spectrum disorders (ASD; American Psychiatric Association, 2013), with this population sometimes described as incapable of making friends. However, the majority of children with ASD indicate a desire for friends, and many report having friends. To what degree, then, do youth with ASD succeed in achieving friendships with peers? If and when they do succeed, by what means do these friendships emerge relative to models of typically developing (TD) youths' friendships? To address these questions, we first meta-analyzed the descriptive friendship literature (peer-reported sociometrics, self-report, parent-report) among school-age boys with ASD. Using random effects models, we found that youth with ASD do make friends according to peers and parents (Hedges's g > 2.84). However, self-reported friendship quality (Hedges's g = -1.09) and parent- and peer-reported quantity (Hedges's g < -0.63) were poorer than TD peers. We consider these findings in light of 2 conceptual frameworks for understanding social deficits in ASD (social cognition and social motivation theory) and in view of a leading model of friendship in TD youth (Hartup & Stevens, 1997). We then present a model that synthesizes these domains through the construct of social information processing speed, and thereby present the first developmental, process-based model of friendship development among youth with ASD. (PsycINFO Database Record PMID- 26752426 TI - Electrochemical Fabrication of Functional Gelatin-Based Bioelectronic Interface. AB - Gelatin remains one of the most important biopolymeric material platforms because of its availability, safety, biocompatibility, biodegradability, and stimuli responsive properties. Here we report a simple, rapid, and reagentless anodic deposition method to assemble gelatin hydrogels from aqueous salt solutions onto an electrode surface. Results indicate that anodic reactions partially oxidize gelatin to yield a covalently cross-linked network that can perform multiple functions. First, anodically deposited gelatin remains activated, allowing covalent protein grafting and thus enabling biofunctionalization for electrochemical biosensing. Second, the anodically deposited gelatin retains its thermally responsive physical cross-linking properties that enable switching functions. Finally, the physical and chemical cross-linking mechanisms are reversible, which enables self-healing functions. Thus, anodic deposition provides a facile method to assemble gelatin-based multifunctional matrices for diverse applications in bioelectronics. PMID- 26752427 TI - Disease specific modeling: Simulation of the pharmacokinetics of meloxicam and ibuprofen in disease state vs. healthy conditions. AB - PURPOSE: Studies have shown altered pharmacokinetic patterns (PK) in patient suffering from acute pain. Thus, we aimed to simulate pharmacokinetics of meloxicam and ibuprofen in pain and pain-free states using a physiological based software program to identify the underlining mechanistic changes for the observed differences. METHOD: Published in vivo data of meloxicam and ibuprofen were used for the simulations. Two drug formulations were studied: a fast dissolving (FD) and regular release (RR) tablet formulation. The oral bioavailability was compared between these formulations in vagally suppressed rats (gastric dysfunction) and a control group. For ibuprofen additional human data of a control and post dental surgery group were used. All simulations were performed using GastroPlusTM. The in vivo drug release and PK of all formulations were estimated for both drugs using the software's immediate release (IR) or gastric release (GR) models. RESULT: For meloxicam, the IR model predicted the in vivo absorption in the control group after administration of the FD and RR formulations. When gastric dysfunction was induced, the IR model did not predict absorption while the GR model did for both formulations, FD and RR. For ibuprofen, the predictions were also very close for both formulations, using the IR model for the control group and the GR model for the vagally suppressed condition in rats and humans. CONCLUSIONS: Gastric control of the drug release in pain/disease state was identified as the major factor causing the observed differences in the pharmacokinetics. Computer simulations of disease states can be employed to optimize drug release from dosage forms to overcome the reported shortfalls in the drug absorption. PMID- 26752429 TI - Characterization of infectious dose and lethal dose of two strains of infectious hematopoietic necrosis virus (IHNV). AB - The ability to infect a host is a key trait of a virus, and differences in infectivity could put one virus at an evolutionary advantage over another. In this study we have quantified the infectivity of two strains of infectious hematopoietic necrosis virus (IHNV) that are known to differ in fitness and virulence. By exposing juvenile rainbow trout (Oncorhynchus mykiss) hosts to a wide range of virus doses, we were able to calculate the infectious dose in terms of ID50 values for the two genotypes. Lethal dose experiments were also conducted to confirm the virulence difference between the two virus genotypes, using a range of virus doses and holding fish either in isolation or in batch so as to calculate LD50 values. We found that infectivity is positively correlated with virulence, with the more virulent genotype having higher infectivity. Additionally, infectivity increases more steeply over a short range of doses compared to virulence, which has a shallower increase. We also examined the data using models of virion interaction and found no evidence to suggest that virions have either an antagonistic or a synergistic effect on each other, supporting the independent action hypothesis in the process of IHNV infection of rainbow trout. PMID- 26752430 TI - Gender-sensitive and youth-friendly physiotherapy: Steps toward a stress management intervention for girls and young women. AB - This article describes and evaluates initial steps of a gender-sensitive, youth friendly group intervention model designed for teenage girls and young women who experience stress-related or psychosomatic problems. Fifty-four young women (16 25 years of age) participated in a gender-sensitive physiotherapy stress management course at a youth health center. Inclusion criteria were self-defined stress-related problems and a wish to participate in the group intervention. Measurements of aspects of body perception, self-image, multiple somatic problems, and mental health symptom areas were assessed both before and after intervention with the Body Perception Questionnaire ad modum Schioler, social analysis of social behavior, and Adult Self-Report scale. Significant positive changes were found in aspects of body perception, self-image, and mental health and somatic symptoms. The changes were most significant in lower internalization of anxiety and depression symptoms. Symptoms such as headaches and sleeping problems decreased. Participants were more satisfied with their bodies and more able to listen to body signals. Among cognitive issues, significant change occurred in thought problems, but not in attention problems. The intervention model needs further evaluation in controlled trials, but is promising and should be developed further in other physiotherapy settings and subgroups of young people. PMID- 26752431 TI - Green synthesis of the Pd nanoparticles supported on reduced graphene oxide using barberry fruit extract and its application as a recyclable and heterogeneous catalyst for the reduction of nitroarenes. AB - Through this manuscript the green synthesis of palladium nanoparticles supported on reduced graphene oxide (Pd NPs/RGO) under the mild conditions through reduction of the graphene oxide and Pd(2+) ions using barberry fruit extract as reducing and stabilizing agent is reported. The as-prepared Pd NPs/RGO was characterized by UV-vis spectroscopy, X-ray diffraction (XRD), Fourier transformed infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy (EDS). The Pd NPs/RGO could be used as an efficient and heterogeneous catalyst for reduction of nitroarenes using sodium borohydride in an environmental friendly medium. Excellent yields of products were obtained with a wide range of substrates and the catalyst was recycled multiple times without any significant loss of its catalytic activity. PMID- 26752433 TI - Controlling the phase structures of polymer/surfactant complexes by changing macromolecular architecture and adding n-alcohols. AB - Phase behavior of complex salts formed by a cationic surfactant and different ethoxylated polyions was investigated in water and with addition of two n alcohols of different chain lengths: n-butanol and n-decanol. The polyion possesses a main chain of methacrylic acid randomly grafted with oligo(ethylene oxide) chains. Strong electrostatic interaction between the anionic main chain and the cationic surfactant hexadecyltrimethylammonium (C16TA) leads to the formation of C16TAP(MA-MAEO(n)) x:y complex salts. Modifications in polyion structure, such as changes in the proportion of grafted comonomers and in the side chain length caused differences in the overall balance of interactions with water and n-alcohols, altering the complex salt solubility and, consequently, the formed liquid-crystalline structures. The role of n-decanol as a cosurfactant was verified, but the hydrophilic side chains expanded the capacity of the formed liquid crystalline phases to incorporate water. Additionally, a novel structure, probably cubic bicontinuous (Pn3m), was observed coexisting with lamellar phases at low water concentration. Because n-butanol is known for being a good solvent for poly(ethylene oxide), these side chains intensified the role of this short chain n-alcohol as cosolvent for C16TAP(MA-MAEO(n)) x:y complex salts, favoring the formation of disordered solutions, including a bicontinuous microemulsion. PMID- 26752428 TI - Optic nerve sonography: A noninvasive means of detecting raised intracranial pressure in a resource-limited setting. AB - OBJECTIVE: The aim was to assess the use of optic nerve sonography (ONS) as a quick, noninvasive diagnostic test tool for detecting raised the intracranial pressure (ICP). MATERIALS AND METHODS: A prospective blinded observational study was conducted at Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile-Ife, Nigeria. The study population consisted of 160 adult patients referred to the radiology department for cranial computed tomography (CT) scan. There were 80 subjects and 80 controls. Optic nerve sheath diameter (ONSD) was measured by a radiologist using a 7.5 Megahertz ultrasound probe while cranial CT was reviewed by other radiologists blinded to the ONSD. RESULTS: Sixty-nine subjects (86.3%) had intracranial space occupying lesions (SOL) with cranial CT confirmed features of increased ICP, mean binocular ONSD of 5.7 +/- 0.59 mm while 11 (13.7%) had intracranial SOL without any cranial CT evidence of increased ICP, mean binocular ONSD of 4.8 +/- 0.39 mm. The difference of mean ONSD of the two groups was statistically significant (P = 0.0001). The controls had a mean binocular ONSD of 4.5 +/- 0.22 mm and the difference in mean binocular ONSD for subjects with raised ICP and the controls were also statistically significant (P = 0.0001). A cut-off value of 5.2 mm (sensitivity 81.2% [95% confidence interval (CI): 69.9 89.6], specificity 100% [95% CI: 71.5-100]) was obtained from the receiver operator characteristics curve as the mean binocular ONSD that best predicts raised ICP confirmed by at least a sign on cranial CT. CONCLUSIONS: Optic nerve sonography can differentiate between normal and elevated ICP and may serve as a useful screening tool in resource-limited practice. PMID- 26752432 TI - Organogels based on 12-hydroxy stearic acid as a leitmotif: Dependence of gelation properties on chemical modifications. AB - Various compounds based on the structural leitmotif of 12-hydroxy stearic acid (HSA) were studied with respect to their ability to form organogels. They were modified by ethoxylation in order to avoid the acid group of HSA, which is unwanted for many of the applications of organogels. In this paper, it is shown that the rheological performance of organogels depends strongly on the extent of ethoxylation, exhibiting an optimum at intermediate degrees of ethoxylation. Furthermore, we reveal that the ability for gelation as well as the mechanical properties are substantially reduced by the presence of stearic acid (SA) in the original reaction mixture, which is a typical contamination of HSA. This is quantified by the amount of gelator required for gelation and the elastic moduli observed for the gels. At the same time the mesoscopic structure, as probed by small-angle neutron scattering (SANS), is almost unchanged for different degrees of ethoxylation or the addition of SA--and similarly thick fibres are observed, while the viscoelastic parameters evolve. Accordingly the elastic efficiency of the individual structural units is responsible for the observed changes in the gelation properties. These findings are relevant for the application of such low molecular weight organogelators in practical formulations, as one can optimise the rheological properties of organogelators by appropriately choosing the degree of ethoxylation. PMID- 26752434 TI - Enhanced photocatalytic performance in Bi2WO6/SnS heterostructures: Facile synthesis, influencing factors and mechanism of the photocatalytic process. AB - Highly-efficient photocatalyst based on Bi2WO6/SnS heterostructure was prepared via a surface functionalization method using 3-mercaptopropionic (MPA) as the surface functionalizing agent. Compared to bare Bi2WO6 and SnS nanoparticles, the as-formed Bi2WO6/SnS heterostructure exhibits enhanced photocatalytic activity for the degradation of Rhodamine B (Rh B). Photoluminescence and photocurrent measurements demonstrate that the enhanced photocatalytic activity during the photocatalytic process is closely related to the enhanced electron-hole separation efficiency. The photocatalytic activity of the as-formed Bi2WO6/SnS heterostructure can be perfectly remained even after being used for five times, showing excellent durability during the photocatalytic process. The influence of pH and inorganic ions are systematically investigated. And the optimum pH for the photocatalytic process is determined to be 6. The addition of chloride ion will exert negative effect on the photodegradation process of Rh B. The mechanism of photodegradation process was investigated by exploring the quenching effects of different scavengers and the results suggest that the reactive holes play the major role in the photodegradation process of Rh B. PMID- 26752435 TI - Physiological and biochemical characterisation of watered and drought-stressed barley mutants in the HvDWARF gene encoding C6-oxidase involved in brassinosteroid biosynthesis. AB - Brassinosteroids (BR) are plant steroid hormones that were discovered more than thirty years ago, but their physiological function has yet to be fully explained. The aim of the study was to answer the question of whether/how disturbances in the production of BR in barley affects the plant's metabolism and development under conditions of optimal watering and drought. Mutants with an impaired production of BR are one of the best tools in research aimed at understanding the mechanisms of action of these hormones. The study used barley cultivars with a normal BR synthesis (wild type) and semi-dwarf allelic mutants with an impaired activity of C6-oxidase (mutation in HvDWARF), which resulted in a decreased BR synthesis. Half of the plants were subjected to drought stress in the seedling stage and the other half were watered optimally. Plants with impaired BR production were characterised by a lower height and developmental retardation. Under both optimal watering and drought, BR synthesis disorders caused the reduced production of ABA and cytokinins, but not auxins. The BR mutants also produced less osmoprotectant (proline). The optimally watered and drought stressed mutants accumulated less sucrose, which was accompanied by changes in the production of other soluble sugars. The increased content of fructooligosaccharide (kestose) in optimally watered mutants would suggest that BR is a negative regulator of kestose production. The decreased level of nystose in the drought-stressed mutants also suggests BR involvement in the regulation of the production of this fructooligosaccharide. The accumulation of the transcripts of genes associated with stress response (hsp90) was lower in the watered and drought-stressed BR-deficient mutants. In turn, the lower efficiency of photosystem II and the net photosynthetic rate in mutants was revealed only under drought conditions. The presented research allows for the physiological and biochemical traits of two BR-barley mutants to be characterised, which helps BR function to be understood. The knowledge can also be a good starting point for some breeding companies that are interested in introducing new semi-dwarf barley cultivars. PMID- 26752436 TI - Hepatitis E Virus Seroprevalence in Free-Ranging Deer in Canada. AB - Hepatitis E virus infection (HEV) is an important public health concern not only in traditional endemic areas, but also in some industrialized countries where both domesticated and wild animals have been recognized as potential zoonotic reservoirs implicated in HEV transmission. While the prevalence of infection in the deer population in Europe and Asia has been thoroughly investigated, it remains largely undetermined in North America. We assessed the presence of HEV in three different species of free-range deer in Canada. The seroprevalence of HEV among deer in Canada was 8.8% in white-tailed deer, 4.5% in mule deer and 3.2% in caribou. Hepatitis E virus RNA was not detected. Overall, data indicate that HEV infection occurs in deer in Canada. The absence of viraemia and the low seroprevalence especially in barren-ground caribou which is an important part of the diet in many northern communities suggests that the risk of zoonotic transmission may be less pronounced compared to other countries. PMID- 26752437 TI - Finite-time stabilization control for discontinuous time-delayed networks: New switching design. AB - This paper discusses the finite-time stabilization problem for time-varying delayed neural networks (DNNs) with discontinuous activation functions. By using fixed point theory and set-valued analysis, we establish the existence theorem of equilibrium point. In order to stabilize the states of this class of discontinuous DNNs in finite time, we design two different kinds of switching controllers which are described by discontinuous functions. Under the framework of Filippov solutions, several new and effective criteria are derived to realize finite-time stabilization of discontinuous DNNs based on the famous finite-time stability theory. Besides, the upper bounds of the settling time of stabilization are estimated. Numerical examples are finally provided to illustrate the correctness of the proposed design method and theoretical results. PMID- 26752438 TI - Existence and global exponential stability of periodic solution of memristor based BAM neural networks with time-varying delays. AB - In this paper, we investigate a class of memristor-based BAM neural networks with time-varying delays. Under the framework of Filippov solutions, boundedness and ultimate boundedness of solutions of memristor-based BAM neural networks are guaranteed by Chain rule and inequalities technique. Moreover, a new method involving Yoshizawa-like theorem is favorably employed to acquire the existence of periodic solution. By applying the theory of set-valued maps and functional differential inclusions, an available Lyapunov functional and some new testable algebraic criteria are derived for ensuring the uniqueness and global exponential stability of periodic solution of memristor-based BAM neural networks. The obtained results expand and complement some previous work on memristor-based BAM neural networks. Finally, a numerical example is provided to show the applicability and effectiveness of our theoretical results. PMID- 26752439 TI - Intergenerational continuity of adverse childhood experiences in homeless families: Unpacking exposure to maltreatment versus family dysfunction. AB - Despite the expanding research on adverse childhood experiences (ACEs) and corpus of studies on intergenerational maltreatment in high-risk families, studies have not examined intergenerational ACEs more broadly, much less in severely disadvantaged families. This study investigated the intergenerational continuity of ACEs in mothers and young children aged 4 to 6 years living in emergency homeless shelters. It also examined whether unpacking ACEs into categories of exposure to maltreatment versus family dysfunction affected intergenerational continuity patterns or child socioemotional problems in school. Negative parenting, in the form of observed inept coercive discipline with children, and cumulative sociodemographic risk were examined as additional predictors of child ACEs and socioemotional problems. Mothers (N = 95; aged 20-45; 64.2% African American, 3.2% African Native, 11.6% Caucasian, 7.4% biracial/multiracial, and 13.6% other) completed questionnaires on parent and child ACEs and cumulative risk factors. They participated in videotaped parent-child interactions rated for observed coercive discipline, and teachers provided reports of children's socioemotional problems. Results indicated that higher parental ACEs predicted higher child ACEs, with higher numbers of parental ACEs in either category (maltreatment or family dysfunction) predicting higher levels of child ACEs in both categories. However, child exposure to maltreatment, but not family dysfunction, significantly predicted elevations in children's socioemotional problems. Findings underscore the role of intergenerational childhood adversity in homeless families and also emphasize that unpacking ACEs in children may illuminate key areas of vulnerability for school adjustment. (PsycINFO Database Record PMID- 26752440 TI - "I used to be an ordinary mom": The maternal identity of mothers of women abused by an intimate partner. AB - Mothers of children who suffer various problems tend to discuss their experience as a crisis in their maternal identity, regardless of whether the children are young or adults. However, the maternal identity of mothers who are aware that their adult daughters are being abused has not yet been explored. This study aims to examine the construction of the maternal identity by Israeli women whose grown daughters have been subjected to intimate partner violence (IPV), in the light of cultural representations of motherhood and domestic violence (DV). Thematic discourse analysis of in-depth interviews with 11 mothers identified discursive strategies that they used to negotiate a troubled maternal identity following their daughters' IPV experience. The mothers asserted a positive maternal identity by referring to common discourses about DV and motherhood, in a bid to bolster their "good mother" identity, to reframe motherhood, and to assign responsibility for the abuse to the abuser, to their daughters, or to the patriarchal social structure. The implications of these findings for motherhood and maternal identity theories and for professionals working in the field of DV are discussed. (PsycINFO Database Record PMID- 26752441 TI - Actors, observers, and causal attributions of homelessness: Differences in attribution for the causes of homelessness among domiciled and homeless people in Madrid (Spain). AB - The study analyzes the differences in causal attributions of homelessness and attributions of responsibility among the members of 3 groups: homeless group, consisting of a representative sample of homeless people in Madrid, Spain (n = 188); domiciled service-users group, consisting of people at risk of homelessness (n = 164); and domiciled nonservice-users group, consisting of people at no imminent risk of homelessness (n = 180). The domiciled service-users group and domiciled nonservice-users group were matched to the homeless group or sex, age, and nationality. The article also analyzes homeless people's causal attributions as regards their own situation. The results show that compared with the domiciled nonservice-users group, a higher percentage of members of the homeless group and domiciled service-users group attributed homelessness to individualistic causes and they blamed homeless people for their situation to a greater extent. The results also show that there was no "actor-observer bias" in causal attributions for homelessness in Madrid. (PsycINFO Database Record PMID- 26752442 TI - Associations of adult separation anxiety disorder with conflict-related trauma, ongoing adversity, and the psychosocial disruptions of mass conflict among West Papuan refugees. AB - Refugees commonly experience traumatic events that threaten the self and close others, suggesting the possibility that they may experience overlapping symptoms of posttraumatic stress disorder (PTSD) and separation anxiety disorder (SAD). We examine this possibility among West Papua refugees (n = 230) displaced to Port Moresby, Papua New Guinea. We also examine associations between the combined PTSD SAD construct and indices of past trauma exposure, ongoing adversity, and the psychosocial disruptions caused by mass conflict and displacement. We applied culturally adapted interview modules to assess symptoms of PTSD, SAD, traumatic events (TEs), ongoing adversity, and 5 psychosocial dimensions. Latent class analysis identified a PTSD class (23%), a posttraumatic (PT) SAD class (22%), and a low-symptom class (55%). Compared with the low-symptom class, both the PTSD and PT-SAD classes endorsed higher levels of exposure to all domains of TEs (conflict related trauma, witnessing murder, childhood related adversities, traumatic losses, and health stress) and ongoing adversity (access to health care, displacement/separation, safety in the community, and access to basic needs), but the 2 comorbid groups did not differ on these indices. The PT-SAD class alone scored higher than the low-symptom reference class in relation to disruptions to the psychosocial domains (safety/security, bonds/network, access to justice, roles/identities, existential meaning) and higher than the PTSD class on safety/security, justice and roles/identities. Our findings suggest that the PT SAD pattern may represent a response to the most severe forms of psychosocial disruptions of mass conflict among refugees. A focus on separation anxiety may enhance psychotherapies designed to treat PTSD in refugees. (PsycINFO Database Record PMID- 26752443 TI - Andrew Carnegie and Bill Gates: Philanthropy and oligarchy, then and now. PMID- 26752444 TI - The increasing impact of socioeconomics and race on standardized academic test scores across elementary, middle, and high school. AB - For students and schools, the current policy is to measure success via standardized testing. Yet the immutable factors of socioeconomic status (SES) and race have, consistently, been implicated in fostering an achievement gap. The current study explores, at the school-level, the impact of these factors on test scores. Percentage of students proficient for Language and Math was analyzed from 452 schools across the state of New Jersey. By high school, 52% of the variance in Language and 59% in Math test scores can be accounted for by SES and racial factors. At this level, a 1% increase in school minority population corresponds to a 0.19 decrease in percent Language proficient and 0.33 decrease for Math. These results have significant implications as they suggest that school-level interventions to improve academic achievement scores will be stymied by socioeconomic and racial factors and efforts to improve the achievement gap via testing have largely measured it. PMID- 26752445 TI - Profiles of bullying victimization, discrimination, social support, and school safety: Links with Latino/a youth acculturation, gender, depressive symptoms, and cigarette use. AB - Latino/a youth are at risk for symptoms of depression and cigarette smoking but this risk varies by acculturation and gender. To understand why some youth are at greater risk than others, we identified profiles of diverse community experiences (perceived discrimination, bullying victimization, social support, perceived school safety) and examined associations between profiles of community experience and depressive symptoms, cigarette smoking, acculturation, and gender. Data came from Project Red (Reteniendo y Entendiendo Diversidad para Salud), a school-based longitudinal study of acculturation among 1,919 Latino/a adolescents (52% female; 84% 14 years old; 87% U.S. born). Latent profile analysis (LPA) revealed 4 distinct profiles of community experience that varied by gender and acculturation. Boys were overrepresented in profile groups with high perceived discrimination, some bullying, and lack of positive experiences, while girls were overrepresented in groups with high bullying victimization in the absence and presence of other community experiences. Youth low on both U.S. and Latino/a cultural orientation described high perceived discrimination and lacked positive experiences, and were predominantly male. Profiles characterized by high perceived discrimination and /or high bullying victimization in the absence of positive experiences had higher levels of depressive symptoms and higher risk of smoking, relative to the other groups. Findings suggest that acculturation comes with diverse community experiences that vary by gender and relate to smoking and depression risk. Results from this research can inform the development of tailored intervention and prevention strategies to reduce depression and/or smoking for Latino/a youth. PMID- 26752448 TI - Cancer Triptych. AB - The author uses personal narrative to show how the cold cloak of cancer covered her family during the polar vortex of 2013-2014. The use of a triptych form hinges together related themes of containment, coping, communicative responses, and social support after a cancer diagnosis. This narrative demonstrates the multiple responses and communicative coping strategies to a cancer diagnosis. PMID- 26752446 TI - Suicidality and sexual orientation: Characteristics of symptom severity, disclosure, and timing across the life course. AB - This investigation explored suicide-related characteristics and help-seeking behavior by sexual orientation. Population-based data are from the California Quality of Life Surveys, which included 1,478 sexual minority (lesbian, gay, bisexual, and homosexually experienced individuals) and 3,465 heterosexual individuals. Bisexual women had a nearly six-fold increased risk of lifetime suicide attempts than heterosexual women (RR = 5.88, 95%CI: 3.89-8.90), and homosexually experienced men had almost 7 times higher risk of lifetime suicide attempts than heterosexual men (RR = 6.93, 95%CI: 3.65-13.15). Sexual minority men and women were more likely than heterosexual men and women to have disclosed suicide attempts to a medical professional (RR = 1.48 and RR = 1.44, respectively). Among persons who ever attempted suicide, sexual minority women had a younger age of index attempt than heterosexual women (15.9 vs. 19.6 years of age, respectively). Healthcare professionals should be aware of suicidal risk heterogeneity among sexual minority individuals, including vulnerable points of risk and evidenced-based treatments. PMID- 26752449 TI - Brain CT to Assess Intracranial Pressure in Patients with Traumatic Brain Injury. AB - INTRODUCTION: Morphologic features of computed tomography (CT) scans of the brain can be used to estimate intracranial pressure (ICP) via an image-processing algorithm. Clinically, such estimations can be used to prognosticate outcomes and avoid placement of invasive intracranial monitors in certain patients with severe traumatic brain injury. Features on a CT scan that may correlate with measurements of low ICP are sought. METHODS: A measure is proposed that is a function of the distribution of cerebrospinal fluid (CSF) in and around the brain. In our method, we present an algorithm that semiautomatically segments brain parenchyma from CSF, and apply standard image processing calculations. The ratio of CSF volume to the size of the intracranial vault (ICV) or volume inside the skull, csf(v) /icv(v) is calculated and then plotted against the actual recorded ICP, yielding a relationship between the image features and ICP. RESULTS: We analyzed a total of 45 scans from 20 patients with severe traumatic brain injury (TBI). We showed that a ratio csf(v)/icv(v) > .034 correlates with an ICP < 20 mmHg (P = .0046). For csf(v)/icv(v) <= .034, a distinction between low and high ICP cannot be effectively estimated by this univariate measure. CONCLUSION: This method permits a noninvasive means of identifying patients who are low risk for having elevated ICP; by following Brain Trauma Foundation guidelines strictly such a patient may be subjected to an unnecessary, invasive procedure. This work is a promising pilot study that will need to be analyzed for a larger population. PMID- 26752447 TI - Social support networks among diverse sexual minority populations. AB - This article reports a study of the function and composition of social support networks among diverse lesbian, gay, and bisexual (LGB) men and women (n = 396) in comparison to their heterosexual peers (n = 128). Data were collected using a structured social support network matrix in a community sample recruited in New York City. Our findings show that gay and bisexual men may rely on "chosen families" more than lesbian and bisexual women. Both heterosexuals and LGBs relied less on family and more on other people (e.g., friends, coworkers) for everyday social support (e.g., recreational and social activities, talking about problems). Providers of everyday social support were most often of the same sexual orientation and race/ethnicity as participants. In seeking major support (e.g., borrowing large sums of money), heterosexual men and women along with lesbian and bisexual women relied primarily on their families, but gay and bisexual men relied primarily on other LGB individuals. Racial/ethnic minority LGBs relied on LGB similar others at the same rate as did White LGBs but, notably, racial/ethnic minority LGBs reported receiving fewer dimensions of support. PMID- 26752453 TI - Shape selective properties of the Al-fumarate metal-organic framework in the adsorption and separation of n-alkanes, iso-alkanes, cyclo-alkanes and aromatic hydrocarbons. AB - The primary goal of this work is to study the adsorption of a wide range of hydrocarbon adsorbates in the Al-fumarate metal-organic framework in order to identify and explore trends in adsorption behaviour that can be related to the sorbate's molecular properties and as well as the properties of this MOF. The pulse chromatographic technique was used to study the adsorption properties of C5 C8 linear, branched, cyclic and aromatic hydrocarbons in vapour phase at low coverage and at high temperatures (150-250 degrees C). Chromatograms of alkanes having the same number of carbon atoms (C5-C8) clearly show that the linear alkane is retained the longest over its branched and cyclic isomers. Moreover, xylene isomers are also clearly separated by Al-fumarate, with retention times increasing in the order: ortho-xylene < meta-xylene < para-xylene. Differences in adsorption enthalpy of more than 10 kJ mol(-1) between linear alkanes and their di/tri-branched or cyclo-alkane isomers were observed, clearly showing that steric effects imposed by the pore structure of the adsorbent cause the difference in adsorption between linear alkanes and their isomers. In conclusion, Al-fumarate behaves as a shape selective material with respect to structural isomers of linear alkanes, with properties resembling those of medium pore size zeolites. PMID- 26752450 TI - Neural basis of understanding communicative actions: Changes associated with knowing the actor's intention and the meanings of the actions. AB - People can communicate by using hand actions, e.g., signs. Understanding communicative actions requires that the observer knows that the actor has an intention to communicate and the meanings of the actions. Here, we investigated how this prior knowledge affects processing of observed actions. We used functional MRI to determine changes in action processing when non-signers were told that the observed actions are communicative (i.e., signs) and learned the meanings of half of the actions. Processing of hand actions activated the left and right inferior frontal gyrus (IFG, BA 44 and 45) when the communicative intention of the actor was known, even when the meanings of the actions remained unknown. These regions were not active when the observers did not know about the communicative nature of the hand actions. These findings suggest that the left and right IFG play a role in understanding the intention of the actor, but do not process visuospatial features of the communicative actions. Knowing the meanings of the hand actions further enhanced activity in the anterior part of the IFG (BA 45), the inferior parietal lobule and posterior inferior and middle temporal gyri in the left hemisphere. These left-hemisphere language regions could provide a link between meanings and observed actions. In sum, the findings provide evidence for the segregation of the networks involved in the neural processing of visuospatial features of communicative hand actions and those involved in understanding the actor's intention and the meanings of the actions. PMID- 26752451 TI - Early neurophysiological indices of second language morphosyntax learning. AB - Humans show variable degrees of success in acquiring a second language (L2). In many cases, morphological and syntactic knowledge remain deficient, although some learners succeed in reaching nativelike levels, even if they begin acquiring their L2 relatively late. In this study, we use psycholinguistic, online language proficiency tests and a neurophysiological index of syntactic processing, the syntactic mismatch negativity (sMMN) to local agreement violations, to compare behavioural and neurophysiological markers of grammar processing between native speakers (NS) of English and non-native speakers (NNS). Variable grammar proficiency was measured by psycholinguistic tests. When NS heard ungrammatical word sequences lacking agreement between subject and verb (e.g. *we kicks), the MMN was enhanced compared with syntactically legal sentences (e.g. he kicks). More proficient NNS also showed this difference, but less proficient NNS did not. The main cortical sources of the MMN responses were localised in bilateral superior temporal areas, where, crucially, source strength of grammar-related neuronal activity correlated significantly with grammatical proficiency of individual L2 speakers as revealed by the psycholinguistic tests. As our results show similar, early MMN indices to morpho-syntactic agreement violations among both native speakers and non-native speakers with high grammar proficiency, they appear consistent with the use of similar brain mechanisms for at least certain aspects of L1 and L2 grammars. PMID- 26752454 TI - E-cigarette use in young Swiss men: is vaping an effective way of reducing or quitting smoking? AB - QUESTION UNDER STUDY: To test longitudinally differences in conventional cigarette use (cigarettes smoked, cessation, quit attempts) between vapers and nonvapers. METHODS: Fifteen months follow-up of a sample of 5 128 20-year-old Swiss men. The onset of conventional cigarette (CC) use among nonsmokers, and smoking cessation, quit attempts, changes in the number of CCs smoked among smokers at baseline were compared between vapers and nonvapers at follow-up, adjusted for nicotine dependence. RESULTS: Among baseline nonsmokers, vapers were more likely to start smoking at follow-up than nonvapers (odds ratio [OR] 6.02, 95% confidence interval [CI] 2.81, 12.88 for becoming occasional smokers, and OR = 12.69, 95% CI 4.00, 40.28 for becoming daily smokers). Vapers reported lower smoking cessation rates among occasional smokers at baseline (OR = 0.43 (0.19, 0.96); daily smokers: OR = 0.42 [0.15, 1.18]). Vapers compared with nonvapers were heavier CC users (62.53 vs 18.10 cigarettes per week, p <0.001) and had higher nicotine dependence levels (2.16 vs 0.75, p <0.001) at baseline. The number of CCs smoked increased between baseline and follow-up among occasional smokers (b = 6.06, 95% CI 4.44, 7.68) and decreased among daily smokers (b = 5.03, 95% CI -8.69, -1.38), but there were no differential changes between vapers and nonvapers. Vapers showed more quit attempts at follow-up compared with nonvapers for baseline occasional smokers (incidence rate ratio [IRR] 1.81, 95% CI 1.24, 2.64; daily smokers IRR 1.28, 95% CI 0.95, 1.73). CONCLUSIONS: We found no beneficial effects of vaping at follow-up for either smoking cessation or smoking reduction. PMID- 26752455 TI - Clinical Characteristics and Treatment Outcome of Chinese Patients With Systemic Amyloid Light-Chain Amyloidosis: A Retrospective Single-Center Analysis. AB - BACKGROUND: Amyloid light-chain (AL) amyloidosis is a disease caused by tissue deposition of light-chain proteins in vital organs that results in progressive organ damage. We analyzed the clinical characteristics of 123 AL amyloidosis patients and performed an overall survival (OS) analysis to identify critical baseline factors. PATIENTS AND METHODS: Patients (median age, 54 years) were diagnosed with organ involvement of kidney (98.4%), gastrointestinal (73%), cardiac (56%), liver (13%), or nervous system (10%), and multiorgan involvement was observed in 91% of patients. Treatment regimens of transplantation, bortezomib plus dexamethasone, melphalan plus dexamethasone, and prednisone-based regimens or no treatment resulted in 3-year OS rates of 72%, 60%, 55%, and 41%, respectively. RESULTS: Median OS was 38 months and was affected by age (>= 65 years), hypoalbuminemia, renal failure, heart involvement, and organ response time (within 3 months). Multivariate analysis indicated that these were independent prognostic factors on OS except for age. CONCLUSION: The AL amyloidosis patients in this study presented somewhat different features and outcomes compared to others, with younger age and higher rates of organ involvement. PMID- 26752457 TI - Nexus between preventive policy inadequacies, workplace bullying, and mental health: Qualitative findings from the experiences of Australian public sector employees. AB - Public sector organizations have been shown to have high levels of workplace bullying, despite widespread adoption of zero-tolerance policy. Given the level of harm that stems from bullying, it has been suggested that it might be one of the most serious problems facing modern organizations. The qualitative findings from a large cross sectional study of public servants in Australia are reported in the present study. The results highlight palpable mental distress and illness stemming from exposure to workplace bullying. This distress was exacerbated by failures in prohibitive workplace procedures. Reporting bullying through formal organization processes did not lead to resolution of the problem; it instead highlighted feelings of powerlessness and mistrust. In light of the findings, we suggest that an alternative discourse is required, one that gives attention to enhancing employee resilience and self-healing behaviours to the emotional trauma of workplaces. Organizations might be better placed investing resources in fostering the resilience and emotional intelligence of their workforce, rather than continuing to invest resources in prohibitive policies that fail to address the problem. Employees should be supported to prioritize responsibility for their own mental health, rather than an overreliance on organizational responses. PMID- 26752458 TI - Self-Catalyzed Assembly of Peptide Scaffolded Nanozyme as a Dynamic Biosensing System. AB - In this work, a new strategy of biosensor design is developed based on the assembly of amyloid beta and its multiple interactions with other bioactive species. These interactions can enable amyloid beta peptide as a multifunctional sensing element, so the immobilization of sensing probe and the step-by-step modification of the sensing interface have all been dispensed with. Instead, the kinetics of the assembly of a peptide-based catalytic network serves to convert the quantity of analyte into amplified signal readout. The designed dynamic assembling and biosensing system has also been successfully applied in detecting the activity of polyglutamylation, an essential post translation modification controlling cell skeleton and cell cycle, in biological complex samples. Further studies reveal that the serum abundance of a polyglutamylase, tubulin tyrosine ligase-like protein 12, may show parallel with the degree of development of prostate cancer and the discrimination between early cancerous development and benign conditions. And the obtained result is more distinct than that based on PSA detection, the current gold standard. This study may also point to the prospective of extending this design strategy to broader range of biosensing applications in the future. PMID- 26752459 TI - In Search for the Optimal Citrate Concentration for Regional Citrate Anticoagulation-Balancing Practical and Safety Aspects. PMID- 26752456 TI - Clofarabine Plus Low-Dose Cytarabine Is as Effective as and Less Toxic Than Intensive Chemotherapy in Elderly AML Patients. AB - INTRODUCTION: Most patients with acute myeloid leukemia (AML) age >= 60 years are not offered intensive induction because of high mortality. Phase 2 studies of clofarabine plus low-dose cytarabine (CLDA) as frontline therapy for elderly AML patients demonstrated high response and acceptable toxicity. PATIENTS AND METHODS: We hypothesized that induction therapy with CLDA provides equivalent outcomes to but is less toxic than intensive induction in these patients. To test this hypothesis, we conducted a propensity score-matched comparison of AML patients age >= 60 years given induction CLDA versus idarubicin and cytarabine (IA). Ninety-five patients in both groups were matched according to their propensity score. RESULTS: We did not observe statistically significant differences in response, overall survival, or mortality rate between the two induction regimens. However, CLDA produced significantly fewer grade 3 or worse toxicities (46% for CLDA vs. 62% for IA; P = .03). Furthermore, among responders, the median response duration was significantly longer with CLDA when we censored patients who underwent stem cell transplantation (15.9 months for CLDA vs. 7.0 months for IA; P = .033). CONCLUSION: Compared with intensive induction, CLDA offers equivalent responses and survival but less toxicity in clinically well matched cohorts of elderly AML patients. Prospective randomized trials to confirm these findings are warranted. PMID- 26752460 TI - Industrial Application of an Improved Multiple Injection and Multiple Staging Combustion Technology in a 600 MWe Supercritical Down-Fired Boiler. AB - To solve the water wall overheating in lower furnace, and further reduce NOx emissions and carbon in fly ash, continuous improvement of the previously proposed multiple injection and multiple staging combustion (MIMSC) technology lies on three aspects: (1) along the furnace arch breadth, changing the previously centralized 12 burner groups into a more uniform pattern with 24 burners; (2) increasing the mass ratio of pulverized coal in fuel-rich flow to that in fuel-lean flow from 6:4 to 9:1; (3) reducing the arch-air momentum by 23% and increasing the tertiary-air momentum by 24%. Industrial-size measurements (i.e., adjusting overfire air (OFA) damper opening of 20-70%) uncovered that, compared with the prior MIMSC technology, the ignition distance of fuel-rich coal/air flow shortened by around 1 m. The gas temperature in the lower furnace was symmetric and higher, the flame kernel moved upward and therefore made the temperature in near-wall region of furnace hopper decrease by about 400 degrees C, the water wall overheating disappeared completely. Under the optimal OFA damper opening (i.e, 55%), NOx emissions and carbon in fly ash attained levels of 589 mg/m(3) at 6% O2 and 6.18%, respectively, achieving NOx and carbon in fly ash significant reduction by 33% and 37%, respectively. PMID- 26752461 TI - NOD2 Loss-of-Function Mutations and Risks of Necrotizing Enterocolitis or Focal Intestinal Perforation in Very Low-birth-weight Infants. AB - BACKGROUND: NOD2 loss-of-function mutations, that is, R702W [rs2066844], G908R [rs2066845], and Leu1007fsinsC [rs5743293], have been linked to inflammatory bowel diseases. It is yet unknown whether these variants are also associated with necrotizing enterocolitis (NEC) or focal intestinal perforation (FIP) in infants of very low birth weight (VLBW). METHODS: To test this hypothesis, we genotyped 9082 VLBW infants with European ancestry enrolled in a prospective, population based cohort study of the German Neonatal Network. We assessed the effect of the NOD2 gene variants on the risk for major morbidities of the gastrointestinal tract, that is, NEC/FIP requiring surgery in multivariable logistic regression analyses. RESULTS: In the whole cohort of VLBW infants, carriers of >= 2 NOD2 variant alleles had an increased risk for NEC requiring surgery (odds ratio [OR], 3.57; 95% confidence interval [CI], 1.27-10.04; P = 0.03) and NEC or FIP requiring surgery (OR, 3.81; 95% CI, 1.70-8.51; P = 0.004) as compared with wild type genotypes. In a multivariable logistic regression analysis including gestational age, birth weight, gender, multiple birth, and inborn delivery, the association between >= 2 NOD2 variant alleles and NEC surgery (OR, 4.14; 95% CI, 1.41-12.12; P = 0.009), FIP surgery (OR, 3.50; 95% CI, 1.02-12.04; P = 0.047), and NEC or FIP surgery (OR, 4.10; 95% CI, 1.74-9.73; P = 0.001) proved to be independent. We also performed a regression analysis in the subgroup of infants with available information on Lactobacillus acidophilus/Bifidobacterium infantis probiotic supplementation (n = 3638). Although probiotics had a protective effect on NEC and NEC or FIP requiring surgery, the NOD2 variants had no significant impact in this subgroup. CONCLUSIONS: VLBW infants carrying >= 2 NOD2 genetic risk factors of inflammatory bowel disease in adults have an increased risk for severe gastrointestinal complications, such as NEC requiring surgery. Therefore, infants might benefit from NOD2 genotyping followed by supplementation with probiotics. Replication studies are needed along with genome-wide arrays to allow risk-adapted prevention and therapeutic strategies. PMID- 26752463 TI - Steroid Administration and Growth Impairment in Children with Crohn's Disease. AB - BACKGROUND: Growth impairment remains a major concern in children with Crohn's disease, but evidence remains unclear, in particular, whether steroid use is implicated. We aimed to (1) determine the frequency of temporary (TGI) and permanent (PGI) growth impairment in children administered steroids and (2) examine whether cumulative steroid administration was associated with TGI and/or PGI. METHODS: A retrospective cohort study was performed in patients with Crohn's disease (<18 yr) administered steroids at the gastroenterology clinics of Sainte Justine Hospital, Montreal. Steroid dosage, height during follow-up, adult height (after age 20), and parental heights were ascertained. Patients with height z score <-1.64 on more than 1 occasion before age 18 were considered as patients with TGI. Patients with adult heights <8.5 cm below the expected target heights were considered as patients with PGI. Association between steroid dosage and TGI/PGI was studied using logistic regression analyses. Data from the Swiss IBD Cohort Study were analyzed for comparison. RESULTS: A total of 221 children were studied. Approximately 19% (42/221) children were deemed as TGI, and 8/137 patients (5.8%) had PGI. TGI was associated with diagnosis at younger age (P value 0.002) and steroid administration at younger age (P value 0.001), but not with steroid dosage. Final adult height was associated with target height, but not with cumulative steroid dosage. Rates of PGI in the Swiss cohort were ~ 9.1% in steroid users and 2.7% in nonusers. CONCLUSIONS: Most children with TGI attain normal adult heights. Cumulative steroid use does not seem to be associated with either TGI or PGI in children with Crohn's disease. PMID- 26752462 TI - Distinct Microbiotas are Associated with Ileum-Restricted and Colon-Involving Crohn's Disease. AB - BACKGROUND: The etiology of inflammatory bowel disease is believed to involve a shift in the microbiota toward more proinflammatory species. Crohn's disease (CD) usually manifests as one of three phenotypes, involving inflammation of the terminal ileum, the colon, or both. However, what determines the particular phenotype and the level of disease activity remains unknown. In this study, we aim to characterize the intestinal microbiota associated with different CD phenotypes. METHODS: DNA was extracted from biopsies of 31 patients with ileal, ileocolic, or colon-restricted CD, and also from 5 non-inflammatory bowel disease control subjects, and analyzed by 16S rRNA gene amplicon pyrosequencing. Data were processed using the Quantitative Insights Into Microbial Ecology pipeline and analyzed using linear discriminant analysis with effect size estimation and PICRUSt algorithms. Two additional recently published cohorts were also analyzed in this study. RESULTS: Highly significant separation was observed between bacterial composition of ileal CD compared with CD with colonic involvement (genus level Bray-Curtis P = 0.005, R = 20%). This separation was unaffected by the biopsy's location or its inflammatory state, or by the patients' condition (remission or relapse). Faecalibacterium was strongly reduced in ileal CD compared with CD with colonic involvement, whereas Enterobacteriaceae were more abundant in the former. Fusobacterium relative abundance was strongly correlated with disease activity in patients with ileal-involving, but not in colon involving, CD. CONCLUSIONS: Ileal and colon-involving CD sustain distinct microbiotas, suggesting that different mechanisms underlie the two major manifestations of CD. The potential contribution of Fusobacterium to inflammation in ileal CD should be further investigated. PMID- 26752464 TI - Current Transition Practices in Pediatric IBD: Findings from a National Survey of Pediatric Providers. AB - BACKGROUND: Although practice guidelines have been published for transition to adult care among general chronic illness populations and specific to pediatric inflammatory bowel disease (IBD), little is known about current transition practices in IBD care. This study presents data characterizing current transition practices as reported by a national sample of pediatric providers in the United States. METHODS: One hundred forty-one pediatric providers completed an online survey designed to assess current transition practices, barriers and challenges to developing and maintaining transition programming, and desired resources to improve transition services. RESULTS: Practices varied greatly in terms of when providers begin discussing transition and transfer, age at transfer to adult care, and patient supports provided to facilitate transition. Multiple disciplines were often involved in transition programming and 75.9% reported using objective assessment of patient transition readiness. Knowledge and application of published transition practice guidelines was limited, and few respondents reported having a written transition policy at their institution (14.2%). 99.3% of respondents reported barriers to their transition programming efforts. Additional time and instrumental supports were the most common desired resources to support transition efforts. CONCLUSIONS: Variability in IBD transition programming, practices, and policies reflect the emerging nature of clinical practice in this area. Understanding the current state of transition programming can inform future programming. Efforts to identify evidence-based practices in transition to adult care are needed. PMID- 26752465 TI - Increased Expression of Interleukin-36, a Member of the Interleukin-1 Cytokine Family, in Inflammatory Bowel Disease. AB - BACKGROUND: Interleukin (IL)-36 (IL-36alpha, IL-36beta, and IL-36gamma) is a recently reported member of the IL-1 cytokine family. In this study, we investigated IL-36 expression in the inflamed mucosa of patients with inflammatory bowel disease and characterized the proinflammatory actions of IL-36 cytokines in human colonic epithelial cells. METHODS: IL-36 mRNA expression was evaluated using real-time PCR. IL-36 protein expression was analyzed using immunoblotting and immunohistochemical technique. Intracellular signaling pathways were evaluated by immunoblotting and by specific siRNA-transfected cells. RESULTS: The mRNA expression of IL-36alpha and IL-36gamma, but not of IL 36beta, was enhanced in the inflamed mucosa of patients with inflammatory bowel disease, in particular, in ulcerative colitis. Immunohistochemical analysis showed that T cells, monocytes, and plasma cells are the source of IL-36alpha and IL-36gamma in colonic mucosa. DNA microarray analysis indicated that IL-36alpha induces the mRNA expression of CXC chemokines and acute phase proteins in intestinal epithelial cell line, HT-29 cells. IL-36alpha and IL-36gamma dose dependently and time-dependently induced the mRNA and protein expression of CXC chemokines (CXCL1, CXCL2, CXCL3 etc.) in HT-29 and Widr cells. Stimulation with IL-36alpha and IL-36gamma assembled MyD88 adaptor proteins (MyD88, TRAF6, IRAK1, and TAK1) into a complex and induced the activation of NF-kappaB and AP-1 and also the phosphorylation of MAPKs. MAPK inhibitors and siRNAs specific for NF kappaB and c-Jun AP-1 significantly reduced IL-36-induced CXC chemokine expression. CONCLUSIONS: IL-36alpha and IL-36gamma may play a proinflammatory role in the pathophysiology of inflammatory bowel disease through induction of CXC chemokines and acute phase proteins. PMID- 26752466 TI - NOD2 Is Regulated By Mir-320 in Physiological Conditions but this Control Is Altered in Inflamed Tissues of Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Large evidence supports the role of microRNAs as new important inflammatory mediators by regulating both the adaptive and innate immunity. In the present study, we speculated that miR-320 controls NOD2 (nucleotide-binding oligomerization domain) expression, because it contains multiple binding sites in the 3'-untranslated region of the gene. NOD2, the first gene associated to increased susceptibility to Crohn's disease, is a cytosolic receptor that senses wall peptides of bacteria and promotes their clearance through initiation of a proinflammatory transcriptional program. This study aims at demonstrating that NOD2 is a target of miR-320 as well as investigating the role of inflammation in modulating the miR-320 control on NOD2 expression and analyzing miR-320 expression in intestinal biopsies of children with inflammatory bowel disease. METHODS: The colonic adenocarcinoma cell line HT29 was used to assess the miR-320 mediated regulation of NOD2 expression. MiR-320 and NOD2 expression were analyzed in mucosal samples of 40 children with inflammatory bowel disease. RESULTS: During inflammation, NOD2 expression is inversely correlated with miR-320 expression in vitro and ex vivo. Exogenous miR-320 transfection in HT29 cells leads to a significant decrease of NOD2 expression, whereas the miR-320 inhibitor transfection leads to increase of NOD2 expression, nuclear translocation of nuclear factor kappaB, and activation of downstream cytokines. CONCLUSIONS: We show for the first time that NOD2 expression is under the control of miR-320. We also show in vitro and ex vivo that inflammation induces a decrease of miR-320 and the latter correlates negatively with NOD2 expression. PMID- 26752467 TI - Pediatric Inflammatory Bowel Disease Among South Asians Living in British Columbia, Canada: A Distinct Clinical Phenotype. AB - BACKGROUND: Inflammatory bowel disease (IBD) incidence is increasing among low risk populations. This study examined a cohort of Canadian South Asian (SA) children with IBD to determine if their disease course differed from non-SA (NSA) children. METHODS: Children of SA ethnicity diagnosed with IBD between 1997 and 2012 were identified and compared with NSA children. Data on duration and the type of presenting symptoms, disease phenotype, corticosteroid exposure (CS), exclusive enteral nutrition use, time to commencement of immunomodulator (IM), biologic therapy, and surgical intervention were extracted. RESULTS: Overall, 160 SA children were identified and compared with 783 NSA patients (Crohn's disease [CD]: 44% versus 72%; ulcerative colitis [UC]: 43% versus 21%; IBD-Unclassified: 13% versus 7%; P < 0.001). SA patients were predominantly second-generation Canadians (92%) and had shorter symptom duration (2 versus 4 months; P < 0.001). SA CD patients were less likely to have a parent with IBD (1% versus 14%; P = 0.003). SA patients had more extensive colonic disease (CD: 55% versus 35%; P = 0.005; UC: 77% versus 58%; P = 0.006); SA CD patients presented with more complicated disease (B2/B3: 39% versus 27%; P = 0.006) and UC patients presented with more severe disease (49% versus 23%; P < 0.001). In SA CD patients, CS use was higher (70% versus 58%; P = 0.045), and IM and biologic therapy were commenced earlier (P = 0.027; P = 0.047). SA UC patients were more likely to need CS and IM (P = 0.024; P < 0.001). CONCLUSIONS: These data describe an ethnically unique clinical phenotype, where SA children have a higher proportion of UC, shorter symptom duration, more extensive colonic disease, and are more likely to require earlier escalation of therapy. PMID- 26752468 TI - Patients with Refractory Crohn's Disease Successfully Treated with Ustekinumab. AB - BACKGROUND: Ustekinumab is a new biologic therapy targeting interleukin-12 and interleukin -23. It is currently approved for the treatment of psoriasis, but clinical trials have shown that it can induce and maintain remission in Crohn's disease (CD). We aim to evaluate effectiveness of ustekinumab in the treatment of CD. METHODS: A retrospective chart review was performed including patients (pts) from 2 academic medical centers with complicated, refractory CD started on ustekinumab between June 2011 and June 2014. Pts were treated based on a novel subcutaneous dosing schedule designed to simulate the intravenous load used in clinical trials. RESULTS: Forty-five pts were treated with ustekinumab during this study period. Of the pts who had clinical parameters available before and after medication start, 46% achieved clinical response (Harvey-Bradshaw index decrease >= 3) and 35% achieved clinical remission (Harvey-Bradshaw index <= 3). Short inflammatory bowel disease questionnaire scores increased significantly (46 [20, 68] to 55 [32, 70], P < 0.05). Erythrocyte sedimentation rate decreased significantly (20 [3, 54] to 12 [0, 42] mm/h, P < 0.05). C-reactive protein decreased significantly (4.9 [0.3, 111] to 3.3 [0.2, 226] mg/L, P < 0.05). Seventy-six percent of patients demonstrated an endoscopic response and 24% achieved complete endoscopic remission. Twelve patients (26%) were hospitalized for IBD-related issues. Four pts had infection-related complications. Six pts (13%) underwent surgery for IBD-related issues. Three pts stopped ustekinumab, 1 for pt preference and 2 for the lack of response. CONCLUSIONS: Using a novel subcutaneous dosing schedule, ustekinumab was successful in improving clinical, laboratory, and endoscopic markers of disease activity in patients with severe, refractory CD. PMID- 26752469 TI - Role of Altered Expression of miR-146a, miR-155, and miR-122 in Pediatric Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Evidence suggests the central role of tumor necrosis factor (TNF) alpha in the pathomechanism of inflammatory bowel disease (IBD); however, its effect on epigenetic factors, including small non-coding microRNAs (miRs), is less known. Our present aim was the comparative investigation of the expression of TNF-alpha and immune response-related miRs in children with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Fresh-frozen (FF) and formalin-fixed, paraffin-embedded (FFPE) biopsies were used to analyze the expression of miR 146a, -155, -122, and TNF-alpha by real-time reverse transcription polymerase chain reaction in macroscopically inflamed (CD: 12 FFPE and 24 FF; UC: 10 FF) and intact (CD: 12 FFPE; 14 FF) colonic biopsies of children with IBD and controls (16 FFPE; 23 FF). The expression of miR-146a, -155, and -122 was also determined in TNF-alpha-treated HT-29 colonic epithelial cells. RESULTS: Increased expression of TNF-alpha was observed in the colonic mucosa of children with CD and UC in comparison with controls. Expression of miR-146a and -155 was higher in the inflamed mucosa of children with CD and UC than in the intact mucosa. Expression of miR-122 elevated in the macroscopically intact colonic regions of CD compared with controls and patients with UC. In HT-29 cells, TNF-alpha treatment increased the expression of miR-146a and -155, but not that of miR-122. CONCLUSIONS: Our results showed altered expression of miR-146a, -155, and -122 in the colonic mucosa of children with IBD and in TNF-alpha-treated colonic epithelial cells. Our data suggest the TNF-alpha-related involvement of these miRs in the pathogenesis of IBD. PMID- 26752471 TI - Preclinical and Undiagnosed Crohn's Disease: The Submerged Iceberg. AB - Little is known on the natural history of Crohn's disease (CD) before diagnosis. By the time the patient is diagnosed, the disease has often produced considerable damage to the intestinal mucosa and sometimes other organs. Such period before diagnosis might involve both a silent and a symptomatic phase. The silent phase, or preclinical CD, might last several years after the biological disease onset. Evidence is accumulating that the symptomatic phase might also go undiagnosed for months or years. In fact, for each established case of CD, there are probably several undiagnosed cases, a classic iceberg phenomenon of disease. Such status quo--lagging behind diagnostic standards for many other diseases--effectively hampers efforts to block disease evolution and the development of complications. This is no longer tenable because CD is a debilitating, severe, and costly affection, whose incidence is rapidly rising worldwide. Here, we will review what is currently known on preclinical and undiagnosed CD and what could be done to improve accuracy and timeliness of diagnosis. PMID- 26752470 TI - Higher Adalimumab Levels Are Associated with Histologic and Endoscopic Remission in Patients with Crohn's Disease and Ulcerative Colitis. AB - BACKGROUND: Optimal levels of adalimumab (ADA) have not been defined according to the ultimate goal of inflammatory bowel disease treatment--histologic and/or endoscopic healing. The aim of this study was to assess the relationship between random serum ADA levels and histologic and endoscopic healing in patients with inflammatory bowel disease. METHODS: This was a cross-sectional study including 66 patients receiving maintenance therapy with ADA for Crohn's disease or ulcerative colitis. ADA levels and anti-adalimumab antibodies (AAA) were measured at the time of colonoscopy. The primary outcome was histologic healing (lack of endoscopic and histologic inflammation) and the secondary outcomes were endoscopic healing and serum levels of C-reactive protein, tumor necrosis factor, ICAM, VCAM, and interleukins 1beta, 6, and 8. RESULTS: Sixty-six patients (59 with Crohn's disease) were included. Mean random ADA levels were significantly lower in patients with histologic and endoscopic inflammation (9.2 [SD: 8.4] versus 14.1 [6.4] MUg/mL, P = 0.03 and 8.5 [SD: 7.8] versus 13.3 [SD: 7.7], P = 0.02, respectively). The ADA level that was best associated with histologic healing was 7.8 MUg/mL (receiver operating characteristic: 0.76 [P = 0.04]), whereas the ADA level that was best associated with endoscopic healing was 7.5 MUg/mL (receiver operating characteristic: 0.73 [P = 0.02]). The presence of AAA was associated with lower random ADA levels (5.7 versus 12.5 MUg/mL, P = 0.002) and higher C-reactive protein levels (30.3 versus 12.0, P = 0.01). CONCLUSIONS: Achievement of histologic and endoscopic healing may require higher levels of ADA than previously described for endoscopic remission. The measurement of random ADA levels and anti-drug antibodies may guide therapy and edify the course of incomplete responses. PMID- 26752472 TI - Telemedicine in Inflammatory Bowel Disease: Opportunity Ahead. PMID- 26752473 TI - Cognitive Behavioral Therapy for IBD. PMID- 26752474 TI - Therapeutic Armamentarium for Stricturing Crohn's Disease: Medical Versus Endoscopic Versus Surgical Approaches. PMID- 26752475 TI - Worsening of Bowel Symptoms Through Diet in Patients With Inflammatory Bowel Disease. PMID- 26752476 TI - Therapeutic Armamentarium for Stricturing Crohn's Disease: Medical Versus Endoscopic Versus Surgical Approaches. PMID- 26752477 TI - Efficient Binding of Heavy Metals by Black Sesame Pigment: Toward Innovative Dietary Strategies To Prevent Bioaccumulation. AB - Black sesame pigment (BSP) was shown to bind lead, cadmium, and mercury at pH 7.0 and to a lower extent at pH 2.0. BSP at 0.05 mg/mL removed the metals at 15 MUM to a significant extent (>65% for cadmium and >90% for mercury and lead), with no changes following simulated digestion. The maximum binding capacities at pH 7.0 were 626.0 mg/g (lead), 42.2 mg/g (cadmium), and 69.3 mg/g (mercury). In the presence of essential metals, such as iron, calcium, and zinc, BSP retained high selectivity toward heavy metals. Model pigments from caffeic acid, ferulic acid, and coniferyl alcohol showed lower or comparable binding ability, suggesting that the marked properties of BSP may result from cooperativity of different sites likely carboxy groups and o-diphenol and guaiacyl functionalities. Direct evidence for the presence of such units was obtained by structural analysis of BSP by solid-state Fourier transform infrared spectroscopy and (13)C nuclear magnetic resonance spectroscopy. PMID- 26752478 TI - A Seamless Navigation to ICD-10-CM for Interventional Pain Physicians: Is a Rude Awakening Avoidable? AB - Since October 1, 2015, the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) was integrated into U.S. medical practices. This monumental transition seemingly occurred rather unceremoniously, despite significant opposition and reservations having been expressed by the provider community. In prior publications, we have described various survival strategies for interventional pain physicians. The regulators and beneficiaries of system-CMS, consultants, and health information technology industry are congratulating themselves for a job well done. Nonetheless, this transition comes at an immeasurable financial and psychological drain on providers. However, a rude awakening may be making its way with expiration of initial concessions from government and private payers.This manuscript provides a template for interventional pain management professionals with multiple steps for seamless navigation, including descriptions of the most commonly used codes, navigation through ICD-10-CM manual, steps for correct coding, and finally, detailed coding descriptions for various interventional techniques. PMID- 26752479 TI - Treatment of Osteoporotic Vertebral Compression Fractures: Applicability of Appropriateness Criteria in Clinical Practice. AB - BACKGROUND: Appropriate treatment choice for osteoporotic vertebral compression fractures (OVCF) is challenging due to patient heterogeneity. Using the RAND/UCLA method, an international multidisciplinary expert panel established patient specific criteria for the choice between non-surgical management (NSM), vertebroplasty (VP), and balloon kyphoplasty (BKP). OBJECTIVES: To assess the applicability of the appropriateness criteria in real-life practice. STUDY DESIGN: Prospective observational study. SETTING: Eight practices of experts who participated in the panel study, including 2 interventional radiologists, one internal medicine specialist, 2 neurosurgeons, and 3 orthopedic/trauma surgeons. Practices were located in Belgium, Germany, Italy, Switzerland, and the United Kingdom. METHODS: Using an online data capture program, participants documented the clinical profile (age, gender, previous VCFs, time since fracture, magnetic resonance imaging (MRI) findings, evolution of symptoms, impact of symptoms on quality of life, spinal deformity, ongoing fracture process, and presence of pulmonary dysfunction) and treatment choice for consecutive patients who consulted them for OVCF. RESULTS: In total 426 patients were included. BKP was the most frequently chosen treatment option (49%), followed by VP (34%) and NSM (14%). When compared with the panel recommendations, inappropriate treatment choices were rare (5% for NSM, 2% for VP, none for BKP). Treatment choice was strongly associated with the clinical variables used in the panel study. Differences in treatment decisions between interventional radiologists and surgeons were largely determined by differences in patient characteristics, with time of clinical presentation being the dominant factor. LIMITATION: The study population was restricted to the practices of the participants of the panel study. CONCLUSION: This international, multi-specialty utilization review showed excellent applicability of, and good adherence with RAND/UCLA-based recommendations on treatment choice in OVCF. PMID- 26752480 TI - A Novel Mini-invasive Approach to the Treatment of Neuropathic Pain: The PENS Study. AB - BACKGROUND: Peripheral neuromodulation is often used as chronic neuropathic pain treatment. Percutaneous electrical nerve stimulation (PENS) is generally utilized with several probes at the same time and repeated treatments. OBJECTIVES: Evaluate the short- and long-term efficacy of a single probe and single shot PENS approach. STUDY DESIGN: Multicenter, prospective, observational study. SETTING: Four Italian pain therapy centers. METHODS: Inclusion criteria were age = 18 and = 80 years, presence of severe peripheral neuropathic pain lasting more than 3 months, localized and refractory to pharmacological therapies. Patients with infection, coagulopathies, psychiatric disorders, pacemakers, or implantable cardiac defibrillators were excluded. PATIENTS: Seventy-six patients (47 women, 29 men), mean age 62 +/- 14 years, affected by neuralgia (21 herpes zoster infection, 31 causalgia, 24 postoperative pain) were enrolled in the study. INTERVENTION: After localization of trigger point and/or allodynic/hyperalgesic area, PENS therapy was achieved with a single 21 gauge conductive probe tunneled percutaneously and a neurostimulator device. MEASUREMENT: Numerical Rating Scale (NRS) and Neuropathic Pain Scale (NPS) were assessed at baseline, 60 minutes after PENS, at one week, after one, 3, and 6 months; perceived health outcome was measured with Euroqol-5 dimension (EQ-5D) questionnaire at baseline and at 6 months. Adverse events and patient satisfaction were reported. RESULTS: NRS and NPS decreased significantly after 60 minutes and the reduction remained constant over time at follow-up. EQ-5D increased significantly with respect to the baseline. Two nonclinically significant adverse events (one contralateral dysestesia and one self-resolving hematoma) were observed. LIMITATIONS: Small sample size and non-randomized observational study; high prevalence of post herpetic and occipital neuralgias. CONCLUSION: PENS therapy produced significant and long-lasting pain relief in chronic peripheral neuropathic pains of different etiology. The present study confirms the feasibility, safety, and repeatability of this minimally invasive technique. PMID- 26752481 TI - Clinical Outcome Following Radiofrequency Denervation for Refractory Sacroiliac Joint Dysfunction Using the Simplicity III Probe: A 12-Month Retrospective Evaluation. AB - BACKGROUND: Sacroiliac joint syndrome (SIJ) is diagnosed in 10% to 25% of cases of lower back pain. The response to traditional radiofrequency (RF) denervation of the SIJ has being inconsistent. The Simplicity III RF probe (Neruotherm. Inc.) offers a novel treatment option. OBJECTIVE: To evaluate the long-term clinical outcome (12 months) refractory SIJ syndrome in terms of pain intensity and functional improvement. A 50% reduction in intensity pain intensity (VAS) at 12 months was deemed clinically significant. STUDY DESIGN: A 12-month retrospective observational evaluation all of adults treated with RF for refractory SIJ. SETTING: Chronic pain management center. METHODS: The medical records of all adults treated with this technique was retrospectively reviewed. The primary outcome was pain intensity scores (VAS) over a 12 months period; Secondary outcomes included Roland-Morris Functional scores (RMF), Brief Pain Inventory (BPI), general health assessment (Sf12), and patient satisfaction scores (GPI), which were recorded pre and post denervation. REULTS: Pain Intensity improved by 4.7 points compared to pre-treatment representing a 61% reduction in pain at 12 months (n=11, P < 0.001). Significant improvements in (a) RMF (P < 0.01, W2 = 0.63 (large effect size); (b) BPI (P < 0.001, W2 = 0.72 (strong effect size); and (c) Sf12 (P < 0.01) were noted. Overall patients were satisfied with the outcome (GPI = 77.7%). LIMITATIONS: The retrospective in nature of the study and the small sample size are limitations. As it was our policy to monitor the progress of the individuals since the introduction of this technique a reliable method of recording the baseline and outcome variables at each point of contact was in place. Access to a complete set of variables in all individuals over a 12-month period was therefore possible, which we feel contributes to the quality of the dataset. CONCLUSION: By creating a consistent radiofrequency lesion between the sacral foramen and the SIJ will reliably capture the innervation to the SIJ with significant long-term clinical improvement. This technique should be considered earlier in the treatment algorithm of individuals suffering from SIJ symptoms. PMID- 26752483 TI - Physician Quality Reporting System (PQRS) for Interventional Pain Management Practices: Challenges and Opportunities. AB - Basing their rationale on multiple publications from Institute of Medicine (IOM), specifically Crossing the Quality Chasm, policy makers have focused on a broad range of issues, including assessment of the influence of medical practice organization structures on quality performance and development of quality measures. The 2006 Tax Relief and Health Care Act established the Physician Quality Reporting System (PQRS), to enable eligible professionals to report health care quality and health outcome information that cannot be obtained from standard Medicare claims. However, the Patient Protection and Affordable Care Act (ACA) of 2010 required the Centers for Medicare and Medicaid Services (CMS) to incorporate a combination of cost and quality into the payment systems for health care as a precursor to value-based payments. The final change to PQRS pending initiation after 2018, is based on the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) which has incorporated alternative payment models and merit based payment systems. Recent publication of quality performance scores by CMS has been less than optimal. When voluntary participation began in July 2007, providers were paid a bonus for reporting quality measures from 2008 through 2014, ranging from 0.5% to 2% of the Medicare Part B allowed charges furnished during the reporting period. Starting in 2015, penalties started for nonparticipation. Eligible professionals and group practices that failed to satisfactorily report data on quality measures during 2014 are subject to a 2% reduction in Medicare fee-for-service amounts for services furnished by the eligible professional or group practice during 2016. The CMS proposed rule for 2016 physician payments contained a number of provisions with proposed updates to the PQRS and Physician Value-Based Payment Modifier among other changes. The proposed rule is the first release since MACRA repealed the sustainable growth rate formula. CMS proposed to continue many existing policies regarding PQRS from 2015 to 2016. In addition, 2016 will be the year that is utilized to determine the 2018 PQRS payment adjustment. However, after 2018 the PQRS payment adjustment will be transitioned to the Merit-Based Incentive Payment System (MIPS), as required by MACRA. Overall, there will be over 280 measures in the 2016 PQRS.Readers might be surprised to find out that despite the cost intensity including time requirements personnel, the negative payment adjustments, are only the tip of the iceberg of cost. Indeed, all of the above may only be one-third or one-fourth of the cost to completely implement the PQRS system. Thus far, data across all specialties shows participation to be around 50%. In addition, penalties for lack of reporting of PQRS measures stands to be controversial to the Supreme Court ruling that unfunded mandates must not be permitted and also lack of significant relationships with improvement in quality in the overall analysis in multiple publications. PMID- 26752482 TI - Subjective Cognitive Symptoms During a Migraine Attack: A Prospective Study of a Clinic-Based Sample. AB - BACKGROUND: A migraine attack aggregates a range of different symptoms, besides pain, that contribute to attack-related disability. Cognitive dysfunction is an unacknowledged part of the migraine attack. OBJECTIVE: To provide a profile of the frequency and character of migraine attack-related cognitive symptoms occurring during the headache phase of the attack. STUDY DESIGN: Cross-sectional survey. SETTING: Clinical-based sample of episodic migraine patients. METHODS: Sequential patients were screened about the occurrence of cognitive symptoms during migraine attacks using an open-ended question followed by a self-fulfilled symptom checklist. RESULTS: Of 165 migraine patients (15 men, age average 37.3 +/ 10.7 years), 89.7% described cognitive symptoms during the headache phase of the migraine attack. On average 2.5 +/- 1.6 symptoms were reported per patient, uninfluenced by demographic or disease-related variables. The most common spontaneous symptoms related to executive functions, such as poor ability to concentrate (37%), difficulty in reasoning (25%), and thinking (23%). The pattern of responses on the symptoms checklist corroborated with those reported spontaneously and quantitative scores of the checklist were higher in patients with spontaneous symptoms. LIMITATIONS: Open-ended questions tend to overestimate frequency; data accuracy may be influenced by the population chosen (clinical based, some using prophylactic treatment). CONCLUSIONS: This study detailed the frequency and characteristics of migraine attack-related subjective cognitive symptoms and found its frequency to be similar to reports of other migraine defining symptoms (ex. nausea, photophobia) in recent clinical series. Patients' reports were consistent and dominated by complaints of attention difficulties, diminished cognitive efficiency, and processing speed impairment. PMID- 26752484 TI - Genotypic Analysis of SCN9A for Prediction of Postoperative Pain in Female Patients Undergoing Gynecological Laparoscopic Surgery. AB - BACKGROUND: The SCN9A gene product is a critical component in human pain perception. Recent studies found that single-nucleotide polymorphisms (SNPs) in this gene contributed to the risk and severity of common pain phenotypes. OBJECTIVES: In this study, we aimed to assess the use of SCN9A SNP screening for predicting postoperative pain. STUDY DESIGN: A retrospective assessment of patients who underwent gynecological laparoscopic surgery. SETTING: Department of anesthesiology, a teaching hospital, in a medical college, major metropolitan city, China. METHODS: Twenty-nine candidate and tag SCN9A SNPs were analyzed in this study. Four hundred twenty-one patients who underwent gynecological laparoscopic surgery and refused postoperative patient controlled analgesia (PCA) were recruited and completed the study protocol. An additional 578 patients who voluntarily received PCA treatment were included for verification. Postoperative pain intensity was evaluated in all patients using numerical rating scale (NRS), and for patients receiving PCA analgesic requirements were also recorded. OUTCOMES ASSESSMENT: The outcome was assessment of postoperative pain NRS and PCA analgesic requirements. RESULTS: Ten different SCN9A SNPs exhibited significant associations with postoperative pain intensity, the incidence of severe postoperative pain, and postoperative PCA requirement. Of the candidate SCN9A SNPs, there was a statistically significant correlation between SNP rs6746030 and higher maximum NRS scores during the postoperative follow-up of non-PCA patients (P < 0.05). Furthermore, there was a significant association between the tag SNP rs4286289 and both increased postoperative maximum NRS scores (P < 0.05) and higher incidences of severe postoperative pain (P < 0.05) in non-PCA patients. Meanwhile, in PCA patients, rs4286289 exhibited the strongest association (P = 0.001) with increased requirements for postoperative analgesics, which indirectly strengthened the significant association between this SNP and higher postoperative pain. LIMITATIONS: The limitations of this study include that it is an assessment of only Chinese women scheduled for gynecological laparoscopic surgery. CONCLUSION: The current study provides evidence that postoperative pain was affected by SCN9A variability in gynecological patients. Notably, our results provide the first indication that SCN9A SNP rs4286289 can be used as a predictor for hypersensitivity to postoperative pain. PMID- 26752485 TI - Musculoskeletal Ultrasonography in CRPS: Assessment of Muscles Before and After Motor Function Recovery with Dry Needling as the Sole Treatment. AB - BACKGROUND: Motor impairment is an important criterion in the Clinical Diagnostic Criteria (CDC) of Complex Regional Pain Syndrome type-1 (CRPS-1) as defined by International Association for Study of Pain (IASP). OBJECTIVE: To describe the changes in musculoskeletal ultrasonography (MSKUSG) in CRPS-1 before and after treatment with ultrasound-guided dry needling (USGDN) in retrospective data from 44 patients. STUDY DESIGN: Patients irrespective of age, gender, or cause of CRPS were included in this retrospective data analysis; the Budapest criteria for the diagnosis of CRPS were stringently adhered to. SETTING: The analysis was done at Ashirvad Institute for Pain Management and Research with the database of CRPS patients who were treated between December 2005 and December 2014. METHODS: The CDC, range of motion at upper extremity joints, dynamometry, Disability of arm, shoulder and hand score (DASH) and ultrasonography were documented on days one, 15, and 45. MSKUSG demonstrated loss of myoarchitecture and reduced bulk. RESULTS: All 44 patients received USGDN as the sole intervention with medications and physiotherapy. MSKUSG at 15 and 45 days after starting USGDN showed a return of normalcy to the myoarchitecture and muscle bulk increase that coincided with the disappearance of CDC and a progressive and predictable improvement of the DASH scores in all the 44 patients. LIMITATION: The analysis focuses on only 2 parameters: the musculoskeletal changes of the forearm flexors and extensors on ultrasound guidance and the efficacy of the dry needling treatment. It is not a comparative study with another accepted form of treatment or intervention. We have not looked into the age and gender predilection of the condition owing to the small sample size of the study. Analysis of long term maintenance of relief and rehabilitation of the disability were limited to one year. CONCLUSION: Myofascial pathology of co-contraction appears to cause CDC of CRPS and probable ischemic loss of myoarchitecture. Relief of co-contraction with USGDN allowed resolution of tenosynovitis causing the CDC and return of normal myoarchitecture. PMID- 26752486 TI - Usefulness of the Brief Pain Inventory in Patients with Opioid Addiction Receiving Methadone Maintenance Treatment. AB - BACKGROUND: Chronic pain is implicated as a risk factor for illicit opioid use among patients with opioid addiction treated with methadone. However, there exists conflicting evidence that supports and refutes this claim. These discrepancies may stem from the large variability in pain measurement reported across studies. OBJECTIVES: We aim to determine the clinical and demographic characteristics of patients reporting pain and evaluate the prognostic value of different pain classification measures in a sample of opioid addiction patients. STUDY DESIGN: Multi-center prospective cohort study. SETTING: Methadone maintenance treatment facilities for managing patients with opioid addiction. METHODS: This study includes participants from the Genetics of Opioid Addiction (GENOA) prospective cohort study. We assessed the prognostic value of different pain measures for predicting opioid relapse. Pain measures include the Brief Pain Inventory (BPI) and patients' response to a direct pain question all study participants were asked from the GENOA case report form (CRF) "are you currently experiencing or have been diagnosed with chronic pain?" Performance characteristics of the GENOA CRF pain measure was estimated with sensitivity and specificity using the BPI as the gold standard reference. Prognostic value was assessed using pain classification as the primary independent variable in an adjusted analysis using 1) the percentage of positive opioid urine screens and 2) high-risk opioid use (= 50% positive opioid urine screens) as the dependent variables in a linear and logistic regression analyses, respectively. RESULTS: Among participants eligible for inclusion (n = 444) the BPI was found to be highly sensitive, classifying a large number of GENOA participants with pain (n = 281 of the 297 classified with pain, 94.6%) in comparison to the GENOA CRF (n = 154 of 297 classified with pain, 51.8%). Participants concordantly classified as having pain according to the GENOA CRF and BPI were found to have an estimated 7.79% increase in positive opioid urine screens (estimated coefficient: 7.79; 95% CI 0.74, 14.85: P = 0.031) and a 4 times greater odds (odds ratio [OR]: 4.10 P = 0.008; 95% CI: 1.44, 11.63) of engaging in a "high risk" level of illicit opioids use. The prognostic relevance of pain classification was not maintained for the additional participants classified by the BPI (n = 143 discordant). CONCLUSION: These results suggest that while the BPI may be more sensitive in capturing pain among patients with opioid addiction, this tool is of less value for predicting the impact of pain on illicit opioid use for opioid addiction patients on methadone maintenance treatment. The GENOA CRF showed high predictive ability, whereby patients classified according to the GENOA CRF are at serious risk for opioid relapse. Using the appropriate tool to assess pain in opioid addiction may serve to improve the current detection and management of comorbid pain. LIMITATIONS: We caution the interpretation of these result since they are still reflective of participants already maintained on an opioid substitution therapy (OST), which can largely differ from patients who drop out of methadone maintenance treatment (MMT) or never seek treatment altogether. PMID- 26752487 TI - Concern about the Expanding Prescription Drug Epidemic: A Survey of Licensed Prescribers and Dispensers. AB - BACKGROUND: Prescription drug misuse and abuse has reached epidemic levels in the U.S., and stands as a leading cause of death. As the primary gatekeepers to the medications contributing to this epidemic, it is critical to understand the views of licensed health care professionals. OBJECTIVE: In this study, we examine health care professionals' concern regarding prescription drug abuse in their communities and the impact their concern has had on their prescribing and dispensing practices. STUDY DESIGN: An online survey of licensed health care providers. SETTING: Conducted in Indiana. METHODS: This study was a state-wide evaluation of Indiana's prescription drug monitoring program. The questionnaire asked respondents how concerned they were about prescription drug abuse in their community. Variation in the level of concern was examined using ordinary least squares regression and information about the respondents' demographic background and clinical experience. In addition, we used logistic regression to examine whether concern was associated with changing prescribing and/or dispensing behavior. RESULTS: The majority of providers indicated they were "moderately" or "extremely concerned" about prescription drug abuse in their communities. The level of concern, however, varied significantly by profession, with pharmacists, physicians, nurse practitioners/physician assistants being more concerned than dentists. Additional analyses indicate that providers with higher levels of concern were those who also reported recently changing their prescribing and/or dispensing behavior. LIMITATIONS: The voluntary nature and geographical focus of the study limits the generalizability of the findings. CONCLUSION: Concern about prescription drug abuse is generally high across the major health care professions; however, a significant minority of providers, particularly among dentists, expressed little or no concern about the epidemic. Increasing health care providers' general level of concern about prescription drug abuse may be an effective public health tool for encouraging voluntary reductions in prescribing and/or dispensing controlled substances. PMID- 26752488 TI - The Extent of Tissue Damage in the Epidural Space by Ho / YAG Laser During Epiduroscopic Laser Neural Decompression. AB - BACKGROUND: Lasers have recently become very useful for epiduroscopy. As the use of lasers increases, the potential for unwanted complications with direct application of laser energy to nerve tissue has also increased. Even using the lowest laser power to test for nerve stimulation, there are still risks of laser ablation. However, there are no studies investigating tissue damage from laser procedures in the epidural space. OBJECTIVE: This is a study on the risks of Ho/YAG laser usage during epiduroscopy. STUDY DESIGN: Observatory cadaver study. SETTING: Department of anatomy and clinical research institute at the University Hospital. METHODS: We used 5 cadavers for this study. After removing the dura and nerve root from the spinal column, laser energy from a Ho/YAG laser was applied directly to the dura and nerve root as well as in the virtual epidural space, which mimicked the conditions of epiduroscopy with the dura folded. Tissue destruction at all laser ablation sites was observed with the naked eye as well as with a microscope. Specimens were collected from each site of laser exposure, fixed in 10% neutral formalin, and dyed with H/E staining. RESULTS: Tissue destruction was observed in all laser ablation sites, regardless of the length of exposure and the power of the laser beam. LIMITATIONS: A cadaver is not exactly the same as a living human because dura characteristics change and tissue damage can be influenced by dura thickness according to the spinal level. CONCLUSION: Even with low power and short duration, a laser can destroy tissue if the laser beam makes direct contact with the tissue. PMID- 26752490 TI - Complex Regional Pain Syndrome-Type 1 Presenting as deQuervain's Stenosing Tenosynovitis. AB - AIM: To report the presentation of complex regional pain syndrome-1 (CRPS-1) as deQuervain's stenosing tenosynovitis (DQST). CASE REPORT: A 24-year-old woman presented with 3-year history of clinical diagnostic criteria (CDC) of CRPS-1. Conservative and surgical treatment for this as DQST had failed to relieve her. We diagnosed the problem as CRPS-1with CDC as inflammatory manifestations of a mechanical tendinoses of all her 5 digital tendons caused by movement of the fingers and hand tethered by agonist (flexor)/ antagonist (extensor) muscles in co-contraction. Ultrasound guided dry needling (USGDN) relaxed the muscles, replacing the abnormal agonist/antagonist co-contraction with normal agonist/antagonist coordination. Resolution of tendinoses reversed the inflammation causing the CDC. Six months later she leads normal personal and professional life, with reduction of scores of painDetect (from 21 to 5), Patient Health Questionnaire (from 13 to 4), Disability of arm, shoulder and hand from 70.8 to 25 and reversal of muscle abnormality characteristic of CRPS-1 on Musculoskeletal Ultrasonography (MSKUSG). CONCLUSION: We believe the primary pathology of CRPS-1 to be co-contraction of agonist (flexor)/antagonist(extensor) muscles of digits resulting in tendinoses akin to DQST. CDC of CRPS are actually inflammatory manifestations of tendinoses amenable to reversal by USGDN which also addresses the disability, a hallmark of CRPS. PMID- 26752489 TI - SIRT1 Inhibits the Catabolic Effect of IL-1beta Through TLR2/SIRT1/NF-kappaB Pathway in Human Degenerative Nucleus Pulposus Cells. AB - BACKGROUND: Low back pain (LBP), one of the most prominent problems worldwide, lacks effective disease-modifying medical therapy. Intervertebral disc degeneration (IVDD) is a major cause of LBP, and proinflammatory cytokines are the key factors involved in the development of IVDD-induced back pain. Sirtuin 1 (SIRT1) is implicated in the molecular control of aging and immune responses in various diseases; however, its effect on IVDD is not clearly understood. OBJECTIVE: To investigate the effects of SIRT1 on proinflammatory stress and signal transduction pathways induced by interleukin-1beta (IL-1beta) in human degenerative nucleus pulposus (NP) cells. STUDY DESIGN: Research study. SETTING: Chongqing Key Laboratory of Ophthalmology. METHODS: Anti-apoptotic and anti catabolic effects of SIRT1 on IL-1beta were investigated using a three dimensional cell culture model of prestimulated human NP cells transfected with a lentiviral vector overexpressing SIRT1 or a small-interfering RNA (siRNA) against the gene encoding SIRT1. In addition, molecular mechanisms underlying the association of SIRT1 with Toll-like receptor-2 (TLR2) and nuclear factor kappa B (NF-kappaB) were investigated. RESULTS: Our results indicated that decreased SIRT1 expression was associated with IVDD. Direct regulation of SIRT1 expression did not affect the synthesis of extracellular matrix (ECM). However, SIRT1 overexpression mediated by the lentiviral vector suppressed IL-1beta-induced ECM degradation and cell apoptosis. In contrast, knockdown of the gene encoding SIRT1 by the siRNA increased MMP expression and cell apoptosis induced by IL-1beta. Furthermore, SIRT1 deacetylated RelA/p65 to inhibit the nuclear translocation of NF-kappaB, thus inhibiting inflammation. On the other hand, IL-1beta downregulated SIRT1 expression by activating TLR2. However, inhibition of TLR2 expression by an siRNA did not inhibit IL-1beta-induced nuclear translocation of NF-kappaB. LIMITATIONS: Limitations of this study were the in vitro study design and lack of in vivo validation of the observed effects of SIRT1 on IVDD. CONCLUSIONS: Our results indicated that SIRT1 exerted anti-inflammatory effects againstIL-1beta-mediated degeneration of NP cells through the TLR2/SIRT1/NF kappaB pathway, suggesting that it could be used as a potential candidate for treating IVDD-mediated back pain. PMID- 26752491 TI - Neuromodulation of the Suprascapular Nerve. AB - Chronic intractable shoulder pain (CISP) is defined as shoulder pain which is present for longer than 6 months and does not respond to standard treatments like medication, physical therapy, rehabilitation, selective nerve blocks and local infiltrations, or orthopedic procedures. The etiology of CISP may be very diverse, varying from many orthopedic conditions to non-orthopedic conditions. The fact that the suprascapular nerve is one of the most important nerves supplying the shoulder region makes this nerve an interesting target in treating patients suffering shoulder pain. Invasive treatment options are peripheral nerve blocks, temporary electrical stimulation, and neurostimulation. To our best knowledge, thus far there are only a few reports describing the technique of permanent neurostimulation of the suprascapular nerve. In this article we present a patient suffering shoulder pain after she underwent surgery for cervical stenosis. After a step by step treatment protocol was done, we finally offered her trial stimulation of the suprascapular nerve. A single quad lead was implanted via a posterior approach under fluoroscopic and ultrasound guidance. Two weeks after successful stimulation, we implanted a permanent neuromodulation system. Permanent neurostimulation of the suprascapular nerve and its end branches may be a new interesting target in treating patients suffering shoulder pain due to various etiologies. In our patient the follow-up period is 9 months with an excellent result in pain relief, we observed no complications thus far, especially no dislocation or breakage of the lead. In this report, literature on this subject is reviewed, and our technique is well documented with additional anatomical illustrations. PMID- 26752492 TI - Ultrasonographic Diagnosis of Calcifying Tenosynovitis of the Finger. PMID- 26752493 TI - Effectiveness of Spinal Cord Stimulation in Chronic Spinal Pain: A Systematic Review. AB - BACKGROUND: Chronic neuropathic pain has been recognized as contributing to a significant proportion of chronic pain globally. Among these, spinal pain is of significance with failed back surgery syndrome (FBSS), generating considerable expense for the health care systems with increasing prevalence and health impact. OBJECTIVE: To assess the role and effectiveness of spinal cord stimulation (SCS) in chronic spinal pain. STUDY DESIGN: A systematic review of randomized controlled trials (RCTs) of SCS in chronic spinal pain. METHODS: The available literature on SCS was reviewed. The quality assessment criteria utilized were Cochrane review criteria to assess sources of risk of bias and Interventional Pain Management Techniques - Quality Appraisal of Reliability and Risk of Bias Assessment (IPM - QRB) criteria for randomized trials.The level of evidence was based on a best evidence synthesis with modified grading of qualitative evidence from Level I to Level V.Data sources included relevant literature published from 1966 through March 2015 that were identified through searches of PubMed and EMBASE, manual searches of the bibliographies of known primary and review articles, and all other sources. OUTCOME MEASURES: RCTs of efficacy with a minimum 12-month follow-up were considered for inclusion. For trials of adaptive stimulation, high frequency stimulation, and burst stimulation, shorter follow-up periods were considered. RESULTS: Results showed 6 RCTs with 3 efficacy trials and 3 stimulation trials. There were also 2 cost effectiveness studies available. Based on a best evidence synthesis with 3 high quality RCTs, the evidence of efficacy for SCS in lumbar FBSS is Level I to II. The evidence for high frequency stimulation based on one high quality RCT is Level II to III. Based on a lack of high quality studies demonstrating the efficacy of adaptive stimulation or burst stimulation, evidence is limited for these 2 modalities. LIMITATIONS: The limitations of this systematic review continue to require future studies illustrating effectiveness and also the superiority of high frequency stimulation and potentially burst stimulation. CONCLUSION: There is significant (Level I to II) evidence of the efficacy of spinal cord stimulation in lumbar FBSS; whereas, there is moderate (Level II to III) evidence for high frequency stimulation; there is limited evidence for adaptive stimulation and burst stimulation. PMID- 26752494 TI - Pneumogastric (Vagus) Nerve Activity Indexed by Heart Rate Variability in Chronic Pain Patients Compared to Healthy Controls: A Systematic Review and Meta Analysis. AB - BACKGROUND: A large body of scientific literature derived from experimental studies emphasizes the vital role of vagal-nociceptive networks in acute pain processing. However, research on vagal activity, indexed by vagally-mediated heart rate variability (vmHRV) in chronic pain patients (CPPs), has not yet been summarized. OBJECTIVES: To systematically investigate differences in vagus nerve activity indexed by time- and frequency-domain measures of vmHRV in CPPs compared to healthy controls (HCs). STUDY DESIGN: A systematic review and meta-analysis, including meta-regression on a variety of populations (i.e., clinical etiology) and study-level (i.e., length of HRV recording) covariates. SETTING: Not applicable (variety of studies included in the meta-analysis). METHODS: Eight computerized databases (PubMed via MEDLINE, PsycNET, PsycINFO, Embase, CINAHL, Web of Science, PSYNDEX, and the Cochrane Library) in addition to a hand search were systematically screened for eligible studies based on pre-defined inclusion criteria. A meta-analysis on all empirical investigations reporting short- and long-term recordings of continuous time- (root-mean-square of successive R-R interval differences [RMSSD]) and frequency-domain measures (high-frequency [HF] HRV) of vmHRV in CPPs and HCs was performed. True effect estimates as adjusted standardized mean differences (SMD; Hedges g) combined with inverse variance weights using a random effects model were computed. RESULTS: CPPs show lower vmHRV than HCs indexed by RMSSD (Z = 5.47, P < .0001; g = -0.24;95% CI [-0.33, 0.16]; k = 25) and HF (Z = 4.54, P < .0001; g = -0.30; 95% CI [-0.44, -0.17]; k = 61).Meta-regression on covariates revealed significant differences by clinical etiology, age, gender, and length of HRV recording. LIMITATIONS: We did not control for other potential covariates (i.e., duration of chronic pain, medication intake) which may carry potential risk of bias. CONCLUSION(S): The present meta-analysis is the most extensive review of the current evidence on vagal activity indexed by vmHRV in CPPs. CPPs were shown to have lower vagal activity, indexed by vmHRV, compared to HCs. Several covariates in this relationship have been identified. Further research is needed to investigate vagal activity in CPPs, in particular prospective and longitudinal follow-up studies are encouraged. PMID- 26752495 TI - Minimum Effective Concentration of Bupivacaine in Ultrasound-Guided Femoral Nerve Block after Arthroscopic Knee Meniscectomy: A Randomized, Double-Blind, Controlled Trial. AB - BACKGROUND: Adequate analgesia is important for early hospital discharge after meniscectomy. A femoral nerve block may reduce the need for systemic analgesics, with fewer side effects; however, motor block can occur. Ultrasound-guided femoral nerve block may reduce the required local anesthetic concentration, preventing motor block. OBJECTIVE: The primary objective of this study was to determine the lowest effective analgesic concentration of bupivacaine in 50% (EC50) and in 90% (EC90) of patients for a successful ultrasound-guided femoral nerve block in arthroscopic knee meniscectomy. STUDY DESIGN: This was a prospective, randomized, double-blind, controlled trial. SETTINGS: This study was conducted at Hospital Sao Domingos. METHODS: A total of 52 patients undergoing arthroscopic knee meniscectomy were submitted to ultrasound-guided femoral nerve block using 22 mL bupivacaine. The bupivacaine concentration given to a study patient was determined by the response of the previous patient (a biased-coin design up-down sequential method). If the previous patient had a negative response, the bupivacaine concentration was increased by 0.05% for the next case. If the previous patient had a positive response, the next patient was randomized to receive the same bupivacaine concentration (with a probability of 0.89) or to have a decrease by 0.05% (with a probability of 0.11). A successful block was defined by a numerical pain intensity scale score < 4 (0 = no pain; 10 = worst imaginable pain) in 3 different evaluations. If the pain intensity score was = 4 (moderate or severe pain) at any time, the block was considered failed. General anesthesia was induced with 30 ug/kg alfentanil and 2 mg/kg propofol, followed by propofol maintanance, plus remifentanil if needed. Postoperative analgesia supplementation was performed with dipyrone; ketoprofen and tramadol were given if needed. DATA MEASUREMENTS: The following parameters were evaluated: numerical pain intensity score, duration of analgesia, supplementary analgesic dose in 24 hours, and need for intraoperative remifentanil. RESULTS: The EC50 was 0.160 (95% CI: 0.150 - 0.189), and EC90 was 0.271 (95% CI: 0.196 - 0.300). There was no difference in numerical pain intensity score for the different concentrations of bupivacaine. A successful block was achieved in 45 patients, with no difference according to bupivacaine concentration. Time to first analgesic supplementation dose was longer for bupivacaine concentrations = 0.3% (543.8 +/- 283.8 min.), compared to 0.25% (391.3 +/- 177.8 min.) and < 0.25% (302.3 +/- 210.1 min.). There were no differences in supplementary analgesic dose in 24 hours nor in the use of intraoperative remifentanil according to bupivacaine concentration. LIMITATIONS: The analgesic effect was measured only during the first 2 hours. CONCLUSIONS: Bupivacaine EC50 for ultrasound-guided femoral nerve block was 0.160 (95% CI: 0.150 - 0.189), and EC90 was 0.271 (95% CI: 0.196 - 0.300). PMID- 26752496 TI - Tetra-ataxiometric Posturography in Patients with Migrainous Vertigo. AB - BACKGROUND: Migraine is a common disorder characterized by headache attacks frequently accompanied by vestibular symptoms like dizziness, vertigo, and balance disorders. Clinical studies support a strong link between migraine and vertigo rather than between other headache types and vertigo or nonvertiginous dizziness. There is a lack of consensus regarding the pathophysiology of migrainous vertigo. Activation of central vestibular processing during migraine attacks and vasospasm-induced ischemia of the labyrinth are reported as the probable responsible mechanisms. Because vestibular examination alone does not provide enough information for diagnosis of migrainous vertigo, posturography systems which provide objective assessment of somatosensory, vestibular, and visual information would be very helpful to show concomitant involvement of the vestibular and somato-sensorial systems. There are few posturographic studies on patients with migraine but it seems that how balance is affected in patients with migraine and/or migrainous vertigo is still not clear. We want to investigate balance function in migraineurs with and without vertigo with a tetra ataxiometric posturography system and our study is the first study in which tetra ataxiometric static posturography was used to evaluate postural abnormalities in a well-defined population of patients with migrainous vertigo. OBJECTIVE: To investigate balance functions in migraineurs with and without vertigo with a tetra-ataxiometric posturography system. STUDY DESIGN: Prospective, nonrandomized, controlled study. SETTING: Pamukkale University Hospital, Neurology and Physical Therapy and Rehabilitation outpatient clinics. METHODS: Sixteen patients with migrainous vertigo, 16 patients with migraine without aura and no vestibular symptoms, and 16 controls were included in the study. Computerized static posturography system was performed and statistical analyses of fall, Fourier, Stability, and Weight distribution indexes were performed. The tetra-ataxiometric posturography device measures vertical pressure fluctuations on 4 independent stable platforms, each placed beneath 2 heels and toe parts of the patient; inputs from these platforms are integrated and processed by a computer digitally. Four separate plates are used and perpendicular pressures of the anterior and posterior feet are measured. Pressure of each force plate is measured and data was analyzed by the software program. LIMITATIONS: A very small, non-randomized, and controlled study with the inability to find an answer to the mechanism of involvement of the somatosensorial system and vestibular system in migrainous headaches. RESULTS: The distribution of patients with posturographical abnormalities in the migrainous vertigo group was significantly different than the control group. Distribution of the patients with posturographical abnormalities in the high frequencies of the head-right position was significantly different in the migrainous vertigo group than in the control group and distribution of the patients with posturographical abnormalities in high frequencies of the head-right position was significantly different in the migraine group than in the controls groups. The stability index of the migrainous vertigo group was significantly higher than in the control group when tested on in the neutral-head position with open eyes. CONCLUSION: In this first study of tetra-ataxiometric static posturography evaluating postural abnormalities in a well-defined population of patients with migrainous vertigo, the central part of the vestibular apparatus would be responsible of postural abnormalities in patients with migraine and migrainous vertigo. PMID- 26752497 TI - Effects of Intravenous and Oral Magnesium on Reducing Migraine: A Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND: Migraine attack has been associated with magnesium deficiency. Previous studies investigating the effect of intravenous and oral magnesium on acute migraine attacks and the prevention of migraine have produced equivocal findings. OBJECTIVE: To evaluate the effects of intravenous magnesium on acute migraine attacks and oral magnesium supplements on migraine prophylaxis. STUDY DESIGN: A meta-analysis of randomized controlled trials (RCTs). Electronic databases, namely EMBASE, PubMed, the Wanfang Data Chinese Database, and the China Knowledge Resource Integrated Database were searched from inception to February 24, 2015. METHODS: This review was conducted according to the guidelines of the PRISMA. Only RCTs evaluating the effects of intravenous or oral magnesium on migraine compared with a control group were included. RESULTS: A total of 21 studies were included. Of which, 11 studies investigated the effects of intravenous magnesium on acute migraine (948 participants) and 10 examined the effects of oral magnesium on migraine prophylaxis (789 participants). Intravenous magnesium significantly relieved acute migraine within 15 - 45 minutes, 120 minutes, and 24 hours after the initial infusion (Odd ratios [ORs] = 0.23, 0.20, and 0.25, respectively). Oral magnesium significantly alleviated the frequency and intensity of migraine (ORs = 0.20 and 0.27). LIMITATIONS: Some of the included studies did not adopt adequate randomization methods. CONCLUSIONS: Intravenous magnesium reduces acute migraine attacks within 15 - 45 minutes, 120 minutes, and 24 hours after the initial infusion and oral magnesium alleviates the frequency and intensity of migraine. Intravenous and oral magnesium should be adapted as parts of multimodal approach to reduce migraine. PMID- 26752498 TI - Establishing components of cultural competence healthcare models to better cater for the needs of migrants with disability: a systematic review. AB - This study examined the challenges of providing services to migrants with disability (MWD), including healthcare providers' (HCP) level of cultural competence, and documented components of the cultural competence framework required to reduce disability-related health inequalities. This systematic review was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Six databases were searched from January 2000 to August 2013: Ovid Medline, Ovid PsychINFO, EMBASE, CINHAL plus, Informit health databases and Scopus. The search focused on MWD, carers of MWD and HCP working with MWD in industrialised countries. The search yielded 271 articles of which 11 met the inclusion criteria (10 qualitative and 1 quantitative). While HCP perceived themselves as being culturally competent, carers of MWD felt that HCP needed to be more culturally competent as MWD's needs were not being adequately addressed due to cultural misunderstandings and disrespect of cultural values, beliefs and traditions. The review found one existing healthcare model intended for use with MWD; however, the lack of specific attention to cultural competency limits its clinical utility. The findings of this review led to the development of suggested components to be included in a cultural competence model for HCP working with MWD. PMID- 26752501 TI - Initial Experiments with the Leap Motion as a User Interface in Robotic Endonasal Surgery. AB - The Leap Motion controller is a low-cost, optically-based hand tracking system that has recently been introduced on the consumer market. Prior studies have investigated its precision and accuracy, toward evaluating its usefulness as a surgical robot master interface. Yet due to the diversity of potential slave robots and surgical procedures, as well as the dynamic nature of surgery, it is challenging to make general conclusions from published accuracy and precision data. Thus, our goal in this paper is to explore the use of the Leap in the specific scenario of endonasal pituitary surgery. We use it to control a concentric tube continuum robot in a phantom study, and compare user performance using the Leap to previously published results using the Phantom Omni. We find that the users were able to achieve nearly identical average resection percentage and overall surgical duration with the Leap. PMID- 26752500 TI - 3D tumor spheroid models for in vitro therapeutic screening: a systematic approach to enhance the biological relevance of data obtained. AB - The potential of a spheroid tumor model composed of cells in different proliferative and metabolic states for the development of new anticancer strategies has been amply demonstrated. However, there is little or no information in the literature on the problems of reproducibility of data originating from experiments using 3D models. Our analyses, carried out using a novel open source software capable of performing an automatic image analysis of 3D tumor colonies, showed that a number of morphology parameters affect the response of large spheroids to treatment. In particular, we found that both spheroid volume and shape may be a source of variability. We also compared some commercially available viability assays specifically designed for 3D models. In conclusion, our data indicate the need for a pre-selection of tumor spheroids of homogeneous volume and shape to reduce data variability to a minimum before use in a cytotoxicity test. In addition, we identified and validated a cytotoxicity test capable of providing meaningful data on the damage induced in large tumor spheroids of up to diameter in 650 MUm by different kinds of treatments. PMID- 26752502 TI - Synthesis and reactions of C-phosphanylated thiazol-2-thiones. AB - The facile regioselective synthesis of the P(iii) substituted thiazol-2-thione 2 is presented. Reaction of 2 with hydrogenperoxide-urea, elemental sulfur and selenium resulted in P(v) chalcogenide thiazol-2-thiones 3-5. All compounds were characterized using (31)P, (1)H, (13)C NMR, IR and elemental analyses and, additionally, by the single-crystal X-ray diffraction technique. Oxidative desulfurization of the 5-phosphinoylated thiazol-2-thione 3 using hydrogenperoxide led to the first C-phosphanoyl substituted thiazolium salt (6). Deprotonation of 6 and in situ reaction with the cyclooctadiene rhodium(i) chloride dimer yielded thiazol-2-ylidene rhodium(i) complex 7 which was confirmed by NMR spectroscopy and ESI-MS spectrometry. PMID- 26752499 TI - Noninvasive Detection of Inflammatory Changes in White Adipose Tissue by Label Free Raman Spectroscopy. AB - White adipose tissue inflammation (WATi) has been linked to the pathogenesis of obesity-related diseases, including type 2 diabetes, cardiovascular disease, and cancer. In addition to the obese, a substantial number of normal and overweight individuals harbor WATi, putting them at increased risk for disease. We report the first technique that has the potential to detect WATi noninvasively. Here, we used Raman spectroscopy to detect WATi with excellent accuracy in both murine and human tissues. This is a potentially significant advance over current histopathological techniques for the detection of WATi, which rely on tissue excision and, therefore, are not practical for assessing disease risk in the absence of other identifying factors. Importantly, we show that noninvasive Raman spectroscopy can diagnose WATi in mice. Taken together, these results demonstrate the potential of Raman spectroscopy to provide objective risk assessment for future cardiometabolic complications in both normal weight and overweight/obese individuals. PMID- 26752503 TI - Robert Williams Wood: pioneer of invisible light. AB - The Wood's lamp aids in the diagnosis of multiple infectious, inflammatory and neoplastic dermatologic conditions. Although the Wood's lamp has many applications, which have improved both the diagnosis and management of disease, the man credited for its invention is relatively unknown in medicine. Robert Williams Wood, a prominent physicist of the early 20th century, is credited for the invention of the Wood's lamp. Wood was the father of infrared and ultraviolet photography and made significant contributions to other areas in optics and spectroscopy. Wood's work encompassed the formative years of American Physics; he published over 200 original papers over his lifetime. A few years after the invention of the Wood's lamp for ultraviolet photography, physicians in Europe adopted the Wood's lamp for dermatologic applications. Wood's lamp remains popular in clinics globally, given its ease of use and ability to improve diagnostic precision. PMID- 26752505 TI - 14.7% efficient mesoscopic perovskite solar cells using single walled carbon nanotubes/carbon composite counter electrodes. AB - A single walled carbon nanotube (SWCNT) possesses excellent hole conductivity. This work communicates an investigation of perovskite solar cells using a mesoscopic TiO2/Al2O3 structure as a framework in combination with a certain amount of SWCNT-doped graphite/carbon black counter electrode material. The CH3NH3PbI3-based device achieves a power conversion efficiency of 14.7% under AM 1.5G illumination. Detailed investigations show an increased charge collection in this device compared to that without the SWCNT additive. PMID- 26752504 TI - Determinants of Glycemic Response to Add-On Therapy with a Dipeptidyl Peptidase-4 Inhibitor: A Retrospective Cohort Study Using a United Kingdom Primary Care Database. AB - BACKGROUND: Apart from baseline glycated hemoglobin (HbA1c), little is known about clinical parameters that affect glycemic response to a dipeptidyl peptidase 4 (DPP4) inhibitor when used in routine clinical practice. We aimed to use a large primary care database to assess the variability in response to a DPP4 inhibitor when used as add-on therapy. MATERIALS AND METHODS: Data on 25,386 patients with type 2 diabetes, newly treated with a DPP4 inhibitor (2007-2013), were sourced from a United Kingdom general practice database via the Health Improvement Network database. Baseline clinical parameters of patients (n = 13,525) for whom a DPP4 inhibitor was added because of suboptimal glucose control (HbA1c >7%) were compared with 12-month follow-up data. An optimum response to the DPP4 inhibitor was defined as an HbA1c level of <7.0% at 12 months. Descriptive analyses and unadjusted comparisons using chi(2) and t tests were carried out to ascertain glycemic and body weight responses to treatment intensification with a DPP4 inhibitor. Predictor of response analyses were performed using multivariate logistic regression. RESULTS: Overall, 1,708 (13%) of our study population achieved an HbA1c level of <7%. Intensification with a DPP4 inhibitor was associated with significant reductions in HbA1c (-0.5%), body weight (-0.9 kg), and total cholesterol (-0.1 mmol/L) (P < 0.001). Independent predictors of achieving optimal HbA1c target of <7% included the use of metformin (adjusted odds ratio [OR] = 2.58; 95% confidence interval [CI], 2.18-3.04) and use of metformin plus sulfonylurea (1.42; 95% CI, 1.21-1.68) as opposed to no use. The independent predictors of suboptimal glucose control included a higher baseline HbA1c level (OR = 0.64; 95% CI, 0.61-0.68) (i.e., 1% increase in HbA1c was associated with a 36% reduced likelihood of response), longer diabetes duration (per every year increase) (OR = 0.85; 95% CI, 0.83-0.88), and intensification therapy below 9 months compared with 9-12 months. CONCLUSIONS: There is a significant variability in glycemic response to a DPP4 inhibitor in routine practice. The best effect is achieved as add-on to metformin and metformin plus sulfonylurea, but responses are significantly lower with increased diabetes duration and among patients with high HbA1c levels at baseline. PMID- 26752506 TI - Association of Psychiatric and Neurologic Comorbidity With Mortality Among Persons With Autism Spectrum Disorder in a Danish Population. AB - IMPORTANCE: Increased mortality has been reported among persons with autism spectrum disorder (ASD), especially among those who also have the comorbid condition of epilepsy or intellectual disability. The effects of psychiatric and neurologic comorbidity on mortality among persons with ASD have not been rigorously examined in large, population-based studies. OBJECTIVE: To investigate the mortality patterns among persons with ASD overall and to assess the associations of comorbid mental, behavioral, and neurologic disorders with mortality among persons with ASD. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal cohort study of children born in Denmark during the period from 1980 to 2010 who were alive at 1.5 years of age and followed up through 2013. This population based sample of children (N = 1,912,904) was identified via linkage between the Danish Civil Registration Service and the Danish Medical Birth Register using a unique 10-digit identifier assigned to all live births and new residents in Denmark. Children were followed up for diagnoses of ASD (International Classification of Diseases, Eighth Revision [ICD-8] codes 299.00, 299.01, 299.02, and 299.03 and ICD-10 codes F84.0, F84.1, F84.5, F84.8, and F84.9) and other mental/behavioral disorders (ICD-8 codes 290-315 and ICD-10 codes F00-F99) in the Danish Psychiatric Central Research Register and for diagnoses of neurologic disorders (ICD-8 codes 320-359 and ICD-10 codes G00-G99) in the Danish National Patient Register. Data analysis was performed in December 2014. MAIN OUTCOMES AND MEASURES: Deaths and causes of death among cohort members were identified via the Danish Civil Registration Service and the Danish Cause of Death Register, respectively. Regressions analyses were performed using Cox regression. RESULTS: Of the 1,912,904 persons included in our study, 20,492 (1.1%) had ASD (15,901 [77.6%] were male). Of the 20,492 persons with ASD, 68 died (0.3%) (57 of 68 [83.8%] had comorbid mental/behavioral or neurologic disorders). The adjusted hazard ratio (aHR) for overall mortality was 2.0 (95% CI, 1.5-2.8) for ASD. The aHRs for ASD-associated mortality among cohort members who did not have neurologic (2.0 [95% CI, 1.4-3.0]) or other mental/behavioral disorders (1.7 [95% CI, 1.0-3.1]) were similar. The co-occurrence of ASD added no additional mortality risk for persons with neurologic (aHR, 0.7 [95% CI, 0.4-1.3]) or mental/behavioral disorders (aHR, 0.8 [95% CI, 0.5-1.2]) compared with persons with these disorders and no ASD. CONCLUSIONS AND RELEVANCE: The mortality risk was 2-fold higher through young adulthood for persons with ASD than for persons without ASD, although mortality affected only 0.3% of persons with ASD. The mechanisms underlying ASD-associated mortality may be mediated through or shared with neurologic or mental/behavioral disorders, thereby providing insights into their potential neurobiological links. Health care professionals and family members should recognize the importance of these disorders with regard to the mortality risk for persons with ASD. PMID- 26752507 TI - Advancing the field of 3D biomaterial printing. AB - 3D biomaterial printing has emerged as a potentially revolutionary technology, promising to transform both research and medical therapeutics. Although there has been recent progress in the field, on-demand fabrication of functional and transplantable tissues and organs is still a distant reality. To advance to this point, there are two major technical challenges that must be overcome. The first is expanding upon the limited variety of available 3D printable biomaterials (biomaterial inks), which currently do not adequately represent the physical, chemical, and biological complexity and diversity of tissues and organs within the human body. Newly developed biomaterial inks and the resulting 3D printed constructs must meet numerous interdependent requirements, including those that lead to optimal printing, structural, and biological outcomes. The second challenge is developing and implementing comprehensive biomaterial ink and printed structure characterization combined with in vitro and in vivo tissue- and organ-specific evaluation. This perspective outlines considerations for addressing these technical hurdles that, once overcome, will facilitate rapid advancement of 3D biomaterial printing as an indispensable tool for both investigating complex tissue and organ morphogenesis and for developing functional devices for a variety of diagnostic and regenerative medicine applications. PMID- 26752508 TI - Performance of First-Principles-Based Reaction Class Transition State Theory. AB - Performance of the Reaction Class Transition State Theory (RC-TST) for prediction of rates constants of elementary reactions is examined using data from its previous applications to a number of different reaction classes. The RC-TST theory is taking advantage of the common structure denominator of all reactions in a given family combined with structure activity relationships to provide a rigorous theoretical framework to obtain rate expression of any reaction within a reaction class in a simple and cost-effective manner. This opens the possibility for integrating this methodology with an automated mechanism generator for "on the-fly" generation of accurate kinetic models of complex reacting systems. PMID- 26752509 TI - Prevention of Low Back Pain: A Systematic Review and Meta-analysis. AB - IMPORTANCE: Existing guidelines and systematic reviews lack clear recommendations for prevention of low back pain (LBP). OBJECTIVE: To investigate the effectiveness of interventions for prevention of LBP. DATA SOURCES: MEDLINE, EMBASE, Physiotherapy Evidence Database Scale, and Cochrane Central Register of Controlled Trials from inception to November 22, 2014. STUDY SELECTION: Randomized clinical trials of prevention strategies for nonspecific LBP. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed the risk of bias. The Physiotherapy Evidence Database Scale was used to evaluate the risk-of-bias. The Grading of Recommendations Assessment, Development, and Evaluation system was used to describe the quality of evidence. MAIN OUTCOMES AND MEASURES: The primary outcome measure was an episode of LBP, and the secondary outcome measure was an episode of sick leave associated with LBP. We calculated relative risks (RRs) and 95% CIs using random-effects models. RESULTS: The literature search identified 6133 potentially eligible studies; of these, 23 published reports (on 21 different randomized clinical trials including 30,850 unique participants) met the inclusion criteria. With results presented as RRs (95% CIs), there was moderate-quality evidence that exercise combined with education reduces the risk of an episode of LBP (0.55 [0.41-0.74]) and low quality evidence of no effect on sick leave (0.74 [0.44-1.26]). Low- to very low quality evidence suggested that exercise alone may reduce the risk of both an LBP episode (0.65 [0.50-0.86]) and use of sick leave (0.22 [0.06-0.76]). For education alone, there was moderate- to very low-quality evidence of no effect on LBP (1.03 [0.83-1.27]) or sick leave (0.87 [0.47-1.60]). There was low- to very low-quality evidence that back belts do not reduce the risk of LBP episodes (1.01 [0.71-1.44]) or sick leave (0.87 [0.47-1.60]). There was low-quality evidence of no protective effect of shoe insoles on LBP (1.01 [0.74-1.40]). CONCLUSION AND RELEVANCE: The current evidence suggests that exercise alone or in combination with education is effective for preventing LBP. Other interventions, including education alone, back belts, and shoe insoles, do not appear to prevent LBP. Whether education, training, or ergonomic adjustments prevent sick leave is uncertain because the quality of evidence is low. PMID- 26752512 TI - From similitude to success: The effects of facial resemblance on perceptions of team effectiveness. AB - Scant empirical research has focused on how impressions of teams are formed based on members' collective appearance, even though team photos are omnipresent in visual communications and teamwork is a common theme to elicit positive responses. Across 4 studies, we show that a subtle increase in the facial resemblance among team members enhances observers' evaluations of team effectiveness. This resemblance effect is mediated by perceived cooperative intent among team players. Furthermore, we demonstrate a reversal of the resemblance effect through the moderating role of information valence and extend the finding from team perception to behavioral intention. These results hold across different manipulations, contexts, stimuli, and sample characteristics. Collectively, this research presents the first empirical evidence that inferences based on facial morphology persist well beyond evaluations of individuals to influence the way a team, as a whole, is perceived. PMID- 26752510 TI - Nasal vaccination stimulates CD8(+) T cells for potent protection against mucosal Brucella melitensis challenge. AB - Brucellosis remains a significant zoonotic threat worldwide. Humans and animals acquire infection via their oropharynx and upper respiratory tract following oral or aerosol exposure. After mucosal infection, brucellosis develops into a systemic disease. Mucosal vaccination could offer a viable alternative to conventional injection practices to deter disease. Using a nasal vaccination approach, the DeltaznuA B. melitensis was found to confer potent protection against pulmonary Brucella challenge, and reduce colonization of spleens and lungs by more than 2500-fold, with >50% of vaccinated mice showing no detectable brucellae. Furthermore, 10-fold more brucellae-specific, interferon-gamma (IFN gamma)-producing CD8(+) T cells than CD4(+) T cells were induced in the spleen and respiratory lymph nodes. Evaluation of pulmonary and splenic CD8(+) T cells from mice vaccinated with DeltaznuA B. melitensis revealed that these expressed an activated effector memory (CD44(hi)CD62L(lo)CCR7(lo)) T cells producing elevated levels of IFN-gamma, tumor necrosis factor-alpha, perforin and granzyme B. To assess the relative importance of these increased numbers of CD8(+) T cells, CD8(-/-) mice were challenged with virulent B. melitensis, and they showed markedly increased bacterial loads in organs in contrast to similarly challenged CD4(-/-) mice. Only DeltaznuA B. melitensis- and Rev-1-vaccinated CD4(-/-) and wild-type mice, not CD8(-/-) mice, were completely protected against Brucella challenge. Determination of cytokines responsible for conferring protection showed the relative importance of IFN-gamma, but not interleukin-17 (IL-17). Unlike wild-type (wt) mice, IL-17 was greatly induced in IFN-gamma(-/-) mice, but IL-17 could not substitute for IFN-gamma's protection, although an increase in brucellae dissemination was observed upon in vivo IL-17 neutralization. These results show that nasal DeltaznuA B. melitensis vaccination represents an attractive means to stimulate systemic and mucosal immune protection via CD8(+) T cell engagement. PMID- 26752513 TI - Can journalistic "false balance" distort public perception of consensus in expert opinion? AB - Media critics have expressed concern that journalistic "false balance" can distort the public's perceptions of what ought to be noncontroversial subjects (e.g., climate change). I report several experiments testing the influence of presenting conflicting comments from 2 experts who disagree on an issue (balance condition) in addition to a complete count of the number of experts on a panel who favor either side. Compared with a control condition, who received only the complete count, participants in the balance condition gave ratings of the perceived agreement among the experts that did not discriminate as clearly between issues with and without strong expert consensus. Participants in the balance condition also perceived less agreement among the experts in general, and were less likely to think that there was enough agreement among experts on the high-consensus issues to guide government policy. Evidently, "false balance" can distort perceptions of expert opinion even when participants would seem to have all the information needed to correct for its influence. PMID- 26752514 TI - Conditional or unconditional? The effects of implementation intentions on driver behavior. AB - Implementation intentions (if-then plans) exert conditional effects on behavior, meaning that their ability to change behavior is conditional upon encountering the critical situation specified in the if component of the plan. In the present study, we tested whether implementation intentions can exert unconditional effects on behavior. Consistent with the process of operant generalization, we hypothesized that implementation intentions would change behavior, not only in situations that are contextually identical to those specified in the if component but also in contextually similar situations. Implementation intentions were not expected to generate behavior-change in contextually different situations to those specified. Participants (N = 139) completed questionnaires measuring speeding behavior and motivation to speed. Experimental participants then specified implementation intentions to avoid speeding in critical situations that were contextually identical, similar, or different to those subsequently encountered on a driving simulator. Control participants received educational information about the risks of speeding. All participants then drove on a driving simulator. Consistent with the hypotheses participants in both the contextually identical and similar conditions exceeded the speed limit less frequently than did controls. There was no difference in speeding behavior between the contextually different and control conditions. Implications of the findings for behavior-change are discussed. PMID- 26752511 TI - The involvement of transient receptor potential canonical type 1 in skeletal muscle regrowth after unloading-induced atrophy. AB - KEY POINTS: Decreased mechanical loading results in skeletal muscle atrophy. The transient receptor potential canonical type 1 (TRPC1) protein is implicated in this process. Investigation of the regulation of TRPC1 in vivo has rarely been reported. In the present study, we employ the mouse hindlimb unloading and reloading model to examine the involvement of TRPC1 in the regulation of muscle atrophy and regrowth, respectively. We establish the physiological relevance of the concept that manipulation of TRPC1 could interfere with muscle regrowth processes following an atrophy-inducing event. Specifically, we show that suppressing TRPC1 expression during reloading impairs the recovery of the muscle mass and slow myosin heavy chain profile. Calcineurin appears to be part of the signalling pathway involved in the regulation of TRPC1 expression during muscle regrowth. These results provide new insights concerning the function of TRPC1. Interventions targeting TRPC1 or its downstream or upstream pathways could be useful for promoting muscle regeneration. ABSTRACT: Decreased mechanical loading, such as bed rest, results in skeletal muscle atrophy. The functional consequences of decreased mechanical loading include a loss of muscle mass and decreased muscle strength, particularly in anti-gravity muscles. The purpose of this investigation was to clarify the regulatory role of the transient receptor potential canonical type 1 (TRPC1) protein during muscle atrophy and regrowth. Mice were subjected to 14 days of hindlimb unloading followed by 3, 7, 14 and 28 days of reloading. Weight-bearing mice were used as controls. TRPC1 expression in the soleus muscle decreased significantly and persisted at 7 days of reloading. Small interfering RNA (siRNA)-mediated downregulation of TRPC1 in weight-bearing soleus muscles resulted in a reduced muscle mass and a reduced myofibre cross sectional area (CSA). Microinjecting siRNA into soleus muscles in vivo after 7 days of reloading provided further evidence for the role of TRPC1 in regulating muscle regrowth. Myofibre CSA, as well as the percentage of slow myosin heavy chain-positive myofibres, was significantly lower in TRPC1-siRNA-expressing muscles than in control muscles after 14 days of reloading. Additionally, inhibition of calcineurin (CaN) activity downregulated TRPC1 expression in both weight-bearing and reloaded muscles, suggesting a possible association between CaN and TRPC1 during skeletal muscle regrowth. PMID- 26752516 TI - Interconnectivity of Macroporous Hydrogels Prepared via Graphene Oxide-Stabilized Pickering High Internal Phase Emulsions. AB - Interconnected macroporous poly(acrylic acid) (PAA) hydrogels are prepared via oil-in-water (o/w) Pickering high internal phase emulsion (HIPE) templates stabilized by graphene oxide (GO). The amphiphilicity of GO is adjusted by slight modification with cetyltrimethylammonium bromide (CTAB). The morphology of macroporous PAA is observed by a field-emission scanning electron microscope (FE SEM). The gas permeability is characterized to evaluate the interconnectivity of polymer foams. The pore and pore throat size can be tailored by varying the wettability and concentration of GO. The selective adsorption toward dyes of PAA hydrogels is proved. Macroporous PAA hydrogels with an open-cell structure show enhanced adsorption behavior of both methylene blue (MB) and copper(II) ions. PMID- 26752517 TI - Killer lymphocytes use granulysin, perforin and granzymes to kill intracellular parasites. AB - Protozoan infections are a serious global health problem. Natural killer (NK) cells and cytolytic T lymphocytes (CTLs) eliminate pathogen-infected cells by releasing cytolytic granule contents--granzyme (Gzm) proteases and the pore forming perforin (PFN)--into the infected cell. However, these cytotoxic molecules do not kill intracellular parasites. CD8(+) CTLs protect against parasite infections in mice primarily by secreting interferon (IFN)-gamma. However, human, but not rodent, cytotoxic granules contain the antimicrobial peptide granulysin (GNLY), which selectively destroys cholesterol-poor microbial membranes, and GNLY, PFN and Gzms rapidly kill intracellular bacteria. Here we show that GNLY delivers Gzms into three protozoan parasites (Trypanosoma cruzi, Toxoplasma gondii and Leishmania major), in which the Gzms generate superoxide and inactivate oxidative defense enzymes to kill the parasite. PFN delivers GNLY and Gzms into infected cells, and GNLY then delivers Gzms to the intracellular parasites. Killer cell-mediated parasite death, which we term 'microbe-programmed cell death' or 'microptosis', is caspase independent but resembles mammalian apoptosis, causing mitochondrial swelling, transmembrane potential dissipation, membrane blebbing, phosphatidylserine exposure, DNA damage and chromatin condensation. GNLY-transgenic mice are protected against infection by T. cruzi and T. gondii, and survive infections that are lethal to wild-type mice. Thus, GNLY-, PFN- and Gzm-mediated elimination of intracellular protozoan parasites is an unappreciated immune defense mechanism. PMID- 26752520 TI - The Role of Platelet-Derived Growth Factor-B/Platelet-Derived Growth Factor Receptor-beta Signaling in Chronic Atrial Fibrillation. AB - OBJECTIVE: To explore the role of platelet-derived growth factor-B (PDGF B)/platelet-derived growth factor receptor-beta (PDGFR-beta) signaling in chronic atrial fibrillation (AF). METHODS: Thirty-nine AF patients and 33 patients with sinus rhythm (SR) were enrolled. Twenty canines were randomized into 5 groups: control, sham and AF lasting 1, 2 or 4 weeks. The AF canine models were made by rapid atrial pacing. Rat atrial fibroblasts were treated with PDGF-BB or PDGF-BB + PDGFR inhibitor AG1295, respectively. Gene expression in the right atrial appendage of patients, the left atrium of canines and rat atrial fibroblasts was measured by quantitative real-time PCR and Western blot, respectively. The degree of atrial fibrosis was evaluated by Masson trichrome staining. RESULTS: The degree of atrial fibrosis and the expression of PDGF-B, PDGFR-beta and collagen type I (COL1) in AF patients significantly increased compared to patients with SR. The degree of atrial fibrosis and the expression of PDGF-B and COL1 in canines increased progressively with the increased duration of AF. The expression of PDGFR-beta increased progressively 2 weeks after AF. PDGF-BB promoted the proliferation and COL1 secretion of rat atrial fibroblasts. AG1295 attenuated these effects. CONCLUSIONS: Our study suggests that PDGF-B/PDGFR-beta signaling, which promotes the proliferation and COL1 secretion of atrial fibroblasts, is an important contributor to atrial fibrosis in AF and may represent a novel target for the intervention of AF. PMID- 26752521 TI - Synthesis of 4H/fcc Noble Multimetallic Nanoribbons for Electrocatalytic Hydrogen Evolution Reaction. AB - Noble multimetallic nanomaterials, if only consisting of Au, Ag, Pt, and Pd, typically adopt the high-symmetry face-centered cubic (fcc) structure. Here for the first time, by using the 4H/fcc Au@Ag nanoribbons (NRBs) as seeds, we report the synthesis of 4H/fcc trimetallic Au@PdAg core-shell NRBs via the galvanic reaction method under ambient conditions. Moreover, this strategy can also be used to synthesize 4H/fcc trimetallic Au@PtAg and quatermetallic Au@PtPdAg core shell NRBs. Impressively, for the first time, these alloy shells, i.e., PdAg, PtAg, and PtPdAg, epitaxially grown on the 4H/fcc Au core with novel 4H hexagonal phase were successfully synthesized. Remarkably, the obtained 4H/fcc Au@PdAg NRBs exhibit excellent electrocatalytic activity toward the hydrogen evolution reaction, which is even quite close to that of the commercial Pt black. We believe that our findings here may provide a novel strategy for the crystal structure-controlled synthesis of advanced functional noble multimetallic nanomaterials with various promising applications. PMID- 26752515 TI - Role of aquaporins in cell proliferation: What else beyond water permeability? AB - In addition to the extensive data demonstrating the importance of mammalian AQPs for the movement of water and some small solutes across the cell membrane, there is now a growing body of evidence indicating the involvement of these proteins in numerous cellular processes seemingly unrelated, at least some of them in a direct way, to their canonical function of water permeation. Here, we have presented a broad range of evidence demonstrating that these proteins have a role in cell proliferation by various different mechanisms, namely, by allowing fast cell volume regulation during cell division; by affecting progression of cell cycle and helping maintain the balance between proliferation and apoptosis, and by crosstalk with other cell membrane proteins or transcription factors that, in turn, modulate progression of the cell cycle or regulate biosynthesis pathways of cell structural components. In the end, however, after discussing all these data that strongly support a role for AQPs in the cell proliferation process, it remains impossible to conclude that all these other functions attributed to AQPs occur completely independently of their water permeability, and there is a need for new experiments designed specifically to address this interesting issue. PMID- 26752518 TI - Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis. AB - Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 A resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness. PMID- 26752523 TI - SOLITARY IDIOPATHIC CHOROIDITIS IN THE SETTING OF EXTENSIVE ANIMAL EXPOSURE. AB - PURPOSE: To describe solitary idiopathic choroiditis in the setting of extensive animal exposure. METHODS: A 56-year-old asymptomatic female equestrian with an extensive history of exposure to horses and dogs and a trapper of wild animals and rodents was discovered to have an amelanotic choroidal mass in the macular region and referred for suspicious atypical nevus. RESULTS: Funduscopy revealed a deep yellow mass with overlying retinal pigment epithelial thinning and without visible subretinal fluid or lipofuscin. Mild hyperautofluorescence represented unmasking of scleral autofluorescence. Ultrasonography showed a 1.8-mm-thick echodense lesion. Enhanced depth imaging-optical coherence tomography disclosed a dense, elevated scleral mass with "volcanic" configuration, demonstrating choroidal compression and trace overlying subretinal fluid. These features were consistent with solitary idiopathic choroiditis/scleritis. Systemic evaluation for standard cat-related bartonellosis, tuberculosis, sarcoidosis, and syphilis were negative. Horse-, dog-, and rodent-related bartonellosis testing was not available. Observation was advised, and the findings remained stable at 6 months. CONCLUSION: Solitary idiopathic choroiditis is best imaged on enhanced depth imaging-optical coherence tomography as a scleral lesion with "volcanic" configuration and often secondary to previous Bartonella infection. Serologic positivity for cat-related Bartonella decays over time, and testing for horse-, dog-, or rodent-related Bartonella is not commonly used. PMID- 26752522 TI - Outcomes of Surgical Repair for Persistent Truncus Arteriosus from Neonates to Adults: A Single Center's Experience. AB - OBJECTIVE: This study aimed to report our experiences with surgical repair in patients of all ages with persistent truncus arteriosus. METHODS: From July 2004 to July 2014, 50 consecutive patients with persistent truncus arteriosus who underwent anatomical repair were included in the retrospective review. Median follow-up time was 3.4 years (range, 3 months to 10 years). RESULTS: Fifty patients underwent anatomical repair at a median age of 19.6 months (range, 20 days to 19.1 years). Thirty patients (60%) were older than one year. The preoperative pulmonary vascular resistance and mean pulmonary artery pressure were 4.1+/-2.1 (range, 0.1 to 8.9) units.m2 and 64.3+/-17.9 (range, 38 to 101) mmHg, respectively. Significant truncal valve regurgitation was presented in 14 (28%) patients. Hospital death occurred in 3 patients, two due to pulmonary hypertensive crisis and the other due to pneumonia. Three late deaths occurred at 3, 4 and 11 months after surgery. The actuarial survival rates were 87.7% and 87.7% at 1 year and 5 years, respectively. Multivariate analysis identified significant preoperative truncal valve regurgitation was a risk factor for overall mortality (odds ratio, 7.584; 95%CI: 1.335-43.092; p = 0.022). Two patients required reoperation of truncal valve replacement. One patient underwent reintervention for conduit replacement. Freedom from reoperation at 5 years was 92.9%. At latest examination, there was one patient with moderate-to-severe truncal valve regurgitation and four with moderate. Three patients had residual pulmonary artery hypertension. All survivors were in New York Heart Association class I-II. CONCLUSIONS: Complete repair of persistent truncus arteriosus can be achieved with a relatively low mortality and acceptable early- and mid-term results, even in cases with late presentation. Significant preoperative truncal valve regurgitation remains a risk factor for overall mortality. The long-term outcomes warrant further follow-up. PMID- 26752519 TI - Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice. AB - Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element binding protein 2 (IRP2) as an important COPD susceptibility gene and have shown that IRP2 protein is increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS) induced experimental COPD. By integrating RNA immunoprecipitation followed by sequencing (RIP-seq), RNA sequencing (RNA-seq), and gene expression and functional enrichment clustering analysis, we identified Irp2 as a regulator of mitochondrial function in the lungs of mice. Irp2 increased mitochondrial iron loading and levels of cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice, which had higher mitochondrial iron loading, showed impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas mice deficient in the synthesis of cytochrome c oxidase, which have reduced COX, were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS induced COPD. Mitochondrial iron chelation also alleviated CS-induced impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD. PMID- 26752524 TI - SOLITARY CIRCUMSCRIBED "PEARL WHITE" RETINAL MASS (SO-CALLED RETINAL ASTROCYTIC PROLIFERATION) RESIDES IN DEEP RETINA OR BENEATH RETINA: FINDINGS ON MULTIMODAL IMAGING IN 4 CASES. AB - PURPOSE: To report novel observations of previously described solitary circumscribed retinal astrocytic proliferation using spectral domain optical coherence tomography that suggests this tumor does not arise in the nerve fiber layer as initially believed, but arises within deep retinal or retinal pigment epithelial structures. METHODS: Retrospective review of four cases. RESULTS: Patient age ranged from 46 to 75 years. The tumor was pearl white or yellow-white (n = 4, 100%), located in the macula (n = 1, 25%) or macula to equator (n = 3, 75%) regions, and with mean tumor base of 1.2 mm and thickness of 0.8 mm. There were no feeding vessels, intrinsic vessels, subretinal fluid, or vitreoretinal traction. Mild surrounding retinal pigment epithelial hyperplasia and atrophy rimmed each tumor (n = 4, 100%). Fluorescein angiography depicted the mass with early hypofluorescence (n = 3/3, 100%) and late hypofluorescence (n = 2/3, 67%). Spectral domain optical coherence tomography demonstrated the mass with an abruptly elevated "snowball" configuration (n = 4, 100%), with smooth or slightly irregular surface (n = 4, 100%), and originating from deep retina or retinal pigment epithelial (n = 4, 100%), with overlying compression and draping of retinal tissue (n = 4, 100%). CONCLUSION: This previously described small yellow white retinal tumor appears to arise in the outer retinal layers and not from the inner retinal layers as formerly believed. This tumor may not be astrocytic as initially believed since it arises deep within the retina, but it could represent a deep glial or pigment epithelial fibrous mass. The pathogenesis and pathology of this rare lesion remain unknown. PMID- 26752537 TI - Contrasts Between Young Males Dying by Suicide, Those Dying From Other Causes and Those Still Living: Observations From the National Longitudinal Survey of Adolescent to Adult Health. AB - Utilizing Add Health longitudinal data, we compared 21 male suicide casualties to 10,101 living respondents identifying suicide correlates. METHOD: 21 suicide decedents completed surveys in 1994/1995 (Wave 1) and 11 completed at Wave 3; responses were compared with Chi-square and oneway ANOVA tests. RESULTS: Suicide decedents were prone to higher delinquency and fighting at Wave 1, but not at Wave 3. At Wave 1 suicide decedents remained undistinguished from living respondents in depression, self-esteem, and drug uses. Yet, after Wave 3, the 11 respondents dying by suicide showed significantly higher depression, drug use and lower self-esteem. CONCLUSION: Delinquency trends can readily understood, but more complex causes are needed to account for unexpected changes in self-esteem, depression and drug uses. PMID- 26752526 TI - De Novo Transcriptome and Expression Profile Analysis to Reveal Genes and Pathways Potentially Involved in Cantharidin Biosynthesis in the Blister Beetle Mylabris cichorii. AB - The dried body of Mylabris cichorii is well-known Chinese traditional medicine. The sesquiterpenoid cantharidin, which is secreted mostly by adult male beetles, has recently been used as an anti-cancer drug. However, little is known about the mechanisms of cantharidin biosynthesis. Furthermore, there is currently no genomic or transcriptomic information for M. cichorii. In this study, we performed de novo assembly transcriptome of M. cichorii using the Illumina Hiseq2000. A single run produced 9.19 Gb of clean nucleotides comprising 29,247 sequences, including 23,739 annotated sequences (about 81%). We also constructed two expression profile libraries (20-25 day-old adult males and 20-25 day-old adult females) and discovered 2,465 significantly differentially-expressed genes. Putative genes and pathways involved in the biosynthesis of cantharidin were then characterized. We also found that cantharidin biosynthesis in M. cichorii might only occur via the mevalonate (MVA) pathway, not via the methylerythritol 4 phosphate/deoxyxylulose 5-phosphate (MEP/DOXP) pathway or a mixture of these. Besides, we considered that cantharidin biosynthesis might be related to the juvenile hormone (JH) biosynthesis or degradation. The results of transcriptome and expression profiling analysis provide a comprehensive sequence resource for M. cichorii that could facilitate the in-depth study of candidate genes and pathways involved in cantharidin biosynthesis, and may thus help to improve our understanding of the mechanisms of cantharidin biosynthesis in blister beetles. PMID- 26752525 TI - Divergent Effects of Dioxin- or Non-Dioxin-Like Polychlorinated Biphenyls on the Apoptosis of Primary Cell Culture from the Mouse Pituitary Gland. AB - Polychlorinated biphenyls (PCBs) can disrupt the endocrine function, promote neoplasms and regulate apoptosis in some tissues; however, it is unknown whether PCBs can affect the apoptosis of pituitary cells. The study evaluated the effect of PCBs on the apoptosis of normal pituitary cells and the underlying mechanisms. Primary cell cultures obtained from mouse pituitary glands were exposed to Aroclor 1254 or selected dioxin-like (PCB 77, PCB 126) or non-dioxin-like (PCB 153, PCB 180) congeners. Apoptosis was evaluated by Annexin V staining, DNA fragmentation, and TUNEL assay. Both the expression and activity of caspases were analyzed. Selective thyroid hormone receptor (TR) or aryl-hydrocarbon receptor (AhR) or CYP1A1 antagonist were used to explore the mechanisms underlying PCBs action. Our results showed that Aroclor 1254 induced the apoptosis of pituitary cells as well as the final caspase-3 level and activity through the extrinsic pathway, as shown by the increased caspase-8 level and activity. On the other hand, the intrinsic pathway evaluated by measuring caspase-9 expression was silent. The selected non-dioxin-like congeners either increased (PCB 180) or reduced (PCB 153) pituitary cell apoptosis, affecting the extrinsic pathway (PCB 180), or both the extrinsic and intrinsic pathways (PCB 153), respectively. In contrast, the dioxin-like congeners (PCB 77 and PCB 126) did not affect apoptosis. The anti-apoptotic phenotype of PCB 153 was counteracted by a TR or a CYP1A1 antagonist, whereas the pro-apoptotic effect of PCB 180 was counteracted by an AhR antagonist. The induced apoptosis of Aroclor 1254 or PCB 180 was associated with a reduction of cell proliferation, whereas the decreased apoptosis due to PCB 153 increased cell proliferation by 30%. In conclusion, our data suggest that non-dioxin-like PCBs may modulate apoptosis and the proliferation rate of pituitary cells that have either pro- or anti-apoptotic effects depending on the specific congeners. However, the impact of PCBs on the process of pituitary tumorigenesis remains to be elucidated. PMID- 26752538 TI - The Role of Helminth Infection and Environment in the Development of Allergy: A Prospective Study of Newly-Arrived Ethiopian Immigrants in Israel. AB - Helminth infection may be protective against allergy and account for the low prevalence of allergy in developing countries. We studied prospectively the prevalence of allergy in Ethiopian immigrants with heavy helminth infection on arrival in Israel, and again after a year of adjustment to an urban industrialized setting, to explore the roles of helminth infection, changed environment and background immunity on the manifestations of allergy. 126 newly arrived Ethiopian immigrants were studied at baseline and 115 after a year of follow up in Israel. Allergic symptoms, Skin prick tests (SPT), Tuberculin (PPD) skin tests, stool and blood samples were obtained for determining parasites, blood IgE and eosinophil levels, respectively. Anti-helminthic therapy was offered to the entire infected individuals, but only 50/108 (46.3%) took the medication. At baseline, there was a significant negative association between helminth infection and allergy, 4/18 (22.2%) of uninfected participants were allergic compared to 7/108 (6.5%) of helminth-infected participants (p = 0.028), as well as between helminth infection and SPT reactivity, 12/18 (66.6%) of uninfected participants compared to 43/108 (39.8%) of helminth-infected participants (p = 0.033). After one year, a significant general increase in allergy and SPT was observed. While only 11/126 (8.7%) were allergic at baseline, 30/115 (26.1%) became allergic at follow-up (p<0.0001), and while 55/126 (43.7%) were SPT+ at baseline, 79/115 (68.7%) became SPT+ at follow-up (p<0.001). A twofold increase in allergen sensitization was also observed after one year in Israel, particularly for dust mites, grasses and olive tree (p<0.001). These results show that: a) Helminth infection is significantly associated with low allergy and low SPT reactivity; b) One year after immigration to Israel, allergy and SPT reactivity increased significantly in all immigrants; c) Higher increases in positive SPT and allergy were observed after a year in the group that remained infected with helminths, even though they had a lowered helminth load; d) The reasons for the increased allergy one year after immigration needs further investigation but probably reflects the combined influence of the decreased helminth load and novel environmental factors. PMID- 26752540 TI - Biosimilar therapies in inflammatory bowel disease: should we care about patient profile? PMID- 26752541 TI - The safety of phosphodiesterase type 5 inhibitors for erectile dysfunction. AB - INTRODUCTION: Phosphodiesterase type 5 inhibitors (PDE5Is) are the leading drugs for the treatment of erectile dysfunction (ED), being recommended as a first line treatment by both the European and US urological guidelines. PDE5Is are highly effective as compared to placebo, well tolerated and have a very low, though not negligible, rate of severe treatment-related adverse events. AREAS COVERED: This paper reviews the safety profile of currently available PDE5Is, comparing them in a broad spectrum ED population and outlining a number of real-life aspects of importance in the real-life everyday clinical setting. EXPERT OPINION: Guidelines unanimously agree in considering PDE5Is as first line treatments for ED when well tolerated and not contraindicated. Despite the fact that no high-grade evidence comparing the efficacy and the safety for PDE5Is is currently available, published data seem to suggest that there are no major differences in their safety profiles. Moreover, although oral PDE5Is were shown to cause more AEs than placebo, they were generally mild and well tolerated. PMID- 26752539 TI - Economic Evaluations of Pharmacogenetic and Pharmacogenomic Screening Tests: A Systematic Review. Second Update of the Literature. AB - OBJECTIVE: Due to extended application of pharmacogenetic and pharmacogenomic screening (PGx) tests it is important to assess whether they provide good value for money. This review provides an update of the literature. METHODS: A literature search was performed in PubMed and papers published between August 2010 and September 2014, investigating the cost-effectiveness of PGx screening tests, were included. Papers from 2000 until July 2010 were included via two previous systematic reviews. Studies' overall quality was assessed with the Quality of Health Economic Studies (QHES) instrument. RESULTS: We found 38 studies, which combined with the previous 42 studies resulted in a total of 80 included studies. An average QHES score of 76 was found. Since 2010, more studies were funded by pharmaceutical companies. Most recent studies performed cost utility analysis, univariate and probabilistic sensitivity analyses, and discussed limitations of their economic evaluations. Most studies indicated favorable cost-effectiveness. Majority of evaluations did not provide information regarding the intrinsic value of the PGx test. There were considerable differences in the costs for PGx testing. Reporting of the direction and magnitude of bias on the cost-effectiveness estimates as well as motivation for the chosen economic model and perspective were frequently missing. CONCLUSIONS: Application of PGx tests was mostly found to be a cost-effective or cost-saving strategy. We found that only the minority of recent pharmacoeconomic evaluations assessed the intrinsic value of the PGx tests. There was an increase in the number of studies and in the reporting of quality associated characteristics. To improve future evaluations, scenario analysis including a broad range of PGx tests costs and equal costs of comparator drugs to assess the intrinsic value of the PGx tests, are recommended. In addition, robust clinical evidence regarding PGx tests' efficacy remains of utmost importance. PMID- 26752543 TI - Epithelioid Schwannomas: An Analysis of 58 Cases Including Atypical Variants. AB - The histologic features and outcome of 58 cases of epithelioid schwannoma were studied to determine the significance of atypical histologic features. Cases were retrieved from personal consultation files from 1999 to 2013. Patients (31 male and 26 female patients) ranged in age from 14 to 80 years (median, 38 y). Two patients had schwannomatosis 1. Tumors developed in the dermis/subcutis (n=56) or muscle (n=2) of the upper extremity (34.5%), lower extremity (34.5%), thorax/abdomen/back (18%), and less common anatomic locations including the scalp, neck, lip, and breast. They ranged in size from 0.25 to 4.5 cm (median, 2.0 cm). Typically circumscribed and surrounded by a perineurium, they comprised single or small groups of epithelioid schwann cells with a moderate amphophilic cytoplasm and occasional nuclear pseudoinclusions. Stroma varied from myxoid to hyalinized, often with thick-walled vessels (55 cases). Mitotic rate ranged from 0 to 9 mitoses/10 high-power field (HPF) (2.37 mm) in the most active areas (mean, 2 to 3 mitoses/10 HPFs). Thirteen cases (22%) were "atypical," defined by a high mitotic rate (>=3 mitoses per 10 HPFs) and nuclear size variation (>=3:1). All (56/56) expressed S100 protein; type IV collagen invested groups or individual cells (16/17). Melanoma markers were negative, except for melan A (1 case). Follow-up in 39 patients (median, 78 mo; range, 6 to 174 mo) indicated that 31 (79%) were alive without disease (including 9/13 atypical cases; median, 78 mo), 7 (18%) were alive with unknown status, and 1 patient had died of unrelated causes. One tumor recurred, but none metastasized. Epithelioid schwannomas, even those with atypical features, are benign and do not constitute a histologic continuum with epithelioid malignant peripheral nerve sheath tumors, which typically occur in deep soft tissues and have more anaplastic features. PMID- 26752544 TI - Prognostic Significance of the Histologic Response of Perihilar Cholangiocarcinoma to Preoperative Neoadjuvant Chemoradiation in Liver Explants. AB - Perihilar cholangiocarcinoma (pCCA) has a dismal prognosis. Protocols incorporating chemotherapy, radiotherapy, and liver transplantation (LT) have emerged as curative options for unresectable tumors with 70% 5-year survival rates. We aimed to assess the value of extent of residual tumor (ERT) and other pathologic factors following chemoradiation in predicting outcome; 152 liver explants with pCCA treated with neoadjuvant chemoradiation and LT between 1993 and 2013 were reviewed for ERT, pathologic stage, histologic grade, and perineural and lymphovascular invasion. ERT was quantified as the percentage of viable carcinoma in the tumor bed. Tumors were classified into 4 ERT categories: (1) complete/near-complete response (<=1% ERT); (2) marked response (>1 to <10% ERT); (3) moderate response (10 to <30% ERT); and (4) minimal response (>=30% ERT). Overall 5-year survival rate was 69%. 5-year disease-free estimate was 74%. 57%, 16%, 18%, and 9% of explants were placed in ERT categories 1, 2, 3, and 4, respectively. ERT correlated significantly with the overall 5-year survival rate and 5-year, disease-free estimate by univariate (P<0.0001) and multivariate analysis (P=0.004 and 0.009, respectively). By multivariate analysis, pathologic stage was also an independent predictor of recurrence (P=0.003). Other variables that correlated with risk of death and recurrence by univariate analysis included perineural (P<0.0001) and lymphovascular invasion (P<0.0001), absence of primary sclerosing cholangitis (P=0.006 and P<0.0001, respectively), and pretreatment CA19-9 level (P=0.001 and 0.02, respectively). Histologic grade did not predict outcome. In summary, ERT independently predicts outcome in pCCA patients following neoadjuvant chemoradiation and LT and can stratify patient prognosis. PMID- 26752542 TI - Immunotherapeutic targeting of LIGHT/LTbetaR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells. AB - Tumor necrosis factor (TNF)/TNF receptor (TNFR) superfamily members play essential roles in the development of the different phases of the immune response. Mouse LIGHT (TNFSF14) is a type II transmembrane protein with a C terminus extracellular TNF homology domain (THD) that assembles in homotrimers and regulates the course of the immune responses by signaling through 2 receptors, the herpes virus entry mediator (HVEM, TNFRSF14) and the lymphotoxin beta receptor (LTbetaR, TNFRSF3). LIGHT is a membrane-bound protein transiently expressed on activated T cells, natural killer (NK) cells and immature dendritic cells that can be proteolytically cleaved by a metalloprotease and released to the extracellular milieu. The immunotherapeutic potential of LIGHT blockade was evaluated in vivo. Administration of an antagonist of LIGHT interaction with its receptors attenuated the course of graft-versus-host reaction and recapitulated the reduced cytotoxic activity of LIGHT-deficient T cells adoptively transferred into non-irradiated semiallogeneic recipients. The lack of LIGHT expression on donor T cells or blockade of LIGHT interaction with its receptors slowed down the rate of T cell proliferation and decreased the frequency of precursor alloreactive T cells, retarding T cell differentiation toward effector T cells. The blockade of LIGHT/LTbetaR/HVEM pathway was associated with delayed downregulation of interleukin-7Ralpha and delayed upregulation of inducible costimulatory molecule expression on donor alloreactive CD8 T cells that are typical features of impaired T cell differentiation. These results expose the relevance of LIGHT/LTbetaR/HVEM interaction for the potential therapeutic control of the allogeneic immune responses mediated by alloreactive CD8 T cells that can contribute to prolong allograft survival. PMID- 26752545 TI - Expression of Programmed Cell Death 1 Ligands (PD-L1 and PD-L2) in Histiocytic and Dendritic Cell Disorders. AB - Programmed cell death 1 ligands 1 and 2 (PD-L1 and PD-L2) are cell surface proteins expressed by activated antigen-presenting cells and by select malignancies that bind PD-1 on T cells to inhibit immune responses. Antibodies targeting PD-1 or PD-L1 elicit antitumor immunity in a subset of patients, and clinical response correlates with PD-1 ligand expression by malignant or immune cells within the tumor microenvironment. We examined the expression of PD-1 ligands on subsets of antigen-presenting cells and 87 histiocytic and dendritic cell disorders including those that are benign, borderline, and malignant. Within reactive lymphoid tissue, strong PD-L1 is detected on most macrophages, subsets of interdigitating dendritic cells, and plasmacytoid dendritic cells, but not on follicular dendritic cells or Langerhans cells. Macrophage/dendritic cell subsets do not express discernible PD-L2. Seven of 7 cases of sarcoidosis (100%), 6 of 6 cases of histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease) (100%), 2 of 11 cases of Rosai-Dorfman disease (18%), and 3 of 15 cases of Langerhans cell histiocytosis (20%) exhibited positivity for PD-L1. All cases of sarcoidosis were also positive for PD-L2. Seven of 14 histiocytic sarcomas (50%), 2 of 5 interdigitating dendritic cell sarcomas (40%), 10 of 20 follicular dendritic cell sarcomas (50%), and none of 9 blastic plasmacytoid dendritic cell neoplasms were positive for PD-L1. Eleven of 20 (55%) follicular dendritic cell sarcomas were also positive for PD-L2. PD-L1 and PD-L2 are useful new markers for identifying select histiocyte and dendritic cell disorders and reveal novel patient populations as rational candidates for immunotherapy. PMID- 26752547 TI - Frequent MYD88 L265P and CD79B Mutations in Primary Breast Diffuse Large B-Cell Lymphoma. AB - Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare disease comprising <3% of extranodal lymphomas. It frequently reveals an activated B-cell (ABC)-like phenotype. ABC-like DLBCL was reported to have gain-of-function mutations in MYD88, CD79B, CARD11, and TNFAIP3, resulting in constitutive activation of the NFkappaB pathway. Because of the rare occurrence of PB-DLBCL, the frequency of MYD88 and CD79B mutations is still unknown. We used Sanger sequencing to study these mutations from 46 breast DLBCL cases and also investigated the associated clinicopathologic factors. MYD88 L265P was confirmed by allele-specific polymerase chain reaction and compared with the Sanger sequencing results. MYD88 L265P and CD79B mutations were detected in 27/46 (58.7%) and 11/33 (33.3%) cases, respectively. Twenty-eight of 46 cases met the criteria for PB-DLBCL, and the latter 18 cases were further classified as clinical breast DLBCL (CLB-DLBCL). The frequency of MYD88 L265P and CD79B mutations was 16/28 (57.1%) and 9/23 (39.1%), respectively, in PB-DLBCL and 11/18 (61.1%) and 2/10 (20%), respectively, in CLB-DLBCL. When the cutoff value was set at DeltaCt<=1, the result of allele-specific polymerase chain reaction for MYD88 corresponded to those of the Sanger sequence at 92.6% sensitivity and 100% specificity. According to Choi's algorithm, 16/27 (59.3%) demonstrated an ABC like phenotype in PB-DLBCL, and 15/18 (83.3%) demonstrated an ABC-like phenotype in CLB-DLBCL. In conclusion, MYD88 L265P and CD79B mutations were frequently detected in PB-DLBCL, and they may be key molecules associated with PB-DLBCL lymphomagenesis. Further analysis will be required to clarify the mechanism of its pathogenesis. PMID- 26752546 TI - Novel BCOR-MAML3 and ZC3H7B-BCOR Gene Fusions in Undifferentiated Small Blue Round Cell Sarcomas. AB - Small blue round cell tumors (SBRCTs) are a heterogenous group of tumors that are difficult to diagnose because of overlapping morphologic, immunohistochemical, and clinical features. About two-thirds of EWSR1-negative SBRCTs are associated with CIC-DUX4-related fusions, whereas another small subset shows BCOR-CCNB3 X chromosomal paracentric inversion. Applying paired-end RNA sequencing to an SBRCT index case of a 44-year-old man, we identified a novel BCOR-MAML3 chimeric fusion, which was validated by reverse transcription polymerase chain reaction and fluorescence in situ hybridization techniques. We then screened a total of 75 SBRCTs lacking EWSR1, FUS, SYT, CIC, and BCOR-CCNB3 abnormalities for BCOR break apart probes by fluorescence in situ hybridization to detect potential recurrent BCOR gene rearrangements outside the typical X-chromosomal inversion. Indeed, 8/75 (11%) SBRCTs showed distinct BCOR gene rearrangements, with 2 cases each showing either a BCOR-MAML3 or the alternative ZC3H7B-BCOR fusion, whereas no fusion partner was detected in the remaining 4 cases. Gene expression of the BCOR MAML3-positive index case showed a distinct transcriptional profile with upregulation of HOX-gene signature, compared with classic Ewing's sarcoma or CIC DUX4-positive SBRCTs. The clinicopathologic features of the SBRCTs with alternative BCOR rearrangements were also compared with a group of BCOR-CCNB3 inversion-positive cases, combining 11 from our files with a meta-analysis of 42 published cases. The BCOR-CCNB3-positive tumors occurred preferentially in children and in bone, in contrast to alternative BCOR-rearranged SBRCTs, which presented in young adults, with a variable anatomic distribution. Furthermore, BCOR-rearranged tumors often displayed spindle cell areas, either well defined in intersecting fascicles or blending with the round cell component, which appears distinct from most other fusion-positive SBRCTs and shares histologic overlap with poorly differentiated synovial sarcoma. PMID- 26752549 TI - Gianni Bonadonna (1934-2015). PMID- 26752548 TI - Children perceive speech onsets by ear and eye. AB - Adults use vision to perceive low-fidelity speech; yet how children acquire this ability is not well understood. The literature indicates that children show reduced sensitivity to visual speech from kindergarten to adolescence. We hypothesized that this pattern reflects the effects of complex tasks and a growth period with harder-to-utilize cognitive resources, not lack of sensitivity. We investigated sensitivity to visual speech in children via the phonological priming produced by low-fidelity (non-intact onset) auditory speech presented audiovisually (see dynamic face articulate consonant/rhyme b/ag; hear non-intact onset/rhyme: -b/ag) vs. auditorily (see still face; hear exactly same auditory input). Audiovisual speech produced greater priming from four to fourteen years, indicating that visual speech filled in the non-intact auditory onsets. The influence of visual speech depended uniquely on phonology and speechreading. Children - like adults - perceive speech onsets multimodally. Findings are critical for incorporating visual speech into developmental theories of speech perception. PMID- 26752551 TI - Twenty Years of Stereotype Threat Research: A Review of Psychological Mediators. AB - This systematic literature review appraises critically the mediating variables of stereotype threat. A bibliographic search was conducted across electronic databases between 1995 and 2015. The search identified 45 experiments from 38 articles and 17 unique proposed mediators that were categorized into affective/subjective (n = 6), cognitive (n = 7) and motivational mechanisms (n = 4). Empirical support was accrued for mediators such as anxiety, negative thinking, and mind-wandering, which are suggested to co-opt working memory resources under stereotype threat. Other research points to the assertion that stereotype threatened individuals may be motivated to disconfirm negative stereotypes, which can have a paradoxical effect of hampering performance. However, stereotype threat appears to affect diverse social groups in different ways, with no one mediator providing unequivocal empirical support. Underpinned by the multi-threat framework, the discussion postulates that different forms of stereotype threat may be mediated by distinct mechanisms. PMID- 26752550 TI - Minor Contribution of Endogenous GLP-1 and GLP-2 to Postprandial Lipemia in Obese Men. AB - CONTEXT: Glucose and lipids stimulate the gut-hormones glucagon-like peptide (GLP)-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP) but the effect of these on human postprandial lipid metabolism is not fully clarified. OBJECTIVE: To explore the responses of GLP-1, GLP-2 and GIP after a fat-rich meal compared to the same responses after an oral glucose tolerance test (OGTT) and to investigate possible relationships between incretin response and triglyceride rich lipoprotein (TRL) response to a fat-rich meal. DESIGN: Glucose, insulin, GLP 1, GLP-2 and GIP were measured after an OGTT and after a fat-rich meal in 65 healthy obese (BMI 26.5-40.2 kg/m(2)) male subjects. Triglycerides (TG), apoB48 and apoB100 in TG-rich lipoproteins (chylomicrons, VLDL1 and VLDL2) were measured after the fat-rich meal. MAIN OUTCOME MEASURES: Postprandial responses (area under the curve, AUC) for glucose, insulin, GLP-1, GLP-2, GIP in plasma, and TG, apoB48 and apoB100 in plasma and TG-rich lipoproteins. RESULTS: The GLP-1, GLP-2 and GIP responses after the fat-rich meal and after the OGTT correlated strongly (r = 0.73, p<0.0001; r = 0.46, p<0.001 and r = 0.69, p<0.001, respectively). Glucose and insulin AUCs were lower, but the AUCs for GLP-1, GLP-2 and GIP were significantly higher after the fat-rich meal than after the OGTT. The peak value for all hormones appeared at 120 minutes after the fat-rich meal, compared to 30 minutes after the OGTT. After the fat-rich meal, the AUCs for GLP-1, GLP-2 and GIP correlated significantly with plasma TG- and apoB48 AUCs but the contribution was very modest. CONCLUSIONS: In obese males, GLP-1, GLP-2 and GIP responses to a fat-rich meal are greater than following an OGTT. However, the most important explanatory variable for postprandial TG excursion was fasting triglycerides. The contribution of endogenous GLP-1, GLP-2 and GIP to explaining the variance in postprandial TG excursion was minor. PMID- 26752558 TI - Feasibility of Capecitabine and Oxaliplatin Combination Chemotherapy Without Central Venous Access Device in Patients With Stage III Colorectal Cancer. AB - BACKGROUND: 5-Fluorouracil and leucovorin plus oxaliplatin (FOLFOX) or capecitabine plus oxaliplatin (XELOX) is a standard adjuvant treatment for patients with stage III colon cancer (CC). Capecitabine is an oral fluoropyrimidine, and administration of oxaliplatin does not necessarily require the insertion of a central venous access device (CVAD). We evaluated the feasibility of XELOX without a CVAD as adjuvant treatment in patients with stage III CC. PATIENTS AND METHODS: We retrospectively studied prospectively collected data from patients with stage III CC treated with XELOX in the International Duration Evaluation of Adjuvant Chemotherapy French trial. Patients were divided into 2 groups: those with a CVAD and those with peripheral venous access (PVA), including patients who had and had not had a CVAD at the first cycle of chemotherapy. Chemotherapy without a CVAD was considered feasible if the patient received all cycles of adjuvant therapy without it. RESULTS: A total of 203 patients were included: 86 (43%) in the PVA group and 116 (57%) in the CVAD group. Of the 85 patients in the PVA group (1 patient was not treated), 69 (81.2%) did not require the insertion of a CVAD. However, 16 (18.8%) required CVAD insertion owing to systematic delay of the initially planned CVAD before the second cycle of chemotherapy in 7, complications related to PVA usage in 5, a switch to the modified FOLFOX6 regimen in 2, and other reasons in 2. The oxaliplatin dose was similar in both groups regardless of the chemotherapy duration. XELOX without a CVAD was feasible for 81.2% of the patients for whom a CVAD had not been planned before chemotherapy and for 88.4% of patients for whom chemotherapy was planned without the use of a CVAD. CONCLUSION: XELOX chemotherapy without a CVAD is a feasible approach for treating patients with stage III CC in the adjuvant setting. PMID- 26752559 TI - A novel 2D silicon nano-mold fabrication technique for linear nanochannels over a 4 inch diameter substrate. AB - A novel low-cost 2D silicon nano-mold fabrication technique was developed based on Cu inclined-deposition and Ar(+) (argon ion) etching. With this technique, sub 100 nm 2D (two dimensional) nano-channels can be etched economically over the whole area of a 4 inch n-type <100> silicon wafer. The fabricating process consists of only 4 steps, UV (Ultraviolet) lithography, inclined Cu deposition, Ar(+) sputter etching, and photoresist &Cu removing. During this nano-mold fabrication process, we investigated the influence of the deposition angle on the width of the nano-channels and the effect of Ar(+) etching time on their depth. Post-etching measurements showed the accuracy of the nanochannels over the whole area: the variation in width is 10%, in depth it is 11%. However, post-etching measurements also showed the accuracy of the nanochannels between chips: the variation in width is 2%, in depth it is 5%. With this newly developed technology, low-cost and large scale 2D nano-molds can be fabricated, which allows commercial manufacturing of nano-components over large areas. PMID- 26752560 TI - Propofol Pharmacokinetics and Estimation of Fetal Propofol Exposure during Mid Gestational Fetal Surgery: A Maternal-Fetal Sheep Model. AB - BACKGROUND: Measuring fetal drug concentrations is extremely difficult in humans. We conducted a study in pregnant sheep to simultaneously describe maternal and fetal concentrations of propofol, a common intravenous anesthetic agent used in humans. Compared to inhalational anesthesia, propofol supplemented anesthesia lowered the dose of desflurane required to provide adequate uterine relaxation during open fetal surgery. This resulted in better intraoperative fetal cardiac outcome. This study describes maternal and fetal propofol pharmacokinetics (PK) using a chronically instrumented maternal-fetal sheep model. METHODS: Fetal and maternal blood samples were simultaneously collected from eight mid-gestational pregnant ewes during general anesthesia with propofol, remifentanil and desflurane. Nonlinear mixed-effects modeling was performed by using NONMEM software. Total body weight, gestational age and hemodynamic parameters were tested in the covariate analysis. The final model was validated by bootstrapping and visual predictive check. RESULTS: A total of 160 propofol samples were collected. A 2-compartment maternal PK model with a third fetal compartment appropriately described the data. Mean population parameter estimates for maternal propofol clearance and central volume of distribution were 4.17 L/min and 37.7 L, respectively, in a typical ewe with a median heart rate of 135 beats/min. Increase in maternal heart rate significantly correlated with increase in propofol clearance. The estimated population maternal-fetal inter-compartment clearance was 0.0138 L/min and the volume of distribution of propofol in the fetus was 0.144 L. Fetal propofol clearance was found to be almost negligible compared to maternal clearance and could not be robustly estimated. CONCLUSIONS: For the first time, a maternal-fetal PK model of propofol in pregnant ewes was successfully developed. This study narrows the gap in our knowledge in maternal fetal PK model in human. Our study confirms that maternal heart rate has an important influence on the pharmacokinetics of propofol during pregnancy. Much lower propofol concentration in the fetus compared to maternal concentrations explain limited placental transfer in in-vivo paired model, and less direct fetal cardiac depression we observed earlier with propofol supplemented inhalational anesthesia compared to higher dose inhalational anesthesia in humans and sheep. PMID- 26752562 TI - Correction: A Comprehensive Analysis of Authorship in Radiology Journals. PMID- 26752561 TI - Proteomics Based Identification of Proteins with Deregulated Expression in B Cell Lymphomas. AB - Follicular lymphoma and diffuse large B cell lymphomas comprise the main entities of adult B cell malignancies. Although multiple disease driving gene aberrations have been identified by gene expression and genomic studies, only a few studies focused at the protein level. We applied 2 dimensional gel electrophoresis to compare seven GC B cell non Hodgkin lymphoma (NHL) cell lines with a lymphoblastoid cell line (LCL). An average of 130 spots were at least two folds different in intensity between NHL cell lines and the LCL. We selected approximately 38 protein spots per NHL cell line and linked them to 145 unique spots based on the location in the gel. 34 spots that were found altered in at least three NHL cell lines when compared to LCL, were submitted for LC-MS/MS. This resulted in 28 unique proteins, a substantial proportion of these proteins were involved in cell motility and cell metabolism. Loss of expression of B2M, and gain of expression of PRDX1 and PPIA was confirmed in the cell lines and primary lymphoma tissue. Moreover, inhibition of PPIA with cyclosporine A blocked cell growth of the cell lines, the effect size was associated with the PPIA expression levels. In conclusion, we identified multiple differentially expressed proteins by 2-D proteomics, and showed that some of these proteins might play a role in the pathogenesis of NHL. PMID- 26752564 TI - The Influence of Culture on Agroecosystem Structure: A Comparison of the Spatial Patterns of Homegardens of Different Ethnic Groups in Thailand and Vietnam. AB - Different ethnic groups have evolved distinctive cultural models which guide their interactions with the environment, including their agroecosystems. Although it is probable that variations in the structures of homegardens among separate ethnic groups reflect differences in the cultural models of the farmers, empirical support for this assumption is limited. In this paper the modal horizontal structural patterns of the homegardens of 8 ethnic groups in Northeast Thailand and Vietnam are described. Six of these groups (5 speaking Tai languages and 1 speaking Vietnamese) live in close proximity to each other in separate villages in Northeast Thailand, and 2 of the groups (one Tai-speaking and one Vietnamese-speaking) live in different parts of Vietnam. Detailed information on the horizontal structure of homegardens was collected from samples of households belonging to each group. Although each ethnic group has a somewhat distinctive modal structure, the groups cluster into 2 different types. The Tai speaking Cao Lan, Kalaeng, Lao, Nyaw, and Yoy make up Type I while both of the Vietnamese groups, along with the Tai speaking Phu Thai, belong to Type II. Type I gardens have predominantly organic shapes, indeterminate boundaries, polycentric planting patterns, and multi-species composition within planting areas. Type II homegardens have geometric shapes, sharp boundaries, lineal planting patterns, and mono-species composition of planting areas. That the homegardens of most of the Tai ethnic groups share a relatively similar horizontal structural pattern that is quite different from the pattern shared by both of the Vietnamese groups suggests that the spatial layout of homegardens is strongly influenced by their different cultural models. PMID- 26752565 TI - Genetic Testing: Understanding the Personal Stories. AB - Twelve personal narratives address the challenges, benefits, and pitfalls of genetic testing. Three commentary articles explore these stories and suggest lessons that can be learned from them. The commentators come from backgrounds that include bioethics, public health, psychology, and philosophy. PMID- 26752563 TI - Inflammatory Breast Cancer: A Distinct Clinicopathological Entity Transcending Histological Distinction. AB - INTRODUCTION: Although well recognized in breast oncology literature, histologic subtypes have not been previously described in inflammatory breast cancer (IBC). The purpose of this study was to describe lobular subtype in IBC and assess the impact of histology on patient outcomes. METHODS: We performed a retrospective analysis of 659 IBC patients at MD Anderson Cancer Center between January 1984 and December 2009. Patients with Invasive Lobular, Mixed Invasive Ductal and Lobular, or Invasive Ducal Carcinomas (ILC, MIC, IDC, respectively) comprise the subject of this report. Patient characteristics and survival estimates were compared by using chi-square test and Kaplan-Meier method with log-rank statistic. Cox proportional hazards models were fit to determine association of histology with outcomes after adjustment for other characteristics. RESULTS: A total of 30, 37, and 592 patients were seen to have invasive lobular, mixed, or ductal histology, respectively. Grade 3 tumors were more common in the ductal group (78%) than in the lobular (60%) or mixed (61%) group (P = 0.01). The 3-year overall survival rates were 68%, 64%, and 62% in the lobular, mixed, and ductal groups, respectively (P = 0.68). After adjustment, histology did not have a significant effect on death in the lobular group (HR = 0.70, 95% confidence interval [CI]: 0.26-1.94; P = 0.50) or mixed group (HR = 0.53, 95% CI: 0.25-1.13; P = 0.10) compared with the ductal group. CONCLUSION: In this cohort of IBC patients, lobular histology was seen in 4.5% cases. Histology does not appear to have a significant effect on survival outcomes in IBC patients, unlike in patients with non-inflammatory breast cancer (n-IBC), indicating the distinct biological behavior of the IBC phenotype. PMID- 26752566 TI - Ethical Issues in Interpretation of Risk, from the Perspective of a Research Subject. PMID- 26752567 TI - Whole Genome Sequencing Solved Our Family's Genetic Mystery: Titin. PMID- 26752568 TI - My Experience with Direct to Consumer Genetic Testing. PMID- 26752569 TI - Illusions of Certainty. PMID- 26752570 TI - 23andMe and Me. PMID- 26752571 TI - I Had Genetic Testing for Alzheimer's Disease Without My Consent. PMID- 26752572 TI - A Test Unlike Any Other. PMID- 26752573 TI - Becoming the "Subject" of My Own Study. PMID- 26752574 TI - "Welcome to You": A Reflection on Genetic Self-Exploration. PMID- 26752575 TI - Peering into Vulnerable Genes: Genetic Risk and Population Screening. PMID- 26752576 TI - The Impact of My Genetic Testing on My Father. PMID- 26752577 TI - A Sister, a Father and a Son: Autism, Genetic Testing, and Impossible Decisions. PMID- 26752578 TI - Personal Narratives of Genetic Testing: Expectations, Emotions, and Impact on Self and Family. AB - The stories in this volume shed light on the potential of narrative inquiry to fill gaps in knowledge, particularly given the mixed results of quantitative research on patient views of and experiences with genetic and genomic testing. Published studies investigate predictors of testing (particularly risk perceptions and worry); psychological and behavioral responses to testing; and potential impact on the health care system (e.g., when patients bring DTC genetic test results to their primary care provider). Interestingly, these themes did not dominate the narratives published in this issue. Rather, these narratives included consistent themes of expectations and looking for answers; complex emotions; areas of contradiction and conflict; and family impact. More narrative research on patient experiences with genetic testing may fill gaps in knowledge regarding how patients define the benefits of testing, changes in psychological and emotional reactions to test results over time, and the impact of testing on families. PMID- 26752579 TI - In Guanine We Trust: Genetic Testing and the Sense of Coherence. AB - Aaron Antonovsky, the medical sociologist, defined the sense of coherence as a pervasive sense that the events in one's life are comprehensible, manageable, and meaningful or worthwhile. Research on the sense of coherence indicates that it is positively correlated with resilience and adaptive coping with disabilities and illnesses. The collection of first-person narratives published in Narrative Inquiry in Bioethics on genetic testing can be understood as expressions of the human effort to restore or sustain a sense of coherence in the face of illness, uncertainty, or even curiosity about one's origins and future wellbeing. While the medical usefulness of the genetic testing that was discussed in the collection of narratives was often modest, the contribution of testing to the sense of coherence was often greater. Understanding the sense of coherence as a possible motive for genetic testing might reshape the way that we conceive of the benefits and the burdens of genetic testing and the disclosure of incidental findings. PMID- 26752580 TI - Appreciating Uncertainty and Personal Preference in Genetic Testing. AB - Genetic testing seems to hold out hope for the cure of a number of debilitating conditions. At the same time, many people fear the information that genetic testing can make available. In this commentary, I argue that as of now, the nature of the information revealed in such tests should lead to cautious views about the value of genetic testing. Moreover, I suggest that our overall views about such testing should account for the fact that individuals place different sorts of value on the possession of their own genetic information. As a result, we should largely defer to personal preference in thinking about the propriety of genetic testing. PMID- 26752581 TI - Physician Religion and End-of-Life Pediatric Care: A Qualitative Examination of Physicians' Perspectives. AB - Physician religion/spirituality has the potential to influence the communication between physicians and parents of children at the end of life. In order to explore this relationship, the authors conducted two rounds of narrative interviews to examine pediatric physicians' perspectives (N=17) of how their religious/spiritual beliefs affect end-of-life communication and care. Grounded theory informed the design and analysis of the study. As a proxy for religiosity/spirituality, physicians were classified into the following groups based on the extent to which religious/spiritual language was infused into their responses: Religiously Rich Responders (RRR), Moderately Religious Responders (MRR), and Low Religious Responders (LRR). Twelve of the 17 participants (71%) were classified into the RRR or MRR groups. The majority of participants suggested that religion/spirituality played a role in their practice of medicine and communication with parents in a myriad of ways and to varying degrees. Participants used their religious/spiritual beliefs to support families' spirituality, uphold hope, participate in prayer, and alleviate their own emotional distress emerging from their patients' deaths. PMID- 26752582 TI - System Failure: No Surgeon To Be Found. AB - A woman admitted to the emergency room of a hospital died because no surgeon could be found to stop the bleeding from injuries she sustained in a farming accident. The case points to ethical shortcomings both institutionally and professionally. The call system is inadequate, and physician fears of being sued or insufficiently compensated contribute to the overall problem. Potential responses include the institutional equivalent of a root cause analysis and an understanding of the pressures brought to bear on physicians to treat emergencies. PMID- 26752583 TI - Ethical Dilemmas Relating to the Management of a Newborn with Down Syndrome and Severe Congenital Heart Disease in a Resource-Poor Setting. AB - Decision-making regarding treatment for newborns with disabilities in resource poor settings is a difficult process that can put parents and caregivers in conflict. Despite several guidelines that have helped to clarify some of the medical decision-making in Ghana, there is still no clear consensus on the specific moral criteria to be used. This article presents the case of a mother who expressed her wish that her child with Down syndrome should not have been resuscitated at birth. It explores the ethical issues at stake in both her misgivings about the resuscitation and her unwillingness to consider surgical repair of an atrioventricular (AV) canal defect. Knowing that children born with Down syndrome are able to pursue life's goals, should our treatment of complete AV canal defect in such children be considered morally obligatory, even in resource-poor settings like Ghana? PMID- 26752584 TI - Editors' Note. PMID- 26752585 TI - Molecular network control through boolean canalization. AB - Boolean networks are an important class of computational models for molecular interaction networks. Boolean canalization, a type of hierarchical clustering of the inputs of a Boolean function, has been extensively studied in the context of network modeling where each layer of canalization adds a degree of stability in the dynamics of the network. Recently, dynamic network control approaches have been used for the design of new therapeutic interventions and for other applications such as stem cell reprogramming. This work studies the role of canalization in the control of Boolean molecular networks. It provides a method for identifying the potential edges to control in the wiring diagram of a network for avoiding undesirable state transitions. The method is based on identifying appropriate input-output combinations on undesirable transitions that can be modified using the edges in the wiring diagram of the network. Moreover, a method for estimating the number of changed transitions in the state space of the system as a result of an edge deletion in the wiring diagram is presented. The control methods of this paper were applied to a mutated cell-cycle model and to a p53 mdm2 model to identify potential control targets. PMID- 26752587 TI - Possible Sirolimus-Induced Acute Pancreatitis in a Renal Transplant Recipient. PMID- 26752586 TI - The randomized controlled trial of Head Start REDI: Sustained effects on developmental trajectories of social-emotional functioning. AB - OBJECTIVE: This study assessed the sustained effects of Head Start REDI (Research based, Developmentally Informed), a randomized controlled preschool preventive intervention, on children's developmental trajectories of social-emotional functioning into elementary school. METHOD: Twenty-five Head Start centers with 44 classrooms were randomly assigned to deliver Head Start REDI or Head Start as usual. Head Start REDI featured an integrated language-emergent literacy and social-emotional skills curriculum and enhanced support for positive teaching practices. The 356 4-year-old children (54% girls; 25% African American; 17% Latino; 70% living in poverty) in those centers and classrooms were followed for 5 years (from preschool through third grade; 91% retention rate). Each year, teachers rated multiple domains of social-emotional functioning. Person-oriented latent class growth models were used to identify the different developmental trajectories of social-emotional functioning that children followed. RESULTS: Tests of proportions revealed that children who had been in the Head Start REDI intervention were statistically significantly more likely than children in the control condition to follow the most optimal developmental trajectories of social competence, aggressive-oppositional behavior, learning engagement, attention problems, student-teacher closeness, and peer rejection (odds ratio = 1.60-1.93). CONCLUSIONS: These findings suggest that enriching Head Start with evidence-based curriculum components and teaching practices can have long-lasting benefits for children's social-emotional functioning. These findings elucidate how high quality preschool experiences promote core competencies that are critical to the school success of children living in poverty. PMID- 26752589 TI - Urticaria pigmentosa. PMID- 26752588 TI - Successful Urgent Liver Retransplantation for Donor-Transmitted Hepatocellular Carcinoma. PMID- 26752590 TI - Management of systemic unfractionated heparin anticoagulation during therapeutic plasma exchange. AB - BACKGROUND: Therapeutic plasma exchange (TPE) may remove medications from the patient's plasma. Data is limited on the effect of TPE on unfractionated heparin (UFH). STUDY DESIGN AND METHODS: A retrospective review was performed of patients receiving TPE and continuous IV infusion UFH from 1/1/2008 to 6/30/2010. TPE with plasma or 5% albumin for replacement fluid and pre and post anti-Xa levels within approximately six hours were analyzed. RESULTS: Three patients had 15 TPE with plasma replacement. Anti-Xa levels decreased 47% (mean, -0.25 IU/mL) for two TPE when UFH was not changed, 78% (-0.35 IU/mL) for one TPE when the UFH rate was decreased 25%; and 61% (mean -0.72 IU/mL) for two single volume TPE and 87% ( 0.65 IU/mL) for one 1.5 plasma volume TPE when UFH was stopped. During nine TPE, the UFH rate was increased by 65% resulting in a mean increase in the anti-Xa level (mean 0.06 IU/mL, 30%). One patient had five single plasma volume TPE with 5% albumin. Anti-Xa levels decreased when the UFH was not changed (-0.06 IU/mL, 38%) and increased when UFH was increased by 30% (0.19 IU/mL, 61%) and 69% (mean 0.04 IU/mL, 15% in three TPE). The PTT increased with all albumin procedures, with more marked increases observed when the UFH rate was increased, while the antithrombin level decreased (mean 65%). CONCLUSION: Heparin was removed from the patient's plasma during TPE. Adjustment of the dose during TPE may be necessary to maintain therapeutic drug levels. Methods for monitoring UFH therapy may not agree. J. Clin. Apheresis 31:507-515, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26752592 TI - Healthcare Service Utilization for Practicing Physicians: A Population-Based Study. AB - BACKGROUND: Physicians are considered to be the most informed consumers in the use of medical services since they have more information about diseases or medical technology. However, although plenty of researchers have suggested that different medical seeking behavior exists among physicians, very few empirical studies have been conducted to investigate differences in medical utilization between physicians and the general population. OBJECTIVE: We explored differences in the utilization of healthcare services between physicians and the general population using a population-based dataset. DESIGN: A cross-sectional study. PARTICIPANTS: Data for this study were sourced from the Taiwan Longitudinal Health Insurance Database 2000. We included 1426 physicians and 1426 sex- and age matched comparison subjects. METHODS: We used Wilcoxon-Mann-Whitney tests to explore differences in variables of healthcare resource utilization between physicians and comparison subjects. We further used Kruskal-Wallis tests to examine differences in variables of healthcare resource utilization between physician practice location and comparison subjects. RESULTS: We found that physicians had significantly fewer outpatient visits (13.2 vs. 15.7, p<0.001) and significantly lower outpatient costs (US$477 vs. US$680, p<0.001) than comparison subjects. Furthermore, physicians had lower total health service costs than comparison subjects (US$643 vs. US$1066, p<0.001). This indicates that the mean total health service costs in the year 2010 was 1.66-fold greater for comparison subjects than for physicians. We also found that there were significant differences in the mean number of outpatient services (p<0.001), outpatient costs (p = 0.001), inpatients costs (p = 0.018), and total costs (p = 0.001) among office-based physicians, hospital-based physicians, and comparison subjects. Specifically, Scheffe contrast tests showed that office-based physicians had significantly more outpatient visits (19.3 vs.10.7, p<0.001) and significantly higher outpatient costs (US$656 vs. US$402, p<0.001) than hospital-based physicians. CONCLUSIONS: Physicians had less healthcare utilization than comparison subjects. Furthermore, hospital-based physicians had higher inpatient costs and less outpatient services and costs than office-based physicians. PMID- 26752591 TI - Anaplastic lymphoma kinase regulates binge-like drinking and dopamine receptor sensitivity in the ventral tegmental area. AB - Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase associated with alcohol dependence in humans and behavioral responses to ethanol in mice. To characterize the ability of ALK to control ethanol consumption, we treated mice with the ALK inhibitors TAE684 or alectinib before testing them for binge-like drinking using the drinking in the dark protocol. Mice treated with ALK inhibitors drank less ethanol than controls. In addition, TAE684 treatment abolished ethanol conditioned place preference, indicating that ALK regulates the rewarding properties of ethanol. Because the ventral tegmental area (VTA) is a key brain region involved in the rewarding effects of ethanol, we determined if Alk expression in the VTA is important for binge-like ethanol consumption. Mice expressing a short hairpin ribonucleic acid targeting Alk in the VTA drank less ethanol compared with controls. ALK is expressed on dopamine (DA) neurons in the VTA, suggesting that ALK might regulate their firing properties. Extracellular recordings of putative DA neurons in VTA slices demonstrated that ALK inhibition did not affect the ability of ethanol to stimulate, or DA to inhibit, the firing of DA neurons. However, inhibiting ALK attenuated the time-dependent reversal of inhibition produced by moderate concentrations of DA, suggesting that ALK affects DA D2 autoreceptor (D2R) desensitization. Altered desensitization of the D2R changes the firing of DA neurons and is predicted to affect DA levels and alcohol drinking. These data support the possibility that ALK might be a novel target of pharmacotherapy for reducing excessive alcohol consumption. PMID- 26752593 TI - The age dependence of T2 relaxation times of N-acetyl aspartate, creatine and choline in the human brain at 3 and 4T. AB - Knowledge of the T2 age dependence is of importance for MRS clinical studies involving subject groups with a wide age range. A number of studies have focused on the age dependence of T2 values in the human brain, with rather conflicting results. The aim of this study was to analyze the age dependence of T2 values of N-acetyl aspartate (NAA), creatine (Cr) and choline (Cho) in the human brain using data acquired at 3T and 4T and to assess the influence of the macromolecule (MM) baseline handling on the obtained results. Two distinct groups of young and elderly controls have been measured at 3T (TE = 30-540 ms, 9 young and 11 elderly subjects) and 4T (TE = 10-180 ms, 18 young and 14 elderly subjects) using single voxel spectroscopy. In addition, MM spectra were measured from two subjects using the inversion-recovery technique at 4T. All spectra were processed with LCModel using basis sets with different MM signals (measured or simulated) and also with MM signals included for a different TE range. Individual estimated T2 values were statistically analyzed using the R programming language for the age dependence of T2 values as well as the influence of the MM baseline handling. A significant decrease of T2 values of NAA and Cr in elderly subjects compared with young subjects was confirmed. The same trend was observed for Cho. Significantly higher T2 values calculated using the measured MM baseline for all studied metabolites at 4T were observed for both young and elderly subjects. To conclude, while the handling of MM and lipid signals may have a significant effect on estimated T2 values, we confirmed the age dependence of T2 values of NAA and Cr and the same trend for Cho in the human brain. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26752594 TI - Dating and biogeographical patterns in the sea slug genus Acanthodoris Gray, 1850 (Mollusca, Gastropoda, Nudibranchia). AB - Recent studies investigating vicariance and dispersal have been focused on correlating major geological events with instances of taxonomic expansion by incorporating the fossil record with molecular clock analyses. However, this approach becomes problematic for soft-bodied organisms that are poorly represented in the fossil record. Here, we estimate the phylogenetic relationships of the nudibranch genus Acanthodoris Gray, 1850 using three molecular markers (16S, COI, H3), and then test two alternative geologically calibrated molecular clock scenarios in BEAST and their effect on ancestral area reconstruction (AAR) estimates employed in LAGRANGE. The global temperate distribution of Acanthodoris spans multiple geological barriers, including the Bering Strait (~5.32 Mya) and the Baja Peninsula (~5.5 Mya), both of which are used in our dating estimates. The expansion of the Atlantic Ocean (~95-105 Mya) is also used to calibrate the relationship between A. falklandica Eliot, 1905 and A. planca Fahey and Valdes, 2005, which are distributed in southern Chile and South Africa respectively. Phylogenetic analyses recovered strong biogeographical signal and recovered two major clades representing northern and southern hemispheric distributions of Acanthodoris. When all three geological events are applied to the calibration analyses, the age for Acanthodoris is estimated to be mid-Cretaceous. When the expansion of the Atlantic Ocean is excluded from our analyses, however, Acanthodoris is estimated to be much younger, with a divergence time estimate during the Miocene. Regardless of divergence estimates, our AAR suggests that Acanthodoris may have origins in the Atlantic Ocean with the Atlantic acting as a dispersal point to the northeastern Pacific. These results suggest that Acanthodoris exhibits a rare instance of western trans arctic expansion. This study also shows that northeast Pacific specimens of A. pilosa should be regarded as A. atrogriseata and that A. serpentinotus should be regarded as a synonym of A. pina. PMID- 26752595 TI - Engineering of a Bacillus amyloliquefaciens Strain with High Neutral Protease Producing Capacity and Optimization of Its Fermentation Conditions. AB - The neutral protease has high potential for industrial applications, and attempts to improve enzyme expression level have important application values. In the present study, a neutral protease-encoding gene, Banpr, was cloned from Bacillus amyloliquefaciens strain K11, and a genetic manipulation method specific for this difficult-to-transform strain was developed for the high-level expression of neutral protease. The recombinant plasmid pUB110-Banpr was constructed in Bacillus subtilis strain WB600 and then transformed into strain K11 under optimized conditions. A positive transformant 110N-6 with the highest protease secreting capacity on skim milk plates and great genetic stability for more than 100 generations was selected for further study. Optimization of the fermentation conditions increased the enzyme activity of strain 110N-6 to 8995 +/- 250 U/ml in flask culture and 28084 +/- 1282 U/ml in 15-l fermentor, which are significantly higher than that of the native strain K11 and industrial strain B. subtilis AS.1398, respectively. The high expression level and extreme genetic stability make B. amyloliquefaciens strain 110N-6 more favorable for mass production of neutral protease for industrial uses. PMID- 26752596 TI - Diabetes Is Associated with Worse Clinical Presentation in Tuberculosis Patients from Brazil: A Retrospective Cohort Study. AB - BACKGROUND: The rising prevalence of diabetes mellitus (DM) worldwide, especially in developing countries, and the persistence of tuberculosis (TB) as a major public health issue in these same regions, emphasize the importance of investigating this association. Here, we compared the clinical profile and disease outcomes of TB patients with or without coincident DM in a TB reference center in Brazil. METHODS: We performed a retrospective analysis of a TB patient cohort (treatment naive) of 408 individuals recruited at a TB primary care center in Brazil between 2004 and 2010. Data on diagnosis of TB and DM were used to define the groups. The study groups were compared with regard to TB disease presentation at diagnosis as well as to clinical outcomes such as cure and mortality rates upon anti-tuberculosis therapy (ATT) initiation. A composite score utilizing clinical, radiological and microbiological parameters was used to compare TB severity between the groups. RESULTS: DM patients were older than non diabetic TB patients. In addition, diabetic individuals more frequently presented with cough, night sweats, hemoptysis and malaise than those without DM. The overall pattern of lung lesions assessed by chest radiographic examination was similar between the groups. Compared to non-diabetic patients, those with TB diabetes exhibited positive acid-fast bacilli in sputum samples more frequently at diagnosis and at 30 days after ATT initiation. Notably, higher values of the TB severity score were significantly associated with TB-diabetes comorbidity after adjustment for confounding factors. Moreover, during ATT, diabetic patients required more frequent transfers to TB reference hospitals for complex clinical management. Nevertheless, overall mortality and cure rates were indistinguishable between the study groups. CONCLUSIONS: These findings reinforce the idea that diabetes negatively impacts pulmonary TB severity. Our study argues for the systematic screening for DM in TB reference centers in endemic areas. PMID- 26752597 TI - Automated Reconstruction of Three-Dimensional Fish Motion, Forces, and Torques. AB - Fish can move freely through the water column and make complex three-dimensional motions to explore their environment, escape or feed. Nevertheless, the majority of swimming studies is currently limited to two-dimensional analyses. Accurate experimental quantification of changes in body shape, position and orientation (swimming kinematics) in three dimensions is therefore essential to advance biomechanical research of fish swimming. Here, we present a validated method that automatically tracks a swimming fish in three dimensions from multi-camera high speed video. We use an optimisation procedure to fit a parameterised, morphology based fish model to each set of video images. This results in a time sequence of position, orientation and body curvature. We post-process this data to derive additional kinematic parameters (e.g. velocities, accelerations) and propose an inverse-dynamics method to compute the resultant forces and torques during swimming. The presented method for quantifying 3D fish motion paves the way for future analyses of swimming biomechanics. PMID- 26752598 TI - Self-Assembly of the Toll-Like Receptor Agonist Macrophage-Activating Lipopeptide MALP-2 and of Its Constituent Peptide. AB - The self-assembly of the macrophage-activating lipopeptide MALP-2 in aqueous solution has been investigated and is compared to that of the constituent peptide GNNDESNISFKEK. MALP-2 is a toll-like receptor agonist lipopeptide with diverse potential biomedical applications and its self-assembly has not previously been examined. It is found to self-assemble, above a critical aggregation concentration (cac), into remarkable "fibre raft" structures, based on lateral aggregation of beta-sheet based bilayer tapes. Peptide GNNDESNISFKEK also forms beta-sheet structures above a cac, although the morphology is distinct, comprising highly extended and twisted tape structures. A detailed insight into the molecular packing within the MALP-2 raft and GNNDESNISFKEK nanotape structures is obtained through X-ray diffraction and small-angle X-ray scattering. These results point to the significant influence of the attached lipid chains on the self-assembly motif, which lead to the raft structure for the lipopeptide assemblies. PMID- 26752599 TI - Evaluation of the acceptability of improved supplementary foods for the treatment of moderate acute malnutrition in Burkina Faso using a mixed method approach. AB - The objective of this study was to evaluate, within the context of a randomized controlled trial of product effectiveness, the acceptability of new formulations of six corn-soy blended flours (CSB) and six lipid-based nutrient supplements (LNS) with different quantities of milk and qualities of soy for the treatment of children with moderate acute malnutrition (MAM). Our study included 1546 children aged 6-23 months and involved questionnaires after one month of supplementation home visits and interviews with a sub-sample of 20 trial participants and their caretakers, and nine focus group discussion. All 12 products were well accepted in terms of organoleptic qualities and received good ratings. However, LNS were more appreciated by caretakers and children. Additionally, an effect of soy isolate was detected on child appreciation where products with high milk content also received better ratings. CSB were not consumed as readily; 33.9% (n = 257) of children receiving CSB were reported to have leftovers compared to 17.3% (n = 134) of children receiving LNS (p=<0.001). Both CSB and LNS were referred to as foods with medicinal properties and perceived as beneficial to child health. They were both reported to have high priority in the daily feeding of the child. In conclusion, there were minimal differences in acceptability of the various CSB and LNS formulations, although CSB were less readily consumed and required smaller meal volumes. Since all products were well-accepted, decisions regarding whether the more expensive products should be used for the treatment of MAM will need to be based on their effect on child nutrition, growth and health. Future supplementary feeding programs in similar contexts could furthermore consider introducing supplementary foods as a medical treatment, as this may increase adherence and decrease sharing. PMID- 26752600 TI - The association of eating styles with weight change after an intensive combined lifestyle intervention for children and adolescents with severe obesity. AB - The main purpose of this prospective intervention study was to determine whether eating styles after an intensive, partly inpatient, one year combined lifestyle intervention are associated with weight change in the following year in severely obese children and adolescents. A total of 120 participants (8-19 years) with an average SDS-BMI of 3.41 (SD = 0.38) was included. Measurements were conducted at baseline (T0), at the end of treatment (T12) and at the end of follow up two years after baseline (T24). The primary outcome measurement was the DeltaSDS-BMI between T12 and T24. As primary determinant of weight change after treatment, the participants eating styles were evaluated with the Dutch Eating Behavior Questionnaire - child report that measures external, emotional and restraint eating. The association between outcome and determinant was assessed in linear regression analyses. Complete data were available for 76 of the 120 participants. This study shows that for girls a higher score on restraint eating at T12 and a higher score on external eating at T12 were associated with more weight (re)gain in the year after treatment. No statistically significant association with emotional eating at T12 was found. In addition for girls a higher score on external eating at T0 was associated with more weight (re)gain in the year after treatment. Furthermore, the observed changes in eating styles suggest that on average it is possible to influence these with treatment, although the detected changes were different for girls and boys and for the different eating styles. More generally, this study indicates that for girls the levels of restraint and external eating after treatment were associated with the weight change during the following year. TRIAL REGISTRATION: Netherlands Trial Register (NTR1678, registered 20-Feb-2009). PMID- 26752602 TI - Commentary. PMID- 26752601 TI - Strategies to mitigate dissociative and psychotomimetic effects of ketamine in the treatment of major depressive episodes: a narrative review. AB - Objectives Replicated evidence has demonstrated that ketamine exerts rapid-acting and potent antidepressant effects. Notwithstanding, its promise to mitigate depressive symptoms and suicidality in antidepressant-resistant populations, several limitations and safety concerns accompany ketamine including, but not limited to, the potential for abuse and psychotomimetic/dissociative experiences. The focus of the current narrative review is to synthesise available evidence of strategies that may mitigate and fully prevent treatment-emergent psychotomimetic and dissociative effects associated with ketamine administration. Methods PubMed, Google Scholar and ClinicalTrials.gov were searched for relevant articles. Results Potential avenues investigated to minimise psychotomimetic effects associated with ketamine administration include the following: (1) altering dosing and infusion rates; (2) route of administration; (3) enantiomer choice; (4) co-administration with mood stabilisers of antipsychotics; and (5) use of alternative N-methyl-d-aspartate (NMDA)-modulating agents. Emerging evidence indicates that dissociative experiences can be significantly mitigated by using an intranasal route of administration, lower dosages, or use of alternative NMDA modulating agents, namely lanicemine (AZD6765) and GLYX-13. Conclusions Currently, intranasal administration presents as the most promising strategy to mitigate dissociative and psychotomimetic effects; however, studies of strategies to mitigate the adverse events of ketamine are limited in number and quality and thus further investigation is still needed. PMID- 26752603 TI - Spatial memory in foraging games. AB - Foraging and foraging-like processes are found in spatial navigation, memory, visual search, and many other search functions in human cognition and behavior. Foraging is commonly theorized using either random or correlated movements based on Levy walks, or a series of decisions to remain or leave proximal areas known as "patches". Neither class of model makes use of spatial memory, but search performance may be enhanced when information about searched and unsearched locations is encoded. A video game was developed to test the role of human spatial memory in a canonical foraging task. Analyses of search trajectories from over 2000 human players yielded evidence that foraging movements were inherently clustered, and that clustering was facilitated by spatial memory cues and influenced by memory for spatial locations of targets found. A simple foraging model is presented in which spatial memory is used to integrate aspects of Levy based and patch-based foraging theories to perform a kind of area-restricted search, and thereby enhance performance as search unfolds. Using only two free parameters, the model accounts for a variety of findings that individually support competing theories, but together they argue for the integration of spatial memory into theories of foraging. PMID- 26752604 TI - Unintentional perspective-taking calculates whether something is seen, but not how it is seen. AB - A long established distinction exists in developmental psychology between young children's ability to judge whether objects are seen by another, known as "level 1" perspective-taking, and judging how the other sees those objects, known as "level-2" perspective-taking (Flavell, Everett, Croft, & Flavell, 1981a; Flavell, Flavell, Green, & Wilcox, 1981b). Samson, Apperly, Braithwaite, Andrews, and Bodley Scott (2010) provided evidence that there are two routes available to adults for level-1 perspective-taking: one which is triggered relatively automatically and the other requiring cognitive control. We tested whether both these routes were available for adults' level-2 perspective-taking. Explicit judgements of both level-1 and level-2 perspectives were subject to egocentric interference, suggesting a need for cognitive control. Evidence of unintentional perspective-taking was limited to level-1 judgements. PMID- 26752605 TI - Mindfulness meditation and consciousness: An integrative neuroscientific perspective. AB - Although mindfulness meditation has been practiced in the East for more than two millennia, Western scientific research and healthcare programs have only recently drawn their attention to it. Basically, the concept of mindfulness hinges on focusing on one's own awareness at the present moment. In this review we analyze different hypotheses about the functioning and the cerebral correlates of mindfulness meditation. Since mindfulness is strictly associated with a particular state of consciousness, we also examine some of the most relevant theories that have been proposed as accounts of consciousness. Finally, we suggest that consciousness and mindfulness meditation can be integrated within a neuroscientific perspective, by identifying the brain areas which seem to play an essential role in both, namely the anterior cingulate cortex, posterior cingulate cortex, insula and thalamus. PMID- 26752606 TI - A Meta-Analysis of the Prevalence of Influenza A H5N1 and H7N9 Infection in Birds. AB - Despite a much higher rate of human influenza A (H7N9) infection compared to influenza A (H5N1), and the assumption that birds are the source of human infection, detection rates of H7N9 in birds are lower than those of H5N1. This raises a question about the role of birds in the spread and transmission of H7N9 to humans. We conducted a meta-analysis of overall prevalence of H5N1 and H7N9 in different bird populations (domestic poultry, wild birds) and different environments (live bird markets, commercial poultry farms, wild habitats). The electronic database, Scopus, was searched for published papers, and Google was searched for country surveillance reports. A random effect meta-analysis model was used to produce pooled estimates of the prevalence of H5N1 and H7N9 for various subcategories. A random effects logistic regression model was used to compare prevalence rates between H5N1 and H7N9. Both viruses have low prevalence across all bird populations. Significant differences in prevalence rates were observed in domestic birds, farm settings, for pathogen and antibody testing, and during routine surveillance. Random effects logistic regression analyses show that among domestic birds, the prevalence of H5N1 is 47.48 (95% CI: 17.15-133.13, P < 0.001) times higher than H7N9. In routine surveillance (where surveillance was not conducted in response to human infections or bird outbreaks), the prevalence of H5N1 is still higher than H7N9 with an OR of 43.02 (95% CI: 16.60 111.53, P < 0.001). H7N9 in humans has occurred at a rate approximately four times higher than H5N1, and for both infections, birds are postulated to be the source. Much lower rates of H7N9 in birds compared to H5N1 raise doubts about birds as the sole source of high rates of human H7N9 infection. Other sources of transmission of H7N9 need to be considered and explored. PMID- 26752607 TI - Morphology and systematics of two freshwater urostylid ciliates, with description of a new species (Protista, Ciliophora, Hypotrichia). AB - The morphology of two freshwater urostylid species, Neourostylopsis flava spec. nov. and Pseudourostyla subtropicaChen et al., 2014, isolated from freshwater ponds in northern and southern China, respectively, was investigated following examination of specimens in vivo and following protargol staining. Neourostylopsis flava spec. nov. is distinguished from its congeners by the following characteristics: body size 150-220 * 50-75 MUm in vivo; yellow in colour; bright yellow to yellow-brownish spherical cortical granules densely arranged along marginal cirral rows and in irregular short rows on dorsal side; adoral zone with 40-55 membranelles; six to eight frontal, three or four buccal, two pretransverse ventral and seven to nine transverse cirri; 27-40 midventral pairs extending to about anterior 55% of cell; four or five left and four right marginal rows; freshwater habitat. A redescription of a freshwater population of P. subtropica is also provided. Phylogenetic analyses based on small subunit ribosomal DNA sequences shows that P. subtropica and N. flava spec. nov. group with their congeners and both Neourostylopsis and Pseudourostyla are monophyletic. PMID- 26752609 TI - Magnetic resonance lymphangiography: How to prove it? PMID- 26752608 TI - Response: Avuncularity and Kin Selection in Homosexuals: A Problematic Test or a Problematic Hypothesis? AB - Here we respond to Vasey et al.'s critical comments regarding our article, "Societal norms rather than sexual orientation influence kin altruism and avuncularity in tribal Urak-Lawoi, Italian, and Spanish adult males" (Camperio Ciani, Battaglia, & Liotta, 2015 , JSR doi:10.1080/00224499.2014.993748). The first regards the selection of the Urak-Lawoi population of Ko Lipeh, which is considered too modern and touristic to be adequate to test the kin selection and avuncular hypothesis for homosexuality. We provide historical evidence of the contrary, and show that the population at the inception of our 10 years research was indeed primitive and tribal, and probands actually grew and lived in such a society. Only a few years after the 2004 tsunami, the island was developed and invaded by mass tourism. The second comment regarded the statistical analysis and interpretation of data. We show that we consistently and conservatively considered the effects of all confounding variables, both with comparative tests, and by a series of multivariate regression analyses. This was the orthodox procedure approved by all other reviewers. In conclusion, even addressing these comments, we maintain that the kin selection and avuncularity hypothesis for homosexuality is not supported by empirical data even in this primitive and tribal society. PMID- 26752610 TI - Dawn-song onset coincides with increased HVC androgen receptor expression but is decoupled from high circulating testosterone in an equatorial songbird. AB - The song of songbirds is a testosterone-sensitive behavior that is controlled by brain regions expressing androgen receptors. At higher latitudes, seasonal singing is stimulated by increasing day-length and elevated circulating testosterone. However, a large number of songbird species inhabit equatorial regions under a nearly constant photoperiod, and the neuroendocrine mechanisms of seasonal song in these species have rarely been investigated. We studied males from an equatorial population of the silver-beaked tanager (Ramphocelus carbo), an Amazonian songbird. We found seasonality in dawn-song behavior, which was displayed continuously for more than half a year throughout an extended breeding territoriality stage. The seasonal activation of dawn-song was correlated with an increased area of androgen receptor expression in HVC, a major brain area of song control. However, testosterone levels remained low for several weeks after activation of dawn-song. Circulating levels of testosterone were elevated only later in the breeding season, coinciding with a higher dawn-song output and with the mating period. Our results suggest that the seasonal activation of dawn-song and territoriality involves an increase of androgen target cells in HVC. This mechanism could potentially function to circumvent adverse effects of high testosterone levels in a species with an extended breeding season. PMID- 26752612 TI - Measurement equivalence of the newly developed Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55). AB - OBJECTIVE: The aim of this study was to examine measurement equivalence of the newly developed Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) across age, sex, and time in a representative sample of children with newly diagnosed epilepsy. METHODS: Data come from 373 children enrolled in the Health related Quality of Life in Children with Epilepsy Study (HERQULES), a multisite prospective cohort study. Measurement equivalence was examined using a multiple group confirmatory factor analysis framework, whereby increasingly stringent parameter constraints are imposed on the model. Comparison groups were stratified based on age (4-7 years vs. 8-12 years), sex (male vs. female), and time (measurement of health-related quality of life at diagnosis vs. 24 months later). RESULTS: The QOLCE-55 demonstrated measurement equivalence at the level of strict invariance for each model tested--age: chi(2) (3,123) = 4,097.3, p < 0.001; Comparative Fit Index (CFI) = 0.968; Root Mean Square Error of Approximation (RMSEA) = 0.042 (0.038, 0.045); sex: chi(2) (3,124) = 4,188.3, p < 0.001; CFI = 0.964; RMSEA = 0.044 (0.040, 0.047); and time: chi(2) (3,121) = 5,185.0, p < 0.001; CFI = 0.965; RMSEA = 0.046 (0.043, 0.048). SIGNIFICANCE: These findings suggest that items comprising the QOLCE-55 are perceived similarly among groups stratified by age, sex, and time and provide further evidence supporting the validity of the scale in children with epilepsy. Health professionals and researchers should be confident that group comparisons made using the QOLCE-55 are unbiased and that any group differences detected are meaningful; that is, not related to differences in the interpretation of items by informants. Future research replicating these findings is encouraged. PMID- 26752613 TI - Laboratory astrochemistry: catalytic conversion of acetylene to polycyclic aromatic hydrocarbons over SiC grains. AB - Catalytic conversion reactions of acetylene on a solid SiC grain surface lead to the formation of polycyclic aromatic hydrocarbons (PAHs) and are expected to mimic chemical processes in certain astrophysical environments. Gas-phase PAHs and intermediates were detected in situ using time-of-flight mass spectrometry, and their formation was confirmed using GC-MS in a separate experiment by flowing acetylene gas through a fixed-bed reactor. Activation of acetylene correlated closely with the dangling bonds on the SiC surface which interact with and break the C-C pi bond. The addition of acetylene to the resulting radical site forms a surface ring structure which desorbs from the surface. The results of HRTEM and TG indicate that soot and graphene formation on the SiC surface depends strongly on reaction temperature. We propose that PAHs as seen through the 'UIR' emission bands can be formed through decomposition of a graphene-like material, formed on the surface of SiC grains in carbon-rich circumstellar envelopes. PMID- 26752611 TI - Sex-dependent and independent effects of long-term voluntary wheel running on Bdnf mRNA and protein expression. AB - The beneficial effects of physical activity on brain health (synaptogenesis, neurogenesis, enhanced synaptic plasticity, improved learning and memory) appear to be mediated through changes in region-specific expression of neurotrophins, transcription factors, and postsynaptic receptors, though investigations of sex differences in response to long-term voluntary wheel running are limited. PURPOSE: To examine the effect of five months of voluntary wheel running on hippocampal mRNA and protein expression of factors critical for exercise-induced structural and functional plasticity in male and female adult mice. METHODS: At 8weeks of age, male and female C57BL/6 mice were individually housed with (PA; n=20; 10 male) or without (SED; n=20; 10 male) access to a computer monitored voluntary running wheel. At 28weeks, all mice were sacrificed and hippocampi removed. Total RNA was isolated from the hippocampus and expression of total Bdnf, Bdnf transcript IV, tPA, Pgc-1a, GluR1, NR2A, and NR2B were assessed with quantitative RT-PCR and total and mature Bdnf protein were assessed with ELISA. RESULTS: We found significantly higher Bdnf IV mRNA expression in PA males (p=0.03) and females (p=0.03) compared to SED animals. Total Bdnf mRNA expression was significantly greater in PA males compared to SED males (p=0.01), but there was no difference in females. Similarly, we observed significantly higher mature Bdnf protein in PA males compared to SED males (p=0.04), but not in females. CONCLUSION: These findings indicate that the impact of long-term voluntary wheel running on transcriptional and post-translational regulation of Bdnf may be sex dependent, though the activity-dependent Bdnf IV transcript is sensitive to exercise independent of sex. PMID- 26752614 TI - Voiding Cystourethrography in the Diagnosis of Anorectal Malformations. AB - Introduction In a newborn with an anorectal malformation (ARM), it is vital to determine the anatomy of the underlying defect. After a colostomy has been created, distal colostography (DCG) is currently the chosen modality for the detection of fistulas. The role of voiding cystourethrography (VCU) is unexplored. Aim The aim of this study was to analyze the reproducibility of DCG and VCU in assessing the underlying malformation in ARM, and to evaluate any degree of concordance among them. Materials and Methods A retrospective evaluation was undertaken comparing DCG and VCU findings with definitive surgical findings in children who received both investigations for the initial management of ARM. Results In this study, 26 boys were included. Malformations were classified according to Krickenbeck classification. Four boys with perineal fistula were excluded from the analysis, as none of them needed a colostomy; therefore, comparison between both methods was not possible. VCU identified a rectourethral fistula in 12 cases, a rectovesical fistula in 4 cases, and excluded a fistula in 6 cases. VCU was false negative for a rectovesical fistula in one case. VCU showed a vesicoureteral reflux in 16 patients. Results obtained by VCU were compared with DCG. DCG showed a rectourethral fistula in 11 cases, a rectovesical in 3 cases, and excluded a fistula in 6 cases correctly. DCG was false negative in two cases, a rectoprostatic and a rectovesical fistula. The diagnostic accuracy, measuring the sensitivity was 95% in VCU (range: 76.18 99.88%) and 90% (range: 68.30-98.77%) in colostogram. Conclusion VCU can be as accurate as distal colostogram in the evaluation of male patients with ARM. VCU uses a natural orifice, without the need of a colostomy. VCU can be performed as an initial modality to determine the type of malformation and to decide on the type of early surgical management. PMID- 26752616 TI - MgxZn1-xO/Ag/MgxZn1-xO Multilayers As High-Performance Transparent Conductive Electrodes. AB - We report on the optical and electrical properties of MgxZn1-xO/Ag/MgxZn1-xO transparent conductive electrodes. The transmittance and sheet resistance of MgxZn1-xO/Ag/MgxZn1-xO multilayers deposited at room temperature were strongly dependent on the thickness and surface morphology of Ag layer. The optical absorption edge of MgxZn1-xO/Ag/MgxZn1-xO showed a blue shift with increasing Mg composition due to the increased band gap of MgxZn1-xO. The Haack figure of merit value of Mg0.28Zn0.72O/Ag/Mg0.28Zn0.72O with a 14 nm-thick Ag layer, which has a sheet resistance of 6.36 Omega/sq and an average transmittance of 89.2% at wavelengths in the range from 350 to 780 nm, was 69% higher than that of a ZnO/Ag/ZnO multilayer electrode. These results indicate that MgxZn1-xO/Ag/MgxZn1 xO multilayers, which also show low surface roughness, can be used as highly conductive transparent electrodes in various optoelectronic devices operating over a wide wavelength region. PMID- 26752615 TI - Candida albicans infection leads to barrier breakdown and a MAPK/NF-kappaB mediated stress response in the intestinal epithelial cell line C2BBe1. AB - Intestinal epithelial cells (IEC) form a tight barrier to the gut lumen. Paracellular permeability of the intestinal barrier is regulated by tight junction proteins and can be modulated by microorganisms and other stimuli. The polymorphic fungus Candida albicans, a frequent commensal of the human mucosa, has the capacity of traversing this barrier and establishing systemic disease within the host. Infection of polarized C2BBe1 IEC with wild-type C. albicans led to a transient increase of transepithelial electric resistance (TEER) before subsequent barrier disruption, accompanied by a strong decline of junctional protein levels and substantial, but considerably delayed cytotoxicity. Time resolved microarray-based transcriptome analysis of C. albicans challenged IEC revealed a prominent role of NF-kappaB and MAPK signalling pathways in the response to infection. Hence, we inferred a gene regulatory network based on differentially expressed NF-kappaB and MAPK pathway components and their predicted transcriptional targets. The network model predicted activation of GDF15 by NF-kappaB was experimentally validated. Furthermore, inhibition of NF kappaB activation in C. albicans infected C2BBe1 cells led to enhanced cytotoxicity in the epithelial cells. Taken together our study identifies NF kappaB activation as an important protective signalling pathway in the response of epithelial cells to C. albicans. PMID- 26752617 TI - Evaluation of pre-eruptive intracoronal resorption on cone-beam computed tomography: A retrospective study. AB - OBJECTIVES: This retrospective study aimed to investigate the prevalence of pre eruptive intracoronal resorption (PIR) in unerupted permanent teeth in a Turkish population using cone beam computed tomography (CBCT). METHOD: A total of 1,317 CBCT images were screened. In all the images, the following were recorded: the number of unerupted teeth, number of teeth with intracoronal resorption, affected tooth type and number, and location of radiolucent defects. Demographic data were also obtained. RESULTS: The prevalence of intracoronal resorption in the study group was 15.1%, with a prevalence in teeth of 3.5%. The prevalence of intracoronal resorption using CBCT was much higher than that recorded previously using panoramic or bitewing radiographs intracoronal resorption was more common in males (57%) than females (43%). Twenty-three cases were located in the maxilla (48%), and 25 were located in the mandible (52%). The mandibular third molar was the most affected tooth type, followed by maxillary third molars and supernumerary teeth. CONCLUSION: CBCT can be useful for diagnosing PIR defects because it provides an accurate representation of internal dental anatomy. SCANNING 38:442-447, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26752618 TI - Integrating Hybrid Life Cycle Assessment with Multiobjective Optimization: A Modeling Framework. AB - By combining life cycle assessment (LCA) with multiobjective optimization (MOO), the life cycle optimization (LCO) framework holds the promise not only to evaluate the environmental impacts for a given product but also to compare different alternatives and identify both ecologically and economically better decisions. Despite the recent methodological developments in LCA, most LCO applications are developed upon process-based LCA, which results in system boundary truncation and underestimation of the true impact. In this study, we propose a comprehensive LCO framework that seamlessly integrates MOO with integrated hybrid LCA. It quantifies both direct and indirect environmental impacts and incorporates them into the decision making process in addition to the more traditional economic criteria. The proposed LCO framework is demonstrated through an application on sustainable design of a potential bioethanol supply chain in the UK. Results indicate that the proposed hybrid LCO framework identifies a considerable amount of indirect greenhouse gas emissions (up to 58.4%) that are essentially ignored in process-based LCO. Among the biomass feedstock options considered, using woody biomass for bioethanol production would be the most preferable choice from a climate perspective, while the mixed use of wheat and wheat straw as feedstocks would be the most cost-effective one. PMID- 26752620 TI - The clock-drawing test as a possible indicator of acute psychosis. AB - The clock-drawing test (CDT) is used widely to evaluate cognitive disorders, but its role in the assessment of psychotic disorders has not been studied. We sought to examine whether the CDT plays a role as an indicator of psychosis and to establish its sensitivity to clinical improvement of psychosis. The CDT was administered twice to 53 hospitalized patients without dementia but with psychosis: once at admission and again before discharge. The CDT scores were calculated in a random order by two independent senior psychiatrists who were blinded to the patients' status (admission or discharge). The inter-rater reliability was high (0.89 at admission, 0.85 at discharge, P<0.01 for both). The severity of psychosis was assessed by the Positive and Negative Syndrome Scale (PANSS). Patients had significantly lower CDT scores at admission than at discharge (2.87+/-1.39 vs. 3.91+/-1.08, respectively, P<0.01). The PANSS-total score of the patients showed a significant improvement (84.90+/-17.77 vs. 69.18+/ 16.23, P<0.01). An inverse correlation was found between CDT performance and psychosis severity, as reflected by the PANSS-positive symptom subscale at admission (R=-0.279, P<0.05). Our findings suggest that the CDT may aid in the assessment of psychotic states and in their clinical monitoring. PMID- 26752619 TI - Effects of the Fruit Ripening Stage on Antioxidant Capacity, Total Phenolics, and Polyphenolic Composition of Crude Palm Oil from Interspecific Hybrid Elaeis oleifera * Elaeis guineensis. AB - In the present study, we assessed for the first time the changes in the antioxidant capacity, total phenolic content, and polyphenolic composition of interspecific hybrid palm oil extracted from Elaeis oleifera * Elaeis guineensis (O * G, Coari * La Me cultivar) during the fruit ripening process 18, 20, 22, and 24 weeks after anthesis. A progressive decrease (p < 0.05) of phenolic content occurred during fruit development together with marked changes in polyphenol profiles. Significant negative correlations were established between antioxidant activity measured by TEAC (R = -0.954; p < 0.05) and ORAC (R = -0.745; p < 0.05) and the fruit ripening stage, while a positive correlation between total phenolic content was found using either the TEAC assay or the ORAC assay. The highest DPPH radical scavenging activity was also obtained with oils extracted at 18 WAA. These results highlight that O * G fruits of early ripeness represent a better source of phenolic compounds and may provide extracts with higher antioxidant activities when hybrid palm oil is aimed to be used as a functional ingredient for the development of food or food products with antioxidant properties. PMID- 26752621 TI - Metabotropic glutamate2/3 receptor agonism facilitates autonomic recovery after pharmacological panic challenge in healthy humans. AB - Group II metabotropic glutamate receptors (mGluR2/3) are suggested to modulate anxiety, arousal, and stress including autonomic control. However, no study has investigated mGluR2/3-related effects on baseline autonomic activity and reactivity to emotional challenge in humans as yet. Using a double-blind, randomized placebo-controlled, cross-over study design, we investigated the influence of a 1-week treatment with the mGluR2/3 agonist LY544344, prodrug of LY354740, on autonomic reactivity to a cholecystokinin tetrapeptide (CCK-4) panic challenge in eight healthy young men. The main outcome measures were time and frequency domain heart rate variability parameters during baseline, CCK-4 challenge, and recovery. There was no evidence for LY544344-mediated effects on baseline and CCK-4 challenge vagal activity, but a significantly lower recovery low frequency (%) and low frequency/high frequency ratio in the LY544344 group, suggesting enhanced autonomic recovery. This pilot study provides first human data indicating that mGluR2/3 agonism is involved in autonomic responsiveness, suggesting an important role of mGluR2/3 in central autonomic regulation. PMID- 26752623 TI - Elucidation of Drug Metabolite Structural Isomers Using Molecular Modeling Coupled with Ion Mobility Mass Spectrometry. AB - Ion mobility-mass spectrometry (IM-MS) in combination with molecular modeling offers the potential for small molecule structural isomer identification by measurement of their gas phase collision cross sections (CCSs). Successful application of this approach to drug metabolite identification would facilitate resource reduction, including animal usage, and may benefit other areas of pharmaceutical structural characterization including impurity profiling and degradation chemistry. However, the conformational behavior of drug molecules and their metabolites in the gas phase is poorly understood. Here the gas phase conformational space of drug and drug-like molecules has been investigated as well as the influence of protonation and adduct formation on the conformations of drug metabolite structural isomers. The use of CCSs, measured from IM-MS and molecular modeling information, for the structural identification of drug metabolites has also been critically assessed. Detection of structural isomers of drug metabolites using IM-MS is demonstrated and, in addition, a molecular modeling approach has been developed offering rapid conformational searching and energy assessment of candidate structures which agree with experimental CCSs. Here it is illustrated that isomers must possess markedly dissimilar CCS values for structural differentiation, the existence and extent of CCS differences being ionization state and molecule dependent. The results present that IM-MS and molecular modeling can inform on the identity of drug metabolites and highlight the limitations of this approach in differentiating structural isomers. PMID- 26752625 TI - Substituent effect and wavelength dependence of the photoinduced Ru-O homolysis in the [Ru(bpy)2(py-SO3)](+)-type complexes. AB - [Ru(bpy)2(py-SO3)](+) (3, bpy = 2,2'-bipyridine, py-SO3 = pyridine-2-sulfonate) was recently found to undergo py-SO3 ligand dissociation and py-SO3 radical generation under hypoxic conditions upon irradiation (Chem. Commun., 2015, 51, 428). To explore the substituent effect on the Ru-O homolysis by which the py-SO3 radical may be produced, [Ru(4,4'-(R)2-bpy)(py-SO3)](+), where R = OCH3 (1), CH3 (2), COOCH3 (4), were synthesized and their photochemical properties were investigated. The py-SO3 radical generation efficiencies followed the order of 4 > 3 > 2 > 1, and the radical generation efficiencies are wavelength dependent. As a result, 3 and 4 may lead to DNA covalent binding and DNA cleavage upon 355 nm irradiation, but merely DNA covalent binding upon 470 nm irradiation. In contrast, 1 and 2 can serve as DNA photo-binding agents only due to their less efficient Ru-O homolysis. The Ru-O homolysis via the (3)sigma(Ru-O)pi*(R-bpy) state is proposed to rationalize the substituent effect and the wavelength dependence, which is supported by TD-DFT calculations. This work gave insights into the mechanism of the Ru-O homolysis and provided guidelines for developing new [Ru(bpy)2(py-SO3)](+)-type complexes with higher Ru-O homolysis efficiency. Such complexes have dual activities of photoactivated chemotherapy (PACT) and photodynamic therapy (PDT) under hypoxic conditions and are therefore promising as a new class of antitumor drugs. PMID- 26752627 TI - The iPlant Collaborative: Cyberinfrastructure for Enabling Data to Discovery for the Life Sciences. AB - The iPlant Collaborative provides life science research communities access to comprehensive, scalable, and cohesive computational infrastructure for data management; identity management; collaboration tools; and cloud, high performance, high-throughput computing. iPlant provides training, learning material, and best practice resources to help all researchers make the best use of their data, expand their computational skill set, and effectively manage their data and computation when working as distributed teams. iPlant's platform permits researchers to easily deposit and share their data and deploy new computational tools and analysis workflows, allowing the broader community to easily use and reuse those data and computational analyses. PMID- 26752626 TI - Differential atrial performance at rest and exercise in athletes: Potential trigger for developing atrial dysfunction? AB - Highly trained athletes show an increased risk of atrial arrhythmias. Little is known about atrial volumes and function during exercise in this population. Our aim was to analyze atrial size and contractile function during exercise. Fifty endurance athletes with 11 +/- 8 h of training per week and 30 sedentary control subjects were included. Echocardiography was performed at baseline and during exercise. Left (LA) and right atrial (RA) size and function were assessed by two dimensional echocardiography. Peak negative strain (Sa) during atrial contraction and active atrial emptying volume (AEV) were measured. Athletes and control subjects showed a significant increment of deformation and AEV of both atria with exercise (P < 0.01 vs baseline for LA and RA). Among athletes, a subgroup with significant LA (n = 8)/RA (n = 15) dilatation (>=40 mL/m2 ) showed a significantly lower increment in AEV with exercise (LA?AEV: 1.4 +/- 1.1 mL/m2 vs 2.1 +/- 0.9 mL/m2 , P = 0.04; RA?AEV: 0.9 +/- 0.8 mL/m2 vs 2.3 +/- 1.1 mL/m2 , P < 0.01) and lower increment in deformation vs other athletes (LA?Sa: -3.2 +/- 2.9% vs -9.5 +/- 4.4%, P < 0.01; RA?Sa: -2.5 +/- 3.3% vs. -9.8 +/- 3.3%, P < 0.01). During exercise, active atrial strain increases, but less in athletes compared to controls, but due to larger atrial volumes, they reached similar increases in atrial emptying volume. However, this overall lesser deformation increases from a subgroup with significant atrial dilatation showing impairment in atrial contractile reserve. PMID- 26752624 TI - Modified inflammation-based score as an independent malignant predictor in patients with pulmonary focal ground-glass opacity: a propensity score matching analysis. AB - Pulmonary focal Ground-glass Opacities (fGGOs) would frequently be identified after widely implementation of low-dose computed tomography (LDCT) screening. Because of the high false-positive rate of LDCT, antibiotics should be regarded as advocates in clinical management for detected fGGOs. Retrospectively review consecutive patients with fGGOs between August 2006 and August 2012. Then, relative Glasgow prognostic score (GPS) were constructed in three different systems, traditional GPS system (tGPS), modified GPS system 1 (m1GPS), and modified GPS system 2 (m2GPS). Moreover, propensity score matching (PSM) was employed in balancing baseline covariates. After PSM, patients were matched and included in benign and malignant groups as 1:1 ratio. All reported parameters were balanced in both groups and no statistical differences could be detected. Finally, m1GPS exhibited remarkable different distribution between benign and malignant fGGOs. In detail, m1GPS 1 was more frequently observed in benign fGGOs nodules, while m1GPS 2 in malignant fGGOs nodules. Modified inflammation-based score was identified as an independent predictor of malignancies in patients with pulmonary fGGOs. Patients with m1GPS 1 were more likely to be benign fGGOs, while victims with m1GPS 2 more likely to be malignant. PMID- 26752628 TI - Caries Epidemiology and Community Dentistry: Chances for Future Improvements in Caries Risk Groups. Outcomes of the ORCA Saturday Afternoon Symposium, Greifswald, 2014. Part 1. AB - This paper reviews the first part of the outcomes of the ORCA Saturday Afternoon Symposium 2014 dealing with 'caries epidemiology and community dentistry: chances for future improvements in caries risk groups'. After the caries decline in many countries, there are remaining pockets of higher caries levels, mostly in the primary dentition and/or linked to a low socio-economic status (SES). The review into the evidence of caries-preventive measures clearly points to the use of fluorides, especially toothbrushing with fluoridated toothpaste and collective measures such as water fluoridation. In contrast to several unsuccessful high risk approaches, community and public health programmes seem to be able to ensure a population-wide access and compliance in risk groups. Their simple and evidence based measures mostly combine regular plaque removal and fluoride applications via toothbrushing, at least for children and adolescents. For the future, the common risk factor approach which addresses associations between oral health, social deprivation, diet, hygiene, smoking, alcohol use and stress should lead to combined efforts with other community health and education specialists. Further engagement with public policy, community leaders and administration is needed in order to strengthen healthy choices and behaviour, e.g. in 'healthy' schools and kindergartens. It seems advisable that these population programmes also aim at improving upstream factors. PMID- 26752629 TI - PpASCL, the Physcomitrella patens Anther-Specific Chalcone Synthase-Like Enzyme Implicated in Sporopollenin Biosynthesis, Is Needed for Integrity of the Moss Spore Wall and Spore Viability. AB - Sporopollenin is the main constituent of the exine layer of spore and pollen walls. The anther-specific chalcone synthase-like (ASCL) enzyme of Physcomitrella patens, PpASCL, has previously been implicated in the biosynthesis of sporopollenin, the main constituent of exine and perine, the two outermost layers of the moss spore cell wall. We made targeted knockouts of the corresponding gene, PpASCL, and phenotypically characterized ascl sporophytes and spores at different developmental stages. Ascl plants developed normally until late in sporophytic development, when the spores produced were structurally aberrant and inviable. The development of the ascl spore cell wall appeared to be arrested early in microspore development, resulting in small, collapsed spores with altered surface morphology. The typical stratification of the spore cell wall was absent with only an abnormal perine recognisable above an amorphous layer possibly representing remnants of compromised intine and/or exine. Equivalent resistance of the spore walls of ascl mutants and the control strain to acetolysis suggests the presence of chemically inert, defective sporopollenin in the mutants. Anatomical abnormalities of late-stage ascl sporophytes include a persistent large columella and an air space incompletely filled with spores. Our results indicate that the evolutionarily conserved PpASCL gene is needed for proper construction of the spore wall and for normal maturation and viability of moss spores. PMID- 26752630 TI - Long-Lasting Immune Protection and Other Epidemiological Findings after Chikungunya Emergence in a Cambodian Rural Community, April 2012. AB - The East/Central/South African genotype of Chikungunya virus with the E1-A226V mutation emerged in 2011 in Cambodia and spread in 2012. An outbreak of 190 cases was documented in Trapeang Roka, a rural village. We surveyed 425 village residents within 3-4 weeks after the outbreak, and determined the sensitivity and specificity of case definitions and factors associated with infection by CHIKV. Self-reported clinical presentation consisted mostly of fever, rash and arthralgia. The presence of all three clinical signs or symptoms was identified as the most sensitive (67%) and specific (84%) self-reported diagnostic clinical indicator compared to biological confirmation by MAC-ELISA or RT-PCR used as a reference. Having an indoor occupation was associated with lower odds of infection compared with people who remained at home (adjOR 0.32, 95%CI 0.12 0.82). In contrast with findings from outbreaks in other settings, persons aged above 40 years were less at risk of CHIKV infection, likely reflecting immune protection acquired when Chikungunya circulated in Cambodia before the Khmer Rouge regime in 1975. In view of the very particular history of Cambodia, our epidemiological data from Trapeang Roka are the first to support the persistence of CHIKV antibodies over a period of 40 years. PMID- 26752632 TI - A quantitative understanding of lac repressor's binding specificity and flexibility. AB - Lac repressor, the first discovered transcriptional regulator, has been shown to confer multiple-modes of binding to its operator sites depending on the central spacer length. Other homolog members in the LacI/GalR family (PurR and YcjW) cannot bind their operator sites with similar structural flexibility. To decipher the underlying mechanism for this unique property, we used Spec-seq approach combined with site-directed mutagenesis to quantify the DNA binding specificity of multiple hybrids of lacI and PurR. We find that lac repressor's recognition di residues YQ and its hinge helix loop regions are both critical for its structural flexibility. Also, specificity profiling of the whole lac operator suggests that a simple additive model from single variants suffice to predict other multivariant sites' energy reasonably well, and the genome occupancy model based on this specificity data correlates well with in vivo lac repressor binding profile. PMID- 26752631 TI - Two-Dimensional Differential Gel Electrophoresis to Identify Protein Biomarkers in Amniotic Fluid of Edwards Syndrome (Trisomy 18) Pregnancies. AB - BACKGROUND: Edwards syndrome (ES) is a severe chromosomal abnormality with a prevalence of about 0.8 in 10,000 infants born alive. The aims of this study were to identify candidate proteins associated with ES pregnancies from amniotic fluid supernatant (AFS) using proteomics, and to explore the role of biological networks in the pathophysiology of ES. METHODS: AFS from six second trimester pregnancies with ES fetuses and six normal cases were included in this study. Fluorescence-based two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) were used for comparative proteomic analysis. The identified proteins were further validated by Western blotting and the role of biological networks was analyzed. RESULTS: Twelve protein spots were differentially expressed by more than 1.5-fold in the AFS of the ES pregnancies. MALDI-TOF/MS identified one up-regulated protein: apolipoprotein A1 (ApoA1), and four under regulated proteins: vitamin D binding protein (VDBP), alpha-1-antitrypsin (A1AT), insulin-like growth factor-binding protein 1 (IGFBP-1), and transthyretin (TTR). Western blot and densitometric analysis of ApoA1, A1AT, IGFBP-1, and TTR confirmed the alteration of these proteins in the amniotic fluid samples. Biological network analysis revealed that the proteins of the ES AFS were involved mainly in lipid and hormone metabolism, immune response, and cardiovascular disease. CONCLUSIONS: These five proteins may be involved in the pathogenesis of ES. Further studies are needed to explore. PMID- 26752633 TI - Linking the Composition of Bacterial and Archaeal Communities to Characteristics of Soil and Flora Composition in the Atlantic Rainforest. AB - The description of microbiomes as intrinsic fractions of any given ecosystem is an important issue, for instance, by linking their compositions and functions with other biotic and abiotic components of natural systems and hosts. Here we describe the archaeal and bacterial communities from soils of the Atlantic Rainforest in Brazil. Based on the comparison of three areas located along an altitudinal gradient-namely, Santa Virginia, Picinguaba and Restinga-we detected the most abundant groups of Bacteria (Acidobacteria and Proteobacteria) and Archaea (Thaumarchaeota, Crenarchaeota and Euryarchaeota). The particular composition of such communities in each of these areas was first evidenced by PCR DGGE patterns [determined for Bacteria, Archaea and ammonia-oxidizing organisms ammonia-oxidizing archaea (AOA) and bacteria (AOB)]. Moreover, sequence-based analysis provided a better resolution of communities, which indicated distinct frequencies of archaeal phyla and bacterial OTUs across areas. We found, as indicated by the Mantel test and multivariate analyses, a potential effect of the flora composition that outpaces the effect of soil characteristics (either physical and chemical) influencing the assembly of these microbial communities in soils. Our results indicate a collective role of the ecosystem underlying observed differences in microbial communities in these soils. Particularly, we posit that rainforest preservation also needs to take into account the maintenance of the soil biodiversity, as this is prompted to influence major processes that affect ecosystem functioning. PMID- 26752634 TI - Benefits and Challenges with Applying Unique Molecular Identifiers in Next Generation Sequencing to Detect Low Frequency Mutations. AB - Indexing individual template molecules with a unique identifier (UID) before PCR and deep sequencing is promising for detecting low frequency mutations, as true mutations could be distinguished from PCR errors or sequencing errors based on consensus among reads sharing same index. In an effort to develop a robust assay to detect from urine low-abundant bladder cancer cells carrying well-documented mutations, we have tested the idea first on a set of mock templates, with wild type and known mutants mixed at defined ratios. We have measured the combined error rate for PCR and Illumina sequencing at each nucleotide position of three exons, and demonstrated the power of a UID in distinguishing and correcting errors. In addition, we have demonstrated that PCR sampling bias, rather than PCR errors, challenges the UID-deep sequencing method in faithfully detecting low frequency mutation. PMID- 26752636 TI - Correction: SNAP23 Regulates Endothelial Exocytosis of von Willebrand Factor. PMID- 26752635 TI - Disposable Soma Theory and the Evolution of Maternal Effects on Ageing. AB - Maternal effects are ubiquitous in nature and affect a wide range of offspring phenotypes. Recent research suggests that maternal effects also contribute to ageing, but the theoretical basis for these observations is poorly understood. Here we develop a simple model to derive expectations for (i) if maternal effects on ageing evolve; (ii) the strength of maternal effects on ageing relative to direct environmental effects; and (iii) the predicted relationships between environmental quality, maternal age and offspring lifespan. Our model is based on the disposable soma theory of ageing, and the key assumption is thus that mothers trade off their own somatic maintenance against investment in offspring. This trade-off affects the biological age of offspring at birth in terms of accumulated damage, as indicated by biomarkers such as oxidative stress or telomere length. We find that the optimal allocation between investment in maternal somatic investment and investment in offspring results in old mothers and mothers with low resource availability producing offspring with reduced life span. Furthermore, the effects are interactive, such that the strongest maternal age effects on offspring lifespan are found under low resource availability. These findings are broadly consistent with results from laboratory studies investigating the onset and rate of ageing and field studies examining maternal effects on ageing in the wild. PMID- 26752638 TI - Molecular and Functional Characterization of a Polygalacturonase-Inhibiting Protein from Cynanchum komarovii That Confers Fungal Resistance in Arabidopsis. AB - Compliance with ethical standards: This study did not involve human participants and animals, and the plant of interest is not an endangered species. Polygalacturonase-inhibiting proteins (PGIPs) are leucine-rich repeat proteins that plants produce against polygalacturonase, a key virulence agent in pathogens. In this paper, we cloned and purified CkPGIP1, a gene product from Cynanchum komarovii that effectively inhibits polygalacturonases from Botrytis cinerea and Rhizoctonia solani. We found the expression of CkPGIP1 to be induced in response to salicylic acid, wounding, and infection with B. cinerea and R. solani. In addition, transgenic overexpression in Arabidopsis enhanced resistance against B. cinerea. Furthermore, CkPGIP1 obtained from transgenic Arabidopsis inhibited the activity of B. cinerea and R. solani polygalacturonases by 62.7 66.4% and 56.5-60.2%, respectively. Docking studies indicated that the protein interacts strongly with the B1-sheet at the N-terminus of the B. cinerea polygalacturonase, and with the C-terminus of the polygalacturonase from R. solani. This study highlights the significance of CkPGIP1 in plant disease resistance, and its possible application to manage fungal pathogens. PMID- 26752640 TI - Generation of a Conditional Allele of the Transcription Factor Atonal Homolog 8 (Atoh8). AB - Atonal Homolog 8 (Atoh8) is a basic helix-loop-helix (bHLH) transcription factor that is highly conserved across species and expressed in multiple tissues during embryogenesis. In the developing pancreas, Atoh8 is expressed in endocrine progenitors but declines in hormone-positive cells, suggesting a role during early stages of the endocrine differentiation program. We previously generated a whole-body Atoh8 knockout but early lethality of null embryos precluded assessment of Atoh8 functions during organ development. Here we report the generation of a conditional Atoh8 knockout mouse strain by insertion of two loxP sites flanking exon 1 of the Atoh8 gene. Pancreas-specific Atoh8 knockout (Atoh8 Deltapanc) mice were obtained by mating this strain with a Pdx1-Cre transgenic line. Atoh8 Deltapanc mice were born at the expected mendelian ratio and showed normal appearance and fertility. Pancreas weight and gross pancreatic morphology were normal. All pancreatic cell lineages were present, although endocrine delta (somatostatin) cells were modestly augmented in Atoh8 Deltapanc as compared to control neonates. This increase did not affect whole-body glucose tolerance in adult knockout animals. Gene expression analysis in embryonic pancreases at the time of the major endocrine differentiation wave revealed modest alterations in several early endocrine differentiation markers. Together, these data argue that Atoh8 modulates activation of the endocrine program but it is not essential for pancreas formation or endocrine differentiation in the mouse. Given the ubiquitous expression pattern of Atoh8, the availability of a mouse strain carrying a conditional allele for this gene warrants further studies using temporally regulated Cre transgenic lines to elucidate time or cell-autonomous functions of Atoh8 during development and in the adult. PMID- 26752642 TI - Understanding Urban Demand for Wild Meat in Vietnam: Implications for Conservation Actions. AB - Vietnam is a significant consumer of wildlife, particularly wild meat, in urban restaurant settings. To meet this demand, poaching of wildlife is widespread, threatening regional and international biodiversity. Previous interventions to tackle illegal and potentially unsustainable consumption of wild meat in Vietnam have generally focused on limiting supply. While critical, they have been impeded by a lack of resources, the presence of increasingly organised criminal networks and corruption. Attention is, therefore, turning to the consumer, but a paucity of research investigating consumer demand for wild meat will impede the creation of effective consumer-centred interventions. Here we used a mixed-methods research approach comprising a hypothetical choice modelling survey and qualitative interviews to explore the drivers of wild meat consumption and consumer preferences among residents of Ho Chi Minh City, Vietnam. Our findings indicate that demand for wild meat is heterogeneous and highly context specific. Wild-sourced, rare, and expensive wild meat-types are eaten by those situated towards the top of the societal hierarchy to convey wealth and status and are commonly consumed in lucrative business contexts. Cheaper, legal and farmed substitutes for wild-sourced meats are also consumed, but typically in more casual consumption or social drinking settings. We explore the implications of our results for current conservation interventions in Vietnam that attempt to tackle illegal and potentially unsustainable trade in and consumption of wild meat and detail how our research informs future consumer-centric conservation actions. PMID- 26752641 TI - The Mexican Cycle of Suicide: A National Analysis of Seasonality, 2000-2013. AB - INTRODUCTION: Suicide is a complex and multifactorial phenomenon with growing importance to public health. An increase in its occurrence has been observed in Mexico over the past 10 years. The present article analyzes the secular trend in suicide at the national level between the years 2000 and 2013. MATERIALS AND METHODS: All suicides during the study period (n = 64,298, of which 82.11% were men) were characterized using a spectral decomposition of the time series and a wavelet analysis to evaluate the effect of seasonal changes, type of area (urban versus rural) and sex. RESULTS: A seasonal pattern was observed with statistically significant cycles every 12 months, where peaks were identified in May but only for men in urban zones as of the year 2007. In addition, specific days of the year were found to have a higher frequency of suicides, which coincided with holidays (New Year, Mother's Day, Mexican Independence Day and Christmas). CONCLUSION: A wavelet analysis can be used to decompose complex time series. To the best of our knowledge, this is the first application of this technique to the study of suicides in developing countries. This analysis enabled identifying a seasonal pattern among urban men in Mexico. The identification of seasonal patterns can help to create primary prevention strategies, increase the dissemination of crisis intervention strategies and promote mental health. These strategies could be emphasized during specific periods of the year and directed towards profiles with a higher risk. PMID- 26752637 TI - Geographic Variations in Retention in Care among HIV-Infected Adults in the United States. AB - OBJECTIVE: To understand geographic variations in clinical retention, a central component of the HIV care continuum and key to improving individual- and population-level HIV outcomes. DESIGN: We evaluated retention by US region in a retrospective observational study. METHODS: Adults receiving care from 2000-2010 in 12 clinical cohorts of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) contributed data. Individuals were assigned to Centers for Disease Control and Prevention (CDC)-defined regions by residential data (10 cohorts) and clinic location as proxy (2 cohorts). Retention was >=2 primary HIV outpatient visits within a calendar year, >90 days apart. Trends and regional differences were analyzed using modified Poisson regression with clustering, adjusting for time in care, age, sex, race/ethnicity, and HIV risk, and stratified by baseline CD4+ count. RESULTS: Among 78,993 adults with 444,212 person-years of follow-up, median time in care was 7 years (Interquartile Range: 4-9). Retention increased from 2000 to 2010: from 73% (5,000/6,875) to 85% (7,189/8,462) in the Northeast, 75% (1,778/2,356) to 87% (1,630/1,880) in the Midwest, 68% (8,451/12,417) to 80% (9,892/12,304) in the South, and 68% (5,147/7,520) to 72% (6,401/8,895) in the West. In adjusted analyses, retention improved over time in all regions (p<0.01, trend), although the average percent retained lagged in the West and South vs. the Northeast (p<0.01). CONCLUSIONS: In our population, retention improved, though regional differences persisted even after adjusting for demographic and HIV risk factors. These data demonstrate regional differences in the US which may affect patient care, despite national care recommendations. PMID- 26752639 TI - Chronic Intake of Japanese Sake Mediates Radiation-Induced Metabolic Alterations in Mouse Liver. AB - Sake is a traditional Japanese alcoholic beverage that is gaining popularity worldwide. Although sake is reported to have beneficial health effects, it is not known whether chronic sake consumption modulates health risks due to radiation exposure or other factors. Here, the effects of chronic administration of sake on radiation-induced metabolic alterations in the livers of mice were evaluated. Sake (junmai-shu) was administered daily to female mice (C3H/He) for one month, and the mice were exposed to fractionated doses of X-rays (0.75 Gy/day) for the last four days of the sake administration period. For comparative analysis, a group of mice were administered 15% (v/v) ethanol in water instead of sake. Metabolites in the liver were analyzed by capillary electrophoresis-time-of flight mass spectrometry one day following the last exposure to radiation. The metabolite profiles of mice chronically administered sake in combination with radiation showed marked changes in purine, pyrimidine, and glutathione (GSH) metabolism, which were only partially altered by radiation or sake administration alone. Notably, the changes in GSH metabolism were not observed in mice treated with radiation following chronic administration of 15% ethanol in water. Changes in several metabolites, including methionine and valine, were induced by radiation alone, but were not detected in the livers of mice who received chronic administration of sake. In addition, the chronic administration of sake increased the level of serum triglycerides, although radiation exposure suppressed this increase. Taken together, the present findings suggest that chronic sake consumption promotes GSH metabolism and anti-oxidative activities in the liver, and thereby may contribute to minimizing the adverse effects associated with radiation. PMID- 26752644 TI - CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5. AB - Recent studies have implicated chemokines in microglial activation and pathogenesis of neuropathic pain. C-X-C motif chemokine 13 (CXCL13) is a B lymphocyte chemoattractant that activates CXCR5. Using the spinal nerve ligation (SNL) model of neuropathic pain, we found that CXCL13 was persistently upregulated in spinal cord neurons after SNL, resulting in spinal astrocyte activation via CXCR5 in mice. shRNA-mediated inhibition of CXCL13 in the spinal cord persistently attenuated SNL-induced neuropathic pain. Interestingly, CXCL13 expression was suppressed by miR-186-5p, a microRNA that colocalized with CXCL13 and was downregulated after SNL. Spinal overexpression of miR-186-5p decreased CXCL13 expression, alleviating neuropathic pain. Furthermore, SNL induced CXCR5 expression in spinal astrocytes, and neuropathic pain was abrogated in Cxcr5-/- mice. CXCR5 expression induced by SNL was required for the SNL-induced activation of spinal astrocytes and microglia. Intrathecal injection of CXCL13 was sufficient to induce pain hypersensitivity and astrocyte activation via CXCR5 and ERK. Finally, intrathecal injection of CXCL13-activated astrocytes induced mechanical allodynia in naive mice. Collectively, our findings reveal a neuronal/astrocytic interaction in the spinal cord by which neuronally produced CXCL13 activates astrocytes via CXCR5 to facilitate neuropathic pain. Thus, miR 186-5p and CXCL13/CXCR5-mediated astrocyte signaling may be suitable therapeutic targets for neuropathic pain. PMID- 26752643 TI - Towards HIV-1 remission: potential roles for broadly neutralizing antibodies. AB - Current antiretroviral drug therapies do not cure HIV-1 because they do not eliminate a pool of long-lived cells harboring immunologically silent but replication-competent proviruses - termed the latent reservoir. Eliminating this reservoir and stimulating the immune response to control infection in the absence of therapy remain important but unsolved goals of HIV-1 cure research. Recently discovered broadly neutralizing antibodies (bNAbs) exhibit remarkable breadth and potency in their ability to neutralize HIV-1 in vitro, and recent studies have demonstrated new therapeutic applications for passively administered bNAbs in vivo. This Review discusses the roles bNAbs might play in HIV-1 treatment regimens, including prevention, therapy, and cure. PMID- 26752645 TI - Transcription factor ICBP90 regulates the MIF promoter and immune susceptibility locus. AB - The immunoregulatory cytokine macrophage migration inhibitory factor (MIF) is encoded in a functionally polymorphic locus that is linked to the susceptibility of autoimmune and infectious diseases. The MIF promoter contains a 4-nucleotide microsatellite polymorphism (-794 CATT) that repeats 5 to 8 times in the locus, with greater numbers of repeats associated with higher mRNA levels. Because there is no information about the transcriptional regulation of these common alleles, we used oligonucleotide affinity chromatography and liquid chromatography-mass spectrometry to identify nuclear proteins that interact with the -794 CATT5-8 site. An analysis of monocyte nuclear lysates revealed that the transcription factor ICBP90 (also known as UHRF1) is the major protein interacting with the MIF microsatellite. We found that ICBP90 is essential for MIF transcription from monocytes/macrophages, B and T lymphocytes, and synovial fibroblasts, and TLR induced MIF transcription is regulated in an ICBP90- and -794 CATT5-8 length dependent manner. Whole-genome transcription analysis of ICBP90 shRNA-treated rheumatoid synoviocytes uncovered a subset of proinflammatory and immune response genes that overlapped with those regulated by MIF shRNA. In addition, the expression levels of ICBP90 and MIF were correlated in joint synovia from patients with rheumatoid arthritis. These findings identify ICBP90 as a key regulator of MIF transcription and provide functional insight into the regulation of the polymorphic MIF locus. PMID- 26752647 TI - Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin. AB - BACKGROUND: Arthrogryposis, defined as congenital joint contractures in 2 or more body areas, is a clinical sign rather than a specific disease diagnosis. To date, more than 400 different disorders have been described that present with arthrogryposis, and variants of more than 220 genes have been associated with these disorders; however, the underlying molecular etiology remains unknown in the considerable majority of these cases. METHODS: We performed whole exome sequencing (WES) of 52 patients with clinical presentation of arthrogryposis from 48 different families. RESULTS: Affected individuals from 17 families (35.4%) had variants in known arthrogryposis-associated genes, including homozygous variants of cholinergic gamma nicotinic receptor (CHRNG, 6 subjects) and endothelin converting enzyme-like 1 (ECEL1, 4 subjects). Deleterious variants in candidate arthrogryposis-causing genes (fibrillin 3 [FBN3], myosin IXA [MYO9A], and pleckstrin and Sec7 domain containing 3 [PSD3]) were identified in 3 families (6.2%). Moreover, in 8 families with a homozygous mutation in an arthrogryposis associated gene, we identified a second locus with either a homozygous or compound heterozygous variant in a candidate gene (myosin binding protein C, fast type [MYBPC2] and vacuolar protein sorting 8 [VPS8], 2 families, 4.2%) or in another disease-associated genes (6 families, 12.5%), indicating a potential mutational burden contributing to disease expression. CONCLUSION: In 58.3% of families, the arthrogryposis manifestation could be explained by a molecular diagnosis; however, the molecular etiology in subjects from 20 families remained unsolved by WES. Only 5 of these 20 unrelated subjects had a clinical presentation consistent with amyoplasia; a phenotype not thought to be of genetic origin. Our results indicate that increased use of genome-wide technologies will provide opportunities to better understand genetic models for diseases and molecular mechanisms of genetically heterogeneous disorders, such as arthrogryposis. FUNDING: This work was supported in part by US National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, and US National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS058529 to J.R. Lupski. PMID- 26752650 TI - Asymmetrical Polyhedral Configuration of Giant Vesicles Induced by Orderly Array of Encapsulated Colloidal Particles. AB - Giant vesicles (GVs) encapsulating colloidal particles by a specific volume fraction show a characteristic configuration under a hypertonic condition. Several flat faces were formed in GV membrane with orderly array of inner particles. GV shape changed from the spherical to the asymmetrical polyhedral configuration. This shape deformation was derived by entropic interaction between inner particles and GV membrane. Because a part of inner particles became to form an ordered phase in the region neighboring the GV membrane, free volume for the other part of particles increased. Giant vesicles encapsulating colloidal particles were useful for the model of "crowding effect" which is the entropic interaction in the cell. PMID- 26752651 TI - Editorial Commentary: Can noninvasive imaging techniques improve care for patients at risk for sudden cardiac death? PMID- 26752646 TI - CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. AB - Colon tumors arise in a stepwise fashion from either discrete genetic perturbations or epigenetic dysregulation. To uncover the key epigenetic regulators that drive colon cancer growth, we used a CRISPR loss-of-function screen and identified a number of essential genes, including the bromodomain and extraterminal (BET) protein BRD4. We found that BRD4 is critical for colon cancer proliferation, and its knockdown led to differentiation effects in vivo. JQ1, a BET inhibitor, preferentially reduced growth in a subset of epigenetically dysregulated colon cancers characterized by the CpG island methylator phenotype (CIMP). Integrated transcriptomic and genomic analyses defined a distinct superenhancer in CIMP+ colon cancers that regulates cMYC transcription. We found that the long noncoding RNA colon cancer-associated transcript 1 (CCAT1) is transcribed from this superenhancer and is exquisitely sensitive to BET inhibition. Concordantly, cMYC transcription and cell growth were tightly correlated with the presence of CCAT1 RNA in a variety of tumor types. Taken together, we propose that CCAT1 is a clinically tractable biomarker for identifying patients who are likely to benefit from BET inhibitors. PMID- 26752649 TI - Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation. AB - Although defects in intestinal barrier function are a key pathogenic factor in patients with inflammatory bowel diseases (IBDs), the molecular pathways driving disease-specific alterations of intestinal epithelial cells (IECs) are largely unknown. Here, we addressed this issue by characterizing the transcriptome of IECs from IBD patients using a genome-wide approach. We observed disease-specific alterations in IECs with markedly impaired Rho-A signaling in active IBD patients. Localization of epithelial Rho-A was shifted to the cytosol in IBDs, and inflammation was associated with suppressed Rho-A activation due to reduced expression of the Rho-A prenylation enzyme geranylgeranyltransferase-I (GGTase I). Functionally, we found that mice with conditional loss of Rhoa or the gene encoding GGTase-I, Pggt1b, in IECs exhibit spontaneous chronic intestinal inflammation with accumulation of granulocytes and CD4+ T cells. This phenotype was associated with cytoskeleton rearrangement and aberrant cell shedding, ultimately leading to loss of epithelial integrity and subsequent inflammation. These findings uncover deficient prenylation of Rho-A as a key player in the pathogenesis of IBDs. As therapeutic triggering of Rho-A signaling suppressed intestinal inflammation in mice with GGTase-I-deficient IECs, our findings suggest new avenues for treatment of epithelial injury and mucosal inflammation in IBD patients. PMID- 26752652 TI - Oral Antiplatelet Therapy in Coronary Disease. AB - Ischemic heart disease is the major isolated cause of death worldwide, responsible for 7,249,000 deaths in 2008, 12.7% of deaths from any causes. The inhibition of platelet activation and aggregation is an important therapeutic target. Cyclooxygenase inhibitors and thienopyridines are currently the 2 most used pharmacological classes, but novel antiplatelet agents have currently an important role. The most recent thienopyridine, prasugrel, allows an irreversible inhibition of the P2Y12 platelet receptor associated to a faster and more consistent onset of action rather the previous antiplatelet agents of the same class. Cyclopentyl-triazolo-pyrimidines, a newer pharmacological class from which ticagrelor is an example, also act at the P2Y12 platelet receptor, and like prasugrel, ticagrelor inhibits platelet aggregation in a fast and consistent manner, however, in a reversible way. This article aims to conduct a review on the literature about the most recent information and guidelines on oral antiplatelet agents available for the management of coronary disease. PMID- 26752648 TI - Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease. AB - Deregulated protein and Ca2+ homeostasis underlie synaptic dysfunction and neurodegeneration in Huntington disease (HD); however, the factors that disrupt homeostasis are not fully understood. Here, we determined that expression of downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, is reduced in murine in vivo and in vitro HD models and in HD patients. DREAM downregulation was observed early after birth and was associated with endogenous neuroprotection. In the R6/2 mouse HD model, induced DREAM haplodeficiency or blockade of DREAM activity by chronic administration of the drug repaglinide delayed onset of motor dysfunction, reduced striatal atrophy, and prolonged life span. DREAM-related neuroprotection was linked to an interaction between DREAM and the unfolded protein response (UPR) sensor activating transcription factor 6 (ATF6). Repaglinide blocked this interaction and enhanced ATF6 processing and nuclear accumulation of transcriptionally active ATF6, improving prosurvival UPR function in striatal neurons. Together, our results identify a role for DREAM silencing in the activation of ATF6 signaling, which promotes early neuroprotection in HD. PMID- 26752653 TI - Different Doses of Clazosentan for Aneurismal Subarachnoid Hemorrhage: A Meta Analysis of Randomized Controlled Trials. AB - Clazosentan therapy has been found to be effective in reducing the incidence of vasospasm after aneurismal subarachnoid hemorrhage (aSAH). The objective of this meta-analysis was to determine whether different doses of clazosentan treatment significantly reduced the incidence of delayed ischemic neurological deficits (DINDs) and new cerebral infarction (NCI). We systematically searched PubMed, Embase, Cochrane library and Medline from inception until October, 2015. All randomized controlled trials related to the functions of clazosentan in aSAH were included. Analyses were performed following the method guideline of Cochrane Back Review Group. Four randomized placebo-controlled trials met eligibility criteria and enrolled a total of 2159 patients. The meta-analysis demonstrated a significant decrease in the incidence of DINDs (relative risk, 0.49 and 95% CI, 0.33-0.73) and NCI (relative risk, 0.42 and 95% CI, 0.25-0.71) in patients treated with a high dose of clazosentan (15 mg/h) after aSAH. In addition, a high dose of clazosentan (15 mg/h) had no more effect on the incidence of adverse events than that of a low dose (1-5 mg/h). The results of the present meta analysis show that a high dose of clazosentan significantly reduced the incidence of the vasospasm-related DINDs and NCI. Further study is required to fully understand the potential usefulness of clazosentan in patients with aSAH. PMID- 26752655 TI - Defined three-dimensional microenvironments boost induction of pluripotency. AB - Since the discovery of induced pluripotent stem cells (iPSCs), numerous approaches have been explored to improve the original protocol, which is based on a two-dimensional (2D) cell-culture system. Surprisingly, nothing is known about the effect of a more biologically faithful 3D environment on somatic-cell reprogramming. Here, we report a systematic analysis of how reprogramming of somatic cells occurs within engineered 3D extracellular matrices. By modulating microenvironmental stiffness, degradability and biochemical composition, we have identified a previously unknown role for biophysical effectors in the promotion of iPSC generation. We find that the physical cell confinement imposed by the 3D microenvironment boosts reprogramming through an accelerated mesenchymal-to epithelial transition and increased epigenetic remodelling. We conclude that 3D microenvironmental signals act synergistically with reprogramming transcription factors to increase somatic plasticity. PMID- 26752656 TI - Role of the Mycoplasma pneumoniae/Interleukin-8/Neutrophil Axis in the Pathogenesis of Pneumonia. AB - Neutrophil infiltration is the characteristic pathological feature of M. pneumoniae pneumonia (MPP). This study aimed to explore the associations among neutrophil activity, clinical presentation, and role of the M. pneumoniae/interleukin-8 (IL-8)/neutrophil axis in the pathogenesis of MPP. A total of 42 patients with MPP were prospectively enrolled in the study. Neutrophil activity, including matrix metalloproteinase-9 (MMP-9), myeloperoxidase (MPO), and neutrophil elastase (NE), were measured. Clinical information was collected for all patients and control group. In vitro, IL-8 production was measured at different time points after M. pneumoniae infection of bronchial epithelial cells, and neutrophil activity was analyzed after IL-8 stimulation. The percentage of neutrophil in the bronchoalveolar lavage fluid was higher in the group of patients with high levels of M. pneumoniae DNA than in those with low levels of M. pneumoniae DNA (P < 0.05). IL-8, MMP-9, and NE in patients with MPP significantly increased compared with controls and decreased after treatment (P < 0.05). MPO and MMP-9 were associated with duration of fever (r = 0.332, P < 0.05) and length of stay (r = 0.342, P < 0.05), respectively. In vitro, M. pneumoniae induced IL-8 production by bronchial epithelial cells in a time dependent manner. MPO, MMP-9 and NE production by neutrophils significantly increased compared with medium controls after IL-8 stimulation. In summary, the M. pneumoniae/IL-8/neutrophil axis likely plays a vital role in the pathogenesis of MPP. PMID- 26752654 TI - Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. AB - Clinical evidence links arterial calcification and cardiovascular risk. Finite element modelling of the stress distribution within atherosclerotic plaques has suggested that subcellular microcalcifications in the fibrous cap may promote material failure of the plaque, but that large calcifications can stabilize it. Yet the physicochemical mechanisms underlying such mineral formation and growth in atheromata remain unknown. Here, by using three-dimensional collagen hydrogels that mimic structural features of the atherosclerotic fibrous cap, and high resolution microscopic and spectroscopic analyses of both the hydrogels and of calcified human plaques, we demonstrate that calcific mineral formation and maturation results from a series of events involving the aggregation of calcifying extracellular vesicles, and the formation of microcalcifications and ultimately large calcification areas. We also show that calcification morphology and the plaque's collagen content-two determinants of atherosclerotic plaque stability-are interlinked. PMID- 26752658 TI - Polymer scaffolds with no skin-effect for tissue engineering applications fabricated by thermally induced phase separation. AB - Thermally induced phase separation (TIPS) based methods are widely used for the fabrication of porous scaffolds for tissue engineering and related applications. However, formation of a less-/non-porous layer at the scaffold's outer surface at the air-liquid interface, often known as the skin-effect, restricts the cell infiltration inside the scaffold and therefore limits its efficacy. To this end, we demonstrate a TIPS-based process involving the exposure of the just quenched poly(lactide-co-caprolactone):dioxane phases to the pure dioxane for a short time while still being under the quenching strength, herein after termed as the second quenching (2Q). Scanning electron microscopy, mercury intrusion porosimetry and contact angle analysis revealed a direct correlation between the time of 2Q and the gradual disappearance of the skin, followed by the widening of the outer pores and the formation of the fibrous filaments over the surface, with no effect on the internal pore architecture and the overall porosity of scaffolds. The experiments at various quenching temperatures and polymer concentrations revealed the versatility of 2Q in removing the skin. In addition, the in vitro cell culture studies with the human primary fibroblasts showed that the scaffolds prepared by the TIPS based 2Q process, with the optimal exposure time, resulted in a higher cell seeding and viability in contrast to the scaffolds prepared by the regular TIPS. Thus, TIPS including the 2Q step is a facile, versatile and innovative approach to fabricate the polymer scaffolds with a skin-free and fully open porous surface morphology for achieving a better cell response in tissue engineering and related applications. PMID- 26752657 TI - Regulation Effects of Water and Nitrogen on the Source-Sink Relationship in Potato during the Tuber Bulking Stage. AB - The source-sink relationship determines crop yield, and it is largely regulated by water and nutrients in agricultural production. This has been widely investigated in cereals, but fewer studies have been conducted in root and tuber crops such as potato (Solanum tuberosum L.). The objective of this study was to investigate the source-sink relationship in potato and the regulation of water and nitrogen on the source-sink relationship during the tuber bulking stage. A pot experiment using virus-free plantlets of the Atlantic potato cultivar was conducted, using three water levels (50%, 70% and 90% of field capacity) and three nitrogen levels (0, 0.2, 0.4 g N?kg-1 soil). The results showed that, under all water and nitrogen levels, plant source capacity were small at the end of the experiment, since photosynthetic activity in leaves were low and non-structural reserves in underground stems were completely remobilized. While at this time, there were very big differences in maximum and minimum tuber number and tuber weight, indicating that the sink tuber still had a large potential capacity to take in assimilates. These results suggest that the source-supplied assimilates were not sufficient enough to meet the demands of sink growth. Thus, we concluded that, unlike cereals, potato yield is more likely to be source-limited than sink limited during the tuber bulking stage. Water and nitrogen are two key factors in potato production management. Our results showed that water level, nitrogen level and the interaction between water and nitrogen influence potato yield mainly through affecting source capacity via the net photosynthetic rate, total leaf area and leaf life span. Well-watered, sufficient nitrogen and well-watered combined with sufficient nitrogen increased yield mainly by enhancing the source capacity. Therefore, this suggests that increasing source capacity is more crucial to improve potato yield. PMID- 26752659 TI - Gliomatosis cerebri: Case series of six cases with review of literature. AB - BACKGROUND: Gliomatosis cerebri is characterized by diffuse infiltration of glial cells with preservation of neuronal architecture. It is an uncommon glial neoplasm of astrocytic origin that occurs in adults and is exceedingly rare in children. MATERIALS AND METHODS: The authors retrospectively analyzed the data of 6 patients of gliomatosis cerebri operated between 2007 and 2012. RESULT: All patients underwent surgical decompression, followed by chemoradiotherapy. The survival ranged between 3 and 45 months. The mean survival was 18.5 years. CONCLUSION: Performance scores at presentation and the nonglioblastomatous histology seems to favorably affect the prognosis. Larger studies are required to comment on the role of combination of surgery, chemoradiotherapy as a treatment modality. PMID- 26752661 TI - Assessing The Predictive Value of Clinical Factors Used to Determine The Presence of Sepsis Causing Shock in the Emergency Department. AB - INTRODUCTION: Differentiating shock etiologies is a challenging task in the Emergency Department (ED); even the strongest clinical predictors leave some diagnostic uncertainty. This study sought to establish an evidence base for using clinical covariates in the diagnostic evaluation of septic shock. METHODS: We conducted a prospective, observational study of consecutive ED patients with shock from November 11, 2012 to September 23, 2013. We included all patients at least 18 years old with shock, defined as new vasopressor requirement, systolic blood pressure less than 90 mmHg after at least 1 L of crystalloid or 2 units packed red blood cells, or systolic blood pressure less than 90 mmHg and fluids withheld due to concern for fluid overload. Multivariate logistic regression and recursive partitioning models were constructed, predicting septic cause of shock. The logistic regression model was derived using first 500 patients, and validated with the subsequent 200 patients. RESULTS: In the derivation cohort, 55.6% (95% confidence interval: 51.2%-60.0%) were septic, and 20.8% (17.2%-24.4%) died during hospitalization. The multivariate model (derivation area under the curve = 0.88, validation area under the curve = 0.89) identified predictors of septic shock, including temperature more than 100.4 degrees F (odds ratio 4.6, 2.3-9.2) and history of fever (odds ratio 9.2, 4.4-19.2); however, only 153 of 277 (55.3%, 49.5%-61.2%) patients with septic shock had either of these findings. In the recursive partitioning model, if all predictors were absent, the probability of sepsis causing shock was 21% (16.6%-25.6%). CONCLUSIONS: Clinical data can predict the presence of sepsis causing shock in the ED in most patients. The remaining diagnostic uncertainty provides an opportunity for adding novel diagnostic testing. PMID- 26752662 TI - Antimicrobial Stewardship in a Long-Term Acute Care Hospital Using Offsite Electronic Medical Record Audit. AB - OBJECTIVE To offer antimicrobial stewardship to a long-term acute care hospital using telemedicine. METHODS We conducted an uninterrupted time-series analysis to measure the impact of antimicrobial stewardship on hospital-acquired Clostridium difficile infection (CDI) rates and antimicrobial use. Simple linear regression was used to analyze changes in antimicrobial use; Poisson regression was used to estimate the incidence rate ratio in CDI rates. The preimplementation period was April 1, 2010-March 31, 2011; the postimplementation period was April 1, 2011 March 31, 2014. RESULTS During the preimplementation period, total antimicrobial usage was 266 defined daily doses (DDD)/1,000 patient-days (PD); it rose 4.54 (95% CI, -0.19 to 9.28) per month then significantly decreased from preimplementation to postimplementation (-6.58 DDD/1,000 PD [95% CI, -11.48 to 1.67]; P=.01). The same trend was observed for antibiotics against methicillin resistant Staphylococcus aureus (-2.97 DDD/1,000 PD per month [95% CI, -5.65 to 0.30]; P=.03). There was a decrease in usage of anti-CDI antibiotics by 50.4 DDD/1,000 PD per month (95% CI, -71.4 to -29.2; P<.001) at program implementation that was maintained afterwards. Anti-Pseudomonas antibiotics increased after implementation (30.6 DDD/1,000 PD per month [95% CI, 4.9-56.3]; P=.02) but with ongoing education this trend reversed. Intervention was associated with a decrease in hospital-acquired CDI (incidence rate ratio, 0.57 [95% CI, 0.35 0.92]; P=.02). CONCLUSION Antimicrobial stewardship using an electronic medical record via remote access led to a significant decrease in antibacterial usage and a decrease in CDI rates. PMID- 26752660 TI - Age protects from harmful effects produced by chronic intermittent hypoxia. AB - Obstructive sleep apnoea (OSA) affects an estimated 3-7% of the adult population, the frequency doubling at ages >60-65 years. As it evolves, OSA becomes frequently associated with cardiovascular, metabolic and neuropsychiatric pathologies defining OSA syndrome (OSAS). Exposing experimental animals to chronic intermittent hypoxia (CIH) can be used as a model of the recurrent hypoxic and O2 desaturation patterns observed in OSA patients. CIH is an important OSA event triggering associated pathologies; CIH induces carotid body (CB)-driven exaggerated sympathetic tone and overproduction of reactive oxygen species, related to the pathogenic mechanisms of associated pathologies observed in OSAS. Aiming to discover why OSAS is clinically less conspicuous in aged patients, the present study compares CIH effects in young (3-4 months) and aged (22-24 months) rats. To define potential distinctive patterns of these pathogenic mechanisms, mean arterial blood pressure as the final CIH outcome was measured. In young rats, CIH augmented CB sensory responses to hypoxia, decreased hypoxic ventilation and augmented sympathetic activity (plasma catecholamine levels and renal artery content and synthesis rate). An increased brainstem integration of CB sensory input as a trigger of sympathetic activity is suggested. CIH also caused an oxidative status decreasing aconitase/fumarase ratio and superoxide dismutase activity. In aged animals, CIH minimally affected CB responses, ventilation and sympathetic-related parameters leaving redox status unaltered. In young animals, CIH caused hypertension and in aged animals, whose baseline blood pressure was augmented, CIH did not augment it further. Plausible mechanisms of the differences and potential significance of these findings for the diagnosis and therapy of OSAS are discussed. PMID- 26752673 TI - Distribution of palytoxin in coral reef organisms living in close proximity to an aggregation of Palythoa tuberculosa. AB - Palytoxin is a strong marine toxin that was first isolated from the zoantharian Palythoa toxica and later from other species of the genus Palythoa. How the toxin gets into the animal remains an unsolved question. To study the specificity of palytoxin distribution, the toxin content of Palythoa tuberculosa and other organisms living in close association on a coral reef in Okinawa were analysed by mass spectrometry. In contrast to earlier reports, palytoxin was only detected in P. tuberculosa colonies. PMID- 26752674 TI - Regulation of the antioxidant system in cells of the fission yeast Schizosaccharomyces pombe after combined treatment with patulin and citrinin. AB - The effects of combined treatment with patulin (PAT) and citrinin (CTN) on Schizosaccharomyces pombe cells were investigated in acute toxicity tests. In comparison with the controls the exposure of fission yeast cells (10(7) cells ml( 1)) to PAT + CTN (250 MUM each) for 1 h at a survival rate of 66.6% significantly elevated the concentration of total reactive oxygen species (ROS) via increased levels of peroxides without affecting the concentrations of superoxides or the hydroxyl radical. This treatment induced a 3.08-fold increase in the specific concentration of glutathione and elevated specific activities of catalase and glutathione S-transferase, while at the same time the activity of glutathione reductase decreased. The pattern of the ROS was the same as that induced by CTN (Mate et al., 2014), while the presence of PAT in the PAT + CTN combination treatment modified the activities of the antioxidant system (Papp et al., 2012) in comparison with the individual PAT or CTN treatment, suggesting toxin-specific regulation of glutathione and the enzymes of the antioxidant system and the possibility that the transcription factor (pap1 and atf1) -regulated processes might be influenced directly by ROS. PMID- 26752675 TI - Microscale screening of antibody libraries as maytansinoid antibody-drug conjugates. AB - Antibody-drug conjugates (ADCs) are of great interest as targeted cancer therapeutics. Preparation of ADCs for early stage screening is constrained by purification and biochemical analysis techniques that necessitate burdensome quantities of antibody. Here we describe a method, developed for the maytansinoid class of ADCs, enabling parallel conjugation of antibodies in 96-well format. The method utilizes ~ 100 ug of antibody per well and requires <5 ug of ADC for characterization. We demonstrate the capabilities of this system using model antibodies. We also provide multiple examples applying this method to early-stage screening of maytansinoid ADCs. The method can greatly increase the throughput with which candidate ADCs can be screened in cell-based assays, and may be more generally applicable to high-throughput preparation and screening of different types of protein conjugates. PMID- 26752677 TI - A Case of ALK-Rearranged Adenocarcinoma with Small Cell Carcinoma-Like Transformation and Resistance to Crizotinib. AB - Histologic changes can be involved in resistance to anticancer drugs. Transformation to small cell lung carcinoma (SCLC) following treatment with EGFR tyrosine kinase inhibitors has been reported in patients with EGFR-mutant lung adenocarcinoma. Herein, we report a case of ALK-rearranged lung adenocarcinoma with SCLC-like histology in a metastatic abdominal nodule that was resistant to crizotinib therapy. PMID- 26752678 TI - Integrating Cadaver Exome Sequencing Into a First-Year Medical Student Curriculum. PMID- 26752676 TI - Identification of Individual Cancer-Specific Somatic Mutations for Neoantigen Based Immunotherapy of Lung Cancer. AB - INTRODUCTION: Two strategies for selecting neoantigens as targets for non-small cell lung cancer vaccines were compared: (1) an "off-the-shelf" approach starting with shared mutations extracted from global databases and (2) a personalized pipeline using whole-exome sequencing data on each patient's tumor. METHODS: The Catalogue of Somatic Mutations in Cancer database was used to create a list of shared missense mutations occurring in more than 1% of patients. These mutations were then assessed for predicted binding affinity to HLA alleles of 15 lung cancer patients, and potential neoantigens (pNeoAgs) for each patient were selected on this basis. In the personalized approach, pNeoAgs were selected from missense mutations detected by whole-exome sequencing of the patient's own samples. RESULTS: The list of shared mutations included 22 missense mutations for adenocarcinoma and 18 for squamous cell carcinoma (SCC), resulting in a median of 10 off-the-shelf pNeoAgs for each adenocarcinoma (range 5-13) and 9 (range 5-12) for each SCC. In contrast, a median of 59 missense mutations were identified by whole-exome sequencing (range 33-899) in adenocarcinoma and 164.5 (range 26-232) in SCC. This resulted in a median of 46 pNeoAgs (range 13-659) for adenocarcinoma and 95.5 (range 10-145) for SCC in the personalized set. We found that only one or two off-the-shelf pNeoAgs were included in the set of personalized pNeoAgs-and then in only three patients, with no overlap seen in the remaining 12 patients. CONCLUSIONS: Use of an off-the-shelf pipeline is feasible but may not be satisfactory for most patients with non-small cell lung cancer. We recommend identifying personal mutations by comprehensive genome sequencing for developing neoantigen-targeted cancer immunotherapies. PMID- 26752679 TI - Runtime verification of embedded real-time systems. AB - We present a runtime verification framework that allows on-line monitoring of past-time Metric Temporal Logic (ptMTL) specifications in a discrete time setting. We design observer algorithms for the time-bounded modalities of ptMTL, which take advantage of the highly parallel nature of hardware designs. The algorithms can be translated into efficient hardware blocks, which are designed for reconfigurability, thus, facilitate applications of the framework in both a prototyping and a post-deployment phase of embedded real-time systems. We provide formal correctness proofs for all presented observer algorithms and analyze their time and space complexity. For example, for the most general operator considered, the time-bounded Since operator, we obtain a time complexity that is doubly logarithmic both in the point in time the operator is executed and the operator's time bounds. This result is promising with respect to a self-contained, non interfering monitoring approach that evaluates real-time specifications in parallel to the system-under-test. We implement our framework on a Field Programmable Gate Array platform and use extensive simulation and logic synthesis runs to assess the benefits of the approach in terms of resource usage and operating frequency. PMID- 26752680 TI - A phase II study of the efficacy, safety, and determinants of response to 5 azacitidine (Vidaza(r)) in patients with chronic myelomonocytic leukemia. PMID- 26752683 TI - US Transplant Policy Should Strengthen Bridges, Not Build Walls. PMID- 26752682 TI - Pediatric Antimicrobial Discharge Stewardship: An Unmet Need. PMID- 26752681 TI - Protein Secondary Structure Prediction Using Deep Convolutional Neural Fields. AB - Protein secondary structure (SS) prediction is important for studying protein structure and function. When only the sequence (profile) information is used as input feature, currently the best predictors can obtain ~80% Q3 accuracy, which has not been improved in the past decade. Here we present DeepCNF (Deep Convolutional Neural Fields) for protein SS prediction. DeepCNF is a Deep Learning extension of Conditional Neural Fields (CNF), which is an integration of Conditional Random Fields (CRF) and shallow neural networks. DeepCNF can model not only complex sequence-structure relationship by a deep hierarchical architecture, but also interdependency between adjacent SS labels, so it is much more powerful than CNF. Experimental results show that DeepCNF can obtain ~84% Q3 accuracy, ~85% SOV score, and ~72% Q8 accuracy, respectively, on the CASP and CAMEO test proteins, greatly outperforming currently popular predictors. As a general framework, DeepCNF can be used to predict other protein structure properties such as contact number, disorder regions, and solvent accessibility. PMID- 26752684 TI - A Mutation in Plant-Specific SWI2/SNF2-Like Chromatin-Remodeling Proteins, DRD1 and DDM1, Delays Leaf Senescence in Arabidopsis thaliana. AB - Leaf senescence is a finely regulated complex process; however, evidence for the involvement of epigenetic processes in the regulation of leaf senescence is still fragmentary. Therefore, we chose to examine the functions of DRD1, a SWI2/SNF2 chromatin remodeling protein, in epigenetic regulation of leaf senescence, particularly because drd1-6 mutants exhibited a delayed leaf senescence phenotype. Photosynthetic parameters such as Fv/Fm and ETRmax were decreased in WT leaves compared to leaves of drd1-6 mutants after dark treatment. The WT leaves remarkably lost more chlorophyll and protein content during dark-induced senescence (DIS) than the drd1-6 leaves did. The induction of senescence associated genes was noticeably inhibited in the drd1-6 mutant after 5-d of DIS. We compared changes in epigenetic regulation during DIS via quantitative expression analysis of 180-bp centromeric (CEN) and transcriptionally silent information (TSI) repeats. Their expression levels significantly increased in both the WT and the drd1-6 mutant, but did much less in the latter. Moreover, the delayed leaf senescence was observed in ddm1-2 mutants as well as the drd1-6, but not in drd1-p mutants. These data suggest that SWI2/SNF2 chromatin remodeling proteins such as DRD1 and DDM1 may influence leaf senescence possibly via epigenetic regulation. PMID- 26752687 TI - DNA polymerase inhibitors for treating hepatitis B: a safety evaluation. AB - INTRODUCTION: Oral nucleoside/ nucleotide analogues (NAs) are currently the mainstay of treatment for patients with chronic hepatitis B virus (HBV) infection. They are generally safe to use. However, since their approval in the last decade and a half, the literature has reported adverse effects associated with the use of NA in HBV patients. A comprehensive review on the drug safety is lacking. AREAS COVERED: Significant adverse effects associated with NA use in HBV patients including muscle toxicity, peripheral neuropathy, nephrotoxicity and lactic acidosis are discussed. The reported prevalence of each adverse effect, as well as their predictive factors, reversibility and their use in pregnancy and lactating mothers are covered in this review. Novel data regarding reno protective effect of telbivudine are also discussed. EXPERT OPINION: Use of NA in HBV is generally safe. Uncommon adverse effects can be minimized or detected early if clinicians exercise adequate precautions when using NA for at-risk populations with regular monitoring. PMID- 26752686 TI - Intradermal Immunization of Leishmania donovani Centrin Knock-Out Parasites in Combination with Salivary Protein LJM19 from Sand Fly Vector Induces a Durable Protective Immune Response in Hamsters. AB - BACKGROUND: Visceral leishmaniasis (VL) is a neglected tropical disease and is fatal if untreated. There is no vaccine available against leishmaniasis. The majority of patients with cutaneous leishmaniasis (CL) or VL develop a long-term protective immunity after cure from infection, which indicates that development of an effective vaccine against leishmaniasis is possible. Such protection may also be achieved by immunization with live attenuated parasites that do not cause disease. We have previously reported a protective response in mice, hamsters and dogs with Leishmania donovani centrin gene knock-out parasites (LdCen-/-), a live attenuated parasite with a cell division specific centrin1 gene deletion. In this study we have explored the effects of salivary protein LJM19 as an adjuvant and intradermal (ID) route of immunization on the efficacy of LdCen-/- parasites as a vaccine against virulent L. donovani. METHODOLOGY/PRINCIPAL FINDINGS: To explore the potential of a combination of LdCen-/- parasites and salivary protein LJM19 as vaccine antigens, LdCen-/- ID immunization followed by ID challenge with virulent L. donovani were performed in hamsters in a 9-month follow up study. We determined parasite burden (serial dilution), antibody production (ELISA) and cytokine expression (qPCR) in these animals. Compared to controls, animals immunized with LdCen-/- + LJM19 induced a strong antibody response, a reduction in spleen and liver parasite burden and a higher expression of pro-inflammatory cytokines after immunization and one month post-challenge. Additionally, a low parasite load in lymph nodes, spleen and liver, and a non-inflamed spleen was observed in immunized animals 9 months after the challenge infection. CONCLUSIONS: Our results demonstrate that an ID vaccination using LdCen-/ parasites in combination with sand fly salivary protein LJM19 has the capability to confer long lasting protection against visceral leishmaniasis that is comparable to intravenous or intracardial immunization. PMID- 26752685 TI - FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1. AB - The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1) is a substrate for hydroxylation by FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, in cultured cells, overexpression of N22A mutant OTUB1 impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. Additionally, we propose that our results provide new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit. PMID- 26752688 TI - Imaging the intratumoral-peritumoral extracellular pH gradient of gliomas. AB - Solid tumors have an acidic extracellular pH (pHe ) but near neutral intracellular pH (pHi ). Because acidic pHe milieu is conducive to tumor growth and builds resistance to therapy, simultaneous mapping of pHe inside and outside the tumor (i.e., intratumoral-peritumoral pHe gradient) fulfills an important need in cancer imaging. We used Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), which utilizes shifts of non-exchangeable protons from macrocyclic chelates (e.g., 1,4,7,10-tetraazacyclododecane-1,4,7,10 tetrakis(methylene phosphonate) or DOTP(8-) ) complexed with paramagnetic thulium (Tm(3) (+) ) ion, to generate in vivo pHe maps in rat brains bearing 9L and RG2 tumors. Upon TmDOTP(5-) infusion, MRI identified the tumor boundary by enhanced water transverse relaxation and BIRDS allowed imaging of intratumoral-peritumoral pHe gradients. The pHe measured by BIRDS was compared with pHi measured with (31) P-MRS. In normal tissue, pHe was similar to pHi , but inside the tumor pHe was lower than pHi . While the intratumoral pHe was acidic for both tumor types, peritumoral pHe varied with tumor type. The intratumoral-peritumoral pHe gradient was much larger for 9L than RG2 tumors because in RG2 tumors acidic pHe was found in distal peritumoral regions. The increased presence of Ki-67 positive cells beyond the RG2 tumor border suggested that RG2 was more invasive than the 9L tumor. These results indicate that extensive acidic pHe beyond the tumor boundary correlates with tumor cell invasion. In summary, BIRDS has sensitivity to map the in vivo intratumoral-peritumoral pHe gradient, thereby creating preclinical applications in monitoring cancer therapeutic responses (e.g., with pHe -altering drugs). Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26752689 TI - Specific cell-derived microvesicles: Linking endothelial function to carotid artery intima-media thickness in low cardiovascular risk menopausal women. AB - BACKGROUND: Decreases in endothelial function measured by reactive hyperemic index (RHI) correlated with increases in carotid intima-media thickness (CIMT) in recently menopausal women with a low risk cardiovascular profile. Factors linking this association are unknown. OBJECTIVE: Assess, longitudinally, markers of platelet activation and cell-derived, blood-borne microvesicles (MV) in relationship to RHI and CIMT in asymptomatic, low risk menopausal women. METHODS: RHI by digital pulse tonometry (n = 93), CIMT by ultrasound (n = 113), measures of platelet activation and specific cell-derived, blood-borne MV were evaluated in women throughout the Kronos Early Estrogen Prevention Study (KEEPS) at Mayo Clinic. RESULTS: CIMT, but not RHI, increased significantly over 4 years. The average change in CIMT correlated significantly with the average follow-up values of MV positive for common leukocyte antigen [CD45; rho = 0.285 (P = 0.002)] and VCAM-1 [rho = 0.270 (P = 0.0040)]. Using principal components analysis (PC) on the aggregate set of average follow-up measures, the first derived PC representing numbers of MV positive for markers of vascular endothelium, inflammatory cells (leukocyte and monocytes), pro-coagulant (tissue factor), and cell adhesion molecules (ICAM-1 and VCAM-1) associated with changes in RHI and CIMT. Changes in RHI associated with another PC defined by measures of platelet activation (dense granular ATP secretion, surface expression of P-selectin and fibrinogen receptors). CONCLUSIONS: MV derived from activated endothelial and inflammatory cells, and those expressing cell adhesion and pro-coagulant molecules may reflect early vascular dysfunction in low risk menopausal women. Assays of MV as non-conventional measures to assess cardiovascular risk in asymptomatic women remain to be developed. PMID- 26752690 TI - Adiposity has no direct effect on carotid intima-media thickness in adolescents and young adults: Use of structural equation modeling to elucidate indirect & direct pathways. AB - BACKGROUND: Carotid intima-media thickness (cIMT) is associated with CV events in adults. Thicker cIMT is found in youth with CV risk factors including obesity. Which risk factors have the most effect upon cIMT in youth and whether obesity has direct or indirect effects is not known. We used structural equation modeling to elucidate direct and indirect pathways through which obesity and other risk factors were associated with cIMT. METHODS: We collected demographics, anthropometrics and laboratory data on 784 subjects age 10-24 years (mean 18.0 +/ 3.3 years). Common, bulb and internal carotid cIMT were measured by ultrasound. Multivariable regression analysis was performed to assess independent determinants of cIMT. Analyses were repeated with structural equation modeling to determine direct and indirect effects. RESULTS: Multivariable regression models explained 11%-22% of variation of cIMT. Age, sex and systolic blood pressure (BP) z-score were significant determinants of all cIMT segments. Body mass index (BMI) z-score, race, presence of type 2 diabetes mellitus (T2DM), hemoglobin A1c (HbA1c) and non-HDL were significant for some segments (all p = 0.05). The largest direct effect on cIMT was age (0.312) followed by BP (0.228), Blood glucose control (0.108) and non-HDL (0.134). BMI only had a significant indirect effect through blood glucose control, BP & non-HDL. High sensitivity C-reactive protein (CRP) had a small indirect effect through blood glucose control (all p = 0.05). CONCLUSIONS: Age and BP are the major factors with direct effect on cIMT. Glucose and non-HDL were also important in this cohort with a high prevalence of T2DM. BMI only has indirect effects, through other risk factors. Traditional CV risk factors have important direct effects on cIMT in the young, but adiposity exerts its influence only through other CV risk factors. PMID- 26752693 TI - Innate Immunity and BK Virus: Prospective Strategies. AB - Recent information demonstrated that BK virus reactivation is a dominant complication after kidney transplantation, which occurs because of immunosuppression. BK virus reactivation is the main reason of transplanted kidney losing. Immune response against BK virus is the major inhibitor of the virus reactivation. Therefore, improving our knowledge regarding the main parameters that fight against BK viruses can shed light on to direct new treatment strategies to suppress BK infection. Innate immunity consists of numerous cell systems and also soluble molecules, which not only suppress virus replication, but also activate adaptive immunity to eradicate the infection. Additionally, it appears that immune responses against reactivated BK virus are the main reasons for induction of BK virus-associated nephropathy (BKAN). Thus, improving our knowledge regarding the parameters and detailed mechanisms of innate immunity and also the status of innate immunity of the patients with BK virus reactivation and its complications can introduce new prospective strategies to either prevent or as therapy of the complication. Therefore, this review was aimed to collate the most recent data regarding the roles played by innate immunity against BK virus and also the status of innate immunity in the patients with reactivation BK virus and BKAN. PMID- 26752691 TI - Low HDL cholesterol as a cardiovascular risk factor in rural, urban, and rural urban migrants: PERU MIGRANT cohort study. AB - INTRODUCTION: Whilst the relationship between lipids and cardiovascular mortality has been well studied and appears to be controversial, very little has been explored in the context of rural-to-urban migration in low-resource settings. OBJECTIVE: Determine the profile and related factors for HDL-c patterns (isolated and non-isolated low HDL-c) in three population-based groups according to their migration status, and determine the effect of HDL-c patterns on the rates of cardiovascular outcomes (i.e. non-fatal stroke and non-fatal myocardial infarction) and mortality. METHODS: Cross-sectional and 5-year longitudinal data from the PERU MIGRANT study, designed to assess the effect of migration on cardiovascular risk profiles and mortality in Peru. Two different analyses were performed: first, we estimated prevalence and associated factors with isolated and non-isolated low HDL-c at baseline. Second, using longitudinal information, relative risk ratios (RRR) of composite outcomes of mortality, non-fatal stroke and non-fatal myocardial infarction were calculated according to HDL-c levels at baseline. RESULTS: Data from 988 participants, rural (n = 201), rural-to-urban migrants (n = 589), and urban (n = 199) groups, was analysed. Low HDL-c was present in 56.5% (95%CI: 53.4%-59.6%) without differences by study groups. Isolated low HDL-c was found in 36.5% (95%CI: 33.5-39.5%), with differences between study groups. In multivariable analysis, urban group (vs. rural), female gender, overweight and obesity were independently associated with isolated low HDL-c. Only female gender, overweight and obesity were associated with non isolated low HDL-c. Longitudinal analyses showed that non-isolated low HDL-c increased the risk of negative cardiovascular outcomes (RRR = 3.46; 95%CI: 1.23 9.74). CONCLUSIONS: Isolated low HDL-c was the most common dyslipidaemia in the study population and was more frequent in rural subjects. Non-isolated low HDL-c increased three-to fourfold the 5-year risk of cardiovascular outcomes. PMID- 26752692 TI - Association between high sensitivity C-Reactive protein and prevalence of asymptomatic carotid artery stenosis. AB - INTRODUCTION: Inflammation plays a key role in the pathophysiology of atherosclerosis. Little is known about the association between high sensitivity C reactive protein (hs-CRP) especially long-term hs-CRP and asymptomatic carotid artery stenosis (ACAS) in healthy Chinese adults. The aim of this study was to assess the relationship between hs-CRP levels and the prevalence of ACAS in a Chinese community-based cohort. METHODS: A sample of 5349 participants aged >= 40 years (40.36% women) were enrolled in this study, all without preexisting stroke. Ultrasonography of the bilateral carotid arteries was performed for the evaluation of carotid stenosis. Participants were stratified into three groups according to hs-CRP levels. We used both baseline (hs-CRP levels analyzed during 2010) and average hs-CRP values for the last four years (the average of hs-CRP levels analyzed at the year of 2006, 2008 and 2010) in the analysis. Multivariable logistic regression models were used to analyze the association between hs-CRP levels and ACAS. RESULTS: A total of 356 (6.66%) subjects showed evidence of ACAS. Multivariate analysis showed that both baseline and average hs CRP values for the last four years were independent indicators for the presence of ACAS (P for trend = 0.007, 0.001, respectively). Stratified by age and sex, higher baseline hs-CRP levels were associated with ACAS in old adults (>= 60 y) (multivariate-adjusted, odds ratio [OR] = 1.03, 95% confidence interval [CI]: 1.01-1.05) and male (multivariate-adjusted, OR = 1.03, 95%CI: 1.01-1.05), but not in middle-aged adults (40-59 y) and female. Similarly, higher average hs-CRP values for the last four years were associated with ACAS in old adults and male, but not in middle-aged adults and female. CONCLUSION: Both baseline and chronic elevation of serum hs-CRP were associated with ACAS, especially in older or male adults. hs-CRP might be used as a useful marker and a potential therapeutic target for carotid atherosclerosis. PMID- 26752694 TI - Ionic Conductivity as a Tool To Study Biocidal Activity of Sulfobetaine Micelles against Saccharomyces cerevisiae Model Cells. AB - Zwitterionic sulfobetaine surfactants are used in pharmaceutical or biomedical applications for the solubilization and delivery of hydrophobic molecules in aqueous medium or in biological environments. In a screening on the biocidal activity of synthetic surfactants on microbial cells, remarkable results have emerged with sulfobetaine amphiphiles. The interaction between eight zwitterionic sulfobetaine amphiphiles and Saccharomyces cerevisiae model cells was therefore analyzed. S. cerevisiae yeast cells were chosen, as they are a widely used unicellular eukaryotic model organism in cell biology. Conductivity measurements were used to investigate the interaction between surfactant solution and cells. Viable counts measurements were performed, and the mortality data correlated with the conductivity profiles very well, in terms of the inflection points (IPs) observed in the curves and in terms of supramolecular properties of the aggregates. A Fourier transform infrared (FTIR)-based bioassay was then performed to determine the metabolomic stress-response of the cells subjected to the action of zwitterionic surfactants. The surfactants showed nodal concentration (IPs) with all the techniques in their activities, corresponding to the critical micellar concentrations of the amphiphiles. This is due to the pseudocationic behavior of sulfobetaine micelles, because of their charge distribution and charge densities. This behavior permits the interaction of the micellar aggregates with the cells, and the structure of the surfactant monomers has impact on the mortality and the metabolomic response data observed. On the other hand, the concentrations that are necessary to provoke a biocidal activity do not promote these amphiphiles as potential antimicrobial agents. In fact, they are much higher than the ones of cationic surfactants. PMID- 26752695 TI - The Relation between Occupational Sitting and Mental, Cardiometabolic, and Musculoskeletal Health over a Period of 15 Years--The Doetinchem Cohort Study. AB - OBJECTIVE: Sedentary behaviors are reported to impose health risks. Since occupational exposure is a major proportion of total sedentary time, we studied the association between occupational sitting and a number of health problems. METHODS: From the longitudinal Doetinchem Cohort Study, we selected those working at baseline with complete data (n = 1,509). Participants were examined four times at 5 year-intervals between 1993 and 2012. We characterized occupational sitting as follows: 1) stable sitters and stable non sitters over a 15-year period, based on job characteristics and (2) having a job with a low, moderate or high amount of sitting, based on tertiles of self-reported number of hours per week of occupational sitting, measured at wave 5. Linear and logistic regression models were used. Outcomes were self-reported mental health, low-back or upper extremity pain, and objectively measured cardiometabolic health (overweight, hypertension, hypercholesterolemia). RESULTS: Compared to stable non sitters, a lower risk of chronic upper extremity pain was observed for stable sitters (OR 0.75, 95% CI: 0.57; 1.00) as well as for those in the two upper tertiles for hours of occupational sitting (>4 hr/wk) (OR 0.65; 95%CI 0.50-0.86). For the other health outcomes studied, no significant associations were found with occupational sitting. CONCLUSION: Our findings do not support the hypothesis that occupational sitting is associated with health problems. The finding that occupational sitting is associated with less upper extremity pain might be due to the association of occupational sitting with less physical load. PMID- 26752697 TI - Iontophoresis Improved Growth Reduction of Invasive Squamous Cell Carcinoma in Topical Photodynamic Therapy. AB - This study examined the potential of iontophoresis in topical photodynamic therapy (PDT) of human invasive squamous cells carcinomas (SCC). SCC was induced in nude BALB/c mice by subcutaneous injection of A431 cells. Tumor penetration and distribution of the photosensitizer tetrasulfonated zinc phthalocyanine (ZnPcS4) was investigated after 10 and 30 min of in vivo iontophoresis of a gel containing ZnPcS4. PDT was performed immediately after iontophoresis using laser at 660 nm with a dose of irradiation of 100 J/cm(2) and irradiance of 48 mW/cm(2) while tumor growth was measured for 30 days. Iontophoresis increased ZnPcS4 penetration into tumors by 6-fold after 30 min when compared with passive delivery. Confocal microscopy analysis showed that ZnPcS4 was homogeneous distributed within deep regions of the tumor after iontophoresis. Irradiation of the tumors immediately after iontophoresis showed reduction in tumor size by more than 2-fold when compared to non-treated tumors. Iontophoretic-PDT treated tumors presented large areas of necrosis. The study concluded that iontophoretic delivery of photosensitizers could be a valuable strategy for topical PDT of invasive SCC. PMID- 26752696 TI - Cone-Beam Computed Tomography Correlates with Conventional Helical Computed Tomography in Evaluation of Lipiodol Accumulation in HCC after Chemoembolization. AB - BACKGROUND & AIMS: The amount of drug-loaded lipiodol in an HCC tumor post transarterial chemoembolization (TACE) correlates with the risk of local tumor recurrence. Lipiodol enhancement of a tumor on conventional CT, measured in Hounsfield units (HU), can predict tumor response. Here we investigate whether cone-beam CT (CBCT) can also be used to predict tumor response, providing the benefit of being able to optimize the patient's treatment plan intra procedurally. METHODS: A total of 82 HCC nodules (82 patients), <=5 cm in diameter, were treated with balloon-occluded TACE using miriplatin between December 2013 and November 2014. For each patient, both CBCT and conventional CT images were obtained post-TACE. The degree of correlation between CBCT and conventional CT was determined by comparing identical regions of interest for each imaging modality using pixel values. RESULTS: The pixel values from conventional CT and CBCT were highly correlated, with a Pearson correlation coefficient of 0.912 (p<0.001). The location of the nodules within the liver did not affect the results; the correlation coefficient was 0.891 (p<0.001) for the left lobe and 0.926 (p<0.001) for the right lobe. The mean pixel value for conventional CT was 439 +/- 279 HU, and the mean pixel value for CBCT was 416 +/- 311 HU. CONCLUSIONS: CBCT may be used as a substitute for conventional CT to quantitatively evaluate the amount of drug-loaded lipiodol within an HCC nodule and, hence, the efficacy of TACE treatment. The major benefit of using CBCT is the ability to predict the likelihood of local recurrence intra-procedurally, enabling subsequent treatment optimization. PMID- 26752699 TI - EDH: endothelium-dependent hyperpolarization and microvascular signalling. AB - Endothelium-dependent hyperpolarizing factor (EDHF) is a powerful vasodilator influence in small resistance arteries and thus an important modulator of blood pressure and flow. As the name suggests, EDHF was thought to describe a diffusible factor stimulating smooth muscle hyperpolarization (and thus vasodilatation). However, this idea has evolved with the recognition that a factor can operate alongside the spread of hyperpolarizing current from the endothelium to the vascular smooth muscle (VSM). As such, the pathway is now termed endothelium-dependent hyperpolarization (EDH). EDH is activated by an increase in endothelial [Ca2+ ]i , which stimulates two Ca2+ -sensitive K channels, SKCa and IKCa . This was discovered because apamin and charybdotoxin applied in combination blocked EDHF responses, but iberiotoxin - a blocker of BKCa - was not able to substitute for charybdotoxin. SKCa and IKCa channels are arranged in endothelial microdomains, particularly within projections towards the adjacent smooth muscle, which are rich in IKCa channels and close to interendothelial gap junctions where SKCa channels, are prevalent. KCa activation hyperpolarizes endothelial cells, and K+ efflux through them can act as a diffusible 'EDHF' by stimulating VSM Na+ ,K+ -ATPase and inwardly rectifying K channels (KIR ). In parallel, hyperpolarizing current spreads from the endothelium to the smooth muscle through myoendothelial gap junctions located on endothelial projections. The resulting radial EDH is complemented by the spread of 'conducted' hyperpolarization along the endothelium of arteries and arterioles to affect conducted vasodilatation (CVD). Retrograde CVD effectively integrates blood flow within the microcirculation, but how the underlying hyperpolarization is sustained is unclear. PMID- 26752698 TI - Gefitinib Synergizes with Irinotecan to Suppress Hepatocellular Carcinoma via Antagonizing Rad51-Mediated DNA-Repair. AB - Chemotherapy is the only choice for most of the advanced hepatocellular carcinoma (HCC) patients, while few agents were available, making it an urgent need to develop new chemotherapy strategies. A phase II clinical trial suggested that the efficacy of irinotecan in HCC was limited due to dose-dependent toxicities. Here, we found that gefitinib exhibited synergistic activity in combination with SN-38, an active metabolite of irinotecan, in HCC cell lines. And the enhanced apoptosis induced by gefitinib plus SN-38 was a result from caspase pathway activation. Mechanistically, gefitinib dramatically promoted the ubiquitin-proteasome dependent degradation of Rad51 protein, suppressed the DNA repair, gave rise to more DNA damages, and ultimately resulted in the synergism of these two agents. In addition, the increased antitumor efficacy of gefitinib combined with irinotecan was further validated in a HepG2 xenograft mice model. Taken together, our data demonstrated for the first time that the combination of irinotecan and gefitinib showed potential benefit in HCC, which suggests that Rad51 is a promising target and provides a rationale for clinical trials investigating the efficacy of the combination of topoisomerase I inhibitors and gefitinib in HCC. PMID- 26752701 TI - Transparent and Nonflammable Ionogel Photon Upconverters and Their Solute Transport Properties. AB - Photon upconversion based on triplet-triplet annihilation (TTA-UC) is a technology to convert presently wasted sub-bandgap photons to usable higher energy photons. In this paper, ionogel TTA-UC samples are first developed by gelatinizing ionic liquids containing triplet-sensitizing and light-emitting molecules using an ionic gelator, resulting in transparent and nonflammable ionogel photon upconverters. The photophysical properties of the ionogel samples are then investigated, and the results suggest that the effect of gelation on the diffusion of the solutes is negligibly small. To further examine this suggestion and acquire fundamental insight into the solute transport properties of the samples, the diffusion of charge-neutral solute species over much longer distances than microscopic interpolymer distances is measured by electrochemical potential-step chronoamperometry. The results reveal that the diffusion of solute species is not affected by gelation within the tested gelator concentration range, supporting our interpretation of the initial results of the photophysical investigations. Overall, our results show that the advantage of nonfluidity can be imparted to ionic-liquid-based photon upconverters without sacrificing molecular diffusion, optical transparency, and nonflammability. PMID- 26752700 TI - Increased Skin Tumor Incidence and Keratinocyte Hyper-Proliferation in a Mouse Model of Down Syndrome. AB - Down syndrome (DS) is a genetic disorder caused by the presence of an extra copy of human chromosome 21 (Hsa21). People with DS display multiple clinical traits as a result of the dosage imbalance of several hundred genes. While many outcomes of trisomy are deleterious, epidemiological studies have shown a significant risk reduction for most solid tumors in DS. Reduced tumor incidence has also been demonstrated in functional studies using trisomic DS mouse models. Therefore, it was interesting to find that Ts1Rhr trisomic mice developed more papillomas than did their euploid littermates in a DMBA-TPA chemical carcinogenesis paradigm. Papillomas in Ts1Rhr mice also proliferated faster. The increased proliferation was likely caused by a stronger response of trisomy to TPA induction. Treatment with TPA caused hyperkeratosis to a greater degree in Ts1Rhr mice than in euploid, reminiscent of hyperkeratosis seen in people with DS. Cultured trisomic keratinocytes also showed increased TPA-induced proliferation compared to euploid controls. These outcomes suggest that altered gene expression in trisomy could elevate a proliferation signalling pathway. Gene expression analysis of cultured keratinocytes revealed upregulation of several trisomic and disomic genes may contribute to this hyperproliferation. The contributions of these genes to hyper proliferation were further validated in a siRNA knockdown experiment. The unexpected findings reported here add a new aspect to our understanding of tumorigenesis with clinical implications for DS and demonstrates the complexity of the tumor repression phenotype in this frequent condition. PMID- 26752703 TI - Volatile organic compounds as new biomarkers for colorectal cancer: a review. AB - Analysis of the volatile part of the metabolome (volatile organic compounds, VOC) present in the gas phase of excreted materials is a promising new screening tool for several cancers, including colorectal cancer (CRC). The VOC signature can reflect health status, like a 'fingerprint', and can be modified in several diseases. Technical difficulties still limit the widespread use of VOC analysis in the clinical setting, but this approach has already been applied successfully in the diagnosis of CRC. The present study reviews the available data on VOC present in the headspace (the gaseous constituents of a closed space above a liquid or solid) of blood, urine, faeces and breath as a potential screening tool for CRC. A systematic electronic literature search was conducted in PubMed, Scirus and Google using the following keywords: Metabolomic, Volatile Organic Compounds (VOC), Electronic-nose and Colorectal Cancer. Only articles published in English between 2000 and 2015 were selected and these were independently checked by two of the authors. Ten papers describing the reliability of VOC analysis in breath and faeces, blood and urine were selected; all indicated good reliability in detecting CRC. The use of different substrates and different analytical platforms has led to the identification of different patterns of VOC. The reliability of a metabolomic approach as a noninvasive biomarker for use in CRC screening is supported by this review despite several limitations due to the number of patients included in each study, the different analytical platforms and biological materials used and different VOC identified. PMID- 26752702 TI - Identification and preliminary characterization of chemosensory perception associated proteins in the melon fly Bactrocera cucurbitae using RNA-seq. AB - An investigation into proteins involved in chemosensory perception in the melon fly, Bactrocera cucurbitae (Diptera: Tephritidae) is described here using a newly generated transcriptome dataset. The melon fly is a major agricultural pest, widely distributed in the Asia-Pacific region and some parts of Africa. For this study, a transcriptome dataset was generated using RNA extracted from 4-day-old adult specimens of the melon fly. The dataset was assembled and annotated via Gene Ontology (GO) analysis. Based on this and similarity searches to data from other species, a number of protein sequences putatively involved in chemosensory reception were identified and characterized in the melon fly. This included the highly conserved "Orco" along with a number of other less conserved odorant binding protein sequences. In addition, several sequences representing putative ionotropic and gustatory receptors were also identified. This study provides a foundation for future functional studies of chemosensory proteins in the melon fly and for making more detailed comparisons to other species. In the long term, this will ultimately help in the development of improved tools for pest management. PMID- 26752711 TI - Functional Brain Connectivity as a New Feature for P300 Speller. AB - The brain is a large-scale complex network often referred to as the "connectome". Cognitive functions and information processing are mainly based on the interactions between distant brain regions. However, most of the 'feature extraction' methods used in the context of Brain Computer Interface (BCI) ignored the possible functional relationships between different signals recorded from distinct brain areas. In this paper, the functional connectivity quantified by the phase locking value (PLV) was introduced to characterize the evoked responses (ERPs) obtained in the case of target and non-targets visual stimuli. We also tested the possibility of using the functional connectivity in the context of 'P300 speller'. The proposed approach was compared to the well-known methods proposed in the state of the art of "P300 Speller", mainly the peak picking, the area, time/frequency based features, the xDAWN spatial filtering and the stepwise linear discriminant analysis (SWLDA). The electroencephalographic (EEG) signals recorded from ten subjects were analyzed offline. The results indicated that phase synchrony offers relevant information for the classification in a P300 speller. High synchronization between the brain regions was clearly observed during target trials, although no significant synchronization was detected for a non-target trial. The results showed also that phase synchrony provides higher performance than some existing methods for letter classification in a P300 speller principally when large number of trials is available. Finally, we tested the possible combination of both approaches (classical features and phase synchrony). Our findings showed an overall improvement of the performance of the P300-speller when using Peak picking, the area and frequency based features. Similar performances were obtained compared to xDAWN and SWLDA when using large number of trials. PMID- 26752710 TI - Insights on chiral, backbone modified peptide nucleic acids: Properties and biological activity. AB - PNAs are emerging as useful synthetic devices targeting natural miRNAs. In particular 3 classes of structurally modified PNAs analogs are herein described, namely alpha, beta and gamma, which differ by their backbone modification. Their mode and binding affinity for natural nucleic acids and their use in medicinal chemistry as potential miRNA binders is discussed. PMID- 26752712 TI - Polyyne Rotaxanes: Stabilization by Encapsulation. AB - Active metal template Glaser coupling has been used to synthesize a series of rotaxanes consisting of a polyyne, with up to 24 contiguous sp-hybridized carbon atoms, threaded through a variety of macrocycles. Cadiot-Chodkiewicz cross coupling affords higher yields of rotaxanes than homocoupling. This methodology has been used to prepare [3]rotaxanes with two polyyne chains locked through the same macrocycle. The crystal structure of one of these [3]rotaxanes shows that there is extremely close contact between the central carbon atoms of the threaded hexayne chains (C...C distance 3.29 A vs 3.4 A for the sum of van der Waals radii) and that the bond-length-alternation is perturbed in the vicinity of this contact. However, despite the close interaction between the hexayne chains, the [3]rotaxane is remarkably stable under ambient conditions, probably because the two polyynes adopt a crossed geometry. In the solid state, the angle between the two polyyne chains is 74 degrees , and this crossed geometry appears to be dictated by the bulk of the "supertrityl" end groups. Several rotaxanes have been synthesized to explore gem-dibromoethene moieties as "masked" polyynes. However, the reductive Fritsch-Buttenberg-Wiechell rearrangement to form the desired polyyne rotaxanes has not yet been achieved. X-ray crystallographic analysis on six [2]rotaxanes and two [3]rotaxanes provides insight into the noncovalent interactions in these systems. Differential scanning calorimetry (DSC) reveals that the longer polyyne rotaxanes (C16, C18, and C24) decompose at higher temperatures than the corresponding unthreaded polyyne axles. The stability enhancement increases as the polyyne becomes longer, reaching 60 degrees C in the C24 rotaxane. PMID- 26752714 TI - Multidrug resistance in Clostridium perfringens isolated from diarrheal neonatal piglets in Thailand. AB - Clostridium perfringens causes diarrhea in neonatal piglets, thereby affecting commercial swine farming. The objective of this study was to determine the prevalence and characterize antimicrobial resistance in C. perfringens isolated from diarrheal neonatal piglets in Thailand. A total of 260 rectal swab samples were collected from 13 farms and were subjected to C. perfringens isolation. A total of 148 samples were PCR-positive for C. perfringens toxin genes, from which 122 were recovered. All isolates were cpb2-encoding C. perfringens type A and enterotoxin gene negative. Most of the isolates were susceptible to ampicillin, bacitracin, chlorotetracycline, doxycycline, and oxytetracycline with MIC50 values ranging from 0.32 to 8 MUg/ml. The high resistance rates were observed for ceftiofur, enrofloxacin, erythromycin, lincomycin, and tylosin. Among resistant isolates, 82% were resistant to more than one type of antibiotics. The distinct pattern of multiple drug resistance in C. perfringens was observed in different regions, potentially reflecting the farm specific usage of these agents. PMID- 26752713 TI - EBNA2 Drives Formation of New Chromosome Binding Sites and Target Genes for B Cell Master Regulatory Transcription Factors RBP-jkappa and EBF1. AB - Epstein-Barr Virus (EBV) transforms resting B-lymphocytes into proliferating lymphoblasts to establish latent infections that can give rise to malignancies. We show here that EBV-encoded transcriptional regulator EBNA2 drives the cooperative and combinatorial genome-wide binding of two master regulators of B cell fate, namely EBF1 and RBP-jkappa. Previous studies suggest that these B-cell factors are statically bound to target gene promoters. In contrast, we found that EBNA2 induces the formation of new binding for both RBP-jkappa and EBF1, many of which are in close physical proximity in the cellular and viral genome. These newly induced binding sites co-occupied by EBNA2-EBF1-RBP-jkappa correlate strongly with transcriptional activation of linked genes that are important for B lymphoblast function. Conditional expression or repression of EBNA2 leads to a rapid alteration in RBP-jkappa and EBF1 binding. Biochemical and shRNA depletion studies provide evidence for cooperative assembly at co-occupied sites. These findings reveal that EBNA2 facilitate combinatorial interactions to induce new patterns of transcription factor occupancy and gene programming necessary to drive B-lymphoblast growth and survival. PMID- 26752716 TI - Cellular Models of Trophoblast Differentiation. AB - Orchestrated trophoblast differentiation is necessary to establish and maintain a normal pregnancy, however the molecular mechanisms that guide this process remain largely unknown. Although early studies of cytotrophoblast differentiation relied on animal models, more recent trophoblast research has involved in vitro models of human tissue. These in vitro models have utilized cultured trophoblast cell lines, primary cell culture, and villous explant cultures-each with its advantages and disadvantages. Traditionally, attempts to develop in vitro models of human placental differentiation have relied on two-dimensional cell culture. Though monolayer culture methods have been refined over time this technique has several limitations, including the inability to study cell-to-cell interactions. Recently, several studies have employed three-dimensional culture methods to overcome many of the limitations of traditional two-dimensional trophoblast culture. These three-dimensional culture systems have an important role in both the study of cytotrophoblast differentiation and development of new therapeutics targeting placenta associated diseases. PMID- 26752718 TI - Effect of the different finishing and polishing procedures on the surface roughness of three different posterior composite resins. AB - Finishing and polishing techniques have great importance on the long term success and aesthetics of the composite restorations. In this study it was aimed to examine the effect of three different posterior composites on surface texture with various finishing and polishing procedures. Three different posterior composites, Filtek P60, Clearfil Majesty Posterior and Cavex Quadent Posterior Dense, and three different finishing and polishing procedures diamond finishing burs, tungsten carbide burs and Sof-Lex discs were used in the study. The specimens were 5 mm in diameter and 2 mm in height. The surface roughness was measured at three seperate points with a profilometer device and the Ra values were recorded. A one-way analysis of variance (ANOVA) and Kruskal-Wallis variance analysis was applied for statistical analysis and p < 0.05 was accepted significant. No statistically significant differences were found between the composite resins with respect to surface roughness (p > 0.05). A statistically significant difference was found between the groups of diamond, carbide, and Sof Lex groups (p < 0.05). Sof-Lex polishing system was more successful than the diamond and carbide burs in the finishing and polishing procedures of composites. SCANNING 38:448-454, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26752719 TI - Use of Unique Doppler Flow-Pattern for the Diagnosis of Left Ventricular Diverticulum. AB - Isolated congenital left ventricular diverticulum (LV) is reportedly a rare finding. It is frequently associated with other congenital defects involving heart, pericardium, sternum, diaphragm, and abdominal wall. It is an outpouching from the ventricle and has all three layers of left ventricular free walls. We present the case of a 53-year-old woman who was discovered to have an outpouching of the LV apex on a nongated chest CT scan raising possibility of a pseudoaneurysm. A transesophageal echocardiogram (TEE) showed systolic diminution of this outpouching with unique Doppler flow-patterns suggesting a diagnosis of a muscular type of LV diverticulum instead of a postinfarct LV pseudoaneurysm. The patient was reassured and treated conservatively. PMID- 26752717 TI - Characterisation of two conopressin precursor isoforms in the land snail, Theba pisana. AB - Increased understanding of the molecular components involved in mollusc reproduction may assist in understanding the evolutionary adaptations used by animals, including hermaphrodites, to produce offspring. The neuropeptide conopressin, a member of the vasopressin/oxytocin-like peptide family, can modulate various reproductive activities in invertebrates. In this study, we used the hermaphroditic land snail, Theba pisana, to investigate the presence and tissue-specific distribution of a conopressin gene. Our transcriptomic analysis of T. pisana CNS sheath tissue has revealed two conopressin gene transcripts (Tpi conopressin-1 and Tpi-conopressin-2), each encoding for precursors containing an identical conopressin nonapeptide and a variable neurophysin. T. pisana conopressins share high identity with other land snails and slugs, as well as other mollusc and vertebrate vasopressin/oxytocin, supported by phylogenetic analysis. Conserved residues in the T. pisana neurophysin are important for peptide binding, and we present molecular dynamic models demonstrating the most likely stable structure of the Tpi-conopressin-1 peptide when associated with neurophysin. RT-PCR shows that Tpi-conopressin-1 is additionally expressed in reproductive tissues, including the dart sac, where abundant spatial expression throughout the sac region is found; this implies a role in 'love' dart synthesis or dart injection during mating. The presence of a conopressin receptor in the CNS sheath indicates CNS neural excitation. In summary, this study represents a detailed molecular analysis of conopressin in a land snail. PMID- 26752715 TI - Animal Models to Study Placental Development and Function throughout Normal and Dysfunctional Human Pregnancy. AB - Abnormalities of placental development and function are known to underlie many pathologies of pregnancy, including spontaneous preterm birth, fetal growth restriction, and preeclampsia. A growing body of evidence also underscores the importance of placental dysfunction in the lifelong health of both mother and offspring. However, our knowledge regarding placental structure and function throughout pregnancy remains limited. Understanding the temporal growth and functionality of the human placenta throughout the entirety of gestation is important if we are to gain a better understanding of placental dysfunction. The utilization of new technologies and imaging techniques that could enable safe monitoring of placental growth and function in vivo has become a major focus area for the National Institutes of Child Health and Human Development, as evident by the establishment of the "Human Placenta Project." Many of the objectives of the Human Placenta Project will necessitate preclinical studies and testing in appropriately designed animal models that can be readily translated to the clinical setting. This review will describe the advantages and limitations of relevant animals such as the guinea pig, sheep, and nonhuman primate models that have been used to study the role of the placenta in fetal growth disorders, preeclampsia, or other maternal diseases during pregnancy. PMID- 26752720 TI - Vascular leakage in dengue--clinical spectrum and influence of parenteral fluid therapy. AB - OBJECTIVE: Clinical management of dengue relies on careful monitoring of fluid balance combined with judicious intravenous (IV) fluid therapy. However, in patients with significant vascular leakage, IV fluids may aggravate serosal fluid accumulation and result in respiratory distress. METHODS: Trained physicians followed suspected dengue cases prospectively at seven hospitals across Asia and Latin America, using a comprehensive case report form that included daily clinical assessment and detailed documentation of parenteral fluid therapy. Applying Cox regression, we evaluated risk factors for the development of shock or respiratory distress with fluid accumulation. RESULTS: Most confirmed dengue patients (1524/1734, 88%) never experienced dengue shock syndrome (DSS). Among those with DSS, 176/210 (84%) had fluid accumulation, and in the majority (83%), this was detectable clinically. Among all cases with clinically detectable fluid accumulation, 179/447 (40%) were diagnosed with shock or respiratory distress. The risk for respiratory distress with fluid accumulation increased significantly as the infused volume over the preceding 24 h increased (hazard ratio 1.18 per 10 ml/kg increase; P < 0.001). Longer duration of IV therapy, use of a fluid bolus in the preceding 24 h, female gender and poor nutrition also constituted independent risk factors. CONCLUSIONS: Shock and respiratory distress are relatively rare manifestations of dengue, but some evidence of fluid accumulation is seen in around 50% of cases. IV fluids play a crucial role in management, but they must be administered with caution. Clinically and/or radiologically detectable fluid accumulations have potential as intermediate severity endpoints for therapeutic intervention trials and/or pathogenesis studies. PMID- 26752721 TI - Problems and preferences in pediatric imaging. AB - Radiological imaging is extremely valuable as a diagnostic tool in the pediatric population, but it comes with a number of distinct challenges as compared to the imaging of adults. This is because of the following: It requires dedicated imaging protocols to acquire the images, there is need for sedation or general anesthesia for longer procedures such as MRI, specific training is required for the healthcare personnel involved, thorough knowledge and expertise should be applied for evaluating the images, and most importantly, it requires consideration for radiation exposure if ionizing radiation is being used. One of the challenges for clinical care personnel is to gain the child's trust and co operation before and throughout the duration of an examination, which can prove to be difficult in children who may be ill and have pain. This is important to acquire quality images and prevent repeat examinations. Even with a quality examination, the accurate interpretation of images requires a thorough knowledge of the intricate and dynamic face of anatomy and specific pathological presentations in children. The increased radiation sensitivity of growing organs and children's longer expected life spans make them more susceptible to the harmful effects of radiation. Imaging pediatric patients in a dedicated pediatric imaging department with dedicated pediatric CT technologists may result in greater compliance with pediatric protocols and significantly reduced patient dose. In order to prevent the harmful effects of ionizing radiation, As Low As Reasonably Achievable (ALARA) principle should be strictly followed. This article seeks to draw attention to various challenges of pediatric imaging and the ways to overcome them. PMID- 26752722 TI - Essential Contribution of CD4+ T Cells to Antigen-Induced Nasal Hyperresponsiveness in Experimental Allergic Rhinitis. AB - Nasal hyperresponsiveness (NHR) is a characteristic feature of allergic rhinitis (AR); however, the pathogenesis of NHR is not fully understood. In this study, during the establishment of an experimental AR model using ovalbumin-immunized and -challenged mice, augmentation of the sneezing reaction in response to nonspecific proteins as well as a chemical stimulant was detected. Whether NHR is independent of mast cells and eosinophils was determined by using mast cell- and eosinophil-deficient mice. NHR was suppressed by treatment with anti-CD4 antibody, suggesting the pivotal contribution of CD4+ T cells. Furthermore, antigen challenge to mice to which in vitro-differentiated Th1, Th2, and Th17 cells but not naive CD4+ T cells had been adoptively transferred led to the development of equivalent NHR. Since antigen-specific IgE and IgG were not produced in these mice and since antigen-specific IgE-transgenic mice did not develop NHR even upon antigen challenge, humoral immunity would be dispensable for NHR. CD4+ T cells play a crucial role in the pathogenesis of AR via induction of NHR, independent of IgE-, mast cell-, and eosinophil-mediated responses. PMID- 26752724 TI - Adolescent Self-Organization and Adult Smoking and Drinking over Fifty Years of Follow-Up: The British 1946 Birth Cohort. AB - Variations in markers of adolescent self-organization predict a range of economic and health-related outcomes in general population studies. Using a population based birth cohort study we investigated associations between adolescent self organization and two common factors over adulthood influencing health, smoking and alcohol consumption. The MRC National Survey of Health and Development (the British 1946 birth cohort) was used to test associations between a dimensional measure of adolescent self-organization derived from teacher ratings, and summary longitudinal measures of smoking and alcohol consumption over the ensuing five decades. Multinomial regression models were adjusted for sex, adolescent emotional and conduct problems, occupational social class of origin, childhood cognition, educational attainment and adult occupational social class. With all covariates adjusted, higher adolescent self-organization was associated with fewer smoking pack years, although not with quitting; there was no association with alcohol consumption across adulthood (none or heavy compared with light to moderate). Adolescent self-organization appears to be protective against smoking, but not against heavy alcohol consumption. Interpretation of this differential effect should be embedded in an understanding of the social and sociodemographic context in which these health behaviours occur over time. PMID- 26752727 TI - Scrub typhus in rural Rajasthan and a review of other Indian studies. AB - BACKGROUND: Scrub typhus is an acute febrile illness which has been reported from various parts of India with Rajasthan recently joining the list of affected states. AIM: To report a series of paediatric scrub typhus cases from rural Rajasthan. STUDY DESIGN: Retrospective review of children with scrub typhus admitted to the wards and paediatric intensive care unit (PICU) of a tertiary care hospital. METHODS: The study was undertaken over an 8-month period from May to December 2013. All patients with a clinical presentation and/or serological confirmation of scrub typhus who tested negative for malaria, enteric fever, dengue, leptospirosis and urinary tract infection (UTI) were included. A range of investigations were undertaken including IgM-ELISA for scrub typhus, followed by appropriate medical management. RESULTS: Thirty patients satisfied the inclusion criteria. The mean (SD, range) age of the patients was 8.56 (3.43, 3-16) years. The most common clinical features were fever (n = 30, 100%), headache (n = 20, 66%), myalgia (n = 15, 50%), hepatosplenomegaly (n = 18, 60%) and pallor (n = 5, 16%). Typical features such as eschar and rash were observed in only one (3.3%) and three (10%) patients, respectively; none had generalised lymphadenopathy or conjunctival congestion. IgM-ELISA for scrub typhus was positive in 28 patients (93.3%) and 27 responded to doxycycline within 24-72 hours. One of the three patients who required PICU support responded to intravenous chloramphenicol and, of the other two (6.6%), one died of acute respiratory distress syndrome and the other owing to acute renal failure. CONCLUSION: A high index of suspicion is essential for early diagnosis and prevention of complications in scrub typhus together with prompt referral from rural areas to a higher centre. Awareness of the disease manifestations may further help to prevent excessive investigations in patients presenting with non-specific febrile illness and reduce the economic burden to the family and society in resource-constrained settings. PMID- 26752728 TI - Oxygen-doped porous silicon carbide spheres as electrode materials for supercapacitors. AB - Oxygen-containing functional groups were introduced onto the surface of the micro and meso-porous silicon carbide sphere (MMPSiC) in order to investigate the relationship between the electric double layer properties and pseudo-capacitive properties; the degree of oxidation of MMPSiC was also optimized. Although the oxygenated surface functionalities can lead to a decrease in the surface area of MMPSiC, the oxygen functional groups attached to the external surface can participate in the redox reaction, resulting in the enhancement of the total super-capacitive performance. The MMPSiC electrode oxidized for 24 h exhibits a high charge storage capacity with a specific capacitance of 301.1 F g(-1) at a scan rate of 5 mV s(-1), with 86.8% rate performance from 5 to 500 mV s(-1) in 1 M KCl aqueous electrolyte. This outstanding capacitive performance of the MMPSiC electrode oxidized for 24 h can be attributed to the harmonious synergistic effect between the electric double layer capacitive contribution of MMPSiC and the pseudo-capacitive contribution of the oxygen-containing functional groups. These encouraging results demonstrate that the MMPSiC electrode oxidized for 24 h is a promising candidate for high performance electrode materials for supercapacitors. PMID- 26752723 TI - Trade-Offs of Escherichia coli Adaptation to an Intracellular Lifestyle in Macrophages. AB - The bacterium Escherichia coli exhibits remarkable genomic and phenotypic variation, with some pathogenic strains having evolved to survive and even replicate in the harsh intra-macrophage environment. The rate and effects of mutations that can cause pathoadaptation are key determinants of the pace at which E. coli can colonize such niches and become pathogenic. We used experimental evolution to determine the speed and evolutionary paths undertaken by a commensal strain of E. coli when adapting to intracellular life. We estimated the acquisition of pathoadaptive mutations at a rate of 10-6 per genome per generation, resulting in the fixation of more virulent strains in less than a hundred generations. Whole genome sequencing of independently evolved clones showed that the main targets of intracellular adaptation involved loss of function mutations in genes implicated in the assembly of the lipopolysaccharide core, iron metabolism and di- and tri-peptide transport, namely rfaI, fhuA and tppB, respectively. We found a substantial amount of antagonistic pleiotropy in evolved populations, as well as metabolic trade-offs, commonly found in intracellular bacteria with reduced genome sizes. Overall, the low levels of clonal interference detected indicate that the first steps of the transition of a commensal E. coli into intracellular pathogens are dominated by a few pathoadaptive mutations with very strong effects. PMID- 26752725 TI - Ultra-Deep Bisulfite Sequencing to Detect Specific DNA Methylation Patterns of Minor Cell Types in Heterogeneous Cell Populations: An Example of the Pituitary Tissue. AB - DNA methylation is an epigenetic modification important for cell fate determination and cell type-specific gene expression. Transcriptional regulatory regions of the mammalian genome contain a large number of tissue/cell type dependent differentially methylated regions (T-DMRs) with DNA methylation patterns crucial for transcription of the corresponding genes. In general, tissues consist of multiple cell types in various proportions, making it difficult to detect T-DMRs of minor cell types in tissues. The present study attempts to detect T-DMRs of minor cell types in tissues by ultra-deep bisulfite sequencing of cell type-restricted genes and to assume proportions of minor cell types based on DNA methylation patterns of sequenced reads. For this purpose, we focused on transcriptionally active hypomethylated alleles (Hypo-alleles), which can be recognized by the high ratio of unmethylated CpGs in each sequenced read (allele). The pituitary gland contains multiple cell types including five hormone expressing cell types and stem/progenitor cells, each of which is a minor cell type in the pituitary tissue. By ultra-deep sequencing of more than 100 reads for detection of Hypo-alleles in pituitary cell type-specific genes, we identified T DMRs specific to hormone-expressing cells and stem/progenitor cells and used them to estimate the proportions of each cell type based on the Hypo-allele ratio in pituitary tissue. Therefore, introduction of the novel Hypo-allele concept enabled us to detect T-DMRs of minor cell types with estimation of their proportions in the tissue by ultra-deep bisulfite sequencing. PMID- 26752726 TI - Strengthening Community-Based Vital Events Reporting for Real-Time Monitoring of Under-Five Mortality: Lessons Learned from the Balaka and Salima Districts in Malawi. AB - BACKGROUND: Malawi ratified a compulsory birth and death registration system in 2009. Until it captures complete coverage of vital events, Malawi relies on other data sources to calculate mortality estimates. We tested a community-based method to estimate annual under-five mortality rates (U5MR) through the Real-Time Monitoring of Under-Five Mortality (RMM) project in Malawi. We implemented RMM in two phases, and conducted an independent evaluation of phase one after 21 months of implementation. We present results of the phase two validation that covers the full project time span, and compare the results to those of the phase one validation. METHODS AND FINDINGS: We assessed the completeness of the counts of births and deaths and the accuracy of disaggregated U5MR from the community-based method against a retrospective full pregnancy history for rolling twelve-month periods after the independent evaluation. We used full pregnancy histories collected through household interviews carried out between November 2013 and January 2014 as the validation data source. Health Surveillance Agents (HSAs) across the 160 catchment areas submitted routine reports on pregnancies, births, and deaths consistently. However, for the 15-month implementation period post evaluation, average completeness of birth event reporting was 76%, whereas average completeness of death event reporting was 67% relative to that expected from a comparable pregnancy history. HSAs underestimated the U5MR by an average of 21% relative to that estimated from a comparable pregnancy history. CONCLUSIONS: On a medium scale, the community-based RMM method in Malawi produced substantial underestimates of annualized U5MR relative to those obtained from a full pregnancy history, despite the additional incentives and quality-control activities. We were not able to achieve an optimum level of incentive and support to make the system work while ensuring sustainability. Lessons learned from the implementation of RMM can inform programs supporting community-based interventions through HSAs in Malawi. PMID- 26752729 TI - Fully automatic segmentation of left atrium and pulmonary veins in late gadolinium-enhanced MRI: Towards objective atrial scar assessment. AB - PURPOSE: To realize objective atrial scar assessment, this study aimed to develop a fully automatic method to segment the left atrium (LA) and pulmonary veins (PV) from late gadolinium-enhanced (LGE) magnetic resonance imaging (MRI). The extent and distribution of atrial scar, visualized by LGE-MRI, provides important information for clinical treatment of atrial fibrillation (AF) patients. MATERIALS AND METHODS: Forty-six AF patients (age 62 +/- 8, 14 female) who underwent cardiac MRI prior to RF ablation were included. A contrast-enhanced MR angiography (MRA) sequence was acquired for anatomy assessment followed by an LGE sequence for LA scar assessment. A fully automatic segmentation method was proposed consisting of two stages: 1) global segmentation by multiatlas registration; and 2) local refinement by 3D level-set. These automatic segmentation results were compared with manual segmentation. RESULTS: The LA and PVs were automatically segmented in all subjects. Compared with manual segmentation, the method yielded a surface-to-surface distance of 1.49 +/- 0.65 mm in the LA region when using both MRA and LGE, and 1.80 +/- 0.93 mm when using LGE alone (P < 0.05). In the PV regions, the distance was 2.13 +/- 0.67 mm and 2.46 +/- 1.81 mm (P < 0.05), respectively. The difference between automatic and manual segmentation was comparable to the interobserver difference (P = 0.8 in LA region and P = 0.7 in PV region). CONCLUSION: We developed a fully automatic method for LA and PV segmentation from LGE-MRI, with comparable performance to a human observer. Inclusion of an MRA sequence further improves the segmentation accuracy. The method leads to automatic generation of a patient-specific model, and potentially enables objective atrial scar assessment for AF patients. J. Magn. Reson. Imaging 2016;44:346-354. PMID- 26752730 TI - Missing a trick: Auditory load modulates conscious awareness in audition. AB - In the visual domain there is considerable evidence supporting the Load Theory of Attention and Cognitive Control, which holds that conscious perception of background stimuli depends on the level of perceptual load involved in a primary task. However, literature on the applicability of this theory to the auditory domain is limited and, in many cases, inconsistent. Here we present a novel "auditory search task" that allows systematic investigation of the impact of auditory load on auditory conscious perception. An array of simultaneous, spatially separated sounds was presented to participants. On half the trials, a critical stimulus was presented concurrently with the array. Participants were asked to detect which of 2 possible targets was present in the array (primary task), and whether the critical stimulus was present or absent (secondary task). Increasing the auditory load of the primary task (raising the number of sounds in the array) consistently reduced the ability to detect the critical stimulus. This indicates that, at least in certain situations, load theory applies in the auditory domain. The implications of this finding are discussed both with respect to our understanding of typical audition and for populations with altered auditory processing. (PsycINFO Database Record PMID- 26752731 TI - Getting more from visual working memory: Retro-cues enhance retrieval and protect from visual interference. AB - Visual working memory (VWM) has a limited capacity. This limitation can be mitigated by the use of focused attention: if attention is drawn to the relevant working memory content before test, performance improves (the so-called retro-cue benefit). This study tests 2 explanations of the retro-cue benefit: (a) Focused attention protects memory representations from interference by visual input at test, and (b) focusing attention enhances retrieval. Across 6 experiments using color recognition and color reproduction tasks, we varied the amount of color interference at test, and the delay between a retrieval cue (i.e., the retro-cue) and the memory test. Retro-cue benefits were larger when the memory test introduced interfering visual stimuli, showing that the retro-cue effect is in part because of protection from visual interference. However, when visual interference was held constant, retro-cue benefits were still obtained whenever the retro-cue enabled retrieval of an object from VWM but delayed response selection. Our results show that accessible information in VWM might be lost in the processes of testing memory because of visual interference and incomplete retrieval. This is not an inevitable state of affairs, though: Focused attention can be used to get the most out of VWM. (PsycINFO Database Record PMID- 26752733 TI - Shifts in attention during mental fatigue: Evidence from subjective, behavioral, physiological, and eye-tracking data. AB - There is an increasing amount of evidence that during mental fatigue, shifts in motivation drive performance rather than reductions in finite mental energy. So far, studies that investigated such an approach have mainly focused on cognitive indicators of task engagement that were measured during controlled tasks, offering limited to no alternative stimuli. Therefore it remained unclear whether during fatigue, attention is diverted to stimuli that are unrelated to the task, or whether fatigued individuals still focused on the task but were unable to use their cognitive resources efficiently. With a combination of subjective, EEG, pupil, eye-tracking, and performance measures the present study investigated the influence of mental fatigue on a cognitive task which also contained alternative task-unrelated stimuli. With increasing time-on-task, task engagement and performance decreased, but there was no significant decrease in gaze toward the task-related stimuli. After increasing the task rewards, irrelevant rewarding stimuli where largely ignored, and task engagement and performance were restored, even though participants still reported to be highly fatigued. Overall, these findings support an explanation of less efficient processing of the task that is influenced by motivational cost/reward tradeoffs, rather than a depletion of a finite mental energy resource. (PsycINFO Database Record PMID- 26752734 TI - Is semantic preview benefit due to relatedness or plausibility? AB - There is increasing evidence that skilled readers of English benefit from processing a parafoveal preview of a semantically related word. However, in previous investigations of semantic preview benefit using the gaze-contingent boundary paradigm the semantic relatedness between the preview and target has been confounded with the plausibility of the preview word in the sentence. In the present study, preview relatedness and plausibility were independently manipulated in neutral sentences read by a large sample of skilled adult readers. Participants were assessed on measures of reading and spelling ability to identify possible sources of individual differences in preview effects. The results showed that readers benefited from a preview of a plausible word, regardless of the semantic relatedness of the preview and the target. However, there was limited evidence of a semantic relatedness benefit when the plausibility of the preview was controlled. The plausibility preview benefit was strongest for low proficiency readers, suggesting that poorer readers were more likely to program a forward saccade based on information extracted from the preview. High proficiency readers showed equivalent disruption from all nonidentical previews suggesting that they were more likely to suffer interference from the orthographic mismatch between preview and target. (PsycINFO Database Record PMID- 26752735 TI - A Novel GBM Saliency Detection Model Using Multi-Channel MRI. AB - The automatic computerized detection of regions of interest (ROI) is an important step in the process of medical image processing and analysis. The reasons are many, and include an increasing amount of available medical imaging data, existence of inter-observer and inter-scanner variability, and to improve the accuracy in automatic detection in order to assist doctors in diagnosing faster and on time. A novel algorithm, based on visual saliency, is developed here for the identification of tumor regions from MR images of the brain. The GBM saliency detection model is designed by taking cue from the concept of visual saliency in natural scenes. A visually salient region is typically rare in an image, and contains highly discriminating information, with attention getting immediately focused upon it. Although color is typically considered as the most important feature in a bottom-up saliency detection model, we circumvent this issue in the inherently gray scale MR framework. We develop a novel pseudo-coloring scheme, based on the three MRI sequences, viz. FLAIR, T2 and T1C (contrast enhanced with Gadolinium). A bottom-up strategy, based on a new pseudo-color distance and spatial distance between image patches, is defined for highlighting the salient regions in the image. This multi-channel representation of the image and saliency detection model help in automatically and quickly isolating the tumor region, for subsequent delineation, as is necessary in medical diagnosis. The effectiveness of the proposed model is evaluated on MRI of 80 subjects from the BRATS database in terms of the saliency map values. Using ground truth of the tumor regions for both high- and low- grade gliomas, the results are compared with four highly referred saliency detection models from literature. In all cases the AUC scores from the ROC analysis are found to be more than 0.999 +/- 0.001 over different tumor grades, sizes and positions. PMID- 26752732 TI - Interaction between object-based attention and pertinence values shapes the attentional priority map of a multielement display. AB - Previous studies have shown that the perceptual organization of the visual scene constrains the deployment of attention. Here we investigated how the organization of multiple elements into larger configurations alters their attentional weight, depending on the "pertinence" or behavioral importance of the elements' features. We assessed object-based effects on distinct aspects of the attentional priority map: top-down control, reflecting the tendency to encode targets rather than distracters, and the spatial distribution of attention weights across the visual scene, reflecting the tendency to report elements belonging to the same rather than different objects. In 2 experiments participants had to report the letters in briefly presented displays containing 8 letters and digits, in which pairs of characters could be connected with a line. Quantitative estimates of top-down control were obtained using Bundesen's Theory of Visual Attention (1990). The spatial distribution of attention weights was assessed using the "paired response index" (PRI), indicating responses for within-object pairs of letters. In Experiment 1, grouping along the task-relevant dimension (targets with targets and distracters with distracters) increased top-down control and enhanced the PRI; in contrast, task-irrelevant grouping (targets with distracters) did not affect performance. In Experiment 2, we disentangled the effect of target-target and distracter-distracter grouping: Pairwise grouping of distracters enhanced top down control whereas pairwise grouping of targets changed the PRI. We conclude that object-based perceptual representations interact with pertinence values (of the elements' features and location) in the computation of attention weights, thereby creating a widespread pattern of attentional facilitation across the visual scene. (PsycINFO Database Record PMID- 26752736 TI - Multivariate time series analysis of neuroscience data: some challenges and opportunities. AB - Neuroimaging data may be viewed as high-dimensional multivariate time series, and analyzed using techniques from regression analysis, time series analysis and spatiotemporal analysis. We discuss issues related to data quality, model specification, estimation, interpretation, dimensionality and causality. Some recent research areas addressing aspects of some recurring challenges are introduced. PMID- 26752737 TI - In situ direct growth of single crystalline metal (Co, Ni) selenium nanosheets on metal fibers as counter electrodes toward low-cost, high-performance fiber-shaped dye-sensitized solar cells. AB - Highly crystalline metal (Co, Ni) selenium (Co0.85Se or Ni0.85Se) nanosheets were in situ grown on metal (Co, Ni) fibers (M-M0.85Se). Both M-M0.85Se (Co-Co0.85Se and Ni-Ni0.85Se) fibers prove to function as excellent, low-cost counter electrodes (CEs) in fiber-shaped dye-sensitized solar cells (FDSSCs) with high power conversion efficiency (Co-Co0.85Se 6.55% and Ni-Ni0.85Se 7.07%), comparable or even superior to a Pt fiber CE (6.54%). The good performance of the present Pt free CE-based solar cell was believed to originate from: (1) the intrinsic electrocatalytic properties of the single-crystalline M-M0.85Se; (2) the enough void space among M0.85Se nanosheets that allows easier redox ion diffusion; (3) the two-dimensional morphology that provides a large contact area between the CE catalytic material and electrolyte; (4) in situ direct growth of the M0.85Se on metal fibers that renders good electrical contact between the active material and the electron collector. PMID- 26752738 TI - Fixation of Soft Tissue to Bone: Techniques and Fundamentals. AB - A myriad of orthopaedic injuries require surgical fixation of torn connective tissue to an osseous insertion site with either direct repair or reconstruction with a soft-tissue graft. Numerous factors influence the strength of a soft tissue-to-bone fixation construct, including tissue quality, implant strength, contact area and pressure, and tensioning. Each fixation technique differs with respect to biologic integration, biomechanical stability, and failure mechanism. Fixation methods may or may not require an implant, such as interference screws, staples, internal buttons, transfixion pins, or suture anchors. Understanding the optimal method of soft-tissue fixation for a given scenario is crucial for successful repair or reconstruction. PMID- 26752739 TI - Metal Hypersensitivity and Total Knee Arthroplasty. AB - Metal hypersensitivity in patients with a total knee arthroplasty (TKA) is a controversial topic. The diagnosis is difficult, given the lack of robust clinical validation of the utility of cutaneous and in vitro testing. Metal hypersensitivity after TKA is quite rare and should be considered after eliminating other causes of pain and swelling, such as low-grade infection, instability, component loosening or malrotation, referred pain, and chronic regional pain syndrome. Anecdotal observations suggest that two clinical presentations of metal hypersensitivity may occur after TKA: dermatitis or a persistent painful synovitis of the knee. Patients may or may not have a history of intolerance to metal jewelry. Laboratory studies, including erythrocyte sedimentation rate, C-reactive protein level, and knee joint aspiration, are usually negative. Cutaneous and in vitro testing have been reported to be positive, but the sensitivity and specificity of such testing has not been defined. Some reports suggest that, if metal hypersensitivity is suspected and nonsurgical measures have failed, then revision to components fabricated of titanium alloy or zirconium coating can be successful in relieving symptoms. Revision should be considered as a last resort, however, and patients should be informed that no evidence-based medicine is available to guide the management of these conditions, particularly for decisions regarding revision. Given the limitations of current testing methods, the widespread screening of patients for metal allergies before TKA is not warranted. PMID- 26752740 TI - Photophysical properties of single core multimodal probe for imaging (SCoMPI) in a membrane model and in cells. AB - The spectroscopic properties of two luminescent Re(i) tricarbonyl complexes conjugated with two cell-penetrating peptides were examined. Fluorescence experiments and IR quantification in membrane models and in cells showed unexpectedly strong luminescence enhancement for one of the complexes in a lipid environment. PMID- 26752741 TI - Promise and Challenge of DNA Barcoding in Venus Slipper (Paphiopedilum). AB - Orchidaceae are one of the largest families of flowering plants, with over 27,000 species described and all orchids are listed in CITES. Moreover, the seedlings of orchid species from the same genus are similar. The objective of DNA barcoding is rapid, accurate, and automated species identification, which may be used to identify illegally traded endangered species from vegetative specimens of Paphiopedilum (Venus slipper), a flagship group for plant conservation with high ornamental and commercial values. Here, we selected eight chloroplast barcodes and nrITS to evaluate their suitability in Venus slippers. The results indicate that all tested barcodes had no barcoding gap and the core plant barcodes showed low resolution for the identification of Venus slippers (18.86%). Of the single locus barcodes, nrITS is the most efficient for the species identification of the genus (52.27%), whereas matK + atpF-atpH is the most efficient multi-locus combination (28.97%). Therefore, we recommend the combination of matK + atpF-atpH + ITS as a barcode for Venus slippers. Furthermore, there is an upper limit of resolution of the candidate barcodes, and only half of the taxa with multiple samples were identified successfully. The low efficiency of these candidate barcodes in Venus slippers may be caused by relatively recent speciation, the upper limit of the barcodes, and/or the sampling density. Although the discriminatory power is relatively low, DNA barcoding may be a promising tool to identify species involved in illegal trade, which has broad applications and is valuable for orchid conservation. PMID- 26752742 TI - Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells. AB - Oral squamous cell carcinoma (OSCC) is a common cancer worldwide. Despite advances in diagnosis and therapy, treatment options for patients with metastatic OSCC are few, due in part to the limited understanding of the molecular events involved in the invasion and metastasis of OSCC. In this study, we investigated the expression of focal adhesion kinase (FAK) and its tyrosine 397 phosphorylation (pY397) in the tissue specimens of OSCC. The roles of pY397 in regulating the activities of Rac1 and cortactin and the invasive properties of OSCC cells were further determined. Results from immunohistochemical analyses in 9 benign, 19 premalignant, and 19 malignant oral tissues showed that the immunoreactivity of FAK was observed in 5 benign (56%), 19 premalignant (100%), and 18 malignant tissues (95%), whereas the immunoreactivity of pY397 was only found in 1 of 9 (11%) benign lesions but was observed in 9 premalignant (47%) and 12 malignant (63%) lesions. Compared with the low-invading SCC4 cells, the high invading OECM-1 cells exhibited higher levels of FAK expression and pY397, correlating with higher levels of GTP-bound Rac1 and cortactin phosphorylation. Manipulation of FAK expression or Y397 phosphorylation in SCC4, FaDu, OECM-1, or HSC-3 cells regulated their Rac1 activities and invasive properties. Furthermore, treatment of NSC23766, a Rac1-specific inhibitor, in OECM-1 and HSC-3 cells led to reduced invasive properties. Nevertheless, knockdown of FAK expression or suppression of pY397 had no effect on the cortactin activity in OECM-1 cells. The data collectively suggest that pY397 plays critical roles in the FAK-promoted Rac1 activation and invasive properties in OSCC cells. Thus, the inhibition of FAK phosphorylation at Y397 or Rac1 activity can serve as a therapeutic strategy for treating patients with metastatic OSCC. PMID- 26752744 TI - Canonical Wnt signaling in systemic sclerosis. AB - Fibrosing disorders are characterized by abundant accumulation of extracellular matrix proteins such as collagen in a variety of organs, which results in structural changes and dysfunction of the affected organ. Thus fibrotic diseases are characterized by a high morbidity and mortality and also lead to major socioeconomic costs. Systemic sclerosis (SSc) is a prototypic multi-systemic fibrosing disease, which affects the skin and a variety of internal organs, including the lungs, heart and gastrointestinal tract. Targeted antifibrotic therapies are not yet available for clinical use in SSc. In recent years, canonical Wnt signaling has been profoundly characterized as an important mediator of sustained fibroblast activation in fibrotic diseases. In the present review, we will summarize current research on the canonical Wnt signaling pathway in SSc and discuss translational implications and potential limitations of prolonged Wnt inhibition. PMID- 26752743 TI - TNF-alpha alters the inflammatory secretion profile of human first trimester placenta. AB - Implantation and subsequent placental development depend on a well-orchestrated interaction between fetal and maternal tissues, involving a fine balanced synergistic cross-talk of inflammatory and immune-modulating factors. Tumor necrosis factor (TNF)-alpha has been increasingly recognized as pivotal factor for successful pregnancy, although high maternal TNF-alpha levels are associated with a number of adverse pregnancy conditions including gestational hypertension and gestational diabetes mellitus. This study describes effects of exogenously applied TNF-alpha, mimicking increased maternal TNF-alpha levels, on the secretion profile of inflammation associated factors in human first trimester villous placenta. Conditioned culture media from first trimester villous placental explants were analyzed by inflammation antibody arrays and ELISA after 48 h culture in the presence or absence of TNF-alpha. Inflammation antibody arrays identified interleukin (IL)-6, IL-8, chemokine (C-C motif) ligand 2 (CCL2), CCL4, and granulocyte-macrophage colony-stimulating factor (GM-CSF) as the most abundantly secreted inflammation-associated factors under basal culture conditions. In the presence of TNF-alpha, secretion of GM-CSF, CCL5, and IL-10 increased, whereas IL-4 and macrophage CSF levels decreased compared with controls. ELISA analysis verified antibody arrays by showing significantly increased synthesis and release of GM-CSF and CCL5 by placental explants in response to TNF-alpha. Immunohistochemistry localized GM-CSF in the villous trophoblast compartment, whereas CCL5 was detected in maternal platelets adhering to perivillous fibrin deposits on the villous surface. mRNA-based in situ padlock probe approach localized GM-CSF and CCL5 transcripts in the villous trophoblast layer and the villous stroma. Results from this study suggest that the inflammatory secretion profile of human first trimester placenta shifts towards increased levels of GM-CSF, CCL5, and IL10 in response to elevated maternal TNF alpha levels, whereas IL-6 and IL-8 remain unaffected. This shift may represent a protective mechanism by human first trimester villous placenta to sustain trophoblast function and dampen inflammatory processes in the intervillous space. PMID- 26752745 TI - Prolyl isomerase Pin1 promotes survival in EGFR-mutant lung adenocarcinoma cells with an epithelial-mesenchymal transition phenotype. AB - The secondary epidermal growth factor receptor (EGFR) T790M mutation is the most prominent mechanism that confers resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) in lung cancer treatment. Although third generation EGFR TKIs can suppress the kinase activity of T790M-positive EGFR, they still cannot eradicate EGFR-mutated cancer cells. We previously reported that a subpopulation of EGFR-mutant lung adenocarcinomas depends on enhanced autophagy, instead of EGFR, for survival, and in this study we explore another mechanism that contributes to TKI resistance. We demonstrate here that an EGFR mutant lung adenocarcinoma cell line, H1975 (L858R+T790M), has a subset of cells that exhibits an epithelial-mesenchymal transition (EMT) phenotype and can thrive in the presence of third-generation EGFR TKIs. These cells depend on not only autophagy but also on the isomerase Pin1 for survival in vitro, unlike their parental cells. The Pin1 protein was expressed in an EGFR-mutant lung cancer tissue that has undergone partial EMT and acquired resistance to EGFR TKIs, but not its primary tumor. These findings suggest that inhibition of Pin1 activity can be a novel strategy in lung cancer treatment. PMID- 26752749 TI - Further evidence for the case against neuropsychoanalysis: How Yovell, Solms, and Fotopoulou's response to our critique confirms the irrelevance and harmfulness to psychoanalysis of the contemporary neuroscientific trend. AB - In their paper "The case for neuropsychoanalysis" Yovell, Solms, and Fotopoulou (2015) respond to our critique of neuropsychoanalysis (Blass & Carmeli, 2007), setting forth evidence and arguments which, they claim, demonstrate why neuroscience is relevant and important for psychoanalysis and hence why dialogue between the fields is necessary. In the present paper we carefully examine their evidence and arguments and demonstrate how and why their claim is completely mistaken. In fact, Yovell, Solms, and Fotopoulou's paper only confirms our position on the irrelevance and harmfulness to psychoanalysis of the contemporary neuroscientific trend. We show how this trend perverts the essential nature of psychoanalysis and of how it is practiced. The clinical impact and its detrimental nature is highlighted by discussion of clinical material presented by Yovell et al (2015). In the light of this we argue that the debate over neuropsychoanalysis should be of interest to all psychoanalysts, not only those concerned with biology or interdisciplinary dialogue. PMID- 26752750 TI - The case for neuropsychoanalysis. PMID- 26752751 TI - Primary shame, mortal wound and tragic circularity: Some new reflections on shame and shame conflicts. AB - Invited to contribute some thoughts on recent developments in psychoanalytic thinking about shame, the author starts off with Aristotle's prescient analysis of shame and then focuses on accumulating experiences in the psychoanalytic treatment of patients with severe neuroses, in particular the close relationship of severe traumatization and chronic states of shame, and how this is reflected in shelfdestructive repetitions. Reminiscent of what we know from tragedy and the tragic dimension of human existence, this repetition compulsion shows a built-in circularity. These circular dynamics have at their core struggles with deep woundedness that can variably be conceived of as primary pain, primary shame and primary anxiety. Consequently, throughout the experiences with these patients goes the absoluteness both of their conscience and of their ideal, what we know as the "archaic superego:". PMID- 26752752 TI - Panel Report, IPA Congress Boston 2015: Advances in Psychoanalytic Field Theory: Changing psychoanalytic models of the mind and technique in a changing world. PMID- 26752753 TI - Panel Report, IPA Congress Boston 2015: Working with transference and countertransference: Special learning moments in our psychoanalytic journey. PMID- 26752747 TI - Versican: a novel modulator of hepatic fibrosis. AB - Little is known about the deposition and turnover of proteoglycans in liver fibrosis, despite their abundance in the extracellular matrix. Versican plays diverse roles in modulating cell behavior in other fibroproliferative diseases, but remains poorly described in the liver. Hepatic fibrosis was induced by carbon tetrachloride treatment of C57BL/6 mice over 4 weeks followed by recovery over a 28-day period. Primary mouse hepatic stellate cells (HSCs) were activated in culture and versican was transiently knocked down in human (LX2) and mouse HSCs. Expression of versican, A Disintegrin-like and Metalloproteinase with Thrombospondin-1 motifs (ADAMTS)-1, -4, -5, -8, -9, -15, and -20, and markers of fibrogenesis were studied using immunohistochemistry, real-time quantitative PCR, and western blotting. Immunohistochemistry showed increased expression of versican in cirrhotic human livers and the mouse model of fibrosis. Carbon tetrachloride treatment led to significant increases in versican expression and the proteoglycanases ADAMTS-5, -9, -15, and -20, alongside TNF-alpha, alpha smooth muscle actin (alpha-SMA), collagen-1, and TGF-beta expression. During recovery, expression of many of these genes returned to control levels. However, expression of ADAMTS-5, -8, -9, and -15 showed delayed increases in expression at 28 days of recovery, which corresponded with decreases in versican V0 and V1 cleavage products (G1-DPEAAE(1401) and G1-DPEAAE(441)). Activation of primary HSCs in vitro significantly increased versican, alpha-SMA, and collagen-1 expression. Transient knockdown of versican in HSCs led to decreases in markers of fibrogenesis and reduced cell proliferation, without inducing apoptosis. Versican expression increases during HSC activation and liver fibrosis, and proteolytic processing occurs during the resolution of fibrosis. Knockdown studies in vitro suggest a possible role of versican in modulating hepatic fibrogenesis. PMID- 26752754 TI - Report on the Panel: "Pathways to Representation: Reveries and Transformations through Dream-work, Playing and Joke-Work". PMID- 26752746 TI - Links between coagulation, inflammation, regeneration, and fibrosis in kidney pathology. AB - Acute kidney injury (AKI) involves nephron injury leading to irreversible nephron loss, ie, chronic kidney disease (CKD). Both AKI and CKD are associated with distinct histological patterns of tissue injury, but kidney atrophy in CKD involves tissue remodeling with interstitial inflammation and scarring. No doubt, nephron atrophy, inflammation, fibrosis, and renal dysfunction are associated with each other, but their hierarchical relationships remain speculative. To better understand the pathophysiology, we provide an overview of the fundamental danger response programs that assure host survival upon traumatic injury from as early as the first multicellular organisms, ie, bleeding control by coagulation, infection control by inflammation, epithelial barrier restoration by re epithelialization, and tissue stabilization by mesenchymal repair. Although these processes assure survival in the majority of the populations, their dysregulation causes kidney disease in a minority. We discuss how, in genetically heterogeneous population, genetic variants shift balances and modulate danger responses toward kidney disease. We further discuss how classic kidney disease entities develop from an insufficient or overshooting activation of these danger response programs. Finally, we discuss molecular pathways linking, for example, inflammation and regeneration or inflammation and fibrosis. Understanding the causative and hierarchical relationships and the molecular links between the danger response programs should help to identify molecular targets to modulate kidney injury and to improve outcomes for kidney disease patients. PMID- 26752755 TI - Panel Report, IPA Congress Boston 2015: Working Parties Today III: Methods and findings from Comparative Clinical Methods (CCM) and Initiating Psychoanalysis (WPIP). PMID- 26752756 TI - Panel Report, IPA Congress Boston 2015: Metaphors and the use of analyst as tools to improve our clinical practisePanel and Small Discussion Group organized by: IPA Project Committee on Clinical Observation. PMID- 26752757 TI - Panel Report, IPA Congress Boston 2015: Insight and Change: Psychoanalytic and Philosophical Perspectives. PMID- 26752758 TI - Panel Report, IPA Congress Boston 2015: The IJP Annuals: Psychoanalysis and Social media - an indecent relationship? PMID- 26752759 TI - Panel Report, IPA Congress Boston 2015: Knowing and Not Knowing Ones' own mind. Is an unconscious at work". PMID- 26752760 TI - Panel Report, IPA Congress Boston 2015: Locating Unrepresented Thought: The relationship between Trauma, Disrupted Object Representations and Evolving Concepts of the Unconscious. PMID- 26752761 TI - Panel Report, IPA Congress Boston 2015: Is translation between psychoanalytic concepts possible? PMID- 26752762 TI - Neuroscience and the "science" of psychoanalysis. PMID- 26752763 TI - Styles of criticism: Answering comments by Florence Guignard, Helmut Hinz and Paulo Sandler on "Transformations in Hallucinosis and the Receptivity of the Analyst". PMID- 26752764 TI - Erratum. PMID- 26752765 TI - Laboratory Findings Suggesting an Association Between BoHV-4 and Bovine Abortions in Southern Belgium. AB - Abortions cause heavy economic losses for the bovine sector. The use of a standardized panel of analyses covering a large spectrum of pathogens responsible of abortion in cattle allowed demonstrating the direct involvement of at least one pathogen in 57% of analysed abortions in the southern part of Belgium. This result suggests a margin of improvement in the diagnostic efficacy. In order to evaluate the interest to broaden the list of pathogens included in the panel of analyses, the implication of bovine herpesvirus 4 (BoHV-4) in abortion was assessed by two different studies. In the first study, coupled serology was performed after abortion on 714 dams to identify specific seroconversion against BoHV-4. The overall seroconversion in cows was 19.5%, with a higher frequency in primiparous compared to multiparous females. In addition, the type of breed (beef cattle) and the time period from the fourth quarter 2008 until the last quarter 2009 were significantly related to the seroconversion of cows. The second study investigated the virus ability to infect the foetus. In this study, 368 cases of bovine abortions were specifically tested for BoHV-4, using PCR on foetus tissues and ELISA on dam and foetus sera. The results showed a maternal seroprevalence of 64.7%, a foetal seroprevalence of 0.8% and a PCR prevalence in foetuses of 1.1%, demonstrating the ability of BoHV-4 to infect the foetus. PMID- 26752766 TI - A Problematic Test of the Kin Selection Hypothesis Among the Urak-Lawoi of Ko Lipe, Thailand: Commentary on Camperio Ciani, Battaglia, and Liotta (2015). AB - Camperio Ciani et al. argued that the Urak-Lawoi people of Ko Lipe island live in a "traditional," "subsistence primitive society" reminiscent of the "ancestral" human past and that their socio-cultural situation is "remarkably similar" to Samoa. On this basis, they asserted that the Ko Lipe Urak-Lawoi are an appropriate population for determining the role that kin selection played in the evolution of male androphilia. The purpose of this commentary is to outline some of our concerns with this characterization and with the statistical analyses conducted by Camperio Ciani et al. in their study of the Urak-Lawoi. PMID- 26752767 TI - Future projections of child oral-related hospital admission rates in Western Australia. AB - This study aimed to project the hospital admission rates of Western Australian children for oral conditions, with a particular focus on dental caries, embedded and impacted teeth, and pulp and periapical conditions through to the year 2026. Two methods were used to generate projection data through to the year 2026, using the Western Australian Hospital Morbidity Dataset for the period 1999-2000 to 2008-2009. The projected admission rate increase in those children aged 14 years and younger from 2000 to 2026 was 43%. The admission rates are expected to more than double over time (7317 cases in 2026 compared to only 3008 cases in 2000) for those children living in metropolitan areas. Dental caries, embedded and impacted teeth, and pulp and periapical conditions will remain the top (mostly) preventable causes of admission throughout this time. Anticipating the future burden of oral-related hospital admissions in children, in terms of expected numbers of cases, is vital for optimising the resource allocation for early diagnosis, prevention and treatment. A concerted effort will be required by policymakers and oral healthcare communities to effect substantial change for the future. PMID- 26752770 TI - Soft Tissue Endoscopy. PMID- 26752768 TI - Predictable tuning of protein expression in bacteria. AB - We comprehensively assessed the contribution of the Shine-Dalgarno sequence to protein expression and used the data to develop EMOPEC (Empirical Model and Oligos for Protein Expression Changes; http://emopec.biosustain.dtu.dk). EMOPEC is a free tool that makes it possible to modulate the expression level of any Escherichia coli gene by changing only a few bases. Measured protein levels for 91% of our designed sequences were within twofold of the desired target level. PMID- 26752771 TI - Endoscopic Transnasal Odontoidectomy. AB - Transoral microscopic odontoidectomy followed by posterior fixation has been accepted as a standard procedure to treat nonreducible basilar invagination during the half past century. In recent years, the development of endoscopic techniques has raised challenges regarding the traditional treatment algorithm. The endoscopic transnasal odontoidectomy is a feasible and effective method in the treatment of irreducible ventral cervicomedullary junction compression, which has several advantages over the transoral approach. The endoscopic odontoidectomy includes transnasal, transoral, and transcervical approaches. The 3 different approaches for endoscopic odontoidectomy present complementary advantages and limitations. The necessity of posterior fixation after odontoidectomy should be considered in every single case on the basis of the peculiar anatomic and clinical conditions. PMID- 26752769 TI - Parallel single-cell sequencing links transcriptional and epigenetic heterogeneity. AB - We report scM&T-seq, a method for parallel single-cell genome-wide methylome and transcriptome sequencing that allows for the discovery of associations between transcriptional and epigenetic variation. Profiling of 61 mouse embryonic stem cells confirmed known links between DNA methylation and transcription. Notably, the method revealed previously unrecognized associations between heterogeneously methylated distal regulatory elements and transcription of key pluripotency genes. PMID- 26752772 TI - Endoscopic Resection of the Bicipitoradial Bursa. AB - The bicipitoradial bursa lies at the insertion of the biceps tendon on the radial tuberosity. It is an unusual site for chronic bursitis. It can be treated conservatively with aspiration and steroid injection. Surgical excision of the bursa is indicated in case of infection cause, failed conservative treatment with recurrence of the enlarged bursa and pain after aspiration, the presence of nerve compression with neurological impairment, mechanical limitation to flexion and extension of the elbow or biceps tendon degeneration, and/or functional impairment. Open resection through the anterior approach requires extensive dissection to expose the radial tuberosity and the radial neck, which increases the risk of neurovascular injury. Endoscopic resection is possible through distal biceps tendoscopy and endoscopy around the radial neck. It is technically demanding and should be reserved to the experienced elbow arthroscopist. PMID- 26752773 TI - Endoscopic Management of Gluteus Medius Tendon Tears. AB - Tears in the gluteus medius and minimus tendons have been recognized as an important cause of recalcitrant greater trochanteric pain syndrome. Because of the frequency of partial-thickness undersurface tears, this relatively unknown pathology is often misdiagnosed and left untreated. Surgery is indicated in case of 4 associated conditions: (i) Failure of conservative treatment with duration of symptoms >6 months; (ii) magnetic resonance imaging showing a tendon tear; (iii) positive ultrasound-guided infiltration test; and (iv) the absence of an evolved fatty degeneration or atrophy of the gluteus medius and minimus muscle. Endoscopic repair of partial or full-thickness tears, with systematic resection of the bony structures implicated in the impingement, and a complete bursectomy appear to give satisfactory results, although these results remain to be confirmed by clinical studies with longer follow-up. The degree of tendon degeneration may compromise the tissue left for reattachment, raising concerns over its healing capacity, durability, and ultimate strength of the repair. PMID- 26752774 TI - Endoscopic-assisted Release of Lower Leg Chronic Exertional Compartment Syndromes: Results of a Systematic Literature Review. AB - Endoscopic treatment of recalcitrant chronic exertional compartment syndromes (CECS) of the lower leg is rarely reported. Until now, endoscopic release of CECS of the lower leg is described in only 3 papers addressing 48 interventions in 30 patients. A systematic literature analysis was performed comparing endoscopic and minimally invasive lower leg CECS releases. No statistically relevant difference was found between the results of endoscopic (unweighted mean success rate=86.3%) and minimally invasive (unweighted mean success rate=80.0%) CECS release. However, the methodological quality of the analyzed studies is not sufficient and the number of endoscopically treated patients are too low to draw final conclusions. PMID- 26752775 TI - Endoscopy of the Posterior Aspect of the Ankle: Double Posteromedial Portals. AB - Posterior and anterior arthroscopy of the ankle and hindfoot may have to be undertaken at the same surgical sitting. Standard arthroscopic practice does not allow to approach both compartments without changing the position of the patient. In the supine position, most intra-articular structures of posterior portion of the ankle joint can be accessed from anterior portals with judicious traction, but visualization of posterior extra-articular compartment and hindfoot are not possible. To avoid repositioning of the patient, we have developed a procedure that allows access to the posterior compartment of the ankle with the patient supine. We describe a 2 posteromedial ankle portals procedure, which allows to reach both the posterior side of the ankle joint and the hindfoot extra-articular compartments keeping the patient supine throughout the procedure. After treatment of anterior compartment disorders using standard anterior portals, 2 posteromedial entry portals permit to visualize and treat pathologies of the posterior ankle and of the hindfoot, without prolonging surgery. PMID- 26752776 TI - Extra-Articular Endoscopy. AB - With the advent of endoscopy in the last 2 decades, a number of procedures, and modifications to them, have been developed and have advanced exponentially. The list of indications was extended over time because of several reasons: better understanding of the pathophysiology, better diagnostics, and advances in endoscopic technology. In this review article, we summarize the most frequently performed extra-articular endoscopic procedures on the extremities. As there are several methods, some have been described briefly, whereas others have been described in greater detail, such as suprascapular nerve entrapment syndrome and Achilles tendon disorders, as they present our area of interest and subspecialty domain. Recent advances in the treatment of versatile pathologic entities have been described, together with new methods, which currently lack sufficient clinical data but still represent promising techniques for the future. PMID- 26752777 TI - Endoscopic-assisted Repair of Neglected Rupture or Rerupture After Primary Repair of Extensor Hallucis Longus Tendon. AB - Rerupture of the extensor hallucis longus tendon after primary repair and neglected rupture of the tendon poses surgical challenges to orthopedic surgeons. Open exploration and repair of the tendon ends usually requires large incision and extensive dissection. This may induce scarring and adhesion around the repaired tendon. Endoscopic-assisted repair has the advantage of minimally invasive surgery including less soft tissue trauma and scar formation and better cosmetic result. The use of Krackow locking suture and preservation of the extensor retinacula allow early mobilization of the great toe. PMID- 26752778 TI - Endoscopic Flexor Hallucis Longus Tendon Transfer for Chronic Achilles Tendon Rupture. AB - Chronic Achilles tendon rupture posed significant disability to the patients. Flexor hallucis longus (FHL) transfer can be used to restore the plantarflexion power of the ankle. Traditionally, a long medial incision with extensive soft tissue dissection is needed for FHL transfer. With the advance in flexor hallucis tendoscopy, endoscopic FHL tendon transfer can be performed without extensive soft tissue dissection. PMID- 26752779 TI - Piriformis Syndrome and Endoscopic Sciatic Neurolysis. AB - Piriformis syndrome is the compression or the irritation of the sciatic nerve by the adjacent piriformis muscle in the buttock leading to symptoms that include buttock pain, leg pain, and altered neurology in the sciatic nerve distribution. Epidemiological figures of the prevalence are unknown, but are estimated to be about 12.2% to 27%. There is no consensus on the diagnostic criteria. Advancement in magnetic resonance imaging allows us to observe unilateral hyperintensity and bowing of the sciatic nerve. The pathophysiology of the disease includes single blunt trauma, overuse causing piriformis hypertrophy, and long-term microtrauma causing scarring. Treatments include physiotherapy, steroid injections, and surgery. Minimally invasive techniques are emerging with the hope that with less postoperative scar tissue formation, there will be less recurrence of the disease. In this chapter, senior author describes his technique for endoscopic sciatic neurolysis. PMID- 26752780 TI - Endoscopic-assisted Correction of Hallux Valgus Deformity. AB - Endoscopic distal soft-tissue procedure is one of the minimally invasive techniques for correction of the hallux valgus deformity. It employs the same principle as the open procedure. The intermetatarsal angle is corrected by screw and interosseous suture instead of first metatarsal osteotomy. The associated procedures of first metatarsal derotation, medial collateral ligament reconstruction, and arthroscopic Lapidus arthrodesis can tackle various problems faced during the endoscopic distal soft-tissue procedure. PMID- 26752782 TI - The surface electromyographic evaluation of the Functional Reach in elderly subjects. AB - This study proposes a comprehensive assessment of myoelectric activity of the main muscles involved in the Functional Reach (FR) test, in 24 elderly subjects. A specific protocol for the surface electromyography (sEMG) signal acquisition during FR-test was developed. Results show that anterior muscles activate following a caudo-cranial order. Tibialis Anterior (TA) is the first to be activated (-18.0+/-16.3% of the FR-period), together with Rectus Femoris (-10.4+/ 17.9%). Then, Rectus Abdominis (19.7+/-24.7%) and Sternocleidomastoideus (19.9+/ 15.6%) activate after the FR-start. Hamstrings, Soleus, and L4-level Erectores Spinae (posterior muscles) activate after the FR-start in this order (11.4+/ 16.8%, 17.7+/-16.6%, and 35.2+/-29.0%, respectively) and remain active until the movement end. The analysis of the kinematic strategies adopted by subjects revealed an association between TA-activation patterns and two kinematic strategies (hip/mixed strategy), quantified by an increase (p<0.05) of TA activity duration in subjects adopting the hip strategy (89.9+/-34.5) vs. subjects adopting the mixed strategy (27.0+/-16.8). This suggests that TA sEMG activity could be able to discriminate among kinematic strategies, providing different information on balance control. Thus, the present analysis represents the first attempt to quantify the sEMG activity during FR-test in elderly subjects, providing an early contribution in building a reference frame for balance assessment in clinical context. PMID- 26752783 TI - Congenital Cytomegalovirus. AB - BACKGROUND: Congenital cytomegalovirus (CMV) is the leading viral intrauterine infection in the United States. It causes more developmental delays and long-term sequelae than Down syndrome (trisomy 21), neural tube defects, or fetal alcohol syndrome combined. Yet, this virus, a member of the herpes virus family, is not well known to the public and its prevention is typically not discussed in obstetric offices. Although many infants with congenital CMV are asymptomatic at birth, a significant proportion still may develop sequelae. Symptomatic infants face potentially devastating consequences. Pharmacologic treatment is reserved for those with severe organ or central nervous system involvement. Treatment of infants with congenital CMV can be complex and requires extensive outpatient follow-up. PURPOSE: To educate nurses and nurse practitioners regarding the risks, signs, treatment, and care related to congenital CMV. METHODS/SEARCH STRATEGIES: PubMed was searched to obtain English language publications from 2005 to 2015 for studies examining the current knowledge base of congenital cytomegalovirus, sequelae, and subsequent treatment using key terms "cytomegalovirus" combined with "congenital." A total of 18 articles were retained for analysis. FINDINGS/RESULTS: Overall, the greatest risk reduction strategy for CMV transmission is education of pregnant women. In the neonate at risk for congenital CMV, early identification, antiviral treatment, and care coordination are pivotal to maximizing outcomes. IMPLICATIONS FOR PRACTICE: Increasing understanding of congenital CMV, modes of transmission, signs of infection, and intervention strategies as well as its impact on development are essential to maximizing outcomes. IMPLICATIONS FOR RESEARCH: The need for research exists in the area of valganciclovir's impact on sensorineural hearing loss as well as potential vaccines to protect against CMV transmission. Research is also being conducted in the area of passive immunity via administration of CMV specific hyperimmune globulin therapy to pregnant women diagnosed with a primary CMV infection. PMID- 26752781 TI - Protection against ventricular fibrillation via cholinergic receptor stimulation and the generation of nitric oxide. AB - KEY POINTS: Animal studies suggest an anti-fibrillatory action of the vagus nerve on the ventricle, although the exact mechanism is controversial. Using a Langendorff perfused rat heart, we show that the acetylcholine analogue carbamylcholine raises ventricular fibrillation threshold (VFT) and flattens the electrical restitution curve. The anti-fibrillatory action of carbamylcholine was prevented by the nicotinic receptor antagonist mecamylamine, inhibitors of neuronal nitric oxide synthase (nNOS) and soluble guanylyl cyclase (sGC), and can be mimicked by the nitric oxide (NO) donor sodium nitroprusside. Carbamylcholine increased NO metabolite content in the coronary effluent and this was prevented by mecamylamine. The anti-fibrillatory action of both carbamylcholine and sodium nitroprusside was ultimately dependent on muscarinic receptor stimulation as all effects were blocked by atropine. These data demonstrate a protective effect of carbamylcholine on VFT that depends upon both muscarinic and nicotinic receptor stimulation, where the generation of NO is likely to be via a neuronal nNOS-sGC dependent pathway. ABSTRACT: Implantable cardiac vagal nerve stimulators are a promising treatment for ventricular arrhythmia in patients with heart failure. Animal studies suggest the anti-fibrillatory effect may be nitric oxide (NO) dependent, although the exact site of action is controversial. We investigated whether a stable analogue of acetylcholine could raise ventricular fibrillation threshold (VFT), and whether this was dependent on NO generation and/or muscarinic/nicotinic receptor stimulation. VFT was determined in Langendorff perfused rat hearts by burst pacing until sustained VF was induced. Carbamylcholine (CCh, 200 nmol l(-1) , n = 9) significantly (P < 0.05) reduced heart rate from 292 +/- 8 to 224 +/- 6 b.p.m. Independent of this heart rate change, CCh caused a significant increase in VFT (control 1.5 +/- 0.3 mA, CCh 2.4 +/- 0.4 mA, wash 1.1 +/- 0.2 mA) and flattened the restitution curve (n = 6) derived from optically mapped action potentials. The effect of CCh on VFT was abolished by a muscarinic (atropine, 0.1 MUmol l(-1) , n = 6) or a nicotinic receptor antagonist (mecamylamine, 10 MUmol l(-1) , n = 6). CCh significantly increased NOx content in coronary effluent (n = 8), but not in the presence of mecamylamine (n = 8). The neuronal nitric oxide synthase inhibitor AAAN (N-(4S)-4 amino-5-[aminoethyl]aminopentyl-N'-nitroguanidine; 10 MUmol l(-1) , n = 6) or soluble guanylate cyclase (sGC) inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3 a]quinoxalin-1-one; 10 MUmol l(-1) , n = 6) prevented the rise in VFT with CCh. The NO donor sodium nitrprusside (10 MUmol l(-1) , n = 8) mimicked the action of CCh on VFT, an effect that was also blocked by atropine (n = 10). These data demonstrate a protective effect of CCh on VFT that depends upon both muscarinic and nicotinic receptor stimulation, where the generation of NO is likely to be via a neuronal nNOS/sGC-dependent pathway. PMID- 26752785 TI - Electrophysiological evidence for the existence of a rare population of C-fiber low threshold mechanoreceptive (C-LTM) neurons in glabrous skin of the rat hindpaw. AB - The mammalian skin in innervated by distinct classes of low-threshold mechanoreceptive (LTM) primary afferent neurons that are classified as Abeta-, Adelta- or C-LTMs according to their axonal conduction velocities (CVs). C-LTMs are thought to signal pleasant and erotic touch sensations in humans, and to exist only in the hairy skin of primates and other species. Using intracellular recordings from rat L4/L5 dorsal root ganglion (DRG) neurons that were classified in vivo as C-nociceptors or C-LTMs, according to their dorsal root CVs and their responses to mechanical and thermal stimuli, the present study provides the first electrophysiological evidence that C-LTMs exist in the glabrous skin of the rat's hindpaw. Indeed 6.4% (5/78) of the total sample of lumbar C-fiber DRG neurons with receptive fields in the glabrous skin of the rat hindpaw were C-LTMs. The electrophysiological properties of this rare subpopulation of C-fiber neurons (mean CV=0.48+/-0.06m/s) are distinct from those of C-fiber high threshold mechanoreceptors (HTMs). Indeed, their mean mechanical (1.7+/-1.1mN) and electrical (4.0+/-0.4V) thresholds was significantly different from that of C HTMs. They also exhibited faster action potential and afterhyperpolarization kinetics than C-HTMs. The present study lends support to previous studies that have provided indirect evidence for the presence of C-LTMs in glabrous skin. If C LTMs are present in human glabrous skin, they may, in this type of skin, represent a novel peripheral neuronal substrate for the pleasant/social touch sensation, and account for or contribute to touch hypersensitivity after injury. PMID- 26752784 TI - Perspectives of Decisional Surrogates and Patients Regarding Critical Illness Genetic Research. AB - BACKGROUND: Critical illness research is challenging due to disease severity and because patients are frequently incapacitated. Surrogates called upon to provide consent might not accurately represent patient preferences. Though commonplace, genetic data collection adds complexity in this context. We undertook this investigation to understand whether surrogate decision makers would be receptive to permitting participation in a critical illness genetics study and whether their decision making was consistent with that of the patient represented. METHODS: We invited individuals identified as surrogates for critically ill adults, if required, as well as patients once recovered to participate in a survey designed to understand attitudes about genetic research. Associations between dependent (receptivity to participation, concordance of responses) and independent variables were tested using bivariate and multivariate logistic regression analyses. RESULTS: Most of the entire surrogate sample (n=439) reported familiarity with research, including genetic research; tended to view research as useful; and were receptive to allowing their family member participate (with 39.6% and 38.1% stating that this would be "very" and "somewhat likely," respectively) even absent direct benefit. Willingness to participate was similar comparing genetic and non-genetic studies (chi2 [1,n=439]=0.00127, p=0.972), though respondents expressed worry regarding lack of confidentiality of genetic data. Responses were concordant in 70.8% of the 192 surrogate-patient pairs analyzed. In multivariate analysis, African American race was associated with less receptivity to genetic data collection (p<0.05). No factors associated with concordance of surrogate-patient response were identified. CONCLUSIONS: Surrogates' receptivity to critical illness research was not influenced by whether the study entailed collection of genetic data. While more than two-thirds of surrogate-patient responses for participation in genetics research were concordant, concerns expressed regarding genetic data often related to breach of confidentiality. Emphasizing safeguards in place to minimize such breeches might prove an effective strategy for enhancing recruitment. PMID- 26752786 TI - Tunable atomic spin-orbit coupling synthesized with a modulating gradient magnetic field. AB - We report the observation of synthesized spin-orbit coupling (SOC) for ultracold spin-1 (87)Rb atoms. Different from earlier experiments where a one dimensional (1D) atomic SOC of pseudo-spin-1/2 is synthesized with Raman laser fields, the scheme we demonstrate employs a gradient magnetic field (GMF) and ground-state atoms, thus is immune to atomic spontaneous emission. The strength of SOC we realize can be tuned by changing the modulation amplitude of the GMF, and the effect of the SOC is confirmed through the studies of: 1) the collective dipole oscillation of an atomic condensate in a harmonic trap after the synthesized SOC is abruptly turned on; and 2) the minimum energy state at a finite adiabatically adjusted momentum when SOC strength is slowly ramped up. The condensate coherence is found to remain very good after driven by modulating GMFs. Our scheme presents an alternative means for studying interacting many-body systems with synthesized SOC. PMID- 26752787 TI - 25-Hydroxyvitamin D in Patients With Cognitive Decline. PMID- 26752788 TI - Anterior temporal lobe involvement: Useful magnetic resonance imaging sign to diagnose Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. PMID- 26752789 TI - Salinity gradient power: influences of temperature and nanopore size. AB - Salinity gradient power is a promising, challenging, and readily available renewable energy. Among various methods for harvesting this clean energy, nanofluidic reverse electrodialysis (NRED) is of great potential. Since ionic transport depends highly on the temperature, so is the efficiency of the associated power generated. Here, we conduct a theoretical analysis on the influences of temperature and nanopore size on NRED, focusing on the temperature and nanopore size. The results gathered reveal that the maximum power increases with increasing temperature, but the conversion efficiency depends weakly on temperature. In general, the smaller the nanopore radius or the longer the nanopore, the better the ion selectivity. These results provide desirable and necessary information for improving the performance of NRED as well as designing relevant units in renewable energy plants. PMID- 26752790 TI - Exaggerated sexual swellings and male mate choice in primates: testing the reliable indicator hypothesis in the Amboseli baboons. AB - The paradigm of competitive males vying to influence female mate choice has been repeatedly upheld, but, increasingly, studies also report competitive females and choosy males. One female trait that is commonly proposed to influence male mate choice is the exaggerated sexual swelling displayed by females of many Old World primate species. The reliable indicator hypothesis posits that females use the exaggerated swellings to compete for access to mates, and that the swellings advertise variation in female fitness. We tested the two main predictions of this hypothesis in a wild population of baboons (Papio cynocephalus). First, we examined the effect of swelling size on the probability of mate-guarding ('consortship') by the highest-ranking male and the behavior of those males that trailed consorshipts ('follower males'). Second, we asked whether a female's swelling size predicted several fitness measures. We found that high-ranking males do not prefer females with larger swellings (when controlling for cycle number and conception) and that females with larger swellings did not have higher reproductive success. Our study-the only complete test of the reliable indicator hypothesis in a primate population-rejects the idea that female baboons compete for mates by advertising heritable fitness differences. Furthermore, we found unambiguous evidence that males biased their mating decisions in favor of females who had experienced more sexual cycles since their most recent pregnancy. Thus, rather than tracking the potential differences in fitness between females, male baboons appear to track and target the potential for a given reproductive opportunity to result in fertilization. PMID- 26752792 TI - Unpacking the psychological weight of weight stigma: A rejection-expectation pathway. AB - The present research tested the hypothesis that the negative effects of weight stigma among higher body-weight individuals are mediated by expectations of social rejection. Women and men who varied in objective body-weight (body mass index; BMI) gave a speech describing why they would make a good date. Half believed that a potential dating partner would see a videotape of their speech (weight seen) and half believed that a potential dating partner would listen to an audiotape of their speech (weight unseen). Among women, but not men, higher body-weight predicted increased expectations of social rejection, decreased executive control resources, decreased self-esteem, increased self-conscious emotions and behavioral displays of self-consciousness when weight was seen but not when weight was unseen. As predicted, higher body-weight women reported increased expectations of social rejection when weight was seen (versus unseen), which in turn predicted decreased self-esteem, increased self-conscious emotions, and increased stress. In contrast, lower body-weight women reported decreased expectations of social rejection when weight was seen (versus unseen), which in turn predicted increased self-esteem, decreased self-conscious emotions, and decreased stress. Men's responses were largely unaffected by body-weight or visibility, suggesting that a dating context may not be identity threatening for higher body-weight men. Overall, the present research illuminates a rejection expectation pathway by which weight stigma undermines higher body-weight women's health. PMID- 26752791 TI - Behavioural differences: a link between biodiversity and pathogen transmission. AB - Biodiversity often serves to reduce zoonotic pathogens, such that prevalence is lower in communities of greater diversity. This phenomenon is termed the dilution effect, and although it has been reported for several pathogens (e.g. Sin Nombre virus, SNV), the mechanism is largely unknown. We investigated a putative mechanism, by testing the hypothesis that higher biodiversity alters behaviours important in pathogen transmission. Using deer mice (Peromyscus maniculatus) and SNV as our host-pathogen system, and a novel surveillance system, we compared host behaviours between high- and low-diversity communities. Behaviours were observed on foraging trays equipped with infrared cameras and passive integrated transponder (PIT) tag readers. Deer mice inhabiting the more diverse site spent less time in behaviours related to SNV transmission compared to deer mice from the less diverse site. The differences were attributed to the composition of behavioural phenotypes ('bold' versus 'shy') on the sites. Bold deer mice were 4.6 times more numerous on the less diverse site and three times more likely to be infected with SNV than shy deer mice. Our findings suggest that biodiversity affects pathogen transmission by altering the presence of different behavioural phenotypes. These findings have implications for human health and conservation. PMID- 26752793 TI - BH-CIFOL: Case-Intensional First Order Logic: (II) Branching Histories. AB - This paper follows Part I of our essay on case-intensional first-order logic (CIFOL; Belnap and Muller (2013)). We introduce a framework of branching histories to take account of indeterminism. Our system BH-CIFOL adds structure to the cases, which in Part I formed just a set: a case in BH-CIFOL is a moment/history pair, specifying both an element of a partial ordering of moments and one of the total courses of events (extending all the way into the future) that that moment is part of. This framework allows us to define the familiar Ockhamist temporal/modal connectives, most notably for past, future, and settledness. The novelty of our framework becomes visible in our discussion of substances in branching histories, i.e., in its first-order part. That discussion shows how the basic idea of tracing an individual thing from case to case via an absolute property is applicable in a branching histories framework. We stress the importance of keeping apart extensionality and moment-definiteness, and give a formal account of how the specification of natural sortals and natural qualities turns out to be a coordination task in BH-CIFOL. We also provide a detailed answer to Lewis's well-known argument against branching histories, exposing the fallacy in that argument. PMID- 26752794 TI - An Asymmetric Organocatalytic Quadruple Domino Reaction Employing a Vinylogous Friedel-Crafts/Michael/Michael/Aldol Condensation Sequence. AB - An organocatalytic quadruple cascade initiated by a Friedel-Crafts-type reaction is described. The (S)-diphenylprolinol trimethylsilyl ether catalyzed reaction yields highly functionalized cyclohexenecarbaldehydes bearing a 1,1-bis[4 (dialkylamino)phenyl]ethene moiety and three contiguous stereogenic centers. The reaction tolerates various functional groups and all products are obtained with very good diastereoselectivity and with virtually complete enantiomeric excess. PMID- 26752796 TI - Approximation of the ruin probability using the scaled Laplace transform inversion. AB - The problem of recovering the ruin probability in the classical risk model based on the scaled Laplace transform inversion is studied. It is shown how to overcome the problem of evaluating the ruin probability at large values of an initial surplus process. Comparisons of proposed approximations with the ones based on the Laplace transform inversions using a fixed Talbot algorithm as well as on the ones using the Trefethen-Weideman-Schmelzer and maximum entropy methods are presented via a simulation study. PMID- 26752795 TI - Asymmetric N-Heterocyclic Carbene Catalyzed Annulation of 2-Alkenylbenzothiazoles with alpha-Chloro Aldehydes. AB - Diastereo- and enantioselective N-heterocyclic carbene catalyzed 1-azadiene Diels Alder reactions of (E)-2-styrylbenzothiazoles with alpha-chloro aldehydes are reported. This annulation strategy provides an efficient access to medicinally important dihydrobenzothiazolopyridin-1-ones in good to excellent yields (44-97%) with very good to excellent stereoselectivities (up to 9:1 dr, 98% ee) and tolerates quite a range of substituents. PMID- 26752797 TI - The Moderating Role of Parental Warmth on the Relation Between Verbal Punishment and Child Problem Behaviors for Same-sex and Cross-sex Parent-Child Groups. AB - This study investigates the relation between parental verbal punishment and externalizing and internalizing behavior problems in Filipino children, and the moderating role of parental warmth in this relation, for same-sex (mothers-girls; fathers-boys) and cross-sex parent-child groups (mothers-boys; fathers-girls). Measures used were the Rohner Parental Acceptance-Rejection and Control Scale (PARQ/Control), the Achenbach Child Behavior Checklist (CBC), and a discipline measure (DI) constructed for the study. Participants were 117 mothers and 98 fathers of 61 boys and 59 girls who responded to a discipline interview, the Parental Acceptance-Rejection and Control scale (PARQ/Control) and the Achenbach Child Behavior Checklist via oral interviews. Hierarchical multiple regression analyses (with Bonferroni-corrected alpha levels) revealed that maternal frequency of verbal punishment was positively related to internalizing and externalizing outcomes in boys and girls whereas paternal frequency of verbal punishment was positively related to girls' externalizing behavior. Significant interactions between verbal punishment and maternal warmth in mother-girl groups were also found for both internalizing and externalizing behaviors. While higher maternal warmth ameliorated the impact of low verbal punishment on girls' internalizing and externalizing behaviors, it exacerbated the effect of high verbal punishment on negative outcomes. PMID- 26752798 TI - Rhodamine analogues for molecular ruler applications. AB - A series of geometrically well-defined cationic fluorophores were designed based on molecular mechanics. They contain biaryl linkers to impart rigidity preventing intramolecular folding between a conjugated biomolecule and fluorophore. All probes have absorption and emission maxima within 20 nm from Texas Red, as predicted by TDDFT calculations and validated experimentally. PMID- 26752799 TI - Marital Status, Hypertension, Coronary Heart Disease, Diabetes, and Death Among African American Women and Men: Incidence and Prevalence in the Atherosclerosis Risk in Communities (ARIC) Study Participants. PMID- 26752800 TI - An Efficient Pattern Mining Approach for Event Detection in Multivariate Temporal Data. AB - This work proposes a pattern mining approach to learn event detection models from complex multivariate temporal data, such as electronic health records. We present Recent Temporal Pattern mining, a novel approach for efficiently finding predictive patterns for event detection problems. This approach first converts the time series data into time-interval sequences of temporal abstractions. It then constructs more complex time-interval patterns backward in time using temporal operators. We also present the Minimal Predictive Recent Temporal Patterns framework for selecting a small set of predictive and non-spurious patterns. We apply our methods for predicting adverse medical events in real world clinical data. The results demonstrate the benefits of our methods in learning accurate event detection models, which is a key step for developing intelligent patient monitoring and decision support systems. PMID- 26752801 TI - Diagnosing limb paresis and paralysis in sheep. AB - Paresis and paralysis are uncommon problems in sheep but are likely to prompt farmers to seek veterinary advice. A thorough and logical approach can aid in determining the cause of the problem and highlighting the benefit of veterinary involvement. While this may not necessarily alter the prognosis for an individual animal, it can help in formulating preventive measures and avoid the costs - both in economic and in welfare terms - of misdirected treatment. Distinguishing between central and peripheral lesions is most important, as the relative prognoses are markedly different, and this can often be achieved with minimal equipment. This article describes an approach to performing a neurological examination of the ovine trunk and limbs, the ancillary tests available and the common and important causes of paresis and paralysis in sheep. PMID- 26752802 TI - Digression and Value Concatenation to Enable Privacy-Preserving Regression. AB - Regression techniques can be used not only for legitimate data analysis, but also to infer private information about individuals. In this paper, we demonstrate that regression trees, a popular data-analysis and data-mining technique, can be used to effectively reveal individuals' sensitive data. This problem, which we call a "regression attack," has not been addressed in the data privacy literature, and existing privacy-preserving techniques are not appropriate in coping with this problem. We propose a new approach to counter regression attacks. To protect against privacy disclosure, our approach introduces a novel measure, called digression, which assesses the sensitive value disclosure risk in the process of building a regression tree model. Specifically, we develop an algorithm that uses the measure for pruning the tree to limit disclosure of sensitive data. We also propose a dynamic value-concatenation method for anonymizing data, which better preserves data utility than a user-defined generalization scheme commonly used in existing approaches. Our approach can be used for anonymizing both numeric and categorical data. An experimental study is conducted using real-world financial, economic and healthcare data. The results of the experiments demonstrate that the proposed approach is very effective in protecting data privacy while preserving data quality for research and analysis. PMID- 26752803 TI - Addiction Science: A Rationale and Tools for a Public Health Response to Drug Abuse. AB - New scientific knowledge and effective, evidence-based interventions have provided health leaders and policymakers a remarkable paradigm to guide the development of addiction treatment services around the world. The definition of addiction as a brain disease, validated screening and assessment tools, medication-assisted treatment, and effective behavioral treatments have served as vehicles for both the United States and other countries to guide the transformation of their substance abuse treatment systems. Seeking to expand international research and infrastructure, the National Institute on Drug Abuse (NIDA)'s International Program has engaged international investigators and institutions in addiction research to promote dissemination of addiction science globally. This paper presents three mixed-methods case studies to exemplify the use of advancements in evidence-based practice in addiction treatment as guides and tools for the creation or further development of treatment systems in three countries, Vietnam, Lebanon, and Abu Dhabi. Results indicate that a framework of evidence-based medicine and empirical science creates a necessary platform from which objective conversations about addictions may begin. Other facilitative factors that help create treatment programs internationally include: a receptive and supportive government, support from international donors and technical experts, networking and interest from other international organizations, and often a synergistic and concerted effort by multiple entities and partners. Despite substantial differences in the circumstances that generated these initiatives and the varying scope of the services, common themes across these efforts have been the implementation of science-based approaches to systems transformation and support for a public health approach to addressing drug abuse and addiction. PMID- 26752804 TI - Orbital tomography: Molecular band maps, momentum maps and the imaging of real space orbitals of adsorbed molecules. AB - The frontier orbitals of molecules are the prime determinants of their chemical, optical and electronic properties. Arguably, the most direct method of addressing the (filled) frontier orbitals is ultra-violet photoemission spectroscopy (UPS). Although UPS is a mature technique from the early 1970s on, the angular distribution of the photoemitted electrons was thought to be too complex to be analysed quantitatively. Recently angle resolved UPS (ARUPS) work on conjugated molecules both, in ordered thick films and chemisorbed monolayers, has shown that the angular (momentum) distribution of the photocurrent from orbital emissions can be simply understood. The approach, based on the assumption of a plane wave final state is becoming known as orbital tomography. Here we will demonstrate, with selected examples of pentacene (5A) and sexiphenyl (6P), the potential of orbital tomography. First it will be shown how the full angular distribution of the photocurrent (momentum map) from a specific orbital is related to the real space orbital by a Fourier transform. Examples of the reconstruction of 5A orbitals will be given and the procedure for recovering the lost phase information will be outlined. We then move to examples of sexiphenyl where we interrogate the original band maps of thick sexiphenyl in the light of our understanding of orbital tomography that has developed since then. With comparison to theoretical simulations of the molecular band maps, the molecular conformation and orientation will be concluded. New results for the sexiphenyl monolayer on Al(1 1 0) will then be presented. From the band maps it will be concluded that the molecule is planarised and adopts a tilted geometry. Finally the momentum maps down to HOMO-11 will be analysed and real space orbitals reconstructed. PMID- 26752805 TI - [THE EMPIRICAL DISTINCTIVENESS OF WORK ENGAGEMENT AND WORKAHOLISM AMONG HOSPITAL NURSES IN JAPAN : THE EFFECT ON SLEEP QUALITY AND JOB PERFORMANCE]. AB - OBJECTIVE: The aim of the present study is to demonstrate the distinctiveness of work engagement and workaholism by examining their relationships with sleep quality and job performance. METHOD: A total of 447 nurses from 3 hospitals in Japan were surveyed using a self-administrated questionnaire including Utrecht Work Engagement Scale (UWES), the Dutch Workaholism Scale (DUWAS), questions on sleep quality (7 items) regarding (1) difficulty initiating sleep, (2) difficulty maintaining sleep, (3) early morning awakening, (4) dozing off or napping in daytime, (5) excessive daytime sleepiness at work, (6) difficulty awakening in the morning, and (7) tiredness awakening in the morning, and the World Health Organization Health Work Performance Questionnaire. RESULTS: The Structural Equation Modeling showed that, work engagement was positively related to sleep quality and job performance whereas workaholism negatively to sleep quality and job performance. CONCLUSION: The findings suggest that work engagement and workaholism are conceptually distinctive and that the former is positively and the latter is negatively related to well-being (i.e., good sleep quality and job performance). PMID- 26752806 TI - Comparison of Objective Screening and Self-Report for Alcohol and Drug Use in Traumatically Injured Patients. AB - Alcohol and drug use is prevalent in trauma patients. Concerns over the validity of self-reporting drug use could make non laboratory screening problematic. This study sought to validate patient self-report of substance use against objective screening to determine the reliability of self-report in trauma patients. Patients admitted to either the Trauma or Burn services who were at least 18 years old were screened for alcohol and drug use with validated screening tools. Exclusion criteria were altered mental status, non English speaking, inability to answer questions for other reasons, under police custody, or admission for < 24 hours. Results from admission Blood Alcohol Concentration BAC and Urine Drug Screen UDS were also collected and compared to self-reported use to determine its reliability. Alcohol use was queried in 128 patients, 101 of whom had a BAC drawn. Of those 101, 34 (33.7%) had a BAC > 0 mg%. Alcohol Use Disorder Identification Test AUDIT screening revealed 13 (12.9%) patients who were self reported non drinkers, none of which had a BAC > 0 mg%. Drug use was queried in 133 patients, 93 of whom had a UDS. A positive was found in 26 (28.0%) of the patients, only 12 (46.2%) of whom reported drug use in the past year. Though substance use in trauma patients is prevalent, self-report screening techniques for drugs may be inadequate at determining those patients whom could benefit from brief interventions while in the hospital. Further investigation is needed to determine the discrepancy between alcohol and drug use screening in trauma patients and more acceptable means of drug use discussion. PMID- 26752807 TI - Transcriptome Profiling of Wild Arachis from Water-Limited Environments Uncovers Drought Tolerance Candidate Genes. AB - Peanut (Arachis hypogaea L.) is an important legume cultivated mostly in drought prone areas where its productivity can be limited by water scarcity. The development of more drought-tolerant varieties is, therefore, a priority for peanut breeding programs worldwide. In contrast to cultivated peanut, wild relatives have a broader genetic diversity and constitute a rich source of resistance/tolerance alleles to biotic and abiotic stresses. The present study takes advantage of this diversity to identify drought-responsive genes by analyzing the expression profile of two wild species, Arachis duranensis and Arachis magna (AA and BB genomes, respectively), in response to progressive water deficit in soil. Data analysis from leaves and roots of A. duranensis (454 sequencing) and A. magna (suppression subtractive hybridization (SSH)) stressed and control complementary DNA (cDNA) libraries revealed several differentially expressed genes in silico, and 44 of them were selected for further validation by quantitative RT-PCR (qRT-PCR). This allowed the identification of drought responsive candidate genes, such as Expansin, Nitrilase, NAC, and bZIP transcription factors, displaying significant levels of differential expression during stress imposition in both species. This is the first report on identification of differentially expressed genes under drought stress and recovery in wild Arachis species. The generated transcriptome data, besides being a valuable resource for gene discovery, will allow the characterization of new alleles and development of molecular markers associated with drought responses in peanut. These together constitute important tools for the peanut breeding program and also contribute to a better comprehension of gene modulation in response to water deficit and rehydration. PMID- 26752808 TI - Cucumber Possesses a Single Terminal Alternative Oxidase Gene That is Upregulated by Cold Stress and in the Mosaic (MSC) Mitochondrial Mutants. AB - Alternative oxidase (AOX) is a mitochondrial terminal oxidase which is responsible for an alternative route of electron transport in the respiratory chain. This nuclear-encoded enzyme is involved in a major path of survival under adverse conditions by transfer of electrons from ubiquinol instead of the main cytochrome pathway. AOX protects against unexpected inhibition of the cytochrome c oxidase pathway and plays an important role in stress tolerance. Two AOX subfamilies (AOX1 and AOX2) exist in higher plants and are usually encoded by small gene families. In this study, genome-wide searches and cloning were completed to identify and characterize AOX genes in cucumber (Cucumis sativus L.). Our results revealed that cucumber possesses no AOX1 gene(s) and only a single AOX2 gene located on chromosome 4. Expression studies showed that AOX2 in wild-type cucumber is constitutively expressed at low levels and is upregulated by cold stress. AOX2 transcripts and protein were detected in leaves and flowers of wild-type plants, with higher levels in the three independently derived mosaic (MSC) mitochondrial mutants. Because cucumber possesses a single AOX gene and its expression increases under cold stress and in the MSC mutants, this plant is a unique and intriguing model to study AOX expression and regulation particularly in the context of mitochondria-to-nucleus retrograde signaling. PMID- 26752809 TI - A Learning-Based CT Prostate Segmentation Method via Joint Transductive Feature Selection and Regression. AB - In1 recent years, there has been a great interest in prostate segmentation, which is a important and challenging task for CT image guided radiotherapy. In this paper, a learning-based segmentation method via joint transductive feature selection and transductive regression is presented, which incorporates the physician's simple manual specification (only taking a few seconds), to aid accurate segmentation, especially for the case with large irregular prostate motion. More specifically, for the current treatment image, experienced physician is first allowed to manually assign the labels for a small subset of prostate and non-prostate voxels, especially in the first and last slices of the prostate regions. Then, the proposed method follows the two step: in prostate-likelihood estimation step, two novel algorithms: tLasso and wLapRLS, will be sequentially employed for transductive feature selection and transductive regression, respectively, aiming to generate the prostate-likelihood map. In multi-atlases based label fusion step, the final segmentation result will be obtained according to the corresponding prostate-likelihood map and the previous images of the same patient. The proposed method has been substantially evaluated on a real prostate CT dataset including 24 patients with 330 CT images, and compared with several state-of-the-art methods. Experimental results show that the proposed method outperforms the state-of-the-arts in terms of higher Dice ratio, higher true positive fraction, and lower centroid distances. Also, the results demonstrate that simple manual specification can help improve the segmentation performance, which is clinically feasible in real practice. PMID- 26752810 TI - N-Heterocyclic Carbene Catalyzed Enantioselective Annulation of Benzothiazolyl Ethyl Acetates with 2-Bromoenals. AB - An N-heterocyclic carbene catalyzed enantioselective [3+3] annulation of benzothiazolyl acetates with 2-bromoenals has been developed. The protocol provides a direct asymmetric synthesis of dihydro-1H-benzothiazolopyridinones in good to very good yields and medium ee values. In many cases, the virtually enantiopure heterocycles are available through a single recrystallization (99% ee). PMID- 26752811 TI - Type of milk typically consumed, and stated preference, but not health consciousness affect revealed preferences for fat in milk. AB - Fat is an important source of both pleasure and calories in the diet. Dairy products are a major source of fat in the diet, and understanding preferences for fat in fluid milk can potentially inform efforts to change fat consumption patterns or optimize consumer products. Here, patterns of preference for fat in milk were determined in the laboratory among 100 free living adults using rejection thresholds. Participants also answered questions relating to their health concerns, the type of fluid milk typically consumed, and their declared preference for type of milk (in terms of fat level). When revealed preferences in blind tasting were stratified by these measures, we observed striking differences in the preferred level of fat in milk. These data indicate a non-trivial number of consumers who prefer low-fat milk to full fat milk, a pattern that would have been overshadowed by the use of a group mean. While it is widely assumed and claimed that increasing fat content in fluid milk universally increases palatability, present data demonstrate this is not true for a segment of the population. These results underscore the need to go look beyond group means to understand individual differences in food preference. PMID- 26752812 TI - The last time, adieu.... PMID- 26752813 TI - Emerging clinical applications of PET based molecular imaging in oncology: the promising future potential for evolving personalized cancer care. AB - This review focuses on the potential of advanced applications of functional molecular imaging in assessing tumor biology and cellular characteristics with emphasis on positron emission tomography (PET) applications with both 18 fluorodeoxyglucose (FDG) and non-FDG tracers. The inherent heterogeneity of cancer cells with their varied cellular biology and metabolic and receptor phenotypic expression in each individual patient and also intra-and inter lesionally in the same individual mandates for transitioning from a generalized "same-size-fits-all" approach to personalized medicine in oncology. The past two decades have witnessed improvement of oncological imaging through CT, MR imaging, PET, subsequent movement through hybrid or fusion imaging with PET/CT and single photon emission computerized tomography (SPECT-CT), and now toward the evolving PET/MR imaging. These recent developments have proven invaluable in enhancing oncology care and have the potential to help image the tumor biology at the cellular level, followed by providing a tailored treatment. Molecular imaging, integrated diagnostics or Radiomics, biology-driven interventional radiology and theranostics, all hold immense potential to serve as a guide to give "start and stop" treatment for a patient on an individual basis. This will likely have substantial impact on both treatment costs and outcomes. In this review, we bring forth the current trends in molecular imaging with established techniques (PET/CT), with particular emphasis on newer molecules (such as amino acid metabolism and hypoxia imaging, somatostatin receptor based imaging, and hormone receptor imaging) and further potential for FDG. An introductory discussion on the novel hybrid imaging techniques such as PET/MR is also made to understand the futuristic trends. PMID- 26752815 TI - Pediatric whole-body magnetic resonance imaging: Intra-individual comparison of technical quality, artifacts, and fixed structure visibility at 1.5 and 3 T. AB - PURPOSE: To compare whole-body magnetic resonance imaging (WBMRI) performed at 1.5 and 3 T for technical quality, artifacts, and visibility of selected fixed structures. PATIENTS AND METHODS: 21 children who had WBMRI at both 1.5 and 3 T scanners within a relatively short interval (3-13 months; average-8.6 months) were included. The images were objectively compared with scores from 4 to 1 for five parameters including severity of artifacts; visibility of liver, vertebral column, and marrow in legs; and overall image quality. Inter-observer agreement was calculated using Kendall's coefficient of Concordance (W) and scores were compared using Signed Rank test. RESULTS: There was substantial inter-observer agreement for all five categories at both field strengths. The difference between averages of mean scores of all five parameters for two field strengths was statistically significant (P < 0.05), indicating less artifact, better fixed structure visibility, and overall image quality at 1.5 T as compared to 3 T. However, scores at 3 T were also rated within a good range (around 3) indicating its feasibility for WBMRI in children. CONCLUSION: WBMRI at 1.5 T has significantly better image quality, fixed structure visibility, and fewer artifacts, as compared to WBMRI at 3 T in children. This difference is unlikely to significantly affect detection of pathology on 3 T WBMRI as the image quality score at 3 T was also within good range. PMID- 26752816 TI - Use of a vascular sheath for introduction of radiofrequency ablation probe during radiofrequency ablation of osteoid osteoma. AB - Radiofrequency ablation (RFA) has now become a preferred treatment option for osteoid osteoma. Accurate placement of RFA probe into the nidus of osteoid osteoma is important for good clinical outcome. Various methods and techniques have been described in the literature available. We describe the technique of using a vascular access sheath for introduction of RFA probe after bone drilling, which prevents loss of access to drill track and also serves as a pathway for accurate placement of RFA probe, thereby reducing the risk of damage to the RFA probe tip itself and the surrounding soft tissue. PMID- 26752814 TI - Integrated (18)F-fluorodeoxyglucose positron emission tomography magnetic resonance imaging ((18)F-FDG PET/MRI), a multimodality approach for comprehensive evaluation of dementia patients: A pictorial essay. AB - Dementia, caused by irreversible neurodegenerative disorders such as Alzheimer's disease or reversible non-degenerative conditions, is rapidly becoming one of the most alarming health problems in our aging society. This cognitive disorder associated with a multitude of clinical differentials with overlapping clinical, pathological, and imaging features is difficult to diagnose and treat, as it often presents late after significant neuronal damage has already occurred. Novel disease-modifying treatments being developed will have to be corroborated with innovative imaging biomarkers so that earlier reliable diagnosis can be made and treatment initiated upon. Along with new specific PET radiotracers, integrated PET/MRI with combined methodological advantage and simultaneously acquired structural-cum-functional information may help achieve this goal. The present pictorial essay details our experiences with PET/MRI in dementing disorders, along with reviewing recent advances and future scope. PMID- 26752817 TI - Endovascular treatment of central venous obstruction as a complication of prolonged hemodialysis - Preliminary experience in a tertiary care center. AB - BACKGROUND: Central venous disease is a serious complication in patients undergoing hemodialysis, often presenting with symptoms of venous hypertension. Treatment is aimed to provide symptomatic relief and to maintain hemodialysis access site patency. AIM: To describe our initial experience in the endovascular treatment of central venous stenosis or obstruction in patients undergoing hemodialysis. SETTINGS AND DESIGN: This was a retrospective study carried out in a tertiary care center. Study duration was 24 months. Follow-up was variable. MATERIALS AND METHODS: Eleven patients of chronic renal failure undergoing hemodialysis presented with central vein stenosis or obstruction having ipsilateral vascular access, between July 2012 and July 2014. All the patients underwent endovascular treatment and were analyzed retrospectively. RESULTS AND CONCLUSION: A total of 11 patients (4 male and 7 female) underwent 18 interventions for 13 stenotic segments during a time period of 2 years. Eight stenotic segments were in brachiocephalic vein, three in subclavian vein, and two in axillary veins. The technical success rate for endovascular treatment was 81.8%. Two patients underwent percutaneous transluminal angioplasty (PTA) alone and presented with restenosis later. Balloon angioplasty followed by stenting was done in seven patients, two of which required reintervention during follow-up. We found endovascular treatment safe and effective in treating central venous disease. PMID- 26752818 TI - Beyond warfarin: The advent of new oral anticoagulants. AB - New oral anticoagulants (NOAC) are the latest addition to anticoagulant armamentarium. Unlike traditional anti-coagulants like warfarin, lab monitoring and management of bleeding complications secondary to these agents is different. As more and more patients are being switched to these drugs, interventional radiologists in particular will benefit from a clinical review of NOAC. PMID- 26752819 TI - Clinical outcomes of endovascularly managed iatrogenic renal hemorrhages. AB - OBJECTIVE: To evaluate the effectiveness of endovascular management in iatrogenic renal injuries with regard to clinical status on follow-up and requirements for repeat angiography and embolization. MATERIALS AND METHODS: This retrospective study included patients who were referred for endovascular management of significant hemorrhage following an iatrogenic injury. Data was recorded from the Picture Archiving and Communication system (PACS) and electronic medical records. The site and type of iatrogenic injury, imaging findings, treatment, angiography findings, embolization performed, clinical status on follow-up, and requirement for repeat embolization were recorded. The outcomes were clinical resolution, nephrectomy, or death. Clinical findings were recorded on follow-up visits to the clinic. Statistical analysis was performed using descriptive statistics. RESULTS: Seventy patients were included in this study between January 2000 and June 2012. A bleeding lesion (a pseudoaneurysm or arteriovenous fistula) was detected during the first angiogram in 55 patients (78.6%) and was selectively embolized. Fifteen required a second angiography as there was no clinical improvement and five required a third angiography. Overall, 66 patients (94.3%) showed complete resolution and 4 patients (5.7%) died. Three patients (4.3%) underwent nephrectomy for clinical stabilization even after embolization. There were no major complications. The two minor complications resolved spontaneously. CONCLUSIONS: Angiography and embolization is the treatment of choice in iatrogenic renal hemorrhage. Upto 20% of initial angiograms may not reveal the bleed and repeat angiography is required to identify a recurrent or unidentified bleed. The presence of multiple punctate bleeders on angiography suggests an enlarging subcapsular hematoma and requires preoperative embolization and nephrectomy. PMID- 26752820 TI - Evaluation of breast parenchymal density with QUANTRA software. AB - PURPOSE: To evaluate breast parenchymal density using QUANTRA software and to correlate numerical breast density values obtained from QUANTRA with ACR BI-RADS breast density categories. MATERIALS AND METHODS: Two-view digital mammograms of 545 consecutive women (mean age - 47.7 years) were categorized visually by three independent radiologists into one of the four ACR BI-RADS categories (D1-D4). Numerical breast density values as obtained by QUANTRA software were then used to establish the cutoff values for each category using receiver operator characteristic (ROC) analysis. RESULTS: Numerical breast density values obtained by QUANTRA (range - 7-42%) were systematically lower than visual estimates. QUANTRA breast density value of less than 14.5% could accurately differentiate category D1 from the categories D2, D3, and D4 [area under curve (AUC) on ROC analysis - 94.09%, sensitivity - 85.71%, specificity - 84.21%]. QUANTRA density values of <19.5% accurately differentiated categories D1 and D2 from D3 and D4 (AUC - 94.4%, sensitivity - 87.50%, specificity - 84.60%); QUANTRA density values of <26.5% accurately differentiated categories D1, D2, and D3 from category D4 (AUC - 90.75%, sensitivity - 88.89%, specificity - 88.621%). CONCLUSIONS: Breast density values obtained by QUANTRA software can be used to obtain objective cutoff values for each ACR BI-RADS breast density category. Although the numerical density values obtained by QUANTRA are lower than visual estimates, they correlate well with the BI-RADS breast density categories assigned visually to the mammograms. PMID- 26752821 TI - Diagnostic value of diffusion tensor imaging derived metrics as biomarkers of cerebral changes in developmental delay. AB - CONTEXT: Children with developmental delay (DD) can be rehabilitated if an early diagnosis and intervention is done. A negative magnetic resonance imaging (MRI) study utilizing routine sequences makes it difficult for the clinician to convince the family toward a long-term rehabilitation schedule. Diffusion tensor imaging (DTI) can demonstrate deranged myelination in developmentally delayed children having normal routine MRI. AIM: To evaluate the role of DTI-derived metrics for assessment of deranged myelination in developmentally delayed children having normal routine MRI. STUDY SETTING AND DESIGN: Prospective case control observational study conducted over a cross-section of referrals at a university-based teaching institute over a period of 2 years. PATIENTS AND METHODS: Fifty cases of DD and 15 age-sex matched controls (age group of 2-12 years) were included from those presenting voluntarily to the pediatric out patient services. Routine MRI and DTI were performed in both the groups following a standard protocol. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were calculated in certain pre-defined regions. STATISTICAL ANALYSIS: Central tendency was measured for each of the metrics using mean. Inter and intra-group comparisons were performed using t-test. RESULTS: Twenty-three regions of interest with 46 variables were included in the final analysis. Nineteen (82.60%) regions of interest showed at least one statistically significant variable, while 24 out of 46 (54.34%) variables showed statistical significance for future consideration. The important regions to be evaluated in a case of DD are the corpus callosum, bilateral forceps minor and forceps major, bilateral parietal lobes, bilateral post-central gyrus, and bilateral posterior limb internal capsule (PLIC). The regions which did not show any significance are bilateral pars triangularis and right frontal lobe. Other regions remained indeterminate and need further evaluation. CONCLUSION: DTI demonstrates myelination abnormality in children with DD, having a normal routine MRI. PMID- 26752823 TI - Imaging and interventions in idiopathic intracranial hypertension: A pictorial essay. AB - Intracranial hypertension is a syndrome of elevated intracranial pressure that can be primary or secondary. The primary form, now termed idiopathic intracranial hypertension (IIH), was in the past a disease of exclusion and imaging played a limited role of excluding organic causes of raised intracranial pressure. However imaging markers have been described with patients with IIH at the orbit, sella and cerebral venous system. We wish to reiterate the characteristic imaging features of this poorly understood disease and also emphasise that stenting of the transverse sinus in select cases of IIH is an efficacious option. PMID- 26752822 TI - Magnetic resonance imaging of optic nerve. AB - Optic nerves are the second pair of cranial nerves and are unique as they represent an extension of the central nervous system. Apart from clinical and ophthalmoscopic evaluation, imaging, especially magnetic resonance imaging (MRI), plays an important role in the complete evaluation of optic nerve and the entire visual pathway. In this pictorial essay, the authors describe segmental anatomy of the optic nerve and review the imaging findings of various conditions affecting the optic nerves. MRI allows excellent depiction of the intricate anatomy of optic nerves due to its excellent soft tissue contrast without exposure to ionizing radiation, better delineation of the entire visual pathway, and accurate evaluation of associated intracranial pathologies. PMID- 26752824 TI - Diffusion tensor imaging in evaluation of posterior fossa tumors in children on a 3T MRI scanner. AB - CONTEXT: Primary intracranial tumors in children are commonly located in the posterior fossa. Conventional MRI offers limited information regarding the histopathological type of tumor which is essential for better patient management. AIMS: The purpose of the study was to evaluate the usefulness of advanced MR imaging techniques like diffusion tensor imaging (DTI) in distinguishing the various histopathological types of posterior fossa tumors in children. SETTINGS AND DESIGN: DTI was performed on a 3T MRI scanner in 34 untreated children found to have posterior fossa lesions. MATERIALS AND METHODS: Using third party software, various DTI parameters [apparent diffusion coefficient (ADC), fractional anisotropy (FA), radial diffusivity, planar index, spherical index, and linear index] were calculated for the lesion. STATISTICAL ANALYSIS USED: Data were subjected to statistical analysis [analysis of variance (ANOVA)] using SPSS 15.0 software. RESULTS: We observed significant correlation (P < 0.01) between ADC mean and maximum, followed by radial diffusivity (RD) with the histopathological types of the lesions. Rest of the DTI parameters did not show any significant correlation in our study. CONCLUSIONS: The results of our study support the hypothesis that most cellular tumors and those with greater nuclear area like medulloblastoma would have the lowest ADC values, as compared to less cellular tumors like pilocytic astrocytoma. PMID- 26752825 TI - Telltale signs of peripheral neurogenic tumors on magnetic resonance imaging. AB - Peripheral nerve sheath tumors are categorized into benign and malignant forms, comprising of neurofibroma and schwannoma in the benign category and malignant peripheral nerve sheath tumors in the malignant category. Magnetic resonance imaging plays an important role in the diagnosis of these lesions. The various imaging features and signs that help to identify and characterize a nerve sheath tumor are, distribution of the tumor along a major nerve, an entering or exiting nerve sign, target sign, a fascicular sign and a split-fat sign. PMID- 26752826 TI - Primary spinal primitive neuroectodermal tumor on MR imaging. AB - Neoplasms in the region of filum terminale are not uncommon. Myxopapillary ependymoma is the commonest tumor at this location. The differentials reported for this entity are nerve sheath tumor, meningioma, paraganglioma, intradural metastases, lymphoma, other varieties of ependymoma, subependymoma, astrocytoma, ganglioglioma, hemangioblastoma, and primitive neuroectodermal tumor (PNET). PNET may very rarely present as an intradural thoracolumbar mass. We present pre- and post-therapy magnetic resonance imaging (MRI) features of a patient with proven primary spinal primitive neuroectodermal tumor (PSPNET) of peripheral subtype. PMID- 26752827 TI - Utility of ultrasound and magnetic resonance imaging in prenatal diagnosis of placenta accreta: A prospective study. AB - CONTEXT: Placenta accreta is the abnormal adherence of the placenta to the uterine wall and the most common cause for emergency postpartum hysterectomy. Accurate prenatal diagnosis of affected pregnancies allows optimal obstetric management. AIMS: To summarize our experience in the antenatal diagnosis of placenta accreta on imaging in a tertiary care setup. To compare the accuracy of ultrasound (USG) with color Doppler (CDUS) and magnetic resonance imaging (MRI) in prenatal diagnosis of placenta accreta. SETTINGS AND DESIGN: Prospective study in a tertiary care setup. MATERIALS AND METHODS: A prospective study was conducted on pregnant females with high clinical risk of placenta accreta. Antenatal diagnosis was established based on CDUS and MRI. The imaging findings were compared with final diagnosis at the time of delivery and/or pathologic examination. STATISTICAL ANALYSIS USED: The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for both CDUS and MRI. The sensitivity and specificity values of USG and MRI were compared by the McNemar test. RESULTS: Thirty patients at risk of placenta accreta underwent both CDUS and MRI. Eight cases of placenta accreta were identified (3 vera, 4 increta, and 1 percreta). All patients had history of previous cesarean section. Placenta previa was present in seven out of eight patients. USG correctly identified the presence of placenta accreta in seven out of eight patients (87.5% sensitivity) and the absence of placenta accreta in 19 out of 22 patients (86.4% specificity). MRI correctly identified the presence of placenta accreta in 6 out of 8 patients (75.0% sensitivity) and absence of placenta accreta in 17 out of 22 patients (77.3% specificity). There were no statistical differences in sensitivity (P = 1.00) and specificity (P = 0.687) between USG and MRI. CONCLUSIONS: Both USG and MRI have fairly good sensitivity for prenatal diagnosis of placenta accreta; however, specificity does not appear to be as good as reported in other studies. Both modalities have complimentary role and in cases of inconclusive findings with one imaging modality, the other modality may be useful for obtaining the diagnosis. CDUS remains the first primary modality for antenatal diagnosis of placenta accreta, with MRI reserved for cases where USG is inconclusive. PMID- 26752828 TI - Fetal echopsy (ultrasonographic autopsy) of an acardius myelancephalus and its correlation with antenatal ultrasonographic findings. AB - Aberrant transplacental arteriovenous shunts between the placental and cord vessels of monozygotic monoamniotic twins or triplets result in the formation of an acardius. The prenatal diagnosis of this condition has been reported occasionally in the literature. A subtype categorized as acardius myelancephalus was diagnosed at 32 weeks of gestation by ultrasonography (USG). The pregnancy was aborted because of poor prognostic predictors and the acardius was subjected to ultrasonographic autopsy (fetal echopsy). The antenatal USG features were correlated with echopsy findings for confirmation of the antenatal findings and for a better visual perception of the prenatal diagnostic features. The echopsy revealed more precise details. Fetal echopsy avoids the medicolegal problems concerned with parental consent for classical invasive fetal autopsy. PMID- 26752829 TI - Imaging in diagnosis and treatment of pulmonary tuberculosis. PMID- 26752830 TI - Author reply to comments. PMID- 26752831 TI - Seronegative spondyloarthropathy imaging: Looking at the past, hitting the future. PMID- 26752832 TI - Caveat emptor. PMID- 26752833 TI - Enamel surface changes caused by hydrogen sulfide. AB - BACKGROUND: Volatile sulfur compounds (VSCs) produced inside the mouth are a well known cause of halitosis. Recent studies have suggested that VSCs modify the pathology of periodontitis by encouraging the migration of bacterial toxins associated with increased permeability of gingival epithelia, and enhancing the production of matrix metalloproteinases in gingival connective tissue. Nonetheless, the effects on the enamel of direct exposure to VSCs within the oral cavity remain unclear. In the present study, we observed the effects of VSCs in the form of hydrogen sulfide (H2S) on enamel surfaces and determined their effects on restorations. MATERIALS AND METHODS: Extracted human tooth and bovine tooth samples were divided into the H2S experimental side and the control side. We observed the effects of H2S on enamel surfaces using electron microscopy and conducted a shear test. RESULTS: We found that exposure to H2S obscured the enamel surface's crystal structure. The surface also exhibited coarseness and reticular changes. Shear testing did not reveal any differences in bond strength. CONCLUSIONS: Our findings suggested that H2S occurring inside the mouth causes changes to the crystal structure of the enamel surface that can lead to tooth wear, but that it does not diminish the effects of dental bonding in adhesive restorations. PMID- 26752834 TI - Apical transportation of manual NiTi instruments and a hybrid technique in severely curved simulated canals. AB - AIM: To evaluate the apical transportation induced by two instrumentation techniques in severely curved simulated canals. MATERIALS AND METHODS: Forty simulated canals were divided into two groups (n = 20), according to the following instrumentation techniques: ProTaper Universal Manual System and a hybrid technique. The simulated canals in the ProTaper group were prepared following the technique recommended by the manufacturer: SX files in the cervical third of the root canal and S1, S2, and F1 files up to the working length. In the hybrid group, preparation was performed with K-files sizes 15, 20, and 25 to the working length, followed by cervical preparation with Gates Glidden burs 1, 2, and 3. Apical finishing was performed with the ProTaper manual files S2 and F1. To analyze apical transportation, the simulated canals were photographed before and after preparation at *8. The images of the root canals pre- and post instrumentation were superimposed to measure the distance between the inner and outer walls along the first 3 mm of the apical third. RESULTS: The hybrid group presented the highest apical transportation values; however, with no statistically significant difference in comparison with the ProTaper group (P > 0.05). CONCLUSIONS: Both techniques induced similar apical transportation in the original path of the simulated root canals. PMID- 26752835 TI - To evaluate the biocompatibility of the Indian Portland cement with potential for use in dentistry: An animal study. AB - AIMS: This study evaluated the biocompatibility of the Indian Portland cement with potential for use in dentistry. MATERIALS AND METHODS: This study was performed in Swiss albino mice, by implanting the Indian Portland cement pellets subcutaneously. After 1, 3, and 6 weeks the tissue specimens were prepared for histological examination. RESULTS: The histological analysis showed moderate to severe inflammation at 1 week. The inflammation gradually decreased by 6 weeks, with most of the specimens showing the absence of inflammatory reaction. CONCLUSIONS: According to these experimental conditions, the tested Indian Portland cement was biocompatible. PMID- 26752836 TI - Comparison of sealing ability of ProRoot MTA, RetroMTA, and Biodentine as furcation repair materials: An ultraviolet spectrophotometric analysis. AB - AIM: To evaluate the sealing ability of ProRooT MTA, RetroMTA, and Biodentine as furcation repair materials using dye extraction leakage method. MATERIALS AND METHODS: Thirty-five mandibular molars were randomly divided into four groups according to the material used for perforation repair. Group I - ProRoot MTA (10 samples), Group II - RetroMTA (10 samples), Group III - Biodentine (10 samples), and Group IV (Control) - left unrepaired (5 samples). All samples were subjected to orthograde and retrograde Methylene blue dye challenge followed by dye extraction with concentration 65% nitric acid. Samples were then analyzed using ultraviolet-visible spectrophotometer using 550 nm wave lengths. STATISTICAL ANALYSIS: One-way analysis of variance, Tukey-Kramer multiple comparisons test. RESULTS: Biodentine showed least dye absorbance while RetroMTA showed highest dye absorbance values when compared with other repair materials. CONCLUSION: Within the limitations of this study, it was observed that Biodentine showed better sealing ability when compared with other root repair materials. PMID- 26752838 TI - Fracture resistance exhibited by endodontically treated and retreated teeth shaped by ProTaper NEXT versus WaveOne: An in vitro study. AB - AIM: To compare the fracture resistance exhibited by teeth after primary endodontic treatment and retreatment. MATERIALS AND METHODS: One hundred freshly extracted human teeth were selected. 20 samples served as control (untreated). Eighty experimental samples were divided into two groups (n = 40) for instrumentation using rotary Protaper NEXT (PTN) or reciprocating WaveOne (WO) files and obturated using warm lateral compaction. Half of the samples (n = 20) from each group were subjected to a load. The remaining half were subjected to retreatment using Protaper universal retreatment files (RFs) followed by a file larger than the master apical file used in groups 1 and 2 and reobturated. Group A: Control, Group B: PTN + obturation, Group C: WO + obturation, Group D: RF + PTN + obturation and Group E: RF + WO + obturation. The retreatment specimens were also subjected to load and the readings acquired were statistically analyzed. RESULT: When compared between the groups, control group exhibited the highest fracture resistance (P < 0.01). When multiple tests were performed, Group E exhibited significantly less fracture resistance (P < 0.01). CONCLUSION: Endodontic treatment and retreatment both results in lowering the fracture resistance of a tooth. PMID- 26752837 TI - One year comparative clinical evaluation of EQUIA with resin-modified glass ionomer and a nanohybrid composite in noncarious cervical lesions. AB - AIMS: Comparative evaluation of EQUIA with a resin-modified glass ionomer cement (RMGIC; GC Gold Label glass ionomer light cured universal restorative cement) and a nanohybrid composite (Tetric N-Ceram) in noncarious cervical lesions (NCCLs). BACKGROUND: To establish the most suitable material for the restoration of NCCLs. SETTINGS AND DESIGN: In vivo study. MATERIALS AND METHODS: Eighty-seven NCCLs were randomly restored with EQUIA, a RMGIC, and a nanohybrid composite. Clinical evaluation of the restorations was done following the Unites States Public Health criteria by a single-blinded investigator. Data were formulated, and statistical analysis was done by Chi-square test. STATISTICAL ANALYSIS USED: Chi-square test. RESULTS: No significant difference was found between EQUIA, RMGIC, and nanohybrid composite at 1-month, at 6 months, and at 1-year (P > 0.05). CONCLUSIONS: EQUIA, resin-modified glass ionomer, and nanohybrid composite performed equally at 1 month, 6 months, and 1-year follow-up periods. PMID- 26752839 TI - Evaluation of antibacterial activity of Calotropis gigentica against Streptococcus mutans and Lactobacillus acidophilus: An in vitro comparative study. AB - BACKGROUND: This study was conducted to evaluate in vitro antibacterial potential of ethanolic extract of Calotropis gigentica. MATERIALS AND METHODS: The inhibitory effect of the ethanolic extract was tested against Streptococcus mutans and Lactobacilli casei by using disc diffusion method. RESULTS: Ethanolic extract of Calotropis gigentica showed 16 mm and 14 mm of minimum inhibition zone at 1.25% concentration for S. mutans and lactobacilli, respectively. CONCLUSION: Calotropis gigentica was found to effective against S. mutans and lactobacilli. PMID- 26752840 TI - Antibacterial efficacy of Azadirachta indica, Mimusops elengi and 2% CHX on multispecies dentinal biofilm. AB - AIMS: To check the antimicrobial activity of Azadirachta indica (Neem), Mimusops elengi (Bakul), and Chlorhexidine gluconate (CHX) on multispecies biofilm of common endodontic pathogens such as Streptococcus mutans, Enterococcus faecalis, Staphylococcus aureus and Candida albicans. SETTINGS AND DESIGN: In vitro dentin disinfection model used to check the antimicrobial efficacy of herbal extracts. MATERIALS AND METHODS: The in vitro dentin disinfection model was used to check the antimicrobial activity of the methanolic extracts of the medicinal plants along with Chlorhexidine gluconate. The polymicrobial biofilm was allowed to grow on extracted teeth sections for a period of 21 days. Remaining microbial load in the form of CFU/ml after the antimicrobial treatment was tabulated, and data were statistically analyzed using ANOVA and Bonferroni post-hoc tests. STATISTICAL ANALYSIS USED: SPSS version 17, one-way ANOVA, Bonferroni post-hoc test. RESULTS: Both the plant extracts showed considerable antimicrobial efficacy as compared to negative control. 2% CHX was the most effective antimicrobial agent having statistically significant difference against plant extracts and negative control (saline). CONCLUSION: The methanolic extract of A. Indica, M. elengi, and Chlorhexidine Gluconate has considerable antimicrobial activity against polymicrobial dentinal biofilm of S. mutans, E. faecalis, S. aureus and C. albicans. PMID- 26752841 TI - Influence of salivary contamination on the dentin bond strength of two different seventh generation adhesive systems: In vitro study. AB - AIM: To investigate the effect of salivary contamination on the bond strength of two different seventh generation adhesive systems. MATERIALS AND METHODS: Sixty caries-free human premolars with flat dentin surfaces were randomly divided into six groups of 10 teeth each and bonding was done using seventh-generation bonding agents Adper Easy One (3M ESPE) and Xeno V (Dentsply). Following the bonding procedure, resin composite was bonded to the surfaces using a plastic mould. The prepared specimen with composite cylinders attached were placed in 37 degrees C distilled water for 24 h and then subjected to shear bond strength (SBS) with 0 h universal testing machine and the data were subjected to one-way analysis of variance and unpaired t-test. RESULTS: Statistical significant difference between the Groups I, II and III in which Adper Easy One was used and similarly for Groups IV, V, and VI in which Xeno V was used. When an intergroup comparison was made using unpaired t-test Group II and Group V showed the nonsignificant difference. CONCLUSION: Salivary contamination significantly affects the SBS of both the seventh generation dentin bonding agents. However, 2-hydroxyethyl methacryate based adhesive has higher bond strength. PMID- 26752842 TI - Comparative evaluation of tensile strength of Gutta-percha cones with a herbal disinfectant. AB - AIM: To evaluate and compare the tensile strength values and influence of taper on the tensile strength of Gutta-percha (GP) cones after disinfection with sodium hypochlorite (SH) and Aloe vera gel (AV). MATERIALS AND METHODS: Sixty GP cones of size 110, 2% taper, 60 GP cones F3 ProTaper, and 60 GP of size 30, 6% taper were obtained from sealed packs as three different groups. Experimental groups were disinfected with 5.25% SH and 90% AV gel except the control group. Tensile strengths of GP were measured using the universal testing machine. RESULTS: The mean tensile strength values for Group IA, IIA and IIIA are 11.8 MPa, 8.69 MPa, and 9.24 MPa, respectively. Results were subjected to statistical analysis one way analysis of variance test and Tukey post-hoc test. 5.25% SH solutions decreased the tensile strength of GP cones whereas with 90% AV gel it was not significantly altered. CONCLUSION: Ninety percent Aloe vera gel as a disinfectant does not alter the tensile strength of GP cones. PMID- 26752843 TI - Antimicrobial efficacy of different root canal sealers by using real-time polymerase chain reaction: An ex vivo study. AB - BACKGROUND: Root canal sealers help to minimize leakage, provides antimicrobial activity to reduce the possibility of residual bacteria, and to resolve periapical lesion. AIM: To compare five different root canal sealers against Enterococcus faecalis in an infected root canal model by using real-time polymerase chain reaction (RT-PCR). SETTINGS AND DESIGN: Sixty human mandibular premolars were sectioned to standardize a uniform length of 14 mm. Fifty microliters of the inoculum containing E. faecalis were transferred into each microcentrifuge tube (n = 60). The samples were divided into six groups Tubli Seal, Apexit Plus, Fillapex, AH Plus, RoekoSeal, and Positive control, respectively. MATERIALS AND METHODS: Five groups after the incubation with the microorganism E. faecalis were coated with different root canal sealers and obturated using F3 ProTaper Gutta-percha point. The dentinal shavings were collected and analyzed for RT-PCR. STATISTICAL ANALYSIS: The mean difference between six groups was calculated using analysis of variance and post-hoc test. RESULTS: The highest antibacterial activity was achieved with Tubli-Seal (1938.13 DNA in pictogram [pg]) and least by RoekoSeal (3034.54 DNA in pg). CONCLUSION: The maximum antimicrobial activity was achieved AH Plus and Tubli-Seal. RT-PCR can be used as a valuable and accurate tool for testing antimicrobial activity. PMID- 26752844 TI - Evaluation of effect of addition of 2% chlorhexidine on the sealing ability of Biodentine: An in vitro study. AB - AIM: To evaluate the effect of the addition of 2% chlorhexidine on the sealing ability of Biodentine. MATERIALS AND METHODS: Forty-six extracted human premolar teeth with single canal and apical foramen were selected, cleaned, and decoronated to standardize the length of 17 mm. Canals were prepared using ProTaper rotary files till size F4. The samples were divided into 2 experimental groups of 20 samples each on the basis of absence/presence of 2% chlorhexidine in liquid: Group BM = Biodentine mixed with the provided liquid, Group BC = Biodentine mixed with 2% chlorhexidine in provided liquid. Three samples, each were assigned to control groups: Group BP (positive control) = No root end filling was placed, Group BN (negative control) = Root ends were filled as in Group BM, and entire external surface was coated with sticky wax. The samples were then evaluated for the apical sealing using fluid filtration method. RESULTS: Results were analyzed using Student's t-test (P <= 0.05). Group BC showed the better sealing ability (3.06) as compared to Group BM (3.85). However, the difference was statistically insignificant (P > 0.05). CONCLUSION: Addition of 2% chlorhexidine to the liquid enhanced the sealing ability of Biodentine. PMID- 26752845 TI - In vitro evaluation of the effect of different polishing techniques on the surface roughness of composite resins submitted to at-home and in-office bleaching procedures. AB - OBJECTIVE: Bleaching agents may affect the properties of dental materials. The aim of this study was to evaluate the effect of different polishing techniques on the surface roughness of composite resins submitted to the at-home and in-office bleaching treatment. MATERIALS AND METHODS: Disc-shaped specimens were carried out of nanofilled and microhybrid composites (n = 10). Finishing step was performed after light curing (L1) and polishing after 24 h with two systems (L2). Then, specimens were submitted to the home or in-office bleaching procedures, and roughness was re-evaluated (L3). The surface roughness (Ra) readings were measured at L1, L2, and L3 times using a profilometer. Data were statistically analyzed by multiple-way analysis of variance and Tukey test (alpha = 0.05). RESULTS: The polishing procedures decreased Ra for both composites compared to baseline values (L1). The roughness of specimens polished with jiffy did not present significant difference after polishing step (L2) and bleaching treatment (L3). However, the groups polished with Sof-Lex discs had increase on the Ra values after bleaching. CONCLUSION: The polishing is an important procedure to reduce the roughness of dental restorations and composite surface polished with jiffy system improved the degradation resistance to the bleaching agents compared to Sof-Lex discs. PMID- 26752846 TI - Effect of silorane-based adhesive system on bond strength between composite and dentin substrate. AB - CONTEXT: The complexities of the oral environment, the dentin substrate, and the different bond and composite resin systems represent a challenge to the maintenance of reasonable bond between the composite resin and the tooth structure. AIMS: To evaluate the effect of the adhesive system on bond strength between silorane-based composite resin and dentin. MATERIALS AND METHODS: Fourteen human molars extracted were selected and vertically cut into 3 dentin fragments, randomly divided among the experimental groups and restored with Z250 and P90 composite resin using different adhesive protocols (Adper Single Bond 2, Silorano primer, Adper SE Plus, and Scotchbond Multiuse). Two composite resin cylinders were built up on each dentin surface (n = 10) and subjected to a micro shear bond strength test. STATISTICAL ANALYSIS USED: Kruskal-Wallis one-way analysis of variance and Tukey test (P = 0.05). RESULTS: According to the results, Kruskal-Wallis test evidenced at least one statistical significant difference (P = 0.001). The Tukey test showed statistically significant differences among the group (P < 0.05). Group PSM8 (P90 + SM) showed statically significant higher results when compared with groups PSP4 (P90 + SP), PSB2 (P90 + SB), and ZSE5 (Z250 + SE). CONCLUSION: The results evidenced that the monomer of the adhesive system has an effect on bond strength between the composite resin and dentin. PMID- 26752849 TI - Direct filling gold and cast gold workshop report. PMID- 26752847 TI - Pulp revascularization of immature maxillary first premolar. AB - An immature maxillary first premolar in an 8-year-old female was treated using a regenerative approach. The root canal was gently irrigated with 5.25% sodium hypochlorite without instrumentation under aseptic conditions and then medicated with calcium hydroxide (Ca[OH]2) for 3 weeks. The Ca(OH)2 was removed, and bleeding was initiated mechanically using a hand file to form an intracanal blood clot. Mineral trioxide aggregate was placed over the blood clot, and the access cavity was sealed with a double filling. Increases in root length and width were radiographically evident, at the 6-month follow-up exam. The case was followed for 3 years. The development of 3 roots with complete apical closure was confirmed using cone beam computed tomography. PMID- 26752848 TI - Autotransplantation. AB - Autogenous tooth transplantation refers to the repositioning of autogenous teeth in another tooth extraction site or a surgically formed recipient site to replace missing teeth due to congenital deformity, grossly decayed carious teeth, mobile teeth due to periodontal disease, teeth lost due to trauma, endodontic failure or any other reason when a suitable donor tooth is available. This is a case report of autotransplantation of impacted #38 with complete root formation into the extraction site of grossly decayed, unrestorable #37 with 18 months follow-up showing excellent periapical healing and tooth stability. In autogenous tooth transplantation, even if the donor's tooth has complete root formation, a high success rate can be achieved if the cases are selected and treated properly. Chances of root resorption are there because of necrotic pulp and periodontal irritation during manipulation. However, autogenous tooth transplantation should always be considered as a good treatment modality in feasible cases. PMID- 26752850 TI - 1(st) International and 4(th) National Conference of Endodontics and Conservative Dentistry Clinical Research 2015: Report. PMID- 26752852 TI - From the Editor's desk. PMID- 26752851 TI - Estrogen modulation of visceral nociceptors. AB - A large body of literature supports the idea that estrogen modulates nociceptive responses in pelvic pain syndromes; however, whether this hormone is pro- or anti nociceptive remains unresolved. The dorsal root ganglion (DRG) is an important site of visceral afferent convergence and cross-sensitization. Within the context of our hypothesis visceral nociception and nociceptor sensitization appear to be regulated by purinergic P2X3 and vanilloid TRPV1 receptors and 17beta-estradiol modulates DRG neuron response to ATP (P2X agonist) and capsaicin (TRPV1 agonist) suggesting that visceral afferent nociceptors are modulated by estrogen in the DRG. 17-beta estradiol (E2), the most common form of estrogen, acts on functional properties of P2X3 and TRPV1 receptors in DRG neurons in vitro. The localization of estrogen receptors (ER) in DRG neurons and the attenuation of ATP/capsaicin induced intracellular calcium concentration [Ca2+]i strongly suggest that E2 modulates visceral pain processing peripherally. Moreover, E2 appears to have different actions on nociceptive signaling depending on the input. Based on our data we propose that E2 can gate primary afferent response to increase or decrease nociception. PMID- 26752853 TI - Trends of male factor infertility, an important cause of infertility: A review of literature. AB - Infertility and problems of impaired fecundity have been a concern through ages and is also a significant clinical problem today, which affects 8-12% of couples worldwide. Of all infertility cases, approximately 40-50% is due to "male factor" infertility and as many as 2% of all men will exhibit suboptimal sperm parameters. It may be one or a combination of low sperm concentration, poor sperm motility, or abnormal morphology. The rates of infertility in less industrialized nations are markedly higher and infectious diseases are responsible for a greater proportion of infertility. The present literature will help in knowing the trends of male factor infertility in developing nations like India and to find out in future, various factors that may be responsible for male infertility. PMID- 26752854 TI - Clomiphene citrate, metformin or a combination of both as the first line ovulation induction drug for Asian Indian women with polycystic ovarian syndrome: A randomized controlled trial. AB - AIM: To compare clomiphene citrate (CC), metformin or the combination of CC and metformin as the first line ovulation induction drug in Asian Indian women with polycystic ovary syndrome (PCOS). METHODS: One hundred and five newly diagnosed, treatment naive PCOS women were recruited. They were randomized into any of the three groups: Group I (CC 50-150 mg/day), Group II (metformin 1700 mg/day), and Group III (CC + metformin in similar dosage to Groups I and II). Patients underwent follicular monitoring and advice on timed intercourse. The study period was 6 months, or till pregnant, or till CC resistant. Primary outcome studied was live birth rate (LBR). Secondary outcomes were ovulation rate, pregnancy rate, and early pregnancy loss rate. RESULTS: There was no significant difference among the groups in baseline characteristics and biochemical parameters. LBR was 41.6%, 37.5%, and 28.1%, respectively in Groups III, II, and I. Group III (CC + metformin) had the highest ovulation (83.3%), pregnancy (50%), and LBRs (41.6%). Group II (metformin) was as good as Group I (CC) in all the outcomes. CC + metformin (Group III) had statistically significantly higher ovulation rate as compared to CC alone (Group I) (P = 0.03; odds ratio: 95% confidence interval: 3.888 [1.08-13.997]). CONCLUSION: Thus, our study shows that metformin was as good as CC in terms of "LBR" and the combination of CC and metformin gave the highest ovulation and LBR. PMID- 26752855 TI - Prevalence of metabolic syndrome in relation to body mass index and polycystic ovarian syndrome in Indian women. AB - OBJECTIVE: To study the prevalence of metabolic syndrome (MBS) in Indian women and to see how does it correlate to body mass index (BMI) and polycystic ovarian syndrome (PCOS) in this population. STUDY DESIGN: Prospective cross-sectional observational study. SETTING: Infertility clinic of a tertiary center. MATERIALS AND METHODS: Two hundred women, 120 with PCOs and 80 age-matched controls were enrolled. The prevalence of MBS was studied in the women with and without and was co related to BMI by further subgrouping as team (BMI <23 kg/m3) and obese (BMI >23 kg/m2). The sample size was: team controls-40, obese controls-40, team PCOS 80. Each subject underwent a physical examination and laboratory evaluation for the diagnosis of MBS, which was defined according to the guidelines of National Cholesterol Education Program Adult Treatment Pamel (NCEP ATP III) 2005. INTERVENTION: None. MAIN OUTCOME MEASURES: MAIN OUTCOME MEASURES: Subjects with and without PCOs were compared with each other for the prevalence of MBS, and similarly team subjects were compared with obese subjects. Receiver operator characteristic (ROC) curves were obtained for both the PCOS and non PCOS population separately, co-relating the prevalence of MBS with BMI. These ROC curves were used to establish the cut off values of BMI, which could best predict the risk of MBS. RESULTS: The prevalence of MBS was significantly higher in the women with PCOS, as compared to age-matched controls. Similarly, when BMI was considered, MBS was more prevalent in overweight subjects than in lean subjects with or without PCOS. In subgroup analysis, the presence of PCOS had a lesser impact on the prevalence of MBS as compared to non-PCOS controls with higher BMI. The relative risk of MBS increased as follows: lean controls-1, lean PCOS-2.66, obese controls-5.33, and obese PCOS-6.5. The most appropriate cut-off level of BMI for predicting the risk of MBS in Indian women without PCOS seems to be 23 kg/m(2), whereas, with PCOS, it was 22.5 kg/m(2). CONCLUSION: MBS is more prevalent in women with PCOS. However, obesity is an independent and stronger risk factor for developing MBS. To reduce the risk of MBS and its related long term health consequences, lifestyle modification is advisable above BMI of 23 kg/m(2) in the normal population and 22.5 kg/m(2) in women with PCOS. PMID- 26752856 TI - Role of Embryo Glue as a transfer medium in the outcome of fresh non-donor in vitro fertilization cycles. AB - BACKGROUND: EmbryoGlue is a hyaluronan-enriched embryo transfer (ET) medium which aids in implantation of embryos, hence, improves pregnancy rates in in-vitro fertilization-ET cycles (IVF-ET). AIM: To evaluate the role of EmbryoGlue in improving implantation and pregnancy rates. DESIGN AND SETTING: A prospective case-control study conducted at assisted reproductive center of a tertiary care hospital. METHOD: In 42 women undergoing IVF, embryos were transferred into 50 MUL of EmbryoGlue for 10 min prior to transfer inside uterine cavity. In the control group (n = 42), embryos were transferred to conventional blastocyst culture medium. Statistical analysis was performed using SPSS IBM version 19.0. RESULTS: Clinical pregnancy rate in the study group was 7% higher than the control group. The difference, however, was not statistically significant. In addition, no improvement in implantation rates was observed in the study group. However, significant difference (P = 0.04) in clinical pregnancy rate was observed with the EmbryoGlue in patients with previous IVF failure. In the study group, 50% patients (6/12) with previous IVF failure had successful implantation, but in the control group none of the patients (0/11) with previous implantation failure could achieve pregnancy. CONCLUSION: It is difficult to conclude a favourable role of EmbryoGlue in IVF-ET cycles with a good prognosis. However, in patients with recurrent implantation failure, it may be considered as a useful transfer medium. PMID- 26752857 TI - Does endometrial injury enhances implantation in recurrent in-vitro fertilization failures? A prospective randomized control study from tertiary care center. AB - BACKGROUND: Though Assisted Reproductive Techniques have overcome many fertility disorders, implantation is still considered, the rate-limiting step for the success of IVF. AIM: The aim of this study was to evaluate the role of endometrial scratching in improving the implantation rate in patients undergoing IVF-ET cycles. DESIGN: Prospective randomized control trial. METHODS: Sixty infertile women with a history of >1 previous failed IVF-ET cycles were randomizedinto two groups of 30 each. The patients in group 1 underwent endometrial scratching once between days 14-21 of menstrual cycle in the cycle prior to embryo transfer (ET), while in group 2scratching were not done. Implantation rate, ongoing pregnancy rate, abortion rate and live birth rate were comparedbetween both groups. STATISTICAL ANALYSIS: Mean values were compared between two groups using Student's't' independent test. Frequency distributions of categorical variables were compared using Chi-Square/Fisher's exact test as appropriate. RESULTS: Implantation rate in group 1 was 19.4% whereas in group 2 it was 8.1%. Difference between two groups was statistically significant (P =0.028). The live birth rate was higher in the group 2 compared to group 1, however this difference was not statistically significant (3.3% vs 10%, P =0.612). No significant difference was observed between the two groups regarding the ongoing pregnancy rate (16.7% vs 0.0%; P =0.052), abortion rate (10.0% vs 3.3%, P =0.612) and miscarriage rate (6.7% vs 3.3%, P =0.99). CONCLUSIONS: Implantation rate increases significantly after endometrial scratching in patients with previous failed IVF-ET. PMID- 26752858 TI - Prevalence and role of antithrombin III, protein C and protein S deficiencies and activated protein C resistance in Kosovo women with recurrent pregnancy loss during the first trimester of pregnancy. AB - CONTEXT: Several studies have reported that thrombophilia is responsible for recurrent pregnancy loss (RPL). AIMS: The aim of this study was to evaluate the prevalence and role of inherited thrombophilia in early pregnancy loss, specifically in the first trimester. MATERIALS AND METHODS: A total of 104 women (patients) with a history of two or more miscarriages during the first trimester of pregnancy and 110 women (controls) who had experienced two or more births without a miscarriage were included in this study. In both groups, we determined the biological activities of antithrombin III (ATIII) and protein C (PC) using the chromogenic method and the biological activity of protein S (PS) and the activated protein C resistance (APCR) were examined using a clotting method. RESULTS: In the patient group, deficiencies of ATIII, PC, and PS were detected in 3 (2.88%), 4 (3.85%), and 6 (5.77%) cases, respectively. In the control group, ATIII (0%) deficiencies were not detected, and deficiencies for PC (0.9%) and PS (0.9%) were each detected in 1 patient. APCR was detected in 9 patients (8.65%) and 4 control subjects (3.63%). CONCLUSION: Based on our results, we can conclude that thrombophilia is a causal factor for miscarriages in the first trimester of pregnancy, although there are the conflicting data in the literature. PMID- 26752859 TI - Novel FSH receptor mutation in a case of spontaneous ovarian hyperstimulation syndrome with successful pregnancy outcome. AB - The objective is to study the FSH receptor (FSHR) for mutations in a case of spontaneous ovarian hyperstimulation syndrome (sOHSS). This is a single case study and it examined patient who presented with spontaneous critical OHSS in early pregnancy and had successful good obstetric outcome. Intervention of this study was analysis of blood for genetic analysis of FSHR postdelivery. The main outcome measure noted was FSHR mutation. The study resulted in a novel, here though unreported, heterozygous mutation in FSHR gene at nucleotide position 1346 (AC(1346)T to AAT) in exon 10 yielding a threonine to asparagine (Thr(449)Asn) substitution in the transmembrane domain helix 3 of the FSHR. To conclude FSHR gene analysis can add to our understanding of sOHSS. PMID- 26752860 TI - Early onset ovarian hyperstimulation syndrome despite use of segmentation approach and ovarian hyperstimulation syndrome prophylaxis. AB - We report a case of early onset severe ovarian hyperstimulation syndrome (OHSS) presenting with oliguria in an antagonist cycle triggered with GnRH agonist and a freeze-all approach. Prophylactic measures in the form of GnRH antagonist, cabergolin and plasma expanders were given after oocyte retrieval. Twenty-four hours after oocyte retrieval patient developed oliguria and moderate ascites. She was managed in ICU with albumin and diuretics. She responded to conservative management and did not require paracentesis. Severe OHSS can occur in PCOS patients even after using a segmented approach i.e. GnRH agonist trigger with a 'freeze all' policy. Patients at risk of OHSS should be closely monitored following ovum pickup even when an agonist trigger has been given, for early detection and management. PMID- 26752861 TI - A rare case of Mayer-Rokitansky-Kuster-Hauser syndrome with multiple leiomyomas in hypoplastic uterus. AB - Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a rare disorder described as aplasia or hypoplasia of uterus and vagina due to an early arrest in development of mullerian ducts. Women with this syndrome are characterized by the presence of 46 XX karyotype, normal female secondary sex characters, normal ovarian functions, and underdeveloped vagina. The presence of leiomyoma in MRKH syndrome is very rare, and only few cases have been reported in the literature. Here, we report a case of MRKH syndrome with multiple leiomyomas originating from the rudimentary horn of uterus in 25 years married, phenotypically female patient. PMID- 26752862 TI - Per-anal discharge: A new face of Dhat syndrome. PMID- 26752863 TI - Dhat syndrome: Will it reach a height or die soon? PMID- 26752864 TI - Retraction: A rare cause for primary amenorrhea. AB - [This retracts the article on p. 218 in vol. 5, PMID: 23162364.]. PMID- 26752865 TI - Predicting Protein Model Quality from Sequence Alignments by Support Vector Machines. AB - Assessing the quality of a protein structure model is essential for protein structure prediction. Here, we developed a Support Vector Machine (SVM) method to predict the quality score (GDT-TS score) of a protein structure model from the features extracted from the sequence alignment used to generate the model. We developed a Support Vector Machine (SVM) model quality assessment method, taking either a query-single-template pairwise alignment or a query-multitemplate alignment as input. For the pairwise alignment scheme, the input features fed into the SVM predictor include the normalized e-value of the given alignment, the percentage of identical residue pairs in the alignment, the percentage of residues of the query aligned with those of the template, and the sum of the BLOSUM scores of all aligned residues divided by the length of the aligned positions. Similarly, for the multiple-alignment scheme, the input features include the percentage of the residues of the target sequence aligned with those in one or more templates, the percentage of aligned residues of the target sequence that are the same as that of any one template, the average BLOSUM score of aligned residues and the average Gonnet160 score of aligned residues. A SVM regression predictor was trained on the training data to predict the GDT-TS scores of the models from the input features. The Root Mean Square Error (RMSE) and the Absolute Mean Error (ABS) between predicted and real GDT-TS scores were calculated to evaluate the performance. A five-fold cross validation was applied to select the best parameter values based on the average RMSE and ABS on the five folds. The RMSE and ABS of the optimized SVM predictor on the testing data were close to 0.1. The good performance of the SVM and sequence alignment based predictor indicates that integrating sequence alignment features with a SVM is effective for protein model quality assessment. PMID- 26752866 TI - State of the Globe: The Rippling Effect of Multidrug-Resistant Gram-negative Infections. PMID- 26752867 TI - The Ebola Outbreak of 2014-2015: From Coordinated Multilateral Action to Effective Disease Containment, Vaccine Development, and Beyond. AB - The Ebola outbreak of 2014-2015 exacted a terrible toll on major countries of West Africa. Latest estimates from the World Health Organization indicate that over 11,000 lives were lost to the deadly virus since the first documented case was officially recorded. However, significant progress in the fight against Ebola was made thanks to a combination of globally-supported containment efforts, dissemination of key information to the public, the use of modern information technology resources to better track the spread of the outbreak, as well as more effective use of active surveillance, targeted travel restrictions, and quarantine procedures. This article will outline the progress made by the global public health community toward containing and eventually extinguishing this latest outbreak of Ebola. Economic consequences of the outbreak will be discussed. The authors will emphasize policies and procedures thought to be effective in containing the outbreak. In addition, we will outline selected episodes that threatened inter-continental spread of the disease. The emerging topic of post-Ebola syndrome will also be presented. Finally, we will touch on some of the diagnostic (e.g., point-of-care [POC] testing) and therapeutic (e.g., new vaccines and pharmaceuticals) developments in the fight against Ebola, and how these developments may help the global public health community fight future epidemics. PMID- 26752868 TI - Retrospective Clinical Study of Eighty-One Cases of Intracranial Mucormycosis. AB - BACKGROUND: Fungal infections of the central nervous system, especially cerebral mucormycosis or brain abscess are very rare.Cerebral mucormycosis is a rare disease. It is not an independent disease, but a secondary opportunistic infectious disease. MATERIALS AND METHODS: This study has collected the data of 81 cases of intracranial mucormycosis from 28 Chinese hospitals, within 37 years, as well as reviewed the literatures and retrospectively analyzed and summarized this disease's background, clinical classifications, risk factors, pathology, clinical manifestations, diagnosis, treatment, and prognosis. RESULTS: The 81 IM cases were aged between 15 days (the youngest) and 79 years (oldest), with a mean age of 41.6 years. Among them, 12 cases were <1 year old (the infant group), six cases were within one to 13 years old (the children group), and 63 cases were >14 years old (the adult group ). 45 cases were male and 36 were female, with a male/female ratio of 1.25:1.0. The shortest duration of the disease was three days, and the longest was 248 days. CONCLUSIONS: This study helped to realize an early diagnosis and treatment, improve the cure rate, and reduce mortality. PMID- 26752869 TI - Tuberculous Drug-induced Liver Injury and Treatment Re-challenge in Human Immunodeficiency Virus Co-infection. AB - BACKGROUND: Tuberculosis drug-induced liver injury (TB-DILI) is the most common adverse event necessitating therapy interruption. The optimal re-challenge strategy for antituberculous therapy (ATT) remains unclear, especially in human immunodeficiency virus (HIV) co-infected individuals in high-prevalence settings such as South Africa. OBJECTIVE: To determine the incidence of and risk factors for the recurrence of TB-DILI with different ATT re-challenge strategies. MATERIALS AND METHODS: We conducted a retrospective chart review of patients managed for TB-DILI from 2005 to 2013 at King Edward VIII Hospital in Durban, South Africa. Relevant clinical and laboratory data at the presentation of TB DILI, time to recovery of liver function, method of ATT re-challenge and outcome of re-challenge were documented. RESULTS: 1016 charts were reviewed, and 53 individuals with TB-DILI (48 HIV-co-infected) were identified. Following discontinuation of ATT, the median time to alanine aminotransferase normalization was 28 days (interquartile range 13-43). Forty-two subjects were re-challenged (30 regimen re-challenges and 12 step-wise re-challenges). 5 (12%) cases of recurrent TB-DILI were noted. Recurrences were not associated with the method of re-challenge. CONCLUSION: Based on the data available, it appears that full ATT can be safely restarted in the majority of subjects with a recurrence of DILI occurring in about 12% of subjects. The method of re-challenge did not appear to impact on the risk of recurrence. Ideally, a prospective randomized trial is needed to determine the best method of re-challenge. PMID- 26752872 TI - Enteric Fistulous Communication with an Aortobifemoral Graft Permitting for Eggerthella Lenta Colonization. AB - The presence of an aortoenteric fistula following aortobifemoral graft repair of an abdominal aortic aneurysm is associated with a high probability of infection leading to clinically significant bacteremia. We report a case of an aortoenteric fistula that developed two years after initial aortic grafting resulting in colonization with the anaerobe, Eggerthella lenta. This dangerous bacterium is difficult to culture, associated with high mortality and the patient may have mild symptoms on presentation. PMID- 26752871 TI - Risk Factors of Delay Proportional Probability in Diphtheria-tetanus-pertussis Vaccination of Iranian Children; Life Table Approach Analysis. AB - Despite success in expanded program immunization for an increase in vaccination coverage in the children of world, timeliness and schedule of vaccination remains as one of the challenges in public health. This study purposed to demonstrate the related factors of delayed diphtheria-tetanus-pertussis (DTP) vaccination using life table approach. A historical cohort study conducted in the poor areas of five large Iran cities. Totally, 3610 children with 24-47 months old age who had documented vaccination card were enrolled. Time of vaccination for the third dose of DTP vaccine was calculated. Life table survival was used to calculate the proportional probability of vaccination in each time. Wilcoxon test was used for the comparison proportional probability of delayed vaccination based on studies factors. The overall median delayed time for DTP3 was 38.52 days. The Wilcoxon test showed that city, nationality, education level of parents, birth order and being in rural areas are related to the high probability of delay time for DTP3 vaccination (P < 0. 001). Moreover, child gender and parent's job were not significant factors (P > 0.05). Being away from the capital, a high concentration of immigrants in the city borders with a low socioeconomic class leads to prolonged delay in DTP vaccination time. Special attention to these areas is needed to increase the levels of parental knowledge and to facilitate access to the health services care. PMID- 26752870 TI - Polymorphisms of Transporter Associated with Antigen Presentation, Tumor Necrosis Factor-alpha and Interleukin-10 and their Implications for Protection and Susceptibility to Severe Forms of Dengue Fever in Patients in Sri Lanka. AB - CONTEXT: To date, a clear understanding of dengue disease pathogenesis remains elusive. Some infected individuals display no symptoms while others develop severe life-threatening forms of the disease. It is widely believed that host genetic factors influence dengue severity. AIMS: This study evaluates the relationship between certain polymorphisms and dengue severity in Sri Lankan patients. SETTINGS AND DESIGN: Polymorphism studies are carried out on genes for; transporter associated with antigen presentation (TAP), promoter of tumor necrosis factor-alpha (TNF-alpha), and promoter of interleukin-10 (IL-10). In other populations, TAP1 (333), TAP2 (379), TNF-alpha (-308), and IL-10 (-1082, 819, -592) have been associated with dengue and a number of different diseases. Data have not been collected previously for these polymorphisms for dengue patients in Sri Lanka. MATERIALS AND METHODS: The polymorphisms were typed by amplification refractory mutation system polymerase chain reaction in 107 dengue hemorrhagic fever (DHF) patients together with 62 healthy controls. STATISTICAL ANALYSIS USED: Pearson's Chi-square contingency table analysis with Yates' correction. RESULTS: Neither the TAP nor the IL-10 polymorphisms considered individually can define dengue disease outcome with regard to severity. However, the genotype combination, IL-10 (-592/-819/-1082) CCA/ATA was significantly associated with development of severe dengue in these patients, suggesting a risk factor to developing DHF. Also, identified is the genotype combination IL-10 ( 592/-819/-1082) ATA/ATG which suggested a possibility for protection from DHF. The TNF-alpha (-308) GG genotype was also significantly associated with severe dengue, suggesting a significant risk factor. CONCLUSIONS: The results reported here are specific to the Sri Lankan population. Comparisons with previous reports imply that data may vary from population to population. PMID- 26752873 TI - Infection Control Care Bundles Prevents Emergence of Multidrug Resistant Nosocomial Pathogens in Newborn Care Units: A Perspective. PMID- 26752874 TI - Achieving global oral health: Aim of all.... PMID- 26752875 TI - Patients awareness and attitude towards dental implants. AB - AIMS: The aim of the study was to assess the awareness of the patients regarding implant-retained prosthesis as an option for tooth replacement and the knowledge about tooth replacement as a whole including source of information and attitude towards it amongst Malaysian population. MATERIALS AND METHODS: Information on demographic characteristics, knowledge about implant as an option for missing tooth replacement, source of information and knowledge about other options of tooth replacement were obtained from patients visiting various dental outpatient departments of hospital and private dental clinics using nationwide self explanatory survey. RESULTS: Amongst the 1013 response retrieved, 27% of respondents felt moderately well informed about the dental implant treatment. Only 9% of the respondents had dental implant treatment before and 17% felt well informed about different alternatives of replacing missing teeth. The dentists were the main source of information regarding dental implant treatment modality followed by friends and electronic media. 55.6% respondents felt implant to be as good as own teeth during function whereas high cost was the major limiting factor for implant treatment. CONCLUSION: 56% of Malaysian population was aware of dental implant as an alternative for replacing missing teeth. Necessary efforts and measures should be made to raise the awareness of dental implant treatment in the country. PMID- 26752876 TI - Comparative evaluation of surface properties of enamel and different esthetic restorative materials under erosive and abrasive challenges: An in vitro study. AB - INTRODUCTION: Noncarious tooth surface loss is a normal physiological process occurring throughout the life, but it can often become a problem affecting function, esthetics or cause pain. AIM: The purpose of this study was to assess the effect of erosive and abrasive challenges on the surface microhardness and surface wear of enamel and three different restorative materials, that is, nanofilled composite, microfilled composite and resin-modified glass ionomer cement (RMGIC) by using Vickers microhardness tester and profilometer respectively. SUBJECTS AND METHODS: Nanofilled composite (Filtek(TM) Z350 * T), microfilled composite (Heliomolar((r))) and RMGIC (Fuji II LC) were used in the study. RESULTS: Nanofilled composite resin has the best resistance to erosion and/or abrasion among all the materials tested, followed by microfilled composite and RMGIC respectively. CONCLUSION: Toothbrush abrasion has a synergistic effect with erosion on substance loss of human enamel, composites, and RMGIC. The susceptibility to acid and/or toothbrush abrasion of human enamel was higher compared to restorative materials. PMID- 26752877 TI - Evaluation of esthetic component of the index of orthodontic treatment need: The orthodontists' perspective. AB - AIM OF THE STUDY: The purpose was to assess orthodontic treatment need in a subpopulation as assessed by the orthodontists. MATERIALS AND METHODS: The study was conducted on a sample population of 753 patients aged 20-25 years to assess the need for orthodontic treatment using the esthetic component (AC) of the index of orthodontic treatment need (IOTN). RESULTS: The AC revealed that 78.1% of the sample exhibited no or slight need for treatment, 13.2% demonstrated moderate to borderline need, and 8.7% proved to have a definite need for orthodontic treatment. CONCLUSIONS: The AC-IOTN can definitely be considered to be used as a powerful tool for prioritizing orthodontic triage, patient counseling, and planning desired orthodontic mechanotherapy. PMID- 26752878 TI - The prevalence of foreign bodies in jaw bones on panoramic radiography. AB - OBJECTIVE: Foreign bodies can be deposited in the oral cavity either by traumatic or iatrogenic injury. The most common foreign bodies of iatrogenic origin encountered are restorative materials, like amalgam, and root canal fillings. The aim of this study was to determine the prevalence of foreign bodies detected with panoramic radiography in the jawbones, as well as to evaluate the etiology and characteristics of these pathologies. MATERIALS AND METHODS: From March 2012 to January 2014, 11,144 panoramic radiographs were taken and retrospectively reviewed. The number, characteristics, location of the foreign bodies, age, and gender of the patients were recorded. RESULTS: Of the 11,144 patients reviewed, 62 of them have a foreign body with a frequency of 0.6%. The patients who had a foreign body were between 14 and 81 years old. Female patients showed more foreign bodies than male patients. Among the 62 patients, 63 filling materials, one stapler, and five shrapnel were detected. Only 8 patients had symptoms associated with foreign bodies and these foreign bodies excised surgically. CONCLUSION: If possible, these pathologies must be removed at the time of detection to prevent further complications; however, in asymptomatic cases, according to location and the characteristic of the foreign body, they can be kept under observation without performing any operations. PMID- 26752879 TI - Antimicrobial effect of an oxazolidinone, lantibiotic and calcium hydroxide against Enterococcus faecalis biofilm: An in vitro study. AB - AIMS: The aim was to evaluate and compare the antimicrobial efficacy of an oxazolidinone (linezolid [LZ]), lantibiotic (nisin), and calcium hydroxide against Enterococcus faecalis biofilm formed on tooth substrate after 2 and 7 days. METHODS: Single rooted human mandibular premolars were decoronated, biomechanically prepared, and vertically sectioned along the midsagittal plane to obtain a standardized tooth substrate. Standardized suspension of E. faecalis and tooth substrate was incubated for 3 weeks to allow growth of biofilm. At the end of 3 weeks, the grouping was done according to the medicament used - Group I - LZ, Group II - nisin, Group III - calcium hydroxide, Group IV - negative treatment. Disk of the medicaments used were prepared and placed upon Petri dishes along with bacterial emulsion on Mueller-Hinton agar. The zones of inhibition were checked after 2 and 7 days. STATISTICAL ANALYSIS USED: The scores were statistically analyzed using Tukey honest significant difference test and one-way analysis of variance. RESULTS: Zone of inhibition obtained with LZ was widest followed by nisin and calcium hydroxide after a period of 2 days (P < 0.001). The size of the zone of inhibition remain unchanged for LZ and nisin group after 7 days (P > 0.001) unlike calcium hydroxide group where the zone decreased (P < 0.001). CONCLUSION: LZ showed maximum antimicrobial potential against E. faecalis biofilm followed by nisin and calcium hydroxide after 2 and 7 days. The antimicrobial effect of LZ and nisin was not affected with the lapse of time, but that of calcium hydroxide significantly decreased. PMID- 26752880 TI - Predetermination of root canal lengths in molar teeth: A comparison between radiovisiography and two-dimensional and three-dimensional measurements using cone-beam computed tomography. AB - INTRODUCTION: Obtaining a correct working length is critical to the success of endodontic therapy. The aim of this clinical study was to compare the effect of working length determination using radiovisiography (RVG) and two-dimensional (2D) and three-dimensional (3D) measurements using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: Thirty mandibular teeth were taken and three groups of 10 each were made. Teeth with previous endodontic treatments, metal restorations, resorptions, incomplete apex formations, and multiple visible foramina were excluded. The root canal length was determined using RVG, CBCT measurement method 2D, and CBCT measurement method 3D. The difference between CBCT measurements, RVG, and the actual canal length were compared to evaluate the accuracy of each method. RESULTS: No significant statistically difference was seen with 3D measurements and actual measurements. Measurements with RVG were better than CBCT 2D. CONCLUSION: Under experimental conditions, CBCT 3D measurements are accurate than RVG and CBCT 2D in the determination of root canal length. PMID- 26752881 TI - Inflammatory linear verrucous epidermal nevus and regional odontodysplasia: A rare sorority. AB - Epidermal nevi are hamartomatous lesion and its association with other developmental defects particularly of the central nervous system, eye and skeletal system are well recognized. We report a rare case of inflammatory linear verrucous epidermal nevus syndrome along with regional odontodysplasia; and to the best of our knowledge this is the second case reported in the literature. PMID- 26752882 TI - The lipoma of tongue - A rare site for a tumor: Case report and review of the literature. AB - Lipoma is the most common tumor of the human body, but their presences in the oral cavity are very rare. Reported cases of lipoma of tongue in English literature are very few. Here, we report a case of lipoma of tongue in 63-year old male patient, with its clinical presentation, the histological picture, classification, and brief review of the literature. PMID- 26752883 TI - Granular cells in ameloblastoma: An enigma in diagnosis. AB - Ameloblastoma is an epithelial odontogenic tumor exhibiting diverse microscopic pattern that occurs singly or in combination with other patterns. This article describes a case of granular cell ameloblastoma (GCA) involving mandible in a 55 year-old male. The possibility of granular component is there in other odontogenic and nonodontogenic lesions. Sometimes dilemma exists in the diagnosis of such lesions. The purpose of this article is to unveil the hidden characteristics in GCA, which might help in differential diagnosis of GCA. PMID- 26752884 TI - Ulcerative sialadenitis of minor salivary gland: A short case report. AB - Minor salivary glands have an important role in the physiology and pathology of the oral cavity though they have been neglected at times. Smoking has a direct effect on the palatal minor salivary glands, and their most common presentation is stomatitis nicotina. We report a case of ulceration in the palatal salivary gland presented with intermittent heavy bleeding from the lesion. PMID- 26752885 TI - Central odontogenic fibroma of the maxilla. AB - Central odontogenic fibroma (COF) is an uncommon tumor that accounts for 0.1% of all odontogenic tumors; it has been defined as a benign neoplasm of the jaw. Clinically, the lesion grows slowly and leads to cortical expansion. Radiologically, the most common finding is multilocular radiolucency. The lesions are associated with the crown of an unerupted molar, premolar, or incisor tooth and in some cases, with root resorption or displacement. Histologically, the lesion is characterized by mature collagen fibers and numerous fibroblasts. COF responds well to surgical enucleation with no tendency for malignancy or recurrence. We report a case of a 15-year-old female patient presented with painless swelling of the left side of the maxilla since her childhood. Radiographs revealed an expanding ill-defined radiolucency with a displacement of the adjacent tooth. The impacted tooth was pushed posteriorly. The lesion was removed surgically. There were no postoperative complications. PMID- 26752886 TI - How to assist parents of children with autism spectrum disorders in rural area? PMID- 26752887 TI - Irritable bowel syndrome: What physicians should know? PMID- 26752888 TI - Epidemiological study of the prevalence of depressive disorders in primary health care in Morocco. AB - OBJECTIVE: To determine the prevalence and the impact of depressive disorders in primary health care and its associated factors. METHODOLOGY: It's a cross sectional study with 351 participants selected from Moroccan primary care facilities, aged above 18 years without chronic somatic or psychiatric disease. The participants answered a questionnaire that included demographic characteristics, the Mini International Neuropsychiatric Interview for major depressive episode (MDE), dysthymic disorder and the Global Assessment of Functioning (GAF). Statistical analysis was performed by the SPSS 13.0 software. RESULTS: The prevalence of depressive disorders in the sample was 13.7%, that of MDE was 9.1%, while dysthymic disorder was 4.3%, the rate of recurrent depressive episodes was 38.2% (6% of participants), and the prevalence of depression over a lifetime was 17.7%. The percentage of depression was higher among women than men (P = 0.01). 6.3% of depressed patients have already attempted to suicide. Analysis of GAF scores showed an average of 76.2 +/- 24, a lower score was significantly found among patients with current MDE (P = 0.001), dysthymic subjects (P = 0.001) and those who suffer from recurrent MDE (P = 0.001). Depressive disorders in univariate analysis were associated with: Female gender P = 0.01 odds ratio (OR) 2.1 (1.09-4.3), unemployment P = 0.02 OR 0.4 (0.2-0.9), and childbearing age P = 0.004 OR 3.5 (1.5-8). Adjusted OR has not demonstrated a significant association. CONCLUSION: The high prevalence of depressive disorders, suicide risk, and the alteration of the quality of life among primary health care patients in Morocco suggest the importance of identifying and treating this population. PMID- 26752889 TI - Blast overpressure induced axonal injury changes in rat brainstem and spinal cord. AB - INTRODUCTION: Blast induced neurotrauma has been the signature wound in returning soldiers from the ongoing wars in Iraq and Afghanistan. Of importance is understanding the pathomechansim(s) of blast overpressure (OP) induced axonal injury. Although several recent animal models of blast injury indicate the neuronal and axonal injury in various brain regions, animal studies related to axonal injury in the white matter (WM) tracts of cervical spinal cord are limited. OBJECTIVE: The purpose of this study was to assess the extent of axonal injury in WM tracts of cervical spinal cord in male Sprague Dawley rats subjected to a single insult of blast OP. MATERIALS AND METHODS: Sagittal brainstem sections and horizontal cervical spinal cord sections from blast and sham animals were stained by neurofilament light (NF-L) chain and beta amyloid precursor protein immunocytochemistry and observed for axonal injury changes. RESULTS: Observations from this preliminary study demonstrate axonal injury changes in the form of prominent swellings, retraction bulbs, and putative signs of membrane disruptions in the brainstem and cervical spinal cord WM tracts of rats subjected to blast OP. CONCLUSIONS: Prominent axonal injury changes following the blast OP exposure in brainstem and cervical spinal WM tracts underscores the need for careful evaluation of blast induced injury changes and associated symptoms. NF-L immunocytochemistry can be considered as an additional tool to assess the blast OP induced axonal injury. PMID- 26752890 TI - Scrub typhus meningoencephalitis, a diagnostic challenge for clinicians: A hospital based study from North-East India. AB - Central nervous system (CNS) involvement is a known complication of scrub typhus which range from mild meningitis to frank meninigoencephalitis. AIMS AND OBJECTIVES: To study the clinical feature, laboratory parameters and response to treatment of scrub typhus meningitis/meningoencephalitis. METHODS AND MATERIALS: This is a hospital based prospective observational study from North Eastern India. Diagnosis was based on clinical features and positive serological test (Weil's Felix test and IgM antibody card test). RESULTS: 13 patients of scrub typhus with features of meningitis/meningoencephalitis were included. The mean duration of fever before presentation was 5.61+/-3.08 days and 4 (30.76 %) patients had eschar. Altered sensorium, headache, seizure and meningeal sign were present in 13 (100%), 13 (100%), 6 (46.15%) and 10 (76.92%) patients respectively. Mean CSF protein, glucose and Adenosine deaminase was 152.16+/ 16.88mg/dl, 55.23+/-21.7mg/dl, and 16.98+/-7.37U/L respectively. Mean total count of CSF leukocyte and lymphocyte percentage was 46.07+/-131 cell/cumm and 98.66+/ 3.09% respectively. Tablet doxycycline with or without injection azithromycin was used and that shows good response 15.38% of patients died and all of them had multi organ dysfunction. CONCLUSION: Meningoencephalitis is a common manifestation of scrub typhus and diagnosis requires high degree of clinical suspicion which if diagnosed early and specific treatment started, patients usually recover completely with few complications. PMID- 26752891 TI - Headache in the presentation of noncephalic acute illness. AB - BACKGROUND: Headache is a frequent symptom of many systemic diseases that do not involve cranial structures. In this observational study, we assessed factors associated with headache in the acute presentation of systemic conditions in a nonsurgical emergency department (ED). METHODS: Consecutive patients, admitted to Soroka University Medical Center ED due to noncephalic illness, were prospectively surveyed using a structured questionnaire focused on the prevalence and characteristics of headache symptoms. Medical data were extracted from the patient's charts. RESULTS: Between 1 and 6/2012, 194 patients aged 64.69 +/- 19.52 years, were evaluated. Headache was reported by 83 (42.7%) patients and was more common among patients with febrile illness (77.5% vs. 22.5%, P < 0.001). Respiratory illness and level of O2 saturation were not associated with headache. Headache in the presentation of a noncephalic illness was associated with younger age (58 vs. 69, P < 0.001) and with suffering from a primary headache disorder (48.2% vs. 10.8%, P < 0.001). Headache was also associated with higher body temperature and lower platelets count. CONCLUSIONS: Headache is a common symptom in acute noncephalic conditions and was found to be associated with younger age and febrile disease on presentation. Patients who present with primary headache disorders are more prone to have headache during acute illness. Acute obstructive respiratory disease, hypercarbia or hypoxemia were not associated with headache. PMID- 26752892 TI - Immunohistochemical expression of glial fibrillary acidic protein and CAM5.2 in glial tumors and their role in differentiating glial tumors from metastatic tumors of central nervous system. AB - BACKGROUND AND OBJECTIVES: Immunohistochemistry (IHC) has become an important tool in the diagnosis of metastatic brain tumors. The judicious use of a panel of selected immunostains is unquestionably helpful in diagnostically challenging cases. In our study, the best combination of immune markers useful in differentiating metastatic carcinoma from high-grade gliomas in central nervous system (CNS) are glial fibrillary acidic protein (GFAP) and cytokeratin (CK) (CAM5.2). MATERIALS AND METHODS: The study was conducted on 80 cases of glial tumors including metastatic tumors to the CNS. Histopathological diagnosis was established on routine hematoxylin and eosin staining of the sections. Special IHC markers, GFAP, and CAM5.2 were used to differentiate glial from metastatic tumors. RESULT: Of total 80 cases, 40 cases of astrocytic tumors, 2 cases of ependymoma, 2 cases of mixed glial tumors, and 16 cases of glioblastoma multiforme were positive for GFAP. Twelve cases of oligodendroglioma were negative for GFAP. The sensitivity of GFAP in glial tumors was statistically significant as 81.1% and specificity 100%, whereas sensitivity and specificity of CAM5.2 in metastatic tumors were 100%. CONCLUSION: IHC plays an important role in diagnosing tumors of CNS and markers such as GFAP and CK (CAM5.2) are quite effective in differentiating glial tumors from metastatic tumors of CNS. PMID- 26752894 TI - Frontal sinus asymmetry: Is it an effect of cranial asymmetry? X-ray analysis of 469 normal adult human frontal sinus. AB - BACKGROUND AND AIMS: There is no study in the literature that investigates an asymmetric morphological feature of the frontal sinus (FS). MATERIALS AND METHODS: Four hundred and sixty-nine consecutive direct X-rays of FSs were analyzed for the asymmetry between the right and left sides. When an asymmetry in the height and contour of the FS existed, this difference was quantified. RESULTS: Of the 469 patients, X-rays of 402 patients (85.7%), there was an asymmetry between right and left sides of the FS. Of these 235 (50.1%) were dominant on the left side, whereas 167 (35.6%) were dominant on the right, the sinuses of remaining 67 patients (14.3%) was symmetric. STATISTICAL ANALYSIS: The comparisons between parameters were performed using Wilkinson signed rank test. The relationship between handedness and sinus asymmetry was also examined by two proportions test. There is statistically significant difference between the dominance of left and right FS. CONCLUSIONS: Hemispheric dominance may have some effect (s) of on sinus asymmetry of the human cranium. Surgeons sometimes enter the cranium through the FS and knowledge of asymmetric FS is important to minimize surgical complications. PMID- 26752893 TI - Carpal tunnel syndrome: Analyzing efficacy and utility of clinical tests and various diagnostic modalities. AB - BACKGROUND: Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy, but not adequately studied in India. OBJECTIVES: To study clinical tests, nerve conduction studies (NCS), ultrasonography (USG), and magnetic resonance imaging (MRI) in diagnosing CTS. MATERIALS AND METHODS: We diagnosed CTS in 54 patients (93 hands) out of 60 screened patients with symptoms compatible with CTS, including 19 control patients (23 hands). We conducted provocative tests and calculated Boston Carpal tunnel Questionnaire (BCTQ) symptom (S) and function (F) scores. NCS positive patients were classified into mild, mild-to-moderate, moderate, severe, and all-CTS groups. Median nerve anteroposterior, transverse, circumference (CIR), and cross-sectional area (CSA) at inlet (I), middle (M), and outlet (O) each was measured by USG in all patients. MRI was done in 26 patients (39 hands). RESULTS: Phalen, hand elevation and pressure provocation tests had higher sensitivity, Tinel's test had higher specificity and tethered median nerve and tourniquet tests had low sensitivity and moderate specificity. USG had low sensitivity but high specificity, and MRI had moderate sensitivity. USG in patients compared to controls was significantly abnormal in CSA-I, CIR-I, and CSA-O. Significant correlation was found between BCTQ-S and NCS and BCTQ-S and CIR-O. CIR-M, CIR-O, CSA-M, and CSA-I had correlation with NCS. MRI was significant in moderate and in moderate + severe groups combined and associated pathologies were detected in 59% patients. CONCLUSION: NCS remain gold standard but USG and MRI help increase sensitivity and detect mass lesions amenable to surgery. PMID- 26752895 TI - Clinico-etiological profile of childhood stroke in a Tertiary Care Hospital in Eastern India. AB - BACKGROUND: The clinical pattern and etiology of stroke may vary over time or with geographical location. In Asian countries, specific etiology and outcome of childhood stroke have been rarely reported. OBJECTIVE: To determine the clinical and etiological pattern of childhood stroke and their outcome in a Tertiary Care Center. MATERIALS AND METHODS: This study was conducted in a Tertiary Care Hospital of Kolkata over a period of 3 years. All children from 6 months to 12 years, diagnosed as childhood stroke by radio-imaging were included in our study. Children presenting with paraplegia/paraparesis were excluded. Etiologies were determined on the basis of clinical examination, related blood investigations and radio-imaging findings. Data gathered from the stroke patients were entered into a preformed proforma and appropriate statistical analyses were done. RESULT: Most commonly found clinical presentation was hemiparesis (70.6%). Next in place was a seizure (61.8%) and alteration of consciousness (58.8%). The most common etiology of childhood stroke in our hospital was found to be an intracranial infection (41.2%), followed by vascular etiology. Stroke was ischemic in nature in 91.2% of cases. Among the clinical features, vomiting, alteration of sensorium, and fever were significantly (P < 0.01) more in infectious cases of stroke, but hemiparesis was significantly (P < 0.05) more common in noninfectious etiology. Most of the cases of noninfectious etiology (95%) completely recovered without any persistent neurodeficit or mortality. CONCLUSION: Intracranial infection is the commonest etiology of stroke in pediatric patients presenting at our hospital. Commonest type is an ischemic stroke. The most of the patients completely recovered from the acute neurological insult after proper and timely management. PMID- 26752896 TI - Remaining unconscious: The burden of traumatic brain injuries in India. AB - INTRODUCTION: It is well-known that severe traumatic brain injuries (TBI) have a poor outcome. However, what is not well-known is the outcome for those who survive but remain unconscious at the time of discharge from the hospital. AIMS AND OBJECTIVES: To assess the outcome of severe TBI patients who have a motor response of M5 or lower on the Glasgow coma score (GCS) at discharge from a single centre in India. MATERIALS AND METHODS: In this retrospective study carried at one trauma centre in India, a prospectively maintained neurotrauma registry was queried from May 2010 to February 2013 for patients who had severe traumatic brain injury (GCS <= 8) at admission and had a motor response of M5 or lower on the GCS at discharge. Demographic and clinical data were analyzed, and outcome Glasgow outcome scale (GOS) assessed at 6 months using a telephonic questionnaire. OBSERVATIONS AND RESULTS: There were a total of 1525 patients with severe TBI in the study period. Of these 166 (10.9%) were unconscious (motor response M5 or lower on the GCS) at discharge from the hospital. 139 were males and 27 females with a mean age of 33.9 years. After a mean hospital stay of 24.31 days, the discharge motor score was M5 in 32 (19.3%), M4 in 44 (26.5%), M3 in 59 (35.5%), M2 in 44 (26.5%), and M1 in 9 (5.4%). Telephonic follow-up was available in 102 (61.4%) of the patients. 54 (52.9%) patients had died and 32 (31.4%) remained unconscious (vegetative) at 6 months. Only 16 patients (15.7%) had a good outcome (GOS 1-2) at 6 months following an injury. CONCLUSIONS: This is the only study of its kind on patients who remain unconscious at discharge following severe TBI and reveals that around 50% will die and another 30% remains vegetative at 6 months of discharge. Only a small percentage (15% in our study) will become conscious and partially integrated in the society. PMID- 26752898 TI - Impact of psychoeducation intervention module on parents of children with autism spectrum disorders: A preliminary study. AB - CONTEXT: Parents of children with autism spectrum disorders (ASD) in India face a host of challenges, while seeking care which ranges from unavailability of information to difficulty in availing services. AIMS: To develop a psycho education intervention module for parents of children with ASD and to study its impact on parent stress and knowledge. SETTINGS AND DESIGN: Child Guidance Clinic Department of Psychiatry, Government Medical College and Hospital, Chandigarh. Interventional study. METHODOLOGY: Parents of children diagnosed with ASD as per Diagnostic and Statistical Manual of Mental Disorders, 4(th) Edition criteria, recruited through consecutive sampling. Total number of 18 participants participated in the two phase study. Phase I included preparation of a parent training module through a four stage process and Phase II was evaluation of impact of the final version of the module on parental stress and knowledge. STATISTICAL ANALYSIS: Wilcoxon Signed-Rank test using SPSS version 17.0. RESULTS: There was an improvement in all the domains of parenting stress and knowledge. Social stress score and total stress score showed significant improvement. CONCLUSIONS: Parent psycho-education intervention module on ASD decreases parenting stress, and improves knowledge about ASD. Psycho-education intervention module is a feasible and acceptable way of parent empowerment. PMID- 26752897 TI - An estimation of the prevalence of intellectual disabilities and its association with age in rural and urban populations in India. AB - BACKGROUND: Intellectual disability (ID) is a global public health concern. Prevalence of ID and its association with age and other demographic factors is required for planning purposes in India. OBJECTIVE: This study analyzed the age adjusted prevalence of ID in rural and urban populations and its correlation with age in children and adults. MATERIALS AND METHODS: Disability data published in the report (2002) of National Sample Survey Organization were analyzed, using Z test to measure differences in age-adjusted prevalence. Spearman rho was calculated to determine strength and direction of the association, and regression analysis was used to predict prevalence rate, based on age in rural and urban population settings. RESULTS: Overall, India has a prevalence of 10.5/1000 in ID. Urban population has slightly higher rate (11/1000) than rural (10.08/1000; P = 0.044). Age was found to be highly correlated with prevalence of ID in rural children (rho =0.981, P = 0.019) as well as in children (rho = -0.954, P = 0.000) and adults (rho = -0.957, P = 0.000) in urban population. The possibility of confounding or the existence of covariates for children in urban settings was noted. CONCLUSION: Results of this study match findings in other epidemiological studies. However, multistage, large-scale studies are recommended for investigating prevalence rates with different severity levels of ID. PMID- 26752899 TI - Elevated antimeasles antibody titre: An association in autoimmune encephalitis. AB - INTRODUCTION: Autoimmune encephalitis is a group of treatable noninfective encephalitic disorders with great clinical implications. They have a close resemblance to prion disease and some slow virus infections. We report the presence of significant titers of antimeasles antibody in some of our patients with autoimmune encephalitis resulting in diagnostic and therapeutic problems. PATIENTS AND METHODS: Patients seen by us in the last 4 years with high titers (1:625 dilution) cerebrospinal fiuid (CSF) antimeasles antibody positivity were reviewed retrospectively. The data collected were assessed using SPSS- Statistical Package for Social Sciences Version 15.0 (IBM corporation) software. The groups which showed elevated antimeasles antibody titers but did not have other parameters suggestive of subacute sclerosing panencephalitis (Group 2) were segregated and compared with those who had the typical features (Group 1) using Fisher's Exact Test. RESULTS: There were 33 patients with antimeasles antibody in CSF. Group 1 had 27 and Group 2 had 6 patients. Group 1 had lower age, cognitive dysfunction, slow myoclonus, less generalized tonic-clonic seizures, and focal seizures. Group 2 patients belonged to the higher age, had significant psychosis (P = 0.02), incontinence of bowel and bladder (P = 0.0001). Slow myoclonus was significant in the first group (P = 0.028), and weakness was significant in the second group (P = 0.028) and double incontinence in the second group (P = 0.0001). Magnetic resonance imaging showed significant gray matter and cerebellar involvement in Group 2 P = 0.005 and P = 0.028, respectively. CONCLUSIONS: Patients who show significant titers of antimeasles antibodies in the CSF but belonging to older age group with psychosis, generalized tonic-clonic seizures, double incontinence, focal myoclonus, and electroencephalographic and imaging noncorroborative need to be investigated for autoimmune encephalitis in view of the great prognostic and therapeutic relevance. PMID- 26752900 TI - Estimation of cerebrospinal fluid cortisol level in tuberculous meningitis. AB - BACKGROUND: Central nervous system (CNS) involvement in tuberculosis is around 5 10%. Of the various manifestations of CNS tuberculosis, meningitis is the most common (70-80%). Delay in diagnosis and treatment results in significant morbidity and mortality. OBJECTIVE: To study the cerebrospinal fluid (CSF) cortisol levels in tubercular meningitis and compare the levels with controls. METHODS: Cross-sectional, prospective, observational, hospital-based study done in 20 patients of tubercular meningitis, 20 patients of aseptic meningitis (AM) and 25 control subjects without any preexisting neurological disorders who have undergone lumbar puncture for spinal anesthesia. RESULTS: Cortisol was detected in all 40 CSF samples of patients (100%). Mean CSF cortisol level was 8.82, 3.47 and 1.05 in tubercular meningitis, AM and controls, respectively. Mean CSF cortisol level in tubercular meningitis was significantly higher as compared to AM and controls (P < 0.0001). CONCLUSION: Cortisol level estimation in CSF is one of the rapid, relatively inexpensive diagnostic markers in early identification of tubercular meningitis along with CSF findings of elevated proteins, hypoglycorrhachia and lymphocytic pleocytosis. This aids in earlier institution of appropriate treatment and thereby decreasing morbidity and mortality. This is the first study on the estimation of CSF cortisol level in tuberculous meningitis. PMID- 26752901 TI - Benign epilepsy with centrotemporal spikes: Relationship between type of seizures and response to medication in a Greek population. AB - PURPOSE: Benign epilepsy with centrotemporal spikes (BECTS) is considered to be the most common childhood epileptic syndrome. We studied the relationship between the type of seizures and response to medication in a Greek population. MATERIALS AND METHODS: We studied 60 neurodevelopmentally normal children diagnosed with BECTS. Children were subdivided into three groups, based on type of seizures: Group A comprised 32 children with generalized tonic-clonic seizures, Group B 19 children with focal seizures and Group C 9 children with focal seizures with secondary generalization. All patients in the present study were started on an antiepileptic medication after the third seizure (sodium valproate, carbamazepine, and oxcarbazepine), and we studied the response to medication. RESULTS: 10 from 13 (76.92%) of patients in Group A, 13 from 15 (86.66%) patients in Group B, and all 6 patients (100%) in Group C started carbamazepine or oxcarbazepine had a favorable respond. Similarly, 16 from 19 (84.2%) of patients in Group A, 3 from 4 patients (75%) in Group B, and 1 from 3 patients (33.3%) in Group C, started sodium valproate responded well to medication. CONCLUSIONS: The majority of children responded well to the first antiepileptic treatment and had a favorable outcome, regardless of type of seizures. 88.3% of children became seizure free by 1 or 2 years after seizure onset. These findings are indicative that the type of seizures has no major effect neither in response to antiepileptic treatment or in the final outcome. Further research in a larger number of children is needed. PMID- 26752902 TI - Epidemiological, clinical and prognostic profile of childhood acute bacterial meningitis in a resource poor setting. AB - BACKGROUND: Childhood bacterial meningitis is a neurologic emergency that continues to kill and maims children particularly in developing countries with poor immunization coverage. OBJECTIVE: This study set out to assess the hospital incidence, pattern of presentation, etiologic agents, outcome and determinants of mortality among the children admitted with bacterial meningitis at the Wesley Guild Hospital (WGH), Ilesa. PATIENTS AND METHODS: We carried out a retrospective review of admitted cases of bacterial meningitis in children aged one month to 15 years at the WGH, Ilesa over a three year period by looking at the hospital records. Factors in the history and examinations were compared among survivors and those that died to determine factors significantly associated with mortality in these children. RESULTS: Eighty-one (5.5%) of the 1470 childhood admissions during the study period had bacterial meningitis. Male preponderance was observed and two-thirds of the children were infants. More cases were admitted during the wet rainy season than during the dry harmattan season. Haemophilus influenzae type B and Streptococcus pneumoniae were the leading etiologic agents and ciprofloxacin and ceftriaxone adequately cover for these organisms. Twenty-two (27.2%) of the 81 children died, while 34 (42.0%) survived with neurologic deficits. Children with multiple seizures, coma, neck retraction, hyponatremia, hypoglycorrhachia, turbid CSF as well as Gram positive meningitis at presentation were found to more likely to die (P < 0.05). None of these factors however independently predict mortality. CONCLUSION: Childhood bacterial meningitis often results in death and neurologic deficit among infants and young children admitted at the WGH, Ilesa. Children diagnosed with meningitis who in addition had multiple seizures, neck retraction and coma at presentation are at increased risk of dying. PMID- 26752903 TI - Stroke outcome after domiciliary use of opioids in the peri-stroke period. AB - BACKGROUND: Stroke affects large number of people worldwide resulting in disability. The people in the northern region of India follow some domiciliary practices, which include administration of opioids at the onset of stroke to retard its progression. AIM: To study the effect of opioids on the outcome and severity of stroke when used as domiciliary treatment in peri-stroke period. MATERIALS AND METHODS: A prospective, observational study on stroke patients was carried out in Department of Neurology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India from March 2012 to March 2013. Data were collected in a semi-structured proforma. The variables which were studied included socio demographic characteristics such as age, gender, religion, socio-economic status, and place of inhabitation. The time of opioid administration, approximate amount administered, frequency of administration, duration of hospital stay, risk factors and co-morbid conditions were also studied. The stroke severity was analyzed by comparing National Institutes of Health Stroke Scale (NIHSS) score and outcome by comparing Modified Rankin Scale (MRS) score in both the groups at the time of admission and at the time of discharge. RESULTS: Out of n = 100 recruited patients, n = 44 (Group A) reported opioid intake in the peri-stroke period and n = 56 (Group B) did not. Proportions of patients from rural areas were 61.4% in Group A and 37.5% in Group B. Mean age in groups A and B was 63 +/- 9.15 and 59.8 +/- 13.87 years, respectively; in these groups male proportions were 70.5% and 60.7%, respectively. At admission, mean NIHSS scores in Groups A and B were 10.0 +/- 4.48 and 10.8 +/- 4.51, respectively; on discharge, these scores were 6.3 +/- 3.83 and 7.7 +/- 3.79, respectively. At admission, mean MRS scores in Groups A and B were 3.7 +/- 1.14 and 3.8 +/- 1.32, respectively; upon discharge, these scores were 2.8 +/- 1.18, 3.1 +/- 1.23 respectively. CONCLUSION: In this cohort, we found that the domiciliary practice of opioids administration in the peri-stroke period is more common among the elderly and in the rural areas. There was no statistically significant difference in the mean NIHSS and MRS scores at admission as well as discharge implying that the opioid administration did not improve outcome or decrease the severity of the stroke. Our findings are robust enough to propose a larger sample size and follow-up in future studies to definitively ascertain the effect of opioids as pretreatment in stroke patients. PMID- 26752906 TI - Commentary. PMID- 26752907 TI - Remote multiple intracranial hemorrhage in multiple metastatic lung adenocarcinoma following decompression of posterior fossa lesion: Unknown cause. AB - Cerebral metastasis can present with hemorrhage. However, multiple hemorrhages in metastatic lesions following surgical decompression of a single lesion are never reported. We report a case of cerebral metastasis from lung cancer that developed multiple hemorrhages in supratentorial metastatic lesions following surgical resection of an infratentorial lesion. PMID- 26752905 TI - A pure non-gestational ovarian choriocarcinoma with delayed solitary brain metastases: Case report and review of the literature. AB - Choriocarcinoma is the most malignant tumour of gestational trophoblastic origin. Most ovarian choriocarcinomas are gestational in origin and usually metastasize to the ovary from uterine or tubal choriocarcinoma. Non gestational choriocarcinoma (NGOC) of the ovary is exceedingly rare and usually seen along with other germ cell tumors. Non gestational choriocarcinoma has been found to be resistant to single-agent chemotherapy and has a worse prognosis than gestational choriocarcinoma. We are reporting long term follow up of published rare case of pure non gestational ovarian choriocarcinoma (NGOC) with concurrent metastases to the spleen and adrenal glands, who developed a delayed solitary brain metastases, two years after completion of primary treatment. Surgery along with triple agent chemotherapy and radiotherapy was found to give good remission in this aggressive disease. PMID- 26752908 TI - Sertraline induced acute mandibular dystonia. AB - Specific serotonin reuptake inhibitors have been linked with the occurrence of drug-induced parkinsonism, dystonia, dyskinesia, and akathisia. Here, we describe a patient with a diagnosis of emotionally unstable personality disorder and depression who developed severe mandibular dystonia with sertraline in the absence of concurrent prescription of medications, which have potential action on the dopaminergic system. This case highlights the need for clinicians to be aware of this alarming acute adverse effect with sertraline, which is conventionally considered to be well-tolerated and safe. PMID- 26752909 TI - Mononeuritis multiplex in acquired amegakaryocytic thrombocytopenia. AB - Mononeuritis multiplex involves inflammation of two or more nerves, typically in unrelated parts of the body. It has been well described in bleeding disorders like idiopathic thrombocytopenic purpura (ITP) and Hemophilia. Acquired amegakaryocytic thrombocytopenia (AAT) is a bleeding diathesis characterized by thrombocytopenia but with reduced number of megakaryocytes in the bone marrow, as against ITP. Though AAT is a well described entity, peripheral nervous system manifestations have not been described so far. We report a young man who has presented with bleeding diathesis and mononeuritis multiplex due to AAT. The mechanism of development of mononeuritis multiplex and treatment options are discussed. PMID- 26752904 TI - Irritable bowel syndrome: Is it "irritable brain" or "irritable bowel"? AB - Irritable bowel syndrome (IBS) has been recognized as one of the most common and best studied disorders among the group of functional gastrointestinal disorders. It is a functional bowel disorder in which abdominal pain or discomfort is associated with defecation or a change in bowel habit. In the Western world, IBS appears to affect up to 20% of the population at any given time but in Asian countries, the median value of IBS prevalence defined by various criteria ranges between 6.5% and 10.1%, and community prevalence of 4% is found in North India. Those attending gastroenterology clinics represent only the tip of the iceberg. The disorder substantially impairs the quality of life, and the overall health care costs are high. IBS has therefore gained increased attention from clinicians, researchers, and pharmaceutical industries. It is often frustrating to both patients and physicians as the disease is usually chronic in nature and difficult to treat. However, the understanding of IBS has been changing from time to time and still most of its concepts are unknown. In this review we have discussed, debated, and synthesized the evidence base, focusing on underlying mechanisms in the brain and bowel. We conclude that it is both brain and bowel mechanisms that are responsible. The clinical implication of such mechanisms is discussed. PMID- 26752910 TI - Corneomandibular reflex: Anatomical basis. AB - Corneomandibular reflex is a pathological phenomenon evident in cases of severe brainstem damage. It is considered to be a pathological exteroceptive reflex, associated with precentro bulbar tract lesions. The sign is useful in distinguishing central neurological injuries to metabolic disorders in acutely comatose patients, localizing lesions to the upper brainstem area, determining the depth of coma and its evolution, providing evidence of uncal or transtentorial herniation in acute cerebral hemisphere lesions, and it is a marker of supraspinal level impairment in amyotrophic lateral sclerosis and multiple sclerosis. This sign was evident in a patient with severe brain damage. We discuss the literature findings and its relevance in prognosis establishment. PMID- 26752911 TI - Tetraventricular central neurocytoma: A rare presentation with imaging-pathologic correlation. AB - Central neurocytoma (CN) is a benign intraventricular neuronal tumor with a favorable prognosis. It accounts approximately 0.25-0.5% of intracranial tumors. In this report, we describe a very rare case of tetraventricular CN with imaging pathologic correlation, and discuss their atypical features in a location together with treatment options. A 27-year-old man was admitted to the hospital with symptoms of progressive headaches of several months' duration. Magnetic resonance imaging of the brain revealed a well-circumscribed, lobulated intraventricular mass with numerous intratumoral cystlike areas. The mass was located in the enlarged lateral ventricles bilaterally extending to the third and the fourth ventricle. Surgical removal of the 4(th) ventricle component of the tumor was performed. Histomorphological and immunohistochemical findings of the tumor were consistent with CN. After pathological diagnosis, gamma knife surgery was performed. CN may present with atypical features in a location with a usual histopathological findings. To our knowledge, we described the third case of tetraventricular CN, which was partially treated with both surgical resection and radiosurgery. PMID- 26752912 TI - Postpartum pituitary apoplexy with isolated oculomotor nerve palsy: A rare medical emergency. AB - Pituitary apoplexy is a clinical syndrome characterized by sudden onset headache, visual deficits, ophthalmoplegia, altered mental status, and hormonal dysfunction due to an expanding mass within the sella turcica resulting from hemorrhage or infarction of pituitary gland. We report a case of pituitary apoplexy that developed in postpartum period following postpartum hemorrhage and presented with isolated third cranial nerve palsy. PMID- 26752913 TI - Hot water epilepsy: A form of reflex epilepsy - from infancy to adolescence. AB - Hot water epilepsy (HWE) is a type of reflex epilepsy which occurs when hot water is poured over the head. Most cases have been reported from Southern India. Genetic, cultural, and geographical factors can be responsible for HWE. HWE can be treated by clobazam 1-2 h prior to take a bath rather than continuous anti epileptic therapy. Medication prior to bathing may be useful in treating older children, eliminating the need to be accompanied by an adult during bathing. It can also be treated by reducing the temperature of the water used for bathing. Here, we report three cases of HWE in varying age groups. PMID- 26752914 TI - The changing profile of infantile tremor syndrome in hilly terrain of India. AB - BACKGROUND: Infantile tremor syndrome (ITS) is characterized by anemia, skin pigmentation, tremors, physical, and mental regression without a defined etiopathogenesis and low incidence. MATERIALS AND METHODS: We have studied 9 patients over 1 year for the changing clinical and laboratory variables of patients with ITS. Neuroregression and anemia were presented in all followed by tremors in 5 and hypotonia in 2. RESULT: Sepsis screen was positive in 6 and urine cultures in 2. Antibiotics were required in 6. ITS with changing parameters still significantly contributes to healthcare burden. CONCLUSION: It is important to screen for urinary infection and septicemia to avoid antibiotic abuse. PMID- 26752916 TI - Commentary. PMID- 26752917 TI - Public health strategies to ensure reduction in suicide incidence in middle and low income nations. AB - Worldwide, the incidence of suicide has increased at an alarming rate and in the year 2012 close to 1 million people died because of suicide. Although, it is a well-acknowledged fact that suicides are completely preventable, the public health authorities have failed to halt the rising trend of the suicide because of the presence of various social and health related factors. As suicide is a complex issue, in the low and middle-income nations, the most cost-effective approach is to ensure the integration of suicide prevention program into the primary health care network. To conclude, suicide is an important public health concern which is definitively preventable. However, the need of the hour is that all the stakeholders should take collective responsibility, and work in collaboration to develop and implement a comprehensive multi-sectoral suicide prevention strategy. PMID- 26752915 TI - Clinicoepidemiological profile of cerebral venous thrombosis in Algarve, Portugal: A retrospective observational study. AB - BACKGROUND: Cerebral venous thrombosis (CVT) is a very uncommon disorder with a wide variety of clinical manifestations. There are few studies describing the clinical and epidemiological profile of CVT in peripheral or rural areas. Over the last decades, the frequency in which this disease is diagnosed has increased due to greater awareness and availability of noninvasive diagnostic techniques. MATERIALS AND METHODS: A hospital-based retrospective case review of adult (>=15 years) patients with CVT between 2001 and 2012 is described. 31 patients with confirmed imagiological diagnosis of CVT were included. STATISTICAL ANALYSIS USED: Statistical analysis was performed using R version 2.15.2. Incidence rate was computed as number of new cases by time. Confidence interval (CI) was set at 95% and P < 0.05 was considered significant. RESULTS: The average annual incidence was 0.84 (CI: 0.58-1.18) to 0.73 (CI: 0.5-1.02) per 100 000 cases for adult population. There were 23 (74%) women and 8 (26%) men. Predominant initial manifestations were headache, followed by altered mental status and seizures. Median diagnostic delay from onset of illness was 8 days. All patients were treated with unfractionated heparin or low-molecular heparin followed by warfarin. Complete recovery occurred in the majority of cases 22 (78.6%) but two patients died during hospitalization. CONCLUSIONS: Albeit with some particularities, the epidemiology and clinical manifestations we found are comparable to what has been reported in western studies. PMID- 26752918 TI - Commentary. PMID- 26752919 TI - Conceptual advantages of using pupil to limbus ratio over absolute pupil diameter. PMID- 26752921 TI - Commentary. PMID- 26752920 TI - Necessity of globally implementing the comprehensive mental health action plan: World Health Organization. PMID- 26752922 TI - Spontaneous intracystic hemorrhage complicating an intracranial arachnoid cyst. PMID- 26752923 TI - Bilateral Facial Palsy a rare presenting symptom of acute lymphoblastic leukemia with CNS and BM Relapses. PMID- 26752924 TI - Better assessment systems will engender better study habits. PMID- 26752925 TI - Schwannoma of the greater occipital nerve: An uncommon cause of occipital neuralgia. PMID- 26752926 TI - Trans-ciliary minimally invasive keyhole craniotomy for skull base and vascular lesions. PMID- 26752927 TI - A lobe-specific lymphadenectomy protocol for solitary pulmonary nodules in non small cell lung cancer. AB - BACKGROUND: We want to establish a lobe-specific mediastinal lymphadenectomy protocol for solitary pulmonary nodules (SPNs) in non-small cell lung cancer (NSCLC). METHODS: We retrospectively analyzed 401 patients with pathological diagnoses of NSCLC who underwent lobectomy, bilobectomy, or pneumonectomy with systematic lymphadenectomy from March 2004 to June 2011 in our hospital. All of the patients enrolled had a SPN preoperatively. Information about the primary tumor location, lymph node metastasis, and other baseline data were collected. Stepwise logistic regression was used to identify the key factors indicating non regional mediastinal lymph node metastases (NRM). RESULTS: Of the primary tumors, 117, 39, 74, 104, and 67 were in the right upper lung (RUL), right middle lung (RML), right lower lung (RLL), left upper lung (LUL), and left lower lung (LLL), respectively. Stepwise regression showed that #2,4, #10,11, and #10,11 as well as #7 was the key lymph node station for RUL, LUL, and lower lobes: #2,4 [odds ratio (OR)=28.000, 95% confidence interval (CI): 2.917-268.790, P=0.004] for RUL, #10,11 (OR=31.667, 95% CI: 2.502-400.833, P=0.008) for LUL, #10,11 (OR=19.540, 95% CI: 4.217-90.541, P<0.001) and #7 (OR=7.395, 95% CI: 1.586-34.484, P=0.011) for lower lobes, respectively. Patients with tumors >2 cm rarely had NRM without primary regional mediastinal involvement. CONCLUSIONS: With rigid consideration, a lobe-specific lymphadenectomy is feasible in practice. This protocol can be used when the lobe-specific key nodes are negative in intraoperative frozen sections, especially for NSCLC diagnosed as SPN <2 cm preoperatively. PMID- 26752928 TI - Breast-conserving therapy and modified radical mastectomy for primary breast carcinoma: a matched comparative study. AB - BACKGROUND: To compare two types of therapy for primary breast carcinoma, breast conserving therapy (BCT) and modified radical mastectomy (MRM), in a matched cohort study. METHODS: A series of 1,746 patients with primary breast cancer treated with BCT or MRM in a single Chinese institute between January 2000 and February 2009 were analyzed retrospectively to compare their outcomes with respect to the incidence of local recurrence (LR), distant metastasis, and survival. The patients were matched with regard to age at diagnosis, spreading to axillary lymph nodes, hormone receptor status, the use of neoadjuvant chemotherapy and maximal tumor diameter. The match ratio was 1:1, and each arm included 873 patients. RESULTS: The median follow-up period was 71 months. The 6 year disease-free survival (DFS) and 6-year distant disease-free survival (DDFS) rates differed significantly between two groups. The 6-year local recurrence-free survival (LRFS) rates were 98.2% [95% confidence interval (CI): 0.973-0.989] in the BCT group and 98.7% (95% CI: 0.980-0.994) in the MRM group (P=0.182), respectively. DFS rates in BCT and MRM groups were 91.3% (95% CI: 0.894-0.932) and 86.3% (95% CI: 0.840-0.886) (P<0.001), respectively, whereas the DDFS rates in BCT and MRM groups were 93.6% (95% CI: 0.922-0.950) and 87.7% (95% CI: 0.854 0.900) (P<0.001), respectively. CONCLUSIONS: BCT in eligible patients is as effective as MRM with respect to local tumor control, DFS and DDFS, and may result in a better outcome than MRM in Chinese primary breast cancer patients. PMID- 26752930 TI - Incidence and mortality rate of esophageal cancer has decreased during past 40 years in Hebei Province, China. AB - BACKGROUND: Hebei province is located in North of China with of approximately 6% of whole national population. It is known as a high-risk area for esophageal cancer in China and worldwide. The aim of our study was to estimate the esophageal cancer burden and trend in Hebei Province. METHODS: Eight cancer registries in Hebei Province submitted cancer registry data to the Hebei Provincial Cancer Registry Center. All data were qualified and compiled for cancer statistics in 2011. The pooled data were stratified by gender and age group (0, 1-4, 5-9, 10-14...80+). Incidence and mortality rates were age standardized to World Segi's population standard and expressed per 100,000 persons. In addition, proportions and cumulative incidence/mortality rates for esophageal cancer were calculated. Esophageal cancer mortality data during the periods 1973-1975, 1990-1992, and 2004-2005 were extracted from the national death surveys. Mortality and incidence rate data from Cixian and Shexian were obtained from population-based cancer registries in each county. RESULTS: The estimated number of newly diagnosed esophageal cancer cases and deaths in 2011 in Hebei Province was 24,318 and 18,226, respectively. The crude incidence rate of esophageal cancer was 33.37/100,000 (males, 42.18/100,000 and females, 24.31/100,000). The age-standardized rate by world standard population (ASRW) was 28.09/100,000, ranking third among all cancers. The esophageal cancer mortality rate was 25.01/100,000 (males, 31.40/100,000 and females, 18.45/100,000), ranking third in deaths among all cancers. The mortality rates of esophageal cancer displayed a significant decreasing trend in Hebei Province from 1973-1975 (ASRW =48.69/100,000) to 2004-2005 (ASRW =28.02/100,000), with a decreased rate of 42.45%. In Cixian, the incidence of esophageal cancer decreased from 250.76/100,000 to 106.74/100,000 in males and from 153.86/100,000 to 75.41/100,000 in females, with annual percentage changes (APC) of 2.13 and 2.16, while the mortality rates declined with an APC of 2.46 for males and 3.10 for females from 1988 to 2011. In Shexian, the incidence rate decreased from 116.90/100,000 to 74.12/100,000 in males and from 46.98/100,000 to 40.64/100,000 in females, while the mortality rates declined, with an APC of 4.89 in males from 2003 to 2011. CONCLUSIONS: Although the incidence and mortality rates of esophageal cancer remain high, an obvious decreasing trend has been observed in Hebei Province, as well as in high-risk regions, such as Cixian and Shexian, over the past 40 years. PMID- 26752929 TI - Association between HER2 status and response to neoadjuvant anthracycline followed by paclitaxel plus carboplatin chemotherapy without trastuzumab in breast cancer. AB - BACKGROUND: We recently showed HER2-positive breast cancers are less likely to respond to neoadjuvant anthracycline chemotherapy. Here, we investigated whether HER2-positive breast cancers responded to sequential neoadjuvant anthracycline followed by paclitaxel plus carboplatin regimen in the absence of trastuzumab. METHODS: Women (n=372) with operable primary breast cancer initially received two cycles of neoadjuvant anthracyclines, the clinical tumor response was assessed, then patients were received four cycles of paclitaxel plus carboplatin regimen. All the patients did not received trastuzumab treatment in the neoadjuvant setting. HER2 status was determined by immunohistochemistry and/or by fluorescence in situ hybridization in core-biopsy breast cancer tissue obtained before the neoadjuvant chemotherapy. RESULTS: Eighteen percent (67/372) of patients achieved a pathologic complete response (pCR) in their breast. HER2 positive tumors had a significant higher pCR rate than HER2-negative tumors (33.0% versus 13.5%, P<0.001) in this cohort of 372 patients, and positive HER2 status remained an independent favorable predictor of pCR in a multivariate analysis [odds ratio (OR), 2.26; 95% confidence interval (CI), 1.18 to 4.36, P=0.015]. Furthermore, patients who responded to initial anthracycline regimens were more likely to respond to paclitaxel plus carboplatin than patients who did not (pCR, 27.2% versus 14.6%, P=0.005). Patients with HER2-positive tumors exhibited a significant higher pCR rate than did patients with HER2-negative tumors in both anthracycline response group (40.5% versus 20.0%, P=0.025) and anthracycline non-response group (28.3% versus 11.3%, P=0.002). CONCLUSIONS: Under the circumstance of no trastuzumab treatment, women with HER2-positive cancers derive a large benefit from paclitaxel-carboplatin-based neoadjuvant chemotherapy. PMID- 26752931 TI - Nomogram for predicting lymph node metastasis rate of submucosal gastric cancer by analyzing clinicopathological characteristics associated with lymph node metastasis. AB - BACKGROUND: To combine clinicopathological characteristics associated with lymph node metastasis for submucosal gastric cancer into a nomogram. METHODS: We retrospectively analyzed 262 patients with submucosal gastric cancer who underwent D2 gastrectomy between 1996 and 2012. The relationship between lymph node metastasis and clinicopathological features was statistically analyzed. With multivariate logistic regression analysis, we made a nomogram to predict the possibility of lymph node metastasis. Receiver operating characteristic (ROC) analysis was also performed to assess the predictive value of the model. Discrimination and calibration were performed using internal validation. RESULTS: A total number of 48 (18.3%) patients with submucosal gastric cancer have pathologically lymph node metastasis. For submucosal gastric carcinoma, lymph node metastasis was associated with age, tumor location, macroscopic type, size, differentiation, histology, the existence of ulcer and lymphovascular invasion in univariate analysis (all P<0.05). The multivariate logistic regression analysis identified that age <=50 years old, macroscopic type III or mixed, undifferentiated type, and presence of lymphovascular invasion were independent risk factors of lymph node metastasis in submucosal gastric cancer (all P<0.05). We constructed a predicting nomogram with all these factors for lymph node metastasis in submucosal gastric cancer with good discrimination [area under the curve (AUC) =0.844]. Internal validation demonstrated a good discrimination power that the actual probability corresponds closely with the predicted probability. CONCLUSIONS: We developed a nomogram to predict the rate of lymph node metastasis for submucosal gastric cancer. With good discrimination and internal validation, the nomogram improved individualized predictions for assisting clinicians to make appropriated treatment decision for submucosal gastric cancer patients. PMID- 26752932 TI - Positive impact of adding No.14v lymph node to D2 dissection on survival for distal gastric cancer patients after surgery with curative intent. AB - BACKGROUND: D2 lymphadenectomy has been increasingly regarded as standard surgical procedure for advanced gastric cancer (GC), while the necessity of No.14v lymph node (14v) dissection for distal GC is still controversial. METHODS: A total of 920 distal GC patients receiving at least a D2 lymph node dissection in Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital were enrolled in this study, of whom, 243 patients also had the 14v dissected. Other 677 patients without 14v dissection were used for comparison. RESULTS: Forty-five (18.5%) patients had 14v metastasis. There was no significant difference in 3-year overall survival (OS) rate between patients with and without 14v dissection. Following stratified analysis, in TNM stages I, II, IIIa and IV, 14v dissection did not affect 3-year OS; in contrast, patients with 14v dissection had a significant higher 3-year OS than those without in TNM stages IIIb and IIIc. In multivariate analysis, 14v dissection was found to be an independent prognostic factor for GC patients with TNM stage IIIb/IIIc disease [hazard ratio (HR), 1.568; 95% confidence interval (CI): 1.186-2.072; P=0.002]. GC patients with 14v dissection had a significant lower locoregional, especially lymph node, recurrence rate than those without 14v dissection (11.7% vs. 21.1%, P=0.035). CONCLUSIONS: Adding 14v to D2 lymphadenectomy may be associated with improved 3-year OS for distal GC staged TNM IIIb/IIIc. PMID- 26752934 TI - Immune responses of dendritic cells combined with tumor-derived autophagosome vaccine on hepatocellular carcinoma. AB - BACKGROUND: To induce and collect tumor-derived autophagosomes (DRibbles) from tumor cells as an antitumor vaccine by inhibiting the functions of proteasomes and lysosomes. METHODS: Dendritic cells (DCs) generated from peripheral blood mononuclear cell (PBMC) of hepatocellular carcinoma (HCC) patients were cocultured with DRibbles, and then surface molecules of DCs, as well as surface molecules on DCs, were determined by flow cytometry. Meanwhile, immune responses of the DCs-DRibbles were examined by mixed lymphocyte reactions. RESULTS: DRibbles significantly induced the expression of CD80, CD83, CD86 and HLA-DR on DCs. The enzyme-linked immunosorbnent assay (ELISA) showed that IFN-gamma levels after vaccination increased than before in most patients, but CD8+ proportion of PBMC increased only in nine patients. Higher levels of IFN-gamma were detected in the CD8+ cells than CD4+ T cells. These results suggested that DCs-DRibbles vaccine could induce antigen-specific cellular immune response on HCC and could prime strong CD8+ T cell responses, supporting it as a tumor vaccine candidate. CONCLUSIONS: Our results demonstrate that HCC/DRibbles-pulsed DCs immunotherapy might be deployed as an effective antitumor vaccine for HCC immunotherapy in clinical trials. PMID- 26752933 TI - Fluorouracil-based preoperative chemoradiotherapy with or without oxaliplatin for stage II/III rectal cancer: a 3-year follow-up study. AB - BACKGROUND: Fluorouracil-based preoperative chemoradiotherapy has become the standard treatment for stage II/III rectal cancer. In order to improve the overall survival (OS) and disease-free survival (DFS), we added oxaliplatin to the standard treatment, and compared the effectiveness of these two treatment patterns. METHODS: A total of 206 patients enrolled in the prospective study had histologically confirmed rectal cancer of clinical stage II/III during July 2007 to July 2010. They were randomized into the experimental group received oxaliplatin and capecitabine in combination with radiotherapy, and the control group received capecitabine in combination with radiotherapy. All patients received surgery in 6-10 weeks after chemoradiotherapy and adjuvant chemotherapy with mFOLFOX6. The primary endpoints were DFS and OS, and the secondary endpoints included toxicity, compliance, and histopathological response. RESULTS: The 3 year OS in the experimental group and the control group was 90.29% vs. 86.41% (P>0.05), and the 3-year DFS was 80.58% vs. 69.90% (P>0.05). The pathological complete remission (pCR) rates were 23.30% and 19.42%, respectively (P=0.497). The 3-year local recurrence rates were 4.85% vs. 5.83% (P=0.694), and the 3-year distant metastasis rates were 16.50% and 28.16%, respectively (P=0.045). There were no significant differences in most grade 3-4 toxicities between two groups, however, grade 3-4 diarrhea occurred in 16.50% (17/103) of the experimental group, compared with 6.80% (7/103) of the control group (P=0.030). Also, the total grade 3-4 acute toxicity showed a significant difference (10.68% vs. 21.36%, P=0.037). CONCLUSIONS: The experimental treatment did not lead significantly improved OS and DFS, and thus longer follow-up is warranted for our patient cohort. Adding oxaliplatin to capecitabine-based preoperative chemoradiotherapy can significantly reduce metastasis, but has only minimal impact on local recurrence. Although grade 3-4 toxicity rate increased (primarily gastrointestinal toxicity), patients can stand to be followed up with allopathic treatment. PMID- 26752935 TI - Outcomes of robotic surgery for pancreatic ductal adenocarcinoma. AB - BACKGROUND: To explore the effectiveness, safety, and efficacy of the robot assisted surgery in the radical resection of pancreatic ductal adenocarcinoma (PDAC). METHODS: The clinical data of 72 patients with PDAC who underwent radical resection using the da Vinci Surgical System from April 2010 to December 2014 were retrospectively analyzed. RESULTS: Among these 72 patients, three were converted to conventional laparotomy due to the vascular invasion or due to the difficulties in tissue isolation from the surrounding organs. Among 39 patients who underwent the pancreatoduodenectomy, the average operative time was 395.3+/ 118.8 min, and the mean intra-operative blood loss was 447.3+/-269.9 mL. Among 31 patients who underwent the distal pancreatectomy (DP), the average operative time was 185.5+/-74.1 min, and the mean intra-operative blood loss was 267.1+/-305.3 mL. In two patients who received the middle pancreatectomy (MP), the average operative time was 225 min and mean intra-operative blood loss was 100 mL. Among all the 72 patients, an average of 4.2+/-2.6 lymph nodes were dissected, with an average hospital stay of 22.6+/-10.7 days. Complications were observed in 18 patients, which included pancreatic fistula (n=11), bile leak (n=5), anastomotic bleeding (n=2), pancreatic fistula complicated with portal vein thrombosis (n=1), and anastomotic bleeding complicated with acute renal failure (n=1). Except that one patient died due to post-operative bleeding and acute renal failure, all the other patients were cured after conservative treatment. These 72 patients were followed for 1-45 (15.6+/-5.8) months, during which 10 patients died. Eleven patients suffered from recurrence or metastasis, among which 6 had local recurrence, 4 had liver metastasis, and 1 had ascites accompnaied with incision site tumor metastasis. CONCLUSIONS: Radical resection of PDAC by robotic surgical system is safe and feasible. It has less surgical trauma and enables faster post operative recovery, and therefore can achieve the lymph node dissection scope and tumor resection margin required by the standards of radical resection for pancreatic cancer. Nevertheless, its long-term efficacy requires further validation. PMID- 26752937 TI - Early screening of lung cancers: an effort arduous but worthwhile. PMID- 26752936 TI - Novel imaging biomarkers of response to transcatheter arterial chemoembolization in hepatocellular carcinoma patients. PMID- 26752940 TI - Scalable Influence Estimation in Continuous-Time Diffusion Networks. AB - If a piece of information is released from a media site, can we predict whether it may spread to one million web pages, in a month ? This influence estimation problem is very challenging since both the time-sensitive nature of the task and the requirement of scalability need to be addressed simultaneously. In this paper, we propose a randomized algorithm for influence estimation in continuous time diffusion networks. Our algorithm can estimate the influence of every node in a network with |V| nodes and |epsilon| edges to an accuracy of epsilon using n = O(1/epsilon2) randomizations and up to logarithmic factors O(n|epsilon|+n|V|) computations. When used as a subroutine in a greedy influence maximization approach, our proposed algorithm is guaranteed to find a set of C nodes with the influence of at least (1 - 1/e) OPT - 2Cepsilon , where OPT is the optimal value. Experiments on both synthetic and real-world data show that the proposed algorithm can easily scale up to networks of millions of nodes while significantly improves over previous state-of-the-arts in terms of the accuracy of the estimated influence and the quality of the selected nodes in maximizing the influence. PMID- 26752939 TI - Understanding Resilience and Other Trajectories of Psychological Distress: a Mixed-Methods Study of Low-Income Mothers Who Survived Hurricane Katrina. AB - Recent longitudinal studies in the aftermath of natural disasters have shown that resilience, defined as a trajectory of consistently low symptoms, is the modal experience, although other trajectories representing adverse responses, including chronic or delayed symptom elevations, occur in a substantial minority of survivors. Although these studies have provided insight into the prototypical patterns of postdisaster mental health, the factors that account for these patterns remain unclear. In the current analysis, we aimed to fill this gap through a mixed-methods study of female participants in the Resilience in Survivors of Katrina (RISK) study. Latent class growth analysis identified six trajectories of psychological distress in the quantitative sample (n=386). Qualitative analysis of in-depth interviews with 54 participants identified predisaster, disaster-related and postdisaster experiences that could account for the trends in the quantitative data. In particular, preexisting and gains in psychosocial resources (e.g., emotion regulation, religiosity) and positive postdisaster impacts (e.g., greater neighborhood satisfaction, improved employment opportunities) were found to underlie resilience and other positive mental health outcomes. Conversely, experiences of childhood trauma, and pre and postdisaster stressors (e.g., difficulties in intimate partner relationships) were common among participants in trajectories representing adverse psychological responses. Illustrative case studies that exemplify each trajectory are presented. The results demonstrate the utility of mixed-methods analysis to provide a richer picture of processes underlying postdisaster mental health. PMID- 26752938 TI - Hurricane Katrina: Maternal Depression Trajectories and Child Outcomes. AB - BACKGROUND: The authors examined depression trajectories over two years among mothers exposed to Hurricane Katrina. Risk and protective factors for depression trajectories, as well as associations with child outcomes were analyzed. METHOD: This study included 283 mothers (age at time 1, M = 39.20 years, SD = 7.21; 62% African American). Mothers were assessed at four time points over two years following Hurricane Katrina. Mothers reported posttraumatic stress symptoms, hurricane exposure, traumatic life events, and social support at time 1. Depressive symptoms were modeled at times 2, 3, and 4. Youth reported their distress symptoms (posttraumatic stress, depression, and anxiety) at time 4. RESULTS: Latent class growth analyses identified three maternal depression trajectories among mothers exposed to Hurricane Katrina: low (61%), resilient (29%), and chronic (10%). Social support was identified as a protective factor among mothers. CONCLUSIONS: Three main trajectories of maternal depression following Hurricane Katrina were identified. Social support was protective for mothers. Identified trajectories were not associated with children's distress outcomes. These results have implications for disaster responses, screening efforts, and interventions targeted towards families. Future studies warrant the investigation of additional risk and protective factors that can affect maternal and child outcomes. PMID- 26752942 TI - A Message-Passing Algorithm for Wireless Network Scheduling. AB - We consider scheduling in wireless networks and formulate it as Maximum Weighted Independent Set (MWIS) problem on a "conflict" graph that captures interference among simultaneous transmissions. We propose a novel, low-complexity, and fully distributed algorithm that yields high-quality feasible solutions. Our proposed algorithm consists of two phases, each of which requires only local information and is based on message-passing. The first phase solves a relaxation of the MWIS problem using a gradient projection method. The relaxation we consider is tighter than the simple linear programming relaxation and incorporates constraints on all cliques in the graph. The second phase of the algorithm starts from the solution of the relaxation and constructs a feasible solution to the MWIS problem. We show that our algorithm always outputs an optimal solution to the MWIS problem for perfect graphs. Simulation results compare our policies against Carrier Sense Multiple Access (CSMA) and other alternatives and show excellent performance. PMID- 26752943 TI - Nonlinear, Nonhomogeneous Periodic Problems with no Growth Control on the Reaction. AB - We consider a nonlinear periodic problem driven by a nonhomogeneous differential operator, which includes as a particular case the scalar p-Laplacian. We assume that the reaction is a Caratheodory function which admits time-dependent zeros of constant sign. No growth control near +/-infinity is imposed on the reaction. Using variational methods coupled with suitable truncation and comparison techniques, we prove two multiplicity theorems providing sign information for all the solutions. PMID- 26752941 TI - Pb, Sr and Ba calix[6]arene hexacarboxylic acid octahedral complexation: a dramatic effect of dealkylation. AB - Calix[6]arene hexacarboxylic acid binds instantly and with low symmetry to Pb, Sr and Ba. Later a highly symmetric up-down alternating conformation emerges. The solution structures are identical to their p-tert-butylcalix[6]arene hexacarboxylic acid counterparts. With either receptor an octahedral cage is formed around the metal. The transformation from low to high symmetry however proceeds at significantly faster rates for the de-t-butylated host. PMID- 26752944 TI - Supporting Gang Violence Prevention Efforts: A Public Health Approach for Nurses. AB - The impact of gang violence on a youth's risk for death or injury is tremendous. Prevention of complex societal problems, such as gang violence, requires a substantial effort and commitment from many sectors and disciplines. Nurses are uniquely positioned to help lead such efforts. Understanding the public health perspective to gang violence may be an important tool for nurses attempting to prevent this problem. The public health approach has four key components: defining and monitoring the problem; identifying risk, protective, and promoting factors; developing and evaluating interventions; and dissemination. This article outlines these components, current research on gang violence, and concludes by summarizing critical challenges for nurses to consider as they contribute to public health initiatives to prevent gang violence. PMID- 26752946 TI - Recent advances in the treatment of colonic diverticular disease and prevention of acute diverticulitis. AB - The incidence of diverticulosis and diverticular disease of the colon is increasing worldwide. Although the majority of patients remains asymptomatic long life, the prevalence of diverticular disease of the colon, including acute diverticulitis, is substantial and is becoming a significant burden on National Health Systems in terms of direct and indirect costs. Focus is now being drawn on identifying the correct therapeutic approach by testing various treatments. Fiber, non-absorbable antibiotics and probiotics seem to be effective in treating symptomatic and uncomplicated patients, and 5-aminosalicylic acid might help prevent acute diverticulitis. Unfortunately, robust evidence on the effectiveness of a medical strategy to prevent acute diverticulitis recurrence is still lacking. We herein provide a concise review on the effectiveness and future perspectives of these treatments. PMID- 26752945 TI - Clinical practice guidelines for the surgical management of colon cancer: a consensus statement of the Hellenic and Cypriot Colorectal Cancer Study Group by the HeSMO. AB - Despite considerable improvement in the management of colon cancer, there is a great deal of variation in the outcomes among European countries, and in particular among different hospital centers in Greece and Cyprus. Discrepancy in the approach strategies and lack of adherence to guidelines for the management of colon cancer may explain the situation. The aim was to elaborate a consensus on the multidisciplinary management of colon cancer, based on European guidelines (ESMO and EURECCA), and also taking into account local special characteristics of our healthcare system. Following discussion and online communication among members of an executive team, a consensus was developed. Statements entered the Delphi voting system on two rounds to achieve consensus by multidisciplinary international experts. Statements with an agreement rate of >=80% achieved a large consensus, while those with an agreement rate of 60-80% a moderate consensus. Statements achieving an agreement of <60% after both rounds were rejected and not presented. Sixty statements on the management of colon cancer were subjected to the Delphi methodology. Voting experts were 109. The median rate of abstain per statement was 10% (range: 0-41%). In the end of the voting process, all statements achieved a consensus by more than 80% of the experts. A consensus on the management of colon cancer was developed by applying the Delphi methodology. Guidelines are proposed along with algorithms of diagnosis and treatment. The importance of centralization, care by a multidisciplinary team, and adherence to guidelines is emphasized. PMID- 26752949 TI - The hidden endoscopic burden of sleeve gastrectomy and its comparison with Roux en-Y gastric bypass. AB - BACKGROUND: This study aimed to assess the endoscopic burden of bariatric surgical procedures at our trust. This is an enhanced parallel study to "The Hidden Endoscopic burden of Roux-en-Y Gastric Bypass" published in Frontline Gastroenterology in 2013 incorporating the data for sleeve gastrectomy and comparison with Roux-en-Y gastric bypass (RYGB). METHODS: This is a retrospective study that included 211 patients undergoing sleeve gastrectomy over a 34-month period. We utilized previously collected data for the RYGB patient cohort which included 553 patients over a 29-month period. We searched our hospital endoscopic database for patients who underwent post-operative endoscopy for indications related to their surgery. RESULTS: 16.6% of the sleeve gastrectomy patients required post-operative endoscopy, of whom 11.4% underwent therapeutic procedures. This compares to 20.4% of the RYGB cohort of whom 50.4% needed therapeutic procedures (P<0.001). 1.9% of sleeve gastrectomy patients encountered a post-operative staple line leak and collectively required 29 endoscopic procedures. One patient also developed stricturing (0.47%) requiring 18 pneumatic dilatations. 11.4% of the RYGB cohort developed an anastomotic stricture requiring 57 balloon dilatation procedures. To date, these procedures have accumulated an equivalent cost of ?159,898 in endoscopy tariffs, or ?177 per RYGB and ?373 per sleeve gastrectomy performed. CONCLUSIONS: Bariatric surgery can have significant implications in terms of patient morbidity and financial cost. Having a local bariatric surgery service increases the demand for endoscopic procedures in our hospital, both in investigating for and dealing with post operative complications. Provision of extra resources and expertise needs to be taken into account. PMID- 26752947 TI - Malignant biliary obstruction: the current role of interventional radiology. AB - Cholangiocarcinoma and pancreatic head cancer are still linked with extremely high 5-year mortality in the western world. The management of such patients is complex and typically requires a multidisciplinary approach in a tertiary care center. Interventional radiology offers minimally invasive, image-guided treatment for a variety of diseases and conditions. Regarding patients with malignant biliary obstruction, IR options are considered for more than two decades as a valid management tool for both operable and non-operable cases. The options include placement of percutaneous transhepatic biliary drains, preoperative embolization of the portal vein and deployment of covered and uncovered biliary stents. The purpose of this review is to describe the current evidence in this continuously evolving field. PMID- 26752948 TI - Inflammatory bowel disease: can omega-3 fatty acids really help? AB - Adjuvants to the traditional therapy of inflammatory bowel disease (IBD) have been studied to enhance the efficacy of the treatment and improve patients' quality of life. Omega-3 polyunsaturated fatty acids (omega3FA) have been associated with attenuation of the inflammatory responses in IBD, possibly acting as substrates for anti-inflammatory eicosanoid production, similar to prostaglandins and leukotrienes. omega3FA also act as substrates for the synthesis of resolvins, maresins and protectins, indispensable in resolving inflammation processes. These acids may influence the development or course of IBD by: reducing oxidative stress, production of tumor necrosis factor-alpha and proinflammatory cytokines; working as chemopreventive agents; and decreasing the expression of adhesion molecules. There are numerous controversies in the literature on the effects of omega3FA in the prevention or treatment of IBD, but their effects in reducing inflammation is incontestable. Therefore, more studies are warranted to elucidate the pathophysiological mechanisms and establish the recommended daily intake to prevent or induce remission in IBD patients. PMID- 26752950 TI - Choice of sedation and its impact on adenoma detection rate in screening colonoscopies. AB - BACKGROUND: Studies have demonstrated that the use of sedation (regardless of type) increases polyp detection rates during colonoscopy. Compared to conscious sedation (CS), propofol sedation (PS) has led to detection of more advanced polyps, yet no apparent difference was found in the overall adenoma detection rate (ADR) in patients undergoing colonoscopy for various reasons. We aimed to assess whether there was a significant difference in the ADR in patients specifically undergoing screening colonoscopies using PS versus CS. METHODS: This is a retrospective analysis of 699 consecutive patients who underwent inpatient screening colonoscopies at one academic inpatient center. The decision to perform endoscopy using PS versus CS was determined on an individual basis by each provider, taking into account various patient parameters. RESULTS: No significant difference was noted between ADR or location of detected adenomas between the CS and PS groups. When accounting for each variable, only total endoscopy time of less than 20 min resulted in a statistically significant ADR difference between the two sedation groups (CS: 15.6% vs PS: 21.3%, P = 0.038). CONCLUSION: ADR in screening colonoscopies is not increased by the use of PS compared to CS. While the use of propofol-based anesthesia is clearly associated with increased patient satisfaction and pain levels, the ADR is not enhanced, and its widespread use in screening colonoscopy sedation should still be investigated. PMID- 26752951 TI - Synbiotics and gastrointestinal function-related quality of life after elective colorectal cancer resection. AB - BACKGROUND: Synbiotics (combination of prebiotics and probiotics) may serve as a supportive dietary supplement-based strategy after colectomy for cancer. The potential benefits of early postoperative administration of synbiotics on the gastrointestinal function-related quality of life inpatients were explored. METHODS: Patients who underwent elective colectomy were prospectively enrolled and randomized to receive either synbiotics (n=38) or placebo (n=37) on the day they tolerated liquid diet and for 15 days thereafter. Primary endpoints were Gastro-Intestinal Quality of Life Index (GIQLI) questionnaire assessments at 1, 3 and 6 months postoperatively. Secondary endpoints were functional bowel disorders ("diarrhea", "constipation") assessed by EORTC QLQ-C30. RESULTS: Patients under synbiotics had a better GIQLI "Global score" compared with those who received placebo [77+/-1.67 vs. 71.36+/-1.69, P=0.01 (1 month); 77+/-1.7 vs. 72.5+/-1.73, P=0.03 (3 months); 79.23+/-1.82 vs. 72.75+/-1.85, P=0.01 (6 months)]. Multivariate linear mixed model analysis showed that synbiotics administration was the only independent significant factor for the "Global score" amelioration (b: 5.42, SE (b)1.8, 95%CI 1.78-9.1, P=0.004). The EORTC QLQ-C30 "diarrhea" domain score differences from baseline were better after synbiotics administration after 3 (P=0.04) and 6 months (P=0.003). No significant effect on "constipation" scores was observed. CONCLUSION: Synbiotics administration may have a beneficial effect on the postcolectomy gastrointestinal function. PMID- 26752952 TI - Changes in serum transforming growth factor-beta1 levels in chronic hepatitis C patients under antiviral therapy. AB - BACKGROUND: Several cytokines including transforming growth factor (TGF)-beta1 have been suggested to be involved in the pathogenesis of fibrosis in chronic hepatitis C. We examined the changes of TGF-beta1 serum levels and their predictive value in patients with chronic hepatitis C under antiviral therapy. METHODS: We included 84 patients with chronic hepatitis C who were treated with pegylated interferon-alpha and ribavirin between 2008 and 2009. Treatment was given for 24-48 weeks depending on HCV genotype. Serum TGF-beta1 levels were measured by an ELISA assay at baseline, at the end of therapy (EOT), and at 6 months after the EOT. Liver fibrosis was evaluated by transient elastography. RESULTS: Of the 84 patients, 76.2% achieved sustained virological response (SVR), 8.3% responded at the EOT but relapsed during post-therapy follow up (RR) and 15.5% had no response (NR). In all patients, mean TGF-beta1 levels were 16,980 pg/mL at baseline and decreased significantly at EOT (12,041 pg/mL) and at 6 months of post-treatment follow up (13,254 pg/mL) (P<=0.001). In particular, mean TGF-beta1 levels decreased significantly from baseline to EOT and to six months of post-treatment follow up in patients with SVR and numerically but not significantly in patients with RR or NR. TGF-beta1 levels were not associated with the severity of liver stiffness estimated by transient elastography. CONCLUSION: Our data show that TGF-beta1 serum levels decrease significantly at the EOT and remain decreased 6 months after the EOT mostly in chronic hepatitis C patients who achieve SVR after pegylated interferon-alpha and ribavirin combination treatment. PMID- 26752954 TI - Visible vessel in diverticular bleeding: a rare sighting. PMID- 26752953 TI - ASGE guidelines result in cost-saving in the management of choledocholithiasis. AB - BACKGROUND: The goal of this study was to determine whether utilization of the ASGE guidelines for the evaluation of bile duct stones (BDS) would result in fewer imaging studies and in turn lead to a lower healthcare expenditure. METHODS: This was a retrospective study set in an urban Teaching Hospital. Patients undergoing evaluation for BDS and who had their gallbladders in situ were included in the study. Data with regard to age, sex, clinical history, pain level, vital signs and laboratory studies as well as diagnostic tests performed were extracted from the hospital's electronic medical record. The ASGE guidelines were applied retrospectively to each patient in the study group and the group was divided into two cohorts: one that followed the ASGE guidelines and one which did not. Patients in the two cohorts were further stratified into high-, intermediate , and low-risk categories. RESULTS: Thirty-eight patients met the criteria and were included in the study. Of the 38 patients, 22 were managed as per the ASGE guidelines and 16 were not. Twenty-seven patients were categorized as high-risk (14 following the correct algorithm, 13 not) and 11 as intermediate-risk (8 following, 3 not). There were no low-risk patients. Twelve of the 27 patients in the high-risk group had stones (56%) while 6 of 11 (55%) had stones in the intermediate-risk group. Fourteen computed tomography scans and 12 magnetic resonance cholangiopancreatographies were deemed inappropriate resulting in unnecessary increased expenditure of $ 22,236. CONCLUSION: The application of ASGE guidelines can minimize redundant investigations and effect cost saving but need to be refined to produce a better yield. PMID- 26752955 TI - Gastrointestinal pseudomelanosis. PMID- 26752956 TI - Histological findings of divided muscle after peroral endoscopic myotomy. AB - Peroral endoscopic myotomy (POEM) is a revolutionary therapy for achalasia and related disorders. POEM utilizes almost the same myotomy procedure as the Heller myotomy; thus, it would be expected to have the same or greater duration of therapeutic effect. However, to date, there have been no reports to prove the basis for this procedure in achalasia. In this case, we were able to histologically show the divided muscle after POEM since the patient had an esophagectomy for esophageal cancer. Histology showed that the muscle tissue divided by the POEM procedure was completely replaced by fibrosis. These findings may indirectly show the permanence of the POEM procedure. PMID- 26752957 TI - Wilson's disease in an adult asymptomatic patient: a potential role for modifying factors of copper metabolism. AB - Diagnosis of Wilson's disease (WD) still remains a challenge since no single test has an accuracy of 100%. Molecular testing for ATP7B gene mutations can help reach the diagnosis when routine testing is equivocal. We herein report an asymptomatic WD patient diagnosed accidentally by genetic analysis. Th is case suggests that WD is a challenge even in particular contexts such as family screening. Genetic testing of ATP7B gene should be recommended in the family members of WD patients with minimal alterations of specific tests such as ceruloplasmin, and presence of steatosis or increased body mass index. PMID- 26752958 TI - Potential impact of Helicobacter pylori-related human beta-defensin-1 on hepatic encephalopathy and neurodegeneration. PMID- 26752959 TI - The role of stomach in neurological disorders: 1000 years historical background. PMID- 26752960 TI - Taurine and vitamin E supplementations have minimal effects on body composition, hepatic lipids, and blood hormone and metabolite concentrations in healthy Sprague Dawley rats. AB - BACKGROUND: As prescriptions for off-label pharmaceutical use and autonomous administration of over-the-counter nutraceuticals become mainstream, thorough assessments of these compounds are warranted. OBJECTIVE: To determine the effects of gemfibrozil, rosiglitazone, metformin, taurine, and vitamin E on body composition, hepatic lipids, and metabolic hormone and blood metabolite concentrations in a healthy, outbred rat cohort. METHODS: Male Sprague Dawley rats were fed a purified 10 kcal% from fat diet for 56 days and assigned to diet alone (control) or diet plus oral administration of gemfibrozil (34 mg/kg), metformin (500 mg/kg), rosiglitazone (3 mg/kg), taurine (520 mg/kg), or vitamin E (200 mg/kg). RESULTS: Rosiglitazone administration resulted in a 56% increase in carcass adiposity, cautioning potential prescriptive off-label use. Taurine supplementation had no adverse effects on evaluated parameters. A modest but significant increase in liver triacylglycerol content was observed with vitamin E supplementation compared with control (Delta 17.2 g triacylglycerol/100 g liver lipid). CONCLUSIONS: The evaluated pharmaceuticals had effects in a healthy population similar to the reported effects in their target population and the nutraceuticals had minimal effects on the measured physiological parameters. PMID- 26752962 TI - The genus Fleischmannia in Argentina, Bolivia, Brazil and Paraguay (Eupatorieae, Asteraceae). AB - Species of the genus Fleischmannia from Argentina, Bolivia, Brazil and Paraguay are reviewed, and keys are provided that cover the species in each country. New taxa described are Fleischmannia hatschbachii, Fleischmannia matogrosensis, Fleischmannia microstemon var. paniculata from Brazil, Fleischmannia hassleri from Paraguay and Fleischmannia neei and Fleischmannia steinbachii from Bolivia, and one new combination for a Fleischmannia prasiifolia variety is provided. The additions bring the total known species of the genus to 102. PMID- 26752961 TI - Aporosa tetragona Tagane & V. S. Dang (Phyllanthaceae), a new species from Mt. Hon Ba, Vietnam. AB - A new species, Aporosa tetragona Tagane & V. S. Dang, sp. nov., is described and illustrated from Mt. Hon Ba located in the Khanh Hoa Province, South Vietnam. This species is characterized by tetragonal pistillate flowers and fruits, which are clearly distinguishable from the other previously known species of the genus. The morphology and phylogeny based on rbcL and matK of this species indicated that the new species belongs to section Appendiculatae Pax & K. Hoffm. PMID- 26752963 TI - Novelties in Selaginella (Selaginellaceae - Lycopodiophyta), with emphasis on Brazilian species. AB - In this paper, I describe five new species of Selaginella from Brazil (Selaginella nanuzae, Selaginella neospringiana, Selaginella pellucidopunctata, Selaginella stomatoloma, and Selaginella trygonoides), compare them to morphologically similar species, and provide a preliminary conservation status assessment for each. The new species are illustrated with scanning electron photomicrographs of stem sections, leaves, and spores, when available. Also discussed in this paper are ten species, mainly from Brazil and with new distribution records, and the forthcoming resurrection of three species also occurring in Brazil. Three further non-native and presumed naturalized species are recognized in Brazil, and publication of one additional taxon is planned. Eighty-six Selaginella species are now known from Brazil and, of these, 80 are native (including 26 / 32.5%, endemic), and six are introduced. Brazil and Mexico have the second highest number of native Selaginella species in the Neotropics after Venezuela, which is estimated to have about 100. Of the newly documented species, Selaginella cabrerensis is now known to occur in French Guiana, Brazil, and Bolivia, in addition to Colombia, and Selaginella arroyoana and Selaginella chiquitana are synonymized under it. Likewise, Selaginella potaroensis is also recorded from Costa Rica and Brazil, and Selaginella seemannii from Panama and Brazil. Finally, leaf marginal stomata are reported on the newly described species and their functionality is discussed under Selaginella stomatoloma. PMID- 26752965 TI - World Checklist of Opiliones species (Arachnida). Part 2: Laniatores - Samooidea, Zalmoxoidea and Grassatoresincertae sedis. AB - Including more than 6500 species, Opiliones is the third most diverse order of Arachnida, after the megadiverse Acari and Araneae. This database is part 2 of 12 of a project containing an intended worldwide checklist of species and subspecies of Opiliones, and it includes the members of the suborder Laniatores, infraorder Grassatores of the superfamilies Samooidea and Zalmoxoidea plus the genera currently not allocated to any family (i.e. Grassatores incertae sedis). In this Part 2, a total of 556 species and subspecies are listed. PMID- 26752964 TI - Nine new species of Itaplectops (Diptera: Tachinidae) reared from caterpillars in Area de Conservacion Guanacaste, northwestern Costa Rica, with a key to Itaplectops species. AB - Nine new species of Itaplectops Townsend (Diptera: Tachinidae) are described from Area de Conservacion Guanacaste (ACG), northwestern Costa Rica. All specimens have been reared from -various species of ACG caterpillars in the families Limacodidae and Dalceridae. By combining morphological, photographic, and genetic barcode data we provide clear yet concise descriptions. The following nine new species are described in the genus Itaplectops: Itaplectops akselpalolai, Itaplectops anikenpalolae, Itaplectops argentifrons, Itaplectops aurifrons, Itaplectops ericpalolai, Itaplectops griseobasis, Itaplectops omissus, Itaplectops shellymcsweeneyae, Itaplectops tristanpalolai. We move Itaplectops to the tribe Uramyini from its original placement within the Blondeliini, and we discuss its systematic placement. We also provide a key differentiating the, genera of the tribe Uramyini as well as the known species of Itaplectops. PMID- 26752966 TI - A companion to Part 2 of the World Checklist of Opiliones species (Arachnida): Laniatores - Samooidea, Zalmoxoidea and Grassatores incertae sedis. AB - BACKGROUND: A series of databases is being prepared to list the valid species of Opiliones worldwide. This paper containing nomenclatural acts is meant to accompany Part 2, which includes the members of the infraorder Grassatores of the superfamilies Samooidea and Zalmoxoidea plus the Grassatores currently not allocated to any family (i.e. Grassatores incertae sedis). NEW INFORMATION: The following 32 taxonomic changes are proposed here: (1-3) The Afrotropical genera Hovanoceros Lawrence, 1959, Malgaceros Lawrence, 1959 and Tetebius Roewer, 1949 (all currently in Samoidae) are all newly transferred to Biantidae. (4-5) Microminua soerenseni Soares & Soares, 1954, from Brazil is newly transferred to Tibangara (Gonyleptoidea: Cryptogeobiidae), newly combined as Tibangara soerenseni new comb., new familial allocation for the species. (6-7) The new genus Llaguenia Gen. nov is erected for the South American species Zamora peruviana Roewer, 1956, newly combined as Llaguenia peruviana new comb., and newly placed in Gonyleptoidea: Cranaidae (Prostygninae). (8) Bebedoura Roewer, 1949, known from a single Brazilian species, is transferred from Tricommatinae to Grassatores incertae sedis. (9) Microconomma Roewer, 1915, known from a single Cameroonian species, is transferred from Samoidae to Grassatores incertae sedis. (10) Stygnomimus Roewer, 1927, with two Indomalayan species and hitherto included in the Stygnommatidae, is here formally considered Grassatores incertae sedis. (11) Bichito Gonzalez-Sponga, 1998, known from a single Venezuelan species, originally described in Phalangodidae: Phalangodinae, and currently in Grassatores incertae sedis is transferred to Samoidae. (12) The Neotropical genus Microminua Sorensen, 1932, currently with two species, is newly transferred from Kimulidae to Samoidae. (13-14) Cornigera Gonzalez-Sponga, 1987 (currently in Samoidae), is newly considered a junior subjective synonym of Microminua, and its single species is combined under Microminua as Microminua flava (Gonzalez-Sponga, 1987) new comb. (15) Niquitaia Gonzalez-Sponga, 1999 (originally in Phalangodidae: Phalangodinae, currently in Zalmoxidae), monotypic from Venezuela, is newly transferred to Samoidae. (16) Heteroscotolemon Roewer, 1912 originally described in Phalangodidae: Phalangodinae, and currently in Grassatores incertae sedis is transferred to Zalmoxidae. (17) While the Australasian genus Zalmoxista Roewer, 1949 is currently in Samoidae and some of its former species have been transferred to Zalmoxis Sorensen, 1886, Zalmoxista americana Roewer, 1952 from Peru, is here newly transferred to Zalmoxidae into Minuides Sorensen, 1932, forming the combination Minuides americanus (Roewer, 1952) new comb. (specific name inflected to match the masculine gender). (18) Neobabrius Roewer, 1949 (currently in Phalangodidae), monotypic from Indonesia, is newly transferred to Zalmoxidae. (19) While Crosbyella Roewer, 1927, belongs to Phalangodidae, Crosbyella roraima Goodnight & Goodnight, 1943 (originally Phalangodinae, but currently Zalmoxidae without generic assignment) is here transferred to Soledadiella Gonzalez-Sponga, 1987, as Soledadiella roraima new comb. (Zalmoxoidea: Zalmoxidae). (20) Zalmoxissus Roewer, 1949 is newly synonymized with Zalmoxis Sorensen, 1886 (Zalmoxidae). (21) The original spelling Zalmoxis sorenseni Simon, 1892 is restored from the unjustified emendation soerenseni. (22) The Neotropical genus Phalangodella Roewer, 1912 (originally in Phalangodidae: Tricommatinae, but currently in Grassatores incertae sedis) is newly transferred to Zalmoxoidea incertae sedis and (23-26) four other genera are newly synonymized with it: Phalangodella Roewer, 1912 = Exlineia Mello-Leitao, 1942 = Langodinus Mello-Leitao, 1949 = Cochirapha Roewer, 1949 = Phalpuna Roewer, 1949, generating the following new combinations (27-32): Phalangodella fulvescens (Mello-Leitao, 1943) new comb., Phalangodella milagroi (Mello-Leitao, 1942) new comb., Phalangodella rhinoceros (Mello-Leitao, 1945) new comb., Phalangodella flavipes (Mello-Leitao, 1949) new comb., Phalangodella rugipes (Roewer, 1949) new comb. and Phalangodella urarmata (Roewer, 1949) new comb. PMID- 26752967 TI - Terrestrial arthropods of Steel Creek, Buffalo National River, Arkansas. I. Select beetles (Coleoptera: Buprestidae, Carabidae, Cerambycidae, Curculionoidea excluding Scolytinae). AB - BACKGROUND: The Ozark Mountains are a region with high endemism and biodiversity, yet few invertebrate inventories have been made and few sites extensively studied. We surveyed a site near Steel Creek Campground, along the Buffalo National River in Arkansas, using twelve trap types - Malaise traps, canopy traps (upper and lower collector), Lindgren multifunnel traps (black, green, and purple), pan traps (blue, purple, red, white, and yellow), and pitfall traps - and Berlese-Tullgren extraction for eight and half months. NEW INFORMATION: We provide collection records of beetle species belonging to eight families collected at the site. Thirty one species represent new state records: (Buprestidae) Actenodes acornis, Agrilus cephalicus, Agrilus ohioensis, Agrilus paracelti, Taphrocerus nicolayi; (Carabidae) Agonum punctiforme, Synuchus impunctatus; (Curculionidae) Acalles clavatus, Acalles minutissimus, Acoptus suturalis, Anthonomus juniperinus, Anametis granulata, Idiostethus subcalvus, Eudociminus mannerheimii, Madarellus undulatus, Magdalis armicollis, Magdalis barbita, Mecinus pascuorum, Myrmex chevrolatii, Myrmex myrmex, Nicentrus lecontei, Otiorhynchus rugosostriatus, Piazorhinus pictus, Phyllotrox ferrugineus, Plocamus hispidulus, Pseudobaris nigrina, Pseudopentarthrum simplex, Rhinoncus pericarpius, Sitona lineatus, Stenoscelis brevis, Tomolips quericola. Additionally, three endemic carabids, two of which are known only from the type series, were collected. PMID- 26752968 TI - A review of the Anomaloninae (Hymenoptera, Ichneumonidae, Anomaloninae) from the Ukrainian Carpathians. AB - BACKGROUND: The Ukrainian Anomaloninae fauna is relatively poorly known. The presence of large under-collected areas, such as the Carpathians, makes taxonomic and faunistic studies concerning these parasitoids from Ukraine urgently relevant. NEW INFORMATION: Based on our ongoing surveys on the Anomaloninae of the Ukrainian Carpathians, we report here the new distribution records for some species. In total 24 Anomaloninae species, belonging to 8 genera (Anomalon Panzer, 1804, Agrypon Forster, 1868, Aphanistes Forster, 1868, Barylypa Forster, 1868, Heteropelma Wesmael, 1849, Perisphincter Townes, 1961, Therion Curtis, 1829, and Trichomma Wesmael, 1849), were recorded from the studied region for the first time. Nine species, Agrypon batis Ratzeburg, 1955, A. scutellatum Hellen, 1926, Aphanistes gliscens Hartig, 1838, A. klugii Hartig, 1838, Heteropelma amictum Fabricius, 1775, Perisphincter gracilicornis Schnee, 1978, Therion giganteum Gravenhorst, 1829, Trichomma fulvidens Wesmael, 1849 and T. occisor Habermehl, 1909 were recorded for the first time in Ukraine. Seasonal dynamics and high-altitude zone of Anomaloninae species' distribution are discussed. PMID- 26752969 TI - Two new species of Limbodessus diving beetles from New Guinea - short verbal descriptions flanked by online content (digital photography, MUCT scans, drawings and DNA sequence data). AB - BACKGROUND: To date only one species of Limbodessus diving beetles has been reported from the Island of New Guinea, L. compactus (Clark, 1862), which is widerspread in the Australian region. NEW INFORMATION: We describe two new species of microendemic New Guinea Limbodessus and use a compact descriptive format flanked by enriched online content in wiki powered species pages. Limbodessus baliem sp.n. is described from ca. 1,600 m altitude in the Baliem Valley of Papua and Limbodessus alexanderi sp.n. from >3,000 m altitude north of Sugapa, Papua. Based on our analysis, we also transfer three species from other genera to Limbodessus Guignot, 1939, with the following changes: Limbodessus deflectus (Ordish, 1966), new combination; Limbodessus leveri (J. Balfour-Browne, 1944), new combination; and Limbodessus plicatus (Sharp, 1882), new combination. PMID- 26752970 TI - A benchmark survey of the common plants of South Northumberland and Durham, United Kingdom. AB - BACKGROUND: It is obvious to anyone studying plants in the landscape that man made environmental change is having profound effects on the abundance, distribution and composition of plant communities. Nevertheless, quantifying these changes and estimating the impact of the different drivers of change is extremely difficult. Botanical surveying can potentially provide insights to the changes that are occurring and inform decisions related to conservation, agriculture and forestry policy. However, much of botanical surveying is conducted in such a way that it is not comparable between dates and places. Any comparison of historical and modern data has to account for biases in the recording of different taxonomic groups, geographic biases and varying surveying effort in time. In 2010 botanical recorders in the Vice Counties of Durham and South Northumberland in the United Kingdom decided to conduct a four year survey specifically to benchmark the abundance and distribution of common plants in their counties. It is intended that this survey will provide a relatively unbiased assessment with which to compare future and past surveys of the area and a means to study the drivers of biodiversity change in the North-east of England. NEW INFORMATION: This survey of Durham and South Northumberland has been designed with two goals, firstly to provide information on common vascular plant species and secondly to provide a dataset that will be versatile with respect to the sorts of questions that can be answered with the data. The survey is primarily an occupancy study of 1km(2) grid squares, however, observers were also asked to provide a relative abundance estimate of the species in each grid square. The collection of relative abundance estimate data was an experiment to assess the repeatablity and useablity of such estimates. PMID- 26752971 TI - Natural History Museum Sound Archive I: Orthoptera: Gryllotalpidae Leach, 1815, including 3D scans of burrow casts of Gryllotalpa gryllotalpa (Linnaeus, 1758) and Gryllotalpa vineae Bennet-Clark, 1970. AB - BACKGROUND: The Natural History Museum (NHM) sound archive contains recordings of Gryllotalpidae, and the NHM collection holds plaster casts of the burrows of two species. These recordings and burrows have until now not been made available through the NHM's collection database, making it hard for researchers to make use of these resources. NEW INFORMATION: Eighteen recordings of mole crickets (three identified species) held by the NHM have been made available under open licenses via BioAcoustica. 3D scans of the burrows of Gryllotalpa gryllotalpa (Linnaeus, 1758) and Gryllotalpa vineae Bennet-Clark, 1970 have been made available via the NHM Data Portal. PMID- 26752973 TI - A Multistate Life Table Approach to Understanding Return and Reentry Migration between Mexico and the United States During Later Life. AB - BACKGROUND: Empirical research describes retirement migration to Mexico as a viable option for some older Americans. However, far less research examines this phenomenon among Mexican immigrants in the United States. The literature that does address this topic treats international migration as a singular occurrence and does not examine the possibility of return and subsequent reentry between countries. This omission creates an important gap in our knowledge of international retirement migration considering the strong transnational ties that Mexican immigrants maintain to the home and destination countries. OBJECTIVE: Using a multistate life table approach, this study examines the rate of return to Mexico and reentry back into the United States among Mexican males aged 50 and older with U.S. migration experience, as well as the number of years spent in both countries. RESULTS: Results show that the rate of reentry from Mexico into the United States declined from 3.33% at age 50-54 to less than 1% at age 70 and older (p-value<0.05). In contrast, the rate of return to Mexico from the United States increased from 3.19% at age 50 to 54 to 4.44%at age 65 to 69 and dropped to less than 2% at age 70 and older (p-value<0.05). CONCLUSIONS: While rates of return and reentry among this population are relatively low, they provide insight on the potential life course factors driving the migration patterns of a population of increasing size and relevance in the United States. PMID- 26752972 TI - A novel copper(II) complex identified as a potent drug against colorectal and breast cancer cells and as a poison inhibitor for human topoisomerase IIalpha. AB - A novel complex, [Cu(acetylethTSC)Cl]Cl*0.25C2H5OH 1 (where acetylethTSC = (E)-N ethyl-2-[1-(thiazol-2-yl)ethylidene]hydrazinecarbothioamide), was shown to have anti-proliferative activity against various colon and aggressive breast cancer cell lines. In vitro studies showed that complex 1 acted as a poison inhibitor of human topoisomerase IIalpha, which may account for the observed anti-cancer effects. PMID- 26752974 TI - Predictors of Attrition in a Cohort Study of HIV Infection and Methamphetamine Dependence. AB - Longitudinal cohort studies of HIV and substance use disorders play an important role in understanding these conditions, but high rates of attrition can threaten their integrity and generalizability. This study aimed to identify factors associated with attrition in a 5-year observational cohort study of 469 individuals with and without HIV infection and methamphetamine (MA) dependence. Rates of attrition in our four study groups were approximately 24% in HIV-MA-, 15% in HIV+MA-, 56% in HIV-MA+, and 47% in HIV+MA+ individuals. Predictors of attrition in the overall cohort included history of MA, alcohol, and other substance dependence, learning impairment, reduced cognitive reserve, and independence in activities of daily living (all ps < .05), but varied somewhat by clinical group. Of particular note, enrollment in a neuroimaging substudy was associated with significantly boosted rates of retention in the MA groups. Results from this investigation highlight the complexity of the clinical factors that influence retention in cohort studies of HIV-infected MA users and might guide the development and implementation of targeted retention efforts. PMID- 26752976 TI - Arterial stiffness and ankle brachial index in patients with rheumatoid arthritis and inflammatory bowel disease. PMID- 26752975 TI - Post cardiac arrest care and follow-up in Sweden - a national web-survey. AB - BACKGROUND: Recent decades have shown major improvements in survival rates after cardiac arrest. However, few interventions have been tested in order to improve the care for survivors and their family members. In many countries, including Sweden, national guidelines for post cardiac arrest care and follow-up programs are not available and current practice has not previously been investigated. The aim of this survey was therefore to describe current post cardiac arrest care and follow-up in Sweden. METHODS: An internet based questionnaire was sent to the resuscitation coordinators at all Swedish emergency hospitals (n = 74) and 59 answers were received. Quantitative data were analysed with descriptive statistics and free text responses were analysed using manifest content analysis. RESULTS: Almost half of the hospitals in Sweden (n = 27, 46 %) have local guidelines for post cardiac arrest care and follow-up. However, 39 % of them reported that these guidelines were not always applied. The most common routine is a follow-up visit at a cardiac reception unit. If the need for neurological or psychological support are discovered the routines are not explicit. In addition, family members are not always included in the follow-up. CONCLUSIONS: Although efforts are already made to improve post cardiac arrest care and follow-up, many hospitals need to focus more on this part of cardiac arrest treatment. In addition, evidence-based national guidelines will have to be developed and implemented in order to achieve a more uniform care and follow-up for survivors and their family members. This national survey highlights this need, and might be helpful in the implementation of such guidelines. PMID- 26752977 TI - Period-doubling and period-tripling in growing bilayered systems. AB - Growing layers on elastic substrates are capable of creating a wide variety of surface morphologies. Moderate growth generates a regular pattern of sinusoidal wrinkles with a homogeneous energy distribution. While the critical conditions for periodic wrinkling have been extensively studied, the rich pattern formation beyond this first instability point remains poorly understood. Here we show that upon continuing growth, the energy progressively localizes and new complex morphologies emerge. Previous studies have often overlooked these secondary bifurcations; they have focused on large stiffness ratios between layer and substrate, where primary instabilities occur early, long before secondary instabilities emerge. We demonstrate that secondary bifurcations are particularly critical in the low stiffness ratio regime, where the critical conditions for primary and secondary instabilities move closer together. Amongst all possible secondary bifurcations, the mode of period-doubling plays a central role - it is energetically favorable over all other modes. Yet, we can numerically suppress period-doubling, by choosing boundary conditions, which favor alternative higher order modes. Our results suggest that in the low stiffness regime, pattern formation is highly sensitive to small imperfections: surface morphologies emerge rapidly, change spontaneously, and quickly become immensely complex. This is a common paradigm in developmental biology. Our results have significantly applications in the morphogenesis of living systems where growth is progressive and stiffness ratios are low. PMID- 26752979 TI - Recruitment techniques for alcohol pharmacotherapy clinical trials: A cost benefit analysis. AB - OBJECTIVES: Alcohol use disorders (AUDs) represent a large public health burden with relatively few efficacious pharmacotherapies. Randomized controlled trials (RCTs) for new AUD therapies can be hampered by ineffective recruitment, leading to increased trial costs. The current analyses examined the effectiveness of recruitment efforts during two consecutive outpatient RCTs of novel AUD pharmacotherapies conducted between 2009 and 2012. METHODS: During an initial phone screen, participants identified an ad source for learning about the study. Qualified persons were then scheduled for in-person screens. The present analyses examined demographic differences amongst the eight ad sources utilized. Recruitment effectiveness was determined by dividing the number of persons meeting criteria for an in-person screen by the total number of callers from each ad source. Cost-effectiveness was determined by dividing total ad source cost by number of screens, participants randomized, and completers. RESULTS: 1,813 calls resulted in 1,005 completed phone screens. The most common ad source was TV (34%), followed by print (29%), word-of-mouth (11%), flyer (8%), internet (5%), radio (5%), bus ad (2%), and billboard (1%). Participants reporting bus ads (46%), billboard (44%), or print ads (34%) were significantly more likely than the other sources to meet criteria to be scheduled for in-person screens. The most cost-effective ad source was print ($2,506 per completer), while bus ad was the least cost-effective ($13,376 per completer). CONCLUSIONS: Recruitment in AUD RCTs can be successful using diverse advertising methods. The present analyses favored use of print ads as most cost-effective. PMID- 26752978 TI - Sexual Violence Victimization and Associations with Health in a Community Sample of Hispanic Women. AB - This study sought to add to the limited information currently available on circumstances of sexual violence victimization and associated negative health experiences among Hispanic women. Data come from a community sample of mostly Mexican women in an urban southwestern city. Household interviews were completed with a sample of 142 women during 3 months in 2010. Findings indicate that 31.2% of women reported rape victimization and 22.7% reported being sexually coerced in their lifetime. Victims of rape and/or sexual coercion were significantly more likely to report symptoms of depression and post-traumatic stress disorder (PTSD) during their lifetime. Among victims whose first unwanted sexual experience resulted in rape and/or sexual coercion, perpetrators were almost always someone known to the victims, and were mostly family members or intimate partners, depending on the victim's age. About one-fifth of victims were injured and 17.1% needed medical services. These findings suggest the need for more attention to the physical and mental health needs of sexually victimized Hispanic women. PMID- 26752980 TI - Aggression as a Predictor of Early Substance Use Initiation among Youth with Family Histories of Substance Use Disorders. PMID- 26752981 TI - Correlates of hopelessness in the high suicide risk police occupation. AB - Police officers are chronically exposed to work stress. We examined specific stressors that may be associated with hopelessness, a possible risk factor for suicide in this high suicide risk population. The study included 378 officers (276 men and 102 women) with complete data. Analysis of variance was used to estimate mean levels of hopelessness scores as associated with stress, adjusted for age, gender, and race/ ethnicity. Posttraumatic symptoms were tested as a modifier of the association between stress and hopelessness. Increasing stress of administrative practices and lack of support were significantly associated with increasing hopelessness among officers (p < .006 - hopelessness range: 1.64-2.65; and p < .001 - hopelessness range 1.60-2.80, respectively). Posttraumatic stress disorder (PTSD) symptoms significantly modified the association between lack of organizational support and hopelessness (p < .010) with significant association only among individuals with higher PTSD symptoms (p < .001). Results suggest that hopelessness is associated with specific stressors in police work, and this is modified by posttraumatic symptomatology. PMID- 26752984 TI - Knockouts of high-ranking males have limited impact on baboon social networks. AB - Social network structures can crucially impact complex social processes such as collective behaviour or the transmission of information and diseases. However, currently it is poorly understood how social networks change over time. Previous studies on primates suggest that 'knockouts' (due to death or dispersal) of high ranking individuals might be important drivers for structural changes in animal social networks. Here we test this hypothesis using long-term data on a natural population of baboons, examining the effects of 29 natural knockouts of alpha or beta males on adult female social networks. We investigated whether and how knockouts affected (1) changes in grooming and association rates among adult females, and (2) changes in mean degree and global clustering coefficient in these networks. The only significant effect that we found was a decrease in mean degree in grooming networks in the first month after knockouts, but this decrease was rather small, and grooming networks rebounded to baseline levels by the second month after knockouts. Taken together our results indicate that the removal of high-ranking males has only limited or no lasting effects on social networks of adult female baboons. This finding calls into question the hypothesis that the removal of high-ranking individuals has a destabilizing effect on social network structures in social animals. PMID- 26752983 TI - Menthol tobacco use is correlated with mental health symptoms in a national sample of young adults: implications for future health risks and policy recommendations. AB - BACKGROUND: Depression and anxiety are correlated with greater nicotine dependence, smoking persistence, and relapse back to smoking after a quit attempt. Menthol cigarette smoking, which is prevalent in young adults, is associated with nicotine dependence, progression to regular smoking, and worse cessation outcomes than non-menthol smoking. Few have established a link between menthol tobacco use, beyond just smoking, with mental health in this high-risk age group. This study examined the association of menthol tobacco use to anxiety and depression in a national sample of young adults. METHODS: Data were from Waves 1 through 7 (n = 9720, weighted) of the Truth Initiative Young Adult Cohort, a national sample of men and women aged 18 to 34 assessed every 6-months. Demographics, past 30-day use of non-menthol and menthol tobacco products, and current alcohol, marijuana, and other drug use were assessed among those with depression and anxiety. RESULTS: Thirty nine percent of current tobacco users used menthol as their preferred brand. Using a cross-sectional analysis (collapsed across waves), past 30-day menthol tobacco was uniquely associated with greater odds of both depression and anxiety, beyond the effects of demographic and substance correlates and non-menthol tobacco product use. CONCLUSIONS: Menthol is disproportionately used among young adults tobacco users with mental health problems, above and beyond the impact of a variety of other mental health and tobacco use risk factors. Findings suggest a strong link between menthol tobacco use and poor health outcomes. Policies should be developed to deter menthol tobacco use in vulnerable groups. PMID- 26752982 TI - Efficacy of lymph node dissection by node zones according to tumor location for esophageal squamous cell carcinoma. AB - BACKGROUND: The extent of node dissection in esophageal cancer surgery is usually estimated by the number of resected nodes, irrespective of the area of dissection. The efficacy of lymph node dissection by area was evaluated according to the location of the primary tumor. METHODS: The study group comprised the 3827 patients who underwent R0 esophagectomy with three-field lymph node dissection for squamous cell carcinoma, registered in a nationwide registry in Japan. The areas of lymph node were classified into zones according to AJCC Staging Manual. The Efficacy Index (EI) calculating the frequency and patient survival of metastases to each zone was investigated according to tumor location. RESULTS: The EI was high in supraclavicular and upper mediastinal zones in patients with upper esophageal tumors, highest in upper mediastinal zone followed by supraclavicular and perigastric zones in patients with middle esophageal tumors, and highest in perigastric zone followed by upper and lower mediastinal zones in patients with lower esophageal tumors. In patients with middle and lower esophageal cT1 tumors, the EIs of upper mediastinal and perigastric zones were higher than middle and lower mediastinal zones. CONCLUSION: The EIs of each zone were differed by tumor location. The extent of lymph node dissection should be estimated by the dissected zones and modified by the tumor location. Supraclavicular dissection is indispensable for patients with upper esophageal tumors, and recommended for patients with middle esophageal tumors. Upper mediastinal dissection is recommended for all patients with thoracic esophageal squamous cell carcinoma, irrespective of the location. PMID- 26752985 TI - Melittin induces in vitro death of Leishmania (Leishmania) infantum by triggering the cellular innate immune response. AB - BACKGROUND: Apis mellifera venom, which has already been recommended as an alternative anti-inflammatory treatment, may be also considered an important source of candidate molecules for biotechnological and biomedical uses, such as the treatment of parasitic diseases. METHODS: Africanized honeybee venom from Apis mellifera was fractionated by RP-C18-HPLC and the obtained melittin was incubated with promastigotes and intracellular amastigotes of Leishmania (L.) infantum. Cytotoxicity to mice peritoneal macrophages was evaluated through mitochondrial oxidative activity. The production of anti- and pro-inflammatory cytokines, NO and H2O2 by macrophages was determined. RESULTS: Promastigotes and intracellular amastigotes were susceptible to melittin (IC50 28.3 MUg.mL(-1) and 1.4 MUg.mL(-1), respectively), but also showed mammalian cell cytotoxicity with an IC50 value of 5.7 MUg.mL(-1). Uninfected macrophages treated with melittin increased the production of IL-10, TNF-alpha, NO and H2O2. Infected melittin treated macrophages increased IL-12 production, but decreased the levels of IL 10, TNF-alpha, NO and H2O2. CONCLUSIONS: The results showed that melittin acts in vitro against promastigotes and intracellular amastigotes of Leishmania (L.) infantum. Furthermore, they can act indirectly on intracellular amastigotes through a macrophage immunomodulatory effect. PMID- 26752986 TI - A comparative histological study on the skin occlusion performance of a cream made of solid lipid nanoparticles and Vaseline. AB - The water content of the epidermis is a main factor in maintaining skin smoothness and elasticity and preventing skin dryness. Occlusive products can greatly affect skin hydration by forming a barrier on the skin following the topical administration of oil-based formulations. These products repair the skin barrier by restoring the skin lipids as well. Solid lipid nanoparticles (SLNs) have recently been introduced as a novel carrier with several benefits in pharmaceutics and cosmeceutics. It has been suggested that SLNs may have an occlusive effect following topical application. In this study, the occlusion effects of lipidic particles in different size ranges were investigated in vitro, ex vivo, and in vivo, and the results were compared with the positive (vaseline) and negative (blank) controls. Although larger lipidic particles showed better occlusion properties than nanoparticles in vitro, but ex vivo experiments confirmed the benefits of nanoparticles (almost 30% higher occlusion factor for particles in the range of 170 nm than ones in the range of 600 and 1800 nm). The superiority of SLN formulation to Vaseline as a positive reference was confirmed by the in vivo study. SLN formulation resulted in much thicker stratum corneum than Vaseline. It was indicated that in vitro and ex vivo study methods may not be a good reflective of the in vivo method for determining the occlusive properties of nanoparticulate systems. It was concluded that formulations containing SLNs can be used as efficient skin moisturizer products. PMID- 26752987 TI - Evaluation of cardioprotective effect of aqueous extract of Garcinia indica Linn. fruit rinds on isoprenaline-induced myocardial injury in Wistar albino rats. AB - In the present study, cardioprotective effect of aqueous extract of Garcinia indica Linn. fruit rinds in isoprenaline-induced myocardial infarction in Wistar albino rats was evaluated. In vitro total phenolic, total flavonoid content and 2, 2'-diphenyl-1-picrylhydrazyl hydrate radical scavenging activity was measured. In vivo effect of aqueous extract of G. indica was evaluated in Wistar albino rats by isoprenaline-induced myocardial injury model. Thirty six rats were randomly divided in 6 groups. Rats were treated with G. indica 250 mg/kg and 500 mg/kg doses for 21 days and myocardial injury was produced by subcutaneous injection of isoprenaline 85 mg/kg on day 20 and 21. Carvedilol 1 mg/kg for 21 days served as active control. Electrocardiogram parameters, cardiac injury markers (serum troponin-I, uric acid, lactate dehydrogenase, creatinine kinase MB, aspartate aminotransferase and alanine aminotransferase), oxidative stress markers (superoxide dismutase, catalase and malondialdehyde level) and histopathological changes were evaluated in each group and compared using appropriate statistical tests. In vitro evaluation of aqueous extract showed significant antioxidant property. Isoprenaline produced significant myocardial ischemia as compared to normal control group (P<0.05). Administration of G. indica in both the doses did not significantly recover the altered electrocardiogram, cardiac injury markers, oxidative stress markers and histopathological myocardial damage as compared to disease control group (P>0.05). The aqueous extract of G. indica was not found to be cardioprotective against myocardial injury. Further study with more sample size and higher dose range may be required to evaluate its cardioprotective effect. PMID- 26752988 TI - Decreased levels of canonical transient receptor potential channel 3 protein in the rat cerebral cortex after chronic treatment with lithium or valproate. AB - Lithium and valproate modulate disturbances in intracellular calcium homeostasis implicated in the pathophysiology of bipolar disorder, but the molecular mechanisms are not fully understood. Two subtypes of transient receptor potential (TRP) channel family, i.e. TRPC3 and TRPM2, are potential candidates involved in calcium signaling and implicated in the pathophysiology of bipolar disorder. This study was designed to investigate whether mood stabilizers such as lithium and valproate affect the expression of TRPC3 and TRPM2. Rats were treated with intraperitoneal injections of lithium (2 mEq/kg b.i.d.) or valproate (300 mg/kg b.i.d.) acutely (for 24 h) or chronically (for 4 weeks). The changes in mRNA and protein levels of TRPC3 and TRPM2 were measured with real-time polymerase chain reaction and western blotting. The chronic administration of lithium and valproate significantly reduced levels of TRPC3 by 19.7% and 19.3%, respectively. No change was detected in the mRNA level of this channel. Neither acute nor chronic treatment with lithium or valproate had any effect on TRPM2 levels. The results suggest that downregulation of the TRPC3 channel is an important shared mechanism by which lithium and valproate can modulate calcium disturbances, whereas the TRPM2 channel does not appear to be affected by mood stabilizers, at least under non stressed conditions. PMID- 26752990 TI - Transdermal iontophoretic delivery of celecoxib from gel formulation. AB - Celecoxib is used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, joint inflammation and sport injuries. Long term administration of the drug results in such complications as gastrointestinaland renal disturbances and cardio-vascular complications. The main objective of the present study was to investigate the feasibility of delivering celecoxib incorporated in gel formulations by iontophoresis. Sodium alginate, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose (HPMC) and carbopol 934P were used to develop topical gel formulations of celecoxib. The gel formulations were evaluated for macroscopic and microscopic properties, pH determination, spreadability, rheological behaviour, and drug release characteristics both in vitro and ex vivo. Drug release was evaluated in the presence of iontophoresis field (0.1 to 0.5 mA/cm(2)) or without electrical current (passive diffusion) and celecoxib was measured spectrophotometrically at 252 nm. Most gel formulations showed acceptable physicochemical properties. Amongst formulations, gel formulation containing HPMC K4M which indicated greater performance in drug release behaviour was selected for further in vivo studies. The cumulative percent of drug released in vitro at the end of each experiment was 36%, 63%, and 89.7% for passive diffusion, direct electric current (DC) current density of 0.3 mA/cm(2), and 0.5 mA/cm(2), respectively. The findings of ex vivo drug transport across rat skin also showed a significantly higher release of celecoxib compared to passive flux for both AC and DC currents. A 0.5 mA/cm(2) of DC current increased drug flux to 73% compared to 41.5% of passive diffusion. It can be concluded from the results of this study that the application of iontophoresis enhances the flux of celecoxib, as compared to the passive diffusion. PMID- 26752989 TI - Effects of long term administration of testosterone and estradiol on spatial memory in rats. AB - There are many discrepancies around the effect of sex hormones on spatial learning and memory in rodents. The aim of the present study was to investigate the effects of chronic administration of estradiol (ES) and testosterone (TES) on spatial memory in adult castrated male rats. Cholinesterase activity of the hippocampus in treated animals was also measured to seek if hormonal treatment can change the acetylcholinesterase (AChE) activity in this region. Six groups of castrated male rats received different doses of ES valerate (1, 4, 10 mg/kg, by subcutaneous, sc) and TES enanthate (10, 20, 40 mg/kg, sc) in weekly injection intervals for 6 weeks. Morris water maze (MWM) was used to assess the spatial reference memory of the rats. The specific activity of AChE in the hippocampus was also measured. The treatment duration and the dose quantity of ES had significant (P<0.001 and P=0.048, respectively) effect on the learning ability in the rats. For TES treated rats, treatment duration showed a significant effect (P<0.001) on learning performance of the rats. The activity of AChE compared to the control group was significantly increased in ES treated rats in a dose dependent manner and it was decreased in the group that received the highest dose of TES. Our results showed that chronic high dose of ES decreased the learning ability of male castrated rats in a reference memory version of MWM test. This can be explained by the decreased AChE activity in the hippocampus. PMID- 26752991 TI - Hydro-alcoholic extract of Raphanus sativus L. var niger attenuates bleomycin induced pulmonary fibrosis via decreasing transforming growth factor beta1 level. AB - Pulmonary fibrosis is a progressive disease of the lungs, which leads to death in human. It has been suggested that transforming growth factor beta 1 (TGF-beta1) together with oxidative stress play a central role in the pathogenesis of the ailment. The objective of this study was to evaluate the possible curative effects of black radish, Raphanus sativus L. var niger (RSN) on bleomycine (BLM) induced pulmonary fibrosis in a rat model. In this study, thirty-six male Wistar rats were divided into six groups, including: (I) positive (BLM) control group, (II) negative (normal saline) control group, (III) sham group (R. sativus extract 150 mg/kg), and (IV-VI) treatment groups. In order to induce pulmonary fibrosis, four groups were treated with a single dose of BLM sulfate (7.5 U/kg) through intratracheal instillation. Treatment groups (IV-VI) received RSN extract (75, 150, and 300 mg/kg) orally a week before and two weeks after the administration of BLM. At the end of the treatment course, blood and lung tissue samples were taken and the measurement of TGF-beta1 and histopathological examination of the lung tissues performed. The results showed that RSN, at 300 mg/kg dose, could significantly decrease the serum level of TGF-beta1 and severity of the histological lesions as compared to the positive control group. The results of the current study indicate that the components present in the extract can remarkably prevent the aggravation of pulmonary fibrosis via decreasing TGF-beta1 level. PMID- 26752992 TI - In silico design, cloning and high level expression of L7/L12-TOmp31 fusion protein of Brucella antigens. AB - Globally, Brucella melitensis and B. abortus are the most common cause of human brucellosis. The outer membrane protein 31 (Omp31) and L7/L12 are immunodominant and protective antigens conserved in human Brucella pathogens which are considered as potential vaccine candidates. We aimed to design the fusion protein from Brucella L7/L12 and truncated Omp31proteins, in silico, clone the fusion in pET28a vector, and express it in Escherichia coli host. Two possible fusion forms, L7/L12-TOmp31 and TOmp31-L7/L12 were subjected to in silico modeling and analysis. Analysis and validation of the fusion proteins with three dimensional (3D) models showed that both models are in the range of native proteins. However, L7/L12-Tomp31 structure was more valid than the TOmp31-L7/L12 model and subjected to in vitro production. The major histocompatibility complex (MHC II) epitope mapping using IEDB database indicated that the model contained good MHC II binders. The L7/L12-TOmp31 coding sequence was cloned in pET28a vector. The integrity of the construct was confirmed by polymerase chain reaction, restriction enzyme mapping, and sequencing. The fusion was successfully expressed in E. coli BL21 (DE3) by induction with isopropyl beta-D-thiogalactopyranoside. The rL7/L12-TOmp31 was purified with Ni-NTA column. The yield of the purified rL7/L12-TOmp31 was estimated by Bradford method and found to be 40 mg/L of the culture. Western blotting with anti-His antibody revealed a specific reactivity with purified rL7/L12-TOmp31 produced in E. coli and showed the functional expression in the prokaryotic system. In this study, a new protein vaccine candidate against brucellosis was constructed with the help of bioinformatics tools and the construct was expressed in the bacterial host. Studies evaluating the immunogenicity and cross-protection of this fusion protein against B. melitensis and B. abortus are underway. PMID- 26752993 TI - Antispasmodic effect of Dracocephalum kotschyi hydroalcoholic extract on rat ileum contraction. AB - Dracocephalum kotschyi Boiss. (Labiatae) is a traditional medicine which is believed to have antispasmodic and analgesic activities. The antispasmodic action of D. kotschyi essential oil has been shown in a previous report. The objective of this research was to study antispasmodic activity of hydroalcoholic extract of D. kotschyi on ileum contractions. Hydroalcoholic extract was obtained from aerial part of D. kotschyi using percolation method. For antispasmodic studies, a portion of rat ileum was suspended under 1g tension in Tyrode's solution at 37 degrees C and gassed with O2. Effect of the D. kotschyi extract was assessed on ileum contractions induced by KCl (80 mM), acetylcholine (ACh, 500 nM) and electrical field stimulation (EFS). The D. kotschyi extract concentration dependently inhibited the response to KCl (IC50 =36 +/- 5.1 MUg/ml), ACh (IC50 =101 +/- 9.5 MUg/ml), EFS-1 (IC50 =96 +/- 7.1 MUg/ml) and EFS-2 (IC50 =53 +/- 4.3 MUg/ml). From this experiment it was concluded that D. kotschyi extract possessed potent antispasmodic activity. Therefore, identification of the active component(s) is (are) recommended in order to find the best lead compound for drug development. PMID- 26752994 TI - Sequence characterized amplified region marker as a tool for selection of high artemisinin containing species of Artemisia. AB - Malaria is currently one of the most important causes of mortality in developing countries. High resistance to available antimalarial drugs has been reported frequently, thus it is crucial to focus on the discovery of new antimalarial drugs. Artemisinin, an effective antimalarial medication, is isolated from various Artemisia species. To identify the Artemisia species producing high quantity of artemisinin, eight species of Artemisia were screened with the genetic sequence characterized amplified region (SCAR) marker for higher quantity of artemisinin. The DNA band corresponding to SCAR marker was cloned into pGEM(r) T Easy vector and sequenced. The content of artemisinin in tested species was also measured using high-performance liquid chromatography (HPLC) assay. The primers designed for high-artemisinin SCAR marker could amplify a specific band of approximately 1000 bp which was present in two Artemisia annua and Artemisia absinthium species. These SCAR marker sequences for two selected species were submitted into the GenBank databases under KC337116 and KC465952 accession numbers. HPLC analysis indicated that two selected Artemisia species, genetically recognized as high-artemisinin yielding plants, had higher artemisinin content in comparison to other examined species. Therefore, in this study, we propose developed SCAR marker as a complementary tool for confidently detection of high artemisinin content in Artemisia species. PMID- 26752995 TI - The effects of doxepin on stress-induced learning, memory impairments, and TNF alpha level in the rat hippocampus. AB - Stress has a profound impact on the nervous system and causes cognitive problems that are partly related to the inflammatory effects. Besides influencing the content of neurotransmitters, antidepressants such as doxepin are likely to have anti-inflammatory, anti-oxidative, and anti-apoptotic effects. Therefore, the present study investigated the effects of doxepin on passive avoidance learning and the levels of tumor necrosis factor-alpha (TNF-alpha) in the rat hippocampus following repeated restraint stress. Male Wistar rats were divided into five groups. Chronic stress was induced by keeping animals within an adjustable restraint chamber for 6 h every day for 21 successive days. In stress-doxepin group, stressed rats were given 1, 5 and 10 mg/kg of doxepin intraperitoneally (i.p) for 21 days and before placing them in restraint chamber. Healthy animals who served as control group and stressed rats received normal saline i.p. For evaluation of learning and memory, initial latency and step-through latency were determined using passive avoidance learning test. TNF-alpha levels were measured in hippocampus by enzyme-linked immunosorbant assay (ELISA) at the end of experiment. Induced stress considerably decreased the step through latencies in the rats (P<0.05) but doxepin administration prevented these changes. Stress doxepin groups did not reveal any differences compared to control group at any given doses. TNF-alpha level was increased significantly (P<0.05) in stress group. Only the low dose of doxepin (1 mg/kg) decreased TNF-alpha level. The present findings indicated that learning and memory are impaired in stressful conditions and doxepin prevented memory deficit. It seems that inflammation may involve in induced stress memory deficits, and that doxepin is helpful in alleviating the neural complications due to stress. PMID- 26752996 TI - Modelling subject-specific childhood growth using linear mixed-effect models with cubic regression splines. AB - BACKGROUND: Childhood growth is a cornerstone of pediatric research. Statistical models need to consider individual trajectories to adequately describe growth outcomes. Specifically, well-defined longitudinal models are essential to characterize both population and subject-specific growth. Linear mixed-effect models with cubic regression splines can account for the nonlinearity of growth curves and provide reasonable estimators of population and subject-specific growth, velocity and acceleration. METHODS: We provide a stepwise approach that builds from simple to complex models, and account for the intrinsic complexity of the data. We start with standard cubic splines regression models and build up to a model that includes subject-specific random intercepts and slopes and residual autocorrelation. We then compared cubic regression splines vis-a-vis linear piecewise splines, and with varying number of knots and positions. Statistical code is provided to ensure reproducibility and improve dissemination of methods. Models are applied to longitudinal height measurements in a cohort of 215 Peruvian children followed from birth until their fourth year of life. RESULTS: Unexplained variability, as measured by the variance of the regression model, was reduced from 7.34 when using ordinary least squares to 0.81 (p < 0.001) when using a linear mixed-effect models with random slopes and a first order continuous autoregressive error term. There was substantial heterogeneity in both the intercept (p < 0.001) and slopes (p < 0.001) of the individual growth trajectories. We also identified important serial correlation within the structure of the data (rho = 0.66; 95 % CI 0.64 to 0.68; p < 0.001), which we modeled with a first order continuous autoregressive error term as evidenced by the variogram of the residuals and by a lack of association among residuals. The final model provides a parametric linear regression equation for both estimation and prediction of population- and individual-level growth in height. We show that cubic regression splines are superior to linear regression splines for the case of a small number of knots in both estimation and prediction with the full linear mixed effect model (AIC 19,352 vs. 19,598, respectively). While the regression parameters are more complex to interpret in the former, we argue that inference for any problem depends more on the estimated curve or differences in curves rather than the coefficients. Moreover, use of cubic regression splines provides biological meaningful growth velocity and acceleration curves despite increased complexity in coefficient interpretation. CONCLUSIONS: Through this stepwise approach, we provide a set of tools to model longitudinal childhood data for non statisticians using linear mixed-effect models. PMID- 26752998 TI - Erratum to: No training required: experimental tests support homology-based DNA assembly as a best practice in synthetic biology. AB - [This corrects the article DOI: 10.1186/s13036-015-0006-z.]. PMID- 26752999 TI - Multi-scale processes of beech wood disintegration and pretreatment with 1-ethyl 3-methylimidazolium acetate/water mixtures. AB - BACKGROUND: The valorization of biomass for chemicals and fuels requires efficient pretreatment. One effective strategy involves the pretreatment with ionic liquids which enables enzymatic saccharification of wood within a few hours under mild conditions. This pretreatment strategy is, however, limited by water and the ionic liquids are rather expensive. The scarce understanding of the involved effects, however, challenges the design of alternative pretreatment concepts. This work investigates the multi length-scale effects of pretreatment of wood in 1-ethyl-3-methylimidazolium acetate (EMIMAc) in mixtures with water using spectroscopy, X-ray and neutron scattering. RESULTS: The structure of beech wood is disintegrated in EMIMAc/water mixtures with a water content up to 8.6 wt%. Above 10.7 wt%, the pretreated wood is not disintegrated, but still much better digested enzymatically compared to native wood. In both regimes, component analysis of the solid after pretreatment shows an extraction of few percent of lignin and hemicellulose. In concentrated EMIMAc, xylan is extracted more efficiently and lignin is defunctionalized. Corresponding to the disintegration at macroscopic scale, SANS and XRD show isotropy and a loss of crystallinity in the pretreated wood, but without distinct reflections of type II cellulose. Hence, the microfibril assembly is decrystallized into rather amorphous cellulose within the cell wall. CONCLUSIONS: The molecular and structural changes elucidate the processes of wood pretreatment in EMIMAc/water mixtures. In the aqueous regime with >10.7 wt% water in EMIMAc, xyloglucan and lignin moieties are extracted, which leads to coalescence of fibrillary cellulose structures. Dilute EMIMAc/water mixtures thus resemble established aqueous pretreatment concepts. In concentrated EMIMAc, the swelling due to decrystallinization of cellulose, dissolution of cross-linking xylan, and defunctionalization of lignin releases the mechanical stress to result in macroscopic disintegration of cells. The remaining cell wall constituents of lignin and hemicellulose, however, limit a recrystallization of the solvated cellulose. These pretreatment mechanisms are beyond common pretreatment concepts and pave the way for a formulation of mechanistic requirements of pretreatment with simpler pretreatment liquors. PMID- 26752997 TI - Mice subjected to aP2-Cre mediated ablation of microsomal triglyceride transfer protein are resistant to high fat diet induced obesity. AB - BACKGROUND: Microsomal triglyceride transfer protein (MTP) is essential for the assembly of lipoproteins. MTP has been shown on the surface of lipid droplets of adipocytes; however its function in adipose tissue is not well defined. We hypothesized that MTP may play critical role in adipose lipid droplet formation and expansion. METHODS: Plasmids mediated overexpression and siRNA mediated knockdown of Mttp gene were performed in 3T3-L1 pre-adipocytes to evaluate the effects of MTP on cell differentiation and triglyceride accumulation. Adipose specific knockdown of MTP was achieved in mice bybreeding MTP floxed (Mttp (fl/fl) ) mice with aP2-Cre recombinase transgenic mice. Adipose-specific MTP deficient (A-Mttp (-/-) ) mice were fed 60 % high-fat diet (HFD), and the effects of MTP knockdown on body weight, body fat composition, plasma and tissues lipid composition, glucose metabolism, lipogenesis and intestinal absorption was studied. Lipids were measured in total fasting plasma and size fractionated plasma using colorimetric assays. Gene expression was investigated by Real-Time quantitative PCR. All data was assessed using t-test, ANOVA. RESULTS: MTP expression increased during early differentiation in 3T3-L1 cells, and declined later. The increases in MTP expression preceded PPARgamma expression. MTP overexpression enhanced lipid droplets formation, and knockdown attenuated cellular lipid accumulation. These studies indicated that MTP positively affects adipogenesis. The ablation of the Mttp gene using aP2-Cre (A-Mttp (-/-) ) in mice resulted in a lean phenotype when fed a HFD. These mice had reduced white adipose tissue compared with wild-type Mttp (fl/fl) mice. The adipose tissue of A-Mttp ( /-) mice had increased number of smaller size adipocytes and less macrophage infiltration. Further, these mice were protected from HFD-induced fatty liver. The A-Mttp (-/-) mice had moderate increase in plasma triglyceride, but normal cholesterol, glucose and insulin levels. Gene expression analysis showed that the adipose tissue of the A-Mttp (-/-) mice had significantly lower mRNA levels of PPARgamma and its downstream targets. CONCLUSION: These data suggest that MTP might modulate adipogenesis by influencing PPARgamma expression, and play a role in the accretion of lipids to form larger lipid droplets. Thus, agents that inactivate adipose MTP may be useful anti-obesity drugs. PMID- 26753000 TI - Roles of cofactors and chromatin accessibility in Hox protein target specificity. AB - BACKGROUND: The regulation of specific target genes by transcription factors is central to our understanding of gene network control in developmental and physiological processes yet how target specificity is achieved is still poorly understood. This is well illustrated by the Hox family of transcription factors as their limited in vitro DNA-binding specificity contrasts with their clear in vivo functional specificity. RESULTS: We generated genome-wide binding profiles for three Hox proteins, Ubx, Abd-A and Abd-B, following transient expression in Drosophila Kc167 cells, revealing clear target specificity and a striking influence of chromatin accessibility. In the absence of the TALE class homeodomain cofactors Exd and Hth, Ubx and Abd-A bind at a very similar set of target sites in accessible chromatin, whereas Abd-B binds at an additional specific set of targets. Provision of Hox cofactors Exd and Hth considerably modifies the Ubx genome-wide binding profile enabling Ubx to bind at an additional novel set of targets. Both the Abd-B specific targets and the cofactor dependent Ubx targets are in chromatin that is relatively DNase1 inaccessible prior to the expression of Hox proteins/Hox cofactors. CONCLUSIONS: Our experiments demonstrate a strong role for chromatin accessibility in Hox protein binding and suggest that Hox protein competition with nucleosomes has a major role in Hox protein target specificity in vivo. PMID- 26753001 TI - HOMA-IR is associated with significant angiographic coronary artery disease in non-diabetic, non-obese individuals: a cross-sectional study. AB - Insulin resistance is a major component of metabolic syndrome, type 2 Diabetes Mellitus (T2DM) and coronary artery disease (CAD). Although important in T2DM, its role as a predictor of CAD in non-diabetic patients is less studied. In the present study, we aimed to evaluate the association of HOMA-IR with significant CAD, determined by coronary angiography in non-obese, non-T2DM patients. We also evaluate the association between 3 oral glucose tolerance test (OGTT) based insulin sensitivity indexes (Matsuda, STUMVOLL-ISI and OGIS) and CAD. We conducted a cross-sectional study with 54 non-obese, non-diabetic individuals referred for coronary angiography due to suspected CAD. CAD was classified as the "anatomic burden score" corresponding to any stenosis equal or larger than 50 % in diameter on the coronary distribution. Patients without lesions were included in No-CAD group. Patients with at least 1 lesion were included in the CAD group. A 75 g oral glucose tolerance test (OGTT) with measurements of plasma glucose and serum insulin at 0, 30, 60, 90 and 120 min was obtained to calculate insulin sensitivity parameters. HOMA-IR results were ranked and patients were also categorized into insulin resistant (IR) or non-insulin resistant (NIR) if they were respectively above or below the 75th percentile (HOMA-IR > 4.21). The insulin sensitivity tests results were also divided into IR and NIR, respectively below and above each 25th percentile. Chi square was used to study association. Poisson Regression Model was used to compare prevalence ratios between categorized CAD and IR groups. RESULTS: Fifty-four patients were included in the study. There were 26 patients (48 %) with significant CAD. The presence of clinically significant CAD was significant associated with HOMA-IR above p75 (Chi square 4.103, p = 0.0428) and 71 % of patients with HOMA-IR above p75 had significant CAD. Subjects with CAD had increased prevalence ratio of HOMA-IR above p75 compared to subjects without CAD (PR 1.78; 95 % CI 1.079-2.95; p = 0.024). Matsuda index, Stumvoll-ISI and OGIS index were not associated with significant CAD. We concluded that, in patients without diabetes or obesity, in whom a coronary angiography study is indicated, a single determination of HOMA-IR above 4.21 indicates increased risk for clinical significant coronary disease. The same association was not seen with insulin sensitivity indexes such as Matsuda, Stunvoll-ISI or OGIS. These findings support the need for further longitudinal research using HOMA-IR as a predictor of cardiovascular disease. PMID- 26753002 TI - rs1888747 polymorphism in the FRMD3 gene, gene and protein expression: role in diabetic kidney disease. AB - BACKGROUND: We carried out a case-control study in patients with type 2 diabetes mellitus (T2DM) to evaluate the association between seven single nucleotide polymorphisms (SNPs) previously described to be linked to diabetic kidney disease (DKD) in type 1 diabetes mellitus (T1DM). Additionally, we evaluated gene and protein expression related to the polymorphism associated with DKD. METHODS: The association study included 1098 T2DM patients (718 with DKD and 380 without DKD). Out of the 13 polymorphisms associated with DKD in a previous study with T1DM, seven were chosen for evaluation in this sample: rs1888747, rs9521445, rs39075, rs451041, rs1041466, rs1411766 and rs6492208. The expression study included 91 patients who underwent nephrectomy. Gene expression was assessed by RT-qPCR and protein expression in kidney samples was quantified by western blot and it localization by immunohistochemistry. RESULTS: The C/C genotype of rs1888747 SNP was associated with protection for DKD (OR = 0.6, 95 % CI 0.3-0.9; P = 0.022). None of the other SNPs were associated with DKD. rs1888747 is located near FRMD3 gene. Therefore, FRMD3 gene and protein expression were evaluated in human kidney tissue according to rs1888747 genotypes. Gene and protein expression were similar in subjects homozygous for the C allele and in those carrying the G allele. CONCLUSIONS: Replication of the association between rs1888747 SNP and DKD in a different population suggests that this link is not the result of chance. rs1888747 SNP is located at the FRMD3 gene, which is expressed in human kidney. Therefore, this gene is a candidate gene for DKD. However, in this study, no rs1888747 genotype or specific allele effect on gene and/or protein expression of the FRMD3 gene was demonstrated. PMID- 26753004 TI - ALK inhibitors in non-small cell lung cancer: the latest evidence and developments. AB - The treatment of patients with advanced non-small cell lung cancer (NSCLC) harbouring chromosomal rearrangements of ALK (anaplastic lymphoma kinase) was revolutionized by crizotinib, a small molecule inhibitor of ALK, ROS1 and MET. Unfortunately, the disease progressed within the first 12 months in most of the patients because of the development of crizotinib resistance in the majority of patients and the emergence of acquired resistance mutations in most of them. Many of them had been reported even before its approval leading to the rapid development of second-generation ALK inhibitors for crizotinib-resistant NSCLC. In the last few years, novel potent ALK inhibitors with promising results and a good toxicity profile have become available: ceritinib (LDK378), alectinib (RG7853/AF-802/RO5424802/CH5424802), brigatinib (AP26113), entrectinib (RXDX-101, NMS-E628), PF-06463922, ASP3026, TSR-011, X-376/X-396 and CEP-28122/CEP-37440. Moreover, HSP90 (90 kDa heat shock protein) inhibitors have demonstrated clinical activity in patients with ALK+ NSCLC. This review focuses on the molecular and clinical properties of this new generation of ALK inhibitors under development in the clinic. PMID- 26753005 TI - Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy. AB - Treatment with BRAF inhibitors such as vemurafenib or dabrafenib in patients with advanced BRAFV600 mutated melanoma has shown objective tumor responses in approximately half of the patients. However, the duration of responses is limited in a majority of these patients, with progression-free survival rates around 6 months due to tumor progression from development of acquired resistance. Preclinical studies have suggested that concurrent inhibition of the BRAF kinases and MEK of the mitogen-activated protein kinase (MAPK) pathway could decrease MAPK-driven acquired resistance, resulting in longer duration of responses, higher rate of tumor responses, and a decrease in the cutaneous toxicities observed from paradoxical MAPK pathway activation with BRAF inhibitor monotherapy. This review provides an overview of the currently available clinical trial data on BRAF and MEK inhibitors together and in combinations with other therapeutic agents. PMID- 26753007 TI - Postmastectomy radiation therapy after neoadjuvant chemotherapy: review and interpretation of available data. AB - Postmastectomy radiotherapy (PMRT) has been shown to decrease locoregional recurrence and improve overall survival in patients with tumors greater than 5 cm or positive nodes. Because neoadjuvant chemotherapy (NAC) can cause significant downstaging, the indications for PMRT in the setting of NAC remain controversial and thus careful consideration of clinical stage at presentation, pathologic response to NAC, and other clinical characteristics, such as grade and biomarker status is required. The current review synthesizes both prospective and retrospective data to provide evidence for recommending PMRT after NAC for patients presenting with cT3-4 disease, cN2-3 disease, and residual nodal disease, as well as rationale for omitting PMRT in patients with cT1-2N0-1 disease who achieve a pathologic complete response. Other scenarios, including nodal complete response in the presence of other risk factors, are also explored. The topics of pre-NAC clinical staging and pathologic axillary nodal staging are reviewed, and radiation portal design is briefly discussed. PMID- 26753006 TI - Pharmacologic resistance in colorectal cancer: a review. AB - Colorectal cancer (CRC) persists as one of the most prevalent and deadly tumor types in both men and women worldwide. This is in spite of widespread, effective measures of preventive screening, and also major advances in treatment options. Despite advances in cytotoxic and targeted therapy, resistance to chemotherapy remains one of the greatest challenges in long-term management of incurable metastatic disease and eventually contributes to death as tumors accumulate means of evading treatment. We performed a comprehensive literature search on the data available through PubMed, Medline, Scopus, and the ASCO Annual Symposium abstracts through June 2015 for the purpose of this review. We discuss the current state of knowledge of clinically relevant mechanisms of resistance to cytotoxic and targeted therapies now in use for the treatment of CRC. PMID- 26753003 TI - Novel cancer antigens for personalized immunotherapies: latest evidence and clinical potential. AB - The clinical success of monoclonal antibody immune checkpoint modulators such as ipilimumab, which targets cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and the recently approved agents nivolumab and pembrolizumab, which target programmed cell death receptor 1 (PD-1), has stimulated renewed enthusiasm for anticancer immunotherapy, which was heralded by Science as 'Breakthrough of the Year' in 2013. As the potential of cancer immunotherapy has been recognized since the 1890s when William Coley showed that bacterial products could be beneficial in cancer patients, leveraging the immune system in the treatment of cancer is certainly not a new concept; however, earlier attempts to develop effective therapeutic vaccines and antibodies against solid tumors, for example, melanoma, frequently met with failure due in part to self-tolerance and the development of an immunosuppressive tumor microenvironment. Increased knowledge of the mechanisms through which cancer evades the immune system and the identification of tumor-associated antigens (TAAs) and negative immune checkpoint regulators have led to the development of vaccines and monoclonal antibodies targeting specific tumor antigens and immune checkpoints such as CTLA-4 and PD-1. This review first discusses the established targets of currently approved cancer immunotherapies and then focuses on investigational cancer antigens and their clinical potential. Because of the highly heterogeneous nature of tumors, effective anticancer immunotherapy-based treatment regimens will likely require a personalized combination of therapeutic vaccines, antibodies and chemotherapy that fit the specific biology of a patient's disease. PMID- 26753008 TI - GENESIS: a hybrid-parallel and multi-scale molecular dynamics simulator with enhanced sampling algorithms for biomolecular and cellular simulations. AB - GENESIS (Generalized-Ensemble Simulation System) is a new software package for molecular dynamics (MD) simulations of macromolecules. It has two MD simulators, called ATDYN and SPDYN. ATDYN is parallelized based on an atomic decomposition algorithm for the simulations of all-atom force-field models as well as coarse grained Go-like models. SPDYN is highly parallelized based on a domain decomposition scheme, allowing large-scale MD simulations on supercomputers. Hybrid schemes combining OpenMP and MPI are used in both simulators to target modern multicore computer architectures. Key advantages of GENESIS are (1) the highly parallel performance of SPDYN for very large biological systems consisting of more than one million atoms and (2) the availability of various REMD algorithms (T-REMD, REUS, multi-dimensional REMD for both all-atom and Go-like models under the NVT, NPT, NPAT, and NPgammaT ensembles). The former is achieved by a combination of the midpoint cell method and the efficient three-dimensional Fast Fourier Transform algorithm, where the domain decomposition space is shared in real-space and reciprocal-space calculations. Other features in SPDYN, such as avoiding concurrent memory access, reducing communication times, and usage of parallel input/output files, also contribute to the performance. We show the REMD simulation results of a mixed (POPC/DMPC) lipid bilayer as a real application using GENESIS. GENESIS is released as free software under the GPLv2 licence and can be easily modified for the development of new algorithms and molecular models. WIREs Comput Mol Sci 2015, 5:310-323. doi: 10.1002/wcms.1220. PMID- 26753010 TI - Myeloid Proliferations Associated with Down Syndrome. PMID- 26753009 TI - The activation strain model and molecular orbital theory. AB - The activation strain model is a powerful tool for understanding reactivity, or inertness, of molecular species. This is done by relating the relative energy of a molecular complex along the reaction energy profile to the structural rigidity of the reactants and the strength of their mutual interactions: DeltaE(zeta) = DeltaEstrain(zeta) + DeltaEint(zeta). We provide a detailed discussion of the model, and elaborate on its strong connection with molecular orbital theory. Using these approaches, a causal relationship is revealed between the properties of the reactants and their reactivity, e.g., reaction barriers and plausible reaction mechanisms. This methodology may reveal intriguing parallels between completely different types of chemical transformations. Thus, the activation strain model constitutes a unifying framework that furthers the development of cross-disciplinary concepts throughout various fields of chemistry. We illustrate the activation strain model in action with selected examples from literature. These examples demonstrate how the methodology is applied to different research questions, how results are interpreted, and how insights into one chemical phenomenon can lead to an improved understanding of another, seemingly completely different chemical process. WIREs Comput Mol Sci 2015, 5:324-343. doi: 10.1002/wcms.1221. PMID- 26753011 TI - "Monoallelic germline methylation and sequence variant in the promoter of the RB1 gene: a possible constitutive epimutation in hereditary retinoblastoma". AB - BACKGROUND: Retinoblastoma is a malignant tumor of the retina in children <5 years of age and occurs after two mutations in the RB1 gene. The first mutation (M1) is germinal and confers predisposition to the hereditary type, which is transmitted as an autosomal dominant highly penetrant trait, so 90 % of carriers develop retinoblastoma; however, 10 % of carriers either do not develop the tumor or develop it unilaterally. Most mutations are point mutations. Inactivation of the RB1 gene is usually caused by mutations affecting the coding region. Silencing by methylation of the RB1 promoter has been observed in retinoblastoma tumors as a second mutation (M2) and is classified as somatic epimutation. Germline methylation of the RB1 gene promoter was studied in a particular pedigree of six generations from the paternal side, with incomplete penetrance and bias towards healthy male carriers and those affected with unilateral retinoblastoma. RESULTS: The methylation status of the 27 CpGs dinucleotides that constitute the core of the RB1 gene promoter, analyzed by cloning and genomic sequencing after DNA sodium bisulfite conversion, demonstrated a monoallelic methylation pattern which coincides with a c. [-187T > G; -188T > G] sequence variant that is found in peripheral blood lymphocytes and tumor DNA. Unexpectedly, it was the mother who transmitted this variant to two more generations. Microsatellite markers of D chromosome showed a biparental contribution of both D13 chromosomes to the retinoblastoma phenotype, conferring double heterozygosity in the affected cases. CONCLUSIONS: The monoallelic genetic epigenetic finding, the sequence variant, and methylation suggest a constitutive epimutation and probably a genetic-epigenetic hereditary predisposition for retinoblastoma in this family. PMID- 26753015 TI - From the Editor-in-Chief: The Next Phase of Discipline-Based Education Research Is Here! PMID- 26753014 TI - Restricted Covariance Priors with Applications in Spatial Statistics. AB - We present a Bayesian model for area-level count data that uses Gaussian random effects with a novel type of G-Wishart prior on the inverse variance- covariance matrix. Specifically, we introduce a new distribution called the truncated G Wishart distribution that has support over precision matrices that lead to positive associations between the random effects of neighboring regions while preserving conditional independence of non-neighboring regions. We describe Markov chain Monte Carlo sampling algorithms for the truncated G-Wishart prior in a disease mapping context and compare our results to Bayesian hierarchical models based on intrinsic autoregression priors. A simulation study illustrates that using the truncated G-Wishart prior improves over the intrinsic autoregressive priors when there are discontinuities in the disease risk surface. The new model is applied to an analysis of cancer incidence data in Washington State. PMID- 26753012 TI - Clinical features and outcomes of germline mutation BRCA1-linked versus sporadic ovarian cancer patients. AB - BACKGROUND: The role of germline mutations in BRCA1 and BRCA2 genes in the risk of the development of ovarian cancer is clinically well established. BRCA1/2 testing seems to have increasing role in clinical management in patients with advanced ovarian cancer who require treatment with poly(ADP-ribose) polymerase inhibitors. METHODS: Between 2002 - 2008, 125 consecutive patients with ovarian cancer were categorized as having three founder mutations in the BRCA1 gene in Poland as: 5382insC [exon 20], 4153delA [exon 11.17], and 300 T > G [exon 5]. PFS (progression free survival) and OS (overall survival) were determined by Kaplan Meier analysis with log rank test, univariate comparisons, and multivariate regression analysis using Cox proportional hazards model. RESULTS: Of the 125 patients, the founder mutations of BRCA1 were reported in 17 patients (13.6 %). The median OS was longer for BRCA mutated patients (not reached vs 35.6 months, p = 0.041). PFS was similar for both kinds of ovarian cancer. In multivariate analysis, age >=70 years, suboptimal surgery, and BRCA1 wild type were poor prognostic factors. The BRCA1 mutation reduced the likelihood of death in ovarian cancer by 86 % (HR 0.14; CI: 0.032-0.650, p = 0.012). CONCLUSION: In conclusion, we found better overall survival for ovarian cancer patients with BRCA1 germline mutations in comparison with patients without these mutations (sporadic) ovarian cancer. Thus, BRCA1 germline mutations appear to be an independent prognostic factor for ovarian cancer. PMID- 26753016 TI - Clarification to Points in "Correlating Student Knowledge and Confidence Using a Graded Knowledge Survey to Assess Student Learning in a General Microbiology Classroom". PMID- 26753017 TI - PULSE Pilot Certification Results. PMID- 26753018 TI - What's Not Being Discussed, or Considered, in Science Publishing? PMID- 26753019 TI - Lifeguard Final Exam-Encouraging the Use of Active Learning. PMID- 26753020 TI - ASM Scientific Writing and Publishing Institute: Program Impacts and Future Expansion. PMID- 26753021 TI - The Climate Experiences of Students in Introductory Biology. AB - Understanding course climate is important for improving students' experiences and increasing the likelihood of their persistence in STEM fields. This study presents climate survey results from 523 students taking introductory biology at the University of Michigan. Principal component analysis revealed that a student's climate experience is comprised of five main elements: comfort, school avoidance, relationship to course, academic stress, and discomfort. Of these climate factors, comfort, school avoidance, and relationship to course were significant predictors of course satisfaction, and academic stress was a significant predictor of persistence. The results indicated the importance of a positive climate that is facilitated by the instructor in order to promote a positive student experience. Climate may be an important metric for institutions to track across time and course. PMID- 26753022 TI - Targeting Critical Thinking Skills in a First-Year Undergraduate Research Course. AB - TH!NK is a new initiative at NC State University focused on enhancing students' higher-order cognitive skills. As part of this initiative, I explicitly emphasized critical and creative thinking in an existing bacteriophage discovery first-year research course. In addition to the typical activities associated with undergraduate research such as review of primary literature and writing research papers, another strategy employed to enhance students' critical thinking skills was the use of discipline-specific, real-world scenarios. This paper outlines a general "formula" for writing scenarios, as well as several specific scenarios created for the described course. I also present how embedding aspects of the scenarios in reviews of the primary literature enriched the activity. I assessed student gains in critical thinking skills using a pre-/posttest model of the Critical Thinking Assessment Test (CAT), developed by Tennessee Technological University. I observed a positive gain trend in most of the individual skills assessed in the CAT, with a statistically significant large effect on critical thinking skills overall in students in the test group. I also show that a higher level of critical thinking skills was demonstrated in research papers written by students who participated in the scenarios compared with similar students who did not participate in the scenario activities. The scenario strategy described here can be modified for use in biology and other STEM disciplines, as well as in diverse disciplines in the social sciences and humanities. PMID- 26753023 TI - A Cross-Course Investigation of Integrative Cases for Evolution Education. AB - Evolution is a cornerstone theory in biology, yet many undergraduate students have difficulty understanding it. One reason for this is that evolution is often taught in a macro-scale context without explicit links to micro-scale processes. To address this, we developed a series of integrative evolution cases that present the evolution of various traits from their origin in genetic mutation, to the synthesis of modified proteins, to how these proteins produce novel phenotypes, to the related macro-scale impacts that the novel phenotypes have on populations in ecological communities. We postulated that students would develop a fuller understanding of evolution when learning biology in a context where these integrative evolution cases are used. We used a previously developed assessment tool, the ATEEK (Assessment Tool for Evaluating Evolution Knowledge), within a pre-course/post-course assessment framework. Students who learned biology in courses using the integrative cases performed significantly better on the evolution assessment than did students in courses that did not use the cases. We also found that student understanding of evolution increased with increased exposure to the integrative evolution cases. These findings support the general hypothesis that students acquire a more complete understanding of evolution when they learn about its genetic and molecular mechanisms along with macro-scale explanations. PMID- 26753024 TI - Action Research to Improve the Learning Space for Diagnostic Techniques. AB - The module described and evaluated here was created in response to perceived learning difficulties in diagnostic test design and interpretation for students in third-year Clinical Microbiology. Previously, the activities in lectures and laboratory classes in the module fell into the lower cognitive operations of "knowledge" and "understanding." The new approach was to exchange part of the traditional activities with elements of interactive learning, where students had the opportunity to engage in deep learning using a variety of learning styles. The effectiveness of the new curriculum was assessed by means of on-course student assessment throughout the module, a final exam, an anonymous questionnaire on student evaluation of the different activities and a focus group of volunteers. Although the new curriculum enabled a major part of the student cohort to achieve higher pass grades (p < 0.001), it did not meet the requirements of the weaker students, and the proportion of the students failing the module remained at 34%. The action research applied here provided a number of valuable suggestions from students on how to improve future curricula from their perspective. Most importantly, an interactive online program that facilitated flexibility in the learning space for the different reagents and their interaction in diagnostic tests was proposed. The methods applied to improve and assess a curriculum refresh by involving students as partners in the process, as well as the outcomes, are discussed. Journal of Microbiology & Biology Education. PMID- 26753025 TI - A Comparison of Two Low-Stakes Methods for Administering a Program-Level Biology Concept Assessment. AB - Concept assessments are used commonly in undergraduate science courses to assess student learning and diagnose areas of student difficulty. While most concept assessments align with the content of individual courses or course topics, some concept assessments have been developed for use at the programmatic level to gauge student progress and achievement over a series of courses or an entire major. The broad scope of a program-level assessment, which exceeds the content of any single course, creates several test administration issues, including finding a suitable time for students to take the assessment and adequately incentivizing student participation. These logistical considerations must also be weighed against test security and the ability of students to use unauthorized resources that could compromise test validity. To understand how potential administration methods affect student outcomes, we administered the Molecular Biology Capstone Assessment (MBCA) to three pairs of matched upper-division courses in two ways: an online assessment taken by students outside of class and a paper-based assessment taken during class. We found that overall test scores were not significantly different and that individual item difficulties were highly correlated between these two administration methods. However, in-class administration resulted in reduced completion rates of items at the end of the assessment. Taken together, these results suggest that an online, outside-of class administration produces scores that are comparable to a paper-based, in class format and has the added advantages that instructors do not have to dedicate class time and students are more likely to complete the entire assessment. PMID- 26753026 TI - Quantitative Analysis of the Trends Exhibited by the Three Interdisciplinary Biological Sciences: Biophysics, Bioinformatics, and Systems Biology. AB - New interdisciplinary biological sciences like bioinformatics, biophysics, and systems biology have become increasingly relevant in modern science. Many papers have suggested the importance of adding these subjects, particularly bioinformatics, to an undergraduate curriculum; however, most of their assertions have relied on qualitative arguments. In this paper, we will show our metadata analysis of a scientific literature database (PubMed) that quantitatively describes the importance of the subjects of bioinformatics, systems biology, and biophysics as compared with a well-established interdisciplinary subject, biochemistry. Specifically, we found that the development of each subject assessed by its publication volume was well described by a set of simple nonlinear equations, allowing us to characterize them quantitatively. Bioinformatics, which had the highest ratio of publications produced, was predicted to grow between 77% and 93% by 2025 according to the model. Due to the large number of publications produced in bioinformatics, which nearly matches the number published in biochemistry, it can be inferred that bioinformatics is almost equal in significance to biochemistry. Based on our analysis, we suggest that bioinformatics be added to the standard biology undergraduate curriculum. Adding this course to an undergraduate curriculum will better prepare students for future research in biology. PMID- 26753027 TI - Reading, Writing, and Presenting Original Scientific Research: A Nine-Week Course in Scientific Communication for High School Students. AB - High school students are not often given opportunities to communicate scientific findings to their peers, the general public, and/or people in the scientific community, and therefore they do not develop scientific communication skills. We present a nine-week course that can be used to teach high school students, who may have no previous experience, how to read and write primary scientific articles and how to discuss scientific findings with a broad audience. Various forms of this course have been taught for the past 10 years as part of an intensive summer research program for rising high school seniors that is coordinated by the Young Scientist Program at Washington University in St. Louis. The format presented here includes assessments for efficacy through both rubric based methods and student self-assessment surveys. PMID- 26753028 TI - Discovery of the Collaborative Nature of Science with Undergraduate Science Majors and Non-Science Majors through the Identification of Microorganisms Enriched in Winogradsky Columns. AB - Today's science classrooms are addressing the need for non-scientists to become scientifically literate. A key aspect includes the recognition of science as a process for discovery. This process relies upon interdisciplinary collaboration. We designed a semester-long collaborative exercise that allows science majors taking a general microbiology course and non-science majors taking an introductory environmental science course to experience collaboration in science by combining their differing skill sets to identify microorganisms enriched in Winogradsky columns. These columns are self-sufficient ecosystems that allow researchers to study bacterial populations under specified environmental conditions. Non-science majors identified phototrophic bacteria enriched in the column by analyzing the signature chlorophyll absorption spectra whereas science majors used 16S rRNA gene sequencing to identify the general bacterial diversity. Students then compiled their results and worked together to generate lab reports with their final conclusions identifying the microorganisms present in their column. Surveys and lab reports were utilized to evaluate the learning objectives of this activity. In pre-surveys, nonmajors' and majors' answers diverged considerably, with majors providing responses that were more accurate and more in line with the working definition of collaboration. In post-surveys, the answers between majors and nonmajors converged, with both groups providing accurate responses. Lab reports showed that students were able to successfully identify bacteria present in the columns. These results demonstrate that laboratory exercises designed to group students across disciplinary lines can be an important tool in promoting science education across disciplines. PMID- 26753029 TI - The Emerging Microbe Project: Developing Clinical Care Plans Based on Pathogen Identification and Clinical Case Studies. AB - For many students in the health sciences, including doctor of pharmacy (PharmD) students, basic and clinical sciences often appear detached from each other. In the infectious disease field, PharmD students additionally struggle with mastering the diversity of microorganisms and the corresponding therapies. The objective of this study was to design an interdisciplinary project that integrates fundamental microbiology with clinical research and decision-making skills. The Emerging Microbe Project guided students through the identification of a microorganism via genetic sequence analysis. The unknown microbe provided the basis for a patient case that asked the student to design a therapeutic treatment strategy for an infected patient. Outside of lecture, students had two weeks to identify the pathogen using nucleotide sequences, compose a microbiology report on the pathogen, and recommend an appropriate therapeutic treatment plan for the corresponding clinical case. We hypothesized that the students would develop a better understanding of the interplay between basic microbiology and infectious disease clinical practice, and that they would gain confidence and skill in independently selecting appropriate antimicrobial therapies for a new disease state. The exercise was conducted with PharmD students in their second professional year of pharmacy school in a required infectious disease course. Here, we demonstrate that the Emerging Microbe Project significantly improved student learning through two assessment strategies (assignment grades and exam questions), and increased student confidence in clinical infectious disease practice. This exercise could be modified for other health sciences students or undergraduates depending upon the level of clinical focus required of the course. PMID- 26753030 TI - Brewing for Students: An Inquiry-Based Microbiology Lab. AB - In an effort to improve and assess student learning, there has been a push to increase the incorporation of discovery-driven modules and those that contain real-world relevance into laboratory curricula. To further this effort, we have developed, implemented, and assessed an undergraduate microbiology laboratory experiment that requires students to use the scientific method while brewing beer. The experiment allows students to brew their own beer and characterize it based on taste, alcohol content, calorie content, pH, and standard reference method. In addition, we assessed whether students were capable of achieving the module learning objectives through a pre-/posttest, student self-evaluation, exam embedded questions, and an associated worksheet. These objectives included describing the role of the brewing ingredients and predicting how altering the ingredients would affect the characteristics of the beer, amongst others. By completing this experimental module, students accomplished the module objectives, had greater interest in brewing, and were more likely to view beer in scientific terms. Journal of Microbiology & Biology Education. PMID- 26753031 TI - Laboratory Activity to Teach about the Proliferation of Salmonella in Vegetables. AB - We designed a three-week laboratory experience that can complement any microbiology teaching laboratory to expand students' knowledge of the ecology of human enteric pathogens outside of their animal hosts. Through their participation in this laboratory activity, students learned that vegetative and reproductive plant parts could be a natural habitat for enteric bacteria such as non-typhoidal strains of Salmonella enterica. This field was recently brought to the forefront of the scientific community and public interest by outbreaks of human illness linked to the consumption of fresh fruits and vegetables. Students were encouraged to develop their own testable hypotheses to compare proliferation of Salmonella enterica sv Typhimurium LT2 in different vegetables: cherry and regular-size tomatoes, onions, lettuce, and yellow and red bell peppers (Escherichia coli can be substituted for BSL1 laboratories). Upon completion of the laboratory experience, students were able to: 1) Develop testable hypotheses addressing the ability of a human pathogen, Salmonella enterica, to colonize and proliferate in vegetables; 2) Determine that different vegetables support the growth of Salmonella to different extents; 3) Conduct statistical analysis and identify any significant differences. The teaching-learning process was assessed with a pre-/posttest, with an average increase in content understanding from ~15% to 85%. We also measured students' proficiency while conducting specific technical tasks, revealing no major difficulties while conducting the experiments. Students indicated satisfaction with the organization and content of the practices. All of the students (100%) agreed that the exercises improved their knowledge of this subject. PMID- 26753032 TI - Biotechnology by Design: An Introductory Level, Project-Based, Synthetic Biology Laboratory Program for Undergraduate Students. AB - Synthetic biology offers an ideal opportunity to promote undergraduate laboratory courses with research-style projects, immersing students in an inquiry-based program that enhances the experience of the scientific process. We designed a semester-long, project-based laboratory curriculum using synthetic biology principles to develop a novel sensory device. Students develop subject matter knowledge of molecular genetics and practical skills relevant to molecular biology, recombinant DNA techniques, and information literacy. During the spring semesters of 2014 and 2015, the Synthetic Biology Laboratory Project was delivered to sophomore genetics courses. Using a cloning strategy based on standardized BioBrick genetic "parts," students construct a "reporter plasmid" expressing a reporter gene (GFP) controlled by a hybrid promoter regulated by the lac-repressor protein (lacI). In combination with a "sensor plasmid," the production of the reporter phenotype is inhibited in the presence of a target environmental agent, arabinose. When arabinose is absent, constitutive GFP expression makes cells glow green. But the presence of arabinose activates a second promoter (pBAD) to produce a lac-repressor protein that will inhibit GFP production. Student learning was assessed relative to five learning objectives, using a student survey administered at the beginning (pre-survey) and end (post survey) of the course, and an additional 15 open-ended questions from five graded Progress Report assignments collected throughout the course. Students demonstrated significant learning gains (p < 0.05) for all learning outcomes. Ninety percent of students indicated that the Synthetic Biology Laboratory Project enhanced their understanding of molecular genetics. The laboratory project is highly adaptable for both introductory and advanced courses. PMID- 26753033 TI - An Alternative Approach to "Identification of Unknowns": Designing a Protocol to Verify the Identities of Nitrogen Fixing Bacteria. AB - Microbiology courses often include a laboratory activity on the identification of unknown microbes. This activity consists of providing students with microbial cultures and running biochemical assays to identify the organisms. This approach lacks molecular techniques such as sequencing of genes encoding 16S rRNA, which is currently the method of choice for identification of unknown bacteria. A laboratory activity was developed to teach students how to identify microorganisms using 16S rRNA polymerase chain reaction (PCR) and validate microbial identities using biochemical techniques. We hypothesized that designing an experimental protocol to confirm the identity of a bacterium would improve students' knowledge of microbial identification techniques and the physiological characteristics of bacterial species. Nitrogen-fixing bacteria were isolated from the root nodules of Medicago truncatula and prepared for 16S rRNA PCR analysis. Once DNA sequencing revealed the identity of the organisms, the students designed experimental protocols to verify the identity of rhizobia. An assessment was conducted by analyzing pre- and posttest scores and by grading students' verification protocols and presentations. Posttest scores were higher than pretest scores at or below p = 0.001. Normalized learning gains (G) showed an improvement of students' knowledge of microbial identification methods (LO4, G = 0.46), biochemical properties of nitrogen-fixing bacteria (LO3, G = 0.45), and the events leading to the establishment of nitrogen-fixing symbioses (LO1&2, G = 0.51, G = 0.37). An evaluation of verification protocols also showed significant improvement with a p value of less than 0.001. PMID- 26753034 TI - Presenting Clicker Questions with an Open- Versus Closed-Response Format. PMID- 26753035 TI - Deciphering Primary and Popular Literature: An Interactive Approach for Promoting Students' Development of Scientific, Digital, and Information Literacy in Post Secondary Contexts. PMID- 26753036 TI - Using a Vaccine Proposal Assignment to Help Students Synthesize Topics Covered in an Undergraduate Immunology Course. PMID- 26753038 TI - There's More to Science than Research: A Team-Based Role Game to Develop School Students' Understanding of Science Careers in Pharmaceutical Quality Control. PMID- 26753037 TI - Self-Driven Service Learning: Community-Student-Faculty Collaboratives Outside of the Classroom. PMID- 26753039 TI - The Use of Online Pre-Lab Assessments Compared with Written Pre-Lab Assignments Requiring Experimental Result Prediction Shows No Difference in Student Performance. PMID- 26753041 TI - Modeling the Dynamic Digestive System Microbiome. PMID- 26753040 TI - A Publicly Available PCR Methods Laboratory Manual and Supporting Material. PMID- 26753043 TI - A Simulation of Communicable Disease and Herd Immunity for the Microbiology Classroom or Laboratory. PMID- 26753042 TI - Nucleotide Manipulatives to Illustrate the Central Dogma. PMID- 26753044 TI - Creating Stop-Motion Animations to Learn Molecular Biology Dynamics. PMID- 26753045 TI - The Use of Stuffed Microbes in an Undergraduate Microbiology Course Increases Engagement and Student Learning. PMID- 26753047 TI - Moss in the Classroom: A Tiny but Mighty Tool for Teaching Biology. PMID- 26753046 TI - Powerful Soil: Utilizing Microbial Fuel Cell Construction and Design in an Introductory Biology Course. PMID- 26753048 TI - Agar Plates Made from Common Supermarket Substances and Bacillus subtilis Natto as an Inexpensive Approach to Microbiology Education. PMID- 26753050 TI - Quantile regression for censored mixed-effects models with applications to HIV studies. AB - HIV RNA viral load measures are often subjected to some upper and lower detection limits depending on the quantification assays. Hence, the responses are either left or right censored. Linear/nonlinear mixed-effects models, with slight modifications to accommodate censoring, are routinely used to analyze this type of data. Usually, the inference procedures are based on normality (or elliptical distribution) assumptions for the random terms. However, those analyses might not provide robust inference when the distribution assumptions are questionable. In this paper, we discuss a fully Bayesian quantile regression inference using Markov Chain Monte Carlo (MCMC) methods for longitudinal data models with random effects and censored responses. Compared to the conventional mean regression approach, quantile regression can characterize the entire conditional distribution of the outcome variable, and is more robust to outliers and misspecification of the error distribution. Under the assumption that the error term follows an asymmetric Laplace distribution, we develop a hierarchical Bayesian model and obtain the posterior distribution of unknown parameters at the pth level, with the median regression (p = 0.5) as a special case. The proposed procedures are illustrated with two HIV AIDS studies on viral loads that were initially analyzed using the typical normal (censored) mean regression mixed effects models, as well as a simulation study. PMID- 26753051 TI - A National Perspective of Do-Not-Resuscitate Order Utilization Predictors in Intracerebral Hemorrhage. AB - Nontraumatic intracerebral hemorrhage (ICH) is associated with substantial morbidity and mortality. Do-not-resuscitate (DNR) orders are linked to poorer outcomes in patients with ICH, possibly due to less active management. Demographic, regional, and social factors, not related to ICH severity, have not been adequately looked at as significant predictors of DNR utilization. We reviewed the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample (NIS) database in 2011 for adult ICH admissions and DNR status. We generated hierarchical 2-level multivariate regression models to estimate adjusted odds ratios. We analyzed 25 768 ICH hospitalizations, 18% of which (4620 hospitalizations) had DNR orders, corresponding to national estimates of 126 254 and 22 668, respectively. In multivariable regression, female gender, white or Hispanic/Latino ethnicity, no insurance coverage, and teaching hospitals were significantly associated with increased DNR utilization after adjusting for confounders. There was also significantly more interhospital variability in the lowest quartile of hospital volume. In conclusion, demographic factors and insurance status are significantly associated with increased DNR utilization, with more individual hospital variability in low-volume hospitals. The reasons for this are likely qualitative and linked to patient, provider, and hospital practices. PMID- 26753052 TI - Patient-Powered Reporting of Modified Rankin Scale Outcomes Via the Internet. AB - BACKGROUND AND PURPOSE: The modified Rankin Scale (mRS) is a common and resource intensive measure of functional outcome in stroke-related conditions. In this observational prospective cohort feasibility study, mRS scores are generated using a patient-powered online survey and compared to scores obtained by structured telephonic interview. MATERIALS AND METHODS: Fifty-one patients with subarachnoid hemorrhage (SAH) or their surrogates responded to an online survey following discharge from the hospital. These responses were used to generate an mRS score and then compared to blinded telephonic assessments by trained personnel. A weighted kappa (Kw) with confidence intervals (CIs) was calculated. RESULTS: The Kw between the patient/surrogate and the trained personnel scores was 0.85 (95% CI, 0.74-0.95, P < .001). CONCLUSION: This study provides first evidence that patient/surrogate survey responses may be an efficient and reliable alternative to generate mRS scores compared to trained personnel after SAH. PMID- 26753053 TI - An Innovative Model of a Home-Like Environment for People in Vegetative and Minimally Conscious States. AB - BACKGROUND AND PURPOSE: Many forms of assisted living have been proposed for people who have a loss of autonomy in activities of daily living. Despite the increasing prevalence of vegetative and minimally conscious states, no dedicated residential accommodation has been implemented for patients with chronic disorders of consciousness (DOCs). METHODS: This is a descriptive study addressing an innovative model of in-house assistance, named Casa Iride, which has recently been implemented in the attempt to ensure health, safety, and well being for people with DOCs and their families. RESULTS: Our findings show that Casa Iride enables severely disabled individuals to live with dignity within a customized domestic environment. At the same time, it provides support for caregivers from both a practical and a psychological point of view. CONCLUSIONS: The results so far indicate a virtuous cycle that brings health, social, psychological, ethical, and economic advantages: the individuals receive all the assistance needed; the families share a place with other people with similar challenges, become more aware of their situation, and learn to cope with it and to maintain their productivity at work; and the care flow of patients through intensive care units and intensive rehabilitation wards is not delayed by a lack of post discharge services. PMID- 26753055 TI - Weakness in an Elderly Woman With Asthma and Chronic Sinusitis. AB - Weakness and sensory changes are common complaints in both the inpatient and the outpatient setting. However, this presentation remains a diagnostic challenge to clinicians due to the many possible underlying etiologies. The initial evaluation of weakness and sensory changes starts a thorough history and physical examination to guide the diagnostic process. In this article, we present the case of an elderly woman with complaints of weakness and sensory changes to highlight a step-wise approach to diagnosis and management. PMID- 26753054 TI - Nonenhancing Leptomeningeal Metastases: Imaging Characteristics and Potential Causative Factors. AB - The diagnosis of leptomeningeal metastasis (LM) has increased in frequency, as new therapies have lengthened the survival of patients with cancer. Early diagnosis and intervention help improve quality of life and prevent further neurological deterioration in LM. The detection of LM is often established by magnetic resonance imaging examinations, cerebrospinal fluid analysis, or both. We present a series of cases where LM was identified on fluid-attenuated inversion recovery or T2-weighted image but was nonenhancing on the traditionally more sensitive postcontrast T1-weighted sequences. Nonenhancing LM is unusual and not yet fully understood but should be considered in the appropriate clinical context and may become more common with increased utilization of antiangiogenic therapies. PMID- 26753056 TI - Robust Identification of Partial-Correlation Based Networks with Applications to Cortical Thickness Data. AB - Insight into brain development and organization can be gained by computing correlations between structural and funtional measures in parcellated cortex. Partial correlations can often reduce ambiguity in correlation data by identifying those pairs of regions whose similarity cannot be explained by the influence of other regions with which they may both interact. Consequently a graph with edges indicating nonzero partial correlations may reveal important subnetworks obscured in the correlation data. Here we describe and investigate PC*, a graph pruning algorithm for identification of the partial correlation network in comparison to direct calculation of partial correlations from the inverse of the sample correlation matrix. We show that PC* is far more robust and illustrate its use in the study of covariation in cortical thickness in ROIs defined on a parcellated cortex. PMID- 26753058 TI - Future of cardiac computed tomography. AB - Coronary computed tomography angiography (CCTA) has become an integral tool in the noninvasive diagnostic workup of patients with suspected coronary artery disease in both elective and emergency settings. Today, it represents a mature technique providing accurate, non-invasive morphological assessment of the coronary arteries and atherosclerotic plaque burden. Iterative reconstruction algorithms, low kV imaging, and single-heart beat acquisitions hold promise to further reduce dose requirements and improve the safety and robustness of the technique in several circumstances including imaging of heavily calcified vessels, patients with morbid obesity or irregular heart rates, and assessment in the emergency setting. However, it has become clear over recent years that cardiac radiologists need to take further steps towards the development and integration of functional imaging with morphological CCTA assessment to truly provide a comprehensive evaluation of the heart. Computed tomography myocardial perfusion imaging, including both dynamic and static dual-energy approaches, has demonstrated the ability to directly assess and quantify myocardial ischemia with simultaneous CCTA acquisition with a reasonable contrast medium volume and radiation dose delivered to the patient. In order to promote CCTA in the clinical and research environments, radiologists should prepare to embrace the change from morphological to functional imaging, furnishing all the necessary resources and information to referring clinicians. PMID- 26753057 TI - Lessons learned from building an infrastructure for community-engaged research. AB - : Before community-based participatory research (CBPR) can commence an infrastructure needs to be established whereby both academic researchers and community members can participate in CBPR as equitable partners throughout the research process. OBJECTIVES: We describe the key principles of the Brooklyn Health Disparities Center (BHDC), a community-academic-government partnership, to guide the development for an infrastructure to support, increase, and sustain the capacity of academics and community members to engage in CBPR to address cardiovascular health disparities in Brooklyn, New York. METHODS: The guiding principles of the BHDC consist of 1) promoting equitable and collaborative partnerships 2) enhancing research capacity and 3) building/sustaining trust. Delphi survey, youth summer internship programs, and workshops were among the tools utilized in enhancing community capacity. RESULTS: Several lessons were gleaned: design programs that are capable of building trust, skills, capacity, and interest of community members concomitantly; be flexible in terms of the priorities and objectives that the partners seek to focus on as these may change over time; and build a groundswell of local advocates to embrace the research and policy agenda of the BHDC. PMID- 26753059 TI - Various diffusion magnetic resonance imaging techniques for pancreatic cancer. AB - Pancreatic cancer is one of the most common malignant tumors and remains a treatment-refractory cancer with a poor prognosis. Currently, the diagnosis of pancreatic neoplasm depends mainly on imaging and which methods are conducive to detecting small lesions. Compared to the other techniques, magnetic resonance imaging (MRI) has irreplaceable advantages and can provide valuable information unattainable with other noninvasive or minimally invasive imaging techniques. Advances in MR hardware and pulse sequence design have particularly improved the quality and robustness of MRI of the pancreas. Diffusion MR imaging serves as one of the common functional MRI techniques and is the only technique that can be used to reflect the diffusion movement of water molecules in vivo. It is generally known that diffusion properties depend on the characterization of intrinsic features of tissue microdynamics and microstructure. With the improvement of the diffusion models, diffusion MR imaging techniques are increasingly varied, from the simplest and most commonly used technique to the more complex. In this review, the various diffusion MRI techniques for pancreatic cancer are discussed, including conventional diffusion weighted imaging (DWI), multi-b DWI based on intra-voxel incoherent motion theory, diffusion tensor imaging and diffusion kurtosis imaging. The principles, main parameters, advantages and limitations of these techniques, as well as future directions for pancreatic diffusion imaging are also discussed. PMID- 26753061 TI - Multi-detector computed tomography imaging of large airway pathology: A pictorial review. AB - The tracheobronchial tree is a musculo-cartilagenous framework which acts as a conduit to aerate the lungs and consequently the entire body. A large spectrum of pathological conditions can involve the trachea and bronchial airways. These may be congenital anomalies, infections, post-intubation airway injuries, foreign body aspiration or neoplasms involving the airway. Appropriate management of airway disease requires an early and accurate diagnosis. In this pictorial essay review, we will comprehensively describe the various airway pathologies and their imaging findings by multi-detector computed tomography. PMID- 26753060 TI - Magnetic resonance imaging of the spinal marrow: Basic understanding of the normal marrow pattern and its variant. AB - For now, magnetic resonance (MR) is the best noninvasive imaging modality to evaluate vertebral bone marrow thanks to its inherent soft-tissue contrast and non-ionizing nature. A daily challenging scenario for every radiologist interpreting MR of the vertebral column is discerning the diseased from normal marrow. This requires the radiologist to be acquainted with the used MR techniques to judge the spinal marrow as well as its normal MR variants. Conventional sequences used basically to image marrow include T1W, fat-suppressed T2W and short tau inversion recovery (STIR) imaging provides gross morphological data. Interestingly, using non-routine MR sequences; such as opposed phase, diffusion weighted, MR spectroscopy and contrasted-enhanced imaging; may elucidate the nature of bone marrow heterogeneities; by inferring cellular and chemical composition; and adding new functional prospects. Recalling the normal composition of bone marrow elements and the physiologic processes of spinal marrow conversion and reconversion eases basic understanding of spinal marrow imaging. Additionally, orientation with some common variants seen during spinal marrow MR imaging as hemangiomas and bone islands is a must. Moreover, awareness of the age-associated bone marrow changes as well as changes accompanying different variations of the subject's health state is essential for radiologists to avoid overrating normal MR marrow patterns as pathologic states and metigate unnecessary further work-up. PMID- 26753062 TI - Amyloid positron emission tomography and cognitive reserve. AB - Alzheimer's disease (AD) is characterized by a non-linear progressive course and several aspects influence the relationship between cerebral amount of AD pathology and the clinical expression of the disease. Brain cognitive reserve (CR) refers to the hypothesized capacity of an adult brain to cope with brain damage in order to minimize symptomatology. CR phenomenon contributed to explain the disjunction between the degree of neurodegeneration and the clinical phenotype of AD. The possibility to track brain amyloidosis (Abeta) in vivo has huge relevance for AD diagnosis and new therapeutic approaches. The clinical repercussions of positron emission tomography (PET)-assessed Abeta load are certainly mediated by CR thus potentially hampering the prognostic meaning of amyloid PET in selected groups of patients. Similarly, amyloid PET and cerebrospinal fluid amyloidosis biomarkers have recently provided new evidence for CR. The present review discusses the concept of CR in the framework of available neuroimaging studies and specifically deals with the reciprocal influences between amyloid PET and CR in AD patients and with the potential consequent interventional strategies for AD. PMID- 26753063 TI - Three-dimensional imaging of the uterus: The value of the coronal plane. AB - Advent in three-dimensional (3D) imaging technology has seen 3D ultrasound establish itself as a useful adjunct complementary to traditional two-dimensional imaging of the female pelvis. This advantage largely arises from its ability to reconstruct the coronal plane of the uterus, which allows further delineation of many gynecological disorders. 3D imaging of the uterus is now the preferred imaging modality for assessing congenital uterine anomalies and intrauterine device localization. Newer indications include the diagnosis of adenomyosis. It can also add invaluable information to delineate other endometrial and myometrial pathology such as fibroids and endometrial polyps. PMID- 26753064 TI - Recovery of serum testosterone following neoadjuvant and adjuvant androgen deprivation therapy in men treated with prostate brachytherapy. AB - AIM: To investigate the time course of testosterone (T) recovery after cessation of androgen deprivation therapy (ADT) in patients treated with brachytherapy. METHODS: One-hundred and seventy-four patients treated between June 1999 and February 2009 were studied. Patients were divided into a short-term usage group (<= 12 mo, n = 91) and a long-term usage group (>= 36 mo, n = 83) according to the duration of gonadotropin-releasing hormone agonist therapy. Median follow-up was 29 mo in the short-term group and was 60 mo in the long-term group. RESULTS: Cumulative incidence rates of T recovery to normal and supracastrate levels at 24 mo after cessation were 28.8% and 74.6%, respectively, in the long-term usage group, whereas these values were 96.4% and 98.8% in the short-term usage group. T recovery to normal and supracastrate levels occurred significantly more rapidly in the short-term than in the long-term usage group (P < 0.001 and P < 0.001, respectively). Five years after cessation, 22.6% of patients maintained a castrate T level in the long-term usage group. On multivariate analysis, lower T levels (< 10 ng/dL) at cessation of ADT was significantly associated with prolonged T recovery to supracastrate levels in the long-term usage group (P = 0.002). CONCLUSION: Lower T levels at cessation of ADT were associated with prolonged T recovery in the long-term usage group. Five years after cessation of long-term ADT, approximately one-fifth of patients still had castrate T levels. When determining the therapeutic effect, especially biochemical control, we should consider this delay in T recovery. PMID- 26753065 TI - Common bile duct diameter in an asymptomatic population: A magnetic resonance imaging study. AB - AIM: To measure the common bile duct (CBD) diameter by magnetic resonance cholangiopancreatography (MRCP) in a large asymptomatic population and analyze its some affecting factors. METHODS: This study included 862 asymptomatic subjects who underwent MRCP. The CBD diameter was measured at its widest visible portion on regular end-expiration MRCP for all subjects. Among these 862 subjects, 221 volunteers also underwent end-inspiration MRCP to study the effect of respiration on the CBD diameter. The age, sex, respiration, body length, body weight, body mass index (BMI), portal vein diameter (PVD), length of the extrahepatic duct and CBD, cystic junction radial orientation and location were recorded. The subjects were divided into 7 groups according to age. All of the above factors were compared with the CBD diameter on end-expiration MRCP. RESULTS: Among the 862 subjects, the CBD diameter was 4.13 +/- 1.11 mm (range, 1.76-9.45 mm) and was correlated with age (r = 0.484; P < 0.05), with a dilation of 0.033 mm per year. The upper limit of the 95% reference range was 5.95 mm, resulting in a reasonable upper limit of 6 mm for the asymptomatic population. Respiration and other factors, including sex, body length, body weight, BMI, PVD, length of the extrahepatic duct and CBD, cystic junction radial orientation and location, were not related to the CBD diameter. CONCLUSION: We established a reference range for the CBD diameter on MRCP for an asymptomatic population. The CBD diameter is correlated with age. Respiration did not affect the non-dilated CBD diameter. PMID- 26753066 TI - Combined value of apparent diffusion coefficient-standardized uptake value max in evaluation of post-treated locally advanced rectal cancer. AB - AIM: To assess the clinical diagnostic value of functional imaging, combining quantitative parameters of apparent diffusion coefficient (ADC) and standardized uptake value (SUV)max, before and after chemo-radiation therapy, in prediction of tumor response of patients with rectal cancer, related to tumor regression grade at histology. METHODS: A total of 31 patients with biopsy proven diagnosis of rectal carcinoma were enrolled in our study. All patients underwent a whole body (18)FDG positron emission tomography (PET)/computed tomography (CT) scan and a pelvic magnetic resonance (MR) examination including diffusion weighted (DW) imaging for staging (PET1, RM1) and after completion (6.6 wk) of neoadjuvant treatment (PET2, RM2). Subsequently all patients underwent total mesorectal excision and the histological results were compared with imaging findings. The MR scanning, performed on 1.5 T magnet (Philips, Achieva), included T2-weighted multiplanar imaging and in addition DW images with b-value of 0 and 1000 mm2/s. On PET/CT the SUVmax of the rectal lesion were calculated in PET1 and PET2. The percentage decrease of SUVmax (DeltaSUV) and ADC (DeltaADC) values from baseline to presurgical scan were assessed and correlated with pathologic response classified as tumor regression grade (Mandard's criteria; TRG1 = complete regression, TRG5 = no regression). RESULTS: After completion of therapy, all the patients were submitted to surgery. According to the Mandard's criteria, 22 tumors showed complete (TRG1) or subtotal regression (TRG2) and were classified as responders; 9 tumors were classified as non responders (TRG3, 4 and 5). Considering all patients the mean values of SUVmax in PET 1 was higher than the mean value of SUVmax in PET 2 (P < 0.001), whereas the mean ADC values was lower in RM1 than RM2 (P < 0.001), with a DeltaSUV and DeltaADC respectively of 60.2% and 66.8%. The best predictors for TRG response were SUV2 (threshold of 4.4) and ADC2 (1.29 * 10(-3) mm(2)/s) with high sensitivity and specificity. Combining in a single analysis both the obtained median value, the positive predictive value, in predicting the different group category response in related to TRG system, presented R(2) of 0.95. CONCLUSION: The functional imaging combining ADC and SUVmax in a single analysis permits to detect changes in cellular tissue structures useful for the assessment of tumour response after the neoadjuvant therapy in rectal cancer, increasing the sensitivity in correct depiction of treatment response than either method alone. PMID- 26753067 TI - Cavernosal nerve functionality evaluation after magnetic resonance imaging-guided transurethral ultrasound treatment of the prostate. AB - AIM: To evaluate the feasibility of using therapeutic ultrasound as an alternative treatment option for organ-confined prostate cancer. METHODS: In this study, a trans-urethral therapeutic ultrasound applicator in combination with 3T magnetic resonance imaging (MRI) guidance was used for real-time multi-planar MRI based temperature monitoring and temperature feedback control of prostatic tissue thermal ablation in vivo. We evaluated the feasibility and safety of MRI-guided trans-urethral ultrasound to effectively and accurately ablate prostate tissue while minimizing the damage to surrounding tissues in eight canine prostates. MRI was used to plan sonications, monitor temperature changes during therapy, and to evaluate treatment outcome. Real-time temperature and thermal dose maps were calculated using the proton resonance frequency shift technique and were displayed as two-dimensional color-coded overlays on top of the anatomical images. After ultrasound treatment, an evaluation of the integrity of cavernosal nerves was performed during prostatectomy with a nerve stimulator that measured tumescence response quantitatively and indicated intact cavernous nerve functionality. Planned sonication volumes were visually correlated to MRI ablation volumes and corresponding histo-pathological sections after prostatectomy. RESULTS: A total of 16 sonications were performed in 8 canines. MR images acquired before ultrasound treatment were used to localize the prostate and to prescribe sonication targets in all canines. Temperature elevations corresponded within 1 degree of the targeted sonication angle, as well as with the width and length of the active transducer elements. The ultrasound treatment procedures were automatically interrupted when the temperature in the target zone reached 56 degrees C. In all canines erectile responses were evaluated with a cavernous nerve stimulator post-treatment and showed a tumescence response after stimulation with an electric current. These results indicated intact cavernous nerve functionality. In all specimens, regions of thermal ablation were limited to areas within the prostate capsule and no damage was observed in periprostatic tissues. Additionally, a visual analysis of the ablation zones on contrast enhanced MR images acquired post ultrasound treatment correlated excellent with the ablation zones on thermal dose maps. All of the ablation zones received a consensus score of 3 (excellent) for the location and size of the correlation between the histologic ablation zone and MRI based ablation zone. During the prostatectomy and histologic examination, no damage was noted in the bladder or rectum. CONCLUSION: Trans-urethral ultrasound treatment of the prostate with MRI guidance has potential to safely, reliably, and accurately ablate prostatic regions, while minimizing the morbidities associated with conventional whole gland resection or therapy. PMID- 26753070 TI - Identification of new cytotypes of Valeriana jatamansi Jones, 1970 (Valerianaceae) from North-Western Himalayan region of India. AB - Valeriana jatamansi, a medicinally important species of the family Valerianaceae, has been cytologically studied in different geographical areas of North-Western Himalayan region of India. The tetraploid cytotype with chromosome numbers 2n=32 is in conformity with the earlier reports of the species from different parts of the world. An octoploid cytotype (2n=64) makes a new addition for the species on a worldwide basis, whereas the diploid cytotype (2n=16) is new to India have been reported for the first time in India. These cytotypes (2n=16, 32, 64) show significant variations with respect to morphology as well as geographical distribution in the Western Indian Himalayas. Further, anomalous populations have been marked with meiotic abnormalities in the form of cytomixis, chromosomal stickiness, unoriented bivalents, formation of laggards and bridges resulting in abnormal microsporogenesis, and production of heterogeneous-sized fertile pollen grains along with reduced pollen fertility. PMID- 26753068 TI - Classifications of mandibular canal branching: A review of literature. AB - AIM: To gather existing radiographic classifications of mandibular canals branching, considering the criteria on which these were based. METHODS: The search for studies on mandibular canals based on imaging exams included literature reviews, epidemiological studies of prevalence, descriptive studies, or case reports. An electronic search in the MEDLINE (OvidSP), PubMed, EMBASE (OvidSP), Web of Science (Thompson Reuters), and Scopus (Elsevier) databases was performed, as well as a manual evaluation of the references of the selected articles. Combinations of key words were placed in each database. No restrictions were imposed regarding the year of publication or language. References collected in duplicate were removed by the authors. A table was drawn up, containing the included studies and respective interest data. RESULTS: Six classifications of mandibular canals branching were selected for the present literature review. Four were based on two-dimensional radiographic exams, and two were performed based on three-dimensional tomographic exams. Three-dimensional classifications were determined based on the analysis found in the least number of exams, comparatively to two-dimensional studies. The prevalence of mandibular canal branching varied from 0% to 38.75% in the works based on two-dimensional exams, while those found in three-dimensional exams ranged from 15.6% to 65%. The studies were mostly referred to branches that began in the mandibular ramus. Just one classification considered the branches that began in the mandibular body region. CONCLUSION: Three-dimensional exams appear to be the best method to view mandibular canal branching. Further studies are warranted to determine its true prevalence and questions concerning to associations. PMID- 26753069 TI - Intragenomic variations of multicopy ITS2 marker in Agrodiaetus blue butterflies (Lepidoptera, Lycaenidae). AB - The eukaryotic ribosomal DNA cluster consists of multiple copies of three genes, 18S, 5. 8S and 28S rRNAs, separated by multiple copies of two internal transcribed spacers, ITS1 and ITS2. It is an important, frequently used marker in both molecular cytogenetic and molecular phylogenetic studies. Despite this, little is known about intragenomic variations within the copies of eukaryotic ribosomal DNA genes and spacers. Here we present data on intraindividual variations of ITS2 spacer in three species of Agrodiaetus Hubner, 1822 blue butterflies revealed by cloning technique. We demonstrate that a distinctly different intragenomic ITS2 pattern exists for every individual analysed. ITS2 sequences of these species show significant intragenomic variation (up to 3.68% divergence), setting them apart from each other on inferred phylogenetic tree. This variation is enough to obscure phylogenetic relationships at the species level. PMID- 26753071 TI - Variability of 18rDNA loci in four lace bug species (Hemiptera, Tingidae) with the same chromosome number. AB - Male karyotypes of Elasmotropis testacea (Herrich-Schaeffer, 1835), Tingis cardui (Linnaeus, 1758), Tingis crispata (Herrich-Schaeffer, 1838), and Agramma femorale Thomson, 1871 (Heteroptera, Cimicomorpha, Tingidae) were analyzed using conventional chromosome staining and FISH with 18S rDNA and (TTAGG) n telomeric probes. The FISH technique was applied for the first time in the Tingidae. In spite of the fact that all species showed the same chromosome number (2n = 12 + XY), they have significant differences in the number and position of rDNA loci. FISH with the classical insect (TTAGG) n probe produced no signals on chromosomes suggesting telomeres in lace bugs to be of some other molecular composition. Tingidae share absence of the (TTAGG) n telomeric sequence with all so far studied taxa of the advanced true bug infraorders Cimicomorpha and Pentatomomorpha. PMID- 26753072 TI - First evidence for (TTAGG)n telomeric sequence and sex chromosome post-reduction in Coleorrhyncha (Insecta, Hemiptera). AB - Telomeric repeats are general and significant structures of eukaryotic chromosomes. However, nothing is known about the molecular structure of telomeres in the enigmatic hemipteran suborder Coleorrhyncha (moss bugs) commonly considered as the sister group to the suborder Heteroptera (true bugs). The true bugs are known to differ from the rest of the Hemiptera in that they display an inverted sequence of sex chromosome divisions in male meiosis, the so-called sex chromosome post-reduction. To date, there has been no information about meiosis in Coleorrhyncha. Here we report a cytogenetic observation of Peloridium pomponorum, a representative of the single extant coleorrhynchan family Peloridiidae, using the standard chromosome staining and fluorescence in situ hybridization (FISH) with a (TTAGG) n telomeric probe. We show that Peloridium pomponorum displays 2n = 31 (30A + X) in males, the classical insect (TTAGG) n telomere organization and sex chromosome post-reduction during spermatocyte meiosis. The plesiomorphic insect-type (TTAGG) n telomeric sequence is suggested to be preserved in Coleorrhyncha and in a basal heteropteran infraorder Nepomorpha, but absent (lost) in the advanced heteropteran lineages Cimicomorpha and Pentatomomorpha. The telomere structure in other true bug infraorders is currently unknown. We consider here the inverted sequence of sex chromosome divisions as a synapomorphy of the group Coleorrhyncha + Heteroptera. PMID- 26753074 TI - Variation of karyotype and nuclear DNA content among four species of Plectranthus L' Heritier, 1788 (Lamiaceae) from Brazil. AB - Plectranthus is a genus which includes species of ornamental and medicinal potential. It faces taxonomic problems due to aggregating species previously belonging to the genus Coleus, a fact that has contributed to the existence of various synonymies. The species Plectranthus amboinicus, Plectranthus barbatus, Plectranthus grandis and Plectranthus neochilus are included in this context. Some authors consider Plectranthus barbatus and Plectranthus grandis as synonyms. The present work was carried out with the aim of comparing plants of the above mentioned species, originating from different localities in Brazil, with regards to chromosome number and karyotypic morphology, correlated to the nuclear DNA content. There was no variation in chromosome number among plants of the same species. Plectranthus amboinicus was the only species to exhibit 2n=34, whereas the others had 2n=30. No karyotypic differences were found among the plants of each species, except for Plectranthus barbatus. The plants of the Plectranthus species revealed little coincidence between chromosome pairs. The nuclear DNA content allowed grouping Plectranthus amboinicus and Plectranthus neochilus, with the highest mean values, and Plectranthus grandis and Plectranthus barbatus with the lowest ones. Differences in DNA amount among the plants were identified only for Plectranthus barbatus. These results allow the inference that the populations of Plectranthus amboinicus and Plectranthus neochilus present coincident karyotypes among their plants, and Plectranthus grandis is probably a synonym of Plectranthus barbatus. PMID- 26753073 TI - (GAA)n microsatellite as an indicator of the A genome reorganization during wheat evolution and domestication. AB - Although the wheat A genomes have been intensively studied over past decades, many questions concerning the mechanisms of their divergence and evolution still remain unsolved. In the present study we performed comparative analysis of the A genome chromosomes in diploid (Triticum urartu Tumanian ex Gandilyan, 1972, Triticum boeoticum Boissier, 1874 and Triticum monococcum Linnaeus, 1753) and polyploid wheat species representing two evolutionary lineages, Timopheevi (Triticum timopheevii (Zhukovsky) Zhukovsky, 1934 and Triticum zhukovskyi Menabde & Ericzjan, 1960) and Emmer (Triticum dicoccoides (Kornicke ex Ascherson & Graebner) Schweinfurth, 1908, Triticum durum Desfontaines, 1798, and Triticum aestivum Linnaeus, 1753) using a new cytogenetic marker - the pTm30 probe cloned from Triticum monococcum genome and containing (GAA)56 microsatellite sequence. Up to four pTm30 sites located on 1AS, 5AS, 2AS, and 4AL chromosomes have been revealed in the wild diploid species, although most accessions contained one-two (GAA)n sites. The domesticated diploid species Triticum monococcum differs from the wild diploid species by almost complete lack of polymorphism in the distribution of (GAA)n site. Only one (GAA)n site in the 4AL chromosome has been found in Triticum monococcum. Among three wild emmer (Triticum dicoccoides) accessions we detected 4 conserved and 9 polymorphic (GAA)n sites in the A genome. The (GAA)n loci on chromosomes 2AS, 4AL, and 5AL found in of Triticum dicoccoides were retained in Triticum durum and Triticum aestivum. In species of the Timopheevi lineage, the only one, large (GAA)n site has been detected in the short arm of 6A(t) chromosome. (GAA)n site observed in Triticum monococcum are undetectable in the A(b) genome of Triticum zhukovskyi, this site could be eliminated over the course of amphiploidization, while the species was established. We also demonstrated that changes in the distribution of (GAA)n sequence on the A-genome chromosomes of diploid and polyploid wheats are associated with chromosomal rearrangements/ modifications, involving mainly the NOR (nucleolus organizer region)-bearing chromosomes, that took place during the evolution of wild and domesticated species. PMID- 26753075 TI - Cytogenetic description of the earthworm Drawida ghilarovi Gates, 1969 (Oligochaeta, Moniligastridae) from the southern Russian Far East. AB - Sixty-six specimens of the earthworm Drawida ghilarovi Gates, 1969 (Oligochaeta, Moniligastridae) from 15 localities of the southern Russian Far East were studied cytogenetically. We examined chromosome sets during mitosis and diakinesis as well as DNA content in the spermatogenous and somatic cell nuclei. The populations and morphs displayed no differences in karyotype and ploidy levels estimated in terms of both chromosome number and DNA mass index: n = 10, 2n = 20; c = 1.1 pg, 2c = 2.2 pg. We conclude that polyploidy as a species- or race forming factor is not typical of these earthworms. PMID- 26753076 TI - Chromosomal distribution of microsatellite repeats in Amazon cichlids genome (Pisces, Cichlidae). AB - Fish of the family Cichlidae are recognized as an excellent model for evolutionary studies because of their morphological and behavioral adaptations to a wide diversity of explored ecological niches. In addition, the family has a dynamic genome with variable structure, composition and karyotype organization. Microsatellites represent the most dynamic genomic component and a better understanding of their organization may help clarify the role of repetitive DNA elements in the mechanisms of chromosomal evolution. Thus, in this study, microsatellite sequences were mapped in the chromosomes of Cichla monoculus Agassiz, 1831, Pterophyllum scalare Schultze, 1823, and Symphysodon discus Heckel, 1840. Four microsatellites demonstrated positive results in the genome of Cichla monoculus and Symphysodon discus, and five demonstrated positive results in the genome of Pterophyllum scalare. In most cases, the microsatellite was dispersed in the chromosome with conspicuous markings in the centromeric or telomeric regions, which suggests that sequences contribute to chromosome structure and may have played a role in the evolution of this fish family. The comparative genome mapping data presented here provide novel information on the structure and organization of the repetitive DNA region of the cichlid genome and contribute to a better understanding of this fish family's genome. PMID- 26753077 TI - First description of the karyotype of a eucharitid wasp (Hymenoptera, Chalcidoidea, Eucharitidae). AB - The haploid karyotype of Kapala sp. (Eucharitidae), a parasite of the Neotropical ant Dinoponera lucida Emery, 1901 (Hymenoptera, Formicidae), is reported for the first time. It consists of four metacentric chromosomes. Chromosomes in the family Eucharitidae were unknown so far; therefore, our results confirm that multiple parallel chromosomal fusions have taken place in several lineages within the superfamily Chalcidoidea. PMID- 26753078 TI - Comparative cytogenetic study of three Macrolophus species (Heteroptera, Miridae). AB - Macrolophus pygmaeus (Rambur, 1839) (Insecta, Heteroptera, Miridae) is a predator of key vegetable crop pests applied as a biocontrol agent in the Mediterranean region. Macrolophus pygmaeus and Macrolophus melanotoma (A. Costa, 1853) are cryptic species with great morphological similarity which results in their misidentification and negative consequences for the conservation of their populations on greenhouse and outdoor crops. In order to find out specific markers for their separation we studied the karyotype, male meiosis and heterochromatin composition of these species and additionally of a third species (as a reference one), Macrolophus costalis Fieber, 1858. We demonstrate here that all the three species share achiasmate male meiosis and sex chromosome pre reduction. On the other hand, the species differ in karyotype, with 2n=28 (26+XY) in Macrolophus pygmaeus, 2n=27 (24+X1X2Y) in Macrolophus costalis, and 2n=34 (32+XY) in Macrolophus melanotoma, and heterochromatin distribution and composition. In addition, the species differ in sperm morphology: sperm cells of Macrolophus costalis are significantly longer with longer head and tail than those of Macrolophus melanotoma and Macrolophus pygmaeus, whereas sperm cells of Macrolophus melanotoma have a longer tail than those of Macrolophus pygmaeus. All these characters can be used as markers to identify the species, in particular the cryptic species Macrolophus melanotoma and Macrolophus pygmaeus. PMID- 26753079 TI - Cytogenetic analyses of five amazon lizard species of the subfamilies Teiinae and Tupinambinae and review of karyotyped diversity the family Teiidae. AB - Lizards of the family Teiidae (infraorder Scincomorpha) were formerly known as Macroteiidae. There are 13 species of such lizards in the Amazon, in the genera Ameiva (Meyer, 1795), Cnemidophorus (Wagler, 1830), Crocodilurus (Spix, 1825), Dracaena (Daudin, 1801), Kentropyx (Spix, 1825) and Tupinambis (Daudin, 1802). Cytogenetic studies of this group are restricted to karyotype macrostructure. Here we give a compilation of cytogenetic data of the family Teiidae, including classic and molecular cytogenetic analysis of Ameiva ameiva (Linnaeus, 1758), Cnemidophorus sp.1, Kentropyx calcarata (Spix, 1825), Kentropyx pelviceps (Cope, 1868) and Tupinambis teguixin (Linnaeus, 1758) collected in the state of Amazonas, Brazil. Ameiva ameiva, Kentropyx calcarata and Kentropyx pelviceps have 2n=50 chromosomes classified by a gradual series of acrocentric chromosomes. Cnemidophorus sp.1 has 2n=48 chromosomes with 2 biarmed chromosomes, 24 uniarmed chromosomes and 22 microchromosomes. Tupinambis teguixin has 2n=36 chromosomes, including 12 macrochromosomes and 24 microchromosomes. Constitutive heterochromatin was distributed in the centromeric and terminal regions in most chromosomes. The nucleolus organizer region was simple, varying in its position among the species, as evidenced both by AgNO3 impregnation and by hybridization with 18S rDNA probes. The data reveal a karyotype variation with respect to the diploid number, fundamental number and karyotype formula, which reinforces the importance of increasing chromosomal analyses in the Teiidae. PMID- 26753081 TI - Whole chromosome painting of B chromosomes of the red-eye tetra Moenkhausia sanctaefilomenae (Teleostei, Characidae). AB - B chromosomes are dispensable genomic elements found in different groups of animals and plants. In the present study, a whole chromosome probe was generated from a specific heterochromatic B chromosome occurring in cells of the characidae fish Moenkhausia sanctaefilomenae (Steindachner, 1907). The chromosome painting probes were used in fluorescence in situ hybridization (FISH) experiments for the assessment of metaphase chromosomes obtained from individuals from three populations of Moenkhausia sanctaefilomenae. The results revealed that DNA sequences were shared between a specific B chromosome and many chromosomes of the A complement in all populations analyzed, suggesting a possible intra-specific origin of these B chromosomes. However, no hybridization signals were observed in other B chromosomes found in the same individuals, implying a possible independent origin of B chromosome variants in this species. FISH experiments using 18S rDNA probes revealed the presence of non-active ribosomal genes in some B chromosomes and in some chromosomes of the A complement, suggesting that at least two types of B chromosomes had an independent origin. The role of heterochromatic segments and ribosomal sequences in the origin of B chromosomes were discussed. PMID- 26753080 TI - Ribosomal DNA in diploid and polyploid Setaria (Poaceae) species: number and distribution. AB - Setaria Beauvois, 1812 is a genus of economically important forage species, including Setaria italica (Linnaeus, 1753) Beauvois, 1812 and Setaria viridis (Linnaeus, 1753) Beauvois, 1812, closely related species and considered as model systems for studies of C4 plants. However, complications and uncertainties related to taxonomy of other species of the genus are frequent due to the existence of numerous synonyms for the same species or multiple species with the same name, and overlapping of morphological characteristics. Cytogenetic studies in Setaria can be useful for taxonomic and evolutionary studies as well as for applications in breeding. Thus, this study is aimed at locating 45S and 5S rDNA sites through fluorescent in situ hybridization (FISH) in Setaria italica, Setaria viridis and Setaria sphacelata (Schumacher, 1827) Stapf, Hubbard, Moss, 1929 cultivars (cvs.) Narok and Nandi. Setaria italica and Setaria viridis have 18 chromosomes with karyotype formulas 6m + 3sm and 9m, respectively. The location of 45S and 5S rDNA for these species was in different chromosome pairs among the evaluated species. Setaria viridis presented a more symmetrical karyotype, strengthening the ancestral relationship with Setaria italica. Setaria sphacelata cvs. Narok and Nandi have 36 chromosomes, and karyotype formulas 11m+7sm and 16m+2sm, respectively. The 45S rDNA signals for both cultivars were also observed in distinct chromosome pairs; however chromosomes bearing 5S rDNA are conserved. Karyotypic variations found among the studied species are evidence of chromosomal rearrangements. PMID- 26753082 TI - First cytogenetic report in Cichlasoma sanctifranciscense Kullander, 1983 (Perciformes, Cichlidae) from northeastern Brazil with inferences on chromosomal evolution of Cichlasomatini. AB - Even though genetic aspects of some cichlids have been widely studied over the last decades, little is known about the genomic structure of Cichlidae when compared to the large number of species in the family. In this paper, the first chromosomal data for Cichlasoma sanctifranciscense Kullander, 1983 are presented and discussed based on cytotaxonomic and karyoevolutionary inferences on Cichlasomatini. All individuals shared a diploid number of 2n=48 distributed as 10sm+28st+10a and Ag-NORs on short arms of a submetacentric pair. Heterochromatin was detected at pericentromeric regions of most chromosomes and at terminal sites of a few pairs. GC-rich regions were observed on short arms of two biarmed pairs, including the pair bearing Ag-NORs. Double-FISH with ribosomal probes revealed 18S rDNA clusters coincident with GC-rich regions in two biarmed pairs and 5S rDNA at interstitial location of an acrocentric pair. Cichlasoma sanctifranciscense shares some symplesiomorphic traits described in Cichlidae (2n=48 and pericentromeric C-bands) while other chromosomal features diverge from the common trend reported in Cichlasomatini, such as multiple 18S rDNA sites combined with high FN values. Finally, the present results are useful to support taxonomic identification once species-specific markers have been provided in Cichlasoma sanctifranciscense. PMID- 26753083 TI - The blue butterfly Polyommatus (Plebicula) atlanticus (Lepidoptera, Lycaenidae) holds the record of the highest number of chromosomes in the non-polyploid eukaryotic organisms. AB - The blue butterfly species Polyommatus (Plebicula) atlanticus (Elwes, 1906) (Lepidoptera, Lycaenidae) is known to have a very high haploid number of chromosomes (n= circa 223). However, this approximate count made by Hugo de Lesse 45 years ago was based on analysis of a single meiotic I metaphase plate, not confirmed by study of diploid chromosome set and not documented by microphotographs. Here I demonstrate that (1) Polyommatus atlanticus is a diploid (non-polyploid) species, (2) its meiotic I chromosome complement includes at least 224-226 countable chromosome bodies, and (3) all (or nearly all) chromosome elements in meiotic I karyotype are represented by bivalents. I also provide the first data on the diploid karyotype and estimate the diploid chromosome number as 2n=ca448-452. Thus, Polyommatus atlanticus is confirmed to possess the highest chromosome number among all the non-polyploid eukaryotic organisms. PMID- 26753084 TI - Access to Safe Water and Personal Hygiene Practices in the Kulandia Refugee Camp (Jerusalem). AB - Diarrheal illness, frequently associated with fecal-oral transmission, is one of the leading causes of death worldwide. It is commonly preventable through the implementation of safe water practices. This experiment concerns how to best implement safe water practices in a quasi-permanent refugee camp setting with limited ability for structural changes. Specifically, we explore how health promotion activities that help identify target groups for hygiene interventions can play a role in disease prevention. An anonymous survey was conducted at the United Nations Relief and Works Agency Health Clinic in the Kulandia refugee camp to assess the safe water and personal hygiene practices. Demographic and social characteristics, accessible water and personal hygiene characteristics, and gastrointestinal (GI) burden for individuals and their households were assessed. A total of 96 individuals were enrolled; 62 females and 34 males. Approximately 58% of the sample had soap available and washed hands before and after eating and when preparing food. Piped water was the main source of drinking water (62%), while 31% of our sample utilized tanker-trucks. 93% of participants had access to toilet facilities, with 86% of these facilities being private households. 55% practice extra water hygiene measures on their household drinking water source. 51.3% considered vendor cleanliness when they were buying food. 51% had received formal health education. 68.8% had been taught by their parents, but only 55.2% were teaching their children and 15.6% had consistent access to a health professional for hygiene inquiries. Individual variables and hygiene practices associated with lower rates of diarrheal illnesses included having water piped into the home, proper hand washing, adequate soap availability, proper consideration of vendor cleanliness, higher income, levels of education, health hygiene education, and having access to healthcare professions to discuss hygiene related matters. This is the first study to assess the water and personal hygiene practices at the Kulandia refugee ramp. This study demonstrates that hygiene education and better practices are closely associated with the rate at which individuals and households suffer from diarrheal illnesses within the Kulandia refugee camp. There are significant hygiene deficits in the camp, which likely result from a lack of formal hygiene education and a lack of awareness concerning the connection between diarrheal illness and hygiene. With respect to practices, our results elucidate several areas where basic, communal programming - including lessons on appropriate hand washing and food preparation - will likely improve hygiene practices and decrease overall GI burden. PMID- 26753085 TI - Reversible Deafness and Blindness in a Patient with Cryptococcal Meningitis in Tanzania. AB - Cryptococcal meningitis is a common and devastating complication of advanced HIV, and is most prevalent in low resource settings in sub Saharan Africa. Raised intracranial pressure is one of the hallmarks of the disease, which can lead to visual and hearing loss and ultimately death. We present the case of a patient with visual and hearing impairment secondary to Cryptococcal meningitis successfully managed by serial cerebrospinal fluid drainage. This case highlights some of the challenges of managing this severe opportunistic infection in a low resource setting. PMID- 26753086 TI - Acute Acalculous Cholecystitis by Epstein-Barr Virus Infection: A Rare Association. AB - Acute acalculous cholecystitis (AAC) is a rare complication of Epstein Barr virus (EBV) infection, with only a few cases reported among pediatric population. This clinical condition is frequently associated with a favorable outcome and, usually, a surgical intervention is not required. We report a 16-year-old girl who presented with AAC following primary EBV infection. The diagnosis of AAC was documented by clinical and ultrasonographic examination, whereas EBV infection was confirmed serologically. A conservative treatment was performed, with a careful monitoring and serial ultrasonographic examinations, which led to the clinical improvement of the patient. Pediatricians should be aware of the possible association between EBV and AAC, in order to offer the patients an appropriate management strategy. PMID- 26753087 TI - The Possible Role of Anti-Methicillin-Resistant Staphylococcus Aureus Antimicrobial Agents in Spontaneous Bacterial Peritonitis. PMID- 26753088 TI - Post Liposuction Mycobacterium Abscessus Surgical Site Infection in a Returned Medical tourist Complicated by a Paradoxical Reaction During Treatment. AB - Rapidly growing mycobacterial skin and soft tissue infections are known to complicate cosmetic surgical procedures. Treatment consists of more surgery and prolonged antibiotic therapy guided by drug susceptibility testing. Paradoxical reactions occurring during antibiotic therapy can further complicate treatment of non-tuberculous mycobacterial infections. We report a case of post liposuction Mycobacterium abscessus surgical site infection in a returned medical tourist and occurrence of paradox during treatment. PMID- 26753089 TI - Reply to: "The Possible Role of Anti-methicillin-resistant Staphylococus Aureus Antimicrobial Agents in Spontaneous Bacterial Peritonitis". PMID- 26753092 TI - Differentials of modern contraceptive methods use by food security status among married women of reproductive age in Wolaita Zone, South Ethiopia. AB - BACKGROUND: In spite of the massive spending and extensive family-planning promotion, many poor people in the third world remain reluctant to use modern contraceptive method. Mostly when they use modern contraceptives, their continuation rates are often low. Reproductive health can improve women's nutrition; in return better nutrition can improve reproductive health. Thus addressing the connection between nutrition and reproductive health is critical to ensure population growth that does not overwhelm world resources. METHODS: A community based cross-sectional study was conducted from March 15-30, 2014 in Soddo Zuria Woreda, Southern Ethiopia. A total of 651 currently married women of reproductive age group were selected using multistage sampling. Probability proportional to the size allocation method was employed to determine the number of households. Multivariable logistic regression was used to assess the association between family planning use and food security status after adjusting for other covariates. RESULTS: Use of modern contraceptive method was significantly low among food insecure women (29.7 %) compared to those who were food secure (52.0 %), (P < 0.001). Women from food secure households were nearly twice likely to use modern contraceptive methods (AOR: 1.69 (CI: 1.03, 2.66)). Similarly, those who had antenatal care (ANC) visit (AOR: 4.56 (CI: 2.45, 7.05)); exposure to media (AOR: 4.92 (CI: 1.84, 13.79)) and those who discussed about contraceptive methods with their partner (AOR: 3.07 (CI: 1.86, 5.22)) were more likely to use modern contraceptive methods. Conversely, women who delivered their last child at home were less likely to use modern contraceptive methods (AOR: 0.08 (CI: 0.03, 0.13)). CONCLUSION: Food insecurity is negatively associated with modern contraceptive method use. Thus food insecurity should be considered as one of the barriers in designing family planning services and needs special arrangement. PMID- 26753091 TI - Serum brain-derived neurotrophic factor (BDNF) is not regulated by testosterone in transmen. AB - Brain morphology significantly differs between the sexes. It has been shown before that some of these differences are attributable to the sex-specific hormonal milieu. Brain-derived neurotrophic factor (BDNF) is involved in myriads of neuroplastic processes and shows a sexual dimorphism. Transsexual persons may serve as a model to study sex steroid-mediated effects on brain plasticity. We have recently demonstrated that serum levels of BDNF are reduced in transwomen following 12 months of cross-sex hormone treatment. We now wanted to look at the effects of testosterone treatment on BDNF in transmen. In contrast to our initial hypothesis, BDNF levels did not significantly change, despite dramatic changes in the sex-hormonal milieu. Our data indicate that testosterone does not seem to play a major role in the regulation of BDNF in females. PMID- 26753090 TI - Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology. AB - BACKGROUND: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders caused by the interaction between genetic vulnerability and environmental factors. MicroRNAs (miRNAs) are key posttranscriptional regulators involved in multiple aspects of brain development and function. Previous studies have investigated miRNAs expression in ASD using non-neural cells like lymphoblastoid cell lines (LCL) or postmortem tissues. However, the relevance of LCLs is questionable in the context of a neurodevelopmental disorder, and the impact of the cause of death and/or post-death handling of tissue likely contributes to the variations observed between studies on brain samples. METHODS: miRNA profiling using TLDA high-throughput real-time qPCR was performed on miRNAs extracted from olfactory mucosal stem cells (OMSCs) biopsied from eight patients and six controls. This tissue is considered as a closer tissue to neural stem cells that could be sampled in living patients and was never investigated for such a purpose before. Real-time PCR was used to validate a set of differentially expressed miRNAs, and bioinformatics analysis determined common pathways and gene targets. Luciferase assays and real-time PCR analysis were used to evaluate the effect of miRNAs misregulation on the expression and translation of several autism-related transcripts. Viral vector-mediated expression was used to evaluate the impact of miRNAs deregulation on neuronal or glial cells functions. RESULTS: We identified a signature of four miRNAs (miR-146a, miR-221, miR-654-5p, and miR 656) commonly deregulated in ASD. This signature is conserved in primary skin fibroblasts and may allow discriminating between ASD and intellectual disability samples. Putative target genes of the differentially expressed miRNAs were enriched for pathways previously associated to ASD, and altered levels of neuronal transcripts targeted by miR-146a, miR-221, and miR-656 were observed in patients' cells. In the mouse brain, miR-146a, and miR-221 display strong neuronal expression in regions important for high cognitive functions, and we demonstrated that reproducing abnormal miR-146a expression in mouse primary cell cultures leads to impaired neuronal dendritic arborization and increased astrocyte glutamate uptake capacities. CONCLUSIONS: While independent replication experiments are needed to clarify whether these four miRNAS could serve as early biomarkers of ASD, these findings may have important diagnostic implications. They also provide mechanistic connection between miRNA dysregulation and ASD pathophysiology and may open up new opportunities for therapeutic. PMID- 26753094 TI - An assessment of spatio-temporal relationships between nocturnal bird migration traffic rates and diurnal bird stopover density. AB - BACKGROUND: Daily magnitudes and fluxes of landbird migration are often measured via nocturnal traffic rates aloft or diurnal densities within terrestrial habitats during stopover. However, these measures are not consistently correlated and at times reveal opposing trends. For this reason we sought to determine how comparison methods (daily magnitude or daily flux), nocturnal monitoring tools (weather surveillance radar, WSR; thermal imaging, TI), and temporal scale (preceding or following diurnal sampling) influenced correlation strength from stopover densities estimated by daily transect counts. We quantified nocturnal traffic rates at two temporal scales; averaged across the entire night and within individual decile periods of the night, and at two spatial scales; within 1 km of airspace surrounding the site via WSR and directly overhead within the narrow beam of a TI. RESULTS: Overall, the magnitude of daily bird density during stopover was positively related to the magnitude of broad-scale radar traffic rates of migrants on preceding and following nights during both the spring and fall. These relationships were strongest on the following night, and particularly from measures early in the night. Only during the spring on the following nights did we find positive correlations between the daily flux of transect counts and migration traffic rates (both WSR and TI). This indicates that our site likely had a more consistent daily turnover of migrants compared to the fall. The lack of general correlations between seasonal trends or daily flux in fine-scale TI traffic rates and stopover densities across or within nights was unexpected and likely due to poor sampling of traffic rates due to the camera's narrow beam. CONCLUSIONS: The order (preceding or following day) and metric of comparisons (magnitude or flux), as well as the tool (WSR or TI) used for monitoring nocturnal migration traffic can have dramatic impacts when compared with ground based estimates of migrant density. WSR provided measures of the magnitude and daily flux in nocturnal migration traffic rates that related to daily stopover counts of migrants during spring and fall. Relationships among migrating bird flux measures are more complex than simple measures of magnitude of migration. Care should be given to address these complexities when comparing data among methods. PMID- 26753093 TI - Influence of heat and moisture exchanger use on measurements performed with manovacuometer and respirometer in healthy adults. AB - BACKGROUND: The use of evaluation tools such as the manovacuometer and respirometer is frequent and disinfection is usually limited to the external surfaces, which is insufficient and raises concerns because of the potential spread of infectious diseases. Hydrophobic heat and moisture exchangers (HME) are used in mechanical ventilation and have microbiological filters, which can possibly reduce contamination, increasing the safety of related procedures. It is unknown, however, if the addition of an exchanger affects the measurements obtained. Aim of this study was to verify if the use of an HME interferes in maximal inspiratory and expiratory pressures assessed using the manovacuometer and vital capacity evaluated using the respirometer in healthy adults. METHODS: A controlled transversal trial was carried out. Twenty healthy young adults were included in the study. Vital capacity by respirometer and, maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) were assessed with and without the use of HME. RESULTS: No significant difference was found between the values pre and post HME use in vital capacity measurements: (3878.8 +/- 202.2 mL vs. 3925.5 +/- 206.0 mL, p = 0.116) and the respiratory muscle strength measurements: MIP (-99.0 +/- 8.9 vs -95.5 +/- 9.0 cm H2O, p = 0.149) and MEP (92.5 +/- 7.5 vs 92.5 +/- 7.7 cm H2O, p = 1.0) respectively. CONCLUSION: We conclude that the use of HME does not modify the lung volumes or respiratory muscle strength, and can be used in order to reduce the occurrence of pulmonary infection. PMID- 26753095 TI - Ambiguine I Isonitrile from Fischerella ambigua Induces Caspase-Independent Cell Death in MCF-7 Hormone Dependent Breast Cancer Cells. AB - Ambiguine I isonitrile (AmbI) obtained from the cultured cyanobacterium Fischerella ambigua was identified as a potent NF-kappaB inhibitor (IC50=30 nM). The cytotoxic effect was evaluated in both HT-29 colon cancer cell line (EC50=4.35 MUM) and MCF-7 breast cancer cell line (EC50=1.7 MUM) using the SRB assay. In the cells treated with AmbI, an increased population of cells was detected in sub G1-phase. The apoptotic effect was associated with block in G1 phase of the cell cycle in treated cells; however, cell death was induced independently of caspase-7. The NF-kappaB expression of p50 and p65 units were also examined in treated cells and compared with the positive control, rocaglamide (IC50=75 nM). Moreover, the expression of mediators of the NF-kappaB pathway such as kinase IKKkappa was studied at increasing concentrations of AmbI. The down stream effect of NF-kappaB inhibition and the effect on the expression of TNF-alpha induced ICAM-1 was evaluated. Thus, the dose-dependent and time dependent effect of AmbI on MCF-7 cells was examined in an attempt to investigate its potential mechanism of action on inducing apoptosis. PMID- 26753096 TI - Comparison of total, salivary and calculated free cortisol levels in patients with severe sepsis. AB - BACKGROUND: The purposes of the study were to compare serum total cortisol (STC), salivary cortisol (SaC) and calculated free cortisol (cFC) levels at baseline and after the adrenocorticotrophic hormone (ACTH) stimulation test in patients with severe sepsis (SS) and determine the suitability of use of SaC and cFC levels instead of STC for the diagnosis of adrenal insufficiency (AI) in patients with SS. And secondary aims of this study were to compare these parameters in patients with SS with healthy controls and check their effects on survival status of the patients. METHODS: Thirty patients with SS (15 men and 15 women) were compared with 16 healthy controls. Low-dose (1 MUg) ACTH stimulation test was performed to the patients on the first, seventh and 28th days of diagnosis of SS, but in control group, 1 MUg ACTH stimulation test was performed only once. STC, SaC and cFC levels were measured during ACTH stimulation test. RESULTS: Patients were categorized as having low or high baseline STC according to a cut-off level of 10 MUg/dL. In high STC group, baseline and peak SaC levels were found to be 2.3 (0.2 9.0) and 3.4 (0.5-17.8) MUg/dL on D1 and 1.1 (0.8-4.6) and 2.6 (1.3-2.9) MUg/dL on D7, respectively. In the control group, baseline and peak SaC levels were 0.4 (0.1-1.4) and 1.1 (0.4-2.5) MUg/dL, respectively. Baseline and peak SaC levels after ACTH stimulation were found to be higher in high STC group than in controls, but they were found to be similar in low STC and control groups. In high STC group, cFC levels were 0.3 (0.1-0.3) and 0.4 (0.3-0.7) MUg/dL on D1 and 0.2 (0.1-0.3) and 0.4 (0.1-0.7) MUg/dL on D7, respectively. In the control group, baseline and peak cFC levels were 1.7 (0.4-1.9) and 1.8 (1.0-6.6) MUg/dL, respectively. cFC levels were found to be lower in patients with SS subgroups than in the control group. Baseline and stimulated STC, SaC and cFC levels did not differ according to the survival status. SaC, cFC and STC levels were found to be correlated with each other. CONCLUSIONS: SS is associated with increased SaC, but decreased cFC levels when baseline STC is assumed to be sufficient. When STC level is assumed to be insufficient, SaC levels remain unchanged, but cFC levels are decreased. Lower STC levels is not associated with increased mortality in patients with SS. More data are needed in order to suggest the use of SaC and cFC instead of STC. TRIAL REGISTRATION: ClinicalTrials.gov No: NCT02589431. PMID- 26753097 TI - Structure, function and cell dynamics during chaetogenesis of abdominal uncini in Sabellaria alveolata (Sabellariidae, Annelida). AB - BACKGROUND: Dynamic apical microvilli of a single cell, called the chaetoblast, inside an ectodermal invagination form the template of annelid chaetae. Changes in the pattern of microvilli are frozen in time by release of chitin, such that the structure of the definitive chaeta reflects its formation. Cellular interactions during chaetogenesis also influence the structure of the chaeta. Analysing chaetogenesis allows for testing hypotheses on the homology of certain chaetal types. We used this approach to test whether the unusual uncini in Sabellaria alveolata are homologous to apparently similar uncini in other annelid taxa. RESULTS: Our study reveals unexpected details of sabellariid uncini, which mechanically reinforce the neuropodia enabling their use as paddles. The final structure of the chaeta is caused by pulses of microvilli formation and dynamic interaction between the chaetoblast and adjoining follicle cells. Cell dynamics during chaetogenesis of the uncini in Sabellaria alveolata exceeds by far that reported in previous studies on the formation of this type of chaetae. CONCLUSION: Despite the superficial similarity of uncini in sabellariids and other annelids, differences in structure and details of formation do not support the homology of this type of chaetae. Chaetogenesis of sabellariid uncini involves unexpected microvilli and cell dynamics, and provides evidence that interactions between cells play a larger role in chaetogenesis than previously expected. In addition to their function as anchors, uncini in Sabellaridae stabilize the paddle-shaped notopodia, as each uncinus possesses a long, thin rod that extends deeply into the notopodium. The rods of all uncini in a single row form a bundle inside the notopodium that additionally serves as a muscle attachment site and thus have a similar function to the inner chaeta (acicula) of errant polychaetes (Aciculata). PMID- 26753098 TI - Blockade of recombinant human IL-6 by tocilizumab suppresses matrix metalloproteinase-9 production in the C28/I2 immortalized human chondrocyte cell line. AB - Two immortalized human juvenile chondrocyte cell lines, T/C28a2 and C28/I2, were employed to determine the extent to which recombinant human (rh) IL-6 or rh-TNF alpha increased the production of matrix metalloproteinase-9 (MMP-9). The effect of rhIL-6 on neutrophil gelatinase-associated lipocalin (NGAL) was also assessed. Although C28/I2 chondrocytes incubated with rhIL-6 (50 ng/ml) increased MMP-9 production which could not be mimicked by the T/C28a2 chondrocyte line, the effect of rhTNF-alpha on MMP-9 was more robust than with rhIL-6. The combinations of rhIL-6 and soluble IL-6 receptor-alpha (sIL-6Ralpha) or rhIL-6 and tocilizumab (TCZ), a fully-humanized recombinant monoclonal antibody that neutralizes the interaction between IL-6 and IL-6R significantly reduced MMP-9 production by C28/I2 chondrocytes. However, TCZ had no effect on rhTNF-alpha-induced MMP-9 production. By contrast, rhIL-6 did not increase the production of NGAL by C28/I2 chondrocytes although the number of NGAL-positive cells was significantly reduced by sIL-6R compared to its control group, but not by the combination of rhIL-6 plus TCZ compared to rhIL-6. In summary, these results showed that rhIL-6 stimulated the production of MMP-9, but not NGAL, in the C28/I2 chondrocyte line. TCZ or sIL-6Ralpha suppressed rhIL-6-induced MMP-9 production. PMID- 26753100 TI - Crystal Structures of New Ammonium 5-Aminotetrazolates. AB - The crystal structures of three salts of anionic 5-aminotetrazole are described. The tetramethylammonium salt (P[Formula: see text]) forms hydrogen-bonded ribbons of anions which accept weak C-H?N contacts from the cations. The cystamine salt (C2/c) shows wave-shaped ribbons of anions linked by hydrogen bonds to screw shaped dications. The tetramethylguanidine salt (P21/c) exhibits layers of anions hydrogen-bonded to the cations. PMID- 26753099 TI - Molecular analysis of CD133-positive circulating tumor cells from patients with metastatic castration-resistant prostate cancer. AB - The function and clinical utility of stem cell markers in metastatic castration resistant prostate cancer (mCRPC) remains unresolved, and their expression may confer important therapeutic opportunities for staging and therapy. In the adult human prostate, CD133 (PROM1) expression identifies infrequent prostate epithelial progenitor cells and putative cancer stem cells. Previous work demonstrated an association with CD133 and cancer cell proliferation using in vitro model systems. The primary objective here was to investigate the expression of CD133 in circulating tumor cells (CTCs) from patients with mCRPC and to test the hypothesis that patients with mCRPC had CD133-positive CTCs associated with increased cell proliferation, changes in the androgen receptor (AR) protein expression, or AR nuclear co-localization. We utilized ImageStreamX technology, which combines flow cytometry and fluorescence microscopy, to capture and analyze CD45-negative/EpCAM-positive CTCs for CD133, Ki-67, and AR. All patient samples (20/20) contained CD133-positive populations of CTCs, and on average 50.9 +/- 28.2% (range of 18.2% to 100%) of CTCs were CD133-positive. CD133-positive CTCs have increased Ki-67 protein expression compared to CD133-negative CTCs, implying that CD133-positive CTCs may have greater proliferative potential when compared to their CD133-negative counterparts. CD133-positive and CD133-negative CTCs have similar levels of AR protein expression and cellular co-localization with nuclear markers, implying that CD133 expression is independent of AR pathway activity and an AR-independent marker of mCRPC proliferation. These studies demonstrate the presence of CD133-positive populations in CTCs from mCRPC with increased proliferative potential. PMID- 26753101 TI - How the Most Trusted Venues for Health-Related Information Influence Physician Referrals to Smoking Cessation Services. AB - Public health programs seek to educate physicians by using a variety of venues. Therefore, it is important to understand which health information sources physicians are using and how these sources affect referrals. We explored how venues for health-related information affect physicians' referral practices to smoking cessation services. The 2008 DocStyles survey asked physicians to rank a list of their most trusted sources of health-related information. The analysis was restricted to 1,617 physicians who responded to all variables of interest. In this sample, the most trusted sources of health-related information cited by physicians were medical journals (95.9%), government health agencies (82.2%), other physicians (76.4%), professional medical societies (75.2%), and medical Web sites or podcasts (65.9%). Medical providers were more likely to refer tobacco users to cessation services if they used professional medical societies as a source to obtain patient health-related information, compared with medical providers not using this source (multivariate odds ratio = 1.31; 95% confidence interval = 1.03-1.66). Physicians use many health information sources. Therefore, to reach physicians effectively, a broad dissemination of guidelines and best practices in tobacco control is needed and should include information for medical societies. PMID- 26753102 TI - Multiple functional linear model for association analysis of RNA-seq with imaging. AB - Emerging integrative analysis of genomic and anatomical imaging data which has not been well developed, provides invaluable information for the holistic discovery of the genomic structure of disease and has the potential to open a new avenue for discovering novel disease susceptibility genes which cannot be identified if they are analyzed separately. A key issue to the success of imaging and genomic data analysis is how to reduce their dimensions. Most previous methods for imaging information extraction and RNA-seq data reduction do not explore imaging spatial information and often ignore gene expression variation at the genomic positional level. To overcome these limitations, we extend functional principle component analysis from one dimension to two dimensions (2DFPCA) for representing imaging data and develop a multiple functional linear model (MFLM) in which functional principal scores of images are taken as multiple quantitative traits and RNA-seq profile across a gene is taken as a function predictor for assessing the association of gene expression with images. The developed method has been applied to image and RNA-seq data of ovarian cancer and kidney renal clear cell carcinoma (KIRC) studies. We identified 24 and 84 genes whose expressions were associated with imaging variations in ovarian cancer and KIRC studies, respectively. Our results showed that many significantly associated genes with images were not differentially expressed, but revealed their morphological and metabolic functions. The results also demonstrated that the peaks of the estimated regression coefficient function in the MFLM often allowed the discovery of splicing sites and multiple isoforms of gene expressions. PMID- 26753104 TI - Alzheimer's Model Develops Early ADHD Syndrome. AB - We describe the first invertebrate model of attention deficit hyperactivity disorder (ADHD) that reproduces its major features, including hyperactivity, male predominance, marked exacerbation by simple carbohydrates, reversible response to dextroamphetamine, and a "paradoxical response" to stimulants. This model may offer new insight into ADHD pathogenesis and treatment. Furthermore, these findings are of particular interest in light of the recent epidemiological evidence showing that patients with dementia have a high frequency of antecedent ADHD symptoms. PMID- 26753103 TI - Determination of specificity influencing residues for key transcription factor families. AB - Transcription factors (TFs) are major modulators of transcription and subsequent cellular processes. The binding of TFs to specific regulatory elements is governed by their specificity. Considering the gap between known TFs sequence and specificity, specificity prediction frameworks are highly desired. Key inputs to such frameworks are protein residues that modulate the specificity of TF under consideration. Simple measures like mutual information (MI) to delineate specificity influencing residues (SIRs) from alignment fail due to structural constraints imposed by the three-dimensional structure of protein. Structural restraints on the evolution of the amino-acid sequence lead to identification of false SIRs. In this manuscript we extended three methods (Direct Information, PSICOV and adjusted mutual information) that have been used to disentangle spurious indirect protein residue-residue contacts from direct contacts, to identify SIRs from joint alignments of amino-acids and specificity. We predicted SIRs forhomeodomain (HD), helix-loop-helix, LacI and GntR families of TFs using these methods and compared to MI. Using various measures, we show that the performance of these three methods is comparable but better than MI. Implication of these methods in specificity prediction framework is discussed. The methods are implemented as an R package and available along with the alignments at stormo.wustl.edu/SpecPred. PMID- 26753106 TI - Building capacity for birth defects surveillance in Africa: Implementation of an intermediate birth defects surveillance workshop. AB - Each year around the world, it is estimated that 300,000 neonates are born with a neural tube defect. Many countries, however, are still lacking comprehensive birth defects surveillance registries. Comprehensive birth defects surveillance systems can help countries understand the magnitude and distribution of the problem. These systems can also provide information about biological, contextual, social and environmental determinants of birth defects. This information in turn can be used to identify effective and implementable solutions, and to evaluate prevention and management strategies to improve quality performance. This paper summarizes the development and implementation of an online pre-course training and in-person surveillance workshop conducted between 2014 December and 2015 March for representatives from six African countries. Feedback given by participants provided valuable lessons learned that can be applied to subsequent trainings and workshops. PMID- 26753105 TI - Mental health impact of the 2010 Haiti earthquake on the Miami Haitian population: A random-sample survey. AB - This study examined the mental health consequences of the January 2010 Haiti earthquake on Haitians living in Miami-Dade County, Florida, 2-3 years following the event. A random-sample household survey was conducted from October 2011 through December 2012 in Miami-Dade County, Florida. Haitian participants (N = 421) were assessed for their earthquake exposure and its impact on family, friends, and household finances; and for symptoms of posttraumatic stress disorder (PTSD), anxiety, and major depression; using standardized screening measures and thresholds. Exposure was considered as "direct" if the interviewee was in Haiti during the earthquake. Exposure was classified as "indirect" if the interviewee was not in Haiti during the earthquake but (1) family members or close friends were victims of the earthquake, and/or (2) family members were hosted in the respondent's household, and/or (3) assets or jobs were lost because of the earthquake. Interviewees who did not qualify for either direct or indirect exposure were designated as "lower" exposure. Eight percent of respondents qualified for direct exposure, and 63% qualified for indirect exposure. Among those with direct exposure, 19% exceeded threshold for PTSD, 36% for anxiety, and 45% for depression. Corresponding percentages were 9%, 22% and 24% for respondents with indirect exposure, and 6%, 14%, and 10% for those with lower exposure. A majority of Miami Haitians were directly or indirectly exposed to the earthquake. Mental health distress among them remains considerable two to three years post-earthquake. PMID- 26753108 TI - The role of the family doctor in the management of adults who are obese: a scoping review protocol. AB - BACKGROUND: The role of family doctors in the management of obesity in primary care will become increasingly important as more of the adult population become overweight or obese. Having a solid understanding of the family doctor's role as a sole practitioner is important for supporting practitioners in providing patient care and for informing future research. OBJECTIVE: The purpose of this paper is to describe a protocol for a scoping review that aims to examine and map the current research base for the role of the family doctor in managing adults who are overweight or obese. METHODS: This scoping review is based on the methodology as described by the Joanna Briggs Institute which involves final consultation with stakeholders. Two reviewers (ES, NE) will be responsible for the iterative development of a search strategy based on the basic initial search terms obesity, doctor and primary care. Black and grey literature will be searched to elucidate any manuscripts involving the family doctor in the management of adults who are overweight or obese. A customised data extraction tool will be used to collect relevant items from each manuscript. RESULTS: Data extraction will expose the role family doctors are playing in obesity management in all stages of research including recruitment, intervention or as a control group. By looking at a broad scope of manuscripts we will discover the family doctor's role as portrayed in research, in international guidelines and by peak bodies. We will also determine if there are any gaps in the research base. CONCLUSION: This protocol describes a scoping review that will illustrate the supporting international research for the role family doctors are playing in the management of adults who are overweight or obese. Scoping of the international literature will then be translated for Australian primary care. PMID- 26753107 TI - In Vivo Evaluation of the Pulmonary Toxicity of Cellulose Nanocrystals: A Renewable and Sustainable Nanomaterial of the Future. AB - The use of cellulose as building blocks for the development of novel functional materials is rapidly growing. Cellulose nanocrystals (CNC), with advantageous chemical and mechanical properties, have gained prominence in a number of applications, such as in nanofillers in polymer composites, building materials, cosmetics, food, and the drug industry. Therefore, it becomes critical to evaluate the potential health effects associated with CNC exposures. The objective of this study was to compare pulmonary outcomes caused by exposure of C57BL/6 mice to two different processed forms of CNC derived from wood, i.e., CNCS (10 wt %; gel/suspension) and CNCP (powder), and compare to asbestos induced responses. Pharyngeal aspiration with CNCS and CNCP was found to facilitate innate inflammatory response assessed by an increase in leukocytes and eosinophils recovered by bronchoalveolar lavage (BAL). Biomarkers of tissue damage were elevated to a higher extent in mice exposed to CNCP. Compared to CNCP, CNCS caused a significant increase in the accumulation of oxidatively modified proteins. The up-regulation of inflammatory cytokines was higher in the lungs after CNCS treatments. Most importantly, CNCP materials were significantly longer than CNCS. Taken together, our data suggests that particle morphology and nanosize dimensions of CNCs, regardless of the same source, may be critical factors affecting the type of innate immune inflammatory responses. Because various processes have been developed for producing highly sophisticated nanocellulose materials, detailed assessment of specific health outcomes with respect to their physical-structural-chemical properties is highly warranted. PMID- 26753109 TI - Impact of preoperative extracorporeal membrane oxygenation on vasoactive inotrope score after implantation of left ventricular assist device. AB - The purpose of this study was to elucidate the difference in inotrope use between patients who underwent left ventricular assist device (LVAD) implantation with preoperative extracorporeal membrane oxygenation (ECMO) and those who underwent LVAD implantation without preoperative ECMO. One hundred and eight patients who underwent LVAD implantation were enrolled in this study. Prior to LVAD implantation, 27 patients received ECMO support (ECMO group) and the other 81 patients did not (non-ECMO group). Cardiac index (CI), mean arterial pressure (MAP), mixed venous oxygen saturation (SvO2), and the vasoactive inotropic score (VIS) were recorded at weaning from cardiopulmonary bypass (CPB), 30 min after weaning from CPB (min after CPB), 60 min after CPB, and at the end of surgery. MAP and VIS were also recorded before induction of anesthesia (baseline). The modified VIS was defined as: (dopamine ug/kg/min * 1 + dobutamine ug/kg/min * 1 + epinephrine ug/kg/min * 100 + noradrenaline ug/kg/min * 100 + milrinone ug/kg/min * 10 + olprinone ug/kg/min * 25). There were no significant differences between the ECMO group and the non-ECMO group in terms of hemodynamic parameters such as MAP, CI, and SvO2. However, the ECMO group had higher VIS and noradrenaline doses than that of non-ECMO group (p = 0.030 and p = 0.044, respectively). VIS was significantly higher in ECMO group at 30 min after CPB (p = 0.03), 60 min after CPB (p = 0.003), and at the end of the surgery (p < 0.001). The doses of noradrenaline were significantly higher in ECMO group at 60 min after CPB (p = 0.013), and at the end of surgery (p = 0.002). Patients who received ECMO support prior to LVAD implantation required significantly more noradrenaline to maintain normal levels of hemodynamic parameters compared with patients without ECMO. PMID- 26753110 TI - Subjective and objective assessment of oxaliplatin-induced peripheral neuropathy. AB - Numbness and pain are currently evaluated using subjective methods such as the visual analog scale (VAS). However, because assessment of pain can vary greatly depending on the mood and physical state of the patient at the time of assessment, it is best to evaluate pain objectively. pain vision PS-2100 (PV) is an analytical instrument that was designed to quantitatively and objectively assess sense perception and nociception in patients. The present study examined the correlation of subjective and objective assessment of oxaliplatin-induced peripheral neuropathy (PN) using VAS and PV, respectively. The mean VAS and PV scores of PN were 20.5 (range 0-100) and 27.9 (range 0-416), respectively. The partial correlation coefficient was 0.274 (p = 0.0003). No strong correlation was observed between the results and a weak correlation was observed between VAS and PV. PMID- 26753112 TI - Vascular graft infection due to Pasteurella multocida. AB - BACKGROUND: Vascular graft infections are infrequent complications with important morbidity and mortality rates. Pasteurella multocida, a Gram negative bacillus, is a normal oral commensal of many animals. For mankind, it is a pathogenous bacillus which is rarely implicated in vascular grafts. CASE REPORT: We report hereafter the fourth case introduced in the international literature about vascular graft infections caused by P. multocida. The patient was successfully treated with a combination of a surgical graft change and a 6 weeks bi-antibiotic therapy. DISCUSSION: There is fours case reported in litterature with quite different antibiotic drugs and duration. CONCLUSION: P. multicoda graft infection should be long with initial intravenous drug and mainteance traitement should not be required. PMID- 26753111 TI - Antibacterial activity of nineteen selected natural products against multi-drug resistant Gram-negative phenotypes. AB - The present study was designed to assess the antimicrobial activity of 19 natural products belonging to terpenoids, alkaloids, thiophenes and phenolics against a panel of 14 Gram-negative multidrug-resistant (MDR) bacteria. The results demonstrated that amongst the studied compounds, alkaloids and terpenoids were less active contrary to flavonoids: neocyclomorusin (3) and candidone (6) and isoflavonoids: neobavaisoflavone (8) and daidzein (12). Thiophene, 2-(penta-1,3 diynyl)-5-(3,4-dihydroxybut-1-ynyl)thiophene (17) showed moderate and selective activities. Compounds 3, 6, 8 and 12 displayed minimal inhibitory concentration (MIC) ranged from 4 to 256 MUg/mL on all the 14 tested bacteria. MIC values below 10 MUg/mL were obtained with 8, 3, 6 and 12 against 50, 42.9, 35.7 and 21.4 % of the tested bacteria. The lowest MIC value of 4 MUg/mL was obtained with compound 3 against Klebsiella pneumoniae ATCC11296, Enterobacter cloacae BM47, compound 6 against Escherichia coli ATCC8739, K. pneumoniae ATCC11296, E. cloacae BM47 and compound 8 against K. pneumoniae ATCC11296 and E. cloacae BM47. The activity of flavonoid 3 was better or equal to that of chloramphenicol in all tested K. pneumoniae, Providencia stuartii, E. aerogenes, E. cloacae and Pseudomonas aeruginosa strains. Within isoflavonoids, neobavaisoflavone scaffold was detected as a pharmacophoric moiety. This study indicates that natural products such as 3, 6 and 8 could be explored more to develop antimicrobial drugs to fight MDR bacterial infections. PMID- 26753113 TI - OnabotulinumtoxinA 155 U in medication overuse headache: a two years prospective study. AB - The efficacy and safety of OnabotulinumtoxinA 155-195 U (BOTOX((r))) in adults with chronic migraine (CM) were demonstrated in both the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) studies. However, data about its long-term efficacy and safety in clinical settings are scanty. Therefore, the objective of this study is to evaluate OnabotulinumtoxinA 155 U treatment in patients affected with CM and co-morbid medication overuse headache (MOH) over 2 year analysis. We prospectively evaluated 155 CM and MOH affected patients started on OnabotulinumtoxinA 155U (PREEMPT injection paradigm) between October 2010 and November 2011 and followed-up for 2 years. All patients failed to positively respond to previous multiple preventive therapies that were withdrawn before starting OnabotulinumtoxinA. Headache days, migraine days, acute pain medication intake days and Headache Impact Test (HIT)-6 score were used as efficacy measures, whereas safety was evaluated with side effects occurrence during the treatment phase. Baseline data were collected from patients headache diary referred to the previous month, and patients were evaluated every 3 months at the time of each injection. OnabotulinumtoxinA 155U significantly reduced the number of headache and migraine days (p < 0.001), acute pain medication intake days (p < 0.001) and HIT-6 score (p < 0.001) when compared with the baseline data. The reduction was significant after the first injection (p < 0.001), and gradually increased during the 2 years of treatment. Treatment related adverse events were transient and mild-moderate (e.g. headache, injection-site pain, eyelid ptosis, musculoskeletal weakness). This prospective 2-years analysis of efficacy and safety of long-term treatment with OnabotulinumtoxinA 155 U in patients affected with CM and MOH confirms the efficacy data from previous Randomized Clinical Trials for CM prophylaxis. Moreover, here we demonstrate that OnabotulinumtoxinA can be safely used for the long-term treatment of MOH comorbidity in CM. PMID- 26753114 TI - Prediction of extubation failure in newborns, infants and children: brief report of a prospective (blinded) cohort study at a tertiary care paediatric centre in India. AB - BACKGROUND: Extubation failure (EF), defined as need for re-intubation within 24 72 h, is multifactorial. Factors predicting EF in adults generally are not useful in children. OBJECTIVE: To determine the factors associated with EF and to facilitate prediction of EF in mechanically ventilated infants and children less than 12 years of age. MATERIAL AND METHODS: Design Prospective cohort study. Setting PICU and NICU of a multispecialty tertiary care institute. Patients All consecutive newborns, infants and children, who remained on the ventilator for more than 12 h, were included. Patients with upper airway obstruction, neuromuscular disorders, complex anatomic malformations, accidental extubation, tracheostomy or death before extubation were excluded. Methods The pre-extubation clinical, laboratory and ventilatory parameters were collected for 92 cases over a one and half year period. The EF rate was calculated for each variable using STATA 9. All the treating physicians were blinded to the data collection procedure. MEASUREMENTS AND RESULTS: Demographics were comparable between the extubation success and EF groups. Respiratory failure was the main cause requiring ventilation (46.74 %, 95 % CI 0.37-0.57) as well as EF (30.23 %, 95 % CI 0.08-0.23). 76.92 % (95 % CI 0.58-0.89) of patients that failed extubation had alterations in respiratory effort, 38.46 % (95 % CI 0.22-0.57) each had either poor or increased respiratory effort. Poor cough reflex (p = 0.001), thick endotracheal secretions (p = 0.02), failed spontaneous breathing trial (SBT) (p = 0.001) and higher rapid shallow breathing index (RSBI) (p = 0.001) were found to be associated with EF. CONCLUSIONS: Paediatric EF is multifactorial. Increased or poor respiratory effort and failed SBT are potential factors in deciding re intubation. Increased RSBI, poor cough reflex and thick. PMID- 26753115 TI - Essential oil composition variability among natural populations of Pinus mugo Turra in Kosovo. AB - Pinus mugo Turra, is a native pine species in central and southern Europe, growing in high mountains area (altitudes 1.800-2.300 m.a.s.l.). In Kosovo, it is one of the native pines too, distributed in high altitudes in the Sharri Mountains and Albanian Alps Mountains. Its populations represent an important wealth of essential oil resources available, which make this species very important in terms of economic values. The chemical composition and yields of the essential oils of dwarf pine (Pinus mugo Turra) needles, twigs and cones from six wild populations in Kosovo were investigated with the aim to assess their natural variability. The identity of P. mugo was confirmed by morphology and DNA barcoding. Sixty-two compounds were identified representing 69-95 % of the total identified compounds. The yield ranged from 0.3-0.8 % v/w in needles, 1.0-2.4 % v/w in twigs and 0.1-0.5 % v/w in cones, depending on the origin of plant material and plant organs. alpha-Pinene (needles: 16.9-24.5 %; twigs: 4.5-8.8 %; cones: 3.1-5.6 %), beta-pinene (needles: 1.5-5.4 %; twigs: 2.2-15.4 %; cones: 1.3 14.2 %), delta-3-carene (needles: 15.4-27.8 %; twigs: 24.0-51.6 %; cones: 10.5 31.5 %), limonene + beta-phellandrene (needles: 1.9-5.9 %; twigs: 12.6-24.2 %; cones: 2.1-9.3 %), (E)-caryophyllene (needles: 4.4-8.9 %; twigs: 4.0-10.8 %; cones: 10.3-26.9 %) and germacrene D (needles: 4.0-8.3 %; twigs: 0.2-6.19 %; cones: 0.1-12.4 %) were the major components of the essential oil. Principal component analysis (PCA) and hierarchical cluster analyses (HCA) suggests that the population of P. mugo clustering is not related to their geographic location, but rather seemed to be linked to local selective forces acting on chemotype diversity. Low variability related to their geographic location has an economic importance since samples originating from different locations in Kosovo can treated with same standards. PMID- 26753116 TI - Molecular cloning and expression analysis of KIN10 and cold-acclimation related genes in wild banana 'Huanxi' (Musa itinerans). AB - Banana cultivars may experience chilling or freezing injury in some of their cultivated regions, where wild banana can still grow very well. The clarification of the cold-resistant mechanism of wild banana is vital for cold-resistant banana breeding. In this study, the central stress integrator gene KIN10 and some cold acclimation related genes (HOS1 and ICE1s) from the cold-resistant wild banana 'Huanxi' (Musa itinerans) were cloned and their expression patterns under different temperature treatments were analyzed. Thirteen full-length cDNA transcripts including 6 KIN10s, 1 HOS1 and 6 ICE1s were successfully cloned. Quantitative real-time PCR (qRT-PCR) results showed that all these genes had the highest expression levels at the critical temperature of banana (13 degrees C). Under chilling temperature (4 degrees C), the expression level of KIN10 reduced significantly but the expression of HOS1 was still higher than that at the optimal temperature (28 degrees C, control). Both KIN10 and HOS1 showed the lowest expression levels at 0 degrees C, the expression level of ICE1, however, was higher than control. As sucrose plays role in plant cold-acclimation and in regulation of KIN10 and HOS1 bioactivities, the sucrose contents of wild banana under different temperatures were detected. Results showed that the sucrose content increased as temperature lowered. Our result suggested that KIN10 may participate in cold stress response via regulating sucrose biosynthesis, which is helpful in regulating cold acclimation pathway in wild banana. PMID- 26753117 TI - The arthroscopical and radiological corelation of lever sign test for the diagnosis of anterior cruciate ligament rupture. AB - The aim of the current study was to evaluate the sensitivity of the lever sign test and the widely used basic tests of the Lachman, anterior drawer and pivot shift tests, both under anaesthesia and without anaesthesia, according to the gold standard diagnostic arthroscopic results in patients undergoing anterior cruciate ligament reconstruction. The study included 117 patients, diagnosed with ACL tear which was definitively determined during an arthroscopic surgical procedure applied. Before anaesthesia and while under anaesthesia, the Lachman, anterior drawer, pivot shift and lever sign tests were applied to all patients. Evaluation was made of MR images for each patient and documented. The patients comprised 96 males and 21 females, witha mean age of 25.8 +/- 5.9 years (range, 17-45 years). Total tear was determined in 82 cases, anteromedial (AM) bundle in 14, posterolateral (PL) bundle in 13 and elongation in 8. Pre-anaesthesia positivity was found in lever sign at 94.2 %, Lachman at 80.5 %, pivot shift at 62.3 % and anterior drawer at 60.1 %. These rates were determined after anaesthesia as lever sign 98.4 %, Lachman 88.7 %, pivot shift 88.3 % and anterior drawer 84.2 %. The lever sign test can be easily applied clinically and it seems to have higher sensitivity than the Lachman test which is the basis of classic information, it should be included in routine clinical practice. In the light of the results of this study, further studies are required to review the accepted view that the Lachmann test is the most reliable test. PMID- 26753118 TI - Parametrized inequality of Hermite-Hadamard type for functions whose third derivative absolute values are quasi-convex. AB - In this paper we present some inequalities of Hermite-Hadamard type for functions whose third derivative absolute values are quasi-convex. Moreover, an application to special means of real numbers is also considered. PMID- 26753119 TI - Blind data hiding technique using the Fresnelet transform. AB - A new blind data hiding scheme is proposed in which data is decomposed using the Fresnelet transform. The inverse Fresnelet transform is performed on decomposed subbands by choosing different key parameters, and the coded pattern of the information data is obtained. This coded pattern is embedded into particular subbands of the cover image using the wavelets. The proposed method has good imperceptibility and large capacity of the information embedded data. Using the Fresnelet transform with a family of wavelet transforms makes the scheme more efficient in terms of extracted accuracy of hidden information. Moreover, the hidden data can be recovered without access to the original cover data. The proposed method is used to resolve privacy and security issues raised with respect to emerging internet applications for the effective handling of confidential data. PMID- 26753121 TI - Inertial sensors for smartphones navigation. AB - The advent of smartphones and tablets, means that we can constantly get information on our current geographical location. These devices include not only GPS/GNSS chipsets but also mass-market inertial platforms that can be used to plan activities, share locations on social networks, and also to perform positioning in indoor and outdoor scenarios. This paper shows the performance of smartphones and their inertial sensors in terms of gaining information about the user's current geographical locatio n considering an indoor navigation scenario. Tests were carried out to determine the accuracy and precision obtainable with internal and external sensors. In terms of the attitude and drift estimation with an updating interval equal to 1 s, 2D accuracies of about 15 cm were obtained with the images. Residual benefits were also obtained, however, for large intervals, e.g. 2 and 5 s, where the accuracies decreased to 50 cm and 2.2 m, respectively. PMID- 26753120 TI - A framework for the first-person internal sensation of visual perception in mammals and a comparable circuitry for olfactory perception in Drosophila. AB - Perception is a first-person internal sensation induced within the nervous system at the time of arrival of sensory stimuli from objects in the environment. Lack of access to the first-person properties has limited viewing perception as an emergent property and it is currently being studied using third-person observed findings from various levels. One feasible approach to understand its mechanism is to build a hypothesis for the specific conditions and required circuit features of the nodal points where the mechanistic operation of perception take place for one type of sensation in one species and to verify it for the presence of comparable circuit properties for perceiving a different sensation in a different species. The present work explains visual perception in mammalian nervous system from a first-person frame of reference and provides explanations for the homogeneity of perception of visual stimuli above flicker fusion frequency, the perception of objects at locations different from their actual position, the smooth pursuit and saccadic eye movements, the perception of object borders, and perception of pressure phosphenes. Using results from temporal resolution studies and the known details of visual cortical circuitry, explanations are provided for (a) the perception of rapidly changing visual stimuli, (b) how the perception of objects occurs in the correct orientation even though, according to the third-person view, activity from the visual stimulus reaches the cortices in an inverted manner and (c) the functional significance of well-conserved columnar organization of the visual cortex. A comparable circuitry detected in a different nervous system in a remote species-the olfactory circuitry of the fruit fly Drosophila melanogaster-provides an opportunity to explore circuit functions using genetic manipulations, which, along with high resolution microscopic techniques and lipid membrane interaction studies, will be able to verify the structure-function details of the presented mechanism of perception. PMID- 26753122 TI - Does malalignment affect revision rate in total knee replacements: a systematic review of the literature. AB - To ensure implant durability following Modern total knee replacement (TKR) surgery, one long held principle in condylar total knee arthroplasty is positioning the components in alignment with the mechanical axis and restoring the overall limb alignment to 180 degrees +/- 3 degrees . However, this view has been challenged recently. Given the high number of TKR performed, clarity on this integral aspect of the procedure is necessary. To investigate the association between malalignment following primary TKR and revision rates. A systematic review of the literature was conducted using a computerised literature search of Medline, CINHAL, and EMBASE to identify English-language studies published from 2000 through to 2014. Studies with adequate information on the correlation between malalignment and revision rate with a minimum follow-up of 6 months were considered for inclusion. A study protocol, including the detailed search strategy was published on the PROSPERO database for systematic reviews. From an initial 2107 citations, eight studies, with variable methodological qualities, were eligible for inclusion. Collectively, nine parameters of alignment were studied, and 20 assessments were made between an alignment parameter and revision rate. Four out of eight studies demonstrated an association between a malalignment parameter and increased revision rates. In the coronal plane, only three studies assessed the mechanical axis. None of these studies found an association with revision rates, whereas four of the five studies investigating the anatomical axis found an association between malalignment and increased revision rate. This study demonstrates the effect of malalignment on revision rates is likely to be modest. Interestingly, studies that used mechanical alignment in the coronal plane demonstrated no association with revision rates. This questions the premise of patient specific instrumentation devices based on the mechanically aligned knee when considering revision as the endpoint. PMID- 26753123 TI - TERT promoter mutations are a rare event in gastrointestinal stromal tumors. AB - Recently, the impact of telomere dysregulation on malignant progression has been reported in many cancers. A few studies have examined TERT promoter mutations in gastrointestinal stromal tumors (GISTs). Irregular telomerase activation can be maintained by TERT hot spot alterations and alternative lengthening of telomeres (ALT) characterized by inactivation of either the alpha-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated protein (DAXX). To elucidate the clinicopathological impact of telomere dysregulation in GISTs, we examined 92 cases of GISTs for TERT promoter hot spot mutations along with immunohistochemical analysis of ATRX and DAXX expression, and compared these findings with the clinicopathological features. Univariate clinicopathological analysis revealed that tumor site, smaller tumor size, presence of necrosis, higher mitotic rate (>5/50 high-power fields) and risk classification were prognostic factors for either disease-free survival or overall survival. Two of 92 informative cases (2.2 %) were found to have heterozygous TERT promoter mutations (C228T), and these mutations occurred in a low-risk and a high-risk tumor, respectively. On immunohistochemical analysis for ATRX and DAXX, 16 (17.4 %) and 3 (3.3 %) of 92 cases showed loss of expression of ATRX and DAXX, respectively. Loss of expression of ATRX and DAXX were mutually exclusive except for one case. TERT promoter mutations were also mutually exclusive of the ALT phenotype. Telomere dysregulation was not associated with patient survival; however, telomere dysregulation was frequently observed in tumors of extra gastric origin, which have an adverse outcome compared to those of gastric origin. PMID- 26753124 TI - Reliability of the American Community Survey for unintentional drowning and submersion injury surveillance: a comprehensive assessment of 10 socioeconomic indicators derived from the 2006-2013 annual and multi-year data cycles. AB - BACKGROUND: Our objective was to evaluate the reliability and predictability of ten socioeconomic indicators obtained from the 2006-2013 annual and multi-year ACS data cycles for unintentional drowning and submersion injury surveillance. METHODS: Each indicator was evaluated using its margin of error and coefficient of variation. For the multi-year data cycles we calculated the frequency that estimates for the same geographic areas from consecutive surveys were statistically significantly different. Relative risk estimates of drowning related deaths were constructed using the National Center for Health Statistics compressed mortality file. All analyses were derived using census counties. RESULTS: Five of the ten socioeconomic indicators derived from the annual and multi-year data cycles produced high reliability CV estimates for at least 85 % of all US counties. On average, differences in socioeconomic characteristics for the same geographic areas for consecutive 3- and 5-year data cycles were unlikely to be caused by sampling error in only 17 % (5-89 %) and 21 % (5-93 %) of all counties. No indicator produced statistically significant relative risk estimates across all data cycles and survey years. CONCLUSIONS: The reliability of the annual and multi-year county-level ACS data cycles varies by census indicator. More than 75 % of the differences in estimates between consecutive multi-year surveys are likely to have occurred as a result of sampling error, suggesting that researchers should be judicious when interpreting overlapping survey data as reflective of real changes in socioeconomic conditions. Although no indicator predicted disparities in drowning-related injury mortality across all data cycles and years, further studies are needed to determine if these associations remain consistent at different geographic scales and for injury morbidity. PMID- 26753126 TI - Reducing protein oxidation in low-flow electrospray enables deeper investigation of proteoforms by top down proteomics. AB - Enabling the implementation of top down proteomic techniques within clinical workflows requires a dramatic increase in sensitivity. It has been previously demonstrated that electrospray ionization (ESI) becomes more efficient with decreasing volumetric flow rates at the emitter. Therefore, narrow inner diameter (I.D.) columns used in front-end chromatographic separations yield increased sensitivity. However, the smaller cross-sectional area of a narrow I.D. column places a larger fraction of the eluent in fluid communication with the electrode within the high voltage union that facilitates electrospray ionization (ESI), leading to increased oxidation of solution-phase proteins. Oxidation of proteins alters their chemical state of the protein, complicates data analysis, and reduces the depth of proteome coverage attained in a typical top-down proteomics experiment. Excessive protein oxidation results in poor deconvolution and exact mass calculations from MS1 spectra, interferes with peak isolation for MS/MS fragmentation, and effectively reduces sensitivity by splitting ion current. All of these factors deteriorate top down mass spectral data quality, an effect that becomes more pronounced as column diameter decreases. Artificial protein oxidation can also mislead investigations of in vivo protein oxidation. All of these effects are accentuated in comparison to bottom up proteomics due to the increased probability of having oxidizable residues within a particular species with increasing mass. Herein, we describe a configuration (which we term "Low Protein Oxidation (LPOx)") for proteomics experiments created by re-arranging liquid chromatography (LC) plumbing and present its application to artificial protein oxidation and show a marked improvement in detection sensitivity. Using a standard mixture of five intact proteins, we demonstrate that the LPOx configuration reduces protein oxidation up to 90% using 50 MUm I.D. columns when compared to a conventional LC plumbing configuration with 50 MUm I.D. column. As a proof-of-concept study, at least 11 distinct proteoforms of serum Apolipoprotein A1 were detected with the LPOx configuration. This innovative LC configuration can be applied to the top down identification and characterization of proteoforms obscured by abundant artificial protein oxidation at low flowrates, all while using reduced amounts of valuable protein samples. PMID- 26753127 TI - Assessing the performance of the Oxford Nanopore Technologies MinION. AB - The Oxford Nanopore Technologies (ONT) MinION is a new sequencing technology that potentially offers read lengths of tens of kilobases (kb) limited only by the length of DNA molecules presented to it. The device has a low capital cost, is by far the most portable DNA sequencer available, and can produce data in real-time. It has numerous prospective applications including improving genome sequence assemblies and resolution of repeat-rich regions. Before such a technology is widely adopted, it is important to assess its performance and limitations in respect of throughput and accuracy. In this study we assessed the performance of the MinION by re-sequencing three bacterial genomes, with very different nucleotide compositions ranging from 28.6% to 70.7%; the high G + C strain was underrepresented in the sequencing reads. We estimate the error rate of the MinION (after base calling) to be 38.2%. Mean and median read lengths were 2 kb and 1 kb respectively, while the longest single read was 98 kb. The whole length of a 5 kb rRNA operon was covered by a single read. As the first nanopore-based single molecule sequencer available to researchers, the MinION is an exciting prospect; however, the current error rate limits its ability to compete with existing sequencing technologies, though we do show that MinION sequence reads can enhance contiguity of de novo assembly when used in conjunction with Illumina MiSeq data. PMID- 26753129 TI - Laboratory system strengthening and quality improvement in Ethiopia. AB - BACKGROUND: In 2010, a National Laboratory Strategic Plan was set forth in Ethiopia to strengthen laboratory quality systems and set the stage for laboratory accreditation. As a result, the Strengthening Laboratory Management Toward Accreditation (SLMTA) programme was initiated in 45 Ethiopian laboratories. OBJECTIVES: This article discusses the implementation of the programme, the findings from the evaluation process and key challenges. METHODS: The 45 laboratories were divided into two consecutive cohorts and staff from each laboratory participated in SLMTA training and improvement projects. The average amount of supportive supervision conducted in the laboratories was 68 hours for cohort I and two hours for cohort II. Baseline and exit audits were conducted in 44 of the laboratories and percent compliance was determined using a checklist with scores divided into zero- to five-star rating levels. RESULTS: Improvements, ranging from < 1 to 51 percentage points, were noted in 42 laboratories, whilst decreases were recorded in two. The average scores at the baseline and exit audits were 40% and 58% for cohort I (p < 0.01); and 42% and 53% for cohort II (p < 0.01), respectively. The p-value for difference between cohorts was 0.07. At the exit audit, 61% of the first and 48% of the second cohort laboratories achieved an increase in star rating. Poor awareness, lack of harmonisation with other facility activities and the absence of a quality manual were challenges identified. CONCLUSION: Improvements resulting from SLMTA implementation are encouraging. Continuous advocacy at all levels of the health system is needed to ensure involvement of stakeholders and integration with other improvement initiatives and routine activities. PMID- 26753128 TI - Altered lipid accumulation in Nannochloropsis salina CCAP849/3 following EMS and UV induced mutagenesis. AB - Microalgae have potential as a chemical feed stock in a range of industrial applications. Nannochloropsis salina was subject to EMS mutagenesis and the highest lipid containing cells selected using fluorescence-activated cell sorting. Assessment of growth, lipid content and fatty acid composition identified mutant strains displaying a range of altered traits including changes in the PUFA content and a total FAME increase of up to 156% that of the wild type strain. Combined with a reduction in growth this demonstrated a productivity increase of up to 76%. Following UV mutagenesis, lipid accumulation of the mutant cultures was elevated to more than 3 fold that of the wild type strain, however reduced growth rates resulted in a reduction in overall productivity. Changes observed are indicative of alterations to the regulation of the omega 6 Kennedy pathway. The importance of these variations in physiology for industrial applications such as biofuel production is discussed. PMID- 26753130 TI - Attaining ISO 15189 accreditation through SLMTA: A journey by Kenya's National HIV Reference Laboratory. AB - BACKGROUND: The National HIV Reference Laboratory (NHRL) serves as Kenya's referral HIV laboratory, offering specialised testing and external quality assessment, as well as operating the national HIV serology proficiency scheme. In 2010, the Kenya Ministry of Health established a goal for NHRL to achieve international accreditation. OBJECTIVES: This study chronicles the journey that NHRL took in pursuit of accreditation, along with the challenges and lessons learned. METHODS: NHRL participated in the Strengthening Laboratory Management Toward Accreditation (SLMTA) programme from 2010-2011. Improvement projects were undertaken to address gaps in the 12 quality system essentials through development of work plans, team formation, training and mentorship of personnel. Audits were conducted and the scores used to track progress along a five-star grading scale. Standard quality indicators (turn-around time, specimen rejection rates and service interruptions) were measured. Costs of improvement projects and accreditation were estimated based on expenditures. RESULTS: NHRL scored 45% (zero stars) at baseline in March 2010 and 95% (five stars) after programme completion in October 2011; in 2013 it became the first public health laboratory in Kenya to attain ISO 15189 accreditation. From 2010-2013, turn-around times decreased by 50% - 95%, specimen rejections decreased by 93% and service interruptions dropped from 15 to zero days. Laboratory expenditures associated with achieving accreditation were approximately US $36 500. CONCLUSION: International accreditation is achievable through SLMTA, even for a laboratory with limited initial quality management systems. Key success factors were dedication to a shared goal, leadership commitment, team formation and effective mentorship. Countries wishing to achieve accreditation must ensure adequate funding and support. PMID- 26753131 TI - Training-of-trainers: A strategy to build country capacity for SLMTA expansion and sustainability. AB - BACKGROUND: The Strengthening Laboratory Management Toward Accreditation (SLMTA) programme uses a training-of-trainers (TOT) model to build capacity for programme scale-up. The TOT strategy is designed to maximise utilisation of its graduates whilst minimising inconsistencies and ensuring high programme quality during global expansion. OBJECTIVES: To describe the SLMTA TOT programme approach. METHODS: The two-week training, led by carefully selected and trained master trainers, enables effective and authentic implementation of the curriculum by its graduates. The teachback methodology used allows participants to practise teaching the curriculum whilst learning its content. A trainer's toolkit provides all the materials necessary for teaching and must be followed faithfully during training. Two surveys were conducted to assess the effectiveness of the TOT strategy: one sent to 316 TOT graduates in 25 countries and the other sent to the programme leaders in 10 countries. RESULTS: By the end of 2013, 433 SLMTA trainers had been trained who, in turn, taught more than 1900 people to implement SLMTA in 617 laboratories in 47 countries. Ninety-seven percent of the 433 TOT graduates and 87% of the 38 master trainers are based in developing countries. Ninety-two per cent of the graduates have been utilised at least once in programme implementation and, as of August 2013, 87% of them were still actively involved in programme activities. Ninety-seven per cent of the graduates stated that the TOT workshop prepared them well for training or other programme tasks. CONCLUSION: The SLMTA TOT strategy is effective in building local capacity for global programme expansion whilst maintaining programme quality. PMID- 26753132 TI - Evidence from 617 laboratories in 47 countries for SLMTA-driven improvement in quality management systems. AB - BACKGROUND: The Strengthening Laboratory Management Toward Accreditation (SLMTA) programme is a large-scale effort to improve the quality of laboratories in resource-limited countries. OBJECTIVES: This study sought to evaluate the first four years (2010-2013) of SLMTA implementation. METHODS: Country-level data were submitted by SLMTA programme leads and compiled globally. Performance was measured before (baseline) and after (exit) SLMTA implementation using an audit checklist which results in a percentage score and a rating of zero to five stars. Some laboratories continued to monitor performance in post-exit surveillance audits. We evaluated score improvements using two-tailed t-tests for equal variances and estimated the number of tests performed by SLMTA laboratories based on star level. RESULTS: SLMTA was implemented in 617 laboratories in 47 countries in Africa, the Caribbean, Latin America and Southeast Asia. At the baseline audit, the laboratories scored an average of 39% on the checklist and 84% of them were rated below one star. As of December 2013, 302 laboratories had completed the SLMTA programme; mean checklist scores increased from 39% at baseline to 64% at exit (p < 0.001) over an average 16-month programme duration. Ninety-two laboratories conducted a surveillance audit at a median of 11 months after their exit audit; 62% further increased their performance. Six SLMTA laboratories have achieved accreditation status. In total, the 617 SLMTA laboratories conduct an estimated 111 million tests annually. Only 16% of these tests were conducted by laboratories with at least one star at baseline, which increased to 68% of tests after SLMTA training. Thus, approximately 23 million tests are conducted annually by laboratories previously at zero stars that now have one to five stars; this number is projected to increase to 58 million when currently-enrolled laboratories complete the programme. CONCLUSION: SLMTA has transformed the laboratory landscape in resource-limited countries worldwide and has the potential to make a substantial and sustainable impact on the quality of laboratory testing and patient care. PMID- 26753125 TI - Recent Scientific Advances Towards the Development of Tendon Healing Strategies. AB - There exists a range of surgical and non-surgical approaches to the treatment of both acute and chronic tendon injuries. Despite surgical advances in the management of acute tears and increasing treatment options for tendinopathies, strategies frequently are unsuccessful, due to impaired mechanical properties of the treated tendon and/or a deficiency in progenitor cell activities. Hence, there is an urgent need for effective therapeutic strategies to augment intrinsic and/or surgical repair. Such approaches can benefit both tendinopathies and tendon tears which, due to their severity, appear to be irreversible or irreparable. Biologic therapies include the utilization of scaffolds as well as gene, growth factor, and cell delivery. These treatment modalities aim to provide mechanical durability or augment the biologic healing potential of the repaired tissue. Here, we review the emerging concepts and scientific evidence which provide a rationale for tissue engineering and regeneration strategies as well as discuss the clinical translation of recent innovations. PMID- 26753135 TI - Bidding adieu. PMID- 26753133 TI - Ultrasound and multidetector computed tomography of mandibular salivary gland adenocarcinoma in two dogs. AB - Malignant tumors of the salivary glands are rare in dogs, with adenocarcinoma being the most represented. Parotid and mandibular glands are most commonly affected in dogs. Because of local invasivity and high metastatic potential, preoperative imaging evaluation of mandibular region and tumoral staging is essential along with biopsy sampling. The present manuscript describes the ultrasound and computed tomographic imaging findings of mandibular gland adenocarcinoma in two dogs and discusses their clinical utility. PMID- 26753134 TI - Lymph node hemangioma in one-humped camel. AB - Hemangioma is a benign tumor of blood and lymphatic vessels. It is common in skin, mucosa and soft tissues, and its occurrence in lymph nodes is extremely rare. A 10 year-old she-camel was slaughtered at Nyala slaughterhouse, South Darfur State, Sudan. Grossly, the carcass was emaciated. The left ventral superficial cervical lymph node was enlarged, hard on palpation and protruded outside the body. Its cut surface was dark red in color and measured (18 cm) in diameter. Histopathologically, the sections revealed vascular masses were composed of non-encapsulated clusters of small and medium sized with thick and thin-walled, filled with blood, separated by courageous stroma and surrounded by closely packed proliferating capillaries. To the best of our knowledge, this is the first record of the left ventral superficial cervical lymph node hemangioma in a camel in the Sudan. PMID- 26753137 TI - Conidiobolomycosis: A case report of rare fungal infection from the eastern India. AB - Conidiobolomycosis is a rare chronic subcutaneous mycosis of nose and paranasal sinuse predominately affects the middle age men in tropical countries. It is caused by a saprophytic fungus "Conodiobolus coronatus", which can survives in soils and dried vegetables for long period of time. C. coronatus belongs to the class Zygomycetes, order Entomophthorales. It is a fungus composed of thick- walled, short hyphae that grows at temperatures of 30 to 37 degrees C. Here we report a case of conidiobolomycosis in a 55- year- old farmer presented with a subcutaneous swelling over the left side of nose extending to left cheek. PMID- 26753136 TI - Clinical study of cutaneous leishmaniasis in the Kashmir Valley. AB - BACKGROUND: Cutaneous leishmaniasis (CL) is an infectious disease of tropical and semitropical areas of the world. The cold and harsh winter conditions of the Kashmir Valley do not favor the survival and growth of the Leishmania parasite or its vector, the sand fly, and the disease was until now practically unheard of in the Kashmir Valley. AIMS: There has been a recent rise in the number of cases of CL in the Kashmir Valley. Against this background, the present study was taken up to describe the epidemiology, clinical features, and management outcomes of CL in the Kashmir Valley, where it represents a new phenomenon. MATERIALS AND METHODS: Patients with direct smear-confirmed CL were evaluated. For each patient, we noted age, gender, geographical origin, stays in endemic areas, clinical aspects, number, site and size of lesions, treatment, and outcome. All the infected patients were treated with sodium stibogluconate. The dose, route of administration, adverse effects, and the clinical response in each patient was noted down. RESULTS: Eighteen patients, 11 males (61.12%) and 7 females (38.88%) were studied. The age of the patients ranged from 3 to 60 years (mean age 29.8). The majority of our patients (16, 88.9%) belonged to two hilly areas, Uri and Karnah. Duration of the disease ranged from a minimum of 1 month to a maximum of 18 months (mean duration 4.6 months). Lesions in most of our patients (16, 88.9%) were located on the face including the lip and nose. The size of lesions varied from 4 to about 50 mm (average 2-3 cm). Most of our patients (13, 73.3%) had only a single lesion and a few (5, 26.7%) had two or three lesions. The clinical type of lesion in most of our patients (16, 88.9%) was noduloulcerative, only two (11.1%) had nodular (nonulcerative) lesions. Sixteen patients; all with facial lesions were treated with intravenous sodium stibogluconate. A complete response was seen in 14 (87%), without any major adverse effect. Two adult patients with extrafacial lesions were treated with four doses of weekly intralesional injections of sodium stibogluconate. A complete response was seen in both, without any major adverse effect. CONCLUSION: The emergence of CL in this nonendemic area is of great epidemiological importance. Because no parasite isolation and characterization was carried out, further epidemiological studies and taxonomic differentiation of the species are required. PMID- 26753138 TI - Carcinoma erysipeloides as a presenting feature of breast carcinoma: A case report and brief review of literature. AB - Carcinoma erysipeloides (CE) is an uncommon but distinctive form of cutaneous metastasis that usually manifests clinically as a fixed erythematous patch or plaque resembling cellulitis or erysipelas. The inflamed area may show a distinct raised edge at the periphery and also edema secondary to lymphatic obstruction. Histologically, dense carcinoma cells in the dermal vascular channels and dense perivascular lymphocytic infiltrate may be seen. CE may rarely be the first sign of "silent" tumor of breast. We report a case of a 52-year-old married lady who presented with a three months history of pruritic erythematous patches over the left side of the breast that was resistant to all topical treatments and was diagnosed as erysipeloid breast carcinoma. PMID- 26753139 TI - Kaposi's varicelliform eruption: A case series. AB - Kaposi's varicelliform eruption is a rare and potentially fatal viral infection caused mainly by reactivation of herpes simplex virus. It concomitantly occurs with pre-existing skin conditions, mostly atopic dermatitis, so it is predominately found in children. We present a case series that includes four adults, familial cases, and previously healthy patients. We also highlight clinical features, associations and therapeutic options. PMID- 26753140 TI - Naegeli-Franceschetti-Jadassohn syndrome: A rare case. AB - Naegeli-Franceschetti-Jadassohn Syndrome (NFJS) is a rare, autosomal dominant inherited form of ectodermal dysplasia, caused by mutation in the KRT14 gene. We report here a case of NFJS in a 27-year-old male who presented with reticulate hyperpigmentation over skin, dental changes, absence of dermatoglyphics, hypohidrosis, and hair changes. PMID- 26753141 TI - Purely cutaneous Langerhans cell histiocytosis presenting as an ulcer on the chin in an elderly man successfully treated with thalidomide. AB - Langerhans cell histiocytosis (LCH) is a rare, clonal proliferative disorder of Langerhans' cells of unknown etiology. Although the clinical presentation and therapeutic approach to the disease in children have been well established; limited data is available about the disease in adults. Purely cutaneous involvement of LCH in a man older than 70 years has rarely been described. Herein we report the case of a 71-year-old man with cutaneous LCH confined to the perioral region, scalp, and flexures successfully treated with thalidomide. PMID- 26753143 TI - Asymptomatic erythematous plaque. PMID- 26753142 TI - Subcutaneous entomophthoromycoses. AB - Subcutaneous entomophthoromycoses is a zygomycosis caused by Basidiobolus ranarum that is endemic in southern India. We report the case of a 63-year-old male from central India who presented with a nontender subcutaneous hyperpigmented plaque on his leg with mild discharge that yielded Basidiobolus ranarum. PMID- 26753144 TI - Multiple nodules on the sole of the foot. AB - Ledderhose disease, or plantar fibromatosis, is a benign hyperproliferative disorder of the plantar aponeurosis. It presents as one or more round, firm slow growing plaques or nodules on the plantar surface of the foot, typically on the medial side. The etiology is unknown, though it has been associated with trauma, liver disease, diabetes mellitus, epilepsy and alcoholism. Histopathological examination of plantar fibromatosis reveals dense fibrocellular tissue with parallel and nodular arrays of fibrocytes and fibrillar collagen with a distinctive cork-screw morphology. The differential diagnosis includes various fibroblastic and myofibroblastic proliferations. PMID- 26753145 TI - Global leprosy program: Does it need uniform-multi-drug therapy now? PMID- 26753147 TI - Aneurysmal benign fibrous histiocytoma presenting as a giant acrochordon on thigh. PMID- 26753148 TI - Hutchinson-Gilford progeria syndrome. PMID- 26753146 TI - Aspirin in dermatology: Revisited. AB - Aspirin has been one of the oldest drugs in the field of medicine, with a wide range of applications. In dermatology, aspirin has shown benefit in a variety of disorders. Recently, reduction of melanoma risk with aspirin has been demonstrated. Although an analgesic to begin with, aspirin has come a long way; after cardiology, it is now found to be useful even in dermatology. PMID- 26753150 TI - A postoperative case of carcinoma erysipeloides arising from ductal carcinoma of the breast. PMID- 26753151 TI - Rituximab therapy in a case of pemphigus vulgaris triggering herpes simplex infection at varied sites. PMID- 26753149 TI - Necrotizing fasciitis associated with systemic lupus erythematosus in a child. PMID- 26753152 TI - Porokeratosis and malignant melanoma: A causal or incidental association? PMID- 26753153 TI - Porokeratosis and malignancy: Incidental or causal association? PMID- 26753155 TI - Linear rays of depigmentation along lymphatics after intralesional corticosteroid therapy. PMID- 26753154 TI - SkIndia Quiz 21: Recurrent papulonodular lesions on elbows, fingers and lower leg. PMID- 26753156 TI - Acrokeratoelastoidosis. PMID- 26753157 TI - Scrotal calcinosis. PMID- 26753158 TI - A seemingly insignificant lesion. PMID- 26753161 TI - The Concept of Care Complexity: A Qualitative Study. AB - BACKGROUND: Hospital organisations based on the level of care intensity have clearly revealed a concept, that of care complexity, which has been widely used for decades in the healthcare field. Despite its wide use, this concept is still poorly defined and it is often confused with and replaced by similar concepts such as care intensity or workload. This study aims to describe the meaning of care complexity as perceived by nurses in their day-to-day experience of hospital clinical care, rehabilitation, home care, and organisation. DESIGN AND METHODS: Fifteen interviews were conducted with nurses belonging to clinical-care areas and to heterogeneous organisational areas. The interview was of an unstructured type. The participants were selected using a propositional methodology. Colaizzi's descriptive phenomenological method was chosen for the analysis of the interviews. RESULTS: The nurses who were interviewed predominantly perceive the definition of care complexity as coinciding with that of workload. Nevertheless, the managerial perspective does not appear to be exclusive, as from the in-depth interviews three fundamental themes emerge that are associated with the concept of care complexity: the patient, the nurse and the organisation. CONCLUSIONS: The study highlights that care complexity consists of both quantitative and qualitative aspects that do not refer only to the organisational dimension. The use of the terminology employed today should be reconsidered: it appears to be inappropriate to talk of measurement of care complexity, as this concept also consists of qualitative - thus not entirely quantifiable - aspects referring to the person being cared for. In this sense, reference should instead be made to the evaluation of care complexity, which would also constitute a better and more complete basis for defining the nursing skills required in professional nursing practice. Significance for public healthIn recent years, reference to the concept of complexity has become increasingly frequent in the management of healthcare systems. This interpretation of reality and of knowledge reflects the increasing use of a multi-disciplinary approach, in both clinical and research fields, that re-evaluates the importance of the environment and the preferences of the individual. The influence of the epistemological theory of complexity in healthcare can also be identified in discussions on the role and methods of epidemiology and public health; in breaking the walls between the exact sciences and the humanities; in the appreciation of qualitative methods of research and the Bayesian approach to biostatistics. PMID- 26753160 TI - An Audit of Diabetes Self-Management Education Programs in South Africa. AB - BACKGROUND: Diabetes is a significant contributor to the burden of disease worldwide. Since its treatment requires extensive self-care, self-management education is widely recommended, particularly in resource limited settings. This study aimed to review the current state of policies and implementation of diabetes self-management education (DSME) in South Africa, with a specific focus on cultural appropriateness. DESIGN AND METHODS: The audit involved a review of policy documents and semi-structured questionnaires with providers and experts in public and private health services. Forty-four respondents were interviewed. Documents were analysed with reference to the International Standards for Diabetes Education from the International Diabetes Federation. Data were entered and analysed in excel to give a description of the DSME programs and ad hoc interventions. RESULTS: Three guidelines for Type 2 diabetes and two for chronic diseases were retrieved, but none were specifically dedicated to DSME. Five structured programs and 22 ad-hoc interventions were identified. DSME is mostly provided by doctors, nurses and dieticians and not consistently linked to other initiatives such as support groups. Health education materials are mainly in English with limited availability. CONCLUSIONS: DSME in South Africa is limited in scope, content and consistency, especially in the public services. A National curricula and materials for diabetes education need to be developed and adapted to the socio-economic context, culture and literacy levels of the target populations. It is recommended that DSME would be addressed in national policies and guidelines to guide the development and implementation of standardised programs. Significance for public healthDiabetes significantly contributes to the global burden of disease. This burden is especially felt in developing countries, where resources are limited and the health system simultaneously has to deal with communicable and non-communicable diseases. While there is a growing body of literature on the development and implementation of diabetes self-management education, nearly all programs originate from developed countries. Very little is known about the current state of diabetes self-management education in developing countries. By focusing on diabetes self-management education in Southern Africa, the current paper provides policy makers and decision makers in South Africa with information that will help decide on where and how to intervene with regard to diabetes self-management education. The paper also has relevance for decision makers from other developing countries by providing recommendations on diabetes policies and diabetes self-management education. PMID- 26753159 TI - Framework for Selecting Best Practices in Public Health: A Systematic Literature Review. AB - Evidence-based public health has commonly relied on findings from empirical studies, or research-based evidence. However, this paper advocates that practice based evidence derived from programmes implemented in real-life settings is likely to be a more suitable source of evidence for inspiring and guiding public health programmes. Selection of best practices from the array of implemented programmes is one way of generating such practice-based evidence. Yet the lack of consensus on the definition and criteria for practice-based evidence and best practices has limited their application in public health so far. To address the gap in literature on practice-based evidence, this paper hence proposes measures of success for public health interventions by developing an evaluation framework for selection of best practices. The proposed framework was synthesised from a systematic literature review of peer-reviewed and grey literature on existing evaluation frameworks for public health programmes as well as processes employed by health-related organisations when selecting best practices. A best practice is firstly defined as an intervention that has shown evidence of effectiveness in a particular setting and is likely to be replicable to other situations. Regardless of the area of public health, interventions should be evaluated by their context, process and outcomes. A best practice should hence meet most, if not all, of eight identified evaluation criteria: relevance, community participation, stakeholder collaboration, ethical soundness, replicability, effectiveness, efficiency and sustainability. Ultimately, a standardised framework for selection of best practices will improve the usefulness and credibility of practice-based evidence in informing evidence-based public health interventions. Significance for public healthBest practices are a valuable source of practice-based evidence on effective public health interventions implemented in real-life settings. Yet, despite the frequent branding of interventions as best practices or good practices, there is no consensus on the definition and desirable characteristics of such best practices. Hence, this is likely to be the first systematic review on the topic of best practices in public health. Having a single widely accepted framework for selecting best practices will ensure that the selection processes by different agencies are fair and comparable, as well as enable public health workers to better appreciate and adopt best practices in different settings. Ultimately, standardisation will improve the credibility and usefulness of practice-based evidence to that of research-based evidence. PMID- 26753162 TI - Influence of Indoor Hygrothermal Conditions on Human Quality of Life in Social Housing. AB - BACKGROUND: Modern societies spend most of their time indoors, namely at home, and the indoor environment quality turns out to be a crucial factor to health, quality of life and well-being of the residents. The present study aims to understand how indoor environment relates with quality of life and how improving housing conditions impacts on individuals' health. DESIGN AND METHODS: This study case will rely on the following assessments in both rehabilitated and non rehabilitated social housing: i) field measurements, in social dwellings (namely temperature, relative humidity, carbon dioxide concentration, air velocity, air change rate, level of mould spores and energy consumption); ii) residents' questionnaires on social, demogaphic, behavioural, health characteristics and quality of life. Also, iii) qualitative interviews performed with social housing residents from the rehabilitated houses, addressing the self-perception of living conditions and their influence in health status and quality of life. All the collected information will be combined and analysed in order to achieve the main objective. EXPECTED IMPACT: It is expected to define a Predicted Human Life Quality (PHLQ) index, that combines physical parameters describing the indoor environment measured through engineering techniques with residents' and neighbourhood quality of life characteristics assessed by health questionnaires. Improvement in social housing should be related with better health indicators and the new index might be an important tool contributing to enhance quality of life of the residents. Significance for public healthThis study will contribute to understand how indoor environment relates with quality of life and how improving housing conditions impacts on individuals' health, in social housing neighbourhoods. As so, it is important to share the undertaken methodology carried out by a multidisciplinary team, in order to allow other researchers following comparable studies to adopt a similar approach. The case study results will allow to define building rehabilitation policies, improving residents' quality of life and adding great contribution to public health promotion. PMID- 26753163 TI - Vitamin D Status, Bone Mineral Density and Mental Health in Young Australian Women: The Safe-D Study. AB - BACKGROUND: Vitamin D deficiency has been associated with both poor bone health and mental ill-health. More recently, a number of studies have found individuals with depressive symptoms tend to have reduced bone mineral density. To explore the interrelationships between vitamin D status, bone mineral density and mental ill health we are assessing a range of clinical, behavioural and lifestyle factors in young women (Part A of the Safe-D study). DESIGN AND METHODS: Part A of the Safe-D study is a cross-sectional study aiming to recruit 468 young females aged 16-25 years living in Victoria, Australia, through Facebook advertising. Participants are required to complete an extensive, online questionnaire, wear an ultra-violet dosimeter for 14 consecutive days and attend a study site visit. Outcome measures include areal bone mineral measures at the lumbar spine, total hip and whole body, as well as soft tissue composition using dual energy x-ray absorptiometry. Trabecular and cortical volumetric bone density at the tibia is measured using peripheral quantitative computed tomography. Other tests include serum 25-hydroxyvitamin D, serum biochemistry and a range of health markers. Details of mood disorder/s and depressive and anxiety symptoms are obtained by self-report. Cutaneous melanin density is measured by spectrophotometry. EXPECTED IMPACT: The findings of this cross-sectional study will have implications for health promotion in young women and for clinical care of those with vitamin D deficiency and/or mental ill-health. Optimising both vitamin D status and mental health may protect against poor bone health and fractures in later life. Significance for public healthVitamin D deficiency, depression and osteoporosis are all major public health issues. Vitamin D deficiency has been associated with both reduced bone mineral density and depressive symptoms. Moreover, cohort studies have found that subjects with depression have lower bone mineral density when compared to healthy controls. Early adulthood is a critical time in young woman's lives as their independence, behaviours and lifestyle choices are established. These choices made as a young adult lay down the foundation for future health trajectories for not only for themselves but also for their potential partners and families. Addressing vitamin D deficiency, poor bone health and mental ill-health at a younger age may ultimately improve their wellbeing, productivity and long-term health outcomes. This study is of particular significance as the interplay between vitamin D, depression and bone health is currently uncertain and such knowledge is crucial for understanding, prevention and treatment of these conditions. PMID- 26753164 TI - A Biotechnological Approach for the Development of New Antifungal Compounds to Protect the Environment and the Human Health. AB - BACKGROUND: In the Po Valley aflatoxins play a relevant role: the local food economy is heavily based on cereal cultivations for animal feed and human nutrition. Aims of this project are the identification of new compounds that inhibit Aspergillus proliferation, the development of new inhibitors of aflatoxins production, and the set-up a practical screening procedure to identify the most effective and safe compounds. DESIGN AND METHODS: New compounds will be synthetized with natural origin molecules as ligands and endogenous metal ions to increase their bioavailability for the fungi as metal complexes. A biotechnological high-throughput screening will be set up to identify efficiently the most powerful substances. The newly synthesized compounds with effective antifungal activities, will be evaluated with battery of tests with different end points to assess the toxic potential risk for environmental and human health. EXPECTED IMPACT OF THE STUDY FOR PUBLIC HEALTH: The fundamental step in the project will be the synthesis of new compounds and the study of their capability to inhibit aflatoxin biosynthesis. A new, simple, inexpensive and high-throughput method to screen the anti-fungine and anti-mycotoxin activity of the new synthesised compounds will be applied. The evaluation of possible risks for humans due to toxic and genotoxic activities of the molecules will be made with a new approach using different types of cells (bacteria, plants and human cells). Significance for public healthAflatoxins contamination constitutes a health emergency because aflatoxins and mycotoxins, besides being toxic, are among the most carcinogenic substances known. Even if Aspergillus are dominant in tropical regions, recently are becoming a serious problem also in Europe and in Italy, especially in area as the Po Valley in which this problem play a particularly important role, because the local food economy is heavily based not only on cereal cultivations aimed at animal feed but also on the production of derivatives to human nutrition. The aims of this research are the development of new bioactive molecules, obtained by natural molecules and metal ions, that are able to reduce the risk of food contamination by aflatoxin, but are harmless for environmental and health and the evaluation of the newly synthesized compounds using a battery of tests with different end-points to assess the toxic potential risk for environmental and human health. PMID- 26753165 TI - Communication in Clinical Handover: Improving the Safety and Quality of the Patient Experience. PMID- 26753168 TI - Low Concordance With Guidelines for Treatment of Acute Cystitis in Primary Care. AB - Background. The updated 2010 Infectious Diseases Society of America guidelines recommended 3 first-line therapies for uncomplicated cystitis: nitrofurantoin, trimethoprim-sulfamethoxazole (TMP-SMX), and fosfomycin, while fluoroquinolones (FQs) remained as second-line agents. We assessed guideline concordance for antibiotic choice and treatment duration after introduction of the updated guidelines and studied patient characteristics associated with prescribing of specific antibiotics and with treatment duration. Methods. We used the Epic Clarity database (electronic medical record system) to identify all female patients aged >=18 years with uncomplicated cystitis in 2 private family medicine clinics in the period of 2011-2014. For each eligible visit, we extracted type of antibiotic prescribed, duration of treatment, and patient and visit characteristics. Results. We included 1546 visits. Fluoroquinolones were the most common antibiotic class prescribed (51.6%), followed by nitrofurantoin (33.5%), TMP-SMX (12.0%), and other antibiotics (3.2%). A significant trend occurred toward increasing TMP-SMX and toward decreasing nitrofurantoin use. The duration of most prescriptions for TMP-SMX, nitrofurantoin, and FQs was longer than guidelines recommendations (longer durations were prescribed for these agents in 82%, 73%, and 71% of the prescriptions, respectively). No patient or visit characteristic was associated with use of specific antibiotics. Older age and presence of diabetes were independently associated with longer treatment duration. Conclusions. We found low concordance with the updated guidelines for both the choice of drug and duration of therapy for uncomplicated cystitis in primary care. Identifying barriers to guideline adherence and designing interventions to decrease overuse of FQs may help preserve the antimicrobial efficacy of these important antimicrobials. PMID- 26753167 TI - Comparison of halocarbon measurements in an atmospheric dry whole air sample. AB - The growing awareness of climate change/global warming, and continuing concerns regarding stratospheric ozone depletion, will require continued measurements and standards for many compounds, in particular halocarbons that are linked to these issues. In order to track atmospheric mole fractions and assess the impact of policy on emission rates, it is necessary to demonstrate measurement equivalence at the highest levels of accuracy for assigned values of standards. Precise measurements of these species aid in determining small changes in their atmospheric abundance. A common source of standards/scales and/or well-documented agreement of different scales used to calibrate the measurement instrumentation are key to understanding many sets of data reported by researchers. This report describes the results of a comparison study among National Metrology Institutes and atmospheric research laboratories for the chlorofluorocarbons (CFCs) dichlorodifluoromethane (CFC-12), trichlorofluoromethane (CFC-11), and 1,1,2 trichlorotrifluoroethane (CFC-113); the hydrochlorofluorocarbons (HCFCs) chlorodifluoromethane (HCFC-22) and 1-chloro-1,1-difluoroethane (HCFC-142b); and the hydrofluorocarbon (HFC) 1,1,1,2-tetrafluoroethane (HFC-134a), all in a dried whole air sample. The objective of this study is to compare calibration standards/scales and the measurement capabilities of the participants for these halocarbons at trace atmospheric levels. The results of this study show agreement among four independent calibration scales to better than 2.5% in almost all cases, with many of the reported agreements being better than 1.0%. PMID- 26753166 TI - Early effect of Botox-A injection into the masseter muscle of rats: functional and histological evaluation. AB - BACKGROUND: The purpose of this study was to evaluate the change of food intake after different dosages of botulinum toxin A (BTX) injection in the animal model. Additionally, the dimensional and histological change at 14 days after BTX injection was also evaluated. METHODS: The comparative study was performed using the BTX injection model in rats (n = 5 for each group). Group 1 was the saline injected group. Group 2 was the 5-unit BTX-injection group to each masseter muscle. Group 3 was the 10-unit BTX-injection group to each masseter muscle. Food intake rates and body weight were checked daily before and after BTX injection until 10 days. All animals were sacrificed at 14 days after BTX injection, and the specimens underwent hematoxylin and eosin stain and immunohistochemical staining for myosin type II (MYH2). RESULTS: The recovery of food intake in groups 2 and 3 decreased significantly compared with group 1 from day 2 to day 7 and day 9 after injection (p < 0.05). The BTX-treated masseter muscles were significantly smaller than those in group 1 (p = 0.015). The immunohistochemical findings demonstrated that the expression of MYH2 was significantly higher in group 3 compared to groups 1 and 2 (p < 0.001). CONCLUSIONS: BTX injection to the masseter muscle in rats demonstrated short food-intake-rate reduction with recovery until 10 days after injection. The thickness of the masseter muscle and MYH2 expression were significantly changed according to the injected dose of BTX. PMID- 26753169 TI - Primary Larynx Cryptococcus neoformans Infection: A Distinctive Clinical Entity. AB - Cryptococcus neoformans can directly infect the vocal cords. Endoscopic findings were undistinctive from most infiltrative diseases. Tissue biopsy was essential for the diagnosis. Inhaled corticosteroids can predispose to the infection, and fluconazole 400 mg daily for at least 6 weeks appeared to be minimal to achieve a permanent cure. PMID- 26753170 TI - Vestibular Function and Activities of Daily Living: Analysis of the 1999 to 2004 National Health and Nutrition Examination Surveys. AB - OBJECTIVE: Vestibular dysfunction increases with age and is associated with mobility difficulties and fall risk in older individuals. We evaluated whether vestibular function influences the ability to perform activities of daily living (ADLs). METHOD: We analyzed the 1999 to 2004 National Health and Nutrition Examination Survey of adults aged older than 40 years (N = 5,017). Vestibular function was assessed with the Modified Romberg test. We evaluated the association between vestibular function and difficulty level in performing specific basic and instrumental ADLs, and total number of ADL impairments. RESULTS: Vestibular dysfunction was associated with significantly higher odds of difficulty with nine ADLs, most strongly with difficulty managing finances (odds ratio [OR] = 2.64, 95% confidence interval [CI] = [1.18, 5.90]). In addition, vestibular dysfunction was associated with a significantly greater number of ADL impairments (beta = .21, 95% CI = [0.09, 0.33]). This effect size was comparable with the influence of heavy smoking (beta = .21, 95% CI = [0.06, 0.36]) and hypertension (beta = .10, 95% CI = [0.02, 0.18]) on the number of ADL impairments. CONCLUSION: Vestibular dysfunction significantly influences ADL difficulty, most strongly with a cognitive rather than mobility-based task. These findings underscore the importance of vestibular inputs for both cognitive and physical daily activities. PMID- 26753171 TI - Impairment of Endothelial Function by Little Cigar Secondhand Smoke. AB - OBJECTIVES: Little cigars and cigarillos are gaining in popularity as cigarette use wanes, mainly due to relaxed regulatory standards that make them cheaper, easier to buy individually, and available in a variety of flavors not allowed in cigarettes. To address whether they should be regulated as strictly as cigarettes, we investigated whether little cigar secondhand smoke (SHS) decreases vascular endothelial function like that of cigarettes. METHODS: We exposed rats to SHS from little cigars, cigarettes, or chamber air, for 10 minutes and measured the resulting acute impairment of arterial flow-mediated dilation (FMD). RESULTS: SHS from both little cigars and cigarettes impaired FMD. Impairment was greater after exposure to little cigar SHS than by cigarette SHS relative to pre exposure values, although the post-exposure FMD values were not significantly different from each other. CONCLUSIONS: Exposure to little cigar SHS leads to impairment of FMD that is at least equal to that resulting from similar levels of cigarette SHS. Our findings support the need to prevent even brief exposure to little cigar SHS, and support tobacco control policies that regulate little cigars as strictly as cigarettes. PMID- 26753172 TI - One-step tumor detection from dynamic morphology tracking on aptamer-grafted surfaces. AB - In this paper, we report a one-step tumor cell detection approach based on the dynamic morphological behavior tracking of cancer cells on a ligand modified surface. Every cell on the surface was tracked in real time for several minutes immediately after seeding until these were finally attached. Cancer cells were found to be very active in the aptamer microenvironment, changing their shapes rapidly from spherical to semi-elliptical, with much flatter spread and extending pseudopods at regular intervals. When incubated on a functionalized surface, the balancing forces between cell surface molecules and the surface-bound aptamers, together with the flexibility of the membranes, caused cells to show these distinct dynamic activities and variations in their morphologies. On the other hand, healthy cells remained distinguishingly inactive on the surface over the same period. The quantitative image analysis of cell morphologies provided feature vectors that were statistically distinct between normal and cancer cells. PMID- 26753173 TI - Early Caregiving and Human Biobehavioral Development: A Comparative Physiology Approach. AB - A large and growing body of evidence demonstrates associations between quality of the early caregiving environment and risk for stress-related illness across the lifespan. The recent research examining associations between early caregiving environments and subsequent development is reviewed, with particular attention to early programming and subsequent malleability of systems underlying stress responsivity. A developmental comparative physiology model is suggested; one in which postnatal programming and phenotypic plasticity act in concert as mechanisms underlying the persisting effects of early care environments for biobehavioral outcomes. PMID- 26753174 TI - Risk stratification in non-ST elevation acute coronary syndromes: Risk scores, biomarkers and clinical judgment. AB - Undifferentiated chest pain is one of the most common reasons for emergency department attendance and admission to hospitals. Non-ST elevation acute coronary syndrome (NSTE-ACS) is an important cause of chest pain, and accurate diagnosis and risk stratification in the emergency department must be a clinical priority. In the future, the incidence of NSTE-ACS will rise further as higher sensitivity troponin assays are implemented in clinical practice. In this article, we review contemporary approaches for the diagnosis and risk stratification of NSTE-ACS during emergency care. We consider the limitations of current practices and potential improvements. Clinical guidelines recommend an early invasive strategy in higher risk NSTE-ACS. The Global Registry of Acute Coronary Events (GRACE) risk score is a validated risk stratification tool which has incremental prognostic value for risk stratification compared with clinical assessment or troponin testing alone. In emergency medicine, there has been a limited adoption of the GRACE score in some countries (e.g. United Kingdom), in part related to a delay in obtaining timely blood biochemistry results. Age makes an exponential contribution to the GRACE score, and on an individual patient basis, the risk of younger patients with a flow-limiting culprit coronary artery lesion may be underestimated. The future incorporation of novel cardiac biomarkers into this diagnostic pathway may allow for earlier treatment stratification. The cost effectiveness of the new diagnostic pathways based on high-sensitivity troponin and copeptin must also be established. Finally, diagnostic tests and risk scores may optimize patient care but they cannot replace patient-focused good clinical judgment. PMID- 26753175 TI - Nanofibrous Snake Venom Hemostat. AB - Controlling perioperative bleeding is of critical importance to minimize hemorrhaging and fatality. Patients on anticoagulant therapy such as heparin have diminished clotting potential and are at risk for hemorrhaging. Here we describe a self-assembling nanofibrous peptide hydrogel (termed SLac) that on its own can act as a physical barrier to blood loss. SLac was loaded with snake-venom derived Batroxobin (50 MUg/mL) yielding a drug-loaded hydrogel (SB50). SB50 was potentiated to enhance clotting even in the presence of heparin. In vitro evaluation of fibrin and whole blood clotting helped identify appropriate concentrations for hemostasis in vivo. Batroxobin-loaded hydrogels rapidly (within 20s) stop bleeding in both normal and heparin-treated rats in a lateral liver incision model. Compared to standard of care, Gelfoam, and investigational hemostats such as Puramatrix, only SB50 showed rapid liver incision hemostasis post surgical application. This snake venom-loaded peptide hydrogel can be applied via syringe and conforms to the wound site resulting in hemostasis. This demonstrates a facile method for surgical hemostasis even in the presence of anticoagulant therapies. PMID- 26753178 TI - Smoothness and Structure Learning by Proxy. AB - As data sets grow in size, the ability of learning methods to find structure in them is increasingly hampered by the time needed to search the large spaces of possibilities and generate a score for each that takes all of the observed data into account. For instance, Bayesian networks, the model chosen in this paper, have a super-exponentially large search space for a fixed number of variables. One possible method to alleviate this problem is to use a proxy, such as a Gaussian Process regressor, in place of the true scoring function, training it on a selection of sampled networks. We prove here that the use of such a proxy is well-founded, as we can bound the smoothness of a commonly-used scoring function for Bayesian network structure learning. We show here that, compared to an identical search strategy using the network's exact scores, our proxy-based search is able to get equivalent or better scores on a number of data sets in a fraction of the time. PMID- 26753179 TI - Detecting Bacterial Vaginosis Using Machine Learning. AB - Bacterial Vaginosis (BV) is the most common of vaginal infections diagnosed among women during the years where they can bear children. Yet, there is very little insight as to how it occurs. There are a vast number of criteria that can be taken into consideration to determine the presence of BV. The purpose of this paper is two-fold; first to discover the most significant features necessary to diagnose the infection, second is to apply various classification algorithms on the selected features. It is observed that certain feature selection algorithms provide only a few features; however, the classification results are as good as using a large number of features. PMID- 26753177 TI - Dynamic Factor Analysis for Multivariate Time Series: An Application to Cognitive Trajectories. AB - We propose a dynamic factor model appropriate for large epidemiological studies and develop an estimation algorithm which can handle datasets with large number of subjects and short temporal information. The algorithm uses a two cycle iterative approach for parameter estimation in such a large dataset. Each iteration consists of two distinct cycles, both following an EM algorithm approach. This iterative process will continue until convergence is achieved. We utilized a dataset from the National Alzheimer Coordinating Center (NACC) to estimate underlying measures of cognition based on a battery of observed neuropsychological tests. We assess the goodness of fit and the precision of the dynamic factor model estimators and compare it with a non-dynamic version in which temporal information is not used. The dynamic factor model is superior to a non-dynamic version with respect to fit statistics shown in simulation experiments. Moreover, it has increased power to detect differences in the rate of decline for a given sample size. PMID- 26753180 TI - Western-trained health care practitioners' knowledge of and experiences with traditional healing. AB - Traditional healing has been used alongside western allopathic medicine for many years. Studies have shown that majority of people in developing countries use the services of traditional healers. The question remains - how much do western trained health care practitioners know about traditional healing and what are their experiences of traditional healing? The objective of this study was to investigate western-trained health care practitioners' knowledge and experiences with traditional healing, in order to contribute to the current debate and discussion on the possible integration of traditional healing and western healing in South Africa. This study used a Within-Stage Mixed Model design to collect data among 319 health care practitioners in South Africa namely Limpopo province and Gauteng province. Participants were sampled by using a convenient sampling method in which only health care practitioners who were at work during data collection had a chance of being selected. The Kruskal-Wallis Test revealed no significant difference in knowledge of traditional healing across the four groups of health care practitioners. However, significant differences were found in experiences with traditional healing across the four groups of health care practitioners. Overall, health care practitioners had a limited knowledge and experience of traditional healing. In conclusion, health care practitioners should be encouraged to engage in activities that would enhance their knowledge and experiences with traditional healing. PMID- 26753181 TI - Non-Rigid Image Registration Using Gaussian Mixture Models. AB - Non-rigid mutual information (MI) based image registration is prone to converge to local optima due to Parzen or histogram based density estimation used in conjunction with estimation of a high dimensional deformation field. We describe an approach for non-rigid registration that uses the log-likelihood of the target image given the deformed template as a similarity metric, wherein the distribution is modeled using a Gaussian mixture model (GMM). Using GMMs reduces the density estimation step to that of estimating the parameters of the GMM, thus being more computationally efficient and requiring fewer number of samples for accurate estimation. We compare the performance of our approach (GMM-Cond) with that of MI with Parzen density estimation (Parzen-MI), on inter-subject and inter modality (CT to MR) mouse images. Mouse image registration is challenging because of the presence of a rigid skeleton within non-rigid soft tissue, and due to major shape and posture variability in inter-subject registration. The results show that GMM-Cond has higher registration accuracy than Parzen-MI in terms of sum of squared difference in intensity and dice coefficients of overall and skeletal overlap. The GMM-Cond approach is a general approach that can be considered a semi-parametric approximation to MI based registration, and can be used an alternative to MI for high dimensional non-rigid registration. PMID- 26753182 TI - Bacterial culture detection and identification in blood agar plates with an optoelectronic nose. AB - Clinical microbiology automation is currently limited by the lack of an in-plate culture identification system. Using an inexpensive, printed, disposable colorimetric sensor array (CSA) responsive to the volatiles emitted into plate headspace by microorganisms during growth, we report here that not only the presence but the species of bacteria growing in plate was identified before colonies are visible. In 1894 trials, 15 pathogenic bacterial species cultured on blood agar were identified with 91.0% sensitivity and 99.4% specificity within 3 hours of detection. The results indicate CSAs integrated into Petri dish lids present a novel paradigm to speciate microorganisms, well-suited to integration into automated plate handling systems. PMID- 26753176 TI - Developmental Insights into Breast Cancer Intratumoral Heterogeneity. AB - Breast cancer is no longer considered a single disease, but instead is made up of multiple subtypes with genetically and most likely epigenetically heterogeneous tumors composed of numerous clones. Both the hierarchical cancer stem cell and clonal evolution models have been invoked to help explain this intratumoral heterogeneity. Several recent studies have helped define the functional interactions among the different cellular subpopulations necessary for the evolution of this complex ecosystem. These interactions involve paracrine interactions that include locally acting Wnt family members, reminiscent of the signaling pathways important for normal mammary gland development and stem cell self-renewal. In this review, we discuss the interactions among various cell populations in both normal and tumor tissues. A better understanding of these interactions, especially in the metastatic setting, will be important for the development of improved combinatorial therapies designed to prevent relapse and to ultimately decrease mortality. PMID- 26753183 TI - Making the invisible visible: improved electrospray ion formation of metalloporphyrins/-phthalocyanines by attachment of the formate anion (HCOO(-)). AB - A protocol is developed for the coordination of the formate anion (HCOO(-)) to neutral metalloporphyrins (Pors) and -phthalocyanines (Pcs) containing divalent metals as a means to improve their ion formation in electrospray ionization (ESI). This method is particularly useful when the oxidation of the neutral metallomacrocycle fails. While focusing on Zn(II)Pors and Zn(II)Pcs, we show that formate is also readily attached to Mn(II), Mg(II) and Co(II)Pcs. However, for the Co(II)Pc secondary reactions can be observed. Upon collision-induced dissociation (CID), Zn(II)Por/Pc.formate supramolecular complexes can undergo the loss of CO2 in combination with transfer of a hydride anion (H(-)) to the zinc metal center. Further dissociation leads to electron transfer and hydrogen atom loss, generating a route to the radical anion of the Zn(II)Por/Pc without the need for electrochemical reduction, although the Zn(II)Por/Pc may have a too low electron affinity to allow electron transfer directly from the formate anion. In addition to single Por molecules, multi Por arrays were successfully analyzed by this method. In this case, multiple addition of formate occurs, giving rise to multiply charged species. In these multi Por arrays, complexation of the formate anion occurs by two surrounding Por units (sandwich). Therefore, the maximum attainment of formate anions in these arrays corresponds to the number of such sandwich complexes rather than the number of porphyrin moieties. The same bonding motif leads to dimers of the composition [(Zn(II)Por/Pc)2.HCOO](-). In these, the formate anion can act as a structural probe, allowing the distinction of isomeric ions with the formate bridging two macrocycles or being attached to a dimer of directly connected macrocycles. PMID- 26753185 TI - A leucine zipper pair-based lipid vesicle for image-guided therapy in breast cancer. AB - We developed a controllable image-guided therapy system as a powerful tool for diagnostic and therapeutic applications. The system uses a two-step pretargeting approach that takes advantage of the highly selective binding interactions between leucine zipper pairs. It consists of the utilization of a tumor pretargeting probe for diagnosis and, if necessary, a probe for therapy. PMID- 26753186 TI - FeCo2O4 submicron-tube arrays grown on Ni foam as high rate-capability and cycling-stability electrodes allowing superior energy and power densities with symmetric supercapacitors. AB - Template-free chemical growth on Ni foam and thermal treatment results in homogeneous FeCo2O4 submicron-tube arrays which serve as binder-free electrodes with high capacitance, rate-capability and cycling-stability owing to FeCo2O4 conductivity, high porosity, and strong bonding between tubes and Ni foam, all allowing even symmetric devices to have superior energy density. PMID- 26753184 TI - Chemically modified inulin microparticles serving dual function as a protein antigen delivery vehicle and immunostimulatory adjuvant. AB - To develop a new subunit vaccine adjuvant, we chemically modified a naturally occurring, immunostimulatory inulin polysaccharide to produce an acid-sensitive biopolymer (acetalated inulin, Ace-IN). Various hydrophobic Ace-IN polymers were formed into microparticles (MPs) by oil-in-water emulsions followed by solvent evaporation These Ace-IN MPs possessed tunable degradation characteristics that, unlike polyesters used in FDA-approved microparticulate formulations, had only pH neutral hydrolytic byproducts. Macrophages were passively targeted with cytocompatible Ace-IN MPs. TNF-alpha production by macrophages treated with Ace IN MPs could be altered by adjusting the polymers' chemistry. Mice immunized with Ace-IN MPs encapsulating a model ovalbumin (OVA) antigen showed higher production of anti-OVA IgG antibody levels relative to soluble antigen. The antibody titers were also comparable to an alum-based formulation. This proof-of-concept establishes the potential for chemically-modified inulin MPs to simultaneously enable dual functionality as a stimuli-controlled antigen delivery vehicle and immunostimulatory adjuvant. PMID- 26753187 TI - A novel p-LaFeO3/n-Ag3PO4 heterojunction photocatalyst for phenol degradation under visible light irradiation. AB - A novel heterojunction photocatalyst p-LaFeO3/n-Ag3PO4 has been prepared via a facile in situ precipitation method. It exhibits higher activity than individual Ag3PO4 and LaFeO3 in the degradation of phenol. The excellent activity is mainly attributed to its more effective separation of electron-hole pairs. PMID- 26753188 TI - Cyclopropane formation under frustrated Lewis pair conditions. AB - Reaction of the -CH2OSiMe3 substituted allyldimesitylphosphane 5 with HB(C6F5)2 resulted in a hydroboration/(C6F5)2BOSiMe3 elimination sequence to give the phosphinomethyl substituted cyclopropane derivative , probably via a phosphiranium type intermediate. Addition of B(C6F5)3 to compound gave the stable phosphiranium/borate zwitterion that was isolated and characterized by X-ray diffraction. PMID- 26753190 TI - [Research on burden of diarrhea based on hospital survey in Henan province, 2007]. PMID- 26753189 TI - [Epidemiological characteristics and molecular typing of Salmonella in Hangzhou in 2013]. PMID- 26753191 TI - Quiz. What is your diagnosis? PMID- 26753192 TI - Emergency Psychiatry: Clinical and Training Approaches. PMID- 26753193 TI - WHO informal consultation on surveillance of respiratory syncytial virus on the WHO Global Influenza Surveillance and Response System (GISRS) platform, 25-27 March 2015, Geneva, Switzerland. PMID- 26753194 TI - Detection of influenza virus subtype A by polymerase chain reaction: WHO external quality assessment programme summary analysis, 2015. PMID- 26753195 TI - Authors' response. PMID- 26753196 TI - [Surgical approaches in surgery for cicatrical tracheal stenosis]. AB - At present time several surgical approaches are being used for cicatrical tracheal stenosis including cervicotomy, longitudinal- circumferential sternotomy and thoracotomy. Besides location of stenosis an approach is being determined by constitutional and anatomical features of patient, surgeon's and anesthesiologist's experience, well-coordinated work of operating team. If pathological process is placed in cervico-laryngeal, cervical and upper thoracic segment cervicotomy is preferable. Partial longitudinal-circumferential sternotomy is believed to be adequate in case of lesion of thoracic trachea and its bifurcation. This approach provides all types of tracheal reconstructions. Technical difficulties appear if process is localized in membranous wall of suprabifurcational part, bifurcation and primary bronchus. In these cases we recommend thoracotomy through the bed of resected the 3rd or the 4th ribs and patient's position on his front. Interventions including pulmonary tissue resection and tracheal edges convergence are possible through thoracotomy. PMID- 26753197 TI - [Repeated lung resection in patients with postoperative recurrent tuberculosis in the operated lung]. AB - The literature data of 18 authors about surgical treatment of 1723 patients with recurrent tuberculosis are presented in the article. Also authors reported their own experience in repeated lung resection in 50 patients. Intraoperative complications were observed in 7 patients including empyema cavity dissection in 2 cases, scalping lung injury in 2 cases, peristump abscess dissection in 1 case, v. azygas injury in 1 patient and rupture of membranous part of trachea due to swollen cuff of intubation tube in 1 case. In postoperative period complications developed in 5 patients including early intrapleural bleeding in 1 case, later intrapleural bleeding in 1 case, empyema with bronchial fistula in 1 patient, residual pleural cavity in 1 patient and wound complication in 1 case. All postoperative complications were eliminated and there was no postoperative mortality. The authors concluded that although severe patients' condition, technical complexity and higher surgical risk of repeated resections compared with organ-preserving and collapsosurgical interventions satisfactory remote results and high proportion of labour rehabilitation earnestly prove advantages of repeated lung resections for recurrent tuberculosis of operated lung. PMID- 26753198 TI - [Actual respiratory technologies in thoracic surgery: traditional problems and innovative solutions]. AB - The problem of efficient gas exchange maintenance is always actual in anesthetic management of thoracic surgery and determines the selection of appropriate method of anesthesia. The article presents an experience of anesthesia during operations on lungs, trachea, bronchi and mediastinal structures performed from 1963 to 2015. Current concept of safety and efficacy of anesthetic management in thoracic surgery is presented. The role of actual current respiratory technologies and methods of anesthesia per se to maximize the efficiency of gas exchange in all stages of thoracicsurgery is emphasized. Absolute coherence of anesthesiologist and surgeon based on correct interaction is the most important condition of successful surgery. Effectiveness of special respiratory technologies for thoracic surgery associated with one-lung ventilation and prolonged wide dissection of airways is described. The research results and pathophysiological rationale for the use of special respiratory technologies including different variants of differentiated independent lung ventilation especially important for patients with concomitant cardiorespiratory pathology are presented. We reported experience of effective gas exchange maintenance in reconstructive surgery of trachea and main bronchi including traditional mechanical ventilation with "shunt breath" system, use of jet high-frequency ventilation and relatively new respiratory technology such as flow apnoeic oxygenation. PMID- 26753199 TI - [Bronchial fistulae after pneumonectomy for lung cancer]. AB - Fistula of bronchial stump developed in 246 (9.4%) cases of 2614 patients who were underwent pneumonectomy for lung cancer in 1964-2013. Mortality rate in case of bronchial fistulae was 17.9%. It was analyzed causes of this complication, an important role of infection for its development was emphasized. So prevention of wound infection is main prophylactic action. Postoperative pneumonia and bleeding are considerable risk factors. Clinico-anatomical type of tumor, stage and technique of bronchial stump treating don't affect incidence of fistulae. Bronchial stump covering is important intraoperative preventive measure. Treatment of this complication includes early drainage and pleural cavity sanitation and isolation of fistula from pleural cavity. Endoscopic procedures (impact with silver nitrate, trichloroacetic acid, laser) are preferred to solve the last problem. It allowed to achieve fistulae healing in 58.1% of cases. PMID- 26753200 TI - [Thoracoscopic lung resection in children]. AB - The spectrum of pulmonary surgical pathology in newborns and infants is mainly presented by congenital diseases. Surgery is the main radical method of treatment of children with congenital lung diseases. By this time in the N.F.Filatov City Children's Hospital No13 it is performed more than 1000 endoscopic operations on the thoracic cavity including more than 300 lung resections. More than 190 cases were caused by congenital lung disease. The results of treatment of 194 infants with congenital lung disease for the period 2005-2014 are analyzed in this article. 14 (22%) patients were operated urgently. 8 patients (12%) with compensated respiratory failure underwent surgery at the age of 8 to 46 days. Children with absence of clinical manifestations underwent thoracoscopic lung resection at the age of 3 to 8 months. Thoracoscopic lobectomy was performed in the 40 cases (62%). There were no intraoperative complications. Thoracoscopic lung resection for malformations in newborns and infants is currently the method of choice. It allows to visualize pathological focus intraoperatively and to perform precise dissection of pulmonary root structures using modern equipment. Thus, it improves course of postoperative period and reduces duration of hospital stay. Repeated lung resection in patients with recurrent tuberculosis of operated lung (literature review and own data). PMID- 26753201 TI - [ACTH-producing tumors of the chest: features of clinical course, diagnosis and surgical treatment]. PMID- 26753202 TI - [Report "Endosurgery for thoracic organs defects in children" Protocol No295 of Moscow Thoracic surgeons Society session from March 24.2015]. PMID- 26753203 TI - [Report "Lungs transplantation: an experience of N.V. Slifosovskiy Research Institute of Emergency Care". Protocol No296 of Moscow Thoracic surgeons Society session from April 28.2015]. PMID- 26753205 TI - [Foreward - Contemporary Polish rheumatology]. PMID- 26753206 TI - [Insulin resistance and metabolic syndrome - a different image of disorders in rheumatoid arthritis and ankylosing spondylitis]. AB - INTRODUCTION: Chronic inflammation is associated with impaired glucose tolerance and insulin resistance (IR) phenomenon. Proinflammatory cytokines such as interleukin-6 and tumor necrosis factorTNF-alpha play a significant role in the pathogenesis of rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, the relationships between prevalence of IR and metabolic syndrome (MetS) in patients (pts) with a different rheumatic diseases have not been yet well characterized. MATERIAL AND METHODS: The study was conducted in 102 pts aged 18 65 years, including 60 pts with RA (45 women, 15 men) and 42 pts with AS (4 women, 38 men). In all of pts serum fasting hemoglobin (Hb), fibrinogen, uric acid, vitamin D3, lipids, ESR, CRP, IL-6, hs-CRP, SAA, IL-6 sR, RF-IgM titer, a CCP, and glucose, insulin after 0, 30, 60, 120 min during the oral glucose tolerance test with the calculation of indicators of IR (HOMA-IR, insulin/glucose) and insulin sensitivity (QUICKI, Matsuda) were performed. Moreover, BMI, WHR, disease activity indices (DAS28 in RA, BASDAI in AS) and the criteria for diagnosis of MetS were evaluated. The results were statistically analyzed. RESULTS: IR and MetS occur more frequently in patients with RA. Forthese disorders a strongly correlation with BMI and WHR, whereas not with disease activity indices has been shown. RA patients with MetS had a higher titers of RF-IgM and hemoglobin concentration. CONCLUSIONS: Patients with RA have an increased risk of MetS with IR compared to patients with AS. In addition, higher RF-IgM titer increases the risk of developing MetS in RA. PMID- 26753207 TI - Autoantibodies against gliadin in rheumatoid arthritis and primary Sjogren's syndrome patients. AB - INTRODUCTION: Patients with rheumatoid arthritis (RA) and those with primary Sjogren's syndrome (pSS), beside non-specific antibodies, present with organ specific autoantibodies, including those typical of celiac disease (CD). In the pathogenesis of CD, a role is played by anti-tissue transglutaminase, anti endomysium, and anti-gliadin (AGA) antibodies. CD can be comorbid with RA and pSS. The aim of the study was to evaluate the prevalence of AGA in RA and pSS patients and discussion of their clinical significance. MATERIAL AND METHODS: The study included 121 patients with RA and 30 patients with pSS. IgG AGA were determined by ELISA method. Additionally, the presence of IgG antimitochondrial antibodies (AMA) was determined in all patients. A further observation included patients with AGA. RESULTS: In the RA group, AGA were detected in five patients (4.1%), and in the pSS group - in two patients (6.7%). All patients in the pSS AGA (+) had AMA and autoimmune thyroid disease (AITD). These differences were statistically significant compared to the pSS AGA (-) and AMA (+) group (p=0.002) and the AGA (-) and AITD (+) group (p=0.003). At the time of the study, none of the patients had been diagnosed with CD. CONCLUSIONS: AGA, typical of CD, are significantly more frequently detected in patients with RA and pSS than in the general population. The presence of autoantibodies may have an impact on the clinical picture of the disease and further medical procedures. CD testing is warranted in selected patients. PMID- 26753208 TI - [Prediction of response to TNF-alpha inhibitors treatment with use of swollen to tender joint count ratio (STR)]. AB - INTRODUCTION: STR is swollen to tender joint count ratio. The aim of this study was to determine the usefulness of STR in predicting response to treatment with biological agents in patients with RA. MATERIAL AND METHODS: The study included 27 biologically naive patients treated with TNF inhibitors: infliximab (6), etanercept (10), adalimumab (5) and certolizumab (6). STR index was assessed at baseline and after 3 and 9 months (m) . Patients due to the STR value were divided into two groups: group1 with value of STR < 1 and group 2 with value of STR >= 1. Group 1 included 18 patients (17 F, 1 M). Group 2 consisted of 9 persons (7 F 2 M). RESULTS: At the beginning of the observation the average values for the group 1 were: the number of swollen joints (SJ) 6/28 (2-14), the number of tender joints (TJ) 11/28 (5-21), STR 0.46 (0.2-0.9), CRP 27.8 mg/I (1 130.2), DAS28 4.95 (4.03-7.56), disease activity VAS 50 mm (20-75), ESR 35 (8 95). In group 1, the DAS28 improved after 3 months on average - 1.68 (0.08-3.91) and ESR decreased about 16 mm. On the assessment after 9 months of treatment DAS 28 improved on average - 2.89 (0.74-5.17); ESR dropped by 21 mm compared to the baseline. At the beginning of the observation average values for group 2 were: SJ 13/28 (8-19), TJ 19 (4-15), STR 1.48 (1-2.5), CRP 19.27 (7.7-32.1), DAS28 5.75 (5.25-6.47), disease activity - VAS 57 mm (47-66), ESR 25 (14-41). After 3 months of treatment DAS28 reduced on average - 2.52 (1.97-3.71), ESR decreased circa 11 mm. Six patients from group 2 were evaluated after 9 months of treatment. There was observed improvement both in DA528 on average 3.28 (1.86-3.95) and ESR, which dropped by 10 mm. Patients with >1 STR achieved greater improvement in DAS28 after 3 m (p=0.0395) and after 9 months (Ns) compared to patients with STR <1. However, decrease of ESR was higher both after 3 and 9 months in patients with STR <1. CONCLUSIONS: We conclude that the STR may be useful in predicting response to treatment with TNF inhibitors. PMID- 26753210 TI - [Treat-to-target in rheumatology]. AB - The treat-to target concept has been widely used in many chronic devastating disorders (like hypertension, diabetes meilitus, caraiovascuiar diseases) for many years. It has been initiated in the cardiovascular diseases treatment where, based on vast clinical databases, it had been proven that the achievement of certain therapeutical results (e.g. blood pressure lowering<140/90; target for HbAlc less than 7%; normalization of lipid concentration) lead to significant reduction of cardiovascular accidents and improved long-term prognosis.The main principles of treat-to-target concept are deeply rooted in the humanistic tradition and nature of medical science including: cooperation between doctor and patient based on mutual understanding, achievement of remission due to effective treatment, avoidance of damage and improvement of patient's quality of life. The principles of T2T were first applied in rheumatic diseases in 2010 to plan the treatment of rheumatoid arthritis. The application of T2T in rheumatoid arthritis treatment, where the achievement of remission or low disease activity can be quite accurately quantified, is now quite widespread. The principles forT2T application within ankylosing spondylitis, psoriatic arthritis and lately systemic lupus erythematosus have been desianed. This study is aimed at making the readers familiar with T2T concept and suggesting the ways of its clinical application. PMID- 26753209 TI - [Evaluation of usefulness of Polycheck method in the detection autoantibodies in patients with systemic lupus erythematosus, Sjogren's syndrome and systemic sclerosis]. AB - INTRODUCTION: To recognize the connective tissue diseases (CTD), which include lupus erythematosus (SLE), Sjogren's syndrome (SS) and Systemic sclerosis (SSc) it is necessary to determine the presence of autoantibodies (Ab). There is still work going on to find effective and equivocal detection methods. THE AIM OF STUDY: To evaluate the usefulness, clinical value and innovativeness of the Polycheck method in the detection of autoantibodies in patients with connective tissue diseases. MATERIALS AND METHODS: The study involved 178 people: 153 patients of the Department of Rheumatology and 25 healthy people. According to the main diagnosis the patients were divided into 3 groups: SLE-59, ZS-45, SSc 49. The presence and concentrations of Ab were determined by using multiparametric enzyme-linked immunosorbent assay Polycheck Rheuma (Biocheck, GmbH, Munster, Germany). Statistical data analysis was performed using Statistica v10.0. RESULTS: In our study we found thatthe frequency of antibodies characteristic of the SS: anti-SS-A/Ro 52, anti-SS-A Ro 60 and anti-SS-B/La was significantly higher in patients with SS group compared to TRU, TU, and GK (p <0.05); concentrations of Ab were lower in TRU and in SSc group. Marker Ab for SLE anti-dsDNA were only present in patients with SLE. Anti-Sm antibodies were more common in this patient population too. Antibodies associated with diagnosis of SSc anti-SCL-70 and anti-CENP B were significantly more often observed in patients with SSc in higher concentrations compared to the other groups examined (anti-SCL-70 p<0,0005). The Ab concentration analysis performed with use of this analysis help us to confirm diagnosis in particular patients. CONCLUSIONS: The multiparametric enzyme-linked immunosorbent assay Polycheck Rheuma is helpful in making a quick and comprehensive identification of autoantibodies in pts with suspected CTD. The concentration analysis performed with use of this method enables an accurate diagnosis despite the ambiguous clinical picture. PMID- 26753211 TI - [Discontinuation of immunosuppressive and immunomodulatory drugs in connective tissue diseases]. AB - Remission in connective tissue diseases became a realistic goal of therapy nowadays. However, there is lack of recommendations on the management after achieving a remission. Chronic exposure to immunosuppressive or immunomodulatory drugs may be associated with adverse events, that is why temporal withdrawal or discontinuation of treatment is advisable. In patients with rheumatoid arthritis (RA) who achieve sustained remission lasting for 6-12 months, an attempt to withdraw biological disease modifying antirheumatic drugs (bDMARDs) may be considered. In most patients with established RA discontinuation of bDMARDs is accompanied by a disease flare, butthe risk of loss of good therapeutic response is lower in case of slowly tapering by expanding the interval between doses or reducing the dose of bDMARDs. Patients with early RA are more likely to have successful discontinuation of therapy. Discontinuation of conventional DMARDs (cDMARDs) is usually associated with a disease flare, that is why tapering of doses is advised rather than stopping cDMARDs. DMARDs free remission occurs relatively rare, more often in patients with seronegative RA and with early onset of modifying treatment. In lupus nephritis (LN) patients with persistent, long term remission, progressive tapering of doses of immunosuppressive drugs and glucocorticoids is recommended, with treatment discontinuation as a goal. An attempt of treatment withdrawal may be taken in patients remaining in LN complete remission as a consequence of maintenance therapy for 3 years.The process of slow tapering of doses preceding discontinuation of drugs, may last several months. The therapy with antimalarial drugs may be helpful to maintain remission after the treatment discontinuation. There is few data on treatment discontinuation in patients with systemic lupus erythematosus (SLE) without kidney involvement. Immunosuppressive drugs withdrawal is usually performed in patients with stable serological and clinically asymptomatic disease lasting for >= 2 years, on maintenance antimalarial therapy. Discontinuation of immunomodulatory treatment seems unlikely in primary systemic vasculitis. PMID- 26753212 TI - [Catastrophic antiphospholipid syndrome]. AB - Catastrophic antiphospholipid syndrome is the most dangerous form of the antiphospholipid syndrome, which is characterized by rapid onset of thrombosis in small vessels of many organs and intravascular coagulation, thrombocytopenia and hemolytic anemia. The syndrome develops over a short period of time with acute multi-organ failure, including kidney, respiratory, cardiovascular, central nervous system and adrenal glands, often associated with disseminated thrombotic microangiopathy. The catastrophic antiphospholipid syndrome involves three or more systems, organs and/or tissues, the development of symptoms must occur within less than one week, it is necessary to confirm the histopathological vascular occlusion in at least one organ or tissue, and laboratory confirmation of the presence of antiphospholipid antibodies in the serum on two occasions over an interval of 12 weeks. This syndrome is characterized by a high mortality despite the use of optimal treatment. Early diagnosis and aggressive treatment of patients with catastrophic antiphospholipid syndrome is essential to save the life of these patients. In the last 10 years, the mortality in this disease decreased from 50% to 30% with simultaneous treatment with anticoagulants, corticosteroids, plasmapheresis and immunoglobulins. PMID- 26753213 TI - [The heart and anticytokine therapy]. AB - Treatment targeting TNF revolutionized management for rheumatoid arthritis patients offering attainment of clinical remission, preventing patients from disability and improving their quality of life. Anti-cytokine therapy, however may in some circumstance contribute to development of serious adverse effects, including congestive heart failure. The heart failure in patients treated with anti-TNF agents seems to be paradoxical as TNF plays an important pathogenetic role in both conditions. In congestive heart failure, TNF may act as a regulatory factor and may stabilize the heart function, so TNF blockade may result in progression of the heart failure. In this paper, the pathogenetic role of TNF has been discussed with the special emphasis to the role of cytokine in conditions of heart failure and systemic inflammation. PMID- 26753214 TI - [Chosen problems of mental functioning in patients with chronic systemic connective tissue diseases base on example of rheumatoid arthritis]. AB - Disorders in mental functioning are indicated as the cause of all connective tissue diseases and also as their consequences. That is why psychologist's help may be very important for patients with rheumatoid arthritis. Psychological observations of patients with chronic systemic connective tissue diseases show a number of negative emotional states such as fear, anxiety, insecurity, depressed mood, depression, impatience, anger and a sense of loss These patients constantly experience pain of varying intensity and location. In many of them progressive disease leads to the advancement of mental crisis. Methods of psychological therapy must be focused on strenghtening mental resilience and helping in surviving mental crisis. Psychological therapy should concentrate on raising self esteem, training interpersonal skills and teaching relaxation techniques to cope better with pain and suffering. Psychological therapy should support the patient in struggling with the problems caused by the disease and developing ways of adapting to life with the disease. PMID- 26753215 TI - Randomized Controlled Trials in Music Therapy: Guidelines for Design and Implementation. AB - BACKGROUND: Evidence from randomized controlled trials (RCTs) plays a powerful role in today's healthcare industry. At the same time, it is important that multiple types of evidence contribute to music therapy's knowledge base and that the dialogue of clinical effectiveness in music therapy is not dominated by the biomedical hierarchical model of evidence-based practice. Whether or not one agrees with the hierarchical model of evidence in the current healthcare climate, RCTs can contribute important knowledge to our field. Therefore, it is important that music therapists are prepared to design trials that meet current methodological standards and, equally important, are able to respond appropriately to those design aspects that may not be feasible in music therapy research. OBJECTIVE: To provide practical guidelines to music therapy researchers for the design and implementation of RCTs as well as to enable music therapists to be well-informed consumers of RCT evidence. METHODS: This article reviews key design aspects of RCTs and discusses how to best implement these standards in music therapy trials. A systematic presentation of basic randomization methods, allocation concealment strategies, issues related to blinding in music therapy trials and strategies for implementation, the use of treatment manuals, types of control groups, outcome selection, and sample size computation is provided. CONCLUSIONS: Despite the challenges of meeting all key design demands typical of an RCT, it is possible to design rigorous music therapy RCTs that accurately estimate music therapy treatment benefits. PMID- 26753217 TI - The Effects of Live Patterned Sensory Enhancement on Group Exercise Participation and Mood in Older Adults in Rehabilitation. AB - BACKGROUND: Older adults in rehabilitation often experience barriers to exercise, which may impede recovery. Patterned sensory enhancement (PSE) is a neurologic music therapy intervention for sensorimotor rehabilitation. The use of live music during patterned sensory enhancement (live-PSE) may be particularly beneficial in meeting patient needs and improving older adults' exercise participation and mood during therapy. OBJECTIVE: To examine the effects of live-PSE on exercise output, exercise adherence, ratings of perceived exertion, and mood for 24 older adult inpatients in a rehabilitation facility attending a group exercise program. METHODS: Using a within-subjects design, results from sessions involving exercise instruction and live-PSE (experimental condition) were compared with sessions of exercise instruction alone (control condition). A logbook documenting participant comments and behaviors was also maintained. RESULTS: There were no significant between condition differences for the exercise outcome measures. Between condition session outcome measures for mood were non-significant for all profiles except confusion, which suggested that some participants might have become more confused during sessions with live-PSE. Unsolicited participant comments and behaviors recorded in the logbook indicated that 21 participants perceived experimental sessions positively, 2 reacted negatively, and 1 did not express any preferences. CONCLUSIONS: Live-PSE did not significantly improve exercise outcomes and there were indications of increased confusion during experimental sessions for some participants. However, participant comments and behaviors also suggested positive experiences during sessions with live-PSE Further research to investigate these discrepant results is warranted, and might best be explored using a mixed methods approach. PMID- 26753216 TI - The Interplay of Preference, Familiarity and Psychophysical Properties in Defining Relaxation Music. AB - BACKGROUND: The stress response has been well documented in past music therapy literature. However, hypometabolism, or the relaxation response, has received much less attention. Music therapists have long utilized various music-assisted relaxation techniques with both live and recorded music to elicit such a response. The ongoing proliferations of relaxation music through commercial media and the dire lack of evidence to support such claims warrant attention from healthcare professionals and music therapists. OBJECTIVE: The purpose of these 3 studies was to investigate the correlational relationships between 12 psychophysical properties of music, preference, familiarity, and degree of perceived relaxation in music. METHODS: Fourteen music therapists recommended and analyzed 30 selections of relaxation music. A group of 80 healthy adults then rated their familiarity, preference, and degree of perceived relaxation in the music. RESULTS: The analysis provided a detailed description of the intrinsic properties in music that were perceived to be relaxing by listeners. These properties included tempo, mode, harmonic, rhythmic, instrumental, and melodic complexities, timbre, vocalization/lyrics, pitch range, dynamic variations, and contour. In addition, music preference was highly correlated with listeners' perception of relaxation in music for both music therapists and healthy adults. The correlation between familiarity and degree of relaxation reached significance in the healthy adult group. CONCLUSIONS: Results from this study provided an in depth operational definition of the intrinsic parameters in relaxation music and also highlighted the importance of preference and familiarity in eliciting the relaxation response. PMID- 26753218 TI - The Effect of Relaxation Music Listening on Sleep Quality in Traumatized Refugees: A Pilot Study. AB - BACKGROUND: Traumatized refugees often suffer from severe sleep problems, with serious consequences in physiological and psychological areas of functioning. Recent research suggests that music may be a viable intervention to improve sleep quality. OBJECTIVE: The aim of this pilot study was to investigate whether sleep quality of traumatized refugees could be improved by listening to relaxation music at bedtime, and whether such an improvement would affect the experience of trauma symptoms and well-being. METHODS: This study used a two-group pretest/posttest design with repeated measures taken for sleep quality. Dependent variables included sleep quality measured by the Pittsburgh Sleep Quality Index, trauma symptoms as measured by the PTSD-8 and well-being measured by the "How Do You Feel?" questionnaire designed specifically for refugees. Fifteen traumatized refugees with sleep problems participated in the study. The intervention group received the music listening condition (relaxing music played at night through a music player nested in an ergonomic pillow); the control group received only the ergonomic pillow. RESULTS: Statistical comparisons showed a significant improvement of sleep quality in the music group, but not in the control group. A significant increase in well-being was found only in the intervention group, but there were no changes in trauma symptoms in either of the groups. CONCLUSIONS: These results support the use of relaxation music listening at bedtime to improve sleep quality in traumatized refugees. PMID- 26753219 TI - Comparison of Models and Indices for Detecting Rater Centrality. AB - To date, much of the research concerning rater effects has focused on rater severity/leniency. Consequently, other potentially important rater effects have largely ignored by those conducting operational scoring projects. This simulation study compares four rater centrality indices (rater fit, residual-expected correlations, rater slope, and rater threshold variance) in terms of their Type I and Type II error rates under varying levels of centrality magnitude, centrality pervasiveness, and rating scale construction when each of four latent trait models is fitted to the simulated data (Rasch rating scale and partial credit models and the generalized rating scale and partial credit models). Results indicate that the residual-expected correlation may be most appropriately sensitive to rater centrality under most conditions. PMID- 26753220 TI - Measuring Psychosocial Impact of CBRN Incidents by the Rasch Model. AB - An effective response to chemical, biological, radiological and nuclear (CBRN) incidents requires capability planning based upon an assessment of risks in which all types of possible consequences of such incidents have been taken into account. CBRN incidents can have a wide range of consequences of which psychological and social effects (possibly leading to societal unrest) are often pointed out as very likely to occur. The goal of our research was to establish an objective measurement of psychosocial impact of CBRN incidents with the use of the Rasch model. We created a list of eleven items, each of which tapped into an aspect of psychosocial impact of incidents. Eleven judges scored ten CBRN scenarios on this list of items. Two items needed to be removed due to misfit. The resulting nine-items test fitted the Rasch model well. Three items showed mild forms of differential item functioning, but were retained in the test. The reliability of the instrument was 0.83. The scale can be used to quantitatively measure the inherently qualitative nature of psychosocial impact of CBRN incident scenarios in order to better compare this type of impact with quantitative impact types such as number of casualties, costs, etc. Administration of the scale is simple and takes about one minute per scenario. We recommend wider use of the Rasch model for improving the quality of total impact measurement in case of being faced with both qualitative and quantitative types of impact. PMID- 26753221 TI - Using the Partial Credit Model to Evaluate the Student Engagement in Mathematics Scale. AB - The Student Engagement in Mathematics Scale (SEMS) is a self-report measure that was created to assess three dimensions of student engagement (social, emotional, and cognitive) in mathematics based on a single day of class. In the current study, the SEMS was administered to a sample of 360 fifth graders from a large Mid-Atlantic district. The Rasch partial credit model (PCM) was used to analyze the psychometric properties of each sub-dimension of the SEMS. Misfitting items were removed from the final analysis. In general, items represented a range of engagement levels. Results show that the SEMS is an effective measure for researchers and practitioners to assess upper elementary school students' perception of their engagement in math. The paper concludes with several recommendations for researchers considering using the SEMS. PMID- 26753222 TI - Estimation of Parameters of the Rasch Model and Comparison of Groups in Presence of Locally Dependent Items. AB - Measurement specialists routinely assume examinee responses to test are independent of one another. However, previous research has shown that many tests contain item dependencies, and not accounting for these dependencies leads to misleading estimates of item and person parameters. In this paper, the marginal maximum likelihood estimation in Rasch model with the violation of the local independence is studied. The power of the Wald test on a group effect parameter on the latent traits in cross-sectional studies is examined under the local independence and the local item dependence assumptions. The different results are illustrated with simulation studies. PMID- 26753223 TI - Help Me Tell My Story: Development of an Oral Language Measurement Scale. AB - Help Me Tell My Story (HMTMS) is an assessment tool that uses a holistic approach and an electronic application to measure the oral language development of pre kindergarten and kindergarten children. It includes access to an online portal that provides meaningful information to caregivers, educators and administrators. This study examines the psychometric properties of one of the five questionnaires included in the HMTMS assessment, which explores the ability of children to talk to family members, friends and teachers. It uses an unrestricted partial credit Rasch version to analyse data from 844. children. Results indicate that, although we obtained a modest reliability index, the scale's psychometric characteristics are within effective ranges, as no response dependency was found and the items constitute a unidimensional scale. There is no differential item functioning (DIF) related to gender, grade levels and ethnicity on this scale. Thus this assessment tools is appropriate for use in early years oral language measurement. PMID- 26753224 TI - A Dual-Purpose Rasch Model with Joint Maximum Likelihood Estimation. AB - In practice, there is a growing need of reporting both overall score for the ranking/decision-making purpose and subscores for the diagnostic purpose. The Rasch model with subdimensions (RMS) was employed in this study to address this problem. A joint maximum likelihood estimation (JMLE) procedure was proposed to obtain computationally efficient estimation for this model. A simulation study was conducted to investigate the properties of this model with the JMLE procedure in conditions with varying sample size, test lengths and subdimension loading structure. Results indicated that in general, parameters were estimated well using the JMLE procedure. The item parameters and overall ability parameters in RMS were in accordance with parameters obtained from the Rasch model. PMID- 26753225 TI - Using Rasch Analysis to Evaluate Accuracy of Individual Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) for Disability Measurement. AB - Our study objectives were to examine the accuracy of individual activities of daily living (ADLs) and instrumental ADLs (IADLs) for disability measurement, and determine whether dependence or difficulty is more useful for disability measurement. We analyzed data from 499 patients with 2+ ADLs or 3+ IADLs who participated in a home visiting nurse intervention study, and whose function had been assessed at study baseline and 22 months. Rasch analysis was used to evaluate accuracy of 24 individual ADL and IADL items. The individual items differed in the amount of information provided in measuring functional disability along the range of disability, providing much more information in (usually) one part of the range. While nearly all of the Item Information Curves (IICs) for the ADL dependence, IADL difficulty, and IADL dependence items were unimodal with one information peak each, the IICs for ADL difficulty exhibited a bimodal pattern with two peaks. Which of the individual items performed better in disability measurement varied by the extent of functional disability (i.e., by how disabled the patients were). The information peaks of most ADLs and many IADLs rise or drop steeply in a relatively short distance. Thus, whether dependence or difficulty is superior often changes very quickly along the disability continuum. There was considerable heterogeneity in which individual items provided the most and the least information at the three points of interest examined across the disability range (-2 SD units, mean, +2 SD units). While the disability region (low, medium, and high disability) for which each individual item provided the most information remained quite stable between baseline and 22 months for ADL difficulty, IADL difficulty, and IADL dependence, relatively large shifts occurred for ADL dependence items. At the disability mean dependence items offered more information for assessment than difficulty. While ADLs also provided more information at -2 and +2 SD units, there was more heterogeneity at these points for IADLs, with little difference between dependence and difficulty assessment for some IADLs. PMID- 26753226 TI - Building a career is a lifetime journey. PMID- 26753227 TI - Under examination. PMID- 26753229 TI - "Over There" in World War II. PMID- 26753228 TI - A made-in-Manitoba model for a strong and unified profession. PMID- 26753230 TI - New harmonized application process for internationally educated nurses. PMID- 26753231 TI - Screening tests and specificity. PMID- 26753232 TI - Certification Program Goes Paperless. PMID- 26753233 TI - Studying the NCLEX-RN. PMID- 26753234 TI - Ethics in Practice: At End of Life--Part 3. PMID- 26753235 TI - Nursing students' initiative improves health-care access. PMID- 26753236 TI - Nurses de-stigmatize mental illness. PMID- 26753237 TI - Our new partners in leadership. PMID- 26753238 TI - Dear next president-elect... Q-and-A with Barb Shellian. PMID- 26753239 TI - Educating and leading by example. PMID- 26753240 TI - A different spin on mentoring. PMID- 26753241 TI - You matter to me. I care about you. PMID- 26753242 TI - Comparing spatial expression dynamics of bovine blastocyst under three different procedures: in-vivo, in-vitro derived, and somatic cell nuclear transfer embryos. AB - There has been no work on spatiotemporal transcriptomic differences of blastocysts using in vivo- and in vitro-derived, and somatic cell nuclear transfer (SCNT) embryos. Here, we first compared the lineage-differentially transcriptomic profiles of in vivo- and in vitro-derived embryos by microarray analysis using divided into inner cell mass (ICM)-and trophectoderm (TE)-side samples, as well as those derived from SCNT in order to explore lineage differentially expressed genes that are associated with preimplantation development in cattle. The transcriptomic profiles of the ICM-specific and TE specific genes were similar between in vitro-derived embryos and in vivo-derived embryos, whereas SCNT embryos exhibited unusual lineage-differentially gene expression regulation at the blastocyst stage. The genes expressed in a spatiotemporal manner between developmentally normal in-vivo derived blastocysts and developmentally abnormal SCNT blastocysts might play critical roles for preimplantation development. Comparing spatial expression dynamics of bovine blastocyst under three different procedures revealed that CIITA was expressed in ICM-side samples of all the embryo types. CIITA is known as the master regulator of major histocompatibility complexes (MHC) class II genes that express in antigen-presenting cells but its biological function in preimplantation embryo is still unknown in mammals. Knockdown of CIITA expression in in vitro-derived embryos did not affect cleavage, but disrupted development of embryos into the blastocyst stage. These findings provide the novel transcriptomic information on blastocyst formation, raising the possibility that immune function-related gene directly plays important roles in bovine preimplantation development. PMID- 26753243 TI - Mutagenicity of modelled-heat-treated meat extracts: Mutagenicity assay, analysis and mechanism of mutagenesis. AB - Cooking of meat usually aims in producing microbiologically safe food suitable for human consumption. However, doing so at such high temperatures may produce some cooking toxicants or mutagens. The objectives of this study were to investigate the mutagenicity of modelled-heat-treated meat after different cooking methods (boiling, pan-frying and charcoal grilling) using Ames Salmonella typhimurium mutagenicity assay. In addition, the content of benzo[a]pyrene (B[a]P) in the meat extracts prepared under different cooking methods were measured using HPLC. In a trial to investigate the causes behind the mutagenicity of different meat extracts, HepG2 cell line was exposed to different modelled heat-treated meat extracts. mRNA expression levels of various phase I and II xenobiotic metabolizing enzymes (XMEs) were examined using real time PCR. The results obtained declared that pan-fried and charcoal grilled-meat extracts significantly induced production of histidine+ revertants in the Ames mutagenicity assay. Grilled-meat extracts had the highest residual concentrations of B[a]P followed by pan-fried-meat, boiled meat and raw meat extracts, respectively. Induction of XMEs especially CYP1A1, CYP1A2 and NQO1 may contribute to the mutagenic ability of these extracts. It is highly advisable to control cooking temperature, time and method in order to reduce cooked-meat mutagens. PMID- 26753245 TI - A preliminary survey of the seroprevalence of Mycobacterium avium subspecies paratuberculosis in Mongolian cattle. AB - Johne's disease is a chronic infection with Mycobacterium avium susp. paratuberculosis (MAP), which causes huge economic losses to cattle industry. The seroprevalence of MAP in cattle of Mongolian was estimated by an ELISA assay using 356 serum samples which were collected from eleven provinces and Ulaanbaatar city. Out of these samples, 3 (0.84%) were found to be seropositive for MAP, originating from Tsenkher sum of Arkhangai province, Murun sum of Khuvsgul province, and Bornuur sum of Tuv province in Mongolia. This study represents first conformation of Johne's disease in Mongolian cattle. These findings provide vital information that can be used for the planning and execution of control measures for Johne's disease in the Mongolian cattle industry. PMID- 26753244 TI - Immunochromatographic strip assay development for avian influenza antibody detection. AB - To detect antibody on pen-side is a rapid way to know the avian influenza (AI) infectious status in a chicken flock. The purpose of this study was to develop an immunochromatographic strip (ICS) assay to detect the antibody against the AI virus (AIV) for field applications. The ICS was constructed by fixing an AIV strain A/chicken/Taiwan/2838V/2000 (H6N1) onto a nitrocellulose membrane as the antigen at the test line and goat anti-rabbit IgG antibody at the control line. The colloidal gold conjugated with rabbit anti-chicken IgG was used as the tracer. The present ICS was used to detect antibodies against avian influenza virus in 326 chicken serum samples from the field. Compared with HI, this ICS could detect antibodies against H5 and H6 AIVs. The hemagglutination inhibition (HI) test was used as the standard to evaluate the ICS accuracy. The results showed that the sensitivity and specificity of this ICS reached 95.2% (159/167) and 94.3% (150/159), respectively. The Kappa value of the HI and ICS was 0.896 (P < 0.001). In conclusion, this ICS could be used as a rapid test to detect antibodies against AIVs in the field. PMID- 26753246 TI - Resistance to non-quinolone antimicrobials in commensal Escherichia coli isolates from chickens treated orally with enrofloxacin. AB - The aim of the present study was evaluate how oral administration of enrofloxacin affected the frequency of resistance to different antimicrobials in commensal Escherichia coli isolates from healthy chickens. A further objective of this study was to characterize the mechanisms of resistance in these isolates. A trend towards increased resistance to enrofloxacin, doxycycline and amoxicillin of E. coli isolates from chickens after enrofloxacin administration was observed. The increase in the resistance to doxycycline and amoxicillin was probably due to a co-selection of tetracycline and beta-lactam resistance genes by the administration of enrofloxacin. The detection of tetM was much higher than expected (50%), which indicates that this gene may play an important role in tetracycline resistance in E. coli from chickens. PMID- 26753247 TI - Utilization of a Preemptive, Multimodal Analgesic Regimen in Adult Ambulatory Septoplasty Patients: A Quality Improvement Project. AB - This paper describes a quality improvement project designed to decrease postoperative pain, decrease post-operative nausea and vomiting (PONV), decrease time in the recovery room, and increase patient satisfaction in adult ambulatory septoplasty patients using a multimodal, preemptive analgesic regimen. The project was conducted in a community hospital setting with nine operating rooms, and a twenty one bed recovery room. Project participants included certified registered nurse anesthetists, anesthesiologists, operating room nurses, recovery room nurses, and otolaryngology surgeons. Following a period of departmental education, adult patients scheduled for outpatient septoplasty surgery received a preoperative regimen of medications that included gabapentin, celecoxib, and acetaminophen. Using a pre-post test design, (intervention group n = 17, non intervention group n = 17) data was collected from patient and analyzed using SPSS version 18.0. The change in practice resulted in a significant decrease in pain scores in the recovery room and on discharge from the recovery room. In addition, patients who received the preemptive regimen also required significantly fewer opioid medications and were ready to be discharged from the recovery room in less time. PMID- 26753249 TI - Moving from data to action--Finding meaning in numbers. PMID- 26753250 TI - Quality management's role evolves as hospitals shift to population health. PMID- 26753248 TI - Samter's Triad to Aspirin-Exacerbated Respiratory Disease: Historical Perspective and Current Clinical Practice. AB - Aspirin-exacerbated respiratory disease (AERD), formerly known as Samter's Triad, is a syndrome of airway inflammation characterized by rhinosinusitis with polyposis, asthma, and nonsteroidal anti-inflammatory drug (NSAID) intolerance. Approximately 7% of patients with asthma will also have AERD making prompt identification, diagnosis, and management of this syndrome important to controlling the disease progression. This paper will provide a brief biographical background on Max Samter, MD, followed by an epidemiologic overview, clinical presentation and diagnosis, and management strategies, which highlight patient counseling and educational needs. PMID- 26753251 TI - Quality department evolution to deeper data, more efficient action. PMID- 26753252 TI - Hospital's sepsis QI program lead to drop in mortality rate. PMID- 26753253 TI - Health organization's PI program speeds up multiple EDs. PMID- 26753255 TI - Study shows a data route tying quality to VBP. PMID- 26753254 TI - "Warm handoffs" can reduce hospitals' readmission rates. PMID- 26753256 TI - Too old, too young, too many, too few. PMID- 26753257 TI - Evidence for everyday midwifery. PMID- 26753258 TI - The maternity time bomb: mothers older, more midwives approach retirement. PMID- 26753259 TI - Advancing maternal age and trisomy screening: the practice challenges of facilitating choice and gaining consent. AB - Antenatal screening for chromosomal anomalies such as Trisomy 13, 18 and 21 (Patau's, Edward's and Down's syndrome respectively) is offered to all pregnant women in the first two trimesters.This article explores the varying considerations of consent for this type of screening, particularly in relation to women of advancing age who are at increased risk of carrying a pregnancy affected by a trisomy. The practical challenges or barriers of gaining valid, meaningful informed consent are discussed. PMID- 26753261 TI - The impact of maternal age on midwifery care. AB - With a changing society, the age range at which women are choosing to become pregnant is increasing. There are different needs associated with each end of this range, with younger and older mothers facing different challenges and decisions. The midwife needs to be confident about the associated needs and potential complications for women at each end of the maternal age spectrum, in order to navigate the journey with the mother. This article aims to address the particular needs of both younger and older mothers, and highlight the midwife's unique role within this process PMID- 26753260 TI - Maternity system failings 'could be happening elsewhere'. PMID- 26753262 TI - Alcohol and pregnancy: a dangerous cocktail. AB - Women have diverse attitudes and behaviours towards alcohol consumption during pregnancy. Contradictory views about the risks associated with alcohol intake influence consumption levels. Many women do not receive detailed advice from healthcare professionals. The woman's assessment of risk is hindered by the contradictory advice from government guidelines, health organisations and the media. Health professionals play a vital role in advising women on health behaviours pre-conception and throughout the antenatal and postnatal period to improve outcomes. Midwives ensure and enable women to make informed choices regarding alcohol consumption during pregnancy. As healthcare professionals we should be providing evidence based, up to date information regarding the potential risks and harms associated with alcohol consumption during pregnancy for the unborn. So why is this not happening? PMID- 26753265 TI - A cautionary holiday tale. AB - In this column, Sara Wickham takes a sideways look at issues relevant to midwives, students, women and families, inviting us to sit down with a cup of tea and ponder what we think we know. This month's seasonal story tells the tale of Rudolph the red-nosed quantity surveyor, who gets more than he has bargained for when he visits the labour ward in order to weigh the birth balls for a trust health and safety exercise and decides to make tea for the tired midwives.... PMID- 26753263 TI - Being a preceptor - rewarding yet challenging. AB - Preceptorship is the 15th series of 'Midwifery basics' targeted at practising midwives.The aim of these articles is to provide information to raise awareness of the impact of the work of midwives on women's experience, and encourage midwives to seek further information through a series of activities relating to the topic. In this third article of the series, Kerry Taylor and Megan Blease look into the role of the preceptor and the value it offers newly qualified midwives, with key recommendations to help trusts support preceptors in this acquired role. PMID- 26753264 TI - New and old. PMID- 26753266 TI - Soranus (Part 2). PMID- 26753267 TI - How should GPs test for dementia? PMID- 26753269 TI - Optimising the management of patients with difficult asthma. AB - Asthma affects 5.4 million people in the UK, around 1 in 12 of the population. Between 5 and 10% of asthma (depending on the definition used) is categorised as difficult asthma, a term which generally refers to patients who continue to experience symptoms and frequent exacerbations despite the prescription of high dose asthma therapy. Difficult asthma is an indication for specialist review by an appropriate respiratory physician, but close liaison between primary, secondary and tertiary care is critical and it is therefore important that primary care health professionals should be aware of the principles of management. One of the most important questions to ask is whether the individual with difficult asthma is taking their treatment Identifying this, however, is not easy. GPs could assess prescription uptake, looking for low use of preventers and excess use of short-acting bronchodilators. Newer means of assessing adherence have been developed. Inhaler devices that can monitor completion and timing of actuations have been produced. Meters that measure FeNO are available. A recent UK study found that 12 out of 100 patients referred for difficult asthma did not have reversible airflow obstruction or a history suggestive of asthma. Diagnoses included COPD, cystic fibrosis, cardiomyopathy, respiratory muscle dysfunction and severe anxiety with vocal cord dysfunction. PMID- 26753268 TI - Improving the diagnosis and management of COPD. AB - COPD is a progressive condition. Therefore, earlier diagnosis allows earlier intervention in particular smoking cessation. Stopping smoking in early middle age where an individual has relatively mild COPD is associated with a slower decline in lung function and reduced mortality. Spirometry should be performed in symptomatic current or former smokers (typically >= 10 pack years) who are aged at least 35 where COPD is a likely differential diagnosis. Once airflow obstruction is proven and a diagnosis of COPD established then a measure of COPD severity can be made based on FEV1 expressed as a percentage of predicted value. When an individual with COPD is assessed it is vital that comorbid conditions are considered and management optimised. Cardiovascular disease and diabetes were seen most commonly in people enrolled in the active and sometimes sleep. The COPD Assessment Tool is a simple measure of health status that takes under five minutes to complete. Performing spirometry each year can identify patients with a rapid, progressive decline in lung function and allow this to be addressed. Inhaler technique should be checked at this review and also when a new type of inhaler is commenced. PMID- 26753270 TI - Early diagnosis improves outcomes in hepatitis C. AB - Chronic hepatitis C (HCV) infection affects 0.8-1.0% of the UK population, with up to 70% having ongoing chronic infection. HCV is curable but if left untreated can progress to end stage liver disease and potentially hepatocellular carcinoma. HCV management options have changed dramatically over the past five years, with improvement in cure rates and tolerability; cure rates of more than 90% can now be achieved. The main risk factors for acquiring HCV infection in the UK are injecting drug use and sharing drug using equipment. Other risk factors include receipt of blood products in the UK before 1991; tattooing or acupuncture with non-sterile equipment; medical procedures; needlestick injuries and contact with blood from an infected person. Acute hepatitis C infection has mild symptoms only and is likely to go undiagnosed. The estimated diagnosis rate in England is 35%, suggesting that 65% of the total HCV-positive population remains undiagnosed. The most common method of detecting HCV is case finding in high- risk groups. Those who test positive for HCV antibodies should be tested for persisting viral presence through HCV PCR testing - a positive result confirms active infection. GPs can play a major role in identifying those at risk of the disease, which includes patients with known risk factors and those with unexplained abnormal liver function tests, providing information and arranging testing. Patients with confirmed active HCV infection should be referred to the local specialist hepatology or infectious disease service in accordance with locally agreed pathways. PMID- 26753271 TI - Urgent referral for skin lesions. PMID- 26753272 TI - PITFALLS IN THE DIAGNOSIS OF APPENDICITIS. PMID- 26753273 TI - The simplest things can make the most difference. PMID- 26753274 TI - [Progress in sample preparation and analytical methods for trace polar small molecules in complex samples]. AB - Small polar molecules such as nucleosides, amines, amino acids are important analytes in biological, food, environmental, and other fields. It is necessary to develop efficient sample preparation and sensitive analytical methods for rapid analysis of these polar small molecules in complex matrices. Some typical materials in sample preparation, including silica, polymer, carbon, boric acid and so on, are introduced in this paper. Meanwhile, the applications and developments of analytical methods of polar small molecules, such as reversed phase liquid chromatography, hydrophilic interaction chromatography, etc., are also reviewed. PMID- 26753275 TI - [Preparation of xylitol and maltitol modified silica as novel stationary phases for hydrophilic interaction liquid chromatography and evaluation of their separation performance]. AB - New types of stationary phases for hydrophilic interaction liquid chromatography (HILIC) with unique selectivity are very important for the separation of various polar and hydrophilic analytes. Two novel HILIC stationary phases based on sugar alcohol modified silica were synthesized by a simple two-step reaction in which xylitol and maltitol were bonded onto the surface of silica particles via the addition reaction between -NCO and -OH. The effect of acetonitrile content on the retention indicated that the two stationary phases were of typical HILIC character and exhibited strong retention for polar and hydrophilic analytes. They succeeded in the separation of a wide range of polar and hydrophilic analytes including water soluble vitamins, salicylic acid and its analogues, nucleic acid bases and nucleosides, and icariin and its analogues with unique selectivity. Especially, the maltitol stationary phase showed unique selectivity on glycosyl group, compared to xylitol stationary phase. Furthermore, the effects of buffer pH as well as salt concentration on the retention indicated that electrostatic interaction played an important role in the separation mechanism of the two stationary phases. For sure, the efficient stationary phases are of great potential applications in HILIC. PMID- 26753276 TI - [Preparation and evaluation of N-acryloyltris (hydroxymethyl) aminomethane-bonded chromatographic stationary phase]. AB - The present study described the preparation of N-acryloyltris (hydroxymethyl) aminomethane-bonded silica (NAS) stationary phase based on "thiol-ene" click chemistry. The composition of the surface grafts of NAS stationary phase was determined by elemental analysis and the results demonstrated the successful introduction of the N-acryloyltris (hydroxymethyl) aminomethane groups to the silica surface. Similar elemental composition of three batches of the NAS stationary phases exhibited good reproducibility of the preparation strategy. A set of standard compounds were employed to investigate the retention mechanism of the NAS stationary phase by three different empirical equations. The results indicated the retention of the tested analytes on the NAS stationary phase was based more on a mixed-mechanism rather than a simple partitioning or adsorption process. Eight compounds were selected to study the hydrophobic and hydrophilic properties of the NAS stationary phase in mobile phase with different ACN contents. Due to its hydrophilic triolacrylamide groups and short hydrophobic alkyl chains, the NAS phase was successfully applied in both reversed-phase liquid chromatography (RPLC) mode and hydrophilic interaction liquid chromatography (HILIC) mode. The influence of flow rate on the column efficiency was compared in these two modes. In contrast to RPLC columns, the overall heights equivalent to a theoretical plate (HETP) in HILIC is weakly dependent on the retention of the analyte and the HETP curve is much flatter in RPLC than in HILIC at larger reduced velocities. Furthermore, the separation of alkylbenzenes, nucleosides and nucleobases, water-soluble vitamins was achieved on the new stationary phase, demonstrating the excellent application potential. PMID- 26753277 TI - Chromatographic evaluation and application of silica based azide-modified stationary phase under hydrophilic interaction liquid Chromatography mode. AB - Hydrophilic interaction liquid chromatography (HILIC) has attracted more and more interests in recent years. However, the stationary phases for HILIC are still scarce. More stationary phases and separation methods should be developed. Silica based azide-modified stationary phase was synthesized and characterized by our group. The nucleosides were selected as the test samples. The retention property of nucleosides on the azide-modified stationary phase was shown with typical HILIC characterization. Moreover, the glycopeptide selectivities of azide modified stationary phase under HILIC mode by adding two species of salts (ammonium bicarbonate and ammonium formate) and acid in mobile phase were compared. The results showed that better glycopeptide selectivity could be obtained under acid condition without adding salt in the mobile phase. With the optimized conditions, nine MS signals of glycopeptides were detected after enrichment from the tryptic digest of horseradish peroxidase (HRP). Silica based azide-modified stationary phase has the potential in further application in glycopeptide enrichment under HILIC mode. PMID- 26753278 TI - [Evaluation of retention behavior of carbohydrate compounds on the zwitterionic hydrophilic interaction liquid chromatographic column]. AB - Because of the strong polarity of carbohydrate compounds which have weak retention in reverse-phase liquid chromatography (RPLC) , hydrophilic interaction liquid chromatography (HILIC) is suitable for the separation and analysis of the carbohydrate compounds. In this study, nine carbohydrate compounds were selected as the test probes to systematically evaluate the retention behavior of the carbohydrate compounds on a Click TE-Cys column with zwitterionic stationary phase. And the effects of the ratio of organic phase and salt concentration in mobile phase on the retention behavior were investigated as well. The experiments proved that the nine carbohydrate compounds could be eluted in the order of their polarities from the Click TE-Cys column. With the increase of organic phase ratio, the retention of carbohydrate compounds was enhanced. As the increase of salt concentration, the retention of the carbohydrate compounds increased except sialic acid. Using displacement-adsorption liquid phase interaction model to simulate the retention behavior of the carbohydrate compounds under HILIC, the retention behavior of HILIC was described by the retention equation of ln k = a + bln C(B) + cC(B), and the retention values of HILIC were analyzed by multiple linear regression. The results demonstrated that the retention behavior of carbohydrate compounds on the Click TE-Cys was in accordance with the retention regularity of HILIC. PMID- 26753279 TI - [Deep eutectic solvent: a new kind of mobile phase modifier for hydrophilic interaction liquid chromatography]. AB - Deep eutectic solvents (DESs) were used as a new kind of mobile phase modifier in hydrophilic interaction liquid chromatography (HILIC). In our experiment, a SiO2 column (150 mm x 4.6 mm, 3 um) was selected to separate several nucleobases and nucleosides by using the mixed solution of acetonitrile and DES (choline chloride ethylene glycol (1:3, mol/mol) ) as mobile phase. Subsequently, the concentrations of DESs in acetonitrile and the column temperature on the effect of separation were investigated. According to the experimental results, better separation of nucleobases and nucleosides was obtained by using acetonitrile and DESs mixed solution as mobile phase than that using traditional water-based solution. For example, a baseline separation between cytosine and cytidine cannot be achieved by HILIC with water-based mobile phase, however, greater improvement was gained by HILIC with modified DES-acetonitrile mobile phase. Meanwhile, the retention times of nucleobases and nucleosides decreased as the proportion of DESs in acetonitrile increased, the most significant decrease of which was with cytidine. Similar retention behavior took place with the effect of column temperature. Decreased retention times of the analytes were observed as column temperature increased. The experimental results indicated that this new method may solve some separation difficulties in traditional water-based HILIC, which also successfully verify the feasibility of DESs as mobile phase modifiers. PMID- 26753280 TI - [Quantitative analysis of five antiviral drugs by hydrophilic interaction liquid chromatography-charged aerosol detection]. AB - Antiviral drugs are widely used for human and animals. However, the analysis of the mixture of antiviral drugs is a challenge for high performance liquid chromatography, since some of the antiviral drugs have weak UV absorbance and poor retention in reversed phase liq- uid chromatography. A method of hydrophilic interaction liquid chromatography-charged aerosol detection (HILIC-CAD) was optimized for the qualitative and quantitative analysis of five antiviral drugs. In this study, Click TE-Cys was used as the stationary phase and CAD was used as the detector. Various chromatographic conditions including the kind of detector, chromatographic mode, column and mobile phase composition were investigated. Compared to UV-Vis, more antiviral drugs could be detected by CAD, since it is a universal detector. HILIC mode is an alternative to reversed phase liquid chromatography mode. HILIC provides higher sensitivity and unique selectivity to target compounds. After the optimized parameters were obtained, the developed method was used for the quantitative analysis of the five antiviral drugs. As a result, the current method has good repeatability, a wide linear range (0.07-2.28 mg/mL) and good sensitivity (LOQ <= 0.04 mg/mL). The RSDs of intra-day and inter day peak areas were less than 3. 06% and 5. 38% respectively. The above results demonstrated that the current method is sensitive, robust and effective for the separation and determination of these five antiviral drugs. PMID- 26753281 TI - [Determination of L-carnitine in milk and dairy products by hydrophilic liquid chromatography-tandem mass spectrometry]. AB - An analytical method was developed for the determination of L-carnitine in milk and dairy products using hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS). The samples were extracted with 2% (v/v) acetic acid solution, and the protein was precipitated with acetonitrile subsequently. The separation of L-carnitine was carried out on an Acquity UPLC BEH HILIC column using ammonium acetate and acetonitrile as mobile phases. The quantification analysis of the target compound was performed under multiple reaction monitoring (MRM) mode by external standard method. A good linear relationship was obtained between the peak area and concentration of L-carnitine in the range of 1-100 ug/L with the correlation coefficient more than 0.99. The limit of quantification (LOQ ) of L-carnitine was 0. 01 mg/kg. The spiked recoveries were 96.0%-103.4%. The precisions (RSDs ) were 1.2%-4.3%. The sample preparation was simple and rapid, and the results were precise and sensitive. The developed method is suitable for the study of concentration of L-carnitine in milk and dairy products, and the technical support for the infant formula is provided. PMID- 26753283 TI - [Analysis of vancomycin and its related impurities by hydrophilic interaction liquid chromatography]. AB - The current reversed-phase liquid chromatography as the main analytical method for vancomycin is inappropriate due to its poor polarity selectivity and mass spectrometry compatibility. Hydrophilic interaction chromatography (HILIC) method has been verified to provide the glycopeptide substances with good retention and polarity selectivity, therefore, an HILIC method was developed for the analysis of vancomycin and its related impurities including norvancomycin, desvancosaminyl vancomycin, dedichloro vancomycin and crystalline degradation product (CDP-1). In this work, a systematic evaluation of retention behavior of vancomycin and its related impurities in hydrophilic interaction chromatography was performed and the influences of stationary phase, acetonitrile content, buffer salt and pH of mobile phase were studied. According to the results, Click XIon column was selected as stationary phase and ammonium formate was additive in the mobile phase. Vancomycin and its related impurities were totally separated under the optimization conditions. It is concluded that hydrophilic interaction chromatography may be a new strategy for the separation of vancomycin and its structural analogues. PMID- 26753282 TI - [Analysis of carbapenems by hydrophilic interaction chromatography and its application]. AB - A hydrophilic interaction chromatographic (HILIC) method has been developed for the determination of the four carbapenems in human urine and tap water. The parameters including acetonitrile amount, buffer concentration and pH on the retention behavior of the four carbapenem antibiotics on an XAmide column were explored and the possible HILIC retention mechanism was proposed. Good linearities were obtained over the mass concentration ranges of 0.1-250 mg/L for biapenem, doripenem and ertapenem with correlation coefficients (R2) = 0.999 9 and while it was 0.5-250 mg/L with R2 = 0.999 8 for meropenem. The limits of quantification (LOQs) of all carbapenems were 0.1-0.5 mg/L. The spiked recoveries were within 100.4%-111.9% (RSD < 1%) for urine samples and 79.6%-107.4% (RSD < 5%) for tap water samples all at the spiked levels of 5 mg/L and 25 mg/L. The proposed method is accurate, sensitive, simple and suitable for the determination of the four carbapenems in human urine samples and tap water samples. PMID- 26753284 TI - [Preparation of surface molecularly imprinted polymers for penicilloic acid, and its adsorption properties]. AB - On account of the specificity and reproducibility for the determination of penicilloic acid in penicillin, this study aims to prepare penicilloic acid imprinted polymers (PEOA-MIPs) by surface polymerization method at the surface of modified silica particles by using penicilloic acid (PEOA) as the template molecule, methacrylic acid (MAA) as the functional monomer, ethylene glycol dimethacrylate ( EGDMA) as the cross linker, and methanol/acetonitrile as the solvents. The synthesis conditions were optimized, and PEOA-MIPs had the best adsorption capacity when the molar ratio of template molecule/functional monomer was 1 :4, cross linking degree was 85% and the solvent ratio of methanol/acetonitrile was 1 :1 (v/v). The adsorption properties were evaluated by adsorption experiments, including the adsorption isotherms, kinetics and selectivity. The adsorption process between PEOA-MIPs and PEOA fitted the Langmuir adsorption isotherm with the maximum adsorption capacity of 122. 78 mg/g and the pseudo-second-order reaction kinetics with fast adsorption kinetics (the equilibrium time of 45 min). The as-synthesized PEOA-MIPs were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT IR), and thermal gravimetric analysis (TGA). The results indicated that the MIPs layer has been successfully grafted on the surface of SiO2 microparticles and the PEOA-MIPs had the excellent thermal stability. The PEOA-MIPs showed the highest selective recognition for PEOA. The PEOA-MIPs possess a high adsorption capacity, rapid mass-transfer rate and high selectivity to PEOA when compared with non imprinted polymers (PEOA-NIPs). The PEOA-MIPs was expected to be used as the solid phase extraction medium and this study provides the potential applications for fast recognition and analysis of the penicilloic acid in penicillin. PMID- 26753286 TI - [Determination of flavonol glycosides in tea samples by ultra-high performance liquid chromatography-photodiode array detection-tandem mass spectrometry]. AB - An ultra-high performance liquid chromatography-photodiode array detection-tandem mass spectrometry (UPLC-PDA-MS/MS) method was developed for the determination of flavonol glycosides in tea samples. The chromatographic separation was performed on an UPLC HSS T3 column by gradient elution with the mobile phases of acetonitrile and water both containing 0.1% (v/v) formic acid. A total of 15 flavonol glycosides which include 3 myricetin glycosides, 6 quercetin glycosides and 6 kaempferol glycosides were positively identified in green and black tea samples by comparing the retention times and mass spectra of the samples with standards and publications. The quantities of flavonol glycosides were relatively calculated with the stand- ard quercetin-3-rhamnosylglucoside (Q-GRh) which was calibrated with external quantification method using multi-reaction monitoring (MRM) mode. The results showed that there were different flavonol glycoside distributions in green tea and black tea. The total amount of flavonol glycosides in green tea was 1. 7 times of that in black tea. The major flavonol glycosides in green tea were myricetin-3-galactoside (M-Ga), myricetin-3-glucoside (M-G), quercetin-3-glucosyl-rhamnosyl-galactoside (Q-GaRhG), quercetin-3-glucosyl rhamnosyl-glucoside (Q-GRhG), kaempferol-3-glucosyl-rhamnosyl-galactoside (K GaRhG) and kaempferol-3-glucosyl- rhamnosyl-glucoside (K-GRhG), but for black tea, the major flavonol glycosides were quercetin-3-rhamnosylglucoside (Q-GRh), quercetin-3-glucoside (Q-G), kaempferol-3-rhamnosylglucoside (K-GRh) and kaempferol-3-galactoside (K-Ga). The present method is accurate, convenient for the rapid identification of flavonol glycosides and analysis of constituent distribution for green and black teas. PMID- 26753285 TI - [Using liquid chromatography-mass spectrometry based metabolomics to discriminate between cold pressed rice bran oils produced from two different cultivars of Oryza sativa L. ssp. indica in Thailand]. AB - A newly developed liquid chromatography-mass spectrometry (LC-MS) method for the analysis of cold pressed rice bran oil (RBO) was established and used to discriminate between RBOs produced from two different cultivars of major Thai fragrant rice species. The cold pressed RBO was prepared using the screw compression method. The LC-MS data were preprocessed with MZmine 2.10 program before evaluating with principal component analysis using SIMCA 13 software. The LC-MS method was able to detect and quantify several kinds of valuable constituents such as fatty acids, vitamin E, and gamma-oryzanol. The chromatographic condition was feasible; short time for analysis and simple method were achieved. From score plot and loading plot of principle component analysis (PCA) , two rice cultivar samples were clearly separated, and it was revealed that Khao-Hom-Pathum was more suitable than Khao-Hom-Mali for cold pressed RBO production since it contained high total gamma-oryzanol and less saturated free fatty acids. As with the fixed price of all the rice brans, this information can be used in order to, if possible, preserve the price of rice brans from different cultivars. PMID- 26753287 TI - [Determination of L-dopa and dopamine in rat brain microdialysate by ultra high performance liquid chromatography-tandem mass spectrometry using stable isotope coded derivatization coupled with dispersive liquid-liquid microextraction]. AB - The sensitive detection method of levodopa (L-DOPA) and dopamine (DA) in rat brain microdialysate of Parkinson's disease (PD) is an essential tool for the clinical study and attenuated synergistic drug screening for L-DOPA from traditional Chinese medicines. Using d0/d3-10-methyl-acridone-2-sulfonyl chloride (d0/d3-MASC) as stable isotope derivatization reagent, a novel ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for L-DOPA and DA by stable isotope- coded derivatization coupled with ultrasonic-assisted dispersive liquid-liquid microextraction (UA-DLLME). d3-MASC (light) and d3-MASC (heavy) were used as derivatization reagents for microdialysate samples and standards, respectively. Mixtures of the two solutions were prepared by UA-DLLME for UHPLC-MS/MS analysis with multiple reaction monitoring (MRM) mode. With d3-MASC heavy derivatives as internal standards for corresponding light derivatives from samples, the stable isotope internal standard quantification for L-DOPA and DA was carried out. The stable derivatives were obtained in aqueous acetonitrile (pH 10.8 sodium carbonate-sodium bicarbonate buffer) at 37 degrees C for 3.0 min, and then were separated within 2.0 min using gradient elution. Linear range was 0.20-1500.0 nmol/L (R > 0.994). LODs were 0.005 and 0.009 nmol/L for DA and L-DOPA (S/N = 3), respectively. This method was validated, and it showed obvious advantages in comparing with the reported methods in terms of sensitivity, analysis speed and anti-matrix interference. This method has been successfully applied to the study of effect of Shouwu Fang on L-DOPA and DA concentration fluctuations in PD rat brain microdialysate. PMID- 26753288 TI - Pressure-assisted electrokinetic injection stacking for citalopram drug to achieve highly sensitive detection and enantioseparation by capillary electrophoresis. AB - Pressure-assisted electrokinetic injection (PAEKI) was applied to the highly sensitive enantioseparation of the positively charged drug citalopram (CIT) by capillary electrophoresis (CE). It was found that the injection discrimination occurred in electrokinetic injection (EKI) process due to the different dynamic equilibrium constant between chiral selector (sulfated-beta-cyclodextrin, S-beta CD) and two isomers of CIT. Herein, it was proposed to use the background electrolyte (BGE) without chiral selector to fill the capillary, and then start the EKI step to eliminate the injection discrimination of free analytes. The critical parameters in PAEKI could be optimized in two steps to seek the balance between the electroosmotic flow (EOF) and the counterbalance pressure. Under the optimized PAEKI conditions (+10 kV, 0.2 psi (ca. 1.4 kPa)), the obtained LODs (S/N = 3) of the two isomers were 1.1 and 2.2 ng/mL under UV detection (205 nm), which was averaged 62-fold improved in comparison with normal hydrodynamic injection (HDI). The proposal offered ng/mL (ppb) level sensitivity of CIT determination and could be an effective method in the applications in human body biofluids. PMID- 26753289 TI - [Determination of 35 antibiotic residues of tetracyclines, sulfonamides, penicillins, macrolides and amphenicols in milk by liquid chromatography-tandem mass spectromtery]. AB - A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for the simultaneous determination of 35 antibiotic residues of tetracyclines, sulfonamides, penicillins, macrolides and amphenicols in milk. The samples were extracted with alkaline acetonitrile and McIlvaine buffer solution under ultrasonication. The separation of target compounds was performed on an Eclipse XDB-C, column (150 mm x 2.1 mm, 3.5 um) with gradient elution at a flow rate of 0.25 mL/min, and with an injection volume of 10 uL. The identification and quantification of the compounds were completed by liquid chromatography tandem mass spectrometry in multiple reaction monitoring ( MRM) mode. The limits of detection were all below 10.0 ug/kg. The average spiked recoveries of the method ranged from 70. 1% to 109. 9% with relative standard deviations (RSDs) of 2.89%-9.99%. After validation, the method was applied to the analysis of antibiotic residues in milk products in China. Fifty samples were screened under the well defined methodology, and the results showed that chloramphenicol, only in one sample, was monitored with the content of 0.48 ug/kg. A risk of contamination of milk with chloramphenicol has been determined to exist. Therefore this method is convenient, rapid, sensitive and reliable, and can be successfully applied to the simultaneous detection of the 35 antibiotic residues of tetracyclines, sulfonamides, penicillins, macrolides and amphenicols in milk. PMID- 26753290 TI - [Simultaneous determination of multi-classes of veterinary drug residues in pork by ultra performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry]. AB - An analytical method was established for the simultaneous determination of six classes of 33 veterinary drug residues in pork by ultra performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UPLC-Q TOF MS). The QuEChERS method has been validated for the extraction. In this method, the sample was extracted by acetonitrile containing 5% (v/v) acetic acid and cleaned-up with C18 and NH2 adsorbents. The extract was measured directly by UPLC-Q-TOF MS with electrospray ionization in positive mode. The compounds were separated on a ZORBAX SB-C18 column (100 mm x 2.1 mm, 3.5 um) with acetonitrile 0.1% formic acid containing 5 mmol/L ammonium acetate as mobile phases under gradient elution. The confirmatory analysis was carried out by determining the retention times and accurate masses of all the compounds and fragment ions upon Target MS/MS. The correlation coefficients of the 33 veterinary drugs were more than 0. 99 within their linear ranges. The limits of quantification (LOQs) were 2.5-100 ug/kg. The recoveries ranged from 67.0% to 109.0% with the relative standard deviations (RSDs, n = 6) not more than 15.1%. The method is rapid, sensitive, and suitable for the simultaneous determination of multi-classes of veterinary drugs in pork. PMID- 26753291 TI - [Separation of C5-C7 hydrocarbon components on Al2O3 capillary column and its application]. AB - The separation and qualitative analysis of 54 common C5-C7 hydrocarbon components on three Al2O3 capillary columns, including S type, KCl type and M type, were investigated in detail. The results showed that the separation of the 54 C5-C7 hydrocarbon components were partly different on these three Al2O3 capillary columns, and the most of C5-C7 hydrocarbon components could be well separated, except that some of them couldn't achieve a baseline separation or co-eluted. Linear temperature programmed retention indices of the 54 C5-C7 hydrocarbon components, including 15 C5 hydrocarbons, 25 C6 hydrocarbons and 14 C7 hydrocarbons, were determined on these three Al2O3 capillary columns. The determination of linear temperature programmed retention indices for these C5-C7 hydrocarbon components on Al2O3 capillary columns provided a basis for the qualitative analysis of them. At the same time, a real pyrolysis gas sample from one of the petrochemical plants was qualitatively analyzed according to the linear temperature programmed retention indices, and the contents of C5-C7 hydrocarbon components were determined. The application field of Al2O3 capillary column was expanded and it is helpful for the analysis of light hydrocarbons in petrochemical enterprises. PMID- 26753292 TI - It's All About Care: The NLN at the Forefront of Nursing. PMID- 26753293 TI - Signs of Maturity . . . Simulations Are Growing and Getting More Attention. PMID- 26753294 TI - Debriefing Practices in Nursing Education Programs: Results from a National Study. AB - AIM: The purpose of the study was to describe debriefing practices in nursing education programs in the United States. BACKGROUND: Despite the acknowledged importance of debriefing, little is known about debriefing practices. It is imperative that debriefing practices be examined in order to establish a baseline understanding of current practice. METHOD: The study design was a cross-sectional Internet-based survey. Surveys were sent to every accredited pre-licensure nursing program in the United States. Regression analysis determined variables that were associated with the use of theory-based debriefing. RESULTS: Data analysis determined that most debriefers do not have training in debriefing and that their competence was not assessed. Factors associated with the use of theory based debriefing included the presence of a designated simulation administrator, training for debriefers, and competence assessment of debriefers. CONCLUSION: These results establish a baseline from which to prioritize faculty development in simulation-based education. PMID- 26753295 TI - Enhancing Empathy in Undergraduate Nursing Students: An Experiential Ostomate Simulation. AB - AIM: The aim of this study was to implement and evaluate an experiential learning simulation created to enhance nursing students' empathy during patient care encounters. BACKGROUND: The investigators proposed that an ostomy simulation experience would be an efficient method for providing this educational content. METHOD: Content analysis was conducted on essays using Krippendorff's technique to quantify the simulation. RESULTS: Each unit of measure, or paper, contained between 1 to 14 empathic comments. Of the total sample, 22.8 percent had three or five empathic comments; 10 percent had four, and 9 percent had six or more comments per paper. Eighty-five percent of participants felt this simulation experience was beneficial for enhancing empathy in clinical practice. CONCLUSION: The assignment was an effective, objective method that utilized simulation to teach empathy to baccalaureate nursing students. PMID- 26753296 TI - Improving Attitudes and Perceived Competence in Caring for Dying Patients: An End of-Life Simulation. AB - AIM: The aim of this study was to assess learning outcomes from a simulation on providing care to a critically ill patient from whom care is ultimately withdrawn. BACKGROUND: Nursing students have anxiety and low perceived competence for caring for dying patients. Effective strategies for teaching communication, assessment, and basic nursing skills are needed. METHOD: A pretest-posttest design compared perceived competence and attitudes in caring for dying patients with three separate cohorts of undergraduate nursing students performing the simulation. RESULTS: The cohorts had significantly improved scores on the perceived competence (p < .001) and attitude (p < .01) measures following the simulation. Reliability for a new instrument to assess perceived competence in caring for dying patients was also established. CONCLUSION: This study's simulation offers a robust teaching strategy for improving nursing students' attitudes and perceived competence in caring for dying patients. PMID- 26753297 TI - Interdisciplinary Disaster Drill Simulation: Laying the Groundwork for Further Research. AB - AIM: The aim of this study was to examine the effect of using serial simulations with progression through the nursing curriculum. BACKGROUND: Simulation provides a way to learn without fear of failure and increase critical thinking and clinical decision-making skills. Learning in an interdisciplinary simulation provides a greater understanding of teamwork and communication skills. METHOD: The NLN/Jeffries Simulation Framework was used in an interactive disaster drill with role-playing patient actors and manikins. In a debriefing session, nursing and radiology students co-presented scenarios. RESULTS: Students displayed critical thinking and clinical decision-making skills. They reported an increase in self-confidence in caring for patients during a disaster, an increase in empathy, and learning by observing others. CONCLUSION: This pilot study revealed that an interdisciplinary disaster drill simulation experience was a positive learning experience for both nursing and radiology students. PMID- 26753299 TI - Determining Content Validity and Reporting a Content Validity Index for Simulation Scenarios. AB - AIM: This article aims to assist educators and researchers in determining content validity (CV) and reporting a content validity index (CVI) for simulation scenarios. BACKGROUND: Educators and researchers involved in health care curricula may not recognize the need to validate and/or do not know how to validate a simulation scenario. METHOD: Two methods based on previous research that can be used to determine CV and report a CVI are discussed (Lynn and Lawshe). RESULTS: Simulation scenarios need to be written so experts can fully understand the entirety of content and accurately assess whether items are relevant. Information for a CV template for experts is provided. CONCLUSION: Determining item CV and reporting an overall CVI are important elements necessary to simulation scenarios, especially when the scenario is used in a high-stakes assessment or research. PMID- 26753298 TI - A Mixed-Methods, International, Multisite Study to Develop and Validate a Measure of Nurse-to-Physician Communication in Simulation. AB - AIM: This study examined the reliability and validity of the ISBAR Interprofessional Communication Rubric (IICR). BACKGROUND: Improving education regarding communication in health care is a global priority. Communication is difficult to measure and no evaluation rubrics were located that uniquely focused on nurse-to-physician communication in simulation. METHOD: This study used a mixed-methods design and included five sites. RESULTS: The IICR was determined reliable among nurse educator raters (r = 0.79). The scale was found valid as assessed by nurse and physician experts (content validity index = 0.92). When describing their experience of using the tool, nurse educator raters described three categories: overall acceptability of the tool, ease of use, and perceptions of the importance of communication skills for patient safety. CONCLUSION: Teaching and evaluating communication in simulation with a standardized rubric is a research area in need of further exploration and refinement. PMID- 26753300 TI - Non-Acute-Care Virtual Simulation: Preparing Students to Provide Chronic Illness Care. AB - This pilot study demonstrated the potential for virtual simulation in nursing education regarding chronic care management in community settings. Observations of faculty characteristics associated with the ability to effectively facilitate simulation experiences and debriefing sessions were consistent with prior studies. PMID- 26753301 TI - Integrating Collaborative Interprofessional Simulation into Pre-Licensure Health Care Programs. AB - This interprofessional education activity incorporated National League of Nursing unfolding case studies and patient simulation with nursing, pharmacy, and medical students. Faculty developed a full-day simulation experience; the most unique element was a team meeting where nursing students presented home health findings to an interprofessional team, and students worked together to design a comprehensive plan of care. All students were in their geriatric specialty program rotations. The interprofessional simulation introduced students across disciplines for the purpose of enhancing communication, developing mutual respect, and identifying role clarity through team learning. PMID- 26753302 TI - Persons with Disability: Their Experiences as Standardized Patients in an Undergraduate Nursing Program. AB - This descriptive qualitative study examined experiences of standardized patients with disabilities (SPWDs) in an undergraduate nursing program through focus group and telephone interviews. Content analysis identified five themes: 1) desire to improve care for others, 2) opportunity to be productive again, 3) joy in seeing students learn, 4) desire for more feedback on performance, and 5) importance of having SPWDs assess accessibility of the facility. SPWDs participated to improve sensitivity of students to disability and appreciated having a voice in educating future nurses. They requested more feedback on their performance and identified accessibility issues in the state-of-the-art nursing school building. PMID- 26753304 TI - Standardized Patient Versus Role-Play Strategies: A Comparative Study Measuring Patient-Centered Care and Safety in Psychiatric Mental Health Nursing. AB - Nursing faculty traditionally use role-play to demonstrate mental health behaviors. However, until students interact with a mental health patient, they may not know what to expect. Standardized patient (SP) interactions can be used to overcome this challenge. This study compared pre-licensure nursing students' knowledge, attitudes, and self-efficacy following a sequence of psychiatric mental health role-play and SP experiences. Results suggest that the order of teaching strategies (role-play first versus SP interaction first) does not significantly impact student knowledge, attitude, or self-efficacy. However, student scores improved in all categories after the second experience. PMID- 26753303 TI - Collaborative Classroom Simulation (CCS): An Innovative Pedagogy Using Simulation in Nursing Education. AB - Collaborative Classroom Simulation (CCS) is a pedagogy designed to provide a simulation learning experience for a classroom of students simultaneously through the use of unfolding case scenarios. The purpose of this descriptive study was to explore the effectiveness of CCS based on student perceptions. Baccalaureate nursing students (n = 98) participated in the study by completing a survey after participation in the CCS experience. Opportunities for collaboration, clinical judgment, and participation as both observer and active participant were seen as strengths of the experience. Developed as a method to overcome barriers to simulation, CCS was shown to be an effective active learning technique that may prove to be sustainable. PMID- 26753305 TI - Simulation STEPS Ahead: Preparing to Engage in Systematic Evaluations of Simulation Activities. AB - Nursing programs need to be prepared to engage in systematic evaluations of simulation activities specifically linked to course and program outcomes. This article describes how components of the Jeffries simulation framework and S.T.E.P. Educator Preparation Plan were used to guide construction, implementation, and evaluation of cost-effective, program-wide simulation experiences with the addition of "S" for systematic evaluation. Expanding the Jeffries plan to STEPS offers a strategic way to evaluate simulation systematically in nursing programs. PMID- 26753306 TI - Using Simulation to Introduce Nursing Students to Caring for Victims of Elder Abuse and Intimate Partner Violence. AB - Learning experiences about domestic violence may not be readily available to nursing students at their traditional clinical sites. Faculty at an associate degree nursing program developed and implemented elder abuse and intimate partner violence simulation scenarios for a Health Systems Concepts course. Learning objectives focused on assessment, safety, communication, education, and legal responsibilities for nurses. After the simulation, students participated in debriefing, completed student evaluations, and responded to three questions about the experience in their reflective journals. Faculty and students expressed satisfaction with this method of learning about domestic violence. PMID- 26753307 TI - Clinical Boot Camp: An Innovative Simulation Experience to Prepare Nursing Students for Obstetric and Pediatric Clinicals. AB - Obstetric and pediatric patients require unique specialized care not included in traditional adult health education. To prepare nursing students for clinical rotations beginning the second week of class, faculty developed an innovative one day simulation seminar, the OB/PEDS Boot Camp, in which groups of students rotated through six stations of obstetric and pediatric simulation exercises. This article provides insight on the development and implementation of the OB/PEDS Boot Camp. PMID- 26753308 TI - Interprofessional Simulation and Education: Physical Therapy, Nursing, and Theatre Faculty Work Together to Develop a Standardized Patient Program. AB - A well-conceived training program for standardized patients (SPs) can increase their effectiveness in portraying actual patients This article describes the development of an SP program that allows graduate and undergraduate students to engage in interprofessional experiences in a multifunctional simulation center. Three academic programs at a midwestern university developed an interdisciplinary course that trains undergraduate students as SPs for nursing and physical therapy simulation experiences. The SP program has opened doors for interprofessional collaboration beyond current simulation experiences and has exposed the university community to simulation. PMID- 26753309 TI - An Introduction to Unexpected Grief for Pre-Licensure Nursing Students: A Simulation and Interprofessional Expert Panel Regarding Fetal Demise. AB - To provide pre-licensure nursing students with a safe, clinically appropriate learning experience in unexpected grief in the obstetric setting, a simulation scenario involving intrauterine fetal demise was implemented. Narrative feedback from students following the simulation indicated that the death of a fetus and the grief of the family were upsetting. For this reason, an interdisciplinary panel to provide pastoral care and grief support was invited to take part in debriefing during subsequent simulations. Evaluations of subsequent simulations were positive. PMID- 26753310 TI - The Qatar Simulation Consortium (QSC): National Simulation Collaboration. AB - This article describes the formation and work of a nationwide Qatar Simulation Consortium. In 2013, members included the schools of medicine, nursing, and allied health in Qatar, as well as the public health care system and a private, publicly funded hospital. The mission of the consortium is to foster simulation collaboration among health care and educational institutions and advance simulation education, research, and practice to align with current global standards. PMID- 26753312 TI - [Packing up and moving on]. PMID- 26753313 TI - [General meeting of the Federation of Veterinarians of Europe (FVE) and its sections in Brussels]. PMID- 26753311 TI - Reflections on NLN Technology Conferences: 10 Years and Counting. PMID- 26753314 TI - [Work clothing--cost for purchase and cleaning]. PMID- 26753315 TI - [New World Camelid Days 2014]. PMID- 26753316 TI - [I have to work a bit in anesthesia]. PMID- 26753317 TI - [Interleukin-2 for the treatment of cows with malignant catarrhal fever]. AB - The goal of this study was to investigate whether administration of interleukin-2 (IL-2) would improve the outcome of cows with malignant catarrhal fever (MCF). The study population consisted of ten healthy control cows and 22 cows with MCF. Nineteen cows with MCF and all of the controls were treated with either 2'500 U IL-2 or 25'000 U IL-2, administered intravenously. Three cows with MCF were not treated with IL-2 (MCF controls). All of the cows with MCF received danofloxacin, flunixin meglumine and intravenous fluid therapy. Blood samples for haematological and biochemical evaluation were collected once daily for six days in all cows. Of the 19 cows treated with IL-2, 13 were eutha nized because of deterioration. All cows with MCF that did not receive IL-2 died. The clinical condition of six cows treated with 2'500 U IL-2 gradually improved. Sur viving cows had significantly higher total leukocyte counts than cows that died or were euthanized. The main reason for leukopenia in non-surviving vs. surviv ing cows was persistent lymphopenia. Use of the lower IL-2 dose was associated with clinical recovery in some cows and this treatment might therefore be considered in valuable cows, provided that the lymphocyte count is within the reference interval. PMID- 26753319 TI - [Spina bifida aperta in a sheep lamb]. AB - The case report describes the symptoms and diagnostic methods of a spina bifida aperta in a new born lamb. The most relevant clinical findings were recumbency immediately after birth with normal consciousness and suckling reflexes, alterations of the skin and coat in the lumbosacral region as well as dysuria. The biochemical and haematological screening of the blood indicated no abnormalities. While the radiological examination of the spine showed no clear evidence of the cause of the clinical sings the ultrasound and computed tomography examination revealed an incomplete closure of the vertebral arch between the 4th lumbar and the 3rd sacral vertebrae. Additionally, a hernia with similar density to the spinal cord was present in the same region of the spine. Based on the findings the lamb was euthanized. The pathological examination confirmed the incomplete closure of the vertebral arch and moreover a myelomeningocele has been diagnosed. In the histopathological examination the white and grey matter were separated in the area of the macroscopic visible lesions. Due to non-specific clinical symptoms imagining diagnostics can be crucial to confirm the diagnosis of this rare syndrome. PMID- 26753320 TI - [Antibiotic use in Swiss calf feedlots]. PMID- 26753318 TI - [Uroliths of dogs in Switzerland from 2003 to 2009]. AB - Information on composition of uroliths collected between 2003 and 2009 from dogs in Switzerland and epidemiologic data of affected dogs are summarised in this paper. Of 490 stones analysed 44% were composed of calcium oxalate, 330% of struvite, 80% of silica, 7% of urate, 3% of cystine, 3% were mixed stones and 1% each were calcium phosphate and xanthine stones. Compared to other dogs, Norwich Terriers, Norfolk Terriers, Miniature Schnauzers, Miniature Pinscher and Yorkshire Terriers had a significantly increased risk to suffer from calcium oxalate stones, Dalmatians and Continental Bulldogs from urate stones and English Bulldogs from cystine stones. No breed had an increased risk of struvite or silica stones. Stones composed of silica were more prevalent in Switzerland compared to other countries and were more common in the eastern part than in the western part of Switzerland. This study shows that there are differences in occurrence and prevalence of uroliths between Switzerland and surveys of other countries. PMID- 26753322 TI - [Together we are strong!]. PMID- 26753321 TI - Quinolone resistance mechanisms among extended-spectrum beta-lacta- mase (ESBL) producing Escherichia coli isolated from farm animals in Switzerland. PMID- 26753323 TI - [Rate of exchange variation of Swiss francs to euros: effects on veterinary products in Switzerland]. PMID- 26753324 TI - [Vacation shortening because of illness]. PMID- 26753325 TI - [PathoPig: results from the pilot phase 2014 and extension of the project to the end of 2015]. PMID- 26753326 TI - [New causes of animal poisoning in Switzerland]. AB - This retrospective study evaluated the frequency, etiology, therapy and prognosis of animal poisoning registered from 2003 to 2012. The relevant cases reported to the Swiss Toxicological Information Center (STIC) were compared with those from previously examined periods. Human medicines not approved for animals and pesticides represented the most common causes of poisoning in dogs. Novel cases occurred as a consequence of the exposure of dogs to ricinus fertilizers, grape residues from wineries, pepper lachrymatory spray and dry bouillon. Cats are still freequently poisoned by pyrethroid drugs that should be administered only to dogs. Agrochmical products are the main source of toxicities in farm animals. Most poisonings in horses and exotic animals took place due to toxic plants. In addition, two tigers died of a secondary poisoning after ingestion of meat from euthanized calves. PMID- 26753327 TI - Success of interventions in mastitis problems with Staphylococcus aureus after the introduction of an automatic milking system. AB - Staphylococcus aureus (S. aureus) is often the cause of mastitis problems in dairy herds and causes great economic losses. In this study, isolates from a dairy herd with a known S. aureus mastitis problem were examined by means of molecular methods (spa typing, PFGE, and DNA microarray) to investigate their epidemiological relationship and the success of intervention measures. The investigated dairy farm has a herd size of 60 cows and uses a fully automated milking system for milk production. A S. aureus strain, which contaminated the automated milking system and was subsequently spread among the herd through the latter, was suspected to be the origin of the mastitis problem within the herd. Thanks to the applied molecular methods, the common origin of the S. aureus isolates from the collected milk and swab samples could be shown. By culling chronically infected cows, optimising dry cow management and ensuring reliable intermediate cluster disinfection, the bulk milk somatic cell count improved. PMID- 26753328 TI - [A case of SRY positive sex reversal in a domestic cat]. AB - The present case report describes a stray cat with a female appearance. The new owners requested to neuter the animal. During surgery the veterinarian could not find any gonadal tissue. After puberty the cat showed more and more male behaviour. The owners of the cat were interested to know the cause of the abnormal behaviour, but forbid any further clinical tests or surgery. Based upon cytogenetic and molecular genetic experiments a diagnosis became possible. The uniform karyotype (38,XY) was in accordance with the karyotype of a male cat and it was possible to amplify the SR Y gene by PCR. The cat represents a case of SRYpositive sex reversal. PMID- 26753330 TI - [First it comes as something else, and then as one imagines!]. PMID- 26753331 TI - [Forms of emergency service]. PMID- 26753332 TI - [European poultry veterinarians meet in Lucerne]. PMID- 26753333 TI - [With a new logo to new shores: the new bovine health service presents itself]. PMID- 26753329 TI - [Changes of the skull of brachycephalic dogs in the last 100 years]. PMID- 26753334 TI - Ultrasonographic assessment of reticuloruminal motility in 45 cows. AB - The goal of this study was to investigate the feasibility of ultrasonographic assessment of reticuloruminal motility in 45 healthy cows. The transducers of five ultrasound machines were connected to a digital video recorder and placed simultaneously at five sites on the left side of the cows to scan the reticulorumen (reticulum; ruminal atrium; dorsal sac of the rumen; left longitudinal groove; ruminal recess, caudodorsal and caudoventral blind sacs). The video streams from all five ultrasound machines were recorded synchronously with the same time line and displayed on a single monitor. Time 0 was defined as the start of a biphasic reticular contraction. The reticulum was visualised in all cows and had 11.0 +/- 2.12 biphasic contractions in 9 min. The ruminal atrium was visualised in 40 (89%) cows and had 10.7 +/- 2.10 contractions in 9 min, which started at the time point 5.0 +/- 0.83 sec and lasted 7.0 +/- 2.14 sec. Contractions of the dorsal sac of the rumen, visible in all cows, were visualised in 29 (64%) cows. There were 9.5 +/- 1.8 contractions in 9 min that started at the time point 4.0 +/- 0.85 sec and lasted 8.2 +/- 1.04 sec. The left longitudinal groove was seen contracting in 39 (87%) cows. There were 10.2 +/- 1.98 contractions in 9 min that started at the time point 4.1 +/- 1.81 sec and lasted 7.8 +/- 1.19 sec. Contractions of the ventral sac of the rumen (ruminal recess) were seen in 31 (69%) cows. There were 7.5 +/- 2.59 contractions in 9 min that started at the time point 14.3 +/- 4.30 sec. Contractions of the caudodorsal and caudoventral blind sacs were seen in 34 (76%) cows. There were 9.0 +/- 2.75 (1.0 +/- 0.31) contractions/min and 9.4 +/- 2.09 (1.0 +/- 0.23) contractions/min of the dorsal and ventral blind sacs, and they started at the time points 6.2 +/- 1.32 sec and 21.3 +/- 6.20 sec, respectively. Primary contraction cycles were seen in all cows and secondary cycles in 22 (49%) cows. The former were complete in 37 (82%) cows and incomplete in 8 (18%). There were 11.0 +/- 2.12 primary and 4.5 +/- 2.15 secondary cycles in 9 min, and the ratio between primary and secondary cycles averaged 2.4:1. Ultrasonography is suitable for the assessment of reticuloruminal motility PMID- 26753335 TI - [Serological course investigations of Haemophilus parasuis and Mycoplasma hyorhinis in three pig farms]. AB - The aim of the study was to investigate the infection dynamic of Haemophilus (H.)parasuis and Mycoplasma (M.) hyorhinis in 3 farms. A total of 61 piglets were clinically investigated at 1., 3., 5., 7., 9., 11., 14., 18. and 22. weeks of life and a blood sample was taken from each piglet as well as from the sows. The serum samples were tested using ELISA for antibodies against H. parasuis and M. hyorhinis. Clinical signs indicating polyserositis were seen in farm 1 and 3. For both pathogens, a decline of the maternal antibodies could be detected up to the 5th or 7th week of life. The duration of persistence depended on the level of the maternal antibodies. In farm 1, all animals were tested positive for antibodies against H. parasuis during the fattening period. In farm 3, several sows were tested positive in the M. hyorhinis ELISA, therefore, positive results in sows can indicate a higher infection dynamic during the fattening period. For H. parasuis as well as for M. hyorhinis a significant correlation between the level of the antibodies in the sows and their piglets could be seen. PMID- 26753336 TI - Preventive incisional negative pressure wound therapy (Prevena) for an at-risk surgical closure in a female Rottweiler. AB - This case report describes a combination of negative pressure-wound-therapy (NPWT) and NPWT assisted incision management after resection of an abscess located at the right thoracic wall in a Rottweiler. The patient had a history of severe incisional complications after surgical interventions performed in the past, including repeated episodes of wound dehiscence, major skin necrosis and infection with and without a multiresistant strain of Staphylococcus aureus and several episodes of open wound management with healing rates between months and a year. Wound closure after resection of the mass was performed as a staged procedure. After two days of open NPWT the wound was primarily closed and a preventive incisional vacuum assisted therapy (CI-NPWT) was started for 7 days. The patient was discharged during therapy with the portable device in place. The Unit was removed at day 7 post wound closure, suture removal followed at day 10. Wound healing was uneventful and no major complications occurred at a follow up time of 8 months. This is the first description of closed incisional negative pressure wound therapy in the dog. PMID- 26753338 TI - [Using old knowledge in the future]. PMID- 26753337 TI - Metastasized Leydig cell tumor in a dog. AB - We present the clinical findings, diagnosis and treatment of an 11-year old intact male Fox Terrier with a malignant Leydig cell tumor of the right testicle, which metastasized to the skeletal musculature of the left hind limb. The primary tumor and the metastasis were resected with narrow margins. The dog was treated with metronomic chemotherapy using thalidomid and dyclophosphamide. Local recurrence at the site of the metastasis and a pulmonary metastasis were present 30 months after surgery. The dog was euthanized. PMID- 26753339 TI - [Swiss Society for Veterinarians Presidential Conference from March 26, 2015]. PMID- 26753340 TI - Joining the dots - understanding the complex interplay between the values we place on wildlife, biodiversity conservation, human and animal health: A review. AB - The value of wildlife has long been ignored or under-rated. However, growing concerns about biodiversity loss and emerging diseases of wildlife origin have enhanced debates about the importance of wildlife. Wildlife-related diseases are viewed through these debates as a potential threat to wildlife conservation and domestic animal and human health. This article provides an overview of the values we place on wildlife (positive: socio-cultural, nutritional, economic, ecological; and negative: damages, health issues) and of the significance of diseases for biodiversity conservation. It shows that the values of wildlife, the emergence of wildlife diseases and biodiversity conservation are closely linked. The article also illustrates why investigations into wildlife diseases are now recognized as an integral part of global health issues. The modern One Health concept requires multi-disciplinary research groups including veterinarians, human physicians, ecologists and other scientists collaborating towards a common goal: prevention of disease emergence and preservation of ecosystems, both of which are essential to protect human life and well-being. PMID- 26753342 TI - First detection of sarcoptic mange in free-ranging wild boar (Sus scrofa) in Switzerland. AB - In Switzerland sarcoptic mange is frequent in free-ranging wild carnivores but until recent years no cases had been recorded in wild ungulates. Since 2010, cases have been observed in wild boar in the cantons of Solothurn, Tessin and Thurgau. Here, we report the detection of mange-like skin lesions in wild boars by photo-trapping and the post-mortem findings in 6 culled animals presenting different stages of the disease. Potential sources of infection include mangy red foxes, outdoor domestic pigs and wild boars from surrounding countries. Disease spread in the wild boar population may become relevant not only for wildlife but also for domestic pig health in the future if piggeries' biosecurity is insufficient to prevent interactions with wild boar. PMID- 26753341 TI - National competence center for wildlife diseases in Switzerland: Mandate, development and current strategies. AB - The need for wildlife health surveillance has become increasingly recognized. However, comprehensive programs which cover a wide spectrum of species, pathogens and geographic areas are still lacking in most European countries and practical examples of systems in place remain scarce. This article provides an overview of the organization of wildlife health surveillance in Switzerland, with a focus on the development, current strategies and the activities of the national program carried out by the Centre for Fish and Wildlife Health (FIWI), University of Bern. This documentation may stimulate on-going discussions on the design and development of national wildlife health surveillance programs in other countries. Investigations into wildlife health in Switzerland date back to the 1950s. The FIWI acts as a national competence center for wildlife diseases on mandate of the Swiss federal authorities. The mandate includes four main activities: disease diagnostics, research, consulting and teaching. In line with this, the FIWI has made continuous efforts to strengthen a national network of field partners and implemented strategies to facilitate long-term and metastudies. PMID- 26753343 TI - Outbreak of severe foot rot associated with benign Dichelobacter nodosus in an Alpine ibex colony in the Swiss Prealps. AB - An outbreak of foot rot occurred in the ibex colony "Vanil Noir" in Switzerland from May to December 2014. This article describes field observations and the analyses carried out on the limbs of 3 animals submitted for postmortem examination. Disease signs observed in the field included lameness, poor body condition and overgrown hooves. Macroscopic examination of selected limbs revealed severe lesions in all of them, including interdigital inflammation with ulceration and malodorous exudation. Histological changes were consistent with chronic laminitis with bone resorption, which was not detected at radiographical examination. Grocott-positive organisms compatible with Dichelobacternodosus were detected in the lesions. Samples collected from the lesions were positive by polymerase chain reaction for benign D. nodosus, which is typically associated with only mild lesions in domestic sheep. Whether D. nodosus is endemic in the colony or had previously been transmitted from sympatric domestic livestock is unclear. The unusual warm and humid weather conditions in 2014 may well have contributed to the outbreak. PMID- 26753344 TI - [The female generation Y and their profession, for example, the veterinary profession]. PMID- 26753345 TI - [Community opposition to entry into the profession]. PMID- 26753346 TI - [As a female veterinarian on the way in the Somali region]. PMID- 26753347 TI - Listeria monocytogenes infection in ruminants: Is there a link to the environment, food and human health? A review. AB - Listeria (L.) monocytogenes is widely distributed in the environment, but also has the ability to cause serious invasive disease in ruminants and humans. This review provides an overview of listeriosis in ruminants and discusses our insufficient understanding of reservoirs and possible cycling ofL. monocytogenes between animal and human hosts, food and the environment. It indicates gaps in our knowledge of the role of genetic subtypes in L. monocytogenes ecology and virulence as well as risk factors, in vivo diagnostics and pathogenesis of listeriosis in ruminants. Filling these gaps will contribute to improving the control of L. monocytogenes and enhancing disease prevention. As the prevalence of listeriosis in ruminants in Switzerland is likely to be underestimated, propositions concerning improvement options for surveillance of listeriosis in ruminants are provided. PMID- 26753348 TI - [Findings in uteri and ovaries from Eringer cows slaughtered due to fertility problems]. AB - Eringer cows are often slaughtered due to fertility problems which result from inflammatory and degenerative changes of the uterus or hormonal imbalances. Twenty-one genital tracts from Eringer cows suffering from fertility problems were collected in the abattoir. The purpose of the study was the macroscopic evaluation of the ovaries and the uterus followed by a histological and microbiological analysis of the uterus. Data from inseminations and calvings were provided by the Eringer breeding association and through the internet portal www.agate.ch. Median age of the cows was 6.9 years, number of calves per cow was 2.5 and median period between last calving and slaughter was 1.5 years. In 13 from 21 of the urogenital tracts examined, macroscopic abnormalities of the ovaries and/or histologic or microbiologic findings in the uterus could explain fertility-associated slaughter. PMID- 26753349 TI - [Haemoabdomen and haemothorax in a cow with metastatic granulosa cell tumor]. AB - This case report describes the clinical, ultrasonographic, pathological and histological findings in a two-year-old Swiss Braunvieh cow with granulosa cell tumor and metastases in the abdomen and thorax. The cow was ill and had tachycardia, coughing, increased breath sounds, positive reticular foreign body tests and a tense abdominal wall. Ultrasonography revealed a massive accumulation of hypoechoic fluid in the thorax and abdomen, and abdomino- and thoracocentesis yielded red fluid indicative of abdominal and thoracic haemorrhage. Because of a poor prognosis, the cow was euthanized and examined postmortem. Multiple nodular lesions were seen in the omentum, liver, spleen and lungs. The left ovary was grossly enlarged and nodular in appearance. Histological examination of the lesions revealed granulosa cell tumour of the left ovary and metastases in the omentum, liver, spleen and lungs. PMID- 26753350 TI - Evaluation of eating and rumination behaviour using a noseband pressure sensor in cows after right-flank laparotomy for correction of left displaced abomasum. PMID- 26753351 TI - [Have I a job or have I a profession? ]. PMID- 26753353 TI - [The member veterinarians of the Commercial, Industrial and Trade Exhibition (HIGA)]. PMID- 26753352 TI - [Society of Swiss Veterinarians membership poll]. PMID- 26753355 TI - [Open door day at the Swiss veterinary faculty in Bern]. PMID- 26753354 TI - [Valuable impulses for the occupational weekday]. PMID- 26753356 TI - [Training of the training recruits in contact with mules]. PMID- 26753357 TI - [Conflicts in the workplace]. PMID- 26753358 TI - [Association of skin problems with coat colour and white markings in three-year old horses of the Franches-Montagnes breed]. AB - In the last 30 years the amount of white markings in the population of Franches Montagnes horses (FM) has more than doubled which has led to some controversy, particularly in respect to the health of the horses. The objective of this study was to investigate if the coat colour and white markings have an impact on selected skin diseases and hoof horn abnormalities. To this purpose 974 three year-old FM were subjected to a clinical examination during the field and station tests organized by the FM breeding association. In 16.9% of the horses, one or several equine sarcoids were detected, 15.2% of the horses showed clinical signs of pastern dermatitis, 1.1% of insect bite hypersensitivity and 18.0% of dermatitis of other aetiology. Abnormalities of the hoof horn were found in 20.1% of the horses. The prevalence of pastern dermatitis was 2.6 times higher in legs with white markings than in legs with pigmented skin (p <0.0001). The probability ofsuffering from sunburn and hoof horn of lesser quality was increased in animals with an elevated white marking index (WAI; p = 0.022 and p = 0.038), on the other hand, horses with sarcoids had a significantly lower WAI than sound horses (p = 0.038). Our study shows that FM horses with more pronounced white markings have an increased risk to suffer from pastern dermatitis, sunburns and hoof horn abnormalities. The coat colour was not associated with skin diseases. PMID- 26753359 TI - [Ceco-cecal intussusception in a Simmental heifer]. AB - This report describes the clinical, laboratory and ultrasonographic findings in a Simmental heifer with a ceco-cecal intussusception. The general condition of the heifer was moderately reduced and it showed mild colic signs. Physical examination revealed a firm longish mass visible and palpable in the right flank. Findings upon rectal examination, fecal output und defecation were normal. Ultrasound examination of the mass revealed features typical for an intussusception. Based on the slow development of symptoms, normal fecal output and ultrasonography findings, a ceco-cecal intussusception was diagnosed. Right flank laparatomy was performed under general anaesthesia, and an end-to-side anastomosis between the jejunum and the spiral colon was made after resection of the intussuscepted intestines. Recovery was uneventful. PMID- 26753360 TI - [Nasal, pulmonary, and abomasal aspergillosis (Aspergillus fumigatus) in a calf]. AB - This study presents a case of nasal aspergillosis in a 17-days old calf (German Fleckvieh): it had been admitted moribund to the Clinic for Ruminants of the University of Munich, and died after a short time. Pathologically, the calf was diagnosed with purulent-necrotizing rhinitis, necrotizing pneumonia, and diphtheroid-necrotizing abomasitis. Histologically, fungal elements were found in all the localizations mentioned before, and mycologically, Aspergillus fumigatus was cultured from nasal cavity. Pathogenesis is discussed. PMID- 26753361 TI - [A small piece of Switzerland]. PMID- 26753362 TI - [These small, largely unknown creatures need our support]. PMID- 26753363 TI - [Barn and clinic duty for the prospective veterinarian in the first animal hospital in Berne]. PMID- 26753364 TI - Cattle movement as a risk factor for epidemics. AB - Cattle movement is one of the most important risk factors for the occurrence of an epidemic. It is a legal requirement in Switzerland that every cattle movement be reported, and this information is held in the Swiss cattle movement database (Tierverkehrsdatenbank, TVD). Using this data we examined all movements, focusing on the geographical distribution of these movements in relation to the spread of epizootic diseases. We considered the period 01 January 2011 through 30 January 2012, in which a total of 786'462 cattle were moved. Looking at premises individually, a maximum of 901 possible transfers of an infectious agent were found on a specific day after the arrival of another cattle. Furthermore, we found that there were more cattle movements in summer than in winter, due to movements of cattle to and from alpine pastures. There were also prominent regional differences. On the first day after the arrival of a cattle there was a minimum of zero and a maximum of 99'168 possible transfers of an infectious agent. Nevertheless, in most cases there were no cattle moved on the first day following the arrival of a cattle (91.4%). In terms of our epizootics of interest, the following numbers of cattle were moved within the relevant incubation periods: 19'779'551 possible transfers for the Lumpy skin disease, with an incubation period of 28 days; 9'891'665 or 15'025'741 possible transfers for foot and mouth disease, depending on the incubation period of 14 or 21 days; 15'025'741 possible transfers for cattle plague and vesicular stomatitis, both with an incubation period of 21 days. The presented data show a large cattle traffic in Switzerland, and therefore suggest that it is very seldom that an infectious agent is able to start an epidemic. PMID- 26753365 TI - [Dog and fox faecal contamination of farmland]. AB - The contamination with faeces from dogs and foxes was documented on 14 different grassland areas in the canton of Zurich, Switzerland, over one year. A total of 402 dog and 58 fox faecal samples were collected from the grasslands, further 236 faecal samples were retrieved from Robidog(r) units (disposal units for dog waste bags) in the immediate vicinity. The degree of fecal contamination per 100 m2 and year was 0.07-0.75 for dog samples and 0-0.06 for fox samples. Dog faeces from Robidog(r) units and grasslands contained stages of the following parasites, respectively (sedimentation/flotation method): Toxocara sp. (2.5%; 1.2%), Taenia crassiceps (with molecular confirmation; 0.8%; 0.2%), Capillaria sp. (0.4%; 0.7%), Trichuris sp. (0.8%; 1%), Isospora sp. (2.1%; 2%) and Angiostrongylus vasorum (0.4%; 0.5%). In fox faeces parasite stages were more frequently detected: 19% Toxocara sp., 8.6% Taenia crassiceps, 6.9% Echinococcus multilocularis, 60.3% Capillaria sp., 29.3% Trichuris sp. In two fecal samples from foxes, Taenia saginata eggs or Toxoplasmagondii oocysts were confirmed by molecular analyses, these findings may be explained as an intestinal passage after coprophagy of human or cat feces, respectively. Therefore, foxes can also indirectly play a role in parasite transmission to livestock. PMID- 26753367 TI - Politicians must police the revolving doors. PMID- 26753368 TI - ON THE IMPORTANCE OF RECOVERY. PMID- 26753366 TI - Ultrasonographic examination of the oesophageal groove reflex in young calves under various feeding conditions. AB - The oesophageal groove reflex was examined in 6 milk-fed Holstein Friesian calves once weekly during the first 17 weeks of life. Additionally, the effect of different feeding methods (bucket, different nipple positions and openings), different milk temperatures (20, 30, 39, 45 degrees C) and milk replacer concentrations (100, 125, 150 grams/litre of water) on oesophageal groove closure was investigated. The reticulum and abomasum were examined ultrasonographically using a 5.0-MHz convex transducer before, during and after feeding, and the oesophageal groove reflex was considered to be functional when milk was seen entering the abomasum during feeding. The reflex was consistently induced throughout the study period in all calves at all examinations and under all experimental conditions. However, it should not be assumed that feeding technique can be neglected in unweaned calves because suboptimal feeding management has been linked to various digestive disorders. PMID- 26753369 TI - CARE QUALITY: WE NEED TO FIX IT. PMID- 26753370 TI - SURVEY: THE VALUE OF PEOPLE SKILLS. PMID- 26753371 TI - DOING THEIR SHARE. PMID- 26753372 TI - WORKFORCE. Rule out the menace of bullying. PMID- 26753374 TI - [SAGE 2015]. PMID- 26753373 TI - SERVICE REDESIGN. OFF THE BEATEN PATH. PMID- 26753375 TI - [Paul Langerhans]. PMID- 26753376 TI - [Infrequent complication of diagnostic colonoscopy]. PMID- 26753378 TI - [Metaplasic Paneth cells in ulcerative colitis]. AB - BACKGROUND: Paneth cells are normally present in small intestine, but its appearance in other areas of the gastrointestinal tract is related to chronic inflammatory processes. MATERIAL AND METHODS: In our study we retrospectively examined 29 patients with diagnosis of ulcerative colitis, from the files of Instituto de Histopatologia de Rosario, and from the casuistry of two authors (O.B. and P.S.M.), during two years. Biopsies corresponded to rectal or sigmoid mucosa and were stained with H.E. RESULTS: Distal Paneth cells in rectum and/or sigmoid colon were found in 60% of patients. This finding was related to the time of evolution of the disease (median 7 years for patients with Paneth cells and 3 years for patients without Paneth cells). With more time of evolution, there were more number of affected crypts and more number of Paneth cells. Some of the patients with longer evolution had 2-5 crypts with Paneth cells (up to 11 Paneth cells). When the time of evolution of the disease was longer, we found an irregular distribution of Paneth cells, with migration from the depth of the crypt to highest crypt levels. There was a relationship between the number of Paneth cells and the degree of leukocyte infiltration of the mucosa. CONCLUSIONS: We observed a direct correlation of the presence of Paneth cells with the time of evolution of the disease and with the leukocyte infiltration of the mucosa. PMID- 26753377 TI - [Rare cause of chest pain and dysphagia]. PMID- 26753379 TI - [Whipple's Disease: retrospective analysis of twelve cases and review of the literature]. AB - BACKGROUND: Whipple's disease is a rare and chronic bacterial disease with multiorganic involvement. Although there is no valid estimate of its actual prevalence, only about 1,000 cases have been reported. OBJECTIVE: To describe the demographic, clinical, laboratory, endoscopic and pathologic features, type of treatment used, its duration and response. METHODS: Based on the duodenal histology, we identified twelve cases of Whipple's disease in the Hospital Centre of Vila Nova de Gaia, between 1997 and 2010. RESULTS. Nine patients (75%) were male and the mean age at diagnosis was 58 years. All patients experienced at least one gastrointestinal and general symptom. Arthralgia were reported in four patients (33%) and occurred on average six years before the onset of gastrointestinal and general symptoms. In 10 patients the initial treatment was trimethoprim-sulfamethoxazole. The initial treatment duration was one year in 8 cases (80%). Seven patients (70%) had a symptomatic resolution between the third and sixth months of antibiotic therapy, as well as an endoscopic and histological improvement. Even in these patients, there was maintenance of periodic acid Schiff positive macrophages, although in small number and with a more diffuse distribution. Gastrointestinal symptoms predominated in cases of clinical relapse. CONCLUSIONS: The gastrointestinal and general symptoms as well as the arthralgia were the predominant manifestations. The majority of patients showed clinical and endoscopic improvement in response to treatment with trimethoprim sulfamethoxazole. However, in these cases periodic acid-Schiff positive macrophages can remain for years. Thus, in the absence of clinical deterioration, the presence of these structures is not indicative ofactive disease. PMID- 26753380 TI - [Distal intramural spread of adenocarcinoma of the rectum after neoadjuvant therapy]. AB - BACKGROUND: The existence of microscopic tumor implants in the rectal wall, distal to the inferior edge of macroscopic tumor in rectal cancer (RC) (either in continuity with, or discontinuously) is called distal intramural spread (DIS). PATIENTS AND METHODS: Between March 2006 and June 2008, in the Instituto de Oncologia Angel H Roffo, Universidad de Buenos Aires, the frequency and distance of DIS was studied in 21 patients undergoing surgery for RC who received neoadjuvant therapy. The study was observational, descriptive, longitudinal and prospective. RESULTS: Median age was 64 years and 66.7% ofpatients were male. Stages pre-treatment were: I in 2 patients (9.5%), II in 9 (42.8%), III in 7 (28.6%), IV in 2 (14.3%), and x in 1 (4.8%). Twenty patients received neoadjuvant combined radiotherapy plus chemotherapy modality. One patient received only radiotherapy. Pathological stages were: 0 in 1 case (4.8%), I in 3 (14.3%), II in 6 (28.6%), III in 6 (28.6%), and IV in 2 (9.5%). Three patients (14.3%) hada complete pathological response. We found DIS in only one case (4.8%) at 9 mm of the macroscopic tumor edge. CONCLUSIONS: According to our experience and as recorded in the literature, we conclude that the DIS in RC is a rare phenomenon. The minimum distal margin to preserve must be at least 10 mm in the formalin fixed specimen. PMID- 26753382 TI - [Hydatidosis: Ultrasonographyc screening in the Rio Negro Province 25 years after the first screening]. AB - INTRODUCTION: Hydatidosis (cystic echinococcosis) is endemic in Rio Negro Province, Argentina. In 1980 started a control program against the disease. In 1984 Frider et al performed the first ultrasound screening in the world at Pilcaniyeu city, later extended to other localities of Rio Negro province. The initial prevalence in asymptomatic people was 7.1% in Pilcaniyeu and 10.1% in Comallo, being all new cases and with surgical indication. OBJECTIVE: The aim of this investigation was to determine the current prevalence and analyze the evolution of the disease across 25 years of the control program. MATERIALS AND METHODS: In 2009 and 2010 ultrasound screening studies were conducted in both locations in all age groups. RESULTS: In 512 ultrasound studies at Pilcaniyeu, the prevalence was 1.5% in children (6to 14years old) and 4.2% in adults (total 2.5%). In 770 ultrasound studies at Comallo, the prevalence was 1.1% in children and 66% in adults (total 3.0%). The overall reduction in the prevalence reached 67.2%. Regarding the age distribution, rates of 1.6%-1.9% were observed in Pilcaniyeu and of 1.0-1.9% in Comallo between 0 and 30 years old, increasing significantly above 10% after 60 years old in Pilcaniyeu and after 40years old in Comallo. CONCLUSIONS: The implementation of the program actions reduced the prevalence of the disease but there are still new cases, and that indicates that some bias persists in the control of the epidemiology of the disease and levels of transmission to humans as a consequence of this failures. So the search of asymptomatic cases is still important and also their management based on the follow-up by ultrasound (watch and wait) or in the treatment with albendazol. PMID- 26753381 TI - Anal squamous cell carcinoma in HIV/AIDS patients in the HAART era: Report of 8 cases and literature review. AB - BACKGROUND: Anal squamous cell carcinoma is a rare neoplasm with a higher incidence in the HIV-seropositive population. PATIENTS AND METHODS: Epidemiologic, clinic, immunologic, virologic and therapeutic characteristics of 8 HIV-positive patients with anal squamous cell carcinoma were descriptively and retrospectively analyzed from 2005 to 2011. RESULTS: Median of age ofpatients was 39 years, 75% were male and 83% were men who have sex with men. Median elapsed time from HIV infection to anal cancer diagnosis was 10.5 +/- 9.5 years. Anal pain and local large tumors detected by physical examination were the most common clinical manifestations; pain with or without itching was marginally correlated with poor survival. The median of CD4 T-cell countfor the whole study group was 330 cells/uL. At the time ofthe neoplasm diagnosis, CD4 T-cell count was more than 200 cell/uL in 62.5% of the patients. In the descriptive analysis, higher CD4 T-cell count was significantly associated with a prolonged survival. In the overall population, 71% were receiving highly active antiretroviral therapy (HAART) and all of them had undetectable viral load at the time ofneoplasm diagnosis. HAART was correlated with better survival in the overallpopulation. Histopathologic examination showed that 4 cases (50%) had in situ carcinoma and 4 patients (50%) had diagnosis of invasive anal carcinoma. One patient underwent surgical tumorectomy plus HAART, 2 patients received chemotherapy plus HAART and 3 patients were treated with fractionated radiotherapy plus systemic chemotherapy plus HAART. One patient died without the possibility of treatment due to his poor clinical condition and for one patient was no available data. After a follow up of 2 years, overall survival rate was 71%. CONCLUSION: A carefully evaluation of anal infiltrative or tumoral lesions is necessary to achieve an early diagnosis and to improve the survival in this kind of patients. PMID- 26753383 TI - Early predictors of renal dysfunction in cirrhotic patients after liver transplantation. AB - BACKGROUND: Assessment of renal function 12 months after liver transplantation (LT) predicts chronic renal failure on long-term follow up. OBJECTIVE: To evaluate pre- and post- LT factors associated with development of renal dysfunction (RD) in cirrhotic patients. METHODS: Between June 2005 and June 2010, 104 cirrhotic patients were selected from 268 consecutively transplanted adult patients. RD was defined as a calculated glomerular filtration rate (cGFR) < 50 ml/min/1.73m2 by modification of diet in renal disease (MDRD), 12 months after LT. RESULTS: Baseline pre-LT creatinine was 1.0 +/- 0.7 mg/dL and cGFR was 64 +/- 32.8 mL/min. At 12 month follow up, creatinine was 1.3 +/- 0.6 mg/dL and cGFR was 47 +/- 18 mL/min. The prevalence of RD was 55%. Variables related to RD on univariate analysis were age (P = 0.007), pre-L T GFR (P = 0.012) and 7th day post-L T GFR (P = 0.003). Risk factors associated with RD on multivariate stepwise regression analysis were patient age [Odds ratio (OR) 1.04 (95% confidence interval (CI) 0.99- 1.09, P = 0.06)] and 7 day post-LT GFR [OR 0.97 (95% CI 0.96-0.99, P = 0.013)]. ROC curve analysis for 7th day post-LT GFR was 0.71 (95% CI 0.61-0.81). CONCLUSION: The 7th day post-LT GFR in cirrhotic patients may be a useful clinical tool to identify which patients might benefit from earlier nephroprotective immunosuppression. PMID- 26753384 TI - [Mirizzi Syndrome: Prevalence, diagnosis and treatment]. AB - BACKGROUND: The Mirizzi syndrome was described by Pablo Luis Mirizzi in 1948, who emphasized this syndrome was characterized by the obstruction of the common hepatic duct due to mechanical compression caused by an impacted stone in the gallbladder neck or in the cystic duct. The incidence ranges from 0.05% to 4%. MATERIAL AND METHODS: We performed a retrospective cross-sectional study. Based on the database of the General Surgery Division of the Prof Alejandro Posadas National Hospital, between July 2007and June 2013, charts of all patients with biliary lithiasis disease operated in this period were analyzed. We analyzed the clinical features, the various diagnostic techniques and the treatment carried out in each of them. RESULTS: Surgery due to biliary lithiasis was performed in 2,160 patients. Fourteen patients, 8 females and 6 males, had Mirizzi syndrome (0.65%). The mean age was 55.3 years old (range 34-70 years old). Four patients were scheduled for elective surgery and 10 were operated during emergency. Preoperative differential diagnosis was: extrahepatic cholestasis 10, cholecystitis 3 and biliary duct stenosis vs gallbladder cancer 1. The treatments performed were: 3 conventional cholecystectomies with intraoperative dynamic cholangiography, 2 conventional cholecystectomies plus choledochoplasty with Kehr tube, 2 laparoscopic cholecystectomies plus choledochoplasty with Kehr tube, 1 partial cholecystectomy with Pezzer catheterization, 3 choledochoduodenostomy, 1 choledochoplasty with gallbladder remnant, 1 hepaticojejunostomy and 1 treatment in two steps (percutaneous biliary drainage and cholecystectomy). Regarding complications, we observed 1 autolimited leak from the choledocoduodenostomy, 1 death in an ederly patient, and 1 hepatic abscess treated by a minimaly invasive approach. CONCLUSIONS: Mirizzi syndrome is a disease with low prevalence, which must be taken into account in biliary surgery, because the treatment varies according to the intraoperative findings and the experience of the surgical team. PMID- 26753385 TI - [Paraneoplastic dermatomyositis as a clue to occult gallbladder carcinoma]. AB - Adult-onset dermatomyositis (DM) is an idiopathic inflam- matory myopathy frequently associated with underlying cancer, including gastrointestinal tumors. However, its as- sociation with carcinomas of the hepatobiliary tract is exceptional. We present a case of paraneoplastic DM occurring as the first and only clinical manifestation of an underlying carcinoma of gallbladder. PMID- 26753386 TI - [Prolonged survival after local excision of a rectal leiomyosarcoma]. AB - Leiomyosarcoma is a stromal tumor, originated from smooth muscle cells. The pathologic diagnosis represents a challenge in terms of differentiation from leiomyomas and gastrointestinal stromal tumors (GIST), defined by immunohistochemistry techniques. Its location in the rectum is extremely rare. So, management is not standardized. However, in the largest published series it was found that the abdominoperineal resection leads to better results in the prevention of local recurrence compared with local excision. We present here the case of a 44-year-old woman, whose first clinical manifestation of the disease was fever of prolonged course. A 5 cm leiomyosarcoma was diagnosed at 4 cm from the anal margin. A local transanal resection was performed. The patient is free of disease after 8 years. PMID- 26753388 TI - [Celiac sprue: A pictorial revision of main imaging findings]. AB - Celiac sprue (CS) is an autoinmune desease caused by gliadin intake. The exposure to this protein produces damage of the intestinal mucosae, primarily of the duodenum and yeyunum, causing different symptoms and diverse imaging findings. The objective of this review is to show a pictorial essay of the main findings of CS and its complications in barited fluroscopy, computed tomography and magnetic resonance. We show different images of patients with certified diagnosis of CS. In summary, these imaging modalities are useful for the diagnosis and follow up of patients with CS, as well as for the detection of complications. We believe that they are useful complementary exams that aid to the existing diagnosis criteria. PMID- 26753387 TI - [Rectal perforation after endoscopic submucosal dissection: conservative management]. AB - Endoscopic mucosal resection and surgery have been the treatments used for resection of early neoplastic colorectal lesions. However, since a few years ago the endoscopic submucosal dissection is a procedure accepted for the curative treatment of these lesions. Among the complications that can occur with this procedure, perforation is one of the most serious ones, requiring in most cases surgical management. A case is reported of a sixty-year-old male patient diagnosed with an extensive flat colorectal polyp, who underwent an endoscopic submucosal dissection, with the subsequent complications of a perforation with subcutaneous emphysema and extra peritoneal air. In conjunction with the surgical team, a decision was made to apply a conservative medical treatment based on suspension of the oral intake and antibiotic therapy, yielding good clinical and imaging evolution. PMID- 26753389 TI - [Thoughts on the Publication of "Physics of Nuclear Medicine"]. PMID- 26753390 TI - [The PET, Past and Future]. AB - Positron emission tomography (PET) is a unique nuclear medicine test using positron emitters such as 18F and 11C. In PET tests, various kinds of functional aspects of human bodies can be evaluated by using compounds labeled by these positron emitters. Recently, combined scanners of PET and anatomical imaging modalities such as CT and MRI have been developed and functional information with anatomical location can be easily obtained, increasing the usefulness of PET tests. PET tests are now essential imaging tools to diagnose various kinds of disease with functional abnormalities. In the field of oncology, 18F-fluorodeoxy glucose PET tests are routinely used in clinical practice under health insurance. In the field of neurology, PET tests are actively used to investigate cerebral function by labeled neurotransmitters and so on. Currently, brain PET tests to detect beta-amyloid are applied to the diagnosis of dementia. In the field of cardiology, cardiac perfusion and myocardial metabolism are quantitatively measured by using PET and obtained results have successfully revealed the pathogenesis of intractable cardiac diseases. Future technical advances will enhance the usefulness of PET tests more and more. PMID- 26753391 TI - [Current Status and Prospects on PET Radiopharmaceuticals for Radiotherapy]. AB - 18F-FDG is a most popular radiopharmaceutical for tumor diagnosis in the world. In addition, 11C-methionine, 18F-FLT and 11C-choline have been used to compensate for drawbacks of 18F-FDG. Now, novel radiopharmaceuticals are required to estimate or predict therapeutic efficacy because we have many strategies to treat tumors. Radiotherapy which damage DNA by producing free radicals is commonly used to treat various types of tumors. Hypoxia is closely associated with resistance to chemo- and/or radiotherapy and is a common feature of solid tumors. Recently, understanding of tumor hypoxia in oncology has led to development of radiopharmaceuticals for hypoxia imaging. This review provides an overview of PET radiopharmaceuticals for hypoxia imaging and 18F-FBPA which is used for boron neutron capture therapy. PMID- 26753392 TI - [Innovation and Future Technologies for PET Scanners]. AB - Positron emission tomography (PET) plays important roles in cancer diagnosis, neuroimaging and molecular imaging research; but potential points remain for which big improvements could be made, including spatial resolution, sensitivity and manufacturing costs. Higher spatial resolution is essential to enable earlier diagnosis, and improved sensitivity results in reduced radiation exposure and shortened measurement time. Therefore, research on next generation PET technologies remains a hot topic worldwide. In this paper, innovation and future technologies for the next generation PET scanners, such as time-of-flight measurement and simultaneous PET/MRI measurement, are described. Among them, depth-of-interaction (DOI) measurement in the radiation sensor will be a key technology to get any significant improvement in sensitivity while maintaining high spatial resolution. DOI measurement also has a potential to expand PET application fields because it allows for more flexible detector arrangement. As an example, the world's first, open-type PET geometry "OpenPET", which is expected to lead to PET imaging during treatment, is under development. The DOI detector itself continues to evolve with the help of recently developed semiconductor photodetectors, often referred to as silicon photomultipliers. PMID- 26753393 TI - [The Quality Assurance (QA) and the Quality Control (QC) of Positron Emission Tomography (PET) Image]. AB - Positron emission tomography (PET) is widely used for image diagnostics; making judgments for early diagnostics, differential diagnostics, staging and treatment effect. As for undertaking the large clinical trial and the multicenter study using several diagnostics, the quantitative standardization of PET images is important. We should maintain the safety and the accuracy of daily clinical images. Moreover, we have to develop a safety treatment manual for instruments, apparatus and radiopharmaceuticals in order to produce PET studies of the highest diagnostic accuracy. In addition, daily quality assurance (QA) and quality control (QC) are very important in order to achieve efficiency and safety of PET studies. The importance of the QA and the QC have been recognized from the view of clinical incident protection points. PET will become more advanced in the future, and therefore the QA and the QC for PET images will continue to important in our work. In the view-risk management, we should reaffirm the importance of both QA and QC. Furthermore, we underline the importance of the constant management system and organization in order to gain the quality enhancement of PET imaging. PMID- 26753394 TI - [Technical Approaches for Quantitative Treatment Responses Using 18F-FDG PET]. AB - Quantitative assessment of 18F-FDG PET can predict treatment responses or outcomes. Here, I briefly describe some world trends in standardizing PET images for image-based assessments of treatment responses, followed by present and future strategies for defining the optimal acquisition conditions for quantitative PET imaging. Finally, information is provided about new technical approaches to improving the quantitation of semi-quantitative indexes such as point spread function, time-of-flight and respiratory gating. PMID- 26753396 TI - [Introduction of the New Product: PET/CT [Discovery IQ]. PMID- 26753395 TI - [Application of the PET for Radiation Therapy]. AB - Because radiotherapy is local treatment, it is very important to define target volume and critical organs based on accurate lesion area. The PET using an index such as the SUV is quantifiable noninvasively with information of the molecular biology for individual case/lesion. In particular, PET with 18F fluorodeoxyglucose (FDG-PET) has been used for the diagnosis and treatment evaluation of various tumors. The radiation therapy based on PET enables the treatment planning that reflected metabolic activity of the lesion. The PET produce an error by various factors, therefore, we must handle the PET image in consideration of this error when apply PET to radiotherapy. PMID- 26753398 TI - [Series: Fundamental Electromagnetics for Beginners (2)]. PMID- 26753397 TI - [Series: Utilization of Differential Equations and Methods for Solving Them in Medical Physics (2)]. AB - In this issue, symbolic methods for solving differential equations were firstly introduced. Of the symbolic methods, Laplace transform method was also introduced together with some examples, in which this method was applied to solving the differential equations derived from a two-compartment kinetic model and an equivalent circuit model for membrane potential. Second, series expansion methods for solving differential equations were introduced together with some examples, in which these methods were used to solve Bessel's and Legendre's differential equations. In the next issue, simultaneous differential equations and various methods for solving these differential equations will be introduced together with some examples in medical physics. PMID- 26753399 TI - [Cell senescence and pathophysiology of chronic lung diseases: role in chronic obstructive pulmonary disease]. AB - Knowledge of the biology of cellular senescence has improved markedly in recent years, helping us to understand the aging process. It is now clear that cellular senescence is involved in the pathogenesis of many age-related diseases, including respiratory diseases such as chronic obstructive pulmonary disease (COPD). COPD occupies a special place among chronic respiratory diseases because of its frequency and socio-economic impact. The high morbidity and mortality associated with COPD are related to multiple systemic manifestations independent of the severity of airway obstruction. COPD, although most often due to smoking, is also an aging-related respiratory disease. According to a newly developed concept, lung-cell senescence could play a key role in the pathophysiology of COPD, including remodeling of blood vessels and lung parenchyma, as well as the characteristic inflammatory process. Systemic manifestations of COPD, including cardiovascular disease, weight loss, bone demineralization and muscle dysfunction, may reflect a general process of premature aging secondary to the pulmonary changes. PMID- 26753400 TI - [Kidney aging: a predictable and partly avoidable fragility]. AB - The 9th World Kidney Day, on 13 March 2014, was devoted to the topic of renal aging. The proportion of older people in the general population is increasing steadily worldwide, with the most rapid growth in developing countries. This demographic upheaval is a consequence of socioeconomic development and increasing life expectancy. Chronic kidney disease is an important public health problem characterized by poor health outcomes and very high healthcare costs. Chronic kidney disease is a major risk multiplier in patients with diabetes, hypertension, heart disease and stroke, all of which are key causes of death and disability among older people. The prevalence of chronic kidney disease is higher in the elderly, in whom it contributes to the effects of aging. The decrease in renal function with age also compounds the effects of renal disease, whether primary or secondary to systemic or urinary tract disorders. This physiological reduction in functional capacity affects the glomerular filtration rate and renal tubular functions, including water and salt regulation and also the elimination of many drugs. The aging kidney is much more sensitive to toxic insults, especially those due to nonsteroidal antiinflammatory drugs and iodinated contrast agents. Prevention of renal deterioration in the elderly is based on monitoring renal function, adapting medications, and maintaining a regular supply of water and salt. PMID- 26753401 TI - [Medical accountability: current elements]. AB - In 2002, a new law significantly modified the legal treatment of medical accidents in France, encouraging dialogue and conciliation rather than litigation. Specific structures were created to settle disputes without recourse to the judiciary system. A mechanismfor national solidarity was also created in order to indemnfy some victims. More than ten years later the number of court cases has diminished but vigilance is still required, notably because of the increasingly large sums awarded to victims of medical accidents. PMID- 26753402 TI - [Presentation of the Commissions of Compensation and Redress]. PMID- 26753403 TI - [Malpractice recent Case Law]. PMID- 26753404 TI - [The Public Health Center confronting technical litigation and multi-victim crimes]. AB - The Public Health division of the criminal court is provided with specific means to conduct special investigations into cases involving complex, technical matters and a large number of victims. PMID- 26753405 TI - [Is medical imaging iatrogenic?]. AB - Imaging is an indispensable element of modern medicine but is not without risk. Low-dose irradiation due to spinal, abdominal, pelvic or cardiac radiography, and the increasing use of CT carries an additional, albeit moderate risk of cancer. Iodinated and gadolinium-containing contrast media, besides their direct toxicity, can trigger hypersensitivity and allergic-like reactions. Spinal and articular diagnostic injections can also lead to complications. This article reviews the direct iatrogenicity of diagnostic imaging and current efforts to limit it through the use of new radiological systems, lower-dose CT non ionic contrast media, and alternative imaging techniques. The authors also examine the less known but more frequent problem of indirect iatrogenesis, which is highly dependent on the quality of the imaging personnel and technique. Finally, we propose some legislative solutions to this problem. PMID- 26753406 TI - [The implementation gap in asthma prevention and control?]. AB - Asthma and allergic diseases generally start early in life and persist throughout life but, for reasons we do not yet understand, they sometimes appear later Prevention, early diagnosis and treatment of these major chronic respiratory diseases is a recognized priority for EU public health policy and for the United Nations. As factors favoring allergy (rapid urbanization, pollution, climate change and infections) are not expected to change in the foreseeable future, it is crucial to develop, strengthen and optimize prevention and treatment. We have developed tools to control asthma but are still unable to prevent children from developing asthma and allergic diseases. This article examines what works and what does not, and analyzes the "missing links" between the creation and effective implementation of a prevention program, otherwise known as the implementation gap. PMID- 26753407 TI - [Alpha-1 antitrypsin deficiency 50 years later]. AB - Alpha-1 antitrypsin deficiency is a frequent genetic disorder associated with pulmonary emphysema in smokers and with liver cirrhosis. Aside from lung or liver transplantation, only replacement therapy can currently slow the progression of emphysema. Progress in the pathogenesis of this disorder (protein misfolding, RER aggregation) is opening the way to new strategies such as proteostasis control. Alpha-1 antitrypsin deficiency remains poorly known and underdiagnosed. PMID- 26753408 TI - [Oncologic outcome of 11.6 lipofilling procedures for reconstructive breast surgery]. AB - AIMS OF THE STUDY: Autologous fat graft injection has been systematically used by our team since 2001 in order to enhance the esthetic outcome of breast reconstruction. However, this technique remains controversial, notably in France. This study evaluated oncologic outcomes at 3 years among 110 patients operated on and monitored by two surgeons. PATIENTS AND METHODS: 116fat graft injections in 110 patients who required reconstructive breast surgery between January 2001 and December 2011 were included in the analysis of oncologic outcomes. The AJCC (American Joint Committee on Staging) stages were: stage 0 (18 %), stage I (44 %), stage II (26.7 %), and stage III (11.3 %). Mean follow-up was 6.3 years (9 months to 17 years) after initial breast cancer surgery, and 3 years (6 months to 9.5 years) after the last lipofilling procedure. RESULTS: The majority of patients (91.8 %) are alive and recurrence-free. Remote metastases occurred in 8.2 % of patients: one patient had a local and systemic recurrence, one patient had a local, regional and systemic recurrence. CONCLUSION: Although confirmation is needed from multicenter randomized trials with longer follow-up, a larger group of patients and a control group matched for the cancer status of the lipofilling group, our results support the view that lipofilling has little or no effect on the risk of locoregional recurrence of breast cancer. PMID- 26753409 TI - [Results and lessons after 10 years of universal neonatal hearing screening in the Champagne-Ardenne region of France]. AB - In France, universal newborn hearing screening has been mandatory since April23rd, 2012, but it began in the Champagne-Ardenne region on January 15th 2004. More than 99 % of 160 196 newborns have since been systematically screened in this region. Bilateral hearing impairment was thus identified in 116 infants when they were around 3.5 months old. Earlier diagnosis improves the outcome of deafness, which is only diagnosed around age 20 months without screening. The authors report their experience and the lessons learnt. PMID- 26753411 TI - [Pregnancy: a model of prevention of HIV transmission]. AB - Antiretroviral drugs are primarily used to treat people living with HIV but can also reduce the risk of transmission. The first application of this prophylactic approach was in the prevention of mother-to-child transmission, which comprises three components: 1) antiretroviral therapy during pregnancy to reduce maternal viral load, 2) pre-exposure prophylactic treatment of the fetus in utero and intrapartum, and 3) postexposure neonatal treatment. This has resulted in a sharp reduction in mother-to-child transmission, to well below 1 % in France today. "Treatment as prevention" (TASP) is now widely recommended to prevent sexual transmission to partners of people living with HIV articularly when a couple wishes to have children. Achieving and sustaining undetectable viral load is an important means of reducing the risk of sexual transmission in serodiscordant couples and also of controlling the pandemic worldwide. The other uses of antiretroviral drugs to protect HIV-negative people at risk include post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP). Prevention has both individual and collective dimensions and involves several components, including behavioral changes, serological testing, and use of antiretrovirals. PMID- 26753410 TI - [HLA-G: from feto-maternal tolerance to organ acceptance]. AB - HLA-G is a nonclassical class I molecule that differs from classical antigens by its restricted expression, very low polymorphism, expression of 7 different protein isoforms, and immune tolerance-inducing activity. HLA-G plays a key role in feto-maternal tolerance. Its interaction with three specific receptors expressed on immune cells (T, B, natural killer and antigen-presenting cells) allows it to act at all levels of the immune response. HLA-G can also be expressed by tumor cells and their microenvironment, endowing them with significant local tolerance. The same is true in some inflammatory and viral diseases. PMID- 26753412 TI - [Risks associated with unrestricted consumption of alkaline-reduced water]. AB - Consumption of alkaline reduced water produced by domestic electrolysis devices was approved in Japan in 1965 by the Minister of Health, Work and Wellbeing, for the treatment of gastrointestinal disorders. Today, these devices are also freely available in France. The commercial information provided with the devices recommends the consumption of 1 to 1.5 liters per day, not only for gastrointestinal disorders but also for numerous other illnesses such as diabetes, cancer and inflammation. Academic research on this subject has been undergoing in Japan since 1990, and has established that the active ingredient is dissolved dihydrogen, which eliminates the free radical HO. in vivo. It has also been shown that electrode degradation during use of the devices releases highly reactive platinum nanoparticles, the toxicity of which is unknown. The authors of this report recommend alerting the French health authorities to the uncontrolled availability of these devices that generate drug substances and should therefore be subject to regulatory requirements. PMID- 26753414 TI - [Domestic violence: any progress?]. AB - Since the publication of the French national survey of violence against women in 2000, the fight against domestic violence has made steady progress. Knowledge of the phenomenon has significantly improved. A nationwide study of murders and manslaughters perpetrated by one partner of a couple against the other has been published annually since 2006. In 2012, domestic violence resulted in the deaths of 314 persons: 166 women, 31 men, 25 children, 9 collateral victims, 14 rivals, and two former spouses killed by their ex-fathers in law. In addition, 67 perpetrators committed suicide (51 men and3 women). The number of victims fluctuates from year to year but has remained fairly stable since 2006 (n=168). Legislation has improved significantly: eight new laws have been passed since 2004, all designed to protect women and to ensure that violent men are restrained and treated. New measures to inform and protect women have been implemented and others have been improved, such as the anonymous helpline (phone no 3919, "domestic violence information"). An inter-ministerial committee on the protection of women from violence and the prevention of human trafficking (MIPROF) was created on 3 January 2013. A website entitled "Stop violence against women " (Stop violences faites aux femmes) is now available. The "Imminent Danger" mobile phone system, designed to alert police if a suspected or known perpetrator breaches restraint conditions, will be extended to the entire country from January 2014. Referees charged with coordinating comprehensive long-tern care of women victims have been deployed at the county level. Information centers on the rights of women and families (CIDFF) now form a local nationwide network. Routine interviews with a midwife during the fourth month of pregnancy, focusing on the woman's emotional, economic and social conditions, have been implemented in 21 % of maternity units and should gradually be generalized. The authorities who have enforced the law have modified their behavior, as have the victims, although for a lesser extent. Perpetrators are increasingly subject to restraining orders, with an obligation to undergo treatment and to attend awareness sessions. Victims are also more likely to go to the police. Social workers, self-help groups and, since 2006, psychologists are now available for victim support in police stations. Management of perpetrators has improved. Finally, despite the continuing reluctance of many physicians, an encouraging trend is emerging among younger members of the profession. A recent survey of 1472 French medical students showed that, while 90 % of them said they had received no training in this area, 93 % considered that doctors should play a role and 95 % said they felt highly concerned. Specific university diplomas have been created and domestic violence is now included in the midwifery curriculum. The delicate question of prevention remains to be resolved; a program is currently being tested. PMID- 26753413 TI - [Antidepressants do prevent suicide, at least pending something better...]. AB - Suicide is a major public health problem worldwide, with about 1.5 million deaths each year France ranks 7th in the EU Patients with depression account for the majority of completed suicides. As most of these individuals are not adequately treated, it is conceivable that better treatment of depression would reduce suicide mortality. However, the last ten years have seen a controversy over a possible suicidogenic effect of antidepressants. Here we summarize data from the different types of studies that have cast a shadow over these drugs which can save lives when used effectively to treat depression. Better knowledge of the pathophysiology of "suicidal behaviour disorder" should identify therapeutic targets for innovative agents capable of preventing suicide. PMID- 26753415 TI - [Development of Human Health Discoveries. 10 years results of Young Innovative Company incubation]. AB - Medicine is evolving every day in its operating procedures and the services offered to patients, emphasizing personalized medicine, safety and medical benefits. The individual patient is more than ever the hub of healthcare organization. Medical innovation is thus a public health priority. However it requires an accurate assessment of medical utility and risk-benefit ratios, and in-depth analysis of economic and organizational impacts. Ten years of experience in the Paris Biotech Sante company incubator has identified key actions for effective support of research projects and the success of innovative companies. Strong expertise is needed to prepare development plans, ensure compliance with regulatory requirements and obtain research funding. During its first decade, this incubator has created 87 innovative companies employing 1500 people, raised more than 90 million euros of funding, and reached a cumulative company value of 1200 million euros. Key factors of success have been identified, but an analysis of the causes of failure shows that operational adjustments are mandatory, particularly a strong commitment from medical experts, in order to promote access to new and useful products for patients while at the same time assessing their social impact. PMID- 26753416 TI - [Surrogate pregnancy with regard to marriage between persons of the same sex]. AB - After first defining surrogacy, distinguishing between cases in which the pregnancy results from the surrogate's own egg or a donor egg, and examining the different configurations of male homosexual families, the authors outline French and foreign legislation and provide a summary of the literature and of French working group hearings. Arguments for and against lifting the ban on surrogacy for gay couples are examined. The main arguments for lifting the ban are the following: 1) the same-sex couple's desire to start a family from their own gene pool, 2) current obstacles to adoption, 3) the notion of equality between heterosexual and homosexual couples, 4) frequent recourse to surrogacy abroad, which is not only very costly but also leaves the child in a state of legal limbo on its return to France, and 5) the lack of access to therapeutic alternatives. Some arguments against lifting the ban are of a medical nature: (1) physical and psychological risks for the surrogate, 2) the fact that exchanges between the mother and fetus during pregnancy are more complex than previously thought (microchimerism, epigenetics) and never negligible, and 3) the physical and psychological risks for the child. Other arguments are of an ethical nature: 1) surrogacy may undermine the status of motherhood, 2) surrogacy is becoming a societal rather than a medical issue, implying a profound bioethical upheaval, 3) the increasing commercialization of the human body, 4) subjugation of women to men's desires, 5) the risks for the surrogate's own couple and children, and for the host couple, 6) unavoidable financial aspects, and (7) the risk of abuse. The aim of this study is to bring together all the factors potentially influencing the health consequences of surrogacy, for both the mother and the child, especially if surrogacy were to be legalized for male homosexual couples. Surrogacy raises issues far beyond purely medical considerations and is primarily a societal issue that must be settled by the legislator: Short-term and especially long-term physical and psychological risks, particularly for the child, are poorly documented. If it is decided to legalize surrogacy, then a rigorous, objective and strictly regulated program must be set up to assess the related risks. PMID- 26753417 TI - [Extension of assisted reproductive technologies with donor sperm (ARTD) to non medical indications]. AB - In France as in other countries, more and more single women and lesbian couples wish to become mothers. To carry through their parenting project they may consult a physician in France and often go abroad in order to get Assisted Reproductive Technologies with donor sperm (ARTD). Should ARTD be available to those women in France? The physician has not to take the decision. In such situations ARTD has no medical indication or contraindication. This assisted procreation raises many questions on children development and well-being. The results of studies made in other countries are often reassuring but their methodologies do not allow any conclusion to be drawn and grey areas persist. Therefore it should be necessary to develop a research effort in the field as it recently started in France. Would ARTD access to women without a male partner be legalized, the law should respect the ethical principles of non-payment and anonymity associated with donation of all body components. In any case, it should also allow an efficient medical care to be performed to ensure under the best conditions the well-being of the children and their mothers. PMID- 26753419 TI - I Am Nurse, Hear Me Roar. PMID- 26753418 TI - Caring for You, the Nurse, Is Required, Not Optional. PMID- 26753420 TI - American Cancer Society Recommends Fewer Mammograms. PMID- 26753421 TI - Palliative Care Consultation Lowers Hospital Costs. PMID- 26753422 TI - New Drug Proves Effective in Treatment of Advanced Kidney Cancer. PMID- 26753423 TI - Compassionate Care Fosters Resiliency. PMID- 26753424 TI - Rhythms of the NIGHT SHIFT. With a Schedule for Sleep, Any Nurse Can Be Successful on the Night Shift. PMID- 26753425 TI - How Does Shift Work Impact Cancer Screening? PMID- 26753426 TI - STOP Bullying and Encourage Civility in the Workplace. PMID- 26753427 TI - How Did You Overcome Horizontal Violence in the Workplace? PMID- 26753428 TI - As Healthcare Costs Continue to Rise, Providers Weigh Care's Expense and Effect. PMID- 26753429 TI - The Case of Developing Delirium. PMID- 26753430 TI - The Critical Role of Nurses in the Care of Patients With Multiple Myeloma. PMID- 26753431 TI - Residential Exposure to Pesticides Tied to Childhood Cancers. PMID- 26753432 TI - The top echorich band in a 50-MHz ultrasound sonogram reflects epidermal properties. AB - High-frequency ultrasonography is a useful noninvasive tool to measure the acoustic properties of skin. Due to the ambiguity or confusion over the meaning of the skin entry echo, measurements have been limited to the dermis or full skin thickness with little data on epidermal properties. The purpose of this study was to better understand the nature of the skin entry echo and determine whether it is related to epidermal structure. We approached the problem by dampening the sudden change in material density from the coupling medium to the skin surface using facial tissue as a masking material. The thickness and acoustic density of bare and masked skin sites were measured using dermal ultrasound with a 50-MHz transducer. Results showed that the original thickness and acoustic density of the skin entry echo did not change when the skin was masked up to two layers. A comparison between the epidermal thicknesses measured using ultrasound and confocal microscopy also indicated that the two methods yielded about the same results with no statistically significant difference detected. This study demonstrates that the purported skin entry echo is not just a meaningless artifact, and it reflects useful properties of epidermal structure. PMID- 26753433 TI - Equivalence evaluation of moisturizers in atopic dermatitis patients. AB - Skin care with moisturizers to compensate for dry skin and decreased barrier function, and to prevent recurrence of inflammation is thought to be very important for management of atopic dermatitis. However, many patients cannot continue the use of moisturizing medications because of unpleasantness. Cosmetics may be able to compensate for such deficiencies. To evaluate the usefulness of cosmetics in maintenance of the skin in remission, we conducted a clinical trial using moisturizing cosmetics of a phospholipid preparation that showed good moisture-retaining effect in dry skin. The utility of moisturizing cosmetics was evaluated by skin findings, subjective symptoms, adverse events, moisture content of the stratum corneum, transepidermal water loss (TEWL), and a questionnaire on feel of use in comparison with a heparinoid preparation as a control product. Degree of improvement in skin findings, dryness and desquamation score, pruritus score, TEWL, and moisture content were nearly the same as with the control product. The result indicated that the moisturizing cosmetic was of equivalent effect compared with the heparinoid control preparation. PMID- 26753434 TI - Twelve-hour skin hydration after a single application of a lamellar moisturizer. PMID- 26753435 TI - Risk assessment of allergen metals in cosmetic products. AB - Cosmetics are one of the most common reasons for hospital referrals with allergic contact dermatitis. Because of the increased use of cosmetics within the population and an increase in allergy cases, monitoring of heavy metals, especially allergen metals, is crucial. The aim of this study was to investigate the concentration of allergen metals, nickel (Ni), cobalt (Co), and chromium (Cr), in the most commonly used cosmetic products including mascara, eyeliner, eye shadow, lipstick, and nail polish. In addition, for safety assessment of cosmetic products, margin of safety of the metals was evaluated. Forty-eight makeup products were purchased randomly from local markets and large cosmetic stores in Istanbul, Turkey, and an atomic absorption spectrometer was used for metal content determination. Risk assessment of the investigated cosmetic products was performed by calculating the systemic exposure dosage (SED) using Scientific Committee on Consumer Safety guideline. According to the results of this investigation in all the samples tested, at least two of the allergen metals, Ni and/or Co and/or Cr were detected. Moreover, 97% of the Ni-detected products, 96% of Cr- and 54% of Co-detected products, contained over 1 MUg/g of this metals, which is the suggested ultimate target value for sensitive population and thereby can be considered as the possible allergen. On the basis of the results of this study, SED of the metals was negligible; however, contact dermatitis caused by cosmetics is most probably due to the allergen metal content of the products. In conclusion, to assess the safety of the finished products, postmarketing vigilance and routine monitoring of allergen metals are very important to protect public health. PMID- 26753436 TI - Computer-Aided Diagnosis of Parkinson's Disease Using Complex-Valued Neural Networks and mRMR Feature Selection Algorithm. AB - Parkinson's disease (PD) is a neurological disorder which has a significant social and economic impact. PD is diagnosed by clinical observation and evaluations, coupled with a PD rating scale. However, these methods may be insufficient, especially in the initial phase of the disease. The processes are tedious and time-consuming, and hence systems that can automatically offer a diagnosis are needed. In this study, a novel method for the diagnosis of PD is proposed. Biomedical sound measurements obtained from continuous phonation samples were used as attributes. First, a minimum redundancy maximum relevance (mRMR) attribute selection algorithm was applied for the identification of the effective attributes. After conversion to a complex number, the resulting attributes are presented as input data to the complex-valued artificial neural network (CVANN). The proposed novel system might be a powerful tool for effective diagnosis of PD. PMID- 26753437 TI - A Fuzzy-Based Decision Support Model for Selecting the Best Dialyser Flux in Haemodialysis. AB - Decision making is an important procedure for every organization. The procedure is particularly challenging for complicated multi-criteria problems. Selection of dialyser flux is one of the decisions routinely made for haemodialysis treatment provided for chronic kidney failure patients. This study provides a decision support model for selecting the best dialyser flux between high-flux and low-flux dialyser alternatives. The preferences of decision makers were collected via a questionnaire. A total of 45 questionnaires filled by dialysis physicians and nephrologists were assessed. A hybrid fuzzy-based decision support software that enables the use of Analytic Hierarchy Process (AHP), Fuzzy Analytic Hierarchy Process (FAHP), Analytic Network Process (ANP), and Fuzzy Analytic Network Process (FANP) was used to evaluate the flux selection model. In conclusion, the results showed that a high-flux dialyser is the best. option for haemodialysis treatment. PMID- 26753438 TI - An Electronic Healthcare Record Server Implemented in PostgreSQL. AB - This paper describes the implementation of an Electronic Healthcare Record server inside a PostgreSQL relational database without dependency on any further middleware infrastructure. The five-part international standard for communicating healthcare records (ISO EN 13606) is used as the information basis for the design of the server. We describe some of the features that this standard demands that are provided by the server, and other areas where assumptions about the durability of communications or the presence of middleware lead to a poor fit. Finally, we discuss the use of the server in two real-world scenarios including a commercial application. PMID- 26753440 TI - Integration of Value Stream Map and Healthcare Failure Mode and Effect Analysis into Six Sigma Methodology to Improve Process of Surgical Specimen Handling. AB - Specimen handling is a critical patient safety issue. Problematic handling process, such as misidentification (of patients, surgical site, and specimen counts), specimen loss, or improper specimen preparation can lead to serious patient harms and lawsuits. Value stream map (VSM) is a tool used to find out non value-added works, enhance the quality, and reduce the cost of the studied process. On the other hand, healthcare failure mode and effect analysis (HFMEA) is now frequently employed to avoid possible medication errors in healthcare process. Both of them have a goal similar to Six Sigma methodology for process improvement. This study proposes a model that integrates VSM and HFMEA into the framework, which mainly consists of define, measure, analyze, improve, and control (DMAIC), of Six Sigma. A Six Sigma project for improving the process of surgical specimen handling in a hospital was conducted to demonstrate the effectiveness of the proposed model. PMID- 26753439 TI - Comparison of Traditional and Open-Access Appointment Scheduling for Exponentially Distributed Service Time. AB - This paper compares the performance measures of traditional appointment scheduling (AS) with those of an open-access appointment scheduling (OA-AS) system with exponentially distributed service time. A queueing model is formulated for the traditional AS system with no-show probability. The OA-AS models assume that all patients who call before the session begins will show up for the appointment on time. Two types of OA-AS systems are considered: with a same-session policy and with a same-or-next-session policy. Numerical results indicate that the superiority of OA-AS systems is not as obvious as those under deterministic scenarios. The same-session system has a threshold of relative waiting cost, after which the traditional system always has higher total costs, and the same-or-next-session system is always preferable, except when the no-show probability or the weight of patients' waiting is low. It is concluded that open access policies can be viewed as alternative approaches to mitigate the negative effects of no-show patients. PMID- 26753441 TI - Examining the Factors Affecting PDA Acceptance among Physicians: An Extended Technology Acceptance Model. AB - This study aims at identifying the factors affecting the intention to use personal digital assistant (PDA) technology among physicians in Turkey using an extended Technology Acceptance Model (TAM). A structural equation-modeling approach was used to identify the variables that significantly affect the intention to use PDA technology. The data were collected from 339 physicians in Turkey. Results indicated that 71% of the physicians' intention to use PDA technology is explained by perceived usefulness and perceived ease of use. On comparing both, the perceived ease of use has the strongest effect, whereas the effect of perceived enjoyment on behavioral intention to use is found to be insignificant. This study concludes with the recommendations for managers and possible future research. PMID- 26753442 TI - Equipment and Energy Usage in a Large Teaching Hospital in Norway. AB - This article presents a study of how equipment is used in a Norwegian University hospital and suggests ways to reduce hospital energy consumption. Analysis of energy data from Norway's newest teaching hospital showed that electricity consumption was up to 50% of the whole-building energy consumption. Much of this is due to the increasing energy intensity of hospital-specific equipment. Measured power and reported usage patterns for equipment in the studied departments show daytime energy intensity of equipment at about 28.5 kBTU/ft2 per year (90 kWh/m2 per year), compared to building code standard value of only 14.9 kBTU/ft2 (47 kWh/m2 per year) for hospitals. This article intends to fill gaps in our understanding of how users and their equipment affect the energy balance in hospitals and suggests ways in which designers and equipment suppliers can help optimize energy performance while maintaining quality in the delivery of health services. PMID- 26753443 TI - 35th Anthropology and Health Meeting: "The convergence of anthropological subfields in research on health and illness: cultural, biological, archaeological, and linguistic factors" August 4th - 9th 2014, Dubrovnik, Croatia. PMID- 26753444 TI - Global Health, Medical Anthropology, and Social Marketing: Steps to the Ecology of Collaboration. AB - Anthropology and global health have long been a focus of research for both biological and medical anthropologists. Research has looked at physiological adaptations to high altitudes, community responses to water-borne diseases, the integration of traditional and biomedical approaches to health, global responses to HIV/AIDS, and more recently, to the application of cultural approaches to the control of the Ebola epidemic. Academic anthropology has employed theory and methods to extend knowledge, but less often to apply that knowledge. However, anthropologists outside of the academy have tackled global health issues such as family planning and breast-feeding by bringing together applied medical anthropology and social marketing. In 2014, that potent and provocative combination resulted in the University of South Florida in Tampa, Florida being made the home of an innovative center designed to combine academic and applied anthropology with social marketing in order to facilitate social change. This article discusses how inter- and intra-disciplinary research/application has led to the development of Florida's first World Health Organization Collaborating Center (WHO CC), and the first such center to focus on social marketing, social change and non-communicable diseases. This article explains the genesis of the Center and presents readers with a brief overview, basic principles and applications of social marketing by reviewing a case study of a water conservation project. The article concludes with thoughts on the ecology of collaboration among global health, medical anthropology and social marketing practitioners. PMID- 26753445 TI - To a Deeper Understanding of Loneliness amongst Older Irish Adults. AB - Loneliness can play a significant role in the wellbeing of older adults. This article describes a qualitative method for using case notes from the clinical records of older individuals in order to investigate the priority concerns spontaneously reported by older adults to deepen our understanding of both the context in which reported loneliness occurs in Ireland and the potential triggers. The participants in this study represent a cross-section of older adults who participated in the Technology Research for Independent Living Clinic (TRIL). Data were collected from participants through interviewer case notes at the TRIL centre in St James's hospital, Dublin. 624 participants (431 females; 193 males) ranging in age from 60-92 years (Mean 73 years, SD 7 years) took part in the study. All were community dwelling and provided consent. A thematic analysis from grounded theory was used to evaluate the case notes for each participant. Preliminary results highlight the richness of phenomenological experience to enhance our understanding of loneliness and provide an opportunity to better understand the precursors and variability that loneliness may take. In this study we found themes in the case note analysis linking social loneliness with self-imposed limitations on social engagement due to declining health while predominate themes for emotionally lonely focused on psychological issues of stress and anxiety associated with adverse life events. The results suggest the importance of case notes to inform clinical practice. Qualitative results provided insights into differing live events of older Irish adults, which help distinguish the causal differences between social and emotional loneliness. PMID- 26753446 TI - Correlates of Frailty among Aging Residents of Upper Selska Valley Villages under Ratitovec Mountain. AB - Frailty, multi-system dysregulation following multiple life stressors, is associated with age and vulnerability to negative health. Our model posits that variables such as age and sex affect biocultural changes resulting from lifestyle and alter frailty. We assessed frailty with a four-factor index. We expand understanding of frailty by examining associations with demographic, health, and lifestyle factors in a Slovenian sample. Between 2008 and 2009, 40 residents of the Selska Valley, Slovenia aged 55 to 85 years (X = 72, SD = 7.24) participated in physical assessments, responded to the SF-36, and self-reported their own and family history of non-communicable diseases. Participants included 26 women (age 59-86) and 14 men (age 57-82). We used linear regression and t-tests to assess associations of these factors with frailty. Frailty was significantly positively associated with age, sex, length of residence in the village, and multiple self reported health factors. Conversely, frailty was significantly negatively associated with height and showed a borderline significant association with diastolic blood pressure. Controlling for age and sex, significant associations remained between frailty and self-reports of health, along with painful and reduced activity levels. Frailty also interacts with lifestyle factors. Results suggest the model proposed by Walston and colleagues (2005) is a valid cross cultural measure of frailty. PMID- 26753447 TI - Sharing Wisdom(s) to Enrich Knowledge: Working in a Transdisciplinary Research Team in Medical Anthropology. AB - This paper explains our experience working in a transdisciplinary research team focused on adolescence mental health. It introduces briefly the two key theoretical concepts: participation and transdisciplinarity. In order to be followed with a deep description of the methodology and the creation of the two principal materials resulting from our research: a guide of best practices in adolescent mental health, and a documentary film. Showing in a practical way how the research could be enhanced by the sharing of knowledge. PMID- 26753448 TI - An Alternative Analysis of the Discourse by Descartes, Kant and Hegel in terms of the Ethical Structure of the Kanun. AB - The ethical structure of the Albanian customary code, the Kanun, is deemed to represent the ethical value system of a society without state power. In spite of the appearance of civilizations and the resultant advent of an incipient state power, humans seemed to have known only the ethical value system of a society without state power until Gotama, Socrates, Plato and Jesus proposed new religious and philosophical doctrines. The basic trait of these religious and philosophical doctrines, which try to antagonize the ethical value system of a society without state power by eliminating the emotional aspect of humanity from the ethical value system, has been inherited by western philosophers such as Descartes, Kant and Hegel. The discourses by Descartes, Kant and Hegel were reviewed while paying attention to how they dealt with the sensuous and emotional aspects of humanity. The metaphysical implications of the ethical structure of the Kanun surfaced through the critical reviewing of their philosophy, and a hypothesis concerning its origin was presented. PMID- 26753449 TI - Gender Differences in Validity Scales of Personality Measuring Instruments in Psychiatric Patients. AB - The main goal of the study was to determine gender differences in validity scales of personality measuring instruments, among the psychiatric patients. Additional goals are to find the differences among male and female psychiatric patients, in relation to their age group, education level and type of psychiatric diagnosis. A total of 331 male and 331 female participants (psychiatric patients) are examined, classified by the categories of diagnosis, as following: Schizophrenia, schizotypal and delusional disorders (F20-F29), Mood (affective) disorders (F30 F39); Neurotic, stress-related and somatoform disorders neurotic, (F40-F48) and Disorders of adult personality and behavior (F60-F69). Four control scales are applied: Lie Scale (MMPIL or L scale), Scale of bizarre and confusing thinking (MMPIF or F scale) K scale of Defensiveness (MMPIK), together with Bias-scale in Plutchik's Emotion Profile Index (EPI). Three-factorial MANOVA was used in the analysis of the main effects, while non-parametric tests in the analysis of differences for each independent variable. Results reflect characteristic statistically significant gender differences in validity scales of personality measuring instruments, in most of the independent variables (the main effects are found for the level of education and age group). These results were interpreted within the theoretical framework of simulation and dissimulation. PMID- 26753450 TI - General Characteristics of Newborn from the Area of Tuzla Canton, Born in the Course of 2007. AB - The paper examined the basic anthropometric characteristics, birth weight and birth length of newborns, from the Tuzla Canton (TC) born during 2007. The study is a retrospective study in which data from the book of protocol of the Obstetrics and Gynecology Clinic - University Clinical Center Tuzla (OGC UCC). There were 4057 births in which 4125 babies were born in the OGC UCC Tuzla between 01 January and 31 December 2007. Of the total number, there were 29 stillborn (0.7%), of which 16 boys and 13 girls. There was 4,096 (99.3%) live born, of which 2,123 (51.83%) boys and 1973 (48.17%) girls. On every 100 girls 108 boys were born. Average values of the observed parameters in the total sample of infants were the following: birth weight 3387.17g; birth length 52.83cm; age of the mother was X(sr) = 26.49 years, and the average order of birth is 1.61. Birth weight in the total sample of male infants ranged from minimal 1130g to 5150g maximum. The average value of birth weight of male newborns was 3443.47g and female 3326.38g. The birth length of male infants in the total sample ranged from minimal 35 cm to 62 cm maximum and average value of the birth length reached 53.16 cm. Infants with low birth weight, hypotrophic newborns, born 123 or 6.24%. There were 1659 or 84.22% eutrophic infants born. There were 188 or 9.54% of high birth weight infants, hypertrophic infants, born. Male infants were more likely hypertrophic than female. PMID- 26753451 TI - The Acceleration of Birth Weight and Birth Length of Hypotrophic and Hypertrophic Newborns from Tuzla Canton from 1976 to 2007. AB - The acceleration or secular changes are long-term systematic changes across a broad spectrum of anthropological variables in successive generations of the population living in the same territory. The phenomenon can be seen in the size of newborns in the period of childhood and early youth, but also at the population level. The research used the data from the book of protocols, from the Departament of Gynecology and Obstetrics, University Clinical Centre in Tuzla. The sample taken from 19312 newborns (10037 boys, or 51.97%, and, 9275 girls, or 48.03%) was composed of four sub-samples of newborns of both sexes, as follows: sub-samples of infants between 01 January and 31 December of the following calendar years: 1976, 1987, 1997 and 2007. The aim of this research paper is to determine the acceleration of birth weight and birth length of hypotrophic (birth weight less than 2500g) and hypertrophic infants (birth weight greater than 4000g) of both sexes in Tuzla Canton, in four time points. On the basis of mathematical-statistical methods, the acceleration of the birth weight of the total sample of hypotrophic neonates with negative values, ranged from -21.39 g / decade and -2.48 g / dec in hypertrophic newborns. The acceleration of birth length of hypotrophic infants in the total sample was 0.14 cm / decade, and in hypertrophic 0.62 cm / decade. Conclusion: it is presumed that this secular change was caused by massive and violent population migrations during the 1992 1996 war in Bosnia and Herzegovina, when there was a change in the genetic composition of the local population. PMID- 26753452 TI - Generic Medicines in Croatia--Regulatory Aspects and Statistics. AB - A generic medicine is an equivalent of an originator pharmaceutical product. It contains the same active substance as, is "essentially similar" to, and is therefore interchangeable with, the originator product. The objective of this study was to determine the share of generic medicines of the total received marketing authorization applications in Croatia, and the specificities in the approval of generic medicines with regard to assessments of their quality documentation. We collected the information from the Agency's medicinal products databases. Absolute numbers are shown for the applications for the authorizations of medicines in total and generics in particular in the period from 2005-2009. Data were analyzed using descriptive statistics. The annual number of marketing authorization applications for generic medicines received in Croatia increased from 148 applications in 2005 to 276 applications in 2009. In the period from 2005-2009, the number of applications for the approval of generic medicines accounted for 55% of all submitted applications. More than five generic medicines were approved for the following active compounds: amlodipine, lisinopril, atorvastatin, tamsulosin and omeprazole. In the following years, the number of applications from international manufacturers stagnated, while the number of applications by local manufacturers is on a steady climb, with the exception of 2008. From 2005-2009, an almost continual increase in the number of applications for the approval of generic medicines is evident. The largest number of generic medicines was approved for generic medicines intended for the treatment of cardiovascular disease (amlodipine, lisinopril, atorvastatin). A continual increase of applications from local manufacturers has been recorded. In the approval of these medicines, it is very important to develop a uniform approach to assessing the quality of each medicine, in order to guarantee a high quality product for the patient. PMID- 26753453 TI - The Relationship between Cognitive and Emotional Intelligence and High School Academic Achievement. AB - The study investigated the relationship between intelligence, emotional intelligence and academic achievement in high school. The study was conducted within the standardization of two instruments for Croatian samples. A total of 369 high school students from the Republic of Croatia participated in the study. They completed the Naglieri Nonverbal Ability Test (NNAT)--a test of cognitive intelligence and the BarOn Emotional Quotient Inventory: Youth Version (EQ-i:YV). Academic achievement criteria were general school achievement, Croatian language and mathematics. Several regression analyses were conducted on the results. The results show that cognitive intelligence and the adaptability scale to be consistent predictors of academic achievement. Emotional intelligence was not shown to be a significant predictor of school success. PMID- 26753454 TI - Efficasy of Different Psychiatric Treatment Methods of Liaison Psychiatrist in Treatment of Women with Breast Cancer. AB - Being diagnosed with breast cancer is a traumatic event that can lead to development of different mental disorders and influences all aspects of affected woman's life. Anxiety and Depressive Disorders in physically ill people still don't have clear diagnostic criteria which make diagnosis and treatment very difficult since different psychiatric therapeutic approaches have different effects. The aim was to evaluate influence of separate and combined psychotherapeutic approach (psychodynamic and cognitive-behavioral) and psychopharmacotherapy on decrease of anxiety and depression in breast cancer patients. The sample consisted of 120 subjects divided into four groups. The first group of patients was treated with psychopharmacotherapy, the second group received psychotherapy, the third group was treated with the combination of psychopharmacotherapy and psychotherapy, and the fourth group of patients didn't receive any kind of psychiatric treatment. We used psychotherapeutic interview with detailed clinical assessment using DSM-IV criteria for mental disorders, specially structured non-standardized questionnaire for assessment of etiological factors in development of mental disorders, Hamilton Anxiety Scale (HAM-A), Hamilton Depression Scale (HAM-D). The subjects filled the questionnaires on entry, one moth and two months after the beginning of research. Psychotherapeutic treatment was conducted once a week. All of the therapeutic approaches of liaison psychiatrist applied in the treatment of women with breast cancer are successful in reduction of anxiety and depression. Liaison psychiatrist's combined approach of psychopharmacological and psychotherapeutic treatment of breast cancer patients with depression obtained better results than separate approach. PMID- 26753455 TI - Plasma Content of Glucose, C-reactive Protein, Uric Acid and Cholesterol in Male, Female and Ovariectomized Rats upon Acute and Chronic Stress--a Path for Development of Cardiovascular Diseases. AB - To explore sex differences in cardiovascular function under stress, we analyzed plasma levels of glucose, C-reactive protein (CRP), uric acid and cholesterol in male, female and ovariectomized rats under acute and chronic stress. Glucose tolerance test (GTT) was performed in all rats before any stress was performed, as well as later in the chronic stress experiment. GTT in control animals showed the same trend as in chronically stressed. Male rats showed the highest plasma level of glucose and uric acid upon acute stress in comparison between the other two groups. Ovariectomized rats reached the highest concentration of plasma cholesterol during acute and chronic stress, respectively and also the highest plasma concentration of CRP during acute stress. Stress, as a risk factor of metabolic syndrome, affected biochemical parameters in males upon acute more than upon chronic stress, but the opposite was observed in female rats. Gender differences supported by ovariectomy show that stress managing could be affected by sexual hormones. PMID- 26753456 TI - Association of IL-1beta and IL-10 Polymorphisms with Prostate Cancer Risk and Grade of Disease in Eastern Croatian Population. AB - Single nucleotide polymorphisms (SNPs) in the promotor regions of cytokine genes included in angiogenesis may influence prostate cancer (PCa) development via regulation of the pathways of tumor angiogenesis. The aim of the present study was to investigate the association of IL-1 female +3954 (rs1143634) and IL-10 1082 (rs1800896) polymorphisms with PCa risk and aggressiveness in eastern Croatian patients. One hundred twenty PCa patients and 120 benign prostatic hyperplasia (BPH) controls were genotyped using real-time PCR (LightCycler Instrument, Roche Diagnostics) and the melting curve analysis method. There was no significant difference in the frequency of genotypes for the two polymorphisms between PCa patients and controls (Chi2 = 0.857, p = 0.355 for IL-female 1; Chi2 = 0.026, p = 0.872 for IL-10). Carriers of the IL-10-1082A>G variant were found to be associated with the Gleason score (GS) > 7 (AA versus GA+GG, OR = 3.47, 95% CI 1.11-10.88, p = 0.033). There was no significant difference in the frequency of genotypes for the two polymorphisms and the presence of metastatic disease in PCa patients. These results suggest that tested SNPs associated with differential production of IL-1 female and IL-10 are not risk factors for PCa and do not correlate with the presence of distant metastasis in eastern Croatians. We found that IL-10-1082 GA+/or GG carriers have a higher risk of developing PCa with GS > 7 in eastern Croatians. PMID- 26753457 TI - Fish and Shellfish Intake and Diabetes in a Costal Population of the Adriatic. AB - The objective of the study was to examine the association between fish and shellfish intake and diabetes in an island population, and the design of the study was Cross-sectional. Two independent population-based field surveys were conducted in Hvar Island of the eastern Adriatic coast of Croatia in May 2007 and May 2008, with a total of 1,379 adult participants. In multivariable logistic regression models, total fish intake was positively associated with diabetes prevalence in the total population (OR(Q4 vs. Q1) = 1.64; 95% CI = 1.01-2.66; p trend = 0.09). Oily fish intake also exhibited a positive association with diabetes prevalence in the total population (OR(Q4 vs. Q1) = 2.22; 95% CI = 1.35 3.64; p-trend = 0.01) and in analyses stratified by body mass index, males and those with a high waist circumference. The study suggests an association between oily fish intake and diabetes in the population of the Hvar Island in Croatia. Longitudinal studies incorporating measures of persistent organic pollutants and local cooking practices are warranted to identify factors in fatty fish that may influence the development or persistence of diabetes. PMID- 26753458 TI - Physical Fitness Comparison and Quality of Life between Spanish and Serbian Elderly Women through a Physical Fitness Program. AB - The aim of this study was to compare the physical fitness and quality of life related to the health of a sample population of older adult women from Spain and Serbia (60-69 years). A total of 127 female participants of physical fitness programs from Spain (64.33 +/- 3.26) and Serbia (63.00 +/- 2.88) have participated. Physical fitness (PF), quality of life (QoL) and sociodemographic characteristics were evaluated by Senior Fitness Test, SF-36 Health Survey and socio-demographic questionnaire, respectively. The anthropometric characteristic was measured by corporal measurement. The physical fitness program comprised exercise of strength, agility and aerobic capacity, centering on the Pilates'program and Aerobic. Mean body mass index was 33.6 +/- 7.4 kg x m(-2) in the Spanish participants and 25.1 +/- 2.6 kg x m(-2) from the Serbian participants (p < 0.001). Similarly, mean waist circumference and body weight of Spanish women was higher than Serbian (p < 0.001; p < 0.05, respectively). Spanish women perceived lower quality of life dimensions than Serbian women, such as physical functioning, social functioning and general health (p < 0.001), general health (p < 0.01) and vitality (p < 0.05). Serbian participants experienced higher physical fitness, such as upper body flexibility (p < 0.05), lower body flexibility, agility and aerobic endurance (p < 0.001). In conclusion, Serbian women were found to have better levels of physical fitness and quality of life than Spanish women. Furthermore, endurance fitness has 73% of explained variance with age, body mass index and fat mass. PMID- 26753460 TI - Influence of Dentifrices pH on Enamel Microhardness In Vitro. AB - Purpose was to evaluate the effect of toothpastes pH on enamel remineralization. Six fluoride toothpaste and one without fluoride were applied to the enamel slabs. Twenty eight enamel slabs were divided into seven groups and subjected to a daily cycling regimen with brushing treatments, demineralization and remineralization in artificial saliva. The surface microhardness (SMH) was calculated from the mean values obtained from six indentations (Vickers hardness number (VHN)) on the enamel surface at baseline and after 12 days. pH of the dentifrices was determined in a slurry with deionized water (1:3). Changes of the enamel surface microhardness at baseline and after remineralization stage were measured and analyzed using the Student t-test and one-way ANOVA. All groups treated with fluorides showed higher SMH values compared to control group. Toothpastes with lower pH (Pronamel, Sensodyne F, Sensodyne Rapid) were statistically superior to other fluoride dentifrices and control group after 12 days pH-cycling regimen (p < 0.001). Obtained results showed that slightly acidified fluoridated toothpastes may have a positive influence on enamel remineralization process. PMID- 26753459 TI - Physical Activity and Quality of Life of Mothers of Preschool Children. AB - The main aim of this study was to explore physical activity regarding mothers of preschool children and connections concerning different aspects of their physical activity (at work, during transport, in free time, while doing housework) with subjective quality of life. Another aim was to investigate factors that are obstacles of living a physically active life in this population. The participants of the study were 252 Croatian women, who have at least one preschool child older than three years. The World Health Organization Quality Of Life - BREF questionnaire and International Physical Activity Questionnaire were used. Participants also gave some personal demographic data, and answered to questions about obstacles for participation in organized physical activity. Results of this research showed that mothers of preschool children were more physically active than the population of adults in general, but their physical activity was mostly housework activity. Physical activity in their free time was the only aspect of physical activity that was significantly correlated with different aspects of mother's subjective quality of life. Employed mothers and those who live in the towns had more physical activities in their free time. Organizational factors and feeling that family suffers for their absence were the most frequently perceived barriers for organized physical activity participation. Results revealed that only the physical activity in their free time contributes to mother's quality of life. Mothers of preschool children mostly do housework physical activity, so support of the social community for physical activity in their free time in this population is recommended. Such activities should be especially directed to unemployed mothers and those who live in the villages. PMID- 26753461 TI - Uyghur Medicine in Practice: A Study in Khotan. AB - In Xinjiang, China, health-seeking behaviors among the Uyghur are not restricted to visitation to doctors of modern medicine because traditional Uyghur medicine is at their disposal as well. As Xinjiang's southernmost city, Khotan is a thriving center of Uyghur medicine, bolstered by a Uyghur Medical College, a marketplace specializing in the trade of Uyghur drugs, and an assemblage of skilled Uyghur doctors. The author conducted a study in Khotan on issues of etiology, diagnosis, and treatment in the practice of Uyghur medicine. Uyghur medicine is sustained a cultural model of illness that continues to define medical choices among the Uyghur people today. This paper focuses the question of how this cultural model of illness is manifested in etiology, diagnosis, and treatment. PMID- 26753462 TI - Manual Snow Removal and Sudden Death. AB - The aim was to analyze the causes of sudden death in middle-aged and elderly men during manual snow removal. During snowy winter months in Zagreb, from January 2013 to January 2014, four males aged 52, 65, 72 and 81, died suddenly while manually removing snow. They were all autopsied. All of them have suffered from arterial hypertension and coronary heart disease, and one suffered from metabolic syndrome. The cause of death in two was probable malignant ventricular arrhythmia. In the third who fell down on the icy surface, consequences were cerebral contusion and neck vertebral luxation. In the fourth who fell down from the top of a 15 m tall building during snow removal, the cause of death were multiple injuries: fractures of both clavicles, ribs and vertebrae's Th5, Th6, hematothorax, cardiac contusion, hematopericardium, thoracic aorta rupture, contusions and ruptures of both lungs, rupture of the diaphragm, liver rupture, hematoperitoneum and cerebral edema. The estimated death rate in the City of Zagreb for males aged 30-64 years is 5.44/1,000,000 inhabitants, which is less than in those aged 65-85 years (40.03/1,000,000; p = 0.2269). Sudden strenuous physical effort due to manual snow removal in two non-trained persons, who have suffered from arterial hypertension and coronary heart disease, was the cause of sudden death. Manual snow removal is an important cause of sudden death, as it is a very arduous effort in non-adapted middle-aged and elderly persons. PMID- 26753463 TI - The Role of Standard Echocardiographic Parameters in Endomyocardial Biopsy Proven Cardiac Amyloidosis. AB - Primary light-chain (AL) amyloidosis is a plasma cell dyscrasia associated with the deposition of immunoglobulin-derived amyloid in multiple organs. In the heart, this results in an infiltrative cardiomyopathy, with increased left ventricular wall thickness, normal or decreased left ventricular (LV) cavity size and congestive heart failure. Cardiac involvement is a major determinant of prognosis of AL amyloidosis. We report a patient with cardiac amyloidosis proven by cardiac biopsy, and aim to point out at transthoracic echocardiography as the hallmark of diagnostics. Echocardiography revealed increased LV thickness at 20mm, impaired LV ejection fraction (EF) at 35%, enlarged atria, transmitral deceleration time at 156 ms and increased E/A ratio at 4.25. Early diagnosis and intervention can have a significant impact on the patient's response to treatment, especially when the underlying condition involves a malignancy or infiltrative disorder. Standard transthoracic echocardiography as a noninvasive diagnostic tool is valuable and has a significant role in diagnosis and prognosis. PMID- 26753464 TI - Acute Coronary Syndrome with ST-segment Elevation in Pregnancy: Anesthetic Management of Delivery. AB - Acute coronary syndrome (ACS) during pregnancy is rare but may be associated with high risk complications. Approximately 150 myocardial infarctions (MI) during pregnancy have been documented in literature worldwide, but we didn't find one with myocardial aneurysm. We describe 2 patients with acute MI; both with ST segment elevation (STEMI), 1 case complicated with heart failure, formation of a myocardial aneurysm and broad QRS arrhythmia; another with uncomplicated course, and their anesthetic management during delivery. Acute MI is rare in reproductive age usually developing in women with cardiovascular risk factors. There is concern about its rising incidence due to the increase of average maternal age. Our cases show that there might be some undiscovered risk factors for pregnancy related myocardial infarction. PMID- 26753465 TI - From Postpartum Metastatic Cancer to Parathyroid Adenoma: A Case Report. AB - We present a 36 year old female patient with suspected postpartum advanced metastatic cancer and multiple osteolytic lesions due to which she was referred to the Internal medicine clinic for further diagnostic evaluation. After extensive investigation, it was discovered that the underlying condition was a parathyroid gland adenoma and the patient was treated surgically. Clinicians should note that parathyroid adenoma can mimic metastatic malignant disease, and should make appropriate diagnostic tests that will lead to the correct diagnosis. PMID- 26753466 TI - Discriminating Between the Roles of Androgens and Estrogens in Cardiovascular Disease. AB - Cardiovascular disease shows a distinct difference in incidence rates between men and women, a fact that has been known for many years. While initial theories supported that this could be attributed to the protective effect of estrogens in women, attempts to correlate endogenous estrogen levels with cardiovascular risk factors and the progression of atherosclerosis-related indexes indicate otherwise. Similarly, endogenous androgen levels seem to correlate with opposite effects in males and females, whereas exogenous treatment with either androgens or estrogens fails to correspond to scientific expectations entirely. A brief discussion of the merits and pitfalls of placing either estrogens or androgens alone at the root of the problem shows that current understanding is inadequate concerning this major anthropological issue, as it refers to the primary global mortality and morbidity cause. PMID- 26753467 TI - Osteoprotegerin and Vascular Calcification: Clinical and Prognostic Relevance. AB - Osteoprotegerin (OPG) is a key regulator in bone metabolism, that also has effect in vascular system. Studies suggest that osteoprotegerin is a critical arterial calcification inhibitor, and is released by endothelial cells as a protective mechanism for their survival in certain pathological conditions, such as diabetes mellitus, chronic kidney disease, and other metabolic disorders. That has been shown in studies in vitro and in animal models. The discovery that OPG deficient mice (OPG -/- mice) develop severe osteoporosis and arterial calcification, has led to conclusion that osteoprotegerin might be mulecule linking vascular and bone system. Paradoxically however, clinical trials have shown recently that OPG serum levels is increased in coronary artery disease and correlates with its severity, ischemic cardial decompensation, and future cardiovascular events. Therefore it is possible that osteoprotegerin could have a new function as a potential biomarker in early identification and monitoring patients with cardiovascular disease. Amongst that osteoprotegerin is in association with well known atherosclerosis risc factors: undoubtedly it is proven its relationship with age, smoking and diabetes mellitus. There is evidence regarding presence of hyperlipoproteinemia and increased serum levels of osteoprotegerin. Also the researches have been directed in genetic level, linking certain single nucleotid genetic polymorphisms of osteoprotegerin and vascular calcification appearance. This review emphasises multifactorial role of OPG, presenting numerous clinical and experimental studies regarding its role in vascular pathology, suggesting a novel biomarker in cardiovascular diseases, showing latest conclusions about this interesting topic that needs to be further explored. PMID- 26753468 TI - (Dis)organization of Palliative Care as a Potential Quality-of-Life Issue in the Senior Population--Croatian Experiences. AB - This paper analyses the current situation in the Croatian health-care system, with special emphasis on the (dis)organization of palliative care within the public health, more precisely gerontology context. Namely, population world-wide is getting older, that is both a statistical and an everyday-medical fact. Today we consider citizens after the age of 65 as the elderly, with a tendency to move the age-limit to 75 years. Croatia on the matter swiftly follows global trends, while literature points to the fact that an increase in the elderly population dictates the need for an organized system of palliative care and hospice building. Although we cannot ignore the fact that children can become palliative care patients, we can conclude that these are predominantly elderly patients. In fact, approximately half of patients--users of palliative care--have some type of oncological diagnosis; a significant number of patients suffer from dementia, stroke, or heart failure. As for the Primorsko-goranska county and the City of Rijeka, they show similar trend, as can be illustrated with data from the 2011 census, when the share of citizens over 65 years in the population of the Primorsko-goranska county reached 18.91%, and in the population of the City of Rijeka 19.74%. Thus, one of the main quality-of-life issues in the Croatian senior population is the (dis)function of the palliative medicine/care system. Practice, namely, shows that there has still been no implementation. In particular, palliative medicine is not yet recognized as a speciality or sub speciality, standards and norms for this activity are not set, palliative care is still not included in the system of obligatory health insurance, and as far as the national strategy of health policy for the area of palliative care, Croatian Government at its meeting held on 27th December 2013 finally adopted the "Strategic Plan for Palliative Care of the Republic of Croatia for the period from 2014 to 2016". Exactly because we are a decade behind European standards (Recommendation Rec (2003) 24 of the Committee of Ministers to member states on the organization of palliative care), it is more than legitimate to place this subject at the centre of the current Croatian gerontology interest. PMID- 26753469 TI - Internal Hernias in Acute Abdomen: Review of Literature and Report of four Cases. AB - Internal hernias are very rare in clinical practice. Because of a wide range of symptoms that can sometimes be non-specific, surgeons often disregard internal hernias in the spectrum of differential diagnosis in acute abdomen. Finding the diagnosis before an internal hernia causes an acute abdomen is sometimes difficult despite modern diagnostic tools. Reason for diagnosis delay is mostly because of wide range of symptoms and variable time period of abdominal pain before patients visit the physician. Furthermore, the delayed diagnosis can put patients in dangerous life threatening condition because internal hernias can cause acute bowel or intestinal obstruction. In such cases high mortality has been recorded so internal hernias presenting as acute abdomen may need operations as soon as possible. Performance of image studies could easily lead to a specific diagnosis and the best surgical strategy. Occasionally, an urgent laparotomy is the only diagnostic procedure and treatment. Here we present four patients with developed acute abdomen due to internal hernia and a course of treatment along with a review of the literature. PMID- 26753470 TI - Display Modes of Personal Ornaments in the Upper Palaeolithic Sites of Istria, Croatia. AB - In the attempt to understand culture and social behavior of prehistoric populations, findings of personal ornaments are of particular interest. Personal ornaments in their formal expressions (marine shells and snails, river snails, animal teeth, modified animal bones etc.) not only point to an universal idea of decoration and aesthetic sensibility, but may also reveal contact zones and communication paths. Perforated animal teeth, mostly deer canines, reveal us not only symbolic, but also some important sociocultural aspects of behavior of prehistoric populations. In order to test whether there are universals in display modes and materials used in this region, we will use the finds of personal ornaments from the Upper Paleolithic strata from five Istrian sites: Ljubiceva cave, Pupicina cave, Romualdova cave, Sandalja II, and Vesanska cave. PMID- 26753471 TI - Diclofenac suppository pretreatment in prevention of vasovagal reflex-associated complications for infertile women undergoing local endometrial injury. AB - PURPOSE OF INVESTIGATION: To assess the effects of the diclofenac suppository pretreatment in prevention of vasovagal reflex-associated complications for infertile women undergoing local endometrial injury (LEI). MATERIALS AND METHODS: Eighty-six infertile outpatients with repeated implantation failure following transfer of morphologically good embryos and/or blastocysts underwent single curettage LEI to improve the pregnancy outcome in the subsequent embryo/blastocyst transfer cycle. Of them, 35 patients chose diclofenac suppository administration prior to LEI, whereas 51 patients did not. The occurrence of palpitations, bradycardia, hypotension, presyncope, and requirement of bed rest was compared between the two groups. RESULTS: There were no significant differences in the demographics between the two groups. The prevalence of presyncope and requirement of bed rest was significantly lower in the diclofenac suppository group than in the control group. The pregnancy outcome was similar between the two groups. CONCLUSION: The diclofenac suppository administration is a low-cost effective method to reduce the risk of the vasovagal reflex-associated complications in infertile women undergoing LEI. PMID- 26753472 TI - Oxidative stress markers in uterine fibroids tissue in pre- and postmenopausal women. AB - Uterine fibroids are common benign tumors of the reproductive organ and occur in approximately 50-80% of women of reproductive age. The pathogenesis of uterine fibroids is multifactorial and includes: sex hormones, genetic factors, cytokines, and oxidative stress. OBJECTIVE: The aim of this study was to investigate the oxidative stress markers in tissue samples of women with uterine fibroids, with further analysis on size and menopausal status. MATERIALS AND METHODS: Fifty-nine patients with the mean age 50.6 (35 premenopausal and 24 postmenopausal) who underwent standard gynecological procedures were recruited in the study. All women had histologically proven uterine leiomyoma. Samples were collected ex vivo immediately after resection. Glutathione peroxidase (GPX), catalase (CAT), and the ferric reducing ability of plasma (FRAP) were measured. RESULTS: The activity of GPX was significantly higher in fibroid samples than in myometrium (0.070 +/- 0.042 vs. 0.057 +/- 0.027 U/mg of protein, p < 0.05), activity of CAT did not differ between samples (1.13 +/- 0.86 vs. 1.23 +/- 0.51 U/mg of protein, p > 0.05), and FRAP presented higher values in fibroid samples than in myometrium (4.58 +/- 6.29 vs. 3.04 +/- 3.81 mM Fe(+2)/mg of protein), but the difference was not statistically significant (p = 0.06). In the subgroups analyses, there were no statistically significant differences when comparing the activity of GPX, CAT, and FRAP in fibroid samples from pre- and postmenopausal women, as well as when comparing fibroid samples of small size (< 50 mm) and large size (>= 50 mm) tumors. CONCLUSION: Oxidative stress markers are changed in fibroid tissue samples showing that oxidative stress may play an important role in this tumor formation, although without influencing menopausal status nor tumor size. PMID- 26753473 TI - Non-association of MMP-9 -1562C/T polymorphism with preeclampsia risk: evidence from a meta-analysis. AB - Individual genetic association studies examining the relationship between the MMP 9 -1562C/T polymorphism (rs3918242) and preeclampsia risk have yielded inconsistent results. OBJECTIVE: This study aims to evaluate the association between the MMP-9 -1562C/T polymorphism and preeclampsia risk using meta analysis. MATERIALS AND METHODS: Relevant studies were identified by searching PubMed database. Data were extracted and statistical analysis was performed using STATA 12.0 software. A total of six publications involving 871 cases and 845 controls were included in this meta-analysis. RESULTS: Combined analysis revealed no association between the MMP-9 -1562C/T polymorphism and preeclampsia risk (allelic model: OR = 1.10, 95% CI 0.86-1.41, Pheterogeneity = 0.07; recessive model: OR = 0.38, 95% CI 0.14-1.01, Pheterogeneity = 0.64; dominant model: OR = 1.09, 95% CI 0.70-1.69, Pheterogeneity = 0.01; homozygous model: OR = 0.41, 95% CI 0.15-1.09, Pheterogeneity = 0.67; heterozygous model: OR = 1.36, 95% CI 0.80 2.29, Pheterogeneity = 0.01). Similarly, subgroup analysis by ethnicity showed that MMP-9 -1562C/T polymorphism was not associated with preeclampsia risk in Brazilian (allelic model: OR = 1.37, 95% CI 0.92-2.05, Pheterogeneity = 0.61; recessive model: OR = 0.80, 95% CI 0.18-3.57, Pheterogeneity = 0.58; dominant model: OR = 1.12, 95% CI 0.60-2.10, Pheterogeneity = 0.03; homozygous model: OR 0.87, 95% CI 0.19-3.94, Pheterogeneity = 0.62; heterozygous model: OR = 1.55, 95% CI 0.99-1.75, Pheterogeneity = 0.32). CONCLUSION: This meta-analysis indicated that MMP-9 -1562C/T polymorphism was not associated with preeclampsia risk. However, large well-designed, multi-center epidemiological studies should be carried out in these and other ethnic populations to confirm our findings. PMID- 26753474 TI - Evaluation of maternal mortality ratio and causes in a university hospital in eastern Turkey. AB - AIM: To investigate the maternal mortality ratio (MMR) and causes of maternal death in order to decrease these deaths. MATERIALS AND METHODS: The number of live births, maternal deaths, and the causes of deaths in Yuzuncu Yil University were recorded between 2004 and 2013. RESULTS: The MMR was 268 per 100,000. Forty nine maternal deaths were examined in terms of cause. The most frequent cause of death is eclampsia (33%) and associated intracerebral complications. The antenatal follow-up rate was 23.3%. The majority of patients had low income (92.3%), 72.2% were from rural areas, and 95.5% were illiterate. CONCLUSION: The high MMR may arise from the high incidence of pregnancy complications in eastern Turkey, the rareness of antenatal follow-ups, and the present hospital being a referral hospital. The most frequent cause of maternal mortality is eclampsia and associated complications, followed by bleeding. PMID- 26753475 TI - Analysis of the use of cyclosporin A to treat refractory immune recurrent spontaneous abortion. AB - PURPOSE: This study aims to determine the curative effect of cyclosporin A (CsA) in treating refractory immune recurrent spontaneous abortion (RSA). Patients with recurrent abortion caused by dysimmunity were enrolled. MATERIALS AND METHODS: The patients were given aspirin, prednisone, heparin, immunotherapy with their husband's leukomonocyte, and intravenous immunoglobulin (IVIG) treatment, but treatment outcomes were unsuccessful. Therefore, CsA was added to treat the women before and after pregnancy. During treatment, CsA concentration was maintained at 80 ng/ml to 150 ng/ml. The clinical effect and pregnancy outcome were observed. RESULTS: Of the 26 patients, 20 cooperated and accomplished complete pregnancy. Twelve cases showed hypertensive disorders during pregnancy but did not exhibit symptoms of preeclampsia. Three cases were lost to follow-up. The success rate was 76.92%. Twenty patients underwent premature labor (34 weeks to 37 weeks). Nevertheless, the mothers and their children were all healthy. CONCLUSION: An appropriate dose of CsA has good curative effects and pregnancy results in the treatment of RSA. PMID- 26753479 TI - Adverse perinatal outcomes of adolescent pregnancies in one center in Istanbul, Turkey. AB - PURPOSE: The objective of this study was to evaluate fetal and perinatal outcomes of pregnancies of adolescents and compare them with adult pregnancies. MATERIALS AND METHODS: This retrospective case-control study was carried out at Bakirkoy Maternity and Children's Diseases Education and Research Hospital in Istanbul, Turkey. It enrolled 2,491 pregnancies who delivered between 2005-2010, of which 998 were adolescent pregnancies and 1,493 were adults as controls. RESULTS: The mean age of the adolescent group was 17.10 years and in the control group the mean age was found to be 26.73 years. Intermarriage, vaginal delivery, preterm rupture of membranes, preterm birth, and preeclampsia were significantly higher in adolescent pregnancies than the control group. Gestational diabetes was more common with increasing age. There was no statistically meaningful difference between the groups in terms of intrauterine growth restriction (IUGR), low birth weight, anemia, 5-minute APGAR score, and intrauterine fetal demise. CONCLUSIONS: Young maternal age is a risk factor for preterm birth, preterm rupture of membranes, and preeclampsia. According to this study, adolescent pregnancies are more risky and more likely to have adverse fetal outcomes. PMID- 26753476 TI - Soy isoflavones, inulin, calcium, and vitamin D3 in post-menopausal hot flushes: an observational study. AB - PURPOSE OF INVESTIGATION: To evaluate the effect of soy isoflavones and inulin (SII) on hot flushes (HF) and quality of life in a clinical setting, the authors conducted an observational study. MATERIALS AND METHODS: The authors performed an observational, prospective, multicentric study on women in peri-/post-menopause treated or untreated with a product present on the Italian market, consisting in a mixture of calcium (500 mg), vitamin D3 (300 IU), inulin (3 g) and soy isoflavones (40 mg). RESULTS: A total of 135 patients, 75 (55.6%) in the SII group and 60 (44.4%) in the untreated group entered the study. After three months, the mean number of HF declined of 2.8 (SD 3.7) in the SII group and 0.0 in the untreated one. The corresponding values after six months were -3.7 (SD 2.7) in the SII group and -0.9 (SD 5.3) in the control group (p = 0.02). CONCLUSION: This observational trial suggests a possible beneficial effect of a dietary soy supplement containing 40 mg of isoflavone/day plus inulin in the management of menopausal symptoms such as hot flashes. PMID- 26753477 TI - Serum oxidized low density lipoprotein levels in preeclamptic and normotensive pregnants. AB - BACKGROUNDS/AIM: The aim of the study was to determine serum lipids and oxidized low density lipoprotein (ox-LDL) levels in preeclamptic pregnants and compare with those of normotensives. MATERIALS AND METHODS: Ox-LDL levels were determined by enzyme linked immunosorbent assay (ELISA); total cholesterol, hight density lipoprotein (HDL)-cholesterol and triglyceride levels were measured by enzymatic colorimetric assay in 26 normotensive and 27 preeclamptic pregnants. LDL and very low density lipoprotein (VLDL) cholesterol was calculated by Friedwald formula. RESULTS: Serum levels of Ox-LDL (U/L), total-cholesterol (mg/dL), HDL-cholesterol (mg/dL), LDL-cholesterol (mg/dL), triglyceride (mg/dL), and VLDL-cholesterol (mg/dL) in normotensive and preeclamptic pregnants were found as 130+/-60 and 133+/-69; 248+/-49 and 248+/-81; 67+/-14 and 61+/-16; 147+/-61 and 135+/-59; 207+/-76 and 256+/-87; 41+/-15 and 50+/-17, respectively. Mean values of Ox-LDL and other lipid parameters were higher than the upper limits of their reference ranges in both of groups. However no significant differences were found in Ox LDL, total, HDL and LDL-cholesterol levels between two groups. However, the levels of triglyceride and VLDL-cholesterol were significantly higher in preeclampsia group. CONCLUSIONS: The present results suggest that the levels of serum Ox-LDL and other lipid parameters rise as a result of pregnancy rather than as a result of preeclampsia. PMID- 26753478 TI - Serum prolactin concentration and severity of depression symptoms in climacteric women. AB - OBJECTIVE: The study was conducted to elucidate the problem of prolactin (PRL) serum concentration in menopausal women and its possible relations with climacteric and depressive symptoms. MATERIALS AND METHODS: The study included 202 women aged 40-65 years admitted to the Department of Gynecological Endocrinology, Poznan University of Medical Sciences, because of climacteric symptoms. The authors assessed the intensity of climacteric and depressive symptoms with the Kupperman index and the Hamilton depression scale, measured BMI index, serum PRL, FSH, LH, 17beta-estradiol, total testosterone, and dehydroepiandrosterone sulfate (DHEAS) levels in all studied women. RESULTS: They found a correlation between serum PRL concentration and result of M. Hamilton depression scale (R = 0.21; p = 0.005) and a between serum PRL concentration and serum 17beta-estradiol concentration (R = 0.21; p = 0.003). CONCLUSION: The authors concluded that serum PRL concentration is related to severity of depressive symptoms in menopausal women. PMID- 26753480 TI - Efficacy of fetal thigh volumetry in predicting birth weight using the virtual organ computer-aided analysis (VOCAL) technique. AB - OBJECTIVES: The present study was conducted to compare the accuracy of formulas used to calculate fetal thigh volume (FTV) using the virtual organ computer-aided analysis (VOCAL) technique with two-dimensional (2D) in formulas predicting birth weight. MATERIALS AND METHODS: This was a prospective, cross-sectional study of 84 pregnant women with 72 hours of delivery evaluated at a university hospital between May, 2008 and April, 2010. After 2D ultrasounds (US) measurement, 3DUS was also used to determine FTV with estimates computed using the VOCAL program. RESULTS: The correlation between fetal weight predicted by the 3D equation of FTV and the actual birth weight was significant. While FTV and the Hadlock II equation exhibited a low sensitivity for detection of low-birth-weight infants, FTV was a more sensitive method of detecting high-birth-weight infants than the Hadlock II equation. CONCLUSIONS: It is clear that using 3DUS-VOCAL to measure FTV provides more accurate estimation of fetal birth weight. PMID- 26753481 TI - Echogenic intracardiac focus in fetus and association with maternal respiratory tract infection in Shanghai, China. AB - PURPOSE OF INVESTIGATION: To evaluate the association between fetal echogenic intracardiac focus (EIF) and maternal respiratory tract infections (RTI) during gestation. MATERIALS AND METHODS: Fetal echocardiography was performed on 1,720 pregnant women (1,723 fe- tuses), and 205 of them showed evidence of fetal EIF. Other 245 pregnancies without fetal EIF were selected randomly as a control group. Comparison was undertaken to evaluate the difference between these two groups, and the possible association between EIF and maternal RTI. RESULTS: EIF was present in 11.9% of the examined fetuses, and the presence of fetal EIF with maternal RTI was significantly higher (p < 0.05) than those without RTI. Multivariate logistic regression correction of RTI showed that the likelihood of EIF was 49 fold higher in pregnant women with RTI than without it (odds ratio [OR] = 49.958, 95% confidence interval [CI], 25.973~96.092, p < 0.05). CONCLUSIONS: Fetal EIF is suggested to be associated with maternal RTI during gestation in the present study population. PMID- 26753483 TI - Expression and significance of CD133 and ABCG2 in endometriosis. AB - BACKGROUND: Endometriosis is a common gynecological disease and exact pathogenesis is still unclear. Recently, an increasing interest has been given to the potential role of stem cells in the development of endometriosis. The aim of this study was to test the expression of sterness-related markers CD133 and ABCG2 in endometriosis. MATERIALS AND METHODS: CD133 and ABCG2 protein expression in eutopic and ectopic endometrial tissue with endometriosis and endometrium tissue without endometriosis were examined by Western blot. RESULTS: Eutopic endometrium showed high level of CD133 and ABCG2 protein when compared with ectopic endometrium (p = 0.042, p = 0.038) and control endometrium (p = 0.000, p = 0.000). The expression of CD133 protein in ectopic endometrium was positively correlated with R-AFS score of endometriosis (p = 0.000, r = 0.793) and no significant relation was noted between ABCG2 and R-AFS score (p = 0.563). Two of three patients with recurrence had much higher expression of ABCG2 protein than the patients without recurrence. CONCLUSION: Aberrant expression of CD133 and ABCG2 in eutopic and ectopic endometrial tissue with endometriosis suggests that they are probably associated with the pathogenesis of endometriosis and stem cells play a possible role in its development. PMID- 26753482 TI - Environmental pollution due to cadmium: measure of semen quality as a marker of exposure and correlation with reproductive potential. AB - PURPOSE: Contradictory reports exist in the literature regarding an association of cadmium with parameters of semen quality. The aim of the study was to assess cadmium levels in both blood and seminal plasma and to analyze the relationships between cadmium concentrations and lifestyle and semen parameters. MATERIAL AND METHODS: Fifty healthy male volunteers were recruited to provide semen and blood samples. Each patient completed an extensive questionnaire regarding his occupation, residence, social status, diet, water source, smoking habits, and medical and surgical history. Semen analysis was carried out according to WHO guidelines. Detection of cadmium in both semen and blood samples was carried out by means of atomic absorption spectrophotometer. RESULTS: Mean concentrations of cadmium were 8.18 +/- 1.6 ng/ml in blood samples and 2.56 +/- 0.9 ng/ml in semen samples. Cadmium blood levels were significantly higher in men from industrialized areas and in current smokers, but were not correlated with semen levels. A significant positive correlation was found between cadmium blood levels, number of immotile spermatozoa, and teratozoospermia index (TZI). Significant inverse relationships between cadmium blood concentration and type-a and type a + b motility were found. CONCLUSIONS: The present data show a significant correlation between blood cadmium concentrations, cigarette smoking, occupational exposure, and parameters of semen quality. Such a reduction in spermiogenetic function could be an early marker of a toxic effect by cadmium pollution. PMID- 26753484 TI - Umbilical cord blood endocan levels according to the delivery mode. AB - PURPOSE OF INVESTIGATION: The authors aimed to evaluate the endocan levels in the umbilical cord blood regarding the delivery mode. MATERIALS AND METHODS: One hundred six women aged between 20 to 35 years, undergoing delivery at term were studied. Three groups were formed; 37 neonates born by spontaneous vaginal delivery (group 1), 34 neonates born by an elective cesarean section with the general anesthesia (group 2), and 35 neonates, born by an elective cesarean section with spinal anesthesia (group 3). In delivery, umbilical cord blood samples were collected and endocan levels were measured. RESULTS: The endocan levels of cord blood (mean +/- standard deviation, ng/ml) were found to be lower in group 2 (1.21 +/- 0.46) compared to group 1 (1.52 +/- 0.52) (p = 0.011). Cord blood endocan levels were not different in group 1 than those of group 3 (p = 0.49). CONCLUSION: It may be concluded that cord blood endocan levels are affected by the delivery mode. PMID- 26753485 TI - The safety and acceptability of intravenous fentanyl versus intramuscular pethidine for pain relief during labour. AB - OBJECTIVES: This trial aimed to ascertain the relative efficacy, adverse effects, and acceptability of fentanyl versus pethidine for pain relief during labour. MATERIALS AND METHODS: Parturients (n=80) in the active phase who requested analgesia were randomly assigned to receive either intravenous fentanyl (n=40) or intramuscular pethidine (n=40). Pain scores hourly, maternal and fetal adverse effects, neonatal outcome, and maternal acceptability were assessed. RESULTS: Pain scores decreased in both groups, the decrease varying from mild to moderate, average pain scores remaining above 3.5 in both groups. Pain scores returned towards baseline over time; three hours after the initiation of treatment in the fentanyl group. Pethidine was associated with more maternal nausea and vomiting (p < 0.05) while fentanyl was associated with more neonates with low Apgar scores at one minute and more need for neonatal resuscitation and naloxone administration when compared to pethidine (p < 0.05). Both drugs were acceptable for pain relief during labour. CONCLUSION: Fentanyl is comparable to pethidine for pain relief during labour regarding efficacy and acceptability, but with more neonates with low Apgar scores at one minute and higher need for neonatal resuscitation and naloxone administration. Further larger trials are needed to confirm its safety. PMID- 26753486 TI - Prevalence of endometriosis at a university hospital in Jeddah, Saudi Arabia. AB - PURPOSE: To determine the prevalence of endometriosis in women who had gynecologic laparoscopy at a university hospital in Saudi Arabia. MATERIALS AND METHODS: The hospital records were reviewed to identify all women who had undergone gynecological laparoscopy between January 2008 and December 2013. RESULTS: A total of 190 gynecologic laparoscopies were performed. The indications for laparoscopy were infertility (n = 76; 40%), chronic pelvic pain (n = 34; 17.9%), infertility and chronic pelvic pain (n = 7; 3.7%), ectopic pregnancy (n = 30; 15.8%), pelvic mass (n = 12; 6.3%), removal of a missing intrauterine contraceptive device (n = 6; 3.2%); other indications were documented in 25 cases (13.1%). Endometriosis was diagnosed in 21 women (11.1%). The presenting complaints in women with endometriosis were pelvic pain (n = 7; 33.3%), infertility (n = 5; 23.8%), pelvic pain and infertility (n = 6; 28.6%), and pelvic mass (n = 2; 9.5%); the complaint was unknown in one patient (4.8%). CONCLUSION: Endometriosis was uncommon in women who had undergone gynecologic laparoscopy. PMID- 26753487 TI - Cell free fetal DNA in the plasma of pregnant women with preeclampsia. AB - OBJECTIVE: Insufficient cytotrophoblast invasion to the myometrium is associated with preeclampsia, especially with the early-onset preeclampsia (before 34 gestational weeks). Several investigations have marked changes in the concentration of cell free fetal DNA in the maternal circulation of women with preeclampsia. However, these studies were not performed for early or late preeclampsia subgroups individually. The present authors planned to determine the levels of the cell free both fetal and maternal DNA in the maternal circulation in early preeclampsia subgroup and compare it with normotensive control cohort. MATERIALS AND METHODS: A total of 16 women; eight of these with preeclampsia and eight normotensive control cohorts with singleton male pregnancy between 28 and 32 gestational weeks were included in the study. Real-time PCR analysis was performed for determining the circulating cell free DNA levels. RESULTS: Cell free fetal DNA concentrations were higher in early preeclamptic women than control subjects. The authors found no statistically significant difference in each levels of maternal and total DNA between hypertensive and normotensive groups. CONCLUSIONS: The present findings suggest that the levels of cell free fetal DNA in maternal circulation were higher in pregnancies which are complicated with early preeclampsia than normotensive controls. PMID- 26753488 TI - Middle cerebral artery Doppler in prediction degree of fetal anemia and the best timing for the second intrauterine intravascular transfusion in red cell alloimmune disease. AB - AIM: To determine the role of fetal multiples of the median of middle cerebral artery peak systolic velocity (MoM MCA-PSV), predicts the rate of decline in fetal hematocrit (Hct) for determination of the best timing for the second intrauterine intravascular transfusion (IUIVT) in fetuses with Rh alloimmunisation. MATERIALS AND METHOD: Retrospective study of 59-monofetal alloimmunized pregnancies from 2005 to 2012 that underwent first and second IUIVT were assessed in Department of Gynecology and Obstetrics, Belgrade, Serbia. RESULT: There was an inverse statistically significant correlation between measurements MCA MoM-1 and fetal Hct-1 before the first IUIVT r = -0.622; p = 0.001 and MCA-MoM-3 and Hct-3 before the second IUIVT r = -0.381; p = 0.001, also as the significant correlation between the interval between both procedures (expressed in day) and measurement MCA-MoM-3, before the second IUIVT r = -0.284; p = 0.029. CONCLUSION: The measurements MoM-MCA before every IUIVT can be useful for prediction of the best timing for the next IUIVT. PMID- 26753489 TI - Application of acoustic radiation force impulse imaging (ARFI) in quantitative evaluation of neonatal brain development. AB - OBJECTIVE: This study aims to quantitatively evaluate the effect of acoustic radiation force impulse imaging (ARFI) in neonatal brain development. MATERIALS AND METHODS: The authors observed 41 neonatal brain different tissues by using traditional two-dimensional gray scale ultrasound and color Doppler flow imaging and frequency spectrum ultrasound. After that they used ARFI to quantitative evaluate white and gray matter of neonatal different tissues in brain with different gestational ages. They also used new technical index: virtual touch tissue quantification (VTQ) to evaluate elastic changes of brain tissues. RESULTS: Different tissues in brain had different elastic numerical values. Neonatal with different gestational ages had different elastic numerical values. The more gestational ages were, the more the elastic numerical values. Elastic numerical values between preterm and full-term infants were different. Elastic numerical values of full-term infants were higher than preterm infants. CONCLUSION: ARFI provides a new quantitative index to evaluate neonatal brain development. It increases objectivity and reliability of clinical analysis. Ultrasound was a noninvasive examination method, safe, simple, and convenient, and it has more usefulness of ARFI in quantitative evaluation of neonatal brain development. PMID- 26753490 TI - Interleukin-6 and C-reactive protein levels in the amniotic fluid as indicators of preterm delivery in Turkish women. AB - OBJECTIVE: The aim of this study was to determine the value of amniotic fluid interleukin-6 (IL-6) and C-reactive protein (CRP) levels in the prediction of preterm delivery in singleton pregnancies without any known risk factors for preterm delivery in Turkish women. MATERIALS AND METHODS: Patients in the present perinatology department who underwent mid-trimester genetic amniocentesis due to evidence of increased risk of aneuploidy in their prenatal serum screening tests were included in the study. A sample of amniotic fluid from each patient was assessed for IL-6 and CRP. Concentrations of IL-6 and CRP in the amniotic fluid of preterm delivery and term delivery groups were compared. RESULTS: Of 151 singleton pregnancies, 142 participants were included in the study. The participants were assigned to either the preterm or term delivery group based on pregnancy outcome. IL-6 levels in the amniotic fluid were significantly higher in the preterm delivery group, and there was a statistically significant negative correlation between IL-6 concentrations in the amniotic fluid and gestational age at delivery (correlation coefficient (CC): -18.5%, p < 0.05). A negative correlation was also detected between CRP levels in the amniotic fluid and gestational age at delivery, but the correlation was not statistically significant (p = 0.068). CONCLUSION: Measuring IL-6 in the amniotic fluid can identify women at risk of preterm delivery. Because it is not acceptable to perform amniocentesis for this screening, it is more convenient for patients in whom genetic amniocentesis is performed. PMID- 26753491 TI - Antenatal counseling against passive smoking may improve birth weight for gestational age. AB - AIM: The authors determined the impact of antenatal counseling against exposure to environmental cigarette smoke on the prevention of reduced neonatal birth weight according to gestational age. MATERIALS AND METHODS: A cross-sectional study was conducted in pregnant women, with 77 passive smokers and 88 non smokers. During motivational interviews, passive smoking status was monitored and additional follow-up visits were arranged to increase the knowledge regarding perinatal risks of passive smoking, including intrauterine growth restriction and low birth weight. The authors aimed to increase the woman's motivation to avoid second-hand tobacco smoke exposure. RESULTS: The demographic and clinical findings of the study groups were found considerably similar, in this context, and the authors found positive and strong correlations between the gestational age and neonatal birth weight (r = 0.80 and r = 0.76, respectively; p < 0.05). CONCLUSIONS: During antenatal care of women, regular counseling against second hand smoke exposure may prevent negative effect of passive smoking on neonatal birth weight according to gestational age. This promising finding needs to be supported by further studies with larger sample size considering covariates relevant to passive smoking. PMID- 26753492 TI - A novel case of an adenomyosis-related uterine rupture in pregnancy. AB - To date, few cases of uterine rupture related to adenomyosis have been reported. The current case report briefly describes a novel case of an adenomyosis related uterine rupture, while focusing on few symptoms that this kind of uterine rupture may have. Due to increasing rate of adenomyosis in Western countries, practicing obstetricians should carefully take in account silent uterine rupture related to adenomyosis. PMID- 26753493 TI - Mature cystic teratoma of both the fallopian tube and contralateral ovary: a case report. AB - Intratubal teratoma is a very rare condition. The authors believe to present the first case of a completely intratubal mature cystic teratoma with a contralateral intraovarian teratoma. Preoperative ultrasound examination allowed the intraoperative diagnosis of this rare condition, hence allowing appropriate surgical management. MATERIALS AND METHODS: A 19-year-old woman presented with a history of pelvic pain and severe dysmenorrhea. Ultrasound examination initially suggested bilateral ovarian dermoids. Upon laparoscopy, the distal left fallopian tube was obstructed and contained an inflammatory mass adhered to the rectosigmoid. The left ovary was entirely normal. A contralateral intraovarian dermoid was also identified. CONCLUSION: Although rare, when an intratubal mass is identified, consideration of intratubal dermoid should be given. Preoperative ultrasound can be of critical importance to the intraoperative diagnosis. PMID- 26753494 TI - Acardius acephalus fetus--report of distinctive anatomical anomalies with regards to pathophysiology of TRAP sequence. AB - Acardiac fetuses are consequences of twin reversed arterial perfusion (TRAP). Here the authors present a case of 40-year-old gravida IX who gave birth to a healthy, 2,900 g female child by a cesarean section. Additionally amorphic 1,020 g maldeveloped fetus was removed. There was a diamnion monochorionic type of twin placenta with incorrect single umbilical arteries (SUA) both in umbilical cord of healthy fetus and in atrophic second umbilical cord. A malformed fetus developed a rather well formed lower leg with four digital foot and oval shape amorphous body mass with omphalocele and eventration of the intestines. X-ray picture showed well visible metatarsal and femur bone and anatomically undefined bones cluster in the central part. A cavity of fetal body contained intestines--the only one well-formed organ, nests of heterotopic pilosebaceous residues, remnants of adrenal glands, well-formed ganglia, and nests of neural tissue covered by neuroepithelium. PMID- 26753495 TI - Early operative treatment of anti-N-methyl D-aspartate (anti-NMDA) receptor encephalitis in a patient with ovarian teratoma. AB - BACKGROUND: Anti-N-methyl D-aspartate (anti-NMDA) receptor encephalitis is often accompanied by ovarian teratoma. Early tumor resection is reported to be effective as a treatment. CASE: A 21-year-old woman presented with anti-NMDA receptor encephalitis which was accompanied by ovarian teratoma. The present case was a very rare case of an early stage of anti-NMDA receptor encephalitis receiving operative treatment before confirming the presence of anti-NMDA receptor antibody. The diagnosis was established postoperatively by identifying anti-NMDA receptor antibody. CONCLUSION: In case of suspecting anti-NMDA receptor encephalitis in a patient with ovarian teratoma, early operative treatment should be considered even before confirming the presence of anti-NMDA receptor antibody. PMID- 26753496 TI - Prenatal diagnosis of congenital syphilis presenting with transient pleural effusion in the fetus: a case report and rising incidence of congenital syphilis in South Korea. AB - Congenital syphilis is preventable and curable if maternal infection is detected early, and pregnant women in Korea are screened routinely for this disease. Nevertheless, the incidence of congenital syphilis is not decreasing. Prenatal diagnosis of congenital syphilis is difficult and treatment is usually based on maternal syphilis serology. Prenatal ultrasonographic examination may sometimes reveal abnormal features suggesting congenital infection. The authors report a case of congenital syphilis that was diagnosed in both fetus and asymptomatic mother following detection on prenatal ultrasonography of transient fetal pleural effusion. The case is noteworthy for its sonographic presentation as fetal pleural effusion rapidly resolved spontaneously. PMID- 26753497 TI - Secondary hypoparathyroidism during pregnancy--a case report and review of the literature. AB - Secondary hypoparathyroidism is seldom seen during pregnancy. Usually, it presents with hypocalcemia. Even if there is no established therapeutic treatment, vitamin D or its analogues are required. In the present case, a 36 year-old, second gravida, with known hypoparathyroidism for the last ten years, was admitted in the prenatal clinic of "Aretaieion" University Hospital in Athens at her 39 weeks of pregnancy. She was treated with calcitriol and calcium and she was monitored monthly. She had a cesarian section and delivered a healthy female baby of 3,380 gr at 39 weeks and 1 day. PMID- 26753498 TI - MRI in the assessment of prolapsed pedunculated submucous leiomyomas: two case reports. AB - Uterine leiomyomas are the most common benign gynecological tumors affecting 20 30% of women in reproductive age. Despite their benignity, in some cases several symptoms may require surgical intervention. Submucosal leiomyomas are less frequent (5-10%), but are usually symptomatic. Approximately 2.5% of the myomas are pedunculated and can protrude in the cervical canal. Symptomatic leiomyomas can be treated either by hysterectomy or myomectomy, and these procedures can be performed with several techniques. Whenever possible, hysteroscopic myomectomy is better because it has many advantages, as it also preserves future fertility. Two interesting cases of prolapsed pedunculated submucous leiomyomas are reported in order to prove that magnetic resonance imaging (MRI) is essential to choose the most appropriate treatment and to perform an adequate presurgical planning, which must be based on an overall assessment of the leiomyoma's characteristics (number, location, size and presence or absence of a stalk) and the patient's characteristics. PMID- 26753499 TI - Pulmonary embolism during delivery--treatment and outcome. AB - Pulmonary embolism during delivery is not a frequent occurrence. It is often impossible to ascertain whether it is a case of embolism by amniotic fluid or thromboembolism. Diagnostics of pulmonary embolism in labor is based solely on clinical symptoms. Immediate interdisciplinary treatment with cardiopulmonary resuscitation, hemodynamic stabilization, and correction of haemostasis disorders play a decisive role in prognosis. This paper presents diagnostics, treatment, and consequences of pulmonary embolism in expulsion phase during delivery in epidural anesthesia of a multiparous patient aged 37. PMID- 26753500 TI - Cesarean scar pregnancy associated with uterine artery pseudoaneurysm: a case report. AB - Cesarean scar pregnancy (CSP) and uterine artery pseudoaneurysms (UAPs) are associated with massive uterine hemorrhage and mortality. As a result of their low prevalence, the occurrence of CSP and a UAP in the same patient is extremely rare. The authors describe a patient who was initially misdiagnosed with trophoblastic disease by ultrasonography. The lesion had a blood-rich area of 75 x 65 x 61 mm on ultrasonography. Pelvic angiography revealed a UAP in the right side of the uterus. The patient underwent uterine artery embolization (UAE) immediately after the correct diagnosis was confirmed. Curettage was undertaken under ultrasound guidance one week postoperatively. Histopathological examination of the resected tissue revealed degenerative chorionic villi and trophoblasts with blood clots. Serum levels of beta-human chorionic gonadotropin (beta-hCG) and uterine ultrasound recovered to normal levels two weeks and three months later, respectively. PMID- 26753501 TI - Minimally invasive semitendinosus tendon harvesting from the popliteal fossa versus conventional hamstring tendon harvesting for ACL reconstruction: A prospective, randomised controlled trial in 100 patients. AB - BACKGROUND: This study aims to compare a technique for hamstring tendon harvesting from a postero-medial incision in the popliteal fossa with the conventional method. METHODS: One hundred patients who underwent anterior cruciate ligament (ACL)-reconstruction were randomised to either have their tendon graft harvested from postero-medial (group 1) or via an antero-medial approach (group 2). Time for tendon harvest, length of skin incision and duration of tendon harvest were recorded as well as complications and sensory disturbances in the lower leg. Pain scores were documented on the VAS scale. RESULTS: Time for tendon harvesting averaged one minute 23 s in group 1 versus five minutes 20 s in group 2 (p<0.01). The skin incision measured 21 mm (group 1) versus 49 mm in group 2 (p<0.01). The length of the harvested tendon averaged 272 mm (group 1) and 292 mm in group 2 (p<0.01). There was one superficial wound infection in group 2 and none in group 1. Postoperative pain scores were similar in both groups. None of the patients in group 1 reported sensory disturbance in the lower leg, whilst seven patients in group 2 were found to have reduced sensation in the distribution of the saphenous nerve postoperatively (p<0.01). CONCLUSION: This study confirms that harvesting the semitendinosus tendon from postero-medial is quicker, results in a shorter scar and reduces the risk of injury to branches of the saphenous nerve. However, harvesting the tendon from postero-medial resulted in a shorter tendon graft. LEVEL OF EVIDENCE: Level I (Randomised, controlled trial). PMID- 26753502 TI - The rearing environment and risk for drug abuse: a Swedish national high-risk adopted and not adopted co-sibling control study. AB - BACKGROUND: Although drug abuse (DA) is strongly familial, with important genetic influences, we need to know more about the role of rearing environment in the risk for DA. To address this question, we utilized a high-risk adopted and non adopted co-sibling control design. METHOD: High-risk offspring had one or more biological parents registered for DA, alcohol use disorders or criminal behavior. Using Swedish registries, we identified 1161 high-risk full-sibships and 3085 high-risk half-sibships containing at least one member who was adopted-away and one member who was not. Registration for DA was via national criminal, medical and pharmacy registers. In Sweden, adoptive families are screened to provide high quality rearing environment for adoptees. RESULTS: Controlling for parental age at birth and gender (and, in half-siblings, high-risk status of the other parent), risk for DA was substantially lower in the full- and half-siblings who were adopted v. not adopted [hazard ratios and 95% confidence intervals: 0.55 (0.45-0.69) and 0.55 (95% CI 0.48-0.63), respectively]. The protective effect of adoption on risk for DA was significantly stronger in the full- and half-sibling pairs with very high familial liability (two high-risk parents) and significantly weaker when the adoptive family was broken by death or divorce, or contained a high-risk parent. CONCLUSIONS: In both full- and half-sibling pairs, we found replicated evidence that rearing environment strongly impacts on risk for DA. High-quality rearing environments can substantively reduce risk for DA in those at high genetic risk. PMID- 26753503 TI - Collagens VI and XII form complexes mediating osteoblast interactions during osteogenesis. AB - Bone formation is precisely regulated by cell-cell communication in osteoblasts. We have previously demonstrated that genetic deletion of Col6a1 or Col12a1 impairs osteoblast connections and/or communication in mice, resulting in bone mass reduction and bone fragility. Mutations of the genes encoding collagen VI cause Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM), which have overlapping phenotypes involving connective tissue and muscle. Recent studies have identified COL12A1 gene mutations in patients with UCMD- and BM-like disorders harboring no COL6 mutations, indicating the shared functions of these collagens in connective tissue homeostasis. The purpose of this investigation has been to test the hypothesis that collagens VI and XII have coordinate regulatory role(s) during bone formation. We analyzed the localization of collagens VI and XII relative to primary osteoblasts during osteogenesis. Immunofluorescence analysis demonstrated that collagens VI and XII colocalized in matrix bridges between adjacent cells during periods when osteoblasts were establishing cell cell connections. Quantification of cells harboring collagen bridges demonstrated that matrix bridges were composed of collagens VI and XII but not collagen I. Interestingly, matrix bridge formation was impaired in osteoblasts deficient in either Col6a1 or Col12a1, suggesting that both collagens were indispensable for matrix bridge formation. These data demonstrate, for the first time, a functional relationship between collagens VI and XII during osteogenesis and indicate that a complex containing collagens VI and XII is essential for the formation of a communicating cellular network during bone formation. PMID- 26753504 TI - Emerging endoscopic techniques for the identification of esophageal disease. AB - Esophageal diseases, both benign and malignant, impose an increasing burden to global health. In the West, gastroesophageal reflux disease (GERD) and Barrett's esophagus are increasing in prevalence and impact. In the East, squamous esophageal cancer remains a large burden, but increasingly, precancerous lesions related to GERD are recognized. We review the various advanced endoscopic techniques that have been developed to improve the accuracy of endoscopic identification of esophageal disease. These techniques are designed to increase the sensitivity of detecting disease and high-risk lesions, enable targeted biopsies, decrease total number of biopsies and costs for surveillance, but also guide therapy in real-time. After proper clinical validation, the widespread use of these technologies will lead to improved outcomes, mostly in cancer prevention. PMID- 26753506 TI - Indeterminacy Problems in the Lisrel Model. AB - The latent variables and errors of the Lisrel model are indeterminate even when the parameters of the model are perfectly identified. The reason for the indeterminacy is that the Lisrel model gives a solution in terms of estimation of latent variables by means of observed variables. The indeterminacy is relevant also in practice; the minimum correlation between equivalent latent variables, is often negative in empirical examples. The degree of indeterminacy of the latent variables depends on the data. The average minimum correlation is a linear combination of the eigenvalues of the correlation matrix of solutions and it is always included in weak bounds which depend on the same eigenvalues. PMID- 26753507 TI - Genotype-Environment Covariance for Multiple Phenotypes: A Multivariate Test Using Adopted and Nonadopted Children. AB - A bivariate generalization of the genotype-environment (GE) covariation is presented. This biometrical parameter measures the relation between genotypic influences in one attribute with environmental influences in another attribute. A multivariate procedure for detecting the presence of both univariate and bivariate GE covariation is also described, based on a test of homogeneity of observed variance-covariance matrices in adopted and nonadopted individuals. An illustrative application to measures of specific cognitive abilities in four-year old children in the Colorado Adoption Project (CAP) is provided. The analyses provided evidence of bivariate but not univariate GE covariance among perceptual speed, memory, verbal and spatial abilities in these children. A comparison of the results from the presently described and other more elaborate model-fitting procedures is made, with a discussion of the merits and disadvantages of each approach. PMID- 26753505 TI - Melanoma of the Oral Cavity: an Analysis of 46 New Cases with Emphasis on Clinical and Histopathologic Characteristics. AB - Melanoma of the oral cavity is a rare malignancy that carries a poor prognosis. We identified 46 new cases of both primary and metastatic melanoma to the oral cavity. Following IRB approval, these cases were obtained from the Oral Pathology Biopsy Service archives of the UF College of Dentistry (1994-2014), the UK College of Dentistry (1997-2015), and the UM Medical Center (1988-2015). All slides were reviewed. The location, age, race, gender, clinical impression, duration of lesion, histopathologic diagnosis, and histopathologic features were recorded. Cases from the facial skin and those with an ambiguous diagnosis were excluded. Forty-six cases fulfilled the inclusion criteria with 32 primary cases, 11 known metastases, and 3 cases where metastasis could not be excluded. The primary cases included a total of 20 females and 12 males with an average age of 66.7 (range 27-95), and the majority (80 %) of the patients were Caucasian when race was known. Twenty-two of the 32 primary cases (68.8 %) were located in the maxillary mucosa, 5 in the mandibular mucosa or bone, and 5 in other locations. The clinicians' impressions varied from benign fibrous growths to high grade malignancies. The histopathology varied widely among the cases, however two cell types predominated (often in combination): epithelioid cells (50.0 %) and spindle cells (50.0 %). Only 53.1 % demonstrated melanin pigmentation. Oral melanoma remains one of the most diverse clinical and histopathologic diagnoses. Better understanding of this neoplasm may promote earlier diagnosis and may lead to improved outcomes. PMID- 26753508 TI - Variation in Initial Procedures and the Stability of Dimensions Extracted from Free Response Data. AB - The purpose of the research was to examine the stability of dimensions extracted from a body of free response data under conditions of variation in the initial data reduction procedures. Data consisted of over 1500 expressions of concern and questions raised by an elderly population. Complete sequences of analytic steps were conducted on the data by two groups of experimenters working independently. These sequences included determining representative units to be scaled, developing instructions for obtaining proximity measures, recruiting subjects, and administering the sorting tasks necessary to obtain proximity measures. In spite of dramatic differences in procedures at each of these steps, the structures of the resulting multidimensional configurations obtained by the two groups were identical. Selected, independently measured properties were used to interpret the configurations. In both cases, a three dimensional solution defined by the properties Health Related, Quality of Lire, and Individual versus Societal Responsibility appeared optimal. PMID- 26753509 TI - Single Sample Cross-Validation Indices for Covariance Structures. AB - This article considers single sample approximations for the cross-validation coefficient in the analysis of covariance structures. An adjustment for predictive validity which may be employed in conjunction with any correctly specified discrepancy function is suggested. In the case of maximum likelihood estimation under normality assumptions the coefficient obtained is a simple linear function of the Akaike Information Criterion. Results of a random sampling experiment are reported. PMID- 26753510 TI - The Structure of Affect and Trait Judgments of Political Figures. AB - The roles of affective and cognitive processes in judgment have been the focus of much recent research and theoretical debate. This study was designed to investigate the structure of voters' affective reactions and trait attributions to national political figures. Three-mode factor analysis was used to determine the structure of the affect and trait scales. Politician factors and subject types were also derived, as were the interrelationships among these modes. Positive and negative affect factors, and affect and trait factors, were distinct but correlated; Democratic and Republican politician factors were uncorrelated. Information on the subject types moderated these relationships. PMID- 26753511 TI - Power and Type I Error Rates for Rank-Score MANOVA Techniques. AB - A Monte Carlo simulation study was performed to compare the power and the Type I errors of the Wilks's lambda statistic and the Purl and Sen (1971) statistic on transformed data in a one-way MANOVA. The behavior of the Wilks's lambda statistic and the Puri and Sen statistic are studied using normal scores and ranks of the data. Both chi-square approximations and F approximations are used to estimate the distribution of these statistics. Various combinations of sample sizes and numbers of variables are used in the simulation study. For the situations considered in both normal and nonnormal homoscedastic conditions, the Wilks's lambda statistic calculated using normal scores and used with the F approximation appeared to be somewhat more robust with respect to maintaining its stated significance level than its competitors. Also, the F approximation for the Puri and Sen statistic is also shown to be more robust with respect to maintaining its stated significance level than the standard chi-square approximation. PMID- 26753512 TI - Multigroup Comparisons and the Assumption of Equivalent Construct Validity Across Groups: Methodological and Substantive Issues. AB - The purposes of this article are (a) to compare construct validity findings from Campbell-Fiske and LISREL confirmatory factor analyses (CFA) of a multitrait multimethod matrix for each of two groups, and then to test for construct validity equivalence across groups -- the methodological issue, and (b) to demonstrate how construct validity can differ across groups -- the substantive issue. Multidimensional self-concept (general, academic, English, mathematics) responses to three types of measurement scales (Likert, semantic differential, Guttman) for low- and high4rack grade 11 and 12 students provided the exemplary data base. Methodologically, findings demonstrate the superiority of CFA over the Campbell-Fiske approach by (a) providing more detailed evidence of construct validity within groups, and (b) testing for the equivalency of construct validity across groups. Substantively, the findings illustrate that the assumption of group-invariant construct validity cannot be taken for granted; differences were found in both the measurement and structure of self-concept. Results bear importantly on the validity of findings based on multigroup comparisons. PMID- 26753513 TI - Human milk fatty acids composition is affected by maternal age. AB - Human colostrums and transition milk were collected from women under the age of 37 years and women aged 37 years and older. Transition milk of the younger group had lower fat content and 10-fold higher concentrations of omega 6 FA, eicosadecanoic, and arachdonic acids. Gestational age affected the colostrum concentration of total fat and omega 3 and omega 6 FA composition only in the older group. We concluded that age may be a factor in the FA composition of human milk. This should be taken into account when planning diets for pregnant women of different ages. PMID- 26753514 TI - Surfactant-associated bacteria in the near-surface layer of the ocean. AB - Certain marine bacteria found in the near-surface layer of the ocean are expected to play important roles in the production and decay of surface active materials; however, the details of these processes are still unclear. Here we provide evidence supporting connection between the presence of surfactant-associated bacteria in the near-surface layer of the ocean, slicks on the sea surface, and a distinctive feature in the synthetic aperture radar (SAR) imagery of the sea surface. From DNA analyses of the in situ samples using pyrosequencing technology, we found the highest abundance of surfactant-associated bacterial taxa in the near-surface layer below the slick. Our study suggests that production of surfactants by marine bacteria takes place in the organic-rich areas of the water column. Produced surfactants can then be transported to the sea surface and form slicks when certain physical conditions are met. This finding has potential applications in monitoring organic materials in the water column using remote sensing techniques. Identifying a connection between marine bacteria and production of natural surfactants may provide a better understanding of the global picture of biophysical processes at the boundary between the ocean and atmosphere, air-sea exchange of greenhouse gases, and production of climate active marine aerosols. PMID- 26753515 TI - Potential Prophylactic Properties of Apple and Characterization of Potent Bioactive from cv. "Granny Smith" Displaying Strong Antimutagenicity in Models Including Human Lymphoblast TK6(+/-) Cell Line. AB - Potential prophylactic attributes in terms of antimutagenicity, antioxidant, and radioprotective properties were evaluated for 8 common apple cultivars namely "Fuji," "Golden Delicious," "Granny Smith," "Ambri Kashmiri," "Kinnaur," "Red Delicious," "Royal Gala," and "Shimla," where cultivar based significant variation was observed. Cv. "Granny Smith" displayed significantly higher and broad spectrum antimutagenicity in Escherichia coli rpoB based rifampicin resistance (Rif(R) ) assay, whereas, "Ambri Kashmiri," "Royal Gala," and "Shimla" showed lower antimutagenicity. Cultivars "Ambri Kashmiri," "Kinnaur," and "Red Delicious" exhibited strong antioxidant activity than cv. "Granny Smith" as assayed by radical scavenging, reducing potential and radioprotective property assays. The antioxidant and radioprotective properties were found to be better correlated than antimutagenicity. Suppression of error-prone DNA repair pathway (such as E. coli SOS response) was found to be one of the possible mechanisms contributing to its antimutagenicity. Phenolic extract of "Granny Smith? showing higher antimutagenicity was HPLC purified and the bioactive fraction (tR 35.4 min) contributing maximally (~80%) to the observed antimutagenicity was identified as procyanidin dimer (PD) by ESI-MS/MS. The above observed antimutagenicity in bacterial assay system was well reproduced in Thymidine Kinase Mutation (TKM) assay performed using human lymphoblast cell line (TK6(+/-) ) cell line making the findings more prophylactically relevant. PMID- 26753516 TI - Multiple copy number variants in a pediatric patient with Hb H disease and intellectual disability. AB - Two distinct syndromes that link alpha-thalassemia and intellectual disability (ID) have been described: ATR-X, due to mutations in the ATRX gene, and ATR-16, a contiguous gene deletion syndrome in the telomeric region of the short arm of chromosome 16. A critical region where the candidate genes for the ID map has been established. In a pediatric patient with Hemoglobin H disease, dysmorphic features and ID, 4 novel and clinically relevant Copy Number Variants were identified. PCR-GAP, MLPA and FISH analyses established the cause of the alpha thalassemia. SNP-array analysis revealed the presence of 4 altered loci: 3 deletions (arr[hg19]Chr16(16p13.3; 88,165-1,507,988) x1; arr[hg19]Chr6(6p21.1; 44,798,701-45,334,537) x1 and arr[hg19]Chr17(17q25.3; 80,544,855-81,057,996) x1) and a terminal duplication (arr[hg19]Chr7(7p22.3-p22.2; 4,935-4,139,785) x3). The -alpha(3.7) mutation and the ~1.51 Mb in 16p13.3 are involved in the alpha thalassemic phenotype. However, the critical region for ATR-16 cannot be narrowed down. The deletion affecting 6p21.1 removes the first 2 exons and part of intron 2 of the RUNX2 gene. Although heterozygous loss of function mutations affecting this gene have been associated with cleidocranial dysplasia, the patient does not exhibit pathognomonic signs of this syndrome, possibly due to the fact that the isoform d of the transcription factor remains unaffected. This work highlights the importance of searching for cryptic deletions in patients with ID and reiterates the need of the molecular analysis when it is associated to microcytic hypochromic anemia with normal iron status. PMID- 26753519 TI - Combining location-and-scale batch effect adjustment with data cleaning by latent factor adjustment. AB - BACKGROUND: In the context of high-throughput molecular data analysis it is common that the observations included in a dataset form distinct groups; for example, measured at different times, under different conditions or even in different labs. These groups are generally denoted as batches. Systematic differences between these batches not attributable to the biological signal of interest are denoted as batch effects. If ignored when conducting analyses on the combined data, batch effects can lead to distortions in the results. In this paper we present FAbatch, a general, model-based method for correcting for such batch effects in the case of an analysis involving a binary target variable. It is a combination of two commonly used approaches: location-and-scale adjustment and data cleaning by adjustment for distortions due to latent factors. We compare FAbatch extensively to the most commonly applied competitors on the basis of several performance metrics. FAbatch can also be used in the context of prediction modelling to eliminate batch effects from new test data. This important application is illustrated using real and simulated data. We implemented FAbatch and various other functionalities in the R package bapred available online from CRAN. RESULTS: FAbatch is seen to be competitive in many cases and above average in others. In our analyses, the only cases where it failed to adequately preserve the biological signal were when there were extremely outlying batches and when the batch effects were very weak compared to the biological signal. CONCLUSIONS: As seen in this paper batch effect structures found in real datasets are diverse. Current batch effect adjustment methods are often either too simplistic or make restrictive assumptions, which can be violated in real datasets. Due to the generality of its underlying model and its ability to perform well FAbatch represents a reliable tool for batch effect adjustment for most situations found in practice. PMID- 26753517 TI - Adipose-derived endothelial and mesenchymal stem cells enhance vascular network formation on three-dimensional constructs in vitro. AB - BACKGROUND: Adipose-derived mesenchymal stem cells (MSCs) have been gaining fame mainly due to their vast clinical potential, simple isolation methods and minimal donor site morbidity. Adipose-derived MSCs and microvascular endothelial cells have been shown to bear angiogenic and vasculogenic capabilities. We hypothesized that co-culture of human adipose-derived MSCs with human adipose-derived microvascular endothelial cells (HAMECs) will serve as an effective cell pair to induce angiogenesis and vessel-like network formation in three-dimensional scaffolds in vitro. METHODS: HAMECs or human umbilical vein endothelial cells (HUVECs) were co-cultured on scaffolds with either MSCs or human neonatal dermal fibroblasts. Cells were immunofluorescently stained within the scaffolds at different time points post-seeding. Various analyses were performed to determine vessel length, complexity and degree of maturity. RESULTS: The HAMEC:MSC combination yielded the most organized and complex vascular elements within scaffolds, and in the shortest period of time, when compared to the other tested cell combinations. These differences were manifested by higher network complexity, more tube alignment and higher alpha-smooth muscle actin expression. Moreover, these generated microvessels further matured and developed during the 14-day incubation period within the three-dimensional microenvironment. CONCLUSIONS: These data demonstrate optimal vascular network formation upon co culture of microvascular endothelial cells and adipose-derived MSCs in vitro and constitute a significant step in appreciation of the potential of microvascular endothelial cells and MSCs in different tissue engineering applications that can also be advantageous in in vivo studies. PMID- 26753518 TI - Dioscorea bulbifera polysaccharide and cyclophosphamide combination enhances anti cervical cancer effect and attenuates immunosuppression and oxidative stress in mice. AB - Cyclophosphamide (CTX) is commonly used in cancer chemotherapy, which causes immunosuppression and tissue oxidative stress at high doses. As potential protective agents, some polysaccharides were shown to have anti-tumor, anti inflammatory and/or anti-oxidant properties. This study explored potential effects of oral treatment of Dioscorea bulbifera polysaccharides (DBLP at 100 or 150 mg/kg) in U14 cervical tumor-bearing mice treated with CTX (25 mg/kg). While CTX suppressed tumor growth (65.4% inhibition) and DBLP alone also inhibited tumor (25.6% at 100 mg/kg or 37.6% at 150 mg/kg), CTX+DBLP combination produced tumor inhibition rates of 5.6 (for 100 mg/kg DBLP) or 9% (for 150 mg/kg) higher than CTX alone. While tumor itself and CTX treatment reduced thymus and/or spleen/body weight indices, DBLP alone or CTX + DBLP combination attenuated this reduction. DBLP lowered peripheral blood T-cell subpopulation CD(4+)/CD(8+) ratio, and DBLP+CTX combination attenuated CTX effect in lifting CD(4+)/CD(8+) ratio. Tumor itself and CTX treatment heightened oxidative stress (with decreased superoxide dismutase but increased lactate dehydrogenase and malondialdehyde levels in serum and tissues), which was attenuated by DBLP treatment, and DBLP+CTX combination suppressed CTX-induced oxidative stress. Combination use of DBLP with CTX can potentially enhance CTX anti-tumor effect and can attenuate CTX induced immunosuppression and oxidative stress in U14 cervical tumor-bearing mice. PMID- 26753520 TI - Ultrasensitive determination of 5-methylcytosine and 5-hydroxymethylcytosine in genomic DNA by sheathless interfaced capillary electrophoresis-mass spectrometry. AB - A newly developed sheathless interface for capillary electrophoresis-mass spectrometry, using a porous tip sprayer, was first applied for highly sensitive determination of cytosine modifications. The system performed well in identification and quantification of both 5-methylcytosine and 5 hydroxymethylcytosine using only 125 pg (~20 cells) genomic DNA samples. PMID- 26753521 TI - Modulation of cadmium bioaccumulation and enhancing cadmium tolerance in Pichia kudriavzevii by sodium chloride preincubation. AB - Application of growing microorganisms for cadmium removal is limited by the sensitivity of living cells to cadmium. The effects of sodium chloride (NaCl) preincubation on the cadmium bioaccumulation and tolerance of Pichia kudriavzevii and Saccharomyces cerevisiae were investigated in this study. NaCl preincubation significantly reduced the intracellular and cell-surface cadmium bioaccumulation of P. kudriavzevii at both 6 and 20 mg L(-1) cadmium, while no obvious effect was observed in S. cerevisiae except that the intracellular cadmium bioaccumulation at 20 mg L(-1) cadmium was reduced obviously by 20-60 g L(-1) NaCl. For both yeasts, the improved contents of protein and proline after NaCl preincubation contributed to the cadmium tolerance. The thiol contents in P. kudriavzevii under cadmium stress were alleviated by NaCl preincubation, which might be due to the decrease of intracellular cadmium bioaccumulation. NaCl preincubation enhanced the contents of glycerol and trehalose in P. kudriavzevii under cadmium stress, while no acceleration was observed in S. cerevisiae. The results suggested that NaCl preincubation could be applied in cadmium removal by growing P. kudriavzevii to increase the cadmium tolerance of the yeast. PMID- 26753522 TI - Universal Fabrication of 2D Electron Systems in Functional Oxides. AB - 2D electron systems (2DESs) in functional oxides are promising for applications, but their fabrication and use, essentially limited to SrTiO3 -based heterostructures, are hampered by the need for growing complex oxide overlayers thicker than 2 nm using evolved techniques. It is demonstrated that thermal deposition of a monolayer of an elementary reducing agent suffices to create 2DESs in numerous oxides. PMID- 26753524 TI - Hematidrosis: a report with histological and biochemical documents. PMID- 26753523 TI - Associations of mutually exclusive categories of physical activity and sedentary time with markers of cardiometabolic health in English adults: a cross-sectional analysis of the Health Survey for England. AB - BACKGROUND: Both physical activity and sedentary behaviour have been individually associated with health, however, the extent to which the combination of these behaviours influence health is less well-known. The aim of this study was to examine the associations of four mutually exclusive categories of objectively measured physical activity and sedentary time on markers of cardiometabolic health in a nationally representative sample of English adults. METHODS: Using the 2008 Health Survey for England dataset, 2131 participants aged >= 18 years, who provided valid accelerometry data, were included for analysis and grouped into one of four behavioural categories: (1) 'Busy Bees': physically active & low sedentary, (2) 'Sedentary Exercisers': physically active & high sedentary, (3) 'Light Movers': physically inactive & low sedentary, and (4) 'Couch Potatoes': physically inactive & high sedentary. 'Physically active' was defined as accumulating at least 150 min of moderate-to-vigorous physical activity (MVPA) per week. 'Low sedentary' was defined as residing in the lowest quartile of the ratio between the average sedentary time and the average light-intensity physical activity time. Weighted multiple linear regression models, adjusting for measured confounders, investigated the differences in markers of health across the derived behavioural categories. The associations between continuous measures of physical activity and sedentary levels with markers of health were also explored, as well as a number of sensitivity analyses. RESULTS: In comparison to 'Couch Potatoes', 'Busy Bees' [body mass index: -1.67 kg/m(2) (p < 0.001); waist circumference: 1.17 cm (p = 0.007); glycated haemoglobin: -0.12% (p = 0.003); HDL-cholesterol: 0.09 mmol/L (p = 0.001)], 'Sedentary Exercisers' [body mass index: -1.64 kg/m(2) (p < 0.001); glycated haemoglobin: -0.11 % (p = 0.009); HDL-cholesterol: 0.07 mmol/L (p < 0.001)] and 'Light Movers' [HDL-cholesterol: 0.11 mmol/L (p = 0.004)] had more favourable health markers. The continuous analyses showed consistency with the categorical analyses and the sensitivity analyses indicated robustness and stability. CONCLUSIONS: In this national sample of English adults, being physically active was associated with a better health profile, even in those with concomitant high sedentary time. Low sedentary time independent of physical activity had a positive association with HDL-cholesterol. PMID- 26753526 TI - Corrigendum: Robustness and period sensitivity analysis of minimal models for biochemical oscillators. PMID- 26753527 TI - Effects of light variation on Schwalbe's line-based anterior chamber angle metrics measured with cirrus spectral domain optical coherence tomography. AB - BACKGROUND: Evaluate the impact of variations in ambient lighting conditions on the reproducibility/reliability of Schwalbe's Line (SL)-based anterior chamber angle (ACA) metrics using spectral domain optical coherence tomography (SD-OCT). DESIGN: Images were taken at Doheny Eye Centers-UCLA clinic, which were randomized, masked and graded twice by dual reading centre graders. PARTICIPANTS: Twenty-five normal/healthy participants with open angles METHODS: Inferior angles were imaged using Cirrus SD-OCT under five light levels (foot-candles (fc) measured at camera-eye interface with Sper light-meter) with the instrument's corneal illumination function set to default level of 50 (CIdef) and low 5 (CIlow). Each eye was imaged 20 times, totaling 500 assessments. MAIN OUTCOME MEASURES: SL-angle-opening-distance (SL-AOD) and SL-trabecular-iris-space-area (SL-TISA) measured using custom ImageJ software. Intra-/inter-grader variability analyses were completed using Statistical-Package-for-Social-Science and Bland Altman plots demonstrated limits of agreement for comparisons. RESULTS: Light level demonstrated a linear relationship with angle size, thus differences from highest to lowest light levels were compared. Decreasing light from 1.0 -> 0.0fc at CIdef decreased SL-AOD from 394 um +/- 137 um -> 356 um +/- 137 um (mean percent difference (MPD) = 10.71%,P < 0.001) and SL-TISA from 297 um(2) +/- 114 um(2) -> 261 um(2) +/- 109 um(2) (MPD = 13.7%, P < 0.001). Decreasing from 1.0 > 0.0fc at CIlow decreased SL-AOD from 366 um +/- 136 um -> 329 um +/- 122 um (MPD = 10.9%, P < 0.001) and SL-TISA from 271 um(2) +/- 113 um(2) -> 234 um(2) +/- 98 um(2) (MPD = 15.8%, P < 0.001). There was 7.9/11.4% (both P < 0.001) difference for SL-AOD/SL-TISA between CIdef -> CIlow at 1.0fc, and 7.7/9.4% (both P < 0.001) difference at 0.0fc. Intra-/inter-grader results showed high reproducibility for all metrics (MPD = 0.33-4.4%; CV = 0.96-1.36; PCC = 0.93 0.95(P < 0.001); R2 = 0.94-0.98). Bland-Altman plots did not demonstrate bias, with repeat-ability and agreement among measurements. CONCLUSIONS: Using Cirrus SD-OCT, we found that SL-based ACA morphometrics are exquisitely sensitive to changes in ambient illumination and also corneal illumination by the OCT instrument. Consistently imaging in the darkest room possible is recommended (<=0.2 fce). PMID- 26753525 TI - Protective effects of Egyptian cloudy apple juice and apple peel extract on lipid peroxidation, antioxidant enzymes and inflammatory status in diabetic rat pancreas. AB - BACKGROUND: Apples possess rich content of varied polyphenolic compounds showing a variety of biological activities that may ascribe to worthy effects against some chronic diseases. The present study was designed to assess the protective effects of the cloudy apple juice (CAJ) and apple peel extract (APE) of Egyptian Anna apple on the complications in experimental diabetes. MATERIALS AND METHODS: Four groups were studied. Diabetes was induced by a single dose of streptozotocin (STZ) to only three groups of albino Wistar rats. Two of the diabetic groups received either CAJ or APE for 21 days. At the end of the study, lipid profile parameters were measured in serum while lipid peroxidation (LPO) level, antioxidant enzyme activities and inflammatory markers were evaluated in pancreas tissue samples. The gas chromatography-mass spectrometry (GC-MS) analysis of phenolic compounds found in CAJ and APE was carried out. Moreover, total phenolic content of CAJ and APE were measured. RESULTS: The significant increase of blood glucose level, serum total cholesterol (TC), triglycerides (TG), low- density lipoprotein cholesterol (LDL-C), and very low-density lipoprotein (VLDL) levels, in addition to tissue malondialdehyde (MDA), nuclear factor kappa B (NF-kB), tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), interleukin 8 (IL 8) levels, but a significant decrease in high-density lipoprotein cholesterol (HDL-C), and the activity of pancreatic antioxidant enzymes were the remarkably parameters observed in diabetic control rats. Dissimilarly, oral supplementation of 15 ml/kg CAJ and 1 g/kg APE for 21 days resulted in a significant decrease in fasting blood glucose, serum TC, TG, LDL-C, VLDL-C and tissue MDA, NF-kB, TNF alpha, IL-6, IL-8 levels coupled with a significant elevation of HDL-C and antioxidant enzymes' activity when compared with diabetic control animals. CONCLUSIONS: The results indicate that Egyptian CAJ and APE supplementation may have protective effects against deleterious complications of diabetes mellitus. PMID- 26753528 TI - Does improving poison prevention practices reduce childhood poisoning rates. PMID- 26753529 TI - Factorial experimental designs. PMID- 26753530 TI - Discovery and profiling of small RNAs responsive to stress conditions in the plant pathogen Pectobacterium atrosepticum. AB - BACKGROUND: Small RNAs (sRNAs) have emerged as important regulatory molecules and have been studied in several bacteria. However, to date, there have been no whole transcriptome studies on sRNAs in any of the Soft Rot Enterobacteriaceae (SRE) group of pathogens. Although the main ecological niches for these pathogens are plants, a significant part of their life cycle is undertaken outside their host within adverse soil environment. However, the mechanisms of SRE adaptation to this harsh nutrient-deficient environment are poorly understood. RESULTS: In the study reported herein, by using strand-specific RNA-seq analysis and in silico sRNA predictions, we describe the sRNA pool of Pectobacterium atrosepticum and reveal numerous sRNA candidates, including those that are induced during starvation-activated stress responses. Consequently, strand-specific RNA-seq enabled detection of 137 sRNAs and sRNA candidates under starvation conditions; 25 of these sRNAs were predicted for this bacterium in silico. Functional annotations were computationally assigned to 68 sRNAs. The expression of sRNAs in P. atrosepticum was compared under growth-promoting and starvation conditions: 68 sRNAs were differentially expressed with 47 sRNAs up-regulated under nutrient deficient conditions. Conservation analysis using BLAST showed that most of the identified sRNAs are conserved within the SRE. Subsequently, we identified 9 novel sRNAs within the P. atrosepticum genome. CONCLUSIONS: Since many of the identified sRNAs are starvation-induced, the results of our study suggests that sRNAs play key roles in bacterial adaptive response. Finally, this work provides a basis for future experimental characterization and validation of sRNAs in plant pathogens. PMID- 26753531 TI - Correction: Reaction mechanisms in ionic liquids: the kinetics and mechanism of the reaction of O,O-diethyl (2,4-dinitrophenyl) phosphate triester with secondary alicyclic amines. AB - Correction for 'Reaction mechanisms in ionic liquids: the kinetics and mechanism of the reaction of O,O-diethyl (2,4-dinitrophenyl) phosphate triester with secondary alicyclic amines' by Paulina Pavez et al., Org. Biomol. Chem., 2016, DOI: 10.1039/c5ob02128f. PMID- 26753532 TI - Establishment and analysis of in vitro biomass from Salvia corrugata Vahl. and evaluation of antimicrobial activity. AB - Demethylfruticuline A and fruticuline A, the most abundant compounds from the surface extract of Salvia corrugata Vahl., have shown antibacterial, antitumor and cytotoxic activities. In order to obtain these icetexane diterpenes from in vitro cultures of S. corrugata, protocols were developed for callus production, micropropagation and shoot regeneration. Analysis of the regenerated shoots showed the presence of both icetexanes, micropropagated plants contained only fruticuline A, while the callus contained trace amounts of both diterpenes. The yield of fruticuline A was higher in the methanolic extract of regenerated shoots than in those of fresh leaves and fresh shoot tips. In addition to these diterpenes, the regenerated shoot and micropropagated plant extracts afforded seven other diterpenes, one icetexane and six abietanes, identified by UV, IR, 1D and 2D-NMR and HR-MS analysis. Five compounds (19-acetoxy-7alpha hydroxyroyleanone, 7beta,20-epoxy-11,12,19-trihydroxyabieta-8,11,13-triene, 7,20 dihydrofruticuline A, 7beta-acetoxy-20-hydroxy-19,20-epoxyroyleanone, 7beta ethoxy-6beta,20:19,20-diepoxyroyleanone) were previously undescribed. Although the crude plant surface extract did not possess any antibacterial activity, methanolic extracts of in vitro tissues and two compounds, namely 7beta-acetoxy 20-hydroxy-19,20-epoxyroyleanone and 7beta-ethoxy-6beta,20:19,20 diepoxyroyleanone, isolated in suitable amounts, were active in varying degrees against multidrug resistant clinical strains of Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis and Enterococcus faecium, displaying MIC values ranging from 32, 64 to 128MUg/mL. PMID- 26753535 TI - Structure-Function Relationship of a Novel PR-5 Protein with Antimicrobial Activity from Soy Hulls. AB - An alkaline isoform of the PR-5 protein (designated GmOLPc) has been purified from soybean hulls and identified by MALDI-TOF/TOF-MS. GmOLPc effectively inhibited in vitro the growth of Phytophthora soja spore and Pseudomonas syringae pv glycinea. The antimicrobial activity of GmOLPc should be mainly ascribed to its high binding affinity with vesicles composed of DPPG, (1,3)-beta-D-glucans, and weak endo-(1,3)-beta-D-glucanase activity. From the 3D models, predicted by the homology modeling, GmOLPc contains an extended negatively charged cleft. The cleft was proved to be a prerequisite for endo-(1,3)-beta-D-glucanase activity. Molecular docking revealed that the positioning of linear (1,3)-beta-D-glucans in the cleft of GmOLPc allowed an interaction with Glu83 and Asp101 that were responsible for the hydrolytic cleavage of glucans. Interactions of GmOLPc with model membranes indicated that GmOLPc possesses good surface activity which could contribute to its antimicrobial activity, as proved by the behavior of perturbing the integrity of membranes through surface hydrophobic amino acid residues (Phe89 and Phe94). PMID- 26753533 TI - An intact Pms2 ATPase domain is not essential for male fertility. AB - The DNA mismatch repair (MMR) machinery in mammals plays critical roles in both mutation avoidance and spermatogenesis. Meiotic analysis of knockout mice of two different MMR genes, Mlh1 and Mlh3, revealed both male and female infertility associated with a defect in meiotic crossing over. In contrast, another MMR gene knockout, Pms2 (Pms2(ko/ko)), which contained a deletion of a portion of the ATPase domain, produced animals that were male sterile but female fertile. However, the meiotic phenotype of Pms2(ko/ko) males was less clear-cut than for Mlh1- or Mlh3-deficient meiosis. More recently, we generated a different Pms2 mutant allele (Pms2(cre)), which results in deletion of the same portion of the ATPase domain. Surprisingly, Pms2(cre/cre) male mice were completely fertile, suggesting that the ATPase domain of Pms2 is not required for male fertility. To explore the difference in male fertility, we examined the Pms2 RNA and found that alternative splicing of the Pms2(cre) allele results in a predicted Pms2 containing the C-terminus, which contains the Mlh1-interaction domain, a possible candidate for stabilizing Mlh1 levels. To study further the basis of male fertility, we examined Mlh1 levels in testes and found that whereas Pms2 loss in Pms2(ko/ko) mice results in severely reduced levels of Mlh1 expression in the testes, Mlh1 levels in Pms2(cre/cre) testes were reduced to a lesser extent. Thus, we propose that a primary function of Pms2 during spermatogenesis is to stabilize Mlh1 levels prior to its critical crossing over function with Mlh3. PMID- 26753534 TI - Reproducibility of transpulmonary thermodilution cardiac output measurements in clinical practice: a systematic review. AB - Measuring cardiac output (CO) is an integral part of the diagnostic and therapeutic strategy in critically ill patients. During the last decade, the single transpulmonary thermodilution (TPTD) technique was implemented in clinical practice. The purpose of this paper was to systematically review and critically assess the existing data concerning the reproducibility of CO measured using TPTD (COTPTD). A total of 16 studies were identified to potentially be included in our study because these studies had the required information that allowed for calculating the reproducibility of COTPTD measurements. 14 adult studies and 2 pediatric studies were analyzed. In total, 3432 averaged CO values in the adult population and 78 averaged CO values in the pediatric population were analyzed. The overall reproducibility of COTPTD measurements was 6.1 +/- 2.0 % in the adult studies and 3.9 +/- 2.9 % in the pediatric studies. An average of 3 boluses was necessary for obtaining a mean CO value. Achieving more than 3 boluses did not improve reproducibility; however, achieving less than 3 boluses significantly affects the reproducibility of this technique. The present results emphasize that TPTD is a highly reproducible technique for monitoring CO in critically ill patients, especially in the pediatric population. Our findings suggest that obtaining a mean of 3 measurements for determining CO values is recommended. PMID- 26753536 TI - Associations between and development of welfare indicators in organic layers. AB - The retail market share of organic eggs in Denmark is high, and the consumers expect high animal welfare standards in the organic production. Documentation of animal welfare is important, however, knowledge about the associations between animal-based welfare indicators is limited. The aims of the study were to investigate the associations between selected welfare indicators at two ages (peak and end of lay), and to examine the development with age of the chosen welfare indicators. The chosen welfare indicators were Ascaridia galli (roundworm) infection, Heterakis sp. (caecal worm) infection, keel bone damages, back feathering, body feathering, foot damages, comb colour and wounds on the body. An observational study with 12 organic egg farms was conducted in 2012 and 2013 with a total of 214 hens assessed individually at the peak and the end of lay. Insufficient data were obtained on helminth infection at the peak of lay. At the end of lay, all helminth infected hens were positive for A. galli, and only three of them had in addition a Heterakis sp. infection. Foot damages, pale combs and wounds on the body occurred at frequencies <5% and were therefore, together with the prevalence of Heterakis sp. infection, left out of the analysis of associations. A graphical model was used to analyse the associations between the remaining clinical welfare indicators, A. galli infection, housing systems and age of the hens at end of lay. A. galli infection was only directly associated with back feathering at end of lay (P=0.011) with an increased incidence of A. galli infection in hens with good back feathering. Between the two visits, the prevalence of hens with keel bone damages increased (P<0.001), and the plumage condition deteriorated (P<0.001), whereas the number of hens with plantar abscess (P=0.037) and pale combs (P=0.020) decreased. No significant differences were found for other foot damages or for skin damage. In conclusion, back feathering at end of lay provided information about a possible helminth infection, but this is not a useful indicator in daily on-farm management. In addition, evidence was found that the deterioration of the plumage condition with age was not only due to accumulation of damage over time. PMID- 26753537 TI - Correlation between preoperative predictions and surgical findings in the parotid surgery for tumors. AB - BACKGROUND: To compare preoperative CT/MRI based predictions with real surgical findings for deep lobe parotid gland surgery. METHODS: The study analyzed 122 parotidectomies (2004-2014) for benign tumor removal. The facial nerve, the Utrecht line, the Conn's arc, and the retromandibular vein were used as landmarks for CT/MRI presurgical evaluation of patients. We assessed 106 CT images and 86 MRI images. The study compared preoperative evaluation of tumor location with its actual location that was revealed during the operation and assessed the importance of the landmarks. RESULTS: In general, the agreement between preoperative CT prediction and actual location of the parotid tumors was achieved in 88.7 % (n = 94/106) when facial nerve line was used as a landmark. However, out of 14 tumors in the deep lobe only 5 were located correctly (35.7 %). Of the other existing CT landmarks, none showed more precision over others. The agreement between MRI based prediction and surgical results on actual location of the tumor was achieved in 94.2 %. Out of 12 MRI-investigated tumors in the deep lobe nine were located correctly that gives 75 % agreement with surgical results. CONCLUSION: Our data suggests that no existing CT landmark can be accepted as completely reliable in cases when selective deep lobe parotidectomy is planned. If tumor location is suspected in the deep lobe of the gland, MRI imaging is necessary to confirm the diagnosis. An operating surgeon should be prepared that in some cases the true location of the tumor would be revealed only during surgery. PMID- 26753538 TI - Symptoms and management of pediatric patients with incurable brain tumors in palliative home care. AB - INTRODUCTION: Brain tumors have the highest disease-related mortality rate of all pediatric cancers. The goal of this study was to determine whether all children with incurable brain tumors cared for by a pediatric palliative care team in a home setting suffer from the same symptoms towards the end of their lives or whether there are differences between the tumor localizations with implications for palliative care. PATIENTS AND METHODS: This study was conducted as a retrospective, single center chart review including all patients treated between January 1st 2000 and December 31st 2013. RESULTS: 70 children, adolescents and young adults were included in the analysis. Symptom burden was high with a mean number of symptoms of 7.2 per patient. 74% of the symptoms already existed one week before death. Within the last week of life, impaired consciousness (75.7%) most often occurred. Furthermore, symptoms considerably depended on tumor localization. Patients with supratentorial tumors presented more frequently with seizures (p < 0.05), coma (p < 0.01), nausea and emesis (p < 0.01). Ataxia (p < 0.001) occurred most frequently in infratentorial tumors and speech disturbances (p < 0.05), cranial nerve paralysis (p < 0.001), and tetraparesis (p < 0.001) in brain stem tumors. 84.3% of the patients needed analgesics, only 64.4% WHO class III analgesics. Anticonvulsants were given more often in supratentorial tumors (p < 0.01). CONCLUSIONS: Caring for a dying child suffering from a brain tumor needs increased awareness of the neurological deterioration. The symptom pattern strongly depends on the tumor localization and significantly differs between supratentorial, infratentorial and brain stem tumors. PMID- 26753539 TI - A Guided Online and Mobile Self-Help Program for Individuals With Eating Disorders: An Iterative Engagement and Usability Study. AB - BACKGROUND: Numerous digital health interventions have been developed for mental health promotion and intervention, including eating disorders. Efficacy of many interventions has been evaluated, yet knowledge about reasons for dropout and poor adherence is scarce. Most digital health intervention studies lack appropriate research design and methods to investigate individual engagement issues. User engagement and program usability are inextricably linked, making usability studies vital in understanding and improving engagement. OBJECTIVE: The aim of this study was to explore engagement and corresponding usability issues of the Healthy Body Image Program-a guided online intervention for individuals with body image concerns or eating disorders. The secondary aim was to demonstrate the value of usability research in order to investigate engagement. METHODS: We conducted an iterative usability study based on a mixed-methods approach, combining cognitive and semistructured interviews as well as questionnaires, prior to program launch. Two separate rounds of usability studies were completed, testing a total of 9 potential users. Thematic analysis and descriptive statistics were used to analyze the think-aloud tasks, interviews, and questionnaires. RESULTS: Participants were satisfied with the overall usability of the program. The average usability score was 77.5/100 for the first test round and improved to 83.1/100 after applying modifications for the second iteration. The analysis of the qualitative data revealed five central themes: layout, navigation, content, support, and engagement conditions. The first three themes highlight usability aspects of the program, while the latter two highlight engagement issues. An easy-to-use format, clear wording, the nature of guidance, and opportunity for interactivity were important issues related to usability. The coach support, time investment, and severity of users' symptoms, the program's features and effectiveness, trust, anonymity, and affordability were relevant to engagement. CONCLUSIONS: This study identified salient usability and engagement features associated with participant motivation to use the Healthy Body Image Program and ultimately helped improve the program prior to its implementation. This research demonstrates that improvements in usability and engagement can be achieved by testing and adjusting intervention design and content prior to program launch. The results are consistent with related research and reinforce the need for further research to identify usage patterns and effective means for reducing dropout. Digital health research should include usability studies prior to efficacy trials to help create more user-friendly programs that have a higher likelihood of "real-world" adoption. PMID- 26753540 TI - Greater serum carotenoid concentration associated with higher bone mineral density in Chinese adults. AB - This cross-sectional study has been performed to investigate the relationship between serum carotenoids and bone mineral density (BMD) in Chinese population. We found that women with higher serum beta-cryptoxanthin, lycopene, or alpha carotene exhibited higher BMD at various bone sites. Similar association was observed between alpha-carotene and BMD in men. INTRODUCTION: Carotenoids may positively regulate bone metabolism through their antioxidant properties; however, few studies have examined the relation between serum carotenoids and bone health. We aimed to determine the associations between the serum concentration of several carotenoid subclasses and BMD in a Chinese population. METHODS: This study was a community-based cross-sectional study. We measured 1898 women and 933 men aged 59.6 years who completed serum beta-cryptoxanthin, zeaxanthin + lutein, lycopene, and alpha-carotene concentration analyses and BMD assessments. Serum individual carotenoids were assessed by the methods of reverse phase high-performance liquid chromatography. Dual-energy X-ray absorptiometry was applied to determine BMD at whole body, lumbar spine, total hip, femur neck, and trochanter. ANCOVA was used to examine the correlations between categorized individual carotenoids and BMD at measured sites. RESULTS: After adjusting for potential covariates, a monotonic dose-response positive correlation between circulating levels of beta-cryptoxanthin, lycopene, and alpha-carotene and BMD at various skeletal sites was observed in women. Women in the top (vs. bottom) quartiles of serum beta-cryptoxanthin, lycopene, or alpha-carotene exhibited 1.8 2.3, 1.5-2.0, or 1.3-2.7 % higher BMD at the bone sites with significant results (P-trend <0.05), respectively. For men, the corresponding values were 2.6-4.0 % for alpha-carotene at the whole body and hip regions (P-trend <0.001-0.023). CONCLUSION: These results suggest that serum carotenoids have a favorable association with bone health in the study population, especially in women. PMID- 26753541 TI - Fracture risk and bone mineral density levels in patients with systemic lupus erythematosus: a systematic review and meta-analysis. AB - Previous studies suggested possible bone loss and fracture risk in patients with systemic lupus erythematosus (SLE). The aim of this systematic review and meta analysis was to assess the strength of the relationship of SLE with fracture risk and the mean difference of bone mineral density (BMD) levels between SLE patients and controls. Literature search was undertaken in multiple indexing databases on September 26, 2015. Studies on the relationship of SLE with fracture risk and the mean difference of BMD levels between SLE patients and controls were included. Data were combined using standard methods of meta-analysis. Twenty-one studies were finally included into the meta-analysis, including 15 studies on the mean difference of BMD levels between SLE patients and controls, and 6 studies were on fracture risk associated with SLE. The meta-analysis showed that SLE patients had significantly lower BMD levels than controls in the whole body (weighted mean difference [WMD] = -0.04; 95 % CI -0.06 to -0.02; P < 0.001), femoral neck (WMD = -0.06; 95 % CI -0.07 to -0.04; P < 0.001), lumbar spine (WMD = -0.06; 95 % CI 0.09 to -0.03; P < 0.001), and total hip (WMD = -0.05; 95 % CI -0.06 to -0.03; P < 0.001). In addition, the meta-analysis also showed that SLE was significantly associated with increased fracture risk of all sites (relative risk [RR] = 1.97, 95 % CI 1.20-3.25; P = 0.008). Subgroup analysis by adjustment showed that SLE was significantly associated with increased fracture risk of all sites before and after adjusting for confounding factors (unadjusted RR = 2.07, 95 % CI 1.46-2.94, P < 0.001; adjusted RR = 1.22, 95 % CI 1.05-1.42, P = 0.01). Subgroup analysis by types of fracture showed that SLE was significantly associated with increased risks of hip fracture (RR = 1.99, 95 % CI 1.55-2.57; P < 0.001), osteoporotic fracture (RR = 1.36, 95 % CI 1.21-1.53; P < 0.001), and vertebral fracture (RR = 2.97, 95 % CI 1.71-5.16; P < 0.001). This systematic review and meta-analysis provides strong evidence for the relationship of SLE with bone loss and fracture risk. PMID- 26753544 TI - Elevated partial antiphospholipid score is a strong risk factor for thrombosis in patients with systemic lupus erythematosus: a validation study. AB - This study aims to identify risk factors for thrombosis in patients with systemic lupus erythematosus (SLE) and to validate the efficacy of the partial antiphospholipid (aPL) score for thrombosis prediction and diagnosis of antiphospholipid syndrome (APS). This study included 325 SLE patients, 188 of whom completed a follow-up of 31.01 months (range 23-48 months). Partial aPL score was calculated by adding up the individual scores for activated partial thromboplastin time (APTT), lupus anticoagulant, IgG/IgM anticardiolipin antibodies (aCL), and IgG/IgM anti-beta2-glycoprotein I (anti-beta2GPI). A simplified aPL score was developed using only APTT, IgG/IgM aCL, and IgG/IgM anti beta2GPI. Partial aPL scores were significantly higher in SLE patients with thrombosis (p < 0.0001). A history of thrombosis (p < 0.0001), a partial aPL score >10 (p < 0.0001), and immunosuppressant use (p = 0.012) were independent risk factors for thrombosis. For patients with a history of thrombosis, partial aPL score was the strongest risk factor for recurrent thrombosis (p < 0.0001, odds ratio = 30.34 (95 % CI 7.70-118.81)). For APS diagnosis, the area under the receiver-operating characteristic curve (AUC) was 0.809 (95 % CI 0.73-0.89) using the partial aPL score. Similarly, the simplified aPL score was significantly associated with thrombosis (p < 0.0001) and was acceptable for APS diagnosis (AUC 0.797, 95 % CI 0.72-0.88). An elevated partial aPL score is a strong risk factor for thrombosis in SLE patients and is a useful tool to predict recurrent thrombosis. Partial aPL score and simplified aPL score, although comprising fewer items than the original aPL score, also represent valuable quantitative indices for APS diagnosis. PMID- 26753542 TI - IL-4 administration exerts preventive effects via suppression of underlying inflammation and TNF-alpha-induced apoptosis in steroid-induced osteonecrosis. AB - Macrophages play an important role during the development of steroid-induced osteonecrosis. Interleukin (IL)-4 administration helped reduce the infiltration of M1 phenotypic macrophages and maintain the activation of M2 phenotypic macrophages, resulting in restriction of inflammation and decrease in osteocyte apoptosis. The results indicated the therapeutic potential of IL-4 in prevention of steroid-induced osteonecrosis. INTRODUCTION: Steroid-induced osteonecrosis (ON) is a debilitating disease characterized by the activation and infiltration of macrophages into the necrotic site. This study aimed to investigate the effects of IL-4 administration on macrophage polarization and the involved signaling pathways. METHODS: Fifty-six BALB/c mice were randomly divided into two groups, group M (model group) and group MI (treatment group), each containing 28 mice. ON model was induced by the injection of methylprednisolone (MPS). The mice in group MI received intra-abdominal injections of 2 MUg/100 g/day of rIL-4 for five consecutive days, following the administration of MPS. Osteonecrosis was verified by histopathological staining. The expression of tumor necrosis factor alpha (TNF-alpha) was analyzed by ELISA and immunohistochemistry. The infiltration of M1/M2 macrophages was examined by the expression of specific makers of F4/80, CD11c, and CD206 protein. Cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and the apoptotic signal molecules such as STAT1 and caspase-3 were examined. RESULTS: Histopathological observations indicated that IL-4 administration reduced the incidence of ON and the accumulation of osteoclasts. IL-4 administration inhibited the expression of TNF-alpha and reduced the infiltration of M1 phenotypic macrophages and maintained relatively high level of M2 phenotypic macrophages. Additionally, TUNEL assay suggested that IL-4 intervention could reduce the number of apoptotic cells in the necrotic zone. The anti-apoptotic mechanisms were related to STAT1 phosphorylation and the activation of caspase-3. CONCLUSIONS: Il-4 administration could alleviate steroid associated ON in mice by inhibiting the inflammatory response, the infiltration of M1 phenotypic macrophages, and suppressing TNF-a-induced osteocytic apoptosis by inhibiting the STAT1-caspase-3 signal pathway. PMID- 26753545 TI - Intracardiac thrombus in patients with Behcet's disease: clinical correlates, imaging features, and outcome: a retrospective, single-center experience. AB - Intracardiac thrombus (ICT) is a rare but serious complication of Behcet's disease (BD). The study was to report the clinical characteristics, imaging features, treatment, and outcomes of BD patients with ICT in a single tertiary center. A series of 626 BD patients admitted to Peking Union Medical College hospital between April 2003 and April 2013 were reviewed. A total of 12 (1.9 %) BD patients with ICT were included. ICT was presenting manifestation of BD in 5 of the 12 patients (41.7 %) and occurred mostly in men (9/12, 75 %) younger than 40 years. Patients with ICT had more arterial (66.7 vs. 7.3 %, p < 0.001) and venous involvement (75.0 vs. 8.1 %, p < 0.001) compared to those without ICT. Right heart was the most frequent site of ICT (11/12, 91.7 %). Thrombus were hyperechogenic and immobile with a broad-based attachment on echocardiography in most cases (11/12, 91.7 %). Cardiac magnetic resonance (CMR) was performed in four patients. All thrombi showed isointense on T1-weighted image, while all but one were hypointense on T2-weighted image without delayed enhancement. Remission of ICT was associated with therapy of anticoagulant, corticosteroid, and immunosuppressant in most cases (10/12, 83.3 %). There was no death, and relapses of ICT occurred in only one patient after tapering of immunosuppressant during follow-up. A diagnosis of BD should be considered when a young male patient presents with a mass in the right-sided heart accompanied by vascular lesions. Medical therapy especially adequate immunosuppressants might be the first choice for BD patients with ICT. PMID- 26753543 TI - Electrophoretic deposition of ligand-free platinum nanoparticles on neural electrodes affects their impedance in vitro and in vivo with no negative effect on reactive gliosis. AB - BACKGROUND: Electrodes for neural stimulation and recording are used for the treatment of neurological disorders. Their features critically depend on impedance and interaction with brain tissue. The effect of surface modification on electrode impedance was examined in vitro and in vivo after intracranial implantation in rats. Electrodes coated by electrophoretic deposition with platinum nanoparticles (NP; <10 and 50 nm) as well as uncoated references were implanted into the rat's subthalamic nucleus. After postoperative recovery, rats were electrostimulated for 3 weeks. Impedance was measured before implantation, after recovery and then weekly during stimulation. Finally, local field potential was recorded and tissue-to-implant reaction was immunohistochemically studied. RESULTS: Coating with NP significantly increased electrode's impedance in vitro. Postoperatively, the impedance of all electrodes was temporarily further increased. This effect was lowest for the electrodes coated with particles <10 nm, which also showed the most stable impedance dynamics during stimulation for 3 weeks and the lowest total power of local field potential during neuronal activity recording. Histological analysis revealed that NP-coating did not affect glial reactions or neural cell-count. CONCLUSIONS: Coating with NP <10 nm may improve electrode's impedance stability without affecting biocompatibility. Increased impedance after NP-coating may improve neural recording due to better signal-to-noise ratio. PMID- 26753546 TI - Contraception and Adolescent Males: An Opportunity for Providers. AB - PURPOSE: To examine young men's awareness of emergency contraception (EC) and its association with their contraceptive decision-making contributions within a relationship. METHODS: A convenience sample of English-speaking male patients aged 13-24 years were surveyed regarding their childbearing intentions, contraceptive awareness (including EC), perceived contraceptive knowledge, and communication about birth control with providers and within a relationship. RESULTS: An ethnically diverse sample of adolescent males was recruited with a mean age of 18.9 years. Most had previously been sexually active (75%) and felt it was important to avoid pregnancy (84%) and 61% reported ever having spoken to a health care provider about birth control (other than condoms), but only 42% had heard of EC. Participants who had heard of EC were more likely to have spoken to a health care provider about contraception in the past (51.5% vs. 29.8%; p = .050), to feel they should participate in contraceptive decisions in a relationship (97.4% vs. 76.5%; p = .006), and to have discussed contraception with a partner (76.9% vs. 29.2%; p < .001). CONCLUSIONS: Counseling young men about EC, as well as other methods of birth control, may empower them to become actively involved in contraceptive decisions within a relationship if they do not desire fatherhood. PMID- 26753547 TI - Evidence of high-elevation amplification versus Arctic amplification. AB - Elevation-dependent warming in high-elevation regions and Arctic amplification are of tremendous interest to many scientists who are engaged in studies in climate change. Here, using annual mean temperatures from 2781 global stations for the 1961-2010 period, we find that the warming for the world's high-elevation stations (>500 m above sea level) is clearly stronger than their low-elevation counterparts; and the high-elevation amplification consists of not only an altitudinal amplification but also a latitudinal amplification. The warming for the high-elevation stations is linearly proportional to the temperature lapse rates along altitudinal and latitudinal gradients, as a result of the functional shape of Stefan-Boltzmann law in both vertical and latitudinal directions. In contrast, neither altitudinal amplification nor latitudinal amplification is found within the Arctic region despite its greater warming than lower latitudes. Further analysis shows that the Arctic amplification is an integrated part of the latitudinal amplification trend for the low-elevation stations (<=500 m above sea level) across the entire low- to high-latitude Northern Hemisphere, also a result of the mathematical shape of Stefan-Boltzmann law but only in latitudinal direction. PMID- 26753548 TI - The Effect(s) of Teen Pregnancy: Reconciling Theory, Methods, and Findings. AB - Although teenage mothers have lower educational attainment and earnings than women who delay fertility, causal interpretations of this relationship remain controversial. Scholars argue that there are reasons to predict negative, trivial, or even positive effects, and different methodological approaches provide some support for each perspective. We reconcile this ongoing debate by drawing on two heuristics: (1) each methodological strategy emphasizes different women in estimation procedures, and (2) the effects of teenage fertility likely vary in the population. Analyses of the Child and Young Adult Cohorts of the National Longitudinal Survey of Youth (N = 3,661) confirm that teen pregnancy has negative effects on most women's attainment and earnings. More striking, however, is that effects on college completion and early earnings vary considerably and are most pronounced among those least likely to experience an early pregnancy. Further analyses suggest that teen pregnancy is particularly harmful for those with the brightest socioeconomic prospects and who are least prepared for the transition to motherhood. PMID- 26753549 TI - Measurements using orthodontic analysis software on digital models obtained by 3D scans of plaster casts : Intrarater reliability and validity. AB - OBJECTIVE: The purpose of this work was to determine the reliability and validity of measurements performed on digital models with a desktop scanner and analysis software in comparison with measurements performed manually on conventional plaster casts. MATERIALS AND METHODS: A total of 20 pairs of plaster casts reflecting the intraoral conditions of 20 fully dentate individuals were digitized using a three-dimensional scanner (D700; 3Shape). A series of defined parameters were measured both on the resultant digital models with analysis software (Ortho Analyzer; 3Shape) and on the original plaster casts with a digital caliper (Digimatic CD-15DCX; Mitutoyo). Both measurement series were repeated twice and analyzed for intrarater reliability based on intraclass correlation coefficients (ICCs). The results from the digital models were evaluated for their validity against the casts by calculating mean-value differences and associated 95 % limits of agreement (Bland-Altman method). Statistically significant differences were identified via a paired t test. RESULTS: Significant differences were obtained for 16 of 24 tooth-width measurements, for 2 of 5 sites of contact-point displacement in the mandibular anterior segment, for overbite, for maxillary intermolar distance, for Little's irregularity index, and for the summation indices of maxillary and mandibular incisor width. Overall, however, both the mean differences between the results obtained on the digital models versus on the plaster casts and the dispersion ranges associated with these differences suggest that the deviations incurred by the digital measuring technique are not clinically significant. CONCLUSION: Digital models are adequately reproducible and valid to be employed for routine measurements in orthodontic practice. PMID- 26753551 TI - Novel missense mutation in the EDA gene in a family affected by oligodontia. AB - BACKGROUND: Mutations in the EDA-EDAR-EDARADD genes and more recently, mutations in the WNT10A gene have been described as the cause of syndromic and nonsyndromic tooth agenesis concomitant with diverse abnormalities of ectodermally derived tissues. AIM: In the present investigation, two brothers presenting severe tooth agenesis (oligodontia) concomitant with subtle signs of ectodermal dysplasia (ED) symptoms, as well as six family relatives were analyzed for a causative mutation. METHODS: Genomic DNA was isolated from saliva, and genetic screening performed via direct sequencing of PCR fragments covering the entire coding regions and the intron-exon junctions of the EDA, EDAR, EDARADD as well as the WNT10A genes. Mutation analysis was conducted using the Mutation Surveyor((r)) Software. RESULTS AND CONCLUSION: We identified a novel G > A mutation located on exon 7 at nucleotide position c.866 in the EDA gene in both patients. The nucleotide change results in a substitution of arginine by histidine (p.Arg289His). According to the programs MutationTaster and PolyPhen2, this mutation is pathogenic. Based on a computerized protein structure analysis, we suggest that the change p.Arg289His in EDA impairs protein stabilization and thus might possibly be involved in the development of oligodontia concomitant with a mild ED phenotype. PMID- 26753550 TI - Precision of implementing virtual setups for orthodontic treatment using CAD/CAM fabricated custom archwires. AB - OBJECTIVES: The SureSmile(r) process (OraMetrix(r); Richardson, TX, USA) utilizes computer-aided design and computer-aided manufacturing (CAD/CAM). A virtual setup is created for treatment planning and chairside implementation using custom archwires fabricated by robots. The objective of this study was to determine the precision of this implementation. METHODS: The setup models of 26 consecutive patients were compared to models of the final outcome. Using a virtual matching process, the planned and the achieved tooth positions were superimposed and the differences between them calculated along three translational planes and three rotational axes, thus, yielding six deviation values for each tooth. RESULTS: The median deviations were 0.19-0.21 mm based on translational movements and 1.77 degrees -3.04 degrees based on rotational movements. The precision of implementing the setups decreased from anterior to posterior, with incisors showing the best outcomes. CONCLUSION: Virtual setups can be implemented in a clinically successful fashion with custom archwires fabricated by CAD/CAM in accordance with the SureSmile(r) process. PMID- 26753552 TI - Evidence, eminence and extrapolation. AB - A full independent drug development programme to demonstrate efficacy may not be ethical and/or feasible in small populations such as paediatric populations or orphan indications. Different levels of extrapolation from a larger population to smaller target populations are widely used for supporting decisions in this situation. There are guidance documents in drug regulation, where a weakening of the statistical rigour for trials in the target population is mentioned to be an option for dealing with this problem. To this end, we propose clinical trials designs, which make use of prior knowledge on efficacy for inference. We formulate a framework based on prior beliefs in order to investigate when the significance level for the test of the primary endpoint in confirmatory trials can be relaxed (and thus the sample size can be reduced) in the target population while controlling a certain posterior belief in effectiveness after rejection of the null hypothesis in the corresponding confirmatory statistical test. We show that point-priors may be used in the argumentation because under certain constraints, they have favourable limiting properties among other types of priors. The crucial quantity to be elicited is the prior belief in the possibility of extrapolation from a larger population to the target population. We try to illustrate an existing decision tree for extrapolation to paediatric populations within our framework. (c) 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. PMID- 26753553 TI - An evaluation of the use of individual grass species in retaining polluted soil and dust particulates in vegetated sustainable drainage devices. AB - A sustainable means of preventing polluted particulates carried in urban storm water entering rivers, groundwater and lakes is by employing vegetated sustainable drainage system (SUDS) devices, or best management practices to trap or biodegrade them. In the UK, a mixture of grass species is recommended for use in devices such as swales or filter strips. However, there is little evidence in support of the efficiency of the individual grasses or mixtures to deal with such contaminated material. A pot-based pollutant retention study was conducted using processed street dust from central Coventry, UK, as a simulated pollutant to be applied in different quantities to a variety of recommended grasses for vegetated SUDS devices. Analysis was conducted on compost cores, roots and shoots for heavy metals (Cd, Cu, Ni, Pb and Zn). Street dust mainly concentrated in the top compost layer for all grasses with only the finer material migrating down the profile. Analysis of roots indicated little accumulation, with ANOVA statistical tests indicating significant differences in heavy metal concentrations, with less in the compost and more in the shoots. Development of root systems on or near the surface possibly explains increased uptake of heavy metals by some species. Overall Agrostis canina and Poa pratensis showed the greatest accumulations compared to their controls although Agrostis capillaris syn.tenuis and Agrostis stolonifera also demonstrated accumulation potential. On ranking, Agrostis canina and Poa pratensis were highest overall. These rankings will assist in selecting the best grasses to address pollution of the urban environment by contaminated particulates. PMID- 26753554 TI - Estimated lead (Pb) exposures for a population of urban community gardeners. AB - Urban community gardens provide affordable, locally grown, healthy foods and many other benefits. However, urban garden soils can contain lead (Pb) that may pose risks to human health. To help evaluate these risks, we measured Pb concentrations in soil, vegetables, and chicken eggs from New York City community gardens, and we asked gardeners about vegetable consumption and time spent in the garden. We then estimated Pb intakes deterministically and probabilistically for adult gardeners, children who spend time in the garden, and adult (non-gardener) household members. Most central tendency Pb intakes were below provisional total tolerable intake (PTTI) levels. High contact intakes generally exceeded PTTIs. Probabilistic estimates showed approximately 40 % of children and 10 % of gardeners exceeding PTTIs. Children's exposure came primarily from dust ingestion and exposure to higher Pb soil between beds. Gardeners' Pb intakes were comparable to children's (in ug/day) but were dominated by vegetable consumption. Adult household members ate less garden-grown produce than gardeners and had the lowest Pb intakes. Our results suggest that healthy gardening practices to reduce Pb exposure in urban community gardens should focus on encouraging cultivation of lower Pb vegetables (i.e., fruits) for adult gardeners and on covering higher Pb non-bed soils accessible to young children. However, the common practice of replacement of root-zone bed soil with clean soil (e.g., in raised beds) has many benefits and should also continue to be encouraged. PMID- 26753556 TI - Large-Area Graphene Nanodot Array for Plasmon-Enhanced Infrared Spectroscopy. AB - Graphene nanodot arrays (GNDAs) are fabricated by block copolymer lithography in a high-throughput manner. The GNDA shows strong broadband plasmonic resonances in the mid-IR region with high localized field enhancement, thus allowing plasmon enhanced infrared spectroscopy with reliable sensitivity and selectivity to be performed. PMID- 26753555 TI - Nature and extent of metal-contaminated soils in urban environments (keynote talk). AB - Research on the nature and extent of metal-contaminated soil began with an urban garden study in Baltimore, MD (USA). Largest quantities of soil metals were clustered in the inner city with lesser amounts scattered throughout metropolitan Baltimore. The probability values of metal clustering varied from P value 10(-15) 10(-23) depending on element. The inner-city clustering of lead (Pb) could not be explained by Pb-based paint alone. A major Pb source was tetraethyl lead (TEL), developed as an anti-knock agent for use in vehicle fuel, thereby making highway traffic flow a toxic substance delivery system in cities. Further study in Minneapolis and St. Paul confirmed the clustering of inner-city soil metals, especially Pb. Based on the evidence, the Minnesota State Legislature petitioned Congress to curtail Pb additives resulting in the rapid phasedown of TEL on January 1, 1986, 10 years ahead of the EPA scheduled ban. Further research in New Orleans, Louisiana (NOLA), verified the link between soil Pb, blood Pb, morbidity, and societal health. Although Pb is a known cause of clinical impairment, there is no known effective medical intervention for reducing children's blood Pb exposure. Ingestion and inhalation are routes of exposure requiring prevention, and soil is a reservoir of Pb. Children's blood Pb exposure observed in pre-Hurricane Katrina (August 29, 2005) NOLA underwent substantial decreases 10 years post-Katrina due to many factors including input of low Pb sediment residues by the storm surge and the introduction of low Pb landscaping materials from outside of the city. Investigation on the topic is ongoing. PMID- 26753557 TI - Handheld real-time PCR device. AB - Here we report one of the smallest real-time polymerase chain reaction (PCR) systems to date with an approximate size of 100 mm * 60 mm * 33 mm. The system is an autonomous unit requiring an external 12 V power supply. Four simultaneous reactions are performed in the form of virtual reaction chambers (VRCs) where a ~200 nL sample is covered with mineral oil and placed on a glass cover slip. Fast, 40 cycle amplification of an amplicon from the H7N9 gene was used to demonstrate the PCR performance. The standard curve slope was -3.02 +/- 0.16 cycles at threshold per decade (mean +/- standard deviation) corresponding to an amplification efficiency of 0.91 +/- 0.05 per cycle (mean +/- standard deviation). The PCR device was capable of detecting a single deoxyribonucleic acid (DNA) copy. These results further suggest that our handheld PCR device may have broad, technologically-relevant applications extending to rapid detection of infectious diseases in small clinics. PMID- 26753558 TI - Conducting Economic Evaluations Alongside Randomised Trials: Current Methodological Issues and Novel Approaches. AB - Trial-based economic evaluations are an important aspect of health technology assessment. The availability of patient-level data coupled with unbiased estimates of clinical outcomes means that randomised controlled trials are effective vehicles for the generation of economic data. However there are methodological challenges to trial-based evaluations, including the collection of reliable data on resource use and cost, choice of health outcome measure, calculating minimally important differences, dealing with missing data, extrapolating outcomes and costs over time and the analysis of multinational trials. This review focuses on the state of the art of selective elements regarding the design, conduct, analysis and reporting of trial-based economic evaluations. The limitations of existing approaches are detailed and novel methods introduced. The review is internationally relevant but with a focus towards practice in the UK. PMID- 26753559 TI - Determining optimal prostate-specific antigen thresholds to identify an increased 4-year risk of prostate cancer development: an analysis within the Veterans Affairs Health Care System. AB - PURPOSE: To assess the prostate-specific antigen (PSA) threshold value that optimally predicts future risk of prostate cancer (overall and by race) for a dispersed US population. METHODS: This was a retrospective analysis of men in the Veterans Affairs (VA) Health Care System database. Men >= 40 years with a baseline PSA <= 4.0 ng/mL, not receiving 5-alpha reductase inhibitors, and without a prostate cancer diagnosis prior to baseline PSA date were included and followed for 4 years. Patients diagnosed with prostate cancer within 6 months of baseline were excluded. The optimal PSA threshold value for future 4-year prostate cancer risk was determined by maximizing Youden's index. RESULTS: The eligible population for the final analysis included 41,250 Caucasian (n = 24,518; 59.4 %) and African American (n = 16,732; 40.6 %) patients. The 4-year prostate cancer rate was 3.08 % overall, and race-specific rates were 3.02 and 3.17 % for Caucasian and African American men, respectively. Mean time to prostate cancer diagnosis was 2.01 years across all patients. Race-specific PSA thresholds that optimally predicted future prostate cancer were 2.5 ng/mL [area under the curve (AUC) = 80.3 %] in Caucasians and a 1.9 ng/mL (AUC = 85.4 %) in African Americans; across all patients, a 2.4 ng/mL threshold was optimal (AUC = 82.5 %). CONCLUSIONS: In the VA population, a relatively low PSA threshold of ~2.5 ng/mL was optimal in predicting prostate cancer within 4 years overall and for Caucasian men, but an even lower threshold of 1.9 ng/mL was applicable for African American men. PMID- 26753562 TI - Concurrent Expression of VEGF-C and Neuropilin-2 Is Correlated with Poor Prognosis in Glioblastoma. AB - Vascular endothelial growth factor-C (VEGF-C) is a secreted growth factor involved in many oncogenic processes, and neuropilin-2 (NRP2) is essential for neuronal guidance as a well-acknowledged co-receptor of VEGF receptors. The overexpression of NRP2 has been reported in many types of cancers, but the significance of NRP2 in glioblastoma is not elucidated. To investigate the clinical significance of VEGF-C and NRP2 in glioblastoma, we detected their expression in 86 cases of glioblastoma with immunohistochemistry and categorized our cohort into high- and low-expression groups according to the immunohistochemistry score, which was the product of the score of staining intensity multiplied by the score reflecting the percentage of positive cells. The proportion of glioblastoma with high VEGF-C expression was 34.9% (30/86), and that with high NRP2 expression was 37.2% (32/86). The proportion of glioblastoma with high expression of both VEGF-C and NRP2 was 15.1% (13/86). Moreover, the proportion of cases with high VEGF-C and low NRP2 was 19.7% (17/86), while the proportion of cases with low VEGF-C and high NRP2 was 22.1% (19/86). The high expression of both VEGF-C and NRP2 was associated with poorer survival rate (P = 0.023), and can be identified as an independent prognostic factor in glioblastoma (P = 0.030). Moreover, cases with low NRP2 expression are easier for complete tumor resection (P = 0.038). In conclusion, the concurrent high expression of VEGF-C and NRP2 is predictive of the unfavorable prognosis in glioblastoma, indicating that the VEGF-C-NRP2 signaling pathway is a potential and promising drug target in glioblastoma therapy. PMID- 26753560 TI - Incidence and Management of Post-Lobectomy and Pneumonectomy Bronchopleural Fistula. AB - INTRODUCTION: Bronchopleural fistula is a rare but potentially fatal complication of pulmonary resections and proper management is essential for its resolution. In this study, we analyzed the incidence of fistula after pulmonary resection and reported data about endoscopic and conservative treatments of this complication. METHODS: From January 2003 to December 2013, 835 patients underwent anatomic lung resections: 786 (94.1 %) had a lobectomy and 49 (5.9 %) a pneumonectomy. Bronchopleural fistula was suspected by clinical signs and confirmed by endoscopic visualization. RESULTS: Eighteen patients (2.2 %) developed a bronchopleural fistula, 11 in lobectomy group (1.4 %) and 7 in pneumonectomy group (14.3 %). The fistula size ranged between <1 mm and 6 mm and mean time of fistula onset was 33.9 +/- 54.9 days after surgery. Of 18 patients who developed fistula, one died due to acute respiratory failure and another one was reoperated and then died to causes unrelated to the treatment. All the remaining 16 patients were treated with a conservative therapy that consisted in keeping or replacing a drainage chest tube. Nine of them underwent also endoscopic closure of the fistula using biological or synthetic glues. The mean period of time elapsed for the resolution of this complication was shorter with combined (conservative + endoscopic) than with conservative treatment alone (15.4 +/- 13.2 vs. 25.8 +/- 13.2 days, respectively), but without significant difference between the two methods (p: 0.299). CONCLUSION: Endoscopic therapy, associated with a conservative treatment, is a safe and useful option in the management of the postoperative bronchopleural fistula. PMID- 26753563 TI - Photoluminescence characterisations of a dynamic aging process of organic inorganic CH3NH3PbBr3 perovskite. AB - After unprecedented development of organic-inorganic lead halide perovskite solar cells over the past few years, one of the biggest barriers towards their commercialization is the stability of the perovskite material. It is thus important to understand the interaction between the perovskite material and oxygen and/or humidity and the associated degradation process in order to improve device and encapsulation design for better durability. Here we characterize the dynamic aging process in vapour-assisted deposited (VASP) CH3NH3PbBr3 perovskite thin films using advanced optical techniques, such as time-resolved photoluminescence and fluorescence lifetime imaging microscopy (FLIM). Our investigation reveals that the perovskite grains grow spontaneously and the larger grains are formed at room temperature in the presence of moisture and oxygen. This crystallization process leads to a higher density of defects and a shorter carrier lifetime, specifically in the larger grains. Excitation-intensity dependent steady-state photoluminescence shows both N2 stored and aged perovskite exhibit a super-linear increase of photoluminescence intensity with increasing excitation intensity; and the larger slope in aged sample suggests a larger density of defects is generated, consistent with time-resolved PL measurements. PMID- 26753561 TI - iMiRNA-SSF: Improving the Identification of MicroRNA Precursors by Combining Negative Sets with Different Distributions. AB - The identification of microRNA precursors (pre-miRNAs) helps in understanding regulator in biological processes. The performance of computational predictors depends on their training sets, in which the negative sets play an important role. In this regard, we investigated the influence of benchmark datasets on the predictive performance of computational predictors in the field of miRNA identification, and found that the negative samples have significant impact on the predictive results of various methods. We constructed a new benchmark set with different data distributions of negative samples. Trained with this high quality benchmark dataset, a new computational predictor called iMiRNA-SSF was proposed, which employed various features extracted from RNA sequences. Experimental results showed that iMiRNA-SSF outperforms three state-of-the-art computational methods. For practical applications, a web-server of iMiRNA-SSF was established at the website http://bioinformatics.hitsz.edu.cn/iMiRNA-SSF/. PMID- 26753565 TI - Diagnostic role of inflammatory markers in pediatric Brucella arthritis. AB - BACKGROUND: As a multisystem infectious disease, there is an inflammation, which causes increase in acute phase reactants in brucellosis. The mean platelet volume (MPV), platelet distribution width (PDW), red cell distribution width (RDW), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) have been identified as markers of inflammation. The present study aimed to evaluate diagnostic values of these biomarkers in brucella arthritis (BA). METHODS: The study included 64 children with BA and 66 healthy control subjects. Demographic features, joint involvement, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and hematological variables were retrospectively recorded. In addition, results of synovial fluid and serum tube agglutination test for brucella together with treatment regimens were recorded. RESULTS: The mean age of the patients (53.1 % male) was 92.3 +/- 41.2 months. The most commonly affected joint was ankle (53.1 %). Synovial fluid puncture-brucella agglutination test was positive in 22 (34.3 %) patients. Puncture culture was positive in 9 patients. Most of the patients (57.8 %) were treated with a combination of rifampicin plus sulfamethoxazole/trimethoprim and gentamicin. Significantly higher mean PDW, RDW, MPV, NLR and PLR values were found in children with BA compared to control subjects (p < 0.05). A positive correlation was found between MPV and NLR values (R (2) = 0.192, p < 0.001). CONCLUSION: Our findings indicated that NLR and PLR are indirect markers of inflammation that may be observed abnormally increased in children with brucella arthritis. Further longitudinal studies are needed to investigate this topic to establish the more clear associations. PMID- 26753564 TI - Placental growth factor inhibition modulates the interplay between hypoxia and unfolded protein response in hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. We previously showed that the inhibition of placental growth factor (PlGF) exerts antitumour effects and induces vessel normalisation, possibly reducing hypoxia. However, the exact mechanism underlying these effects remains unclear. Because hypoxia and endoplasmic reticulum stress, which activates the unfolded protein response (UPR), have been implicated in HCC progression, we assessed the interactions between PlGF and these microenvironmental stresses. METHODS: PlGF knockout mice and validated monoclonal anti-PlGF antibodies were used in a diethylnitrosamine-induced mouse model for HCC. We examined the interactions among hypoxia, UPR activation and PlGF induction in HCC cells. RESULTS: Both the genetic and pharmacological inhibitions of PlGF reduced the chaperone levels and the activation of the PKR-like endoplasmic reticulum kinase (PERK) pathway of the UPR in diethylnitrosamine-induced HCC. Furthermore, we identified that tumour hypoxia was attenuated, as shown by reduced pimonidazole binding. Interestingly, hypoxic exposure markedly activated the PERK pathway in HCC cells in vitro, suggesting that PlGF inhibition may diminish PERK activation by improving oxygen delivery. We also found that PlGF expression is upregulated by different chemical UPR inducers via activation of the inositol-requiring enzyme 1 pathway in HCC cells. CONCLUSIONS: PlGF inhibition attenuates PERK activation, likely by tempering hypoxia in HCC via vessel normalisation. The UPR, in turn, is able to regulate PlGF expression, suggesting the existence of a feedback mechanism for hypoxia-mediated UPR that promotes the expression of the angiogenic factor PlGF. These findings have important implications for our understanding of the effect of therapies normalising tumour vasculature. PMID- 26753599 TI - Infrared Photodetection Based on Colloidal Quantum-Dot Films with High Mobility and Optical Absorption up to THz. AB - Infrared thermal imaging devices rely on narrow band gap semiconductors grown by physical methods such as molecular beam epitaxy and chemical vapor deposition. These technologies are expensive, and infrared detectors remain limited to defense and scientific applications. Colloidal quantum dots (QDs) offer a low cost alternative to infrared detector by combining inexpensive synthesis and an ease of processing, but their performances are so far limited, in terms of both wavelength and sensitivity. Herein we propose a new generation of colloidal QD based photodetectors, which demonstrate detectivity improved by 2 orders of magnitude, and optical absorption that can be continuously tuned between 3 and 20 MUm. These photodetectors are based on the novel synthesis of n-doped HgSe colloidal QDs whose size can be tuned continuously between 5 and 40 nm, and on their assembly into solid nanocrystal films with mobilities that can reach up to 100 cm(2) V(-1) s(-1). These devices can be operated at room temperature with the same level of performance as the previous generation of devices when operated at liquid nitrogen temperature. HgSe QDs can be synthesized in large scale (>10 g per batch), and we show that HgSe films can be processed to form a large scale array of pixels. Taken together, these results pave the way for the development of the next generation mid- and far-infrared low-cost detectors and camera. PMID- 26753601 TI - Vulnerable plaque on the common iliac artery detected by (18)F-FDG PET/MRI. PMID- 26753600 TI - Value of (18)F-FDG PET/CT for therapeutic assessment of patients with polymyalgia rheumatica receiving tocilizumab as first-line treatment. AB - PURPOSE: To evaluate the use of (18)F-FDG PET/CT for the assessment of tocilizumab (TCZ) as first-line treatment in patients with polymyalgia rheumatica (PMR). METHODS: Patients with PMR were prospectively enrolled in a multicentre clinical trial assessing TCZ therapy (the TENOR trial). The patients underwent FDG PET/CT at baseline, after the first infusion of TCZ (TCZ 1) and after the last infusion of TCZ (TCZ 3). Responses to treatment were evaluated in terms of the PMR activity score (PMR-AS), and the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) laboratory tests. Maximal standardized uptake value (SUVmax) was used for assessment of FDG uptake in regions usually affected in PMR (spinous processes, hips, shoulders, sternoclavicular region and ischial tuberosities). The Wilcoxon test was applied to evaluate the changes in parameters after the infusions and Spearman's rank correlation test was applied to assess the correlations between SUVmax and PMR-AS, CRP and ESR. RESULTS: Of 21 patients included in the trial, 18 were evaluated. The median bioclinical parameter values decreased after TCZ 1 (PMR-AS from 38.2 to 15.7, CRP from 65.2 to 0.4 mg/l and ESR from 49 to 6.5 mm; all p < 0.05) as did the median SUVmax (from 5.8 to 5.2; p < 0.05). All values also decreased after TCZ 3 (PMR-AS from 38.2 to 3.9, CRP from 65.2 to 0.2, ESR from 49 to 2, and SUVmax from 5.8 to 4.7; p < 0.05). In a region-based analysis, all SUVmax were significantly reduced after TCZ 3, except the values for the cervical spinous processes and shoulder regions. With regard to correlations, few significant differences were found between ?SUVmax and the other parameters including ?PMR-AS, ?CRP and ?ESR in the patient-based and region-based analysis. CONCLUSION: FDG uptake decreased significantly but moderately after TCZ therapy in PMR patients, and might reflect disease activity. PMID- 26753602 TI - (68)Ga-PSMA-11 dynamic PET/CT imaging in biochemical relapse of prostate cancer. AB - OBJECTIVES: We aim to investigate the pharmacokinetics and distribution of the recently clinically introduced radioligand (68)Ga-PSMA-11 in men with recurrent prostate cancer (PC) by means of dynamic and whole-body PET/CT. The correlation between PSA levels and (68)Ga-PSMA-11 PET parameters is also investigated. METHODS: 31 patients with biochemical failure after primary PC treatment with curative intent (median age 71.0 years) were enrolled in the analysis. The median PSA value was 2.0 ng/mL (range = 0.1 - 130.0 ng/mL) and the median Gleason score was 7 (range = 5 - 9). 8/31 (25.8 %) of the included patients had a PSA value < 0.5 ng/ml. All patients underwent dynamic PET/CT (dPET/CT) scanning (60 min) of the pelvis and lower abdomen as well as whole-body PET/CT with (68)Ga-PSMA-11. dPET/CT assessment was based on qualitative evaluation, SUV calculation, and quantitative analysis based on a two-tissue compartment model and a non compartmental approach leading to the extraction of fractal dimension (FD). RESULTS: 22/31 patients (71.0 %) were (68)Ga-PSMA-11-positive, while 9/31 (29.0 %) patients were (68)Ga-PSMA-11-negative. The median PSA value in the (68)Ga-PSMA 11-positive group was significantly higher (median = 2.35 ng/mL; range = 0.19 - 130.0 ng/mL) than in the (68)Ga-PSMA-11-negative group (median value: 0.34 ng/mL; range = 0.10 - 4.20 ng/mL). A total of 76 lesions were semi-quantitatively evaluated. PC recurrence-associated lesions demonstrated a mean SUVaverage = 12.4 (median = 9.0; range = 2.2 - 84.5) and mean SUVmax = 18.8 (median = 14.1; range = 3.1 - 120.3). Dynamic PET/CT studies of the pelvis revealed the following mean values for the PC recurrence-suspicious lesions: K1 = 0.26, k3 = 0.30, influx = 0.14 and FD = 1.24. Time-activity curves derived from PC-recurrence indicative lesions revealed an increasing (68)Ga-PSMA-11 accumulation during dynamic PET acquisition. Correlation analysis revealed a moderate, but significant, correlation between PSA levels and the number of lesions detected on (68)Ga-PSMA 11 PET/CT (r = 0.54) and between PSA levels and SUVaverage (r = 0.48) or SUVmax (r = 0.44). CONCLUSIONS: Ga-PSMA-11 PET/CT demonstrated an overall detection rate of 71.0 % 60 min p.i. of the radiotracer in a mixed patient population with respect to PSA levels and including patients with very low PSA values. Higher PSA values were associated with a higher detection rate. The tracer uptake in PC recurrence-indicative lesions is increasing during the 60 minutes of dynamic PET acquisition. PMID- 26753603 TI - Comparison of needle aspiration and vacuum-assisted biopsy in the ultrasound guided drainage of lactational breast abscesses. AB - PURPOSE: The purpose of this study was to compare needle aspiration and vacuum assistedbiopsy in the ultrasound-guided treatment of lactational breast abscesses. METHODS: Between January 2005 and December 2014, a total of 74 patients presented withlactational breast abscesses. Thirty of these patients underwent treatment with antibioticsalone, while the remaining 44 lactating women with breast abscesses were treated withneedle aspiration (n=25) or vacuum assisted biopsy (n=19). Age, duration of lactation, abscess diameter, pus culture results, the number of interventions, the healing time, and the cure rate were reviewed and compared between these two groups. The Student's t test and the chi square test were used to compare the variables. RESULTS: No significant difference was found in the cure rate between the needle aspirationgroup (22/25, 88%) and the vacuum-assisted biopsy group (18/19, 94.7%) (P=0.441). However, the mean healing time was significantly shorter in the vacuum-assisted biopsy group (6.7 days) than in the needle aspiration group (9.0 days) (P=0.001). CONCLUSION: Vacuum-assisted biopsy is a viable option for the management of lactational breast abscesses and was found to lead to a shorter healing time than needle aspiration. However, further study is necessary to establish the clinical efficacy of vacuum-assisted biopsy in the management of lactational breast abscesses. PMID- 26753605 TI - Signet-ring cell carcinoma of the appendix: a case report with an emphasis on sonographic findings. AB - In this report, we present a rare case of primary signet-ring cell carcinoma of the appendix in a 51-year-old woman with right lower quadrant pain. Since non specific concentric appendiceal wall thickening was found in a radiologic evaluation, it was misdiagnosed as non-tumorous appendicitis. An in-depth examination of the correlation between sonographic and histopathologic findings demonstrated that a single markedly thickened hypoechoic layer was well correlated with the diffuse infiltration of tumor cells in both the submucosal and muscle layers. If this sonographic finding is observed in certain clinical settings, such as potential ovarian and peritoneal metastasis, submucosal infiltrative tumors, including signet-ring cell carcinoma, should be considered in the differential diagnosis. PMID- 26753604 TI - Current status of ultrasonography of the finger. AB - The recent development of advanced high-resolution transducers has enabled the fast, easy, and dynamic ultrasonographic evaluation of small, superficial structures such as the finger. In order to best exploit these advances, it is important to understand the normal anatomy and the basic pathologies of the finger, as exemplified by the following conditions involving the dorsal, volar, and lateral sections of the finger: sagittal band injuries, mallet finger, and Boutonniere deformity (dorsal aspect); flexor tendon tears, trigger finger, and volar plate injuries (volar aspect); gamekeeper's thumb (Stener lesions) and other collateral ligament tears (lateral aspect); and other lesions. This review provides a basis for understanding the ultrasonography of the finger and will therefore be useful for radiologists. PMID- 26753607 TI - Selective Medial Release Technique Using the Pie-Crusting Method for Medial Tightness During Primary Total Knee Arthroplasty. AB - BACKGROUND: The pie-crusting method is popular in releasing lateral tightness during primary total knee arthroplasty (TKA) but is not well described for medial release. We established a selective medial release technique using the pie crusting technique and investigated the effectiveness and safety of the technique during primary TKA. METHODS: We retrospectively reviewed 729 primary TKAs with varus deformity between October 2009 and June 2012. Medial tightness in flexion was released by traditional subperiosteal stripping for the anterior portion of the medial collateral ligament (aMCL). Medial tightness in extension was released by the pie crusting for the tight fibers in the posterior portion of the MCL and/or posteromedial corner structures (pMCL/PMCS). Clinical outcomes were evaluated by Knee Society (KS) scores and the Western Ontario and McMaster Universities Osteoarthritis Index. Any complications, including late medial instability that may be related to our surgical technique, were carefully inspected. RESULTS: Among the 729 knees, 170 (23.3%) required subperiosteal stripping for balancing in flexion only, 186 (25.5%) required the pie-crusting for balancing in extension only and 142 (19.5%) required subperiosteal stripping and the pie-crusting for balancing in flexion and extension. The KS knee score was improved from 52.5 to 83.4, KS function score from 58.2 to 91.9, and Western Ontario and McMaster Universities Osteoarthritis Index from 42.7 to 21.8 (P < .001, all). No specific complications related to our technique were identified. CONCLUSIONS: The selective medial release technique appears to be an effective and safe method to obtain a balanced mediolateral gap in primary TKA. PMID- 26753606 TI - Vascular Calcifications on the Preoperative Radiograph: Predictor of Ischemic Complications in Total Knee Arthroplasty? AB - BACKGROUND: Vascular calcifications seen on the preoperative radiograph of patients scheduled for total knee arthroplasty (TKA) are intuitively seen as a risk factor for ischemic complications though there is no empiric evidence to support this assumption. The aim of this study was the correlation of perioperative ischemic complications and vascular calcifications of patients undergoing TKA. METHODS: In this retrospective analysis, all 825 patients who had undergone primary TKA in the period 2009-2011 with intraoperative use of a tourniquet were included. Patients with pathologic pulse status and history of vascular intervention were excluded. Vascular calcifications seen on the preoperative radiograph were classified as intimal-type and medial-type calcifications and were correlated to perioperative ischemic complications. RESULTS: Vascular calcifications were seen in 268 patients (medial type: n = 54, intimal type: n = 214). Major ischemic complications such as arterial thrombosis were seen in 2 patients, one of them with intimal-type calcifications and one without (complication rate 0.5% vs 0.2%, P = .715). The rate of minor ischemic complications such as protracted wound healing was significantly elevated in patients with intimal-type calcifications (6.1%) when compared to patients with medial-type calcifications (1.9%) and those without (1.6%, P = .003) even when multiple regression analysis was performed taking into account 2 potential influencing factors "age" and "diabetes mellitus" (P = .008). CONCLUSION: Owing to the significantly increased risk of ischemic complications in patients with intimal-type calcifications undergoing TKA, we recommend high alertness to the presence of calcifications on preoperative radiographs, careful intraoperative soft tissue management, and postoperative monitoring of the vascular status. PMID- 26753609 TI - Many-body dispersion corrections for periodic systems: an efficient reciprocal space implementation. AB - The energy and gradient expressions for the many-body dispersion scheme (MBD@rsSCS) of Ambrosetti et al (2014 J. Chem. Phys. 140 18A508) needed for an efficient implementation of the method for systems under periodic boundary conditions are reported. The energy is expressed as a sum of contributions from points sampled in the first Brillouin zone, in close analogy with planewave implementations of the RPA method for electrons in the dielectric matrix formulation. By avoiding the handling of large supercells, considerable computational savings can be achieved for materials with small and medium sized unit cells. The new implementation has been tested and used for geometry optimization and energy calculations of inorganic and molecular crystals, and layered materials. PMID- 26753608 TI - Can Serum Albumin Level and Total Lymphocyte Count be Surrogates for Malnutrition to Predict Wound Complications After Total Knee Arthroplasty? AB - BACKGROUND: Although the serum albumin level and total lymphocyte count (TLC) have been reported as valid and reliable markers for defining malnutrition, their cutoff levels and predictive values for wound complications in patients undergoing total knee arthroplasty (TKA) remain questionable. METHODS: A total of 3169 TKAs performed between April 2003 and December 2013 were retrospectively reviewed. We determined the prevalence of malnutrition on applying different definitions, with various cutoff values of serum albumin and TLC and analyzed the variations in outcome. The differences between groups with and without malnutrition in terms of functional outcome and complications were determined using Student's t test and analysis of variance. Multivariate logistic regression analysis was conducted to identify the independent risk factors. RESULTS: Among all the patients (N = 3169), the serum albumin level and TLC varied widely, with means of 4.1 g/dL and 2189 cells/mm(3), respectively. The prevalence of malnutrition (21%) as per the conventional definition (serum albumin level <3.5 g/dL or a serum TLC <1500 cells/mm(3)) dropped to only 1.6% when malnutrition was defined as serum albumin <3.5 g/dL "and" TLC <1500/mm(3), indicating a very small overlap between the 2 markers. No differences were observed between 2 groups in functional outcomes and incidence of wound complications. CONCLUSION: Our findings call into question the values of serum albumin level and TLC as a surrogate of malnutrition for predicting wound complications after TKA. PMID- 26753610 TI - Critically appraised topic on adverse food reactions of companion animals (2): common food allergen sources in dogs and cats. AB - BACKGROUND: To diagnose cutaneous adverse food reactions (CAFRs) in dogs and cats, dietary restriction-provocation trials are performed. Knowing the most common offending food allergens for these species would help determining the order of food challenges to optimize the time to diagnosis. RESULTS: The search for, and review and analysis of the best evidence available as of January 16, 2015 suggests that the most likely food allergens contributing to canine CAFRs are beef, dairy products, chicken, and wheat. The most common food allergens in cats are beef, fish and chicken. CONCLUSIONS: In dogs and cats, after a period of dietary restriction leading to the complete remission of clinical signs, food challenges to diagnose CAFR should begin with beef and dairy products, the most commonly recognized food allergens in these two species. PMID- 26753611 TI - Geometrical Patterning of Super-Hydrophobic Biosensing Transistors Enables Space and Time Resolved Analysis of Biological Mixtures. AB - PEDOT: PSS is a conductive polymer that can be integrated into last generation Organic Electrochemical Transistor (OECT) devices for biological inspection, identification and analysis. While a variety of reports in literature demonstrated the chemical and biological sensitivity of these devices, still their ability in resolving complex mixtures remains controversial. Similar OECT devices display good time dynamics behavior but lack spatial resolution. In this work, we integrated PEDOT: PSS with patterns of super-hydrophobic pillars in which a finite number of those pillars is independently controlled for site selective measurement of a solution. We obtained a multifunctional, hierarchical OECT device that bridges the micro- to the nano-scales for specific, combined time and space resolved analysis of the sample. Due to super-hydrophobic surface properties, the biological species in the drop are driven by convection, diffusion, and the externally applied electric field: the balance/unbalance between these forces will cause the molecules to be transported differently within its volume depending on particle size thus realizing a size-selective separation. Within this framework, the separation and identification of two different molecules, namely Cetyl Trimethyl Ammonium Bromid (CTAB) and adrenaline, in a biological mixture have been demonstrated, showing that geometrical control at the micro-nano scale impart unprecedented selectivity to the devices. PMID- 26753612 TI - Mechanism of 2,3-butanediol stereoisomers formation in a newly isolated Serratia sp. T241. AB - Serratia sp. T241, a newly isolated xylose-utilizing strain, produced three 2,3 butanediol (2,3-BD) stereoisomers. In this study, three 2,3-butanediol dehydrogenases (BDH1-3) and one glycerol dehydrogenase (GDH) involved in 2,3-BD isomers formation by Serratia sp. T241 were identified. In vitro conversion showed BDH1 and BDH2 could catalyzed (3S)-acetoin and (3R)-acetoin into (2S,3S) 2,3-BD and meso-2,3-BD, while BDH3 and GDH exhibited the activities from (3S) acetoin and (3R)-acetoin to meso-2,3-BD and (2R,3R)-2,3-BD. Four encoding genes were assembled into E. coli with budA (acetolactate decarboxylase) and budB (acetolactate synthase), responsible for converting pyruvate into acetoin. E. coli expressing budAB-bdh1/2 produced meso-2,3-BD and (2S,3S)-2,3-BD. Correspondingly, (2R,3R)-2,3-BD and meso-2,3-BD were obtained by E. coli expressing budAB-bdh3/gdh. These results suggested four enzymes might contribute to 2,3-BD isomers formation. Mutants of four genes were developed in Serratia sp. T241. Deltabdh1 led to reduced concentration of meso-2,3-BD and (2S,3S)-2,3-BD by 97.7% and 87.9%. (2R,3R)-2,3-BD with a loss of 73.3% was produced by Deltabdh3. Enzyme activity assays showed the decrease of 98.4% and 22.4% by Deltabdh1 and Deltabdh3 compared with the wild strain. It suggested BDH1 and BDH3 played important roles in 2,3-BD formation, BDH2 and GDH have small effects on 2,3-BD production by Serratia sp. T241. PMID- 26753613 TI - Directed Dedifferentiation Using Partial Reprogramming Induces Invasive Phenotype in Melanoma Cells. AB - The combination of cancer-focused studies and research related to nuclear reprogramming has gained increasing importance since both processes-reprogramming towards pluripotency and malignant transformation-share essential features. Studies have revealed that incomplete reprogramming of somatic cells leads to malignant transformation indicating that epigenetic regulation associated with iPSC generation can drive cancer development [J Mol Cell Biol 2011;341-350; Cell 2012;151:1617-1632; Cell 2014;156:663-677]. However, so far it is unclear whether incomplete reprogramming also affects cancer cells and their function. In the context of melanoma, dedifferentiation correlates to therapy resistance in mouse studies and has been documented in melanoma patients [Nature 2012;490:412-416; Clin Cancer Res 2014;20:2498-2499]. Therefore, we sought to investigate directed dedifferentiation using incomplete reprogramming of melanoma cells. Using a murine model we investigated the effects of partial reprogramming on the cellular plasticity of melanoma cells. We demonstrate for the first time that induced partial reprogramming results in a reversible phenotype switch in melanoma cells. Partially reprogrammed cells at day 12 after transgene induction display elevated invasive potential in vitro and increased lung colonization in vivo. Additionally, using global gene expression analysis of partially reprogrammed cells, we identified SNAI3 as a novel invasion-related marker in human melanoma. SNAI3 expression correlates with tumor thickness in primary melanomas and thus, may be of prognostic value. In summary, we show that investigating intermediate states during the process of reprogramming melanoma cells can reveal novel insights into the pathogenesis of melanoma progression. We propose that deeper analysis of partially reprogrammed melanoma cells may contribute to identification of yet unknown signaling pathways that can drive melanoma progression. PMID- 26753614 TI - Correlation between the combination of apparent integrated backscatter-spectral centroid shift and bone mineral density. AB - PURPOSE: To introduce a new diagnostic parameter: the linear combination of apparent integrated backscatter and spectral centroid shift. METHODS: Ultrasonic backscatter measurements were performed at the calcanei of 1262 volunteers in vivo. The hip and spine bone mineral densities of the volunteers were measured using dual X-ray absorptiometry. The apparent integrated backscatter and spectral centroid shift were calculated. A new diagnostic parameter, i.e., the linear combination of apparent integrated backscatter and spectral centroid shift, was introduced and its correlation to bone mineral density was analyzed. RESULTS: The results show that the combination of apparent integrated backscatter and spectral centroid shift is significantly correlated to bone mineral density (R = 0.73 0.84, n = 1262, p < 0.05), and that this correlation is more significant than the correlation between the apparent integrated backscatter and bone mineral density or the correlation between spectral centroid shift and bone mineral density (R = 0.48-0.69, p < 0.05). CONCLUSION: The combination of apparent integrated backscatter and spectral centroid shift can provide the complementary information of attenuation of the two parameters and predict more information about cancellous bone, and may be employed to assess cancellous bone status. PMID- 26753616 TI - A hybrid fault diagnosis method based on second generation wavelet de-noising and local mean decomposition for rotating machinery. AB - In order to extract fault features of large-scale power equipment from strong background noise, a hybrid fault diagnosis method based on the second generation wavelet de-noising (SGWD) and the local mean decomposition (LMD) is proposed in this paper. In this method, a de-noising algorithm of second generation wavelet transform (SGWT) using neighboring coefficients was employed as the pretreatment to remove noise in rotating machinery vibration signals by virtue of its good effect in enhancing the signal-noise ratio (SNR). Then, the LMD method is used to decompose the de-noised signals into several product functions (PFs). The PF corresponding to the faulty feature signal is selected according to the correlation coefficients criterion. Finally, the frequency spectrum is analyzed by applying the FFT to the selected PF. The proposed method is applied to analyze the vibration signals collected from an experimental gearbox and a real locomotive rolling bearing. The results demonstrate that the proposed method has better performances such as high SNR and fast convergence speed than the normal LMD method. PMID- 26753615 TI - Bioconcentration of two basic pharmaceuticals, verapamil and clozapine, in fish. AB - The present study examined the bioconcentration of 2 basic pharmaceuticals: verapamil (a calcium channel blocker) and clozapine (an antipsychotic compound) in 2 fresh water fishes, fathead minnow and channel catfish. In 4 separate bioconcentration factor (BCF) experiments (2 chemicals * 1 exposure concentration * 2 fishes), fathead minnow and channel catfish were exposed to 190 MUg/L and 419 MUg/L of verapamil (500 MUg/L nominal) or 28.5 MUg/L and 40 MUg/L of clozapine (50 MUg/L nominal), respectively. Bioconcentration factor experiments with fathead consisted of 28 d uptake and 14 d depuration, whereas tests conducted on catfish involved a minimized test design, with 7 d each of uptake and depuration. Fish (n = 4-5) were sampled during exposure and depuration to collect different tissues: muscle, liver, gills, kidneys, heart (verapamil tests only), brain (clozapine tests only), and blood plasma (catfish tests only). Verapamil and clozapine concentrations in various tissues of fathead and catfish were analyzed using liquid chromatography-mass spectrometry. In general, higher accumulation rates of the test compounds were observed in tissues with higher perfusion rates. Accumulation was also high in tissues relevant to pharmacological targets in mammals (i.e. heart in verapamil test and brain in the clozapine test). Tissue specific BCFs (wet wt basis) for verapamil and clozapine ranged from 0.7 to 75 and from 31 to 1226, respectively. Tissue-specific concentration data were used to examine tissue-blood partition coefficients. PMID- 26753617 TI - Two-degree-of-freedom fractional order-PID controllers design for fractional order processes with dead-time. AB - Recently, fractional order (FO) processes with dead-time have attracted more and more attention of many researchers in control field, but FO-PID controllers design techniques available for the FO processes with dead-time suffer from lack of direct systematic approaches. In this paper, a simple design and parameters tuning approach of two-degree-of-freedom (2-DOF) FO-PID controller based on internal model control (IMC) is proposed for FO processes with dead-time, conventional one-degree-of-freedom control exhibited the shortcoming of coupling of robustness and dynamic response performance. 2-DOF control can overcome the above weakness which means it realizes decoupling of robustness and dynamic performance from each other. The adjustable parameter eta2 of FO-PID controller is directly related to the robustness of closed-loop system, and the analytical expression is given between the maximum sensitivity specification Ms and parameters eta2. In addition, according to the dynamic performance requirement of the practical system, the parameters eta1 can also be selected easily. By approximating the dead-time term of the process model with the first-order Pade or Taylor series, the expressions for 2-DOF FO-PID controller parameters are derived for three classes of FO processes with dead-time. Moreover, compared with other methods, the proposed method is simple and easy to implement. Finally, the simulation results are given to illustrate the effectiveness of this method. PMID- 26753619 TI - Urology residents experience comparable workload profiles when performing live porcine nephrectomies and robotic surgery virtual reality training modules. AB - In pursuit of improving the quality of residents' education, the Southeastern Section of the American Urological Association (SES AUA) hosts an annual robotic training course for its residents. The workshop involves performing a robotic live porcine nephrectomy as well as virtual reality robotic training modules. The aim of this study was to evaluate workload levels of urology residents when performing a live porcine nephrectomy and the virtual reality robotic surgery training modules employed during this workshop. Twenty-one residents from 14 SES AUA programs participated in 2015. On the first-day residents were taught with didactic lectures by faculty. On the second day, trainees were divided into two groups. Half were asked to perform training modules of the Mimic da Vinci-Trainer (MdVT, Mimic Technologies, Inc., Seattle, WA, USA) for 4 h, while the other half performed nephrectomy procedures on a live porcine model using the da Vinci Si robot (Intuitive Surgical Inc., Sunnyvale, CA, USA). After the first 4 h the groups changed places for another 4-h session. All trainees were asked to complete the NASA-TLX 1-page questionnaire following both the MdVT simulation and live animal model sessions. A significant interface and TLX interaction was observed. The interface by TLX interaction was further analyzed to determine whether the scores of each of the six TLX scales varied across the two interfaces. The means of the TLX scores observed at the two interfaces were similar. The only significant difference was observed for frustration, which was significantly higher at the simulation than the animal model, t (20) = 4.12, p = 0.001. This could be due to trainees' familiarity with live anatomical structures over skill set simulations which remain a real challenge to novice surgeons. Another reason might be that the simulator provides performance metrics for specific performance traits as well as composite scores for entire exercises. Novice trainees experienced substantial mental workload while performing tasks on both the simulator and the live animal model during the robotics course. The NASA TLX profiles demonstrated that the live animal model and the MdVT were similar in difficulty, as indicated by their comparable workload profiles. PMID- 26753618 TI - Malaria transmission dynamics surrounding the first nationwide long-lasting insecticidal net distribution in Papua New Guinea. AB - BACKGROUND: The major malaria vectors of Papua New Guinea exhibit heterogeneities in distribution, biting behaviour and malaria infection levels. Long-lasting, insecticide-treated nets (LLINs), distributed as part of the National Malaria Control Programme, are the primary intervention targeting malaria transmission. This study evaluated the impact of LLINs on anopheline density, species composition, feeding behaviour, and malaria transmission. METHODS: Mosquitoes were collected by human landing catch in 11 villages from East Sepik Province and Madang Province. Mosquitoes were collected for 3 years (1 year before distribution and 2 years after), and assayed to determine mosquito species and Plasmodium spp. infection prevalence. The influence of weather conditions and the presence of people and animals on biting density was determined. Determinants of biting density and sporozoite prevalence were analysed by generalized estimating equations (GEE). RESULTS: Mosquito biting rates and entomological inoculation rates decreased significantly after the distribution. Plasmodium falciparum and P. vivax sporozoite prevalence decreased in year 2, but increased in year 3, suggesting the likelihood of resurgence in transmission if low biting rates are not maintained. An earlier shift in the median biting time of Anopheles punctulatus and An. farauti s.s. was observed. However, this was not accompanied by an increase in the proportion of infective bites occurring before 2200 hours. A change in species composition was observed, which resulted in dominance of An. punctulatus in Dreikikir region, but a decrease in An. punctulatus in the Madang region. When controlling for village and study year, An. farauti s.s., An. koliensis and An. punctulatus were equally likely to carry P. vivax sporozoites. However, An. punctulatus was significantly more likely than An. farauti s.s. (OR 0.14; p = 0.007) or An. koliensis (OR 0.27; p < 0.001) to carry P. falciparum sporozoites. CONCLUSIONS: LLINs had a significant impact on malaria transmission, despite exophagic and crepuscular feeding behaviours of dominant vectors. Changes in species composition and feeding behaviour were observed, but their epidemiological significance will depend on their durability over time. PMID- 26753620 TI - The Atg1-kinase complex tethers Atg9-vesicles to initiate autophagy. AB - Autophagosomes are double-membrane vesicles that sequester cytoplasmic material for lysosomal degradation. Their biogenesis is initiated by recruitment of Atg9 vesicles to the phagophore assembly site. This process depends on the regulated activation of the Atg1-kinase complex. However, the underlying molecular mechanism remains unclear. Here we reconstitute this early step in autophagy from purified components in vitro. We find that on assembly from its cytoplasmic subcomplexes, the Atg1-kinase complex becomes activated, enabling it to recruit and tether Atg9-vesicles. The scaffolding protein Atg17 targets the Atg1-kinase complex to autophagic membranes by specifically recognizing the membrane protein Atg9. This interaction is inhibited by the two regulatory subunits Atg31 and Atg29. Engagement of the Atg1-Atg13 subcomplex restores the Atg9-binding and membrane-tethering activity of Atg17. Our data help to unravel the mechanism that controls Atg17-mediated tethering of Atg9-vesicles, providing the molecular basis to understand initiation of autophagosome-biogenesis. PMID- 26753622 TI - A Pharmacokinetic-Pharmacodynamic Model of Morphine Exposure and Subsequent Morphine Consumption in Postoperative Pain. AB - PURPOSE: To characterize the pharmacokinetic-pharmacodynamic (PK-PD) relationship between exposure of morphine and subsequent morphine consumption and to develop simulation tools for model validation. METHODS: Dose, formulation and time of morphine administration was available from a published study in 63 patients receiving intravenous, oral immediate release or oral controlled release morphine on request after hip surgery. The PK-PD relationship between predicted exposure of morphine and morphine consumption was modeled using repeated time to event (RTTE) modeling in NONMEM. To validate the RTTE model, a visual predictive check method was developed with simulated morphine consumption given the exposure of preceding morphine administration. RESULTS: The probability of requesting morphine was found to be significantly related to the exposure of morphine as well as night/day. Oral controlled release morphine was more effective than intravenous and oral immediate release formulations at equivalent average concentrations. Maximum effect was obtained for 8 h by oral controlled release doses >= 15 mg, where probability of requesting a new dose was reduced to 20% for a typical patient. CONCLUSION: This study demonstrates the first quantitative link between exposure of morphine and subsequent morphine consumption and introduces an efficient visual predictive check approach with simulation of adaptive dosing. PMID- 26753621 TI - Cells Comprising the Prostate Cancer Microenvironment Lack Recurrent Clonal Somatic Genomic Aberrations. AB - Prostate cancer-associated stroma (CAS) plays an active role in malignant transformation, tumor progression, and metastasis. Molecular analyses of CAS have demonstrated significant changes in gene expression; however, conflicting evidence exists on whether genomic alterations in benign cells comprising the tumor microenvironment (TME) underlie gene expression changes and oncogenic phenotypes. This study evaluates the nuclear and mitochondrial DNA integrity of prostate carcinoma cells, CAS, matched benign epithelium and benign epithelium associated stroma by whole-genome copy-number analyses, targeted sequencing of TP53, and FISH. Array comparative genomic hybridization (aCGH) of CAS revealed a copy-neutral diploid genome with only rare and small somatic copy-number aberrations (SCNA). In contrast, several expected recurrent SCNAs were evident in the adjacent prostate carcinoma cells, including gains at 3q, 7p, and 8q, and losses at 8p and 10q. No somatic TP53 mutations were observed in CAS. Mitochondrial DNA (mtDNA) extracted from carcinoma cells and stroma identified 23 somatic mtDNA mutations in neoplastic epithelial cells, but only one mutation in stroma. Finally, genomic analyses identified no SCNAs, LOH, or copy-neutral LOH in cultured cancer-associated fibroblasts, which are known to promote prostate cancer progression in vivo IMPLICATIONS: The gene expression changes observed in prostate cancer-adjacent stroma and the attendant contribution of the stroma to the development and progression of prostate cancer are not due to frequent or recurrent genomic alterations in the TME. PMID- 26753624 TI - Anti-inflammatory terpenylated coumarins from the leaves of Zanthoxylum schinifolium with alpha-glucosidase inhibitory activity. AB - Nine terpenylated coumarins, namely 7-[(E)-3',7'-dimethyl-6'-oxo-2',7' octadienyl]oxy-coumarin (1), schinilenol (2), schinindiol (3), collinin (4), 7 [(E)-7'-hydroxy-3',7'-dimethy-locta-2',5'-dienyloxy]-coumarin (5), 8 methoxyanisocoumarin (6), 7-(6'R-hydroxy-3',7'-dimethyl-2'E,7' octadienyloxy)coumarin (7), (E)-4-methyl-6-(coumarin-7'-yloxy)hex-4-enal (8), and aurapten (9), along with a 4-quinolone alkaloid (10) and integrifoliodiol (11), were isolated from the leaves of Zanthoxylum schinifolium. Of the isolates, compounds 4 and 7 potentially inhibited NO production in lipopolysaccharide (LPS) stimulated macrophage RAW264.7 cells, with IC50 values of 5.9 +/- 0.8 and 18.2 +/ 1.8 MUM, respectively. Furthermore, compounds 4 and 7 dose-dependently reduced the LPS-induced iNOS expression. Moreover, pre-incubation of cells with 4 and 7 significantly suppressed LPS-induced COX-2 protein expression. In addition, compounds 4, 7, 8, and 10 showed strong alpha-glucosidase inhibitory effects, with IC50 values of 92.1 +/- 0.7, 90.6 +/- 0.9, 78.2 +/- 0.2, and 82.4 +/- 0.8 MUM, respectively. Compounds 1, 5, and 11 displayed moderate effects with IC50 values of 161.6 +/- 0.3, 164.4 +/- 1.1, and 155.4 +/- 0.9 MUM, while acarbose, a positive control, possessed an IC50 value of 121.5 +/- 1.0 MUM. This is the first investigation on the alpha-glucosidase inhibitory effect of components from Zanthoxylum schinifolium. Further studies should be made on active compounds. PMID- 26753626 TI - Structural Uncertainty of Markov Models for Advanced Breast Cancer: A Simulation Study of Lapatinib. AB - OBJECTIVE: To examine the impact of structural uncertainty of Markov models in modeling cost-effectiveness for the treatment of advanced breast cancer (ABC). METHODS: Four common Markov models for ABC were identified and examined. Markov models 1 and 2 have 4 health states (stable-disease, responding-to-therapy, disease-progressing, and death), and Markov models 3 and 4 only have 3 health states (stable-disease, disease-progressing, and death). In models 1 and 3, the possibility of death can occur in any health state, while in models 2 and 4, the chance of dying can only occur in the disease-progressing health state. A simulation was conducted to examine the impact of using different model structures on cost-effectiveness results in the context of a combination therapy of lapatinib and capecitabine for the treatment of HER2-positive ABC. Model averaging with an assumption of equal weights in all 4 models was used to account for structural uncertainty. RESULTS: Markov model 3 yielded the lowest incremental cost-effectiveness ratio (ICER) of $303,909 per quality-adjusted life year (QALY), while Markov model 1 produced the highest ICER ($495,800/QALY). At a willingness-to-pay threshold of $150,000/QALY, the probabilities that the combination therapy is considered to be cost-effective for Markov models 1, 2, 3, and 4 were 14.5%, 14.1%, 21.6%, and 17.0%, respectively. When using model averaging to synthesize different model structures, the resulting ICER was $389,270/QALY. CONCLUSIONS: Our study shows that modeling ABC with different Markov model structures yielded a wide range of cost-effectiveness results, suggesting the need to investigate structural uncertainty in health economic evaluation. When applied in the context of HER2-positive ABC treatment, the combination therapy with lapatinib is not cost-effective, regardless of which model was used and whether uncertainties were accounted for. PMID- 26753625 TI - Interactive effects of diabetes and impaired kidney function on cognitive performance in old age: a population-based study. AB - BACKGROUND: The interactive effect between diabetes and impaired kidney function on cognitive impairment in older adults has not yet been reported. The aim of this study was to investigate the association of diabetes and impaired kidney function with cognitive impairment among Chinese older people living in a rural area. METHODS: This cross-sectional study included 1,358 participants (age >=60 years; 60.5% women) in the population-based Confucius Hometown Aging Project in Shandong, China. Data on demographics, lifestyle factors, health history, use of medications, global cognitive function, and kidney function were collected through structured interviews, clinical examinations, and blood tests. We defined diabetes as a fasting plasma glucose level >=7.0 mmol/l or use of hypoglycemic agents, impaired kidney function as glomerular filtration rate estimated from cystatin C (eGFRcys) <60 ml/min/1.73 m(2). Cognitive impairment was defined using the education-based cut-off scores of Mini-Mental State Examination (MMSE). Data were analyzed using multiple general linear and logistic regression models. RESULTS: Cognitive impairment was defined in 197 (14.5%) persons. The multi adjusted beta coefficient of MMSE score associated with diabetes was -0.06 (95% confidence interval [CI], -0.16, 0.03); the corresponding figures associated with eGFRcys <60, 60-89.9, and >=90 ml/min/1.73 m(2) were -0.15 (-0.28, -0.02), -0.01 (-0.10, 0.08), and 0 (reference) (Ptrend = 0.046), respectively. Diabetes and impaired kidney function showed an interactive effect on cognitive impairment ( interaction = 0.02). Compared with individuals having neither diabetes nor impaired kidney function, those with both conditions had a multi-adjusted odds ratio of 4.23 (95% CI, 2.10-8.49) for cognitive impairment. The relative excess risk due to interaction was 2.74. CONCLUSIONS: This study suggests that concurrent presence of diabetes and impaired kidney function is associated with a substantial likelihood for cognitive impairment in older adults. PMID- 26753623 TI - Visualising apoptosis in live zebrafish using fluorescence lifetime imaging with optical projection tomography to map FRET biosensor activity in space and time. AB - Fluorescence lifetime imaging (FLIM) combined with optical projection tomography (OPT) has the potential to map Forster resonant energy transfer (FRET) readouts in space and time in intact transparent or near transparent live organisms such as zebrafish larvae, thereby providing a means to visualise cell signalling processes in their physiological context. Here the first application of FLIM OPT to read out biological function in live transgenic zebrafish larvae using a genetically expressed FRET biosensor is reported. Apoptosis, or programmed cell death, is mapped in 3-D by imaging the activity of a FRET biosensor that is cleaved by Caspase 3, which is a key effector of apoptosis. Although apoptosis is a naturally occurring process during development, it can also be triggered in a variety of ways, including through gamma irradiation. FLIM OPT is shown here to enable apoptosis to be monitored over time, in live zebrafish larvae via changes in Caspase 3 activation following gamma irradiation at 24 hours post fertilisation. Significant apoptosis was observed at 3.5 hours post irradiation, predominantly in the head region. PMID- 26753628 TI - Multimodal imaging with (18)F-FDG-PET/CT and (111)In-Octreotide SPECT in patients with metastatic medullary thyroid carcinoma. AB - OBJECTIVE: The aim of our study was to determine the role of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) and indium-111 Octreotide single photon emission tomography ((111)In Octreotide SPECT) in the evaluation of metastatic medullary thyroid carcinoma (MMTC). METHODS: Twenty-five MMTC patients were retrospectively evaluated. All patients had undergone whole-body (18)F-FDG-PET/CT including 20 who had also undergone (111)In-Octreotide SPECT within a maximum interval of 6 weeks. Diagnostic contrast-enhanced computed tomography (CT) alone or as part of (18)F FDG-PET/CT examination was performed in all patients. RESULTS: Contrast-enhanced CT detected a total of 131 lesions including 79 enlarged lymph nodes and 14 bone lesions. (18)F-FDG-PET/CT visualized a total of 92 true positive lesions (SUVmax range 1.1-10.0, mean 4.0 +/- 1.7) including 66 lymph nodes, 7 of which were not enlarged on CT, and 8 bone metastases. In the 20 patients studied with both techniques, a total of 64 and 46 true positive lesions were detected by (18)F-FDG PET/CT and (111)In-Octreotide SPECT, respectively. In particular, (18)F-FDG uptake was found in 43 lymph nodes and in 7 bone metastases whereas (111)In Octreotide uptake was detected in 27 lymph nodes and in 10 bone metastases. CONCLUSIONS: In MMTC patients, (18)F-FDG-PET/CT provides a useful contribution mainly in evaluating lymph node involvement whereas (111)In-Octreotide SPECT can contribute to the detection and somatostatin receptor characterization especially of bone lesions. PMID- 26753629 TI - Spatial correlativity of atmospheric particulate components simultaneously collected in Japan. AB - The simultaneous sampling of total suspended particles was performed at 14 sites in Japan during July 2008-June 2009. The spatial correlativity of each particulate composition toward Osaka was obtained for nine selected sites to overview the chemical composition and geographical distribution of particulate components across a wide range of areas nationwide. The spatial correlatives of atmospheric particulate components were extended to an even wider range of areas up to 950 km distance (meso-alpha scale region, >200 km) for a far-reaching distance analysis unique in the literature. Overall, the spatial correlations of ionic species and both organic and elemental carbons were significant, suggesting their shared advections, including their long-range transport from East Asia. Although sulfate ions are widely dispersed across Japan, such is not necessarily correlated with organic and elemental carbon, possibly indicating that the sulfate emission source, including long-range transport, differs from that of carbonaceous particulates. By contrast, the characteristics of spatial correlatives of metallic constituents vary; for example, particulate Pb and Cd show a significantly wide range of spatial correlatives to Osaka, while Mn-though limited to cities neighboring Osaka-shows significant spatial correlations. Other metallic constituents showed no significant spatial correlatives, indicating the effects of local pollutants. Moreover, the extent of the spatial dispersion of the particulate components and the relationships among chemical components were analyzed via factor analysis to highlight the effects of long-range inflow and local original emissions. In this treatment, 13 particulate components among the 19 measured were implicated in long-range transport. PMID- 26753631 TI - Interventions to Improve Safe Sleep Among Hospitalized Infants at Eight Children's Hospitals. AB - BACKGROUND AND OBJECTIVES: Within hospital pediatric units, there is a lack of consistent application or modeling of the American Academy of Pediatrics recommendations for safe infant sleep. The purpose of this study was to improve safe sleep practices for infants in nonneonatal pediatric units with implementation of specific interventions. METHODS: This multi-institutional study was conducted by using baseline observations collected for sleep location, position, and environment (collectively, "safe sleep") of infants admitted to pediatric units. Interventions consisted of: (1) staff education, including a commitment to promote safe sleep; (2) implementing site-generated safe sleep policies; (3) designating supply storage in patient rooms; and/or (4) caregiver education. Postintervention observations of safe sleep were collected. Eight hospitals participated from the Inpatient FOCUS Group of the Children's Hospital Association. Each site received institutional review board approval/exemption. RESULTS: Safe sleep was observed for 4.9% of 264 infants at baseline and 31.2% of 234 infants postintervention (P<.001). Extra blankets, the most common of unsafe items, were present in 77% of cribs at baseline and 44% postintervention. However, the mean number of unsafe items observed in each sleeping environment was reduced by >50% (P=.001). CONCLUSIONS: Implementation of site-specific interventions seems to improve overall safe sleep in inpatient pediatric units, although continued improvement is needed. Specifically, extra items are persistently left in the sleeping environment. Moving forward, hospitals should evaluate their compliance with American Academy of Pediatrics recommendations and embrace initiatives to improve modeling of safe sleep. PMID- 26753630 TI - Non-binary or genderqueer genders. AB - Some people have a gender which is neither male nor female and may identify as both male and female at one time, as different genders at different times, as no gender at all, or dispute the very idea of only two genders. The umbrella terms for such genders are 'genderqueer' or 'non-binary' genders. Such gender identities outside of the binary of female and male are increasingly being recognized in legal, medical and psychological systems and diagnostic classifications in line with the emerging presence and advocacy of these groups of people. Population-based studies show a small percentage--but a sizable proportion in terms of raw numbers--of people who identify as non-binary. While such genders have been extant historically and globally, they remain marginalized, and as such--while not being disorders or pathological in themselves--people with such genders remain at risk of victimization and of minority or marginalization stress as a result of discrimination. This paper therefore reviews the limited literature on this field and considers ways in which (mental) health professionals may assist the people with genderqueer and non-binary gender identities and/or expressions they may see in their practice. Treatment options and associated risks are discussed. PMID- 26753632 TI - Approval of psychotherapy and medication for the treatment of mental disorders over the lifespan. An age period cohort analysis. AB - AIMS: Previous cross-sectional studies revealed inconsistent results regarding mental health treatment preferences among the general population. In particular, it is unclear to what extent specific age groups approve psychotherapy or psychotropic medication for the treatment of mental disorders. We explore whether treatment recommendations of either psychotherapy or psychiatric medication change over the lifespan which includes age-related effects due to increasing age of a person, cohort effects that reflect specific opinions during the time a person was born and period effects that reflect societal changes. METHODS: Using data from three identical population surveys in Germany from 1990, 2001 and 2011 (combined n = 9046), we performed age-period-cohort analyses to determine the pure age, birth cohort and time period effects associated with the specific treatment recommendations for a person with either depression or schizophrenia, using logistic Partial Least-Squares regression models. RESULTS: For both disorders, approval of both psychotherapy and medication for a person with mental illness increases with age. At the same time, younger cohorts showed stronger recommendations particularly for psychotherapy (OR around 1.07 per decade). The strongest effects could be observed for time period with an increase in recommendation between 1990 and 2001 with odds ratio of 2.36 in depression and 2.97 in schizophrenia, respectively. In general, the treatment option that showed the strongest increase in recommendation was medication for schizophrenia and psychotherapy for depression. CONCLUSION: Underutilisation of psychotherapy in old age seems not to reflect treatment preferences of older persons. Thus, special treatment approaches need to be offered for this group that seems to be willing for psychotherapy but do not yet use it. Cohort patterns suggest that approval of psychotherapy among older persons will likely further increase in the coming years as these people get older. Finally, strong period effects underpin the importance of changing attitudes in the society. These could reflect reporting changes about psychiatric topics in the media or a general increase in the perception of treatment options. Nevertheless, more treatment offers especially for older people are needed. PMID- 26753627 TI - Understanding the effects of different HIV transmission models in individual based microsimulation of HIV epidemic dynamics in people who inject drugs. AB - We investigated how different models of HIV transmission, and assumptions regarding the distribution of unprotected sex and syringe-sharing events ('risk acts'), affect quantitative understanding of HIV transmission process in people who inject drugs (PWID). The individual-based model simulated HIV transmission in a dynamic sexual and injecting network representing New York City. We constructed four HIV transmission models: model 1, constant probabilities; model 2, random number of sexual and parenteral acts; model 3, viral load individual assigned; and model 4, two groups of partnerships (low and high risk). Overall, models with less heterogeneity were more sensitive to changes in numbers risk acts, producing HIV incidence up to four times higher than that empirically observed. Although all models overestimated HIV incidence, micro-simulations with greater heterogeneity in the HIV transmission modelling process produced more robust results and better reproduced empirical epidemic dynamics. PMID- 26753633 TI - Summary of the proceedings of the International Summit 2015: General and subspecialty radiology. AB - The need for subspecialisation in radiology and the relationship of general and subspecialist radiologists is very diverse in different regions of the world according to the reports presented at the ESR International Summit, organised by the ESR during the European Congress of Radiology in March 2015 in Vienna. The International Summit is held once a year by the ESR and its national and international radiological partner societies from outside Europe with the aim to address and discuss selected subjects of global relevance in radiology. In 2015, the relationship between general and subspecialist radiologists was analysed. It was shown that the situation differs immensely between developed and developing countries; in developed countries, a considerable proportion of radiologists are subspecialty trained; subspecialty radiologists practise mainly in large and academic departments, and many radiologists practise as multispecialty radiologists. In many developing countries only general radiologists-if available at all-practise radiology, and imaging interpretation is often performed by physicians with very limited relevant training or in some cases even by non physicians. MAIN MESSAGES: * Subspecialisation and preservation of the integrity of the radiology profession are relevant for improved patient care. * Subspecialisation is needed in large departments, providing the basis for innovation and research. * Subspecialty sections should preferably remain within the overarching radiology department. * Shared facilities, efficient use of resources and common organisational structures are beneficial. * A multispecialty radiologist model is an option to build robust academic and private practices. PMID- 26753634 TI - mTORC2-Akt signaling axis is implicated in myocardial compensation and fibrosis. AB - mTOR signaling has long been implicated in the mechanisms of cardiomyocyte survival in response to volume or pressure overload. Several studies have focused on the significance of mTORC1 in cardiomyocyte survival, questioning the role of mTORC2. mTORC2?Akt signaling is an emerging axis implicated in cardiomyocyte compensation and thus heart failure. Upon being subjected to chronic stress, cardiomyocytes activate mTORC2?Akt signaling pathway to promote survival by activating the ubiquitin proteasome system, inducing the degradation of pro apoptotic proteins, and altering the actin cytoskeleton. Given the importance of mTORC2 in cardiomyocyte survival, studies suggest that loss of mTORC2 signaling would result in loss of cardiomyocytes, fibrosis, and heart failure. This review serves to elaborate on how mTORC2-Akt signaling plays a role in cardiomyocyte growth and survival under stress and how the loss of the axis would result in fibrosis and heart failure. PMID- 26753636 TI - Fragility fractures: clinical and therapeutic aspects. AB - Osteoporosis is the most important bone metabolic disorder characterized by reduction of bone mass and micro-architectural deterioration associated to an increased risk for fragility fractures. It involves millions of worldwide dispersed individuals of both sexes and, consequently, the elevated morbidity and mortality of fractured subjects and the increased socio-economic costs suggest it must be faced as a major health problem. Thus, there is a need for either a precocious identification of subjects with fragile ?bones? or the institution of specific diagnostic-therapeutical strategies. Improvement in bone pathophysiology knowledge, together with progress in pharmaceutical development has led to an opportunity for early identification and therapy of subjects at high risk of fragility fractures. In this review, we briefly describe the recent acquisitions in bone pathophysiology as well as in the anti-fracture drug development with a brief excursus on those already well established. PMID- 26753635 TI - Link of obesity and gastrointestinal cancer: crossroad of inflammation and oxidative stress. AB - Obesity incidence has reached pandemic levels, and is accompanied by high incidence and poor prognosis of various types of cancers including gastrointestinal ones. Underlying mechanisms include elevated levels of insulin, IGF-I, and altered adipokine concentration, mainly towards leptin and adiponectin levels. However, it is not yet thoroughly understood. It is now widely known that obesity is associated with chronic low-grade inflammation, characteristic of altered immune cell infiltration in adipose tissue, and changed inflammatory cytokines and chemokines: tumor necrosis factor alpha (TNF-a), IL-6, and the chemoattractant monocyte chemoattractant protein 1 (MCP-1) and others, all together eventually promoting caner pathogenesis. Moreover, accumulating reports have shown that excess adipose tissue in obese individuals resulted in elevated levels of systematic oxidative stress, another way of promoting cancer development and progression. In general, altered immunological milieu and oxidative stress in obesity are important determinants for tumorigenesis. PMID- 26753637 TI - Clinical application of shock wave therapy in musculoskeletal disorders: part II related to myofascial and nerve apparatus. AB - Shock waves have been widely recognized in literature as a biological regulator; accordingly we carried out a review on the effect of shock waves on the mesenchymal cells in their various expressions: bone, muscle, ligament and tendon tissue. To date, the application of Shock Wave Therapy (SWT) in musculoskeletal disorders has been primarily used in the treatment of tendinopathies (proximal plantar fasciopathy, lateral elbow tendinopathy, calcific tendinopathy of the shoulder, and patellar tendinopathy, etc.) and bone defects (delayed and non union of bone fractures, avascular necrosis of femoral head, etc.). Although the mechanism of their therapeutic effects is still unknown, the majority of published papers have shown the positive and beneficial effects of using SWT as a treatment for musculoskeletal disorders, with a success rate ranging from 65% to 91%, while the complications are low or negligible. The purpose of this paper is to present the published data on the clinical application of SWT in the treatment of myofascial and nerve disorders. With the help of the relevant literature, in this paper we outline the indications and success rates of SWT, as well as the adequate SWT parameters (e.g., rate of impulses, energy flux density) defined according to the present state of knowledge. PMID- 26753638 TI - Role of TNF in mast cell neuroinflammation and pain. AB - Inflammatory mediators, such as cytokines, chemokines and arachidonic acid compounds, lead to vascular permeability and dilation and increase sensitization and pain receptors. Proinflammatory cytokines, including tumor necrosis factor, are involved in the etiology of clinical neurological disorders. These cytokines activate nuclear factor-kappaB (NF-kappaB) which leads to the activation of different inflammatory genes. TNF implicated in neurological disorders has an important role in the activation of microglia and astrocytes. The inhibition of TNF may lead to the decrease of microglia activation and can be useful for therapeutic intervention. TNF, at the site of nerve injury may activate mast cells (MCs) which mediate pathologic events such as headache and pain. TNF is the only cytokine stored in mast cells and can be rapidly released along with biogenic amines after MC stimulation. Activation of MCs leads to NF-kappaB and AP1 generation with release of many cytokines including TNF, IL-33 and IL-1. In this paper we discuss the role of TNF in MC activation, mediating pain and neurological disorders. PMID- 26753640 TI - Lymphatic edema of the lower limbs after orthopedic surgery: results of a randomized, open-label clinical trial with a new extended-release preparation. AB - The lymphedema is a high interstitial protein concentration edema, caused by impaired lymphatic transport capacity. It can be primary or secondary. The secondary form may be caused by a lesion of the lymphatic vessels and/or lymph nodes during diagnostic or therapeutic procedures such as surgical interventions. Often, in clinical practice, there is lymphedema after orthopedic surgery, even in minor orthopedic surgery. Lymphedema, typically presents symptoms of swelling, pain, inflammation, and itching, and it can generate, over the years, acute disability in the affected limbs. The standard therapy is mainly represented by medical treatment, such as manual lymphatic drainage and compression with bandages and stockings. In literature it is documented that lymphedema is responsive to alpha and the gamma benzopyrones. The aim of this study was to determine the effectiveness of delayed extended-release formulation of a compound containing apha-benzo-pyrone (Coumarin), benzo-gamma-pyrone (Troxuretina) and oligomeric proanthocyanidins from Vitis vinifera (OPC), in addition to compression therapy, in the reduction of lymphatic edema after prosthetic hip and knee surgery. In the group treated, after 30 days, a reduction was observed of the edema of 4.8% in the ankle area (p less than 0.008) and 2.7% in the calf area (p less than 0.013). The control group showed no significant reduction. The treated group showed a marked reduction of all the secondary symptoms considered in the study, although variations were not significant. The results show that the compound used was effective in reducing edema after major orthopedic surgery, and consequently in alleviating some related symptoms, such as pain, itching, and burning. As an edema has extensive inflammatory components in patients with reduced mobility, the final data seems interesting, however, further investigations and a better follow-up are required. PMID- 26753639 TI - Selective inhibitors of aurora kinases inhibit proliferation, reduce cell viability and impair cell cycle progression in papillary thyroid carcinoma cells. AB - The three members of the Aurora kinase family, Aurora-A, -B and -C, regulate several aspects of the mitotic process, and their aberrant expression and/or function causes mitotic abnormalities leading either to cell death or aneuploidy. They are found overexpressed in several human malignancies, including the papillary thyroid carcinoma (PTC). In the present study, we sought to establish whether Aurora kinase inhibition could be of any therapeutic value in the treatment of aggressive forms of PTC, enduring to radioactive iodide (RAI) ablation. To this end, the effects of selective inhibitors of Aurora-A (MLN8237) and Aurora-B (AZD1152) were analyzed on 3 human PTC cell lines expressing either wild-type (K1 and TPC1) or mutant p53 (BCPAP). The two inhibitors were capable of reducing cell proliferation in a time- and dose-dependent manner, with IC50 comprised between 65.4 and 114.9 nM for MLN8237, and between 26.6 and 484.6 nM for AZD1152. Immunofluorescence experiments confirmed that AZD1152 inhibited Aurora-B phosphorylation of histone H3 on Ser10, however, it did not affect Aurora-A autophosphorylation. MLN8237 inhibited Aurora-A autophosphorylation as expected, but at concentrations required to achieve the maximum antiproliferative effects it also abolished H3 (Ser10) phosphorylation. Time-lapse videomicroscopy evidenced that both inhibitors prevented the completion of cytokinesis, and cytofluorimetric analysis showed accumulation of cells in G2/M phase and/or polyploidy. Apoptosis was induced in all the cells by both inhibitors independently from the p53 status. In conclusion, in the present preclinical study MLN8237 and AZD1152 have emerged as promising drug candidates for RAI insensitive PTC. PMID- 26753642 TI - The profile of melatonin receptors gene expression and genes associated with their activity in colorectal cancer: a preliminary report. AB - The antiproliferative and immunomodulatory effects of melatonin (MLT) have been demonstrated in a variety of neoplasms including colorectal cancer (CRC). In humans and other mammals, MLT acts on target tissues through membrane and retinoid nuclear receptors. The aim of this study was to evaluate transcription activity of melatonin receptors and genes associated with regulation of their activity in colorectal adenocarcinoma tissues in relation to clinical stage of cancer. A total of 24 pairs of surgically removed tumoral and healthy (marginal) tissue samples from colorectal cancer patients at clinical stages I-II and III-IV were collected. As an additional control, twenty normal samples were tak!en from people whose large intestine tissues were reported as non-tumoral after colonoscopy. Expression of mRNA genes was studied by microarray HG-U133A analysis. The analysis of gene expression profile was performed using commercially available oligonucleotide microarrays of HG-U133A. High increase of MT1 mRNA expression levels in all cancerous samples vs non-cancerous tissues was observed. The MT2 mRNA expression levels increased slightly in marginal and malignant samples. Among the genes participating in the cascade of signal transfer in cells activated by MLT via melatonin receptors, we found encoding genes (GNA11, OXTR, TPH1) only for differentiating stage III - IV of CRC. Monitoring the expression levels of genes that are related to melatonin receptors may offer a strategy to anticipate tumour development and estimate the molecular changes that occur during carcinogenesis. The mechanism behind this association needs further elucidation. PMID- 26753643 TI - LRIG1 expression during homeostasis and skin wound healing in mice. AB - Leucine-rich repeats and immunoglobulin-like domains (LRIG)-1 belong to the family of proteins known to be expressed in skin. Ablation of LRIG1 in mice results in epidermal hyperplasia and its aberrant expression levels have been reported in pathological conditions such as psoriasis, thus evident of an indispensible role of LRIG1 in maintaining epidermal homeostasis. In order to gain insight into the homeostatic expression of LRIG1 and in various stages of cutaneous wound healing, LRIG1 expression was immunohistochemically analyzed in full thickness skin wounds in mice. The full thickness skin wounds were established on the dorsal back of Balb/c mice (n=6). LRIG1 expression at various post wounding days (1, 2, 3, 6 and 14) was determined through Immunohistochemical analysis (IHC) of the murine skin sections. The injury caused a sharp decline in LRIG1 expression in the basal epidermal cells and appendages surrounding the wound which correlates with the re-epithelialization phase of healing. LRIG1 expression remained down regulated during most of the wound healing stages. LRIG1+ cells were found to re-populate the neo-epidermis on day 14, suggesting an important homeostatic role of LRIG1 in skin. PMID- 26753641 TI - Osteogenic differentiation and gene expression of dental pulp stem cells under low-level laser irradiation: a good promise for tissue engineering. AB - The effects of low-level laser therapy (LLLT) has been the focus of recent studies as being assumed responsible for promoting photostimulatory and photobiomodulatory effects in vivo and in vitro, increasing cell metabolism, improving cell regeneration and invoking an anti-inflammatory response. A positive effect of LLLT on the bone proliferation of some cell types has been observed, but little is known about its effect on dental pulp stem cells (DPSCs). Here, we accurately describe the technical procedure to isolate mesenchymal DPSCs, and assay their osteogenic capacity when irradiated with an LLLT source. These preliminary results show that LLLT irradiation influences the in vitro proliferation of DPSCs and increases the expression of essential proteins for bone formation, although it is necessary to carry out further experiments on other cell types and to uniform the methodological designs. PMID- 26753644 TI - Effects of vascular endothelial growth factor-b on the bioelectric activity of rat atrial myocardium under normal conditions and during gradual stretching. AB - Using a microelectrode technique we studied the effects of vascular endothelial growth factor-B on the activity of rat atrial myocardium under normal conditions and after gradual stretching of the tissue. It was shown that vascular endothelial growth factor-B increased duration of the action potential only at the level of 90% re-polarization. Effects on the frequency and force of contraction were absent. The repetition frequency of the action potentials did not change. Close observation of the vascular endothelial growth factor-B-induced mechanisms and stretch-induced alteration in action potential durations to 90% of repolarization, confirmed the existence of a link between the examining growth factor-B and stretch induced mechanisms. PMID- 26753645 TI - Pre-hospital emergency values of hypertonic-hyperonconic limited resuscitation for traumatic shock. AB - Traumatic shock is a serious threat to life and health. The aim of this study is to investigate the effect of different resuscitation fluid compositions on the emergency resuscitation for patients with traumatic shock. Sixty patients were enrolled and divided into two groups, Group A and Group B. The patients in Group A were treated with resuscitation fluid, with 2:1 ratio of crystal (0.9% sodium chloride injection) and colloid (hydroxyethyl starch 40 injection). The patients in Group B were treated with hypertonic sodium chloride hydroxyethyl starch 40 injection (HSH40). Both vital signs and fluid dosage were monitored and recorded. At the beginning of resuscitation (T0) and 30 min (T1), 60 min (T2) and 120 min (T3) after resuscitation, indicator parameters including hemoglobin (HB), hematocrit (HCT), prothrombin time (PT), arterial blood lacic acid (LA) and C reactive protein (CRP) were monitored and recorded. Tissue oxygenation and hemodynamic profile were also analyzed. At T1, T2and T3after fluid resuscitation, the heart rates of the patients in Group B were lower than those in Group A, whereas the average arterial pressure in Group B was significantly higher than that in Group A. Notably, significant decreases of HB and HCT were detected at T1, T2and T3compared with T0 in Group A. In contrast, no significant difference was shown in detected HCT at T2and T3compared with T0 in Group B, while the detected HB value was smaller. a statistically significant decrease of LA was detected at T1, T2and T3in Group A and Group B compared with that at T0. At T2and T3in Group A and Group B, a statistically significant increase of PT was detected compared with the beginning of resuscitation. At T2and T3after resuscitation, CRP in both Group A and Group B was significantly increased compared with that upon admission to hospital, and was lower in Group B than in Group A. PMID- 26753646 TI - Effect of new-pattern obstetrical nursing in reducing cesarean delivery rate. AB - Spontaneous labor is the preferred delivery way ensuring health of fetus. However, recently, more and more puerperae tend to choose cesarean. However, cesarean delivery is likely to induce various short-term and long-term potential complications, severely threatening maternal and child health. To discuss the clinical effects of new-pattern obstetrical nursing in reducing cesarean delivery rate, 680 primiparas who delivered between December 2011 and December 2013 were selected from Beijing Obstetrics and Gynecology Hospital, Capital Medical University, China as research subjects. They were randomly divided into an observation group (n=340) and a control group (n=340). Primiparas in the observation group were taken care of by new-pattern nursing measures during pregnancy and the puerperal period, while primiparas in the control group received traditional nursing measures. Cesarean delivery rate was compared between two groups. Cesarean delivery rate was statistically significant between the observation group and the control group (21.8% vs 32.9%) (P less than 0.05). Also, it was found that, the incidence rate of perioperative complications of the observation group was much lower than the control group, and the difference was statistically significant (P less than 0.05). The findings suggest that new pattern obstetrical nursing is effective in reducing the cesarean delivery rate, therefore is worth promoting and applying in clinical practice. PMID- 26753647 TI - Expression and clinical significance of P53, O6-methylguanine-dna methyltransferase and epidermal growth factor receptor in glioma. AB - Glioma is a serious life-threatening disease, the pathogenesis of which remains to be investigated. The objective of the present investigation was to explore the expression and clinical significance of tumor suppressor gene (P53), O6 methylguanine-DNA methyltransferase (MGMT) and epidermal growth factor receptor (EGFR) in glioma. Immunohistochemical staining was applied to study the clinical characteristics of 40 samples from glioma patients, detect the expression of and analyse the relationship between P53, MGMT and EGFR and glioma. The results demonstrated that the positive expression rate of P53 was 47.5% in 40 cases of glioma samples, of which the expression of P53 in the high grade glioma was higher than that of the low grade samples (P < 0.05); the positive expression rate of MGMT was 37.5%, but there was no significant significance of MGMT expression between the high grade glioma and the low grade glioma (P >0.05); the positive expression rate of EGFR was 55%, of which the expression of EGFR of the high grade glioma was higher than that of the low grade glioma (P<0.05). There was no significant difference in the expressions of P53, MGMT and EGFR in the glioma patients of different ages, gender and with different tumor sizes. The expressions of P53 and MGMT were negatively correlated (P<0.05). The expressions of P53 and EGFR were positively correlated (P<0.05). In conclusion, P53, EGFR and MGMT could play a role in the occurrence, development and deterioration of glioma. PMID- 26753648 TI - Unexpectedly high occurrence of Escherichia coli and Staphylococcus aureus isolates from raw milk in Ilam, Western Iran. AB - Raw milk contains diverse nutritional components that provide a suitable medium for spoilage and the growth of potentially pathogenic microorganisms. Unpasteurized milk consumption by a large number of people can threaten health and increase public concerns. In this study, sixty-two raw cow?s milk samples were collected from the dairy farms of Ilam, Western Iran. All samples were collected in sterilized containers and were transferred via ice boxes to the laboratory. Isolates were then identified by standard methods. Totally, 88.7% (n=55) of samples were contaminated. Our study also showed that Escherichia coli had a high prevalence among isolates (43: 69.4%), while Klebsiella pneumoniae and Klebsiella planticola showed the lowest prevalence (1: 1.6%). Staphylococcus aureus was also detected in 17.7% (n=11) of samples. The raw milk microbial contamination is complex. Some of the microorganisms threaten public health via different traits, therefore it is recommended that raw milk consumption should be avoided. PMID- 26753649 TI - Neglected giant spinocellular carcinoma of the lower lip. AB - Although squamous cell carcinoma (SCC) is the most common type of lip cancer worldwide, its giant form is extremely rare, due to its easy detection and early diagnosis. The survival rate is good if early eradication is performed, as 5-year survival accounts for approximately 80-90%. We present a rare variant of giant form of SCC on the lower lip in a 70-year-old patient, which had been neglected for many years, due to social disadvantages and absence of any resources for adequate medical help, until the tumor caused total inability of administration of food and drink. The recent diagnostic and therapeutic options are considered. Despite well-known etiologic factors regarding squamous cell carcinoma and the newest prognostic factors on tumor differentiation, such as beta-catenin abnormal expression, the negative influence of the demographic characteristics of the patient were also in focus. Certain outcast ways of living should be considered as potential risk factors for the development of giant forms of SCC. In addition, an improvement of the quality of life of these patients results as being critical for the prevention of various of risk factors, as well as improving the survival rate in general. PMID- 26753651 TI - Expression and diagnosis of transient receptor potential vanilloid1 in urothelium of patients with overactive bladder. AB - This study was carried out to test expression of transient receptor potential vanilloid1 (TRPV1) in urothelium of female patients with overactive bladder (OAB) and explore clinical significance of TRPV1 in diagnosing female OAB. TRPV1 expression in urothelium of female OAB patients (n=21) and healthy females (n=9) was detected using Strept Avidin-Biotin Complex (SABC), an immunohistochemical method and image analysis system. Relative content of TRPV1 was expressed by average optical density (AOD) and was analyzed through data of urodynamics. Compared to TRPV1 expression in urothelium of healthy females (AOD 0.3658 +/- 0.1009), TRPV1 expression in OAB patients was much higher (AOD 0.4834 +/- 0.1252) and the difference was significant P less than 0.05. Observation and comparison in clinic of urodynamic parameters of female patients and healthy females revealed that the former had lower indexes with remarkable differences (P less than 0.05) such as Qmax, first desire volume (FDV), strong desire volume (SDV), maximum cyst capacity (MCC) and bladder compliance (BC). Thus high expression of TRPV1 in urothelium of female OAB patients is closely correlated to OAB occurrence, showing great importance of improved bladder sensitivity in female OAB occurrence mechanism. PMID- 26753650 TI - Expression of mTOR and its inhibitory effect on cell proliferation and apoptosis of breast cancer cells. AB - The aim of this study is to investigate the expression of mTOR in breast cancer and observe the effect of CCI-779 on proliferation and apoptosis of MDA-MB-231 cells. Immunohistochemical staining was used to detect the expression of mTOR protein in breast cancer tissues and MDA-MB-231 cells. MTT assay was used to assess the effect of CCI-779 on proliferation of MDA-MB-231 cells. Annex-inV FITC/ PI assay was utilized to evaluate the effect of CCI-779 on apoptosis of MDA MB-231 cells. Among the 71 cases of breast cancer tissues, 54.9% were mTOR positive that exhibited significantly higher expression than the 32 cases of normal tissues (21.9%); mTOR protein was also found to be expressed in MDA-MB-231 cells. The mTOR inhibitor CCI-779 significantly inhibited the proliferation of MDA-MB-231 cells that was dose- and time-dependent. However, CCI-779 was unable to induce apoptosis of MDA-MB-231 cells as demonstrated with AnnexinV-FITC/PI assay. mTOR plays a key role in the initiation and development of breast cancer, and its inhibitor CCI-779 exerts a strong suppressive activity against MDA-MB-231 cells, suggesting its therapeutic potential to treat breast cancer. PMID- 26753652 TI - Effect and mechanism of dihydroartemisinin on proliferation, metastasis and apoptosis of human osteosarcoma cells. AB - Osteosarcoma represents an aggressive type of bone malignancy that poses a significant health threat. The objective of the current study was to analyze the effect and mechanism of dihydroartemisinin (DHA) on the proliferation, metastasis and apoptosis of human osteosarcoma cells. A gradient concentration of DHA (15, 25 and 35 MUmol.L-1) was used to stimulate the cells, along with control and Dimethyl sulfoxide (DMSO). The phenotypic outcomes were characterized using MTT assay, clone formation assay, Hoechst 33258 staining assay, luciferase reporter plasmid assay, Western blot and wound healing assay. In addition, IBM SPSS Statistics 18.0 software was applied for statistical analysis and all experimental data were expressed as mean +/- s.d. Analysis of variance (ANOVA) was applied to compare the differences among multiple groups. Our results demonstrated that DHA inhibited the proliferation and metastasis of osteosarcoma cells and promoted the apoptosis in the cytomorphosis. PMID- 26753653 TI - Influence of colorectal cancer tumor suppressor gene CHD5 methylation on its clinical and pathological characteristics. AB - Recently, abnormal tumor suppressor gene (TSG) methylation has become a hotspot in the research on colorectal cancer (CRC). This study aimed to explore the influence of CHD5 methylation of CRC TSG on its clinical and pathological characteristics. A total of 40 operation samples as well as corresponding tissue specimens were collected from CRC patients treated in the First Affiliated Hospital of Zhengzhou University from January to December in 2014. CHD5 gene methylation in tissue specimens was detected with methylation specific polymerase chain reaction (MSP); moreover, messenger ribose nucleic acid (mRNA) expression of CHD5 in each tissue was tested using reverse transcription-polymerase chain reaction (RT-PCR), and Western blot was applied to detect the expression of CHD5 protein in those tissues and to analyze the correlation between mRNA and protein of cancer tissue CHD5 as well as the relationship between CHD5 methylation and protein expression. Results revealed that the expression rate of CHD5 methylation in 40 normal mucosal tissues, para-carcinoma tissues, adenoma tissues and CRC tissues was 12.5% (5/40), 22.5% (9/40), 47.5% (19/40) and 72.5% (33/40), respectively. The mRNA expression of CHD5 in the above tissues was 0.225+/-0.276, 0.169+/-0.231, 0.147+/-0.159 and 0.013+/-0.011 and the protein expression of CHD5 was 0.438+/-0.205, 0.398+/-0.180, 0.156+/-0.1 and 0.024+/-0.311, respectively. Methylation rate of CHD5 was 87% (20/23) in 23 cases of CHD5 protein loss expression and 52.9% (9/17) in 17 cases of CHD5 protein expression. Results of chi-squared test indicated that there was a significant difference in methylation rate (P less than 0.05), that is, the methylation rate of negatively expressed CHD5 protein was obviously higher than positively expressed protein. Thus, it can be concluded that the CHD5 methylation rate rises gradually in the evolution of CRC, which is related to the occurrence and development of CRC. Furthermore, CHD5 mRNA is positively correlated with protein expression and CHD5 gene methylation is associated with protein loss expression. Therefore, TSG CHD5 methylation of rectal cancer has a great effect in influencing its clinical and pathological features. PMID- 26753654 TI - Angiogenesis of hepatocellular carcinoma under multislice spiral CT plain scan and enhanced scan. AB - This study explores the value of 64-layer spinal computed tomography (CT) in diagnosing hepatocellular carcinoma (HCC) through performing dynamic contrast enhanced scans. The study includes analysis of enhancement presentation of HCC in dynamic contrast-enhanced scan performed by multislice spinal CT (MSCT), comparison of detection rate and positive predictive value of neoplastic foci in subdivided arterial phases and portal venous phases, optimization of optimal scanning scheme for diagnosing HCC and discussion of the value of quantitative indexes such as T-D curve, maximum enhancement rate and clearance rate in diagnosing and identifying HCC. A total of 61 lesions were detected in 40 patients with HCC who were selected from the First People?s Hospital, Jining, Shandong, China. Density difference was observed with statistical significance between the solid part of tumor and normal liver in different periods after CT scan and enhanced scan (H = 45.208, P less than 0.01), and difference in the late arterial phase was the most obvious; enhanced peak value mostly appeared in the late arterial phase. In terms of lesion detection rate, the difference of HCC detection rate was statistically significant in early, middle and late arterial phase and early and late portal vein phases (chi2 = 32.910, P = 0.001) and the rate was the highest in the late arterial phase (78.689%). Lesions were divided into 3 cm or less group (small HCC) and over 3 cm group based on the maximum parameter. Detection rate of the late arterial phase was the highest, 85% (3 cm or less) and 75.61% (over 3 cm), respectively. When lesions with high density in arterial phase and/or low density in portal venous phase were considered as positive, and moreover, those confirmed clinically or pathologically were as true positive, we found positive predictive value of the over 3 cm group reached 100% in all phases, but that of 3 cm or less group was the highest (100%) in early and late portal venous phases. Among four scanning schemes involving early, middle and late arterial phases, detection rate of the early and late arterial phases and three arterial phases were consistent, reaching the highest value (3 cm or less group: 90%; the 3 cm over group: 78.049%). This study confirmed that the late arterial phase was the best time to detect abundant blood supplied HCC. The scanning scheme involving double arterial phases (early and late), late portal venous phase and stable phase which can help improve detection rate and correct diagnosis rate of HCC, was thought to be the most effective. Using dynamic enhanced CT examination in the diagnosis of HCC is meaningful both in qualitative and quantitative diagnosis. T-D curve, in particular, can intuitively and objectively reflect enhanced characteristics of HCC, and can be used to make a preliminary diagnosis of some atypical liver cancers. PMID- 26753655 TI - Identification of benign and malignant endometrial cancer with transvaginal ultrasonography combined with elastography and tissue hardness analysis. AB - This study was designed to explore tissue hardness and distinguish benign and malignant endometrial cancer with the use of transvaginal ultrasonography combined with elastography. Color Doppler ultrasonic diasonograph was used to carry out transvaginal ultrasonography and elastography. Once the nidus was observed, features of the 2D image were analyzed. Then features of elasticity of the uterine cavity in different states were analyzed by elastography, and strain rate ratio was measured. Finally, elasticity scoring (0~5 points) was made. Receiver operating characteristic (ROC) curve was drawn based on elasticity score and strain rate ratio. The area under the elasticity score curve and strain rate ratio curve was 0.761 and 0.852, respectively, and there was no statistically significant difference between them (c2= 4.663, P>0.05). Then 2.98 was confirmed as the diagnostic cut-off value of benign and malignant lesions, based on strain rate ratio. Ultrasonic elastography as an effective assistance for transvaginal ultrasonography provides more valuable information for confirmation of lesions and offers more accurate evidence for diagnosis of disease in the uterine cavity. PMID- 26753656 TI - Effect of myo-inositol and alpha-lipoic acid on oocyte quality in polycystic ovary syndrome non-obese women undergoing in vitro fertilization: a pilot study. AB - The aim of the present study was to evaluate the effectiveness of the combined administration of myo-inositol and alpha-lipoic acid in polycystic ovary syndrome (PCOS) patients with normal body mass index (BMI), who had previously undergone intracytoplasmic sperm injection (ICSI) and received myo-inositol alone. Thirty six of 65 normal-weight patients affected by PCOS who did not achieve pregnancy and one patient who had a spontaneous abortion were re-enrolled and given a cycle of treatment with myo-inositol and alpha-lipoic acid. For all female partners of the treated couples, the endocrine-metabolic and ultrasound parameters, ovarian volume, oocyte and embryo quality, and pregnancy rates were assessed before and after three months of treatment and compared with those of previous in vitro fertilization (IVF) cycle(s). After supplementation of myo-inositol with alpha lipoic acid, insulin levels, BMI and ovarian volume were significantly reduced compared with myo-inositol alone. No differences were found in the fertilization and cleavage rate or in the mean number of transferred embryos between the two different treatments, whereas the number of grade 1 embryos was significantly increased, with a significant reduction in the number of grade 2 embryos treated with myo-inositol plus alpha-lipoic acid. Clinical pregnancy was not significantly different with a trend for a higher percentage for of myo-inositol and alpha-lipoic acid compared to the myo-inositol alone group. Our preliminary data suggest that the supplementation of myo-inositol and alpha-lipoic acid in PCOS patients undergoing an IVF cycle can help to improve their reproductive outcome and also their metabolic profiles, opening potential for their use in long-term prevention of PCOS. PMID- 26753657 TI - Serum 25-hydroxyvitamin D levels in children with recurrent tonsillitis living in Milan. AB - Involvement of 25-hydroxyvitamin D in the etiopathogenesis of tonsillar disease in children is still debated; this study assesses possible differences in serum 25-hydroxyvitamin D levels between 309 Caucasian children (58.1% males; mean age 55.7 +/- 31.0 months) living in Milan with a history of recurrent tonsillitis (RT) and healthy controls. Mean serum 25(OH)D levels were significantly reduced in the children with a history of RT (22.0 +/- 8.7 ng/mL vs 24.6 +/- 7.8 ng/mL; p=0.03), and the proportion of children with insufficient or deficient serum 25(OH)D levels was higher in the RT group (81.5% and 6.5% respectively) than in the control group (75.1% and 3.5%) (not significant). The multivariable model created to test the independent association between serum 25(OH)D levels and a history of RT after adjusting for age and season showed that the association was not significant. Our study failed to find any significant reduction in serum 25(OH)D levels after adjustment for age and season in a case series of children with RT in comparison with healthy controls, which suggests that vitamin D does not play a relevant role in the etiology of pediatric tonsillar infections. PMID- 26753660 TI - The role of hyaluronic acid in patients affected by glenohumeral osteoarthritis. AB - Persistent shoulder pain is a highly prevalent problem, due to different pathologies, that is frequently associated with limited range of motion and decreased function. The correct diagnosis can lead to the best treatment for each pathology. In this study we tried to understand what could be the role of hyaluronic acid and its effective benefit in patients affected by mild-to moderate glenohumeral osteoarthritis. From January 2013 to June 2014, we prospectively followed-up 61 consecutive patients with shoulder osteoarthritis degrees I, II, and III. We divided the patients into 2 homogeneous groups: 31 patients in the first group treated with 5 intra-articular injections of Hyalgan 20mg/2ml and a specific physiotherapy program, and 30 patients in the second group treated only with physical therapy. The mean follow-up examination was carried out 5.2 months after the beginning of the therapy for both groups. The statistical analysis revealed a significant difference (P less than 0.05) between the two groups in terms of pain reduction and improvement in the activities of daily living. The present study demonstrates the greater and long-lasting efficacy of a five-injection treatment with hyaluronic acid (Hyalgan 20mg/2ml) combined with a physical therapy program in comparison with physical therapy only in patients affected by glenohumeral osteoarthritis degree I, II or III. PMID- 26753658 TI - Treatment with teriparatide might be associated with cardiometabolic changes in postmenopausal severe osteoporotic women. AB - Parathormone (PTH) has been suggested to affect the cardiovascular system. Teriparatide (TPT), the hormonally active 1-34 fragment of PTH, provides an anabolic treatment for osteoporosis. The aim of the present study was to evaluate the cardiometabolic effects of 18-month treatment with 20 MUg/ die teriparatide subcutaneosly. Fourteen women with postmenopausal severe osteoporosis treated with once-daily sc 20 MUg TPT (67.6 +/- 2.5 years; BMI 27.7 +/- 1.0 kg/m2) and 24 age- and BMI-matched severe osteoporotic women treated with iv yearly 5 mg zoledronate (ZLN) were evaluated at baseline and at 12-18 months of treatment for anthropometric measures, calcium, glucose and lipid metabolic parameters, and assessment of cardiac geometry by conventional echocardiography. TPT was effective in increasing mean lumbar spine bone mineral density with no clinically relevant changes in calcium metabolism parameters. TPT patients experienced an increase of BMI (27.7 +/- 1.0 at baseline vs 29.0 +/- 1.0 kg/m2 at last evaluation, P=0.005) and mean whole body fat percentage (37.0 +/- 2.1 vs 40.3 +/- 1.9%, P=0.05), associated with increased serum leptin levels (17.3 +/- 2.1 vs 22.9 +/- 3.0 ng/ml; P=0.049). Glucose and lipid parameters were not affected by TPT as well as by ZLN treatment. Furthermore, TPT was associated with a decrease in systolic blood pressure; a decrease in the fractional shortening (41.2 +/- 2.3 vs 36.9 +/- 1.2; P=0.05) and an increase in the relative wall thickness (0.39 +/- 0.01 vs 0.48 +/- 0.01 mm; P=0.002), suggestive for concentric cardiac remodeling, was detected by echocardiographic monitoring. These changes could not be detected in bone active drug-free age- and metabolic-matched controls. In conclusion, long term TPT therapy might affect cardiometabolic and cardiac geometry parameters in severe osteoporotic women, though changes are not clinically relevant. PMID- 26753659 TI - Nose-bronchi link: does an asthma march exist? AB - Allergic rhinitis is considered a strong risk factor for the onset of asthma. However, few studies have addressed this issue from a functional point of view. In this work the close link between upper and lower airways is highlighted, suggesting that spirometry should be precociously performed on patients with allergic rhinitis. PMID- 26753661 TI - Perisurgical and intra-rehabilitative salivary steroid hormone profiles in bicompartmental arthroplasty. AB - Sex hormones play a role in pain perception, a key variable in evaluating the progression and treatment of osteoarthritis. The aim of this study was to determine the relationship between salivary concentrations of four steroid hormones and functional/clinical outcomes after hip and knee arthroplasty. Saliva samples were collected from 24 otherwise healthy patients with osteoarthritis before surgery, on admission to rehabilitation, and at hospital discharge. Salivary concentrations of testosterone, 17beta-estradiol, dehydroepiandrosterone (DHEA), and cortisol were immunoassayed. Changes in hormone levels were compared with clinical outcomes, as assessed by functional independence measure (FIM(r)), Barthel Index (BI), and visual analog scale for pain (VAS) scores. Changes in testosterone levels were significantly inversely correlated with VAS (r= -0.53, p=0.043) and FIM(r) and BI scores in all patients (r= -0.30, p= 0.043, and r= 0.35, p=0.031, respectively). The testosterone to cortisol ratio was inversely correlated with BI scores in all patients (r= -0.30, p=0.040), and in the men (r= -0.55, p=0.005) and the women (r= -0.28, p=0.042) when analyzed separately. Changes in salivary testosterone concentrations closely correlated with clinical outcome measurements for total hip and knee arthroplasty. Clinical outcome after arthroplasty was generally better among the men. PMID- 26753662 TI - Dental pulp in mature replanted human teeth: morphological alterations and metalloproteineses-2 and -9, Annexin-5, BCL-2 and iNOS modulation. AB - Tooth replantation, as a treatment concept, has been subject to controversies regarding the mechanism as well as the various parameters underlying this process. This work aimed to study time-related changes in the pulp of replanted mature human premolars through the changes in the levels of certain factors involved in the underlying mechanisms of pulpal tissue healing after replantation. Eleven experimental mature teeth were extracted, immediately replanted in the original socket and left without any other intervention for 1, 2, 3 and 12 weeks before re-extraction. Three premolars served as control. All specimens were subject to histological analysis and the levels of MMP-2, MMP-9, Annexin V, iNOS and BCL-2 (anti-apoptotic family) were analyzed employing immunohistochemistry. The results showed degradation of the extracellular matrix (ECM), inflammatory cell infiltrate, loss in pulpo-dentine interface and loss of odontoblasts in the dental pulp tissue. This was accompanied by increase over time of MMP-9, Annexin V, iNOS and a decrease of BCL-2 and MMP-2, suggesting that apoptosis increased throughout the experimental period. PMID- 26753663 TI - Airborne nitric oxide and nasal cytology in patients with chronic rhinosinusitis and nasal polyps. AB - Nitric oxide (NO) is involved in eosinophilic inflammation. The fraction of exhaled nitric oxide (FENO) is increased in chronic rhinosinutis with nasal polyps (CRSwNP), whereas nasal NO (nNO) is reduced in chronic rhinosinutis. Nasal cytology can detect eosinophilic inflammation in CRSwNP. We aimed to describe the baseline rhinocytological characteristics and NO (FENO and nNO) levels in patients with CRSwNP, and assess their possible correlations. This longitudinal study involved 37 consecutive adult outpatients with CRSwNP and 36 healthy controls. They underwent a complete clinical otolaryngological assessment, measurement of FENO and nNO levels, and nasal scraping in order to collect material for nasal cytology. Disease severity was evaluated by means of endoscopic and Lund-Mackay radiological scores. Median FENO level was higher (p less than 0.001) in CRSwNP (28.3 ppb, 95%CI 13.0-33.6 ppb) than in the controls (7.5 ppb, 95%CI 6.1-8.9 ppb). Median nNO levels were lower (255.7, 95%CI 199.7 311.6 vs 385.5, 95%CI 345.0-425.9 ppb; p less than 0.001), and were lower in the patients with severe endoscopic obstruction (p=0.05). Lund-Mackay scores positively correlated with median FENO levels (R=0.11; p=0.05), and inversely with median nNO levels (R=-0.31; p=0.04). Metachromatic nasal cytotypes were more prevalent among CRSwNP patients who had previously undergone surgery (p=0.05). The number of metachromatic elements in the patients with CRSwNP positively correlated with their median FENO levels (R=0.24; p=0.002). Our results confirm the dynamic interplay between the upper and lower airways in patients with CRSwNP. FENO/nNO and nasal cytology can be useful for detecting and monitoring nasal inflammation in CRSwNP. PMID- 26753664 TI - Microbiological investigation of medication-related osteonecrosis of the jaw: preliminary results. AB - Medication-related osteonecrosis of the jaw (MRONJ) is a well-recognized severe complication of bisphosphonate (BPs) treatment in patients with osteoporosis or metastatic cancer. Microbiological infection has been hypothesized as a contributing factor to bisphosphonate related osteonecrosis of the jaw (BRONJ). Despite infection being present in BRONJ patients, there is no clear data as to whether infection plays a role in the pathophysiology. Moreover, microbial cultures have not been helpful in directing therapy because specific pathogens have not been identified. The objective of this study was to determine the bacterial colonization of jawbone and identify the bacterial phylotypes associated with BRONJ. Twenty oncologic patients, aged 48-87 years (average age 70.65 +/- 8.86 years) with BRONJ were enrolled in this study and underwent three different microbiological samplings. Overall, 60 samples were obtained from oral mucosa, necrotic bone fragments and fistula drainage. The same procedure was performed for the laboratory culture of all these specimens. No significant differences regarding either gram+ and gram? species (Chi-squared= 0.1642; p = 0.6854) or aerobes and anaerobes bacteria (Chi-squared= 3.084; p = 0.0791) were found. Compared to other sampling techniques, the oral swab allowed to obtain valuable microbial data in order to recognize pathogens responsible for the infection and to outline a focused antimicrobial therapy. PMID- 26753665 TI - Arthritis and osteoporosis: pathogenetic correlations in function of arthroplasty. AB - Osteoarthritis is being increasingly characterised as an inflammatory incoming and recurrent disease, with the specific symptoms of inflammation at every stage of the disease. With regard to the pathogenesis over time, the degenerative and inflammatory components are combined and lead to osteocartilaginous degeneration. Such deterioration involves other joint tissues as well as the subchondral bone tissue, the suffering of which is the key event of the beginning and progression of OA; its involvement concerns the same pathogenetic mechanisms and the same chemical mediators of the chondropathy. The increase in joint inflammatory events leads to suspect the onset or the worsening of the osteometabolic disorder, which is documented by the MR as ?bone edema? or as algodystrophic syndrome. The pain appears both while moving and resting and with signs of inflammation. The treatment of OA requires drugs, such as paracetamol, selective and nonselective NSAIDs and opiates, for pain control. Treatment should ensure the pharmacological control of the pain related to the osteometabolic juxta-articular alteration, through bisphosphonates, favouring those which can control bone loss, inflammation and pain. PMID- 26753666 TI - Behaviour of dental pulp stem cells on different types of innovative mesoporous and nanoporous silicon scaffolds with different functionalizations of the surfaces. AB - Dental pulp stem cells (DPSCs) are stem cells found in the dental pulp. The ability of DPSCs to differentiate towards odontoblastic and osteoblastic phenotype was reported first in the literature, then in the following years, numerous studies on odontogenesis were carried out, starting from mesenchymal stem cells isolated from tissues of dental and oral origin. The aim of this research was to evaluate the behaviour of DPSCs grown on silicon nanoporous and mesoporous matrices and differentiated towards the osteogenic phenotype, but also to investigate the use of DPSCs in pilot studies focused on the biological compatibility of innovative dental biomaterials. Twenty-eight silicon samples were created with standardized procedures. These scaffolds were divided into samples made of silicon bulk, nanoporous silicon, mesoporous silicon, nanoporous silicon functionalized with (3-Aminopropyl) Trimethoxysilane (APTMS) and methanol (MeOH), nanoporous silicon functionalized with (3-Aminopropyl) Trimethoxysilane (APTMS)/toluene, mesoporous silicon functionalized with (3-Aminopropyl) Trimethoxysilane (APTMS) and methanol (MeOH) andmesoporous silicon functionalized with (3-Aminopropyl) Trimethoxysilane (APTMS)/toluene. DPSC proliferation on the tested silicon scaffolds was analyzed at 3 and 5 days. The assay showed that DPSCs proliferated better on mesoporous scaffolds functionalized with APTMS/toluene compared to a silicon one. These results show that the functionalization of silicon scaffold with APTMS/toluene supports the growth of DPSCs and could be used for future applications in tissue engineering. PMID- 26753667 TI - Hyaluronic acid-based medical device and oral disorders: can it be used in paediatric dentistry? AB - Due to its physical and biological characteristics and safety profile, hyaluronic acid is very widely used in numerous clinical conditions, ranging from its best known use in cosmetic surgery (as a filler and for its ability to promote tissue regeneration and therefore minimise scarring) to lesser-known fields such as ophthalmic surgery, major abdominal surgery (where it is used to prevent the complication of adhesion bands) and intra-articular use. Studies were recently published in which this type of device was also used in paediatric patients for the management of inflammatory disorders of the oral cavity and teething symptoms. As this is a highly topical field for dentists, we felt it would be useful to review the efficacy and safety of the device in the paediatric population treated, and analyse any discrepancies with the results obtained in the adult population. The preparations of hyaluronic acid used in pediatric dentistry, thanks to their anti-inflammatory and angiogenic properties, proved to be very effective in therapy of oral diseases in children. Further clinical research is needed to confirm the effectiveness of these products to dispel doubts about any side effects. PMID- 26753668 TI - Medical treatment of joint prosthesis: indication, opportunities and liability profiles. AB - Orthopaedic specialists should completely and sequentially manage osteoarthritis, from the onset to the prosthesis, with no attitude of resignation, complying with national and international Guidelines (GLs) and abiding by the criteria of appropriateness of drugs, rehabilitation and orthopaedic device prescription, in line with the ethics of the medical profession. The GLs are a paper that rationalises the quantity of existing information for a disease, without abusing the decision of the doctor; a large volume of scientific knowledge is concentrated in a format that is easily accessible to doctors when carrying out their work. The use of drugs has taken on a connotation of a rational and multifactorial choice, rather than an accidental and incremental choice - inspired only by safety, rather than efficacy criteria. The Notes compiled by the Italian Medicines Agency - a legal instrument to define the reimbursability of medicines and, therefore, an instrument for managing pharmaceutical expenditure ? are, in reality, a means to guarantee the appropriateness of the use of medicines, orienting the therapeutic choices according to established Guidelines. In the specific case of osteoarthritis, the knowledge of the GLs is the most appropriate and complete approach towards the disease, in the context of its pathogenetic complexity in its natural history. Moreover, pharmacological treatment of the subchondral osteometabolic damage becomes necessary when documented by magnetic resonance or a scintigraphy; the bone-related pain cannot be challenged through symptomatic analgesic treatment alone. PMID- 26753669 TI - Biophysical stimulation and the periprosthetic bone: is there a rationale in the use of Pulsed Electromagnetic Fields after a hip or knee implant? AB - The biophysical stimulation of bone and cartilage, using Pulsed ElectroMagnetic Fields (PEMF), covers many different aspects of bone formation and/or cartilage repair, such as healing of delayed or non-union of fracture, bone necrosis, osteocartilagineous defects. To date there are no specific data on the effects of PEMFs in osteointegration of prosthetic implants but there are some papers that denote clinical advantages, in terms of early recovery, in patients treated with these procedures. Considering these clinical applications, PEMF stimulation around hip or knee joint implants could be useful to reduce the bone oedema, pain and to reduce excessive bone reabsorption around the femoral stems. PMID- 26753670 TI - Alkaline phosphatase level in gingival crevicular fluid during treatment with Quad-Helix. AB - The aim of this work is to assess the level of the human alkaline phosphatase enzyme (ALP) during palatal expansion with Quad-Helix (QH) appliance. A total of twenty-two orthodontic patients characterized by contraction of the upper jaw, that needed application of a QH in order to treat their condition, were included in this study. Gingival crevicular fluid (GCF) was collected at four different times: before cementation (T0), after two weeks (T1), after four weeks (T2) and after one year (T3) from application of QH. In each patient maxillary first molars, right (UM-right) and left (UM-left), which were connected with bands to QH, were used for testing; first lower molars were used as Controls (LM-right, LM left). Data show that ALP level in tension sites was proportional to the average increase of the inter-molar distance; on the contrary, the enzymatic level in compression sites was characterized by an inverse trend. The only exception to this phenomenon was recorded after one year (T3), when the increase of ALP level in both sites of tension and compression was ascribed to a mild inflammation due to bacterial plaque accumulation. The level of ALP in control sites was constant for the whole period of observation. The described ALP fluctuations in accordance with the inter-molar distance increment, shows that the main action of QH on bone remodelling was exerted during the fourth week (T2); for this reason, the monitoring of this enzyme could be used as a marker of effective function of the QH appliance. PMID- 26753671 TI - Association of monocyte/HDL-C ratio with SYNTAX scores in patients with stable coronary artery disease. AB - PURPOSE: The aim of this study was to investigate the relationship between monocyte count/high density lipoprotein cholesterol (HDL-C) ratio (MHR) and the severity of coronary atherosclerosis, as assessed by the SYNTAX score (SXscore), in patients with stable coronary artery disease (CAD) undergoing coronary angiography. MATERIALS AND METHODS: A total of 428 patients were included in the study between March 2012 and February 2015. The SXscore was determined with baseline coronary angiography. An SXscore >= 23 was regarded as severe CAD by definition, and the patients were divided into two groups: those with low SXscores (< 23) and those with high SXscores (>= 23). RESULTS: MHR and C-reactive protein (CRP) were significantly higher in patients with high SXscores (p < 0.001 and p < 0.001, respectively). Left ventricular ejection fraction (LVEF) was lower in the group with high MHR and high SXscores. The cutoff value of MHR that predicted a high SXscore was 24, with a sensitivity of 66 % and a specificity of 65.1 %. CONCLUSION: To the best of our knowledge, this is the first study in the literature showing that MHR is significantly associated with SXscores. Our results suggest that MHR can be used as a prognostic marker in patients with stable CAD, since it is an easily available and inexpensive test. PMID- 26753672 TI - Asymmetric competition prevents the outbreak of an opportunistic species after coral reef degradation. AB - Disturbance releases space and allows the growth of opportunistic species, excluded by the old stands, with a potential to alter community dynamics. In coral reefs, abundances of fast-growing, and disturbance-tolerant sponges are expected to increase and dominate as space becomes available following acute coral mortality events. Yet, an increase in abundance of these opportunistic species has been reported in only a few studies, suggesting certain mechanisms may be acting to regulate sponge populations. To gain insights into mechanisms of population control, we simulated the dynamics of the common reef-excavating sponge Cliona tenuis in the Caribbean using an individual-based model. An orthogonal hypothesis testing approach was used, where four candidate mechanisms algal competition, stock-recruitment limitation, whole and partial mortality-were incorporated sequentially into the model and the results were tested against independent field observations taken over a decade in Belize, Central America. We found that releasing space after coral mortality can promote C. tenuis outbreaks, but such outbreaks can be curtailed by macroalgal competition. The asymmetrical competitive superiority of macroalgae, given by their capacity to pre-empt space and outcompete with the sponge in a size-dependant fashion, supports their capacity to steal the opportunity from other opportunists. While multiple system stages can be expected in coral reefs following intense perturbation macroalgae may prevent the growth of other space-occupiers, such as bioeroding sponges, under low grazing pressure. PMID- 26753673 TI - Usability Evaluation of a Mobile Monitoring System to Assess Symptoms After a Traumatic Injury: A Mixed-Methods Study. AB - BACKGROUND: Victims of trauma are at high risk for mental health conditions such as posttraumatic stress disorder and depression. Regular assessment of mental health symptoms in the post-trauma period is necessary to identify those at greatest risk and provide treatment. The multiple demands of the acute post trauma period present numerous barriers to such assessments. Mobile apps are a method by which to overcome these barriers in order to regularly assess symptoms, identify those at risk, and connect patients to needed services. OBJECTIVE: The current study conducted a usability evaluation of a system to monitor mental health symptoms after a trauma. The system was developed to promote ease of use and facilitate quick transmission of data. METHODS: A sample of 21 adults with a history of trauma completed a standardized usability test in a laboratory setting followed by a qualitative interview. RESULTS: Usability testing indicated that the app was easy to use and that patients were able to answer several questions in less than 1 minute (mean [SD] 29.37 [7.53]; range 15-57). Qualitative analyses suggested that feedback should be included in such an app and recommendations for the type of feedback were offered. CONCLUSIONS: The results of the current study indicate that a mobile app to monitor post-trauma mental health symptoms would be well received by victims. Personalized feedback to the user was identified as critical to promote the usability of the software. PMID- 26753675 TI - GUEST EDITORIAL MBR: RETROSPECT AND PROSPECT. PMID- 26753674 TI - The effect of transposable elements on phenotypic variation: insights from plants to humans. AB - Transposable elements (TEs), originally discovered in maize as controlling elements, are the main components of most eukaryotic genomes. TEs have been regarded as deleterious genomic parasites due to their ability to undergo massive amplification. However, TEs can regulate gene expression and alter phenotypes. Also, emerging findings demonstrate that TEs can establish and rewire gene regulatory networks by genetic and epigenetic mechanisms. In this review, we summarize the key roles of TEs in fine-tuning the regulation of gene expression leading to phenotypic plasticity in plants and humans, and the implications for adaption and natural selection. PMID- 26753676 TI - PERSON-CLUSTERS ON INTELLECTUAL ABILITIES AND ON MMPI ATTRIBUTES. AB - When persons are observed on multiple dimensions discovered by the objective procedures of the cluster analysis of variables (V-analysis), they can then be allocated to person-clusters by the equally-objective procedures of object clustering (O-analysis). These procedures, called the Condensation Method, are completely worked out on two empirical studies. In the first study on intellectual abilities (the Holzinger Problem) 301 children are assigned to 15 O types. In the second study on self-conceptions (the MMPI), 310 psychiatric patients and normals are allocated to 14 O-types. The means of assigning new individuals to these master types are described. All procedures are executed by computer programs of the BC TRY System, in particular the components FACS, OTYPE, and OSTAT. The logic of the methods is fully developed. PMID- 26753677 TI - ASSOCIATION STRUCTURES OF MENTAL RETARDATES. AB - Free word associations of low level retardates (I.Q., 48) and higher level (I.Q., 67) retardates were examined for evidence of normal adult word association structures (idiodynamic associative sets). Such structures were found in both groups. The low level group, however, evidenced a factor structure different from that typical of normal adults. From a semantic point of view, associations of the low level group were more "concrete" than those of the higher level group. From a syntactic point of view, the lower level group lagged well behind the higher level group on the so-called "syntactic-paradigmatic" shift. PMID- 26753678 TI - THE STRUCTURE OF ORGANIZATION BEHAVIOR. AB - The subjects were 25 foremen, 5 general foremen, and the production manager of a manufacturing plant. Each supervisor described the leader behavior of his immediate superior, and each in turn was described by several subordinates. Both superiors and the subordinates of a supervisor rated or described the productivity, morale, and cohesiveness of the group that he supervised. Thirty variables were intercorrelated and factor analyzed. The resulting 14 factors describe dimensions of employee satisfaction, supervisory behavior and status, and group performance. PMID- 26753679 TI - DETERMINATION AND EVALUATION OF RATE MEASUREMENTS IN THE ANALYSIS OF SPACE MEDICAL DATA. AB - Measures of rate of change and of rate of rate of change are developed for application to physiological and psychological data. Examples are given of the use of these measures with heart-rate data for comparisons within and between subjects. It is shown that the measures provide information over and above that offered by means and variances, and that the measures appropriately reflect the impact of external variables. PMID- 26753680 TI - THE DEVELOPMENT OF NONMETRIC SPACE ANALYSIS: A LETTER TO PROFESSOR JOHN ROSS. PMID- 26753681 TI - A SIMPLICIAL DESIGN FOR THE ANALYSIS OF CORRELATIONAL LEARNING DATA. AB - The usual matrix of intercorrelations among trials in a study of the learning process produces a superdiagonal matrix with resulting factors which are uninteresting: viz, a factor for the early trials and a factor for the later trials; with perhaps also a factor for the middle trials. By introducing several independent measures of learning for each trial a more meaningful factor structure can be obtained. PMID- 26753682 TI - THE PROCRUSTES CLASS OF FACTOR-ANALYTIC TRANSFORMATIONS. AB - The Procrustes method of deriving a reference vector structure from a principal axes factor matrix is shown to be a class of solutions all of which obtain a transformation matrix which "rotates" the principal-axes matrix as close as possible to some desired matrix H. Various factor transformation methods, such as Promax, eigenvector rotation, as well as the classical Procrustes, differ chiefly in their rationale and method of generating H. PMID- 26753683 TI - FIXED EFFECTS ANALYSIS OF VARIANCE BY REGRESSION ANALYSIS. AB - This paper is concerned with the solution of typical analysis of variance problems using general purpose multiple regression computer programs. Specific models, restrictions on the parameters for hypothesis testing, and computational aspects are discussed. It is argued that this approach has many pedagogical advantages over traditional procedures. PMID- 26753684 TI - FACTOR ANALYTICAL TREATMENT OF GROWTH DATA. AB - This paper presents a limited linear factor analysis model for the analysis of repeated measures of several traits on the same subjects. Attention is drawn to the problem of analysing growth in mean scores, and an analytical resolution of this problem, together with an appropriate method of analysis, is presented for the case of independent error terms. A special condition, expected to hold for some data, is discussed, and the corresponding rotational procedures derived. Data from an artificial experiment satisfying the model are analysed to illustrate the methods evolved. PMID- 26753685 TI - ERRATUM. PMID- 26753688 TI - Social interactions, trust and risky alcohol consumption. AB - BACKGROUND: The association of social capital and alcohol consumption is one of the most robust empirical findings in health economics of the past decade. However, the direction of the relationship between the two is heavily dependent on which dimension of social capital is studied and which alcohol measure is used. In this paper, we examine the effect of social interactions and generalised trust on drinking in the general Danish population survey. METHODS: Participants (n = 2569) were recruited as part of a larger study. The double-hurdle model for the volume of alcohol consumption and the multivariate logistic model for heavy episodic drinking were estimated. RESULTS: We found evidence that social networking with male friends, membership in voluntary organisations, and generalised trust were significantly associated with the mean volume of alcohol consumption and heavy drinking. We also observed that social support at the community level had a buffering effect against heavy episodic drinking. CONCLUSIONS: The findings support previous findings in which social interactions and generalised trust were found to predict individuals' volume of drinking and heavy episodic drinking. However, the results varied across the indicators. PMID- 26753687 TI - "Back to the future": Influence of beliefs regarding the future on TTO answers. AB - BACKGROUND: A common approach to obtain health state valuations is the time tradeoff (TTO) method. Much remains unknown regarding the influence of responder characteristics on TTO answers. The objective of this study is to increase understanding of the influence that beliefs regarding future health and death, as well as desires to witness certain life events, have on respondents' health state valuations. METHODS: An online survey was designed, including three TTO questions using a 10 year timeframe. Moreover, respondents completed demographic questions, the Health-Risk Attitude Scale (HRAS), the Expectations Regarding Aging (ERA) questionnaire, questions about beliefs regarding future health (i.e. life expectancy) and death (i.e. fear of death, belief in life after death and opinion about euthanasia), and about important life events taking place within the TTO timeframe. Regression analyses were performed in order to assess the influence of these different variables. RESULTS: One thousand sixty-seven respondents were included in the analyses. The following variables were significantly associated with years traded off: ERA mental health (decrease), ERA physical health (increase), HRAS (increase), support for euthanasia (increase), fear of death (decrease) and consideration of an important life event (decrease). The explained variance of the final model was low (0.08). CONCLUSION: TTO responses may be influenced by considerations of future health, including life events and attitudes regarding health risks and death. Further investigation of TTO responses remains warranted. PMID- 26753686 TI - Cancer Phytotherapy: Recent Views on the Role of Antioxidant and Angiogenesis Activities. AB - Nowadays, increases in resistance of tumors to the current therapeutic agents have become a problematic issue. Therefore, efforts to discover new anticancer compounds with high sensitivity of cancer cells are extending. Animal and laboratory researches have shown that exogenous antioxidants are able to help prevent the free radical damage associated with the development of cancer. However, researches in human beings have not demonstrated convincingly that taking antioxidants can reduce the risk of developing cancer. Angiogenesis is also a natural condition that controls the formation of new blood vessels from the available vessels. Today, it is believed that most of the cancers have angiogenesis potential and their growth, metastasis, and invasion depend on angiogenesis. Several compounds with plant origin and with anti-angiogenic properties have been identified. The aim of this study is to review recently published articles about anticancer drugs obtained from plants with antioxidant and anti-angiogenesis properties. PMID- 26753689 TI - Emotional contagion of distress in young pigs is potentiated by previous exposure to the same stressor. AB - This study tested whether emotional contagion occurs when piglets directly observe a penmate in distress (restraint) and whether there is an effect of previous experience on the response to subsequent restraint or exposure to conspecific distress. Piglets (49.7 +/- 0.7 days) were exposed in pairs to two stress phases (SP1 and SP2) in an arena divided into two pens by a wire mesh wall. During SP1, one of the pigs of a pair was either restrained (Stress treatment) or sham-restrained (Control treatment), while the other pig was considered observer. During SP2, the previous observer was restrained, while its penmate took the observer role. Heart rate variability, locomotion, vocalizations, body/head/ear and tail postures were monitored. During SP1, observer pigs responded to conspecific distress with increased indicators of attention (looking at, proximity to and snout contacts with the distressed pigs) and increased indicators of fear (reduced locomotion, increased freezing). During SP2, the observer pigs that had been restrained previously reacted more strongly (through higher proximity, decreased locomotion, increased freezing) to observing the penmate in restraint than pigs without the previous negative experience. This study suggests that young pigs are susceptible to emotional contagion and that this contagion is potentiated by previous exposure to the same stressor. These findings have implications for pig welfare in practical animal husbandry systems. PMID- 26753690 TI - Investigating patients with an immigration background in Canada: relationships between individual immigrant attitudes, the doctor-patient relationship, and health outcomes. AB - BACKGROUND: Increasing immigration in the world today leads to more intercultural interactions. This is a particularly crucial fact in doctor-patient relationships, which often become more complex and suboptimal within an intercultural context. Since acculturation is a particularly important factor in this process, and the doctor-patient relationship is a key component in patient health outcomes, this study investigates the interrelation of individual immigrant acculturation orientations with the quality of the doctor-immigrant patient relationship, the patients' perceived quality of care, and how this relates to immigrant health behaviours and quality of life of the patients. METHODS: 171 immigrant patients of various backgrounds participated in a paper and pencil questionnaire to assess the role of acculturation orientations (AO) on patients' perceived expectations of their doctor, perceived quality of care (PQOC), health behaviours and quality of life. Data were analyzed using ANOVA, regression and correlation procedures with SPSS statistical software. RESULTS: Significant correlations were found between all AOs and measures of the participant feeling connected to the host or home culture, thereby verifying the measure of AO. All four AOs were significantly interrelated directly with the patient's perception of what the doctor expects of him/her, and the patients' quality of life. Patients' perceived expectations of their doctors were significantly related to the patients' PQOC, and PQOC was associated with improved health behaviours (adherence to doctor recommendations, physical activity maintenance self-efficacy). CONCLUSIONS: AO may be an important factor in the doctor-immigrant patient relationship, via a complex process involving the patients' perceptions of doctors' expectations and perceived quality of care. This has important implications, since such an understanding can be used to create interventions for both doctors and immigrant patients to learn about their own AO, how it can relate to the quality of their relationship, and ultimately, the quality of care, health and quality of life of the patient. PMID- 26753694 TI - Favorable prognostic influence of T-box transcription factor Eomesodermin in metastatic renal cell cancer patients. AB - T-box transcription factors, T-box expressed in T cells (T-bet) encoded by Tbx21 and Eomesodermin (Eomes), drive the differentiation of effector/memory T cell lineages and NK cells. The aim of the study was to determine the prognostic influence of the expression of these transcription factors in peripheral blood (pB) in a cohort of 41 metastatic (m) RCC patients before receiving sorafenib treatment and to analyze their association with the immunophenotype in pB. In contrast to Tbx21, in the multivariate analysis including clinical features, Eomes mRNA expression was identified as an independent good prognostic factor for progression-free survival (PFS, p = 0.042) and overall survival (OS, p = 0.001) in addition to a favorable ECOG performance status (p = 0.01 and p = 0.008, respectively). Eomes expression correlated positively not only with expression of Tbx21 and TGFbeta1 mRNA, but also with mRNA expression of the activation marker ICOS, and with in vivo activated HLA-DR(+) T cells. Eomes expression was negatively associated with TNFalpha-producing T cells. On protein level, Eomes was mainly expressed by CD56(+)CD3(-) NK cells in pB. In conclusion, we identified a higher Eomes mRNA expression as an independent good prognostic factor for OS and PFS in mRCC patients treated with sorafenib. PMID- 26753693 TI - Rifaximin for the treatment of diarrhea-predominant irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is a chronic, functional bowel disorder characterized by abdominal pain or discomfort and altered bowel habit. The pathophysiology is unclear, but may include altered gut motility, visceral hypersensitivity, abnormal central pain processing, chronic low-grade intestinal inflammation, or disturbances in the gut microbiome. These etiological mechanisms, alongside environmental factors such as stress and anxiety, vary between individuals and represent potential targets for treatment. Rifaximin is a poorly absorbed oral antibiotic proposed to act on the gut microenvironment, used in the treatment of travelers' diarrhea and hepatic encephalopathy. Clinical trials suggest the drug can reduce global IBS symptoms and improve bloating, abdominal pain, and stool consistency in some patients with non-constipated IBS, leading to Food and Drug Administration approval in the United States. This article considers the pharmacology of rifaximin, the evidence for its use in IBS, and the safety and tolerability of the drug. PMID- 26753691 TI - Increasing genomic diversity and evidence of constrained lifestyle evolution due to insertion sequences in Aeromonas salmonicida. AB - BACKGROUND: Aeromonads make up a group of Gram-negative bacteria that includes human and fish pathogens. The Aeromonas salmonicida species has the peculiarity of including five known subspecies. However, few studies of the genomes of A. salmonicida subspecies have been reported to date. RESULTS: We sequenced the genomes of additional A. salmonicida isolates, including three from India, using next-generation sequencing in order to gain a better understanding of the genomic and phylogenetic links between A. salmonicida subspecies. Their relative phylogenetic positions were confirmed by a core genome phylogeny based on 1645 gene sequences. The Indian isolates, which formed a sub-group together with A. salmonicida subsp. pectinolytica, were able to grow at either at 18 degrees C and 37 degrees C, unlike the A. salmonicida psychrophilic isolates that did not grow at 37 degrees C. Amino acid frequencies, GC content, tRNA composition, loss and gain of genes during evolution, pseudogenes as well as genes under positive selection and the mobilome were studied to explain this intraspecies dichotomy. CONCLUSION: Insertion sequences appeared to be an important driving force that locked the psychrophilic strains into their particular lifestyle in order to conserve their genomic integrity. This observation, based on comparative genomics, is in agreement with previous results showing that insertion sequence mobility induced by heat in A. salmonicida subspecies causes genomic plasticity, resulting in a deleterious effect on the virulence of the bacterium. We provide a proof-of-concept that selfish DNAs play a major role in the evolution of bacterial species by modeling genomes. PMID- 26753692 TI - Increased mortality and aggravation of heart failure in liver X receptor-alpha knockout mice after myocardial infarction. AB - Liver X receptors, LXRalpha (NR1H3) and LXRbeta (NR1H2), are best known as nuclear oxysterol receptors and physiological master regulators of lipid and cholesterol metabolism. LXRalpha play a protective role in acute myocardial ischemia/reperfusion (MI/R) injury, but its role in myocardial infarction (MI) is unknown. The present study was undertaken to determine the effect of LXRalpha knockout on survival and development of chronic heart failure after MI. Wild-type (WT) and LXRalpha(-/-) mice were subjected to MI followed by serial echocardiographic and histological assessments. Greater myocyte apoptosis and inflammation within the infarcted zones were found in LXRalpha(-/-) group at 3 days after MI. At 4 weeks post-MI, LXRalpha(-/-) MI murine hearts demonstrated significantly increased infarct size, reduced ejection fraction (LXRalpha(-/-) 29.4 % versus WT 34.4 %), aggravated left ventricular (LV) chamber dilation, enhanced fibrosis and reduced angiogenesis. In addition, LXRalpha(-/-) mice had increased mortality compared with WT mice. LXRalpha deficiency increases mortality, aggravates pathological injury and LV remodeling induced by MI. Drugs specifically targeting LXRalpha may be promising in the treatment of MI. PMID- 26753698 TI - "Micro/nanofluidics and Micro/nanotechnologies for Analytical Chemistry: Fundamental Technologies, Characteristic Phenomena, Applications, and Instrumentation". PMID- 26753697 TI - Lithium overdosage and related tests. AB - Lithium acts biochemically through the inositol depletion in brain cortex. At low doses, however, it is partly effective and/or ineffective, whereas in high concentrations is toxic. We would like to make one point about this review. In fact, in our view, the patient should be given a support to correct hypernatremia and even sodium levels should be tested serially-along with serum lithium concentrations-because high sodium levels reduce the rate of elimination of lithium. Lithium is mainly a neurotoxicant. Lithium-related central nervous system toxicity as well as the cardiovascular and thyroid changes are most likely due to the cations (Na2 (+) and K(+)) competition. PMID- 26753699 TI - Microfluidic Approaches for Protein Crystal Structure Analysis. AB - This review summarizes two microfluidic-based protein crystallization methods, protein crystallization behavior in the microfluidic devices, and their applications for X-ray crystal structure analysis. Microfluidic devices provide many advantages for protein crystallography; they require small sample volumes, provide high-throughput screening, and allow control of the protein crystallization. A droplet-based protein crystallization method is a useful technique for high-throughput screening and the formation of a single crystal without any complicated device fabrication process. Well-based microfluidic platforms also enable effective protein crystallization. This review also summarizes the protein crystal growth behavior in microfluidic devices as, is known from viewpoints of theoretical and experimental approaches. Finally, we introduce applications of microfluidic devices for on-chip crystal structure analysis. PMID- 26753700 TI - Interfacial Phenomena and Fluid Control in Micro/Nanofluidics. AB - Fundamental aspects of rapidly advancing micro/nanofluidic devices are reviewed from the perspective of liquid interface chemistry and physics, including the influence of capillary pressure in microfluidic two-phase flows and phase transitions related to capillary condensation. PMID- 26753696 TI - Involvement of NO/cGMP pathway in the antidepressant-like effect of gabapentin in mouse forced swimming test. AB - Based on clinical studies regarding the beneficial effect of gabapentin in depression, we aimed to evaluate the antidepressant-like properties of gabapentin in mice and also the participation of nitric oxide (NO)/cyclic guanosine monophosphate pathway in this effect. The following drugs were used in this study: gabapentin; N(G)-nitro-L-arginine methyl ester (L-NAME), a non-specific NO synthase (NOS) inhibitor; 7-nitroindazole, a specific neuronal NOS inhibitor; aminoguanidine, a specific inducible NOS inhibitor; L-arginine, a NO precursor; and sildenafil, a phosphodiestrase inhibitor. Finally, we studied the behavioral effects through the forced swimming test (FST) and the changes of the hippocampus NO level through nitrite assay. The immobility time was significantly reduced after gabapentin administration. Co-administration of non-effective doses of gabapentin and L-NAME or 7-nitroindazole (7-NI) resulted in antidepressant-like effect in FST, while aminoguanidine did not affect the immobility time of gabapentin-treated mice. Furthermore, the antidepressant-like property of gabapentin was prevented by L-arginine or sildenafil. Also, the hippocampal nitrite level was significantly lower in gabapentin-treated mice relative to saline-injected mice, and co-administration of 7-NI with sub-effective gabapentin caused a significant decrease in hippocampal nitrite levels. Our results indicate that the antidepressant-like effect of gabapentin in the mice FST model is mediated at least in part through nitric oxide/cyclic guanosine monophosphate (cGMP) pathway. PMID- 26753695 TI - Thymoquinone alleviates nonalcoholic fatty liver disease in rats via suppression of oxidative stress, inflammation, apoptosis. AB - Nonalcoholic steatohepatitis (NAFLD) is a progressive form of liver disease that leads to advanced fibrosis. The present study was designed to assess the hepatoprotective effect of thymoquinone (TQ) on liver functions, insulin resistance, and PPAR-gamma expression in NAFLD. Rats were divided into two main groups: one fed with normal rat chow diet and the other with high-fat high cholesterol diet group for 6 weeks. Every group was subdivided into three subgroups (n = 8): treated with saline, low dose TQ (10 mg/kg), high dose TQ (20 mg/kg). High fat high cholesterol diet caused marked liver damage as noted in histopathology and significant increase in liver index, liver enzymes. There was significant increase in the insulin resistance, serum cholesterol, triglyceride, PPAR-gamma gene overexpression with significant decrease in HDL. Additionally, oxidative stress increased by measuring MDA associated with significant decrease in serum total antioxidant capacity. As markers of inflammation, hepatic TNF alpha was significantly increased with decrease in IL10. Further, there was increase in BAX protein with decrease in Bcl as compared to control group. This model of 6 weeks high-fat high-cholesterol diet showed minimal fibrosis as noticed by increase MMP2 and Masson trichrome satin. Co-treatment with TQ improved all previous parameters. High dose was more effective, although mostly non-statistically significant. TQ may have a promising agent to improve hepatic steatosis, oxidative stress; inflammatory, apoptotic status, fibrosis and so prevent liver damage in patients with NAFLD. Although PPAR-gamma was significantly under-expressed by TQ, insulin resistance was improved significantly suggesting a role of liver damage. PMID- 26753701 TI - Fast Screening Techniques for Neurotoxigenic Substances and Other Toxicants and Pollutants Based on Thermal Lensing and Microfluidic Chips. AB - Efficient environment protection and human safety require high-throughput analysis techniques for pollutants or toxicants for large sample sets. State-of the-art HPLC and GC coupled to various detecting strategies offer excellent sensitivity and selectivity, though they are quite time-extensive (2 - 3 samples/h or less when sample preparation is involved). Efforts are made towards screening techniques with high sample throughputs simultaneously providing detection limits below the maximum contaminant levels for the analyte. However, such approaches frequently sacrifice the selectivity or sensitivity (or just give a yes/no response). In this review, we demonstrate thermal-lens spectrometry and microscopy as highly sensitive spectrometric techniques in combination with flow injection analysis (FIA) and microfluidic FIA along with lab-on-a-chip chemistry for fast screening (several samples/h and up to 20 samples/min) exemplified by organophosphates and carbamates as neurotoxigenic compounds. Various approaches to determining other topical toxicants, like microcystin and cyanopigments as its indicators, allergens, and carcinogenic chromate, are also discussed. PMID- 26753702 TI - Determination of Iron Ion in the Water of a Natural Hot Spring Using Microfluidic Paper-based Analytical Devices. AB - Microfluidic paper-based analytical devices (MUPADs) were used to detect the iron ion content in the water of a natural hot spring in order to assess the applicability of this process to the environmental analysis of natural water. The MUPADs were fabricated using a wax printer after the addition of hydroxylamine into the detection reservoirs to reduce Fe(3+) to Fe(2+), 1,10-phenanthroline for the forming of a complex, and poly(acrylic acid) for ion-pair formation with an acetate buffer (pH 4.7). The calibration curve of Fe(3+) showed a linearity that ranged from 100 to 1000 ppm in the semi-log plot whereas the color intensity was proportional to the concentration of Fe(3+) and ranged from 40 to 350 ppm. The calibration curve represented the daily fluctuation in successive experiments during four days, which indicated that a calibration curve must be constructed for each day. When freshly prepared MUPADs were compared with stored ones, no significant difference was found. The MUPADs were applied to the determination of Fe(3+) in a sample of water from a natural hot spring. Both the accuracy and the precision of the MUPAD method were evaluated by comparisons with the results obtained via conventional spectrophotometry. The results of the MUPADs were in good agreement with, but less precise than, those obtained via conventional spectrophotometry. Consequently, the MUPADs offer advantages that include rapid and miniaturized operation, although the precision was poorer than that of conventional spectrophotometry. PMID- 26753704 TI - Staggered-electromagnetophoresis with a Split-flow System for the Separation of Microparticles by a Hollow Fiber-embedded PDMS Microchip. AB - A novel microchip separation system for microparticles based on electromagnetophoresis (EMP) was developed. In this system, focusing and separation of flowing microparticles in a microchannel could be performed by staggered-EMP by controlling the electric current applied to the channel locally combined with the split-flow system for fractionation of eluates. To apply the electric current through the flushing medium in the microchannel, a hollow fiber embedded microchip with multiple electrodes was fabricated. The hollow fiber was made by a semi-permeable membrane and could separate small molecules. This microchip allowed us to apply the electric current to a part of the microchannel without any pressure control device because a main channel contacted with the subchannels that had electrodes through the semi-permeable membrane. Moreover, the separation using this microchip was combined with the split-flow system at two outlets to improve separation efficiency. Using this system, with the split flow ratio of 10:1, 87% of 3 MUm polystyrene (PS) latex particles were isolated from a mixture of 3 and 10 MUm particles. Even the separation of 6 and 10 MUm PS particles was achieved with about 77% recovery and 100% purity. In addition, by controlling the applied current, size fractionation of polypropylene (PP) particles was demonstrated. Moreover, biological particles such as pollens could be separated with high separation efficiency by this technique. PMID- 26753703 TI - Evaluation of a Portable Microchip Electrophoresis Fluorescence Detection System for the Analysis of Amino Acid Neurotransmitters in Brain Dialysis Samples. AB - A portable fluorescence detection system for use with microchip electrophoresis was developed and compared to a benchtop system. Using this system, six neuroactive amines commonly found in brain dialysate (arginine, citrulline, taurine, histamine, glutamate, and aspartate) were derivatized offline with naphthalene-2,3-dicarboxaldehyde/cyanide, separated electrophoretically, and detected by fluorescence. The limits of detection for the analytes of interest were 50 - 250 nM for the benchtop system and 250 nM - 1.3 MUM for the portable system, both of which were adequate for most analyte detection in brain microdialysis samples. The portable system was then demonstrated for the detection of the same six amines in a rat brain microdialysis sample. PMID- 26753705 TI - A Noncontact Picolitor Droplet Handling by Photothermal Control of Interfacial Flow. AB - We present a noncontact handling of droplets in a microfluidic platform by the Marangoni convection, interfacial tension driven flow, generated by a light induced local temperature gradient in the surrounding liquid of the droplet. Droplets flowing in a microchannel experience a force due to the interfacial tension gradient when approaching the heated area. This method provides noncontact, selective and flexible manipulation for droplets flowing in microchannel network. In this study, an O/W emulsion system with oleic acid for the dispersed phase and a buffer solution for the continuous one was used. Trajectory control and trapping for droplets with 5 - 65 pL in volume was achieved by patterned laser irradiation. Also, we quantitatively evaluated the driving force exerted on droplets by measuring the fluidic temperature distribution around the droplet. From the balance of the drag force and the photo induced Marangoni force, the driving force was determined using the measured temperature gradient of the droplet. From the results, the applicability of noncontact droplet manipulation using the photothermal Marangoni effect by continuous-phase heating has been demonstrated. PMID- 26753706 TI - Channel Current Analysis for Pore-forming Properties of an Antimicrobial Peptide, Magainin 1, Using the Droplet Contact Method. AB - This study describes the pore-forming properties of magainin 1 in planar lipid bilayers. These bilayers were prepared by the droplet contact method, which was executed on a microfabricated device for a high-throughput study. We arrayed four droplet chambers parallelly in the single device, and the current measurements were carried out simultaneously. Using this system, we measured the channel current conductance of magainin 1. We determined the pore size and the number of assembling monomers in magainin pores in mammalian and bacterial model membranes. This system is a powerful tool for analyzing transmembrane peptides and their antimicrobial activities. PMID- 26753707 TI - A Bacterial Continuous Culture System Based on a Microfluidic Droplet Open Reactor. AB - Recently, micrometer-sized bacterial culture systems have attracted attention as useful tools for synthetic biology studies. Here, we present the development of a bacterial continuous culture system based on a microdroplet open reactor consisting of two types of water-in-oil microdroplets with diameters of several hundred micrometers. A continuous culture was realized the through supply of nutrient substrates and the removal of waste and excess bacterial cells based on repeated fusion and fission of droplets. The growth dynamics was controlled by the interval of fusion. We constructed a microfluidic system and quantitatively assessed the dynamics of the bacterial growth using a mathematical model. This system will facilitate the study of synthetic biology and metabolic engineering in the future. PMID- 26753708 TI - A Microfluidic Approach to Investigating a Synergistic Effect of Tobramycin and Sodium Dodecyl Sulfate on Pseudomonas aeruginosa Biofilms. AB - In recent years, a microfluidic technology has contributed a significant role in biological research, specifically for the study of biofilms. Bacterial biofilms are a source of infections and contamination in the environment due to an extra polymeric matrix. Inadequate uses of antibiotics make the bacterial biofilms antibiotic resistant. Therefore, it is important to determine the effective concentration of antibiotics in order to eliminate bacterial biofilms. The present microfluidic study was carried out to analyze the activities of tobramycin and sodium dodecyl sulfate (SDS) against Pseudomonas aeruginosa biofilms with a continuous flow in order to achieve a greater delivery of the agents. The results show that a co-treatment of tobramycin and SDS significantly reduced the biomass of biofilms (by more than 99%) after 24 h. Tobramycin and SDS killed and detached bacteria in the cores of biofilms. Evidently, our data suggest that a microchannel would be effective for both quantitative and qualitative evaluations in order to test combinatorial effect of drugs and chemicals on a complexed biological system including biofilm. PMID- 26753709 TI - Living Single Cell Analysis Platform Utilizing Microchannel, Single Cell Chamber, and Extended-nano Channel. AB - Single cell analysis has been of great interest in recent years. In particular, to achieve living single cell analysis is the ultimate goal to study the dynamic process of the single cell. However, single cell volume is pL in scale, and it is difficult to realize living single cell analysis, even by microfluidic technology (nL-sub nL). Herein, a novel microfluidic platform was developed by integrating a single cell chamber and an extended-nano channel (aL-fL volume). A single cell was isolated and cultured for more than 12 h by pressure-driven flow control. In addition, an electric resistance measurement method was developed to monitor the cell viability without fluorescence labeling. This platform will provide a new method for living single cell analysis by utilizing the novel analytical functions of the extended-nano space. PMID- 26753710 TI - Fabrication of Hydrophobic Nanostructured Surfaces for Microfluidic Control. AB - In the field of micro- and nanofluidics, various kinds of novel devices have been developed. For such devices, not only fluidic control but also surface control of micro/nano channels is essential. Recently, fluidic control by hydrophobic nanostructured surfaces have attracted much attention. However, conventional fabrication methods of nanostructures require complicated steps, and integration of the nanostructures into micro/nano channels makes fabrication procedures even more difficult and complicated. In the present study, a simple and easy fabrication method of nanostructures integrated into microchannels was developed. Various sizes of nanostructures were successfully fabricated by changing the plasma etching time and etching with a basic solution. Furthermore, it proved possible to construct highly hydrophobic nanostructured surfaces that could effectively control the fluid in microchannels at designed pressures. We believe that the fabrication method developed here and the results obtained are valuable contributions towards further applications in the field of micro- and nanofluidics. PMID- 26753711 TI - Imprint Molding of a Microfluidic Optical Cell on Thermoplastics with Reduced Surface Roughness for the Detection of Copper Ions. AB - Here, we introduce a simple and facile technique for fabricating microfluidic optical cells by utilizing a micropatterned polymer mold, followed by imprinting on thermoplastic substrates. This process has reduced the surface roughness of the microchannel, making it suitable for microscale optical measurements. The micropatterned polymer mold was fabricated by first micromilling on a poly(methylmethacrylate) (PMMA) substrate, and then transferring the micropattern onto an ultraviolet (UV)-curable optical adhesive. After an anti-adhesion treatment of the polymer mold fabricated using the UV-curable optical adhesive, the polymer mold was used repeatedly for imprinting onto various thermoplastics, such as PMMA, polycarbonate (PC), and poly(ethyleneterephthalate) (PET). The roughness values for the PMMA, PC, and PET microchannels were approximately 11.3, 20.3, and 14.2 nm, respectively, as compared to those obtained by micromilling alone, which were 15.9, 76.8, and 207.5 nm, respectively. Using the imprint molded thermoplastic optical cell, rhodamine B and copper ions were successfully quantified. The reduced roughness of the microchannel surface resulted in improved sensitivity and reduced noise, paving the way for integration of the detection module so as to realize totally integrated microdevices. PMID- 26753713 TI - Integrated Micro-Optics for Microfluidic Detection. AB - A method of embedding micro-optics into a microfluidic device was proposed and demonstrated. First, the usefulness of embedded right-angle prisms was demonstrated in microscope observation. Lateral-view microscopic observation of an aqueous dye flow in a 100-MUm-sized microchannel was demonstrated. Then, the embedded right-angle prisms were utilized for multi-beam laser spectroscopy. Here, crossed-beam thermal lens detection of a liquid sample was applied to glucose detection. PMID- 26753712 TI - Rapid Colorimetric Antibody Detection Using a Dual-function Peptide Probe for Silver Nanoparticle Aggregation and Antibody Recognition. AB - Simple and rapid tools for antibody detection are beneficial for therapeutic monoclonal antibody development. Using a synthetic cationic antibody-recognizing peptide, a label-free colorimetric assay for antibody detection was established, in which a solution containing silver nanoparticles (AgNPs) changes color depending on particle aggregation/dispersion. Among the peptide probes we previously screened as IgG binding, one (NKFRGKYK) has four cationic amino acids and a pI of 10.46. Hence, we hypothesized that the peptide would both bind IgG and induce anionic AgNP aggregation via electrostatic interactions. This dual functionality of the IgG binding peptide could be useful for colorimetric detection. The detection of IgG in a solution containing culture media was investigated, and IgG was successfully detected at 100 to 500 nM within 2 min. This method is promising for high-throughput selection of IgG-producing cells since it is fast, readily observable, and does not involve complicated nanoparticle functionalization. PMID- 26753714 TI - Influence of Sample Volume and Solvent Evaporation on Absorbance Spectroscopy in a Microfluidic "Pillar-Cuvette". AB - Spectroscopic analysis of solutions containing samples at high concentrations or molar absorptivity can present practical challenges. In absorbance spectroscopy, short optical path lengths or multiple dilution is required to bring the measured absorbance into the range of the Beer's Law calibration. We have previously reported an open "pillar-cuvette" with a micropillar array that is spontaneously filled with a precise (nL or MUL) volume to create the well-defined optical path of, for example, 10 to 20 MUm. Evaporation should not be ignored for open cuvettes and, herein, the volume of loaded sample and the rate of evaporation from the cuvette are studied. It was found that the volume of loaded sample (between 1 and 10 MUL) had no effect on the Beer's Law calibration for methyl orange solutions (molar absorptivity of (2.42 +/- 0.02)* 10(4) L mol(-1) cm(-1)) for cuvettes with a 14.2 +/- 0.2 MUm path length. Evaporation rates of water from methyl orange solutions were between 2 and 5 nL s(-1) (30 - 40% relative humidity; 23 degrees C), depending on the sample concentration and ambient conditions. Evaporation could be reduced by placing a cover slip several millimeters above the cuvette. Importantly, the results show that a "drop-and measure" method (measurement within ~3 s of cuvette loading) eliminates the need for extrapolation of the absorbance-time data for accurate analysis of samples. PMID- 26753715 TI - Alternating Current Cloud Point Extraction on a Microfluidic Chip: the Use of Ferrocenyl Surfactants. AB - Alternating current cloud point extraction (ACPE) is a preconcentration technique that can be employed in the analysis of membrane proteins on a microfluidic chip. However, the selectivity of ACPE relies on the hydrophobicity of the analytes. In this study, 11-ferrocenyltrimethylundecylammonium bromide (FTMA) was utilized to introduce electrostatic interaction as part of the ACPE technique. The use of ACPE with oxidized FTMA resulted in efficient concentration of fluorescently labeled anionic membrane proteins. We expect the approach outlined in this report to be useful in the preconcentration technique of microchip electrophoresis. PMID- 26753716 TI - Patterned Co-culture of Live Cells on a Microchip by Photocrosslinking with Benzophenone. AB - The patterned coculture of different types of living cells in a microfluidic device is crucial for the analysis of cellular interactions and cell-cell communication. In the present study, cell patterning was achieved by photocrosslinking benzophenone derivatives in a microfluidic channel. Optimization of UV irradiation conditions enabled successful fixation of live cells. In addition, patterning and co-culture of non-adherent K562 cells and adherent RF-6A cells was achieved by successive rounds of patterning. The present approach is expected to be useful for the development of in vitro methods for studying cell signaling. PMID- 26753717 TI - Polymer-based Photonic Crystal Cavity Sensor for Optical Detection in the Visible Wavelength Region. AB - In this study, a polymer-based two-dimensional photonic crystal (PhC) cavity for visible-light-based optical-sensing applications was designed and fabricated for the first time. The PhC cavity configuration was designed to operate at 650 nm, and fabricated with a polymer (resist) on a silicon substrate using electron-beam lithography. For investigating sensing applications based on shifting of condition exhibiting a photonic bandgap (PBG), the polymer monolayer deposition (layer-by-layer method) was monitored as the light-intensity change at the cavity position. Consequently, the monolayer-level detection of polyions was achieved. PMID- 26753719 TI - Associations among child abuse, mental health, and epigenetic modifications in the proopiomelanocortin gene (POMC): A study with children in Tanzania. AB - Child abuse is associated with a number of emotional and behavioral problems. Nevertheless, it has been argued that these adverse consequences may not hold for societies in which many of the specific acts of abuse are culturally normed. Epigenetic modifications in the genes of the hypothalamus-pituitary-adrenal axis may provide a potential mechanism translating abuse into altered gene expression, which subsequently results in behavioral changes. Our investigation took place in Tanzania, a society in which many forms of abuse are commonly employed as disciplinary methods. We included 35 children with high exposure and compared them to 25 children with low exposure. Extreme group comparisons revealed that children with high exposure reported more mental health problems. Child abuse was associated with differential methylation in the proopiomelanocortin gene (POMC), measured both in saliva and in blood. Hierarchical clustering based on the methylation of the POMC gene found two distinct clusters. These corresponded with children's self-reported abuse, with two-thirds of the children allocated into their respective group. Our results emphasize the consequences of child abuse based on both molecular and behavioral grounds, providing further evidence that acts of abuse affect children, even when culturally acceptable. Furthermore, on a molecular level, our findings strengthen the credibility of children's self reports. PMID- 26753720 TI - One-Pot/Sequential Native Chemical Ligation Using Photocaged Crypto-thioester. AB - A practical and efficient methodology for the chemical synthesis of peptides/proteins using a one-pot/sequential ligation is described. It features the use of photocleavable S-protection on an N-sulfanylethylaniline moiety. Removal of the S-protecting ligated materials under UV irradiation provides a readily usable mixture for subsequent native chemical ligation. PMID- 26753721 TI - Renin gene rs1464816 polymorphism contributes to chronic kidney disease progression in ADPKD. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disorder and is a common genetic cause of chronic renal failure in children and adults. The enzyme renin plays a key role in the RAAS cascade and an important role in the development of hypertension and progression of renal disease in ADPKD. The present study is aimed to investigate the potential modifier effect of REN gene polymorphisms on the progression of chronic kidney disease (CKD) in ADPKD. METHODS: We analyzed 102 ADPKD patients and 106 healthy controls from the same geographic area. FRET-based KASPar single-nucleotide polymorphism (SNP) genotyping assays for REN gene tag-SNPs (rs2887284, rs2368564, rs1464816, rs7521667, rs10900555, rs6693954, rs6676670 and rs11571078) were performed. Cochran-Armitage trend test was used to assess the potential associations between these polymorphisms and CKD stages. Haplotype frequencies and LD measures were estimated by using the software Haploview. Mantel-Haenszel stratified analysis was used to explore confounding and interaction effects of these polymorphisms. RESULTS: Of the eight tag-SNPs genotyped, the rs10900555 polymorphism deviated from the Hardy-Weinberg equilibrium in controls. The presence of ADPKD in general was not significantly associated with the REN tag-SNPs included in this study. Linkage disequilibrium analysis yielded three haplotype blocks and the haplotypes of the respective blocks are not statistically different between ADPKD and controls. In multivariate analysis, the rs1464816 TG genotype showed a significant association with the advancement of CKD in ADPKD (OR = 4.80; 95 % CI = 1.30-17.82; p = 0.019). CONCLUSIONS: The present study provides evidence that the rs1464816 polymorphism in REN is associated with CKD progression in ADPKD. PMID- 26753722 TI - Validation of Urinary PD-1 and FOXP3 mRNA in a Cohort of Egyptian Renal Allograft Recipients. AB - BACKGROUND: We investigated the diagnostic and prognostic value of urinary programmed death 1 (PD-1) and FOXP3 (Forkhead transcription factors) mRNA in acute renal allograft rejection. MATERIAL AND METHODS: Urine samples from 31 acute renal allograft rejection subjects and 23 stable recipients were collected. Messenger RNA of PD-1 and FOXP3 were analyzed with real-time RT-PCR. The associations with acute rejection, disease severity, and outcome were investigated. RESULTS: Both PD-1 and FOXP3 mRNA were higher in acute rejection than subjects with stable grafts. In acute rejection, PD-1 and FOXP3 mRNA were significantly correlated with serum creatinine and Banff histological grade. Both PD-1 and FOXP3 mRNA performed well in diagnosing acute rejection (AUC 0.81 and 0.91, respectively). However, a combination of both FOXP3 mRNA at cutoff level 1.5 and PD-1 mRNA at cutoff level 2.6 had 94% sensitivity, 97% specificity, and AUC 0.98 in diagnosing acute rejection. Only FOXP3 mRNA was correlated with rejection reversibility and predicted graft salvage (98% sensitivity, 87% specificity, and AUC 0.93) at cutoff level 1.7. CONCLUSIONS: PD-1 and FOXP3 mRNA were high in acute rejection, and performed well in diagnosing rejection episodes, and were correlated with rejection severity. The combination of FOXP3 and PD-1 mRNA had better sensitivity and specificity in diagnosing acute rejection than each separately. Only FOXP3 anticipated rejection outcome. PMID- 26753741 TI - MS3ALIGN: an efficient molecular surface aligner using the topology of surface curvature. AB - BACKGROUND: Aligning similar molecular structures is an important step in the process of bio-molecular structure and function analysis. Molecular surfaces are simple representations of molecular structure that are easily constructed from various forms of molecular data such as 3D atomic coordinates (PDB) and Electron Microscopy (EM) data. METHODS: We present a Multi-Scale Morse-Smale Molecular Surface Alignment tool, MS3ALIGN, which aligns molecular surfaces based on significant protrusions on the molecular surface. The input is a pair of molecular surfaces represented as triangle meshes. A key advantage of MS3ALIGN is computational efficiency that is achieved because it processes only a few carefully chosen protrusions on the molecular surface. Furthermore, the alignments are partial in nature and therefore allows for inexact surfaces to be aligned. RESULTS: The method is evaluated in four settings. First, we establish performance using known alignments with varying overlap and noise values. Second, we compare the method with SurfComp, an existing surface alignment method. We show that we are able to determine alignments reported by SurfComp, as well as report relevant alignments not found by SurfComp. Third, we validate the ability of MS3ALIGN to determine alignments in the case of structurally dissimilar binding sites. Fourth, we demonstrate the ability of MS3ALIGN to align iso surfaces derived from cryo-electron microscopy scans. CONCLUSIONS: We have presented an algorithm that aligns Molecular Surfaces based on the topology of surface curvature. A webserver and standalone software implementation of the algorithm available at http://vgl.serc.iisc.ernet.in/ms3align. PMID- 26753742 TI - [Formula: see text]Official Position of the American Academy of Clinical Neuropsychology (AACN): Guidelines for Practicum Training in Clinical Neuropsychology. AB - Practical experience is central to the education and training of neuropsychologists, beginning in graduate school and extending through postdoctoral fellowship. However, historically, little attention has been given to the structure and requirements of practicum training in clinical neuropsychology. A working group of senior-level neuropsychologists, as well as a current postdoctoral fellow, all from a diverse range of settings (The AACN Practicum Guidelines Workgroup), was formed to propose guidelines for practicum training in clinical neuropsychology. The Workgroup reviewed relevant literature and sought input from professional organizations involved in education and training in neuropsychology. The proposed guidelines provide a definition of practicum training in clinical neuropsychology, detail entry and exit criteria across competencies relevant to practicum training in clinical neuropsychology, and discuss the relationship between doctoral training programs and practicum training sites. The proposed guidelines also provide a methodology for competency based evaluation of clinical neuropsychology practicum trainees and outline characteristics and features that are integral to an effective training environment. Although the guidelines discussed below may not be implemented in their entirety across all clinical neuropsychology practicum training sites, they are consistent with the latest developments in competency-based education. PMID- 26753743 TI - Erratum: Dynamic creation of a topologically-ordered Hamiltonian using spin-pulse control in the Heisenberg model. PMID- 26753744 TI - Enhanced electromechanical coupling of a nanomechanical resonator to coupled superconducting cavities. AB - We investigate the electromechanical coupling between a nanomechanical resonator and two parametrically coupled superconducting coplanar waveguide cavities that are driven by a two-mode squeezed microwave source. We show that, with the selective coupling of the resonator to the cavity Bogoliubov modes, the radiation pressure type coupling can be greatly enhanced by several orders of magnitude, enabling the single photon strong coupling to be reached. This allows the investigation of a number of interesting phenomena such as photon blockade effects and the generation of nonclassical quantum states with electromechanical systems. PMID- 26753745 TI - Assembly of Ag3PO4 nanoparticles on two-dimensional Ag2S sheets as visible-light driven photocatalysts. AB - Ag3PO4 has been proven to be a promising catalyst with superior activity compared to other existing visible-light-driven photocatalysts. In this work, Ag3PO4 nanoparticles were deposited on the surface of two-dimensional Ag2S sheets by an in situ synthesis strategy. The microstructure, composition, and performance of the resulting Ag3PO4/Ag2S composites could be tailored by surface-functioned Ag2S sheets. The composite reached optimum performance when the molar ratio of Ag2S to Ag3PO4 was 0.31, showing a 2-fold enhancement in the degradation rate in comparison to pure Ag3PO4. Efficient separation of photogenerated electron-hole pairs was achieved through a Z-scheme system in which Ag particles served as the center for the combination of electrons at the conduction band of Ag3PO4 and holes at the valence band of Ag2S. In addition to the matched band structure of Ag2S and Ag3PO4, the monodispersed Ag3PO4 nanoparticles were efficient in light harvesting due to the presence of Ag2S. The advantageous interface effect produced by Ag2S sheets and nano-sized Ag3PO4 nanoparticles also contributed to the improvement in photocatalytic activity. PMID- 26753746 TI - Enhanced Diterpene Tanshinone Accumulation and Bioactivity of Transgenic Salvia miltiorrhiza Hairy Roots by Pathway Engineering. AB - Tanshinones are health-promoting diterpenoids found in Salvia miltiorrhiza and have wide applications. Here, SmGGPPS (geranylgeranyl diphosphate synthase) and SmDXSII (1-deoxy-D-xylulose-5-phosphate synthase) were introduced into hairy roots of S. miltiorrhiza. Overexpression of SmGGPPS and SmDXSII in hairy roots produces higher levels of tanshinone than control and single-gene transformed lines; tanshinone production in the double-gene transformed line GDII10 reached 12.93 mg/g dry weight, which is the highest tanshinone content that has been achieved through genetic engineering. Furthermore, transgenic hairy root lines showed higher antioxidant and antitumor activities than control lines. In addition, contents of chlorophylls, carotenoids, indoleacetic acid, and gibberellins were significantly elevated in transgenic Arabidopsis thaliana plants. These results demonstrate a promising method to improve the production of diterpenoids including tanshinone as well as other natural plastid-derived isoprenoids in plants by genetic manipulation of the 2-C-methyl-D-erythritol-4 phosphate (MEP) pathway. PMID- 26753748 TI - ALD--tooling up nanotechnology step by step. PMID- 26753749 TI - Temporal and latitudinal trends of p,p'-DDE in eggs and carcasses of North American birds from 1980 to 2005. AB - The use of 1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane (DDT) in agriculture in the United States and Canada was prohibited in the early 1970s; however, it continued to be used restrictively in Mexico until 2000. Forty years later, 1,1 dichloro-2,2-bis(p-chlorophenyl) ethylene (p,p'-DDE), continues to be detected in eggs and bird carcasses in North America. The use of DDE has been associated with reproductive failure of several avian species, primarily through eggshell thinning. To assess the temporal and latitudinal distribution of p,p'-DDE in North America, the authors examined DDE concentrations reported in bird tissues in the scientific literature published between 1980 and 2009. Overall, the majority of supported models suggested that DDE concentrations in birds were greater in the upper mid-latitudes (38 degrees -48 degrees ) than in other parts of North America. However, spatial trends of DDE seemed to be influenced by regions with large amounts of data, such as the Great Lakes area. Concentrations of p,p'-DDE in eggs averaged 2.5 MUg/g, 3.2 MUg/g, and 29.5 MUg/g wet weight in 1980 and decreased to 1.64 MUg/g, 0.87 MUg/g, and 1.01 MUg/g wet weight by the mid-2000s for the central, eastern, and western North America regions, respectively. The results indicate that, over time, all DDE residues observed in birds have decreased significantly in North America. Environ Toxicol Chem 2016;35:1340-1348. (c) 2016 SETAC. PMID- 26753747 TI - FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy. AB - BACKGROUND: Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy causing systolic dysfunction and heart failure. Rare variants in more than 30 genes, mostly encoding sarcomeric proteins and proteins of the cytoskeleton, have been implicated in familial DCM to date. Yet, the majority of variants causing DCM remain to be identified. The goal of the study is to identify novel mutations causing familial dilated cardiomyopathy. RESULTS: We identify FBXO32 (ATROGIN 1), a member of the F-Box protein family, as a novel DCM-causing locus. The missense mutation affects a highly conserved amino acid and is predicted to severely impair binding to SCF proteins. This is validated by co-immunoprecipitation experiments from cells expressing the mutant protein and from human heart tissue from two of the affected patients. We also demonstrate that the hearts of the patients with the FBXO32 mutation show accumulation of selected proteins regulating autophagy. CONCLUSION: Our results indicate that abnormal SCF activity with subsequent impairment of the autophagic flux due to a novel FBXO32 mutation is implicated in the pathogenesis of DCM. PMID- 26753750 TI - Postoperative Infectious Complications are Associated with Adverse Oncologic Outcomes in Esophageal Cancer Patients Undergoing Preoperative Chemotherapy. AB - BACKGROUND: For some types of cancer, postoperative complications can negatively influence survival, but the association between these complications and oncological outcomes is unclear for patients with esophageal cancer who receive preoperative treatments. METHODS: Data were retrospectively analyzed for patients who underwent curative resection following preoperative chemotherapy for esophageal squamous cell carcinoma from 2001 to 2011. Clinicopathological parameters and cancer-specific survival (CSS) were compared between patients with and without severe postoperative complications, grade III or higher, using the Clavien-Dindo classification. RESULTS: Of 255 patients identified, 104 (40.8 %) postoperatively developed severe complications. The most common complication was atelectasis in 61 (23.9 %), followed by pulmonary infection in 22 (8.6 %). Three field lymphadenectomy, longer operation time, and more blood loss were significantly associated with a higher incidence of severe complications. Multivariate analysis of CSS revealed severe complications [hazard ratio (HR) = 1.642, 95 % confidence interval (95 % CI) 1.095-2.460, p = 0.016] as a significant prognostic factor along with pT stage [HR = 2.081, 95 % CI 1.351 3.266, p < 0.001] and pN stage [HR = 3.724, 95 % CI 2.111-7.126, p < 0.001], whereas postoperative serum C-reactive protein value was not statistically significant. Among all complications, severe pulmonary infection was the only independent prognostic factor [HR = 2.504, 95 % CI 1.308-4.427, p = 0.007]. CONCLUSIONS: The incidence of postoperative infectious complications, in particular pulmonary infection, is associated with unfavorable prognosis in patients with esophageal cancer undergoing preoperative chemotherapy. PMID- 26753751 TI - Patients with Peritoneal Carcinomatosis from Gastric Cancer Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Is Cure a Possibility? AB - BACKGROUND: Peritoneal carcinomatosis is an increasingly common finding in gastric carcinoma. Previously, patients were treated as terminal, and median survival was poor. The use of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in this context is still highly debatable. OBJECTIVE: The aim of this study was to evaluate the long-term outcomes associated with CRS and HIPEC, and define prognostic factors for cure, if possible. PATIENTS AND METHODS: All patients with gastric carcinomatosis from five French institutions who underwent combined complete CRS and HIPEC and had a minimum follow-up of 5 years were included in this study. Cure was defined as a disease-free interval of more than 5 years from the last treatment until the last follow-up. RESULTS: Of the 81 patients who underwent CRS and HIPEC from 1989 to 2009, 59 had a completeness of cytoreduction score (CCS) of 0 (complete macroscopic resection), and the median Peritoneal Cancer Index (PCI) score was 6. Mitomycin C was the most commonly used drug during HIPEC (88 %). The 5-year overall survival (OS) rate was 18 %, with nine patients still disease-free at 5 years, for a cure rate of 11 %. All 'cured' patients had a PCI score below 7 and a CCS of 0. Factors associated with improved OS on multivariate analysis were synchronous resection (p = 0.02), a lower PCI score (p = 0.12), and the CCS (p = 0.09). CONCLUSION: The cure rate of 11 % for patients with gastric carcinomatosis who are deemed terminal emphasizes that CRS and HIPEC should be considered in highly selected patients (low disease extent and complete CRS). PMID- 26753752 TI - Adjuvant Therapy Improves Survival for T2N0 Gastric Cancer Patients with Sub optimal Lymphadenectomy. AB - BACKGROUND: The benefit of adjuvant therapy following resection of early stage, node-negative gastric adenocarcinoma following a margin negative (R0) resection is unclear. METHODS: The National Cancer Data Base was used to identify patients with a T2N0 gastric adenocarcinoma (tumor invasion into the muscularis propria) who underwent R0 resection. Patients treated with neoadjuvant therapy and those for whom lymph node count was unavailable were excluded from the analysis. Kaplan Meier and Cox regression were used to evaluate differences in and predictors of overall survival. RESULTS: A total of 1687 patients underwent R0 resection for T2N0 gastric adenocarcinoma between 2003-2011. Adjuvant chemotherapy treatment was administered to 7.1 and 14.1 % received adjuvant chemoradiation; 65.4 % had <15 lymph nodes examined. Multivariate Cox regression identified higher Charlson score, <15 lymph nodes examined, higher tumor grade, and tumor location in the cardia as factors associated with significantly decreased overall survival. With a median follow-up of 36 months, the 5-year overall survival was 71 % for patients with >=15 lymph nodes examined and 53 % for those with <15 lymph nodes (p < 0.001). In patients who had <15 lymph nodes examined, there was an overall survival benefit for adjuvant chemoradiation (hazard ratio 0.71, p = 0.043). In patients with >=15 lymph nodes examined, no survival benefit for adjuvant therapy was identified (p > 0.74). CONCLUSIONS: Adequate lymph node dissection and pathologic staging is critical in directing optimal treatment of patients with early gastric cancer. Understaging as a result of suboptimal lymphadenectomy may explain the perceived benefit of adjuvant chemoradiation after an R0 resection for T2N0 gastric cancer. PMID- 26753753 TI - Mechanism of p47phox-induced increase of reactive oxygen species in peripheral blood mononuclear cells from premature infants on oxygen therapy. AB - OBJECTIVE: This study aimed to explore the mechanism of p47phox-induced increase of reactive oxygen species (ROS) in peripheral blood mononuclear cells (PBMCs) from premature infants after oxygen therapy, and determine a new target for oxidative stress injury alleviation in clinical setting. METHODS: First, ROS levels as well as p47phox translocation and expression in PBMC samples were evaluated after treatment of premature infants with different concentrations of oxygen. Then, changes of all various parameters were detected after in vitro treatment of PBMCs with diphenyleneiodonium (DPI), apocynin, and high oxygen levels. RESULTS: In premature infants, ROS levels increased significantly after treatment with oxygen, in a concentration-dependent manner (p < 0.05); meanwhile, p47phox translocation and expression were significantly enhanced (p < 0.05) as well. In agreement, PBMCs cultured in vitro showed increased ROS levels after treatment with high oxygen concentrations; p47phox translocation, and expression increased as well (p < 0.05). However, treatment with DPI or apocynin resulted in opposite effects. CONCLUSION: Treatment with oxygen increases p47phox translocationand expression, which in turn induce ROS production. DPI and apocynin have the opposite effects. PMID- 26753755 TI - Investigation of Boron-doping Effect on Photoluminescence Properties of CdNb2O6: Eu(3+) Phosphors. AB - Pure, Eu(3+) - doped and Eu(3+),B(3+) co-doped CdNb2O6 powders have been prepared by a molten salt synthesis method using Li2SO4/Na2SO4 salt mixture as a flux at a relatively low temperatures as compared to solid state reaction. X-ray diffraction patterns of pure CdNb2O6 samples indicated orthorhombic single phase. Photoluminescence investigations of CdNb2O6 samples showed a strong blue emission band centered at 460 nm. For Eu-doped CdNb2O6 samples, the luminescence of Eu(3+) was observed with the host red emission varying with the Eu-doping concentrations. This PL characteristic of the doped samples may be attributed to the energy transfer between Eu(3+) and niobate groups (NbO6). Boron incorporation has remarkably increased the luminescence of Eu(3+)-doped CdNb2O6. PMID- 26753754 TI - Prevalence and molecular characterization of G6PD deficiency in two Plasmodium vivax endemic areas in Venezuela: predominance of the African A-(202A/376G) variant. AB - BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency causes acute haemolytic anaemia triggered by oxidative drugs such as primaquine (PQ), used for Plasmodium vivax malaria radical cure. However, in many endemic areas of vivax malaria, patients are treated with PQ without any evaluation of their G6PD status. METHODS: G6PD deficiency and its genetic heterogeneity were evaluated in northeastern and southeastern areas from Venezuela, Cajigal (Sucre state) and Sifontes (Bolivar state) municipalities, respectively. Blood samples from 664 randomly recruited unrelated individuals were screened for G6PD activity by a quantitative method. Mutation analysis for exons 4-8 of G6PD gen was performed on DNA isolated from G6PD-deficient (G6PDd) subjects through PCR-RFLP and direct DNA sequencing. RESULTS: Quantitative biochemical characterization revealed that overall 24 (3.6%) subjects were G6PDd (average G6PD enzyme activity 4.5 +/- 1.2 U/g Hb, moderately deficient, class III), while DNA analysis showed one or two mutated alleles in 19 of them (79.2%). The G6PD A-(202A/376G) variant was the only detected in 17 (70.8%) individuals, 13 of them hemizygous males and four heterozygous females. Two males carried only the 376A -> G mutation. No other mutation was found in the analysed exons. CONCLUSIONS: The G6PDd prevalence was as low as that one shown by nearby countries. This study contributes to the knowledge of the genetic background of Venezuelan population, especially of those living in malaria-endemic areas. Despite the high degree of genetic mixing described for Venezuelan population, a net predominance of the mild African G6PD A-(202A/376G) variant was observed among G6PDd subjects, suggesting a significant flow of G6PD genes from Africa to Americas, almost certainly introduced through African and/or Spanish immigrants during and after the colonization. The data suggest that 1:27 individuals of the studied population could be G6PDd and therefore at risk of haemolysis under precipitating factors. Information about PQ effect on G6PDd individuals carrying mild variant is limited, but since the regimen of 45 mg weekly dose for prevention of malaria relapse does not seem to be causing clinically significant haemolysis in people having the G6PD A-variant, a reasoned weighing of risk-benefit for its use in Venezuela should be done, when implementing public health strategies of control and elimination. PMID- 26753757 TI - A Facile Method for the Synthesis Fluorescent Zinc Chalcogenide (ZnO, ZnS and ZnSe) Nanoparticles in PS and PMMA Polymer Matrix. AB - A simple method for the synthesis of fluorescent zinc chalcogenide (ZnO, ZnS and ZnSe) nanoparticles directly in the transparent PMMA and PS polymer matrices were reported. Highly dispersed small spherical ZnO nanoparticles (3-5 nm) was obtained by hydrothermal reaction of PMMA/PS-Zn(acac)2H2O in toluene. ZnS and ZnSe nanoparticles were prepared by heterogeneous stirring of PMMA/PS Zn(acac)2H2O in toluene with aqueous solution of thiourea or NaHSe. Interestingly, ZnO and ZnS-PMMA thin film showed strong fluorescence quenching upon exposure to ammonia. PMID- 26753758 TI - Monolayer g-C3N4 Fluorescent Sensor for Sensitive and Selective Colorimetric Detection of Silver ion from Aqueous Samples. AB - Rapid and sensitive detection of heavy-metal ions in natural water environments worldwide is urgently needed because of their severe threats to human health. In the present work, monolayer graphite-like flake C3N4 (g-C3N4) materials were applied as a new fluorescent sensor for the detection of trace silver ion in aqueous solution. The thickness of synthesized g-C3N4 was 0.45 nm and obtained by exfoliating twice with ultrasonic. With the presence of ethylene diamine tetraacetic acid as a screening agent, the highly sensitive sensor reached a low detection limit of 52.3 nmol/L for silver (I) ion and there was no disturbance when silver (I) ion coexisted with other metal ions in water samples. Under the optimal conditions, the monolayer g-C3N4 was successfully used to detect trace silver (I) ion in different environmental water and drinking water samples. PMID- 26753756 TI - Transmittance and Autofluorescence of Neonatal Rat Stratum Corneum: Nerolidol Increases the Dynamics and Partitioning of Protoporphyrin IX into Intercellular Membranes. AB - In this work, we developed an experimental apparatus to directly measure transmittance and fluorescence in the stratum corneum (SC) ex vivo. The SC transmittance varied from ~6 to ~52 % in the wavelength range of 280-850 nm. For 260-300 nm excitation, the SC autofluorescence showed a strong emission band between 290 and 425 nm, which is associated with tryptophan, and another in the 600-670 nm range, which we attributed to a process involving resonance energy transfer to very hydrophobic keratin filaments. Weaker emission associated with less hydrophobic keratin filaments was also observed in the wavelength range of 350-480 nm. Protoporphyrin IX (PpIX) was incorporated into SC membranes, and its penetration was further increased by the addition of nerolidol to the treatment suspension. Both PpIX and the endogenous porphyrins showed fluorescence anisotropy consistent with their localization in SC membranes, and their molecular dynamics increased significantly in the presence of 1 % nerolidol. The emission and excitation spectra of PpIX and the endogenous SC porphyrins showed similar alterations during the photobleaching induced by 405-nm irradiation. This work also highlights the SC contribution to skin autofluorescence, which could be useful for fluorescence spectroscopy applications in the early diagnosis of skin diseases. PMID- 26753759 TI - Salicylyl Fluorene Derivatives as Fluorescent Sensors for Cu(II) Ions. AB - Two derivatives of fluorene containing salicylic acid groups are successfully synthesized by palladium-catalyzed coupling reactions and subsequent hydrolysis of salicylate esters. The compounds are characterized by various spectroscopic methods. In phosphate buffer (pH 8.0) solutions, these compounds are well soluble. They show maximum absorption wavelengths in the range of 304-330 nm and exhibit maximum emission wavelength around 420 and 430 nm with the quantum yields of 2.7 and 4.4 %, respectively. The compound with alkynyl salicylate groups (2) exhibits a selective fluorescence quenching towards Cu(II) and Fe(II) with a relatively similar sensitivity. The selectivity favoring Cu(II) over Fe(II) and other metal ions can be achieved upon the addition of 30 MUM Triton X-100. The Cu(II) detection limit in solution phase is 1.47 ppb. The fluorescence signal recovery upon the addition of EDTA indicate a reversible complexation between 2 and Cu(II) ion. Fabrication of 2 on filter paper using a 50 MUM solution in THF affords a naked-eye detection for Cu(II) and Fe(II) in aqueous media at picomole level. PMID- 26753760 TI - TREM-like transcript 2 is stored in human neutrophil primary granules and is up regulated in response to inflammatory mediators. AB - The triggering receptor expressed on myeloid cell locus encodes a family of receptors that is emerging as an important class of molecules involved in modulating the innate immune response and inflammation. Of the 4 conserved members, including triggering receptor expressed on myeloid cells 1 and 2 and triggering receptor expressed on myeloid cell-like transcripts 1 and 2, relatively little is known about triggering receptor expressed on myeloid cell like transcript 2 expression and function, particularly in humans. In this study, experiments were performed to determine if triggering receptor expressed on myeloid cell-like transcript 2 expression is conserved between mouse and human, demonstrating that human triggering receptor expressed on myeloid cell-like transcript 2 is expressed on cells of the lymphoid, as well as myeloid/granuloid lineages, similar to murine triggering receptor expressed on myeloid cell-like transcript 2. Consistent with studies in the mouse, triggering receptor expressed on myeloid cell-like transcript 2 expression is up-regulated in response to inflammatory mediators on human neutrophils. Importantly, it was shown that triggering receptor expressed on myeloid cell-like transcript 2, in resting human neutrophils, is predominantly localized to intracellular vesicles, including secretory vesicles and primary granules; with the majority of triggering receptor expressed on myeloid cell-like transcript 2 stored in primary granules. In contrast to other primary granule proteins, triggering receptor expressed on myeloid cell-like transcript 2 is not expelled on neutrophil extracellular traps but is retained in the plasma membrane following primary granule exocytosis. In summary, these findings establish that triggering receptor expressed on myeloid cell-like transcript 2 expression is conserved between species and is likely to be important in regulating neutrophil antimicrobial function following primary granule exocytosis. PMID- 26753761 TI - The challenge of evolving stable polyploidy: could an increase in "crossover interference distance" play a central role? AB - Whole genome duplication is a prominent feature of many highly evolved organisms, especially plants. When duplications occur within species, they yield genomes comprising multiple identical or very similar copies of each chromosome ("autopolyploids"). Such genomes face special challenges during meiosis, the specialized cellular program that underlies gamete formation for sexual reproduction. Comparisons between newly formed (neo)-autotetraploids and fully evolved autotetraploids suggest that these challenges are solved by specific restrictions on the positions of crossover recombination events and, thus, the positions of chiasmata, which govern the segregation of homologs at the first meiotic division. We propose that a critical feature in the evolution of these more effective chiasma patterns is an increase in the effective distance of meiotic crossover interference, which plays a central role in crossover positioning. We discuss the findings in several organisms, including the recent identification of relevant genes in Arabidopsis arenosa, that support this hypothesis. PMID- 26753762 TI - Synthesis of aligned symmetrical multifaceted monolayer hexagonal boron nitride single crystals on resolidified copper. AB - Atomically smooth hexagonal boron nitride (h-BN) films are considered as a nearly ideal dielectric interface for two-dimensional (2D) heterostructure devices. Reported mono- to few-layer 2D h-BN films, however, are mostly small grain-sized, polycrystalline and randomly oriented. Here we report the growth of centimetre sized atomically thin h-BN films composed of aligned domains on resolidified Cu. The films consist of monolayer single crystalline triangular and hexagonal domains with size of up to ~10 MUm. The domains converge to symmetrical multifaceted shapes such as "butterfly" and "6-apex-star" and exhibit ~75% grain alignment for over millimetre distances as verified through transmission electron microscopy. Scanning electron microscopy images reveal that these domains are aligned for over centimetre distances. Defect lines are generated along the grain boundaries of mirroring h-BN domains due to the two different polarities (BN and NB) and edges with the same termination. The observed triangular domains with truncated edges and alternatively hexagonal domains are in accordance with Wulff shapes that have minimum edge energy. This work provides an extensive study on the aligned growth of h-BN single crystals over large distances and highlights the obstacles that are needed to be overcome for a 2D material with a binary configuration. PMID- 26753763 TI - Detection of hepatic maturation by Raman spectroscopy in mesenchymal stromal cells undergoing hepatic differentiation. AB - INTRODUCTION: Mesenchymal stromal cells (MSCs) are well known for their application potential in tissue engineering. We previously reported that MSCs are able to differentiate into hepatocytes in vitro. However, conventional methods for estimating the maturation of hepatic differentiation require relatively large amounts of cell samples. Raman spectroscopy (RS), a photonic tool for acquisition of cell spectra by inelastic scattering, has been recently used as a label-free single-cell detector for biological applications including phenotypic changes and differentiation of cells and diagnosis. In this study, RS is used to real-time monitor the maturation of hepatic differentiation in live MSCs. METHODS: The MSCs were cultured on the type I collagen pre-coating substrate and differentiated into hepatocytes in vitro using a two-step protocol. The Raman spectra at different time points are acquired in the range 400-3000 cm(-1)and analyzed by quantification methods and principle component analysis during hepatic differentiation from the MSCs. RESULTS: The intensity of the broad band in the range 2800-3000 cm(-1) reflects the amount of glycogen within lipochrome in differentiated hepatocytes. A high correlation coefficient between the glycogen amount and hepatic maturation was exhibited. Moreover, principle component analysis of the Raman spectra from 400 to 3000 cm(-1) indicated that MSC-derived hepatocytes were close to the primary hepatocytes and were distinct from the undifferentiated MSCs. CONCLUSIONS: In summary, RS can serve as a rapid, non invasive, real-time and label-free biosensor and reflects changes in live cell components during hepatic differentiation. The use of RS may thus facilitate the detection of hepatic differentiation and maturation in stem cells. Such an approach may substantially improve the feasibility as well as shorten the time required compared to the conventional molecular biology methods. PMID- 26753764 TI - Manipulation of charge transfer and transport in plasmonic-ferroelectric hybrids for photoelectrochemical applications. AB - Utilizing plasmonic nanostructures for efficient and flexible conversion of solar energy into electricity or fuel presents a new paradigm in photovoltaics and photoelectrochemistry research. In a conventional photoelectrochemical cell, consisting of a plasmonic structure in contact with a semiconductor, the type of photoelectrochemical reaction is determined by the band bending at the semiconductor/electrolyte interface. The nature of the reaction is thus hard to tune. Here instead of using a semiconductor, we employed a ferroelectric material, Pb(Zr,Ti)O3 (PZT). By depositing gold nanoparticle arrays and PZT films on ITO substrates, and studying the photocurrent as well as the femtosecond transient absorbance in different configurations, we demonstrate an effective charge transfer between the nanoparticle array and PZT. Most importantly, we show that the photocurrent can be tuned by nearly an order of magnitude when changing the ferroelectric polarization in PZT, demonstrating a versatile and tunable system for energy harvesting. PMID- 26753765 TI - Erratum to: KPT-330, a potent and selective exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and survivin in prostate cancer models. PMID- 26753766 TI - Association Between Helicobacter pylori Infection and Risk of Periodontal Diseases in Han Chinese: A Case-Control Study. AB - BACKGROUND: This study was performed to test the association between Helicobacter pylori (HP) and periodontal disease (PD). MATERIAL/METHODS: This was a case control study in a comprehensive hospital, including all patients with newly diagnosed PD between 2012 and 2014 as cases and all patients without PD as controls, thorough periodontal examinations. Those who tested positive for HP were examined by means of polymerase chain reaction. Single and multivariate logistic regression was used to analyze the data using SPSS 19.0 software. RESULTS: This case-control study included 212 Han Chinese non-smoking adults. The results indicated that HP-positive status significantly increased the risk of PD (2.63 times higher (odds ratio [OR]=2.63; 95% confidence interval [CI]=1.48 4.67). After adjustment for age, sex, level of education, physical exercise, body mass index, and history of alcohol and diabetes mellitus, this association remained significantly (OR=2.82, 95% CI=1.55-5.13). CONCLUSIONS: PD might be associated with HP infection in adults and HP infection may be a significant and independent risk factor for PD. PMID- 26753767 TI - A survey of study participants' understanding of informed consent to participate in a randomised controlled trial of acupuncture. AB - BACKGROUND: It is important that potential study participants are appropriately informed and understand what is involved with their research participation. A few studies have examined study participants' understanding of the informed consent process and the adequacy of the information they received when agreeing to participate in a randomised controlled trial. Deficiencies in the consent process have been found. This topic remains an under researched area of acupuncture research. The aim of this study was to examine participants' understanding of their informed consent and the adequacy of the information presented when agreeing to participate in a randomised controlled trial of acupuncture. METHODS: All women who participated in a randomised controlled trial over an 11 month period were invited to participate in a survey. An anonymous self-completion questionnaire was designed and covered participants' understanding of informed consent in the clinical trial, their views of the information provided, the opportunity to ask questions, the use of sham acupuncture, their recall of study visits and processes for withdrawal, and their reason for participating in the trial. RESULTS: A response rate of 59% was obtained. Over 90% of subjects indicated there was plenty of opportunity to discuss the study prior to giving consent, and 89% indicated that questions asked were answered to their satisfaction. The majority of women indicated the amount of information describing acupuncture was about right, however 24% would have liked more. Information describing sham acupuncture was not considered adequate by 48% of women, and 35% would have liked more information, 30% could not recall why, or were uncertain why a sham group was used. Participants indicated less understanding of the information relating to payment if they became ill due to study participation, risks and discomforts from the study interventions, which of the procedures were experimental and for how long they would be involved in the study. CONCLUSION: Trial participants' understanding of informed consent was overall satisfactory but highlighted some areas of deficiency. Future studies could consider use of supplementary material such as Q and A fact sheets. PMID- 26753769 TI - Structure/function relationship between wide-scan binocular OCT images and the integrated visual field in glaucoma patients. PMID- 26753770 TI - Aspirin for the Primary Prevention of Cardiovascular Disease: In Need of Clarity. AB - Aspirin remains one of the most extensively studied cardiovascular medications in the history of medicine. However, despite multiple, well-designed, large randomized controlled trials evaluating the potential of aspirin to prevent cardiovascular events in individuals without known cardiovascular disease (CVD), the role of aspirin in primary prevention is currently unclear. The initial aspirin trials included largely low-risk individuals with primary outcomes mostly focused on myocardial infarction (MI) and stroke, and showed a significant reduction in these CVD outcomes, especially MI. The more recently conducted trials have focused on older, higher CVD risk populations with high rates of lipid-lowering and antihypertensive medications use. These studies have used broader CVD outcomes as their primary end points and have failed to show a significant benefit of aspirin therapy in primary prevention. The exact reasons for the lack of efficacy in these recent trials are unclear but may be related to low rate of atherothrombotic events relative to other CVD events in the populations studied. Four large randomized controlled trials are currently underway which should provide some clarity in determining the optimal use of aspirin in the primary prevention of CVD. PMID- 26753771 TI - Dual Antiplatelet Therapy in Patients with Stable Ischemic Heart Disease. AB - Dual antiplatelet therapy (DAPT) is the use of a P2Y12 receptor antagonist (clopidogrel, prasugrel, or ticagrelor) in combination with aspirin. Recommendations for its use are primarily in patients who have experienced acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) in the preceding 12 months. There is a growing body of evidence, however, investigating the use of long-duration DAPT in patients with stable ischemic heart disease (SIHD). SIHD is defined as clinical evidence of ischemic heart disease, without an ACS event in the preceding 12 months, and includes patients with stable angina, elective PCI, and remote history of ACS. The use of DAPT in the SIHD population and the recent advancements in our understanding of its use are the focus of this review. PMID- 26753772 TI - Emergence of a super-synchronized mobbing state in a large population of coupled chemical oscillators. AB - Oscillatory phenomena are ubiquitous in Nature. The ability of a large population of coupled oscillators to synchronize constitutes an important mechanism to express information and establish communication among members. To understand such phenomena, models and experimental realizations of globally coupled oscillators have proven to be invaluable in settings as varied as chemical, biological and physical systems. A variety of rich dynamical behavior has been uncovered, although usually in the context of a single state of synchronization or lack thereof. Through the experimental and numerical study of a large population of discrete chemical oscillators, here we report on the unexpected discovery of a new phenomenon revealing the existence of dynamically distinct synchronized states reflecting different degrees of communication. Specifically, we discover a novel large-amplitude super-synchronized state separated from the conventionally reported synchronized and quiescent states through an unusual sharp jump transition when sampling the strong coupling limit. Our results assume significance for further elucidating globally coherent phenomena, such as in neuropathologies, bacterial cell colonies, social systems and semiconductor lasers. PMID- 26753773 TI - Nitrogen-Doped Porous Carbon Superstructures Derived from Hierarchical Assembly of Polyimide Nanosheets. AB - 3D carbon superstructures are fabricated through the hierarchical assembly of polyimide nanosheets and thermal treatment. Benefiting from the ultrahigh surface area and the hierarchically porous structure, along with the well-distributed highly electroactive sites, the flower-like carbon material exhibits outstanding catalytic activity toward the oxygen reduction reaction and also serves as a highly stable electrode material in supercapacitors. PMID- 26753774 TI - Simeprevir with pegylated interferon alfa 2a plus ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a meta-analysis and historical comparison. AB - BACKGROUND: About one third of patients infected with human immunodeficiency virus (HIV) also have chronic hepatitis due to hepatitis C virus (HCV). HCV therapy with simeprevir, pegylated interferon alfa (PegIFNalpha) and ribavirin (RBV) have been shown to be superior to PegIFNalpha + RBV alone in non-HIV patients, but no randomized trials in patients with HCV genotype 1 (HCV-1)/HIV coinfection are available. METHODS: This was a historical comparison of study C212 (simeprevir + PegIFNalpha-2a + RBV in patients with HCV-1/HIV coinfection) with studies in which HCV-1/HIV coinfected patients were treated with PegIFNalpha 2a + RBV alone. A systematic literature search was performed to identify eligible studies. Efficacy and safety results of PegIFNalpha-2a + RBV studies were combined in random- and fixed-effects inverse-variance weighted meta-analyses of proportions using the Freeman-Tukey double arcsin transformation method, and compared with the results of study C212. RESULTS: The literature search revealed a total of 2392 records, with 206 articles selected for full-text review. Finally, 11 relevant articles reporting on 12 relevant study groups were included. Results on sustained virologic response 24 weeks after end of treatment (SVR24) were available from all 12 study groups. Pooled SVR24 for PegIFNalpha-2a + RBV from the random-effects meta-analysis was 28.2% (95% CI 23.8% to 32.9%). The comparison between study C212 (SVR24 = 72.6%; 95% CI 63.1% to 80.9%) revealed substantial superiority of simeprevir + PegIFNalpha-2a + RBV compared to PegIFNalpha-2a + RBV alone, with an absolute risk difference of 45% (95% CI 34 to 55). This finding was robust in a sensitivity analysis that only included historical studies with a planned treatment duration of at least 48 weeks and the same RBV dose as in study C212. No increases in the frequency of important adverse event categories including anemia were identified, but these analyses were limited by the low number of studies. CONCLUSION: This historical comparison provides first systematic evidence for the superiority of simeprevir + PegIFNalpha-2a + RBV compared to PegIFNalpha-2a + RBV in patients with HCV-1/HIV coinfection. Given the limitations of the historical comparison for safety endpoints, additional data on the comparative safety of simeprevir in patients with HCV-1/HIV coinfection would be desirable. TRIAL REGISTRATION: Identifier for study TMC435-TiDP16-C212 (ClinicalTrials.gov): NCT01479868. PMID- 26753775 TI - Implantable neurotechnologies: electrical stimulation and applications. AB - Neural stimulation using injected electrical charge is widely used both in functional therapies and as an experimental tool for neuroscience applications. Electrical pulses can induce excitation of targeted neural pathways that aid in the treatment of neural disorders or dysfunction of the central and peripheral nervous system. In this review, we summarize the recent trends in the field of electrical stimulation for therapeutic interventions of nervous system disorders, such as for the restoration of brain, eye, ear, spinal cord, nerve and muscle function. Neural prosthetic applications are discussed, and functional electrical stimulation parameters for treating such disorders are reviewed. Important considerations for implantable packaging and enhancing device reliability are also discussed. Neural stimulators are expected to play a profound role in implantable neural devices that treat disorders and help restore functions in injured or disabled nervous system. PMID- 26753779 TI - Unusual clinical manifestations of rubella in the elderly. PMID- 26753778 TI - Dialogue enabling speech-to-text user assistive agent system for hearing-impaired person. AB - A novel approach for assisting bidirectional communication between people of normal hearing and hearing-impaired is presented. While the existing hearing impaired assistive devices such as hearing aids and cochlear implants are vulnerable in extreme noise conditions or post-surgery side effects, the proposed concept is an alternative approach wherein spoken dialogue is achieved by means of employing a robust speech recognition technique which takes into consideration of noisy environmental factors without any attachment into human body. The proposed system is a portable device with an acoustic beamformer for directional noise reduction and capable of performing speech-to-text transcription function, which adopts a keyword spotting method. It is also equipped with an optimized user interface for hearing-impaired people, rendering intuitive and natural device usage with diverse domain contexts. The relevant experimental results confirm that the proposed interface design is feasible for realizing an effective and efficient intelligent agent for hearing-impaired. PMID- 26753780 TI - Geometric effects in microfluidics on heterogeneous cell stress using an Eulerian Lagrangian approach. AB - The response of individual cells at the micro-scale in cell mechanics is important in understanding how they are affected by changing environments. To control cell stresses, microfluidics can be implemented since there is tremendous control over the geometry of the devices. Designing microfluidic devices to induce and manipulate stress levels on biological cells can be aided by computational modeling approaches. Such approaches serve as an efficient precursor to fabricating various microfluidic geometries that induce predictable levels of stress on biological cells, based on their mechanical properties. Here, a three-dimensional, multiphase computational fluid dynamics (CFD) modeling approach was implemented for soft biological materials. The computational model incorporates the physics of the particle dynamics, fluid dynamics and solid mechanics, which allows us to study how stresses affect the cells. By using an Eulerian-Lagrangian approach to treat the fluid domain as a continuum in the microfluidics, we are conducting studies of the cells' movement and the stresses applied to the cell. As a result of our studies, we were able to determine that a channel with periodically alternating columns of obstacles was capable of stressing cells at the highest rate, and that microfluidic systems can be engineered to impose heterogenous cell stresses through geometric configuring. We found that when using controlled geometries of the microfluidics channels with staggered obstructions, we could increase the maximum cell stress by nearly 200 times over cells flowing through microfluidic channels with no obstructions. Incorporating computational modeling in the design of microfluidic configurations for controllable cell stressing could help in the design of microfludic devices for stressing cells such as cell homogenizers. PMID- 26753776 TI - Implantable neurotechnologies: bidirectional neural interfaces--applications and VLSI circuit implementations. AB - A bidirectional neural interface is a device that transfers information into and out of the nervous system. This class of devices has potential to improve treatment and therapy in several patient populations. Progress in very large scale integration has advanced the design of complex integrated circuits. System on-chip devices are capable of recording neural electrical activity and altering natural activity with electrical stimulation. Often, these devices include wireless powering and telemetry functions. This review presents the state of the art of bidirectional circuits as applied to neuroprosthetic, neurorepair, and neurotherapeutic systems. PMID- 26753781 TI - The latent class twin method. AB - The twin method refers to the use of data from same-sex identical and fraternal twins to estimate the genetic and environmental contributions to a trait or outcome. The standard twin method is the variance component twin method that estimates heritability, the fraction of variance attributed to additive genetic inheritance. The latent class twin method estimates two quantities that are easier to interpret than heritability: the genetic prevalence, which is the fraction of persons in the genetic susceptibility latent class, and the heritability fraction, which is the fraction of persons in the genetic susceptibility latent class with the trait or outcome. We extend the latent class twin method in three important ways. First, we incorporate an additive genetic model to broaden the sensitivity analysis beyond the original autosomal dominant and recessive genetic models. Second, we specify a separate survival model to simplify computations and improve convergence. Third, we show how to easily adjust for covariates by extending the method of propensity scores from a treatment difference to zygosity. Applying the latent class twin method to data on breast cancer among Nordic twins, we estimated a genetic prevalence of 1%, a result with important implications for breast cancer prevention research. PMID- 26753777 TI - Implantable neurotechnologies: a review of micro- and nanoelectrodes for neural recording. AB - Electrodes serve as the first critical interface to the biological organ system. In neuroprosthetic applications, for example, electrodes interface to the tissue for either signal recording or tissue stimulation. In this review, we consider electrodes for recording neural activity. Recording electrodes serve as wiretaps into the neural tissues, providing readouts of electrical activity. These signals give us valuable insights into the organization and functioning of the nervous system. The recording interfaces have also shown promise in aiding treatment of motor and sensory disabilities caused by neurological disorders. Recent advances in fabrication technology have generated wide interest in creating tiny, high density electrode interfaces for neural tissues. An ideal electrode should be small enough and be able to achieve reliable and conformal integration with the structures of the nervous system. As a result, the existing electrode designs are being shrunk and packed to form small form factor interfaces to tissue. Here, an overview of the historic and state-of-the-art electrode technologies for recording neural activity is presented first with a focus on their development road map. The fact that the dimensions of recording electrode sites are being scaled down from micron to submicron scale to enable dense interfaces is appreciated. The current trends in recording electrode technologies are then reviewed. Current and future considerations in electrode design, including the use of inorganic nanostructures and biologically inspired or biocomapatible materials are discussed, along with an overview of the applications of flexible materials and transistor transduction schemes. Finally, we detail the major technical challenges facing chronic use of reliable recording electrode technology. PMID- 26753782 TI - Integrating Competition for Food, Hosts, or Mates via Experimental Evolution. AB - Competitive interactions shape the evolution of organisms. However, often it is not clear whether competition is the driving force behind the patterns observed. The recent use of experimental evolution in competitive environments can help establish such causality. Unfortunately, this literature is scattered, as competition for food, mates, and hosts are subject areas that belong to different research fields. Here, we group these bodies of literature, extract common processes and patterns concerning the role of competition in shaping evolutionary trajectories, and suggest perspectives stemming from an integrative view of competition across these research fields. This review reinstates the power of experimental evolution in addressing the evolutionary consequences of competition, but highlights potential pitfalls in the design of such experiments. PMID- 26753783 TI - Resilience in the Studies of Biodiversity-Ecosystem Functioning. PMID- 26753784 TI - China's Degraded Environment Enters A New Normal. AB - China is undergoing unprecedented social and ecological shifts, a harbinger of similar changes that will unfold in developing nations over coming decades. Many of China's degraded environments represent a new normal. Acknowledging this reality will allow societies to make informed decisions that recognize the undervalued costs of environment degradation. PMID- 26753785 TI - Catch bond interaction allows cells to attach to strongly hydrated interfaces. AB - Hyaluronans are a class of glycosaminoglycans that are widespread in the mammalian body and serve a variety of functions. Their most striking characteristic is their pronounced hydrophilicity and their capability to inhibit unspecific adhesion when present at interfaces. Catch-bond interactions are used by the CD44 receptor to interact with this inert material and to roll on the surfaces coated with hyaluronans. In this minireview, the authors discuss the general properties of hyaluronans and the occurrence and relevance of the CD44 catch-bond interaction in the context of hematopoiesis, cancer development, and leukemia. PMID- 26753786 TI - How specific halide adsorption varies hydrophobic interactions. AB - Hydrophobic interactions (HI) are driven by the water structure around hydrophobes in aqueous electrolytes. How water structures at hydrophobic interfaces and how this influences the HI was subject to numerous studies. However, the effect of specific ion adsorption on HI and hydrophobic interfaces remains largely unexplored or controversial. Here, the authors utilized atomic force microscopy force spectroscopy at well-defined nanoscopic hydrophobic interfaces to experimentally address how specific ion adsorption of halide ions as well as NH4 (+), Cs(+), and Na(+) cations alters interaction forces across hydrophobic interfaces. Our data demonstrate that iodide adsorption at hydrophobic interfaces profoundly varies the hydrophobic interaction potential. A long-range and strong hydration repulsion at distances D > 3 nm, is followed by an instability which could be explained by a subsequent rapid ejection of adsorbed iodides from approaching hydrophobic interfaces. In addition, the authors find only a weakly pronounced influence of bromide, and as expected no influence of chloride. Also, all tested cations do not have any significant influence on HI. Complementary, x-ray photoelectron spectroscopy and quartz crystal-microbalance with dissipation monitoring showed a clear adsorption of large halide ions (Br(-)/I(-)) onto hydrophobic self-assembled monolayers (SAMs). Interestingly, iodide can even lead to a full disintegration of SAMs due to specific and strong interactions of iodide with gold. Our data suggest that hydrophobic surfaces are not intrinsically charged negatively by hydroxide adsorption, as it was generally believed. Hydrophobic surfaces rather interact strongly with negatively charged large halide ions, leading to a surface charging and significant variation of interaction forces. PMID- 26753787 TI - Mass spectrometric profiling of lipids in intestinal tissue from rats fed cereals processed for medical conditions. AB - Time-of-flight secondary ion mass spectrometry (ToF-SIMS) was used for lipid profiling of intestine tissue sections from rats fed specially processed cereals and rats fed ordinary feed as a control. This cereal is known to increase the activity of antisecretory factor in plasma and the exact mechanism for the activation process at the cellular level is unclear. ToF-SIMS has been used to track food induced changes in lipid content in intestinal tissue sections to gain insight into the possible mechanisms involved. Data from 20 intestine sections belonging to four different rats from each group of control and specially processed cereals-fed rats were obtained using the stage scan macroraster with a lateral resolution of 5 MUm. Data were subsequently subjected to orthogonal partial least squares discriminant analysis. The data clearly show that changes of certain lipids are induced by the specially processed cereal feed. Scores plots show a well-defined separation between the two groups. The corresponding loading plots reveal that the groups separate mainly due to changes of vitamin E, phosphocholine, and phosphosphingolipid fragments, and that for the c18:2 fatty acid. The observed changes in lipids might give insight into the working mechanisms of antisecretory factor in the body, and this has been successfully used to understand the working mechanism of specially processed cereal-induced antisecretory factor activation in intestine. PMID- 26753788 TI - Enhanced air pollution via aerosol-boundary layer feedback in China. AB - Severe air pollution episodes have been frequent in China during the recent years. While high emissions are the primary reason for increasing pollutant concentrations, the ultimate cause for the most severe pollution episodes has remained unclear. Here we show that a high concentration of particulate matter (PM) will enhance the stability of an urban boundary layer, which in turn decreases the boundary layer height and consequently cause further increases in PM concentrations. We estimate the strength of this positive feedback mechanism by combining a new theoretical framework with ambient observations. We show that the feedback remains moderate at fine PM concentrations lower than about 200 MUg m(-3), but that it becomes increasingly effective at higher PM loadings resulting from the combined effect of high surface PM emissions and massive secondary PM production within the boundary layer. Our analysis explains why air pollution episodes are particularly serious and severe in megacities and during the days when synoptic weather conditions stay constant. PMID- 26753789 TI - Women's health in the Lund area (WHILA)--Alcohol consumption and all-cause mortality among women--a 17 year follow-up study. AB - BACKGROUND: Alcohol consumption contributes to many negative health consequences and is a risk factor for death. Some previous studies however suggest a J-shaped relationship between the level of alcohol consumption and all-cause mortality. These findings have in part been suggested to be due to confounders. The aim of our study was to analyze the relationship between self-reported alcohol intake and all-cause mortality in women, adjusted for sociodemographic, lifestyle factors and diseases such as diabetes and previous ischemic heart disease. METHODS: All women aged 50-59 years (born between 1935 and 1945) that lived in any of the five municipalities in southern Sweden were invited to participate in a health survey. From December 1995 to February 2000 a total of 6916 women (out of 10,766, the total population of women in 1995) underwent a physical examination and answered a questionnaire. We followed the women from the day of screening until death, or if no event occurred until May 31st 2015. Mortality was ascertained through the national cause-of-death register. RESULTS: In this study a total of 6353 women were included. Alcohol consumption showed a J-formed relationship with mortality, when adjusted for education, marital status, smoking, BMI, physical fitness, diabetes and ischemic heart disease before screening. Non consumption of alcohol was associated with increased mortality as well as higher levels of consumption, from 12 grams per day and upwards. CONCLUSIONS: There was a clear J-shaped relation between the amount of alcohol consumption and all-cause mortality even after controlling for sociodemography, lifestyle factors and diseases such as diabetes and previous ischemic heart disease. The observed protective effect of light drinking (1-12 grams/day) could thus not be attributed to any of these known confounders. PMID- 26753790 TI - Novel role for anti-Mullerian hormone in the regulation of GnRH neuron excitability and hormone secretion. AB - Anti-Mullerian hormone (AMH) plays crucial roles in sexual differentiation and gonadal functions. However, the possible extragonadal effects of AMH on the hypothalamic-pituitary-gonadal axis remain unexplored. Here we demonstrate that a significant subset of GnRH neurons both in mice and humans express the AMH receptor, and that AMH potently activates the GnRH neuron firing in mice. Combining in vivo and in vitro experiments, we show that AMH increases GnRH dependent LH pulsatility and secretion, supporting a central action of AMH on GnRH neurons. Increased LH pulsatility is an important pathophysiological feature in many cases of polycystic ovary syndrome (PCOS), the most common cause of female infertility, in which circulating AMH levels are also often elevated. However, the origin of this dysregulation remains unknown. Our findings raise the intriguing hypothesis that AMH-dependent regulation of GnRH release could be involved in the pathophysiology of fertility and could hold therapeutic potential for treating PCOS. PMID- 26753793 TI - Theoretical insights into the photo-protective mechanisms of natural biological sunscreens: building blocks of eumelanin and pheomelanin. AB - Eumelanin (EM) and pheomelanin (PM) are ubiquitous in mammalian skin and hair- protecting against harmful radiation from the sun. Their primary roles are to absorb solar radiation and efficiently dissipate the excess excited state energy in the form of heat without detriment to the polymeric structure. EU and PM exist as polymeric chains consisting of exotic arrangements of functionalised heteroaromatic molecules. Here we have used state-of-the-art electronic structure calculations and on-the-fly surface hopping molecular dynamics simulations to study the intrinsic deactivation paths of various building blocks of EU and PM. Ultrafast excited state decay, via electron-driven proton transfer (in EU and PM) and proton-transfer coupled ring-opening (in PM) reactions, have been identified to proceed along hitherto unknown charge-separated states in EU and PM oligomers. These results shed light on the possible relaxation pathways that dominate the photochemistry of natural skin melanins. Extrapolation of such findings could provide a gateway into engineering more effective molecular constituents in commercial sunscreens--with reduced phototoxicity. PMID- 26753791 TI - Patient-, organization-, and system-level barriers and facilitators to preventive oral health care: a convergent mixed-methods study in primary dental care. AB - BACKGROUND: Dental caries is the most common chronic disease of adult and childhood, a largely preventable yet widespread, costly public health problem. This study identified patient-, organization-, and system-level factors influencing routine delivery of recommended care for prevention and management of caries in primary dental care. METHODS: A convergent mixed-methods design assessed six guidance-recommended behaviours to prevent and manage caries (recording risk, risk-based recall intervals, applying fluoride varnish, placing preventive fissure sealants, demonstrating oral health maintenance, taking dental x-rays). A diagnostic questionnaire assessing current practice, beliefs, and practice characteristics was sent to a random sample of 651 dentists in National Health Service (NHS) Scotland. Eight in-depth case studies comprising observation of routine dental visits and dental team member interviews were conducted. Patient feedback was collected from adult patients with recent checkups at case study practices. Key informant interviews were conducted with decision makers in policy, funding, education, and regulation. The Theoretical Domains Framework within the Behaviour Change Wheel was used to identify and describe patient-, organization-, and system-level barriers and facilitators to care. Findings were merged into a matrix describing theoretical domains salient to each behaviour. The matrix and Behaviour Change Wheel were used to prioritize behaviours for change and plan relevant intervention strategies. RESULTS: Theoretical domains associated with best practice were identified from the questionnaire (N-196), case studies (N = 8 practices, 29 interviews), and patient feedback (N = 19). Using the study matrix, key stakeholders identified priority behaviours (use of preventive fissure sealants among 6-12-year-olds) and strategies (audit and feedback, patient informational campaign) to improve guidance implementation. Proposed strategies were assessed as appropriate for immediate implementation and suitable for development with remaining behaviours. CONCLUSIONS: Specific, theoretically based, testable interventions to improve caries prevention and management were coproduced by patient-, practice-, and policy-level stakeholders. Findings emphasize duality of behavioural determinants as barriers and facilitators, patient influence on preventive care delivery, and benefits of integrating multi-level interests when planning interventions in a dynamic, resource-constrained environment. Interventions identified in this study are actively being used to support ongoing implementation initiatives including guidance, professional development, and oral health promotion. PMID- 26753794 TI - Characterization and putative post-translational regulation of alpha- and beta tubulin gene families in Salix arbutifolia. AB - Microtubules, which are composed of heterodimers of alpha-tubulin (TUA) and beta tubulin (TUB) proteins, are closely associated with cellulose microfibril deposition and play pivotal roles in plant secondary cell wall development. In the present study, we identified eight TUA and twenty TUB genes in willow (Salix arbutifolia). Quantitative real-time PCR analysis showed that the small number of TUA gene family members relative to that of TUBs was complemented by a higher transcript copy number for each TUA gene, which is essential to the maintenance of the tubulin 1:1 heterodimer assembly. In Salix, five of eight TUAs were determined to be unusual because these contained a C-terminal methionine acid, leucine acid, glutamic acid, and glutamine acid, instead of the more typical tyrosine residue, which in turn generated the hypothesis of post-translational modifications (PTMs) that included deleucylation, demethiolation, deglutamynation, and deaspartylation. These PTMs are responsible for the removal of additional amino acid residues from TUAs prior to detyrosination, which is the first step of C-terminal PTMs. The additional PTMs of the TUA gene family might be responsible for the formation of different tubulin heterodimers that may have diverse functions for the adaptation of the woody perennial growth for Salix. PMID- 26753795 TI - Hierarchical Sheet-on-Sheet ZnIn2S4/g-C3N4 Heterostructure with Highly Efficient Photocatalytic H2 production Based on Photoinduced Interfacial Charge Transfer. AB - We have realized in-situ growth of ultrathin ZnIn2S4 nanosheets on the sheet-like g-C3N4 surfaces to construct a "sheet-on-sheet" hierarchical heterostructure. The as-synthesized ZnIn2S4/g-C3N4 heterojunction nanosheets exhibit remarkably enhancement on the photocatalytic activity for H2 production. This enhanced photoactivity is mainly attributed to the efficient interfacial transfer of photoinduced electrons and holes from g-C3N4 to ZnIn2S4 nanosheets, resulting in the decreased charge recombination on g-C3N4 nanosheets and the increased amount of photoinduced charge carriers in ZnIn2S4 nanosheets. Meanwhile, the increased surface-active-sites and extended light absorption of g-C3N4 nanosheets after the decoration of ZnIn2S4 nanosheets may also play a certain role for the enhancement of photocatalytic activity. Further investigations by the surface photovoltage spectroscopy and transient photoluminescence spectroscopy demonstrate that ZnIn2S4/g-C3N4 heterojunction nanosheets considerable boost the charge transfer efficiency, therefore improve the probability of photoinduced charge carriers to reach the photocatalysts surfaces for highly efficient H2 production. PMID- 26753792 TI - A prospective, longitudinal study of sleep disturbance and comorbidity in opiate dependence (the ANRS Methaville study). AB - RATIONALE/OBJECTIVES: Sleep disturbance is frequent in opioid-dependent patients. To date, no data are available about the impact of methadone maintenance treatment on sleep disturbance. Using 1-year follow-up data from the Methaville trial, we investigated the impact of methadone initiation and other correlates on sleep disturbance in opioid-dependent patients. METHODS: Sleep disturbance severity was evaluated using two items from different scales (Center for Epidemiological Studies Depression Scale for depression and Opiate Treatment Index). We assessed the effect of methadone and other correlates on sleep disturbance severity during follow-up (months 0, 6, and 12) using a mixed multinomial logistic regression model. RESULTS: We included 173 patients who had 1-year follow-up data on sleep disturbance, corresponding to 445 visits. At enrolment, 60.5 % reported medium to severe sleep disturbance. This proportion remained stable during methadone treatment: 54.0 % at month 6 and 55.4 % at month 12. The final multivariate model indicated that younger patients (odds ratio (OR) [95 % CI] 0.95 [0.90-1.00]), patients with pain (OR [95 % CI] 2.45 [1.13-5.32]), patients with high or very high nicotine dependence (OR [95 % CI] 5.89 [2.41 14.39]), and patients at suicidal risk (2.50 [1.13-5.52]) had a higher risk of severe sleep disturbance. Because of collinearity between suicidal risk and attention deficit hyperactivity disorder (ADHD) symptoms, ADHD was not associated with sleep disturbance in the final model. Receiving methadone treatment had no significant effect on sleep disturbance. CONCLUSIONS: Sleep disturbance is frequent among opioid-dependent patients. It can be regarded as an important signal of more complex psychiatric comorbidities such as suicidal risk and ADHD. However, sleep disturbance should not be considered an obstacle to methadone maintenance treatment (MMT) initiation or continuation. PMID- 26753796 TI - The Ebola Virus matrix protein, VP40, requires phosphatidylinositol 4,5 bisphosphate (PI(4,5)P2) for extensive oligomerization at the plasma membrane and viral egress. AB - VP40 is one of eight proteins encoded by the Ebola Virus (EBOV) and serves as the primary matrix protein, forming virus like particles (VLPs) from mammalian cells without the need for other EBOV proteins. While VP40 is required for viral assembly and budding from host cells during infection, the mechanisms that target VP40 to the plasma membrane are not well understood. Phosphatidylserine is required for VP40 plasma membrane binding, VP40 hexamer formation, and VLP egress, However, PS also becomes exposed on the outer membrane leaflet at sites of VP40 budding, raising the question of how VP40 maintains an interaction with the plasma membrane inner leaflet when PS is flipped to the opposite side. To address this question, cellular and in vitro assays were employed to determine if phosphoinositides are important for efficient VP40 localization to the plasma membrane. Cellular studies demonstrated that PI(4,5)P2 was an important component of VP40 assembly at the plasma membrane and subsequent virus like particle formation. Additionally, PI(4,5)P2 was required for formation of extensive oligomers of VP40, suggesting PS and PI(4,5)P2 have different roles in VP40 assembly where PS regulates formation of hexamers from VP40 dimers and PI(4,5)P2 stabilizes and/or induces extensive VP40 oligomerization at the plasma membrane. PMID- 26753797 TI - Rye and Wheat Bran Extracts Isolated with Pressurized Solvents Increase Oxidative Stability and Antioxidant Potential of Beef Meat Hamburgers. AB - Rye and wheat bran extracts containing phenolic compounds and demonstrating high DPPH* (2,2-diphenyl-1-picrylhydrazyl), ABTS(*+) (2,2'-azino-bis(3 ethylbenzthiazoline-6-sulphonic acid) scavenging and oxygen radical absorbance capacities (ORAC) were tested in beef hamburgers as possible functional ingredients. Bran extracts significantly increased the indicators of antioxidant potential of meat products and their global antioxidant response (GAR) during physiological in vitro digestion. The extracts also inhibited the formation of oxidation products, hexanal and malondialdehyde, of hamburgers during their storage; however, they did not have significant effect on the growth of microorganisms. Hamburgers with 0.8% wheat bran extract demonstrated the highest antioxidant potential. Some effects of bran extracts on other quality characteristics such as pH, color, formation of metmyoglobin were also observed, however, these effects did not have negative influence on the overall sensory evaluation score of hamburgers. Consequently, the use of bran extracts in meat products may be considered as promising means of increasing oxidative product stability and enriching with functional ingredients which might possess health benefits. PMID- 26753798 TI - Lack of association between the Angiogenin (ANG) rs11701 polymorphism and amyotrophic lateral sclerosis risk: a meta-analysis. AB - To perform a meta-analysis to help resolve the controversy of whether the Angiogenin (ANG) rs11701 polymorphism is associated with amyotrophic lateral sclerosis (ALS) risk. A literature search of PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure, Wanfang and SinoMed was conducted for eligible studies published up to Jun 5, 2015. The strength of the association between the polymorphism and ALS susceptibility was estimated by odds ratio (OR) and associated 95 % confidence interval (CI). The pooled ORs were assessed for the dominant model (TG + GG vs. TT), recessive model (GG vs. TG + TT), heterozygote model (TG vs. TT), homozygote model (GG vs. TT) and allele model (G vs. T). Ten eligible articles were identified, which reported 14 case-control studies and a total of 5807 cases and 3861 controls. Analysis of pooled ORs and 95 % CIs suggested lack of association between the ANG rs11701 polymorphism and risk for ALS, Familial ALS or Sporadic ALS (all p value for z test >0.05). A stratified analysis according to Caucasian or Han Chinese origin further showed that the rs11701 polymorphism was not associated with the disease risk in Caucasians or Han Chinese. There is no difference in the polymorphism frequencies between patients with FALS or SALS. The ANG rs11701 polymorphism was not associated with risk for ALS, FALS or SALS. There is no difference between the polymorphism frequencies in patients with FALS or SALS. Further well-designed studies with larger populations are required to validate these results. PMID- 26753799 TI - Cauda equina syndrome due to large B-cell lymphoma: a case report. PMID- 26753800 TI - The relation of serum uric acid levels with L-Dopa treatment and progression in patients with Parkinson's disease. AB - In this study, we aimed to investigate the association of the serum uric acid (UA) level with disease progression and L-Dopa treatment in PD (Parkinson's disease) patients. Serum UA levels of 80 consecutive PD patients were measured and were matched according to age and sex with 80 healthy controls. The patients were divided into two subgroups according to the pharmaceutical treatment received. First group consisted of patients treated with L-Dopa and a dopamine agonist and the second group consisted of patients treated only with a dopamine agonist. The patients were divided into two other subgroups according to Hoehn and Yahr scale. First group consisted of patients at the first two stages and the second group included patients at the third and upper stages. PD patients were found to have significantly lower levels of serum UA than controls (p = 0.000). Serum UA levels were lower in the group under L-Dopa + dopamine agonist treatment and in patients at third and upper Hoehn and Yahr stages than the patients under only dopamine agonist treatment and in the patients at the first two stages (p = 0.000 and p = 0.000). Multivariate logistic regression showed that advanced stages (OR 0.65, CI 0.50-0.79, p = 0.000) and L-Dopa treatment (OR 1.08, CI 1.03 1.16, p = 0.001) were independently associated with low UA levels. Our study supports that there is an inverse relation between UA levels and L-Dopa treatment and PD stages, and high serum UA levels may decrease the oxidative stress taking part in the pathogenesis of PD. PMID- 26753801 TI - Developing and assessing the utility of a You-Tube based clinical genetics video channel for families affected by inherited tumours. AB - We have designed and implemented the first worldwide You Tube channel with 22 videos covering common questions asked in familial cancer susceptibility clinics. We discuss the use of the videos including demographics of registered You Tube users, and what lessons have been learnt about how the general public uses medical information online. The most popular video on inheritance patterns has been watched on average 84 times per month. The mostly highly viewed videos include inheritance patterns, breast cancer screening and hereditary non polyposis colorectal cancer. Registered viewers were more commonly male and the average age of the registered user was 45-54 years; similar to that seen in Genetics Clinics suggesting that age may not be a major barrier to access to this type of information for patients. The videos have been viewed in more than 140 countries confirming that there is clearly an audience for this type of information. Patient feedback questionnaires indicate that these videos provide a useful aide memoir for the clinic appointment, and most people would recommend them to others. In summary, You Tube videos are easy and cost effective to make. They have the ability to disseminate genetics education to a worldwide audience and may be a useful adjunct to clinical appointments. PMID- 26753802 TI - Scalable and Cost-Effective Synthesis of Highly Efficient Fe2N-Based Oxygen Reduction Catalyst Derived from Seaweed Biomass. AB - A simple and scalable synthesis of a 3D Fe2N-based nanoaerogel is reported with superior oxygen reduction reaction activity from waste seaweed biomass, addressed the growing energy scarcity. The merits are due to the synergistic effect of the 3D porous hybrid aerogel support with excellent electrical conductivity, convenient mass transport and O2 adsorption, and core/shell structured Fe2N/N doped amorphous carbon nanoparticles. PMID- 26753803 TI - Older Adults' Acceptance of Activity Trackers. AB - OBJECTIVE: To assess the usability and acceptance of activity tracking technologies by older adults. METHOD: First in our multimethod approach, we conducted heuristic evaluations of two activity trackers that revealed potential usability barriers to acceptance. Next, questionnaires and interviews were administered to 16 older adults ( Mage = 70, SDage = 3.09, rangeage = 65-75) before and after a 28-day field study to understand facilitators and additional barriers to acceptance. These measurements were supplemented with diary and usage data and assessed whether and why users overcame usability issues. RESULTS: The heuristic evaluation revealed usability barriers in System Status Visibility, Error Prevention, and Consistency and Standards. The field study revealed additional barriers (e.g., accuracy, format) and acceptance-facilitators (e.g., goal tracking, usefulness, encouragement). DISCUSSION: The acceptance of wellness management technologies, such as activity trackers, may be increased by addressing acceptance-barriers during deployment (e.g., providing tutorials on features that were challenging, communicating usefulness). PMID- 26753805 TI - The participant's perspective: learning from an aggression management training course for nurses. Insights from a qualitative interview study. AB - BACKGROUND: Aggression management training for nurses is an important part of a comprehensive strategy to reduce patient and visitor aggression in healthcare. Although training is commonplace, few scientific studies examine its benefits. AIM: To explore and describe, from a nurse's perspective, the learning gained from attending aggression management training. DESIGN AND METHODS: This was a descriptive qualitative interview study. We conducted semi-structured individual interviews with seven nurses before (September/October 2012) and after they attended aggression management training (January/February 2013). Interview transcripts were content-analysed qualitatively. ETHICAL ISSUES: The study plan was reviewed by the responsible ethics committees. Participants gave written informed consent. FINDINGS: Aggression management training did not change nurses' attitude. Coping emotionally with the management of patient and visitor aggression remained a challenge. Nurses' theoretical knowledge increased, but they did not necessarily acquire new strategies for managing patient/visitor aggression. Instead, the course refreshed or activated existing knowledge of prevention, intervention and de-escalation strategies. The training increased nurses' environmental and situational awareness for early signs of patient and visitor. They also acquired some strategies for emotional self-management. Nurses became more confident in dealing with (potentially) aggressive situations. While the training influenced nurses' individual clinical practice, learning was rarely shared within teams. CONCLUSIONS: Aggression management training increases skills, knowledge and confidence in dealing with patient or visitor aggression, but the emotional management remains a challenge. Future research should investigate how aggression management training courses can strengthen nurses' ability to emotionally cope with patient and visitor aggression. More knowledge is needed on how the theoretical and practical knowledge gained from the training may be disseminated more effectively within teams and thus contributed to the creation of low-conflict ward cultures. PMID- 26753809 TI - Role of Cr(III) deposition during the photocatalytic transformation of hexavalent chromium and citric acid over commercial TiO2 samples. AB - Removal of Cr(VI) and citric acid (Cit) by heterogeneous photocatalytic Cr(VI) transformation under UV light over two commercial TiO2 samples (1 g L(-1)), Evonik P25 and Hombikat UV100, was studied at pH 2 and Cr(VI) concentrations between 0.2 and 3 mM, with a fixed [Cit]0/[Cr(VI)]0 molar ratio (MR) of 2.5. In both cases, up to complete Cr(VI) removal, the temporal profiles of Cr(VI) and Cit were well adjusted to a pseudo-first order rate law with the same rate constant, evidencing that Cr(VI) removal controls the kinetics of the system. Once Cr(VI) is fully removed, Cit degradation continues with a Langmuir Hinshelwood behaviour. In all cases, the rate constants decreased with increasing [Cr(VI)]0, and time resolved microwave conductivity (TRMC) measurements revealed that this was due to an increasing retention of Cr(III) on the surface of the photocatalysts, which reduces the lifetime of the electrons. Both kinetic experiments and TRMC measurements confirm that UV100 is not only more efficient than P25 for Cr(VI) and Cit removal, but it is also less influenced by the poisoning of the surface, consistent with its larger specific area. The use of Cit as the sacrificial agent improves the rate and efficiency of the photocatalytic Cr(VI) removal, and also the stability of the photocatalyst by preventing Cr(III) deposition, due to the formation of soluble Cr(III)-complexes, envisaged as a general result of the presence of oligocarboxylic acids in the photocatalytic Cr(VI) system. PMID- 26753807 TI - A novel multitarget stool DNA test for colorectal cancer screening. AB - Review of: Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, Ahlquist DA, Berger BM. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med 2014;370(14):1287-97. This Practice Pearl reviews the results of a prospective, multicenter, cross-sectional clinical study that evaluated the performance of a new multitarget stool DNA (or mt-sDNA) screening test for colorectal cancer (CRC) and compared it with a fecal immunochemical test (FIT) in individuals at average risk for CRC. The potential impact of this test on the future of CRC screening is also discussed in a brief commentary. mt-sDNA testing is a noninvasive screening test designed to detect DNA biomarkers associated with colorectal neoplasia and occult hemoglobin in the stool. The sensitivity of mt-sDNA testing for detection of CRC was 92.3%, compared with 73.8% for FIT (p = 0.002). Sensitivity for detecting advanced precancerous lesions was 42.4% for mt-sDNA testing and 23.8% for FIT (p < 0.001). The specificities of mt-sDNA testing and FIT were 86.6% and 94.9%, respectively (p < 0.001). mt-sDNA testing thus may be a first-line screening option for asymptomatic individuals at average risk for CRC who do not want to have a colonoscopy. PMID- 26753808 TI - The Head Injury Transportation Straight to Neurosurgery (HITS-NS) randomised trial: a feasibility study. AB - BACKGROUND: Reconfiguration of trauma services, with direct transport of traumatic brain injury (TBI) patients to neuroscience centres (NCs), bypassing non-specialist acute hospitals (NSAHs), could potentially improve outcomes. However, delays in stabilisation of airway, breathing and circulation (ABC) and the difficulties in reliably identifying TBI at scene may make this practice deleterious compared with selective secondary transfer from nearest NSAH to NC. National Institute for Health and Care Excellence guidance and systematic reviews suggested equipoise and poor-quality evidence - with regard to 'early neurosurgery' in this cohort - which we sought to address. METHODS: Pilot cluster randomised controlled trial of bypass to NC conducted in two ambulance services with the ambulance station (n = 74) as unit of cluster [Lancashire/Cumbria in the North West Ambulance Service (NWAS) and the North East Ambulance Service (NEAS)]. Adult patients with signs of isolated TBI [Glasgow Coma Scale (GCS) score of < 13 in NWAS, GCS score of < 14 in NEAS] and stable ABC, injured nearest to a NSAH were transported either to that hospital (control clusters) or bypassed to the nearest NC (intervention clusters). PRIMARY OUTCOMES: recruitment rate, protocol compliance, selection bias as a result of non-compliance, accuracy of paramedic TBI identification (overtriage of study inclusion criteria) and pathway acceptability to patients, families and staff. 'Open-label' secondary outcomes: 30-day mortality, 6-month Extended Glasgow Outcome Scale (GOSE) and European Quality of Life-5 Dimensions. RESULTS: Overall, 56 clusters recruited 293 (169 intervention, 124 control) patients in 12 months, demonstrating cluster randomised pre-hospital trials as viable for heath service evaluations. Overall compliance was 62%, but 90% was achieved in the control arm and when face-to-face paramedic training was possible. Non-compliance appeared to be driven by proximity of the nearest hospital and perceptions of injury severity and so occurred more frequently in the intervention arm, in which the perceived time to the NC was greater and severity of injury was lower. Fewer than 25% of recruited patients had TBI on computed tomography scan (n = 70), with 7% (n = 20) requiring neurosurgery (craniotomy, craniectomy or intracranial pressure monitoring) but a further 18 requiring admission to an intensive care unit. An intention-to-treat analysis revealed the two trial arms to be equivalent in terms of age, GCS and severity of injury. No significant 30-day mortality differences were found (8.8% vs. 9.1/%; p > 0.05) in the 273 (159/113) patients with data available. There were no apparent differences in staff and patient preferences for either pathway, with satisfaction high with both. Very low responses to invitations to consent for follow-up in the large number of mild head injury-enrolled patients meant that only 20% of patients had 6-month outcomes. The trial-based economic evaluation could not focus on early neurosurgery because of these low numbers but instead investigated the comparative cost-effectiveness of bypass compared with selective secondary transfer for eligible patients at the scene of injury. CONCLUSIONS: Current NHS England practice of bypassing patients with suspected TBI to neuroscience centres gives overtriage ratios of 13 : 1 for neurosurgery and 4 : 1 for TBI. This important finding makes studying the impact of bypass to facilitate early neurosurgery not plausible using this study design. Future research should explore an efficient comparative effectiveness design for evaluating 'early neurosurgery through bypass' and address the challenge of reliable TBI diagnosis at the scene of injury. TRIAL REGISTRATION: Current Controlled Trials ISRCTN68087745. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 1. See the NIHR Journals Library website for further project information. PMID- 26753810 TI - Evaluation of the antioxidant activity and capacity of some natural N6 substituted adenine derivatives (cytokinins) by fluorimetric and spectrophotometric assays. AB - Four natural N(6)-substituted adenine derivatives (cytokinins) were evaluated for the first time in vitro for they antioxidant capacity by using fluorimetric and spectrophotometric assays, i.e., the oxygen radical absorbance capacity (ORAC), trolox equivalence antioxidant capacity (TEAC) and the 2-deoxyribose degradation (2-DRA) assays. The results from the TEAC assay show that only N(6)-(4 hydroxybenzyl)adenine (p-topolin) shows an electron transfer capacity due to the presence of a phenolic moiety in the N(6)-position. The results from the ORAC test show that the antioxidant activity of N(6)-furfuryladenine (kinetin, K) is the highest up to a concentration of 1 MUM, whereas at concentrations higher than 1 MUM p-topolin is the most efficient antioxidant. Analysis of the kinetic data suggests that, compared to the other cytokinins, more sites of the molecular structure of p-topolin are available for the quenching of peroxyl radicals. The hydroxyl radical scavenger ability, as measured by the 2-DRA assay, showed that all tested cytokinins react in this test and that N(6)-(Delta(2) isopentenyl)adenine is slightly more potent, probably because of the allylic methylene group present in the N(6)-isopentenyl moiety. Our data suggest that a part of the biological activity of the evaluated cytokinins is likely to be related to an intrinsic antioxidant capacity. PMID- 26753812 TI - Gender dysphoria and autism spectrum disorder: A narrative review. AB - The current literature shows growing evidence of a link between gender dysphoria (GD) and autism spectrum disorder (ASD). This study reviews the available clinical and empirical data. A systematic search of the literature was conducted using the following databases: PubMed, Web of Science, PsycINFO and Scopus; utilizing different combinations of the following search terms: autism, autism spectrum disorder (ASD), Asperger's disorder (AD), co-morbidity, gender dysphoria (GD), gender identity disorder (GID), transgenderism and transsexualism. In total, 25 articles and reports were selected and discussed. Information was grouped by found co-occurrence rates, underlying hypotheses and implications for diagnosis and treatment. GD and ASD were found to co-occur frequently - sometimes characterized by atypical presentation of GD, which makes a correct diagnosis and determination of treatment options for GD difficult. Despite these challenges there are several case reports describing gender affirming treatment of co occurring GD in adolescents and adults with ASD. Various underlying hypotheses for the link between GD and ASD were suggested, but almost all of them lack evidence. PMID- 26753811 TI - A cross-sectional study on quality of life among the elderly in non-governmental organizations' elderly homes in Kuala Lumpur. AB - BACKGROUND: There is a rapid increase in the population of the elderly globally, and Malaysia is anticipated to become an ageing nation in 2030. Maintaining health, social participation, reducing institutionalization, and improving quality of life of the elderly are public health challenges of the 21(st) century. Quality of life among elderly in Elderly Homes in Malaysia is under researched. This study aims to determine the quality of life and its associated factors among the Elderly in Elderly Homes in Kuala Lumpur. METHODS: This was a cross-sectional study among 203 residents aged 60 years or more in eight randomly selected Elderly Homes in Kuala Lumpur in September 2014. Stratified simple random sampling was used to select participants. Study instruments included World Health Organization Quality of Life Questionnaire-Brief Version (WHOQOL-BREF), Multidimensional Scale for Perceived Social Support, and a questionnaire for Socio-demographic variables. Data collection was by face to face interview. Univariate and Multivariate analysis were used to determine associations, and P value <0.05 was considered statistically significant. RESULTS: The mean (Standard deviation) for the physical domain was 14.3 (+/-2.7), 13.7 (+/-2.5) for the psychological domain, 10.8 (+/-3.4) for the social domain, and 13.0 (+/-2.5) for the environment domain. Factors significantly associated with quality of life included age, gender, level of education, economic status, outdoor leisure activity, physical activity, duration of residence, type of accommodation, co morbidities, and social support. CONCLUSION: This study confirms that multiple factors are associated with quality of life among elderly in elderly homes. Social support, chronic co-morbidities, gender and outdoor leisure activity were significantly associated with all the domains of quality of life. Among the four domains of quality of life, the physical domain had the highest score while the social domain had the lowest score. This emphasizes the need for more social support-related interventions in these homes. PMID- 26753814 TI - Cyclic RGD peptidomimetics containing 4- and 5-amino-cyclopropane pipecolic acid (CPA) templates as dual alphaVbeta3 and alpha5beta1 integrin ligands. AB - 4-Amino- and 5-amino-cyclopropane pipecolic acids (CPAs) with cis relative stereochemistry between the carboxylic and amino groups were used as templates to prepare cyclic peptidomimetics containing the RGD sequence as possible integrin binders. The peptidomimetic c(RGD8) built on the 5-amino-CPA displayed an inhibition activity (IC50=2.4nM) toward the alphavbeta3 integrin receptor (expressed in M21 human melanoma cell line) comparable to that of the most potent antagonists reported so far and it was ten times more active than the corresponding antagonist c(RGD7) derived from the isomeric 4-amino-CPA. Both compounds were also nanomolar ligands of the alpha5beta1 integrin (expressed in human erythroleukemia cell line K562). These results suggest that the CPA-derived templates are suitable for the preparation of dual alphavbeta3 and alpha5beta1 ligands to suppress integrin-mediated events as well as for targeted drug delivery in cancer therapy. PMID- 26753813 TI - Design and synthesis of an activity-based protein profiling probe derived from cinnamic hydroxamic acid. AB - In our continued effort to discover new anti-hepatitis C virus (HCV) agents, we validated the anti-replicon activity of compound 1, a potent and selective anti HCV hydroxamic acid recently reported by us. Generally favorable physicochemical and in vitro absorption, distribution, metabolism, and excretion (ADME) properties exhibited by 1 made it an ideal parent compound from which activity based protein profiling (ABPP) probe 3 was designed and synthesized. Evaluation of probe 3 revealed that it possessed necessary anti-HCV activity and selectivity. Therefore, we have successfully obtained compound 3 as a suitable ABPP probe to identify potential molecular targets of compound 1. Probe 3 and its improved analogs are expected to join a growing list of ABPP probes that have made important contributions to not only the studies of biochemical and cellular functions but also discovery of selective inhibitors of protein targets. PMID- 26753817 TI - [Assessing the impact of biomedical research: For whom?]. PMID- 26753815 TI - Expanding the structural diversity of diarylureas as multi-target tyrosine kinase inhibitors. AB - Recently approved multi-target inhibitors of receptor tyrosine kinases (RTKs) have significantly improved the clinical treatment of cancers. A series of N,N' diarylureas incorporated with aromatic heterocycle have been designed, synthesized and evaluated as novel multi-target RTK inhibitors. The preliminary biological evaluation indicated that several compounds exhibited comparable potency with Sorafenib. Among them, compound 6f was identified as the most potent multikinase inhibitor of EGFR, KDR and FGFR1 with IC50 values of 14.83nM, 21.57nM, and 28.23nM, respectively. These compounds expanded the structural diversity of diarylureas as RTK inhibitors. The results demonstrated that compound 6f could be served as novel lead compound for further development of multi-target RTK inhibitors. PMID- 26753816 TI - Synthesis and biological evaluation of novel 5-hydroxylaminoisoxazole derivatives as lipoxygenase inhibitors and metabolism enhancing agents. AB - A versatile synthesis of novel 5-hydroxylaminoisoxazoles bearing adamantane moieties has been accomplished using the heterocyclization reactions of readily available unsaturated esters by the treatment with tetranitromethane in the presence of triethylamine and subsequent reduction of resulting 5-nitroisoxazoles by SnCl2 with the participation of THF. A number of obtained isoxazole derivatives were evaluated for their antioxidative activity, inhibition of lipoxygenases and impact on the rat liver mitochondria. The majority of tested compounds demonstrated moderate antiradical activity in DPPH test (up to EC50 16MUM). The same compounds strongly inhibited soybean lipoxygenase (up to IC50 0.4MUM) and Fe(2+)- and Fe(3+)-induced lipid peroxidation (LP) of rat brain cortex homogenate (up to IC50 0.3MUM). All tested isoxazole derivatives promoted the phosphorylating respiratory activity simultaneously with maximal stimulated respiratory activity of mitochondria and do not reveal any toxicity towards the primary culture of rat cortex neurons. PMID- 26753819 TI - Editorial: do we have a new addition to our GERD treatment tool box? PMID- 26753818 TI - Using PG-Liposome-Based System to Enhance Puerarin Liver-Targeted Therapy for Alcohol-Induced Liver Disease. AB - A critical issue for alcohol-induced liver disease (ALD) therapeutics is the lack of a highly efficient delivery system. In this study, a Puerarin-propylene glycol liposome system was prepared for the purpose of targeting puerarin, an isoflavon, to the liver. Transmission electron microscope (TEM) results showed the liposomes to be spherical in shape with an average diameter of 182 nm with a polydispersity index of 0.239. The zeta potential of the particles was about -30 mV. The entrapment efficiency of puerarin was above 90%. MTT-based assay in HpeG2 cells showed no significant cytotoxicity in the presence of up to 25% concentration of the system containing 3% puerarin. In vivo performance of this system was studied in mice. Pharmacokinetics and distribution of puerarin-PG-liposome system was studied relative to puerarin solution at the same dose levels. The results show that puerarin-PG-liposome prolonged drug retention time and decreased elimination of puerarin in mice (AUC of liposome system and solution was 9.5 and 4.0 mg h L 1, respectively). Furthermore, propylene glycol (PG)-liposome system enhanced puerarin distribution into liver and spleen, while decreasing puerarin distribution in other tissues. Overall, the puerarin-PG-liposome system showed enhanced therapeutic effect in mice with ALD. PMID- 26753820 TI - Letter: can persisting liver stiffness indicate increased risk of HCC, after successful anti-HCV therapy? PMID- 26753821 TI - Letter: can persisting liver stiffness indicate increased risk for HCC, after successful anti-HCV therapy? - authors' reply. PMID- 26753822 TI - Letter: can persisting liver stiffness indicate increased risk of hepatocellular cell carcinoma after successful anti-HCV therapy? - authors' reply. PMID- 26753823 TI - The prevalence of implementation of mental health measures in companies and its association with sickness absence. AB - OBJECTIVE: The main objective was to determine the prevalence of implementation of mental health measures aimed at the prevention of high workload (workload measures) and the promotion of work engagement (engagement measures) in companies and sectors. Additionally, its associations with sickness absence was explored. STUDY DESIGN: Cross-sectional survey. METHODS: An internet-based survey among 12,894 company representatives in the Netherlands. Descriptive analyses were performed to determine the prevalence, and differences between sectors were tested using Chi-squared tests. ANOVA was performed to examine the association between companies with or without mental health measures and sickness absence rates. RESULTS: 32.8% and 21.7% of the companies reported to have implemented 'continuously or often' workload measures and engagement measures, respectively. The sectors 'health care and welfare' and 'education' reported to have implemented measures most often. Having implemented engagement measures was significantly associated with lower sickness absence (4.1% vs 4.5%). CONCLUSIONS: Overall, workload measures were more often implemented than engagement measures. Future research is recommended to determine reasons for implementation as well as causality in the association between mental health measures and sickness absence. PMID- 26753825 TI - Latent Transition Modeling of Progression of Health-Risk Behavior. AB - Longitudinal studies are helpful for understanding the complex progression of health-risk behavior over time and for identifying risk factors amenable to intervention. This article focusses on methods for modeling transitions between health-risk states over time when .are common multiple indicators of health-risk are available. Multiple measures of health-rick in studies which utilize questionnaires and surveys involving a series of self-report questions ach providing information regarding health-risk. A latent transition model is presented as am alternative to approaches that analyze indicators separately or use summative indices. These approaches ignore both the correlation between indicators and the multidimensional structure of health-risk. In the present article, transitions between latent health-risk states are modeled using a logistic regression model for nominal responses. A two-stage estimation procedure which is an estimating equations analogue of the pseudo-likelihood method is applied so that the complexity of full maximum likelihood is avoided and standard error calculation is straightforward. This procedure is applied to self-report data on weapons carrying behavior in an urban sample of schoolchildren followed annually for five years. PMID- 26753824 TI - Luminescent Iridium(III) Complex Labeled DNA for Graphene Oxide-Based Biosensors. AB - There has been growing interest in utilizing highly photostable iridium(III) complexes as new luminescent probes for biotechnology and life science. Herein, iridium(III) complex with carboxyl group was synthesized and activated with N hydroxysuccinimide, followed by tagging to the amino terminate of single-stranded DNA (ssDNA). The Ir-ssDNA probe was further combined with graphene oxide (GO) nanosheets to develop a GO-based biosensor for target ssDNA detection. The quenching efficiency of GO, and the photostability of iridium(III) complex and GO Ir-ssDNA biosensor, were also investigated. On the basis of the high luminescence quenching efficiency of GO toward iridium(III) complex, the GO-Ir-ssDNA biosensor exhibited minimal background signals, while strong emission was observed when Ir ssDNA desorbed from GO nanosheets and formed a double helix with the specific target, leading to a high signal-to-background ratio. Moreover, it was found that luminescent intensities of iridium(III) complex and GO-Ir-ssDNA biosensor were around 15 and 3 times higher than those of the traditional carboxyl fluorescein (FAM) dye and the GO-FAM-ssDNA biosensor after UV irradiation, respectively. Our study suggested the sensitive and selective Ir-ssDNA probe was suitable for the development of highly photostable GO-based detection platforms, showing promise for application beyond the OLED (organic light emitting diode) area. PMID- 26753826 TI - A Dynamical Systems Analysis of Adolescent Substance Abuse. AB - Models from dynamical systems theory were fit to the intraindividual variability In adolescent self-reported cigarette and alcohol use. A dampened linear oscillator model (potentially like a pendulum with friction) and a nonlinear oscillator model with two attractors were compared. The nonlinear oscillator model and two coupled oscillators for cigarette and alcohol use were rejected. Independent dampened linear oscillators for smoking and drinking provided high internal R(2) but were unable to account for a substantial correlation between the acceleration in cigarette usage and alcohol usage; thus evidence was found for an intrinsic self-regulation mechanism in both smoking and drinking behavior, but the hypothesis was rejected that the intrinsic mechanism leading to increases in use in one substance directly predicted increased use in the other substance. Given the hypothesis of independent linear oscillators, the sign of the dampening parameter was found to be positive, indicating a system with dynamic instability; a self-regulation mechanism in which small changes in substance use lead to amplified changes after a short period of time. PMID- 26753827 TI - A Cross-Domain Model for Growth in Adolescent Alcohol Expectancies. AB - Methodologists have recently shown how the methods of individual growth modeling and covariance structure analysis can be integrated, bringing the flexibility of the latter to bear on the investigation of inter-individual differences in change. The individual growth-modeling framework uses a pair of hierarchical statistical models to represent: (a) individual status as a function of time, and (b) inter-individual differences in true change. Under the covariance structure approach, these level- I and level-2 models can be reformatted as the "measurement" and "structural" components of the general LISREL model with mean structures. Consequently, a covariance structure analysis of longitudinal panel data can provide maximum-likelihood estimates for all level-2 parameters. In this article, using longitudinal data drawn from a school-based alcohol prevention trial, we demonstrate how the new approach can be used to investigate the inter relationships among simultaneous individual changes in two domains - positive arid negative alcohol expectancies - over the course of early to mid-adolescence, for both boys and girls. We represent individual change over time in positive expectancies with a piecewise growth model, and in negative expectancies with a straight-line growth model. Then, we use multi-sample covariance structure analysis to ask whether individual changes in positive and negative expectancies are related to each other and whether the pattern of inter-relationships differs by gender. Our approach can easily be generalized to more than two domains and has a variety of other advantages that we document in the discussion. PMID- 26753828 TI - Multiple Imputation for Multivariate Missing-Data Problems: A Data Analyst's Perspective. AB - Analyses of multivariate data are frequently hampered by missing values. Until recently, the only missing-data methods available to most data analysts have been relatively ad1 hoc practices such as listwise deletion. Recent dramatic advances in theoretical and computational statistics, however, have produced anew generation of flexible procedures with a sound statistical basis. These procedures involve multiple imputation (Rubin, 1987), a simulation technique that replaces each missing datum with a set of m > 1 plausible values. The rn versions of the complete data are analyzed by standard complete-data methods, and the results are combined using simple rules to yield estimates, standard errors, and p-values that formally incorporate missing-data uncertainty. New computational algorithms and software described in a recent book (Schafer, 1997a) allow us to create proper multiple imputations in complex multivariate settings. This article reviews the key ideas of multiple imputation, discusses the software programs currently available, and demonstrates their use on data from the Adolescent Alcohol Prevention Trial (Hansen & Graham, 199 I). PMID- 26753829 TI - Drug Use Prevention Data, Missed Assessments and Survival Analysis. AB - In prevention studies, researchers often investigate the incidence of initial drug experimentation or other drug use milestones and its relationship to individual attributes such as the level of parental monitoring or rebelliousness. In this case, survival analysis is the methodology of choice. Survival analysis methods deal efficiently with data from individuals who leave the study prematurely and do not return. However often individuals do return to the study. The application of survival analysis to a situation in which individuals miss assessments and later return is nonstandard. This article examines the use of multiple imputation as a methodology for utilizing information from all assessments. PMID- 26753830 TI - Validation of Shoulder Response of Human Body Finite-Element Model (GHBMC) Under Whole Body Lateral Impact Condition. AB - In previous shoulder impact studies, the 50th-percentile male GHBMC human body finite-element model was shown to have good biofidelity regarding impact force, but under-predicted shoulder deflection by 80% compared to those observed in the experiment. The goal of this study was to validate the response of the GHBMC M50 model by focusing on three-dimensional shoulder kinematics under a whole-body lateral impact condition. Five modifications, focused on material properties and modeling techniques, were introduced into the model and a supplementary sensitivity analysis was done to determine the influence of each modification to the biomechanical response of the body. The modified model predicted substantially improved shoulder response and peak shoulder deflection within 10% of the observed experimental data, and showed good correlation in the scapula kinematics on sagittal and transverse planes. The improvement in the biofidelity of the shoulder region was mainly due to the modifications of material properties of muscle, the acromioclavicular joint, and the attachment region between the pectoralis major and ribs. Predictions of rib fracture and chest deflection were also improved because of these modifications. PMID- 26753832 TI - Ultrasound assisted green synthesis of silver nanoparticles using weed plant. AB - This study presents the facile, green and eco-friendly synthesis of silver nanoparticles (AgNPs) using weed plant Lantana camara L. leaf extract. The incorporation of ultrasound into this reduced the time and increased the reaction rate. The results showed that the AgNPs were spherical in shape with the average size of 33.8 nm. The EDAX pattern indicated the presence of abundant silver and XRD indicated that the (111) crystallographic plane more predominant than other planes. The possible functional groups responsible for the reduction and stabilization of AgNPs were identified using Fourier transform infrared spectroscope. The XPS results concluded that the nanoparticles were presented in its reduced metallic state. The antioxidant activity of AgNPs was assayed using 2, 2-diphenyl-1-picrylhydrazyl (DPPH) test. The increase in the concentration of AgNPs increased the DPPH scavenging activity. The AgNPs revealed superior antibacterial activity against Gram positive and Gram negative organisms. PMID- 26753831 TI - Effective pretreatment of dilute NaOH-soaked chestnut shell with glycerol-HClO4 water media: structural characterization, enzymatic saccharification, and ethanol fermentation. AB - In this study, an effective pretreatment of dilute NaOH-soaked chestnut shell (CNS) with glycerol-HClO4-water (88.8:1.2:10, w/w/w) media at 130 degrees C for 30 min was successfully demonstrated. Results revealed that the combination pretreatment removed 66.0 % of lignin and 73.7 % of hemicellulose in untreated CNS. The changes in the structural features (crystallinity, morphology, and porosity) of the solid residue of CNS were characterized with Fourier transform infrared spectroscopy, fluorescent microscope, scanning electron microscopy, and X-ray diffraction. Biotransformation of glycerol-HClO4-water pretreated-NaOH soaked CNS (50 g/L) with a cocktail of enzymes for 72 h, the reducing sugars and glucose were 39.7 and 33.4 g/L, respectively. Moreover, the recovered hydrolyzates containing 20 g/L glucose had no inhibitory effects on the ethanol fermenting microorganism, and the ethanol production was 0.45 g/g glucose within 48 h. In conclusion, this combination pretreatment shows promise as pretreatment solvent for wheat straw, although the in-depth exploration of this subject is needed. PMID- 26753834 TI - Cytokeratin immunohistochemistry improves interobserver variability between unskilled pathologists in the evaluation of tumor budding in T1 colorectal cancer. AB - Tumor budding is a major risk factor for T1 colorectal cancer. Quality control of the pathological diagnosis of budding is crucial, irrespective of the pathologist's experience. This study examines the interobserver variability according to pathologists' experience and evaluates the influence of cytokeratin (CK) immunostaining in the assessment of budding. Hematoxylin-eosin (HE) and CK immunostained slides of 40 cases with T1 primary colorectal cancer were examined. Budding grades were individually evaluated by 12 pathologists who we categorized into three groups by their experience (expert, with >10 years of experience (n = 4), senior, with 5-10 years (n = 4), and junior, < 5 years (n = 4)). The results revealed a tendency for the more experienced pathologists to assign higher budding grades compared to the less-experienced pathologists. In the junior group, the interobserver variability obtained with HE slides was poor, but it was markedly improved in the evaluation using CK-immunostained slides. The benefit of CK immunostaining was only slight in the expert group. CK immunostaining would be useful when a pathologist is not experienced enough or does not have enough confidence in the assessment of budding. PMID- 26753833 TI - Sickle haemoglobin, haemoglobin C and malaria mortality feedbacks. AB - BACKGROUND: Sickle haemoglobin (HbS) and haemoglobin C (HbC) are both caused by point mutations in the beta globin gene, and both offer substantial malaria protection. Despite the fact that the blood disorder caused by homozygosity for HbC is much less severe than that caused by homozygosity for HbS (sickle cell anaemia), it is the sickle mutation which has come to dominate many old-world malarious regions, whilst HbC is highly restricted in its geographical distribution. It has been suggested that this discrepancy may be due to sickle cell heterozygotes enjoying a higher level of malaria protection than heterozygotes for HbC. A higher fitness of sickle cell heterozygotes relative to HbC heterozygotes could certainly have allowed the sickle cell allele to spread more rapidly. However, observations that carrying either HbC or HbS enhances an individual's capacity to transmit malaria parasites to mosquitoes could also shed light on this conundrum. METHODS: A population genetic model was used to investigate the evolutionary consequences of the strength of malaria selection being correlated with either HbS frequency or HbC frequency. RESULTS: If the selection pressure from malaria is positively correlated with the frequency of either HbS or HbC, it is easier for HbS to succeed in the competitive interaction between the two alleles. CONCLUSIONS: A feedback process whereby the presence of variant haemoglobins increases the level of malaria selection in a population could have contributed to the global success of HbS relative to HbC, despite the former's higher blood disorder cost. PMID- 26753835 TI - Verification of absorbed dose using diodes in cobalt-60 radiation therapy. AB - The objective of this work was to enhance the quality and safety of dose delivery in the practice of radiation oncology. To achieve this goal, the absorbed dose verification program was initiated by using the diode in vivo dosimetry (IVD) system (for entrance and exit). This practice was implemented at BINO, Bahawalpur, Pakistan. Diodes were calibrated for making absorbed dose measurements. Various correction factors (SSD, dose non-linearity, field size, angle of incidence, and wedge) were determined for diode IVD system. The measurements were performed in phantom in order to validate the IVD procedure. One hundred and nineteen patients were monitored and 995 measurements were performed. For phantom, the percentage difference between measured and calculated dose for entrance setting remained within +/-2% and for exit setting +/-3%. For patient measurements, the percentage difference between measured and calculated dose remained within +/-5% for entrance/open fields and +/-7% for exit/wedge/oblique fields. One hundred and nineteen patients and 995 fields have been monitored during the period of 6 months. The analysis of all available measurements gave a mean percent deviation of +/-1.19% and standard deviation of +/-2.87%. Larger variations have been noticed in oblique, wedge and exit measurements. This investigation revealed that clinical dosimetry using diodes is simple, provides immediate results and is a useful quality assurance tool for dose delivery. It has enhanced the quality of radiation dose delivery and increased/improved the reliability of the radiation therapy practice in BINO. PMID- 26753836 TI - Antibacterial and antibiotic-modifying activities of three food plants (Xanthosoma mafaffa Lam., Moringa oleifera (L.) Schott and Passiflora edulis Sims) against multidrug-resistant (MDR) Gram-negative bacteria. AB - BACKGROUND: The present study was designed to investigate the antibacterial activities of the methanol extract of three edible plants, namely Xanthosoma mafaffa, Moringa oleifera and Passiflora edulis and their synergistic effects with some commonly used antibiotics against MDR Gram-negative bacteria expressing active efflux pumps. METHODS: Broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) and the minimum bactericidal concentrations (MBCs) of the extracts, as well as those of antibiotics in association with the extracts. RESULTS: The phytochemical test indicate that all tested crude extracts contained polyphenols, triterpenes and steroids whilst other phytochemical classes were selectively distributed. Extracts showed antibacterial activities with minimum inhibitory concentrations ranging from 128 1024 MUg/mL on the majority of the 19 tested Gram-negative bacterial strains. Extract from the pericarp of P. edulis inhibited the growth of 89.5% of the 19 tested bacterial strains, the lowest minimal inhibitory concentration (MIC) value of 128 MUg/mL being recorded against Escherichia coli AG100 strain. In the presence of Phenylalanine-Arginine beta-Naphtylamide (PAbetaN)], an efflux pump inhibitor (EPI), the activity of the extract from X. mafaffa increased on 40% of tested strains. In combination with antibiotics, extracts of X. mafaffa, M. oleifera and pericarp of P. edulis showed synergistic effects with some antibiotics against more than 75% of the tested bacteria. CONCLUSION: The results of the present study indicate that the tested plants may be used in the treatment of bacterial infections including the multi-resistant bacteria. PMID- 26753838 TI - Association of detected depression and undetected depressive symptoms with long term mortality in a cohort of institutionalised older people. AB - BACKGROUND: Studies on depression and mortality in nursing homes have shown inconclusive findings, and none has studied the role of detection. We sought to measure the association of depression with long-term all-cause mortality in institutionalised older people and evaluate a potential modification in the association by its detection status. METHODS: We selected a stratified cluster sample of 591 residents aged 75 years or older (mean age 84.5 years) living in residential and nursing homes of Madrid, Spain, who were free of severe cognitive impairment at the 1998-1999 baseline interview. Mortality was ascertained until age 105 years or September 2013 (median/maximum follow-up 4.8/15.2 years) through linkage to the Spanish National Death Index. Detected depression was defined at baseline as a physician's diagnosis or antidepressant use, undetected depression as significant depressive symptoms (score of 4 or higher on the ten-item version of the Geriatric Depression Scale) without documented diagnosis or treatment, and no depression as the absence of diagnosis, treatment, and symptoms. Constant and age-dependent hazard ratios for mortality comparing detected and undetected depression with no depression were estimated using Cox models, and absolute years of life gained and lost using Weibull models. RESULTS: The baseline prevalences of detected and undetected depression were 25.9 and 18.8%, respectively. A total of 499 participants died during 3575 person-years of follow-up. In models adjusted for age, sex, type of facility, number of chronic conditions, and functional dependency, overall depression was not associated with long-term all cause mortality (hazard ratio 0.87, 95% confidence interval (CI): 0.70-1.08). However, compared with no depression, detected depression showed lower mortality (hazard ratio 0.63, 95% CI: 0.46-0.86), while undetected depression registered higher, not statistically significant, mortality (hazard ratio 1.35, 95% CI: 0.98 1.86). The median life expectancy increased by 1.8 years (95% CI: -3.1 to 6.7 years) in residents with detected depression and decreased by 6.3 years (95% CI: 2.6-10.1 years) in those undetected. Results were more marked in women than men and they were robust to the exclusion of antidepressants from the definition of depression and also to the use of a stricter cut-off for the presence of depressive symptoms. CONCLUSIONS: The long-term mortality risk associated with depression in nursing homes depends on its detection status, with better prognosis in residents with detected depression and worse in those undetected. The absolute impact of undetected depressive symptoms in terms of life expectancy can be prominent. PMID- 26753837 TI - Changes in cardiac arrest patients' temperature management after the 2013 "TTM" trial: results from an international survey. AB - BACKGROUND: Therapeutic hypothermia (TH between 32 and 34 degrees C) was recommended until recently in unconscious successfully resuscitated cardiac arrest (CA) patients, especially after initial shockable rhythm. A randomized controlled trial published in 2013 observed similar outcome between a 36 degrees C-targeted temperature management (TTM) and a 33 degrees C-TTM. The main aim of our study was to assess the impact of this publication on physicians regarding their TTM practical changes. METHODS: A declarative survey was performed using the webmail database of the French Intensive Care Society including 3229 physicians (from May 2014 to January 2015). RESULTS: Five hundred and eighteen respondents from 264 ICUs in 11 countries fulfilled the survey (16 %). A specific attention was generally paid by 94 % of respondents to TTM (hyperthermia avoidance, normothermia, or TH implementation) in CA patients, whereas 6 % did not. TH between 32 and 34 degrees C was declared as generally maintained during 12-24 h by 78 % of respondents or during 24-48 h by 19 %. Since the TTM trial publication, 56 % of respondents declared no modification of their TTM practice, whereas 37 % declared a practical target temperature change. The new temperature targets were 35-36 degrees C for 23 % of respondents, and 36 degrees C for 14 %. The duration of overall TTM (including TH and/or normothermia) was declared as applied between 12 and 24 h in 40 %, and between 24 and 48 h in 36 %. In univariate analysis, the physicians' TTM modification seemed related to hospital category (university versus non-university hospitals, P = 0.045), to TTM-specific attention paid in CA patients (P = 0.008), to TH durations (<12 versus 24-48 h, P = 0.01), and to new targets temperature (32-34 versus 35-36 degrees C, P < 0.0001). CONCLUSIONS: The TTM trial publication has induced a modification of current practices in one-third of respondents, whereas the 32-34 degrees C target temperature remained unchanged for 56 %. Educational actions are needed to promote knowledge translations of trial results into clinical practice. New international guidelines may contribute to this effort. PMID- 26753839 TI - Exploring the linkage between exposure to mass media and HIV testing among married women and men in Ghana. AB - Although HIV testing is critical to the treatment and prevention of HIV/AIDS, utilization rate of HIV testing services among married women and men remains low in Ghana. Mass media, as a tool to increase overall HIV testing turnouts, has been considered one of the important strategies in promoting and enhancing behavioural changes related to HIV/AIDS prevention. Using the 2014 Ghana Demographic and Health Survey, the current study examines the relationship between levels of exposure to print media, radio, and television and the uptake of HIV testing among married women and men in Ghana. Results show that HIV testing is more prevalent among married women than their male counterparts. We also find that higher levels of exposure to radio is associated with HIV testing among women, while higher levels of exposure to print media and television are associated with HIV testing among men. Implications of these findings are discussed for Ghana's HIV/AIDS strategic framework, which aims to expanding efforts at dealing with the HIV/AIDS epidemic. Specifically, it is important for health educators and programme planners to deliver HIV-related messages through television, radio, and print media to increase the uptake of HIV testing particularly among married women and men in Ghana. PMID- 26753840 TI - Ancient DNA and the rewriting of human history: be sparing with Occam's razor. AB - Ancient DNA research is revealing a human history far more complex than that inferred from parsimonious models based on modern DNA. Here, we review some of the key events in the peopling of the world in the light of the findings of work on ancient DNA. PMID- 26753842 TI - Long-term results with the Atlas IIIp elastic cementless acetabular component in total hip replacement. AB - PURPOSE: Modular cementless elastic acetabular systems have advantages over cemented and hard shell cementless acetabular systems. There are few reports on the medium-term and long-term follow up of this particular type of implant. This study describes our experience with the Atlas IIIp modular acetabular system, which is a thin shell cementless elastic acetabular implant for total hip replacement commercialized under this name in many countries. METHODS: We prospectively followed 244 patients treated with Atlas IIIp acetabular system between 2001 and 2004. Minimum ten year follow up was available for 148 hips (139 patients) from the original cohort of 263 hips (244 patients). One hundred five patients had died from unrelated causes and were excluded from the results. Post operative and follow up radiographs of patients were assessed; and Harris hip scores were used as clinical outcome. Revision for any reason was defined as the end point for survivorship analysis. RESULTS: The mean pre-operative Harris hip score was 48 (S.D. 16) and the average post-operative score was 82 (S.D. 12). The mean follow up in our series was 11.5 years, ranging from ten to 13.5 years. Thirteen hips required further surgery in our cohort; of which ten cases required cup revision. The 13-years cumulative implant survival was 91.2 % and the risk of implant revision was 8.8 % at 13 years in 148 hips (139 patients). Kaplan-Meier analysis showed the implant survival rate of 95.2 % at ten years for revision for any reason and 99.4 % for aseptic loosening. CONCLUSIONS: Our clinical experience with this acetabular cup suggests good long-term survival rates that are similar to other cups on the market. The clinical experience in this study shows long term survival rates that are consistent, acceptable and good results achieved with a low revision rate. LEVEL OF EVIDENCE: Therapeutic III; therapeutic study. PMID- 26753841 TI - Identification and validation of risk loci for osteochondrosis in standardbreds. AB - BACKGROUND: Osteochondrosis (OC), simply defined as a failure of endochondral ossification, is a complex disease with both genetic and environmental risk factors that is commonly diagnosed in young horses, as well as other domestic species. Although up to 50 % of the risk for developing OC is reportedly inherited, specific genes and alleles underlying risk are thus far completely unknown. Regions of the genome identified as associated with OC vary across studies in different populations of horses. In this study, we used a cohort of Standardbred horses from the U.S. (n = 182) specifically selected for a shared early environment (to reduce confounding factors) to identify regions of the genome associated with tarsal OC. Subsequently, putative risk variants within these regions were evaluated in both the discovery population and an independently sampled validation population of Norwegian Standardbreds (n = 139) with tarsal OC. RESULTS: After genome-wide association analysis of imputed data with information from >200,000 single nucleotide polymorphisms, two regions on equine chromosome 14 were associated with OC in the discovery cohort. Variant discovery in these and 30 additional regions of interest (including 11 from other published studies) was performed via whole-genome sequencing. 240 putative risk variants from 10 chromosomes were subsequently genotyped in both the discovery and validation cohorts. After correction for population structure, gait (trot or pace) and sex, the variants most highly associated with OC status in both populations were located within the chromosome 14 regions of association. CONCLUSIONS: The association of putative risk alleles from within the same regions with disease status in two independent populations of Standardbreds suggest that these are true risk loci in this breed, although population-specific risk factors may still exist. Evaluation of these loci in other populations will help determine if they are specific to the Standardbred breed, or to tarsal OC or are universal risk loci for OC. Further work is needed to identify the specific variants underlying OC risk within these loci. This is the first step towards the long-term goal of constructing a genetic risk model for OC that allows for genetic testing and quantification of risk in individuals. PMID- 26753843 TI - Risk factors for bone cement leakage in percutaneous vertebroplasty: a retrospective study of four hundred and eighty five patients. AB - PURPOSE: Percutaneous vertebroplasty (PVP) is a common procedure in spine surgery. Bone cement leakage is the most common complication related to this procedure. The purpose of this study was to assess the incidence and risk factors for cement leakage after PVP. METHODS: A total of 485 patients who underwent PVP between August 2003 and August 2013 were enrolled in the study. Clinical and radiological characteristics, including age, gender, diagnosis, operated level, surgical approach, type of anesthesia, volume of bone cement, fracture type, and fracture severity, were considered as potential risk factors. Cement leakage was assessed based on post-operative imaging examination. Six types of leakage were defined and risk factors for each type were analyzed. RESULTS: The incidence of leakage was 58.2 %. Binary logistic analysis revealed that larger volume of bone cement (P < 0.001) and higher fracture severity grade (P < 0.001) were the strongest independent risk factors. Univariate analysis and multinomial logistic analysis showed that surgical approach (P < 0.001), gender (P = 0.016), and operated level (P = 0.032) were additional risk factors for leakage. Further analysis showed that more bone cement was used in bilateral than unilateral approaches, that men had larger volumes of bone cement injected than women, and that more bone cement was injected into lumbar vertebrae than thoracic vertebrae. Therefore, these risk factors (surgical approach, gender, and operated level) could be attributed to excess bone cement usage. CONCLUSIONS: Cement leakage is very common with PVP. Higher fracture severity grade and larger volume of bone cement were the two strongest independent risk factors for leakage. PMID- 26753844 TI - No differences between direct anterior and lateral approach for primary total hip arthroplasty related to muscle damage or functional outcome. AB - PURPOSE: The aim was to compare the muscle damage and functional outcomes between patients who underwent total hip arthroplasty through a direct anterior (49 patients) or a lateral approach (50 patients). METHODS: A randomized, controlled, prospective study. The study variables were muscle damage based on post-operative levels of serum markers (citokynes and acute phase reactants) and MRI, and Harris hip score. RESULTS: Post-operatively, there were significantly higher mean levels in the lateral group related to interleukin 6 and 8, and tumor necrosis factor alpha up to fourth postoperative day. By MRI at six post-operative months, the fatty atrophy in the gluteus muscles was more in the lateral group, but similar in the other muscles. The mean thickness of the tensor fasciae latae was significantly lower in the anterior group. Functional outcome was similar between groups at three and 12 post-operative months. CONCLUSIONS: Muscle damage due to the surgical approach had no influence on functional outcome after three post operative months. Both anterior and lateral approaches for THA are similarly safe and feasible, so the choice depends only on the preference and experience of the surgeon. PMID- 26753845 TI - Analysis of the effects of high tibial osteotomy on tibial rotation. AB - PURPOSE: Limited literature reports on internal and external rotation of the distal fragment in the context of valgus open wedge (OW) high tibial osteotomy (HTO). In the authors clinical observation, the distal fragment was always rotated internally in relation to the proximal fragment by the end of the surgical procedure. The purpose was to evaluate the influence of valgus OW-HTO on post-operative tibial torsion. STUDY DESIGN: Prospective case series. METHODS: Fifty patients (10 female, 40 male; mean age 42.1 +/- 9.4 years) underwent valgus OW- HTO. The osteotomy was spread and fixed with a locking plate at the posteromedial aspect of the proximal tibia. The osteotomy of the tibial tuberosity was performed either proximally or distally dependent on the patello femoral findings. Two independent observers measured axial tibial rotation using K-wires placed into the anterior margin of the tibia proximal and distal to the osteotomy. RESULTS: An overall mean of 4.4 +/- 2.8 degrees internal rotation of the distal tibia has been shown. In four patients with additional single step double bundle ACL-replacement after harvesting ipsilateral autologous hamstring grafts, the distal tibia rotated internally by 0.1 +/- 0.3 degrees , accordingly in the other 46 patients by 4.8 +/- 2.6 degrees . CONCLUSIONS: Valgus OW-HTO produces significant internal axial rotation of the distal tibia. This might be caused by soft tissue tension of the medial hamstrings/soft tissue structures and the location of the lateral tibial hinge. CLINICAL RELEVANCE: Surgeons have to take into consideration that valgus OW HTO might result in significant 3D changes of the tibia. Higher degrees of internal torsion of the tibia might influence overall gait mechanics and specifically alternate patellofemoral kinematics. PMID- 26753846 TI - CD146/MCAM defines functionality of human bone marrow stromal stem cell populations. AB - BACKGROUND: Identification of surface markers for prospective isolation of functionally homogenous populations of human skeletal (stromal, mesenchymal) stem cells (hMSCs) is highly relevant for cell therapy protocols. Thus, we examined the possible use of CD146 to subtype a heterogeneous hMSC population. METHODS: Using flow cytometry and cell sorting, we isolated two distinct hMSC-CD146(+) and hMSC-CD146(-) cell populations from the telomerized human bone marrow-derived stromal cell line (hMSC-TERT). Cells were examined for differences in their size, shape and texture by using high-content analysis and additionally for their ability to differentiate toward osteogenesis in vitro and form bone in vivo, and their migrational ability in vivo and in vitro was investigated. RESULTS: In vitro, the two cell populations exhibited similar growth rate and differentiation capacity to osteoblasts and adipocytes on the basis of gene expression and protein production of lineage-specific markers. In vivo, hMSC-CD146(+) and hMSC CD146(-) cells formed bone and bone marrow organ when implanted subcutaneously in immune-deficient mice. Bone was enriched in hMSC-CD146(-) cells (12.6 % versus 8.1 %) and bone marrow elements enriched in implants containing hMSC-CD146(+) cells (0.5 % versus 0.05 %). hMSC-CD146(+) cells exhibited greater chemotactic attraction in a transwell migration assay and, when injected intravenously into immune-deficient mice following closed femoral fracture, exhibited wider tissue distribution and significantly increased migration ability as demonstrated by bioluminescence imaging. CONCLUSION: Our studies demonstrate that CD146 defines a subpopulation of hMSCs capable of bone formation and in vivo trans-endothelial migration and thus represents a population of hMSCs suitable for use in clinical protocols of bone tissue regeneration. PMID- 26753848 TI - Letter to the editor: Response to two recent articles regarding achondroplasia. PMID- 26753847 TI - Parent and peer influences on emerging adult substance use disorder: A genetically informed study. AB - The present study utilizes longitudinal data from a high-risk community sample to examine the unique effects of genetic risk, parental knowledge about the daily activities of adolescents, and peer substance use on emerging adult substance use disorders (SUDs). These effects are examined over and above a polygenic risk score. In addition, this polygenic risk score is used to examine gene-environment correlation and interaction. The results show that during older adolescence, higher adolescent genetic risk for SUDs predicts less parental knowledge, but this relation is nonsignificant in younger adolescence. Parental knowledge (using mother report) mediates the effects of parental alcohol use disorder (AUD) and adolescent genetic risk on risk for SUD, and peer substance use mediates the effect of parent AUD on offspring SUD. Finally, there are significant gene environment interactions such that, for those at the highest levels of genetic risk, less parental knowledge and more peer substance use confers greater risk for SUDs. However, for those at medium and low genetic risk, these effects are attenuated. These findings suggest that the evocative effects of adolescent genetic risk on parenting increase with age across adolescence. They also suggest that some of the most important environmental risk factors for SUDs exert effects that vary across level of genetic propensity. PMID- 26753849 TI - Prof. Jens Sandahl Christiansen. PMID- 26753851 TI - Reactive oxygen species signaling in the regulation of microglial functions - TRP channel-mediated novel mechanisms of microglial activation. PMID- 26753852 TI - Differential roles of NOX1/NADPH oxidase derived ROS in cardiovascular disease. PMID- 26753853 TI - Role of NADPH oxidase 1 (NOX1) in gut inflammation. PMID- 26753854 TI - Physiological roles of hydrogen sulfide and polysulfides. PMID- 26753850 TI - Suprasellar granular cell tumor of the neurohypophysis: surgical outcome of a very rare tumor. AB - PURPOSE: Granular cell tumors of the neurohypophysis are rare, solitary lesions, mostly presenting in the adult age. They rarely grow to a sufficient size to cause mass effect related symptoms and they may be found in most cases incidentally at autopsy. Because of their rarity as of now they have been described only as case reports or included in small clinical series. METHODS: We report a series of 11 patients, who underwent surgery for granular cell tumors of the neurohypophysis between 1996 and 2013 in a single center. RESULTS: Mean follow-up time after treatment was 92.2 months (range 9-231 months). Mean age at surgery was 40.7 years (range 12-66 years). There were 7 males (63.6 %) and 4 females (36.4 %). Main symptoms at presentation were: hyperprolactinemia (72.7 %), visual impairment (45.5 %) and headache (36 %). Except for 2 patients, all the others underwent surgery as primary treatment at our Institution, through a transsphenoidal (54.5 %) or a transcranial approach (45.5 %). Overall- and progression-free survival times for the entire series (calculated from the time of diagnosis) were 112.9 and 100.5 months respectively. There was one case of perioperative death in a patient who had undergone repeat transcranial surgery for residual tumor. CONCLUSIONS: Although extremely rare, granular cell tumors of the neurohypophysis have to be considered in the differential diagnosis of suprasellar masses, to avoid misleading interpretation and consequent wrong therapeutic management. Early diagnosis, extensive tumor removal, opportune indication of adjuvant radiotherapy are the keys to manage these cases. PMID- 26753855 TI - Novel therapy for arteriogenic erectile dysfunction. PMID- 26753856 TI - Effects of phosphodiesterase 5 inhibitors on testicular dysfunction. PMID- 26753857 TI - Effect of PDE-5 inhibitors on lower urinary tract symptoms in patients with benign prostatic hyperplasia. PMID- 26753858 TI - The future of Men's health with PDE5-inhibitors. PMID- 26753859 TI - Histaminergic neural clusters and those physiological roles. PMID- 26753860 TI - Pharmacological and clinical profile of treprostinil (TREPROST(r) for injection). PMID- 26753861 TI - Inhibitory effects of docosahexaenoic acid (DHA)-derived metabolites on vasoconstrictions. PMID- 26753862 TI - [Establishing and operating a human biobank. Ethical aspects]. AB - Particularly in the past decade which has been marked by efforts to foster individualized/personalized medicine the need for well-characterized high-quality collections of human biological material has significantly increased. When establishing and operating a human biobank the interests and the "freedom" of biomedical research must always be weighed against the interests and rights of patients and/or donors; in this process ethical aspects should be considered systematically. In addition, the importance of quality control and quality assurance has largely increased in human biobanking, both from a scientific and even more from an ethical point of view, because donated biological materials are potentially stored for decades and (on request) might serve for currently not foreseeable biomedical research purposes. In addition, the compatibility of national human biobanks with international biobank networks becomes increasingly important. PMID- 26753863 TI - [Biobanks: in the interests of researchers or donors?]. AB - The establishment and operation of research biobanks are still not regulated by special laws. As a consequence, the acquisition, storage and use of biobank materials and data are only covered by quite general legal regulations. The way in which these rules are to be interpreted in relation to the specific problems of biobanks is rather controversial. The central question revolves around the tense relationship between the right to privacy of the donor and the academic freedom of the researchers. This article gives an overview of the current discussion and suggestions for practice. PMID- 26753864 TI - Genetics, lifestyle and environment. UK Biobank is an open access resource following the lives of 500,000 participants to improve the health of future generations. AB - UK Biobank is a long-term prospective epidemiology study having recruited and now following the lives of 500,000 people in England, Scotland and Wales, aged 40-69 years when they joined the study (Sudlow et al., PLoS Med 12(3):e1001779, 2015). Participants were recruited by letter and asked to attend one of 22 assessment centres in towns and cities across Britain, where they provided consent, answered detailed questions about their health and lifestyle, had body measures taken and donated blood, urine and saliva. Participants provided consent for the long-term follow-up of their health via medical records, such as general practice and hospital records, cancer and death records. Samples are being stored long term for a wide range of analyses, including genetic. The resource is open to all bona fide scientists from the UK and overseas, academic and industry who register via its access management system. Summary of UK Biobank data can be viewed via its Data Showcase and the resource will be strengthened over time as the results of new analyses and studies are returned, health links and participants provide additional information about themselves. Some will attend full repeat assessment visits. UK Biobank is open for business, and it hopes researchers will find it a valuable tool to improve the health of future generations. PMID- 26753865 TI - [Strategies for biobank networks. Classification of different approaches for locating samples and an outlook on the future within the BBMRI-ERIC]. AB - BACKGROUND: Medical research projects often require more biological material than can be supplied by a single biobank. For this reason, a multitude of strategies support locating potential research partners with matching material without requiring centralization of sample storage. OBJECTIVES: Classification of different strategies for biobank networks, in particular for locating suitable samples. Description of an IT infrastructure combining these strategies. MATERIALS AND METHODS: Existing strategies can be classified according to three criteria: (a) granularity of sample data: coarse bank-level data (catalogue) vs. fine-granular sample-level data, (b) location of sample data: central (central search service) vs. decentral storage (federated search services), and (c) level of automation: automatic (query-based, federated search service) vs. semi automatic (inquiry-based, decentral search). All mentioned search services require data integration. Metadata help to overcome semantic heterogeneity. RESULTS: The "Common Service IT" in BBMRI-ERIC (Biobanking and BioMolecular Resources Research Infrastructure) unites a catalogue, the decentral search and metadata in an integrated platform. As a result, researchers receive versatile tools to search suitable biomaterial, while biobanks retain a high degree of data sovereignty. CONCLUSIONS: Despite their differences, the presented strategies for biobank networks do not rule each other out but can complement and even benefit from each other. PMID- 26753866 TI - [Quality of biomaterials in liquid- and tissue-biobanking]. AB - During the last years, many biobanks that collect and provide biomaterials as well as associated phenotypical data have been established on national and international levels. However, due to the heterogeneity in structure and process landscape between biobanks, quality issues arise, which might affect equivalence of sample quality and thus usability of biomaterials for scientific research projects as well as interoperability of biobanks.Here, we will give an overview on the influence of biobanking procedures on sample quality and on potential quality control measures for research biobanks, mainly focusing on tissue and liquid biomaterials. General infrastructural requirements as well as the influence of preanalytical variables affecting sample quality and usability are described and opportunities and drawbacks of different quality assurance procedures are discussed. As there is increasing consensus on national and international levels that evidence-based standardization and harmonization of biobank structures and workflows are urgently needed for quality-assured biobanking, recent activities in the development and implementation of an ISO Standard for biobanks will be illustrated in the last section of this article. PMID- 26753867 TI - [The German Environmental Specimen Bank]. AB - The main objective of the German Environmental Specimen Bank (ESB) is the long term storage of environmental and human samples under stable deep-freeze conditions for future research. The ESB is unique in providing a continuous historical record of environmental and human exposure to chemicals in Germany. ESB was started parallel to the development of the first German Chemicals Legislation in the late 1970s. In 1979, the ESB test operation began. After the Chemicals Law came into force in 1982, the ESB was established as a permanent facility in 1985. With the new European Chemicals Legislation, REACH, in 2007 responsibility for the safety of commercial chemicals and risk assessment was assigned to the industry. Since then, the ESB has become even more important in verifying the self-assessment of the industry, in evaluating the effectiveness of regulations, thus ensuring the protection of humans and the environment against adverse effects caused by exposure to chemicals. These objectives are pursued by the regular monitoring of contaminations and the assessment of temporal trends. Demonstrating the necessity of deriving exposure reduction measures, ESB results serve as key information for policy-makers. Information on preventing exposure to chemicals is available to the general public and to the public health services. The ESB is thus an important monitoring instrument of the Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety. The Federal Environment Agency operates the ESB based on its own concepts, heads the scientific data evaluation and transfers results into the environmental policy arena and to the general public. PMID- 26753868 TI - [Implementation of seasonal influenza and human papillomavirus vaccination recommendations in gynecological practices in Germany]. AB - In Germany, seasonal influenza vaccination has been recommended for pregnant women since 2010 and human papillomavirus (HPV) vaccination for girls since 2007. Gynecologists play an important role in the communication and vaccination of these two target groups. Moreover, seasonal influenza vaccination is also recommended for healthcare workers, as well as adults aged >= 60 years and individuals with underlying chronic diseases. The aim of this study was to gain first insights into the acceptance and implementation of the seasonal influenza und HPV vaccination recommendations in gynecological practices. In the context of the national influenza immunization campaign-which is jointly carried out by the Robert Koch Institute (RKI) and the Federal Centre for Health Education (BZgA)-a questionnaire was sent together with influenza information kits to 7477 gynecologists in September 2014. Data from 1469 (20 %) gynecologists were included in the analysis. 72 % of respondents reported that they themselves received a seasonal influenza shot each year. The majority of gynecologists recommended seasonal influenza vaccination for pregnant women (93 %) and HPV vaccination for girls (97 %). The most commonly stated reasons against influenza vaccination were safety concerns. Those against HPV vaccination were effectiveness concerns. Additionally, for both vaccinations the provision of vaccine-related information to the patient was considered too time consuming.The high acceptance of seasonal influenza and HPV vaccination among gynecologists is discordant with the available vaccination coverage figures in Germany. Gynecologists must be reminded of their important role in the prevention of vaccine-preventable diseases in adolescents and adult women. Immunization and communication skills should be considered more strongly as an integral part of medical education and further training for gynecologists. PMID- 26753869 TI - Molecular dynamics simulation and bioinformatics study on chloroplast stromal ridge complex from rice (Oryza sativa L.). AB - BACKGROUND: Rice (Oryza sativa L.) is one of the most important cereal crops in the world and its yield is closely related to the photosynthesis efficiency. The chloroplast stromal ridge complex consisting of PsaC-PsaD-PsaE plays an important role in plant photosynthesis, which has been a subject of many studies. Till now, the recognition mechanism between PsaC and PsaD in rice is still not fully understood. RESULTS: Here, we present the interaction features of OsPsaC and OsPsaD by molecular dynamics simulations and bioinformatics. Firstly, we identified interacting residues in the OsPsaC-OsPsaD complex during simulations. Significantly, important hydrogen bonds were observed in residue pairs R19-E103, D47-K62, R53-E63, Y81-R20, Y81-R61 and L26-V105. Free energy calculations suggested two salt bridges R19-E103 and D47-K62 were essential to maintain the OsPsaC-OsPsaD interaction. Supportively, electrostatic potentials surfaces of OsPsaD exhibited electrostatic attraction helped to stabilize the residue pairs R19-E103 and D47-K62. In particular, the importance of R19 was further verified by two 500 ns CG-MD simulations. Secondly, this study compared the stromal ridge complex in rice with that in other organisms. Notably, alignments of amino acids showed these two salt bridges R19-E103 and D47-K62 also existed in other organisms. Electrostatic potentials surfaces and X-ray structural analysis strongly suggested the stromal ridge complex in other organisms adopted a similar and general recognition mechanism. CONCLUSIONS: These results together provided structure basis and dynamics behavior to understand recognition and assembly of the stromal ridge complex in rice. PMID- 26753870 TI - Optic Perineuritis. AB - Optic perineuritis (OPN) is now defined as "a form of idiopathic orbital inflammatory disease, in which the specific target tissue is the optic nerve sheath". It may be idiopathic or may occur as part of an underlying systemic inflammatory disease. It is a rare disorder and information regarding its presentation and management is only available in case reports and small case series. This review will discuss the contribution of these recent articles to what is known about idiopathic and secondary OPN. Suggestions will also be made as to how to investigate and treat a patient presenting with OPN. PMID- 26753871 TI - Electrostatic sampling of trace DNA from clothing. AB - During acts of physical aggression, offenders frequently come into contact with clothes of the victim, thereby leaving traces of DNA-bearing biological material on the garments. Since tape-lifting and swabbing, the currently established methods for non-destructive trace DNA sampling from clothing, both have their shortcomings in collection efficiency and handling, we thought about a new collection method for these challenging samples. Testing two readily available electrostatic devices for their potential to sample biological material from garments made of different fabrics, we found one of them, the electrostatic dust print lifter (DPL), to perform comparable to well-established sampling with wet cotton swabs. In simulated aggression scenarios, we had the same success rate for the establishment of single aggressor profiles, suitable for database submission, with both the DPL and wet swabbing. However, we lost a substantial amount of information with electrostatic sampling, since almost no mixed aggressor-victim profiles suitable for database entry could be established, compared to conventional swabbing. This study serves as a proof of principle for electrostatic DNA sampling from items of clothing. The technique still requires optimization before it might be used in real casework. But we are confident that in the future it could be an efficient and convenient contribution to the toolbox of forensic practitioners. PMID- 26753872 TI - Estimating the age of Calliphora vicina eggs (Diptera: Calliphoridae): determination of embryonic morphological landmarks and preservation of egg samples. AB - Blow fly eggs may sometimes be the only entomological evidence recovered in a forensic case, especially in cooler weather when hatching might take several days: hence, a method for estimating their age is greatly needed. However, developmental data on blow fly eggs are mainly limited to records of the time to larval hatching. The current paper describes the morphological changes occurring during embryogenesis of the blow fly Calliphora vicina Robineau-Desvoidy and their timing in relation to temperature, in order to determine those characters which can be used for simple egg age estimation using light microscopy. At 7.3 and 25 degrees C, 15 easily visualised morphological landmarks were determined in C. vicina living embryos, allowing for their age estimation with a resolution of 10-20% of total egg developmental time. The observed age intervals were compared to the embryonic stages described for the fruit fly Drosophila melanogaster Meigen, which are used as reference data in multiple developmental studies. Moreover, current guidelines for preservation of egg samples, which recommend the placement of living eggs directly into 80% ethanol, were tested against the hot water killing (HWK) method prior to preservation in 80% ethanol, recommended for larval and pupal specimens. Direct placement of eggs into 80% ethanol caused marked decomposition of samples, and no morphological landmarks were discernible. On the other hand, HWK fixation prior to preservation in 80% ethanol enabled visualisation of 11 of the 15 age-specific morphological landmarks that were discernible in living embryos. Therefore, HWK fixation prior to preservation in 80% ethanol is recommended for egg samples, thus unifying the protocols for collecting entomological evidence. PMID- 26753873 TI - Ornithine transcarbamylase deficiency of a male newborn with fatal outcome. AB - Ornithine transcarbamylase deficiency (OTCD) is the most common malfunction of ureagenesis. The case of a male newborn who died at the age of 2 days for clinically unclear reasons is presented. The post-mortem routine and esoteric testing methods that finally led to the diagnosis of a fatal case of OTCD are outlined here. PMID- 26753874 TI - Tissue Levels of Stefin A and Stefin B in Hepatocellular Carcinoma. AB - Stefins have been reported to be associated with the progression and metastasis of various malignant tumors. However, the expressions of stefins in hepatocellular carcinoma (HCC) have not been well-defined. In this study, the protein levels of stefin A and stefin B were assessed by immunohistochemical staining, and the mRNA levels were quantified by real-time polymerase chain reaction in 85 primary HCC tissues, 85 surrounding non-cancerous tissues, and 9 normal hepatic tissues. The immunohistochemical staining of cathepsin B and cathepsin D, and the ratio of cathepsins to stefins were assessed. The mRNA expressions of stefin A and stefin B in HCC tissues were significantly higher than surrounding noncancerous tissues and normal hepatic tissues, respectively. A significant positive relationship of stefin A and stefin B was found with node metastasis, tumor size, and Edmondson grade for HCC. Univariate and multivariate analyses revealed that Edmondson grade and stefin B expression were independent factors associated with the risk of lymph node metastasis in HCC. The ratios of cathepsin B to stefin A, cathepsin D to stefin A, cathepsin B to stefin B and cathepsin D to stefin B of the HCC group were significantly higher than that of the surrounding noncancerous group. A significant positive correlation between the ratio of cathepsins to stefins (cathepsin B/stefin A, cathepsin B/stefin B and cathepsin D/stefin B) and node metastasis was demonstrated. We concluded that high expressions of stefin A and stefin B may be an important factor contributing to the development and metastasis of HCC. PMID- 26753876 TI - Non-medical factors affecting antenatal preferences for delivery route and actual delivery mode of women in southwestern Iran. AB - OBJECTIVE: Assessment of the contribution of non-medical factors to mode of delivery and birth preference in Iranian pregnant women in southwestern Iran. STUDY DESIGN: This cohort study used data from a structured questionnaire completed in early pregnancy and information about the subsequent delivery obtained through personal contact. Women were recruited by random sampling from antenatal clinics when scheduling visits over the course of 5 weeks from December 2012 to February 2013 and were followed-up 1 month after birth. Of the 2199 women recruited, 99.63% were eligible for the study. RESULTS: Of the 748 women who expressed a desire to deliver their babies by cesarean section (CS) in early pregnancy, 87% had an elective cesarean section. The logistic regression analyses showed that normative beliefs (odds ratio [OR] 1.792, 95% confidence interval (1) 1.073-2.993), control beliefs (OR: 0.272, 95% CI: 0.162-0.459), and evaluation of outcomes (OR: 0.431, 95% CI: 0.268-0.692) favored the preference for cesarean section. The desire for delivery by elective cesarean section was associated with normative beliefs (OR: 1.138; 95% CI: 1.001-1.294), control beliefs (OR: 0.804; 95% CI: 0.698-0.927), and expectations about maternity care (OR: 0.772; 95% CI: 0.683-0.873), medical influences (OR: 1.150; 95% CI: 1.023-1.291), evaluation of outcome (OR: 0.789; 95% CI: 0.696-0.894), age, preference for cesarean section (OR: 5.445; 95% CI: 3.928-7.546), spouse educational level, and number of live births. CONCLUSIONS: A woman's preference for delivery by cesarean section influenced their subsequent mode of delivery. Asking women in early pregnancy about their preferred mode of delivery provides the opportunity to extend their supports which might reduce the rate of elective cesarean section. This decision is affected by age, spouse educational level, number of live births, and preconceived maternal attitudes about delivery. PMID- 26753875 TI - TNF-alpha and IL-1beta-activated human mesenchymal stromal cells increase airway epithelial wound healing in vitro via activation of the epidermal growth factor receptor. AB - BACKGROUND: Mesenchymal stromal cells (MSCs) are investigated for their potential to reduce inflammation and to repair damaged tissue. Inflammation and tissue damage are hallmarks of chronic obstructive pulmonary disease (COPD) and MSC infusion is a promising new treatment for COPD. Inflammatory mediators attract MSCs to sites of inflammation and affect their immune-modulatory properties, but little is known about their effect on regenerative properties of MSCs. This study investigates the effect of the pro-inflammatory cytokines TNF-alpha and IL-1beta on the regenerative potential of MSCs, using an in vitro wound healing model of airway epithelial cells. METHODS: Standardized circular wounds were created by scraping cultures of the airway epithelial cell line NCI-H292 and primary bronchial epithelial cells cultured at the air-liquid interface (ALI-PBEC), and subsequently incubated with MSC conditioned medium (MSC-CM) that was generated in presence or absence of TNF-alpha/IL-1beta. Remaining wound size was measured up to 72 h. Phosphorylation of ERK1/2 by MSC-CM was assessed using Western blot. Inhibitors for EGFR and c-Met signaling were used to investigate the contribution of these receptors to wound closure and to ERK1/2 phosphorylation. Transactivation of EGFR by MSC-CM was investigated using a TACE inhibitor, and RT PCR was used to quantify mRNA expression of several growth factors in MSCs and NCI-H292. RESULTS: Stimulation of MSCs with the pro-inflammatory cytokines TNF alpha and IL-1beta increased the mRNA expression of various growth factors by MCSs and enhanced the regenerative potential of MSCs in an in vitro model of airway epithelial injury using NCI-H292 airway epithelial cells. Conditioned medium from cytokine stimulated MSCs induced ERK1/2 phosphorylation in NCI-H292, predominantly via EGFR; it induced ADAM-mediated transactivation of EGFR, and it induced airway epithelial expression of several EGFR ligands. The contribution of activation of c-Met via HGF to increased repair could not be confirmed by inhibitor experiments. CONCLUSION: Our data imply that at sites of tissue damage, when inflammatory mediators are present, for example in lungs of COPD patients, MSCs become more potent inducers of repair, in addition to their well-known immune-modulatory properties. PMID- 26753877 TI - Micro/Nano hierarchical peony-like Al doped ZnO superhydrophobic film: The guiding effect of (100) preferred seed layer. AB - In this communication, we present a versatile and controllable strategy for formation of superhydrophobic micro/nano hierarchical Al doped ZnO (AZO) films with a water contact angle (CA) of 170 +/- 4 degrees . This strategy involves a two-step layer-by-layer process employing an atomic layer deposition (ALD) technique followed by a hydrothermal method, and the resulting novel AZO surface layer consists of (100) dominant nano-rice-like AZO seed layer (the water CA of 110 +/- 4 degrees ) covered with micro-peony-like AZO top. The growth mechanisms and superhydrophobic properties of the hierarchical AZO layer are discussed. It is believed that the present route holds promise for future success in the design and development of practical superhydrophobic materials. PMID- 26753878 TI - Usage of a Responsible Gambling Tool: A Descriptive Analysis and Latent Class Analysis of User Behavior. AB - Gambling is a common pastime around the world. Most gamblers can engage in gambling activities without negative consequences, but some run the risk of developing an excessive gambling pattern. Excessive gambling has severe negative economic and psychological consequences, which makes the development of responsible gambling strategies vital to protecting individuals from these risks. One such strategy is responsible gambling (RG) tools. These tools track an individual's gambling history and supplies personalized feedback and might be one way to decrease excessive gambling behavior. However, research is lacking in this area and little is known about the usage of these tools. The aim of this article is to describe user behavior and to investigate if there are different subclasses of users by conducting a latent class analysis. The user behaviour of 9528 online gamblers who voluntarily used a RG tool was analysed. Number of visits to the site, self-tests made, and advice used were the observed variables included in the latent class analysis. Descriptive statistics show that overall the functions of the tool had a high initial usage and a low repeated usage. Latent class analysis yielded five distinct classes of users: self-testers, multi-function users, advice users, site visitors, and non-users. Multinomial regression revealed that classes were associated with different risk levels of excessive gambling. The self-testers and multi-function users used the tool to a higher extent and were found to have a greater risk of excessive gambling than the other classes. PMID- 26753879 TI - Is being overweight associated with engagement in self-injurious behaviours in adolescence, or do psychological factors have more "weight"? AB - INTRODUCTION: The purpose of this study was to examine the prevalence of non suicidal self-injurious behaviours (NSSI) among healthy weight and overweight adolescents and to examine the role of age, gender, weight status, treatment condition for weight control, and psychological variables (psychopathological symptoms and emotional skills) in the prediction of NSSI. METHODS: The study had a cross-sectional design, and participants (n = 370) were aged 14-19 years and were divided in three groups: 205 adolescents with normal weight, 82 adolescents from the community with overweight/obesity, and 83 adolescents with overweight/obesity and in outpatient treatment for weight control. RESULTS: The prevalence of these behaviours in the overweight community group (25.6 %) and in the overweight clinical group (14.5 %) was similar to their healthy weight peers (19 %). Not attending an outpatient treatment for weight control, higher psychopathology and less ability to regulate emotions predict the presence of NSSI. CONCLUSION: Being overweight is not associated with NSSI, but psychosocial variables such as psychopathology, emotional deregulation and the absence of medical care predict these behaviours. PMID- 26753880 TI - (18)F-fluoride positron emission tomography/computed tomography and bone scintigraphy for diagnosis of bone metastases in newly diagnosed, high-risk prostate cancer patients: study protocol for a multicentre, diagnostic test accuracy study. AB - BACKGROUND: For decades, planar bone scintigraphy has been the standard practice for detection of bone metastases in prostate cancer and has been endorsed by recent oncology/urology guidelines. It is a sensitive method with modest specificity. (18)F-fluoride positron emission tomography/computed tomography has shown improved sensitivity and specificity over bone scintigraphy, but because of methodological issues such as retrospective design and verification bias, the existing level of evidence with (18)F-fluoride positron emission tomography/computed tomography is limited. The primary objective is to compare the diagnostic properties of (18)F-fluoride positron emission tomography/computed tomography versus bone scintigraphy on an individual patient basis. METHODS/DESIGN: One hundred forty consecutive, high-risk prostate cancer patients will be recruited from several hospitals in Denmark. Sample size was calculated using Hayen's method for diagnostic comparative studies. This study will be conducted in accordance with recommendations of standards for reporting diagnostic accuracy studies. Eligibility criteria comprise the following: 1) biopsy-proven prostate cancer, 2) PSA >= 50 ng/ml (equals a prevalence of bone metastasis of ~ 50% in the study population on bone scintigraphy), 3) patients must be eligible for androgen deprivation therapy, 4) no current or prior cancer (within the past 5 years), 5) ability to comply with imaging procedures, and 6) patients must not receive any investigational drugs. Planar bone scintigraphy and (18)F-fluoride positron emission tomography/computed tomography will be performed within a window of 14 days at baseline. All scans will be repeated after 26 weeks of androgen deprivation therapy, and response of individual lesions will be used for diagnostic classification of the lesions on baseline imaging among responding patients. A response is defined as PSA normalisation or >= 80% reduction compared with baseline levels, testosterone below castration levels, no skeletal related events, and no clinical signs of progression. Images are read by blinded nuclear medicine physicians. The protocol is currently recruiting. DISCUSSION: To the best of our knowledge, this is one of the largest prospective studies comparing (18)F-fluoride positron emission tomography/computed tomography and bone scintigraphy. It is conducted in full accordance with recommendations for diagnostic accuracy trials. It is intended to provide valid documentation for the use of (18)F-fluoride positron emission tomography/computed tomography for examination of bone metastasis in the staging of prostate cancer. PMID- 26753881 TI - Policing, Community Fragmentation, and Public Health: Observations from Baltimore. AB - Studies show that policing, when violent, and community fragmentation have a negative impact on health outcomes. This current study investigates the connection of policing and community fragmentation and public health. Using an embedded case study analysis, semi-structured interviews were conducted with 21 African-American female and male residents, ages 21-64 years of various neighborhoods of high arrest rates and health and socioeconomic depravation in Baltimore City, MD. Baltimore residents' perceptions of policing, stress, community fragmentation, and solutions are presented. Analysis of the perceptions of these factors suggests that violent policing increases community fragmentation and is a public health threat. Approaches to address this public health threat are discussed. PMID- 26753882 TI - LifeSkills for Men (LS4M): Pilot Evaluation of a Gender-Affirmative HIV and STI Prevention Intervention for Young Adult Transgender Men Who Have Sex with Men. AB - Young adult transgender men who have sex with men (TMSM) engage in sexual behaviors that place them at risk of sexually transmitted infections (STIs) including HIV. To date, no HIV and STI prevention interventions have been developed specifically for young adult TMSM. To address this gap, the current study aimed to (1) adapt a small group-based behavioral HIV prevention intervention designed for young transgender women ("LifeSkills") to address the unique HIV and STI prevention needs of young TMSM ages 18-29 years and (2) conduct a pilot evaluation of the intervention ("LifeSkills for Men"; LS4M). LS4M was carried out in an iterative approach with community input along the way, which allowed for refinement of the intervention manual and enhanced participant acceptability. A LS4M Task Force was convened to guide intervention development/adaptation and study implementation. Initially, focus groups were conducted to examine the sexual health needs, concerns, and stressors facing young TMSM (n = 12; mean age = 23.8 years; 16.7% people of color). Next, LS4M was pilot tested (n = 17; mean age = 24.3 years; 23.5% people of color) to assess acceptability with the study population and feasibility of all study procedures. Overall attendance, participation rates, and positive feedback from participants demonstrate that LS4M is highly acceptable and feasible to carry out with young TMSM. Trends in outcome measures across 4 months of follow-up suggest that participation in the intervention may improve mental health, reduce internalized stigma, and reduce HIV- and STI-related risk behaviors. Further testing of the intervention enrolling young TMSM with recent sexual risk behavior at baseline and with a control group is warranted. Lessons learned for future work with young TMSM are discussed. PMID- 26753885 TI - Welcome to the New Red Section. PMID- 26753884 TI - Colonoscopy Reduces Colorectal Cancer Incidence and Mortality in Patients With Non-Malignant Findings: A Meta-Analysis. AB - OBJECTIVES: Observational studies have shown that colonoscopy reduces colorectal cancer (CRC) incidence and mortality in the general population. We aimed to conduct a meta-analysis quantifying the magnitude of protection by colonoscopy, with screening and diagnostic indications, against CRC in patients with non malignant findings and demonstrating the potentially more marked effect of screening over diagnostic colonoscopy. METHODS: PubMed, EMBASE, and conference abstracts were searched through 30 April 2015. The primary outcomes were overall CRC incidence and mortality. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effect models. RESULTS: Eleven observational studies with a total of 1,499,521 individuals were included. Pooled analysis showed that colonoscopy was associated with a 61% RR reduction in CRC incidence (RR: 0.39; 95% CI: 0.26-0.60; I(2)=93.6%) and a 61% reduction in CRC mortality (RR: 0.39; 95% CI: 0.35-0.43; I(2)=12.0%) in patients with non malignant findings, although there was high heterogeneity for the outcome of CRC incidence. After excluding one outlier study, there was low heterogeneity for the outcome of incidence (I(2)=44.7%). Subgroup analysis showed that the effect of screening colonoscopy was more prominent, corresponding to an 89% reduction in CRC incidence (RR: 0.11; 95% CI: 0.08-0.15), in comparison with settings involving diagnostic colonoscopy (RR: 0.51; 95% CI: 0.43-0.59; P<0.001). CONCLUSIONS: On the basis of this meta-analysis of observational studies, CRC incidence and mortality in patients with non-malignant findings are significantly reduced after colonoscopy. The effect of screening colonoscopy on CRC incidence is more marked than diagnostic colonoscopy. PMID- 26753883 TI - Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress. AB - Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma presenting mostly in children and young adults. The natural progression of this disease is largely unknown as is the identity of its true cell of origin. Here we present a model of peripheral ALCL pathogenesis where the malignancy is initiated in early thymocytes, before T-cell receptor (TCR) beta-rearrangement, which is bypassed in CD4/NPM-ALK transgenic mice following Notch1 expression. However, we find that a TCR is required for thymic egress and development of peripheral murine tumours, yet this TCR must be downregulated for T-cell lymphomagenesis. In keeping with this, clonal TCR rearrangements in human ALCL are predominantly in-frame, but often aberrant, with clonal TCRalpha but no comparable clonal TCRbeta rearrangement, yielding events that would not normally be permissive for survival during thymic development. Children affected by ALCL may thus harbour thymic lymphoma-initiating cells capable of seeding relapse after chemotherapy. PMID- 26753886 TI - Diagnostic Performance of the Simple Clinical Colitis Activity Index Self Administered Online at Home by Patients With Ulcerative Colitis: CRONICA-UC Study. AB - OBJECTIVES: New e-health technologies can improve patient-physician communication and contribute to optimal patient care. We compared the diagnostic performance of the Simple Clinical Colitis Activity Index (SCCAI) self-administered by patients with ulcerative colitis (UC) at home (through a website) with the in-clinic gastroenterologist-assessed SCCAI. METHODS: Patients were followed-up over 6 months. At months 3 and 6, patients completed the SCCAI online at home; within 48 h, gastroenterologists (blinded to patients' scores) completed the in-clinic SCCAI (reference). SCCAI scores were dichotomized to remission or active disease, and SCCAI changes in disease activity from month 3 to 6 were classed as worsening, stability, or improvement. RESULTS: A total of 199 patients (median age: 38 years; 56% female) contributed with 340 pairs of questionnaires. Correlation of SCCAI scores by patients and physicians was good (Spearman's rho=0.79), with 85% agreement for remission or activity (95% CI: 80.8-88.6, kappa=0.66). The negative predictive value for active disease was 94.5% (91.4 96.6); the positive predictive value was 68.0% (58.8-69.2). Agreement between patient and physician was higher in the 168 month 6 pairs than in the 172 month 3 pairs of questionnaires (89.3% (83.6-93.1) vs. 80.8% (74.2-86.0), P=0.027). CONCLUSIONS: In patients with UC, SCCAI self-administration via an online tool resulted in a high percentage of agreement with evaluation by gastroenterologists, with a remarkably high negative predictive value for disease activity. Remote monitoring of UC patients is possible and might reduce hospital visits. PMID- 26753889 TI - How I Approach Retroflexion and Prevention of Right-Sided Colon Cancer Following Colonoscopy. PMID- 26753887 TI - Adverse Event and Complication Management in Gastrointestinal Endoscopy. AB - Gastrointestinal endoscopy is a remarkably safe set of diagnostic and therapeutic techniques, and yet a small number of significant complications and adverse events are expected. Serious complications may have a material effect on the patient's health and well-being. They need to be anticipated and prevented if possible and managed effectively when identified. When complications occur they need to be discussed frankly with patients and their families. Informed consent, prevention, early detection, reporting, and systems improvement are critical aspects of effective complication management. Optimal complication management may improve patient satisfaction and outcome, as well as preserving the reputation and confidence of the endoscopist, and may minimize litigation. PMID- 26753888 TI - In the Intestinal Mucosa of Children With Potential Celiac Disease IL-21 and IL 17A are Less Expressed than in the Active Disease. AB - OBJECTIVES: Potential celiac disease (CD) patients are at an increased risk to developing CD as indicated by positive CD-associated serology. We investigated in duodenal mucosa of such patients the presence of both IL-21 and IL-17A and the role of gliadin peptides and IL-15 in their expression. METHODS: Duodenal biopsies from 76 active CD, 90 potential CD, and 58 control patients were analyzed for IL-21 and/or IL-17A production by quantitative real-time PCR, immunohistochemistry, flow cytometry, and ELISA. The presence of IL-21 receptor was investigated by western blot. Potential CD duodenal fragments were cultured with gliadin peptides (PTG) and/or IL-15 and the expression/production of IL-21 and IL-17A assessed by quantitative real-time PCR and by immunohistochemistry. RESULTS: In potential CD, IL-21 was lower than in active CD, in terms of RNA expression (P<0.01), density of lamina propria (LP) IL-21(+) cells (P<0.05), and protein secretion (P<0.05). Also, IL-21R was weakly detectable in potential CD. Several LP cell types produced IL-21 in CD. In potential CD, CD4(+)IL-21(+) cells increased after PMA-ionomycin stimulation and co-produced IFN-gamma but not IL 17A. After 24 hours of culture stimulation with PTG, IL-21-producing cells increased but not the ones producing IL-17A. This increase was further enhanced by the addition of IL-15 to culture medium. CONCLUSIONS: In potential CD, IL-21 is less expressed than in active CD; however, IL-21-producing cells are present and prone to respond after specific stimuli. This suggests a key role of IL-21 in the progression of mucosal damage in CD. PMID- 26753890 TI - The American Journal of Gastroenterology in 2016: Where Have We Been? Where Are We Going? PMID- 26753891 TI - Worldwide Inverse Association between Gastric Cancer and Esophageal Adenocarcinoma Suggesting a Common Environmental Factor Exerting Opposing Effects. AB - OBJECTIVES: The incidence of esophageal adenocarcinoma (EAC) is increasing while adenocarcinoma of the stomach is decreasing. We have investigated whether the incidences of these two cancers and their time trends might be inversely related pointing to a common environmental factor exerting opposite effects on these cancers. METHODS: For cross-sectional analyses data were abstracted from "Cancer Incidence in Five Continents" (CI5) Volume X and GLOBOCAN 2012. Relevant ICD-10 codes were used to locate esophageal and gastric cancers anatomically, and ICD-O codes for the histological diagnosis of EAC. For longitudinal analyses, age standardized rates (ASRs) of EAC and total gastric cancer (TGC) were extracted from CI5C-Plus. RESULTS: Estimated (2012) ASRs were available for 51 countries and these showed significant negative correlations between EAC and both TGC (males: correlation coefficient (CC)=-0.38, P=0.006, females: CC=-0.41, P=0.003) and non-cardia gastric cancer rates (males: CC=-0.41, P=0.003 and females: CC= 0.43, P=0.005). Annual incidence trends were analyzed for 38 populations through 1989-2007 and showed significant decreases for TGC in 89% and increases for EAC in 66% of these, with no population showing a fall in the latter. Significant negative correlation between the incidence trends of the two cancers was observed in 27 of the 38 populations over the 19-50 years of available paired data. Super imposition of the longitudinal and cross-sectional data indicated that populations with a current high incidence of EAC and low incidence of gastric cancer had previously resembled countries with a high incidence of gastric cancer and low incidence of EAC. CONCLUSIONS: The negative association between gastric cancer and EAC in both current incidences and time trends is consistent with a common environmental factor predisposing to one and protecting from the other. PMID- 26753892 TI - Imipramine for Treatment of Esophageal Hypersensitivity and Functional Heartburn: A Randomized Placebo-Controlled Trial. AB - OBJECTIVES: Tricyclic antidepressants could be effective in the treatment of symptoms related to hypersensitive esophagus through their pain-modulating effect. We therefore assessed the benefit of imipramine in patients with esophageal hypersensitivity and functional heartburn. METHODS: Patients with normal endoscopy findings and typical reflux symptoms despite standard-dose proton-pump inhibitor therapy underwent 24-h pH-impedance monitoring. Patients with established esophageal hypersensitivity or functional heartburn were randomly assigned to receive 8 weeks of either once-daily imipramine 25 mg (n=43) or placebo (n=40). The primary end point was satisfactory relief of reflux symptoms, defined as a >50% reduction in the gastroesophageal reflux disease score. The secondary end point was improvement in quality-of-life (QoL) as assessed by the 36-Item Short Form Health Survey score. RESULTS: Patients receiving imipramine did not achieve a higher rate of satisfactory relief of reflux symptoms than did patients receiving placebo (intention-to-treat (ITT) analysis: 37.2 vs. 37.5%, respectively; odds ratio (OR), 0.99; 95% confidence interval (CI), 0.41-2.41; per-protocol (PP) analysis: 45.5 vs. 41.2%, respectively; OR, 1.19; 95% CI, 0.45-3.13). Subgroup analysis to assess the efficacy of imipramine for either esophageal hypersensitivity or functional heartburn yielded similar results. Treatment with imipramine provided significant improvement of QoL by PP analysis (72+/-17 and 61+/-19, respectively; P=0.048), but ITT analysis did not reveal any differences between imipramine and placebo (68+/-19 and 61+/-19, respectively; P=0.26). Adverse events were similar in both groups; however, constipation was more common with imipramine than placebo (51.2 vs. 22.5%, respectively; P=0.01). CONCLUSIONS: Although low-dose imipramine shows potential QoL benefits, it does not relieve symptoms more effectively than does placebo in patients with either esophageal hypersensitivity or functional heartburn. PMID- 26753893 TI - Anal Intercourse and Fecal Incontinence: Evidence from the 2009-2010 National Health and Nutrition Examination Survey. AB - OBJECTIVES: The aim of this study was to assess the prevalence and associations between anal intercourse and fecal incontinence. METHODS: Analyses were based on data from 6,150 adults (>=20 years) from the 2009-2010 cycle of the National Health and Nutrition Examination Surveys. Fecal incontinence was defined as the loss of liquid, solid, or mucus stool occurring at least monthly on a validated questionnaire. A gender-specific sexual behavior questionnaire assessed any anal intercourse via an audio computer-assisted personal interview. Co-variables included: age, race, education, poverty income ratio, body mass index, chronic illnesses, depression, loose stool consistency (Bristol Stool Scale types 6 or 7), and reproductive variables in women. Prevalence estimates and prevalence odds ratios (PORs) were analyzed in adjusted multivariable models using appropriate sampling weights. RESULTS: Overall, 4,170 adults aged 20-69 years (2,070 women and 2,100 men) completed sexual behavior questionnaires and responded to fecal incontinence questions. Anal intercourse was higher among women (37.3%) than men (4.5%), P<0.001. Fecal incontinence rates were higher among women (9.9 vs. 7.4%, P=0.05) and men (11.6 vs. 5.3%, P=0.03) reporting anal intercourse compared with those not reporting anal intercourse. After multivariable adjustment for other factors associated with fecal incontinence, anal intercourse remained a predictor of fecal incontinence among women (POR: 1.5; 95% confidence interval (CI): 1.0 2.0) and men (POR: 2.8; 95% CI: 1.6-5.0). CONCLUSIONS: The findings support the assessment of anal intercourse as a factor contributing to fecal incontinence in adults, especially among men. PMID- 26753895 TI - Insulin-like growth factor-binding protein-1 (IGFBP-1) in goldfish, Carassius auratus: molecular cloning, tissue expression, and mRNA expression responses to periprandial changes and cadmium exposure. AB - In this study, the cDNA encoding insulin-like growth factor-binding protein-1 (IGFBP-1) was cloned from the liver of goldfish (Carassius auratus). The obtained goldfish IGFBP-1 cDNA sequence was 1037 bp in length and had an open reading frame of 789 bp encoding a predicted polypeptide of 262 amino acid residues. IGFBP-1 transcript was detected in all tested central nervous and peripheral tissues. The relatively higher levels of IGFBP-1 mRNA were observed in the liver, gill, kidney, heart, spleen, fat and testis, while the lower levels were found in all different regions of brain, muscle and intestine. In the skin, IGFBP-1 mRNA expression level was extremely low. The IGFBP-1 mRNA expression level in liver was significantly elevated after feeding. With cadmium exposure for 24 h, IGFBP-1 mRNA expression levels in spleen and liver were significantly increased at different cadmium concentrations ranging from 0.5 to 10 ppm. The results in this study provided the data regarding molecular characteristics and expression patterns of IGFBP-1 in goldfish and showed that the expression of IGFBP-1 mRNA might be associated with metabolic status and heavy metal stress and regulated by metabolic factors and cadmium in fish. PMID- 26753896 TI - Which group of smokers is more vulnerable to the economic crisis? AB - OBJECTIVES: Studies investigating whether smoking increases or decreases during economic downturn provided contrasting results. For the first time, we used direct questions to analyse changes in smoking behaviour due to the 2008 financial crisis, comparing socio-economic characteristics of smokers who changed with those who kept their smoking intensity. STUDY DESIGN: Cross-sectional survey. METHODS: We used data from three annual surveys conducted in Italy in 2012-2014 on representative samples of the Italian general population aged >=15 years. RESULTS: A total of 1919 current smokers were asked specific questions on the influence of the economic crisis that started in 2008 on their smoking behaviour. Overall, 77.4% of 1919 current smokers reported not to have changed their smoking behaviour, 19.1% to have reduced, and 3.5% to have increased their smoking intensity as a consequence of the economic crisis. The reduction in cigarette smoking increased with age: compared to the respondents aged <25 years, the multivariate odds ratio (OR) for those aged 25-44, 45-64 and >=65 years were 0.65, 0.46 and 0.33, respectively (P for trend<0.001). Reduction was significantly lower among intermediate (OR = 0.68 compared to low) and high education levels (OR = 0.28; P for trend<0.001). A significant inverse trend for increasing consumption was observed with age (P = 0.022), education (P = 0.003) and family income (P < 0.001). CONCLUSIONS: The large majority of current smokers did not change their smoking habit following the economic crisis. However, there are specific vulnerable subgroups of smokers, constituted by the young and subjects with low socio-economic status, that were reactive to the global economic crisis. These groups are more prone to change their smoking behaviours, either for better or -, in a smaller proportion -, for worse. PMID- 26753894 TI - Outcomes of Esophageal Dilation in Eosinophilic Esophagitis: Safety, Efficacy, and Persistence of the Fibrostenotic Phenotype. AB - OBJECTIVES: Esophageal dilation is commonly performed in eosinophilic esophagitis (EoE), but there are few long-term data. The aims of this study were to assess the safety and long-term efficacy of esophageal dilation in a large cohort of EoE cases, and to determine the frequency and predictors of requiring multiple dilations. METHODS: We conducted a retrospective cohort study in the University of North Carolina EoE Clinicopathological Database from 2002 to 2014. Included subjects met consensus diagnostic criteria for EoE. Clinical, endoscopic, and histologic features were extracted, as were dilation characteristics (dilator type, change in esophageal caliber, and total number of dilations) and complications. Patients with EoE who had undergone dilation were compared with those who did not and also stratified by whether they required single or multiple dilations. RESULTS: Of 509 EoE patients, 164 were dilated a total of 486 times. Those who underwent dilation had a longer duration of symptoms before diagnosis (11.1 vs. 5.4 years, P<0.001). Ninety-five patients (58%) required >1 dilation (417 dilations total, mean of 4.4+/-4.3 per patient). The only predictor of requiring multiple dilations was a smaller baseline esophageal diameter. Dilation was tolerated well, with no major bleeds, perforations, or deaths. The overall complication rate was 5%, primarily due to post-procedural pain. Of 164 individuals dilated, a majority (58% or 95/164) required a second dilation. Of these individuals, 75% required repeat dilation within 1 year. CONCLUSIONS: Dilation in EoE is well-tolerated, with a very low risk of serious complications. Patients with long-standing symptoms before diagnosis are likely to require dilation. More than half of those dilated will require multiple dilations, often needing a second procedure within 1 year. These findings can be used to counsel patients with fibrostenotic complications of EoE. PMID- 26753897 TI - Spike processing with a graphene excitable laser. AB - Novel materials and devices in photonics have the potential to revolutionize optical information processing, beyond conventional binary-logic approaches. Laser systems offer a rich repertoire of useful dynamical behaviors, including the excitable dynamics also found in the time-resolved "spiking" of neurons. Spiking reconciles the expressiveness and efficiency of analog processing with the robustness and scalability of digital processing. We demonstrate a unified platform for spike processing with a graphene-coupled laser system. We show that this platform can simultaneously exhibit logic-level restoration, cascadability and input-output isolation--fundamental challenges in optical information processing. We also implement low-level spike-processing tasks that are critical for higher level processing: temporal pattern detection and stable recurrent memory. We study these properties in the context of a fiber laser system and also propose and simulate an analogous integrated device. The addition of graphene leads to a number of advantages which stem from its unique properties, including high absorption and fast carrier relaxation. These could lead to significant speed and efficiency improvements in unconventional laser processing devices, and ongoing research on graphene microfabrication promises compatibility with integrated laser platforms. PMID- 26753898 TI - Short-term prognostic factors in myelomeningocele patients. AB - PURPOSE: Patients with myelomeningocele have a high mortality and neurological disabilities that are correlated with the anatomical characteristics of the defect and with the development of acquired complications. The challenge in the postnatal management of myelomeningocele (MMC) is the early recognition of cases at risk for complications in order to establish individualized treatment strategies. This study aims to identify short-term prognostic markers for newborns with MMC. Anatomical characteristics of the spinal defect and technical aspects of the neurosurgical correction were analyzed for this purpose. METHODS: A retrospective cohort study was conducted in 70 patients with MMC born between January 2007 and December 2013. Features of MMC anatomy and neurosurgical treatment were analyzed for the following outcomes: neonatal resuscitation, length of hospital stay, need for ventricular shunt, wound dehiscence, wound infection, central nervous system infection, and sepsis. RESULTS: Large MMC was associated with central nervous system (CNS) infection, wound complications, and longer hospital stay. Patients with thoracic MMC required longer hospital stay. Surgical repair performed after 48 h of life increased in 5.72 times the risk of CNS infection. Absence of antenatal hydrocephalus was a favorable prognostic marker. CONCLUSION: Extent of the spinal cord defect and the time of surgical correction influenced the short-term outcomes of patients with myelomeningocele. Extensive lesions were associated with higher rates of CNS infections, surgical wound complications, and prolonged hospital stay. Interventions performed within 48 h after birth significantly reduced occurrence of CNS infections. Absence of antenatal hydrocephalus was associated with fewer complications in the first days of life. PMID- 26753899 TI - Shotgun pellet embolization to the posterior cerebral artery. AB - INTRODUCTION: Projectile embolization to the cerebral vasculature and is almost exclusively seen in the anterior circulation due to the greater diameter and flow of the internal carotid arteries. In children, this phenomenon is ever rarer. METHODS: We present a case of a 9-year-old boy who suffered from a shotgun blast to the thorax and abdomen. He was subsequently found to have a pellet that had presumably traveled from either the left ventricle or directly via the subclavian artery to the vertebrobasilar system to become lodged in the P3 segment of his posterior cerebral artery. RESULTS: The patient developed a small occipital infarct with a corresponding right superior quadrantanopsia. He was managed as an inpatient non-operatively with a heparin drip and was placed on long-term low dose aspirin on discharge. The patient recovered well from his injury and remains neurologically stable 2 years after the initial injury. Interval imaging demonstrated that the pellet remains stable in its position. DISCUSSION: To our knowledge, this represents the first non-fatal missile embolus to the posterior cerebral artery in a pediatric patient. Patients with minimal symptoms may benefit from conservative management given the inherent risks of embolectomy. PMID- 26753901 TI - Response to comment to "Magnetic resonance imaging findings of bilateral thalamic involvement in severe paroxysmal sympathetic hyperactivity: a pediatric case series". PMID- 26753900 TI - Secondary adult encephalocele with abscess formation of calcified frontal sinus mucocele. AB - INTRODUCTION: Although encephalocele is a rare congenital abnormality, secondary encephalocele is extremely rare and can cause fatal complications. Here, we report a case of secondary encephalocele caused by frontal sinus wall defect due to chronic sinusitis, which was completely removed by cranialization with autologous bone graft. A 50-year-old man with a 10-year history of chronic sinusitis visited our hospital due to suddenly altered mentality characterized by stupor. Computerized tomography scanning and magnetic resonance imaging revealed an enlarged left frontal sinus with sinusitis. The frontal sinus cavity was calcified, and the left frontal lobe had herniated into the cavity accompanied by yellow pus. A large dural defect was also found around the frontal sinus area. After removal of the abscess and some of the frontal lobe, frontal skull base repair by cranialization was performed using autologous bone graft. Streptococcus pneumoniae was cultured from the cerebrospinal fluid (CSF), necessitating treatment with antibiotics. After the operation, the mental status of the patient improved and no CSF leakage was observed. DISCUSSION: In addition to correct diagnosis and early treatment including antibiotics, the surgical repair of defects is needed in patients with secondary encephalocele to prevent further episodes of meningitis. Surgical correction of frontal sinus encephalocele can be achieved through bifrontal craniotomy or endoscopic transnasal repair. If a patient has CSF leakage, open craniotomy may facilitate repair of the dural defect and allow for cranialization of the sinus. CONCLUSIONS: Removal of dysplastic herniated brain tissue and cranialization of the frontal sinus may be a good option for treating secondary encephalocele and its associated complications, including meningitis, abscess formation, and infarction of the herniated brain parenchyma. PMID- 26753902 TI - The natural history and management of patients with congenital deficits associated with lumbosacral lipomas. AB - INTRODUCTION: Many patients with lumbosacral lipoma are asymptomatic; however, a significant proportion will have neurological deficits present at birth. Implication of these deficits with respect to natural history and management are not well understood. METHODS: A retrospective review of all infants with lumbosacral lipoma seen at BCCH between 1997 and 2013 was carried out. The study population was stratified on the presence of a congenital, non-progressive deficit and subdivided on treatment approach. The subsequent developments of deficits resulting in untethering procedures were recorded. RESULTS: Of the 44 infants in this study, 24 patients had no neurologic deficit while 20 patients had a fixed, non-progressive deficit evident at birth. Ten of 24 patients without a neurological deficit at birth underwent a prophylactic untethering with 3 eventually requiring repeat untethering after, on average, 62.7 months. Eleven of 14 asymptomatic, monitored patients required untethering for clinical deterioration. Two required a second untethering procedure after 48.7 months. Ten of 20 infants with congenital deficits present at birth underwent prophylactic untethering, and 4 required further surgery after 124 months. Ten patients underwent observation with 8 eventually requiring surgery. Two required repeat untethered after 154 months. The complication rates and operative burden for patients are similar whether prophylactic or delayed surgery is performed. CONCLUSION: The presence of congenital neurologic deficit does not affect the likelihood of deterioration in patients managed expectantly; prophylactic detethering of these patients did not prevent delayed neurologic deterioration. Comparing the need for repeat surgery in prophylactically untethered patients with initial untethering of patients operated upon at the time of deterioration, prophylactic untethering may confer a benefit with respect to subsequent symptomatic tethering if complication rates are low. However, in a setting with multidisciplinary follow-up, a period of observation for patients and intervention when patients become symptomatic is an acceptable approach for patients with or without congenital deficits. PMID- 26753903 TI - Surgical treatment of Langerhans cell histiocytosis of cervical spine: case report and review of literature. AB - INTRODUCTION: Langerhans cell histiocytosis (LCH) is a rare condition, and even rare is cervical spine involvement. CASE REPORT: A 9-year-old girl had neck pain, neck tilt and left upper limb weakness, occasional fever and positive family history of tuberculosis. Imaging showed C5 vertebral body collapse with epidural and prevertebral soft tissue collection causing cord and nerve root compression. The patient underwent C5 corpectomy and fusion. Histopathological was suggestive of LCH. She underwent radiotherapy and was asymptomatic at 1-year follow-up. CONCLUSION: Despite the rarity of the condition, the possibility of LCH should be considered in such cases. When neurologic deficits are present, operative treatment should be considered. PMID- 26753905 TI - Lacrimal gland anaplastic kinase-positive large B-cell lymphoma (LBCL-ALK+) with an atypical clinical presentation. PMID- 26753904 TI - The Type II Secreted Lipase/Esterase LesA is a Key Virulence Factor Required for Xylella fastidiosa Pathogenesis in Grapevines. AB - Pierce's disease (PD) of grapevines is caused by Xylella fastidiosa (Xf), a xylem limited gamma-proteobacterium that is responsible for several economically important crop diseases. The occlusion of xylem elements and interference with water transport by Xf and its associated biofilm have been posited as the main cause of PD symptom development; however, Xf virulence mechanisms have not been described. Analysis of the Xf secretome revealed a putative lipase/esterase (LesA) that was abundantly secreted in bacterial culture supernatant and was characterized as a protein ortholog of the cell wall-degrading enzyme LipA of Xanthomonas strains. LesA was secreted by Xf and associated with a biofilm filamentous network. Additional proteomic analysis revealed its abundant presence in outer membrane vesicles (OMVs). Accumulation of LesA in leaf regions associated positively with PD symptoms and inversely with bacterial titer. The lipase/esterase also elicited a hypersensitive response in grapevine. Xf lesA mutants were significantly deficient for virulence when mechanically inoculated into grapevines. We propose that Xf pathogenesis is caused by LesA secretion mediated by OMV cargos and that its release and accumulation in leaf margins leads to early stages of observed PD symptoms. PMID- 26753908 TI - Reply to "Intraoperative dynamic pressure measurements in carpal tunnel syndrome: Correlations with clinical signs". PMID- 26753907 TI - Effective Conversion of Metmyoglobin to Oxymyoglobin by Cysteine-Substituted Polyphenols. AB - Reaction products from the peroxidase-catalyzed oxidation of polyphenols in the presence of cysteine showed a potent activity for reducing metmyogolobin (MetMb) to bright-colored oxymyogolobin (MbO2). High-performance liquid chromatography (HPLC) purification of the reaction products from catechin, chlorogenic acid, dihydrocaffeic acid, hydroxytyrosol, nordihydroguaiaretic acid, and rosmarinic acid afforded corresponding S-cysteinyl compounds, the structures of which were determined by nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). The isolated cysteinyl polyphenols showed a concentration-dependent reducing activity for MetMb to MbO2 for the initial 1 h. However, after 1 h, some of them decreased the amount of MbO2 produced. The effect of the number of cysteinyl sulfur substitutions in polyphenols on both MetMb reduction and MbO2 maintenance was examined using hydroxytyrosols with different numbers of cysteine substitutions; these hydroxytyrosols were synthesized from hydroxytyrosol and an N-acetylcysteine methyl ester. The hydroxytyrosol derivative substituted with two N-acetylcysteine esters exhibited the most effective reducing activity without any effect on MbO2. PMID- 26753906 TI - Dynamics of the Transcriptome during Human Spermatogenesis: Predicting the Potential Key Genes Regulating Male Gametes Generation. AB - Many infertile men are the victims of spermatogenesis disorder. However, conventional clinical test could not provide efficient information on the causes of spermatogenesis disorder and guide the doctor how to treat it. More effective diagnosis and treating methods could be developed if the key genes that regulate spermatogenesis were determined. Many works have been done on animal models, while there are few works on human beings due to the limited sample resources. In current work, testis tissues were obtained from 27 patients with obstructive azoospermia via surgery. The combination of Fluorescence Activated Cell Sorting and Magnetic Activated Cell Sorting was chosen as the efficient method to sort typical germ cells during spermatogenesis. RNA Sequencing was carried out to screen the change of transcriptomic profile of the germ cells during spermatogenesis. Differential expressed genes were clustered according to their expression patterns. Gene Ontology annotation, pathway analysis, and Gene Set Enrichment Analysis were carried out on genes with specific expression patterns and the potential key genes such as HOXs, JUN, SP1, and TCF3 which were involved in the regulation of spermatogenesis, with the potential value serve as molecular tools for clinical purpose, were predicted. PMID- 26753909 TI - Strain distribution in single, suspended germanium nanowires studied using nanofocused x-rays. AB - Within the quest for direct band-gap group IV materials, strain engineering in germanium is one promising route. We present a study of the strain distribution in single, suspended germanium nanowires using nanofocused synchrotron radiation. Evaluating the probed Bragg reflection for different illumination positions along the nanowire length results in corresponding strain components as well as the nanowire's tilting and bending. By using these findings we determined the complete strain state with the help of finite element modelling. The resulting information provides us with the possibility of evaluating the validity of the strain investigations following from Raman scattering experiments which are based on the assumption of purely uniaxial strain. PMID- 26753911 TI - Facile one-pot surfactant-free synthesis of uniform Pd6Co nanocrystals on 3D graphene as an efficient electrocatalyst toward formic acid oxidation. AB - Ultrasmall and uniform Pd6Co nanocrystals were deposited on 3D graphene by a facile one-pot surfactant-free route for a catalyst toward formic acid oxidation, showing a much higher electrocatalytic activity, larger peak current density and better stability than Pd/3DG, Pd/C as well as commercial Pd-C, and thus offering great potential for an efficient anode catalyst toward high performance direct formic acid fuel cells. PMID- 26753913 TI - Markovnikov free radical addition reactions, a sleeping beauty kissed to life. AB - This review covers free radical additions, which are initiated by the formal addition of a hydrogen atom to a C[double bond, length as m-dash]C double bond. These reactions originated in the realms of inorganic chemistry, polymer chemistry, and organic chemistry, whereby barriers between these disciplines impeded the rapid implementation of the findings. PMID- 26753912 TI - Multimodality Imaging to Characterize a Metastatic Cardiac Mass. PMID- 26753910 TI - An electrostatic mechanism for Ca(2+)-mediated regulation of gap junction channels. AB - Gap junction channels mediate intercellular signalling that is crucial in tissue development, homeostasis and pathologic states such as cardiac arrhythmias, cancer and trauma. To explore the mechanism by which Ca(2+) blocks intercellular communication during tissue injury, we determined the X-ray crystal structures of the human Cx26 gap junction channel with and without bound Ca(2+). The two structures were nearly identical, ruling out both a large-scale structural change and a local steric constriction of the pore. Ca(2+) coordination sites reside at the interfaces between adjacent subunits, near the entrance to the extracellular gap, where local, side chain conformational rearrangements enable Ca(2+)chelation. Computational analysis revealed that Ca(2+)-binding generates a positive electrostatic barrier that substantially inhibits permeation of cations such as K(+) into the pore. Our results provide structural evidence for a unique mechanism of channel regulation: ionic conduction block via an electrostatic barrier rather than steric occlusion of the channel pore. PMID- 26753914 TI - Discovery of substituted pyrazol-4-yl pyridazinone derivatives as novel c-Met kinase inhibitors. AB - A series of pyridazin-3-one substituted with morpholino-pyrimidine derivatives was synthesized and evaluated as tyrosine kinase inhibitors against c-Met enzyme, and anti-proliferative activities of Hs746T human gastric cancer cell line. Most of compounds exhibited good biological activity, while compound 10, 12a, 14a displayed excellent c-Met enzyme inhibitory activities and Hs746T cell-based activities. PMID- 26753916 TI - The User, not the Tool: Perceptions of Credibility and Relevance Affect the Uptake of Prioritisation. AB - Prioritisation methods have been used in conservation planning for over 20 years. The scientific literature focuses on the technical aspects of prioritisation, providing limited information on factors affecting the uptake of priorities. We focused on the Back on Track species prioritisation program in Queensland, Australia, used to prioritise species conservation efforts across Queensland from 2005. The program had low uptake by intended users. Our study aimed to identify the perceived limitations in the technical-scientific quality of this species based prioritisation process and its outcomes in terms of credibility (scientific adequacy of the technical evidence) and relevance (of information to the needs of decision-makers). These criteria have been used to understand the uptake of scientific information in policy. We interviewed 73 key informants. Perceptions of credibility were affected by concerns related to the use of expert judgement (rather than empirical evidence) to assess species, impressions that key experts were not included in the planning process, and the lack of confidence in the information supporting prioritisation. We identified several trade-offs and synergies between the credibility and relevance of priorities to potential users. The relevance of the output plans was negatively affected by the lack of clarity about who were potential users and implementers of the priorities identified. We conclude with recommendations to enhance the credibility and relevance of such initiatives. PMID- 26753915 TI - Characterization of the interactions of PARP-1 with UV-damaged DNA in vivo and in vitro. AB - The existing methodologies for studying robust responses of poly (ADP-ribose) polymerase-1 (PARP-1) to DNA damage with strand breaks are often not suitable for examining its subtle responses to altered DNA without strand breaks, such as UV damaged DNA. Here we describe two novel assays with which we characterized the interaction of PARP-1 with UV-damaged DNA in vivo and in vitro. Using an in situ fractionation technique to selectively remove free PARP-1 while retaining the DNA bound PARP-1, we demonstrate a direct recruitment of the endogenous or exogenous PARP-1 to the UV-lesion site in vivo after local irradiation. In addition, using the model oligonucleotides with single UV lesion surrounded by multiple restriction enzyme sites, we demonstrate in vitro that DDB2 and PARP-1 can simultaneously bind to UV-damaged DNA and that PARP-1 casts a bilateral asymmetric footprint from -12 to +9 nucleotides on either side of the UV-lesion. These techniques will permit characterization of different roles of PARP-1 in the repair of UV-damaged DNA and also allow the study of normal housekeeping roles of PARP-1 with undamaged DNA. PMID- 26753917 TI - Management of chronic otitis media by subtotal petrosectomy. AB - INTRODUCTION AND OBJECTIVES: Subtotal petrosectomy is the complete exenteration of all air cell tracts of the temporal bone. The isthmus of the Eustachian tube is obliterated and the external auditory canal is closed. The aim of this study was to describe the use of this technique in the management of certain cases of chronic otitis media. MATERIAL AND METHODS: We conducted a retrospective revision of the patients treated in our Institution with this technique for chronic otitis media in a 5-year period (2008-2012). All charts were reviewed and data from the otomicroscopy, audiometry, radiology, surgical findings, postoperative complications and follow-up (including diffusion magnetic resonance imaging, MRI) of a minimum of 24 months were collected. RESULTS: In this period petrosectomy was performed on 28 patients for chronic otitis media. We treated 13 cases as primary cases, while 15 cases were secondary (patients that had already undergone another procedure in that ear). Fifteen cases had no serviceable hearing. Only 1 case had an immediate postoperative complication (infection); during the posterior follow-up, 2 cases had to be reoperated for diffusion restriction in the mastoid area revealed in the MRI 2 years after surgery. CONCLUSIONS: A subtotal petrosectomy is rarely performed for the treatment of chronic otitis media. However, it is a technique that we have to keep in mind for the treatment of certain cases where there is recurrence and deep hearing loss, as well as in cases with good cochlear reserve if the disease coexists with other complications. PMID- 26753918 TI - Venous malformation of right angular vein. PMID- 26753919 TI - New Horizons for Ninhydrin: Colorimetric Determination of Gender from Fingerprints. AB - In the past century, forensic investigators have universally accepted fingerprinting as a reliable identification method via pictorial comparison. One of the most traditional detection methods uses ninhydrin, a chemical that reacts with amino acids in the fingerprint content to produce the blue-purple color known as Ruhemann's purple. It has recently been demonstrated that the amino acid content in fingerprints can be used to differentiate between male and female fingerprints. Here, we present a modified approach to the traditional ninhydrin method. This new approach for using ninhydrin is combined with an optimized extraction protocol and the concept of determining gender from fingerprints. In doing so, we are able to focus on the biochemical material rather than exclusively the physical image. PMID- 26753920 TI - Koninginins N-Q, Polyketides from the Endophytic Fungus Trichoderma koningiopsis Harbored in Panax notoginseng. AB - Four new fungal polyketides named koninginins N-Q (1-4), together with four known analogues (5-8), were isolated from the endophytic fungus Trichoderma koningiopsis YIM PH30002 harbored in Panax notoginseng. Their structures were determined on the basis of spectral data interpretation. These compounds were evaluated for their antifungal activity, nitric oxide inhibition, and anticoagulant activity. PMID- 26753921 TI - Survival with sildenafil and inhaled iloprost in a cohort with pulmonary hypertension: an observational study. AB - BACKGROUND: Combination therapy is frequently used to treat patients with pulmonary hypertension but few studies have compared treatment regimens. This study examined the long-term effect of different combination regimens of inhaled iloprost and oral sildenafil on survival and disease progression. METHODS: This was a retrospective study of patients in the Giessen Pulmonary Hypertension Registry who received iloprost monotherapy followed by addition of sildenafil (iloprost/sildenafil), sildenafil monotherapy followed by addition of iloprost (sildenafil/iloprost), or upfront combination therapy (iloprost + sildenafil). The primary outcome was transplant-free survival (Kaplan-Meier analysis). When available, haemodynamic parameters and 6-minute-walk distance were evaluated. RESULTS: Overall, 148 patients were included. Baseline characteristics were similar across treatment groups; however, the iloprost + sildenafil cohort had higher mean pulmonary vascular resistance and pulmonary arterial pressure than the others. Transplant-free survival differed significantly between groups (P = 0.007, log-rank test). Cumulative transplant-free survival was highest for patients who received iloprost/sildenafil (1 year survival: iloprost/sildenafil, 95.1%; sildenafil/iloprost, 91.8%; iloprost + sildenafil, 62.9%); this group also remained on monotherapy significantly longer than the sildenafil/iloprost group (median 17.0 months vs 7.0 months, respectively; P = 0.004). Compared with pre treatment values, mean 6-minute-walk distance increased significantly for all groups 3 months after beginning combination therapy. CONCLUSIONS: In this observational study of patients with pulmonary hypertension receiving combination therapy with iloprost and sildenafil, cumulative transplant-free survival was highest in those who received iloprost monotherapy initially. However, owing to the size and retrospective design of this study, further research is needed before making firm treatment recommendations. PMID- 26753922 TI - Self-rated health and health-related quality of life among Chinese residents, China, 2010. AB - BACKGROUND: Self-rated health (SRH) and health-related quality of life (HRQOL) are two outcome measures used to assess health status. However, little is known about population-based SRH and HRQOL in China. METHODS: Data from the 2010 China Chronic Disease and Risk Factor Surveillance, a nationally representative sample of 98,658 adults (>=18-year-old) residing in China, were analyzed. SRH was assessed by asking "Would you say that, in general, your health is very good, good, general, poor, or very poor?" HRQOL was assessed by asking "For about how many days during the past 30 days was your health not good due to physical illnesses, injuries, or mental unhealthy?". RESULTS: Overall, 6.3 % of participants rated their health as poor or very poor. The prevalence of poor/very poor health increased with advancing age ranging from 2.0 % in the 18-24 year olds to 14.9 % in those >=75 years-old, while it decreased with education levels from 13.0 % in illiterates/those with some primary school education to 2.2 % in college graduates or above. Additionally, women were more likely than men to rate their health as poor or very poor (7.2 % vs. 5.4 %). The reported rate of poor/very poor health was higher in western region residents compared to those in the east (7.4 % vs. 5.3 %). The mean numbers of self-reported physically unhealthy days, injury-caused unhealthy days, or mentally unhealthy days during the past 30 days were 1.48, 0.20, and 0.54, respectively. Older adults had more physically unhealthy days than the younger ones ranging from 2.92 days in those >= 75 year-old to 0.95 days in 18-24 year-olds. Women had more physically unhealthy days and mentally unhealthy days than men (1.72 vs. 1.23; 0.62 vs. 0.46, respectively). The highest mean number of physically unhealthy days (2.32) was reported by illiterates or those with some primary school education. The highest mean number of mentally unhealthy days (0.86) reported by college graduates or above. CONCLUSIONS: Substantial variations existed in SRH and HRQOL among age groups, gender groups, education groups, and across regions in China. Considering these disparities will be important when developing health policies and allocating resources. PMID- 26753923 TI - Barriers and facilitators to uptake of systematic reviews by policy makers and health care managers: a scoping review. AB - BACKGROUND: We completed a scoping review on the barriers and facilitators to use of systematic reviews by health care managers and policy makers, including consideration of format and content, to develop recommendations for systematic review authors and to inform research efforts to develop and test formats for systematic reviews that may optimise their uptake. METHODS: We used the Arksey and O'Malley approach for our scoping review. Electronic databases (e.g., MEDLINE, EMBASE, PsycInfo) were searched from inception until September 2014. Any study that identified barriers or facilitators (including format and content features) to uptake of systematic reviews by health care managers and policy makers/analysts was eligible for inclusion. Two reviewers independently screened the literature results and abstracted data from the relevant studies. The identified barriers and facilitators were charted using a barriers and facilitators taxonomy for implementing clinical practice guidelines by clinicians. RESULTS: We identified useful information for authors of systematic reviews to inform their preparation of reviews including providing one-page summaries with key messages, tailored to the relevant audience. Moreover, partnerships between researchers and policy makers/managers to facilitate the conduct and use of systematic reviews should be considered to enhance relevance of reviews and thereby influence uptake. CONCLUSIONS: Systematic review authors can consider our results when publishing their systematic reviews. These strategies should be rigorously evaluated to determine impact on use of reviews in decision-making. PMID- 26753924 TI - Streptococcus pneumoniae colonisation in children and adolescents with asthma: impact of the heptavalent pneumococcal conjugate vaccine and evaluation of potential effect of thirteen-valent pneumococcal conjugate vaccine. AB - BACKGROUND: The main aim of this study was to evaluate Streptococcus pneumoniae carriage in a group of school-aged children and adolescents with asthma because these results might indicate the theoretical risk of invasive pneumococcal disease (IPD) of such patients and the potential protective efficacy of the 13 valent pneumococcal conjugate vaccine (PCV13). METHODS: Oropharyngeal samples were obtained from 423 children with documented asthma (300 males, 70.9%), and tested for the autolysin-A-encoding (lytA) and the wzg (cpsA) gene of S. pneumoniae by means of real-time polymerase chain reaction. RESULTS: S. pneumoniae was identified in the swabs of 192 subjects (45.4%): 48.4% of whom were aged <10 years, 46.9% aged 10-14 years, and 4.7% aged >=15 years (p < 0.001). Carriage was significantly less frequent among the children who had received recent antibiotic therapy (odds ratio [OR 0.41]; 95% confidence interval [95% CI] 0.22-0.76). Multivariate analyses showed no association between carriage and vaccination status, with ORs of 1.05 (95% CI 0.70-1.58) for carriers of any pneumococcal serotype, 1.08 (95% CI 0.72-1.62) for carriers of any of the serotypes included in 7-valent pneumococcal conjugate vaccine (PCV7), and 0.76 (95% CI 0.45-1.28) for carriers of any of the six additional serotypes of PCV13. Serotypes 19 F, 4 and 9 V were the most frequently identified serotypes in vaccinated subjects. CONCLUSIONS: These results showed that carriage of S. pneumoniae is relatively common in all school-aged children and adolescents with asthma, regardless of the severity of disease and the administration of PCV7 in the first years of life. This highlights the problem of the duration of the protection against colonisation provided by pneumococcal conjugate vaccine, and the importance of re-colonization by the same pneumococcal serotypes included in the previously used vaccine. PMID- 26753926 TI - 'What About Swallowing?' Diagnostic Performance of Daily Clinical Practice Compared with the Eating Assessment Tool-10. AB - In daily clinical practice, patients are frequently asked about their swallowing as part of the patient-clinician interview. This study compares the diagnostic performance of a single open question 'What about swallowing?' (usual care) with the Eating Assessment Tool (EAT-10) as reference test in screening for oropharyngeal dysphagia (OD). 303 outpatients at risk of OD were recruited at three university hospitals: 162 men and 141 women with a mean age of 70 years. All data were retrieved by phone. To identify patients at risk of dysphagia, two different cut-off scores for the EAT-10 total score were retrieved from the literature. The diagnostic performance of the single question was determined by comparing dichotomized answers to the single question (no problems versus difficulties in swallowing) with the EAT-10 as reference test. Sensitivity, specificity, positive and negative predictive values ranged between 0.75-0.76, 0.75-0.84, 0.93-0.97 and 0.38-0.43, respectively. Mostly, the results of this exploratory study indicate a sufficient diagnostic performance of the single question in identifying patients who are at risk of dysphagia when using the EAT 10 questionnaire as a reference test. Further research, is, however, necessary to provide additional psychometric data on Functional Health Status (FHS) questionnaires including the single question using either FEES or VFS as gold standard or reference test. PMID- 26753925 TI - Biodistribution, migration and homing of systemically applied mesenchymal stem/stromal cells. AB - Mesenchymal stem/stromal cells (MSCs) are increasingly used as an intravenously applied cellular therapeutic. They were found to be potent in situations such as tissue repair or severe inflammation. Still, data are lacking with regard to the biodistribution of MSCs, their cellular or molecular target structures, and the mechanisms by which MSCs reach these targets. This review discusses current hypotheses for how MSCs can reach tissue sites. Both preclinical and clinical studies using MSCs applied intravenously or intra-arterially are discussed in the context of our current understanding of how MSCs might work in physiological and pathological situations. PMID- 26753927 TI - Pharyngeal Residue Severity Rating Scales Based on Fiberoptic Endoscopic Evaluation of Swallowing: A Systematic Review. AB - Identification of pharyngeal residue severity located in the valleculae and pyriform sinuses has always been a primary goal during fiberoptic endoscopic evaluation of swallowing (FEES). Pharyngeal residue is a clinical sign of potential prandial aspiration making an accurate description of its severity an important but difficult challenge. A reliable, validated, and generalizable pharyngeal residue severity rating scale for FEES would be beneficial. A systematic review of the published English language literature since 1995 was conducted to determine the quality of existing pharyngeal residue severity rating scales based on FEES. Databases were searched using controlled vocabulary words and synonymous free text words for topics of interest (deglutition disorders, pharyngeal residue, endoscopy, videofluoroscopy, fiberoptic technology, aspiration, etc.) and outcomes of interest (scores, scales, grades, tests, FEES, etc.). Search strategies were adjusted for syntax appropriate for each database/platform. Data sources included MEDLINE (OvidSP 1946-April Week 3 2015), Embase (OvidSP 1974-2015 April 20), Scopus (Elsevier), and the unindexed material in PubMed (NLM/NIH) were searched for relevant articles. Supplementary efforts to identify studies included checking reference lists of articles retrieved. Scales were compared using qualitative properties (sample size, severity definitions, number of raters, and raters' experience and training) and psychometric analyses (randomization, intra- and inter-rater reliability, and construct validity). Seven articles describing pharyngeal residue severity rating scales met inclusion criteria. Six of seven scales had insufficient data to support their use as evidenced by methodological weaknesses with both qualitative properties and psychometric analyses. There is a need for qualitative and psychometrically reliable, validated, and generalizable pharyngeal residue severity rating scales that are anatomically specific, image-based, and easily learned by both novice and experienced clinicians. Only the Yale Pharyngeal Residue Severity Rating Scale, an anatomically defined and image-based tool, met all qualitative and psychometric criteria necessary for a valid, reliable, and generalizable vallecula and pyriform sinus severity rating scale based on FEES. PMID- 26753928 TI - Clinical Conundrum: Killian-Jamieson Diverticulum with Paraesophageal Hernia. AB - Killian-Jamieson diverticulum is a outpouching of the lateral cervical esophageal wall adjacent to the insertion of the recurrent laryngeal to the larynx and is much less common in clinical practice than Zenkers Diverticulum. Surgical management of Killian-Jamieson diverticulum requires open transcervical diverticulectomy due to the proximity of the recurrent laryngeal nerve to the base of the pouch. We present a case of a Killian-Jamieson diverticulum associated with a concurrent large type III paraesophageal hernia causing significant solid-food dysphagia, post-prandial regurgitation of solid foods, and chronic cough managed with open transcervical diverticulectomy and laparoscopic paraesophageal hernia repair with Nissen fundoplication. PMID- 26753930 TI - A Meta-Analysis of the Incidence of Patient-Reported Dysphagia After Anterior Cervical Decompression and Fusion with the Zero-Profile Implant System. AB - Dysphagia is a well-known complication following anterior cervical surgery. It has been reported that the Zero-profile Implant System can decrease the incidence of dysphagia following surgery, however, dysphagia after anterior cervical decompression and fusion (ACDF) with the Zero-profile Implant System remains controversial. Previous studies only focus on small sample sizes. The objective of this study was to determine the incidence of dysphagia after ACDF with the Zero-profile Implant System. Studies were collected from PubMed, EMBASE, the Cochrane library and the China Knowledge Resource Integrated Database using the keywords "Zero-profile OR Zero-p) AND (dysphagia OR [swallowing dysfunction]". The software STATA (Version 13.0) was used for statistical analysis. Statistical heterogeneity across the various trials, a test of publication bias and sensitivity analysis was performed. 30 studies with a total of 1062 patients were included in this meta-analysis. The occurrence of post-operative transient dysphagia ranged from 0 to 76 % whilst the pooled incidence was 15.6 % (95 % CI, 12.6, 18.5 %). 23 studies reported no persistent dysphagia whilst seven studies reported persistent dysphagia ranging from 1 to 7 %). In summary, the present study observed a low incidence of both transient and persistent dysphagia after ACDF using the Zero-profile Implant System. Most of the dysphagia was mild and gradually decreased during the following months. Moderate or severe dysphagia was uncommon. Future randomized controlled multi-center studies and those focusing on the mechanisms of dysphagia and methods to reduce its incidence are required. PMID- 26753929 TI - Predictive Factors for Prophylactic Percutaneous Endoscopic Gastrostomy (PEG) Tube Placement and Use in Head and Neck Patients Following Intensity-Modulated Radiation Therapy (IMRT) Treatment: Concordance, Discrepancies, and the Role of Gabapentin. AB - The prophylactic placement of a percutaneous endoscopic gastrostomy (PEG) tube in the head and neck cancer (HNC) patient is controversial. We sought to identify factors associated with prophylactic PEG placement and actual PEG use. Since 2010, data regarding PEG placement and use were prospectively recorded in a departmental database from January 2010 to December 2012. HNC patients treated with intensity-modulated radiation therapy (IMRT) were retrospectively evaluated from 2010 to 2012. Variables potentially associated with patient post-radiation dysphagia from previous literature, and our experience was evaluated. We performed multivariate logistic regression on these variables with PEG placement and PEG use, respectively, to compare the difference of association between the two arms. We identified 192 HNC patients treated with IMRT. Prophylactic PEG placement occurred in 121 (63.0 %) patients, with PEG use in 97 (80.2 %) patients. PEG placement was associated with male gender (p < .01), N stage >= N2 (p < .05), pretreatment swallowing difficulties (p < .01), concurrent chemotherapy (p < .01), pretreatment KPS >=80 (p = .01), and previous surgery (p = .02). Concurrent chemotherapy (p = .03) was positively associated with the use of PEG feeding by the patient, whereas pretreatment KPS >=80 (p = .03) and prophylactic gabapentin use (p < .01) were negatively associated with PEG use. The analysis suggests there were discrepancies between prophylactic PEG tube placement and actual use. Favorable pretreatment KPS, no pretreatment dysphagia, no concurrent chemotherapy, and the use of gabapentin were significantly associated with reduced PEG use. This analysis may help refine the indications for prophylactic PEG placement. PMID- 26753933 TI - A Method for Generating Simulated Plasmodes and Artificial Test Clusters with User-Defined Shape, Size, and Orientation. AB - We present a simple method for generating simulated plasmodes and artificial test clusters with user-defined shape, size, and orientation. Our method differs from other cluster generation techniques in that it focuses on the validity of the cluster indicators. For J clusters, indicator validity is defined as the squared correlation ratio between the cluster indicator (i.e., the observed variable) and J-1 dummy variables. The within-cluster correlation structure and the univariate distributions of the cluster indicators are specified with procedures outlined by Fleishman (1978) and Vale and Maurelli (1983). Simulation results illustrate the utility of the method for cluster analysis evaluation research. PMID- 26753932 TI - Utilizing students' experiences and opinions of feedback during problem based learning tutorials to develop a facilitator feedback guide: an exploratory qualitative study. AB - BACKGROUND: Feedback delivery within a Problem Based Learning tutorial is a key activity for facilitators in order to enhance student learning. The purpose of this study was to explore students' experiences of feedback delivery in a PBL tutorial and use this information to design a feasible facilitator feedback delivery guide. METHODS: It was an exploratory qualitative study in which individual interviews and focus group discussions were conducted with students who had an experience of the tutorial process. Data were collected through audio recording and writing of field notes. Thematic analysis was employed to generate the reported themes. RESULTS: Students suggested that facilitators need to give comprehensive feedback on their knowledge construction process as well as feedback on other generic skills outside the knowledge domain such as their communication skills within the tutorial, their participation and team work as well as their interpersonal skills and self-evaluation abilities. From the findings, a structured facilitator feedback delivery guide was developed. CONCLUSION: In this study, we propose a structured feedback delivery guide for PBL facilitators that captures not only knowledge, but also other generic competencies. The guide is feasible in a wide range of contexts where PBL is institutionalized. PMID- 26753931 TI - Seismology-based early identification of dam-formation landquake events. AB - Flooding resulting from the bursting of dams formed by landquake events such as rock avalanches, landslides and debris flows can lead to serious bank erosion and inundation of populated areas near rivers. Seismic waves can be generated by landquake events which can be described as time-dependent forces (unloading/reloading cycles) acting on the Earth. In this study, we conduct inversions of long-period (LP, period >=20 s) waveforms for the landquake force histories (LFHs) of ten events, which provide quantitative characterization of the initiation, propagation and termination stages of the slope failures. When the results obtained from LP waveforms are analyzed together with high-frequency (HF, 1-3 Hz) seismic signals, we find a relatively strong late-arriving seismic phase (dubbed Dam-forming phase or D-phase) recorded clearly in the HF waveforms at the closest stations, which potentially marks the time when the collapsed masses sliding into river and perhaps even impacting the topographic barrier on the opposite bank. Consequently, our approach to analyzing the LP and HF waveforms developed in this study has a high potential for identifying five dam forming landquake events (DFLEs) in near real-time using broadband seismic records, which can provide timely warnings of the impending floods to downstream residents. PMID- 26753934 TI - A Quasi-Metric Approach to Multidimensional Unfolding for Reducing the Occurrence of Degenerate Solutions. AB - In multidimensional unfolding (MDU), one typically deals with two-way, two-mode dominance data in estimating a joint space representation of row and column objects in a derived Euclidean space. Unfortunately, most unfolding procedures, especially nonmetric ones, are prone to yielding degenerate solutions where the two sets of points (row and column objects) are disjointed or separated in the derived joint space, providing very little insight as to the structure of the input data. We present a new approach to multidimensional unfolding which reduces the occurrence of degenerate solutions. We first describe the technical details of the proposed method. We then conduct a Monte Carlo simulation to demonstrate the superior performance of the proposed model compared to two non-metric procedures, namely, ALSCAL and KYST. Finally, we evaluate the performance of alternative models in two applications. The first application deals with student rank-order preferences (nonmetric data) for attending various graduate business (MBA) programs. Here, we compare the performance of our model with those of KYST and ALSCAL. The second application concerns student preference ratings (metric data) for a number of popular brands of analgesics. Here, we compare the performance of the proposed model with those of two metric procedures, namely, SMACOF-3 and GENFOLD 3. Finally, we provide some directions for future research. PMID- 26753935 TI - Structural Equation Modeling with Small Samples: Test Statistics. AB - Structural equation modeling is a well-known technique for studying relationships among multivariate data. In practice, high dimensional nonnormal data with small to medium sample sizes are very common, and large sample theory, on which almost all modeling statistics are based, cannot be invoked for model evaluation with test statistics. The most natural method for nonnormal data, the asymptotically distribution free procedure, is not defined when the sample size is less than the number of nonduplicated elements in the sample covariance. Since normal theory maximum likelihood estimation remains defined for intermediate to small sample size, it may be invoked but with the probable consequence of distorted performance in model evaluation. This article studies the small sample behavior of several test statistics that are based on maximum likelihood estimator, but are designed to perform better with nonnormal data. We aim to identify statistics that work reasonably well for a range of small sample sizes and distribution conditions. Monte Carlo results indicate that Yuan and Bentler's recently proposed F-statistic performs satisfactorily. PMID- 26753936 TI - On Structural Equation Model Equivalence. AB - A necessary and sufficient condition for equivalence of structural equation models is presented. Compared to existing rules for equivalent model generation (Stelzl, 1986; Lee & Hershberger, 1990; Hershberger, 1994), it is applicable to a more general class including models with parameter restrictions and models that may or may not fulfil assumptions of the rules, to show that two models are nonequivalent, or to nonidentified models. The validity of the replacement rule by Lee and Hershberger, Stelzl's rules, and Hershberger's inverse indicator rule is implied from the present method. Its application for studying model equivalence or lack thereof is demonstrated on a series of empirical examples. PMID- 26753937 TI - Confirmatory Analyses of Componential Test Structure Using Multidimensional Item Response Theory. AB - The componential structure of synonym tasks is investigated using confirmatory multidimensional two-parameter IRT models. It was hypothesized that an open synonym task is decomposable into generating synonym candidates and evaluating these candidate words with respect to their synonymy with the stimulus word. Two subtasks were constructed to identify these two components. Different confirmatory models were estimated both with TESTMAP and with NOHARM. The componential hypothesis was supported, but it was found that the generation subtask also involved some evaluation and that generation and evaluation were highly correlated. PMID- 26753938 TI - Do e-cigarettes pose a risk to human health? PMID- 26753939 TI - SEARCHBreast Workshop Proceedings: 3D Modelling of Breast Cancer. AB - SEARCHBreast, a UK initiative supported by the NC3Rs, organised a workshop entitled 3D Modelling of Breast Cancer. The workshop focused on providing researchers with solutions to overcome some of the perceived barriers to working with human-derived tumour cells, cell lines and tissues, namely: a) the limited access to human-derived material; and b) the difficulty in working with these samples. The workshop presentations provided constructive advice and information on how to best prepare human cells or tissues for further downstream applications. Techniques in developing primary cultures from patient samples, and considerations when preserving tissue slices, were discussed. A common theme throughout the workshop was the importance of ensuring that the cells are grown in conditions as similar to the in vivo microenvironment as possible. Comparisons of the advantages of several in vitro options, such as primary cell cultures, cell line cultures, explants or tissue slices, suggest that all offer great potential applications for breast cancer research, and highlight that it need not be a case of choosing one over the other. The workshop also offered cutting-edge examples of on-chip technologies and 3-D tumour modelling by using virtual pathology, which can contribute to clinically relevant studies and provide insights into breast cancer metastatic mechanisms. PMID- 26753940 TI - 3-D tissue modelling and virtual pathology as new approaches to study ductal carcinoma in situ. AB - Widespread screening mammography programmes mean that ductal carcinoma in situ (DCIS), a pre-invasive breast lesion, is now more frequently diagnosed. However, not all diagnosed DCIS lesions progress to invasive breast cancer, which presents a dilemma for clinicians. As such, there is much interest in studying DCIS in the laboratory, in order to help understand more about its biology and determine the characteristics of those that progress to invasion. Greater knowledge would lead to targeted and better DCIS treatment. Here, we outline some of the models available to study DCIS, with a particular focus on animal-free systems. PMID- 26753941 TI - Conditions and possible mechanisms of VCD-induced ovarian failure. AB - Perimenopause is an important period in women's lives, in which they experience a series of physiological changes. Current animal models of perimenopause fail to adequately replicate this particular stage in female life, while current in vitro models are too simplistic and cannot account for systemic effects. Neither the naturally-ageing animal model, nor the ovariectomised animal model, mimic the natural transitional process that is the menopause. In vivo and in vitro studies have confirmed that the occupational chemical, 4-vinylcyclohexene diepoxide (VCD), can cause selective destruction of the ovarian primordial and primary follicles of rats and mice by accelerating the apoptotic process, which successfully mimics the perimenopausal state in women. However, it is the in vivo VCD-induced rodent perimenopausal models that are currently the most widely used in research, rather than any of the available in vitro models. Studies on the mechanisms involved have found that VCD induces ovotoxicity via interference with the c-kit/kit ligand and apoptotic signalling pathways, among others. Overall, the VCD-induced perimenopausal animal models have provided some insight into female perimenopause, but they are far from ideal models of the human situation. PMID- 26753942 TI - Predicting human drug toxicity and safety via animal tests: can any one species predict drug toxicity in any other, and do monkeys help? AB - Animals are still widely used in drug development and safety tests, despite evidence for their lack of predictive value. In this regard, we recently showed, by producing Likelihood Ratios (LRs) for an extensive data set of over 3,000 drugs with both animal and human data, that the absence of toxicity in animals provides little or virtually no evidential weight that adverse drug reactions will also be absent in humans. While our analyses suggest that the presence of toxicity in one species may sometimes add evidential weight for risk of toxicity in another, the LRs are extremely inconsistent, varying substantially for different classes of drugs. Here, we present further data from analyses of other species pairs, including non-human primates (NHPs), which support our previous conclusions, and also show in particular that test results inferring an absence of toxicity in one species provide no evidential weight with regard to toxicity in any other species, even when data from NHPs and humans are compared. Our results for species including humans, NHPs, dogs, mice, rabbits, and rats, have major implications for the value of animal tests in predicting human toxicity, and demand that human-focused alternative methods are adopted in their place as a matter of urgency. PMID- 26753943 TI - Scandinavia and the replacement of in vivo toxicity tests: Some personal reflections. The 2015 Bjorn Ekwall Memorial Award Lecture. AB - A personal, and therefore unavoidably biased, review is given, of the significance of the contributions made by selected Scandinavian individuals, organisations and events, to the development of in vitro toxicology procedures as potential replacements for toxicity tests in laboratory animals. In addition to their wider significance, these contributions had a profound effect on whatever contributions I have been able to make, myself. Nevertheless, while there has been much progress in the last 35 years or so, and many lessons have been learned, there is still much to be done, especially as animal tests remain entrenched as the preferred methods which set the gold standards and make regulators feel comfortable. Many of the clues to dealing with the questions and concerns which plague hazard prediction and risk assessment have long been available, but they have been ignored, largely for reasons which have little to do with the science of toxicology and the need to maintain the highest scientific standards. I have little doubt that Bjorn Ekwall, whose memory I feel privileged to honour, would have agreed with that last statement. PMID- 26753944 TI - On the safety of e-cigarettes: "I can resist anything except temptation". PMID- 26753945 TI - Read-across for hazard assessment: the ugly duckling is growing up. PMID- 26753946 TI - Young researchers--the ethical challenge. PMID- 26753947 TI - 20. On replacing the concept of Replacement. PMID- 26753948 TI - Diversity and Prevalence of Ectoparasites on Backyard Chicken Flocks in California. AB - Peridomestic ("backyard") chicken flocks are gaining popularity in the developed world (e.g., North America or Europe), yet little is known regarding prevalence or severity of their ectoparasites. Therefore, five birds on each of 20 properties throughout southern California were surveyed in summer for on-host (permanent) and off-host dwelling (temporary) ectoparasites. Only four premises (20%) were entirely free of ectoparasites. In declining order of prevalence (% of premises), permanent ectoparasites included six chicken louse species: Menacanthus stramineus (Nitzsch) (50%), Goniocotes gallinae (De Geer) (35%), Lipeurus caponis (L.) (20%), Menopon gallinae (L.) (15%), Menacanthus cornutus (Schommer) (5%), and Cuclotogaster heterographus (Nitzsch) (5%). Only one flea species, Echidnophaga gallinacea (Westwood) (20%), was found. Three parasitic mite species were observed: Ornithonyssus sylviarum (Canestrini & Fanzago) (15%), Knemidocoptes mutans (Robin & Lanquetin) (10%), and Dermanyssus gallinae (De Geer) (5%). Many infestations consisted of a few to a dozen individuals per bird, but M. stramineus, G. gallinae, M. cornutus, and E. gallinacea were abundant (dozens to hundreds of individuals) on some birds, and damage by K. mutans was severe on two premises. Off-host dwelling ectoparasites were rare (D. gallinae) or absent (Cimex lectularius L., Argasidae). Parasite diversity in peridomestic flocks greatly exceeds that is routinely observed on commercial chicken flocks and highlights a need for increased biosecurity and development of ectoparasite control options for homeowners. PMID- 26753950 TI - The gene BRAF is underexpressed in bipolar subject olfactory neuroepithelial progenitor cells undergoing apoptosis. AB - BACKGROUND: Bipolar disorder is a devastating psychiatric condition that frequently results in various degrees of brain tissue loss, cognitive decline, and premature death. The documentation of brain tissue loss implicates apoptosis as the likely underlying degenerative process, but direct experimental demonstration is lacking. METHODS: Olfactory neuroepithelial biopsies from individuals with and without bipolar I disorder yielded olfactory neuroepithelial progenitor cells (ONPs), which spontaneously differentiate into neurons and glia. Glutamate, 0.1M, for 3 and 6h was used to induce apoptosis. Genes involved in the apoptotic pathway were interrogated with micro-array analysis before and after glutamate treatment for 6h. Confirmation was accomplished with real-time PCR. Total and phospho-B-Raf protein levels were measured using Western blot analysis. RESULTS: ONPs from bipolar individuals demonstrated significantly greater apoptosis than cells from non-bipolar subjects. Microarray results revealed 12 differentially expressed genes. Five genes were further examined. BRAF mRNA and protein levels were significantly reduced in bipolar ONPs. CONCLUSIONS: ONPs with the genetic heritage of bipolar I disorder were more sensitive to glutamate induced apoptosis. Under expression of the BRAF gene and protein, which plays a role in regulating the pro-survival MEK/ERK signaling pathway, may contribute to this apoptotic sensitivity. PMID- 26753952 TI - The development of postinstitutionalized versus parent-reared Russian children as a function of age at placement and family type. AB - A total of 149 children, who spent an average of 13.8 months in Russian institutions, were transferred to Russian families of relatives and nonrelatives at an average age of 24.7 months. After residing in these families for at least 1 year (average = 43.2 months), parents reported on their attachment, indiscriminately friendly behavior, social-emotional competencies, problem behaviors, and effortful control when they were 1.5-10.7 years of age. They were compared to a sample of 83 Russian parents of noninstitutionalized children, whom they had reared from birth. Generally, institutionalized children were rated similarly to parent-reared children on most measures, consistent with substantial catch-up growth typically displayed by children after transitioning to families. However, institutionalized children were rated more poorly than parent-reared children on certain competencies in early childhood and some attentional skills. There were relatively few systematic differences associated with age at family placement or whether the families were relatives or nonrelatives. Russian parent reared children were rated as having more problem behaviors than the US standardization sample, which raises cautions about using standards cross culturally. PMID- 26753951 TI - Fetal exposure to maternal stress and risk for schizophrenia spectrum disorders among offspring: Differential influences of fetal sex. AB - Exposure to adverse life events during pregnancy has been linked to increased risk of schizophrenia spectrum disorders (SSD) in offspring. Nevertheless, much of the previous work inferred maternal stress from severe life events rather than directly assessing maternal reports of stress. The present study aimed to examine maternal reports of stress during pregnancy and risk for offspring SSD. Participants were 95 SSD cases and 206 controls who were offspring from a large birth cohort study that followed pregnant women from 1959 to 1966. During pregnancy interviews, women were asked if anything worrisome had occurred recently. Interviews were qualitatively coded for stress-related themes, including reports of daily life stress, by two independent raters. None of the maternal psychosocial stress themes were significantly associated with increased odds of offspring SSD in analyses of the full sample. However, results indicated a significant daily life stress by infant sex interaction. Maternal daily life stress during pregnancy was associated with significantly increased odds of SSD among male offspring. Findings suggest sex-specific fetal sensitivity to maternal reported daily life stress during pregnancy on risk for SSD, with males appearing to be more vulnerable to the influences of maternal stress during pregnancy. PMID- 26753954 TI - Hypersplenism is correlated with increased risk of hepatocellular carcinoma in patients with post-hepatitis cirrhosis. AB - Several risk factors exist for hepatocellular carcinoma in patients with post hepatitis cirrhosis (PHC), including hypersplenism. Splenectomy is a common but controversial procedure in the management of hypersplenism, but its impact on hepatocellular carcinoma (HCC) remains uncertain. We conducted a hospital-based study of PHC patients to identify potential risk factors, including a history of splenectomy, which has been associated with progression from PHC to HCC. From 2002 to 2012, 2678 patients developed hypersplenism secondary to PHC. Of these patients, 828 developed HCC and 1850 did not. Potential risk factors of HCC were determined by univariate and multivariate analyses to exclude confounding variables. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were determined for each factor. Many factors, such as liver function, platelet (PLT) counts, Child-Pugh class, and history of hepatitis, were associated with progression to HCC. PHC patients with hypersplenism who displayed elevated levels of alanine transaminase (ALT), aspartate transaminase (AST), gamma glutamyltransferase (GGT), ALK, phosphatase, and prolonged prothrombin time (PT) had a significantly increased risk of HCC. However, the patients who had splenectomy showed better liver function test results and less progression to HCC. In patients with PHC and hypersplenism, abnormal levels of ALT, AST, ALP, and GGT and prolonged PT are risk factors of HCC. Splenectomy, as the intervention method of hypersplenism, is performed less frequently in patients who developed HCC than in patients who did not develop HCC. Therefore, splenectomy may act as an independent factor that is significantly associated with HCC development. PMID- 26753953 TI - Can ROMA algorithm stratify ovarian tumor patients better when being based on specific age ranges instead of the premenopausal and postmenopausal status? AB - After several years of research, HE4 was found to be characterized by slightly worse sensitivity but significantly higher specificity as compared with CA125. Further studies led to the diagnostic potential of both markers (CA125 and HE4) being combined in a single risk of malignancy algorithm (ROMA) algorithm. The objective of this study was to assess the diagnostic capabilities of the ROMA algorithm using age ranges instead of dichotomization of patients according to the pre- and postmenopausal status. A total of 413 female patients were included in the study, including 162 premenopausal and 251 postmenopausal women. Calculation of the final ROMA values was achieved by means of stepwise reduction of coefficients in the proposed formula of: %ROMA = exp(PI)/[1-exp(PI)]*100) and PI = A + W(HE4)(*)ln(HE4) + W(CA125)(*)ln (CA125) and the arrangement of values with consideration to the age group, HE4 level, differentiation of modification, and directional coefficients as well as determination of individual deviations affecting the widening of the median. The cutoff value of modified algorithm ROMA P for the entire study population was calculated from receiver operating characteristic (ROC) curve and DeLong method at the levels of 23.5 %. Marked higher sensitivity and negative predictive value (NPV) values are observed for the standard ROMA algorithm while higher specificity and positive predictive value (PPV) values are observed for the modified algorithm ROMA P. The proposed age-related modification of algorithm calculation does not require the patients being dichotomized according to their pre- or postmenopausal status, and satisfactory diagnostic values may be obtained using a single cutoff point for the entire population. PMID- 26753955 TI - Comparison of efficacy and safety of three different chemotherapy regimens delivered with concomitant radiotherapy in inoperable stage III non-small cell lung cancer patients. AB - Concomitant administration of chemotherapy and radiotherapy is currently recognized as the standard of treatment in locally advanced inoperable non-small cell lung cancer (NSCLC). Our study aimed to compare the efficacy and toxicities of three different chemotherapy regimens delivered concurrently with radiotherapy. We retrospectively reviewed the clinical records of patients who received the PE (cisplatin, 50 mg/m(2), on days 1, 8, 29, and 36 plus etoposide, 50 mg/m(2), on days 1 to 5 and 29 to 33), PD (docetaxel, 20 mg/m(2), on day 1 plus cisplatin, 20 mg/m(2), on day 1, every week), and PC (carboplatin, AUC 2 plus paclitaxel, 45 mg/m(2), on day 1, every week) regimens concurrently with radiotherapy. A total of 227 patients were evaluated in the study. Median follow up time was 13 months (2-101). There were 27 females (11.9 %) and 200 males (88.1 %) with a median age of 61 (38-82) years. The PD group had higher rates of esophagitis, mucositis, and anemia (p < 0.05). The PC group had higher rates of neuropathy (p = 0.000). The progression-free survival (PFS) time was 10 months for patients in the PC group, 15 months for patients in the PD group, and 21 months for the PE group (p = 0.010). Patients in the PC group had a median overall survival time of 23 months, those in the PD group 27 months, and those in the PE group 36 months (p = 0.098). Combination of cisplatin-etoposide with radiotherapy led to a more favorable outcome compared with the other two regimens. It shows generally manageable toxicity profile and compliance to treatment is noticeable. PMID- 26753956 TI - Vitronectin: a promising breast cancer serum biomarker for early diagnosis of breast cancer in patients. AB - Breast cancer is the most common cancer in women worldwide, identification of new biomarkers for early diagnosis and detection will improve the clinical outcome of breast cancer patients. In the present study, we determined serum levels of vitronectin (VN) in 93 breast cancer patients, 30 benign breast lesions, 9 precancerous lesions, and 30 healthy individuals by enzyme-linked immunosorbent assays. Serum VN level was significantly higher in patients with stage 0-I primary breast cancer than in healthy individuals, patients with benign breast lesion or precancerous lesions, as well as those with breast cancer of higher stages. Serum VN level was significantly and negatively correlated with tumor size, lymph node status, and clinical stage (p < 0.05 in all cases). In addition, VN displayed higher area under curve (AUC) value (0.73, 95 % confidence interval (CI) [0.62-0.84]) than carcinoembryonic antigen (CEA) (0.64, 95 % CI [0.52-0.77]) and cancer antigen 15-3 (CA 15-3) (0.69, 95 % CI [0.58-0.81]) when used to distinguish stage 0-I cancer and normal control. Importantly, the combined use of three biomarkers yielded an improvement in receiver operating characteristic curve with an AUC of 0.83, 95 % CI [0.74-0.92]. Taken together, our current study showed for the first time that serum VN is a promising biomarker for early diagnosis of breast cancer when combined with CEA and CA15-3. PMID- 26753957 TI - High expression of constitutive photomorphogenic 1 (COP1) is associated with poor prognosis in bladder cancer. AB - The present study was to investigate the expression and prognostic value of constitutive photomorphogenic 1 (COP1) in bladder cancer. In our study, real-time quantitative PCR (RT-PCR) was performed to detect 10 pairs of fresh bladder cancer (BCa) and adjacent noncancerous tissues. In addition, immunohistochemistry was utilized to detect the expression of COP1 in 174 clinical bladder cancer samples. What is more, the correlation of COP1 expression and clinicopathological features and clinical outcomes were analyzed. The expression levels of COP1 in clinical bladder cancer were much higher than that in paired adjacent noncancerous tissues (p < 0.0001). High expression of COP1 was closely related with differentiation (p = 0.040) and recurrence (p = 0.001) of patients with bladder cancer. Kaplan-Meier analysis revealed that the expression of COP1 was closely correlated with overall survival (p = 0.048) of bladder cancer, while, recurrence-free survival (p = 0.201). Moreover, Cox multivariate regression analyses showed that COP1 expression was an independent predictor of overall survival (OS; p = 0.027, hazard ratio = 2.127, confidence interval 0.814 to 9.736). Based on our data, the present study suggests that high expression of COP1 may be a novel biological indicator for evaluation of poor prognosis in bladder cancer. PMID- 26753958 TI - Integrative proteomics and transcriptomics identify novel invasive-related biomarkers of non-functioning pituitary adenomas. AB - Non-functioning pituitary adenomas (NFPAs) are usually macroadenomas and display invasion into surrounding tissues. The treatment for invasive NFPAs is still challenging. This study describes the differential patterns of gene expression between invasive and non-invasive NFPAs and identifies novel biomarkers involved in invasion of NFPAs for diagnosis and treatment. Using gene microarray technology, we examined the gene expression profile and found 1160 differentially expressed messenger RNA (mRNA) between invasive and non-invasive NFPAs. Then, we examined the protein profile by liquid chromatography tandem mass spectrometry (LC-MS/MS) and found 433 differentially expressed proteins between invasive and non-invasive NFPAs. Subsequently, we integrated the proteomics and transcriptomics datasets and identified 29 common changed molecules. Through bioinformatics analysis using Ingenuity Pathway Analysis (IPA) software, we showed that the 29 molecules were enriched in 25 canonical signaling pathways, 25 molecular and cellular functions, and 2 networks. Eight genes were identified involved in the invasion function by the molecular and cellular functions analysis, including CAT, CLU, CHGA, EZR, KRT8, LIMA1, SH3GLB2 and SLC2A1. Furthermore, we validated the decreased CHGA expression and increased CLU expression in invasive NFPAs by qRT-PCR and Western blot. Our study demonstrated that integration of proteomics and transcriptomics could prove advantageous for accelerating tumor biomarker discovery and CHGA and CLU might be important novel biomarkers and therapeutic targets for invasion of NFPAs. PMID- 26753959 TI - Down-regulation of miR-320 associated with cancer progression and cell apoptosis via targeting Mcl-1 in cervical cancer. AB - Our previous studies have demonstrated overexpression of Mcl-1 in cervical cancer tumorigenesis. However, the molecular mechanism of its overexpression remains not elucidated. MiR-320 has been reported to be down-regulated in various types of cancer, and bioinformatics prediction indicated that it may regulate the expression of Mcl-1. The aim of this study is to investigate the role of miR-320 and its target gene Mcl-1 in cervical cancer progression and to assess their clinical significance. miR-320 and Mcl-1 expressions in human cervical cancer tissues were investigated by qRT-PCR, in situ hybridization, and immunohistochemical staining, respectively. The clinicopathological implications of these molecules were analyzed. Bioinformatic prediction and luciferase assays were employed to identify the predicted microRNA (miRNA) which regulates Mcl-1. The apoptosis, proliferation, migration, and invasion assays were performed to investigate the effect of miR-320 on the cervical cancer cells. MiR-320 expression is significantly down-regulated versus Mcl-1 expression is up regulated in cervical cancer tissues compared with normal controls with a negative correlation between them. Luciferase assay showed that miR-320 negatively regulates Mcl-1 expression. In addition, miR-320 induces apoptosis via down-regulation of Mcl-1 and activation of caspase-3 but inhibits cell proliferation, migration, invasion, and tumorigenesis in cervical cancer cells. Our studies show that miR-320 expression is decreased in cervical cancer, and its expression is negatively correlated with Mcl-1 expression in cervical cancer. In addition, miR-320 inhibits cervical cancer progression by down-regulation of Mcl 1. These results indicate that miR-320 may be an important biomarker and target for diagnosis and treatment of cervical cancer patient. PMID- 26753960 TI - Downregulation of microRNA-193-3p inhibits tumor proliferation migration and chemoresistance in human gastric cancer by regulating PTEN gene. AB - In this study, we investigated the functional mechanisms of microRNA-193-3p (miR 193-3p) in human gastric cancer. Quantitative RT-PCR (qRT-PCR) was used to assess whether miR-193-3p was aberrantly expressed in gastric cancer cells and clinical samples from gastric cancer patients. Gastric cancer cell line AGS and MKN-45 cells were stably transduced with lentivirus to downregulate endogenous miR-193 3p. The modulation of miR-193-3p downregulation on gastric cancer proliferation, migration, chemo-drug responses, and tumor explant were assessed by MTT, wound healing, 5-FU chemoresistance and in vivo tumorigenicity assays, respectively. Downstream target of miR-193-3p, phosphatase and tensin homolog (PTEN) in gastric cancer, was assessed by dual-luciferase reporter assay, qRT-PCR, and western blot. PTEN was knocked down by siRNA in AGS and MKN-45 cells to assess its direct impact on miR-193-3p modulation in gastric cancer. MiR-193-3p was aberrantly upregulated in both gastric cell lines and human gastric tumors. In AGS and MKN 45 cells, miR-193-3p downregulation reduced cancer proliferation, migration and 5 FU chemoresistance in vitro, and tumorigenicity in vivo. PTEN was confirmed to be targeted by miR-193-3p in gastric cancer. PTEN inhibition in AGS and MKN-45 cells directly reversed the anti-tumor modulations of miR-193-3p downregulation on gastric cancer proliferation, migration, and 5-FU chemoresistance. We presented clear evidence showing miR-193-3p played critical role in regulating human gastric cancer through direct targeting on PTEN gene. PMID- 26753961 TI - DLX4 hypermethylation is a prognostically adverse indicator in de novo acute myeloid leukemia. AB - Hypermethylation of distal-less homeobox 4 (DLX4) has been increasingly identified in several cancers. Our study was aimed to determine the role of DLX4 methylation in regulating DLX4 expression and further analyze its clinical significance in de novo acute myeloid leukemia (AML) patients. DLX4 methylation level was detected by real-time quantitative methylation-specific PCR and bisulfite sequencing PCR. Treatment with 5-aza-2'-deoxycytidine (5-aza-dC) was used for demethylation studies. Clinical significance of DLX4 methylation was obtained by the comparison between the patients with and without DLX4 methylation. DLX4 was significantly methylated in AML patients compared with controls (P < 0.001). DLX4 methylation was negatively associated with DLX7 (the shorter DLX4 isoform) (R = -0.202, P = 0.021) but not BP1 (the longer DLX4 isoform) (R = -0.049, P = 0.582) expression in AML patients. DLX7 and BP1 messenger RNA (mRNA) were significantly increased after 5-aza-dC treatment in leukemic cell lines THP1 and Kasumi-1. DLX4 methylated patients showed significantly higher frequency of U2AF1 mutation compared with DLX4 unmethylated patients (P = 0.043). Both all AML and non-M3 patients with DLX4 methylation presented significantly lower complete remission rate than those with DLX4 unmethylation (P = 0.001 and <0.001, respectively). DLX4 methylated cases had significantly shorter overall survival than DLX4 unmethylated cases among both all AML (P = 0.003), non-M3 AML (P = 0.001), and cytogenetically normal AML (P = 0.032). Multivariate analysis confirmed that DLX4 methylation was independent risk factor in both all AML and non-M3 patients. Our study indicates that DLX4 hypermethylation is negatively associated with DLX7 expression and predicts poor clinical outcome in de novo AML patients. PMID- 26753962 TI - ANRIL: a pivotal tumor suppressor long non-coding RNA in human cancers. AB - Long non-coding RNAs (lncRNAs) are a family of non-protein-coding RNAs with length more than 200 nucleotides. LncRNAs played important roles in many biological processes such as cell development, proliferation, invasion and migration. Deregulation of LncRNAs was found in multiple tumors where they can act as a tumor suppressor gene or oncogene. LncRNA ANRIL was identified as an oncogene involved in a number of tumors such as gastric cancer, lung cancer, hepatocellular carcinoma, and esophageal squamous cell carcinoma. Inhibition of ANRIL suppressed the cancer cell proliferation, migration and invasion. Increasing data has showed that ANRIL may act as a diagnostic and prognostic biomarker for some tumors. In our review, we summarize an overview of current knowledge concerning the expression and role of ANRIL in various cancers. PMID- 26753963 TI - Cediranib in ovarian cancer: state of the art and future perspectives. AB - Despite the dramatic improvements achieved in cancer treatment through a better understanding of the tumor biology, ovarian cancer is still characterized by a poor prognosis: most patients diagnosed with this disease will ultimately die from it. In various clinical trials conducted over a time span of two decades, new combinations of conventional chemotherapy regimens have failed to achieve significant improvements in oncologic outcome in ovarian cancer patients. We have now entered an era of "personalized medicine" in which new medications are designed to specifically target molecular pathways involved in carcinogenesis and cancer progression. Encouraging results in different tumor types have been reported, applying an increasing number of target therapies that are still under evaluation. In this setting, one of the most successfully targeted molecular pathways is tumor angiogenesis. Bevacizumab, a monoclonal antibody binding vascular endothelial growth factor (VEGF), has been recently incorporated in the treatment of primary and recurrent ovarian cancer patients after multiple phase III randomized controlled trials have proven its clinical benefit. Based on these positive results, more anti-angiogenic molecules using different mechanisms of action have been developed and are currently under investigation. Among these molecules, the tyrosine kinases inhibitors are probably the most promising ones. Cediranib is a tyrosine kinase inhibitor targeting VEGF receptors that has been tested in various trials with promising results. The aim of this manuscript is to review the current role of cediranib in the treatment of ovarian cancer and to present an overview of the ongoing clinical trials in this setting. PMID- 26753966 TI - Bioresponsive carbon nano-gated multifunctional mesoporous silica for cancer theranostics. AB - Designing bioresponsive nanocarriers for controlled and efficient intracellular drug release for cancer therapy is a major thrust area in nanomedicine. With recent recognition by the US FDA as a safe material for human trials, mesoporous silica nanoparticles (MSNPs) are being extensively explored as promising theranostic agents. Green fluorescent carbon quantum dots (CQDs), though known as possible alternatives for their more toxic and relatively less efficient predecessors, are less known as gate keepers for drug release control. We report for the first time an efficient bioresponse of CQDs when judiciously designed using glutathione cleavable (redox responsive) disulphide bonds. When the anticancer drug doxorubicin loaded MSNPs are capped with these CQDs, they display promising drug release control on exposure to a mimicked intracellular cancer environment. Their dual functionality is well established with good control on preventing the premature release and exceptional bio-imaging of HeLa cancer cells. Fluorescence images prove selective targeting of HeLa cells by overexpression of folate receptors from the surface functionalised folic acid ligand. Extensive characterisation using XRD, TEM, BET analysis, drug loading tests, drug release kinetics, MTT assay and fluoroscence cell imaging helps in understanding the multifunctionalities of the successful design, extending its scope with exciting prospects towards non-invasive targeted drug delivery and bio imaging for effective cancer diagnosis and treatment. PMID- 26753964 TI - miR-492G>C polymorphism (rs2289030) is associated with overall survival of hepatocellular carcinoma patients. AB - Single-nucleotide polymorphisms (SNPs) of microRNAs (miRNAs) are considered potential markers of cancer risk and prognosis in various cancers. In the current study, the primary aim is to determine whether the miR-492G>C polymorphism (rs2289030) altered hepatocellular carcinoma (HCC) prognosis. The SNP rs2289030 of miR-492 was genotyped using DNA from blood samples of 362 HCC patients that had undergone surgical resection of a HCC tumor. The associations between overall survival and demographic characteristics, clinical features, and the SNP rs2289030 were estimated using the Cox proportional hazards model. Results showed that patients who carried the CG genotype (P = 0.015, hazard ratio [HR] = 0.704, 95 % confidence interval [CI] 0.530-0.934) and CG+GG genotype (P = 0.011, HR = 0.703, 95 % CI 0.536-0.924) had significantly decreased risk of death compared to those with the CC genotype. Similar results were found in the multivariate analysis adjusted by tumor size and venous invasion. Further stratification analysis indicated that the effect of rs2289030 had more prominence in patients <=50 years old and that reported ever using alcohol, male gender, a family history of HCC, being HbsAg or alpha fetoprotein (AFP) positive, differentiation I + II, presence of venous invasion or cirrhosis, multiple tumors, and pTNM stage I + II. Results from this study illustrate the potential use of miR-492 rs2289030 as a prognostic marker for HCC patients that have undergone a surgical resection of the tumor. PMID- 26753965 TI - Prognostic value of preoperative peripheral monocyte count in patients with hepatocellular carcinoma after liver transplantation. AB - Prognostic value of peripheral monocyte, as a member of inflammatory cells, was widely being investigated. The aim of this study was to evaluate the prognostic value of preoperative peripheral blood monocyte count for hepatocellular carcinoma (HCC) patients who underwent liver transplantation (LT) and the relationship between monocyte count and tumor-related characteristics. We retrospectively analyzed the clinical data of 101 HCC patients after LT. Preoperative monocyte count and demographic, clinical, and pathologic data were analyzed. The optimal cutoff value of monocyte count was 456/mm(3), with the sensitivity and specificity of 69.4 and 61.5 %, respectively. Elevated preoperative peripheral blood monocyte count was significantly associated with large tumor size. The 1-, 3-, and 5-year disease-free survival (DFS) (80.9, 70.1, and 53.3 % vs 55.1, 38.7, and 38.7 %, P = 0.007) and overall survival (OS) rates (95.7, 76.6, and 64.8 % vs 72.2, 44.1, and 36.1 %, P = 0.002) of HCC patients in the peripheral blood monocyte count <=456/mm(3) group were higher than those in the peripheral blood monocyte count >456/mm(3) group. In conclusion, elevated preoperative peripheral blood monocyte count was significantly associated with advanced tumor stage and it can be considered as a prognostic factor for HCC patients after LT. PMID- 26753967 TI - FragClust and TestClust, two informatics tools for chemical structure hierarchical clustering analysis applied to lipidomics. The example of Alzheimer's disease. AB - Lipidomic analysis is able to measure simultaneously thousands of compounds belonging to a few lipid classes. In each lipid class, compounds differ only by the acyl radical, ranging between C10:0 (capric acid) and C24:0 (lignoceric acid). Although some metabolites have a peculiar pathological role, more often compounds belonging to a single lipid class exert the same biological effect. Here, we present a lipidomics workflow that extracts the tandem mass spectrometry data from individual files and uses them to group compounds into structurally homogeneous clusters by chemical structure hierarchical clustering analysis (CHCA). The case-to-control peak area ratios of the metabolites are then analyzed within clusters. We created two freely available applications to assist the workflow: FragClust to generate the tables to be subjected to CHCA, and TestClust to perform statistical analysis on clustered data. We used the lipidomics data from the plasma of Alzheimer's disease (AD) patients in comparison with healthy controls to test the workflow. To date, the search for plasma biomarkers in AD has not provided reliable results. This article shows that the workflow is helpful to understand the behavior of whole lipid classes in plasma of AD patients. PMID- 26753968 TI - Recent progress in application of carbon nanomaterials in laser desorption/ionization mass spectrometry. AB - Carbon nanomaterials have attracted great interest over past decades owing to their unique physical properties, versatile functionalization chemistry, and biological compatibility. In this article, we review recent progress in application of carbon nanomaterials in laser desorption/ionization mass spectrometry (LDI MS). Various types of carbon nanomaterials, including fullerenes, carbon nanotubes, graphene, carbon nanodots, nanodiamond, nanofibers, nanohorns, and their derivative forms, are involved. The applications of these materials as new matrices or probes in matrix-assisted or surface-enhanced laser desorption/ionization mass spectrometry (MALDI or SELDI MS) are discussed. Finally, we summarize current challenges and give our perspectives on the future of applications of carbon nanomaterials in LDI MS. PMID- 26753969 TI - Comparative study between macrolide regulatory proteins MphR(A) and MphR(E) in ligand identification and DNA binding based on the rapid in vitro detection system. AB - The macrolide regulatory protein MphR(A) has been widely studied and used in various aspects such as metabolism monitoring, exogenous gene expression, and in vivo and in vitro macrolide antibiotic screening. Another macrolide regulatory protein, MphR(E), has rarely been reported. In this study, in vitro ELISA-type systems were established for MphR(A) and MphR(E) to study their correlation. The reactivity of 14 macrolide antibiotics and pseudo-macrolide antibiotics was tested in the systems. The results indicated that the ligand identification spectra of MphR(A) and MphR(E) were basically consistent. The binding characteristics of MphR(A) and MphR(E) with three corresponding promoter DNA sequences were preliminarily studied. According to the ELISA-type analysis results, MphR(A) and MphR(E) have consistent DNA binding properties, which bind to A-DNA/B-DNA more easily than to C-DNA. This study has confirmed that MphR(E) can bind to the promoter DNA sequences mrx(E) and mph(E) in plasmid pRSB111, and different DNAs can affect the sensitivity of the in vitro detection systems. PMID- 26753971 TI - Electromembrane extraction for the determination of parabens in water samples. AB - To our knowledge, for the first time an electromembrane extraction combined with a high-performance liquid chromatography procedure using diode-array detection has been developed for the determination of five of the most widely used parabens: ethyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate, butyl 4 hydroxybenzoate, isobutyl 4-hydroxybenzoate, and benzyl 4-hydroxybenzoate. Parabens were extracted from pH 4 aqueous sample solutions with use of an Accurel(r) S6/2 polypropylene hollow fiber that supports a liquid membrane of 1 octanol to a pH 12 aqueous acceptor solution placed inside the lumen of the hollow fiber. An electric current of 30 V was applied over the supported liquid membrane by means of platinum wires placed in the donor and acceptor phases. Parabens were extracted in 40 min with enrichment factors in the 30-49 range. The procedure has detection limits between 0.98 and 1.43 MUg L(-1). The method was applied to the determination of parabens in surface environmental waters with excellent results. PMID- 26753970 TI - Ultrasensitive determination of bisphenol A and its chlorinated derivatives in urine using a high-throughput UPLC-MS/MS method. AB - Bisphenol A (BPA) is a well-known endocrine disruptor. Chlorinated derivatives of BPA (ClxBPA) may be formed by reaction of chlorine with BPA present in drinking water. ClxBPA exhibit a higher level of estrogenic activity than BPA. While many studies have reported detectable BPA concentrations in urine, only very few studies were conducted in regards to ClxBPA. Since ClxBPA are potentially more toxic, it is important to assess large-scale exposure of the general population. Indeed, in the field of environment health, large studies are required to assess exposure to pollutants at ultratrace concentrations; therefore, analytical methods have to be rapid and sensitive. This work intends to validate a highly sensitive and rapid analytical method suitable to evaluate BPA and ClxBPA exposures during large-scale biomonitoring studies. For that purpose, a method based on online solid-phase extraction coupled with isotope dilution ultrahigh - performance liquid chromatography-tandem mass spectrometry was developed and validated according to accepted guidelines. The matrix-matched calibration curve ranged from 0.25 to 16.0 ng mL(-1) and from 0.025 to 1.60 ng mL(-1) for BPA and ClxBPA, respectively. This method was precise (the intra- and inter-day coefficients of variation of quality control were <16.4%) and accurate (bias ranged from -4.0 to 16.8%). The limit of quantification was validated at 0.25 and 0.025 ng mL(-1), for BPA and ClxBPA, respectively. The limit of detection was estimated for each experiment performed. Finally, this method is rapid and sensitive enough to be carried out during biomonitoring studies of BPA and ClxBPA in human urine. PMID- 26753972 TI - Testing of complementarity of PDA and MS detectors using chromatographic fingerprinting of genuine and counterfeit samples containing sildenafil citrate. AB - Counterfeit medicines are a global threat to public health. High amounts enter the European market, which is why characterization of these products is a very important issue. In this study, a high-performance liquid chromatography photodiode array (HPLC-PDA) and high-performance liquid chromatography-mass spectrometry (HPLC-MS) method were developed for the analysis of genuine Viagra(r), generic products of Viagra(r), and counterfeit samples in order to obtain different types of fingerprints. These data were included in the chemometric data analysis, aiming to test whether PDA and MS are complementary detection techniques. The MS data comprise both MS1 and MS2 fingerprints; the PDA data consist of fingerprints measured at three different wavelengths, i.e., 254, 270, and 290 nm, and all possible combinations of these wavelengths. First, it was verified if both groups of fingerprints can discriminate between genuine, generic, and counterfeit medicines separately; next, it was studied if the obtained results could be ameliorated by combining both fingerprint types. This data analysis showed that MS1 does not provide suitable classification models since several genuines and generics are classified as counterfeits and vice versa. However, when analyzing the MS1_MS2 data in combination with partial least squares-discriminant analysis (PLS-DA), a perfect discrimination was obtained. When only using data measured at 254 nm, good classification models can be obtained by k nearest neighbors (kNN) and soft independent modelling of class analogy (SIMCA), which might be interesting for the characterization of counterfeit drugs in developing countries. However, in general, the combination of PDA and MS data (254 nm_MS1) is preferred due to less classification errors between the genuines/generics and counterfeits compared to PDA and MS data separately. PMID- 26753973 TI - A label-free method for the detection of specific DNA sequences using gold nanoparticles bifunctionalized with a chemiluminescent reagent and a catalyst as signal reporters. AB - Sensitive, specific, simple, fast, and low-cost DNA detection methods are extremely important in clinical diagnostics, gene therapy, and a variety of biomedical studies. In this work, we developed a general method for the detection of specific DNA sequences from Mycobacterium tuberculosis (TB), hepatitis B virus (HBV), and myelocytomatosis viral oncogene (v-myc) using gold nanoparticles bifunctionalized with both a chemiluminescent (CL) reagent and a catalytic metal complex as signal reporters and a DNA strand complementary to the target as the capture probe. In this CL method, a biotinylated single-strand DNA capture probe was immobilized in a streptavidin-coated microwell. Upon the addition of the target single-strand DNA, the capture probe hybridized with the target DNA. After adding the bifunctionalized gold nanoparticles and H2O2, a well-defined CL signal was obtained, and the CL intensity was observed to change as the target DNA concentration was increased. It was possible to determine the concentration of the target TB single-strand DNA in the range 1.0 * 10-13-1.0 * 10-8 M with a detection limit of 4.8 * 10-14 M. HBV single-strand DNA and v-myc single-strand DNA could also be determined in the range 1.0 * 10-11-1.0 * 10-8 M with detection limits of 5.9 * 10-12 M and 8.0 * 10-12 M, respectively, using this CL technique. The method reported in this paper is the first label-free CL method for the determination of specific DNA sequences to utilize gold nanoparticles bifunctionalized with both a CL reagent and a catalytic metal complex. The sensitivity of this CL method is superior to those of most previously reported label-free methods. Compared with methods that use polymerase chain reaction amplification, this label-free CL method is much simpler, faster, and more economic. This work has thus demonstrated a simple and fast scanning strategy for the detection of specific DNA sequences related to diseases. Graphical Abstract Schematic illustration of label-free CL method for detection of specific DNA sequences. PMID- 26753975 TI - Pushing back the frontiers of mercury speciation using a combination of biomolecular and isotopic signatures: challenge and perspectives. AB - Mercury (Hg) pollution is considered a major environmental problem due to the extreme toxicity of Hg. However, Hg metabolic pathways in biota remain elusive. An understanding of these pathways is crucial to elucidating the (eco)toxic effects of Hg and its biogeochemical cycle. The development of a new analytical methodology based on both speciation and natural isotopic fractionation represents a promising approach for metabolic studies of Hg and other metal(loid)s. Speciation provides valuable information about the reactivity and potential toxicity of metabolites, while the use of natural isotopic signature analysis adds a complementary dynamic dimension that allows the life history of the target element to be probed, the source of the target element (i.e., the source of pollution) to be identified, and reactions to be tracked. The resulting combined (bio)molecular and isotopic signature affords precious insight into the behavior of Hg in biota and Hg detoxification mechanisms. In the long term, this highly innovative methodology could be used in life and environmental science studies of metal(loid)s to push back the frontiers of our knowledge in this field. This paper summarizes the current status of the application of Hg speciation and the isotopic signature of Hg at the biomolecular level in living organisms, and discusses potential future uses of this combination of techniques. PMID- 26753974 TI - Application of a cocktail approach to screen cytochrome P450 BM3 libraries for metabolic activity and diversity. AB - In the present study, the validity of using a cocktail screening method in combination with a chemometrical data mining approach to evaluate metabolic activity and diversity of drug-metabolizing bacterial Cytochrome P450 (CYP) BM3 mutants was investigated. In addition, the concept of utilizing an in-house developed library of CYP BM3 mutants as a unique biocatalytic synthetic tool to support medicinal chemistry was evaluated. Metabolic efficiency of the mutant library towards a selection of CYP model substrates, being amitriptyline (AMI), buspirone (BUS), coumarine (COU), dextromethorphan (DEX), diclofenac (DIC) and norethisterone (NET), was investigated. First, metabolic activity of a selection of CYP BM3 mutants was screened against AMI and BUS. Subsequently, for a single CYP BM3 mutant, the effect of co-administration of multiple drugs on the metabolic activity and diversity towards AMI and BUS was investigated. Finally, a cocktail of AMI, BUS, COU, DEX, DIC and NET was screened against the whole in house CYP BM3 library. Different validated quantitative and qualitative (U)HPLC MS/MS-based analytical methods were applied to screen for substrate depletion and targeted product formation, followed by a more in-depth screen for metabolic diversity. A chemometrical approach was used to mine all data to search for unique metabolic properties of the mutants and allow classification of the mutants. The latter would open the possibility of obtaining a more in-depth mechanistic understanding of the metabolites. The presented method is the first MS-based method to screen CYP BM3 mutant libraries for diversity in combination with a chemometrical approach to interpret results and visualize differences between the tested mutants. PMID- 26753976 TI - Real-time monitoring of the metabolic capacity of ex vivo rat olfactory mucosa by proton transfer reaction mass spectrometry (PTR-MS). AB - Olfactory mucosa (OM) can metabolise odorant volatile organic compounds through various enzymatic mechanisms to produce odorous or non-odorous metabolites. Preliminary ex vivo studies using headspace-gas chromatography (HS-GC) revealed the formation of metabolites when odorant molecules were injected in the headspace above a fresh explant of rat olfactory mucosa. However, this method did not allow accessing the data during the first 5 min of contact between the odorant and the mucosa; thus limiting the olfactory biological significance. Using a direct-injection mass spectrometry technique with a proton transfer reaction instrument (PTR-MS), we have been able, for the first time, to investigate the first moments of the enzymatic process of the metabolic capacity of ex vivo rat olfactory mucosa in real time. Using ethyl acetate as a model volatile odorous substrate, we demonstrated here for the first time that this odorant could be metabolised by an ex vivo olfactory mucosa within seconds, producing ethanol as metabolite. PMID- 26753977 TI - QuEChERS sample preparation prior to LC-MS/MS determination of opiates, amphetamines, and cocaine metabolites in whole blood. AB - Modern LC-MS/MS instruments have sensitivity and scanning velocity high enough to analyze many different compounds in single runs. Consequently, the sample preparation procedure has become the bottleneck for developing efficient, rapid, and cheap multi-compound methods. Here, we examined one-step sample preparation based on quick, easy, cheap, effective, rugged, and safe (QuEChERS) salts to set up and validate a LC-MS/MS method for the simultaneous determination of 35 drugs of abuse and their metabolites in whole blood. Despite large differences in physicochemical properties, this simplified QuEChERS extraction method yielded satisfactory recoveries (until 96%) for the 35 molecules. The amounts of QuEChERS salts had no influence on extraction yield. Chromatographic separation was obtained in less than 6 min. LLOD and LLOQ were 3 and 5 ng/mL, respectively. The procedure was successfully validated and then applied to 253 cases of driving under the influence of drugs (DUID), collected over a 6-month period. PMID- 26753978 TI - Tris-acetate polyacrylamide gradient gel electrophoresis for the analysis of protein oligomerization. AB - Here we report a new approach for studying protein oligomerization in cells using a single electrophoresis gel. We combined the use of a crosslinking reagent for sample preparation, such as glutaraldehyde, with the analysis of oligomers by Tris-acetate polyacrylamide gel electrophoresis. The use of a 3-15% Tris-acetate polyacrylamide gradient gel allows for the simultaneous analysis of proteins of masses ranging from 10 to 500 kDa. We showed the usefulness of this method for analyzing endogenous p53 oligomerization with high resolution and sensitivity in human cells. Oligomerization analysis was dependent on the crosslinker concentration used. We also showed that this method could be used to study the regulation of oligomerization. In all experiments, Tris-acetate polyacrylamide gel electrophoresis proved to be a robust, manageable, and cost- and time efficient method that provided excellent results using a single gel. This approach can be easily extrapolated to the study of other oligomers. All of these features make this method a highly useful tool for the analysis of protein oligomerization. PMID- 26753979 TI - Toward faster and higher resolution LA-ICPMS imaging: on the co-evolution of LA cell design and ICPMS instrumentation. AB - We describe trends in fast, high resolution elemental imaging by laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS). Recently developed low dispersion LA cells deliver quantitative transport of ablated aerosols within 10 ms and also provide enhanced sensitivity compared to conventional LA cells because the analyte ion signal becomes less diluted during aerosol transport. When connected to simultaneous ICPMS instruments, these low dispersion LA cells offer a platform for high speed and high lateral resolution shot-resolved LA ICPMS imaging. Here, we examine the current paradigms of LA-ICPMS imaging and discuss how newly developed LA cell technology combined with simultaneous ICPMS instrumentation is poised to overcome current instrumental limitations to deliver faster, higher resolution elemental imaging. PMID- 26753980 TI - 11th International Workshop on Biosensors and Bioanalytical Microtechniques for Environmental, Food and Clinical Analysis in Regensburg, Germany. PMID- 26753981 TI - Characterization of fortimicin aminoglycoside profiles produced from Micromonospora olivasterospora DSM 43868 by high-performance liquid chromatography-electrospray ionization-ion trap-mass spectrometry. AB - In this study, an efficient high-performance liquid chromatography (HPLC) electrospray ionization (ESI)-ion trap-tandem mass spectrometry (MS/MS) was developed for the identification of the biosynthetic congeners involved in the aminocyclitol aminoglycosidic fortimicin pathway from Micromonospora olivasterospora fermentation. The usage of both acid extraction (pH ~2.5) followed by an cationic-exchanging SPE cleanup and pentafluoropropionic acid mediated ion-pairing chromatography with ESI-ion trap-MS/MS detection was determined to be sufficiently practical to profile the fortimicin (FOR) congeners produced in a culture broth. The limit of the quantification for the fortimicin A (FOR-A) standard spiked in the culture broth was ~1.6 ng mL(-1). The average recovery rate was 93.6%, and the intra- and inter-day precisions were <5% with accuracy in the range from 87.1 to 94.2%. Moreover, the epimeric mixtures including FOR-KH, FOR-KR, and FOR-B were separately resolved through a macrocyclic glycopeptide (teicoplanin)-bonded chiral column. As a result, ten natural FOR pseudodisaccharide analogs were identified and semi-quantified in descending order as follows: FOR-A, FOR-B, DCM, FOR-KH plus FOR-KR, FOR-KK1, FOR AP, FOR-KL1, FOR-AO, and FOR-FU-10. This is the first report on both the simultaneous characterization of diverse structurally closely related FORs derived from bacterial fermentation using HPLC-ESI-ion trap-MS/MS analysis and the chromatographic separation of the three FOR epimers. PMID- 26753982 TI - Identification of a novel mitochondrial interacting protein of C1QBP using subcellular fractionation coupled with CoIP-MS. AB - The study of protein-protein interactions is an essential process to understand the biological functions of proteins and the underlying mechanisms. Co immunoprecipitation coupled with mass spectrometry (CoIP-MS) is one of the most extensively used high-throughput techniques to discover novel protein-protein interactions. However, the traditional CoIP process uses whole cell lysate, disrupts cellular organization, and leads to potential false positives by inducing artificial protein-protein interactions. Here, we have developed a strategy by combining subcellular fractionation with CoIP-MS to study the interacting proteins of the complement component 1, q subcomponent binding protein (C1QBP) in the mitochondria. Using this method, a novel C1QBP interacting protein, dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial (DLAT) was identified and validated. Furthermore, the activity of the pyruvate dehydrogenase (PDH) was found to be affected by the expression level of C1QBP. These results provide novel insights regarding the mitochondrial function of C1QBP in the regulation of cellular energy metabolism. This method could also be used to analyze the subcellular protein-protein interactions for other proteins of interest. PMID- 26753983 TI - Ultrasound-assisted hydrolysis of conjugated parabens in human urine and their determination by UPLC-MS/MS and UPLC-HRMS. AB - Parabens are preservatives widely used in personal care products, pharmaceutical formulations as well as in food, and they are considered endocrine disruptors. For application in biomonitoring studies we developed a method for the determination of eight parabens from human urine. Sample preparation was enhanced and simplified by the combination of ultrasound-assisted enzymatic hydrolysis of conjugates (glucuronide and sulfate) followed by an extraction-free cleanup step. Quantification, using deuterated parabens as internal standards, was performed by ultrahigh-performance liquid chromatography coupled to either triple-quadrupole (UPLC-QqQ) or time-of-flight (UPLC-QqTOF) mass spectrometry. Full chromatographic separation of three butyl paraben isomers was achieved. Limits of quantification for both mass analyzers ranged from 0.1 to 0.5 MUg/L for methyl, ethyl, n /isopropyl, n-/isobutyl, and benzyl paraben in 200 MUL of urine sample. The method was tested for applicability and showed high precision (intra- and interday 0.9-14.5%) as well as high accuracy (relative recovery 95-132%). A total of 39 urine samples were analyzed by both mass analyzers. The results agreed well, with a trend to higher deviation at low concentrations (less than 10 MUg/L). Methyl, ethyl, and n-propyl paraben were detected most frequently (in more than 87% of the samples) with median concentrations ranging from 0.8 to 16.6 MUg/L. Female urine showed higher median concentrations for all parabens, which may indicate higher exposure due to lifestyle. This method permits accurate and high-throughput analysis of parabens for epidemiological studies. Further, the UPLC-QqTOF approach provides additional information on human exposure to other compounds by post-acquisition analysis. PMID- 26753984 TI - Hollow fiber membrane-coated functionalized polymeric ionic liquid capsules for direct analysis of estrogens in milk samples. AB - Protein removal process is always time-consuming for the analysis of milk samples. In this work, hollow fiber membrane-coated functionalized polymeric ionic liquid (HF-PIL) capsules were synthesized and used as solid-phase microextraction (SPME) sorbent for direct analysis of estrogens in milk samples. The functionalized PIL monolith sorbent was obtained by copolymerization between 1-(3-aminopropyl)-3-(4-vinylbenzyl)imidazolium 4-styrenesulfonate IL monomer and 1,6-di(3-vinylimidazolium) hexane bishexafluorophosphate IL-crosslinking agent. A group of four capsules were installed as SPME device, to determine four kinds of estrogens (estrone, diethylstilbestrol, hexestrol, and 17alpha-ethynylestradiol) in milk samples, coupled to high performance liquid chromatography. Extraction and desorption conditions were optimized to get satisfactory extraction efficiency. Good linearity was obtained in the range of 5-200 MUg L(-1). The limits of detection were 1 MUg L(-1) for diethylstilbestrol and 2 MUg L(-1) for 17alpha-ethynylestradiol, estrone, and hexestrol. The present method was applied to analyze the model analytes in different milk samples. Relative recoveries were in the range of 85.5-112%. The HF-PIL SPME capsules showed satisfactory extraction efficiency and high resistance to sample matrix interference. PMID- 26753985 TI - Impact of Added Encapsulated Phosphate Level on Lipid Oxidation Inhibition during the Storage of Cooked Ground Meat. AB - The effect of levels (0.1%, 0.2%, 0.3%, 0.4%, 0.5%) of added encapsulated (e) phosphate (sodium tripolyphosphate, STP; sodium hexametaphosphate, HMP; sodium pyrophosphate, SPP) on lipid oxidation inhibition during storage (0, 1, and 7 d) of ground meat (chicken, beef) was evaluated. The use of eSTP and eSPP resulted in lower and higher cooking loss (CL) compared to eHMP, respectively (P < 0.05). Increasing encapsulated phosphate level (PL) enhanced the impact of phosphates on CL in both chicken and beef samples (P < 0.05). Encapsulated STP increased pH, whereas eSPP decreased pH (P < 0.05). pH was not affected by PL. The highest orthophosphate (OP) was obtained with eSTP, followed by eSPP and eHMP (P < 0.05). The level of OP determined in both chicken and beef samples increased (P < 0.05) during storage. Increasing PL caused an increase in OP (P < 0.05). The highest reduction rate in the formation of thiobarbituric acid reactive substances (TBARS) and LPO for both meat species were obtained with eSPP, followed by eSTP and eHMP (P < 0.05). Increasing PL resulted in lower TBARS and LPO (P < 0.05). Findings suggest that encapsulated phosphates can be a strategy to inhibit lipid oxidation for the meat industry and the efficiency of encapsulated phosphates on lipid oxidation inhibition can be enhanced by increasing PL. PMID- 26753986 TI - Abbreviated Goal Management Training Shows Preliminary Evidence as a Neurorehabilitation Tool for HIV-associated Neurocognitive Disorders among Substance Users. AB - OBJECTIVE: Substance use disorders are highly comorbid with and contribute to the increased prevalence of neurocognitive dysfunction observed in HIV infection. Despite their adverse impact on everyday functioning, there are currently no compensatory-based neurorehabilitation interventions validated for use among HIV+ substance users (HIV/SUD). This study examined the effectiveness of goal management training (GMT) alone or GMT as part of a metacognitive training among HIV/SUD individuals with executive dysfunction. METHODS: Ninety HIV/SUD individuals were randomized to a single 15-min session: (1) GMT (n = 30); (2) GMT plus metacognitive training (neurocognitive awareness; GMT + Meta; n = 30); or (3) active control (n = 30). Following a brief neurocognitive battery and study condition, participants performed a complex laboratory-based function task, Everyday Multitasking Test (Everyday MT), during which metacognition (awareness) was evaluated. RESULTS: There was an increasing, but non-significant tendency for better Everyday MT performances across study conditions (Control <= GMT <= GMT + Meta; ps < .08). Post hoc analyses showed that GMT and GMT + Meta groups demonstrated small benefits (d = .20-.27) compared to the control arm but did not differ from one another (ds < .10). When GMT groups were combined, there were significant medium effect size benefits in Everyday MT performance and metacognitive task appraisals as compared to the control condition. Among participants who underwent GMT, benefits were most prominent in persons with poorer pre-training dual-tasking ability, depression, and methamphetamine use disorders (ds = .35-1.04). CONCLUSIONS: A brief compensatory strategy has benefits for everyday multitasking and metacognition among HIV+ substance users with executive dysfunction. Future work exploring more intensive trainings, potentially complimentary to other restorative approaches and/or pharmacological treatments, is warranted. PMID- 26753988 TI - A class of joint models for multivariate longitudinal measurements and a binary event. AB - Predicting binary events such as newborns with large birthweight is important for obstetricians in their attempt to reduce both maternal and fetal morbidity and mortality. Such predictions have been a challenge in obstetric practice, where longitudinal ultrasound measurements taken at multiple gestational times during pregnancy may be useful for predicting various poor pregnancy outcomes. The focus of this article is on developing a flexible class of joint models for the multivariate longitudinal ultrasound measurements that can be used for predicting a binary event at birth. A skewed multivariate random effects model is proposed for the ultrasound measurements, and the skewed generalized t-link is assumed for the link function relating the binary event and the underlying longitudinal processes. We consider a shared random effect to link the two processes together. Markov chain Monte Carlo sampling is used to carry out Bayesian posterior computation. Several variations of the proposed model are considered and compared via the deviance information criterion, the logarithm of pseudomarginal likelihood, and with a training-test set prediction paradigm. The proposed methodology is illustrated with data from the NICHD Successive Small-for Gestational-Age Births study, a large prospective fetal growth cohort conducted in Norway and Sweden. PMID- 26753987 TI - Mutant p53 determines pancreatic cancer poor prognosis to pancreatectomy through upregulation of cavin-1 in patients with preoperative serum CA19-9 >= 1,000 U/mL. AB - Patients with pancreatic ductal adenocarcinoma (PDAC) and preoperative CA19-9 >= 1,000 U/mL that does not decrease postresection have the worst prognosis, but the mechanism is unclear. Here, we elucidated the relationship between this signature and driver-gene mutations, and the cavins/caveolin-1 axis. Four major driver genes (KRAS, TP53, CDKN2A/p16, and SMAD4/DPC4) that are associated with PDAC and five critical molecules (cavin-1/-2/-3/-4 and caveolin-1) in the cavins/caveolin 1 axis were screened by immunohistochemistry in tumor tissue microarrays. Additionally, six pancreatic cancer cell lines and a spleen subcapsular inoculation nude mouse model were also used. Overexpression of mutant p53 was the major mutational event in patients with the CA19-9 signature. Cavin-1 was also overexpressed, and mutant p53 correlated directly with high cavin-1 expression in pancreatic cancer cell lines and tumor specimens (P < 0.01). Furthermore, mutant p53(R172H) upregulated cavin-1 and promoted invasiveness and metastasis of pancreatic cancer cells in vitro and in vivo. Finally, combination of mutant p53 and high cavin-1 density indicated the shortest survival for patients with PDAC after resection (P < 0.001). Mutant p53-driven upregulation of cavin-1 represents the major mechanism of poor outcome for PDAC patients with the CA19-9 signature after resection, indicating that inhibition of cavin-1 may improve the long-term efficacy of pancreatectomy. PMID- 26753989 TI - Validity and reliability of a food frequency questionnaire to estimate dietary intake among Lebanese children. AB - BACKGROUND: Nutritional status during childhood is critical given its effect on growth and development as well as its association with disease risk later in life. The Middle East and North Africa (MENA) region is experiencing alarming rates of childhood malnutrition, both over- and under-nutrition. Hence, there is a need for valid tools to assess dietary intake for children in this region. To date, there are no validated dietary assessment tools for children in any country of the MENA region. The main objective of this study was to examine the validity and reliability of a Food Frequency Questionnaire (FFQ) for the assessment of dietary intake among Lebanese children. METHODS: Children, aged 5 to 10 years (n = 111), were recruited from public and private schools of Beirut, Lebanon. Mothers (proxies to report their children's dietary intake) completed two FFQs, four weeks apart. Four 24-hour recalls (24-HRs) were collected weekly during the duration of the study. Spearman correlations and Bland-Altman plots were used to assess validity. Linear regression models were used to derive calibration factors for boys and girls. Reproducibility statistics included Intraclass Correlation Coefficient (ICC) and percent agreement. RESULTS: Correlation coefficients between dietary intake estimates derived from FFQ and 24-HRs were significant at p < 0.001 with the highest correlation observed for energy (0.54) and the lowest for monounsaturated fatty acids (0.26). The majority of data points in the Bland Altman plots lied between the limits of agreement, closer to the middle horizontal line. After applying the calibration factors for boys and girls, the mean energy and nutrient intakes estimated by the FFQ were similar to those obtained by the mean 24-HRs. As for reproducibility, ICC ranged between 0.31 for trans-fatty acids and 0.73 for calcium intakes. Over 80 % of study participants were classified in the same or adjacent quartile of energy and nutrients intake. CONCLUSIONS: Findings of this study showed that the developed FFQ is reliable and is also valid, when used with calibration factors. This FFQ is a useful tool in dietary assessment and evaluation of diet-disease relationship in this age group. PMID- 26753990 TI - Hypervirulent Klebsiella pneumoniae induced ventilator-associated pneumonia in mechanically ventilated patients in China. AB - The purpose of this study was to investigate the clinical characteristics of hypervirulent K. pneumoniae (hvKP) induced ventilator-associated pneumonia (VAP) and the microbiological characteristics and epidemiology of the hvKP strains. A retrospective study of 49 mechanically ventilated patients with K. pneumoniae induced VAP was conducted at a university hospital in China from January 2014 to December 2014. Clinical characteristics and K. pneumoniae antimicrobial susceptibility and biofilm formation were analyzed. Genes of capsular serotypes K1, K2, K5, K20, K54 and K57 and virulence factors plasmid rmpA(p-rmpA), iroB, iucA, mrkD, entB, iutA, ybtS, kfu and allS were also evaluated. Multilocus sequence typing (MLST) and random amplified polymorphic DNA (RAPD) analyses were used to study the clonal relationship of the K. pneumoniae strains. Strains possessed p-rmpA and iroB and iucA were defined as hvKP. Of 49 patients, 14 patients (28.6 %) were infected by hvKP. Antimicrobial resistant rate was significantly higher in cKP than that in hvKP. One ST29 K54 extended-spectrum beta-lactamase (ESBL) producing hvKP strain was detected. The prevalence of K1 and K2 in hvKP was 42.9 % and 21.4 %, respectively. The incidences of K1, K2, K20, p-rmpA, iroB, iucA, iutA, Kfu and alls were significantly higher in hvKP than those in cKP. ST23 was dominant among hvKP strains, and all the ST23 strains had identical RAPD pattern. hvKP has become a common pathogen of VAP in mechanically ventilated patients in China. Clinicians should increase awareness of hvKP induced VAP and enhance epidemiologic surveillance. PMID- 26753991 TI - First recurrence of Clostridium difficile infection: clinical relevance, risk factors, and prognosis. AB - Therapy for recurrent Clostridium difficile-associated diarrhea (CDAD) is challenging. We evaluated the frequency, associated risk factors, and prognosis of first CDAD recurrences. Prospective cohort study of all consecutive cases of primary CDAD diagnosed in a university hospital from January 2006 to June 2013. Recurrent infection was defined as reappearance of symptoms within 8 weeks of the primary diagnosis, provided that CDAD symptoms had previously resolved and a new toxin test was positive. Predictors of a first episode of recurrent CDAD were determined by logistic regression analysis. In total, 502 patients (51.6 % men) with a mean age of 62.3 years (SD 18.5) had CDAD; 379 (76 %) were cured, 61 (12 %) had a first recurrence, 52 (10 %) died within 30 days of the CDAD diagnosis, nine (2 %) required colectomy, and one was lost to follow-up. Among the 61 patients with a first recurrence, 36 (59.3 %) were cured, 15 (23.7 %) had a second recurrence, nine (15.3 %) died, and one (1.7 %) required colectomy. On multivariate analysis, age older than 65 years (OR 2.04; 95 % CI, 1.14-3.68; P < 0.02) and enteral nutrition (OR, 3.62; 95%CI, 1.66-7.87; P < 0.01) were predictors of a first recurrence. A risk score was developed for first CDAD recurrence using the predictive factors and selected biological variables. In our CDAD cohort, 12 % of patients had a first recurrence of this disease, in which the prognosis was less favorable than that of the primary episode, as it heralded a higher risk of additional recurrences. Patient age and enteral nutrition were predictors of a first recurrence. PMID- 26753992 TI - Natural history of human papillomavirus infection in non-vaccinated young males: low clearance probability in high-risk genotypes. AB - In this study, we aimed to investigate the clearance of type-specific genital human papillomavirus (HPV) infection in heterosexual, non-HPV-vaccinated males whose female partners were positive to HPV DNA tests. All consecutive men attending the same sexually transmitted diseases (STD) centre between January 2005 and December 2006 were considered for this study. All subjects (n = 1009) underwent a urologic visit and microbiological tests on first void, midstream urine and total ejaculate samples. One hundred and five patients were positive for HPV DNA (10.4 %; mean age: 34.8 +/- 5.8 years) and consented to clinical examination and molecular diagnostic assays for HPV detection scheduled every 6 months (median surveillance period of 53.2 months). HPV genotypes were classified as high risk, probable high risk and low risk. HPV-positive samples which did not hybridise with any of the type-specific probes were referred to as positive non genotypeable. At enrollment, the distribution of HPV genotypes was as follows: high-risk HPV (n = 37), probable high-risk HPV (n = 6), low-risk HPV (n = 23) and non-genotypeable HPV (n = 39). A high HPV genotype concordance between stable sexual partners emerged (kappa = 0.92; p < 0.001). At the end of the study, 71/105 (67.6 %) subjects were negative for HPV (mean virus clearance time: 24.3 months). With regard to the HPV genotype, virus clearance was observed in 14/37 (37.8 %) high-risk HPV cases, 6/6 (100 %) probable high-risk HPV cases, 20/23 (86.9 %) low-risk HPV cases and 31/39 (79.5 %) non-genotypeable cases. The high risk HPV genotypes showed the lowest rate and probability of viral clearance (p < 0.001). In our series, high-risk HPV infections were more likely to persist over time when compared with other HPV genotypes. PMID- 26753993 TI - Presence of multiple bacterial markers in clinical samples might be useful for presumptive diagnosis of infection in cirrhotic patients with culture-negative reports. AB - Bacterial infections in cirrhotic patients with ascites are associated with a severe prognosis and an increased risk of death. The microbiological standard tests for the diagnosis of suspected infection, based on culture test of blood and ascitic fluid, are, in many cases (30-40 %), negative, even when patients show symptoms of infection. A multiple culture-independent protocol was applied and evaluated as a diagnostic and prognostic tool for the detection of bacterial infection in cirrhotic patients. Sixty-four culture-negative samples obtained from 34 cirrhotic patients, with PMN < 250 cells/MUl of ascitic fluid, were screened for the presence of bacterial DNA, endotoxin, peptidoglycan/beta-glucan and microscopically visible bacterial cells. Correlations between the presence of multiple markers and various clinical and laboratory parameters were evaluated. Bacterial DNA was detected in 23 samples collected from 16 patients; a large part of these samples also showed the presence of other bacterial markers, which was associated with a worsening of liver functionality, a higher incidence of infections during the follow-up and a higher mortality rate in our cohort of cirrhotic patients. We believe that the detection of additional bacterial markers in bacterial DNA-positive clinical samples makes the bacterial presence and its clinical significance more realistic and might be useful as early markers of an ongoing bacterial infection and in establishing a clinical prognosis. PMID- 26753995 TI - Mimicking of Chondrocyte Microenvironment Using In Situ Forming Dendritic Polyglycerol Sulfate-Based Synthetic Polyanionic Hydrogels. AB - A stable polymeric network that mimics the highly polyanionic extracellular cartilage matrix still remains a great challenge. The main aim of this study is to present the synthesis of dendritic polyglycerol sulfate (dPGS)-based in situ forming hydrogels using strain promoted azide-alkyne cycloaddition reactions. A real time rheological study has been used to characterize the hydrogel properties. The viability of encapsulated human chondrocytes in the different hydrogels are monitored using live-dead staining. Furthermore, type I and II collagen gene have been analyzed. Hydrogels with elastic moduli ranging from 1 to 5 kPa have been prepared by varying the dPGS amount. The chondrocyte viability in dPGS hydrogels is found to be higher than in pure PEG and alginate-based hydrogels after 21 d. The higher cell viability in the dPGS engineered hydrogels can be explained by the fact that dPGS can interact with different proteins responsible for cell growth and proliferation. PMID- 26753994 TI - Impact of microbiological samples in the hospital management of community acquired, nursing home-acquired and hospital-acquired pneumonia in older patients. AB - We investigated the positivity rate, the detection rates for non-covered pathogens and the therapeutic impact of microbiological samples (MS) in community acquired pneumonia (CAP), nursing home-acquired pneumonia (NHAP) and hospital acquired pneumonia (HAP) in elderly hospitalised patients. Patients aged 75 years and over with pneumonia and hospitalised between 1/1/2013 and 30/6/2013 in the departments of medicine (5) and intensive care (1) of our university hospital were included. Microbiological findings, intra-hospital mortality and one-year mortality were recorded. Among the 217 patients included, there were 138 CAP, 56 NHAP and 23 HAP. MS were performed in 89.9, 91.1 and 95.6 % of CAP, NHAP and HAP, respectively. Microbiological diagnosis was made for 29, 11.8 and 27.3 % of patients for CAP, NHAP and HAP, respectively (p = 0.05). Non-covered pathogens were detected for 8 % of CAP, 2 % of NHAP and 13.6 % of HAP (p = 0.1). The antimicrobial spectrum was significantly more frequently reduced when the MS were positive (46.7 % vs. 10.8 % when MS were negative, p = 10(-7)). The MS positivity rate was significantly lower in NHAP than in CAP and HAP. MS revealed non-covered pathogens in only 2 % of NHAP. These results show the poor efficiency and weak clinical impact of MS in the management of pneumonia in hospitalised older patients and suggest that their use should be rationalised. PMID- 26753997 TI - Genetic oscillators in development. AB - In development, morphogenetic processes are strictly coordinated in time. Cells in a developing tissue would need mechanisms for time-keeping. One such time keeping mechanism is to use oscillations of gene expression. Oscillatory gene expression can be generated by transcriptional/translational feedback loops, usually referred to as a genetic oscillator. In this review article, we discuss genetic oscillators in the presence of developmental processes such as cell division, cell movement and cell differentiation. We first introduce the gene regulatory network for generating a rhythm of gene expression. We then discuss how developmental processes influence genetic oscillators. Examples include vertebrate somitogenesis and neural progenitor cell differentiation, as well as the circadian clock for comparison. To understand the behaviors of genetic oscillators in development, it is necessary to consider both gene expression dynamics and cellular behaviors simultaneously. Theoretical modeling combined with live imaging at single-cell resolution will be a powerful tool to analyze genetic oscillators in development. PMID- 26753998 TI - Patterns of cryptic host specificity in duck lice based on molecular data. AB - Documenting patterns of host specificity in parasites relies on the adequate definition of parasite species. In many cases, parasites have simplified morphology, making species delimitation based on traditional morphological characters difficult. Molecular data can help in assessing whether widespread parasites harbour cryptic species and, alternatively, in guiding further taxonomic revision in cases in which there is morphological variation. The duck louse genus Anaticola (Phthiraptera: Philopteridae), based on current taxonomy, contains both host-specific and widespread species. Mitochondrial and nuclear DNA sequences of samples from this genus were used to document patterns of host specificity. The comparison of these patterns with morphological variations in Anaticola revealed a general correspondence between the groups identified by DNA sequences and morphology, respectively. These results suggest that a more thorough taxonomic review of this genus is needed. In general, the groups identified on the basis of molecular data were associated with particular groups of waterfowl (e.g. dabbling ducks, sea ducks, geese) or specific biogeographic regions (e.g. North America, South America, Australia, Eurasia). PMID- 26753996 TI - Regulation of transforming growth factor-beta1 (TGF-beta1)-induced pro-fibrotic activities by circadian clock gene BMAL1. AB - BACKGROUND: BMAL1 is a transcriptional activator of the molecular clock feedback network. Besides its role in generating circadian rhythms, it has also been shown to be involved in the modulation of cell proliferation, autophagy and cancer cell invasion. However, the role of BMAL1 in pulmonary fibrogenesis is still largely unknown. In this study, we investigated the crosstalk between BMAL1 and the signaling transduction and cellular activities of TGF-beta1, a key player in lung fibrogenesis. METHODS: Lungs from wild type and TGF-beta1-adenovirus-infected mice were harvested and homogenized for isolation of RNA and protein. RT-PCR and Western Blotting were employed to measure the expression level of clock genes and TGF-beta1-induced downstream target genes. siRNA against human BMAL1 gene was transfected by using lipofectamine RNAiMAX to knockdown the endogenous BMAL1 in both lung epithelial cells and fibroblasts. RESULTS: Our results showed that TGF beta1 is able to up-regulate BMAL1 expression in both lung epithelial cells and normal lung fibroblasts. In animal models of pulmonary fibrosis, BMAL1 expression was also significantly higher in adenovirus-TGF-beta1-infected mice than in the control group. Interestingly, BMAL1 was mostly found in a deacetylated form in the presence of TGF-beta1. Importantly, siRNA-mediated knockdown of BMAL1 significantly attenuated the canonical TGF-beta1 signaling pathway and altered TGF-beta1-induced epithelial-mesenchymal transition and MMP9 production in lung epithelial cells. In addition, BMAL1 knockdown inhibited the fibroblast to myofibroblast differentiation of normal human lung fibroblasts. CONCLUSIONS: Our results indicate that activation of TGF-beta1 promotes the transcriptional induction of BMAL1. Furthermore, BMAL1 is required for the TGF-beta1-induced signaling transduction and pro-fibrotic activities in the lung. PMID- 26754000 TI - Trigger sequence can influence final morphology in the self-assembly of asymmetric telechelic polymers. AB - We report on a numerical study of polymer network formation of asymmetric biomimetic telechelic polymers with two reactive ends based on a self-assembling collagen, elastin or silk-like polypeptide sequence. The two reactive ends of the polymer can be activated independently using physicochemical triggers such as temperature and pH. We show, using a simple coarse grained model that the order in which this triggering occurs influences the final morphology. For both of collagen-silk and elastin-silk topologies we find that for relatively short connector chains the morphology of the assembly is greatly influenced by the order of the trigger, whereas for longer chains the equilibrium situation is more easily achieved. Moreover, self-assembly is greatly enhanced at moderate collagen interaction strength, due to facilitated binding and unbinding of the peptides. This finding indicates that both the trigger sequence and strength can be used to steer self-assembly in these biomimetic polymer systems. PMID- 26753999 TI - ["Not a miracle but impressive effects"? : On the discussion about the effects of transcranial direct current stimulation]. PMID- 26754001 TI - RASSF1 tumor suppressor gene in pancreatic ductal adenocarcinoma: correlation of expression, chromosomal status and epigenetic changes. AB - BACKGROUND: The Ras Association Domain Family Member 1 (RASSF1) is one of the most frequently reported methylation-inactivated tumor suppressor genes in primary pancreatic ductal adenocarcinomas (PDAC). Limited information is still available about the impact of RASSF1 gene silencing on the expression of its different isoforms in neoplastic cells. METHODS: A series of 96 primary PDAC, with known clinico-pathological parameters, was tested for RASSF1 methylation status by methylation-specific PCR, RASSF1 locus copy number alterations by fluorescence in situ hybridization, and Rassf1a protein expression by immunohistochemistry. A further series of 14 xenografted primary PDAC and 8 PDAC derived cell lines were tested to obtain a detailed methylation mapping of CpG islands A and C of the RASSF1 locus by pyrosequencing and to evaluate the expression of Rassf1 variants by qRT-PCR. RESULTS: Methylation of CpG island A of the RASSF1 gene was observed in 35% of the tumors and allelic loss of RASSF1 locus was seen in 30 disomic and in 20 polysomic cases (52%). Rassf1a immunohistochemical expression was downregulated in half of primary PDAC, and this downregulation was neither correlated with methylation of RASSF1 promoter nor with RASSF1 copy number alterations. RASSF1 status did not influence patients' prognosis. The expression of the seven RASSF1 isoforms in xenografts and cell lines showed that RASSF1A, RASSF1B, and RASSF1C isoforms were present in all xenografts and cell lines, whereas RASSF1D, RASSF1E, and RASSF1F isoforms were variably expressed among samples. RASSF1G was never expressed in either xenografts or cell lines. The variable expression of RASSF1 isoforms in PDAC xenografts and cell lines was not dependent on RASSF1 methylation status of CpG islands A and C. CONCLUSIONS: RASSF1 alterations occurring in PDAC mainly consist in variations of expression of the different isoforms. Different genetic mechanisms seem to contribute to RASSF1 deregulation in this setting, but RASSF1 methylation does not seem to substantially affect RASSF1 isoforms expression. PMID- 26754002 TI - GBS-SNP-CROP: a reference-optional pipeline for SNP discovery and plant germplasm characterization using variable length, paired-end genotyping-by-sequencing data. AB - BACKGROUND: With its simple library preparation and robust approach to genome reduction, genotyping-by-sequencing (GBS) is a flexible and cost-effective strategy for SNP discovery and genotyping, provided an appropriate reference genome is available. For resource-limited curation, research, and breeding programs of underutilized plant genetic resources, however, even low-depth references may not be within reach, despite declining sequencing costs. Such programs would find value in an open-source bioinformatics pipeline that can maximize GBS data usage and perform high-density SNP genotyping in the absence of a reference. RESULTS: The GBS SNP-Calling Reference Optional Pipeline (GBS-SNP CROP) developed and presented here adopts a clustering strategy to build a population-tailored "Mock Reference" from the same GBS data used for downstream SNP calling and genotyping. Designed for libraries of paired-end (PE) reads, GBS SNP-CROP maximizes data usage by eliminating unnecessary data culling due to imposed read-length uniformity requirements. Using 150 bp PE reads from a GBS library of 48 accessions of tetraploid kiwiberry (Actinidia arguta), GBS-SNP-CROP yielded on average three times as many SNPs as TASSEL-GBS analyses (32 and 64 bp tag lengths) and over 18 times as many as TASSEL-UNEAK, with fewer genotyping errors in all cases, as evidenced by comparing the genotypic characterizations of biological replicates. Using the published reference genome of a related diploid species (A. chinensis), the reference-based version of GBS-SNP-CROP behaved similarly to TASSEL-GBS in terms of the number of SNPs called but had an improved read depth distribution and fewer genotyping errors. Our results also indicate that the sets of SNPs detected by the different pipelines above are largely orthogonal to one another; thus GBS-SNP-CROP may be used to augment the results of alternative analyses, whether or not a reference is available. CONCLUSIONS: By achieving high-density SNP genotyping in populations for which no reference genome is available, GBS-SNP-CROP is worth consideration by curators, researchers, and breeders of under-researched plant genetic resources. In cases where a reference is available, especially if from a related species or when the target population is particularly diverse, GBS-SNP-CROP may complement other reference-based pipelines by extracting more information per sequencing dollar spent. The current version of GBS-SNP-CROP is available at https://github.com/halelab/GBS-SNP-CROP.git. PMID- 26754003 TI - KLHL40-related nemaline myopathy with a sustained, positive response to treatment with acetylcholinesterase inhibitors. AB - Congenital myopathies are a group of inherited muscle disorders characterized by hypotonia, weakness and a non-dystrophic muscle biopsy with the presence of one or more characteristic histological features. Neuromuscular transmission defects have recently been reported in several patients with congenital myopathies (CM). Mutations in KLHL40 are among the most common causes of severe forms of nemaline myopathy. Clinical features of affected individuals include fetal akinesia or hypokinesia, respiratory failure, and swallowing difficulties at birth. Muscle weakness is usually severe and nearly half of the individuals have no spontaneous antigravity movement. The average age of death has been reported to be 5 months in a recent case series. Herein we present a case of a patient with a nemaline myopathy due to KLHL40 mutations (c.604delG, p.Ala202Argfs*56 and c.1513G>C, p.Ala505Pro) with an impressive and prolonged beneficial response to treatment with high-dose pyridostigmine. Myasthenic features or response to ACEI have not previously been reported as a characteristic of nemaline myopathy or KLHL40 related myopathy. PMID- 26754004 TI - Impact of Angiotensin-II receptor blockers on vasogenic edema in glioblastoma patients. AB - Glioblastoma patients often require chronic administration of steroids due to peri-tumoral edema. Preliminary studies showed that treatment with Angiotensin-II Receptor Blockers (ARBs) for high blood pressure might be associated with reduced peri-tumoral edema. In this study, we aim to radiologically assess the effect of ARBs on peri-tumoral edema. We conducted a cross-sectional survey on patients with newly diagnosed GBM. Patients treated with ARBs for high blood pressure were paired to non ARB-treated patients based on similar age, tumor location and tumor size. Patients taking steroids at the time of pre-operative Magnetic Resonance Imaging were excluded from the study. In each pair of patients, we compared the volumes of peri-tumoral hyper T2-Fluid Attenuated Inversion Recovery (FLAIR) signal and the Apparent Diffusion Coefficient (ADC) in the same area. Eleven (11) ARB-treated patients were selected and paired to 11 non ARB-treated controls. Volumes of peri-tumoral hyper T2-FLAIR signal were significantly lower in the ARB treated group than in the non ARB-treated group (p = 0.02). Additionally, peri tumoral ADCs were also significantly lower in the treated group (p = 0.02), suggesting that the peri-tumoral area in this group had less edematous features. These results suggest that ARBs may reduce the volume of peri-tumoral hyper T2 FLAIR signal by decreasing edema. PMID- 26754006 TI - Improvement of lateral axial dystonia following prismatic correction of oculomotor control disorders in Parkinson's disease. PMID- 26754005 TI - An MRI-defined measure of cerebral lesion severity to assess therapeutic effects in multiple sclerosis. AB - Assess the sensitivity of the Magnetic Resonance Disease Severity Scale (MRDSS), based on cerebral lesions and atrophy, for treatment monitoring of glatiramer acetate (GA) in relapsing-remitting multiple sclerosis (MS). This retrospective non-randomized pilot study included patients who started daily GA [n = 23, age (median, range) 41 (26.2, 53.1) years, Expanded Disability Status Scale (EDSS) score 1.0 (0, 3.5)], or received no disease-modifying therapy (noDMT) [n = 21, age 44.8 (28.2, 55.4), EDSS 0 (0, 2.5)] for 2 years. MRDSS was the sum of z scores (normalized to a reference sample) of T2 hyperintense lesion volume (T2LV), the ratio of T1 hypointense LV to T2LV (T1/T2), and brain parenchymal fraction (BPF) multiplied by negative 1. The two groups were compared by Wilcoxon rank sum tests; within group change was assessed by Wilcoxon signed rank tests. Glatiramer acetate subjects had less progression than noDMT on T1/T2 [(median z score change (range), 0 (-1.07, 1.20) vs. 0.41 (-0.30, 2.51), p = 0.003)] and MRDSS [0.01 (-1.33, 1.28) vs. 0.46 (-1.57, 2.46), p = 0.01]; however, not on BPF [0.12 (-0.18, 0.58) vs. 0.10 (-1.47,0.50), p = 0.59] and T2LV [-0.03 (-0.90, 0.57) vs. 0.01 (-1.69, 0.34), p = 0.40]. While GA subjects worsened only on BPF [0.12 (-0.18, 0.58), p = 0.001], noDMT worsened on BPF [0.10 (-1.47, 0.50), p = 0.002], T1/T2 [0.41 (-0.30, 2.51), p = 0.0002], and MRDSS [0.46 (-1.57, 2.46), p = 0.0006]. These preliminary findings show the potential of two new cerebral MRI metrics to track MS therapeutic response. The T1/T2, an index of the destructive potential of lesions, may provide particular sensitivity to treatment effects. PMID- 26754007 TI - Paraneoplastic opsoclonus and cerebellar ataxia related to anti-Ma2 antibody: a case report. PMID- 26754018 TI - Methods for the determination of the substantivity of topical formulations. AB - Skin diseases are usually treated using topical formulations. Frequently, multiple applications per day are necessary, as up to 90% of the formulation (and thus of the active) are withdrawn from the skin by contact with the environment. During the development of topical formulations ex vivo permeation and penetration experiments are deployed to characterize the formulations. Still, these tests do not take into account the removal of formulations during the application period. To date, only few methods exist to probe the substantivity of dermal formulations. The aim of this investigation was to develop methods that simulate skin-to-skin or clothing-to-skin contact and enable the determination of the amount of formulation that is removed from the skin due to the contact. Three different types of formulations were used to validate the systems: a conventional semisolid cream, an oil-in-oil-emulsion, and a film forming formulation. The results showed that the substantivity decreased in the order: film forming formulation > semisolid cream > oil-in-oil-emulsion. A similar trend could be determined with both methods although the total amounts of withdrawn formulation differed. The developed methods can add to the knowledge about the formulation and can be used to develop formulations that exhibit higher substantivity. PMID- 26754017 TI - Gendered differences in the perceived risks and benefits of oral PrEP among HIV serodiscordant couples in Kenya. AB - Pre-exposure prophylaxis (PrEP) is effective for preventing HIV among HIV serodiscordant heterosexual couples. Gender roles may influence perceived personal and social risks related to HIV-prevention behaviors and may affect use of PrEP. In this study, interviews and focus groups were conducted with 68 individuals from 34 mutually disclosed serodiscordant heterosexual partnerships in Thika, Kenya. Sociocultural factors that affect adherence to PrEP were explored using grounded analysis. Three factors were identified, which shape perceptions of PrEP: gendered power dynamics and control over decision-making in the household; conflicts between risk-reduction strategies and male sexual desire; culture-bound definitions of women's work. Adherence to PrEP in the Partners PrEP Study was high; however, participants articulated conflicting interests related to PrEP in connection with traditional gender roles. The successful delivery of PrEP will require understanding of key social factors, particularly related to gender and dyadic dynamics around HIV serostatus. PMID- 26754019 TI - Approaching the histodynamics of celiac disease in modern times: the need of going beyond the dogmas. PMID- 26754020 TI - Autonomous Indication of Mechanical Damage in Polymeric Coatings. AB - High-resolution in situ autonomous visual indication of mechanical damage is achieved through a microcapsule-based polymeric material system. Upon mechanical damage, ruptured microcapsules release a liquid indicator molecule. A sharp color change from light yellow to bright red is triggered when the liberated indicator 2',7'-dichlorofluorescein reacts with the polymeric coating matrix. PMID- 26754021 TI - Long-term outcomes of osteotome sinus floor elevation without bone grafts: a clinical retrospective study of 4-9 years. AB - OBJECTIVE: To evaluate the long-term clinical and radiographic outcomes of dental implant placed using osteotome sinus floor elevation (OSFE) without bone grafts, and to analyze the potential influence factors of implant survival and endo-sinus bone remodeling. MATERIAL AND METHODS: A retrospective study design was adopted. The clinical and radiographic data of 96 implants in 80 patients were collected after 4-9 (mean 5.40) years follow-up. Implant failures, peri-implant marginal bone loss (MBL), and endo-sinus bone remodeling on the radiographs were evaluated. A life-table analysis was used to assess the implant survival. Statistical models were established to investigate the potential influence factors of implant survival and endo-sinus bone gain (ESBG). RESULTS: In total, nine implants in seven patients failed, giving the 9-year cumulative survival rates of 90.6% and 91.3% for implant-based analysis and patient-based analysis, respectively. The mean MBL between implant installation and the 4- and 9-year follow-up visit was 0.46 +/- 0.88 and 0.50 +/- 1.69 mm, respectively. The average ESBG on radiographs was 2.95 +/- 1.25 and 2.16 +/- 1.13 mm at the 4- and 9-year follow-up. The final ESBG was found to be positively correlated to implant protrusion length after surgery without any other factors related. The implant survival rate was significantly lower in severe atrophic site (residual bone height <5 mm). CONCLUSION: Osteotome sinus floor elevation without bone grafts is a predictable treatment modality in the long run. But it should be used with caution when the initial bone height of the edentulous site is lower than 5 mm. The final endo-sinus bone height was found to be positively correlated to implant protrusion length measured on radiographs immediately after implant installation. PMID- 26754022 TI - A glimpse into the future of genome-enabled plant biology from the shores of Cold Spring Harbor. AB - A report on the 10(th) plant genome meeting entitled 'Plant genomes and biotechnology: from genes to networks', held at Cold Spring Harbor Laboratory, 2 5 December, 2015. PMID- 26754024 TI - Handedness and social anxiety: Using Bryden's research as a catalyst to explore the influence of familial sinistrality and degree of handedness. AB - Phil Bryden's work has impacted on many areas of laterality, including degree and measurement of hand preference, as well as influences of familial sinistrality (FS). For example, Bryden[(1977). Measuring handedness with questionnaires. Neuropsychologia, 15, 617-624] is a well-cited and influential paper that remains relevant to this day. Inspired by this we extended our analysis of the relationship between handedness and anxiety in a number of ways. We used familial handedness and strength of handedness to examine their potential influences on anxiety, and extended our research by exploring their relationship to social anxiety, using the Social Phobia Inventory (SPIN). Inconsistent left-handers (ILH) were found to be more socially anxious. In all categories of SPIN except avoidance, ILH were significantly more anxious than consistent right- and left handers. There were FS differences between ILH with a first degree left-handed relative (FS+) compared to ILH with no first degree left-handed relative (FS-) on all categories of anxiety scores. Within FS+ participants, ILH had significantly higher anxiety scores, compared with consistent handers across all categories. This suggests that ILH's social anxiety may be influenced by a close left-handed relative. Inspired by examining Bryden's work for this special issue, we will continue to add both strength of preference and familial handedness to our work. PMID- 26754023 TI - Lateral meningocele (Lehman) syndrome: A child with a novel NOTCH3 mutation. AB - Lateral meningocele syndrome (LMS), or Lehman syndrome, is a rare disorder characterized by multiple lateral spinal meningoceles, distinctive facial features, joint hypermobility and hypotonia, along with skeletal, cardiac, and urogenital anomalies. Heterozygous NOTCH3 mutations affecting the terminal exon 33 were recently reported as causative in six families with LMS. We report a boy with LMS, the fourteenth reported case, with a de novo 80 base pair deletion in exon 33 of NOTCH3. Our patient's prenatal findings, complex cardiac anomalies, and severe feeding difficulties further expand our understanding of this rare condition. PMID- 26754025 TI - The involvement of patient organisations in rare disease research: a mixed methods study in Australia. AB - BACKGROUND: We report here selected findings from a mixed-methods study investigating the role of Australian rare disease patient organisations (RDPOs) in research. Despite there being many examples of RDPOs that have initiated and supported significant scientific advances, there is little information - and none at all in Australia - about RDPOs generally, and their research-related goals, activities, and experiences. This information is a pre-requisite for understanding what RDPOs bring to research and how their involvement could be strengthened. METHODS: We reviewed 112 RDPO websites, conducted an online survey completed by 61 organisational leaders, and interviewed ten leaders and two key informants. Quantitative and qualitative data were analysed using basic descriptive statistics and content analysis, respectively. RESULTS: Although most are small volunteer-based groups, more than 90% of the surveyed RDPOs had a goal to promote or support research on the diseases affecting their members. Nearly all (95 %) had undertaken at least one research-related activity - such as providing funding or other support to researchers - in the previous five years. However, RDPO leaders reported considerable challenges in meeting their research goals. Difficulties most frequently identified were insufficient RDPO resources, and a perceived lack of researchers interested in studying their diseases. Other concerns included inadequate RDPO expertise in governing research "investments", and difficulty engaging researchers in the organisation's knowledge and ideas. We discuss these perceived challenges in the light of two systemic issues: the proliferation of and lack of collaboration between RDPOs, and the lack of specific governmental policies and resources supporting rare disease research and patient advocacy in Australia. CONCLUSION: This study provides unique information about the experiences of RDPOs generally, rather than experiences retrospectively reported by RDPOs associated with successful research. We describe RDPOs' valuable contributions to research, while also providing insights into the difficulties for small organisations trying to promote research. The study is relevant internationally because of what it tells us about RDPOs; however, we draw attention to specific opportunities in Australia to support RDPOs' involvement in research, for the benefit of current and future generations affected by rare diseases. PMID- 26754026 TI - Investigating the reliability and validity of the Dutch versions of the illness management and recovery scales among clients with mental disorders. AB - BACKGROUND: The Illness Management and Recovery scales (IMRS) can measure the progress of clients' illness self-management and recovery. Previous studies have examined the psychometric properties of the IMRS. AIMS: This study examined the reliability and validity of the Dutch version of the IMRS. METHOD: Clients (n = 111) and clinicians (n = 40) completed the client and clinician versions of the IMRS, respectively. The scales were administered again 2 weeks later to assess stability over time. Validity was assessed with the Utrecht Coping List (UCL), Dutch Empowerment Scale (DES), and Brief Symptom Inventory (BSI). RESULTS: The client and clinician versions of the IMRS had moderate internal reliability, with alpha = 0.69 and 0.71, respectively. The scales showed strong test-retest reliability, r = 0.79, for the client version and r = 0.86 for the clinician version. Correlations between client and clinician versions ranged from r = 0.37 to 0.69 for the total and subscales. We also found relationships in expected directions between the client IMRS and UCL, DES and BSI, which supports validity of the Dutch version of the IMRS. CONCLUSIONS: The Dutch version of the IMRS demonstrated good reliability and validity. The IMRS could be useful for Dutch speaking programs interested in evaluating client progress on illness self management and recovery. PMID- 26754027 TI - Genetic polymorphisms in MMP 2, 3 and 9 genes and the susceptibility of osteosarcoma in a Chinese Han population. AB - BACKGROUND: There are no data about the role of MMPs polymorphism in development of osteosarcoma. PATIENTS AND METHODS: Two-hundred fifty-one patients with osteosarcoma and 251 healthy controls were included to investigate the association between the MMP2, 3, 9 polymorphisms and the risk of osteosarcoma. RESULTS: Compared with the MMP2 SNP rs243865 homozygote CC, The heterozygous CT genotype was associated with significantly increased risk for osteosarcoma (OR = 1.86, 95% CI = 1.18-4.22, p = 0.014); the TT genotype was associated with increased risk for osteosarcoma (OR = 1.92, 95% CI = 1.21-3.52, p = 0.028). However, the genotype and allele frequencies of MMP3 rs3025058 and MMP9 rs3918242 polymorphisms were not significantly different. CONCLUSION: MMP2 rs243865 genotype was associated with increased risk for development of osteosarcoma in Chinese Han population. PMID- 26754028 TI - Laser-Directed Assembly of Aligned Carbon Nanotubes in Three Dimensions for Multifunctional Device Fabrication. AB - Laser-directed assembly of multiwalled carbon nanotubes (MWNTs) in 3D space is investigated via a two-photon polymerization technique. MWNT-thiol-acrylate (MTA) composite resins are developed with high MWNT concentrations up to 0.2 wt%, over one order of magnitude higher than previously published work. Significantly enhanced electrical and mechanical properties of the 3D micro-/nanostructures are achieved. Microelectronic devices made of the MTA resins are demonstrated. PMID- 26754029 TI - Bioavailability of cerium oxide nanoparticles to Raphanus sativus L. in two soils. AB - Cerium oxide nanoparticles (CeO2 NP) are a common component of many commercial products. Due to the general concerns over the potential toxicity of engineered nanoparticles (ENPs), the phytotoxicity and in planta accumulation of CeO2 NPs have been broadly investigated. However, most previous studies were conducted in hydroponic systems and with grain crops. For a few studies performed with soil grown plants, the impact of soil properties on the fate and transport of CeO2 NPs was generally ignored even though numerous previous studies indicate that soil properties play a critical role in the fate and transport of environmental pollutants. The objectives of this study were to evaluate the soil fractionation and bioavailability of CeO2 NPs to Raphanus sativus L (radish) in two soil types. Our results showed that the silty loam contained slightly higher exchangeable fraction (F1) of cerium element than did loamy sand soil, but significantly lower reducible (F2) and oxidizable (F3) fractions as CeO2 NPs concentration increased. CeO2 NPs associated with silicate minerals or the residue fraction (F4) dominated in both soils. The cerium concentration in radish storage root showed linear correlation with the sum of the first three fractions (r2 = 0.98 and 0.78 for loamy sand and silty loam respectively). However, the cerium content in radish shoots only exhibited strong correlations with F1 (r2 = 0.97 and 0.89 for loamy sand and silty loam respectively). Overall, the results demonstrated that soil properties are important factors governing the distribution of CeO2 NPs in soil and subsequent bioavailability to plants. PMID- 26754030 TI - Child and youth experiences and perspectives of cerebral palsy: a qualitative systematic review. AB - BACKGROUND: Cerebral palsy (CP) is one of the most common causes of physical disability in childhood, and many children with CP access rehabilitation services throughout their lives. The aim of this qualitative systematic review was to synthesize the experiences and perspectives of youth living with CP to inform the development of rehabilitation and social programmes. METHODS: A thematic qualitative synthesis integrating qualitative evidence was undertaken where six electronic databases (MEDLINE, Embase, Healthstar, Cumulative Index to Nursing and Allied Health Literature, Proquest and PsychInfo) were searched from 1980 to September 2014. RESULTS: Thirty-three articles involving 390 youth, aged from 2 to 25 years, across six countries were included. Themes were classified according to the International Classification of Functioning Child and Youth Version framework. Youth's accounts focused on social inclusion and the physical environment (i.e. services and supports, transportation, accessibility, accommodations, safety and weather), the role of family and peers and participation (i.e. leisure and recreation, school and civic engagement). Youth described how body structure and function (i.e. pain and physical functioning, mental health, fatigue and unpredictability of body function) affected them - often disrupting their biographies. Some youth described personal factors such as independence, coping and body image that affected their ability to cope with their condition. There was much less focus on youth's experiences of mobility, activities of daily living and assistive devices. CONCLUSIONS: Youth with CP experience pain, fatigue and impairments to body function, along with social exclusion, which can affect their biographies. However, youth had strategies to revise their biographies to maintain personal and social normalcy. PMID- 26754031 TI - Long-term impact of temporary and persistent personality disorder on anxiety and depressive disorders. AB - BACKGROUND: It is of interest to know if temporary and persistent personality disorders are associated with different outcomes. METHOD: A cohort of 210 people with anxiety and depressive disorders was followed up on nine occasions over 12 years. During this study, personality status was assessed at baseline and after 2 years using two methods, one linked to the new International Classification of Diseases 11th Revision (ICD-11) severity codes. The impact on the symptomatic outcome and social function of temporary (i.e. personality disorder on one occasion only) and persistent personality disorder (personality disorder present on both occasions) was compared. RESULTS: Of the 162 patients studied we identified four groups (no personality disorder at any time (n = 46), two with temporary personality disorder (baseline only (n = 33) and 2 years only (n = 28), and persistent personality disorder (n = 55). Those with persistent personality disorder had significantly worse outcomes than other groups for self-rated anxiety symptoms (p = 0.02) and overall social function (p < 0.001), 81% had a current DSM diagnosis at 12 years compared with 52-65% in the other groups (p < 0.03). Significantly, more patients with ICD-11 moderate or severe personality disorder at baseline had persistent personality disorder than had temporary disorders (p = 0.017). CONCLUSION: Persistent personality disorder is associated with more severe personality dysfunction and has a negative impact on the outcome of common mental disorder and particularly on long-term social functioning. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26754032 TI - Appropriate Size of Magnetic Nanoparticles for Various Bioapplications in Cancer Diagnostics and Therapy. AB - The development of multifunctional nanoparticles has attracted increasing attention. The versatility of nanoparticles largely depends on their physiochemical properties (especially size). However, the optimized size range may be different for the bioapplications of each function associated with multifunctional nanoparticles. It is important to investigate every optimized size range to ascertain which size enables the best function of the nanoparticles before deciding their final size. In this work, we synthesized a series of monodisperse Fe3O4 nanoparticles with identical surface properties ranging in size from 60 to 310 nm and systematically investigated their biobehavior and application. Our data indicate that compared to their large counterparts, small Fe3O4 nanoparticles exhibited greater cellular internalization and deeper penetration into multicellular spheroids, thus enabling a higher photothermal ablation efficacy in vitro. Interestingly, larger Fe3O4 nanoparticles showed greater accumulation in tumors, thereby inducing more efficient tumor growth inhibition. In addition, 120 nm may be the optimal diameter of Fe3O4 nanoparticles for magnetic resonance imaging and photoacoustic tomography in vitro. However, more efficient in vivo imaging mediated by Fe3O4 nanoparticles will predominantly depend on their high accumulation. Our work presents a different appropriate size range for each biofunction of Fe3O4 nanoparticles, which could be a valuable reference for future nanoparticle design. PMID- 26754034 TI - Vapor and healing treatment for CH3NH3PbI(3-x)Cl(x) films toward large-area perovskite solar cells. AB - Hybrid methyl-ammonium lead trihalide perovskites are promising low-cost materials for use in solar cells and other optoelectronic applications. With a certified photovoltaic conversion efficiency record of 20.1%, scale-up for commercial purposes is already underway. However, preparation of large-area perovskite films remains a challenge, and films of perovskites on large electrodes suffer from non-uniform performance. Thus, production and characterization of the lateral uniformity of large-area films is a crucial step towards scale-up of devices. In this paper, we present a reproducible method for improving the lateral uniformity and performance of large-area perovskite solar cells (32 cm(2)). The method is based on methyl-ammonium iodide (MAI) vapor treatment as a new step in the sequential deposition of perovskite films. Following the MAI vapor treatment, we used high throughput techniques to map the photovoltaic performance throughout the large-area device. The lateral uniformity and performance of all photovoltaic parameters (V(oc), J(sc), Fill Factor, Photo conversion efficiency) increased, with an overall improved photo-conversion efficiency of ~100% following a vapor treatment at 140 degrees C. Based on XRD and photoluminescence measurements, We propose that the MAI treatment promotes a "healing effect" to the perovskite film which increases the lateral uniformity across the large-area solar cell. Thus, the straightforward MAI vapor treatment is highly beneficial for large scale commercialization of perovskite solar cells, regardless of the specific deposition method. PMID- 26754033 TI - Renal Function Following Nephron Sparing Procedures: Simply a Matter of Volume? AB - Partial nephrectomy (PN) is the current standard of care for the management of small renal masses (SRM), providing comparable oncologic control with improved renal functional outcomes. Additionally, new technologies such as thermal ablation provide attractive alternatives to traditional extirpative surgery. The obvious benefit of these nephron sparing procedures (NSPs) is to the preservation of renal parenchymal volume (RPV), but the factors that influence postoperative renal function are complex and inter-related, and include non-modifiable factors such as baseline renal function and tumor size, complexity, and location as well as potentially modifiable factors such as ischemia time, ischemia type, and RPV preservation. Our review presents the most recent evidence analyzing the relationship between the modifiable factors in PN and renal outcomes, with a focus on RPV preservation. Furthermore, novel surgical techniques, imaging modalities, and NSPs are discussed, evaluating their efficacy in maximizing functional nephron mass and improving long-term renal outcomes. PMID- 26754035 TI - Blood-injection-injury phobia in older adults. AB - BACKGROUND: This study aims to (i) estimate the prevalence of blood-injection injury phobia (BIIP) diagnosed as present at any time during the life prior to the interview, with or without another Specific Phobia diagnosed as present during the 12 months prior to the interview, (ii) characterize types and frequencies of co-occurring fears, (iii) evaluate the association with chronic medical conditions and lifetime psychiatric comorbidity, and (iv) explore medical service use associations in a nationally representative sample of older adults. METHODS: A sample of 8,205 older adults, aged 65 years or older, was derived from Wave 1 of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC). RESULTS: The weighted lifetime prevalence of BIIP with and without 12 month Specific Phobia was 0.6% (95% CI: 0.4-0.8) and 4.2% (95% CI: 3.7-4.8), respectively, and these two groups ranked similarly in terms of sociodemographic, health, and psychiatric characteristics. BIIP most frequently co-occurred with other lifetime fears, and was positively associated with hypertension and lifetime history of anxiety and personality disorders after controlling for sociodemographic and psychiatric confounders. CONCLUSIONS: Our findings suggest that lifetime BIIP may bear mental and physical health significance in older adults. PMID- 26754036 TI - Epidemiology of epilepsy. AB - Epilepsy is a burden affecting no fewer than 50 million patients worldwide. It is a heterogeneous group of disorders comprising both common and very rare forms, thus rendering its epidemiological investigations rather difficult. Moreover, making an epilepsy diagnosis per se can be challenging due to an evolving system of classification, and its dependency on local habits and culture. Any attempt at meta-analyses must consider such biases when pooling data from different centers and countries. Differentiating a contextual seizure from chronic epilepsy is every epileptologist's daily mission, yet it is also crucial for achieving a proper estimation of the epidemiology of epilepsy. Our present objective was to provide an overview of the epidemiology of both syndromic and non-syndromic epilepsy. Most epileptic syndromes tend to be rare and, thus, the feasibility of epidemiological quantification in populations is also addressed. Regarding its prevalence and cost, epilepsy deserves greater attention than it generally receives, as it appears to continue to be a condition under persistent taboos. PMID- 26754037 TI - An unusual case of renal failure: Questions. PMID- 26754038 TI - Febrile urinary tract infection after pediatric kidney transplantation: a multicenter, prospective observational study. AB - BACKGROUND: Febrile urinary tract infections (fUTIs) are common after kidney transplantation (KTx); however, prospective data in a multicenter pediatric cohort are lacking. We designed a prospective registry to record data on fUTI before and after pediatric KTx. METHODS: Ninety-eight children (58 boys and 40 girls) <= 18 years from 14 mid-European centers received a kidney transplant and completed a 2-year follow-up. RESULTS: Posttransplant, 38.7% of patients had at least one fUTI compared with 21.4% before KTx (p = 0.002). Before KTx, fUTI was more frequent in patients with congenital anomalies of kidneys and urinary tract (CAKUT) vs. patients without (38% vs. 12%; p = 0.005). After KTx, fUTI were equally frequent in both groups (48.7% vs. 32.2%; p = 0.14). First fUTI posttransplant occurred earlier in boys compared with girls: median range 4 vs. 13.5 years (p = 0.002). Graft function worsened (p < 0.001) during fUTI, but no difference was recorded after 2 years. At least one recurrence of fUTI was encountered in 58%. CONCLUSION: This prospective study confirms a high incidence of fUTI after pediatric KTx, which is not restricted to patients with CAKUT; fUTIs have a negative impact on graft function during the infectious episode but not on 2-year graft outcome. PMID- 26754040 TI - An unusual case of renal failure: Answers. PMID- 26754039 TI - Body composition monitoring-derived urea distribution volume in children on chronic hemodialysis. AB - BACKGROUND: Modern hemodialysis (HD) machines are able to measure ionic dialysance online and thereby continuously monitor Kt/V. The accuracy of measurement depends on the input of the correct urea distribution volume (V), available from anthropometric equations and body composition monitoring (BCM). The latter method, however, has not been validated in children. METHODS: We compared V determined by BCM to that calculated using four different anthropometric formulas (Morgenstern, Mellits and Cheek, Hume-Weyers and Watson equations) in 23 pediatric HD patients. We also compared online Kt/V using BCM derived V with the Kt/V calculated from pre- and post-dialytic urea concentrations using the single-pool second-generation Daugirdas equation. RESULTS: The V calculated by the Morgenstern equation was similar to that derived by BCM, with a mean difference of -0.7% (95% limits of agreement -11.7 to 10.3%). In contrast, the V calculated by the other equations was 5.4, 6.2 and 18%, respectively higher than the BCM-derived V. The mean difference between Kt/V calculated using the Daugirdas equation and online Kt/V determination based on BCM-derived V data was 0.10 (95% limits of agreement -0.50 to 0.70%). CONCLUSIONS: In our pediatric HD patients the V measured by BCM was in agreement with that calculated using the Morgenstern equation, which is the only equation which has been validated to date in children on dialysis. Online determination of Kt/V using a BCM-derived V largely agreed with that calculated by the Daugirdas equation. We therefore conclude that the former approach is suitable for frequent online assessment of dialytic small solute clearance. PMID- 26754042 TI - Multifunctionalized iron oxide nanoparticles for selective drug delivery to CD44 positive cancer cells. AB - Nanomedicine nowadays offers novel solutions in cancer therapy and diagnosis by introducing multimodal treatments and imaging tools in one single formulation. Nanoparticles acting as nanocarriers change the solubility, biodistribution and efficiency of therapeutic molecules, reducing their side effects. In order to successfully apply these novel therapeutic approaches, efforts are focused on the biological functionalization of the nanoparticles to improve the selectivity towards cancer cells. In this work, we present the synthesis and characterization of novel multifunctionalized iron oxide magnetic nanoparticles (MNPs) with antiCD44 antibody and gemcitabine derivatives, and their application for the selective treatment of CD44-positive cancer cells. The lymphocyte homing receptor CD44 is overexpressed in a large variety of cancer cells, but also in cancer stem cells (CSCs) and circulating tumor cells (CTCs). Therefore, targeting CD44 overexpressing cells is a challenging and promising anticancer strategy. Firstly, we demonstrate the targeting of antiCD44 functionalized MNPs to different CD44 positive cancer cell lines using a CD44-negative non-tumorigenic cell line as a control, and verify the specificity by ultrastructural characterization and downregulation of CD44 expression. Finally, we show the selective drug delivery potential of the MNPs by the killing of CD44-positive cancer cells using a CD44 negative non-tumorigenic cell line as a control. In conclusion, the proposed multifunctionalized MNPs represent an excellent biocompatible nanoplatform for selective CD44-positive cancer therapy in vitro. PMID- 26754041 TI - The dose-response effect of insulin sensitivity on albuminuria in children according to diabetes type. AB - BACKGROUND: Insulin resistance is associated with microalbuminuria among youth with diabetes mellitus. We sought to determine the dose-response effect of insulin sensitivity (IS) on the magnitude of albuminuria and whether there is a threshold below which urine albumin excretion increases. METHODS: These analyses included participants from the SEARCH for Diabetes in Youth Study with incident diabetes who completed a baseline study visit (n = 2988). We estimated IS using a validated equation incorporating waist circumference, HbA1C, and fasting serum triglycerides. Multivariate regression analyses were performed to assess the effect of IS on urine albumin creatinine ratio (UACR), stratified by diabetes type. The IS threshold was then determined using segmented regressions within each diabetes type and incorporated into the multivariate model. RESULTS: There was an association between IS and UACR in type 2 diabetes only (beta = -0.39; p < 0.001). There was strong statistical evidence for a threshold effect of IS score on UACR in the group of youth with type 2 (beta = 0.40; p < 0.001) but not type 1 diabetes (p = 0.3). CONCLUSIONS: In cross-sectional analyses, there is a negative association between IS and UACR in youth with type 2 but not type 1 diabetes, and this association likely includes a threshold effect of IS on UACR. PMID- 26754044 TI - Racial Disparities in Children's Health: A Longitudinal Analysis of Mothers Based on the Multiple Disadvantage Model. AB - This secondary data analysis of 4373 mothers and their children investigated racial disparities in children's health and its associations with social structural factors, social relationships/support, health/mental health, substance use, and access to health/mental health services. The study drew on longitudinal records for mother-child pairs created from data in the Fragile Families and Child Wellbeing Study. Generalized estimating equations yielded results showing children's good health to be associated positively with mother's health (current health and health during pregnancy), across three ethnic groups. For African American children, good health was associated with mothers' education level, receipt of informal child care, receipt of public health insurance, uninsured status, and absence of depression. For Hispanic children, health was positively associated with mothers' education level, receipt of substance-use treatment, and non-receipt of public assistance. Implications for policy and intervention are discussed. PMID- 26754043 TI - Roles of NMDA and dopamine in food-foraging decision-making strategies of rats in the social setting. AB - BACKGROUND: In highly complex social settings, an animal's motivational drive to pursue an object depends not only on the intrinsic properties of the object, but also on whether the decision-making animal perceives an object as being the most desirable among others. Mimetic desire refers to a subject's preference for objects already possessed by another subject. To date, there are no appropriate animal models for studying whether mimetic desire is at play in guiding the decision-making process. Furthermore, the neuropharmacological bases of decision making processes are not well understood. In this study, we used an animal model (rat) to investigate a novel food-foraging paradigm for decision-making, with or without a mimetic desire paradigm. RESULTS: Faced with the choice of foraging in a competitive environment, rats preferred foraging for the desirable object, indicating the rats' ability for decision-making. Notably, treatment with the non competitive N-methyl-D-aspartate receptor antagonist MK-801, but not with the dopamine D1 or D2 receptor antagonists, SCH23390 and haloperidol, respectively, suppressed the food foraging preference when there was a competing resident rat in the cage. None of these three antagonists affected the food-foraging preference for palatable food. Moreover, MK-801 and SCH23390, but not haloperidol, were able to abolish the desirable environment effect on standard food-foraging activities in complex social settings. CONCLUSIONS: These results highlight the concept that mimetic desire exerts a powerful influence on food foraging decision-making in rats and, further, illustrate the various roles of the glutamatergic and dopaminergic systems in mediating these processes. PMID- 26754045 TI - Effect of CMC Molecular Weight on Acid-Induced Gelation of Heated WPI-CMC Soluble Complex. AB - Acid-induced gelation properties of heated whey protein isolate (WPI) and carboxymethylcellulose (CMC) soluble complex were investigated as a function of CMC molecular weight (270, 680, and 750 kDa) and concentrations (0% to 0.125%). Heated WPI-CMC soluble complex with 6% protein was made by heating biopolymers together at pH 7.0 and 85 degrees C for 30 min and diluted to 5% protein before acid-induced gelation. Acid-induced gel formed from heated WPI-CMC complexes exhibited increased hardness and decreased water holding capacity with increasing CMC concentrations but gel strength decreased at higher CMC content. The highest gel strength was observed with CMC 750 k at 0.05%. Gels with low CMC concentration showed homogenous microstructure which was independent of CMC molecular weight, while increasing CMC concentration led to microphase separation with higher CMC molecular weight showing more extensive phase separation. When heated WPI-CMC complexes were prepared at 9% protein the acid gels showed improved gel hardness and water holding capacity, which was supported by the more interconnected protein network with less porosity when compared to complexes heated at 6% protein. It is concluded that protein concentration and biopolymer ratio during complex formation are the major factors affecting gel properties while the effect of CMC molecular weight was less significant. PMID- 26754046 TI - Brown adipose and central nervous system glucose uptake is lower during cold exposure in older compared to young men: a preliminary PET study. AB - The purpose of this study was to determine the activity of brown adipose tissue (BAT) and the central nervous system (CNS) during cold exposure in young and older men. Two young, 24 and 21 years, and two older, 76 and 74 years, men participated in the study. Positron emission tomography images showed cold induced BAT activity was absent in older men but clearly present in the clavicular region of the young men (Standardized Uptake Value: SUVmean: 3.12 and 3.71). Statistical parametric mapping revealed cortical brain activity was lower in the older men within areas of the frontal, parietal, temporal, and occipital lobes, and the thalamus (peak-level p uncorr < 0.036). Cervical spinal cord SUVmean values tended to be lower for older (SUVmean: 1.64 and 1.61) compared to young men (SUVmean: 1.91 and 1.71). These preliminary findings suggest lower BAT activity in older men may in part be due to lower CNS activity. PMID- 26754047 TI - The new insight of prostate-specific antigen reduction during finasteride therapy in aging men. AB - OBJECTIVE: To evaluate the effect of finasteride on prostate-specific antigen (PSA) in Chinese population. MATERIALS AND METHODS: From Feb 2011 to Jan 2012, 83 benign prostatic hyperplasia (BPH) patients with prostate volume (PV) >30 mL were enrolled in our study. All the patients were older than 50 years and all of them received combined therapy (finasteride + doxazosin). All the patients were required for 1-year follow-up. PSA level and PV was measured at the start, 6 and 12 months, respectively. RESULTS: 79 patients completed the follow up. PSA level reduced by approximately 40 % during finasteride therapy. We defined baseline PSA as PSA1, PSA at 6 months as PSA2, PSA at 12 months as PSA3. PSA1 was significantly correlated with PSA2/PSA1 and PSA3/PSA1. However, prostate volume was not correlated with PSA1. We divided the patients into three groups according to PSA level. Groups 1, 2, 3 represented the patients with PSA less than 2 ng/mL, between 2 and 4 ng/mL and greater than 4 ng/mL, respectively. Both the PSA2/PSA1 and the PSA3/PSA1 had significant difference among three groups. Furthermore, group 1 and group 2 both showed the fairly large data variance. CONCLUSIONS: When baseline PSA level was greater than 4 ng/mL, the doubling rule could be used for screening. When baseline PSA level was less than 4 ng/Ml, the doubling rule might not be an accurate predictor. We can use the PSA rise from nadir or proPSA to predict prostate cancer. PMID- 26754049 TI - Magnetic-Polaron-Induced Enhancement of Surface Raman Scattering. AB - The studies of the effects of magnetic field on surface enhanced Raman scattering (SERS) have been so far limited to the case of ferromagnetic/noble-metal, core/shell nano-particles, where the influence was always found to be negative. In this work, we investigate the influence of magnetic field on a diluted magnetic semiconductor/metal SERS system. Guided by three dimensional finite difference time-domain simulations, a high efficient SERS substrate was obtained by diluting Mn into Au-capped ZnO, which results in an increase of the dielectric constant and, therefore, an enhancement of Raman signals. More remarkably, an increase of intensities as well as a reduction of the relative standard deviation (RSD) of Raman signals have been observed as a function of the external magnetic strength. We ascribe these positive influences to magnetic-field induced nucleation of bound magnetic polarons in the Mn doped ZnO. The combination of diluted magnetic semiconductors and SERS may open a new avenue for future magneto optical applications. PMID- 26754048 TI - Seeking and sharing: why the pulmonary fibrosis community engages the web 2.0 environment. AB - BACKGROUND: Pulmonary fibrosis (PF) is a rare, progressive disease that affects patients and their loved ones on many levels. We sought to better understand the needs and interests of PF patients and their loved ones (collectively "reader participants") by systematically analyzing their engagement with the World Wide Web (the current version referred to as Web 2.0). METHODS: Data were collected from three PF-focused, interactive websites hosted by physician-investigators with expertise in PF. All data generated by reader-participants for approximately 10 months were downloaded and then analyzed using qualitative content analysis methods. RESULTS: PF experts posted 38 blog entries and reader-participants posted 40 forum entries. Blogs received 363 responses, and forum entries received 108 responses from reader-participants. Reader-participants primarily used the three websites to seek information from or offer a contribution to the PF community. Information was sought about PF symptoms, diagnosis, prognosis, treatments, research, pathophysiology, and disease origin; reader-participants also made requests for new posts and pleas for research and sought clarification on existing content. Contributions included personal narratives about experiences with PF, descriptions of activities or behaviors found to be helpful with PF symptoms, resources or information about PF, and supportive comments to other PF sufferers. CONCLUSIONS: PF patients and their loved ones engage the Web 2.0 environment at these PF-focused sites to satisfy their needs to better understand PF and its impacts and to support others facing similar challenges. Clinicians may find it beneficial to encourage PF patients' involvement in internet forums that foster dynamic, bi-directional information sharing. PMID- 26754050 TI - The effect of medium viscosity on kinetics of ATP hydrolysis by the chloroplast coupling factor CF1. AB - The coupling factor CF1 is a catalytic part of chloroplast ATP synthase which is exposed to stroma whose viscosity is many-fold higher than that of reaction mixtures commonly used to measure kinetics of CF1-catalyzed ATP hydrolysis. This study is focused on the effect of medium viscosity modulated by sucrose or bovine serum albumin (BSA) on kinetics of Ca(2+)- and Mg(2+)-dependent ATP hydrolysis by CF1. These agents were shown to reduce the maximal rate of Ca(2+)-dependent ATPase without changing the apparent Michaelis constant (K m), thus supporting the hypothesis on viscosity dependence of CF1 activity. For the sulfite- and ethanol-stimulated Mg(2+)-dependent reaction, the presence of sucrose increased K m without changing the maximal rate that is many-fold as high as that of Ca(2+) dependent hydrolysis. The hydrolysis reaction was shown to be stimulated by low concentrations of BSA and inhibited by its higher concentrations, with the increasing maximal reaction rate estimated by extrapolation. Sucrose- or BSA induced inhibition of the Mg(2+)-dependent ATPase reaction is believed to result from diffusion-caused deceleration, while its BSA-induced stimulation is probably caused by optimization of the enzyme structure. Molecular mechanisms of the inhibitory effect of viscosity are discussed. Taking into account high protein concentrations in the chloroplast stroma, it was suggested that kinetic parameters of ATP hydrolysis, and probably those of ATP synthesis in vivo as well, must be quite different from measurements taken at a viscosity level close to that of water. PMID- 26754051 TI - Boomerang: A method for recursive reclassification. AB - While there are many validated prognostic classifiers used in practice, often their accuracy is modest and heterogeneity in clinical outcomes exists in one or more risk subgroups. Newly available markers, such as genomic mutations, may be used to improve the accuracy of an existing classifier by reclassifying patients from a heterogenous group into a higher or lower risk category. The statistical tools typically applied to develop the initial classifiers are not easily adapted toward this reclassification goal. In this article, we develop a new method designed to refine an existing prognostic classifier by incorporating new markers. The two-stage algorithm called Boomerang first searches for modifications of the existing classifier that increase the overall predictive accuracy and then merges to a prespecified number of risk groups. Resampling techniques are proposed to assess the improvement in predictive accuracy when an independent validation data set is not available. The performance of the algorithm is assessed under various simulation scenarios where the marker frequency, degree of censoring, and total sample size are varied. The results suggest that the method selects few false positive markers and is able to improve the predictive accuracy of the classifier in many settings. Lastly, the method is illustrated on an acute myeloid leukemia data set where a new refined classifier incorporates four new mutations into the existing three category classifier and is validated on an independent data set. PMID- 26754052 TI - Enhanced Performance of Inverted Polymer Solar Cells by Combining ZnO Nanoparticles and Poly[(9,9-bis(3'-(N,N-dimethylamino)propyl)-2,7-fluorene)-alt 2,7-(9,9-dioctyfluorene)] as Electron Transport Layer. AB - A highly efficient inverted polymer solar cell (PSC) has been successfully demonstrated by using a ZnO nanoparticle (NP) and poly[(9,9-bis(3'-(N,N dimethylamino)propyl)-2,7-fluorene)-alt-2,7-(9,9-dioctyfluorene)] (PFN) bilayer structure as an effective electron collecting layer. This ZnO/PFN bilayer structure is designed to combine the advantages of both ZnO and PFN, based on the performance comparison of ZnO-only, PFN-only, and ZnO/PFN bilayer devices in our work. ZnO NPs can serve as an efficient electron transport and buffer layer for reduced series resistance, while the PFN interlayer can improve the energy level alignment of devices through the formation of an interfacial dipole. With the enhanced electron extraction induced by the ZnO/PFN bilayer structure and PTB7:ICBA:PC71BM ternary system, the corresponding inverted PSC device shows a high PCE of 9.3%, which is more than a 15% improvement compared to the ZnO- or PFN-only devices. PMID- 26754053 TI - An extremely rare clinical manifestation of gallbladder cancer presenting with abdominal wall invasion with an erythematous skin break. PMID- 26754055 TI - The effect of gestational weight gain on likelihood of referral to obstetric care for women eligible for primary, midwife-led care after antenatal booking. AB - OBJECTIVE: to examine the effect of gestational weight gain (GWG) on likelihood of referral from midwife-led to obstetrician-led care during pregnancy and childbirth for women in primary care at the outset of their pregnancy. DESIGN: secondary analysis of data from a prospective cohort study. SETTING: Dutch midwife-led practices. PARTICIPANTS: a cohort of 1288 women of Northern European descent, with uncomplicated, singleton pregnancy at antenatal booking who consequently were eligible for primary, midwife-led care. MEASUREMENTS: because of the absence of an established GWG guideline in the Netherlands, we compared the effect of inadequate and excessive GWG according to two GWG guidelines: the criterion traditionally used, which is based on knowledge of the physiological components of GWG, advising 10-15kg as a normal GWG irrespective of a woman's BMI category, and the 2009 Institute of Medicine recommendations (IOMr) on GWG, which provide BMI related advice. Outcome measures were: number of women referred from midwife-led to obstetrician-led care during pregnancy and during childbirth; indications of referral and birth outcomes. FINDINGS: GWG above traditional criteria (Tc; >15kg between 12 and 36 weeks) was associated with increased odds for referral during childbirth (adjusted odds ratio (aOR) 1.88; 95% confidence interval (CI) 1.22-2.90), but had no effect on referral during pregnancy (aOR .86; 95% CI .57-1.30). No associations were established between GWG below Tc (<10kg) and referral during pregnancy (aOR 1.08; 95% CI .78-1.50) or childbirth (aOR 1.08; 95% CI .74-1.56). No associations were found between GWG below and above the IOMr and referral during pregnancy (below IOMr: aOR 1.01; 95% CI .71 1.45; above IOMr: aOR .89; 95% CI .61-1.28) or childbirth (below IOMr: aOR .85; 95% CI .57-1.25; above IOMr: aOR 1.09; 95% CI .73-1.63). With regard to the effect of GWG according to both recommendations on indications for referral and birth outcomes, GWG above Tc was associated with higher rates of referral for hypertensive disorders (aOR 1.91; 95% CI 1.04-3.50) and for meconium stained liquor (aOR 2.22; CI 1.33-3.71) after adjusting for BMI and parity. CONCLUSIONS: GWG above Tc - irrespective of BMI category - was associated with doubled odds of referral to specialist care during childbirth. GWG below or above IOMR and GWG below TC were not associated with adverse obstetric outcomes in women who were eligible for primary care at the outset of their pregnancy. IMPLICATIONS FOR PRACTICE: weight gain <15kg between 12 and 36 weeks is advised for women in all BMI categories in this population. It is important to validate GWG guidelines in a target population before implementing them. PMID- 26754056 TI - Gender dysphoria in childhood. AB - Gender dysphoria (GD) in childhood is a complex phenomenon characterized by clinically significant distress due to the incongruence between assigned gender at birth and experienced gender. The clinical presentation of children who present with gender identity issues can be highly variable; the psychosexual development and future psychosexual outcome can be unclear, and consensus about the best clinical practice is currently under debate. In this paper a clinical picture is provided of children who are referred to gender identity clinics. The clinical criteria are described including what is known about the prevalence of childhood GD. In addition, an overview is presented of the literature on the psychological functioning of children with GD, the current knowledge on the psychosexual development and factors associated with the persistence of GD, and explanatory models for psychopathology in children with GD together with other co existing problems that are characteristic for children referred for their gender. In light of this, currently used treatment and counselling approaches are summarized and discussed, including the integration of the literature detailed above. PMID- 26754054 TI - Computational analysis of prolyl hydroxylase domain-containing protein 2 (PHD2) mutations promoting polycythemia insurgence in humans. AB - Idiopathic erythrocytosis is a rare disease characterized by an increase in red blood cell mass due to mutations in proteins of the oxygen-sensing pathway, such as prolyl hydroxylase 2 (PHD2). Here, we present a bioinformatics investigation of the pathological effect of twelve PHD2 mutations related to polycythemia insurgence. We show that few mutations impair the PHD2 catalytic site, while most localize to non-enzymatic regions. We also found that most mutations do not overlap the substrate recognition site, suggesting a novel PHD2 binding interface. After a structural analysis of both binding partners, we suggest that this novel interface is responsible for PHD2 interaction with the LIMD1 tumor suppressor. PMID- 26754057 TI - Modified Mixed Lagrangian-Eulerian Method Based on Numerical Framework of MT3DMS on Cauchy Boundary. AB - MT3DMS, a modular three-dimensional multispecies transport model, has long been a popular model in the groundwater field for simulating solute transport in the saturated zone. However, the method of characteristics (MOC), modified MOC (MMOC), and hybrid MOC (HMOC) included in MT3DMS did not treat Cauchy boundary conditions in a straightforward or rigorous manner, from a mathematical point of view. The MOC, MMOC, and HMOC regard the Cauchy boundary as a source condition. For the source, MOC, MMOC, and HMOC calculate the Lagrangian concentration by setting it equal to the cell concentration at an old time level. However, the above calculation is an approximate method because it does not involve backward tracking in MMOC and HMOC or allow performing forward tracking at the source cell in MOC. To circumvent this problem, a new scheme is proposed that avoids direct calculation of the Lagrangian concentration on the Cauchy boundary. The proposed method combines the numerical formulations of two different schemes, the finite element method (FEM) and the Eulerian-Lagrangian method (ELM), into one global matrix equation. This study demonstrates the limitation of all MT3DMS schemes, including MOC, MMOC, HMOC, and a third-order total-variation-diminishing (TVD) scheme under Cauchy boundary conditions. By contrast, the proposed method always shows good agreement with the exact solution, regardless of the flow conditions. Finally, the successful application of the proposed method sheds light on the possible flexibility and capability of the MT3DMS to deal with the mass transport problems of all flow regimes. PMID- 26754060 TI - The 66th Regional Meeting (Kita Area). PMID- 26754059 TI - Highly Robust Nanopore-Based Dual-Signal-Output Ion Detection System for Achieving Three Successive Calibration Curves. AB - In recent years, artificial stimuli-responsive bioinspired nanopores have attracted a lot of attention due to their unique property of confined spaces and flexibility in terms of shapes and sizes. Most of the nanopore systems demonstrated their transmembrane properties and applications in target detections. However, almost all of the nanopores can be used only once due to either the irreversible reactions between targets and probes or the plugged nanopores not easily being unplugged again. In this work, we propose a dual signal-output nanopore system that could detect the cations (Hg(2+)) inducing the plugged nanopores. The detection system is highly recoverable by the anions (S(2 )) inducing the unplugged nanopores. More importantly, as far as we know, it is seldom reported for the same nanopores to achieve successive calibration curves for three times by subsequent reversible plug-unplug processes, which strongly demonstrates the high robustness of this novel nanopore-detection system. In addition, unlike monitoring the plug-unplug phenomena by only one type of signal, we combined the ionic current signal with the fluorescence output and could directly observe that the change of ionic current does in fact correspond to the plug-unplug of the nanopores by the target stimuli. PMID- 26754061 TI - The 133th Regional Meeting (Kanto Area). PMID- 26754058 TI - Impact of L-carnitine on plasma lipoprotein(a) concentrations: A systematic review and meta-analysis of randomized controlled trials. AB - We aimed to assess the impact of L-carnitine on plasma Lp(a) concentrations through systematic review and meta-analysis of available RCTs. The literature search included selected databases up to 31(st) January 2015. Meta-analysis was performed using fixed-effects or random-effect model according to I(2) statistic. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI). The meta-analysis showed a significant reduction of Lp(a) levels following L-carnitine supplementation (WMD: -8.82 mg/dL, 95% CI: -10.09, -7.55, p < 0.001). When the studies were categorized according to the route of administration, a significant reduction in plasma Lp(a) concentration was observed with oral (WMD: -9.00 mg/dL, 95% CI: -10.29, -7.72, p < 0.001) but not intravenous L-carnitine (WMD: -2.91 mg/dL, 95% CI: -10.22, 4.41, p = 0.436). The results of the meta-regression analysis showed that the pooled estimate is independent of L-carnitine dose (slope: -0.30; 95% CI: -4.19, 3.59; p = 0.878) and duration of therapy (slope: 0.18; 95% CI: -0.22, 0.59; p = 0.374). In conclusion, the meta-analysis suggests a significant Lp(a) lowering by oral L carnitine supplementation. Taking into account the limited number of available Lp(a)-targeted drugs, L-carnitine might be an effective alternative to effectively reduce Lp(a). Prospective outcome trials will be required to fully elucidate the clinical value and safety of oral L-carnitine supplementation. PMID- 26754062 TI - An optimised detector for in-situ high-resolution NMR in microfluidic devices. AB - Integration of high-resolution nuclear magnetic resonance (NMR) spectroscopy with microfluidic lab-on-a-chip devices is challenging due to limited sensitivity and line broadening caused by magnetic susceptibility inhomogeneities. We present a novel double-stripline NMR probe head that accommodates planar microfluidic devices, and obtains the NMR spectrum from a rectangular sample chamber on the chip with a volume of 2MUl. Finite element analysis was used to jointly optimise the detector and sample volume geometry for sensitivity and RF homogeneity. A prototype of the optimised design has been built, and its properties have been characterised experimentally. The performance in terms of sensitivity and RF homogeneity closely agrees with the numerical predictions. The system reaches a mass limit of detection of 1.57nmols, comparing very favourably with other micro NMR systems. The spectral resolution of this chip/probe system is better than 1.75Hz at a magnetic field of 7T, with excellent line shape. PMID- 26754064 TI - Magnetic resonance imaging of (1)H long lived states derived from parahydrogen induced polarization in a clinical system. AB - Hyperpolarization is a powerful tool to overcome the low sensitivity of nuclear magnetic resonance (NMR). However, applications are limited due to the short lifetime of this non equilibrium spin state caused by relaxation processes. This issue can be addressed by storing hyperpolarization in slowly decaying singlet spin states which was so far mostly demonstrated for non-proton spin pairs, e.g. (13)C-(13)C. Protons hyperpolarized by parahydrogen induced polarization (PHIP) in symmetrical molecules, are very well suited for this strategy because they naturally exhibit a long-lived singlet state. The conversion of the NMR silent singlet spin state to observable magnetization can be achieved by making use of singlet-triplet level anticrossings. In this study, a low-power radiofrequency pulse sequence is used for this purpose, which allows multiple successive singlet triplet conversions. The generated magnetization is used to record proton images in a clinical magnetic resonance imaging (MRI) system, after 3min waiting time. Our results may open unprecedented opportunities to use the standard MRI nucleus (1)H for e.g. metabolic imaging in the future. PMID- 26754063 TI - Multiband RF pulses with improved performance via convex optimization. AB - Selective RF pulses are commonly designed with the desired profile as a low pass filter frequency response. However, for many MRI and NMR applications, the spectrum is sparse with signals existing at a few discrete resonant frequencies. By specifying a multiband profile and releasing the constraint on "don't-care" regions, the RF pulse performance can be improved to enable a shorter duration, sharper transition, or lower peak B1 amplitude. In this project, a framework for designing multiband RF pulses with improved performance was developed based on the Shinnar-Le Roux (SLR) algorithm and convex optimization. It can create several types of RF pulses with multiband magnitude profiles, arbitrary phase profiles and generalized flip angles. The advantage of this framework with a convex optimization approach is the flexible trade-off of different pulse characteristics. Designs for specialized selective RF pulses for balanced SSFP hyperpolarized (HP) (13)C MRI, a dualband saturation RF pulse for (1)H MR spectroscopy, and a pre-saturation pulse for HP (13)C study were developed and tested. PMID- 26754065 TI - Spatio-temporal propagation of cascading overload failures in spatially embedded networks. AB - Different from the direct contact in epidemics spread, overload failures propagate through hidden functional dependencies. Many studies focused on the critical conditions and catastrophic consequences of cascading failures. However, to understand the network vulnerability and mitigate the cascading overload failures, the knowledge of how the failures propagate in time and space is essential but still missing. Here we study the spatio-temporal propagation behaviour of cascading overload failures analytically and numerically on spatially embedded networks. The cascading overload failures are found to spread radially from the centre of the initial failure with an approximately constant velocity. The propagation velocity decreases with increasing tolerance, and can be well predicted by our theoretical framework with one single correction for all the tolerance values. This propagation velocity is found similar in various model networks and real network structures. Our findings may help to predict the dynamics of cascading overload failures in realistic systems. PMID- 26754066 TI - Reduction of CTRP9, a novel anti-platelet adipokine, contributes to abnormal platelet activity in diabetic animals. AB - Platelet hyper-reactivity is a crucial cause of accelerated atherosclerosis increasing risk of thrombotic vascular events in diabetic patients. The mechanisms leading to abnormal platelet activity during diabetes are complex and not fully defined. The current study attempted to clarify the role of CTRP9, a novel adiponectin paralog, in enhanced platelet activity and determined whether CTRP9 may inhibit platelet activity. Adult male C57BL/6 J mice were randomized to receive high-fat diet (HFD) or normal diet (ND). 8 weeks after HFD, animals were sacrificed, and both plasma CTRP9 and platelet aggregation were determined. HFD fed animals increased weight gain significantly, and became hyperglycemic and hyperinsulinemic 8 weeks post-HFD. Compared to ND animals, HFD animals exhibited significantly decreased plasma CTRP9 concentration and increased platelet response to ADP, evidenced by augmented aggregation amplitude, steeper aggregation slope, larger area under the curve, and shorter lag time (P < 0.01). A significant negative correlation between plasma CTRP9 concentration and platelet aggregation amplitude was observed. More importantly, in vitro pre treatment with CTRP9 significantly inhibited ADP-stimulated platelet activation in platelet samples from both ND and HFD animals. Taken together, our results suggest reduced plasma CTRP9 concentration during diabetes plays a causative role in platelet hyper-activity, contributing to platelet-induced cardiovascular damage during this pathologic condition. Enhancing CTRP9 production and/or exogenous supplementation of CTRP9 may protect against diabetic cardiovascular injury via inhibition of abnormal platelet activity. PMID- 26754067 TI - Reply. PMID- 26754068 TI - Chrysin and its emerging antineoplastic effects. PMID- 26754069 TI - Female sexual function and fertility after ileal pouch-anal anastomosis. AB - PURPOSE: A potential complication in women after ileal pouch-anal anastomosis (IPAA) is sexual impairment and reduced fertility. The aim was to evaluate sexual function and fertility after IPAA. METHODS: All female patients who underwent an IPAA between 2004 and 2013 were retrospectively included. Sexual function, fertility, and continence were explored by the female sexual function index (FSFI), telephonic interview, and Wexner's score. RESULTS: Among 127 women included, 93 responded to the questionnaires (73.2%). Seventy five were sexually active, and 48 (64%) had normal sexual function (FSFI > 26). In univariate analysis, there was a significant relationship between ulcerative colitis (p = 0.0161), age > 40 years (p = 0.01311), number of bowel movements (p = 0.0238), nocturnal pouch activity (p = 0.0094), use of loperamide (p = 0.0283), and existence of sexual dysfunction. After multivariate analysis, age and nocturnal pouch activity were associated with a worse sexual function (p = 0.0235, OR = 3.3 (1.2-9.9) and p = 0.0094, OR = 4.1 (1.4-13.5)). Of 16 patients who wished to have children, 10 (63%) became pregnant without recourse to in vitro fertilization, of whom 3 had two or more pregnancies. In total, there were 13 children born after IPAA. The mean time between the first pregnancy and surgery was 24.8 +/- 22 months. At 12 and 24 months after cessation of contraception, 57 and 67% had at least one pregnancy. CONCLUSIONS: While sexual function is impaired in a limited number of patients, the impact of surgery can be regarded as modest. Age and nocturnal pouch activity were some independent factors of worse sexual function. The risk of infertility should not preclude consideration of IPAA as a treatment option. PMID- 26754070 TI - Complication and local recurrence rate after endoscopic resection of large high risk colorectal adenomas of >=3 cm in size. AB - PURPOSE: Endoscopic resection is a widely used technique for treatment of large colorectal adenomas, but few data are available including only lesions larger than >=2 cm. The aim of this study is to evaluate the complication and recurrence rate after endoscopic resection of high-risk colorectal adenomas >=3 cm in size. METHODS: Retrospective analysis of a prospectively maintained database of patients undergoing polypectomy of large colorectal polyps of >=3 cm. RESULTS: In 341 patients, 360 colorectal adenomas with a mean size of 3.9 cm were resected endoscopically. In 25 patients, a complication including 22 delayed bleedings (6.5%) and three perforations (0.9%) occurred. Single-variate analysis showed an increasing risk of complications for larger adenomas (3.9 vs. 4.6 cm; p <= 0.05). Two hundred twelve patients with 224 adenomas had undergone at least one documented follow-up endoscopy with a medium follow-up period of 16 months. In 95 resected lesions (42.4%), a residual adenoma occurred in the first follow-up colonoscopy (n = 88, 92.6%) or a recurrent adenoma occurred after at least one negative follow-up colonoscopy (n = 7, 7.4%). In multivariate analysis, risk factors were lesion size, sessile growth pattern, and the performing endoscopist. The complication and recurrence rate correlated inversely between endoscopists. CONCLUSIONS: The present study is the largest study showing complication and recurrence rates after colorectal polypectomy of advanced colorectal adenomas of >=3 cm in size. Polyp size was identified as the most important risk factor for complications. For the first time, this study shows that the complication rate after colorectal polypectomy of large adenomas is correlated inversely with the residual and/or recurrence rate. PMID- 26754071 TI - SaFaRI: sacral nerve stimulation versus the FENIX magnetic sphincter augmentation for adult faecal incontinence: a randomised investigation. AB - PURPOSE: Faecal incontinence is a physically, psychologically and socially disabling condition. NICE guidance (2007) recommends surgical intervention, including sacral nerve stimulation (SNS), after failed conservative therapies. The FENIX magnetic sphincter augmentation (MSA) device is a novel continence device consisting of a flexible band of interlinked titanium beads with magnetic cores that is placed around the anal canal to augment anal sphincter tone through passive attraction of the beads. Preliminary studies suggest the FENIX MSA is safe, but efficacy data is limited. Rigorous evaluation is required prior to widespread adoption. METHOD AND DESIGN: The SaFaRI trial is a National Institute of Health Research (NIHR) Health Technology Assessment (HTA)-funded UK multi site, parallel group, randomised controlled, unblinded trial that will investigate the use of the FENIX MSA, as compared to SNS, for adult faecal incontinence resistant to conservative management. Twenty sites across the UK, experienced in the treatment of faecal incontinence, will recruit 350 patients randomised equally to receive either SNS or FENIX MSA. Participants will be followed-up at 2 weeks post-surgery and at 6, 12 and 18 months post randomisation. The primary endpoint is success, as defined by device in use and >=50 % improvement in the Cleveland Clinic Incontinence Score (CCIS) at 18 months post-randomisation. Secondary endpoints include complications, quality of life and cost effectiveness. DISCUSSION: SaFaRI will rigorously evaluate a new technology for faecal incontinence, the FENIXTM MSA, allowing its safe and controlled introduction into current clinical practice. These results will inform the future surgical management of adult faecal incontinence. PMID- 26754073 TI - Aboriginal Health Worker perceptions of oral health: a qualitative study in Perth, Western Australia. AB - BACKGROUND: Improving oral health for Aboriginal Australians has been slow. Despite dental disease being largely preventable, Aboriginal Australians have worse periodontal disease, more decayed teeth and untreated dental caries than other Australians. Reasons for this are complex and risk factors include broader social and historic determinants such as marginalisation and discrimination that impact on Aboriginal people making optimum choices about oral health. This paper presents findings from a qualitative study conducted in the Perth metropolitan area investigating Aboriginal Health Workers' (AHWs) perceptions of barriers and enablers to oral health for Aboriginal people. METHODS: Following extensive consultation with Aboriginal stakeholders, researchers conducted semi-structured interviews and focus groups across 13 sites to investigate AHWs' perceptions of barriers and enablers to oral health based on professional and personal experience. Responses from 35 AHWs were analysed independently by two researchers to identify themes that they compared, discussed, revised and organised under key themes. These were summarised and interrogated for similarities and differences with evidence in the literature. RESULTS: Key findings indicated that broader structural and social factors informed oral health choices. Perceptions of barriers included cost of services and healthy diets on limited budgets, attending services for pain not prevention, insufficient education about oral health and preventing disease, public dental services not meeting demand, and blame and discrimination from some health providers. Suggested improvements included oral health education, delivering flexible services respectful of Aboriginal people, oral health services for 0-4 year olds and role modelling of oral health across generations. CONCLUSION: Reviewing current models of oral health education and service delivery is needed to reduce oral health disparities between Aboriginal and non-Aboriginal Australians. Shifting the discourse from blaming Aboriginal people for their poor oral health to addressing structural factors impacting on optimum oral health choices is important. This includes Aboriginal and non-Aboriginal stakeholders working together to develop and implement policies and practices that are respectful, well-resourced and improve oral health outcomes. PMID- 26754072 TI - Functional outcomes following ileal pouch-anal anastomosis (IPAA) in older patients: a systematic review. AB - AIM: Ileal pouch-anal anastomosis (IPAA) is performed in ulcerative colitis or familial adenomatous polyposis with a view to restoration of GI continuity and prevention of permanent faecal diversion. Debate exists as to its safety in older patients. This review aims to assess functional outcomes and safety of restorative proctocolectomy (RPC) in older compared to younger patients. METHODS: Literature search was performed for age-stratified studies which assessed functional outcomes of IPAA. Twelve papers were included overall. Patients were categorized into 'older' and 'younger' groups. Analysis was split into three separate parts: 1. Age cut-off of 50 +/- 5 years (with sensitivity analysis); 2. Age cut-off of 65 +/- years; 3. Long-term outcomes (>10 years). RESULTS: With an age cut-off of 50 years (4327 versus 513 patients), complication rates were comparable with the exception of an increased rate of small-bowel obstruction in the younger patients (p = 0.034). At 1 year, 24-h stool frequency was significantly higher in the older patient group (p < 0.0001). Daytime (p < 0.0001) and night-time (p < 0.0001) incontinence rates were also significantly higher in older patients. Overall, function deteriorated with time across all ages; however, after 10 years, there was no significant difference in incontinence rates between age groups. Dehydration and electrolyte loss was a significant problem in patients over 65 (p < 0.0001). Despite differences in postoperative function, quality of life was comparable between groups; however, only a few studies reported quality of life data. CONCLUSION: IPAA is safe in older patients, although treating clinicians should bear in mind the increased risk of dehydration. Postoperative function is worse in older patients, but seems to level out with time and does not appear to significantly impact on overall quality of life and patient satisfaction. Assessment for suitability for RPC should not be based on chronological age in isolation. It is imperative that the correct support is given to older patients with worsened postoperative function in order to maintain patient satisfaction and adequate quality of life. PMID- 26754074 TI - Post-Hospital Discharge Venous Thromboembolism in Colorectal Surgery. AB - BACKGROUND: There are limited data regarding the criteria for prophylactic treatment of venous thromboembolism (VTE) after hospital discharge. We sought to identify risk factors of post-hospital discharge VTE events following colorectal surgery. METHODS: The NSQIP database was utilized to examine patients developed VTE after hospital discharge following colorectal surgery during 2005-2013. Multivariate analysis using logistic regression was performed to quantify risk factors of VTE after discharge. RESULTS: We evaluated a total of 219,477 patients underwent colorectal resections. The overall incidence of VTE was 2.1 % (4556). 33.8 % (1541) of all VTE events occurred after hospital discharge. The length of postoperative hospitalization had a strong association with post-discharge VTE, with the highest risk in patients who were hospitalized for more than 1 week after operation (AOR 9.08, P < 0.01). Other factors associated with post discharge VTE included chronic steroid use (AOR 1.81, P < 0.01), stage 4 colorectal cancer (AOR 1.40, P = 0.03), obesity (AOR 1.37, P < 0.01), age >70 (AOR 1.21, P = 0.04), and open surgery (AOR 1.36, P < 0.01). Patients who were hospitalized for more than 1 week after an open colorectal resections had a 12 times higher risk of post-discharge VTE event compared to patients hospitalized less than 4 days after a laparoscopic resection (AOR 12.34, P < 0.01). CONCLUSIONS: VTE is uncommon following colorectal resections; however, a significant proportion occurs after patients are discharged from the hospital (33.8 %). The length of postoperative hospitalization appears to have a strong association with post-discharge VTE. High-risk patients may benefit from continued VTE prophylaxis after discharge. PMID- 26754075 TI - Surgical and Survival Outcome Following Truly Palliative Gastrectomy in Patients with Incurable Gastric Cancer. AB - BACKGROUND AND OBJECTIVES: Gastrectomy is sometimes performed even in patients with incurable factors, particularly when they have urgent symptoms. The aim of this study was to clarify the clinicopathological characteristics of patients undergoing palliative gastrectomy and to identify prognostic factors. METHODS: This study included consecutive 137 gastric cancer patients with urgent symptoms who underwent gastrectomy with macroscopic residual tumor at Shizuoka Cancer Center. Clinicopathological characteristics and surgical outcomes were investigated. In addition, we used the Cox proportional hazards model to identify independent prognostic factors. RESULTS: Of 137 patients, urgent symptoms were bleeding in 58 patients and stenosis in 112 patients. Postoperative complications were observed in 58 patients (42 %). Chemotherapy was given after surgery in 94 patients (70 %). Median survival time for all patients was 9.9 months, and was longer in patients receiving chemotherapy (11.1 months) than in those not receiving chemotherapy (6.8 months; p = 0.002). Multivariate analysis identified macroscopic type (hazard ratio, 0.471; 95 % confidence interval, 0.364-0.927) as an independent prognostic factor. CONCLUSIONS: The postoperative complication rate was high and survival outcome was poor in patients undergoing palliative gastrectomy. Postoperative chemotherapy may carry a better survival outcome, so we should try to give chemotherapy after palliative gastrectomy. PMID- 26754076 TI - In-Hospital Mortality in a 4-Year Cohort Study of 3,093,254 Operations in Seniors. AB - BACKGROUND: Surgery-related mortality depends on a number of factors including the type of surgical procedure, quality of healthcare, co-morbidities, and age of patient. The objective of the study was to assess the in-hospital mortality in the elderly undergoing surgical treatment. METHODS: This was a national data based retrospective cohort study. Data were extracted from the National Health Fund, a public organization financing medical procedures in Poland. Adult citizens who underwent 9,344,384 surgical interventions (including 3,093,254 cases in seniors who were above 65 years old) between 2009 and 2012 were included in this study. Overall, surgery type-dependent, age-stratified in-hospital mortality related to surgery was assessed. RESULTS: Overall in-hospital surgery related mortality rate in seniors was stable (approximately 2 % annually, P for trend = 0.104). It doubled with each successive decade of life (1.2, 2.3, 5.6, and 13 % in 65-74, 75-84, 85-94 and >= 95 years old groups, respectively, in 2012). In >= 75-year-old mortality exceeded 10 % only after neurological surgeries, in >= 85-year-old after neurological, vascular, gastrointestinal, and endocrinological surgeries, and in >= 95-year-old also after heart and circulation, bones and muscles, liver, pancreas, and spleen operations. However, even in the oldest individuals it was low after genitourinary, female genital tract, head and neck, and eye surgeries. CONCLUSIONS: The overall rate of in hospital mortality after surgery, although increasing with age, is rather low up to the ninth decade of life. Whereas some surgeries pose a significant risk, others may be relatively safe even in the oldest subjects. PMID- 26754077 TI - Comparison of Bilateral Axillo-Breast Approach Robotic Thyroidectomy with Open Thyroidectomy for Graves' Disease. AB - BACKGROUND: There is an ongoing debate about whether robotic thyroidectomy (RT) is appropriate for Graves' disease. The aim of this study was to compare the safety of bilateral axillo-breast approach (BABA) RT with that of open thyroidectomy (OT) in patients with Graves' disease. METHODS: From January 2008 to June 2014, 189 (44 BABA RT and 145 OT) patients underwent total thyroidectomy for Graves' disease. Recurrence of Graves' disease, intraoperative blood loss, hospital stay, and complication rates including recurrent laryngeal nerve (RLN) palsy and hypoparathyroidism were analyzed between BABA RT and OT groups, after propensity score matching according to age, gender, body mass index, surgical indication, the extent of operation, excised thyroid weight, and follow-up period. RESULTS: No patient experienced recurrence of Graves' disease after median follow-up of 35.0 months. Intraoperative blood loss (151.8 +/- 165.4 mL vs. 134.5 +/- 75.4 mL; p = 0.534) and hospital stay (3.4 +/- 0.7 day vs. 3.3 +/- 0.7 day; p = 0.564) were not different between BABA RT and OT groups. Complication rates including transient RLN palsy (11.4 vs. 11.4%; p = 1.000), transient hypoparathyroidism (18.2 vs. 20.5%; p = 0.787), permanent RLN palsy (0 vs. 2.3%; p = 0.315), and permanent hypoparathyroidism (2.3 vs. 2.3%; p = 1.000) were also comparable between groups. CONCLUSIONS: BABA RT for Graves' disease showed comparable surgical completeness and complications to conventional OT. BABA RT can be recommended as an alternative surgical option for patients with Graves' disease who are concerned about cosmesis. PMID- 26754078 TI - Transient hyperphosphatasemia after pediatric liver transplantation. AB - BACKGROUND: Transient hyperphosphatasemia (TH), the incidence of which in healthy children is 1.5-2.8%, is associated with a temporary elevation of serum alkaline phosphatase (ALP) without any other liver function test (LFT) abnormalities. Fast alpha2 band, detected on agarose gel electrophoresis, is known to be a highly sensitive phenomenon in TH. The aim of this study was to elucidate the characteristics of TH after liver transplantation (LT). METHODS: Five TH patients (6.0%) out of 83 who underwent LT between October 1996 and October 2014, were included in this study. Patient background, duration of TH, peak ALP, time course of ALP and its isoenzyme in TH, other LFT, and imaging results were retrospectively investigated. RESULTS: Median patient age at the time of peak ALP during TH was 24 months (range, 16-98 months). Mean duration of TH was 111.0 +/- 48.0 days. At 6887 IU/L, median ALP was elevated without any other LFT abnormalities. The first alpha2 band was detected in all patients, and the band disappeared at the same phase of ALP normalization. All of the patients improved without any treatment. The prevalence of TH was significantly higher in the patients after LT than in age-matched healthy children (P < 0.05). CONCLUSIONS: The detection of fast alpha2 band in the early phase allows for effective diagnosis of TH after LT, and 3-4 month follow up without treatment is feasible. PMID- 26754080 TI - A dual-spatially-confined reservoir by packing micropores within dense graphene for long-life lithium/sulfur batteries. AB - In lithium/sulfur batteries, micropores could bring about strong interactions with polysulfides, but could not alleviate the partial polysulfide overflowing outside because of the volume expansion of the lithiated sulfur. A dual-spatially confined reservoir for sulfur by wrapping microporous carbon with dense graphene, micro@meso-porous DSC (dual-spatial carbon), is synthesized to solve this issue. Such a structure is prepared through two distinctive methods: graphene promoted in situ hydrothermal carbonization of organics to grow micropores on itself, and liquid mediated drying of graphene hydrogel to form mesoporous graphene frameworks. In contrast to previously reported hierarchical carbon/S, the inner micropores are mainly responsible for loading sulfur, which could help confine its particle size, thus increasing the electrical/ionic conductivity and the utilization of sulfur, and restrain lithium polysulfide dissolution because of strong interaction with pore walls; while the outer mesopores act as another reservoir to stabilize the overflowed polysulfide and to enhance the Li(+) transport. The S-micro@meso-porous DSC cathode exhibits better discharge capacity and cycling performance than S-microporous AC and S-micro@macro-porous DSC, i.e., 59% and 37% higher capacity remaining at 0.5 C than the latter two, respectively. PMID- 26754081 TI - Design and Analysis of Monte Carlo Experiments: Attacking the Conventional Wisdom. AB - The design and analysis of Monte Carlo experiments, with special reference to structural equation modelling, is discussed in this article. These topics merit consideration, since the validity of the conclusions drawn from a Monte Carlo study clearly hinges on these features. It is argued that comprehensive Monte Carlo experiments can be implemented on a PC if the experiments are adequately designed. This is especially important when investigating modern computer intensive methodologies like resampling and Markov Chain Monte Carlo methods. We are faced with three fundamental challenges in Monte Carlo experimentation. The first problem is statistical precision, which concerns the reliability of the obtained results. External validity, on the other hand, depends on the number of experimental conditions, and is crucial for the prospects of generalising the results beyond the specific experiment. Finally, we face the constraint on available computer resources. The conventional wisdom in designing and analysing Monte Carlo experiments embodies no explicit specification of meta-model for analysing the output of the experiment, the use of case studies or full factorial designs as experimental plans, no use of variance reduction techniques, a large number of replications, and "eyeballing" of the results. A critical examination of the conventional wisdom is presented in this article. We suggest that the following alternative procedures should be considered. First of all, we argue that it is profitable to specify explicit meta-models, relating the chosen performance statistics and experimental conditions. Regarding the experimental plan, we recommend the use of incomplete designs, which will often result in considerable savings. We also consider the use of common random numbers in the simulation phase, since this may enhance the precision in estimating meta-models. The use of fewer replications per trial, enabling us to investigate an increased number of experimental conditions, should also be considered in order to improve the external validity at the cost of the conventionally excessive precision. PMID- 26754079 TI - TRIM25 blockade by RNA interference inhibited migration and invasion of gastric cancer cells through TGF-beta signaling. AB - Tripartite Motif Containing 25 (TRIM25), a member of TRIM proteins, has been found abnormally expressed in cancers of female reproductive system. Here, TRIM25 was conspicuously expressed in human gastric cancer (GC) tissues in which its higher expression generally correlated with the poor prognosis of patients. Small interfering RNA (siRNA)-mediated knockdown of TRIM25 expression in MGC-803 and AGS cells had no effects on cell proliferation, whereas reduced cell migration and invasion. Gene set enrichment analysis on The Cancer Genome Atlas stomach adenocarcinoma (STAD) dataset revealed that several signaling pathways, including the migration, E-cadherin and transforming growth factor-beta (TGF-beta) pathways, were enriched in TRIM25 higher expression patients. Moreover, ectopic expression of TRIM25 in a GC cell line with lower expression of TRIM25 significantly promoted the migration and invasion. Further experiments with TGF beta inhibitor suggested that TRIM25 may exert its function through TGF-beta pathway. In summary, our results indicate that TRIM25 acts as an oncogene in GC and thus presents a novel target for the detection and treatment of GC. PMID- 26754082 TI - Detection of Differential Item Functioning on the Kirton Adaption-Innovation Inventory Using Multiple-Group Mean and Covariance Structure Analyses. AB - This article demonstrates how Sorbom's (1974) mean and covariance structure analysis (MACS) model can be used to detect uniform and non-uniform differential item functioning (DIF) on polytomous ordered response items that are assumed to approximate a continuous scale. Using item responses from 773 civil service employees, the MACS model was applied to three cognitive style scales on the widely-used Kirton Adaption-Innovation Inventory (KAI, Kirton, 1976; 1977). As predicted, DIF across managerial and staff support occupational groups were detected on each of the scales. As expected, there was no evidence of DIF across gender groups and across two groups formed through a random split on any of the scales. Substantive implications for the use of the KAI as well as methodological implications and future research direction for detection of DIF are discussed. PMID- 26754083 TI - Bayesian Interval Estimation of Multiple Correlations with Missing Data: A Gibbs Sampling Approach. AB - A Bayesian method for obtaining an interval estimate of the population squared multiple correlation from an incomplete multivariate normal data set is described. The method is applicable to data sets where values are missing on any combination of the dependent and independent variables. Further, the missing data need not be missing in a completely random fashion. The estimates are constructed using a Markov Chain Monte Carlo procedure known as Gibbs Sampling. The important issues of the convergence properties of the Gibbs sampler, the effect of the choice of a reference prior, and the empirical coverage probabilities of the estimates are considered in detail. Investigations using simulated data suggest that the proposed method can yield accurate interval estimates of the population squared multiple correlation. PMID- 26754084 TI - Using Multidimensional Scaling to Assess the Dimensionality of Dichotomous Item Data. AB - In this study, we investigated the utility of multidimensional scaling (MDS) for assessing the dimensionality of dichotomous test data. Two MDS proximity measures were studied: one based on the PC statistic proposed by Chen and Davison (1996), the other based on inter-item Euclidean distances. Stout's (1987) test of essential unidimensionality (DIMTEST) was also used as a standard for comparison. Twenty different conditions of unidimensional and multidimensional data were simulated, varying the number of test items, correlations among dimensions, and type of data generation model (Rasch or two-parameter IRT model). DIMTEST performed best overall, but had some trouble detecting multidimensionality when the number of test items was small. The PC statistic correctly identified the dimensionality of the unidimensional data, whereas the use of Euclidean distances suggested the two-parameter unidimensional data were multidimensional. Both MDS procedures correctly identified multidimensionality under the low correlation conditions, but were generally unable to detect multidimensionality when the dimensions were highly correlated. Analysis of Euclidean distances were best for determining the precise dimensionality of the multidimensional data under the low correlation condition. Implications of the findings are discussed, and suggestions for future research are provided. PMID- 26754085 TI - Validating Cluster Analysis: Consistent Replication and Symmetry. AB - Two simulation studies evaluated a cross-validation approach for cluster analyses (CA). Study 1 examined the extent to which the magnitude of replication and two aspects of replication, consistency and symmetry indicate recovery of true clusters for ten CA algorithms. Cluster size, number of clusters, covariance structure, number of variables, sample size, and error perturbation were systematically varied. Replication indices significantly predicted recovery. Study 2 evaluated replication as an indicator of the number of true clusters within a sample. Although on the average replication indices peak in the region of the true number of clusters, choosing the number of clusters by maximum replication results in a negatively biased estimate. A proposed "scree test" attenuates this bias, however, and improves accuracy. PMID- 26754086 TI - Recognition of MBR Reviewers. PMID- 26754087 TI - Strongly-motivated positive affects induce faster responses to local than global information of visual stimuli: an approach using large-size Navon letters. AB - Recent studies argue that strongly-motivated positive emotions (e.g. desire) narrow a scope of attention. This argument is mainly based on an observation that, while humans normally respond faster to global than local information of a visual stimulus (global advantage), positive affects eliminated the global advantage by selectively speeding responses to local (but not global) information. In other words, narrowing of attentional scope was indirectly evidenced by the elimination of global advantage (the same speed of processing between global and local information). No study has directly shown that strongly motivated positive affects induce faster responses to local than global information while excluding a bias for global information (global advantage) in a baseline (emotionally-neutral) condition. In the present study, we addressed this issue by eliminating the global advantage in a baseline (neutral) state. Induction of positive affects under this state resulted in faster responses to local than global information. Our results provided direct evidence that positive affects in high motivational intensity narrow a scope of attention. PMID- 26754088 TI - A frameless LNG-IUD may be preferred over framed LNG-IUD for the treatment of primary dysmenorrhea. PMID- 26754089 TI - Reply: LNG-IUDs in treating dysmenorrhea. PMID- 26754090 TI - Editorial. PMID- 26754091 TI - Epigallocatechin-3-O-gallate up-regulates microRNA-let-7b expression by activating 67-kDa laminin receptor signaling in melanoma cells. AB - MicroRNAs (miRNAs) are non-coding RNAs involved in various biological processes by regulating their target genes. Green tea polyphenol (-)-epigallocatechin-3-O gallate (EGCG) inhibits melanoma tumor growth by activating 67-kDa laminin receptor (67LR) signaling. To examine the effect of EGCG on miRNA expression in melanoma cells, we performed miRNA microarray analysis. We showed that EGCG up regulated miRNA-let-7b expression through 67LR in melanoma cells. The EGCG induced up-regulation of let-7b led to down-regulation of high mobility group A2 (HMGA2), a target gene related to tumor progression. 67LR-dependent cAMP/protein kinase A (PKA)/protein phosphatase 2A (PP2A) signaling pathway activation was involved in the up-regulation of let-7b expression induced by EGCG. These findings provide a basis for understanding the mechanism of miRNA regulation by EGCG. PMID- 26754092 TI - Docetaxel and cyclophosphamide as neoadjuvant chemotherapy in HER2-negative primary breast cancer. AB - BACKGROUND: Docetaxel plus cyclophosphamide (TC) has recently been established as a standard adjuvant chemotherapy regimen for HER2-negative (HER2-) operable breast cancer. However, the efficacy and tolerability of TC as neoadjuvant chemotherapy (NAC) remain unclear. We, therefore, conducted a prospective study to evaluate the efficacy of TC NAC in HER2- primary breast cancer. METHODS: Patients who were diagnosed with HER2-, N0-N1, invasive breast cancer between July 2011 and February 2014 and had tumors measuring 1-7 cm were eligible. The subtypes were classified using a core-needle or vacuum-assisted breast biopsy. The efficacy and safety of NAC comprising TC (75 mg/m2 docetaxel and 600 mg/m2 cyclophosphamide, four cycles every 3 weeks) were investigated in a prospective study in patients with HER2- breast cancer. RESULTS: Fifty-two patients were enrolled. Of these, 94.2 % (49/52) completed four cycles of TC. The overall pCR rate was 16.3 % (8/49). The pCR rates for patients with luminal A-like breast cancer [estrogen receptor-positive (ER+), Ki67 index of <20 %, and HER2-], luminal B-like breast cancer (ER+, Ki67 index of >20 %, and HER2-), and triple negative breast cancer [ER-negative (ER-) and HER2-] were 0 % (0/12), 4.3 % (1/23), and 50.0 % (7/14), respectively. Almost all pCRs occurred in triple negative breast cancer patients. CONCLUSIONS: The pCR rate of TC NAC was not very high despite the high completion rate. TC NAC was effective against the triple negative subtype, resulting in a higher pCR rate. Therefore, our results indicated that TC NAC showed limited efficacy in luminal subtype breast cancer with the exception of the triple-negative subtype. PMID- 26754102 TI - Identification and topographical characterisation of microbial nanowires in Nostoc punctiforme. AB - Extracellular pili-like structures (PLS) produced by cyanobacteria have been poorly explored. We have done detailed topographical and electrical characterisation of PLS in Nostoc punctiforme PCC 73120 using transmission electron microscopy (TEM) and conductive atomic force microscopy (CAFM). TEM analysis showed that N. punctiforme produces two separate types of PLS differing in their length and diameter. The first type of PLS are 6-7.5 nm in diameter and 0.5-2 um in length (short/thin PLS) while the second type of PLS are ~20-40 nm in diameter and more than 10 um long (long/thick PLS). This is the first study to report long/thick PLS in N. punctiforme. Electrical characterisation of these two different PLS by CAFM showed that both are electrically conductive and can act as microbial nanowires. This is the first report to show two distinct PLS and also identifies microbial nanowires in N. punctiforme. This study paves the way for more detailed investigation of N. punctiforme nanowires and their potential role in cell physiology and symbiosis with plants. PMID- 26754093 TI - A study on promoter methylation of PTEN in sporadic breast cancer patients from North India. AB - BACKGROUND: Epigenetic silencing of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) through DNA methylation has been implicated in the pathogenesis of breast cancer. Present study investigates the contribution of PTEN promoter methylation and its associated protein expression in sporadic breast cancer patients from North India. METHODS: A total of 360 paired breast carcinoma and adjacent normal tissue samples from 180 sporadic breast cancer patients were included in the present study and examined for PTEN promoter methylation status by methylation-specific polymerase chain reaction. Immunohistochemistry method was used for determining PTEN protein expression. Molecular findings were statistically correlated with various clinicopathological parameters to identify associations of clinical relevance. RESULTS: Presence of PTEN promoter methylation (39.44 %) significantly correlated with its expression downregulation (45.56 %) in breast tumors (P = 0.0001). Furthermore, their interaction with various clinical parameters was evidenced in stratified analysis. Correlation of PTEN promoter methylation with histologically more malignant grade and PTEN expression loss with triple negative tumor status remained significant even after Bonferroni correction (P < 0.003). CONCLUSIONS: Results implicate promoter methylation to be a mechanism partially responsible for PTEN silencing in sporadic breast cancer for North Indian women. Besides, methylation and expression loss of PTEN exhibited promising potential as candidate biomarkers of risk assessment in subcategorized breast tumors with critical pathologic parameters. PMID- 26754103 TI - Erratum to: Faecalibaculum rodentium gen. nov., sp. nov., isolated from the faeces of a laboratory mouse. PMID- 26754104 TI - Lateral asymmetry as a function of motor practice type of complex upper- and lower-limb movement in young children. AB - The influence of different motor practice types on lateral asymmetry of performance was investigated in 40 preschool children. Lateral preference was measured prior the experiment. For the purpose of present study dribbling a ball with a hand and foot was used to assess lateral asymmetry of performance before and after three different motor practice types. Motor practice with the non dominant, dominant, and both (contralateral) limbs took place in the indoor facility 4 times/week for 6 weeks. Each session lasted 30-40 min. Our results showed that unilateral practice of dribbling is more beneficial for diminishing lateral asymmetry of performance in comparison to bilateral practice. Moreover, participants who practiced with their dominant limb diminished lateral asymmetry of performance the most and made the largest overall improvement. We did not find important differences between acquisitions of dribbling with upper- and lower extremity. In this sense, the results support the notion of lateral asymmetry of performance to be task-specific. PMID- 26754106 TI - A draft map of the mouse pluripotent stem cell spatial proteome. AB - Knowledge of the subcellular distribution of proteins is vital for understanding cellular mechanisms. Capturing the subcellular proteome in a single experiment has proven challenging, with studies focusing on specific compartments or assigning proteins to subcellular niches with low resolution and/or accuracy. Here we introduce hyperLOPIT, a method that couples extensive fractionation, quantitative high-resolution accurate mass spectrometry with multivariate data analysis. We apply hyperLOPIT to a pluripotent stem cell population whose subcellular proteome has not been extensively studied. We provide localization data on over 5,000 proteins with unprecedented spatial resolution to reveal the organization of organelles, sub-organellar compartments, protein complexes, functional networks and steady-state dynamics of proteins and unexpected subcellular locations. The method paves the way for characterizing the impact of post-transcriptional and post-translational modification on protein location and studies involving proteome-level locational changes on cellular perturbation. An interactive open-source resource is presented that enables exploration of these data. PMID- 26754108 TI - Long-term recovery from acute cold shock in Caenorhabditis elegans. AB - BACKGROUND: Animals are exposed to a wide range of environmental stresses that can cause potentially fatal cellular damage. The ability to survive the period of stress as well as to repair any damage incurred is essential for fitness. Exposure to 2 degrees C for 24 h or longer is rapidly fatal to the nematode Caenorhabditis elegans, but the process of recovery from a shorter, initially non lethal, cold shock is poorly understood. RESULTS: We report that cold shock of less than 12-hour duration does not initially kill C. elegans, but these worms experience a progression of devastating phenotypes over the next 96 h that correlate with their eventual fate: successful recovery from the cold shock and survival, or failure to recover and death. Cold-shocked worms experience a marked loss of pigmentation, decrease in the size of their intestine and gonads, and disruption to the vulva. Those worms who will successfully recover from the cold shock regain their pigmentation and much of the integrity of their intestine and gonads. Those who will die do so with a distinct phenotype from worms dying during or immediately following cold shock, suggesting independent mechanisms. Worms lacking the G-protein coupled receptor FSHR-1 are resistant to acute death from longer cold shocks, and are more successful in their recovery from shorter sub-lethal cold shocks. CONCLUSIONS: We have defined two distinct phases of death associated with cold shock and described a progression of phenotypes that accompanies the course of recovery from that cold shock. The G-protein coupled receptor FSHR-1 antagonizes these novel processes of damage and recovery. PMID- 26754107 TI - Role of p97/Valosin-containing protein (VCP) and Jab1/CSN5 in testicular ischaemia-reperfusion injury. AB - The most significant complication of testicular ischaemia is loss of the testis, which may lead to infertility. Testicular ischaemia damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated protein aggregates. Despite recent advances, the factors leading to impairment of spermatogenesis owing to testicular ischaemia remain poorly understood. This study was undertaken to gain insight into the cellular and molecular mechanism underlying torsion induced germ cell apoptosis. Male rats were subjected to 2 h torsion, and testes were examined at 2, 4, 12 and 24 h after torsion repair (reperfusion). Ischaemia-reperfusion (IR) of the testes resulted in apoptosis which was revealed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) technique. At 12 h after torsion repair germ cell loss reached peak, then decreased at 24 h repair. Western blotting showed that apoptotic proteins (active caspase 3, caspase 9 and Bax) gradually was upregulated at 12 h reperfusion, however anti-apoptotic protein (Bcl2) was downregulated in the relevant IR treatment. Furthermore, Jab1/CSN5 expression was gradually upregulated and p97/VCP expression was downregulated in IR injury according to western blotting and immunohistochemistry. To test further whether polyubiquitination was also involved in IR injury, the expression of polyubiquitinated proteins was examined, which showed that polyubiquitinated proteins were significantly increased in IR injury. These finding suggest that p97/VCP and Jab1/CSN5 provide a novel signaling pathway for testicular ischaemia and may play an important role in IR injury induced cell death in rat testis. PMID- 26754109 TI - Magnaporthe oryzae aminosugar metabolism is essential for successful host colonization. AB - Pathogens encounter and metabolize a range of host-derived metabolites while proliferating inside the host. Our understanding of these metabolites and their metabolic processes has remained largely incomplete. We investigated the role of the Magnaporthe oryzae N-acetylglucosamine (GlcNAc) catabolic pathway during rice infection. The catabolic pathway is composed of a GlcNAc transporter (MoNgt1), hexokinase(s), a GlcNAc-6-phosphate deacetylase (MoDac) and a GlcN-6-phosphate deaminase (MoDeam). A detailed characterization of the Deltamongt1, Deltamodac and Deltamodeam null mutants revealed that a defect in GlcNAc catabolism impairs the pathogenicity of M. oryzae. These mutants showed severely reduced virulence in susceptible rice cultivar due to their inability to neutralize host-derived reactive oxygen species and their failure to develop invasive hyphal growth within the host tissue. Interestingly, during oxidative stress, M. oryzae proliferated efficiently in GlcNAc-containing media compared with other sugars, and the expression of fungal antioxidant genes was upregulated following GlcNAc treatment. However, GlcNAc inhibited the growth of the Deltamodac and Deltamodeam mutants, and this growth inhibition was enhanced during oxidative stress. These results suggest that GlcNAc helps fungus to overcome oxidative stress inside its host, perhaps by activating an antioxidant defence. In the absence of a functional catabolic pathway, GlcNAc becomes toxic to the cells. PMID- 26754110 TI - The role of tumour necrosis factor alpha and soluble tumour necrosis factor alpha receptors in the symptomatology of schizophrenia. AB - Background Immunological mechanisms may be responsible for the development and maintenance of schizophrenia symptoms. Aim The aim of this study is to measure tumour necrosis factor-alpha (TNF-alpha), soluble tumour necrosis factor-alpha receptor I (sTNF-alphaRI), and soluble tumour necrosis factor-alpha receptor II (sTNF-alphaRII) levels in patients with schizophrenia and healthy individuals, and to determine their relationship with the symptoms of schizophrenia. Methods Serum TNF-alpha, sTNF-alphaRI and sTNF-alphaRII levels were measured. The Positive and Negative Syndrome Scale (PANSS) was administered for patients with schizophrenia (n = 35), and the results were compared with healthy controls (n = 30). Hierarchical regression analyses were undertaken to predict the levels of TNF-alpha, sTNF-alphaRI and sTNF-alphaRII. Results No significant difference was observed in TNF-alpha levels, but sTNF-alphaRI and sTNF-alphaRII levels were lower in patients with schizophrenia. Serum sTNF-alphaRI and sTNF-alphaRII levels were found to be negatively correlated with the negative subscale score of the PANSS, and sTNF-alphaRI levels were also negatively correlated with the total score of the PANSS. Smoking, gender, body mass index were not correlated with TNF alpha and sTNF-alpha receptor levels. Conclusions These results suggest that there may be a change in anti-inflammatory response in patients with schizophrenia due to sTNF-alphaRI and sTNF-alphaRII levels. The study also supports low levels of TNF activity in schizophrenia patients with negative symptoms. PMID- 26754111 TI - Effects of intraocular lenses with different diopters on chromatic aberrations in human eye models. AB - BACKGROUND: In this study, the effects of intraocular lenses (IOLs) with different diopters (D) on chromatic aberration were investigated in human eye models, and the influences of the central thickness of IOLs on chromatic aberration were compared. METHODS: A Liou-Brennan-based IOL eye model was constructed using ZEMAX optical design software. Spherical IOLs with different diopters (AR40e, AMO Company, USA) were implanted; modulation transfer function (MTF) values at 3 mm of pupil diameter and from 0 to out-of-focus blur were collected and graphed. RESULTS: MTF values, measured at 555 nm of monochromatic light under each spatial frequency, were significantly higher than the values measured at 470 to 650 nm of polychromatic light. The influences of chromatic aberration on MTF values decreased with the increase in IOL diopter when the spatial frequency was <=12 c/d, while increased effects were observed when the spatial frequency was >=15 c/d. The MTF values of each IOL eye model were significantly lower than the MTF values of the Liou-Brennan eye models when measured at 555 nm of monochromatic light and at 470 to 650 nm of polychromatic light. The MTF values were also found to be increased with the increase in IOL diopter. CONCLUSION: With higher diopters of IOLs, the central thickness increased accordingly, which could have created increased chromatic aberration and decreased the retinal image quality. To improve the postoperative visual quality, IOLs with lower chromatic aberration should be selected for patients with short axial lengths. PMID- 26754112 TI - Total hip arthroplasty using a Kerboull-type plate for rapidly destructive coxarthrosis: comparison with uncemented acetabular component. AB - INTRODUCTION: Clinical outcomes of total hip arthroplasty (THA) to treat rapidly destructive coxarthrosis (RDC) have been reported, but to our knowledge, there have been no studies comparing implants. The aim of this study was to examine the effectiveness of acetabular reconstruction for RDC by comparing the clinical results of THA using a Kerboull-type plate with an uncemented cup. PATIENTS AND METHODS: Among 921 primary THAs performed between 2006 and 2014, 27 were performed for the treatment for RDC using a Kerboull-type plate or a conventional uncemented cup. A Kerboull-type plate for acetabular reinforcement device was used in 13 hips and an uncemented cup in 14 hips. The mean follow-up period was 61.2 months. RESULTS: The duration of surgery was 156.8 +/- 36.4 min in the Kerboull-type plate group and 103.3 +/- 14.4 min in the uncemented cup group, being significantly longer in the former (P = 0.0002). In the Kerboull-type plate group and the uncemented cup group, the 5-year survival rates were 100 and 83.9 %, respectively. Recurrent dislocation was observed in two cases in which the posterior approach had been used. CONCLUSIONS: In our study, the loosening of the acetabular components was noted in 14.3 % of uncemented cup-applied cases, but no loosening was noted in any Kerboull-type plate-applied case. Therefore, for RDC, in which objective evaluation of fragile bone quality is difficult, the use of the Kerboull-type plate, which disperses weight-bearing of the acetabular, may be an effective means to achieve early functional recovery as well as a long-term favorable outcome. PMID- 26754113 TI - Use of external fixator versus flexible intramedullary nailing in closed pediatric femur fractures: comparing results using data from two cohort studies. AB - PURPOSE: Although external fixation and flexible intramedullary nailing have been extensively used in the management of pediatric femur fractures, there are very few studies, which have compared the results. The purpose of the study was to compare the results of external fixation and flexible intramedullary nailing in pediatric femur fractures. METHODS: Two groups of patients were treated by external fixator (EF) and flexible intramedullary nailing (FIN) over two different but successive time periods and results compared. The first group (EF) consisted of 45 patients, and the second group had 50 patients. RESULTS: The age in EF group ranged from 6 to 14 years (average 9.93 years), and the age in FIN group ranged from 6 to 11 years (average 7.66 years). In the EF group, fixator was removed at an average of 12.23 weeks. In the FIN group, radiographic union was evident at an average time of 10.06 weeks. Pin-site infection was common in EF group. One patient had a re-fracture in EF group, and one patient had to be re operated in FIN group after he developed anterior angulation of more than 30 degrees . CONCLUSION: We believe that it is the discretion of the surgeon to operate on the femur fracture using either of the treatment modalities. Further randomized studies need to be conducted between these two treatment modalities. PMID- 26754114 TI - Cerebral toxoplasmosis in undifferentiated connective disease treated with mycophenolate mofetil: an unusual case report. PMID- 26754115 TI - How Much Clinical and Functional Impairment do Children Treated With Knee Rotationplasty Experience in Adulthood? AB - BACKGROUND: Rotationplasty may be indicated for some children with osteosarcoma in the distal femur or proximal tibia; in properly selected patients, it may offer functional advantages over transfemoral amputation and more durable results than a prosthesis. The clinical and functional outcomes reported for this procedure generally have been limited to studies with a mean followup of approximately 8 years in terms of Musculoskeletal Tumor Society Score (MSTS), physical examination, and gait analysis. However, the effects of residual thigh shank length on gait have not been explored to our knowledge. QUESTIONS/PURPOSES: We asked: (1) Do differences in the length of the surgically treated residual thigh-shank relative to the contralateral thigh result in altered gait patterns? (2) What were the clinical and functional impairments and radiographic findings of patients who underwent rotationplasty and who survived to adulthood? (3) Do gait analysis findings in adults differ from previously reported findings in children in terms of relevant gait parameters such as maximal ground reaction forces and sagittal knee angles? METHODS: From January 1986 to December 2009, 254 children (age range, 3-14 years) affected by high-grade bone sarcomas located in the distal half of the femur were surgically treated at our institute. Forty-two of these patients (16.5%) underwent rotationplasty. During this period, three adolescents older than 15 years were treated by rotationplasty owing to the tumor volume and extracompartmental involvement. In total, 45 patients underwent rotationplasty. From January 1986 to December 2000, rotationplasty generally was the preferred treatment for patients younger than 9 years with a high-grade bone sarcoma calling for an intra- or extraarticular resection of the distal femur, as long as the sciatic nerve could be spared. From January 2001, the procedure was not used as often. Of the 45 patients who underwent a rotationplasty, 14 died of disease at a mean of 37 months (31%); 31 patients (69%) were survivors at the time the study was done, 29 of whom were continuously disease free (64%) and two had no evidence of disease after a pulmonary metastasectomy (5%). These 31 patients were invited to participate in the study, and 25 of the 31 agreed to participate. There were 15 males and 10 females with a mean age of 23.8 years (SD, 7.5 years) and mean followup of 15 years (SD, 5.8 years). Clinical assessment included the MSTS score (total score ranges between 0 and 30 with 0 indicating poor results and 30 indicating good results), obtained by clinical assessment and patient interview, measurements of the residual thigh-shank length and of the contralateral thigh, of the lengths of the surgically treated and contralateral feet, and of active ROM of the rotated and contralateral ankles. Of the 25 patients, 22 (88%) agreed to have lower limb radiographs and 16 (64%) agreed to perform gait analysis. RESULTS: The residual thigh-shank was, on average, 5.8% longer than the contralateral thigh. Differences in the length of the residual thigh-shank relative to the contralateral thigh resulted in altered gait patterns. Patients with longer residual thigh-shank length had greater pseudoknee flexion during stance and swing. Patients with shorter residual thigh shank length walked with a gait similar to that of controls. The mean MSTS score was 25 (SD, 2). With respect to the contralateral foot, the surgically treated foot was 10% shorter, the talus 11% shorter in the long axis and 7.6% in the short axis and the calcaneus was 2.7% shorter in the long axis and 8.6% in the short axis. Radiologic arthritis was present in most patients at the tibiotalar, subtalar, and talonavicular joints. As adults, our patients showed improved gait parameters compared with previously reported findings for children undergoing rotationplasty. Vertical ground reaction force during midstance was reduced by 6% and knee ROM during the gait cycle was increased by 24.6 degrees . CONCLUSIONS: The residual thigh-shank length influences the gait performance, such that patients with smaller discrepancies between the surgically treated and contralateral sides had the best walking performance. The MSTS score at a mean of 15 years after knee rotationplasty confirmed the results reported in the shorter term for function and pain. The foot on the surgically treated side was smaller than the contralateral foot, and degenerative changes were present, which could contribute to impaired function. Gait performance, in terms of ground reaction forces and knee ROM, was improved in our adult patients although a difference in loading was still present between the surgically treated and contralateral limbs. Based on these findings, surgeons should endeavor to have the center axis of rotation of the contralateral knee and pseudoknee at skeletal maturity. An excessive residual thigh-shank length in adult patients could require contralateral lengthening to improve functional results. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 26754116 TI - Follicular fluid norepinephrine and dopamine concentrations are higher in polycystic ovary syndrome. AB - The aim of the present study was to compare follicular fluid (FF) levels of norepinephrine (NE) and dopamine (DA) in polycystic ovary syndrome (PCOS) and non PCOS patients who underwent in vitro fertilization (IVF). Forty-seven PCOS patients (study group) and 61 patients with male factor infertility (control group) who underwent IVF using GnRH agonist protocol were recruited. Concentrations of NE and DA were measured in FF specimens of all patients. Demographic characteristics were comparable between the groups. Significantly higher levels of NE were measured in FF of PCOS patients (median: 61.05 nmol/l) compared to those with male infertility (median: 49.82 nmol/l). Similarly, significantly higher levels of DA were measured in FF of PCOS patients (median: 23.70 nmol/l) compared to those with male infertility (median: 18.28 nmol/l). In conclusion, the FF concentrations of both catecholamine are increased in PCOS patients when compared to non-PCOS patients. PMID- 26754117 TI - A rapid and cost-effective method for genotyping apolipoprotein E gene polymorphism. AB - BACKGROUND: Apolipoprotein E (ApoE) is a major cholesterol carrier and plays an important role in maintaining lipid homeostasis both in the periphery and brain. Human APOE gene is polymorphic at two single nucleotides (rs429358 and rs7412) resulting in three different alleles (epsilon2, epsilon3 and epsilon4). ApoE isoforms modulate the risk for a variety of vascular and neurodegenerative diseases; thus, APOE genotyping is crucial for predicting disease risk and designing individualized therapy based on APOE genotype. RESULTS: We have developed an APOE genotyping method that is based on allele-specific PCR methodology adapted to Real Time PCR monitored by TaqMan probe. Rather than using TaqMan probes specific for the two polymorphic sites, only one TaqMan probe is used as the polymorphic alleles are recognized by site-specific PCR primers. Each genotyping assay can be completed within 90 minutes and is applicable to high throughput analysis. Using this protocol, we genotyped a total of 1158 human DNA samples and obtained a 100% concordance with the APOE genotype determined by sequencing analysis. CONCLUSION: The APOE genotyping assay we have developed is accurate and cost-effective. In addition, our assay can readily be applied to genotyping large sample numbers. Therefore, our APOE genotyping method can be used for assessing the risk for a variety of vascular and neurodegenerative diseases that have been reported to be associated with APOE polymorphism. PMID- 26754119 TI - Numbers of Severely Injured Patients in Germany. A Retrospective Analysis From the DGU (German Society for Trauma Surgery) Trauma Registry. AB - BACKGROUND: Persons who sustain severe traumatic injury, i.e., those with an Injury Severity Score (ISS) of 16 or above, go on to suffer major physical, emotional, and socio-economic consequences. It is important to know the incidence of severe trauma so that these patients can be cared for optimally. METHODS: Data from the year 2012 on severely injured persons with an ISS of 16 or above were obtained from the trauma registry of the German Society for Trauma Surgery (DGU) and analyzed. Further information was obtained from the database of the DGU trauma network. The annual incidence of severe trauma was estimated from these data in three different ways. RESULTS: An extrapolation of hospital-based data to the German population yielded a figure of 16 742 severely injured persons per year. A population-based estimate from the German federal state of Bavaria yielded a figure of 16 514/year, while an area-based extrapolation using data from 17 established networks yielded a figure of 16 554/year. We added 10% to each of these figures as a correction for assumed underreporting. We conclude that the number of persons who sustained a severe traumatic injury in Germany in 2012 lay between 18 209 (95% confidence interval [CI]: 17 751-18 646) and 18 416 (95% CI: 18 156-18 695). This corresponds to an incidence of 0.02% per year. CONCLUSION: Data from a prospectively maintained nationwide trauma registry were used for the first time to calculate the annual incidence of severe traumatic injury in Germany: the expected number of severely injured persons per year is 18 200-18 400. Previous extrapolations yielded values in the range of 32 500-35 300. A high variability of documentation practices among supraregional trauma centers may have distorted the estimate, along with other factors. The figures were not normalized for age or sex. PMID- 26754120 TI - Mechanical Thrombectomy in Stroke. AB - BACKGROUND: The introduction of neurological stroke units and of thrombolysis with the intravenous (IV) administration of recombinant tissue-type plasminogen activator (tPA) have markedly improved the treatment of stroke. Five randomized trials of catheter-based interventional treatment of stroke with special stents were published in 2015. METHODS: Recently published randomized trials of mechanical thrombectomy are selectively reviewed. RESULTS: These trials documented the clinical efficacy of mechanical thrombectomy (MT) in the treatment of occlusion of a major cerebral artery in the distribution of the internal carotid artery (evidence level 1a, recommendation grade A). Roughly 4-10% of all stroke patients could benefit from such an intervention. In the trials, 85% of the patients were first treated with IV-tPA. A recanalization of the occluded vessel was achieved by MT in 59-88% of patients. The percentage of patients with no deficit or only a mild deficit was 33-71% among those who received the intervention, compared to 19-40% in the control groups. The trial data indicate that MT is effective for elderly patients as well (age over 80). Thrombectomy did not increase the rate of secondary, symptomatic intracranial hemorrhage. CONCLUSION: MT can only be used to treat the occlusion of major cerebral arteries. In appropriate patients, it expands the spectrum of treatment options for stroke. Long-term data are not yet available. PMID- 26754122 TI - Prognostic Value of Fat Mass and Skeletal Muscle Mass Determined by Computed Tomography in Patients Who Underwent Transcatheter Aortic Valve Implantation. AB - Body composition (fat mass [FM] and skeletal muscle mass [SMM]) predicts clinical outcomes. In particular, loss of SMM (sarcopenia) is associated with frailty and mortality. There are no data on the prevalence and impact of FM and SMM in patients undergoing transcatheter aortic valve implantation (TAVI). The objective of this study is to determine body composition from pre-TAVI computed tomography (CT) and evaluate its association with clinical outcomes in patients who underwent TAVI. A total of 460 patients (mean age 81 +/- 8 years, men: 51%) were included. Pre-TAVI CTs of the aorto-ilio-femoral axis were analyzed for FM and SMM cross-sectional area at the level of the third lumbar vertebrae (L3). Regression equations correlating cross-sectional area at L3 to total body FM and SMM were used to determine prevalence of sarcopenia, obesity, and sarcopenic obesity in patients (64%, 65%, and 46%, respectively). Most TAVI procedures were performed through a transfemoral approach (59%) using a balloon-expandable valve (94%). The 30-day and mid-term (median 12 months [interquartile range 6 to 27]) mortality rates were 6.1% and 29.6%, respectively. FM had no association with clinical outcomes, but sarcopenia predicted cumulative mortality (hazard ratio 1.55, 95% confidence interval 1.02 to 2.36, p = 0.04). In conclusion, body composition analysis from pre-TAVI CT is feasible. Sarcopenia, obesity, and sarcopenic obesity are prevalent in the TAVI population, with sarcopenia predictive of cumulative mortality. PMID- 26754123 TI - Trends in Ideal Cardiovascular Health Metrics Among Employees of a Large Healthcare Organization (from the Baptist Health South Florida Employee Study). AB - The American Heart Association (AHA)'s 2020 goal is to improve the cardiovascular health (CVH) of people living in the United States (US) by 20% and reduce mortality from cardiovascular diseases and stroke by 20%. Given that 155 million adults are in the US workforce, and >60% have employee-based insurance, workplace studies provide an important opportunity to assess and potentially advance CVH through the use of comprehensive workplace wellness programs. Among a cohort of employees of the Baptist Health System, CVH was assessed annually during voluntary health fairs and health risk assessments (HRA) from 2011 to 2014 using the AHA's 7 CVH metrics: smoking, body mass index (BMI), physical activity, diet, blood pressure, total cholesterol, and blood glucose. Each metric was categorized as ideal, intermediate, or poor according to the AHA criteria. Cochrane-Armitage test was used to detect trends in CVH by year. Ideal CVH, defined as meeting ideal criteria for all 7 metrics, was assessed and compared across years. The overall cohort was 34,746 with 4,895 employees in 2011, 10,724 in 2012, 9,763 in 2013, and 9,364 in 2014. Mean age (SD) was between 43 (+/-12) and 46 years (+/ 12). Female to male ratio was 3:1. The prevalence of study participants who met the ideal criteria for diet, physical activity, and blood pressure increased significantly from 2011 to 2014 but for BMI, total cholesterol, and blood glucose, a significant decrease was noticed. In addition, the prevalence of study participants in ideal CVH although low, increased significantly over time (0.3% to 0.6%, p <0.0001). In conclusion, this study shows the trends of the AHA's CVH metrics in a large health care organization. The positive findings noted for the metrics of smoking, physical activity, total cholesterol, and blood glucose should be reinforced. However, the metrics of diet, BMI, and blood pressure need more attention. PMID- 26754121 TI - Urosepsis--Etiology, Diagnosis, and Treatment. AB - BACKGROUND: Sepsis is among the most common causes of death in Germany. Urosepsis accounts for 9-31% of all cases and has a mortality of 20-40%, which is low compared with that of sepsis in general. As the population ages, the incidence of urosepsis is likely to rise. METHODS: Review of pertinent articles and guidelines retrieved by a selective search in PubMed. RESULTS: Enterobacteria and Gram positive organisms are the pathogens that most commonly cause urosepsis. The diagnosis can and must be made early on the basis of the typical clinical features, altered vital signs, and laboratory abnormalities, so that timely treatment can be initiated. 80% of cases are due to obstructive uropathy. The diagnostic evaluation includes physical examination, blood cultures, urinalysis, procalcitonin measurement, and ultrasonography. In one study, each additional hour of delay in the treatment of urosepsis with antibiotics was found to lower the survival rate by 7.6%. Antibiotics should be chosen in consideration of local resistance patterns and the expected pathogen spectrum. CONCLUSION: Urologists, intensive care specialists, and microbiologists should all be involved in the interdisciplinary treatment of urosepsis. Patients' outcomes have improved recently, probably because of the frequent use of minimally invasive treatments to neutralize foci of infection. New biomarkers and new treatments still need to be validated in multicenter trials. PMID- 26754124 TI - Prognostic Value of Coronary Computed Tomography Imaging in Patients at High Risk Without Symptoms of Coronary Artery Disease. AB - At present, traditional risk factors are used to guide cardiovascular management of asymptomatic subjects. Intensified surveillance may be warranted in those identified as high risk of developing cardiovascular disease (CVD). This study aims to determine the prognostic value of coronary computed tomography (CT) angiography (CCTA) next to the coronary artery calcium score (CACS) in patients at high CVD risk without symptoms suspect for coronary artery disease (CAD). A total of 665 patients at high risk (mean age 56 +/- 9 years, 417 men), having at least one important CVD risk factor (diabetes mellitus, familial hypercholesterolemia, peripheral artery disease, or severe hypertension) or a calculated European systematic coronary risk evaluation of >10% were included from outpatient clinics at 2 academic centers. Follow-up was performed for the occurrence of adverse events including all-cause mortality, nonfatal myocardial infarction, unstable angina, or coronary revascularization. During a median follow-up of 3.0 (interquartile range 1.3 to 4.1) years, adverse events occurred in 40 subjects (6.0%). By multivariate analysis, adjusted for age, gender, and CACS, obstructive CAD on CCTA (>=50% luminal stenosis) was a significant predictor of adverse events (hazard ratio 5.9 [CI 1.3 to 26.1]). Addition of CCTA to age, gender, plus CACS, increased the C statistic from 0.81 to 0.84 and resulted in a total net reclassification index of 0.19 (p <0.01). In conclusion, CCTA has incremental prognostic value and risk reclassification benefit beyond CACS in patients without CAD symptoms but with high risk of developing CVD. PMID- 26754126 TI - Axial spatial distribution focusing: improving MALDI-TOF/RTOF mass spectrometric performance for high-energy collision-induced dissociation of biomolecules. AB - RATIONALE: For the last two decades, curved field reflectron technology has been used in matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometers, assisting in the generation of post-source-decay (PSD) or collision-induced dissociation (CID) without decelerating precursor ions, producing true high-energy CID spectra. The result was the generation of product ion mass spectra with product ions typical of high-energy (10 keV and beyond) collision processes. The disadvantage of this approach was the lack of resolution in CID spectra resulting from the excess laser energy deposition used to generate those MS/MS spectra. The work presented in this study overcomes this limitation and includes comprehensive examples of high-energy and high-resolution CID MALDI MS/MS spectra of biomolecules. METHODS: The devices used in this study are TOF/RTOF instruments equipped with a high-vacuum MALDI ion source. High resolution and high-energy CID spectra result from the use of axial spatial distribution focusing (ASDF) in combination with curved field reflectron technology. RESULTS: A CID spectrum of the P14 R1 peptide exhibits product ion resolution in excess of 10,000 (FWHM) but at the same time yields typical high energy product ions such as w- and [y-2]-type ion series. High-energy CID spectra of lipids, exemplified by a glycerophospholipid and triglyceride, demonstrate C-C backbone fragmentation elucidating the presence of a hydroxyl group in addition to double-bond positioning. A complex high mannose carbohydrate (Man)8 (GlcNAc)2 was also studied at 20 keV collision energy and revealed further high-energy product ions with very high resolution, allowing unambiguous detection and characterization of cross-ring cleavage-related ions. CONCLUSIONS: This is the first comprehensive study using a MALDI-TOF/RTOF instrument equipped with a curved field reflectron and an ASDF device prior to the reflectron. (c) 2015 The Authors. Rapid Communications in Mass Spectrometry published by John Wiley & Sons Ltd. PMID- 26754127 TI - An ambient detection system for visualization of charged particles generated with ionization methods at atmospheric pressure. AB - RATIONALE: With the current state-of-the-art detection of ions only taking place under vacuum conditions, active pixel detectors that operate under ambient conditions are of particular interest. These detectors are ideally suited to study and characterize the charge distributions generated by ambient ionization sources. METHODS: The direct imaging capabilities of the active pixel detector are used to investigate the spatial distributions of charged droplets generated by three ionization sources, named electrospray ionization (ESI), paper spray ionization (PSI) and surface acoustic wave nebulization (SAWN). The ionization spray (ESI/PSI) and ionization plume (SAWN) originating from each source are directly imaged. The effect of source parameters such as spray voltage for ESI and PSI, and the angle of the paper spray tip on the charge distributions, is investigated. Two types of SAWN liquid interface, progressive wave (PW) and standing wave (SW), are studied. RESULTS: Direct charge detection under ambient conditions is demonstrated using an active pixel detector. Direct charge distributions are obtained of weak, homogeneous/focused and dispersed spray plumes by applying low, intermediate and high spray potentials, respectively, for ESI. Spray plume footprints obtained for various angles of PSI shows the possibility to focus the ion beam as a function of the paper angle. Differences between two designs of the SAWN interface are determined. Droplet charge flux changes are illustrated in a way similar to a total ion chromatogram. CONCLUSIONS: The use of this active pixel detector allows the rapid characterization and optimization of different ambient ionization sources without the actual use of a mass spectrometer. Valuable illustrations are obtained of changes in spatial distribution and number of charges detected for ESI, PSI and SAWN ion plumes. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26754125 TI - Association between personal exposure to ambient metals and respiratory disease in Italian adolescents: a cross-sectional study. AB - BACKGROUND: Release of ambient metals during ferroalloy production may be an important source of environmental exposure for nearby communities and exposure to these metals has been linked to adverse respiratory outcomes. We sought to characterize the association between personal air levels of metals and respiratory health in Italian adolescents living in communities with historic and current ferroalloy activity. METHODS: As part of a study in the industrial province of Brescia, Italy, 410 adolescents aged 11-14 years were recruited. Participants were enrolled from three different communities with varying manganese (Mn) levels: Bagnolo Mella which has current ferroalloy activity, Valcamonica, which has historic ferroalloy activity and Garda Lake which has no history of ferroalloy activity. Particulate matter <10 MUm in diameter (PM10) was collected for 24 h in filters using personal sampling. Mn, nickel (Ni), zinc (Zn), chromium (Cr) and iron (Fe) were measured in filters using x-ray fluorescence. Data on respiratory health was collected through questionnaire. Data for 280 adolescents were analyzed using a modified Poisson regression, and risk ratios were calculated for an interquartile (IQR) range increase in each pollutant. RESULTS: In adjusted models including PM10 as a co-pollutant, we found significant associations between concentrations of Mn (RR: 1.09, 95% CI [1.00, 1.18] per 42 ng/m(3) increase), Ni (RR: 1.11, 95% CI [1.03, 1.21] per 4 ng/m(3) increase) and Cr (RR: 1.08, 95% CI [1.06, 1.11] per 9 ng/m(3) increase) and parental report of asthma. We also found significant associations between increased Mn and Ni and increased risk of asthma medication use in the past 12 months (RR: 1.13, 95% CI [1.04, 1.29] and (RR: 1.13, 95 % CI [1.01, 1.27] respectively). CONCLUSIONS: Our findings suggest that exposure to ambient Mn, Ni and Cr may be associated with adverse respiratory outcomes. PMID- 26754129 TI - Ion transfer from an atmospheric pressure ion funnel into a mass spectrometer with different interface options: Simulation-based optimization of ion transmission efficiency. AB - RATIONALE: We optimized an atmospheric pressure ion funnel (APIF) including different interface options (pinhole, capillary, and nozzle) regarding a maximal ion transmission. Previous computer simulations consider the ion funnel itself and do not include the geometry of the following components which can considerably influence the ion transmission into the vacuum stage. METHODS: Initially, a three-dimensional computer-aided design (CAD) model of our setup was created using Autodesk Inventor. This model was imported to the Autodesk Simulation CFD program where the computational fluid dynamics (CFD) were calculated. The flow field was transferred to SIMION 8.1. Investigations of ion trajectories were carried out using the SDS (statistical diffusion simulation) tool of SIMION, which allowed us to evaluate the flow regime, pressure, and temperature values that we obtained. RESULTS: The simulation-based optimization of different interfaces between an atmospheric pressure ion funnel and the first vacuum stage of a mass spectrometer require the consideration of fluid dynamics. The use of a Venturi nozzle ensures the highest level of transmission efficiency in comparison to capillaries or pinholes. However, the application of radiofrequency (RF) voltage and an appropriate direct current (DC) field leads to process optimization and maximum ion transfer. The nozzle does not hinder the transfer of small ions. CONCLUSIONS: Our high-resolution SIMION model (0.01 mm grid unit(-1) ) under consideration of fluid dynamics is generally suitable for predicting the ion transmission through an atmospheric-vacuum system for mass spectrometry and enables the optimization of operational parameters. A Venturi nozzle inserted between the ion funnel and the mass spectrometer permits maximal ion transmission. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26754128 TI - Development of laser ablation multi-collector inductively coupled plasma mass spectrometry for boron isotopic measurement in marine biocarbonates: new improvements and application to a modern Porites coral. AB - RATIONALE: Laser Ablation coupled to Multi-Collector Inductively Coupled Plasma Mass Spectrometry (LA-MC-ICPMS) is a powerful tool for the high-precision measurement of the isotopic ratios of many elements in geological samples, with the isotope ratio ((11) B/(10) B) of boron being used as an indicator of the pH of oceanic waters. Most geological samples or standards are polished and ablation occurs on flat surfaces. However, the shape and the irregularities of marine biocarbonates (e.g., corals, foraminifera) can make precise isotopic measurements of boron difficult. Even after polishing, the porosity properties and the presence of holes or micro-fractures affect the signal and the isotopic ratio when ablating the material, especially in raster mode. METHODS: The effect of porosity and of the crater itself on the (11) B signal and the isotopic ratio acquired by LA-MC-ICPMS in both raster and spot mode was studied. Characterization of the craters was then performed with an optical profilometer to determine their shapes and depths. Surface state effects were examined by analyzing the isotopic fractionation of boron in silicate (NIST-SRM 612 and 610 standards) and in carbonate (corals). RESULTS: Surface irregularities led to a considerable loss of signal when the crater depth exceeded 20 um. The stability and precision were degraded when ablation occurred in a deep cavity. The effect of laser focusing and of blank correction was also highlighted and our observations indicate that the accuracy of the boron isotopic ratio does not depend on the shape of the surface. After validation of the analytical protocol for boron isotopes, a raster application on a Porites coral, which grew for 18 months in an aquarium after field sampling, was carried out. CONCLUSIONS: This original LA-MC-ICPMS study revealed a well-marked boron isotope ratio temporal variability, probably related to growth rate and density changes, irrespective of the pH of the surrounding seawater. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26754130 TI - Cluster secondary ion mass spectrometry imaging of interfacial reactions of TiO2 microspheres embedded in ionic liquids. AB - RATIONALE: Our goal is to develop protocols for the elucidation of the identity and structure of reaction products embedded in a reaction medium. Results should find significance in a variety of disciplines ranging from the study of biological cells and tissues, to the steps associated with the functionalization of nanoparticles. METHODS: We utilize cluster secondary ion mass spectrometry (cluster-SIMS) to acquire three-dimensional (3D) information about 5-30 um TiO2 microspheres imbedded into an ionic liquid. The method allows molecular depth profiling with submicron spatial resolution and depth profiling with a resolution of several tens of nanometers. The ionic liquid matrix enshrouds the spheres, allowing them to be introduced into the vacuum environment of the mass spectrometer. RESULTS: The results provide 3D chemical information about these microspheres as they are synthesized by interfacial sol-gel reactions. We show that with 40 keV C60 (+) , it is possible to erode through the reaction medium and map the distribution of those embedded TiO2 microspheres. Moreover, we demonstrate that it is possible to monitor surface modification of the particles and, via ion beam drilling, elucidate their internal structure. CONCLUSIONS: Using cluster-SIMS imaging, we are able to elucidate the identity and structure of reaction products embedded in a reaction medium, a problem of long-standing interest for materials characterization. With this strategy, we have provided a new approach that may be especially useful for the characterization of biological tissue and cells within the vacuum confines of the mass spectrometer. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26754131 TI - Discovery of a solvent effect preventing quantitative profiling by matrix assisted laser desorption/ionization and its treatment. AB - RATIONALE: In analyte profiling by matrix-assisted laser desorption/ionization (MALDI), drawing a quantitative profile map is an outstanding problem. Recently, we developed a method to quantify an analyte by MALDI, which is needed to solve the problem. Another requirement for quantitative profiling is the quantitative sample-to-matrix analyte transfer, which is investigated in this work. METHODS: MALDI-time-of-flight (TOF) spectra were acquired for samples produced by two methods. In one, a sample solution containing a matrix and an analyte was loaded with a pipet and dried. In the other, a sample was prepared by a consecutive process, i.e., loading-drying of an analyte solution followed by that of a matrix solution. Two different micro-spotters were used in the second method. Various mixtures of organic solvents with water were used to prepare matrix solutions. RESULTS: The organic solvent, matrix, and analyte used in the study did not affect the analyte transfer efficiency, whereas it improved as the water content in the solvent increased. It also improved as the liquid droplet emitted by a micro-spotter got larger. Use of a more polar solvent or a larger droplet increases the contact time between a solution droplet and the sample surface, which seems to be responsible for the improvement in the transfer efficiency. CONCLUSIONS: Sample-to-matrix analyte transfer occurred efficiently when polar solvents and/or large liquid droplets were used to produce solid samples for MALDI profiling with a micro-spotter. A long contact time between the sample surface and a matrix solution droplet is one of the requirements for quantitative profiling. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26754132 TI - Gas-phase reactions of methyl thiocyanate with aliphatic carbanions - A mass spectrometry and computational study. AB - RATIONALE: Methyl thiocyanate, like other organic thiocyanates, is a molecule with many electrophilic reactive sites and it has many synthetic applications. For better understanding of the intrinsic reactivity of alkyl thiocyanates against nucleophiles it was important to study gas-phase reactions of methyl thiocyanate with carbanions differing by structure and proton affinity values. METHODS: All experiments were performed using a modified API 365 triple quadrupole mass spectrometer equipped with a TurboIonSpray electrospray ionization (ESI) source. Carbanions were generated in the ESI source by decarboxylation of the respective carboxylic acid anions. Methyl thiocyanate was delivered as a vapor with nitrogen used as a collision gas to the collision cell where the reactions take place. RESULTS: Mass spectra recorded for the gas-phase reactions of five aliphatic carbanions with methyl thiocyanate showed a variety of product ions formed via different reaction mechanisms, depending on the structure and proton affinity of the carbanion. The pathways considered are: SN 2 nucleophilic substitution, cyanophilic reaction, thiophilic reaction and proton transfer, followed in some instances by subsequent transformations. The proposed reaction pathways are supported by density functional theory (DFT) calculations. CONCLUSIONS: Our preliminary experiments showed that mass spectrometry together with quantum chemical calculations is a good tool for studying gas-phase reactions of alkyl thiocyanates with carbanions. In the gas phase all four theoretically possible products can be observed and their formation can be rationalized by the results of the modelling of the reaction energy profiles. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26754133 TI - Determination of bisphenol A-glucuronide in human urine using ultrahigh-pressure liquid chromatography/tandem mass spectrometry. AB - RATIONALE: Used widely as a plasticizer and as a monomer for plastics, bisphenol A (BPA) is under investigation as a possible endocrine disrupter. As an indication of systemic exposure, a fast and accurate assay was developed for the major BPA metabolite in human urine, BPA-monoglucuronide (BPA-G), using ultrahigh pressure liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS). METHODS: Urine samples were prepared using solid-phase mixed-mode reversed-phase/anion exchange extraction. BPA-G was measured using UHPLC/MS/MS with an amide UHPLC column interfaced to a triple-quadrupole mass spectrometer equipped with negative ion electrospray, collision-induced dissociation and selected reaction monitoring. [(13) C12 ]-BPA-G was used as a surrogate standard. RESULTS: By measuring the glucuronide metabolite of BPA, potential interference due to BPA contamination from containers, solvents, pipette, etc., was avoided. The standard curve had a linear regression coefficient of 0.999, and the intra- and inter assay variations were less than 10%. The assay was validated according to FDA guidelines. CONCLUSIONS: A fast, accurate, and highly selective method for the determination of BPA-G in human urine was developed and validated using UHPLC/MS/MS. This method is suitable for assessing human exposure to BPA. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26754134 TI - Exploration of binding affinity and selectivity of brucine with G-quadruplex in the c-myb proto-oncogene by electrospray ionization mass spectrometry. AB - RATIONALE: The c-myb gene is a potential therapeutic target for human tumors and leukemias. Active ingredients from natural products may be used as drugs in chemotherapy for human cancers. Here, electrospray ionization mass spectrometry (ESI-MS) was used to probe the formation and recognition of the G-quadruplex structure from the G-rich sequence that is found in the c-myb gene promoter, 5' GGGCTGGGCTGGGCGGGG-3'. The aim of our study is to evaluate a potential binder for the c-myb gene from natural products, and thereby to modulate c-myb gene expression. METHODS: ESI-MS, as an effective method, was utilized not only to characterize the formation of the G-quadruplex in the c-myb oncogene, but also as a tool to probe the binding characteristics of alkaloid molecules with the target G-quadruplex DNA. RESULTS: ESI-MS results with the support of circular dichroism (CD) spectra demonstrated the formation of an intramolecular parallel-stranded G quadruplex in the c-myb oncogene promoter. A screening of six alkaloid molecules showed that brucine (P1) had a strong binding affinity to the c-myb G-quadruplex DNA. It is notable that P1 can bind selectively to the c-myb G-quadruplex with respect to duplex DNAs, as well as to G-quadruplexes in other types of gene sequences. According to ESI-MS results, in which the stability was tested by capillary heating and collision-induced dissociation, the binding of P1 could thermally stabilize the c-myb G-quadruplex DNA. CONCLUSIONS: In this work, brucine (P1), an alkaloid molecule, has been found to bind to the intramolecular parallel G-quadruplex in the c-myb oncogene promoter with high affinity and selectivity, and could thermally stabilize the c-myb G-quadruplex DNA, indicating that the binding of P1 has the potential to modulate c-myb gene expression. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26754135 TI - Measurement of extremely (2) H-enriched water samples by laser spectrometry: application to batch electrolytic concentration of environmental tritium samples. AB - RATIONALE: Natural water samples artificially or experimentally enriched in deuterium ((2) H) at concentrations up to 10,000 ppm are required for various medical, environmental and hydrological tracer applications, but are difficult to measure using conventional stable isotope ratio mass spectrometry. METHODS: Here we demonstrate that off-axis integrated cavity output (OA-ICOS) laser spectrometry, along with (2) H-enriched laboratory calibration standards and appropriate analysis templates, allows for low-cost, fast, and accurate determinations of water samples having delta(2) HVSMOW-SLAP values up to at least 57,000 0/00 (~9000 ppm) at a processing rate of 60 samples per day. RESULTS: As one practical application, extremely (2) H-enriched samples were measured by laser spectrometry and compared to the traditional (3) H Spike-Proxy method in order to determine tritium enrichment factors in the batch electrolysis of environmental waters. Highly (2) H-enriched samples were taken from different sets of electrolytically concentrated standards and low-level (<10 TU) IAEA inter comparison tritium samples, and all cases returned accurate and precise initial low-level (3) H results. CONCLUSIONS: The ability to quickly and accurately measure extremely (2) H-enriched waters by laser spectrometry will facilitate the use of deuterium as a tracer in numerous environmental and other applications. For low-level tritium operations, this new analytical ability facilitated a 10-20 % increase in sample productivity through the elimination of spike standards and gravimetrics, and provides immediate feedback on electrolytic enrichment cell performance. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26754137 TI - Stable isotopes reveal spatial variability in the trophic structure of a macro benthic invertebrate community in a tropical coral reef. AB - RATIONALE: Studies of organic matter fluxes in coral reefs are historically based on physical and biogeochemical approaches. It is important to link these approaches to community analysis as the abundance and behaviour of species, populations or trophic groups can have a profound effect on nutrient budgets. METHODS: We determined the carbon and nitrogen isotopic compositions of coral reef organic matter sources and macro-benthic invertebrate communities using a Europa Geo 20/20 isotope ratio mass spectrometer interfaced to an ANCA-SL elemental analyzer in continuous flow mode. Isotopic ecology metrics and a mixing model were used to analyze and interpret the data. RESULTS: The coral reef macro invertebrate community principally relies on detrital or recycled food sources. An increased reliance on reef nitrogen-derived sources was observed in the cold dry season. The community food-web lengths differ noticeably across the coral reef and reflect the characteristics and origin of organic matter reservoirs. CONCLUSIONS: Anthropogenic and terrestrial inputs lead to a loss of biological diversity. Exclusive dominance of suspension-feeding species is observed in areas receiving direct surface riverine particulate organic matter. The accumulation of sediment organic matter in eutrophic areas leads to dominance of deposit-feeding species. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26754136 TI - The power of energy-resolved tandem mass spectrometry experiments for resolution of isomers: the case of drug plasma stability investigation of multidrug resistance inhibitors. AB - RATIONALE: A series of drug plasma stability experiments were carried out to evaluate the bioavailability of three multidrug resistance inhibitors. The studied compounds are positional isomers; therefore, a chromatographic separation or taking advantage of specific collisionally activated decomposition pathways, obtained by tandem mass spectrometry (MS/MS) experiments, is necessary in order to resolve them. METHODS: A method was developed for quantitative determination of the analytes in plasma using liquid chromatography (LC) coupled with a triple quadrupole mass spectrometer operating in MS/MS mode. Different collisional approaches were employed based on the potentiality of a triple quadrupole system. Aside from the classical product ion spectroscopy, energy-resolved MS/MS experiments and a post-processing mathematical algorithm tool (LEDA) were used to distinguish among different kinds of inhibitors present in the sample batch. RESULTS: The developed LC/MS/MS method showed precision between 1.8-7.9%, accuracy ranging from 92.8 to 99.9% and limit of detection (LOD) values in the range 1.0-1.4 ng mL(-1) for all the analytes. The evaluation of matrix effects demonstrated that the sample preparation procedure did not affect the ionization efficiency or recovery (matrix effects and recovery larger than 88%). Finally, the LEDA tool was able to differentiate among the isomers, ensuring their proper monitoring. CONCLUSIONS: The proposed LC/MS/MS method was suitable for evaluating the stability of the analytes in plasma samples, although small concentration variations occurred. Furthermore, the investigation on the energetics of fragmentation pathways allowed the better product ions and optimal abundance ratios to be selected for LEDA application into a multi-component analysis. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26754138 TI - Effects of acidification, lipid removal and mathematical normalization on carbon and nitrogen stable isotope compositions in beaked whale (Ziphiidae) bone. AB - RATIONALE: The analysis of stable isotopes in tissues such as teeth and bones has been used to study long-term trophic ecology and habitat use in marine mammals. However, carbon isotope ratios (delta(13) C values) can be altered by the presence of (12) C-rich lipids and carbonates. Lipid extraction and acidification are common treatments used to remove these compounds. The impact of lipids and carbonates on carbon and nitrogen isotope ratios (delta(15) N values), however, varies among tissues and/or species, requiring taxon-specific protocols to be developed. METHODS: The effects of lipid extraction and acidification and their interaction on carbon and nitrogen isotope values were studied for beaked whale (Ziphiidae) bone samples. delta(13) C and delta(15) N values were determined in quadruplicate samples: control, lipid-extracted, acidified and lipid-extracted followed by acidification. Samples were analyzed by means of elemental analysis isotope ratio mass spectrometry. Furthermore, the efficiency of five mathematical models developed for estimating lipid-normalized delta(13) C values from untreated delta(13) C values was tested. RESULTS: Significant increases in delta(13) C values were observed after lipid extraction. No significant changes in delta(13) C values were found in acidified samples. An interaction between both treatments was demonstrated for delta(13) C but not for delta(15) N values. No change was observed in delta(15) N values for lipid-extracted and/or acidified samples. Although all tested models presented good predictive power to estimate lipid-free delta(13) C values, linear models performed best. CONCLUSIONS: Given the observed changes in delta(13) C values after lipid extraction, we recommend a priori lipid extraction or a posteriori lipid normalization, through simple linear models, for beaked whale bones. Furthermore, acidification seems to be an unnecessary step before stable isotope analysis, at least for bone samples of ziphiids. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26754139 TI - The importance of genetic diagnosis for Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy are caused by mutations in the dystrophin-encoding DMD gene. Large deletions and duplications are most common, but small mutations have been found as well. Having a correct diagnosis is important for family planning and providing proper care to patients according to published guidelines. With mutation-specific therapies under development for DMD, a correct diagnosis is now also important for assessing whether patients are eligible for treatments. This review discusses different mutations causing DMD, diagnostic techniques available for making a genetic diagnosis for children suspected of DMD and the importance of having a specific genetic diagnosis in the context of emerging genetic therapies for DMD. PMID- 26754140 TI - Three surgical planes identified in laparoscopic complete mesocolic excision for right-sided colon cancer. AB - BACKGROUND: Complete mesocolic excision provides a correct anatomical plane for colon cancer surgery. However, manifestation of the surgical plane during laparoscopic complete mesocolic excision versus in computed tomography images remains to be examined. METHODS: Patients who underwent laparoscopic complete mesocolic excision for right-sided colon cancer underwent an abdominal computed tomography scan. The spatial relationship of the intraoperative surgical planes were examined, and then computed tomography reconstruction methods were applied. The resulting images were analyzed. RESULTS: In 44 right-sided colon cancer patients, the surgical plane for laparoscopic complete mesocolic excision was found to be composed of three surgical planes that were identified by computed tomography imaging with cross-sectional multiplanar reconstruction, maximum intensity projection, and volume reconstruction. For the operations performed, the mean bleeding volume was 73+/-32.3 ml and the mean number of harvested lymph nodes was 22+/-9.7. The follow-up period ranged from 6-40 months (mean 21.2), and only two patients had distant metastases. CONCLUSIONS: The laparoscopic complete mesocolic excision surgical plane for right-sided colon cancer is composed of three surgical planes. When these surgical planes were identified, laparoscopic complete mesocolic excision was a safe and effective procedure for the resection of colon cancer. PMID- 26754141 TI - The validity and responsiveness of the ICECAP-A capability-well-being measure in women with irritative lower urinary tract symptoms. AB - PURPOSE: A desire to incorporate broader aspects of well-being in health economic evaluations has led to the development of the ICEpop CAPability measure for Adults (ICECAP-A). The ICECAP-A draws upon Amartya Sen's capability approach and conceptualises well-being as the capability to achieve Stability, Attachment, Autonomy, Achievement, and Enjoyment. The aim of this study was to assess the psychometric performance of the ICECAP-A in a context where patient outcomes can extend beyond health-related quality of life. METHODS: Longitudinal data were collected for 478 women with symptoms of urinary frequency and urgency, with or without incontinence. Women were recruited across 22 hospitals in the UK and had a mean age of 55 (SD 14). The psychometric performance of the measure was evaluated in relation to the EuroQol Five-Dimension Questionnaire (EQ-5D-3L) and the International Consultation on Incontinence Questionnaire for Overactive Bladder (ICIQ-OAB) and involved an assessment of acceptability, construct validity, and responsiveness using parametric and nonparametric methods. RESULTS: ICECAP-A showed good convergence with the ICIQ-OAB with 20 out of 22 expected patterns of relationship confirmed. Findings suggested that the ICECAP-A has better discriminative properties than EQ-5D-3L and as good as those of the ICIQ OAB, confirming expected associations with clinical and demographic factors. The ICECAP-A was more responsive than EQ-5D-3L and ICIQ-OAB to deteriorations of clinical symptoms. Improvements in symptoms were not valued as highly as deteriorations by either ICECAP-A or EQ-5D-3L. CONCLUSIONS: The ICECAP-A is a valid and responsive measure capturing broad emotional and practical impacts of urinary symptoms on women's well-being and could be considered for use in economic evaluations in this context. PMID- 26754142 TI - Direct next-generation sequencing of virus-human mixed samples without pretreatment is favorable to recover virus genome. AB - Next-generation sequencing (NGS) enables the recovery of pathogen genomes from clinical samples without the need for culturing. Depletion of host/microbiota components (e.g., ribosomal RNA and poly-A RNA) and whole DNA/cDNA amplification are routine methods to improve recovery results. Using mixtures of human and influenza A virus (H1N1) RNA as a model, we found that background depletion and whole transcriptome amplification introduced biased distributions of read coverage over the H1N1 genome, thereby hampering genome assembly. Influenza serotyping was also affected by pretreatments. We propose that direct sequencing of noncultured samples without pretreatment is a favorable option for pathogen genome recovery applications. PMID- 26754143 TI - Synthesis of cinnolines via Rh(iii)-catalysed dehydrogenative C-H/N-H functionalization: aggregation induced emission and cell imaging. AB - Rhodium catalysed dehydrogenative C-H/N-H functionalization was developed to construct phthalazino[2,3-a]-/indazolo[1,2-a]cinnolines by reacting N-phenyl phthalazine/indazole with alkynes. The synthesized compounds exhibit prominent fluorescence properties in solid and aggregation states. Their application in cell imaging was investigated using various cancer cell lines. PMID- 26754144 TI - 12th International CHARGE syndrome conference proceedings. AB - The CHARGE Syndrome Foundation holds an International conference for families and professionals every other summer. In July, 2015, the 12th meeting was held in Schaumburg, Illinois, at the Renaissance Schaumburg Hotel. Day one of the 4-day conference was dedicated to professionals caring for and researching various aspects of CHARGE, including education, medical management, animal models, and stem cell-based approaches to understanding and treating individuals with CHARGE. Here, we summarize presentations from the meeting, including a synopsis of each of the three different breakout sessions (Medical/Clinical, Basic Science/CHD7, and Education), followed by a list of abstracts and authors for both platform and poster presentations. PMID- 26754145 TI - Host-Guest Chirality Interplay: A Mutually Induced Formation of a Chiral ZMOF and Its Double-Helix Polymer Guests. AB - A novel homochiral zeolite-like metal-organic framework (ZMOF), [(Cu4I4) (dabco)2].[Cu2(bbimb)].3DMF (JLU-Liu23, dabco =1,4-diazabicyclo[2.2.2]-octane, H2bbimb =1,3-bis(2-benzimidazol)benzene, DMF = N,N-dimethylformamide), has been successfully constructed to host unprecedented DNA-like [Cu2(bbimb)]n polymers with double-helicity. The host-guest chirality interplay permitted the induced formation of an unusual gyroid MOF with homochirality and helical channels in the framework for the first time, JLU-Liu23. Importantly, the enantiomeric pairs (23P, 23M) can be promoted and isolated in the presence of appropriate chiral inducing agents, affording enantioselective separation of chiral molecules as well as small gas molecules. PMID- 26754146 TI - Proteome, Allergenome, and Novel Allergens of House Dust Mite, Dermatophagoides farinae. AB - Dermatophagoides farinae mite is a predominant source of indoor allergens causing high incidence of allergy worldwide. People with different genetic background respond differently to the mite components, and thus the component-resolved diagnosis (CRD) is preferred to the conventional allergy test based on crude mite extract. In this study, proteome and culprit components in the D. farinae whole body extract that sensitized the allergic patients were studied by using SDS-PAGE (1DE) and 2DE-IgE immunoblotting followed by LC-MS/MS and database search for protein identification. From the 1DE, the mite extract revealed 105 proteins that could be classified into seven functionally different groups: allergens, structural components, enzymes, enzyme inhibitor, receptor proteins, transporters, and binding/regulatory/cell signaling proteins. From the 2DE, the mite extract produced 94 spots; 63 were bound by IgE in sera of 20 D. farinae allergic patients. One more protein that was not revealed by the 2DE and protein staining reacted with IgE in 2 allergic patients. Proteins in 40 spots could be identified as 35 different types. Three of them reacted to IgE of >50% of the allergic patients, and hence they are major allergens: tropomyosin or Der f 10 (75%), aconitate hydratase (70%), and one uncharacterized protein (55%). Aconitate hydratase is a novel D. farinae major allergen unraveled in this study. Several mite minor allergens that have never been previously reported are also identified. The data have clinical applications in the component-resolved diagnosis for tailor-designed allergen-specific immunotherapy. PMID- 26754147 TI - Understanding the Roles of the "Two QSARs". AB - Quantitative structure-activity relationship (QSAR) modeling has matured over the past 50 years and has been very useful in discovering and optimizing drug leads. Although its roots were in extra-thermodynamic relationships within small sets of chemically similar molecules focused on mechanistic interpretation, a second class of QSAR models has emerged that relies on machine learning methods to generate models from large, chemically diverse data sets for predictive purposes. There has been a tension between the two groups of QSAR practitioners that is unnecessary and possibly counterproductive. This paper explains the difference in philosophy and application of these two distinct, but equally important, classes of QSAR models and how they can work together synergistically to accelerate the discovery of new drugs or materials. PMID- 26754148 TI - Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants. AB - OBJECTIVE: Very preterm-born neonates (24-32 weeks of gestation) are exposed to stressful and painful procedures during neonatal intensive care. Analgesic and sedation therapies are essential, and opiates and benzodiazepines are commonly used. These medications may negatively impact brain development. The hippocampus may be especially vulnerable to the effects of pain and analgesic and/or sedative therapies and contribute to adverse outcomes. The effect of invasive procedures and analgesic-sedative exposure on hippocampal growth was assessed, as was that of hippocampal growth on neurodevelopmental outcome. METHODS: A total of 138 neonates (51% male, median gestational age = 27.7 weeks) underwent magnetic resonance imaging and diffusion tensor imaging (DTI) scans, early in life (postmenstrual age [PMA] = 32.3 weeks) and at term-equivalent age (PMA = 40.2 weeks). Volumes and DTI measures of axial diffusivity, radial diffusivity, and mean diffusivity (MD) were obtained from the hippocampus. Cognitive, language, and motor abilities were assessed using the Bayley Scales of Infant Development III at 18.7 months median corrected age. Models testing the association of invasive procedures with hippocampal volumes and DTI measures accounted for birth gestational age, sex, PMA, dose of analgesics/sedatives (fentanyl, morphine, midazolam), mechanical ventilation, hypotension, and surgeries. RESULTS: Total midazolam dose predicted decreased hippocampal volumes (beta = -1.8, p < 0.001) and increased MD (beta = 0.002, p = 0.02), whereas invasive procedures did not (beta = 0, p > 0.5 each). Lower cognitive scores were associated with hippocampal growth (beta = -0.31, p = 0.003), midazolam dose (beta = -0.27, p = 0.03), and surgery (beta = -8.32, p = 0.04). INTERPRETATION: Midazolam exposure was associated with macro- and microstructural alterations in hippocampal development and poorer outcomes consistent with hippocampal dysmaturation. Use of midazolam in preterm neonates, particularly those not undergoing surgery, is cautioned. PMID- 26754150 TI - Effects of a collagen membrane positioned between augmentation material and the sinus mucosa in the elevation of the maxillary sinus floor. An experimental study in sheep. AB - OBJECTIVE: To assess the influence of a collagen membrane placed subjacent to a pristine sinus mucosa on the healing outcome of a sinus floor elevation procedure. MATERIALS AND METHODS: Eight Pelibuey sheep (Cubano rojo) underwent sinus floor elevation on both sides of the maxilla. At a randomly selected side (test), a collagen membrane was placed subjacent to the sinus mucosa, while the contralateral side (control) was left without the placement of a membrane. Deproteinized bovine bone mineral (DBBM) was used to fill the space created. A collagen membrane was placed bilaterally to cover the access osteotomy. After 4 months, biopsies were harvested and ground sections prepared. Morphometric analysis was performed in four different regions, three within the elevated area and one at the site of the osteotomy. RESULTS: The total percentages of mineralized new bone within the elevated area were 29.4 +/- 16.2% and 30.9 +/- 9.2% and of marrow spaces 44.0 +/- 23.0% and 45.6 +/- 14.1%, at the Non-membrane and at the Membrane sites, respectively. A low content of connective tissue within the elevated area was noticed. A higher content of connective tissue was found in the osteotomy region, however. Remnants of DBBM granules were found at a percentage of 17-19%. No statistically significant differences were observed between test and control sites. CONCLUSION: The application of a collagen membrane subjacent to the Schneiderian mucosa in a sinus floor elevation procedure did not influence the healing outcomes at all. PMID- 26754149 TI - Nordic hamstring exercise training alters knee joint kinematics and hamstring activation patterns in young men. AB - PURPOSE: To investigate the kinematic and muscle activation adaptations during performance of the Nordic hamstring exercise (NHE) to a 6-week eccentric hamstring training programme using the NHE as the sole mode of exercise. METHODS: Twenty-nine healthy males were randomly allocated to a control (CG) or intervention (IG) group. The IG participated in a 6-week eccentric hamstring exercise programme using the NHE. RESULTS: The findings of the present study were that a 6-week eccentric hamstring training programme improved eccentric hamstring muscle strength (202.4 vs. 177.4 nm, p = 0.0002, Cohen's d = 0.97) and optimized kinematic (longer control of the forward fall component of the NHE, 68.1 degrees vs. 73.7 degrees , p = 0.022, Cohen's d = 0.90) and neuromuscular parameters (increased electromyographic activity of the hamstrings, 83.2 vs. 56.6 % and 92.0 vs. 54.2 %, p < 0.05, Cohen's d > 1.25) associated with NHE performance. CONCLUSION: This study provides some insight into potential mechanisms by which an eccentric hamstring exercise programme utilizing the NHE as the mode of exercise may result in an improvement in hamstring muscle control during eccentric contractions. PMID- 26754151 TI - Glutathione in metastases: From mechanisms to clinical applications. AB - Metastatic spread, not primary tumors, is the leading cause of cancer death. Glutathione (gamma-glutamyl-cysteinyl-glycine, GSH) is particularly relevant in cancer cells as it is involved in regulating carcinogenic mechanisms, growth and dissemination, and multidrug and radiation resistance. Upon interaction of metastatic cells with the vascular endothelium, a high percentage of metastatic cells with high GSH levels survive the combined nitrosative and oxidative stresses elicited by the vascular endothelium. GSH release from different organs, mainly the liver, and its interorgan transport through the blood circulation to metastatic foci, promote their growth. This review focuses on the relationship among GSH and different key mechanisms that facilitate metastatic cell survival and growth, i.e. adaptive responses to stress, cell death evasion and utilization of physiological neuroendocrine mechanisms. Different strategies that are aimed at sensitizing metastases to cancer therapy by depleting metastatic cell GSH are analyzed. PMID- 26754152 TI - WITHDRAWN: Molecular classification of colorectal cancer: Current perspectives and controversies. AB - This article has been withdrawn at the request of the editor. The authors have plagiarized part of a paper that had already appeared in ASCO EDUCATIONAL BOOK (2014), 91-99 (http://meetinglibrary.asco.org/content/114000091-144). One of the conditions of submission of a paper for publication is that authors declare explicitly that their work is original and has not appeared in a publication elsewhere. Re-use of any data should be appropriately cited. As such this article represents an abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). PMID- 26754153 TI - Prolonged Survival of Transplanted Osteoblastic Cells Does Not Directly Accelerate the Healing of Calvarial Bone Defects. AB - Considering the increased interest in cell-based bone regeneration, it is necessary to reveal the fate of transplanted cells and their substantive roles in bone regeneration. The aim of this study was to analyze the fate of transplanted cells and the effect of osteogenic cell transplantation on calvarial bone defect healing. An anti-apoptotic protein, heat shock protein (HSP) 27, was overexpressed in osteoblasts. Then, the treated osteoblasts were transplanted to calvarial bone defect and their fate was analyzed to evaluate the significance of transplanted cell survival. Transient overexpression of Hsp27 rescued MC3T3-E1 osteoblastic cells from H2 O2 -induced apoptosis without affecting osteoblastic differentiation in culture. Transplantation of Hsp27-overexpressing cells, encapsulated in collagen gel, showed higher proliferative activity, and fewer apoptotic cells in comparison with control cells. After 4-week of transplantation, both control cell- and Hsp27 overexpressed cell-transplanted groups showed significantly higher new bone formation in comparison with cell free gel-transplantation group. Interestingly, the prolonged survival of transplanted osteoblastic cells by Hsp27 did not provide additional effect on bone healing. The transplanted cells in collagen gel survived for up to 4-week but did not differentiate into bone-forming osteoblasts. In conclusion, cell containing collagen gel accelerated calvarial bone defect healing in comparison with cell-free collagen gel. However, prolonged survival of transplanted cells by Hsp27 overexpression did not provide additional effect. These results strongly indicate that cell transplantation-based bone regeneration cannot be explained only by the increment of osteogenic cells. Further studies are needed to elucidate the practical roles of transplanted cells that will potentiate successful bone regeneration. J. Cell. Physiol. 231: 1974-1982, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26754154 TI - Characterization of two Austrian porcine reproductive and respiratory syndrome virus (PRRSV) field isolates reveals relationship to East Asian strains. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) causes major problems for the swine industry worldwide. Due to Austria's central location in Europe, a large number of animals are transported through the country. However, little is known about current PRRSV strains and epidemiology. We determined full-length genome sequences of two Austrian field isolates (AUT13-883 and AUT14-440) from recent PRRSV outbreaks and of a related German isolate (GER09-613). Phylogenetic analysis revealed that the strains belong to European genotype 1 subtype 1 and form a cluster together with a South Korean strain. Remarkably, AUT14-440 infected the simian cell line MARC-145 without prior adaptation. In addition, this isolate showed exceptional deletions in nonstructural protein 2, in the overlapping region of glycoprotein 3 and 4 and in the 3' untranslated region. Both Austrian isolates caused similar lung lesions but only pigs infected with AUT14-440 developed clear clinical signs of infection. Taken together, the genetic and biological characterization of two novel Austrian PRRSV field isolates revealed similarities to East Asian strains. This stresses the necessity for a more detailed analysis of current PRRSV strains in Europe beyond the determination of short ORF5 and ORF7 sequences. PMID- 26754156 TI - Reader reaction: Instrumental variable additive hazards models with exposure dependent censoring. AB - Li, Fine, and Brookhart (2015) presented an extension of the two-stage least squares (2SLS) method for additive hazards models which requires an assumption that the censoring distribution is unrelated to the endogenous exposure variable. We present another extension of 2SLS that can address this limitation. PMID- 26754155 TI - Estimating mother-to-child HIV transmission rates in Cameroon in 2011: a computer simulation approach. AB - BACKGROUND: Despite the progress in the Prevention of the Mother-to-Child Transmission of HIV (PMTCT), the paediatric HIV epidemic remains worrying in Cameroon. HIV prevalence rate for the population of pregnant women was 7.6% in 2010 in Cameroon. The extent of the paediatric HIV epidemic is needed to inform policymakers. We developed a stochastic simulation model to estimate the number of new paediatric HIV infections through MTCT based on the observed uptake of services during the different steps of the PMTCT cascade in Cameroon in 2011. Different levels of PMTCT uptake was also assessed. METHODS: A discrete events computer simulation-based approach with stochastic structure was proposed to generate a cohort of pregnant women followed-up until 6 weeks post-partum, and optionally until complete breastfeeding cessation in both prevalent and incident lactating HIV-infected women. The different parameters of the simulation model were fixed using data sources available from the 2011 national registry surveys, and from external cohorts in Cameroon. Different PMTCT coverages were simulated to assess their impact on MTCT. Available data show a low coverage of PMTCT services in Cameroon in 2011. RESULTS: Based on a simulation approach on a population of 995, 533 pregnant women, the overall residual MTCT rate in 2011 was estimated to be 22.1% (95 % CI: 18.6%-25.2%), the 6-week perinatal MTCT rate among prevalent HIV-infected mothers at delivery is estimated at 12.1% (95% CI: 8.1%-15.1%), with an additional postnatal MTCT rate estimated at 13.3% (95% CI: 9.3%-17.8%). The MTCT rate among children whose mothers seroconverted during breastfeeding was estimated at 20.8% (95% CI: 14.1%-26.9%). Overall, we estimated the number of new HIV infections in children in Cameroon to be 10, 403 (95% CI: 9, 054-13, 345) in 2011. When PMTCT uptake have been fixed at 100%, 90% and 80%, global MTCT rate failed to 0.9% (9% CI: 0.5%-1.7%), 2.0% (95% CI: 0.9%-3.2%) and 4.3% (95% CI: 2.4%-6.7%) respectively. CONCLUSIONS: This model is helpful to provide MTCT estimates to guide the national HIV policy in Cameroon. Increasing supply and uptake of PMTCT services among prevalent HIV infected pregnant women, as well as HIV-prevention interventions including the offer and acceptance of HIV testing and counselling in lactating women could reduce significantly the residual HIV MTCT in Cameroon. A public health effort should be made to encourage health care workers and pregnant women to use PMTCT services until complete breastfeeding cessation. PMID- 26754157 TI - Sexual Orientation and Behavior of Adult Jews in Israel and the Association With Risk Behavior. AB - Estimating the size of key risk groups susceptible to HIV/sexually transmitted diseases (STI) is necessary for establishment of interventions and budget allocation. This study aimed to identify various dimensions of sexual orientation and practices in Israel, and correlate the findings with sexual risk behavior (SRB). It used a random representative sample of the Jewish population aged 18-44 years who completed online questionnaires regarding their self-identified sexual orientation, attraction and practices, and SRB. Concordant heterosexuals were those who self-reported heterosexual identity, were attracted and had sex only with the opposite gender. National estimates regarding prevalence of gay, lesbian, and bisexual men and women were based on the civil census. The sample included 997 men and 1005 women, of whom 11.3 and 15.2 % were attracted to the same-gender, 10.2 and 8.7 % reported lifetime same-gender encounters, while 8.2 and 4.8 % self-identified as gay or bisexual men and lesbian or bisexual women, respectively. The estimated population of self-identified Jewish gay or bisexual men and lesbian or bisexual women aged 18-44 in Israel was 94,176, and 57,671, respectively. SRB was more common among self-identified gays or bisexual men and among discordant heterosexual men and women. Those who reported same-gender sexual practices reported greater SRB than those who only had opposite-gender encounters. Interestingly, SRB among discordant heterosexuals was associated with same-sex behavior rather than attraction. Health practitioners should increase their awareness of sexual diversity among their clientele, and should recognize that risk for HIV/STI may exist among self-identified heterosexuals, who may not disclose their actual sexual attraction or practices. PMID- 26754159 TI - High-flow nasal cannula therapy: An un-tapped resource? PMID- 26754158 TI - Paraphilic Sexual Interests and Sexually Coercive Behavior: A Population-Based Twin Study. AB - Prior research with selected clinical and forensic samples suggests associations between paraphilic sexual interests (e.g., exhibitionism and sexual sadism) and sexually coercive behavior. However, no study to date used a large, representative and genetically informative population sample to address the potential causal nature of this association. We used self-report data on paraphilic and sexually coercive behavior from 5990 18- to 32-year-old male and female twins from a contemporary Finnish population cohort. Logistic regression and co-twin control models were employed to examine if paraphilic behaviors were causally related to coercive behavior or if suggested links were confounded by familial (genetic or common family environment) risk factors. Results indicated that associations between four out of five tested paraphilic behaviors (exhibitionism, masochism, sadism, and voyeurism, respectively) and sexually coercive behavior were moderate to strong. Transvestic fetishism was not independently associated with sexual coercion. Comparisons of twins reporting paraphilic behavior with their paraphilic behavior-discordant twin further suggested that associations were largely independent of shared genetic and environmental confounds, consistent with a causal association. In conclusion, similar to previously reported predictive effects of paraphilias on sexual crime recidivism, paraphilic behavior among young adults in the general population increases sexual offending risk. Further, early identification of paraphilic interest and preventive interventions with at-risk individuals might also reduce perpetration of first-time sexual violence. PMID- 26754160 TI - Should hepatic dysplastic nodules and regenerative nodules be regarded as premalignant lesions and treated? PMID- 26754161 TI - The H-index of a network node and its relation to degree and coreness. AB - Identifying influential nodes in dynamical processes is crucial in understanding network structure and function. Degree, H-index and coreness are widely used metrics, but previously treated as unrelated. Here we show their relation by constructing an operator , in terms of which degree, H-index and coreness are the initial, intermediate and steady states of the sequences, respectively. We obtain a family of H-indices that can be used to measure a node's importance. We also prove that the convergence to coreness can be guaranteed even under an asynchronous updating process, allowing a decentralized local method of calculating a node's coreness in large-scale evolving networks. Numerical analyses of the susceptible-infected-removed spreading dynamics on disparate real networks suggest that the H-index is a good tradeoff that in many cases can better quantify node influence than either degree or coreness. PMID- 26754162 TI - Association of longevity with TNF-alpha G308A and IL-6 G174C polymorphic inflammatory biomarkers in Caucasians: a meta-analysis. AB - BACKGROUND: Mutations in genes encoding tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were previously shown to affect mortality. Single nucleotide polymorphisms (SNPs) in the functional promoter regions of TNF-alpha (G308A) and IL-6 (G174C) are among the most widely studied. OBJECTIVES: To determine whether TNF-alpha G308A and IL-6 G174C SNPs confer susceptibility to longevity, we performed a meta-analysis to comprehensively estimate the association between these SNPs and longevity in long-lived individuals (LLI, aged >= 80 years). MATERIALS AND METHODS: Studies addressing the role of TNF-alpha and IL-6 SNPs in longevity were identified from the PubMed database. Pooled ORs with 95 % confidence intervals (CIs) were used to assess the association between SNPs and longevity. RESULTS: The meta-analysis was based on four studies of TNF-alpha G308A and nine of IL-6 G174C, covering a total of 2945 LLI individuals and 2992 controls. Overall, no significantly increased risks were observed for G308A [A vs. G (additive model): OR = 0.98, 95 % CI = 0.79-1.22, p = 0.852; AA + AG vs. GG (dominant model): OR = 0.97, 95 % CI = 0.75-1.24, p = 0.791] or for G174C [C vs. G (additive model): OR = 1.07, 95 % CI = 0.94-1.22, p = 0.293; CC + CG vs. GG (dominant model): OR = 1.09, 95 % CI = 0.93-1.28, p = 0.299]. There was no change in the significance when a cutoff age of >= 90 years was introduced. CONCLUSIONS: We found no evidence that the TNF-alpha G308A and IL-6 G174C SNPs affected the probability of reaching an advanced age in Caucasians, and that they have little effect on delaying the onset and progression of age-related diseases, but this does not rule out the possibility of population-specific effects caused by different genes and/or environmental factors and their interactions. PMID- 26754163 TI - [Volunteer work and potential volunteer work among 55 to 70-year-olds in Germany]. AB - BACKGROUND: The aim of this article is to describe the potential with respect to volunteer work among 55 to 70-year-old persons along with a two-dimensional typology (actual volunteer work and intention of volunteering or expanding actual volunteer work) and to identify the influencing factors. MATERIAL AND METHODS: Based on the dataset from the transitions and old age potential (TOP) study, a total of 4421 men and women born between 1942 and 1958 were included. A multinomial regression model showed the predictors for group affiliation along with an engagement-related typology (internal, utilized and external volunteer potential as well as definite non-volunteers). RESULTS: More than a half of the persons in the study sample could be classified as internal or external volunteer potential. Volunteers and potential volunteers revealed more similarities regarding resources and social factors than potential volunteers and definite non volunteers. Potential volunteers were more active in other informal fields of activity (e.g. nursing or child care) than definite non-volunteers. CONCLUSION: With respect to volunteer work, definite non-volunteers showed various social disadvantages (in particular with respect to education and health) compared to (potential) volunteers. Other informal activities did not seem to be in major conflict with volunteer activities, e.g. nursing or child care, as long as they were carried out with moderate or low intensity. PMID- 26754164 TI - Comparison of methods for the fabrication and the characterization of polymer self-assemblies: what are the important parameters? AB - The ability to self-assemble was evaluated for a large variety of amphiphilic block copolymers, including poly(ethyleneoxide-b-epsilon-caprolactone), poly(ethyleneoxide-b-d,l-lactide), poly(ethyleneoxide-b-styrene), poly(ethyleneoxide-b-butadiene) and poly(ethyleneoxide-b-methylmethacrylate). Different methods of formation are discussed, such as cosolvent addition, film hydration or electroformation. The influence of experimental parameters and macromolecular structures on the size and morphology of the final self-assembled structures is investigated and critically compared with the literature. The same process is carried out regarding the characterization of these structures. This analysis demonstrates the great care that should be taken when dealing with such polymeric assemblies. If the morphology of such assemblies can be predicted to some extent by macromolecular parameters like the hydrophilic/hydrophobic balance, those parameters cannot be considered as universal. In addition, external experimental parameters (methods of preparation, use of co-solvent, ...) appeared as critical key parameters to obtain a good control over the final structure of such objects, which are very often not at thermodynamic equilibrium but kinetically frozen. A principal component analysis is also proposed, in order to examine the important parameters for forming the self-assemblies. Here again, the hydrophilic/hydrophobic fraction is identified as an important parameter. PMID- 26754165 TI - Controllable Mismatched Ligation for Bioluminescence Screening of Known and Unknown Mutations. AB - Single-nucleotide polymorphisms (SNPs) are closely related to human diseases and individual drug responses, and the accurate detection of SNPs is crucial to both clinical diagnosis and development of personalized medicine. Among various SNPs detection methods, ligase detection reaction (LDR) has shown great potential due to its low detection limit and excellent specificity. However, frequent involvement of expensive labels increases the experimental cost and compromises the assay efficiency, and the requirement of careful predesigned probes limits it to only known SNPs assays. In this research, we develop a controllable mismatched ligation for bioluminescence screening of both known and unknown mutations. Especially, the ligation specificity of E. coli ligase is tunable under different experimental conditions. The mismatches locating on the 3'-side of the nick cannot be ligated efficiently by E. coli ligase, whereas all mismatches locating on the 5'-side of the nick can be ligated efficiently by E. coli ligase. We design a 3'-discriminating probe (3'-probe) for the discrimination of known mutation and introduce a T7 Endo I for the detection of unknown mutation. With the integration of bioluminescence monitoring of ligation byproduct adenosine 5' monophosphate (AMP), both known and unknown SNPs can be easily detected without the involvement of any expensive labels and labor-intensive separation. This method is simple, homogeneous, label-free, and cost-effective and may provide a valuable complement to current sequencing technologies for disease diagnostics, personalized medicine, and biomedical research. PMID- 26754166 TI - DNA duplication is essential for the repair of gastrointestinal perforation in the insect midgut. AB - Invertebrate animals have the capacity of repairing wounds in the skin and gut via different mechanisms. Gastrointestinal perforation, a hole in the human gastrointestinal system, is a serious condition, and surgery is necessary to repair the perforation to prevent an abdominal abscess or sepsis. Here we report the repair of gastrointestinal perforation made by a needle-puncture wound in the silkworm larval midgut. Following insect gut perforation, only a weak immune response was observed because the growth of Escherichia coli alone was partially inhibited by plasma collected at 6 h after needle puncture of the larval midgut. However, circulating hemocytes did aggregate over the needle-puncture wound to form a scab. While, cell division and apoptosis were not observed at the wound site, the needle puncture significantly enhanced DNA duplication in cells surrounding the wound, which was essential to repair the midgut perforation. Due to the repair capacity and limited immune response caused by needle puncture to the midgut, this approach was successfully used for the injection of small compounds (ethanol in this study) into the insect midgut. Consequently, this needle-puncture wounding of the insect gut can be developed for screening compounds for use as gut chemotherapeutics in the future. PMID- 26754167 TI - Triggering the decision to undergo medical male circumcision: a qualitative study of adult men in Botswana. AB - In 2007, the World Health Organization endorsed voluntary medical male circumcision (VMMC) as part of comprehensive HIV-prevention strategies. A major challenge facing VMMC programs in sub-Saharan Africa remains demand creation; there is urgent need for data on key elements needed to trigger the decision among eligible men to seek VMMC. Using qualitative methods, we sought to better understand the circumcision decision-making process in Botswana related to VMMC. From July to November 2013, we conducted 27 focus group discussions in four purposively selected communities in Botswana with men (stratified by circumcision status and age), women (stratified by age) and community leaders. All discussions were facilitated by a trained same-sex interviewer, audio recorded, transcribed and translated to English, and analyzed for key themes using an inductive content analytic approach. Improved hygiene was frequently cited as a major benefit of circumcision and many participants believed that cleanliness was directly responsible for the protective effect of VMMC on HIV infection. While protection against HIV was frequently noted as a benefit of VMMC, the data indicate that increased sexual pleasure and perceived attractiveness, not fear of HIV infection, was an underlying reason why men sought VMMC. Data from this qualitative study suggest that more immediate benefits of VMMC, such as improved hygiene and sexual pleasure, play a larger role in the circumcision decision compared with protection from potential HIV infection. These findings have immediate implications for targeted demand creation and mobilization activities for increasing uptake of VMMC among adult men in Botswana. PMID- 26754168 TI - Local and regional variability in snow conditions in northern Finland: A reindeer herding perspective. AB - Weather station measurements were used to force the SNOWPACK snow model and combined with reindeer herders' experiences to study the local and regional variations in snow conditions in a Finnish reindeer herding area for the 1981 2010 period. Winter conditions varied significantly between the four selected herding districts and between open and forest environments within the districts. The highest snow depths and densities, the thicknesses of ground ice, and the lengths of snow cover period were generally found in the northernmost districts. The snow depths showed the strongest regional coherence, whereas the thicknesses of ground ice were weakly correlated among the districts. The local variation in snow depths was higher than the regional variation and limits for rare or exceptional events varied notably between different districts and environments. The results highlight that forests diversify snow and foraging conditions, e.g., ground ice rarely forms simultaneously in different environments. Sufficient and diverse forest pastures are important during the critical winter season if reindeer herding is pursued on natural grazing grounds also in the future. PMID- 26754169 TI - On the decline of ground lichen forests in the Swedish boreal landscape: Implications for reindeer husbandry and sustainable forest management. AB - Lichens are a bottleneck resource for circumpolar populations of reindeer, and as such, for reindeer husbandry as an indigenous Sami land-use tradition in northern Sweden. This study uses ground lichen data and forest information collected within the Swedish National Forest Inventory since 1953, on the scale of northern Sweden. We found a 71 % decline in the area of lichen-abundant forests over the last 60 years. A decline was observed in all regions and age classes and especially coincided with a decrease of >60 year old, open pine forests, which was the primary explanatory factor in our model. The effects of reindeer numbers were inconclusive in explaining the decrease in lichen-abundant forest. The role that forestry has played in causing this decline can be debated, but forestry can have a significant role in reversing the trend and improving ground lichen conditions. PMID- 26754170 TI - The influence of heart failure co-morbidity on high-sensitivity troponin T levels in COPD exacerbation in a prospective cohort study: data from the Akershus cardiac examination (ACE) 2 study. AB - CONTEXT: Troponin (hs-TnT) levels predict mortality after acute exacerbation of COPD (AECOPD). Whether this is independent of heart failure (HF) is not established. MATERIAL AND METHODS: Prospectively included AECOPD patients adjudicated for acute HF categorized into three groups: (A) AECOPD, but acute HF the primary cause for hospitalization; (B) AECOPD the primary cause, but co existing myocardial dysfunction and (C) AECOPD without myocardial dysfunction. RESULTS: About 103 AECOPD patients; 18% A, 27% B and 54% C. Hs-TnT level differed between the groups: (ng/l, median) A: 41, B: 25 and C: 15, p = 0.03 for A versus B and p = 0.005 for B versus C. During a median 826 days, 47% died. In Cox analysis, hs-TnT levels remained associated with mortality (hazard ratio per 10 ng/l 1.3, p < 0.0001). CONCLUSION: hs-TnT levels are influenced by myocardial dysfunction/HF in AECOPD, but provide independent prognostic information. The prognostic merit of hs-TnT cannot be attributed to HF alone. PMID- 26754171 TI - Chytrids dominate arctic marine fungal communities. AB - Climate change is altering Arctic ecosystem structure by changing weather patterns and reducing sea ice coverage. These changes are increasing light penetration into the Arctic Ocean that are forecasted to increase primary production; however, increased light can also induce photoinhibition and cause physiological stress in algae and phytoplankton that can favour disease development. Fungi are voracious parasites in many ecosystems that can modulate the flow of carbon through food webs, yet are poorly characterized in the marine environment. We provide the first data from any marine ecosystem in which fungi in the Chytridiomycota dominate fungal communities and are linked in their occurrence to light intensities and algal stress. Increased light penetration stresses ice algae and elevates disease incidence under reduced snow cover. Our results show that chytrids dominate Arctic marine fungal communities and have the potential to rapidly change primary production patterns with increased light penetration. PMID- 26754173 TI - Reduced T-Cell Thymic Export Reflected by sj-TREC in Patients with Coronary Artery Disease. AB - AIM: Immunologic dysfunction was recently found to be one of the most important mechanisms underlying the initiation and development of atherosclerosis. Thymus involution can contribute to immune disturbance and disequilibrium of T-cell subsets. This study aimed to explore whether recent thymic emigration (RTE) is impaired in patients with coronary artery disease (CAD). METHODS: Content of signal-joint T cell receptor excision circles (sj-TREC) in T lymphocytes, a molecular marker of RTE, was assessed among CAD patients and age-matched controls. Monochrome multiplex quantitative PCR method was used to assess the samples' telomere length in order to exclude the potential influence of T cell proliferation on the dilution of sj-TREC. Patients were grouped according to Gensini score (GS) (low, GS <18; intermediate, GS 18-41; high, GS >41). Ordinary logistic regression models were used to determine potential risk factors for CAD and GS tertiles. RESULTS: Average copy numbers of sj-TREC per 10(6) T lymphocytes among patients with unstable angina, stable angina, and controls were 726+/-429, 1213+/-465, and 1795+/-838, respectively (P<0.001). However, there was no significant difference in telomere length among groups. Moreover, the content of sj-TREC in the high GS group was most significantly reduced than the low GS group (P<0.001). Multivariate logistic regression analysis revealed that lower sj-TREC was independently associated with the progression of CAD (OR=0.44, P<0.001) and higher GS (OR=0.4, P<0.001). CONCLUSION: Impaired RTE could be partly responsible for CAD development. Mechanisms may be involved in the disturbance of T lymphocyte compartment and interruption of maintained immune tolerance resulting from thymus involution. PMID- 26754172 TI - Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer's disease. AB - BACKGROUND: The discovery that heterozygous missense mutations in the gene encoding triggering receptor expressed on myeloid cells 2 (TREM2) are risk factors for Alzheimer's disease (AD), with only the apolipoprotein E (APOE) epsilon4 gene allele conferring a higher risk, has led to increased interest in immune biology in the brain. TREM2 is expressed on microglia, the resident immune cells of the brain and has been linked to phagocytotic clearance of amyloid beta (Abeta) plaques. Soluble TREM2 (sTREM2) has previously been measured in cerebrospinal fluid (CSF) by ELISA but in our hands commercial kits have proved unreliable, suggesting that other methods may be required. We developed a mass spectrometry method using selected reaction monitoring for the presence of a TREM2 peptide, which can be used to quantify levels of sTREM2 in CSF. FINDINGS: We examined CSF samples from memory clinics in Sweden and the UK. For all samples the following were available: clinical diagnosis, age, sex, and measurements of the CSF AD biomarkers Abeta42, T-tau and P-tau181. AD patients (n = 37) all met biomarker (IWG2) criteria for AD. Control individuals (n = 22) were cognitively normal without evidence for AD in CSF. We found significantly higher sTREM2 concentration in AD compared to control CSF. There were significant correlations between CSF sTREM2 and T-tau as well as P-tau181. CSF sTREM2 increase in AD was replicated in a second, independent cohort consisting of 24 AD patients and 16 healthy volunteers. CONCLUSION: CSF concentrations of sTREM2 are higher in AD than in controls, and correlate with markers of neurodegeneration. CSF sTREM2 may be used to quantify glial activation in AD. PMID- 26754174 TI - Qualitative study of barriers to cervical cancer screening among Nigerian women. AB - OBJECTIVES: To explore the barriers to cervical cancer screening, focusing on religious and cultural factors, in order to inform group-specific interventions that may improve uptake of cervical cancer screening programmes. DESIGN: We conducted four focus group discussions among Muslim and Christian women in Nigeria. SETTING: Discussions were conducted in two hospitals, one in the South West and the other in the North Central region of Nigeria. PARTICIPANTS: 27 Christian and 22 Muslim women over the age of 18, with no diagnosis of cancer. RESULTS: Most participants in the focus group discussions had heard about cervical cancer except Muslim women in the South Western region who had never heard about cervical cancer. Participants believed that wizardry, multiple sexual partners and inserting herbs into the vagina cause cervical cancer. Only one participant knew about the human papillomavirus. Among the Christian women, the majority of respondents had heard about cervical cancer screening and believed that it could be used to prevent cervical cancer. Participants mentioned religious and cultural obligations of modesty, gender of healthcare providers, fear of disclosure of results, fear of nosocomial infections, lack of awareness, discrimination at hospitals, and need for spousal approval as barriers to uptake of screening. These barriers varied by religion across the geographical regions. CONCLUSIONS: Barriers to cervical cancer screening vary by religious affiliations. Interventions to increase cervical cancer awareness and screening uptake in multicultural and multireligious communities need to take into consideration the varying cultural and religious beliefs in order to design and implement effective cervical cancer screening intervention programmes. PMID- 26754176 TI - Cellulitis: Home Or Inpatient in Children from the Emergency Department (CHOICE): protocol for a randomised controlled trial. AB - INTRODUCTION: Children needing intravenous antibiotics for cellulitis are usually admitted to hospital, whereas adults commonly receive intravenous treatment at home. This is a randomised controlled trial (RCT) of intravenous antibiotic treatment of cellulitis in children comparing administration of ceftriaxone at home with standard care of flucloxacillin in hospital. The study aims to compare (1) the rate of treatment failure at home versus hospital (2) the safety of treatment at home versus hospital; and (3) the effect of exposure to short course ceftriaxone versus flucloxacillin on nasal and gut micro-organism resistance patterns and the clinical implications. METHODS AND ANALYSIS: INCLUSION CRITERIA: children aged 6 months to <18 years with uncomplicated moderate/severe cellulitis, requiring intravenous antibiotics. EXCLUSIONS: complicated cellulitis (eg, orbital, foreign body) and immunosuppressed or toxic patients. The study is a single-centre, open-label, non-inferiority RCT. It is set in the emergency department (ED) at the Royal Children's Hospital (RCH) in Melbourne, Australia and the Hospital-in-the-Home (HITH) programme; a home-care programme, which provides outreach from RCH. Recruitment will occur in ED from January 2015 to December 2016. Participants will be randomised to either treatment in hospital, or transfer home under the HITH programme. The calculated sample size is 188 patients (94 per group) and data will be analysed by intention-to-treat. PRIMARY OUTCOME: treatment failure defined as a change in treatment due to lack of clinical improvement according to the treating physician or adverse events, within 48 h SECONDARY OUTCOMES: readmission to hospital, representation, adverse events, length of stay, microbiological results, development of resistance, cost effectiveness, patient/parent satisfaction. This study has started recruitment. ETHICS AND DISSEMINATION: This study has been approved by the Human Research Ethics Committee of the RCH Melbourne (34254C) and registered with the ClinicalTrials.gov registry (NCT02334124). We aim to disseminate the findings through international peer-reviewed journals and conferences. CLINICAL TRIAL: Pre results. PMID- 26754175 TI - Using qualitative insights to change practice: exploring the culture of antibiotic prescribing and consumption for urinary tract infections. AB - OBJECTIVES: The aim of this paper is to explore the culture of antibiotic prescribing and consumption in the community for urinary tract infections (UTI) from the perspective of the general practitioners (GPs) and community member. DESIGN: Indepth interviews were conducted with GPs, and focus groups were held with community members. SETTING: General practice and community setting. PARTICIPANTS: 15 GPs practising in rural and urban locations in Ireland participated in the indepth interviews. 6 focus groups (n=42) with participants who had direct or indirect experiences with UTI were also undertaken. RESULTS: The decision to prescribe or consume an antibiotic for a UTI is a set of complex processes including need recognition, information search and evaluation processes governed by the relationship and interactions between the GP and the patient. Different GP and patient decision-making profiles emerged emphasising the diversity and variety of general practice in real-life settings. The GP findings showed a requirement for more microbiological information on antibiotic resistance patterns to inform prescribing decisions. Focus group participants wanted a conversation with the GP about their illness and the treatment options available. CONCLUSIONS: Collectively, this research identified the consultation as a priority intervention environment for stimulating change in relation to antibiotics. This paper demonstrates how qualitative research can identify the interacting processes which are instrumental to the decision to prescribe or consume an antibiotic for a suspected UTI. Qualitative research empowers researchers to investigate the what, how and why of interventions in real-life setting. Qualitative research can play a critical and instrumental role in designing behavioural change strategies with high impact on practice. The results of this research were used to design a complex intervention informed by social marketing. TRIAL REGISTRATION NUMBER: NCT01913860; Pre-results. PMID- 26754177 TI - Exogenous avian leukosis virus-induced activation of the ERK/AP1 pathway is required for virus replication and correlates with virus-induced tumorigenesis. AB - A proteomics approach was used to reveal the up-regulated proteins involved in the targeted mitogen-activated protein kinase (MAPK) signal transduction pathway in DF-1 cells after ALV subgroup J (ALV-J) infection. Next, we found that ALV-J CHN06 strain infection of DF-1 cells correlated with extracellular signal regulated kinase 2 (ERK2) activation, which was mainly induced within 15 min, a very early stage of infection, and at a late infection stage, from 108 h to 132 h post-infection. Infection with other ALV subgroup (A/B) strains also triggered ERK/MAPK activation. Moreover, when activating ERK2, ALV subgroups A, B and J simultaneously induced the phosphorylation of c-Jun, an AP1 family member and p38 activation but had no obvious effect on JNK activation at either 15 min or 120 h. Interestingly, only PD98059 inhibited the ALV-induced c-Jun phosphorylation while SP600125 or SB203580 had no influence on c-Jun activation. Furthermore, the viral gp85 and gag proteins were found to contribute to ERK2/AP1 activation. Additionally, the specific ERK inhibitor, PD980509, significantly suppressed ALV replication, as evidenced by extremely low levels of ALV promoter activity and ALV-J protein expression. In vivo analysis of ERK2 activation in tumor cells derived from ALV-J-infected chicken demonstrated a strong correlation between ERK/MAPK activation and virus-associated tumorigenesis. PMID- 26754179 TI - The efficacy of photon-initiated photoacoustic streaming and sonic-activated irrigation combined with QMiX solution or sodium hypochlorite against intracanal E. faecalis biofilm. AB - The aim of the study was to assess the antibacterial efficacy of photon-initiated photoacoustic streaming (PIPS) using an Er:YAG laser and sonic-activated irrigation combined with QMiX irrigant or sodium hypochlorite against Enterococcus faecalis intracanal biofilm. Root canals of 91 human extracted single-canal teeth were instrumented, sterilized, contaminated with E. faecalis and incubated for 15 days. The infected teeth were then randomly distributed into six experimental groups: G1: PIPS/Er:YAG laser (wavelength 2940 nm, pulse energy 20 mJ, 15 Hz, pulse duration 50 MUs, energy density 2.06 J/cm(2), 3 * 20 s) with the QMiX irrigant; G2: PIPS/Er:YAG laser-activated 2.5 % NaOCl; G3 sonic activated irrigation (EndoActivator system) for 60 s with the QMiX irrigant; G4 sonic-activated irrigation for 60 s with 2.5 % NaOCl; G5 30-gauge needle irrigation with the QMiX irrigant; G6 30-gauge needle irrigation with 2.5 % NaOCl. The positive control group was rinsed with sterile saline solution. The root canals were sampled by flushing with saline solution at baseline and after the treatments, serially diluted and cultured. The number of bacteria in each canal was determined by plate count. The presence and the absence of E. faecalis in root canals were demonstrated by polymerase chain reaction (PCR), and the pattern of the bacteria colonization was visualized by scanning electron microscopy. There was significant reduction in the bacterial population for all groups (p < 0.001). The best antibacterial efficacy was recorded after sonic activated irrigation with both NaOCl (99.999 %) and QMiX (99.999 %) and after PIPS with QMiX (99.999 %), which were more effective than conventional irrigation with NaOCl (99.998 %) and the PIPS with the NaOCl (99.966 %). Also, the PIPS with QMiX solution provided the highest number of sterile samples (five). There was no difference in the bacteria reduction between the active irrigation techniques, regardless of the irrigant used. Although the laser activation did not improve the antimicrobial action of the NaOCl nor QMiX, the fact that it generated the greatest number of sterile samples warrants further investigation. PMID- 26754178 TI - Streptomycin treatment alters the intestinal microbiome, pulmonary T cell profile and airway hyperresponsiveness in a cystic fibrosis mouse model. AB - Cystic fibrosis transmembrane conductance regulator deficient mouse models develop phenotypes of relevance to clinical cystic fibrosis (CF) including airway hyperresponsiveness, small intestinal bacterial overgrowth and an altered intestinal microbiome. As dysbiosis of the intestinal microbiota has been recognized as an important contributor to many systemic diseases, herein we investigated whether altering the intestinal microbiome of BALB/c Cftr(tm1UNC) mice and wild-type littermates, through treatment with the antibiotic streptomycin, affects the CF lung, intestinal and bone disease. We demonstrate that streptomycin treatment reduced the intestinal bacterial overgrowth in Cftr(tm1UNC) mice and altered the intestinal microbiome similarly in Cftr(tm1UNC) and wild-type mice, principally by affecting Lactobacillus levels. Airway hyperresponsiveness of Cftr(tm1UNC) mice was ameliorated with streptomycin, and correlated with Lactobacillus abundance in the intestine. Additionally, streptomycin treated Cftr(tm1UNC) and wild-type mice displayed an increased percentage of pulmonary and mesenteric lymph node Th17, CD8 + IL-17+ and CD8 + IFNgamma+ lymphocytes, while the CF-specific increase in respiratory IL-17 producing gammadelta T cells was decreased in streptomycin treated Cftr(tm1UNC) mice. Bone disease and intestinal phenotypes were not affected by streptomycin treatment. The airway hyperresponsiveness and lymphocyte profile of BALB/c Cftr(tm1UNC) mice were affected by streptomycin treatment, revealing a potential intestinal microbiome influence on lung response in BALB/c Cftr(tm1UNC) mice. PMID- 26754180 TI - Lack of clinical evidence on low-level laser therapy (LLLT) on dental titanium implant: a systematic review. AB - Low-level laser therapy (LLLT) has proved to have biostimulating effects on tissues over which they are applied, therefore accelerating the healing process. Most studies in implantology were focused on a reduction of the duration of osseointegration. There exist few articles analyzing the potential effects of these therapies on the osseointegration of titanium dental implants. The aim of this study was to assess the effect of LLLT on the interaction between the bone and the titanium dental implant and the methodological quality of the studies. We conducted an electronic search in PubMed, ISI Web, and Cochrane Library. From 37 references obtained, only 14 articles met the inclusion criteria. The analysis of the studies shows that most of the experiments were performed in animals, which have a high risk of bias from the methodological point of view. Only two studies were conducted in human bone under different conditions. Several protocols for the use of low-power laser and different types of laser for all studies analyzed were used. Although animal studies have shown a positive effect on osseointegration of titanium implants, it can be concluded that it is necessary to improve and define a unique protocol to offer a more conclusive result by meta analysis. PMID- 26754182 TI - The use of low-level laser therapy for controlling the gag reflex in children during intraoral radiography. AB - The current literature suggests that low-level laser stimulation of the PC 6 acupuncture points may prevent gagging. This study aimed to determine if low level laser therapy (LLLT) can reduce the gag reflex in children undergoing intraoral maxillary radiography. This randomized, controlled, double-blind clinical trial was conducted with 25 children with moderate-to-very severe gag reflexes who required bilateral periapical radiographic examination of the maxillary molar region. Children's anxiety levels were initially evaluated using Corah's Dental Anxiety Scale (DAS) to identify any possible relationship between gagging and anxiety. A control radiograph was taken of one randomly selected side in each patient after simulated laser application so that the patient was blinded to the experimental conditions (control group). Laser stimulation was then performed for the experimental side. A laser probe was placed on the Pericardium 6 (PC 6) acupuncture point on each wrist, and laser energy was delivered for 14 s (300 mW, energy density 4 J/cm(2)) at a distance of 1 cm from the target tissue. Following laser stimulation, the experimental radiograph was taken (experimental group). Gagging responses were measured using the Gagging Severity Criteria for each group. Data were analyzed using Spearman's rho correlations and Mann-Whitney U tests. Both mean and median gagging scores were higher in the control group than in the experimental group. Patients who were unable to tolerate the intraoral control radiography were able to tolerate the procedure after LLLT. Differences between gagging scores of the control and experimental groups were statistically significant (P = .000). There was no significant correlation between gagging severity and anxiety score (P > .05). A negative correlation was found between age and gagging score in the control group (P ? .05). Within the limitations of this study, LLLT of the PC 6 acupuncture points appears to be a useful technique for controlling the gag reflex in children during maxillary radiography. PMID- 26754181 TI - Nonsurgical periodontal therapy with/without diode laser modulates metabolic control of type 2 diabetics with periodontitis: a randomized clinical trial. AB - In order to evaluate whether nonsurgical periodontal treatment with/without diode laser (DL) decontamination improves clinical parameters, the levels of IL-1beta, IL-6, IL-8, intercellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) in gingival crevicular fluid and metabolic control (HbA1c) in chronic periodontitis (CP) patients with diabetes mellitus type 2 (DM2). Sixty patients with DM2 and CP were randomly assigned into two groups to receive scaling and root planing (SRP, n = 30) or SRP followed by diode laser application (SRP + DL, n = 30). Clinical periodontal and gingival crevicular fluid (GCF) parameters were assessed at baseline, 1, and 3 months after periodontal treatment. HbA1c levels were evaluated at baseline and 3 months post-therapy. Total amounts of cytokines and molecules were analyzed by ELISA. Nonsurgical periodontal treatment with/without DL appeared to improve clinical, biochemical parameters, and glycemic control in DM2 patients (BMI < 25 kg/m(2)) with CP. The SRP + DL group provided better reductions in probing depth (PD) and clinical attachment level (CAL) parameters compared to the SRP group (P < 0.05). Significant reductions were found in the total amounts of GCF levels of IL-1, IL 6, IL-8, ICAM, and VCAM after treatment (P < 0.05). HbA1c levels decreased significantly at 3 months after treatment (P < 0.05). SRP + DL reduced HbA1c levels more significantly compared to SRP alone (0.41 vs. 0.22 %, P < 0.05). SRP, especially in combination with DL, shows improvement of glycemic control for DM2 patients with CP. PMID- 26754183 TI - Citrus-Peel-Derived, Nanoporous Carbon Nanosheets Containing Redox-Active Heteroatoms for Sodium-Ion Storage. AB - Advanced design of nanostructured functional carbon materials for use in sustainable energy storage systems suffers from complex fabrication procedures and the use of special methods and/or expensive precursors, limiting their practical applications. In this study, nanoporous carbon nanosheets (NP-CNSs) containing numerous redox-active heteroatoms (C/O and C/N ratios of 5.5 and 34.3, respectively) were fabricated from citrus peels by simply heating the peels in the presence of potassium ions. The NP-CNSs had a 2D-like morphology with a high aspect ratio of >100, high specific surface area of 1167 m(2) g(-1), and a large amount of nanopores between 1 and 5 nm. The NP-CNSs also had an electrical conductivity of 2.6 * 10(1) s cm(-1), which is approximately 50 times higher than that of reduced graphene oxide. These unique material properties resulted in superior electrochemical performance with a high specific capacity of 140 mAh g( 1) in the cathodic potential range. In addition, symmetric full-cell devices based on the NP-CNSs showed excellent cyclic performance over 100,000 repetitive cycles. PMID- 26754184 TI - Why misinformation is reported: evidence from a warning and a source-monitoring task. AB - People report suggested misinformation about a previously witnessed event for manifold reasons, such as social pressure, lack of memory of the original aspect, or a firm belief to remember the misinformation from the witnessed event. In our experiments (N = 429), which follow Loftus's paradigm, we tried to disentangle the reasons for reporting a central and a peripheral piece of misinformation in a recognition task by examining (a) the impact a warning about possible misinformation has on the error rate, and (b) whether once reported misinformation was actually attributed to the witnessed event in a later source monitoring (SM) task. Overall, a misinformation effect was found for both items. The warning strongly reduced the misinformation effect, but only for the central item. In contrast, reports of the peripheral misinformation were correctly attributed to the misinformation source or, at least, ascribed to guesswork much more often than the central ones. As a consequence, after the SM task, the initially higher error rate for the peripheral item was even lower than that of the central item. Results convincingly show that the reasons for reporting misinformation, and correspondingly also the potential to avoid them in legal settings, depend on the centrality of the misinformation. PMID- 26754185 TI - Erratum to: Outer membrane protein C (OmpC) of Escherichia coli induces neurodegeneration in mice by acting as an amyloid. PMID- 26754186 TI - Arrhythmia Secondary to Cold Water Submersion during Helicopter Underwater Escape Training. AB - A 32-year-old, fit and healthy, Caucasian male presented with a less than 24-hour history of palpitations with the onset following participation in helicopter underwater escape training (HUET). He reported no chest pain, shortness of breath, syncope, or pre-syncope symptoms. On examination, an irregularly irregular pulse was noted at a rate of 120 beats per minute with a blood pressure of 132/84. There was no evidence of congestive cardiac failure. The electrocardiogram (ECG) demonstrated atrial fibrillation at 97 beats per minute with a normal axis, normal QRS complexes, and a QTc of 399 ms. Bloods were all within normal limits and a chest x-ray showed no abnormality. The patient was loaded with amiodarone and reverted to sinus rhythm with a normal post-reversion ECG. Five years on, following further HUET, the patient presented with an identical presentation. His ECG showed fast atrial fibrillation at a rate of 115 beats per minute. On this occasion, he was sedated and Direct Current cardioverted with reversal to sinus rhythm after one shock. It was felt that the precipitating factor for this patient's atrial fibrillation, in both cases, was HUET. The case discussed describes a previously fit and well subject who developed a sustained arrhythmia secondary to cold water submersion. Evidence suggests water submersion can provoke cardiac arrhythmias via the suggested theory of "autonomic conflict." It has been proposed that a number of unexplained deaths related to water submersion may be secondary to arrhythmogenic syncope. PMID- 26754187 TI - Early predictive echocardiographic features of hemodynamically significant patent ductus arteriosus in preterm VLBW infants. AB - BACKGROUND: Patent ductus arteriosus (PDA) is associated with increased morbidity and mortality in very low-birthweight (VLBW) preterm infants due to significant left-to-right shunting, which leads to pulmonary edema/hemorrhage, intracranial hemorrhage, acute renal failure and necrotizing enterocolitis. In this prospective study, echocardiography was carried out in VLBW preterm infants soon after birth and at the end of 72 h to evaluate the relationship between early ductal anatomic features and significant ductal shunt during follow up. METHODS: Preterm infants with a gestational age <= 28 weeks, birthweight < 1000 g and who had ductal patency during the first 6-12 h of life underwent color Doppler echocardiograms through the first 3 days after birth. RESULTS: Fifty-eight patients were enrolled. The DA remained open in 42 preterm infants (72.4%) and was hemodynamically significant in 36 (62%) at the end of 72 h postnatal age. The preterm infants with hemodynamically significant PDA (hsPDA) had shorter ductal length from aortic to pulmonary insertion and from ductal constriction to pulmonary insertion in the initial exam. Cut-offs for these lengths were 5.2 and 1.7 mm, respectively. These parameters had significant univariate correlation with ductal closure time after treatment. CONCLUSIONS: Echocardiographic features such as short ductal length and short or absent ductal constriction area can be used to predict hsPDA for early decision making strategies in VLBW preterm infants. PMID- 26754189 TI - Urinary tract obstruction: NLRP3 inhibition prevents BOO. PMID- 26754188 TI - The use of national administrative data to describe the spatial distribution of in-hospital mortality following stroke in France, 2008-2011. AB - BACKGROUND: In the context of implementing the National Stroke Plan in France, a spatial approach was used to measure inequalities in this disease. Using the national PMSI-MCO databases, we analyzed the in-hospital prevalence of stroke and established a map of in-hospital mortality rates with regard to the socio demographic structure of the country. METHODS: The principal characteristics of patients identified according to ICD10 codes relative to stroke (in accordance with earlier validation work) were studied. A map of standardized mortality rates at the level of PMSI geographic codes was established. An exploratory analysis (principal component analysis followed by ascending hierarchical classification) using INSEE socio-economic data and mortality rates was also carried out to identify different area profiles. RESULTS: Between 2008 and 2011, the number of stroke patients increased by 3.85%, notably for ischemic stroke in the 36-55 years age group (60% of men). Over the same period, in-hospital mortality fell, and the map of standardized rates illustrated the diagonal of high mortality extending from the north-east to the south-west of the country. The most severely affected areas were also those with the least favorable socio-professional indicators. CONCLUSIONS: The PMSI-MCO database is a major source of data on the health status of the population. It can be used for the area-by-area observation of the performance of certain healthcare indicators, such as in-hospital mortality, or to follow the implementation of the National Stroke Plan. Our study showed the interplay between social and demographic factors and stroke-related in hospital mortality. The map derived from the results of the exploratory analysis illustrated a variety of areas where social difficulties, aging and high mortality seemed to meet. The study raises questions about access to neuro vascular care in isolated areas and in those in demographic decline. Telemedicine appears to be the solution favored by decision makers. The aging of the population managed for stroke must not mask the growing incidence in younger people, which raises questions about the development of classical (smoking, hypertension) or new (drug abuse) risk factors. PMID- 26754191 TI - Kidney cancer: Programmed death ligand 1 regulation in ccRCC. PMID- 26754192 TI - Sexual dysfunction in 2015: Recovering sex drive in women - progress and opportunities. PMID- 26754193 TI - Scapular and Shoulder Girdle Muscular Anatomy: Its Role in Periscapular Tendon Transfers. AB - The importance of coordinated, normal scapulothoracic motion in facilitating full, pain-free motion of the shoulder complex has been increasingly studied over the past decade, leading to renewed interest in scapular-based reconstructions to improve shoulder girdle motion through the use of muscle advancements and tendon transfers. This article will review recent advances regarding scapulothoracic motion and the muscular stabilizers of the scapula, focusing on clinical diagnosis and anatomy as it pertains to scapular dyskinesis and common periscapular tendon transfers. Although many of these treatment techniques remain in their infancy and further follow-up is necessary before universal adoption, they provide a novel means of addressing difficult-to-treat and complex shoulder girdle pathologies. PMID- 26754194 TI - Brachial Plexopathy Following Wrist Arthroscopy. PMID- 26754190 TI - Lower urinary tract symptoms, benign prostatic hyperplasia and metabolic syndrome. AB - Epidemiological studies have shown that age is the principal unmodifiable risk factor of lower urinary tract symptoms (LUTS). Until the past decade, the process of lower urinary tract ageing was, therefore, considered unmodifiable - as ageing per se. However, the traditional dogma that BPH-related LUTS (BPH-LUTS) is an immutable consequence of old age is no longer acceptable. Results from multiple preclinical and clinical studies indicate that several modifiable, age-related metabolic aberrations (metabolic syndrome, obesity, dyslipidaemia, diabetes) are important determinants in both the development and the progression of BPH-LUTS. Metabolic syndrome and its related comorbidities, such as sex steroid alterations and low-grade inflammation, have been related to BPH-LUTS development and progression. With the correct treatment and recommended lifestyle changes, many individuals with metabolic syndrome might be able to prevent or delay the onset of metabolic-syndrome-related complications; however, whether promoting healthier lifestyles can really alter a man's propensity to develop BPH-LUTS remains to be clarified. PMID- 26754195 TI - Online Patient Ratings: Why They Matter and What They Mean. AB - The increasing focus on patient satisfaction and consumer-driven health care, combined with the recent rise in online social media, have resulted in the growing trend of patients rating physicians on publicly accessible Web sites. The number and use of such Web sites continue to grow despite potential concerns about the validity of these ratings and negative physician perception. These Web sites can influence patient decision making regarding physician selection. In this article, we review the literature regarding the use of such Web sites by patients, the validity of these ratings, potential implications for hand surgical practice, and methods to minimize or challenge inaccurate reviews. PMID- 26754196 TI - Comparison Between an Empirically Derived and a Standard Classification of Amnestic Mild Cognitive Impairment From a Sample Of Adults With Subjective Cognitive Complaints. AB - OBJECTIVE: The aim of this study is to compare an empirically derived classification of amnestic mild cognitive impairment (aMCI) from a sample of adults with subjective cognitive complaints by using cluster analysis of their performance on the California Verbal Learning Test (CVLT) with a classification of aMCI based on standard clinical criteria. METHOD: Three hundred ninety-one individuals aged 48 years and older were diagnosed as aMCI or healthy controls. Cluster analysis of the CVLT performance was conducted, followed by logistic regression analysis. RESULTS: A two-cluster solution performed on the CVLT measures correctly classified 98.0% of the aMCI patients and 73.4% of the healthy controls diagnosed by using standard aMCI criteria. DISCUSSION: The empirically derived classification of aMCI is consistent with the classification based on standard criteria; however, standard criteria should also be considered to prevent false positives. PMID- 26754197 TI - Exploring Associations Between Perceived Measures of the Environment and Walking Among Brazilian Older Adults. AB - OBJECTIVE: To investigate the associations between perceived environment features and walking in older adults. METHOD: A cross-sectional population-based study was performed in Florianopolis, Brazil, including 1,705 older adults (60+ years). Walking was measured by the International Physical Activity Questionnaire (IPAQ), and perceived environment was assessed through the Neighborhood Environment Walkability Scale. We conducted a multinomial logistic regression to examine the association between perceived environment and walking. RESULTS: The presence of sidewalks was related to both walking for transportation and for leisure. Existence of crosswalks in the neighborhood, safety during the day, presence of street lighting, recreational facilities, and having dog were significant predictors of walking for transportation. Safety during the day and social support were significantly associated with walking for leisure. DISCUSSION: The perceived environment may affect walking for specific purposes among older adults. Investments in the environment may increase physical activity levels of older adults in Brazil. PMID- 26754198 TI - Output power enhancement from ZnO nanorods piezoelectric nanogenerators by Si microhole arrays. AB - We demonstrate the enhancement of output power from a ZnO nanorod (NR)-based piezoelectric nanogenerator by using Si microhole (Si-MUH) arrays. The depth controlled Si-MUH arrays were fabricated by using the deep reactive ion etching method. The ZnO NRs were grown along the Si-MUH surface, in holes deeper than 20 MUm. The polymer layer, polydimethylsiloxane, which acts a stress diffuser and electrical insulator, was successfully penetrated into the deep Si-MUH arrays. Optical investigations show that the crystalline quality of the ZnO NRs on the Si MUH arrays was not degraded, even though they were grown on the deeper Si-MUH arrays. As the depth of the Si-MUH arrays increase from 0 to 20 MUm, the output voltage was enhanced by around 8.1 times while the current did not increase. Finally, an output power enhancement of ten times was obtained. This enhancement of the output power was consistent with the increase in the surface area, and was mainly attributed to the accumulation of the potentials generated by the series connected ZnO NR-based nanogenerators, whose number increases as the depth of the Si-MUH increases. PMID- 26754201 TI - Dengue, chikungunya and Zika co-infection in a patient from Colombia. PMID- 26754199 TI - Cell wall proteome of sugarcane stems: comparison of a destructive and a non destructive extraction method showed differences in glycoside hydrolases and peroxidases. AB - BACKGROUND: Sugarcane has been used as the main crop for ethanol production for more than 40 years in Brazil. Recently, the production of bioethanol from bagasse and straw, also called second generation (2G) ethanol, became a reality with the first commercial plants started in the USA and Brazil. However, the industrial processes still need to be improved to generate a low cost fuel. One possibility is the remodeling of cell walls, by means of genetic improvement or transgenesis, in order to make the bagasse more accessible to hydrolytic enzymes. We aimed at characterizing the cell wall proteome of young sugarcane culms, to identify proteins involved in cell wall biogenesis. Proteins were extracted from the cell walls of 2-month-old culms using two protocols, non-destructive by vacuum infiltration vs destructive. The proteins were identified by mass spectrometry and bioinformatics. RESULTS: A predicted signal peptide was found in 84 different proteins, called cell wall proteins (CWPs). As expected, the non-destructive method showed a lower percentage of proteins predicted to be intracellular than the destructive one (33% vs 44%). About 19% of CWPs were identified with both methods, whilst the infiltration protocol could lead to the identification of 75% more CWPs. In both cases, the most populated protein functional classes were those of proteins related to lipid metabolism and oxido-reductases. Curiously, a single glycoside hydrolase (GH) was identified using the non-destructive method whereas 10 GHs were found with the destructive one. Quantitative data analysis allowed the identification of the most abundant proteins. CONCLUSIONS: The results highlighted the importance of using different protocols to extract proteins from cell walls to expand the coverage of the cell wall proteome. Ten GHs were indicated as possible targets for further studies in order to obtain cell walls less recalcitrant to deconstruction. Therefore, this work contributed to two goals: enlarge the coverage of the sugarcane cell wall proteome, and provide target proteins that could be used in future research to facilitate 2G ethanol production. PMID- 26754202 TI - Obesity in critically ill patients is associated with increased need of mechanical ventilation but not with mortality. AB - Worldwide incidence of obesity is increasing and impaired outcome in postoperative patients has been described. Antibiotic prescribing is complicated by different pharmacology in this population. This study evaluates mortality and morbidity of obese postoperative patients and explores possible relation to antibiotic therapy. Therefore, data obtained in a prospective study in 2009-2010 were analysed. Postoperative patients on 5 ICUs were included with >48h of ICU treatment and documented body-mass-index (BMI). Altogether 451 non-obese patients (BMI<30kg/m(2)) were compared with 130 obese patients including propensity score matching. There was significant heterogeneity of baseline characteristics. ICU mortality was 7.5% in non-obese and 7.7% in obese patients (p>0.999), but 65.4% of obese patients required mechanical ventilation compared with only 53.2% of non obese patients (p=0.016). These findings were validated in multivariate regression analyses (adjusted OR for ICU-mortality for obese patients 0.53, 95% CI 0.188-1.321, p=0.197; adjusted OR for mechanical ventilation 1.841, 95%-CI 1.113-3.076, p=0.018). Results were confirmed by propensity score matching. Therapeutic drug monitoring for vancomycin (TDM) showed that underdosing and overdosing occurred more often in obese patients and sufficient TDM levels were less often achieved. In conclusion, obesity is associated with increased morbidity but ICU mortality is equal compared with a non-obese population. Pharmacological differences might explain observed differences in antibiotic therapy and in obese patients TDM might be especially of importance. PMID- 26754204 TI - Correction to Antileishmanial Activity of a Series of N(2),N(4)-Disubstituted Quinazoline-2,4-diamines. PMID- 26754203 TI - Co-infection with Enterobius vermicularis and Taenia saginata mimicking acute appendicitis. AB - In this report, we describe an unusual case of verminous appendicitis due to Enterobius vermicularis and Taenia saginata in a 29-year-old woman from Iran. The histopathological examinations and parasitological descriptions of both worms found in the appendix lumen are discussed. The removed appendix exhibited the macroscopic and microscopic features of acute appendicitis. Antihelminthic therapy was initiated with single doses of praziquantel for the taeniasis and mebendazole for the enterobiasis, and the patient was discharged. PMID- 26754205 TI - HMB-45 negative angiomyolipoma of the orbit: a case report and review of the literature. AB - BACKGROUND: Angiomyolipoma is a benign mesenchymal tumor composed of variable amounts of smooth muscle, adipose tissue and thick-walled blood vessels, and usually named PEComas (perivascular epithelioid cell tumors). PEComas share overlapping histopathological features with epithelioid cells along a perivascular distribution and characteristic immunohistochemistry with coexpression of myoid and melanocytic markers (HMB-45 /or Melan-A). We report the first case of primary orbital angiomyolipoma with negative melanocytic marker. CASE PRESENTATION: An 80-year-old Asian woman had a 2-year history of progressive swelling in the left upper eyelid. External examination revealed 3 cm of relative proptosis of the left eye and a palpable mass in the left superonasal orbit. Computed tomographic scan demonstrated a circumscribed, heterogeneous orbital mass. Excision biopsy was done and the histological finding demonstrated the orbital mass was composed of mature adipocytes, intermingled with spindle or oval shaped cells, and accompanied by thick-walled blood vessels. Immunohistochemically, tumor cells were positive for CD34 and HHF-35, but negative for cytokeratin, HMB-45 and Melan-A. The diagnosis of angiomyolipoma was made. No recurrence was noted at 2-year follow-up. CONCLUSION: In our case, the HMB-45 negativity may be explained by the rarity of the epithelioid cells, and the HMB-45 positivity is often weaker or absent in spindle cells. Angiomyolipoma, although rare, should be added to the differential diagnosis of space-occupying orbital lesion. PMID- 26754207 TI - Acute Respiratory Distress: from syndrome to disease. AB - The acute respiratory distress syndrome (ARDS) is currently one of the most important critical entities given its high incidence, rate of mortality, long term sequelae and non-specific pharmacological treatment. The histological hallmark of ARDS is diffuse alveolar damage (DAD). Approximately 50% of ARDS patients present DAD, the rest is made up of a heterogeneous group of histological patterns, many of which correspond to a well-recognized disease. For that reason, if these patterns could be diagnosed, patients could benefit from a treatment. Recently, the effect of DAD in clinical and analytical evolution of ARDS has been demonstrated, so the classical approach to ARDS as an entity defined solely by clinical, radiological and gasometrical variables should be reconsidered. This narrative review aims to examine the need to evolve from the concept of ARDS as a syndrome to ARDS as a specific disease. So we have raised 4 critical questions: a) What is a disease?; b) what is DAD?; c) how is DAD considered according to ARDS definition?, and d) what is the relationship between ARDS and DAD? PMID- 26754206 TI - Career preferences of final year medical students at a medical school in Kenya--A cross sectional study. AB - BACKGROUND: The World Health Organization (WHO) recommended physician to population ratio is 23:10,000. Kenya has a physician to population ratio of 1.8:10,000 and is among 57 countries listed as having a serious shortage of health workers. Approximately 52% of physicians work in urban areas, 6% in rural and 42% in peri-urban locations. This study explored factors influencing the choice of career specialization and location for practice among final year medical students by gender. METHODS: A descriptive cross-sectional study was carried out on final year students in 2013 at the University of Nairobi's, School of Medicine in Kenya. Sample size was calculated at 156 students for simple random sampling. Data collected using a pre-tested self-administered questionnaire included socio-demographic characteristics of the population, first and second choices for specialization. Outcome variables collected were factors affecting choice of specialty and location for practice. Bivariate analysis by gender was carried out between the listed factors and outcome variables with calculation of odds ratios and chi-square statistics at an alpha level of significance of 0.05. Factors included in a binomial logistic regression model were analysed to score the independent categorical variables affecting choice of specialty and location of practice. RESULTS: Internal medicine, Surgery, Obstetrics/Gynaecology and Paediatrics accounted for 58.7% of all choices of specialization. Female students were less likely to select Obs/Gyn (OR 0.41, 95% CI =0.17-0.99) and Surgery (OR 0.33, 95% CI = 0.13-0.86) but eight times more likely to select Paediatrics (OR 8.67, 95% CI = 1.91-39.30). Surgery was primarily selected because of the 'perceived prestige of the specialty' (OR 4.3 95% CI = 1.35-14.1). Paediatrics was selected due to 'Ease of raising a family' (OR 4.08 95% CI = 1.08-15.4). Rural origin increased the odds of practicing in a rural area (OR 2.5, 95% CI = 1.04-6.04). Training abroad was more likely to result in preference for working abroad (OR 9.27 95% CI = 2.1-41.9). CONCLUSIONS: The 4 core specialties predominate as career preferences. Females are more likely to select career choices due to 'ease of raising a family'. Rural origin of students was found to be the most important factor for retention of rural health workforce. This data can be used to design prospective cohort studies in an effort to understand the dynamic influence that governments, educational institutions, work environments, family and friends exert on medical students' careers. PMID- 26754208 TI - Potent inhibition of angiotensin AT1 receptor signaling by RGS8: importance of the C-terminal third exon part of its RGS domain. AB - R4/B subfamily RGS (regulator of G protein signaling) proteins play roles in regulation of many GPCR-mediated responses. Multiple RGS proteins are usually expressed in a cell, and it is difficult to point out which RGS protein species are functionally important in the cell. To evaluate intrinsic potency of these RGS proteins, we compared inhibitory effects of RGS1, RGS2, RGS3, RGS4, RGS5, RGS8 and RGS16 on AT1 receptor signaling. Intracellular Ca(2+) responses to angiotensin II were markedly attenuated by transiently expressed RGS2, RGS3 and RGS8, compared to weak inhibition by RGS1, RGS4, RGS5 and RGS16. N-terminally deleted RGS2 (RGS2 domain) lost this potent inhibitory effect, whereas RGS domains of RGS3 and RGS8 showed strong inhibition similar to those of the full length proteins. To investigate key determinants that specify the differences in potency, we constructed chimeric domains by replacing one or two of three exon parts of RGS8 domain with the corresponding part of RGS5. The chimeric RGS8 domains containing the first or the second exon part of RGS5 showed strong inhibitory effects similar to that of wild type RGS8, but the chimeric domain with the third exon part of RGS5 lost its activity. On the contrary, replacement of the third exon part of RGS5 with the corresponding residues of RGS8 increased the inhibitory effect. The role of the third exon part of RGS8 domain was further confirmed with the chimeric RGS8/RGS4 domains. These results indicate the potent inhibitory activity of RGS8 among R4/B subfamily proteins and importance of the third exon. PMID- 26754209 TI - CORR Insights((r)): Total Hip Arthroplasty After Acetabular Fracture Is Associated With Lower Survivorship and More Complications. PMID- 26754249 TI - First overall report of Leptospira infections in wild boars in Poland. AB - BACKGROUND: Recently an increase in the population of wild boars (Sus scrofa) in Europe has been observed. This is important from a zoonotic perspective because it influences directly on the spread of many diseases. For the first time, an extensive survey on the prevalence of Leptospira infections in Polish wild boars was performed. During the hunting season 2012-2014, 3621 blood samples from wild boars were collected. The animals originated from different geographical areas across Poland. Serum samples were tested by a microscopic agglutination test (MAT) for the presence of specific antibodies to the following Leptospira serovars: Icterohaemorrhagiae, Grippotyphosa, Sejroe, Tarassovi, Pomona, Canicola, Bratislava, Autumnalis, Hardjo and Ballum. RESULTS: Antibody titers to all Leptospira serovars except serovar Ballum were found in 377 serum samples (10.4 %). The highest number of seropositive wild boars was found in the south eastern part of Poland and in highly urbanized areas such as Silesia and Lodz. CONCLUSIONS: The relatively high prevalence of Leptospira infections in wild boars may constitute a threat to hunters and people having contact with forest lakes or marshlands. The results also indicate that an increasing population of wild boar living close to borders of cities may create additional risk for inhabitants in large urban areas. PMID- 26754250 TI - On the probability of dinosaur fleas. AB - Recently, a set of publications described flea fossils from Jurassic and Early Cretaceous geological strata in northeastern China, which were suggested to have parasitized feathered dinosaurs, pterosaurs, and early birds or mammals. In support of these fossils being fleas, a recent publication in BMC Evolutionary Biology described the extended abdomen of a female fossil specimen as due to blood feeding.We here comment on these findings, and conclude that the current interpretation of the evolutionary trajectory and ecology of these putative dinosaur fleas is based on appeal to probability, rather than evidence. Hence, their taxonomic positioning as fleas, or stem fleas, as well as their ecological classification as ectoparasites and blood feeders is not supported by currently available data. PMID- 26754251 TI - Epidemiology of hepatocellular carcinoma (HCC) in hemophilia. AB - Hepatocellular carcinoma (HCC) is an important cause of increasing mortality in elderly hemophilia population. Majority of the patients treated with virus non inactivated factor concentrates prepared from large plasma pools prior to 1985 have been found to be infected with hepatitis C virus (HCV), a major risk factor for HCC. A PubMed search of articles published until February 2015 was performed utilizing the keywords hemophilia, malignancy, neoplasm, cancer, mortality, ageing hemophilia, epidemiology, hepatocellular carcinoma and liver cancer and the relevant articles were included. Contradictory reports are available in literature on the incidence of cancers in general in hemophilia population. Almost all the studies where the incidence of HCC or mortality due to HCC have been analyzed in hemophilia population show that a vast majority of these patients are HCV infected. The incidence of HCC though higher in hemophilic population is related to the higher incidence of HCV infection and not due to the hemophilia phenotype. PMID- 26754252 TI - Introduction to the Mark Wilson Conference Special Issue. PMID- 26754253 TI - Bioassay-Guided Isolation of Two Flavonoids from Derris scandens with Topoisomerase II Poison Activity. AB - Derris scandens (ROXB.) BENTH. (Fabaceae) is used as an alternative treatment for cancer in Thai traditional medicine. Investigation of the topoisomerase II (Top2) poison of compounds isolated from this plant may reveal new drug leads for the treatment of cancer. Bioassay-guided isolation was performed on an extract of D. scandens stems using a yeast cell-based assay. A yeast strain expressing the top2 1 temperature-sensitive mutant was used to assay Top2 activity. At the permissive temperature of 25 degrees C, yeast cells were highly sensitive to Top2 poison agents. At the semi-permissive temperature of 30 degrees C, where enzyme activity was present but greatly diminished, cells displayed only marginal sensitivity. The bioassay-guided fractionation of the extract led to the isolation of two known isoflavones: 5,7,4'-trihydroxy-6,8-diprenylisoflavone (1) and lupalbigenin (2). These two compounds also displayed cytotoxicity against three different cancer cell lines, KB, MCF-7 and NCI-H187. In conclusion, Top2 poison agents from D. scandens are reported for the first time, substantiating the use of D. scandens in Thai traditional medicine for cancer treatment. PMID- 26754254 TI - Safety Evaluation of Dry Powder Formulations by Direct Dispersion onto Air-Liquid Interface Cultured Cell Layer. AB - Most safety evaluations of dry powder inhalers (DPIs) using cultured cells have been performed with dry powder formulations dissolved in a medium. However, this method is not considered to be suitable to evaluate the safety of inhaled dry powder formulations correctly since it cannot reflect the actual phenomenon on the respiratory epithelial surface. In this study, we established a novel in vitro safety evaluation system suitable for DPIs by combining an air-liquid interface cultured cell layer and a device for dispersing dry powders, and evaluated the safety of candidate excipients of dry powders for inhalation. The safety of excipients (sugars, amino acids, cyclodextrins, and positive controls) in solutions was compared using submerged cell culture systems with a conventional 96-well plate and Transwell((r)). The sensitivity of the cells grown in Transwell((r)) was lower than that of those grown in the 96-well plate. Dry powders were prepared by spray-drying and we evaluated their safety with a novel in-vitro safety evaluation system using an air-liquid interface cultured cell layer. Dry powders decreased the cell viability with doses more than solutions. On the other hand, dissolving the dry powders attenuated their cytotoxicity. This suggested that the novel in-vitro safety evaluation system would be suitable to evaluate the safety of DPIs with high sensitivity. PMID- 26754257 TI - Formation, Migration, and Reactivity of Au-CO Complexes on Gold Surfaces. AB - We report experimental as well as theoretical evidence that suggests Au-CO complex formation upon the exposure of CO to active sites (step edges and threading dislocations) on a Au(111) surface. Room-temperature scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy, transmission infrared spectroscopy, and density functional theory calculations point to Au-CO complex formation and migration. Room-temperature STM of the Au(111) surface at CO pressures in the range from 10(-8) to 10(-4) Torr (dosage up to 10(6) langmuir) indicates Au atom extraction from dislocation sites of the herringbone reconstruction, mobile Au-CO complex formation and diffusion, and Au adatom cluster formation on both elbows and step edges on the Au surface. The formation and mobility of the Au-CO complex result from the reduced Au-Au bonding at elbows and step edges leading to stronger Au-CO bonding and to the formation of a more positively charged CO (CO(delta+)) on Au. Our studies indicate that the mobile Au CO complex is involved in the Au nanoparticle formation and reactivity, and that the positive charge on CO increases due to the stronger adsorption of CO at Au sites with lower coordination numbers. PMID- 26754255 TI - Efficient fermentative production of polymer-grade D-lactate by an engineered alkaliphilic Bacillus sp. strain under non-sterile conditions. AB - BACKGROUND: Polylactic acid (PLA) is one important chemical building block that is well known as a biodegradable and a biocompatible plastic. The traditional lactate fermentation processes need CaCO3 as neutralizer to maintain the desired pH, which results in an amount of insoluble CaSO4 waste during the purification process. To overcome such environmental issue, alkaliphilic organisms have the great potential to be used as an organic acid producer under NaOH-neutralizing agent based fermentation. Additionally, high optical purity property in D-lactic acid is now attracting more attention from both scientific and industrial communities because it can improve mechanical properties of PLA by blending L- or D-polymer together. However, the use of low-price nitrogen source for D-lactate fermentation by alkaliphilic organisms combined with NaOH-neutralizing agent based process has not been studied. Therefore, our goal was the demonstrations of newly simplify high-optical-purity D-lactate production by using low-priced peanut meal combined with non-sterile NaOH-neutralizing agent based fermentation. RESULTS: In this study, we developed a process for high-optical-purity D-lactate production using an engineered alkaliphilic Bacillus strain. First, the native L lactate dehydrogenase gene (ldh) was knocked out, and the D-lactate dehydrogenase gene from Lactobacillus delbrueckii was introduced to construct a D-lactate producer. The key gene responsible for exopolysaccharide biosynthesis (epsD) was subsequently disrupted to increase the yield and simplify the downstream process. Finally, a fed-batch fermentation under non-sterile conditions was conducted using low-priced peanut meal as a nitrogen source and NaOH as a green neutralizer. The D-lactate titer reached 143.99 g/l, with a yield of 96.09 %, an overall productivity of 1.674 g/l/h including with the highest productivity at 16 h of 3.04 g/l/h, which was even higher than that of a sterile fermentation. Moreover, high optical purities (approximately 99.85 %) of D-lactate were obtained under both conditions. CONCLUSIONS: Given the use of a cheap nitrogen source and a non-sterile green fermentation process, this study provides a more valuable and favorable fermentation process for future polymer-grade D-lactate production. PMID- 26754258 TI - Structure of reflective functioning and adult attachment scales: overlap and distinctions. AB - This investigation examined the structure of reflective functioning (RF) - an understanding of the links between mental states and behaviors - and adult attachment scales. Both RF and traditional adult attachment scales were coded based on 194 prebirth Adult Attachment Interviews (AAI). Correlational and factor analyses indicated considerable overlap between RF and traditional AAI coding. Exploratory factor analyses of RF and AAI state-of-mind scales indicated that RF loaded, along with coherence of mind, on the primary factor distinguishing between individuals categorized as secure and dismissing. These findings indicate substantial overlap between RF and AAI scales; however, the magnitude of the correlations between these scales indicates that they are not redundant. PMID- 26754256 TI - Structural analysis and insertion study reveal the ideal sites for surface displaying foreign peptides on a betanodavirus-like particle. AB - Betanodavirus infection causes fatal disease of viral nervous necrosis in many cultured marine and freshwater fish worldwide and the virus-like particles (VLP) are effective vaccines against betanodavirus. But vaccine and viral vector designs of betanodavirus VLP based on their structures remain lacking. Here, the three-dimensional structure of orange-spotted grouper nervous necrosis virus (OGNNV) VLP (RBS) at 3.9 A reveals the organization of capsid proteins (CP). Based on the structural results, seven putative important sites were selected to genetically insert a 6* histidine (His)-tag for VLP formation screen, resulting in four His-tagged VLP (HV) at positions N-terminus, Ala220, Pro292 and C terminus. The His-tags of N-terminal HV (NHV) were concealed inside virions while those of 220HV and C-terminal HV (CHV) were displayed at the outer surface. NHV, 220HV and CHV maintained the same cell entry ability as RBS in the Asian sea bass (SB) cell line, indicating that their similar surface structures can be recognized by the cellular entry receptor(s). For application of vaccine design, chromatography-purified CHV could provoke NNV-specific antibody responses as strong as those of RBS in a sea bass immunization assay. Furthermore, in carrying capacity assays, N-terminus and Ala220 can only carry short peptides and C terminus can even accommodate large protein such as GFP to generate fluorescent VLP (CGV). For application of a viral vector, CGV could be real-time visualized to enter SB cells in invasion study. All the results confirmed that the C terminus of CP is a suitable site to accommodate foreign peptides for vaccine design and viral vector development. PMID- 26754259 TI - Comparison of digit ratio (2D:4D) between Brazilian men with and without prostate cancer. AB - BACKGROUND: Digit ratio (2D:4D) has been suggested as a proxy biomarker for prenatal androgen activity and has been linked to prostate cancer, as the genes that regulate the formation and differentiation of the fingers are also related to the carcinogenesis of prostate cancer. To investigate the possible correlation between right hand, left hand and right hand minus left hand (DR-L) 2D:4D and prostate cancer of Brazilian subjects by comparing 2D:4D ratios of individuals diagnosed with prostate cancer and individuals without the disease. Also, to inquire the relationship between 2D:4D and severity of prostate cancer through Gleason scores. METHODS: Digital measurements of the lengths of the index and ring fingers of both hands of patients diagnosed with prostate cancer (PCA group, n=100) and healthy control individuals (n=100) were obtained using a digital vernier caliper. Means of the 2D:4D ratios were compared. Data were analyzed by the Student's t-test for unpaired samples, Mann-Whitney test and Spearman's correlation with a significance level of 5%. RESULTS: The PCA group presented significantly lower right and left 2D:4D (P=0.001 and P=0.002, respectively) in comparison to healthy controls, but DR-L were not significantly different between groups (P=0.589). In addition, digit ratios were not correlated to Gleason score for either hand or in DR-L. CONCLUSIONS: 2D:4D seems to be a marker for screening patients for prostate cancer in an admixed population, as males with prostate cancer present lower 2D:4D than healthy subjects. On the other hand, 2D:4D does not appear to be associated with the severity of prostate cancer. PMID- 26754260 TI - A phase 2 multimodality trial of docetaxel/prednisone with sunitinib followed by salvage radiation therapy in men with PSA recurrent prostate cancer after radical prostatectomy. AB - BACKGROUND: In men with high Gleason PC and rapid PSA progression after surgery, failure rates remain unacceptably high despite salvage radiation. We explored a novel multimodality approach of docetaxel with anti-angiogenic therapy before salvage radiotherapy (RT). METHODS: This was a phase 2 single-arm prospective open-label trial with historic controls. Eligible men had a rising PSA of 0.1-3.0 ng ml(-1) within 4 years of radical prostatectomy, no metastases except resected nodal disease, no prior androgen-deprivation therapy (ADT) and Gleason 7-10. Men received four cycles of docetaxel 70 mg m(-2) every 3 weeks with low dose prednisone and sunitinib 37.5 mg daily for 14/21 days each cycle, with no ADT. Salvage prostate bed RT (66 Gy) started at day 100. The primary end point was progression-free survival (PFS) rate at 24 months. Safety data, quality of life (QOL) and dose-limiting toxicities (DLTs) were measured over time. RESULTS: Thirty-four men accrued in this multi-institutional clinical trial: 24% of men were node positive, 47% were Gleason 8-10, median PSA at entry was 0.54. The trial was terminated prematurely owing to excess DLTs (nine) including grade 3 hand-foot syndrome (n=4), neutropenic fever (n=2), AST increase (n=1), fatigue (n=1) and vomiting with diarrhea (n=1). PFS rate at 24 months was 51% (95% CI: 33, 67%) with a median PFS of 26.2 months (95% CI: 12.5, -). Six men (17.6%) had an undetectable PSA at 2 years. CONCLUSIONS: Sunitinib and docetaxel/prednisone followed by salvage RT resulted in excess pre-specified DLTs. Although nearly half of the men experienced durable disease control, efficacy was not greater than expected with radiation alone. The use of the intermediate end point of PFS in this salvage setting permitted an early decision on further development of this combination. PMID- 26754261 TI - In vivo prostate cancer detection and grading using restriction spectrum imaging MRI. AB - BACKGROUND: Magnetic resonance imaging (MRI) is emerging as a robust, noninvasive method for detecting and characterizing prostate cancer (PCa), but limitations remain in its ability to distinguish cancerous from non-cancerous tissue. We evaluated the performance of a novel MRI technique, restriction spectrum imaging (RSI-MRI), to quantitatively detect and grade PCa compared with current standard of-care MRI. METHODS: In a retrospective evaluation of 33 patients with biopsy proven PCa who underwent RSI-MRI and standard MRI before radical prostatectomy, receiver-operating characteristic (ROC) curves were performed for RSI-MRI and each quantitative MRI term, with area under the ROC curve (AUC) used to compare each term's ability to differentiate between PCa and normal prostate. Spearman rank-order correlations were performed to assess each term's ability to predict PCa grade in the radical prostatectomy specimens. RESULTS: RSI-MRI demonstrated superior differentiation of PCa from normal tissue, with AUC of 0.94 and 0.85 for RSI-MRI and conventional diffusion MRI, respectively (P=0.04). RSI-MRI also demonstrated superior performance in predicting PCa aggressiveness, with Spearman rank-order correlation coefficients of 0.53 (P=0.002) and -0.42 (P=0.01) for RSI MRI and conventional diffusion MRI, respectively, with tumor grade. CONCLUSIONS: RSI-MRI significantly improves upon current noninvasive PCa imaging and may potentially enhance its diagnosis and characterization. PMID- 26754262 TI - Body mass index and mortality in prostate cancer patients: a dose-response meta analysis. AB - BACKGROUND: Previous studies concerning the association between body mass index (BMI) and mortality in prostate cancer yielded mixed results. We investigated the association by performing a meta-analysis of all available studies. METHODS: Relevant studies were identified by searching PubMed and EMBASE to August 2015. We calculated the summary hazard ratio (HR) and 95% confidence interval (CI) using random-effects models. We estimated combined HRs associated with defined increments of BMI, using random-effects meta-analysis and dose-response meta regression models. RESULTS: Thirty-seven cohort studies and one case-control study involving 27 38 000 patients of prostate cancer were selected for meta analysis. The summary results indicated higher prediagnosis BMI but not postdiagnosis BMI was associated with increased risk of death from prostate cancer. An increment of every 5 kg/m(2) in prediagnosis BMI was associated with a 15% higher prostate cancer-specific mortality (HR=1.15, 95% CI: 1.07-1.23, P<0.01). Prediagnosis or postdiagnosis BMI showed no effect on all-cause mortality in prostate cancer patients. CONCLUSIONS: In conclusion, higher prediagnosis BMI is associated with a higher risk of death from prostate cancer. Considering the significant heterogeneity among included studies, these findings require confirmation in future studies. PMID- 26754265 TI - Exploratory Factor Analysis With Small Sample Sizes. AB - Exploratory factor analysis (EFA) is generally regarded as a technique for large sample sizes (N), with N = 50 as a reasonable absolute minimum. This study offers a comprehensive overview of the conditions in which EFA can yield good quality results for N below 50. Simulations were carried out to estimate the minimum required N for different levels of loadings (lambda), number of factors (f), and number of variables (p) and to examine the extent to which a small N solution can sustain the presence of small distortions such as interfactor correlations, model error, secondary loadings, unequal loadings, and unequal p/f. Factor recovery was assessed in terms of pattern congruence coefficients, factor score correlations, Heywood cases, and the gap size between eigenvalues. A subsampling study was also conducted on a psychological dataset of individuals who filled in a Big Five Inventory via the Internet. Results showed that when data are well conditioned (i.e., high lambda, low f, high p), EFA can yield reliable results for N well below 50, even in the presence of small distortions. Such conditions may be uncommon but should certainly not be ruled out in behavioral research data. * These authors contributed equally to this work. PMID- 26754264 TI - Nonneurological Involvement in Late-Onset Friedreich Ataxia (LOFA): Exploring the Phenotypes. AB - Friedreich's ataxia (FDRA) is the most common inherited ataxia worldwide, caused by homozygous GAA expansions in the FXN gene. Patients usually have early onset ataxia, areflexia, Babinski sign, scoliosis and pes cavus, but at least 25 % of cases have atypical phenotypes. Disease begins after the age of 25 in occasional patients (late-onset Friedreich ataxia (LOFA)). Little is known about the frequency and clinical profile of LOFA patients. One hundred six patients with molecular confirmation of FDRA and followed in three Brazilian outpatient centers were enrolled. General demographics, GAA expansion size, age at onset, cardiac, endocrine, and skeletal manifestations were evaluated and compared between LOFA and classic FDRA (cFDRA) groups. We used Mann-Whitney and Fisher tests to compare means and proportions between groups; p values <0.05 were considered significant. LOFA accounted for 17 % (18/106) and cFDRA for 83 % (88/106) of the patients. There were 13 and 48 women in each group, respectively. LOFA patients were significantly older and had smaller GAA expansions. Clinically, LOFA group had a tendency toward lower frequency of diabetes/impaired glucose tolerance (5.8 vs. 17 %, p = 0.29) and cardiomyopathy (16.6 vs. 28.4 %, p = 0.38). Skeletal abnormalities were significantly less frequent in LOFA (scoliosis 22 vs. 61 %, p = 0.003, and pes cavus 22 vs.75 %, p < 0.001) as were spasticity and sustained reflexes, found in 22 % of LOFA patients but in none of the cFDRA patients (p = 0.001). LOFA accounts for 17 % of Brazilian FDRA patients evaluated herein. Clinically, orthopedic features and spasticity with retained reflexes are helpful tips to differentiate LOFA from cFDRA patients. PMID- 26754266 TI - The Impacts of Ignoring a Crossed Factor in Analyzing Cross-Classified Data. AB - Cross-classified random-effects models (CCREMs) are used for modeling nonhierarchical multilevel data. Misspecifying CCREMs as hierarchical linear models (i.e., treating the cross-classified data as strictly hierarchical by ignoring one of the crossed factors) causes biases in the variance component estimates, which in turn, results in biased estimation in the standard errors of the regression coefficients. Analytical studies were conducted to provide closed form expressions for the biases. With balanced design data structure, ignoring a crossed factor causes overestimation of the variance components of adjacent levels and underestimation of the variance component of the remaining crossed factor. Moreover, ignoring a crossed factor at the kth level causes underestimation of the standard error of the regression coefficient of the predictor associated with the ignored factor and overestimation of the standard error of the regression coefficient of the predictor at the (k-1)th level. Simulation studies were also conducted to examine the effect of different structures of cross-classification on the biases. In general, the direction and magnitude of the biases depend on the level of the ignored crossed factor, the level with which the predictor is associated at, the magnitude of the variance component of the ignored crossed factor, the variance components of the predictors, the sample sizes, and the structure of cross-classification. The results were further illustrated using the Early Childhood Longitudinal Study Kindergarten Cohort data. PMID- 26754263 TI - Association between single-nucleotide polymorphisms in DNA double-strand break repair genes and prostate cancer aggressiveness in the Spanish population. AB - BACKGROUND: Novel predictors of prognosis and treatment response for prostate cancer (PCa) are required to better individualize treatment. Single-nucleotide polymorphisms (SNPs) in four genes directly (XRCC5 (X-ray repair complementing defective repair in Chinese hamster cells 5) and XRCC6 (X-ray repair complementing defective repair in Chinese hamster cells 6)) or indirectly (PARP1 and major vault protein (MVP)) involved in non-homologous end joining were examined in 494 Spanish PCa patients. METHODS: A total of 22 SNPs were genotyped in a Biotrove OpenArray NT Cycler. Clinical tumor stage, diagnostic PSA serum levels and Gleason score at diagnosis were obtained for all participants. Genotypic and allelic frequencies were determined using the web-based environment SNPator. RESULTS: (XRCC6) rs2267437 appeared as a risk factor for developing more aggressive PCa tumors. Those patients carrying the GG genotype were at higher risk of developing bigger tumors (odds ratio (OR)=2.04, 95% confidence interval (CI) 1.26-3.29, P=0.004), present higher diagnostic PSA levels (OR=2.12, 95% CI 1.19-3.78, P=0.011), higher Gleason score (OR=1.65, 95% CI 1.01-2.68, P=0.044) and D'Amico higher risk tumors (OR=2.38, 95% CI 1.24-4.58, P=0.009) than those patients carrying the CC/CG genotypes. Those patients carrying the (MVP) rs3815824 TT genotype were at higher risk of presenting higher diagnostic PSA levels (OR=4.74, 95% CI 1.40-16.07, P=0.013) than those patients carrying the CC genotype. When both SNPs were analyzed in combination, those patients carrying the risk genotypes were at higher risk of developing D'Amico higher risk tumors (OR=3.33, 95% CI 1.56-7.17, P=0.002). CONCLUSIONS: We believe that for the first time, genetic variants at XRCC6 and MVP genes are associated with risk of more aggressive disease, and would be taken into account when assessing the malignancy of PCa. PMID- 26754267 TI - Longitudinal Multitrait-Multimethod Models for Developmental Research. AB - Multitrait-multimethod (MTMM) confirmatory factor models were combined with longitudinal structural equation models to examine trait and method stability over time. A longitudinal correlated-trait correlated-method (CT-CM) model allowed for the study of trait and method variance in observed scores over time. Longitudinal measurement invariance was examined in the longitudinal CT-CM model to determine the invariance of the trait and method factors. The longitudinal MTMM model was then combined with second-order latent curve models to evaluate within-person change and between-person differences change in the trait factors while accounting for method-related variance. These models were developed and applied to longitudinal behavior-rating data from the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care and Youth Development with externalizing, internalizing, and social skills serving as the traits and mother, father, and teacher serving as methods or informants. Methodological extensions of longitudinal MTMM models and benefits of an MTMM approach to developmental research are discussed. PMID- 26754268 TI - Differentiating Categories and Dimensions: Evaluating the Robustness of Taxometric Analyses. AB - Interest in modeling the structure of latent variables is gaining momentum, and many simulation studies suggest that taxometric analysis can validly assess the relative fit of categorical and dimensional models. The generation and parallel analysis of categorical and dimensional comparison data sets reduces the subjectivity required to interpret results by providing an objective Comparison Curve Fit Index (CCFI). This study takes advantage of developments in the generation of comparison data to examine the robustness of taxometric analyses to unfavorable data conditions. Very large comparison data sets are treated as populations from which many samples are drawn randomly, placing the method on a firmer statistical foundation and increasing its run-time efficiency. The impressive accuracy of the CCFI was consistent with prior findings and robust across novel manipulations of asymmetry, tail weight, and heterogeneous variances. Analyses, an empirical illustration using Minnesota Multiphasic Personality Inventory (MMPI) hypochondriasis data, and discussion focus on the practical implications for differentiating categories and dimensions. PMID- 26754269 TI - Covariance Structure Model Fit Testing Under Missing Data: An Application of the Supplemented EM Algorithm. AB - We apply the Supplemented EM algorithm ( Meng & Rubin, 1991 ) to address a chronic problem with the "two-stage" fitting of covariance structure models in the presence of ignorable missing data: the lack of an asymptotically chi-square distributed goodness-of-fit statistic. We show that the Supplemented EM algorithm provides a convenient computational procedure that leads to such a chi-square statistic, and we provide a SAS macro implementing this method. Our derivations are corroborated with results from a small simulation study. We also apply the proposed method to 2 empirical data sets: (a) confirmatory factor analysis of Mardia, Kent, & Bibby's 1979 Open-book Closed-book data and (b) conditional latent curve modeling of adolescent aggressive behavior as discussed by Curran (1997) . PMID- 26754270 TI - Correlation of vermilion symmetry to alveolar cleft defect in unilateral cleft lip repair. AB - Asymmetry is a major problem in repaired unilateral cleft lip (UCL). One of the important manifestations of this is the asymmetry of the vermilion. The aim of this study was to correlate the severity of the asymmetry in the vermilion to the size of the alveolar defect. Twenty patients aged between 6 and 18 months with complete unilateral cleft lip, alveolus, and palate were included. An impression of each patient's alveolus at the time of cheiloplasty was taken using silicon rubber base material, and a study cast was prepared. The width of the cleft alveolus was measured on these casts using a transparent grid. Frontal photographs were taken at 6 months postoperative and vermilion symmetry was measured as the ratio between the cleft and non-cleft sides. The results obtained in this study showed a direct correlation between the size of the alveolar defect and the vermilion symmetry in repaired UCL. The wider the cleft alveolus and greater the antero-posterior discrepancy, the greater is the vermilion asymmetry. The asymmetry of the vermilion in UCL after repair is directly dependent on the size of the alveolar defect. The alveolar discrepancy causes 'in-rolling' of the vermilion on the cleft side and affects the vermilion symmetry. PMID- 26754271 TI - Tuning the thermoelectric properties of metallo-porphyrins. AB - We investigated the thermoelectric properties of metalloporphyrins connected by thiol anchor groups to gold electrodes. By varying the transition metal-centre over the family Mn, Co, Ni, Cu, Fe, and Zn we are able to tune the molecular energy levels relative to the Fermi energy of the electrodes. The resulting single-molecule room-temperature thermopowers range from almost zero for Co and Cu centres, to +80 MUV K(-1) and +230 MUV K(-1) for Ni and Zn respectively. In contrast, the thermopowers with Mn(II) or Fe(II) metal centres are negative and lie in the range -280 to -260 MUV K(-1). Complexing these with a counter anion to form Fe(III) and Mn(III) changes both the sign and magnitude of their thermopowers to +218 and +95 respectively. The room-temperature power factors of Mn(II), Mn(III), Fe(III), Zn and Fe(II) porphyrins are predicted to be 5.9 * 10( 5) W m(-1) K(-2), 5.4 * 10(-4) W m(-1) K(-2), 9.5 * 10(-4) W m(-1) K(-2), 1.6 * 10(-4) W m(-1) K(-2) and 2.3 * 10(-4) W m(-1) K(-2) respectively, which makes these attractive materials for molecular-scale thermoelectric devices. PMID- 26754273 TI - Quick benefits of interval training versus continuous training on bone: a dual energy X-ray absorptiometry comparative study. AB - To delay age-related bone loss, physical activity is recommended during growth. However, it is unknown whether interval training is more efficient than continuous training to increase bone mass both quickly and to a greater extent. The aim of this study was to compare the effects of a 10-week interval training regime with a 14-week continuous training regime on bone mineral density (BMD). Forty-four male Wistar rats (8 weeks old) were separated into four groups: control for 10 weeks (C10), control for 14 weeks (C14), moderate interval training for 10 weeks (IT) and moderate continuous training for 14 weeks (CT). Rats were exercised 1 h/day, 5 day/week. Body composition and BMD of the whole body and femur respectively were assessed by dual-energy X-ray absorptiometry at baseline and after training to determine raw gain and weight-normalized BMD gain. Both trained groups had lower weight and fat mass gain when compared to controls. Both trained groups gained more BMD compared to controls when normalized to body weight. Using a 30% shorter training period, the IT group showed more than 20% higher whole body and femur BMD gains compared to the CT. Our data suggest that moderate IT was able to produce faster bone adaptations than moderate CT. PMID- 26754272 TI - The silencing of cathepsin K used in gene therapy for periodontal disease reveals the role of cathepsin K in chronic infection and inflammation. AB - BACKGROUND AND OBJECTIVE: Periodontitis is a severe chronic inflammatory disease and one of the most prevalent non-communicable chronic diseases that affects the majority of the world's adult population. While great efforts have been devoted toward understanding the pathogenesis of periodontitis, there remains a pressing need for developing potent therapeutic strategies for targeting this dreadful disease. In this study, we utilized adeno-associated virus (AAV) expressing cathepsin K (Ctsk) small hairpin (sh)RNA (AAV-sh-Ctsk) to silence Ctsk in vivo and subsequently evaluated its impact in periodontitis as a potential therapeutic strategy for this disease. MATERIAL AND METHODS: We used a known mouse model of periodontitis, in which wild-type BALB/cJ mice were infected with Porphyromonas gingivalis W50 in the maxillary and mandibular periodontium to induce the disease. AAV-sh-Ctsk was then administrated locally into the periodontal tissues in vivo, followed by analyses to assess progression of the disease. RESULTS: AAV mediated Ctsk silencing drastically protected mice (> 80%) from P. gingivalis induced bone resorption by osteoclasts. In addition, AAV-sh-Ctsk administration drastically reduced inflammation by impacting the expression of many inflammatory cytokines as well as T-cell and dendritic cell numbers in periodontal lesions. CONCLUSION: AAV-mediated Ctsk silencing can simultaneously target both the inflammation and bone resorption associated with periodontitis through its inhibitory effect on immune cells and osteoclast function. Thereby, AAV-sh-Ctsk administration can efficiently protect against periodontal tissue damage and alveolar bone loss, establishing this AAV-mediated local silencing of Ctsk as an important therapeutic strategy for effectively treating periodontal disease. PMID- 26754274 TI - [Neuroimaging of cerebral vasculitis]. AB - Cerebral vasculitis can have a variety of origins. Furthermore, there are no vasculitis-specific symptoms or imaging signs and vasculitis of the CNS can mimic many other neurological diseases, which require different treatment approaches. Thus, the clinical and radiological diagnosis of cerebral vasculitis is challenging. Magnetic resonance imaging (MRI) and MR angiography (MRA) should be the radiological imaging methods of choice to assess the degree of parenchymal damage and to detect vessel wall changes. If the results are unclear digital subtraction angiography (DSA) should be pursued in order to also detect changes in medium sized vessels. Vasculitis of small vessels cannot be detected by vascular imaging and requires brain or leptomeningeal biopsy. In this review we present the current diagnostic approach and a variety of imaging findings in cerebral vasculitis and discuss the main radiological differential diagnoses. PMID- 26754281 TI - Large Scale Synthesis of NiCo Layered Double Hydroxides for Superior Asymmetric Electrochemical Capacitor. AB - We report a new environmentally-friendly synthetic strategy for large-scale preparation of 16 nm-ultrathin NiCo based layered double hydroxides (LDH). The Ni50Co50-LDH electrode exhibited excellent specific capacitance of 1537 F g(-1) at 0.5 A g(-1) and 1181 F g(-1) even at current density as high as 10 A g(-1), which 50% cobalt doped enhances the electrical conductivity and porous and ultrathin structure is helpful with electrolyte diffusion to improve the material utilization. An asymmetric ultracapacitor was assembled with the N-doped graphitic ordered mesoporous carbon as negative electrode and the NiCo LDH as positive electrode. The device achieves a high energy density of 33.7 Wh kg(-1) (at power density of 551 W kg(-1)) with a 1.5 V operating voltage. PMID- 26754283 TI - [Orthostatic tremor: A cause of dizziness]. PMID- 26754284 TI - [Implementation of an automatic alarms system for early detection of patients with severe sepsis]. PMID- 26754282 TI - Functional redundancy in the control of seedling growth by the karrikin signaling pathway. AB - MAIN CONCLUSION: SMAX1 and SMXL2 control seedling growth, demonstrating functional redundancy within a gene family that mediates karrikin and strigolactone responses. Strigolactones (SLs) are plant hormones with butenolide moieties that control diverse aspects of plant growth, including shoot branching. Karrikins (KARs) are butenolide molecules found in smoke that enhance seed germination and seedling photomorphogenesis. In Arabidopsis thaliana, SLs and KARs signal through the alpha/beta hydrolases D14 and KAI2, respectively. The F box protein MAX2 is essential for both signaling pathways. SUPPRESSOR OF MAX2 1 (SMAX1) plays a prominent role in KAR-regulated growth downstream of MAX2, and SMAX1-LIKE genes SMXL6, SMXL7, and SMXL8 mediate SL responses. We previously found that smax1 loss-of-function mutants display constitutive KAR response phenotypes, including reduced seed dormancy and hypersensitive growth responses to light in seedlings. However, smax1 seedlings remain slightly responsive to KARs, suggesting that there is functional redundancy in karrikin signaling. SMXL2 is a strong candidate for this redundancy because it is the closest paralog of SMAX1, and because its expression is regulated by KAR signaling. Here, we present evidence that SMXL2 controls hypocotyl growth and expression of the KAR/SL transcriptional markers KUF1, IAA1, and DLK2 redundantly with SMAX1. Hypocotyl growth in the smax1 smxl2 double mutant is insensitive to KAR and SL, and etiolated smax1 smxl2 seedlings have reduced hypocotyl elongation. However, smxl2 has little or no effect on seed germination, leaf shape, or petiole orientation, which appear to be predominantly controlled by SMAX1. Neither SMAX1 nor SMXL2 affect axillary branching or inflorescence height, traits that are under SL control. These data support the model that karrikin and strigolactone responses are mediated by distinct subclades of the SMXL family, and further the case for parallel butenolide signaling pathways that evolved through ancient KAI2 and SMXL duplications. PMID- 26754285 TI - Direct observation of deterministic domain wall trajectory in magnetic network structures. AB - Controlling the domain wall (DW) trajectory in magnetic network structures is crucial for spin-based device related applications. The understanding of DW dynamics in network structures is also important for study of fundamental properties like observation of magnetic monopoles at room temperature in artificial spin ice lattice. The trajectory of DW in magnetic network structures has been shown to be chirality dependent. However, the DW chirality periodically oscillates as it propagates a distance longer than its fidelity length due to Walker breakdown phenomenon. This leads to a stochastic behavior in the DW propagation through the network structure. In this study, we show that the DW trajectory can be deterministically controlled in the magnetic network structures irrespective of its chirality by introducing a potential barrier. The DW propagation in the network structure is governed by the geometrically induced potential barrier and pinning strength against the propagation. This technique can be extended for controlling the trajectory of magnetic charge carriers in an artificial spin ice lattice. PMID- 26754286 TI - Plasma levels of F-actin and F:G-actin ratio as potential new biomarkers in patients with septic shock. AB - OBJECTIVE: To compare plasma levels of F-actin, G-actin and thymosin beta 4 (TB4) in humans with septic shock, noninfectious systemic inflammatory response syndrome (SIRS) and healthy controls. RESULTS: F-actin was significantly elevated in septic shock as compared with noninfectious SIRS and healthy controls. G-actin levels were greatest in the noninfectious SIRS group but significantly elevated in septic shock as compared with healthy controls. TB4 was not detectable in the septic shock or noninfectious SIRS group above the assay's lowest detection range (78 ng/ml). CONCLUSIONS: F-actin is significantly elevated in patients with septic shock as compared with noninfectious SIRS. F-actin and the F:G-actin ratio are potential biomarkers for the diagnosis of septic shock. PMID- 26754287 TI - A new adjustable parallel drill guide for internal fixation of femoral neck fracture: a developmental and experimental study. AB - BACKGROUND: Internal fixation is one treatment for femoral neck fracture. Some devices and techniques reported improved accuracy and decreased fluoroscopic time. However, these are not widely used nowadays due to the lack of available special instruments and techniques. To improve the surgical procedure, the authors designed a new adjustable drill guide and tested the efficacy of the device. METHODS: The authors developed a new adjustable drill guide for cannulated screw guide wire insertion for multiple screw fixation. Eight orthopaedic surgeons performed the experimental study to evaluate the efficacy of this device. Each surgeon performed guide wire insertion for multiple screw fixation in six synthetic femurs: three times with the new device and three times with the conventional technique. The fluoroscopic time, operative time and surgeon satisfaction were evaluated. RESULTS: In the operations with the new adjustable drill guide, the fluoroscopic and operative times were significantly lower than the operations with the conventional technique (p < 0.05). The mean score for the level of satisfaction of this device was also statistically significantly better (p = 0.02) than the conventional technique. CONCLUSIONS: The fluoroscopic and operative times with the new adjustable drill guide were reduced for multiple screw fixation of femoral neck fracture and the satisfaction of the surgeons was good. PMID- 26754288 TI - Determinants of anemia among 6-59 months aged children in Bangladesh: evidence from nationally representative data. AB - BACKGROUND: Anemia is a global public health problem but the burden of anemia is disproportionately borne among children in developing countries. Anemia in early stages of life has serious consequences on the growth and development of the children. We examine the prevalence of anemia, possible association between anemia and different socio-economic, demographic, health and other factors among children with ages from 6 to 59 months from the nationally representative 2011 Bangladesh Demographic and Health Survey (BDHS). METHODS: Data on hemoglobin (Hb) concentration among the children aged 6-59 months from the most recent BDHS (2011) were used. This nationally representative survey allowed a multistage stratified cluster sampling design and provided data on a wide range of indicators such as fertility, mortality, women and child health, nutrition and other background characteristics. Anemia status was determined using hemoglobin level (<11.0 g/dl), and weighted prevalence of childhood anemia along with 95 % confidence intervals were provided. We also examined the distribution of weighted anemia prevalence across different groups and performed logistic regression to assess the association of anemia with different factors. RESULTS: A total of 2171 children aged 6-59 months were identified for this analysis, with weighted prevalence of anemia being 51.9 % overall- 47.4 % in urban and 53.1 % in rural regions. Results of a multivariable logistic regression analysis showed that, children below 24 months of age (odds ratio, [OR] 3.01; 95 % confidence interval [CI] 2.38-3.81), and those from an anemic mother (OR 1.80; 95 % CI 1.49-2.18) were at higher risk of anemia. Childhood anemia was significantly associated with chronic malnutrition of child, source of drinking water, household wealth and geographical location (defined by division). CONCLUSIONS: A high prevalence of anemia among 6-59 months aged children was observed in Bangladesh. Given the negative impact of anemia on the development of children in future, there is an urgent need for effective and efficient remedial public health interventions. PMID- 26754289 TI - The Impact of Lamarck's Theory of Evolution Before Darwin's Theory. AB - This paper analyzes the impact that Lamarckian evolutionary theory had in the scientific community during the period between the advent of Zoological Philosophy and the publication Origin of Species. During these 50 years Lamarck's model was a well known theory and it was discussed by the scientific community as a hypothesis to explain the changing nature of the fossil record throughout the history of Earth. Lamarck's transmutation theory established the foundation of an evolutionary model introducing a new way to research in nature. Darwin's selectionist theory was proposed in 1859 to explain the origin of species within this epistemological process. In this context, Charles Lyell's Principles of Geology and Auguste Comte's Cours de Philosophie Positive appear as two major works for the dissemination of Lamarck's evolutionary ideology after the death of the French naturalist in 1829. PMID- 26754292 TI - Role of Reversal Learning Impairment in Social Disinhibition following Severe Traumatic Brain Injury. AB - OBJECTIVES: The current study aimed to determine whether reversal learning impairments and feedback-related negativity (FRN), reflecting reward prediction error signals generated by negative feedback during the reversal learning tasks, were associated with social disinhibition in a group of participants with traumatic brain injury (TBI). METHODS: Number of reversal errors on a social and a non-social reversal learning task and FRN were examined for 21 participants with TBI and 21 control participants matched for age. Participants with TBI were also divided into low and high disinhibition groups based on rated videotaped interviews. RESULTS: Participants with TBI made more reversal errors and produced smaller amplitude FRNs than controls. Furthermore, participants with TBI high on social disinhibition made more reversal errors on the social reversal learning task than did those low on social disinhibition. FRN amplitude was not related to disinhibition. CONCLUSIONS: These results suggest that impairment in the ability to update behavior when social reinforcement contingencies change plays a role in social disinhibition after TBI. Furthermore, the social reversal learning task used in this study may be a useful neuropsychological tool for detecting susceptibility to acquired social disinhibition following TBI. Finally, that the FRN amplitude was not associated with social disinhibition suggests that reward prediction error signals are not critical for behavioral adaptation in the social domain. PMID- 26754290 TI - Risk factors associated with Mycobacterium bovis skin positivity in cattle and buffalo in Peshawar, Pakistan. AB - A cross-sectional study was carried out to determine the prevalence of bovine tuberculosis (bTB) and associated risk factors in cattle and buffalo in Peshawar, Pakistan. Cattle and buffalo, randomly selected from all four towns of District Peshawar, were screened for bovine tuberculosis using comparative cervical intradermal tuberculin test (CCIT). For obtaining data on risk factors, sociodemographic condition, animal characteristics, and management, interviewer administered pretested questionnaire to animal owners. Multivariable logistic regression models were used to measure association between risk factors and comparative cervical intradermal tuberculin reactors. A total of 556 cattle and buffalo were screened for bovine tuberculosis. Out of 556 animals screened, 5.75 % (3.9-8.0 %) were found positive. The prevalence was higher in old animals (p = 0.001) as compared to younger animals. Prevalence also varied with source of animal (either raised on farm or purchased), stay of animals at night (indoor or outdoor), and herd size. Farmer's knowledge about transmission of TB from animals to human as well as signs and symptoms of TB was extremely low. Only 3.6 % farmers correctly stated the combination of three major symptoms of TB. Results of the study call for immediate intervention to control bTB in animals as well as its transmission to human population. Furthermore, it is suggested to emphasize on local epidemiology of bTB and husbandry practices of cattle and buffalo during the control program. PMID- 26754291 TI - Anthelmintic administration to small ruminants in emergency drought responses: assessing the impact in two locations of northern Kenya. AB - Internal parasites are a significant determinant of the productivity of ruminant species in the tropics. Provision of anthelmintics has become a predominant part of animal health interventions in emergency drought responses, aiming to maintain the food conversion efficiency of livestock when pasture is scarce. This study aimed to assess the owner-perceived impact of anthelmintic provision on the health and productivity of small ruminants in the drought-prone counties of Isiolo and Marsabit, northern Kenya. Participatory approaches were used to retrospectively measure differences in key indicators of livestock output before and after anthelmintic administration. Results showed that there was no perceived impact of anthelmintic administration during droughts on small ruminant health and productivity, but some benefit of anthelmintic administration during rainy season was perceived. The study also provided some evidence of potential differences in the epidemiology of internal parasites between the counties. These findings may be utilised to inform future livestock intervention programmes in drought-prone areas. PMID- 26754294 TI - miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis. AB - MicroRNAs (miRNAs) play a critical role in regulation of tumor metastasis. However, the role of these molecules in hepatocellular carcinoma (HCC) has not been fully elucidated. In this study, we employed miRNA-sequencing and identified 22 miRNAs involved in HCC metastasis. One of these, miR-28-5p, was down-regulated in HCCs. This down-regulation correlated with tumor metastasis, recurrence, and poor survival. Biofunctional investigations revealed that miR-28-5p deficiency promoted tumor growth and metastasis in nude mice without altering the in vitro biological characteristics of HCC cells. Through gene expression profiles and bioinformatics analysis, we identified interleukin-34 (IL-34) as a direct target of miR-28-5p, and the effects of miR-28-5p deficiency on HCC growth and metastasis was dependent on IL-34-mediated tumor-associated macrophage (TAM) infiltration. Moreover, we found that TAMs induced by miR-28-5p-IL-34 signaling inhibit miR-28-5p expression on HCC cells by transforming growth factor beta 1, resulting in an miR-28-5p-IL-34-macrophage-positive feedback loop. In clinical HCC samples, miR-28-5p levels were inversely correlated with IL-34 expression and the number of TAMs. Patients with low miR-28-5p expression, high IL-34 levels, and high numbers of TAMs had a poor prognosis with shorter overall survival and time to recurrence. CONCLUSION: A miR-28-5p-IL-34-macrophage feedback loop modulates HCC metastasis and serves as a novel prognostic factor as well as a therapeutic target for HCC. PMID- 26754293 TI - Combined multimodal co-registration of PET/CT and MRI images increases diagnostic accuracy in squamous cell carcinoma staging. AB - OBJECTIVES: The purpose of our study was to assess the diagnostic value of multi modal imaging through co-registration of short tau inversion recovery (STIR) and diffusion-weighted imaging (DWI) MRI with (18)FDG-PET/CT in T and N staging of head and neck tumours. MATERIALS AND METHODS: 25 patients with head and neck squamous cell carcinoma who had undergone MRI and PET/CT before treatment were retrospectively evaluated. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PET/CT, MRI and their combined use were assessed in T and N staging. Histopathology and follow-up imaging results were used as the gold standard. RESULTS: In assessing trans-compartmental extensions, PET-MRI showed 93 % sensitivity, 88 % specificity, 94 % PPV, and 88 % NPV, as compared to the 94 and 53 % sensitivity, 75 and 75 % specificity, 89 and 82 % PPV, and 86 and 43 % demonstrated by MRI and PET, respectively. In the identification of pathological lymph nodes, PET-MRI showed 92 % sensitivity, 89 % specificity, 96 % PPV, and 89 % NPV, whereas PET/CT displayed 72 % sensitivity, 89 % specificity, 95 % PPV and 53 % NPV. The corresponding figures for DWI and STIR sequences were 84 and 100 % sensitivity, 67 and 56 % specificity, 88 and 86 % PPV, and 60 and 100 % NPV, respectively. CONCLUSIONS: Multi-modal imaging assessment of co-registered MRI and PET/CT images provides more accurate results for trans-compartmental extensions in T and N staging than the individual techniques alone. PMID- 26754295 TI - The efficacy and safety of S-1-based regimens in the first-line treatment of advanced gastric cancer: a systematic review and meta-analysis. AB - BACKGROUND: S-1 is first-line therapy for advanced gastric cancer in Asia and is used with increased frequency in Western counties. We conducted a meta-analysis to investigate the efficacy and toxicity of S-1-based therapy compared with 5 fluorouracil (5-FU)/capecitabine-based therapy and S-1-based combination therapy compared with S-1 monotherapy. METHODS: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, American Society of Clinical Oncology meeting abstracts, European Society for Medical Oncology meeting abstracts and ClinicalTrials.gov were searched for randomized clinical trials until May 2015. Data were extracted for overall survival (OS), progression-free-survival (PFS), objective response rate (ORR) and grade 1-2 and grade 3-4 adverse events. Stratified OS data for subgroups were extracted. RESULTS: S-1 was not different from 5-FU (eight studies, n = 2788) in terms of OS [hazard ratio (HR) 0.93, 95 % confidence interval (CI) 0.85-1.01] and PFS (HR 0.87, 95 % CI 0.73-1.04), whereas ORR was higher (risk ratio 1.43, 95 % CI 1.05-1.96). There was no subgroup difference in efficacy among Asian and Western patients, but in Western patients S-1 was associated with a lower rate of febrile neutropenia, toxicity-related deaths and grade 3-4 stomatitis and mucositis compared with 5-FU. S-1 showed no difference in efficacy compared with capecitabine (three studies, n = 329), but was associated with a lower rate of grade 3-4 neutropenia and grade 1-2 hand-foot syndrome. S-1-combination therapy was superior to S-1 monotherapy (eight studies, n = 1808) in terms of OS (HR 0.76, 95 % CI 0.65-0.90), PFS (HR 0.68, 95 % CI 0.56 0.82) and ORR (risk ratio 1.20, 95 % CI 1.04-1.38) but was more toxic. Survival benefit of S-1 combination therapy over S-1 monotherapy was most pronounced in patients with non-measurable disease, diffuse-type histological features and peritoneal metastasis. CONCLUSIONS: S-1 is effective and tolerable as first-line therapy for advanced gastric cancer in both Asian and Western countries. PMID- 26754297 TI - Impact of Asia-Pacific guidelines on gastric cancer and Helicobacter pylori infection on prevailing clinical practices. AB - OBJECTIVE: To determine the impact of the Asia-Pacific guidelines on gastric cancer prevention and Helicobacter pylori (H. pylori) infection on clinical practice. METHODS: An electronic survey was carried out among Asian Pacific Digestive Week (APDW) medical delegates in 2012. The survey questionnaire captured details such as participants' characteristics, their awareness of the guidelines and knowledge of the key guideline recommendations, the impact of the guidelines on individual practice and on national policies and the sources of medical information that the individual used to make clinical decisions. A total of 1372 APDW medical delegates were invited via email to participate in the electronic survey and 432 (31.5%) responded. RESULTS: Among the respondents, 57.6% were familiar with at least one of the guidelines. Among those familiar with the guidelines, 85.9% believed that they influenced their clinical practice. More than half (64.9%) reported that the guidelines clarified treatment indications for them. In terms of knowledge content, 85.0% of the participants provided correct responses to at least four of the six questions on understanding. More than half (52.7%) of the participants felt that the guidelines had made an impact on national policies. CONCLUSION: The Asia-Pacific guidelines on gastric cancer and H. pylori had a positive impact on individual clinical practice and national policies. PMID- 26754296 TI - Postoperative bleeding after gastric endoscopic submucosal dissection in patients receiving antithrombotic therapy. AB - BACKGROUND AND AIMS: It is controversial whether antithrombotic therapy increases the risk of bleeding after endoscopic submucosal dissection (ESD). The aim of this study was to evaluate the effects of antithrombotic therapy on gastric ESD. METHODS: Patients who underwent gastric ESD at Toranomon Hospital between April 2005 and July 2014 were enrolled. The risk of post-ESD bleeding was evaluated by multivariate logistic regression analysis. RESULTS: Of 1781 patients enrolled, 253 were taking an antithrombotic; 186 discontinued taking a single antithrombotic (n = 150) or multiple antithrombotics (n = 36) before ESD, whereas 15 continued taking a single antiplatelet agent and another 52 switched to heparin alternative therapy during the peri-ESD period. Post-ESD bleeding occurred in 101 patients (5.7 %): 68 patients (3.8 %) who did not take an antithrombotic, 11 patients (7.3 %) who discontinued taking a single antithrombotic, six patients (16.7 %) who discontinued taking multiple antithrombotics, one patient (6.7 %) who continued taking a single antiplatelet agent, and 15 patients (28.8 %) who switched to heparin therapy. In multivariate analysis, heparin alternative therapy [odds ratio (OR) 10.04, 95 % confidence interval (CI) 4.35-23.16], discontinuation of the use of multiple antithrombotics before ESD (OR 5.44, 95 % CI 2.00-14.79), tumor location in the lower third of the stomach (OR 2.17, 95 % CI: 1.32-3.58), and a long procedure time (100 min or greater; OR 2.00, 95 % CI 1.25-3.20) were independent risk factors for post-ESD bleeding. Among 52 subjects who switched to heparin therapy, one developed acute renal infarction and one developed cerebral bleeding. CONCLUSIONS: Because heparin alternative therapy significantly increases the risk of post-ESD bleeding and may not decrease the risk of thromboembolic events, other options should be considered for patients receiving anticoagulation therapy. PMID- 26754298 TI - Osteonecrosis of the Femoral Head: A Proposed New Treatment in Homozygous Sickle Cell Disease. AB - Possibilities for bone reconstruction in osteonecrosis of the femoral head in sickle cell hemoglobinopathies before the end of growth have not been assessed. The aim of our study was to evaluate the morphological and functional results in 11 osteonecrosis of the femoral head because of homozygous sickle cell disease. Surgical treatment consisted of a triple acetabular osteotomy in seven cases, femoral varus osteotomy in two cases and a combination of both in two cases. The severity of the osteonecrosis was evaluated on radiographs and magnetic resonance imaging (MRI), pre- and postoperative, and function of the hip joint was assessed by Harris and Postel Merle d'Aubigne scores. The anesthetic part (pre- and postoperative) and eventual complications were collected and analyzed. The maximum follow-up was between 1 to 9.6 years. All patients were considered to be satisfactory at maximum follow-up. The severity of the initial damage was not associated with any morphological or functional outcome at maximum follow-up. All patients had an objective functional gain. We found no general complications. We proposed a decision tree for the patient's management of avascular necrosis of the femoral head in sickle cell hemoglobinopathies before bone maturity, and with an Arlet and Ficat's stage of 3 or 4. The results of this study confirmed the interest of conservative surgical treatment in children with homozygous sickle cell anemia in case of osteonecrosis of the femoral head. LEVEL OF EVIDENCE: IV (cases series of our department). PMID- 26754300 TI - The Codon 35 (A > G) (HBB: c.107A > G) at the alpha-beta Chain Interface of the beta-Globin Gene: A Silent Mutation? AB - Tyr35beta is located at the convergence of the alpha1beta1, alpha1beta2 and alpha1alpha2 interfaces of Hb A. We here report a Chinese family in whom the codon 35 (A > G) (HBB: c.107A > G) mutation of the beta-globin gene was not associated with the thalassemic phenotype previously described. PMID- 26754299 TI - Molecular Characterization of delta-Thalassemia in Iran. AB - delta-Thalassemia (delta-thal) (OMIM #142000) resulting from mutations on the HBD gene usually has no clinical consequences. However, it may cause the misdiagnosis of beta-thalassemia (beta-thal) carriers by lowering the Hb A2 level to the normal range. Therefore, a study for delta-thal should be considered as a step in the detection of at-risk couple in our region. The aim of the present study was to characterize the mutations of the HBD gene in beta-thal carriers with normal Hb A2 levels, and also in normal individuals with Hb A2 of less than 2.0%. Four beta-thal carriers with normal Hb A2 and 39 individuals with Hb A2 of less than 2.0% were enrolled. Genomic DNA was extracted by the salting out method and the HBD gene was investigated by polymerase chain reaction (PCR) and direct DNA sequencing. Hb A2-Yialousa (HBD: c.82 G > T) was the most common variant found in the HBD gene, but the following mutations were also found: Hb A2-NYU (HBD: c.39 T > A), Hb A2-Coburg (HBD: c.350 G > A), Hb A2-Etolia (HBD: c.257 T > C), Hb A2 Fitzroy (HBD: c.428 C > A) and the delta-IVS-I-5 (G > T) (HBD: c.92 + 5 G > T). One case was a compound heterozygote for delta-IVS-I-5/Hb A2-Fitzroy. The results of this single center study suggest that the mutations in the HBD gene in the Iranian population are heterogeneous and should be considered in genetic counseling of families. PMID- 26754303 TI - Pharmacokinetics and safety of paroxetine controlled-release tablet in healthy Chinese subjects: a single-dose three-period crossover study. AB - OBJECTIVES: To evaluate the pharmacokinetics of paroxetine controlledrelease tablets after single oral administrations and its safety profile in healthy Chinese subjects. METHODS: This was a phase I, openlabel, single-dose, three period crossover study in which 12 healthy subjects received single oral doses of 12.5, 25, 37.5 mg paroxetine controlled-release tablets with 10-day washout between doses. Serial venous blood samples were collected for 96 hours after study drug administration and analyzed with LC-MS/MS. Pharmacokinetic parameters of paroxetine were calculated using non-compartmental analysis with Win-Nonlin software. RESULTS: The absorption of controlled-release paroxetine was delayed with a median tmax of 8 - 10 hours and the mean t1/2 was 12 - 14 hours across all doses. Over the dose range of 12.5 - 37.5 mg, the mean Cmax increased from 2.62 to 15.13 ng/mL and AUC0-infinity increased from 63.56 to 404.91 h*ng/mL. The 90% CI for the ratio of dose-normalized mean values of Cmax and AUC were not contained within the criteria limits, indicating a greater than doseproportional increase. All reported adverse events were considered to be mild. CONCLUSIONS: Plasma exposure of controlled-release paroxetine increased with dose escalation, but linear pharmacokinetics were not observed over the studied doses. Paroxetine controlled-release tablet was well tolerated in healthy Chinese subjects. PMID- 26754301 TI - Effect of a trans fatty acid-enriched diet on biochemical and inflammatory parameters in Wistar rats. AB - PURPOSE: Recent data regarding trans fatty acids (TFAs) have implicated these lipids as particularly deleterious to human health, causing systemic inflammation, endothelial dysfunction and possibly inflammation in the central nervous system (CNS). We aimed to clarify the impact of partially hydrogenated soybean oil (PHSO) with different TFA concentrations on cerebrospinal fluid (CSF), serum and hepatic parameters in adult Wistar rats. METHODS: Wistar rats (n = 15/group) were fed either a normolipidic diet or a hyperlipidic diet for 90 days. The normolipidic and hyperlipidic diets had the same ingredients except for fat compositions, concentrations and calories. We used lard in the cis fatty acid group and PHSO in the trans fatty acid group. The intervention groups were as follows: (1) low lard (LL), (2) high lard (HL), (3) low partially hydrogenated soybean oil (LPHSO) and (4) high partially hydrogenated soybean oil (HPHSO). Body weight, lipid profiles and the inflammatory responses in the CSF, serum and liver tissue were analyzed. RESULTS: Surprisingly, with the PHSO diet we observed a worse metabolic response that was associated with oxidative stress in hepatic tissue as well as impaired serum and CSF fluid parameters at both PHSO concentrations. In many analyses, there were no significant differences between the LPHSO and HPHSO diets. CONCLUSIONS: Dietary supplementation with PHSO impaired inflammatory parameters in CSF and blood, induced insulin resistance, altered lipid profiles and caused hepatic damage. Overall, these findings suggest that fat composition is more important than the quantity of fat consumed in terms of cis and trans fatty acid diets. PMID- 26754304 TI - A rapid, simple and sensitive method for the determination and bioequivalence study of transdermal fentanyl in human plasma using liquid chromatography electrospray ionization tandem mass spectrometry. AB - OBJECTIVE: Since the 1960s, fentanyl has been used to replace morphine nd other opioids due to its higher potency in the treatment of acute pain; since the 1990s, it has also been administrated to control chronic pain by using transdermal fentanyl device system. It is crucial and of utmost importance and crucial to validate a sensitive method for the quantification of transdermal fentanyl in human plasma. MATERIALS AND METHODS: A rapid, simple and sensitive high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method has been established and validated for the determination of transdermal fentanyl in human plasma using fentanyl-D5 as an internal standard (IS). Following liquid-liquid extraction (LLE) with n-hexane, the extracts were separated on a Thermo Hypersil ODS(C18) column (2.1 * 150 mm i.d., 5 MUm) interfaced with a triple-quadrupole tandem mass spectrometer using positive electrospray ionization. RESULTS AND CONCLUSIONS: Quantification of fentanyl was carried out by multiple reaction monitoring (MRM) of the transitions at m/z 337.1 >188.0 for fentanyl and 341.9->187.9 for IS. The lower limit of quantification was 9.75 pg*mL-1, and the test showed a linear range of 9.75 - 10,000 pg*mL-1. The validated method was subsequently applied to a bioequivalence (BE) study in 24 healthy Chinese volunteers by using transdermal fentanyl patches. PMID- 26754305 TI - Levothyroxine soft capsules demonstrate bioequivalent pharmacokinetic exposure with the European reference tablets in healthy volunteers under fasting conditions. AB - OBJECTIVE: To assess the bioequivalence (BE) potential under fasting conditions between levothyroxine soft capsules and the European reference tablet formulation. METHODS: Two studies were conducted to assess the BE potential as per European regulations. Study 1 was a two-way crossover BE study comparing a high strength of levothyroxine soft capsules versus levothyroxine tablets (200 MUg), while study 2 was a three-way crossover dosage form proportionality study between low, medium, and high strengths of soft capsules. 70 healthy adult subjects participated in the two studies. Each treatment consisted of a 600-MUg dose of levothyroxine sodium, administered under fasting conditions. Blood samples were collected for levothyroxine (T4) assay prior to dosing and up to 72 hours post dose. A washout of 35 days separated treatments in each study. Pharmacokinetics was assessed using noncompartmental methods. RESULTS: A total of 61 subjects completed the studies. Baseline-adjusted total T4 ratios (test/reference) and 90% confidence intervals (CIs) between soft capsules and tablets were within 80.00 - 125.00%. Comparison of the three strengths of soft capsules indicated pharmacokinetic equivalence between them (ratios and 90% CIs were contained within 80.00 - 125.00%). Overall, levothyroxine sodium was well tolerated with all products when given as single oral doses of 600 MUg, except for 1 serious adverse event of secondary bacteremia reported in study 2, deemed not to be related to treatment. CONCLUSION: Levothyroxine soft capsules meet BE criteria in terms of systemic exposure when compared to a European reference tablet under fasting conditions in healthy volunteers. PMID- 26754306 TI - Successful use of infliximab and tacrolimus combination therapy in a patient with ulcerative colitis refractory to infliximab dose intensification plus azathioprine. AB - OBJECTIVE: To report of a case successful use of infliximab (IFX) and tacrolimus (TAC) in a patient with ulcerative colitis (UC). CASE SUMMARY: A 22-year-old woman diagnosed with UC started treatment with azathioprine 2.5 mg/kg. After 3 years of therapy, she developed a severe relapse. A colonoscopy was performed showing diffuse continuous mucosal disease and multiple erosions (< 5 mm) with no signs of spontaneous bleeding. Treatment with IFX 5 mg/kg at weeks 0, 2, and 6 was started. After IFX induction, she remained with symptoms: six stools per day, as well as presenting bloody diarrhea, tenesmus, and no abdominal pain. An IFX dose intensification of 5 mg/kg every 6 weeks was prescribed. After 6 months of azathioprine plus IFX therapy, patient's clinical condition was improved: 3 - 4 stools per day, 20% of bloody diarrhea, tenesmus, and no abdominal pain. Her Mayo endoscopic subscore was 6.3 months later, and a severe relapse of ulcerative colitis was presented. The patient refused a surgical treatment. Azathioprine 2.5 mg/kg/day was suspended and TAC 0.2 mg/kg/day (12 mg/day) as a compassionate use was added to IFX dose intensification of 10 mg/kg every 8 weeks and mesalamine 800 mg 3 times daily. After the first month of combined therapy, the patient's clinical condition improved with no bloody stools and abdominal pain. After 6 months of combination therapy, the patient was in remission, with two stools per day, no tenesmus and no abdominal pain. Due to the patient's clinical remission, IFX was suspended. Tacrolimus was continued on 10 mg/day. After 6 months of TAC monotherapy, the patient continued without symptoms (1 - 2 normal stools per day). CONCLUSIONS: Based on our case, the combination therapy of IFX and TAC could be selected as an effective approach for the patients with UC refractory to IFX dose intensification plus AZA. However, further studies need to be performed to evaluate the efficacy of this combination therapy. PMID- 26754307 TI - Inappropriate prescribing in polypharmacy elderly outpatients taking multiple medications. Are the STOPP criteria useful? AB - OBJECTIVE: To assess potentially inappropriate medications (PIMs) in elderly outpatients taking multiple medications. METHODS: Invoicing data of the prescriptions and electronic medical records were used to apply the STOPP (screening tool of older people's prescriptions) criteria. RESULTS: Three out of 4 patients included in the study received PIMs. The most common criteria found were: duplicate drug class prescriptions (n = 58 (17.4%)), long-term long-acting benzodiazepines (n = 54 (16.2%)), and acetylsalicylic acid with no history of coronary, cerebral, or peripheral vascular symptoms or occlusive event (n = 32 (9.6%)). CONCLUSION: Our results highlight the relevance of the systematic review of the pharmacological treatments in these patients. PMID- 26754308 TI - Sisters who developed piloerection after administration of milnacipran. AB - OBJECTIVE: We previously reported the first case of piloerection in a patient receiving milnacipran hydrochloride (MLP). Here, we now present a second case of MLP-induced piloerection. We discuss this effect in terms of alpha1-adrenoceptor occupancy. CASE SUMMARY: After the first case of MLP-induced piloerection, we monitored occurrence of piloerection in our patients taking MLP. In response to our interview, a 43-year-old woman who had been prescribed MLP by a psychiatrist for depression mentioned that piloerection occurred frequently all over her body, starting soon after initiation of MLP administration (50 mg/day). Although she was concerned at the time, she assumed it might be related to her depression or to coldness in winter. She also mentioned that the incidence of piloerection increased with MLP dose escalation. The piloerection disappeared after several months. Interestingly, the previous patient and the current patient are biological sisters. DISCUSSION: Changes in alpha1-adrenoceptor occupancy by endogenous norepinephrine (as an index of the risk of piloerection) in the presence of MLP were estimated. The occupancy values increased with MLP dose escalation, in accordance with the patient's report of the phenomenon. other concomitant drugs, such as nortriptyline, had little effect. Since the two patients were sisters, genetic factors might influence the risk of piloerection. CONCLUSION: The incidence of piloerection appeared to increase with MLP dose escalation in this patient, who was the biological sister of the previously reported patient. Clinicians should recognize the possibility of MLP-induced piloerection in view of its potential impact on patients' quality of life and on drug compliance. PMID- 26754302 TI - Increasing vegetable intakes: rationale and systematic review of published interventions. AB - PURPOSE: While the health benefits of a high fruit and vegetable consumption are well known and considerable work has attempted to improve intakes, increasing evidence also recognises a distinction between fruit and vegetables, both in their impacts on health and in consumption patterns. Increasing work suggests health benefits from a high consumption specifically of vegetables, yet intakes remain low, and barriers to increasing intakes are prevalent making intervention difficult. A systematic review was undertaken to identify from the published literature all studies reporting an intervention to increase intakes of vegetables as a distinct food group. METHODS: Databases-PubMed, PsychInfo and Medline-were searched over all years of records until April 2015 using pre specified terms. RESULTS: Our searches identified 77 studies, detailing 140 interventions, of which 133 (81 %) interventions were conducted in children. Interventions aimed to use or change hedonic factors, such as taste, liking and familiarity (n = 72), use or change environmental factors (n = 39), use or change cognitive factors (n = 19), or a combination of strategies (n = 10). Increased vegetable acceptance, selection and/or consumption were reported to some degree in 116 (83 %) interventions, but the majority of effects seem small and inconsistent. CONCLUSIONS: Greater percent success is currently found from environmental, educational and multi-component interventions, but publication bias is likely, and long-term effects and cost-effectiveness are rarely considered. A focus on long-term benefits and sustained behaviour change is required. Certain population groups are also noticeably absent from the current list of tried interventions. PMID- 26754309 TI - Association of immune response parameters with virological response in hepatitis C virus patients treated with pegylated consensus interferon. AB - BACKGROUND: A new, potent, long lasting recombinant interferon variant (pegylated consensus interferon, PEGCIFN) was expressed by Escherichia coli. The aim of this study was to test safety and antiviral activity of the new type of interferon in adults with hepatitis C virus (HCV) infection and to determine the relationship between immune response markers and virological response. METHOD: 40 naive HCV patients (1 : 1 : 1 : 1) were injected subcutaneously with PEG-CIFN 1.0, 1.5, 2.0 MUg/kg and peginterferon-alpha 180 MUg once per week for 12 weeks. Serum HCV RNA, cytokines, chemokines levels were tested, and clinical data were collected at this course. RESULTS: PEG-CIFN is safety/tolerability. The serum HCV RNA levels were markedly decreased after therapy. 20% (2/10), 70% (7/10), 70% (7/10), and 60% (6/10) exhibited early virologic responses (EVR (+)) during PEGCIFN 1.0, 1.5, and 2.0 MUg/kg treatment and peginterferon-alpha 180 MUg treatment, respectively. Interleukin-4, interferon induced protein 10 (IP-10), and macrophage inflammatory protein 1beta (MIP-1beta) levels were lower, and granulocyte colony-stimulating factor levels were higher in EVR (+) than in the group not having an EVR (EVR ( )) (p < 0.05) after PEG-CIFN treatment. IP-10 and MIP-1beta levels were associated with HCV RNA values, alanine aminotransferase, and aspartate aminotransferase levels after PEG-CIFN treatment. CONCLUSION: PEGCIFN was well tolerated and effective at inhibiting HCV RNA, which is associated with changes in markers of immune response. PEG-CIFN 1.5 MUg/kg has been selected for further hepatitis C clinical development. PMID- 26754311 TI - Pros and cons of student journals. PMID- 26754310 TI - The progress test of medicine: the Dutch experience. AB - Progress testing in the Netherlands has a long history. It was first introduced at one medical school which had a problem-based learning (PBL) curriculum from the start. Later, other schools with and without PBL curricula joined. At present, approximately 10,000 students sit a test every three months. The annual progress exam is not a single test. It consists of a series of 4 tests per annum which are summative in the end. The current situation with emphasis on the formative and summative aspects will be discussed. The reader will get insight into the way progress testing can be used as feedback for students and schools. PMID- 26754312 TI - Innovating the practice of medical speciality training. AB - Educational innovations are being introduced into medical speciality training. But how do people who participate in medical speciality training (residents, consultants, programme directors) deal with these innovations? And what effects do educational innovations have according to these people?By addressing these questions, this thesis contributes to the knowledge about the challenging process of innovating medical speciality training. PMID- 26754313 TI - The effect of constructing versus solving virtual patient cases on transfer of learning: a randomized trial. AB - The purpose of this study was to explore the effect of actively constructing virtual patient (VP) cases compared with solving VP cases on knowledge gains, skills transfer and time spent on cases. Forty-five fourth-year medical students were randomized to constructing (VP-construction, n = 23) or solving (VP-solving, n = 22) four cardiopulmonary VP cases. Whereas the VP-solving group solved the cases, the VP-construction group only received the final diagnosis and had to complete the history, physical findings, and lab results. After a week, participants completed a transfer test involving two standardized patients representing cardiopulmonary cases. Performances on the transfer test were video recorded and assessed by two blinded raters using the Reporter, Interpreter, Manager, Educator (RIME) framework. Thirty-nine participants completed the transfer test. The VP-construction group spent significantly more time on the VP cases compared with the VP-solving group, p = 0.002. There were no significant differences in RIME scores between the VP-construction group and VP-solving group, p = 0.54.In conclusion, engaging novice students in active VP case construction may be more time consuming than solving VP cases, without resulting in superior skills transfer. PMID- 26754314 TI - Response: "Best practices in the evaluation and treatment of foramen magnum stenosis in achondroplasia during infancy" and "Is there a correlation between sleep disordered breathing and foramen magnum stenosis in children with achondroplasia?". PMID- 26754315 TI - Two-phase quasi-equilibrium in beta-type Ti-based bulk metallic glass composites. AB - The microstructural evolution of cast Ti/Zr-based bulk metallic glass composites (BMGCs) containing beta-Ti still remains ambiguous. This is why to date the strategies and alloys suitable for producing such BMGCs with precisely controllable volume fractions and crystallite sizes are still rather limited. In this work, a Ti-based BMGC containing beta-Ti was developed in the Ti-Zr-Cu-Co-Be system. The glassy matrix of this BMGC possesses an exceptional glass-forming ability and as a consequence, the volume fractions as well as the composition of the beta-Ti dendrites remain constant over a wide range of cooling rates. This finding can be explained in terms of a two-phase quasi-equilibrium between the supercooled liquid and beta-Ti, which the system attains on cooling. The two phase quasi-equilibrium allows predicting the crystalline and glassy volume fractions by means of the lever rule and we succeeded in reproducing these values by slight variations in the alloy composition at a fixed cooling rate. The two phase quasi-equilibrium could be of critical importance for understanding and designing the microstructures of BMGCs containing the beta-phase. Its implications on the nucleation and growth of the crystalline phase are elaborated. PMID- 26754316 TI - The effect of surface wettability on water vapor condensation in nanoscale. AB - The effect of surface wettability on condensation heat transfer in a nanochannel is studied with the molecular dynamics simulations. Different from the conventional size, the results show that the filmwise mode leads to more efficient heat transfer than the dropwise mode, which is attributed to a lower interfacial thermal resistance between the hydrophilic surface and the condensed water compared with the hydrophobic case. The observed temperature jump at the solid-liquid surface confirms that the hydrophilic properties of the solid surface can suppress the interfacial thermal resistance and improve the condensation heat transfer performance effectively. PMID- 26754323 TI - Patient/disease features and glycemic targets in type 2 diabetes: Where do we stand? PMID- 26754324 TI - Psychosocial factors not metabolic control impact the quality of life among patients with type 2 diabetes in China. AB - AIMS: Quality of life is a major focus of health care today. In published studies on patients with type 2 diabetes, findings on quality of life are mixed. Those with diabetes have chronic illness and must adhere to a complicated care regimen daily, which for many patients is challenging. This study analyzed psychosocial factors and metabolic control as potential predictors of quality of life among these patients. METHODS: A cross-sectional study of 397 patients with type 2 diabetes was conducted in a hospital in Nanjing, China. Demographic information and clinical characteristics were collected from the medical record. The World Health Organization Quality of Life-BREF, General Self-Efficacy Scale, Diabetes Distress Scale, and Diabetes Empowerment Scale-Short Form were administered. RESULTS: The mean score of quality of life was 67.80 +/- 13.44 on a 100-point scale. General self-efficacy (beta = 0.340, P < 0.001), diabetes distress (beta = -0.266, P < 0.001), and diabetes empowerment ability (beta = 0.207, P < 0.001) were predictors of quality of life. In contrast, other factors including HbA1c, diabetes complications, and the duration of diabetes were not associated with quality of life (P > 0.05). CONCLUSIONS: Our study indicated that psychosocial factors such as self-efficacy, diabetes distress, and diabetes empowerment ability are related to quality of life. Assessment and interventions aimed at reducing psychosocial problems should be applied in diabetes care. PMID- 26754325 TI - Views from senior Australian cancer researchers on evaluating the impact of their research: results from a brief survey. AB - BACKGROUND: The interest and activity in measuring and reporting the impact of publicly funded health and medical research has grown rapidly in recent years. Research evaluation typically relies on researchers for much of the information for an impact assessment. However, the acceptability and feasibility of this activity among health researchers is unknown. The aim of this study was to understand the role and opinions of cancer researchers in the growing area of impact evaluation activity, to inform the logistics of a sustainable program of impact evaluation. METHODS: A brief anonymous online survey was administered to 95 current and past grant recipients funded through the external grants program at Cancer Council New South Wales. Eleven survey statements were constructed with Likert responses and supplemented with two open-ended questions. The statements covered the conceptual, attitudinal and practical aspects of impact evaluation. The survey targeted researchers from the full spectrum of cancer control research classifications. Descriptive analyses obtained response frequencies and percentages. RESULTS: Forty-five cancer researchers completed the survey (response rate 47%) and 77% were Associate Professors or Professors. Responses were polarised for questions relating to engaging with research end-users, perceived time-pressure to collate data, and pressure to produce research outputs. Some researchers emphasised that quality was an important goal over quantity and warned that collecting impact data created incentives and disincentives for researchers. CONCLUSION: There was mixed support and acceptance among senior cancer researchers in Australia on their perceived role and engagement with research impact activities. Sole reliance on researchers for collating and reporting impact data may be problematic. Requesting information from researchers could be minimised and confined to final reports and possible verification of externally-led evaluations. PMID- 26754327 TI - Mesenchymal Stem Cells Ageing: Targeting the "Purinome" to Promote Osteogenic Differentiation and Bone Repair. AB - Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into bone forming cells. Such ability is compromised in elderly individuals resulting in bone disorders such as osteoporosis, also limiting their clinical usage for cell transplantation and bone tissue engineering strategies. In bone marrow niches, adenine and uracil nucleotides are important local regulators of osteogenic differentiation of MSCs. Nucleotides can be released to the extracellular milieu under both physiological and pathological conditions via (1) membrane cell damage, (2) vesicle exocytosis, (3) ATP-binding cassette transporters, and/or (4) facilitated diffusion through maxi-anion channels, hemichannels or ligand-gated receptor pores. Nucleotides and their derivatives act via adenosine P1 (A1 , A2A , A2B , and A3 ) and nucleotide-sensitive P2 purinoceptors comprising ionotropic P2X and G-protein-coupled P2Y receptors. Purinoceptors activation is terminated by membrane-bound ecto-nucleotidases and other ecto-phosphatases, which rapidly hydrolyse extracellular nucleotides to their respective nucleoside 5'-di- and mono-phosphates, nucleosides and free phosphates, or pyrophosphates. Current knowledge suggests that different players of the "purinome" cascade, namely nucleotide release sites, ecto-nucleotidases and purinoceptors, orchestrate to fine-tuning regulate the activity of MSCs in the bone microenvironment. Increasing studies, using osteoprogenitor cell lines, animal models and, more recently, non-modified MSCs from postmenopausal women, raised the possibility to target chief components of the purinergic signaling pathway to regenerate the ability of aged MSCs to differentiate into functional osteoblasts. This review summarizes the main findings of those studies, prompting for novel therapeutic strategies to control ageing disorders where bone destruction exceeds bone formation, like osteoporosis, rheumatoid arthritis, and fracture mal-union. J. Cell. Physiol. 231: 1852-1861, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26754326 TI - Invariant community structure of soil bacteria in subtropical coniferous and broadleaved forests. AB - Soil bacteria may be influenced by vegetation and play important roles in global carbon efflux and nutrient cycling under global changes. Coniferous and broadleaved forests are two phyletically distinct vegetation types. Soil microbial communities in these forests have been extensively investigated but few studies have presented comparable data regarding the characteristics of bacterial communities in subtropical forests. We investigated soil bacterial biomass and community composition in three pairs of coniferous and broadleaved forests across a subtropical climatic gradient. We found that bacterial biomass differed between the coniferous and broadleaved forests across the subtropical climate gradient; however, this difference disappeared at some individual sites. In contrast, the same 90 bacterial genera were found in both forest types, and their relative abundances didn't differ between the forest types, with the exception of one genus that was more abundant in broadleaved forests. Soil nitrogen or moisture was associated with bacterial groups in the coniferous and broadleaved forests, respectively. Thus, we inferred that these forests can respond differently to future changes in nitrogen deposition or precipitation. This study highlights soil bacterial invariant community composition in contrasting subtropical forests and provides a new perspective on the potential response and feedback of forests to global changes. PMID- 26754328 TI - An interactive, multi-modal Anatomy workshop improves academic performance in the health sciences: a cohort study. AB - BACKGROUND: Students often strategically adopt surface approaches to learning anatomy in order to pass this necessarily content-heavy subject. The consequence of this approach, without understanding and contextualisation, limits transfer of anatomical knowledge to clinical applications. Encouraging deep approaches to learning is challenging in the current environment of lectures and laboratory based practica. A novel interactive anatomy workshop was proposed in an attempt to address this issue. METHODS: This workshop comprised of body painting, clay modelling, white-boarding and quizzes, and was undertaken by 66 health science students utilising their preferred learning styles. Performance was measured prior to the workshop at the mid-semester examination and after the workshop at the end-semester examination. Differences between mid- and end-semester performances were calculated and compared between workshop attendees and non attendees. Baseline, post-workshop and follow-up surveys were administered to identify learning styles, goals for attendance, useful aspects of the workshop and self-confidence ratings. RESULTS: Workshop attendees significantly improved their performance compared to non-attendees (p = 0.001) despite a difference at baseline (p = 0.05). Increased self-confidence was reported by the attendees (p < 0.001). To optimise their learning, 97% of attendees reported utilising multi modal learning styles. Five main goals for participating in the workshop included: understanding, strategic engagement, examination preparation, memorisation and increasing self-confidence. All attendees reported achieving these goals. The most useful components of the workshop were body painting and clay modelling. CONCLUSIONS: This interactive workshop improved attendees' examination performance and promoted engaged-enquiry and deeper learning. This tool accommodates varied learning styles and improves self-confidence, which may be a valuable supplement to traditional anatomy teaching. PMID- 26754329 TI - Shape and Area of Keratocytes Are Related to the Distribution and Magnitude of Their Traction Forces. AB - Fish epidermal keratocytes maintain an overall fan shape during their crawling migration. The shape-determination mechanism has been described theoretically and experimentally on the basis of graded radial extension of the leading edge, but the relationship between shape and traction forces has not been clarified. Migrating keratocytes can be divided into fragments by treatment with the protein kinase inhibitor staurosporine. Fragments containing a nucleus and cytoplasm behave as mini-keratocytes and maintain the same fan shape as the original cells. We measured the shape of the leading edge, together with the areas of the ventral region and traction forces, of keratocytes and mini-keratocytes. The shapes of keratocytes and mini-keratocytes were similar. Mini-keratocytes exerted traction forces at the rear left and right ends, just like keratocytes. The magnitude of the traction forces was proportional to the area of the keratocytes and mini keratocytes. The myosin II ATPase inhibitor blebbistatin decreased the forces at the rear left and right ends of the keratocytes and expanded their shape laterally. These results suggest that keratocyte shape depends on the distribution of the traction forces, and that the magnitude of the traction forces depends on the area of the cells. PMID- 26754330 TI - Atg101: Not Just an Accessory Subunit in the Autophagy-initiation Complex. AB - The Saccharomyces cerevisiae autophagy-initiation complex, Atg1 kinase complex, consists of Atg1, Atg13, Atg17, Atg29, and Atg31, while the corresponding complex in most other eukaryotes, including mammals, is composed of ULK1 (or ULK2), Atg13, FIP200 (also known as RB1CC1), and Atg101. ULKs are homologs of Atg1, and FIP200 is partially homologous to Atg17. However, the sequence of Atg101 is not similar to that of Atg29 or Atg31. Although Atg101 is essential for autophagy and widely conserved in eukaryotes, its precise function and structure have remained largely unknown. Now, structural and cell biological analysis of Atg101 together with its binding partner Atg13 reveal that Atg101 is required for stabilization of "uncapped" Atg13 in most eukaryotes and also for recruitment of downstream Atg proteins through the newly identified WF motif. By contrast, S. cerevisiae has stable "capped" Atg13, which does not require Atg101 for its stabilization. Possible roles for other binding partners such as Atg29, Atg31, and Atg28 in different organisms are also discussed. PMID- 26754332 TI - Robust high-resolution imaging and quantitative force measurement with tuned oscillator atomic force microscopy. AB - Atomic force microscopy (AFM) and spectroscopy are based on locally detecting the interactions between a surface and a sharp probe tip. For highest resolution imaging, noncontact modes that avoid tip-sample contact are used; control of the tip's vertical position is accomplished by oscillating the tip and detecting perturbations induced by its interaction with the surface potential. Due to this potential's nonlinear nature, however, achieving reliable control of the tip sample distance is challenging, so much so that despite its power vacuum-based noncontact AFM has remained a niche technique. Here we introduce a new pathway to distance control that prevents instabilities by externally tuning the oscillator's response characteristics. A major advantage of this operational scheme is that it delivers robust position control in both the attractive and repulsive regimes with only one feedback loop, thereby providing an easy-to implement route to atomic resolution imaging and quantitative tip-sample interaction force measurement. PMID- 26754336 TI - ADDENDUM: Laboratory guideline for Turner syndrome. PMID- 26754331 TI - An open-label, phase 2, single centre, randomized, crossover design bioequivalence study of AndroForte 5 testosterone cream and Testogel 1% testosterone gel in hypogonadal men: study LP101. AB - We compared a novel 5% testosterone (T) cream (AndroForte 5, Lawley Pharmaceuticals, Australia) with a 1% T gel (Testogel, Besins Healthcare, Australia). Using an open-label crossover design, subjects were randomized to one of two treatment sequences using either the T gel or T cream first in a 1 : 1 ratio. Each treatment period was 30 days with a 7-14 days washout period between them. On Days 1 and 30 of each treatment period blood was sampled at -15, -5 min, 0, 2, 4, 5, 6, 7, 8, 9, 10, 12 and 16 h post study drug administration. Sixteen men with established androgen deficiency aged between 29 and 73 years, who had undertaken a washout from prior testosterone therapy participated in the study. One subject failed to complete both arms and another was excluded post-completion because of a major protocol violation. Bioequivalence was established based on key pharmacokinetic (PK) variables: AUC, C(avg), C(max), T(max), % fluctuation (with and without baseline correction) for the two formulations of testosterone on Day 1 and Day 30. The ratio and 90% CI of AUC 0.99 (0.86-1.14), C(max) 1.02 (0.84-1.24) and C(avg) 0.99 (0.86-1.14) for T cream/T gel were within the predetermined bio-equivalence criteria of 80% to 125% at Day 30. There were no statistically significant differences between secondary biochemical markers: serum dihydrotestosterone (DHT), oestradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone (LH) and (FSH). The two testosterone formulations were shown to be bioequivalent. PMID- 26754337 TI - ADDENDUM: Technical standards and guidelines for myotonic dystrophy type 1 testing. PMID- 26754338 TI - ERRATUM: Novel mutations in genes causing hereditary spastic paraplegia and Charcot-Marie-Tooth neuropathy identified by an optimized protocol for homozygosity mapping based on whole-exome sequencing. PMID- 26754339 TI - CORRIGENDUM: The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers. PMID- 26754340 TI - Mitochondrial Dynamics and Metabolic Regulation. AB - Mitochondrial morphology varies tremendously across cell types and tissues, changing rapidly in response to external insults and metabolic cues, such as nutrient status. The many functions of mitochondria have been intimately linked to their morphology, which is shaped by ongoing events of fusion and fission of outer and inner membranes (OM and IM). Unopposed fission causes mitochondrial fragmentation, which is generally associated with metabolic dysfunction and disease. Unopposed fusion results in a hyperfused network and serves to counteract metabolic insults, preserve cellular integrity, and protect against autophagy. Here, we review the ways in which metabolic alterations convey changes in mitochondrial morphology and how disruption of mitochondrial morphology impacts cellular and organismal metabolism. PMID- 26754341 TI - Cell-free DNA testing after combined test: factors affecting the uptake. AB - OBJECTIVE: First, to assess what was the uptake of cell free DNA (cfDNA) testing after a combined test and the maternal and fetal factors that influenced this decision, and second, to assess the uptake and factors that influence the choice of invasive testing. METHODS: This observational retrospective study included 1083 singleton pregnancies who had a combined test for screening for Down syndrome between 11 (+) (0) and 13 (+) (6) weeks. Multivariate logistic regression analysis was used to determine which factors affected the uptake of cfDNA test and invasive testing among risk for trisomies 21, 18, and 13, maternal characteristics and fetal nuchal translucency (NT) thickness. RESULTS: Two hundred fifty-seven (23.7%) women had a cfDNA test, 89 (8.2%) had an invasive test, and 737 (68.1%) had no further test. The uptake of cfDNA increased with the risk for trisomies (p < 0.001), maternal age (p = 0.013), and was higher in nulliparous women (p = 0.004). The uptake of invasive test increased with the risk for trisomies (p < 0.001) and NT thickness (p < 0.001). CONCLUSIONS: This study shows that the uptake of cfDNA testing increases with the risk for trisomies, maternal age, and is higher in nulliparous, whereas the uptake of invasive testing increases with the risk for trisomies and NT thickness. PMID- 26754342 TI - Risk indicators for Peri-implantitis. A cross-sectional study with 916 implants. AB - OBJECTIVES: The aim of this study was to identify systemic and local risk indicators associated with peri-implantitis. MATERIAL AND METHODS: One hundred eighty-three patients treated with 916 osseointegrated titanium implants, in function for at least 1 year, were included in the present study. The implants were installed at the Foundation for Scientific and Technological Development of Dentistry (FUNDECTO) - University of Sao Paulo (USP) - from 1998 to 2012. Factors related to patient's systemic conditions (heart disorders, hypertension, smoking habits, alcoholism, liver disorders, hepatitis, gastrointestinal disease, diabetes mellitus I and II, hyperthyroidism or hypothyroidism, radiation therapy, chemotherapy, menopause, osteoporosis, active periodontal disease, history of periodontal disease and bruxism), implant's characteristics (location, diameter, length, connection, shape, and antagonist), and clinical parameters (wear facets, periodontal status on the adjacent tooth, plaque accumulation on the adjacent tooth, modified plaque index, sulcus bleeding index, probing depth, bleeding on probing, width of keratinized tissue and marginal recession). RESULTS: An increased risk of 2.2 times for history of periodontal disease (PD), 3.6 times for cemented restorations compared to screw-retained prostheses, 2.4 times when wear facets were displayed on the prosthetic crown and 16.1 times for total rehabilitations when compared to single rehabilitations were found. Logistic regression analysis did not show any association between the implant's characteristics and peri-implantitis. CONCLUSIONS: A history of periodontal disease, cemented prostheses, presences of wear facets on the prosthetic crown and full mouth rehabilitations were identified as risk indicators for peri implantitis. Implants' characteristics were not related to the presence of peri implantitis. PMID- 26754343 TI - Sentinel lymph node identification using superparamagnetic iron oxide particles versus radioisotope: The French Sentimag feasibility trial. AB - BACKGROUND AND OBJECTIVES: The French Sentimag feasibility trial evaluated a new method for the localization of breast cancer sentinel lymph node (SLN) using Sienna+(r), superparamagnetic iron oxide particles, and Sentimag(r) detection in comparison to the standard technique (isotopes +/- blue dye). METHODS: We conducted a prospective multicentric paired comparison trial on 115 patients. SLN localization was performed using both the magnetic technique and the standard method. Detection rate and concordance between magnetic and standard tracers were calculated. Post-operative complications were assessed after 30 days. RESULTS: Results are based on 108 patients. SLN identification rate was 98.1% [93.5-99.8] for both methods, 97.2% [92.1-99.4] for Sienna+(r) and 95.4% [89.5-98.5] for standard technique. A mean of 2.1 SLNs per patient was removed. The concordance rate was 99.0% [94.7-100.0%] per patient and 97.4% [94.1-99.2] per node. Forty six patients (43.4%) had nodal involvement. Among involved SLNs, concordance rate was 97.7% [88.0-99.9] per patient and 98.1% [90.1-100.0] per node. CONCLUSIONS: This new magnetic tracer is a feasible method and a promising alternative to the isotope. It could offer benefits for ambulatory surgery or sites without nuclear medicine departments. J. Surg. Oncol. 2016;113:501-507. (c) 2016 Wiley Periodicals, Inc. PMID- 26754345 TI - NMR-Based Lipidomic Approach To Evaluate Controlled Dietary Intake of Lipids in Adipose Tissue of a Rat Mammary Tumor Model. AB - The fatty acids composition of adipose tissue may provide information on the nutritional part of the risk or evolution of breast cancer. To determine whether (1)H NMR of adipose tissue provides information on the nature of the diet consumed, a dietary intervention with increasing percentage of polyunsaturated n 3 docosahexaenoic acid (DHA 22:6n-3, provided as DHASCO oil) was applied to a rat model of N-nitroso-N-methylurea-induced mammary tumors. Spectra of the lipid extracts were obtained from adipose tissues in five groups of Sprague-Dawley rats fed with a diet containing 7% peanut/rapeseed enriched with 8% (w/w) of an oil without (palm oil) or with low (1%), moderate (3%), or high (8%) DHASCO content. A control group received a basal diet with 15% peanut/rapeseed representative of the "Western" diet. After 5 months of those five controlled diets, adipose tissue was collected for analysis of the lipid extract using both (1)H NMR analysis on an 11.7 T spectrometer and gas chromatography considered as gold standard. (1)H NMR analysis showed a dose-dependent increase in DHA in the lipid extract of adipose tissues and a commensurate decrease in n-6 polyunsaturated fatty acids in the three DHA groups, which allowed one to follow n-6/n-3 ratio changes. The highest n-6/n-3 ratio was observed in the control Western diet group compared to the other diet groups. The integrated spectral regions showed separation between groups, thereby documenting a specific NMR lipid profile corresponding to each dietary intervention. Those diet-dependent NMR lipid profiles were consistent with that obtained with gas chromatography analyses of the same samples. This study is a proof of concept highlighting the potential use of the (1)H NMR approach to evaluate dietary intervention in biopsies of adipose tissues. PMID- 26754344 TI - The association of reduced lung function with blood pressure variability in African Americans: data from the Jackson Heart Study. AB - BACKGROUND: African Americans (AAs) have lower lung function, higher blood pressure variability (BPV) and increased risk for hypertension and cardiovascular disease (CVD) compared with whites. The mechanism through which reduced lung function is associated with increased CVD risk is unclear. METHODS: We evaluated the association between percent predicted lung-function and 24-hour BPV in 1008 AAs enrolled in the Jackson Heart Study who underwent ambulatory blood pressure (BP) monitoring. Lung-function was assessed as forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1-to-FVC during a pulmonary function test using a dry rolling sealed spirometer and grouped into gender-specific quartiles. The pairwise associations of these three lung-function measures with two measures of 24-hour BPV, (1) day-night standard deviation (SDdn) and (2) average real variability (ARV) were examined for systolic BP (SBP) and, separately, diastolic BP (DBP). RESULTS: SDdn of SBP was not associated with FEV1 (mean +/- standard deviation from lowest-to-highest quartile: 9.5 +/- 2.5, 9.4 +/- 2.4, 9.1 +/- 2.3, 9.3 +/- 2.6; p-trend = 0.111). After age and sex adjustment, the difference in SDdn of SBP was 0.0 (95% CI -0.4,0.4), -0.4 (95% CI -0.8,0.1) and -0.3 (95% CI -0.7,0.1) in the three progressively higher versus lowest quartiles of FEV1 (p-trend = 0.041). Differences in SDdn of SBP across FEV1 quartiles were not statistically significant after further multivariable adjustment. After multivariable adjustment, no association was present between FEV1 and ARV of SBP or SDdn and ARV of DBP or when evaluating the association of FVC and FEV1-to-FVC with 24-hour BPV. CONCLUSION: Lung-function was not associated with increased 24-hour BPV. PMID- 26754346 TI - Parent-Reported Health Consequences and Relationship to Expenditures in Children with ADHD. AB - OBJECTIVES: (1) To describe parents' report of special needs for children with ADHD on the Children with Special Health Care Needs (CSHCN) Screener; and (2) to assess the association between responses to Screener items and annual mental health and total health expenditures per child. METHODS: In pooled 2002-2011 Medical Expenditure Panel Survey (MEPS) data, we identify children ages 4-17 years with ADHD. We use OLS and two-part regressions to model the relationship between CSHCN Screener items and mental health and total health expenditures. Based on these models we estimate adjusted, average total health expenditures for children with ADHD-both with and without a co-morbid mental health condition-and different combinations of endorsed Screener items. This research was conducted in accordance with prevailing ethical principles. RESULTS: There were 3883 observations on 2591 children with ADHD. Without a co-morbid mental health condition, average total expenditures per year from adjusted, model-based estimates were $865 for those meeting no Screener items, $2664 for those meeting only the medication item, $3595 for those meeting the medication and counseling items, and $4203 for those meeting the medication, counseling, and use of more health services items. Children with a co-morbid mental health condition had greater total health expenditures for each combination of Screener items. The associations between Screener items and mental health expenditures were similar, but with a slightly lower marginal effect of the medication item (p < 0.001 for all comparisons). CONCLUSIONS: Parents' responses on the CSHCN Screener are associated with meaningful variation in expenditures for children with ADHD. Though cross-sectional, this study suggests that the CSHCN Screener can be a useful categorization scheme for children with ADHD. It may be an efficient, standardized tool at the point of care for identifying children who need more resources and for targeting intensive interventions in the context of population health management. PMID- 26754348 TI - Investigating the Decline of Fetal and Infant Mortality Rates in Alaska During 2010 and 2011. AB - INTRODUCTION: The U.S. infant mortality rate has been steadily declining since 2007. Although the downward trend has been notable in Alaska since 2006 when the rate was 6.9 infant deaths per 1000 live births, a dramatic drop in infant mortality occurred in 2010 and 2011 when the infant mortality rate fell to 3.8 infant deaths per 1000 live births during both years. The purpose of this study was to investigate the sudden decrease in fetal and infant mortality rates (FIMR) using the perinatal periods of risk (PPOR) method, an approach that has not been used previously in Alaska. METHODS: The study was conducted for 251 fetal and infant deaths in 2004-2006, 265 deaths in 2007-2009, and 129 deaths in 2010-2011. Data were stratified by Alaska Native (AN) and White maternal race and urban/rural residence. RESULTS: Among both urban and rural White women, the rate ratios (RR) for FIMRs between the earlier and later time periods were not significantly different. The postneonatal mortality rate (PNMR) among AN infants living in rural areas decreased significantly (RR 0.40; 95 % confidence interval 0.21-0.76) between 2007-2009 and 2010-2011. An unexplained increase in sudden unexplained infant death was noted in 2009, followed by a precipitous decrease in 2010-2011. No other unusual distribution of the cause specific mortality rates was observed. DISCUSSION: The decrease in the Alaska Native FIMR might have been due to focused efforts for preventing postneonatal sleep associated deaths. Education for prevention of sleep related deaths, particularly in rural communities, is necessary to maintain Alaska's low PNMR. PMID- 26754347 TI - Improving Data, Enhancing Enrollment: Florida Covering Kids & Families CHIPRA Data System. AB - PURPOSE: According to the Kaiser Family Foundation (2014), 502,866 (11.7 %) of Florida children under 19 years of age are uninsured, giving Florida the second largest number of uninsured children in the United States. Florida Covering Kids & Families (FL-CKF) is dedicated to developing innovative outreach methods for enrolling and retaining eligible children in Florida KidCare, the state's Children's Health Insurance Program. FL-CKF has developed a strong data system that allows it to evaluate the effectiveness and success of statewide enrollment and retention efforts. DESCRIPTION: The data system was created using the Checkbox survey systems. Community and school outreach partners enter data each month on all completed Florida KidCare applications via a secure interface. The system requires data be entered in a uniform format and forces vital data points to be completed. These data are then transmitted to the state to obtain timely application determination information on enrollments. ASSESSMENT: The data system helps FL-CKF to determine which outreach strategies are successful and where changes need to be made to increase effectiveness. The system also provides feedback to community outreach partners in order to enable follow up with families when needed. CONCLUSION: Organizations helping uninsured children apply for health insurance may benefit from creating data collection systems to monitor project efficacy and modify outreach and enrollment strategies for greater effectiveness. PMID- 26754349 TI - Factors associated with long-term CD4 cell recovery in HIV-infected patients on successful antiretroviral therapy. AB - OBJECTIVES: The aim of the study was to study the factors associated with immunological recovery in HIV-infected patients with suppressed viral load. METHODS: Nadir and current CD4 cell counts were recorded in 821 patients, as well as many demographic, epidemiological, lifestyle, clinical, therapeutic, genetic, laboratory, liver fibrosis and viral hepatitis parameters. RESULTS: The median age of the patients was 44.4 years [interquartile range (IQR) 40.3-48.0 years], the median time since HIV diagnosis was 15.3 years (IQR 10.5-18.9 years), the median time of suppressed viral load was 7.0 years (IQR 4.0-10.0 years) and the median time on the current antiretroviral regimen was 2.8 years (IQR 1.4-4.7 years). The median nadir and current CD4 counts were 193.0 (IQR 84.0-301.0) and 522.0 (IQR 361.0-760) cells/MUL, respectively, separated by a median period of 10.2 years (IQR 5.9-12.9 years). The median CD4 count gain during follow-up was 317.0 (IQR 173.0-508.0) cells/MUL. Many variables were associated with CD4 cell gains in univariate analyses, including age, gender, epidemiology, prior clinical conditions, fibrosis stage, transient elastometry, aspartate aminotransferase (AST), nadir CD4 count and hepatitis B and C virus infections and genotypes, as well as the durations of follow-up since nadir CD4 count, overall antiretroviral treatment, current antiretroviral regimen, protease inhibitor therapy and suppression of viral load. Multivariate analysis revealed that longer duration of HIV suppression (P < 0.0001), more advanced clinical Centers for Disease Control and Prevention (CDC) stages (P < 0.0001), younger age (P = 0.0003), hepatitis C virus genotypes 1 and 4 (P = 0.003), sexual acquisition of HIV (P = 0.004), and lower transient elastometry values (P = 0.03) were independent predictors of CD4 cell gains. Overall, the model accounted for 14.2% of the variability in CD4 count. CONCLUSIONS: In addition to the duration of HIV suppression, HIV-related diseases, HIV epidemiology, age, hepatitis C virus genotypes, and liver fibrosis were independently associated with long-term immunological recovery. PMID- 26754350 TI - Seeking sex partners through the internet and mobile phone applications among men who have sex with men in Taiwan. AB - It has become popular for men who have sex with men (MSM) to use mobile-phone geosocial networking applications (mobile apps) to find sex partners. A cross sectional online survey was conducted in Taiwan to compare the sexual and substance-use behaviors of MSM seeking sex partners through the internet and mobile apps. Of the 1060 participants, 65.8% used the internet via computer and 37.7% used a mobile app to find sexual partners, while 30.3% used recreational drugs or alcohol in the previous 6 months. MSM who exclusively used mobile apps to seek sex partners were significantly more likely than MSM seeking sex via computer to be older, to have used recreational drugs or alcohol, and to have sex with HIV-positive partners. Additionally, using mobile apps to seek sex partners was significantly associated with having sex with online partners through either mobile apps or computer-based internet use (adjusted odds ratio (AOR), 7.12 [3.87 13.11]), self-reporting as HIV-positive (AOR, 2.24 [1.12-4.12]), using recreational drugs (AOR, 1.67 [1.21-2.32]), having disclosed HIV status to sexual partners (AOR, 1.44 [1.03-2.02]), and having sex with HIV-positive partners (AOR, 1.81 [1.06-3.10]). In conclusion, the mobile apps may serve as a feasible platform for HIV-positive MSM to find other HIV-positive partners. PMID- 26754351 TI - Clinical characteristics of Chinese patients with duration of type 2 diabetes >40 years. AB - BACKGROUND: Although type 2 diabetes mellitus (T2DM) shortens life expectancy by 10-12 years, some patients survive extremely long durations of diabetes. The clinical characteristics of Chinese patients with >40 years T2DM remain unknown. Thus, the aim of the present study was to document the clinical profile of patients with T2DM for >=40 years. METHODS: The present study evaluated 157 survivors with >40 years T2DM from a total of 582 773 patients with T2DM enrolled in a Chinese national survey of HbA1c. Two matched case-control studies were performed on long T2DM survivors (cases) separately matched according to: (1) survey day, sex, and survey hospital; and (2) age, sex, and survey hospital. Conditional logistic regression analysis was performed to obtain odds ratios (ORs) for long survival. RESULTS: Patients with a long duration of T2DM had a mean (+/- SD) age of 75 +/- 10 years. Their T2DM had been diagnosed at a mean age of 32 years and the median duration of diabetes was 41 years. In both case control studies, long-duration T2DM was associated with an increased risk of hyperglycemia (OR 6.31; 95% confidence interval [CI] 1.89-21.09) and coronary heart disease (CHD; OR 2.18 95% CI 1.01-4.70). However, long-duration T2DM was not associated with a higher likelihood of abnormal lipids, diabetic nephropathy (DN), or stroke compared with patients with a shorter duration of T2DM. CONCLUSIONS: The present study suggests that Chinese patients with long-term T2DM also had increased risks of hyperglycemia and non-fatal CHD. Further studies are needed to investigate whether survival of these patients was associated with non increased risk of DN. PMID- 26754352 TI - Signaling through NOD-2 and TLR-4 Bolsters the T cell Priming Capability of Dendritic cells by Inducing Autophagy. AB - T cells play a cardinal role in mediating protection against intracellular pathogens like Mycobacterium tuberculosis (Mtb). It is important to understand the factors that govern the T cell response; thereby can modulate its activity. Dendritic cells (DCs) are the major player in initiation and augmentation of T cell response. Targeting DCs to induce their optimum maturation and activation can lead to a better T cell response. Interestingly, we observed that combinatorial signaling of DCs through NOD-2 and TLR-4 fortified better yield of IL-12p40/70, IL-6 and IFN-gamma and upregulated the expression of CD40, CD80 and CD86 costimulatory molecules. Further, we noticed improved phagocytic capabilities of DCs. Furthermore, NOD-2 and TLR-4 induced autophagy in DCs, which enhanced the activation of T cells. This study signifies that NOD-2 and TLR-4 exhibit synergism in invigorating the activity of DCs. Consequently, this strategy may have significant immunotherapeutic potential in bolstering the function of DCs and thus improving the immunity against pathogens. PMID- 26754353 TI - Cryopreservation of the gorgonian endosymbiont Symbiodinium. AB - The study focused on finding a suitable cryoprotectant (CPA) and an optimum freezing protocol for the cryopreservation of the endosymbiotic dinoflagellates (Symbiodinium, clade G) of Junceella fragilis wherein the success of experiments is crucial to both scientific and ecology studies. A two-step freezing technique was developed. The viability of the thawed dinoflagellates was assayed using the adenosine triphosphate (ATP) bioassay for the first time and was further confirmed through the culturing of dinoflagellates in vitro. The results suggested that 30 min was the most suitable holding time for the dinoflagellates, and the samples produced highest viability when suspended at 5 cm from the surface of LN2. Results also showed that 1 M methanol with 0.4 M sucrose was the most effective CPA, yielding the highest viability (56.93%). Although cell densities of both cryopreserved and control group suffered an initial decline of culture, the cell densities were maintained throughout the remaining duration. In the present study, the cryopreservation of clade G endosymbiont algae was studied for the first time and the method described here could be applied for future studies on symbiotic algae cryopreservation. PMID- 26754354 TI - What do people think about running barefoot/with minimalist footwear? A thematic analysis. AB - OBJECTIVES: Barefoot running describes when individuals run without footwear. Minimalist running utilizes shoes aimed to mimic being barefoot. Although these forms of running have become increasingly popular, we still know little about how recreational runners perceive them. DESIGN: In-depth interviews with eight recreational runners were used to gather information about their running experiences with a focus on barefoot and minimalist running. METHODS: Interviews were analysed using a latent level thematic analysis to identify and interpret themes within the data. RESULTS: Although participants considered barefoot running to be 'natural', they also considered it to be extreme. Minimalist running did not produce such aversive reactions. 'Support' reassured against concerns and was seen as central in protecting vulnerable body parts and reducing impact forces, but lacked a common or clear definition. A preference for practical over academic knowledge was found. Anecdotal information was generally trusted, as were running stores with gait assessment, but not health professionals. CONCLUSION: People often have inconsistent ideas about barefoot and minimalist running, which are often formed by potentially biased sources, which may lead people to make poor decisions about barefoot and minimalist running. It is important to provide high-quality information to enable better decisions to be made about barefoot and minimalist running. STATEMENT OF CONTRIBUTION: What is already known on this subject? There is no known work on the psychology behind barefoot and minimalist running. We believe our study is the first qualitative study to have investigated views of this increasingly popular form of running. What does this study add? The results suggest that although barefoot running is considered 'natural', it is also considered 'extreme'. Minimalist running, however, did not receive such aversive reactions. 'Support' was a common concern among runners. Although 'support' reassured against concerns and was seen as central in protecting vulnerable body parts and reducing impact forces, it lacked a common or clear definition. A preference for practical over academic knowledge was found. Anecdotal information was generally trusted, as were running stores with gait assessment, but not health professionals. PMID- 26754355 TI - Ancient origin and maternal inheritance of blue cuckoo eggs. AB - Maternal inheritance via the female-specific W chromosome was long ago proposed as a potential solution to the evolutionary enigma of co-existing host-specific races (or 'gentes') in avian brood parasites. Here we report the first unambiguous evidence for maternal inheritance of egg colouration in the brood parasitic common cuckoo Cuculus canorus. Females laying blue eggs belong to an ancient (~2.6 Myr) maternal lineage, as evidenced by both mitochondrial and W linked DNA, but are indistinguishable at nuclear DNA from other common cuckoos. Hence, cuckoo host races with blue eggs are distinguished only by maternally inherited components of the genome, which maintain host-specific adaptation despite interbreeding among males and females reared by different hosts. A mitochondrial phylogeny suggests that blue eggs originated in Asia and then expanded westwards as female cuckoos laying blue eggs interbred with the existing European population, introducing an adaptive trait that expanded the range of potential hosts. PMID- 26754356 TI - Rapid Screening of Acetylcholinesterase Inhibitors by Effect-Directed Analysis Using LC * LC Fractionation, a High Throughput in Vitro Assay, and Parallel Identification by Time of Flight Mass Spectrometry. AB - Effect-directed analysis (EDA) is a useful tool to identify bioactive compounds in complex samples. However, identification in EDA is usually challenging, mainly due to limited separation power of the liquid chromatography based fractionation. In this study, comprehensive two-dimensional liquid chromatography (LC * LC) based microfractionation combined with parallel high resolution time of flight (HR-ToF) mass spectrometric detection and a high throughput acetylcholinesterase (AChE) assay was developed. The LC * LC fractionation method was validated using analytical standards and a C18 and pentafluorophenyl (PFP) stationary phase combination was selected for the two-dimensional separation and fractionation in four 96-well plates. The method was successfully applied to identify AChE inhibitors in a wastewater treatment plant (WWTP) effluent. Good orthogonality (>0.9) separation was achieved and three AChE inhibitors (tiapride, amisulpride, and lamotrigine), used as antipsychotic medicines, were identified and confirmed by two-dimensional retention alignment as well as their AChE inhibition activity. PMID- 26754398 TI - Shape-engineerable composite fibers and their supercapacitor application. AB - Due to excellent electrical and mechanical properties of carbon nano materials, it is of great interest to fabricate flexible, high conductive, and shape engineered carbon based fibers. As part of these approaches, hollow, twist, ribbon, and other various shapes of carbon based fibers have been researched for various functionality and application. In this paper, we suggest simple and effective method to control the fiber shape. We fabricate the three different shapes of hollow, twisted, and ribbon shaped fibers from wet spun giant graphene oxide (GGO)/single walled-nanotubes (SWNTs)/poly(vinyl alcohol) (PVA) gels. Each shaped fibers exhibit different mechanical properties. The average specific strengthes of the hollow, twist, and ribbon fibers presented here are 126.5, 106.9, and 38.0 MPa while strain are 9.3, 13.5, and 5%, respectively. Especially, the ribbon fiber shows high electrical conductivity (524 +/- 64 S cm(-1)) and areal capacitance (2.38 mF cm(-2)). PMID- 26754357 TI - Prediction of early death in adults with relapsed or refractory acute myeloid leukemia. PMID- 26754399 TI - The Effects of Educational Diversity in a National Sample of Law Students: Fitting Multilevel Latent Variable Models in Data With Categorical Indicators. AB - Controversy surrounding the use of race-conscious admissions can be partially resolved with improved empirical knowledge of the effects of racial diversity in educational settings. We use a national sample of law students nested in 64 law schools to test the complex and largely untested theory regarding the effects of educational diversity on student outcomes. Social scientists who study these outcomes frequently encounter both latent variables and nested data within a single analysis. Yet, until recently, an appropriate modeling technique has been computationally infeasible, and consequently few applied researchers have estimated appropriate models to test their theories, sometimes limiting the scope of their research question. Our results, based on disaggregated multilevel structural equation models, show that racial diversity is related to a reduction in prejudiced attitudes and increased perceived exposure to diverse ideas and that these effects are mediated by more frequent interpersonal contact with diverse peers. These findings provide support for the idea that administrative manipulation of educational diversity may lead to improved student outcomes. Admitting a racially/ethnically diverse student body provides an educational experience that encourages increased exposure to diverse ideas and belief systems. PMID- 26754400 TI - American Time-Styles: A Finite-Mixture Allocation Model for Time-Use Analysis. AB - Time-use has already been the subject of numerous studies across multiple disciplines such as economics, marketing, sociology, transportation and urban planning. However, most of this research has focused on comparing demographic groups on a few broadly defined activities (e.g., work for pay, leisure, housework, etc.). In this study we take a holistic perspective, identifying a typology of latent "time-styles," that defines the different ways people allocate the 24 hr in a day across multiple competing daily activities. We propose a finite-mixture time-allocation model that accounts for differences in life priorities across individuals, taking into consideration the fact that we all have the same "budget" of 24 hr to spend every day and that this allocation leads to highly sparse, truncated data. This model is then applied to time-use data from the American Time Use Survey collected by the U.S. Bureau of Labor Statistics in 2006. PMID- 26754401 TI - Commentary on "Exploring the Sensitivity of Horn's Parallel Analysis to the Distributional Form of Random Data". PMID- 26754402 TI - A Note on Confidence Intervals for Two-Group Latent Mean Effect Size Measures. AB - This note suggests delta method implementations for deriving confidence intervals for a latent mean effect size measure for the case of 2 independent populations. A hypothetical kindergarten reading example using these implementations is provided, as is supporting LISREL syntax. PMID- 26754403 TI - Differential effect of clomipramine on habituation and prepulse inhibition in dominant versus subordinate rats. AB - Many patients with depression have comorbidities associated with an impairment of sensorimotor gating, such as e.g. schizophrenia, Parkinson Disease, or Alzheimer disease. Anti-depressants like clomipramine that modulate serotonergic or norepinephrinergic neurotransmission have been shown to impact sensorimotor gating, it is therefore important to study potential effects of clomipramine in order to rule out an exacerbation of sensorimotor gating impairment. Prior studies in animals and humans have been inconclusive. Since serotonin and norepinephrine levels are closely related to anxiety and stress levels and therefore to the social status of an animal, we tested the hypothesis that acute and chronic effects of clomipramine on sensorimotor gating are different in dominant versus subordinate rats, which might be responsible for conflicting results in past animal studies. We used habituation and prepulse inhibition (PPI) of the acoustic startle response as operational measures of sensorimotor gating. After establishing the dominant animal in pair-housed male rats, we injected clomipramine for two weeks and measured acute effects on baseline startle, habituation and PPI after the first injection and chronic effects at the end of the two weeks. Chronic treatment with clomipramine significantly increased habituation in subordinate rats, but had no effect on habituation in dominant animals. Furthermore, PPI was slightly enhanced in subordinate rats upon chronic treatment while no changes occurred in dominant animals. We conclude that the social status of an animal, and therefore the basic anxiety/stress level determines whether or not clomipramine has a beneficial effect on sensorimotor gating and discuss possible underlying mechanisms. PMID- 26754405 TI - Prognostic Significance of EZH2 Expression in Non-Small Cell Lung Cancer: A Meta analysis. AB - Various studies examined the relationship between EZH2 overexpression with the clinical outcome in patients with non-small cell lung cancer (NSCLC), but yielded inconsistent results. Electronic databases updated to Dec 2014 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between EZH2 overexpression and survival of patients with NSCLC Survival data were aggregated and quantitatively analyzed. We performed a meta-analysis of 10 studies (n = 1,695 patients) that evaluated the correlation between EZH2 overexpression and survival in patients with lung cancer. Combined hazard ratios suggested that EZH2 overexpression was associated with poor prognosis of overall survival (OS) (HR = 1.68, 95% CI: 1.42 1.93) in patients with lung cancer. In the stratified analysis, significantly risks were found among Asians (HR = 1.33, 95% CI: 1.62-1.70), lung adenocarcinoma patients (HR = 1.75, 95% CI: 1.38-2.52, in stage I NSCLC patients (HR = 2.51, 95% CI: 1.23-3.79), but not among Caucasians. EZH2 overexpression indicates a poor prognosis for patients with NSCLC, this effect appears also significant when the analysis is restricted in Asian population, lung AC and stage I patients, but not among Caucasians. PMID- 26754404 TI - Intestinal parasitic infections in relation to CD4(+) T cell counts and diarrhea in HIV/AIDS patients with or without antiretroviral therapy in Cameroon. AB - BACKGROUND: Intestinal parasitic infections (IPI) are a major public health concern in HIV/AIDS patients particularly in resource-limited settings of Sub Saharan Africa. Studies investigating the relationship between intestinal parasitic infections and CD4(+) T cell counts and diarrhea in HIV/AIDS patients with or without antiretroviral therapy in the region are not readily available hence the need to perform this study. METHODS: In a comparative cross-sectional study involving 52 pre-ART and 248 on-ART HIV patients. Stool samples were collected and analysed for intestinal parasites by wet and iodine mounts, Kato Katz, formol ether, modified field staining, and modified Ziehl-Neelsen staining techniques. Blood samples were collected and analysed for CD4(+) T cell counts by flow cytometry. A pre-tested semi-structured questionnaire was used to collect data on socio-demographic and clinical presentation. Data were analysed using STATA version 12.1. Statistical tests performed included the Pearson Chi-square, logistic regression and student's t-test. P < 0.05 was considered to be statistically significant. RESULTS: The prevalence of intestinal parasitic infections in pre-ART and on-ART was 84.6% and 82.3% respectively with no significant difference observed with respect to age (p = 0.06), and gender (p = 0.736). All the opportunistic parasites including Cryptosporidium parvum, Cyclospora cayetanensis, Isospora belli and Microsporidium spp. were isolated from both groups, with only Microsporidium spp. significantly associated with CD4(+) T cell counts below 200 cells/MUl in pre-ART (p = 0.006) while Cryptosporidium parvum, Microsporidium spp. and Isospora belli were associated with counts below 200 cells/MUl in on-ART. Cryptosporidium parvum was significantly associated with diarrhea in pre-ART (p = 0.025) meanwhile it was significantly associated with diarrhea in on-ART (p = 0.057). The risk of diarrhea was highest in patients with CD4(+) T cell counts below 200 cells/MUl (COR = 10.21, p = 0.000) for both pre- and on-ART treatment. CONCLUSION: A very high prevalence of intestinal parasitic infections was observed, which did not differ with respect to ART status. All known opportunistic parasites were isolated in both pre-ART and on-ART patients. Low CD4(+) T cell count may appear to be a factor for intestinal parasitic infections and development of diarrhea. Regular screening and treatment of intestinal parasitic infections is very vital in improving the overall quality of care of HIV/AIDS patients. PMID- 26754406 TI - Combination of ionising radiation with hyperthermia increases the immunogenic potential of B16-F10 melanoma cells in vitro and in vivo. AB - Mild hyperthermia (HT) (41.5 degrees C for 30-60 min) has been shown in various cell culture systems, preclinical and clinical models to be a very potent radiosensitiser. Recent research suggests that local HT application in combination with standard tumour therapies such as radiotherapy (RT) and/or chemotherapy may not only improve local tumour control but also lead to systemic and immune mediated anti-tumour responses. Melanoma has been proven to be rather radioresistant and mostly only the addition of immunotherapy is capable of inducing beneficial anti-melanoma responses. This work therefore focuses on whether HT increases the immunogenic potential of B16-F10 mouse melanoma cells in combination with RT. The in vitro experiments revealed that combination of RT with HT resulted in an increased percentage of apoptotic and necrotic melanoma cells and an increased release of the danger signal heat shock protein 70 (Hsp70) and high mobility group box protein 1 (HMGB1). HT alone was also capable of inducing this release. We set up local irradiation and heating procedures of B16 F10 tumour-bearing C57/BL6 mice and revealed that the tumour growth of tumours treated with RT plus HT was significantly retarded compared to tumours treated only with RT. This combined treatment generated a beneficial tumour microenvironment by enhancing the infiltration of CD11c + /MHCII + /CD86+ dendritic cells, CD8+ T cells, and NK cells, and decreasing that of regulatory T cells and myeloid-derived suppressor cells. We conclude that HT in combination with RT has an immune-stimulating potential that might result in anti-tumour immunity. PMID- 26754408 TI - The finer points of writing and refereeing scientific articles. AB - Writing scientific papers is a skill required by all haematologists. Many also need to be able to referee papers submitted to journals. These skills are not often formally taught and as a result may not be done well. We have reviewed published evidence of errors in these processes. Such errors may be ethical, scientific or linguistic, or may result from a lack of understanding of the processes. The objective of the review is, by highlighting errors, to help writers and referees to avoid them. PMID- 26754407 TI - Management behaviors of the urology practitioners to the small lower calyceal stones: the results of a web-based survey. AB - Lower pole calyceal stones (LPS) represent lower spontaneous passage rates and, therefore, require several interventional treatment approaches. The aim of this survey study was to investigate the attitudes of the urology practitioners and the factors affecting their decision making in the management of small asymptomatic LPS. A total of 149 urologists participated to the study via email through the internet-based website. Participating urologists were asked to complete a 29-question survey including personal and academic data, level of surgical experience, available equipment for interventional approaches, which treatment do they prefer for small LPS (>=5 mm and <1 cm), and factors affecting their treatment decision. All data were analyzed to make inferences related with treatment decision and factors affecting decision-making. Mean participant age was 41.57 (26-62) years. The most preferred approach was observation/medical treatment option (52.3 %), subsequently SWL (25.5 %), RIRS (16.1 %), miniPNL (5.4 %) and standard PNL (0.7 %) were chosen by the participants. On the other side, SWL and medical treatment were at the forefront (52 and 16.1 %) among children. In the multivariate analysis of participants' age, academic status, surgical experience and institution, none was significantly associated with treatment decision-making (p > 0.05). The most important factors associated with decision making were calyceal dilatation (85.9 %) and patient preferences (81.2 %). The other factors effecting treatment decision were reported to be recurrent disease (70.5 %), the duration of the stone (74.5 %), patient age (95.3 %), current guidelines (87.9 %), stone density (50.3 %), body mass index (BMI) (73.8 %) and other morbid diseases (91.9 %). Our surveys' greatest value is in demonstrating the preferred treatment options and factors effecting decision-making in the treatment of LPS. The most preferred option in our population was follow-up and medical treatment. The most influencing factors on decision-making were age, patients' preferences, presence of calyceal dilatation, body mass index, comorbid conditions, available options for stone treatment and the surgeon's experience on the existing opportunities. PMID- 26754409 TI - Use of Intrarterial Carbon Dioxide-Enhanced Ultrasonography (COEUS) in Patient with Renal Insufficiency Undergoing Trans Arterial-Chemo-Embolization (TACE). PMID- 26754412 TI - Logic circuit prototypes for three-terminal magnetic tunnel junctions with mobile domain walls. AB - Spintronic computing promises superior energy efficiency and nonvolatility compared to conventional field-effect transistor logic. But, it has proven difficult to realize spintronic circuits with a versatile, scalable device design that is adaptable to emerging material physics. Here we present prototypes of a logic device that encode information in the position of a magnetic domain wall in a ferromagnetic wire. We show that a single three-terminal device can perform inverter and buffer operations. We demonstrate one device can drive two subsequent gates and logic propagation in a circuit of three inverters. This prototype demonstration shows that magnetic domain wall logic devices have the necessary characteristics for future computing, including nonlinearity, gain, cascadability, and room temperature operation. PMID- 26754410 TI - Comparative Effectiveness of Prestroke Aspirin on Stroke Severity and Outcome. AB - OBJECTIVE: The effect of prestroke aspirin use on initial severity, hemorrhagic transformation, and functional outcome of ischemic stroke is uncertain. METHODS: Using a multicenter stroke registry database, patients with acute ischemic stroke of three subtypes (large artery atherosclerosis [LAA], small vessel occlusion [SVO], or cardioembolism [CE]) were identified. NIH stroke scale (NIHSS) and hemorrhagic transformation at presentation and discharge modified Rankin Scale (mRS) were compared between prestroke aspirin users and nonusers. RESULTS: Among the 10,433 patients, 1,914 (18.3%) reported prestroke aspirin use. On crude analysis, initial NIHSS scores of aspirin users were higher than nonusers (mean difference: 0.35; 95% confidence interval [CI]: 0.04-0.66). However, a multivariable analysis with an application of inverse probability of treatment weighting based on a propensity score of prestroke aspirin, having an interaction effect of prestroke aspirin use and stroke subtype in the model, showed less stroke severity for aspirin users in LAA, but not in SVO and CE than for nonusers; mean difference in NIHSS scores in LAA was -0.97 (95% CI: -1.45 to 0.49). With respect to hemorrhagic transformation and mRS, no significant interaction effects were found. Prestroke aspirin use increased the risk of hemorrhagic transformation (adjusted odd ratio: 1.34; 95% CI: 1.05-1.73), but decreased the odds of the higher discharge mRS (0.86; 0.76-0.96). INTERPRETATION: Prestroke aspirin use may reduce initial stroke severity in atherothrombotic stroke and can improve functional outcome at discharge despite an increase of hemorrhagic transformation irrespective of stroke subtype. PMID- 26754413 TI - Transfer Printed P3HT/PCBM Photoactive Layers: From Material Intermixing to Device Characteristics. AB - The fabrication of organic electronic devices involving complex stacks of solution-processable functional materials has proven challenging. Significant material intermixing often occurs as a result of cross-solubility and postdeposition treatments, rendering the realization of even the simplest bilayer architectures rather cumbersome. In this study we investigate the feasibility of a dry transfer printing process for producing abrupt bilayer organic photodiodes (OPDs) and the effect of thermal annealing on the integrity of the bilayer. The process involves the transfer of readily deposited thin films of poly(3 hexylthiophene-2,5-diyl) (P3HT) and [6,6]-phenyl C61 butyric acid methyl ester (PCBM) using a polydimethylsiloxane (PDMS) stamp. Fabricated structures are characterized by means of cross-sectional scanning electron microscopy (SEM), UV/vis absorption spectroscopy, and time-of-flight secondary ion mass spectrometry (TOF-SIMS). Joint consideration of all results unveils abrupt interfaces with no thermal treatment applied and significant material intermixing for samples annealed above 100 degrees C. The role of the thermally assisted intermixing in determining the performance of complete devices is evaluated through the comparison of J-V characteristics and external quantum efficiencies (EQEs) of identical photodiodes subject to different annealing conditions. It is shown that the performance of such devices approaches the one of bulk heterojunction photodiodes upon thermal annealing at 140 degrees C for 5 min. Our results demonstrate that transfer printing is a reliable and simple process for the realization of functional multilayers, paving the way for organic electronic devices incorporating complex stacks. It further contributes to a fundamental understanding of material composition within photoactive layers by elucidating the process of thermally assisted intermixing. PMID- 26754414 TI - Phase separation of comb polymer nanocomposite melts. AB - In this work, the spinodal phase demixing of branched comb polymer nanocomposite (PNC) melts is systematically investigated using the polymer reference interaction site model (PRISM) theory. To verify the reliability of the present method in characterizing the phase behavior of comb PNCs, the intermolecular correlation functions of the system for nonzero particle volume fractions are compared with our molecular dynamics simulation data. After verifying the model and discussing the structure of the comb PNCs in the dilute nanoparticle limit, the interference among the side chain number, side chain length, nanoparticle monomer size ratio and attractive interactions between the comb polymer and nanoparticles in spinodal demixing curves is analyzed and discussed in detail. The results predict two kinds of distinct phase separation behaviors. One is called classic fluid phase boundary, which is mediated by the entropic depletion attraction and contact aggregation of nanoparticles at relatively low nanoparticle-monomer attraction strength. The second demixing transition occurs at relatively high attraction strength and involves the formation of an equilibrium physical network phase with local bridging of nanoparticles. The phase boundaries are found to be sensitive to the side chain number, side chain length, nanoparticle-monomer size ratio and attractive interactions. As the side chain length is fixed, the side chain number has a large effect on the phase behavior of comb PNCs; with increasing side chain number, the miscibility window first widens and then shrinks. When the side chain number is lower than a threshold value, the phase boundaries undergo a process from enlarging the miscibility window to narrowing as side chain length increases. Once the side chain number overtakes this threshold value, the phase boundary shifts towards less miscibility. With increasing nanoparticle-monomer size ratio, a crossover of particle size occurs, above which the phase separation is consistent with that of chain PNCs. The miscibility window for this condition gradually narrows while the other parameters of the PNCs system are held constant. These results indicate that the present PRISM theory can give molecular-level details of the underlying mechanisms of the comb PNCs. It is hoped that the results can be used to provide useful guidance for the future design control of novel, thermodynamically stable comb PNCs. PMID- 26754411 TI - Identification of genomic variants putatively targeted by selection during dog domestication. AB - BACKGROUND: Dogs [Canis lupus familiaris] were the first animal species to be domesticated and continue to occupy an important place in human societies. Recent studies have begun to reveal when and where dog domestication occurred. While much progress has been made in identifying the genetic basis of phenotypic differences between dog breeds we still know relatively little about the genetic changes underlying the phenotypes that differentiate all dogs from their wild progenitors, wolves [Canis lupus]. In particular, dogs generally show reduced aggression and fear towards humans compared to wolves. Therefore, selection for tameness was likely a necessary prerequisite for dog domestication. With the increasing availability of whole-genome sequence data it is possible to try and directly identify the genetic variants contributing to the phenotypic differences between dogs and wolves. RESULTS: We analyse the largest available database of genome-wide polymorphism data in a global sample of dogs 69 and wolves 7. We perform a scan to identify regions of the genome that are highly differentiated between dogs and wolves. We identify putatively functional genomic variants that are segregating or at high frequency [> = 0.75 Fst] for alternative alleles between dogs and wolves. A biological pathways analysis of the genes containing these variants suggests that there has been selection on the 'adrenaline and noradrenaline biosynthesis pathway', well known for its involvement in the fight or-flight response. We identify 11 genes with putatively functional variants fixed for alternative alleles between dogs and wolves. The segregating variants in these genes are strong candidates for having been targets of selection during early dog domestication. CONCLUSIONS: We present the first genome-wide analysis of the different categories of putatively functional variants that are fixed or segregating at high frequency between a global sampling of dogs and wolves. We find evidence that selection has been strongest around non-synonymous variants. Strong selection in the initial stages of dog domestication appears to have occurred on multiple genes involved in the fight-or-flight response, particularly in the catecholamine synthesis pathway. Different alleles in some of these genes have been associated with behavioral differences between modern dog breeds, suggesting an important role for this pathway at multiple stages in the domestication process. PMID- 26754416 TI - Possible pitfalls in the diagnostic of progressive multifocal leukoencephalopathy. AB - The most accurate diagnosis of clinically suspected progressive multifocal leukoencephalopathy (PML) is made by neuronavigated needle brain biopsy and microscopic examination of the specimen confirming typical morphological features of the disease and, additionally, using immunohistochemistry (IHC) for detection of early viral proteins of the etiologic agent - polyoma virus JC (JCV). Due to the small biopsy volume, this approach can sometimes fail to confirm the clinical diagnosis of PML, as demonstrated by the presented clinical case. To check the reliability of using only IHC, we additionally tested 6 archival cases from our institute using IHC, in-situ hybridization (ISH) and real-time polymerase chain reaction (PCR). In the presented case, both biopsy and autopsy material were tested, in three archival cases only biopsy material and in the remaining cases post-mortem brain tissue was available. IHC (Anti-SV40 T antigen, mAb Pab416) was negative in 3 samples, in another 3 fewer than 10 cells per one *20 microscopic field were positive. In our study, ISH proved to be a more sensitive method for JCV detection than IHC, being positive in all cases. Out of 7 tested specimens, realtime PCR failed to confirm the presence of JCV in 1 specimen, which was the oldest brain autopsy of an AIDS patient. Our study demonstrated that, especially when confronted with borderline clinical suspicion of PML and when only a small biopsy specimen is available, a combination of at least two different methods for JCV detection should be considered, preferably IHC with one of the available molecular methods. PMID- 26754417 TI - Fatal recurrent dermatoneuro syndrome associated with systemic AL amyloidosis. AB - A male patient is presented with long-lasting paraproteinemia of monoclonal IgG lambda, who suffered from recurrent, and until the last one, mostly reversible episodes of dermatoneuro syndrome, described exclusively in scleromyxedema. The skin biopsy revealed lambda-light chain amyloid deposition instead of changes typical for scleromyxedema. Systemic AL amyloidosis was diagnosed post mortem since the patient had no clinical signs of any other organ impairment except skin and brain. Neuropathology is described and possible etiopathogenesis of brain involvement is considered. PMID- 26754418 TI - Predicting gestational diabetes mellitus during the first trimester using anthropometric measurements and HOMA-IR. AB - PURPOSE: To determine the predictability of gestational diabetes mellitus (GDM) during the first trimester using the degree of insulin resistance and anthropometric measurements and to assign the risk of developing GDM by weight gained during pregnancy (WGDP). METHODS: A total of 250 singleton pregnancies at 7-12 gestational weeks were studied. Body mass index (BMI), waist/hip ratio (WHR), quantitative insulin sensitivity check index (QUICKI), homeostasis model assessment-insulin resistance (HOMA-IR) scores and WGDP were determined. The backward stepwise method was applied to estimate possible associations with GDM. Cutoff points were estimated using receiver operating characteristic curve analysis. RESULTS: GDM was found in 20 of 227 singleton pregnancies (8.8 %). The calculated HOMA-IR, QUICKI, BMI, WHR, WGDP, and parity were significantly associated with GDM. Logistic regression analyses showed that three covariates (HOMA-IR, BMI, WGDP) remained independently associated with GDM. It was calculated as OR 1.254 (95 % CI 1.006-1.563), AUC 0.809, sensitivity 90 %, specificity 61 % with cutoff = 2.08 for HOMA-IR; OR 1.157 (CI 1.045-1.281), AUC 0.723, sensitivity 80 %, specificity 58 % with cutoff = 25.95 for BMI; OR 1.221, (CI 1.085-1.374), AUC 0.654, sensitivity 80 %, specificity 46 % with cutoff = 4.7 for WGDP. Despite a HOMA-IR score of >3.1 in pregnant women, GDM was detected in only three of 29 patients (10.3 %) if WGDP was <4.7 kg at weeks 24-28. CONCLUSIONS: First trimester screening for GDM can be achieved based on maternal anthropometric measurements and HOMA-IR. In particular, if BMI is >25.95 kg/m(2) and the HOMA-IR score >2.08, controlling weight gain may protect against GDM. PMID- 26754420 TI - Employment and sick leave in patients with prostate cancer before, during and after radiotherapy. AB - OBJECTIVE: The aim of this study was to determine employment outcomes after radiotherapy (RT) for prostate cancer (PCa). MATERIALS AND METHODS: The Danish DREAM database contains information about social benefits paid to Danish citizens. Data are recorded prospectively every week. From the database, it is possible to assess whether a patient is working, on sick leave or retired at a certain time. Data on 417 Danish citizens treated with RT for PCa at Rigshospitalet, Copenhagen, between 1 January 2005 and 1 May 2010 were obtained from the database. The data were collected during a 2 year period from 1 year before RT to 1 year after RT. RESULTS: Among patients of working age, 75% were still available for work 1 year after RT. The degree of sick leave increased almost continuously in the year before the start of RT and reached a maximum of 56% during RT. After RT it gradually declined. There was no significant difference between the number of patients on sick leave 1 year after RT compared to 1 year before RT (p = 0.23). Patients spent a significantly higher number of weeks on sick leave in the year after the start of RT compared to the year before RT (p = 0.001). CONCLUSION: Except for a transient increase in sick leave during treatment, RT did not seem to affect the working lives of patients with PCa significantly. PMID- 26754419 TI - Isolation and fine mapping of Rps6: an intermediate host resistance gene in barley to wheat stripe rust. AB - KEY MESSAGE: We uncouple host and nonhost resistance in barley to Puccinia striiformis ff. spp. hordei and tritici . We isolate, fine map, and physically anchor Rps6 to chromosome 7H in barley. A plant may be considered a nonhost of a pathogen if all known genotypes of a plant species are resistant to all known isolates of a pathogen species. However, if a small number of genotypes are susceptible to some known isolates of a pathogen species this plant may be considered an intermediate host. Barley (Hordeum vulgare) is an intermediate host for Puccinia striiformis f. sp. tritici (Pst), the causal agent of wheat stripe rust. We wanted to understand the genetic architecture underlying resistance to Pst and to determine whether any overlap exists with resistance to the host pathogen, Puccinia striiformis f. sp. hordei (Psh). We mapped Pst resistance to chromosome 7H and show that host and intermediate host resistance is genetically uncoupled. Therefore, we designate this resistance locus Rps6. We used phenotypic and genotypic selection on F2:3 families to isolate Rps6 and fine mapped the locus to a 0.1 cM region. Anchoring of the Rps6 locus to the barley physical map placed the region on a single fingerprinted contig spanning a physical region of 267 kb. Efforts are now underway to sequence the minimal tiling path and to delimit the physical region harboring Rps6. This will facilitate additional marker development and permit identification of candidate genes in the region. PMID- 26754421 TI - Two Variants of a High-Throughput Fluorescent Microplate Assay of Polysaccharide Endotransglycosylases. AB - Polysaccharide endotransglycosylases (PETs) are the cell wall-modifying enzymes of fungi and plants. They catalyze random endo-splitting of the polysaccharide donor molecule and transfer of the newly formed reducing sugar residue to the nonreducing end of an acceptor molecule which can be a polysaccharide or an oligosaccharide. Owing to their important role in the cell wall formation, the inhibition of PETs represents an attractive strategy in the fight against fungal infections. We have elaborated two variants of a versatile high-throughput microplate fluorimetric assay that could be used for effective identification of PETs and screening of their inhibitors. Both assays use the respective polysaccharides as the donors and sulforhodamine-labeled oligosaccharides as the acceptors but differ from each other by mode of how the labeled polysaccharide products of transglycosylation are separated from the unreacted oligosaccharide acceptors. In the first variant, the reactions take place in a layer of agar gel laid on the bottoms of the wells of a microtitration plate. After the reaction, the high-Mr transglycosylation products are precipitated with 66 % ethanol and retained within the gel while the low-Mr products and the unreacted acceptors are washed out. In the second variant, the donor polysaccharides are adsorbed to the surface of a microplate well and remain adsorbed there also after becoming labeled in the course of the transglycosylation reaction whereas the unused low Mr acceptors are washed out. As a proof of versatility, assays of heterologously expressed transglycosylases ScGas1, ScCrh1, and ScCrh2 from the yeast Saccharomyces cerevisiae, CaPhr1 and CaPhr2 from Candida albicans, and of a plant xyloglucan endotransglycosylase (XET) are demonstrated. PMID- 26754422 TI - Enzymatic Hydrophobic Modification of Jute Fibers via Grafting to Reinforce Composites. AB - Horseradish peroxidase (HRP)/H2O2 system catalyzes the free-radical polymerization of aromatic compounds such as lignins and gallate esters. In this work, dodecyl gallate (DG) was grafted onto the surfaces of lignin-rich jute fabrics by HRP-mediated oxidative polymerization with an aim to enhance the hydrophobicity of the fibers. The DG-grafted jute fibers and reaction products of their model compounds were characterized by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS), attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). The results clearly indicated the grafting of DG to the jute fiber by HRP. Furthermore, the hydrophobicity of jute fabrics was determined by measuring the wetting time and static contact angle. Compared to the control sample, the wetting time and static contact angle of the grated fabrics changed from ~1 s to 1 h and from ~0 degrees to 123.68 degrees , respectively. This clearly proved that the hydrophobicity of jute fabrics improved considerably. Conditions of the HRP-catalyzed DG-grafting reactions were optimized in terms of the DG content of modified jute fabrics. Moreover, the results of breaking strength and elongation of DG-grafted jute/polypropylene (PP) composites demonstrated improved reinforcement of the composite due to enzymatic hydrophobic modification of jute fibers. PMID- 26754423 TI - Functional Characterization of a Novel Marine Microbial GDSL Lipase and Its Utilization in the Resolution of (+/-)-1-Phenylethanol. AB - A novel GDSL lipase (MT6) was cloned from the genome of Marinactinospora thermotolerans SCSIO 00652 identified from the South China Sea. MT6 showed its maximum identity of 59 % with a putative lipase from Nocardiopsis dassonville. MT6 was heterologously expressed in E. coli BL21(DE3) and further functionally characterized. MT6 could efficiently resolve racemic 1-phenylethanol and generate (R)-1-phenylethanol with high enantiomeric excess (99 %) and conversion rate (54 %) through transesterification reactions after process optimization. Our report was the first one report about the utilization of one GDSL lipase in the preparation of chiral chemicals by transesterification reactions, and the optical selectivity of MT6 was interestingly opposite to those of other common lipases. GDSL lipases represented by MT6 possess great potential for the generation of valuable chiral chemicals in industry. PMID- 26754426 TI - Nitric oxide function in plant abiotic stress. AB - Abiotic stress is one of the main threats affecting crop growth and production. An understanding of the molecular mechanisms that underpin plant responses against environmental insults will be crucial to help guide the rational design of crop plants to counter these challenges. A key feature during abiotic stress is the production of nitric oxide (NO), an important concentration dependent, redox-related signalling molecule. NO can directly or indirectly interact with a wide range of targets leading to the modulation of protein function and the reprogramming of gene expression. The transfer of NO bioactivity can occur through a variety of potential mechanisms but chief among these is S nitrosylation, a prototypic, redox-based, post-translational modification. However, little is known about this pivotal molecular amendment in the regulation of abiotic stress signalling. Here, we describe the emerging knowledge concerning the function of NO and S-nitrosylation during plant responses to abiotic stress. PMID- 26754425 TI - Correlates of overdose risk perception among illicit opioid users. AB - BACKGROUND: Opioid-related mortality continues to increase in the United States. The current study assesses demographic and behavioral predictors of perceived overdose risk among individuals who use opioids illicitly. By examining these correlates in the context of established overdose risk factors, we aim to assess whether characteristics and behaviors that have been associated with actual overdose risk translate to higher perception of risk. METHODS: We conducted a cross-sectional survey of 172 adult illicit opioid users in San Francisco, CA and used multivariable logistic regression to identify predictors of perception of high risk for opioid overdose. RESULTS: Age (aOR=0.96, 95%CI=0.93-1.00) and number of injection days per month (0.91, 0.86-0.97) were associated with a lower odds of perceived high overdose risk. There was no independent association between use of opioid analgesics, concurrent use of opioids and benzodiazepines or cocaine, or HIV status and overdose risk perception. CONCLUSIONS: Opioid users who injected more frequently and those who were older were less likely to perceive themselves as being at risk of overdose, notwithstanding that those who inject more are at higher risk of overdose and those who are older are at higher risk overdose mortality. In addition, despite being established overdose risk factors, there was no relationship between use of opioid analgesics, concurrent use of opioids and cocaine or benzodiazepines, or self-reported HIV status and overdose risk perception. These findings highlight key populations of opioid users and established risk factors that may merit focused attention as part of education-based overdose prevention and opioid management strategies. PMID- 26754424 TI - MSC surface markers (CD44, CD73, and CD90) can identify human MSC-derived extracellular vesicles by conventional flow cytometry. AB - BACKGROUND: Human mesenchymal stromal cells (hMSC) are multipotent cells with both regenerative and immunomodulatory activities making them an attractive tool for cellular therapy. In the last few years it has been shown that the beneficial effects of hMSC may be due to paracrine effects and, at least in part, mediated by extracellular vesicles (EV). EV have emerged as important mediators of cell-to cell communication. Flow cytometry (FCM) is a routine technology used in most clinical laboratories and could be used as a methodology for hMSC-EV characterization. Although several reports have characterized EV by FCM, a specific panel and protocol for hMSC-derived EV is lacking. The main objective of our study was the characterization of hMSC-EV using a standard flow cytometer. METHODS: Human MSC from bone marrow of healthy donors, mesenchymal cell lines (HS 5 and hTERT) and a leukemic cell line (K562 cells) were used to obtain EV for FCM characterization. EV released from the different cell lines were isolated by ultracentrifugation and were characterized, using a multi-parametric analysis, in a conventional flow cytometer. EV characterization by transmission electron microscopy (TEM), western blot (WB) and Nano-particle tracking analysis (NTA) was also performed. RESULTS: EV membranes are constituted by the combination of specific cell surface molecules depending on their cell of origin, together with specific proteins like tetraspanins (e.g. CD63). We have characterized by FCM the EV released from BM-hMSC, that were defined as particles less than 0.9 MUm, positive for the hMSC markers (CD90, CD44 and CD73) and negative for CD34 and CD45 (hematopoietic markers). In addition, hMSC-derived EV were also positive for CD63 and CD81, the two characteristic markers of EV. To validate our characterization strategy, EV from mesenchymal cell lines (hTERT/HS-5) were also studied, using the leukemia cell line (K562) as a negative control. EV released from mesenchymal cell lines displayed the same immunophenotypic profile as the EV from primary BM-hMSC, while the EV derived from K562 cells did not show hMSC markers. We further validated the panel using EV from hMSC transduced with GFP. Finally, EV derived from the different sources (hMSC, hTERT/HS-5 and K562) were also characterized by WB, TEM and NTA, demonstrating the expression by WB of the exosomal markers CD63 and CD81, as well as CD73 in those from MSC origin. EV morphology and size/concentration was confirmed by TEM and NTA, respectively. CONCLUSION: We described a strategy that allows the identification and characterization by flow cytometry of hMSC-derived EV that can be routinely used in most laboratories with a standard flow cytometry facility. PMID- 26754427 TI - Integrative Advanced Oxidation and Biofiltration for Treating Pharmaceuticals in Wastewater. AB - Advanced oxidation of active pharmaceutical ingredients (APIs) in wastewater produces transformation products (TPs) that are often more biodegradable than the parent compounds. Secondary effluent from a wastewater treatment plant was treated using UV-based advanced oxidation (LPUV/H2O2 and MPUV/NO3) followed by biological aerated filtration (BAF), and different APIs and their transformation products were monitored. The advanced oxidation processes degraded the APIs by 55 87% (LPUV/H2O2) and 58-95% (MPUV/NO3), while minor loss of APIs was achieved in the downstream BAF system. Eleven TPs were detected following oxidation of carbamazepine (5) and iopromide (6); three key TPs were biodegraded in the BAF system. The other TPs remained relatively constant in the BAF. The decrease in UV absorbance (UVA254) of the effluent in the BAF system was linearly correlated to the degradation of the APIs (for the MPUV/NO3-BAF), and can be applied to monitor the biotransformation of APIs in biological-based systems. PMID- 26754428 TI - Effect of spinal immobilisation devices on radiation exposure in conventional radiography and computed tomography. AB - Trauma patients at risk for, or suspected of, spinal injury are frequently transported to hospital using full spinal immobilisation. At the emergency department, immobilisation is often maintained until radiological work-up is completed. In this study, we examined how these devices influence radiation exposure and noise, as a proxy for objective image quality. Conventional radiographs (CR) and computer tomography (CT) scans were made using a phantom immobilised on two types of spineboard and a vacuum mattress and using two types of headblocks. Images were compared for radiation transmission and quantitative image noise. In CR, up to 23 % and, in CT, up to 11 % of radiation were blocked by the devices. Without compensation for the decreased transmission, noise increased by up to 16 % in CT, depending on the device used. Removing the headblocks led to a statistically significant improvement in transmission with automatic exposure control (AEC) enabled. Physicians should make an informed decision whether the increased radiation exposure outweighs the risk of missing a clinically significant injury by not making a CR or CT scan. Manufacturers of immobilisation devices should take radiological properties of their devices into account in the development and production process. PMID- 26754429 TI - Granulomatosis with polyangiitis (Wegener's) hidden in the aortic valve. PMID- 26754430 TI - Comparison of resin bonding improvements to zirconia between one-bottle universal adhesives and tribochemical silica coating, which is better? AB - OBJECTIVES: To evaluate the bonding of resin-cement to yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) via silica coating followed by silanization, and three one-bottle universal adhesives, with or without prior conditioning using a zirconia primer. METHODS: Y-TZP specimens (n=160) were conditioned by tribochemical silica coating and silanization (CS), or alumina sandblasting with one of the following MDP containing adhesives or primers: Z Prime PlusTM (zirconia primer, ZP), Single Bond UniversalTM (SU), Clearfil Universal BondTM (CU) or All-Bond UniversalTM (AU). Additionally, some specimens (ZPSU, ZPCU and ZPAU) received Z-Prime PlusTM followed by one of the three adhesives. After 24h water storage and "aging" (20,000 thermocycles plus additional 40-day water storage), shear bond strength (SBS) was measured. Fourier transform infrared spectroscopy (FTIR) and X-ray Photoelectron Spectroscopy (XPS) were employed for characterization of the chemical bonds between the primer/adhesives and the zirconia. Thermodynamic calculations were used to examine the hydrolytic stability between the MDP-zirconia chemical bonds and the SiO2-silane chemical bonds. RESULTS: The CS and ZPCU groups showed higher SBS than the other six groups. There were no significant pairwise differences amongst ZP, SU and ZPSU, or amongst ZP, AU and ZPAU. Aging led to significantly decreased SBS for all groups except CS and ZPCU. There was no statistically significant interaction between surface treatment and aging. XPS determined the chemical bonds between MDP and zirconia. FTIR showed similar shifts in characteristic phosphate peaks for all the primer and/or adhesive groups. Result of thermodynamic calculation showed that equilibrium constant of SiO2-silane system is much larger than the one of MDP-tetragonal phase zirconia system. SIGNIFICANCE: The application of one-bottle universal adhesives after alumina sandblasting is an alternative to tribochemical silica coating with silanization for bonding to zirconia, while bonding between resin and Y-TZP is more susceptible to hydrolysis when zirconia primer or one-bottle universal adhesive is used. PMID- 26754431 TI - Mono or polycrystalline alumina-modified hybrid ceramics. AB - OBJECTIVES: This study evaluated the effect of addition of alumina particles (polycrystalline or monocrystalline), with or without silica coating, on the optical and mechanical properties of a porcelain. METHODS: Groups tested were: control (C), polycrystalline alumina (PA), polycrystalline alumina-silica (PAS), monocrystalline alumina (MA), monocrystalline alumina-silica (MAS). Polycrystalline alumina powder was synthesized using a polymeric precursor method; a commercially available monocrystalline alumina powder (sapphire) was acquired. Silica coating was obtained by immersing alumina powders in a tetraethylorthosilicate solution, followed by heat-treatment. Electrostatic stable suspension method was used to ensure homogenous dispersion of the alumina particles within the porcelain powder. The ceramic specimens were obtained by heat-pressing. Microstructure, translucency parameter, contrast ratio, opalescence index, porosity, biaxial flexural strength, roughness, and elastic constants were characterized. RESULTS: A better interaction between glass matrix and silica coated crystalline particles is suggested in some analyses, yet further investigation is needed to confirm it. The materials did not present significant differences in biaxial flexural strength, due to the presence of higher porosity in the groups with alumina addition. Elastic modulus was higher for MA and MAS groups. Also, these were the groups with optical qualities and roughness closer to control. The PA and PAS groups were considerably more opaque as well as rougher. SIGNIFICANCE: Porcelains with addition of monocrystalline particles presented superior esthetic qualities compared to those with polycrystalline particles. In order to eliminate the porosity in the ceramic materials investigated herein, processing parameters need to be optimized as well as different glass frites should be tested. PMID- 26754432 TI - Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence. AB - Chronic hepatitis C virus (HCV) infection with advanced cirrhosis or post-liver transplantation recurrence represents a high unmet medical need with no approved therapies effective across all HCV genotypes. The open-label ALLY-1 study assessed the safety and efficacy of a 60-mg once-daily dosage of daclatasvir (pan genotypic NS5A inhibitor) in combination with sofosbuvir at 400 mg once daily (NS5B inhibitor) and ribavirin at 600 mg/day for 12 weeks with a 24-week follow up in two cohorts of patients with chronic HCV infection of any genotype and either compensated/decompensated cirrhosis or posttransplantation recurrence. Patients with on-treatment transplantation were eligible to receive 12 additional weeks of treatment immediately after transplantation. The primary efficacy measure was sustained virologic response at posttreatment week 12 (SVR12) in patients with a genotype 1 infection in each cohort. Sixty patients with advanced cirrhosis and 53 with posttransplantation recurrence were enrolled; HCV genotypes 1 (76%), 2, 3, 4, and 6 were represented. Child-Pugh classifications in the advanced cirrhosis cohort were 20% A, 53% B, and 27% C. In patients with cirrhosis, 82% (95% confidence interval [CI], 67.9%-92.0%) with genotype 1 infection achieved SVR12, whereas the corresponding rates in those with genotypes 2, 3, and 4 were 80%, 83%, and 100%, respectively; SVR12 rates were higher in patients with Child-Pugh class A or B, 93%, versus class C, 56%. In transplant recipients, SVR12 was achieved by 95% (95% CI, 83.5%-99.4%) and 91% of patients with genotype 1 and 3 infection, respectively. Three patients received peritransplantation treatment with minimal dose interruption and achieved SVR12. There were no treatment-related serious adverse events. CONCLUSION: The pan genotypic combination of daclatasvir, sofosbuvir, and ribavirin was safe and well tolerated. High SVR rates across multiple HCV genotypes were achieved by patients with post-liver transplantation recurrence or advanced cirrhosis. PMID- 26754439 TI - Pseudodiastrophic dysplasia: Two cases delineating and expanding the pre and postnatal phenotype. PMID- 26754440 TI - Highly hydrophilic poly(vinylidene fluoride)/meso-titania hybrid mesoporous membrane for photocatalytic membrane reactor in water. AB - The high hydrophobicity of poly(vinylidene fluoride) (PVDF) membrane remains an obstacle to be applied in some purification processes of water or wastewater. Herein, a highly hydrophilic hybrid mesoporous titania membrane composed of mesoporous anatase titania (meso-TiO2) materials inside the three-dimensional (3D) macropores of PVDF membrane was successfully prepared by using the dual templated synthesis method combined with solvent extraction and applied as the photocatalytic membrane reactor for the photodegredation of organic dye in water. The structure and the properties of as-prepared hybrid membranes were characterized by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), transmission electron microscopy (TEM), X-ray diffraction (XRD), nitrogen adsorption-desorption and contact angle measurements. It was found that the hydrophilicity of PVDF membrane can be significantly improved by filling mesoporous TiO2 inside the 3D macropores of PVDF membrane. Moreover, such a PVDF/meso-TiO2 hybrid membrane exhibits promising photocatalytic degradation of dye in water due to the existence of mesoporous anatase TiO2 materials inside PVDF membrane. This study provides a new strategy to simultaneously introduce hydrophilicity and some desirable properties into PVDF and other hydrophobic membranes. PMID- 26754433 TI - Single nucleotide polymorphism rs3774261 in the AdipoQ gene is associated with the risk of coronary heart disease (CHD) in Northeast Han Chinese population: a case-control study. AB - BACKGROUND: Coronary Heart Disease (CHD) is one of the leading causes of death in the world with a projected global 82 million DALYs by 2020. Genetic and environmental factors contribute to CHD development. Here, the authors investigate the association between CHD risk and three Single Nucleotide Polymorphisms (SNPs) in the AdipoQ gene (rs3774261, rs1063537 and rs2082940); and the interaction of this association with environmental factors, in Northeast Han Chinese population. METHODS: Using a case-control study design, 1514 participants (754 cases and 760 controls) were investigated. Three variants in the AdipoQ gene (rs3774261, rs1063537 and rs2082940) were selected and genotyped. The online SNPstats program and SPSS 21.0 software were used for data analyses. RESULTS: The authors found that the rs3774261G allele is associated with the risk of CHD but that the rs2082940T allele protects against CHD. No significant association was found between rs1063537 and CHD risk. The study also found significant interactions between triglyceride levels and the SNPs studied (P < 0.0001 for rs3774261, P = 0.014 for rs1063537, and P = 0.031 for rs2082940). CONCLUSIONS: Variations in AdipoQ gene can protect against CHD (as with rs2082940T) or associated with CHD risk (as with rs3774261G) in Northeast Han Chinese - findings that will help shed light on the reported conflicting roles of AdipoQ in cardiovascular diseases. Serum triglycerides levels also interact in the AdipoQ - CHD association, thus further highlighting the roles environmental factors play in the genetic aspect of diseases. PMID- 26754442 TI - A Bayesian Model For The Estimation Of Latent Interaction And Quadratic Effects When Latent Variables Are Non-Normally Distributed. AB - Structural equation models with interaction and quadratic effects have become a standard tool for testing nonlinear hypotheses in the social sciences. Most of the current approaches assume normally distributed latent predictor variables. In this article, we present a Bayesian model for the estimation of latent nonlinear effects when the latent predictor variables are nonnormally distributed. The nonnormal predictor distribution is approximated by a finite mixture distribution. We conduct a simulation study that demonstrates the advantages of the proposed Bayesian model over contemporary approaches (Latent Moderated Structural Equations [LMS], Quasi-Maximum-Likelihood [QML], and the extended unconstrained approach) when the latent predictor variables follow a nonnormal distribution. The conventional approaches show biased estimates of the nonlinear effects; the proposed Bayesian model provides unbiased estimates. We present an empirical example from work and stress research and provide syntax for substantive researchers. Advantages and limitations of the new model are discussed. PMID- 26754441 TI - Basilar impression presenting as intermittent mechanical neck pain: a rare case report. AB - BACKGROUND: Neck pain is one of the most common musculoskeletal disorders in clinical practice. However neck pain may mask more serious pathology. Although uncommon in most musculoskeletal physiotherapy practices, it is possible to encounter rare and extremely life-threatening conditions, such as craniovertebral congenital anomalies. Basilar invagination is an abnormality where the odontoid peg projects above the foramen magnum and is the commonest malformation of the craniocervical junction. Its prevalence in the general population is estimated to be 1%. Furthermore, it is a well-recognised cause of neck pain insomuch as it can be easily overlooked and mistaken for a musculoskeletal disorder. Diagnosis is based on the patient's symptoms in conjunction with magnetic resonance imaging (MRI). If life-threatening symptoms, or pressure on the spinal cord are present, the recommended treatment is typically surgical correction. CASE PRESENTATION: This case report describes the history, relevant examination findings, and clinical reasoning used for a 37 year old male who had the chief complaint of neck pain and occipital headache. After the history and the physical examination, there were several key indicators in the patient's presentation that appeared to warrant further investigation with diagnostic imaging: (1) the drop attack after a triggering event (i.e., heading a football), (2) several episodes of facial numbness immediately and shortly after the trauma, (3) the poorly defined muscle upper extremity muscle weakness, and (4) the modification of symptoms during the modified Sharp-Purser test. Therefore, the decision was made to contact the referring neurosurgeon to discuss the patient's history and his physical examination. The physician requested immediate cervical spine MRI, which revealed a "basilar impression". CONCLUSION: This case report highlights the need for more research into a number of issues surrounding the prevalence, diagnosis, and the central role of primary care clinicians such as physiotherapists. Furthermore it underlines the importance of including Basilar invagination in the differential diagnosis. Physiotherapists working within a direct access environment must take a comprehensive history and be capable of screening for non-musculoskeletal medical conditions (on a systems, not diagnosis level) in order to avoid providing potentially harmful musculoskeletal treatments (e.g., cervical mobilization or manipulation, stretching, exercise) to patients with sinister medical pathologies, not benign musculoskeletal disorders. PMID- 26754443 TI - A Model-Free Diagnostic for Single-Peakedness of Item Responses Using Ordered Conditional Means. AB - In this article we propose a model-free diagnostic for single-peakedness (unimodality) of item responses. Presuming a unidimensional unfolding scale and a given item ordering, we approximate item response functions of all items based on ordered conditional means (OCM). The proposed OCM methodology is based on Thurstone & Chave's (1929) criterion of irrelevance, which is a graphical, exploratory method for evaluating the "relevance" of dichotomous attitude items. We generalized this criterion to graded response items and quantified the relevance by fitting a unimodal smoother. The resulting goodness-of-fit was used to determine item fit and aggregated scale fit. Based on a simulation procedure, cutoff values were proposed for the measures of item fit. These cutoff values showed high power rates and acceptable Type I error rates. We present 2 applications of the OCM method. First, we apply the OCM method to personality data from the Developmental Profile; second, we analyze attitude data collected by Roberts and Laughlin (1996) concerning opinions of capital punishment. PMID- 26754444 TI - Investigating Reliabilities of Intraindividual Variability Indicators. AB - Reliabilities of the two most widely used intraindividual variability indicators, ISD (2) and ISD, are derived analytically. Both are functions of the sizes of the first and second moments of true intraindividual variability, the size of the measurement error variance, and the number of assessments within a burst. For comparison, the reliability of the intraindividual mean, [Formula: see text], is also derived. Simulations are conducted to confirm accuracy of the derived functions. The influences of different factors on the reliabilities of these indicators are also studied. Results show that the reliabilities of ISD (2) and ISD are lower than the reliability of [Formula: see text] in all studied conditions and the reliability of ISD is lower than that of ISD (2) in most studied conditions. The derived functions are applied to calculate the reliabilities of intraindividual variability indicators of negative affect measured over 56 days and perceptual-motor performance measured over five assessments. Implications for measurement-burst study designs are discussed. PMID- 26754445 TI - Erratum to: Surgical robotics beyond enhanced dexterity instrumentation: a survey of machine learning techniques and their role in intelligent and autonomous surgical actions. PMID- 26754446 TI - Robot-assisted automatic ultrasound calibration. AB - PURPOSE: Ultrasound (US) calibration is the process of determining the unknown transformation from a coordinate frame such as the robot's tooltip to the US image frame and is a necessary task for any robotic or tracked US system. US calibration requires submillimeter-range accuracy for most applications, but it is a time-consuming and repetitive task. We provide a new framework for automatic US calibration with robot assistance and without the need for temporal calibration. METHOD: US calibration based on active echo (AE) phantom was previously proposed, and its superiority over conventional cross-wire phantom based calibration was shown. In this work, we use AE to guide the robotic arm motion through the process of data collection; we combine the capability of the AE point to localize itself in the frame of the US image with the automatic motion of the robotic arm to provide a framework for calibrating the arm to the US image automatically. RESULTS: We demonstrated the efficacy of the automated method compared to the manual method through experiments. To highlight the necessity of frequent ultrasound calibration, it is demonstrated that the calibration precision changed from 1.67 to 3.20 mm if the data collection is not repeated after a dismounting/mounting of the probe holder. In a large data set experiment, similar reconstruction precision of automatic and manual data collection was observed, while the time was reduced by 58 %. In addition, we compared ten automatic calibrations with ten manual ones, each performed in 15 min, and showed that all the automatic ones could converge in the case of setting the initial matrix as identity, while this was not achieved by manual data sets. Given the same initial matrix, the repeatability of the automatic was [0.46, 0.34, 0.80, 0.47] versus [0.42, 0.51, 0.98, 1.15] mm in the manual case for the US image four corners. CONCLUSIONS: The submillimeter accuracy requirement of US calibration makes frequent data collections unavoidable. We proposed an automated calibration setup and showed feasibility by implementing it for a robot tooltip to US image calibration. The automated method showed a similar reconstruction precision as well as repeatability compared to the manual method, while the time consumed for data collection was reduced. The automatic method also reduces the burden of data collection for the user. Thus, the automated method can be a viable solution for applications that require frequent calibrations. PMID- 26754448 TI - In vitro and clinical evaluation of SIG1273: a cosmetic functional ingredient with a broad spectrum of anti-aging and antioxidant activities. AB - BACKGROUND: Isoprenylcysteine (IPC) small molecules were identified as a new class of anti-inflammatory compounds over 20 years ago. Since then, they have been developed as novel cosmetic functional ingredients (CFI) and topical drug candidates. SIG1273 is a second generation CFI that has previously been shown to provide a broad spectrum of benefits for the skin through its anti-inflammatory and antimicrobial properties. OBJECTIVE: To determine whether SIG1273 possesses anti-aging properties in vitro and evaluate the tolerability and activity of SIG1273 when applied topically to human subjects. METHODS: To model photoaging in vitro, human dermal fibroblasts (HDFs) were exposed in culture to UVA to induce collagenase (MMP-1) production. An in vitro wound-healing model was based on the activation of HDF migration into cell-free tissue culture surface. Hydrogen peroxide-induced oxidative stress was performed using HDFs to measure intracellular ROS activity. Radical scavenging capacity was determined using a colorimetric antioxidant assay kit (ABTS method). Lastly, a 4-week, 29-subject study was performed in which SIG1273 was applied topically as a cream to assess its tolerance and activity in reducing the appearance of aging. RESULTS: In vitro studies demonstrate SIG1273 inhibits UVA-induced MMP-1 production, hydrogen peroxide-induced oxidative stress and promotes wound healing. Moreover, SIG1273 was shown to be a radical scavenging antioxidant. Clinical assessment of SIG1273 cream (0.25%) showed it was well tolerated with significant improvement in the appearance of fine lines, coarse wrinkles, radiance/luminosity, pore size, texture/smoothness, hydration and increased firmness. CONCLUSIONS: SIG1273 represents a novel CFI with antioxidant, anti-aging, and anti-inflammatory properties that when applied topically is well tolerated and provides benefits to individuals with aging skin. PMID- 26754449 TI - Magnetic nanoscale metal organic frameworks for potential targeted anticancer drug delivery, imaging and as an MRI contrast agent. AB - The development of a novel multifunctional porous nanoplatform for targeted anticancer drug delivery with cell imaging and magnetic resonance imaging has been realised in the current work. Here we have developed a magnetic nanoscale metal organic frameworks (NMOF) for potential targeted drug delivery. These magnetic NMOFs were fabricated by incorporation of Fe3O4 nanoparticles into porous isoreticular metal organic frameworks (IRMOF-3). To achieve targeted drug delivery towards cancer cells specifically, folic acid was conjugated to the NMOF surface. Then, the fluorescent molecule rhodamine B isothiocyanate (RITC) was conjugated to the NMOFs for biological imaging applications. The synthesized magnetic NMOFs were fully characterised by FTIR, powder XRD, XPS, SQUID, TGA, TEM, FESEM, and DLS. The synthesized magnetic NMOFs were observed to be smaller than 100 nm and were found to be nontoxic towards human cervix adenocarcinoma (HeLa) and murine fibroblast (NIH3T3) cells according to cell viability assays. The cancer chemotherapy drug paclitaxel was conjugated to the magnetic NMOFs through hydrophobic interactions with a relatively high loading capacity. Moreover, these folic acid-conjugated magnetic NMOFs showed stronger T2-weighted MRI contrast towards the cancer cells, justifying their possible significance in imaging. PMID- 26754447 TI - Cardiovascular Health in Anxiety or Mood Problems Study (CHAMPS): study protocol for a randomized controlled trial. AB - BACKGROUND: Previous psychological and pharmacological interventions have primarily focused on depression disorders in populations with cardiovascular diseases (CVDs) and the efficacy of anxiety disorder interventions is only more recently being explored. Transdiagnostic interventions address common emotional processes and the full range of anxiety and depression disorders often observed in populations with CVDs. The aim of CHAMPS is to evaluate the feasibility of a unified protocol (UP) for the transdiagnostic treatment of emotional disorders intervention in patients recently hospitalized for CVDs. The current study reports the protocol of a feasibility randomized controlled trial to inform a future trial. METHODS/DESIGN: This is a feasibility randomized, controlled trial with a single-center design. A total of 50 participants will be block-randomized to either a UP intervention or enhanced usual care. Both groups will receive standard CVD care. The UP intervention consists of 1) enhancing motivation, readiness for change, and treatment engagement; (2) psychoeducation about emotions; (3) increasing present focused emotion awareness; (4) increasing cognitive flexibility; (5) identifying and preventing patterns of emotion avoidance and maladaptive emotion-driven behaviors (EDBs, including tobacco smoking, and alcohol use); (6) increasing tolerance of emotion-related physical sensations; (7) interoceptive and situation-based emotion-focused exposure; and (8) relapse prevention strategies. Treatment duration is 12 to 18 weeks. Relevant outcomes include the standard deviation of self-rated anxiety, depression and quality of life symptoms. Other outcomes include intervention acceptability, satisfaction with care, rates of EDBs, patient adherence, physical activity, cardiac and psychiatric readmissions. Parallel to the main trial, a nonrandomized comparator cohort will be recruited comprising 150 persons scoring below the predetermined depression and anxiety severity thresholds. DISCUSSION: CHAMPS is designed to evaluate the UP for the transdiagnostic treatment of emotional disorders targeting emotional disorder processes in a CVD population. The design will provide preliminary evidence of feasibility, attrition, and satisfaction with treatment to design a definitive trial. If the trial is feasible, it opens up the possibility for interventions to target broader emotional processes in the precarious population with CVD and emotional distress. TRIAL REGISTRATION: ACTRN12615000555550 , registered on 29/05/2015. PMID- 26754450 TI - Sex-specific genetic determinants for arterial stiffness in Dahl salt-sensitive hypertensive rats. AB - BACKGROUND: Arterial stiffness is an independent predictor of cardiovascular outcomes in hypertensive patients including myocardial infarction, fatal stroke, cerebral micro-bleeds which predicts cerebral hemorrhage in hypertensive patients, as well as progression to hypertension in non-hypertensive subjects. The association between arterial stiffness and various cardiovascular outcomes (coronary heart disease, stroke) remains after adjusting for age, sex, blood pressure, body mass index and other known predictors of cardiovascular disease, suggesting that arterial stiffness, measured via carotid-femoral pulse wave velocity, has a better predictive value than each of these factors. Recent evidence shows that arterial stiffening precedes the onset of high blood pressure; however their molecular genetic relationship (s) and sex-specific determinants remain uncertain. We investigated whether distinct or shared genetic determinants might underlie susceptibility to arterial stiffening in male and female Dahl salt-sensitive rats. Thus, we performed a genome-wide scan for quantitative trait loci (QTLs) affecting arterial stiffness in six-week old F2 (Dahl S x R)-intercross male and female rats characterized for abdominal aortic pulse wave velocity and aortic strain by high-resolution ultrasonography. RESULTS: We detected five highly significant QTLs affecting aortic stiffness: two interacting QTLs (AS-m1 on chromosome 4 and AS-m2 on chromosome16, LOD 8.8) in males and two distinct interacting QTLs (AS-f1 on chromosome 9 and AS-f2 on chromosome11, LOD 8.9) in females affecting pulse wave velocity. One QTL (AS-1 on chromosome 3, LOD 4.3) was found to influence aortic strain in a sex-independent manner. None of these arterial stiffness QTLs co-localized with previously reported blood pressure QTLs detected in equivalent genetic intercrosses. CONCLUSIONS: These data reveal sex-specific genetic determinants for aortic pulse wave velocity and suggest distinct polygenic susceptibility for arterial stiffness and salt-sensitive hypertension in Dahl rats based upon reported blood pressure QTLs in equivalent (Dahl S x R)-intercrosses. PMID- 26754451 TI - Exome sequencing analysis in a pair of monozygotic twins re-evaluates the genetics behind their intellectual disability and reveals a CHD2 mutation. AB - BACKGROUND: Neurodevelopmental disorders include a broad spectrum of conditions, which are characterized by delayed motor and/or cognitive milestones and by a variable range of intellectual disability with or without an autistic behavior. Several genetic factors have been implicated in intellectual disability onset and exome sequencing studies have recently identified new inherited or de novo mutations in patients with neurodevelopmental disorders. CASE: We report the case of two monozygotic twins who came for the first time to our attention at the age of 20months for a global neurodevelopmental delay associated with an autism spectrum disorder, hypotonia, postnatal microcephaly, stereotypic movements and circadian rhythm alterations in association with late-onset epilepsy. MECP2 sequence was normal. A CGH-array analysis revealed in both twins two maternally inherited duplications on chromosomes 8p22 and 16p13.11. The latter has been previously associated with neurodevelopmental disorders. We performed an exome sequencing analysis on one twin and her parents and identified a CHD2 mutation, previously described in association with a phenotypic spectrum overlapping our patients' phenotype. CONCLUSIONS: This work underlines the importance to consider a CHD2 involvement in children with intellectual disability and autism spectrum disorder even in the absence of epilepsy at an early age. It also highlights the necessity to re-evaluate inherited copy number variants with low penetrance and/or high phenotypic variability because an underlying de novo molecular event can be the major cause of the phenotype. This is essential in order to reach a correct diagnosis and provide the couple with a proper recurrence risk. PMID- 26754452 TI - Tobacco control research: a tale of two Delphi groups. PMID- 26754454 TI - Epitaxial nickel disilicide with low resistivity and excellent reliability. AB - Ultra-thin epitaxial NiSi2 was formed, and its structure was examined by electron microscopy and x-ray diffraction. Compared with previous reports, the measured resistivity of the epitaxial NiSi2 was unprecedentedly low, reaching 7 MUOmega cm in the experimental results and up to 14.93 MUOmega cm after modification. The reliability, which was investigated under different temperatures and current densities to understand its electronic characteristics, was 1.5 times better than that of the conventional polycrystalline counterpart. Black's equation and the measured mean-time-to-failure (MTTF) were used to obtain the reliability characteristics of epitaxial and poly-NiSi2. Confidence intervals at 95% for each MTTF confirmed the single failure mode. The electromigration phenomenon was observed to be the failure mechanism. Our results provide evidence that epitaxial NiSi2 is a promising contact material for future electronics. PMID- 26754453 TI - Antigen-specific T cells fully conserve antitumour function following cryopreservation. AB - Immunotherapies based on the autologous adoptive transfer of ex vivo-manipulated T cells are rapidly evolving for the treatment of both metastatic and primary malignancies. However, extended ex vivo culturing reduces the functionality of isolated T cells. Cryopreservation of rapidly expanded T cells for subsequent use throughout an immunotherapeutic regimen is a highly desirable recourse, thus far encumbered by a lack of studies investigating its effects on effector T-cell functionality. Here we directly compare murine tumour-reactive CD8(+) T cells cryopreserved during ex vivo expansion to freshly isolated populations. We show that cryopreservation fully conserves the differentiation potential of effector T cells, secretion of pro-inflammatory cytokines, cytotoxic function and does not impair the three-dimensional scanning motility of T cells or their capacity to infiltrate and reject tumours. PMID- 26754455 TI - Using next-generation sequencing to determine potential molecularly guided therapy options for patients with resectable pancreatic adenocarcinoma. AB - BACKGROUND: Genomic sequencing technology may identify personalized treatment options for patients with pancreatic adenocarcinoma. METHODS: The study was conducted using tissue specimens obtained from 2012 to 2014. Patients with resected pancreatic adenocarcinoma were identified. Next-generation sequencing was performed from paraffin-tumor blocks. Mutational profiles were reviewed to determine available targeted therapies and clinical trial eligibility. RESULTS: Thirty patients were identified. The incidence of mutations was: Kirsten rat sarcoma viral oncogene homolong (KRAS) = 87%, tumor protein 53 (TP53) = 63%, cyclin-dependent kinase inhibitor 2A (CDKN2A) = 20%, Mothers Against Decapentaplegic Homolog 4 (SMAD4) = 20%, epidermal growth factor receptor (EGFR) = 7%. Multiple mutations were found in 73%. All CDKN2A mutations occurred in male patients (P = .06), and there was a trend toward younger patient age in this group (P = .13). Potential for Federal Drug Administration (FDA)-approved targeted therapies was identified in 8 of 30 (27%). In addition, 29 of 30 (97%) had mutations applicable for ongoing phase I or II clinical trials. CONCLUSIONS: Next-generation sequencing of resected pancreatic adenocarcinoma specimens can determine common genetic mutations and identify patients who may be eligible for off-label use of targeted therapies or clinical trial enrollment. PMID- 26754456 TI - Control the damage: morbidity and mortality after emergent trauma laparotomy. AB - BACKGROUND: Damage control laparotomy (DCL) is performed for physiologically deranged patients. Recent studies suggest overutilization of DCL, which may be associated with potentially iatrogenic complications. METHODS: We conducted a retrospective study of trauma patients over a 2-year period that underwent an emergent laparotomy and received preoperative blood products. The group was divided into definitive laparotomy and DCL. RESULTS: A total of 237 received were included: 78 in definitive laparotomy group, 144 in the DCL group, and 15 who died in the operating room. The DCL group was more severely injured and required more transfusions. After propensity score matching, DCL was associated with an 18% increase in hospital mortality, a 13% increase in ileus, and a 7% increase in enteric suture line failure, an 11% increase in fascial dehiscence, and a 19% increase in superficial surgical site infection. CONCLUSIONS: The potential overuse of DCL unnecessarily exposes patients to increased morbidity and mortality. PMID- 26754457 TI - Motivational techniques to improve self-care in hemophilia: the need to support autonomy in children. AB - BACKGROUND: In pediatric hemophilia, caregivers are facing unique challenges to adherence and self-care in children and adolescents with hemophilia. Hemophilia treatment requires adequate prophylaxis and on-demand treatment, as well as a clear behavioral strategy to limit risk-taking in terms of physical exercise and diet. Medication adherence rates of hemophilia patients have been reported to decrease during late childhood and adolescence. In the developing child, moving safely from parent-care to self-care is one of the greatest challenges of integrative care within this domain. There is a clear need for initiatives designed to increase an individual's motivation for treatment and self-care activities. DISCUSSION: Among motivational approaches, the self-determination perspective offers a useful framework to explain how the transition to self-care can be facilitated. We discuss how motivation regarding hemophilia treatment may be increased through parental autonomy support and we offer examples of applied communication techniques to facilitate autonomy-supportive caregiving. Although it has not yet been tested in the context of hemophilia, these communication techniques could potentially help caregivers promote adherence and self-care in children. Confronted by unique challenges to adherence and self-care, caregivers of children with hemophilia should move from an exclusive focus on illness management education to an integrative strategy, including motivation-enhancing communication. The self-determination perspective provides important proximal objectives (e.g. autonomy support) to maintain optimal adherence in adolescents as they move from parent-care to self-care. Future research initiatives should address the practice of these communication techniques and evaluate them in the context of hemophilia. PMID- 26754458 TI - Long-term local control and survival after preoperative radiochemotherapy in combination with deep regional hyperthermia in locally advanced rectal cancer. AB - PURPOSE: The aim of this study was to evaluate the impact of deep regional hyperthermia on long-term local control and survival in locally advanced non metastatic rectal cancer. METHODS: In total 103 patients with locally advanced non-metastatic rectal cancer were treated preoperatively with either neoadjuvant radiochemotherapy alone (n = 43) or the same treatment with additional deep regional hyperthermia (n = 60). The two groups were compared with respect to local control, overall survival (OS), disease-free survival (DFS), and distant metastases-free survival (DMFS). RESULTS: Patients receiving additional hyperthermia had excellent long-term local control with a 5-year Kaplan-Meier estimate of 98% compared with 87% in the radiochemotherapy only group (p = 0.09). Five-year rates for OS (88% versus 76%, p = 0.08), DFS (77% versus 73%, p = n.s.) and DMFS (75% versus 77%, p = n.s.) were not statistically different between the two groups. CONCLUSION: Radiochemotherapy combined with hyperthermia results in excellent long-term local control. PMID- 26754459 TI - Manipulating the dimensional assembly pattern and crystalline structures of iron oxide nanostructures with a functional polyolefin. AB - Controlled crystalline structures (alpha- and gamma-phase) and assembly patterns (1-D, 2-D and 3-D) were achieved in the synthesized iron oxide (Fe2O3) nanoparticles (NPs) using polymeric surfactant-polypropylene grafted maleic anhydride (PP-g-MA) with different concentrations. In addition, the change of the crystalline structure from the alpha- and gamma-phase also led to the significantly increased saturation magnetization and coercivity. PMID- 26754460 TI - The audacity of specificity: Moving adolescent developmental neuroscience towards more powerful scientific paradigms and translatable models. PMID- 26754462 TI - Common features in the unfolding and misfolding of PDZ domains and beyond: the modulatory effect of domain swapping and extra-elements. AB - PDZ domains are protein-protein interaction modules sharing the same structural arrangement. To discern whether they display common features in their unfolding/misfolding behaviour we have analyzed in this work the unfolding thermodynamics, together with the misfolding kinetics, of the PDZ fold using three archetypical examples: the second and third PDZ domains of the PSD95 protein and the Erbin PDZ domain. Results showed that all domains passed through a common intermediate, which populated upon unfolding, and that this in turn drove the misfolding towards worm-like fibrillar structures. Thus, the unfolding/misfolding behaviour appears to be shared within these domains. We have also analyzed how this landscape can be modified upon the inclusion of extra elements, as it is in the nNOS PDZ domain, or the organization of swapped species, as happens in the second PDZ domain of the ZO2 protein. Although the intermediates still formed upon thermal unfolding, the misfolding was prevented to varying degrees. PMID- 26754461 TI - Considerations for MRI study design and implementation in pediatric and clinical populations. AB - Human neuroimaging, specifically magnetic resonance imaging (MRI), is being used with increasing popularity to study brain structure and function in development and disease. When applying these methods to developmental and clinical populations, careful consideration must be taken with regard to study design and implementation. In this article, we discuss two major considerations particularly pertinent to brain research in special populations. First, we discuss considerations for subject selection and characterization, including issues related to comorbid conditions, medication status, and clinical assessment. Second, we discuss methods and considerations for acquisition of adequate, useable MRI data. Given that children and patients may experience anxiety with the scanner environment, preventing participation, and that they have a higher risk of motion artifact, resulting in data loss, successful subject compliance and data acquisition are not trivial tasks. We conclude that, as researchers, we must consider a number of issues when using neuroimaging tools to study children and patients, and we should thoughtfully justify our choices of methods and study design. PMID- 26754463 TI - Assembling carbon quantum dots to a layered carbon for high-density supercapacitor electrodes. AB - It is found that carbon quantum dots (CQDs) self-assemble to a layer structure at ice crystals-water interface with freeze- drying. Such layers interconnect with each other, forming a free-standing CQD assembly, which has an interlayer distance of about 0.366 nm, due to the existence of curved carbon rings other than hexagons in the assembly. CQDs are fabricated by rupturing C60 by KOH activation with a production yield of ~15 wt.%. The CQDs obtained have an average height of 1.14 nm and an average lateral size of 7.48 nm, and are highly soluble in water. By packaging annealed CQD assembly to high density (1.23 g cm(-3)) electrodes in supercapacitors, a high volumetric capacitance of 157.4 F cm(-3) and a high areal capacitance of 0.66 F cm(-2) (normalized to the loading area of electrodes) are demonstrated in 6 M KOH aqueous electrolyte with a good rate capability. PMID- 26754464 TI - 'Hot spot' cardiac ischemia imaging with fluorodeoxyglucose positron emission tomography. PMID- 26754465 TI - Primary dorsal buccal mucosa graft urethroplasty for anterior urethral strictures in patients with lichen sclerosus. AB - PURPOSE: To report our ongoing experience with dorsal buccal mucosa graft (BMG) urethroplasty for the primary repair of anterior urethral strictures in patients with lichen sclerosus (LS). PATIENTS AND METHODS: A total of 32 men with LS underwent BMG urethroplasty from January 2010 to September 2012. In 27 patients, stricture was limited to the penile urethra, while in five patients, both bulbar and penile urethra were involved. In these five patients, the entire anterior urethra was replaced with BMG. In nine (28.1%) younger patients (mean age 38.2 years, range 33-45), with adverse local conditions and significant scarring, two stage repair was done. The paired t test was performed on preoperative and postoperative Qmax as well as on preoperative and postoperative post-void residual urine volume, and the Fisher exact test was used to assess success between treatment groups. The chi-squared test was used to compare categorical data. RESULTS: The overall success rate was 90.6%. Complications occurred in 9.4% of the patients (3 of 32) including hematoma in two patients and fistula in one patient. In this cohort of patients, mean preoperative Qmax was 6.2 ml per second (range 2.6-10.2) versus 18.2 (range 15.8-21.2) postoperatively (at 9 months), which was statistically significant (p < 0.002). Also, mean preoperative post void residual urine volume was 110 ml (range 75-180) versus 19 ml (range 10-40) postoperatively at 9 months, which was statistically significant (p < 0.004). CONCLUSION: Buccal mucosa is the most reliable graft for repairing anterior urethral strictures in patients with LS. Minimal complications are observed, even in cases of long stenosis completely afflicting anterior urethra. PMID- 26754466 TI - Developmental mechanisms of the tympanic membrane in mammals and non-mammalian amniotes. AB - The tympanic membrane is a thin layer that originates from the ectoderm, endoderm, and mesenchyme. Molecular-genetic investigations have revealed that interaction between epithelial and mesenchymal cells in the pharyngeal arches is essential for development of the tympanic membrane. We have recently reported that developmental mechanisms underlying the tympanic membrane seem to be different between mouse and chicken, suggesting that the tympanic membrane evolved independently in mammals and non-mammalian amniotes. In this review, we summarize previous studies of tympanic membrane formation in the mouse. We also discuss its formation in amniotes from an evolutionary point of view. PMID- 26754467 TI - Virtual bronchoscopy through the fetal airways in a case of cervical teratoma using magnetic resonance imaging data. PMID- 26754468 TI - The effect of annealing on a 3D SnO2/graphene foam as an advanced lithium-ion battery anode. AB - 3D annealed SnO2/graphene sheet foams (ASGFs) are synthesized by in situ self assembly of graphene sheets prepared by mild chemical reduction. L-ascorbyl acid is used to effectively reduce the SnO2 nanoparticles/graphene oxide colloidal solution and form the 3D conductive graphene networks. The annealing treatment contributes to the formation of the Sn-O-C bonds between the SnO2 nanoparticles and the reduced graphene sheets, which improves the electrochemical performance of the foams. The ASGF has features of typical aerogels: low density (about 19 mg cm(-3)), smooth surface and porous structure. The ASGF anodes exhibit good specific capacity, excellent cycling stability and superior rate capability. The first reversible specific capacity is as high as 984.2 mAh g(-1) at a specific current of 200 mA g(-1). Even at the high specific current of 1000 mA g(-1) after 150 cycles, the reversible specific capacity of ASGF is still as high as 533.7 mAh g(-1), about twice as much as that of SGF (297.6 mAh g(-1)) after the same test. This synthesis method can be scaled up to prepare other metal oxides particles/ graphene sheet foams for high performance lithium-ion batteries, supercapacitors, and catalysts, etc. PMID- 26754469 TI - Prediction of later clinical course by a specific glucose metabolic pattern in non-demented patients with probable REM sleep behavior disorder admitted to a memory clinic: A case study. AB - The present study is a follow-up study of 11 non-demented patients with probable rapid eye movement (REM) sleep behavior disorder (RBD) at our memory clinic. During the follow-up period (mean+/-SD of 46.7+/-6.4 months), all 11 patients exhibited cognitive decline: four (Group A) exhibited core clinical features of dementia with Lewy bodies (DLB), along with severe cognitive decline, and were subsequently diagnosed as having probable DLB; four (Group B) did not exhibit core clinical features of DLB; and the remaining three (Group C) were diagnosed as having Parkinson's disease with dementia (PDD). Positron emission tomography with fluorodeoxyglucose-F18 at baseline revealed that Groups A and B exhibited glucose hypometabolism in the occipital lobe, especially in the primary visual cortex, and Group A tended to present hypometabolism in the parieto-temporal area as well. Group C tended to present hypometabolism in the medial prefrontal area and anterior cingulate gyrus. Neuropsychological examinations indicated poor performance in verbal memory and visuoperception in all groups. This case study suggests that patterns of hypometabolism and neuropsychological examinations at baseline may be indicators of the later clinical course of probable RBD patients. PMID- 26754472 TI - Long-term change in respiratory function following spinal cord injury. AB - STUDY DESIGN: Retrospective study. OBJECTIVES: To model the effect of time since injury on longitudinal respiratory function measures in spinal cord injured individuals and to investigate the effect of patient characteristics. SETTING: A total of 173 people who sustained a spinal cord injury between 1966 and April 2013 and who had previously participated in research or who underwent clinically indicated outpatient respiratory function tests at the Austin Hospital in Melbourne, Australia, were included in the study. At least two measurements over time were available for analysis in 59 patients. METHODS: Longitudinal data analysis was performed using generalised linear regression models to determine changes in respiratory function following spinal cord injury from immediately post injury to many years later. Secondly, we explored whether injury severity, age, gender and body mass index (BMI) at injury altered the time-dependent change in respiratory function. RESULTS: The generalised linear regression model showed no significant change (P=0.276) in respiratory function measured in (forced) vital capacity ((F)VC) after the spinal cord injury. However, significant (P<0.05) differences in respiratory function over time were found when categorising age and BMI. CONCLUSION: This clinical cohort with long-term, repeated measurements of respiratory function showed no significant overall change in respiratory function over 23 years. However, a decline in respiratory function over time was observed in subgroups of individuals older than 30 years at the onset of injury and in those with a BMI>30 kg m(-2). PMID- 26754471 TI - Pain assessment according to the International Spinal Cord Injury Pain classification in patients with spinal cord injury referred to a multidisciplinary pain center. AB - STUDY DESIGN: This is a retrospective study. OBJECTIVES: The aim of this study was to investigate the epidemiology of pain types in patients with spinal cord injury (SCI) according to the International Spinal Cord Injury Pain (ISCIP) classification. SETTING: This study was conducted in a multidisciplinary pain center. METHODS: Socio-demographic and clinical data were examined and ISCIP classification was applied. RESULTS: Sixty-six individuals (51+/-13 years) with SCI had pain, a lesion older than 5 years in 67% and a pain history older than 5 years in 54% of patients. According to the ISCIP classification, nociceptive pain was present in 58% (musculoskeletal pain) and 3% (visceral pain) of the patients. At-level, below-level neuropathic pain and other neuropathic pain were observed, respectively in 53, 42 and 5% of patients. Unknown pain type was found in 8% of patients. Patients with complete lesions showed significantly more frequent neuropathic pain (P=0.021) and more frequent at-level SCI pain (P=0.00) compared with those with incomplete lesions. Patients with paraplegia had more often at level pain (P=0.00), whereas patients with tetraplegia reported more often below level pain (P=0.00). Patients had severe pain (mean intensity: 8.2 (+/-1.6) on a 0 to 10 numerical scale) and showed high grades of pain chronicity. Mild to severe depression and anxiety were present, respectively in 53 and 56% of patients. The health-related quality of life was low. CONCLUSION: The use of the ISCIP classification in a clinical setting is mirroring the very complex pain situation in patients with SCI referred to a multidisciplinary pain center, and it might be an important step for adequate pain therapy. PMID- 26754470 TI - Neuroplasticity of ascending and descending pathways after somatosensory system injury: reviewing knowledge to identify neuropathic pain therapeutic targets. AB - STUDY DESIGN: This is a narrative review of the literature. OBJECTIVES: This review aims to be useful in identifying therapeutic targets. It focuses on the molecular and biochemical neuroplasticity changes that occur in the somatosensory system, including ascending and descending pathways, during the development of neuropathic pain. Furthermore, it highlights the latest experimental strategies, based on the changes reported in the damaged nociceptive neurons during neuropathic pain states. SETTING: This study was conducted in Girona, Catalonia, Spain. METHODS: A MEDLINE search was performed using the following terms: descending pain pathways; ascending pain pathways; central sensitization; molecular pain; and neuropathic pain pharmacological treatment. RESULTS AND CONCLUSION: Neuropathic pain triggered by traumatic lesions leads to sensitization and hyperexcitability of nociceptors and projection neurons of the dorsal horn, a strengthening in the descendent excitatory pathway and an inhibition of the descending inhibitory pathway of pain. These functional events are associated with molecular plastic changes such as overexpression of voltage gated ion channels, algogen-sensitive receptors and synthesis of several neurotransmitters. Molecular studies on the plastic changes in the nociceptive somatosensory system enable the development of new pharmacological treatments against neuropathic pain, with higher specificity and effectiveness than classical drug treatments. Although research efforts have already focused on these aspects, additional research may be necessary to further explore the potential therapeutic targets in neuropathic pain involved in the neuroplasticity changes of neuropathological pathways from the injured somatosensory system. PMID- 26754473 TI - Validity and reliability of a locomotor stage-based functional rating scale in spinal cord injury. AB - STUDY DESIGN: This is a prospective observational cohort study. OBJECTIVES: The objectives of this study were to apply and adapt a rating scale based on locomotor stages (LSs) derived from cerebral palsy (CP) to spinal cord injury (SCI) and to quantify its inter-rater reliability and construct validity. METHODS: The inter-rater reliability of LSs originally developed for children with CP was tested in a chronic SCI cohort. On the basis of the distribution of the LSs for CP, Locomotor Stages in Spinal Cord Injury (LOSSCI) were defined. Their validity was then tested with the Spinal Cord Independence Measure (SCIM) in another acute SCI cohort. RESULTS: The 10-point LSs for CP were assessed by two raters in 65 chronic patients. Weighted Cohen's kappa (WCk) was 0.985 (P<0.0001). Only four mismatches were found, resulting in an accuracy of 93.4%. On the basis of the distribution of the LSs for CP in SCI, the five-point LOSSCI grading scale was developed. WCk of LOSSCI was 0.976 (P<0.0001). Only three mismatches between raters were found, resulting in an overall accuracy of 95.1%. The validity data sets consisted of 448 SCIM records from 161 patients obtained within the first year after injury. Spearman's correlation coefficients were the highest between LOSSCI and SCIM indoor mobility (room and toilet; R=0.82) and the lowest between LOSSCI and SCIM respiration and sphincter management (R=0.68). CONCLUSION: LOSSCI provides a reliable and valid clinical tool to assess locomotor function in SCI. LOSSCI not only reflects bipedal walking but also covers a wide range of key motor skills. PMID- 26754474 TI - Quercetin suppresses NLRP3 inflammasome activation and attenuates histopathology in a rat model of spinal cord injury. AB - STUDY DESIGN: Randomized experimental study. OBJECTIVES: To investigate the molecular mechanisms of quercetin in spinal cord injury (SCI) rats. SETTING: China. METHODS: One hundred female Sprague-Dawley rats were randomly assigned into four groups: sham group, SCI group, SCI+Vehicle (Veh) group, and the SCI+Quercetin (Que) group. The influences of quercetin on proinflammatory cytokine levels, histological changes and locomotion scale were estimated. RESULTS: SCI significantly promoted nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation and increased proinflammatory cytokine productions in the SCI group as compared with the sham group. Quercetin administration significantly decreased reactive oxygen species production, inhibited NLRP3 inflammasome activation and reduced inflammatory cytokine levels. Moreover, quercetin administration attenuated histopathology and promoted locomotion recovery. CONCLUSION: Quercetin can attenuate tissue damage and improve neurological function recovery, and the mechanism may be related to the inhibition of NLRP3 inflammasome activation. PMID- 26754475 TI - Forty-five-year follow-up on the renal function after spinal cord injury. AB - STUDY DESIGN: Retrospective chart review. OBJECTIVES: To investigate the extent of renal deterioration in patients with spinal cord injury (SCI) and to identify risk indicators associated with renal deterioration. SETTING: Clinic for Spinal Cord Injuries, Rigshospitalet, Hornbaek, Denmark. METHODS: This study included 116 patients admitted to our clinic with a traumatic SCI sustained between 1956 and 1975. Results from renography and (51)Cr-EDTA plasma clearance were collected from medical records from time of injury until 2012, and the occurrence of renal deterioration was analysed by cumulative incidence curves. The impact of demographics, neurological level and completeness of SCI, urinary tract stones, dilatation of the upper urinary tract (UUT) and bladder-emptying methods were analysed with Cox proportional hazard ratios. RESULTS: The bladder-emptying methods used for the longest period were reflex triggering (63%), bladder expression (22%), indwelling catheter (5%), normal voiding (4%), ileal conduit (3%) and clean intermittent catheterisation (2%). The cumulative risk of moderate renal deterioration (functional distribution outside 40-60% on renography or relative glomerular filtration rate (GFR) ?75% of expected according to age and gender) was 58%. The cumulative risk of severe renal deterioration (functional distribution outside 30-70% on renography or relative GFR?51%) was 29% after 45 years postinjury. Only dilatation of UUT and renal/ureter stone requiring removal significantly increased the risk of moderate and severe renal deterioration. CONCLUSION: Renal deterioration occurs at any time after injury, suggesting that lifelong follow-up examinations of the renal function are important, especially in patients with dilatation of UUT and/or renal/ureter stones. PMID- 26754478 TI - Knowledge Gaps in ASD Research: Short and Long Term Implications for Policy. PMID- 26754476 TI - The effect of FES-rowing training on cardiac structure and function: pilot studies in people with spinal cord injury. AB - STUDY DESIGN: Two studies were conducted: Study-1 was cross-sectional; and Study 2 a longitudinal repeated measures design. OBJECTIVES: To examine the influence of functional electrical stimulation (FES) rowing training on cardiac structure and function in people with spinal cord injury (SCI). SETTING: A university sports science department and home-based FES-training. METHODS: Fourteen participants with C4-T10 SCI (American Spinal Injury Association Impairment Scale A or B) were recruited for the studies. Cardiac structure and function, and peak: oxygen uptake ([Vdot ]O2peak), power output (POpeak) and heart rate (HRpeak), were compared between two FES-untrained groups (male n=3, female n=3) and an FES trained group (male n=3) in Study-1 and longitudinally assessed in an FES-naive group (male n=1, female n=4) in Study-2. Main outcome measures left ventricular dimensions, volumes, mass, diastolic and systolic function, and [Vdot ]O2peak, POpeak and HRpeak. In Study-2, in addition to peak values, the [Vdot ]O2 sustainable over 30 min and the related PO and HR were also assessed. RESULTS: Sedentary participants with chronic SCI had cardiac structure and function at the lower limits of non-SCI normal ranges. Individuals with chronic SCI who habitually FES-row have cardiac structure and function that more closely resemble non-SCI populations. A programme of FES-rowing training improved cardiac structure and function in previously FES-naive people. CONCLUSION: FES-rowing training appears to be an effective stimulus for positive cardiac remodelling in people with SCI. Further work, with greater participant numbers, should investigate the impact of FES-rowing training on cardiac health in SCI. SPONSORSHIP: We thank the INSPIRE Foundation, UK, for funding these studies. PMID- 26754477 TI - The impact of task-oriented client-centered training on individuals with spinal cord injury in the community. AB - STUDY DESIGN: Quasi-experimental study. OBJECTIVES: The objective of this study was to evaluate the impact of an 8-week, task-oriented client-centered training (TOCCT) on physical function, perception of performance and satisfaction with the activities and achievement of training goals of individuals with spinal cord injury (SCI). SETTING: Khon Kaen, Thailand. METHODS: Participants were 12 persons with SCI living in Ubolratana District, Khon Kaen Province, Thailand. Outcome measures consisted of physical function and perception of performance and satisfaction with the activities, which were assessed at pre- and post-training periods by using the Spinal Cord Independence Measure version III and the Canadian Occupational Performance Measure, respectively. The achievement of training goals was also determined by the Goal Attainment Scale. Data were analyzed by using paired t-tests. RESULTS: The 8-week, TOCCT significantly improved physical function of the participants (P=0.001, 95% confidence interval (CI) 3.22-7.12). Another positive impact of the training was found in the perceived levels of performance and satisfaction with the activities (P=0.001, 95% CI 1.31-3.49 and 1.68-3.67, respectively). Furthermore, at the end of the study, most of the participants could reach their expected training goals. CONCLUSION: The 8-week, TOCCT significantly improved physical function and perception of performance and satisfaction with the activities of individuals with SCI when compared with the pre-training period. The training could also help most of the participants to achieve their training goals. Future studies with randomized controlled trial and longitudinal design are suggested to reveal further benefits of such training on individuals with SCI. PMID- 26754480 TI - Quantitative Energy-Dispersive X-Ray Analysis of Catalyst Nanoparticles Using a Partial Cross Section Approach. AB - The new generation of energy-dispersive X-ray (EDX) detectors with higher count rates than ever before, paves the way for a new approach to quantitative elemental analysis in the scanning transmission electron microscope. Here we demonstrate a method of calculating partial cross sections for use in quantifying EDX data, beneficial especially because of the simplicity of its implementation. Applying this approach to acid-leached PtCo catalyst nanoparticles leads to quantitative determination of the Pt surface enrichment. PMID- 26754479 TI - Assessment of Cognitive Outcome Measures in Teenagers with 15q13.3 Microdeletion Syndrome. AB - 15q13.3 microdeletion syndrome causes a spectrum of cognitive disorders, including intellectual disability and autism. We aimed to determine if any or all of three cognitive testing systems (the KiTAP, CogState, and Stanford-Binet) are suitable for assessment of cognitive function in affected individuals. These three tests were administered to ten individuals with 15q13.3 microdeletion syndrome (14-18 years of age), and the results were analyzed to determine feasibility of use, potential for improvement, and internal consistency. It was determined that the KiTAP, CogState, and Stanford-Binet are valid tests of cognitive function in 15q13.3 microdeletion patients. Therefore, these tests may be considered for use as objective outcome measures in future clinical trials, assessing change in cognitive function over a period of pharmacological treatment. PMID- 26754481 TI - Molecular mechanism of peptide editing in the tapasin-MHC I complex. AB - Immune recognition of infected or malignantly transformed cells relies on antigenic peptides exposed at the cell surface by major histocompatibility complex class I (MHC I) molecules. Selection and loading of peptides onto MHC I is orchestrated by the peptide-loading complex (PLC), a multiprotein assembly whose structure has not yet been resolved. Tapasin, a central component of the PLC, stabilises MHC I and catalyses the exchange of low-affinity against high affinity, immunodominant peptides. Up to now, the molecular basis of this peptide editing mechanism remained elusive. Here, using all-atom molecular dynamics (MD) simulations, we unravel the atomic details of how tapasin and antigen peptides act on the MHC I binding groove. Force distribution analysis reveals an intriguing molecular tug-of-war mechanism: only high-affinity peptides can exert sufficiently large forces to close the binding groove, thus overcoming the opposite forces exerted by tapasin to open it. Tapasin therefore accelerates the release of low-affinity peptides until a high-affinity antigen binds, promoting subsequent PLC break-down. Fluctuation and entropy analyses show how tapasin chaperones MHC I by stabilising it in a peptide-receptive conformation. Our results explain previous experiments and mark a key step towards a better understanding of adaptive immunity. PMID- 26754483 TI - Eriodictyol Inhibits RANKL-Induced Osteoclast Formation and Function Via Inhibition of NFATc1 Activity. AB - Receptor activator of nuclear factor kappa-B ligand (RANKL) induces differentiation and function of osteoclasts through triggering multiple signaling cascades, including NF-kappaB, MAPK, and Ca(2+) -dependent signals, which induce and activate critical transcription factor NFATc1. Targeting these signaling cascades may serve as an effective therapy against osteoclast-related diseases. Here, by screening a panel of natural plant extracts with known anti inflammatory, anti-tumor, or anti-oxidant properties for possible anti osteoclastogenic activities we identified Eriodictyol. This flavanone potently suppressed RANKL-induced osteoclastogenesis and bone resorption in a dose dependent manner without detectable cytotoxicity, suppressing RANKL-induced NF kappaB, MAPK, and Ca(2+) signaling pathways. Eriodictyol also strongly inhibited RANKL-induction of c-Fos levels (a critical component of AP-1 transcription factor required by osteoclasts) and subsequent activation of NFATc1, concomitant with reduced expression of osteoclast specific genes including cathepsin K (Ctsk), V-ATPase-d2 subunit, and tartrate resistant acid phosphatase (TRAcP/Acp5). Taken together, these data provide evidence that Eriodictyol could be useful for the prevention and treatment of osteolytic disorders associated with abnormally increased osteoclast formation and function. J. Cell. Physiol. 231: 1983-1993, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26754482 TI - Adult attachment style and cortisol responses in women in late pregnancy. AB - BACKGROUND: Recent research has documented the association between attachment and cortisol rhythms. During pregnancy, when attachment patterns are likely to be activated, elevated levels of cortisol are associated with negative effects for the mother and the foetus. The aim of the present study was to examine the association of adult attachment style and cortisol rhythms in pregnant women. METHODS: Eighty women in the third trimester of pregnancy participated in the study. Adult attachment was assessed using the Adult Attachment Scale - Revised (AAS-R). Participants collected 4 samples of salivary cortisol at two different days; 3 samples were collected in the morning immediately after wakeup and one sample was collected by bedtime. RESULTS: Results found group significant differences in the cortisol diurnal oscillation (F (1,71) =26.46, p < .001,), with secure women reporting a steep decrease in cortisol from awakening to bedtime, while women with fearful avoidant attachment reported no changes. No group differences were found regarding the cortisol awakening response. CONCLUSIONS: These results highlight the importance of considering attachment patterns during pregnancy, suggesting fearful avoidant attachment style as a possible risk factor for emotional difficulties and dysregulation of the neuroendocrine rhythms. PMID- 26754484 TI - Why do health workers give anti-malarials to patients with negative rapid test results? A qualitative study at rural health facilities in western Uganda. AB - BACKGROUND: The large-scale introduction of malaria rapid diagnostic tests (RDTs) promises to improve management of fever patients and the rational use of valuable anti-malarials. However, evidence on the impact of RDT introduction on the overprescription of anti-malarials has been mixed. This study explored determinants of provider decision-making to prescribe anti-malarials following a negative RDT result. METHODS: A qualitative study was conducted in a rural district in mid-western Uganda in 2011, ten months after RDT introduction. Prescriptions for all patients with negative RDT results were first audited from outpatient registers for a two month period at all facilities using RDTs (n = 30). Facilities were then ranked according to overall prescribing performance, defined as the proportion of patients with a negative RDT result prescribed any anti-malarial. Positive and negative deviant facilities were sampled for qualitative investigation; positive deviants (n = 5) were defined ex post facto as <0.75% and negative deviants (n = 7) as >5%. All prescribing clinicians were targeted for qualitative observation and in-depth interview; 55 fever cases were observed and 22 providers interviewed. Thematic analysis followed the 'framework' approach. RESULTS: 8344 RDT-negative patients were recorded at the 30 facilities (prescription audit); 339 (4.06%) were prescribed an anti-malarial. Of the 55 observed patients, 38 tested negative; one of these was prescribed an anti malarial. Treatment decision-making was influenced by providers' clinical beliefs, capacity constraints, and perception of patient demands. Although providers generally trusted the accuracy of RDTs, anti-malarial prescription was driven by perceptions of treatment failure or undetectable malaria in patients who had already taken artemisinin-based combination therapy prior to facility arrival. Patient assessment and other diagnostic practices were minimal and providers demonstrated limited ability to identify alternative causes of fever. Provider perceptions of patient expectations sometimes appeared to influence treatment decisions. CONCLUSIONS: The study found high provider adherence to RDT results, but that providers believed in certain clinical exceptions and felt they lacked alternative options. Guidance on how the RDT works and testing following partial treatment, better methods for assisting providers in diagnostic decision making, and a context-appropriate provider behaviour change intervention package are needed. PMID- 26754486 TI - What makes a man a man? Prenatal antennapedia expression is involved in the formation of the male phenotype in Daphnia. AB - Cyclic parthenogenetic organisms show a switch in reproductive strategy from asexual to sexual reproduction upon the occurrence of unfavourable environmental conditions. The sexual reproductive mode involves the production of ameiotic diploid males and the fertilization of meiotic haploid eggs. One beautiful example for this switch between parthenogenesis and sexual reproduction is Daphnia. Male and female Daphnia from the same clone are genetically identical. Morphological differences should therefore only be due to differential gene expression. This differential gene expression leads to sexually dimorphic phenotypes with elongated and moveable (i.e. leg-like) first antennae in males in comparison to females. For other arthropods, it has been demonstrated that the formation of differential morphology of legs and antennae involves the regulation of the Hox gene antennapedia (antp). Here, we show that antp is expressed during the embryogenesis of Daphnia, and that adults contain much lower amounts of antp mRNA than eggs. The eggs of mothers that were treated with the juvenile hormone methyl farnesoate (responsible for the production of male offspring) showed lower expression of antp than parthenogenetically produced female eggs. We therefore conclude that differential antp expression is involved in the molecular pathways inducing the male phenotype of Daphnia. PMID- 26754485 TI - High level of microsynteny and purifying selection affect the evolution of WRKY family in Gramineae. AB - The WRKY gene family, which encodes proteins in the regulation processes of diverse developmental stages, is one of the largest families of transcription factors in higher plants. In this study, by searching for interspecies gene colinearity (microsynteny) and dating the age distributions of duplicated genes, we found 35 chromosomal segments of subgroup I genes of WRKY family (WRKY I) in four Gramineae species (Brachypodium, rice, sorghum, and maize) formed eight orthologous groups. After a stepwise gene-by-gene reciprocal comparison of all the protein sequences in the WRKY I gene flanking areas, highly conserved regions of microsynteny were found in the four Gramineae species. Most gene pairs showed conserved orientation within syntenic genome regions. Furthermore, tandem duplication events played the leading role in gene expansion. Eventually, environmental selection pressure analysis indicated strong purifying selection for the WRKY I genes in Gramineae, which may have been followed by gene loss and rearrangement. The results presented in this study provide basic information of Gramineae WRKY I genes and form the foundation for future functional studies of these genes. High level of microsynteny in the four grass species provides further evidence that a large-scale genome duplication event predated speciation. PMID- 26754488 TI - The challenges of choosing and explaining a phenomenon in epidemiological research on the "Hispanic Paradox". AB - According to public health data, the US Hispanic population is far healthier than would be expected for a population with low socioeconomic status. Ever since Kyriakos Markides and Jeannine Coreil highlighted this in a seminal 1986 article, public health researchers have sought to explain the so-called "Hispanic paradox." Several candidate explanations have been offered over the years, but the debate goes on. This article offers a philosophical analysis that clarifies how two sets of obstacles make it particularly difficult to explain the Hispanic paradox. First, different research projects define the Hispanic paradox phenomenon in substantially different ways. Moreover, using Bas van Fraassen's pragmatic theory of explanation and Sean Valles's extension of it with the concept of "phenomenon choice," it also becomes clear that there are also multiple ways of explaining each individual definition of the phenomenon. A second set of philosophical and methodological challenges arises during any attempt to study "Hispanic" phenomena, with one key challenge being that the "Hispanic" panethnic concept was intentionally made vague as it was developed and popularized during the 1960s-1970s. After comparing this case with similar cases in the philosophical literature, the article concludes with observations on what makes this problem unique, particularly its ethical features. PMID- 26754489 TI - Revisiting multiple models of progression of beta-cell loss of function in type 1 diabetes: Significance for prevention and cure. AB - Type 1 diabetes (T1D) results from a chronic autoimmune process that leads to beta-cell destruction and exogenous insulin dependence. The natural history of T1D proposed by Eisenbarth suggested six relatively independent stages over the course of the entire disease process, which was considered to be linear and chronic. Based on this classical theory, immunotherapies aim to prevent or reverse all these periods of beta-cell loss. Over the past 30 years, much novel information about the pathogenesis of T1D proved that there are complex metabolic changes occurring throughout the entire disease process. Therefore, new possible models for the natural history of the disease have been proposed; these models, in turn, may help facilitate fresh avenues for the prevention and cure of T1D. Herein, we briefly review recent findings in this field of research, with the aim of providing a better theoretical basis for clinical practice. PMID- 26754528 TI - Target-specific identification and characterization of the putative gene cluster for brasilinolide biosynthesis revealing the mechanistic insights and combinatorial synthetic utility of 2-deoxy-l-fucose biosynthetic enzymes. AB - Brasilinolides exhibiting potent immunosuppressive and antifungal activities with remarkably low toxicity are structurally characterized by an unusual modified 2 deoxy-l-fucose (2dF) attached to a type I polyketide (PK-I) macrolactone. From the pathogenic producer Nocardia terpenica (Nocardia brasiliensis IFM-0406), a 210 kb genomic fragment was identified by target-specific degenerate primers and subsequently sequenced, revealing a giant nbr gene cluster harboring genes (nbrCDEF) required for TDP-2dF biosynthesis and those for PK-I biosynthesis, modification and regulation. The results showed that the genetic and domain arrangements of nbr PK-I synthases agreed colinearly with the PK-I structures of brasilinolides. Subsequent heterologous expression of nbrCDEF in Escherichia coli accomplished in vitro reconstitution of TDP-2dF biosynthesis. The catalytic functions and mechanisms of NbrCDEF enzymes were further characterized by systematic mix-and-match experiments. The enzymes were revealed to display remarkable substrate and partner promiscuity, leading to the establishment of in vitro hybrid deoxysugar biosynthetic pathways throughout an in situ one-pot (iSOP) method. This study represents the first demonstration of TDP-2dF biosynthesis at the enzyme and molecular levels, and provides new hope for expanding the structural diversity of brasilinolides by combinatorial biosynthesis. PMID- 26754527 TI - The real-world evidence of heart failure: findings from 41 413 patients of the ARNO database. AB - AIMS: Patients with heart failure (HF) randomized in controlled trials are generally selected and do not fully represent the 'real world'. The purpose of this study is to better describe the characteristics of HF by analysing administrative data of a population of nearly 2 500 000 subjects. METHODS AND RESULTS: Data came from the ARNO Observatory including inhabitants of five Local Health Units of the Italian National Health Service (INHS). Patients were selected when discharged for HF (1 January 2008-31 December 2012) and prescribed at least one HF treatment. Clinical characteristics, pharmacological treatments, rehospitalization, and direct costs for the INHS were described during 1-year follow-up (FU). Of the 2 456 739 subjects included in the database, 54 059 (2.2%) were hospitalized for HF: 41 413 were discharged alive and prescribed HF treatments. Mean age was 78 +/- 11 years and 51.4% were females. Just 26.6% were managed in a cardiology setting. The most frequent co-morbidities were diabetes (30.7%), COPD (30.5%), and depression (21%). ACE inhibitors/ARBs, beta-blockers, and mineralocorticoid antagonists were prescribed in 65.8, 49.7, and 42.1% of patients, respectively. During 1-year FU, at least one rehospitalization occurred in 56.6% of patients, 49% of them due to non-cardiovascular causes. The direct cost per patient per year to the INHS was ?11 867, of which 76% was related to hospitalizations. CONCLUSIONS: Real-world evidence provides a description of patient characteristics and treatment patterns that are different from those reported by randomized clinical trials. Costs for the INHS are mainly driven by hospitalizations, which are often due to non-cardiovascular reasons. PMID- 26754490 TI - Discrimination of cirrhotic nodules, dysplastic lesions and hepatocellular carcinoma by their vibrational signature. AB - BACKGROUND: Hepatocarcinogenesis is a multistep process characterized in patients with chronic liver diseases by a spectrum of hepatic nodules that mark the progression from regenerative nodules to dysplastic lesions followed by hepatocellular carcinoma (HCC). The differential diagnosis between precancerous dysplastic nodules and early HCC still represents a challenge for both radiologists and pathologists. We addressed the potential of Fourier transform infrared (FTIR) microspectroscopy for grading cirrhotic nodules on frozen tissue sections. METHODS: The study was focused on 39 surgical specimens including normal livers (n = 11), dysplastic nodules (n = 6), early HCC (n = 1), progressed HCC on alcoholic cirrhosis (n = 10) or hepatitis C virus cirrhosis (n = 11). The use of the bright infrared source emitted by the synchrotron radiation allowed investigating the biochemical composition at the cellular level. Chemical mapping on whole tissue sections was further performed using a FTIR microscope equipped with a laboratory-based infrared source. The variance was addressed by principal component analysis. RESULTS: Profound alterations of the biochemical composition of the pathological liver were demonstrated by FTIR microspectroscopy. Indeed, dramatic changes were observed in lipids, proteins and sugars highlighting the metabolic reprogramming in carcinogenesis. Quantifiable spectral markers were characterized by calculating ratios of areas under specific bands along the infrared spectrum. These markers allowed the discrimination of cirrhotic nodules, dysplastic lesions and HCC. Finally, the spectral markers can be measured using a laboratory FTIR microscope that may be easily implemented at the hospital. CONCLUSION: Metabolic reprogramming in liver carcinogenesis can constitute a signature easily detectable using FTIR microspectroscopy for the diagnosis of precancerous and cancerous lesions. PMID- 26754526 TI - Interrogating cellular fate decisions with high-throughput arrays of multiplexed cellular communities. AB - Recreating heterotypic cell-cell interactions in vitro is key to dissecting the role of cellular communication during a variety of biological processes. This is especially relevant for stem cell niches, where neighbouring cells provide instructive inputs that govern cell fate decisions. To investigate the logic and dynamics of cell-cell signalling networks, we prepared heterotypic cell-cell interaction arrays using DNA-programmed adhesion. Our platform specifies the number and initial position of up to four distinct cell types within each array and offers tunable control over cell-contact time during long-term culture. Here, we use the platform to study the dynamics of single adult neural stem cell fate decisions in response to competing juxtacrine signals. Our results suggest a potential signalling hierarchy between Delta-like 1 and ephrin-B2 ligands, as neural stem cells adopt the Delta-like 1 phenotype of stem cell maintenance on simultaneous presentation of both signals. PMID- 26754529 TI - Species complexes and phylogenetic lineages of Hoferellus (Myxozoa, Cnidaria) including revision of the genus: A problematic case for taxonomy. AB - BACKGROUND: Myxozoans are metazoan parasites whose traditional spore morphology based taxonomy conflicts DNA based phylogenies. Freshwater species of the genus Hoferellus are parasites of the excretory system, with several members infecting food and ornamental fish species, as well as amphibians. This study aims to increase our understanding of their molecular diversity and development, aspects about which little is known, and to generate a molecular diagnostic tool to discriminate between different pathogenic and non-pathogenic Hoferellus spp. METHODS: SSU and ITS rDNA phylogeny, along with morphological descriptions using light and electron microscopy were used to identify and characterize Hoferellus species collected from the urinary system of fishes and frogs. A PCR-based diagnostic assay was designed to differentiate between cryptic Hoferellus spp in cyprinid fishes commonly cultured in Central Europe. RESULTS: Our phylogenetic results separate the species of Hoferellus into two phylogenetic sublineages which are indistinguishable on the basis of generic morphological traits: 1) The Hoferellus sensu stricto sublineage, which is composed of the type species Hoferellus cyprini, Hoferellus carassii and a cryptic species, Hoferellus sp. detected only molecularly in common carp. 2) The Hoferellus sensu lato sublineage into which the new species we described in this study, Hoferellus gnathonemi sp. n. from the kidney of the elephantnose fish and Hoferellus anurae from reed frogs, are placed together with Hoferellus gilsoni previously sequenced from European eel. Apart from phylogenetic analyses, we also provide novel ultrastructural data on the phagocytotic nature of some Hoferellus plasmodia and on the elusive intracellular stages ascribed to the presporogonic development of this genus. CONCLUSIONS: We provide molecular evidence of the polyphyly of the genus Hoferellus and provide novel morphological details of its members. Based on the presented data, we revise and propose emendation of the genus Hoferellus. PMID- 26754530 TI - Distorted Grids as a Spatial Label and Metric. AB - Grid cells have been proposed to encode both the self-location of an animal and the relative position of locations within an environment. We reassess the validity of these roles in light of recent evidence demonstrating grid patterns to be less temporally and spatially stable than previously thought. PMID- 26754531 TI - Comparison of three 18F-labeled carboxylic acids with 18F-FDG of the differentiation tumor from inflammation in model mice. AB - BACKGROUND: The aim of this study was to compare the properties and feasibility of the glucose analog, 2-(18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG), three short (18)F-labeled carboxylic acids, (18)F-fluoroacetate ((18)F-FAC), 2-(18)F fluoropropionic acid ((18)F-FPA) and 4-((18)F)fluorobenzoic acid ((18)F-FBA), for differentiating tumors from inflammation. METHODS: Biodistributions of (18)F-FAC, (18)F-FPA and (18)F-FBA were determined on normal Kunming mice, and positron emission tomography (PET) imaging with these tracers were performed on the separate tumor-bearing mice model and inflammation mice model in comparison with (18)F-FDG. RESULTS: Biodistribution results showed that (18)F-FAC and (18)F-FPA had similar biodistribution profiles and the slow radioactivity clearance from most tissues excluding the in vivo defluorination of (18)F-FAC, and (18)F-FBA demonstrated a lower uptake and fast clearance in most tissues. PET imaging with (18)F-FDG, (18)F-FAC and (18)F-FPA revealed the high uptake in both tumor and inflammatory lesions. The ratios of tumor-to-inflammation were 1.63 +/- 0.28 for (18)F-FDG, 1.20 +/- 0.38 for (18)F-FAC, and 1.41 +/- 0.33 for (18)F-FPA at 60 min postinjection, respectively. While clear tumor images with high contrast between tumor and inflammation lesion were observed in (18)F-FBA/PET with the highest ratio of tumor-to-inflammation (1.98 +/- 0.15). CONCLUSIONS: Our data demonstrated (18)F-FBA is a promising PET probe to distinguish tumor from inflammation. But the further modification of (18)F-FBA structure is required to improve its pharmacokinetics. PMID- 26754532 TI - Gab2 facilitates epithelial-to-mesenchymal transition via the MEK/ERK/MMP signaling in colorectal cancer. AB - BACKGROUND: Grb2-associated binder 2 (Gab2), a scaffolding adaptor protein, has recently been implicated in cancer progression. However, the role of Gab2 in the progression and metastasis of colorectal cancer (CRC) remains unclear. METHODS: Gab2 expression was assessed in CRC patient specimens as well as in CRC cell lines. Recombinant lentivirus vector containing Gab2 gene and its small interfering RNAs were constructed and introduced into CRC cells. Cell migration and invasion ability were evaluated by transwell assays in vitro, and in vivo metastasis was performed on nude mice model. Moreover, the expression of Gab2 and epithelial-to-mesenchymal transition (EMT)-associated proteins (E-cadherin and vimentin) were assessed by western blot and qRT-PCR in CRC cells to evaluate the correlation between Gab2 and EMT. Finally, we evaluated the impact of Gab2 on the activation of its downstream signaling effectors, and furthermore the effects of these pathways on Gab2 induced-EMT were also detected. RESULTS: We confirmed that increased Gab2 expression correlated with higher tumor node metastasis stage and highly invasive CRC cell lines. Ectopic expression of Gab2 promoted metastasis of CRC cells, whereas silencing of Gab2 resulted in inhibited metastasis both in vitro and in vivo. Overexpression of Gab2 in CRC cells induced EMT, whereas knockdown of Gab2 had the opposite effect. Furthermore, upregulation of Gab2 expression obviously stimulated the activation of extracellular signal-regulated kinase-1/2 (ERK1/2), and increased the expression of matrix metalloproteinase-7 (MMP7) and matrix metalloproteinase-9 (MMP9) in CRC cells. Conversely, downregulation of Gab2 expression significantly decreased the activation of ERK1/2, and inhibited MMP7 and MMP9 expression. U0126, an inhibitor of mitogen activated protein kinase (MEK), can reverse the effects of Gab2 on EMT. CONCLUSIONS: Our work highlights that Gab2 induces EMT through the MEK/ERK/MMP pathway, which in turn promotes intestinal tumor metastasis. PMID- 26754533 TI - The leukemic oncoprotein NPM1-RARA inhibits TP53 activity. AB - The variant acute promyelocytic leukemia (APL) translocation t(5;17)(q35;q21) fuses the N-terminus of nucleophosmin (NPM1) to the retinoic acid receptor alpha (RARA). We found that ectopic NPM1-RARA expression decreased TP53 protein levels in target cells. NPM1-RARA impaired TP53-dependent transcription. Cells expressing NPM1-RARA were more resistant to apoptotic stimuli. This work identifies the TP53 tumor suppressor as a novel target through which NPM1-RARA impacts leukemogenesis, and confirms the importance of impairment of TP53 in establishment of the APL phenotype. PMID- 26754534 TI - [New guidelines on resuscitation in adults: What has changed?]. AB - In October 2015, new guidelines for cardiopulmonary resuscitation (CPR) were published, which represent a revision of the guidelines 2010. The new recommendations are based on an update of knowledge on resuscitation, which was evaluated for the first time by GRADE (Grading of Recommendations Assessment, Development and Evaluation). The key messages of the guidelines 2010 were retained in 2015. Adult basic life support consists of a sequence of 30 chest compressions at a rate of 100-120/min with a depth of 5 to maximally 6 cm and 2 ventilations. As soon as possible, an automated external defibrillator (AED) should be applied. Interruptions of chest compressions should be minimized. To improve bystander CPR emergency medical dispatchers should diagnose cardiac arrest when informed about unconscious persons not breathing normally. In this case, emergency medical staff should inform bystanders to resuscitate with compression only CPR until the arrival of an emergency team. In postresuscitation care, mild hypothermia (body temperature 32-34 degrees C) has been replaced by targeted temperature management in unconscious patients. Now, the guidelines recommend a constant body temperature between 32-36 degrees C for at least 24 h. Fever should be prevented or treated. PMID- 26754535 TI - Gender-related differences in susceptibility to oxidative stress in healthy middle-aged Serbian adults. AB - Gender-related differences in the association between polymorphism of xenobiotic metabolising enzymes or non-genetic biomarkers and susceptibility to oxidative stress was assessed in healthy middle-aged Serbian adults, by urinary 8-oxo-7,8 dihydro-2'-deoxyguanosine (8-oxodG/creatinine) and total antioxidant status in serum (TAOS). Females were more susceptible to oxidative stress. In both genders, positive predictor of the antioxidative protection was serum triglyceride, while BMI <25 kg/m(2) was associated with oxidative stress. Susceptibility to oxidative stress in males was associated with GSTT1*null allele and increased serum iron, but in females, it was decreased serum bilirubin. Early identification of the risk factors could be important in the prevention of oxidative stress-related diseases. PMID- 26754536 TI - Why high cholesterol levels help hematological malignancies: role of nuclear lipid microdomains. AB - BACKGROUND: Diet and obesity are recognized in the scientific literature as important risk factors for cancer development and progression. Hypercholesterolemia facilitates lymphoma lymphoblastic cell growth and in time turns in hypocholesterolemia that is a sign of tumour progression. The present study examined how and where the cholesterol acts in cancer cells when you reproduce in vitro an in vivo hypercholesterolemia condition. METHODS: We used non-Hodgkin's T cell human lymphoblastic lymphoma (SUP-T1 cell line) and we studied cell morphology, aggressiveness, gene expression for antioxidant proteins, polynucleotide kinase/phosphatase and actin, cholesterol and sphingomyelin content and finally sphingomyelinase activity in whole cells, nuclei and nuclear lipid microdomains. RESULTS: We found that cholesterol changes cancer cell morphology with the appearance of protrusions together to the down expression of beta-actin gene and reduction of beta-actin protein. The lipid influences SUP-T1 cell aggressiveness since stimulates DNA and RNA synthesis for cell proliferation and increases raf1 and E-cadherin, molecules involved in invasion and migration of cancer cells. Cholesterol does not change GRX2 expression but it overexpresses SOD1, SOD2, CCS, PRDX1, GSR, GSS, CAT and PNKP. We suggest that cholesterol reaches the nucleus and increases the nuclear lipid microdomains known to act as platform for chromatin anchoring and gene expression. CONCLUSION: The results imply that, in hypercholesterolemia conditions, cholesterol reaches the nuclear lipid microdomains where activates gene expression coding for antioxidant proteins. We propose the cholesterolemia as useful parameter to monitor in patients with cancer. PMID- 26754540 TI - User-defined functions in the Arden Syntax: An extension proposal. AB - BACKGROUND: The Arden Syntax is a knowledge-encoding standard, started in 1989, and now in its 10th revision, maintained by the health level seven (HL7) organization. It has constructs borrowed from several language concepts that were available at that time (mainly the HELP hospital information system and the Regenstrief medical record system (RMRS), but also the Pascal language, functional languages and the data structure of frames, used in artificial intelligence). The syntax has a rationale for its constructs, and has restrictions that follow this rationale. The main goal of the Standard is to promote knowledge sharing, by avoiding the complexity of traditional programs, so that a medical logic module (MLM) written in the Arden Syntax can remain shareable and understandable across institutions. OBJECTIVES: One of the restrictions of the syntax is that you cannot define your own functions and subroutines inside an MLM. An MLM can, however, call another MLM, where this MLM will serve as a function. This will add an additional dependency between MLMs, a known criticism of the Arden Syntax knowledge model. This article explains why we believe the Arden Syntax would benefit from a construct for user-defined functions, discusses the need, the benefits and the limitations of such a construct. METHODS AND MATERIALS: We used the recent grammar of the Arden Syntax v.2.10, and both the Arden Syntax standard document and the Arden Syntax Rationale article as guidelines. We gradually introduced production rules to the grammar. We used the CUP parsing tool to verify that no ambiguities were detected. RESULTS: A new grammar was produced, that supports user-defined functions. 22 production rules were added to the grammar. A parser was built using the CUP parsing tool. A few examples are given to illustrate the concepts. All examples were parsed correctly. CONCLUSIONS: It is possible to add user defined functions to the Arden Syntax in a way that remains coherent with the standard. We believe that this enhances the readability and the robustness of MLMs. A detailed proposal will be submitted by the end of the year to the HL7 workgroup on Arden Syntax. PMID- 26754539 TI - Non-cardiovascular findings in clinical cardiovascular magnetic resonance imaging in children. AB - BACKGROUND: With increasing use of pediatric cardiovascular MRI, it is important for all imagers to become familiar with the spectrum of non-cardiovascular imaging findings that can be encountered. OBJECTIVE: This study aims to ascertain the prevalence and nature of these findings in pediatric cardiovascular MRIs performed at our institution. MATERIALS AND METHODS: We retrospectively evaluated reports of all cardiovascular MRI studies performed at our institute from January 2008 to October 2012 in patients younger than18 years. Most studies (98%) were jointly interpreted by a pediatric cardiologist and a radiologist. We reviewed the electronic medical records of all cases with non-cardiovascular findings, defined as any imaging finding outside the cardiovascular system. Non cardiovascular findings were classified into significant and non-significant, based on whether they were known at the time of imaging or they required additional workup or a change in management. RESULTS: In 849 consecutive studies (mean age 9.7 +/- 6.3 years), 145 non-cardiovascular findings were found in 140 studies (16.5% of total studies). Overall, 51.0% (74/145) of non-cardiovascular findings were in the abdomen, 30.3% (44/145) were in the chest, and 18.6% (27/145) were in the spine. A total of 19 significant non-cardiovascular findings were observed in 19 studies in individual patients (2.2% of total studies, 47% male, mean age 5.9 +/- 6.7 years). Significant non-cardiovascular findings included hepatic adenoma, arterially enhancing focal liver lesions, asplenia, solitary kidney, pelvicaliectasis, renal cystic diseases, gastric distention, adrenal hemorrhage, lung hypoplasia, air space disease, bronchial narrowing, pneumomediastinum and retained surgical sponge. CONCLUSION: Non-cardiovascular findings were seen in 16.5% of cardiovascular MRI studies in children, of which 2.2% were clinically significant findings. Prevalence and nature of these non cardiovascular findings are different from those reported in adults. Attention to these findings is important during interpretation. PMID- 26754537 TI - Antenatal and postnatal radiologic diagnosis of holocarboxylase synthetase deficiency: a systematic review. AB - BACKGROUND: Holocarboxylase synthetase deficiency results in impaired activation of enzymes implicated in glucose, fatty acid and amino acid metabolism. Antenatal imaging and postnatal imaging are useful in making the diagnosis. Untreated holocarboxylase synthetase deficiency is fatal, while antenatal and postnatal biotin supplementation is associated with good clinical outcomes. Although biochemical assays are required for definitive diagnosis, certain radiologic features assist in the diagnosis of holocarboxylase synthetase deficiency. OBJECTIVE: To review evidence regarding radiologic diagnostic features of holocarboxylase synthetase deficiency in the antenatal and postnatal period. MATERIALS AND METHODS: A systematic review of all published cases of holocarboxylase synthetase deficiency identified by a search of Pubmed, Scopus and Web of Science. RESULTS: A total of 75 patients with holocarboxylase synthetase deficiency were identified from the systematic review, which screened 687 manuscripts. Most patients with imaging (19/22, 86%) had abnormal findings, the most common being subependymal cysts, ventriculomegaly and intraventricular hemorrhage. CONCLUSION: Although the radiologic features of subependymal cysts, ventriculomegaly, intraventricular hemorrhage and intrauterine growth restriction may be found in the setting of other pathologies, these findings should prompt consideration of holocarboxylase synthetase deficiency in at-risk children. PMID- 26754541 TI - Pharmacological and biochemical studies on the protective effects of melatonin during stress-induced behavioral and immunological changes in relation to oxidative stress in rats. AB - Stress is known to precipitate neuropsychiatric diseases, and depending upon its nature and intensity it can also influence the functioning of the immune system. Melatonin (N-acetyl-5-methoxy tryptamine) a pineal gland hormone and potent antioxidant is known to protect against many diseases. Effect of melatonin in stress-induced neuro-immunomodulation is not well elucidated. Therefore in the present study, the protective effects of melatonin were evaluated in restraint stress (RS)-induced behavioral and immunological changes in rats. RS for 1 h significantly reduces (i) percentage of open-arm entries and (ii) percentage of time spent on open-arm in elevated plus maze (EPM) test parameters (p < 0.01) and significant increase in MDA levels in brain homogenate when compared to non-RS control groups (p < 0.05). In immunological studies, both humoral and cell mediated immune responses to antigen were significantly suppressed by RS for 1 h for 5 consecutive days, as evidenced by significant reduction in (i) anti-SRBC antibody titre, (ii) PFC counts, (iii) percentage change in paw volume, and (iv) Th1 (IFN-gamma) and Th2 (IL-4) cytokine levels (p < 0.001 in all parameters). These RS-induced immunological changes were associated with significantly increased lipid peroxidation (MDA) levels in serum and significantly decreased activity of (i) SOD, (ii) CAT, and (iii) GSH levels in RS (X5)-exposed group (p < 0.02). Pretreatment with melatonin (10, 50, and 100 mg/kg) significantly reversed these RS-induced changes in EPM test parameters and humoral and cell-mediated immunological parameters, as well as oxidative stress markers in a dose-dependent manner by differential degrees (p < 0.001). Results are strongly suggestive of the involvement of free radicals during stress-induced neurobehavioral and immunological changes. These changes were significantly restored by melatonin pretreatment. We can conclude that melatonin may have a protective role during such stress-induced neuro-immunomodulation. PMID- 26754543 TI - Survival, Reproduction, Avoidance Behavior and Oxidative Stress Biomarkers in the Earthworm Octolasion cyaneum Exposed to Glyphosate. AB - The massive use of glyphosate (GLY) in several countries has increased the interest in investigating its potential adverse effects in non-target organisms. The aim of the present study was to assess the potential effects in survival and reproduction; avoidance behavior and oxidative stress under short-term (48 h) and subchronic exposures (28 days) to GLY in the earthworm Octolasion cyaneum. After 48 h no significant changes in the behavior was observed. In addition, a lower catalase activity at 498 MUg GLY kg(-1) dry soil section relative to earthworms from the control section was obtained. After 28 days of exposure inhibition of glutathione S-transferase activity was observed at 535 MUg GLY kg(-1) dry soil while no changes in the other endpoints were detected. These results indicate that environmentally relevant concentrations of GLY (up to 996 ug GLY kg(-1) dry soil) did not exert a toxic effect to O. cyaneum. PMID- 26754542 TI - Hydroxysafflor Yellow A Attenuates Neuron Damage by Suppressing the Lipopolysaccharide-Induced TLR4 Pathway in Activated Microglial Cells. AB - Microglia activation initiates a neurological deficit cascade that contributes to substantial neuronal damage and impairment following ischemia stroke. Toll-like receptor 4 (TLR4) has been demonstrated to play a critical role in this cascade. In the current study, we tested the hypothesis that hydroxysafflor yellow A (HSYA), an active ingredient extracted from Flos Carthami tinctorii, alleviated inflammatory damage, and mediated neurotrophic effects in neurons by inducing the TLR4 pathway in microglia. A non-contact Transwell co-culture system comprised microglia and neurons was treated with HSYA followed by a 1 mg/mL lipopolysaccharide (LPS) stimulation. The microglia were activated prior to neuronal apoptosis, which were induced by increasing TLR4 expression in the activated microglia. However, HSYA suppressed TLR4 expression in the activated microglia, resulting in less neuronal damage at the early stage of LPS stimulation. Western blot analysis and immunofluorescence indicated that dose dependently HSYA down-regulated TLR4-induced downstream effectors myeloid differentiation factor 88 (MyD88), nuclear factor kappa b (NF-kappaB), and the mitogen-activated protein kinases (MAPK)-regulated proteins c-Jun NH2-terminal protein kinase (JNK), protein kinase (ERK) 1/2 (ERK1/2), p38 MAPK (p38), as well as the LPS-induced inflammatory cytokine release. However, HSYA up-regulated brain-derived neurotrophic factor (BDNF) expression. Our data suggest that HSYA could exert neurotrophic and anti-inflammatory functions in response to LPS stimulation by inhibiting TLR4 pathway-mediated signaling. PMID- 26754544 TI - Occurrence and Distribution of Carbamate Pesticides and Metalaxyl in Southern Ontario Surface Waters 2007-2010. AB - Surface water sampling in 2007-2010 measured the occurrence of carbamates and metalaxyl during base flow conditions and wet weather events in southern Ontario surface waters. Carbaryl, metalaxyl and pirimicarb were the most frequently detected compounds. In 2008 these three compounds were detected in over 50 % of the samples. Overall mean concentrations of carbaryl and metalaxyl over the course of the study (2007-2010) were 15 and 18 ng/L, respectively. Elevated concentrations of carbaryl (~100 to ~950 ng/L) appeared associated with wet weather (high flow) events, while highest concentrations of metalaxyl (~20-1330 ng/L) were correlated with base flow conditions. We attributed these observations as the result of runoff of carbaryl from the watershed during rain events, while metalaxyl contamination may have resulted primarily from spray drift. PMID- 26754545 TI - Biomarkers of Cytotoxic, Genotoxic and Apoptotic Effects in Cyprinus carpio Exposed to Complex Mixture of Contaminants from Hospital Effluents. AB - Hospital wastewater is an important source of emerging contaminants. Recent studies emphasize the importance of assessing the effects of mixtures of contaminants rather than environmental risk of their individual components, as well as the determination of intrinsic toxicity of wastewater. Mixtures of pollutants has possible interactions that have notable environmental side effects. The aim of this study is an attempt to characterize biomarkers in Cyprinus carpio related to the exposure to a complex mixture of contaminants found in hospital wastewater. Results of a particular hospital effluent show the presence of traces of heavy metals, high chlorine concentration and emerging contaminants such as non-steroidal anti-inflammatory drugs. The LC50 was of 5.49 % at 96 h. The cytotoxic, genotoxic and apoptotic biomarkers increase when fishes were exposed to wastewater (1/10 CL50) from hospital wastewater. This study emphasizes the importance of identifying and quantifying the effects of contaminants as pharmaceuticals, disinfectants and surfactants in order to design and implement an ecotoxicological plan. PMID- 26754546 TI - Bioaccumulation of Metals in Tissues of Seahorses Collected from Coastal China. AB - Seahorses, which have been used in Chinese traditional medicine, are poor swimmers and easily affected by regional ecological conditions. In this study, we investigated the bioaccumulation of nine metals in different tissues of four seahorse species (Hippocampus trimaculatus, H. histrix, H. kelloggi, and H. kuda) from six locations along the Chinese coast. The present study found relatively low concentrations of metals in the seahorses compared with those in other marine fishes. There was a location-dependent variation in metal concentrations in the seahorses, especially between developed and less developed cities. Results also showed metal concentrations varied among different seahorse species and tissues, with H. kelloggi having higher bioaccumulation ability compared with H. trimaculatus and higher metal levels were found in visceral mass, muscle, and skin tissues than those in brain, lips gill, endoskeleton, and exoskeleton tissues in the seahorses. Among different metals, Mg had the highest tissue concentrations in all the seahorses, followed by Al and Mn. PMID- 26754547 TI - Targeting polo-like kinase 1, a regulator of p53, in the treatment of adrenocortical carcinoma. AB - BACKGROUND: Adrenocortical carcinoma (ACC) is an aggressive cancer with a 5 year survival rate of 20-30 %. Various factors have been implicated in the pathogenesis of ACC including dysregulation of the G2/M transition and aberrant activity of p53 and MDM2. Polo-like kinase 1 (PLK-1) negatively modulates p53 functioning, promotes MDM2 activity through its phosphorylation, and is involved in the G2/M transition. Gene expression profiling of 44 ACC samples showed that increased expression of PLK-1 in 29 % of ACC. Consequently, we examined PLK-1's role in the modulation of the p53 signaling pathway in adrenocortical cancer. METHODS: We used siRNA knock down PLK-1 and pharmacological inhibition of PLK-1 and MDM2 ACC cell lines SW-13 and H295R. We examined viability, protein expression, p53 transactivation, and induction of apoptosis. RESULTS: Knocking down expression of PLK-1 with siRNA or inhibition of PLK-1 by a small molecule inhibitor, BI-2536, resulted in a loss of viability of up to 70 % in the ACC cell lines H295R and SW-13. In xenograft models, BI-2536 demonstrated marked inhibition of growth of SW-13 with less inhibition of H295R. BI-2536 treatment resulted in a decrease in mutant p53 protein in SW-13 cells but had no effect on wild-type p53 protein levels in H295R cells. Additionally, inhibition of PLK-1 restored wild-type p53's transactivation and apoptotic functions in H295R cells, while these functions of mutant p53 were restored only to a smaller extent. Furthermore, inhibition of MDM2 with nutlin-3 reduced the viability of both the ACC cells and also reactivated wild-type p53's apoptotic function. Inhibition of PLK-1 sensitized the ACC cell lines to MDM2 inhibition and this dual inhibition resulted in an additive apoptotic response in H295R cells with wild-type p53. CONCLUSIONS: These preclinical studies suggest that targeting p53 through PLK-1 is an attractive chemotherapy strategy warranting further investigation in adrenocortical cancer. PMID- 26754548 TI - A demonstrated positive effect of a hearing conservation program in the Swedish armed forces. AB - OBJECTIVE: A revised hearing conservation program (HCP) was implemented in the Swedish Armed Forces in 2002. The aim of this study was to evaluate the incidence of significant threshold shifts (STS) in male conscripts heavily exposed to noise after the implementation of the new HCP, comparing the results to those of an earlier study from 1999/2000. DESIGN: The study was prospective and longitudinal, covering the period from reporting to military service to discharge. The outcome measure was the incidence of STS. Statistics from the military insurance system was analysed. STUDY SAMPLE: A total of 395 conscripts were included in the study (mean age 19 years). The control group (n: 839) consisted of men of the same age. RESULTS: In 2004/2005 the incidence rate of STS was 2.3% compared to 7.9% in 1999/2000 and compared to 3.7% among the controls. The number of cases of auditory complications reported from conscripts to the insurance system has decreased, from 16 to 5/100,000 days of military training, during the last decade. CONCLUSIONS: The new HCP apparently reduced the incidence rate of STS to one third compared to before the program was introduced and leveled it to the incidence rate in the control-group not exposed to military noise. PMID- 26754551 TI - Lead Halide Perovskite Photovoltaic as a Model p-i-n Diode. AB - The lead halide perovskite photovoltaic cells, especially the iodide compound CH3NH3PbI3 family, exhibited enormous progress in the energy conversion efficiency in the past few years. Although the first attempt to use the perovskite was as a sensitizer in a dye-sensitized solar cell, it has been recognized at the early stage of the development that the working of the perovskite photovoltaics is akin to that of the inorganic thin film solar cells. In fact, theoretically perovskite is always treated as an ordinary direct band gap semiconductor and hence the perovskite photovoltaics as a p-i-n diode. Despite this recognition, research effort along this line of thought is still in pieces and incomplete. Different measurements have been applied to different types of devices (different not only in the materials but also in the cell structures), making it difficult to have a coherent picture. To make the situation worse, the perovskite photovoltaics have been plagued by the irreproducible optoelectronic properties, most notably the sweep direction dependent current-voltage relationship, the hysteresis problem. Under such circumstances, it is naturally very difficult to analyze the data. Therefore, we set out to make hysteresis-free samples and apply time-tested models and numerical tools developed in the field of inorganic semiconductors. A series of electrical measurements have been performed on one type of CH3NH3PbI3 photovoltaic cells, in which a special attention was paid to ensure that their electronic reproducibility was better than the fitting error in the numerical analysis. The data can be quantitatively explained in terms of the established models of inorganic semiconductors: current/voltage relationship can be very well described by a two-diode model, while impedance spectroscopy revealed the presence of a thick intrinsic layer with the help of a numerical solver, SCAPS, developed for thin film solar cell analysis. These results point to that CH3NH3PbI3 is an ideal intrinsic semiconductor, which happens to be very robust against accidental doping, and that the perovskite photovoltaic cell is in fact a model p-i-n diode. The analytical methods and diagnostic tools available in the inorganic semiconductor PV cells are useful and should be fully exploited in the effort of improving the efficiency. One outstanding question is why the perovskite stays intrinsic. Considering the defects and impurities that must abound in the perovskite layers formed by the spin-coating process, for example, there must be physicochemical mechanism keeping it from being doped. This may be related to the special band structure making up the band gap in this ionic solid. Understanding the mechanism may open a door for the wider utility of this class of solid. PMID- 26754550 TI - Understanding the psychosocial experiences of adults with mild-moderate hearing loss: An application of Leventhal's self-regulatory model. AB - OBJECTIVE: This study explored the psychosocial experiences of adults with hearing loss using the self-regulatory model as a theoretical framework. The primary components of the model, namely cognitive representations, emotional representations, and coping responses, were examined. DESIGN: Individual semi structured interviews were conducted. The data were analysed using an established thematic analysis procedure. STUDY SAMPLE: Twenty-five adults with mild-moderate hearing loss from the UK and nine hearing healthcare professionals from the UK, USA, and Canada were recruited via maximum variation sampling. RESULTS: Cognitive representations: Most participants described their hearing loss as having negative connotations and consequences, although they were not particularly concerned about the progression or controllability/curability of the condition. Opinions differed regarding the benefits of understanding the causes of one's hearing loss in detail. Emotional representations: negative emotions dominated, although some experienced positive emotions or muted emotions. Coping responses: engaged coping (e.g. hearing aids, communication tactics) and disengaged coping (e.g. withdrawal from situations, withdrawal within situations): both had perceived advantages and disadvantages. CONCLUSIONS: This novel application of the self-regulatory model demonstrates that it can be used to capture the key psychosocial experiences (i.e. perceptions, emotions, and coping responses) of adults with mild-moderate hearing loss within a single, unifying framework. PMID- 26754549 TI - The Dendrobium catenatum Lindl. genome sequence provides insights into polysaccharide synthase, floral development and adaptive evolution. AB - Orchids make up about 10% of all seed plant species, have great economical value, and are of specific scientific interest because of their renowned flowers and ecological adaptations. Here, we report the first draft genome sequence of a lithophytic orchid, Dendrobium catenatum. We predict 28,910 protein-coding genes, and find evidence of a whole genome duplication shared with Phalaenopsis. We observed the expansion of many resistance-related genes, suggesting a powerful immune system responsible for adaptation to a wide range of ecological niches. We also discovered extensive duplication of genes involved in glucomannan synthase activities, likely related to the synthesis of medicinal polysaccharides. Expansion of MADS-box gene clades ANR1, StMADS11, and MIKC(*), involved in the regulation of development and growth, suggests that these expansions are associated with the astonishing diversity of plant architecture in the genus Dendrobium. On the contrary, members of the type I MADS box gene family are missing, which might explain the loss of the endospermous seed. The findings reported here will be important for future studies into polysaccharide synthesis, adaptations to diverse environments and flower architecture of Orchidaceae. PMID- 26754553 TI - Antimicrobial activity of selected synbiotics targeted for the elderly against pathogenic Escherichia coli strains. AB - The aim of the present study was to evaluate the antimicrobial activity of two synbiotic combinations, Lactobacillus fermentum with short-chain fructooligosaccharides (FOS-LF) and Bifidobacterium longum with isomaltooligosaccharides (IMO-BL), against enterohaemorrhagic Escherichia coli O157:H7 and enteropathogenic E. coli O86. Antimicrobial activity was determined (1) by co-culturing the synbiotics and pathogens in batch cultures, and (2) with the three-stage continuous culture system (gut model), inoculated with faecal slurry from an elderly donor. In the co-culture experiments, IMO-BL was significantly inhibitory to both E. coli strains, while FOS-LF was slightly inhibitory or not inhibitory. Factors other than acid production appeared to play a role in the inhibition. In the gut models, both synbiotics effectively inhibited E. coli O157 in the first vessel, but not in vessels 2 and 3. E. coli O86 was not significantly inhibited. PMID- 26754552 TI - Effect of body mass index on the performance characteristics of PSA-related markers to detect prostate cancer. AB - To examine whether the predictive performance of prostate-specific antigen (PSA) and PSA-related markers for prostate cancer (PCa) is modified by body mass index (BMI). Patients with a PSA 2-10 ng/mL who underwent multicore prostate biopsies were recruited from three tertiary centers. Serum markers measured included total PSA (tPSA), free-to-total PSA (f/tPSA), p2PSA, percentage of p2PSA (%p2PSA), and prostate health index (PHI). The association between serum markers and PCa risk was assessed by logistic regression. Predictive performance for each marker was quantified using the area under the receiver operator curves (AUC). Among 516 men, 18.2% had PCa at biopsy. For all tested markers, their predictive value on PCa risk was lower in obese patients compared to normal weight patients. We found statistically significant interactions between BMI and tPSA (P = 0.0026) and p2PSA (P = 0.038). PHI achieved an AUC of 0.872 in normal weight patients and 0.745 in obese patients, which outperformed the other predictors regardless of BMI category. In conclusion, PHI achieved the best predictive performance for detecting PCa and was not influenced by BMI. PMID- 26754554 TI - A facile one-pot synthesis of 2,3-diarylated benzo[b]furans via relay NHC and palladium catalysis. AB - An efficient one-pot synthesis of 2,3-diarylated benzo[b]furans was realized through the relay catalysis of N-Heterocyclic Carbene (NHC) and palladium from substituted 2'-bromodiphenylbromomethanes and aryl aldehydes. The easy availability of the starting materials, good compatibility of catalysts, convergent assembly and concomitant modification of the target scaffold, and potential utilization value of the products make this strategy attractive in organic synthesis. PMID- 26754555 TI - Developing a new justification for assent. AB - BACKGROUND: Current guidelines do not clearly outline when assent should be attained from paediatric research participants, nor do they detail the necessary elements of the assent process. This stems from the fact that the fundamental justification behind the concept of assent is misunderstood. In this paper, we critically assess three widespread ethical arguments used for assent: children's rights, the best interests of the child, and respect for a child's developing autonomy. We then outline a newly-developed two-fold justification for the assent process: respect for the parent's pedagogical role in teaching their child to become an autonomous being and respect for the child's moral worth. DISCUSSION: We argue that the ethical grounding for the involvement of young children in medical decision-making does not stem from children's rights, the principle of best interests, or respect for developing autonomy. An alternative strategy is to examine the original motivation to engage with the child. In paediatric settings there are two obligations on the researcher: an obligation to the parents who are responsible for determining when and under what circumstances the child develops his capacity for autonomy and reasoning, and an obligation to the child himself. There is an important distinction between respecting a decision and encouraging a decision. This paper illustrates that the process of assent is an important way in which respect for the child as an individual can be demonstrated, however, the value lies not in the child's response but the fact that his views were solicited in the first place. This paper demonstrates that the common justifications for the process of assent are incomplete. Assent should be understood as playing a pedagogical role for the child, helping to teach him how specific decisions are made and therefore helping him to become a better decision-maker. How the researcher engages with the child supports his obligation to the child's parents, yet why the researcher engages with the child stems from the child's moral worth. Treating a child as having moral worth need not mean doing what they say but it may mean listening, considering, engaging or involving them in the decision. PMID- 26754556 TI - CRLF2 overexpression identifies an unfavourable subgroup of adult B-cell precursor acute lymphoblastic leukemia lacking recurrent genetic abnormalities. AB - BACKGROUND: A deregulated CRLF2 (d-CRLF2) expression was described in B-cell acute lymphoblastic leukemia without recurrent fusion genes (B-NEG ALL). While the role of d-CRLF2 in children has been extensively described, little is known about its role and impact in adult ALL. METHODS: Expression levels of CRLF2 were evaluated by quantitative real-time PCR in 102 newly-diagnosed adult B-NEG ALL and correlated with the clinico-biological characteristics and outcome. Incidence and clinical impact of the P2RY8/CRLF2 transcript was also assessed. RESULTS: High CRLF2 levels, as continuous variable, were significantly associated with hyperleucocytosis (p=0.0002) and thrombocytopenia (p=0.005); when a cut-point at DeltaCt<=8 was applied, 35 cases (34.3%), mostly males (80%), proved positive for CRLF2 expression. High CRLF2 levels, as continuous or categorical variable, were associated with a worse disease-free (p=0.003 and p=0.015) and overall survival (p=0.017 and 0.0038). Furthermore, when CRLF2 was analyzed as a categorical variable, a high statistical association was found with IKZF1 deletion and mutations in the JAK/STAT pathway (p=0.001 and p<0.0001, respectively). Finally, the P2RY8/CRLF2 transcript, identified in 8/102 patients (7.8%), was associated with a poor outcome. CONCLUSIONS: In adult B-NEG ALL, high CRLF2 expression is associated with distinct clinico-biological features and an unfavourable prognosis in both univariate and multivariate analysis; similarly, P2RY8/CRLF2 positivity correlates with a poor outcome. The quantification of CRLF2 is an important prognostic marker in adult B-lineage ALL without known genetic lesions. PMID- 26754557 TI - Impacts of graft-versus-host disease on outcomes after allogeneic hematopoietic stem cell transplantation for chronic myelomonocytic leukemia: A nationwide retrospective study. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a therapeutic option that may lead to improved outcomes in patients with chronic myelomonocytic leukemia (CMML). However, few studies have examined the impact of the grade of graft-versus-host disease (GVHD) on post-transplant outcomes for CMML. We retrospectively analyzed the outcomes of 141 patients with CMML who underwent allo-HSCT between 1987 and 2010, and achieved neutrophil engraftment. The effects of acute GVHD (aGVHD) or chronic GVHD (cGVHD) on overall survival (OS), leukemia associated mortality (LAM), and transplant-related mortality were evaluated by hazards regression models, in which the onset date of aGVHD or cGVHD was treated as a time-dependent covariate. Grade I aGVHD was associated with better OS and lower LAM (P=0.042, P=0.033, respectively) than no GVHD in univariate analyses, but not in the multivariate analyses. The multivariate analyses demonstrated that extensive cGVHD significantly associated with better OS (Hazard Ratio [HR] 0.35 [95% confidence intervals (CI), 0.16-0.74]; P=0.007) and lower LAM (HR 0.36 [95% CI, 0.14-0.92]; P=0.033) in patients who were not in complete remission at transplantation. In conclusion, the occurrence of cGVHD may be an important factor affecting the outcomes of CMML patients who received transplantation. PMID- 26754558 TI - Substituted 5,6-(Dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-methanones as P2X7 Antagonists. AB - We describe the synthesis of a novel class of brain penetrating P2X7 antagonists with high potency at both the rat and human P2X7 receptors. Disclosed herein are druglike molecules with demonstrated target engagement of the rat P2X7 receptors after an oral dose. Specifically, compound 20 occupied the P2X7 receptors >80% over the 6 h time course as measured by an ex vivo radioligand binding experiment. In a dose-response assay, this molecule has a plasma EC50 of 8 ng/mL. Overall, 20 has suitable druglike properties and pharmacokinetics in rat and dog. This molecule and others disclosed herein will serve as additional tools to elucidate the role of the P2X7 receptor in neuropsychiatric disorders. PMID- 26754559 TI - Extent and Impact of Opioid Prescribing for Acute Occupational Low Back Pain in the Emergency Department. AB - BACKGROUND: Initial management of acute occupational low back pain (AOLBP) commonly occurs in the emergency department (ED), where opioid prescribing can vary from the clinical guidelines that recommend limited use. OBJECTIVE: The objective of this study was to explore how opioids are prescribed in the ED and the impact on work disability and other outcomes in AOLBP. METHODS: A retrospective cohort study was conducted. All acute compensable lost-time LBP cases seen initially in the ED with a date of injury from January 1, 2009 to December 31, 2011 were identified within a nationally representative Workers' Compensation dataset. Multivariate models estimated the effect of early opioids (received within 2 days of ED visit) on disability duration, long-term opioid use, total medical costs, and subsequent surgeries. RESULTS: Of the cohort (N = 2887), 12% received early opioids; controlling for severity, this was significantly associated with long-term opioid use (adjusted risk ratio = 1.29; 95% confidence interval 1.05-1.58) and increased total medical costs for those in the highest opioid dosage quartile, but not associated with disability duration or subsequent low back surgery. CONCLUSIONS: Early opioid prescribing in the ED for uncomplicated AOLBP increased long-term opioid use and medical costs, and should be discouraged, as opioid use for low back pain has been associated with a variety of adverse outcomes. However, ED providers may be becoming more compliant with current LBP treatment guidelines. PMID- 26754560 TI - Cofilin contributes to phagocytosis of IgG-opsonized particles but not non opsonized particles in RAW264 macrophages. AB - Cofilin is an actin-binding protein that severs actin filaments. It plays a key role in regulating actin cytoskeletal remodeling, thereby contributing to diverse cellular functions. However, the involvement of cofilin in phagocytosis remains to be elucidated. We examined the spatiotemporal localization of cofilin during phagocytosis of IgG-opsonized erythrocytes, IgG-opsonized latex beads and non opsonized latex beads. Live-cell imaging showed that GFP-cofilin accumulates in the sites of IgG-opsonized particle binding and in phagocytic cups. Moreover, immunofluorescence microscopy revealed that endogenous cofilin localizes to phagocytic cups engulfing IgG-opsonized particles, but not non-opsonized latex beads. Scanning electron microscopy demonstrated a notable difference in morphology between phagocytic structures in IgG-dependent and IgG-independent phagocytosis. In phagocytosis of IgG-opsonized particles, sheet-like pseudopodia extended along the surface of IgG-opsonized particles to form phagocytic cups. In contrast, in opsonin-independent phagocytosis, long finger-like filopodia captured non-opsonized latex beads. Importantly, non-opsonized beads sank into the cells without extending phagocytic cups. Our analysis of cofilin mutant expression demonstrates that phagocytosis of IgG-opsonized particles is enhanced in cells expressing wild-type cofilin or active mutant cofilin-S3A, whereas the uptake of non-opsonized latex beads is not. These data suggest that cofilin promotes actin cytoskeletal remodeling to form phagocytic cups by accelerating actin turnover and thereby facilitating phagosome formation. In contrast, cofilin is not involved in opsonin-independent phagocytosis of latex beads. PMID- 26754562 TI - Application of strain to orbital-spin-coupled system MnV2O4 at cryogenic temperatures within a transmission electron microscope. AB - The impact of mechanical stress on the morphology of crystallographic and magnetic domains in shape-controlled specimens of an orbital-spin-coupled system, MnV2O4, was examined by cryogenic Lorentz microscopy. Because of the difference in thermal expansion coefficients of MnV2O4 and the supporting Mo mesh, compression on the order of 0.01% was applied to the thin-foil specimens near the structural/magnetic phase transformation temperatures. The extent of compression was comparable to the lattice striction associated with the cubic-to-tetragonal phase transformation in MnV2O4 The applied strain thus clearly influenced the morphology of crystallographic domains (i.e. twinning configuration in the tetragonal phase) produced during cooling. The magnetic domain structure was entirely dependent on the configuration of twinning in the tetragonal phase. The observations in this study provided useful information for understanding the relationship between the crystallographic domains and the magnetic domains in MnV2O4. PMID- 26754561 TI - Two-dimensional crystallization of monomeric bovine cytochrome c oxidase with bound cytochrome c in reconstituted lipid membranes. AB - Mitochondrial cytochrome c oxidase utilizes electrons provided by cytochrome c for the active vectorial transport of protons across the inner mitochondrial membrane through the reduction of molecular oxygen to water. Direct structural evidence on the transient cytochrome c oxidase-cytochrome c complex thus far, however, remains elusive and its physiological relevant oligomeric form is unclear. Here, we report on the 2D crystallization of monomeric bovine cytochrome c oxidase with tightly bound cytochrome c at a molar ratio of 1:1 in reconstituted lipid membranes at the basic pH of 8.5 and low ionic strength. PMID- 26754563 TI - Motion analysis and ultrastructural study of a colonial diatom, Bacillaria paxillifer. AB - The pennate diatom, Bacillaria paxillifer, forms a colony in which adjacent cells glide smoothly and almost continuously, yet no obvious apparatus driving the movement, such as flagella or cilia, is observed. Thus far, neither the mechanism nor physiological significance of this movement has been well understood. Here, we report quantitative analysis of the gliding motion of B. paxillifer and morphological analysis of this diatom with light and electron microscopes. The gliding of pairs of adjacent B. paxillifer cells in a colony was cyclic with rather constant periods while the average gliding period varied from a few seconds to multiples of 10 s among colonies. The gliding was compromised reversibly by inhibitors for actin and myosin, suggesting involvement of the actomyosin system. Indeed, we observed two closely apposed actin bundles near the raphe by fluorescence-labeled phalloidin staining. Using electron microscopy, we observed filamentous structures that resemble the actin bundles seen with fluorescence microscopy, and we also found novel electron-dense structures located between the plasma membrane and these actin-like filaments. From these and other observations, we suggest that B. paxillifer also uses actin bundles and propose a putative myosin as a molecular motor in the gliding of unicellular diatoms. PMID- 26754565 TI - Distinct types of eigenvector localization in networks. AB - The spectral properties of the adjacency matrix provide a trove of information about the structure and function of complex networks. In particular, the largest eigenvalue and its associated principal eigenvector are crucial in the understanding of nodes' centrality and the unfolding of dynamical processes. Here we show that two distinct types of localization of the principal eigenvector may occur in heterogeneous networks. For synthetic networks with degree distribution P(q) ~ q(-gamma), localization occurs on the largest hub if gamma > 5/2; for gamma < 5/2 a new type of localization arises on a mesoscopic subgraph associated with the shell with the largest index in the K-core decomposition. Similar evidence for the existence of distinct localization modes is found in the analysis of real-world networks. Our results open a new perspective on dynamical processes on networks and on a recently proposed alternative measure of node centrality based on the non-backtracking matrix. PMID- 26754566 TI - Sexual orientation of trans adults is not linked to outcome of transition-related health care, but worth asking. AB - Since the beginning of contemporary transition-related care at the outset of the 20th century, sexual orientation has ben considered to be closely connected with gender identity and the developmental trajectories of trans people. Specifically, health professionals have regarded the anticipated post-transitional heterosexual behaviour of trans adults as predictive of a good outcome of cross-sex hormones and gender-confirming surgeries. This article reviews the current literature according to the question of whether the sexual orientation of trans people is linked to outcome measures following transition-related interventions. A comprehensive review was undertaken using the Medline database, searching for empirical studies published between 2010 and 2015. Out of a total of 474 studies, only 10 studies reported a follow-up of trans adults and assessed sexual orientation in the study protocol at all. Sexual orientation was predominantly assessed as homosexual versus non-homosexual related to sex assigned at birth. Only one 1 of 10 follow-up studies found a significant association according to the outcome between groups differentiated by sexual orientation. Empirically there is no link between sexual orientation and outcome of transition-related health care for trans adults. In order to provide comprehensive health care, we recommend asking for sexual behaviours, attractions and identities, as well as for gender experiences and expressions; however, this knowledge should not drive, but simply inform, such comprehensive care. PMID- 26754567 TI - Synthesis of 8-heteroaryl nitroxoline analogues via one-pot sequential Pd catalyzed coupling reactions. AB - A series of 8-heteroaryl substituted quinolines were prepared, either by direct C H arylation of five-membered heteroarenes, or Pd-catalyzed coupling of organoboron reagents with bromoquinolines. The use of (benzo)thiophenyl or (benzo)furanyl boron coupling partners allowed further C-H functionalization on the five-membered heteroaryl ring with aryl bromides in one flask to access a variety of polyconjugated molecular architectures. The developed methodology represents a simple approach towards 8-arylated analogues of the biologically interesting nitroxoline core. PMID- 26754564 TI - Antitumor Activity of cGAMP via Stimulation of cGAS-cGAMP-STING-IRF3 Mediated Innate Immune Response. AB - Immunotherapy is one of the key strategies for cancer treatment. The cGAS-cGAMP STING-IRF3 pathway of cytosolic DNA sensing plays a pivotal role in antiviral defense. We report that the STING activator cGAMP possesses significant antitumor activity in mice by triggering the STING-dependent pathway directly. cGAMP enhances innate immune responses by inducing production of cytokines such as interferon-beta, interferon-gamma, and stimulating dendritic cells activation, which induces the cross-priming of CD8(+) T cells. The antitumor mechanism of cGAMP was verified by STING and IRF3, which were up-regulated upon cGAMP treatment. STING-deficiency dramatically reduced the antitumor effect of cGAMP. Furthermore, cGAMP improved the antitumor activity of 5-FU, and clearly reduced the toxicity of 5-FU. These results demonstrated that cGAMP is a novel antitumor agent and has potential applications in cancer immunotherapy. PMID- 26754568 TI - Synthetic polycations with controlled charge density and molecular weight as building blocks for biomaterials. AB - A series of polycations prepared by RAFT copolymerization of N-(3 aminopropyl)methacrylamide hydrochloride (APM) and N-(2 hydroxypropyl)methacrylamide, with molecular weights of 15 and 40 kDa, and APM content of 10-75 mol%, were tested as building blocks for electrostatically assembled hydrogels such as those used for cell encapsulation. Complexation and distribution of these copolymers within anionic calcium alginate gels, as well as cytotoxicity, cell attachment, and cell proliferation on surfaces grafted with the copolymers were found to depend on composition and molecular weight. Copolymers with lower cationic charge density and lower molecular weight showed less cytotoxicity and cell adhesion, and were more mobile within alginate gels. These findings aid in designing improved polyelectrolyte complexes for use as biomaterials. PMID- 26754569 TI - Bilateral thalamic developmental venous variations (DVVs) draining into same internal cerebral vein: a case report and review with emphasis on DVVs with outflow restriction. AB - Developmental venous variations (DVVs) are anatomic variations of normal transmedullary veins which are often discovered incidentally. Although they are accepted as benign compensatory venous drainage systems, they may become symptomatic or clinically significant due to flow-related causes. The fragile venous drainage systems increase vulnerability to in-out flow alterations. Increased inflow or decreased outflow causes rise in venous pressure, which may subsequently produce ischemic symptoms. Obstruction or stenosis of the collector vein is the most common cause of decreased outflow of a DVV. However, in the absence of collecting vein stenosis, venous hypertension may still exist due to volume overload. In case of multiple DVVs with single combined drainage pathway, functional outflow restriction may occur due to diminished capability of the vessel to adapt to pressure changes. In this report, we present a case with bilateral thalamic DVVs, which cause parenchymal amorphous calcification and drain into the left internal cerebral vein. A review of the literature on DVVs with outflow restriction including pathophysiological mechanisms is also discussed. PMID- 26754571 TI - Research at its best: Competency in the complexity of child abuse and neglect. PMID- 26754570 TI - Borderline personality features and emotion regulation deficits are associated with child physical abuse potential. AB - The present study extends prior research examining the association between borderline personality disorder (BPD) features and child physical abuse (CPA) risk. We hypothesized that: (1) high CPA risk parents (compared to low CPA risk parents) would more often report clinically elevated levels of BPD features; (2) high CPA risk parents with elevated BPD features would represent a particularly high-risk subgroup; and (3) the association between elevated BPD features and CPA risk would be partially explained by emotion regulation difficulties. General population parents (N=106; 41.5% fathers) completed self-report measures of BPD features, CPA risk, and emotion regulation difficulties. Results support the prediction that BPD features are more prevalent among high (compared to low) CPA risk parents. Among the parents classified as high CPA risk (n=45), one out of three (33.3%) had elevated BPD features. In contrast, none of the 61 low CPA risk parents reported elevated BPD symptoms. Moreover, 100% of the parents with elevated BPD features (n=15) were classified as high-risk for CPA. As expected, high CPA risk parents with elevated BPD features (compared to high CPA risk parents with low BPD features) obtained significantly higher scores on several Child Abuse Potential Inventory scales, including the overall abuse scale (d=1.03). As predicted, emotion regulation difficulties partially explained the association between BPD features and CPA risk. Findings from the present study suggest that a subset of high CPA risk parents in the general population possess clinically significant levels of BPD symptoms and these parents represent an especially high-risk subgroup. Interventions designed to address BPD symptoms, including emotion regulation difficulties, appear to be warranted in these cases. PMID- 26754572 TI - Fucosylation is associated with the malignant transformation of intraductal papillary mucinous neoplasms: a lectin microarray-based study. AB - PURPOSE: Intraductal papillary mucinous neoplasm (IPMN) is an intraductal mucin producing pancreatic neoplasm with the potential for malignant transformation. Changes in glycans expressed on the cell surface and glycotransferases play important roles in malignant transformation. We conducted this study to analyze glycan alterations in IPMNs by using a lectin microarray and to identify the factors associated with altered glycans and their relationships with malignant transformation. METHODS: Using a lectin microarray, we evaluated glycan expression in 22 samples of IPMN with carcinoma, obtained from curative resections performed in our department. We also used immunohistochemistry to investigate fucosyltransferase 8 (Fut 8) protein expression, which is associated with glycan alterations in IPMNs. RESULTS: The lectin microarray demonstrated that only two lectins, Aleuria aurantia lectin (AAL) and Aspergillus oryzae L fucose-specific lectin (AOL), which bind to fucose, exhibited significant sequential increases from normal pancreatic duct to adenoma and carcinoma. Similarly, Fut 8 protein expression, which is associated with AAL and AOL, sequentially and significantly increased from the normal pancreatic duct to adenoma and carcinoma. CONCLUSIONS: Lectin microarray analysis suggested that fucosylation is associated with the malignant transformation of IPMNs. PMID- 26754574 TI - The value of structured data elements from electronic health records for identifying subjects for primary care clinical trials. AB - BACKGROUND: An increasing number of clinical trials are conducted in primary care settings. Making better use of existing data in the electronic health records to identify eligible subjects can improve efficiency of such studies. Our study aims to quantify the proportion of eligibility criteria that can be addressed with data in electronic health records and to compare the content of eligibility criteria in primary care with previous work. METHODS: Eligibility criteria were extracted from primary care studies downloaded from the UK Clinical Research Network Study Portfolio. Criteria were broken into elemental statements. Two expert independent raters classified each statement based on whether or not structured data items in the electronic health record can be used to determine if the statement was true for a specific patient. Disagreements in classification were discussed until 100 % agreement was reached. Statements were also classified based on content and the percentages of each category were compared to two similar studies reported in the literature. RESULTS: Eligibility criteria were retrieved from 228 studies and decomposed into 2619 criteria elemental statements. 74 % of the criteria elemental statements were considered likely associated with structured data in an electronic health record. 79 % of the studies had at least 60 % of their criteria statements addressable with structured data likely to be present in an electronic health record. Based on clinical content, most frequent categories were: "disease, symptom, and sign", "therapy or surgery", and "medication" (36 %, 13 %, and 10 % of total criteria statements respectively). We also identified new criteria categories related to provider and caregiver attributes (2.6 % and 1 % of total criteria statements respectively). CONCLUSIONS: Electronic health records readily contain much of the data needed to assess patients' eligibility for clinical trials enrollment. Eligibility criteria content categories identified by our study can be incorporated as data elements in electronic health records to facilitate their integration with clinical trial management systems. PMID- 26754573 TI - Dissecting the influence of Neolithic demic diffusion on Indian Y-chromosome pool through J2-M172 haplogroup. AB - The global distribution of J2-M172 sub-haplogroups has been associated with Neolithic demic diffusion. Two branches of J2-M172, J2a-M410 and J2b-M102 make a considerable part of Y chromosome gene pool of the Indian subcontinent. We investigated the Neolithic contribution of demic dispersal from West to Indian paternal lineages, which majorly consists of haplogroups of Late Pleistocene ancestry. To accomplish this, we have analysed 3023 Y-chromosomes from different ethnic populations, of which 355 belonged to J2-M172. Comparison of our data with worldwide data, including Y-STRs of 1157 individuals and haplogroup frequencies of 6966 individuals, suggested a complex scenario that cannot be explained by a single wave of agricultural expansion from Near East to South Asia. Contrary to the widely accepted elite dominance model, we found a substantial presence of J2a M410 and J2b-M102 haplogroups in both caste and tribal populations of India. Unlike demic spread in Eurasia, our results advocate a unique, complex and ancient arrival of J2a-M410 and J2b-M102 haplogroups into Indian subcontinent. PMID- 26754575 TI - The clinical impact of valvular heart disease in a population-based cohort of subjects aged 80 and older. AB - BACKGROUND: In our ageing society, valvular heart diseases (VHD) have become an increasing public health problem. However, the lack of studies describing the impact of these diseases on the outcome of very old subjects makes it difficult to appreciate their real clinical burden. METHODS: Prospective, observational, population-based cohort study in Belgium. Five hundred fifty six subjects aged 80 years and older were followed up for 5.1 +/- 0.25 years for mortality and 3.0 +/- 0.25 years for hospitalization. Echocardiograms were performed at baseline. The Cumulative Illness Rating Scale (CIRS) was calculated for each subject. RESULTS: The prevalence of moderate-to-severe VHD was 17% (n = 97). Mitral stenosis was more prevalent in women and an age-dependent increase of the prevalence of severe aortic stenosis was seen. The overall disease burden was higher in participants with VHD (median CIRS 3 [IQR 3-5] vs 4 [IQR 3-6] (P = 0.008)). Moderate-to-severe VHD, and more specifically mitral stenosis and aortic stenosis, was found to be an independent predictor of both all-cause (HR 1.42 (95% CI 1.04-1.95)) and cardiovascular mortality (HR 2.13 (95% CI 1.38-3.29)). Moderate-to-severe VHD was also found to be an independent predictor of the need for a first unplanned hospitalization (HR 1.43 (95% CI 1.06-1.94)). CONCLUSIONS: A high prevalence of moderate-to-severe VHD was found in the very old. Moderate-to-severe VHD was identified as an independent risk factor for all-cause and cardiovascular mortality and as well for unplanned hospitalizations, independent of other structural cardiac abnormalities, ventricular function and major co-morbidities. PMID- 26754577 TI - Sacral neuromodulation: No more skiing? AB - Patients with spinal cord injury (SCI) commonly suffer from neurogenic lower urinary tract dysfunction (NLUTD). Sacral neuromodulation (SNM) offers an alternative in the treatment of detrusor overactivity in patients with NLUTD. We report the cases of three patients with NLUTD due to SCI who received SNM. Due to treatment success, all patients could resume skiing. All suffered from skiing accidents, leading to a decreased effectiveness of SNM. Subsequent evaluation revealed a defect of the impulse generator (IPG) and/or dislocation of the electrodes. Reprogramming or replacement of the IPG or the electrodes resulted in restoration of SNM function. Trauma due to skiing is a potential risk factor for the integrity of SNM. Patients with SNM should be informed about the potential risk of SNM damage by falls and accidents. PMID- 26754576 TI - The rs5888 single nucleotide polymorphism in scavenger receptor class B type 1 (SCARB1) gene and the risk of premature coronary artery disease: a case-control study. AB - BACKGROUND: Several single nucleotide polymorphisms (SNPs) in lipid transport genes have been shown to be associated with premature coronary artery disease (PCAD). The scavenger receptor BI (SCARB1) is a key component of the reverse cholesterol transport and lipid metabolism. We aimed to examine the relationship between the rs5888 SNP within SCARB1and the risk of angiographically determined PCAD. METHODS: We used an age cut-off of 55 years for women and 45 years for men to define PCAD. Five-hundred and five patients with newly diagnosed angiographically documented PCAD (>= 50 % luminal stenosis of any coronary vessel) as case group compared with 546 controls (subjects with no luminal stenosis at coronary arteries). The severity of CAD was determined by vessel score as well as Gensini score. A real-time polymerase chain reaction (PCR) and High Resolution Melting (HRM) analysis was used to distinguish between genotypes. RESULTS: T allele as compared to C allele was associated with increased odds of PCAD in total population (adjusted OR = 1.3, 95 % CI = 1.0 to 1.5; p = 0.020), and in women (adjusted OR = 1.3, 95 % CI = 1.0 to 1.8; p = 0.037), but not in men (adjusted OR = 1.2, 95 % CI = 0.9 to 1.5; p = 0.311). There was also no significant association between the examined polymorphism and the severity of CAD in whole or in men or women subgroups. CONCLUSIONS: Our findings suggest that the SNP (rs5888) within SCARB1 is independently associated with PCAD in a sex dependent manner. PMID- 26754578 TI - Retrospective evaluation of concurrent intra-abdominal injuries in dogs with traumatic pelvic fractures: 83 cases (2008-2013). AB - OBJECTIVE: To report the occurrence of intra-abdominal injury (IA) in dogs with pelvic fractures due to blunt trauma, to evaluate for association between characterization of pelvic fractures and the presence of IA, and to evaluate for association between IA and other specific clinical conditions. DESIGN: Retrospective case series (2008-2013). SETTING: University teaching hospital. ANIMALS: Eighty-three client-owned dogs with pelvic fractures due to blunt trauma. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pelvic injuries included pubic fractures (90.4%), ischial fractures (80.7%), sacroiliac luxations (57.8%), iliac fractures (43.4%), acetabular fractures (30.1%), and sacral fractures (13.3%). Thirty-one dogs (37%) had IA, which included hemoabdomen (27 dogs), uroabdomen (3), and septic abdomen (3); 2 dogs had 2 types of IA. Dogs with sacral fractures were significantly more likely to have IA than dogs without sacral fractures (P = 0.0162). Characterization of pelvic fractures included the direction of compression, presence of a weight-bearing bone fracture, and degree of pelvic narrowing, none of which had an association with IA (P > 0.05). Dogs were more likely to have IA if they had cardiac dysrhythmia (P = 0.0002) or hematuria (P = 0.0001), and were more likely to have a hemoabdomen if they had cardiac dysrhythmia (P = 0.0005). Dogs with hematochezia were more likely to have a septic abdomen (P = 0.0123). Dogs were more likely to receive a transfusion if they had AI (P = 0.033) or hemoabdomen specifically (P = 0.0033). Overall survival to discharge was 89%, which was significantly greater than survival in dogs with pelvic injury that also had septic abdomen (33%; P = 0.0299). CONCLUSIONS: IA is common in dogs with pelvic fractures, especially those with sacral fractures. Pelvic fracture characterization had no bearing on the presence of IA. PMID- 26754580 TI - Nanosize effects assisted synthesis of the high pressure metastable phase in ZrO2. AB - The size effects on the high pressure behaviors of monoclinic (MI) ZrO2 nanoparticles were studied using in situ high pressure synchrotron X-ray diffraction (XRD) and X-ray absorption spectroscopy (XAS). A size-dependent phase transition behavior under high pressure was found in nanoscale ZrO2. The normal phase transition sequence of MI-orthorhombic I (OI)-orthorhombic II (OII) occurs in 100-300 nm ZrO2 nanoparticles, while only the transition of MI-OI exists in ultrafine ~5 nm ZrO2 nanoparticles up to the highest experimental pressure of ~52 GPa. This indicates that the size effects preclude the transition from the OI to the OII phase in ~5 nm nanoparticles. Upon decompression, the OII and OI phases are retained down to ambient pressure, respectively. This is the first observation of the pure OI phase ZrO2 under ambient conditions. The bulk moduli of the MI ZrO2 nanoparticles were determined to be B0 = 192 (7) GPa for the 100 300 nm nanoparticles and B0 = 218 (12) GPa for the ~5 nm nanoparticles. We suggest that the significant high surface energy precludes the transition from the OI to the OII phase and the nanosize effects enhance the incompressibility in the ultrafine ZrO2 nanoparticles (~5 nm). Our study indicates that this is a potential way of preparing novel nanomaterials with high pressure structures using nanosize effects. PMID- 26754581 TI - The Outflow Pathway: A Tissue With Morphological and Functional Unity. AB - The trabecular meshwork (TM) plays an important role in high-tension glaucomas. Indeed, the TM is a true organ, through which the aqueous humor flows from the anterior chamber to Schlemm's canal (SC). Until recently, the TM, which is constituted by endothelial-like cells, was described as a kind of passive filter. In reality, it is much more. The cells delineating the structures of the collagen framework of the TM are endowed with a cytoskeleton, and are thus able to change their shape. These cells also have the ability to secrete the extracellular matrix, which expresses proteins and cytokines, and are capable of phagocytosis and autophagy. The cytoskeleton is attached to the nuclear membrane and can, in millionths of a second, send signals to the nucleus in order to alter the expression of genes in an attempt to adapt to biomechanical insult. Oxidative stress, as happens in aging, has a deleterious effect on the TM, leading eventually to cell decay, tissue malfunction, subclinical inflammation, changes in the extracellular matrix and cytoskeleton, altered motility, reduced outflow facility, and (ultimately) increased IOP. TM failure is the most relevant factor in the cascade of events triggering apoptosis in the inner retinal layers, including ganglion cells. J. Cell. Physiol. 231: 1876-1893, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26754579 TI - Electrical Stimulation to Enhance Axon Regeneration After Peripheral Nerve Injuries in Animal Models and Humans. AB - Injured peripheral nerves regenerate their lost axons but functional recovery in humans is frequently disappointing. This is so particularly when injuries require regeneration over long distances and/or over long time periods. Fat replacement of chronically denervated muscles, a commonly accepted explanation, does not account for poor functional recovery. Rather, the basis for the poor nerve regeneration is the transient expression of growth-associated genes that accounts for declining regenerative capacity of neurons and the regenerative support of Schwann cells over time. Brief low-frequency electrical stimulation accelerates motor and sensory axon outgrowth across injury sites that, even after delayed surgical repair of injured nerves in animal models and patients, enhances nerve regeneration and target reinnervation. The stimulation elevates neuronal cyclic adenosine monophosphate and, in turn, the expression of neurotrophic factors and other growth-associated genes, including cytoskeletal proteins. Electrical stimulation of denervated muscles immediately after nerve transection and surgical repair also accelerates muscle reinnervation but, at this time, how the daily requirement of long-duration electrical pulses can be delivered to muscles remains a practical issue prior to translation to patients. Finally, the technique of inserting autologous nerve grafts that bridge between a donor nerve and an adjacent recipient denervated nerve stump significantly improves nerve regeneration after delayed nerve repair, the donor nerves sustaining the capacity of the denervated Schwann cells to support nerve regeneration. These reviewed methods to promote nerve regeneration and, in turn, to enhance functional recovery after nerve injury and surgical repair are sufficiently promising for early translation to the clinic. PMID- 26754584 TI - Well-Differentiated Thyroid Cancer: The Philippine General Hospital Experience. AB - BACKGROUND: Well-differentiated thyroid cancer (WDTC) is the most common form of thyroid malignancy. While it is typically associated with good prognosis, it may exhibit higher recurrence and mortality rates in selected groups, particularly Filipinos. This paper aims to describe the experience of a Philippine Hospital in managing patients with differentiated thyroid cancer. METHODS: We performed a retrospective cohort study of 723 patients with WDTC (649 papillary and 79 follicular), evaluating the clinicopathologic profiles, ultrasound features, management received, tumor recurrence, and eventual outcome over a mean follow-up period of 5 years. RESULTS: The mean age at diagnosis was 44+/-13 years (range, 18 to 82), with a majority of cases occurring in the younger age group (<45 years). Most tumors were between 2 and 4 cm in size. The majority of papillary thyroid cancers (PTCs, 63.2%) and follicular thyroid cancers (FTCs, 54.4%) initially presented as stage 1, with a greater proportion of FTC cases (12.7% vs. 3.7%) presenting with distant metastases. Nodal metastases at presentation were more frequent among patients with PTC (29.9% vs. 7.6%). A majority of cases were treated by complete thyroidectomy, followed by radioactive iodine therapy and thyroid stimulating hormone suppression, resulting in a disease-free state. Excluding patients with distant metastases at presentation, the recurrence rates for papillary and FTC were 30.1% and 18.8%, respectively. CONCLUSION: Overall, PTC among Filipinos was associated with a more aggressive and recurrent behavior. FTC among Filipinos appeared to behave similarly with other racial groups. PMID- 26754583 TI - Small Heterodimer Partner and Innate Immune Regulation. AB - The nuclear receptor superfamily consists of the steroid and non-steroid hormone receptors and the orphan nuclear receptors. Small heterodimer partner (SHP) is an orphan family nuclear receptor that plays an essential role in the regulation of glucose and cholesterol metabolism. Recent studies reported a previously unidentified role for SHP in the regulation of innate immunity and inflammation. The innate immune system has a critical function in the initial response against a variety of microbial and danger signals. Activation of the innate immune response results in the induction of inflammatory cytokines and chemokines to promote anti-microbial effects. An excessive or uncontrolled inflammatory response is potentially harmful to the host, and can cause tissue damage or pathological threat. Therefore, the innate immune response should be tightly regulated to enhance host defense while preventing unwanted immune pathologic responses. In this review, we discuss recent studies showing that SHP is involved in the negative regulation of toll-like receptor-induced and NLRP3 (NACHT, LRR and PYD domains-containing protein 3)-mediated inflammatory responses in innate immune cells. Understanding the function of SHP in innate immune cells will allow us to prevent or modulate acute and chronic inflammation processes in cases where dysregulated innate immune activation results in damage to normal tissues. PMID- 26754586 TI - Effect of Pitavastatin Treatment on ApoB-48 and Lp-PLA2 in Patients with Metabolic Syndrome: Substudy of PROspective Comparative Clinical Study Evaluating the Efficacy and Safety of PITavastatin in Patients with Metabolic Syndrome. AB - BACKGROUND: Apolipoprotein (Apo) B-48 is an intestinally derived lipoprotein that is expected to be a marker for cardiovascular disease (CVD). Lipoprotein associated phospholipase A2 (Lp-PLA2) is a vascular-specific inflammatory marker and important risk predictor of CVD. The aim of this study was to explore the effect of pitavastatin treatment and life style modification (LSM) on ApoB-48 and Lp-PLA2 levels in metabolic syndrome (MS) patients at relatively low risk for CVD, as a sub-analysis of a previous multi-center prospective study. METHODS: We enrolled 75 patients with MS from the PROPIT study and randomized them into two treatment groups: 2 mg pitavastatin daily+intensive LSM or intensive LSM only. We measured the change of lipid profiles, ApoB-48 and Lp-PLA2 for 48 weeks. RESULTS: Total cholesterol, low density lipoprotein cholesterol, non-high density lipoprotein cholesterol, and ApoB-100/A1 ratio were significantly improved in the pitavastatin+LSM group compared to the LSM only group (P<=0.001). Pitavastatin+LSM did not change the level of ApoB-48 in subjects overall, but the level of ApoB-48 was significantly lower in the higher mean baseline value group of ApoB-48. The change in Lp-PLA2 was not significant after intervention in either group after treatment with pitavastatin for 1 year. CONCLUSION: Pitavastatin treatment and LSM significantly improved lipid profiles, ApoB-100/A1 ratio, and reduced ApoB-48 levels in the higher mean baseline value group of ApoB 48, but did not significantly alter the Lp-PLA2 levels. PMID- 26754582 TI - Microglia antioxidant systems and redox signalling. AB - : For many years, microglia, the resident CNS macrophages, have been considered only in the context of pathology, but microglia are also glial cells with important physiological functions. Microglia-derived oxidant production by NADPH oxidase (NOX2) is implicated in many CNS disorders. Oxidants do not stand alone, however, and are not always pernicious. We discuss in general terms, and where available in microglia, GSH synthesis and relation to cystine import and glutamate export, and the thioredoxin system as the most important antioxidative defence mechanism, and further, we discuss in the context of protein thiolation of target redox proteins the necessity for tightly localized, timed and confined oxidant production to work in concert with antioxidant proteins to promote redox signalling. NOX2-mediated redox signalling modulates the acquisition of the classical or alternative microglia activation phenotypes by regulating major transcriptional programs mediated through NF-kappaB and Nrf2, major regulators of the inflammatory and antioxidant response respectively. As both antioxidants and NOX-derived oxidants are co-secreted, in some instances redox signalling may extend to neighboring cells through modification of surface or cytosolic target proteins. We consider a role for microglia NOX-derived oxidants in paracrine modification of synaptic function through long term depression and in the communication with the adaptive immune system. There is little doubt that a continued foray into the functions of the antioxidant response in microglia will reveal antioxidant proteins as dynamic players in redox signalling, which in concert with NOX-derived oxidants fulfil important roles in the autocrine or paracrine regulation of essential enzymes or transcriptional programs. LINKED ARTICLES: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc. PMID- 26754585 TI - The Relationship between 10-Year Cardiovascular Risk Calculated Using the Pooled Cohort Equation and the Severity of Non-Alcoholic Fatty Liver Disease. AB - BACKGROUND: We investigated the association between the severity of non-alcoholic fatty liver disease (NAFLD) and the estimated 10-year risk of cardiovascular disease (CVD) calculated by Pooled Cohort Equation (PCE) and Framingham risk score (FRS). METHODS: A total of 15,913 participants (mean age, 46.3 years) in a health screening program were selected for analysis. The presence and severity of fatty liver was assessed by abdominal ultrasonogram. Subjects who drank alcohol more than three times a week were excluded from the study. RESULTS: Among the participants, 57.6% had no NAFLD, 35.4% had grade I, 6.5% had grade II, and 0.5% had grade III NAFLD. Mean estimated 10-year CVD risk was 2.59%, 3.93%, 4.68%, and 5.23% calculated using the PCE (P for trend <0.01) and 4.55%, 6.39%, 7.33%, and 7.13% calculated using FRS, according to NAFLD severity from none to severe (P for trend <0.01). The odds ratio for >=7.5% estimated CVD risk calculated using the PCE showed a higher correlation with increasing severity of NAFLD even after adjustment for conventional CVD risk factors (1.52, 2.56, 3.35 vs. the no NAFLD group as a reference, P<0.01) compared with calculated risk using FRS (1.65, 1.62, 1.72 vs. no NAFLD group as a reference, P<0.01). CONCLUSION: In our study of apparently healthy Korean adults, increasing severity of NAFLD showed a higher correlation with estimated 10-year CVD risk when calculated using the PCE than when calculated using FRS. PMID- 26754587 TI - Association of Waist-Height Ratio with Diabetes Risk: A 4-Year Longitudinal Retrospective Study. AB - BACKGROUND: Waist-to-height ratio (WHtR) is an easy and inexpensive adiposity index that reflects central obesity. In this study, we examined the association of various baseline adiposity indices, including WHtR, with the development of diabetes over 4 years of follow-up in apparently healthy Korean individuals. METHODS: A total of 2,900 nondiabetic participants (mean age, 44.3 years; 2,078 men) in a health screening program, who repeated the medical check-up in 2005 and 2009, were recruited. Subjects were divided into two groups according to development of diabetes after 4 years. The cut-off values of baseline body mass index (BMI), waist circumference (WC), and WHtR for the development of diabetes over 4 years were calculated. The sensitivity, specificity, and mean area under the receiver operator characteristic curve (AUROC) of each index were assessed. The odds ratio (OR) for diabetes development was analyzed for each of the three baseline adiposity indices. RESULTS: During the follow-up period, 101 new cases (3.5%) of diabetes were diagnosed. The cut-off WHtR value for diabetes development was 0.51. Moreover, WHtR had the highest AUROC value for diabetes development among the three adiposity indices (0.716, 95% confidence interval [CI], 0.669 to 0.763; 0.702, 95% CI, 0.655 to 0.750 for WC; 0.700, 95% CI, 0.651 to 0.750 for BMI). After adjusting for confounding variables, the ORs of WHtR and WC for diabetes development were 1.95 (95% CI, 1.14 to 3.34) and 1.96 (95% CI, 1.10 to 3.49), respectively. No significant differences were observed between the two groups regarding BMI. CONCLUSION: Increased baseline WHtR and WC correlated with the development of diabetes after 4 years. WHtR might be a useful screening measurement to identify individuals at high risk for diabetes. PMID- 26754588 TI - Effects of Dipeptidyl Peptidase-4 Inhibitors on Hyperglycemia and Blood Cyclosporine Levels in Renal Transplant Patients with Diabetes: A Pilot Study. AB - BACKGROUND: The use of dipeptidyl peptidase-4 (DPP-4) inhibitors is increasing among renal transplant patients with diabetes. However, the glucose-lowering efficacies of various DPP-4 inhibitors and their effects on blood cyclosporine levels have not been fully investigated. We compared the glucose-lowering efficacies of DPP 4 inhibitors and evaluate their effects on the blood levels of cyclosporine in renal transplant recipients with diabetes. METHODS: Sixty-five renal allograft recipients who received treatment with DPP-4 inhibitors (vildagliptin, sitagliptin, or linagliptin) following kidney transplant were enrolled. The glucose-lowering efficacies of the DPP-4 inhibitors were compared according to the changes in the hemoglobin A1c (HbA1c) levels after 3 months of treatment. Changes in the trough levels of the cyclosporine were also assessed 2 months after treatment with each DPP-4 inhibitor. RESULTS: HbA1c significantly decreased in the linagliptin group in comparison with other DPP-4 inhibitors (vildagliptin -0.38%+/-1.03%, sitagliptin -0.53%+/-0.95%, and linagliptin -1.40+/ 1.34; P=0.016). Cyclosporine trough levels were significantly increased in the sitagliptin group compared with vildagliptin group (30.62+/-81.70 ng/mL vs. 24.22+/-53.54 ng/mL, P=0.036). Cyclosporine trough levels were minimally changed in patients with linagliptin. CONCLUSION: Linagliptin demonstrates superior glucose-lowering efficacy and minimal effect on cyclosporine trough levels in comparison with other DPP-4 inhibitors in kidney transplant patients with diabetes. PMID- 26754590 TI - Wet-Laid Meets Electrospinning: Nonwovens for Filtration Applications from Short Electrospun Polymer Nanofiber Dispersions. AB - Dispersions of short electrospun fibers are utilized for the preparation of nanofiber nonwovens with different weight area on filter substrates. The aerosol filtration efficiencies of suspension-borne nanofiber nonwovens are compared to nanofiber nonwovens prepared directly by electrospinning with similar weight area. The filtration efficiencies are found to be similar for both types of nonwovens. With this, a large potential opens for processing, design, and application of new nanofiber nonwovens obtained by wet-laying of short electrospun nanofiber suspensions. PMID- 26754591 TI - Epigenetic Pathways of Oncogenic Viruses: Therapeutic Promises. AB - Cancerous transformation comprises different events that are both genetic and epigenetic. The ultimate goal for such events is to maintain cell survival and proliferation. This transformation occurs as a consequence of different features such as environmental and genetic factors, as well as some types of infection. Many viral infections are considered to be causative agents of a number of different malignancies. To convert normal cells into cancerous cells, oncogenic viruses must function at the epigenetic level to communicate with their host cells. Oncogenic viruses encode certain epigenetic factors that lead to the immortality and proliferation of infected cells. The epigenetic effectors produced by oncogenic viruses constitute appealing targets to prevent and treat malignant diseases caused by these viruses. In this review, we highlight the importance of epigenetic reprogramming for virus-induced oncogenesis, with special emphasis on viral epigenetic oncoproteins as therapeutic targets. The discovery of molecular components that target epigenetic pathways, especially viral factors, is also discussed. PMID- 26754592 TI - Lanthanide salen-type complexes exhibiting single ion magnet and photoluminescent properties. AB - Salen-type mononuclear lanthanide complexes with formula (Et3NH)[Ln(3-NO2 salen)2].solvent (Ln = Eu (1Eu), Tb (2Tb), Dy (3Dy), Ho (4Ho), Er (5Er), Yb (6Yb); 3-NO2-salen(2-) = N,N'-bis(3-nitro-salicylaldehyde)ethylenediamine dianion) are reported. These compounds are isostructural in which two crystallographically distinct 3-NO2-salen(2-) act as tetradentate ligands encapsulating the lanthanide ions in a meridional mode forming the [LnN4O4] cores. Slow magnetization relaxation processes associated with single ion magnet (SIM) behaviors are observed in complexes 3Dy, 5Er and 6Yb with the Kramer ions but not in 2Tb and 4Ho with non-Kramer ions. Photoluminescence studies reveal that complexes 1Eu, 5Er and 6Yb exhibit characteristic lanthanide luminescence with sharp and well-separated emission bands. Complex 1Eu is of particular interest in which the organic ligand functioning as a powerful absorbing sensitizer apparently broadens the excitation range into 300-500 nm with the maximum of 460 nm. PMID- 26754593 TI - [Lower urinary tract dysfunction and neuropathological findings of the neural circuits controlling micturition in familial amyotrophic lateral sclerosis with L106V mutation in the SOD1 gene]. AB - We report lower urinary tract dysfunction and neuropathological findings of the neural circuits controlling micturition in the patients with familial amyotrophic lateral sclerosis having L106V mutation in the SOD1 gene. Ten of 20 patients showed lower urinary tract dysfunction and 5 patients developed within 1 year after the onset of weakness. In 8 patients with an artificial respirator, 6 patients showed lower urinary tract dysfunction. Lower urinary tract dysfunction and respiratory failure requiring an artificial respirator occurred simultaneously in 3 patients. Neuronal loss and gliosis were observed in the neural circuits controlling micturition, such as frontal lobe, thalamus, hypothalamus, striatum, periaqueductal gray, ascending spinal tract, lateral corticospinal tract, intermediolateral nucleus and Onufrowicz' nucleus. Lower urinary tract dysfunction, especially storage symptoms, developed about 1 year after the onset of weakness, and the dysfunction occurred simultaneously with artificial respirator use in the patients. PMID- 26754589 TI - Propylthiouracil, Perchlorate, and Thyroid-Stimulating Hormone Modulate High Concentrations of Iodide Instigated Mitochondrial Superoxide Production in the Thyroids of Metallothionein I/II Knockout Mice. AB - BACKGROUND: Increased oxidative stress has been suggested as one of the underlying mechanisms in iodide excess-induced thyroid disease. Metallothioneins (MTs) are regarded as scavengers of reactive oxygen species (ROS) in oxidative stress. Our aim is to investigate the effects of propylthiouracil (PTU), a thyroid peroxidase inhibitor, perchlorate (KClO4), a competitive inhibitor of iodide transport, and thyroid stimulating hormone (TSH) on mitochondrial superoxide production instigated by high concentrations of iodide in the thyroids of MT-I/II knockout (MT-I/II KO) mice. METHODS: Eight-week-old 129S7/SvEvBrd Mt1(tm1Bri) Mt2(tm1Bri)/J (MT-I/II KO) mice and background-matched wild type (WT) mice were used. RESULTS: By using a mitochondrial superoxide indicator (MitoSOX Red), lactate dehydrogenase (LDH) release, and methyl thiazolyl tetrazolium (MTT) assay, we demonstrated that the decreased relative viability and increased LDH release and mitochondrial superoxide production induced by potassium iodide (100 MUM) can be relieved by 300 MUM PTU, 30 MUM KClO4, or 10 U/L TSH in the thyroid cell suspensions of both MT-I/II KO and WT mice (P<0.05). Compared to the WT mice, a significant decrease in the relative viability along with a significant increase in LDH release and mitochondrial superoxide production were detected in MT-I/II KO mice(P<0.05). CONCLUSION: We concluded that PTU, KClO4, or TSH relieved the mitochondrial oxidative stress induced by high concentrations of iodide in the thyroids of both MT-I/II KO and WT mice. MT-I/II showed antioxidant effects against high concentrations of iodide-induced mitochondrial superoxide production in the thyroid. PMID- 26754594 TI - [A case of paroxysmal sympathetic storm after acute disseminated encephalomyelitis and hypoxic encephalopathy responding to clonidine hydrochloride]. AB - We report the case of a 17-year-old woman with paroxysmal sympathetic storm (PSS), which was successfully treated with clonidine hydrochloride. The patient was hospitalized for acute disseminated encephalomyelitis in June 2006. Dysphagia led to severe aspiration pneumonia in September 2006, and she suffered cardiopulmonary arrest. She survived but had severe brain damage, with her brain MRI showing diffuse hypoxic encephalopathy. From October 2006, she had several episodes of profound tachypnea (> 60/min), tachycardia (160 to 170 beats/min), hypertension (> 140 mmHg), hyperthermia (39 degrees C), and decerebrate posturing. During the attacks, the levels of catecholamines in the patient's blood and urine were markedly elevated. Accordingly, a diagnosis of PSS associated with hypoxic encephalopathy was made. Her PSS clearly improved after the administration of clonidine hydrochloride (900 MUg/day). This case suggests that clonidine hydrochloride, an alpha2 blocker, may be one therapeutic option for PSS. PMID- 26754595 TI - Use of peripherally inserted central catheters (PICC) via scalp veins in neonates. AB - OBJECTIVE: The objective of this study is to describe the use and complications of peripherally inserted central catheters (PICC) via scalp veins in neonates. METHODS: A retrospective review of neonates who had PICCs inserted, between January 2010 and June 2013, in the NICU at Children's and Women's Health Center of British Columbia. RESULTS: During the study period, 689 PICCs were inserted over a total of 46 728 NICU patient days. The PICC insertion sites were scalp veins (69), upper limb veins (471), and lower limb veins (149). The mean catheter durations were 17 d, 19 d, and 18 d for PICCs inserted through scalp, upper limb, and lower limb veins, respectively. The complication rates were 23%, 23%, and 15% for insertion via scalp, upper, and lower limb veins, respectively. Centrally placed PICCs at the time of insertion were more likely to remain in situ for longer than one week (p < 0.001). The incidence of central line-associated blood stream infection was 4.4, 6.4, and 3.4 per 1000 catheter days, respectively, for scalp, upper, and lower limb PICCs. CONCLUSIONS: Insertion of PICC via the scalp veins are feasible and not associated with higher complication rates compared with insertions via other sites. PMID- 26754598 TI - A CROSS-CULTURAL COMPARISON OF CERTAIN PERSONALITY FACT0R.S. AB - The 1970 version of the Comrey Personality Scales was administered to a analysis of the data confirmed that the basic structure of the scales was almost identical with that found in the American normative sample. It was suggested that further research was needed to explicate the relationship between the traits of orderliness and conformity. group of 179 New Zealand university and teachers' college students. PMID- 26754597 TI - An understanding of potential and limitations of alginate/PLL microcapsules as a cell retention system for perfusion cultures. AB - Microcapsules for high cell density culture of mammalian cells have found an increasing interest, however, the poor stability of the microcapsules and the lack of characterisation methods led to few quantitative results. Alginate-poly-L lysine (PLL) microcapsules have been studied in detail in order to form a basis for comparison of capsules made from different polymers. Since the microcapsules can be easily retained in the bioreactor without the need for a cell separation device, high cell densities were achieved with a maximum of 4 * 10(7) cell/ml(microcapsules), corresponding to a colonisation of 5% of the internal capsule volume. Measurement of microcapsule integrity and mechanical resistance showed that alginate-PLL microcapsules are not suitable for perfusion cultures since they are very sensitive to media composition, mainly the presence of non gelling ions that have a higher affinity for alginate than PLL and Ca(2+), leading to the leakage of PLL and Ca(2+), and to microcapsule rupture. PMID- 26754599 TI - A FACTORIAL STUDY O F THE ATTITUDE SCALES ON THE COLLEGE STUDENT QUESTIONNAIRE WITH STUDENTS AT A PREDOMINANTLY BLACK UNIVERSITY. AB - The study examined the dimensionality of attitudes on the College Student Questionnaires (CSQ). The sample consisted of 772 entering freshmen at a predominantly black liberal arts university. The correlation matrices for the 66 attitude items were factor analyzed using a principal axes factor analysis with an oblique rotation. Among the eleven factors, which accounted for 37% of the variance, the following were interpreted: Family Independence vs. Cohesiveness; Autonomy vs. Influenceability from Peers ; Non-Affiliative vs. Affiliative Peer Orientation; Concern for Social Problems; Aesthetic Interest; and Interest in Politics and World Affairs. These factors were compared with the original CSQ Attitude Scales, and a number of similarities and differences were noted. The items from the CSQ Liberalism Scale did not form any general interpretable factor and the items from the CSQ Peer Independence Scale formed two distinct factors. The findings implied that special scales- corresponding with the factors found in the study-should be considered when studying attitudes of students attending predominantly black colleges and universities. PMID- 26754596 TI - Favorable outcome of intraoperative radiotherapy to the primary site in patients with metastatic prostate cancer. AB - BACKGROUND: The aim of this study was to determine whether local radiotherapy to the prostate by intraoperative radiotherapy (IORT) increases the overall and cancer-specific survival rates of patients with metastatic prostate cancer. METHODS: Between 1993 and 2000, 102 patients with prostate cancer were treated with a combination of (a) IORT of the prostate (25 or 30 Gy per fraction); (b) external beam radiotherapy of the prostate (30 Gy in 10 fractions), starting approximately 1 week post-operatively; and (c) endocrine treatment. Of these, 16 patients had stage D1 disease (D1 IORT group), 32 had stage D2 disease without visceral metastasis (D2 IORT group), and 38 had stage D2 disease without visceral metastasis and did not receive local therapy (D2 control group). Overall and cancer-specific survival rates were compared. RESULTS: The 5- and 10-year cancer specific survival rates were 75.9 and 52.7 %, respectively, in the (D1 + D2) IORT group and 45.8 and 33.5 %, respectively, in the D2 control group, with cancer specific survival being significantly longer in the D2 IORT than in the D2 control group (P = 0.030). Univariate and multivariate reduced-rank regression analyses showed that extent of skeletal disease Grade 4 and non-regional lymph node metastasis were significantly prognostic of poorer cancer-specific survival (P < 0.001 each). CONCLUSIONS: Local radiotherapy to the prostate by IORT in patients with metastatic prostate cancer may contribute to better survival, especially in patients without extent of skeletal disease Grade 4 or non-regional lymph node metastasis. PMID- 26754600 TI - THE IMPACT OF CRISIS UPON THE BEHAVIOR OF NATIONS IN THE 1960's. AB - This study examines international crises in the 1960's, specifically those crises that occurred between June, 1962 and July, 1968. The conflictual aspects of interacting dyads involved in crises during that period were examined t o discern the conflictual dimensions of national behavior in crises. In addition, conflict behavior was examined for those periods immediately prior to and immediately following crisis situations. This resulted in dimensions of conflict behavior for pre-crisis, during-crisis, and post-crisis periods. The periods were contrasted with one another to gain a better conception of the behavior exhibited in international crises. It was found that the dimensions of behavior change in predictable ways in the shift from one period to another. The behavior of individual dyads does shift in ways which are not predictable by simple linear technique. PMID- 26754601 TI - STUDIES O F SINGLE SAMPLES AND WHOLE POPULATIONS : THE POINT BISERIAL AND ITS GENERALIZATIONS. AB - This paper revives an old statistic, the point biserial correlation, reviews some past generalizations of it, generalizes i t further, and shows how thesecorrelations are useful for studying the characteristics of observations in single samples or whole populations. The distinctions between analysis o? variance techniques and complex point serial correlation analyses are examined in considerable detail. PMID- 26754602 TI - THE PERCEPTION OF POLITICIANS AND POLITICAL ISSUES : A MULTIDIMENSIONAL SCALING APPROACH. AB - The multidimensional scaling (MDS) of both attitude statements and political candidates in the same multidimensional space was considered to have several ramifications. First, the position of the attitude statements would explicate the nature of the factorial structure of politicians; second, the underlying dimensions would demonstrate whether candidates are perceived in terms of relevant political dimensions. Third, the scaling would reveal the extent of individual differences, especially those based on political affiliation; and last, as a descriptive tool the scaling is of interest in its own right. One hundred fifteen subjects were recruited from various sources, including local campus political clubs. Tucker's (1972) three-mode model of MDS was used to analyze the similarity judgments of these subjects. Results indicated that politicians are perceived in terms of the relevant issues, and that Republicans and Democrats differ markedly in their perception of the political arena. The present experimental paradigm was suggested as a potentially useful method for a number of research problems. PMID- 26754603 TI - ANALYSIS OF MULTITRAIT-MULTIMETHOD MATRICES: A TWO STEP PRINCIPAL COMPONENTS PROCEDURE. AB - A relatively simple technique for .assessing the convergence of sets of variables across method domains is presented. The technique, two-step principal components analysis, empirically orthogonalizes each method domain into sets of components, and then analyzes convergence among components across domains. The proposed technique is directly compared with Jackson's (1969) multi-method factor analysis (which involves an a priori orthogonalization) in the analysis of data from personality, vocational interest and aptitude domains. While Jackson's technique focuses on individual variables, and the two-step procedure focuses on the components of variable domains, both techniques produced evidence of cross-domain convergence. However, Jackson's method was found t o have several undesirable mathematical and interpretational consequences, while the two-step procedure appears to be a promising technique for the systematic, empirical analysis of multitrait-multimethod matrices. PMID- 26754604 TI - ABSTRACTS FROM THE EUROPEAN 1973 SMEP CONFERENCE. PMID- 26754605 TI - A NOTE ON THE EQUAMAX CRITERION. AB - A desirable property of the equamax criterion for analytic rotation in factor analysis is presented. PMID- 26754606 TI - CORRECTIONS FOR THE "ON THE INTERNAL STRUCTURE OF THE MMPI" PAPER. PMID- 26754607 TI - GENERALITY OF MULTIDIMENSIONAL REPRESENTATIONS. AB - Since multidimensional scaling is being used for the dimensionalization of an increasingly broad variety of objects, it is important to have techniques for evaluating the resulting dimensions. The term "generality" is used to refer to the degree to which a dimensional representation for a set of objects can be used to account for behavior in a variety of tasks or situations. It is asserted that generality of a multidimensional configuration is its most important property and that the generality of the results of any multidimensional scaling analysis is a matter for empirical verification. A method using a factor analytic procedure in conjunction with multidimensional scaling to investigate generality is suggested and an example of its use is presented. PMID- 26754608 TI - ERRATUM. PMID- 26754609 TI - Computational screen and experimental validation of anti-influenza effects of quercetin and chlorogenic acid from traditional Chinese medicine. AB - The Influenza A virus is a great threat for human health, while various subtypes of the virus made it difficult to develop drugs. With the development of state-of art computational chemistry, computational molecular docking could serve as a virtual screen of potential leading compound. In this study, we performed molecular docking for influenza A H1N1 (A/PR/8/34) with small molecules such as quercetin and chlorogenic acid, which were derived from traditional Chinese medicine. The results showed that these small molecules have strong binding abilities with neuraminidase from H1N1 (A/PR/8/34). Further details showed that the structural features of the molecules might be helpful for further drug design and development. The experiments in vitro, in vivo have validated the anti influenza effect of quercetin and chlorogenic acid, which indicating comparable protection effects as zanamivir. Taken together, it was proposed that chlorogenic acid and quercetin could be employed as the effective lead compounds for anti influenza A H1N1. PMID- 26754610 TI - Analysis of the correlative factors in the selection of interbody fusion cage height in transforaminal lumbar interbody fusion. AB - BACKGROUND: Selecting an interbody cage with appropriate height is one of the key steps in lumbar interbody fusion, and has an important impact on clinical efficacy. How to choose the appropriate height of the cage becomes one of the core problems of lumbar interbody fusion for spine surgeons. However, studies about objective selection criteria on interbody cage height was rare. METHODS: One hundred fifty-seven patients with single segment lumbar degenerative diseases treated by TLIF surgery from January 2011 to July 2013 were retrospectively analyzed. Parameters analyzed included: gender, age, body height, clinical diagnosis, pathological segment location and the intervertebral height of pathological segment, pathological segment activity, the intervertebral height of the adjacent segments. And further to analyze the correlation between these parameters and interbody cage height. By measuring the intervertebral height of pathological segment and normal segment to calculate the regression equation of interbody cage height. RESULTS: The average interbody cage height of male patients (12.38 +/- 1.43) mm was significantly higher than female (11.62 +/- 1.45) mm (p < 0.001). The L4-5 segment interbody cage height (12.11 +/- 1.38) mm was significantly greater than the L5-S1 (11.25 +/- 1.32) mm (p = 0.04). Body height, the intervertebral height of pathological segment, and the middle intervertebral heigh of upper adjacent segment were highly positively correlated to the interbody cage height. The range of interbody cage height used in transforaminal lumbar interbody fusion for Chinese patients with lumbar degenerative diseases was: L3-4 (11.28 +/- 3.29) mm ~ (12.76 +/- 2.40) mm, L4-5 (11.62 +/- 2.89) mm ~ (13.18 +/- 1.91) mm, L5-S1 (10.52 +/- 2.22) mm ~ (11.90 +/- 2.80) mm. The regression equation of interbody cage height was: interbody cage height = 11.123-0.563 * (gender) + 0.149 * (the middle intervertebral height of pathological segment). CONCLUSIONS: The selection of interbody cage height was influenced by sex, body height, pathological segment location, the intervertebral height of pathological segment and other factors. The interbody cage height for the lower lumbar spine mostly selected 11,12,13 mm, L3-4, L4-5 segment highly selective in general should not be less than 10 mm, and L5-S1 segments height was relatively small, usually not more than 13 mm. The interbody cage height might be selected based on the regression equation of interbody cage height. But, the regression equation maybe need to be verified in a prospective study. PMID- 26754612 TI - Characteristics of cardiac device infections in the Isala Hospital; a large volume tertiary care cardiology centre. AB - AIMS: To determine the frequency, characteristics and risk factors of cardiac device infections in the Isala Hospital. METHODS: We retrospectively studied all patients who underwent cardiac device procedures performed in the cardiac catheterisation lab and the operating room from 2010 to 2012. All patients who developed a cardiac device infection were reviewed for its characteristics. RESULTS: 31/2026 patients developed a cardiac device infection (1.5 %). One (3.2 %) patient died within 30 days of hospitalisation. Device infection rates for procedures in the catheterisation lab and operating room were similar (p = 0.60). Positive cultures were present in 27/31 (87 %) cases. These consisted predominantly of micro-organisms that are part of the skin flora (84 %). The mean time between device procedure and infection was 14 +/- 21 months (range 0-79). Cardiac device infection was significantly associated with device revision, (65 % were revisions in patients with device infection vs. 30 % revisions in patients without device infection, p = 0.011) and placement of a left ventricular lead in pacemaker implantations (59 % of patients with vs. 51 % of patients without device infection, p < 0.001). CONCLUSION: The frequency of cardiac device infection was 1.5 % with a mortality of 3.2 % within 30 days, which is lower compared with other registries. Cardiac device infections were associated with device revisions and placement of left ventricular leads in pacemaker implantations. PMID- 26754611 TI - The ethnicity-specific association of biomarkers with the angiographic severity of coronary artery disease. AB - BACKGROUND: Risk factor burden and clinical characteristics of patients with coronary artery disease (CAD) differ among ethnic groups. We related biomarkers to CAD severity in Caucasians, Chinese, Indians and Malays. METHODS: In the Dutch Singaporean UNICORN coronary angiography cohort (n = 2033) we compared levels of five cardiovascular biomarkers: N-terminal pro-brain natriuretic peptide (NTproBNP), high-sensitivity C-reactive protein (hsCRP), cystatin C (CysC), myeloperoxidase (MPO) and high-sensitivity troponin I (hsTnI). We assessed ethnicity-specific associations of biomarkers with CAD severity, quantified by the SYNTAX score. RESULTS: Adjusted for baseline differences, NTproBNP levels were significantly higher in Malays than in Chinese and Caucasians (72.1 vs. 34.4 and 41.1 pmol/l, p < 0.001 and p = 0.005, respectively). MPO levels were higher in Caucasians than in Indians (32.8 vs. 27.2 ng/ml, p = 0.026), hsTnI levels were higher in Malays than in Caucasians and Indians (33.3 vs. 16.4 and 17.8 ng/l, p < 0.001 and p = 0.029) and hsTnI levels were higher in Chinese than in Caucasians (23.3 vs. 16.4, p = 0.031). We found modifying effects of ethnicity on the association of biomarkers with SYNTAX score. NTproBNP associated more strongly with the SYNTAX score in Malays than Caucasians (beta 0.132 vs. beta 0.020 per 100 pmol/l increase in NTproBNP, p = 0.032). For MPO levels the association was stronger in Malays than Caucasians (beta 1.146 vs. beta 0.016 per 10 ng/ml increase, p = 0.017). Differing biomarker cut-off levels were found for the ethnic groups. CONCLUSION: When corrected for possible confounders we observe ethnicity-specific differences in biomarker levels. Moreover, biomarkers associated differently with CAD severity, suggesting that ethnicity-specific cut off values should be considered. PMID- 26754614 TI - Seroprevalence of HCV among Cairo University students in Egypt. AB - Hepatitis C virus (HCV) is highly prevalent in Egypt. This work aimed at determining the seroprevalence of HCV among Cairo University students. The present study included 3,000 students from Cairo University, Egypt. Blood sample was obtained from each participant to be tested for HCV seromarker. HCV RNA detection by polymerase chain reaction (PCR) was carried out for those with positive anti-HCV. Overall prevalence rate of HCV antibody (anti-HCV) was 4.6%. It showed that the prevalence was relatively higher among females (86/1660; 5.2%) while males (51/1340; 3.8%) with no significant difference. PCR for HCV RNA was detected in 31.4% of the HCV antibody positive subjects (43/137). Which showed statistical significant difference between males (29/51) and females (14/86) at P = 0.001. Despite the prevalence rate reported in the present study was similar to anti-HCV prevalence among persons in the same age group, confirmed that HCV infection is detected among Cairo University students. J. Med. Virol. 88:1384 1387, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26754613 TI - One-pot green synthesis of 1,3,5-triarylpentane-1,5-dione and triarylmethane derivatives as a new class of tyrosinase inhibitors. AB - A new method was developed for one-pot green synthesis 1,3,5-triarylpentane-1,5 dione, triarylmethane, and flavonoid derivatives from the reaction between 2,4 dihydroxybenzaldehyde and hydroxyacetophenones via Aldol, Michael, and Friedel Crafts additions using boric acid as catalyst in polyethylene glycol 400. The synthetic compounds demonstrated significant tyrosinase inhibitory activities much stronger than that of kojic acid. More important, 1,3,5-triarylpentane-1,5 dione and triarylmethane derivatives were found to be a new class of tyrosinase inhibitors. PMID- 26754615 TI - Quantification of construction waste prevented by BIM-based design validation: Case studies in South Korea. AB - Waste generated in construction and demolition processes comprised around 50% of the solid waste in South Korea in 2013. Many cases show that design validation based on building information modeling (BIM) is an effective means to reduce the amount of construction waste since construction waste is mainly generated due to improper design and unexpected changes in the design and construction phases. However, the amount of construction waste that could be avoided by adopting BIM based design validation has been unknown. This paper aims to estimate the amount of construction waste prevented by a BIM-based design validation process based on the amount of construction waste that might be generated due to design errors. Two project cases in South Korea were studied in this paper, with 381 and 136 design errors detected, respectively during the BIM-based design validation. Each design error was categorized according to its cause and the likelihood of detection before construction. The case studies show that BIM-based design validation could prevent 4.3-15.2% of construction waste that might have been generated without using BIM. PMID- 26754616 TI - Development and usefulness of an immunochromatographic device to detect antibodies for rapid diagnosis of human gnathostomiasis. AB - BACKGROUND: Human gnathostomiasis is a serious tropical disease, which is often overlooked. There is an urgent need to improve tools to aid the potential diagnosis of the disease in endemic regions. To overcome this, we produced the immunochromatographic test (ICT) kit for a rapid and simple diagnosis of human gnathostomiasis. FINDINGS: The recombinant protein (named rGslic18) was applied to ICT kit as the antigen. The diagnostic value of ICT kit was evaluated using serum samples from parasitologically proven and clinically suspected gnathostomiasis patients, healthy volunteers and patients with other parasitic diseases. The ICT kit exhibited quite high sensitivity (93.75%) and specificity (97.01%). CONCLUSIONS: The ICT kit is simple, convenient and easy to implement and expected to provide reliable diagnostic results for human gnathostomiasis. It also will be a promising diagnostic tool not only for large-scale epidemiological surveys in endemic or remote areas where diagnostic facilities are poor but also for a rapid clinical diagnosis in the bedside laboratory. PMID- 26754617 TI - My Changed Body: Background, development and acceptability of a self-compassion based writing activity for female survivors of breast cancer. AB - OBJECTIVE: To assess consumer and health professional user acceptability of a web based self-compassion writing activity to minimize psychological distress related to the negative impact of breast cancer on body image. METHODS: "My Changed Body" is a web-based writing activity that combines expressive writing with a self compassionate approach that focuses on cancer-related adverse body image alterations. Breast cancer survivors (n=15) and health professionals (n=20) provided feedback via a survey regarding the appearance, organization and content of the website and writing activity. RESULTS: Both breast cancer survivors and health professionals rated the website highly in terms of design, layout and content. Participants commented positively on the website's clear wording, appealing design and ease of navigation. Suggestions for improving the website included simplifying the instructions for the writing activity and allowing participants' writing to be saved. CONCLUSION: Results from both breast cancer survivors and health professionals suggest a moderate to high level of user acceptability and positive ratings for the overall impression of the website. PRACTICE IMPLICATIONS: Self-compassion based writing interventions can be translated to a web-based self-administered activity for body image difficulties after breast cancer treatment in a format that is acceptable to consumers and health professionals. PMID- 26754618 TI - Response to Letter to the Editor in Response to "The link between perception of clinical empathy and nonverbal behavior: The effect of a doctor's gaze and body orientation". PMID- 26754619 TI - Can evolution be directional without being teleological? AB - Convergent evolution reveals to us that the number of possibilities available for contingent events is limited, that historically contingent evolution is constrained to occur within a finite number of limited pathways, and that contingent evolution is thus probabilistic and predictable. That is, the phenomenon of convergence proves that truly contingent evolutionary processes can repeatedly produce the same, or very similar, organic designs in nature and that evolution is directional in these cases. For this reason it is argued in this paper that evolution can be directional without being teleological, and that the dichotomy that evolution must either be directionless and unpredictable or directional and predetermined (teleological) is false. PMID- 26754620 TI - Acoustic rhinometry and video endoscopic scoring to evaluate postoperative outcomes in endonasal spreader graft surgery with septoplasty and turbinoplasty for nasal valve collapse. AB - BACKGROUND: Nasal obstruction is a common complaint seen by otolaryngologists. The internal nasal valve (INV) is typically the narrowest portion of the nasal cavity, and if this area collapses on inspiration the patient experiences significant symptoms of nasal obstruction. The nasal obstruction is further compounded if the INV is narrower than normal. Previous studies have evaluated the effectiveness of techniques to alleviate structural nasal obstruction, but none have looked specifically at spreader grafts measured by acoustic rhinometry or validated grading assessment of dynamic INV collapse. Our objective was to evaluate the application of acoustic rhinometry coupled with visual endoscopic grading of the INV, and validated subjective measurements, in patients undergoing endonasal spreader graft surgery with septoplasty and turbinoplasty. METHODS: This is a prospective clinical study conducted within a tertiary care rhinoplasty practice. Patients undergoing septoplasty and bilateral inferior turbinoplasty with bilateral endonasal spreader graft placement for observed internal nasal valve collapse were recruited. Baseline, early and intermediate postoperative measures were obtained. The primary outcome was grading of the INV collapse on video endoscopy. Secondary outcomes included cross-sectional area at the INV measured by acoustic rhinometry, subjective Nasal Obstruction Symptom Evaluation (NOSE) and Sino-Nasal Outcome Tool (SNOT-22) scores. RESULTS: A total of 17 patients, average age of 34.5 +/- 12.2 years, undergoing septoplasty, bilateral endonasal spreader grafts, and bilateral turbinoplasty were included in the study. Postoperative measurements were performed at an average of 8.1 +/- 1.6 weeks and 17.7 +/- 4.2 weeks. Patients had significant improvement for INV collapse grading, cross-sectional area, NOSE and SNOT-22 scores in both the early and intermediate follow up. Endoscopic grading had moderate inter-rater agreement (kappa = 0.579) and average intra-rater agreement (kappa = 0.545). CONCLUSIONS: This study is the first to demonstrate a statistically significant improvement of objective measurement of internal nasal valve function, both static and dynamic, and subjective improvements. This supports endonasal cartilagenous spreader grafts with septoplasty and inferior turbinoplasty for patients with nasal obstruction with internal nasal valve collapse. PMID- 26754621 TI - Impact of monochromatic coronary computed tomography angiography from single source dual-energy CT on coronary stenosis quantification. AB - BACKGROUND: In coronary CT angiography (CTA), stenosis evaluation is limited by artifacts such as blooming. Monochromatic reconstructions from single-source dual energy coronary CTA have shown to reduce image noise and improve image quality. OBJECTIVE: The aim of this study was to analyze the impact of monochromatic coronary CTA reconstructions on stenosis quantification using invasive coronary angiography (ICA) as standard of reference. METHODS: Patients who were referred for clinically indicated assessment of coronary artery disease underwent coronary CTA and ICA within 4 months. In standard polychromatic coronary CTA images as well as 8 monochromatic series (50 keV-140 keV) luminal narrowing of coronary lesions was measured and compared to ICA with quantitative coronary angiography (QCA). RESULTS: In 37 patients with a mean age of 63.4 +/- 8.2 years and a broad range of BMI (19.9-45.5 kg/m(2)), 124 lesions were studied. Throughout all the reconstructions, CT measurements showed a significant correlation with QCA (P < 0.001), except for reconstructions with 50 keV. Luminal narrowing of calcified and partly calcified lesions was generally overestimated, and underestimated in noncalcified plaques. After stepwise regression, reconstructions with 90 keV showed the best relation to QCA (P < 0.001, R2 = 0.9). Analysis by plaque composition suggested a superior performance of reconstructions at 90 keV for calcified and partly calcified plaques and at 140 keV for noncalcified plaques. CONCLUSION: The use of monochromatic reconstructions improves the overall accuracy of lesion assessment. Combining reconstructions at 90 keV for calcified and partly calcified lesions and at 140 keV for noncalcified lesions yielded optimal results. Thus monochromatic reconstruction bears the potential to improve accuracy of coronary CTA. PMID- 26754622 TI - Ab initio molecular dynamic study of solid-state transitions of ammonium nitrate. AB - High-pressure polymorphism and phase transitions have wide ranging consequences on the basic properties of ammonium nitrate. However, the phase diagram of ammonium nitrate at high pressure and high temperature is still under debate. This study systematically investigates the phase transitions and structural properties of ammonium nitrate at a pressure range of 5-60 GPa and temperature range of 250-400 K by ab initio molecular dynamics simulations. Two new phases are identified: one corresponds to the experimentally observed phase IV' and the other is named AN-X. Simultaneously, the lattice strains play a significant role in the formation and stabilization of phase IV', providing a reasonable explanation for experimental observation of phase IV-IV' transition which only appears under nonhydrostatic pressure. In addition, 12 O atoms neighboring the NH (N atom in ammonium cation) atom are selected as reference system to clearly display the tanglesome rotation of ammonium cation. PMID- 26754623 TI - Retinal Information is Independently Associated with Cardiovascular Disease in Patients with Type 2 diabetes. AB - To evaluate the association between a series of retinal information and cardiovascular disease (CVD) and to evaluate whether this association is independent of traditional CVD risk factors in type 2 diabetes patients, we undertook an age-sex matched case-control study with 79 CVD cases and 150 non-CVD controls. All the participants underwent standardized physical examinations and retinal imaging. Retinal information was extracted from the retinal images using a semi-automatic computer program. Three stepwise logistic regression models were evaluated: model 1 with cardiovascular risk factors only; model 2 with retinal information only and model 3 with both cardiovascular risk factors and retinal information. The areas under the receiver operating characteristic curves (AUCs) were used to compare the performances of different models. Results showed that the AUCs were 0.692 (95%CI: 0.622-0.761) and 0.661 (95%CI: 0.588-0.735) for model 1 and model 2, respectively. In addition, model 3 had an AUC of 0.775 (95%CI: 0.716-0.834). Compared to the previous two models, the AUC of model 3 increased significantly (p < 0.05 in both comparisons). In conclusion, retinal information is independently associated with CVD in type 2 diabetes. Further work is needed to validate the translational value of applying retinal imaging analysis into clinical practice. PMID- 26754624 TI - Temporal Trends and Variation in Early Scheduled Follow-Up After a Hospitalization for Heart Failure: Findings from Get With The Guidelines-Heart Failure. AB - BACKGROUND: Previous data demonstrate early follow-up (ie, within 7 days of discharge) after a hospitalization for heart failure is associated with a lower risk of readmission, yet is uncommon and varies widely across hospitals. Limited data exist on whether the use of early follow-up after discharge has improved over time. METHODS AND RESULTS: We used data from Get With The Guidelines-Heart Failure (GWTG-HF) linked to Medicare claims to examine temporal trends in early follow-up and to assess for patient and hospital characteristics associated with early scheduled follow-up. In the overall GWTG-HF cohort, we studied 52,438 patients discharged from 239 hospitals from 2009 to 2012. Scheduled early follow up at the time of hospital discharge rose from 51% to 65% over time (P<0.001). After multivariable adjustment, patients with older age (odds ratio, 1.04; 95% confidence interval, 1.01-1.07), certain comorbidities (anemia, diabetes mellitus, and chronic kidney disease), and the use of anticoagulation at discharge (odds ratio, 1.16; 95% confidence interval, 1.11-1.22) were associated with greater likelihood for early scheduled follow-up. Patients treated in hospitals located in the Midwest (odds ratio, 0.67; 95% confidence interval, 0.50 0.91) were less likely to have early scheduled follow-up. In a subset of patients with linked Medicare claims, we observed smaller improvements in actual early follow-up visits over time from 26% to 30% (P=0.005). CONCLUSIONS: From 2009 to 2012, there was improvement in early scheduled outpatient follow-up and, in the subset analyzed, improvement in actual early follow-up visits for hospitalized patients with heart failure. However, substantial opportunities remain for improving heart failure transitional care. PMID- 26754625 TI - Plasma Biomarkers Reflecting Profibrotic Processes in Heart Failure With a Preserved Ejection Fraction: Data From the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction Study. AB - BACKGROUND: Heart failure with preserved ejection fraction is a clinical syndrome that has been associated with changes in the extracellular matrix. The purpose of this study was to determine whether profibrotic biomarkers accurately reflect the presence and severity of disease and underlying pathophysiology and modify response to therapy in patients with heart failure with preserved ejection fraction. METHODS AND RESULTS: Four biomarkers, soluble form of ST2 (an interleukin-1 receptor family member), galectin-3, matrix metalloproteinase-2, and collagen III N-terminal propeptide were measured in the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction (PARAMOUNT) trial at baseline, 12 and 36 weeks after randomization to valsartan or LCZ696. We examined the relationship between baseline biomarkers, demographic and echocardiographic characteristics, change in primary (change in N-terminal pro B-type natriuretic peptide) and secondary (change in left atrial volume) end points. The median (interquartile range) value for soluble form of ST2 (33 [24.6-48.1] ng/mL) and galectin 3 (17.8 [14.1-22.8] ng/mL) were higher, and for matrix metalloproteinase-2 (188 [155.5-230.6] ng/mL) lower, than in previously published referent controls; collagen III N-terminal propeptide (5.6 [4.3-6.9] ng/mL) was similar to referent control values. All 4 biomarkers correlated with severity of disease as indicated by N-terminal pro B type natriuretic peptide, E/E', and left atrial volume. Baseline biomarkers did not modify the response to LCZ696 for lowering N-terminal pro B-type natriuretic peptide; however, left atrial volume reduction varied by baseline level of soluble form of ST2 and galectin 3; patients with values less than the observed median (<33 ng/mL soluble form of ST2 and <17.8 ng/mL galectin 3) had reduction in left atrial volume, those above median did not. Although LCZ696 reduced N terminal pro B-type natriuretic peptide, levels of the other 4 biomarkers were not affected over time. CONCLUSIONS: In patients with heart failure with preserved ejection fraction, biomarkers that reflect collagen homeostasis correlated with the presence and severity of disease and underlying pathophysiology, and may modify the structural response to treatment. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00887588. PMID- 26754627 TI - Gradual Increases in Scheduled and Actual Early Follow-Up After Heart Failure Hospitalization: Two Steps Forward or One Step Forward? PMID- 26754628 TI - Simple and efficient synthesis of 5'-aryl-5'-deoxyguanosine analogs by azide alkyne click reaction and their antileishmanial activities. AB - A series of non-hydrolysable 5'-aryl substituted GDP analogs has been synthesized by reacting 5'-azido-5'-deoxyguanosine with different aryl- and benzyloxy alkynes. Cu(I) nanoparticles in water were found to be the most efficient catalyst, producing the desired 5'-arylguanosines with good yields. The synthesized compounds were screened for in vitro antileishmanial activity against Leishmania donovani axenic amastigotes and intramacrophage amastigotes stages. The 4-(3-nitrobenzyl)-1,2,3-triazole 5'-substituted guanosine analog was found to be the most active in the series with an IC50 of 8.6 MUM on axenic amastigotes. Despite a rather low in vitro antileishmanial activity on the intramacrophage amastigotes, the absence of cytotoxicity on RAW 264.7 macrophages justifies further pharmacomodulations making this antileishmanial series promising. PMID- 26754629 TI - Facile synthesis and biological assays of novel 2,4-disubstituted hydrazinyl thiazoles analogs. AB - A convenient, one-pot multi-component synthesis of new 2,4-disubstituted hydrazinyl-thiazoles was accomplished using different aldehydes/ketones, thiosemicarbazide, and 4-methoxy phenacyl bromide in the presence of a catalytic amount of AcOH in EtOH. Products were obtained in reasonable yields and high purity. The in vitro antioxidant activity of hydrazinyl-thiazoles was evaluated by DPPH radical scavenging activity in comparison to ascorbic acid. Synthesized thiazoles 14c and 14g possessed the lowest IC50 values. Also, hydrazinyl thiazoles were screened for their in vitro antibacterial activity against six strains of bacteria including S. aureus, M. luteus, E. coli, Ps. aeruginosa, B. subtilis, and A. hydrophila where some products showed good antibacterial activity. Moreover, compound 14a showed anticancer activity against melanoma cancerous cell lines A375 with LC50=0.55 mg/ml, slightly selective versus normal cell lines (Hu-2) with LC50=1.19 mg/ml.. PMID- 26754631 TI - Erratum: Disordering of the vortex lattice through successive destruction of positional and orientational order in a weakly pinned Co0.0075NbSe2 single crystal. PMID- 26754630 TI - JunB promotes cell invasion, migration and distant metastasis of head and neck squamous cell carcinoma. AB - BACKGROUND: While treatment failure in cases of head and neck squamous cell carcinoma (HNSCC) frequently takes the form of locoregional recurrences and distant metastasis, our understanding of the mechanisms of metastasis in HNSCC is limited. We initially performed the upstream and key nodes analysis together with whole gene microarray analysis characterized by distant metastatic potential in vivo with HNSCC cell lines and identified JunB, a member of the activator protein 1 (AP-1) family, as a key molecule in the regulation of the pathways related to distant metastasis in HNSCC. We have therefore tested the hypothesis that JunB plays a crucial role in distant metastasis in HNSCC. METHODS: To study the role of JunB on metastatic potential of HNSCC, small interfering RNA (siRNA)-mediated knockdown and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (cas9) system (CRISPR/Cas9)-mediated knockout of JunB in HNSCC cells were established and the abilities of cell invasion and migration in vitro were examined. The efficacy of knockout of JunB was also examined using an experimental lung metastatic mouse model of HNSCC. In addition, to study if the role of JunB in HNSCC cell migration and invasiveness is related to epithelial-to-mesenchymal transition (EMT), cell morphology and expression of mesenchymal or epithelial marker on siRNA mediated JunB knockdown in HNSCC cells were examined with or without TGF-beta stimulation. RESULTS: siRNA knockdown and sgRNA knockout of JunB in metastatic HNSCC cells significantly suppressed both cell invasion and migration in vitro. In addition, the knockout of JunB in metastatic HNSCC cells significantly repressed the incidence of lung metastases and prolonged the survival in vivo. However, we did not observe any change in cell morphology with the down-regulation of mesenchymal markers and up regulation of epithelial markers in response to siRNA-mediated JunB knockdown in HNSCC cells. CONCLUSION: These results suggested that JunB could play an important role in promoting cell invasion, migration and distant metastasis in HNSCC via pathways other than EMT and that the down-regulation of JunB may become an effective strategy for patients with invasive HNSCC. PMID- 26754632 TI - Acute myeloid leukemia with t(3;8)(q26;q24) complicated by diabetes insipidus. PMID- 26754633 TI - Prognostic factors for re-mobilization using plerixafor and granulocyte colony stimulating factor (G-CSF) in patients with malignant lymphoma or multiple myeloma previously failing mobilization with G-CSF with or without chemotherapy: the Korean multicenter retrospective study. AB - Plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) has been shown to improve the rates of successful peripheral blood stem cell (PBSC) mobilization in patients with malignant lymphoma or multiple myeloma (MM) who experienced prior failure of PBSC mobilization. We evaluated the mobilization results of re-mobilization using plerixafor and G-CSF in insufficiently mobilizing patients. Forty-four patients with lymphoma (n = 29) or MM (n = 15) were included in the study. The median age was 50 (range, 24-64) years. Previous mobilization regimens were chemotherapy with G-CSF (n = 28), including cyclophosphamide with G-CSF (n = 15), and G-CSF only (n = 16). All patients with lymphoma achieved at least partial response (PR) before the mobilization, including 13 complete responses (CRs). Eleven patients with MM achieved at least PR and four patients with MM were in stable disease before mobilization. The median number of apheresis was 3 (range, 1-6). The median yield of PBSC collections was 3.41 (0.13-38.11) * 10(6) CD34(+) cells/kg. Thirty-four (77.3 %) patients had successful collections defined as at least 2 * 10(6) CD34(+) cells/kg. The rate of successful collections was not different between the two underlying diseases (79.3 % in lymphoma and 73.3 % in MM). Of the entire cohort, 38 (86.4 %) of patients went on to receive an autologous transplant. Previous long-term use of high-risk drugs (>4 cycles use of alkylating agents, platinum containing agents, or thalidomide) (HR 10.8, 95 % CI 1.1-110.0, P = 0.043) and low platelet count (<100 * 10(9)/L) 1 day before the first apheresis (HR 27.9, 95 % CI 2.9-273.7, P = 0.004) were independent prognostic factors for predicting failure of PBSC re-mobilization using plerixafor and G-CSF. In conclusion, re mobilization using plerixafor and G-CSF showed a success rate of 77.3 % in patients with lymphoma or MM who experienced prior failure of PBSC mobilization, and the majority of them underwent autologous transplant. Therefore, plerixafor based re-mobilization was an effective method in poor mobilizers. PMID- 26754634 TI - Toxic epidermal necrolysis in adult T cell leukemia/lymphoma treated with mogamulizumab. PMID- 26754635 TI - Subtype distribution of lymphomas in South of Iran, analysis of 1085 cases based on World Health Organization classification. AB - Lymphoma is one of the most common malignancies worldwide. Subtype distribution is different throughout the world. Some reports from the Middle East are in record. This article is trying to report the subtype distribution of lymphoma in Iran and compare it to that of Western, Far East Asian and Middle Eastern countries. A retrospective study was done on all lymphomas diagnosed in a large referral center in the South of Iran during a time period between 2009 and 2014. All diagnoses have been made according to 2008 WHO classification. A total number of 1085 cases with diagnoses of lymphoma retrieved. Twenty-nine cases (2.6 % of all) were precursor lymphoid neoplasm, 608 cases (56 % of all) were mature B cell neoplasm, 115 cases (10.5 % of all) were mature T and NK cell neoplasm, and 333 cases (30.6 % of all) were Hodgkin lymphoma. The six most frequent subtypes of mature B cell neoplasm were diffuse large B cell lymphoma, NOS (57 %), Burkitt lymphoma (7 %), small lymphocytic lymphoma (6.9 %), mantle cell lymphoma (5.7 %), extranodal marginal zone B cell lymphoma (5.2 %) and follicular lymphoma (3.6 %). Among mature T and NK cell neoplasm, mycosis fungoides was the most common type (43.4 %) followed by peripheral T cell lymphoma, NOS (20 %) and angioimmunoblastic T cell lymphoma (9.9 %). Of Hodgkin lymphoma cases, 90.6 % were classical type and 9.3 % were nodular lymphocyte predominant Hodgkin lymphoma. Extranodal involvement was seen in 42.2 % and GI tract was the most common site. Lymphoma frequencies were similar to that of Middle Eastern countries except for lower rate of follicular lymphoma and higher incidence of diffuse large B cell lymphoma, NOS and small lymphocytic lymphoma. PMID- 26754636 TI - Short and long-term prognostic implications of a low embolic burden in oncology patients diagnosed with symptomatic pulmonary embolism. PMID- 26754637 TI - Gastric involvement, a rare site for extramedullary myeloma. PMID- 26754639 TI - Conductive Nanostructured Scaffolds Render Low Local Current Density to Inhibit Lithium Dendrite Growth. AB - A nanostructured lithium-metal anode employing an unstacked graphene "drum" and dual-salt electrolyte brings about a dendrite-free lithium depositing morphology. On the one hand, the unstacked graphene framework with ultrahigh specific surface area guarantees an ultralow local current density that prevents the growth of lithium dendrites. On the other hand, the stable, flexible, and compact solid electrolyte interphase layer induced by the dual-salt electrolyte protects the deposited lithium layers. PMID- 26754638 TI - Evaluation of the 2b-RAD method for genomic selection in scallop breeding. AB - The recently developed 2b-restriction site-associated DNA (2b-RAD) sequencing method provides a cost-effective and flexible genotyping platform for aquaculture species lacking sufficient genomic resources. Here, we evaluated the performance of this method in the genomic selection (GS) of Yesso scallop (Patinopecten yessoensis) through simulation and real data analyses using six statistical models. Our simulation analysis revealed that the prediction accuracies obtained using the 2b-RAD markers were slightly lower than those obtained using all polymorphic loci in the genome. Furthermore, a small subset of markers obtained from a reduced tag representation (RTR) library presented comparable performance to that obtained using all markers, making RTR be an attractive approach for GS purpose. Six GS models exhibited variable performance in prediction accuracy depending on the scenarios (e.g., heritability, sample size, population structure), but Bayes-alphabet and BLUP-based models generally outperformed other models. Finally, we performed the evaluation using an empirical dataset composed of 349 Yesso scallops that were derived from five families. The prediction accuracy for this empirical dataset could reach 0.4 based on optimal GS models. In summary, the genotyping flexibility and cost-effectiveness make 2b-RAD be an ideal genotyping platform for genomic selection in aquaculture breeding programs. PMID- 26754640 TI - Re-emergence of neuroinfectiology. PMID- 26754642 TI - Young Adults With Stiff Arteries: Do They Have to Worry About Their Cognitive Function? PMID- 26754641 TI - Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. AB - Low frequency coding variants in TREM2 are associated with increased Alzheimer disease (AD) risk, while loss of functions mutations in the gene lead to an autosomal recessive early-onset dementia, named Nasu-Hakola disease (NHD). TREM2 can be detected as a soluble protein in cerebrospinal fluid (CSF) and plasma, and its CSF levels are elevated in inflammatory CNS diseases. We measured soluble TREM2 (sTREM2) in the CSF of a large AD case-control dataset (n = 180) and 40 TREM2 risk variant carriers to determine whether CSF sTREM2 levels are associated with AD status or mutation status. We also performed genetic studies to identify genetic variants associated with CSF sTREM2 levels. CSF, but not plasma, sTREM2 was highly correlated with CSF total tau and phosphorylated-tau levels (r = 0.35, P < 1*10(-4); r = 0.40, P < 1*10(-4), respectively), but not with CSF Abeta42. AD cases presented higher CSF sTREM2 levels than controls (P = 0.01). Carriers of NHD-associated TREM2 variants presented significantly lower CSF sTREM2 levels, supporting the hypothesis that these mutations lead to reduced protein production/function (R136Q, D87N, Q33X or T66M; P = 1*10(-3)). In contrast, CSF sTREM2 levels were significantly higher in R47H carriers compared to non-carriers (P = 6*10(-3)), suggesting that this variant does not impact protein expression and increases AD risk through a different pathogenic mechanism than NHD variants. In GWAS analyses for CSF sTREM2 levels the most significant signal was located on the MS4A gene locus (P = 5.45 * 10(-07)) corresponding to one of the SNPs reported to be associated with AD risk in this locus. Furthermore, SNPs involved in pathways related to virus cellular entry and vesicular trafficking were overrepresented, suggesting that CSF sTREM2 levels could be an informative phenotype for AD. PMID- 26754643 TI - Cardiovascular Effects of Unilateral Nephrectomy in Living Kidney Donors. AB - There is a robust inverse graded association between glomerular filtration rate (GFR) and cardiovascular risk, but proof of causality is lacking. Emerging data suggest living kidney donation may be associated with increased cardiovascular mortality although the mechanisms are unclear. We hypothesized that the reduction in GFR in living kidney donors is associated with increased left ventricular mass, impaired left ventricular function, and increased aortic stiffness. This was a multicenter, parallel group, blinded end point study of living kidney donors and healthy controls (n=124), conducted from March 2011 to August 2014. The primary outcome was a change in left ventricular mass assessed by magnetic resonance imaging (baseline to 12 months). At 12 months, the decrease in isotopic GFR in donors was -30+/-12 mL/min/1.73m(2). In donors compared with controls, there were significant increases in left ventricular mass (+7+/-10 versus -3+/-8 g; P<0.001) and mass:volume ratio (+0.06+/-0.12 versus -0.01+/-0.09 g/mL; P<0.01), whereas aortic distensibility (-0.29+/-1.38 versus +0.28+/-0.79*10(-3) mm Hg(-1); P=0.03) and global circumferential strain decreased (-1.1+/-3.8 versus +0.4+/-2.4%; P=0.04). Donors had greater risks of developing detectable highly sensitive troponin T (odds ratio, 16.2 [95% confidence interval, 2.6-100.1]; P<0.01) and microalbuminuria (odds ratio, 3.8 [95% confidence interval, 1.1 12.8]; P=0.04). Serum uric acid, parathyroid hormone, fibroblast growth factor 23, and high-sensitivity C-reactive protein all increased significantly. There were no changes in ambulatory blood pressure. Change in GFR was independently associated with change in left ventricular mass (R(2)=0.28; P=0.01). These findings suggest that reduced GFR should be regarded as an independent causative cardiovascular risk factor. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01028703. PMID- 26754647 TI - Waves, rings, and trails: The scenic landscape of axonal actin. AB - The goal of this article is to provide the reader a snapshot of recent studies on axonal actin--largely emerging from superresolution and live-imaging experiments- and place this new information in context with earlier studies. PMID- 26754644 TI - Association of Aortic Stiffness With Cognition and Brain Aging in Young and Middle-Aged Adults: The Framingham Third Generation Cohort Study. AB - Aortic stiffness is associated with cognitive decline and cerebrovascular disease late in life, although these associations have not been examined in young adults. Understanding the effects of aortic stiffness on the brain at a young age is important both from a pathophysiological and public health perspective. The aim of this study was to examine the cross-sectional associations of aortic stiffness with cognitive function and brain aging in the Framingham Heart Study Third Generation cohort (47% men; mean age, 46 years). Participants completed the assessment of aortic stiffness (carotid-femoral pulse wave velocity), a neuropsychological test battery assessing multiple domains of cognitive performance and magnetic resonance imaging to examine subclinical markers of brain injury. In adjusted regression models, higher aortic stiffness was associated with poorer processing speed and executive function (Trail Making B-A; beta+/-SE, -0.08+/-0.03; P<0.01), larger lateral ventricular volumes (beta+/-SE, 0.09+/-0.03; P<0.01) and a greater burden of white-matter hyperintensities (beta+/-SE, 0.09+/-0.03; P<0.001). When stratifying by age, aortic stiffness was associated with lateral ventricular volume in young adults (30-45 years), whereas aortic stiffness was associated with white-matter injury and cognition in midlife (45-65 years). In conclusion, aortic stiffness was associated with cognitive function and markers of subclinical brain injury in young to middle-aged adults. Prospective studies are needed to examine whether aortic stiffening in young adulthood is associated with vascular cognitive impairment later in life. PMID- 26754645 TI - Myosin-dependent remodeling of adherens junctions protects junctions from Snail dependent disassembly. AB - Although Snail is essential for disassembly of adherens junctions during epithelial-mesenchymal transitions (EMTs), loss of adherens junctions in Drosophila melanogaster gastrula is delayed until mesoderm is internalized, despite the early expression of Snail in that primordium. By combining live imaging and quantitative image analysis, we track the behavior of E-cadherin-rich junction clusters, demonstrating that in the early stages of gastrulation most subapical clusters in mesoderm not only persist, but move apically and enhance in density and total intensity. All three phenomena depend on myosin II and are temporally correlated with the pulses of actomyosin accumulation that drive initial cell shape changes during gastrulation. When contractile myosin is absent, the normal Snail expression in mesoderm, or ectopic Snail expression in ectoderm, is sufficient to drive early disassembly of junctions. In both cases, junctional disassembly can be blocked by simultaneous induction of myosin contractility. Our findings provide in vivo evidence for mechanosensitivity of cell-cell junctions and imply that myosin-mediated tension can prevent Snail driven EMT. PMID- 26754648 TI - My oh my(osin): Insights into how auditory hair cells count, measure, and shape. AB - The mechanisms underlying mechanosensory hair bundle formation in auditory sensory cells are largely mysterious. In this issue, Lelli et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201509017) reveal that a pair of molecular motors, myosin IIIa and myosin IIIb, is involved in the hair bundle's morphology and hearing. PMID- 26754646 TI - Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth. AB - The precise architecture of hair bundles, the arrays of mechanosensitive microvilli-like stereocilia crowning the auditory hair cells, is essential to hearing. Myosin IIIa, defective in the late-onset deafness form DFNB30, has been proposed to transport espin-1 to the tips of stereocilia, thereby promoting their elongation. We show that Myo3a(-/-)Myo3b(-/-) mice lacking myosin IIIa and myosin IIIb are profoundly deaf, whereas Myo3a-cKO Myo3b(-/-) mice lacking myosin IIIb and losing myosin IIIa postnatally have normal hearing. Myo3a(-/-)Myo3b(-/-) cochlear hair bundles display robust mechanoelectrical transduction currents with normal kinetics but show severe embryonic abnormalities whose features rapidly change. These include abnormally tall and numerous microvilli or stereocilia, ungraded stereocilia bundles, and bundle rounding and closure. Surprisingly, espin-1 is properly targeted to Myo3a(-/-)Myo3b(-/-) stereocilia tips. Our results uncover the critical role that class III myosins play redundantly in hair bundle morphogenesis; they unexpectedly limit the elongation of stereocilia and of subsequently regressing microvilli, thus contributing to the early hair bundle shaping. PMID- 26754649 TI - Muscle versus Snail: Muscle wins. AB - Epithelial-mesenchymal transitions (EMTs) are often governed by the transcription factor Snail and entail the loss of apical junctions from epithelial cells. In this issue, Weng and Wieschaus (2016. J Cell Biol. http://dx.doi.org/10.1083/jcb.201508056) report that actomyosin contractility can strengthen junctions to override Snail-dependent junctional disassembly and postpone EMT during Drosophila melanogaster gastrulation. PMID- 26754650 TI - Seasonal variation in haematological and biochemical reference values for healthy young children in The Gambia. AB - BACKGROUND: Haematological and biochemistry reference values for children are important for interpreting clinical and research results however, differences in demography and environment poses a challenge when comparing results. The study defines reference intervals for haematological and biochemistry parameters and examines the effect of seasonality in malaria transmission. METHODS: Blood samples collected from clinically healthy children, aged 12-59 months, in two surveys during the dry and wet season in the Upper River region of The Gambia were processed and the data analysed to generate reference intervals based on the 2.5(th) and 97.5(th) percentiles of the data. RESULTS: Analysis was based on data from 1141 children with median age of 32 months. The mean values for the total white cell count and differentials; lymphocyte, monocyte and neutrophil decreased with increasing age, were lower in males and higher in the wet season survey. However, platelet values declined with age (p < 0.0001). There was no evidence of effect of gender on mean values of AST, ALT, lymphocytes, monocytes, platelets and haemoglobin. CONCLUSION: Mean estimates for haematological and biochemistry reference intervals are affected by age and seasonality in the first five years of life. This consistency is important for harmonisation of reference values for clinical care and interpretation of trial results. PMID- 26754652 TI - Anterior intussusception descent during defecation is correlated with the severity of fecal incontinence in patients with rectoanal intussusception. AB - BACKGROUND: Rectoanal intussusception (RAI) is a common finding on evacuation proctography in patients with defecation disorders. However, it remains unclear whether intussusception morphology affects the severity of fecal incontinence (FI). The aim of this study was to examine the effect of morphology during defecation on the severity of FI in patients with RAI. METHODS: We included 80 patients with FI who were diagnosed as having RAI on evacuation proctography. Various morphological parameters were measured, and the level of RAI was divided by the extent of descent onto (level I) or into (level II) the anal sphincter. FI symptoms were documented using the FI Severity Index (FISI). RESULTS: Twenty eight patients had level I and 52 had level II RAI. The mean (range) FISI score was 24.0 (8-47). FISI scores tended to be significantly higher in level II than in level I [26.3 (10-47) vs. 21.8 (8-42); p = 0.05]. The mean anterior intussusception descent was significantly greater in level II than in level I [24.2 (9.2-39.5) vs. 17.7 (7.8-39.4) mm; p < 0.0001]. Regression analysis showed that anterior intussusception descent was predictive of increased FISI scores. CONCLUSIONS: The severity of FI may be affected by anterior intussusception descent in patients with RAI. PMID- 26754653 TI - Four anastomotic techniques following transanal total mesorectal excision (TaTME). AB - Transanal total mesorectal excision (TaTME) is a novel approach pioneered to tackle the challenges posed by difficult pelvic dissections in rectal cancer and the restrictions in angulation of currently available laparoscopic staplers. To date, four techniques can be employed in order to create the colorectal/coloanal anastomosis following TaTME. We present a technical note describing these techniques and discuss the risks and benefits of each. PMID- 26754651 TI - Update on advances and controversy in rectal cancer treatment. AB - Changes in the multidisciplinary treatment of rectal cancer have been recently proposed. We performed a comprehensive review of the current data on neoadjuvant and adjuvant treatment of rectal cancer, focussing on chemoradiotherapy treatment and timing of surgery. Six components were proposed as the framework for the treatment of rectal cancer: neoadjuvant therapy and changing patterns in patient selection, long- or short-course radiotherapy, adverse effects of radiotherapy, timing of surgery, non-operative management of rectal cancer and postoperative adjuvant therapy. Lack of a consistent difference in terms of local recurrence has been observed between short-course radiotherapy and long-course chemoradiotherapy. Indications for preoperative radiotherapy have been reconsidered in the last years. An interval of 10-11 weeks seemed to be the optimal timing, with no impact on patient safety. Since assessment criteria of clinical complete response are not well defined, and the basis for non-operative management of rectal cancer is still not clear, further investigations are required. There is controversy about standard treatments for patients with locally advanced rectal cancer that are being analyzed by ongoing studies. Tailored treatments could avoid over-treatment for a large number of patients without any impairment of the oncologic results. PMID- 26754655 TI - [Not Available]. PMID- 26754654 TI - Validity and reliability of a Lithuanian version of low anterior resection syndrome score. AB - BACKGROUND: Up to 90 % of patients undergoing low anterior resection complain of increased daily bowel movements, urgency, and a variable degree of incontinence. A symptom-based scoring system for bowel dysfunction after low anterior resection for rectal cancer has recently been developed and validated. The aim of our study was to adapt the low anterior resection syndrome (LARS) scale questionnaire to the Lithuanian language, and assess its psychometric properties. METHODS: The LARS questionnaire was translated into Lithuanian by the Scientific Advisory Committee of the Medical Outcomes Trust using a standard procedure of double-back translation. The Lithuanian version of the LARS (LARS-LT) questionnaire was completed by 111 patients who underwent low anterior resection with total mesorectal excision in the period from January 1, 2008, to December 31, 2012, at the National Cancer Institute. An anchor question from the Wexner score assessing the impact of bowel function on lifestyle was included. A subgroup of 20 patients completed the LARS-LT questionnaire twice. Validity was tested using a factor analysis, and internal reliability was estimated using the Cronbach's alpha and intraclass correlation coefficients. RESULTS: Twenty-seven patients (25 %) had no LARS, 26 (24 %) had minor LARS, and 55 (56 %) had major LARS. The response rate was 60.7 %. The LARS-LT showed significantly high reliability and internal consistency [Cronbach's alpha = 0.88, interclass correlation coefficient-0.86 (0.71-0.98)]. The LARS score showed significant correlations with the lifestyle question (p < 0.05). It could not detect differences between female and male patient groups (p = 0.33), patients' age (p = 0.45), patients who had/had not undergone radiation therapy (p = 0.07), and those in whom the distal edge of the tumor was close to or far from the anal verge (p = 0.17). CONCLUSIONS: The Lithuanian version of the LARS-LT shows acceptable psychometric properties and can be considered a valuable and specific instrument to assess bowel function in rectal cancer patients, both for research purposes and in clinical practice. PMID- 26754656 TI - [Patch augmentation of the rotator cuff. A reasonable choice or a waste of money?]. AB - BACKGROUND: Although reconstruction methods have improved, tendon retears remain a major complication associated with rotator cuff repair. With the application of patches, either by interposition or by augmentation, surgeons can attempt to close an irreparable cuff defect or improve the mechanical and biological properties of tendons respectively. OBJECTIVES: Which factors need to be considered when using a patch and what outcome can be expected? MATERIALS AND METHODS: Based on the current literature, an overview of the techniques and materials in use and biomechanical and clinical experience is provided. RESULTS: The literature shows clear improvements in the biomechanical properties of a repair with patch augmentation; in particular, weakened tendons of the anterior supraspinatus and superior infraspinatus benefit most. It is important to keep in mind that each patch material has its own individual properties, which makes comparison of the various patch types difficult. The current scientific evidence is promising, although larger level 1 studies are still required. CONCLUSIONS: The general use of patches cannot be recommended at this time. Nevertheless, the use of a patch should be considered in patients who are at a high risk of recurrent retears. In future, patches will probably be applied mainly as part of a combined effort, together with biological measures to further reduce retear rates. PMID- 26754659 TI - A new generation of chiral phase-transfer catalysts. AB - Phase-transfer catalysis has long been recognized as a versatile method for organic synthesis. In particular, over more than the past three decades, asymmetric phase-transfer catalysis based on the use of structurally well-defined chiral catalysts has become a topic of great scientific interest. Although various effective chiral catalysts have already been reported and these catalysts were utilized for practical asymmetric transformations, further design and development of new chiral phase-transfer catalysts are still attractive research subjects in organic chemistry due to the high utility and practicability of phase transfer-catalyzed reactions. This review focuses on the recent examples of newly designed effective chiral phase-transfer catalysts. PMID- 26754657 TI - [Rotator cuff avulsion fractures. Current concepts in the surgical treatment]. AB - Rotator cuff avulsion fractures represent rare lesions in younger individuals and are caused by different trauma mechanisms. The present article outlines current concepts regarding diagnosis, indications, and surgical approaches to the treatment of greater and lesser tuberosity fractures, as discussed in the international literature. Modified arthroscopic double-row rotator cuff repair techniques allow for the anatomical reduction and retention of fragments and the treatment of concomitant intra-articular lesions at the same time. Moreover, the article provides practical hints on different surgical repair techniques, their respective limitations and results from the literature. PMID- 26754658 TI - Reduction of circulating FABP4 level by treatment with omega-3 fatty acid ethyl esters. AB - BACKGROUND: Fatty acid-binding protein 4 (FABP4/A-FABP/aP2) mainly expressed in adipocytes is secreted and acts as an adipokine. Increased circulating FABP4 level is associated with obesity, insulin resistance and atherosclerosis. However, little is known about the modulation of serum FABP4 level by drugs including anti-dyslipidemic agents. METHODS: Patients with dyslipidemia were treated with omega-3 fatty acid ethyl esters (4 g/day; n = 14) containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for 4 weeks. Serum FABP4 level was measured before and after treatment. Expression and secretion of FABP4 were also examined in mouse 3T3-L1 adipocytes treated with EPA or DHA. RESULTS: Treatment with omega-3 fatty acid ethyl esters significantly decreased triglycerides and serum FABP4 level (13.5 +/- 1.5 vs. 11.5 +/- 1.1 ng/ml, P = 0.017). Change in FABP4 level by omega-3 fatty acids was negatively correlated with change in levels of EPA + DHA (r = -0.643, P = 0.013), EPA (r = -0.540, P = 0.046) and DHA (r = -0.650, P = 0.011) but not change in the level of triglycerides or other fatty acid composition. Treatment of 3T3-L1 adipocytes with EPA or DHA had no effect on short-term (2 h) secretion of FABP4. However, gene expression and long-term (24 h) secretion of FABP4 were significantly reduced by treatment with EPA or DHA. CONCLUSIONS: Omega-3 fatty acids decrease circulating FABP4 level, possibly by reducing expression and consecutive secretion of FABP4 in adipocytes. Reducing FABP4 level might be involved in suppression of cardiovascular events by omega-3 fatty acids. PMID- 26754660 TI - Association of cord blood des-acyl ghrelin with birth weight, and placental GHS R1 receptor expression in SGA, AGA, and LGA newborns. AB - Although ghrelin in cord blood has been associated to birth weight, its role in fetal and postnatal growth has not been elucidated. The aim of this study was to analyze total ghrelin, acyl ghrelin (AG), and des-acyl ghrelin (DAG) in cord blood of newborns with idiopathic birth weight alterations, and to evaluate protein expression of placental GHS-R1, in order to investigate their correlation with birth weight and placental weight. We performed a cross-sectional comparative study in umbilical cord blood and placentas from healthy mothers of SGA, AGA, and LGA (small, adequate and large for gestational age) term newborns (n = 20 per group). Cord blood total ghrelin, AG, and DAG were measured by ELISA, and placental GHS-R1 expression was evaluated by Western blot. Cord blood DAG was higher in SGA compared to AGA newborns (902.1 +/- 109.1 and 597.4 +/- 58.2 pg/ml, respectively, p = 0.01) while LGA and AGA showed similar values (627.2 +/- 76.4 pg/ml for LGA, p = 0.80). DAG negatively correlated with birthweight (r = -0.31, p = 0.02) and placental weight (r = -0.33, p = 0.02). No differences in AG or total ghrelin were found. GHS-R1 protein in placenta was not differentially expressed among SGA, AGA, and LGA. Our results suggest a role of DAG in intrauterine growth. Further studies are needed in order to elucidate the mechanisms by which DAG participates in fetal growth. PMID- 26754661 TI - The role of ANGPTL3 in controlling lipoprotein metabolism. AB - Angiopoietin-like protein 3 (ANGPTL3) is a secretory protein regulating plasma lipid levels via affecting lipoprotein lipase- and endothelial lipase-mediated hydrolysis of triglycerides and phospholipids. ANGPTL3-deficiency due to loss-of function mutations in the ANGPTL3 gene causes familial combined hypobetalipoproteinemia (FHBL2, OMIM # 605019), a phenotype characterized by low concentration of all major lipoprotein classes in circulation. ANGPTL3 is therefore a potential therapeutic target to treat combined hyperlipidemia, a major risk factor for atherosclerotic coronary heart disease. This review focuses on the mechanisms behind ANGPTL3-deficiency induced FHBL2. PMID- 26754662 TI - Dynamic risk stratification for medullary thyroid cancer according to the response to initial therapy. AB - Detecting persistent/recurrent disease of medullary thyroid carcinoma (MTC) is important. The tumor-node-metastasis (TNM) staging system is useful for predicting disease-specific mortality, but is a static system and does not include postoperative serum calcitonin levels. We have focused on the clinical usefulness of dynamic risk stratification (DRS) using the best response to the initial therapy in MTC patients. A total of 120 MTC patients were classified into three DRS groups based on their responses to initial therapy. Clinical outcomes were assessed according to TNM staging and DRS. In the DRS, 70, 23 and 7 % of the MTC patients were classified into excellent, biochemical incomplete, or structural incomplete response groups, respectively. On TNM staging, 37, 16, 13 and 35 % of patients were stages I-IV, respectively. There were significant differences in survivals according to TNM staging (p = 0.03) and DRS (p = 0.005). During the median follow-up of 6.2 years, 75 patients (63 %) demonstrated no evidence of disease (NED). About 60 and 17 % of patients in stages III and IV were NED, respectively. DRS predicted NED better than TNM staging according to the proportion of variance explained (PVE) (49.1 vs. 28.7 %, respectively). At the final follow-up, 88, 4 and 0 % of patients in excellent, biochemical incomplete, and structural incomplete response groups attained NED, respectively. DRS based on the best response to the initial therapy can provide useful prognostic information in addition to initial TNM staging for predicting of mortality, as well as the likelihood of NED in MTC patients. PMID- 26754664 TI - [Problematic internet use (PIN)--a review of assessment questionnaires and risk factors]. AB - Internet is nowadays an integral part of our lives. However, excessive internet use, which is in many ways comparable to substance addictions and behavioral addictions, has become of growing interest in popular media, health policy and scientific research. Nevertheless, there is still considerable controversy with respect to diagnostic criteria and assessment questionnaires, and the diagnosis does not yet appear in any official diagnostic system such as the DSM-5 or ICD 10. Due to the lack of consistent diagnostic criteria for problematic internet use and both the use of different assessment questionnaires and classification systems, the reported prevalence rates vary significantly across studies. Thus, the comparison of study results is limited.In this review article a brief overview of the various diagnostic criteria and assessment questionnaires as well as the prevalence of problematic internet use (PIN) will be given. Furthermore, several usage-related and person-related risk factors of PIN will be discussed. With regards to the latter, the focus will be on both sociodemographic and psychiatric risk factors and on personality traits. PMID- 26754663 TI - Proteins involved in biophoton emission and flooding-stress responses in soybean under light and dark conditions. AB - To know the molecular systems basically flooding conditions in soybean, biophoton emission measurements and proteomic analyses were carried out for flooding stressed roots under light and dark conditions. Photon emission was analyzed using a photon counter. Gel-free quantitative proteomics were performed to identify significant changes proteins using the nano LC-MS along with SIEVE software. Biophoton emissions were significantly increased in both light and dark conditions after flooding stress, but gradually decreased with continued flooding exposure compared to the control plants. Among the 120 significantly identified proteins in the roots of soybean plants, 73 and 19 proteins were decreased and increased in the light condition, respectively, and 4 and 24 proteins were increased and decreased, respectively, in the dark condition. The proteins were mainly functionally grouped into cell organization, protein degradation/synthesis, and glycolysis. The highly abundant lactate/malate dehydrogenase proteins were decreased in flooding-stressed roots exposed to light, whereas the lysine ketoglutarate reductase/saccharopine dehydrogenase bifunctional enzyme was increased in both light and dark conditions. Notably, however, specific enzyme assays revealed that the activities of these enzymes and biophoton emission were sharply increased after 3 days of flooding stress. This finding suggests that the source of biophoton emission in roots might involve the chemical excitation of electron or proton through enzymatic or non-enzymatic oxidation and reduction reactions. Moreover, the lysine ketoglutarate reductase/saccharopine dehydrogenase bifunctional enzyme may play important roles in responses in flooding stress of soybean under the light condition and as a contributing factor to biophoton emission. PMID- 26754665 TI - Enhanced Stomatal Conductance by a Spontaneous Arabidopsis Tetraploid, Me-0, Results from Increased Stomatal Size and Greater Stomatal Aperture. AB - The rate of gas exchange in plants is regulated mainly by stomatal size and density. Generally, higher densities of smaller stomata are advantageous for gas exchange; however, it is unclear what the effect of an extraordinary change in stomatal size might have on a plant's gas-exchange capacity. We investigated the stomatal responses to CO2 concentration changes among 374 Arabidopsis (Arabidopsis thaliana) ecotypes and discovered that Mechtshausen (Me-0), a natural tetraploid ecotype, has significantly larger stomata and can achieve a high stomatal conductance. We surmised that the cause of the increased stomatal conductance is tetraploidization; however, the stomatal conductance of another tetraploid accession, tetraploid Columbia (Col), was not as high as that in Me-0. One difference between these two accessions was the size of their stomatal apertures. Analyses of abscisic acid sensitivity, ion balance, and gene expression profiles suggested that physiological or genetic factors restrict the stomatal opening in tetraploid Col but not in Me-0. Our results show that Me-0 overcomes the handicap of stomatal opening that is typical for tetraploids and achieves higher stomatal conductance compared with the closely related tetraploid Col on account of larger stomatal apertures. This study provides evidence for whether larger stomatal size in tetraploids of higher plants can improve stomatal conductance. PMID- 26754626 TI - Risk Related to Pre-Diabetes Mellitus and Diabetes Mellitus in Heart Failure With Reduced Ejection Fraction: Insights From Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial. AB - BACKGROUND: The prevalence of pre-diabetes mellitus and its consequences in patients with heart failure and reduced ejection fraction are not known. We investigated these in the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. METHODS AND RESULTS: We examined clinical outcomes in 8399 patients with heart failure and reduced ejection fraction according to history of diabetes mellitus and glycemic status (baseline hemoglobin A1c [HbA1c]: < 6.0% [< 42 mmol/mol], 6.0%-6.4% [42-47 mmol/mol; pre-diabetes mellitus], and >= 6.5% [>= 48 mmol/mol; diabetes mellitus]), in Cox regression models adjusted for known predictors of poor outcome. Patients with a history of diabetes mellitus (n = 2907 [35%]) had a higher risk of the primary composite outcome of heart failure hospitalization or cardiovascular mortality compared with those without a history of diabetes mellitus: adjusted hazard ratio, 1.38; 95% confidence interval, 1.25 to 1.52; P < 0.001. HbA1c measurement showed that an additional 1106 (13% of total) patients had undiagnosed diabetes mellitus and 2103 (25%) had pre-diabetes mellitus. The hazard ratio for patients with undiagnosed diabetes mellitus (HbA1c, > 6.5%) and known diabetes mellitus compared with those with HbA1c < 6.0% was 1.39 (1.17 1.64); P < 0.001 and 1.64 (1.43-1.87); P < 0.001, respectively. Patients with pre diabetes mellitus were also at higher risk (hazard ratio, 1.27 [1.10-1.47]; P < 0.001) compared with those with HbA1c < 6.0%. The benefit of LCZ696 (sacubitril/valsartan) compared with enalapril was consistent across the range of HbA1c in the trial. CONCLUSIONS: In patients with heart failure and reduced ejection fraction, dysglycemia is common and pre-diabetes mellitus is associated with a higher risk of adverse cardiovascular outcomes (compared with patients with no diabetes mellitus and HbA1c < 6.0%). LCZ696 was beneficial compared with enalapril, irrespective of glycemic status. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255. PMID- 26754666 TI - The Dynamics of Transcript Abundance during Cellularization of Developing Barley Endosperm. AB - Within the cereal grain, the endosperm and its nutrient reserves are critical for successful germination and in the context of grain utilization. The identification of molecular determinants of early endosperm development, particularly regulators of cell division and cell wall deposition, would help predict end-use properties such as yield, quality, and nutritional value. Custom microarray data have been generated using RNA isolated from developing barley grain endosperm 3 d to 8 d after pollination (DAP). Comparisons of transcript abundance over time revealed 47 gene expression modules that can be clustered into 10 broad groups. Superimposing these modules upon cytological data allowed patterns of transcript abundance to be linked with key stages of early grain development. Here, attention was focused on how the datasets could be mined to explore and define the processes of cell wall biosynthesis, remodeling, and degradation. Using a combination of spatial molecular network and gene ontology enrichment analyses, it is shown that genes involved in cell wall metabolism are found in multiple modules, but cluster into two main groups that exhibit peak expression at 3 DAP to 4 DAP and 5 DAP to 8 DAP. The presence of transcription factor genes in these modules allowed candidate genes for the control of wall metabolism during early barley grain development to be identified. The data are publicly available through a dedicated web interface (https://ics.hutton.ac.uk/barseed/), where they can be used to interrogate co- and differential expression for any other genes, groups of genes, or transcription factors expressed during early endosperm development. PMID- 26754668 TI - Analysis of the Rice ADP-Glucose Transporter (OsBT1) Indicates the Presence of Regulatory Processes in the Amyloplast Stroma That Control ADP-Glucose Flux into Starch. AB - Previous studies showed that efforts to further elevate starch synthesis in rice (Oryza sativa) seeds overproducing ADP-glucose (ADPglc) were prevented by processes downstream of ADPglc synthesis. Here, we identified the major ADPglc transporter by studying the shrunken3 locus of the EM1093 rice line, which harbors a mutation in the BRITTLE1 (BT1) adenylate transporter (OsBt1) gene. Despite containing elevated ADPglc levels (approximately 10-fold) compared with the wild-type, EM1093 grains are small and shriveled due to the reduction in the amounts and size of starch granules. Increases in ADPglc levels in EM1093 were due to their poor uptake of ADP-[(14)C]glc by amyloplasts. To assess the potential role of BT1 as a rate-determining step in starch biosynthesis, the maize ZmBt1 gene was overexpressed in the wild-type and the GlgC (CS8) transgenic line expressing a bacterial glgC-TM gene. ADPglc transport assays indicated that transgenic lines expressing ZmBT1 alone or combined with GlgC exhibited higher rates of transport (approximately 2-fold), with the GlgC (CS8) and GlgC/ZmBT1 (CS8/AT5) lines showing elevated ADPglc levels in amyloplasts. These increases, however, did not lead to further enhancement in seed weights even when these plant lines were grown under elevated CO2. Overall, our results indicate that rice lines with enhanced ADPglc synthesis and import into amyloplasts reveal additional barriers within the stroma that restrict maximum carbon flow into starch. PMID- 26754671 TI - Ultrastructural effects and antibiofilm activity of LFchimera against Burkholderia pseudomallei. AB - Lactoferrin chimera (LFchimera), a hybrid peptide containing the two antimicrobial stretches of the innate immunity factor bovine lactoferrin, viz. LFampin265-284 and LFcin17-30, has strikingly high antimicrobial activity against the category B pathogen Burkholderia pseudomallei. The action mechanisms of LFchimera against B. pseudomallei is not fully understood. The aim of this study was to further investigate the effect of treated B. pseudomallei with LFchimera using (immune) electron microscopy. The effects of LFchimera on biofilm formation and against preformed biofilm of B. pseudomallei were also determined. After exposure to LFchimera, transmission electron microscopy revealed swelling of the periplasmic space of B. pseudomallei and a highly inhomogeneous electron density in the intracellular DNA region. Localization of LFchimera in B. pseudomallei using immunoelectron microscopy showed gold particles in intracellular structures without accumulation on the membranes. LFchimera also possessed stronger bactericidal activity than ceftazidime against B. pseudomallei grown in biofilm. Moreover, limited exposure of B. pseudomallei to LFchimera at subcidal concentration could reduce biofilm formation. Altogether, the results indicate that LFchimera possesses antibacterial and antibiofilm activities and can modulate B. pseudomallei colonization. Therefore, the efficacy of LFchimera merits further development of this agent for the therapy of melioidosis. PMID- 26754669 TI - FamNet: A Framework to Identify Multiplied Modules Driving Pathway Expansion in Plants. AB - Gene duplications generate new genes that can acquire similar but often diversified functions. Recent studies of gene coexpression networks have indicated that, not only genes, but also pathways can be multiplied and diversified to perform related functions in different parts of an organism. Identification of such diversified pathways, or modules, is needed to expand our knowledge of biological processes in plants and to understand how biological functions evolve. However, systematic explorations of modules remain scarce, and no user-friendly platform to identify them exists. We have established a statistical framework to identify modules and show that approximately one-third of the genes of a plant's genome participate in hundreds of multiplied modules. Using this framework as a basis, we implemented a platform that can explore and visualize multiplied modules in coexpression networks of eight plant species. To validate the usefulness of the platform, we identified and functionally characterized pollen- and root-specific cell wall modules that multiplied to confer tip growth in pollen tubes and root hairs, respectively. Furthermore, we identified multiplied modules involved in secondary metabolite synthesis and corroborated them by metabolite profiling of tobacco (Nicotiana tabacum) tissues. The interactive platform, referred to as FamNet, is available at http://www.gene2function.de/famnet.html. PMID- 26754673 TI - Quality in pathology: how good is good? An introduction. PMID- 26754667 TI - Combined Large-Scale Phenotyping and Transcriptomics in Maize Reveals a Robust Growth Regulatory Network. AB - Leaves are vital organs for biomass and seed production because of their role in the generation of metabolic energy and organic compounds. A better understanding of the molecular networks underlying leaf development is crucial to sustain global requirements for food and renewable energy. Here, we combined transcriptome profiling of proliferative leaf tissue with in-depth phenotyping of the fourth leaf at later stages of development in 197 recombinant inbred lines of two different maize (Zea mays) populations. Previously, correlation analysis in a classical biparental mapping population identified 1,740 genes correlated with at least one of 14 traits. Here, we extended these results with data from a multiparent advanced generation intercross population. As expected, the phenotypic variability was found to be larger in the latter population than in the biparental population, although general conclusions on the correlations among the traits are comparable. Data integration from the two diverse populations allowed us to identify a set of 226 genes that are robustly associated with diverse leaf traits. This set of genes is enriched for transcriptional regulators and genes involved in protein synthesis and cell wall metabolism. In order to investigate the molecular network context of the candidate gene set, we integrated our data with publicly available functional genomics data and identified a growth regulatory network of 185 genes. Our results illustrate the power of combining in-depth phenotyping with transcriptomics in mapping populations to dissect the genetic control of complex traits and present a set of candidate genes for use in biomass improvement. PMID- 26754670 TI - Radiation-induced miR-208a increases the proliferation and radioresistance by targeting p21 in human lung cancer cells. AB - BACKGROUND: Lung cancer has long been the most dangerous malignant tumor among males in both well developed and poorly developed countries. Radiotherapy plays a critical role in the curative management of inoperable non-small cell lung cancer (NSCLC) and is also used as a post-surgical treatment in lung cancer patients. Radioresistance is an important factor that limits the efficacy of radiotherapy for NSCLC patients. Increasing evidence suggests that microRNAs (miRNAs) possess diverse cellular regulatory roles in radiation responses. METHODS: In this study, we used miRNA microarray technology to identify serum miRNAs that were differentially expressed before and after radiotherapy in lung cancer patients. We further examined the biological function of miR-208a on cell viability, apoptotic death and cell cycle distribution in human lung cancer cells and explored the probable mechanism. RESULTS: Nine miRNAs, including miR-29b-3p, miR 200a-3p, and miR-126-3p were significantly down-regulated, whereas miR-208a was the only miRNA that was up-regulated in the serum of the patients after radiation treatment (P < 0.05). The expression of miR-208a could be induced by X-ray irradiation in lung cancer cells. Forced expression of miR-208a promoted cell proliferation and induced radioresistance via targeting p21 with a corresponding activation of the AKT/mTOR pathway in lung cancer cells, whereas down-regulation of miR-208a resulted in the opposite effects. In addition, down-regulation of miR 208a increased the percentage of cells undergoing apoptosis and inhibited the G1 phase arrest in NSCLC cells. Moreover, miR-208a from the serum exosome fraction of lung cancer patients could shuttle to A549 cells in a time-dependent manner, which was likely to contribute to the subsequent biological effects. CONCLUSIONS: The present study provides evidence that miR-208a can affect the proliferation and radiosensitivity of human lung cancer cells by targeting p21 and can be transported by exosomes. Thus, miR-208a may serve as a potential therapeutic target for lung cancer patients. PMID- 26754672 TI - Thermostable microbial xylanases for pulp and paper industries: trends, applications and further perspectives. AB - Xylanases are enzymes with biotechnological relevance in a number of fields, including food, feed, biofuel, and textile industries. Their most significant application is in the paper and pulp industry, where they are used as a biobleaching agent, showing clear economic and environmental advantages over chemical alternatives. Since this process requires high temperatures and alkali media, the identification of thermostable and alkali stable xylanases represents a major biotechnological goal in this field. Moreover, thermostability is a desirable property for many other applications of xylanases. The review makes an overview of xylanase producing microorganisms and their current implementation in paper biobleaching. Future perspectives are analyzed focusing in the efforts carried out to generate thermostable enzymes by means of modern biotechnological tools, including metagenomic analysis, enzyme molecular engineering and nanotechnology. Furthermore, structural and mutagenesis studies have revealed critical sites for stability of xylanases from glycoside hydrolase families GH10 and GH11, which constitute the main classes of these enzymes. The overall conclusions of these works are summarized here and provide relevant information about putative weak spots within xylanase structures to be targeted in future protein engineering approaches. PMID- 26754674 TI - Application of the 2013 ASCO/CAP guideline and the SISH technique for HER2 testing of breast cancer selects more patients for anti-HER2 treatment. AB - The aim of this study is to assess the impact of changes of the 2013 ASCO/CAP guideline on the results of HER2 testing in breast cancer. A series of 916 primary invasive breast cancer cases, assessed as HER2 2+ by IHC in part using the 2007 and in part the 2013 ASCO/CAP criteria, was evaluated for HER2 amplification status by SISH and classified according to both 2007 and 2013 ASCO/CAP ISH guideline criteria. We observed a significant increase of HER2 positive cases (12.4 to 16.8%) and a decrease of HER2-equivocal cases (3.6 to 0.7%). Of the cases studied, 52.1% fulfilled both criteria of HER2/CEP17 ratio and average HER2 copy number per cell to be classified as HER2-positive. Reclassification of the cases from before the introduction of the new ASCO/CAP guideline with the 2013 ISH criteria resulted in an increase of cases with a HER2 positive status (12.4 to 14.2%) and in a decrease of HER2-equivocal cases (3.6 to 1.6%). The 2013 ASCO/CAP guideline selects more patients for anti-HER2 targeted therapy, mostly based on the modifications of criteria to evaluate ISH-HER2. PMID- 26754675 TI - Prognostic significance of tumor regression in lymph nodes after neoadjuvant therapy for rectal carcinoma. AB - Neoadjuvant therapy (NAT) is mainly indicated for locally advanced rectal carcinoma. Many reports have shown that regression of the primary tumor is a prognostic factor. However, few reports to date have analyzed the potential prognostic significance of lymph node regression in rectal carcinoma. The aim of the present study is to describe the pattern of tumor regression in lymph nodes after NAT for rectal carcinoma and its potential prognostic significance. We have retrospectively reviewed 106 cases of rectal carcinoma treated at a single institution. We have retrieved data from the patients and reviewed the histopathological slides to evaluate tumor regression both of the primary tumor and of LN metastases. Prognosis has been defined both in terms of disease-free survival (DFS) and disease-specific survival (DSS). Of the patients, 16% showed complete response of the primary tumor, while 24% showed poor response, according to the CAP regression grading system. Absence of lymph node involvement after therapy was found in 80% of the patients (ypN0 cases), while 20% were ypN+. We reviewed 639 LN; 85 were involved by tumor, and 170 showed histological signs of tumor regression. The main pattern of tumor regression in lymph nodes was fibrosis (66.3%), followed by hystiocytosis (29.1%) and mucin pools (4.6%). We found histological signs of regression in 57% of ypN0 cases and 76% of ypN+ cases. We found a significant association between regression grade of the primary tumor and of lymph node metastases. For ypN0 patients with persistence of the primary tumor after NAT, the median DFS was significantly shorter in patients showing tumor regression in the LN. In a Cox multivariate survival model for DFS, this prognostic influence was independent of the regression grade of the primary tumor and also of the ypTNM stage. We found no significant association between any factor and DSS. The pattern of tumor regression in lymph nodes was not significantly associated with prognosis. Tumor regression in lymph nodes is an important prognostic factor in rectal carcinoma after NAT and should be specifically looked for and included in pathology reports. PMID- 26754676 TI - Surgical resection of synchronous and metachronous metastases from pancreatic adenocarcinoma. Two case reports in the light of recent evidences. AB - Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer-related mortality in the western countries for both men and women. Until in 2015, it remains one of the most challenging malignancies with a dismal prognosis and limited therapeutic options. The 5-year survival rate for pancreatic cancer is around 5%, which is the lowest among all different cancer sites. The poor prognosis of PDAC is largely attributed to delayed diagnosis due to nonspecific symptoms in the early stages of the disease, biological aggressiveness leading to rapid metastases, lack of effective screening methods, and resistance to radiation and chemotherapies. In the event of metastases, patients were traditionally referred to palliative treatments. Thanks to continuous progresses in the surgical expertise, synchronous and metachronous metastases resections seem technically feasible nowadays. These reports describe 2 several clinical cases in which patients with Pancreatic Adenocarcinoma, and synchronous and metachronous liver metastases respectively, were treated with a surgical approach. Patients showed a better survival rate compared current data in the literature. Our results, often in conflict with the guidelines and recent evidences, confirm the need for a new vision of the metastases "problem" in patients with Pancreatic Adenocarcinoma. KEY WORDS: Metastases, Pancreatic Adenocarcinoma, Surgical resection. PMID- 26754677 TI - Interstitial 6q25 microdeletion syndrome: ARID1B is the key gene. AB - Interstitial deletions of the long arm of chromosome 6 are rare. Clinically, these deletions are considered to be part of a unique microdeletion syndrome associated with intellectual disability and speech impairment, typical dysmorphic features, structural anomalies of the brain, microcephaly, and non-specific multiple organ anomalies. The critical region for the interstitial 6q microdeletion phenotype was mapped to 6q24-6q25, particularly the 6q25.3 region containing the genes ARID1B and ZDHHC14. It has been hypothesized that haploinsufficiency of these genes impairs normal development of the brain and is responsible for the phenotype. This case report describes a girl presenting with typical features of 6q microdeletion syndrome, including global developmental delay, speech impairment, distinct dysmorphic features, dysgenesis of the corpus callosum, common limb anomalies, and hearing loss. Chromosome analysis by array CGH revealed a small interstitial 6q deletion spanning approximately 1.1 Mb of DNA and containing only one coding gene, ARID1B. We suggest that ARID1B is the key gene behind 6q microdeletion syndrome, and we discuss its possible role in the phenotypic manifestations. PMID- 26754678 TI - Hepatic arterial infusion chemoembolization therapy for advanced hepatocellular carcinoma: multicenter phase II study. AB - PURPOSE: Portal vein tumor thrombosis is a critical complication in patients with hepatocellular carcinoma (HCC). This prospective multicenter trial assessed the efficacy of hepatic arterial infusion chemoembolization therapy with cisplatin suspended in lipiodol combined with 5-fluorouracil for HCC patients with portal vein tumor thrombosis. METHODS: We enrolled 52 HCC patients with portal vein tumor thrombosis. They received hepatic arterial infusion chemoembolization therapy with cisplatin suspension in lipiodol and 5-fluorouracil. The primary efficacy endpoint was progression-free survival (PFS), while the secondary endpoints were overall survival (OS), tumor response rate, safety, and tolerability. Independent factors for survival were also evaluated. RESULTS: The median PFS and OS were 8.6 and 27.0 months, respectively. Ten patients showed complete response, while 29 had partial response (response rate, 75.0 %). The median survival time of 10 patients with complete response and 29 with partial response was 32 months, while that of 15 patients with partial response who later showed disappearance of HCC following additional therapies was 50 months. Multivariate analysis identified response to treatment and disappearance of viable HCC as independent predictors of survival. The treatment was well tolerated, and the only encountered Grade 3 toxicities were thrombocytopenia and hyperbilirubinemia. CONCLUSIONS: Hepatic arterial infusion chemoembolization therapy with cisplatin suspension in lipiodol combined with 5-fluorouracil is effective treatment for unresectable HCC with portal vein tumor thrombosis. PMID- 26754688 TI - Capsule Commentary on Ganguli et al., Ebola Risk and Preparedness: A National Survey of Internists. PMID- 26754679 TI - A Phase 1, double-blind, 4-period crossover study to investigate the effects of pomalidomide on QT interval in healthy male subjects. AB - PURPOSE: Pomalidomide is a distinct immunomodulatory agent approved for the treatment of relapsed and refractory multiple myeloma. QT interval was monitored in prior studies, and although there was no indication that pomalidomide could induce QT prolongation, a formal analysis was not previously conducted. Therefore, we present here the results of a study evaluating the effects of pomalidomide on QT interval corrected for heart rate (QTc) using Fridericia's formula (QTcF) and other electrocardiogram (ECG) parameters. METHODS: Healthy male volunteers with normal or clinically acceptable laboratory tests and ECG results were randomized to receive single oral doses of placebo, pomalidomide 4 mg, pomalidomide 20 mg, and moxifloxacin 400 mg (positive control) in different sequences. Subjects were evaluated by digital ECG monitoring and underwent blood sampling and standard safety monitoring. RESULTS: Seventy-two subjects were enrolled. In ECG evaluations performed after dosing with pomalidomide 4 mg (therapeutic dose) or 20 mg (supratherapeutic dose), the upper limit of the two sided 90 % CI for mean change from baseline and placebo-corrected QTcF was <10 ms at all postdose time points, which is below the defined threshold of regulatory concern. In contrast, moxifloxacin induced a clear prolongation in QT interval. Changes in heart rate and other ECG parameters after pomalidomide dosing were clinically insignificant. CONCLUSIONS: Pomalidomide given as a single oral dose of up to 20 mg was not associated with QT prolongation in healthy male subjects. PMID- 26754690 TI - Reply. PMID- 26754736 TI - Molecular characterization of a novel capillovirus from red currant. AB - The complete nucleotide sequence of a novel virus from red currant, provisionally named currant virus A (CuVA), was determined. The genome is 7925 nucleotides long and has a 3'-poly(A) tail. The genome organization with two overlapping open reading frames is similar to that of capilloviruses, but the CuVA genome is about 600 nucleotides longer than that of the longest known capillovirus, cherry virus A. The RNA is predicted to encode a polyprotein with domains of methyltransferase, 2OG-Fe(II) oxygenase, papain-like protease, RNA helicase, RdRp, and capsid protein. Phylogenetic analysis confirms that CuVA is a new and distinct member of the genus Capillovirus. PMID- 26754689 TI - Association of Opioids with Falls, Fractures, and Physical Performance among Older Men with Persistent Musculoskeletal Pain. AB - BACKGROUND: Although older adults are disproportionately affected by painful musculoskeletal conditions and receive more opioid analgesics than persons in other age groups, insufficient evidence is available regarding opioid harms in this age group. OBJECTIVE: To examine longitudinal relationships between opioid use and falls, clinical fractures, and changes in physical performance. We hypothesized that opioid use would be associated with greater risks of falling and incident clinical fractures and greater declines in physical performance. DESIGN: We analyzed data from the Osteoporotic Fractures in Men Study (MrOS), a large prospective longitudinal cohort study. Participants completed baseline visits from 2000 to 2002 and were followed for 9.1 (SD 4.0) years. PARTICIPANTS: MrOS enrolled 5994 community-dwelling men >= 65 years of age. The present study included 2902 participants with back, hip, or knee pain most or all of the time at baseline. MAIN MEASURES: The exposure of interest was opioid use, defined at each visit as participant-reported daily or near-daily use of any opioid containing analgesic. Among patients, 309 (13.4 %) reported opioid use at one or more visits. Participants were queried every 4 months about falls and fractures. Physical performance scores were derived from tests of grip strength, chair stands, gait speed, and dynamic balance. KEY RESULTS: In the main analysis, the adjusted risk of falling did not differ significantly between opioid use and non use groups (RR 1.10, 95% CI 0.99, 1.24). Similarly, adjusted rates of incident clinical fracture did not differ between groups (HR 1.13, 95% CI 0.94, 1.36). Physical performance was worse at baseline for the opioid use group, but annualized change in physical performance scores did not differ between groups ( 0.022, 95% CI -0.138, 0.093). CONCLUSIONS: Additional research is needed to determine whether opioid use is a marker of risk or a cause of falls, fractures, and progressive impairment among older adults with persistent pain. PMID- 26754737 TI - Membranoproliferative glomerulonephritis recurrence after kidney transplantation: using the new classification. AB - BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is an uncommon glomerular disorder that may lead to end stage renal disease (ESRD). With new understanding of the disease pathogenesis, the classical classification as MPGN types I, II, III has changed. Data on post-transplant MPGN, in particular with the newly refined classification, is limited. We present our center's experience of MPGN after kidney transplantation using the new classification. METHODS: This is a retrospective study of 34 patients with ESRD due to MPGN who received 40 kidney transplants between 1994 and 2014. We reviewed the available biopsies' data using the new classification. We assessed post transplantation recurrence rate, risk factors of recurrence, the response to therapy and allografts' survival. RESULTS: Median time of follow up was 5.3 years (range 0.5-14 years). Using the new classification, we found that pre-transplant MPGN disease was due to immune complex-mediated glomerulonephritis (ICGN) in 89 % of cases and complement-mediated glomerulonephritis (CGN) in 11 %. Recurrence was detected in 18 transplants (45 %). Living related allografts (P = 0.045), preemptive transplantations (P = 0.018), low complement level (P = 0.006), and the presence of monoclonal gammopathy (P = 0.010) were associated with higher recurrence rate in ICGN cases. Half of the patients with recurrence lost their allografts. The use of ACEi/ARB was associated with a trend toward less allograft loss. CONCLUSIONS: MPGN recurs at a high rate after kidney transplantation. The risk of MPGN recurrence increases with preemptive transplantation, living related donation, low complement level, and the presence of monoclonal gammopathy. Recurrence of MPGN leads to allograft failure in half of the cases. PMID- 26754738 TI - Characterization of the peptide binding specificity of the HLA class I alleles B*38:01 and B*39:06. AB - B*38:01 and B*39:06 are present with phenotypic frequencies <2% in the general population, but are of interest as B*39:06 is the B allele most associated with type 1 diabetes susceptibility and 38:01 is most protective. A previous study derived putative main anchor motifs for both alleles based on peptide elution data. The present study has utilized panels of single amino acid substitution peptide libraries to derive detailed quantitative motifs accounting for both primary and secondary influences on peptide binding. From these analyses, both alleles were confirmed to utilize the canonical position 2/C-terminus main anchor spacing. B*38:01 preferentially bound peptides with the positively charged or polar residues H, R, and Q in position 2 and the large hydrophobic residues I, F, L, W, and M at the C-terminus. B*39:06 had a similar preference for R in position 2, but also well-tolerated M, Q, and K. A more dramatic contrast between the two alleles was noted at the C-terminus, where the specificity of B*39:06 was clearly for small residues, with A as most preferred, followed by G, V, S, T, and I. Detailed position-by-position and residue-by-residue coefficient values were generated from the panels to provide detailed quantitative B*38:01 and B*39:06 motifs. It is hoped that these detailed motifs will facilitate the identification of T cell epitopes recognized in the context of two class I alleles associated with dramatically different dispositions towards type 1 diabetes, offering potential avenues for the investigation of the role of CD8 T cells in this disease. PMID- 26754739 TI - What is the extent of research on the characteristics, behaviors, and impacts of health information technology champions? A scoping review. AB - BACKGROUND: Although champions are commonly employed in health information technology (HIT) implementations, the state of empirical literature on HIT champions' is unclear. The purpose of our review was to synthesize quantitative and qualitative studies to identify the extent of research on the characteristics, behaviors, and impacts of HIT champions. Ultimately, our goal was to identify gaps in the literature and inform implementation science. METHODS: Our review employed a broad search strategy using multiple databases Embase, Pubmed, Cinahl, PsychInfo, Web of Science, and the Cochrane library. We identified 1728 candidate articles, of which 42 were retained for full-text review. RESULTS: Of the 42 studies included, fourteen studies employed a multiple case study design (33 %), 12 additional articles employed a single-case study design (29 %), five used quantitative methods (12 %), two used mixed-methods (5 %), and one used a Delphi methodology (2 %). Our review revealed multiple categories and characteristics of champions as well as influence tactics they used to promote an HIT project. Furthermore, studies have assessed three general types of HIT champion impacts: (1) impacts on the implementation process of a specific HIT; (2) impacts on usage behavior or overall success of a specific HIT; and (3) impacts on general organizational-level innovativeness. However the extent to which HIT projects fail even with a champion and why such failures occur is not clear. Also unclear is whether all organizations require a champion for successful HIT project implementation. In other words, we currently do not know enough about the conditions under which (1) a health IT champion is needed, (2) multiple champions are needed, and (3) an appointed champion-as opposed to an emergent champion-can be successful. CONCLUSIONS: Although champions appear to have contributed to successful implementation of HIT projects, simply measuring the presence or absence of a champion is not sufficient for assessing impacts. Future research should aim for answers to questions about who champions should be, when they should be engaged, what they should do, how management can support their efforts, and what their impact is given the organizational context. PMID- 26754740 TI - Computational Approach for Securing Radiology-Diagnostic Data in Connected Health Network using High-Performance GPU-Accelerated AES. AB - Diagnostic radiology is a core and integral part of modern medicine, paving ways for the primary care physicians in the disease diagnoses, treatments and therapy managements. Obviously, all recent standard healthcare procedures have immensely benefitted from the contemporary information technology revolutions, apparently revolutionizing those approaches to acquiring, storing and sharing of diagnostic data for efficient and timely diagnosis of diseases. Connected health network was introduced as an alternative to the ageing traditional concept in healthcare system, improving hospital-physician connectivity and clinical collaborations. Undoubtedly, the modern medicinal approach has drastically improved healthcare but at the expense of high computational cost and possible breach of diagnosis privacy. Consequently, a number of cryptographical techniques are recently being applied to clinical applications, but the challenges of not being able to successfully encrypt both the image and the textual data persist. Furthermore, processing time of encryption-decryption of medical datasets, within a considerable lower computational cost without jeopardizing the required security strength of the encryption algorithm, still remains as an outstanding issue. This study proposes a secured radiology-diagnostic data framework for connected health network using high-performance GPU-accelerated Advanced Encryption Standard. The study was evaluated with radiology image datasets consisting of brain MR and CT datasets obtained from the department of Surgery, University of North Carolina, USA, and the Swedish National Infrastructure for Computing. Sample patients' notes from the University of North Carolina, School of medicine at Chapel Hill were also used to evaluate the framework for its strength in encrypting decrypting textual data in the form of medical report. Significantly, the framework is not only able to accurately encrypt and decrypt medical image datasets, but it also successfully encrypts and decrypts textual data in Microsoft Word document, Microsoft Excel and Portable Document Formats which are the conventional format of documenting medical records. Interestingly, the entire encryption and decryption procedures were achieved at a lower computational cost using regular hardware and software resources without compromising neither the quality of the decrypted data nor the security level of the algorithms. PMID- 26754741 TI - Determinants of birth weight in Portugal: 1988 to 2011. AB - The objective of this paper is to analyse temporal birth weight variation, its relationship to the frequency of premature births in Portugal, and the influence of native and immigrant mothers' characteristics as well as to determine the possible existence of a pattern of temporal change in birth weight in the Iberian Peninsula as a whole. Individual mother-child data from the Portuguese National Institute of Statistics regarding live births (N = 2,661,542) permitted an analysis, for the first time, of weight at birth in Portugal from a bio demographic perspective. The results obtained show that from 1988 to 2011 there was a gradual decline in the average weight at birth in Portugal that may be related to shifts in the duration of gestation. An initial rapid decline in the relative frequency of post-term births took place, followed by small variations from 1995 on. Logistic regressions indicated a pattern unaffected by maternal origin or the sex of the newborn. With regard to weeks of gestation, the odds values obtained were < 1 when the reference category was < 28 weeks. For this factor, no significant differences were found in relation to the mother's origin. Portuguese mothers over 35 years were associated with a higher incidence of low birth weight. Regardless of maternal origin, being a newborn of parity 1, and with the mother not in a couple, resulted in unfavourable outcomes with regard to low birth weight. On the other hand, long gestation periods and having secondary or university education constituted a protective factor. PMID- 26754742 TI - Pluronic lecithin organogel (PLO) of diltiazem hydrochloride: effect of solvents/penetration enhancers on ex vivo permeation. AB - In the present study, pluronic lecithin organogel (PLO) of diltiazem hydrochloride (DZH) was developed by taking different ratios of organic phase to aqueous phase (1:3, 1:4, and 1:5) with varying concentration of soya lecithin (20, 30, and 40 % w/w) in organic phase (isopropyl myristate, IPM) and pluronic (20, 25, and 30 % w/w) in aqueous phase, respectively, and characterized for in vitro parameters and ex vivo permeation study. The results of in vitro parameters were found to be within permissible limit and all the PLOs were physically stable at refrigeration and ambient temperature. The influence of phase ratio and different concentrations of soya lecithin on DZH release from the PLOs was found to be significant (p < 0.05), whereas the influences of different concentrations of pluronic were insignificant. The effect of different solvents/penetration enhancers viz. IPM, propylene glycol (PG), dimethyl sulphoxide (DMSO), and D limonene, in combination and alone, on the permeation of DZH across the dorsal skin of rat was studied. Among all, formulation containing IPM (PLO6) exhibited highest flux of 147.317 MUg/cm(2)/h. Furthermore, histopathology section of treated skin sample illustrated that lipid bilayer disruption was the mechanism for the DZH permeation. The above results indicated that PLO6 may serve as a promising alternative delivery system for DZH in the effective treatment of hypertension. PMID- 26754743 TI - Cost-minimization analysis of three decision strategies for cardiac revascularization: results of the "suspected CAD" cohort of the european cardiovascular magnetic resonance registry. AB - BACKGROUND: Coronary artery disease (CAD) continues to be one of the top public health burden. Perfusion cardiovascular magnetic resonance (CMR) is generally accepted to detect CAD, while data on its cost effectiveness are scarce. Therefore, the goal of the study was to compare the costs of a CMR-guided strategy vs two invasive strategies in a large CMR registry. METHODS: In 3'647 patients with suspected CAD of the EuroCMR-registry (59 centers/18 countries) costs were calculated for diagnostic examinations (CMR, X-ray coronary angiography (CXA) with/without FFR), revascularizations, and complications during a 1-year follow-up. Patients with ischemia-positive CMR underwent an invasive CXA and revascularization at the discretion of the treating physician (=CMR + CXA strategy). In the hypothetical invasive arm, costs were calculated for an initial CXA and a FFR in vessels with >=50% stenoses (=CXA + FFR-strategy) and the same proportion of revascularizations and complications were applied as in the CMR + CXA-strategy. In the CXA-only strategy, costs included those for CXA and for revascularizations of all >=50% stenoses. To calculate the proportion of patients with >=50% stenoses, the stenosis-FFR relationship from the literature was used. Costs of the three strategies were determined based on a third payer perspective in 4 healthcare systems. RESULTS: Revascularizations were performed in 6.2%, 4.5%, and 12.9% of all patients, patients with atypical chest pain (n = 1'786), and typical angina (n = 582), respectively; whereas complications (=all-cause death and non-fatal infarction) occurred in 1.3%, 1.1%, and 1.5%, respectively. The CMR + CXA-strategy reduced costs by 14%, 34%, 27%, and 24% in the German, UK, Swiss, and US context, respectively, when compared to the CXA + FFR-strategy; and by 59%, 52%, 61% and 71%, respectively, versus the CXA-only strategy. In patients with typical angina, cost savings by CMR + CXA vs CXA + FFR were minimal in the German (2.3%), intermediate in the US and Swiss (11.6% and 12.8%, respectively), and remained substantial in the UK (18.9%) systems. Sensitivity analyses proved the robustness of results. CONCLUSIONS: A CMR + CXA-strategy for patients with suspected CAD provides substantial cost reduction compared to a hypothetical CXA + FFR-strategy in patients with low to intermediate disease prevalence. However, in the subgroup of patients with typical angina, cost savings were only minimal to moderate. PMID- 26754744 TI - Epistaxis in hereditary hemorrhagic telangiectasia: an evidence based review of surgical management. AB - Patients with Hereditary Hemorrhagic Telangiectasia (HHT) frequently present with epistaxis. Up to 98% of these patients will have epistaxis at some point in their life. There are multiple ways to deal with this problem, including conservative, medical and surgical options. We present a case and an update on the treatment options for HHT, with a focus on the newer and experimental techniques. PMID- 26754746 TI - Crude incidence in two-phase designs in the presence of competing risks. AB - BACKGROUND: In many studies, some information might not be available for the whole cohort, some covariates, or even the outcome, might be ascertained in selected subsamples. These studies are part of a broad category termed two-phase studies. Common examples include the nested case-control and the case-cohort designs. For two-phase studies, appropriate weighted survival estimates have been derived; however, no estimator of cumulative incidence accounting for competing events has been proposed. This is relevant in the presence of multiple types of events, where estimation of event type specific quantities are needed for evaluating outcome. METHODS: We develop a non parametric estimator of the cumulative incidence function of events accounting for possible competing events. It handles a general sampling design by weights derived from the sampling probabilities. The variance is derived from the influence function of the subdistribution hazard. RESULTS: The proposed method shows good performance in simulations. It is applied to estimate the crude incidence of relapse in childhood acute lymphoblastic leukemia in groups defined by a genotype not available for everyone in a cohort of nearly 2000 patients, where death due to toxicity acted as a competing event. In a second example the aim was to estimate engagement in care of a cohort of HIV patients in resource limited setting, where for some patients the outcome itself was missing due to lost to follow-up. A sampling based approach was used to identify outcome in a subsample of lost patients and to obtain a valid estimate of connection to care. CONCLUSIONS: A valid estimator for cumulative incidence of events accounting for competing risks under a general sampling design from an infinite target population is derived. PMID- 26754745 TI - Environmental cold exposure increases blood flow and affects pain sensitivity in the knee joints of CFA-induced arthritic mice in a TRPA1-dependent manner. AB - BACKGROUND: The effect of cold temperature on arthritis symptoms is unclear. The aim of this study was to investigate how environmental cold affects pain and blood flow in mono-arthritic mice, and examine a role for transient receptor potential ankyrin 1 (TRPA1), a ligand-gated cation channel that can act as a cold sensor. METHODS: Mono-arthritis was induced by unilateral intra-articular injection of complete Freund's adjuvant (CFA) in CD1 mice, and in mice either lacking TRPA1 (TRPA1 KO) or respective wildtypes (WT). Two weeks later, nociception and joint blood flow were measured following exposure to 10 degrees C (1 h) or room temperature (RT). Primary mechanical hyperalgesia in the knee was measured by pressure application apparatus; secondary mechanical hyperalgesia by automated von Frey system; thermal hyperalgesia by Hargreaves technique, and weight bearing by the incapacitance test. Joint blood flow was recorded by full field laser perfusion imager (FLPI) and using clearance of (99m)Technetium. Blood flow was assessed after pretreatment with antagonists of either TRPA1 (HC 030031), substance P neurokinin 1 (NK1) receptors (SR140333) or calcitonin gene related peptide (CGRP) (CGRP8-37). TRPA1, TAC-1 and CGRP mRNA levels were examined in dorsal root ganglia, synovial membrane and patellar cartilage samples. RESULTS: Cold exposure caused bilateral primary mechanical hyperalgesia 2 weeks after CFA injection, in a TRPA1-dependent manner. In animals maintained at RT, clearance techniques and FLPI showed that CFA-treated joints exhibited lower blood flow than saline-treated joints. In cold-exposed animals, this reduction in blood flow disappears, and increased blood flow in the CFA-treated joint is observed using FLPI. Cold-induced increased blood flow in CFA-treated joints was blocked by HC-030031 and not observed in TRPA1 KOs. Cold exposure increased TRPA1 mRNA levels in patellar cartilage, whilst reducing it in synovial membranes from CFA-treated joints. CONCLUSIONS: We provide evidence that environmental cold exposure enhances pain and increases blood flow in a mono arthritis model. These changes are dependent on TRPA1. Thus, TRPA1 may act locally within the joint to influence blood flow via sensory nerves, in addition to its established nociceptive actions. PMID- 26754747 TI - Socioeconomic factors and self-reported health outcomes in African Americans with rheumatoid arthritis from the Southeastern United States: the contribution of childhood socioeconomic status. AB - BACKGROUND: There is abundant evidence that low socioeconomic status (SES) is associated with worse health outcomes among people with Rheumatoid Arthritis (RA); however, the influence of socioeconomic disadvantage in early life has yet to be studied within that population. METHODS: Data originated from the cross sectional arm of the Consortium Evaluation of African-Americans with Rheumatoid Arthritis (CLEAR II), which recruited African-Americans with RA from six sites in the Southeastern United States. We used linear regression models to evaluate associations of parental homeownership status and educational level at participant time of birth with participant-reported fatigue (Visual Analog scale, cm), pain (Visual Analog scale, cm), disability (Health Assessment Questionnaire) and helplessness (Rheumatology Attitudes Index), independently of participant homeownership status and educational level. Models included random effects to account for intra-site correlations, and were adjusted for variables identified using backward selection, from: age, disease-duration, sex, medication use, body mass index, smoking history. RESULTS: Our sample included 516 CLEAR II participants with full data on demographics and covariates. 89% of participants were women, the mean age was 54.7 years and mean disease duration was 10.8 years. In age adjusted models, parental non-homeownership was associated with greater fatigue (beta = 0.75, 95% CI = 0.36-1.14), disability (beta = 0.12, 95% CI = 0.04 0.19) and helplessness (beta = 0.12, 95% CI = 0.03-0.21), independently of participant homeownership and education; parental education had a further small influence on self-reported fatigue (beta = 0.20, 95% CI = 0.15-0.24). CONCLUSIONS: Parental homeownership, and to a small extent parental education, had modest but meaningful relationships with self-reported health among CLEAR II participants. PMID- 26754748 TI - Anxious and Depressive Symptomatology Among Male Youth: The Joint and Interactive Contribution of Temperament and Executive Functioning. AB - Few studies have investigated the combined effects of temperament and executive functioning (EF) on anxious and depressive symptomatology in youth. The current study is the first to investigate the joint and interactive contribution of mother- and youth self-reported affective dimensions of temperament and EF to the explanation of anxious and depressive symptomatology. Participants included 174 adolescent males (M age = 13.6 +/- 1.35). Results confirmed the joint and interactive contribution of temperament in the explanation of anxious and depressive symptomatology. Further, EF contributed to the explanation of anxious/depressive symptomatology via interaction with youth-, but not mother reported, temperament; it was not a unique predictor. Results support the need to consider both affective dimensions of temperament and EF in etiological models of anxious and depressive symptomatology, which has implications for identifying at risk youth and developing early intervention and targeted problem-specific prevention programs. PMID- 26754749 TI - A combination of hydroxypropyl cellulose and trehalose as supplementation for vitrification of human oocytes: a retrospective cohort study. AB - PURPOSE: This study aimed to determine whether the new formulation of vitrification solutions containing a combination of hydroxypropyl cellulose (HPC) and trehalose does not affect outcomes in comparison with using conventional solutions made of serum substitute supplement (SSS) and sucrose. METHODS: Ovum donation cycles were retrospectively compared regarding the solution used for vitrification and warming of human oocytes. The analysis included 218 cycles (N = 2532 oocytes) in the study group (HPC + trehalose) and 214 cycles (N = 2353 oocytes) in the control group (SSS + sucrose). RESULTS: No statistical differences were found in ovarian stimulation parameters and baseline characteristics of donors and recipients. The survival rate was 91.3% (95% confidence interval (CI) = 89.8-92.9) in the HPC + trehalose group vs. 92.1% (95% CI = 90.4-93.7) in the SSS + sucrose group (NS). The implantation rate (42.8%, 95% CI = 37.7-47.9 vs. 41.2%, 95% CI = 36.0-46.4), clinical pregnancy rate (CPR) per transfer (60.7%, 95% CI = 53.9-67.5 vs. 56.4%, 95% CI = 49.3-63.5), and ongoing pregnancy rate (OPR) per transfer (48.5%, 95% CI = 41.5-55.5 vs. 46.3%, 95% CI = 39.2-53.4) were similar for patients who received either HPC + trehalose vitrified oocytes or SSS + sucrose-vitrified oocytes. Statistical differences were found when analyzing blastocyst rate both per injected oocyte (30.2%, 95% CI = 28.3-32.1 vs. 24.1%, 95% CI = 22.3-25.9) and per fertilized oocyte (40.8%, 95%CI = 38.5-43.1 vs. 33.2%, 95% CI = 30.8-35.5) (P < 0.0001). Delivery rate was comparable between groups (37.2%, 95% CI = 30.8-46.6 vs. 36.9%, 95% CI = 30.4 43.4; NS). CONCLUSIONS: Our data demonstrate that HPC and trehalose are suitable and safe substitutes for serum and sucrose. Therefore, the new commercial media can be used efficiently in the vitrification of human oocytes avoiding viral and endotoxin contamination risk. PMID- 26754750 TI - Intracytoplasmic morphologically selected sperm injection (IMSI) does not improve outcome in patients with two successive IVF-ICSI failures. AB - PURPOSE: Assessment of sperm morphology has been reconsidered since 2001 with the development of motile sperm organelle morphology examination (MSOME). This observation technique that combines high magnification microscopy and the Nomarski interference contrast makes it possible to select spermatozoa with as few vacuoles as possible before microinjection into the oocyte (intracytoplasmic morphologically selected sperm injection, IMSI). More than 10 years after the development of IMSI, the indications of the IMSI technique and its ability to increase pregnancy and/or birthrates (compared with conventional ICSI) are still subject to debate. We aimed to better define the interest of IMSI in the third attempt. METHODS: We assessed the benefit of IMSI by carrying out a retrospective comparative study between IMSI and conventional ICSI during a third ART attempt. Two hundred sixteen couples with two previous ICSI failures were studied between February 2010 and June 2014. RESULTS: IMSI did not significantly improve the clinical outcomes compared with ICSI, either for implantation (12 vs 10%), clinical pregnancy (23 vs 21%), or live birth rates (20 vs 19%). CONCLUSION: This study provides supplementary arguments for not achieving IMSI procedure in the third attempt after two previous ICSI failures. PMID- 26754751 TI - Coupling high-throughput genetics with phylogenetic information reveals an epistatic interaction on the influenza A virus M segment. AB - BACKGROUND: Epistasis is one of the central themes in viral evolution due to its importance in drug resistance, immune escape, and interspecies transmission. However, there is a lack of experimental approach to systematically probe for epistatic residues. RESULTS: By utilizing the information from natural occurring sequences and high-throughput genetics, this study established a novel strategy to identify epistatic residues. The rationale is that a substitution that is deleterious in one strain may be prevalent in nature due to the presence of a naturally occurring compensatory substitution. Here, high-throughput genetics was applied to influenza A virus M segment to systematically identify deleterious substitutions. Comparison with natural sequence variation showed that a deleterious substitution M1 Q214H was prevalent in circulating strains. A coevolution analysis was then performed and indicated that M1 residues 121, 207, 209, and 214 naturally coevolved as a group. Subsequently, we experimentally validated that M1 A209T was a compensatory substitution for M1 Q214H. CONCLUSIONS: This work provided a proof-of-concept to identify epistatic residues by coupling high-throughput genetics with phylogenetic information. In particular, we were able to identify an epistatic interaction between M1 substitutions A209T and Q214H. This analytic strategy can potentially be adapted to study any protein of interest, provided that the information on natural sequence variants is available. PMID- 26754753 TI - Escalation of therapy without evidence: a "may" does not imply a "should"! PMID- 26754755 TI - Is this critically ill patient going to survive? PMID- 26754752 TI - Continuous adductor canal block versus continuous femoral nerve block after total knee arthroplasty for mobilisation capability and pain treatment: a randomised and blinded clinical trial. AB - INTRODUCTION: Continuous femoral nerve blocks for total knee arthroplasty can cause motor weakness of the quadriceps muscle and thus prevent early mobilisation. Perioperative falls may result as an iatrogenic complication. In this randomised and blinded trial, we tested the hypothesis that a continuous adductor canal block is superior to continuous femoral nerve block regarding mobilisation ('timed up-and-go' test and other tests) after total knee arthroplasty under general anaesthesia. METHODS: In our study, we included patients scheduled for unilateral knee arthroplasty under general anaesthesia into a blinded and randomised trial. Patients were allocated to a continuous adductor canal block (CACB) or a continuous femoral nerve block (CFNB) for three postoperative days (POD 1-3); with a bolus of 15 ml ropivacaine 0.375%, followed by continuous infusion of ropivacaine 0.2% and patient-controlled bolus administration. Both groups received an additional continuous sciatic nerve block as well as a multimodal systemic analgesic treatment. The primary outcome parameter was mobilisation capability, assessed by 'timed up-and-go' (TUG) test. Analgesic quality, need for opioid rescue and local anaesthetic consumption were also assessed. RESULTS: Forty-two patients were included and analysed (21 patients per group). No significant difference was noted in respect to mobilisation at POD 3 (TUG [s]: CACB 45, CFNB 51). It is worth saying that pain scores (numeric rating scale, NRS) were similar in both groups at POD 3 {rest [median (interquartile range)]: CACB 0 (0-3), CFNB 1 (0-3); stress: CACB 4 (2-5), CFNB 3 (2-4)}. CONCLUSIONS: Concerning the mobilisation capability, we did not actually observe a superior effect of CACB compared with CFNB technique in our patients following total knee arthroplasty. Moreover, no difference was observed concerning analgesia quality. PMID- 26754756 TI - Ultrasound imaging of saline-filled endotracheal tube cuff for accurate repositioning of tube during percutaneous dilatational tracheostomy. PMID- 26754754 TI - Organ donation in adults: a critical care perspective. AB - PURPOSE: The shortage of organs for transplantation is an important medical and societal problem because transplantation is often the best therapeutic option for end-stage organ failure. METHODS: We review the potential deceased organ donation pathways in adult ICU practice, i.e. donation after brain death (DBD) and controlled donation after circulatory death (cDCD), which follows the planned withdrawal of life-sustaining treatments (WLST) and subsequent confirmation of death using cardiorespiratory criteria. RESULTS: Strategies in the ICU to increase the number of organs available for transplantation are discussed. These include timely identification of the potential organ donor, optimization of the brain-dead donor by aggressive management of the physiological consequence of brain death, implementation of cDCD protocols, and the potential for ex vivo perfusion techniques. CONCLUSIONS: Organ donation should be offered as a routine component of the end-of-life care plan of every patient dying in the ICU where appropriate, and intensivists are the key professional in this process. PMID- 26754757 TI - Does this patient have septic shock? PMID- 26754758 TI - SEPsis REcognition and MAnagement (SEPREMA survey). PMID- 26754759 TI - Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open labelled randomised controlled trial of continuous versus intermittent beta lactam infusion in critically ill patients with severe sepsis. AB - PURPOSE: This study aims to determine if continuous infusion (CI) is associated with better clinical and pharmacokinetic/pharmacodynamic (PK/PD) outcomes compared to intermittent bolus (IB) dosing in critically ill patients with severe sepsis. METHODS: This was a two-centre randomised controlled trial of CI versus IB dosing of beta-lactam antibiotics, which enrolled critically ill participants with severe sepsis who were not on renal replacement therapy (RRT). The primary outcome was clinical cure at 14 days after antibiotic cessation. Secondary outcomes were PK/PD target attainment, ICU-free days and ventilator-free days at day 28 post-randomisation, 14- and 30-day survival, and time to white cell count normalisation. RESULTS: A total of 140 participants were enrolled with 70 participants each allocated to CI and IB dosing. CI participants had higher clinical cure rates (56 versus 34 %, p = 0.011) and higher median ventilator-free days (22 versus 14 days, p < 0.043) than IB participants. PK/PD target attainment rates were higher in the CI arm at 100 % fT >MIC than the IB arm on day 1 (97 versus 70 %, p < 0.001) and day 3 (97 versus 68 %, p < 0.001) post-randomisation. There was no difference in 14-day or 30-day survival between the treatment arms. CONCLUSIONS: In critically ill patients with severe sepsis not receiving RRT, CI demonstrated higher clinical cure rates and had better PK/PD target attainment compared to IB dosing of beta-lactam antibiotics. Continuous beta-lactam infusion may be mostly advantageous for critically ill patients with high levels of illness severity and not receiving RRT. Malaysian National Medical Research Register ID: NMRR-12-1013-14017. PMID- 26754760 TI - Migration of phthalates on culture plates - an important challenge to consider for in vitro studies. AB - Phthalates are endocrine disruptors of the reproductive system and suspected to influence many other organ and hormone systems. They are also semi-volatile organic compounds present in the gas phase in the environment. Their mode of action has been investigated in numerous in vitro studies. Multi-well culture plates are typically used to study phthalates in cell cultures. In a pilot study, we observed evidence of phthalate migration in 24-well culture plates. As this has not previously been described, we investigated the phenomenon in more detail. Primary human thyroid epithelial cell cultures (n = 8 cultures) were exposed to either di-ethyl phthalate (DEP), di-n-butyl phthalate (DnBP), mono-n-butyl phthalate (MnBP) or di-(2-ethylhexyl) phthalate (DEHP). Measurement of phthalate metabolites by mass spectrometry demonstrated that the short-branched DEP was able to migrate to adjacent wells when added to cell culture plates. DnBP also seemed to be able to migrate, unlike the long-branched DEHP or the monoester MnBP which did not seem to have this ability. High background levels of phthalate metabolites were also observed, which might compromise results from low dose phthalate studies. In conclusion, the migration of phthalates which is probably caused by their volatile properties might lead to false interpretation of study results. PMID- 26754761 TI - The balance of the immune system between HLA-G and NK cells in unexplained recurrent spontaneous abortion and polymorphisms analysis. AB - Human leukocyte antigen (HLA)-G is involved in immunoregulatory processes and particularly in pathogenesis of inflammatory disorders such as recurrent spontaneous abortions (RSA). The purpose of the current study was to examine whether two single nucleotide polymorphisms (SNPs) of HLA-G gene (rs1736936 and HLA-G*0105N) influence susceptibility to recurrent spontaneous abortion. Genomic DNA from 117 RSA patients and 117 normal fertile control individuals was isolated using the salted out method. The two single nucleotide polymorphisms in HLA-G gene were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Differences between the two groups were analyzed by SPSS19 software using Chi-square test. The results revealed a significant increase in HLA-G*0105N allele in the proportion of whole group of RSA women compared with fertile controls (P value = 0.015), OR (95 % CI) = 2.054 (1.798 2.347), as well as an absence of homozygosity for HLA-G*0105N in the study population. No significant difference was observed between the RSA and the fertile groups in terms of alleles and genotypes frequency of rs1736936 (P value = 0.323), OR (95 CI %) = 1.056 (0.844-1.319). The presented data suggest that the investigated HLA-G*0105N allele is potentially associated with RSA through linkage disequilibrium with other genetic elements. Meanwhile, the rs1736936 SNP do not predispose to RSA in the study population. PMID- 26754762 TI - Corticotropin-releasing factor augments LPS-induced immune/inflammatory responses in JAWSII cells. AB - The effect of corticotropin-releasing factor (CRF) on gastrointestinal tract inflammation via modulation of the immune system cells such as dendritic cells (DCs) is not known. We investigated the expression of CRF and its receptors CRFR1 and CRFR2 in a colonic DC model (JAWSII cells) in a pro-inflammatory and anti inflammatory milieu. The mRNA expression of CRF and protein expression of CRFR1 and CRFR2 was assessed, and lipopolysaccharide (LPS) was used to induce the maturation of JAWSII cells. JAWSII cells were divided into four groups: control, CRF, LPS, and LPS + CRF. The levels of secreted cytokines IL-6, IL-4, TNF-alpha, and MIP-1alpha were determined, both in JAWSII cells and in the culture supernatant, by qRT-PCR and ELISA. The expression of CRFR1 and CRFR2 in JAWSII cells was accompanied by a low CRF expression. Compared with control group, CRF group did not affect the expression of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and MIP-1alpha, but LPS treatment significantly increased the expression of these cytokines, indicating maturation of JAWSII cells. CRF further augmented the production of IL-6, TNF-alpha, and MIP-1alpha in mature JAWSII cells, with no increase in TNF-alpha mRNA expression. However, the expression of anti-inflammatory factor IL-4 did not change after LPS treatment. CRF treatment decreased the expression of IL-4 in both mature and immature JAWSII cells. JAWSII cells produce low level of CRF and express CRFR1 and CRFR2 surface receptors. CRF promotes immune/inflammatory responses in mature JAWSII cells when induced by LPS treatment. PMID- 26754763 TI - Association of HLA-G +3142 C>G polymorphism and breast cancer in Tunisian population. AB - HLA-G is highly expressed in cancer. Also, it is associated to its progression. Here, we explored the relationship between two HLA-G polymorphisms with breast cancer (BC) and tried to make a correlation with sHLA-G levels. We genotyped 104 patients with BC and 83 controls (CTRL) for HLA-G 14-bp insertion/deletion (Ins/Del) and HLA-G +3142 C>G polymorphisms. The mutations were identified with PCR and PCR-RFLP. The sHLA-G dosage was performed on plasma samples by a specific ELISA. A significant association with BC was found concerning the G allele in the +3142 C>G polymorphism (p = 0.0004). The G/G genotype is the protective genotype (1 % in BC patients vs. 13.1 % in CTRL, OR 0.065, 95 % CI 0.008-0.523). No statistically significant differences were observed for the 14-bp Ins/Del polymorphism between BC patients and controls frequencies. The protection by G/G genotype of +3142 C>G polymorphism is maintained in young patients (<50 years, p = 0.0006) and in early-diagnosed BC patients (<50 years, p = 0.0033). In addition, an association was found between the haplotypes inferred by both HLA-G polymorphisms and BC susceptibility. Indeed, the (DelG) haplotype is found as the protective haplotype against BC (OR 0.269, 95 % CI 0.081-0.895, p = 0.023). The ELISA dosage of sHLA-G revealed increased levels in BC compared to CTRL (p < 0.0001). We demonstrated also that sHLA-G is closely associated with advanced stages of BC without significance. sHLA-G is increased in TNM IV and SBR III subgroups. It is also enhanced in patients with a tumor size over 20 mm and in triple-negative patients. Taken together, our findings demonstrate, for the first time, the association of HLA-G +3142 C>G polymorphism with BC susceptibility in Tunisian population. Our results revealed also a potential implication of sHLA-G in advanced stages of BC. PMID- 26754766 TI - Adverse health consequences of the Vietnam War. AB - The 40th anniversary of the end of the Vietnam War is a useful time to review the adverse health consequences of that war and to identify and address serious problems related to armed conflict, such as the protection of noncombatant civilians. More than 58,000 U.S. servicemembers died during the war and more than 150,000 were wounded. Many suffered from posttraumatic stress disorders and other mental disorders and from the long-term consequences of physical injuries. However, morbidity and mortality, although difficult to determine precisely, was substantially higher among the Vietnamese people, with at least two million of them dying during the course of the war. In addition, more than one million Vietnamese were forced to migrate during the war and its aftermath, including many "boat people" who died at sea during attempts to flee. Wars continue to kill and injure large numbers of noncombatant civilians and continue to damage the health-supporting infrastructure of society, expose civilians to toxic chemicals, forcibly displace many people, and divert resources away from services to benefit noncombatant civilians. Health professionals can play important roles in promoting the protection of noncombatant civilians during war and helping to prevent war and create a culture of peace. PMID- 26754768 TI - Automatic Detection of Pearlite Spheroidization Grade of Steel Using Optical Metallography. AB - To eliminate the effect of subjective factors during manually determining the pearlite spheroidization grade of steel by analysis of optical metallography images, a novel method combining image mining and artificial neural networks (ANN) is proposed. The four co-occurrence matrices of angular second moment, contrast, correlation, and entropy are adopted to objectively characterize the images. ANN is employed to establish a mathematical model between the four co occurrence matrices and the corresponding spheroidization grade. Three materials used in coal-fired power plants (ASTM A315-B steel, ASTM A335-P12 steel, and ASTM A355-P11 steel) were selected as the samples to test the validity of our proposed method. The results indicate that the accuracies of the calculated spheroidization grades reach 99.05, 95.46, and 93.63%, respectively. Hence, our newly proposed method is adequate for automatically detecting the pearlite spheroidization grade of steel using optical metallography. PMID- 26754765 TI - The immunosuppressive domain of the transmembrane envelope protein gp41 of HIV-1 binds to human monocytes and B cells. AB - The induction of the acquired immunodeficiency syndrome by the human immunodeficiency virus-1 (HIV-1) is a complex process which is not yet understood in full detail. Still open is the question whether the highly conserved so-called immunosuppressive (Isu) domain in the transmembrane envelope (TM) protein gp41 of HIV-1 is actively participating in immunopathogenesis. Inactivated virus particles, recombinant gp41 and peptides corresponding to the Isu domain have been reported to inhibit lymphocyte proliferation, as well as to alter cytokine release and gene expression. Here we demonstrate, using fluorescence-activated cell sorting and competition experiments, that homopolymers of the Isu peptide of HIV-1 are binding specifically to human peripheral blood mononuclear cells, mainly to monocytes and B cells. These data suggest that a putative receptor might be involved in the immunomodulatory effects observed previously. PMID- 26754769 TI - Erratum to: Effectiveness of intra-articular injections of sodium hyaluronate chondroitin sulfate in knee osteoarthritis: a multicenter prospective study. PMID- 26754764 TI - The role of complement system in adipose tissue-related inflammation. AB - As the common factor linking adipose tissue to the metabolic context of obesity, insulin resistance and atherosclerosis are associated with a low-grade chronic inflammatory status, to which the complement system is an important contributor. Adipose tissue synthesizes complement proteins and is a target of complement activation. C3a-desArg/acylation-stimulating protein stimulates lipogenesis and affects lipid metabolism. The C3a receptor and C5aR are involved in the development of adipocytes' insulin resistance through macrophage infiltration and the activation of adipose tissue. The terminal complement pathway has been found to be instrumental in promoting hyperglycemia-associated tissue damage, which is characteristic of the major vascular complications of diabetes mellitus and diabetic ketoacidosis. As a mediator of the effects of the terminal complement complex C5b-9, RGC-32 has an impact on energy expenditure as well as lipid and glucose metabolic homeostasis. All of this evidence, taken together, indicates an important role for complement activation in metabolic diseases. PMID- 26754772 TI - Effects of Alkylthio and Alkoxy Side Chains in Polymer Donor Materials for Organic Solar Cells. AB - Side chains play a considerable role not only in improving the solubility of polymers for solution-processed device fabrication, but also in affecting the molecular packing, electron affinity and thus the device performance. In particular, electron-donating side chains show unique properties when employed to tune the electronic character of conjugated polymers in many cases. Therefore, rational electron-donating side chain engineering can improve the photovoltaic properties of the resulting polymer donors to some extent. Here, a survey of some representative examples which use electron-donating alkylthio and alkoxy side chains in conjugated organic polymers for polymer solar cell applications will be presented. It is envisioned that an analysis of the effect of such electron donating side chains in polymer donors would contribute to a better understanding of this kind of side chain behavior in solution-processed conjugated organic polymers for polymer solar cells. PMID- 26754774 TI - A model for the compositions of non-stoichiometric intermediate phases formed by diffusion reactions, and its application to Nb3Sn superconductors. AB - In this work we explore the compositions of non-stoichiometric intermediate phases formed by diffusion reactions: a mathematical framework is developed and tested against the specific case of Nb3Sn superconductors. In the first part, the governing equations for the bulk diffusion and inter-phase interface reactions during the growth of a compound are derived, numerical solutions to which give both the composition profile and growth rate of the compound layer. The analytic solutions are obtained with certain approximations made. In the second part, we explain an effect that the composition characteristics of compounds can be quite different depending on whether it is the bulk diffusion or grain boundary diffusion that dominates in the compounds, and that "frozen" bulk diffusion leads to unique composition characteristics that the bulk composition of a compound layer remains unchanged after its initial formation instead of varying with the diffusion reaction system; here the model is modified for the case of grain boundary diffusion. Finally, we apply this model to the Nb3Sn superconductors and propose approaches to control their compositions. PMID- 26754770 TI - Blue light-induced LOV domain dimerization enhances the affinity of Aureochrome 1a for its target DNA sequence. AB - The design of synthetic optogenetic tools that allow precise spatiotemporal control of biological processes previously inaccessible to optogenetic control has developed rapidly over the last years. Rational design of such tools requires detailed knowledge of allosteric light signaling in natural photoreceptors. To understand allosteric communication between sensor and effector domains, characterization of all relevant signaling states is required. Here, we describe the mechanism of light-dependent DNA binding of the light-oxygen-voltage (LOV) transcription factor Aureochrome 1a from Phaeodactylum tricornutum (PtAu1a) and present crystal structures of a dark state LOV monomer and a fully light-adapted LOV dimer. In combination with hydrogen/deuterium-exchange, solution scattering data and DNA-binding experiments, our studies reveal a light-sensitive interaction between the LOV and basic region leucine zipper DNA-binding domain that together with LOV dimerization results in modulation of the DNA affinity of PtAu1a. We discuss the implications of these results for the design of synthetic LOV-based photosensors with application in optogenetics. PMID- 26754773 TI - Prevalence of depressive symptoms and its correlations with positive psychological variables among Chinese medical students: an exploratory cross sectional study. AB - BACKGROUND: Knowledge about the prevalence of depressive symptoms among Chinese medical students and its related factors is rather limited. Understanding the correlates of depressive symptoms and the roles that positive psychological variables play in depressive symptoms is of vital importance for future interventions. The main objectives of this study were to investigate the prevalence of depressive symptoms and the integrated effects of resilience, hope and optimism on depressive symptoms among Chinese medical students. METHODS: This multi-center cross-sectional study was conducted in June 2014. The questionnaires that consisted of the Center for Epidemiologic Studies Depression Scale (CES-D), Wagnild and Young Resilience Scale-14 (RS-14), Adult Dispositional Hope Scale (ADHS), Life Orientation Test-Revised (LOT-R), and socio-demographic characteristics, were distributed to students at four medical colleges or universities in Liaoning province, China. A total of 2925 medical students became the final subjects. Hierarchical linear regression analyses were used to explore the integrated effects of resilience, hope and optimism on depressive symptoms. RESULTS: The prevalence of depressive symptoms among Chinese medical students was 66.8 % (CES-D >= 16). Resilience, hope and optimism were all negatively correlated with depressive symptoms and they accounted for 26.1 % of the variance in depressive symptoms. CONCLUSIONS: The high prevalence of depressive symptoms among Chinese medical students calls for special attention from all stakeholders, especially university authorities. Intervention strategies that focus on enhancing the positive psychological variables of resilience, hope and optimism can be integrated into depression prevention and treatment programs. PMID- 26754775 TI - Impact of Skin Toxicities Associated with Targeted Cancer Therapies on Body Image: A Prospective Study. AB - BACKGROUND AND OBJECTIVE: Body-image issues associated with dermatological side effects induced by anticancer-targeted therapies have not been specifically explored until now despite growing literature about their impact on quality of life. Prospective and longitudinal investigations were needed. The aim of our study was to describe body-image changes occurring with cutaneous toxicities and their psychosocial impact on patients. PATIENTS AND METHODS: Thirty-three patients were evaluated four times during the first 3 months of targeted therapy in terms of body satisfaction, physical attitudes and depression with validated and ad hoc questionnaires. The NCI-CTCAE V4.0 was used to grade adverse dermatological events. Descriptive and inferential analyses were conducted with SPSS 14.0 software. RESULTS: Ninety-four per cent of the patients developed skin toxicities. Body satisfaction remained stable and slightly better than average over this period. About one-third of the patients reported body-image issues at baseline. Body satisfaction and depression levels at baseline appeared to be significantly associated with body-image issues after 3 months of therapy. CONCLUSION: In the framework of regular dermatological monitoring, skin toxicities did not appear to be associated with body-image issues. Body satisfaction and depressive symptoms at the beginning of targeted therapy emerged as critical factors that practitioners should consider in order to prevent deterioration of body image that could impact on quality of life and compromise compliance. PMID- 26754776 TI - Investigations into Improving Dewaterability at a Bio-P/Anaerobic Digestion Plant. AB - Metropolitan Council Environmental Services has observed poorer than expected dewatering performance at its Empire Plant. This plant has both anaerobic digestion and enhanced biological phosphorus removal in its treatment train. A research program using pilot-scale anaerobic digesters investigated potential solutions to the plant's poor dewaterability. The dewaterability goal was to increase the cake solids from 12% total solids (TS) to 16% TS or higher. This research investigated 20 different reactor conditions including chemical, feed sludge, and digested sludge treatments. At the pilot scale, unaerated storage of waste activated sludge prior to thickening and addition of ferric chloride to digestion was found to achieve dewatered cake solids of nearly 17% TS with the added benefit of reducing polymer demand. Issues including the amount of chemical required and the resulting volatile solids destruction influence the viability of the process change, so a full-scale pilot and financial analysis is recommended before making permanent process changes. PMID- 26754771 TI - Identification of p62/SQSTM1 as a component of non-canonical Wnt VANGL2-JNK signalling in breast cancer. AB - The non-canonical Wnt/planar cell polarity (Wnt/PCP) pathway plays a crucial role in embryonic development. Recent work has linked defects of this pathway to breast cancer aggressiveness and proposed Wnt/PCP signalling as a therapeutic target. Here we show that the archetypal Wnt/PCP protein VANGL2 is overexpressed in basal breast cancers, associated with poor prognosis and implicated in tumour growth. We identify the scaffold p62/SQSTM1 protein as a novel VANGL2-binding partner and show its key role in an evolutionarily conserved VANGL2-p62/SQSTM1 JNK pathway. This proliferative signalling cascade is upregulated in breast cancer patients with shorter survival and can be inactivated in patient-derived xenograft cells by inhibition of the JNK pathway or by disruption of the VANGL2 p62/SQSTM1 interaction. VANGL2-JNK signalling is thus a potential target for breast cancer therapy. PMID- 26754777 TI - The Diagnosis and Treatment of Autoimmune Encephalitis. AB - Autoimmune encephalitis causes subacute deficits of memory and cognition, often followed by suppressed level of consciousness or coma. A careful history and examination may show early clues to particular autoimmune causes, such as neuromyotonia, hyperekplexia, psychosis, dystonia, or the presence of particular tumors. Ancillary testing with MRI and EEG may be helpful for excluding other causes, managing seizures, and, rarely, for identifying characteristic findings. Appropriate autoantibody testing can confirm specific diagnoses, although this is often done in parallel with exclusion of infectious and other causes. Autoimmune encephalitis may be divided into several groups of diseases: those with pathogenic antibodies to cell surface proteins, those with antibodies to intracellular synaptic proteins, T-cell diseases associated with antibodies to intracellular antigens, and those associated with other autoimmune disorders. Many forms of autoimmune encephalitis are paraneoplastic, and each of these conveys a distinct risk profile for various tumors. Tumor screening and, if necessary, treatment is essential to proper management. Most forms of autoimmune encephalitis respond to immune therapies, although powerful immune suppression for weeks or months may be needed in difficult cases. Autoimmune encephalitis may relapse, so follow-up care is important. PMID- 26754779 TI - A Retrospective 10-Year, Single-Institution Study of Carotid Endarterectomy with a Focus on Elderly Patients. AB - BACKGROUND AND PURPOSE: This study evaluated the outcome following surgery for carotid artery stenosis in a single institution during a 10-year period and the relevance of aging to access to surgery. METHODS: Between January 2001 and December 2010, 649 carotid endarterectomies (CEAs) were performed in 596 patients for internal carotid artery occlusive disease at our institution; 596 patients received unilateral CEAs and 53 patients received bilateral CEAs. Data regarding patient characteristics, comorbidities, stroke, mortality, restenosis, and other surgical complications were obtained from a review of medical records. Since elderly and high-risk patients comprise a significant proportion of the patient group undergoing CEAs, differences in comorbidity and mortality were evaluated according to age when the patients were divided into three age groups: <70 years, 70-79 years, and >=80 years. RESULTS: The mean age of the included patients was 67.5 years, and 88% were men. Symptomatic carotid stenosis was observed in 65.7% of patients. The rate of perioperative stroke and death (within 30 days of the procedure) was 1.84%. The overall mortality rate was higher among patients in the 70-79 years and >80 years age groups than among those in the <70 years age group, but there was no significant difference in stroke-related mortality among these three groups. CONCLUSIONS: CEA over a 10-year period has yielded acceptable outcomes in terms of stroke and mortality. Therefore, since CEA is a safe and effective strategy, it can be performed in elderly patients with acceptable life expectancy. PMID- 26754778 TI - Acute Symptomatic Seizures Caused by Electrolyte Disturbances. AB - In this narrative review we focus on acute symptomatic seizures occurring in subjects with electrolyte disturbances. Quite surprisingly, despite its clinical relevance, this issue has received very little attention in the scientific literature. Electrolyte abnormalities are commonly encountered in clinical daily practice, and their diagnosis relies on routine laboratory findings. Acute and severe electrolyte imbalances can manifest with seizures, which may be the sole presenting symptom. Seizures are more frequently observed in patients with sodium disorders (especially hyponatremia), hypocalcemia, and hypomagnesemia. They do not entail a diagnosis of epilepsy, but are classified as acute symptomatic seizures. EEG has little specificity in differentiating between various electrolyte disturbances. The prominent EEG feature is slowing of the normal background activity, although other EEG findings, including various epileptiform abnormalities may occur. An accurate and prompt diagnosis should be established for a successful management of seizures, as rapid identification and correction of the underlying electrolyte disturbance (rather than an antiepileptic treatment) are of crucial importance in the control of seizures and prevention of permanent brain damage. PMID- 26754780 TI - Bilaterally Abnormal Head Impulse Tests Indicate a Large Cerebellopontine Angle Tumor. AB - BACKGROUND AND PURPOSE: Tumors involving the cerebellopontine angle (CPA) pose a diagnostic challenge due to their diverse manifestations. Head impulse tests (HITs) have been used to evaluate vestibular function, but few studies have explored the head impulse gain of the vestibulo-ocular reflex (VOR) in patients with a vestibular schwannoma. This study tested whether the head impulse gain of the VOR is an indicator of the size of a unilateral CPA tumor. METHODS: Twenty eight patients (21 women; age=64+/-12 years, mean+/-SD) with a unilateral CPA tumor underwent a recording of the HITs using a magnetic search coil technique. Patients were classified into non-compressing (T1-T3) and compressing (T4) groups according to the Hannover classification. RESULTS: Most (23/28, 82%) of the patients showed abnormal HITs for the semicircular canals on the lesion side. The bilateral abnormality in HITs was more common in the compressing group than the non-compressing group (80% vs. 8%, Pearson's chi-square test: p<0.001). The tumor size was inversely correlated with the head impulse gain of the VOR in either direction. CONCLUSIONS: Bilaterally abnormal HITs indicate that a patient has a large unilateral CPA tumor. The abnormal HITs in the contralesional direction may be explained either by adaptation or by compression and resultant dysfunction of the cerebellar and brainstem structures. The serial evaluation of HITs may provide information on tumor growth, and thereby reduce the number of costly brain scans required when following up patients with CPA tumors. PMID- 26754781 TI - Epilepsy and Other Neuropsychiatric Manifestations in Children and Adolescents with 22q11.2 Deletion Syndrome. AB - BACKGROUND AND PURPOSE: 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome. Epilepsy and other neuropsychiatric (NP) manifestations of this genetic syndrome are not uncommon, but they are also not well-understood. We sought to identify the characteristics of epilepsy and other associated NP manifestations in patients with 22q11.2DS. METHODS: We retrospectively analyzed the medical records of 145 child and adolescent patients (72 males and 73 females) with genetically diagnosed 22q11.2DS. The clinical data included seizures, growth chart, psychological reports, development characteristics, school performance, other clinical manifestations, and laboratory findings. RESULTS: Of the 145 patients with 22q11.2DS, 22 (15.2%) had epileptic seizures, 15 (10.3%) had developmental delay, and 5 (3.4%) had a psychiatric illness. Twelve patients with epilepsy were classified as genetic epilepsy whereas the remaining were classified as structural, including three with malformations of cortical development. Patients with epilepsy were more likely to display developmental delay (odds ratio=3.98; 95% confidence interval=1.5-10.5; p=0.005), and developmental delay was more common in patients with structural epilepsy than in those with genetic epilepsy. CONCLUSIONS: Patients with 22q11.2DS have a high risk of epilepsy, which in these cases is closely related to other NP manifestations. This implies that this specific genetic locus is critically linked to neurodevelopment and epileptogenesis. PMID- 26754782 TI - Common Neurological Disorders Involving Inpatient Liaisons at a Secondary Referral Hospital in Taiwan: A Retrospective Cross-Sectional Study. AB - BACKGROUND AND PURPOSE: The requirement for neurology liaison is increasing in accordance with the growing health care demands associated with aging populations. The aim of this study was to characterize the nature of neurological inpatient liaisons (NILs) to help plan for the appropriate use of neurology resources. METHODS: This was a retrospective cross-sectional study of NILs in a secondary referral hospital over a 12-month period. RESULTS: There were 853 neurological consultations with a liaison rate of 3% per admission case. Chest medicine, gastroenterology, and infectious disease were the three most frequent specialties requesting liaison, and altered consciousness, seizure, and stroke were the three most frequent disorders for which a NIL was requested. Infection was the most common cause of altered consciousness. Epilepsy, infection, and previous stroke were common causes of seizure disorders. Acute stroke accounted for 44% of all stroke disorders. Electroencephalography was the most recommended study, and was also the most frequently performed. Ninety-five percent of emergency consultations were completed within 2 hours, and 85% of regular consultations were completed within 24 hours. The consult-to-visit times for emergency and regular consultations were 44+/-47 minutes (mean+/-standard deviation) and 730+/-768 minutes, respectively, and were shorter for regular consultations at intensive care units (p=0.0151) and for seizure and stroke disorders (p=0.0032). CONCLUSIONS: Altered consciousness, seizure, and stroke were the most common reasons for NILs. Half of the patients had acute neurological diseases warranting immediate diagnosis and treatment by the consulting neurologists. Balancing increasing neurologist workloads and appropriate health-care resources remains a challenge. PMID- 26754784 TI - Aplasia of the Internal Carotid Artery with Dandy-Walker Variant. PMID- 26754785 TI - Molecular Characterization of a Copper Metallothionein Gene From a Ciliate Tetrahymena farahensis. AB - A new copper metallothionein (TfCuMT) gene has been identified from a locally isolated ciliate Tetrahymena farahensis. It contains 327 nucleotides encoding a peptide chain of 108 amino acids and belongs to class MTT2 and subfamily 7b. Amplification from both gDNA and mRNA confirmed the intronless nature of this gene. Like most of the metallohtioneins, cysteine residues contribute nearly 30% content with the specific CKC motifs. Structural repeats present in peptide sequence of TfCuMT indicate internal duplication of gene at some stage of gene evolution. The predicted model of copper metallothionein protein showed that copper ions are mainly chelated by thiol sulfur of cysteine residues and are embedded in the folds of polypeptide chain. For in vivo expression of TfCuMT in Escherichia coli host cells the classical stop codons, which coded for glutamine in the ciliate were mutated to CAA and CAG through site directed mutagenesis. The mutated gene showed higher expression in pET28a expression vector compared with pET21a. Optimum expression was obtained after 6-8 h of 0.1 mM IPTG induction. Stability of His tagged TfCuMT in 5% SDS was low, with half-life of about 104 min. Presence of 1.0 MUM copper increased the expression level by 1.65-fold. Presence of 100 MUM Cysteine in culture medium caused 2.4-fold increase in expression level. His tagged TfCuMT was purified through affinity chromatography using NTN-His binding resin in the presence of 0.1 M imidazole and NaCl. The modeled structure of the TfCuMT showed a cleft for Cu binding with correct orientation of Cys residues in the motif CKC. J. Cell. Biochem. 117: 1843-1854, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26754783 TI - Spontaneous Low-Frequency Cerebral Hemodynamics Oscillations in Restless Legs Syndrome with Periodic Limb Movements During Sleep: A Near-Infrared Spectroscopy Study. AB - BACKGROUND AND PURPOSE: Periodic limb movements (PLM) during sleep (PLMS) are associated with cortical and cardiovascular activation. Changes in cerebral hemodynamics caused by cortical activity can be measured using near-infrared spectroscopy (NIRS). We investigated oscillatory components of cerebral hemodynamics during PLM and different sleep stages in restless legs syndrome (RLS) patients with PLMS. METHODS: Four female RLS patients with PLMS, and four age- and sex-matched normal controls were included. PLM and sleep stages were scored using polysomnography, while the spontaneous cerebral hemodynamics was measured by NIRS. The phase and amplitude of the cerebral oxyhemoglobin concentration [HbO] and the deoxyhemoglobin concentration [Hb] low-frequency oscillations (LFOs) were evaluated during each sleep stage [waking, light sleep (LS; stages N1 and N2), slow-wave sleep (stage N3), and rapid eye movement (REM) sleep]. In RLS patients with PLMS, the cerebral hemodynamics during LS was divided into LS with and without PLM. RESULTS: The cerebral hemodynamics activity varied among the different sleep stages. There were changes in phase differences between [HbO] and [Hb] LFOs during the different sleep stages in the normal controls but not in the RLS patients with PLMS. The [HbO] and [Hb] LFO amplitudes were higher in the patient group than in controls during both LS with PLM and REM sleep. CONCLUSIONS: The present study has demonstrated the presence of cerebral hemodynamics disturbances in RLS patients with PLMS, which may contribute to an increased risk of cerebrovascular events. PMID- 26754786 TI - Direct Observation of Self-Organized Water-Containing Structures in the Liquid Phase and Their Influence on 5-(Hydroxymethyl)furfural Formation in Ionic Liquids. AB - Water-containing organic solutions are widespread reaction media in organic synthesis and catalysis. This type of multicomponent liquid system has a number of unique properties because of the tendency for water to self-organize in mixtures with other liquids. The characterization of these water domains is a challenging task because of their soft and dynamic nature. In the present study, the morphology and dynamics of micrometer- and nanometer-scale water-containing compartments in ionic liquids were directly observed by electron microscopy. A variety of morphologies, including isolated droplets, dense structures, aggregates, and 2D meshworks, have been experimentally detected and studied. Using the developed method, the impact of water on the acid-catalyzed biomass conversion reaction was studied at the microscopic level. The process that produced nanostructured domains in solution led to better yields and higher selectivities compared with reactions involving the bulk system. PMID- 26754788 TI - Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level. AB - Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient's environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant model of experimental induced pneumonia to investigate whether the systemic SCI-IDS is functional sufficient to cause pneumonia dependent on spinal cord injury lesion level and investigated whether findings are mirrored in a large prospective cohort study after human spinal cord injury. In a mouse model of inducible pneumonia, high thoracic lesions that interrupt sympathetic innervation to major immune organs, but not low thoracic lesions, significantly increased bacterial load in lungs. The ability to clear the bacterial load from the lung remained preserved in sham animals. Propagated immune susceptibility depended on injury of central pre ganglionic but not peripheral postganglionic sympathetic innervation to the spleen. Thoracic spinal cord injury level was confirmed as an independent increased risk factor of pneumonia in patients after motor complete spinal cord injury (odds ratio = 1.35, P < 0.001) independently from mechanical ventilation and preserved sensory function by multiple regression analysis. We present evidence that spinal cord injury directly causes increased risk for bacterial infection in mice as well as in patients. Besides obvious motor and sensory paralysis, spinal cord injury also induces a functional SCI-IDS ('immune paralysis'), sufficient to propagate clinically relevant infection in an injury level dependent manner. PMID- 26754787 TI - Memory network plasticity after temporal lobe resection: a longitudinal functional imaging study. AB - Anterior temporal lobe resection can control seizures in up to 80% of patients with temporal lobe epilepsy. Memory decrements are the main neurocognitive complication. Preoperative functional reorganization has been described in memory networks, but less is known of postoperative reorganization. We investigated reorganization of memory-encoding networks preoperatively and 3 and 12 months after surgery. We studied 36 patients with unilateral medial temporal lobe epilepsy (19 right) before and 3 and 12 months after anterior temporal lobe resection. Fifteen healthy control subjects were studied at three equivalent time points. All subjects had neuropsychological testing at each of the three time points. A functional magnetic resonance imaging memory-encoding paradigm of words and faces was performed with subsequent out-of-scanner recognition assessments. Changes in activations across the time points in each patient group were compared to changes in the control group in a single flexible factorial analysis. Postoperative change in memory across the time points was correlated with postoperative activations to investigate the efficiency of reorganized networks. Left temporal lobe epilepsy patients showed increased right anterior hippocampal and frontal activation at both 3 and 12 months after surgery relative to preoperatively, for word and face encoding, with a concomitant reduction in left frontal activation 12 months postoperatively. Right anterior hippocampal activation 12 months postoperatively correlated significantly with improved verbal learning in patients with left temporal lobe epilepsy from preoperatively to 12 months postoperatively. Preoperatively, there was significant left posterior hippocampal activation that was sustained 3 months postoperatively at word encoding, and increased at face encoding. For both word and face encoding this was significantly reduced from 3 to 12 months postoperatively. Patients with right temporal lobe epilepsy showed increased left anterior hippocampal activation on word encoding from 3 to 12 months postoperatively compared to preoperatively. On face encoding, left anterior hippocampal activations were present preoperatively and 12 months postoperatively. Left anterior hippocampal and orbitofrontal cortex activations correlated with improvements in both design and verbal learning 12 months postoperatively. On face encoding, there were significantly increased left posterior hippocampal activations that reduced significantly from 3 to 12 months postoperatively. Postoperative changes occur in the memory-encoding network in both left and right temporal lobe epilepsy patients across both verbal and visual domains. Three months after surgery, compensatory posterior hippocampal reorganization that occurs is transient and inefficient. Engagement of the contralateral hippocampus 12 months after surgery represented efficient reorganization in both patient groups, suggesting that the contralateral hippocampus contributes to memory outcome 12 months after surgery. PMID- 26754789 TI - Nanoscale mapping of plasmon and exciton in ZnO tetrapods coupled with Au nanoparticles. AB - Metallic nanoparticles can be used to enhance optical absorption or emission in semiconductors, thanks to a strong interaction of collective excitations of free charges (plasmons) with electromagnetic fields. Herein we present direct imaging at the nanoscale of plasmon-exciton coupling in Au/ZnO nanostructures by combining scanning transmission electron energy loss and cathodoluminescence spectroscopy and mapping. The Au nanoparticles (~30 nm in diameter) are grown in situ on ZnO nanotetrapods by means of a photochemical process without the need of binding agents or capping molecules, resulting in clean interfaces. Interestingly, the Au plasmon resonance is localized at the Au/vacuum interface, rather than presenting an isotropic distribution around the nanoparticle. On the contrary, a localization of the ZnO signal has been observed inside the Au nanoparticle, as also confirmed by numerical simulations. PMID- 26754792 TI - Establishment of TBS reference plots and correlation between TBS and BMD in healthy mainland Chinese women. AB - The trabecular bone score (TBS) was obtained from the gray levels of a dual X-ray absorptiometry (DXA) image to evaluate bone microarchitecture. Here, we established the reference plots of TBS in healthy Chinese women of Nanjing area. The TBS references are similar with French and US Caucasian women but higher than Japanese women. PURPOSE: The aim of the study was to establish the reference plots of the TBS in healthy Chinese women of the Nanjing area. METHODS: A total of 537 healthy Chinese women of the Nanjing area were recruited, and the study was approved by the Ethics Committee of the First Affiliated Hospital with Nanjing Medical University. The TBS of the lumbar spine and the bone mineral density (BMD) of the lumbar spine and femur were measured using dual X-ray absorptiometry. The mean +/- standard deviation (SD) of the TBS in women with different age groups was calculated. The correlation of TBS and age and BMD was calculated using regression analysis. RESULTS: The reference plots of the TBS were established in healthy Chinese women of the Nanjing area between the ages of 20 and 89 years. The average TBS for total subjects was 1.32 +/- 0.11 and reached the peak at the age of 20-29 years and then decreased with age thereafter. The determinant coefficient between TBS and age was 0.5065 while between TBS and BMD was 0.5191. After adjusting for lumbar total BMD, the TBS significantly correlated with age in whole subjects and only in the subgroup of ages 50-59 years. CONCLUSIONS: This study suggested that TBS decreased with age and correlated positively with BMD. The TBS reference of Chinese women is similar with those of French and US Caucasian women but higher than that of Japanese women. Furthermore, the TBS may be more significantly applied in women in menopause for less than 10 years. PMID- 26754790 TI - Site-Specifically Labeled Immunoconjugates for Molecular Imaging--Part 1: Cysteine Residues and Glycans. AB - Due to their remarkable selectivity and specificity for cancer biomarkers, immunoconjugates have emerged as extremely promising vectors for the delivery of diagnostic radioisotopes and fluorophores to malignant tissues. Paradoxically, however, these tools for precision medicine are synthesized in a remarkably imprecise way. Indeed, the vast majority of immunoconjugates are created via the random conjugation of bifunctional probes (e.g., DOTA-NCS) to amino acids within the antibody (e.g., lysines). Yet antibodies have multiple copies of these residues throughout their macromolecular structure, making control over the location of the conjugation reaction impossible. This lack of site specificity can lead to the formation of poorly defined, heterogeneous immunoconjugates with suboptimal in vivo behavior. Over the past decade, interest in the synthesis and development of site-specifically labeled immunoconjugates--both antibody-drug conjugates as well as constructs for in vivo imaging--has increased dramatically, and a number of reports have suggested that these better defined, more homogeneous constructs exhibit improved performance in vivo compared to their randomly modified cousins. In this two-part review, we seek to provide an overview of the various methods that have been developed to create site specifically modified immunoconjugates for positron emission tomography, single photon emission computed tomography, and fluorescence imaging. We will begin with an introduction to the structure of antibodies and antibody fragments. This is followed by the core of the work: sections detailing the four different approaches to site-specific modification strategies based on cysteine residues, glycans, peptide tags, and unnatural amino acids. These discussions will be divided into two installments: cysteine residues and glycans will be detailed in Part 1 of the review, while peptide tags and unnatural amino acids will be addressed in Part 2. Ultimately, we sincerely hope that this review fosters interest and enthusiasm for site-specific immunoconjugates within the nuclear medicine and molecular imaging communities. PMID- 26754793 TI - Functional conservation of rice OsNF-YB/YC and Arabidopsis AtNF-YB/YC proteins in the regulation of flowering time. AB - KEY MESSAGE: Rice Os NF - YB and Os NF - YC complement the late flowering phenotype of Arabidopsis nf - yb double and nf - yc triple mutants, respectively. In addition, OsNF-YB and OsNF-YC interact with AtNF-YC and AtNF-YB, respectively. Plant NUCLEAR FACTOR Y (NF-Y) transcription factors play important roles in plant development and abiotic stress. In Arabidopsis thaliana, two NF-YB (AtNF-YB2 and AtNF-YB3) and five NF-YC (AtNF-YC1, AtNF-YC2, AtNF-YC3, AtNF-YC4, and AtNF-YC9) genes regulate photoperiodic flowering by interacting with other AtNF-Y subunit proteins. Three rice NF-YB (OsNF-YB8, OsNF-YB10, and OsNF-YB11) and five rice OsNF-YC (OsNF-YC1, OsNF-YC2, OsNF-YC4, OsNF-YC6, and OsNF-YC7) genes are clustered with two AtNF-YB and five AtNF-YC genes, respectively. To investigate the functional conservation of these NF-YB and NF-YC genes in rice and Arabidopsis, we analyzed the flowering phenotypes of transgenic plants overexpressing the respective OsNF-YB and OsNF-YC genes in Arabidopsis mutants. Overexpression of OsNF-YB8/10/11 and OsNF-YC2 complemented the late flowering phenotype of Arabidopsis nf-yb2 nf-yb3 and nf-yc3 nf-yc4 nf-yc9 mutants, respectively. The rescued phenotype of 35S::OsNF-YC2 nf-yc3 nf-yc4 nf-yc9 plants was attributed to the upregulation of FLOWERING LOCUS T (FT) and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1). In vitro and in planta protein-protein analyses revealed that OsNF-YB8/10/11 and OsNF-YC1/2/4/6/7 interact with AtNF YC3/4/9 and AtNF-YB2/3, respectively. Our data indicate that some OsNF-YB and OsNF-YC genes are functional equivalents of AtNF-YB2/3 and AtNF-YC3/4/9 genes, respectively, and suggest functional conservation of Arabidopsis and rice NF-Y genes in the control of flowering time. PMID- 26754791 TI - Site-Specifically Labeled Immunoconjugates for Molecular Imaging--Part 2: Peptide Tags and Unnatural Amino Acids. AB - Molecular imaging using radioisotope- or fluorophore-labeled antibodies is increasingly becoming a critical component of modern precision medicine. Yet despite this promise, the vast majority of these immunoconjugates are synthesized via the random coupling of amine-reactive bifunctional probes to lysines within the antibody, a process that can result in heterogeneous and poorly defined constructs with suboptimal pharmacological properties. In an effort to circumvent these issues, the last 5 years have played witness to a great deal of research focused on the creation of effective strategies for the site-specific attachment of payloads to antibodies. These chemoselective modification methods yield immunoconjugates that are more homogenous and better defined than constructs created using traditional synthetic approaches. Moreover, site-specifically labeled immunoconjugates have also been shown to exhibit superior in vivo behavior compared to their randomly modified cousins. The over-arching goal of this two-part review is to provide a broad yet detailed account of the various site-specific bioconjugation approaches that have been used to create immunoconjugates for positron emission tomography (PET), single photon emission computed tomography (SPECT), and fluorescence imaging. In Part 1, we covered site specific bioconjugation techniques based on the modification of cysteine residues and the chemoenzymatic manipulation of glycans. In Part 2, we will detail two families of bioconjugation approaches that leverage biochemical tools to achieve site-specificity. First, we will discuss modification methods that employ peptide tags either as sites for enzyme-catalyzed ligations or as radiometal coordination architectures. And second, we will examine bioconjugation strategies predicated on the incorporation of unnatural or non-canonical amino acids into antibodies via genetic engineering. Finally, we will compare the advantages and disadvantages of the modification strategies covered in both parts of the review and offer a brief discussion of the overall direction of the field. PMID- 26754794 TI - PAD4, LSD1 and EDS1 regulate drought tolerance, plant biomass production, and cell wall properties. AB - KEY MESSAGE: Arabidopsis and poplar with modified PAD4, LSD1 and EDS1 genes exhibit successful growth under drought stress. The acclimatory strategies depend on cell division/cell death control and altered cell wall composition. The increase of plant tolerance towards environmental stresses would open much opportunity for successful plant cultivation in these areas that were previously considered as ineligible, e.g. in areas with poor irrigation. In this study, we performed functional analysis of proteins encoded by PHYTOALEXIN DEFICIENT 4 (PAD4), LESION SIMULATING DISEASE 1 (LSD1) and ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1) genes to explain their role in drought tolerance and biomass production in two different species: Arabidopsis thaliana and Populus tremula * tremuloides. Arabidopsis mutants pad4-5, lsd1-1, eds1-1 and transgenic poplar lines PAD4-RNAi, LSD1-RNAi and ESD1-RNAi were examined in terms of different morphological and physiological parameters. Our experiments proved that Arabidopsis PAD4, LSD1 and EDS1 play an important role in survival under drought stress and regulate plant vegetative and generative growth. Biomass production and acclimatory strategies in poplar were also orchestrated via a genetic system of PAD4 and LSD1 which balanced the cell division and cell death processes. Furthermore, improved rate of cell division/cell differentiation and altered physical properties of poplar wood were the outcome of PAD4- and LSD1-dependent changes in cell wall structure and composition. Our results demonstrate that PAD4, LSD1 and EDS1 constitute a molecular hub, which integrates plant responses to water stress, vegetative biomass production and generative development. The applicable goal of our research was to generate transgenic plants with regulatory mechanism that perceives stress signals to optimize plant growth and biomass production in semi stress field conditions. PMID- 26754797 TI - Lipoprotein(a): Revisiting a Next Therapeutic Target. PMID- 26754796 TI - Preventive effects of raloxifene treatment on agerelated weight loss in postmenopausal women. AB - Decline of body weight and body mass index (BMI) with aging is a major risk factor for osteoporosis and fracture, suggesting that treatment for osteoporosis may affect body composition. However, the effects of treatment for osteoporosis on body composition are not well known. The present study aimed to identify the relationship between raloxifene treatment and body composition markers. We measured bone mineral density (BMD), body composition, and bone remodeling markers in 236 Japanese postmenopausal women with raloxifene treatment (N = 50) and without treatment by any osteoporosis drug (N = 186) for 5 years and analyzed the relationship of these with BMD, BMI, body weight, and biochemical markers. The mean (SD) age of the participants was 65.5 (9.3) years. Percent-changes in body weight and BMI were significantly different between women taking raloxifene and those not taking any osteoporosis drugs (P = 0.03 and 0.048, respectively). Raloxifene treatment was a significant independent determinant of body weight and BMI. Long-term treatment with raloxifene prevents age-related weight loss. PMID- 26754795 TI - Treatment-seeking rates in malaria endemic countries. AB - BACKGROUND: The proportion of individuals who seek treatment for fever is an important quantity in understanding access to and use of health systems, as well as for interpreting data on disease incidence from routine surveillance systems. For many malaria endemic countries (MECs), treatment-seeking information is available from national household surveys. The aim of this paper was to assemble sub-national estimates of treatment-seeking behaviours and to predict national treatment-seeking measures for all MECs lacking household survey data. METHODS: Data on treatment seeking for fever were obtained from Demographic and Health Surveys, Malaria Indicator Surveys and Multiple Cluster Indicator Surveys for every MEC and year that data were available. National-level social, economic and health-related variables were gathered from the World Bank as putative covariates of treatment-seeking rates. A generalized additive mixed model (GAMM) was used to estimate treatment-seeking behaviours for countries where survey data were unavailable. Two separate models were developed to predict the proportion of fever cases that would seek treatment at (1) a public health facility or (2) from any kind of treatment provider. RESULTS: Treatment-seeking data were available for 74 MECs and modelled for the remaining 24. GAMMs found that the percentage of pregnant women receiving prenatal care, vaccination rates, education level, government health expenditure, and GDP growth were important predictors for both categories of treatment-seeking outcomes. Treatment-seeking rates, which varied both within and among regions, revealed that public facilities were not always the primary facility type used. CONCLUSIONS: Estimates of treatment-seeking rates show how health services are utilized and help correct reported malaria case numbers to obtain more accurate measures of disease burden. The assembled and modelled data demonstrated that while treatment-seeking rates have overall increased over time, access remains low in some malaria endemic regions and utilization of government services is in some areas limited. PMID- 26754798 TI - Long-term, self-reported health outcomes in kidney donors. AB - BACKGROUND: The wide use of healthy persons as kidney donors calls for awareness of risks associated with donation. Live kidney donation may impair quality of life (QOL) and result in fatigue. Long-term data on these issues are generally lacking in the donor population. Thus we aimed to investigate long-term self reported health outcomes in a nationwide donor cohort. METHODS: We assessed self reported QOL, fatigue and psychosocial issues after donation in 217 donors representing 63 % of those who donated 8-12 years ago. QOL was measured using the generic Short Form-36 Health Survey (SF-36), fatigue using the Multidimensional Fatigue Inventory (MFI) and psychosocial issues using donor specific questions. For each of the 8 domains of SF-36 and the 5 domains of MFI, we performed generalized linear regression. RESULTS: Donors scored high on QOL with mean scores between 63.9 and 91.4 (scale 1-100) for the 8 subscales. Recognition from family and friends was associated with higher QOL scores in four domains. There were no significant gender differences. Fatigue scores were generally low. Females generally scored higher than males on all five dimensions of fatigue, although significantly only on two. Recipient still alive was associated with lower scores on mental fatigue. Regretting donors scored higher than average on all domains of fatigue. Recipient death, worries about own health and worsened relationship with the recipient influenced willingness to donate in retrospect. Donor age did not affect long-term health outcomes. CONCLUSIONS: Eight till 12 years after donation QOL scores were generally high and improved with recogniton from family and friends. Fatigue was independent of donor age and more pronounced in females and in those who regretted donation. PMID- 26754802 TI - Multi-scale MRI spectrum detects differences in myelin integrity between MS lesion types. AB - BACKGROUND: Lesions with different extents of myelin pathology are found at autopsy in multiple sclerosis (MS), but the differences are not discernible in magnetic resonance imaging (MRI). OBJECTIVE: To determine whether analysis of the local spectrum in MRI is sensitive to lesion differences in myelin integrity. METHODS: We imaged fresh brain slices from 21 MS patients using 1.5T scanners. White matter lesions were identified in T2-weighted MRI, matched to corresponding specimens, and then classified into five categories in histology: pre-active (intact myelin); active, chronic active, chronic inactive (complete demyelination); and remyelinated lesions. Voxel-based frequency spectrum was calculated using T2-weighted MRI to characterize lesion structure (image texture). RESULTS: MRI texture heterogeneity resulting from all spectral scales was greater in completely demyelinated lesions than in myelin-preserved lesions (p = 0.02) and normal-appearing white matter (p < 0.01). Moreover, the spectral distribution pattern over low-frequency scales differentiated demyelinated lesions from remyelinated and pre-active lesions (p < 0.01), where different lesion types also showed distinct texture scales. CONCLUSION: Using multi-scale spectral analysis, it may be possible for standard MRI to evaluate myelin integrity in MS lesions. This can be critical for monitoring disease activity and assessing remyelination therapies for MS patients. PMID- 26754799 TI - Regional reduction in cortical blood flow among cognitively impaired adults with relapsing-remitting multiple sclerosis patients. AB - PURPOSE: Detection of cortical abnormalities in relapsing-remitting multiple sclerosis (RRMS) remains elusive. Structural magnetic resonance imaging (MRI) measures of cortical integrity are limited, although functional techniques such as pseudo-continuous arterial spin labeling (pCASL) show promise as a surrogate marker of disease severity. We sought to determine the utility of pCASL to assess cortical cerebral blood flow (CBF) in RRMS patients with (RRMS-I) and without (RRMS-NI) cognitive impairment. METHODS: A total of 19 age-matched healthy controls and 39 RRMS patients were prospectively recruited. Cognition was assessed using the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) battery. Cortical CBF was compared between groups using a mass univariate voxel-based morphometric analysis accounting for demographic and structural variable covariates. RESULTS: Cognitive impairment was present in 51.3% of patients. Significant CBF reduction was present in the RRMS-I compared to other groups in left frontal and right superior frontal cortex. Compared to healthy controls, RRMS-I displayed reduced CBF in the frontal, limbic, parietal and temporal cortex, and putamen/thalamus. RRMS-I demonstrated reduced left superior frontal lobe cortical CBF compared to RRMS-NI. No significant cortical CBF differences were present between healthy controls and RRMS-NI. CONCLUSION: Significant cortical CBF reduction occurs in RRMS-I compared to healthy controls and RRMS-NI in anatomically significant regions after controlling for structural and demographic differences. PMID- 26754800 TI - Serum neurofilament light chain in early relapsing remitting MS is increased and correlates with CSF levels and with MRI measures of disease severity. AB - BACKGROUND/OBJECTIVES: Neurofilament light chain (NfL) levels in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients correlate with the degree of neuronal injury. To date, little is known about NfL concentrations in the serum of relapsing remitting multiple sclerosis (RRMS) patients and their relationship with CSF levels and magnetic resonance imaging (MRI) measures of disease severity. We aimed to validate the quantification of NfL in serum samples of RRMS, as a biofluid source easily accessible for longitudinal studies. METHODS: A total of 31 RRMS patients underwent CSF and serum sampling. After a median time of 3.6 years, 19 of these RRMS patients, 10 newly recruited RRMS patients and 18 healthy controls had a 3T MRI and serum sampling. NfL concentrations were determined by electrochemiluminescence immunoassay. RESULTS: NfL levels in serum were highly correlated to levels in CSF (r = 0.62, p = 0.0002). Concentrations in serum were higher in patients than in controls at baseline (p = 0.004) and follow-up (p = 0.0009) and did not change over time (p = 0.56). Serum NfL levels correlated with white matter (WM) lesion volume (r = 0.68, p < 0.0001), mean T1 (r = 0.40, p = 0.034) and T2* relaxation time (r = 0.49, p = 0.007) and with magnetization transfer ratio in normal appearing WM (r = -0.41, p = 0.029). CONCLUSION: CSF and serum NfL levels were highly correlated, and serum concentrations were increased in RRMS. Serum NfL levels correlated with MRI markers of WM disease severity. Our findings further support longitudinal studies of serum NfL as a potential biomarker of on-going disease progression and as a potential surrogate to quantify effects of neuroprotective drugs in clinical trials. PMID- 26754801 TI - Metabolomics in multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system with inflammatory and degenerative components. The cause of MS remains unknown although genetic and environmental factors appear to play a role in its etiopathogenesis. Metabolomics is a new "omics" technology that aims at measuring small molecules in various biological matrices and can provide information that is not readily obtained from genomics, transcriptomics, or proteomics. Currently, several different analytical platforms exist for metabolomics, and both untargeted and targeted approaches are being employed. Methods of analysis of metabolomics data are also being developed and no consensus currently exists on the optimal approach to analysis and interpretation of these data. Metabolomics has the potential to provide putative biomarkers, insights into the pathophysiology of the disease, and to aid in precision medicine for patients with MS. PMID- 26754803 TI - European multiple sclerosis risk variants in the south Asian population. AB - BACKGROUND: In less than a decade, genomewide association studies have identified over 100 single-nucleotide variants that are associated with increased risk of developing multiple sclerosis. However, since these studies have focused almost exclusively on European populations, it is unclear what role these variants might play in determining risk in other ethnic groups. OBJECTIVE: To assess the effects of European multiple sclerosis-associated risk variants in the south Asian population. METHODS: Using a combination of chip-based genotyping and next generation sequencing, we have assessed 109 European-associated variants in a total of 270 cases and 555 controls from the south Asian population. RESULTS: We found that two-thirds of the tested variants (72/109) showed over representation of the European risk allele in south Asian cases (p < 0.0003). In the rest of the Immunochip array, the most associated variant was rs7318477 which maps close to TNFSF13B, the gene for the B-cell-related protein BAFF. CONCLUSION: Our data indicate substantial overlap in genetic risk architecture between Europeans and south Asians and suggest that the aetiology of the disease may be largely independent of ethnicity. PMID- 26754805 TI - Soluble TREM-2 in cerebrospinal fluid from patients with multiple sclerosis treated with natalizumab or mitoxantrone. AB - BACKGROUND: Microglia-mediated proteolysis of the triggering receptor expressed on myeloid cells-2 (TREM-2) produces soluble TREM-2 (sTREM-2) that can be measured in cerebrospinal fluid (CSF) samples. Loss-of-function mutations in TREM2 or in the gene encoding its adaptor protein cause the rare Nasu-Hakola disease (NHD). Multiple sclerosis (MS) is an autoimmune disease that in common with NHD is characterized by demyelination and microglial activation. OBJECTIVE: To investigate the potential utility of sTREM-2 as a biomarker for MS and to follow treatment effects. METHODS: sTREM-2 was analyzed in CSF samples from subjects with MS (N = 59); relapsing-remitting MS (RRMS) (N = 36), secondary progressive MS (SPMS) (N = 20) and primary progressive MS (PPMS) (N = 3), and controls (N = 27). CSF levels of sTREM-2 were also assessed before and after treatment of patients with natalizumab or mitoxantrone. RESULTS: CSF levels of sTREM-2 were significantly increased in patients with RRMS, SPMS, and PPMS compared with controls. After natalizumab treatment, the levels of sTREM-2 were normalized to control levels. The levels of sTREM-2 were also reduced after mitoxantrone treatment. CONCLUSION: Increased CSF levels of sTREM-2, a new marker of microglial activation, in MS and normalization upon treatment with either natalizumab or mitoxantrone support a role for microglial activation in active MS. PMID- 26754804 TI - Glatiramer acetate during early pregnancy: A prospective cohort study. AB - BACKGROUND: Only limited data are available on whether glatiramer acetate exposure during pregnancy has an effect on perinatal outcome. OBJECTIVE: To determine the effect of glatiramer acetate exposure during pregnancy on pregnancy outcomes in women with multiple sclerosis. METHODS: We compared the outcome of pregnancies of women with multiple sclerosis exposed to glatiramer acetate with pregnancies unexposed to disease-modifying therapies. Women were enrolled into the German Multiple Sclerosis and Pregnancy registry. A standardized questionnaire was administered during pregnancy and postpartum. Detailed information on course of multiple sclerosis and pregnancy, concomitant medications, labor, delivery, and outcome of pregnancy was obtained. RESULTS: We collected data on 246 multiple sclerosis pregnancies, 151 exposed to glatiramer acetate and 95 unexposed to disease-modifying therapies during pregnancy. Three (2.2%) congenital anomalies occurred in the exposed and 6 (6.7%) in the control group. We did not observe an increase in other adverse pregnancy or delivery outcomes including spontaneous abortions, preterm birth, Cesarean sections, or reduced birth weight in the exposed group. CONCLUSION: Our data provide further evidence that glatiramer acetate exposure during the first trimester of pregnancy appears safe and without teratogenic effect. These findings provide important additive knowledge to better counsel women with multiple sclerosis in planning a pregnancy. PMID- 26754806 TI - Elevation of Brain Magnesium Potentiates Neural Stem Cell Proliferation in the Hippocampus of Young and Aged Mice. AB - In the adult brain, neural stem cells (NSCs) can self-renew and generate all neural lineage types, and they persist in the sub-granular zone (SGZ) of the hippocampus and the sub-ventricular zone (SVZ) of the cortex. Here, we show that dietary-supplemented - magnesium-L-threonate (MgT), a novel magnesium compound designed to elevate brain magnesium regulates the NSC pool in the adult hippocampus. We found that administration of both short- and long-term regimens of MgT, increased the number of hippocampal NSCs. We demonstrated that in young mice, dietary supplementation with MgT significantly enhanced NSC proliferation in the SGZ. Importantly, in aged mice that underwent long-term (12-month) supplementation with MgT, MgT did not deplete the hippocampal NSC reservoir but rather curtailed the age-associated decline in NSC proliferation. We further established an association between extracellular magnesium concentrations and NSC self-renewal in vitro by demonstrating that elevated Mg(2+) concentrations can maintain or increase the number of cultured hippocampal NSCs. Our study also suggests that key signaling pathways for cell growth and proliferation may be candidate targets for Mg(2+) 's effects on NSC self-renewal. J. Cell. Physiol. 231: 1903-1912, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26754807 TI - The impact of residual angulation on patient reported functional outcome scores after non-operative treatment for humeral shaft fractures. AB - PURPOSE: To determine if residual angular deformity following non-operative treatment of humeral diaphyseal fractures correlates with patient reported outcomes. METHODS: Skeletally mature patients treated by one of three orthopaedic trauma surgeons at a level 1 trauma centre with humeral shaft fractures treated without surgery were retrospectively identified over a 7 year period. After inclusion and exclusion criteria, 42 patients were eligible for the study. Disabilities of the Arm, Shoulder, and Hand (DASH); Simple Shoulder Test (SST); General health questionnaire SF-12 physical component summary (SF-12 PCS) and mental component summary (SF-12 MCS) were obtained from study participants. Healed angular deformity was obtained from patient charts. RESULTS: Thirty two subjects were successfully recruited (32/42 or 76%). Average age was 45 +/- 22 with average study follow up being 47 +/- 29 months. Average outcome scores were DASH 12 +/- 16, SST 10 +/- 2.7, SF-12 PCS 50 +/- 7.9, and SF-12 MCS 54 +/- 8.8. Healed sagittal plane deformity averaged 8 +/- 5.7 degrees [range 0-18], and 15 +/- 7.9 degrees [range 2-27] in the coronal plane. There was no correlation between residual sagittal or coronal plane deformity and outcome scores (DASH and SST for both p>0.05). Patients with at least 20 degrees (n=7; 22%) of healed coronal deformity had similar outcomes to those with <20 degrees ([DASH (13.2 +/ 18.7 vs 11.7 +/- 16.1; p=0.83]; [SST (10.3 +/- 2 vs 10.0 +/- 2.9; p=0.81]). Higher SF-12 PCS and MCS scores correlated with better DASH and SST scores (p<0.05 for all). CONCLUSION: Residual angular deformity ranging from 0 to 18 degrees in the sagittal plane and from 2 to 27 degrees in the coronal plane after non-operative treatment for humeral shaft fractures had no correlation with patient reported DASH scores, SST scores, or patient satisfaction. Instead, overall physical and mental health status as measured by the SF-12 significantly correlated with patient reported outcomes. PMID- 26754809 TI - Is attention enough? A re-examination of the impact of feature-specific attention allocation on semantic priming effects in the pronunciation task. AB - In a series of articles, Spruyt and colleagues have developed the Feature Specific Attention Allocation framework, stating that the semantic analysis of task-irrelevant stimuli is critically dependent upon dimension-specific attention allocation. In an adversarial collaboration, we replicate one experiment supporting this theory (Spruyt, de Houwer, & Hermans, 2009; Exp. 3), in which semantic priming effects in the pronunciation task were found to be restricted to stimulus dimensions that were task-relevant on induction trials. Two pilot studies showed the capability of our laboratory to detect priming effects in the pronunciation task, but also suggested that the original effect may be difficult to replicate. In this study, we tried to replicate the original experiment while ensuring adequate statistical power. Results show little evidence for dimension specific priming effects. The present results provide further insight into the malleability of early semantic encoding processes, but also show the need for further research on this topic. PMID- 26754808 TI - Follow-up and tracing of tuberculosis patients who fail to attend their scheduled appointments in Cotonou, Benin: a retrospective cohort study. AB - BACKGROUND: In the "Centre National Hospitalier de Pneumo-Phtisiologie" of Cotonou, Benin, little is known about the characteristics of patients who have not attended their scheduled appointment, the results of tracing and the possible benefits on improving treatment outcomes. This study aimed to determine the contribution of tracing activities for those who missed scheduled appointments towards a successful treatment outcome. METHODS: A retrospective cohort study was carried out among all smear-positive pulmonary tuberculosis patients treated between January and September 2013. Data on demographic and diagnostic characteristics and treatment outcomes were accessed from tuberculosis registers and treatment cards. Information on those who missed their scheduled appointments was collected from the tracing tuberculosis register. A univariate analysis was performed to explore factors associated with missing a scheduled appointment. RESULTS: Of 457 patients (410 new smear-positive and 47 retreatment tuberculosis), 37 (8%) missed one or more of their appointments with a total of 44 episodes of missed appointments. The 3.5th (32%) and 5th (43%) month appointments were the ones most likely to be missed. Being male was associated with a higher risk of missing appointments (RR = 4.2; 95% CI = 1.5-11.8, p = 0.004) while having HIV infection was associated with a lower risk (RR = 0.3, 95% CI = 0.1-0.9, p = 0.03). Principal reasons for missed appointments were travelling outside Cotonou (34%) and feeling better (21%). In 24 (55%) of these 44 episodes of missed appointments, contact was made with the patient who returned to the programme. These follow-up activities increased the treatment success by 4%. CONCLUSION: In Cotonou, Benin, less than 10% of tuberculosis patients miss at least one of their scheduled appointments. Tracing activities increase the treatment success rate by 4% and current on-going practices in the Programme need to be endorsed and encouraged. PMID- 26754810 TI - The relationship between sustained inattentional blindness and working memory capacity. AB - Inattentional blindness, whereby observers fail to detect unexpected stimuli, has been robustly demonstrated in a range of situations. Originally research focused primarily on how stimulus characteristics and task demands affect inattentional blindness, but increasingly studies are exploring the influence of observer characteristics on the detection of unexpected stimuli. It has been proposed that individual differences in working memory capacity predict inattentional blindness, on the assumption that higher working memory capacity confers greater attentional capacity for processing unexpected stimuli. Unfortunately, empirical investigations of the association between inattentional blindness and working memory capacity have produced conflicting findings. To help clarify this relationship, we examined the relationship between inattentional blindness and working memory capacity in two samples (Ns = 195, 147) of young adults. We used three common variants of sustained inattentional blindness tasks, systematically manipulating the salience of the unexpected stimulus and primary task practice. Working memory capacity, measured by automated operation span (both Experiments 1 & 2) and N-back (Experiment 1 only) tasks, did not predict detection of the unexpected stimulus in any of the inattentional blindness tasks tested. Together with previous research, this undermines claims that there is a robust relationship between inattentional blindness and working memory capacity. Rather, it appears that any relationship between inattentional blindness and working memory is either too small to have practical significance or is moderated by other factors and consequently varies with attributes such as the sample characteristics within a given study. PMID- 26754812 TI - An informatics-based analysis of developments to date and prospects for the application of microalgae in the biological sequestration of industrial flue gas. AB - The excessive emission of flue gas contributes to air pollution, abnormal climate change, global warming, and sea level rises associated with glacial melting. With the ability to utilize NOx as a nitrogen source and to convert solar energy into chemical energy via CO2 fixation, microalgae can potentially reduce air pollution and relax global warming, while also enhancing biomass and biofuel production as well as the production of high-value-added products. This informatics-based review analyzes the trends in the related literature and in patent activity to draw conclusions and to offer a prospective view on the developments of microalgae for industrial flue gas biosequestration. It is revealed that in recent years, microalgal research for industrial flue gas biosequestration has started to attract increasing attention and has now developed into a hot research topic, although it is still at a relatively early stage, and needs more financial and policy support in order to better understand microalgae and to develop an economically viable process. In comparison with onsite microalgal CO2 capture, microalgae-based biological DeNOx appears to be a more realistic and attractive alternative that could be applied to NOx treatment. PMID- 26754811 TI - Implicit short- and long-term memory direct our gaze in visual search. AB - Visual attention is strongly affected by the past: both by recent experience and by long-term regularities in the environment that are encoded in and retrieved from memory. In visual search, intertrial repetition of targets causes speeded response times (short-term priming). Similarly, targets that are presented more often than others may facilitate search, even long after it is no longer present (long-term priming). In this study, we investigate whether such short-term priming and long-term priming depend on dissociable mechanisms. By recording eye movements while participants searched for one of two conjunction targets, we explored at what stages of visual search different forms of priming manifest. We found both long- and short- term priming effects. Long-term priming persisted long after the bias was present, and was again found even in participants who were unaware of a color bias. Short- and long-term priming affected the same stage of the task; both biased eye movements towards targets with the primed color, already starting with the first eye movement. Neither form of priming affected the response phase of a trial, but response repetition did. The results strongly suggest that both long- and short-term memory can implicitly modulate feedforward visual processing. PMID- 26754813 TI - Bacterial dynamics and metabolite changes in solid-state acetic acid fermentation of Shanxi aged vinegar. AB - Solid-state acetic acid fermentation (AAF), a natural or semi-controlled fermentation process driven by reproducible microbial communities, is an important technique to produce traditional Chinese cereal vinegars. Highly complex microbial communities and metabolites are involved in traditional Chinese solid-state AAF, but the association between microbiota and metabolites during this process are still poorly understood. In this study, we performed amplicon 16S rRNA gene sequencing on the Illumina MiSeq platform, PCR-denaturing gradient gel electrophoresis, and metabolite analysis to trace the bacterial dynamics and metabolite changes under AAF process. A succession of bacterial assemblages was observed during the AAF process. Lactobacillales dominated all the stages. However, Acetobacter species in Rhodospirillales were considerably accelerated during AAF until the end of fermentation. Quantitative PCR results indicated that the biomass of total bacteria showed a "system microbe self-domestication" process in the first 3 days, and then peaked at the seventh day before gradually decreasing until the end of AAF. Moreover, a total of 88 metabolites, including 8 organic acids, 16 free amino acids, and 66 aroma compounds were detected during AAF. Principal component analysis and cluster analyses revealed the high correlation between the dynamics of bacterial community and metabolites. PMID- 26754814 TI - Discovery of pentangular polyphenols hexaricins A-C from marine Streptosporangium sp. CGMCC 4.7309 by genome mining. AB - Many novel microbial nature products were discovered from Actinobacteria by genome mining methods. However, only a few number of genome mining works were carried out in rare actinomycetes. An important reason precluding the genome mining efforts in rare actinomycetes is that most of them are recalcitrant to genetic manipulation. Herein, we chose the rare marine actinomycete Streptosporangium sp. CGMCC 4.7309 to explore its secondary metabolite diversity by genome mining. The genetic manipulation method has never been established for Streptosporangium strains. At first, we set up the genetic system of Streptosporangium sp. CGMCC 4.7309 unprecedentedly. The draft genome sequencing of Streptosporangium sp. CGMCC 4.7309 revealed that it contains more than 20 cryptic secondary metabolite biosynthetic clusters. A type II polyketide synthases-containing cluster (the hex cluster) was predicted to encode compounds with a pentangular polyphenol scaffold by in silico analysis. The products of the hex cluster were uncovered by comparing the metabolic profile of Streptosporangium sp. CGMCC 4.7309 with that of the hex30 inactivated mutant, in which a key ketoreductase gene was disrupted. Finally, three pentangular polyphenols were isolated and named as hexaricins A (1), B (2), and C (3). The inconsistency of the stereochemistry of C-15 in hexaricins A, B, and C indicates a branch point in their biosynthesis. Finally, the biosynthetic pathway of the hexaricins was proposed based on bioinformatics analysis. PMID- 26754815 TI - Rapid drug susceptibility test of Mycobacterium tuberculosis using microscopic time-lapse imaging in an agarose matrix. AB - Tuberculosis (TB) is a major global health problem, and multi-drug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) are spreading throughout the world. However, conventional drug susceptibility test (DST) methods, which rely on the detection of the colony formation on a solid medium, require 1-2 months to the result. A rapid and accurate DST is necessary to identify patients with drug resistant TB and treat them with appropriate drugs. Here, we used microscopic imaging of Mycobacterium tuberculosis (MTB) immobilized in an agarose matrix for a rapid DST. The agarose matrix, which was molded in a microfluidic chip, was inoculated with MTB, and TB drugs in liquid culture medium diffused throughout the agarose to reach the MTB immobilized in the agarose matrix. After the responses of MTB to drugs were tracked with an automated microscopic system, an image-processing program automatically determined the susceptibility and resistance of MTB to specific doses of TB drugs. The automatic DST system was able to assess the drug susceptibility of various drug-resistant clinical TB strains within 9 days with an accuracy comparable to that of conventional method. Our rapid DST method based on microscopic time-lapse imaging greatly reduces the time required for a DST and can be used to rapidly and accurately treat TB patients. PMID- 26754816 TI - Biocatalytic reduction of racemic 2-arenoxycycloalkanones by yeasts P. glucozyma and C. glabrata: one way of achieving chiral 2-arenoxycycloalcohols. AB - Chiral beta-aryloxy alcohols are interesting building blocks that form part of drugs like beta adrenergic antagonists. Acquiring cyclic rigid analogs to obtain more selective drugs is interesting. Thus, we used whole cells of yeast strains Pichia glucozyma and Candida glabrata to catalyze the reduction of several 2 arenoxycycloalkanones to produce chiral 2-arenoxycycloalcohols with good/excellent enantioselectivity. In both cases, the alcohol configuration that resulted from the carbonyl group reduction was S. Yeast P. glucozyma allowed the conversion of both enantiomers of the starting material to produce 2 arenoxycycloalcohols with configuration (1S, 2R) and (1S, 2S). The reaction with C. glabrata nearly always allowed the kinetic resolution of the starting ketone, recovering 2-arenoxycycloalkanone with configuration S and (1S, 2R)-2 arenoxycycloalcohol.All the four possible stereoisomers of 2-phenoxycyclohexanol and the two enantiomers of 2-phenoxycyclohexanone were obtained by combining the biocatalyzed reaction with the oxidation/reduction of the chiral compounds with standard reagents. This is a simple approach for the synthesis of the rigid chiral moiety 2-arenoxycycloalcohols contained in putative beta-blockers 2 arenoxycycloalkanepropanolamines. PMID- 26754818 TI - Replenishment and mobilization of intracellular nitrogen pools decouples wine yeast nitrogen uptake from growth. AB - Wine yeast capacity to take up nitrogen from the environment and catabolize it to support population growth, fermentation, and aroma production is critical to wine production. Under nitrogen restriction, yeast nitrogen uptake is believed to be intimately coupled to reproduction with nitrogen catabolite repression (NCR) suggested mediating this link. We provide a time- and strain-resolved view of nitrogen uptake, population growth, and NCR activity in wine yeasts. Nitrogen uptake was found to be decoupled from growth due to early assimilated nitrogen being used to replenish intracellular nitrogen pools rather than being channeled directly into reproduction. Internally accumulated nitrogen was later mobilized to support substantial population expansion after external nitrogen was depleted. On good nitrogen sources, the decoupling between nitrogen uptake and growth correlated well with relaxation of NCR repression, raising the potential that the latter may be triggered by intracellular build-up of nitrogen. No link between NCR activity and nitrogen assimilation or growth on poor nitrogen sources was found. The decoupling between nitrogen uptake and growth and its influence on NCR activity is of relevance for both wine production and our general understanding of nitrogen use. PMID- 26754817 TI - The Pal pathway required for ambient pH adaptation regulates growth, conidiation, and osmotolerance of Beauveria bassiana in a pH-dependent manner. AB - The Pal/Rim pathway essential for fungal adaptation to ambient pH has been unexplored in Beauveria bassiana, a classic fungal entomopathogen. Here, we show the characterized Pal pathway comprising transcription factor PacC and upstream six Pal partners (PalA/B/C/F/H/I) in B. bassiana. Their coding genes were all transcribed most abundantly in standard wild-type culture under the alkaline condition of pH 9. Deletion of pacC or each pal gene resulted in a significant delay of culture acidification in a minimal broth (initial pH = 7.3). This delay concurred with altered accumulation levels of intra/extracellular organic acids and drastically depressed expression of some enzyme genes required for the syntheses of oxalic and lactic acids. Our deletion mutants except DeltapalI showed growth defects and maximal sensitivity to NaCl, KCl, LiCl, or sorbitol at pH 9, an alkaline condition leading to fragmented vacuoles in their hyphal cells exposed to osmotic stress. In these mutants, conidiation was significantly facilitated at pH 3 more than at pH 7 but suppressed slightly at pH 9. Mild virulence defects also occurred in the absence of pacC or any pal gene. These changes were restored by targeted gene complementation. Taken together, PacC and Pal partners regulate the growth, conidiation, and osmotolerance of B. bassiana in a pH-dependent manner, highlighting their vitality for the fungal pH response. PMID- 26754819 TI - The intronic minisatellite OsMin1 within a serine protease gene in the Chinese caterpillar fungus Ophiocordyceps sinensis. AB - Repetitive DNA sequences make up a significant portion of all genomes and may occur in intergenic, regulatory, coding, or even intronic regions. Partial sequences of a serine protease gene csp1 was previously used as a population genetic marker of the Chinese caterpillar fungus Ophiocordyceps sinensis, but its first intron region was excluded due to ambiguous alignment. Here in this study, we report the presence of a minisatellite OsMin1 within this intron, where a 20(19)-bp repeat motif is duplicated two to six times in different isolates. Fourteen intron alleles and 13 OsMin1 alleles were identified among 125 O. sinensis samples distributed broadly on the Tibetan Plateau. Two OsMin1 alleles were prevalent, corresponding to either two or five repeats of the core sequence motif. OsMin1 appears to be a single locus marker in the O. sinensis genome, but its origin is undetermined. Abundant recombination signals were detected between upstream and downstream flanking regions of OsMin1, suggesting that OsMin1 mutate by unequal crossing over. Geographic distribution, fungal phylogeny, and host insect phylogeny all significantly affected intron distribution patterns but with the greatest influence noted for fungal genotypes and the least for geography. As far as we know, OsMin1 is the first minisatellite found in O. sinensis and the second found in fungal introns. OsMin1 may be useful in designing an efficient protocol to discriminate authentic O. sinensis from counterfeits. PMID- 26754821 TI - Novel technologies provide more engineering strategies for amino acid-producing microorganisms. AB - Traditionally, amino acid-producing strains were obtained by random mutagenesis and subsequent selection. With the development of genetic and metabolic engineering techniques, various microorganisms with high amino acid production yields are now constructed by rational design of targeted biosynthetic pathways. Recently, novel technologies derived from systems and synthetic biology have emerged and open a new promising avenue towards the engineering of amino acid production microorganisms. In this review, these approaches, including rational engineering of rate-limiting enzymes, real-time sensing of end-products, pathway optimization on the chromosome, transcription factor-mediated strain improvement, and metabolic modeling and flux analysis, were summarized with regard to their application in microbial amino acid production. PMID- 26754822 TI - Secular changes in body dimensions and sexual maturation in children of Arkhangelsk city. AB - The aim of the present study was to analyze secular changes in body measurements in children of the Arkhangelsk city from 1988 to 2010. A large number of anthropometric measurements were taken on each individual including height, weight, arm, leg and trunk lengths (estimated), body diameters and circumferences, skinfold thickness. Stages of secondary sex characteristics were also evaluated; data on menarcheal age were collected by status-quo method. It was shown that main differences in stature occurred at puberty while in elder children (16-17-year-olds) no statistically significant differences were found. The same pattern was typical for weight and BMI. Chest circumference significantly increased, particularly in girls. For modern children, changes in body proportions due to a bigger trunk length were typical. There were also significant differences in the distribution of subcutaneous fat layer: in modern children bigger fat accumulation was present on the trunk, particularly in abdomen area, vs. fat layer on the extremities. Process of sexual maturation according to mean ages of development of secondary sex characteristics occurred earlier in modern adolescents, which is more expressed in girls. The results can be interpreted in terms of ongoing secular trend. PMID- 26754823 TI - Enhancing activity of artesunate against breast cancer cells via induced apoptosis pathway by loading into lipid carriers. AB - Artesunate-loaded nanostructured lipid carriers (ART-NLCs) were prepared by hot homogenization followed by ultrasonication technique. The optimized ART-NLC demonstrated a particle size of 117.5 +/- 6.1 nm, with good stability regarding zeta-potential of -19.47 +/- 0.9 mV and drug entrapment efficiency of 92.93 +/- 1.47%. ART-NLC showed good cellular uptake in breast cancer cells, which was confirmed by confocal laser scanning microscopy (CLSM) and flow cytometry analysis. The significantly higher in vitro cytotoxicity of ART-NLCs against human breast cancer MCF-7, MDA-MB-231 cells as compared with the free ART was recorded. Hoechst 33342 staining indicated that ART-NLC induced higher apoptosis rates in MCF-7 as well as MDA-MB-231cells than free ART. PMID- 26754820 TI - Microbial decomposition of keratin in nature-a new hypothesis of industrial relevance. AB - Discovery of keratin-degrading enzymes from fungi and bacteria has primarily focused on finding one protease with efficient keratinase activity. Recently, an investigation was conducted of all keratinases secreted from a fungus known to grow on keratinaceous materials, such as feather, horn, and hooves. The study demonstrated that a minimum of three keratinases is needed to break down keratin, an endo-acting, an exo-acting, and an oligopeptide-acting keratinase. Further, several studies have documented that disruption of sulfur bridges of the keratin structure acts synergistically with the keratinases to loosen the molecular structure, thus giving the enzymes access to their substrate, the protein structure. With such complexity, it is relevant to compare microbial keratin decomposition with the microbial decomposition of well-studied polymers such as cellulose and chitin. Interestingly, it was recently shown that the specialized enzymes, lytic polysaccharide monoxygenases (LPMOs), shown to be important for breaking the recalcitrance of cellulose and chitin, are also found in keratin degrading fungi. A holistic view of the complex molecular self-assembling structure of keratin and knowledge about enzymatic and boosting factors needed for keratin breakdown have been used to formulate a hypothesis for mode of action of the LPMOs in keratin decomposition and for a model for degradation of keratin in nature. Testing such hypotheses and models still needs to be done. Even now, the hypothesis can serve as an inspiration for designing industrial processes for keratin decomposition for conversion of unexploited waste streams, chicken feather, and pig bristles into bioaccessible animal feed. PMID- 26754825 TI - An investigation of selected chemical contaminants in commercial pet foods in Egypt. AB - Our study aimed to identify the levels of various contaminants in both wet and dry commercial pet foods in Egypt. A total of 20 local and imported pet food products (3 samples each) were screened for heavy metals by atomic absorption spectroscopy, for mycotoxins by enzyme-linked immunosorbent assay, and for nitrate and nitrite levels by nitrate-nitrite spectrophotometry. Cat food, on average, had greater concentrations of the metals cadmium, chromium, lead, and tin than dog food. Of the investigated metals, only tin concentration exceeded the safe level compared with the standards of the National Research Council and the European Commission for the dog and cat. According to the guidelines of the Association of American Feed Control Officials for canned pet foods, the nitrate and nitrite contents of examined foods greatly exceeded the recommended level. No total aflatoxins were detected in the surveyed samples. None of the samples analyzed had levels above international limits established by the Food and Agriculture Organization (FAO) of the United Nations for ochratoxin, and only 1 sample exceeded the level for aflatoxin B1. Of the 20 samples analyzed for zearalenone, 4 samples had higher levels than the FAO maximum tolerable levels. These results indicate that pet foods marketed in Egypt, especially cat foods, occasionally contain contaminants that could result in adverse effects in pets. PMID- 26754826 TI - Effectiveness of azacitidine for the treatment of higher-risk myelodysplastic syndromes in daily practice: the authors' reply. PMID- 26754824 TI - miR-133 regulates Evi1 expression in AML cells as a potential therapeutic target. AB - The Ecotropic viral integration site 1 (Evi1) is a zinc finger transcription factor, which is located on chromosome 3q26, over-expression in some acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Elevated Evi1 expression in AML is associated with unfavorable prognosis. Therefore, Evi1 is one of the strong candidate in molecular target therapy for the leukemia. MicroRNAs (miRNAs) are small non-coding RNAs, vital to many cell functions that negatively regulate gene expression by translation or inducing sequence-specific degradation of target mRNAs. As a novel biologics, miRNAs is a promising therapeutic target due to its low toxicity and low cost. We screened miRNAs which down-regulate Evi1. miR-133 was identified to directly bind to Evi1 to regulate it. miR-133 increases drug sensitivity specifically in Evi1 expressing leukemic cells, but not in Evi1-non-expressing cells The results suggest that miR-133 can be promising therapeutic target for the Evi1 dysregulated poor prognostic leukemia. PMID- 26754827 TI - Enhancement of Magnetic Resonance Imaging with Metasurfaces. AB - It is revealed that the unique properties of ultrathin metasurface resonators can improve magnetic resonance imaging dramatically. A metasurface formed when an array of metallic wires is placed inside a scanner under the studied object and a substantial enhancement of the radio-frequency magnetic field is achieved by means of subwavelength manipulation with the metasurface, also allowing improved image resolution. PMID- 26754828 TI - Clear cell carcinoma arising in previous episiotomy scar: a case report and review of the literature. AB - BACKGROUND: Malignant transformation of endometriosis associated with episiotomy scar is a rare event, especially histological type of clear cell adenocarcinoma. There are only three clear cell carcinoma in episiotomy scar reported, no standard treatment established. CASE PRESENTATION: A 36-year-old woman presented with a two-month history of painless but puritic perineal lump which she noticed was gradually enlarging. She had undergone surgical excision of a mass in the episiotomy scar 9 year ago and resequently histological type of endometriosis. Physical examination revealed a 10 * 5 cm soft, purple scar which is closely related to the apex of the episiotomy.We underwent a local excision of the mass for a biopsy . The second surgery performed after one cycle of paclitaxel and cisplatin (TP) to permit clearance of tumor while preserving normal vaginal function.Pathological result was clear cell adenocarcinoma. Two cycles of TP adjuvant chemotherapy were administrated after surgery. CONCLUSIONS: We report a case of primary clear cell carcinoma developing within a previous episiotomy scar in a patient with a history of endometriosis, along with a review of the literature. Accumulation of management data on these rare tumors and Long-term follow-up of such patients is therefore important. PMID- 26754829 TI - Evaluation of anticoagulant effects of direct thrombin inhibitors, dabigatran and argatroban, based on the Lineweaver-Burk plot applied to the Clauss assay. PMID- 26754831 TI - Non-covalent modification of reduced graphene oxide by a chiral liquid crystalline surfactant. AB - In order to effectively disperse reduced graphene oxide (RGO) in functional materials and take full advantage of its exceptional physical and chemical properties, a novel and effective approach for non-covalent modification of RGO by a chiral liquid crystalline surfactant (CLCS) consisting of chiral mesogenic units, nematic mesogenic units with carboxyl groups and non-mesogenic units with a polycyclic conjugated structure is firstly established. The polycyclic conjugated structure can anchor onto the RGO surface via pi-pi interactions, the chiral mesogenic units possess affinity for chiral materials by joining the helical matrix of chiral material and the carboxyl groups in nematic mesogenic units are supposed to form coordination bonds with nano zinc oxide (ZnO) to fabricate functional nano hybrids. The transmittances of CLCS-RGO hybrids exhibit S-shaped nonlinear increase with the increase of wavelength, but the total transmittances from 220 nm to 800 nm show a linear decreasing trend with the increase of RGO content in the CLCS-RGO hybrid. Due to the superior thermal properties of RGO and the interactions between RGO and CLCS, the dispersed RGO can improve the glass transition and increase the thermal stability and decomposition activation energy of CLCS. The intercalation of RGO can decrease the thermochromism temperature and improve the pitch uniformity of CLCS. Furthermore, CLCS can promote the dispersion of RGO in chiral nematic liquid crystals (CNLCs), and the CNLC-RGO-CLCS hybrids present decreased driving voltage and accelerated electro-optical response. The CLCS non-covalently modified RGO can strengthen the photocatalytic degradation of ZnO by suppressing the aggregation of ZnO and RGO. PMID- 26754830 TI - Thrombocytosis and STAT5 activation in chronic myelogenous leukaemia are not associated with JAK2 V617F or calreticulin mutations. AB - AIMS: Marked thrombocytosis is uncommon in chronic myelogenous leukaemia (CML) but may be associated with mutation of JAK2 V617F, calreticulin (CALR) and/or phospho-STAT5 (p-STAT5) activation in other myeloproliferative neoplasms (MPNs), particularly essential thrombocythaemia (ET). We investigated the JAK2 V617F, CALR and STAT5 activation status in patients with CML and thrombocytosis (CML-T) that mimicked ET, trying to identify a common mechanism for thrombocytosis in MPN. METHODS: Blood and bone marrow morphological findings were reviewed from seven CML-T, four otherwise typical CML and one CML in blast phase. All cases were analysed for BCR-ABL1, JAK2 V617F and CALR exon 9 mutation and p-STAT5 expression. RESULTS: Four of seven cases of CML-T had marked thrombocytosis (>1000*10(9)/L). Eleven of 12 cases had megakaryocyte morphology typical for CML. All cases were BCR-ABL1 positive. Eleven of 12 cases were negative for JAK2 V617F, while STAT5 was activated in six of seven CML-T and in four of five CML cases. No case had a detectable CALR exon 9 mutation. One case of CML developed ET-like morphology and had JAK2 V617F detected while in molecular remission for CML. CONCLUSIONS: Detection of BCR-ABL1 is critical in the distinction of ET from CML. Thrombocytosis and STAT5 activation in CML-T are not consistently associated with CALR exon 9 or JAK2 V617F mutation. PMID- 26754832 TI - Lipoprotein(a) concentrations, apolipoprotein(a) isoforms and clinical endpoints in haemodialysis patients with type 2 diabetes mellitus: results from the 4D Study. AB - BACKGROUND: High lipoprotein(a) [Lp(a)] concentrations and low molecular weight (LMW) apolipoprotein(a) [apo(a)] isoforms are associated with cardiovascular disease and mortality in the general population. We examined the association of both with all-cause mortality and cardiovascular endpoints in haemodialysis patients with diabetes mellitus. METHODS: This is a post hoc analysis of the prospective 4D Study (German Diabetes Dialysis Study) that evaluated atorvastatin compared with placebo in 1255 haemodialysis patients with type 2 diabetes mellitus (median follow-up 4 years). The association of natural logarithm transformed Lp(a) concentrations (increment one unit) and apo(a) isoforms with outcomes was analysed by Cox proportional hazards regression. The influence of age (median 66 years) was evaluated by stratified survival analyses. RESULTS: The median baseline Lp(a) concentration was 11.5 mg/dL (IQR 5.0-41.8). A quarter of patients had at least one LMW apo(a) isoform. Increased Lp(a) concentrations were associated with all-cause mortality in the total group [hazard ratio (HR) 1.09 (95% CI 1.03-1.16), P = 0.004]. LMW apo(a) isoforms were only associated with all cause mortality in patients <= 66 years [HR 1.38 (95% CI 1.05-1.80), P = 0.02]. The strongest association for Lp(a) concentrations and LMW apo(a) isoforms was found for death due to infection in patients <= 66 years [HR 1.39 (95% CI 1.14 1.71), P = 0.001; HR 2.17 (95% CI 1.26-3.75), P = 0.005]. Lp(a) concentrations were also associated with fatal stroke in patients <=66 years of age [HR 1.54 (95% CI 1.05-2.24), P = 0.03]. Neither Lp(a) nor LMW apo(a) isoforms were associated with other atherosclerosis-related events. CONCLUSIONS: High Lp(a) concentrations and LMW apo(a) isoforms are risk predictors for all-cause mortality and death due to infection in haemodialysis patients with diabetes mellitus. These associations are modified by age. PMID- 26754834 TI - Cumulative scores based on plasma D-dimer and serum albumin levels predict survival in esophageal squamous cell carcinoma patients treated with transthoracic esophagectomy. AB - BACKGROUND: Recently, studies have shown that plasma D-dimer and serum albumin are prognostic markers for esophageal cancer. The purpose of this study was to evaluate a novel prognostic scoring system--DA score (combination of preoperative plasma D-dimer and serum albumin levels)--and analyze the association between survival of patients with esophageal squamous cell carcinoma (ESCC) and their Glasgow prognostic score. METHODS: In this retrospective study, preoperative biochemical markers and clinicopathologic factors in 260 ESCC patients treated with transthoracic esophagectomy were reviewed. According to receiver operating characteristic analysis, the cutoff values of D-dimer and albumin were defined as 0.5 MUg/mL and 43.8 g/L, respectively. Patients with high D-dimer levels (>=0.5 MUg/mL) and low albumin levels (<43.8 g/L) were assigned a score of 2, those with only one of the two abnormalities were assigned a score of 1, and those with neither of the two abnormalities were assigned a score of 0. RESULTS: ESCC patients with a DA score of 0, 1, and 2 numbered 55, 116, and 89, respectively. Survival analysis showed that patients with a DA score of 2 had lower overall survival (OS) rates than those with DA scores of 1 and 0 (37.1% vs. 52.6% and 76.4%, P < 0.001); similar findings were observed for disease-free survival (DFS) rates (32.6% vs. 44.8% and 67.3%, P < 0.001). In addition, the predictive value of the DA score was also significant in patients with stages I-IIA and stages IIB IV ESCC. Multivariate Cox regression analyses indicated that hazard ratios (HRs) for predicting OS of patients with DA scores 1 and 2 were 2.25 (P = 0.010) and 3.14 (P < 0.001), respectively, compared with those with a DA score of 0, and HRs for predicting DFS of patients with DA scores of 1 and 2 were 1.86 (P = 0.023) and 2.68 (P < 0.001), respectively, compared with those with a DA scores of 0. CONCLUSIONS: Our study suggests that preoperative DA scores are notably associated with postoperative survival of ESCC patients. PMID- 26754833 TI - Use of urine biomarker-derived clusters to predict the risk of chronic kidney disease and all-cause mortality in HIV-infected women. AB - BACKGROUND: Although individual urine biomarkers are associated with chronic kidney disease (CKD) incidence and all-cause mortality in the setting of HIV infection, their combined utility for prediction remains unknown. METHODS: We measured eight urine biomarkers shown previously to be associated with incident CKD and mortality risk among 902 HIV-infected women in the Women's Interagency HIV Study: N-acetyl-beta-d-glucosaminidase (NAG), kidney injury molecule-1 (KIM 1), alpha-1 microglobulin (alpha1m), interleukin 18, neutrophil gelatinase associated lipocalin, albumin-to-creatinine ratio, liver fatty acid-binding protein and alpha-1-acid-glycoprotein. A group-based cluster method classified participants into three distinct clusters using the three most distinguishing biomarkers (NAG, KIM-1 and alpha1m), independent of the study outcomes. We then evaluated associations of each cluster with incident CKD (estimated glomerular filtration rate <60 mL/min/1.73 m(2) by cystatin C) and all-cause mortality, adjusting for traditional and HIV-related risk factors. RESULTS: Over 8 years of follow-up, 177 CKD events and 128 deaths occurred. The first set of clusters partitioned women into three groups, containing 301 (Cluster 1), 470 (Cluster 2) and 131 (Cluster 3) participants. The rate of CKD incidence was 13, 21 and 50% across the three clusters; mortality rates were 7.3, 13 and 34%. After multivariable adjustment, Cluster 3 remained associated with a nearly 3-fold increased risk of both CKD and mortality, relative to Cluster 1 (both P < 0.001). The addition of the multi-biomarker cluster to the multivariable model improved discrimination for CKD (c-statistic = 0.72-0.76, P = 0.0029), but only modestly for mortality (c = 0.79-0.80, P = 0.099). Clusters derived with all eight markers were no better for discrimination than the three-biomarker clusters. CONCLUSIONS: For predicting incident CKD in HIV-infected women, clusters developed from three urine-based kidney disease biomarkers were as effective as an eight-marker panel in improving risk discrimination. PMID- 26754835 TI - A new genotype of bovine leukemia virus in South America identified by NGS-based whole genome sequencing and molecular evolutionary genetic analysis. AB - BACKGROUND: Bovine leukemia virus (BLV) is a member of retroviridae family, together with human T cell leukemia virus types 1 and 2 (HTLV-1 and -2) belonging to the genes deltaretrovirus, and infects cattle worldwide. Previous studies have classified the env sequences of BLV provirus from different geographic locations into eight genetic groups. To investigate the genetic variability of BLV in South America, we performed phylogenetic analyses of whole genome and partial env gp51 sequences of BLV strains isolated from Peru, Paraguay and Bolivia, for which no the molecular characteristics of BLV have previously been published, and discovered a novel BLV genotype, genotype-9, in Bolivia. RESULTS: In Peru and Paraguay, 42.3 % (139/328) and over 50 % (76/139) of samples, respectively, were BLV positive. In Bolivia, the BLV infection rate was up to 30 % (156/507) at the individual level. In Argentina, 325/420 samples were BLV positive, with a BLV prevalence of 77.4 % at the individual level and up to 90.9 % at herd level. By contrast, relatively few BLV positive samples were detected in Chile, with a maximum of 29.1 % BLV infection at the individual level. We performed phylogenetic analyses using two different approaches, maximum likelihood (ML) tree and Bayesian inference, using 35 distinct partial env gp51 sequences from BLV strains isolated from Peru, Paraguay, and Bolivia, and 74 known BLV strains, representing eight different BLV genotypes from various geographical locations worldwide. The results indicated that Peruvian and Paraguayan BLV strains were grouped into genotypes-1, -2, and -6, while those from Bolivia were clustered into genotypes-1, -2, and -6, and a new genotype, genotype-9. Interestingly, these results were confirmed using ML phylogenetic analysis of whole genome sequences obtained by next generation sequencing of 25 BLV strains, assigned to four different genotypes (genotypes-1, -2, -6, and -9) from Peru, Paraguay, and Bolivia. Comparative analyses of complete genome sequences clearly showed some specific substitutions, in both structural and non-structural BLV genes, distinguishing the novel genotype-9 from known genotypes. CONCLUSIONS: Our results demonstrate widespread BLV infection in South American cattle and the existence of a new BLV genotype-9 in Bolivia. We conclude that at least seven BLV genotypes (genotypes-1, -2, -4, -5, -6, -7, and -9) are circulating in South America. PMID- 26754836 TI - Case-control study of pathogens involved in piglet diarrhea. AB - BACKGROUND: Diarrhea in piglets directly affects commercial swine production. The disease results from the interaction of pathogens with the host immune system and is also affected by management procedures. Several pathogenic agents such as Campylobacter spp., Clostridium perfringens, Escherichia coli, Salmonella spp., group A rotavirus (RV-A), coronaviruses (transmissible gastroenteritis virus; porcine epidemic diarrhea virus), as well as nematode and protozoan parasites, can be associated with disease cases. RESULTS: All bacterial, viral, protozoan, and parasitic agents here investigated, with the exception of Salmonella spp. as well as both coronaviruses, were detected in varying proportions in piglet fecal samples, and positive animals were equally distributed between case and control groups. A statistically significant difference between case and control groups was found only for Cystoisospora suis (p = 0.034) and Eimeria spp. (p = 0.047). When co-infections were evaluated, a statistically significant difference was found only for C. perfringens beta2 and C. suis (p = 0.014). CONCLUSIONS: The presence of pathogens in piglets alone does not determine the occurrence of diarrhea episodes. Thus, the indiscriminate use of antibiotic and anthelminthic medication should be re-evaluated. This study also reinforces the importance of laboratory diagnosis and correct interpretation of results as well as the relevance of control and prophylactic measures. PMID- 26754838 TI - Propagation of spontaneous slow-wave activity across columns and layers of the adult rat barrel cortex in vivo. AB - During slow-wave sleep, neocortical networks exhibit self-organized activity switching between periods of concurrent spiking (up-states) and periods of network silence (down-states), a phenomenon also occurring under the effects of different anesthetics and in in vitro brain slice preparations. Although this type of ongoing activity has been implicated into important functions such as memory consolidation and learning, the manner in which it propagates across different cortical modules (i.e., columns and layers) has not been fully characterized. In the present study, we investigated this issue by measuring spontaneous activity at large scale in the adult rat barrel cortex under urethane anesthesia by means of voltage-sensitive dye imaging and 128-channel probe recordings. Up to 74 neurons located in all layers of up to four functionally identified barrel-related columns were recorded simultaneously. The spontaneous activity propagated isotropically across the cortical surface with a median speed of ~35 um/ms. A concomitant radial spread of activation was present from deep to superficial cortical layers. Thus, spontaneous activity occurred rather globally in the barrel cortex, with >=50 % of the up-states presenting spikes in >=3 columns and layers. Temporally precise spike sequences, which occurred repeatedly (although sporadically) within the up-states, were typically led by putative excitatory neurons in the infragranular cortical layers. In summary, our data provide for the first time an overall view of the spontaneous slow-wave activity within the barrel cortex circuit, characterizing its propagation across columns and layers at high spatio-temporal resolution. PMID- 26754837 TI - Microstructural asymmetry of the corticospinal tracts predicts right-left differences in circle drawing skill in right-handed adolescents. AB - Most humans show a strong preference to use their right hand, but strong preference for the right hand does not necessarily imply a strong right-left asymmetry in manual proficiency (i.e., dexterity). Here we tested the hypothesis that intra-individual asymmetry of manual proficiency would be reflected in microstructural differences between the right and left corticospinal tract (CST) in a cohort of 52 right-handed typically-developing adolescents (11-16 years). Participants were asked to fluently draw superimposed circles with their right dominant and left non-dominant hand. Temporal regularity of circle drawing movements was assessed for each hand using a digitizing tablet. Although all participants were right-handed, there was substantial inter-individual variation regarding the relative right-hand advantage for fluent circle drawing. All subjects underwent whole-brain diffusion tensor imaging at 3 Tesla. The right and left CST were defined as regions-of-interest and mean fractional anisotropy (FA) and diffusivity values were calculated for right and left CST. On average, mean FA values were higher in the left CST relative to right CST. The degree of right left FA asymmetry showed a linear relationship with right-left asymmetry in fluent circle drawing after correction for age and gender. The higher the mean FA values were in the left dominant CST relative to the right non-dominant CST, the stronger was the relative right-hand advantage for regular circle drawing. These findings show that right-left differences in manual proficiency are highly variable in right-handed adolescents and that this variation is associated with a right-left microstructural asymmetry of the CST. PMID- 26754842 TI - MK886 inhibits the pioglitazone-induced anti-invasion of MDA-MB-231 cells is associated with PPARalpha/gamma, FGF4 and 5LOX. AB - The goal of this study was to determine the effects of PGZ and MK886 on the mRNA expression of PPARalpha and other associated genes in MDA-MB-231 cells, and the biological mechanisms induced by both drugs were also assessed. The levels of PPARalpha mRNA expression in PGZ-treated and MK886-treated MDA-MB-231 cells were determined using real-time PCR; the growth inhibitory effects of PGZ and MK886 were determined using the trypan blue exclusion assay; the induction of apoptosis by PGZ and MK886 was determined using DNA fragmentation assay and real-time PCR; and the invasion of PGZ-treated and MK886-treated MDA-MB-231 cells was determined using the wound healing and transwell migration assays. In addition, we correlated the expression of PPARalpha mRNA with other genes, including PPARgamma, FGF4 and 5LOX, in drug-treated MDA-MB-231 cells. Our results demonstrated that the treatment of MDA-MB-231 cells with PGZ increased the expression of PPARalpha/gamma mRNA and that this expression could be inhibited by treatment with MK886. Both drugs reduced the viability of MDA-MB-231 cells independently of PPARalpha/gamma mRNA expression but did not induce apoptosis. The wound caused by invasion was not healed by PGZ-treated MDA-MB-231 cells, but it was healed by MK886-treated cancer cells, indicating that the reduction of invasion in PGZ-treated MDA-MB-231 cells was eliminated by treatment with MK886, and this finding was validated by the transwell migration assay. This phenomenon might also be associated with the expression of PPARalpha/gamma, FGF4 and 5LOX mRNA in the treated cancer cells. This study provides useful information regarding the mRNA expression levels of PPARalpha and other related genes in MDA MB-231 cells. These genes could be attractive targets for reducing the invasion of breast cancer. PMID- 26754839 TI - The white matter query language: a novel approach for describing human white matter anatomy. AB - We have developed a novel method to describe human white matter anatomy using an approach that is both intuitive and simple to use, and which automatically extracts white matter tracts from diffusion MRI volumes. Further, our method simplifies the quantification and statistical analysis of white matter tracts on large diffusion MRI databases. This work reflects the careful syntactical definition of major white matter fiber tracts in the human brain based on a neuroanatomist's expert knowledge. The framework is based on a novel query language with a near-to-English textual syntax. This query language makes it possible to construct a dictionary of anatomical definitions that describe white matter tracts. The definitions include adjacent gray and white matter regions, and rules for spatial relations. This novel method makes it possible to automatically label white matter anatomy across subjects. After describing this method, we provide an example of its implementation where we encode anatomical knowledge in human white matter for ten association and 15 projection tracts per hemisphere, along with seven commissural tracts. Importantly, this novel method is comparable in accuracy to manual labeling. Finally, we present results applying this method to create a white matter atlas from 77 healthy subjects, and we use this atlas in a small proof-of-concept study to detect changes in association tracts that characterize schizophrenia. PMID- 26754843 TI - Design of a cone-and-plate device for controlled realistic shear stress stimulation on endothelial cell monolayers. AB - Endothelial cells are constantly exposed to blood flow and the resulting frictional force, the wall shear stress, varies in magnitude and direction with time, depending on vasculature geometry. Previous studies have shown that the structure and function of endothelial cells, and ultimately of the vessel wall, are deeply affected by the nature of wall shear stress waveforms. To investigate the in vitro effects of these stimuli, we developed a compact, programmable, real time operated system based on cone-and-plate geometry, that can be used within a standard cell incubator. To verify the capability to replicate realistic shear stress waveforms, we calculated both analytically and numerically to what extent the system is able to correctly deliver the stimuli defined by the user at plate level. Our results indicate that for radii greater than 25 mm, the shear stress is almost uniform and directly proportional to cone rotation velocity. We further established that using a threshold of 10 Hz of wall shear stress waveform frequency components, oscillating flow conditions can be reproduced on cell monolayer surface. Finally, we verified the capability of the system to perform long-term flow exposure experiments ensuring sterility and cell culture viability on human umbilical vein endothelial cells exposed to unidirectional and oscillating shear stress. In conclusion, the system we developed is a highly dynamic, easy to handle, and able to generate pulsatile and unsteady oscillating wall shear stress waveforms. This system can be used to investigate the effects of realistic stimulations on endothelial cells, similar to those exerted in vivo by blood flow. PMID- 26754840 TI - Increasing rate of inflammatory bowel disease: a 12-year retrospective study in NingXia, China. AB - BACKGROUND: In China, the incidence of Inflammatory bowel disease (IBD) has shown a significant growth trend. Analysis of the epidemiology, clinical manifestations, diagnostic means, and treatment of IBD will further improve the clinician's understanding of IBD, improve knowledge and further enable early diagnosis and standardized therapeutic management. The purpose of this study was to analyze the clinical characteristics of IBD inpatients in General Hospital of NingXia Medical University over a 12-year period to identify trends in clinical and epidemiological features, clinical manifestations, and treatment programs. METHODS: By excluding188 patients with incomplete information or incompatible with the 2012 Guidlines cases, we retrospectively analyzed the case records of 567 inpatients with a diagnosis of IBD admitted to the General Hospital of NingXia Medical University between January 2002 and December 2014. The clinical epidemiological features, clinical manifestations, diagnostic methods, and therapeutic status were analyzed. RESULTS: Over the study period, IBD hospitalization rates in 2002 and 2014 groups was 1.96 % and 4.05 %, increased 2.07 times. Of 567 cases of IBD, 483 (85.19 %) cases were categorized as ulcerative colitis (UC) and 84 as Crohn's disease (CD) (14.81 %). Total male cases were 321 (56.61 %). Mean age of cases was 49.06 +/- 14.92 years for UC and 44.84 +/- 14.67 years for CD. The majority of UC was located in the colon, with a moderate level of disease activity. A combination of clinical manifestations and colonoscopy was mostly used to make a diagnosis; relatively the rate of pathological diagnosis was low, with a small proportion of patient's diagnosed based on radiology. Treatment with SASP/5ASA and steroids was applied to the majority of inpatients and 47.83 % were treated with antibiotics; in contrast, only 1.86 % cases were treated with immunosuppressive therapy. CONCLUSIONS: An increasing trend of admissions for IBD can be observed in our study; there are some differences in clinical features and treatment compared with Western countries, and further research into this is required. PMID- 26754841 TI - Genotoxicity and cytotoxicity of copper oxychloride in cultured human lymphocytes using cytogenetic and molecular tests. AB - The genotoxicity of copper oxychloride was investigated in human lymphocytes using chromosome aberration (CA) and micronucleus (MN) tests and the randomly amplified polymorphic DNA-polymerase chain reaction technique. The lymphocytes were treated with 3, 6, and 12 ug/mL of copper oxychloride for 24 and 48 h. Copper oxychloride increased CA and abnormal cells in a dose-dependent manner. The frequency of MN and micronucleated binuclear cells also increased at all concentrations and treatment periods. However, copper oxychloride cytotoxicity, observed through lower mitotic and nuclear division index, was significantly lower only at the higher concentrations (6 and 12 ug/mL). Copper oxychloride increased the polymorphic bands and decreased genomic template stability. In conclusion, in this study it was confirmed that copper oxychloride has genotoxic potential for human lymphocytes in vitro. Additionally, caution is advised for its use as a fungicide, because it may increase the risk of exposure through the food chain. PMID- 26754845 TI - Bailout technique to rescue the abruptly occluded side branch with collapsed true lumen after main vessel stenting. AB - Guidewire recrossing into the abruptly occluded side branch (SB) after main vessel (MV) stenting in the coronary bifurcation is difficult, particularly if the SB has a dissection because the true lumen of SB is collapsed by a hematoma and the second guidewire easily goes into the false lumen. This paper reports a bailout technique to rescue the occluded SB that was complicated by a hematoma because of an unsuccessful guidewire recrossing after MV stenting using a small balloon dilation in the collapsed SB true lumen behind the stent strut and wire penetration. PMID- 26754844 TI - A beta-solenoid model of the Pmel17 repeat domain: insights to the formation of functional amyloid fibrils. AB - Pmel17 is a multidomain protein involved in biosynthesis of melanin. This process is facilitated by the formation of Pmel17 amyloid fibrils that serve as a scaffold, important for pigment deposition in melanosomes. A specific luminal domain of human Pmel17, containing 10 tandem imperfect repeats, designated as repeat domain (RPT), forms amyloid fibrils in a pH-controlled mechanism in vitro and has been proposed to be essential for the formation of the fibrillar matrix. Currently, no three-dimensional structure has been resolved for the RPT domain of Pmel17. Here, we examine the structure of the RPT domain by performing sequence threading. The resulting model was subjected to energy minimization and validated through extensive molecular dynamics simulations. Structural analysis indicated that the RPT model exhibits several distinct properties of beta-solenoid structures, which have been proposed to be polymerizing components of amyloid fibrils. The derived model is stabilized by an extensive network of hydrogen bonds generated by stacking of highly conserved polar residues of the RPT domain. Furthermore, the key role of invariant glutamate residues is proposed, supporting a pH-dependent mechanism for RPT domain assembly. Conclusively, our work attempts to provide structural insights into the RPT domain structure and to elucidate its contribution to Pmel17 amyloid fibril formation. PMID- 26754846 TI - Successful endovascular treatment with GuideLiner catheter of chronic aortic occlusion with severe calcification. AB - An 80-year-old Japanese woman was referred to our department because of bilateral intermittent claudication. Diagnostic angiography and computed tomography revealed total occlusion with severe calcification in the terminal aorta and bilateral common iliac arteries. We performed endovascular treatment. Although a guidewire antegradely passed the occlusive lesion of the left CIA, no balloon or microcatheter could pass the lesion. Therefore, we used the GuideLiner catheter to facilitate balloon catheter delivery. The GuideLiner catheter advanced into the occlusive lesion, and the balloon crossed the lesion. This is a first report of the use of the GuideLiner catheter in peripheral intervention. PMID- 26754849 TI - RE: A Randomized Phase II/III Study of Dalotuzumab in Combination With Cetuximab and Irinotecan in Chemorefractory, KRAS Wild-Type, Metastatic Colorectal Cancer. PMID- 26754848 TI - Successful every-other-day liothyronine therapy for severe resistance to thyroid hormone beta with a novel THRB mutation; case report. AB - BACKGROUND: Resistance to thyroid hormone beta (RTHbeta) is a rare and usually dominantly inherited syndrome caused by mutations of the thyroid hormone receptor beta gene (THRB). In severe cases, it is rarely challenging to control manifestations using daily therapeutic replacement of thyroid hormone. CASE PRESENTATION: The present case study concerns an 8-year-old Japanese girl with a severe phenotype of RTH (TSH, fT3, and fT4 were 34.0 mU/L, >25.0 pg/mL and, >8.0 ng/dL, respectively), caused by a novel heterozygous frameshift mutation in exon 10 of the thyroid hormone receptor beta gene (THRB), c.1347-1357 del actcttccccc : p.E449DfsX11. RTH was detected at the neonatal screening program. At 4 years of age, the patient continued to suffer from mental retardation, hyperactivity, insomnia, and reduced resting energy expenditure (REE), despite daily thyroxine (L-T4) therapy. Every-other-day high-dose liothyronine (L-T3) therapy improved her symptoms and increased her REE, without thyrotoxicosis. CONCLUSION: In a case of severe RTH, every-other-day L-T3 administration enhanced REE and psychomotor development, without promoting symptoms of thyrotoxicosis. Every-other-day L-T3 administration may be an effective strategy for the treatment of severe RTH. PMID- 26754847 TI - Pangenome-wide and molecular evolution analyses of the Pseudomonas aeruginosa species. AB - BACKGROUND: Drug treatments and vaccine designs against the opportunistic human pathogen Pseudomonas aeruginosa have multiple issues, all associated with the diverse genetic traits present in this pathogen, ranging from multi-drug resistant genes to the molecular machinery for the biosynthesis of biofilms. Several candidate vaccines against P. aeruginosa have been developed, which target the outer membrane proteins; however, major issues arise when attempting to establish complete protection against this pathogen due to its presumably genotypic variation at the strain level. To shed light on this concern, we proposed this study to assess the P. aeruginosa pangenome and its molecular evolution across multiple strains. RESULTS: The P. aeruginosa pangenome was estimated to contain more than 16,000 non-redundant genes, and approximately 15 % of these constituted the core genome. Functional analyses of the accessory genome indicated a wide presence of genetic elements directly associated with pathogenicity. An in-depth molecular evolution analysis revealed the full landscape of selection forces acting on the P. aeruginosa pangenome, in which purifying selection drives evolution in the genome of this human pathogen. We also detected distinctive positive selection in a wide variety of outer membrane proteins, with the data supporting the concept of substantial genetic variation in proteins probably recognized as antigens. Approaching the evolutionary information of genes under extremely positive selection, we designed a new Multi Locus Sequencing Typing assay for an informative, rapid, and cost-effective genotyping of P. aeruginosa clinical isolates. CONCLUSIONS: We report the unprecedented pangenome characterization of P. aeruginosa on a large scale, which included almost 200 bacterial genomes from one single species and a molecular evolutionary analysis at the pangenome scale. Evolutionary information presented here provides a clear explanation of the issues associated with the use of protein conjugates from pili, flagella, or secretion systems as antigens for vaccine design, which exhibit high genetic variation in terms of non-synonymous substitutions in P. aeruginosa strains. PMID- 26754850 TI - Response. PMID- 26754851 TI - Functional neurological disorders in outpatient practice: An Australian cohort. AB - Functional disorders are defined as neurological symptoms without causative organic pathology identified. They are a diverse and often neglected group of disorders. The aim of this was to determine the incidence and outcome of functional neurological disorders in an Australian neurology practice. Over a 17month period, all patients presenting to a single outpatient neurology service were evaluated to determine the incidence and outcome of these disorders. A total of 884 patients were assessed and of these, 137 had a final diagnosis of functional neurological illness, equating to an incidence of 15% of all patients seen. Functional disorders were the third most common presentation overall. Patients with functional disorders were younger, more likely to be female and had a higher rate of current psychiatric comorbidity compared to other neurology patients. Sensory symptoms were the most common manifestation (48%) followed by limb weakness (37%) and psychogenic non-epileptic seizures (14%). Outcome information was available for 49% of patients at an average of 3months follow-up. 45% had some improvement in their symptoms, 43% had static symptoms and 12% had worsening of symptoms. This study confirms the high incidence of functional disorders in outpatient neurology practice. Early improvement was seen in a substantial proportion of patients and is influenced by duration of symptoms. PMID- 26754852 TI - GetReal in network meta-analysis: a review of the methodology. AB - Pairwise meta-analysis is an established statistical tool for synthesizing evidence from multiple trials, but it is informative only about the relative efficacy of two specific interventions. The usefulness of pairwise meta-analysis is thus limited in real-life medical practice, where many competing interventions may be available for a certain condition and studies informing some of the pairwise comparisons may be lacking. This commonly encountered scenario has led to the development of network meta-analysis (NMA). In the last decade, several applications, methodological developments, and empirical studies in NMA have been published, and the area is thriving as its relevance to public health is increasingly recognized. This article presents a review of the relevant literature on NMA methodology aiming to pinpoint the developments that have appeared in the field. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26754853 TI - Seven-year survival after pancreaticoduodenectomy for early recurrent renal cell carcinoma involving the duodenum A case report. AB - RCC has a range of clinical manifestations including vague abdominal symptoms, haematuria, flank pain and a palpable abdominal mass. Generally, 25-30% of patients are found to have metastases at diagnosis but a further 30-50% of patients with local disease will develop metastases during the course of their illness. Spread in RCC is lymphatic, haematogenous, transcoelomic or by direct invasion and the most common sites of metastasis in RCC are the lung, lymph nodes, bones and liver. Metastasis to the small intestine is rare and the duodenum is the segment least often affected. RCC metastasis to the duodenum occurs most commonly in the periampullary region, followed by the bulband usually manifest as gastrointestinal bleeding or obstruction. Bleeding may be the first symptom of metastatic disease in patients who have previously undergone nephrectomy for RCC. Survival is better for patients with localized disease compared with those with regional and distant metastases. This report describes a case of duodenal metastasis from RCC in which the patient presented with upper gastrointestinal bleeding and duodenal obstruction and was treated with pancreaticoduodenectomy with an excellent long-term outcome. Long-term survival was better than survival data reported in the current literature. . KEY WORDS: Duodenal metastasis, Gastrointestinal bleeding, Renal cell carcinoma, Pancreaticoduodenectomy. PMID- 26754854 TI - Molecular characterization of hepatitis C virus core region in moroccan intravenous drug users. AB - Intravenous drug users (IDUs) represent a highly-infected reservoir for Hepatitis C virus (HCV) worldwide, harboring some of the most elevated prevalences and majority of the epidemic in developed nations. Studies aimed at sequencing regions of the viral genome uncovered amino acid mutations, some of which have been implicated in resistance to standard of care pegylated interferon/Ribavirin double therapy. Using the nested PCR method on the Core region of HCV strains in Moroccan IDUs living in the Tangier region this study sought to identify genotype specific amino acid mutations, followed by Phylogenetic methods in order to compare them with international strains so as to identify sequences of highest homology. Genotyping was confirmed and recombination events excluded by line probe assay. Italy was found most homologous for genotypes 1a and 3a, Iran for genotype 1a and Egypt for genotype 4a. Amino Acid Mutation analysis revealed the following novel genotype 3a-specific mutations: N16I, L36V, T49A, P71S, T75S, and T110N. The outcome of this work describes the HCV genetic heterogeneity in high risk intravenous drug users, and it gives clues to the global migratory flow of genotypes as they cross geographical boundaries between various IDU populations and identifies "signature" amino acid mutations traceable to HCV genotype 3a. Identification of key amino acid positions in the HCV Core region with higher rates of mutations paves the way for eventual clinical trials seeking to establish a link between these recurrent mutations and response to standard of care Interferon and Ribavirin antiviral therapy. J. Med. Virol. 88:1376-1383, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26754856 TI - Erratum: Term rules for simple metal clusters. PMID- 26754855 TI - Quantitative evaluation of myocardial fibrosis by cardiac integrated backscatter analysis in Kawasaki disease. AB - BACKGROUND: Kawasaki disease is an acute, systemic vasculitis that affects the coronary arteries. However, the relationship between myocardial fibrosis and Kawasaki disease has been completely unknown until now. We aimed to provide quantitative information about myocardial fibrosis using cardiac integrated backscatter in Han race Kawasaki disease patients. METHODS: Ninety Kawasaki disease patients and 90 healthy control subjects were recruited. Based on Kawasaki disease status, the patients were categorized into 3 groups: acute, subacute, and convalescence phase. Based on coronary artery status, the Kawasaki disease patients were categorized into 3 groups: without coronary artery lesions, with coronary artery dilation, and with coronary artery aneurysms. All subjects underwent two-dimensional and Doppler examinations to measure clinical echocardiographic parameters. Myocardial fibrosis was detected with calibrated integrated backscatter imaging. RESULTS: Left ventricle systolic functions were normal in both the Kawasaki disease and control participants. The myocardial calibrated integrated backscatter values of the left ventricles of the acute (p < 0.001), subacute (p < 0.001) and convalescence phase (p < 0.001) Kawasaki disease patients were significantly greater than those of the healthy controls. The left ventricle myocardial calibrated integrated backscatter values were significantly smaller in the Kawasaki disease patients without coronary artery lesions than in the Kawasaki disease patients with coronary artery dilations and coronary artery aneurysms in different phases. The left ventricle myocardial calibrated integrated backscatter results were positively correlated with coronary artery status in the acute (r = 0.331, p < 0.001), subacute (r = 0.456, p < 0.001) and convalescence phases (r = 0.407, p < 0.001) of Kawasaki disease. CONCLUSION: Our findings may suggest that myocardial fibrosis occurs during early episodes of Kawasaki disease given uncertainties that exist regarding correlations of calibrated integrated backscatter and myocardial fibrosis. PMID- 26754858 TI - Evaluation of agreement and trending ability between transpulmonary thermodilution and calibrated pulse contour and pulse power cardiac output monitoring methods against pulmonary artery thermodilution in anesthetized dogs. AB - OBJECTIVE: To assess agreement and trending ability of transpulmonary thermodilution (TPTD), calibrated pulse contour (PiCCO), and pulse power (PulseCO) methods compared to pulmonary artery thermodilution (PATD) for determination of cardiac output (CO) in anesthetized dogs. DESIGN: Experimental, prospective study. SETTING: University teaching hospital. ANIMALS: Six adult Beagle dogs. INTERVENTIONS: Dogs were anesthetized with sevoflurane and instrumented with pulmonary and femoral artery thermodilution catheters. CO was measured at baseline and at 5, 15, 30, 45, 60, 120, 180, and 240 minutes after IV administration of ketamine or s-ketamine. Baseline PATD and TPTD calibrated PulseCO and PiCCO, respectively. Agreement and trending ability was analyzed with Bland-Altman, concordance, and polar plot methodology. MEASUREMENTS AND MAIN RESULTS: Median (range) CO values of 2.27 (0.98-3.4) L/min were measured with PATD, and 2.8 (1.9-4.04) L/min with TPTD, which resulted in a mean bias (+/- standard deviation) of -0.66 (+/- 0.36) L/min. Concordance rate was 91% and radial limits of agreement (RLOA) were +/-35 degrees . PATD against PiCCO resulted in a mean bias of -0.71 (+/- 0.62) L/min and PATD against PulseCO in a mean bias of 0.13 (+/- 0.46) L/min. The continuous techniques resulted in concordance rates of 77% for PATD-PiCCO and 74% for PATD-PulseCO and RLOA of +/ 57 degrees and +/-60 degrees , respectively. CONCLUSIONS: Intermittent TPTD showed marginal trending ability, while continuous pulse contour and pulse power methods showed poor trending ability over a 4-hour period. The poor performance and possible side effects of the methods tested in this study suggest that they should not be recommended for use in critical patients. PMID- 26754860 TI - Results of a comparative analysis of magnetic resonance imaging-targeted versus three-dimensional transrectal ultrasound prostate biopsies: Size does matter. AB - OBJECTIVE: The aim of this study was to compare the detection rate of clinically significant disease in magnetic resonance imaging (MRI)-targeted biopsies versus three-dimensional transrectal ultrasound (3D TRUS)-guided biopsies according to prostate size. METHODS: The study compared 120 consecutive biopsy-naive men who underwent 3D TRUS-guided systematic biopsy to 120 consecutive men who underwent MRI-targeted biopsy. Stratifications based on tertiles were used for assessing interactions between prostate volume and rates of detection of significant cancer. RESULTS: Older age, higher prostate-specific antigen level, lower prostate volume, increased number of cores and MRI-targeted biopsy were independent predictors of prostate cancer detection in the entire cohort on logistic regression. Clinically significant cancer detection rates were significantly higher in the MRI-targeted group than in the 3D TRUS-guided biopsy group (48.7% vs 29.4%, p = 0.002). When stratified according to prostate volume, these rates were significantly higher only in the third tertile group (volume > 50 cm(3)) for MRI-targeted biopsy compared to 3D TRUS-guided biopsy (56% vs 22%, p = 0.003). CONCLUSION: MRI-targeted biopsies increased the detection rate of clinically significant prostate cancer only in patients with enlarged prostates compared to the 3D TRUS. PMID- 26754857 TI - Differentiation between treatment-related changes and progressive disease in patients with high grade brain tumors using support vector machine classification based on DCE MRI. AB - Differentiation between treatment-related changes and progressive disease (PD) remains a major clinical challenge in the follow-up of patients with high grade brain tumors. The aim of this study was to differentiate between treatment related changes and PD using dynamic contrast enhanced (DCE) MRI. Twenty patients were scanned using conventional, DCE-MRI and MR spectroscopy (total of 44 MR scans). The enhanced lesion area was extracted using independent components analysis of the DCE data. Pharmacokinetic parameters were estimated from the DCE data based on the Extended-Tofts-Model. Voxel based classification for treatment related changes versus PD was performed in a patient-wise leave-one-out manner, using a support vector machine classifier. DCE parameters, K (trans), v e, k ep and v p, significantly differentiated between the tissue types. Classification results were validated using spectroscopy data showing significantly higher choline/creatine values in the extracted PD component compared to areas with treatment-related changes and normal appearing white matter, and high correlation between choline/creatine values and the percentage of the identified PD component within the lesion area (r = 0.77, p < 0.001). On the training data the sensitivity and specificity were 98 and 97 %, respectively, for the treatment related changes component and 97 and 98 % for the PD component. This study proposes a methodology based on DCE-MRI to differentiate lesion areas into treatment-related changes versus PD, prospectively in each scan. Results may have major clinical importance for pre-operative planning, guidance for targeting biopsy, and early prediction of radiological outcomes in patients with high grade brain tumors. PMID- 26754861 TI - Insight into the mechanical, thermodynamics and superconductor properties of NbRuB via first-principles calculation. AB - Using the first-principles calculations, the electronic structure, chemical bonding, mechanical, thermodynamics and superconductor properties of NbRuB are investigated. The optimized lattice parameters were in good agreement with the experimental data. The analysis of the density of states and chemical bonding implies that the metallic behavior of NbRuB originates from the Ru and Nb, and the bonding behaviors are a mixture of covalent-ionic bonds. The bulk modulus, shear modulus, Young's modulus, Poisson's ratio and hardness of NbRuB were calculated. The results reveal that the NbRuB is ductility and the Vickers hardness is 15.06 GPa. Moreover, the 3D dependences of reciprocals of Young's modulus is also calculated and discussed, showing strong anisotropic character for NbRuB. Finally, the Debye temperature and superconducting transition temperature are obtained. PMID- 26754859 TI - Primary anterior dislocation of the shoulder: long-term prognosis at the age of 40 years or younger. AB - PURPOSE: We describe the long-term prognosis in 257 first-time anterior shoulder dislocations (255 patients, aged 12-40 years) registered at 27 Swedish emergency units between 1978 and 1979. METHODS: Half the shoulders were immobilised for 3-4 weeks after repositioning. Follow-ups were performed after two (questionnaire), five (questionnaire), 10 (questionnaire and radiology) and 25 (questionnaire and radiology) years in 227 patients (229 shoulders). Twenty-eight patients died during the 25 years of observation. RESULTS: Early movement or immobilisation after the primary dislocation resulted in the same long-term prognosis. Recurrences increased up to 10 years of follow-up, but, after 25 years, 29 % of the shoulders with >=2 recurrences appeared to have stabilised over time. Arthropathy increased from 9 % moderate to severe and 11 % mild at 10 years, to 34 % moderate to severe and 27 % mild after 25 years. Alcoholics had a poorer prognosis with respect to dislocation arthropathy (P < 0.001). Age <25 years and/or bilateral instability represent a poorer prognosis, where stabilising surgery is necessary in every second shoulder. Fracture of the greater tuberosity means a good prognosis, and we have found no evidence that athletic activity, gender, a Hill-Sachs lesion and minor rim fractures had any prognostic impact. During the 25 years in which these patients were followed, 28/255 died (11 %), representing a mortality rate (SMR) that was more than double that of the general Swedish population (P < 0.001). CONCLUSION: Almost half of all first-time dislocations at the age of <25 years will have stabilising surgery and two-thirds will develop different stages of arthropathy within 25 years. PMID- 26754862 TI - Non-periodic oscillatory deformation of an actomyosin microdroplet encapsulated within a lipid interface. AB - Active force generation in living organisms, which is mainly involved in actin cytoskeleton and myosin molecular motors, plays a crucial role in various biological processes. Although the contractile properties of actomyosin have been extensively investigated, their dynamic contribution to a deformable membrane remains unclear because of the cellular complexities and the difficulties associated with in vitro reconstitution. Here, by overcoming these experimental difficulties, we demonstrate the dynamic deformation of a reconstituted lipid interface coupled with self-organized structure of contractile actomyosin. Therein, the lipid interface repeatedly oscillates without any remarkable periods. The oscillatory deformation of the interface is caused by the aster-like three-dimensional hierarchical structure of actomyosin inside the droplet, which is revealed that the oscillation occurs stochastically as a Poisson process. PMID- 26754863 TI - Nicotinamide found to reduce the rate of nonmelanoma skin cancers in high-risk patients. PMID- 26754864 TI - Introduction. PMID- 26754865 TI - Single cell imprinting on the surface of Ag-ZnO bimetallic nanoparticle modified graphene oxide sheets for targeted detection, removal and photothermal killing of E. Coli. AB - A very cost-effective, fast, sensitive and specific imprinted polymer modified electrochemical sensor for the targeted detection, removal and destruction of Escherichia coli bacteria was developed onto the surface of Ag-ZnO bimetallic nanoparticle and graphene oxide nanocomposite. The nanocomposite played a dual role in this work, as a platform for imprinting of bacteria as well as a participated in their laser-light induced photo killing. In terms of sensing, our proposed sensor can detect E. Coli as few as 10CFUmL-1 and capture 98% of bacterial cells from their very high concentrated solution (105CFUmL-1). Similarly to the quantitative detection, we have also investigated the quantitative destruction of E. Coli and found that 16.0cm2 area of polymer modified glass plate is sufficient enough to kill 105CFUmL-1 in the small time span of 5 minutes. The obtained results suggest that our proposed sensor have potential to serve as a promising candidate for specific and quantitative detection, removal as well as the destruction of a variety of bacterial pathogens. PMID- 26754866 TI - A novel mutation p.Ser348Cys in FGFR3 causes achondroplasia. PMID- 26754867 TI - Risk Factors for Infections Related to Lumbar Drainage in Spontaneous Subarachnoid Hemorrhage. AB - BACKGROUND: A solid knowledge associated with lumbar drainage (LD)-related infections in spontaneous subarachnoid hemorrhage (SAH) patients is necessary and that would be useful in taking effective measures to cope with this complication. We aimed to describe incidence rates and risk factors associated with LD-related infections in SAH patients. METHODS: A retrospective review was performed on SAH patients who underwent LD between July 2010 and August 2015. Patient charts were reviewed to retrieve demographic, clinical, and laboratory data. LD-related infections were defined based on culture results of cerebrospinal fluid in combination with clinical symptoms. Infection rates were calculated, and a logistic regression model was developed to identify risk factors. RESULTS: A total of 629 SAH patients (25-82 years age range, 42.8 % male) were treated with LD in the period. LD-related infections were identified in 36 patients (5.7 %). Longer duration of LD (>=4 days: p = 0.0037) and puncture site leakage (p < 0.0001) appeared to be risk factors for infection. The infection rate increased with length of the hospital stay (16-20 days: p = 0.0032; >=21 days: p = 0.0007). 84.6 % of the isolated bacteria were Gram-positive, and the most commonly associated pathogens were Methicillin-resistant coagulase-negative Staphylococcus (MRCNS, 61.5 %). CONCLUSIONS: The patients with LD for more than 4 days or with puncture site leakage had more risk of infection. Infected patients were more likely to stay longer in the hospital. MRCNS were identified as the most frequent causal pathogens. And the use of antibiotics during LD did not appear to reduce the risk of infection. PMID- 26754875 TI - Cortical connectivity modulation induced by cerebellar oscillatory transcranial direct current stimulation in patients with chronic disorders of consciousness: A marker of covert cognition? AB - OBJECTIVE: Although some patients suffering from unresponsive wakefulness syndrome (UWS) may retain some capacity for covert cognition, it is difficult to directly demonstrate this property by means of tasks needing patient active cooperation and preserved top-down attention processes. Instead, specific passive paradigms may allow identifying a residual theta and gamma band functional connectivity within fronto-parietal networks (FPN), which may sustain covert cognitive processes. METHODS: We attempted to highlight such networks in a sample of minimally conscious state (MCS) and UWS patients by means of a cerebellar 5 Hz oscillatory transcranial direct current stimulation (otDCS), in order to modulate the FPN functional connectivity. RESULTS: We found a FPN theta and gamma power modulation and coherence increase, which were paralleled by a transient coma recovery scale-revised score amelioration, only in MCS individuals. CONCLUSIONS: Our data show a functional link between the FPN coherent theta and gamma oscillations and the cerebellar-cerebral output. Moreover, our data highlighted a residual FPN functional connectivity, which is a fundamental prerequisite for objectifying every aware processes and the potential to cognitive processes (covert cognition). SIGNIFICANCE: Our otDCS cerebellar-cerebral connectivity modulation may be a useful approach in improving chronic disorders of consciousness differential diagnosis and ameliorating the level of consciousness. PMID- 26754877 TI - Preconception endurance training with voluntary exercise during pregnancy positively influences on remodeling markers in female offspring bone. AB - OBJECTIVE: In this study, we investigate the effects of preconception endurance training with or without voluntary exercise during pregnancy on indices of bone formation and resorption in female offspring bone. METHODS: Twenty-four C57BL/6 female mice were randomly divided into four groups: trained in preconception period and exercised during pregnancy (TE); trained in preconception periods but unexercised during pregnancy (TC); untrained in preconception periods but exercised during pregnancy (CE); untrained and unexercised (CC). Trained dams were subjected to a protocol of moderate exercise training over a period of 4 weeks before pregnancy. Analyses were performed on the adult female offspring that did not have access to running wheels in any portion of their lives. RESULTS: The OPG, Runx2, COLI, ALP, and OPN mRNA expression was significantly up regulated in offspring born to dams that was trained in preconception period. However, there was no significant difference in OPG, COLI, Runx2, and ALP expression in TE and TC offspring (p > 0.05). RANKL and osteocalcin expression were significantly down-regulated in TE offspring group (p < 0.001). CONCLUSIONS: Improved physical fitness in preconception period results in significant changes in bone gene expressions of female offspring, in particular towards osteogenic responses with improved RANKL/OPG ratio. PMID- 26754876 TI - Monitoring multiple sclerosis by multimodal evoked potentials: Numerically versus ordinally scaled scoring systems. AB - OBJECTIVE: To compare the ability of different evoked potential scores (EPS) to monitor and predict the disease course in multiple sclerosis (MS). METHODS: Seventy-two patients with MS or clinically isolated syndrome were investigated by visual, motor, and somatosensory EP and expanded disability status scale (EDSS) at baseline (T0) and months 6, 12, 24, 36 (T4). EP results were rated according to ordinal (o), semi-quantitative (sq), and quantitative (q) EPS. Spearman rank correlation and multivariable linear regression were used to investigate the associations between EPS and clinical disability. RESULTS: All EPS correlated with EDSS cross-sectionally (0.72?rho?0.87, all p<0.001) and longitudinally (0.39?rho?0.47, all p?0.004). EPS(T0) and EDSS(T0) together explained 85-86% of EDSS(T4) variance. A posteriori power calculation showed that the sample sizes needed to detect significant changes over 6 months in q-EPS, sq-EPS and o-EPS with 90% certainty would be 50, 129 and 222, respectively. q-EPS change(T1-T0) correlated with EDSS change(T4-T0) (rho=0.56, p<0.001), while sq-EPS and o-EPS changes(T1-T0) did not. CONCLUSION: All three EPS allow disease course monitoring in MS. However, the quantitative EPS detects clinically relevant short-term changes with a smaller sample size than semi-quantitative or ordinal EPS. SIGNIFICANCE: These results underscore the potential of EPS to characterize MS disease evolution. PMID- 26754879 TI - Influence of Surface Wettability on Microbubble Formation. AB - The production and utilization of microbubbles are rapidly becoming of major importance in a number of global applications, from biofuel production to medical imaging contrast agents. Many aspects of bubble formation have been studied, with diffuser characteristics (such as pore size, pore orientation) and gas flow rate all being shown to influence the bubble formation process. However, very little attention has been paid to the influence of surface wettability of the diffuser and the detailed role it plays at the triple interface of gas-liquid-diffuser. Here, we investigate how the wettability of the diffuser surface impacts upon the dynamics of the bubble formation process and examine the effect both at the orifice and upon the bubble cloud produced as a result of the engineered wetting variations. Experimental data shown here indicate the presence of a switching point at a contact angle of theta = 90 degrees , where bubble size vastly changes. When a surface exhibits a contact angle below 90 degrees , bubbles emitted from it are considerably smaller than those emitted from a surface with an angle in excess of 90 degrees . This effect is observable over flow rates ranging from 2.5 to 60 mL min(-1) from a single pore, an array of controlled pores, and the industrially relevant and commercially available sintered metals and sintered ceramic diffusers. It is also observed for both thiol and silane modified surfaces, encompassing a range of contact angles from 10 degrees to 110 degrees . In addition, the importance of the diffuser plate's surface topography is discussed, with elevated roughness acting to reduce the effect of surface chemistry in some instances. PMID- 26754878 TI - A new vinyl selenone-based domino approach to spirocyclopropyl oxindoles endowed with anti-HIV RT activity. AB - Herein, we disclose a general and flexible access to spirocyclopropyl oxindoles by a domino Michael/intramolecular nucleophilic substitution pathway with variously substituted vinyl selenones and enolizable oxindoles in aqueous sodium hydroxide solution. The spirocyclopropyl oxindole being a privileged scaffold, some of the synthesized compounds were selected for biological evaluation. Compound showed selective anti-HIV-1 activity thanks to its ability to inhibit the reverse transcriptase. PMID- 26754911 TI - Synthesis of sub-nanometer gold particles on modified silica. AB - The deposition of gold on silica tends to give large particles when using conventional techniques. We report the preparation of 0.8 +/- 0.2 nm particles on a modified SBA-15 support. The method involves the functionalization of silica with amine groups and deposition of gold at basic pH. These catalysts are highly active and selective in the dehydrogenation of formic acid. PMID- 26754874 TI - The chromosome 3q26 OncCassette: A multigenic driver of human cancer. AB - Recurrent copy number variations (CNVs) are genetic alterations commonly observed in human tumors. One of the most frequent CNVs in human tumors involves copy number gains (CNGs) at chromosome 3q26, which is estimated to occur in >20% of human tumors. The high prevalence and frequent occurrence of 3q26 CNG suggest that it drives the biology of tumors harboring this genetic alteration. The chromosomal region subject to CNG (the 3q26 amplicon) spans from chromosome 3q26 to q29, a region containing ~200 protein-encoding genes. The large number of genes within the amplicon makes it difficult to identify relevant oncogenic target(s). Whereas a number of genes in this region have been linked to the transformed phenotype, recent studies indicate a high level of cooperativity among a subset of frequently amplified 3q26 genes. Here we use a novel bioinformatics approach to identify potential driver genes within the recurrent 3q26 amplicon in lung squamous cell carcinoma (LSCC). Our analysis reveals a set of 35 3q26 amplicon genes that are coordinately amplified and overexpressed in human LSCC tumors, and that also map to a major LSCC susceptibility locus identified on mouse chromosome 3 that is syntenic with human chromosome 3q26. Pathway analysis reveals that 21 of these genes exist within a single predicted network module. Four 3q26 genes, SOX2, ECT2, PRKCI and PI3KCA occupy the hub of this network module and serve as nodal genes around which the network is organized. Integration of available genetic, genomic, biochemical and functional data demonstrates that SOX2, ECT2, PRKCI and PIK3CA are cooperating oncogenes that function within an integrated cell signaling network that drives a highly aggressive, stem-like phenotype in LSCC tumors harboring 3q26 amplification. Based on the high level of genomic, genetic, biochemical and functional integration amongst these 4 3q26 nodal genes, we propose that they are the key oncogenic targets of the 3q26 amplicon and together define a "3q26 OncCassette" that mediates 3q26 CNG-driven tumorigenesis. Genomic analysis indicates that the 3q26 OncCassette also operates in other major tumor types that exhibit frequent 3q26 CNGs, including head and neck squamous cell carcinoma (HNSCC), ovarian serous cancer and cervical cancer. Finally, we discuss how the 3q26 OncCassette represents a tractable target for development of novel therapeutic intervention strategies that hold promise for improving treatment of 3q26-driven cancers. PMID- 26754913 TI - Nanostructured lipid-carrageenan hybrid carriers (NLCCs) for controlled delivery of mitoxantrone hydrochloride to enhance anticancer activity bypassing the BCRP mediated efflux. AB - Novel nanostructured lipid-carrageenan hybrid carriers (NLCCs) were exploited for controlled delivery of water soluble chemotherapeutic agent mitoxantrone hydrochloride (MTO) with high loading capacity, sustained release property, and potential for improving oral bioavailability and antitumor efficacy. By introducing the negative polymer of carrageenan, MTO was highly incorporated into NLCCs with encapsulation efficiency of 95.8% by electrostatic interaction. In vivo pharmacokinetics of MTO solution (MTO-Sol) and MTO-NLCCs in rats demonstrated that the apparent bioavailability of MTO-NLCCs was increased to approximate 3.5-fold compared to that of MTO-Sol. The cytotoxicity investigations by MTT method indicated that NLCCs could significantly enhanced the antitumor efficacy against resistant MCF-7/MX cells. The relative cellular association of MTO-NLCCs was 9.2-fold higher than that of MTO-Sol in breast cancer resistance protein (BCRP) over-expressing MCF-7/MX cells, implying that BCRP-mediated drug efflux was diminished by the introduction of NLCCs. The endocytosis inhibition study implied that the NLCCs entered the MCF-7/MX cells by clathrin-mediated endocytosis process, which can bypass the efflux of MTO mediated by BCRP. The new developed NLCCs provide an effective strategy for oral delivery of water-soluble MTO with improved encapsulation efficiency, oral bioavailability, and cytotoxicity against resistant breast cancer cells. PMID- 26754914 TI - Multiple-breed reaction norm animal model accounting for robustness and heteroskedastic in a Nelore-Angus crossed population. AB - Our objective was to genetically characterize post-weaning weight gain (PWG), over a 345-day period after weaning, of Brangus-Ibage (Nelore*Angus) cattle. Records (n=4016) were from the foundation herd of the Embrapa South Livestock Center. A Bayesian approach was used to assess genotype by environment (G*E) interaction and to identify a suitable model for the estimation of genetic parameters and use in genetic evaluation. A robust and heteroscedastic reaction norm multiple-breed animal model was proposed. The model accounted for heterogeneity of residual variance associated with effects of breed, heterozygosity, sex and contemporary group; and was robust with respect to outliers. Additive genetic effects were modeled for the intercept and slope of a reaction norm to changes in the environmental gradient. Inference was based on Monte Carlo Markov Chain of 110 000 cycles, after 10 000 cycles of burn-in. Bayesian model choice criteria indicated the proposed model was superior to simpler sub-models that did not account for G*E interaction, multiple-breed structure, robustness and heteroscedasticity. We conclude that, for the Brangus Ibage population, these factors should be jointly accounted for in genetic evaluation of PWG. Heritability estimates increased proportionally with improvement in the environmental conditions gradient. Therefore, an increased proportion of differences in performance among animals were explained by genetic factors rather than environmental factors as rearing conditions improved. As a consequence response to selection may be increased in favorable environments. PMID- 26754912 TI - Flavone synthases from Lonicera japonica and L. macranthoides reveal differential flavone accumulation. AB - Flavones are important secondary metabolites found in many plants. In Lonicera species, flavones contribute both physiological and pharmaceutical properties. However, flavone synthase (FNS), the key enzyme responsible for flavone biosynthesis, has not yet been characterized in Lonicera species. In this study, FNSII genes were identified from Lonicera japonica Thunb. and L. macranthoides Hand.-Mazz. In the presence of NADPH, the recombinant cytochrome P450 proteins encoded by LjFNSII-1.1, LjFNSII-2.1, and LmFNSII-1.1 converted eriodictyol, naringenin, and liquiritigenin to the corresponding flavones directly. The different catalytic properties between LjFNSII-2.1 and LjFNSII-1.1 were caused by a single amino acid substitution at position 242 (glutamic acid to lysine). A methionine at position 206 and a leucine at position 381 contributed considerably to the high catalytic activity of LjFNSII-1.1. In addition, LjFNSII-1.1&2.1 and LmFNSII-1.1 also biosynthesize flavones that were further modified by O glycosylation in transgenic tobacco. The expression levels of the FNSII genes were consistent with flavone accumulation patterns in flower buds. Our findings suggested that the weak catalytic activity of LmFNSII-1.1 and the relatively low expression of LmFNSII-1.1 in flowers might be responsible for the low levels of flavone accumulation in flower buds of L. macranthoides. PMID- 26754916 TI - Retraction notice to "Involvement of insulin-like growth factor-1 in chemotherapy related cognitive impairment" [BBR 279, (2015) 112 - 122]. PMID- 26754915 TI - Yap is required for ependymal integrity and is suppressed in LPA-induced hydrocephalus. AB - Timely generation and normal maturation of ependymal cells along the aqueduct are critical for preventing physical blockage between the third and fourth ventricles and the development of fetal non-communicating hydrocephalus. Our study identifies Yap, the downstream effector of the evolutionarily conserved Hippo pathway, as a central regulator for generating developmentally controlled ependymal cells along the ventricular lining of the aqueduct. Yap function is necessary for proper proliferation of progenitors and apical attachment of ependymal precursor cells. Importantly, an injury signal initiated by lysophosphatidic acid (LPA), an upstream regulator of Yap that can cause fetal haemorrhagic hydrocephalus, deregulates Yap in the developing aqueduct. LPA exposure leads to the loss of N-cadherin concentrations at the apical endfeet, which can be partially restored by forced Yap expression and more efficiently by phosphomimetic Yap. These results reveal a novel function of Yap in retaining tissue junctions during normal development and after fetal brain injury. PMID- 26754919 TI - The milk line - where mammary gland meets mathematics. PMID- 26754917 TI - Molecular basis for allosteric specificity regulation in class Ia ribonucleotide reductase from Escherichia coli. AB - Ribonucleotide reductase (RNR) converts ribonucleotides to deoxyribonucleotides, a reaction that is essential for DNA biosynthesis and repair. This enzyme is responsible for reducing all four ribonucleotide substrates, with specificity regulated by the binding of an effector to a distal allosteric site. In all characterized RNRs, the binding of effector dATP alters the active site to select for pyrimidines over purines, whereas effectors dGTP and TTP select for substrates ADP and GDP, respectively. Here, we have determined structures of Escherichia coli class Ia RNR with all four substrate/specificity effector-pairs bound (CDP/dATP, UDP/dATP, ADP/dGTP, GDP/TTP) that reveal the conformational rearrangements responsible for this remarkable allostery. These structures delineate how RNR 'reads' the base of each effector and communicates substrate preference to the active site by forming differential hydrogen bonds, thereby maintaining the proper balance of deoxynucleotides in the cell. PMID- 26754918 TI - Transcriptomic Changes in Osteoblasts Following Endothelial Cell-Cocultivation Suggest a Role of Extracellular Matrix in Cellular Interaction. AB - Vascularization is important for bone development, fracture healing and engineering of artificial bone tissue. In the context of bone tissue engineering, it was shown that coimplantation of human primary umbilical vein endothelial cells (HUVECs) and human osteoblasts (hOBs) results in the formation of functional blood vessels and enhanced bone regeneration. Implanted endothelial cells do not only contribute to blood vessel formation, but also support proliferation, cell survival and osteogenic differentiation of coimplanted hOBs. These effects are partially mediated by direct heterotypic cell contacts. In a previous report we could show that cocultivated hOBs strongly increase the expression of genes involved in extracellular matrix (ECM) formation in HUVECs, suggesting that ECM may be involved in the intercellular communication between hOBs and HUVECs. The present study aimed at investigating whether comparable changes occur in hOBs. We therefore performed a microarray analysis of hOBs cultivated in direct contact with HUVECs, revealing 1,004 differentially expressed genes. The differentially expressed genes could be assigned to the functional clusters ECM, proliferation, apoptosis and osteogenic differentiation. The microarray data could be confirmed by performing quantitative real time RT PCR on selected genes. Furthermore, we could show that the ECM produced by HUVECs increased the expression of the osteogenic differentiation marker alkaline phosphatase (ALP) in hOBs. In summary, our data demonstrate that HUVECs provoke complex changes in gene expression patterns in cocultivated hOBs and that ECM plays and important role in this interaction. J. Cell. Biochem. 117: 1869-1879, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26754921 TI - My approach to using coronary artery calcium scoring in primary prevention of atherosclerotic cardiovascular disease. PMID- 26754920 TI - The cell aggregating propensity of probiotic actinobacterial isolates: isolation and characterization of the aggregation inducing peptide pheromone. AB - The auto-aggregating ability of a probiotic is a prerequisite for colonization and protection of the gastrointestinal tract, whereas co-aggregation provides a close interaction with pathogenic bacteria. Peptide pheromone mediated signaling has been studied in several systems. However, it has not yet been explored in prokaryotes, especially actinobacteria. Hence, in the present study, the diffusible aggregation promoting factor was purified from the culture supernatant of a potent actinobacterial probiont and characterized using 20 different actinobacterial cultures isolated from the gut region of chicken and goat. The results showed that the pheromone-like compound induces the aggregation propensity of treated isolates. The factor was found to be a heat stable, acidic pH resistant, low molecular weight peptide which enhances the biofilm forming ability of other actinobacterial isolates. The aggregation promoting factor represents a bacterial sex factor (pheromone) and its characterization confirms its usage in the probiotic formulation. PMID- 26754923 TI - Diastereodivergent Catalysis Using Modularly Designed Organocatalysts: Synthesis of both cis- and trans-Fused Pyrano[2,3-b]pyrans. AB - Both enantiomers of cis- and trans-fused 3,4,4a,8a-tetrahydro-2H,5H-pyrano[2,3 b]pyran-7-carboxylates have been obtained in high diastereoselectivities and enantioselectivities from the same starting materials using a tandem inverse electron-demand hetero-Diels-Alder/oxa-Michael reaction catalyzed by modularly designed organocatalysts (MDOs). Diastereodivergence was achieved in these reactions through the direct control of the stereochemistry of the bridgehead atoms of the fused ring using new MDOs self-assembled from both enantiomers of proline and cinchona alkaloid thiourea derivatives. PMID- 26754924 TI - Adverse Drug Reaction Reporting in Africa and a Comparison of Individual Case Safety Report Characteristics Between Africa and the Rest of the World: Analyses of Spontaneous Reports in VigiBase(r). AB - INTRODUCTION: Following the start of the World Health Organization (WHO) Programme for International Drug Monitoring (PIDM) by 10 member countries in 1968, it took another 24 years for the first two African countries to join in 1992, by which time the number of member countries in the PIDM had grown to 33. Whilst pharmacovigilance (PV), including the submission of individual case safety reports (ICSR) to VigiBase((r)), the WHO global ICSR database, is growing in Africa, no data have been published on the growth of ICSR reporting from Africa and how the features of ICSRs from Africa compare with the rest of the world (RoW). OBJECTIVE: The objective of this paper was to provide an overview of the growth of national PV centres in Africa, the reporting of ICSRs by African countries, and the features of ICSRs from Africa, and to compare ICSRs from Africa with the RoW. METHODS: The search and analysis interface of VigiBase((r))- VigiLyze((r))--was used to characterise ICSRs submitted by African countries and the RoW. The distribution of ICSRs by African countries was listed and characterised by anatomic therapeutic chemical (ATC) code, Medical Dictionary for Regulatory Activities (MedDRA((r))) system organ class (SOC) classification, and patient age and sex. The case-defining features of ICSRs between Africa and the RoW were also compared. RESULTS: The number of African countries in the PIDM increased from 2 in 1992 to 35 at the end of September 2015, and African PIDM members have cumulatively submitted 103,499 ICSRs (0.88 % of global ICSRs) to VigiBase((r)). The main class of products in African ICSRs are nucleoside and nucleotide reverse transcriptase inhibitors (14.04 %), non-nucleoside reverse transcriptase inhibitors (9.09 %), antivirals for the treatment of HIV infections (5.50 %), combinations of sulfonamides and trimethoprim (2.98 %) and angiotensin converting enzyme (ACE) inhibitors (2.42 %). The main product classes implicated in ICSRs from the RoW are tumour necrosis factor-alpha (TNFalpha) inhibitors (5.29 %), topical nonsteroidal anti-inflammatory preparations (2.26 %), selective immunosuppressants (2.08 %), selective serotonin reuptake inhibitors (2.04 %) and HMG CoA reductase inhibitors (1.85 %). The main SOCs reported from Africa versus the RoW include skin and subcutaneous tissue disorders (31.14 % vs. 19.58 %), general disorders and administration site conditions (20.91 % vs. 30.49 %) and nervous system disorders (17.48 % vs. 19.13 %). The 18-44 years age group dominated ICSRs from Africa, while the 45-64 years age group dominated the RoW. Identical proportions of females (57 % Africa and the RoW) and males (37 % Africa and the RoW) were represented. CONCLUSIONS: As at the end of September 2015, 35 of 54 African countries were Full Member countries of the PIDM. Although the number of ICSRs from Africa has increased substantially, ICSRs from Africa still make up <1 % of the global total in VigiBase((r)). The features of ICSRs from Africa differ to those from the RoW in relation to the classes of products as well as age group of patients affected. The gender of patients represented in these ICSRs are identical. PMID- 26754922 TI - Effective strategies to reduce commercial tobacco use in Indigenous communities globally: A systematic review. AB - BACKGROUND: All over the world, Indigenous populations have remarkably high rates of commercial tobacco use compared to non-Indigenous groups. The high rates of commercial tobacco use in Indigenous populations have led to a variety of health issues and lower life expectancy than the general population. The objectives of this systematic review were to investigate changes in the initiation, consumption and quit rates of commercial tobacco use as well as changes in knowledge, prevalence, community interest, and smoke-free environments in Indigenous populations. We also aimed to understand which interventions had broad reach, what the common elements that supported positive change were and how Aboriginal self-determination was reflected in program implementation. METHODS: We undertook a systematic review of peer-reviewed publications and grey literature selected from seven databases and 43 electronic sources. We included studies between 1994 and 2015 if they addressed an intervention (including provision of a health service or program, education or training programs) aimed to reduce the use of commercial tobacco use in Indigenous communities globally. Systematic cross regional canvassing of informants in Canada and internationally with knowledge of Indigenous health and/or tobacco control provided further leads about commercial tobacco reduction interventions. We extracted data on program characteristics, study design and learnings including successes and challenges. RESULTS: In the process of this review, we investigated 73 commercial tobacco control interventions in Indigenous communities globally. These interventions incorporated a myriad of activities to reduce, cease or protect Indigenous peoples from the harms of commercial tobacco use. Interventions were successful in producing positive changes in initiation, consumption and quit rates. Interventions also facilitated increases in the number of smoke-free environments, greater understandings of the harms of commercial tobacco use and a growing community interest in addressing the high rates of commercial tobacco use. Interventions were unable to produce any measured change in prevalence rates. CONCLUSIONS: The extent of this research in Indigenous communities globally suggests a growing prioritization and readiness to address the high rates of commercial tobacco use through the use of both comprehensive and tailored interventions. A comprehensive approach that uses multiple activities, the centring of Aboriginal leadership, long term community investments, and the provision of culturally appropriate health materials and activities appear to have an important influence in producing desired change. PMID- 26754926 TI - Bayesian estimation of sensitivity and specificity of a commercial serum/milk ELISA against the Mycobacterium avium subsp. Paratuberculosis (MAP) antibody response for each lactation stage in Greek dairy sheep. AB - A total of 854 paired milk and blood samples were collected from ewes of a Greek flock and used to estimate the sensitivity and specificity of a commercial ELISA for detection of Mycobacterium avium subsp. paratuberculosis (MAP) specific antibodies in each stage of lactation. We implemented Bayesian mixture models to derive the distributions of the test response for the healthy and the infected ewes. In the colostrum period, early, mid and late lactation stage the median values of the area under the curves (AUC) were 0.61 (95% credible interval: 0.50; 0.84), 0.61 (0.51;0.84), 0.65 (0.51;0.91), 0.65(0.51;0.89) for the serum ELISA and and 0.60 (0.50; 0.84), 0.61 (0.50; 0.84), 0.67(0.51; 0.91), 0.66(0.50; 0.90) for the milk ELISA, respectively. Both serum and milk ELISA had low to average overall discriminatory ability as measured by the area under the curves and comparable sensitivities and specificities at the recommended cutoffs. PMID- 26754927 TI - Routine clinical inspections in Norwegian marine salmonid sites: A key role in surveillance for freedom from pathogenic viral haemorrhagic septicaemia (VHS). AB - Since the mid-1980s, clinical inspections of aquaculture sites carried out on a regular basis by authorized veterinarians and fish health biologists (known as fish health services: FHS) have been an essential part of aquatic animal health surveillance in Norway. The aims of the present study were (1) to evaluate the performance of FHS routine clinical inspections for the detection of VHS and (2) to explore the effectiveness of risk-based prioritisation of FHS inspections for demonstrating freedom from VHS in marine salmonid sites in Norway. A stochastic simulation model was developed to estimate site sensitivity (SeS), population sensitivity (SeP), and probability of freedom (PFree). The estimation of SeS takes into consideration the probability that FHS submit samples if a site is infected, the probability that a sample is tested if submitted, the effective probability of infection in fish with clinical signs, laboratory test sensitivity, and the number of tested samples. SeP and PFree were estimated on a monthly basis over a 12 month period for six alternative surveillance scenarios and included the risk factors: region, species, area production density, and biosecurity level. Model results indicate that the current surveillance system, based on routine inspections by the FHS has a high capability for detecting VHS and that there is a high probability of freedom from VHS in Norwegian marine farmed salmonids (PFree >95%). Sensitivity analysis identified the probabilities that samples are submitted and submitted samples are tested, as the most influential input variables. The model provides a supporting tool for evaluation of potential changes in the surveillance strategy, and can be viewed as a platform for similar exotic viral infectious diseases in marine salmonid farming in Norway, if they share similar risk factors. PMID- 26754925 TI - IER5 generates a novel hypo-phosphorylated active form of HSF1 and contributes to tumorigenesis. AB - The transcription factors HSF1 and p53 both modulate the stress response, thereby protecting and facilitating the recovery of stressed cells, but both have the potential to promote tumor development. Here we show that a p53 target gene, IER5, encodes an activator of HSF1. IER5 forms a ternary complex with HSF1 and the phosphatase PP2A, and promotes the dephosphorylation of HSF1 at numbers of serine and threonine residues, generating a novel, hypo-phosphorylated active form of HSF1. IER5 is also transcriptionally upregulated in various cancers, although this upregulation is not always p53-dependent. The IER5 locus is associated with a so-called super enhancer, frequently associated with hyperactivated oncogenes in cancer cell lines. Enhanced expression of IER5 induces abnormal HSF1 activation in cancer cells and contributes to the proliferation of these cells under stressed conditions. These results reveal the existence of a novel IER5-mediated cancer regulation pathway that is responsible for the activation of HSF1 observed in various cancers. PMID- 26754928 TI - Fraction of bovine leukemia virus-infected dairy cattle developing enzootic bovine leukosis. AB - Enzootic bovine leucosis (EBL) is a transmissible disease caused by the bovine leukemia virus that is prevalent in cattle herds in many countries. Only a small fraction of infected animals develops clinical symptoms, such as malignant lymphosarcoma, after a long incubation period. In the present study, we aimed to determine the fraction of EBL-infected dairy cattle that develop lymphosarcoma and the length of the incubation period before clinical symptoms emerge. These parameters were determined by a mathematical modeling approach based on the maximum-likelihood estimation method, using the results of a nationwide serological survey of prevalence in cattle and passive surveillance records. The best-fit distribution to estimate the disease incubation period was determined to be the Weibull distribution, with a median and average incubation period of 7.0 years. The fraction of infected animals developing clinical disease was estimated to be 1.4% with a 95% confidence interval of 1.2-1.6%. The parameters estimated here contribute to an examination of efficient control strategies making quantitative evaluation available. PMID- 26754929 TI - Reply to letter inflammatory markers in patients with obstructive sleep apnea. PMID- 26754930 TI - Inflammatory markers in patients with obstructive sleep apnea. PMID- 26754932 TI - Efficacy of EPAP. PMID- 26754931 TI - Oral appliance in sleep apnea treatment: respiratory and clinical effects and long-term adherence. AB - PURPOSE: There is an increasing tendency to use oral appliance (OA) as an alternative treatment for sleep apnea. Here we report the long-term adherence and clinical effects of OA therapy. METHODS: All sleep apnea patients treated at the Department of Dentistry between the years 2006 and 2013 (n = 1208) were reviewed. A questionnaire about OA adherence, asthma symptoms (Asthma Control TestTM, ACT), and general health was sent to all patients who continued OA therapy after the 1 month follow-up visit (n = 811). OA was adjusted to obtain at least 70 % of the maximal protrusion of the mandible. RESULTS: The response rate was 37.4 % (99 women, 204 men). The mean +/- SD age and BMI were 58.7 +/- 10.3 years and 27.3 +/ 4.0 kg/m(2), respectively. During the mean follow-up period of 3.3 years, there was no significant variation in BMI. Forty-one patients abandoned OA therapy yielding an adherence rate of 86 %. Ninety-seven percent of patients used OA >=4 h/day, and the mean daily use was 7.2 +/- 1.1 h. The ACT score improved with OA use from 16.0 +/- 5.9 to 20.1 +/- 3.8 (p = 0.004), indicating better asthma control. The apnea and hypopnea index decreased significantly from 27 +/- 19 at baseline to 10 +/- 10 with OA therapy (p = 0.001). CONCLUSIONS: After a 1-month trial period, the long-term adherence to oral appliance was good. OA therapy decreased apneas and hypopneas significantly, and its long-term use was associated with an improvement in respiratory and asthma symptoms. PMID- 26754934 TI - Preemptive therapy of spontaneous fungal peritonitis. PMID- 26754933 TI - A telehealth program for CPAP adherence reduces labor and yields similar adherence and efficacy when compared to standard of care. AB - PURPOSE: This study evaluated the effectiveness and coaching labor requirements of a web-based automated telehealth (TH) messaging program compared with standard of care (SOC) in newly diagnosed patients with obstructive sleep apnea (OSA). METHODS: In this non-blinded, multicenter, prospective study, all patients were started on continuous positive airway pressure (CPAP) with heated humidification and a wireless modem. They all received standardized CPAP education and setup. Patients in the TH group (n = 58) received an automated series of text messages and/or e-mails that were triggered by preset conditions. Patients in the SOC group (n = 64) received scheduled calls on days 1, 7, 14, and 30. Additional contacts were allowed for patients in both groups as deemed clinically necessary. Coaching labor was calculated by totaling the number and type of patient contacts and assigning historical time values. RESULTS: One hundred twenty-two patients were included in the final analysis. There were no statistically significant differences between the TH and SOC groups for Medicare adherence (83 vs. 73 %), daily CPAP usage (5.1 +/- 1.9 h vs. 4.7 +/- 2.1 h), CPAP efficacy (mean residual apnea-hypopnea index (3.0 +/- 4.1/h vs. 2.8 +/- 3.8/h), or change in Epworth Sleepiness Scale score (-5.8 +/- 5.5 vs. -5.1 +/- 5.9), although all trends favored the TH group. There was, however, a significant reduction in the number of minutes coaching required per patient in the TH vs. SOC group (23.9 +/- 26 vs. 58.3 +/- 25, 59 % reduction; p < 0.0001). CONCLUSIONS: Use of a web-based telehealth program for CPAP adherence coaching significantly reduced the coaching labor requirement compared with SOC, while maintaining similar adherence and effectiveness. PMID- 26754936 TI - Probing Sub-atomistic Free-Volume Imperfections in Dry-Milled Nanoarsenicals with PAL Spectroscopy. AB - Structural transformations caused by coarse-grained powdering and fine-grained mechanochemical milling in a dry mode were probed in high-temperature modification of tetra-arsenic tetra-sulfide known as beta-As4S4. In respect to X ray diffraction analysis, the characteristic sizes of beta-As4S4 crystallites in these coarse- and fine-grained powdered pellets were 90 and 40 nm, respectively. Positron annihilation lifetime spectroscopy was employed to characterize transformations occurred in free-volume structure of these nanoarsenicals. Experimentally measured positron lifetime spectra were parameterized in respect to three- or two-term fitting procedures and respectively compared with those accumulated for single crystalline realgar alpha-As4S4 polymorph. The effect of coarse-grained powdering was found to result in generation of large amount of positron and positronium Ps trapping sites inside arsenicals in addition to existing ones. In fine-grained powdered beta-As4S4 pellets, the positron trapping sites with characteristic free volumes close to bi- and tri-atomic vacancies were evidently dominated. These defects were supposed to originate from grain boundary regions and interfacial free volumes near aggregated beta-As4S4 crystallites. Thus, the cumulative production of different positron traps with lifetimes close to defect-related lifetimes in realgar alpha-As4S4 polymorph was detected in fine grained milled samples. PMID- 26754935 TI - Macrophage Infiltration and Alternative Activation during Wound Healing Promote MEK1-Induced Skin Carcinogenesis. AB - Macrophages are essential for the progression and maintenance of many cancers, but their role during the earliest stages of tumor formation is unclear. To test this, we used a previously described transgenic mouse model of wound-induced skin tumorigenesis, in which expression of constitutively active MEK1 in differentiating epidermal cells results in chronic inflammation (InvEE mice). Upon wounding, the number of epidermal and dermal monocytes and macrophages increased in wild-type and InvEE skin, but the increase was greater, more rapid, and more sustained in InvEE skin. Macrophage ablation reduced tumor incidence. Furthermore, bioluminescent imaging in live mice to monitor macrophage flux at wound sites revealed that macrophage accumulation was predictive of tumor formation; wounds with the greatest number of macrophages at day 5 went on to develop tumors. Gene expression profiling of flow-sorted monocytes, macrophages, and T cells from InvEE and wild-type skin showed that as wound healing progressed, InvEE macrophages altered their phenotype. Throughout wound healing and after wound closure, InvEE macrophages demonstrated sustained upregulation of several markers implicated in alternative macrophage activation including arginase-1 (ARG1) and mannose receptor (CD206). Notably, inhibition of ARG1 activity significantly reduced tumor formation and epidermal proliferation in vivo, whereas addition of L-arginase to cultured keratinocytes stimulated proliferation. We conclude that macrophages play a key role in early, inflammation-mediated skin tumorigenesis, with mechanistic evidence suggesting that ARG1 secretion drives tumor development by stimulating epidermal cell proliferation. These findings highlight the importance of cancer immunotherapies aiming to polarize tumor-associated macrophages toward an antitumor phenotype. PMID- 26754937 TI - Formation of Boron-Carbon Nanosheets and Bilayers in Boron-Doped Diamond: Origin of Metallicity and Superconductivity. AB - The insufficient data on a structure of the boron-doped diamond (BDD) has frustrated efforts to fully understand the fascinating electronic properties of this material and how they evolve with doping. We have employed X-ray diffraction and Raman scattering for detailed study of the large-sized BDD single crystals. We demonstrate a formation of boron-carbon (B-C) nanosheets and bilayers in BDD with increasing boron concentration. An incorporation of two boron atoms in the diamond unit cell plays a key role for the B-C nanosheets and bilayer formation. Evidence for these B-C bilayers which are parallel to {111} planes is provided by the observation of high-order, super-lattice reflections in X-ray diffraction and Laue patterns. B-C nanosheets and bilayers minimize the strain energy and affect the electronic structure of BDD. A new shallow acceptor level associated with B-C nanosheets at ~37 meV and the spin-orbit splitting of the valence band of ~6 meV are observed in electronic Raman scattering. We identified that the superconducting transitions occur in the (111) BDD surfaces only. We believe that the origin of Mott and superconducting transitions is associated with the two dimensional (2D) misfit layer structure of BDD. A model for the BDD crystal structure, based on X-ray and Raman data, is proposed and confirmed by density functional theoretical calculation. PMID- 26754938 TI - Hydrothermal Etching Treatment to Rutile TiO2 Nanorod Arrays for Improving the Efficiency of CdS-Sensitized TiO2 Solar Cells. AB - Highly ordered TiO2 nanorod arrays (NRAs) were directly grown on an F:SnO2 (FTO) substrate without any seed layer by hydrothermal route. For a larger surface area, the second-step hydrothermal treatment in hydrochloric acid was carried out to the as-prepared TiO2 NRAs. The results showed that the center portion of the TiO2 nanorods were dissolved in the etching solution to form a nanocave at the initial etching process. As the etching time extended, the tip parts of the nanocave wall split into lots of nanowires with a reduced diameter, giving rise to a remarkable increase of specific surface area for the TiO2 NRAs. The TiO2 films after etching treatment were sensitized by CdS quantum dots (QDs) to fabricate quantum dot-sensitized solar cells (QDSSCs), which exhibited a significant improvement in the photocurrent density in comparison with that of the un-treated device, this mainly attributed to the enhancement of QD loading and diffused reflectance ability. Through modifying the etching TiO2 films with TiCl4, a relatively high power conversion efficiency (PCE) of 3.14 % was obtained after optimizing the etching time. PMID- 26754939 TI - Photo-Response of Functionalized Self-Assembled Graphene Oxide on Zinc Oxide Heterostructure to UV Illumination. AB - Convective assembly technique which is a simple and scalable method was used for coating uniform graphene oxide (GO) nanosheets on zinc oxide (ZnO) thin films. Upon UV irradiation, an enhancement in the on-off ratio was observed after functionalizing ZnO films by GO nanosheets. The calculations of on-off ratio, the device responsivity, and the external quantum efficiency were investigated and implied that the GO layer provides a stable pathway for electron transport. Structural investigations of the assembled GO and the heterostructure of GO on ZnO were performed using scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). The covered GO layer has a wide continuous area, with wrinkles and folds at the edges. In addition, the phonon lattice vibrations were investigated by Raman analysis. For GO and the heterostructure, a little change in the ratio between the D-band and G-band was found which means that no additional defects were formed within the heterostructure. PMID- 26754940 TI - Simple method for high-performance stretchable composite conductors with entrapped air bubbles. AB - We integrate air bubbles into conductive elastic composite-based stretchable conductors to make them mechanically less stiff and electrically more robust against physical deformations. A surfactant facilitates both the formation and maintenance of air bubbles inside the elastic composites, leading to a simple fabrication of bubble-entrapped stretchable conductors. Based on the unique bubble-entrapped architecture, the elastic properties are greatly enhanced and the resistance change in response to tensile strains can clearly be controlled. The bubble-entrapped conductor achieves ~80 % elongation at ~3.4 times lower stress and ~44.8 % smaller change in the electrical resistance at 80 % tensile strain, compared to bare conductor without air bubbles. PMID- 26754941 TI - Change of Energy of the Cubic Subnanocluster of Iron Under Influence of Interstitial and Substitutional Atoms. AB - Energy change of an iron face-centred cubic subnanocluster was evaluated using molecular mechanics method depending on the position of a carbon interstitial atom and substitutional atoms of nickel. Calculations of all possible positions of impurity atoms show that the energy change of the system are discrete and at certain positions of the atoms are close to continuous.In terms of energy, when all impurity atoms are on the same edge of an atomic cluster, their positions are more advantageous. The presence of nickel atoms on the edge of a cubic cluster resulted in decrease of potential barrier for a carbon atom and decrease in energy in the whole cluster. A similar drift of a carbon atom from central octahedral interstitial site to the surface in the direction <011> occurred under the influence of surface factors.Such configuration corresponds to decreasing symmetry and increasing the number of possible energy states of a subnanocluster, and it corresponds to the condition of spontaneous crystallization process in an isolated system.Taking into account accidental positions of the nickel atom in the iron cluster, such behaviour of the carbon atom can explain the mechanism of growth of a new phase and formation of new clusters in the presence of other kind of atoms because of surface influence. PMID- 26754942 TI - Electrostrictive Mechanism of Nanostructure Formation at Solid Surfaces Irradiated by Femtosecond Laser Pulses. AB - The significance of the mechanical pressure of light in creation of laser-induced periodic surface structures (LIPSSs) is investigated. Distributions of the electrically induced normal pressure and tangential stress at the illuminated solid surface, as well as the field of volume electrostrictive forces, are calculated taking into account surface plasmon polariton (SPP) excitation. Based on these calculations, we predict surface destruction and structure formation due to inelastic deformations during single femtosecond pulses. The calculated fields of the electromagnetic forces are found to agree well with the experimental ripple structures. We thus conclude that the electrostrictive forces can explain the origin of the periodic ripple structures. PMID- 26754943 TI - A yeast strain associated to Anopheles mosquitoes produces a toxin able to kill malaria parasites. AB - BACKGROUND: Malaria control strategies are focusing on new approaches, such as the symbiotic control, which consists in the use of microbial symbionts to prevent parasite development in the mosquito gut and to block the transmission of the infection to humans. Several microbes, bacteria and fungi, have been proposed for malaria or other mosquito-borne diseases control strategies. Among these, the yeast Wickerhamomyces anomalus has been recently isolated from the gut of Anopheles mosquitoes, where it releases a natural antimicrobial toxin. Interestingly, many environmental strains of W. anomalus exert a wide anti bacterial/fungal activity and some of these 'killer' yeasts are already used in industrial applications as food and feed bio-preservation agents. Since a few studies showed that W. anomalus killer strains have antimicrobial effects also against protozoan parasites, the possible anti-plasmodial activity of the yeast was investigated. METHODS: A yeast killer toxin (KT), purified through combined chromatographic techniques from a W. anomalus strain isolated from the malaria vector Anopheles stephensi, was tested as an effector molecule to target the sporogonic stages of the rodent malaria parasite Plasmodium berghei, in vitro. Giemsa staining was used to detect morphological damages in zygotes/ookinetes after treatment with the KT. Furthermore, the possible mechanism of action of the KT was investigated pre-incubating the protein with castanospermine, an inhibitor of beta-glucanase activity. RESULTS: A strong anti-plasmodial effect was observed when the P. berghei sporogonic stages were treated with KT, obtaining an inhibition percentage up to around 90%. Microscopy analysis revealed several ookinete alterations at morphological and structural level, suggesting the direct implication of the KT-enzymatic activity. Moreover, evidences of the reduction of KT activity upon treatment with castanospermine propose a beta-glucanase-mediated activity. CONCLUSION: The results showed the in vitro killing efficacy of a protein produced by a mosquito strain of W. anomalus against malaria parasites. Further studies are required to test the KT activity against the sporogonic stages in vivo, nevertheless this work opens new perspectives for the possible use of killer strains in innovative strategies to impede the development of the malaria parasite in mosquito vectors by the means of microbial symbionts. PMID- 26754947 TI - The association of body height, height variability and inequality. AB - Body height is associated with environmental conditions. It has been suggested that under poor conditions when inequality within a population increases, also the variability in height tends to increase. We studied the association of body height, within-country variability in height and geographic and historic origin in 767 growth studies carried out in 80 countries, published between 1794 and 2013, with data on N = 78,184 infants age 2 years, and N = 2,130,729 juveniles age 7 years. The studies represent almost the whole spectrum of economic diversity in human societies since the end-18(th) century. 207 studies contained data for both infants and juveniles with 50,819 subjects (age 2), and 123,078 subjects (age 7). Multiple linear regressions showed significant interactions between height, sex, historic year of the study, geographic origin, and within study standard deviation for height with multiple R-squared = 0.527, p < 0.001, at age 2, and multiple R-squared = 0.436, p < 0.001, at age 7. Yet, the two age groups differed in respect to within-study standard deviation for height. We found a significant association between body height and within-study standard deviation for height only at age 2: tall infant populations are less variable in height (r = -0.27, p < 0.01). There was no such association in children aged 7 years. Tall children from affluent and short children from less affluent countries do not differ in the variability of body height. The data suggest that the 'environmental adversity' hypothesis for variation in growth: small mean values for height go along with large standard deviations for height, does not apply for children at age 7. PMID- 26754945 TI - Modulation of the human gut microbiota by dietary fibres occurs at the species level. AB - BACKGROUND: Dietary intake of specific non-digestible carbohydrates (including prebiotics) is increasingly seen as a highly effective approach for manipulating the composition and activities of the human gut microbiota to benefit health. Nevertheless, surprisingly little is known about the global response of the microbial community to particular carbohydrates. Recent in vivo dietary studies have demonstrated that the species composition of the human faecal microbiota is influenced by dietary intake. There is now potential to gain insights into the mechanisms involved by using in vitro systems that produce highly controlled conditions of pH and substrate supply. RESULTS: We supplied two alternative non digestible polysaccharides as energy sources to three different human gut microbial communities in anaerobic, pH-controlled continuous-flow fermentors. Community analysis showed that supply of apple pectin or inulin resulted in the highly specific enrichment of particular bacterial operational taxonomic units (OTUs; based on 16S rRNA gene sequences). Of the eight most abundant Bacteroides OTUs detected, two were promoted specifically by inulin and six by pectin. Among the Firmicutes, Eubacterium eligens in particular was strongly promoted by pectin, while several species were stimulated by inulin. Responses were influenced by pH, which was stepped up, and down, between 5.5, 6.0, 6.4 and 6.9 in parallel vessels within each experiment. In particular, several experiments involving downshifts to pH 5.5 resulted in Faecalibacterium prausnitzii replacing Bacteroides spp. as the dominant sequences observed. Community diversity was greater in the pectin-fed than in the inulin-fed fermentors, presumably reflecting the differing complexity of the two substrates. CONCLUSIONS: We have shown that particular non-digestible dietary carbohydrates have enormous potential for modifying the gut microbiota, but these modifications occur at the level of individual strains and species and are not easily predicted a priori. Furthermore, the gut environment, especially pH, plays a key role in determining the outcome of interspecies competition. This makes it crucial to put greater effort into identifying the range of bacteria that may be stimulated by a given prebiotic approach. Both for reasons of efficacy and of safety, the development of prebiotics intended to benefit human health has to take account of the highly individual species profiles that may result. PMID- 26754944 TI - Prevalence, incidence, and natural course of anorexia and bulimia nervosa among adolescents and young adults. AB - We aimed to assess the prevalence, incidence, age-of-onset and diagnostic stability of threshold and subthreshold anorexia nervosa (AN) and bulimia nervosa (BN) in the community. Data come from a prospective-longitudinal community study of 3021 subjects aged 14-24 at baseline, who were followed up at three assessment waves over 10 years. Eating disorder (ED) symptomatology was assessed with the DSM-IV/M-CIDI at each wave. Diagnostic stability was defined as the proportion of individuals still affected with at least symptomatic eating disorders (EDs) at follow-ups. Baseline lifetime prevalence for any threshold ED were 2.9 % among females and 0.1 % among males. For any subthreshold ED lifetime prevalence were 2.2 % for females and 0.7 % for males. Symptomatic expressions of EDs (including core symptoms of the respective disorder) were most common with a lifetime prevalence of 11.5 % among females and 1.8 % among males. Symptomatic AN showed the earliest onset with a considerable proportion of cases emerging in childhood. 47 % of initial threshold AN cases and 42 % of initial threshold BN cases showed at least symptomatic expressions of any ED at any follow-up assessment. Stability for subthreshold EDs and symptomatic expressions was 14-36 %. While threshold EDs are rare, ED symptomatology is common particularly in female adolescents and young women. Especially threshold EDs are associated with a substantial risk for stability. A considerable degree of symptom fluctuation is characteristic especially for subthreshold EDs. PMID- 26754948 TI - Diffusion tensor imaging in acute-to-subacute traumatic brain injury: a longitudinal analysis. AB - BACKGROUND: Diffusion tensor imaging (DTI) may have prognostic utility in patients with traumatic brain injury (TBI), but the optimal timing of DTI data acquisition is unknown because of dynamic changes in white matter water diffusion during the acute and subacute stages of TBI. We aimed to characterize the direction and magnitude of early longitudinal changes in white matter fractional anisotropy (FA) and to determine whether acute or subacute FA values correlate more reliably with functional outcomes after TBI. METHODS: From a prospective TBI outcomes database, 11 patients who underwent acute (<=7 days) and subacute (8 days to rehabilitation discharge) DTI were retrospectively analyzed. Longitudinal changes in FA were measured in 11 white matter regions susceptible to traumatic axonal injury. Correlations were assessed between acute FA, subacute FA and the disability rating scale (DRS) score, which was ascertained at discharge from inpatient rehabilitation. RESULTS: FA declined from the acute-to-subacute period in the genu of the corpus callosum (0.70 +/- 0.02 vs. 0.55 +/- 0.11, p < 0.05) and inferior longitudinal fasciculus (0.54+/-0.07 vs. 0.49+/-0.07, p < 0.01). Acute correlations between FA and DRS score were variable: higher FA in the body (R = -0.78, p = 0.02) and splenium (R = -0.83, p = 0.003) of the corpus callosum was associated with better outcomes (i.e. lower DRS scores), whereas higher FA in the genu of the corpus callosum (R = 0.83, p = 0.02) corresponded with worse outcomes (i.e. higher DRS scores). In contrast, in the subacute period higher FA in the splenium correlated with better outcomes (R = -0.63, p < 0.05) and no inverse correlations were observed. CONCLUSIONS: White matter FA declined during the acute-to-subacute stages of TBI. Variability in acute FA correlations with outcome suggests that the optimal timing of DTI for TBI prognostication may be in the subacute period. PMID- 26754950 TI - The Involvement of Parasympathetic and Sympathetic Nerve in the Inflammatory Reflex. AB - Production of inflammatory cytokines plays important roles in the response against tissue injury and in host defense. Alterations in the production of inflammatory cytokines may cause local or systemic inflammatory imbalance, culminating in organ failure or lethal systemic inflammation. The cholinergic anti-inflammatory pathway has been implicated as an important mechanism to regulate inflammation of targeted tissue. In this review, we discuss important advances, conflicting and controversial findings regarding the involvement of parasympathetic vagus and sympathetic splenic nerve through acetylcholine (ACh) release and alpha7 nicotinic acetylcholine receptor (nAChRalpha7) activation in the spleen. In addition, we address the involvement of cholinergic control of inflammation in other organs innerved by the vagus nerve such as gut, liver, kidney and lung, and independent of parasympathetic innervations such as skin and skeletal muscle. Then, other structures and mechanisms independent of vagus or splenic nerve may be involved in this process, such as local cells and motor neurons producing ACh. Altogether, the convergence of these findings may contribute to current anti-inflammatory strategies involving selective drug targeting and electrical nerve stimulation. J. Cell. Physiol. 231: 1862-1869, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26754949 TI - Feature-based and spatial attentional selection in visual working memory. AB - The contents of visual working memory (VWM) can be modulated by spatial cues presented during the maintenance interval ("retrocues"). Here, we examined whether attentional selection of representations in VWM can also be based on features. In addition, we investigated whether the mechanisms of feature-based and spatial attention in VWM differ with respect to parallel access to noncontiguous locations. In two experiments, we tested the efficacy of valid retrocues relying on different kinds of information. Specifically, participants were presented with a typical spatial retrocue pointing to two locations, a symbolic spatial retrocue (numbers mapping onto two locations), and two feature based retrocues: a color retrocue (a blob of the same color as two of the items) and a shape retrocue (an outline of the shape of two of the items). The two cued items were presented at either contiguous or noncontiguous locations. Overall retrocueing benefits, as compared to a neutral condition, were observed for all retrocue types. Whereas feature-based retrocues yielded benefits for cued items presented at both contiguous and noncontiguous locations, spatial retrocues were only effective when the cued items had been presented at contiguous locations. These findings demonstrate that attentional selection and updating in VWM can operate on different kinds of information, allowing for a flexible and efficient use of this limited system. The observation that the representations of items presented at noncontiguous locations could only be reliably selected with feature based retrocues suggests that feature-based and spatial attentional selection in VWM rely on different mechanisms, as has been shown for attentional orienting in the external world. PMID- 26754951 TI - Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits. AB - Disrupted-in-schizophrenia 1 (DISC1) is a mental illness gene first identified in a Scottish pedigree. So far, DISC1-dependent phenotypes in animal models have been confined to expressing mutant DISC1. Here we investigated how pathology of full-length DISC1 protein could be a major mechanism in sporadic mental illness. We demonstrate that a novel transgenic rat model, modestly overexpressing the full-length DISC1 transgene, showed phenotypes consistent with a significant role of DISC1 misassembly in mental illness. The tgDISC1 rat displayed mainly perinuclear DISC1 aggregates in neurons. Furthermore, the tgDISC1 rat showed a robust signature of behavioral phenotypes that includes amphetamine supersensitivity, hyperexploratory behavior and rotarod deficits, all pointing to changes in dopamine (DA) neurotransmission. To understand the etiology of the behavioral deficits, we undertook a series of molecular studies in the dorsal striatum of tgDISC1 rats. We observed an 80% increase in high-affinity DA D2 receptors, an increased translocation of the dopamine transporter to the plasma membrane and a corresponding increase in DA inflow as observed by cyclic voltammetry. A reciprocal relationship between DISC1 protein assembly and DA homeostasis was corroborated by in vitro studies. Elevated cytosolic dopamine caused an increase in DISC1 multimerization, insolubility and complexing with the dopamine transporter, suggesting a physiological mechanism linking DISC1 assembly and dopamine homeostasis. DISC1 protein pathology and its interaction with dopamine homeostasis is a novel cellular mechanism that is relevant for behavioral control and may have a role in mental illness. PMID- 26754955 TI - Locating single-point sources from arrival times containing large picking errors (LPEs): the virtual field optimization method (VFOM). AB - Microseismic monitoring systems using local location techniques tend to be timely, automatic and stable. One basic requirement of these systems is the automatic picking of arrival times. However, arrival times generated by automated techniques always contain large picking errors (LPEs), which may make the location solution unreliable and cause the integrated system to be unstable. To overcome the LPE issue, we propose the virtual field optimization method (VFOM) for locating single-point sources. In contrast to existing approaches, the VFOM optimizes a continuous and virtually established objective function to search the space for the common intersection of the hyperboloids, which is determined by sensor pairs other than the least residual between the model-calculated and measured arrivals. The results of numerical examples and in-site blasts show that the VFOM can obtain more precise and stable solutions than traditional methods when the input data contain LPEs. Furthermore, we discuss the impact of LPEs on objective functions to determine the LPE-tolerant mechanism, velocity sensitivity and stopping criteria of the VFOM. The proposed method is also capable of locating acoustic sources using passive techniques such as passive sonar detection and acoustic emission. PMID- 26754953 TI - Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression. AB - Inflammation and altered glutamate metabolism are two pathways implicated in the pathophysiology of depression. Interestingly, these pathways may be linked given that administration of inflammatory cytokines such as interferon-alpha to otherwise non-depressed controls increased glutamate in the basal ganglia and dorsal anterior cingulate cortex (dACC) as measured by magnetic resonance spectroscopy (MRS). Whether increased inflammation is associated with increased glutamate among patients with major depression is unknown. Accordingly, we conducted a cross-sectional study of 50 medication-free, depressed outpatients using single-voxel MRS, to measure absolute glutamate concentrations in basal ganglia and dACC. Multivoxel chemical shift imaging (CSI) was used to explore creatine-normalized measures of other metabolites in basal ganglia. Plasma and cerebrospinal fluid (CSF) inflammatory markers were assessed along with anhedonia and psychomotor speed. Increased log plasma C-reactive protein (CRP) was significantly associated with increased log left basal ganglia glutamate controlling for age, sex, race, body mass index, smoking status and depression severity. In turn, log left basal ganglia glutamate was associated with anhedonia and psychomotor slowing measured by the finger-tapping test, simple reaction time task and the Digit Symbol Substitution Task. Plasma CRP was not associated with dACC glutamate. Plasma and CSF CRP were also associated with CSI measures of basal ganglia glutamate and the glial marker myoinositol. These data indicate that increased inflammation in major depression may lead to increased glutamate in the basal ganglia in association with glial dysfunction and suggest that therapeutic strategies targeting glutamate may be preferentially effective in depressed patients with increased inflammation as measured by CRP. PMID- 26754952 TI - The dynamics of the stress neuromatrix. AB - Stressful stimuli in healthy subjects trigger activation of a consistent and reproducible set of brain regions; yet, the notion that there is a single and constant stress neuromatrix is not sustainable. Indeed, after chronic stress exposure there is activation of many brain regions outside that network. This suggests that there is a distinction between the acute and the chronic stress neuromatrix. Herein, a new working model is proposed to understand the shift between these networks. The understanding of the factors that modulate these networks and their interplay will allow for a more comprehensive and holistic perspective of how the brain shifts 'back and forth' from a healthy to a stressed pattern and, ultimately, how the latter can be a trigger for several neurological and psychiatric conditions. PMID- 26754956 TI - Identifying advanced practice: A national survey of a nursing workforce. AB - BACKGROUND: The size and flexibility of the nursing workforce has positioned nursing as central to the goals of health service improvement. Nursing's response to meeting these goals has resulted in proliferation of advanced practice nursing with a confusing array of practice profiles, titles and roles. Whilst numerous models and definitions of advanced practice nursing have been developed there is scant published research of significant scope that supports these models. Consequently there is an ongoing call in the literature for clarity and stability in nomenclature, and confusion in the health industry on how to optimise the utility of advanced practice nursing. OBJECTIVES: To identify and delineate advanced practice from other levels of nursing practice through examination of a national nursing workforce. DESIGN: A cross-sectional electronic survey of nurses using the validated Advanced Practice Role Delineation tool based on the Strong Model of Advanced Practice. PARTICIPANTS: Study participants were registered nurses employed in a clinical service environment across all states and territories of Australia. METHODS: A sample of 5662 registered nurses participated in the study. Domain means for each participant were calculated then means for nursing position titles were calculated. Position titles were grouped by delineation and were compared with one-way analysis of variance on domain means. The alpha for all tests was set at 0.05. Significant effects were examined with Scheffe post hoc comparisons to control for Type 1 error. RESULTS: The survey tool was able to identify position titles where nurses were practicing at an advanced level and to delineate this cohort from other levels of nursing practice, including nurse practitioner. The results show that nurses who practice at an advanced level are characterised by high mean scores across all Domains of the Strong Model of Advanced Practice. The mean scores of advanced practice nurses were significantly different from nurse practitioners in the Direct Care Domain and significantly different from other levels of nurse across all domains. CONCLUSIONS: The study results show that the nurse practitioner, advanced practice nurse and foundation level registered nurse have different patterns of practice and the Advanced Practice Role Delineation tool has the capacity to clearly delineate and define advanced practice nursing. These findings make a significant contribution to the international debate and show that the profession can now identify what is and what is not advanced practice in nursing. PMID- 26754958 TI - Synthesis, self-assembly, and in vitro toxicity of fatty acids-modified Bletilla striata polysaccharide. AB - Hydrophobic modification of Bletilla striata polysaccharide (BSP) was performed by grafting fatty acids to BSP backbone and then characterized on their physicochemical properties. All neutral derivatives were able to self-assemble into spherical particles within the size range of 250-400 nm, their size and critical micelle concentration decreased with increasing hydrophobicity and substitution degree of the fatty acids. Also, the BSP-stearic acid conjugates showed a preferable performance on hemolysis test and cytotoxicity analysis on HepG2 cells, which suggested their potential application as a drug delivery vector. PMID- 26754954 TI - Meta-analysis of genome-wide association studies of anxiety disorders. AB - Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 * 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 * 10(-9)). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs. PMID- 26754957 TI - A Novel Naturally Occurring Class I 5-Enolpyruvylshikimate-3-Phosphate Synthase from Janibacter sp. Confers High Glyphosate Tolerance to Rice. AB - As glyphosate is a broad spectrum herbicide extensively used in agriculture worldwide, identification of new aroA genes with high level of glyphosate tolerance is essential for the development and breeding of transgenic glyphosate tolerant crops. In this study, an aroA gene was cloned from a Janibacter sp. strain isolated from marine sediment (designated as aroAJ. sp). The purified aroAJ. sp enzyme has a Km value of 30 MUM for PEP and 83 MUM for S3P, and a significantly higher Ki value for glyphosate (373 MUM) than aroAE. coli. AroAJ. sp is characterized as a novel and naturally occurring class I aroA enzyme with glyphosate tolerance. Furthermore, we show that aroAJ. sp can be used as an effective selectable marker in both japonica and indica rice cultivar. Transgenic rice lines were tested by herbicide bioassay and it was confirmed that they could tolerate up to 3360 g/ha glyphosate, a dosage four-fold that of the recommended agricultural application level. To our knowledge, it is the first report of a naturally occurring novel class I aroA gene which can be efficiently utilized to study and develop transgenic glyphosate-tolerant crops, and can facilitate a more economical and simplified weed control system. PMID- 26754959 TI - Tuberculosis reactivation in a patient receiving anti-programmed death-1 (PD-1) inhibitor for relapsed Hodgkin's lymphoma. PMID- 26754961 TI - Vacuum Ultraviolet Treatment of Self-Assembled Monolayers: A Tool for Understanding Growth and Tuning Charge Transport in Organic Field-Effect Transistors. AB - Vacuum ultraviolet irradiation is used as a tool to systematically study the morphology, growth, and performance of small-molecule organic field-effect transistors. The surface energy can be carefully and precisely tuned by varying the dose of irradiation, allowing for the systematic study of the growth of an emerging organic semiconductor. This technique helps to methodically control the morphology and performance of organic semiconductors. PMID- 26754960 TI - Influence of the supramolecular order on the electrical properties of 1D coordination polymers based materials. AB - The generation, under self-assembly conditions, of coordination polymers on surface based combinations of a terpyridine-antracene-pyridine based tecton and Co(II) or Pd(II) cations is primarily governed by the coordination geometry of the metal center (octahedral and square planar respectively). While the octahedral Co(II) based polymer self-assembles in insulating films exhibiting randomly oriented crystalline domains, the planarity of Pd(II) based polymers leads to the formation of conductive pi-pi stacked fibrillar structures exhibiting anisotropically oriented domains. In the latter case, the favorable Pd Pd and anthracene-anthracene wavefunction overlaps along the fiber direction are responsible for the large electronic couplings between adjacent chains, whereas small electronic couplings are instead found along individual polymer chains. These results provide important guidelines for the design of conductive metal coordination polymers, highlighting the fundamental role of both intra- as well as inter-chain interactions, thus opening up new perspectives towards their application in functional devices. PMID- 26754962 TI - An Upflow-Type Filtration Device Using Expanded Polypropylene Media (EPM) to Treat First Flush of Rainwater. AB - The first flush of rainwater in urban areas is highly contaminated and causes adverse effects on both the water environment and ecosystem. In this study, a novel filtration device using expanded polypropylene media (EPM) was developed for efficient control of pollutants in first flush of urban runoff. The effect of foaming ratio on EPM for filtration efficiency and clogging potential was examined under various operating conditions. Experimental results using a laboratory-scale filtration device indicated that the removal efficiencies of suspended solids were initially high (>90% removal until 60 minutes) and decreased with filtration time (60% for EPM15 at 180 minutes and less than 10% for EPM45). Similarly, more than 90% of Cr, Pb, and Zn were removed for EPM15 within 30 minutes and decreased with filtration time. The surface area and specific hydraulic resistance of EPM were sensitive to foaming ratio. Optimum conditions for foaming ratio increased pollutant removal and minimized head loss. A simple model was derived and applied for theoretical analysis of the filtration device with EPM. PMID- 26754963 TI - Symbiotic bacteria of helminths: what role may they play in ecosystems under anthropogenic stress? AB - Symbiotic bacteria are a common feature of many animals, particularly invertebrates, from both aquatic and terrestrial habitats. These bacteria have increasingly been recognized as performing an important role in maintaining invertebrate health. Both ecto- and endoparasitic helminths have also been found to harbour a range of bacterial species which provide a similar function. The part symbiotic bacteria play in sustaining homeostasis of free-living invertebrates exposed to anthropogenic pressure (climate change, pollution), and the consequences to invertebrate populations when their symbionts succumb to poor environmental conditions, are increasingly important areas of research. Helminths are also susceptible to environmental stress and their symbiotic bacteria may be a key aspect of their responses to deteriorating conditions. This article summarizes the ecophysiological relationship helminths have with symbiotic bacteria and the role they play in maintaining a healthy parasite and the relevance of specific changes that occur in free-living invertebrate-bacteria interactions under anthropogenic pressure to helminths and their bacterial communities. It also discusses the importance of understanding the mechanistic sensitivity of helminth-bacteria relationships to environmental stress for comprehending the responses of parasites to challenging conditions. PMID- 26754964 TI - Vacuum assisted closure for the treatment of complex wounds and enterocutaneous fistulas in full term and premature neonates: a case report. AB - BACKGROUND: The Vacuum Assisted Closure (VAC) system has become an effective treatment for acute and chronic wound defects. Although its use has been reported in wound care of children and premature infants, the management of the device in this population has not been well established. CASE PRESENTATION: We report the satisfactory results in two neonates (one full-term and one preterm) with complex wounds secondary to major abdominal surgery. In the premature baby an enterocutaneous fistula was also present. Complete epithelialization of the wounds was achieved in both patients within a few weeks thus avoiding any further surgical procedure. CASE PRESENTATION: The use of VAC system in neonates is safe and effective in the management of complex wounds and should be considered as a first line treatment in the event of a major dehiscence. PMID- 26754965 TI - Tobacco is "our industry and we must support it": Exploring the potential implications of Zimbabwe's accession to the Framework Convention on Tobacco Control. AB - BACKGROUND: Zimbabwe is the largest tobacco producer in Africa. Despite expressing opposition in the past, Zimbabwe recently acceded to the World Health Organization's Framework Convention on Tobacco Control (FCTC). We explored why Zimbabwe acceded to the FCTC and the potential implications for tobacco control within Zimbabwe and globally. METHODS: We conducted a qualitative archival case study based on 542 documents collected from 1) the Truth Tobacco Industry Documents; 2) media indexed in the Lexis-Nexis media database; 3) the websites for tobacco growers' associations, tobacco control groups, and international agencies; 4) FCTC reports and Framework Convention Alliance newsletters; 5) Zimbabwe's legal codes; and 6) the peer reviewed scientific literature related to tobacco growing. RESULTS: Zimbabwe has a long history of tobacco growing. There are currently over 90,000 tobacco farmers, and tobacco growing is prioritized, despite widespread food insecurity and environmental degradation. Zimbabwean government officials have been outspoken FCTC critics; but recently joined the accord to better protect Zimbabwe's tobacco growing interests. FCTC membership obligates nations to implement a variety of tobacco control measures; Zimbabwe has implemented several measures aimed at reducing tobacco demand, but fewer aimed at reducing tobacco supply or protecting the environment. Zimbabwe joins the FCTC amid increased efforts to protect FCTC proceedings from industry interference, to adopt recommendations for alternative crops and livelihoods and reduce environmental damage. CONCLUSION: Zimbabwe's decision to accede to the FCTC does not appear to represent a softening of its historical opposition to the treaty. Thus, its status as a Party creates opportunities for it to undermine ongoing efforts to implement and strengthen the treaty. At the same time, however, Zimbabwe's accession could provide much needed international support for Zimbabwe's civic organizations and its Ministry of Health to develop stronger tobacco control measures. How Zimbabwe's participation impacts the work of the FCTC as a whole may ultimately depend on the allegiances of its delegates, and the effectiveness of FCTC measures to limit tobacco industry interference and enforce compliance with FCTC measures. PMID- 26754966 TI - Determinants of postnatal care non-utilization among women in Nigeria. AB - BACKGROUND: Although, there are several programs in place in Nigeria to ensure maternal and child health, maternal and neonatal mortality rates remain high with maternal mortality rates being 576/100,000 and neonatal mortality rates at 37/1000 live births (NDHS, 2013). While there are many studies on the utilization of maternal health services such as antenatal care and skilled delivery at birth, studies on postnatal care are limited. Therefore, the aim of this study is to examine the factors associated with the non-utilization of postnatal care among mothers in Nigeria using the Nigeria Demographic and Health Survey (NDHS) 2013. METHODS: For analysis, the postnatal care uptake for 19,418 children born in the 5 years preceding the survey was considered. The dependent variable was a composite variable derived from a list of questions on postnatal care. A multinomial logistic regression model was applied to examine the adjusted and unadjusted determinants of non-utilization of postnatal care. RESULTS: Results from this study showed that 63% of the mothers of the 19,418 children did not utilize postnatal care services in the period examined. About 42% of the study population between 25 and 34 years did not utilize postnatal care and 61% of the women who did not utilize postnatal care had no education. Results from multinomial logistic regression show that antenatal care use, distance, education, place of delivery, region and wealth status are significantly associated with the non-utilization of postnatal care services. CONCLUSIONS: This study revealed the low uptake of postnatal care service in Nigeria. To increase mothers' utilization of postnatal care services and improve maternal and child health in Nigeria, interventions should be targeted at women in remote areas who don't have access to services and developing mobile clinics. In addition, it is crucial that steps should be taken on educating women. This would have a significant influence on their perceptions about the use of postnatal care services in Nigeria. PMID- 26754968 TI - Standardisation of the (129)I, (151)Sm and (166m)Ho activity concentration using the CIEMAT/NIST efficiency tracing method. AB - The (129)I, (151)Sm and (166m)Ho standardisations using the CIEMAT/NIST efficiency tracing method, that have been carried out in the frame of the European Metrology Research Program project "Metrology for Radioactive Waste Management" are described. The radionuclide beta counting efficiencies were calculated using two computer codes CN2005 and MICELLE2. The sensitivity analysis of the code input parameters (ionization quenching factor, beta shape factor) on the calculated efficiencies was performed, and the results are discussed. The combined relative standard uncertainty of the standardisations of the (129)I, (151)Sm and (166m)Ho solutions were 0.4%, 0.5% and 0.4%, respectively. The stated precision obtained using the CIEMAT/NIST method is better than that previously reported in the literature obtained by the TDCR ((129)I), the 4pigamma-NaI ((166m)Ho) counting or the CIEMAT/NIST method ((151)Sm). PMID- 26754967 TI - Photoreceptor dysfunction in early and intermediate age-related macular degeneration assessed with mfERG and spectral domain OCT. AB - PURPOSE: To evaluate the changes of the photoreceptor layer (PRL) thickness with spectral domain optical coherence tomography (SD-OCT) and the retinal function by mfERG, as well as the correlation of morphology and function parameters in subjects with early and intermediate age-related macular degeneration (AMD). METHODS: Subjects with clinical diagnosis of early or intermediate AMD and age matched healthy subjects were recruited prospectively in this study. Color fundus photography, SD-OCT, and mfERG were conducted. Retinal photoreceptor thickness was measured, and first-order kernel responses were recorded. The differences between AMD group and control group were compared, and the correlations between macular photoreceptor thickness and the mfERG were analyzed. RESULTS: PRL thickness (MUm) in four areas including foveola and 0.5, 1.5, and 3 mm away from foveola was 192.48 +/- 17.37, 163.73 +/- 12.95, 130.93 +/- 9.20, and 108.78 +/- 7.81, respectively, in normal eyes, whereas in AMD group, they were 158.61 +/- 45.25, 138.91 +/- 20.92, 118.91 +/- 12.85, and 95.00 +/- 9.64, respectively (P < 0.001). The mean amplitude response densities of AMD patients decreased significantly compared to the control group in ring 1-6 (P < 0.001). The mean mfERG N1 and P1 latency of AMD patients prolonged compared to the control group, except the ring 1 (P = 0.588 and P = 0.084). The macular PRL thickness was significantly associated with the mfERGN1 and P1 amplitude density in ring 1-4 (r = 0.338-0.533, P < 0.01). CONCLUSIONS: PRL thickness decreases are in accordance with the deterioration of retinal electrophysiological activity. The retinal PRL thickness is important parameter to assess of early and intermediate AMD severity. PMID- 26754970 TI - The development of ethical guidelines for nurses' collegiality using the Delphi method. AB - BACKGROUND: Nurses' collegiality is topical because patient care is complicated, requiring shared knowledge and working methods. Nurses' collaboration has been supported by a number of different working models, but there has been less focus on ethics. AIM: This study aimed to develop nurses' collegiality guidelines using the Delphi method. METHOD: Two online panels of Finnish experts, with 35 and 40 members, used the four-step Delphi method in December 2013 and January 2014. They reformulated the items of nurses' collegiality identified by the literature and rated based on validity and importance. Content analysis and descriptive statistical methods were used to analyze the data, and the nurses' collegiality guidelines were formulated. Ethical considerations: Organizational approval was received, and an informed consent was obtained from all participants. Information about the voluntary nature of participation was provided. RESULTS: During the first Delphi panel round, a number of items were reformulated and added, resulting in 32 reformulated items. As a result of the second round, 8 of the 32 items scored an agreement rate of more than 75%, with the most rated item being collegiality means that professionals respect each other. The item with second highest rating was collegiality has a common objective: what is best for patients, followed by the third highest which was professional ethics is the basis of collegiality. CONCLUSION: Nurses' collegiality and its content are well recognized in clinical practice but seldom studied. Collegiality can be supported by guidelines, and nurses working in clinical practice, together with teachers and managers, have shared responsibilities to support and develop it. More research in different nursing environments is needed to improve understanding of the content and practice of nursing collegiality. PMID- 26754969 TI - Fecal impaction: a systematic review of its medical complications. AB - BACKGROUND: Fecal impaction (FI) is a common problem in the elderly and other at risk groups, such as patients with a neuro-psychiatric disease. It has been associated with medical problems and high morbi-mortality. A systematic review of this topic might be useful to improve the knowledge in this area and helpful to make an appropriate and early diagnosis. METHODS: A PubMed systematic search was performed using relevant keywords. Case reports published in English, Spanish or French till June 2014 were included if they had a diagnosis of FI and a medical complication secondary to it. Each case was classified based on its principal complication. The main objective is to create a classification of FI complications based on published clinical cases. RESULTS: 188 articles met inclusion criteria, comprising 280 clinical cases. Out of the total, 43,5% were over 65 years old, 49% suffered from chronic constipation, 29% had an underlying neuropsychiatric disease and 15% were hospitalised or institutionalised. A total of 346 medical complications secondary to FI were collected. They were divided according to gastrointestinal tract involvement and then classified based on their anatomical and pathophysiological mechanism into three groups: Complications secondary to fecaloma effect on the intestinal wall (73.4%), on the intestinal lumen (14%) and on adjacent structures (12.6%). CONCLUSIONS: FI causes complications that might be fatal. The elderly, underlying neuropsychiatric disease and hospitalised or institutionalised patients integrate the high-risk group in which FI must be suspected. The first FI complications classification is presented to improve the knowledge about this entity. PMID- 26754971 TI - Becoming a nurse as a moral journey: A constructivist grounded theory. AB - BACKGROUND: Nursing students, during their study, experience significant changes on their journey to become nurses. A major change that they experience is the development of their moral competency. OBJECTIVE: The purpose of this study is to explore the process of moral development in Iranian nursing students. RESEARCH DESIGN: A constructivist grounded theory method was adopted. Twenty-five in depth, semi-structured, face-to-face intensive interviews with 22 participants were conducted from September 2013 to October 2014. All interviews were audio taped, transcribed, and analyzed using writing memos and the constant comparative method. Participants and research context: The setting was three major nursing schools within Tehran, the capital of Iran. Nineteen nursing students and three lecturers participated in the study. Ethical considerations: The study was approved by the Tehran University of Medical Sciences Committee for Medical Research Ethics (92/D/130/1781). It was explained to all participants that their responses would be treated with confidentiality and that they would not be identified in any way in the research and any publication ensuing from the research. All participants agreed to be interviewed and signed written consent forms agreeing to the recording and analyses of the interview data gathered. FINDINGS: Findings indicated three levels of moral development along with the formation of professional identity. The three levels of moral development, getting to know the identity of nursing (moral transition), accepting nursing identity (moral reconstruction), and professional identity internalization (professional morality), were connected to the levels of professional identity formation. DISCUSSION: The proposed model added a new insight to professionalism in nursing. CONCLUSION: From the findings, it was concluded that to enhance higher moral practice, nursing instructors should promote the professional identity of nursing students. Reinforcement of moral characteristics and professional identity within registered nurses occurs over a series of phases and, once fully integrated into the identity of nursing students, the moral characteristics that they acquire become part of their both professional and personal identities. PMID- 26754973 TI - Animal Models for the Study of Subarachnoid Hemorrhage: Are We Moving Towards Increased Standardization? PMID- 26754972 TI - Sensory feedback in a bump attractor model of path integration. AB - Mammalian spatial navigation systems utilize several different sensory information channels. This information is converted into a neural code that represents the animal's current position in space by engaging place cell, grid cell, and head direction cell networks. In particular, sensory landmark (allothetic) cues can be utilized in concert with an animal's knowledge of its own velocity (idiothetic) cues to generate a more accurate representation of position than path integration provides on its own (Battaglia et al. The Journal of Neuroscience 24(19):4541-4550 (2004)). We develop a computational model that merges path integration with feedback from external sensory cues that provide a reliable representation of spatial position along an annular track. Starting with a continuous bump attractor model, we explore the impact of synaptic spatial asymmetry and heterogeneity, which disrupt the position code of the path integration process. We use asymptotic analysis to reduce the bump attractor model to a single scalar equation whose potential represents the impact of asymmetry and heterogeneity. Such imperfections cause errors to build up when the network performs path integration, but these errors can be corrected by an external control signal representing the effects of sensory cues. We demonstrate that there is an optimal strength and decay rate of the control signal when cues appear either periodically or randomly. A similar analysis is performed when errors in path integration arise from dynamic noise fluctuations. Again, there is an optimal strength and decay of discrete control that minimizes the path integration error. PMID- 26754975 TI - Corrigendum: Tea polyphenols as an antivirulence compound Disrupt Quorum-Sensing Regulated Pathogenicity of Pseudomonas aeruginosa. PMID- 26754978 TI - Emulating Janus: Inculcating a sense of history. PMID- 26754976 TI - Neurological symptoms in a patient with isolated adrenocorticotropin deficiency: case report and literature review. AB - BACKGROUND: Isolated adrenocorticotropic hormone (ACTH) deficiency is a pituitary disorder characterized by reduction only in the secretion of ACTH. Although the underlying mechanism remains to be elucidated, numbers of cases with this entity have been increasing. We experienced a case presenting with gait disturbance necessitating differential diagnosis from idiopathic normal pressure hydrocephalus (iNPH). CASE PRESENTATION: A 69-year-old female with a complaint of difficulty walking and suspected to have iNPH at a prior hospital was referred to our department. For the prior three years, she had suffered from a progressive gait disturbance. Magnetic resonance imaging (MRI) revealed global ventricular dilatation. The typical features of the gait in iNPH cases were all identifiable. Neuropsychological dementia scale tests showed deterioration. However, the major feature of a disproportionately enlarged subarachnoid-space on MRI was not obvious. The patient developed progressively worsening fatigue during hospitalization. Her symptoms resembled those of hypothalamic-pituitary tumor patients. Serum ACTH and cortisol levels were low. While corticotrophin releasing hormone stress tests showed no response, other stress tests using thyrotropin releasing hormone, luteinizing hormone releasing hormone, and growth hormone releasing hormone yielded normal responses, indicating a diagnosis of isolated ACTH deficiency. We initiated corticosteroid therapy, and her gait disturbance improved promptly. CONCLUSION: Isolated ACTH deficiency may have major significance to the differential diagnosis of iNPH. Early consideration of this entity is anticipated to facilitate making an early diagnosis. PMID- 26754974 TI - Elucidating the molecular physiology of lantibiotic NAI-107 production in Microbispora ATCC-PTA-5024. AB - BACKGROUND: The filamentous actinomycete Microbispora ATCC-PTA-5024 produces the lantibiotic NAI-107, which is an antibiotic peptide effective against multidrug resistant Gram-positive bacteria. In actinomycetes, antibiotic production is often associated with a physiological differentiation program controlled by a complex regulatory and metabolic network that may be elucidated by the integration of genomic, proteomic and bioinformatic tools. Accordingly, an extensive evaluation of the proteomic changes associated with NAI-107 production was performed on Microbispora ATCC-PTA-5024 by combining two-dimensional difference in gel electrophoresis, mass spectrometry and gene ontology approaches. RESULTS: Microbispora ATCC-PTA-5024 cultivations in a complex medium were characterized by stages of biomass accumulation (A) followed by biomass yield decline (D). NAI-107 production started at 90 h (A stage), reached a maximum at 140 h (D stage) and decreased thereafter. To reveal patterns of differentially represented proteins associated with NAI-107 production onset and maintenance, differential proteomic analyses were carried-out on biomass samples collected: i) before (66 h) and during (90 h) NAI-107 production at A stage; ii) during three time-points (117, 140, and 162 h) at D stage characterized by different profiles of NAI-107 yield accumulation (117 and 140 h) and decrement (162 h). Regulatory, metabolic and unknown-function proteins, were identified and functionally clustered, revealing that nutritional signals, regulatory cascades and primary metabolism shift-down trigger the accumulation of protein components involved in nitrogen and phosphate metabolism, cell wall biosynthesis/maturation, lipid metabolism, osmotic stress response, multi-drug resistance, and NAI-107 transport. The stimulating role on physiological differentiation of a TetR-like regulator, originally identified in this study, was confirmed by the construction of an over-expressing strain. Finally, the possible role of cellular response to membrane stability alterations and of multi-drug resistance ABC transporters as additional self-resistance mechanisms toward the lantibiotic was confirmed by proteomic and confocal microscopy experiments on a Microbispora ATCC-PTA-5024 lantibiotic-null producer strain which was exposed to an externally-added amount of NAI-107 during growth. CONCLUSION: This study provides a net contribution to the elucidation of the regulatory, metabolic and molecular patterns controlling physiological differentiation in Microbispora ATCC-PTA-5024, supporting the relevance of proteomics in revealing protein players of antibiotic biosynthesis in actinomycetes. PMID- 26754979 TI - Coexistence of autoimmune diseases and autoantibodies in patients with myasthenia gravis. PMID- 26754980 TI - When to do deep brain stimulation surgery in Parkinson disease? Early or late? PMID- 26754982 TI - Bedside computed tomography in traumatic brain injury. PMID- 26754981 TI - Women authorship in neuroscience publications. PMID- 26754983 TI - Amoebic meningoencephalitis: A high index of suspicion is needed for an early diagnosis. PMID- 26754984 TI - Surgery for multilevel cervical spondylotic myelopathy and ossified posterior longitudinal ligament. PMID- 26754985 TI - Multilevel cervical myelopathy due to cervical spondylosis/ossification of posterior longitudinal ligament-A complex problem. PMID- 26754986 TI - Functional and radiological outcome in patients undergoing a three-level corpectomy for multilevel cervical spondylotic myelopathy and ossified posterior longitudinal ligament. PMID- 26754987 TI - Epidermal growth factor gene amplification in high grade gliomas. PMID- 26754988 TI - Epidermal growth factor receptor (EGFR) gene amplification in high grade gliomas. PMID- 26754989 TI - Genetics of ischemic stroke: An Indian scenario. AB - Stroke, a heterogeneous multifactorial disorder, is known to be a major cause of death and adult disability within both the developed and developing countries. Approximately 85% of stroke cases are ischemic, whereas the remaining 15% are hemorrhagic. It is caused by multiple genetic factors, environmental factors, and interactions among these factors. Several candidate genes have been found to be associated with ischemic stroke. The most extensively studied genes include those involved in hemostasis, inflammation, nitric oxide production, homocysteine and lipid metabolism, and rennin-angiotensin-aldosterone system. Combined linkage/association studies have demonstrated that genes encoding phosphodiesterase 4D (PDE4D) and arachidonate 5-lipoxygenase-activating protein (ALOX5AP) confer risk for stroke. Even though there is substantial evidence for the genetic basis of stroke as provided by the epidemiological data from twin- and family-based studies, the contribution of genetic factors identified till now is either not enough or very less to explain the entire spectrum of encountered phenomena associated with ischemic stroke. Till date, no genome-wide association studies (GWAS) have been carried out in India. We aim to extensively review the studies on candidate genes that may have potential applications in the early diagnosis, prevention, and treatment of ischemic stroke in the Indian population. This article further emphasizes the role of GWAS in ischemic stroke and the need for an extensive GWAS in the Indian population. PMID- 26754990 TI - Underlying neural mechanisms of mirror therapy: Implications for motor rehabilitation in stroke. AB - Mirror therapy (MT) is a valuable method for enhancing motor recovery in poststroke hemiparesis. The technique utilizes the mirror-illusion created by the movement of sound limb that is perceived as the paretic limb. MT is a simple and economical technique than can stimulate the brain noninvasively. The intervention unquestionably has neural foundation. But the underlying neural mechanisms inducing motor recovery are still unclear. In this review, the neural-modulation due to MT has been explored. Multiple areas of the brain such as the occipital lobe, dorsal frontal area and corpus callosum are involved during the simple MT regime. Bilateral premotor cortex, primary motor cortex, primary somatosensory cortex, and cerebellum also get reorganized to enhance the function of the damaged brain. The motor areas of the lesioned hemisphere receive visuo-motor processing information through the parieto-occipital lobe. The damaged motor cortex responds variably to the MT and may augment true motor recovery. Mirror neurons may also play a possible role in the cortico-stimulatory mechanisms occurring due to the MT. PMID- 26754991 TI - Coexistence of autoimmune diseases and autoantibodies in patients with myasthenia gravis. AB - BACKGROUND: In this study, we assessed 75 patients with myasthenia gravis (MG) for coexistent autoimmune diseases (ADs) and for the characteristic autoantibodies that are associated with the most relevant forms of ADs. METHODS: The demographic and clinical characteristics of the patients were recorded. In all patients, thyroid function tests, thyroid autoantibodies, and other autoantibodies were studied. The diagnosis of autoimmune thyroid disease (AITD) was made based on the clinical features, physical examination, and laboratory findings. The diagnoses of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) were made in accordance with the revised criteria of American College of Rheumatology. The presence of other ADs were also recorded which was based on whether or not the patient already had a diagnosis of ADs; or, whether it was detected during the period of the study based on clinical findings and/or laboratory abnormalities. RESULTS: Thirty-nine patients (52%) had autoantibody positivity in their sera. Thyroid autoantibodies and antinuclear antibodies were the main autoantibodies detected. In twenty one of these patients, a diagnosis of AD could not be confirmed. Eighteen patients (24%) had a confirmed diagnosis of a coexisting AD. These ADs included AITD (16%), RA (4%), SLE (2.6%), and Lambert Eaton myasthenic syndrome (1.3%). In ten patients, the diagnosis of ADs had been established before the development of MG; 8 of the patients included those who were newly diagnosed with ADs in the course of the management of MG. CONCLUSIONS: MG has an increased frequency of coexisting ADs. Autoantibodies that are characteristic for ADs can be found in the patients without the presence of any of the clinical findings of ADs. Clinical attention towards the management of ADs is especially needed during the follow-up of patients with MG. PMID- 26754992 TI - Semi-quantitative analysis of cerebrospinal fluid chemistry and cellularity using urinary reagent strip: An aid to rapid diagnosis of meningitis. AB - BACKGROUND: The examination of the cerebrospinal fluid (CSF) for proteins, glucose, and leukocytes still remains the basic gold standard investigation for the initial diagnosis of meningitis. Early diagnosis and initiation of antibiotics within 3 h can reduce the mortality and morbidity associated with meningitis. Hence, we conducted this study to document the usefulness of urinary reagent strip for the semi-quantitative analysis of CSF chemistry and cellularity. MATERIALS AND METHODS: All clear CSF samples were subjected for two types of tests, the definitive test and the index test. CSF microscopy and biochemical values are considered as definitive. Combur-10 urinary reagent strip was used as the index test for proteins, glucose, and leukocytes. The diagnostic accuracy of each index test was calculated using different cut-off levels (leukocyte esterase positivity 1+ vs. CSF granulocytes >=10/cumm, proteins 1+ and 2+ vs. CSF protein >=30 mg/dl and >=100 mg/dl, respectively, and glucose 0 vs. <=40 mg/dl and <=50 mg/dl). Statistical analysis was performed to derive the specificity, sensitivity, positive predictive value, negative predictive value, likelihood ratio (LR)+, LR-, and area under curve (AUC). RESULTS: The study subjects comprised 103 cases. The strip showed a high sensitivity and specificity for leukocytes >=10 cells/cumm. The strip showed a sensitivity of 96% and a specificity of 87.1% for proteins at a cut-off >=100 mg/dl while the strip was less specific at a cut-off of >=30 mg/dl. With respect to glucose, the strip was highly specific (100%) and less sensitive at both the cut-off levels. The AUC for leukocytes >=10 cells/cumm was 99.05%; for proteins >=30 mg/dl and >=100 mg/dl, it was 84.86% and 95.69%, respectively; and, for glucose <=40 mg/dl and <=50 mg/dl, it was 86.51% and 76.99%, respectively. CONCLUSION: The routinely used urinary reagent strip can be utilized for the rapid analysis of CSF. If implemented, this technique will be useful in rural areas. It would also decrease the turnaround time in centers where the facility is available. PMID- 26754993 TI - Rheumatoid arthritis and the risk of dementia: A systematic review and meta analysis. AB - BACKGROUND: The association between chronic inflammation and dementia has been identified in several epidemiologic studies. However, the data on rheumatoid arthritis (RA), one of the most common chronic inflammatory disorders, remains unclear. MATERIALS AND METHODS: We conducted a systematic review and meta analysis of cohort, case-control, and cross-sectional studies that compared the risk of dementia in patients with RA versus non-RA controls. Data from each study were combined using random-effect, generic inverse variance method of DerSimonian and Laird to calculate the pooled risk ratio (RR) and 95% confidence interval (CI). RESULTS: Three cohort studies and two cross-sectional studies were identified and included in the meta-analysis. We found a significantly increased risk of dementia among patients with RA, with the pooled risk ratio of 1.61 (95% CI, 1.10-2.37). The statistical heterogeneity was high, with an I2 of 91%. CONCLUSIONS: Our study demonstrated a statistically significant increase in the risk of dementia among patients with RA. PMID- 26754994 TI - Bedside computed tomography in traumatic brain injury: Experience of 10,000 consecutive cases in neurosurgery at a level 1 trauma center in India. AB - INTRODUCTION: Patients with traumatic brain injury (TBI) need frequent computed tomography (CT) of the head for assessment and management. In view of the associated polytrauma, hemodynamic instability, and various in-dwelling catheters and tubes, shifting of patients for CT scans may be difficult. AIMS AND OBJECTIVES: To assess the role of mobile CT (Ceretom(r); NeuroLogica Corporation, Boston, MA, USA) in a trauma center with respect to patient management. MATERIALS AND METHODS: In this retrospective study over 67 months (June 2009 to January 2015), the number of CT scans done, the time taken for CT and downtime were evaluated. Also, for the first 1000 mobile CT scans, the clinical and radiological records of all patients with TBI who underwent imaging using the mobile CT scanner in the intensive care units (ICUs) were analyzed. OBSERVATIONS AND RESULTS: A total of 10,000 mobile CT scans were done on the mobile CT scanner till January 5, 2015. Of the first 1000 patients evaluated, 75.3% had severe TBI, 15.1% had moderate TBI, and 9.6% had mild TBI. 78.1% patients were on ventilator, with 80.2% requiring sedation and 8.4%, an inotropic support. An in situ intracranial pressure monitoring was present in 21.1% of patients. In all, 12.4% of patients had long-bone fractures requiring skeletal traction; and, the tube thoracostomy was in-situ in 7.4%. No adverse events related to line malfunction/pullout occurred. The mean time for the performance of imaging using the mobile CT scan was 11.6 minutes compared with 47.8 minutes when patients were shifted to a conventional CT scan suite. The machine was nonfunctional 94 times, with an average downtime of 4.2 hours (range 2-72 hours). The life-cycle cost per mobile CT scan was Rs. 1340. CONCLUSIONS: A mobile CT has considerably changed the management response time in the neurosurgical intensive care unit (ICU) setup and decreased patient transfer times and the associated complications. Inclusion of a mobile CT scanner in the armamentarium of a neurosurgeon as a "bedside tool" can dramatically change decision making and the response time. It should be considered as the standard of care in any large-volume emergency department or neurosurgical facility. PMID- 26754995 TI - Tuberculous brain abscesses in immunocompetent patients: A decade long experience with nine patients. AB - OBJECTIVE: To describe the clinical presentation, radiological findings, management details, and outcome in nine cases of tuberculous brain abscess (TBA). MATERIALS AND METHODS: Nine patients (5 females, 4 males) harboring a TBA, as defined by the Whitener's criteria, were managed over a span of one and a half decade by the authors. All, except one patient, underwent contrast-enhanced magnetic resonance imaging scans, followed by surgical excision of the abscesses due to the failure of complete resolution of the lesion after its drainage using a burr-hole. RESULTS: The infra-tentorial location (n = 4) in TBAs was as common as the supra-tentorial location (n = 4). All large TBAs (more than 3 cm in diameter) failed to resolve after tapping of the purulent material and required surgical excision for a favorable long-term outcome. Two patients expired, while seven patients survived with Karnofsky Performance scale of 90 for 3, 80 for 3, and 70 for 1 patient. The follow-up ranged from 2 to 12 years (mean = 5.7 years). CONCLUSION: TBAs should be considered in the list of differential diagnoses for pyogenic abscesses, especially in developing countries, as it is difficult to differentiate between them on the basis of clinical or radiological findings. Hence, all pus samples should be sent for Ziehl-Neelsen staining and culture for Mycobacterium tuberculosis. Surgically excised and pathologically evaluated specimens remain the gold-standard for diagnosing TBAs. Larger abscesses warrant surgical excision, while concomitantly associated smaller lesions tend to resolve with prolonged antituberculous therapy. PMID- 26754997 TI - The decade after subthalamic stimulation in advanced Parkinson's disease: A balancing act. AB - AIM: The duration of improvement in quality of life after subthalamic nucleus deep brain stimulation (STN DBS) for Parkinson's disease (PD) and the presurgical identification of factors predicting sustained clinical benefits have implications in patient selection and timing of surgery. These aspects were assessed in patients who underwent yearly assessment for at least 7 years after surgery. MATERIALS AND METHODS: The quality of life, motor and cognitive outcomes of 25 patients who completed the 7-year assessment, and 12 patients who completed the 10-year assessment, were analyzed. RESULTS: The improvement in quality of life was sustained only for 5 years, while the severity of motor signs and motor fluctuations remained reduced at 7 and 10 years. Tremor and rigidity showed more enduring reduction than bradykinesia and axial signs. The dose reduction in medications could be maintained until 7 years, by which time, the axial scores were worse than that seen at the pre-DBS levels. At 10 years, a higher levodopa requirement and recurrence of dyskinesias were noted. Patients with greater pre DBS levodopa-responsive motor signs had greater long-term motor improvement. CONCLUSIONS: STN DBS performed in patients with advanced motor fluctuations and severe dyskinesias provide only an average of 5 years of quality of life improvement. STN DBS in patients with motor signs that are less responsive to levodopa results in shorter duration of clinical benefits. The improvements in the severity of motor fluctuations, rigidity, and tremor are the most enduring benefits of STN DBS that last a decade . However, these are offset by worsening axial and cognitive functions, bradykinesia, a higher levodopa requirement, and recurrence of dyskinesias by the end of the decade. PMID- 26754996 TI - Endoscopic third ventriculostomy through lamina terminalis: A feasible alternative to standard endoscopic third ventriculostomy. AB - CONTEXT: Endoscopic third ventriculostomy (ETV), wherein a stoma is created in the floor of the third ventricle, has now become the standard procedure for noncommunicating hydrocephalus across the world. However, in certain situations, this procedure may pose technical difficulties. These include a narrow prepontine space, vascularized third ventricular floor, the presence of prominent blood vessels traversing within the prepontine space, significant basal exudates, thickened and ill-defined third ventricular floor, and distorted floor anatomy. In such situations, an endoscopic lamina terminalis opening may provide a safer and more effective alternative to the standard technique. AIMS: The paper aims to discuss the different indications, technical nuances, and outcome of endoscopic third ventriculostomy through the lamina terminalis (ETV LT) utilizing the standard transventricular transforaminal route. SETTINGS AND DESIGN: A total of 240 patients underwent ETV between January 2007 and January 2014. Of these patients, 8 patients required an EVT LT and these patients formed the subset of patients for the present study. In all the 8 patients, the decision to perform fenestration of the LT during the endoscopic procedure was taken intraoperatively. We qualified a procedure to be a success when a second procedure was not required subsequently. RESULTS: Of the eight patients in whom ETV LT was done, four had aqueductal stenosis (including one case of post-primary ETV), three patients were diagnosed with post-meningitic hydrocephalus, and the remaining patient had a posterior fossa tumor. The procedure was successful in 6 of our patients who did not require a second procedure till the last follow-up. CONCLUSIONS: Endoscopic transventricular transforaminal LT fenestration with a flexible neuroendoscope is a feasible alternative to the standard ETV when technical difficulties precludes safe performance of the latter procedure. PMID- 26754998 TI - Functional and radiological outcome in patients undergoing three level corpectomy for multi-level cervical spondylotic myelopathy and ossified posterior longitudinal ligament. AB - BACKGROUND: To review our experience with patients undergoing 3 level cervical central corpectomy (CC) with un-instrumented fibular autograft fusion. MATERIALS AND METHODS: This is a retrospective study, involving 33 patients with cervical spondylotic myelopathy (CSM) or ossified posterior longitudinal ligament (OPLL) who underwent a 3 level CC between 2002 and 2010. The patients were followed up clinically and radiologically. Their functional status was assessed using Nurick's grading system. Parameters such as intraoperative complications, segmental curvature of the cervical spine, graft subsidence, graft fusion and functional outcome of these patients were assessed. RESULTS: There was transient morbidity in 28.6% of patients, with no permanent morbidity or mortality. We obtained follow up in 29 patients (87.9%) with a mean duration of follow up of 65.1 months (range, 12 to 138 months). The mean difference of segmental cervical curvature on follow up was 3.600 and the average graft subsidence was 5.70 mm. We achieved a fusion rate of 90%. There was no instance of graft extrusion in our series. There was a significant improvement in the functional status of our patients (from Nurick grade 3.55 to 2.42; P = 0.0001), with no clinical deterioration in any patient. CONCLUSIONS: Three level cervical corpectomy with un-instrumented fusion is a relatively safe surgery in experienced hands, and can achieve excellent clinical and radiological outcomes. PMID- 26754999 TI - Trends in authorship based on gender and nationality in published neuroscience literature. AB - OBJECTIVE: To evaluate the disparity in authorship based on gender and nationality of institutional affiliation among journals from developed and developing countries. MATERIALS AND METHODS: Original articles from two neuroscience journals, with a 5 year impact factor >15 (Neuron and Nature Neuroscience) and from two neurology journals from a developing country (Neurology India and Annals of Indian Academy of Neurology) were categorized by gender and institutional affiliation of first and senior authors. Articles were further divided by the type of research (basic/translational/clinical), study/target population (adult/pediatrics/both) and field of neurology. Data was collected for the years 2002 and 2012. RESULTS: There are large disparities in authorship by women and from developing countries in high impact factor neuroscience journals. However, there was a non-statistical rise in female first and senior authorship over a 10 year period. Additionally there was a significant increase in first authorship from institutions based in developing countries in the two neuroscience journals examined (P < 0.05). In the two neurology journals based in India there was a significant increase in the number of articles published by international investigators between 2002 and 2012 (P < 0.05). CONCLUSIONS: Over the last decade, there has been a non-statistical increase in proportion of female first and senior authors, and a significant increase in authors from developing countries in high impact factor neuroscience journals. However they continue to constitute a minority. The disparity in authorship based on gender also exists in neurology journals based in a developing country (India). PMID- 26755000 TI - Fatal granulomatous amoebic encephalitis caused by Acanthamoeba in a newly diagnosed patient with systemic lupus erythematosus. AB - Granulomatous amoebic encephalitis (GAE) caused by certain species belonging to the genus Acanthamoeba, Balamuthia, or Naegleria presents as a subacute or chronic illness. Amoebic encephalitis caused by Acanthamoeba is seen more often in immunosuppressed individuals. Thus, it may often be associated with human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS), organ transplantation, administration of steroids and systemic lupus erythematosus (SLE). The clinical progression is rapid, most often leading on to mortality of the patients. The diagnosis in most of these patients is established on postmortem examination. We describe a case of fatal granulomatous amoebic encephalitis in a patient recently diagnosed to be having SLE, who was receiving corticosteroids, cyclophosphamide, methotrexate, and hydroxychloroquine. The patient presented in an altered sensorium and expired after being hospitalized for 6 days. Postmortem examination of the brain showed extensive areas of necrosis and neutrophilic infiltrate with trophozoites and cysts of Acanthamoeba. PMID- 26755001 TI - Nutrition in neurocritical care. AB - Adequate nutritional therapy is essential for recovery from critical illness. Nutritional requirement varies in different patients and varies daily in a single patient. Both under and over feeding are associated with complications. Besides this, not all patients behave in a similar way to nutritional therapy. Appropriate nutritional therapy requires identification of patients "at nutritional risk" and providing aggressive nutritional support to them. The current article deals with nutritional support in critical illness with special emphasis on neurocritical care patients. PMID- 26755003 TI - Gaze disorders: A clinical approach. AB - A single clear binocular vision is made possible by the nature through the oculomotor system along with inputs from the cortical areas as well their descending pathways to the brainstem. Six systems of supranuclear control mechanisms play a crucial role in this regard. These are the saccadic system, the smooth pursuit system, the vestibular system, the optokinetic system, the fixation system, and the vergence system. In gaze disorders, lesions at different levels of the brain spare some of the eye movement systems while affecting others. The resulting pattern of eye movements helps clinicians to localize lesions accurately in the central nervous system. Common lesions causing gaze palsies include cerebral infarcts, demyelinating lesions, multiple sclerosis, tumors, Wernicke's encephalopathy, metabolic disorders, and neurodegenerative disorders such as progressive supranuclear palsy. Evaluation of the different gaze disorders is a bane of most budding neurologists and neurosurgeons. However, a simple and systematic clinical approach to this problem can make their early diagnosis rather easy. PMID- 26755002 TI - Epidermal growth factor receptor (EGFR) gene amplification in high-grade gliomas: Western Indian tertiary cancer center experience. AB - BACKGROUND: EGFR gene amplification is the hallmark of primary glioblastomas; however, its frequency in patients of Indian origin remains sparsely investigated. AIMS: The aim of this study was to explore the frequency of EGFR amplification in high grade gliomas (HGGs) in Indian patients and to study its correlation with p53 protein overexpression. METHODS AND MATERIALS: 324 cases of HGGs, where EGFR gene amplification was evaluated by fluorescence in-situ hybridization formed the study group. Ratio of >2 was considered as EGFR gene amplification. Immunohistochemically, p53 overexpression was evaluated and graded as positive for strong intensity staining in more than 50% of tumour cells. RESULTS: 249 patients were male and 75 female (M: F-3.3:1); their age range was 8 91 years [paediatric glioblastoma (pGBM; 8-18yrs; n = 24)], adult HGGs [>18yrs; n = 300]}. 258 patients were having a GBM [including 31 with a GBM with oligodendroglioma component (GBM-O)], 31 with a gliosarcoma, 13 with an anaplastic astrocytoma (AA), 12 with an anaplastic oligodendroglioma (AO), and 10 with an anaplastic oligoastrocytoma (AOA). 79/233 cases (34%) with an adult GBM, (including 10/31 with a GBM-O [32.2%]), 1/31 (3.2%) with a GS and 1/10 (10%) with an AOA showed EGFR gene amplification. None of the pGBMs (n = 24) showed amplification. Amplification was seen in 19/81 (23.4%) of diffuse p53 protein positive cases and 53/143 (37%) of cases with focal or negative p53 protein expression. CONCLUSIONS: 34% of our adult GBM patients showed EGFR gene amplification. The amplification was uncommonly associated with a strong diffuse p53 protein expression. PMID- 26755004 TI - Standing on the shoulders of giants from the past: The legacy of neurosurgery at Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum. PMID- 26755006 TI - Squash cytopathology of primary meningeal melanocytoma. PMID- 26755007 TI - Neurologic immune reconstitution inflammatory syndrome in a seropositive patient: An interesting case. PMID- 26755008 TI - Carbidopa-induced eosinophilic fasciitis: A review. PMID- 26755010 TI - Lhermitte-Duclos disease as a cranial manifestation of Cowden syndrome. PMID- 26755009 TI - Bilateral lateral geniculate body hemorrhagic infarction: A rare cause of acute bilateral painless vision loss in female patients. PMID- 26755011 TI - Transient cortical blindness and amnesia after cerebral angiography. PMID- 26755012 TI - Primary carnitine deficiency as a cause of metabolic leukoencephalopathy: Report of one case. PMID- 26755013 TI - An uncommon meningitis in an immunocompetent individual. PMID- 26755014 TI - Hereditary spastic paraplegia with a thin corpus callosum due to SPG11 mutation. PMID- 26755015 TI - Atypical initial manifestation of facioscapulohumeral muscular dystrophy mimicking neuralgic amyotrophy. PMID- 26755016 TI - Brain studded with bright spots: The unusual cause. PMID- 26755018 TI - Discal cyst - A rare cause of lumbar radiculopathy in the pediatric population. PMID- 26755017 TI - N-acetyl aspartate peak in extra-axial extraosseous chondrosarcoma of the brain on MRI: Unravelling a diagnostic dilemma. PMID- 26755019 TI - Atypical thalamic neurocytoma: A rare neoplasm. PMID- 26755020 TI - Osseous dysraphic hamartoma - A completely formed, aberrantly located, supralaminar rib in a lumbar lipomyelocele. PMID- 26755022 TI - Reversible cerebral vasoconstriction syndrome presenting with severe headache and seizures. PMID- 26755021 TI - Calcifying pseudoneoplasm of the superior medullary velum: An unusual location for a rare lesion. PMID- 26755023 TI - Isolated cervical intramedullary cysticercosis. PMID- 26755024 TI - Congenital absence of a cervical spine pedicle. PMID- 26755025 TI - Post-traumatic meningiomas-Myth or reality? PMID- 26755026 TI - Black brain caused by primary intracranial malignant melanoma. PMID- 26755027 TI - Brainstem dysfunction due to compression by megadolicho-vertebral arteries. PMID- 26755028 TI - Is adiposity more than a mere bystander in SAH? PMID- 26755029 TI - Disorders of consciousness: A new taxonomy arising from different therapeutic approaches. PMID- 26755030 TI - Bedside computed tomography in traumatic brain injury: Experience of consecutive 10,000 cases in neurosurgery at a level 1 trauma center in India. PMID- 26755032 TI - Bare fiber Bragg grating immunosensor for real-time detection of Escherichia coli bacteria. AB - Escherichia coli (E. coli) bacteria have been identified to be the cause of variety of health outbreaks resulting from contamination of food and water. Timely and rapid detection of the bacteria is thus crucial to maintain desired quality of food products and water resources. A novel methodology proposed in this paper demonstrates for the first time, the feasibility of employing a bare fiber Bragg grating (bFBG) sensor for detection of E. coli bacteria. The sensor was fabricated in a photo-sensitive optical fiber (4.2 um/80 um). Anti-E. coli antibody was immobilized on the sensor surface to enable the capture of target cells/bacteria present in the sample solution. Strain induced on the sensor surface as a result of antibody immobilization and subsequent binding of E. coli bacteria resulted in unique wavelength shifts in the respective recording of the reflected Bragg wavelength, which can be exploited for the application of biosensing. Functionalization and antibody binding on to the fiber surface was cross validated by the color development resulting from the reaction of an appropriate substrate solution with the enzyme label conjugated to the anti-E. coli antibody. Scanning electron microscope image of the fiber, further verified the E. coli cells bound to the antibody immobilized sensor surface. PMID- 26755033 TI - Analysis of red inks by micellar electrokinetic capillary chromatography with laser-induced fluorescence detection. AB - A combination of MEKC with a--highly sensitive but not commonly used--LIF detector was tested regarding the possibility of differentiation of red inks. The separation process was conducted in a fused silica capillary (id 50 MUm, 60/50 cm total/effective length) in BGE consisting of 40 mM sodium borate, 20 mM SDS and 10% v/v ACN with 30 kV applied. The optimized temperature of storage and capillary was 10 and 25 degrees C, respectively. The samples were prepared using 20 dots (o 0.5 mm), extracted in 35 MUL BGE and diluted with 30 MUL of water. The proposed method showed excellent repeatability and reproducibility (RSD (tm ) < 0.8 and < 2.5%, respectively). It was applied to group identification and differentiation of different brands, models, and batches of red printing, stamp, and pen inks. It was demonstrated that differentiation can be performed effectively on the basis of migration times and ratios of peak areas. The high efficiency of the developed method was indicated by discriminating power ranging from 87.3 to 98.8%, for stamp and pen inks, respectively. The results showed that the proposed procedure can be valuable for an objective examination of the red parts of questioned documents. PMID- 26755037 TI - Clinical trial registration: The time has come. PMID- 26755039 TI - Collaborative priority setting for human immunodeficiency virus rehabilitation research: A case report. AB - BACKGROUND: The inclusion of community members and other stakeholders in the establishment of research priorities is vital to ensuring that priorities are congruent with the main concerns of affected communities. PURPOSE: The purpose of this project was to identify priority research topics for addressing the activity and community participation needs of people living with human immunodeficiency virus (HIV) and meaningfully involve multiple stakeholders in the development of those priorities. METHOD: We invited people living with HIV, researchers, service providers, and policy makers to a 2-day forum. Twenty-six people participated in developing priorities through the application of two methodologies, the World Cafe and Dotmocracy. We evaluated the forum though immediate dialogue and a postproject survey. FINDINGS: Participants identified 10 high-priority research topics. Evaluation findings highlighted positive substantive, instrumental, personal, and normative outcomes of stakeholder involvement. IMPLICATIONS: The identified priority topics can guide future occupational therapy practice and research in this emerging area. PMID- 26755042 TI - Attitudes of mental health occupational therapists toward evidence-based practice. AB - BACKGROUND: Evidence-based practice is an important driver in modern health care and has become a priority in mental health occupational therapy in recent years. PURPOSE: The aim of this study was to measure the attitudes of a cohort of mental health occupational therapists toward evidence-based practice. METHOD: Forty-one mental health occupational therapists were surveyed using the Evidence-Based Practice Attitude Scale (EBPAS). Mann-Whitney U tests and Spearman's rho were used to analyze the data. FINDINGS: The occupational therapy respondents had generally positive attitudes toward evidence-based practices comparable to established norms. Respondents with further qualifications beyond their professional degree were significantly more likely to try new interventions (p = .31). Significant negative correlations were found also for the subscales of Appeal and Openness in relation to years of occupational therapy practice (rho = .354, p = .023; rho = -.344, p = 0.28) and mental health experience (rho = -.390, p = 0.12; rho = -.386, p = .013). IMPLICATIONS: Therapist factors can significantly impact attitudes toward evidence-based practice. PMID- 26755040 TI - Social networks and participation with others for youth with learning, attention, and autism spectrum disorders. AB - BACKGROUND: Social participation involves activities and roles providing interactions with others, including those within their social networks. PURPOSE: This study sought to characterize social networks and participation with others for 36 youth, ages 11 to 16 years, with (n = 19) and without (n = 17) learning disability, attention disorder, or high-functioning autism. METHOD: Social networks were measured using methods of personal network analysis. The Children's Assessment of Participation and Enjoyment With Whom dimension scores were used to measure participation with others. Youth from the clinical group were interviewed regarding their experiences within their social networks. FINDINGS: Group differences were observed for six social network variables and in the proportion of overall, physical, recreational, social, and informal activities engaged with family and/or friends. Qualitative findings explicated strategies used in building, shaping, and maintaining social networks. IMPLICATIONS: Social network factors should be considered when seeking to understand social participation. PMID- 26755043 TI - [Intelligent videosurveillance and falls detection: Perceptions of professionals and managers]. AB - DESCRIPTION: Gerontechnologies can be used to detect accidental falls. However, existing systems do not entirely meet users' expectations. Our team developed an intelligent video-monitoring systems to fill these gaps. Authors advocate consulting potential users at the early stages of the design of gerontechnologies and integrating their suggestions. PURPOSE: This study aims to explore health care workers' opinion regarding the intelligent video monitoring to detect falls by older adults living at home. METHOD: This qualitative study explored the opinions of 31 participants using focus groups. Transcripts were analyzed using predetermined codes based on the competence model. FINDINGS: Participants reported several advantages for using the intelligent video monitoring and provided suggestions for improving its use. IMPLICATIONS: The participants' suggestions and comments will help to improve the system and match it to users' needs. PMID- 26755044 TI - Postsecondary academic achievement and first-episode psychosis: A mixed-methods study. AB - BACKGROUND: Postsecondary academic achievement as an area of functional recovery for young adults living with mental illness has received little research attention. PURPOSE: This study had three purposes: to compare rates of participation, performance, and satisfaction in postsecondary education between young adults with first-episode psychosis and closely matched young adults; to identify characteristics associated with academic participation; and to explore the processes associated with educational experiences. METHOD: One hundred young adults ages 18 to 30 participated in the study. Quantitative data on academic engagement, performance, and satisfaction, and qualitative data (n = 52) on academic experiences were integrated through pattern analyzes. FINDINGS: Young adults with psychosis were significantly less likely to be engaged in postsecondary education. No difference appeared for the extent of engagement, but performance and satisfaction were lower among participants with psychosis. Participants engaged in reflexive decision making to access postsecondary education and to maintain adequate academic performance. Strategies used by successful students with mental illness were identified. IMPLICATIONS: Assessment and intervention focused on educational needs and skills should become landmark practices for psychiatric rehabilitation practitioners, including occupational therapists. PMID- 26755045 TI - Occupational balance: A study of the sociocultural perspective of Iranian occupational therapists. AB - BACKGROUND: The concept of occupational balance has always been important to occupational therapists and occupational scientists, but it is often interpreted differently by professionals, particularly in relation to practice. PURPOSE: This study focused on the understanding of occupational balance of a group of experienced occupational therapists who held positions at the time in Iran. METHOD: A preliminary qualitative study from within an interpretive paradigm was employed. A focus group was used for data collection, and the data were analyzed using thematic networks analysis in relation to occupational science concepts. FINDINGS: Four organizing themes were uncovered: integrity in being, equilibrium in doing, contentedness in becoming, and harmony in belonging. The global theme of "fluidity" describes the dynamic nature of occupational balance. IMPLICATIONS: The concept of occupational balance needs to be further explored in different communities. Identifying similarities and differences in its meaning and application will inform culturally relevant client-centred education and practice. PMID- 26755046 TI - Intrapulmonary vascular dilatations are common in portopulmonary hypertension and may be associated with decreased survival. PMID- 26755047 TI - Perspectives in chemosensitivity and chemoresistance assays and their implementation in head and neck cancer. AB - Therapeutic options for patients with head and neck squamous cell carcinoma include surgery, radiation and chemotherapy. The latter plays a major role in the treatment selection of recurrent, metastatic or therapy resistant tumours, these being some of the major challenges in head and neck oncology. For these patients, chemosensitivity and chemoresistance assays would be paramount to identify their individual therapy options. In this review, seven common assays will be described and discussed in the context of several studies. Further, a new assay will also be presented, currently being validated in a European Union funded project. Comparisons will be drawn to evaluate the sensitivity and specificity of these assays in identifying individual treatment options, and their potential implementation in head and neck malignancies will be discussed. There is an unmet demand for the development of ex vivo diagnostic tools that may predict response in head and neck cancer on the way towards an individualized treatment for these patients. PMID- 26755049 TI - Construction and identification of small hairpin RNA plasmids targeting neuropilin-1 gene and their inhibitory effect on human nasopharyngeal carcinoma CNE-2Z cell proliferation in vitro and in vivo. AB - We observed the effects of small hairpin RNA (shRNA) plasmids targeting neuropilin-1 (NRP-1) gene on human nasopharyngeal carcinoma (NPC) CNE-2Z cell growth in vitro and in vivo. Three fluorescein-labeled shRNA eukaryotic expression vectors targeting NRP-1 gene, including pSilencer-shRNA1, pSilencer shRNA2 and pSilencer-shRNA3 were constructed. The three plasmids were, respectively, transfected into human NPC CNE-2Z cells. The most effective plasmid was injected into xenograft tumors in nude mice. The sequencing for these recombinant plasmids was consistent with that of designed shRNA templates. Green fluorescence was seen in the transfected CNE-2Z cells and xenograft tumors in nude mice. MTT assay indicated that CNE-2Z cell proliferation was significantly inhibited. PT-PCR and Western blot displayed that both mRNA and protein of NRP-1 gene were all decreased, particularly in the cells treated with shRNA3. At the end of the experiment, xenograft tumors in plasmid group (0.599 +/- 0.002 cm(3)) were significantly inhibited with a tumor inhibition rate of 48.6 %, as compared to those in negative (1.141 +/- 0.013 cm(3)) and blank control groups (1.165 +/- 0.308 cm(3)) (all P < 0.05). shRNA targeting NRP-1 gene can effectively inhibit human NPC CNE-2Z cell proliferation in vitro and in vivo. This provides an experiment basis for NPC gene therapy. PMID- 26755050 TI - NCI-60 Cell Line Screening: A Radical Departure in its Time. AB - The year 2015 marked the 30th anniversary of National Cancer Institute's (NCI's) initial effort to establish a human cell line panel as the basis for discovering new cancer drugs. At its inception, the NCI-60 panel was a controversial departure, born of frustration with previous efforts that employed murine tumors and grounded in the hope that the biology of human tumors was diverse and somehow quite different than the murine leukemia used for the previous 30 years. And while the NCI-60 has not revolutionized cancer drug discovery in terms of the new drugs that resulted, it represents a turning point in the philosophy and practice of cancer drug research. PMID- 26755048 TI - Clinical practice guideline: tonsillitis I. Diagnostics and nonsurgical management. AB - More than 120,000 patients are treated annually in Germany to resolve repeated episodes of acute tonsillitis. Therapy is aiming at symptom regression, avoidance of complications, reduction in the number of disease-related absences in school or at work, increased cost-effectiveness and improved quality of life. The purpose of this part of the guideline is to provide clinicians in any setting with a clinically focused multi-disciplinary guidance through different conservative treatment options in order to reduce inappropriate variation in clinical care, improve clinical outcome and reduce harm. Surgical management in terms of intracapsular as well as extracapsular tonsillectomy (i.e. tonsillotomy) is the subject of part II of this guideline. To estimate the probability of tonsillitis caused by beta-hemolytic streptococci, a diagnostic scoring system according to Centor or McIsaac is suggested. If therapy is considered, a positive score of >=3 should lead to pharyngeal swab or rapid test or culture in order to identify beta-hemolytic streptococci. Routinely performed blood tests for acute tonsillitis are not indicated. After acute streptococcal tonsillitis, there is no need to repeat a pharyngeal swab or any other routine blood tests, urine examinations or cardiological diagnostics such as ECG. The determination of the antistreptolysin O-titer (ASLO titer) and other antistreptococcal antibody titers do not have any value in relation to acute tonsillitis with or without pharyngitis and should not be performed. First-line therapy of beta-hemolytic streptococci consists of oral penicillin. Instead of phenoxymethylpenicillin potassium (penicillin V potassium), also phenoxymethlpenicillin-benzathine with a clearly longer half-life can be used. Oral intake for 7 days of one of both the drugs is recommended. Alternative treatment with oral cephalosporins (e.g. cefadroxil, cefalexin) is indicated only in cases of penicillin failure, frequent recurrences, and whenever a more reliable eradication of beta-hemolytic streptococci is desirable. In cases of allergy or incompatibility of penicillin, cephalosporins or macrolides (e.g. Erythromycin-estolate) are valuable alternatives. PMID- 26755051 TI - An International Urogynecological Association (IUGA) / International Continence Society (ICS) joint report on the terminology for female pelvic organ prolapse (POP). AB - INTRODUCTION: The terminology for female pelvic floor prolapse (POP) should be defined and organized in a clinically-based consensus Report. METHODS: This Report combines the input of members of two International Organizations, the International Urogynecological Association (IUGA) and the International Continence Society (ICS), assisted at intervals by external referees. Appropriate core clinical categories and a sub-classification were developed to give a coding to definitions. An extensive process of fourteen rounds of internal and external review was involved to exhaustively examine each definition, with decision-making by collective opinion (consensus). RESULTS: A Terminology Report for female POP, encompassing over 230 separate definitions, has been developed. It is clinically based with the most common diagnoses defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in female pelvic floor dysfunction and POP. Female-specific imaging (ultrasound, radiology and MRI) and conservative and surgical managements are major additions and appropriate figures have been included to supplement and clarify the text. Emerging concepts and measurements, in use in the literature and offering further research potential, but requiring further validation, have been included as an appendix. Interval (5-10 year) review is anticipated to keep the document updated and as widely acceptable as possible. CONCLUSION: A consensus-based Terminology Report for female POP has been produced to aid clinical practice and research. PMID- 26755053 TI - Patient reported outcome measures after incontinence and prolapse surgery: are the pictures painted by the ICIQ and PGI-I accurate? PMID- 26755052 TI - Prevalence of obstetric fistula and symptomatic pelvic organ prolapse in rural Ethiopia. AB - INTRODUCTION AND OBJECTIVE: Little is known about the extent to which women in low- and middle-income countries suffer with urological and urogynaecological complications of childbirth. This study measured the prevalence of obstetric fistula and symptomatic pelvic organ prolapse (POP) in east and north Ethiopia. METHODS: We randomly selected 23,023 women of reproductive age (15-49 years) from 113 villages in East Harraghe, South Gondar and West Gojjam, Ethiopia. Trained local health workers administered a validated face-to-face survey and a team of researchers verified data by readministering a random selection (5 %) of the survey. All suspected fistulae were followed up to confirm a clinical diagnosis. RESULTS: Mean age was 29.5 [standard deviation (SD) 8.05] years. Only 22 % of women were knowledgeable about the symptoms of fistula. The prevalence of all obstetric fistulae was 6:10,000 reproductive-aged women [95 % confidence interval (CI) 3-8], of untreated fistula 2:10,000 (95 % CI 0-4) and of symptomatic POP 100:10,000 (95 % CI 86-114). CONCLUSION: The prevalence of obstetric fistula in these rural zones of Ethiopia is relatively low and reflects a substantial reduction from previous reports. Significant numbers of women suffer with symptomatic POP, for which surgical and nonsurgical treatments would be beneficial. Obstetric fistula in north and east Ethiopia is relatively low; however, the many women with symptomatic pelvic organ prolapse could benefit from treatment. PMID- 26755054 TI - TVT ABBREVO: cadaveric study of tape position in foramen obturatum and adductor region. AB - INTRODUCTION AND HYPOTHESIS: The aim of the study was to describe fixation of the TVT ABBREVO and establish whether the tape penetrates through obturator muscles and membrane (obturator complex) into the adductor region and, if so, how far it penetrates. METHODS: Eight formalin-embalmed female cadavers were used to simulate TVT ABBREVO surgery (totalling 16 insertions). Following tape insertion, dissection was performed and ends of the tape were identified. In cases of penetration, the length of tape penetrating into the adductor region was measured. RESULTS: Of the 16 cases, the tape ended in the obturator membrane in eight, in the internal obturator muscle in one, and penetrated through the obturator membrane into the external obturator muscle in five, where it remained. In two cases, it penetrated through the obturator internus muscle, obturator membrane and obturator externus muscle into the group of thigh adductors; one penetration was by 3 mm and the second by 10 mm. No contact with the obturator nerve or its branches was noted in any case. CONCLUSIONS: No TVT contact with the obturator nerve was noted; tape penetrated into the adductor region in two of the 16 cases. PMID- 26755056 TI - Relieving menstrual obstruction: surgical correction of vaginal agenesis. AB - INTRODUCTION AND HYPOTHESIS: Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome includes vaginal agenesis with varied uterine development. The objective of this video is to illustrate our surgical technique to create a cervical and vaginal canal to relieve menstrual obstruction for a teenager with a functional uterus and vaginal agenesis. METHODS: Using vaginal dissection and a mini laparotomy, a sound placed through the fundus of the uterus created an endocervical and vaginal channel to relieve her menstrual obstruction. A Foley catheter stented the cervical canal and a red rubber chest tube catheter stented the vagina until epithelization was achieved. RESULTS: No complications were encountered. The patient was examined with intermittent hysteroscopy with gentle dilation of the cervix. She had the red rubber catheter removed at 3 months, and she started using a small dilator. Her menses were suppressed with a gonadotropin releasing hormone agonist allowing for complete healing. She is now 17. Her vaginal canal is well-epithelialized. Hysteroscopy confirmed a patent endocervical canal and uterine cavity. CONCLUSION: MRKH is rare. A small percentage of affected women has a functional endometrium requiring intervention for menstrual obstruction. Full vaginal reconstruction may be considered, but creation of a small canal to provide menstrual relief can be a temporary solution in those not desiring sexual function. PMID- 26755057 TI - Mobility and stress analysis of different surgical simulations during a sacral colpopexy, using a finite element model of the pelvic system. AB - INTRODUCTION AND HYPOTHESIS: We aim to analyze the combined influence of the size of the mesh, the number of sutures, the combined use of an anterior and posterior mesh, and the tension applied to the promontory, on the mobility of the pelvic organs and on the sutures, using a Finite Element (FE) model of the female pelvic system during abdominal sacral colpopexy. METHODS: We used a FE model of the female pelvic system, which allowed us to simulate the mobility of the pelvic system and to evaluate problems related to female prolapse. The meshes were added to the geometrical model and then transferred to computing software. This analysis allowed us to compare the stress and mobility during a thrust effort in different situations. RESULTS: The bigger the mesh, the less mobility of both anterior and posterior organs there would be. This is accompanied by an increase in stress at the suture level. The combination of a posterior mesh with an anterior one decreases mobility and stress at the suture level. There is a particularly relevant stressing zone on the suture at the cervix. The increase in the number of sutures induces a decrease in the tension applied at each suture zone and has no impact on organ mobility. CONCLUSION: Our model enables us to simulate and analyze an infinite number of surgical hypotheses. Even if these results are not validated at a clinical level, we can observe the importance of the association of both an anterior and a posterior mesh or the number of sutures. PMID- 26755058 TI - Descending perineum syndrome: a review of the presentation, diagnosis, and management. AB - INTRODUCTION AND HYPOTHESIS: Defecatory dysfunction is a relatively common and challenging problem among women and one that practicing pelvic reconstructive surgeons and gynecologists deal with frequently. A subset of defecatory dysfunction includes obstructed defecation, which can have multiple causes, one of which is descending perineum syndrome (DPS). METHODS: A literature search was performed to identify the pathophysiology, diagnosis, and management of DPS. RESULTS: Although DPS has been described in the literature for many decades, it is still uncommonly diagnosed and difficult to manage. A high index of suspicion combined with physical examination consistent with excess perineal descent, patient symptom assessment, and imaging in the form of defecography are required for the diagnosis to be accurately made. Primary management options of DPS include conservative measures consisting of bowel regimens and biofeedback. Although various surgical approaches have been described in limited case series, no compelling evidence can be demonstrated at this point to support surgical intervention. CONCLUSIONS: Knowledge of DPS is essential for the practicing pelvic reconstructive surgeon to make a timely diagnosis, avoid harmful treatments, and initiate therapy early on. PMID- 26755061 TI - Theory of MRI contrast in the annulus fibrosus of the intervertebral disc. AB - OBJECTIVE: Here we develop a three-dimensional analytic model for MR image contrast of collagen lamellae in the annulus fibrosus of the intervertebral disc of the spine, based on the dependence of the MRI signal on collagen fiber orientation. MATERIALS AND METHODS: High-resolution MRI scans were performed at 1.5 and 7 T on intact whole disc specimens from ovine, bovine, and human spines. An analytic model that approximates the three-dimensional curvature of the disc lamellae was developed to explain inter-lamellar contrast and intensity variations in the annulus. The model is based on the known anisotropic dipolar relaxation of water in tissues with ordered collagen. RESULTS: Simulated MRI data were generated that reproduced many features of the actual MRI data. The calculated inter-lamellar image contrast demonstrated a strong dependence on the collagen fiber angle and on the circumferential location within the annulus. CONCLUSION: This analytic model may be useful for interpreting MR images of the disc and for predicting experimental conditions that will optimize MR image contrast in the annulus fibrosus. PMID- 26755062 TI - Principles and methods for automatic and semi-automatic tissue segmentation in MRI data. AB - The development of magnetic resonance imaging (MRI) revolutionized both the medical and scientific worlds. A large variety of MRI options have generated a huge amount of image data to interpret. The investigation of a specific tissue in 3D or 4D MR images can be facilitated by image processing techniques, such as segmentation and registration. In this work, we provide a brief review of the principles and methods that are commonly applied to achieve superior tissue segmentation results in MRI. The impacts of MR image acquisition on segmentation outcome and the principles of selecting and exploiting segmentation techniques tailored for specific tissue identification tasks are discussed. In the end, two exemplary applications, breast and fibroglandular tissue segmentation in MRI and myocardium segmentation in short-axis cine and real-time MRI, are discussed to explain the typical challenges that can be posed in practical segmentation tasks in MRI data. The corresponding solutions that are adopted to deal with these challenges of the two practical segmentation tasks are thoroughly reviewed. PMID- 26755064 TI - Integration of Innate Immune Signaling. AB - The last decades of research in innate immunology have revealed a multitude of sensing receptors that evaluate the presence of microorganisms or cellular damage in tissues. In the context of a complex tissue, many such sensing events occur simultaneously. Thus, the downstream pathways need to be integrated to launch an appropriate cellular response, to tailor the magnitude of the reaction to the inciting event, and to terminate it in a manner that avoids immunopathology. Here, we provide a conceptual overview of the crosstalk between innate immune receptors in the initiation of a concerted immune reaction to microbial and endogenous triggers. We classify the known interactions into categories of communication and provide examples of their importance in pathogenic infection. PMID- 26755063 TI - A method for the automatic segmentation of brown adipose tissue. AB - OBJECTIVE: Brown adipose tissue (BAT) plays a key role for thermogenesis in mammals and infants. Recent confirmation of BAT presence in adult humans has aroused great interest for its potential to initiate weight-loss and normalize metabolic disorders in diabetes and obesity. Reliable detection and differentiation of BAT from the surrounding white adipose tissue (WAT) and muscle is critical for assessment/quantification of BAT volume. This study evaluates magnetic resonance (MR) acquisition for BAT and the efficacy of different automated methods for MR features-based BAT segmentation to identify the best suitable method. MATERIALS AND METHODS: Multi-point Dixon and multi-echo T2 spin echo images were acquired from 12 mice using an Agilent 9.4T scanner. Four segmentation methods: multidimensional thresholding (MTh); region-growing (RG); fuzzy c-means (FCM) and neural-network (NNet) were evaluated for the interscapular region and validated against manually defined BAT, WAT and muscle. RESULTS: Statistical analysis of BAT segmentation yielded a median Dice Statistical-Index, and sensitivity of 89.92% for NNet, 82.86% for FCM, 72.74% for RG, and 72.70%, for MTh, respectively. CONCLUSION: This study demonstrates that NNet improves the specificity to BAT from surrounding tissue based on 3-point Dixon and T2 MRI. This method facilitates quantification and longitudinal measurement of BAT in preclinical-models and human subjects. PMID- 26755065 TI - N-Heterocyclic carbene-catalyzed [3 + 2] annulation of bromoenals with 3 aminooxindoles: highly enantioselective synthesis of spirocyclic oxindolo-gamma lactams. AB - The chiral N-heterocyclic carbene-catalyzed [3 + 2] annulation of alpha bromoenals and 3-aminooxindoles was developed, giving the corresponding spirocyclic oxindolo-gamma-lactams in good yields with high diastereoselectivities and enantioselectivities. PMID- 26755066 TI - Autism spectrum disorder traits in Slc9a9 knock-out mice. AB - Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders which begin in childhood and persist into adulthood. They cause lifelong impairments and are associated with substantial burdens to patients, families, and society. Genetic studies have implicated the sodium/proton exchanger (NHE) nine gene, Slc9a9, to ASDs and attention-deficit/hyperactivity disorder(ADHD). Slc9a9 encodes, NHE9, a membrane protein of the late recycling endosomes. The recycling endosome plays an important role in synapse development and plasticity by regulating the trafficking of membrane neurotransmitter receptors and transporters. Here we tested the hypothesis that Slc9a9 knock-out (KO) mice would show ADHD-like and ASD-like traits. Ultrasonic vocalization (USV) recording showed that Slc9a9 KO mice emitted fewer calls and had shorter call durations, which suggest communication impairment. Slc9a9 KO mice lacked a preference for social novelty, but did not show deficits in social approach; Slc9a9 KO mice spent more time self-grooming, an indicator for restricted and repetitive behavior. We did not observe hyperactivity or other behavior impairments which are commonly comorbid with ASDs in human, such as anxiety-like behavior. Our study is the first animal behavior study that links Slc9a9 to ASDs. By eliminatingNHE9 activity, it provides strong evidence that lack of Slc9a9leads to ASD-like behaviors in mice and provides the field with a new mouse model of ASDs. PMID- 26755067 TI - Erectile dysfunction, loss of libido and low sexual frequency increase the risk of cardiovascular disease in men with low testosterone. AB - INTRODUCTION: Testosterone deficiency increases the cardiovascular disease (CVD) risk. AIM: To evaluate the effect of erectile dysfunction (ED), sexual frequency and hypogonadal symptoms on CVD risk. METHODS: A total of 395 hypogonadal men aged 45-74 years were surveyed using the Androgen Deficiency in the Aging Male and the International Index of Erectile Function. MAIN OUTCOME MEASURES: The 10 year CVD risk was measured with the Framingham Risk Score. Logistic regression was performed to obtain the odds ratios of sexual function and hypogonadal symptoms for a 10-year CVD risk >=20% (high risk). RESULTS: The mean age was 56.1 +/- 6.7 years. The mean 10-year CVD risk of the whole cohort was 18.1% +/- 11.4%, while 131 subjects (33.2%) were classified as high risk. Logistic regression revealed that ED severity was associated with CVD risk [OR = 2.37 (CI 1.24-4.51) for mild-to-moderate ED, OR = 4.39 (1.78-8.43) for moderate ED and OR = 12.81 (4.65-26.11) for severe ED]. Compared to sexual frequency <1 per month, sexual frequency >=4 decreased the risk of high CVD risk [OR = 0.35 (0.23-0.780)]. Loss of libido [OR = 2.95 (1.91-4.12)] and less strong erection [OR = 3.87 (CI 2.11 4.95)] increased the risk of high CVD risk. All remained significant after adjustment for age and testosterone. CONCLUSIONS: ED, decreased sexual frequency and loss of libido predict a high 10-year CVD risk in hypogonadal men. PMID- 26755068 TI - Comparative geometric analysis of renal artery anatomy before and after fenestrated or snorkel/chimney endovascular aneurysm repair. AB - OBJECTIVE: The durability of stent grafts may be related to how procedures and devices alter native anatomy. We aimed to quantify and compare renal artery geometry before and after fenestrated (F-) or snorkel/chimney (Sn-) endovascular aneurysm repair (EVAR). METHODS: Forty patients (75 +/- 6 years) underwent computed tomographic angiography before and after F-EVAR (n = 21) or Sn-EVAR (n = 19), with a total of 72 renal artery stents. Renal artery geometry was quantified using three-dimensional model-based centerline extraction. The stented length was computed from the vessel origin to the stent end. The branch angle was computed relative to the orthogonal configuration with respect to the aorta. The end-stent angle was computed relative to the distal native renal artery. Peak curvature was defined as the inverse of the radius of the circumscribed circle at the highest curvature within the proximal portion from the origin to the stent end and the distal portion from the stent end to the first renal artery bifurcation. RESULTS: Sn-renals had greater stented length compared to F-renals (P < .05). From the pre to the postoperative period, the origins of the Sn-left renal artery and right renal artery (RRA) angled increasingly downward by 21 +/- 19 degrees and 13 +/- 17 degrees , respectively (P < .005). The F-left renal artery and RRA angled upward by 25 +/- 15 degrees and 14 +/- 15 degrees , respectively (P < .005). From the pre- to the postoperative period, the end-stent angle of the Sn-RRA increased by 17 +/- 12 degrees (P < .00001), with greater magnitude change compared to the F-RRA (P < .0005). Peak curvature increased in distal Sn-RRAs by .02 +/- .03 mm(-1) (P < .05). Acute renal failure occurred in 12.5% of patients, although none required dialysis following either F- and Sn-EVAR. Renal stent patency was 97.2% at mean follow-up of 13.7 months. Three type IA endoleaks were identified, prompting one secondary procedure, with the remainder resolving at 6 month follow-up. One renal artery reintervention was performed due to a compressed left renal stent in an asymptomatic patient. CONCLUSIONS: Stented renal arteries were angled more inferiorly after Sn-EVAR and more superiorly after F-EVAR due to stent configuration. Sn-EVAR induced significantly greater angle change at the stent end and curvature change distal to the stent compared to F-EVAR, although no difference in patency was noted in this small series with relatively short follow-up. Sn-RRAs exhibited greater end-stent angle change from the pre- to the postoperative period as compared to the F-RRA. These differences may exert differential effects on long-term renal artery patency, integrity, and renal function following complex EVAR for juxta- or pararenal abdominal aortic aneurysms. PMID- 26755069 TI - Impact of the 2010 Deepwater Horizon oil spill on population size and genetic structure of horse flies in Louisiana marshes. AB - The greenhead horse fly, Tabanus nigrovittatus Macquart, is frequently found in coastal marshes of the Eastern United States. The greenhead horse fly larvae are top predators in the marsh and thus vulnerable to changes in the environment, and the adults potentially are attracted to polarized surfaces like oil. Therefore, horse fly populations could serve as bioindicators of marsh health and toxic effects of oil intrusion. In this study, we describe the impact of the April 2010 Deep Water Horizon oil spill in the Gulf of Mexico on tabanid population abundance and genetics as well as mating structure. Horse fly populations were sampled biweekly from oiled and unaffected locations immediately after the oil spill in June 2010 until October 2011. Horse fly abundance estimates showed severe crashes of tabanid populations in oiled areas. Microsatellite genotyping of six pristine and seven oiled populations at ten polymorphic loci detected genetic bottlenecks in six of the oiled populations in association with fewer breeding parents, reduced effective population size, lower number of family clusters and fewer migrants among populations. This is the first study assessing the impact of oil contamination at the level of a top arthropod predator of the invertebrate community in salt marshes. PMID- 26755070 TI - Quinary wurtzite Zn-Ga-Ge-N-O solid solutions and their photocatalytic properties under visible light irradiation. AB - Wurtzite solid solutions between GaN and ZnO highlight an intriguing paradigm for water splitting into hydrogen and oxygen using solar energy. However, large composition discrepancy often occurs inside the compound owing to the volatile nature of Zn, thereby prescribing rigorous terms on synthetic conditions. Here we demonstrate the merits of constituting quinary Zn-Ga-Ge-N-O solid solutions by introducing Ge into the wurtzite framework. The presence of Ge not only mitigates the vaporization of Zn but also strongly promotes particle crystallization. Synthetic details for these quinary compounds were systematically explored and their photocatalytic properties were thoroughly investigated. Proper starting molar ratios of Zn/Ga/Ge are of primary importance for single phase formation, high particle crystallinity and good photocatalytic performance. Efficient photocatalytic hydrogen and oxygen production from water were achieved for these quinary solid solutions which is strongly correlated with Ge content in the structure. Apparent quantum efficiency for optimized sample approaches 1.01% for hydrogen production and 1.14% for oxygen production. Theoretical calculation reveals the critical role of Zn for the band gap reduction in these solid solutions and their superior photocatalytic acitivity can be understood by the preservation of Zn in the structure as well as a good crystallinity after introducing Ge. PMID- 26755071 TI - Evaluation by obstetric care providers of simulated postpartum blood loss using a collector bag: a French prospective study. AB - OBJECTIVE: Postpartum hemorrhage (PPH) is one of the most common causes of mortality in obstetrics worldwide. Accuracy in the estimated blood loss is a priority in determining appropriate treatment. The aim of this study was to evaluate the accuracy of estimating blood loss by obstetrics care providers during simulated training sessions. METHOD: A prospective study occurred in 2013 in a maternity ward at a teaching hospital. Simulation training sessions recreated a vaginal delivery in which six different scenarios were presented and proposed to each participant for them to estimate the blood loss (from 350 ml to 2500 ml) while using a collector bag graduated every 100 ml from 0 ml to 1500 ml. The primary endpoint was to determine if participants could accurately evaluate blood loss within a 20% error margin. RESULTS: About 90.7% of the medical staff participated. Ninety-three to 98% of the participants were accurate in their answer depending on which volume they had to estimate. For the lowest volume (350 ml), there was 11.1% overestimation between the estimated volume of blood loss (EBV) and the real volume of blood loss (RBV). However, there was an 8.8% underestimation found for the highest volume. CONCLUSION: The accuracy of the estimated blood loss for the obstetrical medical staff, using the collector bag, is more than 96%. PMID- 26755073 TI - An intrinsic DFF40/CAD endonuclease deficiency impairs oligonucleosomal DNA hydrolysis during caspase-dependent cell death: a common trait in human glioblastoma cells. AB - BACKGROUND: Glioblastoma (GBM) or grade IV astrocytoma is one of the most devastating human cancers. The loss of DFF40/CAD, the key endonuclease that triggers oligonucleosomal DNA fragmentation during apoptosis, has been linked to genomic instability and cell survival after radiation. Despite the near inevitability of GBM tumor recurrence after treatment, the relationship between DFF40/CAD and GBM remains unexplored. METHODS: We studied the apoptotic behavior of human GBM-derived cells after apoptotic insult. We analyzed caspase activation and the protein levels and subcellular localization of DFF40/CAD apoptotic endonuclease. DFF40/CAD was also evaluated in histological sections from astrocytic tumors and nontumoral human brain. RESULTS: We showed that GBM cells undergo incomplete apoptosis without generating oligonucleosomal DNA degradation despite the correct activation of executioner caspases. The major defect of GBM cells relied on the improper accumulation of DFF40/CAD at the nucleoplasmic subcellular compartment. Supporting this finding, DFF40/CAD overexpression allowed GBM cells to display oligonucleosomal DNA degradation after apoptotic challenge. Moreover, the analysis of histological slices from astrocytic tumors showed that DFF40/CAD immunoreactivity in tumoral GFAP-positive cells was markedly reduced when compared with nontumoral samples. CONCLUSIONS: Our data highlight the low expression levels of DFF40/CAD and the absence of DNA laddering as common molecular traits in GBM. These findings could be of major importance for understanding the malignant behavior of remaining tumor cells after radiochemotherapy. PMID- 26755074 TI - Epidermal growth factor receptor targeting and challenges in glioblastoma. AB - With the evolution of technology, there is now a deeper understanding of glioblastoma as an inter- and intraheterogeneous disease comprising a multitude of genetically and epigenetically different cancer cells. Greater characterization of glioblastoma at the molecular level has improved its initial pathophysiological staging and classification. With this knowledge comes the hope that more efficacious therapies to combat this highly lethal disease are on the horizon. One possibility for intervention is represented by the targeting of epidermal growth factor receptor (EGFR), which is amplified and mutated in a large subset of patients. In this review, we provide a brief overview of EGFR and its mutated form, EGFR variant III, describing the downstream cellular pathways activated by each receptor, available animal models, therapeutic strategies to inhibit the receptor, and possible intervention routes to efficiently target this receptor and prevent the emergence of resistant mechanisms which to date have hampered a successful therapeutic outcome. PMID- 26755075 TI - Using individual patient anatomy to predict protocol compliance for prostate intensity-modulated radiotherapy. AB - If a prostate intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) plan has protocol violations, it is often a challenge knowing whether this is due to unfavorable anatomy or suboptimal planning. This study aimed to create a model to predict protocol violations based on patient anatomical variables and their potential relationship to target and organ at risk (OAR) end points in the setting of definitive, dose-escalated IMRT/VMAT prostate planning. Radiotherapy plans from 200 consecutive patients treated with definitive radiation for prostate cancer using IMRT or VMAT were analyzed. The first 100 patient plans (hypothesis-generating cohort) were examined to identify anatomical variables that predict for dosimetric outcome, in particular OAR end points. Variables that scored significance were further assessed for their ability to predict protocol violations using a Classification and Regression Tree (CART) analysis. These results were then validated in a second group of 100 patients (validation cohort). In the initial analysis of the hypothesis-generating cohort, percentage of rectum overlap in the planning target volume (PTV) (%OR) and percentage of bladder overlap in the PTV (%OB) were highlighted as significant predictors of rectal and bladder dosimetry. Lymph node treatment was also significant for bladder outcomes. For the validation cohort, CART analysis showed that %OR of < 6%, 6% to 9% and > 9% predicted a 13%, 63%, and 100% rate of rectal protocol violations respectively. For the bladder, %OB of < 9% vs > 9% is associated with 13% vs 88% rate of bladder constraint violations when lymph nodes were not treated. If nodal irradiation was delivered, plans with a %OB of < 9% had a 59% risk of violations. Percentage of rectum and bladder within the PTV can be used to identify individual plan potential to achieve dose volume histogram (DVH) constraints. A model based on these factors could be used to reduce planning time, improve work flow, and strengthen plan quality and consistency. PMID- 26755072 TI - Atypical teratoid/rhabdoid tumors-current concepts, advances in biology, and potential future therapies. AB - Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant CNS tumor of children below 6 months of age. The majority of AT/RTs demonstrate genomic alterations in SMARCB1 (INI1, SNF5, BAF47) or, to a lesser extent, SMARCA4 (BRG1) of the SWItch/sucrose nonfermentable chromatin remodeling complex. Recent transcription and methylation profiling studies suggest the existence of molecular subgroups. Thus, at the root of these seemingly enigmatic tumors lies a network of factors related to epigenetic regulation, which is not yet completely understood. While conventional-type chemotherapy may have significant survival benefit for certain patients, it remains to be determined which patients will eventually prove resistant to chemotherapy and thus need novel therapeutic strategies. Elucidation of the molecular consequences of a disturbed epigenome has led to the identification of a series of transduction cascades, which may be targeted for therapy. Among these are the pathways of cyclin D1/cyclin-dependent kinases 4 and 6, Hedgehog/GLI1, Wnt/beta-catenin, enhancer of zeste homolog 2, and aurora kinase A, among others. Compounds specifically targeting these pathways or agents that alter the epigenetic state of the cell are currently being evaluated in preclinical settings and in experimental clinical trials for AT/RT. PMID- 26755076 TI - A treatment planning comparison between modulated tri-cobalt-60 teletherapy and linear accelerator-based stereotactic body radiotherapy for central early-stage non-small cell lung cancer. AB - We evaluated the feasibility of planning stereotactic body radiotherapy (SBRT) for large central early-stage non-small cell lung cancer with a tri-cobalt-60 (tri-(60)Co) system equipped with real-time magnetic resonance imaging (MRI) guidance, as compared to linear accelerator (LINAC)-based SBRT. In all, 20 patients with large central early-stage non-small cell lung cancer who were treated between 2010 and 2015 with LINAC-based SBRT were replanned using a tri (60)Co system for a prescription dose of 50Gy in 4 fractions. Doses to organs at risk were evaluated based on established MD Anderson constraints for central lung SBRT. R100 values were calculated as the total tissue volume receiving 100% of the dose (V100) divided by the planning target volume and compared to assess dose conformity. Dosimetric comparisons between LINAC-based and tri-(60)Co SBRT plans were performed using Student's t-test and Wilcoxon Ranks test. Blinded reviews by radiation oncologists were performed to assess the suitability of both plans for clinical delivery. The mean planning target volume was 48.3cc (range: 12.1 to 139.4cc). Of the tri-(60)Co SBRT plans, a mean 97.4% of dosimetric parameters per patient met MD Anderson dose constraints, whereas a mean 98.8% of dosimetric parameters per patient were met with LINAC-based SBRT planning (p = 0.056). R100 values were similar between both plans (1.20 vs 1.21, p = 0.79). Upon blinded review by 4 radiation oncologists, an average of 90% of the tri-(60)Co SBRT plans were considered acceptable for clinical delivery compared with 100% of the corresponding LINAC-based SBRT plans (p = 0.17). SBRT planning using the tri (60)Co system with built-in MRI is feasible and achieves clinically acceptable plans for most central lung patients, with similar target dose conformity and organ at risk dosimetry. The added benefit of real-time MRI-guided therapy may further optimize tumor targeting while improving normal tissue sparing, which warrants further investigation in a prospective feasibility clinical trial. PMID- 26755078 TI - Germline mutations in pancreatic cancer become better defined. PMID- 26755077 TI - Empirical determination of collimator scatter data for use in Radcalc commercial monitor unit calculation software: Implication for prostate volumetric modulated arc therapy calculations. AB - PURPOSE: The aim of this work was to determine, by measurement and independent monitor unit (MU) check, the optimum method for determining collimator scatter for an Elekta Synergy linac with an Agility multileaf collimator (MLC) within Radcalc, a commercial MU calculation software package. METHODS: The collimator scatter factors were measured for 13 field shapes defined by an Elekta Agility MLC on a Synergy linac with 6MV photons. The value of the collimator scatter associated with each field was also calculated according to the equation Sc=Sc(mlc)+Sc(corr)(Sc(open)-Sc(mlc)) with Sc(corr) varied between 0 and 1, where Sc(open) is the value of collimator scatter calculated from the rectangular collimator-defined field and Sc(mlc) the value using only the MLC-defined field shape by applying sector integration. From this the optimum value of the correction was determined as that which gives the minimum difference between measured and calculated Sc. Single (simple fluence modulation) and dual-arc (complex fluence modulation) treatment plans were generated on the Monaco system for prostate volumetric modulated-arc therapy (VMAT) delivery. The planned MUs were verified by absolute dose measurement in phantom and by an independent MU calculation. The MU calculations were repeated with values of Sc(corr) between 0 and 1. The values of the correction yielding the minimum MU difference between treatment planning system (TPS) and check MU were established. RESULTS: The empirically derived value of Sc(corr) giving the best fit to the measured collimator scatter factors was 0.49. This figure however was not found to be optimal for either the single- or dual-arc prostate VMAT plans, which required 0.80 and 0.34, respectively, to minimize the differences between the TPS and independent-check MU. Point dose measurement of the VMAT plans demonstrated that the TPS MUs were appropriate for the delivered dose. CONCLUSIONS: Although the value of Sc(corr) may be obtained by direct comparison of calculation with measurement, the efficacy of the value determined for VMAT-MU calculations are very much dependent on the complexity of the MLC delivery. PMID- 26755079 TI - Macrophage Recruitment Contributes to Regeneration of Mechanosensory Hair Cells in the Zebrafish Lateral Line. AB - In vertebrates, damage to mechanosensory hair cells elicits an inflammatory response, including rapid recruitment of macrophages and neutrophils. While hair cells in amniotes usually become permanently lost, they readily regenerate in lower vertebrates such as fish. Damage to hair cells of the fish lateral line is followed by inflammation and rapid regeneration; however the role of immune cells in this process remains unknown. Here, we show that recruited macrophages are required for normal regeneration of lateral line hair cells after copper damage. We found that genetic ablation or local ablation using clodronate liposomes of macrophages recruited to the site of injury, significantly delays hair cell regeneration. Neutrophils, on the other hand, are not needed for this process. We anticipate our results to be a starting point for a more detailed description of extrinsic signals important for regeneration of mechanosensory cells in vertebrates. J. Cell. Biochem. 117: 1880-1889, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26755080 TI - Dual Strategy With Oral Phosphodiesterase Type 5 Inhibition and Intracavernosal Implantation of Mesenchymal Stem Cells Is Superior to Individual Approaches in the Recovery of Erectile and Cavernosal Functions After Cavernous Nerve Injury in Rats. AB - INTRODUCTION: Novel effective therapeutic strategies are necessary for treating erectile dysfunction secondary to cavernous nerve injury (CNI). AIM: To functionally evaluate the benefits of long-term oral treatment with a phosphodiesterase type 5 inhibitor on the potential capacity of intracavernosal cell therapy to recover erectile function after CNI. METHODS: Bilateral crush CNI (BCNI) was produced in anesthetized male rats. After BCNI, rats were treated with the phosphodiesterase type 5 inhibitor tadalafil (TAD; 5 mg/kg/d orally; BCNI + TAD), a single intracavernosal injection of bone marrow-derived mesenchymal stem cells (BMSCs; BCNI + BMSC), or dual therapy (BCNI + BMSC + TAD). Ex vivo function of the corpus cavernosum (CC) and in vivo intracavernosal pressure responses to CN electrical stimulation were evaluated 4 weeks after BCNI. Trichrome staining and terminal 2'-deoxyuridine-5'-triphosphate nick-end labeling assay were used for fibrosis and apoptosis determination, respectively, in the CC. MAIN OUTCOME MEASURES: In vivo erectile responses in anesthetized rats, ex vivo evaluation of endothelium-dependent relaxation, neurogenic relaxation and neurogenic contraction in CC strips, and histologic evaluation of fibrosis and apoptosis in cavernosal tissue. RESULTS: BCNI resulted in a marked decrease of erectile responses that were partly recovered in the BCNI + TAD and BCNI + BMSC groups. Complete recovery of erectile function was achieved only in the BCNI + BMSC + TAD group. Endothelium-dependent and nitric oxide donor-induced relaxations of the CC were not altered by BCNI or the treatments. BCNI resulted in enhanced neurogenic adrenergic contractions and impaired nitrergic relaxations of the CC. The BCNI + TAD group displayed diminished neurogenic contractions, whereas the BCNI + TAD and BCNI + BMSC groups showed partly recovered nitrergic responses. In the BCNI + BMSC + TAD group, neurogenic contractions were decreased and nitrergic relaxations were normalized. Cavernosal apoptosis and fibrosis were similarly prevented in the BCNI + TAD, BCNI + BMSC, and BCNI + BMSC + TAD groups. CONCLUSION: A dual strategy combining the intracavernosal injection of BMSCs and oral administration of TAD was superior to individual approaches in normalizing neurogenic control of cavernosal tone and preserving erectile function after CNI, suggesting the potential of this dual strategy in the future management of erectile dysfunction after radical prostatectomy. PMID- 26755081 TI - Resveratrol Protects and Restores Endothelium-Dependent Relaxation in Hypercholesterolemic Rabbit Corpus Cavernosum. AB - INTRODUCTION: Oxidative stress dependent-decrease in nitric oxide (NO) bioavailability plays an integral role in hypercholesterolemia-induced erectile dysfunction (ED). Resveratrol has been demonstrated to exert beneficial effects against oxidative stress and improve NO bioavailability. AIM: The protective and restorative potentials of resveratrol on endothelium-dependent relaxations were evaluated in hypercholesterolemic rabbit corpus cavernosum (CC). METHODS: Hypercholesterolemia was induced by administering 2% cholesterol diet (CD) (w/w) to the rabbits for 6 weeks. Two different protocols were applied to test the effects of resveratrol on hypercholesterolemia-induced ED. In Protocol-1 (P1), resveratrol was administrated to the rabbits simultaneously with CD in order to evaluate the protective effect, and for Protocol-2 (P2), resveratrol was administrated for 6 weeks after termination of CD in order to evaluate the restorative effect. MAIN OUTCOME MEASURES: Endothelium-dependent relaxations of CC were evaluated by using organ bath studies. In order to elucidate the possible molecular mechanisms, we measured endothelial NO synthase (eNOS) and phosphovasodilator-stimulated phosphoprotein (VASP) expressions and activations, NADPH oxidase, superoxide dismutase (SOD), and catalase (CAT) and glutathione peroxidase (GPx) activity in cavernosal tissues obtained at the end of the study. RESULTS: Resveratrol showed an improvement in the endothelium-dependent relaxation responses in vitro. We demonstrated significantly increased activatory phosphorylation (p[S1177]-eNOS) and activated phosphovasodilator-stimulated phosphoprotein (phospho-VASP) levels, but reduced phosphorylation (p[T495]-eNOS) of eNOS and NADPH oxidase activity in the resveratrol-administered HC animals compared with hypercholesterolemic control rabbits in the P1. In the P2, resveratrol exhibited an improvement in endothelium-dependent relaxation responses and more pronounced effects on eNOS activation. CONCLUSION: Resveratrol administration, either simultaneously with HC diet or after HC, caused an improvement in the endothelium-dependent relaxation responses in the CC, suggesting its potential in both protective and restorative purposes in hypercholesterolemic rabbit CC. PMID- 26755083 TI - Editorial Comment on "Low Energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model". PMID- 26755082 TI - Low-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model. AB - INTRODUCTION: Erectile dysfunction (ED) caused by pelvic injuries is a common complication of civil and battlefield trauma with multiple neurovascular factors involved, and no effective therapeutic approach is available. AIMS: To test the effect and mechanisms of low-energy shock wave (LESW) therapy in a rat ED model induced by pelvic neurovascular injuries. METHODS: Thirty-two male Sprague-Dawley rats injected with 5-ethynyl-2'-deoxyuridine (EdU) at newborn were divided into 4 groups: sham surgery (Sham), pelvic neurovascular injury by bilateral cavernous nerve injury and internal pudendal bundle injury (PVNI), PVNI treated with LESW at low energy (Low), and PVNI treated with LESW at high energy (High). After LESW treatment, rats underwent erectile function measurement and the tissues were harvested for histologic and molecular study. To examine the effect of LESW on Schwann cells, in vitro studies were conducted. MAIN OUTCOME MEASUREMENTS: The intracavernous pressure (ICP) measurement, histological examination, and Western blot (WB) were conducted. Cell cycle, Schwann cell activation-related markers were examined in in vitro experiments. RESULTS: LESW treatment improves erectile function in a rat model of pelvic neurovascular injury by leading to angiogenesis, tissue restoration, and nerve generation with more endogenous EdU(+) progenitor cells recruited to the damaged area and activation of Schwann cells. LESW facilitates more complete re-innervation of penile tissue with regeneration of neuronal nitric oxide synthase (nNOS)-positive nerves from the MPG to the penis. In vitro experiments demonstrated that LESW has a direct effect on Schwann cell proliferation. Schwann cell activation-related markers including p-Erk1/2 and p75 were upregulated after LESW treatment. CONCLUSION: LESW-induced endogenous progenitor cell recruitment and Schwann cell activation coincides with angiogenesis, tissue, and nerve generation in a rat model of pelvic neurovascular injuries. PMID- 26755084 TI - Sexual Function and Depressive Symptoms in Young Women With Nonclassic Congenital Adrenal Hyperplasia. AB - INTRODUCTION: Women with classic forms of congenital adrenal hyperplasia (CAH) or polycystic ovary syndrome have been found to have impaired sexual function. AIM: This study investigated sexual activity in young women with nonclassic CAH (NC CAH). METHODS: The study included 24 untreated women with NC-CAH and 24 age matched healthy women. Plasma levels of free and total testosterone, androstenedione, and dehydroepiandrosterone sulfate were measured. Hirsutism was evaluated according to the modified Ferriman-Gallwey score. Questionnaires assessing female sexual function (Female Sexual Function Index) and the presence and severity of depressive symptoms (Beck Depression Inventory, Second Edition) were completed by each participant. MAIN OUTCOME MEASURES: Sexual function and depressive symptoms in young women with NC-CAH. RESULTS: Women with NC-CAH presented increased plasma levels of 17-hydroxyprogesterone, total and free testosterone, androstenedione, and dehydroepiandrosterone sulfate and higher hirsutism scores compared with healthy women. The study group also showed a lower total Female Sexual Function Index score and lower scores in four domains (sexual arousal, lubrication, sexual satisfaction, and dyspareunia). Scores for sexual desire and orgasm correlated with total hirsutism score and testosterone levels. The Beck Depression Inventory questionnaire showed that the total score was higher in women with NC-CAH than in healthy women, correlating with the hirsutism score and testosterone levels. CONCLUSION: The presence of NC-CAH in young women is associated with impaired sexual function and mild depressive symptoms. PMID- 26755085 TI - Urogenital and Sexual Complaints in Female Club Cyclists-A Cross-Sectional Study. AB - INTRODUCTION: Cycling has gained increased popularity among women, but in contrast to men, literature on urogenital overuse injuries and sexual dysfunctions is scarce. AIM: To determine the prevalence and duration of urogenital overuse injuries and sexual dysfunctions in female cyclists of the largest female cycling association in The Netherlands. METHODS: A cross-sectional questionnaire survey was sent to 350 members of the largest female Dutch cycling association and 350 female members of a Dutch athletics association (runners). MAIN OUTCOME MEASURES: The prevalence and duration of urogenital overuse injuries and sexual complaints were assessed using predefined international definitions. RESULTS: Questionnaire results of 114 cyclists (32.6%) and 33 runners (9.4%) were analyzed. After at least 2 hours of cycling, dysuria, stranguria, genital numbness, and vulvar discomfort were present in 8.8%, 22.2%, 34.9%, and 40.0%, respectively (maximum duration 48 hours). These complaints are not present in the controls (P < .001). In multivariable logistic regression analysis, increased saddle width was significantly associated with the presence of dysuria and stranguria. Older age was significantly associated to the presence of vulvar discomfort. Of the cyclists, 50.9% has at least one urogenital overuse injury. Insertional dyspareunia was present in 40.0% of cyclists and lasted until 48 hours after the effort. The latter complaint was not present in runners (P < .001). Uni- or bilateral vulvar edema was reported by 35.1% of cyclists. As for general complaints, 18.4% of cyclists reported a change in sexual sensations and 12.8% reported difficulties in reaching orgasm owing to cycling-related complaints. Limitations include population size and the use of non-validated questionnaires. CONCLUSIONS: The results of this study suggest that urogenital overuse injuries and sexual complaints are highly prevalent in female cyclists who are active participants in riding groups. PMID- 26755086 TI - Impaired Lipid Profile is a Risk Factor for the Development of Sexual Dysfunction in Women. AB - INTRODUCTION: Dyslipidemia is a common risk factor for cardiovascular disease which may contribute to sexual dysfunction in women. AIMS: To assess the impact of dyslipidemia compared with other metabolic alterations on female sexual function. METHODS: In total, 466 women were enrolled in the study, of which 256 were postmenopausal. Dyslipidemia was defined based on high-density lipoprotein, low-density lipoprotein, or triglycerides levels. Women completed the Female Sexual Function Index (FSFI), the Female Sexual Distress Scale (FSDS), and the Middlesex Hospital Questionnaire (MHQ). Biochemical and anthropometric measurements were performed and the Framingham risk score (FRS) was calculated for each subject. MAIN OUTCOME MEASUREMENTS: FSFI, FSDS, and MHQ scores, prevalence of FSD and FRS. RESULTS: Median age of the population enrolled was 51.5 (range 42.0-58.0) years. The overall prevalence of FSD, according to FSFI and FSDS scores, was 24%. A significantly higher prevalence of FSFI (P = .001) and FSDS (P = .006) pathological scores were found in women with dyslipidemia compared with the control group. The prevalence of FSD was significantly higher in dyslipidemic women (P = .001). Women with dyslipidemia had significantly higher total scores in areas of depression, somatization, and obsession in the MHQ questionnaire compared with control women. Multivariate analysis showed that dyslipidemia (OR:1.7, CI 1.1-2.9, P = .037), postmenopausal status (OR:2.7, CI 1.5-4.7, P = .001), higher education (OR:0.6; CI 0.3-0.9, P = .038), and somatization (OR:1.7, CI 1.0-2.8, P = .045) were independently associated with FSD. The FRS was higher in dyslipidemic women (P = .001) and in those with FSD (P = .001), being associated with an almost doubled risk of developing FSD. CONCLUSION: Our results indicate that dyslipidemia is an independent risk factor for FSD irrespective of postmenopausal status. Also, psychopathological alterations such as somatization are strongly associated with sexual dysfunction. The direct correlation between FSFI score and FRS suggest the importance of cardiovascular integrity in female sexual health. PMID- 26755087 TI - Erectile Dysfunction Is Not a Predictor of Atrial Fibrillation: A Population Based Propensity-Score Matched Cohort Study. AB - INTRODUCTION: Erectile dysfunction (ED) has been regarded a marker of cardiovascular diseases. Nevertheless, the association between ED and incident atrial fibrillation (AF) remains unknown. AIM: To determine the association between ED and incident AF. METHODS: This population-based cohort study was conducted using the National Health Insurance Research Database in Taiwan. In total, 6,273 of patients with ED without a prior diagnosis of AF were enrolled from January 1, 2001 through December 31, 2009, and a propensity-score matching method was used to identify 3,516 patients in the ED and control groups. MAIN OUTCOME MEASURES: Newly incident AF at follow-up was recorded as the end point. RESULTS: The mean age of the study population was 40.0 +/- 17.1 years, and the follow-up period was 8.0 +/- 0.5 years. Compared with the control group, patients with ED were older and had more of the following comorbidities: D'Hoore Charlson Comorbidity Index, hypertension, congestive heart failure, diabetes mellitus, dyslipidemia, chronic kidney disease, coronary artery disease, stroke, chronic lung disease, major depression disorder, obstructive sleep apnea, and hyperthyroidism. After adjusting for confounders, the ED group was not associated with more incident AF compared with the control group (hazard ratio = 1.031, 95% confidence interval = 0.674-1.578, P =.888). In these patients, ED of an organic origin was associated with a trend of having AF more often compared with ED of a psychosexual type (P =.272 by log-rank test). CONCLUSION: Although ED is known as a predictor of atherosclerotic cardiovascular diseases, it is not independently associated with incident AF in men. PMID- 26755089 TI - Sexuality After Cancer: A Model for Male Survivors. AB - INTRODUCTION: For men with cancer, sexual dysfunction is a common issue and has a negative impact on quality of life, regardless of whether he has a partner. In general, sexuality encompasses much more than intercourse; it involves body image, identity, romantic and sexual attraction, and sexual thoughts and fantasies. AIM: Acknowledging that cancer affects multiple physical and psychosocial domains in patients, the authors propose that such changes also inform sexual function for the male survivor. METHODS: An in-depth review of the literature describing alterations to sexual functioning in men with cancer was undertaken. Based on this and the clinical expertise of the authors, a new model was created and is presented. RESULTS: This biopsychosocial model is intended to expand the understanding of male sexuality beyond a purely biomedical model that addresses dysfunction as distinct from the context of a man's life and sexual identity. CONCLUSION: Most data on sexual dysfunction in men with cancer are derived from those with a history of prostate cancer, although other data suggest that men with other types of malignancies are similarly affected. Unfortunately, male sexuality is often reduced to aspects of erection and performance. Acknowledging that cancer affects multiple physical and psychosocial domains in patients, the authors propose that such changes also inform sexual function for the male survivor. This biopsychosocial model might form the basis for interventions for sexual problems after cancer that includes a man and his partner as a complex whole. PMID- 26755088 TI - Peripheral Atherosclerosis in Patients With Erectile Dysfunction: A Population Based Study. AB - INTRODUCTION: The presence of erectile dysfunction (ED) could be a warning of vascular disease in different arterial territories. AIM: The aim of this study was to investigate the association between ED and the presence of atherosclerosis in 2 different vascular beds: carotid and lower limbs. METHODS: A total of 614 volunteers between 45 and 74 years of age (mean age 61.0 years) were randomly selected from the general population. ED was assessed using the International Index of Erectile Function (IIEF-5). Ankle-brachial index (ABI) measurement and carotid atherosclerosis were evaluated by echo-Doppler. MAIN OUTCOME MEASURES: Mean carotid intima-media thickness (IMT), prevalence of carotid plaques, mean ABI, and prevalence of ABI < 0.9 were the main outcome measures. RESULTS: ED was present in 373 subjects (59.7%). Mean carotid IMT was significantly higher in men with ED (0.762 +/- 0.151 mm vs 0.718 +/- 0.114 mm, P < .001). Also the global prevalence of carotid plaques was more frequent in men with ED (63.8% vs 44.8%, P < .001), even after adjusting by age, cardiovascular risk factors, and ongoing treatment (P = .039). Both the IMT and the prevalence of carotid plaques increased significantly with ED severity (P trend .004 and <.001, respectively). There were no significant differences between groups neither in mean ABI nor in the prevalence of subjects with ABI < 0.9. However, there was a trend to a lower ABI and a higher prevalence of ABI < 0.9 with increasing ED severity. CONCLUSION: In the general population, the presence of ED identifies subjects with higher atherosclerosis burden in carotid arteries but not in the lower extremities. PMID- 26755090 TI - Why Us? Perceived Injustice is Associated With More Sexual and Psychological Distress in Couples Coping With Genito-Pelvic Pain. AB - INTRODUCTION: Provoked vestibulodynia (PVD) is the most frequent cause of genito pelvic pain/penetration disorder (GPPPD) and is associated with negative psychological and sexual consequences for affected women and their partners. PVD is often misdiagnosed or ignored and many couples may experience a sense of injustice, due to the loss of their ability to have a normal sexual life. Perceiving injustice has been documented to have important consequences in individuals with chronic pain. However, no quantitative research has investigated the experience of injustice in this population. AIM: The aim of this study was to investigate the associations between perceived injustice and pain, sexual satisfaction, sexual distress, and depression among women with PVD and their partners. METHODS: Women diagnosed with PVD (N = 50) and their partners completed questionnaires of perceived injustice, pain, sexual satisfaction, sexual distress, and depression. MAIN OUTCOME MEASURES: (1) Global Measure of Sexual Satisfaction Scale; (2) Female Sexual Distress Scale; (3) Beck Depression Inventory-II; and (4) McGill-Melzack Pain Questionnaire. RESULTS: After controlling for partners' age, women's higher level of perceived injustice was associated with their own greater sexual distress, and the same pattern was found for partners. Women's higher level of perceived injustice was associated with their own greater depression, and the same pattern was found for partners. Women's higher perceived injustice was not associated with their own lower sexual satisfaction but partners' higher perceived injustice was associated with their own lower sexual satisfaction. Perceived injustice was not associated with women's pain intensity. CONCLUSION: Results suggest that perceiving injustice may have negative consequences for the couple's sexual and psychological outcomes. However, the effects of perceived injustice appear to be intra-individual. Targeting perceived injustice could enhance the efficacy of psychological interventions for women with PVD and their partners. PMID- 26755091 TI - Effectiveness of Cognitive-Behavioral Therapy and Physical Therapy for Provoked Vestibulodynia: A Randomized Pilot Study. AB - INTRODUCTION: Non-medical and non-surgical treatments for provoked vestibulodynia target psychological, sexual, and pelvic floor muscle factors that maintain the condition. AIM: The goal of the study was to compare the effects of cognitive behavioral therapy (CBT) and physical therapy (PT) on pain and psychosexual outcomes in women with provoked vestibulodynia. METHODS: In a clinical trial, 20 women with provoked vestibulodynia were randomly assigned to receive CBT or comprehensive PT. Participants were assessed before treatment, after treatment, and at 6-month follow-up by gynecologic examination, structured interviews, and standardized questionnaires measuring pain, psychological, and sexual variables. MAIN OUTCOME MEASURES: Outcome measurements were based on an adaptation of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials recommendations. The primary outcome was change in intercourse pain intensity. Secondary outcomes included pain during the cotton swab test, pain with various sexual and non-sexual activities, and sexual functioning and negative pain cognitions. RESULTS: The two treatment groups demonstrated significant decreases in vulvar pain during sexual intercourse, with 70% and 80% of participants in the CBT and PT groups demonstrating a moderate clinically important decrease in pain (>=30%) after treatment. Participants in the two groups also had significant improvements in pain during the gynecologic examination, the percentage of painful intercourse attempts, the percentage of activities resulting in pain, and the ability to continue intercourse without stopping because of pain. Psychological outcomes, including pain catastrophizing and perceived control over pain, also showed improvement in the two groups. Significant improvements in sexual functioning were observed only in participants who completed CBT. Few between-group differences were identified other than the PT group showing earlier improvements in some outcomes. Nearly all improvements were maintained at the 6 month follow-up. CONCLUSION: The results of the study suggest that CBT and PT can lead to clinically meaningful improvements in pain and areas of psychosexual functioning. PMID- 26755092 TI - Sexual Problems During Pregnancy and After Delivery Among Women With and Without Anxiety and Depressive Disorders Prior to Pregnancy: A Prospective-Longitudinal Study. AB - INTRODUCTION: Few prospective-longitudinal studies have examined the course of sexual problems during pregnancy and after delivery in women with and without anxiety and depressive disorders prior to pregnancy as well as with and without maternal birth injuries. AIMS: To prospectively investigate associations of anxiety and depressive disorders prior to pregnancy and maternal birth injuries with sexual problems during the peripartum period. METHODS: The Maternal Anxiety in Relation to Infant Development Study is a prospective-longitudinal study of 306 women enrolled during early pregnancy and repeatedly assessed in seven waves during the peripartum period. Anxiety and depressive disorders prior to pregnancy were assessed in early pregnancy (T1) using the Composite International Diagnostic Interview for Women. Maternal birth injuries were assessed by questionnaire shortly after delivery (T4). Sexual problems during pregnancy (T2) as well as 4 months (T6) and 16 months (T7) postpartum were measured using the German version of the Massachusetts General Hospital Sexual Function Questionnaire. MAIN OUTCOME MEASURES: Impairment of sexual interest, arousal, orgasm, lubrication, and overall sexual satisfaction at T2, T6, and T7. RESULTS: Rates of sexual problems generally increased from T2 to T6 and decreased from T6 to T7. Compared with women without anxiety and depressive disorders, those with comorbid anxiety and depressive disorders prior to pregnancy more often specified impairment of overall sexual satisfaction at T2 (odds ratio [OR] = 2.0) and T7 (OR = 2.1). In contrast, sexual problems were not pronounced in those with pure anxiety or pure depressive disorders, and women with pure anxiety disorders often reported even less impairment of sexual interest at T7 (OR = 0.5). Compared with women without birth injury, those with vaginal birth injury more often reported impairment of sexual interest (OR = 1.8) and lubrication (OR = 2.3) at T6. CONCLUSION: Findings suggest that especially women with comorbid anxiety and depression and vaginal birth injury are at increased risk for sexual problems during pregnancy and after delivery and thus might benefit from targeted early interventions. PMID- 26755093 TI - The Influence of Emotion Upregulation on the Expectation of Sexual Reward. AB - INTRODUCTION: Emotion regulation research has shown successful altering of unwanted aversive emotional reactions. Cognitive strategies can also downregulate expectations of reward arising from conditioned stimuli, including sexual stimuli. However, little is known about whether such strategies can also efficiently upregulate expectations of sexual reward arising from conditioned stimuli, and possible gender differences therein. AIM: The present study examined whether a cognitive upregulatory strategy could successfully upregulate sexual arousal elicited by sexual reward-conditioned cues in men and women. METHODS: Men (n = 40) and women (n = 53) participated in a study using a differential conditioning paradigm, with genital vibrostimulation as unconditioned stimulus (US) and sexually relevant pictures as conditional stimuli. MAIN OUTCOME MEASURES: Penile circumference and vaginal pulse amplitude were assessed and ratings of US expectancy, affective value, and sexual arousal value were obtained. Also a stimulus response compatibility task was included to assess automatic approach and avoidance tendencies. RESULTS: Evidence was found for emotion upregulation to increase genital arousal response in the acquisition phase in both sexes, and to enhance resistance to extinction of conditioned genital responding in women. In men, the emotion upregulatory strategy resulted in increased conditioned positive affect. CONCLUSION: The findings support that top-down modulation may indeed influence conditioned sexual responses. This knowledge may have implications for treating disturbances in sexual appetitive responses, such as low sexual arousal and desire. PMID- 26755095 TI - Reoperation Rates for Penile Prosthetic Surgery. AB - INTRODUCTION: In patients with erectile dysfunction refractory to medical treatment, placement of a penile prosthesis is an effective treatment option. Despite advancements in prosthetic design, it is not without complications requiring reoperation. AIM: To evaluate the long-term reoperation rate of penile prosthesis implantation. METHODS: A longitudinal analysis of the California Office of Statewide Health Planning and Development database from 1995 to 2010 was performed. Inclusion criteria were men who underwent their first penile prosthetic surgery. Patients were excluded if they underwent explantation of a prior prosthesis at the time of their first recorded surgery. Statistical analysis was performed by Kaplan-Meier plot, hazard curve, and multivariate analysis adjusting for age, race, comorbidities, insurance status, hospital volume, and hospital teaching status. MAIN OUTCOME MEASURES: Primary outcome was reoperation, specified as the removal or replacement of the prosthesis. RESULTS: In total, 7,666 patients (40,932 patient-years) were included in the study. The 5 and 10-year cumulative reoperation rates were 11.2% (CI = 10.5-12.0) and 15.7% (CI = 14.7-16.8), respectively. Malfunction and infection accounted for 57% and 27% of reoperations. Reoperation rate was highest at 1 year postoperatively and steadily decreased until 2 years postoperatively. Multivariate analysis showed higher rates of reoperation in younger men (hazard ratio [HR] = 1.51, CI = 1.12 2.05), African-American men (HR = 1.30, CI = 1.05-1.62), and Hispanic men (HR = 1.32, CI = 1.12-1.57). Of the reoperations, 22.9% were performed at a hospital different from the initial implantation. CONCLUSION: Reoperation rate for penile prosthetic surgery is highest in the first year postoperatively. Patients with the highest risk for reoperation were African-American, Hispanic, and younger men. Nearly one fourth of reoperations occurred at a hospital different from the initial surgery, suggesting the existing literature does not reflect the true prevalence of penile prosthetic complications. PMID- 26755094 TI - 10 Years' Plaque Incision and Vein Grafting for Peyronie's Disease: Does Time Matter? AB - INTRODUCTION: Surgical correction is advocated in patients with stable Peyronie's disease (PD) and severe curvature of the penis. Contemporary series demonstrate favorable outcomes based on relatively short follow-up periods. However, long term follow-up is rarely reported and there is a paucity of evidence on the influence of patients' age, comorbidities, and natural history on surgical outcomes. AIMS: The present study aims to examine the influence of patient's age, comorbidities, severity of the disease, and natural history of PD on long-term outcomes and satisfaction following plaque incision and vein grafting for PD. METHODS: Patients with follow-up of more than 10 years who underwent plaque incision and grafting (Lue technique) for stable PD were included in the study. MAIN OUTCOME MEASURES: A combination of prospective and retrospective analysis of patients' histories, anatomical, functional, and surgical parameters, development of PD recurrences, improvements of sexual functions, and overall satisfaction were performed between 1992 and 2014. Multiple logistic regression models were applied to calculate adjusted odds ratios for predictors for development of erectile dysfunction (ED) and PD recurrence. RESULTS: Thirty patients with a median age of 57.5 years were eligible for inclusion in the study with a mean follow-up of 13.0 years (range 10.0-17.6). Angle of preoperative penile deviation was 40 degrees to 110 degrees (median 90 degrees ). On follow-up, 26 men (86.7%) had a straight erect penis. Eleven men (36.7%) developed ED, of whom 2 (6.7%) had other comorbidities contributing to their ED. Twenty-five men (83.3%) were still sexually active with or without medication. The mean percentage improvement in sexual function was 69.0%, with 17 men (56.7%) reporting 100% improvement and 7 (23.3%) reporting no improvement. Perceived penile shortening occurred in 13 patients (43.3%) and 6 patients (20.0%) experienced penile hyposensitivity. PD/plaque recurrence was found in 7 men (23.3%). The mean overall satisfaction with the procedure was 73.0%, with 18 men (60.0%) still 100% satisfied and 6 (20.0%) reporting satisfaction below 50%. CONCLUSION: Improvement of sexual function and overall satisfaction remain high at 10 years follow-up and make the technique a safe and effective form of treatment in carefully selected patients. PMID- 26755096 TI - Innate and Adaptive Immune Response to Fungal Products and Allergens. AB - Exposure to fungi and their products is practically ubiquitous, yet most of this is of little consequence to most healthy individuals. This is because there are a number of elaborate mechanisms to deal with these exposures. Most of these mechanisms are designed to recognize and neutralize such exposures. However, in understanding these mechanisms it has become clear that many of them overlap with our ability to respond to disruptions in tissue function caused by trauma or deterioration. These responses involve the innate and adaptive immune systems usually through the activation of nuclear factor kappa B and the production of cytokines that are considered inflammatory accompanied by other factors that can moderate these reactivities. Depending on different genetic backgrounds and the extent of activation of these mechanisms, various pathologies with resulting symptoms can ensue. Complicating this is the fact that these mechanisms can bias toward type 2 innate and adaptive immune responses. Thus, to understand what we refer to as allergens from fungal sources, we must first understand how they influence these innate mechanisms. In doing so it has become clear that many of the proteins that are described as fungal allergens are essentially homologues of our own proteins that signal or cause tissue disruptions. PMID- 26755097 TI - Prospects for Prevention of Food Allergy. AB - A rise in both prevalence and public awareness of food allergy in developed countries means that clinicians and researchers are frequently asked to explain reasons for the increase in food allergy, and families are eager to know whether they can take steps to prevent food allergy in their children. In this review, we outline leading theories on risk factors for early life food allergy. We summarize the leading hypotheses to explain the increase in food allergy as "the 5 Ds": dry skin, diet, dogs, dribble (shared microbial exposure), and vitamin D. We discuss currently available evidence for these theories and how these can be translated into clinical recommendations. With the exception of dietary intervention studies, evidence for each of these theories is observational, and we describe the implications of this for explaining risk to families. Current infant feeding recommendations are that infants should be introduced to solids around the age of 4 to 6 months irrespective of family history risk and that allergenic solids do not need to be avoided, either by infants at the time of solid food introduction or by mothers whilst pregnant or lactating. Additional potential strategies currently being explored include optimization of early life skin barrier function through a decrease in drying soaps and detergents and an increase in the use of nonallergenic moisturizers. The investigation of the role of microbiota and vitamin D is ongoing and cannot yet be translated into clinical recommendations. PMID- 26755098 TI - Sequential Treatment Initiation with Timothy Grass and Ragweed Sublingual Immunotherapy Tablets Followed by Simultaneous Treatment Is Well Tolerated. AB - BACKGROUND: Dual treatment with grass and ragweed sublingual immunotherapy (SLIT) tablets has not been studied. OBJECTIVE: To characterize the safety and tolerability of dual grass and ragweed SLIT-tablet administration. METHODS: This open-label, multicenter trial (NCT02256553) enrolled North American adults (N = 102) allergic to grass and ragweed. The trial had 3 periods, each of 2 weeks duration. In period 1, subjects received once-daily timothy grass SLIT tablet (2800 bioequivalent allergen unit; Merck, Inc, Kenilworth, NJ/ALK, Horsholm, Denmark). In period 2, subjects received a short ragweed SLIT tablet (12 Ambrosia artemisiifolia 1-U; Merck/ALK) every morning and a grass SLIT tablet every evening. In period 3, subjects received once-daily grass and ragweed SLIT tablets within 5 minutes (simultaneous intake). The primary end point was the proportion of subjects with 1 or more local swelling events in each period. Secondary end points were the proportion of subjects with 1 or more local adverse events (AEs), that discontinued the treatment because of AEs, and subjects with 1 or more local AEs requiring treatment. RESULTS: No severe swellings, systemic allergic reactions, asthma attacks, or reactions requiring epinephrine were reported. Most (99%) AEs were graded mild to moderate. The proportions of subjects with 1 or more local swelling events were 14%, 22%, and 15% for periods 1, 2, and 3, respectively. For periods 1, 2, and 3, the proportions of subjects with 1 or more local AEs were 71%, 69%, and 56%, respectively; the proportions discontinuing the treatment because of treatment-related AEs were 5%, 1%, and 2%, and the proportions with 1 or more local AEs requiring treatment were 4%, 4%, and 1%. CONCLUSIONS: In this trial, a 4-week sequential SLIT-tablet dosing schedule followed by simultaneous intake of timothy grass and ragweed tablets was well tolerated. PMID- 26755099 TI - Multiple food protein intolerance of infancy or severe spectrum of non-IgE mediated cow's milk allergy?--A case series. PMID- 26755100 TI - Clinical Evaluation and Management of Patients with Suspected Fungus Sensitivity. AB - Fungus-sensitized patients usually present with symptoms that are similar to symptoms presented by those who are sensitized to other aeroallergens. Therefore, diagnosis and management should follow the same pathways used for patients with allergic conditions in general. The physician should consider that a relationship between fungal exposure and symptoms is not necessarily caused by an IgE-mediated mechanism, even when specific fungal IgE is detected. Until recently, IgE mediated allergy has been documented only for a limited number of fungi. We propose a series of questions to be used to identify symptoms that occur in situations with high fungal exposure and a limited skin-prick-test panel (Alternaria, Cladosporium, Penicillium, Aspergillus, Candida) that can be amplified only in cases of high suspicion of other fungal exposure (eg, postfloods). We also review in vitro testing for fungi-specific IgE. Treatment includes environmental control, medical management, and, when appropriate, specific immunotherapy. Low-quality evidence exists supporting the use of subcutaneous immunotherapy for Alternaria to treat allergic rhinitis and asthma, and very low quality evidence supports the use of subcutaneous immunotherapy for Cladosporium and sublingual immunotherapy for Alternaria. As is the case for many allergens, evidence for immunotherapy with other fungal extracts is lacking. The so-called toxic mold syndrome is also briefly discussed. PMID- 26755101 TI - Collaboration in best practices for care of patients with atopic dermatitis. PMID- 26755127 TI - Pre-employment examinations for preventing injury, disease and sick leave in workers. AB - BACKGROUND: Many employers and other stakeholders believe that health examinations of job applicants prevent occupational diseases and sickness absence. This is an update of the original Cochrane review (Mahmud 2010). OBJECTIVES: To evaluate the effectiveness of pre-employment examinations of job applicants in preventing occupational injury, disease and sick leave compared to no intervention or alternative interventions. SEARCH METHODS: We searched CENTRAL (the Cochrane Library), MEDLINE, EMBASE, CINAHL, PsycINFO and PEDro (up to 31 March 2015). We did not impose any restrictions on date, language or publication type. SELECTION CRITERIA: We included randomised controlled trials (RCTs), controlled before-after (CBA) studies, and interrupted time-series (ITS) studies of health examinations to prevent occupational diseases and injuries in job applicants in comparison to no intervention or alternative interventions. DATA COLLECTION AND ANALYSIS: All five review authors independently selected studies from the updated search for inclusion. We retrieved two new studies with the updated search from 1 April 2008 to 31 March 2015, resulting in a total of eleven studies. MAIN RESULTS: We included two RCTs, seven CBA studies and two ITS studies. Nine studies with 7820 participants evaluated the screening process of pre-employment examinations as a whole, and two studies with 2164 participants evaluated the measures to mitigate the risks found following the screening process. The studies were too heterogeneous for statistical pooling of results. We rated the quality of the evidence for all outcomes as very low quality. The two new CBA studies both used historical controls and both had a high risk of bias.Of those studies that evaluated the screening process, there is very low quality evidence based on one RCT that a general examination for light duty work may not reduce the risk for sick leave (mean difference (MD) -0.09, 95% confidence interval (CI) -0.47 to 0.29). For army recruits, there is very low quality evidence based on one CBA study that there is a positive effect on fitness for duty after 12 months follow-up (odds ratio (OR) 0.40, 95% CI 0.19 to 0.85).We found inconsistent evidence of an effect of job-focused pre-employment examinations on the risk of musculoskeletal injuries in comparison with general or no pre-employment examination based on one RCT with high risk of bias, and four CBA studies. There is very low quality evidence based on one ITS study that incorporation of a bronchial challenge test may decrease occupational asthma (trend change -2.6, 95% CI -3.6 to -1.5) compared to a general pre-employment examination with lung function tests.Pre-employment examinations may also result in a rejection of the applicant for the new job. In six studies, the rates of rejecting job applicants increased because of the studied examinations , on average, from 2% to 35%, but not in one study.There is very low quality evidence based on two CBA studies that risk mitigation among applicants considered not fit for work at the pre-employment examination may result in a similar risk of work related musculoskeletal injury during follow-up compared to workers considered fit for work at the health examination. AUTHORS' CONCLUSIONS: There is very low quality evidence that a general examination for light duty work may not reduce the risk for sick leave, but may have a positive effect on fitness for duty for army recruits after 12 months follow-up.There is inconsistent evidence of an effect of job-focused pre-employment examinations on the risk of musculoskeletal injuries in comparison with general or no pre-employment examination. There is very low quality evidence that incorporation of a bronchial challenge test may decrease occupational asthma compared to a general pre-employment examination with lung function tests. Pre-employment examinations may result in an increase of rejecting job applicants in six out of seven studies. Risk mitigation based on the result of pre-employment examinations may be effective in reducing an increased risk for occupational injuries based on very low quality evidence. This evidence supports the current policy to restrict pre-employment examinations to only job-specific examinations. Better quality evaluation studies on pre employment examinations are necessary, including the evaluation of the benefits of risk mitigation, given the effect on health and on the financial situation for those employees who do not pass the pre-employment examination. PMID- 26755102 TI - The Effects of Weather Factors on Hand, Foot and Mouth Disease in Beijing. AB - The morbidity and mortality of hand, foot and mouth disease (HFMD) are increasing in Beijing, China. Previous studies have indicated an association between incidents of HFMD and weather factors. However, the seasonal influence of these factors on the disease is not yet understood, and their relationship with the enterovirus 71 (EV71) and Coxsackie virus A16 (CV-A16) viruses are not well documented. We analysed 84,502 HFMD cases from 2008 to 2011 in Beijing to explore the seasonal influence of weather factors (average temperature [AT], average relative humidity [ARH], total precipitation [TP] and average wind speed [AWS]) on incidents of HFMD by using a geographically weighted regression (GWR) model. The results indicated that weather factors differ significantly in their influence on HFMD depending on the season. AT had the greatest effect among the four weather factors, and while the influence of AT and AWS was greater in the summer than in the winter, the influence of TP was positive in the summer and negative in the winter. ARH was negatively correlated with HFMD. Also, we observed more EV71-associated cases than CV-A16 but there is no convincing evidence to show significant differences between the influences of the weather factors on EV71 and CV-A16. PMID- 26755128 TI - Effects of simulated acid rain on soil respiration and its components in a subtropical mixed conifer and broadleaf forest in southern China. AB - Soil respiration is a major pathway in the global carbon cycle and its response to environmental changes is an increasing concern. Here we explored how total soil respiration (RT) and its components respond to elevated acid rain in a mixed conifer and broadleaf forest, one of the major forest types in southern China. RT was measured twice a month in the first year under four treatment levels of simulated acid rain (SAR: CK, the local lake water, pH 4.7; T1, water pH 4.0; T2, water pH 3.25; and T3, water pH 2.5), and in the second year, RT, litter-free soil respiration (RS), and litter respiration (RL) were measured simultaneously. The results indicated that the mean rate of RT was 2.84 +/- 0.20 MUmol CO2 m(-2) s(-1) in the CK plots, and RS and RL contributed 60.7% and 39.3% to RT, respectively. SAR marginally reduced (P = 0.08) RT in the first year, but significantly reduced RT and its two components in the second year (P < 0.05). The negative effects were correlated with the decrease in soil microbial biomass and fine root biomass due to soil acidification under the SAR. The temperature coefficients (Q10) of RT and its two components generally decreased with increasing levels of the SAR, but only the decrease of RT and RL was significant (P < 0.05). In addition, the contribution of RL to RT decreased significantly under the SAR, indicating that RL was more sensitive to the SAR than RS. In the context of elevated acid rain, the decline trend of RT in the forests in southern China appears to be attributable to the decline of soil respiration in the litter layer. PMID- 26755129 TI - Continuous low-dose feeding of highly active pharmaceutical ingredients in hot melt extrusion. AB - CONTEXT: Manufacturing solid low-dose pharmaceutical products has always the homogeneity challenge. In continuous manufacturing, there is the additional challenge of feeding active pharmaceutical ingredient (API) dry powder at low rates. This paper presents a method for feeding API particles into a continuous extrusion process using a suspension. The challenges for feeding and the product homogeneity are both addressed. OBJECTIVE: The objective of this study is to demonstrate the feasibility of manufacturing low-dose extrudates by feeding the API particles in a diluted anti-solvent suspension. MATERIALS AND METHODS: Extrudates with an Ibuprofen content of 0.021% and 0.043% (w/w) were prepared by feeding a 0.9% w/w suspension of Ibuprofen particles into a Coperion extruder. RESULTS AND DISCUSSION: The homogeneity (RSD) of extrudates was tested during a time span of 30 min and had values between 2% and 7%. CONCLUSION: Feeding particles in an anti-solvent suspension offers a simple feeding option for API and minor components which yield products of desired homogeneity. The liquid feeding approach offers a simplified process with enhanced process control possibilities. PMID- 26755130 TI - Spatial and Temporal Variability in Pesticide Exposure Downstream of a Heavily Irrigated Cropping Area: Application of Different Monitoring Techniques. AB - Pesticide exposure threatens many freshwater and estuarine ecosystems around the world. This study examined the temporal and spatial trends of pesticide concentrations in a waterway within an agriculturally developed dry-tropics catchment using a combination of grab and passive sampling methods over a continuous two-year monitoring program. A total of 43 pesticide residues were detected with 7 pesticides exceeding ecologically relevant water quality guidelines/trigger values during the study period and 4 (ametryn, atrazine, diuron, and metolachlor) of these exceeding guidelines for several months. The presence and concentration of the pesticides in the stream coincided with seasonal variability in rainfall, harvest timing/cropping cycle, and management changes. The sampling approach used demonstrates that the application of these complementary sampling techniques (both grab and passive sampling methods) was effective in establishing pesticide usage patterns in upstream locations where application data are unavailable. PMID- 26755132 TI - Wall modified photonic crystal fibre capillaries as porous layer open tubular columns for in-capillary micro-extraction and capillary chromatography. AB - Wall modified photonic crystal fibre capillary columns for in-capillary micro extraction and liquid chromatographic separations is presented. Columns contained 126 internal parallel 4 MUm channels, each containing a wall bonded porous monolithic type polystyrene-divinylbenzene layer in open tubular column format (PLOT). Modification longitudinal homogeneity was monitored using scanning contactless conductivity detection and scanning electron microscopy. The multichannel open tubular capillary column showed channel diameter and polymer layer consistency of 4.2 +/- 0.1 MUm and 0.26 +/- 0.02 MUm respectively, and modification of 100% of the parallel channels with the monolithic polymer. The modified multi-channel capillaries were applied to the in-capillary micro extraction of water samples. 500 MUL of water samples containing single MUg L(-1) levels of polyaromatic hydrocarbons were extracted at a flow rate of 10 MUL min( 1), and eluted in 50 MUL of acetonitrile for analysis using HPLC with fluorescence detection. HPLC LODs were 0.08, 0.02 and 0.05 MUg L(-1) for acenaphthene, anthracene and pyrene, respectively, with extraction recoveries of between 77 and 103%. The modified capillaries were also investigated briefly for direct application to liquid chromatographic separations, with the retention and elution of a standard protein (cytochrome c) under isocratic conditions demonstrated, proving chromatographic potential of the new column format, with run-to-run retention time reproducibility of below 1%. PMID- 26755133 TI - New developments in microextraction techniques in bioanalysis. A review. AB - In recent years, the interest in new extraction methods with lower sample volume requirements, simpler equipment and handling, and lower reagent consumption, has led to the development of a series of microextraction methods based on extraction phases in the microliter order. Nowadays, many references can be found for several of these methods, which imply a wide range of applications referred to both the analyte and the sample nature. In this paper, recent developments in both well-established microextraction techniques (solid phase microextraction, hollow-fiber liquid phase microextraction, dispersive liquid-liquid microextraction, etc.) and recently appeared microextraction procedures (nanoextraction systems, microchip devices, etc.) for the clinical analysis of biological samples will be reviewed and discussed. PMID- 26755134 TI - State of the art of environmentally friendly sample preparation approaches for determination of PBDEs and metabolites in environmental and biological samples: A critical review. AB - Green chemistry principles for developing methodologies have gained attention in analytical chemistry in recent decades. A growing number of analytical techniques have been proposed for determination of organic persistent pollutants in environmental and biological samples. In this light, the current review aims to present state-of-the-art sample preparation approaches based on green analytical principles proposed for the determination of polybrominated diphenyl ethers (PBDEs) and metabolites (OH-PBDEs and MeO-PBDEs) in environmental and biological samples. Approaches to lower the solvent consumption and accelerate the extraction, such as pressurized liquid extraction, microwave-assisted extraction, and ultrasound-assisted extraction, are discussed in this review. Special attention is paid to miniaturized sample preparation methodologies and strategies proposed to reduce organic solvent consumption. Additionally, extraction techniques based on alternative solvents (surfactants, supercritical fluids, or ionic liquids) are also commented in this work, even though these are scarcely used for determination of PBDEs. In addition to liquid-based extraction techniques, solid-based analytical techniques are also addressed. The development of greener, faster and simpler sample preparation approaches has increased in recent years (2003-2013). Among green extraction techniques, those based on the liquid phase predominate over those based on the solid phase (71% vs. 29%, respectively). For solid samples, solvent assisted extraction techniques are preferred for leaching of PBDEs, and liquid phase microextraction techniques are mostly used for liquid samples. Likewise, green characteristics of the instrumental analysis used after the extraction and clean-up steps are briefly discussed. PMID- 26755135 TI - Valence properties of tellurium in different chemical systems and its determination in refractory environmental samples using hydride generation - Atomic fluorescence spectroscopy. AB - Using HG - AFS as a powerful tool to study valence transformations of Te, we found that, in presence of HCl and at high temperature, Te can form volatile species and be lost during sample digestion and pre-reduction steps. It was also noticed that the chemical valences of Te can be modified under different chemical and digestion conditions and even by samples themselves with certain matrices. KBr can reduce Te(VI) to Te(IV) in 3.0 M HCl at 100 degrees C, but when HNO3 was >5% (v/v) in solution, Br2 was formed and caused serious interference to Te measurements. HCl alone can also pre-reduce Te(VI) to Te(IV), only when its concentration was >=6.0 M (100 degrees C for 15min). Among 10 studied chemical elements, only Cu(2+) caused severe interference. Thiourea is an effective masking agent only when Cu(2+) concentration is equal or lower than 10 mg/L. Chemical reagents, chemical composition of sample, as well as the modes of digestion can greatly affect Te valences, reagent blanks and analytical precisions. A protocol of 2-step-digestion followed by an elimination of HF is proposed to minimize reagent blank and increase the signal/noise ratios. It is important to perform a preliminary test to confirm whether a pre-reduction step is necessary; this is especially true for samples with complex matrices such as those with high sulfide content. The analytical detection limits of this method in a pure solution and a solid sample were 100 ng/L and 0.10 +/- 0.02 MUg/g, respectively. PMID- 26755136 TI - External calibration strategy for trace element quantification in botanical samples by LA-ICP-MS using filter paper. AB - The use of reference solutions dispersed on filter paper discs is proposed for the first time as an external calibration strategy for matrix matching and determination of As, Cd, Co, Cr, Cu, Mn, Ni, Pb, Sr, V and Zn in plants by laser ablation-inductively coupled plasma mass spectrometry (LA-ICP-MS). The procedure is based on the use of filter paper discs as support for aqueous reference solutions, which are further evaporated, resulting in solid standards with concentrations up to 250 MUg g(-1) of each element. The use of filter paper for calibration is proposed as matrix matched standards due to the similarities of this material with botanical samples, regarding to carbon concentration and its distribution through both matrices. These characteristics allowed the use of (13)C as internal standard (IS) during the analysis by LA-ICP-MS. In this way, parameters as analyte signal normalization with (13)C, carrier gas flow rate, laser energy, spot size, and calibration range were monitored. The calibration procedure using solution deposition on filter paper discs resulted in precision improvement when (13)C was used as IS. The method precision was calculated by the analysis of a certified reference material (CRM) of botanical matrix, considering the RSD obtained for 5 line scans and was lower than 20%. Accuracy of LA-ICP-MS determinations were evaluated by analysis of four CRM pellets of botanical composition, as well as by comparison with results obtained by ICP-MS using solution nebulization after microwave assisted digestion. Plant samples of unknown elemental composition were analyzed by the proposed LA method and good agreement were obtained with results of solution analysis. Limits of detection (LOD) established for LA-ICP-MS were obtained by the ablation of 10 lines on the filter paper disc containing 40 MUL of 5% HNO3 (v v(-1)) as calibration blank. Values ranged from 0.05 to 0.81 MUg g(-1). Overall, the use of filter paper as support for dried aqueous standards showed to be a useful strategy for calibration and plant analysis by LA-ICP-MS. PMID- 26755131 TI - Impairment of PARK14-dependent Ca(2+) signalling is a novel determinant of Parkinson's disease. AB - The etiology of idiopathic Parkinson's disease (idPD) remains enigmatic despite recent successes in identification of genes (PARKs) that underlie familial PD. To find new keys to this incurable neurodegenerative disorder we focused on the poorly understood PARK14 disease locus (Pla2g6 gene) and the store-operated Ca(2+) signalling pathway. Analysis of the cells from idPD patients reveals a significant deficiency in store-operated PLA2g6-dependent Ca(2+) signalling, which we can mimic in a novel B6.Cg-Pla2g6(DeltaEx2-VB) (PLA2g6 ex2(KO)) mouse model. Here we demonstrate that genetic or molecular impairment of PLA2g6 dependent Ca(2+) signalling is a trigger for autophagic dysfunction, progressive loss of dopaminergic (DA) neurons in substantia nigra pars compacta and age dependent L-DOPA-sensitive motor dysfunction. Discovery of this previously unknown sequence of pathological events, its association with idPD and our ability to mimic this pathology in a novel genetic mouse model opens new opportunities for finding a cure for this devastating neurodegenerative disease. PMID- 26755137 TI - Tunable nanogap devices for ultra-sensitive electrochemical impedance biosensing. AB - A wealth of research has been available discussing nanogap devices for detecting very small quantities of biomolecules by observing their electrical behavior generally performed in dry conditions. We report that a gold nanogapped electrode with tunable gap length for ultra-sensitive detection of streptavidin based on electrochemical impedance technique. The gold nanogap is fabricated using simple monolayer film deposition and in-situ growth of gold nanoparticles in a traditional interdigitated array (IDA) microelectrode. The electrochemical impedance biosensor with a 25-nm nanogap is found to be ultra-sensitive to the specific binding of streptavidin to biotin. The binding of the streptavidin hinder the electron transfer between two electrodes, resulting in a large increase in electron-transfer resistance (Ret) for operating the impedance. A linear relation between the relative Ret and the logarithmic value of streptavidin concentration is observed in the concentration range from 1 pM (picomolar) to 100 nM (nanomolar). The lowest detectable concentration actually measured reaches 1 pM. We believe that such an electrochemical impedance nanogap biosensor provides a useful approach towards biomolecular detection that could be extended to a number of other systems. PMID- 26755138 TI - Investigation of MTH1 activity via mismatch-based DNA chain elongation. AB - Accumulation and misincorporation of oxidative damaged 8-oxo-7,8-dihydroguanine triphosphates (8-oxo-dGTP) in genomic DNA may cause serious cellular function disorders. MutT Homolog 1 (MTH1), a protein enzyme that can help to prevent 8-oxo dGTP misincorporation, plays critical roles in oxidative stress neutralization, oncogene-associated tumor malignancy, and anticancer therapies. So, in this work, a simple and function-oriented method is developed for the assay of MTH1 activity. Specifically, a mismatch-based ("8-oxoG: A" mismatch) DNA chain elongation strategy (MB-DCE) is firstly proposed to reveal the misincorporation efficiency of 8-oxo-dGTP. Then, further coupled with the inherent activity of MTH1 to prevent 8-oxo-dGTP misincorporation, a relationship can be established to reveal the activity of MTH1 through MB-DCE. As the method is designed directly towards the cellular function of MTH1, activity of MTH1 in different breast cancer cell lines has been detected, implying the potential application of this assay method for biomedical research and clinical diagnose in the future. PMID- 26755139 TI - NiMoO4 nanofibres designed by electrospining technique for glucose electrocatalytic oxidation. AB - Electrochemical oxidation of glucose is the guarantee to realize nonenzymatic sensing of glucose, but greatly hindered by the slow kinetics of its oxidation process. Herein, various nanomaterials were designed as catalysts to accelerate glucose oxidation reaction. However, how to effectively build an excellent platform for promoting the glucose oxidation is still a great challenge. In our work, 1D CaMoO4 and NiMoO4 nanofibres with same morphologies and sub microstructures were fabricated by electrospinning technique in the first time, and explored to modify the detection electrodes of nonenzymatic glucose sensors. The electrochemical results indicated that the NiMoO4 based sensor exhibited a good catalytic activity toward glucose including the low response potential (0.5 V), high sensitivity(193.8 MUA mM(-1) cm(-2)) with a linear response region of 0.01-8 mM, low detection limit (4.6 MUM) and fast response time (2 s), all of which are superior to the corresponding values of CaMoO4 nanofibres and even higher than those of most reported NiO and Co3O4 catalysts, which is due to the NiMoO4 nanofibres are not only advantageous to electron transfer, but can mediated the electrocatalytic reaction of glucose. This work should provide a new pathway for the design of advanced glucose catalysts for nonenzymatic sensor. PMID- 26755140 TI - Conformationally blocked quinoxaline cavitand as solid-phase microextraction coating for the selective detection of BTEX in air. AB - A tetraquinoxaline cavitand functionalized with methylenoxy bridges at the upper rim is proposed as selective solid-phase microextraction (SPME) coating for the determination of BTEX at trace levels in air. The SPME fibers were characterized in terms of film thickness, morphology, thermal stability and extraction capabilities. An average coating thickness of 35 (+/-4) MUm, a thermal stability up to 350 degrees C and a good fiber-to-fiber and batch-to-batch repeatability with RSD lower than 15% were obtained. Excellent enrichment factors ranging from 360-700 * 10(3) were obtained for the investigated compounds. Finally, method validation proved the capabilities of the developed coating for the selective sampling of BTEX, achieving LOD values in the 0.4-1.2 ng m(-3) range. PMID- 26755141 TI - Development of a novel mixed hemimicelles dispersive micro solid phase extraction using 1-hexadecyl-3-methylimidazolium bromide coated magnetic graphene for the separation and preconcentration of fluoxetine in different matrices before its determination by fiber optic linear array spectrophotometry and mode-mismatched thermal lens spectroscopy. AB - This study aims at developing a novel, sensitive, fast, simple and convenient method for separation and preconcentration of trace amounts of fluoxetine before its spectrophotometric determination. The method is based on combination of magnetic mixed hemimicelles solid phase extraction and dispersive micro solid phase extraction using 1-hexadecyl-3-methylimidazolium bromide coated magnetic graphene as a sorbent. The magnetic graphene was synthesized by a simple coprecipitation method and characterized by X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM). The retained analyte was eluted using a 100 MUL mixture of methanol/acetic acid (9:1) and converted into fluoxetine-beta-cyclodextrin inclusion complex. The analyte was then quantified by fiber optic linear array spectrophotometry as well as mode-mismatched thermal lens spectroscopy (TLS). The factors affecting the separation, preconcentration and determination of fluoxetine were investigated and optimized. With a 50 mL sample and under optimized conditions using the spectrophotometry technique, the method exhibited a linear dynamic range of 0.4 60.0 MUg L(-1), a detection limit of 0.21 MUg L(-1), an enrichment factor of 167, and a relative standard deviation of 2.1% and 3.8% (n = 6) at 60 MUg L(-1) level of fluoxetine for intra- and inter-day analyses, respectively. However, with thermal lens spectrometry and a sample volume of 10 mL, the method exhibited a linear dynamic range of 0.05-300 MUg L(-1), a detection limit of 0.016 MUg L(-1) and a relative standard deviation of 3.8% and 5.6% (n = 6) at 60 MUg L(-1) level of fluoxetine for intra- and inter-day analyses, respectively. The method was successfully applied to determine fluoxetine in pharmaceutical formulation, human urine and environmental water samples. PMID- 26755142 TI - Direct coupling of a flow-flow electromembrane extraction probe to LC-MS. AB - A fully integrated and automated electromembrane extraction LC-MS (EME-LC-MS) system has been developed and characterized. Hyphenation of a flow-flow EME probe to LC-MS was accomplished by using an in-built 10-port switching valve of the LC MS system. The 10-port switching valve decoupled the high pressure of the UHPLC system from the low pressure required for operation of the EME-probe by automated switching between a sample extraction/analysis and a sample load position. In the sample load position the extracted analytes were loaded into a HPLC sample loop. By switching the valve to the sample extraction/analysis position the setup allowed simultaneous analysis of previously loaded analytes while extracting a new sample. Performance of the system was characterized with respect to precision and linearity (RSD < 2.5%, R(2): 0.998) and the setup was applied for studying the in-vitro metabolism of methadone by rat liver microsomes. As the metabolic reaction proceeded, methadone and its metabolites were extracted and analyzed in parallel by LC-MS using either isocratic or gradient elution. Compared to a conventional in-vitro metabolism analysis based on protein precipitation followed by LC-MS analysis the fully automated EME-LC-MS system offers a significant time saving and in addition demonstrates increased sensitivity as the analytes were automatically enriched during the extraction process. The experiment revealed 6 to 16 times higher S/N ratios of the EME-LC-MS method compared to protein precipitation followed by LC-MS and thus concomitantly lower LOD and LOQ. The setup integrates a complete analytical workflow of rapid extraction, enrichment, separation and detection of analytes in a fully automated manner. These attributes make the developed system a powerful alternative approach for a wide range of analytical applications. PMID- 26755143 TI - Ultraviolet irradiation-induced substitution of fluorine with hydroxyl radical for mass spectrometric analysis of perfluorooctane sulfonyl fluoride. AB - A rapid and solvent free substitution reaction of a fluorine atom in perfluorooctane sulfonyl fluoride (PFOSF) with a hydroxyl radical is reported. Under irradiation of ultraviolet laser on semiconductor nanoparticles or metal surfaces, hydroxyl radicals can be generated through hole oxidization. Among all fluorine atoms of PFOSF, highly active hydroxyl radicals specifically substitute the fluorine of sulfonyl fluoride functional group. Resultant perfluorooctane sulfonic acid is further ionized through capture of photo-generated electrons that switch the neutral molecules to negatively charged odd electron hypervalent ions. The unpaired electron subsequently initiates alpha O-H bond cleavage and produces perfluorooctane sulfonate negative ions. Hydroxyl radical substitution and molecular dissociation of PFOSF have been confirmed by masses with high accuracy and resolution. It has been applied to direct mass spectrometric imaging of PFOSF adsorbed on surfaces of plant leaves. PMID- 26755144 TI - Stable isotope labeling - Liquid chromatography/mass spectrometry for quantitative analysis of androgenic and progestagenic steroids. AB - Steroid hormones play important roles in mammal at very low concentrations and are associated with numerous endocrinology and oncology diseases. Therefore, quantitative analysis of steroid hormones can provide crucial information for uncovering underlying mechanisms of steroid hormones related diseases. In the current study, we developed a sensitive method for the detection of steroid hormones (progesterone, dehydroepiandrosterone, testosterone, pregnenolone, 17 hydroxyprogesterone, androstenedione and 17alpha-hydroxypregnenolone) in body fluids by stable isotope labeling coupled with liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) analysis. In this respect, a pair of isotopes labeling reagents, Girard reagent P (GP) and d5-Girard reagent P (d5-GP), were synthesized and utilized to label steroid hormones in follicular fluid samples and steroid hormone standards, respectively. The heavy labeled standards were used as internal standards for quantification to minimize quantitation deviation in MS analysis due to the matrix and ion suppression effects. The ionization efficiencies of steroid hormones were greatly improved by 4-504 folds through the introduction of a permanent charged moiety of quaternary ammonium from GP. Using the developed method, we successfully quantified steroid hormones in human follicular fluid. We found that the contents of testosterone and androstenedione exhibited significant increase while the content of pregnenolone had significant decrease in follicular fluid of polycystic ovarian syndrome (PCOS) patients compared with healthy controls, indicating that these steroid hormones with significant change may contribute to the pathogenesis of PCOS. Taken together, the developed stable isotope labeling coupled LC-ESI-MS/MS analysis demonstrated to be a promising method for the sensitive and accurate determination of steroid hormones, which may facilitate the in-depth investigation of steroid hormones related diseases. PMID- 26755145 TI - Development of a method for enhancing metabolomics coverage of human sweat by gas chromatography-mass spectrometry in high resolution mode. AB - Sweat has recently gained popularity as clinical sample in metabolomics analysis as it is a non-invasive biofluid the composition of which could be modified by certain pathologies, as is the case with cystic fibrosis that increases chloride levels in sweat. However, the whole composition of sweat is still unknown and there is a lack of analytical strategies for sweat analysis. The aim of the present study was to develop and validate a method for metabolomic analysis of human sweat by gas chromatography-time of flight/mass spectrometry (GC-TOF/MS) in high resolution mode. Thus, different sample preparation strategies were compared to check their effect on the profile of sweat metabolites. Sixty-six compounds were tentatively identified by the obtained MS information. Amino acids, dicarboxylic acids and other interesting metabolites such as myo-inositol and urocanic acid were identified. Among the tested protocols, methyoxiamination plus silylation after deproteinization was the most suited option to obtain a representative snapshot of sweat metabolome. The intra-day repeatability of the method ranged from 0.60 to 16.99% and the inter-day repeatability from 2.75 to 31.25%. As most of the identified metabolites are involved in key biochemical pathways, this study opens new possibilities to the use of sweat as a source of metabolite biomarkers of specific disorders. PMID- 26755147 TI - Quartz crystal microbalance genosensor for sequence specific detection of attomolar DNA targets. AB - A mass sensitive quartz crystal microbalance (QCM) based genosensor has been developed using breast cancer 1 (BRCA1) gene as a model gene. We modified the traditional sandwich assay by conjugating reporter probe DNA (DNA-r) with an assembly of gold nanoparticles leading to an increased mass on the surface, which enhanced the sensitivity to few orders of magnitude. The unique cleavage function of endonuclease is used for achieving the selectivity to complementary DNA over mismatched DNA. With this combination, the sensor exhibited excellent sensitivity with a detection limit of 10 aM BRCA1 gene and it showed good selectivity for even single base mismatch DNA targets. This ultrasensitive and cost-effective DNA detection protocol can be extended to the direct analysis of any non-amplified genomic DNA. PMID- 26755148 TI - Universal quantum dot-based sandwich-like immunoassay strategy for rapid and ultrasensitive detection of small molecules using portable and reusable optofluidic nano-biosensing platform. AB - A universal sandwich-like immunoassay strategy based on quantum-dots immunoprobe (QD-labeled anti-mouse IgG antibody) was developed for rapid and ultrasensitive detection of small molecules. A portable and reusable optofluidic nano-biosensing platform was applied to investigate the sandwich-like immunoassay mechanism and format of small molecules, as well as the binding kinetics between QD immunoprobe and anti-small molecule antibody. A two-step immunoassay method that involves pre incubation mixture of different concentration of small molecule and anti-small molecule antibody, and subsequent introduction of QD immunoprobe into the optofluidic cell was conducted for small molecule determination. Compared with the one-step immunoassay method, the two-step immunoassay method can obtain higher fluorescence signal and higher sensitivity index, thus improving the nano biosensing performance. Based on the proposed strategy, two mode targets, namely, microcystin-LR (MC-LR) and Bisphenol A (BPA) were tested with high sensitivity, rapidity, and ease of use. A higher concentration of small molecules in the sample led to less anti-small molecule antibody bound with antigen-carrier protein conjugate immobilized onto the sensor surface, and less QD immunoprobes bound with anti-small molecule antibody. This phenomenon lowered the fluorescence signal detected by nano-biosensing platform. Under optimal operating conditions, MC-LR and BPA exhibited a limit of detection of 0.003 and 0.04 MUg/L, respectively. The LODs were better than those of the indirect competitive immunoassay method for small molecules via Cy5.5-labeled anti-small molecule antibody. The proposed QD-based sandwich-like immunoassay strategy was evaluated in spiked water samples, and showed good recovery, precision and accuracy without complicated sample pretreatments. All these results demonstrate that the new detection strategy could be readily applied to the other trace small molecules in real water samples. PMID- 26755146 TI - Monitoring of malolactic fermentation in wine using an electrochemical bienzymatic biosensor for L-lactate with long term stability. AB - L-lactic acid is monitored during malolactic fermentation process of wine and its evolution is strongly related with the quality of the final product. The analysis of L-lactic acid is carried out off-line in a laboratory. Therefore, there is a clear demand for analytical tools that enabled real-time monitoring of this process in field and biosensors have positioned as a feasible alternative in this regard. The development of an amperometric biosensor for L-lactate determination showing long-term stability is reported in this work. The biosensor architecture includes a thin-film gold electrochemical transducer selectively modified with an enzymatic membrane, based on a three-dimensional matrix of polypyrrole (PPy) entrapping lactate oxidase (LOX) and horseradish peroxidase (HRP) enzymes. The experimental conditions of the biosensor fabrication regarding the pyrrole polymerization and the enzymes entrapment are optimized. The biosensor response to L-lactate is linear in a concentration range of 1 * 10(-6)-1 * 10(-4) M, with a detection limit of 5.2 * 10(-7) M and a sensitivity of - (13500 +/- 600) MUA M( 1) cm(-2). The biosensor shows an excellent working stability, retaining more than 90% of its original sensitivity after 40 days. This is the determining factor that allowed for the application of this biosensor to monitor the malolactic fermentation of three red wines, showing a good agreement with the standard colorimetric method. PMID- 26755149 TI - Aptamers-based sandwich assay for silver-enhanced fluorescence multiplex detection. AB - In this work, aptamers-modified silver nanoparticles (AgNPs) were prepared as capture substrate, and fluorescent dyes-modified aptamers were synthesized as detection probes. The sandwich assay was based on dual aptamers, which was aimed to accomplish the highly sensitive detection of single protein and multiplex detection of proteins on one-spot. We found that aptamers-modified AgNPs based microarray was much superior to the aptamer based microarray in fluorescence detection of proteins. The result shows that the detection limit of the sandwich assay using AgNPs probes for thrombin or platelet-derived growth factor-BB (PDGF BB) is 80 or 8 times lower than that of aptamers used directly. For multiplex detection of proteins, the detection limit was 625 pM for PDGF-BB and 21 pM for thrombin respectively. The sandwich assay based on dual aptamers and AgNPs was sensitive and specific. PMID- 26755150 TI - Surface plasmon resonance immunosensor for ErbB2 breast cancer biomarker determination in human serum and raw cancer cell lysates. AB - A highly sensitive surface plasmon resonance (SPR) immunosensor for the important ErbB2 breast cancer biomarker has been developed. Optimization of the assay has been carried out, including signal enhancement employing gold nanoparticles (GNPs). The effect of the signal amplification of the GNPs has been also studied. The assay has been tested with clinically relevant matrices. Results in 50% human serum yielded a LOD of 180 pg mL(-1) which is a concentration 83 times lower than the clinical cut-off. Raw lysates from model breast cancer cell lines (SK-BR-3, MCF-7 and MDA-MB-436) have been also assayed and higher quantities of the ErbB2 protein were clearly observed in the ErbB2 over-expressing case (SK-BR-3). The results confirmed that the simple and highly sensitive SPR immunosensor represents a feasible tool for ErbB2 detection. PMID- 26755151 TI - A rare site of intrauterine contraceptive device migration. PMID- 26755152 TI - Active sesquiterpene lactones against Leishmania amazonensis and Leishmania braziliensis. AB - Seventeen sesquiterpene lactones (SLs) isolated from five species of the tribe Vernonieae were evaluated for their in vitro activity against promastigotes of Leishmania amazonensis and Leishmania braziliensis. Additionally, a quantitative structure activity relationship has been made, since all these natural compounds were found to have potent to mild antileishmanial properties. The most active compounds against L. braziliensis were 16 and 17 (IC50 values 1.45 and 1.34 MUM, respectively), followed by compound 15 with IC50 value of 1.60 MUM against L. amazonensis. The three glaucolide-type SLs (4-6) were the least active against both parasites. The computational study allowed us to establish that lipophilicity and polarisability play an important role in the antiparasitic activity. This is the first report of the known germacradiendiolides 16 and 17 from Elephantopus mollis. The activity data of the compounds 1-17 assayed against Leishmania parasites are reported here for the first time. PMID- 26755153 TI - Decidual Control of Trophoblast Invasion. AB - At the time of implantation, the trophoblast cells of the embryo adhere and then invade into the maternal endometrium and eventually establish placentation. The endometrium at the same time undergoes decidualization, which is essential for successful pregnancy. While the NK cells of the decidua have been implicated to play a key role in trophoblast invasion, few evidence are now available to demonstrate a pro-invasive property of decidual stromal cells. Secretions from decidualized endometrial stromal cells promote invasion of primary trophoblasts and model cell lines by activating proteases and altering expression of adhesion related molecules. The decidual secretions contain high amounts of pro-invasive factors that include IL-1beta, IL-5, IL-6, IL-7, IL-8, IL-9, IL-13, IL-15, Eotaxin CCL11, IP-10 and RANTES, and anti-invasive factors IL-10, IL-12 and VEGF. It appears that these decidual factors promote invasion by regulating the protease pathways and integrin expression utilizing the STAT pathways in the trophoblast cells. At the same time the decidua also seem to secrete some anti invasive factors that are antagonist to the matrix metalloproteinases and/or are activators of tissue inhibitors of metalloproteinases. This might be essential to neutralize the effects of the invasion-promoting factors and restrain overinvasion. It is tempting to propose that during the course of pregnancy, the decidua must balance the production of these pro and anti-invasive molecules and such harmonizing production would allow a timely and regulated invasion. PMID- 26755155 TI - Depletion of Phagocytic Cells during Nonlethal Plasmodium yoelii Infection Causes Severe Malaria Characterized by Acute Renal Failure in Mice. AB - In the current study, we examined the effects of depletion of phagocytes on the progression of Plasmodium yoelii 17XNL infection in mice. Strikingly, the depletion of phagocytic cells, including macrophages, with clodronate in the acute phase of infection significantly reduced peripheral parasitemia but increased mortality. Moribund mice displayed severe pathological damage, including coagulative necrosis in liver and thrombi in the glomeruli, fibrin deposition, and tubular necrosis in kidney. The severity of infection was coincident with the increased sequestration of parasitized erythrocytes, the systematic upregulation of inflammation and coagulation, and the disruption of endothelial integrity in the liver and kidney. Aspirin was administered to the mice to minimize the risk of excessive activation of the coagulation response and fibrin deposition in the renal tissue. Interestingly, treatment with aspirin reduced the parasite burden and pathological lesions in the renal tissue and improved survival of phagocyte-depleted mice. Our data imply that the depletion of phagocytic cells, including macrophages, in the acute phase of infection increases the severity of malarial infection, typified by multiorgan failure and high mortality. PMID- 26755156 TI - The Variable Region of Pneumococcal Pathogenicity Island 1 Is Responsible for Unusually High Virulence of a Serotype 1 Isolate. AB - Streptococcus pneumoniae is the leading infectious cause of death in children in the world. However, the mechanisms that drive the progression from asymptomatic colonization to disease are poorly understood. Two virulence-associated genomic accessory regions (ARs) were deleted in a highly virulent serotype 1 clinical isolate (strain 4496) and examined for their contribution to pathogenesis. Deletion of a prophage encoding a platelet-binding protein (PblB) resulted in reduced adherence, biofilm formation, reduced initial infection within the lungs, and a reduction in the number of circulating platelets in infected mice. However, the region's overall contribution to the survival of mice was not significant. In contrast, deletion of the variable region of pneumococcal pathogenicity island 1 (vPPI1) was also responsible for a reduction in adherence and biofilm formation but also reduced survival and invasion of the pleural cavity, blood, and lungs. While the 4496DeltaPPI1 strain induced higher expression of the genes encoding interleukin-10 (IL-10) and CD11b in the lungs of challenged mice than the wild type strain, very few other genes exhibited altered expression. Moreover, while the level of IL-10 protein was increased in the lungs of 4496DeltaPPI1 mutant infected mice compared to strain 4496-infected mice, the levels of gamma interferon (IFN-gamma), CXCL10, CCL2, and CCL4 were not different in the two groups. However, the 4496DeltaPPI1 mutant was found to be more susceptible than the wild type to phagocytic killing by a macrophage-like cell line. Therefore, our data suggest that vPPI1 may be a major contributing factor to the heightened virulence of certain serotype 1 strains, possibly by influencing resistance to phagocytic killing. PMID- 26755154 TI - Nonselective Persistence of a Rickettsia conorii Extrachromosomal Plasmid during Mammalian Infection. AB - Scientific analysis of the genus Rickettsia is undergoing a rapid period of change with the emergence of viable genetic tools. The development of these tools for the mutagenesis of pathogenic bacteria will permit forward genetic analysis of Rickettsia pathogenesis. Despite these advances, uncertainty still remains regarding the use of plasmids to study these bacteria in in vivo mammalian models of infection, namely, the potential for virulence changes associated with the presence of extrachromosomal DNA and nonselective persistence of plasmids in mammalian models of infection. Here, we describe the transformation of Rickettsia conorii Malish 7 with the plasmid pRam18dRGA[AmTrCh]. Transformed R. conorii stably maintains this plasmid in infected cell cultures, expresses the encoded fluorescent proteins, and exhibits growth kinetics in cell culture similar to those of nontransformed R. conorii. Using a well-established murine model of fatal Mediterranean spotted fever, we demonstrate that R. conorii(pRam18dRGA[AmTrCh]) elicits the same fatal outcomes in animals as its untransformed counterpart and, importantly, maintains the plasmid throughout infection in the absence of selective antibiotic pressure. Interestingly, plasmid transformed R. conorii was readily observed both in endothelial cells and within circulating leukocytes. Together, our data demonstrate that the presence of an extrachromosomal DNA element in a pathogenic rickettsial species does not affect either in vitro proliferation or in vivo infectivity in models of disease and that plasmids such as pRam18dRGA[AmTrCh] are valuable tools for the further genetic manipulation of pathogenic rickettsiae. PMID- 26755157 TI - Analysis of TcdB Proteins within the Hypervirulent Clade 2 Reveals an Impact of RhoA Glucosylation on Clostridium difficile Proinflammatory Activities. AB - Clostridium difficile strains within the hypervirulent clade 2 are responsible for nosocomial outbreaks worldwide. The increased pathogenic potential of these strains has been attributed to several factors but is still poorly understood. During a C. difficile outbreak, a strain from this clade was found to induce a variant cytopathic effect (CPE), different from the canonical arborizing CPE. This strain (NAP1V) belongs to the NAP1 genotype but to a ribotype different from the epidemic NAP1/RT027 strain. NAP1V and NAP1 share some properties, including the overproduction of toxins, the binary toxin, and mutations in tcdC. NAP1V is not resistant to fluoroquinolones, however. A comparative analysis of TcdB proteins from NAP1/RT027 and NAP1V strains indicated that both target Rac, Cdc42, Rap, and R-Ras but only the former glucosylates RhoA. Thus, TcdB from hypervirulent clade 2 strains possesses an extended substrate profile, and RhoA is crucial for the type of CPE induced. Sequence comparison and structural modeling revealed that TcdBNAP1 and TcdBNAP1V share the receptor-binding and autoprocessing activities but vary in the glucosyltransferase domain, consistent with the different substrate profile. Whereas the two toxins displayed identical cytotoxic potencies, TcdBNAP1 induced a stronger proinflammatory response than TcdBNAP1V as determined in ex vivo experiments and animal models. Since immune activation at the level of intestinal mucosa is a hallmark of C. difficile induced infections, we propose that the panel of substrates targeted by TcdB is a determining factor in the pathogenesis of this pathogen and in the differential virulence potential seen among C. difficile strains. PMID- 26755158 TI - Regulation of Expression of Uropathogenic Escherichia coli Nonfimbrial Adhesin TosA by PapB Homolog TosR in Conjunction with H-NS and Lrp. AB - Urinary tract infections (UTIs) are a major burden to human health. The overwhelming majority of UTIs are caused by uropathogenic Escherichia coli (UPEC) strains. Unlike some pathogens, UPEC strains do not have a fixed core set of virulence and fitness factors but do have a variety of adhesins and regulatory pathways. One such UPEC adhesin is the nonfimbrial adhesin TosA, which mediates adherence to the epithelium of the upper urinary tract. The tos operon is AT rich, resides on pathogenicity island aspV, and is not expressed under laboratory conditions. Because of this, we hypothesized that tosA expression is silenced by H-NS. Lrp, based on its prominent function in the regulation of other adhesins, is also hypothesized to contribute to tos operon regulation. Using a variety of in vitro techniques, we mapped both the tos operon promoter and TosR binding sites. We have now identified TosR as a dual regulator of the tos operon, which could control the tos operon in association with H-NS and Lrp. H-NS is a negative regulator of the tos operon, and Lrp positively regulates the tos operon. Exogenous leucine also inhibits Lrp-mediated tos operon positive regulation. In addition, TosR binds to the pap operon, which encodes another important UPEC adhesin, P fimbria. Induction of TosR synthesis reduces production of P fimbria. These studies advance our knowledge of regulation of adhesin expression associated with uropathogen colonization of a host. PMID- 26755159 TI - Analysis of Noncanonical Calcium-Dependent Protein Kinases in Toxoplasma gondii by Targeted Gene Deletion Using CRISPR/Cas9. AB - Calcium-dependent protein kinases (CDPKs) are expanded in apicomplexan parasites, especially in Toxoplasma gondii where 14 separate genes encoding these enzymes are found. Although previous studies have shown that several CDPKs play a role in controlling invasion, egress, and cell division in T. gondii, the roles of most of these genes are unexplored. Here we developed a more efficient method for gene disruption using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9) that was modified to completely delete large, multiexonic genes from the genome and to allow serial replacement by recycling of the selectable marker using Cre-loxP. Using this system, we generated a total of 24 mutants in type 1 and 2 genetic backgrounds to ascertain the functions of noncanonical CDPKs. Remarkably, although we were able to confirm the essentiality of CDPK1 and CDPK7, the majority of CDPKs had no discernible phenotype for growth in vitro or infection in the mouse model. The exception to this was CDPK6, loss of which leads to reduced plaquing, fitness defect in a competition assay, and reduced tissue cyst formation in chronically infected mice. Our findings highlight the utility of CRISPR/Cas9 for rapid serial gene deletion and also suggest that additional models are needed to reveal the functions of many genes in T. gondii. PMID- 26755161 TI - Characterization of RNA Helicase CshA and Its Role in Protecting mRNAs and Small RNAs of Staphylococcus aureus Strain Newman. AB - The toxin MazFsa in Staphylococcus aureus is a sequence-specific endoribonuclease that cleaves the majority of the mRNAs in vivo but spares many essential mRNAs (e.g., secY mRNA) and, surprisingly, an mRNA encoding a regulatory protein (i.e., sarA mRNA). We hypothesize that some mRNAs may be protected by RNA-binding protein(s) from degradation by MazFsa. Using heparin-Sepharose-enriched fractions that hybridized to sarA mRNA on Northwestern blots, we identified among multiple proteins the DEAD box RNA helicase CshA (NWMN_1985 or SA1885) by mass spectroscopy. Purified CshA exhibits typical RNA helicase activities, as exemplified by RNA-dependent ATPase activity and unwinding of the DNA-RNA duplex. A severe growth defect was observed in the cshA mutant compared with the parent when grown at 25 degrees C but not at 37 degrees C. Activation of MazFsa in the cshA mutant resulted in lower CFU per milliliter accompanied by a precipitous drop in viability (~40%) compared to those of the parent and complemented strains. NanoString analysis reveals diminished expression of a small number of mRNAs and 22 small RNAs (sRNAs) in the cshA mutant versus the parent upon MazFsa induction, thus implying protection of these RNAs by CshA. In the case of the sRNA teg049 within the sarA locus, we showed that the protective effect was likely due to transcript stability as revealed by reduced half-life in the cshA mutant versus the parent. Accordingly, CshA likely stabilizes selective mRNAs and sRNAs in vivo and as a result enhances S. aureus survival upon MazFsa induction during stress. PMID- 26755160 TI - Intestinal Epithelial Toll-Like Receptor 4 Signaling Affects Epithelial Function and Colonic Microbiota and Promotes a Risk for Transmissible Colitis. AB - Evidence obtained from gene knockout studies supports the role of Toll-like receptor 4 (TLR4) in intestinal inflammation and microbiota recognition. Increased epithelial TLR4 expression is observed in patients with inflammatory bowel disease. However, little is known of the effect of increased TLR4 signaling on intestinal homeostasis. Here, we examined the effect of increased TLR4 signaling on epithelial function and microbiota by using transgenic villin-TLR4 mice that overexpress TLR4 in the intestinal epithelium. Our results revealed that villin-TLR4 mice are characterized by increases in the density of mucosa associated bacteria and bacterial translocation. Furthermore, increased epithelial TLR4 signaling was associated with an impaired epithelial barrier, altered expression of antimicrobial peptide genes, and altered epithelial cell differentiation. The composition of the colonic luminal and mucosa-associated microbiota differed between villin-TLR4 and wild-type (WT) littermates. Interestingly, WT mice cohoused with villin-TLR4 mice displayed greater susceptibility to acute colitis than singly housed WT mice did. The results of this study suggest that epithelial TLR4 expression shapes the microbiota and affects the functional properties of the epithelium. The changes in the microbiota induced by increased epithelial TLR4 signaling are transmissible and exacerbate dextran sodium sulfate-induced colitis. Together, our findings imply that host innate immune signaling can modulate intestinal bacteria and ultimately the host's susceptibility to colitis. PMID- 26755164 TI - Catalyst-Controlled Switch in Chemo- and Diastereoselectivities: Annulations of Morita-Baylis-Hillman Carbonates from Isatins. AB - Regulating both the chemo- and diastereoselectivity, divergently, of a reaction is highly attractive but extremely challenging. Presented herein is a catalyst controlled switch in the chemo- and diastereodivergent annulation reactions of Morita-Baylis-Hillman carbonates, derived from isatins and 2-alkylidene-1H-indene 1,3(2H)-diones, in exclusive alpha-regioselectivity. alpha-Isocupreine efficiently catalyzed [2+1] reactions to access cyclopropane derivatives, and the diastereodivergent [3+2] annulations were accomplished by employing either a chiral phosphine or a DMAP-type molecule. All reactions exhibited excellent chemoselectivities, and good to remarkable stereoselectivities were furnished, thus leading to a collection of compounds with skeletal and stereogenic diversity. Moreover, DFT computational calculations elucidated the catalyst-based switch in mechanism. PMID- 26755163 TI - An approach for improving repeatability and reliability of non-negative matrix factorization for muscle synergy analysis. AB - The aim of this study was to evaluate non-negative matrix factorization (NMF) and concatenated NMF (CNMF) to analyze and reliably extract muscle synergies. NMF and CNMF were used to extract knee joint muscle synergies from surface EMGs collected during a weight bearing, force matching task. Repeatability and between subject similarity were evaluated for each method using intra-class correlation coefficients (ICCs). High repeatability was found for CNMF (>0.99; 0.99-1.0) compared to NMF (>0.26; range 0.26-0.98). Reasonable consistency across subjects was improved using the CNMF over the NMF approach. CNMF was found to be a more reliable approach than NMF and suitable for between subject comparison of muscle synergies. PMID- 26755162 TI - MyD88 Mediates Instructive Signaling in Dendritic Cells and Protective Inflammatory Response during Rickettsial Infection. AB - Spotted fever group rickettsiae cause potentially life-threatening infections throughout the world. Several members of the Toll-like receptor (TLR) family are involved in host response to rickettsiae, and yet the mechanisms by which these TLRs mediate host immunity remain incompletely understood. In the present study, we found that host susceptibility of MyD88(-/-)mice to infection with Rickettsia conorii or Rickettsia australis was significantly greater than in wild-type (WT) mice, in association with severely impaired bacterial clearance in vivo R. australis-infected MyD88(-/-)mice showed significantly lower expression levels of gamma interferon (IFN-gamma), interleukin-6 (IL-6), and IL-1beta, accompanied by significantly fewer inflammatory infiltrates of macrophages and neutrophils in infected tissues, than WT mice. The serum levels of IFN-gamma, IL-12, IL-6, and granulocyte colony-stimulating factor were significantly reduced, while monocyte chemoattractant protein 1, macrophage inflammatory protein 1alpha, and RANTES were significantly increased in infected MyD88(-/-)mice compared to WT mice. Strikingly, R. australis infection was incapable of promoting increased expression of MHC-II(high)and production of IL-12p40 in MyD88(-/-)bone marrow derived dendritic cells (BMDCs) compared to WT BMDCs, although costimulatory molecules were upregulated in both types of BMDCs. Furthermore, the secretion levels of IL-1beta by Rickettsia-infected BMDCs and in the sera of infected mice were significantly reduced in MyD88(-/-)mice compared to WT controls, suggesting that in vitro and in vivo production of IL-1beta is MyD88 dependent. Taken together, our results suggest that MyD88 signaling mediates instructive signals in DCs and secretion of IL-1beta and type 1 immune cytokines, which may account for the protective inflammatory response during rickettsial infection. PMID- 26755165 TI - Quality of life outcomes from a dose-per-fraction escalation trial of hypofractionation in prostate cancer. AB - OBJECTIVE: This multi-institutional phase I/II trial explored patient-assessed tolerance of increasingly hypofractionated (HPFX) radiation for low/intermediate risk prostate cancer. METHODS: 347 patients enrolled from 2002 to 2010. Three increasing dose-per-fraction schedules of 64.7 Gy/22 fx, 58.08 Gy/16 fx and 51.6 Gy/12 fx were each designed to yield equivalent predicted late toxicity. Three quality of life (QoL) surveys were administered prior to treatment and annually upto 3 years. RESULTS: Bowel QoL data at 3years revealed no significant difference among regimens (p=0.469). Bowel QoL for all regimens declined transiently, largely recovering by three years, with only the 22 fraction decrement reaching significance. Bladder outcomes at 3 years were comparable (p=0.343) although, for all patients combined, a significant decline was observed from the baseline (p=0.008). Spitzer quality of life data revealed similarly excellent, 3-year means (p=0.188). International erectile function data also revealed no significant differences at 3 years although all measures except intercourse satisfaction worsened post-treatment. CONCLUSIONS: Three-year QoL changes for bowel, bladder and SQLI were modest and similar for 3 HPFX regimens spanning 2.94-4.3 Gy per fraction. These favorable patient-scored outcomes demonstrate the safety and tolerability of such regimens and may be leveraged to support further implementation of mild to moderately hypofractionated radiotherapy in the setting of low and intermediate-risk prostate cancer. PMID- 26755168 TI - Erratum to: Studying Human Brain Inflammation in Leptomeningeal and Choroid Plexus Explant Cultures. PMID- 26755167 TI - Cure prevents more than transmission of hepatitis C virus. PMID- 26755166 TI - APN1 is a functional receptor of Cry1Ac but not Cry2Ab in Helicoverpa zea. AB - Lepidopteran midgut aminopeptidases N (APNs) are phylogenetically divided into eight clusters, designated as APN1-8. Although APN1 has been implicated as one of the receptors for Cry1Ac in several species, its potential role in the mode of action of Cry2Ab has not been functionally determined so far. To test whether APN1 also acts as one of the receptors for Cry1Ac in Helicoverpa zea and even for Cry2Ab in this species, we conducted a gain of function analysis by heterologously expressing H. zea APN1 (HzAPN1) in the midgut and fat body cell lines of H. zea and the ovarian cell line of Spodoptera frugiperda (Sf9) and a loss of function analysis by RNAi (RNA interference) silencing of the endogenous APN1 in the three cell lines using the HzAPN1 double strand RNA (dsRNA). Heterologous expression of HzAPN1 significantly increased the susceptibility of the three cell lines to Cry1Ac, but had no effects on their susceptibility to Cry2Ab. Knocking down of the endogenous APN1 made the three cell lines resistant to Cry1Ac, but didn't change cell lines susceptibility to Cry2Ab. The findings from this study demonstrate that HzAPN1 is a functional receptor of Cry1Ac, but not Cry2Ab. PMID- 26755170 TI - Erratum to: New insight into molecular interaction of heavy metal pollutant cadmium(II) with human serum albumin. PMID- 26755169 TI - Wealth-related versus income-related inequalities in dental care use under universal public coverage: a panel data analysis of the Japanese Study of Aging and Retirement. AB - BACKGROUND: There is a substantial body of evidence of income-related inequalities in dental care use, attributed to the fact that dental care is often not covered by public health insurance. Wealth-related inequalities have also been shown to be greater than income-related inequalities. Japan is one of the exceptions, as the the universal pubic health insurance system has covered dental care. The aim of this study was therefore to compare wealth- and income-related inequalities in dental care use among middle-aged and older adults in Japan to infer the mechanisms of wealth-related inequalities in dental care use. METHODS: Data were derived from the Japanese Study of Aging and Retirement, a survey of community-dwelling middle-aged and older adults living in five municipalities in eastern Japan. Of the participants in the second wave conducted in 2009, we analyzed 2581 residents. Dental care use was measured according to whether the participant had been seen by a dentist or a dental hygienist in the past year. The main explanatory variables were income and wealth (financial assets, real assets and total wealth). The need for dental care was measured using age, the use of dentures and chewing ability. The concentration indices for the distribution of actual and need-standardized dental care use were calculated. RESULTS: Among the respondents, 47.9% had received dental care in the past year. The concentration index of actual dental care use (CI) showed a pro-rich inequality for both income and wealth. The CIs for all three wealth measures were larger than that for income. A broadly comparable pattern was seen after need standardization (income: 0.020, financial assets: 0.035, real assets: 0.047, total wealth: 0.050). CONCLUSIONS: The results showed that wealth-related inequalities in dental care use were greater than income-related inequalities in Japan, where most dental care is covered by the public health insurance system. This suggests that wealth-related inequalities in dental care use cannot be explained by economic budget constraints alone. Further studies should investigate the mechanisms of wealth-related inequalities in dental care use. PMID- 26755171 TI - Microbial fuel cell assisted nitrate nitrogen removal using cow manure and soil. AB - Microbial fuel cells (MFCs) are emerging wastewater treatment systems with a proven potential for denitrification. In this study, we have developed a high rate denitrifying MFC. The anode consisted of cow manure and fruit waste and the cathode consisted of cow manure and soil. The initial chemical oxygen demand (COD)/nitrate nitrogen (NO3 (-)-N) was varied from 2 to 40 at the cathode while keeping the anode ratio fixed at 100. NO3 (-)-N removal rate of 7.1 +/- 0.9 kg NO3 (-)-N/m(3) net cathodic compartment (NCC)/day was achieved at cathode COD/NO3 (-)-N ratio 7.31 with the current density of 190 +/- 9.1 mA/m(2) and power density of 31.92 +/- 4 mW/m(2) of electrode surface area. We achieved an open circuit voltage (OCV) of 410 +/- 20 mV at initial cathodic NO3 (-)-N of 0.345 g/l. The cathode COD/NO3 (-)-N ratio had a significant influence on MFC's OCV and nitrate removal rate. Lower OCV (<150 mV) and NO3 (-)-N removal rates were observed at COD/NO3 (-)-N ratio >12 and <7. Experiments done at different cathode pH values indicated that the optimum pH for denitrification was 7. Under optimized biochemical conditions, nitrate removal rate of 6.5 kg NO3 (-)-N/m(3) net cathodic compartment (NCC)/day and power density of 210 mW/m(2) were achieved in a low resistance MFC. The present study thus demonstrates the utility of MFCs for the treatment of high nitrate wastes. PMID- 26755173 TI - Vermicomposting of sludge from animal wastewater treatment plant mixed with cow dung or swine manure using Eisenia fetida. AB - Vermicomposting of animal wastewater treatment plant sludge (S) mixed with cow dung (CD) or swine manure (SM) employing Eisenia fetida was tested. The numbers, weights, clitellum development, and cocoon production were monitored for 60 days at a detecting interval of 15 days. The results indicated that 100 % of the sludge can be the suitable food for growth and fecundity of E. fetida, while addition of CD or SM in sludge significantly (P < 0.05) increased the worm biomass and reproduction. The sludge amended with 40 % SM can be a great medium for the growth of E. fetida, and the sludge amended with 40 % CD can be a suitable medium for the fecundity of E. fetida. The addition of CD in sludge provided a better environment for the fecundity of earthworm than SM did. Moreover, vermicomposts obtained in the study had lower pH value, lower total organic carbon (TOC), lower NH4 (+)-N, lower C/N ratio, higher total available phosphorous (TAP) contents, optimal stability, and maturity. NH4 (+)-N, pH and TAP of the initial mixtures explained high earthworm growth. The results provided the theory basic both for management of animal wastes and the production of earthworm proteins using E. fetida. PMID- 26755172 TI - Effectiveness of lime and peat applications on cadmium availability in a paddy soil under various moisture regimes. AB - In paddy soils, amendments and moisture play important role in the immobilization of cadmium (Cd). The effects of applying lime, peat, and a combination of both on soil Eh, pH, and Cd availability in contaminated soils were investigated under wetted (80 +/- 5 % of water holding capacity) and flooded (completely submerged) conditions. In wetted soils, there was little change in Eh, compared to flooded soils where Eh reduced rapidly. Amendments of lime only or in a mixture with peat increased soil pH to different degrees, depending on the lime application rate. However, peat addition only slightly affected soil pH. The decreased Cd availability in flooded soils was related to submergence duration and was significantly lower than that in wetted soils after 14 days. Liming wetted and flooded soils decreased exchangeable Cd and increased carbonates or Fe-Mn oxides bound fractions, while peat addition transformed Cd from carbonates to organic matter bound fractions. The combined application of peat and lime generally showed better inhibitory effects on the availability of Cd than separately application of lime or peat. Higher application rates of lime, peat, or their mixture were more effective at reducing Cd contamination in flooded soil. This indicates that application of peat and lime mixture under flooded conditions was most effective for in situ remediation of Cd-contaminated soils. Further studies are required to assess the long-term effectiveness of the peat and lime mixture on Cd availability in paddy soils. PMID- 26755174 TI - Bioaugmentation in a pilot-scale constructed wetland to treat domestic wastewater in summer and autumn. AB - In order to determine whether bioaugmentation is an effective technique in wetlands before the plants were harvested, the nitrogen (N) removal from a constructed wetland (CW) planted with Phragmites was evaluated after inoculating with Paenibacillus sp. XP1 in Northern China. The experiment was loaded with secondary effluent of rural domestic wastewater (RDW) using the batch-loaded method for over a 17-day period in summer and autumn. Chemical oxygen demand (CODcr), ammonia nitrogen (NH3-N), and total nitrogen (TN) decreased significantly in the CW with Phragmites inoculated with Paenibacillus sp. XP1. Four days after treatments were set up, the removal efficiencies were found to be 76.2 % for CODcr, 83 % for NH3-N, and 63.8 % for TN in summer and 69.5 % for CODcr, 76.9 % for NH3-N, and 55.6 % for TN in autumn, which were higher than the control group without inoculation during the entire 17-day experiment. The inoculated bacteria did not have a noticeable effect on total phosphorus (TP) removal in autumn. However, bioaugmentation still keep a low P concentration in the whole CW. First-order kinetic model represented well the CODcr, TN, and TP decay in CWs with bioaugmentation, resulting in very good coefficients of determination, which ranged from 0.97 to 0.99. It indicated that bioaugmentation would be an effective treatment for pollutant removal from RDW in the CWs. PMID- 26755175 TI - Effects of the novel cis-nitromethylene neonicotinoid insecticide Paichongding on enzyme activities and microorganisms in yellow loam and Huangshi soils. AB - Soil enzyme activity and microbial population play important roles in maintaining soil fertility and ensure crop yield. Paichongding (IPP) is a novel cis nitromethylene neonicotinoid insecticide, which was recently developed in China. In this study, in order to better understand IPP ecological toxicity, the impact of IPP on soil enzyme activity and microbial population in soils was investigated. The results showed that, urease activity was inhibited by IPP before 75 days incubation, after that this inhibiting effect gradually weakened. IPP had different stimulating effects on the activities of dehydrogenase, protease, and catalase. They were consistently stimulated from the initial time in soils. The results of microbial population indicated that the number of bacteria increased after IPP application compared with the control, fungal number increased before 45 days incubation and then decreased. While actinomycete number decreased during degradation period. DT50 (half-life value), k (degradation rate constant) of IPP in S1 (yellow loam soil), and S2 (Huangshi soil) were found 90 days and 173 days, 0.0077 day(-1), and 0.0040 day(-1), respectively. PMID- 26755176 TI - Toxicity of the mixture of selected antineoplastic drugs against aquatic primary producers. AB - The residues of antineoplastic drugs are considered as new and emerging pollutants in aquatic environments. Recent experiments showed relatively high toxicity of 5-fluorouracil (5-FU), imatinib mesylate (IM), etoposide (ET) and cisplatin (CP) that are currently among most widely used antineoplastic drugs, against phytoplankton species. In this study, we investigated the toxic potential of the mixture of 5-FU + IM + ET against green alga Pseudokirchneriella subcapitata and cyanobacterium Synechococcus leopoliensis, and the stability and sorption of these drugs to algal cells. Toxic potential of the mixture was predicted by the concepts of 'concentration addition' and 'independent action' and compared to the experimentally determined toxicity. In both test species, the measured toxicity of the mixture was at effects concentrations EC10-EC50 higher than the predicted, whereas at higher effect concentration (EC90), it was lower. In general, P. subcapitata was more sensitive than S. leopoliensis. The stability studies of the tested drugs during the experiment showed that 5-FU, IM and CP are relatively stable, whereas in the cultures exposed to ET, two transformation products with the same mass as ET but different retention time were detected. The measurements of the cell-linked concentrations of the tested compounds after 72 h exposure indicated that except for CP (1.9 % of the initial concentration), these drugs are not adsorbed or absorbed by algal cells. The results of this study showed that in alga and cyanobacteria exposure to the mixture of 5-FU + ET + IM, in particular at low effect concentration range, caused additive or synergistic effect on growth inhibition, and they suggest that single compound toxicity data are not sufficient for the proper toxicity prediction for aquatic primary producers. PMID- 26755177 TI - Health risk assessment of trace elements via dietary intake of 'non-piscine protein source' foodstuffs (meat, milk and egg) in Bangladesh. AB - Concentrations of six trace elements [chromium (Cr), nickel (Ni), copper (Cu), cadmium (Cd), lead (Pb) and arsenic (As)] were assessed in 'non-piscine protein source' foodstuffs (meat, milk and eggs) to evaluate contamination level and human health risks in Bangladesh. The range of Cr, Ni, Cu, Cd, Pb and As in the investigated foodstuffs was 1.24-2.17, 1.29-2.56, 0.92-2.31, 0.12-0.44, 0.15-0.48 and 0.14-0.57 mg kg fresh weight(-1), respectively. The estimated mean levels of most of the elements were higher than the maximum allowable concentration (MAC) for dietary foods. The estimated daily intakes (EDIs) of Cr and Cd were higher than the maximum tolerable daily intake (MTDI) for children, indicating that they are more susceptible to toxic elements through food consumption. The target hazard quotients (THQs) and target carcinogenic risk (TCR) of As (THQ > 1 and TCR > 10(-4)) for both the adults and children suggest that the consumers of non piscine foodstuffs (especially cow milk and chicken meat) are exposed chronically to metal pollution with carcinogenic and non-carcinogenic health consequences. PMID- 26755178 TI - Isolation and characterization of a hydrocarbonoclastic bacterial enrichment from total petroleum hydrocarbon contaminated sediments: potential candidates for bioaugmentation in bio-based processes. AB - Seven hydrocarbonoclastic new bacterial isolates were isolated from dredged sediments of a river estuary in Italy. The sediments were contaminated by shipyard activities since decades, mainly ascribable to the exploitation of diesel oil as the fuel for recreational and commercial navigation of watercrafts. The bacterial isolates were able to utilize diesel oil as sole carbon source. Their metabolic capacities were evaluated by GC-MS analysis, with reference to the depletion of both the normal and branched alkanes, the nC18 fatty acid methyl ester and the unresolved complex mixture of organic compounds. They were taxonomically identified as different species of Stenotrophomonas and Pseudomonas spp. by the combination of amplified ribosomal DNA restriction analysis (ARDRA) and repetitive sequence-based PCR (REP-PCR) analysis. The metabolic activities of interest were analyzed both in relation to the single bacterial strains and to the combination of the latter as a multibacterial species system. After 6 days of incubation in mineral medium with diesel oil as sole carbon source, the Stenotrophomonas sp. M1 strain depleted 43-46 % of Cn-alkane from C28 up to C30, 70 % of the nC18 fatty acid methyl ester and the 46 % of the unresolved complex mixture of organic compounds. On the other hand, the Pseudomonas sp. NM1 strain depleted the 76 % of the nC18 fatty acid methyl ester, the 50 % of the unresolved complex mixture of organic compounds. The bacterial multispecies system was able to completely deplete Cn-alkane from C28 up to C30 and to deplete the 95 % of the unresolved complex mixture of organic compounds. The isolates, either as single strains and as a bacterial multispecies system, were proposed as candidates for bioaugmentation in bio-based processes for the decontamination of dredged sediments. PMID- 26755181 TI - Letter to the Editor: Comment on "The Impact of Psychological Support on Weight Loss Post Weight Loss Surgery: a Randomised Control Trial". PMID- 26755180 TI - Inhaled Umeclidinium in COPD Patients: A Review and Meta-Analysis. AB - A number of new agents for the management of chronic obstructive pulmonary disease (COPD) are at different stages of development, including several inhaled long-acting antimuscarinics (LAMA). Long-acting bronchodilators are considered to be central to the management of COPD due to the evidence supporting their efficacy and safety. Umeclidinium, a LAMA, has recently been approved for the maintenance treatment of moderate to very severe COPD in a number of countries. This comprehensive review and pooled meta-analysis provides detailed information about the efficacy and safety of this agent. The pharmacokinetics and pharmacodynamics of umeclidinium observed in phase I and II studies support its once-daily administration. Umeclidinium is rapidly cleared from blood, and renal or hepatic impairment do not lead to significant changes in drug disposition. A pooled analysis of phase III and comparative studies of umeclidinium in patients with moderate to very severe COPD showed significant improvement in lung function measures, including trough forced expiratory volume in 1 s (FEV1), as well as in acute exacerbations of COPD, dyspnea, and quality of life. Adverse effects, including known anticholinergic effects, were uncommon with umeclidinium. Limited data suggest the efficacy of umeclidinium is similar to that of tiotropium. Umeclidinium is administered as a dry powder inhaler, provides adequate lung delivery in patients with moderate to very severe airflow obstruction, and appears to be easily used by patients. Umeclidinium provides a safe and effective option as an inhaled LAMA for the management of COPD. PMID- 26755179 TI - What to Do, and What Not to Do, When Diagnosing and Treating Breakthrough Cancer Pain (BTcP): Expert Opinion. AB - Clinical management of breakthrough cancer pain (BTcP) is still not satisfactory despite the availability of effective pharmacological agents. This is in part linked to the lack of clarity regarding certain essential aspects of BTcP, including terminology, definition, epidemiology and assessment. Other barriers to effective management include a widespread prejudice among doctors and patients concerning the use of opioids, and inadequate assessment of pain severity, resulting in the prescription of ineffective drugs or doses. This review presents an overview of the appropriate and inappropriate actions to take in the diagnosis and treatment of BTcP, as determined by a panel of experts in the field. The ultimate aim is to provide a practical contribution to the unresolved issues in the management of BTcP. Five 'things to do' and five 'things not to do' in the diagnosis and treatment of BTcP are proposed, and evidence supporting said recommendations are described. It is the duty of all healthcare workers involved in managing cancer patients to be mindful of the possibility of BTcP occurrence and not to underestimate its severity. It is vital that all the necessary steps are carried out to establish an accurate and timely diagnosis, principally by establishing effective communication with the patient, the main information source. It is crucial that BTcP is treated with an effective pharmacological regimen and drug(s), dose and administration route prescribed are designed to suit the particular type of pain and importantly the individual needs of the patient. PMID- 26755182 TI - Continuous Glucose Monitoring After Gastric Bypass to Evaluate the Glucose Variability After a Low-Carbohydrate Diet and to Determine Hypoglycemia. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) alters glucose metabolism and can cause postprandial hypoglycemia. Continuous glucose monitoring (CGM) has been proposed as an evaluation tool in hypoglycemic RYGB individuals. The objective of this study is to investigate the use of CGM in clinical decision-making including diagnosing hypoglycemia and evaluating treatment effects. Furthermore, we aim to assess its accuracy in RYGB-operated individuals. METHODS: Thirteen RYGB individuals with symptomatic hypoglycemia and 13 asymptomatic RYGB individuals underwent CGM for 5 days. During this period, a mixed-meal test with concomitant plasma glucose (PG) measurements was performed. Furthermore, the RYGB individuals followed a low-carbohydrate diet (LCD) for 1 day and maintained their ordinary diet (OD) for the rest of the period. RESULTS: LCD reduced the CGM-determined glycemic variability of the mean interstitial fluid glucose (IFG) significantly compared to OD (p < 0.0001). Receiver operating characteristic analysis confirmed that low blood glucose index (e.g., the frequency and amplitude of hypoglycemic events) is the most reliable parameter related to the development of symptomatic hypoglycemia, with a sensitivity of 0.91 (confidence interval [CI] 0.59; 1.00) and a specificity of 0.77 (CI 0.46; 0.95). However, CGM, measuring the IFG in the subcutaneous adipose tissue, overestimated the minimum glucose levels by 1.1 +/- 0.9 mmol/l compared with PG. CONCLUSIONS: CGM was a good method for demonstrating increased glycemic variability among RYGB individuals and for displaying dietary effects on reducing this glycemic variability, including hypoglycemic events. In RYGB individuals, CGM-measured IFG overestimated the real glucose value by about 1 mmol/l in the hypoglycemic range. This should be taken into consideration if CGM is used to diagnose hypoglycemia after RYGB. PMID- 26755183 TI - European conformation and fat scores have no relationship with eating quality. AB - European conformation and fat grades are a major factor determining carcass value throughout Europe. The relationships between these scores and sensory scores were investigated. A total of 3786 French, Polish and Irish consumers evaluated steaks, grilled to a medium doneness, according to protocols of the ???Meat Standards Australia??? system, from 18 muscles representing 455 local, commercial cattle from commercial abattoirs. A mixed linear effects model was used for the analysis. There was a negative relationship between juiciness and European conformation score. For the other sensory scores, a maximum of three muscles out of a possible 18 demonstrated negative effects of conformation score on sensory scores. There was a positive effect of European fat score on three individual muscles. However, this was accounted for by marbling score. Thus, while the European carcass classification system may indicate yield, it has no consistent relationship with sensory scores at a carcass level that is suitable for use in a commercial system. The industry should consider using an additional system related to eating quality to aid in the determination of the monetary value of carcasses, rewarding eating quality in addition to yield. PMID- 26755185 TI - Analysis of the validity of assumptions underlying a research on the heritability of quantitative traits. AB - INTRODUCTION: Heritability is a statistical measure, expressing the proportion of phenotypic variance that is explained by the genetic variance. Heritability of a given trait can vary in time and may differ between populations, which is inter alia associated with interactions and correlations between genotype and environment or population-specific differences. Therefore, heritability measures are modulated by both genetic and environmental factors. Twin studies constitute one of the methods used to determine contributions of genes and environment to a given trait. However, studies of this type suffer from some methodological limitations and require certain conditions to be satisfied; both these factors were analyzed in the present study. MATERIAL AND METHODS: The studied material, including 1,263 pairs of male and female twins (among them 424 pairs of monozygotic twins and 839 pairs of dizygotic twins), born between the 22nd and 41st week of gestation, was collected at the Department of Perinatology and Gynecology, Poznan University of Medical Sciences, between 2002 and 2009. We analyzed the variance of six somatic traits. The contribution of genetic factors to the phenotypic variance of the studied twin population was estimated on the basis of the two heritability measures. RESULTS: Failure to meet the assumption of additivity of genetic and environmental effects probably is the cause of high values of heritability coefficients documented in our study. Analyzing the phenotypic variance of a trait, one cannot ignore the role of genotype environment interactions and covariance, as these are their effects which increase the genetic variance and related coefficients of heritability. Therefore, it can be concluded that the genotypic component of the phenotypic variance of the trait is potentiated by the effects of various environmental factors. CONCLUSIONS: Our study confirmed that the critical remarks regarding the methodology of heritability estimation are fully justified. Consequently, the heritability indices of somatic traits should be considered only a provisional measure of genetic polymorphism, expressing an estimated relative contribution of genotypic variance to the phenotypic variance of a given trait. PMID- 26755184 TI - Ethnic variations in asthma hospital admission, readmission and death: a retrospective, national cohort study of 4.62 million people in Scotland. AB - BACKGROUND: Our previous meta-analysis found that South Asians and Blacks in the UK were at a substantially increased risk of hospital admission from asthma. These estimates were, however, derived from pooling data from a limited number of now dated studies, confined to only three very broad ethnic groups (i.e. Whites, South Asians and Blacks) and failed to take account of possible sex-related differences in outcomes within these ethnic groups. We undertook the first study investigating ethnic variations in asthma outcomes across an entire population. METHODS: This retrospective 9-year cohort study linked Scotland's hospitalisation/death records on asthma to the 2001 census (providing ethnic group). We calculated age, country of birth and Scottish Index of Multiple Deprivation adjusted incident rate ratios (IRRs) for hospitalisation or death by sex for the period May 2001-2010. We calculated hazard ratios (HRs) for asthma readmission and subsequent asthma death. RESULTS: We were able to link data on 4.62 million people (91.8% of the Scottish population), yielding over 38 million patient-years of data, 1,845 asthma deaths, 113,795 first asthma admissions, and 107,710 readmissions (40,075 of which were for asthma). There were substantial ethnic variations in the rate of hospitalisation/death in both males and females. When compared to the reference Scottish White population, the highest age adjusted rates were in Pakistani males (IRR = 1.59; 95% CI, 1.30-1.94) and females (IRR = 1.50; 95% CI, 1.06-2.11) and Indian males (IRR = 1.34; 95% CI, 1.16-1.54), and the lowest were seen in Chinese males (IRR = 0.62; 95% CI, 0.41 0.94) and females (IRR = 0.49; 95% CI, 0.39-0.61). CONCLUSION: There are very substantial ethnic variations in hospital admission/deaths from asthma in Scotland, with Pakistanis having the worst and Chinese having the best outcomes. Cultural factors, including self-management and health seeking behaviours, and variations in the quality of primary care provision are the most likely explanations for these differences and these now need to be formally investigated. PMID- 26755186 TI - Signaling and Gene Regulatory Networks Governing Definitive Endoderm Derivation From Pluripotent Stem Cells. AB - The generation of definitive endoderm (DE) from pluripotent stem cells (PSCs) is a fundamental stage in the formation of highly organized visceral organs, such as the liver and pancreas. Currently, there is a need for a comprehensive study that illustrates the involvement of different signaling pathways and their interactions in the derivation of DE cells from PSCs. This study aimed to identify signaling pathways that have the greatest influence on DE formation using analyses of transcriptional profiles, protein-protein interactions, protein DNA interactions, and protein localization data. Using this approach, signaling networks involved in DE formation were constructed using systems biology and data mining tools, and the validity of the predicted networks was confirmed experimentally by measuring the mRNA levels of hub genes in several PSCs-derived DE cell lines. Based on our analyses, seven signaling pathways, including the BMP, ERK1-ERK2, FGF, TGF-beta, MAPK, Wnt, and PIP signaling pathways and their interactions, were found to play a role in the derivation of DE cells from PSCs. Lastly, the core gene regulatory network governing this differentiation process was constructed. The results of this study could improve our understanding surrounding the efficient generation of DE cells for the regeneration of visceral organs. J. Cell. Physiol. 231: 1994-2006, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26755187 TI - On testing the strength independence assumption in retrieval-induced forgetting. AB - Strength independence refers to the assumption that in a retrieval-induced forgetting paradigm, the increase in performance for the practiced items (RP+) is independent of the decrease for the related and supposedly inhibited items (RP-). One way in which this assumption has been tested is by examining the correlation over subjects between these two measures. The finding that there is no such correlation has been taken as evidence for the inhibition account and against noninhibitory accounts of retrieval induced forgetting. We report several, large scale simulation studies using a simplified version of the SAM model (Raaijmakers & Shiffrin, Psychological Review, 88, 93-134, 1981). The results clearly show that such a noninhibitory model is not likely to predict a significant correlation, despite the fact that on the level of the predicted probabilities such a correlation is clearly present. Additional simulations show that this is a very general result and not specifically related to the SAM model that was used. We conclude that such correlations do not provide a good test for the strength independence assumption and will not be able to distinguish between inhibitory and noninhibitory explanations of retrieval-induced forgetting. PMID- 26755188 TI - A rational analysis of the approximate number system. AB - It is well-known in numerical cognition that higher numbers are represented with less absolute fidelity than lower numbers, often formalized as a logarithmic mapping. Previous derivations of this psychological law have worked by assuming that relative change in physical magnitude is the key psychologically-relevant measure (Fechner, 1860; Sun et al., 2012; Portugal & Svaiter, Minds and Machines, 21(1), 73-81, 2011). Ideally, however, this property of psychological scales would be derived from more general, independent principles. This paper shows that a logarithmic number line is the one which minimizes the error between input and representation relative to the probability that subjects would need to represent each number. This need probability is measured here through natural language and matches the form of need probabilities found in other literatures. The derivation does not presuppose anything like Weber's law and makes minimal assumptions about both the nature of internal representations and the form of the mapping. More generally, the results prove in a general setting that the optimal psychological scale will change with the square root of the probability of each input. For stimuli that follow a power-law need distribution this approach recovers either a logarithmic or power-law psychophysical mapping (Stevens, 1957, 1961, 1975). PMID- 26755189 TI - Erratum to: Beninese children with cerebral malaria do not develop humoral immunity against the IT4-VAR19-DC8 PfEMP1 variant linked to EPCR and brain endothelial binding. PMID- 26755190 TI - On the properties of Se?N interaction: the analysis of substituent effects by energy decomposition and orbital interaction. AB - The nature and strength of intermolecular Se?N interaction between selenium containing compounds HSeX (X = CH3, NH2, CF3, OCH3, CN, OH, NO2, Cl, F), and NH3 have been investigated at the MP2/aug-cc-pVDZ level. The Se?N interaction is found to be dependent on the substituent groups, which greatly affect the positive electrostatic potential of Se atoms and the accepting electron ability of X-Se sigma(*) antibonding orbital. Energy decomposition of the Se ?N interaction reveals that electrostatic and induction forces are comparable in the weak-bonded complexes and induction becomes more significant in the complexes with strong electron-withdrawing substituents. Natural bond orbital (NBO) analysis indicates that the primary source of the induction is the electron transfer from the N lone pair to the X-Se sigma(*) antibonding orbital. The geometry of the complex and the interaction directionality of NH3 to X-Se bond can be regarded as a consequence of the exchange-repulsion. The topological analysis on the electron density reveals the nature of closed-shell interaction in these X-Se?N contacts. The Se?N interaction in the complexes with the strong electron-withdrawing substituent has a partly covalent character. PMID- 26755191 TI - The effect of training during treatment with chemotherapy on muscle strength and endurance capacity: A systematic review. AB - Background Treatment of cancer with chemotherapy decreases endurance capacity and muscle strength. Training during chemotherapy might prevent this. There are no clear guidelines concerning which type of training and which training dose are effective. This review aims to gain insight into the different training modalities during chemotherapy and the effects of such training to improve endurance capacity and muscle strength in order to obtain the knowledge to compose a future training program which trains cancer patients in the most effective way. Material and methods A systematic search of PubMed was carried out. In total, 809 studies of randomized controlled trials studying the effects of training during chemotherapy on endurance capacity and muscle strength were considered. Only 14 studies met all the inclusion criteria. The studies were assessed on methodological quality by using Cochrane criteria for randomized controlled trials. Results The quality of the studies was generally poor and the study populations varied considerably as the training programs were very heterogeneous. Variables of endurance capacity reported beneficial effects in 10 groups (59%). Increases due to training ranged from 8% to 31%. Endurance capacity decreased in nine of 13 control groups (69%), which ranged from 1% to 32%. Muscle strength improved significantly in 17 of 18 intervention groups (94%), ranging from 2% to 38%. Muscle strength also improved in 11 of 14 control groups (79%), but this increase was only minimal, ranging from 1.3% to 6.5%. Conclusions This review indicates that training during chemotherapy may help in preventing the decrease in muscle strength and endurance capacity. It is important to know which training intensity and duration is the most effective in training cancer patients, to provide a training program suitable for every cancer patient. Training should be based on good research and should be implemented into international guidelines and daily practice. More research is needed. PMID- 26755195 TI - Friedreich Ataxia and nephrotic syndrome: a series of two patients. AB - BACKGROUND: Friedreich Ataxia (FRDA) is a neurodegenerative disorder characterized by gait and balance abnormalities, sensory loss, weakness, loss of reflexes, and ataxia. Previously, two cases of FRDA and Nephrotic Syndrome (NS) have been reported. Here we report two additional individuals with NS and FRDA, providing further evidence for a possible connection between the two diseases and focusing on the neuromuscular responsiveness of one individual to corticosteroid treatment, an effect not previously described in FRDA. CASE PRESENTATIONS: We describe two patients with FRDA also presenting with NS. The first patient was diagnosed with FRDA at age 5 and NS at age 7 following the development of periorbital edema, abdominal swelling, problems with urination, and weight gain. The second patient was diagnosed with NS at age 2 after presenting with periorbital edema, lethargy, and abdominal swelling. He was diagnosed with FRDA at age 10. Nephrotic syndrome was confirmed by laboratory testing in both cases and both individuals were treated with corticosteroids. CONCLUSIONS: Nephrotic syndrome may occur in individuals with FRDA, but was not associated with myoclonic epilepsy in our patients as previously described. It is unlikely that this association is coincidental given the rarity of both conditions and the association of NS with mitochondrial disease in model systems, though coincidental coexistence is possible. One patient showed neurological improvement following steroid treatment. Although neurological improvement could be attributed to the treatment of NS, we also identified some degree of steroid responsiveness in a series of patients with FRDA but without NS. PMID- 26755196 TI - High-Mobility Transistors Based on Large-Area and Highly Crystalline CVD-Grown MoSe2 Films on Insulating Substrates. AB - Large-area and highly crystalline CVD-grown multilayer MoSe2 films exhibit a well defined crystal structure (2H phase) and large grains reaching several hundred micrometers. Multilayer MoSe2 transistors exhibit high mobility up to 121 cm(2) V(-1) s(-1) and excellent mechanical stability. These results suggest that high mobility materials will be indispensable for various future applications such as high-resolution displays and human-centric soft electronics. PMID- 26755198 TI - GO-induced assembly of gelatin toward stacked layer-like porous carbon for advanced supercapacitors. AB - Layer-like nanocarbons with high surface area and good conductivity are promising materials for supercapacitors due to their good ability for effective charge transfer and mass-transfer. In this paper, stacked layer-like porous carbon containing RGO (reduced graphene oxides) (LPCG) was constructed via the GO induced assembly of gelatin followed by carbonization and activation processes. Under suitable conditions, LPCG-based materials with a thickness of about 100 nm and a high specific surface area (up to 1476 m(2) g(-1)) could be obtained. In the materials, the closed combination of RGO and porous carbon can be observed, which is favourable for the development of the synergistic effects of both components. The presence of GO can not only enhance the conductivity of LPCG based materials, but also is essential for the formation of a thin carbon sheet with a stacked structure. Otherwise, the plate-like, non-stacked carbon with a thickness of about 500 nm could be formed in the absence of RGO. The porous structure along with the presence of RGO allows rapid charge-transfer and easy access and diffusion of electrolyte ions. As a result, the materials exhibited a high discharge specific capacitance (455 F g(-1) at 0.5 A g(-1), 366 F g(-1) at 1 A g(-1)), good rate capability (221 F g(-1) at density 30 A g(-1)) and good cycling stability. In aqueous electrolytes, the energy density could be up to 9.32 W h kg(-1) at a relatively low power density of 500 W kg(-1) with a good cycling stability (>96% over 5000 cycles). It was found that (1) the rational combination of RGO and porous carbon is essential for enhancing the capacitance performance and improving the cycling stability and (2) the high conductivity is favorable for improving the rate performance of the materials. The LPCG-based materials have extensive potential for practical applications in energy storage and conversion devices. PMID- 26755197 TI - BayesFlow: latent modeling of flow cytometry cell populations. AB - BACKGROUND: Flow cytometry is a widespread single-cell measurement technology with a multitude of clinical and research applications. Interpretation of flow cytometry data is hard; the instrumentation is delicate and can not render absolute measurements, hence samples can only be interpreted in relation to each other while at the same time comparisons are confounded by inter-sample variation. Despite this, most automated flow cytometry data analysis methods either treat samples individually or ignore the variation by for example pooling the data. A key requirement for models that include multiple samples is the ability to visualize and assess inferred variation, since what could be technical variation in one setting would be different phenotypes in another. RESULTS: We introduce BayesFlow, a pipeline for latent modeling of flow cytometry cell populations built upon a Bayesian hierarchical model. The model systematizes variation in location as well as shape. Expert knowledge can be incorporated through informative priors and the results can be supervised through compact and comprehensive visualizations. BayesFlow is applied to two synthetic and two real flow cytometry data sets. For the first real data set, taken from the FlowCAP I challenge, BayesFlow does not only give a gating which would place it among the top performers in FlowCAP I for this dataset, it also gives a more consistent treatment of different samples than either manual gating or other automated gating methods. The second real data set contains replicated flow cytometry measurements of samples from healthy individuals. BayesFlow gives here cell populations with clear expression patterns and small technical intra-donor variation as compared to biological inter-donor variation. CONCLUSIONS: Modeling latent relations between samples through BayesFlow enables a systematic analysis of inter-sample variation. As opposed to other joint gating methods, effort is put at ensuring that the obtained partition of the data corresponds to actual cell populations, and the result is therefore directly biologically interpretable. BayesFlow is freely available at GitHub. PMID- 26755199 TI - Izhakiella capsodis gen. nov., sp. nov., in the family Enterobacteriaceae, isolated from the mirid bug Capsodes infuscatus. AB - Gram-stain-negative, oxidase-negative, facultatively anaerobic, motile, rod shaped, non-pigmented bacterial strains (N6PO6T, N8PO1 and N8PI1) were isolated from the mirid bug Capsodes infuscatus captured on Asphodelus aestivus plants. The 16S rRNA gene sequences of the strains shared 94.7-95.7 % similarity with species of the genus Pantoea and 95.6 % or less with species from other genera in the family Enterobacteriaceae. A polyphasic approach that included determination of phenotypic properties and phylogenetic analysis based on 16S rRNA, rpoB, gyrB and atpD gene sequences supported the classification of strains N6PO6T, N8PO1 and N8PI1 as representing a novel species of a new genus in the family Enterobacteriaceae. Strain N6PO6T, and the two reference strains of the novel species, grew at 1-37 degrees C, and in the presence of NaCl (up to 7.5 %, w/v) and sucrose (up to 60 %). Their major cellular fatty acids were C16 : 0, C17 : 0 cyclo, C18 : 1omega7c, summed feature 2 (C14 : 0 3-OH and/or iso-C16 : 1 I) and summed feature 3 (C16 : 1omega7c and/or iso-C15 : 0 2-OH). The DNA G+C content of strain N6PO6T was 49.9 mol%. On the basis of phenotypic properties and phylogenetic distinctiveness, the mirid bug isolates are classified as representing a novel species in a new genus Izhakiella, in the family Enterobacteriaceae, for which the name Izhakiella capsodis gen. nov., sp. nov. is proposed. The type strain of Izhakiella capsodis is N6PO6T ( = LMG 28430T = DSM 29293T). PMID- 26755200 TI - Astrocyte-derived adenosine is central to the hypnogenic effect of glucose. AB - Sleep has been hypothesised to maintain a close relationship with metabolism. Here we focus on the brain structure that triggers slow-wave sleep, the ventrolateral preoptic nucleus (VLPO), to explore the cellular and molecular signalling pathways recruited by an increase in glucose concentration. We used infrared videomicroscopy on ex vivo brain slices to establish that glucose induces vasodilations specifically in the VLPO via the astrocytic release of adenosine. Real-time detection by in situ purine biosensors further revealed that the adenosine level doubles in response to glucose, and triples during the wakefulness period. Finally, patch-clamp recordings uncovered the depolarizing effect of adenosine and its A2A receptor agonist, CGS-21680, on sleep-promoting VLPO neurons. Altogether, our results provide new insights into the metabolically driven release of adenosine. We hypothesise that adenosine adjusts the local energy supply to local neuronal activity in response to glucose. This pathway could contribute to sleep-wake transition and sleep intensity. PMID- 26755201 TI - The outcome of short- and long-term psychotherapy 10 years after start of treatment. AB - BACKGROUND: Empirical evidence on whether patients' mental health and functioning will be more improved after long-term than short-term therapy is scarce. We addressed this question in a clinical trial with a long follow-up. METHOD: In the Helsinki Psychotherapy Study, 326 out-patients with mood or anxiety disorder were randomly assigned to long-term psychodynamic psychotherapy (LPP), short-term psychodynamic psychotherapy (SPP) or solution-focused therapy (SFT) and were followed for 10 years. The outcome measures were psychiatric symptoms, work ability, personality and social functioning, need for treatment, and remission. RESULTS: At the end of the follow-up, altogether 74% of the patients were free from clinically elevated psychiatric symptoms. Compared with SPP, LPP showed greater reductions in symptoms, greater improvement in work ability and higher remission rates. A similar difference in symptoms and work ability was observed in comparison with SFT after adjustment for violations of treatment standards. No notable differences in effectiveness between SFT and SPP were observed. The prevalence of auxiliary treatment was relatively high, 47% in SFT, 58% in SPP and 33% in LPP, and, accordingly, the remission rates for general symptoms were 55, 45 and 62%, respectively. CONCLUSIONS: After 10 years of follow-up, the benefits of LPP in comparison with the short-term therapies are rather small, though significant in symptoms and work ability, possibly due to more frequent use of auxiliary therapy in the short-term therapy groups. Further studies should focus on the choice of optimal length of therapy and the selection of factors predicting outcome of short- v. long-term therapy. PMID- 26755203 TI - CD26 costimulatory blockade improves lung allograft rejection and is associated with enhanced interleukin-10 expression. AB - BACKGROUND: The ectoenzyme CD26/dipeptidyl peptidase 4 (DPP4) has costimulatory activity that contributes to T cell activation and proliferation. Here, we aimed to target this costimulatory activity for the attenuation of the alloreactive Th17-cell response during acute rejection after mouse lung transplantation. METHODS: To test the CD26-costimulatory blockade in vitro, mixed lymphocyte reaction was performed between major histocompatibility complex class I and II fully mismatched cells (CD4(+) splenocytes, C57BL/6, responders, and antigen presenting cells, BALB/c, stimulators) by adding the CD26 inhibitor vildagliptin (0-15 MUg). Lung transplantation between BALB/c (donor) and C57BL/6 (recipient) mice was performed, including controls, CD26-inhibited (CD26-I, daily administration of vildagliptin [GLSynthesis, Worcester, MA], 10 mg/kg subcutaneous), and CD26 knockout (CD26KO) mice was performed. Analysis on Day 1 and 5 after transplant included immunohistochemistry, fluorescence-activated cell sorting, and enzyme-linked immunosorbent assay (ELISA) for immune cell detection and their key cytokines. RESULTS: In vitro, there was a significant reduction of the Th17 cytokines interleukin (IL)-17 and IL-21. In vivo, CD26-I-treated and CD26KO mice showed significantly preserved macroscopic and histologic characteristics on Day 5 (p < 0.01), a higher partial pressure of arterial oxygen/fraction of inspired oxygen ratio (p <= 0.05), fewer infiltrating CD3(+) T cells (p < 0.01), but more interstitial macrophages on Day 1 (p < 0.01) compared with control. Fewer IL-17(+) cells were found in CD26-I allografts on Day 1 (p = 0.05). Higher levels of IL-10 in CD26-I and CD26KO allografts on day 5 were seen (p < 0.05). IL-10/CD206 double-staining (alternative macrophages) revealed more positive cells in CD26-I and CD26KO on Day 1 and 5 (p < 0.01). CONCLUSIONS: CD26 costimulatory blockade promotes lung allograft acceptance via reduced T cell infiltration, less expression of IL-17, and increased expression of IL-10, likely to be derived from alternatively activated macrophages. PMID- 26755202 TI - MicroRNA let-7i regulates dendritic cells maturation targeting interleukin-10 via the Janus kinase 1-signal transducer and activator of transcription 3 signal pathway subsequently induces prolonged cardiac allograft survival in rats. AB - BACKGROUND: In this study, we investig1ated whether microRNA let-7i regulates dendric cell maturation targeting interleukin-10 (IL-10) via the Janus kinase 1 signal transducer and activator of transcription 3 (JAK1-STAT3) signal pathway subsequently prolongs rat cardiac allograft survival. METHODS: Quantitative real time reverse transcriptase polymerase chain reaction, enzyme linked immunosorbent assay, and dual-luciferase assay were performed to verify whether IL-10 was the target of let-7i, and regulatory T cells were assessed by flow cytometry and immunohistochemical study. Western blot was performed to detect JAK1, STAT3, and phosphorylated STAT3 expression. Lewis recipients of Dark Agouti hearts were transfused with phosphate-buffered saline, lipopolysaccharide (LPS)-mature dendritic cells (mDCs), or let-7i-inhibitor-mDCs. Allograft survival times were recorded, and histologic studies were performed. RESULTS: Expression of IL-10 messenger RNA level and production of IL-10 were increased in let-7i-inhibitor mDCs compared with LPS-mDCs. Luciferase activity showed that the translational level of the IL-10 luciferase reporter was decreased by let-7i mimic but increased by let-7i-inhibitor. MicroRNA let-7i inhibitor suppressed DC maturation; however, pretreatment of IL-10 small interfering RNA attenuated the suppression. Expression of JAK1, STAT3, and phosphorylated STAT3 in mDCs were suppressed by let-7i mimic, and pre-treatment of IL-10 small interfering RNA, however, were upregulated by let-7i inhibitor. Lewis recipients transfused with let-7i-inhibitor-mDCs significantly prolonged Dark Agouti cardiac allograft survival. The allografts transfused with let-7i-inhibitor-mDCs showed slight cell infiltration and significantly preserved graft structure. Inhibition of let-7i increased CD4(+)CD25(+)forkhead box P3(+) regulatory T cells and modulated cytokine profiles in vivo and in vitro. CONCLUSIONS: MicroRNA let-7i regulated DC maturation and function targeting IL-10 through the JAK1-STAT3 pathway. Moreover, transfusion of LPS-induced mDCs transfected with let-7i inhibitor induced prolonged cardiac allograft survival and generated regulatory T cells. PMID- 26755205 TI - Cu2+-attached pumice particles embedded composite cryogels for protein purification. AB - In this study, chromatographic performance of Cu2+-attached pumice particles embedded to monolithic cryogels (Cu2+-APPsEMC) for human serum albumin (HSA) was investigated. Monolithic composite cryogels were prepared by means of polymerization of gel-forming precursors at sub-zero temperatures. The chemical composition of pumice and surface of composite cryogels were determined by X-ray fluorescence spectrometer and scanning electron microscopy, respectively. The highest adsorption capacity (549.5 mg/g pumice) of cryogels was achieved at phosphate buffer of pH 8.0 with initial HSA solution of 3 mg/ml. SDS-PAGE analysis was performed for the samples studied on human serum to determine HSA adsorption/desorption performance of cryogel qualitatively. PMID- 26755204 TI - Embryonal rhabdomyosarcoma arising from the uterine corpus in a postmenopausal female: a surgical case challenging the genuine diagnosis on a cytology specimen. AB - A 55-year-old postmenopausal female presented with genital bleeding and lower abdominal mass. An abdominal MRI revealed a heterogeneously enhanced, 15 * 10 cm mass, completely filling the lumen of the enlarged uterus. The cytologic analysis of the mass showed tumor cells in small clusters and as individual cells showing hyperchromatic round to oval nuclei, and pleomorphic and occasionally unipolar "tadpole"-shaped cytoplasm, in a background of severe necrosis and many degenerated squamous cells. We first interpreted it merely as atypical cells, possibly originated from sarcoma. A total abdominal hysterectomy and salpingo oophorectomy were performed, and gross examination showed an exophytic polypoid mass with a whitish to white-grayish, necrotic appearance, protruding from the endometrial mucosa. Microscopically, the tumor was composed of a diffuse proliferation of highly atypical spindle-shaped cells, admixed with many characteristic rhabdomyoblasts having abundant densely eosinophilic cytoplasm with sometimes distinct cross-striations, coexisted with cellular primitive small blue round to oval cells foci. However, neither carcinoma nor additional heterologous sarcoma components were completely seen within our thorough investigation. Therefore, we finally made a diagnosis of embryonal rhabdomyosarcoma arising from the uterine corpus. We should be aware that owing to its characteristic features, cytopathologists might be able to determine a genuine diagnosis, based on multiple and adequate cytology samplings. PMID- 26755206 TI - Factors influencing home discharge after inpatient rehabilitation of older patients: a systematic review. AB - BACKGROUND: Although rehabilitation for older patients has the potential to improve function and prevent admission to nursing homes, returning home after discharge is not possible for all patients. Better understanding of patient factors related to discharge home may lead to more realistic rehabilitation goals, more targeted rehabilitation interventions and better preparation of both patient and informal caregiver for discharge. Various studies provided insight into factors related to home discharge after stroke rehabilitation, but we still lack insight into factors related to home discharge in non-stroke patients. Therefore, the aim of this review is to provide an overview of factors influencing home discharge in older non-stroke patients admitted to an inpatient rehabilitation unit. METHODS: A systematic literature search was executed in the databases PubMed, EMBASE, CINAHL and Web of Science to retrieve articles published between January 2000 and October 2015. The search focused on factors related to home discharge after rehabilitation for older patients. Studies were included if home discharge after rehabilitation was assessed as an outcome measure and if the non-stroke population was, on average, 65 years or older and admitted to an inpatient rehabilitation unit. RESULTS: Eighteen studies were included. The methodological quality was moderate to good in 15 studies. The factors significantly associated with home discharge are younger age, non-white ethnicity, being married, better functional and cognitive status, and the absence of depression. CONCLUSIONS: Because various factors are significantly associated with home discharge of older non-stroke patients after rehabilitation, we recommend assessing these factors at admission to the rehabilitation unit. Further research into the factors that lack sufficient evidence concerning their association with home discharge is recommended. PMID- 26755207 TI - Implantable cardioverter-defibrillator elective generator replacement: a procedure for all? AB - PURPOSE: Six risk stratification scores have been developed to estimate mortality risk in patients receiving an implantable cardioverter-defibrillator (ICD). This study aims at validating and comparing these risk scores in patients having elective ICD generator replacement (GR) and assessing the outcome of patients submitted to this procedure. METHODS: Two hundred twenty three consecutive patients with ischaemic or non-ischaemic dilated cardiomyopathy submitted to elective ICD GR and followed-up for 44 +/- 19 months were included. We evaluated which of six previously developed risk scores could predict post-discharge all cause mortality risk in this context with the highest efficacy. Comparisons between these scores were made using receiver-operating characteristic curves and the integrated discrimination improvement (IDI) index. We further assessed risk of appropriate ICD therapies and all-cause mortality following ICD GR. RESULTS: The prognostic utility of the six scores was assessed by calculating the AUC for follow-up all-cause mortality prediction: Goldenberg - 0.758 +/- 0.042, p < 0.001; Parkash - 0.754 +/- 0.042, p < 0.001; Bilchick - 0.813 +/- 0.038, p < 0.001; Kraaier - 0.721 +/- 0.043, p < 0.001; REPLACE DARE - 0.746 +/- 0.048, p < 0.001; Providencia - 0.739 +/- 0.043, p < 0.001. Through measures of risk reclassification (IDI and relative IDI), the score by Bilchick et al. was shown to outperform all other scores. Binary logistic regression identified pre-GR appropriate ICD therapy as an independent predictor of post-GR ICD therapy (OR 6.2, CI 95% 3.0-12.7, p < 0.001), along with male gender (OR 6.6, CI 95% 0.8-55, p = 0.082) and history of atrial fibrillation (OR 2.28, CI 95% 1.1-4.5, p = 0.019). CONCLUSIONS: Current prediction scores are useful in predicting mortality risk of patients considered for ICD generator replacement and can potentially help identify patients who may not benefit from continuous ICD treatment due to high mortality rates regardless of the ICD. PMID- 26755209 TI - A quasi randomized-controlled trial to evaluate the effectiveness of clowntherapy on children's anxiety and pain levels in emergency department. AB - The aim of the study is to investigate if the presence of medical clowns during painful procedures in the emergency department (ED) affects children's anxiety and pain. Forty children (4-11 years) admitted to the ED with the need of painful procedures were prospectively enrolled. They were randomly assigned to the clown group, where children interacted with clowns or to the control group in which they were entertained by parents and ED nurses. The children's anxiety was assessed by the Children's Anxiety and Pain Scales; pain was evaluated with the Numerical Rating Scale and Wong-Backer Scale, according to the children's age. Staff and clown's opinions were evaluated by means of dedicated questionnaires. Children's anxiety levels in the clown group were significantly lower than those compared with the control group, while children's pain levels did not change between the two groups. CONCLUSION: The presence of clowns in the ED before and during painful procedures was effective in reducing children's anxiety. WHAT IS KNOWN: * Anxiety and fear caused by medical procedures exacerbate children's pain and may interfere with the procedure. * To reduce anxiety, fear, and pain and to facilitate patient's evaluation, different non-pharmacological approaches have been proposed and positive effects of laughter and humor have been reported. What is New: * The presence of clowns in the waiting room and in the ED during medical evaluation and painful procedures helps to reduce children's anxiety. PMID- 26755208 TI - Functional properties of flagellin as a stimulator of innate immunity. AB - We report the development of a well-defined flagellin-based nanoparticle stimulator and also provide a new mechanism of action model explaining how flagellin-triggered innate immunity has evolved to favor localized rather than potentially debilitating systemic immune stimulation. Cell-free protein synthesis (CFPS) was used to facilitate mutational analysis and precisely orientated display of flagellin on Hepatitis B core (HBc) protein virus-like particles (VLPs). The need for product stability and an understanding of mechanism of action motivated investigations indicating that the D0 domain of flagellin is sensitive to amino acid sequence independent hydrolysis - apparently due to the need for structural flexibility during natural flagellin polymerization. When D0 stabilized flagellin was attached to HBc VLPs with the D0 domain facing outward, flagellin's tendency to polymerize caused the VLPs to precipitate. However, attaching the D0 domain to the VLP surface produced a stable nanoparticle adjuvant. Surprisingly, attaching only 2 flagellins per VLP provided the same 1 pM potency as did VLPs with about 33 attached flagellins suggesting that the TLR5 receptor is highly effective in delivering its intracellular signal. These observations suggest that flagellin's protease sensitivity, tendency to aggregate, and very high affinity for TLR5 receptors limit its systemic distribution to favor localized immune stimulation. PMID- 26755211 TI - To the core. PMID- 26755212 TI - The burden and management of neonatal jaundice in Nigeria: A scoping review of the literature. AB - Neonatal jaundice is a leading cause of hospitalization in the first week of life worldwide. If inappropriately managed, it may result in significant bilirubin induced mortality and disability. We set out to describe the epidemiology of neonatal hyperbilirubinemia as well as the practices and challenges in the care of infants with significant neonatal hyperbilirubinemia (SNH) in Nigeria, as basis for policy intervention and research priorities. We systematically searched PubMed, Scopus, EMBASE, Cumulative Index to Nursing and Allied Health Literature, WHO Library Database, African Index Medicus, African Journals Online, and local journals for studies published between January 1960 and December 2014. We included studies, without restriction on methodological design that provided evidence on the incidence/prevalence, etiological /risk factors and adverse outcomes of hyperbilirubinemia, care-seeking practices, diagnosis and treatment, as well as follow-up evaluation of infants with SNH in Nigeria. A total of 558 studies were identified from all sources out of which 198 (35.5%) were finally selected. SNH accounted for about one in five neonatal admissions and has been associated consistently with substantial case fatality and neuro-developmental sequelae such as cerebral palsy and auditory impairments, especially among out born babies. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, prematurity/low birth weight, infection, and ABO incompatibility were most frequently, and Rhesus disease rarely, associated with SNH. Late presentation at appropriate health facilities was common and resulted in high rates of acute bilirubin encephalopathy (ABE), kernicterus and avoidable exchange transfusions. Uniform practice guidelines, including developmental assessment and surveillance of infants with SNH, were rare at all levels of healthcare delivery. In summary, since 1960, SHN persists as a major contributor to neonatal mortality and developmental disabilities in Nigeria. The underpinning maternal, perinatal and neonatal factors as well as systems-based constraints are not insurmountable. Systematic and sustained interventions are warranted to curtail the disproportionate and perennial burden of this condition in this population. PMID- 26755210 TI - Transcriptomic analysis reveals the gene expression profile that specifically responds to IBA during adventitious rooting in mung bean seedlings. AB - BACKGROUND: Auxin plays a critical role in inducing adventitious rooting in many plants. Indole-3-butyric acid (IBA) is the most widely employed auxin for adventitious rooting. However, the molecular mechanisms by which auxin regulate the process of adventitious rooting are less well known. RESULTS: The RNA-Seq data analysis indicated that IBA treatment greatly increased the amount of clean reads and the amount of expressed unigenes by 24.29 % and 27.42 % and by 4.3 % and 5.04 % at two time points, respectively, and significantly increased the numbers of unigenes numbered with RPKM = 10-100 and RPKM = 500-1000 by 13.04 % and 3.12 % and by 24.66 % and 108.2 % at two time points, respectively. Gene Ontology (GO) enrichment analysis indicated that the enrichment of down-regulated GOs was 2.87-fold higher than that of up-regulated GOs at stage 1, suggesting that IBA significantly down-regulated gene expression at 6 h. The GO functional category indicated that IBA significantly up- or down-regulated processes associated with auxin signaling, ribosome assembly and protein synthesis, photosynthesis, oxidoreductase activity and extracellular region, secondary cell wall biogenesis, and the cell wall during the development process. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment indicated that ribosome biogenesis, plant hormone signal transduction, pentose and glucuronate interconversions, photosynthesis, phenylpropanoid biosynthesis, sesquiterpenoid and triterpenoid biosynthesis, ribosome, cutin, flavonoid biosynthesis, and phenylalanine metabolism were the pathways most highly regulated by IBA. A total of 6369 differentially expressed (2-fold change > 2) unigenes (DEGs) with 3693 (58 %) that were up-regulated and 2676 (42 %) down-regulated, 5433 unigenes with 2208 (40.6 %) that were up-regulated and 3225 (59.4 %) down-regulated, and 7664 unigenes with 3187 (41.6 %) that were up-regulated and 4477 (58.4 %) down regulated were detected at stage 1, stage 2, and between stage 1 and stage 2, respectively, suggesting that IBA treatment increased the number of DEGs. A total of 143 DEGs specifically involved in plant hormone signaling and 345 transcription factor (TF) genes were also regulated by IBA. qRT-PCR validation of the 36 genes with known functions indicated a strong correlation with the RNA-Seq data. CONCLUSIONS: The changes in GO functional categories, KEGG pathways, and global DEG profiling during adventitious rooting induced by IBA were analyzed. These results provide valuable information about the molecular traits of IBA regulation of adventitious rooting. PMID- 26755214 TI - Radiation pneumonitis in non-small-cell lung cancer patients treated with helical tomotherapy. AB - OBJECTIVE: In this study, we investigated the incidence of radiation pneumonitis (RP) in non-small-cell lung cancer (NSCLC) patients undergoing helical tomotherapy (HT) and the clinical and dosimetric factors associated with it. MATERIALS AND METHODS: We analyzed data from the treatment protocols of 62 NSCLC patients. The median total radiation dose was 64 Gy (range 57.6-66 Gy) at 1.8-2.2 Gy/fraction. Thirty-four of these patients underwent HT alone and 28 underwent HT in combination with chemotherapy. Treatment-related pneumonitis was graded according to the Common Terminology Criteria for Adverse Events, version 3.0. RESULTS: We found that RP grades 1, 2, 3 and 5 occurred in 29 (46.8%), 23 (37.1%), 8 (12.9%), and 2 (3.2%) patients, respectively. Using univariate analyses, we found that a grade >=3 RP was associated with poor performance status (PS), age, planning target volume, mean lung dose, and relative V5through V25, in increments of 5 Gy (P < 0.005). We determined that PS and V5V15were the most significant factors associated with grade >=3 RP using multivariate analysis. CONCLUSIONS: We found that poor PS and V5-V15 were the risk factors associated with grade >=3 RP in NSCLC patients treated with HT. Thus, for NSCLC patients treated with HT, the volume of total lung with low-dose region (V5-V15) should be carefully regulated and the use of HT should be restricted in patients with Eastern Cooperative Oncology Group >=2. PMID- 26755213 TI - Caesarean delivery: An experience from a tertiary institution in north western Nigeria. AB - OBJECTIVE: To assess the overall caesarean section (CS) rate, indications and outcomes in a tertiary hospital in North-western Nigeria. MATERIALS AND METHODS: A cross-sectional study carried out over a period of two years. All patients who had caesarean section at any time within the day were noted and followed up till discharge. The socio-demographic data, types of CS, anaesthesia, indications, abdominal wall and uterine incisions, cadre of surgeon and feto-maternal outcomes were documented in a proforma. Statistical analysis was carried out using the EPI INFO 3.5.1 (CDC Atlanta Georgia, USA). RESULT: The caesarean section rate was 11.3% (504/4462) of total deliveries. The highest rate of 44.6% (225/504) was among the primipara. The most common age group involved was 25 to 29 years. The emergency rate was 57.1% (288/504), while elective CS constituted 42.9% (216/504) of cases. The most common indication for emergency CS was obstructed labour 25.7% (30/288) and previous CS 39.8% (86/216) for elective CS. The complication rate was 13.3% (67/504) and the main complication was haemorrhage 59.7% (40/67). Complications were more with emergency CS compared to elective surgery (chi2 = 6.633, df = 1, P < 0.01) and with junior residents (chi2 = 15.9, df = 1, P < 0.001). There were 10 maternal and 60 perinatal deaths. CONCLUSIONS: The rate of caesarean section has been increasing gradually. There is need to improve on facilities and manpower in order to reduce morbidity and mortality. PMID- 26755215 TI - Finite element analysis of thermal stress distribution in different restorative materials used in class V cavities. AB - PURPOSE: Cervical lesions are restored with class V preparation. The aim of this study was to use a three-dimensional finite element method to carry out a thermal analysis of the temperature and stress distributions of three different restorative materials used for class V cavities of maxillary molar teeth. MATERIALS AND METHODS: A maxillary left first molar tooth was modeled and a class V cavity was prepared on the cervical 1/3 of the buccal surface. This cavity was restored with three different materials (Group I: Resin composite, Group II: Glass ionomer cement, and Group III: Amalgam). Loads of 400 N were applied at an angle of 90 degrees to the longitudinal axis of the tooth on the restorative material at 5 and 55 degrees C temperatures. Von Mises and thermal stress distributions were evaluated. RESULTS: In all groups, the von Mises stress values increased with temperature. The highest von Mises stress distribution was observed at 55 degrees C in Group II (144.53 MPa). The lowest von Mises stress distribution was observed at 5 degrees C in Group III (70.81 MPa). CONCLUSION: Amalgam is the most suitable restorative material for class V restorations because of minimal stress distribution. PMID- 26755216 TI - Comparative periodontal status of human immunodeficiency virus-positive patients and controls in a dedicated human immunodeficiency virus clinic in Nigeria. AB - BACKGROUND: There are diverse reports on the prevalence and severity of chronic periodontitis in human immunodeficiency virus (HIV) positive persons. Few studies have been carried out in developing countries in Sub-Saharan Africa. This study was aimed at comparing the prevalence and severity of chronic periodontitis of HIV-seropositive patients with that of HIV-seronegative persons using the community periodontal index (CPI). METHODOLOGY: This was a comparative study of the periodontal status of 110 HIV-positive subjects and 110 age and gender matched HIV-negative controls attending a dedicated HIV Clinic in a Teaching Hospital in Lagos, Nigeria. The CPI and simplified oral hygiene index score were used in the periodontal examination. Highest CPI scores and percentages of CPI sextants assessed the prevalence and severity of chronic periodontitis respectively. Logistic regression was used in adjusting demographic differences in the study population. P <= 0.05 was considered as significant. RESULTS: A significant proportion of the HIV-positive patients 61 (55.5%) and the HIV negative controls 53 (48.7%) had shallow pockets (4-5 mm) (CPI code 3). The prevalence of deep pockets (>= 6mm) (CPI code 4) was higher among HIV-positive patients 9 (8.2%) than the controls 4 (3.5%) (P = 0.079). HIV-positive patients had a greater percentage of CPI codes 3, 4 and fewer CPI code 0 sextants than controls (P = 0.000). Both groups had comparable oral hygiene status (P = 0.209). Using a logistic regression analysis, HIV-positive status and lower education accounted for the greater severity of chronic periodontitis. CONCLUSION: HIV seropositive patients had more severe chronic periodontitis than the HIV seronegative controls, which was independent of lower education. PMID- 26755218 TI - The efficiency of routine endotracheal aspirate cultures compared to bronchoalveolar lavage cultures in ventilator-associated pneumonia diagnosis. AB - OBJECTIVE: Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in Intensive Care Units (ICUs) and its mortality rate varies from 24% to 50%. The most important factor in decreasing the mortality is administering adequate antibiotics as early as possible. In this study, we investigate the efficiency of routine endotracheal aspirate (EA) cultures to identify the etiology of VAP earlier. MATERIALS AND METHODS: Fifty-nine patients who were accepted to our ICU with acute cerebrovascular disease with mechanical ventilation (MV) requirement were chosen for this study over a 12-month period. The patients intubated in our ICU were included in the study to exclude prior colonization. Upon ICU admission, the patient's; age, sex, comorbidities, diagnosis, acute physiology and chronic health evaluation II score, and sequential organ failure assessment (SOFA) score were recorded. When bronchoalveolar lavage (BAL) was performed, the SOFA score, temperature, leukocyte count, C-reactive protein levels, PaO2/FiO2ratio, PCO2, clinical pulmonary infection score value, length of MV, and presence of antimicrobiological treatments were recorded. Routine microbiological analysis was performed by EA (pre-VAP EA) twice weekly in all patients until the endotracheal tube was removed. When VAP was suspected, fiberoptic bronchoscopy examination with BAL was performed. A diagnosis of VAP was established when the BAL quantitative culture grew at least one microorganism at a concentration >=104 cfu/mL. RESULTS: VAP was diagnosed in 41 (69%) of the 59 patients based on BAL culture results. Among 41 positive BAL cultures, pre-VAP EA identified the same microorganism with the same antibiotics resistance pattern in 23 (56%) patients. Regarding only late-onset VAP, pre-VAP EA identified the same microorganisms found by BAL culture in 17 (63%) of the 27 cases. Among 18 BAL culture negative patients, 7 (39%) patients had negative prior pre-VAP EA culture results. Acinetobacter baumannii was the most frequently isolated microorganism from BAL cultures (n = 21, 51%). The diagnostic value of pre-VAP EA results in predicting A. baumannii VAP documented with the following values (sensitivity: 62%; specificity: 95%, positive predictive value: 87%, negative predictive value: 82%). CONCLUSION: VAP patients should be treated with international guidelines, but if pre-VAP EA cultures identify multidrug resistant pathogens, the initial antibiotic therapy should cover these microorganisms. Thus, quantitative EA cultures are a useful noninvasive diagnostic tool in critically ill patients suspected of having pneumonia especially in the case of VAP. PMID- 26755217 TI - Clinical features of emergency department patients with depression who had attempted to commit suicide by poisoning. AB - BACKGROUND: Many patients present to the emergency department (ED) complaining of intentional poisoning. Of those, some have major depressive disorder (MDD) in their medical history. The aim of this study was to investigate the prevalence of MDD patients who were treated for poisoning in the ED. MATERIALS AND METHODS: A retrospective review was performed on 268 patients who were treated with poisoning between July 2007 and November 2011. Of these patients, we only included those who were over 18 years of age. Information regarding age, gender, cause, time of ingestion, type of drug, history of attempting suicide, and outcome, among other characteristics, was collected and compared to patients who did not have MDD. RESULTS: A total of 244 patients were included in this study. Of those, 52 patients (21.3%) had a history of MDD. Compared to non-MDD patients, a majority (34.6% vs. 19.8%) of those in the MDD group had a history of suicide attempts (P = 0.027), and 34 (65.4% in the MDD group vs. 34.4% in the non-MDD group) took more than two types of drugs (P < 0.001). There were no differences in age, sex, time of ingestion or disease severity between MDD and non-MDD patients. CONCLUSION: In poisoning patients with MDD, physicians in the ED must consider that they have a higher tendency to show suicidal behavior and to have ingested multiple types of drugs. PMID- 26755219 TI - Comparative evaluation of mineral trioxide aggregate and bioaggregate as apical barrier material in traumatized nonvital, immature teeth: A clinical pilot study. AB - BACKGROUND: Clinical research examining the use of mineral trioxide aggregate (MTA) as an apical barrier material are limited, and no studies have so far examined the clinical performance of BioAggregate as apical barrier material in nonvital immature teeth. AIM: This study was aimed to provide a comparative evaluation of the clinical and radiographic success of MTA and BioAggregate as an apical barrier material in children with traumatized nonvital, immature permanent maxillary incisors. SUBJECTS AND METHODS: A total of 26 maxillary incisor teeth in 20 children aged 7-11 were chosen for this study. Teeth were randomly divided into two groups according to the material to be applied, and the apical barrier was performed. Following treatment, for 24-month, teeth were clinically and radiographically evaluated once every 3- and 6-month, respectively. RESULTS: All teeth treated with MTA and BioAggregate were clinically and radiographically successful throughout the 24-month follow-up period. CONCLUSIONS: Similar success was achieved in the apical barrier that using BioAggregate and MTA. BioAggregate would be considered suitable materials for apical barrier technique and can be used as an alternative to MTA. PMID- 26755220 TI - Graphical modeling for item difficulty in medical faculty exams. AB - BACKGROUND: There are different indexes used in the evaluation of exam results. One important index is the difficulty level of the item that is also used in this study to obtain control charts. This article offers some suggestions for the improvement of multiple-choice tests using item analysis statistics. MATERIALS AND METHODS: The graphical modeling is important for the rapid and comparative evaluation of test results. The control chart is a tool that can be used to sharpen our teaching and testing skills by inspecting the weaknesses of measurements and producing reliable items. The research data for the application of control charts were obtained using the results of the fourth and fifth-grade student's exams at Ondokuz Mayis University, Faculty of Medicine. I-chart or moving range chart (MR) is preferred for whole variable data. RESULTS: It is seen that all observations are within control limits for I-chart, but three points on MR-chart are settled on the LCL. Using X--chart with subgroups, it was determined that control measurements were within the upper and lower limits in both charts. The difficulty levels of items were examined by obtaining different variable control charts. The difficulty level of the two items exceeded the upper control limit in R- and S-charts. CONCLUSION: The control charts have the advantage for classifying items as acceptable or unacceptable based on item difficulty criteria. PMID- 26755221 TI - Pulmonary function tests in patients with Parkinson's disease: A case-control study. AB - BACKGROUND: In Parkinson's disease (PD), morbidity and mortality are commonly caused by respiratory disorders from pulmonary function impairments. AIM: The study aims to evaluate pulmonary functions in a cohort of patients with PD in comparison with age- and sex-matched control. METHODS: Pulmonary function test (PFT) was conducted using the Spirolab Spirometry kit, and results of forced vital capacity (VC), forced expiratory volume 1 (FEV1), FEV1/VC, and peak expiratory flow rate (PEFR) were obtained from 78 PD patients and 78 healthy controls. RESULTS: A total of 78 patients and 78 age- and sex-matched control comprising 60 (76.9%) males and 18 (23.1%) females were evaluated. The mean age +/- standard deviation of the patients were 62.32 +/- 8.67 and 62.31 +/- 8.66, respectively; the difference in their age was not statistically significant (P = 0.993). The majority (38.5%) of the patients was in stage II of Hoehn and Yahr of PD. Vital capacity (VC) in PD patients and control was 2.481 and 3.106; the difference was statistically significant (P < 0.0001). The mean FEV1 in PD patients and control were 1.887 and 2.494; the difference was statistically significant (P < 0.0001). The mean FEV1/VC percent in PD patients and control were 75.812 and 80.303; the difference was statistically significant (P < 0.0001). The mean PEFR in PD patients and control were 45.58 and 67.46; the difference was statistically significant (P < 0.0001). Considering PD arm of the study, with the exception of FEV1/VC, there was significant negative correlation between all the parameters of PFT and patients age (VC, FEV1, PEFR, r = -422 and P = 0.0001, r = -391 and P = 0.0001, and r = -0.244 and P = 0.031, respectively). CONCLUSION: In this study, the values of the evaluated PFTs (VC, FEV1, FEV1/VC, and PEFR) parameters were significantly lower in PD compared with age- and sex matched control. PMID- 26755222 TI - Apical extrusion of debris using reciprocating files and rotary instrumentation systems. AB - BACKGROUND: To compare the preparation time and amount of apically extruded debris after the preparation of root canals in extracted human teeth using the reciprocating files and rotary nickel-titanium systems. PROCEDURE: Sixty extracted human mandibular premolars were used. The root canals were instrumented using reciprocating (WaveOne, Reciproc, SafeSider) or rotary motion (Typhoon, ProTaper Universal, Mtwo), and the debris produced was collected in glass vials. The remaining debris was assessed using a microbalance and statistically analyzed using the one-way ANOVA and Duncan multiple range tests at a significance level of P < 0.05. The time required to prepare the canals with different instruments was also recorded. RESULTS: The Reciproc group produced significantly less debris when compared to the Typhoon group (P < 0.05), and instrumentation with the single-file systems was significantly faster than in the multi-file systems (P < 0.05). The WaveOne group extruded significantly more debris per unit of time than the other groups, with the exception of the Typhoon group (P < 0.05). CONCLUSION: According to our study, all systems caused apical debris extrusion. However, the Reciproc group was associated with less debris extrusion when compared to the other groups. PMID- 26755224 TI - Testicular volume of healthy term neonates: Determination of normative values among Igbo babies in South-Eastern Nigeria. AB - BACKGROUND: Testicular volume (TV) in neonates has some predictive values of clinical importance. Establishing the normal values of TV among term newborn males of every population is important as differences exist among different populations. Much is not known on TV among Igbo newborns. AIM: The aim of this study was to determine the normative values of TV in apparently healthy term Igbo newborn males in Enugu, South-Eastern Nigeria and its relationship with gestational age (GA), birth weight (BW), and birth length (BL). SUBJECTS AND METHODS: This was a hospital-based, cross-sectional and descriptive study. Eight hundred and eleven apparently healthy term Igbo male neonates within the first 3 days of life were studied. The TV was measured with Prader Orchidometer (ZKL-135 H), ESP Model. Smoothed centiles (3-97th percentile values) for TV by GA were determined. Data were analyzed using the Statistical Package for Social Sciences (SPSS) version 17.0 (Chicago). P < 0.05 were regarded as statistically significant. RESULTS: The mean TV was 1.74 +/- 0.62 ml ranging from 1 to 3 ml. The TV increased with increasing GA (P = 0.00). Pearson's correlation test between TV and birth length (r = 0.301, P = 0.001), as well as with BW (r = 0.247, P = 0.001) were significant. A linear regression demonstrated correlation between TV and birth length (P = 0.0001, r2 = 0.091). CONCLUSION: The mean TV among male Igbo newborn is 1.74 +/- 0.62 ml. Also, the first smoothed percentile values for TV by GA for Nigerian Igbo babies is created. PMID- 26755225 TI - Effect of sodium ascorbate and delayed treatment on the shear bond strength of composite resin to enamel following bleaching. AB - BACKGROUND: The effect of bleaching on enamel surfaces, as well as exploring methods of preventing the weakening of bond strength of two different adhesives to bleached enamel surfaces. OBJECTIVE: This study compared the shear bond strength (SBS) of two different adhesives on bleached enamel immediately after bleaching, with a 1-week delay, and following application of an antioxidizing agent after bleaching. Materilas and Method: The enamel surfaces of 140 incisors were divided into 14 groups. Two unbleached enamel groups (n = 20) were prepared as negative controls of the Adper Single Bond 2 total-etch and Clearfil Tri S Bond self-etch adhesives. The remaining surfaces were randomly divided into two bleaching groups treated with 35% Beyond Max (n = 60) and 38% Opalescence Xtra Boost (n = 60). Each bleaching group was then divided into two subgroups using the total and self-etch adhesive systems. Specimens were bonded immediately after bleaching, after treatment with 10% sodium ascorbate (SA) gel, or after 1-week of immersion in artificial saliva. All groups were restored with composite resin. After thermocycling, SBS was measured and data were analyzed. RESULTS: In the control groups, there was no statistically-significant difference in SBS between self-and total-etch adhesives. Among all bleaching groups, no statistically significant differences in SBS were noted, although the SA-treated delayed bonding (1-week) groups had the highest values. The lowest values were noted for the groups bonded immediately after bleaching. PMID- 26755223 TI - Medication education program for Indian children with asthma: A feasibility stud. AB - OBJECTIVE: It is postulated that children with asthma who receive an interactive, comprehensive, culturally relevant education program would improve their asthma knowledge (AK), asthma control, and adherence compared with children receiving usual care. The aim of this study was to develop, implement, and evaluate the efficacy of a culturally relevant asthma education intervention for children with asthma and their parents in India. METHODS: Children with asthma (7-12 years) and their parents were recruited from an outpatient clinic in a Chest Diseases Hospital in New Delhi, and were randomly assigned to either an intervention or usual care group. At baseline, outcome data collected included pediatric asthma caregiver quality of life (PACQL, primary outcome), AK, asthma control, adherence, inhaler technique, action plan ownership, and goal achievement. These data were collected again at 1 and 6 months after baseline. Outcomes were compared within and between groups using ANOVA techniques. RESULTS: Forty parent child pairs were recruited. Of these, 24 pairs of children with asthma and their parents received the educational intervention. The PACQL significantly improved from baseline to 6 months in the intervention (5.87 +/- 0.94-7.00 +/- 0.03) versus the usual care group (5.90 +/- 0.52-6.34 +/- 0.56) (P < 0.001). Other outcomes such as the parents' and child's AK, child's asthma control and inhaler technique were significantly improved in the intervention group across the study. All the participants possessed a written asthma action plan at the end of the intervention. Eighty-five goals were set by children with asthma across all the visits and were achieved by completion. CONCLUSION: An asthma educator delivered interactive program simultaneously involving children with asthma and their parents, improved quality of life, empowered and promoted better self-management skills. PMID- 26755227 TI - Socioeconomic inequities and payment coping mechanisms used in the treatment of type 2 diabetes mellitus in Nigeria. AB - AIM: Given the enormous economic burden of diabetes in Nigeria and in sub-Saharan Africa, the study was designed to determine how different population groups cope with payment for type 2 diabetes mellitus (DM). MATERIALS AND METHODS: A total of 292 exit interviews were conducted with patients who attended the outpatient diabetic clinic in a specialist public health facility in southeast Nigeria. The monthly expenditures and strategies that were used to cope with payments for diabetic treatment were determined. A socioeconomic status (SES) index was used to divide the respondents into SES quartiles (Q1 (poorest), Q2, Q3, Q4 (least poor)). The coping mechanisms were disaggregated by SES. RESULTS: The mean monthly expenditure for the treatment of diabetes was ?56,245.11 ($356). Expenditures were mostly incurred through out-of-pocket payments. The most common coping strategy utilized was household savings (99.0%) followed by support from family members (85.3%). All SES groups used more than one payment coping method. Borrowing, skipping of appointments, and stopping children education were significantly significant (P < 0.05). CONCLUSION: The mean monthly direct cost in the treatment of type 2 diabetes among the study group was high. There were SES inequities in the use of coping mechanisms, with the poorest SES group (Q1) being worse off than other groups. The financial risk protection mechanisms such as health insurance that will reduce the economic burden of type 2 diabetes on households and provide universal health coverage to people suffering from DM more especially to the disadvantaged group should be developed and implemented. PMID- 26755228 TI - Patients attitudes to vaginal examination and use of chaperones at a public hospital in South Africa. AB - BACKGROUND: Obstetrics and gynecology units in public hospitals in South Africa (SA) are often overloaded with patients. Most physical examinations/consultations in these units involve vaginal examination (VE) and often because of the rapid turnover of patients the pelvic examination may be performed hurriedly without due consideration being given to the psychosocial aspects of such procedures. OBJECTIVE: This study surveyed the attitudes of patients to VE and the use of chaperones. METHODS: A descriptive cross-sectional survey of patients attending obstetrics and gynecology clinics at a public hospital in SA was carried out. A structured questionnaire was used to collect sociodemographic data such as age, ethnic group, gravidity, feelings toward VE, and preferences about the gender of the examining doctor, as well as the presence of a chaperone. RESULTS: Most women (68%) were aged between 20 and 35 years. The respondents stated that the most intimate examination was VE in 48.3% and abdominal in 25% of cases; 19.0% and 1.5% of respondents felt that breast and rectal examinations, respectively, was the most intimate. On the response to the statement "there is no need for chaperone during VE;" 54% of the participants were in support of chaperone while 45.1% were against chaperone. Women aged 20-35 years, preferred a nurse as their chaperone; younger women, aged <=19 years preferred their mother as a chaperone. CONCLUSION: In an SA public hospital, women are more likely to regard VE as the most intimate examination. Women are equivocal on the use of a chaperone and if it was necessary; nurses are their preferred choice except for teenagers, who preferred their mothers. PMID- 26755226 TI - Beneficial effects of hesperidin following cis-diamminedichloroplatinum-induced damage in heart of rats. AB - BACKGROUND: Increased oxidative stress and histopathological damage have been implicated in the cardiotoxicity that limits the clinical therapy of cisplatin (CP) as an anti-cancer drug. OBJECTIVES: This study aimed to investigate the protective effect of hesperidin (HP) against CP-induced cardiotoxicity in rats. MATERIALS AND METHODS: Rats were divided into four groups (n = 7/group), and the first group served as the control group. Animals in Group CP and Group CP + HP received a single dose of CP (CP - 7 mg/kg); animals in Group HP and Group CP + HP received 50 mg/kg/day HP with gavage for 14 days. At the end of day 14, cardiac tissue samples were histologically and biochemically examined. RESULTS: In this experimental study, thiobarbituric acid reactive substances levels in the cardiac tissue were significantly higher in the CP group, whereas glutathione (GSH), superoxide dismutase (SOD), and CAT levels were significantly lower in this group. On the other hand, GSH and SOD levels in the CP + HP group were similar to the control group. There was no significant difference in cardiac CAT levels between Group CP and Group CP + HP. CONCLUSION: Hesperetin treatment leads to a decrease in oxidative stress, and associated histological damage. The findings of the current study suggest that HP has a protective effect against CP induced cardiotoxicity. PMID- 26755229 TI - The effect of colloid preload versus prophylactic ephedrine administration on QTc intervals during cesarean delivery: A randomized controlled study. AB - AIM: We aimed to investigate the effect of colloid infusion immediately before the spinal anesthesia, and the prophylactic intravenous (IV) infusion of ephedrine after injection of intrathecal bupivacaine on hemodynamic parameters, QT, The QT interval corrected for heart rate (QTc), and dispersion of QTc (QTcDisp) intervals in women undergoing the elective cesarean section. MATERIALS AND METHODS: Sixty women scheduled for elective cesarean delivery with spinal anesthesia were allocated randomly to receive either IV fluid preloading with 0.5 L of 6% w/v hydroxyethyl starch solution immediately before the spinal anesthesia (colloid group, n = 30) or prophylactic IV infusion of 15 mg ephedrine (diluted with 10 ml saline, n = 30) over 1-min period after the injection of intrathecal bupivacaine (ephedrine group). Electrocardiography (ECG) tracings were recorded before anesthesia procedure at baseline (T0), 5 min (T1), 10 min (T2), 30 min (T3), 60 min (T4), and 120 min (T5) after the spinal anesthesia. Systolic blood pressure, diastolic blood pressure, mean arterial pressure (MAP), heart rate (HR), and peripheral oxygen saturation (SpO2) values were also recorded at the same time intervals. RESULTS: There were no significant differences between groups with respect to MAP, HR, SpO2, QT, and QTc intervals at any time points (P > 0.05). When compared with the colloid group, the QTcDisp interval at T1was significantly longer in the ephedrine group (P < 0.05). CONCLUSION: Both methods have similar effects on the ECG and hemodynamic parameters during cesarean section. So, both methods may be used in patients undergoing elective cesarean delivery under spinal anesthesia. PMID- 26755230 TI - Neuroimaging findings in pediatric patients with seizure from an institution in Enugu. AB - BACKGROUND: Pediatric seizures in developing countries are often poorly investigated and consequently poorly managed. Sociocultural misconceptions, financial difficulties, and lack of facilities are often blamed. This study studies the structural intracranial abnormalities associated with pediatric seizures and the proportion of these structural lesions that may benefit from surgery. METHODS: Prospective study of 311 pediatric patients referred with seizure disorders, for computed tomography and magnetic resonance imaging to the Memfys Hospital for Neurosurgery, Enugu, between 2003 and 2014. All patients had contrast studies. Angiography was done for selected cases. Demography, imaging findings, and potential benefits of surgery were analyzed using descriptive and inferential statistics. RESULT: Analysis of 311 patients representing 21% of all pediatric head scans. Male to female ratio was 1.2:1.0. Definite structural lesion was identified in 53.4%. Lesions that may benefit from surgery were identified in 27.7% of all cases representing 51.8% of abnormal scan findings. Under-5 had the least scan rate of 25.1% compared with 42.4% in the adolescents. Although the older age groups had more abnormal findings, the proportion of abnormal to normal scan findings was the highest (1.7:1.0) in the under-5. Under 5 age group had more lesions that may benefit from surgery (P = 0.001). Intracranial tumor was diagnosed in 10.6%, vascular abnormalities (10.3%), hydrocephalus (5.8%), brain abscess (2.9%), and chronic subdural hematoma (2.6%) (P = 0.001). CONCLUSION: Structural lesions are common and diverse in pediatric seizures. Significant proportion of these patients may benefit from surgery, and these benefits override financial and sociocultural considerations. PMID- 26755231 TI - Oxidative stress among subjects with metabolic syndrome in Sokoto, North-Western Nigeria. AB - BACKGROUND: Oxidative stress is known to play a role in the pathophysiology of metabolic syndrome and its components. Racial differences may exist in the level of markers of oxidative stress and antioxidants in patients with metabolic syndrome. AIM: The aim of this study was to determine the oxidative stress and antioxidants status in subjects with metabolic syndrome in Sokoto, North-Western Nigeria. METHODS: A cross-sectional community-based study was carried out. Two hundred subjects (96 males and 104 females) were recruited for the study using a multi-stage sampling technique. Demographic data were obtained from the participants. Evaluation of anthropometric variables, blood pressure, blood glucose levels, lipid profiles, plasma insulin levels, total antioxidant status, and oxidative stress markers was performed. RESULTS: The subjects with metabolic syndrome had significantly higher malondialdehyde as compared to those without metabolic syndrome (236.4 [92.2] vs. 184 [63.2] nmol/l). The antioxidant enzymes (superoxide dismutase, glutathione peroxidase and catalase) were significantly lower in subjects with metabolic syndrome than in those without metabolic syndrome (11.3 [4.2] vs. 13.9 [4.1] U/ml, 160[42] vs. 220[32] U/ml, and 2.12 [0.2] vs. 2.42 [0.2] U/ml, respectively). Similarly, the antioxidant Vitamins (A, C, and E) levels were significantly lower in subjects with metabolic syndrome than in those without metabolic syndrome (7.1 [4.1] vs. 7.7 [4.2] MUmol/L, 225 [55.3] vs. 227.6 [62.3] MUmol/L, and 75.9 [13.9] vs. 82.8 [18.6] mg/dl, respectively). There was a positive correlation between components of metabolic syndrome and free radicals. CONCLUSION: Significantly increased oxidative stress and diminished antioxidant defenses were found among Nigerians with metabolic syndrome. PMID- 26755232 TI - Virologic responses and tolerance of peginterferon alfa plus ribavirin treatment for patients with chronic hepatitis C virus infection in different age categories. AB - OBJECTIVE: This study aimed to evaluate the effect of age on the treatment comprising peginterferon plus ribavirin administered to patients with chronic hepatitis C (CHC). MATERIALS AND METHODS: A total of 314 patients with CHC treated with peginterferon plus ribavirin were classified into three categories according to age. The efficacy and safety outcomes were compared between groups. RESULTS: Elderly patients yielded significantly lower rapid virological response and sustained virological response (SVR) (31.3% and 35.4%, respectively, P < 0.05) rates than younger patients. The discontinuation rate of the patients aged >= 60 years were significantly higher (29.2%, P = 0.004) than that of the younger patients. The elderly patients suffered from adverse events, such as fatigue (P = 0.005), neutropenia (P = 0.013), jaundice (P = 0.013), hepatocellular carcinoma (P = 0.013), and gastric cancer (P = 0.018), more frequently than the younger patients. In multivariable analysis, age was a negative factor that affected the SVR of the patients with CHC (odds ratio [OR] =0.983, 95% confidence interval [95% CI] =0.967-1.0, P = 0.05). The SVR rate of the patients with hepatitis C virus (HCV) genotype non-1 was significantly higher than that of the patients with HCV-1 (OR = 0.559, 95% CI = 0.349-0.895, P = 0.015). An early virological response could be considered as a powerful positive predictor to obtain an SVR (OR = 2.353, 95% CI = 1.411-3.922, P = 0.001). CONCLUSIONS: Increasing age negatively affected the efficacy of peginterferon and ribavirin therapy in the treatment of patients with CHC. Elderly patients experienced poorer treatment tolerance and adherence, and as a result, treatment efficacy is poor. PMID- 26755233 TI - Biomechanical analysis of titanium fixation plates and screws in sagittal split ramus osteotomies. AB - OBJECTIVE: The aim of the study was to evaluate the mechanical behavior of three different fixation methods used in the bilateral sagittal split ramus osteotomy. MATERIALS AND METHODS: Three different three-dimensional finite element models were created, each corresponding to three different fixation methods. The mandibles were fixed with double straight 4-hole, square 4-hole, and 5-hole Y plates. 150 N incisal occlusal loads were simulated on the distal segments. ANSYS software ((v 10; ANSYS Inc., Canonsburg, PA) was used to calculate the Von Mises stresses on fixative appliances. RESULTS: The highest Von Mises stress values were found in Y plate. The lowest values were isolated in double straight plate group. CONCLUSIONS: It was concluded that the use of double 4-hole straight plates provided the sufficient stability on the osteotomy site when compared with the other rigid fixation methods used in this study. PMID- 26755234 TI - Co-morbid obsessive compulsive and hypochondriac disorders complicated by tardive dyskinesia in a Nigerian man. AB - The objective was to report a case of obsessive-compulsive disorder (OCD) with comorbid somatic symptoms that was complicated by movement disorders. A literature search on related issues was done online with Google Scholar, followed by a chronological report of the index case. This case presents a 52-year-old man who presented with intrusive, disturbing, and unreasonable thoughts at the mid adolescent time. Following these were complaints of multiple somatic symptoms which the patient labeled with different disease terms. The illness affected his academic, occupational, social, and marital role obligations. And lately, in the illness due to underlying predispositions, developed drug-related movement problems that worsened his state of handicap. This case attempts to point out the importance of early detection and cautious use of medications in patients, who present with OCDs with or without other psychiatric co-morbidities. PMID- 26755235 TI - Peripheral gangrene in a case of severe dengue. AB - We report the case of a 10-year-old male who developed gangrene of his fingers and toes following severe dengue fever complicated by disseminated intravascular coagulation (DIC). Child developed bilateral dry gangrene of fingers and toes. All the peripheral pulses of the affected limbs were palpable. The child had no history of taking B-blockers, ergot alkaloids or other related medications. Color Doppler of peripheral arterial and venous systems of all limbs indicated normal flow. Blood was positive for D-dimers and fibrin degradation products. The patient was managed with broad spectrum antibiotics, fluid resuscitation, low molecular weight heparin, blood transfusions, fresh frozen plasma and other supportive measures. Peripheral gangrene seen in DIC associated with dengue is very rare and carries a higher mortality. PMID- 26755236 TI - Osteoblastoma originating from frontoethmoidal sinus causing personality disorders and superior gaze palsy. AB - Osteoblastoma is a rare, solitary benign tumor that is usually situated in axial skeleton mainly in vertebra. It is rarely seen in ethmoid and frontal sinuses. A 40-year-old man who had osteoblastoma originated from frontal and ethmoidal sinuses that extends up to frontal lobe and gave rise to personality disorders by compressing the frontal lobe, and caused superior gaze palsy by compressing the superior rectus muscle. We present this rare case with clinical, radiological and histopathological findings. PMID- 26755237 TI - Determining in vivo elasticity and viscosity with dynamic Scheimpflug imaging analysis in keratoconic and healthy eyes. AB - The paper presents a novel analysis method of corneal elasticity and viscosity based on corneal visualization Scheimpflug technology (CorVis ST) for keratoconus diagnosis. Methods for air puff force measurement and corneal imaging boundary extraction were proposed. Corneal biomechanical properties, described as tangent stiffness coefficient (STSC ) and energy absorbed area (Aabsorbed ), were assessed using the curves of the applied air puff force with corneal displacement to form a loading-unloading cycle. Twenty-five patients with keratoconus and 34 healthy control subjects, matched for intraocular pressure (IOP), were enrolled in this prospective study. The results showed that the intraclass correlation coefficients (ICC) of the STSC and Aabsorbed were 0.941 and 0.878 in Healthy group; and were 0.891 and 0.809 in Keratoconus group, respectively. Both STSC and Aabsorbed of keratoconus patients were significantly different from that of controls (both probability value P < 0.001). ROC curve analysis showed that the area under curve for STSC was 0.918 and for Aabsorbed was 0.894, which reached a good level of predictive accuracy for detecting keratoconus. Our results demonstrated that this new analysis method could be used to characterize the biomechanical properties of corneas. (a) The air puff force of CorVis ST was measured by a custom-designed force detection system. (b) Corneal displacement was extracted from CorVis ST using a proposed imaging analysis. (c) With the utilization of the air puff force and corneal dynamic displacement, an analysis method was developed to introduce new corneal biomechanical parameters - STSC and Aabsorbed . PMID- 26755239 TI - A New Face at the Door.... PMID- 26755238 TI - Evaluation of Breast Cancer Knowledge and Awareness Among Hospital Staff in a Women Heath Hospital in Turkey. AB - The purpose of this study was to examine breast cancer prevention knowledge, beliefs, and information sources among people which are employed in healthcare system including nurses and hospital staff. A cross-sectional survey was conducted among hospital staff of the largest women health hospital in Turkey. Self-administered questionnaires were delivered to participants. A total of 200 hospital staff participated to the study with a response rate of 80.5 %. One-way ANOVA with post-hoc Tukey test was used for multiple comparisons. The results showed that the overall knowledge of hospital staff about breast cancer is inadequate. The mean total knowledge score of the participants was approximately 60 %. The overall mean score of the survey for all participants was 16.69 (SD, 3.12) out of 27. Significant difference was detected in mean total score among educational levels. Education and increasing awareness about the disease can be identified as the major determinants for improving the percentages of early diagnosis and decreasing the mortality rates. Hospital staff education should be the key target for increasing the awareness of whole population especially for developing countries. PMID- 26755240 TI - Isolation and identification of Bacillus megaterium YB3 from an effluent contaminated site efficiently degrades pyrene. AB - Industrial effluents contaminated sites may serve as repositories of ecologically adapted efficient pyrene degrading bacteria. In the present study, six bacterial isolates from industrial effluents were purified using serial enrichment technique and their pyrene degrading potential on pyrene supplemented mineral salt medium was assessed. 16S rRNA sequence analysis showed that they belong to four bacterial genera, namely Acinetobacter, Bacillus, Microbacterium, and Ochrobactrum. Among these isolates, Bacillus megaterium YB3 showed considerably good growth and was further evaluated for its pyrene-degrading efficiency. B. megaterium YB3 could degrade 72.44% of 500 mg L(-1) pyrene within 7 days. GC-MS analysis of ethyl acetate extracted fractions detected two relatively less toxic metabolic intermediates of the pyrene degradation pathway. B. megaterium YB3 also tested positive for catechol 1, 2-dioxygenase and aromatic-ring-hydroxylating dioxygenase indole-indigo conversion assays. Considering the ability and efficiency of B. megaterium YB3 to degrade high pyrene content, the strain can be used as a tool to develop bioremediation technologies for the effective biodegradation of pyrene and possibly other PAHs in the environment. PMID- 26755242 TI - Primary Cardiac Lymphoma: Diagnosis and the Impact of Chemotherapy on Cardiac Structure and Function. AB - We report a case of primary cardiac lymphoma presenting as myopericarditis and rapidly deteriorating into biventricular heart failure and ventricular arrhythmias. Computed tomography and cardiac magnetic resonance (CMR) imaging showed extensive myocardial infiltration with typical patterns on tissue characterization CMR images, raising clinical suspicion. Diagnosis was confirmed by myocardial histologic examination. Marked regression of tumor burden was apparent after 6 cycles of anthracycline-based chemotherapy. This case illustrates that a high degree of suspicion for this rare entity is mandated to institute timely treatment. Rapid tumor lysis may induce life-threatening acute cardiac decompensation that requires intensive monitoring and support therapy. PMID- 26755243 TI - Left Atrial Appendage Closure for Atrial Fibrillation: A Story Still Being Written. PMID- 26755241 TI - Direct Actions of Kisspeptins on GnRH Neurons Permit Attainment of Fertility but are Insufficient to Fully Preserve Gonadotropic Axis Activity. AB - Kisspeptins, ligands of the receptor, Gpr54, are potent stimulators of puberty and fertility. Yet, whether direct kisspeptin actions on GnRH neurons are sufficient for the whole repertoire of their reproductive effects remains debatable. To dissect out direct vs. indirect effects of kisspeptins on GnRH neurons in vivo, we report herein the detailed reproductive/gonadotropic characterization of a Gpr54 null mouse line with selective re-introduction of Gpr54 expression only in GnRH cells (Gpr54(-/-)Tg; rescued). Despite preserved fertility, adult rescued mice displayed abnormalities in gonadal microstructure, with signs of precocious ageing in females and elevated LH levels with normal-to low testosterone secretion in males. Gpr54(-/-)Tg rescued mice showed also altered gonadotropin responses to negative feedback withdrawal, while luteinizing hormone responses to various gonadotropic regulators were variably affected, with partially blunted relative (but not absolute) responses to kisspeptin-10, NMDA and the agonist of tachykinin receptors, NK2R. Our data confirm that direct effects of kisspeptins on GnRH cells are sufficient to attain fertility. Yet, such direct actions appear to be insufficient to completely preserve proper functionality of gonadotropic axis, suggesting a role of kisspeptin signaling outside GnRH cells. PMID- 26755244 TI - Urgent Transcatheter Aortic Valve Implantation in Patients With Severe Aortic Stenosis and Acute Heart Failure: Procedural and 30-Day Outcomes. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is recommended for patients with severe symptomatic aortic stenosis (AS) who are at prohibitive/high risk for surgical aortic valve replacement (SAVR). Patients with severe AS may experience acute decompensated heart failure (HF) that is resistant to medical therapy. We report our TAVI experience in treating patients with unstable AS who require urgent intervention for their aortic valve disease. METHODS: Patients were restrictively included in the urgent TAVI registry if they were admitted with acute refractory and persistent HF despite medical therapy and had TAVI performed during the same hospital stay. All others were included in the elective TAVI group. RESULTS: Between November 2008 and April 2015, 410 consecutive patients underwent TAVI at our centre-27 (6.6%) urgently. Patients operated on urgently were more likely to be frail and carry higher SAVR mortality risk based on The Society of Thoracic Surgeons Predicted Risk of Mortality/logistic EuroSCORE (LES) measures. Pulmonary edema was the most common clinical presentation. Preprocedural assessment used fewer imaging modalities, yet implantation success remained high and reached 96.3% using an additional valve (valve-within-valve) required in 3 patients, with no difference in periprocedural complications according to the Valve Academic Research Consortium-2 definitions. Although 30-day functional capacity was reduced, patients had similar 30-day mortality and major adverse cardiovascular event rates compared with patients who underwent elective TAVI. CONCLUSIONS: Short-term outcome after urgent TAVI appears to be reasonable. For patients with severe AS who experience acute decompensated HF that is recalcitrant to optimal medical therapy and who are at high risk with SAVR, urgent TAVI may be a viable treatment strategy. Larger prospective studies and data on long-term outcomes are needed. PMID- 26755245 TI - Preterm premature rupture of membrane assessment via transperineal ultrasonography: a diagnostic accuracy study. AB - OBJECTIVE: The objective of this study is to evaluate diagnostic accuracy of transperineal ultrasound assessment compared to speculum examination by using placental alfa-microglobulin (PAMG)-1 tests as reference. METHODS: This was a prospective observational study conducted in Ankara University Hospital. Women with early and late preterm pregnancies with suspected rupture of membranes, i.e. women with a complaint of fluid leakage (105 in total) were enrolled. Prior to speculum examination, sagittal and transverse plane views of the fornices and cervix were obtained via transperineal ultrasonography and images were stored. Then the speculum examination for amniotic fluid pooling was performed. Definite diagnoses were made with PAGM-1 assays. After collection of the data, ultrasound images were analyzed by an observer blind to physical examination findings. Hypoechogenic fluid appearance around the cervix and in the fornices was considered positive for preterm premature rupture of membranes (PPROM). Results of physical and ultrasound examination were compared with PAMG-1 test as a reference method. The diagnostic performance of transperineal ultrasound was tested with accuracy parameters and receiver-operating characteristics (ROC) curves. Inter-rater reliability was analyzed with Cohen's kappa. RESULTS: In total, 103 pregnant women were evaluated. The prevalence of PPROM in our study population was 43.14%. At a 5 mm diagnostic threshold, the sensitivity and specificity values of transperineal assessment were 95.45% (95% CI: 84.50-99.31%) and 96.55% (95% CI: 88.07-99.48%), respectively, and they were comparable with speculum examination in a population of preterm pregnant women with suspected PPROM (p > 0.05). Interobserver reliability analysis with Cohen's kappa has shown good very good agreement with the kappa value of 0.93 (95% CI 0.87-1.00). CONCLUSIONS: Transperineal ultrasonography is a novel method that can be used to assess vaginal pooling of amniotic fluid. Ultrasonography offers similar sensitivity and specificity compared with speculum examination and it is non invasive. PMID- 26755246 TI - Commencement Address Delivered to Medical Graduates of Ramaiah Medical College in 2014. PMID- 26755247 TI - Editorial-Integrative Pediatrics is Good Medicine. PMID- 26755260 TI - Preface. PMID- 26755257 TI - The Effects of Severe Hypoxia on Glycolytic Flux and Enzyme Activity in a Model of Solid Tumors. AB - Solid tumors contend with, and adapt to, a hostile micro-environment that includes limited availability of nutrient fuels and oxygen. The presence of hypoxia (O2 <5%) stabilizes the transcription factor Hif1 and results in numerous cellular adaptations including increased flux of glucose through glycolysis. Increasingly, more sophisticated analysis of tumor oxygenation has revealed large gradients of oxygen tension and significant regions under severe hypoxia (O2 ~0.1%). The present investigation has demonstrated a significant increase in the glycolytic flux rate when tumor spheroids were exposed to 0.1% O2 . The severe hypoxia was associated with uniform pimonidazole adduct formation and elevated levels of Hif1alpha and c-Myc. This resulted in elevated expression of GLUT and MCT transporters, in addition to increased activity of PFK1 in comparison to that observed in normoxia. However, the protein expression and enzymatic capacity of HK2, G6PDH, PK, and LDH were all reduced by severe hypoxia. Clearly, the effects of exposure to severe hypoxia lead to a significantly abridged Hif1 response, yet one still able to elevate glycolytic flux and prevent loss of intermediates to anabolism. J. Cell. Biochem. 117: 1890-1901, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26755261 TI - Introduction. PMID- 26755259 TI - Chronic medical conditions in adult survivors of retinoblastoma: Results of the Retinoblastoma Survivor Study. AB - BACKGROUND: Limited data are available regarding long-term morbidity in adult survivors of retinoblastoma (Rb). METHODS: The Retinoblastoma Survivor Study is a retrospective cohort of adult survivors of Rb diagnosed between 1932 and 1994. Participants completed a comprehensive questionnaire adapted from the Childhood Cancer Survivor Study surveys. Chronic conditions were classified using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 4.03). Multivariate Poisson regression was used to compare survivors of Rb with 2377 non-Rb controls, consisting of the Childhood Cancer Survivor Study sibling cohort and survivors with bilateral versus unilateral disease. RESULTS: Survivors of Rb (53.6% with bilateral disease) and non-Rb controls had a mean age of 43.3 years (standard deviation, 11 years) and 37.6 years (SD, 8.6 years), respectively, at the time of study enrollment. At a median follow-up of 42 years (range, 15-75 years), 86.6% of survivors of Rb had at least 1 condition and 71.1% had a severe/life-threatening (grade 3-4) condition. The adjusted relative risk (RR) of a chronic condition in survivors compared with non-Rb controls was 1.4 (95% confidence interval [95% CI], 1.3-1.4; P<.01); for a grade 3 to 4 condition, the RR was 7.6 (95% CI, 6.4-8.9; P<.01). Survivors were at an excess risk regardless of laterality. After stratifying by laterality and excluding ocular conditions and second malignant neoplasms (SMNs), only those with bilateral disease were found to be at an increased risk of any nonocular, non-SMN condition (RR, 1.2; 95% CI, 1.1-1.2) and for grade 3 to 4 nonocular, non-SMN conditions (RR, 1.7; 95% CI, 1.2-2.5). CONCLUSIONS: Survivors of Rb have an increased risk of chronic conditions compared with non-Rb controls. After excluding ocular conditions and SMNs, this excess risk was found to persist only for those with bilateral disease. Cancer 2016;122:773-781. (c) 2016 American Cancer Society. PMID- 26755262 TI - Kidney. AB - Kidney transplant provides significant survival, cost, and quality-of-life benefits over dialysis in patients with end-stage kidney disease, but the number of kidney transplant candidates on the waiting list continues to grow annually. By the end of 2014, nearly 100,000 adult candidates and 1500 pediatric candidates were waiting for kidney transplant. Not surprisingly, waiting times also continued to increase, along with the number of adult candidates removed from the list due to death or deteriorating medical condition. Death censored graft survival has increased after both living and deceased donor transplants over the past decade in adult recipients. The majority of the trends seen over the past 5 years continued in 2014. However, the new allocation system was implemented in late 2014, providing an opportunity to assess changes in these trends in the coming years. PMID- 26755263 TI - Pancreas. AB - Even though pancreas transplant numbers have steadily declined over the past decade, new listings increased in 2014 compared with the previous year, notably for pancreas transplant alone (PTA) and simultaneous pancreas-kidney transplant. The number of new PTAs also increased over the past two years. Whether this is a sustainable trend remains to be seen. Significant events in 2014 included implementation of a new pancreas allocation system and development of a proposed uniform definition of pancreas graft failure. Meanwhile, overall pancreas transplant rates and outcomes continued to improve. Substantial decline in pancreas after kidney transplants remains a serious concern. SRTR has not published pancreas graft failure data in the program-specific reports for the past two years. While this will not change in the near future, the acceptance of a uniform definition of graft failure is a crucial first step toward resuming graft failure reporting. Continued improvements and innovation, both surgical and immunological, will be critical to keep pancreas transplant as a viable option for treatment of insulin-dependent diabetes. As alternative therapies for diabetes such as islet transplant and artificial pancreas are evolving, improved outcomes with minimizations of complications are more important than ever. PMID- 26755264 TI - Liver. AB - The median waiting time for patients with MELD >= 35 decreased from 18 days in 2012 to 9 days in 2014, after implementation of the Share 35 policy in June 2013. Similarly, mortality among candidates listed with MELD >= 35 decreased from 366 per 100 waitlist years in 2012 to 315 in 2014. The number of new active candidates added to the pediatric liver transplant waiting list in 2014 was 655, down from a peak of 826 in 2005. The number of prevalent candidates (on the list on December 31 of the given year) continued to decline, 401 active and 173 inactive. The number of deceased donor pediatric liver transplants peaked at 542 in 2008 and was 478 in 2014. The number of living donor liver pediatric transplants was 52 in 2014; most were from donors closely related to the recipients. Graft survival continued to improve among pediatric recipients of deceased donor and living donor livers. PMID- 26755265 TI - Intestine. AB - Intestine and intestine-liver transplant plays an important role in the treatment of intestinal failure, despite decreased morbidity associated with parenteral nutrition. In 2014, 210 new patients were added to the intestine transplant waiting list. Among prevalent patients on the list at the end of 2014, 65% were waiting for an intestine transplant and 35% were waiting for an intestine-liver transplant. The pretransplant mortality rate decreased dramatically over time for all age groups. Pretransplant mortality was highest for adult candidates, at 22.1 per 100 waitlist years compared with less than 3 per 100 waitlist years for pediatric candidates, and notably higher for candidates for intestine-liver transplant than for candidates for intestine transplant without a liver. Numbers of intestine transplants without a liver increased from a low of 51 in 2013 to 67 in 2014. Intestine-liver transplants increased from a low of 44 in 2012 to 72 in 2014. Short-gut syndrome (congenital and other) was the main cause of disease leading to both intestine and intestine-liver transplant. Graft survival improved over the past decade. Patient survival was lowest for adult intestine-liver recipients and highest for pediatric intestine recipients. PMID- 26755266 TI - Heart. AB - As the number of candidates listed for heart transplant continues to rise, it is encouraging that the number of heart transplants also continues to rise steadily each year. Evaluation of waitlist activity demonstrates a growing number of adult candidates removed from the list due to undergoing transplant, but also growing numbers of adult candidates added to the list over the past 3 years. In 2014, 2679 heart transplants were performed, an increase of 28.4% since 2003, and the number of people living with a transplanted heart continued to increase. The number of new pediatric candidates added to the heart transplant waiting list increased to 593 in 2014. The number of pediatric heart transplants performed each year increased from 293 in 2003 to 410 in 2014. Almost 60% of pediatric candidates waiting on December 31, 2014, had been waiting for less than 1 year, compared with 43.0% in 2004. Among pediatric patients who underwent transplant in 2008-2012, overall cumulative incidence of death at 1, 3, and 5 years was 9.2%, 14.7%, and 18.3%, respectively. PMID- 26755267 TI - Lung. AB - Lungs are allocated to adult and adolescent transplant candidates (aged >= 12 years) on the basis of age, geography, blood type compatibility, and the lung allocation score (LAS), which reflects risk of waitlist mortality and probability of posttransplant survival. In 2014, 2458 active candidates aged 12 years or older, the most of any year, were added to the list; 1949 transplants were performed. Overall median waiting time to transplant for candidates listed in 2014 was 3.7 months. Candidates undergoing lung transplant in 2014 were sicker than ever before with median LAS 44.4. Measures of short-term survival continue to improve; however, long-term survival has plateaued since the implementation of the LAS in 2005; at 5 years posttransplant, 42.4% of recipients had died. In 2014, 30 new active child (ages 0-11) candidates were added to the list; 19 transplants were performed. Incidence of patient death was 7.1% at 6 months and 10.8% at 1 year for transplants in 2013, 29.7% at 3 years for transplants in 2009 2010, and 42.7% at 5 years for transplants in 2007-2008. By age, 5-year patient survival was poorest for recipients aged younger than 1 year. PMID- 26755268 TI - Economics. AB - While the costs to Medicare of solid organ transplants are varied and considerable, the total Medicare expenditure of $4.2 billion for solid organ transplant recipients in 2013 remains less than 1% of all Medicare expenditures. Kidney transplant remains one of the most cost-effective surgical interventions in medicine and exhibits a rare feature in that it is generally known to be cost saving in the long term. For patients covered by Medicare, lung transplant is one of the more costly solid organ transplants performed. This chapter reports pretransplant costs for lung candidates to allow investigators to further explore the relative cost of lung transplant compared with alternative management. PMID- 26755269 TI - Deceased Organ Donation. AB - SRTR uses data collected by OPTN to calculate metrics such as donation/conversion rate, organ yield, and rate of organs recovered for transplant but not transplanted. In 2014, 9252 eligible deaths were reported by organ procurement organizations, a slight increase from 8944 in 2012, and the donation/conversation rate was 73.4 eligible donors per 100 eligible deaths, a slight increase from 71.3 in 2013. Some metrics show variation across organ procurement organizations, suggesting that sharing best practices could lead to gains in efficiency and organ retrieval. PMID- 26755270 TI - Comment on "Chemoradiotherapy regimens for locoregionally advanced nasopharyngeal carcinoma: a Bayesian network meta-analysis", published in Eur J Cancer 51 (2015), 1570-1579. PMID- 26755271 TI - Acoustofluidic particle manipulation inside a sessile droplet: four distinct regimes of particle concentration. AB - In this study, we have investigated the motion of polystyrene microparticles inside a sessile droplet of water actuated by surface acoustic waves (SAWs), which produce an acoustic streaming flow (ASF) and impart an acoustic radiation force (ARF) on the particles. We have categorized four distinct regimes (R1-R4) of particle aggregation that depend on the particle diameter, the SAW frequency, the acoustic wave field (travelling or standing), the acoustic waves' attenuation length, and the droplet volume. The particles are concentrated at the centre of the droplet in the form of a bead (R1), around the periphery of the droplet in the form of a ring (R2), at the side of the droplet in the form of an isolated island (R3), and close to the centre of the droplet in the form of a smaller ring (R4). The ASF-based drag force, the travelling or standing SAW-based ARF, and the centrifugal force are utilized in various combinations to produce these distinct regimes. For simplicity, we fixed the fluid volume at 5 MUL, varied the SAW actuation frequency (10, 20, 80, and 133 MHz), and tested several particle diameters in the range 1-30 MUm to explicitly demonstrate the regimes R1-R4. We have further demonstrated the separation of particles (1 and 10 MUm, 3 and 5 MUm) using mixed regime configurations (R1 and R2, R2 and R4, respectively). PMID- 26755272 TI - Conformation-controlled binding kinetics of antibodies. AB - Antibodies are large, extremely flexible molecules, whose internal dynamics is certainly key to their astounding ability to bind antigens of all sizes, from small hormones to giant viruses. In this paper, we build a shape-based coarse grained model of IgG molecules and show that it can be used to generate 3D conformations in agreement with single-molecule Cryo-Electron Tomography data. Furthermore, we elaborate a theoretical model that can be solved exactly to compute the binding rate constant of a small antigen to an IgG in a prescribed 3D conformation. Our model shows that the antigen binding process is tightly related to the internal dynamics of the IgG. Our findings pave the way for further investigation of the subtle connection between the dynamics and the function of large, flexible multi-valent molecular machines. PMID- 26755273 TI - Use of Rheumatology Laboratory Studies Among Primary Pediatricians. AB - Rheumatology laboratory tests are often inappropriately ordered in situations for which they are of low diagnostic utility. We surveyed pediatricians to investigate reasons for ordering these tests. The response rate was 15.3% (93/609). The most commonly ordered tests were antinuclear antibody (ANA), anti double-stranded DNA (dsDNA) antibody, and rheumatoid factor (RF). Of the 89% (83/93) who ordered an ANA, 86% ordered it for correct/possibly correct reasons; of the 73% (68/93) who ordered RF, 80% did so for correct/possibly correct reasons; and among the 59% (54/92) who had ordered anti-dsDNA antibody, 34% ordered it for correct reasons. A positive relationship was seen between years since residency completion and correct use of ANA. However, positive associations were not seen between measures of pediatric rheumatology experience and correct use of other tests. Interventions are needed to improve pediatricians' utilization of rheumatology tests. PMID- 26755274 TI - Dual Positive Regulation of Embryo Implantation by Endocrine and Immune Systems- Step-by-Step Maternal Recognition of the Developing Embryo. AB - In humans, HCG secreted from the implanting embryo stimulates progesterone production of the corpus luteum to maintain embryo implantation. Along with this endocrine system, current evidence suggests that the maternal immune system positively contributes to the embryo implantation. In mice, immune cells that have been sensitized with seminal fluid and then the developing embryo induce endometrial differentiation and promote embryo implantation. After hatching, HCG activates regulatory T and B cells through LH/HCG receptors and then stimulates uterine NK cells and monocytes through sugar chain receptors, to promote and maintain pregnancy. In accordance with the above, the intrauterine administration of HCG-treated PBMC was demonstrated to improve implantation rates in women with repeated implantation failures. These findings suggest that the maternal immune system undergoes functional changes by recognizing the developing embryos in a stepwise manner even from a pre-fertilization stage and facilitates embryo implantation in cooperation with the endocrine system. PMID- 26755276 TI - Replicating Cluster Analysis: Method, Consistency, and Validity. AB - To replicate a cluster analysis, clusters must first be described in terms of an objective classification rule. The effectiveness of three rules (nearest neighbor classification, nearest centroid assignment, and quadratic discriminant analysis) for replicating Ward's algorithm (Ward, 1963) is evaluated by Monte Carlo study. Consistent replication links clusters and their replicas identically over alternative cross-validation sequences (i.e., A replicates B, B replicates A) and is associated with recovery of known clusters. Replication using nearest neighbor classification results in superior goodness-of-fit, more frequent consistent replication, and significant prediction of recovery. Although moderate or greater replication dentoes good recovery, replication is not a necessary condition of recovery of true clusters. PMID- 26755277 TI - A Study of the Beta-Flexible Clustering Method. AB - The beta-flexible clustering method has exhibited good recovery performance in the few comparative simulation studies that have included the procedure. Further, the beta-flexible technique has not been examined in a systematic manner over the range of parameter values that can be specified for the method. The present report was designed to provide a more complete study of the recovery characteristics of the method. Artificial data were generated with a wide range of cluster configurations. Each data set was subjected to a series of different techniques for the introduction of error. The results indicate that the beta flexible method with beta=-.25 or .2 generally produces recovery rates that are competitive with the group average and Ward's (1963) technique. When outliers are present in the data, values in the range -.7 <= beta <= -.4 are needed. The beta flexible method showed a more stable or robust performance pattern than the two competing procedures across the differing error conditions. Finally, results on the impact of reduced coverage levels as originally proposed by Edelbrock (1979) are reinterpreted in the light of an improved measure of recovery of true cluster structure. PMID- 26755278 TI - Factor Structure of the WISC-R. AB - A simultaneous maximum likelihood confirmatory factor analysis was performed on the 12 subtests the WISC-R in the 11 age groups of normative sample. Several models were fit to the data and compared, including: a single-factor model; orthogonal and oblique two-factor models, comprised of the Virbal and Performance subtests, respectively; and orthogonal and two oblique three-factor models, the third factor involving the Digit Span, Arthmetic, and Coding subtests. These analyses were subsequentlyb replicated in 11 samples in reported in 9 separate published articles. Results of the analyses in the normative sample suggest: 1) the single-factor model fits the data fairly well, although there is clearly some misspecification in this model; 2) the oblique multi-factor models do fit the data better than the single-factor model, though these models are also misspecified; and, 3) the single-factor, oblique two-factor and oblique three factor structures are fairly consistent across the age groups. Results of the re analyses of the published studies are quite similar to the results found in the normative sample, regardless of the population studied. It is concluded: 1) that the WISC-R largly consists of a general intellectual factor; and 2) all the critical models proposed in the literature to explain WISC-R performance are only partially correct. PMID- 26755279 TI - Cognitive Schemas in Social Perception. AB - This paper explores the cognitive schemas involved in ingroup and outgroup perceptions of three U. S. religious denominations (Baptists, Lutherans, and Catholics) based on a factor analytically derived rating scale. Two principal techniques are used for assessing these perceptions, that is, Similarity Structure Analysis, SSA, and Procrustean Individual Differences Scaling, PINDIS. The first is used to determine what the within-group and between-group perceptual structures are, while the latter is used to determine communalities among the various structures (stereotypy). Results revealed a high communality between denominational self-perceptions as well as some stereotypic misperceptions of Baptists and Catholics, but not of Lutherans. PMID- 26755280 TI - Performance Ratings in Organizations: A Facet Analysis Interpretation of the Multitrait-Multirater Approach. AB - The multi-dimensional nature of job performance has led to the use of the multitrait-multirater method for analyzing performance evaluation data (Lawler, 1967). The requirements of convergent and discriminant validity of that approach were seldom satisfied in empirical studies. Arguments were made against the simple notion of convergent validity and for the separation of the analysis of ratings coming from raters at different organizational levels (cf. Borman, 1974). The Present paper discusses the multitrait-multirater method from a facet analytic perspective. It is proposed that performance evaluation variable can be constructed by a mapping with two facets: a rater's facet and a trait's facet. The former is specified as an ordered facet and the latter as a non-ordered facet. The resulting predicted structure is a cylindrex. Data from four different studies are analyzed and basically support the proposed framework. The regularity of the pattern of the variables' intercorrelations across different rater groups is remarkable. Different aspects of the cylindrex structure are discussed as alternatives for the requirements of the multitrait-multirater method. PMID- 26755281 TI - Social Support Among Young Adults: Latent-Variable Models of Quantity and Satisfaction Within Six Life Areas. AB - Although a variety of social support measures have been developed, their conceptual distinctiveness and similarity have not been addressed in an empirical manner. This study presents a latent-variable approach to separate several sources and types of support and to determine the validity of a social support battery administered to a group of 739 young adults. Three theoretically distinct components of social support were considered: Type of support, source of support, and functional area of support. Type of support was reflected by amount (quantity) and satisfaction (quality); sources of support included family, friends, and organizations; and functional areas considered were drug use, finances, health, intimate relationships, psychological or emotional distress, and work or employment. A total of 36 (=2*3*6) social support items were developed by fully crossing the combinations among the components. Latent variable models verified a clear hypothesized structure of traits, indicating that these social support items very adequately reflected their underlying constructs. A second-order latent factor captured the association among the six functional area factors of social support. This suggests that the areas considered in assessing social support may generalize, and reflect a life experience that is broadly supported or not supported by important others in one's social network. PMID- 26755275 TI - Circulating Metabolites and Survival Among Patients With Pancreatic Cancer. AB - BACKGROUND: Pancreatic tumors cause changes in whole-body metabolism, but whether prediagnostic circulating metabolites predict survival is unknown. METHODS: We measured 82 metabolites by liquid chromatography-mass spectrometry in prediagnostic plasma from 484 pancreatic cancer case patients enrolled in four prospective cohort studies. Association of metabolites with survival was evaluated using Cox proportional hazards models adjusted for age, cohort, race/ethnicity, cancer stage, fasting time, and diagnosis year. After multiple hypothesis testing correction, a P value of .0006 or less (.05/82) was considered statistically significant. Based on the results, we evaluated 33 tagging single nucleotide polymorphisms (SNPs) in the ACO1 gene, requiring a P value of less than .002 (.05/33) for statistical significance. All statistical tests were two sided. RESULTS: Two metabolites in the tricarboxylic acid (TCA) cycle--isocitrate and aconitate--were statistically significantly associated with survival. Participants in the highest vs lowest quintile had hazard ratios (HRs) for death of 1.89 (95% confidence interval [CI] = 1.06 to 3.35, Ptrend < .001) for isocitrate and 2.54 (95% CI = 1.42 to 4.54, Ptrend < .001) for aconitate. Isocitrate is interconverted with citrate via the intermediate aconitate in a reaction catalyzed by the enzyme aconitase 1 (ACO1). Therefore, we investigated the citrate to aconitate plus isocitrate ratio and SNPs in the ACO1 gene. The ratio was strongly associated with survival (P trend < .001) as was the SNP rs7874815 in the ACO1 gene (hazard ratio for death per minor allele = 1.37, 95% CI = 1.16 to 1.61, P < .001). Patients had an approximately three-fold hazard for death when possessing one or more minor alleles at rs7874851 and high aconitate or isocitrate. CONCLUSIONS: Prediagnostic circulating levels of TCA cycle intermediates and inherited ACO1 genotypes were associated with survival among patients with pancreatic cancer. PMID- 26755282 TI - Contribution of Sample Processing to Variability and Accuracy of the Results of Pesticide Residue Analysis in Plant Commodities. AB - Significant reduction of concentration of some pesticide residues and substantial increase of the uncertainty of the results derived from the homogenization of sample materials have been reported in scientific papers long ago. Nevertheless, performance of methods is frequently evaluated on the basis of only recovery tests, which exclude sample processing. We studied the effect of sample processing on accuracy and uncertainty of the measured residue values with lettuce, tomato, and maize grain samples applying mixtures of selected pesticides. The results indicate that the method is simple and robust and applicable in any pesticide residue laboratory. The analytes remaining in the final extract are influenced by their physical-chemical properties, the nature of the sample material, the temperature of comminution of sample, and the mass of test portion extracted. Consequently, validation protocols should include testing the effect of sample processing, and the performance of the complete method should be regularly checked within internal quality control. PMID- 26755330 TI - Glutamine supplementation to prevent morbidity and mortality in preterm infants. AB - BACKGROUND: Glutamine is a conditionally essential amino acid. Endogenous biosynthesis may be insufficient for tissue needs in states of metabolic stress. Evidence exists that glutamine supplementation improves clinical outcomes in critically ill adults. It has been suggested that glutamine supplementation may also benefit preterm infants. OBJECTIVES: To determine the effects of glutamine supplementation on mortality and morbidity in preterm infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 12), MEDLINE, EMBASE and Maternity and Infant Care (to December 2015), conference proceedings and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared glutamine supplementation versus no glutamine supplementation in preterm infants at any time from birth to discharge from hospital. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two review authors. We synthesised data using a fixed-effect model and reported typical relative risk, typical risk difference and weighted mean difference. MAIN RESULTS: We identified 12 randomised controlled trials in which a total of 2877 preterm infants participated. Six trials assessed enteral glutamine supplementation and six trials assessed parenteral glutamine supplementation. The trials were generally of good methodological quality. Meta-analysis did not find an effect of glutamine supplementation on mortality (typical relative risk 0.97, 95% confidence interval 0.80 to 1.17; risk difference 0.00, 95% confidence interval -0.03 to 0.02) or major neonatal morbidities including the incidence of invasive infection or necrotising enterocolitis. Three trials that assessed neurodevelopmental outcomes in children aged 18 to 24 months and beyond did not find any effects. AUTHORS' CONCLUSIONS: The available trial data do not provide evidence that glutamine supplementation confers important benefits for preterm infants. PMID- 26755329 TI - Physiological ranges of matrix rigidity modulate primary mouse hepatocyte function in part through hepatocyte nuclear factor 4 alpha. AB - Matrix rigidity has important effects on cell behavior and is increased during liver fibrosis; however, its effect on primary hepatocyte function is unknown. We hypothesized that increased matrix rigidity in fibrotic livers would activate mechanotransduction in hepatocytes and lead to inhibition of liver-specific functions. To determine the physiologically relevant ranges of matrix stiffness at the cellular level, we performed detailed atomic force microscopy analysis across liver lobules from normal and fibrotic livers. We determined that normal liver matrix stiffness was around 150 Pa and increased to 1-6 kPa in areas near fibrillar collagen deposition in fibrotic livers. In vitro culture of primary hepatocytes on collagen matrix of tunable rigidity demonstrated that fibrotic levels of matrix stiffness had profound effects on cytoskeletal tension and significantly inhibited hepatocyte-specific functions. Normal liver stiffness maintained functional gene regulation by hepatocyte nuclear factor 4 alpha (HNF4alpha), whereas fibrotic matrix stiffness inhibited the HNF4alpha transcriptional network. Fibrotic levels of matrix stiffness activated mechanotransduction in primary hepatocytes through focal adhesion kinase. In addition, blockade of the Rho/Rho-associated protein kinase pathway rescued HNF4alpha expression from hepatocytes cultured on stiff matrix. CONCLUSION: Fibrotic levels of matrix stiffness significantly inhibit hepatocyte-specific functions in part by inhibiting the HNF4alpha transcriptional network mediated through the Rho/Rho-associated protein kinase pathway. Increased appreciation of the role of matrix rigidity in modulating hepatocyte function will advance our understanding of the mechanisms of hepatocyte dysfunction in liver cirrhosis and spur development of novel treatments for chronic liver disease. (Hepatology 2016;64:261-275). PMID- 26755331 TI - SSRP1 Contributes to the Malignancy of Hepatocellular Carcinoma and Is Negatively Regulated by miR-497. AB - The aim of this study is to clarify the clinical implication and functional role of structure specific recognition protein 1 (SSRP1) in hepatocellular carcinoma (HCC) and explore the underlying mechanism of aberrant high expression of SSRP1 in cancers. In the present investigation, we validated that SSRP1 was upregulated in HCC samples. We also demonstrated that its upregulation was associated with several clinicopathologic features such as higher serum AFP level, larger tumor size, and higher T stage of HCC patients; and its high expression indicated shorter overall survival and faster recurrence. To investigate the role of SSRP1 in HCC progression, both loss- and gain-function models were established. We demonstrated that SSPR1 modulated both proliferation and metastasis of HCC cells in vitro and vivo. Furthermore, we demonstrated that SSRP1-modulated apoptosis process and its knockdown increased the sensitivity of HCC cells to doxorubicin, 5-Fluorouracil, and cisplatin. We also identified microRNA-497 (miR-497) as a posttranscriptional regulator of SSRP1. Ectopic expression of miR-497 inhibited 3'-untranslated-region-coupled luciferase activity and suppressed endogenous SSRP1 expression at both messenger RNA and protein levels. For the first time, we proved that SSRP1 upregulation contributed to HCC development and the tumor suppressive miR-497 served as its negative regulator. PMID- 26755332 TI - Genome-wide Profiling Reveals Remarkable Parallels Between Insertion Site Selection Properties of the MLV Retrovirus and the piggyBac Transposon in Primary Human CD4(+) T Cells. AB - The inherent risks associated with vector insertion in gene therapy need to be carefully assessed. We analyzed the genome-wide distributions of Sleeping Beauty (SB) and piggyBac (PB) transposon insertions as well as MLV retrovirus and HIV lentivirus insertions in human CD4(+) T cells with respect to a panel of 40 chromatin states. The distribution of SB transposon insertions displayed the least deviation from random, while the PB transposon and the MLV retrovirus showed unexpected parallels across all chromatin states. Both MLV and PB insertions are enriched at transcriptional start sites (TSSs) and co-localize with BRD4-associated sites. We demonstrate physical interaction between the PB transposase and bromodomain and extraterminal domain proteins (including BRD4), suggesting convergent evolution of a tethering mechanism that directs integrating genetic elements into TSSs. We detect unequal biases across the four systems with respect to targeting genes whose deregulation has been previously linked to serious adverse events in gene therapy clinical trials. The SB transposon has the highest theoretical chance of targeting a safe harbor locus in the human genome. The data underscore the significance of vector choice to reduce the mutagenic load on cells in clinical applications. PMID- 26755335 TI - Presynaptic GABAB receptors reduce transmission at parabrachial synapses in the lateral central amygdala by inhibiting N-type calcium channels. AB - The nocioceptive information carried by neurons of the pontine parabrachial nucleus to neurons of the lateral division of the central amydala (CeA-L) is thought to contribute to the affective components of pain and is required for the formation of conditioned-fear memories. Importantly, excitatory transmission between parabrachial axon terminals and CeA-L neurons can be inhibited by a number of presynaptic receptors linked to Gi/o-type G-proteins, including alpha2 adrenoceptors and GABAB receptors. While the intracellular signalling pathway responsible for alpha2-adrenoceptor inhibition of synaptic transmission at this synapse is known, the mechanism by which GABAB receptors inhibits transmission has not been determined. The present study demonstrates that activation of presynaptic GABAB receptors reduces excitatory transmission between parabrachial axon terminals and CeA-L neurons by inhibiting N-type calcium channels. While the involvement of Gbetagamma subunits in mediating the inhibitory effects of GABAB receptors on N-type calcium channels is unclear, this inhibition does not involve Gbetagamma-independent activation of pp60C-src tyrosine kinase. The results of this study further enhance our understanding of the modulation of the excitatory input from parabrachial axon terminals to CeA-L neurons and indicate that presynaptic GABAB receptors at this synapse could be valuable therapeutic targets for the treatment of fear- and pain-related disorders. PMID- 26755334 TI - MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy. AB - Spinal and bulbar muscular atrophy (SBMA) is a currently untreatable adult-onset neuromuscular disease caused by expansion of a polyglutamine repeat in the androgen receptor (AR). In SBMA, as in other polyglutamine diseases, a toxic gain of function in the mutant protein is an important factor in the disease mechanism; therefore, reducing the mutant protein holds promise as an effective treatment strategy. In this work, we evaluated a microRNA (miRNA) to reduce AR expression. From a list of predicted miRNAs that target human AR, we selected microRNA-298 (miR-298) for its ability to downregulate AR mRNA and protein levels when transfected in cells overexpressing wild-type and mutant AR and in SBMA patient-derived fibroblasts. We showed that miR-298 directly binds to the 3' untranslated region of the human AR transcript, and counteracts AR toxicity in vitro. Intravenous delivery of miR-298 with adeno-associated virus serotype 9 vector resulted in efficient transduction of muscle and spinal cord and amelioration of the disease phenotype in SBMA mice. Our findings support the development of miRNAs as a therapeutic strategy for SBMA and other neurodegenerative disorders caused by toxic proteins. PMID- 26755336 TI - Increased bioavailability of celecoxib under fed versus fasted conditions is determined by postprandial bile secretion as demonstrated in a dynamic gastrointestinal model. AB - The objective of this study was to utilize physiologically relevant dynamic dissolution testing with the TNO intestinal model (TIM-1) in vitro gastrointestinal model to investigate the bioaccessibility of celecoxib. A single 200-mg dose of celecoxib was evaluated under average adult human physiological conditions simulated in the TIM-1 system. The in vitro data were compared with the clinically established pharmacokinetic data. When expressed as a percent of drug that progresses from the duodenum to the jejunum and ileum compartments (bioaccessible sites), the study demonstrated a 2-fold increase in the total bioaccessibility for celecoxib when co-administered with a high-fat meal as opposed to co-administration with a glass of water (fasted conditions). That increase in bioaccessibility was similar to a 1.2 to 1.6-fold increase in systemic exposure in adults and children following co-administration with a high fat meal when compared to the exposure measured when celecoxib was co administered with only water. Following that comparison, the flexibility of the TIM-1 system was used to more specifically investigate individual parameters of gastrointestinal conditions, such as the rate of bile secretion (emptying of the bile bladder) that accompanies high-fat meal consumption. We demonstrated that increased bile secretion after co-administration of a high-fat meal played a more important role in the increased celecoxib bioaccessibility than did the food matrix. This indicates that in humans without a bile bladder the exposure of celecoxib administered with food might be as low as under fasted state. PMID- 26755338 TI - Measuring to Improve: Peer and Crowd-sourced Assessments of Technical Skill with Robot-assisted Radical Prostatectomy. AB - Because surgical skill may be a key determinant of patient outcomes, there is growing interest in skill assessment. In the Michigan Urological Surgery Improvement Collaborative (MUSIC), we assessed whether peer and crowd-sourced (ie, layperson) video review of robot-assisted radical prostatectomy (RARP) could distinguish technical skill among practicing surgeons. A total of 76 video clips from 12 MUSIC surgeons consisted of one of four parts of RARP and underwent blinded review by MUSIC peer surgeons and prequalified crowd-sourced reviewers. Videos were rated for global skill (Global Evaluation Assessment of Robotic Skills) and procedure-specific skill (Robotic Anastomosis and Competency Evaluation). We fit linear mixed-effects models to estimate mean peer and crowd ratings for each video. Individual video ratings were aggregated to calculate surgeon skill scores. Peers (n=25) completed 351 video ratings over 15 d, whereas crowd-sourced reviewers (n=680) completed 2990 video ratings in 38 h. Surgeon global skill scores ranged from 15.8 to 21.7 (peer) and from 19.2 to 20.9 (crowd). Peer and crowd ratings demonstrated strong correlation for both global (r=0.78) and anastomosis (r=0.74) skills. The two groups consistently agreed on the rank order of lower scoring surgeons, suggesting a potential role for crowd sourced methodology in the assessment of surgical performance. Lack of patient outcomes is a limitation and forms the basis of future study. PATIENT SUMMARY: We demonstrated the large-scale feasibility of assessing the technical skill of robotic surgeons and found that online crowd-sourced reviewers agreed with experts on the rank order of surgeons with the lowest technical skill scores. PMID- 26755339 TI - Prostate Volume as a Risk Factor for Lower Urinary Tract Symptoms: The Quest Continues. PMID- 26755337 TI - Metabolic response to dietary fibre composition in horses. AB - The hypothesis for this study was that a higher dietary proportion of soluble fibre would result in stable and constant plasma metabolite and regulatory hormone concentrations. The study was a 4*4 Latin Square design with a sequence of 17 days adaptation to the ration followed by 8 sampling days. The feed rations consisted of only timothy hay (H), hay plus molassed sugar beet pulp combined with either whole oats (OB) or barley (BB) and hay plus a loose chaff-based concentrate (M). Four horses were fitted with permanent caecal cannulas and liquid caecal content was withdrawn manually and blood was drawn from the jugular vein at 0, 3 and 9 h postprandial. The horses were exercised daily at medium level for about 1 h. Samples were analysed for short-chain fatty acids (SCFA) and metabolic traits. Caecal SCFA and propionic acid concentrations increased with increased dietary starch and soluble fibre. The diet highest in soluble fibre (M) resulted in the highest plasma glucose and insulin concentrations in the morning, which then remained stable and constant throughout the day. A strong interaction (P<0.01) between time and diet was measured for plasma urea, glucose, insulin and leptin. The greatest variations in plasma glycaemic and insulinaemic responses were associated with the cereal grain diets (OB and BB). There were indications of a negative energy balance, which was reflected in a significantly higher plasma beta-hydroxybutyrate concentration and a numerically higher non-esterified fatty acid concentration. In conclusion, this study found that inclusion of soluble fibre resulted in increased total caecal SCFA and propionic acid concentrations. This consequently resulted in stable and constant plasma glycaemic and insulinaemic responses. Diets with a high content of soluble fibre provided enough energy for horses at medium work level. PMID- 26755340 TI - Assessing the Evidence for the Surgical Management of Renal Cell Carcinoma with Venous Tumor Thrombus: Room to Grow. PMID- 26755341 TI - Expression of Ribosomal RNA and Protein Genes in Human Embryonic Stem Cells Is Associated With the Activating H3K4me3 Histone Mark. AB - Embryonic stem cells (ESCs) exhibit unrestricted and indefinite, but stringently controlled, proliferation, and can differentiate into any lineage in the body. In the current study, we test the hypothesis that expression of ribosomal RNA (rRNA) and ribosomal protein genes (RPGs) contribute to the ability of hESCs to proliferate indefinitely. Consistent with the accelerated growth rate of hESCs, we find that hESC lines H1 and H9 both exhibit significantly higher levels of rRNA when compared to a panel of normal and cancer human cell lines. Although many RPGs are expressed at levels that comparable to other human cell lines, a few RPGs also exhibit higher expression levels. In situ nuclear run-on assays reveal that both nucleoli in hESCs actively transcribe nascent rRNA. Employing genome-wide chromatin immunoprecipitation-deep sequencing and bioinformatics approaches, we discovered that, RPGs are dominantly marked by the activating H3K4me3 histone mark in the G1, M, and G2 phases of the cell cycle. Interestingly, the rDNA repeats are marked by the activating H3K4me3 only in the M phase, and repressive H3K27me3 histone mark in all three cell cycle phases. Bioinformatics analyses also reveal that Myc, a known regulator of cell growth and proliferation, occupies both the rRNA genes and RPGs. Functionally, down regulation of Myc expression by siRNA results in a concomitant decrease in rRNA levels. Together, our results show that expression of rRNA, which is regulated by the Myc pluripotency transcription factor, and of RPGs in hESCs is associated with the activating H3K4me3 modification. J. Cell. Physiol. 231: 2007-2013, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26755342 TI - Construction of a subunit-fusion nitrile hydratase and discovery of an innovative metal ion transfer pattern. AB - Metallochaperones are metal-binding proteins designed to deliver the appropriate metal to a target protein. The metal is usually transferred between different proteins. In this study, we discovered that metal was transferred between the same subunit of a mutant nitrile hydratase (NHase). Various "activator proteins" mediate the trafficking of metal ions into NHases. We constructed fusion NHases by fusing the beta- and alpha-subunits and/or the "activator proteins" of the NHase from Pseudomonas putida. The fusion NHases exhibited higher thermostability and tolerance to high concentrations of the product amide. The mechanism of the cobalt incorporation changed from a self-subunit swapping pattern to an apoprotein-specific molecular chaperone pattern in vivo and a metallochaperone pattern in vitro. Notably, the cobalt transfer occurred between the same alpha subunit in the metallochaperone pattern. These results not only demonstrated the superiority of fusion-type NHases, but also revealed an innovative metal ion transfer pattern in metalloprotein biosynthesis. PMID- 26755343 TI - Differential ascending and descending aortic mechanics parallel aneurysmal propensity in a mouse model of Marfan syndrome. AB - Marfan syndrome (MFS) is a multi-system connective tissue disorder that results from mutations to the gene that codes the elastin-associated glycoprotein fibrillin-1. Although elastic fibers are compromised throughout the arterial tree, the most severe phenotype manifests in the ascending aorta. By comparing biaxial mechanics of the ascending and descending thoracic aorta in a mouse model of MFS, we show that aneurysmal propensity correlates well with both a marked increase in circumferential material stiffness and an increase in intramural shear stress despite a near maintenance of circumferential stress. This finding is corroborated via a comparison of the present results with previously reported findings for both the carotid artery from the same mouse model of MFS and for the thoracic aorta from another model of elastin-associated glycoprotein deficiency that does not predispose to thoracic aortic aneurysms. We submit that the unique biaxial loading of the ascending thoracic aorta conspires with fibrillin-1 deficiency to render this aortic segment vulnerable to aneurysm and rupture. PMID- 26755345 TI - Mind the gap: residual malaria transmission, veterinary endectocides and livestock as targets for malaria vector control. PMID- 26755333 TI - Genome-editing Technologies for Gene and Cell Therapy. AB - Gene therapy has historically been defined as the addition of new genes to human cells. However, the recent advent of genome-editing technologies has enabled a new paradigm in which the sequence of the human genome can be precisely manipulated to achieve a therapeutic effect. This includes the correction of mutations that cause disease, the addition of therapeutic genes to specific sites in the genome, and the removal of deleterious genes or genome sequences. This review presents the mechanisms of different genome-editing strategies and describes each of the common nuclease-based platforms, including zinc finger nucleases, transcription activator-like effector nucleases (TALENs), meganucleases, and the CRISPR/Cas9 system. We then summarize the progress made in applying genome editing to various areas of gene and cell therapy, including antiviral strategies, immunotherapies, and the treatment of monogenic hereditary disorders. The current challenges and future prospects for genome editing as a transformative technology for gene and cell therapy are also discussed. PMID- 26755344 TI - Percutaneous Renal Cryoablation: Short-Axis Ice-Ball Margin as a Predictor of Outcome. AB - PURPOSE: To determine if CT characteristics of intraprocedural ice balls correlate with outcomes after cryoablation. MATERIALS AND METHODS: A retrospective review was performed on 63 consecutive patients treated with renal cryoablation. Preprocedural and intraprocedural images were used to identify the size and location of renal tumors and ice balls as well as the tumor coverage and ice-ball margins. Review of follow-up imaging (1 mo and then 3-6-mo intervals) distinguished successful ablations from cases of residual tumor. RESULTS: Patients who underwent successful ablation (n = 50; 79%) had a mean tumor diameter of 2.5 cm (range, 0.9-4.3 cm) and mean ice-ball margin of 0.4 cm (range, 0.2-1.2 cm). Patients with residual tumor (n = 13; 21%) had a mean tumor diameter of 3.8 cm (range, 1.8-4.5 cm) and mean ice-ball margin of -0.4 cm (range, -0.9 to 0.4 cm). Residual and undertreated tumors were larger and had smaller ice-ball margins than successfully treated tumors (P < .01). Ice-ball diameters were significantly smaller after image reformatting (P < .01). Ice-ball margins of 0.15 cm had 90% sensitivity, 92% specificity, and 98% positive predictive value for successful ablation. Success was independent of tumor location or number of cryoprobes. CONCLUSIONS: Ice-ball margin and real-time intraprocedural reformatting could be helpful in predicting renal cryoablation outcomes. Although a 0.5-cm margin is preferred, a well-centered ice ball with a short-axis margin greater than 0.15 cm strongly correlated with successful ablation. PMID- 26755346 TI - Photocurrent enhancement of SiNW-FETs by integrating protein-shelled CdSe quantum dots. AB - We proposed a new strategy to increase the photoresponsivity of silicon NW field effect transistors (FETs) by integrating CdSe quantum dots (QDs) using protein shells (PSs). CdSe QDs were synthesized using ClpP, a bacterial protease, as protein shells to control the size and stability of QD and to facilitate the mounting of QDs on SiNWs. The photocurrent of SiNW-FETs in response to light at a wavelength of 480 nm was enhanced by a factor of 6.5 after integrating CdSe QDs because of the coupling of the optical properties of SiNWs and QDs. As a result, the photoresponsivity to 480 nm light reached up to 3.1 * 10(6), the highest value compared to other SiNW-based devices in the visible light range. PMID- 26755347 TI - Systematic Analysis of Sex-Linked Molecular Alterations and Therapies in Cancer. AB - Though patient sex influences response to cancer treatments, little is known of the molecular causes, and cancer therapies are generally given irrespective of patient sex. We assessed transcriptomic differences in tumors from men and women spanning 17 cancer types, and we assessed differential expression between tumor and normal samples stratified by sex across 7 cancers. We used the LincsCloud platform to perform Connectivity Map analyses to link transcriptomic signatures identified in male and female tumors with chemical and genetic perturbagens, and we performed permutation testing to identify perturbagens that showed significantly differential connectivity with male and female tumors. Our analyses predicted that females are sensitive and males are resistant to tamoxifen treatment of lung adenocarcinoma, a finding which is consistent with known male female differences in lung cancer. We made several novel predictions, including that CDK1 and PTPN1 knockdown would be more effective in males with hepatocellular carcinoma, and SMAD3 and HSPA4 knockdown would be more effective in females with head and neck squamous cell carcinoma. Our results provide a new resource for researchers studying male-female biological and treatment response differences in human cancer. The complete results of our analyses are provided at the website accompanying this manuscript (http://becklab.github.io/SexLinked). PMID- 26755348 TI - Regeneration of tracheal epithelium using mouse induced pluripotent stem cells. AB - Conclusion The findings demonstrated the potential use of induced pluripotent stem cells for regeneration of tracheal epithelium. Objective Autologous tissue implantation techniques using skin or cartilage are often applied in cases of tracheal defects with laryngeal inflammatory lesions and malignant tumor invasion. However, these techniques are invasive with an unstable clinical outcome. The purpose of this study was to investigate regeneration in a tracheal defect site of nude rats after implantation of ciliated epithelium that was differentiated from induced pluripotent stem cells. Method Embryoid bodies were formed from mouse induced pluripotent stem cells. They were cultured with growth factors for 5 days, and then cultured at the air-liquid interface. The degree of differentiation achieved prior to implantation was determined by histological findings and the results of real-time polymerase chain reaction. Embryoid bodies including ciliated epithelium were embedded into collagen gel that served as an artificial scaffold, and then implanted into nude rats, creating an 'air-liquid interface model'. Histological evaluation was performed 7 days after implantation. Results The ciliated epithelial structure survived on the lumen side of regenerated tissue. It was demonstrated histologically that the structure was composed of ciliated epithelial cells. PMID- 26755349 TI - A Qualitative Study into Dependent Relationships and Voluntary Informed Consent for Research in Pediatric Oncology. AB - BACKGROUND: In pediatric oncology, many oncologists invite their own patients to participate in research. Inclusion within a dependent relationship is considered to potentially compromise voluntariness of consent. Currently, it is unknown to what extent those involved in pediatric oncology experience the dependent relationship as a threat to voluntary informed consent, and what they see as safeguards to protect voluntary informed consent within a dependent relationship. AIM: We performed a qualitative study among key actors in pediatric oncology to explore their experiences with the dependent relationship and voluntary informed consent. METHODS: We conducted three focus groups and 25 semi-structured, in depth interviews with pediatric oncologists, research coordinators, Research Ethics Committee members, parents of children with cancer, and adolescents with cancer. RESULTS: Professionals regarded the dependent relationship both as a potential threat to and as a positive influence on voluntary decision making. Parents and adolescents did not feel as though dependency upon the oncologist influenced their decisions. They valued the involvement of their own physician in the informed consent process. The professionals suggested three strategies to protect voluntariness: emphasizing voluntariness; empowering families; involvement of an independent person. CONCLUSIONS: Although the dependent relationship between pediatric oncologists, patients and parents may be problematic for voluntary informed consent, this is not necessarily the case. Moreover, the involvement of treating physicians may even have a positive impact on the informed consent process. Although we studied pediatric oncology, our results may also apply to many other fields of pediatric medicine where research and care are combined, for example, pediatric rheumatology, neurology and nephrology. Clinical trials in these fields are inevitably often designed, initiated and conducted by medical specialists closely involved in patient care. PMID- 26755350 TI - Approach to the sonographic evaluation of fetal ventriculomegaly at 11 to 14 weeks gestation. AB - BACKGROUND: The aim of the study was to report the prevalence and associated findings of fetal ventriculomegaly between 11 + 0 and 13 + 6 gestational weeks and to evaluate a sonographic approach to classify first trimester ventriculomegaly in the standard axial plane used for biparietal diameter (BPD) measurement. METHODS: The ratio between choroid plexus and lateral ventricle diameter (PDVDR), between the choroid plexus and lateral ventricle length (PLVLR) and between the choroid plexus and lateral ventricle area (PAVAR) were calculated from stored 2D images of the axial head plane in 100 normal fetuses and 17 fetuses with ventriculomegaly. RESULTS: The PDVDR, the PLVLR and the PAVAR were below the 5(th) percentile in 82.4%, 94.1% and 94.1% of the cases with ventriculomegaly. Ventriculomegaly was isolated in 29.4% and associated with further anomalies in 70.6% at the initial evaluation. The mean PLVLR in euploid compared to aneuploid fetuses was significantly lower (0.40 versus 0.53 (p = 0.0332)). CONCLUSIONS: The measurements of PDVDR, PLVLR and PAVAR are helpful to objectify ventriculomegaly at 11-14 gestational weeks. The PLVLR and PAVAR were superior to PDVDR, since there seems to be rather shrinkage of the choroid plexus than an increased width of the lateral ventricles in the first trimester. PMID- 26755351 TI - Insomnia, anxiety, and heart rate variability among nurses working different shift systems in Taiwan. AB - This cross-sectional comparative study investigated the levels of insomnia, anxiety, and heart rate variability of nurses members working different shift systems. One hundred and twenty-four participants were recruited from members of the nurses of two Taiwanese hospitals. Data were collected using the Chinese versions of the Athens Insomnia Scale and Beck Anxiety Scale questionnaires and electrocardiograms recorded immediately upon completion of each participant's work shift. A binary logistic regression model was used for analysis. Insomnia, anxiety, and abnormal parasympathetic activity were more acute in nurses who worked a rotating shift than in those performing day or night shift work. Logistic regression analysis showed that age significantly increased the incidence and level of insomnia. Age, years of service, and nurses' status as a parent significantly intensified incidences of anxiety and abnormal parasympathetic activity. Rotating shift work is one of the main factors causing adverse effects on the physical and psychological health of nurses; therefore, when a shift work system cannot be avoided, a practice of day and night shifts for nurses is preferable to rotating shifts. PMID- 26755352 TI - Two-dimensional honeycomb network through sequence-controlled self-assembly of oligopeptides. AB - The sequence of a peptide programs its self-assembly and hence the expression of specific properties through non-covalent interactions. A large variety of peptide nanostructures has been designed employing different aspects of these non covalent interactions, such as dispersive interactions, hydrogen bonding or ionic interactions. Here we demonstrate the sequence-controlled fabrication of molecular nanostructures using peptides as bio-organic building blocks for two dimensional (2D) self-assembly. Scanning tunnelling microscopy reveals changes from compact or linear assemblies (angiotensin I) to long-range ordered, chiral honeycomb networks (angiotensin II) as a result of removal of steric hindrance by sequence modification. Guided by our observations, molecular dynamic simulations yield atomistic models for the elucidation of interpeptide-binding motifs. This new approach to 2D self-assembly on surfaces grants insight at the atomic level that will enable the use of oligo- and polypeptides as large, multi-functional bio-organic building blocks, and opens a new route towards rationally designed, bio-inspired surfaces. PMID- 26755353 TI - Diploid versus haploid models of neutral speciation. AB - Neutral models of speciation based on isolation by distance and assortative mating, termed topopatric, have shown to be successful in describing abundance distributions and species-area relationships. Previous works have considered this type of process in the context of haploid genomes. Here we discuss the implementation of two schemes of dominance to analyze the effects of diploidy: a complete dominance model in which one allele dominates over the other and a perfect codominant model in which heterozygous genotypes give rise to a third phenotype. In the case of complete dominance, we observe that speciation requires stronger spatial inbreeding in comparison to the haploid model. For perfect codominance, instead, speciation demands stronger genetic assortativeness. Nevertheless, once speciation is established, the three models predict the same abundance distributions even at the quantitative level, revealing the robustness of the original mechanism to describe biodiversity features. PMID- 26755354 TI - Streptomyces daqingensis sp. nov., isolated from saline-alkaline soil. AB - A novel strain of actinobacteria, designated strain NEAU-ZJC8T, was isolated from a saline-alkaline soil collected from Heilongjiang Province, north-east China and characterized using a polyphasic approach. Strain NEAU-ZJC8T exhibited morphological, cultural and chemotaxonomic features consistent with its classification as representing a member of the genus Streptomyces. Growth occurred at 16-35 degrees C, pH 5.0-11.0 and in the presence of 0-11 % (w/v) NaCl. The cell-wall peptidoglycan contained ll-diaminopimelic acid and glycine. Whole-cell hydrolysates mainly contained glucose, galactose and ribose. Predominant menaquinones were MK-9(H6), MK-9(H4) and MK-9(H8). The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannoside and two unidentified phospholipids. The major cellular fatty acids (>10 %) were iso-C16 : 0, iso-C15 : 0, anteiso-C17 : 0 and C16 : 0. The G+C content of the DNA was 72.7 mol%. A phylogenetic tree based on 16S rRNA sequences showed that strain NEAU-ZJC8T formed a distinct clade within the genus Streptomyces and was closely related to Streptomyces haliclonae DSM 41970T (98.56 % similarity) and Streptomyces marinus NBRC 105047T (97.96 % similarity). A combination of DNA-DNA hybridization results and some phenotypic characteristics demonstrated that strain NEAU-ZJC8T could be distinguished from its closest phylogenetic relatives. Therefore, strain NEAU-ZJC8T represents a novel species of the genus Streptomyces, for which the name Streptomyces daqingensis sp. nov. is proposed. The type strain is NEAU-ZJC8T ( = CGMCC 4.7178T = JCM 30057T). PMID- 26755355 TI - An Adult Case of Bartter Syndrome Type III Presenting with Proteinuria. AB - Bartter syndrome (BS) I-IV is a rare autosomal recessive disorder affecting salt reabsorption in the thick ascending limb of the loop of Henle. This report highlights clinicopathological findings and genetic studies of classic BS in a 22 year-old female patient who presented with persistent mild proteinuria for 2 years. A renal biopsy demonstrated a mild to moderate increase in the mesangial cells and matrix of most glomeruli, along with marked juxtaglomerular cell hyperplasia. These findings suggested BS associated with mild IgA nephropathy. Focal tubular atrophy, interstitial fibrosis, and lymphocytic infiltration were also observed. A genetic study of the patient and her parents revealed a mutation of the CLCNKB genes. The patient was diagnosed with BS, type III. This case represents an atypical presentation of classic BS in an adult patient. Pathologic findings of renal biopsy combined with genetic analysis and clinicolaboratory findings are important in making an accurate diagnosis. PMID- 26755356 TI - Intramuscular Tenosynovial Giant Cell Tumor, Diffuse-Type. PMID- 26755358 TI - Primary Cutaneous Adenoid Cystic Carcinoma Arising in Umbilicus. PMID- 26755357 TI - Gastric Mixed Adenoneuroendocrine Carcinoma with Squamous Differentiation: A Case Report. PMID- 26755359 TI - IgG4-Related Sclerosing Mesenteritis. PMID- 26755360 TI - Isolated Mass-Forming IgG4-Related Cholangitis as an Initial Clinical Presentation of Systemic IgG4-Related Disease. AB - IgG4-related disease (IgG4-RD) may involve multiple organs. Although it usually presents as diffuse organ involvement, localized mass-forming lesions have been occasionally encountered in pancreas. However, the same pattern has been seldom reported in biliary tract. A 61-year-old male showed a hilar bile duct mass with multiple enlarged lymph nodes in imaging studies and he underwent trisectionectomy under impression of cholangiocarcinoma. Gross examination revealed a mass-like lesion around hilar bile duct. Histopathologically, dense lymphoplasmacytic infiltration and storiform fibrosis were identified without evidence of malignancy. Immunohistochemical stain demonstrated rich IgG4-positive plasma cell infiltration. Follow-up imaging studies disclosed multiple enlarged lymph nodes with involvement of pancreas and perisplenic soft tissue. The lesions have been significantly reduced after steroid treatment, which suggests multi organ involvement of systemic IgG4-RD. Here, we report an unusual localized mass forming IgG4-related cholangitis as an initial presentation of IgG4-RD, which was biliary manifestation of systemic IgG4-related autoimmune disease. PMID- 26755361 TI - DNA sequence analysis suggests that cytb-nd1 PCR-RFLP may not be applicable to sandfly species identification throughout the Mediterranean region. AB - Molecular methods are increasingly used for both species identification of sandflies and assessment of their population structure. In general, they are based on DNA sequence analysis of targets previously amplified by PCR. However, this approach requires access to DNA sequence facilities, and in some circumstances, it is time-consuming. Though DNA sequencing provides the most reliable information, other downstream PCR applications are explored to assist in species identification. Thus, it has been recently proposed that the amplification of a DNA region encompassing partially both the cytochrome-B (cytb) and the NADH dehydrogenase 1 (nd1) genes followed by RFLP analysis with the restriction enzyme Ase I allows the rapid identification of the most prevalent species of phlebotomine sandflies in the Mediterranean region. In order to confirm the suitability of this method, we collected, processed, and molecularly analyzed a total of 155 sandflies belonging to four species including Phlebotomus ariasi, P. papatasi, P. perniciosus, and Sergentomyia minuta from different regions in Spain. This data set was completed with DNA sequences available at the GenBank for species prevalent in the Mediterranean basin and the Middle East. Additionally, DNA sequences from 13 different phlebotomine species (P. ariasi, P. balcanicus, P. caucasicus, P. chabaudi, P. chadlii, P. longicuspis, P. neglectus, P. papatasi, P. perfiliewi, P. perniciosus, P. riouxi, P. sergenti, and S. minuta), from 19 countries, were added to the data set. Overall, our molecular data revealed that this PCR-RFLP method does not provide a unique and specific profile for each phlebotomine species tested. Intraspecific variability and similar RFLP patterns were frequently observed among the species tested. Our data suggest that this method may not be applicable throughout the Mediterranean region as previously proposed. Other molecular approaches like DNA barcoding or phylogenetic analyses would allow a more precise molecular species identification. PMID- 26755362 TI - Schistosoma haematobium in Guinea-Bissau: unacknowledged morbidity due to a particularly neglected parasite in a particularly neglected country. AB - Schistosomiasis is the major neglected tropical helminthic disease worldwide. Current knowledge on the epidemiology of schistosomiasis in Guinea-Bissau is scarce and regarding to the absence of Schistosoma haematobium (S.h.). Therefore, a pilot study was undertaken to assess the prevalence and morbidity due to S.h. infection in randomly selected 90 children and adolescents aged 6 to 15 years. Prevalence of S.h. infection was 20.00 % (18/90). Microhematuria was observed in 61.11 % (11/18) of S.h.-egg-excreting vs. 37.50 % (27/72) of non-S.h.-egg excreting children p <= 0.01. Body mass index (BMI) was less than 15 kg/m(2) in 52/90 (57.78 %) of all children and adolescents, but this proportion increased to 66.67 % (12/18) in S.h.-infected children who were more frequently stunted and wasted than in non-infected children. The mean weight-for-age Z score (WAZ) was reduced in S.h. infected as compared to non-infected children (-1.48 +/- 1.08 SD vs. -0.80 +/- 1.11 SD; p <= 0.01). To our knowledge, this is the first epidemiologic report on S. haematobium infection in Guinea-Bissau since 22 years. Even in this relatively small study sample, it appears that S. haematobium, besides the well-known symptoms such as hematuria, leads to significant, albeit commonly unacknowledged morbidity such as stunting and wasting. These observations underscore the notion that this vulnerable but neglected population urgently needs to be targeted for implementation of measures for treatment and control. PMID- 26755380 TI - What is your diagnosis? Submandibular mass in an alpaca. PMID- 26755379 TI - Glycomacropeptide administration attenuates airway inflammation and remodeling associated to allergic asthma in rat. AB - OBJECTIVE: Glycomacropeptide (GMP) is a bioactive peptide derived from milk that has been reported to exhibit a range of anti-inflammatory and immunomodulatory properties. The aim of this study was to analyze the prophylactic effect of GMP administration on airway inflammation and remodeling in an experimental model of asthmatic rat. METHODS: Animals treated orally with or without GMP (500 mg/kg/day) were ovalbumin-sensitized and -nebulized and several indicators of Th2 response, airway structural changes and inflammatory cells recruitment were evaluated. RESULTS: Treatment with GMP prior and during asthma development resulted in reduction of allergen-specific IgE titers in serum and blood eosinophilia. Also, GMP substantially suppressed the recruitment of inflammatory cells to bronchoalveolar compartment. Histological studies demonstrated that GMP markedly inhibits eosinophils infiltration, goblet cells hyperplasia and collagen deposit in lung tissue. The latter effect was related with an inhibition in transforming growth factor-beta expression. In addition, expression of interleukin-5 and -13 were substantially inhibited in lung while that of interleukin-10 was increased. CONCLUSION: Our results suggest that administration of GMP may prevent the development of an excessive Th2 response in asthma and effectively ameliorates the progression of the disease. PMID- 26755381 TI - Factors affecting extension lag after tendon reconstruction for finger extensor tendon rupture due to distal radioulnar lesion. AB - BACKGROUND: Although extensor tendon rupture associated with distal radioulnar joint disorder is often encountered, its treatment has not yet been established. We report the postoperative results for reconstruction of finger extensor tendon rupture due to distal radioulnar lesion and analyse the factors affecting postoperative extension lag. METHODS: We examined 74 index, middle, ring, or little fingers with extensor tendon rupture of 34 hands. Primary diseases were rheumatoid arthritis in 24 hands and osteoarthritis in 10. Reconstruction methods included tendon graft in 45 fingers, extensor indicis proprius tendon transfer in 15, and end-to-side adjacent tendon suture in 14. At final postoperative follow up ranging from 12 to 40 (mean: 18) months, we measured metacarpophalangeal (MCP) joint range of motion and extension lag and statistically evaluated the relationship between postoperative extension lag and several clinical factors. RESULTS: We encountered no cases of re-rupture or worsening of finger flexion range after reconstruction. Mean postoperative active flexion of the MCP joint was 78.1 (range: 45-95) degrees. Mean postoperative extension lag was 10.3 (range: 0-50) degrees. We observed that postoperative extension lag was significantly larger in fingers associated with extensor tendon rupture in two or three additional fingers in the affected hand or in fingers of patients aged 80 years or over. The interval from rupture to reconstruction, reconstruction method, or arthritis type did not remarkably affect outcome. CONCLUSIONS: This study uncovered that surgical intervention for extensor tendon rupture should be performed before three fingers become affected. PMID- 26755382 TI - Single intradiscal injection of the interleukin-6 receptor antibody tocilizumab provides short-term relief of discogenic low back pain; prospective comparative cohort study. AB - BACKGROUND: Inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha, are gaining attention as important etiologic factors associated with discogenic low back pain. We conducted a prospective cohort study to evaluate the efficacy and safety of intradiscal injection of the interleukin-6 receptor antibody tocilizumab in patients with discogenic low back pain. METHODS: Thirty-two consecutive patients were intradiscally injected with 2 mL of 0.5% bupivacaine (control group). Another 31 consecutive patients were intradiscally injected with 40 mg tocilizumab and 1-2 mL of 0.5% bupivacaine (tocilizumab group) at the same time. Prior to treatment, the vertebral origin of low back pain was confirmed in all patients based on pain provocation during discography and pain relief with 1 mL of 1% xylocaine. Numeric rating scale and Oswestry disability index scores were used to evaluate pain level before and after treatment between the 2 groups. The association between pain relief with tocilizumab and intervertebral disc degeneration grade was also determined. RESULTS: At the end of the study (8 weeks after treatment), 30 patients in each group were evaluable. In the tocilizumab group, numeric rating scale and Oswestry disability index scores improved significantly at 2 and 4 weeks after treatment, respectively. Intervertebral disc degeneration was not associated with improvement of numeric rating scale score in the tocilizumab group. Local infection (i.e., discitis) was observed in 1 patient in the tocilizumab group. CONCLUSIONS: The results demonstrate the clinical relevance of interleukin-6 in discogenic low back pain. Intradiscal tocilizumab injection was shown to exert a short-term analgesic effect in patients with discogenic low back pain. Further research is required to determine the long-term effects of intradiscal tocilizumab therapy in patients with discogenic low back pain. PMID- 26755383 TI - The relationship between medial meniscal subluxation and stress distribution pattern of the knee joint: Finite element analysis. AB - BACKGROUND: Degenerative changes of the knee joint and clinical follow-up after meniscal subluxation are well documented. In the current study three-dimensional (3D) finite element analysis (FEA) of human lower limb was used to investigate the effect medial meniscal subluxation on the loadings of the knee structures. METHODS: Apart from the reference model, a total of ten 3D models were created, according to amount of medial meniscal subluxation. ANSYS(r) 14 was used to analyze the stress/load distribution, that is to say the maximum equivalent stress (MES) (von Mises stress) on bones, cartilages, ligaments and menisci. MES was expressed as Newton/mm(2) = Megapascal (MPa). RESULTS: In a static and standing upright position the MES on all knee structures were evaluated in the reference model. Although MES increased in all structures with the increase of medial meniscal subluxation degree, tibia cartilage was found to be the most affected structure with an increase of 22.73-fold in the 10 mm subluxation model when compared with references values. CONCLUSION: This study showed that medial meniscus subluxation is associated with increased loadings on all knee structures especially the tibia cartilage. Also the degree of the medial meniscal subluxation correlates with distribution and the amount of loadings on tibia cartilage which may be a prominent feature of knee osteoarthritis. PMID- 26755384 TI - Quadriceps strength affects patient satisfaction after total knee arthroplasty. AB - BACKGROUND: Total knee arthroplasty is one of the most successful surgeries with respect to relieving pain and restoring function of the knee. However, some studies have reported that patients are not always satisfied with their results after total knee arthroplasty. The aim of this study was to determine whether the muscle strength around the knee joint and the walking status influence patients' expectations and satisfaction before and after total knee arthroplasty. METHODS: We evaluated 28 patients who underwent 30 primary total knee arthroplasties from March 2012 to June 2013. We assessed patient-reported scores using the 2011 Knee Society Scoring System, knee extensor and flexor strength, the 10-m walking test, and the timed up-and-go test. All assessments were performed preoperatively and 1 year after total knee arthroplasty. We determined the correlation between the patient-reported scores and each variable. RESULTS: Preoperative patient satisfaction was significantly correlated with knee symptoms and functional activities, but not with muscle strength or walking status. Postoperative patient satisfaction was significantly correlated with knee symptoms, functional activities, knee extensor strength, and walking status, including the 10-m walking test and timed up-and-go test, after total knee arthroplasty. In stepwise regression analysis, predictors of patient satisfaction with total knee arthroplasty were knee symptoms, functional ability, and knee extensor strength. CONCLUSIONS: Our study demonstrates that pain relief and restoration of functional activity are highly correlated with increasing patient satisfaction after total knee arthroplasty. The results also indicate that the quadriceps is important for patient satisfaction and restoration of functional activity following total knee arthroplasty. PMID- 26755385 TI - Comparison between topical and intravenous administration of tranexamic acid in primary total hip arthroplasty. AB - BACKGROUND: Tranexamic acid has been reported to be safer with topical administration than with intravenous administration in total knee arthroplasty. However, the most effective administration route of tranexamic acid in total hip arthroplasty remains controversial. This study compared the effectiveness of topical tranexamic acid administration with that of intravenous tranexamic acid administration in total hip arthroplasty. METHODS: We retrospectively examined the medical records of 886 patients with osteoarthritis of the hip joint, who had undergone unilateral primary total hip arthroplasty. The patients were divided into a control group (n = 302; did not receive tranexamic acid), topical group (n = 265; topically administered 2 g tranexamic acid in 30 mL normal saline via drain tubes placed in the joint before wound closure along with posterior soft tissue repair), and intravenous group (n = 319; intravenously administered 1 g tranexamic acid before skin incision along with posterior soft tissue repair). Data on blood loss, hemoglobin levels, transfusion rates, and occurrence of deep vein thrombosis and pulmonary embolization were collected. RESULTS: The mean operation times were approximately 40 min in all of the groups. The operation time and intra-operative blood loss were significantly lower in the control group than in the topical and intravenous groups. However, the post-operative blood loss, total blood loss, and decrease in the hemoglobin level were significantly higher in the control group than in the topical and intravenous groups. There were no significant differences in terms of blood loss and systemic complications between the tranexamic acid administration methods. CONCLUSIONS: Tranexamic acid reduces both post-operative and total blood loss in total hip arthroplasty. Moreover, a lower amount of tranexamic acid can be used to reduce blood loss in total hip arthroplasty with intravenous tranexamic acid administration than with topical tranexamic acid administration. Therefore, we suggest that tranexamic acid should be intravenously administered pre-operatively and the posterior soft tissue should be repaired to decrease total hip arthroplasty-related complications. PMID- 26755386 TI - Walking ability before and after a hip fracture in elderly predict greater long term survivorship. AB - AIM: The morbidity and mortality after a hip fracture in the elderly population are multifactorial. The aim of this study is to determine the long-term impact of specific factors to mortality rate and mobility after a hip fracture in the elderly. MATERIALS AND METHODS: Elderly suffering a hip fracture after a low energy trauma was included in the study, whereas moribund patients with severe comorbid conditions and high-energy trauma were excluded. All the patients were treated operatively during 2003. Data for survivorship and mobilization was collected six months, one and ten years after the operation. Kaplan-Meier log rang test was used for the survival analysis and cox regression for multivariate analysis of prediction factors such as age, gender, time to surgery after trauma, type of fracture, ambulation status before injury and early walking ability after the surgery. RESULTS: Two hundred and thirty three patients were finally included to the study. Gender (p = 0.64) and type of fracture (p = 0.92) seem to have no statistically significant impact on survivorship. Age (p < 0.001), time of surgery after the trauma (p = 0.001), ambulation status (p < 0.001) and early walking ability after the surgery (p < 0.001) seem to have statistically significant impact on mortality, as independent factors. The significance is present one year and ten years after the surgery. However, according to the multivariate analysis, time to surgery after trauma and age lose significance, while early walking ability remain significant one and ten years after surgery (p < 0.001). Ambulation status seem to lose significance early after surgery, but reach significance ten years postoperatively (p < 0.001). CONCLUSION: In summary, it could be stated that early walking ability after an operation for a hip fracture in elderly is the most significant prediction factor of survivorship one and ten years postoperatively. Ambulation status before injury is a significant long-term predictor factor for survivorship. PMID- 26755387 TI - Effects of the belt electrode skeletal muscle electrical stimulation system on lower extremity skeletal muscle activity: Evaluation using positron emission tomography. AB - BACKGROUND: Lower-extremity muscle weakness in athletes after lower limb trauma or surgery can hinder their return to sports, and the associated muscle atrophy may lead to deterioration in performance after returning to sports. Recently, belt electrode skeletal muscle electrical stimulation (B-SES) which can contract all the lower limb skeletal muscles simultaneously was developed. However, no study has evaluated skeletal muscle activity with B-SES. Since only superficial muscles as well as a limited number of muscles can be investigated using electromyography, we investigated whether positron emission tomography (PET) can evaluate the activity of all the skeletal muscles in the body simultaneously. The purpose of this study was to evaluate the effectiveness of the B-SES system using PET. METHODS: Twelve healthy males (mean age, 24.3 years) were divided into two groups. The subjects in the control group remained in a sitting position for 10 min, and [(18)F] fluorodeoxyglucose (FDG) was intravenously injected. In the exercise group, subjects exercised using the B-SES system for 20 min daily for three consecutive days as a pre-test exercise. On the measurement day, they exercised for 10 min, received an injection of FDG, and exercised for another 10 min. PET-computed tomography images were obtained in each group 60 min after the FDG injection. Regions of interest were drawn in each lower-extremity muscle. We compared each skeletal muscle metabolism using the standardized uptake value. RESULTS: In the exercise group, FDG accumulation in the gluteus maximus, gluteus medius, gluteus minimus, quadriceps femoris, sartorius, and hamstrings was significantly higher than the muscles in the control (P < 0.05). CONCLUSION: Exercise with B-SES increased the skeletal muscle activity of the gluteal muscles as well as the most lower-extremity muscles simultaneously. PMID- 26755388 TI - Clinical and radiographic evaluation of cemented socket fixation concomitant to acetabular bone grafting fixed with absorbable hydroxyapatite-poly-l-lactide composite screws. AB - BACKGROUND: The durability of uncalcined and unsintered hydroxyapatite-poly-l lactide composite screws is unclear when used for the fixation of acetabular bone graft in total hip arthroplasty under full-weight conditions. We have used this type of screw for the fixation of acetabular bone graft in cemented or reverse hybrid total hip arthroplasty since 2003. Hence, we conducted a follow-up study to assess the safety and efficacy of these screws when used for cemented socket fixation. METHODS: In this study, 98 patients (106 cases) who underwent fixation of acetabular bone graft in cemented or reverse-hybrid total hip arthroplasty using hydroxyapatite-poly-l-lactide composite screws were followed up for over 5 years and evaluated clinically and radiographically. The patient population comprised 10 men and 88 women with a mean age of 60.3 years (range, 41-81 years) at the time of surgery. The original diagnosis for primary total hip arthroplasty was secondary osteoarthritis in 97 cases and high hip dislocation in nine cases. RESULTS: The mean follow-up period was 7.6 years (range, 5-11 years). No patient in this series required revision surgery, and no radiographical loosening occurred during the follow-up period. The mean Japanese Orthopaedic Association score improved from 48 (range, 7-73) preoperatively to 87 (range, 50-100) at the final follow-up. Radiographically bone graft consolidation was confirmed in all cases, and no apparent osteolysis around the cemented socket or composite screws was detected. Kaplan-Meier survival analyses with socket revision surgery for any reason, socket loosening, and appearance of a radiolucent line >1 mm in any zone as the endpoints yielded survival rates of 100%, 100%, and 86.8% at 5 years, and 100%, 100%, and 81.0% at 10 years, respectively. CONCLUSION: This absorbable screw seems to have no negative effects on the mid-term clinical results of cemented socket fixation. PMID- 26755389 TI - Factors affecting clinical outcomes after treatment of extra-articular open tibial fractures. AB - BACKGROUND: Tibial fractures are the most common long bone fracture and are often associated with severe soft tissue and bone defects. The objectives of our study were to describe the management and clinical results of patients with extra articular open tibial fractures and to identify factors associated with a poor functional outcome. METHODS: This study included 82 adults available for follow up for over 1 year after surgery. According to the AO Foundation/Orthopedic Trauma Association fracture classification, 26 fractures were type 41 A, 34 were type 42, and 22 were type 43 A. In accordance with the Gustilo-Anderson classification system, 31 were type I, 19 were type II, and 32 were type III. Initial nerve injury was confirmed in 18 cases. RESULTS: Definitive fixation occurred at a mean of 6.73 days (range, 0-16 days) after the injury. Soft tissue reconstruction was as follows: primary closure with debridement, 50 patients; split-thickness skin graft, 5; perforator based rotational flaps, 10; and free flaps, 17. Complications occurred in 29 cases (35.4%): superficial infection, 5 patients; deep infection, 3; primary suture site skin necrosis, 7; partial flap necrosis, 4; malalignment, 7; joint stiffness, 2; and hardware breakage, 1. Thirty additional operations (36.6%) were performed during the hospital stay. Mean bone union time was 20.4 weeks (range, 13-63 weeks) and the mean Lower Extremity Functional Scale score (LEFS) was 70.93 (range, 36-79). Multiple linear regression analysis indicated that skin defect size (p = 0.002), and occurrence of complications (p < 0.001) correlated with the LEFS score. CONCLUSION: Functional outcome after treatment of extra-articular open tibial fractures was influenced by the skin defect size and the presence of any complications. This suggests that good clinical results can be expected if complications are prevented through proper reduction, firm fixation, early soft tissue reconstruction, and early rehabilitation. PMID- 26755390 TI - A case of radial nerve paralysis associated with lateral humeral condyle fracture in a child. PMID- 26755391 TI - Tardy radial nerve palsy in congenital pseudarthrosis of the olecranon: A case report. PMID- 26755392 TI - Atypical manifestation of lung metastasis 17 years after initial diagnosis of low grade central osteosarcoma. PMID- 26755393 TI - Synthesis, in vitro antimycobacterial evaluation and docking studies of some new 5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one schiff bases. AB - Development of multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis (TB) has been considered as major health burden, globally. In order to develop novel, potential molecules against drug resistant TB, twenty two (22) new 3-substituted-7-benzyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3 d]pyrimidin-4(3H)-one (6a-k) and 3-substituted-7-benzyl-2-methyl-5,6,7,8 tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (7a-k) derivatives were designed and synthesized by using appropriate synthetic protocols. Pantothenate synthetase (PS) was considered as the target for the molecular docking studies and evaluated the binding pattern at active site, as PS plays a significant role in the biosynthesis of pantothenate in Mycobacterium tuberculosis (MTB). The preliminary in vitro antibacterial screening of test compounds was carried out against two strains of Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacteria. The antimycobacterial screening was performed against MTB H37Rv and an isoniazid-resistant clinical isolate of MTB. The compounds 6b, 6c, 6d, 6k, 7b, 7c, 7d and 7k exhibited promising antibacterial activity MIC in the range of 15-73 MUM against all bacterial strains used and compounds 6d and 7b showed antimycobacterial activity (IC50 <340 MUM in LRP assay) and (MIC <9 MUM in broth microdilution method). PMID- 26755394 TI - Identification of benzothiophene amides as potent inhibitors of human nicotinamide phosphoribosyltransferase. AB - Nicotinamide phosphoribosyltransferase (Nampt) is an attractive therapeutic target for cancer. A Nampt inhibitor with novel benzothiophene scaffold was discovered by high throughput screening. Herein the structure-activity relationship of the benzothiophene Nampt inhibitor was investigated. Several new inhibitors demonstrated potent activity in both biochemical and cell-based assays. In particular, compound 16b showed good Nampt inhibitory activity (IC50=0.17 MUM) and in vitro antitumor activity (IC50=3.9 MUM, HepG2 cancer cell line). Further investigation indicated that compound 16b could efficiently induce cancer cell apoptosis. Our findings provided a good starting point for the discovery of novel antitumor agents. PMID- 26755395 TI - Gene silencing by 2'-O-methyldithiomethyl-modified siRNA, a prodrug-type siRNA responsive to reducing environment. AB - RNAs bearing various 2'-modifications have been synthesized in an effort to improve nuclease resistance. However, the gene silencing activity of small interfering RNAs (siRNAs) has been decreased or sometimes completely suppressed by the chemical modifications. We previously developed a post-synthetic approach for the synthesis of 2'-O-methyldithiomethyl-modified RNA, which can be converted into unmodified RNA under reducing conditions, and named it Reducing-Environment Dependent Uncatalyzed Chemical Transforming RNA (REDUCT RNA). Here, the gene silencing activity of REDUCT siRNA bearing 2'-O-methyldithiomethyl groups was evaluated. REDUCT siRNA showed more effective gene silencing than unmodified siRNA regardless of the modification site. This result suggests that REDUCT siRNA is converted into unmodified siRNA inside cells as a prodrug-type siRNA. PMID- 26755398 TI - Photonic quantum information: science and technology. AB - Recent technological progress in the generation, manipulation and detection of individual single photons has opened a new scientific field of photonic quantum information. This progress includes the realization of single photon switches, photonic quantum circuits with specific functions, and the application of novel photonic states to novel optical metrology beyond the limits of standard optics. In this review article, the recent developments and current status of photonic quantum information technology are overviewed based on the author's past and recent works. PMID- 26755399 TI - HIV-1 Infection Dysregulates Cell Cycle Regulatory Protein p21 in CD4+ T Cells Through miR-20a and miR-106b Regulation. AB - Both CD4+ T lymphocytes and macrophages are the major targets of human immunodeficiency virus type 1 (HIV-1); however, they respond differently to HIV-1 infection. We hypothesized that HIV-1 infection alters gene expression in CD4+ T cells and monocyte-derived macrophages (MDMs) in a cell specific manner and microRNAs (miRNAs) in part play a role in cell-specific gene expression. Results indicate that 183 and 31 genes were differentially regulated in HIV-1 infected CD4+ T cells and MDMs, respectively, compared to their mock-infected counterparts. Among the differentially expressed genes, cell cycle regulatory gene, p21 (CDKN1A) was upregulated in virus infected CD4+ T cells both at the mRNA and protein level in CD4+ T cells, whereas no consistent change was observed in MDMs. Productively infected CD4+ T cells express higher amount of p21 compared to bystander cells. In determining the mechanism(s) of cell type specific regulation of p21, we found that the miRNAs miR-106b and miR-20a that target p21 were specifically downregulated in HIV-1 infected CD4+ T cells. Overexpression of these two miRNAs reduced p21 expression significantly in HIV-1 infected CD4+ T cells. These findings provide a potential mechanism, by which, HIV-1 could exploit host cellular machineries to regulate selective gene expression in target cells. J. Cell. Biochem. 117: 1902-1912, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26755396 TI - From migration to settlement: the pathways, migration modes and dynamics of neurons in the developing brain. AB - Neuronal migration is crucial for the construction of the nervous system. To reach their correct destination, migrating neurons choose pathways using physical substrates and chemical cues of either diffusible or non-diffusible nature. Migrating neurons extend a leading and a trailing process. The leading process, which extends in the direction of migration, determines navigation, in particular when a neuron changes its direction of migration. While most neurons simply migrate radially, certain neurons switch their mode of migration between radial and tangential, with the latter allowing migration to destinations far from the neurons' site of generation. Consequently, neurons with distinct origins are intermingled, which results in intricate neuronal architectures and connectivities and provides an important basis for higher brain function. The trailing process, in contrast, contributes to the late stage of development by turning into the axon, thus contributing to the formation of neuronal circuits. PMID- 26755397 TI - Novel concept of iSALT (inducible skin-associated lymphoid tissue) in the elicitation of allergic contact dermatitis. AB - Allergic contact dermatitis (ACD) is one of the most common inflammatory skin diseases, which is classified as a delayed-type hypersensitivity immune response. The development of ACD is divided into two phases: sensitization and elicitation. In the sensitization phase, antigen-specific effector T cells are induced in the draining lymph nodes by antigen-captured cutaneous dendritic cells (DCs) that migrate from the skin. In the elicitation phase, the effector T cells are activated in the skin by antigen-captured cutaneous DCs and produce various chemical mediators, which create antigen-specific inflammation. In this review, we discuss the recent advancements in the immunological mechanisms of ACD, focusing on the mechanisms in the elicitation phase. The observations of elicitation of CHS lead to the emerging novel concept of iSALT (inducible skin associated lymphoid tissue). PMID- 26755402 TI - Cardiovascular risk scores: Usefulness and limitations. PMID- 26755401 TI - Four hours is enough for lactation interruption after high-dose methylprednisolone treatment in multiple sclerosis mothers by measuring milk cortisol levels. PMID- 26755403 TI - Rehabilitation Following Meniscal Root Repair: A Clinical Commentary. AB - SYNOPSIS: There is a growing body of evidence surrounding the pathology and treatment of meniscal root tears. As surgical techniques are being developed and refined, rehabilitation protocols for meniscal root repairs must be defined and tested. Little information has been published regarding specific rehabilitation parameters for meniscal root repairs through all phases of rehabilitation. The goal of this commentary is to describe a rehabilitation program for meniscal root repairs that is founded on anatomical, physiological, and biomechanical principles with criteria-based progressions. PMID- 26755400 TI - Ammonia-induced miRNA expression changes in cultured rat astrocytes. AB - Hepatic encephalopathy is a neuropsychiatric syndrome evolving from cerebral osmotic disturbances and oxidative/nitrosative stress. Ammonia, the main toxin of hepatic encephalopathy, triggers astrocyte senescence in an oxidative stress dependent way. As miRNAs are critically involved in cell cycle regulation and their expression may be regulated by oxidative stress, we analysed, whether astrocyte senescence is a consequence of ammonia-induced miRNA expression changes. Using a combined miRNA and gene microarray approach, 43 miRNA species which were downregulated and 142 genes which were upregulated by NH4Cl (5 mmol/l, 48 h) in cultured rat astrocytes were found. Ammonia-induced miRNA and gene expression changes were validated by qPCR and 43 potential miRNA target genes, including HO-1, were identified by matching upregulated mRNA species with predicted targets of miRNA species downregulated by ammonia. Inhibition of HO-1 targeting miRNAs which were downregulated by NH4Cl strongly upregulated HO-1 mRNA and protein levels and inhibited astrocyte proliferation in a HO-1-dependent way. Preventing ammonia-induced upregulation of HO-1 by taurine (5 mmol/l) as well as blocking HO-1 activity by tin-protoporphyrine IX fully prevented ammonia-induced proliferation inhibition and senescence. The data suggest that ammonia induces astrocyte senescence through NADPH oxidase-dependent downregulation of HO-1 targeting miRNAs and concomitant upregulation of HO-1 at both mRNA and protein level. PMID- 26755404 TI - Conservative Management of Second Metatarsophalangeal Joint Instability in a Professional Dancer: A Case Report. AB - STUDY DESIGN: Case report. BACKGROUND: Professional ballet and modern dancers spend an inordinate amount of time on demi pointe (rising onto their forefeet), placing excessive force on the metatarsophalangeal joints and putting them at risk of instability. Surgical treatment of this condition is well described in the literature. However, studies describing conservative management, particularly in dance populations, are lacking. CASE DESCRIPTION: A 33-year-old dancer presented with insidious onset of medial arch and second and third metatarsophalangeal joint pain. Functional deficits included the inability to walk barefoot, perform demi releve, or balance on demi pointe. Imaging studies revealed osteoarthritis of the first metatarsophalangeal joint, second metatarsophalangeal joint calcification, capsulitis, and plantar plate rupture, leading to a diagnosis of instability. The dancer underwent a treatment program that included taping, padding, physical therapy, a series of prolotherapy injections, and activity modification. OUTCOMES: The dancer was seen for a total of 37 physical therapy sessions over the 16-week rehabilitation period. At the time of discharge, the patient had returned to full duty and performed all choreography with taping and padding. Repeated single-leg jumps and turns on the right foot, however, still caused discomfort. At her 6-month follow-up, the dancer's total Dance Functional Outcome Survey (DFOS) score had improved from 16% to 86%, and her Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) physical scores improved from 24 to 47. One year after discharge, the dancer reported pain-free dancing with no taping or padding. DISCUSSION: This case report describes early diagnosis and a multimodal treatment approach in a professional dancer with significant disability secondary to metatarsophalangeal joint instability. LEVEL OF EVIDENCE: Therapy, level 4. PMID- 26755405 TI - A Comparison of the Effects of Stabilization Exercises Plus Manual Therapy to Those of Stabilization Exercises Alone in Patients With Nonspecific Mechanical Neck Pain: A Randomized Clinical Trial. AB - STUDY DESIGN: Randomized clinical trial. BACKGROUND: Little is known about the efficacy of providing manual therapy in addition to cervical and scapulothoracic stabilization exercises in people with mechanical neck pain (MNP). Objectives To compare the effects of stabilization exercises plus manual therapy to those of stabilization exercises alone on disability, pain, range of motion (ROM), and quality of life in patients with MNP. METHODS: One hundred two patients with MNP (18-65 years of age) were recruited and randomly allocated into 2 groups: stabilization exercise without (n = 51) and with (n = 51) manual therapy. The program was carried out 3 days per week for 4 weeks. The Neck Disability Index, visual analog pain scale, digital algometry of pressure pain threshold, goniometric measurements, and Medical Outcomes Study 36-Item Short-Form Health Survey were used to assess participants at baseline and after 4 weeks. RESULTS: Improvements in Neck Disability Index score, night pain, rotation ROM, and the Medical Outcomes Study 36-Item Short-Form Health Survey score were greater in the group that received stabilization exercise with manual therapy compared to the group that only received stabilization exercise. Between-group differences (95% confidence interval) were 2.2 (0.1, 4.3) points for the Neck Disability Index, 1.1 (0.0, 2.3) cm for pain at night measured on the visual analog scale, -4.3 degrees (-8.1 degrees , -0.5 degrees ) and -5.0 degrees (-8.2 degrees , -1.7 degrees ) for right and left rotation ROM, respectively, and -2.9 (-5.4, -0.4) points and -3.1 (-6.2, 0.0) points for the Medical Outcomes Study 36-Item Short Form Health Survey physical and mental components, respectively. Changes in resting and activity pain, pressure pain threshold, and cervical extension or lateral flexion ROM did not differ significantly between the groups. Pressure pain threshold increased only in those who received stabilization exercise with manual therapy (P<.05). CONCLUSION: The results of this study suggest that stabilization exercises with manual therapy may be superior to stabilization exercises alone for improving disability, pain intensity at night, cervical rotation motion, and quality of life in patients with MNP. LEVEL OF EVIDENCE: Therapy, level 1b. PMID- 26755406 TI - Timing of Physical Therapy Initiation for Nonsurgical Management of Musculoskeletal Disorders and Effects on Patient Outcomes: A Systematic Review. AB - STUDY DESIGN: Systematic review. BACKGROUND: Current US practice guidelines suggest an initial "wait-and-see" approach following onset of musculoskeletal pain, particularly for spinal pain. Several studies suggest that early, compared with delayed, initiation of physical therapy for musculoskeletal conditions may decrease health costs and improve outcomes. OBJECTIVE: To compare early and delayed initiation of physical therapy for individuals with musculoskeletal conditions and to assess effects on patient-important outcomes and cost. METHODS: MEDLINE (Ovid), CINAHL (EBSCO), Web of Science, and PEDro were the data sources. We included studies that compared early and delayed initiation of physical therapy for patients with musculoskeletal disorders. Studies in which early and delayed interventions differed were excluded. Two independent reviewers extracted study characteristics and outcomes, and determined eligibility and quality through consensus with a third reviewer. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used in summary conclusions. Standardized effect sizes (d) and odds ratios were calculated to assess the effect strength of early versus delayed physical therapy for each included study. RESULTS: Of the 3855 articles initially screened, 14 studies were included. The majority of articles studied low back pain (only 2 articles studied cervical pain). For spinal pain, there was low-quality evidence that early versus delayed physical therapy was associated with decreased cost and decreased frequency of opioid prescriptions, advanced imaging, and surgeries without compromising patient-important outcomes. One subgroup analyzed showed improved function/disability with early physical therapy in an occupational health setting. CONCLUSION: Although there were consistent results across studies favoring early physical therapy for decreased cost and medical utilization, quality was limited. Preliminary evidence suggests that early physical therapy may decrease cost without compromising outcomes. The primary limitation of the current research on this topic is in study design. Additional high-quality research involving prospective randomized designs and economic impact analyses is required to further investigate the outcomes associated with early initiation of physical therapy. LEVEL OF EVIDENCE: Therapy, level 1a. PMID- 26755407 TI - Division I College Football Concussion Rates Are Higher at Higher Altitudes. AB - STUDY DESIGN: Retrospective cohort. BACKGROUND: Participating in sports at high altitude may have a protective effect on the brain, according to research studies. Research using validated data-collection methods in a previously unexplored cohort may better estimate the association between concussion injury risk and altitude. OBJECTIVES: To determine the association between concussion rates and altitude during college football games. METHODS: Athletic trainers from 21 Division I football programs provided exposure and injury data to the National Collegiate Athletic Association (NCAA) Injury Surveillance Program (ISP) from the 2009-2010 to 2013-2014 academic years. The elevation of each stadium was determined. Concussion rates per 1000 athlete-exposures (AEs) were compared in 2 ways, based on the sample of stadium elevations: (1) median split (elevation higher than 178 m or lower than 178 m), and (2) quartile split. Rate ratios (RRs), rate differences, and 95% confidence intervals (CIs) were computed. RESULTS: One hundred sixty-nine concussions were reported over 49 040 AEs (3.45/1000 AEs). Using the median split, the concussion rate above 178 m (RR = 4.18/1000 AEs) was 1.47 times the concussion rate below 178 m (RR = 2.84/1000 AEs; 95% CI: 1.09, 2.00; P = .01). The concussion rate at the highest altitude quartile (higher than 284 m; RR = 5.01/1000 AEs) was 1.67 times greater than the concussion rate at the lowest altitude quartile (lower than 43 m; RR = 3.00/1000 AEs; 95% CI: 1.13, 2.48; P = .01). CONCLUSION: College football game concussion rates appear to increase at higher altitudes. The clinical significance of this relatively small increase is unknown. Future research should explore potential physiologic underpinnings associated with concussion risk at relatively higher and lower altitudes. LEVEL OF EVIDENCE: Prognosis, level 2b. PMID- 26755408 TI - Exercise and Cognitive Functioning in People With Chronic Whiplash-Associated Disorders: A Controlled Laboratory Study. AB - STUDY DESIGN: Controlled laboratory study. BACKGROUND: In addition to persistent pain, people with chronic whiplash-associated disorders (WAD) commonly deal with cognitive dysfunctions. In healthy individuals, aerobic exercise has a positive effect on cognitive performance, and preliminary evidence in other chronic pain conditions reveals promising results as well. However, there is evidence that people with chronic WAD may show a worsening of the symptom complex following physical exertion. OBJECTIVE: To examine postexercise cognitive performance in people with chronic WAD. METHODS: People with chronic WAD (n = 27) and healthy, inactive, sex- and age-matched controls (n = 27) performed a single bout of an incremental submaximal cycling exercise. Before and after the exercise, participants completed 2 performance-based cognitive tests assessing selective and sustained attention, cognitive inhibition, and simple and choice reaction time. RESULTS: At baseline, people with chronic WAD displayed significantly lower scores on sustained attention and simple reaction time (P<.001), but not on selective attention, cognitive inhibition, and choice reaction time (P>.05), compared with healthy controls. Postexercise, both groups showed significantly improved selective attention and choice reaction time (chronic WAD, P = .001; control, P<.001), while simple reaction time significantly increased (P = .037) only in the control group. In both groups, no other significant changes in sustained attention, cognitive inhibition, pain, and fatigue were observed (P>.05). CONCLUSION: In the short term, postexercise cognitive functioning, pain, and fatigue were not aggravated in people with chronic WAD. However, randomized controlled trials are required to study the longer-term and isolated effects of exercise on cognitive functioning. PMID- 26755409 TI - The Effect of an In-shoe Orthotic Heel Lift on Loading of the Achilles Tendon During Shod Walking. AB - STUDY DESIGN: Controlled laboratory study. BACKGROUND: Orthotic heel lifts are thought to lower tension in the Achilles tendon, but evidence for this effect is equivocal. OBJECTIVE: To investigate the effect of a 12-mm, in-shoe orthotic heel lift on Achilles tendon loading during shod walking using transmission-mode ultrasonography. METHODS: The propagation speed of ultrasound, which is governed by the elastic modulus and density of tendon and proportional to the tensile load to which it is exposed, was measured in the right Achilles tendon of 12 recreationally active men during shod treadmill walking at matched speeds (3.4 +/ 0.7 km/h), with and without addition of a heel lift. Vertical ground reaction force and spatiotemporal gait parameters were simultaneously recorded. Data were acquired at 100 Hz during 10 seconds of steady-state walking. Statistical comparisons were made using paired t tests (alpha = .05). RESULTS: Ultrasound transmission speed in the Achilles tendon was characterized by 2 maxima (P1, P2) and minima (M1, M2) during walking. Addition of a heel lift to footwear resulted in a 2% increase and 2% decrease in the first vertical ground reaction force peak and the local minimum, respectively (P<.05). Ultrasonic velocity in the Achilles tendon (P1, P2, M2) was significantly lower with the addition of an orthotic heel lift (P<.05). CONCLUSION: Peak ultrasound transmission speed in the Achilles tendon was lower with the addition of a 12-mm orthotic heel lift, indicating that the heel lift reduced tensile load in the Achilles tendon, thereby counteracting the effect of footwear observed in previous studies. These findings support the addition of orthotic heel lifts to footwear in the rehabilitation of Achilles tendon disorders where management aims to lower tension within the tendon. PMID- 26755410 TI - Scleral tunnel intraocular lens explantation: comment. PMID- 26755411 TI - Melatonin-based pickering emulsion for skin's photoprotection. AB - CONTEXT: Based on its antioxidant activity, melatonin was recently found to have a protection effect against photocarcinogenesis. OBJECTIVE: This work aimed to develop an innovative sunscreen formulation based on the Pickering emulsions concept, stabilized by physical UV filters, modified starch and natural oils associated to melatonin as a key strategy for prevention against UV-induced skin damage. MATERIALS AND METHODS: For this purpose, melatonin was incorporated in Pickering emulsions that were characterized using physicochemical, in vitro and in vivo testing. Physicochemical studies included physical and chemical stability by a thorough pharmaceutical control. The possible protective effects of melatonin against UV-induced cell damage in HaCaT cell lines were investigated in vitro. The safety assessment and the in vivo biological properties of the final formulations, including Human Repeat Insult Patch Test and sunscreen water resistance tests were also evaluated. RESULTS AND DISCUSSION: These studies demonstrated that melatonin sunscreen Pickering emulsion was beneficial and presented a powerful protection against UVB-induced damage in HaCat cells, including inhibition of apoptosis. The inclusion of zinc oxide, titanium dioxide, green coffee oil and starch ensured a high SPF (50+) against UVA and UVB. CONCLUSION: The combination of melatonin, multifunctional solid particles and green coffee oil, contributed to achieve a stable, effective and innovative sunscreen with a meaningful synergistic protection against oxidative stress. PMID- 26755413 TI - Grafting iminodiacetic acid on silica nanoparticles for facilitated refolding of like-charged protein and its metal-chelate affinity purification. AB - A series of highly charged nanoscale chelators were fabricated by grafting of poly(glycidyl methacrylate-iminodiacetic acid) (pGI) chains with iminodiacetic acid (IDA) chelating group on silica nanoparticles (SNPs) via atom transfer radical polymerization (ATRP). The nanoscale chelators, denoted as SNPs-pGI, possessed a nickel ion chelating capacity as high as 2800 MUmol/g, 50 times higher than the IDA-modified Sepharose FF (IDA-Sepharose) resin reported in literature and offered a high affinity binding capacity for hexahistidine-tagged enhanced green fluorescence protein (6 * His-EGFP) after nickel ion loading. More importantly, the anionic SNPs-pGI of high charge densities displayed much better performance than IDA-Sepharose in facilitating the refolding of like-charged 6 * His-EGFP from inclusion bodies (IBs). For example, for 0.2mg/mL 6 * His-EGFP IB refolding, addition of 6.2 MUL/mL SNPs-pGI with the highest charge density led to a refolding yield of 90%, over 43% higher than that obtained with 460 MUL/mL IDA Sepharose. It is notable that the much higher efficiency of the nanoscale chelator was obtained with a chelator consumption corresponding to only 1.4% of IDA-Sepharose. Moreover, the highly charged SNPs-pGI could efficiently facilitate the refolding of 6 * His-EGFP at higher IB concentrations (0.4 and 0.8 mg/mL). After refolding, nickel ions addition led to the recovery of the refolded 6 * His EGFP with high yield (80%), purity (96%) and enrichment ratio (1.8). All the results suggest that the SNPs-pGI of high charge densities were promising for cost-effective recovery of His-tagged proteins expressed as IBs with the integrative like-charge facilitated refolding and metal-chelate affinity purification strategy. PMID- 26755412 TI - Fast, rugged and sensitive ultra high pressure liquid chromatography tandem mass spectrometry method for analysis of cyanotoxins in raw water and drinking water- First findings of anatoxins, cylindrospermopsins and microcystin variants in Swedish source waters and infiltration ponds. AB - Freshwater blooms of cyanobacteria (blue-green algae) in source waters are generally composed of several different strains with the capability to produce a variety of toxins. The major exposure routes for humans are direct contact with recreational waters and ingestion of drinking water not efficiently treated. The ultra high pressure liquid chromatography tandem mass spectrometry based analytical method presented here allows simultaneous analysis of 22 cyanotoxins from different toxin groups, including anatoxins, cylindrospermopsins, nodularin and microcystins in raw water and drinking water. The use of reference standards enables correct identification of toxins as well as precision of the quantification and due to matrix effects, recovery correction is required. The multi-toxin group method presented here, does not compromise sensitivity, despite the large number of analytes. The limit of quantification was set to 0.1 MUg/L for 75% of the cyanotoxins in drinking water and 0.5 MUg/L for all cyanotoxins in raw water, which is compliant with the WHO guidance value for microcystin-LR. The matrix effects experienced during analysis were reasonable for most analytes, considering the large volume injected into the mass spectrometer. The time of analysis, including lysing of cell bound toxins, is less than three hours. Furthermore, the method was tested in Swedish source waters and infiltration ponds resulting in evidence of presence of anatoxin, homo-anatoxin, cylindrospermopsin and several variants of microcystins for the first time in Sweden, proving its usefulness. PMID- 26755414 TI - Prototype sphere-on-sphere silica particles for the separation of large biomolecules. AB - The goal of this study was to evaluate the possibilities offered by a prototype HPLC column packed with ~2.5MUm narrow size distribution sphere-on-sphere (SOS) silica particles bonded with C4 alkyl chains, for the analytical characterization of large biomolecules. The kinetic performance of this material was evaluated in both isocratic and gradient modes using various model analytes. The data were compared to those obtained on other widepore state-of-the-art fully core-shell and fully porous materials commonly employed to separate proteins moreover to a reference 5MUm wide pore material that is still often used in QC labs. In isocratic mode, minimum reduced plate height values of hmin=2.6, 3.3 and 3.3 were observed on butylparaben, decapeptide and glucagon, respectively. In gradient elution mode, the SOS column performs very high efficiency when working with fast gradients. This prototype column was also comparable (and sometimes superior) to other widepore stationary phases, whatever the gradient time and flow rate, when analyzing the largest model protein, namely BSA. These benefits may be attributed to the SOS particle morphology, minimizing the intra-particle mass transfer resistance. Finally, the SOS column was also applied for the analytical characterization of commercial monoclonal antibody (mAb) and antibody-drug conjugate (ADC) samples. With these classes of proteins, the performance of SOS column was similar to the best widepore stationary phases available on the market. PMID- 26755415 TI - Acid-base reaction-based dispersive liquid-liquid microextraction method for extraction of three classes of pesticides from fruit juice samples. AB - A sample preparation method involving acid-base reaction-based dispersive liquid liquid microextraction coupled with gas chromatography using nitrogen-phosphorous detection has been developed for the analysis of three classes of pesticides in juice samples. In this method, a basic organic solvent (p-chloroaniline) is used as an extraction solvent. It is dissolved in acidified deionized water and then injected into an alkaline aqueous sample solution. After injection, an acid-base reaction occurs and deprotonation of the organic solvent leads to formation of tiny droplets of the extractant and subsequent extraction of the analytes from sample solution. Under the optimum extraction conditions, the method showed low limits of detection and quantification in the range of 0.05-0.43ngmL(-1) and 0.17 1.43ngmL(-1), respectively. Extraction recoveries and enrichment factors were between 39.2 and 84.1% and between 548 and 1178, respectively. Relative standard deviations of less than 8.6% for the extraction of 2.0ngmL(-1) of each pesticide were obtained for intra- (n=6) and inter-day (n=4) precisions. Finally, different juice samples were successfully analyzed using the proposed method, and penconazole, diniconazole, triadimenol, and acetamiprid were determined in some samples at ngmL(-1) levels. PMID- 26755416 TI - Simultaneous analysis of silicon and boron dissolved in water by combination of electrodialytic salt removal and ion-exclusion chromatography with corona charged aerosol detection. AB - Selective separation and sensitive detection of dissolved silicon and boron (DSi and DB) in aqueous solution was achieved by combining an electrodialytic ion isolation device (EID) as a salt remover, an ion-exclusion chromatography (IEC) column, and a corona charged aerosol detector (CCAD) in sequence. DSi and DB were separated by IEC on the H(+)-form of a cation exchange resin column using pure water eluent. DSi and DB were detected after IEC separation by the CCAD with much greater sensitivity than by conductimetric detection. The five-channel EID, which consisted of anion and cation acceptors, cathode and anode isolators, and a sample channel, removed salt from the sample prior to the IEC-CCAD. DSi and DB were scarcely attracted to the anion accepter in the EID and passed almost quantitatively through the sample channel. Thus, the coupled EID-IEC-CCAD device can isolate DSi and DB from artificial seawater and hot spring water by efficiently removing high concentrations of Cl(-) and SO4(2-) (e.g., 98% and 80% at 0.10molL(-1) each, respectively). The detection limits at a signal-to-noise ratio of 3 were 0.52MUmolL(-1) for DSi and 7.1MUmolL(-1) for DB. The relative standard deviations (RSD, n=5) of peak areas were 0.12% for DSi and 4.3% for DB. PMID- 26755417 TI - Use of a pre-analysis osmolality normalisation method to correct for variable urine concentrations and for improved metabolomic analyses. AB - Metabolomics analyses of urine have the potential to provide new information on the detection and progression of many disease processes. However, urine samples can vary significantly in total solute concentration and this presents a challenge to achieve high quality metabolomic datasets and the detection of biomarkers of disease or environmental exposures. This study investigated the efficacy of pre- and post-analysis normalisation methods to analyse metabolomic datasets obtained from neat and diluted urine samples from five individuals. Urine samples were extracted by solid phase extraction (SPE) prior to metabolomic analyses using a sensitive nanoflow/nanospray LC-MS technique and the data analysed by principal component analyses (PCA). Post-analysis normalisation of the datasets to either creatinine or osmolality concentration, or to mass spectrum total signal (MSTS), revealed that sample discrimination was driven by the dilution factor of urine rather than the individual providing the sample. Normalisation of urine samples to equal osmolality concentration prior to LC-MS analysis resulted in clustering of the PCA scores plot according to sample source and significant improvements in the number of peaks common to samples of all three dilutions from each individual. In addition, the ability to identify discriminating markers, using orthogonal partial least squared-discriminant analysis (OPLS-DA), was greatly improved when pre-analysis normalisation to osmolality was compared with post-analysis normalisation to osmolality and non normalised datasets. Further improvements for peak area repeatability were observed in some samples when the pre-analysis normalisation to osmolality was combined with a post-analysis mass spectrum total useful signal (MSTUS) or MSTS normalisation. Future adoption of such normalisation methods may reduce the variability in metabolomics analyses due to differing urine concentrations and improve the discovery of discriminating metabolites associated with sample source. PMID- 26755418 TI - A capillary liquid chromatography method for benzalkonium chloride determination as a component or contaminant in mixtures of biocides. AB - A method for quantifying benzalkonium chloride (BAK), an alkyl dimethyl benzyl ammonium compound, in several biocides formulations is proposed. A tertiary amine like N-(3-aminopropyl)-N-dodecyl-1,3-propanediamine (TA) and a straight-chain alkyl ammonium compound like trimethyl-tetradecyl ammonium chloride (TMTDAC), have been employed as trade surfactants besides BAK. Two capillary analytical columns with different polarities are tested: inertsil CN-3 capillary column (150mm*0.5mm i.d., 3MUm particle diameter) and a non endcapped Zorbax C18 capillary column (35mm*0.5mm i.d., 5MUm particle diameter). This latter column provided the best separation of the BAK homologues in less than 12min using acetonitrile:acetate buffer (50mM, pH 5) 85:15 at 20MULmin(-1). The proposed method combines on-line in-tube solid-phase microextraction (IT-SPME) coupled to capillary liquid chromatography (CapLC) and UV diode array detection. Matrix effect was present when TA were in excess to BAK. If TMTDAC is the co-biocide, matrix effect is always present. A decreasing of analytical response mainly for C12-BAK homologue was found using both chromatographic columns. The charged amount of mixture in the system was the most important parameter for obtaining reliable results. 1mL was the on line processed sample volume optimum for concentrations lower than 35MUgmL(-1) of total surfactants. LODs were 0.03MUgmL( 1) and 0.006MUgmL(-1) for C12-BAK and C14-BAK, respectively. This method is also of use to evaluate the unwanted presence of BAK in biocide formulations due to industrial processes. PMID- 26755420 TI - Versatile size-dependent sorting of C. elegans nematodes and embryos using a tunable microfluidic filter structure. AB - The roundworm Caenorhabditis elegans (C. elegans) is a powerful model organism for addressing fundamental biological questions related to human disease and aging. Its life cycle consists of an embryo stage, four larval stages that can be clearly distinguished by size and different morphological features, and adulthood. Many worm-based bio-assays require stage- or age-synchronized worm populations, for example for studying the life cycle and aging of worms under different pharmacological conditions or to avoid misinterpretation of results due to overlap of stage-specific response in general. Here, we present a new microfluidic approach for size-dependent sorting of C. elegans nematodes on-chip. We take advantage of the external pressure-deformable profile of polydimethylsiloxane (PDMS) transfer channels that connect two on-chip worm chambers. The pressure-controlled effective cross-section of these channels creates adjustable filter structures that can be easily tuned for a specific worm sorting experiment, without changing the design parameters of the device itself. By optimizing the control pressure settings, we can extract larvae of a specific development stage from a mixed worm culture with an efficiency close to 100% and with a throughput of up to 3.5 worms per second. Our approach also allows us to generate mixed populations of larvae of adjacent stages or to adjust their ratio directly in the microfluidic chamber. Moreover, using the same device, we demonstrated extraction of embryos from adult worm populations for subsequent culture of accurately age-synchronized nematode populations or embryo-based assays. Considering that our sorting device is merely based on geometrical parameters and operated by simple fluidic and pressure control, we believe that it has strong potential for use in advanced, automated, microfluidic C. elegans based assay platforms. PMID- 26755419 TI - Livestock-associated methicillin and multidrug resistant S. aureus in humans is associated with occupational pig contact, not pet contact. AB - This study aimed to explore the association of livestock-associated S. aureus with occupational pig contact and pet contact. In this cross-sectional study, 1,422 participants (including 244 pig workers, 200 pet-owning workers and 978 control workers) responded to a questionnaire and provided a nasal swab for S. aureus analysis. Resulting isolates were tested for antibiotic susceptibility, the immune evasion cluster (IEC) genes, and multilocus sequence type. Compared with controls, the pig workers demonstrated a greater prevalence of multidrug resistant S. aureus (MDRSA) [prevalence ratio (PR) = 3.38; 95% CI: 2.07-5.53] and methicillin-resistant S. aureus (MRSA) (PR = 7.42; 95% CI: 3.71-14.83), but the prevalence of MDRSA and MRSA was similar in pet-owning workers and controls. There was a positive relation of frequency of pig contact with prevalence of MDRSA and MRSA carriage. Only pig workers carried MDRSA CC9 (16 isolates) and MRSA CC9 (16 isolates), and all of these isolates were tetracycline resistant and absent of IEC genes. These findings suggest that livestock-associated MRSA and MDRSA(CC9, IEC-negative, tetracycline-resistant) in humans is associated with occupational pig contact, not pet contact, and support growing concern about antibiotics use in pig farms and raising questions about the potential for occupational exposure to opportunistic S. aureus. PMID- 26755421 TI - Musculoskeletal fitness and balance in older individuals (65-85 years) and its association with steps per day: a cross sectional study. AB - BACKGROUND: There is limited normative, objective data combining musculoskeletal fitness (MSF), balance and physical activity (PA) among older adults. The aims were therefore to; 1) describe MSF and balance in older Norwegian adults focusing on age- and sex-related differences; 2) investigate the associations among MSF, balance and objectively-assessed PA levels. METHODS: This was part of a national multicenter study. Participants (65-85 years) were randomly selected from the national population registry. We used ActiGraph GT1M accelerometers to measure PA. Balance and MSF were assessed using: one leg standing (OLS), handgrip strength (HG), static back extension (SBE), sit and reach (SR), back scratch right, left arm over (BSR, BSL). Univariate analyses of variance were used to assess sex differences within the different MSF and balance tests and for comparisons among multiple age groups. Linear regression analysis was used to investigate how PA (expressed in 1000 steps increments) was associated with MSF and balance. RESULTS: 85 women and 76 men were included. Mean age (standard deviation (SD)) was 73.2 (5.4) years for women and 72.3 (4.8) years for men. The youngest participants (65-69 years) had significantly better mean OLS- and SBE results compared with older participants. Women (65-85 years) had significantly better mean SR, BSR, BSL and SBE results compared with men (65-85 years). Men had significantly better mean HG results compared with women. No sex differences in mean OLS results were observed. A daily increment of 1000 steps was associated with better mean test scores for OLS- and SBE tests (b = 1.88, 95% CI: 0.85 to 2.90 (p <= 0.001) and b = 4.63, 95% CI: 1.98 to 7.29 (p = 0.001), respectively). CONCLUSION: The youngest (65-69 years) had better static balance and muscular endurance in trunk extensors compared with older participants. Older women (65-85 years) had better joint flexibility than older men (65-85 years), whereas older men had better handgrip strength than older women. A higher PA level was associated with better static balance and muscular endurance in trunk extensors in older individuals. This study provides important normative data, and further investigation of trunk endurance and static balance as key foci for PA interventions in elderly is warranted. PMID- 26755422 TI - In vivo characterization of early-stage radiation skin injury in a mouse model by two-photon microscopy. AB - Ionizing radiation (IR) injury is tissue damage caused by high energy electromagnetic waves such as X-ray and gamma ray. Diagnosis and treatment of IR injury are difficult due to its characteristics of clinically latent post irradiation periods and the following successive and unpredictable inflammatory bursts. Skin is one of the many sensitive organs to IR and bears local injury upon exposure. Early-stage diagnosis of IR skin injury is essential in order to maximize treatment efficiency and to prevent the aggravation of IR injury. In this study, early-stage changes of the IR injured skin at the cellular level were characterized in an in vivo mouse model by two-photon microscopy (TPM). Various IR doses were applied to the mouse hind limbs and the injured skin regions were imaged daily for 6 days after IR irradiation. Changes in the morphology and distribution of the epidermal cells and damage of the sebaceous glands were observed before clinical symptoms. These results showed that TPM is sensitive to early-stage changes of IR skin injury and may be useful for its diagnosis. PMID- 26755431 TI - Physicochemical property profile for brain permeability: comparative study by different approaches. AB - A comparative study of classification models of brain penetration by different approaches was carried out on a training set of 1000 chemicals and drugs, and an external test set of 100 drugs. Ten approaches were applied in this work: seven medicinal chemistry approaches (including "rule of 5" and multiparameter optimization) and also three SAR techniques: logistic regression (LR), random forest (RF) and support vector machine (SVM). Forty-one different medicinal chemistry descriptors representing diverse physicochemical properties were used in this work. Medicinal chemistry approaches based on the intuitive estimation of preference zones of CNS or non-CNS chemicals, with different rules and scoring functions, yield unbalanced models with poor classification accuracy. RF and SVM methods yielded 82% and 84% classification accuracy respectively for the external test set. LR was also successful in CNS/non-CNS (denoted in this study as CNS+/CNS-) classification and yielded an overall accuracy equivalent to that of SVM and RF. At the same time, LR is especially valuable for medicinal chemists because of its simplicity and the possibility of clear mechanistic interpretation. PMID- 26755432 TI - Pressure-Tuned Structure and Property of Optically Active Nanocrystals. AB - Investigations through high-pressure X-ray scattering and spectroscopy in combination with theoretical computations shows that high-pressure compression can systematically tune the optical properties and mechanical stability of the molecular nanocrystals. PMID- 26755433 TI - The Dietary Flavonoid Fisetin Causes Cell Cycle Arrest, Caspase-Dependent Apoptosis, and Enhanced Cytotoxicity of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells. AB - Fisetin (3,3',4',7-tetrahydroxyflavone), a flavonoid found in a number of fruits and vegetables, has diverse biological activities, including cytotoxic effects on cancer cells. In this study, we investigated the effect of fisetin on triple negative breast cancer (TNBC) cells. TNBC has a poorer prognosis than other types of breast cancer and treatment options for this disease are limited. Fisetin inhibited the growth of MDA-MB-468 and MDA-MB-231 TNBC cells, as well as their ability to form colonies, without substantially affecting the growth of non malignant cells. In addition, fisetin inhibited the growth of estrogen receptor bearing MCF-7 breast cancer cells and human epidermal growth factor receptor 2 overexpressing SK-BR-3 breast cancer cells. Fisetin inhibited TNBC cell division and induced apoptosis, which was associated with mitochondrial membrane permeabilization and the activation of caspase-9 and caspase-8, as well as the cleavage of poly(ADP-ribose) polymerase-1. Induction of caspase-dependent apoptosis by fisetin was confirmed by reduced killing of TNBC cells in the presence of the pan-caspase inhibitors Z-VAD-FMK and BOC-D-FMK. Decreased phosphorylation of histone H3 at serine 10 in fisetin-treated TNBC cells at G2/M phase of the cell cycle suggested that fisetin-induced apoptosis was the result of Aurora B kinase inhibition. Interestingly, the cytotoxic effect of cisplatin, 5-fluorouracil, and 4-hydroxycyclophosphamide metabolite of cyclophosphamide on TNBC cells was increased in the presence of fisetin. These findings suggest that further investigation of fisetin is warranted for possible use in the management of TNBC. J. Cell. Biochem. 117: 1913-1925, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26755434 TI - Material properties of evolutionary diverse spider silks described by variation in a single structural parameter. AB - Spider major ampullate gland silks (MAS) vary greatly in material properties among species but, this variation is shown here to be confined to evolutionary shifts along a single universal performance trajectory. This reveals an underlying design principle that is maintained across large changes in both spider ecology and silk chemistry. Persistence of this design principle becomes apparent after the material properties are defined relative to the true alignment parameter, which describes the orientation and stretching of the protein chains in the silk fiber. Our results show that the mechanical behavior of all Entelegynae major ampullate silk fibers, under any conditions, are described by this single parameter that connects the sequential action of three deformation micromechanisms during stretching: stressing of protein-protein hydrogen bonds, rotation of the beta-nanocrystals and growth of the ordered fraction. Conservation of these traits for over 230 million years is an indication of the optimal design of the material and gives valuable clues for the production of biomimetic counterparts based on major ampullate spider silk. PMID- 26755437 TI - CASE 7-2016 Choice of Percutaneous Mechanical Assistance During Cardiopulmonary Instability: Heart, Lungs, or Both? PMID- 26755435 TI - Molecular mechanisms that underpin EML4-ALK driven cancers and their response to targeted drugs. AB - A fusion between the EML4 (echinoderm microtubule-associated protein-like) and ALK (anaplastic lymphoma kinase) genes was identified in non-small cell lung cancer (NSCLC) in 2007 and there has been rapid progress in applying this knowledge to the benefit of patients. However, we have a poor understanding of EML4 and ALK biology and there are many challenges to devising the optimal strategy for treating EML4-ALK NSCLC patients. In this review, we describe the biology of EML4 and ALK, explain the main features of EML4-ALK fusion proteins and outline the therapies that target EML4-ALK. In particular, we highlight the recent advances in our understanding of the structures of EML proteins, describe the molecular mechanisms of resistance to ALK inhibitors and assess current thinking about combinations of ALK drugs with inhibitors that target other kinases or Hsp90. PMID- 26755436 TI - Enhanced genome editing in mammalian cells with a modified dual-fluorescent surrogate system. AB - Programmable DNA nucleases such as TALENs and CRISPR/Cas9 are emerging as powerful tools for genome editing. Dual-fluorescent surrogate systems have been demonstrated by several studies to recapitulate DNA nuclease activity and enrich for genetically edited cells. In this study, we created a single-strand annealing directed, dual-fluorescent surrogate reporter system, referred to as C-Check. We opted for the Golden Gate Cloning strategy to simplify C-Check construction. To demonstrate the utility of the C-Check system, we used the C-Check in combination with TALENs or CRISPR/Cas9 in different scenarios of gene editing experiments. First, we disrupted the endogenous pIAPP gene (3.0 % efficiency) by C-Check validated TALENs in primary porcine fibroblasts (PPFs). Next, we achieved gene editing efficiencies of 9.0-20.3 and 4.9 % when performing single- and double gene targeting (MAPT and SORL1), respectively, in PPFs using C-Check-validated CRISPR/Cas9 vectors. Third, fluorescent tagging of endogenous genes (MYH6 and COL2A1, up to 10.0 % frequency) was achieved in human fibroblasts with C-Check validated CRISPR/Cas9 vectors. We further demonstrated that the C-Check system could be applied to enrich for IGF1R null HEK293T cells and CBX5 null MCF-7 cells with frequencies of nearly 100.0 and 86.9 %, respectively. Most importantly, we further showed that the C-Check system is compatible with multiplexing and for studying CRISPR/Cas9 sgRNA specificity. The C-Check system may serve as an alternative dual-fluorescent surrogate tool for measuring DNA nuclease activity and enrichment of gene-edited cells, and may thereby aid in streamlining programmable DNA nuclease-mediated genome editing and biological research. PMID- 26755440 TI - Maternal serum interleukin 6 levels and fetomaternal outcomes in women with preterm premature rupture of membranes in Lagos, South-western Nigeria. AB - OBJECTIVE: This study was done to assess the relationship between maternal serum IL-6 levels and fetomaternal outcome following PPROM. METHODOLOGY: This was a prospective cohort study comprising 45 cases of PPROM and 45 controls of similar age, parity, and gestational age. Five milliliters of maternal serum was collected after obtaining informed consent. They were followed up till delivery and records of the delivery and neonatal outcomes were obtained. Serum IL-6 levels were determined by standard enzyme-linked immunosorbent assay [ELISA]. PPROM patients were categorized into two groups using a threshold of 14 pg/ml. Chi-square (chi2) test was used to compare categorical outcomes. p values of < 0.05 were taken as significant. RESULTS: The mean serum IL-6 level for the women with PPROM was (20.2 +/- 11.0 pg/ml), which was significantly greater than for the control subjects (13.9 +/- 5.8 pg/ml, p < 0.001). Fetomaternal outcomes were all worse in those with IL-6 >= 14 pg/ml. Nevertheless, only the difference in early neonatal deaths was statistically significant. CONCLUSION: Measurement of maternal serum IL-6 can help to indicate hostile intrauterine environments to the fetus as well as identify patients who may benefit from pregnancy prolongation or intervention. PMID- 26755439 TI - Obesity-Associated Adipose Tissue Inflammation and Transplantation. AB - Obesity is often associated with the development of adipose tissue (AT) inflammation, resulting in metabolic dysfunction and an increased risk for developing type 2 diabetes. It is also associated with multiple chronic diseases, including cardiovascular, liver, and kidney disease, and thus can contribute to organ failure. Several studies have investigated whether there is a correlation between obesity and outcomes in transplantation, but there is currently very limited information on the specific role of AT inflammation in the rejection process or on the overall function of the transplanted organ. Here, we provide a brief review of the current understanding of the cellular mechanisms that control obesity-associated AT inflammation and summarize knowledge about how obesity affects clinical outcomes following solid organ or hematopoietic stem cell transplantation. We also highlight opportunities for more research to better understand how obesity affects outcomes of transplantation. PMID- 26755441 TI - Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. AB - BACKGROUND: Ovarian cancer tends to be chemosensitive and confine itself to the surface of the peritoneal cavity for much of its natural history. These features have made it an obvious target for intraperitoneal (IP) chemotherapy. Chemotherapy for ovarian cancer is usually given as an intravenous (IV) infusion repeatedly over five to eight cycles. Intraperitoneal chemotherapy is given by infusion of the chemotherapeutic agent directly into the peritoneal cavity. There are biological reasons why this might increase the anticancer effect and reduce some systemic adverse effects in comparison to IV therapy. OBJECTIVES: To determine if adding a component of the chemotherapy regime into the peritoneal cavity affects overall survival, progression-free survival, quality of life (QOL) and toxicity in the primary treatment of epithelial ovarian cancer. SEARCH METHODS: We searched the Gynaecological Cancer Review Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2011, MEDLINE (1951 to May 2011) and EMBASE (1974 to May 2011). We updated these searches in February 2007, August 2010, May 2011 and September 2015. In addition, we handsearched and cascade searched the major gynaecological oncology journals up to May 2011. SELECTION CRITERIA: The analysis was restricted to randomised controlled trials (RCTs) assessing women with a new diagnosis of primary epithelial ovarian cancer, of any FIGO stage, following primary cytoreductive surgery. Standard IV chemotherapy was compared with chemotherapy that included a component of IP administration. DATA COLLECTION AND ANALYSIS: We extracted data on overall survival, disease-free survival, adverse events and QOL and performed meta-analyses of hazard ratios (HR) for time-to-event variables and relative risks (RR) for dichotomous outcomes using RevMan software. MAIN RESULTS: Nine randomised trials studied 2119 women receiving primary treatment for ovarian cancer. We considered six trials to be of high quality. Women were less likely to die if they received an IP component to chemotherapy (eight studies, 2026 women; HR = 0.81; 95% confidence interval (CI): 0.72 to 0.90). Intraperitoneal component chemotherapy prolonged the disease-free interval (five studies, 1311 women; HR = 0.78; 95% CI: 0.70 to 0.86). There was greater serious toxicity with regard to gastrointestinal effects, pain, fever and infection but less ototoxicity with the IP than the IV route. AUTHORS' CONCLUSIONS: Intraperitoneal chemotherapy increases overall survival and progression-free survival from advanced ovarian cancer. The results of this meta-analysis provide the most reliable estimates of the relative survival benefits of IP over IV therapy and should be used as part of the decision making process. However, the potential for catheter related complications and toxicity needs to be considered when deciding on the most appropriate treatment for each individual woman. The optimal dose, timing and mechanism of administration cannot be addressed from this meta-analysis. This needs to be addressed in the next phase of clinical trials. PMID- 26755438 TI - Impact of vision loss among survivors of childhood central nervous system astroglial tumors. AB - BACKGROUND: The impact of impaired vision on cognitive and psychosocial outcomes among long-term survivors of childhood low-grade gliomas has not been investigated previously but could inform therapeutic decision making. METHODS: Data from the Childhood Cancer Survivor Study were used to investigate psychological outcomes (measures of cognitive/emotional function) and socioeconomic outcomes (education, income, employment, marital status, and independent living) among astroglial tumor survivors grouped by 1) vision without impairment, 2) vision with impairment (including unilateral blindness, visual field deficits, and amblyopia), or 3) bilateral blindness. The effect of vision status on outcomes was examined with multivariate logistic regression with adjustments for age, sex, cranial radiation therapy, and medical comorbidities. RESULTS: Among 1233 survivors of childhood astroglial tumors 5 or more years after their diagnosis, 277 (22.5%) had visual impairment. In a multivariate analysis, survivors with bilateral blindness were more likely to be unmarried (adjusted odds ratio (OR), 4.7; 95% confidence interval [CI], 1.5-15.0), live with a caregiver (adjusted OR, 3.1; 95% CI, 1.3-7.5), and be unemployed (adjusted OR, 2.2; 95% CI, 1.1-4.5) in comparison with those without visual impairment. Bilateral blindness had no measurable effect on cognitive or emotional outcomes, and vision with impairment was not significantly associated with any psychological or socioeconomic outcomes. CONCLUSIONS: Adult survivors of childhood astroglial tumors with bilateral blindness were more likely to live unmarried and dependently and to be unemployed. Survivors with visual impairment but some remaining vision did not differ significantly with respect to psychological function and socioeconomic status from those without visual impairment. Cancer 2016;122:730-739. (c) 2016 American Cancer Society. PMID- 26755442 TI - Strength in Diversity: Hidden Genetic Depths of Mycobacterium tuberculosis. AB - Next-generation whole genome sequencing data is currently being utilised to explore Mycobacterium tuberculosis genetic diversity. Studies have focused in particular on the evolution of drug resistance, and have revealed a surprising degree of dynamic population heterogeneity, with implications for transmission studies, treatment regimens and new drug target development. PMID- 26755443 TI - Uniform distributions of glucose oxidation and oxygen extraction in gray matter of normal human brain: No evidence of regional differences of aerobic glycolysis. AB - Regionally variable rates of aerobic glycolysis in brain networks identified by resting-state functional magnetic resonance imaging (R-fMRI) imply regionally variable adenosine triphosphate (ATP) regeneration. When regional glucose utilization is not matched to oxygen delivery, affected regions have correspondingly variable rates of ATP and lactate production. We tested the extent to which aerobic glycolysis and oxidative phosphorylation power R-fMRI networks by measuring quantitative differences between the oxygen to glucose index (OGI) and the oxygen extraction fraction (OEF) as measured by positron emission tomography (PET) in normal human brain (resting awake, eyes closed). Regionally uniform and correlated OEF and OGI estimates prevailed, with network values that matched the gray matter means, regardless of size, location, and origin. The spatial agreement between oxygen delivery (OEF~0.4) and glucose oxidation (OGI ~ 5.3) suggests that no specific regions have preferentially high aerobic glycolysis and low oxidative phosphorylation rates, with globally optimal maximum ATP turnover rates (VATP ~ 9.4 umol/g/min), in good agreement with (31)P and (13)C magnetic resonance spectroscopy measurements. These results imply that the intrinsic network activity in healthy human brain powers the entire gray matter with ubiquitously high rates of glucose oxidation. Reports of departures from normal brain-wide homogeny of oxygen extraction fraction and oxygen to glucose index may be due to normalization artefacts from relative PET measurements. PMID- 26755445 TI - Curcumin-Loading-Dependent Stability of PEGMEMA-Based Micelles Affects Endocytosis and Exocytosis in Colon Carcinoma Cells. AB - Polymeric micelles were formed from poly(poly(ethylene glycol) methyl ether methacrylate)-block-poly(styrene) (P(PEGMEMA)-b-PS) block copolymer of two different chain lengths. The micelles formed were approximately 16 and 46 nm in diameter and used to encapsulate curcumin. Upon loading of the curcumin into the micelles, their size increased to approximately 34 and 80 nm in diameter, respectively, with a loading efficiency of 58%. The unloaded micelles were not cytotoxic to human colon carcinoma cells, whereas only the smaller loaded micelles were cytotoxic after 72 h of exposure. The micelles were rapidly internalized by the cells within minutes of exposure, with the loaded micelles internalized to a greater extent owing to their enhanced stability compared to that of the unloaded micelles. The larger micelles were more rapidly internalized and exocytosed than the smaller micelles, demonstrating the effect of micelle size and drug loading on drug delivery and cytotoxicity. PMID- 26755444 TI - Unilateral fetal-type circle of Willis anatomy causes right-left asymmetry in cerebral blood flow with pseudo-continuous arterial spin labeling: A limitation of arterial spin labeling-based cerebral blood flow measurements? AB - The accuracy of cerebral blood flow measurements using pseudo-continuous arterial spin labeling can be affected by vascular factors other than cerebral blood flow, such as flow velocity and arterial transit time. We aimed to elucidate the effects of common variations in vascular anatomy of the circle of Willis on pseudo-continuous arterial spin labeling signal. In addition, we investigated whether possible differences in pseudo-continuous arterial spin labeling signal could be mediated by differences in flow velocities. Two hundred and three elderly participants underwent magnetic resonance angiography of the circle of Willis and pseudo-continuous arterial spin labeling scans. Mean pseudo-continuous arterial spin labeling-cerebral blood flow signal was calculated for the gray matter of the main cerebral flow territories. Mean cerebellar gray matter pseudo continuous arterial spin labeling-cerebral blood flow was significantly lower in subjects having a posterior fetal circle of Willis variant with an absent P1 segment. The posterior fetal circle of Willis variants also showed a significantly higher pseudo-continuous arterial spin labeling-cerebral blood flow signal in the ipsilateral flow territory of the posterior cerebral artery. Flow velocity in the basilar artery was significantly lower in these posterior fetal circle of Willis variants. This study indicates that pseudo-continuous arterial spin labeling measurements underestimate cerebral blood flow in the posterior flow territories and cerebellum of subjects with a highly prevalent variation in circle of Willis morphology. Additionally, our data suggest that this effect is mediated by concomitant differences in flow velocity between the supplying arteries. PMID- 26755447 TI - Mobilisporobacter senegalensis gen. nov., sp. nov., an anaerobic bacterium isolated from tropical shea cake. AB - A Gram-stain positive, endospore-forming, strictly anaerobic bacterium, designated strain Gal1T, was isolated from shea cake, a waste material from the production of shea butter, originating from Saraya, Senegal. The cells were rod shaped, slightly curved, and motile with peritrichous flagella. The strain was oxidase-negative and catalase-negative. Growth was observed at temperatures ranging from 15 to 45 degrees C (optimum 30 degrees C) and at pH 6.5-9.3 (optimum pH 7.8). The salinity range for growth was 0-3.5 % NaCl (optimum 1 %). Yeast extract was required for growth. Strain Gal1T fermented various carbohydrates such as mannose, mannitol, arabinose, cellobiose, fructose, glucose, maltose, sucrose, trehalose and lactose and the major end-products were ethanol and acetate. The only major cellular fatty acid was C16 : 0 (19.6 %). The DNA base G+C content of strain Gal1T was 33.8 mol%. Analysis of the 16S rRNA gene sequence of the isolate indicated that this strain was related to Mobilitalea sibirica DSM 26468T with 94.27 % similarity, Clostridium populeti ATTC 35295T with 93.94 % similarity, and Clostridium aminovalericum DSM 1283T and Anaerosporobacter mobilis DSM 15930T with 93.63 % similarity. On the basis of phenotypic characteristics, phylogenetic analysis and the results of biochemical and physiological tests, strain Gal1T was clearly distinguished from closely related genera, and strain Gal1T can be assigned to a novel species of a new genus for which the name Mobilisporobacter senegalensis gen. nov., sp. nov. is proposed. The type strain is Gal1T ( = DSM 26537T = JCM 18753T). PMID- 26755446 TI - A Viral mRNA Motif at the 3'-Untranslated Region that Confers Translatability in a Cell-Specific Manner. Implications for Virus Evolution. AB - Sindbis virus (SINV) mRNAs contain several motifs that participate in the regulation of their translation. We have discovered a motif at the 3' untranslated region (UTR) of viral mRNAs, constituted by three repeated sequences, which is involved in the translation of both SINV genomic and subgenomic mRNAs in insect, but not in mammalian cells. These data illustrate for the first time that an element present at the 3'-UTR confers translatability to mRNAs from an animal virus in a cell-specific manner. Sequences located at the beginning of the 5'-UTR may also regulate SINV subgenomic mRNA translation in both cell lines in a context of infection. Moreover, a replicon derived from Sleeping disease virus, an alphavirus that have no known arthropod vector for transmission, is much more efficient in insect cells when the repeated sequences from SINV are inserted at its 3'-UTR, due to the enhanced translatability of its mRNAs. Thus, these findings provide a clue to understand, at the molecular level, the evolution of alphaviruses and their host range. PMID- 26755449 TI - Aplasia cutis congenita in a Blaschkoid distribution: a lesser known variant. PMID- 26755448 TI - Alloantibody Responses After Renal Transplant Failure Can Be Better Predicted by Donor-Recipient HLA Amino Acid Sequence and Physicochemical Disparities Than Conventional HLA Matching. AB - We have assessed whether HLA immunogenicity as defined by differences in donor recipient HLA amino-acid sequence (amino-acid mismatch score, AMS; and eplet mismatch score, EpMS) and physicochemical properties (electrostatic mismatch score, EMS) enables prediction of allosensitization to HLA, and also prediction of the risk of an individual donor-recipient HLA mismatch to induce donor specific antibody (DSA). HLA antibody screening was undertaken using single antigen beads in 131 kidney transplant recipients returning to the transplant waiting list following first graft failure. The effect of AMS, EpMS, and EMS on the development of allosensitization (calculated reaction frequency [cRF]) and DSA was determined. Multivariate analyses, adjusting for time on the waiting list, maintenance on immunosuppression after transplant failure, and graft nephrectomy, showed that AMS (odds ratio [OR]: 1.44 per 10 units, 95% CI: 1.02 2.10, p = 0.04) and EMS (OR: 1.27 per 10 units, 95% CI: 1.02-1.62, p = 0.04) were independently associated with the risk of developing sensitization to HLA (cRF > 15%). AMS, EpMS, and EMS were independently associated with the development of HLA-DR and HLA-DQ DSA, but only EMS correlated with the risk of HLA-A and -B DSA development. Differences in donor-recipient HLA amino-acid sequence and physicochemical properties enable better assessment of the risk of HLA-specific sensitization than conventional HLA matching. PMID- 26755450 TI - Streptosporangium saharense sp. nov., an actinobacterium isolated from Saharan soil. AB - A novel actinobacterium, designated strain SG20T, was isolated from a Saharan soil sample collected from Beni-isguen (Mzab), Ghardaia province, southern Algeria. The micro-organism developed small roundish sporangia on aerial mycelium that were sessile or carried by very short sporangiophores. The cell-wall peptidoglycan contained meso-diaminopimelic acid and the whole-cell sugars comprised glucose, ribose and mannose, but madurose was not detected. The predominant menaquinones were MK-9(H4), MK-9(H6) and MK-9(H2). The major fatty acids were iso-C16 : 0 and C16 : 0. The phospholipids detected were diphosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine and unknown lipids. The phenotypic and chemotaxonomic characteristics of the novel strain resembled those of recognized members of the genus Streptosporangium. Moreover, phylogenetic analysis based on a 16S rRNA gene sequence generated from the strain identified its closest relative as Streptosporangium jomthongense BCC 53154T (98.5 % similarity), which produces single spores on aerial mycelium, but no sporangia. In hybridization experiments, the DNA-DNA relatedness values recorded between strain SG20T and S. jomthongense DSM 46822T fell well below 70 %. On the basis of phenotypic and genotypic data, strain SG20T can be distinguished as representing a novel species of the genus Streptosporangium, for which the name Streptosporangium saharense sp. nov. is proposed. The type strain is SG20T ( = DSM 46743T = CECT 8840T). PMID- 26755451 TI - Identification of small for gestational age by population-based and customized growth charts in newborns of obese and normal-weight primiparous women. AB - OBJECTIVE: Our hypothesis was that newborns of obese mothers would be more likely to be classified as small for gestational age (SGA) by their customized growth curves than by the standard growth curves when compared to newborns of normal weight mothers. METHODS: This is a retrospective cohort of primiparous patients delivering between 1 July 2008 and 30 June 2012. Normal-weight was defined as BMI <=25 kg/m(2) and obese as BMI >= 30 kg/m(2). Infant birth-weight was characterized as SGA or non-SGA from the Lubchenco curve, the Fenton Preterm Growth Chart, and the customized growth curve. RESULTS: Infants were more likely to be classified as SGA on the customized curve compared with Lubchenco curve. Odds ratio was 2.8 (CI: 1.7-4.4; p = 0.001) for obese women and was 2.9 (CI: 1.7 5.1; p < 0.001) for normal-weight women. Infants were also more likely to be classified as SGA based on the customized curve compared with the Fenton Preterm Growth Curve. The odds ratio was 2.3 (CI: 1.4-3.8; p = 0.001) for obese women and was 1.5 (CI: 1.01-2.33; p = 0.04) for normal-weight women. CONCLUSIONS: Population-based curves may mask SGA in obese women. Our study demonstrates that customized growth curves identify more SGA than population-based growth curves in obese and normal-weight women. PMID- 26755452 TI - Prognosis of patients in coma after acute subdural hematoma due to ruptured intracranial aneurysm. AB - Acute subdural hematomas (aSDH) secondary to intracranial aneurysm rupture are rare. Most patients present with coma and their functional prognosis has been classically considered to be very poor. Previous studies mixed good-grade and poor-grade patients and reported variable outcomes. We reviewed our experience by focusing on patients in coma only and hypothesized that aSDH might worsen initial mortality but not long-term functional outcome. Between 2005 and 2013, 440 subarachnoid hemorrhage (SAH) patients were admitted to our center. Nineteen (4.3%) were found to have an associated aSDH and 13 (2.9%) of these presented with coma. Their prospectively collected clinical and outcome data were reviewed and compared with that of 104 SAH patients without aSDH who presented with coma during the same period. Median aSDH thickness was 10mm. Four patients presented with an associated aneurysmal cortical laceration and only one had good recovery. Overall, we observed good long-term outcomes in both SAH patients in coma with aSDH and those without aSDH (38.5% versus 26.4%). Associated aSDH does not appear to indicate a poorer long-term functional prognosis in SAH patients presenting with coma. Anisocoria and brain herniation are observed in patients with aSDH thicknesses that are smaller than those observed in trauma patients. Despite a high initial mortality, early surgery to remove the aSDH results in a good outcome in over 60% of survivors. Aneurysmal cortical laceration appears to be an independent entity which shows a poorer prognosis than other types of aneurysmal aSDH. PMID- 26755453 TI - Spinal cord glioblastoma: 25years of experience from a single institution. AB - Accounting for less than 0.2% of all glioblastomas, high grade gliomas of the spinal cord are very rare. Here, we discuss our approach to managing patients with high grade spinal cord glioma and review the literature on the subject. Six patients with high grade spinal cord gliomas who presented to our institution between 1990 and 2015 were reviewed. Each patient underwent subtotal surgical resection, with a subset receiving adjuvant chemotherapy and radiation. Our primary outcomes of interest were pre-operative and post-operative functional status. One year survival rate was 100%. All patients had stable or improved American Spine Injury Association score immediately after surgery, which was maintained at 3months in 83.3% of patients. Karnofsky Performance Status (KPS) was stable at 3month follow up in 50% of patients, but all had decreased KPS 1year after surgery. A subset of patients received post-operative radiation and chemotherapy with 0% tumor recurrence rate at 3months. We assessed the molecular profiles of tumors from two patients in our series and found that each had mutations in TP53, but had wildtype BRAF, IDH-1, and MGMT. Taken together, our data show that patients with high grade spinal cord gliomas have an excellent survival at 1year, but with some decline in functional status within this period. Further studies are needed to elucidate the natural history of the disease and to explore the role of adjuvant targeted molecular therapies. PMID- 26755454 TI - Homozygous c.1160C>T (P38L) in the MECP2 gene in a female Rett syndrome patient. AB - Rett syndrome is a severe X-linked dominant neurodevelopmental disorder. Mutations in the MECP2 gene on chromosome Xq28 have been shown to be the cause of Rett syndrome. Sequencing of the MECP2 gene in a patient with clinical suspicion of Rett syndrome revealed c.1160C>T (P387L) in exon 4 of the MECP2 gene homozygously. Females with Rett syndrome are usually heterozygous for a mutation in MECP2. Uniparental disomy as a probable cause for the homozygous presence of this mutation was ruled out by quantitative fluorescence-polymerase chain reaction. Moreover to our knowledge this mutation has only been reported in males with X-linked mental retardation (MRX). We hypothesize that the presence of this mutation c.1160C>T (P387L) in the homozygous form is responsible for the Rett syndrome-like phenotype seen in this patient. This novel report reveals for the first time the homozygous presence of a mutation which has hitherto only been reported in males with MRX. PMID- 26755455 TI - Multimodal neuromonitoring for traumatic brain injury: A shift towards individualized therapy. AB - Multimodal neuromonitoring in the management of traumatic brain injury (TBI) enables clinicians to make individualized management decisions to prevent secondary ischemic brain injury. Traditionally, neuromonitoring in TBI patients has consisted of a combination of clinical examination, neuroimaging and intracranial pressure monitoring. Unfortunately, each of these modalities has its limitations and although pragmatic, this simplistic approach has failed to demonstrate improved outcomes, likely owing to an inability to consider the underlying heterogeneity of various injury patterns. As neurocritical care has evolved, so has our understanding of underlying disease pathophysiology and patient specific considerations. Recent additions to the multimodal neuromonitoring platform include measures of cerebrovascular autoregulation, brain tissue oxygenation, microdialysis and continuous electroencephalography. The implementation of neurocritical care teams to manage patients with advanced brain injury has led to improved outcomes. Herein, we present a narrative review of the recent advances in multimodal neuromonitoring and highlight the utility of dedicated neurocritical care. PMID- 26755456 TI - Posterior reversible encephalopathy syndrome following hemodynamic treatment of aneurysmal subarachnoid hemorrhage-induced vasospasm. AB - Posterior reversible encephalopathy syndrome (PRES) is an uncommon but significant complication of hemodynamic therapy after aneurysmal subarachnoid hemorrhage (aSAH)-induced vasospasm. We performed a PubMed literature search for the period January 1999 to January 2015 using the search terms "posterior reversible encephalopathy syndrome", "subarachnoid hemorrhage", "vasospasm", and "hypertensive encephalopathy", and identified nine cases of PRES after aSAH induced vasospasm in the literature. We also present a 63-year-old man with aSAH complicated by vasospasm treated with hemodynamic augmentation who subsequently developed PRES. Imaging following development of PRES symptoms shows vasogenic edema in the white matter of the parietal and occipital lobes. Age, sex, history of hypertension, and baseline blood pressure were variable among patients in the literature review. In all cases, patients improved both from a radiological and clinical perspective following blood pressure reduction. To summarize, PRES is a rare complication of hemodynamic therapy for vasospasm following aSAH. The literature at the time of writing demonstrates no common pattern with regard to patient demographics, medical history, or mode of treatment for symptomatic vasospasm. Given its sporadic and unpredictable nature, considering PRES in the differential diagnosis is important when addressing neurological decline following hemodynamic treatment of vasospasm related to aSAH. PMID- 26755457 TI - Prevalence, diagnosis, and management of diabetes mellitus among older Chinese: results from the China Health and Retirement Longitudinal Study. AB - OBJECTIVES: To estimate prevalence of diabetes mellitus (DM), success in diagnosing, and methods of diabetes management in China. METHODS: China Health and Retirement Longitudinal Study, a representative survey of the Chinese population at least 45 years old, is used to estimate diabetes and prediabetes prevalence, diagnosis, and treatment and their associations with residence, socioe-conomic, and demographic factors. RESULTS: Almost 60 % of middle-aged and elderly Chinese have prediabetes or diabetes in 2011-2012. DM prevalence increases with age, but the oldest group is least likely to be diagnosed. Prevalence is higher with higher body mass index, fasting cholesterol, and larger waist circumference. Higher prevalence is found in urban areas among residents with urban registration status (the Chinese administrative registration system or hukou), especially in coastal regions. Better rates of diagnosis, management, and education regarding diabetes are strongly associated with urban hukou, living in coastal areas, and in families with higher per capita expenditures, the appropriate economic resources measure in China. CONCLUSIONS: Diagnosis and management of diabetes is highly differential within China but recent efforts to improve health systems are succeeding in reducing undiagnosed disease. Current high prevalence of prediabetes suggests a more intensive effort is required in the future. PMID- 26755458 TI - Fatigue and Vitamin D Status in Iranian Female Nurses. AB - INTRODUCTION: Given that nurses are among professions with frequent problems of fatigue, and given the nature of their profession that provides little exposure to sunlight and the subsequent deficiency of vitamin D, the present study examined the relation between fatigue and circulating vitamin D levels in female nurses working in Shahid Beheshti Hospital, Kashan, Iran in 2013. MATERIAL & METHODS: This cross-sectional study was conducted in 200 female nurses working in Shahid Beheshti Hospital. To measure fatigue, fatigue questionnaire containing 9 questions eliciting the subject's feeling in scales of 1 to 7, getting a possible score of 9 to 63, and Visual Analogue Scale in which nurses specified their fatigue in a band of zero to 10 were used. The 25-hydroxyvitamin D, which is the most important vitamin D metabolite, also was determined. The data was analyzed by SPSS-16. The Pearson's correlation of coefficients, t-test, and multiple regression analysis were used in this study. RESULTS: The mean fatigue score of nurses was 38.76+/-12.66 in questionnaire and 5.73+/-2.12 in Visual Analog Scale. The 89 per cent of nurses suffered from vitamin D deficiency, 9.5 percent of them had normal level and 1.5 per cent had toxicity level of vitamin D. There was a significant relationship between vitamin D level and fatigue scores (P<0.0001), and visual fatigue scores (P<0.0001). According to multivariate regression analysis, vitamin D level accounted for 13 per cent of the fatigue based on data on questionnaire and 18.6 per cent of fatigue according to Visual Analog Scale. CONCLUSION: High prevalence of fatigue among nurses could be attributed to vitamin D deficiency. PMID- 26755459 TI - Optimizing Quality of Care and Patient Safety in Malaysia: The Current Global Initiatives, Gaps and Suggested Solutions. AB - BACKGROUND & OBJECTIVE: Demand for health care service has significantly increased, while the quality of healthcare and patient safety has become national and international priorities. This paper aims to identify the gaps and the current initiatives for optimizing the quality of care and patient safety in Malaysia. DESIGN: Review of the current literature. Highly cited articles were used as the basis to retrieve and review the current initiatives for optimizing the quality of care and patient safety. The country health plan of Ministry of Health (MOH) Malaysia and the MOH Malaysia Annual Reports were reviewed. RESULTS: The MOH has set four strategies for optimizing quality and sustaining quality of life. The 10th Malaysia Health Plan promotes the theme "1 Care for 1 Malaysia" in order to sustain the quality of care. Despite of these efforts, the total number of complaints received by the medico-legal section of the MOH Malaysia is increasing. The current global initiatives indicted that quality performance generally belong to three main categories: patient; staffing; and working environment related factors. CONCLUSIONS: There is no single intervention for optimizing quality of care to maintain patient safety. Multidimensional efforts and interventions are recommended in order to optimize the quality of care and patient safety in Malaysia. PMID- 26755460 TI - Challenges in Patient Discharge Planning in the Health System of Iran: A Qualitative Study. AB - BACKGROUND: One of the main factors relating to quality of hospitals is effective discharge planning. Discharge planning promotes the quality of inpatient care and reduces unplanned hospital readmission. The current study investigated the challenges of discharge planning observed in the health system of Iran. METHODS: This qualitative research was conducted using a thematic and framework analyses to identify the challenges under each themes defined by the World Health Organization (WHO), to understand barriers in developing an effective discharge planning system in Iran health system. The data was collected from detailed semi structured interviews and sessions of focus group discussions. This study involved 51 participants including health policy makers, hospital and health managers, faculty members, nurses, practitioners, community medicine specialists and other professionals of the Ministry of Health and Medical Education (MOHME). To reduce the bias and to increase the credibility of the study, evaluation criteria from Lincoln and Guba were used. All interviews and FGDs were recorded and transcribed, then analyzed by the software MAXQDA-11 and also manually. RESULTS: According to the WHO health systems framework, challenges of effective hospital discharge planning were divided into six areas, leadership/governance, service delivery, information, financing, health workforce, and medical production(themes), in which there were 5,3,2,2,3,1 subthemes respectively. CONCLUSION: It is evident from the findings of this study that changes in the perspective of policy makers, health staff and managers, strengthening of systematic approach, and establishment of required infrastructures are essential for successful implementation of effective discharge planning in health systems in Iran. PMID- 26755461 TI - Correlations Between Clinical Judgement and Learning Style Preferences of Nursing Students in the Simulation Room. AB - BACKGROUND: Health care educators account for variables affecting patient safety and are responsible for developing the highly complex process of education planning. Clinical judgement is a multidimensional process, which may be affected by learning styles. The aim was to explore three specific hypotheses to test correlations between nursing students' team achievements in clinical judgement and emotional, sociological and physiological learning style preferences. METHODS: A descriptive cross-sectional study was conducted with Swedish university nursing students in 2012-2013. Convenience sampling was used with 60 teams with 173 nursing students in the final semester of a three-year Bachelor of Science in nursing programme. Data collection included questionnaires of personal characteristics, learning style preferences, determined by the Dunn and Dunn Productivity Environmental Preference Survey, and videotaped complex nursing simulation scenarios. Comparison with Lasater Clinical Judgement Rubric and Non parametric analyses were performed. RESULTS: Three significant correlations were found between the team achievements and the students' learning style preferences: significant negative correlation with 'Structure' and 'Kinesthetic' at the individual level, and positive correlation with the 'Tactile' variable. No significant correlations with students' 'Motivation', 'Persistence', 'Wish to learn alone' and 'Wish for an authoritative person present' were seen. DISCUSSION & CONCLUSION: There were multiple complex interactions between the tested learning style preferences and the team achievements of clinical judgement in the simulation room, which provides important information for the becoming nurses. Several factors may have influenced the results that should be acknowledged when designing further research. We suggest conducting mixed methods to determine further relationships between team achievements, learning style preferences, cognitive learning outcomes and group processes. PMID- 26755462 TI - What Strategies Do the Nurses Apply to Cope With Job Stress?: A Qualitative Study. AB - BACKGROUND: Nursing staff encounter a lot of physical, psychological and social stressors at work. Because the adverse effects of job stress on the health of this group of staff and subsequently on the quality of care services provided by nurses; study and identify how nurses cope with the job stress is very important and can help prevent the occurrence of unfavorable outcomes. OBJECTIVES: The aim of this study was to explore the experiences of nurses to identify the strategies they used to cope with the job stress. METHODS: In this qualitative study content analysis approach was used. Purposive sampling approach was applied. The sample population included 18 nurses working in three hospitals. Data collection was conducted through face to face unstructured interview and was analyzed using conventional content analysis approach. FINDINGS: The analysis of the data emerged six main themes about the strategies used by nurses to cope with job stress, which, include: situational control of conditions, seeking help, preventive monitoring of situation, self-controlling, avoidance and escape and spiritual coping. CONCLUSIONS: Exploring experiences of nurses on how to cope with job stress emerged context-dependent and original strategies and this knowledge can pave the ground for nurses to increase self-awareness of how to cope with job stress. And could also be the basis for planning and the adoption of necessary measures by the authorities to adapt nurses with their profession better and improves their health which are essential elements to fulfill high quality nursing care. PMID- 26755463 TI - Goal Setting and Treatment Adherence Among Patients With Chronic Illness and Depressive Symptoms: Applying a Patient-Centered Approach. AB - OBJECTIVE: Poor treatment adherence is a major problem among individuals with chronic illness. Research indicates that adherence is worsened when accompanied by depressive symptoms. In this preliminary study, we aimed to describe how a patient-centered approach could be employed to aid patients with depressive symptoms in following their treatment regimens. METHODS: The sample consisted of 14 patients undergoing antiretroviral therapy (ART) for HIV who reported clinically-significant depressive symptoms. Participant ratings of 23 treatment related statements were examined using two assessment and analytic techniques. Interviews were conducted with participants to determine their views of information based on the technique. RESULTS: Results indicate that while participants with optimal adherence focused on views of treatment associated with side effects to a greater extent than participants with poor adherence, they tended to relate these side effects to sources of intrinsic motivation. CONCLUSION: The study provides examples of how practitioners could employ the assessment techniques outlined to better understand how patients think about treatment and aid them in effectively framing their health-related goals. PMID- 26755464 TI - Effectiveness of Combined Copying Skills Training and Pharmacological Therapy for Patients with Migraine. AB - Headache is one of the most common complaints in neurological clinics. The current study carried out to determine the benefits of combined Coping Skills Training (CST) and Pharmacotherapy (Ph) for patients with migraine. Forty patients with migraine recruited from the outpatient clinics of Zahedan University of Medical Sciences( Iran) and randomly assigned to one of two treatment groups: the first group received combined coping skills training (CST) and pharmacotherapy(Ph); and the second group received the pharmacotherapy alone(Ph). Five patients due to lack of regular presence or filling out the questionnaires excluded from the study. Finally, the results of 35 subjects were analyzed. Data collection was done using the World Health Organization Quality of Life Questionnaire, General Self-Efficacy Scale-Sherer, Ways of Coping Questionnaire and Migraine Headache Index. The results of ANCOVA on post-test, after controlling the pre-test scores, suggested a significant difference in self efficacy scores between CST+Ph and Ph groups. Moreover, results of ANCOVA did not show significant differences between the two groups in the scores of pain severity, quality of life, and the use of coping strategies. Findings of the present study indicated that coping-skills training, as a psychological intervention, improved self-efficacy. Further longitudinal studies are needed to confirm this conclusion. PMID- 26755465 TI - Factors Affecting Cervical Cancer Screening Behaviors Based On the Precaution Adoption Process Model: A Qualitative Study. AB - One of the most preventable cancers in women is cervical cancer. Pap smear test is an effective screening program; however, it is not conducted very frequently. The aim of this study is explaining the determinants affecting women's participation in the Pap smear test based on precaution adoption process model with a qualitative approach. This study was a qualitative approach using a Directed Content Analysis methodology which was conducted in 2014. Participants were 30 rural women who participated in this study voluntarily in sarvabad, Iran. Purposive sampling was initiated and continued until data saturation. Semi structured interviews were the primary method of data collection. Data were analyzed using qualitative content analysis and continuous comparisons. Women's information and awareness about cervical cancer and Pap smear is insufficient and most of them believed that they were not at risk; however, they perceived the severity of the disease. Some of them had no adequate understanding of the test benefits. They pointed to the lack of time, financial difficulties, fear of test result and lack of awareness as the main barriers against the Pap smear test; however, they did not say that they were not willing to do the test. Findings could help health policy makers to find the right area and purpose to facilitate the participation of women in the Pap smear test. PMID- 26755466 TI - The Effectiveness of Cognitive-Existential Group Therapy on Increasing Hope and Decreasing Depression in Women-Treated With Haemodialysis. AB - INTRODUCTION: Hopefulness is one of the most significant predictors of adaptation in hemodialysis patients, and plays a vital role in the recovery process. In contrast to hopefulness, depression is a frequent psychological reaction of the hemodialysis treatment with many negative consequences. The current research was designed to examine the effect of cognitive-existential treatment on the level of hopefulness and depression in hemodialysis patients. MATERIALS & METHODS: This quasi-experimental research included 22 female patients suffering from chronic kidney failure disease undergoing hemodialysis treatment for at least 3 months. The patients were randomly assigned into two groups of experimental and control conditions. The experimental group received a combination of treatment including some elements of "existentialism" philosophy and a "cognitive" approach designed for the Iranian population. The treatment protocol lasted for 12 sessions of 90 minutes twice per week prior to the entry of the patient to the dialysis session. Miller's hope scale and BDI-II-21 were employed to collect the data. Statistical analysis was performed on the data using analysis of covariance by SPSS: 16 software. RESULTS: The result of the analysis indicated that there was a significant improvement in hopefulness level and decrease in depression of the patients in the experiment condition (P<0.01). CONCLUSION: The result of analysis showed that cognitive-existential treatment resulted in the increase of hopefulness and decrease level of depression in the hemodialysis patients suffering from chronic kidney failure. PMID- 26755468 TI - Epidemiology of Pediatric Trauma and Its Patterns in Western Iran: A Hospital Based Experience. AB - BACKGROUND & OBJECTIVE: Trauma is a major cause of mortality in children aged 1 to 14 years old and its patterns differs from country to country. In this study we investigated the epidemiology and distribution of non-intentional trauma in the pediatric population. MATERIALS & METHODS: The archives of 304 children below 10 years old who presented to Taleghani trauma care center in Kermanshah, Iran from March to September 2008, were reviewed. Patients' demographic and injury related information were registered. The participants were categorized into three age groups of 0-2, 3-6 and 7-10 years old and the data was compared among age groups and between both sexes. FINDINGS: The most common cause for trauma was falling from heights (65.5%) and road traffic accidents (16.4%). The most common anatomical sites of injury were the upper limbs followed by the head and neck (36.8% and 31.2%, respectively). Injuries mostly occurred in homes (67.4%). The injuries were mostly related to the orthopedics and the neurosurgery division (84.1% and 13.1%, respectively). Accident rates peaked during the hours of 18-24 (41.3%). Male and female patients did display any difference regarding the variables.Children between the ages of 0-2 years old had the highest rate of injury to the head and neck area (40.3%) (p=0.024). Falls and road traffic accidents displayed increasing rates from the ages of 0-2 to 3-6 and decreasing rates to the ages of 7-10 years old (p=0.013). From the ages of 0-2 to 3-6 years old, street accidents increased and household traumas decreased. After that age household trauma rates increased and street accidents decreased (p=0.005). Children between the ages of 7-10 years old had the highest rate of orthopedic injury (p=0.029). CONCLUSION: Special planning and health policies are needed to prevent road accidents especially in children between the ages of 3-6 years old. Since homes were the place where children between the ages of 0-2 were mostly injured, parents should be educated about the correct safety measures that they need to take regarding their children's environments. The orthopedics department needs to receive the most training and resources for the management of pediatric trauma. PMID- 26755467 TI - Association of Tumor Growth Factor-beta and Interferon-gamma Serum Levels With Insulin Resistance in Normal Pregnancy. AB - Pregnancy is related to change in glucose metabolism and insulin production. The aim of our study was to determine the association of serum IFN-gamma and TGF- beta levels with insulin resistance during normal pregnancy. This cross sectional study was carried out on 97 healthy pregnant (in different trimesters) and 28 healthy non-pregnant women. Serum TGF-beta and IFN- gamma level were measured by ELISA method. Pregnant women had high level TGF-beta and low level IFN-gamma as compared non-pregnant women. Maternal serum TGF-beta concentration significantly increased in third trimester as compared first and second trimester of pregnancy. Maternal serum IFN-gamma concentration significantly decreased in third trimester as compared first and second trimester of pregnancy. Pregnant women exhibited higher score of HOMA IR as compared non-pregnant women. There were association between gestational age with body mass index (r=0.28, P=0.005), TGF-beta (r=0.45, P<0.001) and IFN-gamma (r=-0.50, P<0.001). There was significant association between Insulin resistance and TGF-beta (r=0.17, p=0.05). Our findings suggest that changes in maternal cytokine level in healthy pregnant women were anti inflammatory. Furthermore, Tumor Growth Factor-beta appears has a role in induction insulin resistance in healthy pregnant women. However, further studies needed to evaluate role of different cytokines on insulin resistance in normal pregnancy. PMID- 26755469 TI - Patient Involvement in Safe Delivery: A Qualitative Study. AB - INTRODUCTION: Patient involvement in safe delivery planning is considered important yet not widely practiced. The present study aimed at identifythe factors that affect patient involvementin safe delivery, as recommended by parturient women. METHODS: This study was part of a qualitative research conducted by content analysis method and purposive sampling in 2013.The data were collected through 63 semi-structured interviews in4 hospitalsand analyzed using thematic content analysis. The participants in this research were women before discharge and after delivery. Findings were analyzed using Colaizzi's method. RESULTS: Four categories of factors that could affect patient involvement in safe delivery emerged from our analysis: patient-related (true and false beliefs, literacy, privacy, respect for patient), illness-related (pain, type of delivery, patient safety incidents), health care professional-relatedand task-related factors (behavior, monitoring &training), health care setting-related (financial aspects, facilities). CONCLUSION: More research is needed to explore the factors affecting the participation of mothers. It is therefore, recommended to: 1) take notice of mother education, their husbands, midwives and specialists; 2) provide pregnant women with insurance coverage from the outset of pregnancy, especially during prenatal period; 3) form a labor pain committee consisting of midwives, obstetricians, and anesthesiologists in order to identify the preferred painless labor methods based on the existing facilities and conditions, 4) carry out research on observing patients' privacy and dignity; 5) pay more attention on the factors affecting cesarean. PMID- 26755470 TI - Frequency of Celiac Disease in Patients With Increased Intestinal Gas (Flatulence). AB - Excessive flatulence which impairs social performance in patients is one of the common reasons for referrals to gastroenterology clinics. Celiac Disease is a rare but important cause of increased intestinal gas (bloating) and if not diagnosed, patients face complications such as malabsorption, anemia, osteoporosis and even intestinal lymphoma. This study aimed to determine the frequency of Celiac Disease in patients with excessive flatulence.One hundred and fifty patients with a chief complaint of experiencing flatulence more than 15 times a day and lasting for three months were referred to the gastroenterology clinic of Rasoul-e-Akram Teaching Hospital. Serological tests for Celiac Disease, Anti TTG Ab (IgA-IgG) were requested and the patients with positive tests underwent upper GI endoscopy. Biopsies of the second part of the duodenum were then sent to the laboratory.From one hundred and thirty patients who completed the study, 92 (70.7%) were female. Mean age of the patients was 32 +/- 13 years. Anti TTG Ab was found in 5 patients (3.85%). Only 2 patients (1.5%) had a documented positive pathology for Celiac Disease.According to the results of this study and other studies, we conclude that Celiac Disease is an uncommon etiology for excessive flatulence but it is of importance to investigate it in excessive flatulence patients. PMID- 26755471 TI - Association Between Characteristics of Hospitalized Heart Failure Patients With Their Needs. AB - INTRODUCTION: During recent years that life expectancy of heart failure patients has been increased, health professionals put more emphasis on assessing their needs in daily clinical practice. The aim of the present study was to explore the association between characteristics of hospitalized heart failure patients with their needs. METHODS: A sample of 190 hospitalized patients with HF, recruited from public hospitals in Greece, was enrolled in the study. Data were collected by the completion of a questionnaire which included socio-demographic and clinical characteristics and the questionnaire "Needs of hospitalized patients with coronary artery disease" which is consisted of 6 subscales. Statistical methods used were Kruskal wallis-test or Mann-Whitney test and Spearmans' rho coefficient. Multiple regression analysis was performed in order to evaluate the association between patients' characteristics and the significance of their needs. RESULTS: 124 (65.3%) of hospitalized heart failure participants were men and 89 (46.8%) of participants were more than 70 years old. 145 (76.3%) had prior experience of hospitalization due to heart failure. The need for support and guidance was statistically significantly associated with the degree of information, (p=<0.001). The need for information from the medical and nursing staff was significantly associated with marital status and degree of information (p=0.001 and p<0.001 respectively). The need for need for being in contact with other patient groups, and ensuring communication with relatives was statistically significantly associated with the professional status and degree of information, (p=0.037 and p=<0.001 respectively). The need for individualized treatment and the need for patient's personal participation to his/her treatment as well as the need to meet the emotional and physical needs were statistically significant associated with the degree of information, (p=<0.001, p=<0.001 respectively). Lastly, the need to trust the medical and nursing staff was statistically significantly associated with the place of residence and the degree of information, (p=0.023 and p<0.001). These results were confirmed by the multiple linear regression after controlling for potential confounders. CONCLUSIONS: Information seems to be of vital importance when assessing the needs of heart failure patients. Therefore, providing elaborate information should be an integral part of their therapeutic regimen. PMID- 26755472 TI - Needs of Hemodialysis Patients and Factors Affecting Them. AB - PURPOSE: Of this study was to explore the needs of hemodialysis patients and the factors that affect them. MATERIAL & METHODS: The sample of the study included 141 patients undergoing hemodialysis. Data collection was performed by the method of interview using a specially designed questionnaire which served the purposes of the study. The needs were grouped into six categories. Patients were asked to answer how important was for them each of the statements in the questionnaire. Furthermore, there were collected socio-demographic characteristics, information on health status and relations with the physicians and nurses, as well as data on the incidence of the disease in their social life. RESULTS: The results of this study showed that patients evaluated as fairly important all six categories of their needs, with similar results in both sexes. Age was found to be statistically significantly associated with 'the need for support and guidance', 'the need to be informed' and 'the need to meet the emotional and physical needs', (p=0.023, p=0.012, p=0.028 respectively). Education level was found to be statistically significantly associated with all patients' needs with the exception of 'the need to trust the medical and nursing staff', (p=<0.05). Place of residence was statistically significantly associated with 'the need for support and guidance', (p=0.029). Furthermore, difficulties in relations with family members was found to be statistically significantly associated with 'the need for support, the need for communication and individualization of care', (p=0.014, p=0.040, p=0.041). After multivariate analysis, however, it was shown that the only independent factor affecting 'the need for support and guidance', 'the need for individualized care' and 'the need to meet the emotional and physical needs', was if the patients reported themselves as anxious or not (p=0,024, p=0,012 and p=0,004, respectively). In particular, patients who considered themselves anxious had 1.38, 1.5 and 1.6 points respectively higher score in the evaluation of the importance of needs compared to patients who did not consider themselves anxious. CONCLUSIONS: Factors affecting needs of hemodialysis patients are age, education level, place of residence difficulties in relations with family members as well as anxious personality as reported by the patients. PMID- 26755473 TI - Lack of Association Between rs17568 Polymorphism in OX40 Gene and Myocardial Infarction, Southern of Iran. AB - Tumor necrosis factor (TNF) is one of the inflammatory cytokines which has an important role in inflammation and migration of other inflammatory cells to the atherosclerotic plaques. OX40 is a member of the TNF super family receptor protein. OX40 and OX40 ligand are co-stimulators for T-cells and can increase inflammatory response in atherosclerotic plaques. The aim of this study was to determine the association of rs17568 polymorphism in OX40 gene with premature myocardial infarction. This case control study was done on 100 patients with premature acute myocardial infarction (AMI) and a similar number of sex, age and some other cardiovascular risk factor matched healthy people. The OX40 rs17568 polymorphism was genotyped, using PCR-RFLP method. A-allele frequency of rs17568 SNP was lower non-significantly in Premature AMI, compared to healthy subjects (49% vs. 51%). The analysis of rs17568 (A/G) polymorphism showed an odds ratio of 1.127 (95% CI: 0.635-1.999; P= 0.686) for the GG genotype and 5.761 (95% CI: 1.200-27.655; P= 0.029) for the AG genotype, compared to the AA genotype. The results of this study indicate that the rs17568 SNP of OX40 gene is not associated with premature AMI in the evaluated population. PMID- 26755474 TI - Pain Management Practices by Nurses: An Application of the Knowledge, Attitude and Practices (KAP) Model. AB - Pain is one of the most common reasons that drive people to go to hospitals. It has been found that several factors affect the practices of pain management. In this regard, this study aimed at investigating the underlying determinants in terms of pain management practices. Based on reviewing the previous studies and the suggestions of the KAP model, it was hypothesized that the main elements of the KAP model (attitudes and knowledge) significantly predict the variation in the practices of nurses regarding pain management. A questionnaire comprising the KAP model' s constructs, i.e. knowledge and attitude towards pain management, as well as pain management practices, was used to collect data from 266 registered nurses (n=266) who are deemed competent in the management of patients' pain in the Jordanian public hospitals. The two constructs, attitude and knowledge, which are the main determinants of the KAP model were found to independently predict nurses' practices of managing patients' pain. Knowledge of pain management was found to be the strongest predictor. Additionally, it was found that about 69% of the variance in pain management could be explained by the constructs of the KAP model. Therefore, it is recommended that the Jordanian hospitals and universities focus on nurses' knowledge and attitude towards pain management in order to enhance their practices in the field of pain management. PMID- 26755475 TI - Communication Barriers Perceived by Nurses and Patients. AB - Communication, as a key element in providing high-quality health care services, leads to patient satisfaction and health. The present Cross sectional, descriptive analytic study was conducted on 70 nurses and 50 patients in two hospitals affiliated to Alborz University of Medical Sciences, in 2012. Two separate questionnaires were used for nurses and patients, and the reliability and validity of the questionnaires were assessed. In both groups of nurses and patients, nurse-related factors (mean scores of 2.45 and 2.15, respectively) and common factors between nurses and patients (mean scores of 1.85 and 1.96, respectively) were considered the most and least significant factors, respectively. Also, a significant difference was observed between the mean scores of nurses and patients regarding patient-related (p=0.001), nurse-related (p=0.012), and environmental factors (p=0.019). Despite the attention of nurses and patients to communication, there are some barriers, which can be removed through raising the awareness of nurses and patients along with creating a desirable environment. We recommend that nurses be effectively trained in communication skills and be encouraged by constant monitoring of the obtained skills. PMID- 26755476 TI - Association Between Lifestyle and Hypertension in Patients Referred to Health Care Centers of Ilam City in 2014. AB - INTRODUCTION: Lifestyle is referred to an individual's healthy and unhealthy behaviors that can affect their health statues. The present study aim was association between lifestyle and hypertension in patients referred to healthcare centers of Ilam city in 2014. MATERIALS & METHODS: This research study was a case control study. The data were collected through a standard questionnaire of health promoting lifestyle profile (HPLPII) as well as the researcher's direct visit to the health care centers in the city of Ilam. After the questionnaires were collected and classified, the data were entered into SPSS software and analyzed by descriptive statistics, chi-square tests, T-Tests and logistic regression. RESULTS: The mean and the standard deviation of the age of the main and the control groups were 57.1 (2.22) and 56.5 (2.99) years old, respectively. 10.9%of the control group and 25.5. % of the cases was smoking cigarettes or hookah. The results of the data analysis showed that the mean scores obtained by the main and the control groups on measures of physical activity, psychological growth, stress and total lifestyleare significantly different, so that the obtained score in the dimensions in patients with hypertension was significantly lower than the score obtained among the healthy individuals. CONCLUSIONS: According to the results it seems that educational interventions in the field of healthy lifestyle for individuals with hypertension risk can have an effect on controlling this disease and reducing its incidence. PMID- 26755477 TI - Cost Analysis of Selected Patient Categories Within A Dermatology Department Using an ABC Approach. AB - BACKGROUND: Present trends in hospital management are facilitating the utilization of more accurate costing methods, which potentially results in superior cost-related information and improved managerial decision-making. However, the Activity-Based Costing method (ABC), which was designed for cost allocation purposes in the 1980s, is not widely used by healthcare organizations. This study analyzes costs related to selected categories of patients, those suffering from psoriasis, varicose ulcers, eczema and other conditions, within a dermatology department at a Czech regional hospital. METHODS: The study was conducted in a hospital department where both inpatient and outpatient care are offered. Firstly, the diseases treated at the department were identified. Further costs were determined for each activity using ABC. The study utilized data from managerial and financial accounting, as well as data obtained through interviews with departmental staff. Using a defined cost-allocation procedure makes it possible to determine the cost of an individual patient with a given disease more accurately than via traditional costing procedures. RESULTS: The cost analysis focused on the differences between the costs related to individual patients within the selected diagnoses, variations between inpatient and outpatient treatments and the costs of activities performed by the dermatology department. Furthermore, comparing the costs identified through this approach and the revenue stemming from the health insurance system is an option. CONCLUSIONS: Activity Based Costing is more accurate and relevant than the traditional costing method. The outputs of ABC provide an abundance of additional information for managers. The benefits of this research lie in its practically-tested outputs, resulting from calculating the costs of hospitalization, which could prove invaluable to persons involved in hospital management and decision-making. The study also defines the managerial implications of the performed cost analysis for the hospital management. Based on the analysis results, it is possible to standardize activities and performance appraisal (Benchmarking), and provide all necessary information for hospital budgeting practices, especially Activity-Based Budgeting (ABB). PMID- 26755478 TI - Implementation of Hepatitis Information Management System in Iran. AB - INTRODUCTION: Nowadays, hepatitis is of the most important health priorities around the world, where information plays a very significant role in specialized diseases prevention planning, and policy- and decision-making processes. Thus, this study addressed challenges of hepatitis information management and investigated the outcomes of establishing a hepatitis information management system to overcome such challenges. To this end, this research intended to study the implementation of an Electronic hepatitis information management system. METHODOLOGY: This is an applied-developmental study with following specifications and procedures: preparation of study proposal and design, justification of the design's stakeholders, approval of the design by the Postgraduate Education Council of Faculty, determination of pilot hepatitis control center, software development, deciding on control, prevention, and treatment centers, and finally development of a network-based system for collecting and managing hepatitis information. FINDINGS: Results indicated that the inconsistency and lack of integrity of data, as well as the lack of communication between related units prevented timely information register of viral hepatic patients and services that are provided to them. This inhibited the possibility of considering a follow-up process. However, the implementation of this system and involvement of relevant units greatly solved these problems. CONCLUSION: Results show that the implementation of an electronic system for the management of hepatitis control, prevention, and treatment is a regional and national requirement; since, this system with its empowered infrastructure is capable in providing desired services to all laboratories, counseling and health centers, specialized clinics, and physicians connected to the hepatitis network. This enables them to follow up and monitor patients' conditions. That mentioned system paves the way for the analysis of gathered information, managers' and specialists' access in different regions to the data for making appropriate and accurate decisions. PMID- 26755479 TI - Determination of Effective Factors on Survival of GI Cancers: Results of Five Years Follow up in Iranian Population. AB - BACKGROUND: The gastrointestinal cancers are among the most common cause of cancer-related death and their long term survival is very low. This study was aimed to determine the effective factors on survival of gastrointestinal cancers among Iranian population during 5 years of follow up. METHODS: In total, 157 patients diagnosed as gastrointestinal cancers from 2007 to 2009 in the only center of endoscopy in Alvand city, northwest of Qazvin province were included and followed for five years. The univariate and multivariate analysis were done using Kaplan-Meier method and the Cox model respectively. RESULTS: Observations of 146 patients were analyzed (99 (67.8%) males and 47 (32.2%) females). The mean age was 64.73+/- 13.23 and 58.28+/-13.91 for females and males respectively. The one and three years survival rates for esophageal cancer were 28% and 9% and the one, three and five years survival rates for gastric cancer were 31%, 26% and 14% and for colorectal cancer were 96%, 86% and 75% respectively. In the univariate analysis, variables of age, educational level, ethnicity, smoking, type of cancer, stage of disease and type of treatment had significant effects on survival. In the multivariate analysis, the type of cancer and type of treatment affected the survival of patients as effective factors (p<005). CONCLUSION: Patients with esophageal cancer and those who underwent RT &/or CT are exposed to higher risk of death. Combination therapies (Surgery and adjuvant or neoadjuvant therapy) were related to be her survival. Early diagnosis and use of extended cancer screening programs seem necessary to improve survival. PMID- 26755480 TI - A Review of Visiting Policies in Intensive Care Units. AB - Admission to intensive care units is potentially stressful and usually goes together with disruption in physiological and emotional function of the patient. The role of the families in improving ill patients' conditions is important. So this study investigates the strategies, potential challenges and also the different dimensions of visiting hours' policies with a narrative review. The search was carried out in scientific information databases using keywords "visiting policy", "visiting hours" and "intensive care unit" with no time limitation on accessing the published studies in English or Farsi. Of a total of 42 articles, 22 conformed to our study objectives from 1997 to 2013. The trajectory of current research shows that visiting in intensive care units has, since their inception in the 1960s, always considered the nurses' perspectives, patients' preferences and physiological responses, and the outlook for families. However, little research has been carried out and most of that originates from the United States, Europe and since 2010, a few from Iran. It seems that the need to use the research findings and emerging theories and practices is necessary to discover and challenge the beliefs and views of nurses about family-oriented care and visiting in intensive care units. PMID- 26755482 TI - The Nutrition and Dietetics Workforce Needs Skills and Expertise in the New York Metropolitan Area. AB - BACKGROUND: There is an increased demand in the Nutrition and Dietetics field which has fostered credentialing to ensure competent graduates. The objective of this study is to conduct an exploratory analysis to identify nutrition/dietetics workforce needs, skills and expertise in the New York metropolitan area as exemplified in position announcements over a 4 year period. METHODS: We recorded position announcements for jobs in nutrition and dietetics from the New York State Registered Dietitian Yahoo group, and the Hunter College Nutrition and Food Sciences student and alumni listserv (NFS-L) over a 4 year period. Keywords were identified using job categories defined by the Academy of Nutrition and Dietetics (AND) compensation and benefits survey. This served as a starting point to enumerate the types of positions that have been posted for the New York metropolitan area in recent years. RESULTS: Four hundred and twelve (412) unique job postings were recorded. Various educational levels, credentials, and skills desired by these employers were identified, assessed, and compared with similar data from the "supply side" reports from AND. CONCLUSIONS: The credentials and skills most desired by employers are similar to some of the learning objectives set forth for DPD and DI programs by ACEND, but not entirely congruent. The need for both client/customer focus and computer literacy may be implicit in the standards, but a more overt inclusion of these skills would likely be of benefit to ensure these are inculcated into every program and student. PMID- 26755481 TI - Predictors of Knowledge of Coronary Intervention in a Group of PCI Patients. AB - OBJECTIVE: This study was performed to assess the knowledge of CAD risk factors and post management of coronary intervention among sample of population who were hospitalized for PCI. METHODOLOGY: A cross-sectional, descriptive survey was conducted in Cardiology ward of a tertiary care hospital from July 2013 to May 2015 on 600 patients. A structured questionnaire was used to interview the patients. In univariate analysis, t-tests were employed to assess association of knowledge of CAD risk factors with gender, education level and monthly household income. RESULTS: The mean score of participants with no education was 4.42 and patients with education of bachelors or higher was 8.59 (p-value: 0.01). Similarly, the mean score for participants with monthly household income less than 5000 was 3.32 and participants with income higher than 50,000 had a score of 8.31 (p-value: 0.01). Furthermore, only 28% (N=168) claimed aerobic exercise as a key part of angioplasty recovery. CONCLUSIONS: Our results indicate the lack of good level of knowledge of risk factors for CAD and post management of coronary intervention among PCI patients of Pakistan. There is urgent need for targeted educational programs on national basis to reduce mortality associated with CAD in Pakistani population. PMID- 26755483 TI - The Effectiveness of Group Training of CBT-Based Stress Management on Anxiety, Psychological Hardiness and General Self-Efficacy Among University Students. AB - BACKGROUND: Admission to university is a very sensitive period of life for efficient, active, and young workforces in any country, and it is mostly associated with many changes in social and human relationships. These changes lead to anxiety in students. Moreover, humans need certain functions in order to adaptively deal with different life situations and challenges. By training stress management, these functions can help human acquire the required abilities. OBJECTIVE: The present study was aimed at investigating the effectiveness of stress management training in anxiety, psychological hardiness, and general self efficacy among university students. METHOD: The study was a quasi-experimental intervention (pretest-posttest-follow-up) including a control group, it was a fundamental applied study. The statistical population consisted of all students of Islamic Azad University, Karaj, Iran. Convenient sampling was employed to select 30 students who were divided into an experimental group (n=15) and a control group (n=15). Before stress management training, both groups filled out Beck Anxiety Inventory, Long and Goulet scale of psychological hardiness, and General Self-efficacy Scale (GSE-10). Afterwards, the experimental group was provided with stress management training. And after the experiment, the abovementioned questionnaires and scales were responded by the two groups. Finally the collected data were analyzed and compared using one-way MANOVA. RESULTS: The results of MANOVA indicated that there was a significant difference between the two groups in terms of anxiety, hardiness, and general self-efficacy (p<0.001). CONCLUSION: According to the results of the present study and those of previous investigations that are in agreement with those of the present study, it can be concluded that stress management among university students cause anxiety to drop; moreover, it enhances their psychological hardiness and self-efficacy. In regard with the role and importance of stress management, training this skill should be included in educational plans of university. PMID- 26755485 TI - Effect of Self-Care Education by Face-to-Face Method on the Quality of Life in Hemodialysis Patients (Relying on Ferrans and Powers Questionnaire). AB - INTRODUTION: One of the most common methods to control chronic renal failure, Hemodialysis creates numerous changes in the style and the quality of life in patients. Educating patients is one of effective factors to improve the quality of life. The present study aims to investigate influences of self-care education by face-to-face method on determining quality of life in hemodialysis patients in Jahrom, Iran, during 2014-2015. METHODS: This is a quasi-experimental, single blind study in which 50 patients undergoing hemodialysis at Shahaid Mottahari Hospital, Jahrom. The patients were placed in two groups of 25 individuals: the face to face educational group and the control group. The control group received only routine care in hemodialysis unit. The face to face educational group received 8 instruction sessions of 60 minutes before starting dialysis and received an instruction booklet. Data collection tools were a questionnaire consisting of demographic characteristics, a checklist of needs assessment for hemodialysis patients and a quality of life questionnaire, whose reliability and validity were previously approved. The questionnaires were completed face to face, before and after the intervention. RESULTS: The results show that the research units did not have any significant difference in terms of demographic variables. Also increase in various aspects of the quality of life compared with the control group is observed after the intervention in the face to face educational group (p<0.001). DISCUSSION & CONCLUSION: Given the results, representation of adequate training in hemodialysis ward can cause improve in physical function, mental health and thus increase the quality of life in hemodialysis patients, through raising the awareness level. PMID- 26755486 TI - Quality of Life Variables Assessment, Before and After Pancreatoduodenectomy (PD): Prospective Study. AB - INTRODUCTION: The treatment of pancreatic cancer is a complex problem, due to late diagnosis, the need for specialized surgical treatment, the large number of relapses and poor survival. OBJECTIVE: To evaluate the quality of life of patients with periampulary pancreatic cancer before and after pancreatoduodenectomy (PD). MATERIAL & METHOD: The sample was collected in the "Attikon" University General Hospital (Chaidari). It consists of 20 subjects with a mean age of 65.9 years (SD = 10,2 years). For the quality of life measurement, we used the (EORTC) QLQ-C30 version 3.0., as well as the EORTC QOL-PAN26. RESULTS: From the sample of 20 patients who participated, full data were collected for 18 of them during the first month, 17 during the third month and 16 during the sixth month.Regarding symptoms, as they were recorded with the QLQ-30 questionnaire, there was a significant increase of fatigue, a significant reduction of pain and constipation, while economic difficulties increased. As for the mean and median values for the dimensions of the PAN-26 questionnaire during monitoring, there was a significant decrease in pancreatic and liver pain symptoms during follow-up, while the gastrointestinal symptoms increased in frequency. In addition, the body image and sexuality worsened. CONCLUSIONS: The surgical treatment of pancreatic cancer with pancreatoduodenectomy (PD), according to the early survey data using the (EORTC) QLQ-C30 version3.0, and the EORTC QOL-PAN26 questionnaires, seems to have a favorable impact on quality of life, as evidenced by the improvement of most parameters evaluated during the study period. PMID- 26755484 TI - Using Health Information Technology to Reach Patients in Underserved Communities: A Pilot Study to Help Close the Gap With Health Disparities. AB - INTRODUCTION: In the current era of medical education and curriculum reform, medical schools across the United States are launching innovative approaches to teaching students in order to improve patient outcomes and increase patient safety. One such innovation is the use information technology (IT) that can be used to disseminate health information, especially for patients with limited access to care. Strategies for using health IT to enhance communication between providers and patients in low-income communities can be incorporated into undergraduate medical education (UME) curriculum. METHODS: A pilot study was conducted to determine if IT could serve as an effective means of communication with patients at a free clinic where 100% of the patients are uninsured; the clinic is located in an urban setting and primarily serves Latinos, the working poor, and the homeless. An anonymous survey was administered to patients to assess rates of IT ownership, general IT use, and IT use for health and medical information. RESULTS: The majority of study participants owned a cell phone (92%); one-third used their cell phone to access health or medical information (38%). Most study participants reported using the Internet (72%), and two-thirds had used the Internet to obtain health and medical information (64%). CONCLUSION: Given the difficulties faced by low income and medically underserved communities in accessing healthcare services, the use of IT tools may improve their' access to health information in ways that could enhance patient knowledge and self management, and perhaps positively impact health outcomes. Therefore, it is essential to incorporate use of IT tools in training for medical students and residents to enhance communication with patients in underserved communities. PMID- 26755487 TI - Nurses' Awareness of Preterm Neonates' Sleep in the NICU. AB - INTRODUCTION: Fetus and neonate spend most of their time sleeping inside and outside the womb. Sleep is considered a crucial action of neonatal period similar to breathing and nutrition. It plays a key role in brain development. Today, it is shown that sleep plays a predominant role in body temperature regulation, energy saving and neuronal detoxification. Sleep is the most important behavioral state of neonates, particularly in preterm ones. Noise, light, invasive treatment and caring activities are among disturbing factors in the neonatal intensive care unit (NICU) that leave negative impacts on brain development through disturbing the sleep process. MATERIALS & METHODS: This descriptive study assessed all NICU nurses of Ali-ibn-Abitaleb hospital using the census sampling method. Demographic data was collected through a questionnaire with 10 questions about active sleep (AS) cycles, also referred to as REM, methods for inducing AS and AS specifications in neonates. The questionnaire was distributed between the nurses. After completion, data was analyzed using SPSS 16 and descriptive statistics method. FINDINGS: According to analyses, 24%, 20%, 48% and 92% of nurses gave correct answers to questions about AS cycle, AS in neonates, the role of sleep in saving energy and ideal noise level, respectively. CONCLUSION: According to results, nurses had a low level of knowledge towards neonatal sleep. All nurses need to know the importance of sleep in preterm neonates. The main role of inducing sleep is to protect the development of the neonates' brain in the NICU. Those nurses who spend a remarkable portion of their time for caring neonates in the NICU play a significant role in neonatal sleep care. PMID- 26755489 TI - Imaging features of spinal tanycytic ependymoma. AB - Tanycytic ependymoma is an unusual morphological variant of WHO grade II ependymoma, typically arising from the cervical or thoracic spinal cord. Although the literature deals extensively with pathological features of this tumour entity, imaging features have not been well characterised. The purpose of this study was to review magnetic resonance imaging (MRI) features of spinal tanycytic ependymomas reported in the literature to date, exemplified by a case of a patient with tanycytic ependymoma of the conus medullaris presenting to our hospital. A Medline search of the English literature for all previously published cases of spinal tanycytic ependymoma was carried out and the reported MRI features reviewed. The tumours were found to be typically well-demarcated masses, predominantly showing isointensity on T1-weighted signal, and T2-weighted hyperintensity, with variable patterns of contrast enhancement. A cystic component was seen in half of the cases, and in a minority a mural nodule was present within the cyst wall. Associated syrinx formation was observed in one third of the cases and haemorrhage was rare, which may be helpful pointers in differentiating the lesion from other ependymoma subtypes. In conclusion, MRI characteristics of spinal tanycytic ependymoma are variable and non-specific, and radiological diagnosis thus remains challenging, although certain predominant features are identified in this report. Knowledge of these is important in the diagnostic differentiation from other intramedullary and extramedullary spinal tumours in order to guide appropriate surgical management. PMID- 26755488 TI - Brain MRI abnormalities in the adult form of myotonic dystrophy type 1: A longitudinal case series study. AB - This study aimed to verify whether brain abnormalities, previously described in patients with myotonic dystrophy type 1 (DM1) by magnetic resonance imaging (MRI), progressed over time and, if so, to characterize their progression. Thirteen DM1 patients, who had at least two MRI examinations, were retrospectively evaluated and included in the study. The mean duration (+/- standard deviation) of follow-up was 13.4 (+/-3.8) years, over a range of 7-20 years. White matter lesions (WMLs) were rated by semi-quantitative method, the signal intensity of white matter poster-superior to trigones (WMPST) by reference to standard images and brain atrophy by ventricular/brain ratio (VBR). At the end of MRI follow-up, the scores relative to lobar, temporal and periventricular WMLs, to WMPST signal intensity and to VBR were significantly increased compared to baseline, and MRI changes were more evident in some families than in others. No correlation was found between the MRI changes and age, onset, disease duration, muscular involvement, CTG repetition and follow-up duration. These results demonstrated that white matter involvement and brain atrophy were progressive in DM1 and suggested that progression rate varied from patient to patient, regardless of age, disease duration and genetic defect. PMID- 26755491 TI - Retrospective evaluation of toceranib phosphate (Palladia) in cats with oral squamous cell carcinoma. AB - Objectives The aim of the study was to determine the clinical benefit and adverse event profile of toceranib phosphate in the treatment of feline oral squamous cell carcinoma (FOSCC). Methods Data obtained from the medical records of cats with oral squamous cell carcinoma diagnosed between 2010 and 2014 treated with toceranib phosphate were compared with medical record data from cats that did not receive toceranib, cytotoxic chemotherapy or radiation, to determine the response to toceranib treatment and adverse event profile of toceranib in cats. Concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) was allowed. Results Forty six cats with FOSCC were included; 23 received treatment with toceranib (group 1) and 23 did not (group 2). The overall biological response rate in group 1 was 56.5%. Median survival time of toceranib-treated cats was significantly longer at 123 days compared with 45 days in cats not treated with toceranib ( P = 0.01). Cats achieving stable disease or better on toceranib therapy had significantly longer progression-free survival ( P <0.0001) and median survival ( P = 0.0042) times than those with progressive disease on toceranib. Administration of NSAIDs was also associated with significantly improved survival time ( P = 0.0038) among all cats. Anorexia was common but may reflect the underlying disease in these patients. Toceranib was well tolerated in cats, with the most common side effect being mild gastrointestinal toxicity. Conclusions and relevance Toceranib was well tolerated in cats with oral squamous cell carcinoma and may lead to improved survival times, especially when combined with NSAIDs. NSAID administration was also associated with improved survival times, and the relative benefit of toceranib and NSAIDs is difficult to determine from this retrospective study. Despite improvement in survival times, long-term survival in this patient population remained poor. As toceranib was well tolerated and may improve survival time, prospective evaluation of toceranib alone is warranted to assess response as a single agent and as part of multimodal therapy in an effort to achieve a more durable response in FOSCC. PMID- 26755490 TI - Characteristic brain MRI findings in ataxia-neuropathy spectrum related to POLG mutation. AB - Patients with mutations in the polymerase gamma gene (POLG) may present with progressive ataxia and in such situations neuroimaging findings may suggest the diagnosis. Herein we report a patient with a POLG gene W748S homozygous mutation and characteristic lesions in the thalamus, cerebellum and inferior olivary nucleus seen on magnetic resonance imaging. PMID- 26755494 TI - ESBL-producing Enterobacteriaceae in 24 neonatal units and associated networks in the south of England: no clustering of ESBL-producing Escherichia coli in units or networks. AB - OBJECTIVES: The objectives of this study were to characterize ESBL-producing Enterobacteriaceae present in 24 neonatal units (NNUs) in eight networks participating in a multicentre probiotic study and to test the hypothesis that specific strains would cluster within individual units and networks. METHODS: We performed analysis of stool samples for the presence of ESBL-producing Enterobacteriaceae at 2 weeks post-natal age and 36 weeks post-menstrual age. ESBL-producing Enterobacteriaceae were characterized and typed using molecular methods. RESULTS: ESBL-producing Enterobacteriaceae (n = 71) were isolated from 67/1229 (5.5%) infants from whom we received a sample at either sampling time or both sampling times, and from infants in 18 (75%) of the 24 recruiting NNUs. Thirty-three Escherichia coli, 23 Klebsiella spp. and 6 Enterobacter spp. strains were characterized. ESBL-producing E. coli were all distinguishable within individual NNUs by antibiotic resistance genotype, serogroup (O25b), phenotype, phylotype or ST. Ten of the 33 were ST131 and 9 of the 10 ST131 isolates were ciprofloxacin resistant. Seven of the 10 ST131 isolates carried genes encoding CTX-M group 1 enzymes. ST131 isolates were isolated from centres within five of the eight NNU networks. There were clusters of indistinguishable ESBL-producing Klebsiella and Enterobacter isolates associated with specific NNUs. CONCLUSIONS: Strains of E. coli ST131 were distributed across neonatal networks in the south of England. There was no evidence of clustering of clonally related ESBL producing E. coli strains, by contrast with Klebsiella spp. and Enterobacter spp., which did cluster within units. The possibility that ESBL-producing E. coli strains are spread by vertical transmission requires further investigation. PMID- 26755493 TI - Prevalence and risk factors for carriage of ESBL-producing Enterobacteriaceae in Amsterdam. AB - OBJECTIVES: The objectives of this study were to determine the prevalence of carriage of ESBL-producing Enterobacteriaceae (ESBL-E) in a representative sample of the general adult Dutch community, to identify risk factors and to gain understanding of the epidemiology of these resistant strains. METHODS: Adults enrolled in five general practices in Amsterdam were approached by postal mail and asked to fill in a questionnaire and to collect a faecal sample. Samples were analysed for the presence of ESBL-E. ESBL genes were characterized by PCR and sequencing. Strains were typed using MLST and amplified fragment length polymorphism (AFLP) and plasmids were identified by PCR-based replicon typing. Risk factors for carriage were investigated by multivariate analysis. RESULTS: ESBL-E were found in 145/1695 (8.6%) samples; 91% were Escherichia coli. Most ESBL genes were of the CTX-M group (blaCTX-M-1 and blaCTX-M-15). MLST ST131 was predominant and mainly associated with CTX-M-15-producing E. coli. One isolate with reduced susceptibility to ertapenem produced OXA-48. In multivariate analyses, use of antimicrobial agents, use of antacids and travel to Africa, Asia and Northern America were associated with carriage of ESBL-E, in particular strains with blaCTX-M-14/15. CONCLUSIONS: This study showed a high prevalence of ESBL-E carriage in the general Dutch community. Also, outside hospitals, the use of antibiotics was a risk factor; interestingly, use of antacids increased the risk of carriage. A major risk factor in the general population was travel to countries outside Europe, in particular to Asia, Africa and Northern America. PMID- 26755492 TI - Colonization and infection with extended-spectrum beta-lactamase-producing Enterobacteriaceae in ICU patients: what impact on outcomes and carbapenem exposure? AB - OBJECTIVES: It remains uncertain whether colonization and infection with ESBL producing Enterobacteriaceae (ESBL-PE) affect the outcomes for ICU patients. Our objectives were to measure the effects of ESBL-PE carriage and infection on mortality, ICU length of stay (LOS) and carbapenem exposure in this population. METHODS: A cause-specific hazard model based on prospectively collected data was built to assess the impact of ESBL-PE colonization and infection on competing risks of death and ICU discharge at day 28 in a multicentre cohort of ICU patients. Carbapenem exposure during the ICU stay was compared between infected carriers, uninfected carriers and non-carriers. RESULTS: Among the 16,734 included patients, 594 (3.5%) were ESBL-PE carriers, including 98 (16.4%) with one or more ESBL-PE infections during the ICU stay. After adjustment for baseline and time-dependent confounders, ESBL-PE infections increased the probability of death at day 28 [adjusted cause-specific hazard ratio (aCSHR), 1.825, 95% CI 1.235-2.699, P = 0.0026] and the ICU LOS (aCSHR for discharge alive at day 28, 0.563, 95% CI 0.432-0.733, P < 0.0001). ESBL-PE carriage without infection extended the LOS (aCSHR, 0.623, 95% CI, 0.553-0.702, P < 0.0001), without affecting mortality (aCSHR, 0.906, 95% CI, 0.722-1.136, P = 0.3916). Carbapenem exposure increased in both infected and uninfected carriers when compared with non-carriers (627, 241 and 69 carbapenem days per 1000 patient days, respectively, P < 0.001). CONCLUSIONS: ESBL-PE infections increased carbapenem consumption, LOS and day 28 mortality. ESBL-PE infections were rather infrequent in carriers; however, even ESBL-PE carriage without infection increased carbapenem exposure and delayed discharge, thereby amplifying the selective pressure and the colonization pressure in the ICU. PMID- 26755495 TI - Efficacy of vancomycin extended-dosing regimens for treatment of simulated Clostridium difficile infection within an in vitro human gut model. AB - OBJECTIVES: Effects of two vancomycin extended-dosing regimens on microbiota populations within an in vitro gut model of simulated Clostridium difficile infection (CDI) were evaluated. METHODS: Two chemostat gut models were inoculated with faecal emulsion and clindamycin instilled to induce CDI. Simulated CDI was treated with vancomycin (125 mg/L four times daily, 7 days) followed by different vancomycin dosing extensions totalling 7 g (lower dose) or 9.5 g (higher dose) over 6 weeks in Model A and Model B, respectively. Microbiota populations, C. difficile vegetative cells and spores, cytotoxin, antimicrobial concentrations and vancomycin-tolerant enterococci (VTE) were measured every 1-2 days. RESULTS: In both models, vancomycin instillation caused a rapid decline in vegetative cells and cytotoxin, and declines in the Bacteroides fragilis group, bifidobacteria and clostridia populations to the lower limit of detection. Bifidobacteria failed to recover for the remainder of the experiment. B. fragilis group populations recovered to pre-dosing levels during the dosing extension in Model A and after dosing ceased in Model B. Recurrent CDI was observed on the penultimate day of Model B, but not Model A. VTE were observed throughout the experiment in both models, but populations increased during vancomycin instillation and post-vancomycin instillation. CONCLUSIONS: The two vancomycin extended-dosing regimens were efficacious in initial treatment of simulated CDI. Both had a prolonged deleterious effect on the indigenous gut microbiota, a factor that may contribute to recurrence; recurrence was observed only in Model B, although the potential for vegetative regrowth within Model A cannot be excluded. Vancomycin exposure appeared to select for VTE populations. PMID- 26755496 TI - Structure and context of Acinetobacter transposons carrying the oxa23 carbapenemase gene. AB - Theoxa23gene encoding the OXA-23 carbapenemase (and several minor variants of it) is widespread inAcinetobacter baumanniiclinical isolates and compromises treatment with carbapenem antibiotics. The gene is derived from the chromosome ofAcinetobacter radioresistenswhere it is an intrinsic gene, here designatedoxaAr InA. baumanniiand otherAcinetobacterspecies,oxa23is usually preceded by an IS, ISAba1, which supplies the strong promoter required for the gene to confer clinically relevant levels of resistance. TheoxaArgene appears to have been mobilized twice creating Tn2008and Tn2008B, both of which consist of a single ISAba1 and anA. radioresistens-derived fragment. Tn2006and Tn2009are clearly derived from Tn2008Band are each made up of Tn2008Bwith an additional segment of unknown origin and an additional ISAba1, creating a compound transposon. Tn2006, Tn2008and possibly Tn2008Bare globally disseminated, while Tn2009has as yet only been found in China. Of the four ISAba1-associated transposons, Tn2006has been most frequently observed worldwide and Tn2006in Tn6022, known as AbaR4, appears to contribute significantly to the dissemination ofoxa23 Moreover, AbaR4, Tn2006, Tn2008and Tn2009have each been found in conjugative plasmids, further facilitating their spread. PMID- 26755497 TI - Reduced raltegravir clearance in HIV-infected liver transplant recipients: an unexpected interaction with immunosuppressive therapy? AB - OBJECTIVES: Liver transplantation (LTx) is considered a safe procedure in selected HIV-infected patients. In this clinical setting raltegravir is the antiretroviral of choice due to its optimal tolerability and its negligible interactions with immunosuppressive drugs. We aimed at providing data on the pharmacokinetics of raltegravir in LTx recipients, on which the available information is inconclusive. METHODS: In this retrospective multicentre study we characterized the pharmacokinetics of raltegravir in a consecutive series of HIV infected LTx recipients referred to our laboratory for therapeutic drug monitoring (TDM) and compared the obtained profiles with those collected from a control group of HIV-infected patients. RESULTS: Seventeen HIV-infected LTx patients were considered. LTx recipients had significantly higher raltegravir AUC0-12 compared with the control group of HIV-infected patients [14 314 (11 627 19 998) versus 8795 (5218-12 954) ng.h/mL; P < 0.01]. Two LTx patients experienced moderate increments in serum transaminases, nausea and vomiting that improved after raltegravir dose reduction. CONCLUSIONS: High raltegravir exposure and acceptable safety profile were observed in HIV-infected LTx recipients. Our results highlight that some patients may obtain an advantage from TDM-guided raltegravir dose adjustments with potential benefits in terms of drug tolerability. PMID- 26755498 TI - Voriconazole and cobicistat-boosted antiretroviral salvage regimen co administration to treat invasive aspergillosis in an HIV-infected patient. PMID- 26755500 TI - Analytical Enantioseparation of beta-Substituted-2-Phenylpropionic Acids by High Performance Liquid Chromatography with Hydroxypropyl-beta-Cyclodextrin as Chiral Mobile Phase Additive. AB - Analytical enantioseparation of five beta-substituted-2-phenylpropionic acids by high-performance liquid chromatography with hydroxypropyl-beta-cyclodextrin (HP beta-CD) as chiral mobile phase additive was established in this paper, and chromatographic retention mechanism was studied. The effects of various factors such as the organic modifier, different ODS C18 columns and concentration of HP beta-CD were investigated. The chiral mobile phase was composed of methanol or acetonitrile and 0.5% triethylamine acetate buffer at pH 3.0 added with 25 mmol L(-1) of HP-beta-CD, and baseline separations could be reached for all racemates. As for chromatographic retention mechanism, it was found that there was a negative correlation between the concentration of HP-beta-CD in mobile phase and the retention factor under constant pH value and column temperature. PMID- 26755499 TI - Pharmacodynamics of vancomycin for CoNS infection: experimental basis for optimal use of vancomycin in neonates. AB - OBJECTIVES: CoNS are the most common cause of neonatal late-onset sepsis. Information on the vancomycin pharmacokinetics/pharmacodynamics against CoNS is limited. The aim of this study was to characterize vancomycin pharmacokinetic/pharmacodynamic relationships for CoNS and investigate neonatal optimal dosage regimens. METHODS: A hollow fibre and a novel rabbit model of neonatal central line-associated bloodstream CoNS infections were developed. The results were then bridged to neonates by use of population pharmacokinetic techniques and Monte Carlo simulations. RESULTS: There was a dose-dependent reduction in the total bacterial population and C-reactive protein levels. The AUC/MIC and Cmax/MIC ratios were strongly linked with total and mutant resistant cell kill. Maximal amplification of resistance was observed in vitro at an fAUC/MIC of 200 mg . h/L. Simulations predicted that neonates <29 weeks post menstrual age are underdosed with standard regimens with respect to older age groups. CONCLUSIONS: The AUC/MIC and Cmax/MIC ratios are the pharmacodynamic indices that best explain total and resistant cell kill in CoNS infection. This suggests that less-fractionated regimens are appropriate for clinical use and continuous infusions may be associated with increased risk of emergence of antimicrobial resistance. This study has provided the pharmacodynamic evidence to inform an optimized neonatal dosage regimen to take into a randomized controlled trial. PMID- 26755501 TI - Host receptors for bacteriophage adsorption. AB - The adsorption of bacteriophages (phages) onto host cells is, in all but a few rare cases, a sine qua non condition for the onset of the infection process. Understanding the mechanisms involved and the factors affecting it is, thus, crucial for the investigation of host-phage interactions. This review provides a survey of the phage host receptors involved in recognition and adsorption and their interactions during attachment. Comprehension of the whole infection process, starting with the adsorption step, can enable and accelerate our understanding of phage ecology and the development of phage-based technologies. To assist in this effort, we have established an open-access resource--the Phage Receptor Database (PhReD)--to serve as a repository for information on known and newly identified phage receptors. PMID- 26755502 TI - Metabolic modeling of clostridia: current developments and applications. AB - Anaerobic Clostridium spp. is an important bioproduction microbial genus that can produce solvents and utilize a broad spectrum of substrates including cellulose and syngas. Genome-scale metabolic (GSM) models are increasingly being put forth for various clostridial strains to explore their respective metabolic capabilities and suitability for various bioconversions. In this study, we have selected representative GSM models for six different clostridia (Clostridium acetobutylicum, C. beijerinckii, C. butyricum, C. cellulolyticum, C. ljungdahlii and C. thermocellum) and performed a detailed model comparison contrasting their metabolic repertoire. We also discuss various applications of these GSM models to guide metabolic engineering interventions as well as assessing cellular physiology. PMID- 26755503 TI - Genetic delineation of local provenance defines seed collection zones along a climate gradient. AB - Efforts to re-establish native plant species should consider intraspecific variation if we are to restore genetic diversity and evolutionary potential. Data describing spatial genetic structure and the scale of adaptive differentiation are needed for restoration seed sourcing. Genetically defined provenance zones provide species-specific guidelines for the distance within which seed transfer likely maintains levels of genetic diversity and conserves locally adapted traits. While a growing number of studies incorporate genetic marker data in delineation of local provenance, they often fail to distinguish the impacts of neutral and non-neutral variation. We analysed population genetic structure for 134 amplified fragment length polymorphism (AFLP) markers in Stylidium hispidum (Stylidiaceae) along a north-south transect of the species' range with the goal to estimate the distance at which significant genetic differences occur among source and recipient populations in restoration. In addition, we tested AFLP markers for signatures of selection, and examined the relationship of neutral and putatively selected markers with climate variables. Estimates of population genetic structure revealed significant levels of differentiation (PhiPT = 0.23) and suggested a global provenance distance of 45 km for pairwise comparisons of 16 populations. Of the 134 markers, 13 exhibited evidence of diversifying selection (PhiPT = 0.52). Using data for precipitation and thermal gradients, we compared genetic, geographic and environmental distance for subsets of neutral and selected markers. Strong isolation by distance was detected in all cases, but positive correlations with climate variables were present only for markers with signatures of selection. We address findings in light of defining local provenance in ecological restoration. PMID- 26755504 TI - Reducing Intake of Sugar-Sweetened Beverages Is Vital to Improving Our Nation's Health. PMID- 26755505 TI - Sugar-Sweetened Beverage Consumption Is Associated With Change of Visceral Adipose Tissue Over 6 Years of Follow-Up. AB - BACKGROUND: Sugar-sweetened beverage (SSB) intake has been linked to abnormal abdominal adipose tissue. We examined the prospective association of habitual SSB intake and change in visceral adipose tissue (VAT) and subcutaneous adipose tissue. METHODS AND RESULTS: The quantity (volume, cm(3)) and quality (attenuation, Hounsfield Unit) of abdominal adipose tissue were measured using computed tomography in 1003 participants (mean age 45.3 years, 45.0% women) at examination 1 and 2 in the Framingham's Third Generation cohort. The 2 exams were ~ 6 years apart. At baseline, SSB and diet soda intake were assessed using a valid food frequency questionnaire. Participants were categorized into 4 groups: none to <1 serving/mo (nonconsumers), 1 serving/mo to <1 serving/week, 1 serving/week to 1 serving/d, and >= 1 serving/d (daily consumers) of either SSB or diet soda. After adjustment for multiple confounders including change in body weight, higher SSB intake was associated with greater change in VAT volume (P trend<0.001). VAT volume increased by 658 cm(3) (95% confidence interval [CI], 602 to 713), 649 cm(3) (95% CI, 582 to 716), 707 cm(3) (95% CI, 657 to 757), and 852 cm(3) (95% CI, 760 to 943) from nonconsumers to daily consumers. Higher SSB intake was also associated with greater decline of VAT attenuation (P trend=0.007); however, the association became nonsignificant after additional adjustment for VAT volume change. In contrast, diet soda consumption was not associated with change in abdominal adipose tissue. CONCLUSIONS: Regular SSB intake was associated with adverse change in both VAT quality and quantity, whereas we observed no such association for diet soda. PMID- 26755506 TI - Efficacy of the Sequential Administration of Melatonin, Hydroxyzine, and Chloral Hydrate for Recording Sleep EEGs in Children. AB - Sedation of children for electroencephalography (EEG) recordings is often required. Chloral hydrate (CH) requires medical clearance and continuous monitoring. To try to reduce personnel and time resources associated with CH administration, a new sedation policy was formulated. This study included all children who underwent an EEG during a consecutive 3-month period following the implementation of the new sedation policy, which consists of the sequential administration of melatonin, hydroxyzine (if needed), and CH (if needed). The comparator group included all children with a recorded EEG during a consecutive 3 month period when the sedation policy consisted of the sole administration of CH. A total of 803 children with a mean age of 7.9 years (SD = 5.1, range = 0.5-17.7 years) were included. Sleep EEG recordings were obtained in 364 of 385 children (94.6%) using the old sedation policy and in 409 of 418 children (97.9%) using the new one. With the new sedation policy, the percentage of children requiring CH dropped from 37.1% to 6.7% (P < .001). Time to sleep onset and duration of sleep were not significantly different between the 2 policies. The new sedation policy was very well tolerated. The new sedation policy is very safe, is highly efficacious in obtaining sleep EEG recordings, and will result in substantial saving of time and personnel resources. PMID- 26755508 TI - Reply to Y.H. Kim and M. Mishima. PMID- 26755507 TI - Volasertib Versus Chemotherapy in Platinum-Resistant or -Refractory Ovarian Cancer: A Randomized Phase II Groupe des Investigateurs Nationaux pour l'Etude des Cancers de l'Ovaire Study. AB - PURPOSE: Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. This phase II trial evaluated volasertib or single-agent chemotherapy in patients with platinum resistant or -refractory ovarian cancer who experienced failure after treatment with two or three therapy lines. PATIENTS AND METHODS: Patients were randomly assigned to receive either volasertib 300 mg by intravenous infusion every 3 weeks or an investigator's choice of single-agent, nonplatinum, cytotoxic chemotherapy. The primary end point was 24-week disease control rate. Secondary end points included best overall response, progression-free survival (PFS), safety, quality of life, and exploratory biomarker analyses. RESULTS: Of the 109 patients receiving treatment, 54 received volasertib and 55 received chemotherapy; demographics were well balanced. The 24-week disease control rates for volasertib and chemotherapy were 30.6% (95% CI, 18.0% to 43.2%) and 43.1% (95% CI, 29.6% to 56.7%), respectively, with partial responses in seven (13.0%) and eight (14.5%) patients, respectively. Median PFS was 13.1 weeks and 20.6 weeks for volasertib and chemotherapy (hazard ratio, 1.01; 95% CI, 0.66 to 1.53). Six patients (11%) receiving volasertib achieved PFS fore more than 1 year, whereas no patient receiving chemotherapy achieved PFS greater than 1 year. No relationship between the expression of the biomarkers tested and their response was determined. Patients treated with volasertib experienced more grade 3 and 4 drug-related hematologic adverse events (AEs) and fewer nonhematologic AEs than did patients receiving chemotherapy. Discontinuation resulting from AEs occurred in seven (13.0%) and 15 (27.3%) patients in the volasertib and chemotherapy arms, respectively. Both arms showed similar effects on quality of life. CONCLUSION: Single-agent volasertib showed antitumor activity in patients with ovarian cancer. AEs in patients receiving volasertib were mainly hematologic and manageable. PMID- 26755509 TI - Consolidation Chemotherapy After Concurrent Chemoradiotherapy in Patients With Stage III Non-Small-Cell Lung Cancer. PMID- 26755511 TI - Looking Deep Into the Heterogeneity of Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer: Can We Understand It Better? PMID- 26755512 TI - Reply to H.J.A. Adams and T.C. Kwee. PMID- 26755510 TI - Effect of Pretreatment Renal Function on Treatment and Clinical Outcomes in the Adjuvant Treatment of Older Women With Breast Cancer: Alliance A171201, an Ancillary Study of CALGB/CTSU 49907. AB - PURPOSE: CALGB 49907 showed the superiority of standard therapy, which included either cyclophosphamide/doxorubicin (AC) or cyclophosphamide/methotrexate/fluorouracil over single-agent capecitabine in the treatment of patients age >= 65 with early-stage breast cancer. The treatment allowed dosing adjustments of methotrexate and capecitabine for pretreatment renal function. The purpose of the current analysis was to assess the relationship between pretreatment renal function and five end points: toxicity, dose modification, therapy completion, relapse-free survival, and overall survival. METHODS: Pretreatment renal function was defined as creatinine clearance (CrCl) using the Cockcroft-Gault equation. Multivariable logistic and proportional hazards regression were used to model separately for each regimen the relationship between CrCl and the first three binary end points and the last two time-to-event end points, respectively, after adjusting for variables of prognostic importance. RESULTS: Six hundred nineteen assessable patients were analyzed. The incidence of stage III (moderate) or stage IV (severe) renal dysfunction was 72%, 64%, and 75% for treatment with cyclophosphamide/methotrexate/fluorouracil, AC, and capecitabine, respectively. There was no relationship for any regimen between pretreatment renal function and the five end points. For AC, as CrCl increased, the odds of nonhematologic toxicity decreased (P = .008), whereas for capecitabine, as CrCl increased, the odds of experiencing toxicity of any type also increased (P = .035). Patients with renal insufficiency who received dose modifications were not at increased risk for complications compared with those who did not have renal insufficiency and received a full dose. CONCLUSION: Excluding from clinical trials patients with renal insufficiency but good performance status on the basis of concern of excessive hematologic toxicity or poor outcomes may not be justified with appropriate dosing modifications. Results should be considered in the design of clinical trials for older patients. PMID- 26755513 TI - Potential Simpson's Paradox in Multicenter Study of Intraperitoneal Chemotherapy for Ovarian Cancer. PMID- 26755514 TI - Reply to M.P. Decatris et al. PMID- 26755516 TI - Reply to G.B. Holt. PMID- 26755517 TI - Both Interim and End-of-Treatment 18F-Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography Scans Have Low Value in Diffuse Large B-Cell Lymphoma. PMID- 26755515 TI - Assessment of Primary Site Response in Children With High-Risk Neuroblastoma: An International Multicenter Study. AB - PURPOSE: The International Neuroblastoma Response Criteria (INRC) require serial measurements of primary tumors in three dimensions, whereas the Response Evaluation Criteria in Solid Tumors (RECIST) require measurement in one dimension. This study was conducted to identify the preferred method of primary tumor response assessment for use in revised INRC. PATIENTS AND METHODS: Patients younger than 20 years with high-risk neuroblastoma were eligible if they were diagnosed between 2000 and 2012 and if three primary tumor measurements (antero posterior, width, cranio-caudal) were recorded at least twice before resection. Responses were defined as >= 30% reduction in longest dimension as per RECIST, >= 50% reduction in volume as per INRC, or >= 65% reduction in volume. RESULTS: Three-year event-free survival for all patients (N = 229) was 44% and overall survival was 58%. The sensitivity of both volume response measures (ability to detect responses in patients who survived) exceeded the sensitivity of the single dimension measure, but the specificity of all response measures (ability to identify lack of response in patients who later died) was low. In multivariable analyses, none of the response measures studied was predictive of outcome, and none was predictive of the extent of resection. CONCLUSION: None of the methods of primary tumor response assessment was predictive of outcome. Measurement of three dimensions followed by calculation of resultant volume is more complex than measurement of a single dimension. Primary tumor response in children with high risk neuroblastoma should therefore be evaluated in accordance with RECIST criteria, using the single longest dimension. PMID- 26755519 TI - Building a Rapid Learning Health Care System for Oncology: Why CancerLinQ Collects Identifiable Health Information to Achieve Its Vision. AB - The ever-increasing volume of scientific discoveries, clinical knowledge, novel diagnostic tools, and treatment options juxtaposed with rising costs in health care challenge physicians to identify, prioritize, and use new information rapidly to deliver efficient and high-quality care to a growing and aging patient population. CancerLinQ, a rapid learning health care system in oncology, is an initiative of the American Society of Clinical Oncology and its Institute for Quality that addresses these challenges by collecting information from the electronic health records of large numbers of patients with cancer. CancerLinQ is first and foremost a quality measurement and reporting system through which oncologists can harness the depth and power of their patients' clinical records and other data to assess, monitor, and improve the care they deliver. However, in light of privacy and security concerns with regard to collection, use, and disclosure of patient information, this article addresses the need to collect protected health information as defined under the Health Insurance Portability and Accountability Act of 1996 to drive rapid learning through CancerLinQ. PMID- 26755518 TI - Mantle Cell Lymphoma. AB - Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma previously considered to have a poor prognosis. Large gains were made in the first decade of the new century when clinical trials established the importance of high-dose therapy and autologous stem-cell rescue and high-dose cytarabine in younger patients and the benefits of maintenance rituximab and bendamustine in older patients. In particular, greater depth of understanding of the molecular pathophysiology of MCL has resulted in an explosion of specifically targeted new efficacious agents. In particular, agents recently approved by the Food and Drug Administration include the proteasome inhibitor bortezomib, immunomodulator lenalidomide, and Bruton's tyrosine kinase inhibitor ibrutinib. We review recent advances in the understanding of MCL biology and outline our recommended approach to therapy, including choice of chemoimmunotherapy, the role of stem-cell transplantation, and mechanism-based targeted therapies, on the basis of a synthesis of the data from published clinical trials. PMID- 26755521 TI - Clinician Perspective on Molecular Profiling of Non-Small-Cell Lung Cancer. PMID- 26755520 TI - Atezolizumab, an Anti-Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study. AB - PURPOSE: The objective was to determine the safety and clinical activity of atezolizumab (MPDL3280A), a humanized programmed death-ligand 1 (PD-L1) antibody, in renal cell carcinoma (RCC). Exploratory biomarkers were analyzed and associated with outcomes. PATIENTS AND METHODS: Seventy patients with metastatic RCC, including clear cell (ccRCC; n = 63) and non-clear cell (ncc; n = 7) histologies, received atezolizumab intravenously every 3 weeks. PD-L1 expression was scored at four diagnostic levels (0/1/2/3) that were based on PD-L1 staining on tumor cells and tumor-infiltrating immune cells (IC) with the SP142 assay. Primary end points were safety and toxicity; secondary end points assessed clinical activity per Response Evaluation Criteria in Solid Tumors version 1.1 and immune-related response criteria. Plasma and tissue were analyzed for potential biomarkers of atezolizumab response. RESULTS: Grade 3 treatment-related and immune-mediated adverse events occurred in 17% and 4% of patients, respectively, and there were no grade 4 or 5 events. Sixty-three patients with ccRCC were evaluable for overall survival (median, 28.9 months; 95% CI, 20.0 months to not reached) and progression-free survival (median, 5.6 months; 95% CI, 3.9 to 8.2 months), and 62 patients were evaluable for objective response rate (ORR; 15%; 95% CI, 7% to 26%). ORR was evaluated on the basis of PD-L1 IC expression (IC1/2/3: n = 33; 18%; 95% CI, 7% to 35%; and IC0: n = 22; 9%; 95% CI, 1% to 29%). The ORR for patients with Fuhrman grade 4 and/or sarcomatoid histology was 22% (n = 18; 95% CI, 6% to 48%). Decreases in circulating plasma markers and acute-phase proteins and an increased baseline effector T-cell-to regulatory T-cell gene expression ratio correlated with response to atezolizumab. CONCLUSION: Atezolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with metastatic RCC. Correlative studies identified potential predictive and pharmacodynamic biomarkers. These results have guided ongoing studies and combinations with atezolizumab in RCC. PMID- 26755522 TI - Reply to M.P. Decatris et al. PMID- 26755525 TI - Corrigendum to: Treatment outcomes of patients with FIGO Stage I/II uterine cervical cancer treated with definitive radiotherapy: a multi-institutional retrospective research study. PMID- 26755524 TI - Improving the appropriateness of prescribing in older patients: a systematic review and meta-analysis of pharmacists' interventions in secondary care. AB - INTRODUCTION: potentially inappropriate prescribing (PIP) in older hospitalised patients, and in particular those with dementia, is associated with poorer health outcomes. PIP reduction is therefore essential in this population. METHODS: a comprehensive electronic literature search was conducted using 12 databases from inception up to and including September 2014. Inclusion criteria were controlled trials (randomised or non-randomised) of interventions involving pharmacists conducted in hospitals, with an objective of the study being PIP reduction in patients 65 years or older or patients with dementia of any age, using any validated PIP tool as an outcome measure. Risk of bias assessments were conducted utilising the Cochrane Collaboration's tool. RESULTS: a total of 1,752 records were found after duplicates were removed. Four trials (n = 1,164 patients; two randomised, two non-randomised) from three countries were included in the quantitative analysis. All studies were at moderate risk of bias. No study focused specifically on dementia patients. Three trials reported statistically significant reductions in the Medication Appropriateness Index score in the intervention group (mean difference from admission to discharge = -7.45, 95% CI: 11.14, -3.76) and other PIP tools such as Beers Criteria. One trial reported reduced drug-related readmissions and another reported increased adverse drug reactions. CONCLUSION: multi-disciplinary teams involving pharmacists may improve prescribing appropriateness in older inpatients, though the clinical significance of observed reductions is unclear. More research is required into the effectiveness of pharmacists' interventions in reducing PIP in dementia patients. Additionally, easily assessed and clinically relevant measures of PIP need to be developed. PMID- 26755523 TI - Influence of Cranial Radiotherapy on Outcome in Children With Acute Lymphoblastic Leukemia Treated With Contemporary Therapy. AB - PURPOSE: We sought to determine whether cranial radiotherapy (CRT) is necessary to prevent relapse in any subgroup of children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: We obtained aggregate data on relapse and survival outcomes for 16,623 patients age 1 to 18 years old with newly diagnosed ALL treated between 1996 and 2007 by 10 cooperative study groups from around the world. The proportion of patients eligible for prophylactic CRT varied from 0% to 33% by trial and was not related to the proportion eligible for allogeneic stem cell transplantation in first complete remission. Using a random effects model, with CRT as a dichotomous covariate, we performed a single-arm meta-analysis to compare event-free survival and cumulative incidence of isolated or any CNS relapse and isolated bone marrow relapse in high-risk subgroups of patients who either did or did not receive CRT. RESULTS: Although there was significant heterogeneity in all outcome end points according to trial, CRT was associated with a reduced risk of relapse only in the small subgroup of patients with overt CNS disease at diagnosis, who had a significantly lower risk of isolated CNS relapse (4% with CRT v 17% without CRT; P = .02) and a trend toward lower risk of any CNS relapse (7% with CRT v 17% without CRT; P = .09). However, this group had a relatively high rate of events regardless of whether or not they received CRT (32% [95% CI, 26% to 39%] v 34% [95% CI, 19% to 54%]; P = .8). CONCLUSION: CRT does not have an impact on the risk of relapse in children with ALL treated on contemporary protocols. PMID- 26755526 TI - Survey Methods to Optimize Response Rate in the National Dental Practice-Based Research Network. AB - Surveys of health professionals typically have low response rates, and these rates have been decreasing in the recent years. We report on the methods used in a successful survey of dentist members of the National Dental Practice-Based Research Network. The objectives were to quantify the (1) increase in response rate associated with successive survey methods, (2) time to completion with each successive step, (3) contribution from the final method and personal contact, and (4) differences in response rate and mode of response by practice/practitioner characteristics. Dentist members of the network were mailed an invitation describing the study. Subsequently, up to six recruitment steps were followed: initial e-mail, two e-mail reminders at 2-week intervals, a third e-mail reminder with postal mailing a paper questionnaire, a second postal mailing of paper questionnaire, and staff follow-up. Of the 1,876 invited, 160 were deemed ineligible and 1,488 (87% of 1,716 eligible) completed the survey. Completion by step: initial e-mail, 35%; second e-mail, 15%; third e-mail, 7%; fourth e mail/first paper, 11%; second paper, 15%; and staff follow-up, 16%. Overall, 76% completed the survey online and 24% on paper. Completion rates increased in absolute numbers and proportionally with later methods of recruitment. Participation rates varied little by practice/practitioner characteristics. Completion on paper was more likely by older dentists. Multiple methods of recruitment resulted in a high participation rate: Each step and method produced incremental increases with the final step producing the largest increase. PMID- 26755528 TI - Modern scurvy. AB - Scurvy is a disease that played an important role in ancient history and used to be a notorious cause of death in sailors. Nowadays, scurvy is not a common diagnosis in the civilized world, but this case report indicates that this old fashioned disease is not extinct at all and still exists but in a different patient category. PMID- 26755527 TI - How Physicians, Patients, and Observers Compare on the Use of Qualitative and Quantitative Measures of Physician-Patient Communication. AB - The purpose of this study was to compare several different measures of physician patient communication. We compared data derived from different measures of three communication behaviors, patient participation, physician information giving, and physician participatory decision-making (PDM) style, from 83 outpatient visits to oncology or thoracic surgery clinics for pulmonary nodules or lung cancer. Communication was measured with rating scales completed by patients and physicians after the consultation and by two different groups of external observers who used rating scales or coded the frequency of communication behaviors, respectively, after listening to an audio recording of the consultation. Measures were compared using Pearson's correlations. Correlations of patients' and physicians' ratings of patient participation (r = .04) and physician PDM style (r = .03) were low and not significant (p > .0083, Bonferroni adjusted). Correlations of observers' ratings with patients' or physicians' ratings for patient participation and physician PDM style were moderate or low (r = .15, .27, .07, and .01, respectively) but were not statistically significant (p > .0083, Bonferroni-adjusted). Correlations between observers' ratings and frequency measures were .31, .52, and .63 and were statistically significant with p values .005, <.0001, and <.0001, respectively, for PDM style, information giving, and patient participation. Our findings highlight the potential for using observers' ratings as an alternate measure of communication to more labor intensive frequency measures. PMID- 26755531 TI - Augmentation of Immune Checkpoint Cancer Immunotherapy with IL18. AB - PURPOSE: Recent clinical trials and animal models demonstrated that immune checkpoint blockade enhanced effector cell responses and tumor rejection; however, further development and improvement of cancer immunotherapy is necessary for more favorable objective responses. In this study, we examined the effect of IL18 on the antitumor effect of immune checkpoint inhibitors. EXPERIMENTAL DESIGN: We examined the effect of IL18 on the peritoneal dissemination of CT-26 cells or tail vein injection metastasis of B16/F10 cells using antiprogrammed death-1 ligand-1 (alphaPD-L1) and/or anti-CTL-associated antigen-4 (alphaCTLA-4) mAbs. RESULT: Massive ascites developed after intraperitoneal inoculation of CT 26, resulting in animal death within 30 days. Treatment of mice with alphaPD-L1 and/or alphaCTLA-4 significantly prolonged their survival, and a combination of the antibodies and IL18 provided a much greater therapeutic benefit. The combination modality led to the accumulation of precursor of mature natural killer (pre-mNK) cells in the peritoneal cavity together with increased CD8(+) T and decreased CD4(+)CD25(+)Foxp3(+) T cells. Depletion of the pre-mNK cells abrogated the therapeutic effects and increased the number of CD4(+)CD25(+)Foxp3(+) T cells. The combination treatment also suppressed tail vein injection metastasis of B16/F10 cells. CONCLUSIONS: The results demonstrated that IL18 enhanced therapeutic effects of immune checkpoint blockade against peritoneal dissemination of carcinoma or tail vein injection metastasis of melanoma through accumulation of pre-mNK cells, memory-type CD8(+) T cells, and suppression of CD4(+)CD25(+)Foxp3(+) T cells. A combination of immune checkpoint inhibitors with IL18 may give a suggestion to the development of next-generation cancer immunotherapy. Clin Cancer Res; 22(12); 2969-80. (c)2016 AACR. PMID- 26755532 TI - Interkingdom cooperation between Candida albicans, Streptococcus oralis and Actinomyces oris modulates early biofilm development on denture material. AB - Candida-associated stomatitis affects up to 60% of denture wearers, and Candida albicans remains the most commonly isolated fungal species. The oral bacteria Actinomyces oris and Streptococcus oralis are abundant in early dental plaque. The aims of this study were to determine the effects of S. oralis and A. oris on the development of C. albicans biofilms on denture material. Resin discs were coated with saliva and at early (1.5 h) or later (24 h) stages of biofilm development, cell numbers of each species were determined. Spatial distribution of microorganisms was visualized by confocal scanning laser microscopy of biofilms labelled by differential fluorescence or by fluorescence in situ hybridization. Interkingdom interactions underpinning biofilm development were also evaluated planktonically utilizing fluorescence microscopy. Synergistic interactions between all three species occurred within biofilms and planktonically. Bacterial cells coaggregated with each other and adhered singly or in coaggregates to C. albicans hyphal filaments. Streptococcus oralis appeared to enhance hyphal filament production and C. albicans biovolume was increased 2 fold. Concomitantly, cell numbers of S. oralis and A. oris were enhanced by C. albicans. Thus, cooperative physical and metabolic processes occurring between these three microbial species intensify pathogenic plaque communities on denture surfaces. PMID- 26755530 TI - The MCT4 Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer. AB - PURPOSE: The management of castration-resistant prostate cancer (CRPC) is a major challenge in the clinic. Androgen receptor signaling-directed strategies are not curative in CRPC therapy, and new strategies targeting alternative, key cancer properties are needed. Using reprogrammed glucose metabolism (aerobic glycolysis), cancer cells typically secrete excessive amounts of lactic acid into their microenvironment, promoting cancer development, survival, and progression. Cellular lactic acid secretion is thought to be predominantly mediated by MCT4, a plasma membrane transporter protein. As such, the MCT4 gene provides a unique, potential therapeutic target for cancer. EXPERIMENTAL DESIGN: A tissue microarray of various Gleason grade human prostate cancers was stained for MCT4 protein. Specific, MCT4-targeting antisense oligonucleotides (MCT4 ASO) were designed and candidate MCT4 ASOs checked for effects on (i) MCT4 expression, lactic acid secretion/content, glucose consumption, glycolytic gene expression, and proliferation of human CRPC cells and (ii) growth of PC-3 tumors in nude mice. RESULTS: Elevated MCT4 expression was associated with human CRPC and an earlier time to relapse. The treatment of PC-3, DU145, and C4-2 CRPC cultures with candidate MCT4 ASOs led to marked inhibition of MCT4 expression, lactic acid secretion, to increased intracellular lactic acid levels, and markedly reduced aerobic glycolysis and cell proliferation. Treatment of PC-3 tumor-bearing nude mice with the MCT4 ASOs markedly inhibited tumor growth without inducing major host toxicity. CONCLUSIONS: MCT4-targeting ASOs that inhibit lactic acid secretion may be useful for therapy of CRPC and other cancers, as they can interfere with reprogrammed energy metabolism of cancers, an emerging hallmark of cancer. Clin Cancer Res; 22(11); 2721-33. (c)2016 AACR. PMID- 26755529 TI - Low Cancer Stem Cell Marker Expression and Low Hypoxia Identify Good Prognosis Subgroups in HPV(-) HNSCC after Postoperative Radiochemotherapy: A Multicenter Study of the DKTK-ROG. AB - PURPOSE: To investigate the impact of hypoxia-induced gene expression and cancer stem cell (CSC) marker expression on outcome of postoperative cisplatin-based radiochemotherapy (PORT-C) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). EXPERIMENTAL DESIGN: Expression of the CSC markers CD44, MET, and SLC3A2, and hypoxia gene signatures were analyzed in the resected primary tumors using RT-PCR and nanoString technology in a multicenter retrospective cohort of 195 patients. CD44 protein expression was further analyzed in tissue microarrays. Primary endpoint was locoregional tumor control. RESULTS: Univariate analysis showed that hypoxia-induced gene expression was significantly associated with a high risk of locoregional recurrence using the 15 gene signature (P = 0.010) or the 26-gene signature (P = 0.002). In multivariate analyses, in patients with HPV16 DNA-negative but not with HPV16 DNA-positive tumors the effect of hypoxia-induced genes on locoregional control was apparent (15-gene signature: HR 4.54, P = 0.006; 26-gene signature: HR 10.27, P = 0.024). Furthermore, MET, SLC3A2, CD44, and CD44 protein showed an association with locoregional tumor control in multivariate analyses (MET: HR 3.71, P = 0.016; SLC3A2: HR 8.54, P = 0.037; CD44: HR 3.36, P = 0.054; CD44 protein n/a because of no event in the CD44-negative group) in the HPV16 DNA-negative subgroup. CONCLUSIONS: We have shown for the first time that high hypoxia-induced gene expression and high CSC marker expression levels correlate with tumor recurrence after PORT-C in patients with HPV16 DNA-negative HNSCC. After validation in a currently ongoing prospective trial, these parameters may help to further stratify patients for individualized treatment de-escalation or intensification strategies. Clin Cancer Res; 22(11); 2639-49. (c)2016 AACR. PMID- 26755535 TI - Torsional Failure of Carbon Fiber Composite Plates Versus Stainless Steel Plates for Comminuted Distal Fibula Fractures. AB - BACKGROUND: Carbon fiber composite implants are gaining popularity in orthopedics, but with few independent studies of their failure characteristics under supra-physiologic loads. The objective of this cadaveric study was to compare torsional failure properties of bridge plating a comminuted distal fibula fracture with carbon fiber polyetheretherketone (PEEK) composite and stainless steel one-third tubular plates. METHODS: Comminuted fractures were simulated in 12 matched pairs of fresh-frozen human fibulas with 2-mm osteotomies located 3 cm proximal to the tibiotalar joint. Each fibula pair was randomized for fixation and implanted with carbon fiber and stainless steel 5-hole one-third tubular plates. The constructs were loaded in external rotation at a rate of 1-degree/sec until failure with a materials testing system. Torsional stiffness and mode of failure, as well as displacement, torque, and energy absorption for the first instance of failure and peak failure, were determined. Statistical analysis was performed with paired t tests and chi-square. RESULTS: There were no significant differences among the 12 pairs for torsional stiffness, first failure torque, peak failure displacement, peak failure torque, or peak failure energy. Stainless steel plates exhibited significantly higher displacement (P < .001) and energy absorption (P = .001) at the first indication of failure than the carbon fiber plates. Stainless steel plates permanently deformed significantly more often than the carbon fiber plates (P = .035). Carbon fiber plates exhibited no plastic deformation with delamination of the composite, and brittle catastrophic failure in 1 specimen. CONCLUSIONS: In a comminuted human fibula fracture fixation model, carbon fiber implants exhibited multiple pre-peak failures at significantly lower angles than the first failure for the stainless steel implants, with some delamination of composite layers and brittle catastrophic failure rather than plastic deformation. CLINICAL RELEVANCE: The torsional failure properties of carbon fiber composite one-third tubular plates determined in this independent study provide novel in vitro data for this alternative implant material. PMID- 26755533 TI - IgA modulates respiratory dysfunction as a sequela to pulmonary chlamydial infection as neonates. AB - Neonatal Chlamydia lung infections are associated with serious sequelae such as asthma and airway hyper-reactivity in children and adults. Our previous studies demonstrated the importance of Th-1 type cytokines, IL-12 and IFN-gamma in protection against neonatal pulmonary chlamydial challenge; however, the role of the humoral arm of defense has not been elucidated. We hypothesized that B-cells and IgA, the major mucosal antibody, play a protective role in newborns against development of later life respiratory sequelae to Chlamydia infection. Our studies using neonatal mice revealed that all WT and IgA-deficient (IgA(-/-)) animals survived a sublethal pulmonary Chlamydia muridarum challenge at one day after birth with similar reduction in bacterial burdens over time. In contrast, all B-cell-deficient (MUMT) mice succumbed to infection at the same challenge dose correlating to failure to control bacterial burdens in the lungs. Although IgA may not be important for bacterial clearance, we observed IgA(-/-) mice displayed greater respiratory dysfunction 5 weeks post challenge. Specifically, comparative respiratory functional analyses revealed a significant shift upward in P-V loops, and higher dynamic resistance in IgA(-/-) animals. This study provides insight(s) into the protective role of IgA in neonates against pulmonary chlamydial infection induced respiratory pathological sequelae observed later in life. PMID- 26755536 TI - Sweat chloride and immunoreactive trypsinogen in infants carrying two CFTR mutations and not affected by cystic fibrosis. AB - Newborns with raised immunotrypsinogen levels who have non-pathological sweat chloride values and carry two cystic fibrosis transmembrane regulator (CFTR) mutations of which at least one is not acknowledged to be cystic fibrosis (CF) causing are at risk of developing clinical manifestations consistent with CFTR related disorders or even CF. It is not known whether newborns with similar genotypes and normal immunoreactive trypsinogen (IRT) may share the same risk. This study found that newborns with these characteristics and normal IRT have lower sweat chloride values than those with raised IRT (p=0.007). PMID- 26755537 TI - Inequalities in childhood height persist and may vary by ethnicity in England. PMID- 26755534 TI - The chromosomal nature of LT-II enterotoxins solved: a lambdoid prophage encodes both LT-II and one of two novel pertussis-toxin-like toxin family members in type II enterotoxigenic Escherichia coli. AB - Heat-labile enterotoxins (LT) of enterotoxigenic Escherichia coli (ETEC) are structurally and functionally related to cholera toxin (CT). LT-I toxins are plasmid-encoded and flanked by IS elements, while LT-II toxins of type II ETEC are chromosomally encoded with flanking genes that appear phage related. Here, I determined the complete genomic sequence of the locus for the LT-IIa type strain SA53, and show that the LT-IIa genes are encoded by a 51 239 bp lambdoid prophage integrated at the rac locus, the site of a defective prophage in E. coli K12 strains. Of 50 LT-IIa and LT-IIc, 46 prophages also encode one member of two novel two-gene ADP-ribosyltransferase toxin families that are both related to pertussis toxin, which I named eplBA or ealAB, respectively. The eplBA and ealAB genes are syntenic with the Shiga toxin loci in their lambdoid prophages of the enteric pathogen enterohemorrhagic E. coli. These novel AB(5) toxins show pertussis-toxin-like activity on tissue culture cells, and like pertussis toxin bind to sialic acid containing glycoprotein ligands. Type II ETEC are the first mucosal pathogens known to simultaneously produce two ADP-ribosylating toxins predicted to act on and modulate activity of both stimulatory and inhibitory alpha subunits of host cell heterotrimeric G-proteins. PMID- 26755538 TI - Comparison of LC-MS-MS and GC-MS Analysis of Benzodiazepine Compounds Included in the Drug Demand Reduction Urinalysis Program. AB - Liquid chromatography-tandem mass spectrometry (LC-MS-MS) offers specific advantages over gas chromatography-mass spectrometry (GC-MS) such as the ability to identify and measure a broader range of compounds with minimal sample preparation. Comparative analysis of LC-MS-MS versus GC-MS was performed for urinalysis detection of five benzodiazepine compounds currently part of the Department of Defense (DoD) Drug Demand Reduction Program (DDRP) testing panel; alpha-hydroxyalprazolam, oxazepam, lorazepam, nordiazepam and temazepam. In the analyses of internally prepared control urine samples at concentrations around the DDRP administrative decision point for benzodiazepines (100 ng/mL), both technologies produced comparable results with average accuracies between 99.7 and 107.3% and average coefficients of variation (%CV) <9%. Analysis of service member specimens that screened positive for benzodiazepines using both technologies produced comparable results for all analytes. Different degrees of matrix effect were observed for all analytes in the LC-MS-MS analysis. However, the effects were controlled by using deuterated internal standards (ISTDs). Additionally, there was a 39% increase in nordiazepam mean concentration analyzed by LC-MS-MS due to suppression of the ISTD ion by the flurazepam metabolite 2 hydroxyethylflurazepam. The ease and speed of sample extraction, the broader range of compounds that can be analyzed and shorter run time make the LC-MS-MS technology a suitable and expedient alternative confirmation technology for benzodiazepine testing. PMID- 26755539 TI - Death Associated With the Use of the Synthetic Cannabinoid ADB-FUBINACA. AB - Synthetic cannabinoids have been found in herbal incense products for the last several years. We report the rapid death of an individual that was certified as synthetic cannabinoid-associated. The autopsy blood specimen was extracted by a liquid-liquid extraction at pH 10.2 into a hexane-ethyl acetate mixture and analyzed by a generalized synthetic cannabinoid LC-MS-MS method. For this case report, we briefly describe the instrumental analysis and extraction methods for the detection of ADB-FUBINACA in postmortem blood, toxicological results for the postmortem blood specimen (ADB-FUBINACA, 7.3 ng/mL; THC, 1.1 ng/mL; THC-COOH, 4.7 ng/mL), case information and circumstances and pertinent findings at autopsy. The cause of death was certified as coronary arterial thrombosis in combination with synthetic cannabinoid use. Manner of death was accident. PMID- 26755540 TI - Validated LC-MS-MS Method for Multiresidual Analysis of 13 Illicit Phenethylamines in Amniotic Fluid. AB - A multi-residue analytical method was developed for the determination in amniotic fluid (AF) of 13 illicit phenethylamines, including 12 compounds never investigated in this matrix before. Samples were subject to solid-phase extraction using; hydrophilic-lipophilic balance cartridges which gave good recoveries and low matrix effects on analysis of the extracts. The quantification was performed by liquid chromatography electrospray tandem mass spectrometry. The water-acetonitrile mobile phase containing 0.1% formic acid, used with a C18 reversed phase column, provided adequate separation, resolution and signal-to noise ratio for the analytes and the internal standard. The final optimized method was validated according to international guidelines. A monitoring campaign to assess fetal exposure to these 13 substances of abuse has been performed on AF test samples obtained from pregnant women. All mothers (n = 194) reported no use of drugs of abuse during pregnancy, and this was confirmed by the analytical data. PMID- 26755542 TI - High Intraindividual Variation of N-Terminal Pro-B-Type Natriuretic Peptide in Urine of Patients with Stable Chronic Heart Failure: Comparison with Plasma. PMID- 26755541 TI - Liquid-Phase Microextraction and Gas Chromatographic-Mass Spectrometric Analysis of Antidepressants in Vitreous Humor: Study of Matrix Effect of Human and Bovine Vitreous and Saline Solution. AB - In forensic bioanalytical methods, there is a general agreement that calibrators should be prepared by fortifying analytes in matrix-based blank samples (matrix based). However, in the case of vitreous humor (VH), the collection of blank samples for the validation and for routine analysis would require the availability of many cadavers. Besides the difficulty of obtaining enough blank VH, this procedure could also represent an ethical issue. Here, a study of matrix effect was performed taking into consideration human and bovine vitreous and saline solution (SS) (NaCl 0.9%). Tricyclic antidepressants [amitriptyline (AMI), nortriptyline (NTR), imipramine (IMI) and desipramine (DES)] were used as model analytes and were extracted from samples by means of liquid-phase microextraction and detected by gas chromatography-mass spectrometry. Samples of human and bovine VH and SS were prepared in six different concentrations of antidepressants (5, 40, 80, 120, 160 and 200 ng/mL) and were analyzed. Relative matrix effect was evaluated by applying a two-tailed homoscedastic Student's t-test, comparing the results obtained with the set of data obtained with human VH and bovine VH and SS. No significant matrix effect was found for AMI and NTR in the three evaluated matrices. However, a great variability was observed for IMI and DES for all matrices. Once compatibilities among the matrices were demonstrated, the method was fully validated for AMI and NTR in SS. The method was applied to six VH samples deriving from real cases whose femoral whole blood (FWB) was analyzed by a previously published method. An average ratio (VH/FWB) of ~ 0.1 was found for both compounds. PMID- 26755544 TI - White-matter connectivity related to paliperidone treatment response in patients with schizophrenia. AB - The objective of this study was to examine whether white-matter (WM) connectivity of patients with schizophrenia at early stage of treatment is related to treatment response after paliperidone extended-release (ER) treatment. Forty-one patients with schizophrenia and 17 age- and sex-matched healthy control subjects were included in this study. Brain magnetic resonance scans at 3 Tesla were conducted at early stage of treatment. Voxel-wise statistical analysis of the fractional anisotropy (FA) data was performed using Tract-Based Spatial Statistics. At baseline and eight weeks after paliperidone treatment, patients were assessed using the Positive and Negative Syndrome Scale, the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms. Among the patients with schizophrenia, the FA values of the corpus callosum, corona radiata, internal capsule, external capsule, superior longitudinal fasciculus and fronto-temporal WM regions showed significant negative correlations with scores of the treatment response. The current study suggests that the treatment response after paliperidone ER treatment may be associated with the fronto-temporo-limbic WM connectivity at early stage of treatment in patients with schizophrenia, and it could be used as a predictor of treatment response to paliperidone ER treatment after studies with large samples verify these results. PMID- 26755545 TI - The role of CA3 GABAA receptors on anxiolytic-like behaviors and avoidance memory deficit induced by NMDA receptor antagonists. AB - Cognitive functions are influenced by memory and anxiety states. However, a non linear relation has been shown between these two domains. The important role of the hippocampus in memory and emotional responses may link the pathogenesis of anxiety to memory-related GABAergic and glutamatergic processes in the hippocampus. To investigate the role of GABAA receptors in relation to blocking N methyl-D-aspartate (NMDA) receptors in the CA3 region, and balancing the glutamatergic and GABAergic system activities as an approach for the management of related disorders, the elevated plus-maze test-retest paradigm was used to investigate the anxiolytic-like state on the test day and avoidance memory state on the retest day. The data showed that injection of D-AP5, the NMDA receptor antagonist, induced anxiolytic-like behavior and impaired avoidance memory. Injection of GABAA agonist (muscimol), but not the antagonist (bicuculline), induced avoidance memory impairment. Neither muscimol nor bicuculline altered anxiety-like behaviors. Muscimol pretreatment did not change D-AP5-induced anxiolytic-like behaviors but potentiated avoidance memory impairment. Bicuculline pretreatment blocked D-AP5-induced anxiolytic-like behaviors and contradicted its effect on avoidance memory. Our findings indicate that alteration of the CA3 GABAA receptor activity can effectively affect the anxiolytic-like behaviors and avoidance memory deficit induced by D-AP5. PMID- 26755543 TI - The effects of acute tryptophan depletion on speech and behavioural mimicry in individuals at familial risk for depression. AB - Major depressive disorder (MDD) has been associated with abnormalities in speech and behavioural mimicry. These abnormalities may contribute to the impairments in interpersonal functioning that are often seen in MDD patients. MDD has also been associated with disturbances in the brain serotonin system, but the extent to which serotonin regulates speech and behavioural mimicry remains unclear. In a randomized, double-blind, crossover study, we induced acute tryptophan depletion (ATD) in individuals with or without a family history of MDD. Five hours afterwards, participants engaged in two behavioural-mimicry experiments in which speech and behaviour were recorded. ATD reduced the time participants waited before speaking, which might indicate increased impulsivity. However, ATD did not significantly alter speech otherwise, nor did it affect mimicry. This suggests that a brief lowering of brain serotonin has limited effects on verbal and non verbal social behaviour. The null findings may be due to low test sensitivity, but they otherwise suggest that low serotonin has little effect on social interaction quality in never-depressed individuals. It remains possible that recovered MDD patients are more strongly affected. PMID- 26755546 TI - Norms for healthy adults aged 18-87 years for the Cognitive Drug Research System: An automated set of tests of attention, information processing and memory for use in clinical trials. AB - The Cognitive Drug Research (CDR) System is a set of nine computerized tests of attention, information processing, working memory, executive control and episodic memory which was designed for repeated assessments in research projects. The CDR System has been used extensively in clinical trials involving healthy volunteers for over 30 years, and a database of 7751 individuals aged 18-87 years has been accumulated for pre-treatment data from these studies. This database has been analysed, and the relationships between the various scores with factors, including age, gender and years of full-time education, have been identified. These analyses are reported in this paper, along with tables of norms for the various key measures from the core tasks stratified by age and gender. These norms can be used for a variety of purposes, including the determination of eligibility for participation in clinical trials and the everyday relevance of research findings from the system. In addition, these norms provide valuable information on gender differences and the effects of normal ageing on major aspects of human cognitive function. PMID- 26755548 TI - Neurotensin: A role in substance use disorder? AB - Neurotensin is a tridecapeptide originally identified in extracts of bovine hypothalamus. This peptide has a close anatomical and functional relationship with the mesocorticolimbic and nigrostriatal dopamine system. Neural circuits containing neurotensin were originally proposed to play a role in the mechanism of action of antipsychotic agents. Additionally, neurotensin-containing pathways were demonstrated to mediate some of the rewarding and/or sensitizing properties of drugs of abuse.This review attempts to contribute to the understanding of the role of neurotensin and its receptors in drug abuse. In particular, we will summarize the potential relevance of neurotensin, its related compounds and neurotensin receptors in substance use disorders, with a focus on the preclinical research. PMID- 26755549 TI - Life according to ME: Caught in the ebb-tide. AB - In this article, we explore the role of 'place' in shaping people's illness experiences through a data-led inductive case-study based on experiential data from people living with myalgic encephalomyelitis (ME) in Norway. Our main aim is to understand how they experience, interpret and attach meaning to various places in which they reside, and how they construct the course of a life influenced by chronic illness. The study is based on stories containing photographs and written texts, received from 10 women and men. In their stories, they describe those places where they experience their illness in the least and most taxing ways. Through a narrative and photographic analysis of their stories, we explore how they perceive the relationship between place and illness as experienced, managed and endured. Our analysis is based on a place-sensitive sociology, in which we approach place both as physicality and a symbolic construction. The participants describe how a wide range of places are intimately linked to their illness experiences, and they interpret these links by referring to both physical and symbolic factors. They describe their lives in terms of a need for equilibrium between activity and rest. Risk is a strong underlying theme: whatever they do, they risk losing something. Most of all, the participants describe how they are looking for places to escape to and from. Places to escape to are those places where privacy and peace can be found, which primarily revolve around being at home. Places to escape from are those places that make their energy 'slowly ebb away'. PMID- 26755551 TI - Biomarkers and the Fontan Circulation. PMID- 26755552 TI - Digoxin Use Is Associated With Reduced Interstage Mortality in Patients With No History of Arrhythmia After Stage I Palliation for Single Ventricle Heart Disease. AB - BACKGROUND: Interstage mortality (IM) remains significant after stage 1 palliation (S1P) for single-ventricle heart disease (SVD), with many deaths sudden and unexpected. We sought to determine whether digoxin use post-S1P is associated with reduced IM, utilizing the multicenter database of the National Pediatric Cardiology Quality Improvement Collaborative (NPCQIC). METHODS AND RESULTS: From June 2008 to July 2013, 816 infants discharged after S1P from 50 surgical sites completed the interstage to stage II palliation, transplant, or IM. Arrhythmia during S1P hospitalization or discharge on antiarrhythmic medications were exclusions (n=270); 2 patients were lost to follow-up. Two analyses were performed: (1) propensity-score adjusted logistic regression with IM as outcome and (2) retrospective cohort analysis for patients discharged on digoxin versus not, matched for surgical site and other established IM risk factors. Of 544 study patients, 119 (21.9%) were discharged on digoxin. Logistic regression analysis with propensity score, site-size group, and digoxin use as predictor variables showed an increased risk of IM in those not discharged on digoxin (odds ratio, 8.6; lower confidence limit, 1.9; upper confidence limit, 38.3; P<0.01). The retrospective cohort analysis for 60 patients on digoxin (matched for site of care, type of S1P, post-S1P ECMO use, genetic syndrome, discharge feeding route, ventricular function, tricuspid regurgitation, and aortic arch gradient) showed 0% IM in the digoxin at discharge group and an estimated IM difference between the 2 groups of 9% (P=0.04). CONCLUSIONS: Among SVD infants in the NPCQIC database discharged post-S1P with no history of arrhythmia, use of digoxin at discharge was associated with reduced IM. PMID- 26755547 TI - The effects of methylphenidate on cerebral responses to conflict anticipation and unsigned prediction error in a stop-signal task. AB - To adapt flexibly to a rapidly changing environment, humans must anticipate conflict and respond to surprising, unexpected events. To this end, the brain estimates upcoming conflict on the basis of prior experience and computes unsigned prediction error (UPE). Although much work implicates catecholamines in cognitive control, little is known about how pharmacological manipulation of catecholamines affects the neural processes underlying conflict anticipation and UPE computation. We addressed this issue by imaging 24 healthy young adults who received a 45 mg oral dose of methylphenidate (MPH) and 62 matched controls who did not receive MPH prior to performing the stop-signal task. We used a Bayesian Dynamic Belief Model to make trial-by-trial estimates of conflict and UPE during task performance. Replicating previous research, the control group showed anticipation-related activation in the presupplementary motor area and deactivation in the ventromedial prefrontal cortex and parahippocampal gyrus, as well as UPE-related activations in the dorsal anterior cingulate, insula, and inferior parietal lobule. In group comparison, MPH increased anticipation activity in the bilateral caudate head and decreased UPE activity in each of the aforementioned regions. These findings highlight distinct effects of catecholamines on the neural mechanisms underlying conflict anticipation and UPE, signals critical to learning and adaptive behavior. PMID- 26755550 TI - Galectin-3 Is Elevated and Associated With Adverse Outcomes in Patients With Single-Ventricle Fontan Circulation. AB - BACKGROUND: Galectin-3 may play a role in cardiac and noncardiac fibrosis, and elevated circulating levels of this protein predict adverse outcomes in patients with heart failure who do not have congenital heart disease. We investigated galectin-3 in adults with single-ventricle Fontan circulation, patients who are prone to premature clinical deterioration in the context of extensive multiorgan fibrosis. METHODS AND RESULTS: We measured plasma galectin-3 concentrations in 70 ambulatory adult Fontan patients and 21 age- and sex-matched control participants. Galectin-3 level was significantly higher in the Fontan group (11.85 ng/mL, interquartile range 9.9 to 15.0 ng/mL) versus the control group (9.4 ng/mL, interquartile range 8.2 to 10.8 ng/mL; P<0.001). Among Fontan patients, galectin-3 was positively correlated with age, uric acid, and high sensitivity C-reactive protein and negatively correlated with estimated glomerular filtration rate. There was no significant relationship between galectin-3 and oxygen saturation, Fontan type, or ventricular morphology. Over a median follow-up of 461 days, 15 events occurred among the Fontan patients: 12 nonelective hospitalizations (with 2 subsequent deaths) and 3 deaths without prior hospitalization. Patients with elevated galectin-3 (n=19, defined as >2 SD above the control group mean value) had a higher risk of nonelective hospitalization or death (hazard ratio 6.0, 95% CI 2.1 to 16.8, P<0.001). This relationship persisted after individual adjustment for covariates including age, New York Heart Association functional class, C-reactive protein, and estimated glomerular filtration rate and after multivariable adjustment for independently predictive covariates (hazard ratio 9.2, 95% CI 2.4 to 35.2, P=0.001). CONCLUSIONS: Galectin-3 concentrations are elevated among adults with a Fontan circulation, and elevated galectin-3 is associated with an increased risk of nonelective cardiovascular hospitalization or death. PMID- 26755553 TI - Mitochondrial Reactive Oxygen Species Mediate Cardiac Structural, Functional, and Mitochondrial Consequences of Diet-Induced Metabolic Heart Disease. AB - BACKGROUND: Mitochondrial reactive oxygen species (ROS) are associated with metabolic heart disease (MHD). However, the mechanism by which ROS cause MHD is unknown. We tested the hypothesis that mitochondrial ROS are a key mediator of MHD. METHODS AND RESULTS: Mice fed a high-fat high-sucrose (HFHS) diet develop MHD with cardiac diastolic and mitochondrial dysfunction that is associated with oxidative posttranslational modifications of cardiac mitochondrial proteins. Transgenic mice that express catalase in mitochondria and wild-type mice were fed an HFHS or control diet for 4 months. Cardiac mitochondria from HFHS-fed wild type mice had a 3-fold greater rate of H2O2 production (P=0.001 versus control diet fed), a 30% decrease in complex II substrate-driven oxygen consumption (P=0.006), 21% to 23% decreases in complex I and II substrate-driven ATP synthesis (P=0.01), and a 62% decrease in complex II activity (P=0.002). In transgenic mice that express catalase in mitochondria, all HFHS diet-induced mitochondrial abnormalities were ameliorated, as were left ventricular hypertrophy and diastolic dysfunction. In HFHS-fed wild-type mice complex II substrate-driven ATP synthesis and activity were restored ex vivo by dithiothreitol (5 mmol/L), suggesting a role for reversible cysteine oxidative posttranslational modifications. In vitro site-directed mutation of complex II subunit B Cys100 or Cys103 to redox-insensitive serines prevented complex II dysfunction induced by ROS or high glucose/high palmitate in the medium. CONCLUSION: Mitochondrial ROS are pathogenic in MHD and contribute to mitochondrial dysfunction, at least in part, by causing oxidative posttranslational modifications of complex I and II proteins including reversible oxidative posttranslational modifications of complex II subunit B Cys100 and Cys103. PMID- 26755554 TI - Intravenous Lipid Infusion Induces Endoplasmic Reticulum Stress in Endothelial Cells and Blood Mononuclear Cells of Healthy Adults. AB - BACKGROUND: Endoplasmic reticulum (ER) stress and the subsequent unfolded protein response may initially be protective, but when prolonged, have been implicated in atherogenesis in diabetic conditions. Triglycerides and free fatty acids (FFAs) are elevated in patients with diabetes and may contribute to ER stress. We sought to evaluate the effect of acute FFA elevation on ER stress in endothelial and circulating white cells. METHODS AND RESULTS: Twenty-one healthy subjects were treated with intralipid (20%; 45 mL/h) plus heparin (12 U/kg/h) infusion for 5 hours. Along with increased triglyceride and FFA levels, intralipid/heparin infusion reduced the calf reactive hyperemic response without a change in conduit artery flow-mediated dilation consistent with microvascular dysfunction. To investigate the short-term effects of elevated triglycerides and FFA, we measured markers of ER stress in peripheral blood mononuclear cells (PBMCs) and vascular endothelial cells (VECs). In VECs, activating transcription factor 6 (ATF6) and phospho-inositol requiring kinase 1 (pIRE1) proteins were elevated after infusion (both P<0.05). In PBMCs, ATF6 and spliced X-box-binding protein 1 (XBP-1) gene expression increased by 2.0- and 2.5-fold, respectively (both P<0.05), whereas CHOP and GADD34 decreased by ~67% and 74%, respectively (both P<0.01). ATF6 and pIRE1 protein levels also increased (both P<0.05), and confocal microscopy revealed the nuclear localization of ATF6 after infusion, suggesting activation. CONCLUSIONS: Along with microvascular dysfunction, intralipid infusion induced an early protective ER stress response evidenced by activation of ATF6 and IRE1 in both leukocytes and endothelial cells. Our results suggest a potential link between metabolic disturbances and ER stress that may be relevant to vascular disease. PMID- 26755556 TI - The INO80 Complex Requires the Arp5-Ies6 Subcomplex for Chromatin Remodeling and Metabolic Regulation. AB - ATP-dependent chromatin remodeling complexes are essential for transcription regulation, and yet it is unclear how these multisubunit complexes coordinate their activities to facilitate diverse transcriptional responses. In this study, we found that the conserved Arp5 and Ies6 subunits of the Saccharomyces cerevisiae INO80 chromatin-remodeler form an abundant and distinct subcomplex in vivo and stimulate INO80-mediated activity in vitro. Moreover, our genomic studies reveal that the relative occupancy of Arp5-Ies6 correlates with nucleosome positioning at transcriptional start sites and expression levels of >1,000 INO80-regulated genes. Notably, these genes are significantly enriched in energy metabolism pathways. Specifically, arp5Delta, ies6Delta, and ino80Delta mutants demonstrate decreased expression of genes involved in glycolysis and increased expression of genes in the oxidative phosphorylation pathway. Deregulation of these metabolic pathways results in constitutively elevated mitochondrial potential and oxygen consumption. Our results illustrate the dynamic nature of the INO80 complex assembly and demonstrate for the first time that a chromatin remodeler regulates glycolytic and respiratory capacity, thereby maintaining metabolic stability. PMID- 26755555 TI - Implementation of Pit Crew Approach and Cardiopulmonary Resuscitation Metrics for Out-of-Hospital Cardiac Arrest Improves Patient Survival and Neurological Outcome. AB - INTRODUCTION: Survival from out-of-hospital cardiac arrest (OHCA) varies by community and emergency medical services (EMS) system. We hypothesized that the adoption of multiple best practices to focus EMS crews on high-quality, minimally interrupted cardiopulmonary resuscitation (CPR) would improve survival of OHCA patients in Salt Lake City. METHODS AND RESULTS: In September 2011, Salt Lake City Fire Department EMS providers underwent a systemwide restructuring of care for OHCA patients that focused on the adoption of high-quality CPR with minimal interruptions and offline medical review of defibrillator data and feedback on CPR metrics. Victims were directed to ST-elevation myocardial infarction receiving centers. Prospectively collected data on patient survival and neurological outcome for all OHCAs were compared. In the postintervention period, there were 407 cardiac arrests with 65 neurologically intact survivors (16%), compared with 330 cardiac arrests with 25 neurologically intact survivors (8%) in the preintervention period. Among patients who survived to hospital admission, a higher proportion in the postintervention period survived to hospital discharge (71/141 [50%] versus 36/98 [37%], P=0.037) and had a favorable neurological outcome (65 [46%] versus 25 [26%], P=0.0005) compared with patients treated before the protocol changes. The univariate odds ratio or the association between neurologically intact survival (cerebral performance category 1 and 2) and protocol implementation was 2.3 (95% CI 1.4 to 3.7, P=0.001). Among discharged patients, the distribution of cerebral performance category scores was more favorable in the postintervention period (P<0.0001). CONCLUSIONS: A multifaceted protocol, including several American Heart Assocation best practices for the resuscitation of patients with OHCA, was associated with improved survival and neurological outcome. PMID- 26755557 TI - Regulation of Antisense Transcription by NuA4 Histone Acetyltransferase and Other Chromatin Regulatory Factors. AB - NuA4 histone lysine (K) acetyltransferase (KAT) promotes transcriptional initiation of TATA-binding protein (TBP)-associated factor (TAF)-dependent ribosomal protein genes. TAFs have also been recently found to enhance antisense transcription from the 3' end of the GAL10 coding sequence. However, it remains unknown whether, like sense transcription of the ribosomal protein genes, TAF dependent antisense transcription of GAL10 also requires NuA4 KAT. Here, we show that NuA4 KAT associates with the GAL10 antisense transcription initiation site at the 3' end of the coding sequence. Such association of NuA4 KAT depends on the Reb1p-binding site that recruits Reb1p activator to the GAL10 antisense transcription initiation site. Targeted recruitment of NuA4 KAT to the GAL10 antisense transcription initiation site promotes GAL10 antisense transcription. Like NuA4 KAT, histone H3 K4/36 methyltransferases and histone H2B ubiquitin conjugase facilitate GAL10 antisense transcription, while the Swi/Snf and SAGA chromatin remodeling/modification factors are dispensable for antisense, but not sense, transcription of GAL10. Taken together, our results demonstrate for the first time the roles of NuA4 KAT and other chromatin regulatory factors in controlling antisense transcription, thus illuminating chromatin regulation of antisense transcription. PMID- 26755560 TI - Cognitive representations in low back pain in patients receiving chiropractic versus physiotherapy treatment. AB - This study focused on cognitive representations of low back pain patients receiving chiropractic ( n = 213) versus physiotherapy treatment ( n = 125). Variables assessed included satisfaction with care, illness perceptions, beliefs about pain and medicines, attitudes towards doctors and medicine, suffering, adherence and functional incapacity. In the chiropractic treatment, functional incapacity was predicted by painful symptoms, suffering and personal control, and in the physiotherapy treatment by age, pain intensity, positive suffering, care satisfaction, illness identity and medication adherence. The groups differed on all cognitive variables assessed. Interventions should take into consideration cognitive dimensions, across treatment modalities. PMID- 26755559 TI - Mutational Analysis of Glycogen Synthase Kinase 3beta Protein Kinase Together with Kinome-Wide Binding and Stability Studies Suggests Context-Dependent Recognition of Kinases by the Chaperone Heat Shock Protein 90. AB - The heat shock protein 90 (HSP90) and cell division cycle 37 (CDC37) chaperones are key regulators of protein kinase folding and maturation. Recent evidence suggests that thermodynamic properties of kinases, rather than primary sequences, are recognized by the chaperones. In concordance, we observed a striking difference in HSP90 binding between wild-type (WT) and kinase-dead (KD) glycogen synthase kinase 3beta (GSK3beta) forms. Using model cell lines stably expressing these two GSK3beta forms, we observed no interaction between WT GSK3beta and HSP90, in stark contrast to KD GSK3beta forming a stable complex with HSP90 at a 1:1 ratio. In a survey of 91 ectopically expressed kinases in DLD-1 cells, we compared two parameters to measure HSP90 dependency: static binding and kinase stability following HSP90 inhibition. We observed no correlation between HSP90 binding and reduced stability of a kinase after pharmacological inhibition of HSP90. We expanded our stability study to >50 endogenous kinases across four cell lines and demonstrated that HSP90 dependency is context dependent. These observations suggest that HSP90 binds to its kinase client in a particular conformation that we hypothesize to be associated with the nucleotide-processing cycle. Lastly, we performed proteomics profiling of kinases and phosphopeptides in DLD-1 cells to globally define the impact of HSP90 inhibition on the kinome. PMID- 26755561 TI - Parental bonding during childhood affects stress-coping ability and stress reaction. AB - An online survey examined the effects of parental bonding during childhood on adult workers' stress-coping ability (Sense of Coherence) and stress reactions (General Health Questionnaire and Self-Rating Depression Scale). Participants who completed the questionnaire were grouped into optimal bonding and poor bonding groups. Analyses of covariance by gender with age as a covariate were conducted for the Sense of Coherence, General Health Questionnaire, and Self-Rating Depression Scale scores for 9525 participants. For both genders, the scores of the poor bonding group were significantly lower for the Sense of Coherence and significantly higher for the General Health Questionnaire and Self-Rating Depression Scale compared to those of the optimal bonding group. PMID- 26755562 TI - Evaluation of a Structured Predeparture Orientation at the David Geffen School of Medicine's Global Health Education Programs. AB - Given the lack of a standardized approach to medical student global health predeparture preparation, we evaluated an in-person, interactive predeparture orientation (PDO) at the University of California Los Angeles (UCLA) to understand program strengths, weaknesses, and areas for improvement. We administered anonymous surveys to assess the structure and content of the PDO and also surveyed a subset of students after travel on the utility of the PDO. We used Fisher's exact test to evaluate the association between prior global health experience and satisfaction with the PDO. One hundred and five students attended the PDO between 2010 and 2014 and completed the survey. One hundred and four students (99.0%) reported learning new information. Major strengths included faculty mentorship (N = 38, 19.7%), opportunities to interact with the UCLA global health community (N = 34, 17.6%), and sharing global health experiences (N = 32, 16.6%). Of students surveyed after their elective, 94.4% (N = 51) agreed or strongly agreed that the PDO provided effective preparation. Students with prior global health experience found the PDO to be as useful as students without experience (92.7% versus 94.4%, P = 1.0). On the basis of these findings, we believe that a well-composed PDO is beneficial for students participating in global health experiences and recommend further comparative studies of PDO content and delivery. PMID- 26755563 TI - One in Five Maternal Deaths in Bangladesh Associated with Acute Jaundice: Results from a National Maternal Mortality Survey. AB - We estimated the proportion of maternal deaths in Bangladesh associated with acute onset of jaundice. We used verbal autopsy data from a nationally representative maternal mortality survey to calculate the proportion of maternal deaths associated with jaundice and compared it to previously published estimates. Of all maternal deaths between 2008 and 2010, 23% were associated with jaundice, compared with 19% from 1998 to 2001. Approximately one of five maternal deaths was preceded by jaundice, unchanged in 10 years. Our findings highlight the need to better understand the etiology of these maternal deaths in Bangladesh. PMID- 26755558 TI - Different Facets of Copy Number Changes: Permanent, Transient, and Adaptive. AB - Chromosomal copy number changes are frequently associated with harmful consequences and are thought of as an underlying mechanism for the development of diseases. However, changes in copy number are observed during development and occur during normal biological processes. In this review, we highlight the causes and consequences of copy number changes in normal physiologic processes as well as cover their associations with cancer and acquired drug resistance. We discuss the permanent and transient nature of copy number gains and relate these observations to a new mechanism driving transient site-specific copy gains (TSSGs). Finally, we discuss implications of TSSGs in generating intratumoral heterogeneity and tumor evolution and how TSSGs can influence the therapeutic response in cancer. PMID- 26755564 TI - Clinical and Environmental Surveillance for Vibrio cholerae in Resource Constrained Areas: Application During a 1-Year Surveillance in the Far North Region of Cameroon. AB - Biological confirmation of the presence of Vibrio cholerae in clinical and environmental samples is often constrained due to resource- and labor-intensive gold standard methods. To develop low-cost, simple, and sustainable surveillance techniques, we modified previously published specimen sampling and culture techniques and applied the use of enriched dipstick testing in conjunction with the use of filter paper for DNA specimen preservation during clinical and environmental surveillance in the Far North of Cameroon from August 2013 to October 2014. The enriched dipstick methodology during routine use in a remote setting demonstrated a specificity of 99.8% compared with polymerase chain reaction (PCR). The novel application of filter paper as a preservation method for cholera DNA specimens reduced the need for cold chain storage and allowed for PCR characterization and confirmation of V. cholerae. The application of basic technologies such as the enriched dipstick, the use of simplified gauze filtration for environmental sample collection, and the use of filter paper for sample preservation enabled early case identification with reduced logistics and supply cost while reporting minimal false-positive results. Simplified laboratory and epidemiological methodologies can improve the feasibility of cholera surveillance in rural and resource-constrained areas, facilitating early case detection and rapid response implementation. PMID- 26755565 TI - Comparison of Schistosoma mansoni Prevalence and Intensity of Infection, as Determined by the Circulating Cathodic Antigen Urine Assay or by the Kato-Katz Fecal Assay: A Systematic Review. AB - The relationship between results from Kato-Katz (KK) fecal microscopy and urine based point-of-care circulating cathodic antigen (POC-CCA) assays for Schistosoma mansoni infection remains a critical issue. This systematic literature review of 25 published papers compares prevalence of S. mansoni infection by KK with that by the POC-CCA assay. Nineteen published studies met our inclusion criteria for data extraction and analysis. Above a prevalence of 50% by KK, KK and POC-CCA results yielded essentially the same prevalence. Below 50% prevalence by KK, the prevalence by the POC-CCA assay was between 1.5- and 6-fold higher and increased as prevalence by KK decreased. Five of nine publications met inclusion criteria for extractable data on intensity of S. mansoni infection by KK assay and visual band density using the POC-CCA assay. A clear positive relationship exists between intensity by the KK and POC-CCA assays. This systematic review indicates that below 50% prevalence, the POC-CCA assay is much more sensitive than the KK assay. However, the existing data are inadequate to precisely define the relationship between POC-CCA and KK at lower levels of KK prevalence. More studies directly comparing the two assays in low-prevalence areas are essential to inform decision-making by national schistosomiasis control programs. PMID- 26755566 TI - Infection with Leptospira kirschneri Serovar Mozdok: First Report from the Southern Hemisphere. AB - Leptospirosis is a global zoonosis caused by pathogenic Leptospira spp. In this study, we characterized two Leptospira kirschneri serogroup Pomona serovar Mozdok isolates, one obtained from a dog and the other from a patient with severe leptospirosis, 4 years later. Histopathological analysis showed that both isolates caused severe tissue damage when used to infect hamsters. While L. kirschneri serogroup Pomona serovar Mozdok is endemic in animals in Europe, there is only one report of human leptospirosis in the literature. Although strains belonging to L. kirschneri serogroup Pomona have been identified in cases of human leptospirosis in Europe, serovar Mozdok has not yet been implicated. The 4 year interval between isolations and the fact that this is the first report of serovar Mozdok as the causative agent of human leptospirosis in the southern hemisphere, demonstrates its epidemiological importance to public health. Moreover, the presence of serovar Mozdok in Brazil has the potential to affect vaccine and diagnostic test development. PMID- 26755567 TI - Multidrug-Resistant Tuberculosis Complicated by Nosocomial Infection with Multidrug-Resistant Enterobacteriaceae. AB - Treatment of mycobacterial diseases such as tuberculosis (TB) entails long and intense antimicrobial therapy. TB patients are at risk of coinfection with other multidrug-resistant bacteria, such as those from Enterobacteriaceae family, because of antimicrobial selection pressure and nosocomial transmission during prolonged hospital admission. Here, we report on two patients treated for multidrug-resistant TB, who developed severe sepsis due to an extended spectrum beta-lactamase producing organism. Diagnostic culture identified the venous access port as source, and upon surgical removal and antimicrobial therapy rapid clinical improvement was achieved. Increased awareness and knowledge on the prevalence of multi-resistant Enterobacteriaceae is needed, notably in TB centers, to provide a safe hospital environment to our patients. PMID- 26755568 TI - An Improved Ward Architecture for Treatment of Patients with Ebola Virus Disease in Liberia. AB - During the recent outbreak of Ebola virus disease (EVD) in west Africa, we established an Ebola treatment center (ETC) with improved ward architecture. The ETC was built with movable prefabricated boards according to infectious disease unit standard requirements. The clinical staff ensured their own security while providing patients with effective treatment. Of the 180 admissions to the ETC, 10 cases were confirmed with EVD of which six patients survived. None of the clinical staff was infected. We hope that our experience will enable others to avoid unnecessary risks while delivering EVD care. PMID- 26755569 TI - Executive Functions Contribute Uniquely to Reading Competence in Minority Youth. AB - Competent reading requires various skills beyond those for basic word reading (i.e., core language skills, rapid naming, phonological processing). Contributing "higher-level" or domain-general processes include information processing speed and executive functions (working memory, strategic problem solving, attentional switching). Research in this area has relied on largely Caucasian samples, with limited representation of children from racial or ethnic minority groups. This study examined contributions of executive skills to reading competence in 761 children of minority backgrounds. Hierarchical linear regressions examined unique contributions of executive functions (EF) to word reading, fluency, and comprehension. EF contributed uniquely to reading performance, over and above reading-related language skills; working memory contributed uniquely to all components of reading; while attentional switching, but not problem solving, contributed to isolated and contextual word reading and reading fluency. Problem solving uniquely predicted comprehension, suggesting that this skill may be especially important for reading comprehension in minority youth. Attentional switching may play a unique role in development of reading fluency in minority youth, perhaps as a result of the increased demand for switching between spoken versus written dialects. Findings have implications for educational and clinical practice with regard to reading instruction, remedial reading intervention, and assessment of individuals with reading difficulty. PMID- 26755570 TI - Developmental Delays in Executive Function from 3 to 5 Years of Age Predict Kindergarten Academic Readiness. AB - Substantial evidence has established that individual differences in executive function (EF) in early childhood are uniquely predictive of children's academic readiness at school entry. The current study tested whether growth trajectories of EF across the early childhood period could be used to identify a subset of children who were at pronounced risk for academic impairment in kindergarten. Using data that were collected at the age 3, 4, and 5 home assessments in the Family Life Project ( N = 1,120), growth mixture models were used to identify 9% of children who exhibited impaired EF performance (i.e., persistently low levels of EF that did not show expected improvements across time). Compared to children who exhibited typical trajectories of EF, the delayed group exhibited substantial impairments in multiple indicators of academic readiness in kindergarten (Cohen's ds = 0.9-2.7; odds ratios = 9.8-23.8). Although reduced in magnitude following control for a range of socioeconomic and cognitive (general intelligence screener, receptive vocabulary) covariates, moderate-sized group differences remained (Cohen's ds = 0.2-2.4; odds ratios = 3.9-5.4). Results are discussed with respect to the use of repeated measures of EF as a method of early identification, as well as the resulting translational implications of doing so. PMID- 26755571 TI - Clopidogrel Versus Aspirin as an Antiplatelet Monotherapy After 12-Month Dual Antiplatelet Therapy in the Era of Drug-Eluting Stents. AB - BACKGROUND: The use of dual-antiplatelet therapy (DAPT) exceeding 12 months may increase a bleeding risk despite a lower risk of ischemic events. There is no study to compare clinical outcomes in patients treated with a single-antiplatelet drug after DAPT in the era of drug-eluting stents (DES). We sought to investigate the efficacy and safety of clopidogrel versus aspirin monotherapy after 12-month DAPT after DES implantation using an institutional registry. METHODS AND RESULTS: This observational study was conducted on consecutive patients receiving DES between January 2003 and December 2010. A total of 3243 patients receiving 12 month DAPT after DES implantation without adverse clinical outcomes were divided into 2 groups based on prescribed antiplatelet status: aspirin (n=2472) and clopidogrel (n=771). Clinical, angiographic, and procedural characteristics revealed more comorbidities and more complex lesions in the clopidogrel group than in the aspirin group. At 36 months after initiation of antiplatelet monotherapy, clopidogrel was associated with a reduction in risk for a composite of cardiac death, myocardial infarction, or stroke (aspirin versus clopidogrel; 3.8% versus 2.6%; hazard ratio, 0.54; 95% confidence interval, 0.32-0.92; P=0.02). The risk of cardiac death was lower with clopidogrel monotherapy than with aspirin monotherapy (1.4% versus 0.5%; hazard ratio, 0.31; 95% confidence interval, 0.11-0.93; P=0.04). Thrombolysis in myocardial infarction major bleeding occurred similarly between both groups (0.9% versus 1.3%; hazard ratio, 1.03; 95% confidence interval, 0.46-2.32; P=0.95). CONCLUSIONS: After 12-month DAPT, clopidogrel monotherapy, when compared with aspirin monotherapy, might be associated with a reduced risk of recurrent ischemic events in patients receiving DES. PMID- 26755572 TI - Efficacy and Safety of Available Protocols for Aspirin Hypersensitivity for Patients Undergoing Percutaneous Coronary Intervention: A Survey and Systematic Review. AB - BACKGROUND: The most suitable approach for patients with aspirin hypersensitivity undergoing percutaneous coronary intervention remains to be assessed. METHODS AND RESULTS: Pubmed, Google Scholar, and Cochrane were systematically searched for papers describing protocols about aspirin hypersensitivity in the percutaneous coronary intervention setting. Discharge from hospital with aspirin was the primary end point, whereas rates of adverse reactions being a secondary outcome. An online international survey was performed to critically analyze rates of aspirin hypersensitivity and its medical and interventional management. Eleven studies with 283 patients were included. An endovenous desensitization protocol was performed on one of them, with high efficacy rate (98%) and a low adverse reaction rate when compared with oral administration. No significant differences were reported among the oral protocols in terms of efficacy (less versus more fractionated [95.8% {95.4%-96.2%} versus 95.9% {95.2-96.5%}]), whereas higher incidence of rash and angioedema were reported for protocols with <6 doses escalation (2.6% [1.1%-4.1%] versus 2.6% [1.9%-3.2%]). In the survey, we collected answer from 86 physician of the 100 interviewed. Fifty-six percent of them managed aspirin hypersensitivity changing the therapeutic regimen (eg, clopidogrel monotherapy and indobufen). Despite the previous safety data, desensitization protocols were adopted by only 42% of surveyed cardiologist. CONCLUSIONS: Available protocols for aspirin hypersensitivity are effective and safe, representing a feasible approach for patients needing dual antiplatelet therapy. PMID- 26755573 TI - Letter by Hoeper and Galie Regarding Article, "Hemodynamic, Functional, and Clinical Responses to Pulmonary Artery Denervation in Patients With Pulmonary Arterial Hypertension of Different Causes: Phase II Results From the Pulmonary Artery Denervation-1 Study". PMID- 26755574 TI - Response to Letter Regarding Article, "Hemodynamic, Functional, and Clinical Responses to Pulmonary Artery Denervation in Patients With Pulmonary Arterial Hypertension of Different Causes: Phase II Results From the Pulmonary Artery Denervation-1 Study". PMID- 26755575 TI - Fetal/placental weight ratio in a mouse model of maternal diet-induced obesity. PMID- 26755576 TI - Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies. AB - Gain-of-function (GOF) mutations of protein tyrosine phosphatase nonreceptor type 11 Ptpn11 (Shp2), a protein tyrosine phosphatase implicated in multiple cell signaling pathways, are associated with childhood leukemias and solid tumors. The underlying mechanisms are not fully understood. Here, we report that Ptpn11 GOF mutations disturb mitosis and cytokinesis, causing chromosomal instability and greatly increased susceptibility to DNA damage-induced malignancies. We find that Shp2 is distributed to the kinetochore, centrosome, spindle midzone, and midbody, all of which are known to play critical roles in chromosome segregation and cytokinesis. Mouse embryonic fibroblasts with Ptpn11 GOF mutations show a compromised mitotic checkpoint. Centrosome amplification and aberrant mitosis with misaligned or lagging chromosomes are significantly increased in Ptpn11 mutated mouse and patient cells. Abnormal cytokinesis is also markedly increased in these cells. Further mechanistic analyses reveal that GOF mutant Shp2 hyperactivates the Polo-like kinase 1 (Plk1) kinase by enhancing c-Src kinase mediated tyrosine phosphorylation of Plk1. This study provides novel insights into the tumorigenesis associated with Ptpn11 GOF mutations and cautions that DNA damaging treatments in Noonan syndrome patients with germ-line Ptpn11 GOF mutations could increase the risk of therapy-induced malignancies. PMID- 26755578 TI - Close relation between quantum interference in molecular conductance and diradical existence. AB - An empirical observation of a relationship between a striking feature of electronic transmission through a pi-system, destructive quantum interference (QI), on one hand, and the stability of diradicals on the other, leads to the proof of a general theorem that relates the two. Subject to a number of simplifying assumptions, in a pi-electron system, QI occurs when electrodes are attached to those positions of an N-carbon atom N-electron closed-shell hydrocarbon where the matrix elements of the Green's function vanish. These zeros come in two types, which are called easy and hard. Suppose an N+2 atom, N+2 electron hydrocarbon is formed by substituting 2 CH2 groups at two atoms, where the electrodes were. Then, if a QI feature is associated with electrode attachment to the two atoms of the original N atom system, the resulting augmented N+2 molecule will be a diradical. If there is no QI feature, i.e., transmission of current is normal if electrodes are attached to the two atoms, the resulting hydrocarbon will not be a diradical but will have a classical closed-shell electronic structure. Moreover, where a diradical exists, the easy zero is associated with a nondisjoint diradical, and the hard zero is associated with a disjoint one. A related theorem is proven for deletion of two sites from a hydrocarbon. PMID- 26755577 TI - Critical roles of Gi/o proteins and phospholipase C-delta1 in the activation of receptor-operated TRPC4 channels. AB - Transient Receptor Potential Canonical (TRPC) proteins form nonselective cation channels commonly known to be activated downstream from receptors that signal through phospholipase C (PLC). Although TRPC3/C6/C7 can be directly activated by diacylglycerols produced by PLC breakdown of phosphatidylinositol 4,5 bisphosphate (PIP2), the mechanism by which the PLC pathway activates TRPC4/C5 remains unclear. We show here that TRPC4 activation requires coincident stimulation of Gi/o subgroup of G proteins and PLCdelta, with a preference for PLCdelta1 over PLCdelta3, but not necessarily the PLCbeta pathway commonly thought to be involved in receptor-operated TRPC activation. In HEK293 cells coexpressing TRPC4 and Gi/o-coupled u opioid receptor, u agonist elicited currents biphasically, with an initial slow phase preceding a rapidly developing phase. The currents were dependent on intracellular Ca(2+) and PIP2. Reducing PIP2 through phosphatases abolished the biphasic kinetics and increased the probability of channel activation by weak Gi/o stimulation. In both HEK293 cells heterologously expressing TRPC4 and renal carcinoma-derived A-498 cells endogenously expressing TRPC4, channel activation was inhibited by knocking down PLCdelta1 levels and almost completely eliminated by a dominant-negative PLCdelta1 mutant and a constitutively active RhoA mutant. Conversely, the slow phase of Gi/o-mediated TRPC4 activation was diminished by inhibiting RhoA or enhancing PLCdelta function. Our data reveal an integrative mechanism of TRPC4 on detection of coincident Gi/o, Ca(2+), and PLC signaling, which is further modulated by the small GTPase RhoA. This mechanism is not shared with the closely related TRPC5, implicating unique roles of TRPC4 in signal integration in brain and other systems. PMID- 26755580 TI - Endogenous sources of variation in language acquisition. AB - A fundamental question in the study of human language acquisition centers around apportioning explanatory force between the experience of the learner and the core knowledge that allows learners to represent that experience. We provide a previously unidentified kind of data identifying children's contribution to language acquisition. We identify one aspect of grammar that varies unpredictably across a population of speakers of what is ostensibly a single language. We further demonstrate that the grammatical knowledge of parents and their children is independent. The combination of unpredictable variation and parent-child independence suggests that the relevant structural feature is supplied by each learner independent of experience with the language. This structural feature is abstract because it controls variation in more than one construction. The particular case we examine is the position of the verb in the clause structure of Korean. Because Korean is a head-final language, evidence for the syntactic position of the verb is both rare and indirect. We show that (i) Korean speakers exhibit substantial variability regarding this aspect of the grammar, (ii) this variability is attested between speakers but not within a speaker, (iii) this variability controls interpretation in two surface constructions, and (iv) it is independent in parents and children. According to our findings, when the exposure language is compatible with multiple grammars, learners acquire a single systematic grammar. Our observation that children and their parents vary independently suggests that the choice of grammar is driven in part by a process operating internal to individual learners. PMID- 26755579 TI - Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure. AB - Chronic nicotine exposure (CNE) alters synaptic transmission in the ventral tegmental area (VTA) in a manner that enhances dopaminergic signaling and promotes nicotine use. The present experiments identify a correlation between enhanced production of the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) and diminished release of the inhibitory neurotransmitter GABA in the VTA following CNE. To study the functional role of on-demand 2-AG signaling in GABAergic synapses, we used 1,2,3-triazole urea compounds to selectively inhibit 2-AG biosynthesis by diacylglycerol lipase (DAGL). The potency and selectivity of these inhibitors were established in rats in vitro (rat brain proteome), ex vivo (brain slices), and in vivo (intracerebroventricular administration) using activity-based protein profiling and targeted metabolomics analyses. Inhibition of DAGL (2-AG biosynthesis) rescues nicotine-induced VTA GABA signaling following CNE. Conversely, enhancement of 2-AG signaling in naive rats by inhibiting 2-AG degradation recapitulates the loss of nicotine-induced GABA signaling evident following CNE. DAGL inhibition reduces nicotine self-administration without disrupting operant responding for a nondrug reinforcer or motor activity. Collectively, these findings provide a detailed characterization of selective inhibitors of rat brain DAGL and demonstrate that excessive 2-AG signaling contributes to a loss of inhibitory GABAergic constraint of VTA excitability following CNE. PMID- 26755581 TI - Identification of a mammalian glycerol-3-phosphate phosphatase: Role in metabolism and signaling in pancreatic beta-cells and hepatocytes. AB - Obesity, and the associated disturbed glycerolipid/fatty acid (GL/FA) cycle, contribute to insulin resistance, islet beta-cell failure, and type 2 diabetes. Flux through the GL/FA cycle is regulated by the availability of glycerol-3 phosphate (Gro3P) and fatty acyl-CoA. We describe here a mammalian Gro3P phosphatase (G3PP), which was not known to exist in mammalian cells, that can directly hydrolyze Gro3P to glycerol. We identified that mammalian phosphoglycolate phosphatase, with an uncertain function, acts in fact as a G3PP. We found that G3PP, by controlling Gro3P levels, regulates glycolysis and glucose oxidation, cellular redox and ATP production, gluconeogenesis, glycerolipid synthesis, and fatty acid oxidation in pancreatic islet beta-cells and hepatocytes, and that glucose stimulated insulin secretion and the response to metabolic stress, e.g., glucolipotoxicity, in beta-cells. In vivo overexpression of G3PP in rat liver lowers body weight gain and hepatic glucose production from glycerol and elevates plasma HDL levels. G3PP is expressed at various levels in different tissues, and its expression varies according to the nutritional state in some tissues. As Gro3P lies at the crossroads of glucose, lipid, and energy metabolism, control of its availability by G3PP adds a key level of metabolic regulation in mammalian cells, and G3PP offers a potential target for type 2 diabetes and cardiometabolic disorders. PMID- 26755582 TI - A dynamic Asp-Arg interaction is essential for catalysis in microsomal prostaglandin E2 synthase. AB - Microsomal prostaglandin E2 synthase type 1 (mPGES-1) is responsible for the formation of the potent lipid mediator prostaglandin E2 under proinflammatory conditions, and this enzyme has received considerable attention as a drug target. Recently, a high-resolution crystal structure of human mPGES-1 was presented, with Ser-127 being proposed as the hydrogen-bond donor stabilizing thiolate anion formation within the cofactor, glutathione (GSH). We have combined site-directed mutagenesis and activity assays with a structural dynamics analysis to probe the functional roles of such putative catalytic residues. We found that Ser-127 is not required for activity, whereas an interaction between Arg-126 and Asp-49 is essential for catalysis. We postulate that both residues, in addition to a crystallographic water, serve critical roles within the enzymatic mechanism. After characterizing the size or charge conservative mutations Arg-126-Gln, Asp 49-Asn, and Arg-126-Lys, we inferred that a crystallographic water acts as a general base during GSH thiolate formation, stabilized by interaction with Arg 126, which is itself modulated by its respective interaction with Asp-49. We subsequently found hidden conformational ensembles within the crystal structure that correlate well with our biochemical data. The resulting contact signaling network connects Asp-49 to distal residues involved in GSH binding and is ligand dependent. Our work has broad implications for development of efficient mPGES-1 inhibitors, potential anti-inflammatory and anticancer agents. PMID- 26755584 TI - Covert digital manipulation of vocal emotion alter speakers' emotional states in a congruent direction. AB - Research has shown that people often exert control over their emotions. By modulating expressions, reappraising feelings, and redirecting attention, they can regulate their emotional experience. These findings have contributed to a blurring of the traditional boundaries between cognitive and emotional processes, and it has been suggested that emotional signals are produced in a goal-directed way and monitored for errors like other intentional actions. However, this interesting possibility has never been experimentally tested. To this end, we created a digital audio platform to covertly modify the emotional tone of participants' voices while they talked in the direction of happiness, sadness, or fear. The result showed that the audio transformations were being perceived as natural examples of the intended emotions, but the great majority of the participants, nevertheless, remained unaware that their own voices were being manipulated. This finding indicates that people are not continuously monitoring their own voice to make sure that it meets a predetermined emotional target. Instead, as a consequence of listening to their altered voices, the emotional state of the participants changed in congruence with the emotion portrayed, which was measured by both self-report and skin conductance level. This change is the first evidence, to our knowledge, of peripheral feedback effects on emotional experience in the auditory domain. As such, our result reinforces the wider framework of self-perception theory: that we often use the same inferential strategies to understand ourselves as those that we use to understand others. PMID- 26755583 TI - Testing the kinship theory of intragenomic conflict in honey bees (Apis mellifera). AB - Sexual reproduction brings genes from two parents (matrigenes and patrigenes) together into one individual. These genes, despite being unrelated, should show nearly perfect cooperation because each gains equally through the production of offspring. However, an individual's matrigenes and patrigenes can have different probabilities of being present in other relatives, so kin selection could act on them differently. Such intragenomic conflict could be implemented by partial or complete silencing (imprinting) of an allele by one of the parents. Evidence supporting this theory is seen in offspring-mother interactions, with patrigenes favoring acquisition of more of the mother's resources if some of the costs fall on half-siblings who do not share the patrigene. The kinship theory of intragenomic conflict is little tested in other contexts, but it predicts that matrigene-patrigene conflict may be rife in social insects. We tested the hypothesis that honey bee worker reproduction is promoted more by patrigenes than matrigenes by comparing across nine reciprocal crosses of two distinct genetic stocks. As predicted, hybrid workers show reproductive trait characteristics of their paternal stock, (indicating enhanced activity of the patrigenes on these traits), greater patrigenic than matrigenic expression, and significantly increased patrigenic-biased expression in reproductive workers. These results support both the general prediction that matrigene-patrigene conflict occurs in social insects and the specific prediction that honey bee worker reproduction is driven more by patrigenes. The success of these predictions suggests that intragenomic conflict may occur in many contexts where matrigenes and patrigenes have different relatednesses to affected kin. PMID- 26755585 TI - Altered short-term synaptic plasticity and reduced muscle strength in mice with impaired regulation of presynaptic CaV2.1 Ca2+ channels. AB - Facilitation and inactivation of P/Q-type calcium (Ca(2+)) currents through the regulation of voltage-gated Ca(2+) (CaV) 2.1 channels by Ca(2+) sensor (CaS) proteins contributes to the facilitation and rapid depression of synaptic transmission in cultured neurons that transiently express CaV2.1 channels. To examine the modulation of endogenous CaV2.1 channels by CaS proteins in native synapses, we introduced a mutation (IM-AA) into the CaS protein-binding site in the C-terminal domain of CaV2.1 channels in mice, and tested synaptic facilitation and depression in neuromuscular junction synapses that use exclusively CaV2.1 channels for Ca(2+) entry that triggers synaptic transmission. Even though basal synaptic transmission was unaltered in the neuromuscular synapses in IM-AA mice, we found reduced short-term facilitation in response to paired stimuli at short interstimulus intervals in IM-AA synapses. In response to trains of action potentials, we found increased facilitation at lower frequencies (10-30 Hz) in IM-AA synapses accompanied by slowed synaptic depression, whereas synaptic facilitation was reduced at high stimulus frequencies (50-100 Hz) that would induce strong muscle contraction. As a consequence of altered regulation of CaV2.1 channels, the hindlimb tibialis anterior muscle in IM-AA mice exhibited reduced peak force in response to 50 Hz stimulation and increased muscle fatigue. The IM-AA mice also had impaired motor control, exercise capacity, and grip strength. Taken together, our results indicate that regulation of CaV2.1 channels by CaS proteins is essential for normal synaptic plasticity at the neuromuscular junction and for muscle strength, endurance, and motor coordination in mice in vivo. PMID- 26755587 TI - Reply to Underdown and Oppenheimer: Roles of selection, plasticity, and genetics in the integration of human pelvis shape and head size. PMID- 26755588 TI - Stochastic modeling reveals an evolutionary mechanism underlying elevated rates of childhood leukemia. AB - Young children have higher rates of leukemia than young adults. This fact represents a fundamental conundrum, because hematopoietic cells in young children should have fewer mutations (including oncogenic ones) than such cells in adults. Here, we present the results of stochastic modeling of hematopoietic stem cell (HSC) clonal dynamics, which demonstrated that early HSC pools were permissive to clonal evolution driven by drift. We show that drift-driven clonal expansions cooperate with faster HSC cycling in young children to produce conditions that are permissive for accumulation of multiple driver mutations in a single cell. Later in life, clonal evolution was suppressed by stabilizing selection in the larger young adult pools, and it was driven by positive selection at advanced ages in the presence of microenvironmental decline. Overall, our results indicate that leukemogenesis is driven by distinct evolutionary forces in children and adults. PMID- 26755586 TI - Neuregulin1 displayed on motor axons regulates terminal Schwann cell-mediated synapse elimination at developing neuromuscular junctions. AB - Synaptic connections in the nervous system are rearranged during development and in adulthood as a feature of growth, plasticity, aging, and disease. Glia are implicated as active participants in these changes. Here we investigated a signal that controls the participation of peripheral glia, the terminal Schwann cells (SCs), at the neuromuscular junction (NMJ) in mice. Transgenic manipulation of the levels of membrane-tethered neuregulin1 (NRG1-III), a potent activator of SCs normally presented on motor axons, alters the rate of loss of motor inputs at NMJs during developmental synapse elimination. In addition, NMJs of adult transgenic mice that expressed excess axonal NRG1-III exhibited continued remodeling, in contrast to the more stable morphologies of controls. In fact, synaptic SCs of these adult mice with NRG1-III overexpression exhibited behaviors evident in wild type neonates during synapse elimination, including an affinity for the postsynaptic myofiber surface and phagocytosis of nerve terminals. Given that levels of NRG1-III expression normally peak during the period of synapse elimination, our findings identify axon-tethered NRG1 as a molecular determinant for SC-driven neuromuscular synaptic plasticity. PMID- 26755589 TI - Nuclear TRAF3 is a negative regulator of CREB in B cells. AB - The adaptor protein TNF receptor-associated factor 3 (TRAF3) regulates signaling through B-lymphocyte receptors, including CD40, BAFF receptor, and Toll-like receptors, and also plays a critical role inhibiting B-cell homoeostatic survival. Consistent with these findings, loss-of-function human TRAF3 mutations are common in B-cell cancers, particularly multiple myeloma and B-cell lymphoma. B cells of B-cell-specific TRAF3(-/-) mice (B-Traf3(-/-)) display remarkably enhanced survival compared with littermate control (WT) B cells. The mechanism for this abnormal homeostatic survival is poorly understood, a key knowledge gap in selecting optimal treatments for human B-cell cancers with TRAF3 deficiency. We show here for the first time to our knowledge that TRAF3 is a resident nuclear protein that associates with the transcriptional regulator cAMP response element binding protein (CREB) in both mouse and human B cells. The TRAF-C domain of TRAF3 was necessary and sufficient to localize TRAF3 to the nucleus via a functional nuclear localization signal. CREB protein was elevated in TRAF3(-/-) B cells, without change in mRNA, but with a decrease in CREB ubiquitination. CREB mediated transcriptional activity was increased in TRAF3-deficient B cells. Consistent with these findings, Mcl-1, an antiapoptotic target of CREB-mediated transcription, was increased in the absence of TRAF3 and enhanced Mcl-1 was suppressed with CREB inhibition. TRAF3-deficient B cells were also preferentially sensitive to survival inhibition with pharmacologic CREB inhibitor. Our results identify a new mechanism by which nuclear TRAF3 regulates B-cell survival via inhibition of CREB stability, information highly relevant to the role of TRAF3 in B-cell malignancies. PMID- 26755591 TI - Hiding personal information reveals the worst. AB - Seven experiments explore people's decisions to share or withhold personal information, and the wisdom of such decisions. When people choose not to reveal information--to be "hiders"--they are judged negatively by others (experiment 1). These negative judgments emerge when hiding is volitional (experiments 2A and 2B) and are driven by decreases in trustworthiness engendered by decisions to hide (experiments 3A and 3B). Moreover, hiders do not intuit these negative consequences: given the choice to withhold or reveal unsavory information, people often choose to withhold, but observers rate those who reveal even questionable behavior more positively (experiments 4A and 4B). The negative impact of hiding holds whether opting not to disclose unflattering (drug use, poor grades, and sexually transmitted diseases) or flattering (blood donations) information, and across decisions ranging from whom to date to whom to hire. When faced with decisions about disclosure, decision-makers should be aware not just of the risk of revealing, but of what hiding reveals. PMID- 26755590 TI - Developmental accumulation of inorganic polyphosphate affects germination and energetic metabolism in Dictyostelium discoideum. AB - Inorganic polyphosphate (polyP) is composed of linear chains of phosphate groups linked by high-energy phosphoanhydride bonds. However, this simple, ubiquitous molecule remains poorly understood. The use of nonstandardized analytical methods has contributed to this lack of clarity. By using improved polyacrylamide gel electrophoresis we were able to visualize polyP extracted from Dictyostelium discoideum. We established that polyP is undetectable in cells lacking the polyphosphate kinase (DdPpk1). Generation of this ppk1 null strain revealed that polyP is important for the general fitness of the amoebae with the mutant strain displaying a substantial growth defect. We discovered an unprecedented accumulation of polyP during the developmental program, with polyP increasing more than 100-fold. The failure of ppk1 spores to accumulate polyP results in a germination defect. These phenotypes are underpinned by the ability of polyP to regulate basic energetic metabolism, demonstrated by a 2.5-fold decrease in the level of ATP in vegetative ppk1. Finally, the lack of polyP during the development of ppk1 mutant cells is partially offset by an increase of both ATP and inositol pyrophosphates, evidence for a model in which there is a functional interplay between inositol pyrophosphates, ATP, and polyP. PMID- 26755592 TI - Pedothem carbonates reveal anomalous North American atmospheric circulation 70,000-55,000 years ago. AB - Our understanding of climatic conditions, and therefore forcing factors, in North America during the past two glacial cycles is limited in part by the scarcity of long, well-dated, continuous paleoclimate records. Here, we present the first, to our knowledge, continuous, millennial-resolution paleoclimate proxy record derived from millimeter-thick pedogenic carbonate clast coatings (pedothems), which are widely distributed in semiarid to arid regions worldwide. Our new multiisotope pedothem record from the Wind River Basin in Wyoming confirms a previously hypothesized period of increased transport of Gulf of Mexico moisture northward into the continental interior from 70,000 to 55,000 years ago based on oxygen and carbon isotopes determined by ion microprobe and uranium isotopes and U-Th dating by laser ablation inductively coupled plasma mass spectrometry. This pronounced meridional moisture transport, which contrasts with the dominant zonal transport of Pacific moisture into the North American interior by westerly winds before and after 70,000-55,000 years ago, may have resulted from a persistent anticyclone developed above the North American ice sheet during Marine Isotope Stage 4. We conclude that pedothems, when analyzed using microanalytical techniques, can provide high-resolution paleoclimate records that may open new avenues into understanding past terrestrial climates in regions where paleoclimate records are not otherwise available. When pedothem paleoclimate records are combined with existing records they will add complimentary soil-based perspectives on paleoclimate conditions. PMID- 26755595 TI - Do patterns of covariation between human pelvis shape, stature, and head size alleviate the obstetric dilemma? PMID- 26755593 TI - Systems biology of immunity to MF59-adjuvanted versus nonadjuvanted trivalent seasonal influenza vaccines in early childhood. AB - The dynamics and molecular mechanisms underlying vaccine immunity in early childhood remain poorly understood. Here we applied systems approaches to investigate the innate and adaptive responses to trivalent inactivated influenza vaccine (TIV) and MF59-adjuvanted TIV (ATIV) in 90 14- to 24-mo-old healthy children. MF59 enhanced the magnitude and kinetics of serum antibody titers following vaccination, and induced a greater frequency of vaccine specific, multicytokine-producing CD4(+) T cells. Compared with transcriptional responses to TIV vaccination previously reported in adults, responses to TIV in infants were markedly attenuated, limited to genes regulating antiviral and antigen presentation pathways, and observed only in a subset of vaccinees. In contrast, transcriptional responses to ATIV boost were more homogenous and robust. Interestingly, a day 1 gene signature characteristic of the innate response (antiviral IFN genes, dendritic cell, and monocyte responses) correlated with hemagglutination at day 28. These findings demonstrate that MF59 enhances the magnitude, kinetics, and consistency of the innate and adaptive response to vaccination with the seasonal influenza vaccine during early childhood, and identify potential molecular correlates of antibody responses. PMID- 26755594 TI - Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to short-term synaptic plasticity in hippocampal neurons. AB - Short-term synaptic plasticity is induced by calcium (Ca(2+)) accumulating in presynaptic nerve terminals during repetitive action potentials. Regulation of voltage-gated CaV2.1 Ca(2+) channels by Ca(2+) sensor proteins induces facilitation of Ca(2+) currents and synaptic facilitation in cultured neurons expressing exogenous CaV2.1 channels. However, it is unknown whether this mechanism contributes to facilitation in native synapses. We introduced the IM-AA mutation into the IQ-like motif (IM) of the Ca(2+) sensor binding site. This mutation does not alter voltage dependence or kinetics of CaV2.1 currents, or frequency or amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs); however, synaptic facilitation is completely blocked in excitatory glutamatergic synapses in hippocampal autaptic cultures. In acutely prepared hippocampal slices, frequency and amplitude of mEPSCs and amplitudes of evoked EPSCs are unaltered. In contrast, short-term synaptic facilitation in response to paired stimuli is reduced by ~ 50%. In the presence of EGTA-AM to prevent global increases in free Ca(2+), the IM-AA mutation completely blocks short-term synaptic facilitation, indicating that synaptic facilitation by brief, local increases in Ca(2+) is dependent upon regulation of CaV2.1 channels by Ca(2+) sensor proteins. In response to trains of action potentials, synaptic facilitation is reduced in IM-AA synapses in initial stimuli, consistent with results of paired-pulse experiments; however, synaptic depression is also delayed, resulting in sustained increases in amplitudes of later EPSCs during trains of 10 stimuli at 10-20 Hz. Evidently, regulation of CaV2.1 channels by CaS proteins is required for normal short-term plasticity and normal encoding of information in native hippocampal synapses. PMID- 26755596 TI - In-cell thermodynamics and a new role for protein surfaces. AB - There is abundant, physiologically relevant knowledge about protein cores; they are hydrophobic, exquisitely well packed, and nearly all hydrogen bonds are satisfied. An equivalent understanding of protein surfaces has remained elusive because proteins are almost exclusively studied in vitro in simple aqueous solutions. Here, we establish the essential physiological roles played by protein surfaces by measuring the equilibrium thermodynamics and kinetics of protein folding in the complex environment of living Escherichia coli cells, and under physiologically relevant in vitro conditions. Fluorine NMR data on the 7-kDa globular N-terminal SH3 domain of Drosophila signal transduction protein drk (SH3) show that charge-charge interactions are fundamental to protein stability and folding kinetics in cells. Our results contradict predictions from accepted theories of macromolecular crowding and show that cosolutes commonly used to mimic the cellular interior do not yield physiologically relevant information. As such, we provide the foundation for a complete picture of protein chemistry in cells. PMID- 26755597 TI - Neotropical forest expansion during the last glacial period challenges refuge hypothesis. AB - The forest refuge hypothesis (FRH) has long been a paradigm for explaining the extreme biological diversity of tropical forests. According to this hypothesis, forest retraction and fragmentation during glacial periods would have promoted reproductive isolation and consequently speciation in forest patches (ecological refuges) surrounded by open habitats. The recent use of paleoclimatic models of species and habitat distributions revitalized the FRH, not by considering refuges as the main drivers of allopatric speciation, but instead by suggesting that high contemporary diversity is associated with historically stable forest areas. However, the role of the emerged continental shelf on the Atlantic Forest biodiversity hotspot of eastern South America during glacial periods has been ignored in the literature. Here, we combined results of species distribution models with coalescent simulations based on DNA sequences to explore the congruence between scenarios of forest dynamics through time and the genetic structure of mammal species cooccurring in the central region of the Atlantic Forest. Contrary to the FRH predictions, we found more fragmentation of suitable habitats during the last interglacial (LIG) and the present than in the last glacial maximum (LGM), probably due to topography. We also detected expansion of suitable climatic conditions onto the emerged continental shelf during the LGM, which would have allowed forests and forest-adapted species to expand. The interplay of sea level and land distribution must have been crucial in the biogeographic history of the Atlantic Forest, and forest refuges played only a minor role, if any, in this biodiversity hotspot during glacial periods. PMID- 26755598 TI - Prolongevity hormone FGF21 protects against immune senescence by delaying age related thymic involution. AB - Age-related thymic degeneration is associated with loss of naive T cells, restriction of peripheral T-cell diversity, and reduced healthspan due to lower immune competence. The mechanistic basis of age-related thymic demise is unclear, but prior evidence suggests that caloric restriction (CR) can slow thymic aging by maintaining thymic epithelial cell integrity and reducing the generation of intrathymic lipid. Here we show that the prolongevity ketogenic hormone fibroblast growth factor 21 (FGF21), a member of the endocrine FGF subfamily, is expressed in thymic stromal cells along with FGF receptors and its obligate coreceptor, betaKlotho. We found that FGF21 expression in thymus declines with age and is induced by CR. Genetic gain of FGF21 function in mice protects against age-related thymic involution with an increase in earliest thymocyte progenitors and cortical thymic epithelial cells. Importantly, FGF21 overexpression reduced intrathymic lipid, increased perithymic brown adipose tissue, and elevated thymic T-cell export and naive T-cell frequencies in old mice. Conversely, loss of FGF21 function in middle-aged mice accelerated thymic aging, increased lethality, and delayed T-cell reconstitution postirradiation and hematopoietic stem cell transplantation (HSCT). Collectively, FGF21 integrates metabolic and immune systems to prevent thymic injury and may aid in the reestablishment of a diverse T-cell repertoire in cancer patients following HSCT. PMID- 26755600 TI - Origin of the p-process radionuclides 92Nb and 146Sm in the early solar system and inferences on the birth of the Sun. AB - The abundances of (92)Nb and (146)Sm in the early solar system are determined from meteoritic analysis, and their stellar production is attributed to the p process. We investigate if their origin from thermonuclear supernovae deriving from the explosion of white dwarfs with mass above the Chandrasekhar limit is in agreement with the abundance of (53)Mn, another radionuclide present in the early solar system and produced in the same events. A consistent solution for (92)Nb and (53)Mn cannot be found within the current uncertainties and requires the (92)Nb/(92)Mo ratio in the early solar system to be at least 50% lower than the current nominal value, which is outside its present error bars. A different solution is to invoke another production site for (92)Nb, which we find in the alpha-rich freezeout during core-collapse supernovae from massive stars. Whichever scenario we consider, we find that a relatively long time interval of at least ~ 10 My must have elapsed from when the star-forming region where the Sun was born was isolated from the interstellar medium and the birth of the Sun. This is in agreement with results obtained from radionuclides heavier than iron produced by neutron captures and lends further support to the idea that the Sun was born in a massive star-forming region together with many thousands of stellar siblings. PMID- 26755599 TI - Intermediates in the assembly of mitotic checkpoint complexes and their role in the regulation of the anaphase-promoting complex. AB - The mitotic (or spindle assembly) checkpoint system prevents premature separation of sister chromatids in mitosis and thus ensures the fidelity of chromosome segregation. Kinetochores that are not attached properly to the mitotic spindle produce an inhibitory signal that prevents progression into anaphase. The checkpoint system acts on the Anaphase-Promoting Complex/Cyclosome (APC/C) ubiquitin ligase, which targets for degradation inhibitors of anaphase initiation. APC/C is inhibited by the Mitotic Checkpoint Complex (MCC), which assembles when the checkpoint is activated. MCC is composed of the checkpoint proteins BubR1, Bub3, and Mad2, associated with the APC/C coactivator Cdc20. The intermediary processes in the assembly of MCC are not sufficiently understood. It is also not clear whether or not some subcomplexes of MCC inhibit the APC/C and whether Mad2 is required only for MCC assembly and not for its action on the APC/C. We used purified subcomplexes of mitotic checkpoint proteins to examine these problems. Our results do not support a model in which Mad2 catalytically generates a Mad2-free APC/C inhibitor. We also found that the release of Mad2 from MCC caused a marked (although not complete) decrease in inhibitory action, suggesting a role of Mad2 in MCC for APC/C inhibition. A previously unknown species of MCC, which consists of Mad2, BubR1, and two molecules of Cdc20, contributes to the inhibition of APC/C by the mitotic checkpoint system. PMID- 26755601 TI - Molecular mechanism of viomycin inhibition of peptide elongation in bacteria. AB - Viomycin is a tuberactinomycin antibiotic essential for treating multidrug resistant tuberculosis. It inhibits bacterial protein synthesis by blocking elongation factor G (EF-G) catalyzed translocation of messenger RNA on the ribosome. Here we have clarified the molecular aspects of viomycin inhibition of the elongating ribosome using pre-steady-state kinetics. We found that the probability of ribosome inhibition by viomycin depends on competition between viomycin and EF-G for binding to the pretranslocation ribosome, and that stable viomycin binding requires an A-site bound tRNA. Once bound, viomycin stalls the ribosome in a pretranslocation state for a minimum of ~ 45 s. This stalling time increases linearly with viomycin concentration. Viomycin inhibition also promotes futile cycles of GTP hydrolysis by EF-G. Finally, we have constructed a kinetic model for viomycin inhibition of EF-G catalyzed translocation, allowing for testable predictions of tuberactinomycin action in vivo and facilitating in-depth understanding of resistance development against this important class of antibiotics. PMID- 26755603 TI - Intuition, deliberation, and the evolution of cooperation. AB - Humans often cooperate with strangers, despite the costs involved. A long tradition of theoretical modeling has sought ultimate evolutionary explanations for this seemingly altruistic behavior. More recently, an entirely separate body of experimental work has begun to investigate cooperation's proximate cognitive underpinnings using a dual-process framework: Is deliberative self-control necessary to reign in selfish impulses, or does self-interested deliberation restrain an intuitive desire to cooperate? Integrating these ultimate and proximate approaches, we introduce dual-process cognition into a formal game theoretic model of the evolution of cooperation. Agents play prisoner's dilemma games, some of which are one-shot and others of which involve reciprocity. They can either respond by using a generalized intuition, which is not sensitive to whether the game is one-shot or reciprocal, or pay a (stochastically varying) cost to deliberate and tailor their strategy to the type of game they are facing. We find that, depending on the level of reciprocity and assortment, selection favors one of two strategies: intuitive defectors who never deliberate, or dual process agents who intuitively cooperate but sometimes use deliberation to defect in one-shot games. Critically, selection never favors agents who use deliberation to override selfish impulses: Deliberation only serves to undermine cooperation with strangers. Thus, by introducing a formal theoretical framework for exploring cooperation through a dual-process lens, we provide a clear answer regarding the role of deliberation in cooperation based on evolutionary modeling, help to organize a growing body of sometimes-conflicting empirical results, and shed light on the nature of human cognition and social decision making. PMID- 26755602 TI - Imaging of the cross-presenting dendritic cell subsets in the skin-draining lymph node. AB - Dendritic cells (DCs) are antigen-presenting cells specialized for activating T cells to elicit effector T-cell functions. Cross-presenting DCs are a DC subset capable of presenting antigens to CD8(+) T cells and play critical roles in cytotoxic T-cell-mediated immune responses to microorganisms and cancer. Although their importance is known, the spatiotemporal dynamics of cross-presenting DCs in vivo are incompletely understood. Here, we study the T-cell zone in skin-draining lymph nodes (SDLNs) and find it is compartmentalized into regions for CD8(+) T cell activation by cross-presenting DCs that express the chemokine (C motif) receptor 1 gene, Xcr1 and for CD4(+) T-cell activation by CD11b(+) DCs. Xcr1 expressing DCs in the SDLNs are composed of two different populations: migratory (CD103(hi)) DCs, which immigrate from the skin, and resident (CD8alpha(hi)) DCs, which develop in the nodes. To characterize the dynamic interactions of these distinct DC populations with CD8(+) T cells during their activation in vivo, we developed a photoconvertible reporter mouse strain, which permits us to distinctively visualize the migratory and resident subsets of Xcr1-expressing DCs. After leaving the skin, migratory DCs infiltrated to the deep T-cell zone of the SDLNs over 3 d, which corresponded to their half-life in the SDLNs. Intravital two-photon imaging showed that after soluble antigen immunization, the newly arriving migratory DCs more efficiently form sustained conjugates with antigen-specific CD8(+) T cells than other Xcr1-expressing DCs in the SDLNs. These results offer in vivo evidence for differential contributions of migratory and resident cross-presenting DCs to CD8(+) T-cell activation. PMID- 26755604 TI - Lignin engineering in field-grown poplar trees affects the endosphere bacterial microbiome. AB - Cinnamoyl-CoA reductase (CCR), an enzyme central to the lignin biosynthetic pathway, represents a promising biotechnological target to reduce lignin levels and to improve the commercial viability of lignocellulosic biomass. However, silencing of the CCR gene results in considerable flux changes of the general and monolignol-specific lignin pathways, ultimately leading to the accumulation of various extractable phenolic compounds in the xylem. Here, we evaluated host genotype-dependent effects of field-grown, CCR-down-regulated poplar trees (Populus tremula * Populus alba) on the bacterial rhizosphere microbiome and the endosphere microbiome, namely the microbiota present in roots, stems, and leaves. Plant-associated bacteria were isolated from all plant compartments by selective isolation and enrichment techniques with specific phenolic carbon sources (such as ferulic acid) that are up-regulated in CCR-deficient poplar trees. The bacterial microbiomes present in the endosphere were highly responsive to the CCR deficient poplar genotype with remarkably different metabolic capacities and associated community structures compared with the WT trees. In contrast, the rhizosphere microbiome of CCR-deficient and WT poplar trees featured highly overlapping bacterial community structures and metabolic capacities. We demonstrate the host genotype modulation of the plant microbiome by minute genetic variations in the plant genome. Hence, these interactions need to be taken into consideration to understand the full consequences of plant metabolic pathway engineering and its relation with the environment and the intended genetic improvement. PMID- 26755605 TI - Decanalization of wing development accompanied the evolution of large wings in high-altitude Drosophila. AB - In higher organisms, the phenotypic impacts of potentially harmful or beneficial mutations are often modulated by complex developmental networks. Stabilizing selection may favor the evolution of developmental canalization--that is, robustness despite perturbation--to insulate development against environmental and genetic variability. In contrast, directional selection acts to alter the developmental process, possibly undermining the molecular mechanisms that buffer a trait's development, but this scenario has not been shown in nature. Here, we examined the developmental consequences of size increase in highland Ethiopian Drosophila melanogaster. Ethiopian inbred strains exhibited much higher frequencies of wing abnormalities than lowland populations, consistent with an elevated susceptibility to the genetic perturbation of inbreeding. We then used mutagenesis to test whether Ethiopian wing development is, indeed, decanalized. Ethiopian strains were far more susceptible to this genetic disruption of development, yielding 26 times more novel wing abnormalities than lowland strains in F2 males. Wing size and developmental perturbability cosegregated in the offspring of between-population crosses, suggesting that genes conferring size differences had undermined developmental buffering mechanisms. Our findings represent the first observation, to our knowledge, of morphological evolution associated with decanalization in the same tissue, underscoring the sensitivity of development to adaptive change. PMID- 26755606 TI - Private algorithms for the protected in social network search. AB - Motivated by tensions between data privacy for individual citizens and societal priorities such as counterterrorism and the containment of infectious disease, we introduce a computational model that distinguishes between parties for whom privacy is explicitly protected, and those for whom it is not (the targeted subpopulation). The goal is the development of algorithms that can effectively identify and take action upon members of the targeted subpopulation in a way that minimally compromises the privacy of the protected, while simultaneously limiting the expense of distinguishing members of the two groups via costly mechanisms such as surveillance, background checks, or medical testing. Within this framework, we provide provably privacy-preserving algorithms for targeted search in social networks. These algorithms are natural variants of common graph search methods, and ensure privacy for the protected by the careful injection of noise in the prioritization of potential targets. We validate the utility of our algorithms with extensive computational experiments on two large-scale social network datasets. PMID- 26755607 TI - Quantitative proteomics identify DAB2 as a cardiac developmental regulator that inhibits WNT/beta-catenin signaling. AB - To reveal the molecular mechanisms involved in cardiac lineage determination and differentiation, we quantified the proteome of human embryonic stem cells (hESCs), cardiac progenitor cells (CPCs), and cardiomyocytes during a time course of directed differentiation by label-free quantitative proteomics. This approach correctly identified known stage-specific markers of cardiomyocyte differentiation, including SRY-box2 (SOX2), GATA binding protein 4 (GATA4), and myosin heavy chain 6 (MYH6). This led us to determine whether our proteomic screen could reveal previously unidentified mediators of heart development. We identified Disabled 2 (DAB2) as one of the most dynamically expressed proteins in hESCs, CPCs, and cardiomyocytes. We used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) mutagenesis in zebrafish to assess whether DAB2 plays a functional role during cardiomyocyte differentiation. We found that deletion of Dab2 in zebrafish embryos led to a significant reduction in cardiomyocyte number and increased endogenous WNT/beta catenin signaling. Furthermore, the Dab2-deficient defects in cardiomyocyte number could be suppressed by overexpression of dickkopf 1 (DKK1), an inhibitor of WNT/beta-catenin signaling. Thus, inhibition of WNT/beta-catenin signaling by DAB2 is essential for establishing the correct number of cardiomyocytes in the developing heart. Our work demonstrates that quantifying the proteome of human stem cells can identify previously unknown developmental regulators. PMID- 26755609 TI - Contrasting effects of intralocus sexual conflict on sexually antagonistic coevolution. AB - Evolutionary conflict between the sexes can induce arms races in which males evolve traits that are detrimental to the fitness of their female partners, and vice versa. This interlocus sexual conflict (IRSC) has been proposed as a cause of perpetual intersexual antagonistic coevolution with wide-ranging evolutionary consequences. However, theory suggests that the scope for perpetual coevolution is limited, if traits involved in IRSC are subject to pleiotropic constraints. Here, we consider a biologically plausible form of pleiotropy that has hitherto been ignored in treatments of IRSC and arrive at drastically different conclusions. Our analysis is based on a quantitative genetic model of sexual conflict, in which genes controlling IRSC traits have side effects in the other sex, due to incompletely sex-limited gene expression. As a result, the genes are exposed to intralocus sexual conflict (IASC), a tug-of-war between opposing male- and female-specific selection pressures. We find that the interaction between the two forms of sexual conflict has contrasting effects on antagonistic coevolution: Pleiotropic constraints stabilize the dynamics of arms races if the mating traits are close to evolutionary equilibrium but can prevent populations from ever reaching such a state. Instead, the sexes are drawn into a continuous cycle of arms races, causing the buildup of IASC, alternated by phases of IASC resolution that trigger the next arms race. These results encourage an integrative perspective on the biology of sexual conflict and generally caution against relying exclusively on equilibrium stability analysis. PMID- 26755608 TI - Purinergic receptor P2RY12-dependent microglial closure of the injured blood brain barrier. AB - Microglia are integral functional elements of the central nervous system, but the contribution of these cells to the structural integrity of the neurovascular unit has not hitherto been assessed. We show here that following blood-brain barrier (BBB) breakdown, P2RY12 (purinergic receptor P2Y, G-protein coupled, 12)-mediated chemotaxis of microglia processes is required for the rapid closure of the BBB. Mice treated with the P2RY12 inhibitor clopidogrel, as well as those in which P2RY12 was genetically ablated, exhibited significantly diminished movement of juxtavascular microglial processes and failed to close laser-induced openings of the BBB. Thus, microglial cells play a previously unrecognized protective role in the maintenance of BBB integrity following cerebrovascular damage. Because clopidogrel antagonizes the platelet P2Y12 receptor, it is widely prescribed for patients with coronary artery and cerebrovascular disease. As such, these observations suggest the need for caution in the postincident continuation of P2RY12-targeted platelet inhibition. PMID- 26755610 TI - Enzyme catalysis by entropy without Circe effect. AB - Entropic effects have often been invoked to explain the extraordinary catalytic power of enzymes. In particular, the hypothesis that enzymes can use part of the substrate-binding free energy to reduce the entropic penalty associated with the subsequent chemical transformation has been very influential. The enzymatic reaction of cytidine deaminase appears to be a distinct example. Here, substrate binding is associated with a significant entropy loss that closely matches the activation entropy penalty for the uncatalyzed reaction in water, whereas the activation entropy for the rate-limiting catalytic step in the enzyme is close to zero. Herein, we report extensive computer simulations of the cytidine deaminase reaction and its temperature dependence. The energetics of the catalytic reaction is first evaluated by density functional theory calculations. These results are then used to parametrize an empirical valence bond description of the reaction, which allows efficient sampling by molecular dynamics simulations and computation of Arrhenius plots. The thermodynamic activation parameters calculated by this approach are in excellent agreement with experimental data and indeed show an activation entropy close to zero for the rate-limiting transition state. However, the origin of this effect is a change of reaction mechanism compared the uncatalyzed reaction. The enzyme operates by hydroxide ion attack, which is intrinsically associated with a favorable activation entropy. Hence, this has little to do with utilization of binding free energy to pay the entropic penalty but rather reflects how a preorganized active site can stabilize a reaction path that is not operational in solution. PMID- 26755612 TI - Reply to Carbillon: Fetal/placental weight ratio and placental function. PMID- 26755611 TI - Attention promotes episodic encoding by stabilizing hippocampal representations. AB - Attention influences what is later remembered, but little is known about how this occurs in the brain. We hypothesized that behavioral goals modulate the attentional state of the hippocampus to prioritize goal-relevant aspects of experience for encoding. Participants viewed rooms with paintings, attending to room layouts or painting styles on different trials during high-resolution functional MRI. We identified template activity patterns in each hippocampal subfield that corresponded to the attentional state induced by each task. Participants then incidentally encoded new rooms with art while attending to the layout or painting style, and memory was subsequently tested. We found that when task-relevant information was better remembered, the hippocampus was more likely to have been in the correct attentional state during encoding. This effect was specific to the hippocampus, and not found in medial temporal lobe cortex, category-selective areas of the visual system, or elsewhere in the brain. These findings provide mechanistic insight into how attention transforms percepts into memories. PMID- 26755613 TI - Wooden breast lesions in broiler chickens in the UK. PMID- 26755615 TI - Syntelencephaly associated with cystic cochleovestibular malformations. PMID- 26755614 TI - Prion protein genotype survey confirms low frequency of scrapie-resistant K222 allele in British goat herds. AB - Scrapie in goats is a transmissible, fatal prion disease, which is endemic in the British goat population. The recent success in defining caprine PRNP gene variants that provide resistance to experimental and natural classical scrapie has prompted the authors to conduct a survey of PRNP genotypes in 10 goat breeds and 52 herds to find goats with the resistant K222 allele. They report here the frequencies in 1236 tested animals of the resistance-associated K222 and several other alleles by breed and herd. Eight animals were found to be heterozygous QK222 goats (0.64 per cent genotype frequency, 95 per cent CI 0.28 to 1.27 per cent) but no homozygous KK222 goats were detected. The K222 allele was found in Saanen, Toggenburg and Anglo-Nubian goats. The fact that only a few goats with the K222 allele have been identified does not preclude the possibility to design and implement successful breeding programmes at national level. PMID- 26755618 TI - Resting brain activity in disorders of consciousness: A systematic review and meta-analysis. PMID- 26755616 TI - Resting brain activity in disorders of consciousness: A systematic review and meta-analysis. PMID- 26755617 TI - Migraine prevention with a supraorbital transcutaneous stimulator: A randomized controlled trial. PMID- 26755619 TI - Education Research: The pod system: An innovative strategy to reform residency teaching sessions in neurology. PMID- 26755620 TI - Pearls & Oy-sters: Limbic encephalitis associated with positive anti-LGI1 and antithyroid antibodies. PMID- 26755621 TI - Teaching NeuroImages: Hyperintense acute reperfusion marker in ischemic stroke with transient symptoms. PMID- 26755622 TI - Careers in neurology in a globalizing world. PMID- 26755623 TI - MTG2: an efficient algorithm for multivariate linear mixed model analysis based on genomic information. AB - We have developed an algorithm for genetic analysis of complex traits using genome-wide SNPs in a linear mixed model framework. Compared to current standard REML software based on the mixed model equation, our method is substantially faster. The advantage is largest when there is only a single genetic covariance structure. The method is particularly useful for multivariate analysis, including multi-trait models and random regression models for studying reaction norms. We applied our proposed method to publicly available mice and human data and discuss the advantages and limitations. AVAILABILITY AND IMPLEMENTATION: MTG2 is available in https://sites.google.com/site/honglee0707/mtg2 CONTACT: hong.lee@une.edu.au SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26755626 TI - Integration of string and de Bruijn graphs for genome assembly. AB - MOTIVATION: String and de Bruijn graphs are two graph models used by most genome assemblers. At present, none of the existing assemblers clearly outperforms the others across all datasets. We found that although a string graph can make use of entire reads for resolving repeats, de Bruijn graphs can naturally assemble through regions that are error-prone due to sequencing bias. RESULTS: We developed a novel assembler called StriDe that has advantages of both string and de Bruijn graphs. First, the reads are decomposed adaptively only in error-prone regions. Second, each paired-end read is extended into a long read directly using an FM-index. The decomposed and extended reads are used to build an assembly graph. In addition, several essential components of an assembler were designed or improved. The resulting assembler was fully parallelized, tested and compared with state-of-the-art assemblers using benchmark datasets. The results indicate that contiguity of StriDe is comparable with top assemblers on both short-read and long-read datasets, and the assembly accuracy is high in comparison with the others. AVAILABILITY AND IMPLEMENTATION: https://github.com/ythuang0522/StriDe CONTACT: : ythuang@cs.ccu.edu.tw SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26755624 TI - Computational discovery of pathway-level genetic vulnerabilities in non-small cell lung cancer. AB - MOTIVATION: Novel approaches are needed for discovery of targeted therapies for non-small-cell lung cancer (NSCLC) that are specific to certain patients. Whole genome RNAi screening of lung cancer cell lines provides an ideal source for determining candidate drug targets. RESULTS: Unsupervised learning algorithms uncovered patterns of differential vulnerability across lung cancer cell lines to loss of functionally related genes. Such genetic vulnerabilities represent candidate targets for therapy and are found to be involved in splicing, translation and protein folding. In particular, many NSCLC cell lines were especially sensitive to the loss of components of the LSm2-8 protein complex or the CCT/TRiC chaperonin. Different vulnerabilities were also found for different cell line subgroups. Furthermore, the predicted vulnerability of a single adenocarcinoma cell line to loss of the Wnt pathway was experimentally validated with screening of small-molecule Wnt inhibitors against an extensive cell line panel. AVAILABILITY AND IMPLEMENTATION: The clustering algorithm is implemented in Python and is freely available at https://bitbucket.org/youngjh/nsclc_paper CONTACT: marcotte@icmb.utexas.edu or jon.young@utexas.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26755625 TI - Collaborative analysis of multi-gigapixel imaging data using Cytomine. AB - MOTIVATION: Collaborative analysis of massive imaging datasets is essential to enable scientific discoveries. RESULTS: We developed Cytomine to foster active and distributed collaboration of multidisciplinary teams for large-scale image based studies. It uses web development methodologies and machine learning in order to readily organize, explore, share and analyze (semantically and quantitatively) multi-gigapixel imaging data over the internet. We illustrate how it has been used in several biomedical applications. AVAILABILITY AND IMPLEMENTATION: Cytomine (http://www.cytomine.be/) is freely available under an open-source license from http://github.com/cytomine/ A documentation wiki (http://doc.cytomine.be) and a demo server (http://demo.cytomine.be) are also available. CONTACT: info@cytomine.be SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26755628 TI - Inositol-Requiring Enzyme 1-Dependent Activation of AMPK Promotes Brucella abortus Intracellular Growth. AB - AMP-activated protein kinase (AMPK) is a serine/threonine kinase that is well conserved during evolution. AMPK activation inhibits production of reactive oxygen species (ROS) in cells via suppression of NADPH oxidase. However, the role of AMPK during the process of Brucella infection remains unknown. Our data demonstrate that B. abortus infection induces AMPK activation in HeLa cells in a time-dependent manner. The known AMPK kinases LKB1, CAMKKbeta, and TAK1 are not required for the activation of AMPK by B. abortus infection. Instead, this activation is dependent on the RNase activity of inositol-requiring enzyme 1 (IRE1). Moreover, we also found that B. abortus infection-induced IRE1-dependent activation of AMPK promotes B. abortus intracellular growth with peritoneal macrophages via suppression of NADPH-derived ROS production. IMPORTANCE: Previous studies showed that B. abortus infection does not promote any oxidative burst regulated by NADPH oxidase. However, the underlying mechanism remains elusive. We report for the first time that AMPK activation caused by B. abortus infection plays important role in NADPH oxidase-derived ROS production. PMID- 26755627 TI - The Pseudomonas aeruginosa PAO1 Two-Component Regulator CarSR Regulates Calcium Homeostasis and Calcium-Induced Virulence Factor Production through Its Regulatory Targets CarO and CarP. AB - Pseudomonas aeruginosa is an opportunistic human pathogen that causes severe, life-threatening infections in patients with cystic fibrosis (CF), endocarditis, wounds, or artificial implants. During CF pulmonary infections, P. aeruginosa often encounters environments where the levels of calcium (Ca(2+)) are elevated. Previously, we showed that P. aeruginosa responds to externally added Ca(2+) through enhanced biofilm formation, increased production of several secreted virulence factors, and by developing a transient increase in the intracellular Ca(2+) level, followed by its removal to the basal submicromolar level. However, the molecular mechanisms responsible for regulating Ca(2+)-induced virulence factor production and Ca(2+) homeostasis are not known. Here, we characterized the genome-wide transcriptional response of P. aeruginosa to elevated [Ca(2+)] in both planktonic cultures and biofilms. Among the genes induced by CaCl2 in strain PAO1 was an operon containing the two-component regulator PA2656-PA2657 (here called carS and carR), while the closely related two-component regulators phoPQ and pmrAB were repressed by CaCl2 addition. To identify the regulatory targets of CarSR, we constructed a deletion mutant of carR and performed transcriptome analysis of the mutant strain at low and high [Ca(2+)]. Among the genes regulated by CarSR in response to CaCl2 are the predicted periplasmic OB-fold protein, PA0320 (here called carO), and the inner membrane-anchored five-bladed beta propeller protein, PA0327 (here called carP). Mutations in both carO and carP affected Ca(2+) homeostasis, reducing the ability of P. aeruginosa to export excess Ca(2+). In addition, a mutation in carP had a pleotropic effect in a Ca(2+)-dependent manner, altering swarming motility, pyocyanin production, and tobramycin sensitivity. Overall, the results indicate that the two-component system CarSR is responsible for sensing high levels of external Ca(2+) and responding through its regulatory targets that modulate Ca(2+) homeostasis, surface-associated motility, and the production of the virulence factor pyocyanin. IMPORTANCE: During infectious disease, Pseudomonas aeruginosa encounters environments with high calcium (Ca(2+)) concentrations, yet the cells maintain intracellular Ca(2+) at levels that are orders of magnitude less than that of the external environment. In addition, Ca(2+) signals P. aeruginosa to induce the production of several virulence factors. Compared to eukaryotes, little is known about how bacteria maintain Ca(2+) homeostasis or how Ca(2+) acts as a signal. In this study, we identified a two-component regulatory system in P. aeruginosa PAO1, termed CarRS, that is induced at elevated Ca(2+) levels. CarRS modulates Ca(2+) signaling and Ca(2+) homeostasis through its regulatory targets, CarO and CarP. The results demonstrate that P. aeruginosa uses a two-component regulatory system to sense external Ca(2+) and relays that information for Ca(2+) dependent cellular processes. PMID- 26755629 TI - The LonA Protease Regulates Biofilm Formation, Motility, Virulence, and the Type VI Secretion System in Vibrio cholerae. AB - The presence of the Lon protease in all three domains of life hints at its biological importance. The prokaryotic Lon protease is responsible not only for degrading abnormal proteins but also for carrying out the proteolytic regulation of specific protein targets. Posttranslational regulation by Lon is known to affect a variety of physiological traits in many bacteria, including biofilm formation, motility, and virulence. Here, we identify the regulatory roles of LonA in the human pathogen Vibrio cholerae. We determined that the absence of LonA adversely affects biofilm formation, increases swimming motility, and influences intracellular levels of cyclic diguanylate. Whole-genome expression analysis revealed that the message abundance of genes involved in biofilm formation was decreased but that the message abundances of those involved in virulence and the type VI secretion system were increased in a lonA mutant compared to the wild type. We further demonstrated that a lonA mutant displays an increase in type VI secretion system activity and is markedly defective in colonization of the infant mouse. These findings suggest that LonA plays a critical role in the environmental survival and virulence of V. cholerae. IMPORTANCE: Bacteria utilize intracellular proteases to degrade damaged proteins and adapt to changing environments. The Lon protease has been shown to be important for environmental adaptation and plays a crucial role in regulating the motility, biofilm formation, and virulence of numerous plant and animal pathogens. We find that LonA of the human pathogen V. cholerae is in line with this trend, as the deletion of LonA leads to hypermotility and defects in both biofilm formation and colonization of the infant mouse. In addition, we show that LonA regulates levels of cyclic diguanylate and the type VI secretion system. Our observations add to the known regulatory repertoire of the Lon protease and the current understanding of V. cholerae physiology. PMID- 26755633 TI - Decomposing the effects of time on the social acceptability of biotechnology using age-period-cohort-country models. AB - The study of European attitudes toward biotechnologies underlines a situation that is relatively contrasting in Europe. However, as different effects of time can influence the social attitudes (a life-cycle effect, a generational effect, and an exogenous temporal effect potentially affecting the entire population), an appropriate methodology should be used. To this end, age-period-cohort-country models have thus been estimated based on Eurobarometer data from 1991 onward. Applied to different data subsets, these models give similar results underlining the importance of the life-cycle effects as well as the heterogeneity of the link between political affiliation and biotechnologies attitudes across the European countries. PMID- 26755630 TI - Succinic Semialdehyde Promotes Prosurvival Capability of Agrobacterium tumefaciens. AB - Succinic semialdehyde (SSA), an important metabolite of gamma-aminobutyric acid (GABA), is a ligand of the repressor AttJ regulating the expression of the attJ attKLM gene cluster in the plant pathogen Agrobacterium tumefaciens. While the response of A. tumefaciens to GABA and the function of attKLM have been extensively studied, genetic and physiological responses of A. tumefaciens to SSA remain unknown. In combination with microarray and genetic approaches, this study sets out to explore new roles of the SSA-AttJKLM regulatory mechanism during bacterial infection. The results showed that SSA plays a key role in regulation of several bacterial activities, including C4-dicarboxylate utilization, nitrate assimilation, and resistance to oxidative stress. Interestingly, while the SSA relies heavily on the functional AttKLM in mediating nitrate assimilation and oxidative stress resistance, the compound could regulate utilization of C4 dicarboxylates independent of AttJKLM. We further provide evidence that SSA controls C4-dicarboxylate utilization through induction of an SSA importer and that disruption of attKLM attenuates the tumorigenicity of A. tumefaciens. Taken together, these findings indicate that SSA could be a potent plant signal which, together with AttKLM, plays a vital role in promoting the bacterial prosurvival abilities during infection. IMPORTANCE: Agrobacterium tumefaciens is a plant pathogen causing crown gall diseases and has been well known as a powerful tool for plant genetic engineering. During the long history of microbe-host interaction, A. tumefaciens has evolved the capabilities of recognition and response to plant-derived chemical metabolites. Succinic semialdehyde (SSA) is one such metabolite. Previous results have demonstrated that SSA functions to activate a quorum-quenching mechanism and thus to decrease the level of quorum sensing signals, thereby avoiding the elicitation of a plant defense. Here, we studied the effect of SSA on gene expression at a genome-wide level and reported that SSA also promotes bacterial survival during infection. These findings provide a new insight on the biological significance of chemical signaling between agrobacteria and plant hosts. PMID- 26755632 TI - Impact of Different Target Sequences on Type III CRISPR-Cas Immunity. AB - Clustered regularly interspaced short palindromic repeat (CRISPR) loci encode an adaptive immune system of prokaryotes. Within these loci, sequences intercalated between repeats known as "spacers" specify the targets of CRISPR immunity. The majority of spacers match sequences present in phages and plasmids; however, it is not known whether there are differences in the immunity provided against these diverse invaders. We studied this issue using the Staphylococcus epidermidis CRISPR system, which harbors spacers matching both phages and plasmids. We determined that this CRISPR system provides similar levels of defense against the conjugative plasmid pG0400 and the bacteriophage CNPX. However, whereas antiplasmid immunity was very sensitive to the introduction of mismatches in the target sequence, mutations in the phage target were largely tolerated. Placing the phage and plasmid targets into a vector that can be both conjugated and transduced, we demonstrated that the route of entry of the target has no impact on the effect of the mismatches on immunity. Instead, we established that the specific sequences of each spacer/target determine the susceptibility of the S. epidermidis CRISPR system to mutations. Therefore, spacers that are more resistant to mismatches would provide long-term immunity against phages and plasmids that otherwise would escape CRISPR targeting through the accumulation of mutations in the target sequence. These results uncover an unexpected complexity in the arms race between CRISPR-Cas systems and prokaryotic infectious genetic elements. IMPORTANCE: CRISPR-Cas loci protect bacteria and archaea from both phage infection and plasmid invasion. These loci harbor short sequences of phage and plasmid origin known as "spacers" that specify the targets of CRISPR-Cas immunity. The presence of a spacer sequence matching a phage or plasmid ensures host immunity against infection by these genetic elements. In turn, phages and plasmids constantly mutate their targets to avoid recognition by the spacers of the CRISPR-Cas immune system. In this study, we demonstrated that different spacer sequences vary in their ability to tolerate target mutations that allow phages and plasmids to escape from CRISPR-Cas immunity. These results uncover an unexpected complexity in the arms race between CRISPR-Cas systems and prokaryotic infectious genetic elements. PMID- 26755631 TI - Association of O-Antigen Serotype with the Magnitude of Initial Systemic Cytokine Responses and Persistence in the Urinary Tract. AB - Urinary tract infection (UTI) is one of the most common ailments requiring both short-term and prophylactic antibiotic therapies. Progression of infection from the bladder to the kidney is associated with more severe clinical symptoms (e.g., fever and vomiting) as well as with dangerous disease sequelae (e.g., renal scaring and sepsis). Host-pathogen interactions that promote bacterial ascent to the kidney are not completely understood. Prior studies indicate that the magnitude of proinflammatory cytokine elicitation in vitro by clinical isolates of uropathogenic Escherichia coli (UPEC) inversely correlates with the severity of clinical disease. Therefore, we hypothesize that the magnitude of initial proinflammatory responses during infection defines the course and severity of disease. Clinical UPEC isolates obtained from patients with a nonfebrile UTI elicited high systemic proinflammatory responses early during experimental UTI in a murine model and were attenuated in bladder and kidney persistence. Conversely, UPEC isolates obtained from patients with febrile UTI elicited low systemic proinflammatory responses early during experimental UTI and exhibited prolonged persistence in the bladder and kidney. Soluble factors in the supernatant from saturated cultures as well as the lipopolysaccharide (LPS) serotype correlated with the magnitude of proinflammatory responses in vitro. Our data suggest that the structure of the O-antigen sugar moiety of the LPS may determine the strength of cytokine induction by epithelial cells. Moreover, the course and severity of disease appear to be the consequence of the magnitude of initial cytokines produced by the bladder epithelium during infection. IMPORTANCE: The specific host-pathogen interactions that determine the extent and course of disease are not completely understood. Our studies demonstrate that modest changes in the magnitude of cytokine production observed using in vitro models of infection translate into significant ramifications for bacterial persistence and disease severity. While many studies have demonstrated that modifications of the LPS lipid A moiety modulate the extent of Toll-like receptor 4 (TLR4) activation, our studies implicate the O-antigen sugar moiety as another potential rheostat for the modulation of proinflammatory cytokine production. PMID- 26755634 TI - Children's respiratory health and oxidative potential of PM2.5: the PIAMA birth cohort study. AB - INTRODUCTION: The oxidative potential (OP) of particulate matter (PM) has been proposed as a health-relevant metric, but currently few epidemiological studies investigated associations of OP with health. Our main aim was to assess associations of long-term exposure to OP with respiratory health in children. Our second aim was to evaluate whether OP is more consistently associated with respiratory health than PM mass, PM composition or nitrogen dioxide (NO2). METHODS: For 3701 participants of a prospective birth cohort, annual average concentrations of OP (assessed by spin resonance (OP(ESR)) and dithiothreitol assay (OP(DTT))), PM with an aerodynamic diameter of less than 2.5 um (PM2.5) mass, NO2, and PM2.5 constituents at the home addresses at birth and at all follow-up addresses were estimated by land-use regression. Repeated questionnaire reports of asthma and hay fever until age 14 years, and measurements of allergic sensitisation, lung function and fractional exhaled nitric oxide at age 12 years were linked with air pollution concentrations. RESULTS: Asthma incidence, prevalence of asthma symptoms and rhinitis were positively associated with OP(DTT) (adjusted OR (95% CI) per IQR increase in exposure 1.10 (1.01 to 1.20), 1.08 (1.02 to 1.16), 1.15 (1.05 to 1.26), respectively). These associations persisted after adjustment for most co-pollutants. Forced expiratory volume in 1s and forced vital capacity were negatively associated with OP(DTT). These associations were sensitive to adjustment for NO2. Respiratory health was not significantly associated with PM2.5 mass and OP(ESR). CONCLUSIONS: Respiratory health was more strongly associated with OP(DTT) than with PM2.5 mass; OP(DTT) associations with lung function, but not symptoms, were sensitive to adjustment for NO2. PMID- 26755635 TI - APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication. AB - APOBEC3A and APOBEC3B, cytidine deaminases of the APOBEC family, are among the main factors causing mutations in human cancers. APOBEC deaminates cytosines in single-stranded DNA (ssDNA). A fraction of the APOBEC-induced mutations occur as clusters ("kataegis") in single-stranded DNA produced during repair of double stranded breaks (DSBs). However, the properties of the remaining 87% of nonclustered APOBEC-induced mutations, the source and the genomic distribution of the ssDNA where they occur, are largely unknown. By analyzing genomic and exomic cancer databases, we show that >33% of dispersed APOBEC-induced mutations occur on the lagging strand during DNA replication, thus unraveling the major source of ssDNA targeted by APOBEC in cancer. Although methylated cytosine is generally more mutation-prone than nonmethylated cytosine, we report that methylation reduces the rate of APOBEC-induced mutations by a factor of roughly two. Finally, we show that in cancers with extensive APOBEC-induced mutagenesis, there is almost no increase in mutation rates in late replicating regions (contrary to other cancers). Because late-replicating regions are depleted in exons, this results in a 1.3-fold higher fraction of mutations residing within exons in such cancers. This study provides novel insight into the APOBEC-induced mutagenesis and describes the peculiarity of the mutational processes in cancers with the signature of APOBEC-induced mutations. PMID- 26755637 TI - 'A Drink That Makes You Feel Happier, Relaxed and Loving': Young People's Perceptions of Alcohol Advertising on Facebook. AB - AIMS: To explore young people's perceptions of alcohol advertising on Facebook and investigate perceived compliance with the Alcohol Beverages Advertising Code (ABAC). METHODS: An online cross-sectional survey with 172 Australians aged 16-29 years recruited from a market research website and via Facebook. We compiled advertisements from six popular alcohol brands' Australian Facebook pages and asked respondents for their perceptions and interpretations in open and closed ended questions. RESULTS: Open-ended responses most commonly indicated that the main messages of the advertisements related to social success. In closed-ended questions, respondents perceived advertisements implied that alcohol facilitated relaxation (67%), improved mood (65%), social success (57%) and confidence (49%). CONCLUSION: Young people identified the main themes of alcohol advertising on Facebook as related to social success and significant improvement in mood. Young people's interpretations of Facebook alcohol advertising suggest breaches of ABAC guidelines. Strengthening the enforcement and application of the ABAC and social media alcohol advertising policies is justified. PMID- 26755636 TI - Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice. AB - The CRISPR/Cas technology enables targeted genome editing and the rapid generation of transgenic animal models for the study of human genetic disorders. Here we describe an autosomal recessive human disease in two unrelated families characterized by a split-foot defect, nail abnormalities of the hands, and hearing loss, due to mutations disrupting the SAM domain of the protein kinase ZAK. ZAK is a member of the MAPKKK family with no known role in limb development. We show that Zak is expressed in the developing limbs and that a CRISPR/Cas mediated knockout of the two Zak isoforms is embryonically lethal in mice. In contrast, a deletion of the SAM domain induces a complex hindlimb defect associated with down-regulation of Trp63, a known split-hand/split-foot malformation disease gene. Our results identify ZAK as a key player in mammalian limb patterning and demonstrate the rapid utility of CRISPR/Cas genome editing to assign causality to human mutations in the mouse in <10 wk. PMID- 26755639 TI - Evaluating Alcohol Industry Action to Reduce the Harmful Use of Alcohol. PMID- 26755638 TI - Genetic Modification of the Relationship between Parental Rejection and Adolescent Alcohol Use. AB - AIMS: Parenting practices are associated with adolescents' alcohol consumption, however not all youth respond similarly to challenging family situations and harsh environments. This study examines the relationship between perceived parental rejection and adolescent alcohol use, and specifically evaluates whether youth who possess greater genetic sensitivity to their environment are more susceptible to negative parental relationships. METHODS: Analyzing data from the National Longitudinal Study of Adolescent Health, we estimated a series of regression models predicting alcohol use during adolescence. A multiplicative interaction term between parental rejection and a genetic index was constructed to evaluate this potential gene-environment interaction. RESULTS: Results from logistic regression analyses show a statistically significant gene-environment interaction predicting alcohol use. The relationship between parental rejection and alcohol use was moderated by the genetic index, indicating that adolescents possessing more 'risk alleles' for five candidate genes were affected more by stressful parental relationships. CONCLUSIONS: Feelings of parental rejection appear to influence the alcohol use decisions of youth, but they do not do so equally for all. Higher scores on the constructed genetic sensitivity measure are related to increased susceptibility to negative parental relationships. PMID- 26755640 TI - Major Anaerobic Bacteria Responsible for the Production of Carcinogenic Acetaldehyde from Ethanol in the Colon and Rectum. AB - AIMS: The importance of ethanol oxidation by intestinal aerobes and facultative anaerobes under aerobic conditions in the pathogenesis of ethanol-related colorectal cancer has been proposed. However, the role of obligate anaerobes therein remains to be established, and it is still unclear which bacterial species, if any, are most important in the production and/or elimination of carcinogenic acetaldehyde under such conditions. This study was undertaken to address these issues. METHODS: More than 500 bacterial strains were isolated from the faeces of Japanese alcoholics and phylogenetically characterized, and their aerobic ethanol metabolism was studied in vitro to examine their ability to accumulate acetaldehyde beyond the minimum mutagenic concentration (MMC, 50 uM). RESULTS: Bacterial strains that were considered to potentially accumulate acetaldehyde beyond the MMC under aerobic conditions in the colon and rectum were identified and referred to as 'potential acetaldehyde accumulators' (PAAs). Ruminococcus, an obligate anaerobe, was identified as a genus that includes a large number of PAAs. Other obligate anaerobes were also found to include PAAs. The accumulation of acetaldehyde by PAAs colonizing the colorectal mucosal surface could be described, at least in part, as the response of PAAs to oxidative stress. CONCLUSION: Ethanol oxidation by intestinal obligate anaerobes under aerobic conditions in the colon and rectum could also play an important role in the pathogenesis of ethanol-related colorectal cancer. PMID- 26755641 TI - A Meta-analysis of Theory of Mind in Alcohol Use Disorders. AB - AIM: Research into Theory of Mind (ToM) in alcohol use disorder (AUD) is sparse and the extant findings contradictory. The objective of this paper was to conduct a meta-analysis to determine whether individuals with AUD show ToM deficits across the available published literature. METHOD: A comprehensive literature search was performed with the PsychInfo, PubMed and Web Science databases for studies from 1990 to March 2015, pairing the keywords 'alcohol' and 'theory of mind'. Results were filtered and eight studies met the inclusion criteria and were included in the final meta-analysis. RESULTS: Results showed that individuals with AUD (n = 187) displayed reduced ToM compared to controls (n = 187). Hedges' g was -1.62 [(-2.28, -0.96), SE = 0.66, P < 0.01], which is indicative of a large effect size. The percentage of males had a significant impact on the effect size, Q = 7.90, P = 0.005, while IQ and level of education did not. CONCLUSIONS: Results of this study suggest that AUD may be associated with impaired understanding of others' intentions and emotions, which can leave an individual vulnerable to misinterpreting social cues. Clinical care implications of the findings, limitations of the study, and suggestions for future research are discussed. PMID- 26755642 TI - Changing from a pro re nata treatment regimen to a treat and extend regimen with ranibizumab in neovascular age-related macular degeneration. AB - BACKGROUND: Treat and extend (TE) treatment regimens have the potential to reduce the treatment burden placed upon patients receiving ranibizumab for neovascular age-related macular degeneration (nAMD). This study aimed to analyse changes in best corrected visual acuity (BCVA) and anatomical parameters in patients switching from a pro re nata (PRN) to a TE regimen during routine clinical practice. METHODS: Retrospective, consecutive, comparative case series of treatment-naive patients who were initially treated with 0.5 mg ranibizumab according to a PRN schedule, and subsequently switched to a TE schedule (12-month follow-up). RESULTS: 146 eyes from 134 consecutive treatment-naive patients were included. Mean BCVA (decimal+/-SD) increased from 0.39+/-0.23 to 0.55+/-0.22 (p<0.001) during the PRN loading regimen, declining to 0.49+/-0.22 (p<0.001) during the PRN maintenance phase (mean duration 17 months; range 3-55). Following the switch to TE, BCVA improved to 0.55+/-0.23 and 0.56+/-0.24 by 6 and 12 months, respectively (p<0.001). Mean intraindividual variance in BCVA was higher during the PRN phase than at 12 months for TE (0.30+/-0.18 vs 0.09+/-0.08, respectively; p<0.001). After switching to TE, mean central retinal thickness decreased from 355+/-112 um to 330+/-105 and 320+/-103 um at 6 and 12 months, respectively (p<0.001). Mean number of visits per month was higher during PRN than TE periods (1.05+/-0.13 vs 0.73+/-0.18; respectively; p<0.001). CONCLUSIONS: A TE regimen can improve and stabilise patient outcomes in nAMD compared with PRN, with the potential to reduce the healthcare resource burden incurred from fixed monitoring requirements. PMID- 26755643 TI - Wide field of view swept-source optical coherence tomography for peripheral retinal disease. AB - BACKGROUND/AIMS: To assess peripheral retinal lesions and the posterior pole in single widefield optical coherence tomography (OCT) volumes. METHODS: A wide field of view (FOV) swept-source OCT (WFOV SSOCT) system was developed using a commercial swept-source laser and a custom sample arm consisting of two indirect ophthalmic lenses. Twenty-seven subjects with peripheral lesions (choroidal melanomas, choroidal naevi, sclerochoroidal calcification, retinitis pigmentosa, diabetic retinopathy, retinoschisis and uveitis) were imaged with the WFOV SSOCT. Volumes were taken in primary gaze. Using the optic nerve to fovea distance as a reference measurement, comparisons were made between the lateral FOV of the WFOV SSOCT, current generation spectral-domain OCT (SDOCT) and widefield scanning laser ophthalmoscopy (SLO) of the same eyes. RESULTS: Peripheral pathologies were captured with WFOV SSOCT in 26 of the 27 subjects. The one not captured was in the far nasal periphery and was not seen in the primary gaze volume. Posterior pole associated pathologies were captured in all subjects. Current generation SDOCT had a mean lateral FOV of 2.08+/-0.21 optic nerve to fovea distance units, WFOV SSOCT had an FOV of 4.62+/-0.62 units and SLO had an FOV of 9.35+/-1.02 units. CONCLUSIONS: WFOV OCT can be used to examine both peripheral retinal pathology and the posterior pole within a single volume acquisition. SLO had the greatest FOV, but does not provide depth information. Future studies using widefield OCT systems will help further delineate the role of WFOV OCT to quantitatively assess and monitor peripheral retinal disease in three dimensions. PMID- 26755644 TI - IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in JAK2V617F-positive myeloproliferative neoplasms. AB - The recurrent V617F mutation in JAK2 (JAK2V617F) has emerged as the primary contributor to the pathogenesis of myeloproliferative neoplasms (MPN). However, the lack of complete response in most patients treated with the JAK1/2 inhibitor, ruxolitinib, indicates the need for identifying pathways that cooperate with JAK2. Activated JAK2 was found to be associated with the insulin receptor substrate 2 (IRS2) in non-hematological cells. We identified JAK2/IRS2 binding in JAK2V617F HEL cells, but not in the JAK2WT U937 cell line. In HEL cells, IRS2 silencing decreased STAT5 phosphorylation, reduced cell viability and increased apoptosis; these effects were enhanced when IRS2 silencing was combined with ruxolitinib. In U937 cells, IRS2 silencing neither reduced cell viability nor induced apoptosis. IRS1/2 pharmacological inhibition in primary MPN samples reduced cell viability in JAK2V617F-positive but not JAK2WT specimens; combination with ruxolitinib had additive effects. IRS2 expression was significantly higher in CD34+ cells from essential thrombocythemia patients compared to healthy donors, and in JAK2V617F MPN patients when compared to JAK2WT. Our data indicate that IRS2 is a binding partner of JAK2V617F in MPN. IRS2 contributes to increased cell viability and reduced apoptosis in JAK2 mutated cells. Combined pharmacological inhibition of IRS2 and JAK2 may have a potential clinical application in MPN. PMID- 26755645 TI - STAT3-survivin signaling mediates a poor response to radiotherapy in HER2 positive breast cancers. AB - Although radiotherapy resistance is associated with locoregional recurrence and distant metastasis in breast cancers, clinically relevant molecular markers and critical signaling pathways of radioresistant breast cancer are yet to be defined. Herein, we show that HER2-STAT3-survivin regulation is associated with radiotherapy resistance in HER2-positive breast cancers. Depletion of HER2 by siRNA sensitized HER2-positive breast cancer cells to irradiation by decreasing STAT3 activity and survivin, a STAT3 target gene, expression in HER2-positive breast cancer cells. Furthermore, inhibition of STAT3 activation or depletion of survivin also sensitized HER2-positive breast cancer cells to irradiation, suggesting that the HER2-STAT3-survivin axis is a key pathway in radiotherapy resistance of HER2-positive breast cancer cells. In addition, our clinical analysis demonstrated the association between HER2-positive breast cancers and radiotherapy resistance. Notably, we found that increased expression of phosphorylated STAT3, STAT3, and survivin correlated with a poor response to radiotherapy in HER2-positive breast cancer tissues. These findings suggest that the HER2-STAT3-survivin axis might serve as a predictive marker and therapeutic target to overcome radiotherapy resistance in HER2-positive breast cancers. PMID- 26755647 TI - A meta-analysis comparing cisplatin-based to carboplatin-based chemotherapy in moderate to advanced squamous cell carcinoma of head and neck (SCCHN). AB - PURPOSE: This study was performed to compare the efficacies and toxicities of cisplatin (CDDP)- and carboplatin (CBDCA)-based chemotherapy (CT) in patients with SCCHN. METHODS: The search strategy included Pubmed, Science Direct, the Cochrane Library, and the China National Knowledge Internet Web. Statistical analyses were performed using RevMan 5.2. The primary endpoint was overall survival (OS) with secondary endpoints of locoregional control (LRC) and grade >= 3 toxicity. RESULTS: Overall, 12 studies and 1165 patients were included. CDDP based CT significantly improved 5-year OS (HR=0.67, 95% CI, 0.49 to 0.91; P=0.01) compared to the CBDCA group. No difference in the 3-year OS/LRC was observed, but a subgroup analysis showed a better 3-year OS in the CDDP arm for non-nasopharynx carcinoma (non-NPC) SCCHN (HR=0.66, 95% CI, 0.48 to 0.91; P=0.01). The CDDP-based CT was associated with more gastrointestinal toxicities (RR=4.58; P=0.005) and nephrotoxicity (4/110=3.6%) compared to the CBDCA group, but fewer anemia, leukopenia and thrombocytopenia with RRs of 0.27, 0.71, and 0.28 respectively. CONCLUSIONS: Patients with CDDP-based CT can achieve a higher OS, but there is no significant difference in LRC. The CDDP-based CT is associated with fewer hematological toxicities but more gastrointestinal toxicities and nephrotoxicity compared to the CBDCA arm. PMID- 26755646 TI - A synthetic lethal screen identifies ATR-inhibition as a novel therapeutic approach for POLD1-deficient cancers. AB - The phosphoinositide 3-kinase-related kinase ATR represents a central checkpoint regulator and mediator of DNA-repair. Its inhibition selectively eliminates certain subsets of cancer cells in various tumor types, but the underlying genetic determinants remain enigmatic. Here, we applied a synthetic lethal screen directed against 288 DNA-repair genes using the well-defined ATR knock-in model of DLD1 colorectal cancer cells to identify potential DNA-repair defects mediating these effects. We identified a set of DNA-repair proteins, whose knockdown selectively killed ATR-deficient cancer cells. From this set, we further investigated the profound synthetic lethal interaction between ATR and POLD1. ATR-dependent POLD1 knockdown-induced cell killing was reproducible pharmacologically in POLD1-depleted DLD1 cells and a panel of other colorectal cancer cell lines by using chemical inhibitors of ATR or its major effector kinase CHK1. Mechanistically, POLD1 depletion in ATR-deficient cells caused caspase-dependent apoptosis without preceding cell cycle arrest and increased DNA damage along with impaired DNA-repair. Our data could have clinical implications regarding tumor genotype-based cancer therapy, as inactivating POLD1 mutations have recently been identified in small subsets of colorectal and endometrial cancers. POLD1 deficiency might thus represent a predictive marker for treatment response towards ATR- or CHK1-inhibitors that are currently tested in clinical trials. PMID- 26755648 TI - Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistance via a BMP4/HH signaling loop. AB - The tumor microenvironment is critical to cancer growth and therapy resistance. We previously characterized human ovarian carcinoma-associated mesenchymal stem cells (CA-MSCs). CA-MSCs are multi-potent cells that can differentiate into tumor microenvironment components including fibroblasts, myofibroblasts and adipocytes. We previously reported CA-MSCs, compared to normal MSCs, express high levels of BMP proteins and promote tumor growth by increasing numbers of cancer stem-like cells (CSCs). We demonstrate here that ovarian tumor cell-secreted Hedgehog (HH) induces CA-MSC BMP4 expression. CA-MSC-derived BMP4 reciprocally increases ovarian tumor cell HH expression indicating a positive feedback loop. Interruption of this loop with a HH pathway inhibitor or BMP4 blocking antibody decreases CA-MSC-derived BMP4 and tumor-derived HH preventing enrichment of CSCs and reversing chemotherapy resistance. The impact of HH inhibition was only seen in CA-MSC-containing tumors, indicating the importance of a humanized stroma. These results are reciprocal to findings in pancreatic and bladder cancer, suggesting HH signaling effects are tumor tissue specific warranting careful investigation in each tumor type. Collectively, we define a critical positive feedback loop between CA-MSC-derived BMP4 and ovarian tumor cell-secreted HH and present evidence for the further investigation of HH as a clinical target in ovarian cancer. PMID- 26755649 TI - 4-Methoxydalbergione suppresses growth and induces apoptosis in human osteosarcoma cells in vitro and in vivo xenograft model through down-regulation of the JAK2/STAT3 pathway. AB - Although the heartwood of Dalbergia odorifera T. Chen (Leguminosae) is an important source of traditional Korean and Chinese medicines, the effects of novel compound methoxydalbergione (4-MD) isolated from Dalbergia odorifera was not reported. Herein, we investigated the effects of the 4-MD in vitro and in vivo against osteosarcoma cells and its molecular mechanisms. 4-MD inhibited the proliferation of osteosarcoma cells and induced apoptosis as evidenced by Annexin V + and TUNEL + cells. This apoptosis was accompanied by upregulation of apoptotic proteins (procaspase-3 and PARP), but downregulation of anti-apoptotic proteins (Bcl-2, Bcl-xL, and Survivin). 4-MD inhibited phosphorylation of JAK2 and STAT3 with the inactivation of mitogen-activated protein kinases (MAPKs) and CREB, and the upregulation of PTEN in osteosarcoma cells. Importantly, 4-MD reduced colony formation in soft agar and inhibited tumor growth in mice xenograft model in association with the reduced expression of PCNA, Ki67, p STAT3, and Survivin. Taken together, the present study for the first time demonstrates that 4-MD exerts in vitro and in vivo anti-proliferative effects against osteosarcoma cells through the inhibition of the JAK2/STAT3 pathway, and suggest the potential for therapeutic application of 4-MD in the treatment of osteosarcoma. PMID- 26755650 TI - Longitudinal monitoring of EGFR mutations in plasma predicts outcomes of NSCLC patients treated with EGFR TKIs: Korean Lung Cancer Consortium (KLCC-12-02). AB - We hypothesized that plasma-based EGFR mutation analysis for NSCLC may be feasible for monitoring treatment response to EGFR TKIs and also predict drug resistance.Clinically relevant mutations including exon 19 deletion (ex19del), L858R and T790M were analyzed using droplet digital PCR (ddPCR) in longitudinally collected plasma samples (n = 367) from 81 NSCLC patients treated with EGFR TKI. Of a total 58 baseline cell-free DNA (cfDNA) samples available for ddPCR analysis, 43 (74.1%) had the same mutation in the matched tumors (clinical sensitivity: 70.8% [17/24] for L858R and 76.5% [26/34] for ex19del). The concordance rates of plasma with tissue-based results of EGFR mutations were 87.9% for L858R and 86.2% for ex19del. All 40 patients who were detected EGFR mutations at baseline showed a dramatic decrease of mutant copies (>50%) in plasma during the first two months after treatment. Median progression-free survival (PFS) was 10.1 months for patients with undetectable EGFR v 6.3 months for detectable EGFR mutations in blood after two-month treatment (HR 3.88, 95% CI 1.48-10.19, P = 0.006). We observed emerging resistance with early detection of T790M as a secondary mutation in 14 (28.6%) of 49 patients. Plasma-based EGFR mutation analysis using ddPCR can monitor treatment response to EGFR TKIs and can lead to early detection of EGFR TKIs resistance. Further studies confirming clinical implications of EGFR mutation in plasma are warranted to guide optimal therapeutic strategies upon knowledge of treatment response and resistance. PMID- 26755651 TI - Cdk3-promoted epithelial-mesenchymal transition through activating AP-1 is involved in colorectal cancer metastasis. AB - Cyclin dependent kinase-3 (Cdk3) is a positive regulator of the G1 mammalian cell cycle phase. Cdk3 is involved in cancer progression, but very little is known about its mechanism in cancer development and progression. Herein, we found that Cdk3 increased colorectal cancer metastasis through promoting epithelial mesenchymal transition (EMT) shift. Cdk3 was found to highly express in metastatic cancer and induce cell motility and invasion. Cdk3 was shown to phosphorylate c-Jun at Ser 63 and Ser 73 in vitro and ex vivo. Cdk3 phosphorylated c-Jun at Ser 63 and Ser 73 resulted in an increased AP-1 activity. Ectopic expression of Cdk3 promoted colorectal cancer from epithelial to mesenchymal transition conjugating AP-1 activation, while AP-1 inhibition dramatically decreased Cdk3-increased EMT shift. These results showed that the Cdk3/c-Jun signaling axis mediating epithelial-mesenchymal transition plays an important role in colorectal cancer metastasis. PMID- 26755652 TI - MiRNA-133b promotes the proliferation of human Sertoli cells through targeting GLI3. AB - Sertoli cells play critical roles in regulating spermatogenesis and they can be reprogrammed to the cells of other lineages, highlighting that they have significant applications in reproductive and regenerative medicine. The fate determinations of Sertoli cells are regulated precisely by epigenetic factors. However, the expression, roles, and targets of microRNA (miRNA) in human Sertoli cells remain unknown. Here we have for the first time revealed that 174 miRNAs were distinctly expressed in human Sertoli cells between Sertoli-cell-only syndrome (SCOS) patients and obstructive azoospermia (OA) patients with normal spermatogenesis using miRNA microarrays and real time PCR, suggesting that these miRNAs may be associated with the pathogenesis of SCOS. MiR-133b is upregulated in Sertoli cells of SCOS patients compared to OA patients. Proliferation assays with miRNA mimics and inhibitors showed that miR-133b enhanced the proliferation of human Sertoli cells. Moreover, we demonstrated that GLI3 was a direct target of miR-133b and the expression of Cyclin B1 and Cyclin D1 was enhanced by miR 133b mimics but decreased by its inhibitors. Gene silencing of GLI3 using RNA inference stimulated the growth of human Sertoli cells. Collectively, miR-133b promoted the proliferation of human Sertoli cells by targeting GLI3. This study thus sheds novel insights into epigenetic regulation of human Sertoli cells and the etiology of azoospermia and offers new targets for treating male infertility. PMID- 26755653 TI - Ablation of Neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression. AB - Gliomas are the most commonly diagnosed primary tumors of the central nervous system (CNS). Median times of survival are dismal regardless of the treatment approach, underlying the need to develop more effective therapies. Modulation of the immune system is a promising strategy as innate and adaptive immunity play important roles in cancer progression. Glioma associated microglia and macrophages (GAMs) can comprise over 30% of the cells in glioma biopsies. Gliomas secrete cytokines that suppress the anti-tumorigenic properties of GAMs, causing them to secrete factors that support the tumor's spread and growth. Neuropilin 1 (Nrp1) is a transmembrane receptor that in mice both amplifies pro-angiogenic signaling in the tumor microenvironment and affects behavior of innate immune cells. Using a Cre-lox system, we generated mice that lack expression of Nrp1 in GAMs. We demonstrate, using an in vivo orthotopic glioma model, that tumors in mice with Nrp1-deficient GAMs exhibit less vascularity, grow at a slower pace, and are populated by increased numbers of anti-tumorigenic GAMs. Moreover, glioma survival times in mice with Nrp1-deficient GAMs were significantly longer. Treating wild-type mice with a small molecule inhibitor of Nrp1's b1 domain, EG00229, which we show here is selective for Nrp1 over Nrp2, yielded an identical outcome. Nrp1-deficient or EG00229-treated wild-type microglia exhibited a shift towards anti-tumorigenicity as evident by altered inflammatory marker profiles in vivo and decreased SMAD2/3 activation when conditioned in the presence of glioma derived factors. These results provide support for the proposal that pharmacological inhibition of Nrp1 constitutes a potential strategy for suppressing glioma progression. PMID- 26755655 TI - Low protein and high-energy diet: a possible natural cause of fatty liver hemorrhagic syndrome in caged White Leghorn laying hens. AB - Fatty liver hemorrhagic syndrome (FLHS) is a metabolic condition of chicken and other birds caused by diverse nutritional, hormonal, environmental, and metabolic factors. Here we studied the effect of different diet composition on the induction of FLHS in single comb White Leghorn (WL) Hy-line laying hens. Seventy six (76) young WL (26 wks old) laying hens and 69 old hens (84 wks old) of the same breed were each divided into 4 treatment groups and provided 4 different diet treatments. The diet treatments included: control (C), 17.5% CP, 3.5% fat (F); normal protein, high fat (HF), 17.5% CP, 7% F; low protein, normal fat (LP), 13% CP, 3.5% F; and low protein, high fat (LPHF), 13% CP, 6.5% F. The diets containing high fat also had a higher ME of 3,000 kcal/kg of feed while the other 2 diets with normal fat had a regular lower amount of ME (2750 kcal/kg). Hen-day egg production (HDEP), ADFI, BW, egg weight, plasma enzymes indicating liver damage (alkaline phosphatase [ALP], aspartate aminotransferase [AST], gamma glutamyl transferase [GGT]), liver and abdominal fat weight, liver color score (LCS), liver hemorrhagic score (LHS), liver fat content (LFC), liver histological examination, lipid peroxidation product in the liver, and genes indicating liver inflammation were evaluated. HDEP, ADFI, BW, and egg weight were significantly decreased in the LPHF diet group, while egg weight was also decreased in the LP diet group. In the young hens (LPHF group), ALP was found significantly higher at 30 d of diet treatment and was numerically higher throughout the experiment, while AST was significantly higher at 105 d of treatment. LCS, LHS, and LFC were significantly higher in young hens on the LPHF diet treatment. A liver histological examination shows more lipid vacuolization in the LPHF treatment diet. HF or LP alone had no significant effect on LFC, LHS, or LCS. We suggest that LP in the diet with higher ME from fat can be a possible natural cause for predisposing laying hens to FLHS. PMID- 26755656 TI - The effects of maternal dietary vitamin premixes, canthaxanthin, and 25 hydroxycholecalciferol on the performance of progeny ducklings. AB - This trial studied the effects of maternal dietary vitamin premixes, and the mixture of canthaxanthin (CX) and 25-hydroxycholecalciferol (25-OH-D3) on the performance of progeny ducklings. Four maternal diets were used under a 2 * 2 factorial arrangement with 2 kinds of vitamin premixes (Regular and High; High premix had higher levels of all vitamins except K3 than the Regular premix), and with or without the addition of the mixture of CX (6 mg/kg) and 25-OH-D3 (0.069 mg/kg). Cherry Valley duck breeders (38-wk-old) were fed with corn-wheat flour soybean meal-based diets for 8 wk, and then eggs were collected and hatched. Healthy ducklings (equal number of female and male) from each maternal group were randomly selected and received the same commercial starter (1 to 14 d) and grower (15 to 35 d) pellet diet for 35 d. Maternal High vitamin premix increased shank pigmentation (1 d, P = 0.001), BW (1 d, P < 0.001 and 14 d, P = 0.006), BW gain (1 to 14 d, P = 0.008), G:F ratio (1 to 14 d, P = 0.007), superoxide dismutase (SOD; 1 d liver, P = 0.027 and 14 d serum, P = 0.031), and total antioxidant capacity (1 d liver, P < 0.001); and decreased protein carbonyl (14 d serum, P = 0.011) of ducklings. The mixture of CX and 25-OH-D3 increased yolk pigmentation (P < 0.001); increased shank pigmentation (1 d, P < 0.001 and 14 d, P < 0.001), BW (1 d, P < 0.001), feed intake (15-35 d, P = 0.014), SOD (1 d liver, P = 0.032), and tibia ash (14 d, P = 0.010) of ducklings; and decreased malondialdehyde (P < 0.001) and protein carbonyl (P = 0.044) of yolks, and malondialdehyde (14 d serum, P < 0.001) of ducklings. In conclusion, either maternal High vitamin premix or maternal supplementation of the CX and 25-OH-D3 mixture improves growth performance and antioxidant status of ducklings. PMID- 26755657 TI - The addition of charcoals to broiler diets did not alter the recovery of Salmonella Typhimurium during grow-out. AB - Two experiments evaluated prebiotics added to feed on the recovery of Salmonella in broilers during grow-out and processing. In Experiment 1, "seeder" chicks were inoculated with Salmonella Typhimurium and placed with penmates. Treatments were: basal control diet, added 0.3% bamboo charcoal, 0.6% bamboo charcoal, or 0.12% Aromabiotic (medium chain fatty acids). The ceca from seeders and penmates were sampled to confirm Salmonella colonization at 3, 4, and 6 wk, and pen litter was sampled weekly. At 3 wk, charcoal fed chicks had significantly lower cecal recovery (37% lower) of Salmonella via direct plating but no differences at wk 4 or 6. At 6 wk, broilers fed Aromabiotic had no recovery of Salmonella from ceca with direct plating and significantly, 18%, lower recovery with enrichment. In Experiment 2, the treatments were: basal control diet, added 0.3% bamboo charcoal, 0.3% activated bamboo charcoal, or 0.3% pine charcoal. At placement, 2 seeders were challenged with Salmonella and commingled with penmates and ceca sampled at 1 and 2 wk, and ceca from 5 penmates/pen at 3 to 6 wk. Weekly, the pH of the crop and duodenum was measured from 1 penmate/pen and the litter surface sampled. At the end of grow-out broilers were processed. Results showed that penmates had colonized at 1 and 2 wk. Cecal Salmonella showed no differences except at 4 wk, when activated bamboo charcoal had a 18% lower recovery of Salmonella (enrichment) compared to the control (88%). Similar to Experiment 1, the recovery of Salmonella from the litter was not significantly different among treatments, however an overall decrease in recovery by 4 wk with direct plating reoccurred. The pH of the duodenum and the crop were not different among treatments. Crop pH (6.0) for all treatments were significantly higher at wk 1 compared to wk 2 to 6. Charcoals had minimal effect on Salmonella recovery in the ceca, but following defeathering, broilers fed charcoals had significantly lower Salmonella recovery from breast skin (charcoals 5+/60 compared to control 8+/20). While the addition of charcoals to broilers feed did not significantly affect Salmonella recovery during production (from litter or ceca samples) there was a lower Salmonella recovery from breast skin following scalding and defeathering. PMID- 26755654 TI - Virus and host genomic, molecular, and cellular interactions during Marek's disease pathogenesis and oncogenesis. AB - Marek's Disease Virus (MDV) is a chicken alphaherpesvirus that causes paralysis, chronic wasting, blindness, and fatal lymphoma development in infected, susceptible host birds. This disease and its protective vaccines are highly relevant research targets, given their enormous impact within the poultry industry. Further, Marek's disease (MD) serves as a valuable model for the investigation of oncogenic viruses and herpesvirus patterns of viral latency and persistence--as pertinent to human health as to poultry health. The objectives of this article are to review MDV interactions with its host from a variety of genomic, molecular, and cellular perspectives. In particular, we focus on cytogenetic studies, which precisely assess the physical status of the MDV genome in the context of the chicken host genome. Combined, the cytogenetic and genomic research indicates that MDV-host genome interactions, specifically integration of the virus into the host telomeres, is a key feature of the virus life cycle, contributing to the viral achievement of latency, transformation, and reactivation of lytic replication. We present a model that outlines the variety of virus-host interactions, at the multiple levels, and with regard to the disease states. PMID- 26755659 TI - Is It Truly the Answer? Personalized Oxycodone Dosing Based on Pharmacogenetic Testing and the Corresponding Pharmacokinetics. PMID- 26755658 TI - Opioid Tapering in Fibromyalgia Patients: Experience from an Interdisciplinary Pain Rehabilitation Program. AB - OBJECTIVE: Despite current guideline recommendations against the use of opioids for the treatment of fibromyalgia pain, opioid use is reported in approximately 30% of the patient population. There is a lack of information describing the process and results of tapering of chronic opioids. The purpose of this study is to describe opioid tapering and withdrawal symptoms in fibromyalgia patients on opioids. DESIGN, SETTING, AND SUBJECTS: This retrospective research study included a baseline analysis of 159 patients consecutively admitted to the Mayo Clinic Pain Rehabilitation Center from 2006 through 2012 with a pain diagnosis of fibromyalgia completing a 3-week outpatient interdisciplinary pain rehabilitation program. Opioid tapering analysis included 55 (35%) patients using daily opioids. METHODS: Opioid tapering was individualized to each patient based on interdisciplinary pain rehabilitation team determination. Opioid withdrawal symptoms were assessed daily, utilizing the Clinical Opioid Withdrawal Scale. RESULTS: Patients taking daily opioids had a morphine equivalent mean dose of 99 mg/day. Patients on < 100 mg/day were tapered off over a mean of 10 days compared with patients on > 200 mg/day over a mean of 28 days (P < 0.001). Differences in peak withdrawal symptoms were not statistically significant based on the mean equivalent dose (P = 22). Patients taking opioids for <2 years did not differ in length of tapering (P =0.63) or peak COWS score (P =0.80) compared with >2 years duration. Patients had significant improvements in pain-related measures including numeric pain scores, depression catastrophizing, health perception, interference with life, and perceived life control at program completion. CONCLUSION: Fibromyalgia patients on higher doses of opioids were tapered off over a longer period of time but no differences in withdrawal symptoms were seen based on opioid dose. Duration of opioid use did not affect the time to complete opioid taper or withdrawal symptoms. Despite opioid tapering, pain-related measures improved at the completion of the rehabilitation program. PMID- 26755660 TI - Hypoxia-induced lncRNA-NUTF2P3-001 contributes to tumorigenesis of pancreatic cancer by derepressing the miR-3923/KRAS pathway. AB - Recent studies indicate that long non-coding RNAs (lncRNAs) play crucial roles in numerous cancers, while their function in pancreatic cancer is rarely elucidated. The present study identifies a functional lncRNA and its potential role in tumorigenesis of pancreatic cancer. Microarray co-assay for lncRNAs and mRNAs demonstrates that lncRNA-NUTF2P3-001 is remarkably overexpressed in pancreatic cancer and chronic pancreatitis tissues, which positively correlates with KRAS mRNA expression. After downregulating lncRNA-NUTF2P3-001, the proliferation and invasion of pancreatic cancer cell are significantly inhibited both in vitro and vivo, accompanying with decreased KRAS expression. The dual-luciferase reporter assay further validates that lncRNA-NUTF2P3-001 and 3'UTR of KRAS mRNA competitively bind with miR-3923. Furthermore, miR-3923 overexpression simulates the inhibiting effects of lncRNA-NUTF2P3-001-siRNA on pancreatic cancer cell, which is rescued by miR-3923 inhibitor. Specifically, the present study further reveals that lncRNA-NUTF2P3-001 is upregulated in pancreatic cancer cells under hypoxia and CoCl2 treatment, which is attributed to the binding of hypoxia inducible factor-1alpha (HIF-1alpha) to hypoxia response elements (HREs) in the upstream of KRAS promoter. Data from pancreatic cancer patients show a positive correlation between lncRNA-NUTF2P3-001 and KRAS, which is associated with advanced tumor stage and worse prognosis. Hence, our data provide a new lncRNA mediated regulatory mechanism for the tumor oncogene KRAS and implicate that lncRNA-NUTF2P3-001 and miR-3923 can be applied as novel predictors and therapeutic targets for pancreatic cancer. PMID- 26755661 TI - Axon guidance molecule semaphorin3A is a novel tumor suppressor in head and neck squamous cell carcinoma. AB - Semaphorin3A (SEMA3A), an axon guidance molecule in the nervous system, plays an inhibitory role in oncogenesis. Here, we investigated the expression pattern and biological roles of SEMA3A in head and neck squamous cell carcinoma (HNSCC) by gain-of-function assays using adenovirus transfection and recombinant human SEMA3A protein. In addition, we explored the therapeutic efficacy of SEMA3A against HNSCC in vivo. We found that lower expression of SEMA3A correlated with shorter overall survival and had independent prognostic importance in patients with HNSCC. Both genetic and recombinant SEMA3A protein inhibited cell proliferation and colony formation and induced apoptosis, accompanied by decreased cyclin E, cyclin D, CDK2, CDK4 and CDK6 and increased P21, P27, activated caspase-5 and caspase-7. Moreover, over-expression of SEMA3A suppressed migration, invasion and epithelial-to-mesenchymal transition due in part to the inhibition of NF-kappaB and SNAI2 in HNSCC cell lines. Furthermore, intratumoral SEMA3A delivery significantly stagnated tumor growth in a xenograft model. Taken together, our results indicate that SEMA3A serves as a tumor suppressor during HNSCC tumorigenesis and a new target for the treatment of HNSCC. PMID- 26755662 TI - Inhibition of endothelial Cdk5 reduces tumor growth by promoting non-productive angiogenesis. AB - Therapeutic success of VEGF-based anti-angiogenic tumor therapy is limited due to resistance. Thus, new strategies for anti-angiogenic cancer therapy based on novel targets are urgently required. Our previous in vitro work suggested that small molecule Cdk5 inhibitors affect angiogenic processes such as endothelial migration and proliferation. Moreover, we recently uncovered a substantial role of Cdk5 in the development of lymphatic vessels. Here we pin down the in vivo impact of endothelial Cdk5 inhibition in angiogenesis and elucidate the underlying mechanism in order to judge the potential of Cdk5 as a novel anti angiogenic and anti-cancer target. By the use of endothelial-specific Cdk5 knockout mouse models and various endothelial and tumor cell based assays including human tumor xenograft models, we show that endothelial-specific knockdown of Cdk5 results in excessive but non-productive angiogenesis during development but also in tumors, which subsequently leads to inhibition of tumor growth. As Cdk5 inhibition disrupted Notch function by reducing the generation of the active Notch intracellular domain (NICD) and Cdk5 modulates Notch-dependent endothelial cell proliferation and sprouting, we propose that the Dll4/Notch driven angiogenic signaling hub is an important and promising mechanistic target of Cdk5. In fact, Cdk5 inhibition can sensitize tumors to conventional anti angiogenic treatment as shown in tumor xenograft models. In summary our data set the stage for Cdk5 as a drugable target to inhibit Notch-driven angiogenesis condensing the view that Cdk5 is a promising target for cancer therapy. PMID- 26755663 TI - Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target. AB - Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM. PMID- 26755666 TI - Wellens syndrome. PMID- 26755665 TI - The Medicines Advice Service Evaluation (MASE): a randomised controlled trial of a pharmacist-led telephone based intervention designed to improve medication adherence. AB - AIM: To test the effectiveness of a tailored, pharmacist-led centralised advice service to improve adherence to patients on established medications. METHODS: A parallel group randomised controlled trial was conducted. Patients prescribed at least one oral medication for type 2 diabetes and/or lipid regulation were eligible to participate. 677 patients of a mail-order pharmacy were recruited and randomised (340 intervention, 337 control). The intervention comprised two tailored telephone consultations with a pharmacist, 4-6 weeks apart, plus a written summary of the discussion and a medicines reminder chart. The primary outcome was self-reported adherence to medication at 6-month follow-up, collected via a postal questionnaire, analysed using generalised estimating equations. Secondary outcomes included prescription refill adherence, lipid and glycaemic control and patient satisfaction. RESULTS: In intention-to-treat analysis 36/340 (10.6%) of the intervention group were non-adherent (<90% of medication taken in the past 7 days) at 6 months compared with 66/337 (19.6%) in the control group, yielding an unadjusted OR of 1.54 (95% CI 1.11 to 2.15, p=0.01). Analyses of dispensing data also showed that the odds of being classified as adherent (>=90%) were 60% greater for the intervention group compared with the control group (OR 1.60, 95% CI 1.14 to 2.24, p<0.01). In a subsample of patients who provided blood samples, glycaemic and lipid control did not differ significantly between groups (p=0.06 and p=0.24, respectively) but positive trends were observed. Ninety-two per cent of intervention group patients reported that they were satisfied with the service overall. CONCLUSIONS: A telephone intervention, led by a pharmacist and tailored to the individuals' needs, can significantly improve medication adherence in patients with long-term conditions, using a mail-order pharmacy. Further work is needed to confirm a trend towards improved clinical outcome. TRIAL REGISTRATION NUMBER: NCT01864239. PMID- 26755664 TI - Preferential expression of functional IL-17R in glioma stem cells: potential role in self-renewal. AB - Gliomas are the most common primary brain tumor and one of the most lethal solid tumors. Mechanistic studies into identification of novel biomarkers are needed to develop new therapeutic strategies for this deadly disease. The objective for this study was to explore the potential direct impact of IL-17-IL-17R interaction in gliomas. Immunohistochemistry and flow cytometry analysis of 12 tumor samples obtained from patients with high grade gliomas revealed that a considerable population (2-19%) of cells in all malignant gliomas expressed IL-17RA, with remarkable co-expression of the glioma stem cell (GSC) markers CD133, Nestin, and Sox2. IL-17 enhanced the self-renewal of GSCs as determined by proliferation and Matrigel(r) colony assays. IL-17 also induced cytokine/chemokine (IL-6, IL-8, interferon-gamma-inducible protein [IP-10], and monocyte chemoattractant protein 1 [MCP-1]) secretion in GSCs, which were differentially blocked by antibodies against IL-17R and IL-6R. Western blot analysis showed that IL-17 modulated the activity of signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), glycogen synthase kinase-3beta (GSK-3beta) and beta-catenin in GSCs. While IL-17R-mediated secretion of IL-6 and IL-8 were significantly blocked by inhibitors of NF-kappaB and STAT3; NF-kappaB inhibitor was more potent than STAT3 inhibitor in blocking IL-17-induced MCP-1 secretion. Overall, our results suggest that IL-17-IL-17R interaction in GSCs induces an autocrine/paracrine cytokine feedback loop, which may provide an important signaling component for maintenance/self-renewal of GSCs via constitutive activation of both NF-kappaB and STAT3. The results also strongly implicate IL-17R as an important functional biomarker for therapeutic targeting of GSCs. PMID- 26755667 TI - Naming and classifying old and new ECG phenomena. PMID- 26755668 TI - de Winter syndrome. PMID- 26755669 TI - Caring for a newly arrived Syrian refugee family. PMID- 26755670 TI - Myanmar's Mother Teresa. PMID- 26755671 TI - Profile: Dr. Jane Philpott. PMID- 26755673 TI - Residents talking to Ontario over new entry program. PMID- 26755672 TI - A 3-year study of high-cost users of health care. AB - BACKGROUND: Characterizing high-cost users of health care resources is essential for the development of appropriate interventions to improve the management of these patients. We sought to determine the concentration of health care spending, characterize demographic characteristics and clinical diagnoses of high-cost users and examine the consistency of their health care consumption over time. METHODS: We conducted a retrospective analysis of all residents of Ontario, Canada, who were eligible for publicly funded health care between 2009 and 2011. We estimated the total attributable government health care spending for every individual in all health care sectors. RESULTS: More than $30 billion in annual health expenditures, representing 75% of total government health care spending, was attributed to individual costs. One-third of high-cost users (individuals with the highest 5% of costs) in 2009 remained in this category in the subsequent 2 years. Most spending among high-cost users was for institutional care, in contrast to lower-cost users, among whom spending was predominantly for ambulatory care services. Costs were far more concentrated among children than among older adults. The most common reasons for hospital admissions among high cost users were chronic diseases, infections, acute events and palliative care. INTERPRETATION: Although high health care costs were concentrated in a small minority of the population, these related to a diverse set of patient health care needs and were incurred in a wide array of health care settings. Improving the sustainability of the health care system through better management of high-cost users will require different tactics for different high-cost populations. PMID- 26755674 TI - Why are doctors joining ISIS? PMID- 26755675 TI - Tests for Gene-Environment Interactions and Joint Effects With Exposure Misclassification. AB - The number of methods for genome-wide testing of gene-environment (G-E) interactions continues to increase, with the aim of discovering new genetic risk factors and obtaining insight into the disease-gene-environment relationship. The relative performance of these methods, assessed on the basis of family-wise type I error rate and power, depends on underlying disease-gene-environment associations, estimates of which may be biased in the presence of exposure misclassification. This simulation study expands on a previously published simulation study of methods for detecting G-E interactions by evaluating the impact of exposure misclassification. We consider 7 single-step and modular screening methods for identifying G-E interaction at a genome-wide level and 7 joint tests for genetic association and G-E interaction, for which the goal is to discover new genetic susceptibility loci by leveraging G-E interaction when present. In terms of statistical power, modular methods that screen on the basis of the marginal disease-gene relationship are more robust to exposure misclassification. Joint tests that include main/marginal effects of a gene display a similar robustness, which confirms results from earlier studies. Our results offer an increased understanding of the strengths and limitations of methods for genome-wide searches for G-E interaction and joint tests in the presence of exposure misclassification. PMID- 26755678 TI - Tennis injury data from The Championships, Wimbledon, from 2003 to 2012. AB - OBJECTIVE: The primary aims of this retrospective study were to describe the burden of injury presenting to the medical team and the changes in injury profile over 10 years (2003-2012) at The Championships, Wimbledon. Secondary aims included description of gender difference in rates, distribution and pathology of injuries. DESIGN: Retrospective observational cohort of player injury presentations over 10 years (2003-2012) at The Championships, Wimbledon. RESULTS: The overall rate of presentation of injury for all players over the 10-year period was 20.7 per 1000 sets played. Injury rates were lower for male players (17.7 injuries per 1000 sets played) than female players (23.4 injuries per 1000 sets played). There was variability in the numbers of injuries reported by men and women players over the 10-year period. CONCLUSIONS: The rates of presentation of injury at this Grand Slam tennis tournament varied between male and female players, and between years. More robust systems of data collection are required in professional tennis to enable more sophisticated injury data analysis between sexes, years and different playing surfaces. PMID- 26755676 TI - Associations of Dietary Long-Chain omega-3 Polyunsaturated Fatty Acids and Fish Consumption With Endometrial Cancer Risk in the Black Women's Health Study. AB - Dietary long-chain (LC) omega-3 polyunsaturated fatty acids (PUFAs), which derive primarily from intakes of fatty fish, are thought to inhibit inflammation and de novo estrogen synthesis. This study prospectively examined the associations of dietary LC omega-3 PUFAs and fish with endometrial cancer risk in 47,602 African American women living in the United States, aged 21-69 years at baseline in 1995, and followed them until 2013 (n = 282 cases). Multivariable-adjusted Cox regression models estimated hazard ratios and 95% confidence intervals for associations of LC omega-3 PUFA (quintiled) and fish (quartiled) intake with endometrial cancer risk, overall and by body mass index (BMI; weight (kg)/height (m)(2)). The hazard ratio for quintile 5 of total dietary LC omega-3 PUFAs versus quintile 1 was 0.79 (95% confidence interval (CI): 0.51, 1.24); there was no linear trend. Hazard ratios for the association were smaller among normal-weight women (BMI <25: hazard ratio (HR) = 0.53, 95% CI: 0.18, 1.58) than among overweight/obese women (BMI >= 25: HR = 0.88, 95% CI: 0.54, 1.43), but these differences were not statistically significant. Fish intake was also not associated with risk (quartile 4 vs. quartile 1: HR = 0.86, 95% CI: 0.56, 1.31). Again hazard ratios were smaller among normal-weight women (HR = 0.65) than among overweight/obese women (HR = 0.94). While compatible with no association, the hazard ratios observed among leaner African-American women are similar to those from recent prospective studies conducted in predominantly white populations. PMID- 26755679 TI - Effect of DA-9701 on the Normal Motility and Clonidine-induced Hypomotility of the Gastric Antrum in Rats. AB - BACKGROUND/AIMS: DA-9701 is a novel prokinetic agent. In the present study, we investigated the effect of DA-9701 on the motility of the gastric antrum in the normal and clonidine-induced hypomotility in an in vivo animal model. METHODS: A strain gauge force transducer was sutured on the gastric antrum to measure the contractile activity in rats. A total of 28 rats were subclassified into the 4 groups: (1) the placebo group, (2) the DA-9701 group, (3) the placebo group in the clonidine-pretreated rats, and (4) the DA-9701 group in the clonidine pretreated rats. After the basal recording, either placebo (3% [w/v] hydroxypropylmethyl cellulose) or DA-9701 was administered. Contractile signals were measured after the administration and after a meal. In the clonidinepretreated rats, either placebo or DA-9701 was administered. Contractile signals were measured after the administration and after a meal. RESULTS: Oral administration of DA-9701 did not significantly alter the motility index of the gastric antrum in the preprandial and postprandial periods, compared with the placebo group. The administration of clonidine decreased the motility index of the gastric antrum in the preprandial and postprandial periods, compared with the administration of placebo. This reduction of the antral motility by the administration of clonidine was not observed in the clonidine-pretreated DA-9701 group. The percentage of the motility index in the postprandial period was significantly greater in the clonidine-pretreated DA-9701 group, compared with the clonidine-pretreated placebo group. CONCLUSIONS: DA-9701 improves the hypomotility of the gastric antrum induced by clonidine, suggesting its gastroprokinetic effect in the pathologic condition. PMID- 26755680 TI - Genetic Influence on the Peripheral Blood CD4+ T-cell Differentiation Status in CMV Infection. AB - A latent infection with cytomegalovirus (CMV), a ubiquitous beta herpesvirus, is associated with an accumulation of late-differentiated memory T-cells, often accompanied by a reciprocal reduced frequency of early-differentiated cells (commonly also referred to as "naive"). However, this impact of CMV on T-cell phenotypes is variable between individuals. Our previous findings in a subgroup of participants in the Leiden familial Longevity Study indicated an important role of genetics. For further testing, we have analyzed middle-aged monozygotic (MZ, n = 42) and dizygotic (DZ, n = 39) twin pairs from the Danish Twin Registry for their T-cell differentiation status, assessed by surface expression of CD27, CD28, CD57, and KLRG-1. We observed a significant intraclass correlation between cotwins of MZ, but not DZ pairs for the differentiation status of CD4+ and CD8+ subsets. Classical heritability analysis confirmed a substantial contribution of genetics to the differentiation status of T-cells in CMV infection. The humoral (IgG) response to different CMV antigens also seems to be genetically influenced, suggesting that a similar degree of immune control of the virus in MZ twins might be responsible for their similar T-cell differentiation status. Thus, the way T cells differentiate in the face of a latent CMV infection, and the parallel humoral responses, both controlling the virus, are genetically influenced. PMID- 26755681 TI - Predictors of New Onset Sleep Medication and Treatment Utilization Among Older Adults in the United States. AB - BACKGROUND: Sleep disturbances are common among older adults resulting in frequent sleep medication utilization, though these drugs are associated with a number of risks. We examine rates and predictors of new prescription sleep medications and sleep treatments, as well as sleep treatments without a doctor's recommendation. METHODS: Participants were 8,417 adults aged 50 and older from two waves of the nationally representative Health and Retirement Study (HRS) who were not using a sleep medication or treatment at baseline (2006). Logistic regression analyses are run with sociodemographic, health, and mental health factors as predictors of three outcomes: new prescription medication use, sleep treatment use, and sleep treatment out of a doctor's recommendation in 2010. RESULTS: New sleep medication prescriptions were started by 7.68%, 12.62% started using a new sleep treatment, and 31.93% were using the treatment outside of their doctor's recommendation. Common predictors included greater severity of insomnia, worsening insomnia, older age, and use of psychiatric medications. New prescription medication use was also associated with poorer mental and physical health, whereas new sleep treatment was associated with being White, higher educated, and drinking less alcohol. CONCLUSIONS: Starting a new prescription sleep medication may reflect poorer health and higher health care utilization, whereas beginning a sleep treatment may reflect an individual's awareness of treatments and determination to treat their problem. Clinicians should be aware of predictors of new sleep medication and treatment users and discuss various forms of treatment or behavioral changes to help patients best manage sleep disturbance. PMID- 26755684 TI - Effects of Hearing Status and Sign Language Use on Working Memory. AB - Deaf individuals have been found to score lower than hearing individuals across a variety of memory tasks involving both verbal and nonverbal stimuli, particularly those requiring retention of serial order. Deaf individuals who are native signers, meanwhile, have been found to score higher on visual-spatial memory tasks than on verbal-sequential tasks and higher on some visual-spatial tasks than hearing nonsigners. However, hearing status and preferred language modality (signed or spoken) frequently are confounded in such studies. That situation is resolved in the present study by including deaf students who use spoken language and sign language interpreting students (hearing signers) as well as deaf signers and hearing nonsigners. Three complex memory span tasks revealed overall advantages for hearing signers and nonsigners over both deaf signers and deaf nonsigners on 2 tasks involving memory for verbal stimuli (letters). There were no differences among the groups on the task involving visual-spatial stimuli. The results are consistent with and extend recent findings concerning the effects of hearing status and language on memory and are discussed in terms of language modality, hearing status, and cognitive abilities among deaf and hearing individuals. PMID- 26755683 TI - Cerebral White Matter and Slow Gait: Contribution of Hyperintensities and Normal appearing Parenchyma. AB - BACKGROUND: White matter hyperintensities (WMH), a common marker of cerebral small vessel disease, and lower microstructural integrity of normal-appearing white matter are associated with slower gait. How these cerebral measures interact in relation to slower gait is unknown. We assessed whether microstructural integrity of normal-appearing white matter, measured by fractional anisotropy (FA), moderates the association of higher WMH with slower gait. METHODS: WMH, FA, and gait speed were acquired for 265 community-dwelling older adults (average age = 82.9 years). RESULTS: The inverse association between WMH and gait was robust to adjustment for age, gender, muscle strength, obesity, stroke, and hypertension (fully adjusted model: betas = -0.19, p = .001). The interaction between WMH and FA was significant; analyses stratified by FA showed that the inverse association between WMH and gait speed was significant only for those with low FA (FA < median, fully adjusted model: betas = -0.28, p = .001). Voxel-based results were similar for participants with FA less than median, there was an inverse association between gait speed and WMH which extended throughout the white matter (genu and body of corpus callosum, anterior limb of internal capsule, corona radiata, and superior longitudinal and fronto-occipital fasciculus). In contrast, for participants with FA >= median, the association was limited to the genu of corpus callosum, the cingulum, and the inferior longitudinal fasciculus. CONCLUSIONS: Microstructural integrity is a moderating factor in the association between WMH and gait. Future studies should examine whether higher microstructural integrity represents a source of compensation in those with greater WMH burden to maintain function in late life. PMID- 26755685 TI - Upper Gastrointestinal Symptoms Are More Frequent in Female than Male Young Healthy Japanese Volunteers as Evaluated by Questionnaire. AB - BACKGROUND/AIMS: Upper gastrointestinal symptoms are more frequent and severe in female than in male outpatients in Japan. This study compared theupper gastrointestinal symptoms between healthy male and female young adult volunteers using a questionnaire. METHODS: In total, 581 third-grade medical students at Saga Medical School aged 22 to 30 years underwent upper gastrointestinal endoscopyand completed a questionnaire (frequency scale for symptoms of gastroesophageal reflux disease) from 2007 to 2013. Of these 581students, 298 who were negative for Helicobacter pylori infection and had no particular lesions on endoscopic examination wereenrolled in the present evaluation. A symptom was defined as positive when the subject evaluated the frequency of the symptom assometimes, often, or always. RESULTS: The subjects comprised of 163 males (average age, 23.7 years) and 135 females (average age, 23.1 years). Upper gastrointestinalsymptoms were more frequent in the females (75 of 135, 55.6%) than males (69 of 163, 42.3%; P < 0.05), with a high score for 4symptoms (bloated stomach, heavy feeling in the stomach after meals, subconscious rubbing of the chest with the hand, and feeling of fullness while eating meals). Of the 144 subjects (69 males and 75 females) who complained of these symptoms, the females complained of dysmotility symptoms more often than did the males, but this was not true for reflux symptoms. CONCLUSIONS: This study suggests that females develop upper gastrointestinal symptoms more frequently than do males among the young healthyJapanese population. PMID- 26755682 TI - Characterizing Frailty Status in the Systolic Blood Pressure Intervention Trial. AB - BACKGROUND: The Systolic Blood Pressure Intervention Trial (SPRINT) is testing whether a lower systolic blood pressure (BP) target of 120 mm Hg leads to a reduction in cardiovascular morbidity and mortality among hypertensive, nondiabetic adults. Because there may be detrimental effects of intensive BP control, particularly in older, frail adults, we sought to characterize frailty within SPRINT to address ongoing questions about the ability of large-scale trials to enroll representative samples of noninstitutionalized, community dwelling, older adults. METHODS: We constructed a 36-item frailty index (FI) in 9,306 SPRINT participants, classifying participants as fit (FI <= 0.10), less fit (0.10 < FI <= 0.21), or frail (FI > 0.21). Recurrent event models were used to evaluate the association of the FI with the incidence of self-reported falls, injurious falls, and all-cause hospitalizations. RESULTS: The distribution of the FI was comparable with what has been observed in population studies, with 2,570 (27.6%) participants classified as frail. The median FI was 0.18 (interquartile range = 0.14 to 0.24) in participants aged 80 years and older (N = 1,159), similar to the median FI of 0.17 reported for participants in the Hypertension in the Very Elderly Trial. In multivariable analyses, a 1% increase in the FI was associated with increased risk for self-reported falls (hazard ratio [HR] = 1.030), injurious falls (HR = 1.035), and all-cause hospitalizations (HR = 1.038) (all p values < .0001). CONCLUSIONS: Large clinical trials assessing treatments to reduce cardiovascular disease risk, such as SPRINT, can enroll heterogeneous populations of older adults, including the frail elderly, comparable with general population cohorts. PMID- 26755687 TI - Combined albumin and bicarbonate induces head-to-head sperm agglutination which physically prevents equine sperm-oviduct binding. AB - In many species, sperm binding to oviduct epithelium is believed to be an essential step in generating a highly fertile capacitated sperm population primed for fertilization. In several mammalian species, this interaction is based on carbohydrate-lectin recognition. D-galactose has previously been characterized as a key molecule that facilitates sperm-oviduct binding in the horse. We used oviduct explant and oviduct apical plasma membrane (APM) assays to investigate the effects of various carbohydrates; glycosaminoglycans; lectins; S-S reductants; and the capacitating factors albumin, Ca(2+) and HCO3(-) on sperm oviduct binding in the horse. Carbohydrate-specific lectin staining indicated that N-acetylgalactosamine, N-acetylneuraminic acid (sialic acid) and D-mannose or D-glucose were the most abundant carbohydrates on equine oviduct epithelia, whereas D-galactose moieties were not detected. However, in a competitive binding assay, sperm-oviduct binding density was not influenced by any tested carbohydrates, glycosaminoglycans, lectins or D-penicillamine, nor did the glycosaminoglycans induce sperm tail-associated protein tyrosine phosphorylation. Furthermore, N-glycosidase F (PNGase) pretreatment of oviduct explants and APM did not alter sperm-oviduct binding density. By contrast, a combination of the sperm-capacitating factors albumin and HCO3(-) severely reduced (>10-fold) equine sperm-oviduct binding density by inducing rapid head-to-head agglutination, both of which events were independent of Ca(2+) and an elevated pH (7.9). Conversely, neither albumin and HCO3(-) nor any other capacitating factor could induce release of oviduct-bound sperm. In conclusion, a combination of albumin and HCO3( ) markedly induced sperm head-to-head agglutination which physically prevented stallion sperm to bind to oviduct epithelium. PMID- 26755688 TI - Effect of single post-ovulatory administration of mifepristone (RU486) on transcript profile during the receptive period in human endometrium. AB - Progesterone regulates uterine function during the luteal phase and is essential for the acquisition of endometrial receptivity. The objective of the present study was to identify endometrial transcripts whose expression is altered during the window of implantation after the administration of 200 mg of the antiprogestin mifepristone, 48 h after the LH peak (LH+2, LH+0=LH peak), and to determine the relationship of these transcripts with those regulated during the acquisition of receptivity. Endometrial samples were obtained in LH+7 from seven women of proven fertility, each one contributing with one cycle treated with placebo and another with mifepristone. Additionally, endometrial samples were obtained in LH+2 and LH+7 during a single untreated spontaneous cycle from seven normal fertile women as a reference. DNA microarrays were used to identify transcripts significantly regulated (defined as >= 2.0-fold change with false discovery rate below 1% using t-test) with the administration of mifepristone vs placebo, or during the transition from pre-receptive to receptive (LH+2 vs LH+7). Approximately 2000 transcripts were significantly regulated in both comparisons (mifepristone vs placebo and LH+2 vs LH+7), but only 777 of them were coincident and displayed opposite regulation except for 25. The mRNA level for eight selected genes regulated by mifepristone was confirmed by real-time RT-PCR. We conclude that not all changes in endometrial transcript levels occurring in the transition from LH+2 to LH+7 seem to be regulated by the progesterone receptor and ~ 37% of the genes whose transcript levels changed by effect of mifepristone could be associated with the acquisition of receptivity. PMID- 26755689 TI - An Anatomic Investigation of the Ober Test. AB - BACKGROUND: Recent studies have questioned the importance of the iliotibial band (ITB) in lateral knee pain. The Ober test or modified Ober test is the most commonly recommended physical examination tool for assessment of ITB tightness. No studies support the validity of either Ober test for measuring ITB tightness. PURPOSE/HYPOTHESIS: The purpose of this study was to assess the effects of progressive transection of the ITB, gluteus medius and minimus (med/min) muscles, and hip joint capsule of lightly embalmed cadavers on Ober test results and to compare them with assessment of all structures intact. In addition, thigh position change between gluteus med/min transection and hip capsule transection was also assessed for both versions of the Ober test. It was hypothesized that transection of the ITB would significantly increase thigh adduction range of motion as measured by an inclinometer when performing either Ober test and that subsequent structure transections (gluteus med/min muscles followed by the hip joint capsule) would cause additional increases in thigh adduction. STUDY DESIGN: Controlled laboratory study. METHODS: The lower limbs of lightly embalmed cadavers were assessed for midthigh ITB transection versus intact by use of the Ober (n = 28) and modified Ober (n = 34) tests; 18 lower limbs were assessed for all conditions (intact band, followed by sequential transections of the ITB midthigh, gluteus med/min muscles, hip joint capsule) by use of both Ober tests. Paired t tests were used to compare changes in Ober test results between conditions. RESULTS: No significant changes in thigh position (adduction) occurred in either version of the Ober test after ITB transection. Significant differences were noted for intact band versus gluteus med/min transection and intact band versus hip joint capsule transection (P < .0001) for all findings for both tests. Mean inclinometer measurements for the modified Ober were 4.28 degrees (n = 34 for intact vs ITB transection comparisons), 3.33 degrees (n = 18 for subsequent intact vs gluteus muscle and hip capsule transection comparisons), 5.00 degrees (n = 34 for midthigh ITB transection), 11.20 degrees (gluteus med/min transection), and 13.20 degrees (hip capsule transection). For the Ober test, measures were -2.90 degrees (n = 28 for intact vs ITB transection comparisons), -2.20 degrees (n = 18 for subsequent intact vs gluteus muscle and hip capsule transection comparisons), -2.20 degrees (n = 34 for midthigh ITB transection), 6.50 degrees (gluteus med/min transection), and 9.53 degrees (hip capsule transection). Statistically significant differences were also noted between test findings comparing gluteus med/min transection to hip capsule transection (Ober, P < .0001; modified Ober, P = .0036). CONCLUSION: The study findings refute the hypothesis that the ITB plays a role in limiting hip adduction during either version of the Ober test and question the validity of these tests for determining ITB tightness. The findings underscore the influence of the gluteus medius and minimus muscles as well as the hip joint capsule on Ober test findings. CLINICAL RELEVANCE: The results of this study suggest that the Ober test assesses tightness of structures proximal to the hip joint, such as the gluteus medius and minimus muscles and the hip joint capsule, rather than the ITB. PMID- 26755686 TI - Mast Cells and Irritable Bowel Syndrome: From the Bench to the Bedside. AB - Irritable bowel syndrome (IBS) is traditionally defined as a functional disorder since it lacks demonstrable pathological abnormalities. However, in recent years, low grade inflammatory infiltration, often rich in mast cells, in both the small and large bowel, has been observed in some patients with IBS. The close association of mast cells with major intestinal functions, such as epithelial secretion and permeability, neuroimmune interactions, visceral sensation, and peristalsis, makes researchers and gastroenterologists to focus attention on the key roles of mast cells in the pathogenesis of IBS. Numerous studies have been carried out to identify the mechanisms in the development, infiltration, activation, and degranulation of intestinal mast cells, as well as the actions of mast cells in the processes of mucosal barrier disruption, mucosal immune dysregulation, visceral hypersensitivity, dysmotility, and local and central stress in IBS. Moreover, therapies targeting mast cells, such as mast cell stabilizers (cromoglycate and ketotifen) and antagonists of histamine and serotonin receptors, have been tried in IBS patients, and have partially exhibited considerable efficacy. This review focuses on recent advances in the role of mast cells in IBS, with particular emphasis on bridging experimental data with clinical therapeutics for IBS patients. PMID- 26755690 TI - Long-term Results After Hyaluronan-based MACT for the Treatment of Cartilage Lesions of the Patellofemoral Joint. AB - BACKGROUND: Cartilage lesions of the patellofemoral joint are a challenging condition. Hyaluronan-based matrix-assisted autologous chondrocyte transplantation (MACT) has been shown to offer a significant improvement in the short term but has a tendency to worsen at midterm follow-up. HYPOTHESIS: Patients treated with MACT for lesions of the articular surface of the patellofemoral joint will present further clinical worsening at long-term follow up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Thirty-two patients with full-thickness chondral lesions in the patellofemoral joint were treated with hyaluronan-based MACT and were prospectively evaluated preoperatively and at 2-, 5-, and 10-year follow-up. The mean defect size was 4.45 cm(2). There were 20 lesions located on the patella and 8 on the trochlea, and 4 patients had multiple lesions: 3 with patellar and trochlear lesions and 1 with patellar and lateral femoral condyle lesions. Results were evaluated using International Knee Documentation Committee (IKDC) subjective scores, EuroQol visual analog scale (EQ VAS) scores, and Tegner scores. Surgical and clinical failures were documented. RESULTS: All scores showed a statistically significant improvement at 2-, 5-, and 10-year follow-up with respect to the preoperative level. No worsening was observed at the last follow-up, and results were stable up to 10 years. The improvement in mean (+/-SD) outcome scores from preoperatively to 2-, 5-, and 10 year follow-up was as follows: IKDC, from 46.0 +/- 19.8 to 77.1 +/- 17.4, 72.0 +/ 20.4, and 78.6 +/- 16.4, respectively; Tegner, from 2.5 +/- 1.4 to 4.7 +/- 1.8, 4.7 +/- 1.6, and 4.4 +/- 1.5, respectively; and EQ VAS, from 56.9 +/- 18.4 to 81.7 +/- 13.2, 79.2 +/- 17.9, and 78.9 +/- 1.7, respectively. Four patients did not achieve significant clinical improvement, and 1 of these patients required further surgical treatment. All failures were female patients with patellar defects, and 3 of them had degenerative lesions and underwent a previous or combined realignment procedure. CONCLUSION: The clinical results of hyaluronan based MACT treatment of chondral lesions of the patellofemoral joint do not worsen over time but remain stable and show a low rate of failure at long-term follow-up. PMID- 26755691 TI - Plant Morphology of Heterotrimeric G Protein Mutants. AB - The heterotrimeric G protein complex, comprising Galpha, Ggamma and Ggamma subunits, is an evolutionarily conserved signaling molecular machine that transmits signals from transmembrane receptors to downstream target proteins. Plants conserved the core G protein elements, while developing their own regulatory systems differently from animals. Genetic evidence supports the conclusion that the heterotrimeric G proteins regulate shoot, root and epidermis development, as well as sugar sensing, hormone responsiveness and abiotic and biotic stress tolerance. This review is a compendium of the known morphological changes conferred by loss- and gain-of-function mutations of the G protein subunit genes across three higher land plant models, namely Arabidopsis, rice and maize. PMID- 26755692 TI - Quantitative Proteomics-Based Reconstruction and Identification of Metabolic Pathways and Membrane Transport Proteins Related to Sugar Accumulation in Developing Fruits of Pear (Pyrus communis). AB - During their 6 month development, pear (Pyrus communis) fruits undergo drastic changes in their morphology and their chemical composition. To gain a better understanding of the metabolic pathways and transport processes active during fruit development, we performed a time-course analysis using mass spectrometry (MS)-based protein identification and quantification of fruit flesh tissues. After pre-fractionation of the samples, 2,841 proteins were identified. A principal component analysis (PCA) separated the samples from seven developmental stages into three distinct clusters representing the early, mid and late developmental phase. Over-representation analysis of proteins characteristic of each developmental phase revealed both expected and novel biological processes relevant at each phase. A high abundance of aquaporins was detected in samples from fruits in the cell expansion stage. We were able quantitatively to reconstruct basic metabolic pathways such as the tricarboxylic acid (TCA) cycle, which indicates sufficient coverage to reconstruct other metabolic pathways. Most of the enzymes that presumably contribute to sugar accumulation in pear fruits could be identified. Our data indicate that invertases do not play a major role in the sugar conversions in developing pear fruits. Rather, sucrose might be broken down by sucrose synthases. Further focusing on sugar transporters, we identified several putative sugar transporters from diverse families which showed developmental regulation. In conclusion, our data set comprehensively describes the proteome of developing pear fruits and provides novel insights about sugar accumulation as well as candidate genes for key reactions and transport steps. PMID- 26755694 TI - Outcomes From Polyhydramnios With Normal Ultrasound. AB - OBJECTIVE: To investigate the short- and long-term outcomes of children from pregnancies complicated with polyhydramnios, defined as amniotic fluid index (AFI) >24 cm, and with a normal detailed ultrasound examination. METHODS: This retrospective cohort study examined 134 children aged 4 to 9 years with polyhydramnios and normal detailed ultrasound examination during pregnancy compared with 268 controls with normal AFI and normal detailed ultrasound examination matched for maternal age, year of delivery, gestational week at delivery, and presence or absence of diabetes. The primary outcome was the rate of malformations diagnosed postnatally. Additional outcomes were obstetrics outcomes, genetic syndromes, and neurodevelopment. RESULTS: Polyhydramnios was associated with increased risk for cesarean delivery (CD) and birth weight >90th percentile. This elevation in CD was attributed to increased rate of elective CD due to suspected macrosomia. Polyhydramnios was associated with increased risk for congenital malformations (n = 25 [19%] compared with 27 [10%], respectively; P = .016) without a statistically significant increase in the rate of major malformations (11 [8%] vs. 10 [4%]; P = .057). Genetic syndromes were more prevalent in the polyhydramnios group (5 [3.7%] vs. 2 [0.75%]; P = .043), as were neurologic disorders and developmental delay (9.7% vs. 3%; P = .004). CONCLUSIONS: Despite a normal detailed ultrasound examination, polyhydramnios is associated with increased rate of fetal malformations, genetic syndromes, neurologic disorders, and developmental delay, which may be diagnosed only after birth. PMID- 26755693 TI - The DbpA catalytic core unwinds double-helix substrates by directly loading on them. AB - DbpA is a DEAD-box RNA helicase implicated in the assembly of the large ribosomal subunit. Similar to all the members of the DEAD-box family, the DbpA protein has two N-terminal RecA-like domains, which perform the RNA unwinding. However, unlike other members of this family, the DbpA protein also possesses a structured C-terminal RNA-binding domain that mediates specific tethering of DbpA to hairpin 92 of the Escherichia coli 23S ribosomal RNA. Previous studies using model RNA molecules containing hairpin 92 show that the RNA molecules support the DbpA protein's double-helix unwinding activity, provided that the double helix has a 3' single-stranded region. The 3' single-stranded region was suggested to be the start site of the DbpA protein's catalytic unwinding activity. The data presented here demonstrate that the single-stranded region 3' of the double-helix substrate is not required for the DbpA protein's unwinding activity and the DbpA protein unwinds the double-helix substrates by directly loading on them. PMID- 26755695 TI - A Multidisciplinary Children's Airway Center: Impact on the Care of Patients With Tracheostomy. AB - BACKGROUND: Children with complex airway problems see multiple specialists. To improve outcomes and coordinate care, we developed a multidisciplinary Children's Airway Center. For children with tracheostomies, aspects of care targeted for improvement included optimizing initial hospital discharge, promoting effective communication between providers and caregivers, and avoiding tracheostomy complications. METHODS: The population includes children up to 21 years old with tracheostomies. The airway center team includes providers from pediatric pulmonology, pediatric otolaryngology/head and neck surgery, and pediatric gastroenterology. Improvement initiatives included enhanced educational strategies, weekly care conferences, institutional consensus guidelines and care plans, personalized clinic schedules, and standardized intervals between airway examinations. A patient database allowed for tracking outcomes over time. RESULTS: We initially identified 173 airway center patients including 123 with tracheostomies. The median number of new patients evaluated by the center team each year was 172. Median hospitalization after tracheostomy decreased from 37 days to 26 days for new tracheostomy patients <1 year old discharged from the hospital. A median of 24 care plans was evaluated at weekly conferences. Consensus protocol adherence increased likelihood of successful decannulation from 68% to 86% of attempts. The median interval of 8 months between airway examinations aligned with published recommendations. CONCLUSIONS: For children with tracheostomies, our Children's Airway Center met and sustained goals of optimizing hospitalization, promoting communication, and avoiding tracheostomy complications by initiating targeted improvements in a multidisciplinary team setting. A multidisciplinary approach to management of these patients can yield measurable improvements in important outcomes. PMID- 26755696 TI - Prevalence and Determinants of Secondhand Smoke Exposure Among Middle and High School Students. AB - BACKGROUND: Secondhand smoke (SHS) causes disease and death among nonsmokers. Private settings are major sources of exposure for children. We assessed prevalence and determinants of self-reported SHS exposure in homes and vehicles, as well as school, work, and indoor/outdoor public areas, among US students in grades 6 through 12. METHODS: Data were from the 2013 National Youth Tobacco Survey (n = 18 406). Self-reported SHS exposure within the past 7 days was assessed overall and by extent of smoke-free home and vehicle rules among never users of 10 tobacco product types. Descriptive statistics were used to compare estimates, and adjusted prevalence ratios were calculated to assess determinants of SHS exposure. RESULTS: Among never tobacco users, 48.0% reported SHS exposure in 1 or more locations, including 15.5% in the home, 14.7% in a vehicle, 16.8% at school, 27.1% at work, and 35.2% in an indoor/outdoor public area. Home exposure was 8.5%, 55.3%, and 79.4% among never tobacco users with complete, partial, or no smoke-free home rules, respectively (P < .05). Vehicle exposure was 7.1%, 44.8%, and 70.2% among never tobacco users with complete, partial, or no smoke free vehicle rules, respectively (P < .05). Factors associated with higher prevalence ratio of SHS exposure included current tobacco use, truant behavior, and having tobacco using household members/friends CONCLUSIONS: Approximately half of US students in grades 6 through 12 reported exposure to SHS in 2013. Smoke-free home and vehicle rules, coupled with intensified implementation and enforcement of comprehensive smoke-free laws, could help protect youth from this preventable health hazard. PMID- 26755698 TI - Disruption of CXCR4 signaling in pharyngeal neural crest cells causes DiGeorge syndrome-like malformations. AB - DiGeorge syndrome (DGS) is a congenital disease causing cardiac outflow tract anomalies, craniofacial dysmorphogenesis, thymus hypoplasia, and mental disorders. It results from defective development of neural crest cells (NCs) that colonize the pharyngeal arches and contribute to lower jaw, neck and heart tissues. Although TBX1 has been identified as the main gene accounting for the defects observed in human patients and mouse models, the molecular mechanisms underlying DGS etiology are poorly identified. The recent demonstrations that the SDF1/CXCR4 axis is implicated in NC chemotactic guidance and impaired in cortical interneurons of mouse DGS models prompted us to search for genetic interactions between Tbx1, Sdf1 (Cxcl12) and Cxcr4 in pharyngeal NCs and to investigate the effect of altering CXCR4 signaling on the ontogeny of their derivatives, which are affected in DGS. Here, we provide evidence that Cxcr4 and Sdf1 are genetically downstream of Tbx1 during pharyngeal NC development and that reduction of CXCR4 signaling causes misrouting of pharyngeal NCs in chick and dramatic morphological alterations in the mandibular skeleton, thymus and cranial sensory ganglia. Our results therefore support the possibility of a pivotal role for the SDF1/CXCR4 axis in DGS etiology. PMID- 26755700 TI - The LGN protein promotes planar proliferative divisions in the neocortex but apicobasal asymmetric terminal divisions in the retina. AB - Cell division orientation is crucial to control segregation of polarized fate determinants in the daughter cells to produce symmetric or asymmetric fate outcomes. Most studies in vertebrates have focused on the role of mitotic spindle orientation in proliferative asymmetric divisions and it remains unclear whether altering spindle orientation is required for the production of asymmetric fates in differentiative terminal divisions. Here, we show that the GoLoco motif protein LGN, which interacts with Galphai to control apicobasal division orientation in Drosophila neuroblasts, is excluded from the apical domain of retinal progenitors undergoing planar divisions, but not in those undergoing apicobasal divisions. Inactivation of LGN reduces the number of apicobasal divisions in mouse retinal progenitors, whereas it conversely increases these divisions in cortical progenitors. Although LGN inactivation increases the number of progenitors outside the ventricular zone in the developing neocortex, it has no effect on the position or number of progenitors in the retina. Retinal progenitor cell lineage analysis in LGN mutant mice, however, shows an increase in symmetric terminal divisions producing two photoreceptors, at the expense of asymmetric terminal divisions producing a photoreceptor and a bipolar or amacrine cell. Similarly, inactivating Galphai decreases asymmetric terminal divisions, suggesting that LGN function with Galphai to control division orientation in retinal progenitors. Together, these results show a context-dependent function for LGN and indicate that apicobasal divisions are not involved in proliferative asymmetric divisions in the mouse retina, but are instead essential to generate binary fates at terminal divisions. PMID- 26755699 TI - Epithelial stratification and placode invagination are separable functions in early morphogenesis of the molar tooth. AB - Ectodermal organs, which include teeth, hair follicles, mammary ducts, and glands such as sweat, mucous and sebaceous glands, are initiated in development as placodes, which are epithelial thickenings that invaginate and bud into the underlying mesenchyme. These placodes are stratified into a basal and several suprabasal layers of cells. The mechanisms driving stratification and invagination are poorly understood. Using the mouse molar tooth as a model for ectodermal organ morphogenesis, we show here that vertical, stratifying cell divisions are enriched in the forming placode and that stratification is cell division dependent. Using inhibitor and gain-of-function experiments, we show that FGF signalling is necessary and sufficient for stratification but not invagination as such. We show that, instead, Shh signalling is necessary for, and promotes, invagination once suprabasal tissue is generated. Shh-dependent suprabasal cell shape suggests convergent migration and intercalation, potentially accounting for post-stratification placode invagination to bud stage. We present a model in which FGF generates suprabasal tissue by asymmetric cell division, while Shh triggers cell rearrangement in this tissue to drive invagination all the way to bud formation. PMID- 26755701 TI - RNA-Seq identifies SPGs as a ventral skeletal patterning cue in sea urchins. AB - The sea urchin larval skeleton offers a simple model for formation of developmental patterns. The calcium carbonate skeleton is secreted by primary mesenchyme cells (PMCs) in response to largely unknown patterning cues expressed by the ectoderm. To discover novel ectodermal cues, we performed an unbiased RNA Seq-based screen and functionally tested candidates; we thereby identified several novel skeletal patterning cues. Among these, we show that SLC26a2/7 is a ventrally expressed sulfate transporter that promotes a ventral accumulation of sulfated proteoglycans, which is required for ventral PMC positioning and skeletal patterning. We show that the effects of SLC perturbation are mimicked by manipulation of either external sulfate levels or proteoglycan sulfation. These results identify novel skeletal patterning genes and demonstrate that ventral proteoglycan sulfation serves as a positional cue for sea urchin skeletal patterning. PMID- 26755702 TI - Chondrocytic ephrin B2 promotes cartilage destruction by osteoclasts in endochondral ossification. AB - The majority of the skeleton arises by endochondral ossification, whereby cartilaginous templates expand and are resorbed by osteoclasts then replaced by osteoblastic bone formation. Ephrin B2 is a receptor tyrosine kinase expressed by osteoblasts and growth plate chondrocytes that promotes osteoblast differentiation and inhibits osteoclast formation. We investigated the role of ephrin B2 in endochondral ossification using Osx1Cre-targeted gene deletion. Neonatal Osx1Cre.Efnb2(Delta/Delta) mice exhibited a transient osteopetrosis demonstrated by increased trabecular bone volume with a high content of growth plate cartilage remnants and increased cortical thickness, but normal osteoclast numbers within the primary spongiosa. Osteoclasts at the growth plate had an abnormal morphology and expressed low levels of tartrate-resistant acid phosphatase; this was not observed in more mature bone. Electron microscopy revealed a lack of sealing zones and poor attachment of Osx1Cre.Efnb2(Delta/Delta) osteoclasts to growth plate cartilage. Osteoblasts at the growth plate were also poorly attached and impaired in their ability to deposit osteoid. By 6 months of age, trabecular bone mass, osteoclast morphology and osteoid deposition by Osx1Cre.Efnb2(Delta/Delta) osteoblasts were normal. Cultured chondrocytes from Osx1Cre.Efnb2(Delta/Delta) neonates showed impaired support of osteoclastogenesis but no significant change in Rankl (Tnfsf11) levels, whereas Adamts4 levels were significantly reduced. A population of ADAMTS4(+) early hypertrophic chondrocytes seen in controls was absent from Osx1Cre.Efnb2(Delta/Delta) neonates. This suggests that Osx1Cre-expressing cells, including hypertrophic chondrocytes, are dependent on ephrin B2 for their production of cartilage-degrading enzymes, including ADAMTS4, and this might be required for attachment of osteoclasts and osteoblasts to the cartilage surface during endochondral ossification. PMID- 26755703 TI - Differences in the spatiotemporal expression and epistatic gene regulation of the mesodiencephalic dopaminergic precursor marker PITX3 during chicken and mouse development. AB - Mesodiencephalic dopaminergic (mdDA) neurons are located in the ventral mesencephalon and caudal diencephalon of all tetrapod species studied so far. They are the most prominent DA neuronal population and are implicated in control and modulation of motor, cognitive and rewarding/affective behaviors. Their degeneration or dysfunction is intimately linked to several neurological and neuropsychiatric human diseases. To gain further insights into their generation, we studied spatiotemporal expression patterns and epistatic interactions in chick embryos of selected marker genes and signaling pathways associated with mdDA neuron development in mouse. We detected striking differences in the expression patterns of the chick orthologs of the mouse mdDA marker genes Pitx3 and Aldh1a1, which suggests important differences between the species in the generation/generating of these cells. We also discovered that the sonic hedgehog signaling pathway is both necessary and sufficient for the induction of ectopic PITX3 expression in chick mesencephalon downstream of WNT9A-induced LMX1a transcription. These aspects of early chicken development resemble the ontogeny of zebrafish diencephalic DA neuronal populations, and suggest a divergence between birds and mammals during evolution. PMID- 26755704 TI - IL-33 amplifies an innate immune response in the degenerating retina. AB - Age-related macular degeneration (AMD), a leading cause of vision impairment in the ageing population, is characterized by irreversible loss of retinal pigment epithelial (RPE) cells and photoreceptors and can be associated with choroidal neovascularization. Mononuclear phagocytes are often present in AMD lesions, but the processes that direct myeloid cell recruitment remain unclear. Here, we identify IL-33 as a key regulator of inflammation and photoreceptor degeneration after retina stress or injury. IL-33(+) Muller cells were more abundant and IL-33 cytokine was elevated in advanced AMD cases compared with age-matched controls with no AMD. In rodents, retina stress resulted in release of bioactive IL-33 that in turn increased inflammatory chemokine and cytokine expression in activated Muller cells. Deletion of ST2, the IL-33 receptor alpha chain, or treatment with a soluble IL-33 decoy receptor significantly reduced release of inflammatory mediators from Muller cells, inhibited accumulation of mononuclear phagocytes in the outer retina, and protected photoreceptor rods and cones after a retina insult. This study demonstrates a central role for IL-33 in regulating mononuclear phagocyte recruitment to the photoreceptor layer and positions IL-33 signaling as a potential therapeutic target in macular degenerative diseases. PMID- 26755705 TI - Identification of CD112R as a novel checkpoint for human T cells. AB - T cell immunoglobulin and ITIM domain (TIGIT) and CD226 emerge as a novel T cell cosignaling pathway in which CD226 and TIGIT serve as costimulatory and coinhibitory receptors, respectively, for the ligands CD155 and CD112. In this study, we describe CD112R, a member of poliovirus receptor-like proteins, as a new coinhibitory receptor for human T cells. CD112R is preferentially expressed on T cells and inhibits T cell receptor-mediated signals. We further identify that CD112, widely expressed on antigen-presenting cells and tumor cells, is the ligand for CD112R with high affinity. CD112R competes with CD226 to bind to CD112. Disrupting the CD112R-CD112 interaction enhances human T cell response. Our experiments identify CD112R as a novel checkpoint for human T cells via interaction with CD112. PMID- 26755706 TI - Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide. AB - Type I interferon (IFN) is crucial in host antiviral defense. Previous studies have described the pleiotropic role of type I IFNs on innate and adaptive immune cells during viral infection. Here, we demonstrate that natural killer (NK) cells from mice lacking the type I IFN-alpha receptor (Ifnar(-/-)) or STAT1 (which signals downstream of IFNAR) are defective in expansion and memory cell formation after mouse cytomegalovirus (MCMV) infection. Despite comparable proliferation, Ifnar(-/-) NK cells showed diminished protection against MCMV infection and exhibited more apoptosis compared with wild-type NK cells. Furthermore, we show that Ifnar(-/-) NK cells express increased levels of NK group 2 member D (NKG2D) ligands during viral infection and are susceptible to NK cell-mediated fratricide in a perforin- and NKG2D-dependent manner. Adoptive transfer of Ifnar(-/-) NK cells into NK cell-deficient mice reverses the defect in survival and expansion. Our study reveals a novel type I IFN-dependent mechanism by which NK cells evade mechanisms of cell death after viral infection. PMID- 26755707 TI - Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice. AB - Hepcidin, the main regulator of iron homeostasis, is repressed when erythropoiesis is acutely stimulated by erythropoietin (EPO) to favor iron supply to maturing erythroblasts. Erythroferrone (ERFE) has been identified as the erythroid regulator that inhibits hepcidin in stress erythropoiesis. A powerful hepcidin inhibitor is the serine protease matriptase-2, encoded by TMPRSS6, whose mutations cause iron refractory iron deficiency anemia. Because this condition has inappropriately elevated hepcidin in the presence of high EPO levels, a role is suggested for matriptase-2 in EPO-mediated hepcidin repression. To investigate the relationship between EPO/ERFE and matriptase-2, we show that EPO injection induces Erfe messenger RNA expression but does not suppress hepcidin in Tmprss6 knockout (KO) mice. Similarly, wild-type (WT) animals, in which the bone morphogenetic protein-mothers against decapentaplegic homolog (Bmp-Smad) pathway is upregulated by iron treatment, fail to suppress hepcidin in response to EPO. To further investigate whether the high level of Bmp-Smad signaling of Tmprss6 KO mice counteracts hepcidin suppression by EPO, we generated double KO Bmp6-Tmprss6 KO mice. Despite having Bmp-Smad signaling and hepcidin levels that are similar to WT mice under basal conditions, double KO mice do not suppress hepcidin in response to EPO. However, pharmacologic downstream inhibition of the Bmp-Smad pathway by dorsomorphin, which targets the BMP receptors, improves the hepcidin responsiveness to EPO in Tmprss6 KO mice. We concluded that the function of matriptase-2 is dominant over that of ERFE and is essential in facilitating hepcidin suppression by attenuating the BMP-SMAD signaling. PMID- 26755708 TI - What is going on between defibrotide and endothelial cells? Snapshots reveal the hot spots of their romance. AB - Defibrotide (DF) has received European Medicines Agency authorization to treat sinusoidal obstruction syndrome, an early complication after hematopoietic cell transplantation. DF has a recognized role as an endothelial protective agent, although its precise mechanism of action remains to be elucidated. The aim of the present study was to investigate the interaction of DF with endothelial cells (ECs). A human hepatic EC line was exposed to different DF concentrations, previously labeled. Using inhibitory assays and flow cytometry techniques along with confocal microscopy, we explored: DF-EC interaction, endocytic pathways, and internalization kinetics. Moreover, we evaluated the potential role of adenosine receptors in DF-EC interaction and if DF effects on endothelium were dependent of its internalization. Confocal microscopy showed interaction of DF with EC membranes followed by internalization, though DF did not reach the cell nucleus even after 24 hours. Flow cytometry revealed concentration, temperature, and time dependent uptake of DF in 2 EC models but not in other cell types. Moreover, inhibitory assays indicated that entrance of DF into ECs occurs primarily through macropinocytosis. Our experimental approach did not show any evidence of the involvement of adenosine receptors in DF-EC interaction. The antiinflammatory and antioxidant properties of DF seem to be caused by the interaction of the drug with the cell membrane. Our findings contribute to a better understanding of the precise mechanisms of action of DF as a therapeutic and potential preventive agent on the endothelial damage underlying different pathologic situations. PMID- 26755709 TI - Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. AB - Few patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) achieve prolonged disease-free survival. Blinatumomab, a bispecific T-cell engaging antibody construct, transiently links CD3-positive T cells to CD19 positive B cells. This phase 2 study evaluated stepwise (9-28-112 MUg/d with weekly dose increases; n = 23) or flat (112 MUg/d; n = 2) dosing of blinatumomab by continuous infusion, with dexamethasone prophylaxis, in patients with relapsed/refractory DLBCL. Patients received a median of 3 prior lines of therapy. Median time since last regimen was 1.5 months. Seventeen patients ended treatment in cycle 1 (induction), 7 in cycle 2 (consolidation), and 1 in retreatment. Among 21 evaluable patients, the overall response rate after 1 blinatumomab cycle was 43%, including complete responses (CRs) in 19%. Three patients had late CR in follow-up without other treatment. The most common adverse events with stepwise dosing were tremor (48%), pyrexia (44%), fatigue (26%), and edema (26%). Grade 3 neurologic events with stepwise dosing were encephalopathy and aphasia (each 9%) and tremor, speech disorder, dizziness, somnolence, and disorientation (each 4%). Of 5 (22%) patients who discontinued stepwise dosing because of adverse events, 4 (17%) had neurologic events. Most neurologic events resolved. The flat-dose cohort was stopped because of grade 3 neurologic events in both patients. Blinatumomab monotherapy appears effective in patients with relapsed/refractory DLBCL, a heavily pretreated patient population with a high unmet medical need. Further studies need to define the optimal approach to achieve the target dose without early dropout. The study was registered at www.clinicaltrials.gov as #NCT01741792. PMID- 26755710 TI - Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. AB - A global phase 3 study evaluated the pharmacokinetics, efficacy, and safety of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in 63 previously treated male patients (12-61 years) with severe hemophilia B (factor IX [FIX] activity <=2%). The study included 2 groups: group 1 patients received routine prophylaxis once every 7 days for 26 weeks, followed by either 7 , 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively; group 2 patients received on-demand treatment of bleeding episodes for 26 weeks and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks. The mean terminal half-life of rIX-FP was 102 hours, 4.3-fold longer than previous FIX treatment. Patients maintained a mean trough of 20 and 12 IU/dL FIX activity on prophylaxis with rIX-FP 40 IU/kg weekly and 75 IU/kg every 2 weeks, respectively. There was 100% reduction in median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on demand to prophylaxis treatment with rIX-FP (P< .0001). The median AsBR was 0.00 for all prophylaxis regimens. Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection. No patient developed an inhibitor, and no safety concerns were identified. These results indicate rIX-FP is safe and effective for preventing and treating bleeding episodes in patients with hemophilia B at dosing regimens of 40 IU/kg weekly and 75 IU/kg every 2 weeks. This trial was registered at www.clinicaltrials.gov as #NCT0101496274. PMID- 26755711 TI - Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance. AB - Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) is associated with inferior survival in multiple myeloma (MM). Thus, characterization of the minor MRD subclone may represent a unique model to understand chemoresistance, but to our knowledge, the phenotypic and genetic features of the MRD subclone have never been investigated. Here, we compared the antigenic profile of MRD vs diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study and showed that the MRD subclone is enriched in cells overexpressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4), and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs diagnostic PCs was performed in 12 patients; 3 of them showed identical copy number alterations (CNAs), in another 3 cases, MRD clonal PCs displayed all genetic alterations detected at diagnosis plus additional CNAs that emerged at the MRD stage, whereas in the remaining 6 patients, there were CNAs present at diagnosis that were undetectable in MRD clonal PCs, but also a selected number of genetic alterations that became apparent only at the MRD stage. The MRD subclone showed significant downregulation of genes related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and may identify chemoresistant PCs in vitro. Altogether, our results suggest that therapy-induced clonal selection could be already present at the MRD stage, where chemoresistant PCs show a singular phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles. This trial was registered atwww.clinicaltrials.gov as #NCT01237249. PMID- 26755715 TI - Arias-Stella Reaction in Progestin-Treated Endometrioid Adenocarcinoma: A Potential Diagnostic Pitfall. PMID- 26755714 TI - Composite Mucoepidermoid Carcinoma and Columnar Cell Variant of Papillary Carcinoma of the Thyroid: A Case Report and Review of the Literature. AB - Primary mucoepidermoid carcinoma (MEC) of the thyroid and columnar cell variant of papillary carcinoma of the thyroid (PCT) are uncommon neoplasms. We report the first case of composite MEC and columnar cell variant of PCT. An 86-year-old man consulted for a 47-mm thyroid nodule, cytologically compatible with PCT. Total thyroidectomy was performed. Histological diagnosis, with support of histochemistry and immunohistochemistry, was mixed primary carcinoma of the thyroid, associating an MEC component with predominantly columnar cell variant of PCT. Sixteen months after surgery and external beam radiation therapy, the patient was free of recurrence or distant metastasis. This case report offers an opportunity to highlight the potential pitfalls concerning the interpretation of mucin histochemistry in thyroid tumors. PMID- 26755712 TI - Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups. AB - The initial report of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group trial E1900 (#NCT00049517) showed that induction therapy with high-dose (HD) daunorubicin (90 mg/m(2)) improved overall survival in adults <60 years old with acute myeloid leukemia (AML); however, at initial analysis, the benefit was restricted to younger patients (<50 years) and patients without unfavorable cytogenetics or aFLT3-ITD mutation. Here, we update the results of E1900 after longer follow-up (median, 80.1 months among survivors), focusing on the benefit of HD daunorubicin on common genetic subgroups. Compared with standard-dose daunorubicin (45 mg/m(2)), HD daunorubicin is associated with a hazard ratio (HR) for death of 0.74 (P= .001). Younger patients (<50 years) benefited from HD daunorubicin (HR, 0.66;P= .002), as did patients with favorable and intermediate cytogenetics (HR, 0.51;P= .03 and HR, 0.68;P= .01, respectively). Patients with unfavorable cytogenetics were shown to benefit from HD daunorubicin on multivariable analysis (adjusted HR, 0.66;P= .04). Patients with FLT3-ITD (24%),DNMT3A(24%), and NPM1(26%) mutant AML all benefited from HD daunorubicin (HR, 0.61,P= .009; HR, 0.62,P= .02; and HR, 0.50,P= .002; respectively). HD benefit was seen in the subgroup of older patients (50-60 years) with the FLT3-ITD or NPM1 mutation. Additionally, the presence of an NPM1 mutation confers a favorable prognosis only for patients receiving anthracycline dose intensification during induction. PMID- 26755716 TI - Control or overcontrol for covariates? AB - Covariate adjustment can adjust for baseline differences in randomised controlled trials (RCTs) that may have arisen by chance. Furthermore, even if the groups do not differ significantly on any factors, using baseline variables that may be related to the outcome as covariates can reduce the within-group variance, thus increasing the accuracy of the estimates of treatment effects and the power of the statistical test. However, improper use of covariate adjustment can either magnify or diminish the difference between the groups. In RCTs, covariates must be chosen carefully and should not include variables that may have been affected by the treatment itself. The use of covariate adjustment in cohort studies is even more fraught and may result in paradoxical situations, in which there can be opposite interpretations of the results. PMID- 26755717 TI - Targeting social and non-social cognition to improve cognitive remediation outcomes in schizophrenia. PMID- 26755713 TI - Lysyl oxidase is associated with increased thrombosis and platelet reactivity. AB - Lysyl oxidase (LOX) is overexpressed in various pathologies associated with thrombosis, such as arterial stenosis and myeloproliferative neoplasms (MPNs). LOX is elevated in the megakaryocytic lineage of mouse models of MPNs and in patients with MPNs. To gain insight into the role of LOX in thrombosis and platelet function without compounding the influences of other pathologies, transgenic mice expressing LOX in wild-type megakaryocytes and platelets (Pf4 Lox(tg/tg)) were generated. Pf4-Lox(tg/tg) mice had a normal number of platelets; however, time to vessel occlusion after endothelial injury was significantly shorter in Pf4-Lox(tg/tg) mice, indicating a higher propensity for thrombus formation in vivo. Exploring underlying mechanisms, we found that Pf4-Lox(tg/tg) platelets adhere better to collagen and have greater aggregation response to lower doses of collagen compared with controls. Platelet activation in response to the ligand for collagen receptor glycoprotein VI (cross-linked collagen related peptide) was unaffected. However, the higher affinity of Pf4-Lox(tg/tg) platelets to the collagen sequence GFOGER implies that the collagen receptor integrin alpha2beta1 is affected by LOX. Taken together, our findings demonstrate that LOX enhances platelet activation and thrombosis. PMID- 26755718 TI - Tolerable Levels of Nonclinical Vehicles and Formulations Used in Studies by Multiple Routes in Multiple Species With Notes on Methods to Improve Utility. AB - Formulation of nonclinical evaluations is a challenge, with the fundamental need to achieve multiples of the clinical exposure complicated by differences in species and routes of administration-specific tolerances, depending on concentrations, volumes, dosing regimen, duration of each administration, and study duration. Current practice to approach these differences is based on individual experience and scattered literature with no comprehensive data source (the most notable exception being our 2006 publication on this same subject). Lack of formulation tolerance data results in excessive animal use, unplanned delays in the evaluation and development of drugs, and vehicle-dependent results. A consulting firm, a chemical company, and 4 contract research organizations conducted a rigorous data mining operation of vehicle data from studies dating from 1991 to 2015, enhancing the data from this author's 2006 publication (3 of the six 2015 contributors were also 2006 contributors). Additional data were found in the published literature. The results identified 108 single-component vehicles (and 305 combination formulations) used in more than 1,040 studies across multiple species (dog, primate, rat, mouse, rabbit, guinea pig, minipig, pig, chick embryo, and cat) by multiple routes for a wide range of study durations. The tabulated data include maximum tolerated use levels by species, route, duration of study, dose-limiting toxicity where reported, review of the available literature on each vehicle, guidance on syringe selection, volume and pH limits by route with basic guidance on nonclinical formulation development, and guidance on factors to be considered in nonclinical route selection. PMID- 26755719 TI - Retinoblastoma survivors face raised risk of serious health problems, study finds. PMID- 26755720 TI - Structure of the Regulator of G Protein Signaling 8 (RGS8)-Galphaq Complex: MOLECULAR BASIS FOR Galpha SELECTIVITY. AB - Regulator of G protein signaling (RGS) proteins interact with activated Galpha subunits via their RGS domains and accelerate the hydrolysis of GTP. Although the R4 subfamily of RGS proteins generally accepts both Galphai/o and Galphaq/11 subunits as substrates, the R7 and R12 subfamilies select against Galphaq/11. In contrast, only one RGS protein, RGS2, is known to be selective for Galphaq/11. The molecular basis for this selectivity is not clear. Previously, the crystal structure of RGS2 in complex with Galphaq revealed a non-canonical interaction that could be due to interfacial differences imposed by RGS2, the Galpha subunit, or both. To resolve this ambiguity, the 2.6 A crystal structure of RGS8, an R4 subfamily member, was determined in complex with Galphaq. RGS8 adopts the same pose on Galphaq as it does when bound to Galphai3, indicating that the non canonical interaction of RGS2 with Galphaq is due to unique features of RGS2. Based on the RGS8-Galphaq structure, residues in RGS8 that contact a unique alpha helical domain loop of Galphaq were converted to those typically found in R12 subfamily members, and the reverse substitutions were introduced into RGS10, an R12 subfamily member. Although these substitutions perturbed their ability to stimulate GTP hydrolysis, they did not reverse selectivity. Instead, selectivity for Galphaq seems more likely determined by whether strong contacts can be maintained between alpha6 of the RGS domain and Switch III of Galphaq, regions of high sequence and conformational diversity in both protein families. PMID- 26755722 TI - Direct Interaction between the Voltage Sensors Produces Cooperative Sustained Deactivation in Voltage-gated H+ Channel Dimers. AB - The voltage-gated H(+) channel (Hv) is a voltage sensor domain-like protein consisting of four transmembrane segments (S1-S4). The native Hv structure is a homodimer, with the two channel subunits functioning cooperatively. Here we show that the two voltage sensor S4 helices within the dimer directly cooperate via a pi-stacking interaction between Trp residues at the middle of each segment. Scanning mutagenesis showed that Trp situated around the original position provides the slow gating kinetics characteristic of the dimer's cooperativity. Analyses of the Trp mutation on the dimeric and monomeric channel backgrounds and analyses with tandem channel constructs suggested that the two Trp residues within the dimer are functionally coupled during Hv deactivation but are less so during activation. Molecular dynamics simulation also showed direct pi-stacking of the two Trp residues. These results provide new insight into the cooperative function of voltage-gated channels, where adjacent voltage sensor helices make direct physical contact and work as a single unit according to the gating process. PMID- 26755721 TI - Unique Regulatory Properties of Heterotetrameric Inositol 1,4,5-Trisphosphate Receptors Revealed by Studying Concatenated Receptor Constructs. AB - The ability of inositol 1,4,5-trisphosphate receptors (IP3R) to precisely initiate and generate a diverse variety of intracellular Ca(2+) signals is in part mediated by the differential regulation of the three subtypes (R1, R2, and R3) by key functional modulators (IP3, Ca(2+), and ATP). However, the contribution of IP3R heterotetramerization to Ca(2+) signal diversity has largely been unexplored. In this report, we provide the first definitive biochemical evidence of endogenous heterotetramer formation. Additionally, we examine the contribution of individual subtypes within defined concatenated heterotetramers to the shaping of Ca(2+) signals. Under conditions where key regulators of IP3R function are optimal for Ca(2+) release, we demonstrate that individual monomers within heteromeric IP3Rs contributed equally toward generating a distinct 'blended' sensitivity to IP3 that is likely dictated by the unique IP3 binding affinity of the heteromers. However, under suboptimal conditions where [ATP] were varied, we found that one subtype dictated the ATP regulatory properties of heteromers. We show that R2 monomers within a heterotetramer were both necessary and sufficient to dictate the ATP regulatory properties. Finally, the ATP-binding site B in R2 critical for ATP regulation was mutated and rendered non-functional to address questions relating to the stoichiometry of IP3R regulation. Two intact R2 monomers were sufficient to maintain ATP regulation in R2 homotetramers. In summary, we demonstrate that heterotetrameric IP3R do not necessarily behave as the sum of the constituent subunits, and these properties likely extend the versatility of IP3-induced Ca(2+) signaling in cells expressing multiple IP3R isoforms. PMID- 26755723 TI - Identification of the Gene Encoding Isoprimeverose-producing Oligoxyloglucan Hydrolase in Aspergillus oryzae. AB - Aspergillus oryzae produces a unique beta-glucosidase, isoprimeverose-producing oligoxyloglucan hydrolase (IPase), that recognizes and releases isoprimeverose (alpha-D-xylopyranose-(1 -> 6)-D-glucopyranose) units from the non-reducing ends of oligoxyloglucans. A gene encoding A. oryzae IPase, termed ipeA, was identified and expressed in Pichia pastoris. With the exception of cellobiose, IpeA hydrolyzes a variety of oligoxyloglucans and is a member of the glycoside hydrolase family 3. Xylopyranosyl branching at the non-reducing ends was vital for IPase activity, and galactosylation at a alpha-1,6-linked xylopyranosyl side chain completely abolished IpeA activity. Hepta-oligoxyloglucan saccharide (Xyl3Glc4) substrate was preferred over tri- (Xyl1Glc2) and tetra- (Xyl2Glc2) oligoxyloglucan saccharides substrates. IpeA transferred isoprimeverose units to other saccharides, indicating transglycosylation activity. The ipeA gene was expressed in xylose and xyloglucan media and was strongly induced in the presence of xyloglucan endo-xyloglucanase-hydrolyzed products. This is the first study to report the identification of a gene encoding IPase in eukaryotes. PMID- 26755724 TI - Regulatory Characteristics of Vibrio vulnificus gbpA Gene Encoding a Mucin binding Protein Essential for Pathogenesis. AB - Binding to mucin is the initial step for enteropathogens to establish pathogenesis. An open reading frame, gbpA, of Vibrio vulnificus was identified and characterized in this study. Compared with wild type, the gbpA mutant was impaired in binding to mucin-agar and the mucin-secreting HT29-methotrexate cells, and the impaired mucin binding was restored by the purified GbpA provided exogenously. The gbpA mutant had attenuated virulence and ability of intestinal colonization in a mouse model, indicating that GbpA is a mucin-binding protein and essential for pathogenesis of V. vulnificus. The gbpA transcription was growth phase-dependent, reaching a maximum during the exponential phase. The Fe-S cluster regulator (IscR) and the cyclic AMP receptor protein (CRP) coactivated, whereas SmcR, a LuxR homologue, repressed gbpA. The cellular levels of IscR, CRP, and SmcR were not significantly affected by one another, indicating that the regulator proteins function cooperatively to regulate gbpA rather than sequentially in a regulatory cascade. The regulatory proteins directly bind upstream of the gbpA promoter PgbpA. DNase I protection assays, together with the deletion analyses of PgbpA, demonstrated that IscR binds to two specific sequences centered at -164.5 and -106, and CRP and SmcR bind specifically to the sequences centered at -68 and -45, respectively. Furthermore, gbpA was induced by exposure to H2O2, and the induction appeared to be mediated by elevated intracellular levels of IscR. Consequently, the combined results indicated that IscR, CRP, and SmcR cooperate for precise regulation of gbpA during the V. vulnificus pathogenesis. PMID- 26755726 TI - Regulation of Transient Site-specific Copy Gain by MicroRNA. AB - Intra-tumor copy number heterogeneity is commonly observed in cancer; however, the molecular mechanisms that contribute to heterogeneity remain poorly understood. Up-regulation of the histone demethylase KDM4A promotes transient site-specific copy gain (TSSG) in cells; therefore, uncovering how KDM4A levels are controlled is important for understanding the regulation of copy number heterogeneity. Here, we demonstrate that KDM4A is regulated by hsa-mir-23a-3p, hsa-mir-23b-3p, and hsa-mir-137. Altering expression of these microRNAs (miRNAs) regulates KDM4A-dependent TSSG. miRNA inhibition promoted copy gains and increased expression of the drug-resistant oncogene CKS1B, which was further substantiated in primary breast tumors. Consistent with increased CKS1B expression, miRNA inhibition reduced breast cancer cell sensitivity to cisplatin. Our data identify these miRNAs as regulators of TSSG and copy gains of a drug resistance gene. PMID- 26755725 TI - The Rab-binding Profiles of Bacterial Virulence Factors during Infection. AB - Legionella pneumophila, the causative agent of Legionnaire's disease, uses its type IV secretion system to translocate over 300 effector proteins into host cells. These effectors subvert host cell signaling pathways to ensure bacterial proliferation. Despite their importance for pathogenesis, the roles of most of the effectors are yet to be characterized. Key to understanding the function of effectors is the identification of host proteins they bind during infection. We previously developed a novel tandem-affinity purification (TAP) approach using hexahistidine and BirA-specific biotinylation tags for isolating translocated effector complexes from infected cells whose composition were subsequently deciphered by mass spectrometry. Here we further advanced the workflow for the TAP approach and determined the infection-dependent interactomes of the effectors SidM and LidA, which were previously reported to promiscuously bind multiple Rab GTPases in vitro. In this study we defined a stringent subset of Rab GTPases targeted by SidM and LidA during infection, comprising of Rab1A, 1B, 6, and 10; in addition, LidA targets Rab14 and 18. Taken together, this study illustrates the power of this approach to profile the intracellular interactomes of bacterial effectors during infection. PMID- 26755727 TI - The N-terminal Acetyltransferase Naa10/ARD1 Does Not Acetylate Lysine Residues. AB - The N-terminal acetyltransferase NatA is a heterodimeric complex consisting of a catalytic subunit (Naa10/ARD1) and an auxiliary subunit (Naa15). NatA co translationally acetylates the N termini of a wide variety of nascent polypeptides. In addition, Naa10 can act independently to posttranslationally acetylate a distinct set of substrates, notably actin. Recent structural studies of Naa10 have also revealed the molecular basis for N-terminal acetylation specificity. Surprisingly, recent reports claim that Naa10 may also acetylate lysine residues of diverse targets, including methionine sulfoxide reductase A, myosin light chain kinase, and Runt-related transcription factor 2. Here we used recombinant proteins to reconstitute and assess lysine acetylation events catalyzed by Naa10 in vitro. We show that there is no difference in lysine acetylation of substrate proteins with or without Naa10, suggesting that the substrates may be acetylated chemically rather than enzymatically. Together, our data argue against a role for Naa10 in lysine acetylation. PMID- 26755729 TI - Structures of Xenopus Embryonic Epidermal Lectin Reveal a Conserved Mechanism of Microbial Glycan Recognition. AB - Intelectins (X-type lectins), broadly distributed throughout chordates, have been implicated in innate immunity. Xenopus laevis embryonic epidermal lectin (XEEL), an intelectin secreted into environmental water by the X. laevis embryo, is postulated to function as a defense against microbes. XEEL is homologous (64% identical) to human intelectin-1 (hIntL-1), which is also implicated in innate immune defense. We showed previously that hIntL-1 binds microbial glycans bearing exocyclic vicinal diol groups. It is unknown whether XEEL has the same ligand specificity. Also unclear is whether XEEL and hIntL-1 have similar quaternary structures, as XEEL lacks the corresponding cysteine residues in hIntL-1 that stabilize the disulfide-linked trimer. These observations prompted us to further characterize XEEL. We found that hIntL-1 and XEEL have similar structural features. Even without the corresponding intermolecular disulfide bonds present in hIntL-1, the carbohydrate recognition domain of XEEL (XEELCRD) forms a stable trimer in solution. The structure of XEELCRD in complex with d-glycerol-1 phosphate, a residue present in microbe-specific glycans, indicated that the exocyclic vicinal diol coordinates to a protein-bound calcium ion. This ligand binding mode is conserved between XEEL and hIntL-1. The domain architecture of full-length XEEL is reminiscent of a barbell, with two sets of three glycan binding sites oriented in opposite directions. This orientation is consistent with our observation that XEEL can promote the agglutination of specific serotypes of Streptococcus pneumoniae. These data support a role for XEEL in innate immunity, and they highlight structural and functional conservation of X type lectins among chordates. PMID- 26755730 TI - The Quaternary Structure of a Glycoside Hydrolase Dictates Specificity toward beta-Glucans. AB - In the Carbohydrate-Active Enzyme (CAZy) database, glycoside hydrolase family 5 (GH5) is a large family with more than 6,000 sequences. Among the 51 described GH5 subfamilies, subfamily GH5_26 contains members that display either endo beta(1,4)-glucanase or beta(1,3;1,4)-glucanase activities. In this study, we focused on the GH5_26 enzyme fromSaccharophagus degradans(SdGluc5_26A), a marine bacterium known for its capacity to degrade a wide diversity of complex polysaccharides.SdGluc5_26A displays lichenase activity toward beta(1,3;1,4) glucans with a side cellobiohydrolase activity toward beta(1,4)-glucans. The three-dimensional structure ofSdGluc5_26A adopts a stable trimeric quaternary structure also observable in solution. The N-terminal region ofSdGluc5_26A protrudes into the active site of an adjacent monomer. To understand whether this occupation of the active site could influence its activity, we conducted a comprehensive enzymatic characterization ofSdGluc5_26A and of a mutant truncated at the N terminus. Ligand complex structures and kinetic analyses reveal that the N terminus governs the substrate specificity ofSdGluc5_26A. Its deletion opens the enzyme cleft at the -3 subsite and turns the enzyme into an endo-beta(1,4) glucanase. This study demonstrates that experimental approaches can reveal structure-function relationships out of reach of current bioinformatic predictions. PMID- 26755731 TI - The Nutrient and Energy Sensor Sirt1 Regulates the Hypothalamic-Pituitary-Adrenal (HPA) Axis by Altering the Production of the Prohormone Convertase 2 (PC2) Essential in the Maturation of Corticotropin-releasing Hormone (CRH) from Its Prohormone in Male Rats. AB - Understanding the role of hypothalamic neuropeptides and hormones in energy balance is paramount in the search for approaches to mitigate the obese state. Increased hypothalamic-pituitary-adrenal axis activity leads to increased levels of glucocorticoids (GC) that are known to regulate body weight. The axis initiates the production and release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus (PVN) of the hypothalamus. Levels of active CRH peptide are dependent on the processing of its precursor pro-CRH by the action of two members of the family of prohormone convertases 1 and 2 (PC1 and PC2). Here, we propose that the nutrient sensor sirtuin 1 (Sirt1) regulates the production of CRH post-translationally by affecting PC2. Data suggest that Sirt1 may alter the preproPC2 gene directly or via deacetylation of the transcription factor Forkhead box protein O1 (FoxO1). Data also suggest that Sirt1 may alter PC2 via a post translational mechanism. Our results show that Sirt1 levels in the PVN increase in rats fed a high fat diet for 12 weeks. Furthermore, elevated Sirt1 increased PC2 levels, which in turn increased the production of active CRH and GC. Collectively, this study provides the first evidence supporting the hypothesis that PVN Sirt1 activates the hypothalamic-pituitary-adrenal axis and basal GC levels by enhancing the production of CRH through an increase in the biosynthesis of PC2, which is essential in the maturation of CRH from its prohormone, pro-CRH. PMID- 26755733 TI - Anti-Tumour Necrosis Factor alpha Therapies and Inflammatory Bowel Disease Pregnancy Outcomes: A Meta-analysis. AB - BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) commonly affects women during their reproductive years, leading to concerns regarding pregnancy outcomes and therapeutic safety. The aim of this study was to assess the risks associated with anti-tumour necrosis factor alpha (anti-TNFalpha) therapy for pregnancy outcomes, including rates of congenital abnormality, based on published studies. METHODS: Published studies were screened from on-line databases and international meeting abstracts. A meta-analysis was performed for adverse pregnancy outcomes (APOs), congenital abnormalities (CAs), preterm birth (PTB) and low birth weight (LBW). The prevalence of CAs was compared with whole-population pooled registry data. RESULTS: In women exposed to anti-TNFalpha the pooled odds ratio for APOs was 1.14 (95% confidence interval [CI] 0.73-1.78; p = 0.55) compared with disease matched controls. The pooled odds ratios for CAs, PTB and LBW were 0.89 (0.37 2.13; p = 0.79), 1.21 (0.74-2.00; p = 0.45) and 1.36 (0.77-2.38; p = 0.29) respectively. The rate of CAs in TNFalpha-exposed women was not statistically different from that in population-wide registries (difference 0.4%, 95% CI -2.0 to +2.7). CONCLUSIONS: Anti-TNFalpha therapy does not increase the risk of APOs, CAs, PTB or LBW compared with disease-matched controls. Furthermore, the risk of CAs is not increased when published prevalence data are compared with data for the general population. These findings may offer some reassurance for women and physicians regarding the safety profile of anti-TNFalpha during pregnancy in IBD. PMID- 26755734 TI - Organ transplantation may link to deaths from cancer, study finds. PMID- 26755728 TI - gamma-Secretase Activity Is Required for Regulated Intramembrane Proteolysis of Tumor Necrosis Factor (TNF) Receptor 1 and TNF-mediated Pro-apoptotic Signaling. AB - The gamma-secretase protease and associated regulated intramembrane proteolysis play an important role in controlling receptor-mediated intracellular signaling events, which have a central role in Alzheimer disease, cancer progression, and immune surveillance. An increasing number of gamma-secretase substrates have a role in cytokine signaling, including the IL-6 receptor, IL-1 receptor type I, and IL-1 receptor type II. In this study, we show that following TNF-converting enzyme-mediated ectodomain shedding of TNF type I receptor (TNFR1), the membrane bound TNFR1 C-terminal fragment is subsequently cleaved by gamma-secretase to generate a cytosolic TNFR1 intracellular domain. We also show that clathrin mediated internalization of TNFR1 C-terminal fragment is a prerequisite for efficient gamma-secretase cleavage of TNFR1. Furthermore, using in vitro and in vivo model systems, we show that in the absence of presenilin expression and gamma-secretase activity, TNF-mediated JNK activation was prevented, assembly of the TNFR1 pro-apoptotic complex II was reduced, and TNF-induced apoptosis was inhibited. These observations demonstrate that TNFR1 is a gamma-secretase substrate and suggest that gamma-secretase cleavage of TNFR1 represents a new layer of regulation that links the presenilins and the gamma-secretase protease to pro-inflammatory cytokine signaling. PMID- 26755732 TI - Mechanistic Target of Rapamycin Complex 1 (mTORC1) and mTORC2 as Key Signaling Intermediates in Mesenchymal Cell Activation. AB - Fibrotic diseases display mesenchymal cell (MC) activation with pathologic deposition of matrix proteins such as collagen. Here we investigate the role of mTOR complex 1 (mTORC1) and mTORC2 in regulating MC collagen expression, a hallmark of fibrotic disease. Relative to normal MCs (non-Fib MCs), MCs derived from fibrotic human lung allografts (Fib-MCs) demonstrated increased phosphoinositide-3kinase (PI3K) dependent activation of both mTORC1 and mTORC2, as measured by increased phosphorylation of S6K1 and 4E-BP1 (mTORC1 substrates) and AKT (an mTORC2 substrate). Dual ATP-competitive TORC1/2 inhibitor AZD8055, in contrast to allosteric mTORC1-specific inhibitor rapamycin, strongly inhibited 4E BP1 phosphorylation and collagen I expression in Fib-MCs. In non-Fib MCs, increased mTORC1 signaling was shown to augment collagen I expression. mTORC1/4E BP1 pathway was identified as an important driver of collagen I expression in Fib MCs in experiments utilizing raptor gene silencing and overexpression of dominant inhibitory 4E-BP1. Furthermore, siRNA-mediated knockdown of rictor, an mTORC2 partner protein, reduced mTORC1 substrate phosphorylation and collagen expression in Fib-, but not non-Fib MCs, revealing a dependence of mTORC1 signaling on mTORC2 function in activated MCs. Together these studies suggest a novel paradigm where fibrotic activation in MCs increases PI3K dependent mTORC1 and mTORC2 signaling and leads to increased collagen I expression via the mTORC1-dependent 4E-BP1/eIF4E pathway. These data provide rationale for targeting specific components of mTORC pathways in fibrotic states and underscore the need to further delineate mTORC2 signaling in activated cell states. PMID- 26755735 TI - Plasma cell-free mitochondrial DNA declines in response to prolonged moderate aerobic exercise. AB - Increased plasma cell-free mitochondrial DNA (cf-mDNA), a damage-associated molecular pattern (DAMP) produced by cellular injury, contributes to neutrophil activation/inflammation in trauma patients and arises in cancer and autoimmunity. To further understand relationships between cf-mDNA released by tissue injury, inflammation, and health benefits of exercise, we examined cf-mDNA response to prolonged moderate aerobic exercise. Seven healthy moderately trained young men (age = 22.4 +/- 1.2) completed a treadmill exercise trial for 90 min at 60% VO2 max and a resting control trial. Blood was sampled immediately prior to exercise (0 min = baseline), during (+18, +54 min), immediately after (+90 min), and after recovery (R40). Plasma was analyzed for cf-mDNA, IL-6, and lactate. A significant difference in cf-mDNA response was observed between exercise and control trials, with cf-mDNA levels reduced during exercise at +54 and +90 (with or without plasma volume shift correction). Declines in cf-mDNA were accompanied by increased lactate and followed by an increase in IL-6, suggesting a temporal association with muscle stress and inflammatory processes. Our novel finding of cf-mDNA decline with prolonged moderate treadmill exercise provides evidence for increased clearance from or reduced release of cf-mDNA into the blood with prolonged exercise. These studies contrast with previous investigations involving exhaustive short-term treadmill exercise, in which no change in cf-mDNA levels were reported, and contribute to our understanding of differences between exercise- and trauma-induced inflammation. We propose that transient declines in cf-mDNA may induce health benefits, by reducing systemic inflammation. PMID- 26755737 TI - Metabolomics revealed diurnal heat stress and zinc supplementation-induced changes in amino acid, lipid, and microbial metabolism. AB - Heat stress (HS) dramatically disrupts the events in energy and nutrient metabolism, many of which requires zinc (Zn) as a cofactor. In this study, metabolic effects of HS and Zn supplementation were evaluated by examining growth performance, blood chemistry, and metabolomes of crossbred gilts fed with ZnNeg (no Zn supplementation), ZnIO (120 ppm ZnSO4), or ZnAA (60 ppm ZnSO4 + 60 ppm zinc amino acid complex) diets under diurnal HS or thermal-neutral (TN) condition. The results showed that growth performance was reduced by HS but not by Zn supplementation. Among measured serum biochemicals, HS was found to increase creatinine but decrease blood urea nitrogen (BUN) level. Metabolomic analysis indicated that HS greatly affected diverse metabolites associated with amino acid, lipid, and microbial metabolism, including urea cycle metabolites, essential amino acids, phospholipids, medium-chain dicarboxylic acids, fatty acid amides, and secondary bile acids. More importantly, many changes in these metabolite markers were correlated with both acute and adaptive responses to HS. Relative to HS-induced metabolic effects, Zn supplementation-associated effects were much more limited. A prominent observation was that ZnIO diet, potentially through its influences on microbial metabolism, yielded different responses to HS compared with two other diets, which included higher levels of short-chain fatty acids (SCFAs) in cecal fluid and higher levels of lysine in the liver and feces. Overall, comprehensive metabolomic analysis identified novel metabolite markers associated with HS and Zn supplementation, which could guide further investigation on the mechanisms of these metabolic effects. PMID- 26755736 TI - Possible role for nephron-derived angiotensinogen in angiotensin-II dependent hypertension. AB - The role of intranephron angiotensinogen (AGT) in blood pressure (BP) regulation is not fully understood. Previous studies showed that proximal tubule-specific overexpression of AGT increases BP, whereas proximal tubule-specific deletion of AGT did not alter BP. The latter study may not have completely eliminated nephron AGT production; in addition, BP was only assessed on a normal salt diet. To evaluate this issue in greater detail, we developed mice with inducible nephron wide AGT deletion. Mice were generated which were hemizygous for the Pax8-rtTA and LC-1 transgenes and homozygous for loxP-flanked AGT alleles to achieve nephron-wide AGT disruption after doxycycline induction. Compared to controls, AGT knockout (KO) mice demonstrated markedly reduced renal AGT immunostaining, mRNA, and protein levels; unexpectedly AGT KO mice had reduced AGT mRNA levels in the liver along with 50% reduction in plasma AGT levels. BP was significantly lower in the AGT KO mice compared to controls fed a normal, low, or high Na(+) intake, with the highest BP reduction on a low Na(+) diet. Regardless of Na(+) intake, AGT KO mice had higher plasma renin concentration (PRC) and markedly reduced urinary AGT levels compared to controls. Following angiotensin-II (Ang II) infusion, AGT KO mice demonstrated an attenuated hypertensive response despite similar suppression of PRC in the two groups. Taken together, these data suggest that nephron-derived AGT may be involved in Ang-II-dependent hypertension, however, a clear role for nephron-derived AGT in physiological BP regulation remains to be determined. PMID- 26755738 TI - Hemodynamic responses to acute angiotensin II infusion are exacerbated in male versus female spontaneously hypertensive rats. AB - We previously reported that male spontaneously hypertensive rats (SHRs) are more sensitive to chronic angiotensin (Ang) II-induced hypertension compared with female rats. This study was designed to test the hypothesis that anesthetized male SHRs are also more responsive to acute Ang II-induced increases in blood pressure and renal hemodynamic changes when compared with female SHRs. Baseline mean arterial pressure (MAP) was higher in male SHRs than in female SHRs (135 +/- 2 vs. 124 +/- 4 mmHg, P < 0.05). Acute intravenous infusion of Ang II (5 ng/kg/min) for 60 minutes significantly increased MAP to 148 +/- 2 mmHg in male SHRs (P < 0.05) without a significant change in MAP in female SHRs. Baseline glomerular filtration rate (GFR) was also higher in male SHRs than in female SHRs (2.6 +/- 0.3 vs. 1.3 +/- 0.1 mL/min, P < 0.05). Ang II infusion for 60 min significantly decreased GFR in male SHRs (2.0 +/- 0.2 mL/min; P < 0.05) without significant changes in urine flow rate, sodium, or chloride excretion. In contrast, Ang II infusion increased GFR in female SHRs (1.9 +/- 0.2 mL/min; P < 0.05). The increase in GFR upon Ang II infusion in female SHRs was associated with increases in urine flow rate (4.3 +/- 0.3 to 7.1 +/- 0.9 MUL/min), sodium excretion (0.16 +/- 0.04 to 0.4 +/- 0.1 MUmol/min), and chloride excretion (0.7 +/- 0.08 to 1.1 +/- 0.1 MUmol/min; for all P < 0.05). These findings support the hypothesis that there is sex difference in response to acute Ang II infusion in SHRs with females being less responsive to Ang II-induced elevations in blood pressure and decreases in GFR relative to male SHRs. PMID- 26755739 TI - TNF ROCKs the boat as the kidney endothelium springs a leak. PMID- 26755740 TI - Orai1 forms a signal complex with BKCa channel in mesenteric artery smooth muscle cells. AB - Orai1, a specific nonvoltage-gated Ca(2+) channel, has been found to be one of key molecules involved in store-operated Ca(2+) entry (SOCE). Orai1 may associate with other proteins to form a signaling complex, which is essential for regulating a variety of physiological functions. In this study, we studied the possible interaction between Orai1 and large conductance Ca(2+)-activated potassium channel (BKC a). Using RNA interference technique, we demonstrated that the SOCE and its associated membrane hyperpolarization were markedly suppressed after knockdown of Orai1 with a specific Orai1 siRNA in rat mesenteric artery smooth muscle. Moreover, isometric tension measurements showed that agonist induced vasocontraction was increased after Orai1 was knocked down or the tissue was incubated with BKC a blocker iberiotoxin. Coimmunoprecipitation data revealed that BKC a and Orai1 could reciprocally pull down each other. In situ proximity ligation assay further demonstrated that Orai1 and BKC a are in close proximity. Taken together, these results indicate that Orai1 physically associates with BKC a to form a signaling complex in the rat mesenteric artery smooth muscle. Ca(2+) influx via Orai1 stimulates BKC a, leading to membrane hyperpolarization. This hyperpolarizing effect of Orai1-BKC a coupling could contribute to reduce agonist induced membrane depolarization, therefore preventing excessive contraction of the rat mesenteric artery smooth muscle in response to contractile agonists. PMID- 26755741 TI - Full-Contact Practice and Injuries in College Football. AB - BACKGROUND: Despite recent restrictions being placed on practice in college football, there are little data to correlate such changes with injuries. HYPOTHESIS: Football injuries will correlate with a team's exposure to full contact practice, total practice, and total games. STUDY DESIGN: Descriptive epidemiological study. METHODS: All injuries and athlete injury exposures (AE * Min = athletes exposed * activity duration in minutes) were recorded for an intercollegiate football team over 4 consecutive fall seasons. Weekly injuries and injury rates (injuries per athletic injury exposure) were correlated with the weekly exposures to full-contact practices, total practices, formal scrimmages, and games. RESULTS: The preseason practice injury rate was over twice the in season practice injury rate ( P < 0.001). For preseason, injury exposures were higher for full-contact practice ( P = 0.0166), total practices ( P = 0.015), and scrimmages/games ( P = 0.034) compared with in-season. Preseason and in-season practice injuries correlated with exposure to full-contact practice combined with scrimmages for preseason ( P < 0.008) and full-contact practice combined with games for in-season ( P = 0.0325). The game injury rate was over 6 times greater than the practice injury rate ( P < 0.0001). Concussions constituted 14.5% of all injuries, and the incidence of concussions correlated with the incidence of all injuries ( P = 0.0001). Strength training did not correlate with injuries. CONCLUSION: Decreased exposure to full-contact practice may decrease the incidence of practice injuries and practice concussions. However, the game injury rate was over 6 times greater than the practice injury rate and had an inverse correlation with full-contact practice. PMID- 26755742 TI - A non-canonical function of Plk4 in centriolar satellite integrity and ciliogenesis through PCM1 phosphorylation. AB - Centrioles are the major constituents of the animal centrosome, in which Plk4 kinase serves as a master regulator of the duplication cycle. Many eukaryotes also contain numerous peripheral particles known as centriolar satellites. While centriolar satellites aid centriole assembly and primary cilium formation, it is unknown whether Plk4 plays any regulatory roles in centriolar satellite integrity. Here we show that Plk4 is a critical determinant of centriolar satellite organisation. Plk4 depletion leads to the dispersion of centriolar satellites and perturbed ciliogenesis. Plk4 interacts with the satellite component PCM1, and its kinase activity is required for phosphorylation of the conserved S372. The nonphosphorylatable PCM1 mutant recapitulates phenotypes of Plk4 depletion, while the phosphomimetic mutant partially rescues the dispersed centriolar satellite patterns and ciliogenesis in cells depleted of PCM1. We show that S372 phosphorylation occurs during the G1 phase of the cell cycle and is important for PCM1 dimerisation and interaction with other satellite components. Our findings reveal that Plk4 is required for centriolar satellite function, which may underlie the ciliogenesis defects caused by Plk4 dysfunction. PMID- 26755745 TI - US dietary guidelines make no recommendation on sugar tax. PMID- 26755743 TI - NgBR is essential for endothelial cell glycosylation and vascular development. AB - NgBR is a transmembrane protein identified as a Nogo-B-interacting protein and recently has been shown to be a subunit required for cis-prenyltransferase (cisPTase) activity. To investigate the integrated role of NgBR in vascular development, we have characterized endothelial-specific NgBR knockout embryos. Here, we show that endothelial-specific NgBR knockout results in embryonic lethality due to vascular development defects in yolk sac and embryo proper. Loss of NgBR in endothelial cells reduces proliferation and promotes apoptosis of the cells largely through defects in the glycosylation of key endothelial proteins including VEGFR2, VE-cadherin, and CD31, and defective glycosylation can be rescued by treatment with the end product of cisPTase activity, dolichol phosphate. Moreover, NgBR functions in endothelial cells during embryogenesis are Nogo-B independent. These data uniquely show the importance of NgBR and protein glycosylation during vascular development. PMID- 26755744 TI - An Evaluation of the Crystal Structure of C-terminal Truncated Apolipoprotein A-I in Solution Reveals Structural Dynamics Related to Lipid Binding. AB - Apolipoprotein (apo) A-I mediates many of the anti-atherogenic functions attributed to high density lipoprotein. Unfortunately, efforts toward a high resolution structure of full-length apoA-I have not been fruitful, although there have been successes with deletion mutants. Recently, a C-terminal truncation (apoA-I(Delta185-243)) was crystallized as a dimer. The structure showed two helical bundles connected by a long, curved pair of swapped helical domains. To compare this structure to that existing under solution conditions, we applied small angle x-ray scattering and isotope-assisted chemical cross-linking to apoA I(Delta185-243) in its dimeric and monomeric forms. For the dimer, we found evidence for the shared domains and aspects of the N-terminal bundles, but not the molecular curvature seen in the crystal. We also found that the N-terminal bundles equilibrate between open and closed states. Interestingly, this movement is one of the transitions proposed during lipid binding. The monomer was consistent with a model in which the long shared helix doubles back onto the helical bundle. Combined with the crystal structure, these data offer an important starting point to understand the molecular details of high density lipoprotein biogenesis. PMID- 26755747 TI - India to track progress of 75 cities to improve sanitation. PMID- 26755748 TI - Prehospital emergency services screening and referral to reduce falls in community-dwelling older adults: a systematic review. AB - BACKGROUND: Falls represent an increasing source of geriatric morbidity and mortality. Prehospital emergency services may be uniquely suited to screen and refer subsets of high-risk older adults to fall prevention programmes. This systematic review assesses the effectiveness of such screening and referral programmes. METHODS: We searched PubMed, Embase, CINAHL, Web of Science, Scopus, the Cochrane Library and OTseeker for English-language peer-reviewed randomised trials, non-randomised trials and cohort studies evaluating prehospital fall risk screening and referral programmes for community-dwelling adults >=60 years of age. Risk of bias was assessed using the Cochrane Collaboration's tool. Primary outcomes included the risk and rate of falling. Secondary outcomes included successful follow-up to address fall risks and adverse events. RESULTS: From 6187 unique records, 6 studies were included. Screening varied from using semistructured risk assessments to recording chief complaints. All studies were at high risk of bias. One unblinded trial of a multifactorial fall prevention programme demonstrated a 14.3% (95% CI 6.1% to 22.5%) absolute reduction in annual fall risk and a relative fall incidence of 0.45 (95% CI 0.35 to 0.58). The probability of successful follow-up varied from 9.8% to 81.0%. No studies demonstrated any attributable adverse events. CONCLUSIONS: No high-quality evidence demonstrates that prehospital services reduce falls in community dwelling older adults. Screening by prehospital personnel using semistructured risk assessments appears feasible, but it is unclear whether this is superior to referral based on fall-related chief complaints. TRIAL REGISTRATION NUMBER: PROSPERO 2012:CRD42012002782. PMID- 26755746 TI - The emerging role of endothelin-1 in the pathogenesis of pre-eclampsia. AB - Pre-eclampsia (PE) is the most frequently encountered medical complication during pregnancy. It is characterized by a rise in systemic vascular resistance with a relatively low cardiac output and hypovolemia, combined with severe proteinuria. Despite the hypovolemia, renin-angiotensin system (RAS) activity is suppressed and aldosterone levels are decreased to the same degree as renin. This suggests that the RAS is not the cause of the hypertension in PE, but rather that its suppression is the consequence of the rise in blood pressure. Abnormal placentation early in pregnancy is widely assumed to be an important initial event in the onset of PE. Eventually, this results in the release of anti angiogenic factors [in particular, soluble Fms-like tyrosine kinase-1 (sFlt-1)] and cytokines, leading to generalized vascular dysfunction. Elevated sFlt-1 levels bind and inactivate vascular endothelial growth factor (VEGF). Of interest, VEGF inhibition with drugs like sunitinib, applied in cancer patients, results in a PE-like syndrome, characterized by hypertension, proteinuria and renal toxicity. Both in cancer patients treated with sunitinib and in pregnant women with PE, significant rises in endothelin-1 occur. Multiple regression analysis revealed that endothelin-1 is an independent determinant of the hypertension and proteinuria in PE, and additionally a renin suppressor. Moreover, studies in animal models representative of PE, have shown that endothelin receptor blockers prevent the development of this disease. Similarly, endothelin receptor blockers are protective during sunitinib treatment. Taken together, activation of the endothelin system emerges as an important pathway causing the clinical manifestations of PE. This paper critically addresses this concept, taking into consideration both clinical and preclinical data, and simultaneously discusses the therapeutic consequences of this observation. PMID- 26755750 TI - RETRACTED: Association of Angiotensin-Converting Enzyme Insertion/Deletion Gene Polymorphism With Lung Cancer Susceptibility. PMID- 26755749 TI - Dosimetric Considerations in Respiratory-Gated Deep Inspiration Breath-Hold for Left Breast Irradiation. AB - PURPOSE: To present our clinical workflow of incorporating AlignRT for left breast deep inspiration breath-hold treatments and the dosimetric considerations with the deep inspiration breath-hold protocol. MATERIAL AND METHODS: Patients with stage I to III left-sided breast cancer who underwent lumpectomy or mastectomy were considered candidates for deep inspiration breath-hold technique for their external beam radiation therapy. Treatment plans were created on both free-breathing and deep inspiration breath-hold computed tomography for each patient to determine whether deep inspiration breath-hold was beneficial based on dosimetric comparison. The AlignRT system was used for patient setup and monitoring. Dosimetric measurements and their correlation with chest wall excursion and increase in left lung volume were studied for free-breathing and deep inspiration breath-hold plans. RESULTS: Deep inspiration breath-hold plans had significantly increased chest wall excursion when compared with free breathing. This change in geometry resulted in reduced mean and maximum heart dose but did not impact lung V20 or mean dose. The correlation between chest wall excursion and absolute reduction in heart or lung dose was found to be nonsignificant, but correlation between left lung volume and heart dose showed a linear association. It was also identified that higher levels of chest wall excursion may paradoxically increase heart or lung dose. CONCLUSION: Reduction in heart dose can be achieved for many left-sided breast and chest wall patients using deep inspiration breath-hold. Chest wall excursion as well as left lung volume did not correlate with reduction in heart dose, and it remains to be determined what metric will provide the most optimal and reliable dosimetric advantage. PMID- 26755752 TI - Solar photochemical and thermochemical splitting of water. AB - Artificial photosynthesis to carry out both the oxidation and the reduction of water has emerged to be an exciting area of research. It has been possible to photochemically generate oxygen by using a scheme similar to the Z-scheme, by using suitable catalysts in place of water-oxidation catalyst in the Z-scheme in natural photosynthesis. The best oxidation catalysts are found to be Co and Mn oxides with the e(1) g configuration. The more important aspects investigated pertain to the visible-light-induced generation of hydrogen by using semiconductor heterostructures of the type ZnO/Pt/Cd1-xZnxS and dye-sensitized semiconductors. In the case of heterostructures, good yields of H2 have been obtained. Modifications of the heterostructures, wherein Pt is replaced by NiO, and the oxide is substituted with different anions are discussed. MoS2 and MoSe2 in the 1T form yield high quantities of H2 when sensitized by Eosin Y. Two-step thermochemical splitting of H2O using metal oxide redox pairs provides a strategy to produce H2 and CO. Performance of the Ln0.5A0.5MnO3 (Ln = rare earth ion, A = Ca, Sr) family of perovskites is found to be promising in this context. The best results to date are found with Y0.5Sr0.5MnO3. PMID- 26755753 TI - A stereospecific solid-phase screening assay for colonies expressing both (R)- and (S)-selective omega-aminotransferases. AB - A novel solid-phase screening assay was developed for colonies expressing both (R)- and (S)-selective omega-aminotransferases. This high-throughput assay can be used to screen rapidly large variant libraries with enhanced substrate selectivity and enantioselectivities. PMID- 26755751 TI - Norcantharidin Inhibits SK-N-SH Neuroblastoma Cell Growth by Induction of Autophagy and Apoptosis. AB - Norcantharidin, a low-toxic analog of the active anticancer compound cantharidin in Mylabris, can inhibit proliferation and induce apoptosis of multiple types of cancer cells. However, the anticancer activities of norcantharidin with respect to neuroblastoma, and its underlying mechanisms, have not been investigated. Therefore, our study was designed to determine the efficacy of norcantharidin on SK-N-SH neuroblastoma cell death and to elucidate detailed mechanisms of activity. In the present study, norcantharidin suppressed the proliferation and cloning ability of SK-N-SH cells in a dose-dependent manner, apparently by reducing the mitochondrial membrane potential and arresting SK-N-SH cells at the G2/M stage, accompanied by elevated expressions of p21 and decreased expressions of cyclin B1 and cell division control 2. Treatment by norcantharidin induced significant mitophagy and autophagy, as demonstrated by a decrease in Translocase Of Outer Mitochondrial Membrane 20 (TOM20), increased beclin1 and LC3-II protein expression, reduced protein SQSTM1/p62 expression, and accumulation of punctate LC3 in the cytoplasm of SK-N-SH cells. In addition, norcantharidin induced apoptosis through regulating the expression of B-cell lymphoma 2-associated X protein/B-cell lymphoma 2 and B-cell lymphoma 2-associated X protein/myeloid cell leukemia 1 and activating caspase-3 and caspase-9-dependent endogenous mitochondrial pathways. We also observed an increase in phosphor-AMP-activated protein kinase accompanied with a decrease in phosphor-protein kinase B and mammalian target of rapamycin expression after treatment with norcantharidin. Subsequent studies indicated that norcantharidin participates in cellular autophagy and apoptosis via activation of the c-Jun NH2-terminal kinases/c-Jun pathway. In conclusion, our results demonstrate that norcantharidin can reduce the mitochondrial membrane potential, induce mitophagy, and subsequently arouse cellular autophagy and apoptosis; the AMP-activated protein kinase, protein kinase B/mammalian target of rapamycin, and c-Jun NH2-terminal kinases/c-Jun signaling pathways are widely involved in these processes. Thus, the traditional Chinese medicine norcantharidin could be a novel therapeutic strategy for treating neuroblastoma. PMID- 26755755 TI - Catalyst design for biorefining. AB - The quest for sustainable resources to meet the demands of a rapidly rising global population while mitigating the risks of rising CO2 emissions and associated climate change, represents a grand challenge for humanity. Biomass offers the most readily implemented and low-cost solution for sustainable transportation fuels, and the only non-petroleum route to organic molecules for the manufacture of bulk, fine and speciality chemicals and polymers. To be considered truly sustainable, biomass must be derived from resources which do not compete with agricultural land use for food production, or compromise the environment (e.g. via deforestation). Potential feedstocks include waste lignocellulosic or oil-based materials derived from plant or aquatic sources, with the so-called biorefinery concept offering the co-production of biofuels, platform chemicals and energy; analogous to today's petroleum refineries which deliver both high-volume/low-value (e.g. fuels and commodity chemicals) and low volume/high-value (e.g. fine/speciality chemicals) products, thereby maximizing biomass valorization. This article addresses the challenges to catalytic biomass processing and highlights recent successes in the rational design of heterogeneous catalysts facilitated by advances in nanotechnology and the synthesis of templated porous materials, as well as the use of tailored catalyst surfaces to generate bifunctional solid acid/base materials or tune hydrophobicity. PMID- 26755754 TI - Towards rational catalyst design: a general optimization framework. AB - Rational catalyst design is one of the most fundamental goals in heterogeneous catalysis. Herein, we briefly review our previous design work, and then introduce a general optimization framework, which converts catalyst design into an optimization problem. Furthermore, an example is given using the gradient ascent method to show how this framework can be used for rational catalyst design. This framework may be applied to other design schemes. PMID- 26755756 TI - Catalyst design for enhanced sustainability through fundamental surface chemistry. AB - Decreasing energy consumption in the production of platform chemicals is necessary to improve the sustainability of the chemical industry, which is the largest consumer of delivered energy. The majority of industrial chemical transformations rely on catalysts, and therefore designing new materials that catalyse the production of important chemicals via more selective and energy efficient processes is a promising pathway to reducing energy use by the chemical industry. Efficiently designing new catalysts benefits from an integrated approach involving fundamental experimental studies and theoretical modelling in addition to evaluation of materials under working catalytic conditions. In this review, we outline this approach in the context of a particular catalyst nanoporous gold (npAu)-which is an unsupported, dilute AgAu alloy catalyst that is highly active for the selective oxidative transformation of alcohols. Fundamental surface science studies on Au single crystals and AgAu thin-film alloys in combination with theoretical modelling were used to identify the principles which define the reactivity of npAu and subsequently enabled prediction of new reactive pathways on this material. Specifically, weak van der Waals interactions are key to the selectivity of Au materials, including npAu. We also briefly describe other systems in which this integrated approach was applied. PMID- 26755757 TI - The effect of soot on ammonium nitrate species and NO2 selective catalytic reduction over Cu-zeolite catalyst-coated particulate filter. AB - A selective catalytic reduction (SCR)-coated particulate filter was evaluated by means of dynamic tests performed using NH3, NO2, O2 and H2O. The reactions were examined both prior to and after soot removal in order to study the effect of soot on ammonium nitrate formation and decomposition, ammonia storage and NO2 SCR. A slightly larger ammonia storage capacity was observed when soot was present in the sample, which indicated that small amounts of ammonia can adsorb on the soot. Feeding of NO2 and NH3 in the presence of O2 and H2O at low temperature (150, 175 and 200 degrees C) leads to a large formation of ammonium nitrate species and during the subsequent temperature ramp using H2O and argon, a production of nitrous oxides was observed. The N2O formation is often related to ammonium nitrate decomposition, and our results showed that the N2O formation was clearly decreased by the presence of soot. We therefore propose that in the presence of soot, there are fewer ammonium nitrate species on the surface due to the interactions with the soot. Indeed, we do observe CO2 production during the reaction conditions also at 150 degrees C, which shows that there is a reaction with these species and soot. In addition, the conversion of NOx due to NO2 SCR was significantly enhanced in the presence of soot; we attribute this to the smaller amount of ammonium nitrate species present in the experiments where soot is available since it is well known that ammonium nitrate formation is a major problem at low temperature due to the blocking of the catalytic sites. Further, a scanning electron microscopy analysis of the soot particles shows that they are about 30-40 nm and are therefore too large to enter the pores of the zeolites. There are likely CuxOy or other copper species available on the outside of the zeolite crystallites, which could have been enhanced due to the hydrothermal treatment at 850 degrees C of the SCR-coated filter prior to the soot loading. We therefore propose that soot is interacting with the ammonium nitrate species on the CuxOy or other copper species on the surface of the zeolite particles, which reduces the ammonium nitrate blocking of the catalyst and thereby results in higher NO2 SCR activity. PMID- 26755759 TI - Synthesis of highly stable metal-containing extra-large-pore molecular sieves. AB - The isomorphic substitution of two different metals (Mg and Co) within the framework of the ITQ-51 zeotype (IFO structure) using bulky aromatic proton sponges as organic structure-directing agents (OSDAs) has allowed the synthesis of different stable metal-containing extra-large-pore zeotypes with high pore accessibility and acidity. These metal-containing extra-large-pore zeolites, named MgITQ-51 and CoITQ-51, have been characterized by different techniques, such as powder X-ray diffraction, scanning electron microscopy, energy dispersive X-ray spectrometry, UV-Vis spectroscopy, temperature programmed desorption of ammonia and Fourier transform infrared spectroscopy, to study their physico chemical properties. The characterization confirms the preferential insertion of Mg and Co atoms within the crystalline structure of the ITQ-51 zeotype, providing high Bronsted acidity, and allowing their use as efficient heterogeneous acid catalysts in industrially relevant reactions involving bulky organic molecules. PMID- 26755760 TI - The effect of Mg location on Co-Mg-Ru/gamma-Al2O3 Fischer-Tropsch catalysts. AB - The effectiveness of Mg as a promoter of Co-Ru/gamma-Al2O3 Fischer-Tropsch catalysts depends on how and when the Mg is added. When the Mg is impregnated into the support before the Co and Ru addition, some Mg is incorporated into the support in the form of MgxAl2O3+x if the material is calcined at 550 degrees C or 800 degrees C after the impregnation, while the remainder is present as amorphous MgO/MgCO3 phases. After subsequent Co-Ru impregnation MgxCo3-xO4 is formed which decomposes on reduction, leading to Co(0) particles intimately mixed with Mg, as shown by high-resolution transmission electron microscopy. The process of impregnating Co into an Mg-modified support results in dissolution of the amorphous Mg, and it is this Mg which is then incorporated into MgxCo3-xO4. Acid washing or higher temperature calcination after Mg impregnation can remove most of this amorphous Mg, resulting in lower values of x in MgxCo3-xO4. Catalytic testing of these materials reveals that Mg incorporation into the Co oxide phase is severely detrimental to the site-time yield, while Mg incorporation into the support may provide some enhancement of activity at high temperature. PMID- 26755761 TI - Summarizing comments on the discussion and a prospectus for urgent future action. AB - Following my personal reactions to some of the key points made in this Discussion (Part I), I present, in Part II, what I perceive to be the most important, and, in some cases, urgent actions that now need to be taken in the following inter related fields: (i) design of catalysts, especially for the production of materials using anthropogenic carbon dioxide, CO2, as feedstock; (ii) the continuing role of catalysis in the protection of the environment; (iii) the importance of catalysis in the generation of fuel and the release of energy; and (iv) the wisdom of conducting life cycle and techno-economic analyses continually during the development of new catalysts, as well as of those in regular use. A brief account is also given of the prospect of designing atom-efficient catalysts in which either atomically dispersed rare (and expensive) metals such as Ir or Pt or the use of single-site earth-abundant elements (Al, Si, O) can be employed to facilitate important industrial reactions. PMID- 26755762 TI - Harnessing renewable energy with CO2 for the chemical value chain: challenges and opportunities for catalysis. PMID- 26755758 TI - Catalysts for CO2/epoxide ring-opening copolymerization. AB - This article summarizes and reviews recent progress in the development of catalysts for the ring-opening copolymerization of carbon dioxide and epoxides. The copolymerization is an interesting method to add value to carbon dioxide, including from waste sources, and to reduce pollution associated with commodity polymer manufacture. The selection of the catalyst is of critical importance to control the composition, properties and applications of the resultant polymers. This review highlights and exemplifies some key recent findings and hypotheses, in particular using examples drawn from our own research. PMID- 26755763 TI - Catalysis making the world a better place: satellite meeting. PMID- 26755764 TI - An investigation of anode and cathode materials in photomicrobial fuel cells. AB - Photomicrobial fuel cells (p-MFCs) are devices that use photosynthetic organisms (such as cyanobacteria or algae) to turn light energy into electrical energy. In a p-MFC, the anode accepts electrons from microorganisms that are either growing directly on the anode surface (biofilm) or are free floating in solution (planktonic). The nature of both the anode and cathode material is critical for device efficiency. An ideal anode is biocompatible and facilitates direct electron transfer from the microorganisms, with no need for an electron mediator. For a p-MFC, there is the additional requirement that the anode should not prevent light from perfusing through the photosynthetic cells. The cathode should facilitate the rapid reaction of protons and oxygen to form water so as not to rate limit the device. In this paper, we first review the range of anode and cathode materials currently used in p-MFCs. We then present our own data comparing cathode materials in a p-MFC and our first results using porous ceramic anodes in a mediator-free p-MFC. PMID- 26755765 TI - Robust synthesis of epoxy resin-filled microcapsules for application to self healing materials. AB - Mechanically and thermally robust microcapsules containing diglycidyl ether bisphenol A-based epoxy resin and a high-boiling-point organic solvent were synthesized in high yield using in situ polymerization of urea and formaldehyde in an oil-in-water emulsion. Microcapsules were characterized in terms of their size and size distribution, shell surface morphology and thermal resistance to the curing cycles of commercially used epoxy polymers. The size distribution of the capsules and characteristics such as shell thickness can be controlled by the specific parameters of microencapsulation, including concentrations of reagents, stirrer speed and sonication. Selected microcapsules, and separated core and shell materials, were analysed using thermogravimetric analysis and differential scanning calorimetry. It is demonstrated that capsules lose minimal 2.5 wt% at temperatures no higher than 120 degrees C. These microcapsules can be applied to self-healing carbon fibre composite structural materials, with preliminary results showing promising performance. PMID- 26755766 TI - Catalysis making the world a better place. PMID- 26755767 TI - BODY SIZE-SPECIFIC EFFECTIVE DOSE CONVERSION COEFFICIENTS FOR CT SCANS. AB - Effective dose from computed tomography (CT) examinations is usually estimated using the scanner-provided dose-length product and using conversion factors, also known as k-factors, which correspond to scan regions and differ by age according to five categories: 0, 1, 5, 10 y and adult. However, patients often deviate from the standard body size on which the conversion factor is based. In this study, a method for deriving body size-specific k-factors is presented, which can be determined from a simple regression curve based on patient diameter at the centre of the scan range. Using the International Commission on Radiological Protection reference paediatric and adult computational phantoms paired with Monte Carlo simulation of CT X-ray beams, the authors derived a regression-based k-factor model for the following CT scan types: head-neck, head, neck, chest, abdomen, pelvis, abdomen-pelvis (AP) and chest-abdomen-pelvis (CAP). The resulting regression functions were applied to a total of 105 paediatric and 279 adult CT scans randomly sampled from patients who underwent chest, AP and CAP scans at the National Institutes of Health Clinical Center. The authors have calculated and compared the effective doses derived from the conventional age-specific k-factors with the values computed using their body size-specific k-factor. They found that by using the age-specific k-factor, paediatric patients tend to have underestimates (up to 3-fold) of effective dose, while underweight and overweight adult patients tend to have underestimates (up to 2.6-fold) and overestimates (up to 4.6-fold) of effective dose, respectively, compared with the effective dose determined from their body size-dependent factors. The authors present these size specific k-factors as an alternative to the existing age-specific factors. The body size-specific k-factor will assess effective dose more precisely and on a more individual level than the conventional age-specific k-factors and, hence, improve awareness of the true exposure, which is important for the clinical community to understand. PMID- 26755769 TI - Neural connections foster social connections: a diffusion-weighted imaging study of social networks. AB - Although we know the transition from childhood to adulthood is marked by important social and neural development, little is known about how social network size might affect neurocognitive development or vice versa. Neuroimaging research has identified several brain regions, such as the amygdala, as key to this affiliative behavior. However, white matter connectivity among these regions, and its behavioral correlates, remain unclear. Here we tested two hypotheses: that an amygdalocentric structural white matter network governs social affiliative behavior and that this network changes during adolescence and young adulthood. We measured social network size behaviorally, and white matter microstructure using probabilistic diffusion tensor imaging in a sample of neurologically normal adolescents and young adults. Our results suggest amygdala white matter microstructure is key to understanding individual differences in social network size, with connectivity to other social brain regions such as the orbitofrontal cortex and anterior temporal lobe predicting much variation. In addition, participant age correlated with both network size and white matter variation in this network. These findings suggest the transition to adulthood may constitute a critical period for the optimization of structural brain networks underlying affiliative behavior. PMID- 26755768 TI - Control your anger! The neural basis of aggression regulation in response to negative social feedback. AB - Negative social feedback often generates aggressive feelings and behavior. Prior studies have investigated the neural basis of negative social feedback, but the underlying neural mechanisms of aggression regulation following negative social feedback remain largely undiscovered. In the current study, participants viewed pictures of peers with feedback (positive, neutral or negative) to the participant's personal profile. Next, participants responded to the peer feedback by pressing a button, thereby producing a loud noise toward the peer, as an index of aggression. Behavioral analyses showed that negative feedback led to more aggression (longer noise blasts). Conjunction neuroimaging analyses revealed that both positive and negative feedback were associated with increased activity in the medial prefrontal cortex (PFC) and bilateral insula. In addition, more activation in the right dorsal lateral PFC (dlPFC) during negative feedback vs neutral feedback was associated with shorter noise blasts in response to negative social feedback, suggesting a potential role of dlPFC in aggression regulation, or top-down control over affective impulsive actions. This study demonstrates a role of the dlPFC in the regulation of aggressive social behavior. PMID- 26755770 TI - Measuring distances between TRPV1 and the plasma membrane using a noncanonical amino acid and transition metal ion FRET. AB - Despite recent advances, the structure and dynamics of membrane proteins in cell membranes remain elusive. We implemented transition metal ion fluorescence resonance energy transfer (tmFRET) to measure distances between sites on the N terminal ankyrin repeat domains (ARDs) of the pain-transducing ion channel TRPV1 and the intracellular surface of the plasma membrane. To preserve the native context, we used unroofed cells, and to specifically label sites in TRPV1, we incorporated a fluorescent, noncanonical amino acid, L-ANAP. A metal chelating lipid was used to decorate the plasma membrane with high-density/high-affinity metal-binding sites. The fluorescence resonance energy transfer (FRET) efficiencies between L-ANAP in TRPV1 and Co(2+) bound to the plasma membrane were consistent with the arrangement of the ARDs in recent cryoelectron microscopy structures of TRPV1. No change in tmFRET was observed with the TRPV1 agonist capsaicin. These results demonstrate the power of tmFRET for measuring structure and rearrangements of membrane proteins relative to the cell membrane. PMID- 26755771 TI - Kv5, Kv6, Kv8, and Kv9 subunits: No simple silent bystanders. AB - Members of the electrically silent voltage-gated K(+) (Kv) subfamilies (Kv5, Kv6, Kv8, and Kv9, collectively identified as electrically silent voltage-gated K(+) channel [KvS] subunits) do not form functional homotetrameric channels but assemble with Kv2 subunits into heterotetrameric Kv2/KvS channels with unique biophysical properties. Unlike the ubiquitously expressed Kv2 subunits, KvS subunits show a more restricted expression. This raises the possibility that Kv2/KvS heterotetramers have tissue-specific functions, making them potential targets for the development of novel therapeutic strategies. Here, I provide an overview of the expression of KvS subunits in different tissues and discuss their proposed role in various physiological and pathophysiological processes. This overview demonstrates the importance of KvS subunits and Kv2/KvS heterotetramers in vivo and the importance of considering KvS subunits and Kv2/KvS heterotetramers in the development of novel treatments. PMID- 26755772 TI - Transition metal ion FRET to measure short-range distances at the intracellular surface of the plasma membrane. AB - Biological membranes are complex assemblies of lipids and proteins that serve as platforms for cell signaling. We have developed a novel method for measuring the structure and dynamics of the membrane based on fluorescence resonance energy transfer (FRET). The method marries four technologies: (1) unroofing cells to isolate and access the cytoplasmic leaflet of the plasma membrane; (2) patch clamp fluorometry (PCF) to measure currents and fluorescence simultaneously from a membrane patch; (3) a synthetic lipid with a metal-chelating head group to decorate the membrane with metal-binding sites; and (4) transition metal ion FRET (tmFRET) to measure short distances between a fluorescent probe and a transition metal ion on the membrane. We applied this method to measure the density and affinity of native and introduced metal-binding sites in the membrane. These experiments pave the way for measuring structural rearrangements of membrane proteins relative to the membrane. PMID- 26755773 TI - Carbenoxolone inhibits Pannexin1 channels through interactions in the first extracellular loop. AB - Pannexin1 (Panx1) is an ATP release channel important for controlling immune responses and synaptic strength. Various stimuli including C-terminal cleavage, a high concentration of extracellular potassium, and voltage have been demonstrated to activate Panx1. However, it remains unclear how Panx1 senses and integrates such diverse stimuli to form an open channel. To provide a clue on the mechanism underlying Panx1 channel gating, we investigated the action mechanism of carbenoxolone (CBX), the most commonly used small molecule for attenuating Panx1 function triggered by a wide range of stimuli. Using a chimeric approach, we discovered that CBX reverses its action polarity and potentiates the voltage gated channel activity of Panx1 when W74 in the first extracellular loop is mutated to a nonaromatic residue. A systematic mutagenesis study revealed that conserved residues in this loop also play important roles in CBX function, potentially by mediating CBX binding. We extended our experiments to other Panx1 inhibitors such as probenecid and ATP, which also potentiate the voltage-gated channel activity of a Panx1 mutant at position 74. Notably, probenecid alone can activate this mutant at a resting membrane potential. These data suggest that CBX and other inhibitors, including probenecid, attenuate Panx1 channel activity through modulation of the first extracellular loop. Our experiments are the first step toward identifying a previously unknown mode of CBX action, which provide insight into the role of the first extracellular loop in Panx1 channel gating. PMID- 26755775 TI - False-negative type-specific glycoprotein G antibody responses in STI clinic patients with recurrent HSV-1 or HSV-2 DNA positive genital herpes, The Netherlands. AB - OBJECTIVES: Herpes simplex virus (HSV) type-discriminating antibody tests (glycoprotein G (gG) directed) are used to identify naive persons and differentiate acute infections from recurrences. We studied test characteristics of three commercially available antibody tests in patients with recurrent (established by viral PCR tests) herpes simplex virus type 1 (HSV-1) or herpes simplex virus type 2 (HSV-2) genital herpes episodes. METHODS: Serum samples (at minimum 3 months after t=0) were examined for the presence of gG-1-specific or gG 2-specific antibodies using the HerpeSelect 1 and 2 Immunoblot IgG, the HerpeSelect 1 and 2 enzyme linked immunoassays IgG and the LIAISON HSV-1 and HSV 2 IgG indirect chemiluminescence immunoassays. RESULTS: The immunoblot was HSV-1 positive in 70.6% (95% CI 44.0% to 89.7%), the LIAISON in 88.2% (95% CI 63.5% to 98.5%) and the ELISA in 82.4% (95% CI 56.6% to 96.2%) of the 17 patients with a recurrent HSV-1 episode. From 33 patients with a recurrent HSV-2 episode, the immunoblot was HSV-2 positive in 84.8% (95% CI 68.1% to 94.9%), the LIAISON in 69.7% (95% CI 51.3% to 84.4%) and the ELISA in 84.8% (95% CI 68.1% to 94.9%). Among 15/17 (88.2%; 95% CI 63.5% to 98.5%) patients with HSV-1 and 30/33 (90.1%; 95% CI 75.7% to 98.1%) patients with HSV-2, HSV-1 or HSV-2 antibodies, respectively, were detected in at least one of the three antibody tests. CONCLUSIONS: Commercial type-specific gG HSV-1 or HSV-2 antibody assays were false negative in 12-30% of patients with recurrent HSV-1 or HSV-2 DNA positive genital lesions. The clinical and epidemiological use of type-specific HSV serology can be hampered by false-negative results, especially if based on a single test. PMID- 26755776 TI - Achieving PCMH Status May Not Be Meaningful for Small Practices. PMID- 26755774 TI - Distinct alpha2 Na,K-ATPase membrane pools are differently involved in early skeletal muscle remodeling during disuse. AB - The Na,K-ATPase is essential for the contractile function of skeletal muscle, which expresses the alpha1 and alpha2 subunit isoforms of Na,K-ATPase. The alpha2 isozyme is predominant in adult skeletal muscles and makes a greater contribution in working compared with noncontracting muscles. Hindlimb suspension (HS) is a widely used model of muscle disuse that leads to progressive atrophy of postural skeletal muscles. This study examines the consequences of acute (6-12 h) HS on the functioning of the Na,K-ATPase alpha1 and alpha2 isozymes in rat soleus (disused) and diaphragm (contracting) muscles. Acute disuse dynamically and isoform-specifically regulates the electrogenic activity, protein, and mRNA content of Na,K-ATPase alpha2 isozyme in rat soleus muscle. Earlier disuse induced remodeling events also include phospholemman phosphorylation as well as its increased abundance and association with alpha2 Na,K-ATPase. The loss of alpha2 Na,K-ATPase activity results in reduced electrogenic pump transport and depolarized resting membrane potential. The decreased alpha2 Na,K-ATPase activity is caused by a decrease in enzyme activity rather than by altered protein and mRNA content, localization in the sarcolemma, or functional interaction with the nicotinic acetylcholine receptors. The loss of extrajunctional alpha2 Na,K-ATPase activity depends strongly on muscle use, and even the increased protein and mRNA content as well as enhanced alpha2 Na,K-ATPase abundance at this membrane region after 12 h of HS cannot counteract this sustained inhibition. In contrast, additional factors may regulate the subset of junctional alpha2 Na,K-ATPase pool that is able to recover during HS. Notably, acute, low-intensity muscle workload restores functioning of both alpha2 Na,K-ATPase pools. These results demonstrate that the alpha2 Na,K-ATPase in rat skeletal muscle is dynamically and acutely regulated by muscle use and provide the first evidence that the junctional and extrajunctional pools of the alpha2 Na,K-ATPase are regulated differently. PMID- 26755777 TI - The Paradox of Size: How Small, Independent Practices Can Thrive in Value-Based Care. PMID- 26755778 TI - Solo and Small Practices: A Vital, Diverse Part of Primary Care. AB - PURPOSE: Solo and small practices are facing growing pressure to consolidate. Our objectives were to determine (1) the percentage of family physicians in solo and small practices, and (2) the characteristics of and services provided by these practices. METHODS: A total of 10,888 family physicians seeking certification through the American Board of Family Medicine in 2013 completed a demographic survey. Their practices were split into categories by size: solo, small (2 to 5 providers), medium (6 to 20 providers), and large (more than 20 providers). We also determined the rurality of the county where the physicians practiced. We developed 2 logistic regression models: one assessed predictors of practicing in a solo or small practice, while the other was restricted to solo and small practices and assessed predictors of practicing in a solo practice. RESULTS: More than one-half of respondents worked in solo or small practices. Small practices were the largest group (36%) and were the most likely to be located in a rural setting (20%). The likelihood of having a care coordinator and medical home certification increased with practice size. Physicians were more likely to be practicing in small or solo practices (vs medium-sized or large ones) if they were African American or Hispanic, had been working for more than 30 years, and worked in rural areas. Physicians were more likely to be practicing in small practices (vs solo ones) if they worked in highly rural areas. CONCLUSIONS: Family physicians in solo and small practices comprised the majority among all family physicians seeking board certification and were more likely to work in rural geographies. Extension programs and community health teams have the potential to support transformation within these practices. PMID- 26755779 TI - Large Independent Primary Care Medical Groups. AB - PURPOSE: In the turbulent US health care environment, many primary care physicians seek hospital employment. Large physician-owned primary care groups are an alternative, but few physicians or policy makers realize that such groups exist. We wanted to describe these groups, their advantages, and their challenges. METHODS: We identified 21 groups and studied 5 that varied in size and location. We conducted interviews with group leaders, surveyed randomly selected group physicians, and interviewed external observers-leaders of a health plan, hospital, and specialty medical group that shared patients with the group. We triangulated responses from group leaders, group physicians, and external observers to identify key themes. RESULTS: The groups' physicians work in small practices, with the group providing economies of scale necessary to develop laboratory and imaging services, health information technology, and quality improvement infrastructure. The groups differ in their size and the extent to which they engage in value-based contracting, though all are moving to increase the amount of financial risk they take for their quality and cost performance. Unlike hospital-employed and multispecialty groups, independent primary care groups can aim to reduce health care costs without conflicting incentives to fill hospital beds and keep specialist incomes high. Each group was positively regarded by external observers. The groups are under pressure, however, to sell to organizations that can provide capital for additional infrastructure to engage in value-based contracting, as well as provide substantial income to physicians from the sale. CONCLUSIONS: Large, independent primary care groups have the potential to make primary care attractive to physicians and to improve patient care by combining human scale advantages of physician autonomy and the small practice setting with resources that are important to succeed in value-based contracting. PMID- 26755780 TI - Primary Care Physician Panel Size and Quality of Care: A Population-Based Study in Ontario, Canada. AB - PURPOSE: The purpose of this study was to determine the relationship between the number of patients under a primary care physician's care (panel size) and primary care quality indicators. METHODS: We conducted a cross-sectional, population based study of fee-for-service and capitated interprofessional and non interprofessional primary health care practices in Ontario, Canada between April 2008 and March 2010, encompassing 4,195 physicians with panel sizes >=1,200 serving 8.3 million patients. Data was extracted from multiple linked, health related administrative databases and covered 16 quality indicators spanning 5 dimensions of care: access, continuity, comprehensiveness, and evidence-based indicators of cancer screening and chronic disease management. RESULTS: The likelihood of being up-to-date on cervical, colorectal, and breast cancer screening showed relative decreases of 7.9% (P <.001), 5.9% (P = .01), and 4.6% (P <.001), respectively, with increasing panel size (from 1,200 to 3,900). Eight chronic care indicators (4 medication-based and 4 screening-based) showed no significant association with panel size. The likelihood of individuals with a new diagnosis of congestive heart failure having an echocardiogram, however, increased by a relative 8.1% (P <.001) with higher panel size. Increasing panel size was also associated with a 10.8% relative increase in hospitalization rates for ambulatory-care-sensitive conditions (P = .04) and a 10.8% decrease in non urgent emergency department visits (P = .004). Continuity was highest with medium panel sizes (P <.001), and comprehensiveness had a small decrease (P = .03) with increasing panel size. CONCLUSIONS: Increasing panel size was associated with small decreases in cancer screening, continuity, and comprehensiveness, but showed no consistent relationships with chronic disease management or access indicators. We found no panel size threshold above which quality of care suffered. PMID- 26755781 TI - Willingness to Exchange Health Information via Mobile Devices: Findings From a Population-Based Survey. AB - PURPOSE: The rapid proliferation of mobile devices offers unprecedented opportunities for patients and health care professionals to exchange health information electronically, but little is known about patients' willingness to exchange various types of health information using these devices. We examined willingness to exchange different types of health information via mobile devices, and assessed whether sociodemographic characteristics and trust in clinicians were associated with willingness in a nationally representative sample. METHODS: We analyzed data for 3,165 patients captured in the 2013 Health Information National Trends Survey. Multinomial logistic regression analysis was conducted to test differences in willingness. Ordinal logistic regression analysis assessed correlates of willingness to exchange 9 types of information separately. RESULTS: Participants were very willing to exchange appointment reminders (odds ratio [OR] = 6.66; 95% CI, 5.68-7.81), general health tips (OR = 2.03; 95% CI, 1.74-2.38), medication reminders (OR = 2.73; 95% CI, 2.35-3.19), laboratory/test results (OR = 1.76; 95% CI, 1.62-1.92), vital signs (OR = 1.63; 95% CI, 1.48-1.80), lifestyle behaviors (OR = 1.40; 95% CI, 1.24-1.58), and symptoms (OR = 1.62; 95% CI, 1.46 1.79) as compared with diagnostic information. Older adults had lower odds of being more willing to exchange any type of information. Education, income, and trust in health care professional information correlated with willingness to exchange certain types of information. CONCLUSIONS: Respondents were less willing to exchange via mobile devices information that may be considered sensitive or complex. Age, socioeconomic factors, and trust in professional information were associated with willingness to engage in mobile health information exchange. Both information type and demographic group should be considered when developing and tailoring mobile technologies for patient-clinician communication. PMID- 26755782 TI - Rates and Predictors of Uncontrolled Hypertension Among Hypertensive Homeless Adults Using New York City Shelter-Based Clinics. AB - PURPOSE: We undertook a study to determine the rates, predictors, and barriers to blood pressure control among homeless and nonhomeless hypertensive adult patients from 10 New York City shelter-based clinics. METHODS: The study was a retrospective chart review of blood pressure measurements, sociodemographic characteristics, and factors associated with homelessness and hypertension extracted from the medical records of a random sample of hypertensive patients (N = 210) in 2014. RESULTS: Most patients were African American or Hispanic; 24.8% were female, and 84.3% were homeless for a mean duration of 3.07 years (SD = 5.04 years). Homeless adult patients were younger, had less insurance, and were more likely to be a current smoker and alcohol abuser. Of the 210 hypertensive patients, 40.1% of homeless and 33.3% of nonhomeless patients had uncontrolled blood pressure (P = .29) when compared with US rates for hypertensive adults, which range between 19.6% and 24.8%, respectively; 15.8% of homeless patients had stage 2 hypertension (P = .27). Homeless hypertensive patients with diabetes or multiple chronic diseases had better blood pressure control (P <.01). In logistic regression, lack of insurance was associated with inadequate blood pressure control (P <.05). CONCLUSIONS: The high rate of uncontrolled hypertension among hypertensive homeless adults is alarming. We propose comprehensive approaches to improve social support, access to medical insurance, and medication adherence, the lack of which complicate blood pressure control, targeted health education, and life style modifications using mobile health strategies for this mobile population. PMID- 26755783 TI - The 12-Month Incidence and Predictors of PHQ-9-Screened Depressive Symptoms in Chinese Primary Care Patients. AB - PURPOSE: Evidence regarding the onset of depressive symptoms in primary care is rarely available but can help inform policy development, service planning, and clinical decision making. The objective of this study was to estimate the 12 month cumulative incidence and predictors of a positive screen for depressive symptoms on the 9-item Patient Health Questionnare-9 (PHQ-9) among primary care patients with no history of physician-diagnosed depression. METHODS: We monitored a cohort of 2,929 adult primary care patients with no past history of physician diagnosed depression and with baseline PHQ-9 scores of 9 or lower by telephone interview at 3, 6, and 12 months. A generalized linear mixed effects Poisson Model was used to explore factors associated with the incidence of PHQ-positive symptoms. RESULTS: The cumulative incidence of positive screening on the PHQ-9 over 12 months was 5.23% (95% CI, 3.83%-6.64%). Positive predictors included being female, coming from a lower-income household, being a smoker, having at least 2 comorbidities, having a family history of depression, and having consulted a physician at least twice in the past 4 weeks. Consulting a physician with qualifications in both family medicine and psychological medicine was a negative predictor. CONCLUSIONS: The cumulative incidence of PHQ-9-screened depressive symptoms in this study population was higher than those reported for depressive disorders in earlier systematic reviews. Groups who may warrant greater treatment attention include women, patients with multimorbidity, smokers, patients with recent high rates of medical consultations, and those who are from lower-income households or who have a family history of depression. Greater physician training may have a protective effect. PMID- 26755786 TI - Split-Session Focus Group Interviews in the Naturalistic Setting of Family Medicine Offices. AB - PURPOSE: When recruiting health care professionals to focus group interviews, investigators encounter challenges such as busy clinic schedules, recruitment, and a desire to get candid responses from diverse participants. We sought to overcome these challenges using an innovative, office-based, split-session focus group procedure in a project that elicited feedback from family medicine practices regarding a new preventive services model. This procedure entails allocating a portion of time to the entire group and the remaining time to individual subgroups. We discuss the methodologic procedure and the implications of using this approach for data collection. METHODS: We conducted split-session focus groups with physicians and staff in 4 primary care practices. The procedure entailed 3 sessions, each lasting 30 minutes: the moderator interviewed physicians and staff together, physicians alone, and staff alone. As part of the focus group interview, we elicited and analyzed participant comments about the split-session format and collected observational field notes. RESULTS: The split session focus group interviews leveraged the naturalistic setting of the office for context-relevant discussion. We tested alternate formats that began in the morning and at lunchtime, to parallel each practice's workflow. The split-session approach facilitated discussion of topics primarily relevant to staff among staff, topics primarily relevant to physicians among physicians, and topics common to all among all. Qualitative feedback on this approach was uniformly positive. CONCLUSION: A split-session focus group interview provides an efficient, effective way to elicit candid qualitative information from all members of a primary care practice in the naturalistic setting where they work. PMID- 26755785 TI - Pragmatic Method Using Blood Pressure Diaries to Assess Blood Pressure Control. AB - PURPOSE: Twenty-four-hour ambulatory blood pressure (ABP) is the reference standard of blood pressure control. Home blood pressure (HBP) is superior to clinic blood pressure for assessing control, but a barrier to its use is the need for physicians to calculate average blood pressure from patient diaries. We sought to develop a quick and pragmatic method to assess blood pressure control from patients' HBP diaries. METHODS: Seven-day HBP and 24-hour ABP were measured in 286 patients with uncomplicated treated hypertension (aged 64 +/- 8 years; 53% female). We determined the optimal ratio of home systolic blood pressure readings above threshold (>=135 mm Hg) for the last 10 recorded that would best predict elevated 24-hour ABP. Uncontrolled blood pressure was defined as 24-hour ABP systolic blood pressure >=130 mm Hg or 24-hour ABP daytime systolic blood pressure >=135 mm Hg. Validation by corroborative evidence was tested by association with markers of end-organ disease. RESULTS: The best predictor of 24 hour ABP systolic blood pressure above treatment/target threshold was having 3 or more (>=30%) of the last 10 home systolic blood pressure readings >=135 mm Hg (area under the receiver operating characteristic curve = 0.71). Importantly, patients meeting this criterion had evidence of target organ disease, with significantly higher aortic stiffness, left ventricular relative wall thickness, and left atrial area, and lower left ventricular ejection fraction, compared with those who did not meet this criterion. CONCLUSIONS: To facilitate uptake of HBP monitoring, we propose that physicians can determine the percentage of the last 10 home systolic blood pressure values >=135 mm Hg for a patient and tailor management accordingly. PMID- 26755788 TI - White Nights. AB - "How can you sleep at night after you ruined my life?" Arthur, a veteran patient of mine, implored after receiving his test results. This essay recounts my experience as a physician in coping with an extremely anxious patient, its influence on me, and some of my reflections on the ensuing white nights. PMID- 26755784 TI - Prescription Opioid Duration, Dose, and Increased Risk of Depression in 3 Large Patient Populations. AB - PURPOSE: Recent results suggests the risk of a new onset of depression increases with longer duration of opioid analgesic use. It is unclear whether new-onset depression related to opioid analgesic use is a function of the dose prescribed or the duration of use or both. METHODS: Using a retrospective cohort design, we collected patient data from 2000 to 2012 from the Veterans Health Administration (VHA), and from 2003 to 2012 from both Baylor Scott & White Health (BSWH) and the Henry Ford Health System (HFHS). Patients (70,997 VHA patients, 13,777 BSWH patients, and 22,981 HFHS patients) were new opioid users, aged 18 to 80 years, without a diagnosis of depression at baseline. Opioid analgesic use duration was defined as 1 to 30, 31 to 90, and more than 90 days, and morphine equivalent dose (MED) was defined as 1 to 50 mg/d, 51 to 100 mg/d, and greater than 100 mg/d of analgesic. Pain and other potential confounders were controlled for by inverse probability of treatment-weighted propensity scores. RESULTS: New-onset depression after opioid analgesic use occurred in 12% of the VHA sample, 9% of the BSWH sample, and 11% of the HFHS sample. Compared with 1- to 30-day users, new-onset depression increased in those with longer opioid analgesic use. Risk of new-onset depression with 31 to 90 days of opioid analgesic use ranged from hazard ratio [HR] = 1.18 (95% CI, 1.10-1.25) in VHA to HR = 1.33 (95% CI, 1.16 1.52) in HFHS; in opioid analgesic use of more than 90 days, it ranged from HR = 1.35 (95% CI, 1.26-1.44) in VHA to HR = 2.05 (95% CI, 1.75-2.40) in HFHS. Dose was not significantly associated with a new onset of depression. CONCLUSIONS: Opioid-related new onset of depression is associated with longer duration of use but not dose. Patients and practitioners should be aware that opioid analgesic use of longer than 30 days imposes risk of new-onset depression. Opioid analgesic use, not just pain, should be considered a potential source when patients report depressed mood. PMID- 26755787 TI - Healing. AB - My personal ethos of healing is an expression of the belief that I can and do act to heal patients while I attend to the traditional goals of medicine. The 7 supporting principles that inform my ethos are dignity, authenticity, integrity, transparency, solidarity, generosity, and resiliency. I invite others, including medical students, residents, and practicing physicians, to reflect and discover their own ethos of healing and the principles that guide their professional growth. A short digital documentary accompanies this essay for use as a reflective prompt to encourage personal and professional development. PMID- 26755790 TI - AAFP EXPENDS HUGE EFFORT TO SHAPE NEW PAYMENT SYSTEM. PMID- 26755789 TI - BUILDING RESEARCH & SCHOLARSHIP CAPACITY IN DEPARTMENTS OF FAMILY MEDICINE: A NEW JOINT ADFM-NAPCRG INITIATIVE. PMID- 26755793 TI - THE RESIDENCY CURRICULUM RESOURCE: A USERS' PERSPECTIVE. PMID- 26755795 TI - Evaluation of Autologous Fascia Implantation With Controlled Release of Fibroblast Growth Factor for Recurrent Laryngeal Nerve Paralysis Due to Long-term Denervation. AB - OBJECTIVES: Paralyzed tissue due to long-term denervation is resistant to many treatments because it induces irreversible histological changes and disorders of deglutition or phonation. We sought to determine the effect of autologous transplantation of fascia into the vocal fold (ATFV) with controlled release of basic fibroblast growth factor (bFGF) on long-term unilateral vocal fold paralysis (UVFP). METHODS: Unilateral recurrent laryngeal nerve (RLN) section was performed on 20 rats. Five rats were implanted with autologous fascia only (fascia group), and 10 rats were implanted with autologous fascia and a gelatin hydrogel sheet with 1 MUg (1 MUg bFGF + fascia group) or 0.1 MUg (0.1 MUg bFGF + fascia group) of bFGF 4 months after RLN section. We evaluated the normalized glottal gap and laryngeal volume and histological changes 3 months after implantation. RESULTS: The normalized glottal gap was significantly reduced in the 3 fascia implantation groups. Normalized laryngeal volume, fat volume, and lateral thyroarytenoid muscle volume were significantly increased in the 2 fascia implantation with bFGF groups. CONCLUSIONS: The ATFV with controlled release of bFGF repaired the glottal gap and laryngeal volume after RLN section and may reduce the occurrence of aspiration and hoarseness. We speculate that this treatment improves laryngeal function in long-term RLN denervation. PMID- 26755798 TI - Mental health screening in immigration detention: A fresh look at Australian government data. AB - OBJECTIVES: The poor mental health of asylum seekers and refugees in immigration detention has consistently been reported in peer-reviewed literature internationally; however, data on the mental health of asylum seekers and refugees detained in Australian immigration has been very limited. METHODS: We re analysed mental health screening data obtained by the Human Rights Commission. RESULTS: Longer time in detention was associated with higher self-reported depression scores, with female individuals being more vulnerable to time in detention than those of male gender. Approximately one-half of the refugee group who agreed to complete the Harvard Trauma Questionnaire had post-traumatic stress disorder symptoms. On clinician-rated measures, one-third of the children, adolescents and adults suffered with clinical symptoms requiring tertiary outpatient assessment. CONCLUSIONS: This paper consolidates the findings of the 2014 Australian Human Rights Commission report and it provides an argument for public reporting of refugee data. PMID- 26755796 TI - Relationships between Personal Measurements of 'Total' Dust, Respirable, Thoracic, and Inhalable Aerosol Fractions in the Cement Production Industry. AB - AIMS: The aims of this study were to examine the relationships and establish conversion factors between 'total' dust, respirable, thoracic, and inhalable aerosol fractions measured by parallel personal sampling on workers from the production departments of cement plants. 'Total' dust in this study refers to aerosol sampled by the closed face 37-mm Millipore filter cassette. METHODS: Side by-side personal measurements of 'total' dust and respirable, thoracic, and inhalable aerosol fractions were performed on workers in 17 European and Turkish cement plants. Simple linear and mixed model regressions were used to model the associations between the samplers. RESULTS: The total number of personal samples collected on 141 workers was 512. Of these 8.4% were excluded leaving 469 for statistical analysis. The different aerosol fractions contained from 90 to 130 measurements and-side-by side measurements of all four aerosol fractions were collected on 72 workers.The median ratios between observed results of the respirable, 'total' dust, and inhalable fractions relative to the thoracic aerosol fractions were 0.51, 2.4, and 5.9 respectively. The ratios between the samplers were not constant over the measured concentration range and were best described by regression models. Job type, position of samplers on left or right shoulder and plant had no substantial effect on the ratios. CONCLUSIONS: The ratios between aerosol fractions changed with different air concentrations. Conversion models for estimation of the fractions were established. These models explained a high proportion of the variance (74-91%) indicating that they are useful for the estimation of concentrations based on measurements of a different aerosol fraction. The calculated uncertainties at most observed concentrations were below 30% which is acceptable for comparison with limit values (EN 482, 2012). The cement industry will therefore be able to predict the health related aerosol fractions from their former or future measurements of one of the fractions. PMID- 26755799 TI - Closing up and moving on: a personal perspective of psychiatric practice closure. AB - OBJECTIVES: This paper sets out a process for the elective closure of a clinical practice. The details are described for a particular example of a practice closure. The common elements to all practice closures are identified. A range of other factors which may be relevant to other practice closure circumstances are also listed and the literature is referenced. CONCLUSIONS: The closure of a clinical practice is a major stage in professional life and merits preparation, support and accessible resources. PMID- 26755797 TI - Do RA or TNF inhibitors increase the risk of cervical neoplasia or of recurrence of previous neoplasia? A nationwide study from Sweden. AB - OBJECTIVES: To examine screening patterns and the risk of cervical neoplasia in women with rheumatoid arthritis (RA) treated or not with tumour necrosis factor inhibitors (TNFi). METHODS: We performed a nationwide register-based cohort study in Sweden of women with RA who started a first TNFi (n=9629), biologics-naive women with RA (n=34 984) and general population comparators (matched 1:10, n=300 331), followed up from 1999 to 2012. Outcomes were first cytology screening with normal outcome, first ever cervical intraepithelial neoplasia (CIN) grade 1, first ever CIN 2-3 or adenocarcinoma in situ and first ever invasive cervical cancer during follow-up. HRs were assessed through Cox regressions adjusted for age, educational level, prior cervical screens, comorbidities, marital status and prior hospitalisations. RESULTS: Biologic-naive women with RA had more screenings (HR 1.08, 95% CI 1.06 to 1.10), were at greater risk of CIN 1 (HR 1.53, 1.23 to 1.89) and CIN 2-3 (HR 1.39, 1.16 to 1.66), but not of invasive cervical cancer (HR 1.09, 0.71 to 1.65) compared with the general population. Patients who initiated TNFi therapy had similar screening patterns (HR 1.01, 0.98 to 1.05), were not at increased risk of CIN 1 (HR 1.23, 0.87 to 1.74), but were at increased risk of CIN 2-3 (HR 1.36, 1.01 to 1.82) and invasive cervical cancer (HR 2.10, 1.04 to 4.23) compared with biologics-naive women with RA. Estimates varied little with successive adjustments, but were attenuated/absent in sensitivity analyses restricted to 2006-2012 and a disease-modifying antirheumatic drugs-treated comparator. CONCLUSIONS: Women with RA in general are at elevated risk of cervical dysplasia. Compared with biologics-naive patients, women treated with TNFi are at increased risk of cervical cancer. Whether this increase is causally linked with TNFi could not be fully disentangled. PMID- 26755807 TI - Development of a Dutch intervention for obese young children. AB - The objective of this article is to provide insight in the five-step development process of the best evidence, best practice intervention for obese young children 'AanTafel!'. A set of requirements for intervention development was developed to guide the data inquiry: the use of theory, influencing factors, tailoring, multi disciplinarity, duration/frequency and evaluation and monitoring. Step I retrieved evidence from clinical guidelines, followed by a systematic review with meta-analysis (Step II) and an extended literature review (Step III). Evidence was consistent with regard to parent-focus, targeting family level, including diet, physical activity and behaviour change techniques and tailoring to age. However, no evidence or inconsistent evidence emerged from the theory-basis, group-versus-individual sessions, face-to-face contact versus Internet-mediated contact, which disciplines to involve and how to involve them, as well as intervention duration and intensity. Hence, practice-based insights from parental interviews (Step IV) and involved therapists were added and subsequently integrated to the intervention 'AanTafel!' (Step V). 'AanTafel!' is a multi component, multi-disciplinary, family-based, parent-focused, age-specific intervention, which is tailored to individual children and families with a duration of 1 year, and using a combination of individual and group sessions as well as a Web-based learning module. Changes in scientific working principles with regard to data collection, reporting and translation to guidelines are required. Practice and science may benefit from close collaboration in designing, implementing and evaluating interventions. PMID- 26755806 TI - Diverse molecular recognition properties of blood group A binding monoclonal antibodies. AB - Information about specificity and affinity is critical for use of carbohydrate binding antibodies. Herein, we evaluated eight monoclonal antibodies to the blood group A (BG-A) antigen. Antibodies 87-G, 9A, HE-10, HE-24, HE-193, HE-195, T36 and Z2A were profiled on a glycan microarray to assess specificity, relative affinity and the influence of glycan density on recognition. Our studies highlight several noteworthy recognition properties. First, most antibodies bound GalNAcalpha1-3Gal and the BG-A trisaccharide nearly as well as larger BG-A oligosaccharides. Second, several antibodies only bound the BG-A trisaccharide when displayed on certain glycan chains. These first two points indicate that the carrier glycan chains primarily influence selectivity, rather than binding strength. Third, binding of some antibodies was highly dependent on glycan density, illustrating the importance of glycan presentation for recognition. Fourth, some antibodies recognized the tumor-associated Tn antigen, and one antibody only bound the variant composed of a GalNAc-alpha-linked to a serine residue. Collectively, these results provide new insights into the recognition properties of anti-BG-A antibodies. PMID- 26755808 TI - Relaunching JIM. PMID- 26755809 TI - Harnessing immune cells to enhance beta-cell mass in type 1 diabetes. AB - Type 1 diabetes is characterized by early beta-cell loss leading to insulin dependence in virtually all patients with the disease in order to maintain glucose homeostasis. Most studies over the past few decades have focused on limiting the autoimmune attack on the beta cells. However, emerging data from patients with long-standing diabetes who continue to harbor functional insulin producing cells in their diseased pancreas have prompted scientists to examine whether proliferation of existing beta cells can be enhanced to promote better glycemic control. In support of this concept, several studies indicate that mononuclear cells that infiltrate the islets have the capacity to trigger proliferation of islet cells including beta cells. These observations indicate the exciting possibility of identifying those mononuclear cell types and their soluble factors and harnessing their ability to promote beta-cell growth concomitant with autoimmune therapy to prevent the onset and/or halt the progression of the disease. PMID- 26755810 TI - Oxidative challenge in Alzheimer's disease: state of knowledge and future needs. AB - A large body of experimental and postmortem findings indicate that Alzheimer's disease (AD) is associated with increased oxidative stress (OxS) levels in the brain. Despite the current limitations of OxS assessment in living subjects, recent data suggest that oxidative challenge might increase early both in the central nervous system and peripheral fluids. The aim of this review was to provide an overview of the existing literature linking systemic OxS to brain OxS in AD. We firmly believe that continued research aimed at overcoming the methodological and design issues affecting the body of studies in this field is mandatory for successful development of an effective antioxidant-based treatment of AD. PMID- 26755811 TI - Hepatorenal syndrome in hospitalized patients with chronic liver disease: results from the Nationwide Inpatient Sample 2002-2012. AB - Hepatorenal syndrome (HRS) is one of the leading causes of hospitalizations in patients with chronic liver disease (CLD). We conducted a retrospective national database study to determine the epidemiology of HRS in hospitalized patients with CLD. Data from a Nationwide Inpatient Sample were extracted from 2002 to 2012 using ICD-9-CM codes related to CLD and HRS. The following outcomes were examined: in-hospital mortality, total charges, length of stay (LOS), patient demographics, procedures, complications, and comorbidities. Statistical analysis including regression was performed to examine factors associated with HRS. During 2002-2012, hospital discharges related to CLD increased from 407,246 to 836,475 with an increase of 37.9% for HRS as a complication in this population. Patients with CLD and HRS had worse outcomes compared with patients with CLD without HRS. This was manifested as a higher mortality rate (32.0% vs 10.3%), increased LOS (median 7 vs 5 days), and increased hospital costs (median $16,000 vs $11,000). Logistic regression demonstrated that HIV/AIDS (adjusted OR 2.9, 95% CI 2.2 to 3.9), pneumonia (aOR 2.8, 95% CI 2.3 to 3.2), and esophageal variceal bleeding (aOR 1.9, 95% CI 1.7 to 2.0) were associated with higher mortality in patients with HRS. Conversely, liver transplantation (aOR 0.1, 95% CI 0.1 to 0.1), transjugular intrahepatic portosystemic shunt (aOR 0.5, 95% CI 0.4 to 0.6), and hospitalization in the Midwest region of the USA (aOR 0.7, 95% CI 0.6 to 0.7) were associated with reduced mortality. The incidence of HRS in hospitalized patients with CLD increased during 2002-2012. HRS is associated with significant mortality and morbidity in these patients. PMID- 26755812 TI - Risk stratification using gated stress myocardial perfusion imaging: comparison between patients with and without sexual dysfunction. AB - Sexuality is an indispensable part of life. When a problem is encountered related to this topic, the quality of life is negatively affected. Therefore, every problem related to sexuality is extremely private and important to an individual. This study aims to investigate the use of myocardial perfusion scintigraphy (MPS) for advanced assessment of patients with known or suspected coronary artery disease, cardiovascular disease, and in the intermediate risk group for SD. The study included 250 patients (150 male, 100 female, mean age 54+/-12.10) sent by the Cardiology Clinic to the Nuclear Medicine Clinic for MPS due to suspected cardiovascular disease (CVD). The questionnaire study was applied by two methods as face-to-face interviews or online. Data on sociodemographic characteristics and cardiovascular diseases together with risk factors for sexual activity were collected using a general information form. Patients were divided into three categories of risk depending on major risk factors for cardiovascular diseases: low, intermediate, and high risk. On comparing the risk scores between the groups, it was seen that there was a statistically clear reduction in the intermediate risk group of patients with SD according to MPS scoring. MPS is a cost-effective, reliable, and accurate non-invasive diagnostic method necessary for routine use to assess cardiovascular disease and in the intermediate risk group for SD. PMID- 26755813 TI - Mibefradil suppresses the proliferation of pulmonary artery smooth muscle cells. AB - Intracellular Ca(2+) levels play a critical role in the regulation of vasodilation and vasoconstriction by stimulating pulmonary artery smooth muscle cell (PASMC) proliferation, which is important in the pathogenesis of pulmonary arterial hypertension (PAH); however, L-type Ca(2+) channel antagonists are useful in only few patients with PAH. The present study sought to assess the effect of mibefradil, which blocks T-type Ca(2+) channels, on PASMC proliferation and Ca(2+) channel profile. Human PASMCs were stimulated with 25 ng/mL platelet derived growth factor-BB (PDGF-BB) with and without 10 uM mibefradil or 100 nM sildenafil. After 48 or 72 h, PASMC proliferation and Ca(2+) channel expression were assessed by MTT assays and western blot analysis, respectively. PDGF-BB induced PASMC proliferation at 72 h (p<0.01), which was inhibited by both sildenafil and mibefradil (p<0.01). Transient receptor potential Ca(2+) channel 6 (TRPC6) expression was significantly increased with PDGF-BB stimulation (p=0.009); however, no changes in TRPC1, TRPC3, CAV1.2, and CAV3.2 levels were observed. Although both TRPC1 and CAV1.2 expression levels were increased in PDGF stimulated PASMCs on mibefradil and sildenafil treatment, it was not statistically significant (p=0.086 and 1.000, respectively). Mibefradil inhibits PDGF-BB-stimulated PASMC proliferation; however, the mechanism through which it functions remains to be determined. Further studies are required to elucidate the full therapeutic value of mibefradil for PAH. PMID- 26755814 TI - Pharmacological priming of adipose-derived stem cells promotes myocardial repair. AB - Adipose-derived stem cells (ADSCs) have myocardial regeneration potential, and transplantation of these cells following myocardial infarction (MI) in animal models leads to modest improvements in cardiac function. We hypothesized that pharmacological priming of pre-transplanted ADSCs would further improve left ventricular functional recovery after MI. We previously identified a compound from a family of 3,5-disubstituted isoxazoles, ISX1, capable of activating an Nkx2-5-driven promoter construct. Here, using ADSCs, we found that ISX1 (20 mM, 4 days) triggered a robust, dose-dependent, fourfold increase in Nkx2-5 expression, an early marker of cardiac myocyte differentiation and increased ADSC viability in vitro. Co-culturing neonatal cardiomyocytes with ISX1-treated ADSCs increased early and late cardiac gene expression. Whereas ISX1 promoted ADSC differentiation toward a cardiogenic lineage, it did not elicit their complete differentiation or their differentiation into mature adipocytes, osteoblasts, or chondrocytes, suggesting that re-programming is cardiomyocyte specific. Cardiac transplantation of ADSCs improved left ventricular functional recovery following MI, a response which was significantly augmented by transplantation of ISX1- pretreated cells. Moreover, ISX1-treated and transplanted ADSCs engrafted and were detectable in the myocardium 3 weeks following MI, albeit at relatively small numbers. ISX1 treatment increased histone acetyltransferase (HAT) activity in ADSCs, which was associated with histone 3 and histone 4 acetylation. Finally, hearts transplanted with ISX1-treated ADSCs manifested significant increases in neovascularization, which may account for the improved cardiac function. These findings suggest that a strategy of drug-facilitated initiation of myocyte differentiation enhances exogenously transplanted ADSC persistence in vivo, and consequent tissue neovascularization, to improve cardiac function. PMID- 26755815 TI - Plasma thyroid hormone concentration is associated with hepatic triglyceride content in patients with type 2 diabetes. AB - The underlying mechanisms responsible for the development and progression of non alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) are unclear. Since the thyroid hormone regulates mitochondrial function in the liver, we designed this study in order to establish the association between plasma free T4 levels and hepatic triglyceride accumulation and histological severity of liver disease in patients with T2DM and NAFLD. This is a cross sectional study including a total of 232 patients with T2DM. All patients underwent a liver MR spectroscopy ((1)H-MRS) to quantify hepatic triglyceride content, and an oral glucose tolerance test to estimate insulin resistance. A liver biopsy was performed in patients with a diagnosis of NAFLD. Patients were divided into 5 groups according to plasma free T4 quintiles. We observed that decreasing free T4 levels were associated with an increasing prevalence of NAFLD (from 55% if free T4>=1.18 ng/dL to 80% if free T4<0.80 ng/dL, p=0.016), and higher hepatic triglyceride accumulation by (1)H-MRS (p<0.001). However, lower plasma free T4 levels were not significantly associated with more insulin resistance or more severe liver histology (ie, inflammation, ballooning, or fibrosis). Decreasing levels of plasma free T4 are associated with a higher prevalence of NAFLD and increasing levels of hepatic triglyceride content in patients with T2DM. These results suggest that thyroid hormone may play a role in the regulation of hepatic steatosis and support the notion that hypothyroidism may be associated with NAFLD. No NCT number required. PMID- 26755818 TI - Hepatic Stellate Cells Directly Inhibit B Cells via Programmed Death-Ligand 1. AB - We demonstrated previously that mouse hepatic stellate cells (HSCs) suppress T cells via programmed death-ligand 1 (PD-L1), but it remains unknown whether they exert any effects on B cells, the other component of the adaptive immune system. In this study, we found that mouse HSCs directly inhibited B cells and that PD-L1 was also integrally involved. We found that HSCs inhibited the upregulation of activation markers on activated B cells, as well as the proliferation of activated B cells and their cytokine/Ig production in vitro, and that pharmaceutically or genetically blocking the interaction of PD-L1 with programmed cell death protein 1 impaired the ability of HSCs to inhibit B cells. To test the newly discovered B cell-inhibitory activity of HSCs in vivo, we developed a protocol of intrasplenic artery injection to directly deliver HSCs into the spleen. We found that local delivery of wild-type HSCs into the spleens of mice that had been immunized with 4-hydroxy-3-nitrophenylacetyl-Ficoll, a T cell independent Ag, significantly suppressed Ag-specific IgM and IgG production in vivo, whereas splenic artery delivery of PD-L1-deficient HSCs failed to do so. In conclusion, in addition to inhibiting T cells, mouse HSCs concurrently inhibit B cells via PD-L1. This direct B cell-inhibitory activity of HSCs should contribute to the mechanism by which HSCs maintain the liver's immune homeostasis. PMID- 26755819 TI - Multiple Inflammatory Cytokines Converge To Regulate CD8+ T Cell Expansion and Function during Tuberculosis. AB - The differentiation of effector CD8(+) T cells is a dynamically regulated process that varies during different infections and is influenced by the inflammatory milieu of the host. In this study, we define three signals regulating CD8(+) T cell responses during tuberculosis by focusing on cytokines known to affect disease outcome: IL-12, type I IFN, and IL-27. Using mixed bone marrow chimeras, we compared wild-type and cytokine receptor knockout CD8(+) T cells within the same mouse following aerosol infection with Mycobacterium tuberculosis. Four weeks postinfection, IL-12, type 1 IFN, and IL-27 were all required for efficient CD8(+) T cell expansion in the lungs. We next determined if these cytokines directly promote CD8(+) T cell priming or are required only for expansion in the lungs. Using retrogenic CD8(+) T cells specific for the M. tuberculosis Ag TB10.4 (EsxH), we observed that IL-12 is the dominant cytokine driving both CD8(+) T cell priming in the lymph node and expansion in the lungs; however, type I IFN and IL-27 have nonredundant roles supporting pulmonary CD8(+) T cell expansion. Thus, IL-12 is a major signal promoting priming in the lymph node, but a multitude of inflammatory signals converge in the lung to promote continued expansion. Furthermore, these cytokines regulate the differentiation and function of CD8(+) T cells during tuberculosis. These data demonstrate distinct and overlapping roles for each of the cytokines examined and underscore the complexity of CD8(+) T cell regulation during tuberculosis. PMID- 26755820 TI - IL-4 Inhibits the Biogenesis of an Epigenetically Suppressive PIWI-Interacting RNA To Upregulate CD1a Molecules on Monocytes/Dendritic Cells. AB - The discovery of PIWI-interacting RNAs (piRNAs) revealed the complexity of the RNA world. Although piRNAs were first deemed to be germline specific, substantial evidence shows their various roles in somatic cells; however, their function in highly differentiated immune cells remains elusive. In this study, by initially screening with a small RNA deep-sequencing analysis, we found that a piRNA, tRNA Glu-derived piRNA [td-piR(Glu)], was expressed much more abundantly in human monocytes than in dendritic cells. By regulating the polymerase III activity, IL 4 potently decreased the biogenesis of tRNA-Glu and, subsequently, td-piR(Glu). Further, we revealed that the td-piR(Glu)/PIWIL4 complex recruited SETDB1, SUV39H1, and heterochromatin protein 1beta to the CD1A promoter region and facilitated H3K9 methylation. As a result, the transcription of CD1A was significantly inhibited. Collectively, we demonstrated that a piRNA acted as the signal molecule for a cytokine to regulate the expression of an important membrane protein for lipid Ag presentation. PMID- 26755821 TI - Low-Intensity Focused Ultrasound Induces Reversal of Tumor-Induced T Cell Tolerance and Prevents Immune Escape. AB - Immune responses against cancer cells are often hindered by immunosuppressive mechanisms that are developed in the tumor microenvironment. Induction of a hyporesponsive state in tumor Ag-specific T cells is one of the major events responsible for the inability of the adaptive immune system to mount an efficient antitumor response and frequently contributes to lessen the efficacy of immunotherapeutic approaches. Treatment of localized tumors by focused ultrasound (FUS) is a minimally invasive therapy that uses a range of input energy for in situ tumor ablation through the generation of thermal and cavitation effect. Using a murine B16 melanoma tumor model, we show that a variant of FUS that delivers a reduced level of energy at the focal point and generates mild mechanical and thermal stress in target cells has the ability to increase immunogenic presentation of tumor Ags, which results in reversal of tumor-induced T cell tolerance. Furthermore, we show that the combination of nonablative low energy FUS with an ablative hypofractionated radiation therapy results in synergistic control of primary tumors and leads to a dramatic reduction in spontaneous pulmonary metastases while prolonging recurrence-free survival only in immunocompetent mice. PMID- 26755822 TI - Local GM-CSF-Dependent Differentiation and Activation of Pulmonary Dendritic Cells and Macrophages Protect against Progressive Cryptococcal Lung Infection in Mice. AB - Patients with acquired deficiency in GM-CSF are susceptible to infections with Cryptococcus neoformans and other opportunistic fungi. We previously showed that GM-CSF protects against progressive fungal disease using a murine model of cryptococcal lung infection. To better understand the cellular and molecular mechanisms through which GM-CSF enhances antifungal host defenses, we investigated temporal and spatial relationships between myeloid and lymphoid immune responses in wild-type C57BL/6 mice capable of producing GM-CSF and GM-CSF deficient mice infected with a moderately virulent encapsulated strain of C. neoformans (strain 52D). Our data demonstrate that GM-CSF deficiency led to a reduction in: 1) total lung leukocyte recruitment; 2) Th2 and Th17 responses; 3) total numbers of CD11b(+) dendritic cells (DC) and CD11b(-) and CD11b(+) macrophages (Mphi); 4) DC and Mphi activation; and 5) localization of DC and Mphi to the microanatomic sites of alveolar infection. In contrast, GM-CSF deficiency resulted in increased accumulation of DC and Mphi precursors, namely Ly-6C(high) monocytes, in the blood and lungs of infected mice. Collectively, these results show that GM-CSF promotes the local differentiation, accumulation, activation, and alveolar localization of lung DC and Mphi in mice with cryptococcal lung infection. These findings identify GM-CSF as central to the protective immune response that prevents progressive fungal disease and thus shed new light on the increased susceptibility to these infections observed in patients with acquired GM-CSF deficiency. PMID- 26755823 TI - Molecular Analysis of Lipid-Reactive Vdelta1 gammadelta T Cells Identified by CD1c Tetramers. AB - CD1c is abundantly expressed on human dendritic cells (DC) and B cells, where it binds and displays lipid Ags to T cells. In this study, we report that CD1c tetramers carrying Mycobacterium tuberculosis phosphomycoketide bind gammadelta TCRs. An unbiased method of ligand-based TCR selection detects interactions only with Vdelta1(+) TCRs, and mutational analyses demonstrate a role of the Vdelta1 domain during recognition. These results strengthen evidence for a role of CD1c in the gammadelta T cell response, providing biophysical evidence for CD1c gammadelta TCR interactions and a named foreign Ag. Surprisingly, TCRs also bind CD1c complexes formed with diverse lipids such as lysophosphatidylcholine, sulfatide, or mannosyl-phosophomycoketide, but not lipopeptide ligands. Dissection of TCR interactions with CD1c carrying foreign Ags, permissive ligands, and nonpermissive lipid ligands clarifies the molecular basis of the frequently observed but poorly understood phenomenon of mixed self- and foreign Ag reactivity in the CD1 system. PMID- 26755824 TI - Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes. AB - Over 100 associated genetic loci have been robustly associated with schizophrenia. Gene prioritization and pathway analysis have focused on a priori hypotheses and thus may have been unduly influenced by prior assumptions and missed important causal genes and pathways. Using a data-driven approach, we show that genes in associated loci: (1) are highly expressed in cortical brain areas; (2) are enriched for ion channel pathways (false discovery rates <0.05); and (3) contain 62 genes that are functionally related to each other and hence represent promising candidates for experimental follow up. We validate the relevance of the prioritized genes by showing that they are enriched for rare disruptive variants and de novo variants from schizophrenia sequencing studies (odds ratio 1.67, P = 0.039), and are enriched for genes encoding members of mouse and human postsynaptic density proteomes (odds ratio 4.56, P = 5.00 * 10(-4); odds ratio 2.60, P = 0.049).The authors wish it to be known that, in their opinion, the first 2 authors should be regarded as joint First Author. PMID- 26755825 TI - Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms. AB - Mutations in the ALS2 gene result in early-onset amyotrophic lateral sclerosis, infantile-onset ascending hereditary spastic paraplegia and juvenile primary lateral sclerosis, suggesting prominent upper motor neuron involvement. However, the importance of alsin function for corticospinal motor neuron (CSMN) health and stability remains unknown. To date, four separate alsin knockout (Alsin(KO)) mouse models have been generated, and despite hopes of mimicking human pathology, none displayed profound motor function defects. This, however, does not rule out the possibility of neuronal defects within CSMN, which is not easy to detect in these mice. Detailed cellular analysis of CSMN has been hampered due to their limited numbers and the complex and heterogeneous structure of the cerebral cortex. In an effort to visualize CSMN in vivo and to investigate precise aspects of neuronal abnormalities in the absence of alsin function, we generated Alsin(KO)-UeGFP mice, by crossing Alsin(KO) and UCHL1-eGFP mice, a CSMN reporter line. We find that CSMN display vacuolated apical dendrites with increased autophagy, shrinkage of soma size and axonal pathology even in the pons region. Immunocytochemistry coupled with electron microscopy reveal that alsin is important for maintaining cellular cytoarchitecture and integrity of cellular organelles. In its absence, CSMN displays selective defects both in mitochondria and Golgi apparatus. UCHL1-eGFP mice help understand the underlying cellular factors that lead to CSMN vulnerability in diseases, and our findings reveal unique importance of alsin function for CSMN health and stability. PMID- 26755826 TI - Cockayne syndrome-derived neurons display reduced synapse density and altered neural network synchrony. AB - Cockayne syndrome (CS) is a rare genetic disorder in which 80% of cases are caused by mutations in the Excision Repair Cross-Complementation group 6 gene (ERCC6). The encoded ERCC6 protein is more commonly referred to as Cockayne Syndrome B protein (CSB). Classical symptoms of CS patients include failure to thrive and a severe neuropathology characterized by microcephaly, hypomyelination, calcification and neuronal loss. Modeling the neurological aspect of this disease has proven difficult since murine models fail to mirror classical neurological symptoms. Therefore, a robust human in vitro cellular model would advance our fundamental understanding of the disease and reveal potential therapeutic targets. Herein, we successfully derived functional CS neural networks from human CS induced pluripotent stem cells (iPSCs) providing a new tool to facilitate studying this devastating disease. We identified dysregulation of the Growth Hormone/Insulin-like Growth Factor-1 (GH/IGF-1) pathway as well as pathways related to synapse formation, maintenance and neuronal differentiation in CSB neurons using unbiased RNA-seq gene expression analyses. Moreover, when compared to unaffected controls, CSB-deficient neural networks displayed altered electrophysiological activity, including decreased synchrony, and reduced synapse density. Collectively, our work reveals that CSB is required for normal neuronal function and we have established an alternative to previously available models to further study neural-specific aspects of CS. PMID- 26755828 TI - Haploinsufficiency of BAZ1B contributes to Williams syndrome through transcriptional dysregulation of neurodevelopmental pathways. AB - Williams syndrome (WS) is a neurodevelopmental disorder caused by a genomic deletion of ~28 genes that results in a cognitive and behavioral profile marked by overall intellectual impairment with relative strength in expressive language and hypersocial behavior. Advancements in protocols for neuron differentiation from induced pluripotent stem cells allowed us to elucidate the molecular circuitry underpinning the ontogeny of WS. In patient-derived stem cells and neurons, we determined the expression profile of the Williams-Beuren syndrome critical region-deleted genes and the genome-wide transcriptional consequences of the hemizygous genomic microdeletion at chromosome 7q11.23. Derived neurons displayed disease-relevant hallmarks and indicated novel aberrant pathways in WS neurons including over-activated Wnt signaling accompanying an incomplete neurogenic commitment. We show that haploinsufficiency of the ATP-dependent chromatin remodeler, BAZ1B, which is deleted in WS, significantly contributes to this differentiation defect. Chromatin-immunoprecipitation (ChIP-seq) revealed BAZ1B target gene functions are enriched for neurogenesis, neuron differentiation and disease-relevant phenotypes. BAZ1B haploinsufficiency caused widespread gene expression changes in neural progenitor cells, and together with BAZ1B ChIP-seq target genes, explained 42% of the transcriptional dysregulation in WS neurons. BAZ1B contributes to regulating the balance between neural precursor self-renewal and differentiation and the differentiation defect caused by BAZ1B haploinsufficiency can be rescued by mitigating over-active Wnt signaling in neural stem cells. Altogether, these results reveal a pivotal role for BAZ1B in neurodevelopment and implicate its haploinsufficiency as a likely contributor to the neurological phenotypes in WS. PMID- 26755827 TI - Exploring the complete mutational space of the LDL receptor LA5 domain using molecular dynamics: linking SNPs with disease phenotypes in familial hypercholesterolemia. AB - Familial hypercholesterolemia (FH), a genetic disorder with a prevalence of 0.2%, represents a high-risk factor to develop cardiovascular and cerebrovascular diseases. The majority and most severe FH cases are associated to mutations in the receptor for low-density lipoproteins receptor (LDL-r), but the molecular basis explaining the connection between mutation and phenotype is often unknown, which hinders early diagnosis and treatment of the disease. We have used atomistic simulations to explore the complete SNP mutational space (227 mutants) of the LA5 repeat, the key domain for interacting with LDL that is coded in the exon concentrating the highest number of mutations. Four clusters of mutants of different stability have been identified. The majority of the 50 FH known mutations (33) appear distributed in the unstable clusters, i.e. loss of conformational stability explains two-third of FH phenotypes. However, one-third of FH phenotypes (17 mutations) do not destabilize the LR5 repeat. Combining our simulations with available structural data from different laboratories, we have defined a consensus-binding site for the interaction of the LA5 repeat with LDL-r partner proteins and have found that most (16) of the 17 stable FH mutations occur at binding site residues. Thus, LA5-associated FH arises from mutations that cause either the loss of stability or a decrease in domain's-binding affinity. Based on this finding, we propose the likely phenotype of each possible SNP in the LA5 repeat and outline a procedure to make a full computational diagnosis for FH. PMID- 26755830 TI - Quantification of the increase in thyroid cancer prevalence in Fukushima after the nuclear disaster in 2011--a potential overdiagnosis? AB - A thyroid ultrasound examination programme has been conducted in Fukushima Prefecture, Japan, after the nuclear disaster in 2011. Although remarkably high prevalence of thyroid cancer was observed, no relevant quantitative evaluation was conducted. We calculated the observed/expected (O/E) ratio of thyroid cancer prevalence for the residents aged <=20 years. Observed prevalence was the number of thyroid cancer cases detected by the programme through the end of April 2015. Expected prevalence was calculated as cumulative incidence by a life-table method using the national estimates of thyroid cancer incidence rate in 2001-10 (prior to the disaster) and the population of Fukushima Prefecture. The underlying assumption was that there was neither nuclear accident nor screening intervention. The observed and estimated prevalence of thyroid cancer among residents aged <=20 years was 160.1 and 5.2, respectively, giving an O/E ratio of 30.8 [95% confidence interval (CI): 26.2, 35.9]. When the recent increasing trend in thyroid cancer was considered, the overall O/E ratio was 22.2 (95% CI: 18.9, 25.9). The cumulative number of thyroid cancer deaths in Fukushima Prefecture, estimated with the same method (annual average in 2009-13), was 0.6 under age 40. Combined with the existing knowledge about radiation effect on thyroid cancer, our descriptive analysis suggests the possibility of overdiagnosis. Evaluation including individual-level analysis is required to further clarify the contribution of underlying factors. PMID- 26755829 TI - Safety of a short hydration method for cisplatin administration in comparison with a conventional method-a retrospective study. AB - OBJECTIVE: Cisplatin is administered in combination with massive hydration to avoid renal toxicity, making its administration difficult in an outpatient setting. Although a short hydration protocol for cisplatin has been recently developed, its safety is not fully understood. METHODS: Consecutive patients with lung or other cancer and an Eastern Cooperative Oncology Group performance status of 0-2 who were receiving chemotherapy containing cisplatin at a dose of >=60 mg/m(2) in a single administration were evaluated. Seventy-four patients were treated with a short hydration protocol consisting of 1750-2250 ml of hydration with mannitol and magnesium supplementation over a period of 3.75-4.75 h on Day 1. Sixty-nine patients were treated with a conventional hydration protocol consisting of 2100-2600 ml of hydration over 6.5-7.5 h on Day 1 with pre- and post-hydration on Days 0, 2 and 3. Toxicity was then compared between the two groups. RESULTS: An elevated serum creatinine level >=grade 1 was significantly less frequent in the group receiving the short hydration protocol than in the group receiving conventional hydration. Other toxicities were similar between the two groups. Consequently, the completion rate for the planned treatment in the short hydration group (73.0%, 54/74) was significantly higher than that in the conventional hydration group (53.6%, 37/69). CONCLUSIONS: Short hydration is safe, making cisplatin-containing chemotherapy easier to perform. PMID- 26755832 TI - Development of a Germanium Small-Animal SPECT System. AB - Advances in fabrication techniques, electronics, and mechanical cooling systems have given rise to germanium detectors suitable for biomedical imaging. We are developing a small-animal SPECT system that uses a double-sided Ge strip detector. The detector's excellent energy resolution may help to reduce scatter and simplify processing of multi-isotope imaging, while its ability to measure depth of interaction has the potential to mitigate parallax error in pinhole imaging. The detector's energy resolution is <1% FWHM at 140 keV and its spatial resolution is approximately 1.5 mm FWHM. The prototype system described has a single-pinhole collimator with a 1-mm diameter and a 70-degree opening angle with a focal length variable between 4.5 and 9 cm. Phantom images from the gantry mounted system are presented, including the NEMA NU-2008 phantom and a hot-rod phantom. Additionally, the benefit of energy resolution is demonstrated by imaging a dual-isotope phantom with 99mTc and 123I without cross-talk correction. PMID- 26755831 TI - Long-term survival of nasopharyngeal carcinoma patients with Stage II in intensity-modulated radiation therapy era. AB - OBJECTIVES: To evaluate the long-term survival and the role of chemotherapy in nasopharyngeal carcinoma (NPC) patients in Stage II treated by intensity modulated radiation therapy (IMRT). METHODS: Three hundred and eleven NPC patients in Stage II were reviewed. All were treated with IMRT with or without chemotherapy, with 191, 20 and 100 patients being defined as T1N1M0, T2N0M0 and T2N1M0 stage, respectively. RESULTS: At a median follow-up of 57 months, the 5 year overall survival, disease-specific survival, distant metastasis-free survival, loco-regional relapse-free survival (LRRFS) and progression-free survival were 91.1, 93.5, 90.6, 95.9 and 87.6%, respectively. T2N1 patients had significant poorer survival outcomes than T1N1 patients, with T2N0 patients in between. Further analysis showed that the addition of chemotherapy could only improve LRRFS [hazard ratio (HR) 0.263, 95% confidence interval (CI) 0.083-0.839, P = 0.024], especially for T1N1 patients (HR 0.209, 95% CI 0.046-0.954, P = 0.043). For those in the T2N1M0 group, chemotherapy, as used in our series, added no benefit to any endpoint. CONCLUSIONS: IMRT in NPC patients in Stage II was quite therapeutic; however, different subgroups have distinct survival outcomes. Distant metastasis was the main failure pattern, especially for those with T2N1 disease, and the chemotherapy currently in use failed to treat subclinical metastatic foci effectively. Further prospective study is warranted to find out the role and the optimal schedule of chemotherapy in this subgroup of patients. PMID- 26755833 TI - Consent and the Indian medical practitioner. AB - Consent is a legal requirement of medical practice and not a procedural formality. Getting a mere signature on a form is no consent. If a patient is rushed into signing consent, without giving sufficient information, the consent may be invalid, despite the signature. Often medical professionals either ignore or are ignorant of the requirements of a valid consent and its legal implications. Instances where either consent was not taken or when an invalid consent was obtained have been a subject matter of judicial scrutiny in several medical malpractice cases. This article highlights the essential principles of consent and the Indian law related to it along with some citations, so that medical practitioners are not only able to safeguard themselves against litigations and unnecessary harassment but can act rightfully. PMID- 26755834 TI - Effect of 50% enantiomeric excess bupivacaine mixture combined with pancuronium on neuromuscular transmission in rat phrenic nerve-diaphragm preparation; a pilot study. AB - BACKGROUND AND AIMS: Local anaesthetics are drugs that are widely used in clinical practice. However, the effects of these drugs on the neuromuscular junction and their influence on the blockade produced by non-depolarising neuromuscular blocking drugs are still under investigation. The aim of this study was to evaluate, in vitro, the influence of a 50% enantiomeric excess bupivacaine mixture on neuromuscular transmission and neuromuscular block produced by pancuronium. METHODS: Rats were distributed into three groups (n = 5) according to the drug studied namely, 50% enantiomeric excess bupivacaine mixture (5 MUg/mL); pancuronium (2 MUg/mL); 50% enantiomeric excess bupivacaine mixture + pancuronium. The following parameters were evaluated: (1) Effects of a 50% enantiomeric excess bupivacaine mixture on membrane potential (MP) and miniature endplate potentials (MEPPs); (2) amplitude of diaphragmatic response before and 60 min after the addition of a 50% enantiomeric excess bupivacaine mixture; the degree of neuromuscular block with pancuronium and pancuronium combined with a 50% enantiomeric excess bupivacaine mixture. RESULTS: A 50% enantiomeric excess bupivacaine mixture did not alter the amplitude of muscle response (MP) but decreased the frequency and amplitude of MEPP. The block produced by pancuronium was potentiated by a 50% enantiomeric excess bupivacaine mixture. CONCLUSION: A 50% enantiomeric excess bupivacaine mixture used alone did not affect neuromuscular transmission, but potentiated the neuromuscular block produced by pancuronium. No action was shown on the muscle fibre, and alterations on MEPPs demonstrated a presynaptic action. PMID- 26755835 TI - Anaesthesia practice and reproductive outcomes: Facts unveiled. AB - BACKGROUND AND AIMS: Anaesthetic practice is associated with a risk of chronic exposure to anaesthetic agents. With the advent of newer inhalational agents and changing anaesthetic practices, the risks for anaesthesiologists with regard to adverse reproductive outcomes is unknown. Hence, a nationwide online survey was conducted to study the anaesthetic practices prevalent in India and their association, if any, with poor reproductive outcomes. METHODS: The online survey involved 9974 anaesthesiologists. A questionnaire soliciting information regarding anaesthetic practice techniques, reproductive outcomes and perinatal outcomes was designed. All the anaesthesiologists in the ISA National database were mailed a link to the above questionnaire. RESULTS: Female anaesthesiologists and spouses of male anaesthesiologists had a higher incidence of first trimester spontaneous abortions than the general population. Female anaesthesiologists when compared with spouses of male anaesthesiologists faced more difficulty with conception (P = 0.015). Female anaesthesiologists who worked in the operating room (OR) in their first trimester of gestation had a higher incidence of spontaneous abortions than those who did not work in the OR (P = 0.05). Longer hours of general anaesthesia conducted in the first trimester of pregnancy was associated with a higher risk of birth defects in their progeny (P = 0.05). CONCLUSION: Spontaneous abortions and birth defects were higher in female anaesthesiologists who worked in the OR in the first trimester of gestation. Both female anaesthesiologists and spouses of male anaesthesiologists had a greater risk for a first trimester miscarriage than the general population. PMID- 26755836 TI - A retrospective study of clinical profile and outcomes of critically ill patients with heat-related illness. AB - BACKGROUND AND AIMS: Heat-related illness (HRI) due to high ambient temperatures is a common feature during the Indian summer. HRI often results in Intensive Care Unit (ICU) admissions and are associated with significant morbidity and mortality. However, published report on the effects of HRI among the Indian population is lacking. This study was undertaken to identify the profile of patients admitted to ICU with clinical features of HRI and study their clinical outcomes. METHODS: This was a retrospective case series of patients admitted with features of HRI during the summer of 2012 in our multidisciplinary ICU. Data on demographics, co-morbid illness, admission severity of illness (Acute Physiology and Chronic Health Evaluation II [APACHE II]), organ failure scores (Sequential Organ Failure Assessment [SOFA]) and neuroimaging studies were collected. Outcome data studied included mortality, ICU length of stay (LOS), ventilator days and hospital LOS. Statistical analysis was performed using Student's t-test, Chi square test and multivariate analysis. RESULTS: Twenty-six patients met the diagnostic criteria for HRI. Fifteen were males. The mean age was 53.12 +/- 18.6 years. Mean APACHE II score was 19.6 +/- 7.7 and mean SOFA score was 7.5 +/- 2.6. The common presenting symptoms were fever with neurological impairment (100%) and gastrointestinal symptoms (30%). Major organ systems involvement include neurological (100%), renal (57%), hepatic (34%) and coagulation abnormalities (26%). Most common metabolic abnormality noted was hyponatraemia (73%). Magnetic resonance imaging findings suggestive of heat stroke were seen in 5 of 26 patients. Mortality rate was 34%. 8 of 17 survivors had residual neurological impairment. CONCLUSION: HRI carries a high mortality and significant neurological morbidity. PMID- 26755837 TI - Drug utilisation and off-label use of medications in anaesthesia in surgical wards of a teaching hospital. AB - BACKGROUND AND AIMS: When a drug is used in a way that is different from that described in regulatory body approved drug label, it is said to be 'off label use'. Perioperative phase is sensitive from the point of view of patient safety and off-label drug use in this setup can prove to be hazardous to patient. Hence, it was planned to assess the pattern of drug utilisation and off-label use of perioperative medication during anaesthesia. METHODS: Preoperatively, demographic details and adverse events check list were filled from a total of 400 patients from general surgery, paediatric surgery and orthopaedics departments scheduled to undergo surgery. The perioperative assessment form was assessed to record all prescriptions followed by refilling of adverse events checklist in case record form. World Health Organization (WHO) prescribing indicators were used for analysis of drug utilisation data. National Formulary of India 2011 was used as reference material to decide off-label drug use in majority instances along with package insert. RESULTS: A total of 3705 drugs were prescribed to the 400 participants and average number of drugs per patient was 9.26 +/- 3.33. Prescriptions by generic name were 68.07% whereas 85.3% drugs were prescribed from hospital schedule. Off-label drugs overall formed 20.19% of the drugs prescribed. At least one off-label drug was prescribed to 82.5% of patients. Inappropriate dose was the most common form of off-label use. There was 1.6 times greater risk of occurrence of adverse events associated with the use of off-label drugs. CONCLUSION: Prescription indicators were WHO compliant. Off-label drug use was practiced in anaesthesia department with questionable clinical justification in some instances. PMID- 26755838 TI - The effect of alfentanil on maternal haemodynamic changes due to tracheal intubation in elective caesarean sections under general anaesthesia. AB - BACKGROUND AND AIMS: Endotracheal intubation can produce severe maternal haemodynamic changes during caesarean sections under general anaesthesia. However, administration of narcotics before endotracheal intubation to prevent these changes may affect the Apgar score in neonates. This study was designed to evaluate the effect of intravenous alfentanil on haemodynamic changes due to endotracheal intubation in elective caesarean sections performed under general anaesthesia. METHODS: Fifty parturients were randomly divided into two equal groups. Patients in the first group received alfentanil 10 MUg/kg and in the second group received placebo intravenously 1 min before induction of anaesthesia for elective caesarean section. Haemodynamic parameters and bispectral index system (BIS) in mothers, peripheral capillary oxygen saturation (SpO2) and Apgar score in the newborn were assessed. RESULTS: Changes in systolic blood pressure were significant at 1, 5 and 10 min after intubation between two groups. Changes in diastolic blood pressure were significantly less in alfentanil group, 1 min after induction of anaesthesia and 1 min after endotracheal intubation. Mean heart rate at 1 min after induction and at 1 and 5 min after intubation also reduced significantly in this group. CONCLUSION: Alfentanil use was associated with decreases or minimal increases in maternal systolic and diastolic blood pressures and heart rate after endotracheal intubation. PMID- 26755840 TI - Peri-operative concerns in a patient with thyroid storm secondary to molar pregnancy. AB - Awareness of the presence of thyroid function abnormalities in patients with molar pregnancy is important for its prompt diagnosis and management. We report the development of thyroid storm in the immediate post-operative period in a 25 year-old female who underwent evacuation of her molar pregnancy under saddle spinal block after being controlled for her thyrotoxicosis with a combination of antithyroid drugs, iodine, steroids and adrenergic blocking agents. We advocate the use of esmolol infusions up to a maximum dose of 200 MUg/kg/min for immediate haemodynamic management of the patient. Optimum time needed for stabilisation of the hyper metabolic state after initiation of antithyroid drugs is still not known and evacuation of molar pregnancy remains the only definitive management of the thyrotoxic state. PMID- 26755839 TI - Comparison of clonidine and dexmedetomidine as adjuncts to intravenous regional anaesthesia. AB - BACKGROUND AND AIMS: Intravenous regional anaesthesia (IVRA) provides reliable and rapid analgesia with good muscular relaxation of the extremity distal to the tourniquet, but tourniquet pain and absence of post-operative analgesia are major drawbacks. alpha2 agonists, clonidine and dexmedetomidine are known to potentiate peripheral nerve blocks. The aim of this study was to compare clonidine and dexmedetomidine as adjuvants to IVRA with respect to block characteristics, tourniquet pain and post-operative analgesia. METHODS: A prospective, randomised, double-blind study was conducted on 60 adult patients of American Society of Anesthesiologists physical status grades I and II, in two groups of 30 each, to receive either clonidine 1 MUg/kg or dexmedetomidine 1 MUg/kg added to 40 ml 0.5% preservative-free lignocaine. Independent samples t-test was used for analysing demographic data, haemodynamic data and block characteristics and Mann-Whitney U test for skewed data. RESULTS: Sensorimotor block onset was significantly faster and recovery delayed with dexmedetomidine as compared to clonidine. Intra operative visual analogue scale (VAS) at 10 min, 15 min and 40 min and post operative VAS at 30 min and 2 h were significantly higher with clonidine. Fentanyl consumption and sedation were comparable. Duration of analgesia was significantly longer with dexmedetomidine. Haemodynamic parameters were comparable. CONCLUSIONS: Dexmedetomidine significantly facilitates onset, prolongs recovery of sensory as well as motor block and also prolongs duration of analgesia as compared to clonidine. Both decrease tourniquet pain satisfactorily and have comparable intra-operative fentanyl requirement . Patient satisfaction is better with dexmedetomidine. PMID- 26755841 TI - A rare cause of respiratory distress after transthoracic oesophagectomy. AB - Transthoracic oesophagectomy is a standard surgical procedure for oesophageal cancer. Because of thoracotomy and lung handling, perioperative pulmonary complications make such procedures challenging. The issues related to respiratory complications may be predicted and managed accordingly. However, we report two cases of respiratory compromise caused due to a peculiar iatrogenic component. PMID- 26755842 TI - Anaesthetic management of a patient with tuberous sclerosis for partial nephrectomy. PMID- 26755843 TI - Opioid sparing effect of diclofenac sodium when used as an intra-operative analgesic during maxillofacial cancer surgeries. PMID- 26755845 TI - Transversus abdominis plane block as sole anaesthetic technique for inguinal hernia repair in two patients having complex medical conditions. PMID- 26755844 TI - Role of transoesophageal echocardiography in peri-operative management of cardiac hydatid cyst. PMID- 26755846 TI - Repair of late-presenting right Bochdalek hernia in a patient with uncorrected tetralogy of Fallot: Anaesthetic management. PMID- 26755847 TI - Superior vena cava syndrome due to catheter related thrombus in a patient with a permanent pacemaker. PMID- 26755848 TI - Air leak with intact cuff inflation system: A case report with brief review of literature. PMID- 26755849 TI - Comments: New approach to treat an old problem: Mannitol for post dural puncture headache. PMID- 26755850 TI - Temperature and cisatracurium degradation: So what is new? PMID- 26755851 TI - "No rent is small for migration of epidural catheter into sub-arachnoid space". PMID- 26755852 TI - In response to comments on: No rent is small for migration of epidural catheter into subarachnoid space. PMID- 26755853 TI - Erratum: Safety of post-operative epidural analgesia in the paediatric population: A retrospective analysis. AB - [This corrects the article on p. 636 in vol. 59, PMID: 26644609.]. PMID- 26755854 TI - Development of Selective Lamellar Keratoplasty within an Asian Corneal Transplant Program: The Singapore Corneal Transplant Study (An American Ophthalmological Society Thesis). AB - PURPOSE: To evaluate outcomes of anterior lamellar keratoplasty (ALK) and endothelial keratoplasty (EK) within the Singapore Corneal Transplant Study (SCTS), with the hypothesis that both ALK and EK are able to provide equivalent or improved clinical outcomes, compared to penetrating keratoplasty (PK), and to determine changing trends globally with other international databases. METHODS: Clinical data on all transplants performed was derived from our SCTS database, a prospective national keratoplasty registry, and clinical outcomes (graft survival, endothelial cell loss, complications, visual acuity) were compared between PK, ALK, and EK. Global trends on indications and forms of keratoplasty performed in 2011/2012 were obtained from national keratoplasty or eye banking registries, corneal/ophthalmological societies, national eye banks, and national ophthalmic institutions. RESULTS: Global rates of EK surgery vary widely, from 52% (Sweden) to 0% (South Africa), with higher adoption by industrialized countries. ALK adoption rates similarly vary from 28.7% (China) to 1.0% (Philippines). SCTS data show high adoption rates in Singapore: EK 44% and ALK 28%. Our surgical modifications to big-bubble deep anterior lamellar keratoplasty (DALK) surgery resulted in visual outcomes matching PK, and a low conversion to PK of 2.1%, whereas our evolving approaches to donor insertion in Descemet's stripping automated endothelial keratoplasty (DSAEK) show significant reduction in 1-year postoperative endothelial cell loss rates from 60% (folding), to 22% to 30% (Sheets Glide), to 15% (EndoGlide inserter). CONCLUSION: Improvements in various forms of ALK and EK surgery can lead to better visual outcomes, longer graft survival, and reduced complications, as compared to PK. Global trends suggest adoption of these procedures at different rates. PMID- 26755856 TI - Current understanding of the functional roles of aberrantly expressed microRNAs in esophageal cancer. AB - The incidence of esophageal cancer is rising, mostly because the increasing incidence of esophageal adenocarcinoma in Western countries. Despite improvements in diagnosis and treatment, the overall 5-year survival rates remain low. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of target genes. Recently, disease specific miRNAs have been identified, which act as tumor suppressors or oncogenes. In this review, we will summarize the current knowledge about the function of aberrantly expressed miRNAs in esophageal cancer. We selected 5 miRNAs (miRNA-21, -143, -145, -196a and let 7) based on the available literature, and described their potential role in regulating pathways that are deregulated in esophageal cancer. Finally we will highlight the current achievements of using and targeting miRNAs. Because these miRNAs likely have important regulatory roles in cancer development, they open a therapeutic window for new treatment modalities. PMID- 26755855 TI - Long-Term Outcome of Half-Dose Verteporfin Photodynamic Therapy for the Treatment of Central Serous Chorioretinopathy (An American Ophthalmological Society Thesis). AB - PURPOSE: To evaluate whether half-dose verteporfin photodynamic therapy (PDT) is better than natural history for the treatment of central serous chorioretinopathy (CSC). METHODS: Retrospective review of consecutive CSC patients treated with half-dose verteporfin PDT or untreated with observation and a minimum follow-up of 36 months. The main outcome measures included mean change in visual acuity and CSC recurrence. Survival analysis was performed to compare the CSC recurrence rates between the two groups. RESULTS: A total of 192 eyes of 192 patients were included; 75 eyes were treated with half-dose verteporfin PDT and 117 were untreated. The mean follow-up duration was 74.1 months. At the last follow-up, the mean logMAR visual acuity was significantly better in the half-dose verteporfin PDT group compared with the untreated control group (P=.005). The mean visual improvement of the half-dose verteporfin PDT group at the last follow up was 1.8 lines, compared with 0.0 line in the untreated control group (P<.001). Recurrence of CSC developed in 15 eyes (20%) in the half-dose verteporfin PDT group compared with 63 eyes (53.8%) in the untreated control group (P<.001). Survival analysis demonstrated that eyes treated with half-dose verteporfin PDT were significantly less likely to develop CSC recurrence compared with untreated controls (P<.001). Regression analysis showed that half-dose verteporfin PDT was the only significant factor in reducing the risk of CSC recurrence. CONCLUSIONS: Half-dose verteporfin PDT for the treatment of CSC resulted in significantly better visual acuity outcomes and lower recurrence rate in the long term compared with untreated controls. PMID- 26755857 TI - Optimal management for alcoholic liver disease: Conventional medications, natural therapy or combination? AB - Alcohol consumption is the principal factor in the pathogenesis of chronic liver diseases. Alcoholic liver disease (ALD) is defined by histological lesions on the liver that can range from simple hepatic steatosis to more advanced stages such as alcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma and liver failure. As one of the oldest forms of liver injury known to humans, ALD is still a leading cause of liver-related morbidity and mortality and the burden is exerting on medical systems with hospitalization and management costs rising constantly worldwide. Although the biological mechanisms, including increasing of acetaldehyde, oxidative stress with induction of cytochrome p450 2E1, inflammatory cytokine release, abnormal lipid metabolism and induction of hepatocyte apoptosis, by which chronic alcohol consumption triggers serious complex progression of ALD is well established, there is no universally accepted therapy to prevent or reverse. In this article, we have briefly reviewed the pathogenesis of ALD and the molecular targets for development of novel therapies. This review is focused on current therapeutic strategies for ALD, including lifestyle modification with nutrition supplements, available pharmacological drugs and new agents that are under development, liver transplantation, application of complementary medicines, and their combination. The relevant molecular mechanisms of each conventional medication and natural agent have been reviewed according to current available knowledge in the literature. We also summarized efficacy vs safety on conventional and herbal medicines which are specifically used for the prevention and treatment of ALD. Through a system review, this article highlighted that the combination of pharmaceutical drugs with naturally occurring agents may offer an optimal management for ALD and its complications. It is worthwhile to conduct large-scale, multiple centre clinical trials to further prove the safety and benefits for the integrative therapy on ALD. PMID- 26755858 TI - Multipotent mesenchymal stromal cells: A promising strategy to manage alcoholic liver disease. AB - Chronic alcohol consumption is a major cause of liver disease. The term alcoholic liver disease (ALD) refers to a spectrum of mild to severe disorders including steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. With limited therapeutic options, stem cell therapy offers significant potential for these patients. In this article, we review the pathophysiologic features of ALD and the therapeutic mechanisms of multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSCs), based on their potential to differentiate into hepatocytes, their immunomodulatory properties, their potential to promote residual hepatocyte regeneration, and their capacity to inhibit hepatic stellate cells. The perfect match between ALD pathogenesis and MSC therapeutic mechanisms, together with encouraging, available preclinical data, allow us to support the notion that MSC transplantation is a promising therapeutic strategy to manage ALD onset and progression. PMID- 26755859 TI - Relationships among alcoholic liver disease, antioxidants, and antioxidant enzymes. AB - Excessive consumption of alcoholic beverages is a serious cause of liver disease worldwide. The metabolism of ethanol generates reactive oxygen species, which play a significant role in the deterioration of alcoholic liver disease (ALD). Antioxidant phytochemicals, such as polyphenols, regulate the expression of ALD associated proteins and peptides, namely, catalase, superoxide dismutase, glutathione, glutathione peroxidase, and glutathione reductase. These plant antioxidants have electrophilic activity and may induce antioxidant enzymes via the Kelch-like ECH-associated protein 1-NF-E2-related factor-2 pathway and antioxidant responsive elements. Furthermore, these antioxidants are reported to alleviate cell injury caused by oxidants or inflammatory cytokines. These phenomena are likely induced via the regulation of mitogen-activating protein kinase (MAPK) pathways by plant antioxidants, similar to preconditioning in ischemia-reperfusion models. Although the relationship between plant antioxidants and ALD has not been adequately investigated, plant antioxidants may be preventive for ALD because of their electrophilic and regulatory activities in the MAPK pathway. PMID- 26755863 TI - Magnetic resonance imaging of the cirrhotic liver in the era of gadoxetic acid. AB - Gadoxetic acid improves detection and characterization of focal liver lesions in cirrhotic patients and can estimate liver function in patients undergoing liver resection. The purpose of this article is to describe the optimal gadoxetic acid study protocol for the liver, the unique characteristics of gadoxetic acid, the differences between gadoxetic acid and extra-cellular gadolium chelates, and the differences in phases of enhancement between cirrhotic and normal liver using gadoxetic acid. We also discuss how to obtain and recognize an adequate hepatobiliary phase. PMID- 26755861 TI - Molecular changes in hepatic metabolism and transport in cirrhosis and their functional importance. AB - Liver cirrhosis is the common endpoint of many hepatic diseases and represents a relevant risk for liver failure and hepatocellular carcinoma. The progress of liver fibrosis and cirrhosis is accompanied by deteriorating liver function. This review summarizes the regulatory and functional changes in phase I and phase II metabolic enzymes as well as transport proteins and provides an overview regarding lipid and glucose metabolism in cirrhotic patients. Interestingly, phase I enzymes are generally downregulated transcriptionally, while phase II enzymes are mostly preserved transcriptionally but are reduced in their function. Transport proteins are regulated in a specific way that resembles the molecular changes observed in obstructive cholestasis. Lipid and glucose metabolism are characterized by insulin resistance and catabolism, leading to the disturbance of energy expenditure and wasting. Possible non-invasive tests, especially breath tests, for components of liver metabolism are discussed. The heterogeneity and complexity of changes in hepatic metabolism complicate the assessment of liver function in individual patients. Additionally, studies in humans are rare, and species differences preclude the transferability of data from rodents to humans. In clinical practice, some established global scores or criteria form the basis for the functional evaluation of patients with liver cirrhosis, but difficult treatment decisions such as selection for transplantation or resection require further research regarding the application of existing non-invasive tests and the development of more specific tests. PMID- 26755862 TI - Four-dimensional flow magnetic resonance imaging in cirrhosis. AB - Since its introduction in the 1970's, magnetic resonance imaging (MRI) has become a standard imaging modality. With its broad and standardized application, it is firmly established in the clinical routine and an essential element in cardiovascular and abdominal imaging. In addition to sonography and computer tomography, MRI is a valuable tool for diagnosing cardiovascular and abdominal diseases, for determining disease severity, and for assessing therapeutic success. MRI techniques have improved over the last few decades, revealing not just morphologic information, but functional information about perfusion, diffusion and hemodynamics as well. Four-dimensional (4D) flow MRI, a time resolved phase contrast-MRI with three-dimensional (3D) anatomic coverage and velocity encoding along all three flow directions has been used to comprehensively assess complex cardiovascular hemodynamics in multiple regions of the body. The technique enables visualization of 3D blood flow patterns and retrospective quantification of blood flow parameters in a region of interest. Over the last few years, 4D flow MRI has been increasingly performed in the abdominal region. By applying different acceleration techniques, taking 4D flow MRI measurements has dropped to a reasonable scanning time of 8 to 12 min. These new developments have encouraged a growing number of patient studies in the literature validating the technique's potential for enhanced evaluation of blood flow parameters within the liver's complex vascular system. The purpose of this review article is to broaden our understanding of 4D flow MRI for the assessment of liver hemodynamics by providing insights into acquisition, data analysis, visualization and quantification. Furthermore, in this article we highlight its development, focussing on the clinical application of the technique. PMID- 26755860 TI - Metabolic derivatives of alcohol and the molecular culprits of fibro hepatocarcinogenesis: Allies or enemies? AB - Chronic intake of alcohol undoubtedly overwhelms the structural and functional capacity of the liver by initiating complex pathological events characterized by steatosis, steatohepatitis, hepatic fibrosis and cirrhosis. Subsequently, these initial pathological events are sustained and ushered into a more complex and progressive liver disease, increasing the risk of fibro-hepatocarcinogenesis. These coordinated pathological events mainly result from buildup of toxic metabolic derivatives of alcohol including but not limited to acetaldehyde (AA), malondialdehyde (MDA), CYP2E1-generated reactive oxygen species, alcohol-induced gut-derived lipopolysaccharide, AA/MDA protein and DNA adducts. The metabolic derivatives of alcohol together with other comorbidity factors, including hepatitis B and C viral infections, dysregulated iron metabolism, abuse of antibiotics, schistosomiasis, toxic drug metabolites, autoimmune disease and other non-specific factors, have been shown to underlie liver diseases. In view of the multiple etiology of liver diseases, attempts to delineate the mechanism by which each etiological factor causes liver disease has always proved cumbersome if not impossible. In the case of alcoholic liver disease (ALD), it is even more cumbersome and complicated as a result of the many toxic metabolic derivatives of alcohol with their varying liver-specific toxicities. In spite of all these hurdles, researchers and experts in hepatology have strived to expand knowledge and scientific discourse, particularly on ALD and its associated complications through the medium of scientific research, reviews and commentaries. Nonetheless, the molecular mechanisms underpinning ALD, particularly those underlying toxic effects of metabolic derivatives of alcohol on parenchymal and non-parenchymal hepatic cells leading to increased risk of alcohol-induced fibro-hepatocarcinogenesis, are still incompletely elucidated. In this review, we examined published scientific findings on how alcohol and its metabolic derivatives mount cellular attack on each hepatic cell and the underlying molecular mechanisms leading to disruption of core hepatic homeostatic functions which probably set the stage for the initiation and progression of ALD to fibro-hepatocarcinogenesis. We also brought to sharp focus, the complex and integrative role of transforming growth factor beta/small mothers against decapentaplegic/plasminogen activator inhibitor-1 and the mitogen activated protein kinase signaling nexus as well as their cross-signaling with toll-like receptor-mediated gut-dependent signaling pathways implicated in ALD and fibro hepatocarcinogenesis. Looking into the future, it is hoped that these deliberations may stimulate new research directions on this topic and shape not only therapeutic approaches but also models for studying ALD and fibro hepatocarcinogenesis. PMID- 26755866 TI - Overview of hepatitis B virus mutations and their implications in the management of infection. AB - Hepatitis B virus (HBV) affects approximately two billion people worldwide and more than 240 million people in the world are currently chronic carrier that could develop serious complications in the future, like liver cirrhosis and hepatocellular carcinoma. Although an extended HBV immunization program is being carried out since the early '80s, representing effective preventive measure, leading to a dramatic reduction of HBV hepatitis incidence, globally HBV infection still represents a major public health problem. The HBV virus is a DNA virus belongs to the Hepadnaviridae family. The HBV-DNA is a circular, partial double strand genome. All coding information is on the minus DNA strand and it is organized into four open reading frames. Despite hepatitis B virus is a DNA virus, it has a high mutation rate due to its replicative strategy, that leads to the production of many non-identical variants at each cycle of replication. In fact, it contains a polymerase without the proofreading activity, and uses an RNA intermediate (pgRNA) during its replication, so error frequencies are comparable to those seen in retroviruses and other RNA viruses rather than in more stable DNA viruses. Due to the low fidelity of the polymerase, the high replication rate and the overlapping reading frames, mutations occur throughout the genome and they have been identified both in the structural and not structural gene. The arise of mutations being to develop of a whole of viral variants called "quasi species" and the prevalent population, which favors virus replication, was selected by viral fitness, host's immune pressure and external pressure, i.e., vaccination or antiviral therapy. Naturally occurring mutations were found both in acute and chronic subjects. In the present review we examine and discuss the most recent available data about HBV genetic variability and its significance. PMID- 26755864 TI - Left ventricular function assessment in cirrhosis: Current methods and future directions. AB - Cirrhotic cardiomyopathy has been defined as a chronic cardiac dysfunction in patients with cirrhosis characterized by impaired contractile responsiveness to stress and/or altered diastolic relaxation with electrophysiological abnormalities in the absence of other known cardiac disease. Non-invasive cardiovascular imaging modalities play a major role in unmasking systolic and diastolic dysfunction in patients with cirrhosis. Echocardiography has been the most commonly used modality for assessing myocardial function in these patients. Conventional echocardiographic indices rely on several assumptions that may limit their applicability in patients with a hyperdynamic circulation. Newer imaging modalities may contribute to a more accurate diagnosis of cardiovascular abnormalities in cirrhotic patients, thereby influencing clinical management. We aimed to review the different non-invasive imaging technologies currently used for assessing left ventricular systolic and diastolic function in cirrhosis, as well as to describe new imaging modalities with potential clinical applicability in the near future. PMID- 26755867 TI - Association between hepatitis B and metabolic syndrome: Current state of the art. AB - Chronic hepatitis B (CHB) is a global health issue that increases the risk of liver cirrhosis and hepatocellular carcinoma in infected patients. Metabolic syndrome (MetS) is a disease endemic mostly to the developed countries. It is associated with high cardiovascular mortality and morbidity, diabetes mellitus as well as cancer. In this manuscript, we systematically review the published data on the relationship between MetS and CHB infection. Multiple studies have described highly variable correlations between CHB on one hand and MetS, non alcoholic fatty liver disease and dyslipidemia on the other. No association between CHB and diabetes mellitus or atherosclerosis has been described as of now. The presence of MetS in patients infected with hepatitis B virus increases the risk of fibrosis, cirrhosis and hepatocellular carcinoma. Appropriate lifestyle, but also pharmacological interventions are needed to prevent the development of these complications. PMID- 26755865 TI - Genetic variation of hepatitis B virus and its significance for pathogenesis. AB - Hepatitis B virus (HBV) has a worldwide distribution and is endemic in many populations. Due to its unique life cycle which requires an error-prone reverse transcriptase for replication, it constantly evolves, resulting in tremendous genetic variation in the form of genotypes, sub-genotypes, and mutations. In recent years, there has been considerable research on the relationship between HBV genetic variation and HBV-related pathogenesis, which has profound implications in the natural history of HBV infection, viral detection, immune prevention, drug treatment and prognosis. In this review, we attempted to provide a brief account of the influence of HBV genotype on the pathogenesis of HBV infection and summarize our current knowledge on the effects of HBV mutations in different regions on HBV-associated pathogenesis, with an emphasis on mutations in the preS/S proteins in immune evasion, occult HBV infection and hepatocellular carcinoma (HCC), mutations in polymerase in relation to drug resistance, mutations in HBV core and e antigen in immune evasion, chronicalization of infection and hepatitis B-related acute-on-chronic liver failure, and finally mutations in HBV x proteins in HCC. PMID- 26755869 TI - Autophagy and microRNA in hepatitis B virus-related hepatocellular carcinoma. AB - Approximately 350 million people worldwide are chronically infected by hepatitis B virus (HBV). HBV causes severe liver diseases including cirrhosis and hepatocellular carcinoma (HCC). In about 25% of affected patients, HBV infection proceeds to HCC. Therefore, the mechanisms by which HBV affects the host cell to promote viral replication and its pathogenesis have been the subject of intensive research efforts. Emerging evidence indicates that both autophagy and microRNAs (miRNAs) are involved in HBV replication and HBV-related hepatocarcinogenesis. In this review, we summarize how HBV induces autophagy, the role of autophagy in HBV infection, and HBV-related tumorigenesis. We further discuss the emerging roles of miRNAs in HBV infection and how HBV affects miRNAs biogenesis. The accumulating knowledge pertaining to autophagy and miRNAs in HBV replication and its pathogenesis may lead to the development of novel strategies against HBV infection and HBV-related HCC tumorigenesis. PMID- 26755868 TI - Prophylactic managements of hepatitis B viral infection in liver transplantation. AB - Liver transplantation (LT) is a considerably effective treatment for patients with end-stage hepatitis B virus (HBV)-related liver disease. However, HBV infection often recurs after LT without prophylaxis. Since the 1990s, the treatment for preventing HBV reinfection after LT has greatly progressed with the introduction of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues (NAs), resulting in improved patient survival. The combination therapy consisting of high-dose HBIG and lamivudine is highly efficacious for preventing the recurrence of HBV infection after LT and became the standard prophylaxis for HBV recurrence. However, mainly due to the high cost of HBIG treatment, an alternative protocol for reducing the dose and duration of HBIG has been evaluated. Currently, combination therapy using low-dose HBIG and NAs is considered as the most efficacious and cost-effective prophylaxis for post-LT HBV reinfection. Recently, NA monotherapy and withdrawal of HBIG from combination therapy, along with the development of new, potent high genetic barrier NAs, have provided promising efficacy, especially for low-risk recipients. This review summarizes the prophylactic protocol and their efficacy including prophylaxis of de novo HBV infection from anti-HBc antibody-positive donors. In addition, challenging approaches such as discontinuation of all prophylaxis and active immunity through hepatitis B vaccination are discussed. PMID- 26755870 TI - Naturally derived anti-hepatitis B virus agents and their mechanism of action. AB - Despite that some approved drugs and genetically engineered vaccines against hepatitis B virus (HBV) are available for HBV patients, HBV infection is still a severe public health problem in the world. All the approved therapeutic drugs (including interferon-alpha and nucleoside analogues) have their limitations. No drugs or therapeutic methods can cure hepatitis B so far. Therefore, it is urgently needed to discover and develop new anti-HBV drugs, especially non nucleoside agents. Naturally originated compounds with enormous molecular complexity and diversity offer a great opportunity to find novel anti-HBV lead compounds with specific antiviral mechanisms. In this review, the natural products against HBV are discussed according to their chemical classes such as terpenes, lignans, phenolic acids, polyphenols, lactones, alkaloids and flavonoids. Furthermore, novel mode of action or new targets of some representative anti-HBV natural products are also discussed. The aim of this review is to report new discoveries and updates pertaining to anti-HBV natural products in the last 20 years, especially novel skeletons and mode of action. Although many natural products with various skeletons have been reported to exhibit potent anti-HBV effects to date, scarcely any of them are found in the list of conventional anti-HBV drugs worldwide. Additionly, in anti-HBV mechanism of action, only a few references reported new targets or novel mode of action of anti-HBV natural products. PMID- 26755871 TI - Advances in computed tomography and magnetic resonance imaging of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Imaging is important for establishing a diagnosis of HCC and early diagnosis is imperative as several potentially curative treatments are available when HCC is small. Hepatocarcinogenesis occurs in a stepwise manner on a background of chronic liver disease or cirrhosis wherein multiple genes are altered resulting in a range of cirrhosis-associated nodules. This progression is related to increased cellularity, neovascularity and size of the nodule. An understanding of the stepwise progression may aid in early diagnosis. Dynamic and multiphase contrast-enhanced computed tomography and magnetic resonance imaging still form the cornerstone in the diagnosis of HCC. An overview of the current diagnostic standards of HCC in accordance to the more common practicing guidelines and their differences will be reviewed. Ancillary features contribute to diagnostic confidence and has been incorporated into the more recent Liver Imaging Reporting and Data System. The use of hepatocyte-specific contrast agents is increasing and gradually changing the standard of diagnosis of HCC; the most significant benefit being the lack of uptake in the hepatocyte phase in the earlier stages of HCC progression. An outline of supplementary techniques in the imaging of HCC will also be reviewed. PMID- 26755872 TI - Molecular imaging and therapy targeting copper metabolism in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Significant efforts have been devoted to identify new biomarkers for molecular imaging and targeted therapy of HCC. Copper is a nutritional metal required for the function of numerous enzymatic molecules in the metabolic pathways of human cells. Emerging evidence suggests that copper plays a role in cell proliferation and angiogenesis. Increased accumulation of copper ions was detected in tissue samples of HCC and many other cancers in humans. Altered copper metabolism is a new biomarker for molecular cancer imaging with position emission tomography (PET) using radioactive copper as a tracer. It has been reported that extrahepatic mouse hepatoma or HCC xenografts can be localized with PET using copper-64 chloride as a tracer, suggesting that copper metabolism is a new biomarker for the detection of HCC metastasis in areas of low physiological copper uptake. In addition to copper modulation therapy with copper chelators, short-interference RNA specific for human copper transporter 1 (hCtr1) may be used to suppress growth of HCC by blocking increased copper uptake mediated by hCtr1. Furthermore, altered copper metabolism is a promising target for radionuclide therapy of HCC using therapeutic copper radionuclides. Copper metabolism has potential as a new theranostic biomarker for molecular imaging as well as targeted therapy of HCC. PMID- 26755874 TI - Current status and perspectives of immune-based therapies for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a frequent cancer with a high mortality. For early stage cancer there are potentially curative treatments including local ablation, resection and liver transplantation. However, for more advanced stage disease, there is no optimal treatment available. Even in the case of a "curative" treatment, recurrence or development of a new cancer in the precancerous liver is common. Thus, there is an urgent need for novel and effective (adjuvant) therapies to treat HCC and to prevent recurrence after local treatment in patients with HCC. The unique immune response in the liver favors tolerance, which remains a genuine challenge for conventional immunotherapy in patients with HCC. However, even in this "immunotolerant" organ, spontaneous immune responses against tumor antigens have been detected, although they are insufficient to achieve significant tumor death. Local ablation therapy leads to immunogenic tumor cell death by inducing the release of massive amounts of antigens, which enhances spontaneous immune response. New immune therapies such as dendritic cell vaccination and immune checkpoint inhibition are under investigation. Immunotherapy for cancer has made huge progress in the last few years and clinical trials examining the use of immunotherapy to treat hepatocellular carcinoma have shown some success. In this review, we discuss the current status of and offer some perspectives on immunotherapy for hepatocellular carcinoma, which could change disease progression in the near future. PMID- 26755876 TI - Glypican-3 is a prognostic factor and an immunotherapeutic target in hepatocellular carcinoma. AB - Glypican-3 (GPC3) is a cell surface oncofetal proteoglycan that is anchored by glycosylphosphatidylinositol. Whereas GPC3 is abundant in fetal liver, its expression is hardly detectable in adult liver. Importantly, GPC3 is overexpressed in hepatocellular carcinoma (HCC), and several immunohistochemical studies reported that overexpression predicts a poorer prognosis for HCC patients. Therefore, GPC3 would serve as a useful molecular marker for HCC diagnosis and also as a target for therapeutic intervention in HCC. Indeed, some immunotherapy protocols targeting GPC3 are under investigations; those include humanized anti-GPC3 cytotoxic antibody, peptide vaccine and immunotoxin therapies. When considering the clinical requirements for GPC3-targeting therapy, companion diagnostics to select the appropriate HCC patients are critical, and both immunohistochemical analysis of tissue sections and measurement of serum GPC3 level have been suggested for this purpose. This review summarizes current knowledge regarding the clinical implication of GPC3 detection and targeting in the management of patients with HCC. PMID- 26755875 TI - Controversies regarding and perspectives on clinical utility of biomarkers in hepatocellular carcinoma. AB - The prevalence of hepatocellular carcinoma (HCC) worldwide parallels that of persistent infection with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV). According to recommendations by the World Health Organization guidelines for HBV/HCV, alpha-fetoprotein (AFP) testing and abdominal ultrasound should be performed in routine surveillance of HCC every 6 mo for high-risk patients. These examinations have also been recommended worldwide by many other HCC guidelines over the past few decades. In recent years, however, the role of AFP in HCC surveillance and diagnosis has diminished due to advances in imaging modalities. AFP was excluded from the surveillance and/or diagnostic criteria in the HCC guidelines published by the American Association for the Study of Liver Diseases in 2010, the European Association for the Study of the Liver in 2012, and the National Comprehensive Cancer Network in 2014. Other biomarkers, including the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), des-gamma carboxyprothrombin, Dickkopf-1, midkine, and microRNA, are being studied in this regard. Furthermore, increasing attention has focused on the clinical utility of biomarkers as pre-treatment predictors for tumor recurrence and as post-treatment monitors. Serum and tissue-based biomarkers and genomics may aid in the diagnosis of HCC, determination of patient prognosis, and selection of appropriate treatment. However, further studies are needed to better characterize the accuracy and potential role of these approaches in clinical practice. PMID- 26755877 TI - Differentiation of hepatocellular carcinoma from its various mimickers in liver magnetic resonance imaging: What are the tips when using hepatocyte-specific agents? AB - Hepatocellular carcinoma is the most common primary hepatic malignant tumor. With widespread use of liver imaging, various cirrhosis-related nodules are frequently detected in patients with chronic liver disease, while diverse hypervascular hepatic lesions are incidentally detected but undiagnosed on dynamic computed tomography and magnetic resonance imaging (MRI). However, use of hepatocyte specific MR contrast agents with combined perfusion and hepatocyte-selective properties have improved diagnostic performance in detection and characterization of focal liver lesions. Meanwhile, the enhancement patterns observed during dynamic phases using hepatocyte-specific agents may be different from those observed during MRI using conventional extracellular fluid agents, leading to confusion in diagnosis. Therefore, we discuss useful tips for the differentiation of hepatocellular carcinoma from similar lesions in patients with and without chronic liver disease using liver MRI with hepatocyte-specific agents. PMID- 26755873 TI - Prediction of hepatocellular carcinoma biological behavior in patient selection for liver transplantation. AB - Morphological criteria have always been considered the benchmark for selecting hepatocellular carcinoma (HCC) patients for liver transplantation (LT). These criteria, which are often inappropriate to express the tumor's biological behavior and aggressiveness, offer only a static view of the disease burden and are frequently unable to correctly stratify the tumor recurrence risk after LT. Alpha-fetoprotein (AFP) and its progression as well as AFP-mRNA, AFP-L3%, des gamma-carboxyprothrombin, inflammatory markers and other serological tests appear to be correlated with post-transplant outcomes. Several other markers for patient selection including functional imaging studies such as (18)F-FDG-PET imaging, histological evaluation of tumor grade, tissue-specific biomarkers, and molecular signatures have been outlined in the literature. HCC growth rate and response to pre-transplant therapies can further contribute to the transplant evaluation process of HCC patients. While AFP, its progression, and HCC response to pre transplant therapy have already been used as a part of an integrated prognostic model for selecting patients, the utility of other markers in the transplant setting is still under investigation. This article intends to review the data in the literature concerning predictors that could be included in an integrated LT selection model and to evaluate the importance of biological aggressiveness in the evaluation process of these patients. PMID- 26755879 TI - Targeting adeno-associated virus and adenoviral gene therapy for hepatocellular carcinoma. AB - Human hepatocellular carcinoma (HCC) heavily endangers human heath worldwide. HCC is one of most frequent cancers in China because patients with liver disease, such as chronic hepatitis, have the highest cancer susceptibility. Traditional therapeutic approaches have limited efficacy in advanced liver cancer, and novel strategies are urgently needed to improve the limited treatment options for HCC. This review summarizes the basic knowledge, current advances, and future challenges and prospects of adeno-associated virus (AAV) and adenoviruses as vectors for gene therapy of HCC. This paper also reviews the clinical trials of gene therapy using adenovirus vectors, immunotherapy, toxicity and immunological barriers for AAV and adenoviruses, and proposes several alternative strategies to overcome the therapeutic barriers to using AAV and adenoviruses as vectors. PMID- 26755881 TI - Combination antiretroviral studies for patients with primary biliary cirrhosis. AB - Following the characterization of a human betaretrovirus in patients with primary biliary cirrhosis (PBC), pilot studies using antiretroviral therapy have been conducted as proof of principal to establish a link of virus with disease and with the eventual aim to find better adjunct therapies for patients unresponsive to ursodeoxycholic acid. In the first open label pilot study, the reverse transcriptase inhibitor lamivudine had little demonstrable biochemical or histological effect after 1 year. Whereas, lamivudine in combination with zidovudine was associated with a significant reduction in alkaline phosphatase as well as improvement in necroinflammatory score, cholangitis and ductopenia over a 12 mo period. A double blind, multi-center randomized controlled trial using lamivudine with zidovudine for 6 mo confirmed a significant reduction in alkaline phosphatase, ALT and AST in patients on antiviral therapy. However, none of the patients achieved the stringent endpoint criteria for normalization of alkaline phosphatase. Furthermore, some patients developed biochemical rebound consistent with drug resistance. A major fault of these studies has been the inability to measure the viral load in peripheral blood and therefore, provide a direct correlation between improvement of hepatic biochemistry and reduction in viral load. Nevertheless, viral mutants to lamivudine with zidovudine were later characterized in the NOD.c3c4 mouse model of PBC that has been used to test other antiretroviral regimens to betaretrovirus. The combination of tenofovir and emtricitabine reverse transcriptase inhibitors and the HIV protease inhibitor, lopinavir were found to abrogate cholangitis in the NOD.c3c4 mouse model and the same regimen normalized the liver tests in a PBC patient with HIV and human betaretrovirus infection. This combination antiretroviral therapy has now been used in a double blind randomized controlled crossover study for patients with PBC followed by an open label extension study. Only a third of the PBC patients were able to tolerate the lopinavir but those maintained on tenofovir, emtricitabine and lopinavir experienced sustained and clinically meaningful reduction in hepatic biochemistry. While we await the histological and virological evaluation, it is clear that better tolerated regimens of antiretroviral treatment will be required in future clinical trials. PMID- 26755878 TI - Hepatocellular carcinoma mouse models: Hepatitis B virus-associated hepatocarcinogenesis and haploinsufficient tumor suppressor genes. AB - The multifactorial and multistage pathogenesis of hepatocellular carcinoma (HCC) has fascinated a wide spectrum of scientists for decades. While a number of major risk factors have been identified, their mechanistic roles in hepatocarcinogenesis still need to be elucidated. Many tumor suppressor genes (TSGs) have been identified as being involved in HCC. These TSGs can be classified into two groups depending on the situation with respect to allelic mutation/loss in the tumors: the recessive TSGs with two required mutated alleles and the haploinsufficient TSGs with one required mutated allele. Hepatitis B virus (HBV) is one of the most important risk factors associated with HCC. Although mice cannot be infected with HBV due to the narrow host range of HBV and the lack of a proper receptor, one advantage of mouse models for HBV/HCC research is the numerous and powerful genetic tools that help investigate the phenotypic effects of viral proteins and allow the dissection of the dose-dependent action of TSGs. Here, we mainly focus on the application of mouse models in relation to HBV-associated HCC and on TSGs that act either in a recessive or in a haploinsufficient manner. Discoveries obtained using mouse models will have a great impact on HCC translational medicine. PMID- 26755882 TI - Gut microbiota in autism and mood disorders. AB - The hypothesis of an important role of gut microbiota in the maintenance of physiological state into the gastrointestinal (GI) system is supported by several studies that have shown a qualitative and quantitative alteration of the intestinal flora in a number of gastrointestinal and extra-gastrointestinal diseases. In the last few years, the importance of gut microbiota impairment in the etiopathogenesis of pathology such as autism, dementia and mood disorder, has been raised. The evidence of the inflammatory state alteration, highlighted in disorders such as schizophrenia, major depressive disorder and bipolar disorder, strongly recalls the microbiota alteration, highly suggesting an important role of the alteration of GI system also in neuropsychiatric disorders. Up to now, available evidences display that the impairment of gut microbiota plays a key role in the development of autism and mood disorders. The application of therapeutic modulators of gut microbiota to autism and mood disorders has been experienced only in experimental settings to date, with few but promising results. A deeper assessment of the role of gut microbiota in the development of autism spectrum disorder (ASD), as well as the advancement of the therapeutic armamentarium for the modulation of gut microbiota is warranted for a better management of ASD and mood disorders. PMID- 26755880 TI - Xenobiotics and loss of tolerance in primary biliary cholangitis. AB - Data from genome wide association studies and geoepidemiological studies established that a combination of genetic predisposition and environmental stimulation is required for the loss of tolerance in primary biliary cholangitis (PBC). The serologic hallmark of PBC are the presence of high titer anti mitochondrial autoantibodies (AMA) that recognize the lipoyl domain of the mitochondrial pyruvate dehydrogenase E2 (PDC-E2) subunit. Extensive efforts have been directed to investigate the molecular basis of AMA. Recently, experimental data has pointed to the thesis that the breaking of tolerance to PDC-E2 is a pivotal event in the initial etiology of PBC, including environmental xenobiotics including those commonly found in cosmetics and food additives, suggesting that chemical modification of the PDC-E2 epitope may render its vulnerable to become a neo-antigen and trigger an immune response in genetically susceptible hosts. Here, we will discuss the natural history, genetics and immunobiology of PBC and structural constraints of PDC-E2 in AMA recognition which makes it vulnerable to chemical modification. PMID- 26755883 TI - Capsule endoscopy: The road ahead. AB - Since its introduction into clinical practice 15 years ago, capsule endoscopy (CE) has become the first-line investigation procedure in some small bowel pathologies, and more recently, dedicated esophageal and colon CE have expanded the fields of application to include the upper and lower gastrointestinal disorders. During this time, CE has become increasingly popular among gastroenterologists, with more than 2 million capsule examinations performed worldwide, and nearly 3000 PubMed-listed studies on its different aspects published. This huge interest in CE may be explained by its non-invasive nature, patient comfort, safety, and access to anatomical regions unattainable via conventional endoscopy. However, CE has several limitations which impede its wider clinical applications, including the lack of therapeutic capabilities, inability to obtain biopsies and control its locomotion. Several research groups are currently working to overcome these limitations, while novel devices able to control capsule movement, obtain high quality images, insufflate the gut lumen, perform chromoendoscopy, biopsy of suspect lesions, or even deliver targeted drugs directly to specific sites are under development. Overlooking current limitations, especially as some of them have already been successfully surmounted, and based on the tremendous progress in technology, it is expected that, by the end of next 15 years, CE able to perform both diagnostic and therapeutic procedures will remain the major form of digestive endoscopy. This review summarizes the literature that prognosticates about the future developments of CE. PMID- 26755887 TI - Nuclear magnetic resonance based metabolomics and liver diseases: Recent advances and future clinical applications. AB - Metabolomics is defined as the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification. It is an "omics" technique that is situated downstream of genomics, transcriptomics and proteomics. Metabolomics is recognized as a promising technique in the field of systems biology for the evaluation of global metabolic changes. During the last decade, metabolomics approaches have become widely used in the study of liver diseases for the detection of early biomarkers and altered metabolic pathways. It is a powerful technique to improve our pathophysiological knowledge of various liver diseases. It can be a useful tool to help clinicians in the diagnostic process especially to distinguish malignant and non-malignant liver disease as well as to determine the etiology or severity of the liver disease. It can also assess therapeutic response or predict drug induced liver injury. Nevertheless, the usefulness of metabolomics is often not understood by clinicians, especially the concept of metabolomics profiling or fingerprinting. In the present work, after a concise description of the different techniques and processes used in metabolomics, we will review the main research on this subject by focusing specifically on in vitro proton nuclear magnetic resonance spectroscopy based metabolomics approaches in human studies. We will first consider the clinical point of view enlighten physicians on this new approach and emphasis its future use in clinical "routine". PMID- 26755884 TI - Proteoglycans in liver cancer. AB - Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain, such as a heparan, dermatan, chondroitin, or keratan sulfate, covalently attached to the protein core. These molecules are categorized based on their structure, localization, and function, and can be found in the extracellular matrix, on the cell surface, and in the cytoplasm. Cell-surface heparan sulfate proteoglycans, such as syndecans, are the primary type present in healthy liver tissue. However, deterioration of the liver results in overproduction of other proteoglycan types. The purpose of this article is to provide a current summary of the most relevant data implicating proteoglycans in the development and progression of human and experimental liver cancer. A review of our work and other studies in the literature indicate that deterioration of liver function is accompanied by an increase in the amount of chondroitin sulfate proteoglycans. The alteration of proteoglycan composition interferes with the physiologic function of the liver on several levels. This article details and discusses the roles of syndecan-1, glypicans, agrin, perlecan, collagen XVIII/endostatin, endocan, serglycin, decorin, biglycan, asporin, fibromodulin, lumican, and versican in liver function. Specifically, glypicans, agrin, and versican play significant roles in the development of liver cancer. Conversely, the presence of decorin could potentially provide protective effects. PMID- 26755886 TI - Treatment of hepatocellular carcinoma with portal venous tumor thrombosis: A comprehensive review. AB - The natural history of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is dismal (approximately 2-4 mo), and PVTT is reportedly found in 10%-40% of HCC patients at diagnosis. According to the Barcelona Clinic Liver Cancer (BCLC) Staging System (which is the most widely adopted HCC management guideline), sorafenib is the standard of care for advanced HCC (i.e., BCLC stage C) and the presence of PVTT is included in this category. However, sorafenib treatment only marginally prolongs patient survival and, notably, its therapeutic efficacy is reduced in patients with PVTT. In this context, there have been diverse efforts to develop alternatives to current standard systemic chemotherapies or combination treatment options. To date, many studies on transarterial chemoembolization, 3-dimensional conformal radiotherapy, hepatic arterial chemotherapy, and transarterial radioembolization report better overall survival than sorafenib therapy alone, but their outcomes need to be verified in future prospective, randomized controlled studies in order to be incorporated into current treatment guidelines. Additionally, combination strategies have been applied to treat HCC patients with PVTT, with the hope that the possible synergistic actions among different treatment modalities would provide promising results. This narrative review describes the current status of the management options for HCC with PVTT, with a focus on overall survival. PMID- 26755888 TI - Solid, non-skin, post-liver transplant tumors: Key role of lifestyle and immunosuppression management. AB - Liver transplantation has been the treatment of choice for end-stage liver disease since 1983. Cancer has emerged as a major long-term cause of death for liver transplant recipients. Many retrospective studies that have explored standardized incidence ratio have reported increased rates of solid organ cancers post-liver transplantation; some have also studied risk factors. Liver transplantation results in a two to five-fold mean increase in the rate of solid organ cancers. Risk of head and neck, lung, esophageal, cervical cancers and Kaposi's sarcoma is high, but risk of colorectal cancer is not clearly demonstrated. There appears to be no excess risk of developing breast or prostate cancer. Environmental risk factors such as viral infection and tobacco consumption, and personal risk factors such as obesity play a key role, but recent data also implicate the role of calcineurin inhibitors, whose cumulative and dose-dependent effects on cell metabolism might play a direct role in oncogenesis. In this paper, we review the results of studies assessing the incidence of non-skin solid tumors in order to understand the mechanisms underlying solid cancers in post-liver transplant patients and, ultimately, discuss how to prevent these cancers. Immunosuppressive protocol changes, including a calcineurin inhibitor-free regimen, combined with dietary guidelines and smoking cessation, are theoretically the best preventive measures. PMID- 26755889 TI - Endoscopic submucosal tunnel dissection for large superficial esophageal squamous cell neoplasms. AB - Endoscopic submucosal dissection (ESD) is a well-established treatment for superficial esophageal squamous cell neoplasms (SESCNs) with no risk of lymphatic metastasis. However, for large SESCNs, especially when exceeding two-thirds of the esophageal circumference, conventional ESD is time-consuming and has an increased risk of adverse events. Based on the submucosal tunnel conception, endoscopic submucosal tunnel dissection (ESTD) was first introduced by us to remove large SESCNs, with excellent results. Studies from different centers also reported favorable results. Compared with conventional ESD, ESTD has a more rapid dissection speed and R0 resection rate. Currently in China, ESTD for large SESCNs is an important part of the digestive endoscopic tunnel technique, as is peroral endoscopic myotomy for achalasia and submucosal tunnel endoscopic resection for submucosal tumors of the muscularis propria. However, not all patients with SESCNs are candidates for ESTD, and postoperative esophageal strictures should also be taken into consideration, especially for lesions with a circumference greater than three-quarters. In this article, we describe our experience, review the literature of ESTD, and provide detailed information on indications, standard procedures, outcomes, and complications of ESTD. PMID- 26755885 TI - Chemoprevention of obesity-related liver carcinogenesis by using pharmaceutical and nutraceutical agents. AB - Obesity and its related metabolic disorders are serious health problems worldwide, and lead to various health-related complications, including cancer. Among human cancers, hepatocellular carcinoma (HCC) is one of the most common malignancies affected by obesity. Therefore, obesity and its related disorders might be a key target for the prevention of HCC. Recently, new research indicates that the molecular abnormalities associated with obesity, including insulin resistance/hyperinsulinemia, chronic inflammation, adipokine imbalance, and oxidative stress, are possible molecular mechanisms underlying the pathogenesis of obesity-related hepatocarcinogenesis. Green tea catechins and branched-chain amino acids, both of which are classified as nutraceutical agents, have been reported to prevent obesity-related HCC development by improving metabolic abnormalities. The administration of acyclic retinoid, a pharmaceutical agent, reduced the incidence of HCC in obese and diabetic mice, and was also associated with improvements in insulin resistance and chronic inflammation. In this article, we review the detailed molecular mechanisms that link obesity to the development of HCC in obese individuals. We also summarize recent evidence from experimental and clinical studies using either nutraceutical or pharmaceutical agents, and suggest that nutraceutical and pharmaceutical approaches targeting metabolic abnormalities might be a promising strategy to prevent the development of obesity-related HCC. PMID- 26755892 TI - Resilience and Disparities among Lesbian, Gay, Bisexual, and Transgender Older Adults. PMID- 26755891 TI - Reward-Modulated Response Inhibition, Cognitive Shifting, and the Orbital Frontal Cortex in Early Adolescence. AB - Immaturities in cognitive shifting are associated with adolescent risk behaviors. The orbital frontal cortex (OFC) regulates reward processing and response inhibition. This study tested the relationship between cognitive shifting, OFC activity, and reward-modulated response inhibition in young adolescents. An fMRI antisaccade (AS) paradigm examined the effects of reward conditions on inhibitory response and OFC processing. A validated self-report inventory assessed cognitive shifting. Compared to neutral, reward trials showed better AS performance and increased OFC activation. Cognitive shifting positively associated with AS performance in reward and neutral trials. Poorer cognitive shifting predicted greater OFC activation. Results indicate lower OFC efficiency, as greater activation to achieve correct performance, underlies cognitive shifting problems. These neurocognitive impairments are relevant for understanding adolescent risk behaviors. PMID- 26755893 TI - Statistical Significance of Clustering using Soft Thresholding. AB - Clustering methods have led to a number of important discoveries in bioinformatics and beyond. A major challenge in their use is determining which clusters represent important underlying structure, as opposed to spurious sampling artifacts. This challenge is especially serious, and very few methods are available, when the data are very high in dimension. Statistical Significance of Clustering (SigClust) is a recently developed cluster evaluation tool for high dimensional low sample size data. An important component of the SigClust approach is the very definition of a single cluster as a subset of data sampled from a multivariate Gaussian distribution. The implementation of SigClust requires the estimation of the eigenvalues of the covariance matrix for the null multivariate Gaussian distribution. We show that the original eigenvalue estimation can lead to a test that suffers from severe inflation of type-I error, in the important case where there are a few very large eigenvalues. This paper addresses this critical challenge using a novel likelihood based soft thresholding approach to estimate these eigenvalues, which leads to a much improved SigClust. Major improvements in SigClust performance are shown by both mathematical analysis, based on the new notion of Theoretical Cluster Index, and extensive simulation studies. Applications to some cancer genomic data further demonstrate the usefulness of these improvements. PMID- 26755894 TI - Smoking and Cellular Telephone Use Among Pregnant Women Seeking Prenatal Care: Opportunities for Intervention. AB - OBJECTIVES: Although smoking during pregnancy is associated with poor pregnancy outcomes, many women continue to smoke throughout pregnancy. Behavioral interventions for smoking cessation yield modest benefits, particularly in lower socioeconomic groups. Pharmacotherapy, a first-line option for smoking cessation, has not shown clear benefits for pregnant smokers, partly due to limited adherence. We evaluated the feasibility of conducting a pharmacotherapy trial for smoking cessation in pregnant women, using text messaging to enhance medication adherence. METHODS: We surveyed 724 predominantly minority pregnant women to examine the prevalence and correlates of smoking and the use of cellular telephones and text messaging. RESULTS: Nearly 18% of the respondents were current smokers, with a majority (67.7%) expressing interest in participating in a smoking cessation trial. Only about 6% of women with a smoking history ever received nicotine dependence treatment. Smokers were significantly more likely to be depressed than non-smokers. The vast majority of respondents (92.1%) owned cell phones, with 93.2% having an unlimited text-messaging plan. CONCLUSIONS: These data support the feasibility of conducting a pharmacotherapy smoking cessation trial and using text messaging to enhance medication adherence in a predominantly minority population of pregnant smokers. PMID- 26755890 TI - Distinctive aspects of peptic ulcer disease, Dieulafoy's lesion, and Mallory Weiss syndrome in patients with advanced alcoholic liver disease or cirrhosis. AB - AIM: To systematically review the data on distinctive aspects of peptic ulcer disease (PUD), Dieulafoy's lesion (DL), and Mallory-Weiss syndrome (MWS) in patients with advanced alcoholic liver disease (aALD), including alcoholic hepatitis or alcoholic cirrhosis. METHODS: Computerized literature search performed via PubMed using the following medical subject heading terms and keywords: "alcoholic liver disease", "alcoholic hepatitis"," alcoholic cirrhosis", "cirrhosis", "liver disease", "upper gastrointestinal bleeding", "non variceal upper gastrointestinal bleeding", "PUD", ''DL'', ''Mallory-Weiss tear", and "MWS''. RESULTS: While the majority of acute gastrointestinal (GI) bleeding with aALD is related to portal hypertension, about 30%-40% of acute GI bleeding in patients with aALD is unrelated to portal hypertension. Such bleeding constitutes an important complication of aALD because of its frequency, severity, and associated mortality. Patients with cirrhosis have a markedly increased risk of PUD, which further increases with the progression of cirrhosis. Patients with cirrhosis or aALD and peptic ulcer bleeding (PUB) have worse clinical outcomes than other patients with PUB, including uncontrolled bleeding, rebleeding, and mortality. Alcohol consumption, nonsteroidal anti-inflammatory drug use, and portal hypertension may have a pathogenic role in the development of PUD in patients with aALD. Limited data suggest that Helicobacter pylori does not play a significant role in the pathogenesis of PUD in most cirrhotic patients. The frequency of bleeding from DL appears to be increased in patients with aALD. DL may be associated with an especially high mortality in these patients. MWS is strongly associated with heavy alcohol consumption from binge drinking or chronic alcoholism, and is associated with aALD. Patients with aALD have more severe MWS bleeding and are more likely to rebleed when compared to non-cirrhotics. Pre endoscopic management of acute GI bleeding in patients with aALD unrelated to portal hypertension is similar to the management of aALD patients with GI bleeding from portal hypertension, because clinical distinction before endoscopy is difficult. Most patients require intensive care unit admission and attention to avoid over-transfusion, to correct electrolyte abnormalities and coagulopathies, and to administer antibiotic prophylaxis. Alcoholics should receive thiamine and be closely monitored for symptoms of alcohol withdrawal. Prompt endoscopy, after initial resuscitation, is essential to diagnose and appropriately treat these patients. Generally, the same endoscopic hemostatic techniques are used in patients bleeding from PUD, DL, or MWS in patients with aALD as in the general population. CONCLUSION: Nonvariceal upper GI bleeding in patients with aALD has clinically important differences from that in the general population without aALD, including: more frequent and more severe bleeding from PUD, DL, or MWS. PMID- 26755895 TI - Edge Sharpness Assessment by Parametric Modeling: Application to Magnetic Resonance Imaging. AB - In biomedical imaging, edge sharpness is an important yet often overlooked image quality metric. In this work, a semi-automatic method to quantify edge sharpness in the presence of significant noise is presented with application to magnetic resonance imaging (MRI). The method is based on parametric modeling of image edges. First, an edge map is automatically generated and one or more edges-of interest (EOI) are manually selected using graphical user interface. Multiple exclusion criteria are then enforced to eliminate edge pixels that are potentially not suitable for sharpness assessment. Second, at each pixel of the EOI, an image intensity profile is read along a small line segment that runs locally normal to the EOI. Third, the profiles corresponding to all EOI pixels are individually fitted with a sigmoid function characterized by four parameters, including one that represents edge sharpness. Last, the distribution of the sharpness parameter is used to quantify edge sharpness. For validation, the method is applied to simulated data as well as MRI data from both phantom imaging and cine imaging experiments. This method allows for fast, quantitative evaluation of edge sharpness even in images with poor signal-to-noise ratio. Although the utility of this method is demonstrated for MRI, it can be adapted for other medical imaging applications. PMID- 26755896 TI - Pilot Study of Reimbursement Practices in Private Healthcare Centers in the Eastern Province of Saudi Arabia: To What Extent Do They Meet International Best Practices? AB - This pilot study examines reimbursement practices in private healthcare centers in the Eastern Province of Saudi Arabia. The objective of the study was to assess the extent to which the private healthcare sector in Saudi Arabia follows international best practices in reimbursement, as identified in a literature review. The study examined reimbursement practices in a sample of six private healthcare facilities through the use of similar questionnaire guidelines with each facility. Similarities among the facilities' practices included the use of contracts with insurance companies and the availability of a chargemaster. Differences included the types of reimbursement software used. Bundled payment systems were identified in four facilities but were not examined in all of the facilities studied. International best practices that were not present in any of the facilities in the study included electronic transfer protocols to link healthcare facilities, insurance companies, and banks; the use of reimbursement key performance indicators; the use of diagnosis-related groups; and the integration of disease coding into the reimbursement process. Major findings of this pilot study are that diverse types of reimbursement systems are in use in Saudi healthcare facilities and that these systems are preliminary and are largely unregulated. The authors suggest that regulation and standardization would therefore be easier at this stage than at later stages of the development of private healthcare systems in Saudi Arabia. PMID- 26755897 TI - Diffusion and Use of Tethered Personal Health Records in Primary Care. AB - BACKGROUND: Personal health records (PHRs) enable patients to access their healthcare information in a secure environment, increasing patient engagement in medical care. PHRs can be tethered to a patient's electronic health record (EHR). Tethered PHRs, also known as patient portals, allow patients to access relevant medical information from their provider. Despite recent policy efforts to promote the use of health information technology and increased availability of PHRs in the clinical setting, PHR adoption rates remain relatively low overall. This article examines physician characteristics of high vs. low PHR adopters. OBJECTIVE: The objectives of this study were to (1) examine PHR use patterns in the primary care setting, (2) identify physician characteristics affecting PHR adoption, and (3) explore physician perspectives encouraging and deterring use. METHODS: Information technology records provided data on primary care patient portal use at a large Midwestern academic medical center. Electronic surveys were administered to affiliated primary care physicians to measure their perceived use of patient portals. A focus group consisting of physician providers who completed the survey was used to further elucidate the trends and perceived utilization of the patient portal in the clinical setting. RESULTS: While they expended significant time communicating with patients using the portal, physicians generally overestimated the time spent per week on the system. Physicians who had been in practice longer estimated a higher average time spent on the system when compared to newer physicians. Patient portal activation rates and use decreased with increased years in practice. During the focus groups, physicians voiced motivation to use patient portals because they perceived improved patient communication and satisfaction with use. However, continued lack of reimbursement for time spent in portal communication was reported as a major barrier to providers' engagement with this technology. DISCUSSION: Physician endorsement and engagement is critical to achieve widespread adoption of PHRs. Such endorsement can be obtained through (1) providing rewards from health system employers for high use of PHRs, (2) providing financial reimbursement for time spent electronically communicating with patients via the PHR from federal initiatives incentivizing meaningful use of health information technology, (3) building robust support staff assistance for PHR communication into primary care workflows, and (4) integrating more PHR-specific education into providers' EHR training. PMID- 26755898 TI - The Blue Button Project: Engaging Patients in Healthcare by a Click of a Button. AB - The Blue Button project has become a way for many Americans to download their health records by just a click in any way that suits them, such as in print, on a thumb drive, or on their mobile devices and smartphones. Several organizations have developed and applied Blue Buttons on their websites to allow beneficiaries to securely access and view personal medical information and claims. The purpose of this literature review is to highlight the significance of the Blue Button project in the field of health information management. Findings suggest that the project could empower and engage consumers and patients in a healthcare system by allowing access to medical records, thereby promoting better management and overall improvement of their healthcare. To date, the project has gained wide support from insurers, technology companies, and health providers despite the challenges of standardization and interoperability. PMID- 26755899 TI - The Self-Assessment Process and Impacts on the Health Information Management Program Performance: A Case Study. AB - This study examined how health information management (HIM) educational programs can use the Malcolm Baldrige National Quality Award Model (MBNQAM) educational criteria to meet the self-assessment requirement for Commission on Accreditation for Health Informatics and Information Management Education (CAHIIM) accreditation. An existing instrument, Quantum Performance Group's Organizational Assessment Survey authored by Dr. Mark Blazey, was used in this study. The instrument was designed to self-assess the entire organization. Results of the study demonstrate how the MBNQAM can be used to successfully self-assess HIM programs. This research adds to the body of literature surrounding the application of the MBNQAM for HIM programs and provides new information to deans, administrators, and educators that may be useful, as an added component, when self-assessing HIM programs. The results of this study will help to establish a foundation for HIM programs to strengthen the self-assessment process, providing a strong starting point for strategic planning prioritization for HIM program improvement initiatives. The improved process will help in maturing the HIM program while fulfilling accreditation requirements for self-assessment. As additional HIM programs formalize the self-assessment process, benchmarking opportunities with other HIM programs will be created. PMID- 26755901 TI - Patient Matching within a Health Information Exchange. AB - The purpose of this article is to describe the patient matching problems resulting from the Nationwide Health Information Network's automated patient discovery specification and propose a more effective and secure approach for patient matching between health information organizations participating in a health information exchange. This proposed approach would allow the patient to match his or her identity between a health information organization's electronic health records (EHRs) at the same time the patient identifies which EHR data he or she consents to share between organizations. The patient's EHR username/password combination would be the credential used to establish and maintain health information exchange identity and consent data. The software developed to support this approach (e.g., an EHR health information exchange module) could also allow a patient to see what health information was shared when and with whom. PMID- 26755900 TI - Meaningful Use Attestations among US Hospitals: The Growing Rural-Urban Divide. AB - The purpose of this study was to assess EHR Incentive Program attestations of eligible US hospitals across geography and hospital type. The proportions of attestations were compared between metropolitan, micropolitan, and rural hospitals and by whether a hospital was critical access or prospective payment system. From 2011 until December 2013, rural and critical access hospitals were attesting to meaningful use and receiving federal incentive payments at a significantly lower proportion than their urban counterparts. The data suggest that the digital divide between urban and rural hospitals that are adopting electronic health records and using the technology effectively is widening. These findings illustrate that the needs of rural hospitals currently and into the future are different than urban hospitals, and the meaningful use program does not appear to provide the resources needed to propel these rural hospitals forward. PMID- 26755902 TI - Accessibility of mHealth Self-Care Apps for Individuals with Spina Bifida. AB - As the smartphone becomes ubiquitous, mobile health is becoming a viable technology to empower individuals to engage in preventive self-care. An innovative mobile health system called iMHere (Internet Mobile Health and Rehabilitation) has been developed at the University of Pittsburgh to support self-care and adherence to self-care regimens for individuals with spina bifida and other complex conditions who are vulnerable to secondary complications. The goal of this study was to explore the accessibility of iMHere apps for individuals with spina bifida. Six participants were asked to perform tasks in a lab environment. Though all of the participants were satisfied with the iMHere apps and would use them again in the future, their needs and preferences to access and use iMHere apps differed. Personalization that provides the ability for a participant to modify the appearance of content, such as the size of the icons and the color of text, could be an ideal solution to address potential issues and barriers to accessibility. The importance of personalization--and potential strategies--for accessibility are discussed. PMID- 26755904 TI - Allergen Challenge Chamber: an innovative solution in allergic rhinitis diagnosis. AB - The Allergen Challenge Chamber (ACC) is definitely a serious challenge on the one hand and an innovative solution in allergic rhinitis diagnosis on the other. The gradual validation of the chamber (according to the test protocol) will allow for standardisation, which is a process undertaken by centres worldwide. The process of designing a consistent system that allows for creating conditions as those in the case of natural inhalation took into account all the aspects (technical specification) necessary to ensure appropriate inhalation. PMID- 26755903 TI - Role of primary and secondary prevention in atopic dermatitis. AB - Atopic dermatitis (AD) is a serious epidemiological problem in industrialized countries. The incidence of AD has increased considerably over the last 30 years. Atopic dermatitis is a chronic, recurrent, inflammatory skin disease accompanied by strong itching. It is characterized by typical features depending on age. The parents of children suffering from AD must be prepared to change their lifestyle. They should avoid factors which can promote skin lesions and apply appropriate, regular skin care. The article describes primary prevention of AD as well as prophylactic measures to avoid skin eczema. It presents the role of infections, vaccinations, breastfeeding and the influence of domestic animals, house renovation and moulds on development of AD. The article also describes the significance of the epidermal barrier, skin colonization by microbial agents, pruritus, stress, food and inhalant allergy among people who suffer from AD. PMID- 26755905 TI - Itching sensation in psoriatic patients and its relation to body mass index and IL-17 and IL-31 concentrations. AB - INTRODUCTION: According to available data, pruritus is a common symptom of psoriasis, however its characteristics and pathogenesis are not clearly understood. AIM: The main aim of this study was to assess itching sensation among patients suffering from psoriasis, including its incidence and severity. All factors triggering and worsening pruritic symptoms were also carefully analyzed. The authors assessed the relationship of itch with body mass index (BMI) and severity of disease. Moreover, serum levels of interleukin 17 (IL-17) and IL-31 were analyzed in relation to Psoriasis Activity and Severity Index, BMI and severity of pruritus. MATERIAL AND METHODS: The study group consisted of 60 patients with plaque-type psoriasis. Analysis of impact of pruritus on the quality of life and worsening factors was based on the questionnaire. The severity of pruritus was assessed with the use of two independent scales. Serum IL-17 and IL-31 levels were measured in 30 patients suffering from psoriasis and in 10 healthy controls using immunoassay tests. RESULTS: 88.3% of analyzed patients complained of itch and the most common factor which exacerbated pruritus was stress (39.6%). Pruritus in psoriasis was independent of gender, illness duration and extent of skin lesions. The average intensity of pruritus was assessed as moderate and did not correlate significantly with BMI level, IL-17 and IL-31. CONCLUSIONS: Since the pathogenesis of pruritus in psoriasis is not fully understood, further investigation in this area needs to be conducted. Pruritus may be considered as a characteristic feature of psoriasis and, besides the skin lesions, should be a target in dermatological treatment to improve patient's quality of life. PMID- 26755906 TI - Extrabronchial symptoms and late phase reaction enhance the diagnostic value of aspirin bronchial challenge. AB - INTRODUCTION: Lysine aspirin (l-ASA) bronchial challenge can be used in the diagnostics of aspirin exacerbated respiratory disease. It is safer than oral challenge, however it is characterized by a lower sensitivity. AIM: We sought to investigate whether additional indicators of the positive result of l-ASA bronchial challenge, i.e. late phase reaction (LPR) and extrabronchial symptoms (EBS), may enhance its diagnostic value. MATERIAL AND METHODS: Sixty-seven patients with a positive history of asthma exacerbated by aspirin and/or other non-steroidal inflammatory drugs underwent l-ASA bronchial challenge. The control groups comprised 15 aspirin tolerant asthmatics and 15 healthy subjects. Forced expiratory volume in 1 s (FEV1) and 24-hour peak expiratory flow (PEF) measurements were performed in all subjects in order to recognize early and late response to l-ASA. All subjects underwent oral ASA challenge 2 weeks after l-ASA bronchial challenge. RESULTS: Basing on FEV1 and PEF results, early reaction was present in 50.7% of patients, early and LPR in 29.9% and LPR in only 10.4% of aspirin exacerbated respiratory disease patients. The EBS were noted in 31.3% of subjects. Inclusion of LPR and EBS as positive criteria of the challenge increased sensitivity to 94.0%. CONCLUSIONS: These results indicate that both LPR and EBS should be considered as positive criteria of aspirin bronchial challenge as they enhance its diagnostic value. PMID- 26755907 TI - Expression of CXCR4 and CXCL12 and their correlations to the cell proliferation and angiogenesis in mycosis fungoides. AB - INTRODUCTION: Chemokines play an important role in tumor growth, invasion and metastasis. The CXCR4/CXCL12 axis has been implicated in development of both solid tumors and hematological malignancies and is also relevant in the pathogenesis of the most common primary cutaneous T-cell lymphoma, mycosis fungoides (MF). AIM: To evaluate the expression of CXCR4 and CXCL12 in MF and to examine their associations with cell proliferation and angiogenesis. MATERIAL AND METHODS: The material for the study consisted of skin samples obtained from 56 patients with MF and 20 healthy volunteers. The expression of CXCR4 and CXCL12 was assessed by immunohistochemistry on the paraffin blocks and compared to the expression of angiogenesis marker (CD34) and proliferation indicators (Ki-67, AgNORs). RESULTS: The expression of chemokine CXCL12 and its receptor CXCR4 was significantly higher in MF than in the healthy skin (p < 0.001). There was no significant difference between early and advanced stages of MF. Similarly, there was no statistically important correlation between the expression of CXCR4/CXCL12 and angiogenesis and proliferation markers, however a significant correlation between CD34 and AgNORs expression was found (p < 0.001). CONCLUSIONS: The CXCR4/CXCL12 axis seems to play an important role in MF development in the early as well as in the advanced stages of the disease. Therefore, the CXCR4/CXCL12 axis seems to be an interesting potential target for the future strategies of new drug development, giving hope for more efficacious therapies for mycosis fungoides. PMID- 26755909 TI - Optical rhinometry in nasal provocation testing. AB - INTRODUCTION: Optical rhinometry (ORM) is a technique that allows for direct continuous measurement of changes in blood flow (optical density) in nasal vessels, at the same time analyzing changes per unit of time in the evaluated variable: intravascular blood flow and oxygen saturation. AIM: To assess the extent to which ORM can be used as an objective measure of nasal mucosal edema following a nasal allergen provocation test in a group of patients with allergic rhinitis versus healthy controls. MATERIAL AND METHODS: The study group included 60 subjects: 30 patients diagnosed with an allergy to common environmental allergens (dust mites/grasses) and 30 healthy controls. The method used in the study was a nasal provocation test with an allergen, with a standard dose of a control solution and an allergen (5,000 SBU/ml) administered using a calibrated atomizer into both nostrils in room temperature. RESULTS: The mean delay to the onset of nasal mucosal response as measured by ORM was 3.15 min and the level of light extinction returned to baseline after 28.15 min (change in optical density 0.431). These objective changes in optical density strongly correlated with subjective perception measured via a visual analog scale. CONCLUSIONS: Optical rhinometry is a valuable tool for nasal allergen provocation testing. PMID- 26755908 TI - Concentration of angiopoietins 1 and 2 and their receptor Tie-2 in peripheral blood in patients with chronic obstructive pulmonary disease. AB - INTRODUCTION: Both angiopoietins (angiopoietin 1 - Ang-1, angiopoietin 2 - Ang-2) and angiopoietin receptors (Tie) are involved in angiogenesis and vascular remodeling. AIM: To assess concentrations of Ang-1, Ang-2 and Tie-2 in blood of patients with chronic obstructive pulmonary disease (COPD) and evaluate if their concentrations depend on the severity of the disease. MATERIAL AND METHODS: Thirty patients with COPD (stage II-IV) and 8 healthy smokers as well as 8 healthy non-smokers were included in the study. Detailed history was taken, physical examination and spirometry tests were done and blood samples were taken for evaluation of serum concentrations of Ang-1, Ang-2 and Tie. RESULTS: Among COPD patients, 8 patients suffered from moderate disease, 8 patients had severe, while 14 patients had very severe disease. The concentrations of Ang-1 and Ang-2 were not significantly greater in patients with COPD than in healthy controls. The highest concentrations of Ang-1 and Ang-2 were observed in patients with moderate COPD, and levels of Ang-2 correlated with Tie-2 in this group of patients. The levels of Ang-1 were the lowest in healthy non-smokers and in patients with severe COPD, where they inversely correlated with Tie-2. The concentrations of Ang-2 were not significantly higher in patients with moderate COPD when compared with those with severe and very severe disease and healthy smokers, and were significantly higher than in healthy non-smokers. CONCLUSIONS: It is possible that Ang-1, Ang-2 and Tie-2 play an important role especially in the early stage of COPD but not in the late phase when vascular complications of the disease occur. PMID- 26755910 TI - Frequency of streptococcal upper respiratory tract infections and HLA-Cw*06 allele in 70 patients with guttate psoriasis from northern Poland. AB - INTRODUCTION: The association of guttate psoriasis with a streptococcal throat infection and HLA-Cw*06 allele is well established in different populations. Nevertheless, only few studies on this form of disease have been performed in the Polish population. AIM: To analyze the frequencies of streptococcal-induced guttate psoriasis and HLA-Cw*06 allele in 70 patients with guttate psoriasis originating from northern Poland. MATERIAL AND METHODS: Seventy patients with guttate psoriasis and 24 healthy volunteers were enrolled into the study. Both groups were sex- and age-matched. The evidence of streptococcal infection was based on the positive throat swabs and/or elevated ASO titers. The modified method, including PCR-SSP and PCR-RFLP, was applied to HLA-Cw*06 genotyping. RESULTS: HLA-Cw*06 allele was confirmed in 49 (70%) out of 70 patients, which is significantly higher than in the control population (30%) (p = 0.001). Evidence for streptococcal infection was found in 34 (48.5%) subjects with psoriasis. Twenty-seven of them (79%) carried HLA-Cw*06 allele. In 36 individuals in whom no evidence of streptococcal infection was found, 14 (39%) did not carry HLA-Cw*06 allele. CONCLUSIONS: Our data confirm that HLA-Cw*06 is a major, but not imperative, genetic determinant for guttate psoriasis. PMID- 26755911 TI - Self-assessment of striae gravidarum prophylaxis. AB - INTRODUCTION: Striae are the most frequently occurring pathology of connective tissue during pregnancy. According to the statistical data, 70-90% of women suffer from striae gravidarum. AIM: To assess effectiveness of topical products and massage used by pregnant women in striae gravidarum prophylaxis. MATERIAL AND METHODS: The questionnaire study was conducted among 299 women who were maximum 6 months after delivery at term. The questionnaire included questions concerning age, occurrence of striae gravidarum during pregnancy, their location, week of gestation when the lesions appeared and used striae prophylaxis as well as its effectiveness in respondents' opinion. RESULTS: Analysis of the correlation between striae gravidarum occurrence and use of different types of cosmetics showed that this kind of prophylaxis is effective when applied at least twice a day (63.7% vs. 77.6%). No correlation between the type of cosmetics and presence of striae was observed (p > 0.05). CONCLUSIONS: Use of prophylactic measures like skin emollients and oils with the appropriate frequency significantly reduces the risk of striae gravidarum occurrence. PMID- 26755912 TI - Quality of life in patients with leg ulcers or skin lesions - a pilot study. AB - INTRODUCTION: Attempts to determine the quality of life are advisable in patients with ulcers as the group affected with this problem is relatively large. According to one Polish randomized trial, approximately 0.3-2% of the adult population suffers from active or healed venous ulcers. AIM: To compare the quality of life of patients with leg ulcers of venous and arterial etiology and those with lower limb skin lesions due to chronic venous insufficiency. MATERIAL AND METHODS: This study included 90 consecutive patients with ulcers of venous (n = 30) or arterial etiology (n = 30), or patients with trophic disorders of the skin associated with chronic venous insufficiency (n = 30) treated at the Venous Ulceration Outpatient Clinic and at the Department and Clinic of General Surgery, Dr. J. Biziel Memorial University Hospital No. 2, in Bydgoszcz. This study was designed as a questionnaire survey and included the Skindex-29 instrument for the assessment of quality of life in patients with dermatological conditions. RESULTS: Overall, the global Skinndex-29 scores of all studied participants ranged between 37 and 136 points, 23.93 points on average. The analyzed groups of patients differed significantly with respect to the average level of the global quality of life determined using the Skindex-29 questionnaire. CONCLUSIONS: Significant differences were observed in the global quality of life of patients who suffered from venous or arterial leg ulcers or skin lesions resulting from chronic venous insufficiency. PMID- 26755913 TI - Seckel syndrome with cutaneous pigmentary changes: two siblings and a review of the literature. PMID- 26755914 TI - Interstitial granulomatous dermatitis: a characteristic histological pattern with variable clinical manifestations. PMID- 26755915 TI - Effectiveness of omalizumab in an asthmatic patient with severe airway and blood eosinophilia. PMID- 26755916 TI - Successful treatment of multiple cutaneous leiomyomas with carbon dioxide laser ablation. PMID- 26755917 TI - Melanoma in pregnancy: a case report and review of the literature. PMID- 26755919 TI - Comparative analysis of growth characteristics of Sprague Dawley rats obtained from different sources. AB - Genetic background in animal models is an intrinsic research variable in biomedical research. Although inbred strains offer genetic uniformity, the outbred stocks, known for genetic variability are often used to develop animal models of human disease. The genetic variability is considered to be even higher when outbred stocks are obtained from different sources. In order to examine the degree of variability of an outbred stock obtained from various sources, Sprague Dawley (SD) rat lines obtained from two sources were evaluated for their growth characteristics. The SD rats from Charles River laboratories (CRL) and Harlan Laboratories (HAR) were monitored for weight gain from the age of 6 weeks to 24 weeks. Food intake was monitored between 13 and 24 weeks. Body composition, organ weights, tibial lengths and blood parameters were measured. There was no difference observed in food intake per 100 gram body weight at most of the time points. CRL rats showed higher body fat mass (49.6%), higher gross liver weights (22.2%), lower testicular weights (30.8%) and lower cholesterol levels (25.4%) than HAR rats. Phenotypic differences may be attributed to genetic heterogeneity of the SD outbred stock between the two sources and represent a significant research variable impacting studies especially related to metabolic diseases. Therefore, in order the minimize research variables for those studies where genetic diversity is not a basis for experimental design, the use of single source genetically uniform inbred animal models is highly recommended over the use of outbred stocks. PMID- 26755918 TI - Modeling Parkinson's disease in the common marmoset (Callithrix jacchus): overview of models, methods, and animal care. AB - The common marmoset (Callithrix jacchus) is a small-bodied, popular New World monkey and is used widely in reproductive biology, neuroscience, and drug development, due to its comparative ease of handling, high reproductive efficiency, and its unique behavioral characters. In this review, we discuss the marmoset models in Parkinson's disease (PD), which is a neurological movement disorder primarily resulting from a degeneration of dopaminergic neurons with clinical features of tremor, rigidity, postural instability, and akinesia. The most common PD models involve the administration of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) or 6-hydroxydopamine to study the pathogenesis and to evaluate novel therapies. Following the systemic or local administration of these neurotoxins, the marmosets with very severe Parkinson's symptoms are recommended to be placed in an intensive care unit with artificial feeding to increase survival rate. All procedures with MPTP should be conducted in a special room with enclosed cages under negative-pressure by trained researchers with personal protection. Behavioral tests are conducted to provide an external measure of the brain pathology. Along with several biomarkers, including alpha-synuclein and DJ 1, non-invasive neuroimaging techniques such as positron emission tomography and magnetic resonance imaging are used to evaluate the functional changes associated with PD. With the recent growing interest in potential and novel therapies such as stem cell and gene therapy for PD in Korea, the marmoset can be considered as a suitable non-human primate model in PD research to bridge the gap between rodent studies and clinical applications. PMID- 26755920 TI - Intraperitoneal co-administration of low dose urethane with xylazine and ketamine for extended duration of surgical anesthesia in rats. AB - Procedures involving complex surgical techniques in rats, such as placement of abdominal aortic graft require extended duration of surgical anesthesia, which often can be achieved by repeated administrations of xylazine-ketamine combination. However such repeated anesthetic administration, in addition to being technically challenging, may be associated with potential adverse events due to cumulative effects of anesthesia. We report here the feasibility of using urethane at low dose (~1/10 the recommended anesthetic dose) in combination with a xylazine-ketamine mix to achieve an extended duration of surgical anesthesia in rats. The anesthesia induction phase was quick and smooth with an optimal phase of surgical anesthesia achieved for up to 90 minutes, which was significantly higher compared to that achieved with use of only xylazine-ketamine combination. The rectal temperature, heart rate and respiratory rate were within the physiological range with an uneventful recovery phase. Post surgery the rats were followed up to 3 months without any evidence of tumor or any other adverse effects related to the use of the urethane anesthetic combination. We conclude that low dose urethane can be effectively used in combination with xylazine and ketamine to achieve extended duration of surgical anesthesia up to 90 minutes in rats. PMID- 26755921 TI - Supraphysiologic glucocorticoid administration increased biomechanical bone strength of rats' vertebral body. AB - The aim of this study is to assess the effects of different glucocorticoid administration protocols on biomechanical properties of the first lumbar vertebral body in rats. We divided 40 male rats into the following groups: control, dexamethasone (7 mg/week), dexamethasone (0.7 mg/week), methylprednisolone (7 mg/kg/week), methylprednisolone (5 mg/kg twice weekly), dexamethasone (7 mg/kg three times per week), dexamethasone (0.7 mg/kg three times per week, and low-level laser treated rats. Lumbar vertebrae in rats were exposed to the pulsed laser. We conducted a biomechanical test to examine the mechanical properties of vertebral body in rats' lumbar bone. Supraphysiologic glucocorticoid administration protocols did not impair the biomechanical properties of rats' vertebral bodies compared to control and laser-treated rats. Supraphysiologic glucocorticoid administration caused an anabolic effect on the vertebral bodies. PMID- 26755922 TI - Tissue transglutaminase-interleukin-6 axis facilitates peritoneal tumor spreading and metastasis of human ovarian cancer cells. AB - Inflammation has recently been implicated in cancer formation and progression. As tissue transglutaminase (TG2) has been associated with both inflammatory signaling and tumor cell behavior, we propose that TG2 may be an important link inducing interleukin-6 (IL-6)-mediated cancer cell aggressiveness, including cancer stem cell-like characteristics and distant hematogenous metastasis. We evaluated the effect of differential TG2 and IL-6 expression on in vivo distant metastasis of human ovarian cancer cells. IL-6 production in human ovarian cancer cells was dependent on their TG2 expression levels. The size and efficiency of tumor sphere formation were correlated with TG2 expression levels and were dependent on TG2-mediated IL-6 secretion in human ovarian cancer cells. Primary tumor growth and propagation in the peritoneum and distant hematogenous metastasis into the liver and lung were also dependent on TG2 and downstream IL-6 expression levels in human ovarian cancer cells. In this report, we provide evidence that TG2 is an important link in IL-6-mediated tumor cell aggressiveness, and that TG2 and downstream IL-6 could be important mediators of distant hematogenous metastasis of human ovarian cancer cells. Intervention specific to TG2 and/or downstream IL-6 in ovarian cancer cells could provide a promising means to control tumor metastasis. PMID- 26755923 TI - Curcumin attenuates the middle cerebral artery occlusion-induced reduction in gamma-enolase expression in an animal model. AB - Curcumin exerts a protective effect in cerebral ischemia through its anti-oxidant and anti-inflammatory activities. gamma-enolase is a glycolytic enzyme expressed in neurons that is known to exerts a neuroprotective effect. We investigated whether curcumin regulates gamma-enolase expression in focal cerebral ischemic injury in rats. Middle cerebral artery occlusion (MCAO) was performed to induce focal cerebral ischemia. Adult male rats were injected intraperitoneally with either vehicle or curcumin (50 mg/kg) 1 h after MCAO and cerebral cortex tissues were isolated 24 h after MCAO. We found that MCAO-induced injury resulted in a reduction in gamma-enolase expression in vehicle-treated animals using a proteomics approach. However, this reduction was attenuated in animals with MCAO treated with curcumin. Reverse-transcription PCR and Western blot analyses also showed that curcumin treatment prevented the MCAO injury-induced reduction in gamma-enolase expression. The results of this study suggest that curcumin exerts its neuroprotective function in focal cerebral ischemia by regulating the expression of gamma-enolase. PMID- 26755924 TI - Radiation-induced eosinophilic, polymorphic, and pruritic eruption in a pig skin model. AB - Eosinophilic, polymorphic and pruritic eruption associated with radiotherapy (EPPER) can occur in cancer patients after irradiation. In this study, we characterized the clinical and histopathological features of pig skin that developed widespread polymorphic and pruritic skin lesions following localized 50 Gy gamma-irradiation. The pigs developed pruritus 5-7 weeks after irradiation, and infiltration of the dermis by eosinophils was detected 4-7 weeks after irradiation. The irradiated animals also showed transiently increased numbers of peripheral eosinophils 5-7 weeks after treatment. Irradiation induced desquamation after 2-4 weeks, which and the desquamation gradually resolved after 7 weeks. These pathological changes correspond to those seen in irradiated human skin, indicating that this model could be useful for elucidating the pathogenesis of EPPER and for developing therapeutic and prophylactic methods. PMID- 26755925 TI - UV-Vis/FT-NIR in situ monitoring of visible-light induced polymerization of PEGDA hydrogels initiated by eosin/triethanolamine/O2. AB - In conjunction with a tertiary amine coinitiator, eosin, a photoreducible dye, has been shown to successfully circumvent oxygen inhibition in radical photopolymerization reactions. However, the role of O2 in the initiation and polymerization processes remains inconclusive. Here, we employ a UV-Vis/FT-NIR analytical tool for real-time, simultaneous monitoring of chromophore and monomer reactive group concentrations to investigate the eosin-activated photopolymerization of PEGDA-based hydrogels under ambient conditions. First, we address the challenges associated with spectroscopic monitoring of the polymerization of hydrogels using UV-Vis and FT-NIR, proposing metrics for quantifying the extent of signal loss from reflection and scattering, and showing their relation to microgelation and network formation. Second, having established a method for extracting kinetic information by eliminating the effects of changing refractive index and scattering, the coupled UV-Vis/FT-NIR system is applied to the study of eosin-activated photopolymerization of PEGDA in the presence of O2. Analysis of the inhibition time, rate of polymerization, and rate of eosin consumption under ambient and purged conditions indicates that regeneration of eosin in the presence of oxygen and consumption of oxygen occur via a nonchain process. This suggests that the uniquely high O2 resilience is due to alternative processes such as energy transfer from photo-activated eosin to oxygen. Uncovering the intricacies of the role of O2 in eosin-mediated initiation aids the design of O2 resistant free radical polymerization systems relevant to photonics, optoelectronics, biomaterials, and biosensing. PMID- 26755926 TI - Reassessing the Usefulness of Coronary Artery Calcium Score among Varying Racial and Ethnic Groups by Geographic Locations: Relevance of the Korea Initiatives on Coronary Artery Calcification Registry. AB - There is some disparity in the morbidity and mortality rates of cardiovascular disease (CVD) according to race, ethnicity, and geographic regions. Although prediction algorithms that evaluate risk of cardiovascular events have been established using traditional risk factors, they have also demonstrated a number of differences along with race and ethnicity. Of various risk assessment modalities, coronary artery calcium (CAC) score is a sensitive marker of calcific atherosclerosis and correlates well with atherosclerotic plaque burden. Although CAC score is now utilized as a useful tool for early detection of coronary artery disease, prior studies have suggested some variability in the presence and severity of coronary calcification according to race, ethnicity, and/or geographic regions. Among Asian populations, it would appear necessary to reappraise the utility of CAC score and whether it remains superior over and above established clinical risk prediction algorithms. To this end, the Korea initiatives on coronary artery calcification (KOICA) registry has been designed to identify the effectiveness of CAC score for primary prevention of CVD in asymptomatic Korean adults. This review discusses the important role of CAC score for prognostication, while also describing the design and rationale of the KOICA registry. PMID- 26755928 TI - How Could Pre-Procedural Imaging Guide Successful Left Atrial Appendage Closure? PMID- 26755927 TI - How to Utilize Coronary Computed Tomography Angiography in the Treatment of Coronary Artery Disease. AB - Coronary computed tomography angiography (CCTA) has high negative predictive power for detecting coronary artery disease. However CCTA is limited by moderate positive predictive power in the detection of myocardial ischemia. This is not unexpected because the diameter of a stenosis is a poor indicator of myocardial ischemia and discrepancy between the severity of stenosis and noninvasive tests is not uncommon. The value of stenosis for predicting future development of acute coronary syndrome represented by plaque rupture has been questioned. CCTA identifies the characteristics of high-risk plaque including positive remodeling, low density plaque and spotty or micro-calcification. Also, additional evaluation of myocardial ischemia using computational flow dynamics, and luminal attenuation gradient are expected to increase both diagnostic performance for hemodynamically significant stenosis and the predictive power for future cardiovascular risk. Technical advances in CCTA would enable evaluation of both coronary artery stenosis and myocardial ischemia simultaneously with high predictive performance, and would improve vastly the clinical value of CCTA. PMID- 26755930 TI - Reduced Longitudinal Function in Chronic Aortic Regurgitation. AB - BACKGROUND: Chronic aortic regurgitation (AR) patients demonstrate left ventricular (LV) remodeling with increased LV mass and volume but may have a preserved LV ejection fraction (EF). We hypothesize that in chronic AR, global longitudinal systolic and diastolic function will be reduced despite a preserved LV EF. METHODS: We studied with Doppler echocardiography 27 normal subjects, 87 patients with chronic AR with a LV EF > 50% (AR + PEF), 66 patients with an EF < 50% [AR + reduced LV ejection fraction (REF)] and 82 patients with hypertensive heart disease. LV volume, transmitral spectral and tissue Doppler were obtained. Myocardial velocities and their timing and longitudinal strain of the proximal and mid wall of each of the 3 apical views were obtained. RESULTS: As compared to normals, global longitudinal strain was reduced in AR + PEF (13.8 +/- 4.0%) and AR + REF (11.4 +/- 4.7%) vs. normals (18.4 +/- 3.6%, both p < 0.001). As an additional comparison group for AR + PEF, global longitudinal strain was reduced as compared to patients with hypertensive heart disease (p = 0.032). The average peak diastolic annular velocity (e') was decreased in AR + PEF (6.9 +/- 3.3 cm/s vs. 13.4 +/- 2.6 cm/s, p < 0.001) and AR + REF (4.8 +/- 2.1 cm/s, p < 0.001). Peak rapid filling velocity/e' (E/e') was increased in both AR + PEF (14.4 +/- 6.2 vs. 6.2 +/- 1.3, p < 0.001) and AR + REF (18.8 +/- 6.4, p < 0.001 vs. normals). Independent correlates of global longitudinal strain (r = 0.6416, p < 0.001) included EF (p < 0.0001), E/e' (p < 0.0001), and tricuspid regurgitation velocity (p = 0.0176). CONCLUSION: With chronic AR, there is impaired longitudinal function despite preserved EF. Moreover, global longitudinal strain was well correlated with noninvasive estimated LV filling pressures and pulmonary systolic arterial pressures. PMID- 26755929 TI - Predicting Peri-Device Leakage of Left Atrial Appendage Device Closure Using Novel Three-Dimensional Geometric CT Analysis. AB - BACKGROUND: After left atrial appendage (LAA) device closure, peri-device leakage into the LAA persists due to incomplete occlusion. We hypothesized that pre procedural three-dimensional (3D) geometric analysis of the interatrial septum (IAS) and LAA orifice can predict this leakage. We investigated the predictive parameters of LAA device closure obtained from baseline cardiac computerized tomography (CT) using a novel 3D analysis system. METHODS: We conducted a retrospective study of 22 patients who underwent LAA device closure. We defined peri-device leakage as the presence of a Doppler signal inside the LAA after device deployment (group 2, n = 5) compared with patients without peri-device leakage (group 1, n = 17). Conventional parameters were measured by cardiac CT. Angles theta and phi were defined between the IAS plane and the line, linking the LAA orifice center and foramen ovale. RESULTS: Group 2 exhibited significantly better left atrial (LA) function than group 1 (p = 0.031). Pre-procedural theta was also larger in this group (41.9 degrees vs. 52.3 degrees , p = 0.019). The LAA cauliflower-type morphology was more common in group 2. Overall, the patients' LA reserve significantly decreased after the procedure (21.7 mm(3) vs. 17.8 mm(3), p = 0.035). However, we observed no significant interval changes in pre- and post-procedural values of theta and phi in either group (all p > 0.05). CONCLUSION: Angles between the IAS and LAA orifice might be a novel anatomical parameter for predicting peri-device leakage after LAA device closure. In addition, 3D CT analysis of the LA and LAA orifice could be used to identify clinically favorable candidates for LAA device closure. PMID- 26755931 TI - Echocardiographic Assessment of Pulmonary Arteries Pulsatility Index in Fontan Circulation. AB - BACKGROUND: Late complications after Fontan procedure may be due to the absence of pump and pulsatile pulmonary blood flow in this type of palliation. Our aim was to quantify the degree of pulsation by echocardiographic method in patients with extracardiac total cavopulmonary connection (ECTCPC) in comparison with biventricular circulation and few cases of pulsatile Fontan. METHODS: In a case series study, pulsatility index (PI) derived by echocardiographic method were compared between 20 patients with ECTCPC, 6 patients with pulsatile Fontan and 18 normal individual aged 4 to 20 years old. All patients were in New York Heart Association class of I and there was no report of complication. RESULTS: In patients with ECTCPC pulmonary artery branches Doppler flow study showed lower peak and mean velocities compared to the pulsatile Fontan and normal groups. ECTCPC patients had PI of 0.59 +/- 0.14 and 0.59 +/- 0.09 for right and left pulmonary arteries (RPA and LPA) respectively. PI was higher in patients with preserved antegrade flow (RPA PI = 0.94 +/- 0.26, LPA PI = 0.98 +/- 0.27) and in normal individuals (RPA PI = 1.59 +/- 0.12, LPA PI = 1.64 +/- 0.17) for both branches (p = 0.000). CONCLUSION: Using a Doppler derived index for pulsatility, patients with ECTCPC had the least pulsation. The pulmonary artery flow pattern in patients with preserved antegrade flow showed higher pulsatility indices in both branches. Normal individuals had the greatest pulsatility index. PMID- 26755932 TI - Effect of Dipeptidyl Peptidase-4 Inhibitor on All-Cause Mortality and Coronary Revascularization in Diabetic Patients. AB - BACKGROUND: Anti-atherosclerotic effect of dipeptidyl peptidase-4 (DPP-4) inhibitors has been suggested from previous studies, and yet, its association with cardiovascular outcome has not been demonstrated. We aimed to evaluate the effect of DPP-4 inhibitors in reducing mortality and coronary revascularization, in association with baseline coronary computed tomography (CT). METHODS: The current study was performed as a multi-center, retrospective observational cohort study. All subjects with diabetes mellitus who had diagnostic CT during 2007-2011 were included, and 1866 DPP-4 inhibitor users and 5179 non-users were compared for outcome. The primary outcome was all-cause mortality and secondary outcome included any coronary revascularization therapy after 90 days of CT in addition to all-cause mortality. RESULTS: DPP-4 inhibitors users had significantly less adverse events [0.8% vs. 4.4% in users vs. non-users, adjusted hazard ratios (HR) 0.220, 95% confidence interval (CI) 0.102-0.474, p = 0.0001 for primary outcome, 4.1% vs. 7.6% in users vs. non-users, HR 0.517, 95% CI 0.363-0.735, p = 0.0002 for secondary outcome, adjusted variables were age, sex, presence of hypertension, high sensitivity C-reactive protein, glycated hemoglobin, statin use, coronary artery calcium score and degree of stenosis]. Interestingly, DPP-4 inhibitor seemed to be beneficial only in subjects without significant stenosis (adjusted HR 0.148, p = 0.0013 and adjusted HR 0.525, p = 0.0081 for primary and secondary outcome). CONCLUSION: DPP-4 inhibitor is associated with reduced all cause mortality and coronary revascularization in diabetic patients. Such beneficial effect was significant only in those without significant coronary stenosis, which implies that DPP-4 inhibitor may have beneficial effect in earlier stage of atherosclerosis. PMID- 26755935 TI - Mitral-Aortic Intervalvular Fibrosa Pseudoaneurysm. AB - Pseudoaneurysm of the mitral aortic intervalvular fibrosa (MAIVF-P) usually ensues as a complication of endocarditis or aortic valve surgery. When large, symptomatic or related to complications (rupture, compression of adjacent structures, embolic events, mitral regurgitation or heart failure) it warrants surgical excision. The natural course of uncomplicated/asymptomatic MAIVF-Ps is largely unknown since most patients are offered surgery. Increased surgical risk imposed by repeat operations in the majority of these patients is an important consideration and conservative treatment should not be excluded in selected cases. Herein we present two illustrative cases of MAIVF-P manifesting with significant arrhythmogenesis and complex endocarditis respectively. Both patients were managed conservatively. By briefly reviewing the existing literature, we discuss important diagnostic and therapeutic issues for MAIVF-Ps. To our knowledge complex ventricular arrhythmia has not been previously described as a prominent manifestation of MAIVF-P. PMID- 26755936 TI - Biventricular Takotsubo Cardiomyopathy Associated with Epilepsy. AB - We describe a case of Takotsubo cardiomyopathy in an elderly woman after status epilepticus. In an emergency echocardiography, not only left ventricular apical ballooning but also right ventricular apical hypokinesia was observed. After a medical management, the patient's condition was improved and a follow-up echocardiography showed substantial recovery of left and right ventricular apical ballooning. PMID- 26755934 TI - Recurrent Acute Decompensated Heart Failure Owing to Severe Iron Deficiency Anemia Caused by Inappropriate Habitual Bloodletting. AB - A 68-year-old woman visited the emergency department twice with symptoms of acute heart failure including shortness of breath, general weakness, and abdominal distension. Laboratory findings showed extremely low level of serum hemoglobin at 1.4 g/dL. Echocardiographic examination demonstrated dilated left ventricular cavity with systolic dysfunction and moderate amount of pericardial effusion. In this patient, acute heart failure due to severe iron deficiency anemia was caused by inappropriate habitual bloodletting. PMID- 26755933 TI - Differential Prognostic Value of Coronary Computed Tomography Angiography in Relation to Exercise Electrocardiography in Asymptomatic Subjects. AB - BACKGROUND: To explore the prognostic performance of coronary computed tomography angiography (CCTA) and exercise electrocardiography (XECG) in asymptomatic subjects. METHODS: We retrospectively enrolled 812 (59 +/- 9 years, 60.8% male) asymptomatic subjects who underwent CCTA and XECG concurrently from 2003 through 2009. Subjects were followed-up for major adverse cardiac events (MACE) including cardiac death, nonfatal myocardial infarction, unstable angina, and revascularization after 90 days from index CCTA. RESULTS: The prevalence of occult coronary artery disease (CAD) detected by CCTA was 17.5% and 120 subjects (14.8%) had positive XECG. During a mean follow-up of 37 +/- 16 months, nine subjects experienced MACE. In multivariable Cox-regression analysis, only the presence of CAD by CCTA independently predicted future MACE (p = 0.002). Moreover, CAD by CCTA improved the predictive value when added to a clinical risk factor model using the likelihood ratio test (p < 0.001). Notably, the prognostic value of CCTA persisted in the moderate-to-high-risk group as classified by the Duke treadmill score (p = 0.040), but not in the low-risk group (p = 0.991). CONCLUSION: CCTA provides incremental prognostic benefit over and above XECG in an asymptomatic population, especially for those in a moderate-to-high-risk group as classified by the Duke treadmill score. Risk stratification using XECG may prove valuable for identifying asymptomatic subjects who can benefit from CCTA. PMID- 26755937 TI - A Case of Klippel-Trenaunay Syndrome with Acute Submassive Pulmonary Thromboembolism Treated with Thrombolytic Therapy. AB - Klippel-Trenaunay syndrome is a rare congenital mesodermal abnormality characterized by varicose veins, cutaneous hemangiomas, soft tissue and bony hypertrophy of limb. Potential complications such as deep venous thrombosis and pulmonary thromboembolism have not been reported in Korea to date. We demonstrate the case of a 48-year-old woman with Klippel-Trenaunay syndrome with extensive varicose veins on right lower limb, hypertrophy of left big toe and basilar artery tip aneurysm, complicated with acute submassive pulmonary thromboembolism treated successfully with intravenous thrombolytic therapy. PMID- 26755938 TI - Unexpected Pathologic Diagnosis of the Mitral Valvular Mass. AB - A 59-year-old man with multifocal cerebral infarction was found to have the large obstructive mitral valvular mass. Although benign tumor was under suspicion before surgery, he was finally diagnosed as chronic infective endocarditis by microscopic evaluation. The precise diagnosis and the proper management of a cardiac mass are very important since even the benign tumor may cause fatal complications. However, primary cardiac mass has the broad spectrum from pseudo tumor to malignancy and the differential diagnosis using non-invasive methods is not easy even with the currently available imaging techniques. PMID- 26755940 TI - Huge Multilobulated Left Ventricular Outflow Tract Pseudoaneurysm Presenting with Ventricular Tachycardia. PMID- 26755939 TI - Lipomatous Hypertrophy of the Interatrial Septum: A 3-Dimensional Transesophageal Echocardiography Appearance. PMID- 26755941 TI - Respiratory syncytial virus (RSV) disease - new data needed to guide future policy. AB - RSV is the main cause of childhood lower respiratory infections, globally, an important cause of childhood wheeze and may be responsible for a substantial burden of disease in the very elderly and in adults with chronic medical problems, such as COPD. It is thus responsible for substantial healthcare and social costs. There are currently many companies and academic groups developing and testing candidate vaccines and there is an expectation that these will lead to effective and safe vaccines which will be available to health systems globally in the short - medium term. Despite this, there is an incomplete understanding of RSV disease, especially in adult groups, and large scale data are only available from a few countries and settings leading to low levels of awareness of the importance of this pathogen. We discuss the need for widespread national sentinel systems of RSV surveillance and some means by which this could be achieved. These data will be needed by national policy makers and immunisation advisory groups to guide future priority setting and decision making. PMID- 26755943 TI - Tissue specific reactions to positional discontinuities in the regenerating axolotl limb. AB - We investigated cellular contributions to intercalary regenerates and 180 degrees supernumerary limbs during axolotl limb regeneration using the cell autonomous GFP marker and exchanged blastemas between white and GFP animals. After distal blastemas were grafted to proximal levels tissues of the intercalary regenerate behaved independently with regard to the law of distal transformation; graft epidermis was replaced by stump epidermis, muscle-derived cells, blood vessels and Schwann cells of the distal blastema moved proximally to the stylopodium and cartilage and dermal cells conformed to the law. After 180 degrees rotation, blastemas showed contributions from stump tissues which failed to alter patterning of the blastema. Supernumerary limbs were composed of stump and graft tissues and extensive contributions of stump tissues generated inversions or duplications of polarity to produce limbs of mixed handedness. Tail skeletal muscle and cardiac muscle broke the law with cells derived from these tissues exhibiting an apparent anteroposterior polarity as they migrated to the anterior side of the blastema. We attribute this behavior to the possible presence of a chemotactic factor from the wound epidermis. PMID- 26755944 TI - A synonymous mutation of uncoupling protein 2 (UCP2) gene is associated with growth performance, carcass characteristics and meat quality in rabbits. AB - BACKGROUND: Uncoupling proteins 2 (UCP2) plays an important role in energy regulation, previous studies suggested that UCP2 is an excellent candidate gene for human obesity and growth-related traits in cattle and chicks. The current study was designed to detect the genetic variation of UCP2 gene, and to explore the association between polymorphism of UCP2 gene and growth, carcass and meat quality traits in rabbits. RESULTS: A synonymous mutation in exon 1 and four variants in the first intron of the UCP2 gene were identified by using PCR sequencing. The synonymous mutation c.72G>A was subsequently genotyped by MassArray system (Sequenom iPLEXassay) in 248 samples from three meat rabbit breeds (94 Ira rabbits, 83 Champagne rabbits, and 71 Tianfu black rabbits). Association analysis suggested that the individuals with AA and AG genotypes showed greater 70 d body weight (P < 0.05), 84 d body weight (P < 0.01), ADG from 28 to 84 days of age (P < 0.05), eviscerated weight (P < 0.01), semi-eviscerated weight (P < 0.01) and semi-eviscerated slaughter percentage (P < 0.05), respectively. Additionally, the individuals with AA and AG genotype had a lower pH value of longissimus muscle (P < 0.01) and hind leg muscle (P < 0.05) after slaughter 24 h. CONCLUSIONS: These findings indicated that UCP2 could be a candidate gene that associated with growth performance, body composition and meat quality in rabbits, and this would contribute to advancements in meat rabbit breeding practice. PMID- 26755945 TI - Culturally adapted mental healthcare: evidence, problems and recommendations. AB - Evidence suggests disparities in the prevalence of mental health problems and access to mental healthcare for a number of minority groups. The main response from mental health services falls into two related categories: (a) cultural adaptations of existing evidence-based interventions (EBIs) and/or (b) cultural competence of mental health professionals. This editorial looks at the evidence on culturally adapted EBIs and argues that although such interventions can be effective, they also carry the risk of alienating members of the groups they are aimed at. Recommendations focus on identifying issues that pertain to being from a racial minority and/or possessing other stigmatised identities that can have an impact on mental health problems, which may be overlooked by mental health services by assuming an overarching predominant cultural identity. PMID- 26755946 TI - Brain fag syndrome: a culture-bound syndrome that may be approaching extinction. AB - Aims and method To explore the current salience of 'brain fag' as a nosological, diagnostic and clinical construct in modern West African psychiatry. A semi structured questionnaire and vignette based on classical symptoms of brain fag syndrome were used to explore current knowledge, explanatory models and practice among Nigerian psychiatrists. Results Of 102 psychiatrists who responded, 98% recognised the term 'brain fag syndrome' and most recognised the scenario presented. However, only 22% made a diagnosis of brain fag syndrome in their practice preferring diagnoses of anxiety, affective and somatic disorders. Clinical implications A decreasing number of Nigerian psychiatrists are making a diagnosis of 'brain fag syndrome'. We found strong evidence of nosological and diagnostic decline in the syndrome in its place of birth. This may signal the early extinction of this disorder or nosological metamorphosis from a 'culture bound' syndrome in West African psychiatric practice. PMID- 26755947 TI - Dementia in a Black and minority ethnic population: characteristics of presentation to an inner London memory service. AB - Aims and method To examine data on referrals to an inner-city London memory service to explore any differences in referral rates, cognitive assessments and stages of dementia at presentation between ethnic groups. Results African Caribbean patients were well represented in the memory service. They were diagnosed with dementia on average 4.5 years younger than their White British counterparts and were more likely to be diagnosed with a vascular or mixed type dementia. However, scores on initial cognitive testing were significantly lower in the African-Caribbean group, possibly representing more advanced disease at presentation. Clinical implications Initiatives to access Black and minority ethnic populations earlier in the course of their illness should be considered. Professionals need to consider the potential for cultural bias in memory testing and diagnosing dementia in these populations, and the importance of cultural competency in assessments. PMID- 26755948 TI - Stigma and self-esteem across societies: avoiding blanket psychological responses to gay men experiencing homophobia. AB - Aims and method The relationship between homophobia (varying from actual and perceived to internalised) and measures of well-being is well documented. A study in Athens, Greece and London, UK attempted to examine this relationship in two cities with potentially different levels of homophobia. One-hundred and eighty eight men who have sex with men (MSM) living in London and 173 MSM living in Athens completed a survey investigating their views on their sexuality, perceptions of local homophobia and their identity evaluation in terms of global self-esteem. Results The results confirmed a negative association between homophobia and self-esteem within each city sample. However, Athens MSM, despite perceiving significantly higher levels of local homophobia than London MSM, did not differ on most indicators of internalised homophobia and scored higher on global self-esteem than London MSM. The city context had a significant impact on the relationship. Clinical implications The findings are discussed in relation to the implications they pose for mental health professionals dealing with MSM from communities experiencing variable societal stigmatisation and its effect on a positive sense of self. PMID- 26755949 TI - Illness perceptions in adolescents with a psychiatric diagnosis in Pakistan. AB - Aims and method To assess adolescents' perceptions of their psychiatric illness and the role of various demographic factors in a Pakistani setting. Adolescents with various psychiatric diagnoses were interviewed using a structured questionnaire including the Illness Perceptions Questionnaire-Revised (IPQ-R). Results Fifty-two adolescents with various psychiatric illnesses were interviewed; their mean age was 12.7 years and the majority (67%) were female. Males had significantly higher scores on timeline and emotional representation (P<0.05), suggesting strongly held beliefs about chronicity of their illness and anger and worry about their condition. Adolescents' own emotional state, stress, family problems and bad luck were endorsed by participants as some of the causal factors in their mental illness. Clinical implications Despite the importance of early intervention in psychiatric problems, engaging youth in the treatment process in Pakistan remains difficult. Better understanding of how adolescents perceive their psychiatric difficulties may play a significant role in developing culturally sensitive interventions and better utilisation of services. PMID- 26755942 TI - Global and regional estimates of COPD prevalence: Systematic review and meta analysis. AB - BACKGROUND: The burden of chronic obstructive pulmonary disease (COPD) across many world regions is high. We aim to estimate COPD prevalence and number of disease cases for the years 1990 and 2010 across world regions based on the best available evidence in publicly accessible scientific databases. METHODS: We conducted a systematic search of Medline, EMBASE and Global Health for original, population-based studies providing spirometry-based prevalence rates of COPD across the world from January 1990 to December 2014. Random effects meta-analysis was conducted on extracted crude prevalence rates of COPD, with overall summaries of the meta-estimates (and confidence intervals) reported separately for World Health Organization (WHO) regions, the World Bank's income categories and settings (urban and rural). We developed a meta-regression epidemiological model that we used to estimate the prevalence of COPD in people aged 30 years or more. FINDINGS: Our search returned 37 472 publications. A total of 123 studies based on a spirometry-defined prevalence were retained for the review. From the meta regression epidemiological model, we estimated about 227.3 million COPD cases in the year 1990 among people aged 30 years or more, corresponding to a global prevalence of 10.7% (95% confidence interval (CI) 7.3%-14.0%) in this age group. The number of COPD cases increased to 384 million in 2010, with a global prevalence of 11.7% (8.4%-15.0%). This increase of 68.9% was mainly driven by global demographic changes. Across WHO regions, the highest prevalence was estimated in the Americas (13.3% in 1990 and 15.2% in 2010), and the lowest in South East Asia (7.9% in 1990 and 9.7% in 2010). The percentage increase in COPD cases between 1990 and 2010 was the highest in the Eastern Mediterranean region (118.7%), followed by the African region (102.1%), while the European region recorded the lowest increase (22.5%). In 1990, we estimated about 120.9 million COPD cases among urban dwellers (prevalence of 13.2%) and 106.3 million cases among rural dwellers (prevalence of 8.8%). In 2010, there were more than 230 million COPD cases among urban dwellers (prevalence of 13.6%) and 153.7 million among rural dwellers (prevalence of 9.7%). The overall prevalence in men aged 30 years or more was 14.3% (95% CI 13.3%-15.3%) compared to 7.6% (95% CI 7.0%-8.2%) in women. CONCLUSIONS: Our findings suggest a high and growing prevalence of COPD, both globally and regionally. There is a paucity of studies in Africa, South East Asia and the Eastern Mediterranean region. There is a need for governments, policy makers and international organizations to consider strengthening collaborations to address COPD globally. PMID- 26755950 TI - Trauma exposure and refugee status as predictors of mental health outcomes in treatment-seeking refugees. AB - Aims and method This study aimed to identify predictors of symptom severity for post-traumatic stress disorder (PTSD) and depression in asylum seekers and refugees referred to a specialised mental health centre. Trauma exposure (number and domain of event), refugee status and severity of PTSD and depression were assessed in 688 refugees. Results Symptom severity of PTSD and depression was significantly associated with lack of refugee status and accumulation of traumatic events. Four domains of traumatic events (human rights abuse, lack of necessities, traumatic loss, and separation from others) were not uniquely associated with symptom severity. All factors taken together explained 11% of variance in PTSD and depression. Clinical implications To account for multiple predictors of symptom severity including multiple traumatic events, treatment for traumatised refugees may need to be multimodal and enable the processing of multiple traumatic memories within a reasonable time-frame. PMID- 26755951 TI - Difficult to treat? A comparison of the effectiveness of treatment as usual in refugees and non-refugees. AB - Aims and method To examine treatment response in traumatised refugees, we compared routine outcome monitoring data (Harvard Trauma Questionnaire) of two refugee populations with those of individuals experiencing profession-related trauma who were treated at a specialised psychotrauma institute. Results Asylum seekers/temporary refugees (n = 21) and resettled refugees (n = 169) showed significantly lower post-traumatic stress disorder (PTSD) symptom reduction between intake and 1 year after intake than did a comparison group of non refugees (n = 37), but the interaction effect was clinically small (partial eta(2) = 0.03). Refugees who had more severe symptoms at intake showed significantly greater symptom reduction after 1 year. Clinical implications Therapists and refugee patients should have realistic expectations about response to treatment as usual. Additional treatment focusing on improving quality of life may be needed for refugees whose PTSD symptom severity remains high. At the same time, novel approaches may be developed to boost treatment response in refugee patients with low responsiveness. PMID- 26755952 TI - What is culturally informed psychiatry? Cultural understanding and withdrawal in the clinical encounter. AB - What is culturally informed psychiatry? What does it mean, and why is it important? These questions are discussed with a focus on the cultural aspects of the clinical encounter. The DSM-5 Outline for Cultural Formulation was developed as a method of assessing the cultural factors affecting the clinical encounter. It calls for the assessment of the cultural features of the relationship between the patient and the clinician; however, there is a lack of debate about what this means in practice. Clinicians run the risk of withdrawal rather than cultural understanding when facing patients with different cultural backgrounds. Using ethnographic material from anthropological fieldwork, I suggest that the encounter with cultural differences could be a useful point of departure for the clinician to develop cultural understanding. It is argued that recognising the experiences of differences is crucial in strengthening transcultural communication and preventing misdiagnosis in the clinician-patient encounter. PMID- 26755953 TI - 'Spirituality' and 'cultural adaptation' in a Latino mutual aid group for substance misuse and mental health. AB - A previously unknown Spanish-language mutual aid resource for substance use and mental health concerns is available in Latino communities across the USA and much of Latin America. This kind of '4th and 5th step' group is a 'culturally adapted' version of the 12-step programme and provides empirical grounds on which to re theorise the importance of spirituality and culture in mutual aid recovery groups. This article presents ethnographic data on this organisation. PMID- 26755955 TI - A guide to a new short course to promote interest and engagement in psychiatry in medical students. AB - This article describes a new course for preclinical medical undergraduates designed to promote interest and engagement in psychiatry. The course employed a range of innovative teaching techniques alongside ward visits to provide students with early clinical experience. Unusually, assessment for the course involved the production of creative works as well as reflective writing about students' experiences. We collected a variety of feedback from participants showing that they found the course enjoyable and educational. We conclude that, overall, the course had a positive effect on student perceptions of psychiatry. PMID- 26755954 TI - Impact of involuntary out-patient commitment on reducing hospital services: 2 year follow-up. AB - Aims and method To evaluate whether involuntary out-patient commitment (OPC) in patients with severe mental disorder reduces their use of hospital services. This is a retrospective case-control study comparing a group of patients on OPC (n = 75) and a control group (n = 75) which was composed of patients whose sociodemographic variables and clinical characteristics were similar to those of the OPC group. Each control case is paired with an OPC case, so the control case must have an involuntary admission in the month that the index OPC case admission occurred. Emergency room visits, admissions and average length of hospital stay over a 2-year follow-up after the initiation of OPC were compared. Results No statistically significant evidence was found in the use of mental healthcare services between the two groups. Different reasons for admission found between the groups limit similarity when comparing the two. Clinical implications The findings cast doubt over the effectiveness of this legal measure to reduce emergency visits, the number of admissions and the length of stay in the hospital. PMID- 26755956 TI - Effectiveness increases with integration in primary care. PMID- 26755957 TI - CMHTs provide follow-up for patients with dementia and behavioural and psychological symptoms of dementia in both service models. PMID- 26755958 TI - Thoughts on the development of liaison psychiatry services in London. PMID- 26755959 TI - 'Background' and 'foreground' knowledge: targeting learning materials to trainees' needs. PMID- 26755960 TI - 'Legal highs' - what's in a name? PMID- 26755961 TI - National Confidential Inquiry. PMID- 26755962 TI - Payment by results in forensic mental health. AB - Forensic mental health services are low-volume, high-cost services. Payment by results (PbR) is the UK s latest attempt to improve efficiency and controls pending behaviours within the secure services. This article discusses the utility of the PbR mechanic in forensic mental health. It explores PbR implementation in non-forensic mental health settings, similar funding processes internationally, and early PbR implementation work in the UK's secure services. Finally, the article discusses the challenges faced when implementing PbR in forensic mental health services and puts forward possible next steps in determining the utility of PbR in forensic mental health. PMID- 26755963 TI - Psychiatric morbidity and socio-occupational dysfunction in residents of a drug rehabilitation centre: challenges of substance misuse management in a Bruneian context. AB - Aims and method In 2011, a psychiatric clinic was started in Pusat Al-Islah, a drug rehabilitation centre. Our aim was to record self-reported socio occupational dysfunction and patterns of drug misuse and to evaluate the usefulness of a psychiatric screening tool. A two-phased approach using the Self Reporting Questionnaire (SRQ) and the Mini International Neuropsychiatric Interview (MINI) was used to examine the rates of psychiatric diagnoses. Results Methamphetamine was the most commonly misused substance in 94.5% of residents. High levels of socio-occupational dysfunction were reported. In total, 5.5% met criteria for major depressive disorder, 4.8% for lifetime psychotic disorder and 11.5% for suicidal ideation. In addition, 13.3% reported previous untreated mental health problems. Clinical implications A screening tool such as the SRQ can be used to identify those needing further psychiatric assessment. Interventions to address amphetamine misuse and associated socio-occupational dysfunction are required. Societal views and legislation influence the management of substance misuse problems in Brunei. PMID- 26755964 TI - The methamphetamine problem: Commentary on ... Psychiatric morbidity and socio occupational dysfunction in residents of a drug rehabilitation centre. AB - This paper introduces the reader to the characteristics of methamphetamine. Explored within are the drug's effects on those who consume it as well as the history and prevalence of its use. The highly addictive nature of methamphetamine is compounded by its affordability and the ease with which it is produced, with North America and East Asia having become established as heartlands for both consumption and manufacture. The paper discusses recent cultural depictions of the drug and also the role that mental health professionals may take in designing and delivering interventions to treat methamphetamine addiction. PMID- 26755965 TI - Patient characteristics and predictors of completion in residential treatment for substance use disorders. AB - Aims and method To identify the patient characteristics and rates of retention in a residential rehabilitation drug and alcohol service (Springhill) based on an eclectic model of care. Patients were assessed using the Alcohol and Drug Outcome Measure (ADOM), a brief tool designed for the New Zealand setting. We looked at correlations between demographic, social and drug use parameters. Logistic regression assessed the relative impact of each variable on completion. Results The 183 patients who completed the data collection did not differ from 47 non completers by demographic data; 62.2% of patients completed the programme, with equal number of men and women. One in five participants was Maori, the indigenous minority. Alcohol (51.9%) was the commonest drug of misuse, with methamphetamine (16.4%) and cannabis (14.2%) also significant. Completers were more likely to be Maori, have conflict with family and housing problems, although the last became non-significant in logistic regression. Clinical implications Retention rates are higher in Springhill than in comparable programmes. Ethnicity and family conflict predict completion, although the reasons for this are unclear. ADOM is an effective tool that can be used in a clinical setting to enable analysis of service provision. PMID- 26755966 TI - New patient assessment in old age psychiatry: the importance of risk assessment. AB - Aims and method In recent years, the role of non-medical community mental health team (CMHT) clinicians has widened to include new patient assessments. It is unclear whether all professionals have the skills and confidence to undertake these to a high quality. This project investigated which professionals are doing new assessments, evaluated their quality and explored the assessors' unmet training needs. The study was based on the data extracted from electronic notes and a complete audit cycle in South Oxfordshire Older Adults CMHT; this was a cross-sectional study across Oxfordshire older adults services. Results Most new assessments (72.4%) were done by non-medical clinicians; the majority were missing important information, especially relating to medications and risk assessment. Only 75% of assessors felt at least 'partially confident' to do assessments and found them stressful, with 86% keen to undertake further training. Clinical implications Simple measures such as an assessment form, a programme of training seminars and adequate supervision, delivered to all CMHT clinicians, can ensure high-quality assessment in diverse clinical environments. PMID- 26755967 TI - Experiences of ward rounds among in-patients on an acute mental health ward: a qualitative exploration. AB - Aims and method To address the gap in qualitative research examining patients' experiences of ward rounds. In-depth interviews were conducted with five in patients on an acute mental health ward. Data were analysed using thematic analysis. Results Data were organised into three first-order themes, positioned within an overarching theme relating to patients' perceptions of the use of power and control within ward rounds. Clinical implications Systemic factors may make it difficult to facilitate ward rounds in a manner which leaves patients feeling fully empowered or in control, but there are practical measures to address these issues, drawn from participants' accounts. PMID- 26755968 TI - Lurasidone: a novel antipsychotic agent for the treatment of schizophrenia and bipolar depression. AB - Lurasidone is a novel antipsychotic agent approved for the treatment of schizophrenia in a number of countries including the UK, and is also approved in the USA and Canada for the treatment of major depressive episodes associated with bipolar I disorder as either a monotherapy or adjunctive therapy with lithium or valproate. In addition to full antagonist activity at dopamine D2 (K i(D2) = 1 nM) and serotonin 5-HT2A (K i(5-HT2A) = 0.5 nM) receptors, the pharmacodynamic profile of lurasidone is notable for its high affinity for serotonin 5-HT7 receptors (K i(5-HT7) = 0.5 nM) and its partial agonist activity at 5-HT1A receptors (K i(5-HT1A) = 6.4 nM). Long-term treatment of schizophrenia with lurasidone has been shown to reduce the risk of relapse. Lurasidone appears associated with minimal effects on body weight and low risk for clinically meaningful alterations in glucose, lipids or electrocardiogram parameters. PMID- 26755970 TI - Update on the Improving Access to Psychological Therapies programme in England: Commentary on ... Children and Young People's Improving Access to Psychological Therapies. AB - Professor Sami Timimi recently expressed concerns about the Improving Access to Psychological Therapies (IAPT) programme. We argue that the concerns are largely unfounded and provide readers with an update on the programme. PMID- 26755969 TI - Epidemiology on demand: population-based approaches to mental health service commissioning. AB - One in three people will experience a mental health problem in their lifetime, but the causes and consequences of psychiatric morbidity are socially patterned. Epidemiological studies can provide aetiological clues about the causes of disorder, and when they can provide robust estimates about risk in different strata of the population these can also be used translationally, to provide commissioners and service planners with detailed information about local service need. This approach is illustrated using a newly developed population-level prediction tool for first-episode psychosis, PsyMaptic. Such public mental health prediction tools could be used to improve allocation of finite resources, by integrating evidence-based healthcare, public health and epidemiology together. PMID- 26755971 TI - Update on the Improving Access to Psychological Therapies programme in England: author's reply. AB - Fonagy & Clark confirm in their rebuttal that they have an ideological commitment to the failed technical model of understanding and intervening in mental health problems that dominates current service provision. They fail to acknowledge the limitations and problems associated with Improving Access to Psychological Therapies (IAPT) and Children's and Young People's IAPT (CYP-IAPT) and offer an unconvincing explanation for why they did not allow some of the vast tax payers' money that they had at their dispoal to be used to implement evidence supported relational models. PMID- 26755972 TI - Exit examination: a survey of UK psychiatrists' views. AB - Aims and method The Royal College of Psychiatrists is considering how best to introduce a post-MRCPsych-examination assessment ('exit examination') in anticipation of external pressures to ensure patient safety through the use of such assessments. The Psychiatric Trainees' Committee conducted an online survey to gather the views of psychiatrists regarding the possible format and content of this examination in the hope that this information can be used to design a satisfactory assessment. Results Of the 2082 individuals who started the survey, 1735 completed all sections (83.3%). Participants included consultants and trainees from a range of subspecialties. There was general agreement that the content and structure of the exit examination should include assessment of clinical and communication skills. Clinical implications UK psychiatrists believe that an exit assessment should focus on clinical and communication skills. It should assess both generic and subspecialty-specific competencies and incorporate a mixture of assessment techniques. PMID- 26755973 TI - Bulletin comment: In praise of the psychiatric ward round. PMID- 26755974 TI - Fair criticism also needs to be based on evidence. PMID- 26755976 TI - Raising the standard: it's time to review the MRCPsych examinations. PMID- 26755975 TI - Encouraging dialogue for better collaboration and service improvement. PMID- 26755977 TI - The Royal College of Psychiatrists' response. PMID- 26755978 TI - A more practicel solution is needed. PMID- 26755979 TI - Psychiatry is more than neuropsychiatry. PMID- 26755980 TI - Fully inform the Martian. PMID- 26755981 TI - Can psychiatry and neurology 'simply' merge? PMID- 26755982 TI - Are psychiatrists only fools and horses to be open all hours? AB - The UK government's proposal for 24-hour healthcare means effectively asking doctors to work more unsociable hours for relatively little financial gain. In our opinion, psychiatry is particularly vulnerable to deterioration owing to negotiations of the terms of the current Consultant Contract that ensures fewer antisocial hours, whereas without parallel appropriate internal team and intra agency working, provisions for which are not included in the government's proposals to extend care, patient care is vulnerable. Clarification and a narrower redefinition of what constitutes a psychiatric emergency is called for. PMID- 26755983 TI - Newspaper reporting of homicide-suicide and mental illness. AB - Aims and method To explore the portrayal of homicide-suicide in newspaper articles, particularly how mental illness was reported. We carried out a qualitative study in England and Wales (2006-2008). Data from newspaper articles obtained via the LexisNexis database were used to examine a consecutive series of 60 cases. Results A fascination with extreme violence, vulnerable victims and having someone to blame made homicide-suicides newsworthy. Some offenders were portrayed in a stereotypical manner and pejorative language was used to describe mental illness. The findings showed evidence of inaccurate and speculative reference to mental disorder in newspaper reports. Clinical implications The media should avoid speculation on people's mental state. Accurate reporting is essential to reduce stigma of mental illness, which may in turn encourage people to seek help if they experience similar emotional distress. PMID- 26755984 TI - Mental health problems associated with female genital mutilation. AB - Aims and method To study the mental health status of 66 genitally mutilated immigrant women originating from Africa (i.e. Somalia, Sudan, Eritrea and Sierra Leone). Scores on standardised questionnaires (Harvard Trauma Questionnaire-30, Hopkins Symptom Checklist-25, COPE-Easy, Lowlands Acculturation Scale) and demographic and psychosocial correlates were analysed. Results A third of the respondents reported scores above the cut-off for affective or anxiety disorders; scores indicative for post-traumatic stress disorder were presented by 17.5% of women. Type of circumcision (infibulation), recollection of the event (a vivid memory), coping style (avoidance, in particular substance misuse) and employment status (lack of income) were significantly associated with psychopathology. Clinical implications A considerable minority group, characterised by infibulated women who have a vivid memory of the circumcision and cope with their symptoms in an avoidant way, reports to experience severe consequences of genital circumcision. In terms of public healthcare, interventions should target these groups as a priority. PMID- 26755985 TI - Should psychiatrists 'Google' their patients? AB - Since its beginnings in the 1980s the internet has come to shape our everyday lives, but doctors still seem rather afraid of it. This anxiety may be explained by the fact that researchers and regulatory bodies focus less on the way that the internet can be used to enhance clinical work and more on the potential and perceived risks that this technology poses in terms of boundary violations and accidental breaches of confidentiality. Some aspects of the internet's impact on medicine have been better researched than others, for example, whether email communication, social media and teleconferencing psychotherapy could be used to improve the delivery of care. However, few authors have considered the specific issue of searching online for information about patients and much of the guidance published by regulatory organisations eludes this issue. In this article we provide clinical examples where the question 'should I Google the patient?' may arise and present questions for future research. PMID- 26755986 TI - The changing face(book) of psychiatry: can we justify 'following' patients' social media activity? AB - Individuals with mental health issues may post information on social networking sites that can provide an insight into their mental health status. It could be argued that doctors (and specifically psychiatrists) should understand the way in which social media is used by their patients to gain a better insight into their illnesses. However, choosing to actively monitor a patient's social media activity raises important questions about the way in which medical students, qualified clinicians and other healthcare professionals obtain information about patients. While this may be framed as a mere form of 'collateral history-taking', there are obvious practical and ethical problems with doing so. Here, a case is made against monitoring the social media activity of patients involved with psychiatric services. PMID- 26755987 TI - YouTube and 'psychiatry'. AB - YouTube is a video-sharing website that is increasingly used to share and disseminate health-related information, particularly among younger people. There are reports that social media sites, such as YouTube, are being used to communicate an anti-psychiatry message but this has never been confirmed in any published analysis of YouTube clip content. This descriptive study revealed that the representation of 'psychiatry' during summer 2012 was predominantly negative. A subsequent smaller re-analysis suggests that the negative portrayal of 'psychiatry' on YouTube is a stable phenomenon. The significance of this and how it could be addressed are discussed. PMID- 26755988 TI - Mobile telephone apps in mental health practice: uses, opportunities and challenges. AB - Smartphones are used by patients and clinicians alike. Vast numbers of software applications (apps) run on smartphones and carry out useful functions. Clinician- and patient-oriented mental health apps have been developed. In this article, we provide an overview of apps that are relevant for mental health. We look at clinician-oriented apps that support assessment, diagnosis and treatment as well as patient-oriented apps that support education and self-management. We conclude by looking at the challenges that apps pose with a discussion of possible solutions. PMID- 26755990 TI - Provision of neuropsychiatry services: variability and unmet need. AB - Aims and method Neuropsychiatry services remain underdeveloped and underprovided. Previous studies have shown variability in service provision in the UK. In this survey we approached all mental health and neuropsychiatric service providers within London to map current neuropsychiatric service provision and explore perceived barriers. Results All the specialist mental health service providers responded. There was huge variability in neuropsychiatric service provision within different parts of London. There was evidence of significant unmet need and variability in service pathways. Lack of earmarked funds for neuropsychiatry and disjointed funding stream for such services were identified by providers as a barrier. Clinical implications This study provides further evidence of an ongoing lack of adequate neuropsychiatric service provision. Reasons for variability and unmet need are discussed. Adoption of a previously proposed hub-and-spoke model of service provision and the removal of commissioning barriers through uniform national commissioning may help deal with this problem. PMID- 26755989 TI - Commissioning neuropsychiatry services: barriers and lessons. AB - Aims and method Previous studies have shown variations in commissioning of neuropsychiatry services and this makes access to neuropsychiatric services a post-code lottery. In this survey, we approached all mental health and neuropsychiatric service commissioners within London to map current funding and commissioning arrangements, and explored perceived barriers to neuropsychiatric service commissioning. Results 83% of commissioners within London responded. There was significant variability between neuropsychiatric services commissioned through the mental health stream. Contracting arrangements were variable. Lack of earmarked fund for neuropsychiatry and disjointed funding stream for such services were identified by commissioners as a barrier, as was the critical mass of neuropsychiatric cases. Clinical implications Neuropsychiatric service development continues to be hindered by lack of clear commissioning process. Strategic drive is needed to promote more equitable neuropsychiatric services. National or regional commissioning covering a large population will provide a better model for neuropsychiatric services to be commissioned. PMID- 26755991 TI - The application of mental health legislation in younger children. AB - We review a case history of a young child who was admitted to an in-patient mental health unit due to extremely challenging behaviour and review the legal issues that had to be considered in ensuring that there was appropriate legal authority for the child's admission and treatment. In this particular case, the patient was detained for assessment under section 2 of the Mental Health Act 1983. This case demonstrates that all clinicians working in this area require a good understanding of the law in relation to treatment of children with mental disorder, which is extremely complex. PMID- 26755992 TI - Chemotherapy for Hodgkin's lymphoma in a patient receiving clozapine for treatment-resistant schizophrenia: use of the Mental Capacity Act 2005. AB - Treatment resistance occurs in approximately 30% of individuals with schizophrenia and is commonly treated with clozapine. Nodular sclerosing Hodgkin's lymphoma is a subtype of Hodgkin's lymphoma predominantly affecting those under 50 years of age. In this case report, an individual with treatment resistant schizophrenia developed nodular sclerosing Hodgkin's lymphoma and is treated with concurrent clozapine and systemic chemotherapy. The aim of this case report is to act as guidance for clinicians and to outline the difficulties of treating individuals with psychiatric illness under the Mental Capacity Act 2005 when the proposed treatment could lead to high levels of morbidity and mortality. PMID- 26755993 TI - ECT practices in Iraq: a national audit. AB - Aims and method This national audit examined practice of electroconvulsive therapy (ECT) in Iraq against local standards. Data were collected by a questionnaire sent to heads of departments or medical directors in the 10 Iraqi hospitals which provide ECT and by examining case notes of all patients who had ECT in the first 6 months of 2013. Results Of the 26 psychiatric hospitals in Iraq, 10 provide ECT. There were some resource shortcomings in the ECT clinics (e.g. only 2 had a minimum of 2 rooms and all had no EEG monitoring). During the audit period, 251 patients had ECT. The mean age was 36.2 years and 51.8% were males. Bilateral ECT was used in all cases, general anaesthesia in 77.15%. The main indication for ECT was schizophrenia, followed by severe depression, resistant mania, catatonia and others. Clinical implications More work is needed to ensure all patients receive modified ECT. ECT is still used widely for schizophrenia. This needs further exploration and training. PMID- 26755994 TI - Debate: Can and should psychiatrists use online information? PMID- 26755996 TI - Plus ca change. PMID- 26755995 TI - Replication and contradiction of highly cited research papers: a lesson for the Secretary of State for Health? PMID- 26755997 TI - Can training schemes incorporate valuable out-of-hours experience to reflect patient need? PMID- 26755998 TI - Legal highs, NPS, head shop drugs? Whatever you call them, we need to know more about prevalence. PMID- 26755999 TI - The GMC review of fitness to practise investigations and its impact on doctors. PMID- 26756000 TI - Prevalence of Ureaplasma urealyticum and Mycoplasma hominis in High Vaginal Swab Samples of Infertile Females. AB - BACKGROUND: Mycoplasma hominis and Ureaplasma urealyticum are important causative agents of vaginitis, cervicitis, postpartum sepsis, reproductive infections and infertility in both males and females. OBJECTIVES: According to the uncertain prevalence of U. urealyticum and M. hominis in Iranian infertile females, the present study was carried out to determine the prevalence of U. urealyticum and M. hominis in high vaginal swab samples of fertile and infertile females. PATIENTS AND METHODS: A total of 350 high vaginal swab specimens were taken from fertile and infertile females. Samples were cultured and those that were positive for bacteria were subjected to the polymerase chain reaction (PCR) for further confirmation. RESULTS: Of the 350 collected samples, eleven were positive for M. hominis (3.14%), fifteen were positive for U. urealyticum (4.28%) and five were positive for both of them (1.42%). Prevalence of U. urealyticum and M. hominis in the high vaginal parts of infertile females was higher than fertile females (P < 0.05). The results of traditional method were also confirmed, using the PCR amplification of urease gene of U. urealyticum and 16SrRNA gene of the M. hominis. Ureaplasma urealyticum and M. hominis had a higher prevalence in the high vaginal samples collected during the summer season. CONCLUSIONS: Considerable prevalence of M. hominis and U. urealyticum in the high vaginal swab samples of infertile females compared to the low prevalence in fertile females may suggest that these two pathogens can be cause infertility. Application of the PCR method is recommended for rapid and sensitive detection of M. hominis and U. urealyticum in high vaginal swab samples. PMID- 26756001 TI - Antimicrobial Susceptibility Patterns of Ureaplasma urealyticum and Mycoplasma hominis Isolated From Pregnant Women. AB - BACKGROUND: Mycoplasma hominis and Ureaplasma urealyticum bring with them an increased risk of pregnancy complications, such as premature membrane rupture, vaginitis and preterm birth. OBJECTIVES: The present investigation was carried out to study the prevalence of M. hominis and U. urealyticum in pregnant women and to study their resistance against commonly used antibiotics. MATERIALS AND METHODS: Three hundred and fifty high vaginal swabs were taken from pregnant women. Commercial Mycoplasma IST-2 kit was used for bacterial isolation. The results of the kits were confirmed using the PCR. The pattern of antibiotic resistance was determined using the disk diffusion method. RESULTS: Of 350 samples collected, 32 samples (9.14%) were positive for U. urealyticum and 10 samples (2.85%) were positive for M. hominis (P = 0.025). Both U. urealyticum and M. hominis were simultaneously detected in 1.14% of samples. In addition, 40 - 45 year-old pregnant women had the highest levels of U. urealyticum (27.5%), M. hominis (12.5%), and both bacteria (7.5%). U. urealyticum and M. hominis isolates harbored the highest levels of resistance against ciprofloxacin, ofloxacin, erythromycin, and tetracycline. Both isolates were susceptible to pefloxacin, clarithromycin, josamycin, and pristinamycin. CONCLUSIONS: According to the direct correlation between the increase in the prevalence rate of genital mycoplasmas and increased age of pregnancy, initially, it is better to prevent pregnancy at older ages, and then, should a pregnancy occur, the highest levels of health cares should be provided to older pregnant women. PMID- 26756002 TI - The Prevalence of Thyroid Dysfunction in Patients With Systemic Lupus Erythematosus. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease caused by immune system-mediated tissue damage. Autoimmune thyroiditis (AT) is an organ-specific disease associated with production of a variety of antibodies such as antinuclear antibodies, anti-double-stranded DNA, anti-Ro antibodies and anti-cardiolipin antibodies. OBJECTIVES: The aim of this study was to evaluate the prevalence of thyroid dysfunction and thyroid auto-antibodies in patients with SLE and its relation to SLE disease and other autoantibodies. PATIENTS AND METHODS: This was a case-control study. The study included a total of 88 patients with SLE and 88 age- and sex-matched healthy volunteers as control group. Two study groups were compared regarding thyroid function test, antinuclear antibody (ANA), antibodies to double-stranded DNA (dsDNA), anti- thyroglobulin antibody (anti-Tg), and anti-thyroid peroxidase (anti-TPO) antibody. RESULTS: The mean age of SLE patients and controls were 32.16 +/- 9.19 and 32.48 +/- 9.47 years, respectively (P = 0.821). Patients had significantly higher prevalence (43.2% vs. 23.9%; P = 0.015) and titers (221.8 +/- 570.5 vs. 78.2 +/- 277.2; P = 0.036) of antibodies to Tg compared to controls. The patients had significantly lower titers of T3 compared to controls (125.2 +/- 35.6 vs. 136.2 +/- 26.5; P = 0.021). The titers of T4, TSH and anti-TPO antibody did not differ significantly between the two study groups. CONCLUSIONS: Thyroid dysfunction was not higher in SLE patients compared to healthy individuals. However, anti-Tg antibodies were higher in SLE patients. It has not yet been established that thyroid function tests should be performed routinely in SLE patients. PMID- 26756003 TI - Peutz-Jeghers Syndrome With Diffuse Gastrointestinal Polyposis: Three Cases in a Family With Different Manifestations and No Evidence of Malignancy During 14 Years Follow Up. AB - INTRODUCTION: Peutz-Jeghers syndrome (PJS) is a rare disorder characterized by mucocutaneous perioral pigmentation, gastrointestinal hamartomatous polyposis, and an increased risk of malignancy. Families with PJS may show a variable spectrum of manifestations in spite of their consecutive generations. A probable explanation is novel mutations in contributing genes. CASE PRESENTATION: This report describes 3 cases of a family. Two daughters presented the classic PJS, while their father only manifested mucocutaneous perioral pigmentation. The junior daughter was underwent 3 and the eldest daughter 2 laparotomies for intussusception. The patients were visited annually and their medical findings were recorded during a follow-up period of 14 years. They were periodically examined in our hospital and despite conveying diffuse polyposis from the esophagus throughout the rectum in these three cases, even a simple hyperplasia was not found in obtained specimens. CONCLUSIONS: The patients with diffuse PJS may be asymptomatic and without gastrointestinal or extragastrointestinal malignancies. PMID- 26756004 TI - The Effect of Testosterone on Men With Andropause. AB - BACKGROUND: Andropause is the gradual reduction of the male sex hormone (testosterone) with increasing age. Its symptoms are sexual dysfunction, weakness, fatigue, insomnia, loss of motivation, mood disorders and reduction of bone density. Treatment of andropause with testosterone has been recently considered. OBJECTIVES: The aim of this study was to evaluate the effect of testosterone in the treatment of andropause in men. PATIENTS AND METHODS: For men who met the inclusion criteria (50 years of age and older) laboratory tests and clinical examinations were conducted by an urologist in order to diagnose prostate cancer, prostate disease, urinary tract infection and active urinary retention. After obtaining consent, the patients were enrolled in the study. Data were analyzed using SPSS version 20. Descriptive statistics (frequency and percentage, mean, standard deviation) and the paired t-test were used to compare levels of testosterone. To determine the correlation between age and testosterone levels, the Pearson correlation was used. Finally, to compare the treatment processes during the treatment period the repeated measures ANOVA was used. RESULTS: The mean age of patients was 56.57 +/- 3.21 years. A total of 31 patients (39%) were smokers, among them 30% smoked daily, 2.5% weekly and 6% smoked for fun. The mean testosterone level before treatment was 240.6 +/- 125.4 and at 1, 3 and 6 months after treatment the level was raised, so that at the end of the sixth months it was 578.7 +/- 141.7. The level of increase was statistically significant (P = 0.0001). CONCLUSIONS: Treatment with testosterone in men over 50 years with andropause will increase testosterone levels and also quality of life, sexual desire, erection, energy levels, ability to exercise and feel the joy of life more than before. Depression was decreased and they had sleepy feelings after dinner. PMID- 26756005 TI - Students' Aggression and Its Relevance to Personal, Family, and Social Factors. AB - BACKGROUND: Aggression is defined as behaviors intended to hurt, harm, or injure another person. Aggression is by no means a new concern in human society, especially in youth. Universities are among the institutions in which most of the members are young people and because of facing with various personal and social stressors, the students usually experience high level of stress. OBJECTIVES: This study aimed to determine aggression among university students and its association with their personal, family, and social characteristics. MATERIALS AND METHODS: This cross-sectional, analytic study was conducted on a representative sample (n = 809) of university students (1 state university and 2 private universities) locating in Gonabad, Iran in 2012. Using proportional to size stratified sampling, we selected the respondents and gathered the required data using a valid and reliable questionnaire. The data were entered into SPSS (version 20) and analyzed through t test, ANOVA, and regression model. RESULTS: A total of 381 (47.2%) male and 428 (52.8%) female students participated in the study. Mean (SD) age of the respondents was 21.79 (2.86) years. Overall mean aggression score (SD) in the students was 72.45 (15.49) and this score for in dorm and out of dorm students was 74.31 (15.59) and 70.93 (15.23), respectively. There were significant associations between the mean aggression score of dormitory students and sex (P = 0.004), age (P = 0.044), and type of the university (P = 0.039). On the other hand, there was no significant association between all independent factors and mean aggression score of students living out of dorm. CONCLUSIONS: Regarding the control of aggressive behaviors, paying attention to male, young students living in dormitory, especially in non-governmental universities has the highest priority. PMID- 26756006 TI - Efficacy of Tiotropium Bromide and Rehabilitation Treatment on Pulmonary Function of Patients With Sulfur Mustard Lung Injury. AB - BACKGROUND: Chronic pulmonary complication is the most common delayed toxic effect of sulfur mustard (SM) and it has no treatment so far. OBJECTIVES: To evaluate short-term therapeutic effects of inhaled tiotropium bromide and pulmonary rehabilitation on pulmonary function of patients with SM induced lung injury. PATIENTS AND METHODS: In a randomized clinical trial, using convenient sampling method, 54 patients with chronic lung disease due to SM exposure were recruited in Baqiyatallah General Hospital, Tehran, Iran for a period of 2-month study. They were randomly divided into 3 groups of 18 participants each. Group 1 received routine drugs (Serevent, Flixotide), pulmonary rehabilitation 30 minutes/2 times a week, and tiotropium bromide 18 ug/day. Group 2 was treated with routine drugs and pulmonary rehabilitation and group 3 was only on the routine drugs. cardiopulmonary exercise test (CPET), plethysmographic measurements, and respiratory symptoms evaluation were performed before and after medical intervention. RESULTS: In group 1, compared to group 3, significant differences were found with regard to symptoms of cough ([difference between the first and last visit in group 1: Diff 1] = -1.6, Diff 3 = -0.3, P = 0.01) and nocturnal dyspnea (Diff 1 = -1.9, Diff 3 = 0.0, P = 0.01), likewise, compared to group 2, significant differences were found with regard to lung function parameters of forced vital capacity (Diff 1 = 3.0, Diff 2 = -3.5, P = 0.03), forced expiratory volume in one second (Diff 1 = 3.9, Diff 2 = -5.6, P = 0.009), maximal mid-expiratory flow rate 25% - 75% (Diff 1 = 1.5, Diff 2 = -3.2, P = 0.007) and peak expiratory flow (Diff 1 = -2.06, Diff 2 = -4.3, P = 0.04). Total lung capacity (Diff 2 = 9.28, Diff 3 = -12.07, P = 0.02) and residual volume (Diff2 = 32.1, Diff3 = -27.6, P = 0.04) were increased in group 2 compared to group 3. There were no significant differences with regard to CPET results among all groups (P > 0.05). CONCLUSIONS: Inhalation of tiotropium bromide in combination with pulmonary rehabilitation could improve some plethysmographic lung volumes and clinical outcomes in patients with chronic pulmonary disease due to SM. Short-term prescription of pulmonary rehabilitation has no effect on CPET of patients. PMID- 26756007 TI - Comparison of Metformin and Simvastatin Administration in Women With Polycystic Ovary Syndrome Before Intra-Cytoplasmic Sperm Injection Cycle: A Prospective, Randomized, Clinical Trial Study. AB - BACKGROUND: Drugs administration as a pretreatment regiment before ICSI cycle in PCOs patients could enhance the success rate. OBJECTIVES: The aim of this study was to compare the effectiveness of metformin with Simvastatin in patients with polycystic ovary syndrome (PCOs) candidates for intra-cytoplasmic sperm injection (ICSI) before starting the cycle. PATIENTS AND METHODS: In this prospective, double blind, randomized clinical trial the efficacy of these drugs was evaluated in 40 women with PCO syndrome (20 patients in each group; A: simvastatin and B: metformin) candidates for ICSI. In the both groups, metformin and simvastatin administrated for eight weeks before starting the ICSI cycle. Endocrine, metabolic and clinical parameters were measured before and after drug therapy; also, the results of ICSI cycle evaluated in the both groups. RESULTS: Both drugs improved hirsutism score significantly, but simvastatin better than metformin (Group A, 24.5 +/- 3.6 P: 0.0001 VS Group B, 22.9 +/- 5.9 P: 0.003). The reduction in body mass index (BMI) was not significant in the groups. Simvastatin reduced some biochemical parameters such as FSH, LH, testosterone, total cholesterol, LDL and increased HDL level significantly, whereas metformin decreased FSH, TG, testosterone and total cholesterol significantly. Overall, respectively 35% and 30% of patients treated with metformin and Simvastatin became pregnant. There was no significant difference between the effects of these two drugs on ICSI cycle results like oocyte in meiosis2 (M2) phase (1.35 +/- 1.6 vs. 2 +/- 3.87, P value: 0.4) and the number of Grade A, embryo (1.2 +/- 1.3 vs. 1.1 +/- 1.4, P value: 0.7). CONCLUSIONS: Simvastatin effectively improved hyperandrogenism signs and symptoms in patients with PCO, but this effect as a pretreatment regiment was not more expressive than metformin in ICSI cycle outcome. PMID- 26756008 TI - Comparison of Two Different Protocols of Methotrexate Therapy in Medical Management of Ectopic Pregnancy. AB - BACKGROUND: Ectopic pregnancy (EP) is one of the most dangerous complications of pregnancy and without prompt diagnosis and treatment, it could become a major cause of maternal morbidity and mortality. OBJECTIVES: In this randomized controlled study, we compared single and double dose of methotrexate (MTX) therapy in the treatment of ectopic pregnancy. PATIENTS AND METHODS: This study was performed on 76 patients who were admitted to Obstetrics Ward with primary diagnosis of ectopic pregnancy based on their medical history, physical examination, beta subunit (beta-HCG) level, and transvaginal ultrasonography. Using random block allocation, the patients were classified in two groups of single dose and double dose administration of MTX. In single dose group, 50 mg/m(2) of MTX was given at day 0 and in double dose group, the patients received two doses of MTX at day 0 and 4. The level of beta-HCG was measured at day 0, 4, 7 in both groups. The successful treatment was defined as 15% reduction in beta HCG level between day 4 and 7. The two groups were compared with each other with regard to their need for operation, or extra dose of MTX; duration of hospitalization; and MTX complications. RESULTS: Results showed that the rate of success in double dose method was more than single dose one (79% versus 69%) but the difference was not significant (P = 0.29). Although the need for operation and extra dose of MTX were lower in the double dose group (15.8% vs. 18.8% and 5.26% vs. 13.2%, respectively), these differences were not significant too. Duration of hospitalization was significantly lower in double dose compared to the single dose (11.55 d vs. 14.76 d, P < 0.001). CONCLUSIONS: Single dose therapy of MTX has sufficient power and efficacy in the treatment of ectopic pregnancy, however in patients with higher serum level of beta-HCG, the successful treatment increases by using double dose method. Using double dose also could decrease the necessity of operation, re-administration of MTX, and duration of hospitalization. PMID- 26756009 TI - A Comparative Analysis of Diagnostic Accuracy of Focused Assessment With Sonography for Trauma Performed by Emergency Medicine and Radiology Residents. AB - BACKGROUND: Focused assessment with sonography in trauma (FAST) is a method for prompt detection of the abdominal free fluid in patients with abdominal trauma. OBJECTIVES: This study was conducted to compare the diagnostic accuracy of FAST performed by emergency medicine residents (EMR) and radiology residents (RRs) in detecting peritoneal free fluids. PATIENTS AND METHODS: Patients triaged in the emergency department with blunt abdominal trauma, high energy trauma, and multiple traumas underwent a FAST examination by EMRs and RRs with the same techniques to obtain the standard views. Ultrasound findings for free fluid in peritoneal cavity for each patient (positive/negative) were compared with the results of computed tomography, operative exploration, or observation as the final outcome. RESULTS: A total of 138 patients were included in the final analysis. Good diagnostic agreement was noted between the results of FAST scans performed by EMRs and RRs (kappa = 0.701, P < 0.001), also between the results of EMRs-performed FAST and the final outcome (kappa = 0.830, P < 0.0010), and finally between the results of RRs-performed FAST and final outcome (kappa = 0.795, P < 0.001). No significant differences were noted between EMRs- and RRs performed FASTs regarding sensitivity (84.6% vs 84.6%), specificity (98.4% vs 97.6%), positive predictive value (84.6% vs 84.6%), and negative predictive value (98.4% vs 98.4%). CONCLUSIONS: Trained EMRs like their fellow RRs have the ability to perform FAST scan with high diagnostic value in patients with blunt abdominal trauma. PMID- 26756010 TI - Incidence and Risk Factors of an Intraoperative Arrhythmia in Transhiatal Esophagectomy. AB - BACKGROUND: Transhiatal esophagectomy (THE) is a widely used technique for carcinoma of the esophagus and other conditions, such as benign strictures and motility disorders. OBJECTIVES: The aim of our study was to quantify the incidence, predisposing factors, as well as types of arrhythmias in transhiatal esophagectomy. PATIENTS AND METHODS: In this prospective study, we selected 61 patients undergoing transhiatal esophagectomy during 2012 - 2013 in our hospital. The demographic information, site of the tumor, cardiopulmonary function, transfusion, preoperative and postoperative complications (i.e. arrhythmias, hypotension), operation time, duration of mediastinal manipulation, amount of hemorrhage, volume loss, volume intake, mean systolic and diastolic pressure, and death rate were evaluated by chi-square, Fisher's exact test, ANOVA, and t-tests. RESULTS: The mean age of patients was 61.24 +/- 11.48. In the study group, 8.2% of the patients before, 50.8% during, and 11.2% after mediastinal manipulation showed arrhythmia. Tumor location, the need for transfusion, pathology of the tumor, presence of arrhythmia before the operation, FEV1 (Forced Expiratory Volume) > 2 liters, and mean volume intake were significantly different between the patients with and without arrhythmia. Hypotension was shown in 8.2% of the patients before and 57.7% during mediastinal manipulation. Manipulation times, volume loss, mean systolic and diastolic blood pressure before the operation, and FEV1 > 2 liters were statistically significant in occurrence of hypotension. CONCLUSIONS: Our data showed that the amount of hydration, transfusion, pre manipulation arrhythmia, and pulmonary function should be controlled to decrease the risk of arrhythmias. Minor mediastinal manipulation, few intraoperative hemorrhages, improvement of pulmonary function, and careful blood pressure monitoring can reduce the risk of hypotension. PMID- 26756011 TI - Cutaneous Metaplastic Synovial Cyst: A Case Report and Literature Review. AB - INTRODUCTION: Cutaneous metaplastic synovial cyst (CMSC) is a rare cutaneous lesion characterized by a tender subcutaneous nodule, which usually occurs at the site of previous surgical or local trauma. Histologically, the lesion includes a cystic structure with villous-like projections and a lining mimicking hyperplastic synovium. CASE PRESENTATION: We reported the first case of CMSC which developed at the surgical incision site of treatment of a maxillofacial fracture. In addition, we reviewed English literature to evaluate all previously reported CMSC cases and discussed its clinical and histopathological features and etiology. From 1987 to now, reviewing the English literature about CMSC includes 17 studies that described 28 cases, and our presented case was the 29th. There was no sex predilection and age of patients ranged from 7 to 82 years, but most of them were over 40 years. We can see this lesion in any site of the body and hand/arm is the most prevalent involved region (28% cases). Most of the patients had a history of previous local trauma or operation in the involved area. CONCLUSIONS: Although the actual etiology of CMSC remains unclear, trauma, as the most probable etiologic factor, plays a role in development of CMSC. Surgical excision of the lesion is the preferable treatment choice and rate of recurrence is low. PMID- 26756012 TI - The Effect of ISO 9001 and the EFQM Model on Improving Hospital Performance: A Systematic Review. AB - CONTEXT: This study aimed to explore the effect of the International Organization for Standardization (ISO) ISO 9001 standard and the European foundation for quality management (EFQM) model on improving hospital performance. EVIDENCE ACQUISITION: PubMed, Embase and the Cochrane Library databases were searched. In addition, Elsevier and Springer were searched as main publishers in the field of health sciences. We included empirical studies with any design that had used ISO 9001 or the EFQM model to improve the quality of healthcare. Data were collected and tabulated into a data extraction sheet that was specifically designed for this study. The collected data included authors' names, country, year of publication, intervention, improvement aims, setting, length of program, study design, and outcomes. RESULTS: Seven out of the 121 studies that were retrieved met the inclusion criteria. Three studies assessed the EFQM model and four studies assessed the ISO 9001 standard. Use of the EFQM model increased the degree of patient satisfaction and the number of hospital admissions and reduced the average length of stay, the delay on the surgical waiting list, and the number of emergency re-admissions. ISO 9001 also increased the degree of patient satisfaction and patient safety, increased cost-effectiveness, improved the hospital admissions process, and reduced the percentage of unscheduled returns to the hospital. CONCLUSIONS: Generally, there is a lack of robust and high quality empirical evidence regarding the effects of ISO 9001 and the EFQM model on the quality care provided by and the performance of hospitals. However, the limited evidence shows that ISO 9001 and the EFQM model might improve hospital performance. PMID- 26756013 TI - Gene Expression ????Profiles of BAD and Bcl-xL in the CA1 Region of the Hippocampus Following Global Ischemic/Reperfusion and FK-506 Administration. AB - BACKGROUND: The hippocampus is a tiny nub in the mammalian brain that is involved in forming, organizing, and storing memories. Global cerebral ischemia (GCI) and reperfusion induced apoptosis lead to cell injury and death. FK-506 is a strong immunosuppressant drug that has neuroprotective effects on the hypoxic-ischemic effects of brain damage. BAD and Bcl-xL are pro-apoptotic and anti-apoptotic genes, respectively. These genes belong to The B-cell lymphoma-2 (Bcl-2) family. OBJECTIVES: In this study, we assessed the neurotrophic properties of FK-506 on expression of the BAD and Bcl-xL genes in the hippocampus following global ischemia and reperfusion. MATERIALS AND METHODS: In the present experimental study, adult male Wistar rats were obtained and housed under standard conditions in the Tehran University of Medical Science in Iran. Rats were equally distributed in groups of three among the following groups: normal control, treated-1 (ischemia/reperfusion), and treated-2 (ischemia/reperfusion followed by FK-506). Global ischemia was induced for animals in the treated-1 and treated-2 groups. In treated-2, two doses of FK-506 were injected: one dose as an IV injection immediately after reperfusion and another as an intra-peritoneal (IP) injection after 48 hours. Then, the hippocampus tissue was removed after anaesthetizing the rats. RNA was isolated, cDNA was synthesized, and real-time PCR was performed. Finally, the obtained data were analyzed statistically (P value ? 0.05). RESULTS: The quantitative results of real-time PCR show that the mRNA expression ratio of Bcl-xL down-regulated was 0.75 +/- 0.06 in the ischemia/reperfusion group versus 1.57 +/- 0.09 in the control group (P value < 0.001), whereas Bcl-xL gene expression was greater in the ischemia/reperfusion +FK506 group (1.93 +/- 0.15) than in the ischemia/reperfusion group. Moreover, the mRNA expression ratio of BAD up-regulated in the ischemia/reperfusion + FK506 group was 3.65 +/- 0.49 compared to Normal control (1.39 +/- 0.09) and Ischemia/reperfusion + FK506 was 1.09 +/- 0.20 (P value < 0.001). CONCLUSIONS: The analysis of the pro-apoptotic gene to anti-apoptotic gene expression ratio (BAD /Bcl-xL) confirmed that expression of the pro-apoptotic gene significantly decreased (P value ? 0.001) under the ischemia/reperfusion condition. In contrast, the expression of the anti-apoptotic gene increased after administration of FK-506 (P value ? 0.001). PMID- 26756014 TI - Restless Legs Syndrome During Pregnancy and Preterm Birth in Women Referred to Health Centers of Ardabil. AB - BACKGROUND: The physiological changes of pregnancy may predispose females to develop restless legs syndrome (RLS). Studies evaluating outcomes of RLS symptoms in pregnancy are scarce. OBJECTIVES: We examined the risk of preterm birth in pregnant women with and without restless legs syndrome (RLS). MATERIALS AND METHODS: A cohort study included 231 pregnant women attending Ardabil health care centers for prenatal care and delivery in the period of 2010, without any risk factors for preterm delivery and low birth weight. The instruments used were questionnaires about RLS, the Epworth sleepiness scale (ESS), demographic data, and hemoglobin values. Data were analyzed via SPSS software using descriptive statistics, the t-test, chi2, Fisher's exact test, Pearson's correlation, and the Mann-Whitney U test. RESULTS: RLS complicated 43.7 percent of pregnancies. Sleepiness (ESS score > 8) was reported in 36.4% of the subjects with preterm birth and 35.9% of the term group. No significant correlation was found between the ESS score and the term and preterm groups (P = 0.843). The prevalence of preterm birth in the subjects with and without RLS was 69.7% and 30.3%, respectively: As a result, it significantly increased in the RLS group (P = 0.001). CONCLUSIONS: Pregnancies complicated by RLS are at increased risk for preterm birth. The improved sleep health of pregnant women could decrease pregnancy complications. PMID- 26756016 TI - Etiologies and Treatments of Odontogenic Maxillary Sinusitis: A Systematic Review. AB - CONTEXT: Maxillary sinusitis is an important issue in dentistry and maxillofacial surgery. This study aims to present a systematic review of etiologies and treatments of odontogenic maxillary sinusitis. EVIDENCE ACQUISITION: An electronic database search was performed based on related MeSH keywords. Articles published between January 2001 and December 2014 was selected according to the inclusion criteria. The information extracted from various studies was categorized in various tables. RESULTS: The study selected 19 studies. In most studies, oroantral fistula (OAF) was the most common etiology of odontogenic sinusitis. Alpha-hemolytic streptococcus was the most common flora in sinusitis with dental origin. The literature shows that the Caldwell-Luc approach may be the best method for treating sinusitis in cases of displaced teeth. CONCLUSIONS: OAF is a common cause of odontogenic maxillary sinusitis and may easily be treated by endoscopy and fistula closure. Maxillofacial surgeons and dentists should consider this problem to avoid misdiagnosis and prevent complications. PMID- 26756015 TI - Prevalence of Metabolic Syndrome and Its Components in the Iranian Adult Population: A Systematic Review and Meta-Analysis. AB - CONTEXT: Metabolic syndrome (MetS) increases the risk of most non-communicable diseases; gathering information about its prevalence can be very effective in formulating preventive strategies for metabolic diseases. There are many different studies about the prevalence of MetS in Iran, but the results and the study populations of these studies are very different; therefore, it is very important to have an overall estimation of its prevalence in Iran. OBJECTIVES: This study systematically reviewed the findings of all available studies on MetS in the adult Iranian population and estimated the overall prevalence of MetS in this population. DATA SOURCES: International databases (Scopus, ISI Web of Science, and PubMed) were searched for papers published from January, 2000 to December, 2013 using medical subject headings (MeSH), Emtree, and related keywords (metabolic syndrome, dysmetabolic syndrome, cardiovascular syndrome, and insulin resistance syndrome) combined with the words "prevalence" and "Iran." The Farsi equivalent of these terms and all probable combinations were used to search Persian national databases (IranMedex, Magiran, SID, and Irandoc). STUDY SELECTION: All population-based studies and national surveys that reported the prevalence of MetS in healthy Iranian adults were included. DATA EXTRACTION: After quality assessment, data were extracted according to a standard protocol. Because of between-study heterogeneity, data were analyzed by the random effect method. RESULTS: We recruited the data of 27 local studies and one national study. The overall estimation of MetS prevalence was 36.9% (95% CI: 32.7 - 41.2%) based on the Adult Treatment Panel III (ATP III) criteria, 34.6% (95% CI: 31.7 - 37.6%) according to the International Diabetes Federation (IDF), and 41.5% (95% CI: 29.8 - 53.2%) based on the Joint Interim Societies (JIS) criteria. The prevalence of MetS determined by JIS was significantly higher than those determined by ATP III and IDF. The prevalence of MetS was 15.4% lower in men than in women (27.7% versus 43.1%) based on the ATP III criteria, and it was 11.3% lower in men based on the IDF criteria; however according to the JIS criteria, it was 8.4% more prevalent in men. CONCLUSIONS: There is a high prevalence of MetS in the Iranian adult population, with large variations based on different measurement criteria. Therefore, prevention and control of MetS should be considered a priority. PMID- 26756017 TI - Profile of Virulence Factors in the Multi-Drug Resistant Pseudomonas aeruginosa Strains of Human Urinary Tract Infections (UTI). AB - BACKGROUND: Putative virulence factors are responsible for the pathogenicity of UTIs caused by Pseudomonas aeruginosa (P. aeruginosa). Resistance of P. aeruginosa to commonly used antibiotics is caused by the extreme overprescription of those antibiotics. OBJECTIVES: The goal of the present study was to investigate the prevalence of virulence factors and the antibiotic resistance patterns of P. aeruginosa isolates in UTI cases in Iran. PATIENTS AND METHODS: Two hundred and fifty urine samples were collected from patients who suffered from UTIs. Samples were cultured immediately, and those that were P. aeruginosa positive were analyzed for the presence of virulence genes using polymerase chain reaction (PCR) testing. Antimicrobial susceptibility testing (AST) was performed using the disk diffusion method. RESULTS: Of the 250 urine samples analyzed, 8 samples (3.2%) were positive for P. aeruginosa. The prevalence of P. aeruginosa in male and female patients was 2.7% and 3.5%, respectively, (P = 0.035). In patients less than 10 years old, it was 4.2%, and in patients more than 55 years old, it was 4.2%. These were the most commonly infected groups. The highest levels of resistance were seen against ampicillin (87.5%), norfloxacin (62.5%), gentamycin (62.5%), amikacin (62.5%), and aztreonam (62.5%), while the lowest were seen for meropenem (0%), imipenem (12.5%), and polymyxin B (12.5%). LasB (87.5%), pclH (75%), pilB (75%), and exoS (75%) were the most commonly detected virulence factors in the P. aeruginosa isolates. CONCLUSIONS: It is logical to first prescribe meropenem, imipenem, and polymyxin B in cases of UTIs caused by P. aeruginosa. Medical practitioners should be aware of the presence of levels of antibiotic resistance in hospitalized UTI patients in Iran. PMID- 26756018 TI - Full-Ring Intracorneal Implantation in Corneas With Pellucid Marginal Degeneration. AB - BACKGROUND: Keratoconus (KCN) is a progressive, non-inflammatory ectacic disorder characterized by bilateral and asymmetrical conical protrusion of the cornea. MyoRing implantation and Collagen Crosslink (CXL) are two separate effective treatments for all stages of keratoconous. This study wants to show the effect of these treatments combination in patients with moderate and severe keratoconus. OBJECTIVES: The aim of this study was to report on the visual and refractive outcomes of corneas with pellucid marginal degeneration following MyoRing implantation (DIOPTEX GmbH). PATIENTS AND METHODS: This study included 15 eyes of 15 patients, with an age range from 22 to 49 years old, and pellucid marginal degeneration. An intrastromal corneal ring (MyoRing) was inserted by the means of mechanical dissection using a PocketMaker microkeratome. The main outcome measures were uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest refraction, and keratometry readings. The mean postoperative follow-up was ten months (range 6 - 12 months). RESULTS: The mean UDVA (LogMAR) improved significantly from 1.13 +/- 0.21 preoperatively to 0.24 +/ 0.13 postoperatively (P < 0.001), and the mean CDVA (LogMAR) improved significantly from 0.39 +/- 0.12 to 0.19 +/- 0.09 (P < 0.001). The mean cylinder of manifest refraction decreased significantly by 4.00 diopter (D) (P < 0.001). The mean spherical equivalent error (SE) decreased significantly from -6.00 +/- 3.60 D to -0.70 +/- 1.90 D, at the end of the follow-up period. Furthermore, with regards to corneal topography, a significant reduction was observed in keratometric values. The Kmax, Kmin and Kaverage decreased significantly by 5.00, 1.10 and 4.00 D, respectively (P < 0.001). CONCLUSIONS: MyoRing implantation using the PocketMaker microkeratome appears to provide an effective method for treating pellucid marginal degeneration. Both UDVA and CDVA improved significantly. The corneal steepening and astigmatism were reduced in all subjects after MyoRing implantation. PMID- 26756020 TI - Anbarnesa: The Past Tradition, the Future Medicine. AB - CONTEXT: In the Iranian traditional medicine, anbarnesa smoke derived from burning female donkey's dung has long been used for treatment of inflammatory ulcers and infections of the middle and external ear with no significant side effects. The aim of this study was to introduce anbarnesa and discuss its therapeutic effects. EVIDENCE ACQUISITION: We conducted a systematic search in PubMed, Medline, Google, and Google Scholar databases to find studies on anbarnesa. The keywords searched were as follows: "anbarnesa," "traditional medicine," "medicinal smoke," "donkey," "dung," "antimicrobial," "inflammation," "infection," and "cytotoxicity. RESULTS: Literature review reveals that ANNAS (anbarnesa smoke) enhances wound healing, decreases scar formation, inhibits growth of cancer cells (Hela and KB) and has antimicrobial properties. Also, ANNAS combined with propylene glycol is nontoxic in 1/64, 1/128, and 1/256 dilutions. CONCLUSIONS: The constituents of anbarnesa smoke mainly possess antibacterial, anti-inflammatory, and growth inhibition effects on cancer cells. PMID- 26756019 TI - Effect of Pentoxifylline Administration on an Experimental Rat Model of Femur Fracture Healing With Intramedullary Fixation. AB - BACKGROUND: Globally, musculoskeletal injuries comprise a major public health problem that contributes to a large burden of disability and suffering. Pentoxifylline (PTX) has been originally used as a hemorheologic drug to treat intermittent claudication. Previous test tube and in vivo studies reported the beneficial effects of PTX on bony tissue. OBJECTIVES: This study aims to evaluate the effects of different dosages of PTX on biomechanical properties that occur during the late phase of the fracture healing process following a complete femoral osteotomy in a rat model. We applied intramedullary pin fixation as the treatment of choice. MATERIALS AND METHODS: This experimental study was conducted at the Shahid Beheshti University of Medical Sciences, Tehran, Iran. We used the simple random technique to divide 35 female rats into five groups. Group 1 received intraperitoneal (i.p.) PTX (50 mg/kg, once daily) injections, starting 15 days before surgery, and group 2, group 3, and group 4 received 50 mg/kg, 100 mg/kg, and 200 mg/kg i.p. PTX injections, respectively, once daily after surgery. All animals across groups received treatment for six weeks (until sacrificed). Complete surgical transverse osteotomy was performed in the right femur of all rats. At six weeks after surgery, the femurs were subjected to a three-point bending test. RESULTS: Daily administration of 50 mg/kg PTX (groups 1 and 2) decreased the high stress load in repairing osteotomized femurs when compared with the control group. The highest dose of PTX (200 mg/kg) significantly increased the high stress load when compared with the control group (P = 0.030), group 1 (P = 0.023), group 2 (P = 0.008), and group 3 (P = 0.010), per the LSD findings. CONCLUSIONS: Treatment with 200 mg/kg PTX accelerated fracture healing when compared with the control group. PMID- 26756021 TI - Depression, Anxiety and Disease-Related Variables and Quality of Life Among Individuals With Systemic Lupus Erythematosus Living in Kermanshah Province, Iran. AB - BACKGROUND: Health-related quality of life (HRQoL) is affected by numerous variables including depression and anxiety. However, these associations have not yet been described among patients with systemic lupus erythematosus (SLE) and the impact of SLE-related clinical variables remains unknown. OBJECTIVES: In this cross-sectional study, the prevalence of depression and anxiety among Iranian patients with SLE living in Kermanshah province, Iran, has been estimated and the determinants of HRQoL in comparison with healthy subjects have been identified. PATIENTS AND METHODS: Sampling was performed based on recruitment of subjects according to inclusion and exclusion criteria. Systemic lupus erythematosus related variables including cutaneous manifestations, pericarditis, arthritis, history of seizure and psychosis were recorded. Blood samples were taken to measure antinuclear antibodies (ANA), anti-double stranded DNA (anti-dsDNA), Anti Smith (Anti-SM), anticardiolipin antibody. Matched healthy subjects in demographic characteristics were selected from general population of Kermanshah province, Iran. Depression and anxiety and HRQoL were assessed using the Beck depression inventory-II, Beck anxiety inventory and short-form 36 health survey, respectively. RESULTS: A total of 310 individuals (160 patients with SLE and 150 healthy subjects) participated in this study. The prevalence of depression and anxiety was about 20% among people with SLE, which was noticeably high but not significantly different from healthy individuals. More severe depression was associated with lower scores in domains of physical functioning (PF), role limitation due to physical problems (RP) and subsequently physical component summary (PCS) in the SLE group (P < 0.0001 for all). A higher anxiety level was negatively correlated with PF, RP, social functioning (SF), general health (GH) and PCS in the SLE group (P = 0.01, < 0.0001, 0.004, 0.02 and 0.005, respectively). Scores of PF and PCS were significantly lower among patients with SLE compared to the control group (P = 0.001 for both). Malar rash, photosensitivity, discoid rash, pleuritis, pericarditis, history of seizure and positive Anti-SM Ab were associated with poorer SF (P = 0.003, 0.003, 0.018, 0.001, < 0.0001, 0.021 and 0.002, respectively). CONCLUSIONS: The results of this study show that patients with SLE have poorer HRQoL in physical components whereas the mental component of QoL is relatively similar to healthy individuals. Depression and anxiety were not related to clinical manifestations of SLE. However, the SF domain of HRQoL was the most susceptible component of QoL, which was affected by SLE clinical variables. The high estimated prevalence of depression and anxiety among patients with SLE requires attention. PMID- 26756022 TI - The Effect of Alendronate on Various Graft Materials Used in Maxillary Sinus Augmentation: A Rabbit Study. AB - BACKGROUND: Increasing sinus pneumatization and the accompanying alveolar bone resorption complicate dental implant placement. This problem can be overcome today by raising the maxillary sinus floor with graft materials. Bisphosphonates are commonly used to accelerate the recovery of the graft materials and to prevent resorption. OBJECTIVES: The purpose of this study is to investigate whether systemic administration of a bisphosphonate (alendronate) would improve new bone formation and reduce fibrous tissue formation over a 6-week follow-up in rabbits treated with two different grafting materials for maxillary sinus floor augmentation. MATERIALS AND METHODS: This experimental animal study was conducted at the Experimental Medical Application and Research Center at Erzurum/ Turkey. Twelve New Zealand rabbits, each weighing between 2.7 and 3.3 kg, were used. Twenty-four maxillary sinus floor elevation operations were performed, two on each animal (n = 24). Each elevation was repaired with either deproteinized bovine bone (xenograft) or autogenous bone graft obtained from the iliac crest. Both groups were divided into 2 subgroups: saline-treated and alendronate treated. All groups underwent the same surgical procedures and evaluation, and were sacrificed at the 6th postoperative week. Sinuses augmented with deproteinized bovine bone (xenograft) and autogenous bone graft were examined histopathologically and histomorphometrically. RESULTS: At 6 weeks, the bone area was significantly larger in the Xenograft-Alendronate group (33.0% +/- 5.0%) than in the Xenograft-Saline group (20.8% +/- 4.9%) and the bone area was significantly larger in the Autogenous-Alendronate group (43.3% +/- 3.8%) than in the Autogenous-Saline group (37.5% +/- 6.6%) (P = 0.001). The histomorphometric and histopathological results consistently showed that alendronate stimulated bone formation and reduced fibrous tissue formation in maxillary sinus augmentation grafts, especially in the deproteinized bovine bone group (xenograft). CONCLUSIONS: Alendronate may be considered a therapeutic option for improving the bone formation process and reducing resorption in different bone grafting procedures. Further detailed studies should focus on dosage and time dependent effects of alendronate on bone remodeling. PMID- 26756024 TI - The Influence of Word Retrieval and Planning on Phonetic Variation: Implications for Exemplar Models. AB - Over the past several decades, an increasing number of empirical studies have documented the interaction of information across the traditional linguistic modules of phonetics, phonology, and lexicon. For example, the frequency with which a word occurs influences its phonetic properties of its sounds; high frequency words tend to be reduced relative to low frequency words. Lexicalist Exemplar Models have been successful in accounting for this body of results through a single mechanism, exemplars- memory representations that integrate lexical, phonological, and phonetic information into a single structure. We review recent studies that suggest there are critical limitations to assuming that phonetic variation solely reflects the storage of word labels and sound structure in exemplars. Specifically, these studies show that factors related to the on-line retrieval and planning of lexical items also influence phonetic variation. The implications of these findings for exemplar models are discussed; the relationship of exemplar storage to the broader cognitive system is examined, as well as alternative theoretical frameworks incorporating gradience at all levels of linguistic representation. PMID- 26756026 TI - Radiobiological mechanisms of stereotactic body radiation therapy and stereotactic radiation surgery. AB - Despite the increasing use of stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS) in recent years, the biological base of these high-dose hypo-fractionated radiotherapy modalities has been elusive. Given that most human tumors contain radioresistant hypoxic tumor cells, the radiobiological principles for the conventional multiple-fractionated radiotherapy cannot account for the high efficacy of SBRT and SRS. Recent emerging evidence strongly indicates that SBRT and SRS not only directly kill tumor cells, but also destroy the tumor vascular beds, thereby deteriorating intratumor microenvironment leading to indirect tumor cell death. Furthermore, indications are that the massive release of tumor antigens from the tumor cells directly and indirectly killed by SBRT and SRS stimulate anti-tumor immunity, thereby suppressing recurrence and metastatic tumor growth. The reoxygenation, repair, repopulation, and redistribution, which are important components in the response of tumors to conventional fractionated radiotherapy, play relatively little role in SBRT and SRS. The linear-quadratic model, which accounts for only direct cell death has been suggested to overestimate the cell death by high dose per fraction irradiation. However, the model may in some clinical cases incidentally do not overestimate total cell death because high-dose irradiation causes additional cell death through indirect mechanisms. For the improvement of the efficacy of SBRT and SRS, further investigation is warranted to gain detailed insights into the mechanisms underlying the SBRT and SRS. PMID- 26756023 TI - When Anti-Aging Studies Meet Cancer Chemoprevention: Can Anti-Aging Agent Kill Two Birds with One Blow? AB - Recent evidence has strongly supported that the rate of aging is controlled, at least to some extent, by evolutionarily conserved nutrient sensing pathways (e.g. the insulin/IGF-1-signaling, mTOR, AMPK, and sirtuins) from worms to humans. These pathways are also commonly involved in carcinogenesis and cancer metabolism. Agents (e.g. metformin, resveratrol, and Rhodiola) that target these nutrient sensing pathways often have both anti-aging and anti-cancer efficacy. These agents not only reprogram energy metabolism of malignant cells, but also target normal postmitotic cells by suppressing their conversion into senescent cells, which confers systematic metabolism benefits. These agents are fundamentally different from chemotherapy (e.g. paclitaxel and doxorubicin) or radiation therapy that causes molecular damage (e.g. DNA and protein damages) and thereby no selection resistance may be expected. By reviewing molecular mechanisms of action, epidemiological evidence, experimental data in tumor models, and early clinical study results, this review provides information supporting the promising use of agents with both anti-aging and anti-cancer efficacy for cancer chemoprevention. PMID- 26756027 TI - Treatment outcome of hepatic re-irradiation in patients with hepatocellular carcinoma. AB - PURPOSE: We evaluated the efficacy and toxicity of repeated high dose 3 dimensional conformal radiation therapy (3D-CRT) for patients with unresectable hepatocellular carcinoma. MATERIALS AND METHODS: Between 1998 and 2011, 45 patients received hepatic re-irradiation with high dose 3D-CRT in Samsung Medical Center. After excluding two ineligible patients, 43 patients were retrospectively reviewed. RT was delivered with palliative or salvage intent, and equivalent dose of 2 Gy fractions for alpha/beta = 10 Gy ranged from 31.25 Gy10 to 93.75 Gy10 (median, 44 Gy10). Tumor response and toxicity were evaluated based on the modified Response Evaluation Criteria in Solid Tumors criteria and the Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0. RESULTS: The median follow-up duration was 11.2 months (range, 4.1 to 58.3 months). An objective tumor response rate was 62.8%. The tumor response rates were 81.0% and 45.5% in patients receiving >=45 Gy10 and <45 Gy10, respectively (p = 0.016). The median overall survival (OS) of all patients was 11.2 months. The OS was significantly affected by the Child-Pugh class as 14.2 months vs. 6.1 months (Child-Pugh A vs. B, p < 0.001), and modified Union for International Cancer Control (UICC) T stage as 15.6 months vs. 8.3 months (T1-3 vs. T4, p = 0.004), respectively. Grade III toxicities were developed in two patients, both of whom received >=50 Gy10. CONCLUSION: Hepatic re-irradiation may be an effective and tolerable treatment for patients who are not eligible for further local treatment modalities, especially in patients with Child-Pugh A and T1-3. PMID- 26756025 TI - Waterpipe tobacco smoking: A new smoking epidemic among the young? AB - Waterpipe (hookah, narghile) tobacco smoking (WTS) is becoming prevalent worldwide and is one of the most popular forms of tobacco use among youth. WTS prevalence has increased dramatically among youth in the United States within the past decade. Misperceived as less harmful than cigarette smoking, WTS is associated with many of the same chronic health effects such as lung cancer, chronic obstructive pulmonary disease, cardiovascular disease, bronchitis, and asthma. Much of this risk is due to the fact that a single WTS session exposes users to large volumes of smoke that contain toxic chemicals such as carbon monoxide, cancer-causing polycyclic aromatic hydrocarbons, and volatile aldehydes. Unlike cigarette smoking, WTS poses unique risks of acute negative health outcomes including carbon monoxide poisoning and the spread of communicable diseases such as herpes and tuberculosis. Because waterpipe tobacco smoke contains the addictive chemical nicotine, youth who smoke tobacco from a waterpipe may be at risk for dependence. As a result, many youth may initiate WTS and continue to use despite negative health effects. Considering many of the potential negative health effects associated with WTS affect the pulmonary system, pulmonologists and primary care providers may treat patients who are waterpipe tobacco smokers and should be aware of the risk associated with WTS. The purpose of this review is to describe a waterpipe, the prevalence and correlates of WTS, the toxicants found in waterpipe tobacco smoke, the health effects of WTS, and implications for pulmonologists and other clinicians. PMID- 26756028 TI - Definitive radiotherapy with or without chemotherapy for clinical stage T4N0-1 non-small cell lung cancer. AB - PURPOSE: To determine failure patterns and survival outcomes of T4N0-1 non-small cell lung cancer (NSCLC) treated with definitive radiotherapy. MATERIALS AND METHODS: Ninety-five patients with T4N0-1 NSCLC who received definitive radiotherapy with or without chemotherapy from May 2003 to October 2014 were retrospectively reviewed. The standard radiotherapy scheme was 66 Gy in 30 fractions. The main concurrent chemotherapy regimen was 50 mg/m(2) weekly paclitaxel combined with 20 mg/m(2) cisplatin or AUC 2 carboplatin. The primary outcome was overall survival (OS). Secondary outcomes were failure patterns and toxicities. RESULTS: The median age was 64 years (range, 34 to 90 years). Eighty eight percent of patients (n = 84) had an Eastern Cooperative Oncology Group performance status of 0-1, and 42% (n = 40) experienced pretreatment weight loss. Sixty percent of patients (n = 57) had no metastatic regional lymph nodes. The median radiation dose was EQD2 67.1 Gy (range, 56.9 to 83.3 Gy). Seventy-one patients (75%) were treated with concurrent chemotherapy; of these, 13 were also administered neoadjuvant chemotherapy. At a median follow-up of 21 months (range, 1 to 102 months), 3-year OS was 44%. The 3-year cumulative incidences of local recurrence and distant recurrence were 48.8% and 36.3%, respectively. Pretreatment weight loss and combined chemotherapy were significant factors for OS. Acute esophagitis over grade 3 occurred in three patients and grade 3 chronic esophagitis occurred in one patient. There was no grade 3-4 radiation pneumonitis. CONCLUSION: Definitive radiotherapy for T4N0-1 NSCLC results in favorable survival with acceptable toxicity rates. Local recurrence is the major recurrence pattern. Intensity modulated radiotherapy and radio-sensitizing agents would be needed to improve local tumor control. PMID- 26756029 TI - Concurrent chemoradiotherapy improves survival outcome in muscle-invasive bladder cancer. AB - PURPOSE: To evaluate survival rates and prognostic factors related to treatment outcomes after bladder preserving therapy including transurethral resection of bladder tumor, radiotherapy (RT) with or without concurrent chemotherapy in bladder cancer with a curative intent. MATERIALS AND METHODS: We retrospectively studied 50 bladder cancer patients treated with bladder-preserving therapy at Keimyung University Dongsan Medical Center from January 1999 to December 2010. Age ranged from 46 to 89 years (median, 71.5 years). Bladder cancer was the American Joint Committee on Cancer (AJCC) stage II, III, and IV in 9, 27, and 14 patients, respectively. Thirty patients were treated with concurrent chemoradiotherapy (CCRT) and 20 patients with RT alone. Nine patients received chemotherapy prior to CCRT or RT alone. Radiation was delivered with a four-field box technique (median, 63 Gy; range, 48.6 to 70.2 Gy). The follow-up periods ranged from 2 to 169 months (median, 34 months). RESULTS: Thirty patients (60%) showed complete response and 13 (26%) a partial response. All patients could have their own bladder preserved. Five-year overall survival (OS) rate was 37.2%, and the 5-year disease-free survival (DFS) rate was 30.2%. In multivariate analysis, tumor grade and CCRT were statistically significant in OS. CONCLUSION: Tumor grade was a significant prognostic factor related to OS. CCRT is also considered to improve survival outcomes. Further multi-institutional studies are needed to elucidate the impact of RT in bladder cancer. PMID- 26756030 TI - Prognostic factors in breast cancer with extracranial oligometastases and the appropriate role of radiation therapy. AB - PURPOSE: To identify prognostic factors for disease progression and survival of patients with extracranial oligometastatic breast cancer (EOMBC), and to investigate the role of radiation therapy (RT) for metastatic lesions. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 50 patients who had been diagnosed with EOMBC following standard treatment for primary breast cancer initially, and received RT for metastatic lesions, with or without other systemic therapy between January 2004 and December 2008. EOMBC was defined as breast cancer with five or less metastases involving any organs except the brain. All patients had bone metastasis (BM) and seven patients had pulmonary, hepatic, or lymph node metastasis. Median RT dose applied to metastatic lesions was 30 Gy (range, 20 to 60 Gy). RESULTS: The 5-year tumor local control (LC) and 3-year distant progression-free survival (DPFS) rate were 66.1% and 36.8%, respectively. High RT dose (>=50 Gy10) was significantly associated with improved LC. The 5 year overall survival (OS) rate was 49%. Positive hormone receptor status, pathologic nodal stage of primary cancer, solitary BM, and whole-lesion RT (WLRT), defined as RT whose field encompassed entire extent of disease, were associated with better survival. On analysis for subgroup of solitary BM, high RT dose was significantly associated with improved LC and DPFS, shorter metastasis to-RT interval (<=1 month) with improved DPFS, and WLRT with improved DPFS and OS, respectively. CONCLUSION: High-dose RT in solitary BM status and WLRT have the potential to improve the progression-free survival and OS of patients with EOMBC. PMID- 26756031 TI - Radiotherapy as an effective treatment modality for follicular lymphoma: a single institution experience. AB - PURPOSE: Follicular lymphoma (FL) is an indolent non-Hodgkin's lymphoma that is highly sensitive to radiotherapy (RT). However, the effectiveness of RT has not been well established. We reviewed our experiences to assess the role of RT for FL and analyze treatment results. MATERIALS AND METHODS: Retrospective analysis was done on 29 patients who received first RT between January 2003 and August 2013. Of 23 early stage (stage I, II) patients, 16 received RT alone, four received chemotherapy followed by RT, two received RT postoperatively, and one received salvage RT for relapse after resection. Six advanced-stage (stage III, IV) patients received RT after chemotherapy: two received consolidation RT, three received salvage RT for residual lesions, and one received RT for progressive sites. Median RT dose was 30.6 Gy (range, 21.6 to 48.6 Gy). Median follow-up duration was 62 months (range, 6 to 141 months). RESULTS: All patients showed complete response in the radiation field. Eight outfield relapses were reported. Seven patients received salvage treatment (three chemotherapy, four RT). Four patients showed excellent responses, especially to RT. Estimated 5-year and 10 year relapse-free survivals were 72% and 60%. In the RT-alone group, 5-year relapse-free survival was 74.5%. All advanced-stage patients were disease-free with 100% 5-year overall survival. Disease-specific death was noted in only one patient; four others died of other unrelated causes. No significant toxicity was reported. CONCLUSION: RT resulted in excellent treatment outcomes for all FL stages when used as a primary treatment modality for early stage or salvage treatment modality for advanced-stage disease. PMID- 26756032 TI - Feasibility and response of helical tomotherapy in patients with metastatic colorectal cancer. AB - PURPOSE: To investigate the treatment outcome and the toxicity of helical tomotherapy (HT) in patients with metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: We retrospectively reviewed 18 patients with 31 lesions from mCRC treated with HT between 2009 and 2013. The liver (9 lesions) and lymph nodes (9 lesions) were the most frequent sites. The planning target volume (PTV) ranged from 12 to 1,110 mL (median, 114 mL). The total doses ranged from 30 to 70 Gy in 10-30 fractions. When the alpha/beta value for the tumor was assumed to be 10 Gy for the biologically equivalent dose (BED), the total doses ranged from 39 to 119 Gy10 (median, 55 Gy10). Nineteen lesions were treated with concurrent chemotherapy (CCRT). RESULTS: With a median follow-up time of 16 months, the median overall survival for 18 patients was 33 months. Eight lesions (26%) achieved complete response. The 1- and 3-year local progression free survival (LPFS) rates for 31 lesions were 45% and 34%, respectively. On univariate analysis, significant parameters influencing LPFS rates were chemotherapy response before HT, aim of HT, CCRT, PTV, BED, and adjuvant chemotherapy. On multivariate analysis, PTV <=113 mL and BED >48 Gy10 were associated with a statistically significant improvement in LFPS. During HT, four patients experienced grade 3 hematologic toxicities, each of whom had also received CCRT. CONCLUSION: The current study demonstrates the efficacy and tolerability of HT for mCRC. To define optimal RT dose according to tumor size of mCRC, further study should be needed. PMID- 26756033 TI - Met inactivation by S-allylcysteine suppresses the migration and invasion of nasopharyngeal cancer cells induced by hepatocyte growth factor. AB - PURPOSE: Past studies have reported that S-allylcysteine (SAC) inhibits the migration and invasion of cancer cells through the restoration of E-cadherin, the reduction of matrix metalloproteinase (MMP) and Slug protein expression, and inhibition of the production of reactive oxygen species (ROS). Furthermore, evidence is emerging that shows that ROS induced by radiation could increase Met activation. Following on these reports of SAC and Met, we investigated whether SAC could suppress Met activation. MATERIALS AND METHODS: Wound healing, invasion, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium (MTT), soft agar colony forming, western blotting, and gelatin zymography assays were performed in the human nasopharyngeal cancer cell lines HNE1 and HONE1 treated with SAC (0, 10, 20, or 40 mM) and hepatocyte growth factor (HGF). RESULTS: This study showed that SAC could suppress the migration and invasion of HNE1 and HONE1 cell lines by inhibiting p-Met. An increase of migration and invasion induced by HGF and its decrease in a dose dependent manner by SAC in wound healing and invasion assays was observed. The reduction of p-Met by SAC was positively correlated with p focal adhesion kinase (p-FAK) and p-extracellular related kinase (p-ERK in both cell lines). SAC reduced Slug, MMP2, and MMP9 involved in migration and invasion with the inhibition of Met-FAK signaling. CONCLUSION: These results suggest that SAC inhibited not only Met activation but also the downstream FAK, Slug, and MMP expression. Finally, SAC may be a potent anticancer compound for nasopharyngeal cancer treated with radiotherapy. PMID- 26756036 TI - Faciobrachio-crural dystonic seizures in LGI1 limbic encephalitis: A treatable cause of falls. PMID- 26756035 TI - Neck muscle atrophy and soft-tissue fibrosis after neck dissection and postoperative radiotherapy for oral cancer. AB - Late complications of head and neck cancer survivors include neck muscle atrophy and soft-tissue fibrosis. We present an autopsy case of neck muscle atrophy and soft-tissue fibrosis (sternocleidomastoid, omohyoid, digastric, sternohyoid, sternothyroid, and platysma muscles) within the radiation field after modified radical neck dissection type I and postoperative radiotherapy for floor of mouth cancer. A 70-year-old man underwent primary tumor resection of the left floor of mouth, left marginal mandibulectomy, left modified radical neck dissection type I, and reconstruction with a radial forearm free flap. The patient received adjuvant radiotherapy. The dose to the primary tumor bed and involved neck nodes was 63 Gy in 35 fractions over 7 weeks. Areas of subclinical disease (left lower neck) received 50 Gy in 25 fractions over 5 weeks. Adjuvant chemotherapy was not administered. PMID- 26756037 TI - Subtype-specific therapy for autoimmune neuropathies? PMID- 26756034 TI - The first private-hospital based proton therapy center in Korea; status of the Proton Therapy Center at Samsung Medical Center. AB - PURPOSE: The purpose of this report is to describe the proton therapy system at Samsung Medical Center (SMC-PTS) including the proton beam generator, irradiation system, patient positioning system, patient position verification system, respiratory gating system, and operating and safety control system, and review the current status of the SMC-PTS. MATERIALS AND METHODS: The SMC-PTS has a cyclotron (230 MeV) and two treatment rooms: one treatment room is equipped with a multi-purpose nozzle and the other treatment room is equipped with a dedicated pencil beam scanning nozzle. The proton beam generator including the cyclotron and the energy selection system can lower the energy of protons down to 70 MeV from the maximum 230 MeV. RESULTS: The multi-purpose nozzle can deliver both wobbling proton beam and active scanning proton beam, and a multi-leaf collimator has been installed in the downstream of the nozzle. The dedicated scanning nozzle can deliver active scanning proton beam with a helium gas filled pipe minimizing unnecessary interactions with the air in the beam path. The equipment was provided by Sumitomo Heavy Industries Ltd., RayStation from RaySearch Laboratories AB is the selected treatment planning system, and data management will be handled by the MOSAIQ system from Elekta AB. CONCLUSION: The SMC-PTS located in Seoul, Korea, is scheduled to begin treating cancer patients in 2015. PMID- 26756039 TI - Composition, Diversity and Abundance of Gut Microbiome in Prediabetes and Type 2 Diabetes. AB - Association between type 2 diabetes (T2DM) and compositional changes in the gut micro biota is established, however little is known about the dysbiosis in early stages of Prediabetes (preDM). The purpose of this investigation is to elucidate the characteristics of the gut micro biome in preDM and T2DM, compared to Non Diabetic (nonDM) subjects. Forty nine subjects were recruited for this study, 15 nonDM, 20 preDM and 14 T2DM. Bacterial community composition and diversity were investigated in fecal DNA samples using Illumina sequencing of the V4 region within the 16S rRNA gene. The five most abundant phyla identified were: Bacteroidetes, Firmicutes, Proteobacteria, Verrucomicrobia, and Actinobacteria. Class Chloracido bacteria was increased in preDM compared to T2DM (p = 0.04). An unknown genus from family Pseudonocardiaceae was significantly present in preDM group compared to the others (p = 0.04). Genus Collinsella, and an unknown genus belonging to family Enterobacteriaceae were both found to be significantly increased in T2DM compared to the other groups (Collinsella, and p = 0.03, Enterobacteriaceae genus p = 0.02). PERMANOVA and Mantel tests performed did not reveal a relationship between overall composition and diagnosis group or HbA1C level. This study identified dysbiosis associated with both preDM and T2DM, specifically at the class and genus levels suggesting that earlier treatment in preDM could possibly have an impact on the intestinal micro flora transitioning to T2DM. PMID- 26756040 TI - A Lanthanum-Tagged Chemotherapeutic Agent HA-Pt to Track the In Vivo Distribution of Hyaluronic Acid Complexes. AB - Hyaluronic acid drug conjugates can target anti-cancer drugs directly to tumor tissue for loco-regional treatment with enhanced bioavailability, local efficacy and reduced toxicity. In this study, the distribution and pharmacokinetics of hyaluronic acid carrier and a conjugated cisplatin anti-cancer drug were tracked by lanthanum (III) [La(III)] affinity tagging of the nanocarrier. The strong binding affinity of La(III) to HA enabled the simple preparation of a physiologically stable complex HA-Pt-La and straightforward simultaneous detection of HA-La and Pt in biological matrices using inductively coupled plasma mass spectrometry (ICP-MS). Consequently, after subcutaneous injection of HA-Pt La nanoparticles in human head and neck squamous cell carcinoma (HNSCC) tumor bearing mice, the HA and Pt content were detected and quantified simultaneously in the plasma, primary tumor, liver and spleen. PMID- 26756038 TI - Clonal Analysis of Newborn Hippocampal Dentate Granule Cell Proliferation and Development in Temporal Lobe Epilepsy. AB - Hippocampal dentate granule cells are among the few neuronal cell types generated throughout adult life in mammals. In the normal brain, new granule cells are generated from progenitors in the subgranular zone and integrate in a typical fashion. During the development of epilepsy, granule cell integration is profoundly altered. The new cells migrate to ectopic locations and develop misoriented "basal" dendrites. Although it has been established that these abnormal cells are newly generated, it is not known whether they arise ubiquitously throughout the progenitor cell pool or are derived from a smaller number of "bad actor" progenitors. To explore this question, we conducted a clonal analysis study in mice expressing the Brainbow fluorescent protein reporter construct in dentate granule cell progenitors. Mice were examined 2 months after pilocarpine-induced status epilepticus, a treatment that leads to the development of epilepsy. Brain sections were rendered translucent so that entire hippocampi could be reconstructed and all fluorescently labeled cells identified. Our findings reveal that a small number of progenitors produce the majority of ectopic cells following status epilepticus, indicating that either the affected progenitors or their local microenvironments have become pathological. By contrast, granule cells with "basal" dendrites were equally distributed among clonal groups. This indicates that these progenitors can produce normal cells and suggests that global factors sporadically disrupt the dendritic development of some new cells. Together, these findings strongly predict that distinct mechanisms regulate different aspects of granule cell pathology in epilepsy. PMID- 26756043 TI - Ordered mesoporous TiC-C composites as cathode materials for Li-O2 batteries. AB - Ordered mesoporous TiC-C (OMTC) composites were prepared and served as catalysts for nonaqueous Li-O2 batteries. The OMTC cathodes showed high specific capacity, low overpotential and good cyclability. Furthermore, the reaction mechanism of Li O2 batteries during charge and discharge processes was investigated extensively by XRD, XPS and in situ GC-MS methods. PMID- 26756041 TI - Synthesis of ROS scavenging microspheres from a dopamine containing poly(beta amino ester) for applications for neurodegenerative disorders. AB - Parkinson's disease (PD) is a common neurodegenerative disease characterized by a substantial decrease of dopaminergic neurons in the substantia nigra pars compacta. The neurological deterioration during PD can be, in part, attributed to elevated levels of reactive oxygen species (ROS). Radical scavengers have previously been shown to protect dopaminergic cells from toxic effects in vitro. Hence, new approaches need to be investigated to improve the administration of antioxidants in order to provide neuroprotection. Polymers exhibiting catechol structures offer one such approach due to their interesting physicochemical properties. In the present study a photocrosslinkable dopamine-containing poly(beta-amino ester) (DPAE) was synthesized from poly(ethylene glycol) diacrylate (PEGDA) and dopamine hydrochloride using Michael type addition. A water-in-oil emulsion technique was used to photo-crosslink the polymer into spherical microparticles. DPAE microspheres featured excellent scavenging properties towards 1,1-Diphenyl-2-picryl-hydrazyl (DPPH) radicals in a dose dependent manner and could even reduce the dissolved oxygen content of physiological solution. Furthermore, the concentrations required for radical scavenging were shown to be non-toxic towards dopaminergic SH-SY5Y cells as well as primary astrocytes and primary embryonic rat ventral midbrain cultures. PMID- 26756042 TI - A new class of Ru(II) polyazine agents with potential for photodynamic therapy. AB - Appending anthracene units to [(bpy)2Ru(dpp)](2+) results in Ru(II) agents that exhibit dynamic photoreactivity towards DNA and protein. [(Anthbpy)(bpy)Ru(dpp)](2+) and [(Anthbpy)2Ru(dpp)](2+) are the first metal organic Ru(II) agent with dpp ligands shown to photomodify DNA in the presence or absence of oxygen, while also binding protein in an oxygen-dependent manner. PMID- 26756044 TI - Thermally induced formal [3+2] cyclization of ortho-aminoaryl-tethered alkylidenecyclopropanes: facile synthesis of furoquinoline and thienoquinoline derivatives. AB - We have developed a facile synthetic method to access furoquinoline and thienoquinoline derivatives via a thermally induced ring-opening and cyclization reaction from ortho-aminoaryl-tethered alkylidenecyclopropanes with the in situ generation of isocyanates or isothiocyanates. These reactions exhibited excellent yields and functional group tolerance under metal-free conditions. PMID- 26756045 TI - Cobalt(III)-catalyzed alkenylation of arenes and 6-arylpurines with terminal alkynes: efficient access to functional dyes. AB - Alkenylation of unactivated arenes and 6-arylpurines with terminal alkynes in high yields using Cp*Co(CO)I2 as catalyst under mild conditions is described. This method shows outstanding functional group compatibility and can be applied in the design of a mitochondria-targeted imaging dye. PMID- 26756047 TI - Centro Nacional de Investigaciones Cardiovasculares. PMID- 26756049 TI - Mechanistic mapping of cardiac arrhythmias. PMID- 26756048 TI - An initiative to extend testing for familial hypercholesterolaemia across the U.K. PMID- 26756050 TI - in memory of Michele La Placa. PMID- 26756046 TI - Role of saliva proteinase 3 in dental caries. AB - Salivary analysis can be used to assess the severity of caries. Of the known salivary proteins, a paucity of information exists concerning the role of proteinase 3 (PR3), a serine protease of the chymotrypsin family, in dental caries. Whole, unstimulated saliva was collected from children with varying degrees of active caries and tested using a Human Protease Array Kit and an enzyme-linked immunosorbent assay. A significantly decreased concentration of salivary PR3 was noted with increasing severity of dental caries (P<0.01); a positive correlation (r=0.87; P<0.01; Pearson's correlation analysis) was also observed between salivary pH and PR3 concentration. In an antibacterial test, a PR3 concentration of 250 ng.mL-1 or higher significantly inhibited Streptococcus mutans UA159 growth after 12 h of incubation (P<0.05). These studies indicate that PR3 is a salivary factor associated with the severity of dental caries, as suggested by the negative relationship between salivary PR3 concentration and the severity of caries as well as the susceptibility of S. mutans to PR3. PMID- 26756051 TI - Preface. PMID- 26756052 TI - Atypical plasma cell leukemia mistaken for lymphocytosis on blood count. PMID- 26756053 TI - Leukemic phase of a large B-cell lymphoma arising in KSHV-associated multicentric Castleman disease. PMID- 26756055 TI - Asking Hard Questions. PMID- 26756054 TI - I Wonder ... . PMID- 26756057 TI - The Medical Response to Sex Trafficking of Minors in Wisconsin. AB - Medical professionals are in a unique position to identify and assist pediatric victims of sex trafficking, who experience a high prevalence of physical, mental, and sexual health problems. However, providers report a need for education and guidelines for medical care of this population. A literature review was conducted on the nature and scope of pediatric sex trafficking in Wisconsin, the medical and mental health needs of victims, and existing guidelines for medical management. Few existing medical guidelines for the care of trafficking victims are specific to pediatrics or include specific recommendations for the forensic medical evaluation. Because of legislation and resources specific to Wisconsin, national guidelines may not apply locally. Based on the literature review, as well as input from community partners and medical professionals who frequently provide services to victims, guidelines for the medical care of pediatric sex trafficking victims in Wisconsin were developed. Additional community barriers that may prevent an effective medical response also are discussed. PMID- 26756056 TI - Development and Distribution of Educational Materials for Carbapenem-Resistant Enterobacteriaceae Among Acute and Long-term Care Facilities. AB - INTRODUCTION: Carbapenem-resistant Enterobacteriaceae (CRE) are multidrug resistant organisms emerging in the United States. The Wisconsin Division of Public Health implemented mandatory hospital-based CRE surveillance starting in December 2011 and assessed educational needs of health care personnel to guide education for statewide CRE prevention. METHODS: Pre- and post-intervention electronic surveys were distributed to infection control practitioners and local health departments to determine success of educational intervention. Pre intervention telephone interviews were conducted with infection control practitioners who reported at least 1 case of CRE. RESULTS: The pre-intervention survey indicated that 20 (34%) responding infection control practitioners distributed educational materials to patients or staff and 13 (57%) responding local health departments had some CRE knowledge. A pre-intervention survey and interviews identified the need for educational materials such as fact sheets, brochures, and toolkits. Five months after materials were produced and distributed, 31 (63%) responding infection control practitioners had shared educational materials with patients or staff and 11 (100%) responding local health departments indicated some CRE knowledge. CONCLUSION: Overall, use of CRE educational material increased and improved general CRE knowledge among health care personnel following development and distribution of educational materials. Small sample size prevents determination of statistical significance between pre- and post-intervention responses. PMID- 26756058 TI - A Review of Clinical Signs Related to Ecchymosis. AB - Ecchymosis is a large area of discoloration caused by extravasation of blood into the subcutaneous tissue. It is an objective physical finding that may provide valuable clues as to its possible etiology. Ecchymosis is associated with eponyms based on the physician who first described the physical findings, which can be divided into 4 anatomical categories: base of the skull, abdominal wall and retroperitoneum, groin and scrotum, and lower extremity. Classic external signs and eponyms associated with ecchymosis are reviewed. Knowledge of these signs on physical examination may prove to be a useful clue directing the examiner to consider potentially serious causes of disease. PMID- 26756059 TI - Tolvaptan for SIADH in Myelodysplastic Syndrome with Blast Crisis. AB - Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia in cancer patients. It is most frequently reported in association with small-cell lung cancer, but has been reported in other cancers as well. Here we report the case of a patient with myelodysplastic syndrome and blast crisis who developed concurrent hyponatremia. The patient failed to respond to fluid restriction and administration of hypertonic saline. She was treated with tolvaptan, a vasopressin antagonist licensed for the treatment of adult patients with hyponatremia secondary to syndrome of inappropriate antidiuretic hormone secretion. We conclude that in myelodysplastic syndrome patients with blast crisis, inappropriate antidiuretic hormone secretion should be considered as a cause of hyponatremia and be treated with tolvaptan. PMID- 26756060 TI - Acute Central Vision Loss in an IV Drug User. AB - This report describes the case of a 21-year-old heroin user who presented with a 6-day history of decreased vision in her right eye, preceded by 1 week of headache and tender scalp nodules, neck stiffness, and photophobia. A broad infectious workup for acute vision loss was completed, and she was ultimately presumed to have acquired toxoplasmic chorioretinitis (ocular toxoplasmosis). We review the initial workup for chorioretinitis, and the epidemiology, diagnosis, and treatment of ocular toxoplasmosis. Intravenous drug users may be at increased risk of acquired ocular toxoplasmosis. PMID- 26756061 TI - Rural Surgery--A Crisis in Wisconsin. AB - Recruitment of general surgeons to practice in rural environments is challenging. We believe that innovative training programs focusing on the specific needs and experiences of rural surgical practice can play an important role in addressing this clinical workforce issue. For practical reasons, our program will start out small, but if 50 centers around the nation were to establish a similar rural track, we could see a substantial collective impact over time. We hope our new program will serve as a model for the development of other university-based residency training programs with similar opportunities. We are grateful to have received state funding to support the development and early implementation of this program (see Table). We commend the state for understanding the importance of primary care surgery, and we look forward to measuring and reporting the impact of our rural training program on rural surgical care in Wisconsin. PMID- 26756062 TI - Preventing Adverse Drug Events. PMID- 26756064 TI - Nursing Education Program Improves Care for Patients With Delirium. PMID- 26756063 TI - Become a More Resilient Nurse--Reduce Burnout, Prevent Compassion Fatigue, and Take Better Care of Your Patients. PMID- 26756065 TI - Tackling the Taboo of Substance Abuse Among Nurses. PMID- 26756067 TI - Epitaxial Growth of Room-Temperature Ferromagnetic MnAs Segments on GaAs Nanowires via Sequential Crystallization. AB - We investigate the incorporation of manganese into self-catalyzed GaAs nanowires grown in molecular beam epitaxy. Our study reveals that Mn accumulates in the liquid Ga droplet and that no significant incorporation into the nanowire is observed. Using a sequential crystallization of the droplet, we then demonstrate a deterministic and epitaxial growth of MnAs segments at the nanowire tip. This technique may allow the seamless integration of multiple room-temperature ferromagnetic segments into GaAs nanowires with high-crystalline quality. PMID- 26756066 TI - Roles of Periostin in Respiratory Disorders. AB - Periostin is a matricellular protein that has been implicated in many disease states. It interacts with multiple signaling cascades to modulate the expression of downstream genes that regulate cellular interactions within the extracellular matrix. This review focuses on the role of periostin in respiratory diseases, including asthma and idiopathic pulmonary fibrosis, and its potential to help guide treatment or assess prognosis. Epithelial injury is a common feature of many respiratory diseases, resulting in the secretion, among others, of periostin, which is subsequently involved in airway remodeling and other aspects of pulmonary pathophysiology. In asthma, periostin is recognized as a biomarker of type 2 inflammation; POSTN gene expression is up-regulated in bronchial epithelial cells by IL-13 and IL-4. Serum periostin has been evaluated for the identification of patients with increased clinical benefit from treatment with anti-IL-13 (lebrikizumab, tralokinumab) and anti-IgE (omalizumab) therapy and may be prognostic for increased risk of asthma exacerbations and progressive lung function decline. Furthermore, in asthma, periostin may regulate subepithelial fibrosis and mucus production and may serve as a systemic biomarker of eosinophilic airway inflammation. Periostin is also highly expressed in the lungs of patients with idiopathic pulmonary fibrosis, and its serum levels may predict clinical progression. Overall, periostin contributes to multiple pathogenic processes across respiratory diseases, and peripheral blood levels of periostin may have utility as a biomarker of treatment response and disease progression. PMID- 26756083 TI - Cooperativity in Tetrel Bonds. AB - A theoretical study of the cooperativity in linear chains of (H3SiCN)n and (H3SiNC)n complexes connected by tetrel bonds has been carried out by means of MP2 and CCSD(T) computational methods. In all cases, a favorable cooperativity is observed, especially in some of the largest linear chains of (H3SiNC)n, where the effect is so large that the SiH3 group is almost equidistant to the two surrounding CN groups and it becomes planar. In addition, the combination of tetrel bonds with other weak interactions (halogen, chalcogen, pnicogen, triel, beryllium, lithium, and hydrogen bond) has been explored using ternary complexes, (H3SiCN)2:XY and (H3SiNC)2:XY. In all cases, positive cooperativity is obtained, especially in the (H3SiNC)2:ClF and (H3SiNC)2:SHF ternary complexes, where, respectively, halogen and chalcogen shared complexes are formed. PMID- 26756068 TI - Uterine artery embolization for heavy menstrual bleeding. AB - Uterine artery embolization (UAE) as a treatment option for fibroids was first reported by Ravina in 1995. Although rapidly adopted by enthusiasts, many were skeptical and its introduction varied widely across the globe. It was not until randomized controlled trials and registries were published and national guidance statements issued that UAE was accepted as a safe and proven treatment for fibroids. The technique is now established as one of the treatment options to be discussed with patients as an alternative to surgery for fibroid-associated heavy menstrual bleeding. Research is on-going to evaluate the relative merits of UAE compared with other medical and surgical treatment options for heavy menstrual bleeding, particularly for women wishing to maintain their fertility. PMID- 26756069 TI - Propagation of Information About Preexposure Prophylaxis (PrEP) for HIV Prevention Through Twitter. AB - Previous literature has suggested that examining Twitter messages can be productive for studying how the public shares and spreads health information on social media. Preexposure prophylaxis (PrEP) is a promising approach to HIV prevention, yet there are many issues that may influence its effective implementation. This study examined social representations of PrEP on Twitter. One thousand four hundred and thirty-five Tweets were collected and 774 English Tweets were content-analyzed to explore propagation of various issues around daily oral PrEP, as well as characteristics of the sources of those Tweets. We also examined how Twitter message content influenced information propagation. Our findings revealed that PrEP-related information on Twitter covered a wide range of issues, and individual users constituted the majority of the Tweet creators among all the sources, including news media, nonprofit and academic groups, and commercial entities. Using Poisson regression, we also found that a Tweet's affective tone was a significant predictor of message propagation frequency. Implications for health practitioners are discussed. PMID- 26756084 TI - Fetal cerebro-placental ratio and adverse perinatal outcome: systematic review and meta-analysis of the association and diagnostic performance. AB - OBJECTIVE: The objective of this meta-analysis is to assess the value of fetal cerebro-placental Doppler ratio (CPR) in predicting adverse perinatal outcome in pregnancies with fetal growth restriction (FGR). METHODS: Three databases were used: MEDLINE, EMBASE (with online Ovid interface) and SCOPUS and studies from inception to April 2015 were included. Studies that reported perinatal outcomes of fetuses at risk of FGR or sonographically diagnosed FGR that were evaluated with CPR were considered eligible. Perinatal outcomes include cesarean section (CS) for fetal distress, APGAR scores at 5 min, neonatal complications and admission to neonatal intensive care unit (NICU). Pooled data were expressed as odds ratio (OR) and confidence intervals (CI), and the summary receiver operating characteristic (SROC) curve was used to illustrate the diagnostic accuracy of CPR. RESULTS: Seven studies were eligible (1428 fetuses). Fetuses with abnormal CPR were at higher risk of CS for fetal distress (OR=4.49, 95% CI [1.63, 12.42]), lower APGAR scores (OR=4.01, 95% CI [2.65, 6.08]), admission to NICU (OR=9.65, 95% CI [3.02, 30.85]), and neonatal complications (OR=11.00, 95% [3.64, 15.37]) than fetuses who had normal CPR. These risks were higher among studies that included fetuses diagnosed with FGR than fetuses at risk of FGR. Abnormal CPR had higher diagnostic accuracy for adverse perinatal outcomes among "sonographically diagnosed FGR" studies than "at risk of FGR" studies. CONCLUSION: Abnormal CPR is associated with substantial risk of adverse perinatal outcomes. The test seems to be particularly useful for follow up of fetuses with sonographically diagnosed FGR. PMID- 26756085 TI - Higher D-dimer level in the early third trimester predicts the occurrence of postpartum hemorrhage. AB - AIMS: This study aimed to determine effective predictive factors for primary postpartum hemorrhage (PPH) among clinical blood parameters associated with coagulation and fibrinolysis and demographic characteristics. METHODS: We retrospectively studied 1032 women who underwent determinations of clinical blood parameters at gestational week (GW) 29-32 and GW 35-37 and gave birth to singleton infants at our hospital between January 2011 and December 2013. PPH was defined as estimated blood loss >=700 mL. Multivariate logistic regression analyses were used to determine independent risk factors and odds ratios (OR) for PPH. RESULTS: PPH occurred in 104 of 1032 women (10%). Three blood variables, fibrinogen level <4.0 g/L (OR [95% CI], 1.96 [1.18-3.27]), antithrombin activity <85% of normal activity level (1.84 [1.05-3.21]), and D-dimer level >2.7 MUg/mL (2.03 [1.29-3.19]) at GW 35-37, and three demographic characteristics, maternal age >=35 years (1.75 [1.15-2.68]), BMI >28.2 kg/m2 on admission for childbirth (1.95 [1.20-3.16]), and previous cesarean delivery (2.77 [1.31-5.83]), were identified as independent risk factors for PPH. CONCLUSION: Among blood parameters, higher D-dimer levels and lower levels of antithrombin activity and fibrinogen in late gestation were independent risk factors for PPH. PMID- 26756087 TI - Clinical chorioamnionitis--an ongoing obstetrical conundrum. PMID- 26756086 TI - Arterio-venous differences in cord levels of catecholamines, glucose, lactate and blood gases. AB - BACKGROUND: Norepinephrine (NE) and epinephrine (EPI) levels are higher in cord arterial blood relative to venous blood, consistent with active mechanisms of placental-maternal clearance. There are no contemporary studies of cord arteriovenous blood levels of sulfated and non-sulfated catechols. AIM: To assess the arteriovenous differences in cord blood levels of dopamine (DA), the sulfated catecholamines and their sulfated and non-sulfated metabolites. To correlate levels of oxygen, H+/CO2, and glucose with cord catecholamine levels. METHODS: Fifty-seven term infants, delivered by elective cesarean section, were recruited. Cord arterial and venous blood was sampled; levels of glucose, lactate, blood gases, six catechols and their sulfated conjugates were measured. RESULTS: With one exception (DOPA sulfate), mean cord arterial levels of sulfated and non sulfated catechols were significantly higher than venous levels. Arterial lactate and glucose levels were independently associated with NE levels, but only lactate was associated with levels of EPI and DA. CONCLUSION: This study establishes that in vivo metabolic parameters of hypoxia, respiratory and metabolic acidosis are associated with catecholamine levels, a key relationship for perinatal adaptation and homeostasis, and findings that are consistent with in vitro studies of the regulators of catecholamine secretion. PMID- 26756088 TI - Newborn screening of metabolic disorders. PMID- 26756089 TI - The mental time travel continuum: on the architecture, capacity, versatility and extension of the mental bridge into the past and future. AB - Mental time travel (MTT) is the ability to remember past events and to anticipate or imagine events in the future. MTT globally serves to optimize decision-making processes, improve problem-solving capabilities and prepare for future needs. MTT is also essential in providing our concept of self, which includes knowledge of our personality, our strengths and weaknesses, as well as our preferences and aversions. We will give an overview in which ways the capacity of animals to perform MTT is different from humans. Based on the existing literature, we conclude that MTT might represent a quantitative rather than qualitative entity with a continuum of MTT capacities in both humans and nonhuman animals. Given its high complexity, MTT requires a large processing capacity in order to integrate multimodal stimuli during the reconstruction of past and/or future events. We suggest that these operations depend on a highly specialized working memory subsystem, 'the MTT platform', which might represent a necessary additional component in the multi-component working memory model by Alan Baddeley. PMID- 26756090 TI - Cognitive function in schizophrenia: conflicting findings and future directions. AB - INTRODUCTION: Schizophrenia is a severe mental disorder with multiple psychopathological domains being affected. Several lines of evidence indicate that cognitive impairment serves as the key component of schizophrenia psychopathology. Although there have been a multitude of cognitive studies in schizophrenia, there are many conflicting results. We reasoned that this could be due to individual differences among the patients (i.e. variation in the severity of positive vs. negative symptoms), different task designs, and/or the administration of different antipsychotics. METHODS: We thus review existing data concentrating on these dimensions, specifically in relation to dopamine function. We focus on most commonly used cognitive domains: learning, working memory, and attention. RESULTS: We found that the type of cognitive domain under investigation, medication state and type, and severity of positive and negative symptoms can explain the conflicting results in the literature. CONCLUSIONS: This review points to future studies investigating individual differences among schizophrenia patients in order to reveal the exact relationship between cognitive function, clinical features, and antipsychotic treatment. PMID- 26756091 TI - Alkaloid profiles and acetylcholinesterase inhibitory activities of Fumaria species from Bulgaria. AB - GC-MS analysis of alkaloid profiles of five Fumaria species, naturally grown in Bulgaria (F. officinalis, F. thuretii, F. kralikii, F. rostellata and F. schrammii) and analysis of acetylcholinesterase inhibitory activity of alkaloid extracts were performed. Fourteen isoquinoline alkaloids were identified, with the principle ones being protopine, cryptopine, sinactine, parfumine, fumariline, fumarophycine, and fumaritine. Protopine contents, defined by HPLC analysis varied between 210.6 +/- 8.8 MUg/g DW (F. schrammii) and 334.5 +/- 7.1 MUg/g DW. (F. rostellata). While all of the investigated alkaloid extracts significantly inhibited acetylcholinesterase activity, the F. kralikii demonstrated the highest level of inhibition (IC(50) 0.13 +/- 0.01 mg extract/mL). PMID- 26756092 TI - The protective effect of daidzein on high glucose-induced oxidative stress in human umbilical vein endothelial cells. AB - Endothelial cell dysfunction is considered a major cause of vascular complications in diabetes. In the present study, we investigated the protective effect of daidzein, a natural isoflavonoid, against high-glucose-induced oxidative damage in human umbilical vein endothelial cells (HUVECs). Treatment with a high concentration of glucose (30 mM) induced oxidative stress in the endothelial cells, against which daidzein protected the cells as demonstrated by significantly increased cell viability. In addition, lipid peroxidation, intracellular reactive oxygen species (ROS) generation, and indirect nitric oxide levels induced by the high glucose treatment were significantly reduced in the presence of daidzein (0.02-0.1 mM) in a dose-dependent manner. High glucose levels induced the overexpression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and NF-kappaB proteins in HUVECs, which was suppressed by treatment with 0.04 mM daidzein. These findings indicate the potential of daidzein to reduce high glucose-induced oxidative stress. PMID- 26756093 TI - Activation of corticotropin releasing factor receptors up regulates collagen production by hepatic stellate cells via promoting p300 expression. AB - Liver fibrosis is characterized with the over expression and excessive accumulation of extracellular matrix proteins, including collagens. The causative factors in the over production of collagens are not fully understood. This study aims to test a hypothesis that activation of corticotropin releasing factor receptors up regulates the expression of collagen in hepatic stellate cells. In this study, human hepatic stellate cell line, LX-2 cells were cultured. Expression of collagens by LX-2 cells was assessed by real time RT-PCR, Western blotting. The results showed that, upon exposure to urocortin in the culture, LX 2 cells (a human hepatic stellate cell line) increased the expression of collagen IV (Col4) markedly. The exposure to urocortin also enhanced the levels of pTip60, H3K9, RNA polymerase II and forkhead box protein 3 at the collagen promoter locus as well as increase in the expression of Col4 mRNA and protein in the cells. Blocking p300 efficiently suppressed the urocortin-induced Col4 expression in LX 2 cells and unveiled an apoptosis-inducing effect of urocortin. In conclusion, activation of CRF receptors is capable of enforcing the production of Col4 by LX 2 cells via up regulating the p300 pathway, which may contribute to the development of liver fibrosis. PMID- 26756094 TI - Increased secretory sphingomyelinase activity in the first trimester of pregnancy in women later developing preeclampsia: a nested case-control study. AB - The pathogenic basis of abnormal placentation and dysfunction in preeclampsia (PE) is highly complex and incompletely understood. Secretory sphyngomyelinase activity (S-ASM) was analyzed in plasma samples from 158 pregnant women developing PE and 112 healthy pregnant controls. Serum PlGF, sFlt-1, s-Endoglin and sVCAM were measured. Results showed S-ASM activity to be higher in women who later developed PE than in those with uncomplicated pregnancies (40.6% and 28.8% higher in the late- and early-onset groups, respectively). Plasma S-ASM activity correlated significantly with circulating markers of endothelial damage in the late-PE group (endoglin and sVCAM-1), with plasma cholesterol and total lipid levels. However, these significant associations were not observed in the early-PE or control groups. This work provides the first evidence of significantly elevated circulating S-ASM activity in the first trimester of pregnancy in women who go on to develop PE; thus, it may be deduced that the circulating form of ASM is biologically active in PE and could contribute to promoting endothelial dysfunction and cardiovascular programming. Plasma S-ASM measurement may have clinical relevance as a further potential biomarker contributing to the earliest identification of women at risk of developing preeclampsia. PMID- 26756095 TI - Identification of consistent functional genetic modules. AB - It is often of scientific interest to find a set of genes that may represent an independent functional module or network, such as a functional gene expression module causing a biological response, a transcription regulatory network, or a constellation of mutations jointly causing a disease. In this paper we are specifically interested in identifying modules that control a particular outcome variable such as a disease biomarker. We discuss the statistical properties that functional networks should possess and introduce the concept of network consistency which should be satisfied by real functional networks of cooperating genes, and directly use the concept in the pathway discovery method we present. Our method gives superior performance for all but the simplest functional networks. PMID- 26756096 TI - Phytochemistry and gastrointestinal benefits of the medicinal spice, Capsicum annuum L. (Chilli): a review. AB - Dietary spices and their active constituents provide various beneficial effects on the gastrointestinal system by variety of mechanisms such as influence of gastric emptying, stimulation of gastrointestinal defense and absorption, stimulation of salivary, intestinal, hepatic, and pancreatic secretions. Capsicum annuum (Solanaceae), commonly known as chilli, is a medicinal spice used in various Indian traditional systems of medicine and it has been acknowledged to treat various health ailments. Therapeutic potential of chilli and capsaicin were well documented; however, they act as double-edged sword in many physiological circumstances. In traditional medicine chilli has been used against various gastrointestinal complains such as dyspepsia, loss of appetite, gastroesophageal reflux disease, gastric ulcer, and so on. In chilli, more than 200 constituents have been identified and some of its active constituents play numerous beneficial roles in various gastrointestinal disorders such as stimulation of digestion and gastromucosal defense, reduction of gastroesophageal reflux disease (GERD) symptoms, inhibition of gastrointestinal pathogens, ulceration and cancers, regulation of gastrointestinal secretions and absorptions. However, further studies are warranted to determine the dose ceiling limit of chilli and its active constituents for their utilization as gastroprotective agents. This review summarizes the phytochemistry and various gastrointestinal benefits of chilli and its various active constituents. PMID- 26756097 TI - Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 7. Synthesis and Pharmacological Evaluation of 4-Quinolone-3-carboxamides and 4-Hydroxy-2 quinolone-3-carboxamides as High Affinity Cannabinoid Receptor 2 (CB2R) Ligands with Improved Aqueous Solubility. AB - 4-Quinolone-3-carboxamide derivatives have long been recognized as potent and selective cannabinoid type-2 receptor (CB2R) ligands. With the aim to improve their physicochemical properties, basically aqueous solubility, two different approaches were followed, entailing the substitution of the alkyl chain with a basic replacement or scaffold modification to 4-hydroxy-2-quinolone structure. According to the first approach, compound 6d was obtained, showing slightly reduced receptor affinity (K(i) = 60 nM) compared to the lead compound 4 (0.8 nM) but greatly enhanced solubility (400-3400 times depending on the pH of the medium). On the other hand, shifting from 4-quinolone to 4-hydroxy-2-quinolone structure enabled the discovery of a novel class of CB2R ligands, such as 7b and 7c, characterized by K(i) < 1 nM and selectivity index [SI = K(i)(CB1R)/K(i)(CB2R)] > 1300. At pH 7.4, compound 7c resulted by 100-fold more soluble than 4. PMID- 26756098 TI - Molecular Imaging of Chemokine Receptor CXCR4 in Non-Small Cell Lung Cancer Using 68Ga-Pentixafor PET/CT: Comparison With 18F-FDG. AB - We report the case of a 62-year-old woman with a history of ST-elevation myocardial infarction who underwent 68Ga-Pentixafor PET/CT for characterization of postinfarct myocardial inflammation. 68Ga-Pentixafor PET/CT incidentally demonstrated marked CXCR4 expression in a space-occupying lesion in the right upper lobe. Corresponding 18F-FDG PET/CT showed increased metabolism, and subsequent biopsy revealed non-small cell lung cancer. Immunohistochemistry confirmed that CXCR4 was highly expressed on tumor cells. 68Ga-Pentixafor is a novel CXCR4-targeted probe for PET imaging of CXCR4-positive tumors and holds promise for tumor staging and prognostic stratification. CXCR4-targeted radionuclide therapy represents a therapy option in metastasized diseases. PMID- 26756099 TI - Increased 18F-FDG Uptake on PET/CT is Associated With Poor Arterial and Portal Perfusion on Multiphase CT. AB - PURPOSE: To correlate 18F-FDG uptake on PET/CT with patterns of arterial and portal perfusion on multi-detector CT (MDCT) in patients with hepatocellular carcinoma (HCC) and to assess the value of variables from PET/CT and MDCT in predicting histological grades and overall survival. METHODS: We retrospectively analyzed MDCT and PET/CT of 66 patients with HCC who underwent surgical treatment. Tumor peak standard uptake value (SUV) was divided by the mean liver SUV (T/LSUV). The mean tumor Hounsfield unit (HU) to mean liver HU was calculated for arterial (T/LHU-A) and portal phases (T/LHU-P). All patients were divided into three groups: I, T/LHU-A <=l and T/LHU-P <1; II, T/LHU-A >1 and T/LHU-P <1; and III, T/LHU-A >1 and T/LHU-P >=1. The relationships between the CT perfusion groups and T/LSUV were assessed. Multivariate logistic regression analyses were performed using clinical and imaging parameters for predicting histological grade. Overall survival curves stratified by T/LSUV and CT perfusion groups were estimated using the Kaplan-Meier method. RESULTS: Statistically significant differences in T/LSUV were noted between groups I and II (2.29 [range 1.74-3.60] vs. 1.20 [range 1.07-1.58], P < 0.001) and groups I and III (2.29 [range 1.74 3.60] vs. 1.30 [range 1.07-1.43], P < 0.001). In multivariate analysis, a T/LSUV cutoff of >1.46 was the only independent predictor of tumor grade, with an odds ratio of 8.462 (95% confidence interval 1.799-39.803). Kaplan-Meier curves showed significant differences in OS according to T/LSUV >1.62, group I perfusion pattern, and T/LSUV >1.62 plus group I perfusion pattern (P = 0.04, P = 0.021, and P = 0.002, respectively). CONCLUSION: 18F-FDG PET/CT is not commonly used for detecting HCC due to its limited sensitivity. We found that increased 18F-FDG uptake is associated with decreased arterial and portal perfusion on MDCT. This can be used to preselect patients who would benefit the most from PET/CT. Meanwhile, 18F-FDG uptake remained as the only independent predictor of histological grade, and higher 18F-FDG uptake and lower perfusion pattern on MDCT were significantly related to shorter OS. PMID- 26756100 TI - Aflatoxin M1 in raw milk and aflatoxin B1 in feed from household cows in Singida, Tanzania. AB - Aflatoxin M1 (AFM1) contamination in raw milk from household cows fed with sunflower seedcakes or sunflower-based seedcake feeds was determined in 37 milk samples collected randomly from different locations in Singida region, Tanzania. Aflatoxin B1 (AFB1) contamination in sunflower-based seedcake feed was determined in 20 feed samples collected from the same household dairy farmers. The samples were analysed by RP-HPLC using fluorescent detection after immunoaffinity column clean-up. Recoveries were 88.0% and 94.5%, while the limits of detection (LOD) were 0.026 ng mL(-1) and 0.364 ng g(-1) for AFM1 and AFB1, respectively. Of the analysed cow's milk samples, 83.8% (31/37) contained AFM1, with levels ranging from LOD to 2.007 ng mL(-1), exceeding both the European Commission (EC) and Tanzania Food and Drug Authority (TFDA) limit of 0.05 ng mL(-1). Of the contaminated samples, 16.1% exceeded the Codex Alimentarius limit of 0.5 ng mL( 1). AFB1 was present in 65% (13/20) of the feed samples with levels ranging from LOD to 20.47 ng g(-1), 61.53% exceeding the TFDA and EC maximum limits of 5 ng g( 1) for complete dairy animal feed. The observed AFM1 and AFB1 contamination necessitates the need to raise awareness to dairy farmers in Tanzania to safeguard the health of the end-users. PMID- 26756102 TI - Opportunities and Challenges of Telemedicine: Observations from the Wild West in Pediatric Type 1 Diabetes. PMID- 26756103 TI - Upcoming Trends for Inpatient Diabetes Management. PMID- 26756101 TI - Automated segmentation of chronic stroke lesions using LINDA: Lesion identification with neighborhood data analysis. AB - The gold standard for identifying stroke lesions is manual tracing, a method that is known to be observer dependent and time consuming, thus impractical for big data studies. We propose LINDA (Lesion Identification with Neighborhood Data Analysis), an automated segmentation algorithm capable of learning the relationship between existing manual segmentations and a single T1-weighted MRI. A dataset of 60 left hemispheric chronic stroke patients is used to build the method and test it with k-fold and leave-one-out procedures. With respect to manual tracings, predicted lesion maps showed a mean dice overlap of 0.696 +/- 0.16, Hausdorff distance of 17.9 +/- 9.8 mm, and average displacement of 2.54 +/- 1.38 mm. The manual and predicted lesion volumes correlated at r = 0.961. An additional dataset of 45 patients was utilized to test LINDA with independent data, achieving high accuracy rates and confirming its cross-institutional applicability. To investigate the cost of moving from manual tracings to automated segmentation, we performed comparative lesion-to-symptom mapping (LSM) on five behavioral scores. Predicted and manual lesions produced similar neuro cognitive maps, albeit with some discussed discrepancies. Of note, region-wise LSM was more robust to the prediction error than voxel-wise LSM. Our results show that, while several limitations exist, our current results compete with or exceed the state-of-the-art, producing consistent predictions, very low failure rates, and transferable knowledge between labs. This work also establishes a new viewpoint on evaluating automated methods not only with segmentation accuracy but also with brain-behavior relationships. LINDA is made available online with trained models from over 100 patients. PMID- 26756105 TI - Ischemic Gastritis: A Multicenter Case Series of a Rare Clinical Entity and a Review of the Literature. AB - GOALS: To report a case series of ischemic gastritis and discuss its etiology, management, and associated mortality according to our results and the published English literature. BACKGROUND: Ischemic gastritis is rare, given the rich blood supply of the stomach. It has been reported in isolated case reports and small case series. Most cases are vascular in origin and associated with a high mortality. STUDY: Pathology databases from 3 hospitals affiliated with the University of Minnesota Medical School were searched for cases of ischemic gastritis in the last 10 years. Patients' demographics, clinical course, and 1 month and 1-year mortalities were collected from electronic medical records. RESULTS: A total of 12 patients were identified (age range, 32.1 to 83.2), the largest series reported to date. The presenting symptom was gastrointestinal bleeding (8), abdominal pain (2), nausea (1), and symptomatic anemia (1). The etiology included postinterventional radiology embolization (2), hemodynamic changes in the setting of celiac axis stenosis (2), vasculitis (1), systemic hypotension (1), and unknown (6). Treatment included steroid therapy, revascularization by interventional radiology, surgery, or supportive treatment. Thirty-day and 1-year mortalities were 33% and 41%, respectively. CONCLUSIONS: Ischemic gastritis is rare, but associated with a high mortality. Evaluation for treatable etiologies should be sought and corrected if present. PMID- 26756104 TI - Model-Based Quantification of Glucagon-Like Peptide-1-Induced Potentiation of Insulin Secretion in Response to a Mixed Meal Challenge. AB - BACKGROUND: Glucagon-like peptide-1 (GLP-1) is a powerful insulin secretagogue that is secreted in response to meal ingestion. The ability to quantify the effect of GLP-1 on insulin secretion could provide insights into the pathogenesis and treatment of diabetes. We used a modification of a model of GLP-1 action on insulin secretion using data from a hyperglycemic clamp with concomitant GLP-1 infusion. We tested this model using data from a mixed meal test (MMT), thereby measuring GLP-1-induced potentiation of insulin secretion in response to a meal. MATERIALS AND METHODS: The GLP-1 model is based on the oral C-peptide minimal model and assumes that over-basal insulin secretion depends linearly on GLP-1 concentration through the parameter Pi, representing the beta-cell sensitivity to GLP-1. The model was tested on 62 subjects across the spectrum of glucose tolerance (age, 53 +/- 1 years; body mass index, 29.7 +/- 0.6 kg/m(2)) studied with an MMT and provided a precise estimate of both beta-cell responsivity and Pi indices. By combining Pi with a measure of L-cell responsivity to glucose, one obtains a potentiation index (PI) (i.e., a measure of the L-cell's function in relation to prevailing beta-cell sensitivity to GLP-1). RESULTS: Model-based measurement of GLP-1-induced insulin secretion demonstrates that the PI is significantly reduced in people with impaired glucose tolerance, compared with those with normal glucose tolerance. CONCLUSIONS: We describe a model that can quantitate the GLP-1-based contribution to insulin secretion in response to meal ingestion. This methodology will allow a better understanding of beta-cell function at various stages of glucose tolerance. PMID- 26756106 TI - High-resolution Anorectal Manometry in Parkinson Disease With Defecation Disorder: A Comparison With Functional Defecation Disorder. AB - GOAL: To investigate the characteristics of high-resolution anorectal manometry (HR-ARM) in Parkinson disease (PD) patients with defecation disorder (DD) compared with patients with functional defecation disorder (FDD). BACKGROUND: DD is a common gastrointestinal symptom in PD. HR-ARM is a relatively new and reliable method for detecting DD. STUDY: A cohort of PD patients with DD was matched with FDD patients. Defecatory symptoms were investigated by questionnaire. Anorectal motility and sensation were evaluated by HR-ARM. Differences in defecatory symptoms, sensorimotor parameters, and DD type were analyzed. Defecatory symptoms and manometric variables obtained in early-stage PD were compared with advanced stage, and relationships between manometric parameters and evacuatory symptoms explored. RESULTS: Straining and sensation of blockage was experienced significantly more in PD than FDD, and stool consistency more severely affected. Maximum squeeze and intrarectal pressure during defecation in PD was lower than in FDD. Anal resting and residual pressures, duration of sustained squeeze, threshold volumes for first sensation, urgency, and maximum discomfort were similar between groups. PD patients presented predominantly with inadequate propulsive forces, whereas FDD patients showed dyssynergic defecation. Defecatory symptoms and manometric parameters did not differ between stages of PD. CONCLUSIONS: PD patients with DD experienced more straining and sensation of blockage than FDD patients, possibly related to inadequate anorectal motility and paradoxical anal contraction of pelvic floor. Impaired squeeze response and inadequate propulsive forces are specific to anorectal function of PD patients with DD, compared with FDD, with abnormalities unchanged between early and advanced PD. PMID- 26756108 TI - Esophageal Perforation After Pneumatic Dilation for Achalasia: Successful Closure With an Over-the-Scope Clip. PMID- 26756107 TI - Systemic Prophylactic Antibiotics for the Modified Introducer Method for Percutaneous Endoscopic Gastrostomy: A Prospective, Randomized, Double-Blind Study. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is the most common method of enteral nutrition in patients who require long-term tube feeding. According to meta-analyses, administration of systemic prophylactic antibiotics for PEG reduces peristomal infection. However, with several recent developments in the procedure and instruments, the risk of infection might have been reduced. The aim of this study was to evaluate the use of systemic antibiotic prophylaxis for a modified introducer method of PEG. METHODS: This prospective, randomized, double blind trial assessed 278 patients undergoing PEG for inclusion. Ninety-one patients with an indication for PEG who gave informed consent to participate were randomized. Forty-six patients received prophylactic ampicillin and 45 patients received a placebo. A modified introducer method of PEG using a Seldinger PEG kit was performed. The primary outcome was the occurrence of clinically evident wound infection within 3 days after PEG. RESULTS: Wound infection within 3 days was observed in none in the prophylaxis group and in 1 patient in the control group (P=0.4945). There was no significant difference between 2 groups in the other parameters, including peristomal infection within 7 days, overall infection, white blood cell counts, C-reactive protein level, and successive rate of finishing antibiotics. CONCLUSIONS: For wound infection within 3 days, noninferiority of the placebo group to the antibiotics group was preliminarily suggested with our criteria, but not for peristomal infection within 7 days. More strict criteria for noninferiority should be examined in a further large sample study. PMID- 26756109 TI - Effect of solar radiation on the functional components of mulberry (Morus alba L.) leaves. AB - BACKGROUND: The functional components of mulberry leaves have attracted the attention of the health food industry, and increasing their concentrations is an industry goal. This study investigated the effects of solar radiation, which may influence the production of flavonol and 1-deoxynojirimycin (DNJ) functional components in mulberry leaves, by comparing a greenhouse (poor solar radiation) and outdoor (rich solar radiation) setting. RESULTS: The level of flavonol in leaves cultivated in the greenhouse was markedly decreased when compared with those cultivated outdoors. In contrast, the DNJ content in greenhouse-cultivated plants was increased only slightly when compared with those cultivated outdoors. Interestingly, the flavonol content was markedly increased in the upper leaves of mulberry trees that were transferred from a greenhouse to the outdoors compared with those cultivated only in the outdoors. CONCLUSION: Solar radiation conditions influence the synthesis of flavonol and DNJ, the functional components of mulberry leaves. Under high solar radiation, the flavonol level becomes very high but the DNJ level becomes slightly lower, suggesting that the impact of solar radiation is great on flavonol but small on DNJ synthesis. (c) 2016 Society of Chemical Industry. PMID- 26756111 TI - Effects of methylphenidate on body index and physical fitness in Korean children with attention deficit hyperactivity disorder. AB - OBJECTIVE: The side effects of methylphenidate (MPH) on growth remain a controversial concern. This study aimed to investigate the effect of MPH on clinical symptoms, growth, and physical fitness in Korean children. METHODS: Fifty male children with attention deficit hyperactivity disorder (ADHD) treated with methylphenidate (MPH-ADHD), 69 MPH-naive male children with ADHD (Naive ADHD), and 60 age-matched and sex-matched healthy control subjects were recruited. Intelligence quotient (IQ), clinical symptoms of ADHD, body index (height, weight, and body mass index [BMI]), and physical fitness (muscular strength, endurance, flexibility, agility, speed, and balance) were assessed. RESULTS: Total IQ and performance IQ scores were significantly different among the three groups, as were mean Korean Attention Deficit Hyperactivity Disorder (K ARS)-total, K-ARS-inattention, and K-ARS-hyperactivity scores. There was no significant difference in height, weight, or BMI among the three groups. There were significant differences in skill-related fitness scores for balance (healthy controls > MPH-ADHD > Naive-ADHD) and agility shuttle test time (healthy controls < MPH-ADHD < Naive-ADHD). CONCLUSIONS: Our findings support the effectiveness of MPH treatment for improving IQ, attention, and balance and agility measures of skill-related fitness in Korean children with ADHD. MPH was not associated with growth delays in height, weight, and BMI. PMID- 26756110 TI - Enzymatic phosphorylation of hair keratin enhances fast adsorption of cationic moieties. AB - The current study describes the in vitro phosphorylation of a human hair keratin, using protein kinase for the first time. Phosphorylation of keratin was demonstrated by (31)P NMR (Nuclear Magnetic Resonance) and Diffuse Reflectance Infrared Fourier Transform (DRIFT) techniques. Phosphorylation induced a 2.5 fold increase of adsorption capacity in the first 10 min for cationic moiety like methylene blue (MB). Thorough description of MB adsorption process was performed by several isothermal models. Reconstructed fluorescent microscopy images depict distinct amounts of dye bound to the differently treated hair. The results of this work suggest that the enzymatic phosphorylation of keratins might have significant implications in hair shampooing and conditioning, where short application times of cationic components are of prime importance. PMID- 26756112 TI - Association of Serum Fetuin-A Levels With the Risk of Albuminuria in Middle-Aged and Elderly Chinese. AB - CONTEXT: Fetuin-A is an important hepatokine associated with many cardiometabolic abnormities. The association between fetuin-A and albuminuria has not been investigated in a prospective cohort. OBJECTIVE: The objective of the study was to prospectively investigate whether serum fetuin-A levels were associated with albuminuria in middle-aged and elderly Chinese. DESIGN, SETTING, AND PARTICIPANTS: A community-based study was conducted at baseline in 2009, including 3102 individuals aged 40 years or older and followed up for 4 years. MAIN OUTCOME MEASURES: Baseline and follow-up urine samples were collected to measure urinary albumin and creatinine concentrations. Albuminuria was defined as urinary albumin to creatinine ratio (UACR) of 30 mg/g or greater. RESULTS: A total of 194 participants (8.5%) developed albuminuria during the follow-up. Men who developed albuminuria had significantly higher baseline levels of fetuin-A compared with those who did not (338.2 vs 292.9 mg/L, P = .02). Among men, after adjustment for traditional risk factors, each 1-SD increase of fetuin-A level (131.6 mg/L) was associated with a 32% higher risk for developing albuminuria (odds ratio 1.32, 95% confidence interval 1.07-1.62). In addition, among men, compared with participants in the lowest tertile (<253.1 mg/L) of serum fetuin-A levels, those in the highest tertile (>338.2 mg/L) had a 2-fold risk for developing albuminuria (odds ratio 2.07, 95% confidence interval 1.04-4.12) after multivariate adjustment. No association between fetuin-A levels and incident albuminuria was observed in women. CONCLUSIONS: High serum fetuin-A levels were independently associated with an increased risk of developing albuminuria in middle-aged and elderly men, whereas no significant associations were found in women. PMID- 26756113 TI - Histologic and Molecular Profile of Pediatric Insulinomas: Evidence of a Paternal Parent-of-Origin Effect. AB - CONTEXT: Acquired insulinomas are rare causes of hyperinsulinemic hypoglycemia in children and are much less common than focal lesions of congenital hyperinsulinism. The latter are known to be associated with isodisomy for paternally transmitted ATP-sensitive potassium channel mutations on 11p15; however, the molecular basis for pediatric insulinomas is not well characterized. OBJECTIVE: The purpose of this study was to characterize the histopathological and molecular defects in a large group of 12 pediatric insulinomas seen at The Children's Hospital of Philadelphia. RESULTS: Twelve children with insulinomas were seen between 1971 and 2013, compared to 201 cases with focal congenital hyperinsulinism seen between 1997 and 2014. The age of insulinoma patients ranged from 4-16 years at the time of surgery. Features of MEN1 syndrome were present in five of the 12, including four cases with heterozygous mutations of MEN1 on 11q. Immunohistochemical analysis revealed nuclear loss of p57 staining consistent with loss of the maternal 11p15 allele in 11 of the 12 insulinomas, including all five MEN1-associated tumors. Imbalance of the paternal 11p allele was confirmed by single nucleotide polymorphism genotyping and methylation assays of the 11p imprinting control loci in four of five MEN1-associated tumors and six of seven sporadic insulinomas. In addition, single nucleotide polymorphism genotyping revealed extensive tumor aneuploidy beyond chromosome 11. CONCLUSIONS: These data indicate that MEN1 mutations are more common in insulinomas in children than in adults. Aneuploidy of chromosome 11 and other chromosomes is common in both MEN1 and non-MEN1 insulinomas. The novel observation of a paternal parent-of-origin effect in all MEN1 and most non-MEN1 tumors suggests a critical role for imprinted growth-regulatory genes in the 11p region in the genesis of beta-cell endocrine tumors in children. PMID- 26756114 TI - FSH Levels Predict Bone Loss in Premenopausal Women Treated for Breast Cancer More Than One Year After Treatment. AB - CONTEXT: Biomarkers to predict bone loss in premenopausal women after breast cancer treatment have not been examined. OBJECTIVE: To determine whether baseline FSH predicts subsequent bone loss. DESIGN: Secondary data analysis of the Exercise for Bone Health: Young Breast Cancer Survivors study, in which women were randomized to a 12-month exercise program or monthly health newsletter. SETTING: Community dwelling women. PARTICIPANTS: A total of 206 women age less than or equal to 55 years at breast cancer diagnosis who had received adjuvant chemotherapy and were at least 1 year after diagnosis. INTERVENTION: Serum collected at baseline (an average of 302 +/- 148 d after completing chemotherapy) was analyzed for FSH. MAIN OUTCOME MEASURE: Change in bone mineral density. RESULTS: In linear regression models, baseline FSH levels predicted bone loss over the ensuing 12 months at the lumbar spine and femoral neck including after adjustment for age, ethnicity, treatment group (exercise vs control), baseline bone density, and high-sensitivity C-reactive protein (P < .001). In multiply adjusted models, the 12-month rate of change in bone density was +0.007% in the lowest tertile of FSH (FSH = 9 +/- 7 IU/L, mean +/- SD), -0.96% in the middle tertile (mean FSH = 41 +/- 11 IU/L), and -2.2% in the highest tertile (mean FSH = 86 +/- 19 IU/L), P for trend <.001. CONCLUSIONS: Among premenopausal women with breast cancer treated with chemotherapy, baseline FSH levels are strongly associated with subsequent bone loss. Further studies are needed to establish the optimal timing of FSH measurement in relation to breast cancer treatment and to investigate potential strategies to prevent bone loss. PMID- 26756117 TI - Bone Structure and Predictors of Fracture in Type 1 and Type 2 Diabetes. AB - CONTEXT: Type 1 and type 2 diabetes mellitus are associated with an increased risk of fracture. OBJECTIVE: The objective of the study was to compare the bone structure and density between type 1 and type 2 diabetes patients and to investigate fracture associations. DESIGN: This was a cross-sectional study. SETTING AND PATIENTS: Physician-diagnosed type 1 and type 2 diabetes patients were included from the outpatient clinics at two university hospitals participated in the study. MAIN OUTCOME MEASURES: Bone density and structure were assessed by dual-energy x-ray absorptiometry and high-resolution peripheral quantitative computed tomography. Blood samples were collected for bone turnover markers. Prevalent vertebral fractures were assessed by vertebral fracture assessment and x-ray, and incident fractures were collected from The Danish National Hospital Discharge Register. RESULTS: Bone mineral density (BMD) was higher in type 2 than type 1 diabetes patients at the hip, femur, and spine; however, only the hip differed in multivariate-adjusted models. Bone tissue stiffness at the tibia was increased in type 2 diabetes patients also in adjusted models. Sclerostin levels were inversely associated with fracture in type 1 diabetes patients. The patients with the highest tertile of sclerostin had an 81% decreased risk of a fracture compared with the lowest tertile. CONCLUSIONS: Type 1 and type 2 diabetes patients differ in BMD of the hip and tissue stiffness at the tibia. Sclerostin may be a marker independent of BMD to predict fractures in type 1 diabetes patients and thus potentially of clinical importance. Studies with longer follow-up are needed. PMID- 26756116 TI - A Novel CYP11B2-Specific Imaging Agent for Detection of Unilateral Subtypes of Primary Aldosteronism. AB - CONTEXT: Although adrenal vein sampling is the standard method to distinguish unilateral from bilateral forms of primary aldosteronism, it is an invasive and technically difficult procedure. (11)C-metomidate (MTO)-positron emission tomography was reported as a potential replacement for adrenal vein sampling. However, MTO has low selectivity for CYP11B2 over CYP11B1. OBJECTIVE: This study aimed to determine the selectivity of (18)F-CDP2230, a new imaging agent, for CYP11B2 over CYP11B1 and determine whether the biodistribution profile of (18)F CDP2230 is favorable for imaging CYP11B2. METHODS: The IC50 of CDP2230 for the enzymatic activities of CYP11B2 and CYP11B1 was determined using cells with stable expression of either enzyme. In vitro autoradiography of human adrenal sections with aldosterone-producing adenomas was performed to confirm the specific binding ability of (18)F-CDP2230 to CYP11B2-expressing regions. Furthermore, positron emission tomography and magnetic resonance imaging were performed to evaluate the biodistribution of (18)F-CDP2230 in rats. RESULTS: Although CDP2230 showed a significantly lower affinity for CYP11B2 and CYP11B1 than did MTO analogues, its selectivity for CYP11B2 over CYP11B1 was higher than that of MTO analogues. In vitro autoradiography revealed that the binding of (18)F-CDP2230 to CYP11B2-expressing regions in the adrenal gland was more specific than that of (123)I-IMTO. Moreover, the biodistribution study showed that (18)F-CDP2230 accumulated in adrenal glands with low background uptake. CONCLUSIONS: Our study showed a high selectivity of (18)F-CDP2230 for CYP11B2 over CYP11B1 with a favorable biodistribution for imaging CYP11B2. (18)F-CDP2230 is a promising imaging agent for detecting unilateral subtypes of primary aldosteronism. PMID- 26756115 TI - Insulin Enhances Endothelial Function Throughout the Arterial Tree in Healthy But Not Metabolic Syndrome Subjects. AB - CONTEXT: Insulin reportedly impairs endothelial function in conduit arteries but improves it in resistance and microvascular arterioles in healthy humans. No studies have assessed endothelial function at three arterial levels in healthy or metabolic syndrome (METSYN) subjects. OBJECTIVE: The objective of the study was to compare endothelial responsiveness of conduit arteries, resistance, and microvascular arterioles to insulin in healthy and METSYN subjects. DESIGN: We assessed conduit, resistance, and microvascular arterial function in the postabsorptive and postprandial states and during euglycemic hyperinsulinemia (insulin clamp). SETTING: The study was conducted at a clinical research unit. PARTICIPANTS: Age-matched healthy and METSYN subjects participated in the study. INTERVENTIONS: We used brachial flow-mediated dilation, forearm postischemic flow velocity, and contrast-enhanced ultrasound to assess the conduit artery, resistance arteriole, and microvascular arteriolar endothelial function, respectively. We also assessed the conduit artery stiffness (pulse wave velocity and augmentation index) and measured the plasma concentrations of 92 cardiovascular disease biomarkers at baseline and after the clamp. RESULTS: Postabsorptive and postprandial endothelial function was similar in controls and METSYN in all tested vessels. METSYN subjects were metabolically insulin resistant (P < .005). In controls, but not METSYN subjects, during euglycemic hyperinsulinemia, endothelial function improved at each level of arterial vasculature (P < .05 or less for each). Conduit vessel stiffness (pulse wave velocity) was increased in the METSYN group. Twelve of 92 biomarkers differed at baseline (P < .001) and remained different at the end of the insulin clamp. CONCLUSIONS: We conclude that insulin enhances arterial endothelial function in health but not in METSYN, and this vascular insulin resistance may underlie its increased cardiovascular disease risk. PMID- 26756118 TI - Prediction of Future Osteoporotic Fracture Occurrence by Genetic Profiling: A 6 Year Follow-Up Observational Study. AB - CONTEXT: Heredity is an important risk factor for osteoporotic fracture, but it remains unclear whether genetic factors improve the predictability of future fracture occurrence. OBJECTIVE: To compare an integration model of genetic profiling with the current model for predicting future fracture occurrence. DESIGN AND SETTING: A retrospective observational cohort study. PARTICIPANTS: Postmenopausal women aged 45-93 years who were untreated (n = 117), hormone treated (n = 491), or bisphosphonate (BP)-treated (n = 415), with a mean 6.1-year follow-up. MAIN OUTCOMES MEASURES: The main outcome was incident fractures. Ninety-five single nucleotide polymorphisms were genotyped. We calculated the Korean-specific genetic risk score 35 (GRS35) from 35 single nucleotide polymorphisms associated with osteoporosis-related traits at the baseline visit. RESULTS: Osteoporotic fracture occurred more frequently in the highest GRS35 tertile group than in the lower two tertile groups after adjustments for confounders (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.17-2.55). The associations of the GRS35 with incident fracture were only significant in the BP group (HR, 2.25; 95% CI, 1.28-3.95) and not in the untreated (HR, 1.26; 95% CI, 0.34-4.66) and hormone-treated (HR, 1.21; 95% CI, 0.62-2.36) groups. Integration of the GRS35 into the current model further improved its predictability for incident fracture occurrence by 6.3% (P = .010). CONCLUSIONS: Genetic profiling can more accurately predict future fracture risk, especially in individuals taking BPs. PMID- 26756121 TI - Vessel involvement in giant cell arteritis: an imaging approach. AB - Vasculitis is classified based on the size of the involved vessels. The two major forms are small vessel vasculitis and large vessel vasculitis (LVV). Main forms of LVV are Takayasu arteritis, giant cell arteritis (GCA), isolated aortitis and chronic periaortitis. This manuscript will focus on GCA, named after the presence of giant cells in the artery vessel wall. A positive biopsy of the temporal artery is the gold standard for making a diagnosis of GCA. In the past 10 years the introduction of new imaging techniques in GCA patients has revealed a variable prevalence of extra cranial involvement, challenging the temporal artery biopsy as gold standard. Also, imaging has become important not only for diagnosing GCA but also for assessment of vascular damage in GCA and for the evaluation of treatment. PMID- 26756119 TI - Dysfunctional Subcutaneous Fat With Reduced Dicer and Brown Adipose Tissue Gene Expression in HIV-Infected Patients. AB - CONTEXT: HIV patients are at an increased risk for cardiometabolic disease secondary to depot-specific alterations in adipose function, but mechanisms remain poorly understood. OBJECTIVE: The endoribonuclease Dicer has been linked to the modulation of brown and white adipocyte differentiation. We previously demonstrated that Dicer knockout mice undergo transformation of brown adipose tissue to white adipose tissue and develop a lipodystrophic phenotype. We hypothesized reduced Dicer and brown adipose tissue gene expression from nonlipomatous sc fat among HIV patients with a lipodystrophic phenotype. DESIGN: Eighteen HIV (nine with and without lipodystrophic changes in fat distribution, characterized by excess dorsocervical adipose tissue [DCAT]) and nine non-HIV subjects underwent punch biopsy of abdominal sc fat to determine expression of Dicer and other adipose-related genes. RESULTS: HIV subjects with long-duration antiretroviral use demonstrated excess DCAT vs non-HIV subjects (9.8 +/- 1.0 vs 6.6 +/- 0.8 cm(2), P = .02) with similar body mass index. Dicer expression was decreased in abdominal sc fat of HIV vs non-HIV (4.88 [1.91, 11.93] vs 17.69 [10.72, 47.91], P = .01), as were PPARalpha, ZIC1, PRDM16, DIO2, and HSP60 (all P <= .03). Moreover, the expression of Dicer (2.49 [0.02, 4.88] vs 11.20 [4.83, 21.45], P = .006), brown fat (PPARalpha [P = .002], ZIC1 [P = .004], LHX8 [P = .03], PRDM16 [P = .0008], PAT2 [P = .008], P2RX5 [P = .02]), beige fat (TMEM26 [P = .004], CD137 [P = .008]), and other genes (DIO2 [P = .002], leptin [P = .003], HSP60 [P = .0004]) was further decreased in abdominal sc fat comparing HIV subjects with vs without excess DCAT. Down-regulation of Dicer in the abdominal sc fat correlated with the down-regulation of all brown and beige fat genes (all P <= .01). CONCLUSION: Our results demonstrate dysfunctional sc adipose tissue marked by reduced Dicer in relationship to the down-regulation of brown and beige fat-related genes in lipodystrophic HIV patients and may provide a novel mechanism for metabolic dysregulation. A strategy to increase browning of white adipose tissue may improve cardiometabolic health in HIV. PMID- 26756123 TI - SDE and SPME Analysis of Flavor Compounds in Jin Xuan Oolong Tea. AB - Simultaneous distillation-extraction (SDE) and solid phase micro extraction (SPME) are procedures used for the isolation of flavor compounds in foods. The purpose of this study was to optimize SDE conditions (solvent and time) and to compare SDE with SPME for the isolation of flavor compounds in Jin Xuan oolong tea using GC-MS and GC-O. The concentration of volatile compounds isolated with diethyl ether was higher (P < 0.05) than for dichloromethane and concentration was higher at 40 min (P < 0.05) than 20 or 60 min extractions. For SDE, 128 volatiles were identified using GC-MS and 45 aroma active compounds using GC-O. Trans-nerolidol was the most abundant compound in oolong tea. The number of volatiles identified using GC-MS was lower in SPME than SDE. For SPME, 59 volatiles and 41 aroma active compounds were identified. The composition of the volatiles isolated by the 2 methods differed considerably but provided complementary information. PMID- 26756120 TI - Response of Simulated Drinking Water Biofilm Mechanical and Structural Properties to Long-Term Disinfectant Exposure. AB - Mechanical and structural properties of biofilms influence the accumulation and release of pathogens in drinking water distribution systems (DWDS). Thus, understanding how long-term residual disinfectants exposure affects biofilm mechanical and structural properties is a necessary aspect for pathogen risk assessment and control. In this study, elastic modulus and structure of groundwater biofilms was monitored by atomic force microscopy (AFM) and optical coherence tomography (OCT) during three months of exposure to monochloramine or free chlorine. After the first month of disinfectant exposure, the mean stiffness of monochloramine- or free-chlorine-treated biofilms was 4 to 9 times higher than those before treatment. Meanwhile, the biofilm thickness decreased from 120 +/- 8 MUm to 93 +/- 6-107 +/- 11 MUm. The increased surface stiffness and decreased biofilm thickness within the first month of disinfectant exposure was presumably due to the consumption of biomass. However, by the second to third month during disinfectant exposure, the biofilm mean stiffness showed a 2- to 4-fold decrease, and the biofilm thickness increased to 110 +/- 7-129 +/- 8 MUm, suggesting that the biofilms adapted to disinfectant exposure. After three months of the disinfectant exposure process, the disinfected biofilms showed 2-5 times higher mean stiffness (as determined by AFM) and 6-13-fold higher ratios of protein over polysaccharide, as determined by differential staining and confocal laser scanning microscopy (CLSM), than the nondisinfected groundwater biofilms. However, the disinfected biofilms and nondisinfected biofilms showed statistically similar thicknesses (t test, p > 0.05), suggesting that long-term disinfection may not significantly remove net biomass. This study showed how biofilm mechanical and structural properties vary in response to a complex DWDS environment, which will contribute to further research on the risk assessment and control of biofilm-associated-pathogens in DWDS. PMID- 26756122 TI - Model assessment in dynamic treatment regimen estimation via double robustness. AB - Dynamic treatment regimens (DTRs) recommend treatments based on evolving subject level data. The optimal DTR is that which maximizes expected patient outcome and as such its identification is of primary interest in the personalized medicine setting. When analyzing data from observational studies using semi-parametric approaches, there are two primary components which can be modeled: the expected level of treatment and the expected outcome for a patient given their other covariates. In an effort to offer greater flexibility, the so-called doubly robust methods have been developed which offer consistent parameter estimators as long as at least one of these two models is correctly specified. However, in practice it can be difficult to be confident if this is the case. Using G estimation as our example method, we demonstrate how the property of double robustness itself can be used to provide evidence that a specified model is or is not correct. This approach is illustrated through simulation studies as well as data from the Multicenter AIDS Cohort Study. PMID- 26756124 TI - Protocol proposal for, and evaluation of, consistency in nicotine delivery from the liquid to the aerosol of electronic cigarettes atomizers: regulatory implications. AB - AIMS: To propose a protocol and evaluate the consistency in nicotine delivery to the aerosol of different types of electronic cigarette (EC) atomizers, as required by regulatory authorities. DESIGN: Three cartomizer and four tank-type atomizer products were tested (three samples per product). The aerosol from three 20-puff sessions from each sample was collected using a smoke machine. Three cartridges from a nicotine inhaler and three tobacco cigarettes were also tested. SETTING: Analytical laboratory in Greece. MEASUREMENTS: Aerosol nicotine levels were measured. Relative standard deviation (RSD, i.e. coefficient of variation) was calculated separately for each cartomizer and replacement atomizer head sample (intrasample RSD) and between different samples (intersample RSD). The percentage difference from the mean, which is used to assess the quality of medicinal nebulizers, was also calculated. FINDINGS: The aerosol nicotine levels were 1.01-10.61 mg/20 puffs for ECs, 0.12-0.18 mg/20 puffs for the nicotine inhaler and 1.76-2.20 mg/cigarette for the tobacco cigarettes. The intrasample RSDs were 3.7-12.5% for ECs and 14.3% for the nicotine inhaler and 11.1% for the tobacco cigarettes. The intersample RSDs were higher in cartomizers (range: 6.9 37.8%) compared with tank systems (range: 6.4-9.3%). All tank-type atomizers and one cartomizer were within 75-125% of the mean, as dictated for medicinal nebulizers. CONCLUSIONS: Electronic cigarettes that use tank-type atomizers appear to deliver nicotine in more consistent quantities (within the acceptable limits for medicinal nebulizers and similar to the nicotine inhaler) than electronic cigarettes that use cartomizers. The protocol for testing nicotine delivery consistency described in this paper could be used effectively for regulatory purposes. PMID- 26756126 TI - Benign paroxysmal positional vertigo: Diagnostic criteria. AB - This article presents operational diagnostic criteria for benign paroxysmal positional vertigo (BPPV), formulated by the Committee for Classification of Vestibular Disorders of the Barany Society. The classification reflects current knowledge of clinical aspects and pathomechanisms of BPPV and includes both established and emerging syndromes of BPPV. It is anticipated that growing understanding of the disease will lead to further development of this classification. PMID- 26756125 TI - Palladium-Catalyzed Asymmetric Allylic Alkylations with Toluene Derivatives as Pronucleophiles. AB - The first two highly enantioselective palladium-catalyzed allylic alkylations with benzylic nucleophiles, activated with Cr(CO)3 , have been developed. These methods enable the enantioselective synthesis of alpha-2-propenyl benzyl motifs, which are important scaffolds in natural products and pharmaceuticals. A variety of cyclic and acyclic allylic carbonates are competent electrophilic partners furnishing the products in excellent enantioselectivity (up to 99 % ee and 92 % yield). This approach was employed to prepare a nonsteroidal anti-inflammatory drug analogue. PMID- 26756127 TI - Perceived radial translation during centrifugation. AB - BACKGROUND: Linear acceleration generally gives rise to translation perception. Centripetal acceleration during centrifugation, however, has never been reported giving rise to a radial, inward translation perception. OBJECTIVE: To study whether centrifugation can induce a radial translation perception in the absence of visual cues. METHODS: To that end, we exposed 12 subjects to a centripetal acceleration with eyes closed. To avoid confounding with angular motion perception, subjects were fist rotated on-axis, and were shifted out fast and slow only after rotation sensation had vanished. They were asked for translation direction and velocity right after the shift-out, as well as after about 60 seconds of constant centrifugation. RESULTS: Independent of fast or slow shift out, the vast statistically significant majority of trials yielded an inward radial translation perception, which velocity was constant after 60 seconds of constant centrifugation. CONCLUSIONS: We therefore conclude that during centrifugation, an inward radial translation perception does exist in humans, which perception reaches a constant, non-zero value during constant rotation, lasting for at least one minute. These results can be understood by high-pass filtering of otolith afferents to make a distinction between inertial and gravitational acceleration, followed by a mere integration over time to reach a constant velocity perception. PMID- 26756128 TI - The influence of yaw motion on the perception of active vs passive visual curvilinear displacement. AB - Self-motion perception, which partly determines the realism of dynamic driving simulators, is based on multisensory integration. However, it remains unclear how the brain integrates these cues to create adequate motion perception, especially for curvilinear displacements. In the present study, the effect of visual, inertial and visuo-inertial cues (concordant or discordant bimodal cues) on self motion perception was analyzed. Subjects were asked to evaluate (externally produced) or produce (self-controlled) curvilinear displacements as accurately as possible. The results show systematic overestimation of displacement, with better performance for active subjects than for passive ones. Furthermore, it was demonstrated that participants used unimodal or bimodal cues differently in performing their activity. When passive, subjects systematically integrated visual and inertial cues even when discordant, but with weightings that depended on the dynamics. On the contrary, active subjects were able to reject the inertial cue when the discordance became too high, producing self-motion perception on the basis of more reliable information. Thereby, multisensory integration seems to follow a non-linear integration model of, i.e., the cues' weight changes with the cue reliability and/or the intensity of the stimuli, as reported by previous studies. These results represent a basis for the adaptation of motion cueing algorithms are developed for dynamic driving simulators, by taking into account the dynamics of simulated motion in line with the status of the participants (driver or passenger). PMID- 26756129 TI - Ocular vestibular evoked myogenic potentials in response to air-conducted 500 Hz short tones: Effect of stimulation procedure (monaural or binaural), age and gender. AB - BACKGROUND: The ocular vestibular myogenic potentials (oVEMP) can be elicited by monaural air-conducted sound stimulation, and are usually recorded from the contralateral eye. In clinical setting a binaural stimulation would save time and require less effort from the subjects. OBJECTIVE: We evaluated the differences between monaural and binaural stimulation, and the possible effect of age and gender on oVEMP parameters. METHODS: Air-conducted oVEMP were recorded by binaural and by monaural stimulation in a group of 54 normal subjects, aged from 12 to 83 years, and in 50 vestibular patients. From each side, we measured the latency of the N1 component, and the peak-to-peak N1-P1 amplitude. For both parameters we also computed the asymmetry ratio. RESULTS: In normal subjects binaural stimulation produced slightly larger responses than monaural stimulation; detectability, latency and amplitude ratio were the same for the two techniques. We found no differences related to gender, and the age-induced amplitude decline was likely to be negligible.oVEMP recorded not in an acute phase of their disorder, proved to be abnormal in about 20% of the patients, and the normal or abnormal findings obtained either with monaural or with binaural stimulation were always concordant. CONCLUSIONS: The oVEMP obtained after binaural and monaural stimulation are very similar, and they are largely independent from age and gender. PMID- 26756130 TI - Test-retest reliability of binaural simultaneous cervical vestibular evoked myogenic potential recording. AB - AIMS: The purpose of this study is to compare the test-retest reliability of cervical vestibular evoked myogenic potential (cVEMP) parameters between monaural sequential (mSEQ) cVEMP and binaural simultaneous (bSIM) cVEMP recordings. MATERIALS AND METHODS: Twenty two volunteers aged 22 from 38 years were enrolled. Two different methods of cVEMP measurement were performed in the subjects. The two methods were (1) monaural sequential (mSEQ) measurement and (2) binaural simultaneous (bSIM) measurement. After a mean test-retest interval of 7.1 +/- 2.8 days, the second run of the cVEMP measurement was performed in a random order. To compare the test-retest reliability of mSEQ and bSIM cVEMP responses, Intraclass correlation coefficient (ICC) and Spearman correlation were applied. RESULTS: Both p13 and n23 latencies did not show a statistically significant difference between the two cVEMP recording methods. Also, there were no significant differences in the inter-peak amplitude (IPA) and interaural amplitude difference (IAD) ratio between the two methods. The test-retest reliability of inter-peak amplitude (IPA) demonstrated a positive correlation for both mSEQ and bSIM cVEMP methods. The IAD ratio of bSIM cVEMP response demonstrated a statistically significant test-retest reliability (ICC = 0.691, p= 0.015). However, the IAD ratio of mSEQ cVEMP response did not demonstrate a statistically significant test retest correlation. CONCLUSION: Results implicate that bSIM cVEMP not only saves time, but it also has an advantage of a more reliable test-retest outcome. PMID- 26756131 TI - Ocular and Cervical Vestibular Evoked Myogenic Potentials (VEMPs) in healthy volunteers: the intra-, interobserver, and the test re-test reliability. AB - OBJECTIVE: The aims of the study are to determine the intra-, interobserver, and the test re-test reliability of the cervical and ocular vestibular evoked myogenic potentials (VEMPs). METHODS: Twenty healthy subjects underwent acoustically and forehead tap elicited cervical and ocular VEMPs. The measurements were repeated one week later. RESULTS: The intra- and interobserver reliability of both ocular and cervical VEMPs is excellent. The test re-test reliability of the raw p13n23 peak-to-peak amplitudes of the cervical VEMPs is excellent (ICC: 0.76, 0.87) and the p13 latencies show a good reliability (ICC: 0.56, 0.73). The raw n1p1 peak-to-peak amplitudes of the ocular VEMPs show a fair to-good test re-test reliability (ICC: 0.51, 0.64) and the n1 and p1 latencies show a poor reliability (ICC: -0.17 <= x <= 0.44). CONCLUSIONS: The intra- and interobserver reliability of the cervical and ocular VEMPs is excellent. The raw ocular and cervical VEMP peak-to-peak amplitudes are the most reliable parameters, followed by the cervical VEMP latencies. The ocular VEMP latencies shows a poor test re-test reliability. The individual VEMP results, however, remained within normal limits despite the test re-test variability. PMID- 26756132 TI - Spontaneous inversion of nystagmus without a positional change in the horizontal canal variant of benign paroxysmal positional vertigo. AB - OBJECTIVE: We investigated the neuro-otological findings, including nystagmus, and the clinical course of patients with the horizontal canal variant of benign paroxysmal positional vertigo (HC-BPPV), who showed spontaneous inversion of nystagmus without a positional change. Furthermore, we speculated on the possible mechanism of spontaneous inversion of nystagmus without a positional change. PATIENTS AND METHODS: The characteristics of spontaneous inversion of positional nystagmus without a positional change were analyzed in 7 patients with HC-BPPV. RESULTS: All patients were diagnosed as having HC-BPPV. During the positional test, the spontaneous inversion of nystagmus was observed in the same head position in all patients. Spontaneous inversion was observed on both sides in 5 patients, and only on 1 side in 2 patients. All patients presented with geotropic nystagmus in the first phase, and ageotropic nystagmus in the second phase. CONCLUSIONS: The coexistence of cupulolithiasis and canalolithiasis appears to be a possible mechanism of the spontaneous inversion of positional nystagmus. PMID- 26756133 TI - Ototoxicity from organic solvents assessed by an inner ear test battery. AB - OBJECTIVE: This study adopted an inner ear test battery comprising audiometry, and ocular vestibular-evoked myogenic potential (oVEMP), cervical VEMP (cVEMP) and caloric tests to assess inner ear function in patients with long term exposure to organic solvents. METHODS: Eighteen patients exposed to organic solvents and another 18 non-exposed controls from the same environment were enrolled in this study. Each subject underwent an inner ear test battery. RESULTS: The percentages of abnormalities identified by the oVEMP test, cVEMP test, audiometry and caloric test for the exposed group were 85%, 54%, 50% and 33%, respectively, which showed significant differences when compared with the respective 8%, 8%, 6% and 0 for the non-exposed group. Additionally, a significantly declining trend of inner ear deficits from the utricle to the saccule, cochlea, and semicircular canals was noted in the exposed group, but not in the non-exposed group. CONCLUSION: Ototoxicity was identified in those exposed to organic solvents, with the sequence of abnormal inner ear function from the utricle to the saccule, cochlea, and semicircular canals. PMID- 26756134 TI - Variables associated with outcome in patients with bilateral vestibular hypofunction: Preliminary study. AB - BACKGROUND: Vestibular rehabilitation (VR) improves symptoms and function in some but not all patients with bilateral vestibular hypofunction (BVH). OBJECTIVE: The purpose of this retrospective study was to examine change following vestibular rehabilitation and to identify factors associated with rehabilitation outcome in patients with BVH. METHODS: Data from 69 patients with BVH were analyzed. Factors studied included patient characteristics, subjective complaints and physical function. Outcome measures included symptom intensity, balance confidence, quality of life, gait speed, fall risk, and dynamic visual acuity. Bivariate correlations were used to examine relationships of patient characteristics and baseline measures with outcome measures. One-way ANOVAs were used to compare outcomes in patients with BVH versus unilateral vestibular hypofunction (UVH). RESULTS: As a group, patients with BVH improved in all outcome measures except disability following a course of vestibular rehabilitation (VR); however, only 38 86% demonstrated a meaningful improvement, depending on the specific outcome measure examined. Several factors measured at baseline - age, DGI score, gait speed and perceived dysequilibrium - were associated with outcomes. For example, greater age was related to higher DVA scores at discharge; lower initial DGI scores were related to higher Disability scores at discharge. Compared to patients with UVH, reported previously [9], a smaller percentage of patients with BVH improve and to a lesser extent. CONCLUSION: Consideration of baseline factors may provide guidance for setting patient goals. Further research is needed determine what factors predict outcome and to develop more effective treatment strategies for those patients who do not improve. PMID- 26756135 TI - Valorization of agroindustrial wastes: Identification by LC-MS and NMR of benzylglucosinolate from papaya (Carica papaya L.) seeds, a protective agent against lipid oxidation in edible oils. AB - In the present study we report the characterization of benzylglucosinolate (BG) isolated from papaya (Carica papaya L.) seeds. A methanolic extract was fractionated and further purified by solid phase extraction (SPE). It was analyzed by liquid chromatography-electrospray ionization-mass spectrometry (LC ESI-MS), and nuclear magnetic resonance spectroscopy ((1) H and (13) C-NMR) as well, and the target compound BG was identified by these two techniques. The effect of BG on lipid oxidation in edible vegetable oil (EO) was shown by observing some lipid oxidation products (linoleic acid hydroperoxides, LHP; hexanal, HEX; nonanal, NON; thiobarbituric acid reactives species, TBARS). BG reduced lipid oxidation production in EO by over 80%, as compared to a control sample and in this way has proved to be a useful antioxidant, even more effective than some antioxidants used by food industry. PMID- 26756136 TI - Convergence and Divergence Around Breast Cancer Screening. PMID- 26756137 TI - Predicting the consequences of species loss using size-structured biodiversity approaches. AB - Understanding the consequences of species loss in complex ecological communities is one of the great challenges in current biodiversity research. For a long time, this topic has been addressed by traditional biodiversity experiments. Most of these approaches treat species as trait-free, taxonomic units characterizing communities only by species number without accounting for species traits. However, extinctions do not occur at random as there is a clear correlation between extinction risk and species traits. In this review, we assume that large species will be most threatened by extinction and use novel allometric and size spectrum concepts that include body mass as a primary species trait at the levels of populations and individuals, respectively, to re-assess three classic debates on the relationships between biodiversity and (i) food-web structural complexity, (ii) community dynamic stability, and (iii) ecosystem functioning. Contrasting current expectations, size-structured approaches suggest that the loss of large species, that typically exploit most resource species, may lead to future food webs that are less interwoven and more structured by chains of interactions and compartments. The disruption of natural body-mass distributions maintaining food web stability may trigger avalanches of secondary extinctions and strong trophic cascades with expected knock-on effects on the functionality of the ecosystems. Therefore, we argue that it is crucial to take into account body size as a species trait when analysing the consequences of biodiversity loss for natural ecosystems. Applying size-structured approaches provides an integrative ecological concept that enables a better understanding of each species' unique role across communities and the causes and consequences of biodiversity loss. PMID- 26756138 TI - Clinical, cytogenetic, and molecular outcomes in a series of 66 patients with Pierre Robin sequence and literature review: 22q11.2 deletion is less common than other chromosomal anomalies. AB - Pierre Robin sequence (PRS) is an important craniofacial anomaly that can be seen as an isolated finding or manifestation of multiple syndromes. 22q11.2 deletion and Stickler syndrome are cited as the two most common conditions associated with PRS, but their frequencies are debated. We performed a retrospective study of 66 patients with PRS and reviewed their genetic testing, diagnoses, and clinical findings. The case series is complemented by a comprehensive literature review of the nature and frequency of genetic diagnosis in PRS. In our cohort 65% of patients had associated anomalies; of these, a genetic diagnosis was established in 56%. Stickler syndrome was the most common diagnosis, comprising approximately 11% of all cases, followed by Treacher Collins syndrome (9%). The frequency of 22q11.2 deletion was 1.5%. Chromosome arrays, performed for 72% of idiopathic PRS with associated anomalies, revealed two cases of 18q22->qter deletion, a region not previously reported in association with PRS. A review of the cytogenetic anomalies identified in this population supports an association between the 4q33 qter, 17q24.3, 2q33.1, and 11q23 chromosomal loci and PRS. We found a low frequency of 22q11.2 deletion in PRS, suggesting it is less commonly implicated in this malformation. Our data also indicate a higher frequency of cytogenetic anomalies in PRS patients with associated anomalies, and a potential new link with the 18q22->qter locus. The present findings underscore the utility of chromosomal microarrays in cases of PRS with associated anomalies and suggest that delaying testing for apparently isolated cases should be considered. PMID- 26756139 TI - Achieving Single-Nucleotide Specificity in Direct Quantitative Analysis of Multiple MicroRNAs (DQAMmiR). AB - Direct quantitative analysis of multiple miRNAs (DQAMmiR) utilizes CE with fluorescence detection for fast, accurate, and sensitive quantitation of multiple miRNAs. Here we report on achieving single-nucleotide specificity and, thus, overcoming a principle obstacle on the way of DQAMmiR becoming a practical miRNA analysis tool. In general, sequence specificity is reached by raising the temperature to the level at which the probe-miRNA hybrids with mismatches melt while the matches remain intact. This elevated temperature is used as the hybridization temperature. Practical implementation of this apparently trivial approach in DQAMmiR has two major challenges. First, melting temperatures of all mismatched hybrids should be similar to each other and should not reach the melting temperature of any of the matched hybrids. Second, the elevated hybridization temperature should not deteriorate CE separation of the hybrids from the excess probes and the hybrids from each other. The second problem is further complicated by the reliance of separation in DQAMmiR on single-strand DNA binding protein (SSB) whose native structure and binding properties may be drastically affected by the elevated temperature. These problems were solved by two approaches. First, locked nucleic acid (LNA) bases were incorporated into the probes to normalize the melting temperatures of all target miRNA hybrids allowing for a single hybridization temperature; binding of SSB was not affected by LNA bases. Second, a dual-temperature CE was developed in which separation started with a high capillary temperature required for proper hybridization and continued at a low capillary temperature required for quality electrophoretic separation of the hybrids from excess probes and the hybrids from each other. The developed approach was sufficiently robust to allow its integration with sample preconcentration by isotachophoresis to achieve a limit of detection below 10 pM. PMID- 26756141 TI - The Utility of a Predictive Model for Cochlear Implant Operating Time. AB - OBJECTIVE: This study analyzes multiple factors and their significance in determining the operative timing for cochlear implants at one institution over a 10-year period. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: All patients including both adult and pediatric undergoing cochlear implantation from 2002 through January 2012. INTERVENTION(S): Cochlear implantation. MAIN OUTCOME MEASURE(S): The overall operative room time and surgical duration for patients undergoing cochlear implantation. Individual factors analyzed for influence on timing included center experience, surgeon experience, location (main OR, children's OR, outpatient OR), patient age, patient sex, bilaterality, anatomical consideration, complications, and the involvement of residents and fellows. RESULTS: ANOVA analysis of individual factors. Factors associated with increased surgical duration included bilateral implants, abnormal inner ear anatomy, and intraoperative complications. Factors associated with time outside the operation included surgical duration, the surgical suite type, and the availability of a fellow. Total operating room time was significantly reduced in an outpatient setting and in quicker performed procedures. CONCLUSIONS: The influence of factors affecting both surgical duration and time in the operating room can be predicted and used to provide more accurate estimates of operating room time. PMID- 26756140 TI - Temporal-Bone Measurements of the Maximum Equivalent Pressure Output and Maximum Stable Gain of a Light-Driven Hearing System That Mechanically Stimulates the Umbo. AB - HYPOTHESIS: That maximum equivalent pressure output (MEPO) and maximum stable gain (MSG) measurements demonstrate high output and high gain margins in a light driven hearing system (Earlens). BACKGROUND: The nonsurgical Earlens consists of a light-activated balanced-armature transducer placed on the tympanic membrane (Lens) to drive the middle ear through direct umbo contact. The Lens is driven and powered by encoded pulses of light. In comparison to conventional hearing aids, the Earlens is designed to provide higher levels of output over a broader frequency range, with a significantly higher MSG. MEPO provides an important fitting guideline. METHODS: Four fresh human cadaveric temporal bones were used to measure MEPO directly. To calculate MEPO and MSG, we measured the pressure close to the eardrum and the stapes velocity, for sound drive and light drive using the Earlens. RESULTS: The baseline sound-driven measurements are consistent with previous reports. The average MEPO (n = 4) varies from 116 to 128 dB SPL in the 0.7 to 10 kHz range, with the peak occurring at 7.6 kHz. From 0.1 to 0.7 kHz, it varies from 83 to 121 dB SPL. For the average MSG, a broad minimum of about 10 dB occurs in the 1 to 4 kHz range, above which it rises as high as 42 dB at 7.6 kHz. From 0.2 to 1 kHz, the MSG decreases linearly from approximately 40 dB to 10 dB. CONCLUSION: With high output and high gain margins, the Earlens may offer broader-spectrum amplification for treatment of mild-to-severe hearing impairment. PMID- 26756142 TI - Project ASPIRE: Spoken Language Intervention Curriculum for Parents of Low socioeconomic Status and Their Deaf and Hard-of-Hearing Children. AB - OBJECTIVE: To investigate the impact of a spoken language intervention curriculum aiming to improve the language environments caregivers of low socioeconomic status (SES) provide for their D/HH children with CI & HA to support children's spoken language development. STUDY DESIGN: Quasiexperimental. SETTING: Tertiary. PATIENTS: Thirty-two caregiver-child dyads of low-SES (as defined by caregiver education <= MA/MS and the income proxies = Medicaid or WIC/LINK) and children aged < 4.5 years, hearing loss of >= 30 dB, between 500 and 4000 Hz, using at least one amplification device with adequate amplification (hearing aid, cochlear implant, osseo-integrated device). INTERVENTION: Behavioral. Caregiver-directed educational intervention curriculum designed to improve D/HH children's early language environments. MAIN OUTCOME MEASURES: Changes in caregiver knowledge of child language development (questionnaire scores) and language behavior (word types, word tokens, utterances, mean length of utterance [MLU], LENA Adult Word Count (AWC), Conversational Turn Count (CTC)). RESULTS: Significant increases in caregiver questionnaire scores as well as utterances, word types, word tokens, and MLU in the treatment but not the control group. No significant changes in LENA outcomes. CONCLUSION: Results partially support the notion that caregiver directed language enrichment interventions can change home language environments of D/HH children from low-SES backgrounds. Further longitudinal studies are necessary. PMID- 26756144 TI - Introduction to the 14th Symposium on Cochlear Implants in Children, Nashville, TN Papers. PMID- 26756143 TI - Outcomes of Adolescents With a Short Electrode Cochlear Implant With Preserved Residual Hearing. AB - OBJECTIVE: The purpose of this study was to determine if adolescents with preserved residual low-frequency hearing can develop improved speech perception and maintain localization abilities by combining their acoustic hearing with electrical processing from a short electrode cochlear implant. STUDY DESIGN: Repeated-measure, single-subject experiment. SETTING: Research hospital. PATIENTS: Adolescents with sensorineural hearing loss with a pure-tone average (PTA) between 60 and 90 dB HL between 125 and 1500 Hz and profound loss at higher frequencies. INTERVENTION(S): rehabilitative. MAIN OUTCOME MEASURE(S): Five adolescents received a short electrode cochlear implant in their poorer ear. Audiometric, speech perception in quiet (CNC words), localization, speech production, and language outcomes were collected pre- and postoperatively at 4, 8, 12, and 24 months. RESULTS: Functional hearing preservation was accomplished in all subjects at initial activation and was maintained through 24 months. In the Combined and Hybrid conditions, all subjects showed significant improvements by 4 months postimplantation, with exception of Subject 2 in the Combined condition, who showed a significant improvement by 8 months postimplantation. Results also indicated that all subjects continue to have localization abilities postimplantation. CONCLUSIONS: All of the subjects have benefitted from the combined electric and acoustic processing for speech perception abilities. The results from this study suggest that it could be worthwhile to consider acoustic and electric hearing in the adolescent population that have some low-frequency residual hearing and are struggling with hearing aids. PMID- 26756146 TI - Improving Spoken Language Outcomes for Children With Hearing Loss: Data-driven Instruction. AB - OBJECTIVE: To assess the effects of data-driven instruction (DDI) on spoken language outcomes of children with cochlear implants and hearing aids. STUDY DESIGN: Retrospective, matched-pairs comparison of post-treatment speech/language data of children who did and did not receive DDI. SETTING: Private, spoken language preschool for children with hearing loss. SUBJECTS: Eleven matched pairs of children with cochlear implants who attended the same spoken language preschool. Groups were matched for age of hearing device fitting, time in the program, degree of predevice fitting hearing loss, sex, and age at testing. INTERVENTION: Daily informal language samples were collected and analyzed over a 2-year period, per preschool protocol. Annual informal and formal spoken language assessments in articulation, vocabulary, and omnibus language were administered at the end of three time intervals: baseline, end of year one, and end of year two. MAIN OUTCOME MEASURES: The primary outcome measures were total raw score performance of spontaneous utterance sentence types and syntax element use as measured by the Teacher Assessment of Spoken Language (TASL). In addition, standardized assessments (the Clinical Evaluation of Language Fundamentals- Preschool Version 2 (CELF-P2), the Expressive One-Word Picture Vocabulary Test (EOWPVT), the Receptive One-Word Picture Vocabulary Test (ROWPVT), and the Goldman-Fristoe Test of Articulation 2 (GFTA2)) were also administered and compared with the control group. RESULTS: The DDI group demonstrated significantly higher raw scores on the TASL each year of the study. The DDI group also achieved statistically significant higher scores for total language on the CELF-P and expressive vocabulary on the EOWPVT, but not for articulation nor receptive vocabulary. Post-hoc assessment revealed that 78% of the students in the DDI group achieved scores in the average range compared with 59% in the control group. CONCLUSION: The preliminary results of this study support further investigation regarding DDI to investigate whether this method can consistently and significantly improve the achievement of children with hearing loss in spoken language skills. PMID- 26756147 TI - Measuring Success: Cost-Effectiveness and Expanding Access to Cochlear Implantation. AB - Only a small fraction of patients with profound sensorineural hearing loss have access to cochlear implantation with the majority of these affected people living in developing countries. Cost effectiveness analysis (CEA) is an important tool to demonstrate the value of this technology to healthcare policy makers. This approach requires that hearing healthcare professionals incorporate methods of assessing long-term benefits of cochlear implantation that include psychosocial, quality of life, and disability outcomes. This review explores different aspects of CEA methodology relevant to cochlear implants and discusses ways that we can improve global access by addressing factors that influence cost-effectiveness. PMID- 26756145 TI - A Comprehensive Study on the Etiology of Patients Receiving Cochlear Implantation With Special Emphasis on Genetic Epidemiology. AB - OBJECTIVE: Cochlear implantation is the most important treatment currently available for profound sensorineural hearing loss. The aim of this study was to investigate the etiology of hearing loss in patients with cochlear implantation, and to compare outcomes. METHODS: Japanese hearing loss patients who received cochlear implants (CIs) or electric acoustic stimulation (EAS) in Shinshu University hospital (n = 173, prelingual onset: 92, postlingual onset: 81) participated in this study. Invader assay followed by the targeted exon sequencing of 63 deafness genes using Massively parallel DNA sequencing (MPS) was applied. For prelingual patients, additional imaging examination, cCMV screening, and pediatric examination were performed for precise diagnosis. RESULTS: Genetic screening successfully identified the causative mutation in 60% of patients with prelingual onset hearing loss and in 36% of those with postlingual hearing loss. Differences in the kinds of genes identified were observed between the two groups. Although there were marked variations in the outcome of cochlear implantation, patients with specific deafness gene mutations showed relatively good results. CONCLUSION: The present study showed genetic etiology is a major cause of hearing loss in CI/EAS patients. Patients possessing mutations in a number of deafness genes known to be expressed within inner ear have achieved satisfactory auditory performance, suggesting that the identification of the genetic background facilitates the prediction of post-CI performance. MPS is a powerful tool for the identification of causative deafness genes in patients receiving cochlear implantation. Therefore, determination of the involved region inside/outside of the cochlea by identification of the responsible gene is essential. PMID- 26756149 TI - Using the Implant Electrode Array to Conduct Real-time Intraoperative Hearing Monitoring During Pediatric Cochlear Implantation: Preliminary Experiences. AB - OBJECTIVES: To present the preliminary experiences and findings from a pilot study evaluating a novel technique for monitoring cochlear electrophysiological function during electrode insertion in cochlear implantation surgery. STUDY DESIGN: Prospective pilot cohort study. SETTING: Tertiary academic neuro-otology center. PATIENTS: Pediatric patients with residual hearing undergoing hearing preservation cochlear implant surgery. INTERVENTION: Monitoring of intraoperative cochlear microphonics during cochlear implant surgery. MAIN OUTCOME MEASURE: Intraoperative intracochlear microphonic measurement, preservation of these responses postoperatively and preservation of hearing as measured by audiometry. RESULTS: Intracochlear microphonics could be identified in both patients presented and were preserved during the surgical procedure and postoperatively. The preservation of intracochlear microphonics correlates with preservation of hearing. CONCLUSION: The novel approach using the electrode array to detect and measure intracochlear microphonics during cochlear implantation surgery shows promise as an instrument to alert the operating surgeon to hair cell damage during electrode insertion. Further refinement of the technique is required to better understand the measurements and correlate these with pre- and postoperative hearing and risk of hearing loss from surgery. Improvements in the software algorithm will reduce the time required for each measurement, leading to the development a more real-time monitoring technique. PMID- 26756148 TI - Music Perception of Adolescents Using Electroacoustic Hearing. AB - BACKGROUND: Preserved residual hearing in adult recipients of short electrode cochlear implants (CIs) contributes to improve perception of speech in noise as well as music. Recently, children and adolescents with sufficient low-frequency hearing but profound loss at higher frequencies enrolled in a FDA trial intended to evaluate the benefit of a short electrode device on the maintenance of residual hearing. This article reports on the perception of several music listening tasks by adolescents using electroacoustic hearing. METHODS: Five adolescents (13-18 yr) with 18-24 months of electroacoustic experience, 73 children (LEC) and adolescents (LEA) who use traditional implants, and 87 children with normal hearing (NH) tested on 3 measures of music perception: Complex Pitch Ranking (PR-C); Melodic Error Detection (MED); Melody Recognition X Information Cue (MRIC). The participants with ipsilateral residual hearing were tested preoperatively at intervals up to 24 months. RESULTS: Pitch ranking scores for the electroacoustic group were significantly better than the LEC and LEA (p < 0.0002 and p = 0.0076, respectively) and were not significantly different from the NH group. On the MED, although scores were more accurate than those of the LEC and LEA groups, they were not significantly better. For the MRIC, the electroacoustic group was significantly better than both LEA and LEC on melody with and without rhythm. NH subjects were significantly better than both LE groups, but not the electroacoustic group. CONCLUSION: Low-frequency information available to electroacoustic users was associated with more accurate perception on three pitch-based music listening tasks. Greater residual hearing during auditory development may also contribute to more "normal" mental representation of musical elements. PMID- 26756150 TI - Single-sided Deafness Cochlear Implantation: Candidacy, Evaluation, and Outcomes in Children and Adults. AB - OBJECTIVES: Although there are various available treatment options for unilateral severe-to-profound hearing loss, these options do not provide the benefits of binaural hearing since sound is directed from the poorer ear to the better ear. The purpose of this investigation was to review our center's experience with cochlear implantation in such patients in providing improved auditory benefits and useful binaural hearing. STUDY DESIGN: Retrospective chart review. METHODS: Twelve adult patients and four pediatric patients with unilateral severe-to profound hearing loss received an implant in the poorer ear. Outcome measures performed preoperatively on each ear and binaurally included consonant-nucleus consonant (CNC) monosyllabic words and sentences in noise. The mean pure-tune average in the better ear was within normal range. RESULTS: Test scores revealed a significant improvement in CNC and sentence in noise test scores from the preoperative to most recent postoperative evaluation in the isolated implant ear. All adult subjects use the device full-time. CONCLUSIONS: The data reveal significant improvement in speech perception performance in quiet and in noise in patients with single-sided deafness after implantation. Performance might depend on factors including length of hearing loss, age at implantation, and device usage. PMID- 26756151 TI - Speech Recognition of Bimodal Cochlear Implant Recipients Using a Wireless Audio Streaming Accessory for the Telephone. AB - OBJECTIVE: The goals of the present investigation were (1) to evaluate recognition of recorded speech presented over a mobile telephone for a group of adult bimodal cochlear implant users, and (2) to measure the potential benefits of wireless hearing assistance technology (HAT) for mobile telephone speech recognition using bimodal stimulation (i.e., a cochlear implant in one ear and a hearing aid on the other ear). STUDY DESIGN: A three-by-two-way repeated measures design was used to evaluate mobile telephone sentence-recognition performance differences obtained in quiet and in noise with and without the wireless HAT accessory coupled to the hearing aid alone, CI sound processor alone, and in the bimodal condition. SETTING: Outpatient cochlear implant clinic. SUBJECTS: Sixteen bimodal users with Nucleus 24, Freedom, CI512, or CI422 cochlear implants participated in this study. INTERVENTION (S): Performance was measured with and without the use of a wireless HAT for the telephone used with the hearing aid alone, CI alone, and bimodal condition. MAIN OUTCOME MEASURE(S): CNC word recognition in quiet and in noise with and without the use of a wireless HAT telephone accessory in the hearing aid alone, CI alone, and bimodal conditions. RESULTS: Results suggested that the bimodal condition gave significantly better speech recognition on the mobile telephone with the wireless HAT. CONCLUSIONS: A wireless HAT for the mobile telephone provides bimodal users with significant improvement in word recognition in quiet and in noise over the mobile telephone. PMID- 26756152 TI - Cortical Plasticity and Reorganization in Pediatric Single-sided Deafness Pre- and Postcochlear Implantation: A Case Study. AB - HYPOTHESIS: The purpose of this study was to examine changes in cortical development and neuroplasticity in a child with single-sided deafness (SSD) before and after cochlear implantation (CI). BACKGROUND: The extent to which sensory pathways reorganize in childhood SSD is not well understood and there is currently little evidence demonstrating the efficacy of CI in children with SSD. METHODS: High-density 128-channel electroencephalography (EEG) was used to collect cortical auditory evoked potentials (CAEP), cortical visual evoked potentials (CVEP), and cortical somatosensory evoked potentials (CSSEP) in a child with SSD, pre-CI and at subsequent sessions until approximately 3 years post-CI in her right ear which occurred at age 9.86 years. Behavioral correlates of speech perception and sound localization were also measured. RESULTS: Pre-CI, high-density EEG showed evidence of delayed auditory cortical response morphology, auditory cortical development strongly contralateral (to the normal hearing ear), evidence of increased cognitive load, and cross-modal reorganization by the visual and somatosensory modalities. The post-CI developmental trajectory provided clear evidence of age-appropriate development of auditory cortical responses, and decreased cross-modal reorganization, consistent with improved speech perception and sound localization. CONCLUSION: Post-CI, the child demonstrated age-appropriate auditory cortical development and improved speech perception and sound localization suggestive of significant benefits from cochlear implantation. Reversal of somatosensory recruitment was clearly apparent, and only a residual amount of visual cross-modal plasticity remained postimplantation. Overall, our results suggest that CI in pediatric SSD patients may benefit from a highly plastic cortex in childhood. PMID- 26756153 TI - Does Bilateral Experience Lead to Improved Spatial Unmasking of Speech in Children Who Use Bilateral Cochlear Implants? AB - HYPOTHESIS: In children with bilateral cochlear implants (BiCIs), experience over a 1 to 3-year period can improve speech understanding and spatial unmasking of speech. BACKGROUND: One reason for providing children with BiCIs is to improve spatial hearing abilities. Little is known about changes in performance with added bilateral experience, and the relation between sound localization and spatial unmasking of speech. METHODS: Twenty children with BiCIs participated. Testing was conducted typically within a year of bilateral activation, and at 1, 2, or 3 follow-up annual intervals. All testing was done while children listened with both devices activated. Target speech was presented from front (co-located); interfering speech was from front, right (asymmetrical), or right and left (symmetrical). Speech reception thresholds (SRTs) were measured in each condition. Spatial release from masking (SRM) was quantified as the difference in SRTs between conditions with interferers at 0 degrees and 90 degrees. For 11 of the children, data are also compared with sound localization measures obtained on the same visit to the laboratory but published elsewhere. RESULTS: Change in SRM with bilateral experience varied; some children showed improvement and others did not. Regression analyses identified relationships between SRTs and SRM. Comparison of the SRM with localization data suggests little evidence for correlations between the two spatial tasks. CONCLUSION: In children with BiCIs spatial hearing mechanisms involved in SRM and sound localization may be different. Reasons for reduced SRM include asymmetry between the ears, and individual differences in the ability to inhibit interfering information, switch and/or sustain attention. PMID- 26756154 TI - Beyond Early Intervention: Supporting Children With CIs Through Elementary School. AB - BACKGROUND: The development of cochlear implants (CIs) and the broader availability of early intervention, made possible by newborn hearing screening, have raised prospects that deaf children can be mainstreamed at the start of elementary school and fare well with minimal support. This report examines the veracity of that perspective. METHODS: This report specifically: (1) reviews progress made by deaf children in spoken language acquisition over the past 25 years; (2) presents data collected from 104 children in the early elementary grades (49 with normal hearing (NH) and 55 with severe-to-profound hearing loss who use CIs); (3) describes language acquisition that typically occurs in elementary school; and (4) highlights intervention strategies for school-age deaf children with CIs. RESULTS: The spoken language skills of deaf children have improved thanks to CIs and early intervention, but remain below those of children with NH. The amount of deficit varies across the language construct examined, with the greatest deficit found for skills dependent upon phonological (speech sound) sensitivity, and the mildest associated with morphosyntactic (grammatical) skills. There is substantial development in both phonological and morphosyntactic skills that typically occurs during the elementary school years. CONCLUSION: Both the data and theoretical models of language acquisition indicate that even with the availability of CIs and early intervention, deaf children are behind their peers with NH when they enter school. And there is much language learning that lies ahead for them. Thus, there is a need for us to enhance our intervention with deaf children during the early elementary grades. PMID- 26756155 TI - Speech Understanding in Children With Normal Hearing: Sound Field Normative Data for BabyBio, BKB-SIN, and QuickSIN. AB - OBJECTIVE: The primary goal was to establish normative data for the Pediatric AzBio "BabyBio," QuickSIN, and BKB-SIN measures in the sound field for children with normal hearing. SETTING: Tertiary care hospital; cochlear implant (CI) program. PATIENTS: Forty-one children with normal hearing were recruited across four age groups (5-6, 7-8, 9-10, and 11-12 yr). INTERVENTIONS: Sentence recognition testing was assessed at four different signal-to-noise ratios (SNRs, +10, +5, 0, and -5 dB) for BabyBio sentences as well as for the BKB-SIN and QuickSIN tests. All measures were presented in the sound field at 60 dBA except QuickSIN, which was presented at 70 dBA. MAIN OUTCOME MEASURES: BabyBio sentence recognition, BKB-SIN SNR-50, and QuickSIN SNR-50 were analyzed to establish sound field norms. RESULTS: BabyBio sentence recognition approached ceiling at all SNRs with mean scores ranging from 86% at -5 dB SNR to 99.3% at +10 dB SNR. Mean QuickSIN SNR-50 was 6.6 dB. Mean BKB-SIN SNR-50 was 1.6 dB with sound field data being consistent with insert earphone normative data in the BKB-SIN manual. Performance for all measures improved with age. CONCLUSION: Children with normal hearing achieve ceiling-level performance for BabyBio sentence recognition at SNRs used for clinical CI testing (>= 0 dB SNR) and approach ceiling level even at -5 dB SNR. Consistent with previous reports, speech recognition in noise improved with age from 5 to 12 years in children with normal hearing. Thus, speech recognition in noise might also increase in the CI population across the same age range warranting age-specific norms for CI recipients. Last, the QuickSIN test could be substituted for the BKB-SIN test with appropriate age normative data. PMID- 26756156 TI - Language Development in the First Year of Life: What Deaf Children Might Be Missing Before Cochlear Implantation. AB - OBJECTIVES: Language development is a multifaceted, dynamic process involving the discovery of complex patterns, and the refinement of native language competencies in the context of communicative interactions. This process is already advanced by the end of the first year of life for hearing children, but prelingually deaf children who initially lack a language model may miss critical experiences during this early window. The purpose of this review is twofold. First, we examine the published literature on language development during the first 12 months in typically developing children. Second, we use this literature to inform our understanding of the language outcomes of prelingually deaf children who receive cochlear implants (CIs), and therefore language input, either before or after the first year. CONCLUSIONS: During the first 12 months, typically developing infants exhibit advances in speech segmentation, word learning, syntax acquisition, and communication, both verbal and nonverbal. Infants and their caregivers coconstruct a communication foundation during this time, supporting continued language growth. The language outcomes of hearing children are robustly predicted by their experiences and acquired competencies during the first year; yet these predictive links are absent among prelingually deaf infants lacking a language model (i.e., those without exposure to sign). For deaf infants who receive a CI, implantation timing is crucial. Children receiving CIs before 12 months frequently catch up with their typically developing peers, whereas those receiving CIs later do not. Explanations for the language difficulties of late implanted children are discussed. PMID- 26756158 TI - Method of Speech Stimulus Presentation Impacts Pediatric Speech Recognition: Monitored Live Voice Versus Recorded Speech. AB - OBJECTIVE: To characterize the potential differences in speech understanding performance on word and sentence tests assessed using live voice and recorded speech measures for pediatric cochlear implant (CI) recipients. STUDY DESIGN: This clinical study used a combination of retrospective and prospective study designs exploring within-subject performance for recorded versus monitored-live voice presentation methods on pediatric word and sentence measures. METHODS: Word and/or sentence recognition was obtained for 29 pediatric CI recipients using both recorded stimuli and monitored-live-voice (MLV) within a single-test session with a single experimenter for each session. The difference score was calculated for word and sentence measures allowing a comparison across conditions. SETTING: Ambulatory. PATIENTS: Pediatric patients aged 4 to 17 years. INTERVENTION(S): Cochlear implants. MAIN OUTCOME MEASURE(S): Speech recognition testing. RESULTS: There was a significant difference between recorded and MLV speech understanding with mean recorded word scores being 13-percentage points lower than those obtained via MLV. CONCLUSIONS: The results of this project suggest that the use of MLV for the assessment of speech perception in the pediatric Audiology clinic may overinflate children's performance and thereby runs the risk of failing to identify poorer or at-risk performance. PMID- 26756157 TI - Initial Results With Image-guided Cochlear Implant Programming in Children. AB - HYPOTHESIS: Image-guided cochlear implant (CI) programming can improve hearing outcomes for pediatric CI recipients. BACKGROUND: CIs have been highly successful for children with severe-to-profound hearing loss, offering potential for mainstreamed education and auditory-oral communication. Despite this, a significant number of recipients still experience poor speech understanding, language delay, and, even among the best performers, restoration to normal auditory fidelity is rare. Although significant research efforts have been devoted to improving stimulation strategies, few developments have led to significant hearing improvement over the past two decades. Recently introduced techniques for image-guided CI programming (IGCIP) permit creating patient customized CI programs by making it possible, for the first time, to estimate the position of implanted CI electrodes relative to the nerves they stimulate using CT images. This approach permits identification of electrodes with high levels of stimulation overlap and to deactivate them from a patient's map. Previous studies have shown that IGCIP can significantly improve hearing outcomes for adults with CIs. METHODS: The IGCIP technique was tested for 21 ears of 18 pediatric CI recipients. Participants had long-term experience with their CI (5 mo to 13 yr) and ranged in age from 5 to 17 years old. Speech understanding was assessed after approximately 4 weeks of experience with the IGCIP map. RESULTS: Using a two tailed Wilcoxon signed-rank test, statistically significant improvement (p < 0.05) was observed for word and sentence recognition in quiet and noise, as well as pediatric self-reported quality-of-life (QOL) measures. CONCLUSION: Our results indicate that image guidance significantly improves hearing and QOL outcomes for pediatric CI recipients. PMID- 26756160 TI - Long-term Communication Outcomes for Children Receiving Cochlear Implants Younger Than 12 Months: A Multicenter Study. AB - OBJECTIVE: Examine the influence of age at implant on speech perception, language, and speech production outcomes in a large unselected paediatric cohort. STUDY DESIGN: This study pools available assessment data (collected prospectively and entered into respective databases from 1990 to 2014) from three Australian centers. PATIENTS: Children (n = 403) with congenital bilateral severe to profound hearing loss who received cochlear implants under 6 years of age (excluding those with acquired onset of profound hearing loss after 12 mo, those with progressive hearing loss and those with mild/moderate/severe additional cognitive delay/disability). MAIN OUTCOME MEASURE(S): Speech perception; open-set words (scored for words and phonemes correct) and sentence understanding at school entry and late primary school time points. Language; PLS and PPVT standard score equivalents at school entry, CELF standard scores. Speech Production; DEAP percentage accuracy of vowels, consonants, phonemes-total and clusters, and percentage word-intelligibility at school entry. RESULTS: Regression analysis indicated a significant effect for age-at-implant for all outcome measures. Cognitive skills also accounted for significant variance in all outcome measures except open-set phoneme scores. ANOVA with Tukey pairwise comparisons examined group differences for children implanted younger than 12 months (Group 1), between 13 and 18 months (Group 2), between 19 and 24 months (Group 3), between 25 and 42 months (Group 4), and between 43 and 72 months (Group 5). Open-set speech perception scores for Groups 1, 2, and 3 were significantly higher than Groups 4 and 5. Language standard scores for Group 1 were significantly higher than Groups 2, 3, 4, and 5. Speech production outcomes for Group 1 were significantly higher than scores obtained for Groups 2, 3, and 4 combined. Cross tabulation and chi2 tests supported the hypothesis that a greater percentage of Group 1 children (than Groups 2, 3, 4, or 5) demonstrated language performance within the normative range by school entry. CONCLUSIONS: Results support provision of cochlear implants younger than 12 months of age for children with severe to profound hearing loss to optimize speech perception and subsequent language acquisition and speech production accuracy. PMID- 26756161 TI - Bilateral Sequential Cochlear Implantation in Patients With Enlarged Vestibular Aqueduct (EVA) Syndrome. AB - OBJECTIVES: To analyze audiometric outcomes after bilateral cochlear implantation in patients with isolated enlarged vestibular aqueduct (EVA) syndrome and associated incomplete partition (IP) malformations. Secondary objective was to analyze rate of cerebrospinal fluid (CSF) gusher in patients with IP-EVA spectrum deformities and compare this with the existing literature. STUDY DESIGN: Retrospective chart review. METHODS: Thirty-two patients with EVA syndrome who received unilateral or bilateral cochlear implants between June 1999 and January 2014 were identified in the University Hospitals Case Medical Center cochlear implant database. Isolated EVA (IEVA) and Incomplete Partition Type II (IP-II) malformations were identified by reviewing high-resolution computed tomography (HRCT) imaging. Demographic information, age at implantation, surgical details, postimplantation audiometric data including speech reception thresholds (SRT), word, and sentence scores were reviewed and analyzed. Intra- and postoperative complications were analyzed as well and compared with the literature. RESULTS: Seventeen patients (32 implanted ears) had pediatric cochlear implantation for EVA-associated hearing loss. Data from 16 controls (32 implanted ears) were used to compare audiometric and speech outcomes of EVA cohort. Mean age at implantation was 6.8 years for EVA cohort and 6.0 years for controls. There was no statistically significant difference in long-term postoperative SRT, monaurally aided word scores, and binaurally tested word scores between pediatric EVA group and controls. The EVA patients had a long-term mean sentence score of 85.92%. A subset of EVA patients implanted at mean age of 3.18 years (n = 15 ears) had similar audiometric outcomes to another control group with Connexin 26 mutations (n = 20 ears) implanted at a similar age. Further subset analysis revealed no significant differences in age at implantation, SRT, and word scores in patients with IEVA and IP-II malformation. There was no significant association between size of vestibular aqueduct and age at implantation. There was no CSF gusher or other intra- or postoperative complications reported in our series. CONCLUSION: Bilateral sequential cochlear implantation can be performed safely in patients with EVA. Audiometric outcomes are excellent and comparable to pediatric cochlear implant patients with no malformations. CSF gusher rates can be minimized by trans-round window approach. Further long-term studies are needed to identify differences within IP-EVA spectrum deformities, audiometric outcomes, and proportions of EVA patients who will need cochlear implantation for hearing rehabilitation. PMID- 26756159 TI - Sentence Recognition in Quiet and Noise by Pediatric Cochlear Implant Users: Relationships to Spoken Language. AB - OBJECTIVE: We investigated associations between sentence recognition and spoken language for children with cochlear implants (CI) enrolled in the Childhood Development after Cochlear Implantation (CDaCI) study. STUDY DESIGN: In a prospective longitudinal study, sentence recognition percent-correct scores and language standard scores were correlated at 48-, 60-, and 72-months post-CI activation. SETTING: Six tertiary CI centers in the United States. PATIENTS: Children with CIs participating in the CDaCI study. INTERVENTION (S): Cochlear implantation. MAIN OUTCOME MEASURE (S): Sentence recognition was assessed using the Hearing In Noise Test for Children (HINT-C) in quiet and at +10, +5, and 0 dB signal-to-noise ratio (S/N). Spoken language was assessed using the Clinical Assessment of Spoken Language (CASL) core composite and the antonyms, paragraph comprehension (syntax comprehension), syntax construction (expression), and pragmatic judgment tests. RESULTS: Positive linear relationships were found between CASL scores and HINT-C sentence scores when the sentences were delivered in quiet and at +10 and +5 dB S/N, but not at 0 dB S/N. At 48 months post-CI, sentence scores at +10 and +5 dB S/N were most strongly associated with CASL antonyms. At 60 and 72 months, sentence recognition in noise was most strongly associated with paragraph comprehension and syntax construction. CONCLUSIONS: Children with CIs learn spoken language in a variety of acoustic environments. Despite the observed inconsistent performance in different listening situations and noise-challenged environments, many children with CIs are able to build lexicons and learn the rules of grammar that enable recognition of sentences. PMID- 26756162 TI - Point-to-Plane Nonhomogeneous Electric-Field-Induced Simultaneous Formation of Giant Unilamellar Vesicles (GUVs) and Lipid Tubes. AB - It is well-known that homogeneous electric fields can be used to generate giant unilamellar vesicles (GUVs). Herein we report an interesting phenomenon of formation of GUVs and lipid tubes simultaneously using a nonhomogeneous electric field generated by point-to-plane electrodes. The underlying mechanism was analyzed using finite element analysis. The two forces play main roles, that is, the pulling force (F) to drag GUVs into lipid tubes induced by fluid flow, and the critical force (Fc) to prevent GUVs from deforming into lipid tubes induced by electric fields. In the center area underneath the needle electrode, the GUVs were found because F is less than Fc in that region, whereas in the edge area the lipid tubes were obtained because F is larger than Fc. The diffusion coefficient of lipid in the tubes was found to be 4.45 MUm(2) s(-1) using a fluorescence recovery after photobleaching (FRAP) technique. The method demonstrated here is superior to conventional GUV or lipid tube fabrication methods, and has great potential in cell mimic or hollow material fabrication using GUVs and tubes as templates. PMID- 26756163 TI - SPECIFIC MOOD SYMPTOMS CONFER RISK FOR SUBSEQUENT SUICIDAL IDEATION IN BIPOLAR DISORDER WITH AND WITHOUT SUICIDE ATTEMPT HISTORY: MULTI-WAVE DATA FROM STEP-BD. AB - BACKGROUND: Little is known about specific mood symptoms that may confer risk for suicidal ideation (SI) among patients with bipolar disorder (BD). We evaluated prospectively whether particular symptoms of depression and mania precede the onset or worsening of SI, among adults with or without a history of a suicide attempt. METHODS: We examined prospective data from a large (N = 2,741) cohort of patients participating in the Systematic Treatment Enhancement Program for BD (STEP-BD). We evaluated history of suicide attempts at baseline, and symptoms of depression and mania at baseline and follow-up visits. Hierarchical linear modeling tested whether specific mood symptoms predicted subsequent levels of SI, and whether the strength of the associations differed based on suicide attempt history, after accounting for the influence of other mood symptoms and current SI. RESULTS: Beyond overall current depression and mania symptom severity, baseline SI, and illness characteristics, several mood symptoms, including guilt, reduced self-esteem, psychomotor retardation and agitation, increases in appetite, and distractibility predicted more severe levels of subsequent SI. Problems with concentration, distraction, sleep loss and decreased need for sleep predicted subsequent SI more strongly among individuals with a suicide attempt history. CONCLUSIONS: Several specific mood symptoms may confer risk for the onset or worsening of SI among treatment-seeking patients with BD. Individuals with a previous suicide attempt may be at greater risk in part due to greater reactivity to certain mood symptoms in the form of SI. However, overall, effect sizes were small, suggesting the need to identify additional proximal predictors of SI. PMID- 26756165 TI - Antenna Biphenols: Development of Extended Wavelength Chiroptical Reporters. AB - Molecular hosts capable of chiroptical sensing of complexed guest molecules offer an attractive alternative to conventional methods for the analysis of the absolute configuration and enantiopurity. Sensors based on the Pfeiffer effect rely on complexation-driven asymmetric transformation of the first kind and can produce a chiroptical signal against an otherwise null background. To be most effective, the wavelength of the induced chiroptical sensor readout should be free and clear of interfering signals coming from the sample under investigation. In this study, we report the introduction of stereodynamic zinc complexes of antenna biphenols, a new class of sensors bearing antenna-like appendages that can extend the wavelength of the chiroptical signal while also improving enantioselective guest recognition. PMID- 26756166 TI - Depression in multiple sclerosis: effect of brain derived neurotrophic factor Val66Met polymorphism and disease perception. AB - BACKGROUND AND PURPOSE: Depression is common amongst subjects with multiple sclerosis (MS), and several investigations have explored different determinants of this condition, including physical disability, psychological and psychosocial factors. The brain derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with depression. The aim of this study was to analyze the influence of disease-related factors, BDNF Val66Met polymorphism and perception of disease on the severity of depression in MS. METHOD: In total, 136 MS patients (88 women) were recruited and genotyped for BDNF rs6265 polymorphism at nucleotide 196 (G/A) using 'high resolution melting'. Depressive symptoms were assessed by the Multiple Sclerosis Depression Rating Scale. Perception of health status was assessed using the SF-36 questionnaire. RESULTS: A multivariable linear regression model showed that the best predictors of depression were the SF 36 General health (beta = -0.209; P = 0.013), Mental health (beta = -0.410; P < 0.001) and Social activity (beta = -0.195; P = 0.035) scores; physical disability (assessed by the Extended Disability Status Scale score) was directly correlated to depression severity on univariate analysis, but it was not a relevant predictor of depression on multivariate analysis; other variables directly related to the disease (treatment, annual relapsing rate) and the BDNF Val66Met polymorphism were not significantly associated with depression. CONCLUSION: Perception of the health status is the principal predictor of depressive symptoms in our sample. This result supports the hypothesis that the subjective interpretation of the disease's consequences is one of the main factors in determining depression in MS. PMID- 26756164 TI - USP2-45 Is a Circadian Clock Output Effector Regulating Calcium Absorption at the Post-Translational Level. AB - The mammalian circadian clock influences most aspects of physiology and behavior through the transcriptional control of a wide variety of genes, mostly in a tissue-specific manner. About 20 clock-controlled genes (CCGs) oscillate in virtually all mammalian tissues and are generally considered as core clock components. One of them is Ubiquitin-Specific Protease 2 (Usp2), whose status remains controversial, as it may be a cogwheel regulating the stability or activity of core cogwheels or an output effector. We report here that Usp2 is a clock output effector related to bodily Ca2+ homeostasis, a feature that is conserved across evolution. Drosophila with a whole-body knockdown of the orthologue of Usp2, CG14619 (dUsp2-kd), predominantly die during pupation but are rescued by dietary Ca2+ supplementation. Usp2-KO mice show hyperabsorption of dietary Ca2+ in small intestine, likely due to strong overexpression of the membrane scaffold protein NHERF4, a regulator of the Ca2+ channel TRPV6 mediating dietary Ca2+ uptake. In this tissue, USP2-45 is found in membrane fractions and negatively regulates NHERF4 protein abundance in a rhythmic manner at the protein level. In clock mutant animals (Cry1/Cry2-dKO), rhythmic USP2-45 expression is lost, as well as the one of NHERF4, confirming the inverse relationship between USP2-45 and NHERF4 protein levels. Finally, USP2-45 interacts in vitro with NHERF4 and endogenous Clathrin Heavy Chain. Taken together these data prompt us to define USP2-45 as the first clock output effector acting at the post translational level at cell membranes and possibly regulating membrane permeability of Ca2+. PMID- 26756168 TI - Free-Standing Membranes to Study the Optical Properties of Anodic TiO2 Nanotube Layers. AB - In the present work we investigate various optical properties (such as light absorption and reflectance) of anodic TiO2 nanotube layers directly transferred as self-standing membranes onto quartz substrates. This allows investigation in a transmission geometry which provides significantly more reliable data than measurements on the metallic Ti substrate. Light transmission and reflectance measurements were carried out for layers of thickness varying from 1.8 to 50 MUm, and the layers were investigated in their amorphous and crystalline forms. A series of wavelength-dependent light attenuation coefficients are extrapolated and found to match the photocurrent versus irradiation wavelength behavior. A feature specific to anodic nanotubes is that their intrinsic carbon contamination content causes a proportional sub-bandgap response. Overall, the extracted data provide a valuable basis and understanding for the design of photo electrochemical devices based on TiO2 nanotubes. PMID- 26756167 TI - Subjective cognitive impairment of older adults: a comparison between the US and China. AB - Subjective assessment may be incomparable across countries due to differences in reporting styles. Based on two nationally representative surveys from the US and China, this study used data from three anchoring vignettes to estimate to what extent the US and Chinese older adults aged 50 and above differed in their reporting styles of subjective cognitive impairment. Cross country differences of subjective cognitive impairment were then estimated, both before and after adjusting for reporting heterogeneity. Directly assessed word recall test scores were analyzed to evaluate whether findings based on subjective cognitive impairment was consistent with objective performance. The results revealed a discrepancy between self-reported subjective cognitive impairment and directly assessed memory function among older adults: while Chinese respondents reported lower severity levels of subjective cognitive impairment, the US respondents demonstrated better performance in immediate word recall tests. By accounting for differences in reporting styles using anchoring vignettes data, Chinese older adults showed higher levels of subjective cognitive impairment than the US older adults, which was consistent with results from direct assessment of memory function. Non-negligible differences are present in reporting styles of subjective cognitive impairment. Cross country comparison needs to take into account such reporting heterogeneity. PMID- 26756169 TI - Three Month Follow-Up of Rat Mild Traumatic Brain Injury: A Combined [18F]FDG and [11C]PK11195 Positron Emission Study. AB - Mild traumatic brain injury (mTBI) is the most common cause of head trauma. The time course of functional pathology is not well defined, however. The purpose of this study was to evaluate the consequences of mTBI in rats over a period of 3 months by determining the presence of neuroinflammation ([11C]PK11195) and changes in brain metabolism ([18F]FDG) with positron emission tomography (PET) imaging. Male Sprague-Dawley rats were divided in mTBI (n = 8) and sham (n = 8) groups. In vivo PET imaging and behavioral tests (open field, object recognition, and Y-maze) were performed at different time points after induction of the trauma. Differences between groups in PET images were explored using volume-of interest and voxel-based analysis. mTBI did not result in death, skull fracture, or suppression of reflexes. Weight gain was reduced (p = 0.003) in the mTBI group compared with the sham-treated group. No statistical differences were found in the behavioral tests at any time point. Volume-of-interest analysis showed neuroinflammation limited to the subacute phase (day 12) involving amygdala, globus pallidus, hypothalamus, pons, septum, striatum, and thalamus (p < 0.03, d > 1.2). Alterations in glucose metabolism were detected over the 3 month period, with increased uptake in the medulla (p < 0.04, d >= 1.2), and decreased uptake in the globus pallidus, striatum, and thalamus (p < 0.04, d <= 1.2). Similar findings were observed in the voxel-based analysis (p < 0.05 at corrected cluster level). As a consequence of the mTBI, and in the absence of apparent behavioral alterations, relative brain glucose metabolism was found altered in several brain regions, which mostly correspond with those presenting neuroinflammation in the subacute stage. PMID- 26756171 TI - Patient factors associated with onabotulinum toxin A treatment outcome in women with detrusor overactivity. AB - OBJECTIVE: To evaluate potential predictors of non-response to treatment with 200U onabotulinum toxin A (onaBoNTA) in women with refractory detrusor overactivity (DO). SUBJECTS AND METHODS: A secondary analysis of a randomized trial of 200U onaBoNTA versus placebo in women with refractory DO analyzed baseline and 6 week follow-up data. Univariate and multivariate logistic regression were used to assess demographic factors and baseline clinical parameters on non-response to treatment defined as 20% or less improvement in urinary urgency and leakage episodes, 10% or less in voiding frequency, not achieving continence, and "no change" or worse on PGI-I score at 6 weeks. RESULTS: One Hundred and twenty-two women were included. Twenty-nine (23.8%), 24 (19.7%), and 19 (15.6%) were non-responders to treatment for urgency, voiding, and leakage episodes, respectively. Fifty-nine (48.4%) failed to achieve continence, and 28 (23%) were non-responders on the PGI-I scale. Smoking status (OR: 2.89 95%CI 1.08, 7.73, P = 0.034) predicted non-response in urgency episodes, and higher baseline leakage episodes (OR: 1.17 95%CI 1.04, 1.31, P = 0.007) predicted non-response in achieving continence. Increasing age (OR 1.04, 95%CI 1.0, 1.09, P = 0.063) and body mass index (BMI) (OR 1.07, 95%CI 1.0, 1.16, P = 0.065) showed marginal associations with non-response on the PGI-I scale. CONCLUSION: onaBoNTA is an effective treatment for refractory DO, but some fail to respond. For identification of women at risk, our data indicate smokers should be advised of a lesser chance of successful treatment. Older women, those with high BMI and with more severe leakage also have a higher risk of failure. Neurourol. Urodynam. 36:426-431, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26756170 TI - The Outlier in All of Us: Why Implementing Pharmacogenomics Could Matter for Everyone. AB - The field of pharmacogenomics originally emerged in the 1950s from observations that a few rare individuals had unexpected, severe reactions to drugs. As recently as just 6 years ago, prominent views on the subject had largely remained unchanged, with authors from the US Food and Drug Administration (FDA) citing the purpose of pharmacogenetics as "tailoring treatment for the outliers." It should not be surprising if this is the prevailing view--the best-studied pharmacogenomic drug examples are indeed just that, genetic explanations of extreme responses or susceptibilities among usually a very small fraction of the human population. Thiopurine methyltransferase (TPMT) deficiency as a cause of severe myelosuppression upon treatment with azathioprine or mercaptopurine is found as a heterozygous trait in only ~ 10% of patients, and homozygous (deficiency) carriers are even more rare--occurring in fewer than 1 in 300 patients. Malignant hyperthermia resulting from inhaled anesthetics and succinylcholine is believed to have a genetic incidence of only about 1 in 2000 people. PMID- 26756173 TI - Low-level awareness accompanies "unconscious" high-level processing during continuous flash suppression. AB - The scope and limits of unconscious processing are a matter of ongoing debate. Lately, continuous flash suppression (CFS), a technique for suppressing visual stimuli, has been widely used to demonstrate surprisingly high-level processing of invisible stimuli. Yet, recent studies showed that CFS might actually allow low-level features of the stimulus to escape suppression and be consciously perceived. The influence of such low-level awareness on high-level processing might easily go unnoticed, as studies usually only probe the visibility of the feature of interest, and not that of lower-level features. For instance, face identity is held to be processed unconsciously since subjects who fail to judge the identity of suppressed faces still show identity priming effects. Here we challenge these results, showing that such high-level priming effects are indeed induced by faces whose identity is invisible, but critically, only when a lower level feature, such as color or location, is visible. No evidence for identity processing was found when subjects had no conscious access to any feature of the suppressed face. These results suggest that high-level processing of an image might be enabled by-or co-occur with-conscious access to some of its low-level features, even when these features are not relevant to the processed dimension. Accordingly, they call for further investigation of lower-level awareness during CFS, and reevaluation of other unconscious high-level processing findings. PMID- 26756172 TI - Identifying separate components of surround suppression. AB - Surround suppression is a well-known phenomenon in which the response to a visual stimulus is diminished by the presence of neighboring stimuli. This effect is observed in neural responses in areas such as primary visual cortex, and also manifests in visual contrast perception. Studies in animal models have identified at least two separate mechanisms that may contribute to surround suppression: one that is monocular and resistant to contrast adaptation, and another that is binocular and strongly diminished by adaptation. The current study was designed to investigate whether these two mechanisms exist in humans and if they can be identified psychophysically using eye-of-origin and contrast adaptation manipulations. In addition, we examined the prediction that the monocular suppression component is broadly tuned for orientation, while suppression between eyes is narrowly tuned. Our results confirmed that when center and surrounding stimuli were presented dichoptically (in opposite eyes), suppression was orientation-tuned. Following adaptation in the surrounding region, no dichoptic suppression was observed, and monoptic suppression no longer showed orientation selectivity. These results are consistent with a model of surround suppression that depends on both low-level and higher level components. This work provides a method to assess the separate contributions of these components during spatial context processing in human vision. PMID- 26756175 TI - Motion and texture shape cues modulate perceived material properties. AB - Specular and matte surfaces can project identical images if the surface geometry and light field are appropriately configured. Our previous work has shown that the visual system can exploit stereopsis and contour cues to 3D shape to disambiguate different surface reflectance interpretations. Here, we test whether material perception depends on information about surface geometry provided by structure from motion and shape from texture. Different surface textures were superimposed on a fixed pattern of luminance gradients to generate two different 3D shape interpretations. Each shape interpretation of the luminance gradients promoted a different experience of surface reflectance and illumination direction, which varied from a specular surface in frontal illumination to a comparatively matte surface in grazing illumination. The shape that appeared most specular exhibited the steepest derivatives of luminance with respect to surface orientation, consistent with physical differences between specular and diffuse reflectance. The effect of apparent shape on perceived reflectance occurred for a variety of surface textures that provided either structure from motion, shape from texture, or both optical sources of shape information. In conjunction with previous findings (Marlow, Todorovic, & Anderson, 2015; Marlow & Anderson, 2015), these results suggest that any cue that provides sufficient information about 3D shape can also be used to derive material properties from the rate that luminance varies as a function of surface curvature. PMID- 26756174 TI - Perceived azimuth direction is exaggerated: Converging evidence from explicit and implicit measures. AB - Recent observations suggest that perceived visual direction in the sagittal plane (angular direction in elevation, both upward and downward from eye level) is exaggerated. Foley, Ribeiro-Filho, and Da Silva's (2004) study of perceived size of exocentric ground extent implies that perceived angular direction in azimuth may also be exaggerated. In the present study, we directly examined whether perceived azimuth direction is overestimated. In Experiment 1, numeric estimates of azimuth direction (-48 degrees to 48 degrees relative to straight ahead) were obtained. The results showed a linear exaggeration in perceived azimuth direction with a gain of about 1.26. In Experiment 2, a perceptual extent matching task served as an implicit measure of perceived azimuth direction. Participants matched an egocentric distance in one direction to a frontal extent in nearly the opposite direction. The angular biases implied by the matching data well replicated Foley et al.'s finding and were also fairly consistent with the azimuth bias function found in Experiment 1, although a slight overall shift was observed between the results of the two experiments. Experiment 3, in which half the observers were tilted sideways while making frontal/depth extent comparisons, suggested that the discrepancy between the results of Experiment 1 and 2 can partially be explained by a retinal horizontal vertical illusion affecting distance estimation tasks. Overall the present study provides converging evidence to suggest that the perception of azimuth direction is overestimated. PMID- 26756177 TI - Working memory delay period activity marks a domain-unspecific attention mechanism. AB - Working memory (WM) recruits neural circuits that also perform perception- and action-related functions. Among the functions that are shared between the domains of WM and perception is selective attention, which supports the maintenance of task-relevant information during the retention delay of WM tasks. The tactile contralateral delay activity (tCDA) component of the event-related potential (ERP) marks the attention-based rehearsal of tactile information in somatosensory brain regions. We tested whether the tCDA reflects the competition for shared attention resources between a WM task and a perceptual task under dual-task conditions. The two tasks were always performed on opposite hands. In different blocks, the WM task had higher or lower priority than the perceptual task. The tCDA's polarity consistently reflected the hand where the currently prioritized task was performed. This suggests that the process indexed by the tCDA is not specific to the domain of WM, but mediated by a domain-unspecific attention mechanism. The analysis of transient ERP components evoked by stimuli in the two tasks further supports the interpretation that the tCDA marks a goal-directed bias in the allocation of selective attention. Larger spatially selective modulations were obtained for stimulus material related to the high-, as compared to low-priority, task. While our results generally indicate functional overlap between the domains of WM and perception, we also found evidence suggesting that selection in internal (mnemonic) and external (perceptual) stimulus representations involves processes that are not active during shifts of preparatory attention. PMID- 26756176 TI - CC chemokine ligand 18(CCL18) promotes migration and invasion of lung cancer cells by binding to Nir1 through Nir1-ELMO1/DOC180 signaling pathway. AB - Non-small cell lung cancer (NSCLC) comprises nearly 80% of lung cancers and the poor prognosis is due to its high invasiveness and metastasis. CC chemokine ligand 18 (CCL18) is predominantly secreted by M2-tumor associated macrophages (TAMs) and promotes malignant behaviors of various human cancer types. In this study, we report that the high expression of CCL18 in TAMs of NSCLC tissues and increased expression of CCL18 in TAMs is correlated with the lymph node metastasis, distant metastasis, and poor prognosis NSCLC patients. CCL18 can increase the invasive ability of NSCLC cells by binding to its receptor Nir1. In addition, CCL18 is capable of modulating cell migration and invasion by regulating the activation of RAC1 which resulted in cytoskeleton reorganization in an ELMO1 dependent manner. Furthermore, we found that CCL18 could enhance adhesion of NSCLC cells via activating ELMO1-integrin beta1 signaling. Thus, CCL18 and its downstream molecules may be used as targets to develop novel NSCLC therapy. (c) 2016 Wiley Periodicals, Inc. PMID- 26756178 TI - Effects of Water on Tribochemical Wear of Silicon Oxide Interface: Molecular Dynamics (MD) Study with Reactive Force Field (ReaxFF). AB - Molecular dynamics (MD) simulations with the ReaxFF reactive force field were carried out to find the atomistic mechanisms for tribochemical reactions occurring at the sliding interface of fully hydroxylated amorphous silica and oxidized silicon as a function of interfacial water amount. The ReaxFF-MD simulations showed a significant amount of atom transfers across the interface occurs during the sliding. In the absence of water molecules, the interfacial mixing is initiated by dehydroxylation followed by the Si-O-Si bond formation bridging two solid surfaces. In the presence of submonolayer thick water, the dissociation of water molecules can provide additions reaction pathways to form the Si-O-Si bridge bonds and atom transfers across the interface. However, when the amount of interfacial water molecules is large enough to form a full monolayer, the degree of atom transfer is substantially reduced since the silicon atoms at the sliding interface are terminated with hydroxyl groups rather than forming interfacial Si-O-Si bridge bonds. The ReaxFF-MD simulations clearly showed the role of water molecules in atomic scale mechanochemical processes during the sliding and provided physical insights into tribochemical wear processes of silicon oxide surfaces observed experimentally. PMID- 26756179 TI - Serum haptoglobin as a novel molecular biomarker predicting colorectal cancer hepatic metastasis. AB - Early detection of liver metastasis is important for improving colorectal cancer (CRC) patient survival. Our previous studies showed haptoglobin was highly expressed in primary CRC tissues, especially in heterochronous metastatic cases. Here, we assessed the potential of serum haptoglobin (sHP) as a biomarker for early detection of CRC liver metastasis by evaluating the sHP in 475 CRC patients and 152 healthy volunteers. In the training set (250 cases), sHP level in CRC-M1 (1773.18 +/- 690.25 ng/mL) were significantly increased as compared to in CRC-M0 (1544.37 +/- 1497.65 ng/mL) or healthy (917.76 +/- 571.59 ng/mL). And the high sHP level was correlated with poor survival. Logistic regression analysis revealed that sHP, serum carcinoembryonic antigen (sCEA) and serum carbohydrate antigen 19.9 (sCA19.9) level were the significant parameters for detecting liver metastasis. In leave-one-out-cross-validation, these three markers resulted in 89.1% sensitivity and 85.8% specificity for hepatic metastasis detection. In an independent test set (225 cases), receiver operating characteristic curve analysis of sHP in CRC liver metastasis showed an area under the curve of 0.735, with a sensitivity of 87.2% and a specificity of 59.9%. Combination of sHP, sCEA and sCA19.9 improved diagnostic accuracy to 0.880, with a sensitivity of 88.5% and a specificity of 87.8%. Silencing of HP by specific shRNA significantly inhibited the LOVO and SW620 cell invasion, and suppressed xenograft tumor invasive growth. In summary, these results demonstrate that sHP is associated with poor prognosis of CRC patients and that HP promotes colorectal cancer cell invasion. sHP combining with sCA19.9 and sCEA may be used as accurate predictors of CRC liver metastasis. PMID- 26756182 TI - Enantioselective Total Syntheses of Kuwanon X, Kuwanon Y, and Kuwanol A. AB - The first enantioselective total syntheses of (-)-kuwanon X, (+)-kuwanon Y, and (+)-kuwanol A have been accomplished by using asymmetric Diels-Alder cycloaddition promoted by chiral VANOL or VAPOL/boron Lewis acid. The biosynthesis-inspired asymmetric Diels-Alder cycloaddition shows high exo selectivity (exo/endo = 13/1), which was unprecedented in the previous total syntheses of related prenylflavonoid Diels-Alder natural products. An acid catalyzed intramolecular ketalization process enabled a biomimetic transformation to construct the polycyclic skeleton of kuwanol A efficiently. PMID- 26756181 TI - Impact of deprivation on breast cancer survival among women eligible for mammographic screening in the West Midlands (UK) and New South Wales (Australia): Women diagnosed 1997-2006. AB - Women diagnosed with breast cancer in the UK display marked differences in survival between categories defined by socio-economic deprivation. Timeliness of diagnosis is one of the possible explanations for these patterns. Women whose cancer is screen-detected are more likely to be diagnosed at an earlier stage. We examined deprivation and screening-specific survival in order to evaluate the role of early diagnosis upon deprivation-specific survival differences in the West Midlands (UK) and New South Wales (Australia). We estimated net survival for women aged 50-65 years at diagnosis and whom had been continuously eligible for screening from the age of 50. Records for 5,628 women in West Midlands (98.5% of those eligible, mean age at diagnosis 53.7 years) and 6,396 women in New South Wales (99.9% of those eligible, mean age at diagnosis 53.8 years). In New South Wales, survival was similar amongst affluent and deprived women, regardless of whether their cancer was screen-detected or not. In the West Midlands, there were large and persistent differences in survival between affluent and deprived women. Deprivation differences were similar between the screen-detected and non-screen detected groups. These differences are unlikely to be solely explained by artefact, or by patient or tumour factors. Further investigations into the timeliness and appropriateness of the treatments received by women with breast cancer across the social spectrum in the UK are warranted. PMID- 26756183 TI - Professor Shu-Ting Chang on His 85th Birthday. PMID- 26756184 TI - Current Advances in the Antimicrobial Potential of Species of Genus Ganoderma (Higher Basidiomycetes) against Human Pathogenic Microorganisms (Review). AB - Ganoderma spp. are very important therapeutic mushrooms and have been used traditionally for 4000 years in the treatment of various human disorders. Different species of Ganoderma possess bioactive compounds, which have already demonstrated antiviral, antibacterial, and antifungal activities. Various bioactive compounds such as triterpenoids, colossolactones, and polysaccharides, which are responsible for the antimicrobial potential of the genus, are discussed here in detail. Some Ganoderma spp. have been reported to be potential agents for the synthesis of metal nanoparticles. These nanoparticles have demonstrated antimicrobial activity and also are reviewed herein. The main aim of this review is to discuss the possible use of Ganoderma extracts and their active principles in antimicrobial therapy. PMID- 26756185 TI - Antioxidant Capacity and Total Phenolics Content of the Fruiting Bodies and Submerged Cultured Mycelia of Sixteen Higher Basidiomycetes Mushrooms from India. AB - The fruiting bodies and the submerged cultured mycelia of 16 higher Basidiomycetes mushrooms- Agaricus bisporus, Armillaria mellea, Auricularia auricula-judae, Ganoderma applanatum, G. lucidum, Laetiporus sulphureus, Lentinus tigrinus, Lycoperdon pyriforme, Phellinus linteus, Pleurotus ostreatus, P. sajor caju, Polyporus arcularius, Russula brevipes, Schizophyllum commune, Sparassis crispa, and Spongipellis unicolor-from different taxonomic groups were examined for their antioxidant capacity (AOXC) and total phenolics content (TPC). Extraction of the freeze-dried and pulverized fruiting bodies and mycelia with methanol and water (8:2, v/v), followed by evaporation of the solvent under a vacuum, created their extracts, which were analyzed for their AOXC and TPC using a DPPH. scavenging assay and the Folin-Ciocalteu method, respectively. The fruiting bodies and the culture mycelia of all the mushroom species exhibited varied antioxidant capacity; however, the fruiting bodies had more potent DPPH. scavenging than the corresponding mycelia irrespective of the mushroom species, as evident by the effective concentrations of extract that scavenges 50% of DPPH. (EC50) of the former (0.56-1.24 mg mL-1) being lower than those of the latter (2.51-8.39 mg mL-1). TPC in the fruiting bodies (6.08-24.85 mg gallic acid equivalent [GAE] g-1) were higher than those in the mycelia (4.17-13.34 mg GAE g 1). AOXC of the fruiting bodies (r = -0.755) and the culture mycelia (r = -0.903) also was correlated to their TPC. Among the cultured mycelia, A. bisporus, A. mellea, L. tigrinus, P. ostreatus, and S. crispa were highly promising in terms of their highest TPC (10.55, 13.34, 11.00, 10.37, and 10.19 mg GAE g-1, respectively) and the lowest EC50 values (3.33, 2.85, 2.51, 3.65, and 3.17 mg mL 1, respectively) as they relate to the development of antioxidants. PMID- 26756186 TI - Antioxidant Effects of Medicinal Mushrooms Agaricus brasiliensis and Ganoderma lucidum (Higher Basidiomycetes): Evidence from Animal Studies. AB - With diabetes mellitus and increased glucose concentrations, the mitochondria electron transport chain is disrupted, superoxide anions are overproduced, and oxidative stress develops in cells. Thus, preventing oxidative stress can produce a decrease in the antioxidant system activity and an increase in apoptosis in immune cells. The application of medicinal mushrooms is a new possible approach to diabetes mellitus treatment. Therefore, the aim of this work was to investigate the influence of administration of the medicinal mushrooms Agaricus brasiliensis and Ganoderma lucidum on antioxidant enzyme activity in rat leukocytes. Wistar outbred white rats were used in the study. Streptozotocin was intraperitoneally injected once at a dose of 50 mg/kg body weight. Mushroom preparations were orally administered at a dose of 1 g/kg/day for 2 weeks. This revealed that in diabetes mellitus, the level of antioxidant enzyme activity is significantly decreased compared with control values, whereas the levels of lipid peroxidation is increased; this manifested in an increase in the amount of thiobarbituric acid reactive substances (TBARS). The medicinal mushrooms' administration is accompanied by an increase in antioxidant enzyme activity to control values and is even higher in the case of A. brasiliensis administration when compared with the diabetic group. As for the indicators of lipid peroxidation under mushroom administration of A. brasiliensis and G. lucidum, we observed a significant decrease of TBARS levels compared with the diabetic group. Increased activity of antioxidant enzymes and reduction of TBARS level indicate pronounced antioxidant properties of studied mushrooms. PMID- 26756187 TI - Hypoglycemic Activity of Polysaccharide from Fruiting Bodies of the Shaggy Ink Cap Medicinal Mushroom, Coprinus comatus (Higher Basidiomycetes), on Mice Induced by Alloxan and Its Potential Mechanism. AB - Three polysaccharide fractions from fruiting bodies of Coprinus comatus-CC30, CC60, and CC80-are obtained by water extraction and ethanol precipitation with ethanol percentages of 30%, 60%, and 80%, respectively. The hypoglycemic activity of the three fractions was tested based on mice with alloxan-induced diabetes. Results indicate that fraction CC60 is the most effective fraction in water extract from C. comatus; it can remarkably reduce the blood glucose concentration in 120 min at a dosage of 1000 mg/kg administered orally. It also presents a long term hypoglycemic effect during 21 days of injection at the same dosage. This polysaccharide fraction provide a novel path to improve the treatment currently used for patients with diabetes. The data on mice spleen lymphocyte proliferation and protein tyrosine phosphatase 1B (PTP1B)-inhibiting activity of fractions indicate that the hypoglycemic activity of CC60 is possibly activated through immune stimulation, not PTP1B inhibition. PMID- 26756188 TI - Hypocholesterolemic Effects of the Cauliflower Culinary-Medicinal Mushroom, Sparassis crispa (Higher Basidiomycetes), in Diet-Induced Hypercholesterolemic Rats. AB - The cauliflower culinary-medicinal mushroom, Sparassis crispa, possesses various biological activities that have been widely reported to have therapeutic applications. We examined the effects of S. crispa on serum cholesterol, hepatic enzymes related to cholesterol metabolism, and fecal sterol excretion in rats fed a cholesterol-rich diet for 4 weeks. Male Sprague-Dawley rats (8 weeks old) were randomly divided into 5 groups (n = 6 mice per group): normal diet (normal control [NC]), cholesterol-rich diet (cholesterol control [CC]), cholesterol-rich diet plus S. crispa fruiting body (SC), cholesterol-rich diet plus S. crispa extract (SCE), and cholesterol-rich diet plus S. crispa residue (SCR). SCE supplementation significantly enhanced hepatic cholesterol catabolism through the upregulation of cholesterol 7alpha-hydroxylase (CYP7A1) messenger RNA (mRNA) expression (2.55-fold compared with that in the NC group; P < 0.05) and the downregulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mRNA expression (0.57-fold compared with that in the NC group; P < 0.05). Additionally, the SCE diet resulted in the highest fecal excretion of cholesterol and bile acid in hypercholesterolemic rats. In conclusion, mRNA expression of CYP7A1 and HMG-CoA reductase were significantly modulated by the absorption of SCE samples. Also, SCE samples had a significant effect on fecal bile acid and cholesterol excretion. These results suggest that SCE samples can induce hypocholesterolic effects through cholesterol metabolism and the reduction of circulating cholesterol levels. PMID- 26756189 TI - Statistical Optimization of the Content Composition Precursors Using Response Surface Methodology to Enhance Agaricoglyceride A Production from the Shaggy Ink Cap Medicinal Mushroom, Coprinus comatus (Higher Basidiomycetes) Mycelia. AB - Coprinus comatus, a novel cultivated edible mushroom, has a various of pharmacological effects due to its many active components. In this study, agaricoglycerides, a new class of fungal secondary metabolites that have strong activity against neurolysin, were isolated from C. comatus mycelia. Simultaneously, a 3-level Box-Behnken factorial design was used, combined with response surface methodology, to optimize the precursor composition of agaricoglycerides for the production of agaricoglyceride A. The model estimated that a maximal yield of agaricoglyceride A (20.105 mg/L) could be obtained when the concentrations of 4-hydroxybenzoic acid, glycerol, and methanol (MeOH) were set at 75 mg/L, 0.75 mL/L, and 0.75 mL/L, respectively. The verified experiments showed that the model was significantly consistent with the model prediction. These results showed that appropriately adding the precursors could increase the production of agaricoglyceride A. PMID- 26756190 TI - Complex Enzyme-Assisted Extraction, Purification, and Antioxidant Activity of Polysaccharides from the Button Mushroom, Agaricus bisporus (Higher Basidiomycetes). AB - Agaricus bisporus polysaccharides (ABP) were extracted by complex enzyme-assisted extraction methodology. The following were optimal conditions for the extraction of crude ABP: complex enzyme amount, 2.2%; temperature, 62 degrees C; time, 3 h; and pH, 4. Under these conditions, the experimental yield of crude ABP was 6.87%. The crude ABP was purified by diethylaminoethyl-cellulose 52 chromatography and Sephadex G-100 chromatography, and one fraction-namely, ABP-1-was produced. The ABP-1 contained 93.67% carbohydrate, 1.46% protein, and 0.62% uronic acid. The constituent monosaccharides were predominantly glucose, galactose, mannose, and xylose. The antioxidant activities of ABP-1 were investigated by measuring its scavenging ability on 2,2-diphenyl-1-picrylhydrazyl and hydroxyl radicals, its ferric-reducing activity power, and the reducing power assay. At a concentration of 1.2 mg/mL, ABP-1 seemed to possess good free radical scavenging activity, with a scavenging value of about 56%. The results indicate that ABP-1 has good antioxidant activity. PMID- 26756191 TI - Protective Effect of Ethanol Extracts of the Chinese Caterpillar Mushroom, Ophiocordyceps sinensis (Ascomycetes), on the Experimental Middle Cerebral Artery Occlusion/Reperfusion (MCAO/R) Model. AB - In this study, we investigated the effects of ethanol extracts of Ophiocordyceps sinensis (EEOS) on neuroprotective efficacy in a rat model of focal cerebral ischemia/reperfusion (IR). The effects of EEOS on mortality rate, neurobehavior, grip strength, polymorphonuclear (PMN) cells, interleukin (IL)-1beta, inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-alpha, intracellular adhesion molecule 1 (ICAM-1), and cyclooxygenase-2 (COX-2) were determined by enzyme-linked immunosorbent assay and immunohistochemistry. The cerebral infarction was examined through tetrazolium chloride staining. EEOS significantly inhibited IR-induced brain production of IL-1beta, TNF-alpha, iNOS, ICAM-1, and COX-2. Moreover, EEOS suppressed infiltration of PMN cells. EEOS caused a significant reduction in the infarct size compared with the middle cerebral artery occlusion group. The study demonstrates the neuroprotective potential of EEOS inhibition of IR through anti-inflammatory activity in a rat model of IR. PMID- 26756192 TI - Novel Bioactive Wild Medicinal Mushroom--Xylaria sp. R006 (Ascomycetes) against Multidrug Resistant Human Bacterial Pathogens and Human Cancer Cell Lines. AB - In the present study, the fruiting body extracts of Xylaria sp. strain R006 were obtained from hexane, ethyl acetate and methanol. Among them, the ethyl acetate extract exhibited significant antimicrobial activities against bacterial and fungal pathogens. Based on the effective antimicrobial activity, the crude ethyl acetate extract was fractionized by two-step siliga gel column chromatography. All the fractions were tested for antibacterial activity against drug resistant Staphylococcus aureus strains (1-10) and Pseudomonas aeruginosa strains (1-8). The fraction E showed a maximum inhibition zone of 27.9 mm against drug resistant S. aureus strain 3 and 29.4 mm against drug resistant P. aeruginosa strain 4. Minimal inhibitory concentration of fraction E showed potential result against all the drug resistant strains however, the lowest concentration of 75 ug/mL-1 was observed against S. aureus strains 1 and 6 and P. aeruginosa strain 3. Further, 60 ug/mL of fraction E had significant cytotoxic activity of 54.9, 55.1 and 54.9% against MDA-MB-231 (breast carcinoma cells), A-549 (lung carcinoma cells) and MCF-7 (breast carcinoma cells) human cancer cell lines, respectively. The spectral data revealed that the fraction E has chromophoric groups in it and had the C = O stretching, C-C = C asymmetric stretch, N-H stretch and C-O stretch as functional groups. The results indicate that the metabolites of fruiting bodies of Xylaria sp. R006 are the potential natural source for the development of new anticancer agents. PMID- 26756194 TI - Reply to: Validation of database search strategies for the epidemiological study of pemphigus and pemphigoid: reply from the authors. PMID- 26756193 TI - A Systematic Review of Self-Management Interventions for Inflammatory Bowel Disease. AB - PURPOSE: To conduct a systematic review of self-management interventions for adults with inflammatory bowel disease (IBD) to (a) describe self-management skills in the interventions and (b) describe the effects of the interventions on the health-related outcomes measured. DESIGN: Systematic review of self management interventions for adults with IBD using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. METHODS: The search was conducted using Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, and Proquest databases. Search terms were inflammatory bowel disease OR Crohn* disease OR ulcerative colitis AND self management. We also used additional limits (adults >= 18 years of age and published in English). The self-management skills were organized according to Lorig and Holman's five self-management skills. FINDINGS: Six reports met the inclusion criteria. One intervention contained all five of the self-management skills. Most interventions contained two skills. Four studies demonstrated positive effects of self-management on disease activity. Two interventions revealed positive effects on disease-specific health-related quality of life (HRQOL), and one intervention revealed positive effects on generic HRQOL. One study showed positive effects of symptoms. CONCLUSIONS: The interventions reviewed varied in the approaches, theoretical perspectives, self-management skills, and outcomes measured. Additional research is needed to understand which are the active components of self-management. CLINICAL RELEVANCE: Support for self-management skills is an important component of nursing care for people with IBD. PMID- 26756195 TI - Serglycin determines secretory granule repertoire and regulates natural killer cell and cytotoxic T lymphocyte cytotoxicity. AB - The anionic proteoglycan serglycin is a major constituent of secretory granules in cytotoxic T lymphocyte (CTL)/natural killer (NK) cells, and is proposed to promote the safe storage of the mostly cationic granule toxins, granzymes and perforin. Despite the extensive defects of mast cell function reported in serglycin gene-disrupted mice, no comprehensive study of physiologically relevant CTL/NK cell populations has been reported. We show that the cytotoxicity of serglycin-deficient CTL and NK cells is severely compromised but can be partly compensated in both cell types when they become activated. Reduced intracellular granzyme B levels were noted, particularly in CD27(+) CD11b(+) mature NK cells, whereas serglycin(-/-) TCR-transgenic (OTI) CD8 T cells also had reduced perforin stores. Culture supernatants from serglycin(-/-) OTI T cells and interleukin-2 activated NK contained increased granzyme B, linking reduced storage with heightened export. By contrast, granzyme A was not significantly reduced in cells lacking serglycin, indicating differentially regulated trafficking and/or storage for the two granzymes. A quantitative analysis of different granule classes by transmission electronmicroscopy showed a selective loss of dense-core granules in serglycin(-/-) CD8(+) CTLs, although other granule types were maintained quantitatively. The findings of the present study show that serglycin plays a critical role in the maturation of dense-core cytotoxic granules in cytotoxic lymphocytes and the trafficking and storage of perforin and granzyme B, whereas granzyme A is unaffected. The skewed retention of cytotoxic effector molecules markedly reduces CTL/NK cell cytotoxicity, although this is partly compensated for as a result of activating the cells by physiological means. PMID- 26756196 TI - Design of Effective Primary MicroRNA Mimics With Different Basal Stem Conformations. AB - Primary microRNA (pri-miRNA) mimics are important mediators of effective gene silencing and are well suited for sustained therapeutic applications. Pri-miRNA mimics are processed in the endogenous miRNA biogenesis pathway, where elements of the secondary RNA structure are crucial for efficient miRNA production. Cleavage of the pri-miRNA to a precursor miRNA (pre-miRNA) by Drosha-DGCR8 typically occurs adjacent to a basal stem of ~11 bp. However, a number of pri miRNA structures are expected to contain slightly shorter or longer basal stems, which may be further disrupted in predicted folding of the expressed pri-miRNA sequence. We investigated the function and processing of natural and exogenous RNA guides from pri-miRNAs with various basal stems (9-13 bp), where a canonical hairpin was predicted to be well or poorly maintained in predicted structures of the expressed sequence. We have shown that RNA guides can be effectively derived from pri-miRNAs with various basal stem conformations, while predicted guide region stability can explain the function of pri-miRNA mimics, in agreement with previously proposed design principles. This study provides insight for the design of effective mimics based on naturally occurring pri-miRNAs and has identified several novel scaffolds suitable for use in gene silencing applications. PMID- 26756198 TI - Peroxide Coordination of Tellurium in Aqueous Solutions. AB - Tellurium-peroxo complexes in aqueous solutions have never been reported. In this work, ammonium peroxotellurates (NH4 )4 Te2 (MU-OO)2 (MU-O)O4 (OH)2 (1) and (NH4 )5 Te2 (MU-OO)2 (MU-O)O5 (OH)?1.28 H2 O?0.72 H2 O2 (2) were isolated from 5 % hydrogen peroxide aqueous solutions of ammonium tellurate and characterized by single-crystal and powder X-ray diffraction analysis, by Raman spectroscopy and thermal analysis. The crystal structure of 1 comprises ammonium cations and a symmetric binuclear peroxotellurate anion [Te2 (MU-OO)2 (MU-O)O4 (OH)2 ](4-) . The structure of 2 consists of an unsymmetrical [Te2 (MU-OO)2 (MU-O)O5 (OH)](5-) anion, ammonium cations, hydrogen peroxide, and water. Peroxotellurate anions in both 1 and 2 contain a binuclear Te2 (MU-OO)2 (MU-O) fragment with one MU-oxo- and two MU-peroxo bridging groups. (125) Te NMR spectroscopic analysis shows that the peroxo bridged bitellurate anions are the dominant species in solution, with 3-40 %wt H2 O2 and for pH values above 9. DFT calculations of the peroxotellurate anion confirm its higher thermodynamic stability compared with those of the oxotellurate analogues. This is the first direct evidence for tellurium-peroxide coordination in any aqueous system and the first report of inorganic tellurium peroxo complexes. General features common to all reported p-block element peroxides could be discerned by the characterization of aqueous and crystalline peroxotellurates. PMID- 26756200 TI - Electroresponsive Structurally Colored Materials: A Combination of Structural and Electrochromic Effects. AB - Electroresponsive structurally colored materials composed of ordered arrays of polyaniline@poly(methyl methacrylate) (PANI@PMMA) core-shell nanoparticles have been successfully prepared. The core-shell nanoparticles were synthesized by deposition of PANI shells on the surfaces of the PMMA cores by the oxidative polymerization of anilinium chloride. Ordered arrays were then fabricated by using the fluidic cell method. Because the ordered arrays and the PANI shells generate structural and electrochromic colors, respectively, these core-shell colloidal crystals exhibited colors resulting from the combined effects of these materials. The crystal colors depended greatly on the size of PANI@PMMA particles and could also be varied by the application of a voltage. The electrochromic colors of these arrays were found to be quite different from those exhibited by pure PANI films prepared by electrochemical oxidation. PMID- 26756197 TI - Using hydrogen deuterium exchange mass spectrometry to engineer optimized constructs for crystallization of protein complexes: Case study of PI4KIIIbeta with Rab11. AB - The ability of proteins to bind and interact with protein partners plays fundamental roles in many cellular contexts. X-ray crystallography has been a powerful approach to understand protein-protein interactions; however, a challenge in the crystallization of proteins and their complexes is the presence of intrinsically disordered regions. In this article, we describe an application of hydrogen deuterium exchange mass spectrometry (HDX-MS) to identify dynamic regions within type III phosphatidylinositol 4 kinase beta (PI4KIIIbeta) in complex with the GTPase Rab11. This information was then used to design deletions that allowed for the production of diffraction quality crystals. Importantly, we also used HDX-MS to verify that the new construct was properly folded, consistent with it being catalytically and functionally active. Structures of PI4KIIIbeta in an Apo state and bound to the potent inhibitor BQR695 in complex with both GTPgammaS and GDP loaded Rab11 were determined. This hybrid HDX MS/crystallographic strategy revealed novel aspects of the PI4KIIIbeta-Rab11 complex, as well as the molecular mechanism of potency of a PI4K specific inhibitor (BQR695). This approach is widely applicable to protein-protein complexes, and is an excellent strategy to optimize constructs for high resolution structural approaches. PMID- 26756199 TI - Calnuc Function in Endosomal Sorting of Lysosomal Receptors. AB - Calnuc is a ubiquitous Ca(2+)-binding protein present on the trans-Golgi network (TGN) and endosomes. However, the precise role of Calnuc in these organelles is poorly characterized. We previously highlighted the role of Calnuc in the transport of LRP9, a new member of a low-density lipoprotein (LDL) receptor subfamily that cycles between the TGN and endosomes. The objective of this study was to explore the role of Calnuc in the endocytic sorting of mannose-6-phosphate receptor (MPR) and Sortilin, two well-characterized lysosomal receptors that transit between the TGN and endosomes. Using biochemical and microscopy assays, we showed that Calnuc depletion [by small interfering RNA (siRNA)] causes the misdelivery to and degradation in lysosomes of cationic-independent mannose-6 phosphate receptor (CI-MPR) and Sortilin due to a defect in the endosomal recruitment of retromers, which are key components of the endosome-to-Golgi retrieval machinery. Indeed, we demonstrated that Calnuc depletion impairs the activation and membrane association of Rab7, a small G protein required for the endosomal recruitment of retromers. Overall, our data indicate a novel role for Calnuc in the endosome-to-TGN retrograde transport of lysosomal receptors through the regulation of Rab7 activity and the recruitment of retromers to endosomes. PMID- 26756201 TI - Quality in epidemiological surveillance of contact allergy. AB - The reporting of scientific results (in the field of contact dermatitis/allergy) should include a description of the methods used, including, but not limited to, standardized patch testing. Several aspects always need to be reported, such as duration of exposure, reading times, vehicle, and concentration of allergens. However, concerning other aspects, explicit compliance with international patch testing guidelines, notably the European Society of Contact Dermatitis guideline, which covers all relevant general aspects, is deemed to be a sufficient description of methods, supplemented by study-specific information, including partial non-compliance with the guideline, as indicated. Besides technical aspects, the quality of reporting of scientific results has several other dimensions, including epidemiological and biostatistical aspects discussed in this article. Prospectively, when a study is planned, performed, and reported, issues such as selection of patients and sample size and their impact on power and precision, the role of misclassification and potential conflicts of interests need to be addressed and discussed, respectively. Retrospectively, when a study is read and analysed, all relevant aspects of quality should be considered when the weight of evidence that a study publication provides is evaluated. Employing rigid 'quality criteria' may have the detrimental effect of relevant, if slightly imperfect, evidence being deliberately excluded. PMID- 26756202 TI - Familial partial lipodystrophy linked to a novel peroxisome proliferator activator receptor -gamma (PPARG) mutation, H449L: a comparison of people with this mutation and those with classic codon 482 Lamin A/C (LMNA) mutations. AB - AIMS: To describe the phenotype associated with a novel heterozygous missense PPARG mutation discovered in a Turkish family and to compare the fat distribution and metabolic characteristics of subjects with the peroxisome proliferator activator receptor -gamma (PPARG) mutation with those of a cluster of patients with familial partial lipodystrophy with classic codon 482 Lamin A/C (LMNA) mutations. METHODS: The study involved four subjects with familial partial lipodystrophy who had a novel PPARG mutation (H449L) and six subjects with classic codon 482 LMNA mutations (R482W). RESULTS: Compared with subjects with LMNA R482W mutation, fat loss was generally less prominent in subjects with the PPARG H449L mutation. Partial fat loss was limited to the extremities, whilst truncal fat mass was preserved. The PPARG H449L mutation was associated with insulin resistance, hypertriglyceridaemia and non-alcoholic fatty liver disease in all affected subjects, but the severity was variable. Three out of four mutation carriers had overt diabetes or impaired glucose tolerance. Pioglitazone therapy in these three individuals resulted in a modest improvement in their metabolic control, and regular menstrual cycles in the two female subjects. CONCLUSIONS: We suggest that relatively modest fat loss in patients with PPARG mutations may render the recognition of the syndrome more difficult in routine clinical practice. The PPARG H449L mutation is associated with insulin resistance and metabolic complications, but their severity is variable among the affected subjects. PMID- 26756203 TI - Enhanced Photocatalytic Degradation of 17alpha-Ethinylestradiol Exhibited by Multifunctional ZnFe2 O4 -Ag/rGO Nanocomposite Under Visible Light. AB - In this paper, ZnFe2 O4 , a visible light active photocatalyst, was comodified by graphene oxide (GO) and Ag nanoparticles (NPs) to form ZnFe2 O4 -Ag/rGO nanocomposite (NC) by facile one-pot hydrothermal method. Reduction of GO and formation of ZnFe2 O4 and Ag nanoparticles occurred simultaneously during hydrothermal reaction. The photocatalytic activity of the NC was investigated under visible light, for the degradation of 17alpha-ethinylestradiol (EE2), a nondye compound, which also is an emerging pollutant with endocrine-disrupting activity. The pseudo rate constant (k') of as-synthesized ZnFe2 O4 -Ag/rGO NC was higher by the factor of 14.6 and 5.6 times than the corresponding ZnFe2 O4 and ZnFe2 O4 /rGO respectively. The synergistic interactions between ZnFe2 O4 , Ag and rGO leading to decreased aggregation of the NPs, increased surface area, better absorption in visible region, effective electron-hole generation transfer. However, in the presence of humic acid (HA), the photosensitization effect was predominated by competitive interaction resulting in only 80% removal of EE2 within the same time. Moreover, the composite can easily be magnetically separated for reuse. PMID- 26756204 TI - Erratum. PMID- 26756205 TI - Computational Trials: Unraveling Motility Phenotypes, Progression Patterns, and Treatment Options for Glioblastoma Multiforme. AB - Glioblastoma multiforme is a malignant brain tumor with poor prognosis and high morbidity due to its invasiveness. Hypoxia-driven motility and concentration driven motility are two mechanisms of glioblastoma multiforme invasion in the brain. The use of anti-angiogenic drugs has uncovered new progression patterns of glioblastoma multiforme associated with significant differences in overall survival. Here, we apply a mathematical model of glioblastoma multiforme growth and invasion in humans and design computational trials using agents that target angiogenesis, tumor replication rates, or motility. The findings link highly dispersive, moderately-dispersive, and hypoxia-driven tumors to the patterns observed in glioblastoma multiforme treated by anti-angiogenesis, consisting of progression by Expanding FLAIR, Expanding FLAIR + Necrosis, and Expanding Necrosis, respectively. Furthermore, replication rate-reducing strategies (e.g. Tumor Treating Fields) appear to be effective in highly-dispersive and moderately dispersive tumors but not in hypoxia-driven tumors. The latter may respond to motility-reducing agents. In a population computational trial, with all three phenotypes, a correlation was observed between the efficacy of the rate-reducing agent and the prolongation of overall survival times. This research highlights the potential applications of computational trials and supports new hypotheses on glioblastoma multiforme phenotypes and treatment options. PMID- 26756206 TI - Heterogeneity of patients receiving artificial nutrition in Japanese psychiatric hospitals: a cross-sectional study. AB - AIM: Artificial nutrition, including tube feeding, continues to be given to dementia patients in numerous geriatric facilities in Japan. However, the clinical characteristics of patients receiving artificial nutrition have not been fully investigated. Therefore, we tried to evaluate the clinical features of those patients in this study. METHODS: Various clinical characteristics of all inpatients at 18 of 20 psychiatric hospitals in Okayama Prefecture, Japan, with a percutaneous endoscopic gastrostomy tube, nasogastric tube, or total parenteral nutrition were evaluated. RESULTS: Two hundred twenty-one patients (5.4% of all inpatients) had been receiving artificial nutrition for more than 1 month, and 187 (130 women, 57 men; 84.6% of 221 patients) were fully investigated. The mean age was 78.3 years old, and the mean duration of artificial nutrition was 29.8 months. Eighty-four patients (44.7% of 187 patients) were receiving artificial nutrition for more than 2 years. Patients with Alzheimer's disease (n = 78) formed the biggest group, schizophrenia (n = 37) the second, and vascular dementia (n = 26) the third. CONCLUSION: About one-fifth of the subjects receiving artificial nutrition were in a vegetative state. More than a few patients with mental disorders, including schizophrenia, also received long-term artificial nutrition. We should pay more attention to chronic dysphasia syndrome in mental disorders. PMID- 26756208 TI - Is infant body mass index associated with adulthood body composition trajectories? An exploratory analysis. AB - BACKGROUND: Infant body mass index (BMI) is increasingly used as a marker of obesity risk based on its association with young-adulthood BMI. OBJECTIVES: The aim of this study is to test the association of infant BMI with young-adulthood fat mass and fat-free mass, and how this association changes during advancing adulthood. METHODS: Body mass index Z-score at age 9 months was measured in 350 White, non-Hispanic Fels Longitudinal Study participants. This exposure was entered into multilevel models to test its association with trajectories describing 2665 BMI observations and 1388 observations of fat mass index (FMI, kg m-2 ) and fat-free mass index (FFMI, kg m-2 ) between ages 20 and 60 years. RESULTS: Partitioning young-adulthood BMI into its fat and fat-free components, infant BMI Z-score was associated with FFMI (beta = 0.745; 95% confidence interval = 0.367 to 1.124) but not FMI (0.528; -0.055 to 1.110) at age 20 years. Greater infant BMI Z-score was associated with slower age-related increases in all outcomes, such that (looking at 10-year intervals) only FFMI at age 30 years was related to infant BMI Z-score (0.338; 0.119, 0.557). CONCLUSIONS: Focus on infant BMI reduction for adulthood obesity prevention warrants caution as high infant BMI values are associated with greater lean mass, which is protective against ageing changes. PMID- 26756207 TI - Targeted Curing of All Lysogenic Bacteriophage from Streptococcus pyogenes Using a Novel Counter-selection Technique. AB - Streptococcus pyogenes is a human commensal and a bacterial pathogen responsible for a wide variety of human diseases differing in symptoms, severity, and tissue tropism. The completed genome sequences of >37 strains of S. pyogenes, representing diverse disease-causing serotypes, have been published. The greatest genetic variation among these strains is attributed to numerous integrated prophage and prophage-like elements, encoding several virulence factors. A comparison of isogenic strains, differing in prophage content, would reveal the effects of these elements on streptococcal pathogenesis. However, curing strains of prophage is often difficult and sometimes unattainable. We have applied a novel counter-selection approach to identify rare S. pyogenes mutants spontaneously cured of select prophage. To accomplish this, we first inserted a two-gene cassette containing a gene for kanamycin resistance (KanR) and the rpsL wild-type gene, responsible for dominant streptomycin sensitivity (SmS), into a targeted prophage on the chromosome of a streptomycin resistant (SmR) mutant of S. pyogenes strain SF370. We then applied antibiotic counter-selection for the re establishment of the KanS/SmR phenotype to select for isolates cured of targeted prophage. This methodology allowed for the precise selection of spontaneous phage loss and restoration of the natural phage attB attachment sites for all four prophage-like elements in this S. pyogenes chromosome. Overall, 15 mutants were constructed that encompassed every permutation of phage knockout as well as a mutant strain, named CEM1DeltaPhi, completely cured of all bacteriophage elements (a ~10% loss of the genome); the only reported S. pyogenes strain free of prophage-like elements. We compared CEM1DeltaPhi to the WT strain by analyzing differences in secreted DNase activity, as well as lytic and lysogenic potential. These mutant strains should allow for the direct examination of bacteriophage relationships within S. pyogenes and further elucidate how the presence of prophage may affect overall streptococcal survival, pathogenicity, and evolution. PMID- 26756209 TI - The Dance of Tusks: Rediscovery of Lower Incisors in the Pan-American Proboscidean Cuvieronius hyodon Revises Incisor Evolution in Elephantimorpha. AB - The incisors of proboscideans (tusks and tushes) are one of the most important feature in conservation, ecology and evolutionary history of these mammals. Although the absence of upper incisors is rare in proboscideans (occurring only in deinotheres), the independent losses of lower incisors are recognized for most of its lineages (dibelodont condition). The presence of lower incisors in the Pan American gomphothere Cuvieronius hyodon was reported a few times in literature, but it was neglected in systematic studies. We analyzed several specimens of Cuvieronius hyodon from the Americas and recognized that immature individuals had lower incisors during very early post-natal developmental stages. Subsequently, these are lost and lower incisors alveoli close during later developmental stages, before maturity. Moreover, for the first time in a formal cladistic analysis of non-amebelodontine trilophodont gomphotheres, Rhynchotherium and Cuvieronius were recovered as sister-taxa. Among several non-ambiguous synapomorphies, the presence of lower incisors diagnoses this clade. We recognize that the presence of lower incisors in Cuvieronius and Rhynchotherium is an unique case of taxic atavism among the Elephantimorpha, since these structures are lost at the origin of the ingroup. The rediscovery of the lower incisors in Cuvieronius hyodon, their ontogenetic interpretation and the inclusion of this feature in a revised phylogenetic analysis of trilophodont gomphotheres brought a better understanding for the evolutionary history of these proboscideans. PMID- 26756210 TI - Q Fever Knowledge, Attitudes and Vaccination Status of Australia's Veterinary Workforce in 2014. AB - Q fever, caused by Coxiella burnetii, is a serious zoonotic disease in humans with a worldwide distribution. Many species of animals are capable of transmitting C. burnetii, and consequently all veterinary workers are at risk for this disease. An effective Q fever vaccine has been readily available and used in Australia for many years in at-risk groups, and the European Centre for Disease Prevention and Control has recently also called for the use of this vaccine among at-risk groups in Europe. Little is known about attitudes towards this vaccine and vaccine uptake in veterinary workers. This study aimed to determine the Q fever vaccination status of veterinarians and veterinary nurses in Australia and to assess and compare the knowledge and attitudes towards Q fever disease and vaccination of each cohort. An online cross-sectional survey performed in 2014 targeted all veterinarians and veterinary nurses in Australia. Responses from 890 veterinarians and 852 veterinary nurses were obtained. Binary, ordinal and multinomial logistic regression were used to make comparisons between the two cohorts. The results showed that 74% of veterinarians had sought vaccination compared to only 29% of veterinary nurses. Barriers to vaccination among those not vaccinated did not differ between cohorts, and included a lack of perceived risk, financial expense, time constraints, and difficulty in finding a vaccine provider. Poor knowledge and awareness of Q fever disease and vaccination were additional and notable barriers for the veterinary nursing cohort, suggesting veterinary clinics and veterinarians may not be meeting their legal responsibility to educate staff about risks and risk prevention. Further evaluation is needed to identify the drivers behind seeking and recommending vaccination so that recommendations can be made to improve vaccine uptake. PMID- 26756211 TI - Polymicrobial Biofilm Inhibition Effects of Acetate-Buffered Chitosan Sponge Delivery Device. AB - Polymicrobial biofilm-associated implant infections present a challenging clinical problem. Through modifications of lyophilized chitosan sponges, degradable drug delivery devices for antibiotic solution have been fabricated for prevention and treatment of contaminated musculoskeletal wounds. Elution of amikacin, vancomycin, or a combination of both follows a burst release pattern with vancomycin released above minimum inhibitory concentration for Staphylococcus aureus for 72 h and amikacin released above inhibitory concentrations for Pseudomonas aeruginosa for 3 h. Delivery of a vancomycin, amikacin, or a combination of both reduces biofilm formation on polytetrafluoroethylene catheters in an in vivo model of contamination. Release of dual antibiotics from sponges is more effective at preventing biofilm formation than single-loaded chitosan sponges. Treatment of pre-formed biofilm with high-dose antibiotic release from chitosan sponges shows minimal reduction after 48 h. These results demonstrate infection-preventive efficacy for antibiotic-loaded sponges, as well as the need for modifications in the development of advanced materials to enhance treatment efficacy in removing established biofilm. PMID- 26756212 TI - Perception of Nepalese dental hygiene and dentistry students towards the dental hygienists profession. AB - OBJECTIVES: This study investigates student and stakeholder perceptions of the role of the dental hygienist in Nepal. The impact of these perceptions on the professionalization of dental hygienists is described whilst exploring the consequences for oral health workforce planning. METHODS: Dentistry and dental hygiene students from one dental college in Nepal were asked to complete an anonymous questionnaire; 171 students returned the questionnaire containing a mix of forced response and open-ended items. Quantitative data were analysed using SPSS(r) 22. These data were complemented with qualitative information from survey open questions and from semi-structured interviews with key informants from several relevant organizations. Qualitative data were manually analysed and coded. Data were triangulated to contextualize quantitative data. RESULTS: A high level of positive regard for the role of the dental hygienist in Nepal was evident amongst dentistry and dental hygiene students in this college. Both groups believe that the dental hygienist can play a major role in raising oral health awareness in Nepal. The scope of practice of the dental hygienist was unclear with issues surrounding the scope of practice and reports of illegal practice by dental hygienists. Significant differences (P < 0.001) were noted between dental hygiene and dentistry students in relation to their opinion regarding independent practice and the need of supervision by a dentist. DISCUSSION AND CONCLUSION: Supervision of the dental hygienist by dentists and issues surrounding the scope of practice are polarizing the relationship between dentists, dental hygienists and the relevant professional organizations. This could hinder cooperation between these oral health professionals and might lead to underutilization of the dental hygienist. To improve the understanding about the roles of each oral health professional, establishing functional relationships and intraprofessional education involving dentistry and dental hygiene students needs to be introduced. This will benefit the introduction of preventative oral health services in Nepal. Government jobs and incentives to increase the retention and distribution of oral health professionals should be created. The government and professional organizations need to consider professionalizing the dental hygiene workforce and formalize the scope of practice. The unique demographic details of Nepal require a paradigm shift in oral health workforce management in Nepal. PMID- 26756214 TI - A comparison of two stretching programs for hamstring muscles: A randomized controlled assessor-blinded study. AB - Most parameters regarding hamstring flexibility training programs have been investigated; however, the joint (i.e. hip or knee) on which the stretching should preferentially be focused needs to be further explored. This randomized controlled assessor-blinded study aimed to investigate the influence of this parameter. We randomly assigned 111 asymptomatic participants with tight hamstring muscles in three groups: a control group and two groups following a different home-based 8-week (five 10-minute sessions per week) hamstring stretching program (i.e. stretching performed by flexing the hip while keeping the knee extended [SH] or by first flexing the hip with a flexed knee and then extending the knee [SK]). Range of motion (ROM) of hip flexion and knee extension were measured before and after the stretching program by means of the straight leg raising test and the passive knee extension angle test, respectively. Eighty nine participants completed the study. A significant increase in ROM was observed at post-test. Analyses showed significant group-by-time interactions for changes regarding all outcomes. Whereas the increase in hip flexion and knee extension ROM was higher in the stretching groups than in the CG (especially for the SH group p < 0.05), no differences between the two stretching groups were observed (p > 0.05). In conclusion, the fact that both stretching programs resulted in similar results suggests no influence of the joint at which the stretching is focused upon, as assessed by the straight leg raising and knee extension angle tests. PMID- 26756213 TI - No Effect of Rapamycin on Cardiac Adhesion Formation: A Drug-Loaded Bioresorbable Polylactone Patch in a Porcine Cardiac Surgical Model. AB - BACKGROUND: The fusing of the epicardium and sternum due to adhesion is a common problem during repeated cardiac surgery and carries with it an increased risk of bleeding. The use of barriers and patches has been tested to prevent the formation of adhesions, but the very presence of a patch can provoke adhesion formation. The objective of this study was, therefore, to investigate both biodegradable and bioresorbable polylactone patches [(polycaprolactone poly(ethylene oxide)-polycaprolactone tri-block copolymer (PCE)]. The patches were also tested with a controlled release of rapamycin, which prevents cell migration and extracellular matrix deposition. The clinical effectiveness of rapamycin in pericardial patches has not previously been examined. MATERIALS AND METHODS: Three groups of 6 female Danish Landrace pigs underwent sternotomy and abrasion of the epicardium, before being randomized to either group 1--the control group (with no patch), group 2--PCE patch implanted between the sternum and epicardium, or group 3--PCE patch and slow-release 1.6-mg rapamycin. After a median time period of 26 days, the pigs were euthanized and their hearts removed en bloc with the sternum, for macroscopic, histological and pathological examination. RESULTS: Upon macroscopic examination, a significantly lower degree of adhesion in group 2, as compared to group 1 (p < 0.05), was found. Histological analysis of the tissues showed significantly more fibrosis, inflammation and foreign body granulomas (p < 0.05) in both group 2 and group 3, when compared to group 1. CONCLUSION: A PCE patch following sternotomy in animal subjects reduces postoperative macroscopic adhesions without reducing microscopic fibrosis or inflammation. Loading the patch with rapamycin was found not to increase the antifibrotic effect. PMID- 26756215 TI - Chronic NF-kappaB activation links COPD and lung cancer through generation of an immunosuppressive microenvironment in the lungs. AB - Nuclear Factor (NF)-kappaB is positioned to provide the interface between COPD and carcinogenesis through regulation of chronic inflammation in the lungs. Using a tetracycline-inducible transgenic mouse model that conditionally expresses activated IkappaB kinase beta (IKKbeta) in airway epithelium (IKTA), we found that sustained NF-kappaB signaling results in chronic inflammation and emphysema by 4 months. By 11 months of transgene activation, IKTA mice develop lung adenomas. Investigation of lung inflammation in IKTA mice revealed a substantial increase in M2-polarized macrophages and CD4+/CD25+/FoxP3+ regulatory T lymphocytes (Tregs). Depletion of alveolar macrophages in IKTA mice reduced Tregs, increased lung CD8+ lymphocytes, and reduced tumor numbers following treatment with the carcinogen urethane. Alveolar macrophages from IKTA mice supported increased generation of inducible Foxp3+ Tregs ex vivo through expression of TGFbeta and IL-10. Targeting of TGFbeta and IL-10 reduced the ability of alveolar macrophages from IKTA mice to induce Foxp3 expression on T cells. These studies indicate that sustained activation of NF-kappaB pathway links COPD and lung cancer through generation and maintenance of a pro tumorigenic inflammatory environment consisting of alternatively activated macrophages and regulatory T cells. PMID- 26756216 TI - Lanatoside C suppressed colorectal cancer cell growth by inducing mitochondrial dysfunction and increased radiation sensitivity by impairing DNA damage repair. AB - Cardiac glycosides are clinically used for cardiac arrhythmias. In this study, we investigated the mechanism responsible for anti-cancer and radiosensitizing effects of lanatoside C in colorectal cancer cells. Lanatoside C-treated cells showed classic patterns of autophagy, which may have been caused by lanatoside C induced mitochondrial aggregation or degeneration. This mitochondrial dysfunction was due to disruption of K+ homeostasis, possibly through inhibition of Na+/K+ ATPase activity. In addition, lanatoside C sensitized HCT116 cells (but not HT-29 cells) to radiation in vitro. gamma-H2AX, a representative marker of DNA damage, were sustained longer after combination of irradiation with lanatoside C, suggesting lanatoside C impaired DNA damage repair processes. Recruitment of 53BP1 to damaged DNA, a critical initiation step for DNA damage repair signaling, was significantly suppressed in lanatoside C-treated HCT116 cells. This may have been due to defects in the RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A that increases 53BP1 recruitment to DNA damage sites. Although lanatoside C alone reduced tumor growth in the mouse xenograft tumor model, combination of lanatoside C and radiation inhibited tumor growth more than single treatments. Thus, lanatoside C could be a potential molecule for anti-cancer drugs and radiosensitizing agents. PMID- 26756217 TI - Generation and characterization of a tetraspanin CD151/integrin alpha6beta1 binding domain competitively binding monoclonal antibody for inhibition of tumor progression in HCC. AB - Our previous studies revealed that tetraspanin CD151 plays multiple roles in the progression of hepatocellular carcinoma (HCC) by forming a functional complex with integrin alpha6beta1. Herein, we generated a monoclonal antibody (mAb) that dissociates the CD151/integrin alpha6beta1 complex, and we evaluated its bioactivity in HCCs. A murine mAb, tetraspanin CD151 (IgG1, called CD151 mAb 9B), was successfully generated against the CD151-integrin alpha6beta1 binding site of CD151 extracellular domains. Co-immunoprecipitation using CD151 mAb 9B followed by Western blotting detected a 28 kDa protein. Both immunofluorescent and immunohistochemical staining showed a good reactivity of CD151 mAb 9B in the plasma membrane and cytoplasm of HCC cells, as well as in liver cells. In vitro assays demonstrated that CD151 mAb 9B could inhibit neoangiogenesis and both the mobility and the invasiveness of HCC cells. An in vivo assay showed that CD151 mAb 9B inhibited tumor growth potential and HCC cells metastasis. We successfully produced a CD151 mAb 9B targeting the CD151/integrin alpha6beta1-binding domain, which not only can displayed good reactivity to the CD151 antigen but also prevented tumor progression in HCC. PMID- 26756218 TI - Thrombospondin-1 might be a therapeutic target to suppress RB cells by regulating the DNA double-strand breaks repair. AB - Retinoblastoma (RB) arises from the retina, and its growth usually occurs under the retina and toward the vitreous. Ideal therapy should aim to inhibit the tumor and protect neural cells, increasing the patient's life span and quality of life. Previous studies have demonstrated that Thrombospondin-1 (TSP-1) is associated with neurogenesis, neovascularization and tumorigenesis. However, at present, the bioactivity of TSP-1 in retinoblastoma has not been defined. Herein, we demonstrated that TSP-1 was silenced in RB cell lines and clinical tumor samples. HDAC inhibitor, Trichostatin A (TSA), could notably transcriptionally up-regulate TSP-1 in RB cells, WERI-Rb1 cells and Y79 cells. Moreover, we found human recombinant TSP-1 (hTSP-1) could significantly inhibit the cell viability of RB cells both in vitro and in vivo. Interestingly, hTSP-1 could significantly induce the expression of gamma-H2AX, a well-characterized in situ marker of DNA double strand breaks (DSBs) in RB cells. The DNA NHEJ pathway in WERI-Rb1 cells could be significantly inhibited by hTSP-1. A mutation in Rb1 might be involved in the hTSP-1-medicated gamma-H2AX increasing in WERI-Rb1 cells. Furthermore, hTSP-1 could inhibit RB cells while promoting retinal neurocyte survival in the neuronal and retinoblastoma cell co-culture system. As such, TSP-1 may become a therapeutic target for treatment of retinoblastoma. PMID- 26756221 TI - Unveiling the Mode of Interaction of Berberine Alkaloid in Different Supramolecular Confined Environments: Interplay of Surface Charge between Nano Confined Charged Layer and DNA. AB - In this Article, we demonstrate a detailed characterization of binding interaction of berberine chloride (BBCl) with calf-thymus DNA (CT-DNA) in buffer solution as well as in two differently charged reverse micelles (RMs). The photophyscial properties of this alkaloid have been modulated within these microheterogeneous bioassemblies. The mode of binding of this alkaloid with DNA is of debate to date. However, fluorescence spectroscopic measurements, circular dichroism (CD) measurement, and temperature-dependent study unambiguously establish that BBCl partially intercalates into the DNA base pairs. The nonplanarity imposed by partial saturation in their structure causes the nonclassical types of intercalation into DNA. Besides the intercalation, electrostatic interactions also play a significant role in the binding between BBCl and DNA. DNA structure turns into a condensed form after encapsulation into RMs, which is followed by the CD spectra and microscopy study. The probe location and dynamics in the nanopool of the RMs depended on the electrostatic interaction between the charged surfactants and cationic berberine. The structural alteration of CT-DNA from B form to condensed form and the interplay of surface charge between RMs and DNA determine the interaction between the alkaloid and DNA in RMs. Time-resolved study and fluorescence anisotropy measurements successfully provide the binding interaction of BBCl in the nanopool of the RMs in the absence and in the presence of DNA. This study motivates us to judge further the potential applicability of this alkaloid in other biological systems or other biomimicking organized assemblies. PMID- 26756220 TI - Antitumoral effect of Ocoxin on acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy whose incidence is growing in developed countries. In the relapse setting, very limited therapeutic options are available and in most cases only palliative care can be offered to patients. The effect of a composite formulation that contains several antioxidants, Ocoxin Oral solution (OOS), was tested in this condition. When analyzed in vitro, OOS exhibited anti-AML action that was both time and dose dependent. In vivo OOS induced a ralentization of tumor growth that was due to a decrease in cell proliferation. Such effect could, at least partially, be due to an increase in the cell cycle inhibitor p27, although other cell cycle proteins seemed to be altered. Besides, OOS induced an immunomodulatory effect through the induction of IL6. When tested in combination with other therapeutic agents normally used in the treatment of AML patients, OOS demonstrated a higher antiproliferative action, suggesting that it may be used in combination with those standard of care treatments to potentiate their antiproliferative action in the AML clinic. PMID- 26756223 TI - Correct Quantum Chemistry in a Minimal Basis from Effective Hamiltonians. AB - We describe how to create ab initio effective Hamiltonians that qualitatively describe correct chemistry even when used with a minimal basis. The Hamiltonians are obtained by folding correlation down from a large parent basis into a small, or minimal, target basis, using the machinery of canonical transformations. We demonstrate the quality of these effective Hamiltonians to correctly capture a wide range of excited states in water, nitrogen, and ethylene and to describe ground and excited state bond breaking in nitrogen and the chromium dimer, all in small or minimal basis sets. PMID- 26756219 TI - The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma. AB - Deregulation of mTOR and IGF pathways is frequent in hepatocellular carcinoma (HCC), thus mTOR and IGF1R represent suitable therapeutic targets in HCC. The aim of this study was to evaluate the effects of mTOR inhibitors (mTORi) and OSI-906, blocker of IGF1R/IR, on HCC cell proliferation, viability, migration and invasion, and alpha-fetoprotein (alpha-FP) secretion. In HepG2 and HuH-7 we evaluated, the expression of mTOR and IGF pathway components; the effects of Sirolimus, Everolimus, Temsirolimus and OSI-906 on cell proliferation; the effects of Sirolimus, OSI-906, and their combination, on cell secretion, proliferation, viability, cell cycle, apoptosis, invasion and migration. Moreover, intracellular mechanisms underlying these cell functions were evaluated in both cell lines. Our results show that HepG2 and HuH-7 present with the same mRNA expression profile with high levels of IGF2. OSI-906 inhibited cell proliferation at high concentration, while mTORi suppressed cell proliferation in a dose-time dependent manner in both cell lines. The co-treatment showed an additive inhibitory effect on cell proliferation and viability. This effect was not related to induction of apoptosis, but to G0/G1 phase block. Moreover, the co treatment prevented the Sirolimus-induced AKT activation as escape mechanism. Both agents demonstrated to be differently effective in inhibiting alpha-FP secretion. Sirolimus, OSI-906, and their combination, blocked cell migration and invasion in HuH-7. These findings indicate that, co-targeting of IGF1R/IR and mTOR pathways could be a novel therapeutic approach in the management of HCC, in order to maximize antitumoral effect and to prevent the early development of resistance mechanisms. PMID- 26756225 TI - Polarons in pi-Conjugated Polymers: Anderson or Landau? AB - Using both analytical expressions and the density matrix renormalization group method, we study the fully quantized disordered Holstein model to investigate the localization of charges and excitons by vibrational or torsional modes-i.e., the formation of polarons-in conformationally disordered pi-conjugated polymers. We identify two distinct mechanisms for polaron formation, namely Anderson localization via disorder (causing the formation of Anderson polarons) and self localization by self-trapping via normal modes (causing the formation of Landau polarons). We identify the regimes where either description is more valid. The key distinction between Anderson and Landau polarons is that for the latter the particle wave function is a strong function of the normal coordinates, and hence the "vertical" and "relaxed" wave functions are different. This has theoretical and experimental consequences for Landau polarons. Theoretically, it means that the Condon approximation is not valid, and so care needs to be taken when evaluating transition rates. Experimentally, it means that the self-localization of the particle as a consequence of its coupling to the normal coordinates may lead to experimental observables, e.g., ultrafast fluorescence depolarization. We apply these ideas to poly(p-phenylenevinylene). We show that the high frequency C C bond oscillation only causes Landau polarons for a very narrow parameter regime; generally we expect disorder to dominate and Anderson polarons to be a more applicable description. Similarly, for the low frequency torsional fluctuations we show that Anderson polarons are expected for realistic parameters. PMID- 26756224 TI - Polydopamine-Templated Hydroxyapatite Reinforced Polycaprolactone Composite Nanofibers with Enhanced Cytocompatibility and Osteogenesis for Bone Tissue Engineering. AB - Nanohydroxyapatite (HA) synthesized by biomimetic strategy is a promising nanomaterial as bone substitute due to its physicochemical features similar to those of natural nanocrystal in bone tissue. Inspired by mussel adhesive chemistry, a novel nano-HA was synthesized in our work by employing polydopamine (pDA) as template under weak alkaline condition. Subsequently, the as-prepared pDA-templated HA (tHA) was introduced into polycaprolactone (PCL) matrix via coelectrospinning, and a bioactive tHA/PCL composite nanofiber scaffold was developed targeted at bone regeneration application. Our research showed that tHA reinforced PCL composite nanofibers exhibited favorable cytocompatibility at given concentration of tHA (0-10 w.t%). Compared to pure PCL and traditional nano HA enriched PCL (HA/PCL) composite nanofibers, enhanced cell adhesion, spreading and proliferation of human mesenchymal stem cells (hMSCs) were observed on tHA/PCL composite nanofibers on account of the contribution of pDA present in tHA. More importantly, tHA nanoparticles exposed on the surface of composite nanofibers could further promote osteogenesis of hMSCs in vitro even in the absence of osteogenesis soluble inducing factors when compared to traditional HA/PCL scaffolds, which was supported by in vivo test as well according to the histological analysis. Overall, our study demonstrated that the developed tHA/PCL composite nanofibers with enhanced cytocompatibility and osteogenic capacity hold great potential as scaffolds for bone tissue engineering. PMID- 26756222 TI - Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants. AB - First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR. PMID- 26756226 TI - Quantification of the Range of Motion of Kidney and Ureteral Stones During Shockwave Lithotripsy in Conscious Patients. AB - Effective shockwave lithotripsy requires accurate targeting of the stone throughout the course of treatment. Stone movement secondary to respiratory movement can make this more difficult. In vitro work has shown that stone motion outside the focal region reduces the efficacy of stone fragmentation; however, there are few clinical data on the degree of stone movement in patients during treatment. To investigate this, X-ray fluoroscopic images of the kidney and ureteral stones at the upper and lower limits of the normal respiratory cycle were acquired during shock wave lithotripsy of 58 conscious patients, and stone excursion was calculated from these images. In addition, the respiration rate and patient perceived pain were recorded during the course of the treatment. It was found that stone motion secondary to respiration was 7.7 +/- 2.9 mm for kidney stones and 3.6 +/- 2.1 mm for ureteral stones-less than has been reported in studies with anesthetized patients. There was no significant change of motion over the course of treatment although pain was found to increase. These data suggest that stone motion in conscious patients is less than in anesthetized patients. Furthermore, it suggests that lithotripters with focal regions of 8 mm or greater should not suffer from a marked drop in fragmentation efficiency due to stone motion. PMID- 26756227 TI - Circulating Myeloid-Derived Suppressor Cells Predict Differentiated Thyroid Cancer Diagnosis and Extent. AB - BACKGROUND: Establishing the preoperative diagnosis and long-term prognosis of differentiated thyroid cancer (DTC) remain challenging in some patients. Myeloid derived suppressor cells (MDSC) are tumor-induced cells mediating immune tolerance that are detectable in the peripheral blood of cancer patients. The authors previously developed a novel clinical assay to detect the phenotypes of two human MDSC subsets in peripheral blood, and hypothesize that higher MDSC levels measured by this assay correlate positively with both malignancy and worse patient outcomes. METHODS: A prospective observational pilot study was performed of patients undergoing thyroidectomy for a solitary thyroid nodule. The presence of a thyroid nodule >1 cm was confirmed sonographically, and fine-needle aspiration biopsy performed prior to surgery in all cases. Peripheral blood collected preoperatively was analyzed using a novel flow cytometry-based immunoassay to detect and quantify two subsets of human MDSC. Circulating MDSC levels were compared by histopathologic diagnosis, stage, and presence of persistent disease after treatment. RESULTS: Of 50 patients included in this study, MDSC measurement was successful in 47 (94%). One patient was found to have a concurrent cancer, leaving 46 patients for primary analysis. The cytologic diagnoses were benign in five (10.8%), atypia or follicular lesion of undetermined significance in five (10.8%), suspicious for follicular neoplasm in five (10.8%), suspicious for malignant in three (6.5%), and malignant in 28 (60.1%) of the 46 nodules. Final histopathology was benign in 11 (24%) and DTC in 35 (76%), encompassing 34 PTC cases and one follicular thyroid carcinoma. Mean percentages of CD11b(+)HLA-DR(low)HIF1a(+) MDSC (CD11b(+)MDSC) were 14.0 +/- 6.2% and 7.9 +/- 3.6% in DTC versus benign nodules, respectively (p < 0.005). A cutoff of 12% yielded a specificity of 0.91, a sensitivity of 0.72, and a likelihood ratio of 7.9. Mean CD11b(+)MDSC levels increased linearly with higher TNM stage (p < 0.01), and were 19.4 +/- 5.4 in patients with persistent cancer after surgery compared with 13.2 +/- 6.8 in those without evidence of disease (p < 0.05). CONCLUSION: MDSC measurement using this flow cytometry-based assay represents a novel approach for preoperatively assessing malignancy risk and cancer extent in patients with thyroid nodules. While further validation is needed, these data suggest that MDSC assessment may serve as a useful adjunct when cytology is indeterminate, and predict tumor stage and recurrence risk in cases of thyroid cancer. PMID- 26756228 TI - High on Attractiveness, Low on Nutrition: An Over-Time Comparison of Advertising Food Products on Israeli Television. AB - This content analysis examines Israeli television food advertising. It compares 2008-2009 and 2012-2013, two periods immediately before and several years after regulatory, educational, and public-advocacy efforts have been advanced to raise awareness of and tackle the television-obesity link. Advertisements were drawn from a composite week sample aired on Israeli broadcast channels from 4:00 p.m. until midnight in each of the two periods. Nearly a quarter of ads were for food products, even after a significant drop over the years. The most common food categories included candies and sweetened drinks, whereas fruit and vegetables were among the least common products advertised. The most prevalent central message in food advertisements was that the product makes for an economically sensible purchase, with a much lower focus on the health qualities of the food products. Food advertisements were characterized by a very short duration and an increased reliance on emotional, rather than cognitive, appeal, especially in ads for low-nutrient foods. A significant increase was observed in 2012-2013 in the reliance on thin models in food advertisements, and these were most often associated with high levels of physical attractiveness, promoting the thin ideal. Findings are discussed in light of theory, previous research conducted worldwide, and audience effects. Implications are addressed for health and media industry regulation efforts. PMID- 26756250 TI - 3d-4f Metal-Organic Framework with Dual Luminescent Centers That Efficiently Discriminates the Isomer and Homologues of Small Organic Molecules. AB - A 3d-4f luminescent metal-organic framework (MOF), [Tb2(Cu8I8)(C12H8NO2)6(H2O)4].5C4H8O2 (4), and three analogues {[La2(Cu8I8)(C12H8NO2)6(C4H8O2)2(H2O)2].3C4H8O2.2H2O (1), [Ce2(Cu8I8)(C12H8NO2)6(H2O)4].5C4H8O2 (2), and [Eu2(Cu8I8)(C12H8NO2)6(H2O)4].5C4H8O2 (3)}, were self-assembled from copper(I) halide clusters and lanthanide metal ions with an organic linker [3-(pyridin-4 yl)benzoic acid] under solvothermal conditions. Compound 4 with high quantum yield (Phi = 68%) exhibits reversible luminescence behavior, accompanying the removal and recovery of guest molecules (1,4-dioxane). Because of the unique porous structure and dual luminescent centers of compound 4, it can efficiently differentiate benzene series with different sizes and provide readouts in corresponding optical signals. Furthermore, it also can unambiguously discriminate the isomers, homologues, and other small molecules with similar structural motifs from one another. The luminescent color of the MOF sensor in different guest solvents has obvious changes that can be clearly distinguished by the naked eye. This multicolor luminescence originates from emissions of the dual luminescent centers, and the emissions have shifted, enhanced, weakened, or quenched to different degrees. PMID- 26756229 TI - Breast cancer subtypes: morphologic and biologic characterization. AB - Advances in basic science, technology and translational research have created a revolution in breast cancer diagnosis and therapy. Researchers' discoveries of genes defining variability in response to therapy and heterogeneity in clinical presentations and tumor biology are the foundation of the path to personalized medicine. The success of personalized breast cancer care depends on access to pertinent clinical information and risk factors, optimal imaging findings, well established morphologic features, and traditional and contemporary prognostic/predictive testing. The integration of these entities provides an opportunity to identify patients who can benefit from specific therapies, and demonstrates the link between breast cancer subtypes and their association with different tumor biology. It is critical to recognize specific types of breast cancer in individual patients and design optimal personalized therapy. This article will highlight the roles of morphologic features and established tumor biomarkers on patient outcome. PMID- 26756251 TI - Roflumilast Ameliorates Airway Hyperresponsiveness Caused by Diet-Induced Obesity in a Murine Model. AB - Obese patients with asthma respond poorly to conventional asthma medications, resulting in severe symptoms and poor prognosis. Roflumilast, a phosphodiesterase 4 inhibitor that lowers the levels of various substances that are implicated in obese subjects with asthma, may be effective in the treatment of those subjects. We evaluated the potential of roflumilast as a novel therapeutic agent for obese subjects with asthma. We designed three models: diet-induced obesity (DIO); DIO with ovalbumin (OVA); and OVA. We fed C57BL/6J mice a high-fat diet for 3 months with or without OVA sensitization and challenge. Roflumilast or dexamethasone was administered orally three times at 2-day intervals in the last experimental week. Airway hyperresponsiveness resulting from DIO significantly improved in the roflumilast-treated group compared with the dexamethasone-treated groups. Although DIO did not affect the cell proliferation in bronchoalveolar lavage fluid, increased fibrosis was seen in the DIO group, which significantly improved from treatment with roflumilast. DIO-induced changes in adiponectin and leptin levels were improved by roflumilast, whereas dexamethasone aggravated them. mRNA levels and proteins of TNF-alpha, transforming growth factor-beta, IL-1beta, and IFN-gamma increased in the DIO group and decreased with roflumilast. The reactive oxygen species levels were also increased in the DIO group and decreased by roflumilast. In the DIO plus OVA and OVA models, roflumilast improved Th1 and Th2 cell activation to a greater extent than dexamethasone. Roflumilast is significantly more effective than dexamethasone against airway hyperresponsiveness caused by DIO in the murine model. Roflumilast may represent a promising therapeutic agent for the treatment of obese patients with asthma. PMID- 26756252 TI - Study of a Bifunctional Abeta Aggregation Inhibitor with the Abilities of Antiamyloid-beta and Copper Chelation. AB - In this study, a bifunctional Abeta aggregation inhibitor peptide, GGHRYYAAFFARR (GR), with the abilities to bind copper and antiamyloid was designed to inhibit the neurotoxicity of the Abeta-Cu(II) complex. The thioflavin T (ThT) assay, turbidimetric analysis, transmission electron microscopy (TEM), and (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay were used to study its potential inhibitory effect on Abeta aggregation. Our findings indicate that GGH was the specific chelating sequence and that the RYYAAFFARR (RR) component acted as an aggregation inhibitor. More importantly, GR significantly decreased the cytotoxicity of the Abeta-Cu(II) complex. The cell viability improved to 88%, which was higher than with the single functional peptide GGH and RR by 39% and 20%, respectively. Moreover, the qualitative effect of Cu(II) on the Abeta-Cu(II) complex was also studied. Our results indicate that Cu(II) induces the formation of the beta-sheet structure with a subequimolar Cu(II):Abeta molar ratio (0.25:1) but led to increased ROS production at a supra equimolar ratio. PMID- 26756253 TI - Decompressive craniectomy and hydrocephalus: proposal of a therapeutic flow chart. AB - Decompressive craniectomy (DC) may be necessary to save the lives of patients suffering from intracranial hypertension. However, this procedure is not complication-free. Its two main complications are hydrocephalus and the sinking skin-flap syndrome (SSFS). The radiological findings and the clinical evaluation may be not enough to decide when and/or how to treat hydrocephalus in a decompressed patient. SSFS and hydrocephalus may be not unrelated. In fact, a patient affected by hydrocephalus, after the ventriculo-peritoneal shunt, can develop SSFS; on the other hand, SSFS per se can cause hydrocephalus. Treating hydrocephalus in decompressed patients can be challenging. Radiological findings and clinical evaluation may not be enough to define the most appropriate therapeutic strategy. Cerebrospinal fluid (CSF) dynamics and metabolic evaluations can represent important diagnostic tools for assessing the need of a CSF shunt in patients with a poor baseline neurologic status. Based on our experience, we propose a flow chart for treating decompressed patients affected by ventriculomegaly. PMID- 26756254 TI - Correction to Small Molecule Inhibitors of Bromodomain-Acetyl-lysine Interactions. PMID- 26756258 TI - ACNS Guideline: Transcranial Electrical Stimulation Motor Evoked Potential Monitoring. PMID- 26756259 TI - Intrapartum Management of the Obese Gravida. AB - Obese women are at increased risk for multiple labor abnormalities, including postdates pregnancy, failed induction of labor, prolonged labor, cesarean delivery, and postpartum hemorrhage (PPH). Prolonged labor among obese women is confined to the first stage of labor. In the setting of reassuring fetal and maternal status, increased time to progress in the first stage of labor should be allowed. Uterine atony occurs more frequently in obese women and vigilance in the prevention of PPH is critical. There is a lack of high-quality data to guide the management of induction, labor, and PPH prevention among obese women. PMID- 26756260 TI - Antepartum Care of the Obese Patient. AB - In the United States, roughly half of women are either overweight (24.5%) or obese (21.4%) when they become pregnant. Women who are obese before pregnancy are at increased risk for a number of pregnancy complications relative to normal weight women. Specifically, obesity is associated with significantly increased maternal risks, including gestational diabetes mellitus, hypertensive disorders of pregnancy, and sleep disordered breathing. Maternal obesity is also associated with increased risks of adverse fetal outcomes, including prematurity, stillbirth, congenital anomalies, and abnormal fetal growth. In this review, we will discuss the implications of obesity with respect to antepartum care. PMID- 26756262 TI - Optimal Mixing Rate in Linear Solvent Strength Gradient Liquid Chromatography. AB - The mixing rate (Rphi) is the temporal rate of increase in the solvent strength in gradient LC. The optimal Rphi (Rphi,Opt) for a gradient analysis is the one at which a required separation capacity and peak capacity of the analysis are obtained in the shortest time. The Rphi,Opt of LSS (linear solvent strength) gradient LC is found in dimensionless form (rphi,Opt) expressing Rphi,Opt in units of hold-up time (t0) and characteristic strength-constant (Phichar). Previously unknown effect of the gradient band compression on the peak capacity is taken into account. The rphi,Opt depends on the solvent composition range covered by the mixing ramp and on the available pressure. A default rphi at which the analysis time is contained within 30% margin of its minimum at rphi,Opt for a broad range of conditions is proposed. As an example, the recommended default for small-molecule samples is 5% increase in the solvent strength per each t0-long increment in time. At this rate, approximately 0.2?N units of peak capacity are generated per each 10% solvent strength increment. The effect of a column kinetic optimization is also evaluated. PMID- 26756263 TI - The apoptotic effect of simvastatin via the upregulation of BIM in nonsmall cell lung cancer cells. AB - PURPOSE: Statins are known to have pleiotropic effects that induce cell death in certain cancer cells. BIM is a member of the bcl-2 gene family, which promotes apoptotic cell death. This study investigated the hypothesis that simvastatin has pro-apoptotic effects in epidermal growth factor receptor (EGFR)-mutated lung cancer cell lines via the upregulation of the expression of the BIM protein. MATERIALS AND METHODS: The cytotoxic effects of simvastatin on gefitinib sensitive (HCC827, E716-A750del) and -resistant (H1975, T790M + L858R) nonsmall cell lung cancer (NSCLC) cells were compared. Cell proliferation and expression of apoptosis-related and EGFR downstream signaling proteins were evaluated. Expression of BIM was compared in H1975 cells after treatment with simvastatin or gefitinib. SiRNA-mediated BIM depletion was performed to confirm whether the cytotoxicity of simvastatin was mediated by the expression of BIM. RESULTS: H1975 cells showed significantly reduced viability compared with HCC827 cells after treatment with simvastatin (2 MUM) for 48 hours. In simvastatin-treated H1975 cells, expression of pro-apoptotic proteins was increased and the phosphorylation of ERK 1/2 (p-ERK 1/2) was reduced. Expression of BIM was suppressed by gefitinib (1 MUM) treatment in H1975 cells, but it was significantly increased by treatment with simvastatin. BIM depletion by siRNA transfection enhanced the viability of H1975 cells that received simvastatin treatment and increased their expression of anti-apoptotic proteins. CONCLUSIONS: Simvastatin restored the expression of BIM to induce apoptotic cell death in NSCLC cells harboring an EGFR-resistant mutation. Our study suggests the potential utility of simvastatin as a BIM targeted treatment for NSCLC. PMID- 26756264 TI - Unsuspected Congenital Tuberculosis. PMID- 26756261 TI - An Evidence-based Approach to the Medical Management of Fibroids: A Systematic Review. AB - Fibroids are the most common tumor of the female reproductive tract, but approved medical treatments are limited. Patients demand uterine-sparing treatments which preserve fertility and avoid surgery. We systematically reviewed PubMed and Cochrane databases from January 1985 to November 2015 for evidence-based medical therapies for fibroids in the context of disease prevention, treatment of early disease, treatment of symptomatic disease, and preoperative management. We identified 2182 studies, of which 52 studies met inclusion and exclusion criteria. Published data affirm the efficacy of multiple agents, which are promising avenues for the development of medical alternatives to surgery. PMID- 26756265 TI - Mycobacterium chelonae Infection Involving a Percutaneous Gastrostomy Tube Tract in a Seven-year-old Child With Acute Lymphoblastic Leukemia. PMID- 26756266 TI - A 15-year-old Nigerian Female with Fever, Shock and Multiple Negative Malaria Smears. PMID- 26756267 TI - Bacterial Tracheitis and Septic Shock. PMID- 26756268 TI - Steroid-responsive Status Epilepticus Caused by Human Parvovirus B19 Encephalitis. PMID- 26756269 TI - Femoral Agminated Petechiae Associated with Acute Parvovirus B19 Infection. PMID- 26756270 TI - Importance of Local Epidemiology in Prevalence and Resistance of Cystic Fibrosis related Pathogens. PMID- 26756271 TI - A Serendipitous Synthesis of Bis-Heterocyclic Spiro 3(2H)-Furanones. AB - (Z) Enol triflates 6, 11b-d, (E) enol triflate 11e, and phenol triflate 11a, derived from beta-keto esters or 2-carboalkoxy phenols, respectively, react with N-Boc 2-lithiopyrrolidine (5a), N-Boc N-methylaminomethyllithium (5b), or 2 lithio-1,3-dithiane (14) to afford 3(2H)-furanones in modest to good yields (38 81%). Product and carbanion reagent studies suggest that the 3(2H)-furanone is formed in a cascade of reactions involving nucleophilic acyl substitution, enolate formation, trifluoromethyl transfer, iminium or sulfenium ion formation, and subsequent ring closure to form the 3(2H)-furanone. The use of 2-lithio-1,3 dithiane affords a cyclic alpha-keto-S,S,O-orthoester in which the functionality can be selectively manipulated for synthetic applications. PMID- 26756272 TI - Injury of the Corticospinal Tract in Patients with Mild Traumatic Brain Injury: A Diffusion Tensor Tractography Study. AB - Motor weakness is an important sequela after traumatic brain injury (TBI). Although the majority of cases of TBI are classified as mild TBI, little is known about motor weakness in mild TBI. In this study, we attempted to investigate injury of the corticospinal tract (CST), an important neural tract for motor function, in patients with mild TBI, using diffusion tensor tractography (DTT). There were 53 patients with mild TBI and 36 control subjects who were recruited. The patients were assigned to two groups according to the presence of abnormality of the right (dominant) hand function in terms of fine motor activity and grip strength: group A-abnormal hand function, group B-normal hand function. The left CST was reconstructed, and DTT parameters (fractional anisotropy [FA] and fiber number) and configuration were estimated. There were 35 (66%) patients who had an abnormal function of the right hand. The values of FA and fiber number of patient group A were significantly lower than those of patient group B and the control group (p < 0.001). On configurational analysis of DTT for the left CST in patient group A, 80% showed partial tearing at the subcortical white matter and 20% showed narrowing. We found that in terms of DTT parameters and configuration, a significant portion of patients with mild TBI showed injury of the CST. These results suggest that DTT could provide useful information in detecting injury of the CST, and evaluation of the CST using DTT would be necessary for patients who complain of hand weakness after mild TBI. PMID- 26756275 TI - Exposure assessment of dogs to mycotoxins through consumption of dry feed. AB - BACKGROUND: The Brazilian exportation of pet food has shown high growth rates in the last two years and determination of the exposure degree is one of the most important parameters for the risk assessment of chemical compounds. In this study the exposure degree of dogs to mycotoxins was estimated and acceptable daily intake (ADI) and safe pet dietary level (SPDL) were calculated. Thus the natural occurrence of fumonisins, zearalenone and aflatoxins was evaluated in 100 dry dog feed samples provided by pet owners in Parana State, Brazil. RESULTS: Despite the high frequency of fumonisins (68%), zearalenone (95%) and aflatoxins (68%) in feed samples, the mean levels detected were low. ADI for fumonisins and zearalenone was 20.0 and 1.00 ug kg(-1) body weight (BW) day(-1) respectively and SPDL for fumonisins was 2000 ug kg(-1) feed. The probable daily intake values (1.83 ug fumonisins, 0.93 ug zearalenone and 0.02 ug aflatoxins kg(-1) BW day(-1) ) were low. CONCLUSION: The exposure degree of dogs could be assumed to be very low. However, the co-occurrence of these three or other mycotoxins, and possible synergic or additive effects, should be taken into account when determining the maximum allowed levels or risk assessment. (c) 2016 Society of Chemical Industry. PMID- 26756273 TI - Genetics of psychosis of Alzheimer disease. AB - Psychotic symptoms, comprised of delusions and hallucinations, occur in about half of individuals with Alzheimer disease (AD with psychosis, AD+P). These individuals have greater agitation, aggression, depression, functional impairment, and mortality than individuals without psychosis (AD-P). Although the exact etiopathogenesis of AD+P is unclear, the rapidly developing field of genomics continues to expand our understanding of this disease. Several independent studies have demonstrated familial aggregation and heritability of AD+P. Linkage studies have been suggestive of loci on several chromosomes associated with AD+P. Association studies examining apolipoprotein E gene, the best established genetic risk factor for late-onset AD, did not find any significant association of this gene with AD+P. Other candidate gene studies focusing on monoamine neurotransmitter systems have yielded equivocal results. A genome-wide association study and studies examining copy number variations recently have detected suggestive associations, but have been underpowered. Approaches to increase sizes of AD+P samples for genome wide association studies are discussed. (c) 2016 Wiley Periodicals, Inc. PMID- 26756276 TI - Lichen scrofulosorum and endometrial tuberculosis: a novel association. AB - BACKGROUND: Lichen scrofulosorum (LS) is a rare tuberculid with an underlying systemic focus of tuberculosis (Tb) detected in majority of cases. The associated Tb foci reported in literature include pulmonary, lymph node, intracranial, abdominal, and cutaneous Tb. We report two women who presented with LS and infertility due to endometrial Tb; an association hitherto undescribed. CASE REPORT: Case 1: A 24-year-old woman presented with asymptomatic grouped papules of LS over the trunk associated with secondary infertility. Endometrial biopsy was suggestive of endometrial Tb, and PCR was positive for M. tuberculosis. The skin lesions resolved after 3 months of anti-tubercular therapy (ATT). Case 2: A 27-year-old woman presented with erythematous, grouped, perifollicular papules over the trunk 5 weeks after starting ATT for endometrial Tb that was diagnosed during work up for primary infertility. A skin biopsy confirmed the diagnosis of LS, and lesions resolved with continuation of ATT for 10 weeks. CONCLUSION: LS can mimic several dermatologic diseases, and a high index of suspicion is required for the diagnosis and initiation of investigations to detect the underlying Tb focus. A good obstetric history in females will aid in early diagnosis and initiation of appropriate therapy. PMID- 26756274 TI - Addressing issues associated with evaluating prediction models for survival endpoints based on the concordance statistic. AB - Prediction models for disease risk and prognosis play an important role in biomedical research, and evaluating their predictive accuracy in the presence of censored data is of substantial interest. The standard concordance (c) statistic has been extended to provide a summary measure of predictive accuracy for survival models. Motivated by a prostate cancer study, we address several issues associated with evaluating survival prediction models based on c-statistic with a focus on estimators using the technique of inverse probability of censoring weighting (IPCW). Compared to the existing work, we provide complete results on the asymptotic properties of the IPCW estimators under the assumption of coarsening at random (CAR), and propose a sensitivity analysis under the mechanism of noncoarsening at random (NCAR). In addition, we extend the IPCW approach as well as the sensitivity analysis to high-dimensional settings. The predictive accuracy of prediction models for cancer recurrence after prostatectomy is assessed by applying the proposed approaches. We find that the estimated predictive accuracy for the models in consideration is sensitive to NCAR assumption, and thus identify the best predictive model. Finally, we further evaluate the performance of the proposed methods in both settings of low dimensional and high-dimensional data under CAR and NCAR through simulations. PMID- 26756277 TI - SCAI Expert consensus statement: Evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory (endorsed by the cardiological society of india, and sociedad Latino Americana de Cardiologia intervencionista). AB - In the United States alone, there are currently approximately 14.5 million cancer survivors, and this number is expected to increase to 20 million by 2020. Cancer therapies can cause significant injury to the vasculature, resulting in angina, acute coronary syndromes (ACS), stroke, critical limb ischemia, arrhythmias, and heart failure, independently from the direct myocardial or pericardial damage from the malignancy itself. Consequently, the need for invasive evaluation and management in the cardiac catheterization laboratory (CCL) for such patients has been increasing. In recognition of the need for a document on special considerations for cancer patients in the CCL, the Society for Cardiovascular Angiography and Interventions (SCAI) commissioned a consensus group to provide recommendations based on the published medical literature and on the expertise of operators with accumulated experience in the cardiac catheterization of cancer patients. PMID- 26756278 TI - Is there a role of pulsed electromagnetic fields in management of patellofemoral pain syndrome? Randomized controlled study at one year follow-up. AB - Patellofemoral pain syndrome (PFPS) is a common cause of recurrent or chronic knee pain in young adults, generally located in the retropatellar region. Etiology is controversial and includes several factors, such as anatomical defects, muscular imbalance, or joint overuse. Good results have been reported with exercise therapy, including home exercise program (HEP). Joint inflammation with increase of pro-inflammatory cytokines levels in the synovial fluid might be seen especially when chondromalacia becomes evident. Biophysical stimulation with pulsed electromagnetic fields (PEMFs) has shown anti-inflammatory effects and anabolic chondrocyte activity. The purpose of this randomized controlled study was to evaluate if the combination of HEP with PEMFs was more effective than HEP alone in PFPS treatment. Thirty-one PFPS patients were enrolled in this study. All patients were instructed to train with HEP. Patients in the PEMFs group associated HEP with PEMFs. Function and pain were assessed with Victorian Institute of Sport Assessment score (VISA), Visual Analog Scale (VAS), and Feller's Patella Score at baseline at 2, 6, and 12 months of follow-up. Drug assumption was also recorded. Increase in VISA score was significantly higher in PEMFs group compared to controls at 6 and 12 months, as well as the increase in the Feller's Patella Score at 12 months. VAS score became significantly lower in the PEMFs group with respect to control group since 6 month follow-up. Pain reduction obtained with PEMFs enhanced practicing therapeutic exercises leading to a better recovery process; this is extremely important in addressing the expectations of young patients, who wish to return to sporting activities. PMID- 26756279 TI - Use of a "Catalytic" Cosolvent, N,N-Dimethyl Octanamide, Allows the Flow Synthesis of Imatinib with no Solvent Switch. AB - A general, efficient method for C-N cross-coupling has been developed using N,N dimethyloctanamide as a catalytic cosolvent for biphasic continuous-flow applications. The described method was used to generate a variety of biarylamines and was integrated into a two-step sequence which converted phenols into biarylamines via either triflates or tosylates. Additionally, the method was applied to a three-step synthesis of imatinib, the API of Gleevec, in good yield without the need of solvent switches. PMID- 26756280 TI - Hemorheological effects of secoisolariciresinol in ovariectomized rats. AB - BACKGROUND: Postmenopausal women often develop hemorheological disorders which may affect the systemic blood circulation and present a cardiovascular risk factor. OBJECTIVE: We evaluated effects of secoisolariciresinol (SECO), a phytoestrogen, on hemorheological parameters and lipid peroxidation in a model of the age-related and/or surgical menopause induced by ovariectomy in rats. METHODS: Arterial blood was sampled from sham-operated female rats, ovariectomized rats (OVX), and OVX treated with SECO (OVXSECO) (20 mg/kg/day intragastrically for two weeks). Plasma estrogen concentration and the following hemorheological parameters were measured: RBC aggregation (half-time of aggregation, T1/2; amplitude of aggregation, AMP; aggregation index, AI), RBC deformability (elongation index, EI), whole blood viscosity at the shear rate of 3-300 s-1, plasma viscosity, hematocrit, plasma fibrinogen. Lipid peroxidation was evaluated by measuring conjugated dienes (CD) and thiobarbituric acid reactive substances (TBARS) in plasma. RESULTS: Ovariectomy in rats caused a 60% decrease in plasma estrogen level and triggered the development of macro- and microhemorheological abnormalities. Blood viscosity increased by 12-31%, RBC elongation index reduced by 16-28%, and T1/2 and AI increased by 35% and 29% respectively. The increase in blood viscosity correlated predominantly with reduced RBC deformability. Plasma CD and TBARS were elevated by 47% and 104% respectively. SECO therapy for OVX rats reduced blood viscosity by 9-18% and T1/2 by 32%, and increased EI by 4-17%. SECO therapy disrupted the correlation between blood viscosity and RBC deformability. Lipid peroxidation was significantly inhibited, as shown by the reduction in CD and TBARS plasma concentrations by 89% and 70% respectively. SECO did not affect plasma viscosity, estrogen or fibrinogen levels. CONCLUSIONS: SECO treatment for OVX rats improves blood macro- and microrheological parameters, possibly through antioxidant protection of RBC. PMID- 26756282 TI - Improved nonparametric estimation of the optimal diagnostic cut-off point associated with the Youden index under different sampling schemes. AB - A diagnostic cut-off point of a biomarker measurement is needed for classifying a random subject to be either diseased or healthy. However, the cut-off point is usually unknown and needs to be estimated by some optimization criteria. One important criterion is the Youden index, which has been widely adopted in practice. The Youden index, which is defined as the maximum of (sensitivity + specificity -1), directly measures the largest total diagnostic accuracy a biomarker can achieve. Therefore, it is desirable to estimate the optimal cut-off point associated with the Youden index. Sometimes, taking the actual measurements of a biomarker is very difficult and expensive, while ranking them without the actual measurement can be relatively easy. In such cases, ranked set sampling can give more precise estimation than simple random sampling, as ranked set samples are more likely to span the full range of the population. In this study, kernel density estimation is utilized to numerically solve for an estimate of the optimal cut-off point. The asymptotic distributions of the kernel estimators based on two sampling schemes are derived analytically and we prove that the estimators based on ranked set sampling are relatively more efficient than that of simple random sampling and both estimators are asymptotically unbiased. Furthermore, the asymptotic confidence intervals are derived. Intensive simulations are carried out to compare the proposed method using ranked set sampling with simple random sampling, with the proposed method outperforming simple random sampling in all cases. A real data set is analyzed for illustrating the proposed method. PMID- 26756283 TI - Cytotoxicity of Postmodified Zeolitic Imidazolate Framework-90 (ZIF-90) Nanocrystals: Correlation between Functionality and Toxicity. AB - Using a simple method, the aldehyde groups of zeolitic imidazolate framework-90 (ZIF-90) nanocrystals were converted into carboxyl, amino, and thiol groups, without affecting the integrity of the framework. Notably, for the first time, correlations between functionality and cytotoxicity are also demonstrated via in vitro cytotoxicity assays. The positive charged aminated-ZIF-90 presumably results in either perturbation of cell membrane, more efficient cell uptake, or both. Therefore, the half-maximal effective (EC50 ) concentration of aminated-ZIF 90 has a higher cytotoxicity of about 30 MUg mL(-1) . PMID- 26756281 TI - Family-based interventions to increase physical activity in children: a systematic review, meta-analysis and realist synthesis. AB - OBJECTIVE: Family-based interventions represent a potentially valuable route to increasing child physical activity (PA) in children. A dual meta-analysis and realist synthesis approach examined existing interventions to assist those developing programmes to encourage uptake and maintenance of PA in children. DESIGN: Studies were screened for inclusion based on including participants aged 5-12 years, having a substantive aim of increasing PA by engaging the family and reporting on PA outcome. Duplicate data extraction and quality assessment were conducted. Meta-analysis was conducted in STATA. Realist synthesis included theory development and evidence mapping. RESULTS: Forty-seven studies were included, of which three received a 'strong' quality rating, 21 'moderate' and 23 'weak'. The meta-analysis (19 studies) demonstrated a significant small effect in favour of the experimental group (standardized mean difference: 0.41; 95%CI 0.15 0.67). Sensitivity analysis, removing one outlier, reduced this to 0.29 (95%CI 0.14-0.45). Realist synthesis (28 studies) provided insight into intervention context (particularly, family constraints, ethnicity and parental motivation), and strategies to change PA (notably, goal-setting and reinforcement combined). CONCLUSION: This review provides key recommendations to inform policy makers and other practitioners in developing evidence-based interventions aimed at engaging the family to increase PA in children, and identifies avenues for future research. PMID- 26756284 TI - Permanent Pacemaker Implantation Early After Cardiac Surgery: A Descriptive Study of Pacemaker Utility After One Year of Follow-Up. AB - BACKGROUND: Complete heart block (CHB) is a common complication of cardiac surgery, which may resolve spontaneously. The optimal number of days to wait for resolution of CHB prior to proceeding with a permanent pacemaker (PPM) and the long-term utility of PPMs placed in this setting remain uncertain. METHODS AND RESULTS: This was a retrospective cohort study, which included members of Kaiser Permanente Northern California who had cardiac surgery, a PPM placed within 30 days after surgery, and one year of follow-up time. Chart review was performed to determine the frequency of ventricular pacing at each PPM interrogation visit up to one year after surgery. A PPM was categorized as underutilized at the time of an interrogation if none of the following were present: underlying rhythm <40 bpm, persistent CHB, or >1% ventricular pacing. The study included 247 patients with a mean time from cardiac surgery to PPM of 6.5 days. In 33 cases (13%), underutilized status was confirmed. The time from surgery to PPM implant was significantly higher in the underutilized group (8.1 +/- 4.2 days vs. 6.2 +/- 4.2 days, p = 0.003). CONCLUSIONS: The majority of PPMs placed early after cardiac surgery are not underutilized. In this retrospective, observational study, longer delay from surgery to PPM implantation was not associated with a greater likelihood that the PPM would be utilized long term. A prospective study is required to determine optimal timing of PPM implantation in this setting. PMID- 26756285 TI - Engineered, Robust Polyelectrolyte Multilayers by Precise Control of Surface Potential for Designer Protein, Cell, and Bacteria Adsorption. AB - Cross-linked layer-by-layer (LbL) assemblies with a precisely tuned surface zeta potential were fabricated to control the adsorption of proteins, mammalian cells, and bacteria for different biomedical applications. Two weak polyions including a synthesized polyanion and polyethylenimine were assembled under controlled conditions and cross-linked to prepare three robust LbL films as model surfaces with similar roughness and water affinity but displaying negative, zero, and positive net charges at the physiological pH (7.4). These surfaces were tested for their abilities to adsorb proteins, including bovine serum albumin (BSA) and lysozyme (LYZ). In the adsorption tests, the LbL films bind more proteins with opposite charges but less of those with like charges, indicating that electrostatic interactions play a major role in protein adsorption. However, LYZ showed higher nonspecific adsorption than BSA, because of the specific behavior of LYZ molecules, such as stacked multilayer formation during adsorption. To exclude such stacking effects from experiments, protein molecules were covalently immobilized on AFM colloidal probes to measure the adhesion forces against the model surfaces utilizing direct protein molecule-surface contacts. The results confirmed the dominating role of electrostatic forces in protein adhesion. In fibroblast cell and bacteria adhesion tests, similar trends (high adhesion on positively charged surfaces, but much lower on neutral and negatively charged surfaces) were observed because the fibroblast cell and bacterial surfaces studied possess negative potentials. The cross-linked LbL films with improved stability and engineered surface charge described in this study provide an excellent platform to control the behavior of different charged objects and can be utilized in practical biomedical applications. PMID- 26756286 TI - Performance of the CORE-10 and YP-CORE measures in a sample of youth engaging with a community mental health service. AB - This article assesses the performance and psychometric properties of two versions of the Clinical Outcomes in Routine Evaluation (CORE) measures that assess psychological distress: the Young Person's CORE (YP-CORE) for 11-16 year olds and the CORE-10 for those 17 or older. The sample comprised 1592 young people aged 12 25 who completed the YP-CORE and CORE-10 during their initial engagement with an early intervention service. Total and average scores were examined for both measures. Gender and age differences were evaluated using t-tests and analysis of variance. The factor structures were assessed with principal axis and confirmatory factor analyses. Multigroup confirmatory factor analyses were then employed to evaluate measurement invariance across age and gender. Analyses were supportive of the CORE measures as reliable instruments to assess distress in 12 25 year olds. Based upon eigenvalues in combination with the comparative fit index, the Tucker-Lewis Index, and the root-mean-square error of approximation, both measures were unidimensional. Analysis indicated the factor structure, loadings, item thresholds, and residuals were invariant across age and gender, although partial support for strict invariance was found for gender among 12-16 year olds. Results are compared to previous studies and discussed in the context of program planning, service delivery, and evaluation. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26756287 TI - Dying Care Interventions in the Intensive Care Unit. AB - PURPOSE: Providing high-quality end-of-life care is a challenging area in intensive care practice. The aim of the current study was to assess the practice of registered nurses (RNs) with respect to dying care and spiritual support interventions in intensive care units (ICUs) in the Czech Republic (CR) and find correlations between particular factors or conditions and the frequency of NIC interventions usage. DESIGN AND METHODS: A cross-sectional, descriptive study was designed. A questionnaire with Likert scales included the particular activities of dying care and spiritual support interventions and an evaluation of the factors influencing the implementation of the interventions in the ICU. The group of respondents consisted of 277 RNs working in 29 ICUs in four CR regions. The Mann-Whitney U test and Pearson correlation coefficient were used for statistical evaluation. FINDINGS: The most and least frequently reported RN activities were "treat individuals with dignity and respect" and "facilitate discussion of funeral arrangements," respectively. The frequencies of the activities in the biological, social, psychological, and spiritual dimensions were negatively correlated with the frequency of providing care to dying patients. A larger number of activities were related to longer lengths of stay in the ICU, higher staffing, more positive opinions of the RNs regarding the importance of education in a palliative care setting, and attending a palliative care education course. CONCLUSIONS: The psychosocial and spiritual activities in the care of dying patients are used infrequently by RNs in CR ICUs. The factors limiting the implementation of palliative care interventions and strategies improving implementation warrant further study. CLINICAL RELEVANCE: Assessment of nursing activities implemented in the care of dying patients in the ICU may help identify issues specific to nursing practice. PMID- 26756288 TI - Remote C-H Activation of Quinolines through Copper-Catalyzed Radical Cross Coupling. AB - Achieving site selectivity in carbon-hydrogen (C-H) functionalization reactions is a formidable challenge in organic chemistry. Herein, we report a novel approach to activating remote C-H bonds at the C5 position of 8-aminoquinoline through copper-catalyzed sulfonylation under mild conditions. Our strategy shows high conversion efficiency, a broad substrate scope, and good toleration with different functional groups. Furthermore, our mechanistic investigations suggest that a single-electron-transfer process plays a vital role in generating sulfonyl radicals and subsequently initiating C-S cross-coupling. Importantly, our copper catalyzed remote functionalization protocol can be expanded for the construction of a variety of chemical bonds, including C-O, C-Br, C-N, C-C, and C-I. These findings provide a fundamental insight into the activation of remote C-H bonds, while offering new possibilities for rational design of drug molecules and optoelectronic materials requiring specific modification of functional groups. PMID- 26756290 TI - Immunobullous disease and ulcerative colitis - the need of an accurate diagnosis. PMID- 26756291 TI - Natural history of non-neurogenic overactive bladder and urinary incontinence over 5 years in community-dwelling older men: The concord health and aging in men project. AB - AIMS: To describe the natural history of non-neurogenic overactive bladder (OAB) and urgency incontinence in community-dwelling older men. METHODS: A representative sample of 1,705 community-dwelling men aged 70 and older in a defined geographic area of Sydney, Australia, had their urinary symptoms assessed using the International Prostate Symptom Scores (IPSS) and the International Consultation of Incontinence Questionnaire (ICIQ) at baseline, 2-year follow-up, and 5-year follow-up. Four hundred and eighty-eight men without neurological diseases or prostate cancer during follow-up, or history of urological treatment at baseline were included in the analysis. Urgency incontinence was defined as leakage of urine occurring more than weekly in the above-defined population. OAB was defined as either urgency or urgency incontinence according to 2002 International Continence Society consensus. RESULTS: Of the men with OAB at baseline, 29% received treatment for OAB or benign prostatic enlargement over 5 years. Of the remaining men, 33% had sustained remission at 2-year and 5-year follow-ups without treatment. Of the men with OAB at 2-year follow-up, remission rate at 5-year follow-up was 53% in men without OAB at baseline and 27% in men with OAB at baseline (P = 0.23). No statistically significant difference was found in baseline characteristics between men with sustained remission and men with persistent symptoms. CONCLUSIONS: One in three older men with non-neurogenic OAB had sustained remission of symptoms without medical or surgical interventions. No significant predictor of sustained remission was identified. Neurourol. Urodynam. 36:443-448, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26756289 TI - Management of Periprocedural and Early Pericardial Effusions With Tamponade Following Ablation of Atrial Fibrillation With Uninterrupted Factor Xa Inhibitors: A Case Series. AB - INTRODUCTION: Because of the absence of a dedicated reversal agent, the outcome of pericardial effusion (PE) following procedures performed with uninterrupted apixaban or rivaroxaban is unknown. We report the characteristics of PEs presenting with tamponade in patients undergoing AF ablation with uninterrupted factor Xa inhibition (FXaI) to understand their management and prognosis. METHODS AND RESULTS: We performed a multicenter cross-sectional survey in 10 centers across the United States. Patient data were obtained by chart review. In all patients the procedure was performed with uninterrupted FXaI. A total of 16 PEs requiring intervention were reported from 5 centers. Two patients were on apixaban 5 mg BD, the remaining on rivaroxaban 20 mg OD. Eleven PEs occurred in the periprocedural setting, and 5 PEs occurred from 1 to 28 days after the procedure. Pericardiocentesis and drainage were performed in all cases. Protamine and 4-factor prothrombin complex concentrate (4F-PCC) were given in all periprocedural cases. Two patients required surgery: in one case coagulation of the pericardial blood prevented effective drainage, and in the other bleeding was secondary to a steam pop-induced atrial tear. None of the postprocedural cases required FXaI reversal and the dose of rivaroxaban was temporarily reduced. No fatal outcomes or thromboembolic events were reported. CONCLUSION: Pericardiocentesis and drainage with FXaI reversal proved effective in the management of acute PEs with tamponade occurring periprocedurally in patients undergoing AF ablation with uninterrupted FXaI. Early postprocedural effusions can be treated with pericardiocentesis without the need of a reversal agent. PMID- 26756292 TI - Role of genomics and transcriptomics in selection of reintroduction source populations. AB - The use and importance of reintroduction as a conservation tool to return a species to its historical range from which it has been extirpated will increase as climate change and human development accelerate habitat loss and population extinctions. Although the number of reintroduction attempts has increased rapidly over the past 2 decades, the success rate is generally low. As a result of population differences in fitness-related traits and divergent responses to environmental stresses, population performance upon reintroduction is highly variable, and it is generally agreed that selecting an appropriate source population is a critical component of a successful reintroduction. Conservation genomics is an emerging field that addresses long-standing challenges in conservation, and the potential for using novel molecular genetic approaches to inform and improve conservation efforts is high. Because the successful establishment and persistence of reintroduced populations is highly dependent on the functional genetic variation and environmental stress tolerance of the source population, we propose the application of conservation genomics and transcriptomics to guide reintroduction practices. Specifically, we propose using genome-wide functional loci to estimate genetic variation of source populations. This estimate can then be used to predict the potential for adaptation. We also propose using transcriptional profiling to measure the expression response of fitness-related genes to environmental stresses as a proxy for acclimation (tolerance) capacity. Appropriate application of conservation genomics and transcriptomics has the potential to dramatically enhance reintroduction success in a time of rapidly declining biodiversity and accelerating environmental change. PMID- 26756293 TI - Open-Label Study of the Influence of Food Containing the Royal Sun Mushroom, Agaricus brasiliensis KA21 (Higher Basidiomycetes), on the Quality of Life of Healthy Human Volunteers. AB - We conducted an open-label study in which food containing Agaricus brasiliensis KA21 was consumed continuously for 12 weeks. A questionnaire for subjective evaluation of the efficacy of this food (hereafter, subjective evaluation questionnaire) revealed significant improvements compared with before its intake; there were improvements in the scores of the amounts of hair loss and gray hair, fatigue and general malaise, eye strain, shoulder stiffness, coldness of extremities, difficulty staying awake during the day, and ease of getting out of bed. These findings suggest that intake of food containing A. brasiliensis KA21 results in the above-mentioned subjectively evaluated improvements, and the possibility that A. brasiliensis KA21 improves the body's immunity. Moreover, no issues regarding the safety of the test food were found. PMID- 26756294 TI - Antiviral Activity of a Cloned Peptide RC28 Isolated from the Higher Basidiomycetes Mushroom Rozites caperata in a Mouse Model of HSV-1 Keratitis. AB - An Escherichia coli-expressed peptide with a molecular weight of 28.26, derived from the complementary DNA of antiviral protein RC28 isolated from the mushroom Rozites caperata (=Cortinarius caperatus), demonstrated potent antiviral activity against herpes simplex virus-1 in Vero cells and in a herpes simplex virus-1 mouse keratitis model. Plaque assays in Vero cells showed that the peptide reduced viral yields by at least 1.2 logs; in the animal model the cloned peptide delayed the occurrence of stromal keratitis and alleviated the severity of the disease. We believe this is the first report of a cloned mushroom peptide with antiviral activity for the prevention and treatment of a viral disease. PMID- 26756295 TI - Protective Efficacy of the Caterpillar Mushroom, Ophiocordyceps sinensis (Ascomycetes), from India in Neuronal Hippocampal Cells against Hypoxia. AB - This study demonstrated the protective efficiency of extracts of the Indian variety of Ophiocordyceps sinensis (=Cordyceps sinensis) (CSEs) in HT22 (murine hippocampal) cells under hypoxic conditions. Various parameters such as cell viability, reactive oxygen species, levels of endogenous antioxidants, inflammatory cytokines, transcription factors, and oxidation of macromolecules were analyzed. In addition, the radical scavenging abilities of hydroxyl radicals, nitric oxide, and superoxide radicals were also studied. Antioxidant compounds, ascorbic acid, hesperidin, and rutin were quantified by high performance thin-layer chromatography. The information acquired from high performance thin-layer chromatography profiling was subjected to principal component analysis for data clustering. Findings of this research revealed that ascorbic acid and rutin were highest in aqueous CSE, whereas the maximum amount of hesperidin was found in 25% alcoholic CSE. In vitro studies showed that all the CSEs protected HT22 cells well by upregulating the level of endogenous antioxidants and preventing the oxidation of lipids and proteins. These extracts also reduced the amount of hypoxia-induced inflammatory cytokines and transcription factors on par with the normoxic control with more or less equal protection in the cells under hypoxia, and indicated significant radical scavenging potential. PMID- 26756296 TI - Molecular Markers to Detect the Formation of Heterokaryon and Homokaryon from Asexual Spores of the Caterpillar Medicinal Mushroom, Cordyceps militaris (Ascomycetes). AB - Cordyceps militaris is widely cultivated on artificial media in China; however, the cultures often are afflicted with the degeneration of nonfruiting strains. To understand the mechanism of degeneration of C. militaris, from the heterokaryotic strain into the homokaryotic strain, we examined the mating-type genes present in individual asexual spores. Further, we determined the distribution ratio of the different mating-type genes among a sample of asexual spores and the growth rate of heterokaryotic and homokaryotic strains of C. militaris. The distribution ratio of 3 groups of asexual spores from C. militaris heterokaryotic strains was determined as 1:1:1 by statistical analysis, whereas that of the two types of nuclei among asexual spores was 1:1. Nearly two-thirds of the asexual spore isolates were homokaryon, which showed a growth speed similar to the heterokaryon. However, the homokaryon (bearing mating-type MAT-HMG) grew significantly faster at times compared with the heterokaryon. Therefore, the purity of the spawn was difficult to establish. C. militaris heterokaryotic strains can transform into a homokaryotic strain following continued subculture. PMID- 26756297 TI - In Vivo Iron-Chelating Activity and Phenolic Profiles of the Angel's Wings Mushroom, Pleurotus porrigens (Higher Basidiomycetes). AB - Pleurotus porrigens is an culinary-medicinal mushroom. It is locally called sadafi and is found in the northern regions of Iran, especially in Mazandaran. This mushroom is used to prepare a variety of local and specialty foods. Because of the phenol and flavonoid contents and the strong iron-chelating activity of this mushroom, it was selected for an assay of in vivo iron-chelating activity. Methanolic extract was administered intraperitoneally to iron-overloaded mice at two dosages (200 and 400 mg/kg/24 hours) for a total of 20 days, with a frequency of 5 times a week for 4 successive weeks. The total iron content was determined by atomic absorption spectroscopy. Plasma Fe3+ content was determined using a kit. Liver sections were stained by hematoxylin and eosin and Perls stain. A significant decrease in the plasma concentration of iron was observed in mice treated with extracts (P < 0.001). The animals showed a dramatic decrease in plasma Fe3+ content when compared with the control group (P < 0.001). Also, Perls stain improved the smaller amount of deposited iron in the liver of iron overloaded mice treated with the extract. Liver sections revealed a marked reduction in the extent of necrotic hepatocytes, fibrous tissues, and pseudo lobules. A high-performance liquid chromatography method was developed to simultaneously separate 7 phenolic acids in extract. Rutin (1.784 +/- 0.052 mg g( 1) of extract) and p-coumaric acid (1.026 +/- 0.043 mg g(-1) of extract) were detected as the main flavonoid and phenolic acids in extract, respectively. The extract exhibited satisfactory potency to chelate excessive iron in mice, potentially offering new natural alternatives to treat patients with iron overload. More studies are needed to determine which compounds are responsible for these biological activities. PMID- 26756298 TI - Optimization, Purification, Characterization, and Antioxidant Activity of Exopolysaccharide Produced by the Northern Tooth Mushroom, Climacodon septentrionalis (Basidiomycota). AB - The optimization, purification, and characterization of exopolysaccharide (EPS) from Climacodon septentrionalis were investigated. The results showed that the optimal incubation time was 8 days for EPS production by C. septentrionalis; maltose and soy extract were the best carbon and nitrogen sources, respectively. One kind of EPS fraction was purified; it had a molecular weight of about 3.4 * 10(5) Da and mainly comprised glucose (98%). The main structure of EPS is alpha glucopyranose. In addition, the EPS showed good antioxidant properties in vitro. The thermal stability of EPS also was investigated, and the results suggest that to maintain its bioactivity the processing temperature of EPS should not be more than 200 degrees C. The structural characteristics of EPS, such as molecular weight, functional groups, monosaccharide constituents, and configuration of the glycosidic bond give EPS great potential for application as a natural antioxidant material in health, food, and therapeutics. PMID- 26756299 TI - Structural Changes of Erythrocyte Surface Glycoconjugates after Treatment with Medicinal Mushrooms. AB - Under conditions of chronic hyperglycemia there is dysregulation of ion homeostasis, violation of redox metabolism and functioning of membrane enzymes, as well as changes in the structural and functional states of erythrocyte membranes. As a result, the aggregation ability of erythrocytes increased and their deformability decreased. These changes lead to complications to microcirculation blood flow and provoke the development of vascular complications caused by diabetes mellitus. This study investigated the effect of the medicinal mushrooms Agaricus brasiliensis and Ganoderma lucidum on the structure of carbohydrate determinants of surface membrane glycoconjugates of rat peripheral blood erythrocytes under both normal conditions and streptozotocin-induced diabetes mellitus. The research was carried out using Wistar outbred white rats. Diabetes was induced by streptozotocin intraperitoneally injected once at a dose of 50 mg/kg body weight. The mushroom preparations were orally administered at a dose of 1 g/kg for 14 days. The treatment of diabetic rats by submerged culture mycelium powder restored the physiological balance between sialylation and desialylation processes, renewed the membrane surface charge of red blood cells, normalized aggregation properties, and caused the structural recovery of oligosaccharide chains of erythrocyte membrane surface glycoconjugates. The discovered changes show an improvement in the erythrocyte functional state and rejuvenation of their population caused by biologically active compounds of the studied medicinal mushrooms. PMID- 26756300 TI - A Water-Ethanol Extract from the Willow Bracket Mushroom, Phellinus igniarius (Higher Basidiomycetes), Reduces Transient Cerebral Ischemia-Induced Neuronal Death. AB - This study investigated the potential neuroprotective effect of a mushroom extract from Phellinus igniarius (Piwep) after transient cerebral ischemia. Ph. Igniarius, which has a history of traditional medicinal use, contains immunomodulatory compounds that have been described to have effects on the human immune system. Using a model of transient cerebral ischemia induced by both common carotid artery occlusion and hypovolemia, a water-ethanol extract precipitate of Ph. Igniarius (Piwep) was delivered intraperitoneally immediately after the insult and was injected subsequently every other day for the experimental course. Neuronal death was examined by Fluoro-Jade B staining 1 week after the insult. Piwep injection lead to decreased hippocampal neuronal death, suppression of oxidative injury, activation of microglia, and disruption of the blood-brain barrier. We conclude that Piwep potently inhibits hippocampal neuronal death following ischemia and may have a high therapeutic potential for ameliorating stroke-induced neuron death in the clinical setting. PMID- 26756301 TI - Antitumor and Immunomodulating Activities of Exopolysaccharide Produced by Big Cup Culinary- Medicinal Mushroom Clitocybe maxima (Higher Basidiomycetes) in Liquid Submerged Culture. AB - Water-soluble polysaccharides extracted from mushrooms have been found to have some physiological effects. In this study, exopolysaccharides (EPSs) were extracted by alcohol precipitation from cultivated broth of the mushroom Clitocybe maxima. EPSs with molecular weights of 10(4) and 10(5) Da were obtained by ultrafiltration; they are referred to as EPA and EPB, respectively. The major components of these EPSs were glucose, galactose, mannose, rhamnose, and arabinose. ICR mice with artificially induced metastatic pulmonary tumors were fed a daily diet containing EPA or EPB at doses of 8, 20, or 50 mg/kg. Results showed that the proliferation of pulmonary sarcoma lesions was lower in the groups fed EPS. In addition, the numbers of total T cells, CD4+ cells, CD8+ cells, and macrophages significantly increased in EPS-fed mice compared with the negative control group. The antitumor and immunomodulating effects observed in the EPB-fed groups were higher than those of EPA-fed groups. These results demonstrate the ability of EPSs of C. maxima to inhibit tumor cells while enhancing immune response. PMID- 26756302 TI - Adjustment disorder and risk of Parkinson's disease. AB - BACKGROUND AND PURPOSE: It has been postulated that stress is part of the etiological process of Parkinson's disease (PD). The risk of PD was examined in a cohort of patients with adjustment disorders, a diagnosis made in the presence of a severe response to a stressful life event. METHODS: Using Danish medical registries, PD occurrence was examined in a nationwide population-based cohort of patients with adjustment disorder diagnosed between 1995 and 2011. The standardized incidence ratio of PD was calculated as the ratio of observed to expected cases, stratified by time and potential risk factors, including depression and anxiety. RESULTS: Our adjustment disorder cohort (67 786 patients) was followed for a median of 8 years (interquartile range 4, 12.6 years). During follow-up, 119 patients developed PD, versus 64 expected, corresponding to a standardized incidence ratio of 1.84 (95% confidence interval 1.53, 2.20). Consistent results were observed after stratification on potential risk factors, including depression and anxiety. CONCLUSION: Adjustment disorder, a diagnosis made in the presence of severe response to stressful life events, was associated with an increased risk of PD. PMID- 26756303 TI - Absolute Configuration of Hydroxysqualene. An Intermediate in Bacterial Hopanoid Biosynthesis. AB - Squalene (SQ) is a key intermediate in hopanoid biosynthesis. Many bacteria synthesize SQ from farnesyl diphosphate (FPP) in three steps: FPP to (1R,2R,3R) presqualene diphosphate (PSPP), (1R,2R,3R)-PSPP to hydroxysqualene (HSQ), and HSQ to SQ. Chemical, biochemical, and spectroscopic methods were used to establish that HSQ synthase synthesizes (S)-HSQ. In contrast, eukaryotic squalene synthase catalyzes solvolysis of (1R,2R,3R)-PSPP to give (R)-HSQ. The bacterial enzyme that reduces HSQ to SQ does not accept (R)-HSQ as a substrate. PMID- 26756304 TI - Integrated analysis of DNA methylation and mutations in esophageal squamous cell carcinoma. AB - The recent development of next-generation sequencing technology for extensive mutation analysis, and beadarray technology for genome-wide DNA methylation analysis has made it possible to obtain integrated pictures of genetic and epigenetic alterations, using the same cancer samples. In this study, we aimed to characterize such a picture in esophageal squamous cell carcinomas (ESCCs). Base substitutions of 55 cancer-related genes and copy number alterations (CNAs) of 28 cancer-related genes were analyzed by targeted sequencing. Forty-four of 57 ESCCs (77%) had 64 non-synonymous somatic mutations, and 24 ESCCs (42%) had 35 CNAs. A genome-wide DNA methylation analysis using an Infinium HumanMethylation450 BeadChip array showed that the CpG island methylator phenotype was unlikely to be present in ESCCs, a different situation from gastric and colon cancers. Regarding individual pathways affected in ESCCs, the WNT pathway was activated potentially by aberrant methylation of its negative regulators, such as SFRP1, SFRP2, SFRP4, SFRP5, SOX17, and WIF1 (33%). The p53 pathway was inactivated by TP53 mutations (70%), and potentially by aberrant methylation of its downstream genes. The cell cycle was deregulated by mutations of CDKN2A (9%), deletions of CDKN2A and RB1 (32%), and by aberrant methylation of CDKN2A and CHFR (9%). In conclusion, ESCCs had unique methylation profiles different from gastric and colon cancers. The genes involved in the WNT pathway were affected mainly by epigenetic alterations, and those involved in the p53 pathway and cell cycle regulation were affected mainly by genetic alterations. (c) 2016 Wiley Periodicals, Inc. PMID- 26756305 TI - PLASMA OXYTOCIN CONCENTRATION AND DEPRESSIVE SYMPTOMS: A REVIEW OF CURRENT EVIDENCE AND DIRECTIONS FOR FUTURE RESEARCH. AB - There is substantial recent interest in the role of oxytocin in social and affiliative behaviors-animal models of depression have suggested a link between oxytocin and mood. We reviewed literature to date for evidence of a potential relationship between peripheral oxytocin concentration and depressive symptoms in humans. Pubmed((r)) and PsychINFO((r)) were searched for biomedical and social sciences literature from 1960 to May 19, 2015 for empirical articles in English involving human subjects focused on the relationship between peripheral oxytocin concentration and depressive symptoms, excluding articles on the oxytocin receptor gene, or involving exogenous (i.e. intranasal) administration of oxytocin. Eight studies meeting criteria were identified and formally reviewed. Studies of pregnant women suggested an inverse relationship between oxytocin level and depressive symptom severity. Findings in nonpregnant women were broadly consistent with the role of oxytocin release in response to stress supported by animal studies. The relationship between oxytocin and depression in men appeared to be in the opposite direction, possibly reflecting the influence of gonadal hormones on oxytocinergic functioning found in other mammalian species. Overall, small sample sizes, heterogeneity in study designs, and other methodological limitations may account for inconsistent findings. Future research utilizing reliable oxytocin measurement protocols including measurements across time, larger sample sizes, and sample homogeneity with respect to multiple possible confounders (age, gender, race and ethnicity, ovarian status among women, and psychosocial context) are needed to elucidate the role of oxytocin in the pathogenesis of depression, and could guide the design of novel pharmacologic agents. PMID- 26756306 TI - Are international differences in breast cancer survival between Australia and the UK present amongst both screen-detected women and non-screen-detected women? survival estimates for women diagnosed in West Midlands and New South Wales 1997 2006. AB - We examined survival in screened-detected and non-screen-detected women diagnosed in the West Midlands (UK) and New South Wales (Australia) in order to evaluate whether international differences in survival are related to early diagnosis, or to other factors relating to the healthcare women receive. Data for women aged 50 - 65 years who had been eligible for screening from 50 years were examined. Data for 5,628 women in West Midlands and 6,396 women in New South Wales were linked to screening service records (mean age at diagnosis 53.7 years). We estimated net survival and modelled the excess hazard ratio of breast cancer death by screening status. Survival was lower for women in the West Midlands than in New South Wales (5-year net survival 90.9% [95% CI 89.9%-91.7%] compared with 93.4% [95% CI 92.6% 94.1%], respectively). The difference was greater between the two populations of non-screen-detected women (4.9%) compared to between screen-detected women, (1.8% after adjustment for lead-time and over-diagnosis). The adjusted excess hazard ratio of breast cancer death for West Midlands compared with New South Wales was greater in the non-screen-detected group (EHR 2.00, 95% CI 1.70 - 2.31) but not significantly different to that for women whose cancer had been screen-detected (EHR 1.72, 95% CI 0.87 - 2.56). In this study more than one in three breast cancer deaths in the West Midlands would have been avoided if survival had been the same as in New South Wales. The possibility that women in the UK receive poorer treatment is an important potential explanation which should be examined with care. PMID- 26756307 TI - WCRF/AICR recommendation adherence and breast cancer incidence among postmenopausal women with and without non-modifiable risk factors. AB - Taller height, family history of breast cancer, greater number of years of potential fertility and nulliparity are established non-modifiable risk factors for postmenopausal breast cancer. Greater adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) diet, physical activity and body weight recommendations has previously been shown to be associated with lower breast cancer risk. However, no prior studies have evaluated whether women with non-modifiable risk factors receive similar benefits from recommendation adherence compared to women without these risk factors. In the Iowa Women's Health Study prospective cohort, we investigated whether associations of WCRF/AICR recommendation adherence differed by the presence/absence of non modifiable breast cancer risk factors. Baseline (1986) questionnaire data from 36,626 postmenopausal women were used to create adherence scores for the WCRF/AICR recommendations (maximum score = 8.0). Overall and single recommendation adherence in relation to breast cancer risk (n = 3,189 cases) across levels of non-modifiable risk factors were evaluated using proportional hazards regression. Mean adherence score was 5.0 points (range: 0.5-8.0). Higher adherence scores (score >= 6.0 vs. <= 3.5, HR = 0.76, 95% CI = 0.67-0.87), and adherence to the individual recommendations for body weight and alcohol intake were associated with a lower breast cancer incidence. While not statistically significant among women with more non-modifiable risk factors (score >= 6.0 vs. <= 3.5, HR = 0.76, 95% CI = 0.36-1.63), hazard ratios were comparable to women with the no non-modifiable risk factors (score >= 6.0 vs. <= 3.5, HR = 0.74, 95% CI = 0.49-0.93) (p-interaction = 0.57). WCRF/AICR recommendation adherence is associated with lower breast cancer risk, regardless of non-modifiable risk factor status. PMID- 26756308 TI - Genome-wide analyses in neuronal cells reveal that upstream transcription factors regulate lysosomal gene expression. AB - The upstream transcription factors (USFs) USF1 and USF2 are ubiquitously expressed transcription factors that are characterized by a conserved basic helix loop-helix/leucine zipper DNA-binding domain. They form homo- or heterodimers, and recognize E-box motifs to modulate gene expression. They are known to regulate diverse cellular functions, including the cell cycle, immune responses and glucose/lipid metabolism, but their roles in neuronal cells remain to be clarified. Here, we performed chromatin immunoprecipitation of USF1 from mouse brain cortex. Subsequent promoter array analysis (ChIP-chip) indicated that USF1 exclusively bound to the CACGTG E-box motifs in the proximal promoter regions. Importantly, functional annotation of the USF1-binding targets revealed an enrichment of genes related to lysosomal functions. Gene expression array analysis using a neuronal cell line subsequently revealed that knockdown of USFs de-regulated lysosomal gene expression. Altered expression was validated by quantitative RT-PCR, supporting the conclusion that USFs regulate lysosomal gene expression. Furthermore, USF knockdown slightly increased LysoTracker Red staining, implying a role for USFs in modulating lysosomal homeostasis. Together, our comprehensive genome-scale analyses identified lysosomal genes as targets of USFs in neuronal cells, suggesting a potential additional pathway of lysosomal regulation. DATABASE: The data for the gene expression array and ChIP-chip have been submitted to the Gene Expression Omnibus (GEO) under accession numbers GSE76615 and GSE76616, respectively. PMID- 26756310 TI - Limited dispersal in an ectoparasitic mite, Laelaps giganteus, contributes to significant phylogeographic congruence with the rodent host, Rhabdomys. AB - To explore how biogeography, parasite life history and host vagility influences evolutionary codivergences, we followed a comparative phylogeography approach using a host-specific nonpermanent mite, Laelaps giganteus, that occurs on four rodent species within the genus Rhabdomys. A mtDNA COI haplotype network derived for 278 parasite specimens showed marked phylogeographic congruence with host distributions. Analysis of the less variable nuclear intron Tropomyosin was in part consistent with these results. Although distance-based cophylogenetic analyses in axparafit failed to support significant mtDNA codivergences (P >= 0.02), event-based analyses revealed significant cophylogeny between sampling localities of Rhabdomys and Laelaps using core-pa (P = 0.046) and jane (P = 0.026; P = 0.00). These findings, in conjunction with the weak congruence previously reported among the permanent ectoparasitic lice Polyplax and Rhabdomys, suggest that host-parasite intimacy is not the most important driver of significant codivergence in our study system. Instead, the more restricted dispersal ability of L. giganteus, when compared to Polyplax, resulted in stronger spatial structuring and this could have resulted in significant codivergence. Host switching occurred predominantly on the edges of host distributions and was probably facilitated by climate-induced range shifts. When host ranges shift, the phylogeographic structure of L. giganteus is not reflecting the host movements as most of the nest bound parasites do not disperse with the host (they miss the boat) and the genetic contribution of the few dispersing mite individuals is often overwhelmed by the large number of individuals already present in nests within the new environment (causing them to drown on arrival). PMID- 26756309 TI - Effect of oral hygiene maintenance on HbA1c levels and peri-implant parameters around immediately-loaded dental implants placed in type-2 diabetic patients: 2 years follow-up. AB - OBJECTIVE: The aim of the present 2-year follow-up study was to assess the effect of oral hygiene maintenance on hemoglobin Alc (HbA1c) levels and peri-implant parameters around immediately-loaded dental implants placed in type-2 diabetic patients with varying glycemic levels. MATERIAL AND METHODS: Ninety-one individuals were divided into three groups. In group 1, 30 systemically healthy individuals were included (HbA1c < 6%). Patients in group 2 and 3, comprised of 30 patients with T2DM (HbA1c 6.1-8%); and 31 patients with T2DM (HbA1c 8.1-10%) respectively. In all groups, patients received immediately loaded bone level implants. All participants were enrolled in a 6 monthly periodontal/peri-implant maintenance program. Peri-implant bleeding on probing (BOP), probing depth (PD), and marginal bone loss (MBL) were measured at 6, 12, and 24 months of follow-up. RESULTS: Mean preoperative HbA1c levels in patients in groups 1, 2, and 3 were 4.5%, 6.8%, and 8.7% respectively. In group-1, there was no significant difference in HbA1c levels at all follow-up durations. Among patients in groups 2 and 3, there was a significant decrease in HbA1c levels at 24-months follow-up than 6-months follow-up. At 6 months follow-up, BOP, PD, and MBL were significantly higher among patients in group-3 than group-1. At 12 and 24 months follow-up, there was no significant difference in BOP, PD, and MBL in all groups. CONCLUSIONS: Oral hygiene maintenance reduces hyperglycemia and peri-implant inflammatory parameters around immediately loaded dental implants placed in type 2 diabetic patients. PMID- 26756311 TI - The Chemical Bond in C2. AB - Quantum chemical calculations using the complete active space of the valence orbitals have been carried out for Hn CCHn (n=0-3) and N2. The quadratic force constants and the stretching potentials of Hn CCHn have been calculated at the CASSCF/cc-pVTZ level. The bond dissociation energies of the C-C bonds of C2 and HC=CH were computed using explicitly correlated CASPT2-F12/cc-pVTZ-F12 wave functions. The bond dissociation energies and the force constants suggest that C2 has a weaker C-C bond than acetylene. The analysis of the CASSCF wavefunctions in conjunction with the effective bond orders of the multiple bonds shows that there are four bonding components in C2, while there are only three in acetylene and in N2. The bonding components in C2 consist of two weakly bonding sigma bonds and two electron-sharing pi bonds. The bonding situation in C2 can be described with the sigma bonds in Be2 that are enforced by two pi bonds. There is no single Lewis structure that adequately depicts the bonding situation in C2. The assignment of quadruple bonding in C2 is misleading, because the bond is weaker than the triple bond in HC=CH. PMID- 26756312 TI - Molecular Basis for the Interaction Between AP4 beta4 and its Accessory Protein, Tepsin. AB - The adaptor protein 4 (AP4) complex (epsilon/beta4/MU4/sigma4 subunits) forms a non-clathrin coat on vesicles departing the trans-Golgi network. AP4 biology remains poorly understood, in stark contrast to the wealth of molecular data available for the related clathrin adaptors AP1 and AP2. AP4 is important for human health because mutations in any AP4 subunit cause severe neurological problems, including intellectual disability and progressive spastic para- or tetraplegias. We have used a range of structural, biochemical and biophysical approaches to determine the molecular basis for how the AP4 beta4 C-terminal appendage domain interacts with tepsin, the only known AP4 accessory protein. We show that tepsin harbors a hydrophobic sequence, LFxG[M/L]x[L/V], in its unstructured C-terminus, which binds directly and specifically to the C-terminal beta4 appendage domain. Using nuclear magnetic resonance chemical shift mapping, we define the binding site on the beta4 appendage by identifying residues on the surface whose signals are perturbed upon titration with tepsin. Point mutations in either the tepsin LFxG[M/L]x[L/V] sequence or in its cognate binding site on beta4 abolish in vitro binding. In cells, the same point mutations greatly reduce the amount of tepsin that interacts with AP4. However, they do not abolish the binding between tepsin and AP4 completely, suggesting the existence of additional interaction sites between AP4 and tepsin. These data provide one of the first detailed mechanistic glimpses at AP4 coat assembly and should provide an entry point for probing the role of AP4-coated vesicles in cell biology, and especially in neuronal function. PMID- 26756313 TI - Magnolol protects against trimethyltin-induced neuronal damage and glial activation in vitro and in vivo. AB - Trimethyltin (TMT), an organotin with potent neurotoxic effects by selectively damaging to hippocampus, is used as a tool for creating an experimental model of neurodegeneration. In the present study, we investigated the protective effects of magnolol, a natural biphenolic compound, on TMT-induced neurodegeneration and glial activation in vitro and in vivo. In HT22 murine neuroblastoma cells, TMT induced necrotic/apoptotic cell death and oxidative stress, including intracellular reactive oxygen species (ROS), protein carbonylation, induction of heme oxygenase-1 (HO-1), and activation of all mitogen-activated protein kinases (MAPKs) family proteins. However, magnolol treatment significantly suppressed neuronal cell death by inhibiting TMT-mediated ROS generation and activation of JNK and p38 MAPKs. In BV-2 microglial cells, magnolol efficiently attenuated TMT induced microglial activation via suppression of ROS generation and activation of JNK, p38 MAPKs, and nuclear factor-kappaB (NF-kappaB) signaling. In an in vivo mouse study, TMT induced massive neuronal damage and enhanced oxidative stress at day 2. We also observed a concomitant increase in glial cells and inducible nitric oxide synthase (iNOS) expression on the same day. These features of TMT toxicity were reversed by treatment of magnolol. We observed that p-JNK and p-p38 MAPK levels were increased in the mouse hippocampus at day 1 after TMT treatment and that magnolol blocked TMT-induced JNK and p38 MAPK activation. Magnolol administration prevented TMT-induced hippocampal neurodegeneration and glial activation, possibly through the regulation of TMT-mediated ROS generation and MAPK activation. PMID- 26756314 TI - Cross-protective efficacy from a immunogen firstly identified in Leishmania infantum against tegumentary leishmaniasis. AB - Experimental vaccine candidates have been evaluated to prevent leishmaniasis, but no commercial vaccine has been proved to be effective against more than one parasite species. LiHyT is a Leishmania-specific protein that was firstly identified as protective against Leishmania infantum. In this study, LiHyT was evaluated as a vaccine to against two Leishmania species causing tegumentary leishmaniasis (TL): Leishmania major and Leishmania braziliensis. BALB/c mice were immunized with rLiHyT plus saponin and lately challenged with promastigotes of the two parasite species. The immune response generated was evaluated before and 10 weeks after infection, as well as the parasite burden at this time after infection. The vaccination induced a Th1 response, which was characterized by the production of IFN-gamma, IL-12 and GM-CSF, as well as by high levels of IgG2a antibodies, after in vitro stimulation using both the protein and parasite extracts. After challenge, vaccinated mice showed significant reductions in their infected footpads, as well as in the parasite burden in the tissue and organs evaluated, when compared to the control groups. The anti-Leishmania Th1 response was maintained after infection, being the IFN-gamma production based mainly on CD4(+) T cells. We described one conserved Leishmania-specific protein that could compose a pan-Leishmania vaccine. PMID- 26756315 TI - Design and synthesis of pyrrolobenzodiazepine-gallic hybrid agents as p53 dependent and -independent apoptogenic signaling in melanoma cells. AB - A new class of pyrrolo[2,1-c][1,4]benzodiazepine-Gallic hybrid agents (PBD-GA) conjugated through alkyl spacers has been designed and synthesized. The combination of these two core pharmacophores with modification in the C-8 position of the PBD ring with alkyl spacers afforded oxygen-tethered compounds 5a 5d and amide-tethered analogues 11a-11d with improved anticancer activity for two melanoma cell lines, A375 and RPMI7951, differing in their p53 status. The agents 5a-5d were cytotoxic in melanoma compared to agents 11a-11d. In particular, compounds 5b and 5c were found to possess the most potent activity compared with other hybrid agents and were proved with the help of quantitative structure activity relationship studies (QSAR). These PBD conjugates caused S phase arrest for the A375 cell line via increased reactive oxygen species (ROS) generation, deoxyribonucleic acid (DNA) damage, ataxia telangiectasia mutated (ATM)/ATM-Rad3 related (ATR) and checkpoint kinases 1 (Chk1) activation. Moreover, the PBD-GA induced A375 apoptotic cell death followed through p53 (ATM downstream target) increase, B-cell leukemia-xL (Bcl-xL) and mitochondrial membrane potential (DeltaPsimt) decrease, cytochrome c release, and caspase-3/Poly Adp Ribose Polymerase (PARP) cleavage. On the other hand, mutant p53 RPMI7951 cell death occurred by PBD-GA-mediated mitochondria- and caspase-dependent pathways via lysosomal membrane permeabilization (LMP), but not through p53 signaling. Finally, compound 5b was shown to reduce murine melanoma size in a mouse model. These results suggest that the PBD-GA could be used as a useful chemotherapeutic agent in melanoma with activated p53 or mutant p53. PMID- 26756316 TI - Phospha-Michael Addition as a New Click Reaction for Protein Functionalization. AB - A new type of click reaction between an alkyl phosphine and acrylamide was developed and applied for site-specific protein labeling in vitro and in live cells. Acrylamide is a small electrophilic olefin that readily undergoes phospha Michael addition with an alkyl phosphine. Our kinetic study indicated a second order rate constant of 0.07 m(-1) s(-1) for the reaction between tris(2 carboxyethyl)phosphine and acrylamide at pH 7.4. To demonstrate its application in protein functionalization, we used a dansyl-phosphine conjugate to successfully label proteins that were site-specifically installed with N(E) acryloyl-l-lysine and employed a biotin-phosphine conjugate to selectively probe human proteins that were metabolically labeled with N-acryloyl-galactosamine. PMID- 26756317 TI - On the Margins of Pharmaceutical Citizenship: Not Taking HIV Medication in the "Treatment Revolution" Era. AB - With the expanding pharmaceuticalization of public health, anthropologists have begun to examine how biomedicine's promissory discourses of normalization and demarginalization give rise to new practices of and criteria for citizenship. Much of this work focuses on the biomedicine-citizenship nexus in less-developed, resource-poor contexts. But how do we understand this relationship in resource rich settings where medicines are readily available, often affordable, and a highly commonplace response to illness? In particular, what does it mean to not use pharmaceuticals for a treatable infectious disease in this context? We are interested in these questions in relation to the recent push for early and universal treatment for HIV infection in Australia for the twin purposes of individual and community health. Drawing on Ecks's concept of pharmaceutical citizenship, we examine the implications for citizenship among people with HIV who refuse or delay recommended medication. We find that moral and normative expectations emerging in the new HIV "treatment revolution" have the capacity to both demarginalize and marginalize people with HIV. PMID- 26756318 TI - Comparison of UV Protection Properties of Cotton Fabrics Treated with Aqueous and Methanolic Extracts of Achyranthes aspera and Alhagi maurorum Plants. AB - UV radiations are high-energy radiations present in sunlight that can damage human skin. Protection against these radiations becomes vital especially in those areas of the globe where UV index is quite high that makes the inhabitants more prone to dangerous effects of UV radiations. Clothing materials are good blockers of UV radiations, particularly when the fabric cover factor is high and/or the fabrics contain suitable UV-blocking finishes. In this study, effect of application of aqueous and methanolic extracts of two different plants, i.e., Achyranthes aspera and Alhagi maurorum on UV protection properties of cotton fabric was investigated. The results showed that the fabric samples treated with extracts of both the plants have excellent UV protection properties as indicated by their ultraviolet protection factor. It was concluded that both the aqueous and methanolic plant extracts are very effective in blocking UVA and UVB radiations, when applied on cotton fabrics. The UV protection performance of Achyranthes aspera extracts was much better as compared to that of Alhagi maurorum, and methanolic extracts of both the plants outperformed the aqueous extracts in terms of UV protection. PMID- 26756319 TI - Reversal of cerebral glucose hypometabolism on positron emission tomography with electroconvulsive therapy in an elderly patient with a psychotic episode. AB - AB, a 74-year-old Caucasian woman, was admitted for acute onset of psychosis, anxiety, and cognitive impairment. Pharmacotherapy was unsuccessful and the patient was referred for electroconvulsive therapy (ECT). Pre-ECT, 18 F fluorodeoxyglucose-positron emission tomography (PET)/computed tomography showed extensive frontal, parietal, and temporal cortical hypometabolism suggestive of a neurodegenerative disease. After eight ECT sessions, the psychotic and anxiety symptoms as well as the cognitive impairment resolved. The rapid improvement in symptoms was more suggestive of a psychotic episode rather than dementia. Two days after the ECT course, 18 F-fluorodeoxyglucose-PET/computed tomography showed improvements in cerebral cortical hypometabolism, especially in the left parietal cortex, left temporal/occipital cortex. and bifrontal regions. At a follow-up visit 2 months after the ECT course, the psychotic episode was still in remission, and 18 F-fluorodeoxyglucose-PET/computed tomography continued to show improved cerebral cortical hypometabolism in these areas. This case illustrated the effect of ECT in reversing cerebral glucose hypometabolism on PET. The improvement in cerebral glucose hypometabolism may represent the neurophysiological mechanism of ECT in the treatment of a psychotic episode. Improved cerebral glucose hypometabolism was present 2 months post-ECT, which suggests that ECT caused sustained functional neural changes. PMID- 26756320 TI - The scope of Metallomics. AB - The field of metallomics is still emerging and has grown rapidly over the last few years which, in part, led the Royal Society of Chemistry to launch the associated journal of the field, Metallomics, in 2009. It envisioned to be the leading journal dedicated to metallomics research - investigations of metals within a system. PMID- 26756322 TI - Nanoglasses: A New Kind of Noncrystalline Material and the Way to an Age of New Technologies? AB - Today's technologies are primarily based on crystalline materials (metals, semiconductors, etc.), as their properties can be controlled by varying their chemical and/or defect microstructures. This is not possible in today's glasses. The new features of nanoglasses--consisting of nanometer-sized glassy regions connected by interfaces--are that their properties may be controlled by varying their chemical and/or defect microstructures, and that their interfaces have a new kind of non-crystalline structure. By utilizing these new features, an age of new technologies based on non-crystalline materials (a "glass age") may be initiated. PMID- 26756321 TI - Three-Layered PCL Grafts Promoted Vascular Regeneration in a Rabbit Carotid Artery Model. AB - In this study, a three layered poly (epsilon-caprolactone) (PCL) graft (tPCL) was fabricated by electrospinning PCL and electrospraying poly (ethylene oxide) (PEO), which has a thin dense inner layer, a loose middle layer, and a dense outer layer. Regular PCL grafts (rPCL) with only a dense layer were used as control. In vivo evaluation was performed in rabbit carotid artery. Enhanced cell infiltration, rapid regeneration of endothelium and smooth muscle layers, and increased elastin deposition were observed within the tPCL graft wall. After 3 months, tPCL grafts showed faster PCL degradation than the rPCL grafts. Infiltrated macrophages in the tPCL grafts secreted higher level of monocyte chemoattractant protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) which enhanced vascular regeneration. In conclusion, the tPCL graft may be a useful vascular prosthesis and worth for further investigation. PMID- 26756323 TI - The effect of crutches, an orthosis TheraTogs, and no walking aids on the recovery of gait in a patient with delayed healing post hip fracture: A case report. AB - Accelerated rehabilitation following hip fracture and joint replacement, including early unrestricted weight-bearing and muscle strengthening, has gained importance in hastening functional recovery and hospital discharge. The influence of walking aids on these parameters is sparsely investigated. In this case report, we document the effect of walking with crutches; an orthotic garment and strapping system, TheraTogs; and no walking aids over 3-4-week periods on walking speed, trunk sway, and muscle activity measured with electromyography (EMG). The patient was a 49-year-old female showing delayed healing following a conservatively treated avulsion fracture of the greater trochanter 12 weeks previously with a 14-year history of total hip arthroplasty. EMG analysis showed muscle activity increased with TheraTogs and decreased with crutches compared with walking with no aids. Walking speed improved at a faster rate in the TheraTogs phase than in the crutches phase and reduced in no-walking-aids phase. Mean speed (SD) for each phase was: crutches 1.11 (0.08) m/s, TheraTogs 1.35 (0.11) m/s, and no-aids 1.19 (0.14) m/s. Trunk sway increased in the crutch and no-aids phases, and became more stable in the TheraTogs phase. In this patient, function and recovery rate of all measured parameters increased more in the TheraTogs phase than the crutches or no-aids phase. This may be because muscle activity was facilitated enabling active support of recovering structures. PMID- 26756324 TI - Distinct Patterns of Cognitive Aging Modified by Education Level and Gender among Adults with Limited or No Formal Education: A Normative Study of the Mini-Mental State Examination. AB - BACKGROUND: Dementia is increasingly prevalent due to rapid aging of the population, but under-recognized among people with low education levels. This is partly due to a lack of appropriate and precise normative data, which underestimates cognitive aging in the use of screening tools for dementia. OBJECTIVE: We aimed to improve the precision of screening for cognitive impairment, by characterizing the patterns of cognitive aging and derived normative data of the Mini-Mental State Examination (MMSE) for illiterate and low educated populations. METHODS: This community-based study included data from 2,280 individuals aged 40 years or older from two rural areas. Multiple linear modeling examined the effect of aging on cognition reflected by the MMSE, stratified by education level and gender. Threshold effect of age on cognition was performed using a smoothing function. RESULTS: The majority of participants (60.4%) were illiterate or had attended only primary school (24.6%). The effect of aging on cognition varied by gender and education. Primary-school educated females and males remained cognitively stable up to 62 and 71 years of age, respectively, with MMSE score declining 0.4 and 0.8 points/year in females and males thereafter. Illiterates females scored 2.3 points lower than illiterate males, and scores for both declined 0.2 points/year. According to these results, normative data stratified by age, education and gender was generated. CONCLUSION: This study suggests gender and educational differences exist in cognitive aging among adults with limited or no formal education. To improve screening precision for cognitive impairment with the use of MMSE in low-educated population, age, gender, and education level should be considered. PMID- 26756325 TI - Social Cognition Deficits: The Key to Discriminate Behavioral Variant Frontotemporal Dementia from Alzheimer's Disease Regardless of Amnesia? AB - Relative sparing of episodic memory is a diagnostic criterion of behavioral variant frontotemporal dementia (bvFTD). However, increasing evidence suggests that bvFTD patients can show episodic memory deficits at a similar level as Alzheimer's disease (AD). Social cognition tasks have been proposed to distinguish bvFTD, but no study to date has explored the utility of such tasks for the diagnosis of amnestic bvFTD. Here, we contrasted social cognition performance of amnestic and non-amnestic bvFTD from AD, with a subgroup having confirmed in vivo pathology markers. Ninety-six participants (38 bvFTD and 28 AD patients as well as 30 controls) performed the short Social-cognition and Emotional Assessment (mini-SEA). BvFTD patients were divided into amnestic versus non-amnestic presentation using the validated Free and Cued Selective Reminding Test (FCSRT) assessing episodic memory. As expected, the accuracy of the FCSRT to distinguish the overall bvFTD group from AD was low (69.7% ) with ~50% of bvFTD patients being amnestic. By contrast, the diagnostic accuracy of the mini-SEA was high (87.9% ). When bvFTD patients were split on the level of amnesia, mini-SEA diagnostic accuracy remained high (85.1% ) for amnestic bvFTD versus AD and increased to very high (93.9% ) for non-amnestic bvFTD versus AD. Social cognition deficits can distinguish bvFTD and AD regardless of amnesia to a high degree and provide a simple way to distinguish both diseases at presentation. These findings have clear implications for the diagnostic criteria of bvFTD. They suggest that the emphasis should be on social cognition deficits with episodic memory deficits not being a helpful diagnostic criterion in bvFTD. PMID- 26756326 TI - Limiting Factors of Brain Donation in Neurodegenerative Diseases: The Example of French Memory Clinics. AB - Postmortem neuropathological examination of the brain is essential in neurodegenerative diseases, to ensure accurate diagnosis, to obtain an a posteriori critical assessment of the adequacy of clinical care, and to validate new biomarkers, but is only rarely performed. The purpose of this study was to assess factors limiting brain donation, such as reluctance of physicians to seek donation consent, opposition from patients and families, and organizational constraints. We conducted a survey across French memory clinics and major neuropathological centers. Few postmortem examinations were performed annually, as less than one third of the centers had performed at least five autopsies, and 41% had performed none. The main limiting factor was the lack of donation requests made by physicians, as half of them never approach patients for brain donation. Reasons for not seeking donation consent often include discomfort broaching the subject and lack of awareness of the medical and scientific benefit of postmortems (77%), organizational constraints (61%), and overestimation of families' negative reaction (51%). Family refusals represented a second major obstacle, and were often caused by misconceptions. Identifying and addressing these biases early could help improve physicians' rate of making requests and the public's awareness about the importance of brain donation. PMID- 26756327 TI - Lifetime History of Depression Predicts Increased Amyloid-beta Accumulation in Patients with Mild Cognitive Impairment. PMID- 26756328 TI - Specialized Pro-Resolving Mediators from Omega-3 Fatty Acids Improve Amyloid-beta Phagocytosis and Regulate Inflammation in Patients with Minor Cognitive Impairment. PMID- 26756331 TI - Anticoagulant treatment for subsegmental pulmonary embolism. AB - BACKGROUND: Acute pulmonary embolism (PE) is a common cause of death, accounting for 50,000 to 200,000 deaths annually. It is the third most common cause of mortality among the cardiovascular diseases, after coronary artery disease and stroke.The advent of multi-detector computed tomographic pulmonary angiography (CTPA) has allowed better assessment of PE regarding visualisation of the peripheral pulmonary arteries, increasing its rate of diagnosis. More cases of peripheral PEs, such as isolated subsegmental PE (SSPE) and incidental PE, have thereby been identified. These two conditions are usually found in patients with few or none of the classic PE symptoms such as haemoptysis or pleuritic pain, acute dyspnoea or circulatory collapse. However, in patients with reduced cardio pulmonary (C/P) reserve the classic PE symptoms can be found with isolated SSPEs. Incidental SSPE is found casually in asymptomatic patients, usually by diagnostic imaging performed for other reasons (for example routine CT for cancer staging in oncologic patients).Traditionally, all PEs are anticoagulated in a similar manner independent of the location, number and size of the thrombi. It has been suggested that many patients with SSPE may be treated without benefit, increasing adverse events by possible unnecessary use of anticoagulants.Patients with isolated SSPE or incidental PE may have a more benign clinical presentation compared with those with proximal PEs. However, the clinical significance in patients and their prognosis have to be studied to evaluate whether anticoagulation therapy is required.This review is an update of a Cochrane systematic review first published in 2014. OBJECTIVES: To assess the effectiveness and safety of anticoagulation therapy versus no intervention in patients with isolated subsegmental pulmonary embolism (SSPE) or incidental SSPE. SEARCH METHODS: The Cochrane Vascular Trials Search Co-ordinator searched the Specialised Register (last searched December 2015) and CENTRAL (2015, Issue 11). MEDLINE, EMBASE, LILACS and clinical trials databases were also searched. SELECTION CRITERIA: Randomised controlled trials of anticoagulation therapy versus no intervention in patients with SSPE or incidental SSPE. DATA COLLECTION AND ANALYSIS: Two review authors inspected all citations to ensure reliable selection. We planned for two review authors to independently extract data and to assess the methodological quality of identified trials using the criteria recommended in the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: No studies were identified that met the inclusion criteria. AUTHORS' CONCLUSIONS: There is no randomised controlled trial evidence for the effectiveness and safety of anticoagulation therapy versus no intervention in patients with isolated subsegmental pulmonary embolism (SSPE) or incidental SSPE, and therefore we can not draw any conclusions. Well-conducted research is required before informed practice decisions can be made. PMID- 26756333 TI - Hydration Free Energies of Molecular Ions from Theory and Simulation. AB - We present a theoretical/computational framework for accurate calculation of hydration free energies of ionized molecular species. The method is based on a molecular theory, 3D-RISM, combined with a recently developed pressure correction (PC+). The 3D-RISM/PC+ model can provide ~3 kcal/mol hydration free energy accuracy for a large variety of ionic compounds, provided that the Galvani potential of water is taken into account. The results are compared with direct atomistic simulations. Several methodological aspects of hydration free energy calculations for charged species are discussed. PMID- 26756332 TI - The Effect of Treatment Advances on the Mortality Results of Breast Cancer Screening Trials: A Microsimulation Model. AB - BACKGROUND: Mammography trials, which are the primary sources of evidence for screening benefit, were conducted decades ago. Whether advances in systemic therapies have rendered previously observed benefits of screening less significant is unknown. OBJECTIVE: To compare the outcomes of breast cancer screening trials had they been conducted using contemporary systemic treatments with outcomes of trials conducted with previously used treatments. DESIGN: Computer simulation model of 3 virtual screening trials with similar reductions in advanced-stage cancer cases but reflecting treatment patterns in 1975 (prechemotherapy era), 1999, or 2015 (treatment according to receptor status). DATA SOURCES: Meta-analyses of screening and treatment trials; study of dissemination of primary systemic treatments; SEER (Surveillance, Epidemiology, and End Results) registry. TARGET POPULATION: U.S. women aged 50 to 74 years. TIME HORIZON: 10 and 25 years. PERSPECTIVE: Population. INTERVENTION: Mammography, chemotherapy, tamoxifen, aromatase inhibitors, and trastuzumab. OUTCOME MEASURES: Breast cancer mortality rate ratio (MRR) and absolute risk reduction (ARR) obtained by the difference in cumulative breast cancer mortality between control and screening groups. RESULTS OF BASE-CASE ANALYSIS: At 10 years, screening in a 1975 trial yielded an MRR of 90% and an ARR of 5 deaths per 10,000 women. A 2015 screening trial yielded a 10-year MRR of 90% and an ARR of 3 deaths per 10,000 women. RESULTS OF SENSITIVITY ANALYSIS: Greater reductions in advanced stage disease yielded a greater screening effect, but MRRs remained similar across trials. However, ARRs were consistently lower under contemporary treatments. When contemporary treatments were available only for early-stage cases, the MRR was 88%. LIMITATION: Disease models simplify reality and cannot capture all breast cancer subtypes. CONCLUSION: Advances in systemic therapies for breast cancer have not substantively reduced the relative benefits of screening but have likely reduced the absolute benefits because of their positive effect on breast cancer survival. PRIMARY FUNDING SOURCE: University of Washington and National Cancer Institute. PMID- 26756334 TI - Nmnat3 Is Dispensable in Mitochondrial NAD Level Maintenance In Vivo. AB - Nicotinamide adenine dinucleotide (NAD) is an essential co-enzyme mediating various enzymatic reactions. Mitochondrial NAD particularly occupies a considerable amount of total NAD in cells, and serves as a co-enzyme in tricarboxylic acid cycle (TCA cycle), beta-oxidation, and oxidative phosphorylation. Despite the importance of mitochondrial NAD, its synthesis pathway remains unknown. It has been proposed that NAD synthesis enzyme, Nmnat3, was localized in mitochondria, but its physiological relevance to the metabolism in mitochondria was not fully elucidated. Previously, we have reported that murine Nmnat3 protein was strongly expressed in the cytoplasm of mature erythrocytes, in which mitochondria were absent, and Nmnat3-deficient mice (Nmnat3-KO mice) exhibited splenomegaly and hemolytic anemia due to reduced NAD levels in mature erythrocytes. These results challenged the role of Nmnat3 in mitochondrial NAD synthesis. In this study, we demonstrated that mitochondrial NAD levels in various tissues, except for red blood cells, were unchanged in Nmnat3-KO mice. We also analyzed the metabolites in glycolysis and TCA cycle and found that there were no differences between Nmnat3-KO and WT mice. In addition, the aged Nmnat3-KO mice had comparable NAD levels to that observed in WT mice. Our results indicated that Nmnat3 is dispensable in the maintenance of mitochondrial NAD levels, and that other NAD regulatory pathways may exist in mitochondria. PMID- 26756336 TI - Comparisons of Adherence to Antiretroviral Therapy in a High-Risk Population in China: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Reports on antiretroviral therapy (ART) adherence are scare in China; we performed this meta-analysis to estimate ART adherence rates in different populations at high risk for HIV transmission in China. METHODS: We searched PubMed, Chinese Biomedical Literature Database (Chinese), China National Knowledge Infrastructure (Chinese), and Wanfang (Chinese) to identify studies published from January 1985 to May 2015. We used random-effects meta-analysis to calculate weighted mean estimates across studies and 95% CIs. Data were pooled with proportions transformed prior to pooling using the Freeman-Tukey double arcsine transformation and then back transformed to the original scale. We calculated the I2 (and its 95% confidence intervals) and tau2 to assess between study heterogeneity. RESULTS: We identified 36 eligible articles, including 6885 HIV-positive individuals, reporting ART adherence. Pooled analysis produced an estimate of 77.61% (95% CI = 71.63-83.08) of patients with HIV with adequate adherence; however, high heterogeneity was observed between studies (I2 = 96.60%, 95%CI = 96.00%-97.20%; tau2 = 0.16). Three studies, which included 149 old HIV infected patients, reported the highest ART adequate adherence rate (89.39%, 95% CI = 72.01-99.26) with high heterogeneity between the studies (I2 = 86.20%, 95%CI = 60.00-95.20%; tau2 = 0.13). While, only two studies, which included 143 heterosexual transmission group (HTG) patients, reported the lowest ART adequate adherence rate (51.55%, 95% CI = 41.33-61.71) with low heterogeneity between the studies (I2 = 31.3%, tau2 = 0.007). In the multivariable meta-regression model, high-risk populations was the main factor explaining heterogeneity (variance explained 28.14%). CONCLUSIONS: ART adherence in some high-risk populations (e.g., heterosexual transmission group) is below the recommended levels for maintaining virologic suppression. It is crucial to develop comprehensive intervention strategies to promote ART adherence in high-risk populations and effectively prevent the spread of HIV/AIDS in China. PMID- 26756335 TI - A Novel Triazolopyridine-Based Spleen Tyrosine Kinase Inhibitor That Arrests Joint Inflammation. AB - Autoantibodies and the immunoreceptors to which they bind can contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). Spleen Tyrosine Kinase (Syk) is a non-receptor tyrosine kinase with a central role in immunoreceptor (FcR) signaling and immune cell functionality. Syk kinase inhibitors have activity in antibody-dependent immune cell activation assays, in preclinical models of arthritis, and have progressed into clinical trials for RA and other autoimmune diseases. Here we describe the characterization of a novel triazolopyridine-based Syk kinase inhibitor, CC-509. This compound is a potent inhibitor of purified Syk enzyme, FcR-dependent and FcR-independent signaling in primary immune cells, and basophil activation in human whole blood. CC-509 is moderately selective across the kinome and against other non-kinase enzymes or receptors. Importantly, CC-509 was optimized away from and has modest activity against cellular KDR and Jak2, kinases that when inhibited in a preclinical and clinical setting may promote hypertension and neutropenia, respectively. In addition, CC-509 is orally bioavailable and displays dose-dependent efficacy in two rodent models of immune-inflammatory disease. In passive cutaneous anaphylaxis (PCA), CC-509 significantly inhibited skin edema. Moreover, CC-509 significantly reduced paw swelling and the tissue levels of pro-inflammatory cytokines RANTES and MIP-1alpha in the collagen-induced arthritis (CIA) model. In summary, CC-509 is a potent, moderately selective, and efficacious inhibitor of Syk that has a differentiated profile when compared to other Syk compounds that have progressed into the clinic for RA. PMID- 26756337 TI - Long Lasting Microvascular Tone Alteration in Rat Offspring Exposed In Utero to Maternal Hyperglycaemia. AB - Epidemiologic studies have demonstrated that cardiovascular risk is not only determined by conventional risk factors in adulthood, but also by early life events which may reprogram vascular function. To evaluate the effect of maternal diabetes on fetal programming of vascular tone in offspring and its evolution during adulthood, we investigated vascular reactivity of third order mesenteric arteries from diabetic mother offspring (DMO) and control mother offspring (CMO) aged 3 and 18 months. In arteries isolated from DMO the relaxation induced by prostacyclin analogues was reduced in both 3- and 18-month old animals although endothelium (acetylcholine)-mediated relaxation was reduced in 18-month old DMO only. Endothelium-independent (sodium nitroprusside) relaxation was not affected. Pressure-induced myogenic tone, which controls local blood flow, was reduced in 18-month old CMO compared to 3-month old CMO. Interestingly, myogenic tone was maintained at a high level in 18-month old DMO even though agonist-induced vasoconstriction was not altered. These perturbations, in 18-months old DMO rats, were associated with an increased pMLC/MLC, pPKA/PKA ratio and an activated RhoA protein. Thus, we highlighted perturbations in the reactivity of resistance mesenteric arteries in DMO, at as early as 3 months of age, followed by the maintenance of high myogenic tone in older rats. These modifications are in favour of excessive vasoconstrictor tone. These results evidenced a fetal programming of vascular functions of resistance arteries in adult rats exposed in utero to maternal diabetes, which could explain a re-setting of vascular functions and, at least in part, the occurrence of hypertension later in life. PMID- 26756339 TI - Trace Solvent as a Predominant Factor To Tune Dipeptide Self-Assembly. AB - Solvent molecules such as water are of key importance for tuning self-assembly in biological systems. However, it remains a great challenge to detect the role of different types of noncovalent interactions between trace solvents and biomolecules such as peptides. In this work, we discover a dominant role of trace amounts of solvents for mediation of dipeptide self-assembly, in which solvent bridged hydrogen bonding is demonstrated as a crucial force in directing fiber formation. Hydrogen-bond-forming solvents (including ethanol, N,N dimethylformamide, and acetone) can affect the hydrogen bonding of C?O and N-H in diphenylalanine (FF) molecules with themselves, but this does not induce pi-pi stacking between FF molecules. The directional hydrogen bonding promotes a long range-ordered arrangement of FF molecules, preferentially along one dimension to form nanofibers or nanobelts. Furthermore, we demonstrate that water with strong hydrogen-bond-forming capability can notably speed up structure formation with long-range order, revealing the importance of water as a trace solvent for regulation of persistent and robust fiber formation. PMID- 26756340 TI - [Waiting times in cancer care is a patient safety issue]. AB - Waiting times in cancer care is a patient safety risk that needs increased attention. Mechanisms and effects need to be clarified, waiting time statistics should be openly presented and evidence--based strategies should be implemented. Cancer patient pathways are implemented in Sweden during 2015-2018 and are expected to reduce waiting times for some patient groups, but cannot be expected to present a complete solution to the waiting time problem. Strategic work on waiting times requires knowledge about the differ-ent symptom profiles in various cancer types, understanding of the impact from waiting times in different cancer types and increased knowledge about the mechanisms in the health care system that cause waiting times. PMID- 26756338 TI - Functional Profiling of Unfamiliar Microbial Communities Using a Validated De Novo Assembly Metatranscriptome Pipeline. AB - BACKGROUND: Metatranscriptomic landscapes can provide insights in functional relationships within natural microbial communities. Analysis of complex metatranscriptome datasets of these communities poses a considerable bioinformatic challenge since they are non-restricted with a varying number of participating strains and species. For RNA-Seq data a standard approach is to align the generated reads to a set of closely related reference genomes. This only works well for microbial communities for which a near complete catalogue of reference genomes is available at a small evolutionary distance. In this study, we focus on the design of a validated de novo metatranscriptome assembly pipeline for single-end Illumina RNA-Seq data to obtain functional and taxonomic profiles of murine microbial communities. RESULTS: The here developed de novo assembly metatranscriptome pipeline combined rRNA removal, IDBA-UD assembler, functional annotation and taxonomic classification. Different assemblers were tested and validated using RNA-Seq data from an in silico generated mock community and in vivo RNA-Seq data from a restricted microbial community taken from a mouse model colonized with Altered Schaedler Flora (ASF). Precision and recall of resulting gene expression, functional and taxonomic profiles were compared to those obtained with a standard alignment method. The validated pipeline was subsequently used to generate expression profiles from non-restricted cecal communities of four C57BL/6J mice fed on a high-fat high-protein diet spiked with an RNA-Seq data set from a well-characterized human sample. The spike in control was used to estimate precision and recall at assembly, functional and taxonomic level of non-restricted communities. CONCLUSIONS: A generic de novo assembly pipeline for metatranscriptome data analysis was designed for microbial ecosystems, which can be applied for microbial metatranscriptome analysis in any chosen niche. PMID- 26756341 TI - [Not Available]. AB - A case is presented, where preoperative malnutrition was the most likely explanation to elevated lactate levels during and after surgery. Poor circulation, a common cause of elevated lactate during surgery, was excluded. The elevated lactate levels were normalized after intravenous administration of thiamine. Thiamine is an essential cofactor in carbohydrate metabolism for energy production. Thiamine deficiency is common among ICU patients. Clinical suspicion of malnutrition should lead to early parenteral administration of thiamine without specific laboratory confirmation of thiamine deficiency. PMID- 26756342 TI - [Careful medical history taking is worthwhile in child sleep disorders]. AB - Sleeping disturbances are common in children and adolescents and in rare cases signal underlying disease. Complete history and diagnosis are mandatory for treatment. The basis for pharmacologic treatment is unsatisfactory but phenotiazides and benzodiazepines should not be used because of lack of documented effects and potentially serious side effects. Melatonin may be used in selected cases. PMID- 26756343 TI - [Substitution therapy tested against amphetamine dependence]. AB - Amphetamine dependence is relatively common in Sweden and it is the most frequently used substance among patients with intravenous drug abuse. Current treatment options are limited but recently substitution therapy with psychostimulant medication has been evaluated in several clinical trials. Such treatment is controversial in Sweden, perhaps due to the failure of experimental prescription of psychostimulants in the 1960s. Recent clinical trials however indicate that structured treatment programs with psychostimulants might have positive effects, although the results are inconsistent and the evidence base is still limited. Future research is needed in order to determine the potential role of substitution therapy for amphetamine dependence in clinical practice. PMID- 26756344 TI - [Eternal youth--an ancient concept]. PMID- 26756345 TI - [Not Available]. PMID- 26756346 TI - [Who is responsible for the investigation]. PMID- 26756348 TI - [Not Available]. PMID- 26756347 TI - [Not Available]. PMID- 26756349 TI - [Health initiatives for refugee children must be better structured]. PMID- 26756350 TI - Doping Graphene Transistors Using Vertical Stacked Monolayer WS2 Heterostructures Grown by Chemical Vapor Deposition. AB - We study the interactions in graphene/WS2 two-dimensional (2D) layered vertical heterostructures with variations in the areal coverage of graphene by the WS2. All 2D materials were grown by chemical vapor deposition and transferred layer by layer. Photoluminescence (PL) spectroscopy of WS2 on graphene showed PL quenching along with an increase in the ratio of exciton/trion emission, relative to WS2 on SiO2 surface, indicating a reduction in the n-type doping levels of WS2 as well as reduced radiative recombination quantum yield. Electrical measurements of a total of 220 graphene field effect transistors with different WS2 coverage showed double-Dirac points in the field effect measurements, where one is shifted closer toward the 0 V gate neutrality position due to the WS2 coverage. Photoirradiation of the WS2 on graphene region caused further Dirac point shifts, indicative of a reduction in the p-type doping levels of graphene, revealing that the photogenerated excitons in WS2 are split across the heterostructure by electron transfer from WS2 to graphene. Kelvin probe microscopy showed that regions of graphene covered with WS2 had a smaller work function and supports the model of electron transfer from WS2 to graphene. Our results demonstrate the formation of junctions within a graphene transistor through the spatial tuning of the work function of graphene using these 2D vertical heterostructures. PMID- 26756351 TI - Targeting the Bacterial Division Protein FtsZ. AB - Similar to its eukaryotic counterpart, the prokaryotic cytoskeleton is essential for the structural and mechanical properties of bacterial cells. The essential protein FtsZ is a central player in the cytoskeletal family, forms a cytokinetic ring at mid-cell, and recruits the division machinery to orchestrate cell division. Cells depleted of or lacking functional FtsZ do not divide and grow into long filaments that eventually lyse. FtsZ has been studied extensively as a target for antibacterial development. In this Perspective, we review the structural and biochemical properties of FtsZ, its role in cell biochemistry and physiology, the different mechanisms of inhibiting FtsZ, small molecule antagonists (including some misconceptions about mechanisms of action), and their discovery strategies. This collective information will inform chemists on different aspects of FtsZ that can be (and have been) used to develop successful strategies for devising new families of cell division inhibitors. PMID- 26756353 TI - Charge Separation in TiO2/BDD Heterojunction Thin Film for Enhanced Photoelectrochemical Performance. AB - Semiconductor photocatalysis driven by electron/hole has begun a new era in the field of solar energy conversion and storage. Here we report the fabrication and optimization of TiO2/BDD p-n heterojunction photoelectrode using p-type boron doped diamond (BDD) and n-type TiO2 which shows enhanced photoelectrochemical activity. A p-type BDD was first deposited on Si substrate by microwave plasma chemical vapor deposition (MPCVD) method and then n-type TiO2 was sputter coated on top of BDD grains for different durations. The microstructural studies reveal a uniform disposition of anatase TiO2 and its thickness can be tuned by varying the sputtering time. The formation of p-n heterojunction was confirmed through I V measurement. A remarkable rectification property of 63773 at 5 V with very small leakage current indicates achieving a superior, uniform and precise p-n junction at TiO2 sputtering time of 90 min. This suitably formed p-n heterojunction electrode is found to show 1.6 fold higher photoelectrochemical activity than bare n-type TiO2 electrode at an applied potential of +1.5 V vs SHE. The enhanced photoelectrochemical performance of this TiO2/BDD electrode is ascribed to the injection of hole from p-type BDD to n-type TiO2, which increases carrier separation and thereby enhances the photoelectrochemical performance. PMID- 26756354 TI - Factor Analysis of Conformations and NMR Signals of Rotaxanes: AIMD and Polarizable MD Simulations. AB - The interlocked ?rod | ring? structures of pseudorotaxanes and [2]rotaxanes are usually maintained by the complex hydrogen-bonding (H-bonding) network between the rod and ring. Ab initio molecular dynamics (AIMD) using generalized energy based fragmentation approach and polarizable force field (polar FF)-based molecular dynamics (MD) simulations were performed to investigate the conformational changes of mechanically interlocked systems and to obtain the ensemble-averaged NMR chemical shifts. Factor analysis (FA) demonstrates that the ring H-donor (2,6 pyridinedicarboxamide group) plays an important role in the ring-rod recognition. In comparison to the conventional fixed-charge force field, the polarization effect is crucial to account for the H-bonding interactions in supramolecular systems. In the hybrid scheme, the polar FF-based MD simulations are used to generate different initial states for the AIMD simulations, which are able to give better prediction of ensemble-averaged NMR signals for chemically equivalent amide protons. The magnitude of the deshielding shift of NMR signal is correlated with the length of hydrogen bond. The polar FF model with variable charges shows that the dipole-dipole interactions between the flexible diethylene glycol chain of ring and polar solvents induce the upfield shifts of NMR signals of rod H-donors and the directional distribution of the neighboring CH3CN solvents. PMID- 26756352 TI - Periprostatic adipocytes act as a driving force for prostate cancer progression in obesity. AB - Obesity favours the occurrence of locally disseminated prostate cancer in the periprostatic adipose tissue (PPAT) surrounding the prostate gland. Here we show that adipocytes from PPAT support the directed migration of prostate cancer cells and that this event is strongly promoted by obesity. This process is dependent on the secretion of the chemokine CCL7 by adipocytes, which diffuses from PPAT to the peripheral zone of the prostate, stimulating the migration of CCR3 expressing tumour cells. In obesity, higher secretion of CCL7 by adipocytes facilitates extraprostatic extension. The observed increase in migration associated with obesity is totally abrogated when the CCR3/CCL7 axis is inhibited. In human prostate cancer tumours, expression of the CCR3 receptor is associated with the occurrence of aggressive disease with extended local dissemination and a higher risk of biochemical recurrence, highlighting the potential benefit of CCR3 antagonists in the treatment of prostate cancer. PMID- 26756357 TI - Informing or Exploiting? Public Reponses to Giuliana Rancic's Health Narrative. AB - Popular entertainment journalist Giuliana Rancic has shared her struggles with pregnancy loss, infertility, and breast cancer in an array of public forums. In this study, we analyzed online comments responding to public discourses surrounding Rancic's revelations, including her miscarriage and fertility treatments, her breast cancer diagnosis, and her decision to undergo a double mastectomy. Our goal was to explore how the public framed Rancic's health challenges. Using a narrative lens, we argue that online comments reveal the tensions that celebrities like Rancic must manage as they contend with public scrutiny of their stories. Online commenters in this study framed Rancic's narrative as a privileged vantage point in which she exploited her health struggles for personal and financial gain. Our analysis of these comments also demonstrates how Rancic's narrative exists in concert with other discourses that challenge and disrupt her own account of events. The examination of these mediated discourses has implications for understanding the role of celebrity experiences in personal and public conversations about health. PMID- 26756355 TI - Epigenetics of the myotonic dystrophy-associated DMPK gene neighborhood. AB - AIM: Identify epigenetic marks in the vicinity of DMPK (linked to myotonic dystrophy, DM1) that help explain tissue-specific differences in its expression. MATERIALS & METHODS: At DMPK and its flanking genes (DMWD, SIX5, BHMG1 and RSPH6A), we analyzed many epigenetic and transcription profiles from myoblasts, myotubes, skeletal muscle, heart and 30 nonmuscle samples. RESULTS: In the DMPK gene neighborhood, muscle-associated DNA hypermethylation and hypomethylation, enhancer chromatin, and CTCF binding were seen. Myogenic DMPK hypermethylation correlated with high expression and decreased alternative promoter usage. Testis/sperm hypomethylation of BHMG1 and RSPH6A was associated with testis specific expression. G-quadruplex (G4) motifs and sperm-specific hypomethylation were found near the DM1-linked CTG repeats within DMPK. CONCLUSION: Tissue specific epigenetic features in DMPK and neighboring genes help regulate its expression. G4 motifs in DMPK DNA and RNA might contribute to DM1 pathology. PMID- 26756374 TI - Synthetic and Structural Studies of 2-Acylmethyl-6-R-Difunctionalized Pyridine Ligand-Containing Iron Complexes Related to [Fe]-Hydrogenase. AB - As active site models of [Fe]-hydrogenase, tridentate 2-acylmethyl-6 methoxymethoxy-difunctionalized pyridine-containing complexes eta(3)-(2-COCH2-6 MeOCH2OC5H3N)Fe(CO)2(L1) (4, L1 = I; 5, SCN; 6, PhCS2) were prepared via the following multistep reactions: (i) etherification of 2-MeO2C-6-HOC5H3N with ClCH2OMe to give 2-MeO2C-6-MeOCH2OC5H3N (1), (ii) reduction of 1 with NaBH4 to give 2-HOCH2-6-MeOCH2OC5H3N (2), (iii) esterification of 2 with 4-toluenesulfonyl chloride to give 2-TsOCH2-6-MeOCH2OC5H3N (3), (iv) nucleophilic substitution of 3 with Na2Fe(CO)4 followed by treatment of the resulting Fe(0) intermediate Na[(2 CH2-6-MeOCH2OC5H3N)Fe(CO)4] (M1) with I2 to give complex 4, and (v) condensation of 4 with KSCN and PhCS2K to give complexes 5 and 6, respectively. In contrast to the preparation of complexes 4-6, bidentate 2-acylmethyl-6-methoxymethoxy difunctionalized pyridine-containing model complexes eta(2)-(2-COCH2-6 MeOCH2OC5H3N)Fe(CO)2(I)(L2) (7, L2 = PPh3; 8, Cy-C6H11NC) and eta(2)-(2-COCH2-6 MeOCH2OC5H3N)Fe(CO)2(L3) (9, L3 = 2-SC5H4N; 10, 8-SC9H6N) were prepared by ligand exchange reactions of 4 with PPh3, Cy-C6H11NC, 2-KSC5H4N, and 8-KSC9H6N, respectively. Particularly interesting is that the tridentate 2,6 bis(acylmethyl)pyridine- and 2-acylmethyl-6-arylthiomethylpyridine-containing model complexes eta(3)-[2,6-(COCH2)2C5H3N]Fe(CO)2(L4) (11, L4 = PPh3; 12, CO) and eta(3)-2-(COCH2-6-ArSCH2C5H3N)Fe(CO)2(ArS) (13, ArS = PhS; 14, 2-S-5-MeC4H2O) were obtained, unexpectedly, when 2,6-(TsOCH2)2C5H3N reacted with Na2Fe(CO)4 followed by treatment of the resulting mixture with ligands PPh3 and CO or disulfides (PhS)2 and (2-S-5-MeC4H2O)2. Reactions of ligand precursors 3 and 2,6 (TsOCH2)2C5H3N with Na2Fe(CO)4 were monitored by in situ IR spectroscopy, and the possible pathways for producing complexes 4 and 11-14 via intermediates Na[(2-CH2 6-MeOCH2OC5H3N)Fe(CO)4] (M1), Na[(2-CH2-6-TsOCH2C5H3N)Fe(CO)4] (M2), and (2-COCH2 6-CH2C5H3N)Fe(CO)3 (M3) are suggested. New compounds 1-14 were characterized by elemental analysis, spectroscopy, and, for some of them, X-ray crystallography. PMID- 26756358 TI - Prevention of a sexually transmitted disease versus prevention of a serious female cancer: remarkably divergent views of HPV vaccination. PMID- 26756375 TI - Dimensional accuracy of ceramic self-ligating brackets and estimates of theoretical torsional play. AB - OBJECTIVE: To ascertain the dimensional accuracies of some commonly used ceramic self-ligation brackets and the amount of torsional play in various bracket archwire combinations. MATERIALS AND METHODS: Four types of 0.022-inch slot ceramic self-ligating brackets (upper right central incisor), three types of 0.018-inch ceramic self-ligating brackets (upper right central incisor), and three types of rectangular archwires (0.016 * 0.022-inch beta-titanium [TMA] (Ormco, Orange, Calif), 0.016 * 0.022-inch stainless steel [SS] (Ortho Technology, Tampa, Fla), and 0.019 * 0.025-inch SS (Ortho Technology)) were measured using a stereomicroscope to determine slot widths and wire cross sectional dimensions. The mean acquired dimensions of the brackets and wires were applied to an equation devised by Meling to estimate torsional play angle (gamma). RESULTS: In all bracket systems, the slot tops were significantly wider than the slot bases (P < .001), yielding a divergent slot profile. Clarity-SLs (3M Unitek, Monrovia, Calif) showed the greatest divergence among the 0.022-inch brackets, and Clippy-Cs (Tomy, Futaba, Fukushima, Japan) among the 0.018-inch brackets. The Damon Clear (Ormco) bracket had the smallest dimensional error (0.542%), whereas the 0.022-inch Empower Clear (American Orthodontics, Sheboygan, Wis) bracket had the largest (3.585%). CONCLUSIONS: The largest amount of theoretical play is observed using the Empower Clear (American Orthodontics) 0.022-inch bracket combined with the 0.016 * 0.022-inch TMA wire (Ormco), whereas the least amount occurs using the 0.018 Clippy-C (Tomy) combined with 0.016 * 0.022-inch SS wire (Ortho Technology). PMID- 26756356 TI - Anthropometric Factors and Thyroid Cancer Risk by Histological Subtype: Pooled Analysis of 22 Prospective Studies. AB - BACKGROUND: Greater height and body mass index (BMI) have been associated with an increased risk of thyroid cancer, particularly papillary carcinoma, the most common and least aggressive subtype. Few studies have evaluated these associations in relation to other, more aggressive histologic types or thyroid cancer-specific mortality. METHODS: This large pooled analysis of 22 prospective studies (833,176 men and 1,260,871 women) investigated thyroid cancer incidence associated with greater height, BMI at baseline and young adulthood, and adulthood BMI gain (difference between young-adult and baseline BMI), overall and separately by sex and histological subtype using multivariable Cox proportional hazards regression models. Associations with thyroid cancer mortality were investigated in a subset of cohorts (578,922 men and 774,373 women) that contributed cause of death information. RESULTS: During follow-up, 2996 incident thyroid cancers and 104 thyroid cancer deaths were identified. All anthropometric factors were positively associated with thyroid cancer incidence: hazard ratios (HR) [confidence intervals (CIs)] for height (per 5 cm) = 1.07 [1.04-1.10], BMI (per 5 kg/m2) = 1.06 [1.02-1.10], waist circumference (per 5 cm) = 1.03 [1.01 1.05], young-adult BMI (per 5 kg/m2) = 1.13 [1.02-1.25], and adulthood BMI gain (per 5 kg/m2) = 1.07 [1.00-1.15]. Associations for baseline BMI and waist circumference were attenuated after mutual adjustment. Baseline BMI was more strongly associated with risk in men compared with women (p = 0.04). Positive associations were observed for papillary, follicular, and anaplastic, but not medullary, thyroid carcinomas. Similar, but stronger, associations were observed for thyroid cancer mortality. CONCLUSION: The results suggest that greater height and excess adiposity throughout adulthood are associated with higher incidence of most major types of thyroid cancer, including the least common but most aggressive form, anaplastic carcinoma, and higher thyroid cancer mortality. Potential underlying biological mechanisms should be explored in future studies. PMID- 26756376 TI - Do prenatal and postnatal hypothyroidism affect the craniofacial structure?: An experimental study. AB - OBJECTIVE: To investigate the effect of experimental prenatal and postnatal hypothyroidism (HT) on the craniofacial structure in rats. MATERIALS AND METHODS: Female Wistar albino rats were mated with males for fertilization. Pregnant rats were divided into three groups. Group 1 (methimazole [MMI]-induced prenatal hypothyroidism group) mother rats were given MMI water during and after pregnancy. Group 2 (MMI-induced postnatal hypothyroidism group) mother rats were given MMI water after pregnancy. After the breast-feeding period, group 1 and 2 rat pups received the same water as their lactating mothers drank. Group 3 (control group) pregnant rats and rat pups were given normal tap water. When the rat pups were 90 days of age, lateral cephalometric and posteroanterior films were taken under anesthesia. RESULTS: Posteroanterior radiographs revealed that palatal, cranial, bizygomatic arch, and bigonial width measurements were significantly shorter in prenatal HT and postnatal HT groups compared to the control group (P < .001). Intragroup comparisons in lateral cephalometric radiographs showed that, nearly all of the comparisons were statistically significant (P < .05), with the exception of the Co-Gn, E-Pg/S-Gn measurements between the prenatal and postnatal HT groups. CONCLUSIONS: Sagittal and transverse measurements showed that untreated HT has detrimental effects on the growth of the maxilla and mandible. PMID- 26756377 TI - Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II-III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas. PMID- 26756378 TI - Validation of a novel index of hemorrhage using a lower body negative pressure shock model. AB - BACKGROUND: Vital signs are late indicators of blood loss in trauma patients. Indexed Heart to Arm Time (iHAT) is a non-invasive index based on a modified pulse transit time (mPTT) indexed to the time between R waves on the electrocardiogram (RR interval). We aimed to investigate how early iHAT is able to detect central hypovolemia during the progression from mild to severe simulated hemorrhage induced by applying lower body negative pressure (LBNP). METHODS: Thirty healthy volunteers were enrolled. Central hypovolemia was induced by application of increasing LBNP from 0 to -80 mmHg. At every step, non-invasive blood pressure, heart rate, cardiac echo Doppler measurements and iHAT were recorded. RESULTS: Aortic flow Velocity Time Integral (VTI) reduction from 21.8+/ 3.7 (baseline) to 11.2+/-3 cm (-70 mmHg) (P<0.001) was progressive with LBNP increase and represented a significant change in stroke volume and preload and induced an increase in heart rate from 69+/-2 to 107+/-4 bpm. iHAT increased from 34.2+/-4.65% (baseline) to 53.9+/-14.34% (-80 mmHg), P<0.001. The increase in iHAT became significant after -30 mmHg level was reached, corresponding to 500 1000 mL blood loss. CONCLUSIONS: iHAT measures both the reduction in preload and the parabolic heart rate increase due to the linear decrease in stroke volume. iHAT was able to detect a progressive central volume loss in a model of hemorrhage in healthy volunteers undergoing LBNP. A rising trend in iHAT can be a useful marker for progressive volume loss during moderate to severe bleeding. PMID- 26756379 TI - I have a dream.... PMID- 26756381 TI - The Linus blanket. PMID- 26756380 TI - Red blood cell transfusion strategies in critically ill patients: lessons from recent randomized clinical studies. AB - A randomized, multicenter trial conducted in 32 northern European general intensive care units (ICUs) enrolled some patients with septic shock randomly assigned to receive a red blood cell transfusion when the hemoglobin (Hb) level was <=7 g/dL ("lower threshold"; N.=502) or <=9 g/dL ("higher threshold"; N.=496) throughout the ICU stay. Patients were excluded if they had an acute coronary syndrome, life-threatening bleeding, acute burn injury, had already been transfused or had previously experienced transfusion-related reactions. The two groups of patients had comparable severity of disease scores and chronic cardiovascular conditions. Median Hb values were 7.7 g/dL in the lower and 9.3 g/dL in the higher threshold groups and these values remained stable during the study period. There was no significant difference in 90-day mortality (primary end-point) between the two groups (216/502, 43.0% in the lower vs. 223/496, 45.0% in the higher group, RR 0.94 [95% CI: 0.78-1.09; P=0.44]), even after adjustment for several confounders. In the higher threshold group, approximately twice as many transfusions were given (3088 vs. 1545 units transfused, P<0.001) as in the lower threshold group. In the lower threshold group, more patients received no RBC transfusion (36% vs. 1.2%, P<0.001) than in the higher threshold group, but there were also more temporary protocol suspensions (5.9 % vs. 2.2%, P=0.004), in particular because of myocardial ischemia (6/488, 1.2% vs. 0/489), life threatening bleeding (18/488, 3.7% vs. 9/489, 1.8%) and need for higher Hb levels during extracorporeal membrane oxygenation therapy. We discuss how anemia should be managed in patients with sepsis or other critical illness, especially in the context of the potential risks associated with RBC transfusion and data from other recent large randomized trials. PMID- 26756382 TI - Birth Weight Could Influence Bone Mineral Contents of 10- to 18-Year-Old Korean Adolescents: Results from the Korea National Health and Nutrition Examination Survey (KNHANES) 2010. AB - BACKGROUND: We investigate the relationship between birth weight (BW) and bone mineral content (BMC) in Korean adolescents. METHODS: Data were obtained from the Korea National Health and Nutrition Examination Survey conducted in 2010. Baseline characteristics were compared according to age- and sex-specific BMC quartiles of total body less head (TBLH), lumbar spine (LS) and femur neck (FN) in 10- to 18-year-old adolescents (male = 474, female = 394). RESULTS: BW showed a positive correlation with current weight-SDS (p = 0.006 in males, p = 0.008 in females). BW according to TBLH-BMC quartile groups (p for trend <0.003 in males, <0.0001 in females), LS-BMC quartile groups (p for trend <0.034 in males) and FN BMC quartile groups (p for trend <0.008 in males, <0.020 in females) showed significant differences. The odds ratio (OR) of being in the highest BMC quartile, per 1-kg increase in BW, was significantly increased in TBLH-BMC (OR = 2.14 in males, OR = 3.26 in >16-year-old adolescents) and FN-BMC (OR = 2.62 in males, OR = 3.06 in >16-year-old adolescents) after adjusting for age, height, smoking, drinking, metabolic equivalent of task, and gestational age. CONCLUSION: BW might be one of the determinant factors of BMC in Korean adolescents. PMID- 26756383 TI - Retinal Vein Occlusions: Therapeutic Switch in Macular Oedema Treatment with a 12 Month Follow-Up. AB - PURPOSE: To compare the visual and anatomical outcomes of patients with macular oedema secondary to retinal vein occlusion (RVO) after a switch from bevacizumab to intravitreal injection of a dexamethasone implant (IVI-DEX) or conversely. METHODS: 48 patients - 40 in the antivascular endothelial growth factor (VEGF) DEX sequence (AD group), 8 in the DEX anti-VEGF sequence (DA group) - were included in this multicentre retrospective study and evaluated at baseline, 1, 3, 6 and 12 months after the switch. The outcome measurements were visual acuity (VA) and central macular thickness (CMT) evaluated by spectral domain optical coherence tomography. Patients were defined as 'good responders' if CMT was <= 300 um after the switch. RESULTS: VA significantly improved at 1 month in the AD group (p = 0.03) but not in the DA group (p = 0.40). CMT decreased significantly in the AD group at 1, 6 and 12 months (p = 0.002, p = 0.005 and p = 0.002, respectively). In the DA group, VA did not change from baseline at any time point, and CMT decreased at 1 month (p = 0.02) but not later on. CONCLUSIONS: In patients with macula oedema secondary to RVO, the switch from bevacizumab to IVI DEX seems more beneficial in terms of short-term VA and long-term reduction of CMT than the DEX anti-VEGF agent sequence. PMID- 26756384 TI - Predictive biomarkers for programmed death-1/programmed death ligand immune checkpoint inhibitors in nonsmall cell lung cancer. AB - PURPOSE OF REVIEW: Immune checkpoint inhibitors, antiprogrammed death receptor 1 (anti-PD-1)/antiprogrammed death-ligand 1 (anti-PD-L1), are new therapeutic regimens for managing advanced nonsmall cell lung cancer patients, giving an overall response rate of approximately 20% as monotherapy in second-line treatment. The use of predictive biomarkers for identifying patients suitable for these therapies is an important issue not only for making treatment decisions, but also from a medical economic point of view. RECENT FINDINGS: Among potential predictive biomarker candidates for anti-PD-1/PD-L1 treatments in nonsmall cell lung cancer, the expression of PD-L1 (as determined by immunohistochemistry) is currently the most studied. PD-L1 positivity has been associated with higher response rate to anti-PD-1/PD-L1 therapies. However, several observations suggest that the predictive value of PD-L1 expression is not clear-cut. We review other potential predictive biomarkers, including programmed death-ligand 2, IFN-gamma, and genetic signatures. SUMMARY: Standardized techniques and conditions for evaluating PD-L1 expression (tissue quality and age, percentage positivity threshold, managing heterogeneous and dynamic expression) are critical for establishing the use of this protein as a predictive marker. Care should be also taken when using anti-PD-1/PD-L1 therapies in combination with other therapies, which may impact the predictive value of PD-L1 expression. PMID- 26756385 TI - Epileptic Seizures in Alzheimer Disease: A Review. AB - Alzheimer disease (AD) is the most frequent cause of major neurocognitive disorders with a huge economical and medical burden. Several studies pointed out that AD is associated with a high risk for developing epileptic seizures. The aims of our review were to evaluate and to summarize the current literature (ending in September 2015) of animal and human studies in the relation of AD and epileptic seizures. It seems likely that epileptic hyperexcitation could be partially responsible for the progression of AD due to the increased rate of amyloid deposition. Pathologic changes in animal models of AD are similar to those seen in human temporal lobe epilepsy. Antiepileptic treatment had a positive effect on cognitive function in animal and human studies. Because the detection of seizures in patients with cognitive decline is extremely difficult because of methodological problems, the true prevalence of seizures has remained unclear. Nonconvulsive seizures with no overt clinical symptoms may be frequent seizure types in AD. These are difficult to detect by clinical observation and with standard scalp electroencephalogram (EEG) methods. We propose that long-term EEG recording and video-EEG monitoring is necessary to prove the presence of epileptiform activity in demented patients. PMID- 26756388 TI - Gene polymorphisms and therapy in rheumatoid arthritis. PMID- 26756386 TI - A Cross-Sectional Analysis of Late-Life Cardiovascular Factors and Their Relation to Clinically Defined Neurodegenerative Diseases. AB - Studies have demonstrated associations between cardiovascular factors and Alzheimer disease (AD) with minimal focus on other neurodegenerative diseases. Utilizing cross-sectional data from 17,532 individuals in the National Alzheimer's Coordinating Center, Uniform Data Set, we compared the presence of cardiovascular factors [body mass index (BMI), atrial fibrillation, hypertension, hyperlipidemia, and diabetes] in individuals carrying a diagnosis of Probable AD (ProbAD), Possible AD, vascular dementia, dementia with Lewy bodies (DLB), frontotemporal dementia, Parkinson disease, progressive supranuclear palsy, or corticobasal degeneration, with that of normals. Generalized linear mixed models were fitted with age at visit, gender, and cardiovascular factors as fixed effects and Alzheimer's Disease Centers as random effects. In late life, only BMI of ProbAD and DLB patients was statistically significantly lower than that in normals (P-values <0.001). When accounting for colinearity within cardiovascular factors, a low BMI was a comorbidity of certain dementia etiologies as compared with normals. These data support a concept of disease-specific associations with certain cardiovascular factors. PMID- 26756387 TI - Using an Alzheimer Disease Polygenic Risk Score to Predict Memory Decline in Black and White Americans Over 14 Years of Follow-up. AB - Evidence on whether genetic predictors of Alzheimer disease (AD) also predict memory decline is inconsistent, and limited data are available for African ancestry populations. For 8253 non-Hispanic white (NHW) and non-Hispanic black (NHB) Health and Retirement Study participants with memory scores measured 1 to 8 times between 1998 and 2012 (average baseline age=62), we calculated weighted polygenic risk scores [AD Genetic Risk Score (AD-GRS)] using the top 22 AD associated loci, and an alternative score excluding apolipoprotein E (APOE) (AD GRSexAPOE). We used generalized linear models with AD-GRS-by-age and AD-GRS-by age interactions (age centered at 70) to predict memory decline. Average NHB decline was 26% faster than NHW decline (P<0.001). Among NHW, 10% higher AD-GRS predicted faster memory decline (linear beta=-0.058 unit decrease over 10 y; 95% confidence interval,-0.074 to -0.043). AD-GRSexAPOE also predicted faster decline for NHW, although less strongly. Among NHB, AD-GRS predicted faster memory decline (linear beta=-0.050; 95% confidence interval, -0.106 to 0.006), but AD GRSexAPOE did not. Our nonsignificant estimate among NHB may reflect insufficient statistical power or a misspecified AD-GRS among NHB as an overwhelming majority of genome-wide association studies are conducted in NHW. A polygenic score based on previously identified AD loci predicts memory loss in US blacks and whites. PMID- 26756389 TI - PTSD, Depression, and Substance Use in Relation to Suicidality Risk among Traumatized Minority Lesbian, Gay, and Bisexual Youth. AB - Youths who are lesbian, gay, or bisexual (LGB) are more likely than heterosexuals to commit suicide. Substance use, PTSD, and depression are independent risk factors for suicidality; however, the extent to which these factors interact to predict suicidality is unclear. The current study examined the association between substance use, PTSD symptoms (PTSS), depressive symptoms, and suicidality in a sample of 68 traumatized minority LGB youths. Participants were recruited from an LGBT community center and completed a packet of questionnaires. Substance use and depressive symptoms were positively associated with prior suicide attempts. A significant three-way interaction revealed that substance use interacted with both PTSS and depressive symptoms to increase the odds of attempted suicide. Results underscore the importance of integrating substance use components into PTSD/depression treatment to reduce suicide risk in LGB youth. PMID- 26756391 TI - Molecular Rods Based on Oligo-spiro-thioketals. AB - We report on an extension of the previously established concept of oligospiroketal (OSK) rods by replacing a part or all ketal moieties by thioketals leading to oligospirothioketal (OSTK) rods. In this way, some crucial problems arising from the reversible formation of ketals are circumvented. Furthermore, the stability of the rods toward hydrolysis is considerably improved. To successfully implement this concept, we first developed a number of new oligothiol building blocks and improved the synthetic accessibility of known oligothiols, respectively. Another advantage of thioacetals is that terephthalaldehyde (TAA) sleeves, which are too flexible in the case of acetals can be used in OSTK rods. The viability of the OSTK approach was demonstrated by the successful preparation of some OSTK rods with a length of some nanometers. PMID- 26756392 TI - Minor Functional Deficits in Basic Response Patterns for Reinforcement after Frontal Traumatic Brain Injury in Rats. AB - Traumatic brain injury (TBI) is a major contributor to numerous psychiatric conditions and chronic behavioral dysfunction. Recent studies in experimental brain injury have begun to adopt operant methodologies to assess these deficits, all of which rely on the process of reinforcement. No studies have directly examined how reinforced behaviors are affected by TBI, however. The current study assessed performance under the four most common schedules of reinforcement (fixed ratio, variable ratio, fixed interval, variable interval) and one higher order schedule assessing motivation (progressive ratio) after bilateral, pre-frontal controlled cortical impact injury. TBI-induced differences on the basic schedules were minor, with the exception of the variable ratio, where increased efficacy (more reinforcers, higher response rates, lower interresponse times) at higher requirements was observed as a result of brain injury. Performance on the progressive ratio schedule showed some gross differences between the groups, in that sham rats became more efficient under this schedule while injured rats perseverated in lever pressing. Further, injured rats were specifically impaired at lower response requirements on the progressive ratio. Taken together, these findings indicate that simple reinforced behaviors are mostly unaffected after TBI, except in the case of variable ratio schedules, but the altered performance on the higher-order progressive ratio schedule suggests changes involving motivation or potentially perseveration. These findings validate operant measures of more complex behaviors for brain injury, all of which rely on reinforcement and can be taken into consideration when adapting and developing novel functional assessments. PMID- 26756390 TI - Persistence of Bactericidal Antibodies After Infant Serogroup B Meningococcal Immunization and Booster Dose Response at 12, 18 or 24 Months of Age. AB - BACKGROUND: A serogroup B meningococcal vaccine (4CMenB) is licensed for infant use in countries including Canada, Australia and those of the European Union. Data on serum bactericidal antibody (hSBA) waning and the ideal timing of a "toddler" booster dose are essential to optimize vaccine utilization. METHODS: An open-labeled, multicenter phase-2b follow-on European study conducted from 2009 to 2012. Participants previously receiving 4CMenB with routine vaccines at 2, 4 and 6 or 2, 3 and 4 months (246Con and 234Con) or at 2, 4 and 6 months intercalated with routine vaccines (246Int) received a booster dose at 12, 18 or 24 months. 4CMenB-naive "Control" participants aged 12, 18 or 24 months received 2 doses of 4CMenB 2 months apart. RESULTS: One thousand five hundred eighty-eight participants were recruited. At 12 months, before any booster doses, the proportions with hSBA titers >=1:5 for strain 44/76-SL (testing vaccine component fHBP) were 73% (120/165) for the "246Con" group, 85% (125/147) for "246Int," 57% (51/90) for "234Con" and 13% (26/199) for Controls. For strain 5/99 (NadA) proportions were >=96% (all 4CMenB-recipients) and 1% (Controls). For strain NZ98/254 (PorA), these were 18-35% (4CMenB-recipients) and 1% (Controls). By 24 months, 4CMenB-recipient proportions were 13-22% (44/76-SL), 82-94% (5/99) and 7 13% (NZ98/254) and in controls <=4%. After a 12-month booster-dose, >=95% of previously immunized participants had titers >=1:5 (all strains). CONCLUSIONS: A 4CMenB booster-dose can overcome waning hSBA titers after early-infant immunization. Administration at 12 months could help to maintain immunity during an age of high risk, and the persistence of this response requires further study. PMID- 26756394 TI - Three-dimensional structure, binding, and spectroscopic characteristics of the monoclonal antibody 43.1 directed to the carboxyphenyl moiety of fluorescein. AB - Unlike other known anti-fluorescein antibodies, the monoclonal antibody 43.1 is directed toward the fluorescein's carboxyl phenyl moiety. It demonstrates a very high affinity (KD ~ 70 pM) and a fast association rate (kon ~ 2 * 10(7) M(-1 ) s( 1) ). The three-dimensional structure of the Fab 43.1-fluorescein complex was resolved at 2.4 A resolution. The antibody binding site is exclusively assembled by the CDR loops. It is comprised of a 14 A groove-shaped entrance leading to a 9 A by 7 A binding pocket. The highly polar binding pocket complementary encloses the fluorescein's carboxyphenyl moiety and tightly fixes it by multiple hydrogen bonds. The fluorescein's xanthene ring is embedded in the more hydrophobic groove and stacked between the side chains of Tyr37L and of Arg99H providing conditions for an excited state electron transfer process. In comparison to fluorescein, the absorption spectrum of the complex in the visible region is shifted to the "red" by 23 nm. The complex demonstrates a very weak fluorescence (Phic = 0.0018) with two short lifetime components: 0.03 ns (47%) and 0.8 ns (24%), which reflects a 99.8% fluorescein emission quenching effect upon complex formation. The antibody 43.1 binds fluorescein with remarkable affinity, fast association rate, and strongly quenches its emission. Therefore, it may present a practical interest in applications such as molecular sensors and switches. PMID- 26756396 TI - Linear extensions of hypopigmentation as a side effect of topical corticosteroid application. PMID- 26756393 TI - Longitudinal predictors of cannabis use and dependence in offspring from families at ultra high risk for alcohol dependence and in control families. AB - Cannabis use is common among adolescents. Identification of the factors associated with continued heavy use into young adulthood and development of cannabis abuse and dependence is of considerable importance. The role of familial risk for addiction and an associated endophenotype, P300 amplitude, has not previously been related to cannabis use and dependence. A prospective longitudinal study spanning childhood and young adulthood provided the opportunity for exploring these factors, along with genetic variation, in the cannabis use behaviors of 338 young adult offspring from high and low familial risk for alcohol dependence families (ages 19-30). P300 data were collected multiple times in childhood. The association between young adult patterns of cannabis use or cannabis abuse/dependence was tested with genetic variation in the cannabinoid gene, CNR1, the ANKK1-DRD2 gene, and childhood developmental trajectories of P300. Young adult patterns of cannabis use was characterized by three patterns: (i) no use throughout; (ii) declining use from adolescence through young adulthood; and (iii) frequent use throughout. Following the low P300 trajectory in childhood predicted cannabis abuse and dependence by young adulthood. A four SNP ANKK1-DRD2 haplotype (G-G-G-C) was found to be significantly associated with the frequency of use patterns (P = 0.0008). Although CNR1 variation overall was not significantly associated with these patterns, among individuals with cannabis abuse/dependence the presence of one or both copies of the rs806368 A > G minor allele conferred a 5.4-fold increase (P = 0.003) in the likelihood that they would be in the frequent and persistent use group rather than the declining use group. PMID- 26756395 TI - Multicenter clinical trial of the Nucleus Hybrid S8 cochlear implant: Final outcomes. AB - OBJECTIVES/HYPOTHESIS: The concept of expanding electrical speech processing to those with more residual acoustic hearing with a less-invasive shorter cochlear implant (CI) has been ongoing since 1999. A multicenter study of the Nucleus Hybrid S8 CI took place between 2002 and 2011. This report describes the final outcomes of this clinical trial. STUDY DESIGN: Multicenter, longitudinal, single subject design. METHODS: Eighty-seven subjects received a Nucleus Hybrid S8 CI in their poorer ear. Speech perception in quiet (Consonant-Nucleus-Consonant [CNC] words) and in noise (Bamford-Kowal-Bench Sentences-In-Noise [BKB-SIN]) were collected pre- and postoperatively at 3, 6, and 12 months. Subjective questionnaire data using the Abbreviated Profile for Hearing Aid Benefit (APHAB) were also collected. RESULTS: Some level of hearing preservation was accomplished in 98% subjects, with 90% maintaining a functional low-frequency pure-tone average (LFPTA) at initial activation. By 12 months, five subjects had total hearing loss, and 80% of subjects maintained functional hearing. CNC words demonstrated that 82.5% and 87.5% of subjects had significant improvements in the hybrid and combined conditions, respectively. The majority had improvements with BKB-SIN. Results also indicated that as long as subjects maintained at least a severe LFPTA, there was significant improvement in speech understanding. Furthermore, all subjects reported positive improvements in hearing in three of the four subscales of the APHAB. CONCLUSIONS: The concept of hybrid speech processing has significant advantages for subjects with residual low-frequency hearing. In this study, the Nucleus Hybrid S8 provided improved word understanding in quiet and noise. Additionally, there appears to be stability of the residual hearing after initial activation of the device. LEVEL OF EVIDENCE: 2c. PMID- 26756397 TI - Comparison of 2 electrophoretic methods and a wet-chemistry method in the analysis of canine lipoproteins. AB - BACKGROUND: The evaluation of lipoprotein metabolism in small animal medicine is hindered by the lack of a gold standard method and paucity of validation data to support the use of automated chemistry methods available in the typical veterinary clinical pathology laboratory. The physical and chemical differences between canine and human lipoproteins draw into question whether the transference of some of these human methodologies for the study of canine lipoproteins is valid. Validation of methodology must go hand in hand with exploratory studies into the diagnostic or prognostic utility of measuring specific lipoproteins in veterinary medicine. OBJECTIVE: The goal of this study was to compare one commercially available wet-chemistry method to manual and automated lipoprotein electrophoresis in the analysis of canine lipoproteins. METHODS: Canine lipoproteins from 50 dogs were prospectively analyzed by 2 electrophoretic methods, one automated and one manual method, and one wet-chemistry method. RESULTS: Electrophoretic methods identified a higher proportion of low-density lipoproteins than the wet-chemistry method. Automated electrophoresis occasionally failed to identify very low-density lipoproteins. CONCLUSIONS: Wet chemistry methods designed for evaluation of human lipoproteins are insensitive to canine low-density lipoproteins and may not be applicable to the study of canine lipoproteins. Automated electrophoretic methods will likely require significant modifications if they are to be used in the analysis of canine lipoproteins. Studies aimed at determining the impact of a disease state on lipoproteins should thoroughly investigate the selected methodology prior to the onset of the study. PMID- 26756398 TI - Stereoselective Synthesis of Polycycles Containing an Aziridine Group: Intramolecular aza-Diels-Alder Reactions of Unactivated 2H-Azirines with Unactivated Dienes. AB - Vinyl azide with a pendent diene can undergo thermal decomposition to a related azirine intermediate, which was used immediately in an intramolecular aza-Diels Alder reaction to furnish an aziridine-containing trans-fused tricyclic core structure with excellent stereoselectivity. The method provides a facile entry to complex polycyclic alkaliods which can be further elaborated by ring-opening reactions and ring expansion of the aziridine moiety, as well as by dihydroxylation of the alkene group. PMID- 26756399 TI - The Workplace Experiences of Women with Fibromyalgia. AB - PURPOSE: Fibromyalgia (FM) is a common pain syndrome that mostly affects women. Chronic pain and other symptoms often chalenge work for women with FM. This study aimed to explore how women with FM experience their work situations. METHOD: A purposive sample of 15 women with FM was interviewed with in-depth qualitative interviews. Data were analysed using a hermeneutic approach. RESULTS: The results revealed that women with FM experienced incapacity to work as they had previously and eventually accepted that their work life had changed or reached its end. Since their work had great significance in their lives, feelings of loss and sorrow were common. Women who were working, unemployed, or on sick leave described feelings of fear for their future work situations. CONCLUSIONS: Women with FM greatly value their work. Their wish to perform work as before is however, not consistent with their abilities. As such, women with FM need support in continuing to work for as long as possible, after which they need support in finding new values in life. PMID- 26756401 TI - Continuous-Flow Microwave Synthesis of Metal-Organic Frameworks: A Highly Efficient Method for Large-Scale Production. AB - Metal-organic frameworks are having a tremendous impact on novel strategic applications, with prospective employment in industrially relevant processes. The development of such processes is strictly dependent on the ability to generate materials with high yield efficiency and production rate. We report a versatile and highly efficient method for synthesis of metal-organic frameworks in large quantities using continuous flow processing under microwave irradiation. Benchmark materials such as UiO-66, MIL-53(Al), and HKUST-1 were obtained with remarkable mass, space-time yields, and often using stoichiometric amounts of reactants. In the case of UiO-66 and MIL-53(Al), we attained unprecedented space time yields far greater than those reported previously. All of the syntheses were successfully extended to multi-gram high quality products in a matter of minutes, proving the effectiveness of continuous flow microwave technology for the large scale production of metal-organic frameworks. PMID- 26756400 TI - Cellular and molecular modifier pathways in tauopathies: the big picture from screening invertebrate models. AB - Abnormal tau accumulations were observed and documented in post-mortem brains of patients affected by Alzheimer's disease (AD) long before the identification of mutations in the Microtubule-associated protein tau (MAPT) gene, encoding the tau protein, in a different neurodegenerative disease called Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). The discovery of mutations in the MAPT gene associated with FTDP-17 highlighted that dysfunctions in tau alone are sufficient to cause neurodegeneration. Invertebrate models have been diligently utilized in investigating tauopathies, contributing to the understanding of cellular and molecular pathways involved in disease etiology. An important discovery came with the demonstration that over-expression of human tau in Drosophila leads to premature mortality and neuronal dysfunction including neurodegeneration, recapitulating some key neuropathological features of the human disease. The simplicity of handling invertebrate models combined with the availability of a diverse range of experimental resources make these models, in particular Drosophila a powerful invertebrate screening tool. Consequently, several large-scale screens have been performed using Drosophila, to identify modifiers of tau toxicity. The screens have revealed not only common cellular and molecular pathways, but in some instances the same modifier has been independently identified in two or more screens suggesting a possible role for these modifiers in regulating tau toxicity. The purpose of this review is to discuss the genetic modifier screens on tauopathies performed in Drosophila and C. elegans models, and to highlight the common cellular and molecular pathways that have emerged from these studies. Here, we summarize results of tau toxicity screens providing mechanistic insights into pathological alterations in tauopathies. Key pathways or modifiers that have been identified are associated with a broad range of processes including, but not limited to, phosphorylation, cytoskeleton organization, axonal transport, regulation of cellular proteostasis, transcription, RNA metabolism, cell cycle regulation, and apoptosis. We discuss the utility and application of invertebrate models in elucidating the cellular and molecular functions of novel and uncharacterized disease modifiers identified in large-scale screens as well as for investigating the function of genes identified as risk factors in genome-wide association studies from human patients in the post-genomic era. In this review, we combined and summarized several large scale modifier screens performed in invertebrate models to identify modifiers of tau toxicity. A summary of the screens show that diverse cellular processes are implicated in the modification of tau toxicity. Kinases and phosphatases are the most predominant class of modifiers followed by components required for cellular proteostasis and axonal transport and cytoskeleton elements. PMID- 26756402 TI - COMSAT: Residue contact prediction of transmembrane proteins based on support vector machines and mixed integer linear programming. AB - In this article, we present COMSAT, a hybrid framework for residue contact prediction of transmembrane (TM) proteins, integrating a support vector machine (SVM) method and a mixed integer linear programming (MILP) method. COMSAT consists of two modules: COMSAT_SVM which is trained mainly on position-specific scoring matrix features, and COMSAT_MILP which is an ab initio method based on optimization models. Contacts predicted by the SVM model are ranked by SVM confidence scores, and a threshold is trained to improve the reliability of the predicted contacts. For TM proteins with no contacts above the threshold, COMSAT_MILP is used. The proposed hybrid contact prediction scheme was tested on two independent TM protein sets based on the contact definition of 14 A between Calpha-Calpha atoms. First, using a rigorous leave-one-protein-out cross validation on the training set of 90 TM proteins, an accuracy of 66.8%, a coverage of 12.3%, a specificity of 99.3% and a Matthews' correlation coefficient (MCC) of 0.184 were obtained for residue pairs that are at least six amino acids apart. Second, when tested on a test set of 87 TM proteins, the proposed method showed a prediction accuracy of 64.5%, a coverage of 5.3%, a specificity of 99.4% and a MCC of 0.106. COMSAT shows satisfactory results when compared with 12 other state-of-the-art predictors, and is more robust in terms of prediction accuracy as the length and complexity of TM protein increase. COMSAT is freely accessible at http://hpcc.siat.ac.cn/COMSAT/. PMID- 26756403 TI - Anodic Methods for Covalent Attachment of Ethynylferrocenes to Electrode Surfaces: Comparison of Ethynyl Activation Processes. AB - The electrochemical oxidation of ferrocenes having an H- or Li-terminated ethynyl group has been studied, especially as it relates to their covalent anchoring to carbon surfaces. The anodic oxidation of lithioethynylferrocene (1-Li) results in rapid loss of Li(+) and formation of the ethynyl-based radical FeCp(eta(5) C5H4)(C=C), (1, Cp = eta(5)-C5H5), which reacts with the electrode. Chemically modified electrodes (CMEs) were thereby produced containing strongly bonded, ethynyl-linked monolayers and electrochemically controlled multilayers. Strong attachments of ethynylferrocenes to gold and platinum surfaces were also possible. The lithiation/anodic oxidation process is a mirror analogue of the diazonium/cathodic reduction process for preparation of aryl-modified CMEs. A second method produced an ethynylferrocene-modified electrode by direct anodic oxidation of the H-terminated ethynylferrocene (1-H) at a considerably more positive potential. Both processes produced robust modified electrodes with well defined ferrocene-based surface cyclic voltammetry waves that remained unchanged for as many as 10(4) scans. Ferrocene derivatives in which the ethynyl moiety was separated from the cyclopentadienyl ring by an ether group showed very similar behavior. DFT calculations were performed on the relevant redox states of 1-H, 1 Li, and 1, with emphasis on the ferrocenyl vs ethynyl character of their high valence orbitals. Whereas the HOMOs of both 1-H and 1-Li have some ethynyl character, the SOMOs of the corresponding monocations are strictly ferrocenium in makeup. Predominant ethynyl character returns to the highest valence orbitals after loss of Li(+) from [1-Li](+) or loss of H(+) from [1-H](2+). These anodic processes hold promise for the controlled chemical modification of carbon and other electrode surfaces by a variety of ethynyl or alkynyl-linked organic and metal-containing systems. PMID- 26756404 TI - Metal artifact reduction and image quality evaluation of lumbar spine CT images using metal sinogram segmentation. AB - Metal artifacts often appear in the images of computed tomography (CT) imaging. In the case of lumbar spine CT images, artifacts disturb the images of critical organs. These artifacts can affect the diagnosis, treatment, and follow up care of the patient. One approach to metal artifact reduction is the sinogram completion method. A mixed-variable thresholding (MixVT) technique to identify the suitable metal sinogram is proposed. This technique consists of four steps: 1) identify the metal objects in the image by using k-mean clustering with the soft cluster assignment, 2) transform the image by separating it into two sinograms, one of which is the sinogram of the metal object, with the surrounding tissue shown in the second sinogram. The boundary of the metal sinogram is then found by the MixVT technique, 3) estimate the new value of the missing data in the metal sinogram by linear interpolation from the surrounding tissue sinogram, 4) reconstruct a modified sinogram by using filtered back-projection and complete the image by adding back the image of the metal object into the reconstructed image to form the complete image. The quantitative and clinical image quality evaluation of our proposed technique demonstrated a significant improvement in image clarity and detail, which enhances the effectiveness of diagnosis and treatment. PMID- 26756406 TI - Efficient and robust 3D CT image reconstruction based on total generalized variation regularization using the alternating direction method. AB - Iterative reconstruction algorithms for computed tomography (CT) through total variation regularization based on piecewise constant assumption can produce accurate, robust, and stable results. Nonetheless, this approach is often subject to staircase artefacts and the loss of fine details. To overcome these shortcomings, we introduce a family of novel image regularization penalties called total generalized variation (TGV) for the effective production of high quality images from incomplete or noisy projection data for 3D reconstruction. We propose a new, fast alternating direction minimization algorithm to solve CT image reconstruction problems through TGV regularization. Based on the theory of sparse-view image reconstruction and the framework of augmented Lagrange function method, the TGV regularization term has been introduced in the computed tomography and is transformed into three independent variables of the optimization problem by introducing auxiliary variables. This new algorithm applies a local linearization and proximity technique to make the FFT-based calculation of the analytical solutions in the frequency domain feasible, thereby significantly reducing the complexity of the algorithm. Experiments with various 3D datasets corresponding to incomplete projection data demonstrate the advantage of our proposed algorithm in terms of preserving fine details and overcoming the staircase effect. The computation cost also suggests that the proposed algorithm is applicable to and is effective for CBCT imaging. Theoretical and technical optimization should be investigated carefully in terms of both computation efficiency and high resolution of this algorithm in application-oriented research. PMID- 26756405 TI - Low dose high energy x-ray in-line phase sensitive imaging prototype: Investigation of optimal geometric conditions and design parameters. AB - The objective of this study was to investigate the optimization of a high energy in-line phase sensitive x-ray imaging prototype under different geometric and operating conditions for mammography application. A phase retrieval algorithm based on phase attenuation duality (PAD) was applied to the phase contrast images acquired by the prototype. Imaging performance was investigated at four magnification values of 1.67, 2, 2.5 and 3 using an acrylic edge, an American College of Radiology (ACR) mammography phantom and contrast detail (CD) phantom with tube potentials of 100, 120 and 140 kVp. The ACR and CD images were acquired at the same mean glandular dose (MGD) of 1.29 mGy with a computed radiography (CR) detector of 43.75 MUm pixel pitch at a fixed source to image distance (SID) of 170 cm. The x-ray tube focal spot size was kept constant as 7 MUm while a 2.5 mm thick aluminum (Al) filter was used for beam hardening. The performance of phase contrast and phase retrieved images were compared with computer simulations based on the relative phase contrast factor (RPF) at high x-ray energies. The imaging results showed that the x-ray tube operated at 100 kVp under the magnification of 2.5 exhibits superior imaging performance which is in accordance to the computer simulations. As compared to the phase contrast images, the phase retrieved images of the ACR and CD phantoms demonstrated improved imaging contrast and target discrimination. We compared the CD phantom images acquired in conventional contact mode with and without the anti-scatter grid using the same prototype at 1.295 mGy and 2.59 mGy using 40 kVp, a 25 MUm rhodium (Rh) filter. At the same radiation dose, the phase sensitive images provided improved detection capabilities for both the large and small discs, while compared to the double dose image acquired in conventional mode, the observer study also indicated that the phase sensitive images provided improved detection capabilities for the large discs. This study therefore validates the potential of using high energy phase contrast x-ray imaging to improve lesion detection and reduce radiation dose for clinical applications such as mammography. PMID- 26756407 TI - Accurate low-dose iterative CT reconstruction from few projections by Generalized Anisotropic Total Variation minimization for industrial CT. AB - BACKGROUND: Reducing the amount of time for data acquisition and reconstruction in industrial CT decreases the operation time of the X-ray machine and therefore increases the sales. This can be achieved by reducing both, the dose and the pulse length of the CT system and the number of projections for the reconstruction, respectively. OBJECTIVE: In this paper, a novel generalized Anisotropic Total Variation regularization for under-sampled, low-dose iterative CT reconstruction is discussed and compared to the standard methods, Total Variation, Adaptive weighted Total Variation and Filtered Backprojection. METHOD: The novel regularization function uses a priori information about the Gradient Magnitude Distribution of the scanned object for the reconstruction. We provide a general parameterization scheme and evaluate the efficiency of our new algorithm for different noise levels and different number of projection views. RESULTS: When noise is not present, error-free reconstructions are achievable for AwTV and GATV from 40 projections. In cases where noise is simulated, our strategy achieves a Relative Root Mean Square Error that is up to 11 times lower than Total Variation-based and up to 4 times lower than AwTV-based iterative statistical reconstruction (e.g. for a SNR of 223 and 40 projections). CONCLUSION: To obtain the same reconstruction quality as achieved by Total Variation, the projection number and the pulse length, and the acquisition time and the dose respectively can be reduced by a factor of approximately 3.5, when AwTV is used and a factor of approximately 6.7, when our proposed algorithm is used. PMID- 26756408 TI - Quantitative evaluation of correlation of dose and FDG-PET uptake value with clinical chest wall complications in patients with lung cancer treated with stereotactic body radiation therapy. AB - The aim of this study was to investigate quantitatively the dosimetric factors that increase the risk of clinical complications of rib fractures or chest wall pain after stereotactic body radiation therapy (SBRT) to the lung. The correlations of clinical complications with standard-uptake values (SUV) and FDG PET activity distributions from post-treatment PET-imaging were studied. Mean and maximum doses from treatment plans, FDG-PET activity values on post-SBRT PET scans and the presence of clinical complications were determined in fifteen patients undergoing 16 SBRT treatments for lung cancer. SBRT treatments were delivered in 3 to 5 fractions using 5 to 7 fields to prescription doses in the range from 39.0 to 60.0 Gy. The dose and FDG-PET activity values were extracted from regions of interest in the chest wall that matched anatomically. Quantitative evaluation of the correlation between dose deposition and FDG-PET activity was performed by calculating the Pearson correlation coefficient using pixel-by-pixel analysis of dose and FDG-PET activity maps in selected regions of interest associated with clinical complications. Overall, three of fifteen patients developed rib fractures with chest wall pain, and two patients developed pain symptoms without fracture. The mean dose to the rib cage in patients with fractures was 37.53 Gy compared to 33.35 Gy in patients without fractures. Increased chest wall activity as determined by FDG-uptake was noted in patients who developed rib fractures. Enhanced activity from PET-images correlated strongly with high doses deposited to the chest wall which could be predicted by a linear relationship. The local enhanced activity was associated with the development of clinical complications such as chest wall inflammation and rib fracture. This study demonstrates that rib fractures and chest wall pain can occur after SBRT treatments to the lung and is associated with increased activity on subsequent PET scans. The FDG-PET activity provides a useful parameter that can be used clinically to predict chest wall complication in lung patients. PMID- 26756409 TI - Role of CT perfusion imaging in patients with variously differentiated gastric adenocarcinoma. AB - PURPOSE: To explore the characteristics of variously differentiated gastric cancers on computed tomography (CT) perfusion imaging, including specific perfusion parameter values, and potential clinical applications in the prognosis assessment of gastric cancer. MATERIALS AND METHODS: Fifty patients with gastric cancer confirmed by gastroscope pathology were studied prospectively using CT perfusion imaging examinations on a 64-slice spiral CT scanner. The acquired volume data were used for calculations, mapping, and analysis by using an abdominal tumor perfusion protocol (deconvolution method) in the CT perfusion software package to measure 4 parameters: blood flow (BF), blood volume (BV), mean transit time (MTT), and the permeability surface (PS) area product. The different differentiated Gastric cancers with CT perfusion values were divided into 3 groups: well-differentiated, moderately differentiated and poorly differentiated gastric adenocarcinoma, and compared statistically with one another by statistical software. RESULTS: The mean perfusion values of 10 patients with well-differentiated gastric adenocarcinoma were as follows: BF, 75.28 +/- 6.81 mL/100 g/min; BV, 9.01 +/- 0.94 mL/100 g; MTT, 9.89 +/- 1.65 s; and PS, 10.05 +/- 0.71 mL/100 g/min. The mean perfusion values of 24 patients with moderately differentiated gastric adenocarcinoma were as follows: BF, 110.01 +/- 31.90 mL/100 g/min; BV, 18.18 +/- 5.62 mL/100 g; MTT, 9.81 +/- 3.69 s; and PS, 40.08 +/- 15.82 mL/100 g/min. The mean perfusion values of 16 patients with poorly differentiated gastric adenocarcinoma were as follows: BF, 138.59 +/- 38.09 mL/100 g/min; BV, 21.08 +/- 4.11 mL/100 g; MTT, 9.47 +/- 1.80 s; and PS, 57.50 +/- 13.28 mL/100 g/min. Comparing the 3 groups, differences between the well-differentiated group and the moderate differentiation group were all statistically significant for BF, BV, and PS (p < 0.05, respectively), differences between the well-differentiated group and the poor differentiation group were all statistically significant for BF, BV, and PS (p < 0.05,respectively) as well; While MTT value showed no statistical difference among the 3 groups (p > 0.05). CONCLUSION: Stomach CT perfusion imaging is a functional imaging technology from the perspective of hemodynamics with potential clinical applications. The BF, BV and PS values could serve as indicators of the degree of malignancy and aid in prognostic assessment of gastric cancer. PMID- 26756410 TI - The impact of the number of projections on image quality in Compton scatter tomography. AB - The availability of high resolution, energy discriminating photon counting detectors should make it possible to use Compton scattered photons to improve the diagnostic capability of computed tomography (CT). With high, spatial and energy resolution detectors Compton scatter tomography (CST) images of adequate quality can be obtained with a single projection. In practice, the limitations of realistic detectors require multiple projections for good quality images. The relationship between the number of projections used for reconstruction and the reconstructed image quality obtained for conventional CT does not necessarily apply to multi-projection Compton scatter tomography (MPCST). The purpose of this work was to investigate the dependence of the reconstructed image quality on the number of projections for MPCST. Analytical simulations and reconstructions were used to evaluate the contrast and spatial resolution for images reconstructed with one to 720 projections. Contrast-to-noise ratios (CNR) and the modulation transfer functions (MTF) demonstrated that the contrast increases monotonically with the number of projections while spatial resolution was independent of the number of projections. The contrast initially increases rapidly with projection number, becoming more gradual as the number of projections increase, with the rate of change being a function of fluence. The number of projections required to asymptotically approach the maximum contrast decreases as the fluence increases, with no indication of an optimal value for the range of fluences and projections investigated. For the projections considered, an increase in the number of projections increases the CNR even though the number of photons per projection decreases. PMID- 26756411 TI - Prior image constrained low-rank matrix decomposition method in limited-angle reverse helical cone-beam CT. AB - BACKGROUND: Limited-angle problem occurs in many applications of X-ray computed tomography (CT) and it will lead to artifacts. OBJECTIVE: In this paper, we present the tomographic imaging of pipeline which is in service by cone-beam computed tomography (CBCT). And our purpose is to suppress the artifacts caused by the limited-angle problem. METHODS: First, traditional helical scanning strategy is adopted for the pipeline where can be fully scanned, and the slices with less or no defects from the reconstructed image are selected to constitute the prior image. Then a limited-angle reverse helical scanning strategy is developed for the pipeline where can be scanned within limited angular range. Second, considering the constraint of the prior image and the resemblance among slices of pipeline, an image model which incorporates the Schatten p(0 0.05). The number of the incidence of >=two injuries increased as the academic year progressed, and there was a weak positive association between the variables (P < 0.05, Cramer's V = 0.311). One out of six injuries were intentional, with the highest incidence in the 6-9 year age group (20.5%) and boys sex (19.8%; P > 0.05). CONCLUSIONS: School-based injuries at primary and secondary school still challenge the health as well as the security of the students. (c) 2016 Japan Pediatric Society. PMID- 26756434 TI - Cancer incidence among alcoholic liver disease patients in Finland: A retrospective registry study during years 1996-2013. AB - Both alcohol abuse and liver cirrhosis are known risk factors for various cancers. This article was aimed to assess the long-term risk of malignancies among patients with severe alcoholic liver disease (ALD), i.e., alcoholic liver cirrhosis and alcoholic hepatitis. A cohort of 8,796 male and 3,077 female ALD patients from 1996 to 2012 was identified from the Finnish National Hospital Discharge Register. This nationwide cohort was combined with the data from the Finnish Cancer Registry for incidence of malignancies during the years 1996-2013. The cancer cases diagnosed were compared with the number of cancers in the general population. The number of malignancies in our cohort was 1,052 vs. 368 expected. There was statistically significant excess of cancers of the liver, (standardized incidence ratio [SIR] 59.20; 95% CI 53.11-65.61), pancreas (SIR 3.71; 95% CI 2.72-4.94), pharynx (SIR 9.25; 95% CI 6.05-13.56), mouth (SIR 8.31; 95% CI 4.84-13,29), oesophagus (SIR 7.92; 95% CI 5.49-11.07), tongue (SIR 7,21; 95% CI 3.60-12.89), larynx (SIR 5.20; 95% CI 2.77-8.89), lung (SIR 2.77; 95% CI 2.27-3.32), stomach (SIR 2.76; 95% CI 1.79-4.07), kidney (SIR 2.69; 95% CI 1.84 3.79) and colon (SIR 2.33; 95% CI 1.70-3.11). There was no decreased risk of any cancer among ALD patients. Severe ALD is associated with markedly increased risk of malignancies. The risk is especially high for hepatocellular carcinoma, but also significantly increased for cancers of the upper aerodigestive tract, pancreas and kidneys, and warrants cancer surveillance in selected cases. PMID- 26756435 TI - The TDP-43 N-terminal domain structure at high resolution. AB - Transactive response DNA-binding protein 43 kDa (TDP-43) is an RNA transporting and processing protein whose aberrant aggregates are implicated in neurodegenerative diseases. The C-terminal domain of this protein plays a key role in mediating this process. However, the N-terminal domain (residues 1-77) is needed to effectively recruit TDP-43 monomers into this aggregate. In the present study, we report, for the first time, the essentially complete (1) H, (15) N and (13) C NMR assignments and the structure of the N-terminal domain determined on the basis of 26 hydrogen-bond, 60 torsion angle and 1058 unambiguous NOE structural restraints. The structure consists of an alpha-helix and six beta strands. Two beta-strands form a beta-hairpin not seen in the ubiquitin fold. All Pro residues are in the trans conformer and the two Cys are reduced and distantly separated on the surface of the protein. The domain has a well defined hydrophobic core composed of F35, Y43, W68, Y73 and 17 aliphatic side chains. The fold is topologically similar to the reported structure of axin 1. The protein is stable and no denatured species are observed at pH 4 and 25 degrees C. At 4 kcal.mol(-1) , the conformational stability of the domain, as measured by hydrogen/deuterium exchange, is comparable to ubiquitin (6 kcal.mol(-1) ). The beta-strands, alpha-helix, and three of four turns are generally rigid, although the loop formed by residues 47-53 is mobile, as determined by model-free analysis of the (15) N{(1) H}NOE, as well as the translational and transversal relaxation rates. DATABASE: Structural data have been deposited in the Protein Data Bank under accession code: 2n4p. The NMR assignments have been deposited in the BMRB database under access code: 25675. PMID- 26756437 TI - Seed-Mediated Growth of Silver Nanocubes in Aqueous Solution with Tunable Size and Their Conversion to Au Nanocages with Efficient Photothermal Property. AB - Two seed-mediated approaches for the growth of silver nanocubes in aqueous solution have been developed. Addition of a silver-seed solution to a mixture of cetyltrimethylammonium chloride (CTAC), silver trifluoroacetate, and ascorbic acid and heating the solution at 60 degrees C for 1.5 h produces uniform Ag nanocubes with tunable sizes from 23 to 60 nm by simply adjusting the volume of silver-seed solution introduced. Alternatively, the silver-seed solution can be injected into a mixture of cetyltrimethylammonium bromide (CTAB), silver nitrate, copper sulfate, and ascorbic acid and heated to 80 degrees C for 2 h to generate 46 nm silver nanocubes. Plate-like Ag nanocrystals exposing {111} surfaces can be synthesized by reducing Ag(NH3 )2 (+) with ascorbic acid in a CTAC solution. Relatively large Ag nanocubes were converted to cuboctahedral Au/Ag and Au nanocages and nanoframes with empty {111} faces through a galvanic replacement reaction. The nanocages showed a progressive plasmonic band red-shift with increasing Au content. The nanocages exhibited high and stable photothermal efficiency with solution temperatures quickly reaching beyond 100 degrees C when irradiated with an 808 nm laser for large heat and water vapor generation. PMID- 26756438 TI - Genetic inviability is a major driver of type III survivorship in experimental families of a highly fecund marine bivalve. AB - The offspring of most highly fecund marine fish and shellfish suffer substantial mortality early in the life cycle, complicating prediction of recruitment and fisheries management. Early mortality has long been attributed to environmental factors and almost never to genetic sources. Previous work on a variety of marine bivalve species uncovered substantial genetic inviability among the offspring of inbred crosses, suggesting a large load of early-acting deleterious recessive mutations. However, genetic inviability of randomly bred offspring has not been addressed. Here, genome-wide surveys reveal widespread, genotype-dependent mortality in randomly bred, full-sib progenies of wild-caught Pacific oysters (Crassostrea gigas). Using gene-mapping methods, we infer that 11-19 detrimental alleles per family render 97.9-99.8% of progeny inviable. The variable genomic positions of viability loci among families imply a surprisingly large load of partially dominant or additive detrimental mutations in wild adult oysters. Although caution is required in interpreting the relevance of experimental results for natural field environments, we argue that the observed genetic inviability corresponds with type III survivorship, which is characteristic of both hatchery and field environments and that our results, therefore, suggest the need for additional experiments under the near-natural conditions of mesocosms. We explore the population genetic implications of our results, calculating a detrimental mutation rate that is comparable to that estimated for conifers and other highly fecund perennial plants. Genetic inviability ought to be considered as a potential major source of low and variable recruitment in highly fecund marine animals. PMID- 26756433 TI - Exploring circulating micro-RNA in the neoadjuvant treatment of breast cancer. AB - Breast cancer is the most frequently diagnosed malignancy amongst females worldwide. In recent years the management of this disease has transformed considerably, including the administration of chemotherapy in the neoadjuvant setting. Aside from increasing rates of breast conserving surgery and enabling surgery via tumour burden reduction, use of chemotherapy in the neoadjuvant setting allows monitoring of in vivo tumour response to chemotherapeutics. Currently, there is no effective means of identifying chemotherapeutic responders from non-responders. Whilst some patients achieve complete pathological response (pCR) to chemotherapy, a good prognostic index, a proportion of patients derive little or no benefit, being exposed to the deleterious effects of systemic treatment without any knowledge of whether they will receive benefit. The identification of predictive and prognostic biomarkers could confer multiple benefits in this setting, specifically the individualization of breast cancer management and more effective administration of chemotherapeutics. In addition, biomarkers could potentially expedite the identification of novel chemotherapeutic agents or increase their efficacy. Micro-RNAs (miRNAs) are small non-coding RNA molecules. With their tissue-specific expression, correlation with clinicopathological prognostic indices and known dysregulation in breast cancer, miRNAs have quickly become an important avenue in the search for novel breast cancer biomarkers. We provide a brief history of breast cancer chemotherapeutics and explore the emerging field of circulating (blood-borne) miRNAs as breast cancer biomarkers for the neoadjuvant treatment of breast cancer. Established molecular markers of breast cancer are outlined, while the potential role of circulating miRNAs as chemotherapeutic response predictors, prognosticators or potential therapeutic targets is discussed. PMID- 26756439 TI - Chronic cerebral hypoperfusion induces long-lasting cognitive deficits accompanied by long-term hippocampal silent synapses increase in rats. AB - Synaptic dysfunction underlies cognitive deficits induced by chronic cerebral hypoperfusion (CCH). There are silent synapses in neural circuits, but the effect of CCH on silent synapses is unknown. The present study was designed to explore learning and memory deficits and dynamic changes in silent synapses by direct visualization in a rat model of CCH. Adult male Sprague-Dawley rats were subjected to permanent bilateral common carotid artery occlusion (BCCAO) to reproduce CCH. Learning and memory effects were examined at 1, 4, 12, and 24 weeks after BCCAO. In addition, immunofluorescent confocal microscopy was used to detect AMPA and N-methyl-d-aspartate receptors colocalized with synaptophysin, and Golgi-Cox staining was used to observe dendritic spine density. We found that BCCAO rats exhibited recognition memory deficits from 4 weeks; spatial learning and memory, as well as working memory impairment began at 1 week and persistent to 24 weeks after surgery. Following BCCAO, the percentage of silent synapses increased by 29.81-55.08% compared with the controls at different time points (P<0.001). Compared with control groups, dendritic spine density in the CA1 region of BCCAO groups significantly decreased (P<0.001). Thus, the present study suggests that CCH can induce long-lasting cognitive deficits and long-term increase in the number of silent synapses. Furthermore, the decrease in dendritic spine density was correlated with the decrease in the number of functional synapses. The results suggest a potential mechanism by which CCH can induce learning and memory deficits. PMID- 26756440 TI - Age-related disorders of sleep and motor control in the rat models of functionally distinct cholinergic neuropathology. AB - We studied the impact of aging during sleep in the rat models of Alzheimer's (AD) and Parkinson's (PD) disease cholinergic neuropathology to determine the possible different and earlier onset of age-related sleep disorder during the neurodegenerative diseases vs. healthy aging. We used the bilateral nucleus basalis (NB) and pedunculopontine tegmental nucleus (PPT) lesioned rats as the in vivo models of functionally distinct cholinergic neuropathology, and we followed the impact of aging on sleep architecture, the electroencephalographic (EEG) microstructure and motor control across sleep/wake states. Our results have shown for the first time that the earliest signs of aging during distinct cholinergic neuropathology were expressed through a different and topographically specific EEG microstructure during rapid eye movement sleep (REM). EEG delta amplitude attenuation within the sensorimotor cortex (SMCx) during REM was the earliest sign of aging in the NB lesion. EEG sigma amplitude augmentation within the motor cortex (MCx) during REM was the earliest sign of aging in the PPT lesion. In addition, aging was differently expressed through the SMCx drive alterations, but it was commonly expressed through the MCx drive alterations during all sleep/wake states. Our study provided evidence of distinct REM sleep disorders and sleep state related cortical drives as the signs of aging onset during functionally distinct cholinergic neuropathologies (NB lesion vs. PPT lesion). PMID- 26756442 TI - Simultaneous Identification of Neutral and Anionic Species in Complex Mixtures without Separation. AB - A chemosensory system is reported that operates without the need for separation techniques and is capable of identifying anions and structurally similar bioactive molecules. In this strategy, the coordination of analytes to a metal complex with an open binding cleft generates "static structures" on the NMR timescale. Unique signals are created by strategically placing fluorine atoms in close proximity to bound analytes so that small structural differences induce distinct (19)F NMR shifts that can be used to identify each analyte. The utility of this method is illustrated by quantifying caffeine levels in coffee, by identifying ingredients in tea and energy drinks, and by discriminating between multiple biogenic amines with remote structural differences six carbon atoms away from the binding site. We further demonstrate the simultaneous identification of multiple neutral and anionic species in a complex mixture. PMID- 26756443 TI - Facile Generation of Tumor-pH-Labile Linkage-Bridged Block Copolymers for Chemotherapeutic Delivery. AB - Successful bench-to-bedside translation of nanomedicine relies heavily on the development of nanocarriers with superior therapeutic efficacy and high biocompatibility. However, the optimal strategy for improving one aspect often conflicts with the other. Herein, we report a tactic of designing tumor-pH-labile linkage-bridged copolymers of clinically validated poly(D,L-lactide) and poly(ethylene glycol) (PEG-Dlink(m)-PDLLA) for safe and effective drug delivery. Upon arriving at the tumor site, PEG-Dlink(m)-PDLLA nanoparticles will lose the PEG layer and increase zeta potential by responding to tumor acidity, which significantly enhances cellular uptake and improves the in vivo tumor inhibition rate to 78.1% in comparison to 47.8% of the non-responsive control. Furthermore, PEG-Dlink(m)-PDLLA nanoparticles show comparable biocompatibility with the clinically used PEG-b-PDLLA micelle. The improved therapeutic efficacy and safety demonstrate great promise for our strategy in future translational studies. PMID- 26756444 TI - Nickel-Catalyzed Allylic Alkylation with Diarylmethane Pronucleophiles: Reaction Development and Mechanistic Insights. AB - Palladium-catalyzed allylic substitution reactions are among the most efficient methods to construct C-C bonds between sp(3)-hybridized carbon atoms. In contrast, much less work has been done with nickel catalysts, perhaps because of the different mechanisms of the allylic substitution reactions. Palladium catalysts generally undergo substitution by a "soft"-nucleophile pathway, wherein the nucleophile attacks the allyl group externally. Nickel catalysts are usually paired with "hard" nucleophiles, which attack the metal before C-C bond formation. Introduced herein is a rare nickel-based catalyst which promotes substitution with diarylmethane pronucleophiles by the soft-nucleophile pathway. Preliminary studies on the asymmetric allylic alkylation are promising. PMID- 26756445 TI - Chain Walking of Allylrhodium Species Towards Esters During Rhodium-Catalyzed Nucleophilic Allylations of Imines. AB - Allylrhodium species derived from delta-trifluoroboryl beta,gamma-unsaturated esters undergo chain walking towards the ester moiety. The resulting allylrhodium species react with imines to give products containing two new stereocenters and a Z-alkene. By using a chiral diene ligand, products can be obtained with high enantioselectivities, where a pronounced matched/mismatched effect with the chirality of the allyltrifluoroborate is evident. PMID- 26756446 TI - Switching on the Metathesis Activity of Re Oxo Alkylidene Surface Sites through a Tailor-Made Silica-Alumina Support. AB - Re oxo alkylidene surface species are putative active sites in classical heterogeneous Re-based alkene-metathesis catalysts. However, the lack of evidence for such species questions their existence and/or relevance as reaction intermediates. Using Re(O)(=CH-CH=CPh2)(OtBuF6)3(THF), the corresponding well defined Re oxo alkylidene surface species can be generated on both silica and silica-alumina supports. While inactive on the silica support, it displays very good activity, even for functionalized olefins, on the silica-alumina support. PMID- 26756447 TI - Medical Cosmopolitanism in Global Dubai: A Twenty-first-century Transnational Intracytoplasmic Sperm Injection (ICSI) Depot. AB - Dubai-one of the seven United Arab Emirates and the Middle East's only "global city"-is gaining a reputation as a transnational medical tourism hub. Characterized by its "medical cosmopolitanism," Dubai is now attracting medical travelers from around the world, some of whom are seeking assisted conception. Dubai is fast becoming known as a new transnational "reprohub" for intracytoplasmic sperm injection (ICSI), the variant of in vitro fertilization designed to overcome male infertility. Based on ethnographic research conducted in one of the country's most cosmopolitan clinics, this article explores the ICSI treatment quests of infertile men coming to Dubai from scores of other nations. The case of an infertile British-Moroccan man is highlighted to demonstrate why ICSI is a particularly compelling "masculine hope technology" for infertile Muslim men. Thus, Muslim men who face barriers to ICSI access in their home countries may become "reprotravelers" to Dubai, an emergent ICSI depot. PMID- 26756448 TI - The assisted presentations of self in nursing home life. AB - In this paper, based on ethnographic data from five nursing homes, we introduce the concept of assisted self-presentation as an analytical tool for exploring how different care practices affect nursing home residents' dignity and sense of self. Practices of assisted self-presentation are geared at recognizing and preserving the individuality and autonomy of residents in situations where it may otherwise come under threat or be misrecognized. Sufficient or appropriate forms of attentiveness to residents' selves and sense of dignity is thus a matter of finding the right balance between intervening too much or too little in residents' production of their physical or social appearance. Here, staff members' knowledge and recognition of the individuality of residents is essential. Whereas intervening too much in residents' appearance or performance of self might be perceived and experienced as pacifying, infantilizing, or as paternalistic overbearingness, intervening too little might be seen as neglectfulness or inhumane. Since practices of assisted self-presentation refer to a kind of social action, which will always be contingent upon the specific capacities and conditions of performing actors, it allows for the simultaneous recognition of failed or perverted work practices as well as promising practices through which residents' selves are successfully recognized. PMID- 26756449 TI - Silk Fibroin Degradation Related to Rheological and Mechanical Properties. AB - Regenerated silk fibroin has been proposed as a material substrate for biomedical, optical, and electronic applications. Preparation of the silk fibroin solution requires extraction (degumming) to remove contaminants, but results in the degradation of the fibroin protein. Here, a mechanism of fibroin degradation is proposed and the molecular weight and polydispersity is characterized as a function of extraction time. Rheological analysis reveals significant changes in the viscosity of samples while mechanical characterization of cast and drawn films shows increased moduli, extensibility, and strength upon drawing. Fifteen minutes extraction time results in degraded fibroin that generates the strongest films. Structural analysis by wide angle X-ray scattering (WAXS) and Fourier transform infrared spectroscopy (FTIR) indicates molecular alignment in the drawn films and shows that the drawing process converts amorphous films into the crystalline, beta-sheet, secondary structure. Most interesting, by using selected extraction times, films with near-native crystallinity, alignment, and molecular weight can be achieved; yet maximal mechanical properties for the films from regenerated silk fibroin solutions are found with solutions subjected to some degree of degradation. These results suggest that the regenerated solutions and the film casting and drawing processes introduce more complexity than native spinning processes. PMID- 26756450 TI - The presence of cutan limits the interpretation of cuticular chemistry and structure: Ficus elastica leaf as an example. AB - Plant cuticles have been traditionally classified on the basis of their ultrastructure, with certain chemical composition assumptions. However, the nature of the plant cuticle may be misinterpreted in the prevailing model, which was established more than 150 years ago. Using the adaxial leaf cuticle of Ficus elastica, a study was conducted with the aim of analyzing cuticular ultrastructure, chemical composition and the potential relationship between structure and chemistry. Gradual chemical extractions and diverse analytical and microscopic techniques were performed on isolated leaf cuticles of two different stages of development (i.e. young and mature leaves). Evidence for the presence of cutan in F. elastica leaf cuticles has been gained after chemical treatments and tissue analysis by infrared spectroscopy and electron microscopy. Significant calcium, boron and silicon concentrations were also measured in the cuticle of this species. Such mineral elements which are often found in plant cell walls may play a structural role and their presence in isolated cuticles further supports the interpretation of the cuticle as the most external region of the epidermal cell wall. The complex and heterogeneous nature of the cuticle, and constraints associated with current analytical procedures may limit the chance for establishing a relationship between cuticle chemical composition and structure also in relation to organ ontogeny. PMID- 26756452 TI - Steric Effects Govern the Photoactivation of Phytochromes. AB - Phytochromes constitute a superfamily of photoreceptor proteins existing in two forms that absorb red (Pr) and far-red (Pfr) light. Although it is well-known that the conversion of Pr into Pfr (the biologically active form) is triggered by a Z->E photoisomerization of the linear tetrapyrrole chromophore, direct evidence is scarce as to why this reaction always occurs at the methine bridge between pyrrole rings C and D. Here, we present hybrid quantum mechanics/molecular mechanics calculations based on a high-resolution Pr crystal structure of Deinococcus radiodurans bacteriophytochrome to investigate the competition between all possible photoisomerizations at the three different (AB, BC and CD) methine bridges. The results demonstrate that steric interactions with the protein are a key discriminator between the different reaction channels. In particular, it is found that such interactions render photoisomerizations at the AB and BC bridges much less probable than photoisomerization at the CD bridge. PMID- 26756451 TI - Disturbed social recognition and impaired risk judgement in older residents with mild cognitive impairment after the Great East Japan Earthquake of 2011: the Tome Project. AB - AIM: After the Great East Japan Earthquake of 2011, we investigated the safety of residents in the affected communities. Most of the people requiring help were elderly and had previously been assessed as Clinical Dementia Rating (CDR) 0.5 (i.e. as having mild cognitive impairment (MCI)). We examined how well they understood the television news and whether they could make appropriate decisions. METHODS: This community-based study of dementia and difficulties following a disaster started in Tome, northern Japan. The subjects were 188 randomly selected older residents who underwent CDR, blood tests, magnetic resonance imaging, and cognitive tests, including an original visual risk cognition task. They were shown NHK news broadcasts from the day of the earthquake to determine whether they could understand the content. RESULTS: Neither the CDR 0 (healthy) nor the CDR 0.5 (MCI) subjects fully understood the television news. Some subjects did not recognize the danger of aftershocks and engaged in risky behaviour. CDR 0.5 subjects who exhibited such behaviour scored lower on the visual risk cognition task. CONCLUSIONS: It is noteworthy that television news is difficult to understand, even for healthy older adults. We found that MCI subjects had particular difficulties due to the disaster and suggest that risk cognition could be evaluated using visually presented materials. PMID- 26756454 TI - Face processing in autism: Reduced integration of cross-feature dynamics. AB - Characteristic problems with social interaction have prompted considerable interest in the face processing of individuals with Autism Spectrum Disorder (ASD). Studies suggest that reduced integration of information from disparate facial regions likely contributes to difficulties recognizing static faces in this population. Recent work also indicates that observers with ASD have problems using patterns of facial motion to judge identity and gender, and may be less able to derive global motion percepts. These findings raise the possibility that feature integration deficits also impact the perception of moving faces. To test this hypothesis, we examined whether observers with ASD exhibit susceptibility to a new dynamic face illusion, thought to index integration of moving facial features. When typical observers view eye-opening and -closing in the presence of asynchronous mouth-opening and -closing, the concurrent mouth movements induce a strong illusory slowing of the eye transitions. However, we find that observers with ASD are not susceptible to this illusion, suggestive of weaker integration of cross-feature dynamics. Nevertheless, observers with ASD and typical controls were equally able to detect the physical differences between comparison eye transitions. Importantly, this confirms that observers with ASD were able to fixate the eye-region, indicating that the striking group difference has a perceptual, not attentional origin. The clarity of the present results contrasts starkly with the modest effect sizes and equivocal findings seen throughout the literature on static face perception in ASD. We speculate that differences in the perception of facial motion may be a more reliable feature of this condition. PMID- 26756453 TI - Nanosensors for Continuous and Noninvasive Monitoring of Mesenchymal Stem Cell Osteogenic Differentiation. AB - Assessing mesenchymal stem cell (MSC) differentiation status is crucial to verify therapeutic efficacy and optimize treatment procedures. Currently, this involves destructive methods including antibody-based protein detection and polymerase chain reaction gene analysis, or laborious and technically challenging genetic reporters. Development of noninvasive methods for real-time differentiation status assessment can greatly benefit MSC-based therapies. This report introduces a nanoparticle-based sensing platform that encapsulates two molecular beacon (MB) probes within the same biodegradable polymeric nanoparticles. One MB targets housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal reference, while another detects alkaline phosphatase (ALP), a functional biomarker. Following internalization, MBs are gradually released as the nanoparticle degrades. GAPDH MBs provide a stable reference signal throughout the monitoring period (18 days) regardless of differentiation induction. Meanwhile, ALP mRNA undergoes well-defined dynamics with peak expression observed during early stages of osteogenic differentiation. By normalizing ALP-MB signal with GAPDH-MB, changes in ALP expression can be monitored, to noninvasively validate osteogenic differentiation. As proof-of-concept, a dual-colored nanosensor is applied to validate MSC osteogenesis on 2D culture and polycaprolactone films containing osteo-inductive tricalcium phospate. PMID- 26756455 TI - Correction: Division time-based amplifiers for stochastic gene expression. AB - Correction for 'Division time-based amplifiers for stochastic gene expression' by Haohua Wang et al., Mol. BioSyst., 2015, 11, 2417-2428. PMID- 26756456 TI - Peak torque, reaction time, and rate of torque development of hip abductors and adductors of older women. AB - Impaired muscle function at the hip has been implicated to be a major factor related to falls in older adults. Therefore, the aim of this study was to analyze the rate of torque development (RTD), reaction time (RT), and peak torque (PT) of hip abductors and hip adductors in young women (YW), older women nonfallers (ONF), and older women fallers (OF). Eighteen YW and 44 older women divided among OF (n = 20) and ONF (n = 24) performed maximum isometric hip abductor and adduction contractions on a dynamometer. YW had 40% greater PT and 61.5% greater RTD for hip abductors than the ONF. Compared with OF, YW had 47.5% greater PT and 68% greater RTD. OF showed less RTD at 150 ms (31%) and 200 ms (34.5%) than ONF for hip abductors. PT of hip adductors was 52% greater in YW than in the two older groups, whereas RTD was 71% greater. OF showed less RTD than ONF for hip abductors according to standardized effect sizes. No RT differences were observed between the three groups. We conclude that older women (OF and ONF) have less strength and ability to develop force rapidly than YW for hip abductors and adductors. Low hip strength and slowed force development in ONF during hip abduction may increase fall risk in older women. PMID- 26756457 TI - Cerebral Amyloid Angiopathy-Related Inflammation Biomarkers: Where are we Now? AB - Cerebral amyloid angiopathy- related inflammation (CAA-ri) is an aggressive disease subtype of CAA with characteristic clinical and radiological findings. CAA-ri is an important diagnosis to reach in clinical practice, as patients typically respond to prompt immunosuppressive treatment. A definitive diagnosis of CAA-ri still requires a brain biopsy, and hence developing non-invasive diagnostic criteria and biomarkers for this syndrome are key priorities in the field. CAA-ri has gained additional interest for its notable similarities to amyloid-related imaging abnormalities, a complication of immunotherapy treatments in Alzheimer's disease patients. In this commentary, the current state of biomarkers research for CAA-ri and recently suggested diagnostic criteria are put into context. PMID- 26756459 TI - Intranasal or transdermal nicotine for the treatment of postoperative pain. AB - BACKGROUND: Acute pain frequently occurs after surgical procedures. Nicotine has been explored as an adjunctive medication for management of postoperative pain. OBJECTIVES: To assess the effect of transdermal or intranasal nicotine administration on postoperative pain, opioid analgesic use, and opioid-related adverse events. SEARCH METHODS: We searched MEDLINE (1966 to 20 March 2014), the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 3), EMBASE (1980 to 20 March 2014), and also databases of ongoing trials (www.controlled-trials.com/ and http://clinicaltrials.gov/). We re-ran the search on 28 April 2015. We will assess the one study of interest when we update the review. SELECTION CRITERIA: We included randomized, placebo-controlled clinical trials that evaluated the effects of perioperative (pre-, intra-, or postoperative) administration of nicotine on postoperative pain, opioid use, and opioid-related adverse events. We excluded all other studies. DATA COLLECTION AND ANALYSIS: Two authors independently screened all titles and abstracts for eligibility and documented reasons for exclusion. In case of disagreement, a third author decided on the inclusion or exclusion of a trial report. When additional information was needed in order to decide if a trial should be included, one of the authors contacted the corresponding author of the trial in question. MAIN RESULTS: Nine trials (666 participants) evaluated nicotine for postoperative pain. Nicotine may reduce postoperative pain scores at 24 hours by a small amount compared with placebo (eight trials, mean difference -0.88 on a 0 to 10 scale, 95% confidence interval (CI) -1.58 to -0.18; low quality evidence). The effect on pain at one hour and 12 hours postoperatively was less certain (very low quality evidence). Statistical heterogeneity was substantial and not adequately explained by stratification of trials according to type of surgical procedure, smoking status, mode of nicotine administration, timing of administration, or assessed risk of bias. Excluding one trial at high risk of bias resulted in similar findings. The effect of nicotine on postoperative opioid use was uncertain due to small number of participants in the studies. Nicotine probably increases the risk of postoperative nausea (seven trials, RR 1.24, 95% CI 1.03 to 1.50; moderate quality evidence). Three trials assessed sedation but the effect is very uncertain due to the very low quality of evidence. We found no evidence that nicotine increased the risk of vomiting (seven studies, risk difference (RD) 0.03, 95% CI -0.04 to 0.09; low quality evidence). The results from one single small trial were insufficient to establish whether nicotine led to an earlier hospital discharge (very low quality evidence). AUTHORS' CONCLUSIONS: Based on evidence of generally low quality, nicotine may reduce postoperative pain at 24 hours compared with placebo, but the effects were relatively small (less than 1 point on a 10 point pain scale) and there was substantial heterogeneity in the results of our analyses. Nicotine does not appear to reduce postoperative use of opioids or opioid-related adverse events but probably increases the risk of nausea. More research is needed to determine the effectiveness of nicotine for postoperative pain and to understand the optimal timing, dose, and method of delivery of nicotine. PMID- 26756461 TI - Impact of low-level viraemia on virological failure in HIV-1-infected patients with stable antiretroviral treatment. AB - BACKGROUND: Low-level viraemia (LLV) occurs in 20-40% of patients achieving viral suppression with antiretroviral therapy (ART). The risk of virological failure (VF: confirmed HIV RNA >200 copies/ml) in these patients is still a matter of debate. METHODS: This is a prospective cohort study in HIV-infected adults attending the HIV clinic of a tertiary care hospital in Spain. Patients with HIV RNA <25 copies/ml and stable ART for at least 6 months presenting LLV (defined as HIV RNA between 25-1,000 copies/ml) from January 2011 to January 2013 were included and followed until VF or end of follow-up in June 2014. RESULTS: A total of 300 out of 1,733 (17.3%) patients with undetectable viraemia for 4.2 years showed LLV: 25-50 copies/ml in 167 (55.7%) patients, 51-200 copies/ml in 111 (37%) and 201-1,000 copies/ml in 22 (7.3%) cases. After a median follow-up of 2.6 years, 23 (7.7%) patients presented VF. No patient with a single or multiple unconfirmed LLV went on to develop VF. HIV RNA >200 copies/ml (HR 59.6; 95% CI 15.7, 227), ritonavir-boosted protease inhibtor (PI/r)-based dual therapy (HR 10.2; 95% CI 2.1, 49.8) and PI/r monotherapy (HR 7.9; 95% CI 1.4, 43.3) were associated with VF. Persistent LLV, defined as HIV RNA <200 copies/ml in at least three consecutive samples, for at least 12 weeks, was detected in 27 (1.6%) patients and 14 (51.9%) of those evolved to VF. CONCLUSIONS: Nearly one-fifth of patients on suppressive ART showed LLV and 8% of them developed VF. HIV RNA >200 copies/ml was the strongest predictor of VF. Over half of patients with persistent viraemia <200 copies/ml showed VF. PMID- 26756460 TI - Radiation-Induced Breast Cancer Incidence and Mortality From Digital Mammography Screening: A Modeling Study. AB - BACKGROUND: Estimates of risk for radiation-induced breast cancer from mammography screening have not considered variation in dose exposure or diagnostic work-up after abnormal screening results. OBJECTIVE: To estimate distributions of radiation-induced breast cancer incidence and mortality from digital mammography screening while considering exposure from screening and diagnostic mammography and dose variation among women. DESIGN: 2 simulation modeling approaches. SETTING: U.S. population. PATIENTS: Women aged 40 to 74 years. INTERVENTION: Annual or biennial digital mammography screening from age 40, 45, or 50 years until age 74 years. MEASUREMENTS: Lifetime breast cancer deaths averted (benefits) and radiation-induced breast cancer incidence and mortality (harms) per 100,000 women screened. RESULTS: Annual screening of 100,000 women aged 40 to 74 years was projected to induce 125 breast cancer cases (95% CI, 88 to 178) leading to 16 deaths (CI, 11 to 23), relative to 968 breast cancer deaths averted by early detection from screening. Women exposed at the 95th percentile were projected to develop 246 cases of radiation-induced breast cancer leading to 32 deaths per 100,000 women. Women with large breasts requiring extra views for complete examination (8% of population) were projected to have greater radiation-induced breast cancer risk (266 cancer cases and 35 deaths per 100,000 women) than other women (113 cancer cases and 15 deaths per 100,000 women). Biennial screening starting at age 50 years reduced risk for radiation induced cancer 5-fold. LIMITATION: Life-years lost from radiation-induced breast cancer could not be estimated. CONCLUSION: Radiation-induced breast cancer incidence and mortality from digital mammography screening are affected by dose variability from screening, resultant diagnostic work-up, initiation age, and screening frequency. Women with large breasts may have a greater risk for radiation-induced breast cancer. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality, U.S. Preventive Services Task Force, National Cancer Institute. PMID- 26756464 TI - Ligand-Mediated Interactions between Nanoscale Surfaces Depend Sensitively and Nonlinearly on Temperature, Facet Dimensions, and Ligand Coverage. AB - Nanoparticles are often covered in ligand monolayers, which can undergo a temperature-dependent order-disorder transition that switches the particle particle interaction from repulsive to attractive in solution. In this work, we examine how changes in the ligand surface coverage and facet dimensions affect the ordering of ligands, the arrangement of nearby solvent molecules, and the interaction between ligand monolayers on different particles. In particular, we consider the case of strongly bound octadecyl ligands on the (100) facet of CdS in the presence of an explicit n-hexane solvent. Depending on the facet dimensions and surface coverage, we observe three distinct ordered states that differ in how the ligands are packed together, and which affect the thickness of the ligand shell and the structure of the ligand-solvent interface. The temperature dependence of the order-disorder transition also broadens and shifts to lower temperature in a nonlinear manner as the nanoscale is approached from above. We find that ligands on nanoscale facets can behave very similarly to those on macroscopic surfaces in solution, and that some facet dimensions affect the ligand alignment more strongly than others. As the ligands order, the interaction between opposing monolayers becomes attractive, even well below full surface coverage. The strength of attraction per unit surface area is strongly affected by ligand coverage, but only weakly by facet width. Conversely, we find that bringing two monolayers together just above the order-disorder transition temperature can induce ordering and attraction. PMID- 26756463 TI - High-Performance Ferrite Nanoparticles through Nonaqueous Redox Phase Tuning. AB - From magnetic resonance imaging to cancer hyperthermia and wireless control of cell signaling, ferrite nanoparticles produced by thermal decomposition methods are ubiquitous across biomedical applications. While well-established synthetic protocols allow for precise control over the size and shape of the magnetic nanoparticles, structural defects within seemingly single-crystalline materials contribute to variability in the reported magnetic properties. We found that stabilization of metastable wustite in commonly used hydrocarbon solvents contributed to significant cation disorder, leading to nanoparticles with poor hyperthermic efficiencies and transverse relaxivities. By introducing aromatic ethers that undergo radical decomposition upon thermolysis, the electrochemical potential of the solvent environment was tuned to favor the ferrimagnetic phase. Structural and magnetic characterization identified hallmark features of nearly defect-free ferrite nanoparticles that could not be demonstrated through postsynthesis oxidation with nearly 500% increase in the specific loss powers and transverse relaxivity times compared to similarly sized nanoparticles containing defects. The improved crystallinity of the nanoparticles enabled rapid wireless control of intracellular calcium. Our work demonstrates that redox tuning during solvent thermolysis can generate potent theranostic agents through selective phase control in ferrites and can be extended to other transition metal oxides relevant to memory and electrochemical storage devices. PMID- 26756462 TI - Charge, Color, and Conformation: Spectroscopy on Isomer-Selected Peptide Ions. AB - Monitoring the chromism induced by intramolecular hydrogen and charge transfers within proteins as well as the isomerization of both protein and cofactor is essential not only to understand photoactive signaling pathways but also to design targeted opto-switchable proteins. We used a dual-ion mobility drift tube coupled to a tunable picosecond laser to explore the optical and structural properties of a peptide chain bound to a chromophore-a prototype system allowing for a proton transfer coupled to conformational change. With the support of molecular dynamics and DFT calculations, we show how proton transfer between the peptide and its cofactor can dramatically modify the optical properties of the system and demonstrate that these changes can be triggered by collisional activation in the gas phase. PMID- 26756465 TI - Association of Smoking, Alcohol, and Obesity with Cardiovascular Death and Ischemic Stroke in Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study and Cardiovascular Health Study (CHS). AB - Atrial fibrillation (AF) is associated with an increased risk of ischemic stroke and cardiovascular (CV) death. Whether modifiable lifestyle risk factors are associated with these CV outcomes in AF is unknown. Among Atherosclerosis Risk in Communities (ARIC) study and Cardiovascular Health Study (CHS) participants with incident AF, we estimated the risk of composite endpoint of ischemic stroke or CV death associated with candidate modifiable risk factor (smoking, heavy alcohol consumption, or high body mass index [BMI]), and computed the C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) of incorporating each factor into the CHA2DS2-VASc. Among 1222 ARIC (mean age: 63.4) and 756 CHS (mean age: 79.1) participants with incident AF, during mean follow-up of 6.9 years and 5.7 years, there were 332 and 335 composite events respectively. Compared with never smokers, current smokers had a higher incidence of the composite endpoint in ARIC [HR: 1.65 (1.21-2.26)] but not in CHS [HR: 1.05 (0.69-1.61)]. In ARIC, the addition of current smoking did not improve risk prediction over and above the CHA2DS2-VASc. No significant associations were observed with alcohol consumption or BMI with CVD outcomes in AF patients from either cohort. Smoking is associated with an increased risk of ischemic stroke or CV death in ARIC, which comprised mostly middle-aged to young-old (65-74 years), but not in CHS, which comprised mostly middle-old or oldest-old (>=75 years) adults with AF. However, addition of smoking to the CHA2DS2-VASc score did not improve risk prediction of these outcomes. PMID- 26756467 TI - Identification of Genes Associated with Papillary Thyroid Carcinoma (PTC) for Diagnosis by Integrated Analysis. AB - Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma, and our understanding of its pathogenesis is incomplete. To elucidate the mechanisms underlying such progression and identify novel diagnostic markers, we aimed to discover the underlying gene associated with PTC. Integrated analysis of microarray datasets was performed to identify differentially expressed genes (DEGs) between PTCs and normal tissues. GO enrichment analysis and KEGG pathway enrichment analysis were then performed to uncover the functions of DEGs. Furthermore, the protein-protein interaction (PPI) network of DEGs was constructed. Five GEO datasets were obtained. Totally, 154 DEGs across the studies were identified, including 26 upregulated and 128 downregulated DEGs. In the PPI network, MLLT1, DLG2, and EFEMP1 were the hub proteins, in which DLG2 and EFEMP1 were involved in tumor progression. Among the top 10 up- and downregulated genes, the dysregulation genes of TPO, CDH16, and MPPED2 may be closely related to the tumorigenesis of PTC. By integrated analysis of multiple gene expression profiles, we propose that the dysregulation genes of TPO and MPPED2 will be the promising diagnostic markers for PTCs. PMID- 26756469 TI - Modeling of Platinum-Aryl Interaction with Amyloid-beta Peptide. AB - Ligand field molecular mechanics (LFMM), density functional theory (DFT), and semiempirical PM7 methods are used to study the binding of two Pt(II)-L systems to an N-terminal fragment of the amyloid-beta peptide, where L = 2,2-bipyridyl or 1,10-phenanthroline. Molecular dynamics simulations are used to explore the conformational freedom of the peptide using LFMM combined with AMBER molecular mechanics parameters. We establish a modeling protocol, allowing for identification and analysis of favorable platinum-binding modes and peptide conformations. Preferred binding modes are identified for each ligand investigated; metal coordination occurs via Nepsilon in His residues for both ligands--His6epsilon-His13epsilon and His6epsilon-His14epsilon for the bipyridyl and phenanthroline ligands, respectively. The observed change in binding mode for the different ligands suggests that the binding mode of these platinum-based structures can be controlled by the choice of ligand. In the bipy systems, Boltzmann population at 310 K is dominated by a single conformer, while in the phenanthroline case, three conformations make significant contributions to the ensemble. The relative stability of these conformations is due to the inherent stability of binding platinum via Nepsilon in addition to subtle H-bonding effects. PMID- 26756468 TI - Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity. AB - A series of N(6)-bicyclic and N(6)-(2-hydroxy)cyclopentyl derivatives of adenosine were synthesized as novel A1R agonists and their A1R/A2R selectivity assessed using a simple yeast screening platform. We observed that the most selective, high potency ligands were achieved through N(6)-adamantyl substitution in combination with 5'-N-ethylcarboxamido or 5'-hydroxymethyl groups. In addition, we determined that 5'-(2-fluoro)thiophenyl derivatives all failed to generate a signaling response despite showing an interaction with the A1R. Some selected compounds were also tested on A1R and A3R in mammalian cells revealing that four of them are entirely A1R-selective agonists. By using in silico homology modeling and ligand docking, we provide insight into their mechanisms of recognition and activation of the A1R. We believe that given the broad tissue distribution, but contrasting signaling profiles, of adenosine receptor subtypes, these compounds might have therapeutic potential. PMID- 26756466 TI - Inhibition of NAPDH Oxidase 2 (NOX2) Prevents Oxidative Stress and Mitochondrial Abnormalities Caused by Saturated Fat in Cardiomyocytes. AB - Obesity and high saturated fat intake increase the risk of heart failure and arrhythmias. The molecular mechanisms are poorly understood. We hypothesized that physiologic levels of saturated fat could increase mitochondrial reactive oxygen species (ROS) in cardiomyocytes, leading to abnormalities of calcium homeostasis and mitochondrial function. We investigated the effect of saturated fat on mitochondrial function and calcium homeostasis in isolated ventricular myocytes. The saturated fatty acid palmitate causes a decrease in mitochondrial respiration in cardiomyocytes. Palmitate, but not the monounsaturated fatty acid oleate, causes an increase in both total cellular ROS and mitochondrial ROS. Palmitate depolarizes the mitochondrial inner membrane and causes mitochondrial calcium overload by increasing sarcoplasmic reticulum calcium leak. Inhibitors of PKC or NOX2 prevent mitochondrial dysfunction and the increase in ROS, demonstrating that PKC-NOX2 activation is also required for amplification of palmitate induced ROS. Cardiomyocytes from mice with genetic deletion of NOX2 do not have palmitate induced ROS or mitochondrial dysfunction. We conclude that palmitate induces mitochondrial ROS that is amplified by NOX2, causing greater mitochondrial ROS generation and partial depolarization of the mitochondrial inner membrane. The abnormal sarcoplasmic reticulum calcium leak caused by palmitate could promote arrhythmia and heart failure. NOX2 inhibition is a potential therapy for heart disease caused by diabetes or obesity. PMID- 26756470 TI - Clouds enhance Greenland ice sheet meltwater runoff. AB - The Greenland ice sheet has become one of the main contributors to global sea level rise, predominantly through increased meltwater runoff. The main drivers of Greenland ice sheet runoff, however, remain poorly understood. Here we show that clouds enhance meltwater runoff by about one-third relative to clear skies, using a unique combination of active satellite observations, climate model data and snow model simulations. This impact results from a cloud radiative effect of 29.5 (+/-5.2) W m(-2). Contrary to conventional wisdom, however, the Greenland ice sheet responds to this energy through a new pathway by which clouds reduce meltwater refreezing as opposed to increasing surface melt directly, thereby accelerating bare-ice exposure and enhancing meltwater runoff. The high sensitivity of the Greenland ice sheet to both ice-only and liquid-bearing clouds highlights the need for accurate cloud representations in climate models, to better predict future contributions of the Greenland ice sheet to global sea level rise. PMID- 26756473 TI - Grain-Size-Tuned Highly H2-Selective Chemiresistive Sensors Based on ZnO-SnO2 Composite Nanofibers. AB - We investigated the effect of grain size on the H2-sensing behavior of SnO2-ZnO composite nanofibers. The 0.9SnO2-0.1ZnO composite nanofibers were calcined at 700 degrees C for various times to control the size of nanograins. A bifunctional sensing mechanism, which is related not only to the SnO2-SnO2 nanograins, but also to the ZnO-SnO2 nanograins with surface metallization effect, is responsible for the grain-oriented H2-sensing properties and the selective improvement in sensing behavior to H2 gas compared to other gases. Smaller grains are much more favorable for superior H2 sensing in SnO2-ZnO composite nanofibers, which will be an important guideline for their use in H2 sensors. The one-dimensional nanofiber-based structures in the present study will be efficient in maximizing the sensing capabilities by providing a larger amount of junctions. PMID- 26756471 TI - Cross-Fostering of Male Mice Subtly Affects Female Olfactory Preferences. AB - The maternal environment has been shown to influence female olfactory preferences through early chemosensory experience. However, little is known about the influence of the maternal environment on chemosignals. In this study, we used two inbred mouse strains, C57BL/6 (C57) and BALB/c (BALB), and explored whether adoption could alter male chemosignals and thus influence female olfactory preferences. In Experiment 1, C57 pups were placed with BALB dams. Adult BALB females then served as the subjects in binary choice tests between paired male urine odours (BALB vs. C57, BALB vs. adopted C57 and C57 vs. adopted C57). In Experiment 2, BALB pups were placed with C57 dams, and C57 females served as the subjects in binary choice tests between paired male urine odours (C57 vs. BALB, C57 vs. adopted BALB, and BALB vs. adopted BALB). In both experiments, we found that females preferred the urine of males from different genetic backgrounds, suggesting that female olfactory preferences may be driven by genetic compatibility. Cross-fostering had subtle effects on female olfactory preferences. Although the females showed no preference between the urine odours of adopted and non-adopted males of the other strain, the BALB females preferred the urine odour of BALB males to that of adopted C57 males, whereas the C57 females showed no preference between the urine odour of C57 and adopted BALB males. Using gas chromatography-mass spectrometry (GC-MS) and stepwise discriminant analysis, we found that the ratios of volatile chemicals from urine and preputial gland secretions were altered in the fostered male mice; these changes may have resulted in the behavioural changes observed in the females. Overall, the results suggest that female mice prefer urine odours from males with different genetic backgrounds; this preference may be driven by genetic compatibility. The early maternal environment influences the chemosignals of males and thus may influence the olfactory preferences of females. Our study provides additional evidence in support of genotype-dependent maternal influences on phenotypic variability in adulthood. PMID- 26756472 TI - The Relationship between the Second-to-Fourth Digit Ratio and Behavioral Sexual Dimorphism in School-Aged Children. AB - Sexually dimorphic brain development and behavior are known to be influenced by sex hormones exposure in prenatal periods. On the other hand, second-to forth digit ratio (2D/4D) has been used as an indirect method to investigate the putative effects of prenatal exposure to androgen. In the present study, we herein investigated the relationship between gender-role play behavior and the second-to-fourth digit ratio (2D/4D), which has been used as an indirect method to investigate the putative effects of prenatal exposure to androgens, in school aged children. Among 4981 children who became 8 years old by November 2014 and were contactable for this survey by The Hokkaido Study of Environment and Children's Health, 1631 (32.7%), who had data for 2D/4D and Pre-school Activities Inventory (PSAI) as well as data for the survey at baseline, were available for analysis. Parents sent reports of PSAI on the sex-typical characteristics, preferred toys, and play activities of children, and black and white photocopies of the left and right hand palms via mail. PSAI consisted of 12 masculine items and 12 feminine items, and a composite score was created by subtracting the feminine score from the masculine score, with higher scores representing masculine-typical behavior. While composite scores in PSAI were significantly higher in boys than in girls, 2D/4D was significantly lower in boys than in girls. Although the presence or absence of brothers or sisters affected the composite, masculine, and feminine scored of PSAI, a multivariate regression model revealed that 2D/4D negatively correlated with the composite scores of PSAI in boys, whereas no correlation was found in girls. Although 2D/4D negatively correlated with the masculine score in boys and girls, no correlation was observed between 2D/4D and the feminine score. In conclusion, although social factors, such as the existence of brother or sisters, affect dimorphic brain development and behavior in childhood, the present study revealed that the prenatal hormonal environment was an important factor influencing masculine typical dimorphic brain development and behavior in school-aged children. PMID- 26756474 TI - Complex and Conflicting Social Norms: Implications for Implementation of Future HIV Pre-Exposure Prophylaxis (PrEP) Interventions in Vancouver, Canada. AB - BACKGROUND: HIV Pre-Exposure Prophylaxis (PrEP) has been found to be efficacious in preventing HIV acquisition among seronegative individuals in a variety of risk groups, including men who have sex with men and people who inject drugs. To date, however, it remains unclear how socio-cultural norms (e.g., attitudes towards HIV; social understandings regarding HIV risk practices) may influence the scalability of future PrEP interventions. The objective of this study is to assess how socio-cultural norms may influence the implementation and scalability of future HIV PrEP interventions in Vancouver, Canada. METHODS: We conducted 50 interviews with young men (ages 18-24) with a variety of HIV risk behavioural profiles (e.g., young men who inject drugs; MSM). Interviews focused on participants' experiences and perceptions with various HIV interventions and policies, including PrEP. RESULTS: While awareness of PrEP was generally low, perceptions about the potential personal and public health gains associated with PrEP were interconnected with expressions of complex and sometimes conflicting social norms. Some accounts characterized PrEP as a convenient form of reliable protection against HIV, likening it to the female birth control pill. Other accounts cast PrEP as a means to facilitate 'socially unacceptable' behaviour (e.g., promiscuity). Stigmatizing rhetoric was used to position PrEP as a tool that could promote some groups' proclivities to take 'risks'. CONCLUSION: Stigma regarding 'risky' behaviour and PrEP should not be underestimated as a serious implementation challenge. Pre-implementation strategies that concomitantly aim to improve knowledge about PrEP, while addressing associated social prejudices, may be key to effective implementation and scale-up. PMID- 26756475 TI - Infrared Spectroscopy and Structure of (NO)(n) Clusters. AB - Nitrogen oxide clusters (NO)n have been studied in He droplets via infrared depletion spectroscopy and by quantum chemical calculations. The nu1 and nu5 bands of cis-ON-NO dimer have been observed at 1868.2 and 1786.5 cm(-1), respectively. Furthermore, spectral bands of the trimer and tetramer have been located in the vicinity of the corresponding dimer bands in accord with computed frequencies that place NO-stretch bands of dimer, trimer, and tetramer within a few wavenumbers of each other. In addition, a new line at 1878.1 cm(-1) close to the band origin of single molecules was assigned to van der Waals bound dimers of (NO)2, which are stabilized due to the rapid cooling in He droplets. Spectra of larger clusters (n > 5), have broad unresolved features in the vicinity of the dimer bands. Experiments and calculations indicate that trimers consist of a dimer and a loosely bound third molecule, whereas the tetramer consists of two weakly bound dimers. PMID- 26756476 TI - Thyroid Imaging Reporting and Data System Risk Stratification of Thyroid Nodules: Categorization Based on Solidity and Echogenicity. AB - BACKGROUND: Although ultrasonography (US) has an essential role in assessing the malignancy risk of thyroid nodules, a malignancy risk-stratification system has not been established. The purpose of this study was to develop a clinically feasible US risk-stratification system--the Thyroid Imaging Reporting and Data System (TIRADS)--primarily based on the solidity and echogenicity of thyroid nodules. METHODS: From January 2010 to May 2011, a total of consecutive 2000 thyroid nodules (>= 1 cm) with final diagnoses were enrolled from the database of low and high cancer volume institutions (1000 nodules from each institution). For the development of TIRADS, the type and predictive value of US predictors in the groups categorized by solidity and echogenicity were analyzed, and the US predictors were integrated and categorized according to the malignancy risk. RESULTS: The suspicious US features of microcalcification, taller than wide shape, and spiculated/microlobulated margin were independently predictive of malignancy in the solid or hypoechoic nodule group (p < 0.001, respectively). Meanwhile, only microcalcification was independently predictive of malignancy in the partially cystic nodule group (p = 0.006), and microcalcification and spiculated/microlobulated margin were independently predictive of malignancy in the iso- and hyperechoic nodule group (p = 0.002 and p = 0.015, respectively). Although the presence of any suspicious US features had a high malignancy risk in the group of solid hypoechoic nodules, it had an intermediate malignancy risk in the group of partially cystic or iso- and hyperechoic nodules. The malignancy risk of thyroid nodules was stratified into five TIRADS categories by integrating the type and predictive values of US predictors based on solidity and echogenicity. CONCLUSION: The malignancy risk of thyroid nodules can be stratified by TIRADS according to US patterns by combining solidity, echogenicity, and suspicious US features. The proposed risk-stratification system based on solidity and echogenicity will be useful for risk stratification and management decision of thyroid nodules. PMID- 26756477 TI - The Counseling, Self-Care, Adherence Approach to Person-Centered Care and Shared Decision Making: Moral Psychology, Executive Autonomy, and Ethics in Multi Dimensional Care Decisions. AB - This article argues that standard models of person-centred care (PCC) and shared decision making (SDM) rely on simplistic, often unrealistic assumptions of patient capacities that entail that PCC/SDM might have detrimental effects in many applications. We suggest a complementary PCC/SDM approach to ensure that patients are able to execute rational decisions taken jointly with care professionals when performing self-care. Illustrated by concrete examples from a study of adolescent diabetes care, we suggest a combination of moral and psychological considerations to support the claim that standard PCC/SDM threatens to systematically undermine its own goals. This threat is due to a tension between the ethical requirements of SDM in ideal circumstances and more long-term needs actualized by the context of self-care handled by patients with limited capacities for taking responsibility and adhere to their own rational decisions. To improve this situation, we suggest a counseling, self-care, adherence approach to PCC/SDM, where more attention is given to how treatment goals are internalized by patients, how patients perceive choice situations, and what emotional feedback patients are given. This focus may involve less of a concentration on autonomous and rational clinical decision making otherwise stressed in standard PCC/SDM advocacy. PMID- 26756478 TI - Indian Fertility Society good clinical practice PCOS guidelines. AB - Sonia Malik is President of the Indian Fertility Society, Chair of the Infertility Committee of FOGSI, Chair of the Scientific Committee of IFFS 2016, Scientific Collaborator at the Reproductive Research Centre at the Cleveland Clinic (USA), Past President of the Indian Menopause Society and Co-Editor in Chief of the Journal of Midlife Health. Her areas of interest cover reproductive endocrinology, reproductive immunology, genital tuberculosis and premature ovarian failure. PMID- 26756498 TI - Influence of Li(+) and H(+) Distribution on the Crystal Structure of Li(7 x)H(x)La3Zr2O12 (0 <= x <= 5) Garnets. AB - With appropriate doping or processing, Li7La3Zr2O12 (LLZO) is an excellent candidate to be used in Li batteries either as a solid electrolyte or as a separator between the Li anode and a liquid electrolyte. For both uses, the reactivity with water either from the air or in aqueous media is a matter of interest. We address here the structural changes undergone by LLZO as a result of H(+)/Li(+) exchange and relate them with the amount of H content and atomic distribution. Neutron diffraction is performed to elucidate Li and H location. Two different cubic phases derive from LLZO through H(+)/Li(+) exchange: Deep hydration up to 150 degrees C yields a noncentrosymmetric I43d phase in which octahedral Li ions are exchanged by H ions, tetrahedral Li ions split into two sites with very different occupancies, and H ions form O4H4 entities around the less occupied tetrahedral site. Annealing above 300 degrees C results in a centrosymmetric Ia3d phase with lower H content in which Li ions occupy the usual sites of the cubic garnets and H ions occupy a split pseudooctahedral site. The centrosymmetric or noncentrosymmetric character is determined by the temperature at which exchange is performed and the H content. Both factors are not independent: at low temperature, the high H content favors H ordering around the vacant tetrahedra, while low H content and higher mobility at 350 degrees C lead to a disordered configuration of Li and H ions. The deeply hydrated garnets are stable up to at least 300 degrees C and also upon aging at room temperature. PMID- 26756499 TI - A Letter to Prospective and Emerging Clinician Educators. PMID- 26756501 TI - Optimizing oncologic outcomes in upper tract urothelial carcinoma. AB - Upper tract urothelial carcinoma is a disease with rapidly changing management. Though rare, recent multi-institutional collaborations have allowed for study of its biology and treatment outcomes in greater detail than ever before. In coming years physicians treating ureteral cancers will have an expanded armamentarium of treatment options and better data on which to base treatment decisions. Currently there is exciting work underway both in terms of developmental therapies, including neoadjuvant chemotherapy, as well as improved prognostics allowing for better utilization of nephron-sparing approaches where applicable. We present a review of current management techniques and the data on which to base management choices for surgeons treating upper tract urothelial carcinoma. The ultimate goal is improving outcomes for patients; with recent developments and current work in the field, there is reason to be optimistic for the future in this rare, challenging disease. PMID- 26756500 TI - Increased Lung Cancer Mortality in Taconite Mining: The Potential for Disease from Elongate Mineral Particle Exposure. AB - Taconite mining involves potential exposure to non-asbestiform amphibole mineral fiber. More recent studies have demonstrated increased mortality from respiratory cancers and heart disease among workers in the taconite industry. This finding is not consistent with recent exposure assessment findings, nor is the toxicology of this mineral suggestive of neoplastic disease. The understanding of respiratory disease in taconite mining is hampered by the lack of exposure data to asbestiform mineral fibers that occurred in the 1950s and 1960s. Other industries with similar mineral exposure have not demonstrated definitive associations with respiratory cancer, although non-malignant respiratory disease is a consistent finding in epidemiological studies. PMID- 26756503 TI - Anesthesia in Patients With Postconcussion Syndrome: Is There Evidence? PMID- 26756502 TI - A Randomized Controlled Trial Studying the Role of Dexamethasone in Scalp Nerve Blocks for Supratentorial Craniotomy. AB - BACKGROUND: The aim of this double-blinded randomized control study was to examine the role of the steroid dexamethasone as an adjuvant to lignocaine and ropivacaine in scalp nerve blocks in adults undergoing supratentorial craniotomy under general anesthesia. We compared the intraoperative anesthetic and postoperative analgesic requirement with and without the addition of dexamethasone to the local anesthetics. METHODS: The consented 90 patients were randomized into 2 groups: one group received 8 mg (2 mL) of dexamethasone, whereas the other received 2 mL of normal saline along with the local anesthetics in the scalp nerve block administered soon after induction of general anesthesia. All patients received oral/intravenous dexamethasone perioperatively to decrease cerebral edema. The general anesthetic technique for induction, maintenance, and recovery was standardized in the 2 groups. The primary outcome assessed was the time to administration of the first dose of analgesic postoperatively. The secondary outcomes included intraoperative opioid requirement, time to emergence, and incidence of postoperative nausea and vomiting. RESULTS: There was no significant difference between the dexamethasone and saline groups with respect to time to first analgesic requirement, intraoperative fentanyl requirements, time to emergence from general anesthesia, and incidence of postoperative nausea and vomiting. CONCLUSIONS: Addition of dexamethasone as an adjuvant to local anesthetics in scalp nerve blocks in the setting of perioperative steroid therapy does not appear to provide any additional benefit with respect to prolongation of the duration of the block. PMID- 26756504 TI - Unanticipated Bleeding From the Tongue During Intubation of a Craniocerebral Trauma Patient. PMID- 26756505 TI - Pneumothorax, Pneumomediastinum, and Pneumorrhachis: A Rare Presentation in a Neurological Patient. PMID- 26756506 TI - 2015 Society for Neuroscience in Anesthesiology and Critical Care Annual Meeting Report. PMID- 26756508 TI - Cobalt. AB - Cobalt has been a recognized allergen capable of causing contact dermatitis for decades. Why, therefore, has it been named 2016 "Allergen of the Year"? Simply put, new information has come to light in the last few years regarding potential sources of exposure to this metallic substance. In addition to reviewing some background on our previous understanding of cobalt exposures, this article will highlight the recently recognized need to consider leather as a major site of cobalt and the visual cues suggesting the presence of cobalt in jewelry. In addition, a chemical spot test for cobalt now allows us to better identify its presence in suspect materials. PMID- 26756509 TI - American Contact Dermatitis Society Contact Allergy Management Program: An Epidemiologic Tool to Determine Relative Prevalence of Contact Allergens. AB - BACKGROUND: Data on the prevalence of contact allergy in North America are currently reported by groups of academic contact allergy specialists at select academic centers. Sampling of data from numerous centers across North America, including practices performing more limited patch testing, would provide a broader perspective of contact allergen prevalence in North America. The American Contact Dermatitis Society Contact Allergy Management Program is an ideal tool for collection of epidemiologic data regarding contact allergy prevalence in North America. OBJECTIVE: The aim of the study was to identify the relative prevalence of contact allergy to common contact allergens in North America. METHODS: Mapping of Contact Allergy Management Program (CAMP) data was performed to allow analysis of how frequently searches were performed for various contact allergens. The number of searches performed for specific allergens provides a measure of the relative prevalence of contact allergy to these allergens. RESULTS: The top 35 allergens for the period from November 18, 2012 to November 18, 2013 are reported. Although these data are useful, specific recommendations for minor alterations to CAMP are discussed, which will allow future CAMP data to be stratified and more powerful. CONCLUSIONS: With minor modifications, CAMP can provide a quantum leap in the reporting of contact allergy epidemiologic data in North America. PMID- 26756510 TI - American Contact Dermatitis Society Contact Allergy Management Program: An Epidemiologic Tool to Quantify Ingredient Usage. AB - BACKGROUND: The usage prevalence of ingredients in topical products is important to dermatologists and industry. OBJECTIVE: To determine the prevalence of methylisothiazolinone (MI) in various types of consumer products METHODS: The Contact Allergy Management Program (CAMP) database was mapped and sorted in spreadsheet format to determine the prevalence of MI in various types of consumer products. RESULTS: Methylisothiazolinone was found in 13.2% of 4660 total products in CAMP. High usage of MI was seen in dishwashing products (64%), shampoos (53%), bathroom/kitchen/all-purpose cleaners (47%), hair conditioners (45%), hair dyes (43%), laundry additives/fresheners/softeners (30%), soaps/cleansers (29%), and surface cleaners/disinfectants (27%). Of the products containing MI, MI alone (without methylchloroisothiazolinone) was most common in makeup products (100%), cleaning/dish/laundry products (>99%), moisturizers (82%), shaving products (78%), sunscreens (71%), and antiaging products (67%). CONCLUSIONS: The American Contact Dermatitis Society's CAMP is a valuable tool to collect epidemiologic data on the incidence of specific ingredient usage in various types of topical products. PMID- 26756511 TI - Benzalkonium Chloride: A Known Irritant and Novel Allergen. AB - BACKGROUND: Benzalkonium chloride (BAK), a detergent and preservative found in health care and household products, is an established irritant, yet BAK is seldom considered to cause allergic contact dermatitis. We have, however, observed positive patch test reactions more often than is typically reported. From 2001 through 2005 and 2006 through 2010, BAK was among the top 10 most frequent allergens in our standard series. OBJECTIVE: The aim of this study was to review the Mayo Clinic experience from 2000 to 2012 with patch testing to BAK. METHODS: An electronic patch test database was used to acquire results of patients who underwent patch testing for BAK 0.1% aqueous after it was introduced to the standard series in 2000 until 2012. Previous reports (1998-2000, 2001-2005, 2006 2010) from our institution were also reviewed. CONCLUSIONS: Our study showed BAK to be an allergen of increasing importance. From 1998 through 2000, 2001 through 2005, and 2006 through 2010, the rate of allergic patch test results to BAK increased. More than half of the reactions in each period studied were graded as macular erythema, with at least one third of all reactions deemed to be relevant. Irritancy rates were consistently low. PMID- 26756512 TI - Sensitization to Formaldehyde in Northeastern Italy, 1996 to 2012. AB - BACKGROUND: Formaldehyde is a widely used organic compound, used in several applications (hard thermoset resins, adhesives, disinfectants, tissue fixatives, etc), in its free form or released by formaldehyde releaser products. Its use is under control due to its toxic, carcinogenic, and allergenic properties. OBJECTIVE: The aim of this study was to investigate the frequency of formaldehyde sensitization, time trend, and correlation to occupations. METHODS: This study is a cross-sectional study on a population of 23,774 patients tested from 1996 to 2012 in Northeastern Italy. RESULTS: Frequency of sensitization was 3.3%, without any significant time trend. Hands (39.8% overall) and face (25.6% females, 15.5% males) were mainly involved. We found a trend toward decrease by age in females (3.11% in first quintile [14-26 years], 2.29% in fifth quintile [59-97 years], P < 0.01). On a logistic regression analysis (control group: white-collar workers), we found associations in health care (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.04-1.81), wood (OR, 2.14; 95% CI, 1.30-3.51), and textile (OR, 1.79; 95% CI, 1.14-2.79) sectors and professional drivers (OR, 1.94; 95% CI, 1.05 3.60). We found a high rate of cosensitization to formaldehyde in patients with positive patch test reactions to quaternium-15 (OR, 18.7; 95% CI, 12.6-27.7). CONCLUSIONS: Sensitization to formaldehyde is relevant in our population, especially in the health care sector, wood and textile industries, and professional drivers. No significant time trend was found. PMID- 26756513 TI - Instrument-related Skin Disorders in Musicians. AB - BACKGROUND: Among artists, musicians may suffer from occupational skin problems; notwithstanding, these conditions have been rarely reviewed. The characteristics of individual performer and the type of instrument will determine the kind of disease. Moreover, the hours that the musician spent to advance artistic skill may influence the severity. OBJECTIVE: The frequency and risk factors of instrument-related skin disorders in musicians from southern Italy were analyzed. METHODS: An observational study was conducted in 628 musicians. A questionnaire including questions related to age, sex, instrument played, musical activity, previous or current skin disorders, and impact of skin symptoms on music making was submitted. RESULTS: Of 628 musicians, 199 (31.7%) reported suffering from at least 1 skin disease. Cutaneous diseases likely directly correlated with the use of the musical instrument were found in 129 (20.5%) of the 628 subjects. In particular, different patterns of irritant contact dermatitis were found. CONCLUSIONS: Skin conditions may be a significant problem in professional instrumentalists. They are mainly related to musical activity. Preventive measures should be established. PMID- 26756514 TI - Glove Use and Glove Education in Workers with Hand Dermatitis. AB - BACKGROUND: Occupational skin diseases are common. The occurrence of occupational skin diseases represents a failure of primary prevention strategies that may include the use of personal protective equipment, most commonly gloves. OBJECTIVE: The objective of this study was to describe current glove use and education practices related to gloves in workers being assessed for possible work related hand dermatitis. METHODS: Participants included consecutive patients being assessed for possible work-related hand dermatitis. A self-administered questionnaire obtained information on demographics, workplace characteristics and exposures, glove use, and education regarding gloves. RESULTS: Ninety percent of the 105 participants reported using gloves. Only 44% had received training related to glove use in the workplace. Major gaps in training content included skin care when using gloves, warning signs of skin problems, and glove size. If the worker indicated no glove training received, the majority reported they would have used gloves if such training was provided. CONCLUSIONS: Although the majority of workers being assessed wore gloves, the minority had received training related to glove use. Particular gaps in training content were identified. Those who had not received training noted they would likely have used gloves if training had been provided. PMID- 26756515 TI - Almost Missed It! Photo-contact Allergy to Octocrylene in a Ketoprofen-sensitized Subject. PMID- 26756516 TI - Elevation of IL-9 in Extreme Patch Test Reactions Suggests It Is an Inflammatory Mediator in Allergic Contact Dermatitis. PMID- 26756517 TI - Extracorporeal Carbon Dioxide Removal Enhanced by Lactic Acid Infusion in Spontaneously Breathing Conscious Sheep. AB - BACKGROUND: The authors studied the effects on membrane lung carbon dioxide extraction (VCO2ML), spontaneous ventilation, and energy expenditure (EE) of an innovative extracorporeal carbon dioxide removal (ECCO2R) technique enhanced by acidification (acid load carbon dioxide removal [ALCO2R]) via lactic acid. METHODS: Six spontaneously breathing healthy ewes were connected to an extracorporeal circuit with blood flow 250 ml/min and gas flow 10 l/min. Sheep underwent two randomly ordered experimental sequences, each consisting of two 12 h alternating phases of ALCO2R and ECCO2R. During ALCO2R, lactic acid (1.5 mEq/min) was infused before the membrane lung. Caloric intake was not controlled, and animals were freely fed. VCO2ML, natural lung carbon dioxide extraction, total carbon dioxide production, and minute ventilation were recorded. Oxygen consumption and EE were calculated. RESULTS: ALCO2R enhanced VCO2ML by 48% relative to ECCO2R (55.3 +/- 3.1 vs. 37.2 +/- 3.2 ml/min; P less than 0.001). During ALCO2R, minute ventilation and natural lung carbon dioxide extraction were not affected (7.88 +/- 2.00 vs. 7.51 +/- 1.89 l/min, P = 0.146; 167.9 +/- 41.6 vs. 159.6 +/- 51.8 ml/min, P = 0.063), whereas total carbon dioxide production, oxygen consumption, and EE rose by 12% each (223.53 +/- 42.68 vs. 196.64 +/- 50.92 ml/min, 215.3 +/- 96.9 vs. 189.1 +/- 89.0 ml/min, 67.5 +/- 24.0 vs. 60.3 +/ 20.1 kcal/h; P less than 0.001). CONCLUSIONS: ALCO2R was effective in enhancing VCO2ML. However, lactic acid caused a rise in EE that made ALCO2R no different from standard ECCO2R with respect to ventilation. The authors suggest coupling lactic acid-enhanced ALCO2R with active measures to control metabolism. PMID- 26756518 TI - Mild Sedation Exacerbates or Unmasks Focal Neurologic Dysfunction in Neurosurgical Patients with Supratentorial Brain Mass Lesions in a Drug-specific Manner. AB - BACKGROUND: Sedation is commonly used in neurosurgical patients but has been reported to produce transient focal neurologic dysfunction. The authors hypothesized that in patients with frontal-parietal-temporal brain tumors, focal neurologic deficits are unmasked or exacerbated by nonspecific sedation independent of the drug used. METHODS: This was a prospective, randomized, single blind, self-controlled design with parallel arms. With institutional approval, patients were randomly assigned to one of the four groups: "propofol," "midazolam," "fentanyl," and "dexmedetomidine." The sedatives were titrated by ladder administration to mild sedation but fully cooperative, equivalent to Observer's Assessment of Alertness and Sedation score = 4. National Institutes of Health Stroke Scale (NIHSS) was used to evaluate the neurologic function before and after sedation. The study's primary outcome was the proportion of NIHSS positive change in patients after sedation to Observer's Assessment of Alertness and Sedation = 4. RESULTS: One hundred twenty-four patients were included. Ninety had no neurologic deficits at baseline. The proportion of NIHSS-positive change was midazolam 72%, propofol 52%, fentanyl 27%, and dexmedetomidine 23% (P less than 0.001 among groups). No statistical difference existed between propofol and midazolam groups (P = 0.108) or between fentanyl and dexmedetomidine groups (P = 0.542). Midazolam and propofol produced more sedative-induced focal neurologic deficits compared with fentanyl and dexmedetomidine. The neurologic function deficits were mainly limb motor weakness and ataxia. Patients with high-grade gliomas were more susceptible to the induced neurologic dysfunction regardless of the sedative. CONCLUSIONS: Midazolam and propofol augmented or revealed neurologic dysfunction more frequently than fentanyl and dexmedetomidine at equivalent sedation levels. Patients with high-grade gliomas were more susceptible than those with low-grade gliomas. PMID- 26756519 TI - Activation of Peripheral MU-opioid Receptors by Dermorphin [D-Arg2, Lys4] (1-4) Amide Leads to Modality-preferred Inhibition of Neuropathic Pain. AB - BACKGROUND: Opioids have long been regarded as the most effective drugs for the treatment of severe acute and chronic pain. Unfortunately, their therapeutic efficacy and clinical utility have been limited because of central and peripheral side effects. METHODS: To determine the therapeutic value of peripheral MU-opioid receptors as a target for neuropathic pain treatment, the authors examined the effects of dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a hydrophilic, peripherally acting MU-opioid receptor agonist, in male and female rats with spinal nerve ligation-induced neuropathic pain. The authors also utilized behavioral, pharmacologic, electrophysiologic, and molecular biologic tools to characterize DALDA's possible mechanisms of action in male rats. RESULTS: DALDA, administered subcutaneously, had 70 times greater efficacy for inhibiting thermal (n = 8 to 11/group) than mechanical hypersensitivity (n = 6 to 8/group) in male rats. The pain inhibitory effects of DALDA on mechanical and heat hypersensitivity were abolished in animals pretreated with systemic methylnaltrexone (n = 7 to 9/group), a peripheral MU-opioid receptor antagonist. In the spinal wide-dynamic range neurons, systemic DALDA inhibited C-fiber mediated, but not A-fiber-mediated, response in neuropathic male rats (n = 13). In primary sensory neurons, DALDA inhibited the capsaicin-induced [Ca2+] increase more than the beta-alanine-induced [Ca] increase (n = 300); capsaicin and beta alanine activate subpopulations of neurons involved in the signaling of heat and mechanical pain, respectively. DALDA-treated rats (n = 5 to 8/group) did not exhibit motor deficits and locomotor impairment suggesting that it does not induce central side effects. CONCLUSIONS: These findings suggest that DALDA may represent a potential alternative to current opioid therapy for the treatment of neuropathic pain and is likely to be associated with minimal adverse effects. PMID- 26756521 TI - Social Information Processing and Cluster B Personality Pathology among Clinic Referred Adolescents. AB - BACKGROUND: This study investigated relations between personality pathology and mentalizing capacities reflected in social information processing (SIP) of adolescents. SAMPLING AND METHODS: 96 adolescent outpatients completed a structured interview regarding SIP. Their clinicians completed a checklist based on DSM-IV, assessing severity of personality pathology. RESULTS: Significant relations were found between the severity of personality pathology and SIP: the more severe the personality pathology, the higher the intensity of reported emotions, the more likely adolescents were to choose inadequate coping strategies and aggressive reactions in social situations, and the more positively they evaluated aggressive reactions. Severity of traits of antisocial (ASPD) and borderline personality disorder (BPD) had unique associations with distinctive SIP variables: ASPD being more related to inadequate coping strategies, less reflection on other's motives and aggressive responses, and BPD being more related to avoidant or prosocial responses and in particular to memories of frustrating events. CONCLUSIONS: This study provides evidence for difficulties in SIP among adolescents with more severe personality pathology, suggesting that the steps in the SIP model can be used to operationalize mentalizing problems. The results seem to paint a picture of ASPD and BPD having a shared background, but their own specific problems concerning SIP. PMID- 26756520 TI - Common Anesthetic-binding Site for Inhibition of Pentameric Ligand-gated Ion Channels. AB - BACKGROUND: Identifying functionally relevant anesthetic-binding sites in pentameric ligand-gated ion channels (pLGICs) is an important step toward understanding the molecular mechanisms underlying anesthetic action. The anesthetic propofol is known to inhibit cation-conducting pLGICs, including a prokaryotic pLGIC from Erwinia chrysanthemi (ELIC), but the sites responsible for functional inhibition remain undetermined. METHODS: We photolabeled ELIC with a light-activated derivative of propofol (AziPm) and performed fluorine-19 nuclear magnetic resonance experiments to support propofol binding to a transmembrane domain (TMD) intrasubunit pocket. To differentiate sites responsible for propofol inhibition from those that are functionally irrelevant, we made an ELIC-gamma aminobutyric acid receptor (GABAAR) chimera that replaced the ELIC-TMD with the alpha1beta3GABAAR-TMD and compared functional responses of ELIC-GABAAR and ELIC with propofol modulations. RESULTS: Photolabeling showed multiple AziPm-binding sites in the extracellular domain (ECD) but only one site in the TMD with labeled residues M265 and F308 in the resting state of ELIC. Notably, this TMD site is an intrasubunit pocket that overlaps with binding sites for anesthetics, including propofol, found previously in other pLGICs. Fluorine-19 nuclear magnetic resonance experiments supported propofol binding to this TMD intrasubunit pocket only in the absence of agonist. Functional measurements of ELIC-GABAAR showed propofol potentiation of the agonist-elicited current instead of inhibition observed on ELIC. CONCLUSIONS: The distinctly different responses of ELIC and ELIC-GABAAR to propofol support the functional relevance of propofol binding to the TMD. Combining the newly identified TMD intrasubunit pocket in ELIC with equivalent TMD anesthetic sites found previously in other cationic pLGICs, we propose this TMD pocket as a common site for anesthetic inhibition of pLGICs. PMID- 26756523 TI - INTRAARTERIAL CHEMOTHERAPY FOR RETINOBLASTOMA IN A 2-MONTH-OLD INFANT. AB - PURPOSE: Intraarterial chemotherapy for retinoblastoma is usually reserved for infants aged 3 months or older because of the intricacy of the newborn vascular anatomy making the procedure technically challenging. The authors report a successful case of intraarterial chemotherapy performed in a 2-month-old infant using a minimal exposure approach. METHODS: Case report. RESULTS: A 2-month-old infant presented with leukocoria and was subsequently diagnosed with an exophytic Group D retinoblastoma in the right eye. The infant received melphalan 3 mg delivered into the ostium of the ophthalmic artery of the right eye under fluoroscopic guidance. Examination under anesthesia a month later showed complete tumor regression to a calcified Type I scar. After a second cycle of intraarterial chemotherapy, no further treatment was necessary. There were no complications. CONCLUSION: Intraarterial chemotherapy is generally used for retinoblastoma in infants aged 3 months or older. The patient was successfully catheterized and treated at 2 months of age, with complete tumor regression after a single chemotherapy dose. Thus, in expert hands, intraarterial chemotherapy can be considered in such young infants. PMID- 26756525 TI - Pentacenequinone-Stabilized Silver Nanoparticles: A Reusable Catalyst for the Diels-Alder [4 + 2] Cycloaddition Reactions. AB - Silver nanoparticles (AgNPs) stabilized by aggregates of derivative 4 have been used as catalyst for the construction of synthetically and biologically important [4 + 2] cycloadducts at room temperature. PMID- 26756526 TI - Occupational health in fairy tales. AB - Myths and folklore, as expressions of popular beliefs, provide valuable information on medical knowledge in earlier times. Fairy tales have often recounted occupational maladies throughout the ages and also provide some insight into the toxic effects of certain metals, such as mercury. Much historical information can be gleaned from unexpected sources, and as such, fairy tales should be more carefully scrutinized by contemporary researchers with an interest in the historical origins of workplace injury and disease. PMID- 26756524 TI - ACQUIRED VITELLIFORM DETACHMENT IN MULTIPLE MYELOMA. AB - PURPOSE: To report a case of subfoveal acquired vitelliform detachment in a patient with multiple myeloma. METHODS: Case report. RESULTS: A 65-year-old man was referred for treatment of a serous macular detachment considered to be caused from chronic central serous chorioretinopathy or adult pseudovitelliform macular dystrophy. His medical history revealed an untreated multiple myeloma. Systemic chemotherapy was undertaken and resulted in a rapid resolution of the detachment. CONCLUSION: Multiple myeloma may be considered as a possible cause of vitelliform macular detachment. PMID- 26756527 TI - The impact of CACNA1C allelic variation on regional gray matter volume in Chinese population. AB - The SNP rs1006737 in CACNA1C gene has been significantly associated with psychiatric disorders (e.g., schizophrenia and bipolar disorder) in European populations. In Han Chinese, rs1006737 is also strongly associated with schizophrenia, although the effects of the psychosis risk SNP on related brain functions and structures in this population remain unclear. Here, we examined the association of rs1006737 with gray matter volume in a sample of 278 healthy Han Chinese. A whole-brain voxel-based morphometry (VBM) analysis revealed a significant association in the region around right superior occipital gyrus (family-wise error corrected, P = 0.023). Our data provides initial evidence for the involvement of this psychosis genetic risk locus in brain structure variations in Chinese population, and calls for further investigations. PMID- 26756522 TI - Inside-Out Signaling Pathways from Nuclear Reactive Oxygen Species Control Pulmonary Innate Immunity. AB - The airway mucosa is responsible for mounting a robust innate immune response (IIR) upon encountering pathogen-associated molecular patterns. The IIR produces protective gene networks that stimulate neighboring epithelia and components of the immune system to trigger adaptive immunity. Little is currently known about how cellular reactive oxygen species (ROS) signaling is produced and cooperates in the IIR. We discuss recent discoveries about 2 nuclear ROS signaling pathways controlling innate immunity. Nuclear ROS oxidize guanine bases to produce mutagenic 8-oxoguanine, a lesion excised by 8-oxoguanine DNA glycosylase1/AP lyase (OGG1). OGG1 forms a complex with the excised base, inducing its nuclear export. The cytoplasmic OGG1:8-oxoG complex functions as a guanine nucleotide exchange factor, triggering small GTPase signaling and activating phosphorylation of the nuclear factor (NF)x03BA;B/RelA transcription factor to induce immediate early gene expression. In parallel, nuclear ROS are detected by ataxia telangiectasia mutated (ATM), a PI3 kinase activated by ROS, triggering its nuclear export. ATM forms a scaffold with ribosomal S6 kinases, inducing RelA phosphorylation and resulting in transcription-coupled synthesis of type I and type III interferons and CC and CXC chemokines. We propose that ATM and OGG1 are endogenous nuclear ROS sensors that transmit nuclear signals that coordinate with outside-in pattern recognition receptor signaling, regulating the IIR. PMID- 26756528 TI - Interpretation of fluorescence correlation spectra of biopolymer solutions. AB - Fluorescence correlation spectroscopy (FCS) is regularly used to study diffusion in non-dilute "crowded" biopolymer solutions, including the interior of living cells. For fluorophores in dilute solution, the relationship between the FCS spectrum G(t) and the diffusion coefficient D is well-established. However, the dilute-solution relationship between G(t) and D has sometimes been used to interpret FCS spectra of fluorophores in non-dilute solutions. Unfortunately, the relationship used to interpret FCS spectra in dilute solutions relies on an assumption that is not always correct in non-dilute solutions. This paper obtains the correct form for interpreting FCS spectra of non-dilute solutions, writing G(t) in terms of the statistical properties of the fluorophore motions. Approaches for applying this form are discussed. PMID- 26756529 TI - Nitrogen limitation disappears with succession in many lowland tropical rainforests - as expected. Why the persistence in temperate latitudes? PMID- 26756530 TI - Mycorrhizal phosphorus economies: a field test of the MANE framework. PMID- 26756531 TI - Climate refugees going underground - a response to Maurin et al. (2014). PMID- 26756532 TI - Multiple routes underground? Frost alone cannot explain the evolution of underground trees. PMID- 26756533 TI - Mycorrhizas across scales: a journey between genomics, global patterns of biodiversity and biogeochemistry. PMID- 26756534 TI - Mycorrhizal symbioses: today and tomorrow. PMID- 26756536 TI - Unusual primary syphilis: Presentation of a likely case with a review of the stages of acquired syphilis, its differential diagnoses, management, and current recommendations. AB - Syphilis is an ancient disease that has re-emerged in the last decade. It is prevalent among men who have sex with men and has increased in incidence with certain ethnic groups. It usually presents as primary or secondary syphilis and can progress to tertiary syphilis if not treated. Primary syphilis will classically manifest as a single, painless ulcer with smooth, clean, and raised borders on the genitals or less often on the oral mucosa. Unusual primary syphilis cases have been reported and can be easily misdiagnosed with a resulting delay of treatment. Secondary syphilis is a systemic disease, wherein the treponemes have disseminated to various organ systems, typically presenting with characteristic mucocutaneous lesions. Tertiary syphilis has a higher rate of morbidity and mortality; as such, the aim of this article is to provide the readers with tools to recognize early syphilis and prevent its progression to late stages. In this review, we present a likely case of unusual primary syphilis mimicking herpes progenitalis as well as a compilation of all atypical cases of primary syphilis from 1973 to 2015. We will also review the differential diagnosis, management, and recommendations for each stage of syphilis. PMID- 26756535 TI - Comparative genomic de-convolution of the cotton genome revealed a decaploid ancestor and widespread chromosomal fractionation. AB - The 'apparently' simple genomes of many angiosperms mask complex evolutionary histories. The reference genome sequence for cotton (Gossypium spp.) revealed a ploidy change of a complexity unprecedented to date, indeed that could not be distinguished as to its exact dosage. Herein, by developing several comparative, computational and statistical approaches, we revealed a 5* multiplication in the cotton lineage of an ancestral genome common to cotton and cacao, and proposed evolutionary models to show how such a decaploid ancestor formed. The c. 70% gene loss necessary to bring the ancestral decaploid to its current gene count appears to fit an approximate geometrical model; that is, although many genes may be lost by single-gene deletion events, some may be lost in groups of consecutive genes. Gene loss following cotton decaploidy has largely just reduced gene copy numbers of some homologous groups. We designed a novel approach to deconvolute layers of chromosome homology, providing definitive information on gene orthology and paralogy across broad evolutionary distances, both of fundamental value and serving as an important platform to support further studies in and beyond cotton and genomics communities. PMID- 26756537 TI - Microvascular dysfunction in the immediate aftermath of chronic total coronary occlusion recanalization. AB - OBJECTIVES: The aim of this study was to compare microvascular resistance under both baseline and hyperemic conditions immediately after percutaneous coronary intervention (PCI) of a chronic total occlusion (CTO) with an unobstructed reference vessel in the same patient BACKGROUND: Microvascular dysfunction has been reported to be prevalent immediately after CTO PCI. However, previous studies have not made comparison with a reference vessel. Patients with a CTO may have global microvascular and/or endothelial dysfunction, making comparison with established normal values misleading. METHODS: After successful CTO PCI in 21 consecutive patients, coronary pressure and flow velocity were measured at baseline and hyperemia in distal segments of the CTO/target vessel and an unobstructed reference vessel. Hemodynamics including hyperemic microvascular resistance (HMR), basal microvascular resistance (BMR), and instantaneous minimal microvascular resistance at baseline and hyperemia were calculated and compared between reference and target/CTO vessels. RESULTS: After CTO PCI, BMR was reduced in the target/CTO vessel compared with the reference vessel: 3.58 mm Hg/cm/s vs 4.94 mm Hg/cm/s, difference -1.36 mm Hg/cm/s (-2.33 to -0.39, p = 0.008). We did not detect a difference in HMR: 1.82 mm Hg/cm/s vs 2.01 mm Hg/cm/s, difference 0.20 (-0.78 to 0.39, p = 0.49). Instantaneous minimal microvascular resistance correlated strongly with the length of stented segment at baseline (r = 0.63, p = 0.005) and hyperemia (r = 0.68, p = 0.002). CONCLUSIONS: BMR is reduced in a recanalized CTO in the immediate aftermath of PCI compared to an unobstructed reference vessel; however, HMR appears to be preserved. A longer stented segment is associated with increased microvascular resistance. (c) 2016 Wiley Periodicals, Inc. PMID- 26756538 TI - Initial analytic quality assessment and method comparison of an immunoassay for adrenocorticotropic hormone measurement in equine samples. AB - BACKGROUND: Equine pituitary pars intermedia dysfunction (PPID) may be diagnosed by measuring baseline plasma adrenocorticotrophic hormone (ACTH). The Immulite 1000 analyzer uses an automated chemiluminescence enzyme assay, previously validated for measuring equine ACTH. Recently, an automated bench-top immunoassay analyzer (AIA-360), designed for analytes in people, became available for veterinary use. OBJECTIVES: Objectives were to evaluate analytic performance of the AIA immunoassay for measuring equine ACTH, and compare the results with those obtained by the Immulite. METHODS: Adrenocorticotrophic hormone was measured in plasma samples from 52 clinical cases. For the AIA, within- and between-run coefficients of variation (CV) were assessed, linearity and recovery studies performed, and observed total error (TEobs ) calculated. Correlation and agreement between the 2 analyzers were also evaluated. RESULTS: Within-run and between-run CV of the AIA ranged from 2.3% to 4% and 3.5% to 8%, respectively. ACTH recoveries ranged from 89.5% to 115.9%. TEobs at 26.5 pg/mL ACTH was 4.1 pg/mL. The ACTH results (median: 25.9 pg/mL; range: 4.3-276.7 pg/mL) with AIA were significantly lower (P < .0001) than with the Immulite (median: 29.9 pg/mL; range: 10.3-639.0 pg/mL). Correlation between the 2 analyzers was r = 0.882 (P < .0001), with a significant bias for the AIA of -16 pg/mL. The 2 methods were not identical within inherent imprecision. CONCLUSION: The AIA is precise for measuring ACTH in horses. Although correlation between the instruments is good, the values obtained by the immunoassays cannot be used interchangeably and should be interpreted using reference intervals established for each analyzer to avoid false negatives. Diagnostic sensitivity and specificity of the AIA-360 should be evaluated before clinical use. PMID- 26756539 TI - Solid-State NMR of PEGylated Proteins. AB - PEGylated proteins are widely used in biomedicine but, in spite of their importance, no atomic-level information is available since they are generally resistant to structural characterization approaches. PEGylated proteins are shown here to yield highly resolved solid-state NMR spectra, which allows assessment of the structural integrity of proteins when PEGylated for therapeutic or diagnostic use. PMID- 26756540 TI - Scapulothoracic Muscle Strength Changes Following a Single Session of Manual Therapy and an Exercise Programme in Subjects with Neck Pain. AB - INTRODUCTION: Scapulothoracic muscle weakness has been associated with neck pain (NP). Little evidence exists regarding lower trapezius (LT), middle trapezius (MT) and serratus anterior (SA) strength in this population. LT strength changes have been observed following thoracic manipulation in healthy subjects. The purpose of the present study was to examine scapulothoracic strength changes following cervical manipulation in subjects with NP. METHODS: Twenty-two subjects with NP and 17 asymptomatic control (AC) subjects underwent strength testing of the LT, MT and SA using a hand-held dynamometer. Subjects with NP were treated with passive intervertebral neck manipulation and neck range of motion exercises. The AC group received no intervention. Strength testing was repeated after manipulation, then 48 and 96 hours later. Change scores were calculated for strength over time. Paired t-tests were done for strength change between painful and non-painful sides in the NP group. Independent t-tests were done for strength change between the NP group and AC group. RESULTS: There was no significant difference between groups for age, gender, hand dominance or body mass index. Mean (standard deviation) symptom duration for subjects in the NP group was 43.27 (62.71) months. There was no significant difference in strength change over time between painful and non-painful sides in the NP group for any muscle; however, there was a significant difference in strength change over time between those in the NP group and AC group for the LT (p < 0.01), SA (p < 0.01) and MT (p < 0.01). DISCUSSION: Scapulothoracic muscle strength improvements were observed in both extremities following passive intervertebral neck manipulation and neck range of motion exercises. Improvements lasted up to 96 hours following manipulation, even though no strengthening exercises were prescribed. CONCLUSIONS: Manipulation and range of motion should be considered as a component of intervention programmes for patients with NP and scapulothoracic muscle weakness. Future studies should compare manipulation alone to exercise alone to determine impact on strength. Copyright (c) 2016 The Authors Musculoskeletal Care Published by John Wiley & Sons Ltd. PMID- 26756541 TI - Experimental Information on the Adsorbed Phase of Water Formed in the Inner Pore of Single-Walled Carbon Nanotube Itself. AB - Thus far, nobody has successfully obtained the accurate information on the properties of the adsorbed phases of gases or vapors formed inside a cylindrical micropore of single-walled carbon nanotube (SWCNT) itself based on the experimental procedure. In this work, we succeeded in analyzing experimentally the properties of adsorbed nitrogen and water confined in the inner pore of SWCNT itself by opening the pore composed of close-ended SWCNT without any changes in the surface state and also by applying the unique method for characterization; both the amounts, as well as properties, of surface functional groups and the bundle structure are the same even after the treatments for introducing an open ended structure to a close-ended one. As a result, the average pore sizes, as well as characteristic adsorption behavior, on the two types of sample were available from the analysis of respective difference adsorption isotherms of nitrogen measured at 77 K between the adsorbed amounts on the open-ended SWCNT and that on the close-ended one. The evaluated pore sizes well coincide with the results estimated by Raman data. These results strongly support that we could analyze the adsorbed phases formed only in the inner pore of SWCNTs by applying the present method. Furthermore, we could analyze the adsorbed phase of water formed inside the cylindrical micropore of SWCNTs, showing the difference in the densities of adsorbed water depending on the pore sizes from the value of bulk water; the densities of the adsorbed water were evaluated to be 0.62 and 0.71 g mL(-1) for SWCNTs having average pore sizes of 1.3 and 1.7 nm, respectively, which were in harmony with those obtained by the theoretical calculations reported by other researchers. The proposed analysis method makes it possible to recognize the focused states of the adsorbed water formed inside the cylindrical micropore of SWCNT more precisely and correctly. The method proposed will shed light on the discussion related to the detailed nature of various adsorbed gases into SWCNT, to the detailed role of adsorbed species formed inside pore in various phenomena, and to the designing the useful materials based on the gained knowledge. PMID- 26756542 TI - Identification of putative unfolding intermediates of the mutant His-107-tyr of human carbonic anhydrase II in a multidimensional property space. AB - In this article, we develop an extensive search procedure of the multi dimensional folding energy landscape of a protein. Our aim is to identify different classes of structures that have different aggregation propensities and catalytic activity. Following earlier studies by Daggett et al. [Jong, D. D.; Riley, R.: Alonso, D.O.: Dagett, V. J. Mol. Biol. 2002, 319, 229], a series of high temperature all-atom classical molecular simulation studies has been carried out to derive a multi-dimensional property space. Dynamical changes in these properties are then monitored by projecting them along a one-dimensional reaction coordinate, dmean . We have focused on the application of this method to partition a wide array of conformations of wild type human carbonic anhydrase II (HCA II) and its unstable mutant His-107-Tyr along dmean by sampling a 35 dimensional property space. The resultant partitioning not only reveals the distribution of conformations corresponding to stable structures of HCA II and its mutant, but also allows the monitoring of several partially unfolded and less stable conformations of the mutant. We have investigated the population of these conformations at different stages of unfolding and collected separate sets of structures that are widely separated in the property space. The dynamical diversity of these sets are examined in terms of the loading of their respective first principal component. The partially unfolded structures thus collected are qualitatively mapped on to the experimentally postulated light molten globule (MGL) and molten globule (MG) intermediates with distinct aggregation propensities and catalytic activities. Proteins 2016; 84:726-743. (c) 2016 Wiley Periodicals, Inc. PMID- 26756543 TI - Elevated serum miR-93, miR-191, and miR-499 are noninvasive biomarkers for the presence and progression of traumatic brain injury. AB - The levels of miR-93, miR-191, and miR-499 have been reported to be up-regulated in the tissues of experimental traumatic brain injury (TBI) rat models. However, the clinical diagnostic and prognostic values of the serum signatures of these 3 miRNAs in TBI remain unclear. The purpose of this study was to determine the expression levels of these 3 microRNAs (miRNAs) in the sera of TBI patients and to evaluate their relationships with the severity and clinical outcome of TBI. The serum levels of these miRNAs were assessed in TBI patients (n = 76) and healthy controls (n = 38) by quantitative reverse-transcription PCR. The severities and clinical outcomes of the TBI patients were evaluated with the Glasgow coma scale and the Glasgow outcome scale. The serum miR-93, miR-191, and miR-499 levels were significantly increased in the TBI patients compared with the controls at all examined time points, and these levels were significantly higher in the patients with severe TBI than in those with moderate or mild TBI (p < 0.05). The serum miR-93, miR-191, and miR-499 levels were significantly higher in the patients with a poor outcome than in those with a good outcome (p < 0.05). The AUCs of miR-93, miR-191, and miR-499 for distinguishing the TBI patients from the healthy controls were 1.000 (p < 0.001), 0.727 (p < 0.001) and 0.801 (p < 0.001), respectively. Interestingly, the AUCs of miR-93, miR-191, and miR-499 for distinguishing the mild TBI patients from the healthy controls were 1.000 (p < 0.001), 0.742 (p < 0.001) and 0.819 (p < 0.001), respectively. Taken together, these results indicate that miR-93, miR-191, and miR-499 are potentially valuable indicators of the diagnosis, severity, and prognosis of TBI. Our study showed that the serum levels of miR-93, miR-191, and miR-499 are all increased in traumatic brain injury (TBI) patients. Their serum levels are associated with TBI severity and outcome, which suggest that these miRNAs play important roles in the pathogenesis and progression of TBI. We think these findings should provide a new strategy for the diagnostic, prognostic, and treatment of TBI. PMID- 26756544 TI - Alterations of neocortico-limbic association fibers and correlation with diet in prediabetes diagnosed by impaired fasting glucose. AB - PURPOSE: To assess the existence of alterations in the micro-integrity of the fasciculus in prediabetic subjects. The issue of micro-integrity in white matter tracts has not been adequately addressed in prediabetes. MATERIALS AND METHODS: Sixty-four prediabetic subjects and 54 controls were enrolled. All participants completed 24-hour diet records and 3-day diet records and received diffusion tensor imaging at 3T. The data for white matter micro-integrity were analyzed and compared between prediabetic subjects and controls with age and gender as covariates. In addition, voxel-wise regression between white matter micro integrity, diet, and preprandial glucose levels were used to explore the relationship between white matter micro-integrity and diet or serum glucose levels. RESULTS: We found that prediabetic subjects had significant reductions in the micro-integrity of bilateral anterior thalamic radiation, left inferior longitudinal fasciculus, and left superior longitudinal fasciculus (corrected P < 0.05). In addition, total carbohydrate intake amount and preprandial serum glucose levels were negatively correlated with the micro-integrity in the left inferior longitudinal fasciculus and left anterior thalamic radiation (r: -0.47, corrected P < 0.05). CONCLUSION: Restrictive alterations in the white matter micro-integrity of the anterior thalamic radiation and inferior and superior longitudinal fasciculi might represent the initial "hot spots" for white matter tract alterations, which might play a role in the development of prediabetes. J. Magn. Reson. Imaging 2016;43:1500-1506. PMID- 26756545 TI - Enantioselective Total Synthesis of (+)-Neostenine. AB - A chirality transfer approach using acyclic polyol intermediates for the synthesis of (+)-neostenine (1) has been developed. The sequential Overman/Claisen rearrangement of an allylic 1,2-diol was especially useful, installing two contiguous stereocenters with complete diastereoselectivity in a one-pot sequence. The SmI2 -mediated cyclization and the subsequent chemoselective reduction of a lactam moiety accomplished the first enantioselective total synthesis of (+)-neostenine (1). PMID- 26756546 TI - The bvg-repressed gene brtA, encoding biofilm-associated surface adhesin, is expressed during host infection by Bordetella bronchiseptica. AB - Bordetella species display phase modulation between Bvg(+) and Bvg(-) phases. Because expression of known virulence factors is up-regulated in the Bvg(+) phase, bacteria in this phase are considered competent for infection. However, the Bvg(-) phase is of negligible importance for infection. No studies have shown that bacterial factors specific to the Bvg(-) phase (bvg-repressed factors) are expressed in the course of Bordetella infection. In the present study, the gene brtA (Bordetella RTX-family Adhesin), which is a typical bvg-repressed gene but is expressed in B. bronchiseptica infecting hosts, was characterized. BrtA is composed of repeated pairs of the VCBS unit and dystroglycan-type cadherin-like unit, the von Willebrand Factor A domain, RTX motif and type I secretion target signal. It is herein demonstrated that BrtA is secreted by the type I secretion system and is essential for Ca(2+) -dependent bacteria-to-substrate adherence, followed by biofilm formation. Although the contribution of BrtA to bacterial colonization of the rat trachea currently remains unclear, this is the first study to present concrete evidence for the expression of a bvg-repressed gene during infection, which may provide a novel aspect for analyses of Bordetella pathogenesis. PMID- 26756549 TI - Observation of an improved healing process in superficial skin wounds after irradiation with a blue-LED haemostatic device. AB - The healing process of superficial skin wounds treated with a blue-LED haemostatic device is studied. Four mechanical abrasions are produced on the back of 10 Sprague Dawley rats: two are treated with the blue-LED device, while the other two are left to naturally recover. Visual observations, non-linear microscopic imaging, as well as histology and immunofluorescence analyses are performed 8 days after the treatment, demonstrating no adverse reactions neither thermal damages in both abraded areas and surrounding tissue. A faster healing process and a better-recovered skin morphology are observed: the treated wounds show a reduced inflammatory response and a higher collagen content. Blue LED induced photothermal effect on superficial abrasions. PMID- 26756548 TI - "I need someone to keep an eye on me:" the power of attention in patient practitioner interactions. AB - PURPOSE: The purpose of this paper is to illuminate the importance of patient care and to explicate the impact of attention on my recovery from bilateral knee replacement surgery and a subsequent revision. METHOD: The paper uses vignettes to illustrate attention in patient-practitioner interaction. RESULTS: Attention is a precursor to understanding the patient as a unique individual and the problems the patient brings to the therapy experience. CONCLUSIONS: The capacity of practitioners to attend to their patients has an impact on patient satisfaction and recovery. Implications for Rehabilitation Attention is the precursor to establishing positive therapeutic alliances with patients. It is essential to attend to the patient as a person with unique experiences, perspectives, and attitudes and to modify treatment based on the person's priorities and desires. Practitioners need to develop the interaction skills necessary to understand their patients as unique individuals. PMID- 26756547 TI - Hair Follicle Bulge Stem Cells Appear Dispensable for the Acute Phase of Wound Re epithelialization. AB - The cutaneous healing response has evolved to occur rapidly, in order to minimize infection and to re-establish epithelial homeostasis. Rapid healing is achieved through complex coordination of multiple cell types, which importantly includes specific cell populations within the hair follicle (HF). Under physiological conditions, the epithelial compartments of HF and interfollicular epidermis remain discrete, with K15(+ve) bulge stem cells contributing progeny for HF reconstruction during the hair cycle and as a basis for hair shaft production during anagen. Only upon wounding do HF cells migrate from the follicle to contribute to the neo-epidermis. However, the identity of the first-responding cells, and in particular whether this process involves a direct contribution of K15(+ve) bulge cells to the early stage of epidermal wound repair remains unclear. Here we demonstrate that epidermal injury in murine skin does not induce bulge activation during early epidermal wound repair. Specifically, bulge cells of uninjured HFs neither proliferate nor appear to migrate out of the bulge niche upon epidermal wounding. In support of these observations, Diphtheria toxin mediated partial ablation of K15(+ve) bulge cells fails to delay wound healing. Our data suggest that bulge cells only respond to epidermal wounding during later stages of repair. We discuss that this response may have evolved as a protective safeguarding mechanism against bulge stem cell exhaust and tumorigenesis. Stem Cells 2016;34:1377-1385. PMID- 26756550 TI - Confidence intervals for the symmetry point: an optimal cutpoint in continuous diagnostic tests. AB - Continuous diagnostic tests are often used for discriminating between healthy and diseased populations. For this reason, it is useful to select an appropriate discrimination threshold. There are several optimality criteria: the North-West corner, the Youden index, the concordance probability and the symmetry point, among others. In this paper, we focus on the symmetry point that maximizes simultaneously the two types of correct classifications. We construct confidence intervals for this optimal cutpoint and its associated specificity and sensitivity indexes using two approaches: one based on the generalized pivotal quantity and the other on empirical likelihood. We perform a simulation study to check the practical behaviour of both methods and illustrate their use by means of three real biomedical datasets on melanoma, prostate cancer and coronary artery disease. PMID- 26756552 TI - Screening Algorithm for BK Virus-Associated Nephropathy Using Sequential Testing of Urinary Cytology: A Probabilistic Model Analysis. AB - BACKGROUND: Incorporating urinary cytology in BK virus (BKV) screening algorithm potentially reduces the screening cost for BK viral nephropathy. We aimed to evaluate the test performances and screening cost of sequential 2-stage screening consisting of urine cytology followed by BKV serum quantitative polymerase chain reaction (PCR). METHODS: Ninety-five kidney transplant recipients who had BKV serum quantitative PCR/urine cytology tested and verified with histopathology (the reference gold standard) were included. A probabilistic model was constructed to evaluate the test performance and screening cost of 2-stage screening, and was compared with screening with urine cytology or serum viral load alone. RESULTS: At a viral load threshold of >=104 copies/ml, the sensitivity and specificity of quantitative PCR alone were 83% (95% CI 69-96) and 91% (95% CI 83-97), respectively. The sensitivity and specificity of urine cytology alone were 91% (95% CI 79-100) and 74% (95% CI 60-91), respectively. Sequential 2-stage screening resulted in loss in sensitivity but a net gain in specificity (viral load threshold >=104 copies/ml - sensitivity, 75% (95% CI 60 91); specificity, 98% (95% CI 95-99)). Two-stage screening also had superior positive predictive value and is cost effective when BKV-associated nephropathy prevalence is below 94%. CONCLUSIONS: Our study had demonstrated a favorable test performance and cost efficiency of 2-stage BKV screening. PMID- 26756553 TI - Coefficient of Variation of P-Wave Duration Is a Novel Atrial Heterogeneity Index to Predict Recurrence of Atrial Fibrillation After Catheter Ablation. AB - INTRODUCTION: Atrial conduction heterogeneity is associated with progression of atrial fibrillation (AF). However, the relationship between P-wave parameters representing atrial conduction heterogeneity and AF recurrence after catheter ablation (ABL) is still unclear. METHODS AND RESULTS: Subjects of the study were 126 consecutive patients with AF (78 paroxysmal and 48 persistent) who had received ABL. Coefficient of variation of P-wave duration (CV-PWD) was determined with all 12 surface electrocardiographic leads as an index of atrial conduction heterogeneity. Rates of freedom from AF recurrence were 78% and 77% in patients with paroxysmal and persistent AF, respectively, over a 12-month follow-up. CV PWD measured before ABL was smaller in AF-free patients compared with AF recurrent patients (0.089 +/- 0.019 vs. 0.129 +/- 0.042, P < 0.001). CV-PWD significantly decreased after ABL in AF-free patients, but did not change in AF recurrent patients. CV-PWD after ABL was also smaller in AF-free patients compared with AF-recurrent patients (0.087 +/- 0.025 vs. 0.133 +/- 0.035, P < 0.001). In receiver operating curve analysis, CV-PWD before and after ABL achieved area under the curve of 0.829 and 0.854, respectively, for the ability to predict AF recurrence. CV-PWD correlated positively with left atrial (LA) diameter and negatively with LA appendage flow velocity. CONCLUSION: CV-PWD is a useful index to predict AF recurrence after ABL for both patients with paroxysmal and persistent AF. ABL may suppress AF by decreasing atrial conduction heterogeneity. PMID- 26756551 TI - Eact, a small molecule activator of TMEM16A, activates TRPV1 and elicits pain- and itch-related behaviours. AB - BACKGROUND AND PURPOSE: TMEM16A, also known as anoctamin 1 channel, is a member of the Ca(2+)-activated chloride channels family and serves as a heat sensor in the primary nociceptors. Eact is a recently discovered small molecule activator of the TMEM16A channel. Here, we asked if Eact produces pain- and itch-related responses in vivo and investigated the cellular and molecular basis of Eact elicited responses in dorsal root ganglia (DRG) neurons. EXPERIMENTAL APPROACH: We employed behavioural testing combined with pharmacological inhibition and genetic ablation approaches to identify transient receptor potential vanilloid 1 (TRPV1) as the prominent mediator for Eact-evoked itch- or pain-related responses. We investigated the effects of Eact on TRPV1 and TMEM16A channels expressed in HEK293T cells and in DRG neurons isolated from wild type and Trpv1( /-) mice using Ca(2+) imaging and patch-clamp recordings. We also used site directed mutagenesis to determine the molecular basis of Eact activation of TRPV1. KEY RESULTS: Administration of Eact elicited both itch- and pain-related behaviours. Unexpectedly, the Eact-elicited behavioural responses were dependent on the function of TRPV1, as shown by pharmacological inhibition and genetic ablation studies. Eact activated membrane currents and increased intracellular free Ca(2+) in both TRPV1-expressing HEK293T cells and isolated DRG neurons in a TRPV1-dependent manner. Eact activation of the TRPV1 channel was severely attenuated by mutations disrupting the capsaicin-binding sites. CONCLUSIONS AND IMPLICATIONS: Our results suggest that Eact activates primary sensory nociceptors and produces both pain and itch responses mainly through direct activation of TRPV1 channels. PMID- 26756554 TI - Efficacy and safety of two administration modes of an intra-detrusor injection of 750 units dysport(r) (abobotulinumtoxinA) in patients suffering from refractory neurogenic detrusor overactivity (NDO): A randomised placebo-controlled phase IIa study. AB - AIMS: Assess the efficacy and safety of abobotulinumtoxinA (Dysport(r)) in adult patients with neurogenic detrusor overactivity (NDO). METHODS: This Phase IIa, international, multicentre, double-blind, randomised, placebo controlled, pilot study enrolled 47 patients with NDO and urinary incontinence resulting from spinal cord injury (SCI) or multiple sclerosis (MS). Patients were treated with 15 intra-detrusor injections of Dysport 750 U or the equivalent placebo (n = 16 and 7) or 30 injections of Dysport 750 U or the equivalent placebo (n = 17 and 7). Primary endpoint was change from baseline in mean number of daily incontinence episode frequency (IEF) at day 84. Secondary endpoints included change from baseline in urodynamic parameters and quality of life (QOL). A safety assessment was also conducted. RESULTS: Adjusted mean changes from baseline in IEF were -3.2 (-76%) and -1.7 (-15%) for 15 injections Dysport and placebo groups, respectively, (P = 0.1103) and -3.2 (-88%) and -2.6 (-73%) for 30 injections Dysport and placebo groups, respectively, (P = 0.0686). Statistically significant improvements in maximum cystometric capacity, maximum detrusor pressure and volume at first contraction were reported in the Dysport groups compared with placebo (P < 0.05). Improvements in QOL were reported. Three muscle weakness episodes were reported as serious adverse events in two tetraplegic and one paraplegic patient, all in the 15 injections Dysport group. CONCLUSIONS: Both 15 and 30 injections administration modes of Dysport decreased daily IEF and resulted in significant improvements in urodynamic parameters in NDO patients with MS or SCI. Reduction to 15 injection sites did not appear to be associated with any impact on efficacy. Neurourol. Urodynam. 36:457-462, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26756555 TI - Total Knee Arthroplasty after Complete Patellectomy: A Review. AB - The absence or dysfunction of the knee extensor mechanism accelerates degenerative joint disease and complicates knee arthroplasty. Various treatment strategies have been suggested to improve outcomes in total knee arthroplasties after patellectomy (semi- or constrained components, autograft, allograft, prosthetic reconstruction), but the optimal management of this condition is not known. The purpose of this report is to review the relevant basic biology and biomechanics of the patella and the extensor mechanism, and to review the current literature on the management of complete patellectomy during total knee arthroplasty. Tissue engineered heart valves, BMMSCs, oscillatory shear stress, nicotine, F-actin filaments, cell differentiation, endothelial cells. PMID- 26756556 TI - Implant Fracture after Long-Stemmed Cemented Hemiarthroplasty for Oncologic Indications. AB - Although a long-stemmed cemented hemiarthroplasty is frequently recommended for oncologic lesions of proximal femur, we have observed an alarming number of spontaneous stem fractures. The purpose of this retrospective study was to identify the associated risk factors for stem fractures in a study cohort of 60 (61 prostheses) during 1983-2007. At a mean follow-up of 41 months, 4/61 (6.6%) stems had fractured after a mean of 36 (12-92) months after surgery. All failed implants were Osteonics Omnifit (4/27; 14.8%) and multivariate analysis did not show any correlation with other studied variables. While the failures were successfully salvaged by conversion to a modular proximal femoral replacement, any implant failure in this population is devastating. Spontaneous onset of thigh pain in patients with long stems, particularly if associated with other risk factors, should raise suspicion of a fatigue fracture of the stem. PMID- 26756558 TI - Use of a Flexible Intramedullary Rod and its Influence on Patient Satisfaction and Femoral Size in Total Knee Arthroplasty. AB - Improper femoral component size remains a source of multiple postoperative complications following total knee arthroplasty (TKA). However, the use of a flexible intramedullary (IM) rod may help optimize femoral component size and therefore improve outcomes. The purpose of this study was to assess (1) patient reported functional outcomes, (2) overall quality of life, and (3) changes in implant sizing associated with total knee arthroplasties performed with a flexible IM rod compared to a conventional, rigid rod. We reviewed 277 patients who had surgery using the rigid rod and 364 using the flexible rod to determine the tendency of each rod for selecting particular component sizes. Additionally, 100 patients were prospectively randomized (1:1) to the flexible or the conventional rigid IM rod cohorts. Outcomes were assessed using Knee Society scores (KSSs), SF-36 physical scores, and SF-36 mental scores preoperatively and at 6 weeks, 3 months, 1 year, and 2 years postoperatively. The retrospective arm of the study showed that the flexible IM rod cohort tends to have smaller component sizes than their conventional counterparts. In the prospective phase of the study, the increase in clinical KSSs from preoperative levels was better in the flexible rod cohort (160% vs. 143% increases, respectively). The functional KSSs had slightly higher increases in the flexible rod cohort from their preoperative levels (68% vs. 62% increases, respectively). With both clinical and functional KSSs, the flexible rod cohort had a higher score than the rigid rod cohort at all follow-up points. There was better postoperative range of motion (ROM) in the flexible rod cohort (28% vs. 22% increases, respectively). The SF-36 physical scores were slightly different, with the flexible IM rod cohort having a more marked improvement in scores (64% vs. 46% increases, respectively). The SF 36 mental score had a slightly better improvement at latest follow-up in the flexible IM rod cohort (12% vs. 6% increases, respectively). Those patients who underwent TKA using a flexible IM rod had better improvements in their patient reported outcomes and decreased risk of oversizing the femoral component. The use of such a rod is not detrimental to outcomes and may have a positive impact on outcomes. Future studies should focus on alignment and long-term outcomes associated with the use of a flexible rod. PMID- 26756557 TI - A Floating Thrombus Anchored at the Proximal Anastomosis of a Woven Thoracic Graft Mimicking a Genuine Aortic Dissection. AB - An aortoesophageal fistula following surgery for a ruptured 6.6-cm thoracic aneurysm in a 69-year-old female was repaired using a 34-mm woven prosthetic graft. A follow-up computed tomography (CT) scan at 10 days postoperatively revealed a dissection-like picture in the region of the graft, which was treated conservatively. The patient eventually died from sepsis and multiorgan failure. At autopsy, the graft was retrieved in situ and studied by detailed gross, microscopy, and scanning electron microscopy (SEM) examination. Gross observation confirmed that the dissection resulted from the rolling of the internal capsule downstream. A massive thrombus anchored at the proximal anastomosis and held by a narrow head was also noted. The thrombus demonstrated reorganization in the area of the anastomosis, with a false lumen in its distal half. The reminder of the thrombus consisted of layered fibrin. After gross examination, the fabric graft was found to be flawless. Additional detailed studies were also done using microscopy, SEM, and gross examination. PMID- 26756560 TI - Ethical and Methodological Issues Surrounding the Use of Appropriate Comparators in Orthopaedic Surgery Randomized Controlled Trials. AB - Although randomized controlled trials (RCTs) have the ability to provide researchers with more concrete evidence than that of their nonrandomized counterparts, conducting an RCT brings with it many ethical and methodological considerations. It is understood that in order to progress knowledge, and create new knowledge to benefit future patients, research must include human subjects; however, the desire to further knowledge must be placed second to the safety and respect for trial participants. An important ethical and methodological step in the design of any trial once the intervention is established is the selection of the comparator treatment. This is especially a topic of interest in orthopaedic surgery trials, in which a placebo comparator is not always possible and, arguably, sometimes never ethical. We review the use of different comparators in the treatment of orthopaedic surgery injuries and conditions, taking into consideration methodological and ethical issues. Comparators assessed are established treatments, standard-of-care treatments, conservative treatments, placebos, and sham surgeries. PMID- 26756559 TI - High Insertion Torque and Peri-Implant Bone Loss: Is There a Relationship? AB - Because primary stability has a critical role in implant osseointegration, greater insertion torque is more desirable. However, excessive pressure on the peri-implant bone may lead to bone resorption. This study evaluates the effect of insertion torque on crestal bone level. Periapical radiographs of 136 bone-level implants were assessed in this retrospective cohort study. Sixty-four implants were inserted with high insertion torques (45-70 N/cm) and 72 implants were placed with a torque in the range of 20 to 30 N/cm. The distance between implant shoulder and proximal bone crest was measured on radiographs taken immediately after the insertion and compared to those calculated after uncovering surgeries (inserting the healing abutment). The mean bone resorption around implants placed with high and lower insertion torques was 0.33 and 0.4, respectively; thus, the difference between the two groups was insignificant (p = 0.88). High insertion torques (up to 70 N/cm) did not significantly increase bone resorption around implants. PMID- 26756561 TI - Cost Effectiveness and Economic Impact of the KineSpring Knee Implant System in the Treatment of Knee Osteoarthritis in Spain. AB - We investigated the efficacy and cost effectiveness of the KineSpring System in the Spanish healthcare system, as compared to other standard treatments methods. Cost-utility ratios were calculated using derived cost data and we calculated quality-adjusted life years (QALYs) gained for each method of treatment. Cost utility ratios were calculated assuming lifetime and 10-year durability. Assuming lifetime durability, cost-utility ratios of total knee arthroplasty (TKA), unicompartmental knee arthroplasty (UKA), high tibial osteotomy (HTO), KineSpring System, and conservative treatments, compared to no treatment, are ?2348 +/- 70/QALYs, ?2040 +/- 61/QALYs, ?2281 +/- 68/ QALY, ?1669 +/- 268/QALYs, and ?11,688 +/- 2185/QALYs, respectively. Assuming a treatment durability of 10 years, the cost-utility ratio of TKA, UKA, HTO, KineSpring System, and conservative treatments, compared to no treatment, are ?4884 +/- 323/QALYs, ?4243 +/- 280/QALYs, ?4744 +/- 313/QALYs, ?3757 +/- 1353/QALYs, and ?10,575 +/- 4414/QALYs, respectively. In comparison to current standard-of-care treatments, the KineSpring System has a favorable cost-utility ratio, making it an effective treatment option and a suitable cost-saving alternative. The KineSpring System is associated with lower cost and increased QALYs. PMID- 26756562 TI - Orthopedic Implant Value Drivers: A Qualitative Survey Study of Hospital Purchasing Administrators. AB - Osteoarthritis (OA) is a chronic, degenerative disease that is highly prevalent in the population, yet the factors that affect purchasing decisions related to this condition are poorly understood. A questionnaire was developed and administered to hospital executives across North America to determine the factors that affect purchasing decisions related to OA. Thirty-four individuals participated in the survey. Clinical evidence and cost effectiveness were deemed to be the most important factors in the process of making purchasing decisions. The most important considerations for adopting new technology were whether there was sufficient evidence in the literature, followed by thoughts of key opinion leaders, and cost of intervention/device. Ongoing research is still needed, but the current study allowed us to identify some trends in the data, providing new insight on how hospital purchasing decisions are made, which could have an immediate impact on those currently involved with making these decisions. PMID- 26756563 TI - Economic Impact of the Use of an Absorbable Adhesion Barrier in Preventing Adhesions Following Open Gynecologic Surgeries. AB - We used an economic model to assess the impact of using the GYNECARE INTERCEED absorbable adhesion barrier for reducing the incidence of postoperative adhesions in open surgical gynecologic procedures. Caesarean section surgery, hysterectomy, myomectomy, ovarian surgery, tubal surgery, and endometriosis surgery were modeled with and without the use of GYNECARE INTERCEED absorbable adhesion barrier. Incremental GYNECARE INTERCEED absorbable adhesion barrier material costs, medical costs arising from complications, and adhesion-related readmissions were considered. GYNECARE INTERCEED absorbable adhesion barrier use was assumed in 75% of all procedures. The economic impact was reported during a 3 year period from a United States hospital perspective. Assuming 100 gynecologic surgeries of each type and an average of one GYNECARE INTERCEED absorbable adhesion barrier sheet per surgery, a net savings of $540,823 with GYNECARE INTERCEED absorbable adhesion barrier during 3 years is estimated. In addition, GYNECARE INTERCEED absorbable adhesion barrier use resulted in 62 fewer cases of patients developing adhesions. Although the use of GYNECARE INTERCEED absorbable adhesion barrier added $137,250 in material costs, this was completely offset by the reduction in length of stay ($178,766 savings), fewer adhesion-related readmissions ($458,220 savings), and operating room cost ($41,078 savings). Adoption of the GYNECARE INTERCEED absorbable adhesion barrier for appropriate gynecologic surgeries would likely result in significant savings for hospitals, driven primarily by clinical patient benefits in terms of decreased length of stay and adhesion-related readmissions. PMID- 26756564 TI - Hereditary diffuse leukoencephalopathy with spheroids - a volumetric and radiological comparison with multiple sclerosis patients and healthy controls. AB - BACKGROUND AND PURPOSE: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder caused by colony-stimulating factor 1 receptor (CSF1R) gene mutations, resulting in demyelination and axonal degeneration with spheroids. The clinical expression is variable, including behavioral changes, cognitive impairment, motor symptoms and parkinsonism. Magnetic resonance imaging (MRI) reveals white matter (WM) changes and atrophy. The indistinct phenotype has led to misdiagnoses. This study's aim was to compare brain volumetry and radiological ratings in HDLS with multiple sclerosis (MS) patients and controls. METHODS: Five HDLS patients with c.2562T>A p.Asn854Lys CSF1R mutation, five age- and gender-matched MS patients and five healthy controls were cross-sectionally studied. All patients were examined neurologically. HDLS patients underwent Mini-Mental State Examination (MMSE). Brain MRI scans were analyzed volumetrically with FreeSurfer and Lesion Segmentation Toolbox and neuroradiologically with the brain MRI scoring system for HDLS. RESULTS: Patients with HDLS had lower brain, grey matter and WM fractions (66.3%; 37.9%; 27.6%) compared with controls (78.5%, P = 0.008; 44.4%, P = 0.008; 32.0%, P = 0.008), but not compared with MS patients (65.7%, P = 0.7; 36.8%, P = 0.4; 27.3%, P = 0.7). Cerebellar WM changes and atrophy were not seen in the HDLS group. The HDLS lesion volume fraction correlated with MMSE scores (r = -0.90, P = 0.04). CONCLUSIONS: Brain volume fractions in HDLS were lower than in controls and similar to those seen in MS. The cerebellum was relatively spared in HDLS, which may help in differentiating HDLS WM changes from MS. The strong relationship of HDLS lesions with MMSE scores indicates that accumulating WM pathology in HDLS is associated with cognitive decline. PMID- 26756565 TI - The Impact of Arteriovenous Fistulae for Hemodialysis on the Cardiovascular System. AB - An arteriovenous fistula (AVF) is critical for the provision of optimal chronic hemodialysis. Its creation causes significant hemodynamic alterations in cardiovascular parameters, and can result in progressive left and right heart failure. Despite successful kidney transplantation, many patients retain a functional AVF indefinitely, which may contribute to ongoing adverse cardiovascular outcomes. A similar high risk:benefit ratio may exist in peritoneal dialysis patients with "backup" AVF. PMID- 26756567 TI - A Route to alpha-Fluoroalkyl Sulfides from alpha-Fluorodiaroylmethanes. AB - alpha,alpha-Difluorodiaroylmethane can be used as a nucleophilic difluoromethylation reagent for generating alpha-thioaryl-alpha,alpha difluoroacetophenones (Ar(1)COCF2SAr) and difluoromethylthiolated arenes (ArSCF2H) under transition-metal-free conditions. The reaction selectivity is mainly dependent on temperature. The method has also been extended to the synthesis of alpha-thioaryl-alpha-monofluoroacetophenones using alpha monofluorodibenzoylmethane. Moreover, the benzoyl cation derived from alpha,alpha difluorodibenzoylmethane can react with nucleophiles to afford the desired products in a one-pot process. PMID- 26756566 TI - Six minute walk test versus incremental shuttle walk test in cystic fibrosis. AB - BACKGROUND: Although both self-paced and externally paced field tests are widely used in cystic fibrosis (CF), it is still unclear whether they induce clinically relevant and similar cardiorespiratory responses. The aim of this study was therefore to compare the incremental shuttle walk test (ISWT) and 6 min walk test (6MWT), and to determine the factors influencing exercise capacity in CF. METHODS: Fifty clinically stable CF patients were included in the study. Pulmonary function, peripheral and respiratory muscle strength were assessed, anthropometric measurements were recorded, and 6MWT and ISWT carried out. RESULTS: The CF patients covered significantly more distance in the ISWT than 6MWT (P < 0.001). Heart rate response and dyspnea score at the end of the tests and during the recovery phase were significantly higher in the ISWT compared with the 6MWT (P < 0.05). The 6MWT and ISWT had similar moderate-strong correlations with age, height, weight, pulmonary function, respiratory and peripheral muscle strength (P < 0.05). Forty-nine percent of the variance in 6MWT distance was explained by age and forced expiratory volume in 1 s (FEV1 ; R(2) = 0.49, F(2 48) = 22.033, P < 0.001). The variables contributing to ISWT distance were FEV1 , inspiratory muscle strength, and body mass index (R(2) = 0.596, F(3-44) = 20.176, P < 0.001). CONCLUSIONS: The ISWT is a better reflection of exercise tolerance in CF than 6MWT. ISWT is a preferable alternative assessment of exercise tolerance in terms of cardiorespiratory response. PMID- 26756570 TI - Resolution, target density and labeling effects in colocalization studies - suppression of false positives by nanoscopy and modified algorithms. AB - Colocalization analyses of fluorescence images are extensively used to quantify molecular interactions in cells. In recent years, fluorescence nanoscopy has approached resolutions close to molecular dimensions. However, the extent to which image resolution influences different colocalization estimates has not been systematically investigated. In this work, we applied simulations and resolution tunable stimulated emission depletion microscopy to evaluate how the resolution, molecular density and label size of targeted molecules influence estimates of the most commonly used colocalization algorithms (Pearson correlation coefficient, Manders' M1 and M2 coefficients), as well as estimates by the image cross correlation spectroscopy method. We investigated the practically measureable extents of colocalization for stimulated emission depletion microscopy with positive and negative control samples with an aim to identifying the strengths and weaknesses of nanoscopic techniques for colocalization studies. At a typical optical resolution of a confocal microscope (200-300 nm), our results indicate that the extent of colocalization is typically overestimated by the tested algorithms, especially at high molecular densities. Only minor effects of this kind were observed at higher resolutions (< 60 nm). By contrast, underestimation of colocalization may occur if the resolution is close to the size of the label/affinity molecules themselves. To suppress false positives at confocal resolutions and high molecular densities, we introduce a statistical variant of Costes' threshold searching algorithm, used in combination with correlation-based methods like the Pearson coefficient and the image cross-correlation spectroscopy approach, to set intensity thresholds separating background noise from signals. PMID- 26756569 TI - Assessment of mediators of racial disparities in cervical cancer survival in the United States. AB - Cervical cancer (CC) morbidity and mortality have decreased in the United States, but they remain high among black women. We assessed racial disparities in CC mortality, accounting for socioeconomic status (SES). We linked data from the 1988 to 2007 Surveillance Epidemiology and End Results (SEER) database to the US Census. Additional SES information was obtained through linkage with Area Resource Files. We used the Kaplan-Meier method for estimating probabilities following CC diagnosis and Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CC mortality by race. The models were incrementally adjusted for marital status, registry, period, stage, age at diagnosis, histology, treatment, household income, poverty and unemployment rates. We stratified the analyses by disease stage and American state. A total of 44,554 women with CC were identified. Compared to white women, black women had a higher risk of dying from CC; crude and adjusted HRs were 1.41 (CI: 1.34-1.48) and 1.09 (CI: 1.03-1.15), respectively. Corresponding estimates for Hispanic women were 0.85 (CI: 0.80-0.89) and 0.75 (CI: 0.71-0.80). Black women diagnosed at late disease stages had a higher risk of CC death, whereas Hispanic women diagnosed at early and late stages had significantly lower risks. Black CC patients in California experienced poorer survival relative to white women. Conversely, longer CC survival was seen among Hispanic women in California, Georgia and Utah. While crude estimates indicated an increased CC death risk among black women, risks diminished upon adjustment for clinical and sociodemographic characteristics. PMID- 26756571 TI - Biomarker-based diagnostic work-up of invasive pulmonary aspergillosis in immunocompromised paediatric patients--is Aspergillus PCR appropriate? AB - Invasive aspergillosis (IA) is an important cause of morbidity and mortality in children and adults with haematologic malignancies or undergoing allogeneic haematopoietic stem cell transplantation, and early diagnosis and adequate antifungal treatment improve outcome. However, important differences exist between children and adults regarding epidemiology, underlying disease, and comorbidities, and the value of diagnostic tools to detect IA may also differ between these patient populations. Imaging studies are important to detect IA early, but typical findings of IA in chest computed tomography of adults are not detected in the majority of children. Whereas the value of the serum marker galactomannan seems to be comparable in children and adults, data on the performance of beta-d-glucan in children are too limited for firm conclusions. PCR-based assays are a promising diagnostic approach to rapidly and reliably detect and identify Aspergillus species in various clinical samples. However, as the majority of data on PCR-based approaches has been obtained in adult patients, the value of this method in paediatric patients has not been defined to date. The present review focuses on studies of PCR-based methods to diagnose IA in immunocompromised paediatric patients. PMID- 26756568 TI - High expression of long non-coding RNA AFAP1-AS1 predicts chemoradioresistance and poor prognosis in patients with esophageal squamous cell carcinoma treated with definitive chemoradiotherapy. AB - To evaluate the clinical significance of lncRNAs in the resistance to cisplatin based chemoradiotherapy in esophageal squamous cell carcinoma (ESCC). We focused on lncRNAs which were frequently reported in ESCC or were involved in chemoradiotherapy resistance. LncRNA expressions were examined in paired cisplatin-resistant and parental ESCC cell lines. Dysregulated lncRNAs were further measured in 162 pretreatment biopsy specimens of ESCC who received definitive chemoradiotherapy (dCRT). Then the correlations between lncRNA expression and response to dCRT and prognosis were analyzed. Three lncRNAs (AFAP1 AS1, UCA1, HOTAIR) were found to be deregulated in cisplatin-resistant cells compared with their parent cells. AFAP1-AS1 was significantly up-regulated in tumor tissues compared with adjacent normal tissues (P = 0.006). Furthermore, overexpression of AFAP1-AS1 was closely associated with lymph node metastasis (P < 0.001), distant metastasis (P = 0.016), advanced clinical stage (P = 0.002), and response to dCRT (P < 0.001). Kaplan-Meier survival analysis revealed that high expression of AFAP1-AS1 was significantly associated with shorter progression free survival (PFS) (median, 15 months vs. 27 months, P < 0.001) and overall survival (OS) (median, 29 months vs. 42 months, P < 0.001). In the multivariate analysis, high expression of AFAP1-AS1 was found to be an independent risk factor to predict poor PFS (HR, 1.626; P = 0.027) and OS (HR, 1.888; P = 0.004). Thus, high expression of AFAP1-AS1 could serve as a potential biomarker to predict tumor response and survival. Determination of this lncRNA expression might be useful for selection ESCC patients for dCRT. (c) 2016 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc. PMID- 26756572 TI - Visualization of Protein-Specific Glycosylation inside Living Cells. AB - Protein glycosylation is a ubiquitous post-translational modification that is involved in the regulation of many aspects of protein function. In order to uncover the biological roles of this modification, imaging the glycosylation state of specific proteins within living cells would be of fundamental importance. To date, however, this has not been achieved. Herein, we demonstrate protein-specific detection of the glycosylation of the intracellular proteins OGT, Foxo1, p53, and Akt1 in living cells. Our generally applicable approach relies on Diels-Alder chemistry to fluorescently label intracellular carbohydrates through metabolic engineering. The target proteins are tagged with enhanced green fluorescent protein (EGFP). Forster resonance energy transfer (FRET) between the EGFP and the glycan-anchored fluorophore is detected with high contrast even in presence of a large excess of acceptor fluorophores by fluorescence lifetime imaging microscopy (FLIM). PMID- 26756573 TI - Decarboxylative Trifluoromethylating Reagent [Cu(O2 CCF3 )(phen)] and Difluorocarbene Precursor [Cu(phen)2 ][O2 CCF2 Cl]. AB - This article describes the new economic decarboxylative trifluoromethylating reagent [Cu(phen)(O2 CCF3 )] (1; phen=1,10-phenanthroline) and the efficient difluorocarbene precursor [Cu(phen)2 ][O2 CCF2 Cl] (2). Treatment of copper tert butoxide with phen and subsequent addition of trifluoroacetic acid or chlorodifluoroacetic acid afforded air-stable complexes 1 and 2, respectively, which were characterized by X-ray crystallography. The copper(I) ion in 1 is coordinated by a bidentate phen ligand, a monodentate trifluoroacetate group, and a molecule of CH3 CN in a distorted tetrahedral coordination geometry. The molecular structure of 2 adopts an ionic form that consists of a [Cu(phen)2 ]+ cation and a chlorodifluoroacetate anion. Complex 1 reacted with a variety of aryl and heteroaryl halides to form trifluoromethyl (hetero)arenes in good yields. The corresponding Hammett plot exhibited a linear relationship and a reaction parameter (rho)=+0.56+/-0.02, which indicated that the trifluoromethylation reaction proceeded via a nucleophilic reactive species. Complex 2 reacts with phenols to produce aryl difluoromethyl ethers in modest-to excellent yields. Mechanistic investigations revealed that the difluoromethylation reaction proceeds by initial copper-mediated formation of difluorocarbene and subsequent concerted addition of difluorocarbene to the phenol to form a three-center transition state. PMID- 26756574 TI - The stigma of making a living from garbage: Meta-sterotypes of trash-pickers in Leon (Nicaragua). AB - The article analyzes various aspects related to the meta-stereotype of 99 trash pickers who made their living from the garbage dumps in Leon (Nicaragua). This group is difficult to access, heavily stigmatized, and lives in extreme poverty. All the pickers in the city were interviewed using a heteroapplied structured interview. The results show that people who obtained their livelihood from garbage in the city of Leon had a mainly negative meta-stereotype, albeit one to which was some extent indulgent, which could have a negative impact on their processes of social inclusion. The content of the meta-stereotype had a high degree of uniformity, with few variations between the respondents. However, some differences were observed in the use of some attributes in the meta-stereotype according to age, cohabitation with a partner and/or with parents, income level, engagement in paid work apart from picking garbage and the respondents' expectations for the future. PMID- 26756575 TI - Association of PDE4B Polymorphisms with Susceptibility to Schizophrenia: A Meta Analysis of Case-Control Studies. AB - BACKGROUND: The PDE4B single nucleotide polymorphisms (SNPs) have been reported to be associated with schizophrenia risk. However, current findings are ambiguous or even conflicting. To better facilitate the understanding the genetic role played by PDE4B in susceptibility to schizophrenia, we collected currently available data and conducted this meta-analysis. METHODS: A comprehensive electronic literature searching of PubMed, Embase, Web of Science and Cochrane Library was performed. The association between PDE4B SNPs and schizophrenia was evaluated by odds ratios (ORs) and 95% confidence intervals (CIs) under allelic, dominant and recessive genetic models. The random effects model was utilized when high between-study heterogeneity (I2 > 50%) existed, otherwise the fixed effects model was used. RESULTS: Five studies comprising 2376 schizophrenia patients and 3093 controls were finally included for meta-analysis. The rs1040716 was statistically significantly associated with schizophrenia risk in Asian and Caucasian populations under dominant model (OR = 0.87, 95% CI: 0.76-0.99, P = 0.04). The rs2180335 was significantly related with schizophrenia risk in Asian populations under allelic (OR = 0.82, 95% CI: 0.72-0.93, P = 0.003) and dominant (OR = 0.75, 95% CI: 0.64-0.88, P < 0.001) models. A significant association was also observed between rs4320761 and schizophrenia in Asian populations under allelic model (OR = 0.87, 95% CI: 0.75-1.00, P = 0.048). In addition, a strong association tendency was found between rs6588190 and schizophrenia in Asian populations under allelic model (OR = 0.87, 95% CI: 0.76-1.00, P = 0.055). CONCLUSION: This meta-analysis suggests that PDE4B SNPs are genetically associated with susceptibility to schizophrenia. However, due to limited sample size, more large-scale, multi-racial association studies are needed to further clarify the genetic association between various PDE4B variants and schizophrenia. PMID- 26756577 TI - Construction of recombinant pseudorabies viruses by using PRV BACs deficient in IE180 or pac sequences: Application of vBAC90D recombinant virus to production of PRV amplicons. AB - We describe a simple and efficient method to obtain recombinant pseudorabies virus (PRV) in mammalian cells by using the PRV BACs, PBAC80 deficient in pac sequences and PBAC90 deficient in the IE180 gene. These essential viral sequences were used as targets to obtain viable recombinant viruses. PBAC80 was constructed, confirmed to encode a copy of the IE180 gene regulated by the inducible Ptet promoter, and used to obtain recombinant attenuated PRV viruses that express the EGFP protein (PRV-BT80GF virus). PBAC90 was used to obtain the vBAC90D virus, deficient in IE180 and free of replication-competent revertants, and which can be used as a helper in the production of PRV amplicons. PMID- 26756578 TI - Direct Growth of MoS2/h-BN Heterostructures via a Sulfide-Resistant Alloy. AB - Improved properties arise in transition metal dichalcogenide (TMDC) materials when they are stacked onto insulating hexagonal boron nitride (h-BN). Therefore, the scalable fabrication of TMDCs/h-BN heterostructures by direct chemical vapor deposition (CVD) growth is highly desirable. Unfortunately, to achieve this experimentally is challenging. Ideal substrates for h-BN growth, such as Ni, become sulfides during the synthesis process. This leads to the decomposition of the pregrown h-BN film, and thus no TMDCs/h-BN heterostructure forms. Here, we report a thoroughly direct CVD approach to obtain TMDCs/h-BN vertical heterostructures without any intermediate transfer steps. This is attributed to the use of a nickel-based alloy with excellent sulfide-resistant properties and a high catalytic activity for h-BN growth. The strategy enables the direct growth of single-crystal MoS2 grains of up to 200 MUm(2) on h-BN, which is approximately 1 order of magnitude larger than that in previous reports. The direct band gap of our grown single-layer MoS2 on h-BN is 1.85 eV, which is quite close to that for free-standing exfoliated equivalents. This strategy is not limited to MoS2-based heterostructures and so allows the fabrication of a variety of TMDCs/h-BN heterostructures, suggesting the technique has promise for nanoelectronics and optoelectronic applications. PMID- 26756576 TI - Insulin-Producing Cells Differentiated from Human Bone Marrow Mesenchymal Stem Cells In Vitro Ameliorate Streptozotocin-Induced Diabetic Hyperglycemia. AB - BACKGROUND: The two major obstacles in the successful transplantation of islets for diabetes treatment are inadequate supply of insulin-producing tissue and immune rejection. Induction of the differentiation of human bone marrow-derived mesenchymal stem cells (hMSCs) into insulin-producing cells (IPCs) for autologous transplantation may alleviate those limitations. METHODS: hMSCs were isolated and induced to differentiate into IPCs through a three-stage differentiation protocol in a defined media with high glucose, nicotinamide, and exendin-4. The physiological characteristics and functions of IPCs were then evaluated. Next, about 3 * 10(6) differentiated cells were transplanted into the renal sub capsular space of streptozotocin (STZ)-induced diabetic nude mice. Graft survival and function were assessed by immunohistochemistry, TUNEL staining and measurements of blood glucose levels in the mice. RESULTS: The differentiated IPCs were characterized by Dithizone (DTZ) positive staining, expression of pancreatic beta-cell markers, and human insulin secretion in response to glucose stimulation. Moreover, 43% of the IPCs showed L-type Ca2+ channel activity and similar changes in intracellular Ca2+ in response to glucose stimulation as that seen in pancreatic beta-cells in the process of glucose-stimulated insulin secretion. Transplantation of functional IPCs into the renal subcapsular space of STZ-induced diabetic nude mice ameliorated the hyperglycemia. Immunofluorescence staining revealed that transplanted IPCs sustainably expressed insulin, c peptide, and PDX-1 without apparent apoptosis in vivo. CONCLUSIONS: IPCs derived from hMSCs in vitro can ameliorate STZ-induced diabetic hyperglycemia, which indicates that these hMSCs may be a promising approach to overcome the limitations of islet transplantation. PMID- 26756579 TI - PD-1 Expression and Cytokine Secretion Profiles of Mycobacterium tuberculosis Specific CD4+ T-Cell Subsets; Potential Correlates of Containment in HIV-TB Co Infection. AB - HIV co-infection is an important risk factor for tuberculosis (TB) providing a powerful model in which to dissect out defective, protective and dysfunctional Mycobacterium tuberculosis (MTB)-specific immune responses. To identify the changes induced by HIV co-infection we compared MTB-specific CD4+ responses in subjects with active TB and latent TB infection (LTBI), with and without HIV co infection. CD4+ T-cell subsets producing interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and tumour necrosis factor-alpha (TNF-alpha) and expressing CD279 (PD-1) were measured using polychromatic flow-cytometry. HIV-TB co infection was consistently and independently associated with a reduced frequency of CD4+ IFN-gamma and IL-2-dual secreting T-cells and the proportion correlated inversely with HIV viral load (VL). The impact of HIV co-infection on this key MTB-specific T-cell subset identifies them as a potential correlate of mycobacterial immune containment. The percentage of MTB-specific IFN-gamma secreting T-cell subsets that expressed PD-1 was increased in active TB with HIV co-infection and correlated with VL. This identifies a novel correlate of dysregulated immunity to MTB, which may in part explain the paucity of inflammatory response in the face of mycobacterial dissemination that characterizes active TB with HIV co-infection. PMID- 26756580 TI - Generation of Knock-In Pigs Carrying Oct4-tdTomato Reporter through CRISPR/Cas9 Mediated Genome Engineering. AB - The porcine pluripotent cells that can generate germline chimeras have not been developed. The Oct4 promoter-based fluorescent reporter system, which can be used to monitor pluripotency, is an important tool to generate authentic porcine pluripotent cells. In this study, we established a porcine Oct4 reporter system, wherein the endogenous Oct4 promoter directly controls red fluorescent protein (RFP). 2A-tdTomato sequence was inserted to replace the stop codon of the porcine Oct4 gene by homogenous recombination (HR). Thus, the fluorescence can accurately show the activation of endogenous Oct4. Porcine fetal fibroblast (PFF) lines with knock-in (KI) of the tdTomato gene in the downstream of endogenous Oct4 promoter were achieved using the CRISPR/CAS9 system. Transgenic PFFs were used as donor cells for somatic cell nuclear transfer (SCNT). Strong RFP expression was detected in the blastocysts and genital ridges of SCNT fetuses but not in other tissues. Two viable transgenic piglets were also produced by SCNT. Reprogramming of fibroblasts from the fetuses and piglets by another round of SCNT resulted in tdTomato reactivation in reconstructed blastocysts. Result indicated that a KI porcine reporter system to monitor the pluripotent status of cells was successfully developed. PMID- 26756581 TI - Exploring natural variation of Pinus pinaster Aiton using metabolomics: Is it possible to identify the region of origin of a pine from its metabolites? AB - Natural variation of the metabolome of Pinus pinaster was studied to improve understanding of its role in the adaptation process and phenotypic diversity. The metabolomes of needles and the apical and basal section of buds were analysed in ten provenances of P. pinaster, selected from France, Spain and Morocco, grown in a common garden for 5 years. The employment of complementary mass spectrometry techniques (GC-MS and LC-Orbitrap-MS) together with bioinformatics tools allowed the reliable quantification of 2403 molecular masses. The analysis of the metabolome showed that differences were maintained across provenances and that the metabolites characteristic of each organ are mainly related to amino acid metabolism, while provenances were distinguishable essentially through secondary metabolism when organs were analysed independently. Integrative analyses of metabolome, environmental and growth data provided a comprehensive picture of adaptation plasticity in conifers. These analyses defined two major groups of plants, distinguished by secondary metabolism: that is, either Atlantic or Mediterranean provenance. Needles were the most sensitive organ, where strong correlations were found between flavonoids and the water regime of the geographic origin of the provenance. The data obtained point to genome specialization aimed at maximizing the drought stress resistance of trees depending on their origin. PMID- 26756583 TI - Lysyl oxidase like-4 monoclonal antibody demonstrates therapeutic effect against head and neck squamous cell carcinoma cells and xenografts. AB - A new member of the lysyl oxidase (LOX) family, lysyl oxidase-like 4 (LOXL4), is overexpressed in head and neck squamous cell carcinoma (HNSCC) compared to normal squamous epithelium. A monoclonal antibody (mAb) derived from fusion of Balb/c mouse splenocytes immunized with LOXL4 specific peptide was used to evaluate its therapeutic efficacy in 15 HNSCC cell lines associated with LOXL4 overexpression. For xenograft experiments 41 severe combined immunodeficient (SCID) mice were used to analyze LOXL4-mAb mediated tumor regression. Cell viability was analyzed using cytotoxicity-, and clonogenic-assays. Significant suppression of tumor cell growth was observed in 12 out of 15 (80%) tumor cell lines after 48 hr exposure to the mAb (LD50 of 15 ug/ml to 45 ug/ml). The effect induced by the antibody could be blocked by pre-incubation of the antibody with the peptide used for immunization of the mice and antibody generation, indicating that the effect of the antibody is specific. In mice inoculated with HNSCC cells, i.v. injections of the LOXL4-mAb resulted within 70 days in extensive tumor destruction in all treated animals whereas no tumor regression occurred in control animals. In mice pre-immunized i.v. with LOXL4-mAb and subsequently injected with HNSCC cells, tumor development was considerably delayed in contrast to non LOXL4-mAb pre immunized animals. These results demonstrate that the LOXL4-mAb has potent antitumor activity and suggest its suitability as a therapeutic immune agent applicable to HNSCC exhibiting tumor specific upregulation of LOXL4. PMID- 26756582 TI - Maleimide-Functionalized Poly(2-Oxazoline)s and Their Conjugation to Elastin-Like Polypeptides. AB - The design of drug delivery systems capable of efficiently delivering poorly soluble drugs to target sites still remains a major challenge. Such materials require several different functionalities; typically, these materials should be biodegradable and nontoxic, nonimmunogenic, responsive to their environment, and soluble in aqueous solution while retaining the ability to solubilize hydrophobic drugs. Here, a polypeptide-polymer hybrid of elastin-like polypeptides (ELPs) and poly(2-oxazoline)s (POx) is reported. This paper describes the chemical synthesis, physical characteristics, and drug loading potential of these novel hybrid macromolecules. A novel method is introduced for terminal functionalization of POx with protected maleimide moieties. Following recovery of the maleimide group via a retro Diels-Alder reaction, the consecutive Michael addition of thiol-functionalized ELPs yields the desired protein-polymer conjugate. These conjugates form nanoparticles in aqueous solution capable of solubilizing the anti-cancer drug paclitaxel with up to 8 wt% loading. PMID- 26756584 TI - Caring for Strangers: Aging, Traditional Medicine, and Collective Self-care in Post-socialist Russia. AB - This article explores how aging patients in Russia assemble strategies of care in the face of commercialization of medical services and public health discourses and initiatives aimed at improving the population's lifestyle habits. By focusing on how the formation of pensioner publics intersects with the health-seeking trajectories of elderly patients, it tracks an emerging ethic of collective self care-a form of therapeutic collectivity that challenges articulations of good health as primarily an extension of personal responsibility or solely as a corollary of access to medical resources. By drawing on traditional medicine, these pensioners rely on and advocate for stranger intimacies that offer tactics for survival in the present through the care of (and for) a shared and embodied post-socialist condition of social, economic, and bodily precarity. PMID- 26756585 TI - Impulse Oscillometry as a Predictor of Asthma Exacerbations in Young Children. AB - BACKGROUND: In a post-hoc analysis of a pediatric asthma study, we identified the predictors of asthma exacerbations (AEs) and related them to forced expiratory volume (FEV1), the FEV1/FVC ratio, and bronchial hyperresponsiveness (BHR). OBJECTIVES: We sought to detect predictors of AEs in a prospective study that utilizes impulse oscillometry (IOS) and to compare the results to previously determined predictors. METHODS: A moderate AE was defined as an increased use of salbutamol during coughing episodes. Pulmonary function and BHR were measured during symptom- and medication-free periods. Additionally, allergen testing and IOS were included. To calculate the sensitivity and specificity of AE detection, a receiver-operating characteristic (ROC) curve was plotted, and accuracy was measured with the area under the ROC curve (AUC). A logistic regression analysis was used to predict the probability of an exacerbation. RESULTS: Seventy-five pediatric patients (4-7 years of age) with intermittent asthma were included. In 69 patients, the following cut-off values demonstrated the best sensitivity and specificity combination for predicting an AE: FEV1 103.2% (AUC 0.62), BHR (PD20methacholine) 0.13 mg (AUC 0.61), and, in 54 children, Rrs5 0.78 kPa * l-1 * s (AUC 0.80). Logistic regression analysis demonstrated that the combination of all parameters predicted the individual risk of AEs with an accuracy of 86%. CONCLUSIONS: IOS, a simple method, predicted the probability of AEs in young children. Airway resistance, measured by IOS, was superior to FEV1 and methacholine testing. The current data suggest that peripheral airway obstruction is present during symptom-free periods and that these children more likely experience AEs. PMID- 26756586 TI - Increased Plasma PCSK9 Levels Are Associated with Reduced Endotoxin Clearance and the Development of Acute Organ Failures during Sepsis. AB - PURPOSE: We have recently shown that PCSK9 reduces the clearance of endotoxin and is therefore a critical regulator of the innate immune response during infection. However, plasma PCSK9 levels during human sepsis and their relationship to outcomes are not known. Our objective was to determine the relationship between plasma PCSK9 levels and the rate of endotoxin clearance, and then correlate PCSK9 levels with the development of acute organ failures in a cohort of patients with sepsis. METHODS: Using human hepatocyte cells, we determined the threshold at which PCSK9 is able to reduce Escherichia coli endotoxin uptake by cultured human hepatocytes. In a single-centre observational cohort at St. Paul's Hospital in Vancouver, Canada, we recruited 200 patients who activated our Emergency Department's sepsis protocol and measured plasma PCSK9 and lipid levels at triage and throughout the admission. Outcomes were the development of sepsis-induced cardiovascular or respiratory failure. RESULTS: We reviewed the literature and determined that the normal human range of PCSK9 found in plasma is 170-220 ng/ml, while levels of 250 ng/ml and above reduced E. coli endotoxin clearance in cultured human hepatocytes. In septic patients, the median levels associated with new-onset respiratory and cardiovascular failure were 370 (250-500) and 380 (270 530) ng/ml, respectively, versus 270 (220-380) ng/ml in patients who did not go on to develop any organ failure (p = 0.003 and 0.005, respectively). CONCLUSIONS: Plasma PCSK9 levels are greatly increased in sepsis. At normal levels, PCSK9 has no influence upon hepatocyte bacterial endotoxin clearance, but as levels rise, there is a progressive inhibition of clearance. During sepsis, PCSK9 levels are highly correlated with the development of subsequent multiple organ failure. Inhibition of PCSK9 activity is an attractive target for treating the spectrum of sepsis and septic shock. PMID- 26756587 TI - Exploring Managers' Perspectives on MNCH Program in Pakistan: A Qualitative Study. AB - BACKGROUND: Pakistan's Maternal, Newborn and Child Health (MNCH) Program is faced with multiple challenges in service delivery, financial and logistic management, training and deployment of human resources, and integration within the existing health system. There is a lack of evidence on managerial aspects of the MNCH program management and implementation. METHODS AND FINDINGS: This study used qualitative methods to explore the challenges national, provincial and district program managers have faced in implementing a community midwifery program in province of Punjab while also exploring future directions for the program under a devolved health system. While the program had been designed in earnest, the planning lacked critical elements of involving relevant stakeholders in design and implementation, socio-demographic context and capacity of the existing health system. Financial limitations, weak leadership and lack of a political commitment to the problem of maternal health have also had an impact on program implementation. CONCLUSIONS: Our study results suggest that there is a need to re structure the program while ensuring sustainability and collaboration within the health sector to increase uptake of skilled birth attendance and improve maternal health care in Pakistan. PMID- 26756588 TI - Effectiveness of Breast Cancer Screening: Systematic Review and Meta-analysis to Update the 2009 U.S. Preventive Services Task Force Recommendation. AB - BACKGROUND: In 2009, the U.S. Preventive Services Task Force recommended biennial mammography screening for women aged 50 to 74 years and selective screening for those aged 40 to 49 years. PURPOSE: To review studies of the effectiveness of breast cancer screening in average-risk women. DATA SOURCES: MEDLINE and Cochrane databases to 4 June 2015. STUDY SELECTION: English-language randomized, controlled trials and observational studies of screening with mammography, magnetic resonance imaging, and ultrasonography that reported breast cancer mortality, all-cause mortality, or advanced breast cancer outcomes. DATA EXTRACTION: Investigators extracted and confirmed data and dual rated study quality; discrepancies were resolved through consensus. DATA SYNTHESIS: Fair quality evidence from a meta-analysis of mammography trials indicated relative risks (RRs) for breast cancer mortality of 0.92 for women aged 39 to 49 years (95% CI, 0.75 to 1.02) (9 trials; 3 deaths prevented per 10,000 women over 10 years); 0.86 for those aged 50 to 59 years (CI, 0.68 to 0.97) (7 trials; 8 deaths prevented per 10,000 women over 10 years); 0.67 for those aged 60 to 69 years (CI, 0.54 to 0.83) (5 trials; 21 deaths prevented per 10,000 women over 10 years); and 0.80 for those aged 70 to 74 years (CI, 0.51 to 1.28) (3 trials; 13 deaths prevented per 10,000 women over 10 years). Risk reduction was 25% to 31% for women aged 50 to 69 years in observational studies of mammography screening. All-cause mortality was not reduced with screening. Advanced breast cancer was reduced for women aged 50 years or older (RR, 0.62 [CI, 0.46 to 0.83]) (3 trials) but not those aged 39 to 49 years (RR, 0.98 [CI, 0.74 to 1.37]) (4 trials); less evidence supported this outcome. LIMITATIONS: Most trials used imaging technologies and treatments that are now outdated, and definitions of advanced breast cancer were heterogeneous. Studies of effectiveness based on risk factors, intervals, or other modalities were unavailable or methodologically limited. CONCLUSION: Breast cancer mortality is generally reduced with mammography screening, although estimates are not statistically significant at all ages and the magnitudes of effect are small. Advanced cancer is reduced with screening for women aged 50 years or older. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 26756589 TI - Functional Brain Correlates of Neuropsychiatric Symptoms in Presymptomatic Huntington's Disease: The IMAGE-HD Study. AB - BACKGROUND: Neuropsychiatric disturbances are common in Huntington's Disease (HD) and have been observed in gene-positive individuals several years prior to the onset of motor symptoms. The neural mechanism underpinning the development of neuropsychiatric problems in HD remain unclear. OBJECTIVE: To investigate whether neural activity during working memory is associated with neuropsychiatric symptoms in premanifest Huntington's Disease. METHODS: functional magnetic resonance imaging (fMRI) data from Pre-HD far from onset (pre-HDfar, n = 18), pre HD close to onset (pre-HDclose, n = 17), and controls (n = 32) were analysed. Correlations were performed between fMRI activity in three regions of interest [bilateral dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC)] and neuropsychiatric scores. RESULTS: In the pre-HDclose group, increased symptoms of obsessive compulsion and depression were associated with decreased blood-oxygen-level-dependent (BOLD) fMRI activity in the right DLPFC and ACC during 1-BACK and 2-BACK working memory conditions. In the pre-HDfar group increased symptoms of depression was associated with decreased right DLPFC BOLD fMRI activity during 2-BACK working memory only. CONCLUSIONS: The findings suggest that association between neuropsychiatric function and fMRI activity is more readily detectable at higher working memory loads, and becomes more pronounced in those closer to onset. PMID- 26756590 TI - Longitudinal Diffusion Tensor Imaging Shows Progressive Changes in White Matter in Huntington's Disease. AB - BACKGROUND: Huntington's disease is marked by progressive neuroanatomical changes, assumed to underlie the development of the disease's characteristic symptoms. Previous work has demonstrated longitudinal macrostructural white matter atrophy, with some evidence of microstructural change focused in the corpus callosum. OBJECTIVE: To more accurately characterise longitudinal patterns, we examined white matter microstructural change using Diffusion Tensor Imaging (DTI) data from three timepoints over a 15 month period. METHODS: In 48 early-stage HD patients and 36 controls from the multi-site PADDINGTON project, diffusion tensor imaging (DTI) was employed to measure changes in fractional anisotropy (FA) and axial (AD) and radial diffusivity (RD) in 24 white matter regions-of-interest (ROIs). RESULTS: Cross-sectional analysis indicated widespread baseline between-group differences, with significantly decreased FA and increased AD and RD found in HD patients across multiple ROIs. Longitudinal rates of change differed significantly between HD patients and controls in the genu and body of corpus callosum, corona radiata and anterior limb of internal capsule. Change in RD in the body of the corpus callosum was significantly associated with baseline disease burden, but other clinical associations were not significant. CONCLUSIONS: We detected subtle longitudinal white matter changes in early HD patients. Progressive white matter abnormalities in HD may not be uniform throughout the brain, with some areas remaining static in the early symptomatic phase. Longer assessment periods across disease stages will help map this progressive trajectory. PMID- 26756591 TI - Exploring the Validity of the Short Version of the Problem Behaviours Assessment (PBA-s) for Huntington's disease: A Rasch Analysis. AB - BACKGROUND: The short version of the Problem Behaviours Assessment (PBA-s) is the recommended outcome measure for behavioural symptoms in Huntington's disease. Rasch analysis was used to further investigate the measurement limitations of the PBA-s. OBJECTIVES: 1) To assess the psychometric properties of the 11 severity and frequency items within the PBA-s and 2) to determine the construct validity of using a total PBA-s score as a clinical outcome measure. METHODS: PBA-s data for 517 participants from Enroll-HD were included in the Rasch analysis. Separate analyses were conducted for the severity and frequency items of the PBA-s, using RUMM2030 software. Achieving fit to the model provides supporting evidence that all items contribute to a single underlying latent trait. This property is defined as internal construct validity. RESULTS: The total PBA-s severity score demonstrated several important limitations, including disordered response categories for all 11 severity items, local dependency and poor targeting. However, modifying the original five-point scoring system to a four-point system resulted in ordered response categories for seven of the severity items and achieved a good overall fit to the Rasch model. For the total PBA-s frequency score, fit to the model was not achieved even after amendments to the scoring system. CONCLUSIONS: This study suggests that with reduction to a four-point scoring system, the total PBA-s severity score may be considered a valid clinical outcome measure. This study also suggests limitations in the use of a total PBA-s frequency score. PMID- 26756592 TI - Analysis of White Adipose Tissue Gene Expression Reveals CREB1 Pathway Altered in Huntington's Disease. AB - BACKGROUND: In addition to classical neurological symptoms, Huntington's disease (HD) is complicated by peripheral pathology and both the mutant gene and the protein are found in cells and tissues throughout the body. Despite the adipose tissue gene expression alterations described in HD mouse models, adipose tissue and its gene expression signature have not been previously explored in human HD. OBJECTIVE: We investigated gene expression signatures in subcutaneous adipose tissue obtained from control subjects, premanifest HD gene carriers and manifest HD subjects with the aim to identify gene expression changes and signalling pathway alterations in adipose tissue relevant to HD. METHODS: Gene expression was assessed using Affymetrix GeneChip(r) Human Gene 1.0 ST Array. Target genes were technically validated using real-time quantitative PCR and the expression signature was validated in an independent subject cohort. RESULTS: In subcutaneous adipose tissue, more than 500 genes were significantly different in premanifest HD subjects as compared to healthy controls. Pathway analysis suggests that the differentially expressed genes found here in HD adipose tissue are involved in fatty acid metabolism pathways, angiotensin signalling pathways and immune pathways. Transcription factor analysis highlights CREB1. Using RT qPCR, we found that MAL2, AGTR2, COBL and the transcription factor CREB1 were significantly upregulated, with CREB1 and AGT also being significantly upregulated in a separate cohort. CONCLUSIONS: Distinct gene expression profiles can be seen in HD subcutaneous adipose tissue, with CREB1 highlighted as a key transcription factor. PMID- 26756595 TI - Cassane Diterpenoids from the Pericarps of Caesalpinia bonduc. AB - Ten new cassane-type diterpenoids, caesalbonducins D-F (1-3), 6 deacetoxybonducellpin B (4), 3-acetoxy-alpha-caesalpin (5), 2(3)-en-alpha caesalpin (6), 1alpha-hydroxycaesalpinin J (7), 1alpha-hydroxy-6 decaetoxysalpinin J (8), 6alpha-hydroxycaesall M (9), and 6alpha-hydroxy-14(17) dehydrocaesalpin F (10), along with eight known compounds (11-18), were isolated from the pericarps of Caesalpinia bonduc. Compounds 1-3 and 11 are methyl migrated cassane-type diterpenoids with a 19(4->3)-cassane skeleton. The structures of 1-10 were elucidated on the basis of 1D and 2D NMR methods and other spectroscopic analysis. The neuroprotective effects of the isolated compounds were evaluated. PMID- 26756597 TI - Tribute to Professor Sun Lee--Experimental Microsurgery Pioneer. PMID- 26756598 TI - Repair of a Complicated Calvarial Defect: Reconstruction of an Infected Wound With rhBMP-2. AB - BACKGROUND: Management of the previously infected craniofacial defect remains a significant clinical challenge, posing obstacles such as wound healing complications, lack of donor site availability, and predisposition to failure of the repair. Optimal therapy would reconstruct like with like, without donor site morbidity. The purpose of this study was to compare the efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2)-mediated bone regeneration with the current standard of autologous bone graft for repair of previously infected calvarial defects. METHODS: Nineteen adult New Zealand white rabbits underwent subtotal calvariectomy. Bone flaps were inoculated with Staphylococcus aureus and replanted. After 1 week of infection, bone flaps were removed, and wounds were debrided, followed by 10 days of antibiotic treatment. After 6 weeks, animals underwent scar debridement followed by definitive reconstruction in 1 of 4 groups: empty control (n = 3), vehicle control (buffer solution on absorbable collagen sponge [ACS], n = 3), autologous bone graft (n = 3), or rhBMP-2 repair (rhBMP-2/ACS, n = 10). Animals underwent computed tomography imaging at 0, 2, 4, and 6 weeks postoperatively, followed by euthanization and histological analysis. Percent healing was determined by 3-dimensional analysis. A (time * group) 2-way analysis of variance was performed on healing versus treatment group and postoperative time. RESULTS: At 6 weeks postoperatively, rhBMP-2/ACS and autologous bone graft resulted in 93% and 68% healing, respectively, whereas the empty and vehicle control treatment resulted in 27% and 26% healing (P < 0.001). Histologically, compared to autologous bone graft, bone in the rhBMP-2/ACS group was more cellular and more consistently continuous with wound margins. CONCLUSIONS: The rhBMP-2 therapy is effective in achieving radiographic coverage of previously infected calvarial defects. PMID- 26756596 TI - Patterns of hippocampal atrophy differ among Alzheimer's disease, amnestic mild cognitive impairment, and late-life depression. AB - AIM: This study investigated whether the characteristic changes in hippocampal atrophy seen in coronal scans are useful for differentiating Alzheimer's disease (AD), amnestic mild cognitive impairment (aMCI), and major depressive disorder (MDD). METHODS: Subjects included 58 patients with AD, 33 with aMCI, 20 with MDD, and 22 normal controls, all aged 60 years or older. For each subject, eight coronal short TI inversion recovery images perpendicular to the hippocampal longitudinal axis were obtained. Images were manually measured using the conventional region of interest method of quantitative analysis. RESULTS: The overall trend in the corrected volumes of the hippocampus was AD < aMCI < MDD < normal controls. We found atrophy in all slices in AD, atrophy centred on the hippocampal head in aMCI, and atrophy in the slice of the hippocampal body 12 mm from the amygdala in MDD. CONCLUSIONS: The present study suggested that our method of comparing hippocampal atrophy by region may be useful in distinguishing AD, aMCI, MDD, and normal controls. PMID- 26756599 TI - Deep Inferior Epigastric Artery Perforator Flap Breast Reconstruction in Patients With Previous Bariatric Surgery: Is It Safe and Feasible? AB - BACKGROUND: Obesity is widely recognized as a major health concern and a leading cause of preventable death. The correlation between obesity and breast cancer has been thoroughly described by several authors. Bariatric surgery is often associated with redundant abdominal tissue, often leading patients to consider body-contouring procedures. Autologous tissue breast reconstruction using the deep inferior epigastric artery perforator (DIEP) flap has advantages because it is tissue that is normally discarded during postbariatric body contouring. METHODS: We conducted a retrospective chart review of 18 DIEP flaps performed by the senior author in 9 patients for breast reconstruction between February 2008 and May 2013. All patients underwent mastectomies. All patients underwent bariatric surgery preceding breast reconstruction. Breast reconstruction was performed immediately in 13 cases and delayed in 5 cases. RESULTS: Mean age of the study population was 44.6 years (range, 41-57 years). The mean maximum body mass index of the patients was 44 (range, 37.6-52.1), and the mean current body mass index at the time of the reconstruction was 30.7 (range, 24.3-38.1). No intraoperative complications were reported. No fascia or muscle was taken during flap dissection. Mean operative time was 632 minutes (range, from 480 to 750 minutes). Average hospital stay was 4 days. No partial or total flap loss was reported. There were no postoperative hernias or bulges at the abdominal donor site. CONCLUSIONS: This series represents the largest group of patients undergoing DIEP flap breast reconstruction after bariatric surgery. In the hands of experienced microsurgeons, breast reconstruction with the DIEP flap in postbariatric patients represents a low-risk option with high satisfaction. PMID- 26756600 TI - Avoiding Complications in Abdominal Wall Surgery: A Mathematical Model to Predict the Course of the Motor Innervation of the Rectus Abdominis. AB - Ever since its introduction, the transverse rectus abdominis myocutaneous flap has become the mainstay of autologous breast reconstruction. However, concerns regarding donor site morbidity due to the breach of abdominal wall musculature integrity soon followed. Muscle-sparing techniques, eventually eliminating the muscle from the flap all-together with the deep inferior epigastric artery perforator flap, did not eliminate the problem of abdominal wall weakness. This led to the conclusion that motor innervation might be at fault. Studies have shown that even in the presence of an intact rectus abdominis muscle, and an intact anterior rectus sheath, denervation of the rectus abdominis muscle results in significant abdominal wall weakness leading to superior and inferior abdominal bulges, and abdominal herniation. Our aim was to establish a mathematical model to predict the location of the motor innervation to the rectus abdominis muscle, and thus provide surgeons with a tool that will allow them to reduce abdominal morbidity during deep inferior epigastric artery perforator and free muscle sparing transverse rectus abdominis myocutaneous surgery. We dissected 42 cadaveric hemiabdomens and mapped the course of the thoracolumbar nerves. We then standardized and analyzed our findings and presented them as a relative map which can be adjusted to body type and dimensions. Our dissections show that the motor innervation is closely related to the lateral vascular supply. Thus, when possible, we support the preferred utilization of the medial vascular supply, and the preservation of the lateral supply and motor innervation. PMID- 26756602 TI - Intraoperative Adjustment of Eyelid Level in Aponeurotic Blepharoptosis Surgery. PMID- 26756601 TI - Drug-Induced Atrial Fibrillation Complicates the Results of Flap Surgery in a Rat Model. AB - The relationship between atrial fibrillation (AF) and flap survival has not been fully characterized. Therefore, the goal of this study was to investigate the effect of AF on survival areas of pedicled flap and survival rates of free flap in an experimental rat AF model. An aconitine-induced rat AF model was established without intubation anesthesia. Survival areas of the pedicled rectangular epigastric flap were compared between AF rats (n = 7) and control rats (n = 7), and survival rates of the free epigastric flap were compared between AF rats (n = 10) and control rats (n = 10). Animals that died during the study or in which AF was not induced were excluded from study. A total of 64 rats were assessed in this study. Atrial fibrillation was induced with a success rate of 77.8% (21/27) throughout the study. Pedicled flap survival area was significantly higher in controls (75.1 +/- 9.0%; n = 7) than that in AF animals (55.7 +/- 13.0%; n = 7) (P < 0.01, nonpaired Student t test). Free flap survival rates were 80% in controls and 40% in AF animals (P = 0.07, chi2 test). This is the first study to develop an aconitine-induced model of AF in rats. Atrial fibrillation has a detrimental effect on survival areas of the pedicled flap and survival rates of the free flap. PMID- 26756603 TI - Tissue Expander Complications Predict Permanent Implant Complications and Failure of Breast Reconstruction. PMID- 26756604 TI - Hepatitis E virus outbreak in postearthquake Nepal: is a vaccine really needed? PMID- 26756605 TI - In Diabetic Kidney Disease Urinary Exosomes Better Represent Kidney Specific Protein Alterations Than Whole Urine. AB - BACKGROUND: Predicting or diagnosing underlying kidney disease by analyzing whole urine remains the mainstay of nephrology practice. However, whole urine is a poor compartment to assess many structural changes in the kidney because whole urine contains only a few proteins derived from the kidney itself. Urinary exosomes, on the other hand, which are derived from the kidney, contain proteins secreted by the kidney. We experimentally tested the hypothesis that 'urinary exosomes more faithfully represent changes in the kidney tissue than whole urine'. A direct comparison between whole urine and urine exosomal levels of two chosen kidney disease markers, gelatinase and ceruloplasmin, was carried out on diabetic kidney disease patients. METHODS: Urinary exosomes were separated from whole urine by sequential centrifugation including ultra-centrifugation. Gelatinase activity was measured using fluorosceinated gelatin as the substrate, and ceruloplasmin was measured by sandwich ELISA. A few kidney specimens from patients biopsied for atypical features were histochemically stained for validation of the biochemical results. RESULTS: We found that changes in both, gelatinase (decreased activity) and ceruloplasmin (increased levels), in the urinary exosomes of diabetic kidney patients were in agreement with the alterations of these two proteins in the kidney tissue. In contrast, the levels of these two proteins in whole urine were highly variable and did not correlate with levels in the diabetic kidney tissue. CONCLUSION: In conclusion, these results confirmed our hypothesis that protein markers in urinary exosomes better reflected the underlying protein changes in the kidney than in whole urine samples. PMID- 26756607 TI - Rapid Self-Assembly of Shaped Microtiles into Large, Close-Packed Crystalline Monolayers on Solid Surfaces. AB - The rapid self-assembly of photolithographic microtiles into large crystalline monolayers is achieved. Crystalline monolayers get trapped at the liquid-liquid interface and re-emerge at the air-liquid interface by mixing a cosolvent, which then deposits on the solid surface in seconds. This method has the potential to assemble different shapes and sizes of microtiles into complex architectures. PMID- 26756608 TI - Locating Instantons in Calculations of Tunneling Splittings: The Test Case of Malonaldehyde. AB - The recently developed ring-polymer instanton (RPI) method [J. Chem. Phys. 2011, 134, 054109] is an efficient technique for calculating approximate tunneling splittings in high-dimensional molecular systems. The key step is locating the instanton tunneling-path at zero temperature. Here, we show that techniques previously designed for locating instantons in finite-temperature rate calculations can be adapted to the RPI method, where they become extremely efficient, reducing the number of potential energy calls by 2 orders of magnitude. We investigate one technique that employs variable time steps to minimize the action integral, and two that employ equally spaced position steps to minimize the abbreviated (i.e., Jacobi) action integral, using respectively the nudged elastic band (NEB) and string methods. We recommend use of the latter because it is parameter-free, but all three methods give comparable efficiency savings. Having located the instanton pathway, we then interpolate the instanton path onto a fine grid of imaginary time points, allowing us to compute the fluctuation prefactor. The crucial modification needed to the original finite temperature algorithms is to allow the end points of the zero-temperature instanton path to describe overall rotations, which is done using a standard quaternion algorithm. These approaches will allow the RPI method to be combined effectively with expensive potential energy surfaces or on-the-fly electronic structure methods. PMID- 26756606 TI - Collaborative Modeling of the Benefits and Harms Associated With Different U.S. Breast Cancer Screening Strategies. AB - BACKGROUND: Controversy persists about optimal mammography screening strategies. OBJECTIVE: To evaluate screening outcomes, taking into account advances in mammography and treatment of breast cancer. DESIGN: Collaboration of 6 simulation models using national data on incidence, digital mammography performance, treatment effects, and other-cause mortality. SETTING: United States. PATIENTS: Average-risk U.S. female population and subgroups with varying risk, breast density, or comorbidity. INTERVENTION: Eight strategies differing by age at which screening starts (40, 45, or 50 years) and screening interval (annual, biennial, and hybrid [annual for women in their 40s and biennial thereafter]). All strategies assumed 100% adherence and stopped at age 74 years. MEASUREMENTS: Benefits (breast cancer-specific mortality reduction, breast cancer deaths averted, life-years, and quality-adjusted life-years); number of mammograms used; harms (false-positive results, benign biopsies, and overdiagnosis); and ratios of harms (or use) and benefits (efficiency) per 1000 screens. RESULTS: Biennial strategies were consistently the most efficient for average-risk women. Biennial screening from age 50 to 74 years avoided a median of 7 breast cancer deaths versus no screening; annual screening from age 40 to 74 years avoided an additional 3 deaths, but yielded 1988 more false-positive results and 11 more overdiagnoses per 1000 women screened. Annual screening from age 50 to 74 years was inefficient (similar benefits, but more harms than other strategies). For groups with a 2- to 4-fold increased risk, annual screening from age 40 years had similar harms and benefits as screening average-risk women biennially from 50 to 74 years. For groups with moderate or severe comorbidity, screening could stop at age 66 to 68 years. LIMITATION: Other imaging technologies, polygenic risk, and nonadherence were not considered. CONCLUSION: Biennial screening for breast cancer is efficient for average-risk populations. Decisions about starting ages and intervals will depend on population characteristics and the decision makers' weight given to the harms and benefits of screening. PRIMARY FUNDING SOURCE: National Institutes of Health. PMID- 26756611 TI - Controlling amyloid fibril formation by partial stirring. AB - Many proteins undergoe self-assembly into fibrillar structures known as amyloid fibrils. During the self-assembly process, related structures known as spherulites can be formed. Herein we report a facile method where the balance between amyloid fibrils and spherulites can be controlled by stirring of the reaction mixture during the initial stages of the self-assembly process. Moreover, we report how this methodology can be used to prepare non-covalently functionalized amyloid fibrils. By stirring the reaction mixture continuously or for a limited time during the lag phase, the fibril length, and hence the propensity to form liquid crystalline phases, can be influenced. This phenomena is utilized in order to prepare films consisting of aligned protein fibrils incorporating the laser dye Nile red. The resulting films display polarized Nile red fluorescence. PMID- 26756609 TI - Global marine protected areas do not secure the evolutionary history of tropical corals and fishes. AB - Although coral reefs support the largest concentrations of marine biodiversity worldwide, the extent to which the global system of marine-protected areas (MPAs) represents individual species and the breadth of evolutionary history across the Tree of Life has never been quantified. Here we show that only 5.7% of scleractinian coral species and 21.7% of labrid fish species reach the minimum protection target of 10% of their geographic ranges within MPAs. We also estimate that the current global MPA system secures only 1.7% of the Tree of Life for corals, and 17.6% for fishes. Regionally, the Atlantic and Eastern Pacific show the greatest deficit of protection for corals while for fishes this deficit is located primarily in the Western Indian Ocean and in the Central Pacific. Our results call for a global coordinated expansion of current conservation efforts to fully secure the Tree of Life on coral reefs. PMID- 26756610 TI - Controlling Catalyst Bulk Reservoir Effects for Monolayer Hexagonal Boron Nitride CVD. AB - Highly controlled Fe-catalyzed growth of monolayer hexagonal boron nitride (h-BN) films is demonstrated by the dissolution of nitrogen into the catalyst bulk via NH3 exposure prior to the actual growth step. This "pre-filling" of the catalyst bulk reservoir allows us to control and limit the uptake of B and N species during borazine exposure and thereby to control the incubation time and h-BN growth kinetics while also limiting the contribution of uncontrolled precipitation-driven h-BN growth during cooling. Using in situ X-ray diffraction and in situ X-ray photoelectron spectroscopy combined with systematic growth calibrations, we develop an understanding and framework for engineering the catalyst bulk reservoir to optimize the growth process, which is also relevant to other 2D materials and their heterostructures. PMID- 26756612 TI - Conformation of membrane-bound proteins revealed by vacuum-ultraviolet circular dichroism and linear-dichroism spectroscopy. AB - Knowledge of the conformations of a water-soluble protein bound to a membrane is important for understanding the membrane-interaction mechanisms and the membrane mediated functions of the protein. In this study we applied vacuum-ultraviolet circular-dichroism (VUVCD) and linear-dichroism (LD) spectroscopy to analyze the conformations of alpha-lactalbumin (LA), thioredoxin (Trx), and beta lactoglobulin (LG) bound to phosphatidylglycerol liposomes. The VUVCD analysis coupled with a neural-network analysis showed that these three proteins have characteristic helix-rich conformations involving several helical segments, of which two amphiphilic or hydrophobic segments take part in interactions with the liposome. The LD analysis predicted the average orientations of these helix segments on the liposome: two amphiphilic helices parallel to the liposome surface for LA, two hydrophobic helices perpendicular to the liposome surface for Trx, and a hydrophobic helix perpendicular to and an amphiphilic helix parallel to the liposome surface for LG. This sequence-level information about the secondary structures and orientations was used to formulate interaction models of the three proteins at the membrane surface. This study demonstrates the validity of a combination of VUVCD and LD spectroscopy in conformational analyses of membrane-binding proteins, which are difficult targets for X-ray crystallography and nuclear magnetic resonance spectroscopy. PMID- 26756613 TI - Inflammatory cytokines and non-small cell lung cancer in a CT-scan screening cohort: Background review of the literature. AB - BACKGROUND: Inflammatory cytokines are at the intersection of tumor cell biology and host immune response. Peripheral cytokine expression levels may reflect the microscopic tumor milieu, and specific cytokines play an integral role in tumor initiation, growth, and metastasis. High-throughput cytokine analysis may identify panels for early-stage non-small cell lung cancer (NSCLC) diagnosis and identify individuals at high-risk for lung cancer with indeterminate lung nodules 8-20 mm in size. METHODS: Thirteen serum cytokines from the NYU Lung Cancer Biomarker Center cohort with early-stage NSCLC were analyzed using bead-based immunoassay technology. RESULTS: In the NYU cohort, a one unit increase in interferon-gamma increased risk of lung cancer by 3% (OR = 1.03, 95% CI, 1.02 1.05) and a one unit increase in TNF-alpha decreased the risk of lung cancer by 53% (OR = 0.47, 95% Cl, 0.31-0.71) when both cytokines were included in a logistic regression model with adjustments for age and pack-years of smoking. The resulting AUC for the Receiver Operating Characteristic (ROC) curve was 0.88; the sensitivity and specificity at the optimal cutpoint were 78.9% and 90.3%, respectively. CONCLUSIONS: Cytokines have limited value in the early diagnosis of early-stage NSCLC. Our review of the literature suggests that although inflammation is important for the development of NSCLC, that cytokines are increased in more advanced lung cancer than when the diagnosis occurs at presentation. PMID- 26756615 TI - Clinical and prognostic significance of Arl4c expression in colorectal cancer. AB - BACKGROUND: ADP-ribosylation factor (ARF)-like 4c (Arl4c) has been reported to promote tumorigenesis in colorectal and lung cancers and may represent a novel therapeutic target. The aim of this study was to investigate the expression of ADP-ribosylation factor (ARF)-like 4c (Arl4c) in colorectal cancer (CRC) in Chinese populations and an AOM/DSS-induced mouse colorectal carcinogenesis model, and its prognostic value in patients with CRC. MATERIALS AND METHODS: Expression of Arl4c in CRC patients and AOM/DSS-induced colorectal tumors was detected using immunohistochemistry and real- Real time PCR. In addition, the correlations between Arl4c expression and clinicopathological characteristics and overall survival were evaluated using Kaplan-Meier analysis. RESULTS: The Arl4c was statistically significantly overexpressed in CRC tissues relative to adjacent normal tissue (p= 0.001). CRC patients with high Arl4c expression tended to show poorer survival than patients with lower Arl4c expression (p= 0.069). However, the level of Arl4c expression was not visibly correlated with age, gender or tumor stage. In addition, increased expression of Arl4c was also found in AOM/DSS induced colorectal tumors (p= 0.001), which indicated that Arl4c might play an important role in colon tumorigenesis. CONCLUSIONS: Results indicated that overexpression of Arl4c might contribute to the tumorigenesis and might play a pivotal role in the progression of CRC. PMID- 26756614 TI - The association between preoperative serum CEA concentrations and synchronous liver metastasis in colorectal cancer patients. AB - OBJECTIVE: Liver is the primary site for the metastasis from colorectal cancer (CRC). It has been proposed that carcinoembryonic antigen (CEA) might have an instrumental role in the development of hepatic metastasis from human CRC. The aim of the present study was therefore to investigate the association between preoperative serum CEA concentrations and the incidence of synchronous CRC-liver metastasis. METHODS: A total of 199 patients with CRC who underwent radical surgery at the Shiraz University hospitals were enrolled in this study. The preoperative serum CEA levels of patients without distant metastasis were compared with those with hepatic metastasis and those with other organs metastasis at the time of initial diagnosis. RESULTS: Preoperative serum CEA concentrations were found to be significantly higher in patients with distant metastases compared to patients with local CRC (P < 0.001). Moreover, the mean serum CEA level in patients with liver metastasis was higher than non-metastasis group (42.89 ng/ml vs 9.62 ng/ml) (p < 0.001). We did not find significant differences in serum CEA concentrations between non-metastasis and the other organ metastasis groups (p> 0.05). CONCLUSIONS: We conclude that patients with high preoperative serum CEA levels should have more intensive follow-up for detection of synchronous liver metastasis. PMID- 26756616 TI - Fecal miR-29a and miR-224 as the noninvasive biomarkers for colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most common causes of cancer related death around the world. MicroRNAs (miRNAs) are small non-coding RNAs that often are abnormally expressed in tumors. Detection and quantitation of miRNAs may provide information for the screening and early diagnosis of CRC. OBJECTIVES: The objective of our study was to determine whether fecal microRNAs (miR-29a, miR 145, miR-223, miR-224) could be used as biomarkers for the screening and early diagnosis of colorectal cancer. METHODS: We carried out a retrospective analysis of the miRNAs in fecal samples from 80 CRC patients and 51 normal controls. The levels of 4 miRNAs (miR-29a, miR-145, miR-223, and miR-224) were quantitated using the SYBR Green miScript PCR system and 2( - Delta Delta Ct) method. RESULTS: Our data indicated that the expression levels of miR-29a (p< 0.001), miR 223 (p< 0.001) and miR-224 (p< 0.001) are significantly lower in feces from CRC patients than these from normal volunteers, whereas their miR-145 levels are not significantly different (p= 0.59). Interestingly, the level of miR-29a (p< 0.001) in feces from individuals with rectum cancer is also significantly higher than that from patients with colon cancer. CONCLUSION: There are reduced expression of miR-29a, miR-223, and miR-224 in the feces from the CRC patients, which could be an informative biomarker for screening and early diagnosis of CRC. PMID- 26756617 TI - Predictive value of plasma miRNA-718 for esophageal squamous cell carcinoma. AB - BACKGROUND: Increasing evidence demonstrated that circulating miRNAs could serve as meaningfully non-invasive and reliable biomarkers for the detection of various cancers. OBJECTIVE: To investigate the expression level of plasma miRNA-718 in esophageal squamous cell carcinoma (ESCC) patients and its diagnostic value. METHODS: Quantitative real time polymerase chain reaction (qRT-PCR) method was performed to examine the expression levels of plasma miRNA-718 in 120 consecutive ESCC patients and 51 healthy controls. The difference of plasma miRNA-718 expression level between the paired pre- and postoperative patients was compared. The correlation between plasma miRNA-718 expression levels and clinicopathological characteristics was further analyzed and the receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic power of plasma miRNA-718 for ESCC. RESULTS: Plasma miRNA-718 expression level of ESCC patients was significantly lower than that of healthy controls. Compared with preoperative patients, the plasma miRNA-718 expression level of postoperative patients was significantly upregulated. Plasma miRNA-718 expression level was inversely correlated with the lymph node metastasis and TNM stage. The ROC curve analysis showed that plasma miRNA-718 yielded AUCs of 0.715, 0.689 and 0.620 for the detection of ESCC patients, early patients with Tis-T1 or early patients with TNM 0-I, respectively. CONCLUSION: Plasma miRNA-718 is downregulated in ESCC patients and might serve as a potential diagnostic marker for ESCC. PMID- 26756619 TI - Clinicopathological significance of matrix metalloproteinase 2 protein expression in patients with renal cell carcinoma: A case-control study and meta-analysis. AB - BACKGROUND: Numerous previous studies explored the influence of matrix metalloproteinase 2 (MMP-2) expressions on renal cell carcinoma (RCC), yet inconsistent results were reported. OBJECTIVE: This study aims to derive a more precise estimation of the associations between MMP-2 and RCC. METHODS: A total of 115 patients with RCC were selected; meanwhile, 45 patients with traumatic rupture of renal cysts or renal calculi were recruited and normal kidney tissues were collected as control group. The expression level of MMP-2 protein was detected by using immunohistochemistry. A meta-analysis was performed by using Comprehensive Meta-analysis 2.0 (CMA 2.0). RESULTS: The positive expression rate of MMP-2 protein in the RCC tissues was evidently higher than that in the normal renal tissues (P < 0.001). The positive expression rate of MMP-2 protein in patients with tumor size > 5 cm, with lymph node metastasis (LNM), with well differentiated RCC, and stage III-IV RCC was significantly higher, compared with the patients with tumor size <= 5 cm, without LNM, with moderate/low differentiated RCC, and with stage I-II RCC, respectively (all P < 0.05). There was statistical significance in the 5-year survival rate between the patients with positive MMP-2 protein expression and those with negative MMP-2 protein expression (P = 0.037). These results were further confirmed by the meta analysis. CONCLUSION: MMP-2 protein expression is significantly associated with historical grade, TNM stage, tumor size and LNM in RCC, suggesting that MMP-2 may serve as a biological marker for the prognosis in RCC. PMID- 26756618 TI - Evaluation of the CD44 isoform v-6 (sCD44var, v6) in the saliva of patients with laryngeal carcinoma and its prognostic role. AB - BACKGROUND: The soluble fraction of the CD44 protein (solCD44) may constitute a valuable biological marker of Cancer Stem Cells (CSCs), useful for screening/early detection of laryngeal cancer, and for the prognosis. In previous papers, in fact, we have studied the expression of salivary solCD44 in patients with laryngeal tumors, supporting its use for early diagnosis of laryngeal carcinoma with high sensitivity and specificity, also with prognostic role, useful for clinical outcome. OBJECTIVE: The purpose of present study was to verify the levels of solCD44 isoform v6, sCD44var (v6), in saliva samples of patients with laryngeal carcinoma in our tumoral biobank, to evaluate possible correlations with clinical-anamnestic and prognostic data. METHODS: Study design was retrospective. Salivary samples of 66 patients with laryngeal cancer recruited from January 2012 to December 2013 were selected from our tumoral biobank. For each salivary sample was performed the determination of solCD44 and its isoform v6, sCD44var (v6), by ELISA. Qualitative and quantitative results of the test were correlated with clinical and medical history data. For statistical analysis we used the software MedCalc (versione 12.2.1.0). RESULTS: Concentrations of salivary sCD44var v6 were significantly higher according to the size of the primary tumor (T) (p= 0.001), the tumor site glottic or supraglottic transglottic (p= 0.005) and according to the metastatic lymph node involvement (p= 0005). Furthermore, tumors in advanced disease (stage III-IV) showed values of salivary sCD44var v6 higher than the tumors in early stage, with a statistically significant difference (p= 0.005). CONCLUSIONS: The determination of the levels of salivary solCD44 v6 may represent a promising prognostic test in laryngeal carcinomas. PMID- 26756620 TI - Long non-coding RNA HNF1A-AS is upregulated and promotes cell proliferation and metastasis in nasopharyngeal carcinoma. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is a common head and neck cancer with an incidence of 10-30 cases per 100,000 in southern China. Although primary treatment includes radiation therapy, prognosis is still unsatisfactory. OBJECTIVE: In this study, we examined the role of HNF1A-AS in NPC progression in vitro and in vivo. METHODS: Relative levels of long non-coding RNA (LncRNA), HNF1A-AS, were evaluated in tumor tissues from 20 patients with NPC as well as from cultured NPC cell lines. Lentivirus-mediated HNF1A-AS knockdown was conducted in NPC cell lines, CNE-2 and SUNE-1. Cell migration and invasion abilities were estimated in vitro by colony-formation, wound-healing, and transwell assays. Cell cycle analysis was used to further examine the role of HNF1A-AS in cell proliferation. The tumor size of 24 male mice with or without HNF1A-AS knockdown was monitored once a week. The underlying mechanism of HNF1A AS-mediated cell proliferation was studied by western blot analysis. RESULTS: Lentivirus-mediated HNF1A-AS knockdown suppressed cell proliferation and migration abilities. In mice injected with CNE-2 and SUNE-1, depletion of HNF1A AS caused inhibition of tumor growth, whereas cell cycle analysis showed that HNF1A-AS-knockdown resulted in cell accumulation in the G0/G1 phase. Moreover, HNF1A-AS was found to be associated with epithelial to mesenchymal transition. CONCLUSIONS: Overall, our results suggest that LncRNA, HNF1A-AS potentially regulates NPC tumorigenesis. This could help in development of new strategies for NPC diagnosis and treatment. PMID- 26756622 TI - Phase Space Bottlenecks in Enzymatic Reactions. AB - The definition of a transition state on an individual reactive trajectory is made via a committor analysis. In the past, the bottleneck definition has often been applied in configuration space. This is an approximation, and in order to expand this definition, we are revisiting an enzyme in which we had identified a fast subpicosecond motion that makes the reaction possible. First we used a time series analysis method to identify the exact time when this motion initiates donor-acceptor compression. Then we modified the standard committor analysis of transition path sampling to identify events in phase space and found that there is a dividing surface in phase space significantly earlier than the configurationally defined transition-state crossing. PMID- 26756621 TI - Intrinsic motivation as a mediator between metacognition deficits and impaired functioning in psychosis. AB - OBJECTIVE: Poor functioning has long been observed in individuals with psychosis. Recent studies have identified metacognition - one's ability to form complex ideas about oneself and others and to use that information to respond to psychological and social challenges-as being an important determinant of functioning. However, the exact process by which deficits in metacognition lead to impaired functioning remains unclear. This study first examined whether low intrinsic motivation, or the tendency to pursue novel experiences and to engage in self-improvement, mediates the relationship between deficits in metacognition and impaired functioning. We then examined whether intrinsic motivation significantly mediated the relationship when controlling for age, education, symptoms, executive functioning, and social cognition. DESIGN: Mediation models were examined in a cross-sectional data set. METHODS: One hundred and seventy five individuals with a psychotic disorder completed interview-based measures of metacognition, intrinsic motivation, symptoms, and functioning and performance based measures of executive functioning and social cognition. RESULTS: Analyses revealed that intrinsic motivation mediated the relationship between metacognition deficits and impaired functioning (95% CI of indirect effect [0.12 0.43]), even after controlling for the aforesaid variables (95% CI of indirect effect [0.04-0.29]). CONCLUSIONS: Results suggest that intrinsic motivation may be a mechanism that underlies the link between deficits in metacognition and impaired functioning and indicate that metacognition and intrinsic motivation may be important treatment targets to improve functioning in individuals with psychosis. PRACTITIONER POINTS: The findings of this study suggest that deficits in metacognition may indirectly lead to impaired functioning through their effect on intrinsic motivation in individuals with psychosis. Psychological treatments that target deficits in both metacognition and intrinsic motivation may help to alleviate impaired functioning in individuals with psychosis. LIMITATIONS: The cross-sectional design of this study is a limitation, and additional longitudinal studies are needed to confirm the direction of the findings and rule out rival hypotheses. Generalization of the findings may be limited by the sample composition. It may be that different relationships exist between metacognition, intrinsic motivation, and functioning in those with early psychosis or among those in an acute phase or who decline treatment. PMID- 26756623 TI - Feasibility and effectiveness of adding object-related bilateral symmetrical training to mirror therapy in chronic stroke: A randomized controlled pilot study. AB - PURPOSE: To evaluate the feasibility and effectiveness of adding object-related bilateral symmetrical training to mirror therapy (MT) to improve upper limb (UL) activity in chronic stroke patients. METHOD: Sixteen patients with moderate UL impairment were randomly allocated to either the experimental (EG) or control (CG) group. Both groups performed 1 hour sessions, 3 days/week for 4 weeks, involving object-related bilateral symmetrical training. EG performed the tasks observing their nonparetic UL reflected in the mirror, while CG observed the paretic UL directly. The primary outcome measure was unilateral and bilateral UL activity according to the Test d'Evaluation des Membres Superieurs de Personnes Agees (TEMPA). All measurements were taken at baseline, post-training, and follow up (2 weeks). RESULTS: TEMPA total score showed the main effect of time. Significant improvement was found for bilateral but not unilateral tasks. Both groups showed gains after training, with no differences between them. CONCLUSIONS: This study showed the feasibility of adding object-related bilateral training to MT. Both types of training improved UL bilateral activity; however, a larger sample is required for a definitive study. Other studies need to be carried out to evaluate the effectiveness of combining more distal-oriented movements and object-related unilateral training to improve these effects in chronic stroke patients. PMID- 26756625 TI - Cardiovascular Adaptations to Exercise Training. AB - Aerobic exercise training leads to cardiovascular changes that markedly increase aerobic power and lead to improved endurance performance. The functionally most important adaptation is the improvement in maximal cardiac output which is the result of an enlargement in cardiac dimension, improved contractility, and an increase in blood volume, allowing for greater filling of the ventricles and a consequent larger stroke volume. In parallel with the greater maximal cardiac output, the perfusion capacity of the muscle is increased, permitting for greater oxygen delivery. To accommodate the higher aerobic demands and perfusion levels, arteries, arterioles, and capillaries adapt in structure and number. The diameters of the larger conduit and resistance arteries are increased minimizing resistance to flow as the cardiac output is distributed in the body and the wall thickness of the conduit and resistance arteries is reduced, a factor contributing to increased arterial compliance. Endurance training may also induce alterations in the vasodilator capacity, although such adaptations are more pronounced in individuals with reduced vascular function. The microvascular net increases in size within the muscle allowing for an improved capacity for oxygen extraction by the muscle through a greater area for diffusion, a shorter diffusion distance, and a longer mean transit time for the erythrocyte to pass through the smallest blood vessels. The present article addresses the effect of endurance training on systemic and peripheral cardiovascular adaptations with a focus on humans, but also covers animal data. PMID- 26756624 TI - A Prototype Recombinant-Protein Based Chlamydia pecorum Vaccine Results in Reduced Chlamydial Burden and Less Clinical Disease in Free-Ranging Koalas (Phascolarctos cinereus). AB - Diseases associated with Chlamydia pecorum infection are a major cause of decline in koala populations in Australia. While koalas in care can generally be treated, a vaccine is considered the only option to effectively reduce the threat of infection and disease at the population level. In the current study, we vaccinated 30 free-ranging koalas with a prototype Chlamydia pecorum vaccine consisting of a recombinant chlamydial MOMP adjuvanted with an immune stimulating complex. An additional cohort of 30 animals did not receive any vaccine and acted as comparison controls. Animals accepted into this study were either uninfected (Chlamydia PCR negative) at time of initial vaccination, or infected (C. pecorum positive) at either urogenital (UGT) and/or ocular sites (Oc), but with no clinical signs of chlamydial disease. All koalas were vaccinated/sampled and then re-released into their natural habitat before re-capturing and re-sampling at 6 and 12 months. All vaccinated koalas produced a strong immune response to the vaccine, as indicated by high titres of specific plasma antibodies. The incidence of new infections in vaccinated koalas over the 12-month period post-vaccination was slightly less than koalas in the control group, however, this was not statistically significant. Importantly though, the vaccine was able to significantly reduce the infectious load in animals that were Chlamydia positive at the time of vaccination. This effect was evident at both the Oc and UGT sites and was stronger at 6 months than at 12 months post-vaccination. Finally, the vaccine was also able to reduce the number of animals that progressed to disease during the 12-month period. While the sample sizes were small (statistically speaking), results were nonetheless striking. This study highlights the potential for successful development of a Chlamydia vaccine for koalas in a wild setting. PMID- 26756626 TI - Fetal and Neonatal HPA Axis. AB - Stress is an integral part of life. Activation of the hypothalamus-pituitary adrenal (HPA) axis in the adult can be viewed as mostly adaptive to restore homeostasis in the short term. When stress occurs during development, and specifically during periods of vulnerability in maturing systems, it can significantly reprogram function, leading to pathologies in the adult. Thus, it is critical to understand how the HPA axis is regulated during developmental periods and what are the factors contributing to shape its activity and reactivity to environmental stressors. The HPA axis is not a passive system. It can actively participate in critical physiological regulation, inducing parturition in the sheep for instance or being a center stage actor in the preparation of the fetus to aerobic life (lung maturation). It is also a major player in orchestrating mental function, metabolic, and cardiovascular function often reprogrammed by stressors even prior to conception through epigenetic modifications of gametes. In this review, we review the ontogeny of the HPA axis with an emphasis on two species that have been widely studied-sheep and rodents because they each share many similar regulatory mechanism applicable to our understanding of the human HPA axis. The studies discussed in this review should ultimately inform us about windows of susceptibility in the developing brain and the crucial importance of early preconception, prenatal, and postnatal interventions designed to improve parental competence and offspring outcome. Only through informed studies will our public health system be able to curb the expansion of many stress-related or stress-induced pathologies and forge a better future for upcoming generations. PMID- 26756627 TI - Measuring Selection on Physiology in the Wild and Manipulating Phenotypes (in Terrestrial Nonhuman Vertebrates). AB - To understand why organisms function the way that they do, we must understand how evolution shapes physiology. This requires knowledge of how selection acts on physiological traits in nature. Selection studies in the wild allow us to determine how variation in physiology causes variation in fitness, revealing how evolution molds physiology over evolutionary time. Manipulating phenotypes experimentally in a selection study shifts the distribution of trait variation in a population to better explore potential constraints and the adaptive value of physiological traits. There is a large database of selection studies in the wild on a variety of traits, but very few of those are physiological traits. Nevertheless, data available so far suggest that physiological traits, including metabolic rate, thermal physiology, whole-organism performance, and hormone levels, are commonly subjected to directional selection in nature, with stabilizing and disruptive selection less common than predicted if physiological traits are optimized to an environment. Selection studies on manipulated phenotypes, including circulating testosterone and glucocorticoid levels, reinforce this notion, but reveal that trade-offs between survival and reproduction or correlational selection can constrain the evolution of physiology. More studies of selection on physiological traits in nature that quantify multiple traits are necessary to better determine the manner in which physiological traits evolve and whether different types of traits (dynamic performance vs. regulatory) evolve differently. PMID- 26756628 TI - Epigenetics/Programming in the HPA Axis. AB - The hypothalamic-pituitary-adrenal axis provides physiological adaptations to various environmental stimuli in mammals. These stimuli including maternal care, diet, immune challenge, stress, and others have the potential to stably modify or program the functioning of the HPA axis when experienced early in life or at later critical stages of development. Epigenetic mechanisms mediate the biological embedding of environmental stimuli or conditions. These changes are influenced by the genotype and both, environment and genotype contribute to the development of a specific phenotype with regard to the stress response that might be more susceptible or resilient to the development of mental conditions. The effects of stress might be a result of cumulative stress or a mismatch between the environments experienced early in life versus the conditions much later. These effects including the associated epigenetic modifications are potentially reversible. PMID- 26756629 TI - Mechanics of Vascular Smooth Muscle. AB - Vascular smooth muscle (VSM; see Table 1 for a list of abbreviations) is a heterogeneous biomaterial comprised of cells and extracellular matrix. By surrounding tubes of endothelial cells, VSM forms a regulated network, the vasculature, through which oxygenated blood supplies specialized organs, permitting the development of large multicellular organisms. VSM cells, the engine of the vasculature, house a set of regulated nanomotors that permit rapid stress-development, sustained stress-maintenance and vessel constriction. Viscoelastic materials within, surrounding and attached to VSM cells, comprised largely of polymeric proteins with complex mechanical characteristics, assist the engine with countering loads imposed by the heart pump, and with control of relengthening after constriction. The complexity of this smart material can be reduced by classical mechanical studies combined with circuit modeling using spring and dashpot elements. Evaluation of the mechanical characteristics of VSM requires a more complete understanding of the mechanics and regulation of its biochemical parts, and ultimately, an understanding of how these parts work together to form the machinery of the vascular tree. Current molecular studies provide detailed mechanical data about single polymeric molecules, revealing viscoelasticity and plasticity at the protein domain level, the unique biological slip-catch bond, and a regulated two-step actomyosin power stroke. At the tissue level, new insight into acutely dynamic stress-strain behavior reveals smooth muscle to exhibit adaptive plasticity. At its core, physiology aims to describe the complex interactions of molecular systems, clarifying structure-function relationships and regulation of biological machines. The intent of this review is to provide a comprehensive presentation of one biomachine, VSM. PMID- 26756631 TI - Pathophysiology of Heart Failure. AB - Heart failure is considered an epidemic disease in the modern world affecting approximately 1% to 2% of adult population. It presents a multifactorial, systemic disease, in which--after cardiac injury--structural, neurohumoral, cellular, and molecular mechanisms are activated and act as a network to maintain physiological functioning. These coordinated, complex processes lead to excessive volume overload, increased sympathetic activity, circulation redistribution, and result in different, parallel developing clinical signs and symptoms. These signs and symptoms sum up to an unspecific clinical picture; thus invasive and noninvasive diagnostic tools are used to get an accurate diagnosis and to specify the underlying cause. The most important, outcome determining factor in heart failure is its constant progression. Constant optimizing of pharmatherapeutical regimes, novel targets, and fine regulation of these processes try to keep these compensatory mechanisms in a physiological range. Beside pharmacological therapy, interventional and surgical therapy options give new chances in the management of heart failure. For the optimization and establishment of these and novel therapeutical approaches, complete and comprehensive understanding of the underlying mechanisms is essentially needed. Besides diagnosis and treatment, efforts should be made for better prevention in heart failure by treatment of risk factors, or identifying and following risk groups. This summary of the pathophysiology of heart failure tries to give a compact overview of basic mechanisms and of the novel unfolding, progressive theory of heart failure to contribute to a more comprehensive knowledge of the disease. PMID- 26756632 TI - Salt, Angiotensin II, Superoxide, and Endothelial Function. AB - Proper function of the vascular endothelium is essential for cardiovascular health, in large part due to its antiproliferative, antihypertrophic, and anti inflammatory properties. Crucial to the protective role of the endothelium is the production and liberation of nitric oxide (NO), which not only acts as a potent vasodilator, but also reduces levels of reactive oxygen species, including superoxide anion (O2*-). Superoxide anion is highly injurious to the vasculature because it not only scavenges NO molecules, but has other damaging effects, including direct oxidative disruption of normal signaling mechanisms in the endothelium and vascular smooth muscle cells. The renin-angiotensin system plays a crucial role in the maintenance of normal blood pressure. This function is mediated via the peptide hormone angiotensin II (ANG II), which maintains normal blood volume by regulating Na+ excretion. However, elevation of ANG II above normal levels increases O2*- production, promotes oxidative stress and endothelial dysfunction, and plays a major role in multiple disease conditions. Elevated dietary salt intake also leads to oxidant stress and endothelial dysfunction, but these occur in the face of salt-induced ANG II suppression and reduced levels of circulating ANG II. While the effects of abnormally high levels of ANG II have been extensively studied, far less is known regarding the mechanisms of oxidant stress and endothelial dysfunction occurring in response to chronic exposure to abnormally low levels of ANG II. The current article focuses on the mechanisms and consequences of this less well understood relationship among salt, superoxide, and endothelial function. PMID- 26756633 TI - Thermal Indices and Thermophysiological Modeling for Heat Stress. AB - The assessment of the risk of human exposure to heat is a topic as relevant today as a century ago. The introduction and use of heat stress indices and models to predict and quantify heat stress and heat strain has helped to reduce morbidity and mortality in industrial, military, sports, and leisure activities dramatically. Models used range from simple instruments that attempt to mimic the human-environment heat exchange to complex thermophysiological models that simulate both internal and external heat and mass transfer, including related processes through (protective) clothing. This article discusses the most commonly used indices and models and looks at how these are deployed in the different contexts of industrial, military, and biometeorological applications, with focus on use to predict related thermal sensations, acute risk of heat illness, and epidemiological analysis of morbidity and mortality. A critical assessment is made of tendencies to use simple indices such as WBGT in more complex conditions (e.g., while wearing protective clothing), or when employed in conjunction with inappropriate sensors. Regarding the more complex thermophysiological models, the article discusses more recent developments including model individualization approaches and advanced systems that combine simulation models with (body worn) sensors to provide real-time risk assessment. The models discussed in the article range from historical indices to recent developments in using thermophysiological models in (bio) meteorological applications as an indicator of the combined effect of outdoor weather settings on humans. PMID- 26756634 TI - Neural Control of Vascular Function in Skeletal Muscle. AB - The sympathetic nervous system represents a fundamental homeostatic system that exerts considerable control over blood pressure and the distribution of blood flow. This process has been referred to as neurovascular control. Overall, the concept of neurovascular control includes the following elements: efferent postganglionic sympathetic nerve activity, neurotransmitter release, and the end organ response. Each of these elements reflects multiple levels of control that, in turn, affect complex patterns of change in vascular contractile state. Primarily, this review discusses several of these control layers that combine to produce the integrative physiology of reflex vascular control observed in skeletal muscle. Beginning with three reflexes that provide somewhat dissimilar vascular patterns of response despite similar changes in efferent sympathetic nerve activity, namely, the baroreflex, chemoreflex, and muscle metaboreflex, the article discusses the anatomical and physiological bases of postganglionic sympathetic discharge patterns and recruitment, neurotransmitter release and management, and details of regional variations of receptor density and responses within the microvascular bed. Challenges are addressed regarding the fundamentals of measurement and how conclusions from one response or vascular segment should not be used as an indication of neurovascular control as a generalized physiological dogma. Whereas the bulk of the article focuses on the vasoconstrictor function of sympathetic neurovascular integration, attention is also given to the issues of sympathetic vasodilation as well as the impact of chronic changes in sympathetic activation and innervation on vascular health. (c) 2016 American Physiological Society. PMID- 26756630 TI - Pathophysiological Functions of Rnd3/RhoE. AB - Rnd3, also known as RhoE, belongs to the Rnd subclass of the Rho family of small guanosine triphosphate (GTP)-binding proteins. Rnd proteins are unique due to their inability to switch from a GTP-bound to GDP-bound conformation. Even though studies of the biological function of Rnd3 are far from being concluded, information is available regarding its expression pattern, cellular localization, and its activity, which can be altered depending on the conditions. The compiled data from these studies implies that Rnd3 may not be a traditional small GTPase. The basic role of Rnd3 is to report as an endogenous antagonist of RhoA signaling mediated actin cytoskeleton dynamics, which specifically contributes to cell migration and neuron polarity. In addition, Rnd3 also plays a critical role in arresting cell cycle distribution, inhibiting cell growth, and inducing apoptosis and differentiation. Increasing data have shown that aberrant Rnd3 expression may be the leading cause of some systemic diseases; particularly highlighted in apoptotic cardiomyopathy, developmental arrhythmogenesis and heart failure, hydrocephalus, as well as tumor metastasis and chemotherapy resistance. Therefore, a better understanding of the function of Rnd3 under different physiological and pathological conditions, through the use of suitable models, would provide a novel insight into the origin and treatment of multiple human diseases. PMID- 26756636 TI - Thyroid Hormone, Hormone Analogs, and Angiogenesis. AB - Modulation by thyroid hormone and hormone analogs of angiogenesis in the heart after experimental infarction, and in other organs, has been appreciated for decades. Description of a plasma membrane receptor for thyroid hormone on the extracellular domain of integrin alphavbeta3 on endothelial cells has revealed the complexity of the nongenomic regulation of angiogenesis by the hormone. From alphavbeta3, the hormone directs transcription of specific vascular growth factor genes, regulates growth factor receptor/growth factor interactions and stimulates endothelial cell migration to a vitronectin cue; these actions are implicated experimentally in tumor-relevant angiogenesis and angioproliferative pulmonary hypertension. Derived from L-thyroxine (T4), tetraiodothyroacetic acid (tetrac) can be covalently bound to a polymer and as Nanotetrac acts exclusively at the hormone receptor on alphavbeta3 to block actions of T4 and 3,5,3'-triiodo-L thyronine (T3) on angiogenesis. Other antiangiogenic actions of Nanotetrac include disruption of crosstalk between integrin alphavbeta3 and adjacent cell surface vascular growth factor receptors, resulting in disordered vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF; FGF2) actions at their respective plasma membrane receptors. From alphavbeta3, Nanotetrac also downregulates expression of VEGFA and epidermal growth factor receptor (EGFR) genes, upregulates transcription of the angiogenesis suppressor gene, thrombospondin 1 (THBS1; TSP1) and decreases cellular abundance of Ang-2 protein and matrix metalloproteinase-9. Existence of this receptor provides new insights into the multiple mechanisms by which thyroid hormone and hormone analogs may regulate angiogenesis at the molecular level. The receptor also offers pharmacological opportunities for interruption of pathological angiogenesis via integrin alphavbeta3. PMID- 26756637 TI - Evolution, Development, and Function of the Pulmonary Surfactant System in Normal and Perturbed Environments. AB - Surfactant lipids and proteins form a surface active film at the air-liquid interface of internal gas exchange organs, including swim bladders and lungs. The system is uniquely positioned to meet both the physical challenges associated with a dynamically changing internal air-liquid interface, and the environmental challenges associated with the foreign pathogens and particles to which the internal surface is exposed. Lungs range from simple, transparent, bag-like units to complex, multilobed, compartmentalized structures. Despite this anatomical variability, the surfactant system is remarkably conserved. Here, we discuss the evolutionary origin of the surfactant system, which likely predates lungs. We describe the evolution of surfactant structure and function in invertebrates and vertebrates. We focus on changes in lipid and protein composition and surfactant function from its antiadhesive and innate immune to its alveolar stability and structural integrity functions. We discuss the biochemical, hormonal, autonomic, and mechanical factors that regulate normal surfactant secretion in mature animals. We present an analysis of the ontogeny of surfactant development among the vertebrates and the contribution of different regulatory mechanisms that control this development. We also discuss environmental (oxygen), hormonal and biochemical (glucocorticoids and glucose) and pollutant (maternal smoking, alcohol, and common "recreational" drugs) effects that impact surfactant development. On the adult surfactant system, we focus on environmental variables including temperature, pressure, and hypoxia that have shaped its evolution and we discuss the resultant biochemical, biophysical, and cellular adaptations. Finally, we discuss the effect of major modern gaseous and particulate pollutants on the lung and surfactant system. PMID- 26756639 TI - Cold Stress Effects on Exposure Tolerance and Exercise Performance. AB - Cold weather can have deleterious effects on health, tolerance, and performance. This paper will review the physiological responses and external factors that impact cold tolerance and physical performance. Tolerance is defined as the ability to withstand cold stress with minimal changes in physiological strain. Physiological and pathophysiological responses to short-term (cold shock) and long-term cold water and air exposure are presented. Factors (habituation, anthropometry, sex, race, and fitness) that influence cold tolerance are also reviewed. The impact of cold exposure on physical performance, especially aerobic performance, has not been thoroughly studied. The few studies that have been done suggest that aerobic performance is degraded in cold environments. Potential physiological mechanisms (decreases in deep body and muscle temperature, cardiovascular, and metabolism) are discussed. Likewise, strength and power are also degraded during cold exposure, primarily through a decline in muscle temperature. The review also discusses the concept of thermoregulatory fatigue, a reduction in the thermal effector responses of shivering and vasoconstriction, as a result of multistressor factors, including exhaustive exercise. PMID- 26756640 TI - Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging. AB - The importance of homocysteine in vascular function and arteriosclerosis was discovered by demonstration of arteriosclerotic plaques in children with homocystinuria caused by inherited enzymatic deficiencies of cystathionine synthase, methionine synthase, or methylene-tetrahydrofolate reductase. According to the homocysteine theory of arteriosclerosis, an elevated blood homocysteine level is an important risk factor for atherosclerosis in subjects without these rare enzymatic abnormalities. The homocysteine theory is supported by demonstration of arterial plaques in experimental animals with hyperhomocysteinemia, by discovery of a pathway for conversion of homocysteine thiolactone to sulfate in cell cultures from children with homocystinuria, and by demonstration of growth promotion by homocysteic acid in normal and hypophysectomized animals. Studies with cultured malignant cells revealed abnormal homocysteine thiolactone metabolism, resulting in homocysteinylation of proteins, nucleic acids, and glycosaminoglycans, explaining the abnormal oxidative metabolism, abnormalities of cellular membranes, and altered genetic expression observed in malignancy. Abnormal homocysteine metabolism in malignant cells is attributed to deficiency of thioretinamide, the amide synthesized from retinoic acid and homocysteine thiolactone. Two molecules of thioretinamide combine with cobalamin to form thioretinaco. Based on the molecular structure of thioretinaco, a theory of oxidative phosphorylation was proposed, involving oxidation to a disulfonium derivative by ozone, and binding of oxygen, nicotinamide adenine dinucleotide and phosphate as the active site of adenosine triphosphate synthesis in mitochondria. Obstruction of vasa vasorum by aggregates of microorganisms with homocysteinylated low-density lipoproteins is proposed to cause ischemia of arterial wall and a microabscess of the intima, the vulnerable atherosclerotic plaque. PMID- 26756638 TI - Cytochrome P450 and Lipoxygenase Metabolites on Renal Function. AB - Arachidonic acid metabolites have a myriad of biological actions including effects on the kidney to alter renal hemodynamics and tubular transport processes. Cyclooxygenase metabolites are products of an arachidonic acid enzymatic pathway that has been extensively studied in regards to renal function. Two lesser-known enzymatic pathways of arachidonic acid metabolism are the lipoxygenase (LO) and cytochrome P450 (CYP) pathways. The importance of LO and CYP metabolites to renal hemodynamics and tubular transport processes is now being recognized. LO and CYP metabolites have actions to alter renal blood flow and glomerular filtration rate. Proximal and distal tubular sodium transport and fluid and electrolyte homeostasis are also significantly influenced by renal CYP and LO levels. Metabolites of the LO and CYP pathways also have renal actions that influence renal inflammation, proliferation, and apoptotic processes at vascular and epithelial cells. These renal LO and CYP pathway actions occur through generation of specific metabolites and cell-signaling mechanisms. Even though the renal physiological importance and actions for LO and CYP metabolites are readily apparent, major gaps remain in our understanding of these lipid mediators to renal function. Future studies will be needed to fill these major gaps regarding LO and CYP metabolites on renal function. PMID- 26756642 TI - Extracellular Ubiquitin: Role in Myocyte Apoptosis and Myocardial Remodeling. AB - Ubiquitin (UB) is a highly conserved low molecular weight (8.5 kDa) protein. It consists of 76 amino acid residues and is found in all eukaryotic cells. The covalent linkage of UB to a variety of cellular proteins (ubiquitination) is one of the most common posttranslational modifications in eukaryotic cells. This modification generally regulates protein turnover and protects the cells from damaged or misfolded proteins. The polyubiquitination of proteins serves as a signal for degradation via the 26S proteasome pathway. UB is present in trace amounts in body fluids. Elevated levels of UB are described in the serum or plasma of patients under a variety of conditions. Extracellular UB is proposed to have pleiotropic roles including regulation of immune response, anti inflammatory, and neuroprotective activities. CXCR4 is identified as receptor for extracellular UB in hematopoietic cells. Heart failure represents a major cause of morbidity and mortality in western society. Cardiac remodeling is a determinant of the clinical course of heart failure. The components involved in myocardial remodeling include-myocytes, fibroblasts, interstitium, and coronary vasculature. Increased sympathetic nerve activity in the form of norepinephrine is a common feature during heart failure. Acting via beta-adrenergic receptor (beta-AR), norepinephrine is shown to induce myocyte apoptosis and myocardial fibrosis. beta-AR stimulation increases extracellular levels of UB in myocytes, and UB inhibits beta-AR-stimulated increases in myocyte apoptosis and myocardial fibrosis. This review summarizes intracellular and extracellular functions of UB with particular emphasis on the role of extracellular UB in cardiac myocyte apoptosis and myocardial remodeling. PMID- 26756644 TI - Creation of a Hybrid Scaffold with Dual Configuration of Aligned and Random Electrospun Fibers. AB - A novel hybrid construct was developed by combining aligned fibers (AFs) and random fibers (RFs) to form a scaffolding system. Homogeneous fiber-based structures were fabricated by electrospinning, which produced both random and aligned fiber mats depending on the collection method. The upper part of the scaffold contained an AF layer, which possessed a well-organized configuration that provided uniaxial topographic guidance. For mechanical stability and support, the lower part of the scaffold was composed of an RF layer. Despite the presence of randomly distributed RFs, desirable alignment and differentiation could be achieved in cultured C2C12 myoblasts by controlling the density of AF layer. The fibrous structure of the hybrid scaffold also exhibited high porosity and therefore reasonable permeability. Owing to the structural stability provided by the underlying RFs, the cell-laden fibrous scaffolds were amenable to physical manipulation, such as multilayering. Collectively, the morphological features and manipulable architecture of the developed scaffolds suggest that they would perform well in practical applications. PMID- 26756643 TI - Intra-Arterial Chemotherapy (Ophthalmic Artery Chemosurgery) for Group D Retinoblastoma. AB - PURPOSE: To report globe salvage rates, patient survival and adverse events of ophthalmic artery chemosurgery (OAC) for International Classification of Retinoblastoma (ICRB) group D retinoblastoma (naive and after prior failures). METHODS: Single institution retrospective review of all Group D eyes treated with OAC from 5/2006-12/2012. Patients were treated according to our previously published techniques. Primary outcome was globe retention without need for external beam radiotherapy (EBRT). Demographics, prior treatments, OAC agents used, and adverse events were also recorded. RESULTS: 112 group D eyes (103 patients) that underwent OAC were included (average follow-up was 34 months, range: 2-110 months). 47 eyes were treatment-naive, 58 eyes received prior treatments elsewhere, and 7 young infants (7 eyes) underwent our published "bridge therapy" (single agent intravenous carboplatin) until old enough to undergo OAC. Median number of OAC sessions/eye was 3 (range 1-9). 110/112 eyes received intra-arterial melphalan, but only 31 eyes received melphalan alone. 43 eyes received carboplatin, and 78 eyes received topotecan (never as a single agent). 80/112 eyes received >1 drug over their treatment course, and 39 eyes received all three agents. 24 eyes (16 pretreated, 7 treatment-naive, 1 bridge) failed treatment and required enucleation during the study period. Enucleation and EBRT were avoided in 88/112 eyes (78.6%; including 40/47 [85.1%] treatment naive eyes, 42/58 [72.4%] previously-treated eyes, and 6/7 eyes [85.7%] among bridge patients). By Kaplan-Meier survival analysis, globe salvage rate was 74% at 110 months among all patients, and 85% at 110 months in the treatment-naive subgroup. Transient grade 3/4 neutropenia was more common in patients receiving OAC bilaterally. No child died of metastatic disease. CONCLUSIONS: OAC is effective for curing group D retinoblastoma, achieving rates of globe salvage many times higher than systemic chemotherapy (10-47%), even in eyes that previously failed other treatments. OAC can be performed multiple times, using multiple agents, on one or both eyes of patients. PMID- 26756645 TI - Static and Dynamical Structural Investigations of Metal-Oxide Nanocrystals by Powder X-ray Diffraction: Colloidal Tungsten Oxide as a Case Study. AB - We have developed a general X-ray powder diffraction (XPD) methodology for the simultaneous structural and compositional characterization of inorganic nanomaterials. The approach is validated on colloidal tungsten oxide nanocrystals (WO3-x NCs), as a model polymorphic nanoscale material system. Rod-shaped WO3-x NCs with different crystal structure and stoichiometry are comparatively investigated under an inert atmosphere and after prolonged air exposure. An initial structural model for the as-synthesized NCs is preliminarily identified by means of Rietveld analysis against several reference crystal phases, followed by atomic pair distribution function (PDF) refinement of the best-matching candidates (static analysis). Subtle stoichiometry deviations from the corresponding bulk standards are revealed. NCs exposed to air at room temperature are monitored by XPD measurements at scheduled time intervals. The static PDF analysis is complemented with an investigation into the evolution of the WO3-x NC structure, performed by applying the modulation enhanced diffraction technique to the whole time series of XPD profiles (dynamical analysis). Prolonged contact with ambient air is found to cause an appreciable increase in the static disorder of the O atoms in the WO3-x NC lattice, rather than a variation in stoichiometry. The time behavior of such structural change is identified on the basis of multivariate analysis. PMID- 26756646 TI - PD-L1 and Lung Cancer: The Era of Precision-ish Medicine? AB - The success of immune checkpoint inhibitor therapy in lung cancer, both in squamous and nonsquamous non-small cell carcinoma, has led to US Food and Drug Administration approval for 2 medications that have as part of their prescribing information an associated immunohistochemistry-based companion or complementary diagnostic test for programmed death ligand-1 (PD-L1). The intense interest in drug development in this area has resulted in additional agents with associated diagnostics looming on the horizon in 2016. In the era of precision medicine, the paradigm of paired molecular target and molecular test, which serves as a model of oncogenic mutation-driven cancer therapy, is challenged by the proliferation of immunohistochemistry-based tests with different antibodies, instruments, and scoring. The difficulty inherent to targeted therapy aimed at a moving target is discussed, as well as the emerging challenges to pathologists and oncologists who seek to optimize care in this complex therapeutic arena. PMID- 26756641 TI - Mitochondrial Dynamics and Heart Failure. AB - Mitochondrial dynamics, fission and fusion, were first identified in yeast with investigation in heart cells beginning only in the last 5 to 7 years. In the ensuing time, it has become evident that these processes are not only required for healthy mitochondria, but also, that derangement of these processes contributes to disease. The fission and fusion proteins have a number of functions beyond the mitochondrial dynamics. Many of these functions are related to their membrane activities, such as apoptosis. However, other functions involve other areas of the mitochondria, such as OPA1's role in maintaining cristae structure and preventing cytochrome c leak, and its essential (at least a 10 kDa fragment of OPA1) role in mtDNA replication. In heart disease, changes in expression of these important proteins can have detrimental effects on mitochondrial and cellular function. PMID- 26756648 TI - It's Our Turn: Implications for Pathology From the Institute of Medicine's Report on Diagnostic Error. PMID- 26756647 TI - Programmed Death Ligand-1 Immunohistochemistry: Friend or Foe? AB - The approval of anti-programmed death receptor (PD)-1 therapies for non-small cell lung cancer has directed the spotlight on programmed death ligand-1 (PD-L1) immunohistochemistry as the latest predictive biomarker potentially required in this disease. Several other drugs in this class will likely be approved in the future and each has been developed with a unique anti-PD-L1 immunohistochemistry test. The prospect of 5 drugs competing in the same treatment area, each possibly requiring PD-L1 immunohistochemistry testing, presents a challenge for pathologists unlike any previously faced. The key issue is whether laboratories will attempt to deliver the trial-validated assays for one or more of these treatments, or introduce instead one or more laboratory developed tests, or attempt to provide a single PD-L1 immunohistochemistry assay for all possible anti-PD-1 and anti-PD-L1 treatments that may be used. This paper discusses some of the issues, challenges, hazards, and possible solutions that have recently emerged in this most complex interface between cancer therapeutics and laboratory biomarker testing. PMID- 26756635 TI - Glucose Transporters in Cardiac Metabolism and Hypertrophy. AB - The heart is adapted to utilize all classes of substrates to meet the high-energy demand, and it tightly regulates its substrate utilization in response to environmental changes. Although fatty acids are known as the predominant fuel for the adult heart at resting stage, the heart switches its substrate preference toward glucose during stress conditions such as ischemia and pathological hypertrophy. Notably, increasing evidence suggests that the loss of metabolic flexibility associated with increased reliance on glucose utilization contribute to the development of cardiac dysfunction. The changes in glucose metabolism in hypertrophied hearts include altered glucose transport and increased glycolysis. Despite the role of glucose as an energy source, changes in other nonenergy producing pathways related to glucose metabolism, such as hexosamine biosynthetic pathway and pentose phosphate pathway, are also observed in the diseased hearts. This article summarizes the current knowledge regarding the regulation of glucose transporter expression and translocation in the heart during physiological and pathological conditions. It also discusses the signaling mechanisms governing glucose uptake in cardiomyocytes, as well as the changes of cardiac glucose metabolism under disease conditions. PMID- 26756649 TI - Prostate Cancer Grading: A Decade After the 2005 Modified Gleason Grading System. AB - Since 1966, when Donald Gleason, MD, first proposed grading prostate cancer based on its histologic architecture, there have been numerous changes in clinical and pathologic practices relating to prostate cancer. Patterns 1 and 2, comprising more than 30% of cases in the original publications by Gleason, are no longer reported on biopsy and are rarely diagnosed on radical prostatectomy. Many of these cases may even have been mimickers of prostate cancer that were described later with the use of contemporary immunohistochemistry. The original Gleason system predated many newly described variants of prostate cancer and our current concept of intraductal carcinoma. Gleason also did not describe how to report prostate cancer on biopsy with multiple cores of cancer or on radical prostatectomy with separate tumor nodules. To address these issues, the International Society of Urological Pathology first made revisions to the grading system in 2005, and subsequently in 2014. Additionally, a new grading system composed of Grade Groups 1 to 5 that was first developed in 2013 at the Johns Hopkins Hospital and subsequently validated in a large multi-institutional and multimodal study was presented at the 2014 International Society of Urological Pathology meeting and accepted both by participating pathologists as well as urologists, oncologists, and radiation therapists. In the present study, we describe updates to the grading of prostate cancer along with the new grading system. PMID- 26756650 TI - Genotyping of clinical and environmental Aspergillus flavus isolates from Iran using microsatellites. AB - Aspergillus flavus is the second most important Aspergillus species causing human infections in tropical countries. Despite an increasing number of infections of A. flavus in Iran, the molecular epidemiology of clinical and environmental strains has not been well studied. We used a panel of nine microsatellite markers to analyse the genetic relatedness of A. flavus. Microsatellite typing of 143 (n = 119 clinical and n = 24 environmental) isolates demonstrated 118 different genotypes. A possible outbreak at a pulmonary ward was discovered. The discriminatory power for the individual markers ranged from 0.4812 to 0.9457 and the panel of all nine markers combined yielded a diversity index of 0.9948. This high-resolution typing method assists in better understanding of the molecular epidemiology of A. flavus. PMID- 26756651 TI - [Clinical status in Otolaryngology--ear and nose]. PMID- 26756652 TI - [Tips & Tricks--epistaxis management in consideration of contamination]. PMID- 26756653 TI - [Optimal Postoperative Pain Management After Tonsillectomy: An Unsolved Problem]. AB - Tonsillectomy is one of the most painful surgical procedures. Unfortunately, it is not unusual that the patient hear statement like: "There is no way around" or "You receive already enough pain killers". Asking the anesthetist or the otorhinolaryngologist, one may get to hear: "Pain after tonsillectomy is not a real problem. We have a reliable pain management protocol". In contradiction, many clinical studies are showing that many patients have persistent and even severe pain after tonsillectomy despite postoperative pain therapy. Considering the results of many controlled clinical trials analyzing manifold varieties of pain management regimes it becomes obvious that there is no standard pain therapy after tonsillectomy with reliable proof of sufficient pain suppression. This review wants to give an overview on the current status of clinical research on pain measurement methods and pain management after tonsillectomy. PMID- 26756654 TI - [A Rare Cause of Nasal Congestion]. PMID- 26756655 TI - [A bluish sublimity of pharyngeal wall]. PMID- 26756656 TI - [Obituary of Prof. Dr med. Klaus Jahnke]. PMID- 26756657 TI - [From the Expert's Office: The Scale of Graz--Examination of Bell's Palsy in Consideration of the Principles of the Austrian Social Accident Insurance]. PMID- 26756658 TI - [Surgery of the nose and paranasal sinuses]. AB - A compromised overview of surgical techniques regarding the nose (functional) and para nasal sinus inflammation surgical treatment is exposed in this article. The nasal septum is within the focus for function, form and stability for the nasal structure (especially for tip and back of the nose) and for success of a rhinoplasty. An important role play the lower nasal turbinates regulating nasal air flow and thus having a great effect after turbinate surgery (submucosal resection and lateral fracturing).The endonasal endoscopy is of utmost importance for diagnosis, therapy and detection of recurrence. In severe cases of nasal polyps, functional endoscopic sinus surgery (FESS) remains the ultimate therapy. However, the indication to operate will be carried out after exhaustion of medical treatment. The most important recurrent prophylaxis for rhino sinusitis and nasal polyps is an appropriate post operative nasal care. PMID- 26756659 TI - [Not Available]. PMID- 26756660 TI - [Not Available]. PMID- 26756661 TI - When a Spoonful of Fallacies Helps the Sweetener Go Down: The Corn Refiner Association's Use of Straw-Person Arguments in Health Debates Surrounding High Fructose Corn Syrup. AB - The American public is increasingly concerned about risks associated with food additives like high-fructose corn syrup (HFCS). To promote its product as safe, the Corn Refiners Association (CRA) employed two forms of straw-person arguments. First, the CRA opportunistically misrepresented HFCS opposition as inept. Second, the CRA strategically chose to refute claims that were easier to defeat while remaining ambiguous about more complex points of contention. We argue that CRA's discursive contributions represented unreasonable yet sustainable use of straw person arguments in debates surrounding health and risk. PMID- 26756664 TI - Bringing the multicellular fern meristem into focus. PMID- 26756663 TI - Single-Cell Mass Spectrometry for Discovery Proteomics: Quantifying Translational Cell Heterogeneity in the 16-Cell Frog (Xenopus) Embryo. AB - We advance mass spectrometry from a cell population-averaging tool to one capable of quantifying the expression of diverse proteins in single embryonic cells. Our instrument combines capillary electrophoresis (CE), electrospray ionization, and a tribrid ultrahigh-resolution mass spectrometer (HRMS) to enable untargeted (discovery) proteomics with ca. 25 amol lower limit of detection. CE-MUESI-HRMS enabled the identification of 500-800 nonredundant protein groups by measuring 20 ng, or <0.2% of the total protein content in single blastomeres that were isolated from the 16-cell frog (Xenopus laevis) embryo, amounting to a total of 1709 protein groups identified between n=3 biological replicates. By quantifying ~150 nonredundant protein groups between all blastomeres and replicate measurements, we found significant translational cell heterogeneity along multiple axes of the embryo at this very early stage of development when the transcriptional program of the embryo has yet to begin. PMID- 26756662 TI - Metabolic voxel-based analysis of the complete human brain using fast 3D-MRSI: Proof of concept in multiple sclerosis. AB - PURPOSE: To detect local metabolic abnormalities over the complete human brain in multiple sclerosis (MS) patients, we used optimized fast volumic echo planar spectroscopic imaging (3D-EPSI). MATERIALS AND METHODS: Weighted mean combination of two 3D-EPSI covering the whole brain acquired at 3T in AC-PC and AC-PC+15 degrees axial planes was performed to obtain high-quality metabolite maps for five metabolites: N-acetyl aspartate (NAA), glutamate+glutamine (Glx), choline (Cho), myo-inositol (m-Ins), and creatine+phosphocreatine (tCr). After spatial normalization, maps from 19 patients suffering from relapsing-remitting MS were compared to 19 matched controls using statistical mapping analyses to determine the topography of metabolic abnormalities. Probabilistic white matter (WM) T2 lesion maps and gray matter (GM) atrophy maps were also generated. RESULTS: Two group analysis of variance (ANOVA) (SPM8, P < 0.005, false discovery rate [FDR] corrected P < 0.05 at the cluster level with age and sex as confounding covariates) comparing patients and controls matched for age and sex showed clusters of abnormal metabolite levels with 1) decreased NAA (around -15%) and Glx (around 20%) predominantly in GM within prefrontal cortices, motor cortices, bilateral thalami, and mesial temporal cortices in line with neuronal/neuro astrocytic dysfunction; 2) increased m-Ins (around + 20%) inside WM T2 lesions and in the normal-appearing WM of temporal-occipital lobes, suggesting glial activation. CONCLUSION: We demonstrate the ability to noninvasively map over the complete brain-from vertex to cerebellum-with a validated sequence, the metabolic abnormalities associated with MS, for characterizing the topography of pathological processes affecting widespread areas of WM and GM and its functional impact. J. Magn. Reson. Imaging 2016;44:411-419. PMID- 26756665 TI - Short Communication: Phylogenetic and Molecular Characterization of Six Full Length HIV-1 Genomes from India Reveals a Monophyletic Lineage of Indian Sub Subtype A1. AB - Although HIV-1 epidemic in India is mainly driven by subtype C, subtype A has been reported for over two decades. This is the first comprehensive analysis of sequences of HIV-1 subtype A from India, based on the near full-length genome sequences of six different HIV-1 subtype A Indian isolates along with available partial gene sequences from India and global sequences. The phylogenetic analyses revealed the convergence of all Indian whole-genome sequences and majority of the partial gene sequences to a single node with the sequences most closely related to African sub-subtype A1. The presence of the signature motifs consistent with those observed in subtype A and CTL epitopes characterized specifically for subtype A1 were observed among the study sequences. Deletion of LY amino acid of LYPXnL motif of p6gag and one amino acid in V3 loop have been observed among the study isolates, which have also been observed in a few sequences from East Africa. Overall, the results are indicative of a monophyletic lineage or founder effect of the Indian epidemic due to sub-subtype A1 and supportive of a possible migration of subtype A1 into India from East Africa. PMID- 26756666 TI - Update on the End-Stage Renal Disease Quality Incentive Program. AB - The End-Stage Renal Disease Quality Incentive Program continues to evolve and expand. In this article, we will review the program's structure and critically assess the clinical metrics in place. In addition, we will discuss upcoming program changes to help prepare dialysis facilities and nephrologists to meet new proposed metrics. PMID- 26756669 TI - Correction to "Excited State Relaxation of Neutral and Basic 8-Oxoguanine". PMID- 26756667 TI - Sleep quality in healthy and mood-disordered persons predicts daily life emotional reactivity. AB - Disordered sleep has been linked to impaired emotional functioning in healthy and depressed individuals. Little is known, however, about how chronic sleep problems influence emotional reactivity in everyday life. Participants with major or minor unipolar depressive disorder (n = 60) and healthy controls (n = 35) reported on sleep and emotional responses to daily life events using a computerised Experience Sampling Method. We examined whether impaired sleep quality influenced emotional reactivity to daily events, and if this relationship was altered by unipolar mood disorders. Among healthy individuals, sleep difficulties were associated with enhanced negative affect (NA) to unpleasant events and a dulled response to neutral events. However, among mood-disordered persons, sleep difficulties were associated with higher NA across all types of everyday life events. Impaired sleep quality differentially affects daily life emotional reactions as a function of depression. PMID- 26756668 TI - Endometrial ablation for heavy menstrual bleeding. AB - Endometrial ablation can be described as one of the great gynecological success stories. It has changed the management of heavy menstrual bleeding dramatically. The development of newer (second generation) endometrial ablative techniques has enabled clinicians to set up comprehensive 'one stop clinics' based on an outpatient service to treat heavy menstrual bleeding effectively without the need for general anesthetic or conscious sedation. This article describes the rationale and evidence for use of different endometrial auto-ablative systems along with relevant technical and clinical aspects. It also addresses the essentials of a successful approach to outpatient endometrial ablation along with discussion on risks, complications and contraindications of the procedure. PMID- 26756671 TI - Catheter Ablation of Ventricular Tachycardia in the Setting of Known LV Thrombus: Between Scylla and Charybdis? PMID- 26756670 TI - Using narrow-band imaging with conventional hysteroscopy increases the detection of chronic endometritis in abnormal uterine bleeding and postmenopausal bleeding. AB - AIM: A preliminary study was designed to evaluate whether a narrow-band imaging (NBI) endoscopic light source could detect chronic endometritis that was not identifiable with a white light hysteroscope. MATERIAL AND METHODS: A total of 86 patients with endometrial pathology (71 abnormal uterine bleeding and 15 postmenopausal bleeding) were examined by NBI endoscopy and white light hysteroscopy between February 2010 and February 2011. The surgeon initially observed the uterine cavity using white light hysteroscopy and made a diagnostic impression, which was recorded. Subsequently, after pressing a button on the telescope, NBI was used to reevaluate the endometrial mucosa. RESULTS: The median age of the patients was 40 years (range: 30-60 years). Endometritis was diagnosed histologically. Six cases of abnormal uterine bleeding (6/71, 8.4%, 95% confidence interval [CI] 0.03-0.17) and one case of postmenopausal bleeding (1/15, 6%, 95%CI 0.01-0.29) were only diagnosed with chronic endometritis by NBI (7/86, 8.1%, 95%CI 0.04-0.15). CONCLUSION: Capillary patterns of the endometrium can be observed by NBI and this method can be used to assess chronic endometritis. PMID- 26756673 TI - Quantitative T1 and proton density mapping with direct calculation of radiofrequency coil transmit and receive profiles from two-point variable flip angle data. AB - Quantitative T1 mapping of brain tissue is frequently based on the variable flip angle (VFA) method, acquiring spoiled gradient echo (GE) datasets at different excitation angles. However, accurate T1 calculation requires a knowledge of the sensitivity profile B1 of the radiofrequency (RF) transmit coil. For an additional derivation of proton density (PD) maps, the receive coil sensitivity profile (RP) must also be known. Mapping of B1 and RP increases the experiment duration, which may be critical when investigating patients. In this work, a method is presented for the direct calculation of B1 and RP from VFA data. Thus, quantitative maps of T1 , PD, B1 and RP can be obtained from only two spoiled GE datasets. The method is based on: (1) the exploitation of the linear relationship between 1/PD and 1/T1 in brain tissue and (2) the assumption of smoothly varying B1 and RP, so that a large number of data points can be fitted across small volume elements where B1 and RP are approximately constant. The method is tested and optimized on healthy subjects. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26756674 TI - A liver-on-a-chip platform with bioprinted hepatic spheroids. AB - The inadequacy of animal models in correctly predicting drug and biothreat agent toxicity in humans has resulted in a pressing need for in vitro models that can recreate the in vivo scenario. One of the most important organs in the assessment of drug toxicity is liver. Here, we report the development of a liver-on-a-chip platform for long-term culture of three-dimensional (3D) human HepG2/C3A spheroids for drug toxicity assessment. The bioreactor design allowed for in situ monitoring of the culture environment by enabling direct access to the hepatic construct during the experiment without compromising the platform operation. The engineered bioreactor could be interfaced with a bioprinter to fabricate 3D hepatic constructs of spheroids encapsulated within photocrosslinkable gelatin methacryloyl (GelMA) hydrogel. The engineered hepatic construct remained functional during the 30 days culture period as assessed by monitoring the secretion rates of albumin, alpha-1 antitrypsin, transferrin, and ceruloplasmin, as well as immunostaining for the hepatocyte markers, cytokeratin 18, MRP2 bile canalicular protein and tight junction protein ZO-1. Treatment with 15 mM acetaminophen induced a toxic response in the hepatic construct that was similar to published studies on animal and other in vitro models, thus providing a proof of-concept demonstration of the utility of this liver-on-a-chip platform for toxicity assessment. PMID- 26756675 TI - Approach and Coalescence of Gold Nanoparticles Driven by Surface Thermodynamic Fluctuations and Atomic Interaction Forces. AB - The approach and coalescence behavior of gold nanoparticles on a silicon surface were investigated by experiments and molecular dynamics simulations. By analyzing the behavior of the atoms in the nanoparticles in the simulations, it was found that the atoms in a single isolated nanoparticle randomly fluctuated and that the surface atoms showed greater fluctuation. The fluctuation increased as the temperature increased. When there were two or more neighboring nanoparticles, the fluctuating surface atoms of the nanoparticles "flowed" toward the neighboring nanoparticle because of atomic interaction forces between the nanoparticles. With the surface atoms "flowing", the gold nanoparticles approached and finally coalesced. The simulation results were in good agreement with the experimental results. It can be concluded that surface thermodynamic fluctuations and atomic interaction forces are the causes of the approach and coalescence behavior of the gold nanoparticles. PMID- 26756672 TI - Phosphorylation Regulates Id2 Degradation and Mediates the Proliferation of Neural Precursor Cells. AB - Inhibitor of DNA binding proteins (Id1-Id4) function to inhibit differentiation and promote proliferation of many different cell types. Among the Id family members, Id2 has been most extensively studied in the central nervous system (CNS). Id2 contributes to cultured neural precursor cell (NPC) proliferation as well as to the proliferation of CNS tumors such as glioblastoma that are likely to arise from NPC-like cells. We identified three phosphorylation sites near the N-terminus of Id2 in NPCs. To interrogate the importance of Id2 phosphorylation, Id2(-/-) NPCs were modified to express wild type (WT) Id2 or an Id2 mutant protein that could not be phosphorylated at the identified sites. We observed that NPCs expressing this mutant lacking phosphorylation near the N-terminus had higher steady-state levels of Id2 when compared to NPCs expressing WT Id2. This elevated level was the result of a longer half-life and reduced proteasome mediated degradation. Moreover, NPCs expressing constitutively de-phosphorylated Id2 proliferated more rapidly than NPCs expressing WT Id2, a finding consistent with the well-characterized function of Id2 in driving proliferation. Observing that phosphorylation of Id2 modulates the degradation of this important cell cycle regulator, we sought to identify a phosphatase that would stabilize Id2 enhancing its activity in NPCs and extended our analysis to include human glioblastoma-derived stem cells (GSCs). We found that expression of the phosphatase PP2A altered Id2 levels. Our findings suggest that inhibition of PP2A may be a novel strategy to regulate the proliferation of normal NPCs and malignant GSCs by decreasing Id2 levels. Stem Cells 2016;34:1321-1331. PMID- 26756676 TI - Cognitive trajectories in rare neurogenetic diseases: minding the gaps and filling the potholes. PMID- 26756693 TI - Correction to: Thyroid 2015;25(11):1191-1198. PMID- 26756677 TI - Proportion of premenopausal and postmenopausal breast cancers attributable to known risk factors: Estimates from the E3N-EPIC cohort. AB - Breast cancer is the most frequently diagnosed cancer among women worldwide. Breast cancer risk factors have been widely explored individually; however, little is known about their combined impact. We included 67,634 women from the French E3N prospective cohort, aged 42-72 at baseline. During a 15-year follow-up period, 497 premenopausal and 3,138 postmenopausal invasive breast cancer cases were diagnosed. Population-attributable fractions (PAFs) were used to estimate cases proportions attributable to risk factors under hypothetical scenarios of lowest exposure. We examined overall premenopausal and postmenopausal invasive breast cancers and tumour subtypes (ER status and HER2 expression). Premenopausal breast cancer was not significantly attributable to non-behavioral (61.2%, -15.5 to 91.88%) nor to behavioral (39.9%, -71.0 to 93.9%) factors, contrary to postmenopausal breast cancer (41.9%, 4.5 to 68.7% and 53.5%, 12.8 to 78.7%, respectively). Individually, the highest statistically significant PAFs were obtained in premenopause for birth weight (33.6%, 5.7 to 56.6%) and age at menarche (19.8%, 5.2 to 33.6%) for non-behavioral factors and in postmenopause for history of benign breast diseases (14.9%, 11.6 to 18.0%) and age at menarche (9.7%, 3.9 to 15.5%) for non-behavioral factors and for body shape at menarche (17.1%, 9.7 to 24.3%), use of hormone replacement therapy (14.5%, 9.2 to 19.6%), dietary pattern (10.1%, 2.6 to 17.4%) and alcohol consumption (5.6%, 1.9 to 9.3%) for behavioral factors. These proportions were higher for ER+, HER2- and ER+/HER2 postmenopausal breast cancers. Our data support the hypothesis that in postmenopause, never starting unhealthy behaviors can reduce the number of diagnosed breast cancers. PMID- 26756694 TI - Feeling Fine: Anxiety and Depressive Symptoms in Youth with Established IBD. AB - BACKGROUND: Previous research is discrepant with respect to the prevalence of internalizing symptoms (i.e., depressive and anxiety symptoms) in pediatric inflammatory bowel disease (IBD) samples. Moreover, few studies have examined the combined influence of demographic and disease-related risk factors for internalizing symptoms. This study described rates of depressive, anxiety, and overall internalizing symptomatology in a multisite sample of youth with established IBD diagnoses. Additionally, the study examined risk factors for elevated depressive, anxiety, and internalizing symptoms, including those in demographic (i.e., family income and sex) and disease (i.e., disease activity and functional disability) domains. METHODS: One hundred sixty-one youth (aged 11-18 yr) with established IBD diagnoses, primarily inactive disease, prescribed oral medications, and who were not taking corticosteroids were recruited from outpatient Gastroenterology Clinics at 3 children's hospitals. This article reflects a secondary analysis of data collected from 2 larger studies examining oral medication adherence and psychosocial functioning in pediatric IBD. After providing written consent/assent, participants completed questionnaires assessing demographics, functional disability, and internalizing symptoms. Medical records were reviewed for disease information and clinical disease activity ratings. RESULTS: Only 13% of the sample reported clinically elevated anxiety or depressive symptoms. Perceived functional disability, but not clinical disease activity, was associated with higher depressive and anxiety symptoms, and higher overall internalizing symptomatology. CONCLUSIONS: Current results highlight the need to look beyond disease severity and examine the perception of functional disability of patients with IBD when seeking to identify youth at risk for internalizing symptoms such as depression and anxiety. PMID- 26756695 TI - Translation of Hypothesis to Therapy in Crohn's Disease. PMID- 26756697 TI - Asymptomatic atrial fibrillation and risk of stroke. AB - The incidence of atrial fibrillation rises with advancing age. About 10% of patients over 80 years suffer from atrial fibrillation, but episodes are often not recognized. However, about 25% of cryptogenic strokes are caused by asymptomatic atrial fibrillation showing a significant risk of thromboembolism by this condition. New insertable cardiac monitors or wearable sensors offer the opportunity of continuous rhythm monitoring over wider time spans. Thereby, they enable detection of asymptomatic atrial fibrillation episodes. Several lines of evidence point towards an association between duration of asymptomatic episodes and thromboembolic risk. However, definite data on optimal risk stratification and therapy is missing in this collective. Currently, oral anticoagulation should be initiated according to the CHA2DS2VASc Score. Given the better safety profile of direct oral anticoagulants these substances should be preferred. In patients with high bleeding risk and asymptomatic atrial fibrillation, catheter-based left appendage occlusion may represent a valuable alternative to oral anticoagulation. PMID- 26756696 TI - Repairing the efficiency loss due to varying cluster sizes in two-level two-armed randomized trials with heterogeneous clustering. AB - In two-armed trials with clustered observations the arms may differ in terms of (i) the intraclass correlation, (ii) the outcome variance, (iii) the average cluster size, and (iv) the number of clusters. For a linear mixed model analysis of the treatment effect, this paper examines the expected efficiency loss due to varying cluster sizes based upon the asymptotic relative efficiency of varying versus constant cluster sizes. Simple, but nearly cost-optimal, correction factors are derived for the numbers of clusters to repair this efficiency loss. In an extensive Monte Carlo simulation, the accuracy of the asymptotic relative efficiency and its Taylor approximation are examined for small sample sizes. Practical guidelines are derived to correct the numbers of clusters calculated under constant cluster sizes (within each treatment) when planning a study. Because of the variety of simulation conditions, these guidelines can be considered conservative but safe in many realistic situations. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26756698 TI - Generation of Oxazolidine-2,4-diones Bearing Sulfur-Substituted Quaternary Carbon Atoms by Oxothiolation/Cyclization of Ynamides. AB - A novel method for metal-free oxothiolation of ynamides to construct oxazolidine 2,4-diones bearing sulfur-substituted quaternary carbon atoms has been developed. It represents a rare C-O bond cleavage of ynamides, as well as a facile and tandem approach for the formation of C-O, C-S, and C-Cl bonds. This redox-neutral protocol can be applied to the synthesis of multisubstituted oxazolidine-2,4 diones with good chemoselectivity and good yields of isolated products under mild conditions. PMID- 26756699 TI - Successful ageing in lesbian, gay and bisexual older people: a concept analysis. AB - AIMS AND OBJECTIVES: The aim of this study was to report on an analysis of the concept of successful ageing in lesbian, gay and bisexual older people. BACKGROUND: Research indicates that lesbian, gay and bisexual older people experience significant health disparities. Yet there is a lack of understanding on what factors contribute to successful ageing in this population. Nursing has lagged behind other disciplines in investigating the health of lesbian, gay and bisexual older people. DESIGN: A concept analysis using Rodgers' evolutionary method. DATA SOURCES: Twenty studies were retrieved by searching PubMed, CINAHL, PsycInfo, EMBASE, Cochrane Library and Scopus for English-language peer-reviewed studies published from January 2004 to March 2014. METHODS: The antecedents, attributes and consequences of the concept were identified through the Rodgers' method of concept analysis. RESULTS: Attributes included support from families of origin and/or families of choice, access to lesbian, gay, and bisexual-friendly services and crisis competence. Self-realisation of lesbian, gay and bisexual identity (coming out to oneself) and age >50 were identified as antecedents. Three consequences of successful ageing in lesbian, gay and bisexual older people were social engagement, optimism and resilience. CONCLUSION: Successful ageing in lesbian, gay and bisexual older people is defined as a subjective and multifactorial concept that is characterised by support from families of origin/families of choice, access to lesbian, gay, and bisexual-friendly services and the development of crisis competence skills which impact the ageing experience of LGB individuals. IMPLICATIONS FOR PRACTICE: Successful ageing models can provide a roadmap for developing culturally competent interventions to address key healthcare issues present in this population. The nursing profession's multidisciplinary knowledge and competence in providing health promotion makes nurses well positioned to take a leading role in reducing disparities of lesbian, gay and bisexual older people. PMID- 26756700 TI - Correction to "Effect of the DNA End of Tethering to Electrodes on Electron Transfer in Methylene Blue-Labeled DNA Duplexes". PMID- 26756703 TI - PbMn(IV)TeO6: A New Noncentrosymmetric Layered Honeycomb Magnetic Oxide. AB - PbMnTeO6, a new noncentrosymmetric layered magnetic oxide was synthesized and characterized. The crystal structure is hexagonal, with space group P62m (No. 189), and consists of edge-sharing (Mn(4+)/Te(6+))O6 trigonal prisms that form honeycomb-like two-dimensional layers with Pb(2+) ions between the layers. The structural difference between PbMnTeO6, with disordered/trigonal prisms of Mn(4+)/Te(6+), versus the similar chiral SrGeTeO6 (space group P312), with long range order of Ge(4+) and Te(6+) in octahedral coordination, is attributed to a difference in the electronic effects of Ge(4+) and Mn(4+). Temperature-dependent second harmonic generation by PbMnTeO6 confirmed the noncentrosymmetric character between 12 and 873 K. Magnetic measurements indicated antiferromagnetic order at T(N) ~ 20 K and a frustration parameter (|theta|/T(N)) of ~2.16. PMID- 26756702 TI - Impact of body mass index on the outcomes following transcatheter aortic valve implantation. AB - OBJECTIVES: To investigate the influence of body mass index (BMI) on short- and midterm outcomes following transcatheter aortic valve implantation (TAVI). BACKGROUND: Although obesity is a major risk factor for cardiovascular mortality, numerous studies reported a beneficial effect of obesity on survival in patients with cardiovascular disease and in patients after cardiac interventions. Moreover, all previous reports examining the relation between BMI and outcomes following TAVI have underscored the "obesity paradox" in these patients. METHODS: During a 3 year period, 805 patients with severe aortic stenosis that underwent TAVI at our institute were evaluated. Based on baseline BMI, patients were classified as normal weight (18.5-24.9 kg/m(2) ), overweight (25.0-29.9 kg/m(2) ), or obese (>=30 kg/m(2) ). TAVI endpoints, device success, and adverse events were considered according to the Valve Academic Research Consortium (VARC)-2 definitions. RESULTS: Obese patients were significantly younger, had higher prevalence of diabetes mellitus and chronic lung disease, and had lower prevalence of frailty. Device success was similar between the 3 groups. All-cause mortality up to 30 days was 2.9% (10/340) vs 4.5% (12/268) vs 0.5% (1/186) in patients with normal weight, overweight, and obesity, respectively (p = 0.048). In a multivariable model, overweight and obese patients had similar overall mortality compared to patients with normal weight. CONCLUSIONS: We found no evidence for the existence of an obesity paradox following TAVI. Correction for possible confounders such as frailty in the present cohort may explain the discrepancy between the current report and the previous reports that suggested a protective effect for increased BMI following TAVI. (c) 2016 Wiley Periodicals, Inc. PMID- 26756705 TI - Pd/C-Catalyzed Aminocarbonylation of Aryl Iodides via Oxidative C-N Bond Activation of Tertiary Amines to Tertiary Amides. AB - This work reports oxidative N-dealkylation/carbonylation of tertiary amines to tertiary amides by using molecular oxygen as a sole oxidant using a Pd/C catalyst. This protocol is free from ligands, additives, bases, and cocatalysts. Different tertiary amines as well as aryl iodides have been examined for this transformation, providing desired products in good to excellent yield. PMID- 26756701 TI - RUNX3 is down-regulated in glioma by Myc-regulated miR-4295. AB - MicroRNAs are increasingly reported as tumour suppressors that regulate gene expression after transcription. Our results demonstrated that miR-4295 is overexpression in glioma tissues and its level is significantly correlated with clinical stage. We also found that miR-4295 inhibited the cell G0/G1 arrest and apoptosis leading to promoted cell proliferation and activity. The murine modelling study revealed that female nude mice injected with U87/anti-miR-4295 exhibit subcutaneous tumours in the right groin. Compared with anti-NC, the tumour volume was significantly decreased in anti-miR-4295 treatment group. Furthermore, we confirmed miR-4295 mediates the expression of RUNX3 by targeting its 3'untranslation region. In addition, N-myc protein also could bind to the promoter of pri-miR-4295 and inhibit the expression of RUNX3 in glioma cells. These results validate a pathogenetic role of a miR-4295 in gliomas and establish a potentially regulatory and signalling pathway involving N-myc/miR-4295/RUNX3 in gliomas. PMID- 26756704 TI - Reference values for frequency volume chart and uroflowmetry parameters in adolescent and adult enuresis patients. AB - AIMS: Reference values of Frequency Volume Chart (FVC) and uroflowmetry parameters for adolescent and adult enuresis patients are lacking. In this study, we aim to describe those parameters, in order to interpret findings from FVCs and uroflowmetries in those patients. METHODS: Retrospective, descriptive cohort study, concerning 907 patients aged 11 years and older, suffering from enuresis of at least one wet night per fortnight, treated in a secondary/tertiary centre, between 2003 and 2013. The main FVC parameters of interest were: maximum voided volume (MVV), 24 hr urine production and nocturnal urine volume (NUV) including first morning void (FMV). Nocturnal polyuria (NP) was defined based on both International Children's Continence Society (ICCS, 2014) and International Continence Society (ICS, 2002) definitions. Data of all patients were collected from the medical files. RESULTS: Age had an impact on diurnal and nocturnal FVC parameters. Median MVV excluding FMV was 250 ml in the youngest, 11-year-old males and 363 ml in the eldest, >=18-yr-old males. For females, these values were 230 ml and 310 ml. Median 24 hr urine production increased from 1,025 ml to 1,502 ml (males) and from 1,007 ml to 1,557 ml (females). Median NUV showed an increase from 387 ml to 519 ml (males) and from 393 ml to 525 (females). Forty-two percent of men and 30% of women had a small MVV (for age). Prevalence of NP differed when assessed by the ICS or the ICCS definition: following ICS guidelines, NP was present in 96% of our male and 93% of our female population, compared to 27% and 41%, respectively, following ICCS guidelines. CONCLUSIONS: Both small MVV and NP were found frequently in our adolescent and adult enuresis patients, which is in line with the current thoughts on causal factors. NP prevalence is quite different when using ICS or ICCS definitions, respectively. We would like to encourage the development of an unambiguous definition of NP to use both in pediatric and adult urology. Neurourol. Urodynam. 36:463-468, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26756706 TI - Platelet storage: a license to chill! PMID- 26756707 TI - What do we know about intracranial hemorrhage in fetal and neonatal alloimmune thrombocytopenia? PMID- 26756708 TI - Can we "terminate" alloimmune platelet transfusion refractoriness? PMID- 26756709 TI - Transfusion medicine illustrated. Massive transfusion in an obstetric emergency. PMID- 26756711 TI - Reducing red blood cell shelf life would frequently compromise inventory. PMID- 26756713 TI - The societal cost of Taenia solium cysticercosis in Tanzania. AB - Taenia solium is a zoonotic parasite prevalent in many low income countries throughout Latin America, Asia and sub-Saharan Africa, including Tanzania. The parasite is recognized as a public health threat; however the burden it poses on populations of Tanzania is unknown. The aim of this study was to estimate the societal cost of T. solium cysticercosis in Tanzania, by assessing both the health and economic burden. The societal cost of T. solium cysticercosis was assessed in humans and pigs based on data obtained by a systematic review. Experts' opinion was sought in cases where data were not retrievable. The health burden was assessed in terms of annual number of neurocysticercosis (NCC) associated epilepsy incident cases, deaths and disability-adjusted life years (DALYs), while the economic burden was assessed in terms of direct and indirect costs imposed by NCC-associated epilepsy and potential losses due to porcine cysticercosis. Based on data retrieved from the systematic review and burden assessments, T. solium cysticercosis contributed to a significant societal cost for the population. The annual number of NCC-associated epilepsy incident cases and deaths were 17,853 (95% Uncertainty Interval (UI), 5666-36,227) and 212 (95% UI, 37-612), respectively. More than 11% (95% UI, 6.3-17) of the pig population was infected with the parasite when using tongue examination as diagnostic method. For the year 2012 the number of DALYs per thousand person-years for NCC associated epilepsy was 0.7 (95% UI, 0.2-1.6). Around 5 million USD (95% UI, 797,535-16,933,477) were spent due to NCC-associated epilepsy and nearly 3 million USD (95% UI, 1,095,960-5,366,038) were potentially lost due to porcine cysticercosis. Our results show that T. solium imposes a serious public health, agricultural and economic threat for Tanzania. We urge that a One Health approach, which involves the joint collaboration and effort of veterinarians, medical doctors, agricultural extension officers, researchers and relevant governmental agencies, is taken to find sustainable solutions for prevention, control and elimination of T. solium. PMID- 26756714 TI - The power and promise of RNA-seq in ecology and evolution. AB - Reference is regularly made to the power of new genomic sequencing approaches. Using powerful technology, however, is not the same as having the necessary power to address a research question with statistical robustness. In the rush to adopt new and improved genomic research methods, limitations of technology and experimental design may be initially neglected. Here, we review these issues with regard to RNA sequencing (RNA-seq). RNA-seq adds large-scale transcriptomics to the toolkit of ecological and evolutionary biologists, enabling differential gene expression (DE) studies in nonmodel species without the need for prior genomic resources. High biological variance is typical of field-based gene expression studies and means that larger sample sizes are often needed to achieve the same degree of statistical power as clinical studies based on data from cell lines or inbred animal models. Sequencing costs have plummeted, yet RNA-seq studies still underutilize biological replication. Finite research budgets force a trade-off between sequencing effort and replication in RNA-seq experimental design. However, clear guidelines for negotiating this trade-off, while taking into account study-specific factors affecting power, are currently lacking. Study designs that prioritize sequencing depth over replication fail to capitalize on the power of RNA-seq technology for DE inference. Significant recent research effort has gone into developing statistical frameworks and software tools for power analysis and sample size calculation in the context of RNA-seq DE analysis. We synthesize progress in this area and derive an accessible rule-of-thumb guide for designing powerful RNA-seq experiments relevant in eco-evolutionary and clinical settings alike. PMID- 26756715 TI - Urgent and Elective Robotic Single-Site Cholecystectomy: Analysis and Learning Curve of 150 Consecutive Cases. AB - BACKGROUND: The use of robotic single-site cholecystectomy has increased exponentially. There are few reports describing the safety, efficacy, and operative learning curve of robotic single-site cholecystectomy either in the community setting or with nonelective surgery. MATERIALS AND METHODS: We performed a retrospective review of a prospective database of our initial experience with robotic single-site cholecystectomy. Demographics and perioperative outcomes were evaluated for both urgent and elective cholecystectomy. Cumulative sum analysis was performed to determine the surgeon's learning curve. RESULTS: One hundred fifty patients underwent robotic single-site cholecystectomy. Seventy-four (49.3%) patients underwent urgent robotic single site cholecystectomy, and 76 (50.7%) underwent elective robotic single-site cholecystectomy. Mean total operative time for robotic single-site cholecystectomy was 83.3 +/- 2.7 minutes. Mean operative time for the urgent cohort was significantly longer than for the elective cohort (95.0 +/- 4.4 versus 71.9 +/- 2.6 minutes; P < .001). There was one conversion in the urgent cohort and none in the elective cohort. There was one bile duct injury (0.7%) in the urgent cohort. Perioperative complications occurred in 8.7% of patients, and most consisted of superficial surgical-site infections. There were no incisional hernias detected. The surgeon's learning curve, inclusive of urgent and elective cases, was 48 operations. CONCLUSIONS: Robotic single-site cholecystectomy can be performed safely and effectively in both elective and urgent cholecystectomy with a reasonable learning curve and acceptable perioperative outcomes. PMID- 26756716 TI - Simultaneity and Temporal Order Judgments Exhibit Distinct Reaction Times and Training Effects. AB - A considerable body of sensory research has addressed the rules governing simultaneity judgments (SJs) and temporal order judgments (TOJs). In principle, neural events that register stimulus-arrival-time differences at an early sensory stage could set the limit on SJs and TOJs alike. Alternatively, distinct limits on SJs and TOJs could arise from task-specific neural events occurring after the stimulus-driven stage. To distinguish between these possibilities, we developed a novel reaction-time (RT) measure and tested it in a perceptual-learning procedure. The stimuli comprised dual-stream Rapid Serial Visual Presentation (RSVP) displays. Participants judged either the simultaneity or temporal order of red-letter and black-number targets presented in opposite lateral hemifield streams of black-letter distractors. Despite identical visual stimulation across tasks, the SJ and TOJ tasks generated distinct RT patterns. SJs exhibited significantly faster RTs to synchronized targets than to subtly asynchronized targets; TOJs exhibited the opposite RT pattern. These task-specific RT patterns cannot be attributed to the early, stimulus-driven stage and instead match what one would predict if the limits on SJs and TOJs arose from task-specific decision spaces. That is, synchronized targets generate strong evidence for simultaneity, which hastens SJ RTs. By contrast, synchronized targets provide no information about temporal order, which slows TOJ RTs. Subtly asynchronizing the targets reverses this information pattern, and the corresponding RT patterns. In addition to investigating RT patterns, we also investigated training-transfer between the tasks. Training to improve SJ precision failed to improve TOJ precision, and vice versa, despite identical visual stimulation across tasks. This, too, argues against early, stimulus-driven limits on SJs and TOJs. Taken together, the present study offers novel evidence that distinct rules set the limits on SJs and TOJs. PMID- 26756717 TI - Age and active navigation effects on episodic memory: A virtual reality study. AB - We investigated the navigation-related age effects on learning, proactive interference semantic clustering, recognition hits, and false recognitions in a naturalistic situation using a virtual apartment-based task. We also examined the neuropsychological correlates (executive functioning [EF] and episodic memory) of navigation-related age effects on memory. Younger and older adults either actively navigated or passively followed the computer-guided tour of an apartment. The results indicated that active navigation increased recognition hits compared with passive navigation, but it did not influence other memory measures (learning, proactive interference, and semantic clustering) to a similar extent in either age group. Furthermore, active navigation helped to reduce false recognitions in younger adults but increased those made by older adults. This differential effect of active navigation for younger and older adults was accounted for by EF score. Like for the subject-performed task effects, the effects from the navigation manipulation were well accounted for by item specific/relational processing distinction, and they were also consistent with a source monitoring deficit in older adults. PMID- 26756718 TI - Oriented Circular Dichroism: A Method to Characterize Membrane-Active Peptides in Oriented Lipid Bilayers. AB - The structures of membrane-bound polypeptides are intimately related to their functions and may change dramatically with the lipid environment. Circular dichroism (CD) is a rapid analytical method that requires relatively low amounts of material and no labeling. Conventional CD is routinely used to monitor the secondary structure of peptides and proteins in solution, for example, in the presence of ligands and other binding partners. In the case of membrane-active peptides and transmembrane proteins, these measurements can be applied to, and remain limited to, samples containing detergent micelles or small sonicated lipid vesicles. Such traditional CD analysis reveals only secondary structures. With the help of an oriented circular dichroism (OCD) setup, however, based on the preparation of macroscopically oriented lipid bilayers, it is possible to address the membrane alignment of a peptide in addition to its conformation. This approach has been mostly used for alpha-helical peptides so far, but other structural elements are conceivable as well. OCD analysis relies on Moffitt's theory, which predicts that the electronic transition dipole moments of the backbone amide bonds in helical polypeptides are polarized either parallel or perpendicular to the helix axis. The interaction of the electric field vector of the circularly polarized light with these transitions results in an OCD spectrum of a membrane-bound alpha-helical peptide, which exhibits a characteristic line shape and reflects the angle between the helix axis and the bilayer normal. For parallel alignment of a peptide helix with respect to the membrane surface (S state), the corresponding "fingerprint" CD band around 208 nm will exhibit maximum negative amplitude. If the helix changes its alignment via an obliquely tilted (T-state) to a fully inserted transmembrane orientation (I-state), the ellipticity at 208 nm decreases and the value approaches zero due to the decreased interactions between the field and the transition dipole. Compared to conventional CD, OCD data are not only collected in the biologically relevant environment of a highly hydrated planar lipid bilayer (whose composition can be varied at will), but in addition it provides information about the tilt angle of the polypeptide in the membrane. It is the method of choice for screening numerous different conditions, such as peptide concentration, lipid composition, membrane additives, pH, temperature, and sample hydration. All these factors have been found to affect the peptide alignment in membrane, while having little or no influence on conformation. In many cases, the observed realignment could be related to biological action, such as pore formation by antimicrobial and cell penetrating peptides, or to binding events of transmembrane segments of integral membrane proteins. Likewise, any lipid-induced conversion from alpha-helix to beta-sheeted conformation is readily picked up by OCD and has been interpreted in terms of protein instability or amyloid-formation. PMID- 26756719 TI - Possible Involvement of the Inhibition of NF-kappaB Factor in Anti-Inflammatory Actions That Melatonin Exerts on Mast Cells. AB - Melatonin is a molecule endogenously produced in a wide variety of immune cells, including mast cells (RBL-2H3). It exhibits immunomodulatory, anti-inflammatory and anti-apoptotic properties. The physiologic mechanisms underlying these activities of melatonin have not been clarified in mast cells. This work is designed to determine the anti-inflammatory effect and mechanism of action of melatonin on activated mast cells. RBL-2H3 were pre-treated with exogenous melatonin (MELx) at physiological (100nM) and pharmacological (1 mM) doses for 30 min, washed and activated with PMACI (phorbol 12-myristate 13-acetate plus calcium ionophore A23187) for 2 h and 12 h. The data shows that pre-treatment of MELx in stimulated mast cells, significantly reduced the levels of endogenous melatonin production (MELn), TNF-alpha and IL-6. These effects are directly related with the MELx concentration used. MELx also inhibited IKK/NF-kappaB signal transduction pathway in stimulated mast cells. These results indicate a molecular basis for the ability of melatonin to prevent inflammation and for the treatment of allergic inflammatory diseases through the down-regulation of mast cell activation. J. Cell. Biochem. 117: 1926-1933, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26756720 TI - Redirecting pedicle screws: a revision spinal fusion strategy using three dimensional image guidance. AB - BACKGROUND: Pedicle screws are a preferred method for spinal fixation because of their three-column support and rigid posterior stabilization. The purpose of this study was to evaluate the outcome of patients requiring pedicle screw redirection, and to describe a technique using cone-beam computed tomography (cbCT). METHODS: A retrospective review of 30 patients undergoing revision spinal fusion with redirection of pedicle screws was performed. Fifty pedicle screws were redirected in these patients using cbCT-based 3D image guidance. They were graded pre- and post-operatively using an established grading system. RESULTS: No complications occurred in this study as a result of redirection. No pedicle breach was noted in all of the redirected pedicle screws. CONCLUSION: Redirection of misplaced pedicle screws using cbCT-based 3D image guidance seems to be safe and accurate in our experience. Further studies are needed to establish its safety, accuracy, fusion rate, and clinical outcome compared with other methods. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26756721 TI - Small-Molecule PROTACS: New Approaches to Protein Degradation. AB - The current inhibitor-based approach to therapeutics has inherent limitations owing to its occupancy-based model: 1) there is a need to maintain high systemic exposure to ensure sufficient in vivo inhibition, 2) high in vivo concentrations bring potential for off-target side effects, and 3) there is a need to bind to an active site, thus limiting the drug target space. As an alternative, induced protein degradation lacks these limitations. Based on an event-driven model, this approach offers a novel catalytic mechanism to irreversibly inhibit protein function by targeting protein destruction through recruitment to the cellular quality control machinery. Prior protein degrading strategies have lacked therapeutic potential. However, recent reports of small-molecule-based proteolysis-targeting chimeras (PROTACs) have demonstrated that this technology can effectively decrease the cellular levels of several protein classes. PMID- 26756722 TI - Giving new life to old lungs: methods to produce and assess whole human paediatric bioengineered lungs. AB - We report, for the first time, the development of an organ culture system and protocols to support recellularization of whole acellular (AC) human paediatric lung scaffolds. The protocol for paediatric lung recellularization was developed using human transformed or immortalized cell lines and single human AC lung scaffolds. Using these surrogate cell populations, we identified cell number requirements, cell type and order of cell installations, flow rates and bioreactor management methods necessary for bioengineering whole lungs. Following the development of appropriate cell installation protocols, paediatric AC scaffolds were recellularized using primary lung alveolar epithelial cells (AECs), vascular cells and tracheal/bronchial cells isolated from discarded human adult lungs. Bioengineered paediatric lungs were shown to contain well-developed vascular, respiratory epithelial and lung tissue, with evidence of alveolar capillary junction formation. Types I and II AECs were found thoughout the paediatric lungs. Furthermore, surfactant protein-C and -D and collagen I were produced in the bioengineered lungs, which resulted in normal lung compliance measurements. Although this is a first step in the process of developing tissues for transplantation, this study demonstrates the feasibility of producing bioengineered lungs for clinical use. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26756724 TI - Two Cultures in Modern Science and Technology: For Safety and Validity Does Medicine Have to Update? AB - Two different scientific cultures go unreconciled in modern medicine. Each culture accepts that scientific knowledge and technologies are vulnerable to and easily invalidated by methods and conditions of acquisition, interpretation, and application. How these vulnerabilities are addressed separates the 2 cultures and potentially explains medicine's difficulties eradicating errors. A traditional culture, dominant in medicine, leaves error control in the hands of individual and group investigators and practitioners. A competing modern scientific culture accepts errors as inevitable, pernicious, and pervasive sources of adverse events throughout medical research and patient care too malignant for individuals or groups to control. Error risks to the validity of scientific knowledge and safety in patient care require systemwide programming able to support a culture in medicine grounded in tested, continually updated, widely promulgated, and uniformly implemented standards of practice for research and patient care. Experiences from successes in other sciences and industries strongly support the need for leadership from the Institute of Medicine's recommended Center for Patient Safely within the Federal Executive branch of government. PMID- 26756723 TI - Factors Influencing Time-Dependent Quality Indicators for Patients With Suspected Acute Coronary Syndrome. AB - OBJECTIVES: Rapid risk stratification and timely treatment are critical to favorable outcomes for patients with acute coronary syndrome (ACS). Our objective was to identify patient and system factors that influence time-dependent quality indicators (QIs) for patients with unstable angina/non-ST elevation myocardial infarction (NSTEMI) in the emergency department (ED). METHODS: A retrospective, cohort study was conducted during a 42-month period of all patients 24 years or older suspected of having ACS as defined by receiving an electrocardiogram and at least 1 cardiac biomarker test. Cox regression was used to model the effects of patient characteristics, ancillary service use, staffing provisions, equipment availability, and ED and hospital crowding on ACS QIs. RESULTS: Emergency department adherence rates to national standards for electrocardiogram readout time and biomarker turnaround time were 42% and 37%, respectively. Cox regression models revealed that chief complaints without chest pain and the timing of stress testing and medication administration were associated with the most significant delays. CONCLUSIONS: Patient and system factors both significantly influenced QI times in this cohort with unstable angina/NSTEMI. These results illustrate both the complexity of diagnosing patients with NSTEMI and the competing effects of clinical and system factors on patient flow through the ED. PMID- 26756726 TI - The Potential of Twitter as a Data Source for Patient Safety. AB - BACKGROUND: Error-reporting systems are widely regarded as critical components to improving patient safety, yet current systems do not effectively engage patients. We sought to assess Twitter as a source to gather patient perspective on errors in this feasibility study. METHODS: We included publicly accessible tweets in English from any geography. To collect patient safety tweets, we consulted a patient safety expert and constructed a set of highly relevant phrases, such as "doctor screwed up." We used Twitter's search application program interface from January to August 2012 to identify tweets that matched the set of phrases. Two researchers used criteria to independently review tweets and choose those relevant to patient safety; a third reviewer resolved discrepancies. Variables included source and sex of tweeter, source and type of error, emotional response, and mention of litigation. RESULTS: Of 1006 tweets analyzed, 839 (83%) identified the type of error: 26% of which were procedural errors, 23% were medication errors, 23% were diagnostic errors, and 14% were surgical errors. A total of 850 (84%) identified a tweet source, 90% of which were by the patient and 9% by a family member. A total of 519 (52%) identified an emotional response, 47% of which expressed anger or frustration, 21% expressed humor or sarcasm, and 14% expressed sadness or grief. Of the tweets, 6.3% mentioned an intent to pursue malpractice litigation. CONCLUSIONS: Twitter is a relevant data source to obtain the patient perspective on medical errors. Twitter may provide an opportunity for health systems and providers to identify and communicate with patients who have experienced a medical error. Further research is needed to assess the reliability of the data. PMID- 26756725 TI - Sustaining Innovations in Complex Health Care Environments: A Multiple-Case Study of Rapid Response Teams. AB - OBJECTIVES: Rapid response teams (RRTs) are one innovation previously deployed in U.S. hospitals with the goal to improve the quality of care. Sustaining RRTs is important to achieve the desired implementation outcomes, reduce the risk of program investment losses, and prevent employee disillusionment and dissatisfaction. This study sought to examine factors that do and do not support the sustainability of RRTs. METHODS: The study was conceptually guided by an adapted version of the Planning Model of Sustainability. A multiple-case study was conducted using a purposive sample of 2 hospitals with high RRT sustainability scores and 2 hospitals with low RRT sustainability scores. Data collection methods included (a) a hospital questionnaire that was completed by a nurse administrator at each hospital; (b) semistructured interviews with leaders, RRT members, and those activating RRT calls; and (c) a review of internal documents. Quantitative data were analyzed using descriptive statistics; qualitative data were analyzed using content analysis. RESULTS: Few descriptive differences were found between hospitals. However, there were notable differences in the operationalization of certain factors between high- and low-sustainability hospitals. Additional sustainability factors other than those captured by the Planning Model of Sustainability were also identified. CONCLUSIONS: The sustainability of RRTs is optimized through effective operationalization of organizational and project design and implementation factors. Two additional factors-individual and team characteristics-should be included in the Planning Model of Sustainability and considered as potential facilitators (or inhibitors) of RRT sustainability. PMID- 26756727 TI - Comparison of Health Care Costs Between Claimants and Nonclaimants in the No Fault Compensation System of Finland. AB - OBJECTIVES: If patients experience health care-related adverse events, they may claim for compensation. Adverse events of claimants are generally more severe and presumably involve higher health care costs than those of nonclaimants. The aim of this study was to estimate the cost differential between claimants and nonclaimants in the no-fault system in Finland. METHODS: We compiled register data on patients having had coronary artery bypass grafting (CABG, n = 20,500), total hip arthroplasty (n = 17,506), or knee arthroplasty (TKA, n = 18,512) and calculated risk-adjusted cost differentials by using a gamma distributed, log linked generalized linear model. The explained variable comprised costs, whereas the main explanatory variables were whether the patient filed a claim and whether he or she received compensation. RESULTS: Uncompensated claimants had higher admission costs (CABG, &OV0556;3660, 29%; total hip arthroplasty, &OV0556;418, 5%; TKA, &OV0556;359, 4%) compared with nonclaimants, whereas the differential between compensated claimants and uncompensated claimants was statistically insignificant. Significant associations emerged concerning CABG 1-year costs: uncompensated claimants had &OV0556;12,990 (71%) higher costs than nonclaimants, whereas compensated claimants had &OV0556;6388 (20%) higher costs than uncompensated claimants. CONCLUSIONS: Although the precise cost differentials may be specific to Finland, the implications may apply also to other countries. (1) Excess costs of claimants should motivate efforts to reduce adverse events. (2) Analyses of claims to improve patient safety should not be restricted to compensated claims only but should equally concern uncompensated claims. A further implication regarding Finland is that additional approaches to identify and report adverse events are necessary.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. PMID- 26756728 TI - Tune-in and Time-out: Toward Surgeon-Led Prevention of "Never" Events. AB - INTRODUCTION: The World Health Organization (WHO) distributed a surgical safety checklist in 2008 in a bid to improve patient safety and quality of care in the operating theater. Adherence to the checklist has been shown to reduce "never" events, for example, wrong site surgery. The aim of this quality improvement study was to determine the current adherence by surgeons to the checklist at The Royal Hobart Hospital. METHODS: This is a retrospective audit of the digital medical records of 100 consecutive emergency operations performed at The Royal Hobart Hospital. The time-out section of the WHO Surgical Safety Checklist was assessed for completeness. Second, an anonymized survey of theater nursing staff was performed to determine current adherence by surgeons with the time-out. RESULTS: The time-out was completed in 79% of emergency procedures. There were no never events in the patient cohort studied. There was overwhelming support among theater nurses for a surgeon-led time-out. Formal education on the use of the WHO Safe Surgery Checklist is lacking. Most theater nurses have experienced hostility from surgeons when conducting a time-out. DISCUSSION: This work is a step on the way to surgeon-led prevention of never events. Finding a completed time-out in the patient notes does not guarantee surgeon support for or contribution to the time-out process. The findings will inform combined nursing and surgeon education sessions, and together with executive-level support, improved surgeon cooperation with the time-out will inculcate a culture of safety for patients and improve harmony among staff groups. PMID- 26756729 TI - A Systems Approach to Analyzing and Preventing Hospital Adverse Events. AB - OBJECTIVE: This study aimed to demonstrate the use of a systems theory-based accident analysis technique in health care applications as a more powerful alternative to the chain-of-event accident models currently underpinning root cause analysis methods. METHOD: A new accident analysis technique, CAST [Causal Analysis based on Systems Theory], is described and illustrated on a set of adverse cardiovascular surgery events at a large medical center. The lessons that can be learned from the analysis are compared with those that can be derived from the typical root cause analysis techniques used today. RESULTS: The analysis of the 30 cardiovascular surgery adverse events using CAST revealed the reasons behind unsafe individual behavior, which were related to the design of the system involved and not negligence or incompetence on the part of individuals. With the use of the system-theoretic analysis results, recommendations can be generated to change the context in which decisions are made and thus improve decision making and reduce the risk of an accident. CONCLUSIONS: The use of a systems-theoretic accident analysis technique can assist in identifying causal factors at all levels of the system without simply assigning blame to either the frontline clinicians or technicians involved. Identification of these causal factors in accidents will help health care systems learn from mistakes and design system level changes to prevent them in the future. PMID- 26756730 TI - Does Physician's Training Induce Overconfidence That Hampers Disclosing Errors? AB - PURPOSE: Although transparency is critical for reducing medical errors, physicians feel discomfort with disclosure. We explored whether overconfidence relates to physician's reluctance to admit that an error may have occurred. METHOD: At 3 university medical centers, a survey presented a clinical vignette of a girl with urinary infection and penicillin allergy to medical students and physicians, asking them to rate their level of confidence for each step of the diagnosis and management. After anaphylaxis develops after cephalosporin administration, respondents were asked about their willingness to admit that an error might have occurred and to rate their level of discomfort in doing so. We analyzed levels of confidence, accuracy, willingness to admit mistake, and discomfort. RESULTS: Respondents reported high levels of confidence for their answers to the questions of diagnosis and management, even when wrong-indicating miscalibration of confidence and accuracy. Compared with students, physicians had significantly higher levels of confidence, lower accuracy, and lower willingness to admit mistake. Although most respondents agreed in principle that errors should be disclosed, in the presented case, significantly less agreed to admit that a mistake might have occurred or to say so explicitly to the family. An association was found between overconfidence and discomfort with disclosure. CONCLUSIONS: Our study shows overconfidence associated with clinician's training and with reluctance to admit mistake, suggesting a contributing role to the difficulty in leveraging safety events into quality improvement. Training physicians to have both knowledge and adequate self-doubt is an educational challenge. PMID- 26756731 TI - A point prevalence study of the use of psychotropic medication in an acute general hospital. AB - BACKGROUND: There are high rates of cognitive problems and organic and functional psychiatric disorders in patients admitted to general hospital wards, which may necessitate the use of psychotropic medications. There is evidence of over prescription of medications such as antipsychotics and antidepressants in community settings such as residential care. However, the prevalence of psychotropic use in general hospitals is unknown. METHODS: A point prevalence study of the use of psychotropic medications in an acute general hospital was conducted by auditing medication charts for type, dose, indication, and other clinical processes associated with their use. RESULTS: The files of 197 patients were audited, 139 (70%) were aged 65 years and over. Eighty-nine (45%) of patients were prescribed a psychotropic, with 35 (17.7%) antidepressants; 21 (11%) antipsychotics; 19 (10%) benzodiazepines; six (3%) mood stabilizer; five (2%) cholinesterase inhibitors; one (0.5%) anti-parkinsonian medication, and one (1%) patient on zolpidem and another patient melatonin (1%). Most prescriptions (72%) were in people 65 years and over and 27 (20%) of indications were found to be off label prescribing. There were deficits in the documentation of indications for the use of psychotropic medications and follow up arrangements. CONCLUSIONS: Rates of benzodiazepines use were less than that reported incomparable settings. Concerns regarding off label prescribing, under-dosing, and lack of adequate documentation of indications and follow-up instructions were raised. Given the potential adverse effects of psychotropic medication, improved governance, and education regarding their use is required. PMID- 26756733 TI - "Just One Thing after Another": Recursive Cascades and Chronic Conditions. AB - Chronic conditions and their resultant difficulties in daily living frequently occur with other health problems, sometimes due to interactions or complications at a biological level, or as a result of common pathogens or risk factors. On other occasions, they develop independently. Drawing on research conducted with Australian women that began in the mid-2000s and is still ongoing, we highlight how chronic structural factors shape the risk factors of "chronic" conditions, influencing health seeking, continuity of care, and health outcomes. Institutional, economic, and other circumstantial factors pertain and impact health trajectories as much in highly industrialized as in resource poor settings. In illustrating how poverty and social exclusion create the preconditions of multiple chronic health problems, and how chronic health problems increase such disadvantages for individuals and their households, we introduce the idea of "recursive cascades" to capture the often inevitable trajectory of increasing ill health and growing empoverishment. PMID- 26756732 TI - The role of folate in malaria - implications for home fortification programmes among children aged 6-59 months. AB - Folic acid and iron supplementation has historically been recommended as the preferred anaemia control strategy among preschoolers in sub-Saharan Africa and other resource-poor settings, but home fortification of complementary foods with multiple micronutrient powders (MNPs) can now be considered the preferred approach. The World Health Organization endorses home fortification with MNPs containing at least iron, vitamin A and zinc to control childhood anaemia, and calls for concomitant malaria control strategies in malaria endemic regions. Among other micronutrients, current MNP formulations generally include 88 MUg folic acid (corresponding to 100% of the Recommended Nutrient Intake). The risks and benefits of providing supplemental folic acid at these levels are unclear. The limited data available indicate that folate deficiency may not be a major public health problem among children living in sub-Saharan Africa and supplemental folic acid may therefore not have any benefits. Furthermore, supraphysiological, and possibly even physiological, folic acid dosages may favour Plasmodium falciparum growth, inhibit parasite clearance of sulphadoxine pyrimethamine (SP)-treated malaria and increase subsequent recrudescence. Even though programmatic options to limit prophylactic SP use or to promote the use of insecticide treated bed nets may render the use of folic acid safer, programmatic barriers to these approaches are likely to persist. Research is needed to characterise the prevalence of folate deficiency among young children worldwide and to design safe MNP and other types of fortification approaches in sub-Sahara Africa. In parallel, updated global guidance is needed for MNP programmes in these regions. PMID- 26756734 TI - Investigating the role of tumour cell derived iNOS on tumour growth and vasculature in vivo using a tetracycline regulated expression system. AB - Nitric oxide (NO) is a free radical signalling molecule involved in various physiological and pathological processes, including cancer. Both tumouricidal and tumour promoting effects have been attributed to NO, making its role in cancer biology controversial and unclear. To investigate the specific role of tumour derived NO in vascular development, C6 glioma cells were genetically modified to include a doxycycline regulated gene expression system that controls the expression of an antisense RNA to inducible nitric oxide synthase (iNOS) to manipulate endogenous iNOS expression. Xenografts of these cells were propagated in the presence or absence of doxycycline. Susceptibility magnetic resonance imaging (MRI), initially with a carbogen (95% O2/5% CO2) breathing challenge and subsequently an intravascular blood pool contrast agent, was used to assess haemodynamic vasculature (DeltaR2*) and fractional blood volume (fBV), and correlated with histopathological assessment of tumour vascular density, maturation and function. Inhibition of NO production in C6 gliomas led to significant growth delay and inhibition of vessel maturation. Parametric fBV maps were used to identify vascularised regions from which the carbogen-induced DeltaR2* was measured and found to be positively correlated with vessel maturation, quantified ex vivo using fluorescence microscopy for endothelial and perivascular cell staining. These data suggest that tumour-derived iNOS is an important mediator of tumour growth and vessel maturation, hence a promising target for anti-vascular cancer therapies. The combination of DeltaR2* response to carbogen and fBV MRI can provide a marker of tumour vessel maturation that could be applied to non-invasively monitor treatment response to iNOS inhibitors. PMID- 26756735 TI - Proteases in cancer drug delivery. AB - Whereas protease inhibitors have been developed successfully against hypertension and viral infections, they have failed thus far as cancer drugs. With advances in cancer profiling we now better understand that the tumor "degradome" (i.e. the repertoire of proteases and their natural inhibitors and interaction partners) forms a complex network in which specific nodes determine the global outcome of manipulation of the protease web. However, knowing which proteases are active in the tumor micro-environment, we may tackle cancers with the use of Protease Activated Prodrugs (PAPs). Here we exemplify this concept for metallo-, cysteine and serine proteases. PAPs not only exist as small molecular adducts, containing a cleavable substrate sequence and a latent prodrug, they are presently also manufactured as various types of nanoparticles. Although the emphasis of this review is on PAPs for treatment, it is clear that protease activatable probes and nanoparticles are also powerful tools for imaging purposes, including tumor diagnosis and staging, as well as visualization of tumor imaging during microsurgical resections. PMID- 26756736 TI - Use of a Fitness Tracker to Promote Physical Activity in Children With Acute Lymphoblastic Leukemia. AB - BACKGROUND: Children with cancer identify fatigue as a pervasive symptom, which increases during the corticosteroid pulse in acute lymphoblastic leukemia (ALL) maintenance. The FitBit is a fitness tracker that downloads activity measurements to the Internet in real time. In this feasibility study, we explored if children who received daily FitBit coaching for 2 weeks before a maintenance steroid pulse had an increase in steps per day and determined the relationship between steps per day prepulse and fatigue postpulse. PROCEDURE: Seventeen children in ALL maintenance, aged 6-15, wore the FitBit for 3 days to establish a baseline. A tailored weekly step goal was then set with the child and parent. Daily emails with feedback and FitBit screenshots were sent over the 2-week intervention. Self report of fatigue was measured at baseline, after 2 weeks (i.e. before the steroid pulse), and after 5 days of steroids. RESULTS: There was a trend toward increased steps per day from weeks 1-2 (P = 0.079); fatigue was low and did not increase during the corticosteroid pulse. A significant correlation (r = -0.66, P = 0.005) was found between the steps per day during week 2 and fatigue after the steroid pulse with higher steps associated with lower fatigue. CONCLUSIONS: The intervention was feasible in this small sample. The average steps each time period (week 1, week 2, and during steroids) was over 10,000, demonstrating that children with ALL can be active during treatment. Physical activity may be protective of fatigue during a corticosteroid pulse. PMID- 26756737 TI - Harms of Breast Cancer Screening: Systematic Review to Update the 2009 U.S. Preventive Services Task Force Recommendation. AB - BACKGROUND: In 2009, the U.S. Preventive Services Task Force recommended biennial mammography screening for women aged 50 to 74 years and selective screening for those aged 40 to 49 years. PURPOSE: To review studies of screening in average risk women with mammography, magnetic resonance imaging, or ultrasonography that reported on false-positive results, overdiagnosis, anxiety, pain, and radiation exposure. DATA SOURCES: MEDLINE and Cochrane databases through December 2014. STUDY SELECTION: English-language systematic reviews, randomized trials, and observational studies of screening. DATA EXTRACTION: Investigators extracted and confirmed data from studies and dual-rated study quality. Discrepancies were resolved through consensus. DATA SYNTHESIS: Based on 2 studies of U.S. data, 10 year cumulative rates of false-positive mammography results and biopsies were higher with annual than biennial screening (61% vs. 42% and 7% vs. 5%, respectively) and for women aged 40 to 49 years, those with dense breasts, and those using combination hormone therapy. Twenty-nine studies using different methods reported overdiagnosis rates of 0% to 54%; rates from randomized trials were 11% to 22%. Women with false-positive results reported more anxiety, distress, and breast cancer-specific worry, although results varied across 80 observational studies. Thirty-nine observational studies indicated that some women reported pain during mammography (1% to 77%); of these, 11% to 46% declined future screening. Models estimated 2 to 11 screening-related deaths from radiation-induced cancer per 100,000 women using digital mammography, depending on age and screening interval. Five observational studies of tomosynthesis and mammography indicated increased biopsies but reduced recalls compared with mammography alone. LIMITATIONS: Studies of overdiagnosis were highly heterogeneous, and estimates varied depending on the analytic approach. Studies of anxiety and pain used different outcome measures. Radiation exposure was based on models. CONCLUSION: False-positive results are common and are higher for annual screening, younger women, and women with dense breasts. Although overdiagnosis, anxiety, pain, and radiation exposure may cause harm, their effects on individual women are difficult to estimate and vary widely. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 26756738 TI - Loss of stability and hydrophobicity of presenilin 1 mutations causing Alzheimer's disease. AB - Nearly 200 mutations in the gene coding for presenilin 1 (PSEN1) cause early onset Alzheimer's disease, yet the molecular mechanism remains obscure. As a meta analysis, we compiled available clinical and biochemical data for PSEN1 variants and correlated these to chemical properties of the mutants. We found statistically significant relationships between relative Abeta42 levels and clinical age of onset. We then computed chemical properties of the mutants from a variety of computational chemistry tools. Relative Abeta42 levels correlated significantly (95% confidence or more from p-values of linear regression) with loss of hydrophobicity for four different regression analyses (squared correlation coefficient of linear regression R(2) of 0.41-0.53) and with increased polarity (R(2) = 0.47, 0.59) and loss of protein stability (R(2) = 0.39, 0.63) for two independent data sets. Age of onset of patients carrying PSEN1 variants correlated with increased polarity (R(2) = 0.49, 0.40) and loss of stability (R(2) = 0.75, 0.44) of the protein for both data sets. These relations suggest that mutants impair the membrane-associated structural integrity of presenilin by reducing hydrophobic membrane association and overall protein stability. This explains why the many mutations that spread out across the protein and far from the catalytic aspartates can cause disease. The identified molecular determinants of clinical age of symptom onset may be relevant to future presenilin-modulating therapies specifically directed towards increasing the structural integrity and packing of the protein. Close to 200 mutations in presenilin 1 (PSEN1) cause Alzheimer's disease, but the biochemical relating these to disease remains debated. The chemical properties of PSEN1 variants were computed and correlated against clinical age of symptom onset. Loss of stability and hydrophobicity and gain of polarity relate to disease onset, suggesting that mutants impair the membrane structure of PSEN1 and that therapies should increase PSEN1 structural integrity. PMID- 26756739 TI - Suppression of phospho-p85alpha-GTP-Rac1 lipid raft interaction by bichalcone analog attenuates cancer cell invasion. AB - The p85alpha subunit of phosphatidylinositol 3-kinase (PI3K) acts as a key regulator of cell proliferation and motility, which mediates signals that confer chemoresistance to many human cancer cells. Using small interfering RNAs against matrix metalloproteinase-2 (MMP-2) and the MMP-2 promoter-driven luciferase assay, we showed that the new synthetic bichalcone analog TSWU-CD4 inhibits the invasion of human cancer cells by down-regulating MMP-2 expression. Treatment with TSWU-CD4 inhibited MMP-2 expression and cell invasion, which were restored by ectopic wild type (wt) p85alpha or a constitutively active form of MAPK kinase 3 (CA MKK3), CA MKK6, or CA p38alpha mitogen-activated protein kinase (MAPK). The attenuated formation of lipid raft-associated phospho (p)-p85alpha-GTP-Rac1 complexes, protein kinase B (Akt) Ser 473 phosphorylation, and cell invasion by TSWU-CD4 was reversed by overexpression of wt p85alpha or the p85alpha Brc homology (BH) domain. The ectopic expression of CA Rac1L61 (but not wt Rac1) could overcome the suppression of Ser 473 phosphorylation, lipid raft association of Akt, the interaction between GTP-bound Rac1 and p85alpha in lipid rafts, and cell invasion by TSWU-CD4. The involvement of Akt activity in the functions of NF kappaB-mediated MMP-2 was further confirmed through the attenuation of Akt phosphorylation signaling using the Akt-specific inhibitor MK-2206 and ectopic expression of NF-kappaB p65. Collectively, the inhibitory effect of TSWU-CD4 on cancer cell invasion was likely to suppress the p-p85alpha-GTP-Rac1 interaction in lipid rafts by targeting the p85alpha BH domain, which resulted in the suppression of MMP-2 expression via the PI3K-Akt-mediated ERK-MKK3/MKK6-p38 MAPK NF-kappaB signaling pathway. (c) 2016 Wiley Periodicals, Inc. PMID- 26756740 TI - Type 1 Diabetes Duration Decreases Pulmonary Diffusing Capacity during Exercise. AB - BACKGROUND: Diabetes damages peripheral tissues; however, its effects on the lung are less known. Lung diffusing capacity (DLCO) is influenced by alveolar capillary membrane conductance (DM) and pulmonary capillary blood volume (VC), both of which are reduced in adults with type 1 diabetes (T1D). OBJECTIVE: We sought to determine if diabetes duration affects DLCO, DM, VC, and cardiac output (Q). METHODS: 24 T1D patients (10.7-52.8 years) and 24 non-diabetic controls were recruited and had DLCO, DM, VC, and Q measured at rest and during exercise (40, 70 and 90% VO2max). RESULTS: When stratified into two groups based on age (young, <20.6 years old), there were no significant differences in DLCO, DM, VC, or Q (all of which were normalized to body surface area [BSA]) in the young group or in the old group. When stratified by diabetes duration (short duration, 0.33-8.9 years vs. long duration, 9.6-28 years), the T1D patients in the long duration group had lower DLCO/BSA and DM/BSA compared to the controls (p < 0.05). There were no differences in any of the variables in the short duration group. CONCLUSIONS: This study has shown that duration of diabetes is associated with decrements in diffusing capacity and its components. PMID- 26756743 TI - Impaired gait kinematics in type 1 Gaucher's Disease. AB - Type 1 Gaucher's disease (GD1) is traditionally regarded as "non-neurological". Spatiotemporal and kinematic analysis of gait was carried on thirteen GD1 patients and thirteen healthy controls. We identified a previously unknown subclinical reduction of amplitude of movements in GD1. Articular excursion of ankle, knee and hip was reduced during the swing phase of gait (p < 0.0001). Furthermore, the excursion of the knee appeared also significantly more asymmetric in GD1 patients (p = 0.02). Correction for age, BMI and basal walking speed did not modify the significance. Accordingly to the recent observations that GD1 predisposes to Parkinson's disease, the impaired and asymmetric gait kinematics that we observed might be interpreted as a form of extrapyramidal involvement. PMID- 26756742 TI - Prevalence, Patterns and Predictors of Psychotropic Polypharmacy Among Elderly Individuals with Parkinson's Disease In Long Term Care Settings In The United States. AB - BACKGROUND: Elderly individuals with Parkinson's disease (PD) generally suffer from more than one psychiatric comorbidity, which necessitates the use of concurrent psychotropic medications. To the best of the author's knowledge there are no nationally representative estimates of psychotropic polypharmacy among elderly individuals with PD in the United States (US). OBJECTIVE: Therefore, the primary objective of this study was to examine the prevalence, patterns and predictors of psychotropic polypharmacy among elderly individuals with PD in the (US). METHODS: A retrospective, cross-sectional study design with 2004 National Nursing Home Survey (NNHS) and 2007 National Home and Hospice Care Survey (NHHCS) data was used. The analytic sample included elderly (age >=65 years) individuals with PD. Antidepressants, antipsychotics, sedative/hypnotics, and anti-anxiety medications constituted the psychotropic medication classes. Concurrent use of two or more psychotropic medications was classified as psychotropic polypharmacy. RESULTS: Approximately 93,648 and 37,439 elderly individuals with PD resided in nursing homes and home health settings respectively. Among elderly nursing home residents with PD, the nationally representative prevalence of psychotropic polypharmacy was 26.28%, whereas, it was 21.36% in the home health setting. Use of antidepressant medications constituted the majority of the psychotropic medication use among both nursing home (48.91%) and home health (40.98%) residents with PD. Multiple logistic regression analyses revealed that specific comorbidities were significantly associated with psychotropic polypharmacy among elderly nursing home residents with PD. CONCLUSIONS: These findings underscore the importance of evidence-based prescribing when psychotropic medications are used in elderly individuals with PD to reduce unnecessary polypharmacy. PMID- 26756741 TI - Systematic Review of the Relationship between Vitamin D and Parkinson's Disease. AB - BACKGROUND: Although vitamin D may have both protective and symptomatic effects in Parkinson's disease (PD), the evidence is scarce and not well understood. Also, 25-hydroxyvitamin D (vitamin D) is suggested to play a neuroprotective and neurotrophic role in the brain. Therefore, this review investigates the relationship between vitamin D and PD. OBJECTIVE: Investigate the evidence for a relationship between vitamin D and PD by summarizing observational and interventional studies in humans, as well as relevant experimental studies. METHODS: A systematic search was made in the Medline, Cochrane and Embase databases (from inception to March 2014). All identified titles were independently evaluated by two reviewers. Articles were selected based on the presence of PD-related outcome data. Included were observational studies (including genetic studies) and interventional studies in humans, as well as relevant animal studies. RESULTS: A total of 20 studies (14 observational, 1 interventional and 5 rodent studies) were selected for analysis. Eight observational studies showed that serum 25(OH) D levels tend to be low in PD. One observational study indicated that low serum 25(OH) D may worsen automatic postural responses and one interventional study suggested that vitamin D supplementation can prevent worsening (based on the Hoehn and Yahr rating scale). Studies in rodent models of PD showed a protective effect of vitamin D treatment on dopaminergic neurons in the substantia nigra. Results of genetic studies on the association between vitamin D receptor polymorphisms and the risk of PD were contradictory. CONCLUSION: The literature supports possible protective and symptomatic effects of vitamin D in PD. However, more observational and interventional studies in humans are needed to confirm and further elucidate the suggested beneficial effect of vitamin D on PD. PMID- 26756745 TI - Associations between TOMM40 Poly-T Repeat Variants and Dementia in Cases with Parkinsonism. AB - BACKGROUND: Mitochondrial dysfunction has been implicated in the pathophysiology of Parkinson's disease (PD)-related pathologies. OBJECTIVE: To investigate the role of the Translocase of the Outer Mitochondrial Membrane 40 homolog (TOMM40) variants in PD without dementia (PDND), PD with dementia (PDD) and in Dementia with Lewy bodies (DLB). METHODS: 248 individuals, including 92 PDND, 55 PDD, and 101 DLB, were included. The rs10524523 locus in the TOMM40 gene (TOMM40 poly-T repeat) is characterized by a variable number of T residues that were classified into three groups based on length; short (S), long (L), and very long (VL). We tested log-additive genetic model of association with dementia and adjusted for age, sex, and APOEE4 carrier status. We analyzed cerebrospinal fluid (CSF) levels of Abeta42 and Tau, biomarkers related to Alzheimer's disease (AD). RESULTS: PDD/DBL status and abnormal CSF AD biomarkers (Abeta42 and Abeta42/Tau ratio) were both associated with the APOEE4 allele (p < 0.014) and the L allele of TOMM40 poly-T repeat (p < 0.008). The VL allele was less frequently observed in the PDD/DLB group (p = 0.013). In APOE-E4 adjusted analyses, the relationships between the L and VL alleles and dementia status as well as CSF AD biomarkers were not significant. When adjusting for APOE-E4, however, there were associations between S carrier status and PDD/DLB (p = 0.019) and abnormal CSF levels of Abeta42/Tau ratio (p = 0.037) although these were not significant after adjustment for multiple comparisons. CONCLUSION: Our results do not support the notion that TOMM40 poly-T repeat variants have independent effects on PDD and DLB pathology. This relationship seems to be driven by APOE-E4. PMID- 26756744 TI - Prevalence of Submandibular Gland Synucleinopathy in Parkinson's Disease, Dementia with Lewy Bodies and other Lewy Body Disorders. AB - BACKGROUND: Clinical misdiagnosis, particularly at early disease stages, is a roadblock to finding new therapies for Lewy body disorders. Biopsy of a peripheral site might provide improved diagnostic accuracy. Previously, we reported, from both autopsy and needle biopsy, a high prevalence of submandibular gland synucleinopathy in Parkinson's disease (PD). Here, we report on an extension of these studies to subjects with dementia with Lewy bodies (DLB) and other Lewy body disorders in 228 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders. OBJECTIVE: To provide an estimate of the prevalence of histological synucleinopathy in the submandibular glands of subjects with PD and other Lewy body disorders. METHODS: Submandibular gland sections from autopsied subjects were stained with an immunohistochemical method for alpha-synuclein phosphorylated at serine 129. Included were 146 cases with CNS Lewy-type synucleinopathy (LTS), composed of 46 PD, 28 DLB, 14 incidental Lewy body disease (ILBD), 33 Alzheimer's disease with Lewy bodies (ADLB) and 2 with progressive supranuclear palsy and Lewy bodies (PSPLB). Control subjects included 79 normal elderly, 15 AD, 12 PSP, 2 conticobasal degeneration (CBD) and 2 multiple system atrophy (MSA). RESULTS: Submandibular gland LTS was found in 42/47 (89%) of the PD subjects, 20/28 (71%) DLB, 4/33 (12%) ADLB and 1/9 (11%) ILBD subjects but none of the 110 control subjects. CONCLUSIONS: These results provide support for further clinical trials of in vivo submandibular gland diagnostic biopsy for PD and DLB. An accurate peripheral biopsy diagnosis would assist subject selection for clinical trials and could also be used to verify other biomarkers. PMID- 26756748 TI - Effects of Titanium Doping in Titanomagnetite on Neptunium Sorption and Speciation. AB - Neptunium-237 is a radionuclide of great interest owing to its long half-life (2.14 * 10(6) years) and relative mobility as the neptunyl ion (NpO2(+)) under many surface and groundwater conditions. Reduction to tetravalent neptunium (Np(IV)) effectively immobilizes the actinide in many instances due to its low solubility and strong interactions with natural minerals. One such mineral that may facilitate the reduction of neptunium is magnetite (Fe(2+)Fe(3+)2O4). Natural magnetites often contain titanium impurities which have been shown to enhance radionuclide sorption via titanium's influence on the Fe(2+)/Fe(3+) ratio (R) in the absence of oxidation. Here, we provide evidence that Ti-substituted magnetite reduces neptunyl species to Np(IV). Titanium-substituted magnetite nanoparticles were synthesized and reacted with NpO2(+) under reducing conditions. Batch sorption experiments indicate that increasing Ti concentration results in higher Np sorption/reduction values at low pH. High-resolution transmission electron microscopy of the Ti-magnetite particles provides no evidence of NpO2 nanoparticle precipitation. Additionally, X-ray absorption spectroscopy confirms the nearly exclusive presence of Np(IV) on the titanomagnetite surface and provides supporting data indicating preferential binding of Np to terminal Ti-O sites as opposed to Fe-O sites. PMID- 26756746 TI - Cerebral beta-Amyloid Angiopathy Is Associated with Earlier Dementia Onset in Alzheimer's Disease. AB - BACKGROUND: Cerebral beta-amyloid angiopathy (CAA) occurs when beta-amyloid (Abeta) is deposited in the vascular media and adventitia. It is a common pathology in the brains of older individuals and has been linked to cognitive decline, but relatively little is known about the influence that CAA has on the clinical manifestation of Alzheimer's disease (AD). The aim of this retrospective analysis was to quantify the effect that CAA had on the manifestation of initial AD-related cognitive change and subsequent progression of dementia. METHODS: We analyzed neuropathological data from the National Alzheimer's Coordinating Center's data set, performing parametric analyses to assess differences in age of progression to moderate-stage dementia. RESULTS: We found that individuals with both CAA burden and Abeta neuritic plaque burden at death had the greatest risk of earlier conversion to very mild and moderate-stage dementia, but not necessarily faster progression. CONCLUSIONS: Our results suggest that CAA contributes to changes in early AD pathogenesis. This supports the idea that vascular change and neuritic plaque deposition are not just parallel processes but reflect additive pathological cascades that influence the course of clinical AD manifestation. Further inquiry into the role of CAA and its contribution to early cognitive change in AD is suggested. PMID- 26756750 TI - Clinical Decision Analysis and Markov Modeling for Surgeons: An Introductory Overview. AB - This study addresses the use of decision analysis and Markov models to make contemplated decisions for surgical problems. Decision analysis and decision modeling in surgical research are increasing, but many surgeons are unfamiliar with the techniques and are skeptical of the results. The goal of this review is to familiarize surgeons with techniques and terminology used in decision analytic papers, to provide the reader a practical guide to read these papers, and to ensure that surgeons can critically appraise the quality of published clinical decision models and draw well founded conclusions from such reports.First, a brief explanation of decision analysis and Markov models is presented in simple steps, followed by an overview of the components of a decision and Markov model. Subsequently, commonly used terms and definitions are described and explained, including quality-adjusted life-years, disability-adjusted life-years, discounting, half-cycle correction, cycle length, probabilistic sensitivity analysis, incremental cost-effectiveness ratio, and the willingness-to-pay threshold.Finally, the advantages and limitations of research with Markov models are described, and new modeling techniques and future perspectives are discussed. It is important that surgeons are able to understand conclusions from decision analytic studies and are familiar with the specific definitions of the terminology used in the field to keep up with surgical research. Decision analysis can guide treatment strategies when complex clinical questions need to be answered and is a necessary and useful addition to the surgical research armamentarium. PMID- 26756747 TI - Comparison of the Effects of Dorzolamide/Timolol Fixed Combination versus Latanoprost on Intraocular Pressure and Ocular Perfusion Pressure in Patients with Normal-Tension Glaucoma: A Randomized, Crossover Clinical Trial. AB - BACKGROUD: To assess the noninferiority of a dorzolamide-timolol fixed combination (DTFC) versus latanoprost in terms of intraocular pressure (IOP) and to compare blood pressure (BP), ocular perfusion pressure (OPP) and diastolic ocular perfusion pressure (DOPP) between the latanoprost and DTFC groups in patients with normal-tension glaucoma (NTG). METHODS: Prospective, interventional, randomized, single-blinded, crossover design study. Patients with newly diagnosed NTG that had not been treated with a glaucoma medication in the most recent 2 months were recruited. In total, 44 patients with NTG were randomly allocated to one of two groups. Patients in group A were treated with DTFC, lubricant, and latanoprost for 4 weeks each, whereas patients in group B were treated with latanoprost, lubricant, and DTFC for 4 weeks each. Patients were examined on day 1 (without medication), week 4 (under medication), week 8 (without medication), and week 12 (under medication). At weeks 4 and 12, diurnal IOP, systolic and diastolic BP, and OPP were measured at 8:00 AM, 10:00 AM, 12:00 PM, 4:00 PM, and 8:00 PM. RESULTS: Baseline demographic characteristics showed no difference in terms of age, sex, central corneal thickness, spherical equivalent, or stage of glaucoma between the groups. The between-group difference was -0.19 +/- 0.18 mmHg (mean +/- SE, upper bound of one-sided 95% CI, 0.12). Diurnal IOP showed no difference between the groups with an average IOP reduction of 13.1% using latanoprost and 12.3% using DTFC. Diurnal systolic and diastolic BP were lower in the DTFC group than the latanoprost group; however, the difference between the groups was not statistically significant. Diurnal OPP and DOPP also showed no statistically significant difference between the groups. CONCLUSIONS: IOP lowering efficacy of DTFC was noninferior to that of latanoprost in newly diagnosed NTG patients. There was no difference in BP, OPP, or DOPP between the latanoprost and DTFC groups. This prospective, randomized, single-blinded, crossover study demonstrated the noninferiority of DTFC versus latanoprost in terms of IOP in patients with NTG. TRIAL REGISTRATION: ClinicalTrials.gov NCT01175902. PMID- 26756749 TI - Hospital Analgesia Practices and Patient-reported Pain After Colorectal Resection. AB - OBJECTIVE: The aim of the study was to characterize patient-reported outcomes of analgesia practices in a population-based surgical collaborative. BACKGROUND: Pain control among hospitalized patients is a national priority and effective multimodal pain management is an essential component of postoperative recovery, but there is little understanding of the degree of variation in analgesia practice and patient-reported pain between hospitals. METHODS: We evaluated patient-reported pain scores after colorectal operations in 52 hospitals in a state-wide collaborative. We stratified hospitals by quartiles of average pain scores, identified hospital characteristics, pain management practices, and clinical outcomes associated with highest and lowest case-mix-adjusted pain scores, and compared against Hospital Consumer Assessment of Healthcare Providers and Systems pain management metrics. RESULTS: Hospitals with the lowest pain scores were larger (503 vs 452 beds; P < 0.001), higher volume (196 vs 112; P = 0.005), and performed more laparoscopy (37.7% vs 27.2%; P < 0.001) than those with highest scores. Their patients were more likely to receive local anesthesia (31.1% vs 12.9%; P < 0.001), nonsteroidal anti-inflammatory drugs (33.5% vs 14.4%; P < 0.001), and patient-controlled analgesia (56.5% vs 22.8%; P < 0.001). Adverse postoperative outcomes were less common in hospitals with lowest pain scores, including complications (20.3% vs 26.4%; P < 0.001), emergency department visits (8.2% vs 15.8%; P < 0.001), and readmissions (11.3% vs 16.2%; P = 0.01). CONCLUSIONS: Pain management after colorectal surgery varies widely and predicts significant differences in patient-reported pain and clinical outcomes. Enhanced postoperative pain management requires dissemination of multimodal analgesia practices. Attention to patient-reported outcomes often omitted from surgical outcomes registries is essential to improving quality from the patient's perspective. PMID- 26756751 TI - Underreporting of Secondary Endpoints in Randomized Trials: Cross-sectional, Observational Study. AB - OBJECTIVE: To determine if underreporting of secondary endpoints in randomized controlled trials occurs, using surgical site infection (SSI) as an example. BACKGROUND: SSI is a commonly measured endpoint in surgical trials and can act as a proxy marker for primary and secondary endpoint assessments across trials in a range of medical specialties. METHODS: Cross-sectional observational study of randomized trials including patients undergoing gastrointestinal surgery published in a representative selection of general medical and general surgical journals. Studies were included if SSI assessment was a prespecified endpoint. Adjusted binary logistic regression was used to identify factors associated with a high rate of SSI detection (>=10%). RESULTS: From 216 trials including 45,633 patients, the pooled SSI rate was 7.7% (3519/45,633), which was significantly higher when assessed as a primary endpoint (12.6%, 1993/15,861, 49 studies) vs as a secondary endpoint (5.1%, 1526/29,772, 167 studies, P < 0.001). When assessed as a secondary outcome, standardized definitions and formal clinical reviews were used significantly less often. When adjusted for surgical contamination and methodological confounders, secondary assessment was associated with reduced SSI detection compared with primary assessment (adjusted odds ratio 0.24, 95% confidence interval 0.08-0.69, P = 0.008). CONCLUSIONS: Secondary endpoint assessment of SSI in randomized trials was associated with significantly reduced rigor and subsequent detection rates compared with assessment as a primary endpoint. Trial investigators should ensure that primary and secondary endpoint assessments are equally robust. PRISMA guidelines should be updated to promote the conduct of meta-analysis based only on primary outcomes from randomized controlled trials. PMID- 26756752 TI - Oral and Parenteral Versus Parenteral Antibiotic Prophylaxis in Elective Laparoscopic Colorectal Surgery (JMTO PREV 07-01): A Phase 3, Multicenter, Open label, Randomized Trial. AB - OBJECTIVE: To confirm the efficacy of oral and parenteral antibiotic prophylaxis (ABX) in the elective laparoscopic colorectal surgery. BACKGROUND: There is no evidence for the establishment of an optimal ABX regimen for laparoscopic colorectal surgery, which has become an important choice for the colorectal cancer patients. METHODS: The colorectal cancer patients scheduled to undergo laparoscopic surgery were eligible for this multicenter, open-label, randomized trial. They were randomized to receive either oral and parenteral prophylaxis (1 g cefmetazole before and every 3 h during the surgery plus 1 g oral kanamycin and 750 mg metronidazole twice on the day before the surgery; Oral-IV group) or parenteral prophylaxis alone (the same IV regimen; IV group). The primary endpoint was the incidence of surgical site infections (SSIs). Secondary endpoints were the incidence rates of Clostridium difficile colitis, other infections, and postoperative noninfectious complications, as well as the frequency of isolating specific organisms. RESULTS: Between November 2007 and December 2012, 579 patients (289 in the Oral-IV group and 290 in IV group) were evaluated for this study. The incidence of SSIs was 7.26% (21/289) in the Oral-IV group and 12.8% (37/290) in the IV group with an odds ratio of 0.536 (95% CI, 0.305-0.940; P = 0.028). The 2 groups had similar incidence rates of C difficile colitis (1/289 vs 3/290), other infections (6/289 vs 5/290), and postoperative noninfectious complications (11/289 vs 12/290). CONCLUSIONS: Our oral-parenteral ABX regimen significantly reduced the risk of SSIs following elective laparoscopic colorectal surgery. PMID- 26756755 TI - Columnar Metaplasia in the Esophageal Remnant After Esophagectomy: A Common Occurrence and a Valuable Insight Into the Development of Barrett Esophagus. AB - OBJECTIVE: This study aimed to establish the incidence of postesophagectomy columnar metaplasia and dysplasia, and the timescale over which it develops. It also aimed to assess if this epithelium is molecularly similar to sporadic Barrett esophagus, thereby confirming suitability as a research model. BACKGROUND: Metaplasia in the esophageal remnant after esophagectomy is well described, but incidence and the potential for dysplasia are uncertain, and the clinical relevance unclear. Although proposed as a model for Barrett esophagus, no large studies have examined the molecular phenotype of postesophagectomy metaplasia. METHODS: Patients underwent prospective endoscopic evaluation having previously undergone esophagectomy. The macroscopic appearance of the esophageal remnant was noted and biopsies taken. Specimens were stained using hematoxylin and eosin and by immunohistochemistry for cytokeratins 7 and 20, and Chromogranin A-proteins which have a well described expression pattern in sporadic Barrett esophagus. RESULTS: Of the 126 eligible patients, 45 (36%) had evidence of metaplasia. There were no cases of dysplasia. Nonintestinalized columnar epithelium occurred earlier than specialized intestinal metaplasia (median 4.8 vs 8.1 yr; P = 0.025). Thirty-seven samples underwent immunohistochemical analysis. A classic cytokeratin 7/20 staining pattern was present in 23 cases (62%), within the prevalence range reported for sporadic Barrett. CONCLUSIONS: Columnar metaplasia is common following esophagectomy, but the absence of dysplasia in this large cohort is reassuring. Presence of specialized intestinal metaplasia is associated with increased time from surgery, suggesting this represents later disease. Immunohistochemistry staining is similar to sporadic Barrett, suggesting that this group of patients represent an accurate human model for the development of Barrett. PMID- 26756753 TI - Acute and Chronic Kidney Disease and Cardiovascular Mortality After Major Surgery. AB - OBJECTIVE: The aim of the study was to determine the long-term cardiovascular specific mortality in patients with acute kidney injury (AKI) or chronic kidney disease (CKD) after major surgery. BACKGROUND: In surgical patients, pre-existing CKD and postoperative AKI are associated with increases in all-cause mortality. METHODS: In a single-center cohort of 51,457 adult surgical patients undergoing major inpatient surgery, long-term cardiovascular-specific mortality was modeled using a multivariable subdistributional hazards model while treating any other cause of death as a competing risk and accounting for the progression to end stage renal disease (ESRD) after discharge. Pre-existing CKD and ESRD, and postoperative AKI were the main independent predictors. RESULTS: Before the admission, 4% and 8% of the cohort had pre-existing ESRD and CKD not requiring renal replacement therapy, respectively. During hospitalization, 39% developed AKI. At 10-year follow-up, adjusted cardiovascular-specific mortality estimates were 6%, 11%, 12%, 19%, and 27% for patients with no kidney disease, AKI with no CKD, CKD with no AKI, AKI with CKD, and ESRD, respectively (P < 0.001). This association remained after excluding 916 patients who progressed to ESRD after discharge, although it was significantly amplified among them. Compared with patients having no kidney disease, adjusted hazard ratios for cardiovascular mortality were significantly higher among patients with kidney disease, ranging from 1.95 (95% confidence interval, 1.80-2.11) for patients with de novo AKI to 5.70 (95% confidence interval, 5.00-6.49) for patients with pre-existing ESRD. CONCLUSIONS: Both AKI and CKD were associated with higher long-term cardiovascular-specific mortality compared with patients having no kidney disease. PMID- 26756756 TI - Clinicopathological Parameters in Patient Selection for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Cancer Metastases: A Meta-analysis. AB - OBJECTIVE: To improve patient selection for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) by evaluating various preoperatively assessable clinicopathological parameters as markers for survival after CRS and HIPEC. SUMMARY BACKGROUND DATA: Peritoneal metastases (PMs) originating from colorectal cancer are treated with CRS and HIPEC. Despite increasing survival, high morbidity and mortality warrant selection of patients with optimal benefit from this treatment. Many studies report a number of variables to be associated with survival after CRS and HIPEC, but no definitive analysis has been made to validate various markers. METHODS: In concordance with PRISMA guidelines, we performed a literature search encompassing 4110 articles to select 50 articles that reported the influence of 1 or more clinicopathological variables on overall survival after CRS and HIPEC. In absence of RCTs, 25 cohort studies could be used to perform a meta-analysis on 10 prognostic variables. RESULTS: We determined that concurrent liver metastasis, lymph node metastasis, Eastern Cooperative Oncology Group score, tumor differentiation, and signet ring cell histology are all negative prognostic variables on overall survival after CRS and HIPEC. Conversely, sex and location of primary could not be validated as prognostic markers. More research is required to make definitive conclusions about neoadjuvant chemotherapy, onset of PMs, and mucinous histology. CONCLUSIONS: Current clinical practice, which selects patients based on extraperitoneal metastasis, lymph node stage, performance status, and tumor histology, is validated by our pooled analysis. Our data merit further research into neoadjuvant chemotherapy in the setting of CRS and HIPEC for PMs. PMID- 26756757 TI - Using Surgical Video to Improve Technique and Skill. PMID- 26756764 TI - Drop of Total Liver Function in the Interstages of the New Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy Technique: Analysis of the "Auxiliary Liver" by HIDA Scintigraphy. PMID- 26756760 TI - Circulating Tumor Cell Phenotype Predicts Recurrence and Survival in Pancreatic Adenocarcinoma. AB - OBJECTIVE: We assessed circulating tumor cells (CTCs) with epithelial and mesenchymal phenotypes as a potential prognostic biomarker for patients with pancreatic adenocarcinoma (PDAC). BACKGROUND: PDAC is the fourth leading cause of cancer death in the United States. There is an urgent need to develop biomarkers that predict patient prognosis and allow for better treatment stratification. METHODS: Peripheral and portal blood samples were obtained from 50 patients with PDAC before surgical resection and filtered using the Isolation by Size of Epithelial Tumor cells method. CTCs were identified by immunofluorescence using commercially available antibodies to cytokeratin, vimentin, and CD45. RESULTS: Thirty-nine patients (78%) had epithelial CTCs that expressed cytokeratin but not CD45. Twenty-six (67%) of the 39 patients had CTCs which also expressed vimentin, a mesenchymal marker. No patients had cytokeratin-negative and vimentin-positive CTCs. The presence of cytokeratin-positive CTCs (P < 0.01), but not mesenchymal like CTCs (P = 0.39), was associated with poorer survival. The presence of cytokeratin-positive CTCs remained a significant independent predictor of survival by multivariable analysis after accounting for other prognostic factors (P < 0.01). The detection of CTCs expressing both vimentin and cytokeratin was predictive of recurrence (P = 0.01). Among patients with cancer recurrence, those with vimentin-positive and cytokeratin-expressing CTCs had decreased median time to recurrence compared with patients without CTCs (P = 0.02). CONCLUSIONS: CTCs are an exciting potential strategy for understanding the biology of metastases, and provide prognostic utility for PDAC patients. CTCs exist as heterogeneous populations, and assessment should include phenotypic identification tailored to characterize cells based on epithelial and mesenchymal markers. PMID- 26756765 TI - Association Between Intraoperative Low Blood Pressure and Development of Surgical Site Infection After Colorectal Surgery: A Retrospective Cohort Study. AB - OBJECTIVE: We tested the primary hypothesis that surgical site infections (SSIs) are more common in patients who had longer periods of intraoperative low blood pressure. Our secondary hypothesis was that hospitalization is prolonged in patients experiencing longer periods of critically low systolic blood pressure (SBP) and/or mean arterial pressure (MAP). BACKGROUND: Hypotension compromises local tissue perfusion, thereby reducing tissue oxygenation. Hypotension might thus be expected to promote infection, but the extent to which low blood pressure contributes remains unclear. METHODS: We considered patients who had colorectal surgery lasting at least 1 hour at the Cleveland Clinic between 2009 and 2013. The duration of hypotensive exposure and development of SSI was assessed with logistic regression; the association between hypotensive exposure and duration of hospitalization was assessed with Cox proportional hazard regression. RESULTS: A total of 2521 patients were eligible for analysis. There was no adjusted association between SBP hypotension < 80 mm Hg and SSI, with an estimated odds ratio (95% confidence interval) of 0.97 (0.81, 1.17) per 5-minute increase in SBP hypotension (P = 0.54). There was also no adjusted association between MAP hypotension time and SSI, with estimated odds ratio of 0.97 (0.81, 1.17) for a 5 minute increase in MAP hypotension < 55 mm Hg time (P = 0.71). There was no association between duration of hypotension and time to discharge. CONCLUSIONS: Intraoperative hypotension does not seem to be a clinically important predictor of SSI after colorectal surgery, probably because the outcomes are overwhelmingly determined by other baseline and surgical factors-and perhaps postoperative hypotension. PMID- 26756763 TI - Targeted Nanotherapies for the Treatment of Surgical Diseases. AB - OBJECTIVE: To describe the components of targeted nanotherapeutics and to review their applications in the treatment of surgical diseases. BACKGROUND: Targeted nanotherapeutic is a novel strategy for treating a variety of diseases and is an emerging technology that offers advantages over current treatment strategies. The nanoscale size, combined with the ability to surface functionalize the delivery vehicle to enable targeting and incorporate a therapeutic payload, provides a new and innovative therapeutic platform to treat surgical diseases that has yet to be fully realized in the surgical arena. METHODS: A comprehensive literature review of nanotherapeutics, targeting strategies, and their utility in treating surgical diseases is performed. RESULTS: Targeted nanotherapeutics have demonstrated safety and biocompatibility in treating surgical diseases. The ability to surface functionalize the nanoparticles affords a unique tailorability that enables targeting specificity and therapeutic payload delivery to treat a variety of surgical diseases. Moreover, the small size and targeting capabilities allow access to biological compartments, such as the blood-brain barrier, that have previously been difficult to treat. CONCLUSIONS: Targeted nanotherapeutics represent a novel therapeutic platform and have great potential to impact the treatment of surgical diseases. PMID- 26756766 TI - Preoperative Supervised Exercise Improves Outcomes After Elective Abdominal Aortic Aneurysm Repair: A Randomized Controlled Trial. AB - OBJECTIVE: The aim of the study was to assess the impact of a preoperative medically supervised exercise program on outcomes after elective abdominal aortic aneurysm (AAA) repair. BACKGROUND: Functional capacity is an important predictor of postoperative outcomes after elective AAA repair. Improving patients' preoperative fitness with exercise has the potential to positively influence recovery. METHODS: A randomized controlled trial was performed at a tertiary vascular unit. Patients scheduled for open or endovascular AAA repair were randomized to either 6 weeks of preoperative supervised exercise or standard treatment using sealed envelopes. The primary outcome measure was a composite endpoint of cardiac, pulmonary, and renal complications. Secondary outcome measures were 30-day mortality, lengths of hospital and critical care stay, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, reoperation, and postoperative bleeding. RESULTS: One hundred twenty-four patients were randomized (111 men, mean [SD] age 73 [7] y). Fourteen patients sustained postoperative complications in the exercise group (22.6%), compared with 26 in the nonexercise group (41.9%; P = 0.021). Four patients (2 in each group) died within the first 30 postoperative days. Duration of hospital stay was significantly shorter in the exercise group (median 7 [interquartile range 5-9] vs 8 [interquartile range 6 12.3] d; P = 0.025). There were no significant differences between the groups in the length of critical care stay (P = 0.845), APACHE II scores (P = 0.256), incidence of reoperations (P = 1.000), or postoperative bleeding (P = 0.343). CONCLUSIONS: A period of preoperative supervised exercise training reduces postoperative cardiac, respiratory, renal complications, and length of hospital stay in patients undergoing elective AAA repair. PMID- 26756767 TI - Routine Neurectomy of Inguinal Nerves During Open Onlay Mesh Hernia Repair: A Meta-analysis of Randomized Trials. AB - OBJECTIVE: The aim of the study was to establish whether an inguinal neurectomy at the time of hernia repair would reduce the risk of postoperative pain for open tension-free sutured mesh repair. BACKGROUND: Inguinal hernia repair is a common operative procedure. The development of postoperative pain is uncommon, but at times debilitating. The role of inguinal neurectomy is currently unknown, with no single large study available, and previous reviews included only a few heterogeneous studies. METHODS: Relevant randomized trials were identified from searches of MEDLINE, EMBASE, and EBM Review databases until October 2014. Meta analysis was performed based on Cochrane Methods using RevMan v5.3 software. Pain, pain scores, sensory changes, and complications over short (half to <3 months), mid (3 to <12 mo), and long term (>=12 mo) were recorded. RESULTS: All included studies performed Lichtenstein hernia repair. Eleven studies on 1031 patients showed significant reduction in pain with neurectomy for short (RR = 0.61, 0.40-0.93) and midterm (RR = 0.30, 0.20-0.46), but not for long term (RR = 0.50, 0.25-1.01). Three studies (270 patients) showed significantly reduced short term pain (RR = 0.69, 0.52-0.90). No studies included genitofemoral neurectomy. Rates of hematoma, infection, urinary retention, and recurrence were not different between groups. CONCLUSIONS: Routine ilioinguinal neurectomy during Lichtenstein-type herniorrhaphy seems to be a safe and effective method to reduce pain in the short and midterm, but may have little long-term impact. Iliohypogastric neurectomy seems to reduce pain in at least the short term. PMID- 26756770 TI - Rating the Raters: The Inconsistent Quality of Health Care Performance Measurement. PMID- 26756771 TI - ALPPS--Where Do We Stand, Where Do We Go?: Eight Recommendations From the First International Expert Meeting. PMID- 26756778 TI - Life After Discharge Following Major Injury: Expanding Our Notion of Quality in Trauma Care. PMID- 26756780 TI - Coupled Motions in beta2AR:Galphas Conformational Ensembles. AB - G protein-coupled receptors (GPCRs) act as conduits in the plasma membrane, facilitating cellular responses to physiological events by activating intracellular signal transduction pathways. Extracellular signaling molecules can induce conformational changes in GPCR, which allow it to selectively activate intracellular protein partners such as heterotrimeric protein G. However, a major unsolved problem is how GPCRs and G proteins form complexes and how their interaction results in G protein activation. Here, we show that an inactive, agonist-free beta2AR:Galphas complex can collectively sample intermediate states of the receptor on an activation pathway. An in silico conformational ensemble around the inactive state manifests significant conformational coupling between structural elements implicated in G protein activation throughout the complex. While Galphas helix alpha5 has received much attention as a driver for nucleotide exchange, we also observe interactions between helix alphaN with Intra Cellular Loop 2, which can be transmitted by beta1 to facilitate nucleotide exchange by disrupting a salt bridge between the P-loop and Switch I. These interactions are moderated in an active state ensemble. Collectively, our results support an alternative view of G protein activation, in which precoupling can allosterically modulate an agonist-free receptor. Subsequent selective agonist recruitment would result in collective activation of the complex. This alternative view can help us understand how distinct extracellular binding partners result in different but interdependent signaling pathways, with broad implications for GPCR drug discovery. PMID- 26756779 TI - Carolignans from the Aerial Parts of Euphorbia sikkimensis and Their Anti-HIV Activity. AB - Seven new carolignans, including two pairs of enantiomers (+/-)-erythro-7' methylcarolignan E (1a/1b) and (+/-)-threo-7'-methylcarolignan E (2a/2b), (+) threo-carolignan E (3a), (+)-erythro-carolignan E (4a), and (-)-erythro carolignan Z (5), together with four known lignans (3b, 4b, 6, and 7) and six polyphenols (8-13) were isolated from the aerial parts of Euphorbia sikkimensis. The structures of the new compounds were elucidated by spectroscopic analysis, and their absolute configurations were determined by electronic circular dichroism calculations. Seven of the isolates were examined for anti-HIV effects, and compounds 1a and 1b showed moderate anti-HIV activity with EC50 values of 6.3 and 5.3 MUM. PMID- 26756782 TI - P-glycoprotein in the developing human blood-brain barrier. PMID- 26756781 TI - Dose-dependent effects of glucocorticoids on pulmonary vascular development in a murine model of hyperoxic lung injury. AB - BACKGROUND: Exposure of neonatal mice to hyperoxia results in pulmonary vascular remodeling and aberrant phosphodiesterase type 5 (PDE5) signaling. Although glucocorticoids are frequently utilized in the NICU, little is known about their effects on the developing pulmonary vasculature and on PDE5. We sought to determine the effects of hydrocortisone (HC) on pulmonary vascular development and on PDE5 in a neonatal mouse model of hyperoxic lung injury. METHODS: C57BL/6 mice were placed in 21% O2 or 75% O2 within 24 h of birth and received HC (1, 5, or 10 mg/kg subcutaneously every other day) or vehicle. At 14 d, right ventricular hypertrophy (RVH), medial wall thickness (MWT), lung morphometry, and pulmonary artery (PA) PDE5 activity were assessed. PDE5 activity was measured in isolated pulmonary artery smooth muscle cells exposed to 21 or 95% O2 +/- 100 nmol/l HC for 24 h. RESULTS: Hyperoxia resulted in alveolar simplification, RVH, increased MWT, and increased PA PDE5 activity. HC decreased hyperoxia-induced RVH and attenuated MWT. HC had dose-dependent effects on alveolar simplification. HC decreased hyperoxia-induced PDE5 activity both in vivo and in vitro. CONCLUSIONS: HC decreases hyperoxia-induced pulmonary vascular remodeling and attenuates PDE5 activity. These findings suggest that HC may protect against hyperoxic injury in the developing pulmonary vasculature. PMID- 26756783 TI - Predictive factors and practice trends in red blood cell transfusions for very low-birth-weight infants. AB - BACKGROUND: Red blood cell (RBC) transfusions in very-low-birth-weight (VLBW) infants, while common, carry risk. Our objective was to determine clinical predictors of and trends in RBC transfusions among VLBW infants. METHODS: RBC transfusion practice and its clinical predictors in 1,750 VLBW (<=1,500 g) infants were analyzed in a single-center cohort across sequential epochs: 2000 2004 (Epoch 1), 2005-2009 (Epoch 2), and 2010-2013 (Epoch 3). RESULTS: Overall, 1,168 (67%) infants received >=1 transfusions. The adjusted likelihood of >=1 transfusions decreased for each 1-g/dl increment in initial hemoglobin concentration following birth, for females, and for each 100-g increment in birth weight. The adjusted likelihood of >=1 transfusions increased with infants receiving mechanical ventilation, with increasing length of hospital stay, necrotizing enterocolitis, and nonlethal congenital anomalies requiring surgery. The adjusted mean (SEM) number of transfusions per patient was decreased in Epoch 3, compared with Epoch 1 and Epoch 2. For an initial hemoglobin of >=16.5 g/dl, the predicted probability of being transfused was <=50%. CONCLUSION: Adjusted RBC transfusions declined and female sex conferred an unexplained protection over the study period. Modest increases in initial hemoglobin by placentofetal transfusion at delivery may reduce the need for RBC transfusion. PMID- 26756784 TI - Bacterial microbiome of breast milk and child saliva from low-income Mexican American women and children. AB - BACKGROUND: The childhood salivary microbiome, which plays an important role in healthy development, may be influenced by breast milk consumption. The composition of the milk microbiome and the role it plays in the establishment of the infant microbiome are not well understood. METHODS: Here, we sequenced the bacterial 16S rRNA gene to characterize microbial communities in breast milk and 5-year-old child saliva from 10 low-income, Mexican-American mother-child pairs with a high prevalence of obesity. RESULTS: Members of the genus Streptococcus dominated both milk and salivary microbial communities in most subjects. Staphylococcus was observed predominately in milk samples while Prevotella was more prevalent in child saliva. No statistically significant relationships were observed between maternal and child microbiomes or between child microbiome and BMI. However, prepregnancy BMI was correlated with both lower Streptococcus abundance (r = -0.67) and higher microbial diversity (r = 0.77) in breast milk (P < 0.05 for both). Diversity estimates were notably similar to data from other low income cohorts or children. CONCLUSION: These findings contribute to the currently limited state of knowledge regarding the breast milk and salivary microbiomes in mother-child pairs and may inform future studies seeking to elucidate the relationship between early-life microbial exposures and pediatric health. PMID- 26756785 TI - Role of PPARalpha in the attenuation of bile acid-induced apoptosis by omega-3 long-chain polyunsaturated fatty acids in cultured hepatocytes. AB - BACKGROUND: Omega-3 long-chain polyunsaturated fatty acids (omega3PUFA) have been shown to be antiinflammatory in the attenuation of hepatocellular injury. Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor transcription factor that inhibits the activation of nuclear factor kappaB, thereby repressing inflammation, and omegaPUFA are PPARalpha ligands. The purpose of this study was to determine if omega3PUFA attenuate bile acid-induced apoptosis via PPARalpha. METHODS: Human hepatocellular carcinoma (HepG2) cells were treated with chenodeoxycholic acid (CDCA) +/- omega3PUFA. Activation of PPARalpha was evaluated, and expression of PPARalpha, farnesoid X receptor, liver X receptor alpha (LXRalpha), and retinoid X receptor mRNA was evaluated by reverse-transcriptase PCR. RESULTS: PPARalpha activation was increased in HepG2 cells treated with omega3PUFA, and decreased in the presence of CDCA when compared with untreated cells. PPARalpha mRNA was reduced by 67% with CDCA and restored to the level of control with omega3PUFA. LXRalpha mRNA increased twofold with CDCA treatment and was significantly reduced by omega3PUFA. CONCLUSION: Expression of PPARalpha, as well as LXRalpha mRNA levels, was reduced with CDCA treatment and restored with the addition of omega3PUFA. These results suggest that PPARalpha and LXRalpha may be mediators by which omega3PUFA attenuate bile acid-induced hepatocellular injury. PMID- 26756786 TI - Associations of TM6SF2 167K allele with liver enzymes and lipid profile in children: the PANIC Study. AB - BACKGROUND: The 167K allele in the TM6SF2 gene has been suggested to protect against cardiovascular disease at the cost of developing nonalcoholic fatty liver disease in adults. METHODS: We performed a cross-sectional study in a population sample of 462 Caucasian children aged 6-9 y, genotyped the polymorphism using HumanCoreExome BeadChip, and assessed several cardiometabolic risk factors. RESULTS: The 51 (11%) carriers of the 167K allele had higher plasma alanine aminotransferase (ALT) (20.8 vs. 18.4 U/l, P = 0.011) but lower plasma triglycerides (0.54 vs. 0.61 mmol/l, P = 0.024), total cholesterol (4.08 vs. 4.30 mmol/l, P = 0.016), and low-density lipoprotein (LDL) cholesterol (2.22 vs. 2.38 mmol/l, P = 0.012) than the 411 noncarriers. In factor analysis, the first factor was heavily loaded by plasma ALT (factor loading 0.63), triglycerides (-0.82), LDL cholesterol (-0.71), and waist circumference (0.61) in the carriers but not in the noncarriers. CONCLUSIONS: The carriers of the 167K allele have higher plasma ALT but lower plasma triglycerides and total and LDL cholesterol than the noncarriers already in childhood. PMID- 26756787 TI - Health-related quality of life as a predictor of recurrent falling in Parkinson's disease: 1-year follow-up study. AB - OBJECTIVE: The aim of this study was to assess whether various domains related to health-related quality of life could be predictive of recurrent falls among persons with Parkinson's disease (PD) during a 1-year follow-up study. METHODS: A total of 120 consecutive persons with PD who had denied falling in past 6 months were recruited at regular check-ups at the Department of Movement Disorders, Neurology Clinic, Clinical Center of Serbia in Belgrade, from 15 August 2011 to 15 December 2012. At baseline, study participants were clinically assessed. Health-related quality of life was evaluated with the generic 36-item Short Form Health Survey. Participants were prospectively followed for 1 year, and occurrence of falls was registered. RESULTS: The median age of subjects was 60.0 years, with a median disease duration of 4.0 years. Of 120 persons with PD, 42 (35%) experienced falls during the 12-month study period, including 23 (19.2%) who fell repeatedly. After adjustment for gender, age, PD duration, levodopa dosage, Hoehn and Yahr stage, Unified Parkinson's Disease Rating Scale I-IV, Hamilton Depression Rating Scale, and Hamilton Anxiety Rating Scales, we identified the 36-item Short Form Health Survey domains of role physical (P = 0.033) and vitality (P = 0.019) as being associated with recurrent falls of persons with PD within the 1-year follow-up period. CONCLUSION: Baseline 36-item Short Form Health Survey scores regarding both the physical and mental components of overall health may be related to recurrent falling among persons with PD. These HRQoL domains could be considered as potential markers for persons with PD who are prone to recurrent falls. PMID- 26756788 TI - The Evolution of Critical Care Nephrology in Edmonton. AB - The University of Alberta (UofA) in Edmonton, Canada has a rich and productive history supporting the development of critical care medicine, nephrology and the evolving subspecialty of critical care nephrology. The first hemodialysis program for patients with chronic renal failure in Canada was developed at the University of Alberta Hospital. The UofA is also recognized for its early pioneering work on the diagnosis, etiology and outcomes associated with acute kidney injury (AKI), the development of a diagnostic scheme renal allograft rejection (Banff classification), and contributions to the Renal Disaster Relief Task Force. Edmonton was one of the first centers in Canada to provide continuous renal replacement therapy. This has grown into a comprehensive clinical, educational and research center for critical care nephrology. Critical care medicine in Edmonton now leads and participates in numerous critical care nephrology initiatives dedicated to AKI, renal replacement therapy, renal support in solid organ transplantation, and extracorporeal blood purification. Critical care medicine in Edmonton is recognized across Canada and across the globe as a leading center of excellence in critical care nephrology, as an epicenter for research innovation and for training a new generation of clinicians with critical care nephrology expertise. PMID- 26756789 TI - Two-Dimensional Nanoparticle Supracrystals: A Model System for Two-Dimensional Melting. AB - In a Langmuir trough, successive compression cycles can drive a two-dimensional (2D) nanoparticle supracrystal (NPSC) closer to its equilibrium structure. Here, we show a series of equilibrated 2D NPSCs consisting of gold NPs of uniform size, varying solely in the length of their alkanethiol ligands. The ordering of the NPSC is governed by the ligand length, thus providing a model system to investigate the nature of 2D melting in a system of NPs. As the ligand length increases the supracrystal transitions from a crystalline to a liquid-like phase with evidence of a hexatic phase at an intermediate ligand length. The phase change is interpreted as an entropy-driven phenomenon associated with steric constraints between ligand shells. The density of topological defects scales with ligand length, suggesting an equivalence between ligand length and temperature in terms of melting behavior. On the basis of this equivalence, the experimental evidence indicates a two-stage 2D melting of NPSCs. PMID- 26756790 TI - Efficient Treatments Reduce the Cost-Efficiency of Breast Cancer Screening. PMID- 26756791 TI - Dehydrins from wheat x Thinopyrum ponticum amphiploid increase salinity and drought tolerance under their own inducible promoters without growth retardation. AB - Dehydrins confer abiotic stress tolerance in seedlings, but few dehydrins have been studied by transgenic analysis under their own promoters in relation to abiotic stress tolerance. Also the inducible promoters for transgenic engineering are limited. In this study, we isolated from wheat three salt-induced YSK2 dehydrin genes and their promoters. The cDNA sequences were 711, 785, and 932 bp in length, encoding proteins containing 133, 166 and 231 amino acids, respectively, and were named TaDHN1, TaDHN2, and TaDHN3. TaDHN2 doesn't contain introns, while the other two genes each contain one. Semi-quantitative reverse transcription PCR analysis revealed all three dehydrin genes are substantially induced by ABA and NaCl, but only TaDHN2 is induced in seedlings by PEG and by cold (4 degrees C). Regulatory sequences upstream of the first translation codon (775, 1615 and 889 bp) of the three dehydrin genes were also cloned. Cis-element prediction indicated the presence of ABRE and other abiotic-stress-related elements. Histochemical analysis using GUS expression demonstrated that all three promoters were induced by ABA, cold or NaCl. Ectopic over-expression of TaDHN1 or TaDHN3 in Arabidopsis under their own inducible promoters enhanced NaCl- and drought-stress tolerance without growth retardation. PMID- 26756792 TI - Nanoscale Plasmon-Enhanced Spectroscopy in Memristive Switches. AB - Resistive switching memories are nonvolatile memory cells based on nano-ionic redox processes and offer prospects for high scalability, ultrafast write and read access, and low power consumption. In two-terminal cation based devices a nanoscale filament is formed in a switching material by metal ion migration from the anode to the cathode. However, the filament growth and dissolution mechanisms and the dynamics involved are still open questions, restricting device optimization. Here, a spectroscopic technique to optically characterize in situ the resistive switching effect is presented. Resistive switches arranged in a nanoparticle-on-mirror geometry are developed, exploiting the high sensitivity to morphological changes occurring in the tightly confined plasmonic hotspot within the switching material. The focus is on electrochemical metallization and the optical signatures detected over many cycles indicate incomplete removal of metal particles from the filament upon RESET and suggest that the filament can nucleate from different positions from cycle to cycle. The technique here is nondestructive and the measurements can be easily performed in tunable ambient conditions and with realistic cell geometries. PMID- 26756793 TI - Electrostatic theory of the assembly of PAMAM dendrimers and DNA. AB - The electrostatic interactions mediated by counterions between a cationic PAMAM dendrimer, modelized as a sphere of radius and cationic surface charge highly increasing with generation, and a DNA, modelized as an anionic elastic line, are analytically calculated in the framework of condensation theory. Under these interactions the DNA is wrapped around the sphere. For excess phosphates relative to dendrimer primary amines, the free energy of the DNA-dendrimer complex displays an absolute minimum when the complex is weakly negatively overcharged. This overcharging opposes gene delivery. For a highly positive dendrimer and a DNA fixed by experimental conditions to a number of phosphates less than the number of dendrimer primary amines, excess amine charges, the dendrimer may at the same time bind stably DNA and interact with negative cell membranes to activate cell transfection in fair agreement with molecular simulations and experiments. PMID- 26756795 TI - Effect of Excipients on Liquid-Liquid Phase Separation and Aggregation in Dual Variable Domain Immunoglobulin Protein Solutions. AB - Liquid-liquid phase separation (LLPS) and aggregation can reduce the physical stability of therapeutic protein formulations. On undergoing LLPS, the protein rich phase can promote aggregation during storage due to high concentration of the protein. Effect of different excipients on aggregation in protein solution is well documented; however data on the effect of excipients on LLPS is scarce in the literature. In this study, the effect of four excipients (PEG 400, Tween 80, sucrose, and hydroxypropyl beta-cyclodextrin (HPbetaCD)) on liquid-liquid phase separation and aggregation in a dual variable domain immunoglobulin protein solution was investigated. Sucrose suppressed both LLPS and aggregation, Tween 80 had no effect on either, and PEG 400 increased LLPS and aggregation. Attractive protein-protein interactions and liquid-liquid phase separation decreased with increasing concentration of HPbetaCD, indicating its specific binding to the protein. However, HPbetaCD had no effect on the formation of soluble aggregates and fragments in this study. LLPS and aggregation are highly temperature dependent; at low temperature protein exhibits LLPS, at high temperature protein exhibits aggregation, and at an intermediate temperature both phenomena occur simultaneously depending on the solution conditions. PMID- 26756794 TI - CASP 11 target classification. AB - Protein target structures for the Critical Assessment of Structure Prediction round 11 (CASP11) and CASP ROLL were split into domains and classified into categories suitable for assessment of template-based modeling (TBM) and free modeling (FM) based on their evolutionary relatedness to existing structures classified by the Evolutionary Classification of Protein Domains (ECOD) database. First, target structures were divided into domain-based evaluation units. Target splits were based on the domain organization of available templates as well as the performance of servers on whole targets compared to split target domains. Second, evaluation units were classified into TBM and FM categories using a combination of measures that evaluate prediction quality and template detectability. Generally, target domains with sequence-related templates and good server prediction performance were classified as TBM, whereas targets without sequence-identifiable templates and low server performance were classified as FM. As in previous CASP experiments, the boundaries for classification were blurred due to the presence of significant insertions and deteriorations in the targets with respect to homologous templates, as well as the presence of templates with partial coverage of new folds. The FM category included 45 target domains, which represents an unprecedented number of difficult CASP targets provided for modeling. Proteins 2016; 84(Suppl 1):20-33. (c) 2016 Wiley Periodicals, Inc. PMID- 26756797 TI - Differential Sphingolipid and Phospholipid Profiles in Alcohol and Nicotine Derived Nitrosamine Ketone-Associated White Matter Degeneration. AB - BACKGROUND: Alcohol-mediated neurodegeneration is associated with white matter (WM) atrophy due to targeting of myelin and oligodendrocytes. However, variability in disease severity suggests cofactors contribute to WM degeneration. We examined the potential cofactor role of the tobacco-specific nitrosamine, nicotine-derived nitrosamine ketone (NNK), because smoking causes WM atrophy and most heavy drinkers consume tobacco products. METHODS: This 8-week study of Long Evans rats had 4 treatment groups: control; NNK-2 mg/kg, 3*/wk in weeks 3 to 8; ethanol (EtOH) (chronic-26% caloric + binge-2 g/kg, 3*/wk in weeks 7 to 8); and EtOH + NNK. Exposure effects on WM lipid biochemical profiles and in situ distributions were examined using matrix-assisted laser desorption/ionization imaging mass spectrometry and tandem mass spectrometry. RESULTS: NNK mainly caused WM fiber degeneration and fiber loss, EtOH caused demyelination, and dual exposures had additive effects. EtOH and EtOH + NNK decreased WM (including corpus callosum) and/or gray matter (hypothalamus, cortex, medial temporal) levels of several phosphatidylserine, phosphatidylinositol, and sphingolipid (sulfatide [ST]) species, while NNK increased or had minimal effect on these lipids. EtOH + NNK had broader and larger inhibitory effects on phospholipids and ST than EtOH or NNK alone. Principal component analysis clustered control with NNK, and EtOH with EtOH + NNK groups, highlighting the independent EtOH- rather than NNK-driven responses. CONCLUSIONS: Chronic EtOH exposures decreased several phospholipid and sphingolipid species in brain, while concomitant NNK exposures exacerbated these effects. These findings support our hypothesis that tobacco smoking is a pathogenic cofactor in alcohol-mediated WM degeneration. PMID- 26756798 TI - Genetic Versus Pharmacological Assessment of the Role of Cannabinoid Type 2 Receptors in Alcohol Reward-Related Behaviors. AB - BACKGROUND: Emerging evidence suggests that the endocannabinoid system (ECS) is involved in modulating the rewarding effects of abused drugs. Recently, the cannabinoid receptor 2 (CB2R) was shown to be expressed in brain reward circuitry and is implicated in modulating the rewarding effects of alcohol. METHODS: CB2 ligands and CB2R knockout (KO) mice were used to assess CB2R involvement in alcohol reward-related behavior in 2 well-established behavioral models: limited access 2-bottle choice drinking and conditioned place preference (CPP). For the pharmacological studies, mice received pretreatments of either vehicle, the CB2R agonist JWH-133 (10 and 20 mg/kg) or the CB2R antagonist AM630 (10 and 20 mg/kg) 30 minutes before behavioral testing. For the genetic studies, CB2R KO mice were compared to wild-type (WT) littermate controls. RESULTS: CB2R KO mice displayed increased magnitude of alcohol-induced CPP compared to WT mice. Neither agonism nor antagonism of CB2R affected alcohol intake or the expression of CPP, and antagonism of CB2R during CPP acquisition trials also did not affect CPP. CONCLUSIONS: The CB2R KO CPP data provide partial support for the hypothesis that CB2Rs are involved in the modulation of alcohol reward-related behaviors. However, pharmacological manipulation of CB2Rs did not alter alcohol's rewarding effects in the alcohol-seeking models used here. These results highlight the importance of pharmacological validation of effects seen with lifetime KO models. Given the ongoing efforts toward medications development, future studies should continue to explore the role of the CB2R as a potential neurobiological target for the treatment of alcohol use disorders. PMID- 26756799 TI - Are Barroom and Neighborhood Characteristics Independently Related to Local-Area Assaults? AB - BACKGROUND: Two separate but complementary literatures examine bar-related violence: one has focused on barroom features, and the other has focused on features of neighborhoods near bars. This study unifies these 2 perspectives using a microenvironmental approach. METHODS: In a purposive sample of 65 bars in 4 California cities, we used premise assessments to characterize the physical, social, and economic environments of barrooms (e.g., patron count, average pace of drinking, and restaurant service); and a combination of systematic social observation, census, and alcohol license data to characterize the neighborhoods in which they were located (e.g., physical disorder, alcohol outlet density, and median household income). Hierarchical Poisson models then assessed relationships between these features and counts of police-reported assaults within buffer areas around bars. RESULTS: Aspects of both barroom environments (more patrons, more dancing, and louder music) and neighborhood environments (greater bar density, greater physical disorder, lower population density, and lower income) were independently related to increased incidence of assaults. CONCLUSIONS: Preventive intervention to reduce bar-area violence may be directed at both bar environments (e.g., limiting the number of patrons) and neighborhood environments (e.g., limiting outlet density). PMID- 26756802 TI - Dynamic Heterogeneity in the Monoclinic Phase of CCl4. AB - Carbon tetrachloride (CCl4) is one of the simplest compounds having a translationally stable monoclinic phase while exhibiting a rich rotational dynamics below 226 K. Recent nuclear quadrupolar resonance experiments revealed that the dynamics of CCl4 is similar to that of the other members of the isostructural series CBrnCl4-n, suggesting that the universal relaxation features of canonical glasses such as alpha and beta relaxation are also present in nonglass formers. Using molecular dynamics simulations we studied the rotational dynamics in the monoclinic phase of CCl4. The molecules undergo C3-type jump-like rotations around each one of the four C-Cl bonds. The rotational dynamics is very well described with a master equation using as the only input the rotational rates measured from the simulated trajectories. It is found that the heterogeneous dynamics emerges from faster and slower modes associated with different rotational axes, which have fixed orientations relative to the crystal and are distributed among the four nonequivalent molecules of the unit cell. PMID- 26756800 TI - Individual Differences in Approach and Avoidance Inclinations Moderate the Effect of Self-Control Depletion on Ad-Lib Drinking. AB - BACKGROUND: This study sought to examine how exerting self-control to inhibit stereotype use affects alcohol consumption. In addition, we sought to expand previous findings via examination of how individual differences in motivations to approach or avoid alcohol consumption interact with self-control depletion to determine the regulation of ad-lib drinking behavior. METHODS: Sixty-one social drinkers (31 female) were recruited to participate in a socially relevant self control depletion task in which they were randomly assigned to 1 of 2 creative writing conditions: (i) the self-control depletion condition with explicit instructions to refrain from using stereotypes, or (ii) the nondepletion condition in which no instructions were given regarding the use of stereotypes. Participants then completed an ad-lib drinking task and self-report questionnaires pertaining to their motivation to consume alcohol. RESULTS: As predicted, results indicated a significant 3-way interaction between depletion condition, approach inclinations, and avoidance inclinations. Specifically, self control depletion predicted greater drinking disinhibition (i.e., mean sip size, total alcohol consumption) only among participants high in both approach and avoidance. CONCLUSIONS: Taken together, results from this study highlight the importance of both approach and avoidance inclinations in the failure to regulate alcohol consumption following a routine, socially relevant form of self-control depletion. Our results also suggest that the high approach/high avoidance motivational profile may predict the greatest risk among those actively trying to regulate their drinking. PMID- 26756803 TI - Using near infrared light to manage symptoms associated with restless legs syndrome. AB - The purpose of this study was to determine whether the application of near infrared (NIR) light could positively modulate symptoms associated with restless legs syndrome (RLS). Twenty-one subjects with RLS were treated with NIR three times weekly for four weeks. Baseline measures of: (1) international restless legs syndrome rating scale (IRLSRS) score; (2) Semmes Weinstein monofilament (SWM) test; (3) visual analog pain scale (VAS); (4) ankle-brachial index (ABI); and (5) sonographic imaging of the popliteal and posterior tibial arteries were compared to post-treatment values. NIR (850 nm) was delivered transcutaneously at 8 J/cm(2) to four locations on each leg and the plantar surface of each foot. A pre-test-post-test one group design was employed. Baseline and post-treatment measures were compared using either a dependent t-test when data were normal or the Wilcoxon signed rank test in the absence of normality. A significant improvement in IRLSRS scores was observed. Sensation improved from less than protective in 16.6% of sites tested at the baseline to 13.4% post-intervention. There was a significant improvement in ABI scores. VAS and sonographic imaging measures other than ABI remained unchanged. The use of NIR to modulate symptoms associated with RLS was supported by the data. PMID- 26756804 TI - Evaluation of a patient self-directed mealtime insulin titration algorithm: a US payer perspective. AB - Objective To model the potential economic impact of implementing the AUTONOMY once daily (Q1D) patient self-titration mealtime insulin dosing algorithm vs standard of care (SOC) among a population of patients with Type 2 diabetes living in the US. Methods Three validated models were used in this analysis: The Treatment Transitions Model (TTM) was used to generate the primary results, while both the Archimedes (AM) and IMS Core Diabetes Models (IMS) were used to test the veracity of the primary results produced by TTM. Models used data from a 'real world' representative sample of patients (2012 US National Health and Nutrition Examination Survey) that matched the characteristics of US patients enrolled in the randomized controlled trial 'AUTONOMY' cohort. The base-case time horizon was 10 years. Results The modeling results from TTM demonstrated that total costs in the base-case were reduced by $1732, with savings predicted to occur as early as year 1. Results from the three models were consistent, showing a reduction in total costs for all sensitivity analyses. Limitations Data from short-term clinical trials were used to develop long-term projections. The nature of such extrapolation leads to increased uncertainty. Conclusion The results from all three models indicate that the AUTONOMY Q1D algorithm has the potential to abate total costs as early as the first year. PMID- 26756806 TI - COMPARATIVE EVALUATION OF SEQUENTIAL INTRAOPERATIVE USE OF WHOLE BLOOD FOLLOWED BY BRILLIANT BLUE VERSUS CONVENTIONAL BRILLIANT BLUE STAINING OF INTERNAL LIMITING MEMBRANE IN MACULAR HOLE SURGERY. AB - PURPOSE: To compare the structural and functional outcome of use of autologous heparinized whole blood before staining internal limiting membrane with brilliant blue (BB) versus conventional BB-assisted macular hole surgery. METHODS: Sixty eyes of 60 patients were randomly divided equally in Group A (BB staining using whole blood) and Group B (conventional BB staining). Clinical assessment and spectral domain optical coherence tomography was done at baseline and 3 weeks, 6 weeks, 16 weeks, and 6 months postoperatively. RESULTS: Group A eyes had a significantly higher best-corrected visual acuity as compared with Group B postoperatively (P < 0.001, <0.001, 0.004, 0.04 at 3, 6, 16 weeks, and 6 months). Inner segment/outer segment junction continuity was noted in greater number of eyes in Group A compared with Group B (P = 0.02, 0.002, 0.003, and 0.03 at 3, 6, 16 weeks, and 6 months). Eyes in Group A had significantly higher outer foveal thickness at 3 weeks (P = 0.001) and 6 weeks (P < 0.001) compared with Group B. CONCLUSION: Use of whole blood before staining internal limiting membrane with BB causes earlier and better visual rehabilitation postoperatively, which could be attributed to earlier photoreceptor regeneration as evidenced by inner segment/outer segment junction continuity and increase in outer foveal thickness. PMID- 26756805 TI - Clinical correlates of memory complaints during AED treatment. AB - OBJECTIVES: To investigate clinical correlates of memory complaints (MC) during anti-epileptic drug (AEDs) treatment in adults with epilepsy with special attention to the role of depression, using user-friendly standardized clinical instruments which can be adopted in any outpatient setting. MATERIALS & METHODS: Data from a consecutive sample of adult outpatients with epilepsy assessed with the Neurological Disorder Depression Inventory for Epilepsy (NDDIE), the Adverse Event Profile (AEP) and the Emotional Thermometer (ET) were analysed. RESULTS: From a total sample of 443 patients, 28.4% reported MC as 'always' a problem. These patients were less likely to be seizure free (18.3% vs 34.3%; P < 0.001), had a high number of previous AED trials (4 vs 3; P < 0.001) and high AEP total scores (49 vs 34.2; P < 0.001). There was no correlation with specific AED type or combination. Depression was the major determinant with a 2-fold increased risk (95%CI 1.15-3.86; P = 0.016). When depression was already known and under treatment, patients with MC were less likely to be in remission from depression despite antidepressant treatment (11.9% vs 1.6% P < 0.001). Among patients without depression, those reporting MC presented with significantly high scores for depression (3.3 vs 2; t = 3.07; P = 0.003), anxiety (4.5 vs 2.7; t = 4.43; P < 0.001), anger (3 vs 2; t = 2.623; P = 0.009) and distress (3.8 vs 2.2; t = 4.027; P < 0.001) than those without MC. CONCLUSIONS: Depression has to be appropriately treated and full remission from depression should represent the ultimate goal as subthreshold or residual mood and anxiety symptoms can contribute to MC. PMID- 26756807 TI - Spectral Domain Optical Coherence Tomography Angiography Features in a Patient of Central Retinal Arterial Occlusion Before and After Paracentesis. PMID- 26756808 TI - CLINICAL CHARACTERISTICS OF IDIOPATHIC FOVEOMACULAR RETINOSCHISIS. AB - PURPOSE: To describe the clinical features of idiopathic foveomacular retinoschisis not in association with myopia, glaucoma, optic disk pit, or juvenile retinoschisis. METHODS: Retrospective observational case series. Five eyes of five patients with idiopathic foveomacular retinoschisis were included. RESULTS: The patients were 2 men and 3 women (average age, 75.2 years; range, 71 78 years). The average spherical equivalent was +2.40 diopters (range, +0.88 to +5.75 diopters), and the average axial length was 22.0 mm (range, 21.1-23.1 mm). All patients had retinoschisis from the macula to the optic disk in the affected eye. No patients had retinoschisis in the fellow eye. The average best-corrected visual acuity was 20/44 (68 Early Treatment Diabetic Retinopathy Study letter score). CONCLUSION: Idiopathic foveomacular retinoschisis is not inherited or associated with myopia, vitreomacular traction syndrome, optic pit, or glaucoma but is associated with older age, unilaterality, hyperopia with short axial length, complete posterior vitreous detachment, and weak leakage from the optic disk on fluorescein angiography. PMID- 26756810 TI - Uncorrected binocular visual acuity at far, intermediate and near distances as the new standards for vision outcome in modern cataract surgery. PMID- 26756809 TI - Effect of Sterilization Methods on Electrospun Poly(lactic acid) (PLA) Fiber Alignment for Biomedical Applications. AB - Medically approved sterility methods should be a major concern when developing a polymeric scaffold, mainly when commercialization is envisaged. In the present work, poly(lactic acid) (PLA) fiber membranes were processed by electrospinning with random and aligned fiber alignment and sterilized under UV, ethylene oxide (EO), and gamma-radiation, the most common ones for clinical applications. It was observed that UV light and gamma-radiation do not influence fiber morphology or alignment, while electrospun samples treated with EO lead to fiber orientation loss and morphology changing from cylindrical fibers to ribbon-like structures, accompanied to an increase of polymer crystallinity up to 28%. UV light and gamma radiation sterilization methods showed to be less harmful to polymer morphology, without significant changes in polymer thermal and mechanical properties, but a slight increase of polymer wettability was detected, especially for the samples treated with UV radiation. In vitro results indicate that both UV and gamma radiation treatments of PLA membranes allow the adhesion and proliferation of MG 63 osteoblastic cells in a close interaction with the fiber meshes and with a growth pattern highly sensitive to the underlying random or aligned fiber orientation. These results are suggestive of the potential of both gamma radiation sterilized PLA membranes for clinical applications in regenerative medicine, especially those where customized membrane morphology and fiber alignment is an important issue. PMID- 26756812 TI - Dosimetric characteristics of brass mesh as bolus under megavoltage photon irradiation. AB - OBJECTIVE: This article presents a set of dosimetric measurements describing the properties of brass mesh (Whiting and Davis, Attleboro Falls, MA) under megavoltage photon irradiation conditions, with particular relevance to its use in breast radiotherapy. METHODS: The effectiveness of brass mesh as a bolus material was investigated using 6-, 15- and 6-MV flattening filter-free photon beams. The effect on dose build-up at the entrance surface, build-down at the beam-exit surface, dose with surface entrance obliquity, beam profiles, penumbra and percentage depth doses were investigated. RESULTS: One layer of the brass mesh produces a build-up effect equivalent to 1.1 mm of water at 6 MV and 1.9 mm at 15 MV. The brass generates a backscattered component of dose, if the photon beam exits through it. Percentage depth-dose curves are largely unaffected by the mesh and are shown to be equivalent to plain-field data. Beam penumbra and profiles are unchanged by the brass except within the first millimetre (mm) of phantom, where a periodic pattern of dose enhancement is seen. CONCLUSION: The data presented demonstrate that one layer of brass mesh provides a similar dose build-up effect equivalent to only a few millimetres of water. However, backscatter from the high atomic number (Z) mesh, at the beam exit, contributes appreciably to the overall dose surface enhancement. This dosimetric consequence cannot be neglected and indeed should be considered and accounted for, when determining the bolus effect of the brass mesh in the case of tangential breast irradiation. Advance in knowledge: This article provides dosimetric data necessary for the introduction of brass mesh bolus into the clinical setting for external-beam breast radiotherapy. PMID- 26756811 TI - Prognostic value of fluorine-18 fludeoxyglucose positron emission tomography parameters differs according to primary tumour location in small-cell lung cancer. AB - OBJECTIVE: To investigate the prognostic value of fluorine-18 fludeoxyglucose (FDG) positron emission tomography (PET) parameters for small-cell lung cancer (SCLC), according to the primary tumour location, adjusted by conventional prognostic factors. METHODS: From 2008 to 2013, we enrolled consecutive patients with histologically proven SCLC, who had undergone FDG-PET/CT prior to initial therapy. The primary tumour location was categorized into central or peripheral types. PET parameters and clinical variables were evaluated using univariate and multivariate analysis. RESULTS: A total of 69 patients were enrolled in this study; 28 of these patients were categorized as having the central type and 41 patients as having the peripheral type. In univariate analysis, stage, serum neuron-specific enolase, whole-body metabolic tumour volume (WB-MTV) and whole body total lesion glycolysis (WB-TLG) were found to be significant in both types of patients. In multivariate analysis, the independent prognostic factor was found to be stage in the central type, but WB-MTV and WB-TLG in the peripheral type. Kaplan-Meier analysis demonstrated that patients with peripheral type with limited disease and low WB-MTV or WB-TLG showed significantly better overall survival than all of the other groups (p < 0.0083). CONCLUSION: The FDG-PET volumetric parameters were demonstrated to be significant and independent prognostic factors in patients with peripheral type of SCLC, while stage was the only independent prognostic factor in patients with central type of SCLC. ADVANCES IN KNOWLEDGE: FDG-PET is a non-invasive method that could potentially be used to estimate the prognosis of patients, especially those with peripheral-type SCLC. PMID- 26756813 TI - Evidences for Chlorogenic Acid--A Major Endogenous Polyphenol Involved in Regulation of Ripening and Senescence of Apple Fruit. AB - To learn how the endogenous polyphenols may play a role in fruit ripening and senescence, apple pulp discs were used as a model to study the influences of chlorogenic acid (CHA, a major polyphenol in apple pulp) on fruit ripening and senescence. Apple ('Golden Delicious') pulp discs prepared from pre-climacteric fruit were treated with 50 mg L(-1) CHA and incubated in flasks with 10 mM MES buffer (pH 6.0, 11% sorbitol). Compared to the control samples, treatment with CHA significantly reduced ethylene production and respiration rate, and enhanced levels of firmness and soluble solids content of the pulp discs during incubation at 25 degrees C. These results suggested that CHA could retard senescence of the apple pulp discs. Proteomics analysis with sodium dodecyl sulfate-polyacrylamide gel electrophoresis and mass spectrometry (MALDI-TOF/TOF) revealed that the expressions of several key proteins correlated to fruit ripening and senescence were affected by the treatment with CHA. Further study showed that treating the pulp discs with CHA remarkably reduced levels of lipoxygenase, beta galactosidase, NADP-malic enzyme, and enzymatic activities of lipoxygenase and UDP-glucose pyrophosphorylase, all of which are known as promoters of fruit ripening and senescence. These results could provide new insights into the functions of endogenous phenolic compounds in fruit ripening and senescence. PMID- 26756816 TI - Editorial: Hello - and Good-bye. PMID- 26756815 TI - Caries and Candida colonisation in adult patients in Basque Country (Spain). AB - Candida albicans is one of the most frequent pathogens of the oral cavity, as a major cause of opportunistic disease. Moreover, Candida could be a cofactor of common oral diseases, such as dental caries. The aim of this study was to analyse the oral yeast colonisation in adults with dental caries and to evaluate its relationship with this clinical entity. We studied 190 patients distributed into controls (58 patients) and patients with caries (132 patients). Oral samples were collected by oral rinse and cultured in a chromogenic agar. C. albicans was the most prevalent species isolated from oral specimens in both groups. Patients with caries had a greater Candida colonisation (74 patients, 56.1%), than persons without caries (18 patients, 31%, P < 0.01). Patients with caries were significantly more colonised by non-C. albicans species than individuals without caries (P = 0.006). Moreover, the diversity of Candida species was richer in patients suffering from caries. The odds ratio of the colonisation of patients with caries was 3.144 (95% CI 1.525-5.478). There is a significant clinical correlation between dental caries and oral Candida colonisation in adults. PMID- 26756814 TI - Predicting Fecundity of Fathead Minnows (Pimephales promelas) Exposed to Endocrine-Disrupting Chemicals Using a MATLAB(r)-Based Model of Oocyte Growth Dynamics. AB - Fish spawning is often used as an integrated measure of reproductive toxicity, and an indicator of aquatic ecosystem health in the context of forecasting potential population-level effects considered important for ecological risk assessment. Consequently, there is a need for flexible, widely-applicable, biologically-based models that can predict changes in fecundity in response to chemical exposures, based on readily measured biochemical endpoints, such as plasma vitellogenin (VTG) concentrations, as input parameters. Herein we describe a MATLAB(r) version of an oocyte growth dynamics model for fathead minnows (Pimephales promelas) with a graphical user interface based upon a previously published model developed with MCSim software and evaluated with data from fathead minnows exposed to an androgenic chemical, 17beta-trenbolone. We extended the evaluation of our new model to include six chemicals that inhibit enzymes involved in steroid biosynthesis: fadrozole, ketoconazole, propiconazole, prochloraz, fenarimol, and trilostane. In addition, for unexposed fathead minnows from group spawning design studies, and those exposed to the six chemicals, we evaluated whether the model is capable of predicting the average number of eggs per spawn and the average number of spawns per female, which was not evaluated previously. The new model is significantly improved in terms of ease of use, platform independence, and utility for providing output in a format that can be used as input into a population dynamics model. Model-predicted minimum and maximum cumulative fecundity over time encompassed the observed data for fadrozole and most propiconazole, prochloraz, fenarimol and trilostane treatments, but did not consistently replicate results from ketoconazole treatments. For average fecundity (eggs*female(-1)*day(-1)), eggs per spawn, and the number of spawns per female, the range of model-predicted values generally encompassed the experimentally observed values. Overall, we found that the model predicts reproduction metrics robustly and its predictions capture the variability in the experimentally observed data. PMID- 26756818 TI - Topical Treatment of Hair Loss with Formononetin by Modulating Apoptosis. AB - Formononetin is one of the main components of red clover plants and its role on hair regrowth against hair loss has not been established yet. In the present study, we assessed the potential effects of formononetin on alopecia, along with impaired hair cycles by induction of apoptosis-regression.Depilated C57BL/6 mice were used for monitoring the hair cycles. Formononetin (1 and 100 uM) was topically treated to the dorsal skin for 14 days. Topical formononetin treatment induced miniaturized hair follicles to recover to normal sizes. Tapering hair shaft began to grow newly, emerging from the hair follicles by formononetin. In addition, formononetin inhibited the activation of caspase-8 and decreased the procaspase-9 expression. As a result of formononetin treatment, anti-apoptotic Bcl-2 was up-regulated, whereas pro-apoptotic Bax and p53 were down-regulated, resulting in a decrease of caspase-3 activation. Formononetin showed the obvious inhibition of apoptosis under terminal deoxynucleotidyl transferase dUTP nick end labeling staining thereafter.Taken together, our findings demonstrate that formononetin exerted the hair regrowth effect on hair loss, in which the underlying mechanisms were associated with Fas/Fas L-induced caspase activation, thus inhibiting apoptosis. PMID- 26756819 TI - Appetite-enhancing Effects of trans-Cinnamaldehyde, Benzylacetone and 1-Phenyl-2 butanone by Inhalation. AB - Fragrance in the air and odours of foods and drinks are reported to affect feeding behaviours of humans and other animals. Many previous studies focusing on the relationship between fragrance and appetite have described a reduction of food intake by fragrance administration to help prevent lifestyle diseases. Aromatic herbal medicines, such as cinnamon bark and fennel fruit, are considered to have appetite-enhancing effects and they are often blended in stomachics for relief of asitia and gastric distress in Japan. These fragrant herbal medicines contain many essential oils and their fragrances are hypothesised to be active substances. In this study, food intake and the expression of neuropeptide Y and proopiomelanocortin in the hypothalamus after inhalation of fragrant compounds or essential oils were investigated in mice. Food intake was increased 1.2-fold and the neuropeptide Y mRNA expression in the hypothalamus was increased significantly in mice that inhaled trans-cinnamaldehyde, benzylacetone or 1 phenyl-2-butanone, compared with the control group. These compounds might be effective for treating loss of appetite (anorexia) or eating disorders in elderly and infirm people via a non-invasive route of administration, namely, inhalation. PMID- 26756820 TI - Identification of New Diterpenes as Putative Marker Compounds Distinguishing Agnus Castus Fruit (Chaste Tree) from Shrub Chaste Tree Fruit (Viticis Fructus). AB - Agnus Castus Fruit is defined in the European Pharmacopoeia as the dried ripe fruit of Vitex agnus-castus. In Europe it is used as a medicine targeting premenstrual syndrome and climacteric disorder. In Japan, Agnus Castus Fruit is becoming popular as a raw material for over-the-counter drugs and health food products, though its congenic species, Vitex rotundifolia and Vitex trifolia, have been used as Shrub Chaste Tree Fruit in traditional medicines. Therefore, it is important to discriminate these Vitex plants from the viewpoint of regulatory science. Here we tried to identify putative marker compounds that distinguish between Agnus Castus Fruit and Shrub Chaste Tree Fruit. We analyzed extracts of each crude drug by liquid chromatography-mass spectrometry, and performed differential analysis by comparison of each chromatogram to find one or more peaks characteristic of Agnus Castus Fruit. A peak was isolated and identified as an equilibrium mixture of new compounds named chastol (1) and epichastol (1a). The planar structures of 1 and 1a were determined spectroscopically. Their relative configurations were revealed by nuclear Overhauser effect spectroscopy and differential nuclear Overhauser effect-NMR data. Since avoiding contamination from closely related species is needed for the quality control of natural pharmaceuticals, this information will be valuable to establish a method for the quality control of both, Agnus Castus Fruit and Shrub Chaste Tree Fruit products. PMID- 26756821 TI - Sexual Desire Inventory: Two or Three Dimensions? AB - The Sexual Desire Inventory (SDI), developed by Spector, Carey, and Steinberg in 1996, has been widely used to assess sexual desire in men and women throughout the world. This questionnaire categorizes sexual desire in two dimensions: dyadic sexual desire and solitary sexual desire. Our study addressed the factorial structure of the SDI, an aspect that until now has been largely neglected. We recruited two samples of Spanish men and women involved in stable heterosexual relationships. The first sample consisted of 3,417 subjects (1,600 males and 1,817 females), ages 18 to 84; the second sample consisted of 677 subjects (285 males and 392 females), ages 18 to 50. The results of an exploratory factor analysis (EFA) showed that instead of two dimensions the SDI should have three: (1) partner-focused dyadic sexual desire, (2) general dyadic sexual desire for an attractive person, and (3) solitary sexual desire. A confirmatory factor analysis (CFA) supported the robustness of this new three-factor structure. No gender differences were revealed, except for dyadic sexual desire for an attractive person, for which men reported higher scores. Good validity and reliability values were obtained. Moreover, standard scores for men and women by different age groups were developed. PMID- 26756822 TI - Response-Scale Heterogeneity in the EQ-5D. AB - This paper discusses two types of response-scale heterogeneity, which may impact upon the EQ-5D. Response-scale heterogeneity in reporting occurs when individuals systematically differ in their use of response scales when responding to self assessments. This type of heterogeneity is widely observed in relation to other self-assessed measures but is often overlooked with regard to the EQ-5D. Analogous to this, preference elicitation involving the EQ-5D could be subject to a similar type of heterogeneity, where variations across respondents may occur in the interpretations of the levels (response categories) being valued. This response-scale heterogeneity in preference elicitation may differ from variations in preferences for health states, which have been observed in the literature. This paper explores what these forms of response-scale heterogeneity may mean for the EQ-5D and the potential implications for researchers who rely on the instrument as a measure of health and quality of life. We identify situations where they are likely to be problematic and present potential avenues for overcoming these issues. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26756823 TI - Genome evolution of ferns: evidence for relative stasis of genome size across the fern phylogeny. AB - The genome evolution of ferns has been considered to be relatively static compared with angiosperms. In this study, we analyse genome size data and chromosome numbers in a phylogenetic framework to explore three hypotheses: the correlation of genome size and chromosome number, the origin of modern ferns from ancestors with high chromosome numbers, and the occurrence of several whole genome duplications during the evolution of ferns. To achieve this, we generated new genome size data, increasing the percentage of fern species with genome sizes estimated to 2.8% of extant diversity, and ensuring a comprehensive phylogenetic coverage including at least three species from each fern order. Genome size was correlated with chromosome number across all ferns despite some substantial variation in both traits. We observed a trend towards conservation of the amount of DNA per chromosome, although Osmundaceae and Psilotaceae have substantially larger chromosomes. Reconstruction of the ancestral genome traits suggested that the earliest ferns were already characterized by possessing high chromosome numbers and that the earliest divergences in ferns were correlated with substantial karyological changes. Evidence for repeated whole-genome duplications was found across the phylogeny. Fern genomes tend to evolve slowly, albeit genome rearrangements occur in some clades. PMID- 26756824 TI - Impairment of Immunoproteasome Function by Cigarette Smoke and in Chronic Obstructive Pulmonary Disease. AB - RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) and in particular smokers are more susceptible to respiratory infections contributing to acute exacerbations of disease. The immunoproteasome is a specialized type of proteasome destined to improve major histocompatibility complex (MHC) class I mediated antigen presentation for the resolution of intracellular infections. OBJECTIVES: To characterize immunoproteasome function in COPD and its regulation by cigarette smoke. METHODS: Immunoproteasome expression and activity were determined in bronchoalveolar lavage (BAL) and lungs of human donors and patients with COPD or idiopathic pulmonary fibrosis (IPF), as well as in cigarette smoke exposed mice. Smoke-mediated alterations of immunoproteasome activity and MHC I surface expression were analyzed in human blood-derived macrophages. Immunoproteasome-specific MHC I antigen presentation was evaluated in spleen and lung immune cells that had been smoke-exposed in vitro or in vivo. MEASUREMENTS AND MAIN RESULTS: Immunoproteasome and MHC I mRNA expression was reduced in BAL cells of patients with COPD and in isolated alveolar macrophages of patients with COPD or IPF. Exposure of immune cells to cigarette smoke extract in vitro reduced immunoproteasome activity and impaired immunoproteasome-specific MHC I antigen presentation. In vivo, acute cigarette smoke exposure dynamically regulated immunoproteasome function and MHC I antigen presentation in mouse BAL cells. End stage COPD lungs showed markedly impaired immunoproteasome activities. CONCLUSIONS: We here show that the activity of the immunoproteasome is impaired by cigarette smoke resulting in reduced MHC I antigen presentation. Regulation of immunoproteasome function by cigarette smoke may thus alter adaptive immune responses and add to prolonged infections and exacerbations in COPD and IPF. PMID- 26756826 TI - Genetically Divergent Types of the Wheat Leaf Fungus Puccinia triticina in Ethiopia, a Center of Tetraploid Wheat Diversity. AB - Collections of Puccinia triticina, the wheat leaf rust fungus, were obtained from tetraploid and hexaploid wheat in the central highlands of Ethiopia, and a smaller number from Kenya, from 2011 to 2013, in order to determine the genetic diversity of this wheat pathogen in a center of host diversity. Single-uredinial isolates were derived and tested for virulence phenotype to 20 lines of Thatcher wheat that differ for single leaf rust resistance genes and for molecular genotypes with 10 simple sequence repeat (SSR) primers. Nine virulence phenotypes were described among the 193 isolates tested for virulence. Phenotype BBBQJ, found only in Ethiopia, was predominantly collected from tetraploid wheat. Phenotype EEEEE, also found only in Ethiopia, was exclusively collected from tetraploid wheat and was avirulent to the susceptible hexaploid wheat 'Thatcher'. Phenotypes MBDSS and MCDSS, found in both Ethiopia and Kenya, were predominantly collected from common wheat. Phenotypes CCMSS, CCPSS, and CBMSS were found in Ethiopia from common wheat at low frequency. Phenotypes TCBSS and TCBSQ were found on durum wheat and common wheat in Kenya. Four groups of distinct SSR genotypes were described among the 48 isolates genotyped. Isolates with phenotypes BBBQJ and EEEEE were in two distinct SSR groups, and isolates with phenotypes MBDSS and MCDSS were in a third group. Isolates with CCMSS, CCPSS, CBMSS, TCBSS, and TCBSQ phenotypes were in a fourth SSR genotype group. The diverse host environment of Ethiopia has selected and maintained a genetically divergent population of P. triticina. PMID- 26756825 TI - A Patient-Centered Approach to Hemodialysis Vascular Access in the Era of Fistula First. AB - The primary vascular access options for the hemodialysis population are arteriovenous fistulas (AVF), arteriovenous grafts, and cuffed central venous catheters (CVC). AVFs are associated with the most favorable outcomes with respect to complications, interventions required to maintain functionality and patency, and overall cost. These population-based outcomes, in conjunction with the efforts of the Fistula First Breakthrough Initiative, have propelled the prevalence of AVFs in the US hemodialysis population. While this endeavor remains steadfast in assuring the continued dominance of this policy for AVF preference, it fails to take into account a subset of the dialysis population who will fail to see the benefits of an AVF. This subset of patients may include the elderly, those with poor vasculature anatomy, those with slowly progressive CKD who are more likely to die than progress to ESRD, and those with an overall poor long term prognosis and shortened life expectancy. Thus, in an effort to avoid numerous unnecessary surgical and interventional procedures with minimal to no gains in clinical outcomes, an individualized patient approach must be adopted. The Centers for Medicare and Medicaid Services-instituted quality incentive program is designed to reward high AVF prevalence while also penalizing high CVC prevalence. The current model is devoid of case-based adjustment, thus penalties are disbursed to dialysis providers in accordance with a "one-size-fits-all" fistula only approach. The most suitable access for a patient remains the one that takes into account the characteristics unique to the individual patient with a primary focus on patient comfort, satisfaction, quality of life, and clinical outcomes. PMID- 26756827 TI - Embryo Localization Enhances the Survival of Acidovorax citrulli in Watermelon Seeds. AB - Acidovorax citrulli, the causal agent of bacterial fruit blotch (BFB) of cucurbits has been observed to survive for >34 years in stored melon and watermelon seeds. To better understand this remarkable longevity, we investigated the bacterium's tolerance to desiccation and the effect of bacterial localization in different watermelon seed tissues on its survival. We compared the ability of A. citrulli to tolerate desiccation on filter paper discs and on host (watermelon) and nonhost (cabbage, corn and tomato) seeds to two seedborne (Xanthomonas campestris pv. campestris and Pantoea stewartii subsp. stewartii) and one soilborne (Ralstonia solanacearum) plant-pathogenic bacteria. A. citrulli survival on dry filter paper (>12 weeks) was similar to that of X. campestris pv. campestris but longer than P. stewartii subsp. stewartii. Ralstonia solanacearum survived longer than all other bacteria tested. On all seeds tested, A. citrulli and X. campestris pv. campestris populations declined by 5 orders of magnitude after 12 weeks of incubation at 4 degrees C and 50% relative humidity, while R. solanacearum populations declined by 3 orders. P. stewartii subsp. stewartii was not recovered after 12 weeks of incubation. To determine the effect of tissue localization on bacterial survival, watermelon seeds infested with A. citrulli by flower stigma inoculation (resulting in bacterial localization in the embryo/endosperm) or by ovary pericarp inoculations (resulting in bacterial localization under the testa) were treated with peroxyacetic acid or chlorine (Cl2) gas. Following these treatments, a significantly higher reduction in BFB seed-to-seedling transmission was observed for seeds generated by ovary pericarp inoculation (>=89.5%) than for those generated by stigma inoculation (<=76.5%) (P<0.05). Additionally, higher populations of A. citrulli survived when the bacteria were localized to the embryo/endosperm versus the seed coat, suggesting that tissue localization is important for bacterial survival in seed. This observation was confirmed when P. stewartii subsp. stewartii survived significantly longer in stigma-inoculated (embryo/endosperm-localized) watermelon seeds than in vacuum-infiltrated (testa-localized) seeds. Based on these results we conclude that A. citrulli cells are not intrinsically tolerant to desiccation and that localization of the bacterium to testa tissues does not enhance A. citrulli survival. In contrast, it is likely that embryo/endosperm localization enhances the survival of A. citrulli and other bacteria in seeds. PMID- 26756828 TI - RNA1-Independent Replication and GFP Expression from Tomato marchitez virus Isolate M Cloned cDNA. AB - Tomato marchitez virus (ToMarV; synonymous with Tomato apex necrosis virus) is a positive-strand RNA virus in the genus Torradovirus within the family Secoviridae. ToMarV is an emergent whitefly-transmitted virus that causes important diseases in tomato (Solanum lycopersicum) in Mexico. Here, the genome sequence of the ToMarV isolate M (ToMarV-M) was determined. We engineered full length cDNA clones of the ToMarV-M genomic RNA (RNA1 and RNA2), separately, into a binary vector. Coinfiltration of both triggered systemic infections in Nicotiana benthamiana, tomato, and tomatillo (Physalis philadelphica) plants and recapitulated the biological activity of the wild-type virus. The viral progeny generated from tomato and tomatillo plants were transmissible by the whitefly Bemisia tabaci biotype B. Also, we assessed whether these infectious clones could be used for screening tomato cultivars for resistance to ToMarV and our results allowed us to differentiate resistant and susceptible tomato lines. We demonstrated that RNA1 of ToMarV-M is required for the replication of RNA2, and it can replicate independently of RNA2. From this, ToMarV-M RNA2 was used to express the green fluorescent protein in N. benthamiana plants, which allowed us to track cell-to-cell movement. The construction of full-length infectious cDNA clones of ToMarV-M provides an excellent tool to investigate virus-host-vector interactions and elucidate the functions of torradovirus-encoded proteins or the mechanisms of replication of torradovirus genomic RNA. PMID- 26756829 TI - The Sclerotinia sclerotiorum FoxE2 Gene Is Required for Apothecial Development. AB - Sclerotinia sclerotiorum is a widely dispersed plant pathogenic fungus causing many diseases such as white mold, Sclerotinia stem rot, stalk rot, and Sclerotinia head rot on many varieties of broadleaf crops worldwide. Previous studies have shown that the Forkhead-box transcription factors (FOX TFs) play key regulatory roles in the sexual reproduction of some fungi. Ss-FoxE2 is one of four FOX TF family member genes in S. sclerotiorum. Based on ortholog function in other fungi it is hypothesized to function in S. sclerotiorum sexual reproduction. In this study, the role of Ss-FoxE2 in S. sclerotiorum was identified with a gene knock-out strategy. Following transformation and screening, strains having undergone homologous recombination in which the hygromycin resistance gene replaced the gene Ss-FoxE2 from the genomic DNA were identified. No difference in hyphae growth, number, and weight of sclerotia and no obvious change in virulence was observed among the wild type Ss-FoxE2 knock out mutant and genetically complemented mutant; however, following induction of sclerotia for sexual development, apothecia were not formed in Ss-FoxE2 knock-out mutant. The Ss-FoxE2 gene expressed significantly higher in the apothecial stages than in other developmental stages. These results indicate that Ss-FoxE2 appears to be necessary for the regulation of sexual reproduction, but may not affect the pathogenicity and vegetative development of S. sclerotiorum significantly. PMID- 26756831 TI - An Unusual Atrial Tachycardia in a Cardiac Transplant Patient. PMID- 26756830 TI - Hysterectomy for heavy menstrual bleeding. AB - Hysterectomy is the most frequently performed major surgical intervention in gynecology. Although surgically removing the uterus is invasive, it represents the most definitive treatment option for heavy menstrual bleeding. In this article, we will discuss the indications for hysterectomy as a treatment for heavy menstrual bleeding, the different approaches to perform the hysterectomy, the complications which may occur during and after this procedure and finally the outcomes in comparison with other treatment options. PMID- 26756832 TI - Development of a drug-coated microneedle array and its application for transdermal delivery of interferon alpha. AB - Interferon alpha (IFNalpha) is one of the most famous drugs for the treatment of chronic hepatitis C and various types of human malignancy. Protein drugs, including IFNalpha, are generally administered by subcutaneous or intramuscular injection due to their poor permeability and low stability in the bloodstream or gastrointestinal tract. Therefore, in the present study, novel IFNalpha-coated polyvinyl alcohol-based microneedle arrays (IFNalpha-MNs) were fabricated for the transdermal delivery of IFNalpha without the painful injection. IFNalpha was rapidly released from MNs in phosphate buffered solution and these MNs presented piercing ability in the rat skin. Slight erythema and irritation were observed when MNs were applied to the rat skin, but these skin damages completely disappeared within 24 h after removing the IFNalpha-MNs. Furthermore, the pharmacokinetic parameters of IFNalpha-MNs were similar to those of IFNalpha subcutaneous administration. Finally, IFNalpha-MNs showed a significant antitumor effect in tumor bearing mice similar to that of IFNalpha subcutaneous administration. These results indicate that IFNalpha-MNs are a useful biomaterial tool for protein drug therapy and can improve the quality of life in patients by avoidance of painful injections. PMID- 26756833 TI - The CLAVATA signaling pathway mediating stem cell fate in shoot meristems requires Ca(2+) as a secondary cytosolic messenger. AB - CLAVATA1 (CLV1) is a receptor protein expressed in the shoot apical meristem (SAM) that translates perception of a non-cell-autonomous CLAVATA3 (CLV3) peptide signal into altered stem cell fate. CLV3 reduces expression of WUSCHEL (WUS) and FANTASTIC FOUR 2 (FAF2) in the SAM. Expression of WUS and FAF2 leads to maintenance of undifferentiated stem cells in the SAM. CLV3 binding to CLV1 inhibits expression of these genes and controls stem cell fate in the SAM through an unidentified signaling pathway. Cytosolic Ca(2+) elevations, cyclic nucleotide (cGMP)-activated Ca(2+) channels, and cGMP have been linked to signaling downstream of receptors similar to CLV1. Hence, we hypothesized that cytosolic Ca(2+) elevation mediates the CLV3 ligand/CLV1 receptor signaling that controls meristem stem cell fate. CLV3 application to Arabidopsis seedlings results in elevation of cytosolic Ca(2+) and cGMP. CLV3 control of WUS was prevented in a genotype lacking a functional cGMP-activated Ca(2+) channel. In wild-type plants, CLV3 inhibition of WUS and FAF2 expression was impaired by treatment with either a Ca(2+) channel blocker or a guanylyl cyclase inhibitor. When CLV3-dependent repression of WUS is blocked, altered control of stem cell fate leads to an increase in SAM size; we observed a larger SAM size in seedlings treated with the Ca(2+) channel blocker. These results suggest that the CLV3 ligand/CLV1 receptor system initiates a signaling cascade that elevates cytosolic Ca(2+), and that this cytosolic secondary messenger is involved in the signal transduction cascade linking CLV3/CLV1 to control of gene expression and stem cell fate in the SAM. PMID- 26756835 TI - Asymmetric Conjugate Addition of Organoboron Reagents to Common Enones Using Copper Catalysts. AB - Copper complexes of phosphoramidites efficiently catalyzed asymmetric addition of arylboron reagents to acyclic enones. Importantly, rare 1,4-insertion of arylcopper(I) was identified which led directly to O-bound copper enolates. The new mechanism is fundamentally different from classical oxidative addition/reductive elimination of organocopper(I) on enones. PMID- 26756836 TI - Raman Signatures of Polytypism in Molybdenum Disulfide. AB - Since the stacking order sensitively affects various physical properties of layered materials, accurate determination of the stacking order is important for studying the basic properties of these materials as well as for device applications. Because 2H-molybdenum disulfide (MoS2) is most common in nature, most studies so far have focused on 2H-MoS2. However, we found that the 2H, 3R, and mixed stacking sequences exist in few-layer MoS2 exfoliated from natural molybdenite crystals. The crystal structures are confirmed by HR-TEM measurements. The Raman signatures of different polytypes are investigated by using three different excitation energies that are nonresonant and resonant with A and C excitons, respectively. The low-frequency breathing and shear modes show distinct differences for each polytype, whereas the high-frequency intralayer modes show little difference. For resonant excitations at 1.96 and 2.81 eV, distinct features are observed that enable determination of the stacking order. PMID- 26756848 TI - A model for predicting individuals' absolute risk of esophageal adenocarcinoma: Moving toward tailored screening and prevention. AB - Esophageal adenocarcinoma (EAC) is characterized by rapidly increasing incidence and poor prognosis, stressing the need for preventive and early detection strategies. We used data from a nationwide population-based case-control study, which included 189 incident cases of EAC and 820 age- and sex-matched control participants, from 1995 through 1997 in Sweden. We developed risk prediction models based on unconditional logistic regression. Candidate predictors included established and readily identifiable risk factors for EAC. The performance of model was assessed by the area under receiver operating characteristic curve (AUC) with cross-validation. The final model could explain 94% of all case patients with EAC (94% population attributable risk) and included terms for gastro-esophageal reflux symptoms or use of antireflux medication, body mass index (BMI), tobacco smoking, duration of living with a partner, previous diagnoses of esophagitis and diaphragmatic hernia and previous surgery for esophagitis, diaphragmatic hernia or severe reflux or gastric or duodenal ulcer. The AUC was 0.84 (95% confidence interval [CI] 0.81-0.87) and slightly lower after cross-validation. A simpler model, based only on reflux symptoms or use of antireflux medication, BMI and tobacco smoking could explain 91% of the case patients with EAC and had an AUC of 0.82 (95% CI 0.78-0.85). These EAC prediction models showed good discriminative accuracy, but need to be validated in other populations. These models have the potential for future use in identifying individuals with high absolute risk of EAC in the population, who may be considered for endoscopic screening and targeted prevention. PMID- 26756849 TI - Effects of an aerobic exercise program on driving performance in adults with cardiovascular disease. AB - Cardiovascular disease (CVD) has been linked to decreases in driving performance and an increased crash risk. Regular exercise has been linked to improved driving performance among healthy adults. The aim of the current study was to investigate the relationship between a 12-week cardiac rehabilitation (CR) program and driving performance among individuals with CVD. Twenty-five individuals, including 12 cardiac adults and 13 healthy adults, took part in this study. Simulated driving performance was assessed using a standardized demerit-based scoring system at 0 and 12 weeks. Cardiac participants completed a 12-week CR program between evaluations. At baseline, cardiac participants had a higher number of demerit points than healthy adults (120.9+/-38.1 vs. 94.7+/-28.3, P=0.04). At follow-up, there was an improvement in both groups' driving evaluations, but the improvement was greater among the cardiac group such that there was no longer a difference in driving performance between both groups (94.6+/-30 vs. 86.9+/-34.8, P=0.51). Participation in an aerobic exercise-based CR program appears to lead to improvements in simulated driving performances of individuals with CVD. PMID- 26756850 TI - BPS-ICF model, a tool to measure biopsychosocial functioning and disability within ICF concepts: theory and practice updated. AB - The transformation of International Classification of Impairments, Disabilities and Handicaps into International Classification of Functioning, Disability and Health (ICF) meant a lot for those needing to communicate in terms of functioning concept in their daily work. With ICF's commonly understood language, the decades' uncertainty on what concepts and terms describe functioning and disabilities seemed to be dispelled. Instead, operationalizing ICF to measure the level of functioning along with the new nomenclature has not been as unambiguous. Transforming linguistic terms into quantified functioning seems to need another type of theorizing. Irrespective of challenging tasks, numerous projects were formulated during the past decades to apply ICF for measurement purposes. This article updates one of them, the so-called biopsychosocial-ICF model, which uses all ICF categories but classifies them into more components than ICF for measurement purposes. The model suggests that both disabilities and functional resources should be described by collecting and organizing functional measurement data in a multidisciplinary, biopsychosocial data matrice. PMID- 26756851 TI - The role and experiences of family members during the rehabilitation of mentally ill offenders. AB - Taking care of a family member with a mental illness imposes a burden on various aspects of family life. This burden may be enhanced if the mentally ill individual has a criminal history. This paper aims to summarize the scientific literature dealing with the experiences, needs and burdens of families of mentally ill offenders. We aim to explore the roles that family members play in the rehabilitation of their relative and review the families' needs and burdens. Finally, we aim to investigate whether or not the family strengths are considered in the literature. A literature search in line with the PRISMA statement for systematic reviews and with the recommendations for an integrative review was performed in the ISI Web of Science, PubMed, Elsevier Science Direct and ProQuest databases. Limited research has been carried out into the experiences, needs and burdens of families of mentally ill offenders, with only eight studies fulfilling the inclusion criteria. Families of mentally ill offenders experience more stress than those of mentally ill individuals with no judicial involvement. This is because of the fact that these family members have to deal with both mental health services and judicial systems. The eight retrieved studies focus on needs and burdens, with little reference to strengths or capabilities. The review has highlighted the need for further research into the needs and burdens of families with mentally ill offenders, with a focus on strengths rather than an exclusively problem-oriented perspective. It is important that families become more involved in the health and social care of their relatives to avoid being considered 'second patients'. PMID- 26756852 TI - Fully C/N-Polynitro-Functionalized 2,2'-Biimidazole Derivatives as Nitrogen- and Oxygen-Rich Energetic Salts. AB - Through the use of a fully C/N-functionalized imidazole-based anion, it was possible to prepare nitrogen- and oxygen-rich energetic salts. When N,N dinitramino imidazole was paired with nitrogen-rich bases, versatile ionic derivatives were prepared and fully characterized by IR, and 1 H, and 13 C NMR spectroscopy and elemental analysis. Both experimental and theoretical evaluations show promising properties for these energetic compounds, such as high density, positive heats of formation, good oxygen balance, and acceptable stabilities. The energetic salts exhibit promising energetic performance comparable to the benchmark explosive RDX (1,3,5-trinitrotriazacyclohexane). PMID- 26756853 TI - Vehicle emission implications of drivers' smart advisory system for traffic operations in work zones. AB - Wireless communication systems have been broadly applied in various complicated traffic operations to improve mobility and safety on roads, which may raise a concern about the implication of the new technology on vehicle emissions. This paper explores how the wireless communication systems improve drivers' driving behaviors and its contributions to the emission reduction, in terms of Operating Mode (OpMode) IDs distribution used in emission estimation. A simulated work zone with completed traffic operation was selected as a test bed. Sixty subjects were recruited for the tests, whose demographic distribution was based on the Census data in Houston, Texas. A scene of a pedestrian's crossing in the work zone was designed for the driving test. Meanwhile, a wireless communication system called Drivers Smart Advisory System (DSAS) was proposed and introduced in the driving simulation, which provided drivers with warning messages in the work zone. Two scenarios were designed for a leading vehicle as well as for a following vehicle driving through the work zone, which included a base test without any wireless communication systems, and a driving test with the trigger of the DSAS. Subjects' driving behaviors in the simulation were recorded to evaluate safety and estimate the vehicle emission using the Environmental Protection Agency (EPA) released emission model MOVES. The correlation between drivers' driving behavior and the distribution of the OpMode ID during each scenario was investigated. Results show that the DSAS was able to induce drivers to accelerate smoothly, keep longer headway distance and stop earlier for a hazardous situation in the work zone, which driving behaviors result in statistically significant reduction in vehicle emissions for almost all studied air pollutants (p-values range from 4.10E-51 to 2.18E-03). The emission reduction was achieved by the switching the distribution of the OpMode IDs from higher emission zones to lower emission zones. IMPLICATIONS: Transportation section is a significant source of greenhouse gas emissions. Many studies demonstrate that the wireless communication system dedicated for safety and mobility issues may contribute to the induction in vehicle emissions through changing driving behaviors. An insight into the correlation between the driving behaviors and the distribution of Operating Mode (OpMode) IDs is essential to enhance the emission reduction. The result of this study shows that with a Drivers Smart Advisory System (DSAS) drivers accelerated smoothly and stopped earlier for a hazardous situation, which induce the switch of the OpMode IDs from high emission zones to lower emission zones. PMID- 26756854 TI - Integrative and regularized principal component analysis of multiple sources of data. AB - Integration of data of disparate types has become increasingly important to enhancing the power for new discoveries by combining complementary strengths of multiple types of data. One application is to uncover tumor subtypes in human cancer research in which multiple types of genomic data are integrated, including gene expression, DNA copy number, and DNA methylation data. In spite of their successes, existing approaches based on joint latent variable models require stringent distributional assumptions and may suffer from unbalanced scales (or units) of different types of data and non-scalability of the corresponding algorithms. In this paper, we propose an alternative based on integrative and regularized principal component analysis, which is distribution-free, computationally efficient, and robust against unbalanced scales. The new method performs dimension reduction simultaneously on multiple types of data, seeking data-adaptive sparsity and scaling. As a result, in addition to feature selection for each type of data, integrative clustering is achieved. Numerically, the proposed method compares favorably against its competitors in terms of accuracy (in identifying hidden clusters), computational efficiency, and robustness against unbalanced scales. In particular, compared with a popular method, the new method was competitive in identifying tumor subtypes associated with distinct patient survival patterns when applied to a combined analysis of DNA copy number, mRNA expression, and DNA methylation data in a glioblastoma multiforme study. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26756855 TI - Therapeutic results after ultrasound-guided intratissue percutaneous electrolysis (EPI(r)) in the treatment of rectus abdominis-related groin pain in professional footballers: a pilot study. AB - BACKGROUND: Rectus abdominis-related groin pain (RAGP) is one of the possible clinical patterns that determine pubalgia. RAGP is one of the typical patterns in footballers and is due to the degeneration and tendinopathy of the distal tendon, at the level of the two pubic tubercles. Intratissue percutaneous electrolysis (EPI) is a novel technique used in the treatment of tendinopathies. The aim of this study was to examine the therapeutic benefits of EPI by contrasting the two basic components that characterize RAGP: painful symptoms and resultant functional deficits. METHODS: Eight professional footballers at Udinese Calcio Spa Football Club underwent ultrasound-guided EPI intervention. No other type of treatment was combined with EPI. Pain was monitored with the Verbal Rating Scale, while functional deficit was monitored using the Patient Specific Functional Scale. The scales implementation took place before treatment, then 24 hours, 1 week, 1 month and 6 months after the end of treatment. RESULTS: Treatment with EPI produced a complete reduction of pain symptoms in one month and enabled excellent functional recovery for walking and jogging in one week; for getting out of bed, running, jumping and kicking within one month from the end of the treatment. CONCLUSIONS: Treatment with ultrasound-guided EPI has shown encouraging clinical results for RAGP. Data are preliminary: considering the limitations of this study more complex design studies are necessary to test the efficacy of the technique. This study introduces the EPI technique for the first time in the treatment of professional footballers suffering from RAGP. Its future use is proposed as a treatment solution, including complementary to conservative treatment. PMID- 26756856 TI - Autonomic control of heart rate during non-linear incremental upper-limb resistance exercise with elastic bands in young healthy female subjects. AB - BACKGROUND: Elastic bands are therapeutic tools widely used in rehabilitation. However, knowledge regarding autonomic cardiovascular overload during this type of resistance exercise is limited. This study assessed the autonomic control of heart rate during an incremental exercise protocol with elastic bands in sedentary healthy young individuals. METHODS: Ten young women were subjected to an exercise protocol involving bilateral shoulder flexion to 90 degrees with various thicknesses of elastic bands; the exercise was performed for 36 uninterrupted repetitions with a 15-minute rest interval between sets. During the exercise, the RR intervals (R-Ri) were collected and determined, the heart rate variability was analyzed. RESULTS: All subjects completed the exercise protocol. Heart rate increased, and RR intervals decreased from the yellow elastic band onward. However, the square root of the sum of the square of the difference of RR intervals divided by the number of RR interval, standard deviation of the arithmetic mean of all normal RR intervals, and standard deviation of the RR interval instantaneous intervals of type I decreased significantly when performed with the green band onward (P<0.05). CONCLUSIONS: Exercise with progressive elastic load increases heart rate. However, the green elastic band induces less total and parasympathetic modulation heart rate variability. PMID- 26756857 TI - Clinical effects of image-guided hyaluronate injections for the osteochondral lesions of ankle in sport active population. AB - BACKGROUND: Hyaluronic acid injections are effective as intra-articular treatment, but their use in the ankle has been hindered for the difficulty of execution in this area. Use of a guidance of musculo-skeleletal ultrasound could improve the success rate and the subsequent clinical outcome, for the ameliorating placement of the needle tip. The aim of this pilot study was to assess the short-term efficacy in terms of functional outcomes and pain of a image-guided intra-articular hyaluronic acid injections of post-traumatic osteochondral lesions (OLs) of the ankle. METHODS: Thirty sport active patients (21 males; mean age 27.6+/-7.46) with a clinical and radiological diagnosis of post-traumatic ankle OLs at initial stage, received a course of three injections within a month. Patients were evaluated for pain (with Numerical Rating Scale, NRS) e function (Ankle-Hindfoot Scale, AHS, and range of motion, ROM) before every injection and ninety days after the last injection (T0-T3). RESULTS: Pain showed a significant and clinically relevant improvement during the period of treatment (P<0.001), even if pain was still presented at last follow-up assessment. Also for AHS e ROM, it was recorded a similar positive trend during time (P<0.001 for both measurements). Before intervention, pain and function resulted correlated (P<0.001), while at follow-up assessment these correlations were reduced, remaining only between pain at rest and plantar-flexion range. CONCLUSIONS: These results showed positive effects of the intra-articular hyaluronic acid for the osteochondral lesions, with a full recovery of the functional activity and a significant reduction of pain. PMID- 26756859 TI - Impact of coronary artery calcification in percutaneous coronary intervention with paclitaxel-eluting stents: Two-year clinical outcomes of paclitaxel-eluting stents in patients from the ARRIVE program. AB - OBJECTIVES: The purpose of this study was to evaluate clinical outcomes after percutaneous coronary intervention (PCI) in patients with coronary artery calcification (CAC). BACKGROUND: Smaller studies have reported worse clinical outcomes in patients with CAC who undergo PCI. The impact of CAC in the drug eluting stent era is unclear. METHODS: Data from 7,492 patients treated by PCI with >=1 TAXUS Express stent in the ARRIVE registry with no inclusion/exclusion criteria were stratified by the severity of CAC, as determined by the operator. Endpoints were independently adjudicated. All major adverse cardiac events were assessed at 2 years. RESULTS: Moderate/severe CAC was present in 19.6%. The nil/mild CAC group had higher rate of current smokers. The moderate/severe CAC group was older and had a higher prevalence of hypertension, kidney disease, prior coronary artery bypass grafting, congestive heart failure, and left main disease. After adjustment for imbalanced baseline variables, patients with moderate/severe CAC had higher 2 year rates of major adverse cardiac events (18.3% vs 13.5%, p = 0.01) and death (10.3% vs 5.6%, p = 0.02). CONCLUSIONS: Moderate/severe CAC was associated with increased clinical events in patients who underwent PCI with TAXUS stents. This may be explained in part due to differences important baseline characteristics including more patients with more comorbidities and more complex lesions. After adjustment for imbalanced baseline variables, the moderate/severe CAC group had a higher risk of major adverse cardiac events and death. Improvements in treatment strategies are needed for this high-risk group of patients who undergo PCI. (c) 2016 Wiley Periodicals, Inc. PMID- 26756858 TI - Alpha fetoprotein plays a critical role in promoting metastasis of hepatocellular carcinoma cells. AB - A high level of serum alpha fetoprotein (AFP) is positively associated with human hepatocellular carcinoma (HCC) carcinogenesis and metastasis; however, the function of AFP in HCC metastasis is unknown. This study has explored the effects of AFP on regulating metastatic and invasive capacity of human HCC cells. Forty seven clinical patients' liver samples were collected and diagnosed; HCC cells line, Bel 7402 cells (AFP-producing) and liver cancer cell line cells (non-AFP producing) were selected to analyse the role of AFP in the metastasis of HCC cells. The results indicated that high serum concentration of AFP was positively correlated with HCC intrahepatic, lymph nodes and lung metastasis. Repressed expression of AFP significantly inhibited the capability of migration and invasion of Bel 7402 cells, expression of keratin 19 (K19), epithelial cell adhesion molecule (EpCAM), matrix metalloproteinase 2/9 (MMP2/9) and CXC chemokine receptor 4 (CXCR4) were also down-regulated in Bel 7402 cells; migration and invasion, expression of K19, EpCAM, MMP2/9 and CXCR4 were significantly enhanced when HLE cells were transfected with AFP-expressed vector. The results demonstrated that AFP plays a critical role in promoting metastasis of HCC; AFP promoted HCC cell invasion and metastasis via up-regulating expression of metastasis-related proteins. Thus, AFP may be used as a novel therapeutic target for treating HCC patients. PMID- 26756860 TI - Lead-Free MA2CuCl(x)Br(4-x) Hybrid Perovskites. AB - Despite their extremely good performance in solar cells with efficiencies approaching 20% and the emerging application for light-emitting devices, organic inorganic lead halide perovskites suffer from high content of toxic, polluting, and bioaccumulative Pb, which may eventually hamper their commercialization. Here, we present the synthesis of two-dimensional (2D) Cu-based hybrid perovskites and study their optoelectronic properties to investigate their potential application in solar cells and light-emitting devices, providing a new environmental-friendly alternative to Pb. The series (CH3NH3)2CuCl(x)Br(4-x) was studied in detail, with the role of Cl found to be essential for stabilization. By exploiting the additional Cu d-d transitions and appropriately tuning the Br/Cl ratio, which affects ligand-to-metal charge transfer transitions, the optical absorption in this series of compounds can be extended to the near infrared for optimal spectral overlap with the solar irradiance. In situ formation of Cu(+) ions was found to be responsible for the green photoluminescence of this material set. Processing conditions for integrating Cu based perovskites into photovoltaic device architectures, as well as the factors currently limiting photovoltaic performance, are discussed: among them, we identified the combination of low absorption coefficient and heavy mass of the holes as main limitations for the solar cell efficiency. To the best of our knowledge, this is the first demonstration of the potential of 2D copper perovskite as light harvesters and lays the foundation for further development of perovskite based on transition metals as alternative lead-free materials. Appropriate molecular design will be necessary to improve the material's properties and solar cell performance filling the gap with the state-of-the-art Pb-based perovskite devices. PMID- 26756861 TI - Influence of rotator cuff tears on glenohumeral stability during abduction tasks. AB - One of the main goals in reconstructing rotator cuff tears is the restoration of glenohumeral joint stability, which is subsequently of utmost importance in order to prevent degenerative damage such as superior labral anterior posterior (SLAP) lesion, arthrosis, and malfunction. The goal of the current study was to facilitate musculoskeletal models in order to estimate glenohumeral instability introduced by muscle weakness due to cuff lesions. Inverse dynamics simulations were used to compute joint reaction forces for several static abduction tasks with different muscle weakness. Results were compared with the existing literature in order to ensure the model validity. Further arm positions taken from activities of daily living, requiring the rotator cuff muscles were modeled and their contribution to joint kinetics computed. Weakness of the superior rotator cuff muscles (supraspinatus; infraspinatus) leads to a deviation of the joint reaction force to the cranial dorsal rim of the glenoid. Massive rotator cuff defects showed higher potential for glenohumeral instability in contrast to single muscle ruptures. The teres minor muscle seems to substitute lost joint torque during several simulated muscle tears to maintain joint stability. Joint instability increases with cuff tear size. Weakness of the upper part of the rotator cuff leads to a joint reaction force closer to the upper glenoid rim. This indicates the comorbidity of cuff tears with SLAP lesions. The teres minor is crucial for maintaining joint stability in case of massive cuff defects and should be uprated in clinical decision-making. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1628-1635, 2016. PMID- 26756862 TI - Impact of phosphatidylcholine liposomes on the compositional changes of VLDL during lipoprotein lipase (LPL)-mediated lipolysis. AB - Lipoprotein lipase (LPL)-mediated triacylglycerol (TAG) hydrolysis in very low density lipoprotein (VLDL) is accompanied by the release of surface material containing phospholipids (PL), free cholesterol (FC) and apolipoproteins, E (apoE) and Cs (apoCII, apoCIII). The released molecules are accepted by high density lipoprotein (HDL), and new HDL-sized apoE-containing particles are also generated. A decrease in the number of HDL particles or abnormalities in their structure is associated with unfavourable changes in the features of VLDL remnants. Phosphatidylcholine liposomes (PC-L) can also act as acceptors of surface material components released from lipoproteins. Thus, the aim of this study was to assess the impact of liposomes on compositional changes of VLDL during its LPL-mediated lipolysis. VLDL isolated from human sera was incubated with LPL (LPL:VLDLTAG; 24 MUg/ml:90 mg/dl) and/or PC-L (VLDLPL:PC-LPL; 1:30 weight ratio). After incubation (2h, 37 degrees C) VLDL was separated from other reaction products, and VLDL lipid and apolipoprotein content were analysed. Newly generated HDL-sized apoE-containing lipoproteins were separated by two dimensional non-denaturing gradient gel electrophoresis (2D-PAGGE). The reaction of VLDL with PC-L in the presence or absence of LPL significantly affected the VLDL composition. The ratio of core (TAG+cholesteryl ester) to surface (PL+FC) lipids in VLDL decreased 1.8-fold with PC-L, 1.2-fold with LPL and 3-fold with PC L+LPL. The reaction with PC-L and PC-L+LPL caused a 3.7-fold and 3.2-fold decrease of apoCs/apoE average weight ratio, respectively. Compositional changes in VLDL under the influence of PC-L were accompanied by an increase in the efficiency of VLDL lipolysis and the generation of apoE-containing HDL-sized particles, heterogeneous in size (from ~ 9 to ~ 18.8 nm) and mobility (gamma and prebeta). We conclude that PL-rich particles, similarly to HDL, promote the release of surface material components from VLDL during LPL-mediated lipolysis and positively influence VLDL features which can facilitate VLDL metabolism. Such PC-L activity may impact on its antiatherogenic properties. PMID- 26756863 TI - Ligand-Accelerated Stereoretentive Suzuki-Miyaura Coupling of Unprotected 3,3' Dibromo-BINOL. AB - An efficient synthesis of the enantiomerically pure 3,3'-bis-arylated BINOL derivatives is accomplished through the palladium-catalyzed Suzuki-Miyaura coupling of the unprotected 3,3'-dibromo-BINOL with complete retention of enantiopurity. The active catalyst system Pd(OAc)2/BI-DIME has enabled mild reaction conditions at palladium loads as low as 500 ppm. PMID- 26756864 TI - Producing megakaryocytes from a human peripheral blood source. AB - BACKGROUND: Cultured megakaryocytes could prove useful in the study of human diseases, but it is difficult to produce sufficient numbers for study. We describe and evaluate the use of an expansion process to develop mature megakaryocytes from peripheral blood-derived human hematopoietic stem and progenitor cells (HSPCs). STUDY DESIGN AND METHODS: HSPCs (CD34+) were isolated from peripheral blood by positive selection and expanded using an optimal CD34+ expansion supplement. We evaluated megakaryocyte growth, maturation, and morphology in response to thrombopoietin (TPO) stimulation using flow cytometry and electron microscopy. TPO demonstrated a dose-dependent stimulatory effect on both megakaryocyte number and maturation. RESULTS: From 90 to 120 mL of unmanipulated peripheral blood, we isolated a mean of 1.5 * 10(5) HSPCs (1.5 * 10(3) cells/mL of whole blood). HSPCs expanded nine-fold after a 4-day culture using an expansion supplement. Expanded cells were cultured for an additional 8 days with TPO (20 ng/mL), which resulted in a 2.9-fold increase in megakaryocytic cells where 83% of live cells expressed CD41a+, a marker of megakaryocyte commitment, and 50% expressed CD42b+, a marker for megakaryocyte maturation. The expanded HSPCs responded to TPO stimulation to yield more than 1.0 * 10(6) megakaryocytes. This cell number was sufficient for morphologic studies that demonstrated these expanded HSPCs produced mature polyploid megakaryocytes capable of forming proplatelet extensions. CONCLUSIONS: Peripheral blood HSPCs can be expanded and differentiated into functional, mature megakaryocytes, a finding that supports the use of this process to study inherent platelet (PLT) production disorders as well as study factors that impair normal PLT production. PMID- 26756865 TI - Navigating the pitfalls and promise of landscape genetics. AB - The field of landscape genetics has been evolving rapidly since its emergence in the early 2000s. New applications, techniques and criticisms of techniques appear like clockwork with each new journal issue. The developments are an encouraging, and at times bewildering, sign of progress in an exciting new field of study. However, we suggest that the rapid expansion of landscape genetics has belied important flaws in the development of the field, and we add an air of caution to this breakneck pace of expansion. Specifically, landscape genetic studies often lose sight of the fundamental principles and complex consequences of gene flow, instead favouring simplistic interpretations and broad inferences not necessarily warranted by the data. Here, we describe common pitfalls that characterize such studies, and provide practical guidance to improve landscape genetic investigation, with careful consideration of inferential limits, scale, replication, and the ecological and evolutionary context of spatial genetic patterns. Ultimately, the utility of landscape genetics will depend on translating the relationship between gene flow and landscape features into an understanding of long-term population outcomes. We hope the perspective presented here will steer landscape genetics down a more scientifically sound and productive path, garnering a field that is as informative in the future as it is popular now. PMID- 26756866 TI - PM10 emissions and PAHs: The importance of biomass type and combustion conditions. AB - The aim of the present work was to investigate the impact of biomass combustion with respect to conditions and fuel types on particle emissions (PM10) and their PAHs content. Special concern was on sampling, quantification and characterization of PM using different appliances, fuels and operating procedures. For this purpose different lab-scale burning conditions, two pellets stoves (8.5 and 10 kW) and one open fireplace were tested by using eight fuel types of biomass. An analytical method is described for the quantitative determination of 16 PAHs using liquid-liquid extraction and subsequent measurement by gas chromatography coupled to a mass spectrometer (GC-MS). Average PM10 emissions ranged from about 65 to 170 mg/m(3) at lab-scale combustions with flow oxygen at 13% in the exhaust gas, 85-220 mg/m(3) at 20% O2, 47-83 mg/m(3) at pellet stove of 10 kW, 34-69 mg/m(3) at pellet stove of 8.5 kW and 106-194 mg/m(3) at the open fireplace. The maximum permitted particle emission limit is 150 mg/m(3). Pellets originated from olive trees and from nonmixture trees were found to emit the lowest particulate matter in relation to the others, so they are considered healthiest and suitable for domestic heating reasons. In general, the results show that biomass open burning is an important PM10 and PAHs emission source. PMID- 26756867 TI - Factors related to dementia patients' length of day-care clinic attendance. AB - BACKGROUND: In our previous study, we reported that patients using a day-care clinic for less than 1 year were older than those who continued day-care activities for more than 1 year. We found that dementia symptoms, as assessed by caregivers using the initial Assessment Scale for Symptoms of Dementia score, influenced the length of day-care clinic attendance (LDC). However, these results were obtained by univariate analysis. In this study, we investigated the factors that influenced LDC using multivariate analysis. METHODS: We studied data from 457 patients with dementia who attended our day-care clinic for dementia patients from 1 April 2000 to 31 March 2012 and continued intervention until 31 March 2013. We evaluated the factors that influenced LDC using Cox's proportional hazards model for each sex. RESULTS: Kaplan-Meier analysis showed a gender difference in LDC. The median LDC was 18 months (interquartile range: 3-37 months) for men and 21 months (interquartile range: 5-53 months) for women (P = 0.027). In model 1, the low initial Assessment Scale for Symptoms of Dementia score for each sex and high initial scores for Hasegawa's Dementia Scale-Revised and Nishimura's activity of daily living scale in women were related to the long term use of day care. Model 2 indicated that a low final score for Nishimura's activity of daily living scale increased LDC for each sex. LDC was not affected by variables related to the caregiving system except for the number of cohabitants in men. CONCLUSIONS: It was suggested that patients with high cognitive and physical functions attend the day-care clinic for a long time. It was necessary to control the behavioural and psychological symptoms of dementia for those using day care in the long term. However, patients with low physical function at the end of day-care attendance may also attend our day-care service in the long term if they receive favourable assistance. PMID- 26756868 TI - Conceptual Change in Science Is Facilitated Through Peer Collaboration for Boys but Not for Girls. AB - Three hundred and forty-one children (Mage = 9,0 years) engaged in a series of science tasks in collaborative, same-sex pairs or did not interact. All children who collaborated on the science tasks advanced in basic-level understanding of the relevant task (motion down an incline). However, only boys advanced in their conceptual understanding at a 3-week posttest. Discussion of concepts and procedural aspects of the task led to conceptual development for boys but not girls. Gender differences in behavioral style did not influence learning. Results are discussed in terms of the links between gender and engagement in conversations, and how gender differences in collaboration may relate to differences in participation in science. PMID- 26756869 TI - Where Are Socioeconomically Deprived Immigrants Located in Chile? A Spatial Analysis of Census Data Using an Index of Multiple Deprivation from the Last Three Decades (1992-2012). AB - INTRODUCTION AND PURPOSE OF THE STUDY: Immigrants in Chile have diverse characteristics and include socioeconomically deprived populations. The location of socioeconomically deprived immigrants is important for the development of public policy intelligence at the local and national levels but their areas of residence have not been mapped in Chile. This study explored the spatial distribution of socioeconomic deprivation among immigrants in Chile, 1992-2012, and compared it to the total population. MATERIAL AND METHODS: Areas with socioeconomically deprived populations were identified with a deprivation index which we developed modelled upon the Index of Multiple Deprivation (IMD) for England. Our IMD was based upon the indicators of unemployment, low educational level (primary) and disability from Census data at county level for the three decades 1992, 2002 and 2012, for 332, 339 and 343 counties respectively. We developed two versions of the IMD one based on disadvantage among the total population and another focused upon the circumstances of immigrants only. We generated a spatial representation of the IMD using GIS, for the overall IMD score and for each dimension of the index, separately. We also compared the immigrants' IMD to the total population's IMD using Pearson's correlation test. RESULTS: Results showed that socioeconomically deprived immigrants tended to be concentrated in counties in the northern and central area of Chile, in particular within the Metropolitan Region of Santiago. These were the same counties where there was the greatest concentration of socioeconomic deprivation for the total population during the same time periods. Since 1992 there have been significant change in the location of the socioeconomically deprived populations within the Metropolitan Region of Santiago with the highest IMD scores for both the total population and immigrants becoming increasingly concentrated in the central and eastern counties of the Region. CONCLUSION: This is the first study analysing the spatial distribution of socioeconomic deprivation among international immigrants and the total population in a Latin American country. Findings could inform policy makers about location of areas of higher need of social protection in Chile, for both immigrants and the total resident population in the country. PMID- 26756870 TI - ECM-Dependence of Endothelial Progenitor Cell Features. AB - Preserving self-renewal, multipotent capacity, and large-scale expansion of highly functional progenitor cells, including endothelial progenitor cells (EPCs), is a controversial issue. These current limitations, therefore, raise the need of developing promising in vitro conditions for prolonged expansion of EPCs without loss of their stemness feature. In the current study, the possible role of three different natural extracellular substrates, including collagen, gelatin, and fibronectin, on multiple parameters of EPCs such as cell morphology, phenotype, clonogenic, and vasculogenic properties was scrutinized. Next, EPCs from GFP-positive mice were pre-expanded on each of these ECM substrates and then systemically transplanted into sublethaly irradiated mice to analyze the potency of these cells for marrow reconstitution. Our results revealed considerable promise for fibronectin for EPC expansion with maintenance of stemness characteristics, whereas gelatin and collagen matrices directed the cells toward a mature endothelial phenotype. Transplantation of EPCs pre-expanded on fibronectin resulted in widespread distribution and appropriate engraftment to various tissues with habitation in close association with the microvasculature. In addition, fibronectin pre-expanded cells were gradually enriched in the bone marrow after transplantation, resulting in marrow repopulation and hematologic recovery, leading to improved survival of recipient mice whereas gelatin- and collagen-expanded cells failed to reconstitute the bone marrow. This study demonstrated that, cell characteristics of in vitro expanded EPCs are determined by the subjacent matrix. Fibronectin-expanded EPCs are heralded as a source of great promise for bone marrow reconstitution and neo-angiogenesis in therapeutic bone marrow transplantation. J. Cell. Biochem. 117: 1934-1946, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26756871 TI - BisGMA-induced cytotoxicity and genotoxicity in macrophages are attenuated by wogonin via reduction of intrinsic caspase pathway activation. AB - Bisphenol-A-glycidyldimethacrylate (BisGMA) is a frequently used monomer in dental restorative resins. However, BisGMA could leach from dental restorative resins after polymerization leading to inflammation in the peripheral environment. Wogonin, a natural flavone derivative, has several benefits, such as antioxidative, anti-inflammatory and neuroprotective properties. Pretreatment of macrophage RAW264.7 cells with wogonin inhibited cytotoxicity which is induced by BisGMA in a concentration-dependent manner. BisGMA induced apoptotic responses, such as redistribution of phosphatidylserine from the internal to the external membrane and DNA fragmentation, were decreased by wogonin in a concentration dependent manner. In addition, BisGMA-induced genotoxicity, which detected by cytokinesis-blocked micronucleus and single-cell gel electrophoresis assays, were inhibited by wogonin in a concentration-dependent manner. Furthermore, wogonin suppressed BisGMA-induced activation of intrinsic caspase pathways, such as caspases-3 and -8. Parallel trends were observed in inhibition of caspase-3 and 8 activities, apoptosis, and genotoxicity. These results indicate wogonin suppressed the BisGMA-induced apoptosis and genotoxicity mainly via intrinsic caspase pathway in macrophages. PMID- 26756872 TI - Absence of Maternal Microchimerism in Regional Lymph Nodes of Children With Biliary Atresia. AB - OBJECTIVE: Maternal lymphocytes have been cited as a potential cause of infantile biliary atresia (BA). When hepatoportoenterostomy is performed, locoregional lymphadenopathy is frequently encountered. METHODS: We screened enlarged nodes from 6 consecutive nonsyndromatic BA patients (age: 68 days +/- 18.9 days) for maternal elements using DNA fingerprinting with short tandem repeat analysis and quantitative real-time polymerase chain reaction for allelic (single nucleotide) sequence polymorphisms. RESULTS: Although being partly positive in infants' peripheral blood, no maternal microchimerism could be demonstrated in any of the lymph nodes. CONCLUSION: This result challenges the hypothesis that maternal cells play a role in hilar lymphadenopathy of children with BA. PMID- 26756873 TI - Clinical Experience of Use of High-dose Intravenous Methylprednisolone in Children With Acute Moderate to Severe Colitis. AB - OBJECTIVES: Treatment of acute severe colitis (ASC) has been associated with high morbidity and high colectomy rate in children. In the prebiologics era, our centre used short-term high-dose intravenous corticosteroids (IVCS) at 2 to 30 mg . kg . day. We conducted a retrospective review to compare efficacy of different dosing regimes of IVCS. METHODS: Thirty-four children treated with IVCS for ASC were included over 8 years. Patients were studied as 2 groups with similar pretreatment patient characteristics. Group 1 (standard dose) received IVCS at 2 mg . kg . day and group 2 (high dose) received IVCS at 10 to 30 mg . kg . day. Safety, efficacy, and follow-up of the entire cohort for >1 year were studied. The median IVCS dose in the standard- and high-dose cohort was 1.5 mg . kg . day (maximum 60 mg . kg . day) and 24.8 mg . kg . day (maximum 1000 mg . kg . day), respectively. RESULTS: Pediatric Ulcerative Colitis Activity Index scores at day 5 were significantly lower in high-dose (15, interquartile range 8.5-20) than in standard-dose IVCS (30, interquartile range 20-30). IVCS side effects were minor and reversible. Overall, medical salvage therapy was required in 5.8% (2 children) before discharge, and in 17% (6 children) at follow-up after 1 year. The colectomy rate of the entire cohort was remarkably low with 0% during admission and 11% (4 children) after 1 year, with a trend of less colectomies in high-dose (4.8%-1 child) than in standard-dose (23%-3 children). CONCLUSIONS: Our data show that in paediatric ASC, the short-term use of high-dose IVCS is safe and effective. Prospective studies are needed to define the role of IVCS within salvage therapy protocols. PMID- 26756874 TI - Corticosteroid Dosing in Pediatric Acute Severe Ulcerative Colitis: A Propensity Score Analysis. AB - OBJECTIVES: We aimed to explore the optimal dosing of intravenous-corticosteroids (IVCS) using a robust statistical method on the largest pediatric cohort of acute severe colitis to date. METHODS: Two hundred eighty-three children treated with IVCS for ulcerative colitis were included and studied for 1 year (46% boys, age 12.1 +/- 3.9 years, disease duration 2 (interquartile range [IQR] 0-14) months, baseline Pediatric Ulcerative Colitis Activity Index 69 +/- 13 points). Confounding by indication was addressed by matching high- and low-IVCS dose patients according to the propensity score method, using 3 cutoffs (1 mg . kg . methylprednisolone to 40 mg . day, 1.25 mg . kg to 50 mg . day and 2 mg . kg to 80 mg . day). RESULTS: The median IVCS dose in the entire cohort was 1.0 mg . kg . day (IQR 0.8-1.4) and 44 mg . kg . day (32-60). Ninety-four of 283 children were matched in the low-dose cutoff (1 mg . kg . day), 218 of 283 were matched in the middle cutoff (1.25 mg . kg . day), and 86/283 in the high dose cutoff (2 mg . kg . day). No differences were found in 25 pretreatment baseline variables in the three cutoffs, implying successful matching. There were no statistical differences in the outcomes of the two lower cutoffs (including need for salvage therapy during admission and by 1 years, admission duration, and day-5 Pediatric Ulcerative Colitis Activity Index<35 points; all P > 0.05). In the high cutoff, the higher doses were somewhat better but this benefit reversed in a sensitivity analysis excluding one center. High doses were not associated with better outcome also in a propensity score-weighted regression model on the entire cohort. CONCLUSIONS: Our data support present guidelines that doses of IVCS >1 to 1.5 mg . kg . day (maximum 40-60 mg . kg . day) are not justified in acute severe colitis. PMID- 26756876 TI - Possible Phenylacetate Hepatotoxicity During 4-Phenylbutyrate Therapy of Byler Disease. AB - In vitro studies have suggested that 4-phenylbutyrate (PBA) may rescue missense mutated proteins that underlie some forms of progressive familial intrahepatic cholestasis. Encouraging preliminary responses to 4-PBA have been reported in liver disease secondary to mutations in ABCB11 and ATP8B1. A 4-year-old boy with Byler disease was treated with 4-PBA in the forms of sodium PBA (5 months) and then glycerol PBA (7 months) as part of expanded access single patient protocols. During this therapy serum total bilirubin fell and his general well-being was reported to be improved, although total serum bile acids were not reduced. Discontinuation of rifampin therapy, which had been used to treat pruritus, resulted in reversible severe acute liver injury that was potentially the result of phenylacetate toxicity. Interactions between 4-PBA and cytochrome P450 enzymes should be considered in the use of this agent with special attention to potential phenylacetate toxicity. PMID- 26756875 TI - Clinical Features and Risk Factors of Autoimmune Liver Involvement in Pediatric Inflammatory Bowel Disease. AB - OBJECTIVES: Autoimmune liver disease is reported in up to 7.8% of children with inflammatory bowel disease. A distinct inflammatory bowel disease phenotype has been suggested in adults and in small pediatric cohorts. The aim of the study was to evaluate the features of inflammatory bowel disease associated with autoimmune liver diseases and to analyze the characteristics of the liver disease. METHODS: Information on patients was obtained from the Italian Pediatric Inflammatory Bowel Disease Registry. Data of patients with and without autoimmune liver disease were compared. RESULTS: Autoimmune liver disease was detected in 6.8% of the 677 patients enrolled and was significantly associated with the diagnosis of ulcerative colitis (83%), with pancolonic involvement (84%), and with perinuclear antineutrophil cytoplasmic antibody positivity (41%) (all Ps < 0.05). Autoimmune liver disease was defined as sclerosing cholangitis in 61% of the patients and as an overlap syndrome in 33%. Concomitant intra- and extrahepatic biliary involvement was reported in 61% of cases, whereas exclusive extrahepatic lesions were reported in 21%. Hepatobiliary complications were observed in 9% of the patients during follow-up. CONCLUSIONS: Autoimmune liver disease, especially sclerosing cholangitis, was significantly more common in patients with extensive ulcerative colitis. Although complications are relatively rare in the pediatric age, monitoring is recommended. PMID- 26756877 TI - Probiotics for the Prevention of Antibiotic-Associated Diarrhea in Children. AB - This article provides recommendations, developed by the Working Group (WG) on Probiotics of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition, for the use of probiotics for the prevention of antibiotic associated diarrhea (AAD) in children based on a systematic review of previously completed systematic reviews and of randomized controlled trials published subsequently to these reviews. The use of probiotics for the treatment of AAD is not covered. The recommendations were formulated only if at least 2 randomized controlled trials that used a given probiotic (with strain specification) were available. The quality of evidence (QoE) was assessed using the Grading of Recommendations Assessment, Development, and Evaluation guidelines. If the use of probiotics for preventing AAD is considered because of the existence of risk factors such as class of antibiotic(s), duration of antibiotic treatment, age, need for hospitalization, comorbidities, or previous episodes of AAD diarrhea, the WG recommends using Lactobacillus rhamnosus GG (moderate QoE, strong recommendation) or Saccharomyces boulardii (moderate QoE, strong recommendation). If the use of probiotics for preventing Clostridium difficile-associated diarrhea is considered, the WG suggests using S boulardii (low QoE, conditional recommendation). Other strains or combinations of strains have been tested, but sufficient evidence is still lacking. PMID- 26756878 TI - Spray Dried, Pasteurised Bovine Colostrum Protects Against Gut Dysfunction and Inflammation in Preterm Pigs. AB - OBJECTIVE: Feeding bovine colostrum (BC) improves gut maturation and function and protects against necrotizing enterocolitis, relative to formula in newborn preterm pigs. Before BC can be used for preterm infants, it is important to test if the milk processing, required to reduce bacterial load and increase shelf life, may affect bioactivity and efficacy of a BC product. METHODS: We investigated if spray dried, pasteurised BC had protective effects on gut function in preterm pigs, relative to formula. After a 2-day total parenteral nutrition period, preterm pigs were fed formula for a few hours (to induce a proinflammatory state) followed by 2 days of formula (FORM, n = 14), BC (colostrum [COLOS], n = 14), spray-dried BC (POW, n = 8), or pasteurised, spray dried BC (POWPAS, n = 9). RESULTS: Spray drying and pasteurisation of BC decreased the concentration of transforming growth factor-beta1, -beta2 and increased protein aggregation. All of the 3 BC groups had reduced necrotizing enterocolitis severity, small intestinal levels of IL-1beta, -8, and colonic lactic acid levels, and increased intestinal villus height, hexose absorption, and digestive enzyme activities, relative to the FORM group (all P < 0.05). All of the 3 BC diets stimulated epithelial cell migration in a wound-healing model with IEC-6 cells. CONCLUSIONS: Spray drying and pasteurisation affect BC proteins, but do not reduce the trophic and anti-inflammatory effects of BC on the immature intestine. It remains to be studied if BC products will benefit preterm infants just after birth when human milk is often not available. PMID- 26756879 TI - Comparative facile methods for preparing graphene oxide-hydroxyapatite for bone tissue engineering. AB - Motivated by the success of using graphene oxide (GO) as a nanofiller of composites, there is a drive to search for this new kind of carbon material as a bioactive component in ceramic materials. In the present study, biomineralized GO was prepared by two different approaches, represented by in situ sol-gel synthesis and biomimetic treatment. It was found that in the biocomposites obtained by the sol-gel approach, the spindle-like hydroxyapatite nanoparticles, with a diameter of ca. 5 +/- 0.37 nm and a length of ca. 70 +/- 2.5 nm, were presented randomly and strongly on the surface. The oxygen-containing functional groups, such as hydroxyl and carbonyl, present on the basal plane and edges of the GO sheets, play an important role in anchoring calcium ions, as demonstrated by FT-IR and TEM investigations. A different result was obtained for biocomposites after biomimetic treatment: an amorphous calcium phosphate on GO sheet was observed after 5 days of treatment. These different approaches resulted in a diverse effect on the proliferation and differentiation of osteogenic mesenchymal stem cells. In fact, in biocomposites prepared by the sol-gel approach the expression of an early marker of osteogenic differentiation, ALP, increases with the amount of GO in the first days of cell culture. Meanwhile, biomimetic materials sustain cell viability and proliferation, even if the expression of alkaline phosphatase activity in a basal medium is delayed. These findings may provide new prospects for utilizing GO-based hydroxyapatite biocomposites in bone repair, bone augmentation and coating of biomedical implants and broaden the application of GO sheets in biological areas. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26756881 TI - Glass ionomer cements functionalised with a concentrated paste of chlorhexidine hexametaphosphate provides dose-dependent chlorhexidine release over at least 14 months. AB - OBJECTIVES: The aim of this study was to create prototype glass ionomer cements (GICs) incorporating a concentrated paste of chlorhexidine-hexametaphosphate (CHX HMP), and to investigate the long-term release of soluble chlorhexidine and the mechanical properties of the cements. The purpose is the design of a glass ionomer with sustained anticaries efficacy. METHODS: CHX-HMP paste was prepared by mixing equimolar solutions of chlorhexidine digluconate and sodium hexametaphosphate, adjusting ionic strength, decanting and centrifuging. CHX-HMP paste was incorporated into a commercial GIC in substitution for glass powder at 0.00, 0.17, 0.34, 0.85 and 1.70% by mass CHX-HMP. Soluble chlorhexidine release into artificial saliva was observed over 436 days using absorbance at 255nm. Diametral tensile and compressive strength were measured after 7 days' setting (37 degrees C, 100% humidity) and tensile strength after 436 days' aging in artificial saliva. 0.34% CHX-HMP GICs were tested for their ability to inhibit growth of Streptococcus mutans in vitro. RESULTS: GICs supplemented with CHX-HMP exhibited a sustained dose-dependent release of soluble chlorhexidine. Diametral tensile strength of new specimens was unaffected up to and including 0.85% CHX HMP, and individual values of tensile strength were unaffected by aging, but the proportion of CHX-HMP required to adversely affect tensile strength was lower after aging, at 0.34%. Compressive strength was adversely affected by CHX-HMP at substitutions of 0.85% CHX-HMP and above. CONCLUSIONS: Supplementing a GIC with CHX-HMP paste resulted in a cement which released soluble chlorhexidine for over 14 months in a dose dependent manner. 0.17% and 0.34% CHX-HMP did not adversely affect strength at baseline, and 0.17% CHX-HMP did not affect strength after aging. 0.34% CHX-HMP GICs inhibited growth of S. mutans at a mean distance of 2.34mm from the specimen, whereas control (0%) GICs did not inhibit bacterial growth. CLINICAL SIGNIFICANCE: Although GICs release fluoride in vivo, there is inconclusive evidence regarding any clinical anticaries effect. In this study, GICs supplemented with a paste of chlorhexidine-hexametaphosphate (CHX-HMP) exhibited a sustained release of chlorhexidine over at least 14 months, and small additions of CHX-HMP did not adversely affect strength. PMID- 26756880 TI - Optimal Synthetic Glycosylation of a Therapeutic Antibody. AB - Glycosylation patterns in antibodies critically determine biological and physical properties but their precise control is a significant challenge in biology and biotechnology. We describe herein the optimization of an endoglycosidase catalyzed glycosylation of the best-selling biotherapeutic Herceptin, an anti HER2 antibody. Precise MS analysis of the intact four-chain Ab heteromultimer reveals nonspecific, non-enzymatic reactions (glycation), which are not detected under standard denaturing conditions. This competing reaction, which has hitherto been underestimated as a source of side products, can now be minimized. Optimization allowed access to the purest natural form of Herceptin to date (>=90 %). Moreover, through the use of a small library of sugars containing non-natural functional groups, Ab variants containing defined numbers of selectively addressable chemical tags (reaction handles at Sia C1) in specific positions (for attachment of cargo molecules or "glycorandomization") were readily generated. PMID- 26756882 TI - Long-term evaluation of cantilevered versus fixed-fixed resin-bonded fixed partial dentures for missing maxillary incisors. AB - OBJECTIVES: To evaluate the long-term longevity and patient-reported outcomes of two-unit cantilevered (CL2) and three-unit fixed-fixed (FF3) resin-bonded fixed partial dentures (RBFPDs) for the replacement of a maxillary permanent incisor. MATERIALS AND METHODS: Twenty-eight subjects were randomly assigned to receive either a CL2 or FF3 RBFPD placed by one operator. Prosthesis longevity was determined by clinical examination and history. Success was defined as absence of complications requiring intervention and survival as retention of the original prosthesis in mouth. Subjects' satisfaction was assessed using visual analogue scale (VAS) and oral health-related quality of life (OHRQoL) using Oral Health Impact Profile (OHIP-49). Outcomes were analysed with t-test/Mann-Whitney U test, chi-square and log-rank test at significance level alpha=0.05. RESULTS: Twenty two subjects were reviewed. Thirteen of fifteen CL2 and ten of fourteen FF3 RBFPDs were examined (79.3 percent response rate) with a mean service life of 216.5+/-20.8months. All CL2 RBFPDs survived with no complications while only 10 percent of FF3 experienced no complications and only 50 percent of them survived (both P=0.000). CL2 had a significantly better success and survival rate than FF3 (P=0.000 and P=0.009, respectively). There was no significant difference in subjects' satisfaction and OHRQoL apart from CL2 group subjects had a higher satisfaction in cleaning of the prosthesis (84.1+/-13.6) than FF3 group (72.6+/ 11.7) (P=0.05). CONCLUSIONS: Two-unit cantilevered RBFPDs were observed to have a significantly better success and survival than the FF3 design for the replacement of a maxillary incisor. Good patient-reported outcomes have been found for RBFPDs in single-tooth replacement in aesthetic zone. PMID- 26756884 TI - Yeast 2.0: a new chapter. PMID- 26756885 TI - 'An IPTG-inducible derivative of the fission yeast nmt promoter' Soeren Kjaerulff, Olaf Nielsen. PMID- 26756883 TI - Histology, Fusion Status, and Outcome in Alveolar Rhabdomyosarcoma With Low-Risk Clinical Features: A Report From the Children's Oncology Group. AB - BACKGROUND: Distinguishing alveolar rhabdomyosarcoma (ARMS) from embryonal rhabdomyosarcoma (ERMS) is of prognostic and therapeutic importance. Criteria for classifying these entities evolved significantly from 1995 to 2013. ARMS is associated with inferior outcome; therefore, patients with alveolar histology have generally been excluded from low-risk therapy. However, patients with ARMS and low-risk stage and group (Stage 1, Group I/II/orbit III; or Stage 2/3, Group I/II) were eligible for the Children's Oncology Group (COG) low-risk rhabdomyosarcoma (RMS) study D9602 from 1997 to 1999. The characteristics and outcomes of these patients have not been previously reported, and the histology of these cases has not been reviewed using current criteria. PROCEDURE: We re reviewed cases that were classified as ARMS on D9602 using current histologic criteria, determined PAX3/PAX7-FOXO1 fusion status, and compared these data with outcome for this unique group of patients. RESULTS: Thirty-eight patients with ARMS were enrolled onto D9602. Only one-third of cases with slides available for re-review (11/33) remained classified as ARMS by current histologic criteria. Most cases were reclassified as ERMS (17/33, 51.5%). Cases that remained classified as ARMS were typically fusion-positive (8/11, 73%), therefore current classification results in a similar rate of fusion-positive ARMS for all clinical risk groups. In conjunction with data from COG intermediate-risk treatment protocol D9803, our data demonstrate excellent outcomes for fusion-negative ARMS with otherwise low-risk clinical features. CONCLUSIONS: Patients with fusion positive RMS with low-risk clinical features should be classified and treated as intermediate risk, while patients with fusion-negative ARMS could be appropriately treated with reduced intensity therapy. PMID- 26756886 TI - Erratum: Sarcoma of the Uterus. Guideline of the DGGG (S2k-Level, AWMF Registry No. 015/074, August 2015). AB - [This corrects the article DOI: 10.1055/s-0035-1558120.]. PMID- 26756887 TI - The influence of myeloid-derived suppressor cells on angiogenesis and tumor growth after cancer surgery. AB - While myeloid-derived suppressor cells (MDSCs) have been reported to participate in the promotion of angiogenesis and tumor growth, little is known about their presence and function during perioperative period. Here, we demonstrated that human MDSCs expressing CD11b(+), CD33(+) and HLA-DR(-) significantly increased in lung cancer patients after thoracotomy. CD11b(+) CD33(+) HLA-DR(-) MDSCs isolated 24 hr after surgery from lung cancer patients were more efficient in promoting angiogenesis and tumor growth than MDSCs isolated before surgical operation in allograft tumor model. In addition, CD11b(+) CD33(+) HLA-DR(-) MDSCs produced high levels of MMP-9. Using an experimental lung metastasis mouse model, we demonstrated that the numbers of metastases on lung surface and Gr-1(+) CD11b(+) MDSCs at postoperative period were enhanced in proportion to the degree of surgical manipulation. We also examined that syngeneic bone marrow mesenchymal stem cells (BMSCs) significantly inhibited the induction and proliferation of Gr 1(+) CD11b(+) MDSCs and further prevented lung metastasis formation in the mice undergoing laparotomy. Taken together, our results suggest that postoperatively induced MDSCs were qualified with potent proangiogenic and tumor-promotive ability and this cell population should be considered as a target for preventing postoperative tumor metastasis. PMID- 26756889 TI - Potential malignant cell contamination in transplanted ovarian tissue. PMID- 26756890 TI - Prescribing errors in two ICU wards in a large teaching hospital in Iran. AB - BACKGROUND: Despite efforts to improve the patients' safety, medical errors especially prescription errors can lead to morbidity and mortality in patients. The present study was conducted to assess the prescription errors in the intensive care units (ICU) in Shiraz, Southwest of Iran. METHODS: We reviewed the all recorded orders in the two ICU wards of the Shiraz largest hospital in the south of Iran. Data were collected from the two wards and hospital archive using a structured checklist. Descriptive statistics, Chi-square and logistic regression tests were used to analyze the data. RESULTS: Among the 2230 recorded prescriptions for 40 hospitalized patients, 387 prescribed orders (251 in the General ICU and 136 in the Central ICU) had at least one error which occurred in the three months of the study. The study revealed that illegible orders have the highest error frequency in the two wards. The mean prescription error in the two ICU wards was 17.3 (0.19 errors in the General and 0.14 errors in The Central ICU, respectively). Lack of drug dosage was more than that in the larger wards (P = 0.037); moreover, illegible order and mistaken dosage were more in smaller wards (OR 1.84, CI = 1.18-2.86 and OR 2.55, CI = 1.08-6.00, P = 0.007 and P = 0.031, respectively). CONCLUSION: The rate of prescription errors in ICU wards was high and it was higher in crowded wards. Illegible orders were the majority of important errors in prescriptions. In the majority of orders, physicians did not write the drug form and drug dose which could be potentially harmful to patients. It is recommended that a computerized physician order should be used because it can decrease prescription errors. PMID- 26756888 TI - Calpastatin inhibits motor neuron death and increases survival of hSOD1(G93A) mice. AB - Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with a poorly understood cause and no effective treatment. Given that calpains mediate neurodegeneration in other pathological states and are abnormally activated in ALS, we investigated the possible ameliorative effects of inhibiting calpain over activation in hSOD1(G93A) transgenic (Tg) mice in vivo by neuron-specific over expression of calpastatin (CAST), the highly selective endogenous inhibitor of calpains. Our data indicate that over-expression of CAST in hSOD1(G93A) mice, which lowered calpain activation to levels comparable to wild-type mice, inhibited the abnormal breakdown of cytoskeletal proteins (spectrin, MAP2 and neurofilaments), and ameliorated motor axon loss. Disease onset in hSOD1(G93A) /CAST mice compared to littermate hSOD1(G93A) mice is delayed, which accounts for their longer time of survival. We also find that neuronal over-expression of CAST in hSOD1(G93A) transgenic mice inhibited production of putative neurotoxic caspase-cleaved tau and activation of Cdk5, which have been implicated in neurodegeneration in ALS models, and also reduced the formation of SOD1 oligomers. Our data indicate that inhibition of calpain with CAST is neuroprotective in an ALS mouse model. CAST (encoding calpastatin) inhibits hyperactivated calpain to prevent motor neuron disease operating through a cascade of events as indicated in the schematic, with relevance to amyotrophic lateral sclerosis (ALS). We propose that over-expression of CAST in motor neurons of hSOD1(G93A) mice inhibits activation of CDK5, breakdown of cytoskeletal proteins (NFs, MAP2 and Tau) and regulatory molecules (Cam Kinase IV, Calcineurin A), and disease-causing proteins (TDP-43, alpha-Synuclein and Huntingtin) to prevent neuronal loss and delay neurological deficits. In our experiments, CAST could also inhibit cleavage of Bid, Bax, AIF to prevent mitochondrial, ER and lysosome-mediated cell death mechanisms. Similarly, CAST over-expression in neurons attenuated pathological effects of TDP-43, alpha-synuclein and Huntingtin. These results suggest a potential value of specific small molecule inhibitors of calpains in delaying the development of ALS. Read the Editorial Highlight for this article on page 140. PMID- 26756891 TI - Prevalence of inappropriate medication prescription in the elderly in Nigeria: A comparison of Beers and STOPP criteria. AB - BACKGROUND: Inappropriate medication prescription among the elderly is a major problem with significant negative health consequences. The Beers and STOPP (Screening Tool of Older Persons' potentially inappropriate Prescription) criteria are common tools used for screening of potentially inappropriate medications. The primary objective of the study was to estimate the incidence of PIM among elderly Nigerian patients using the earlier mentioned tools. METHODOLOGY: This prospective study was conducted among elderly patients attending the general outpatients' clinics of two tertiary healthcare institutions in the South-Western part of Nigeria. The patients' age, gender, diagnosis for which the patient was receiving treatment and prescribed drugs were the information retrieved from the medical records. The WHO drug use indicators were applied in the drug utilization aspect of the study while the Beers and STOPP criteria were used to define the inappropriateness or otherwise of the prescribed medications. RESULTS: The mean number of drugs per prescription was 4.1 +/- 1.2 while the median number of drugs prescribing by generic name was 46.5% (IQR: 35). Using Beers criteria for the assessment of prescription of potentially inappropriate medications, 106 (30.3%) of all patients had at least one inappropriate medication prescribed with a total of one hundred and twenty six cases recorded. Screening for PIM using the STOPP criteria, we found 55 (15.7%) of the study participants with at least one potential encounter. Female sex, number of prescribed medications and co-morbidities were positively associated with prescription of a PIM using both tools. CONCLUSION: Prescription of PIM is highly prevalent among elderly Nigerian patients. There is a need for continuing education of prescribers on rational prescribing in the elderly using some of the screening tools. PMID- 26756892 TI - High risk use of OTC NSAIDs and ASA in family medicine: A retrospective chart review. AB - BACKGROUND: Complications associated with the use of NSAIDs, antiplatelet agents, and anticoagulants are among the top causes of preventable drug-related ER visits, hospitalizations and death. Although over-the-counter (OTC) NSAIDs and ASA also contribute to this preventable risk, it is unclear how well these medications are documented in primary care records. METHODS: A retrospective electronic and paper chart review was conducted to evaluate the prevalence of 13 evidence-based high-risk prescriptions and the contribution of OTC NSAIDs and ASA to these potentially inappropriate prescriptions (PIPs). RESULTS: Of the 148 patients included in the review, ASA was taken by 117 patients (79%) while OTC NSAIDs were taken by 36 (24%). OTC NSAIDs were never documented within the "medication" section of the electronic record, whereas ASA was documented in 65 (56%) cases. Eighty percent (118/148) taking either OTC NSAIDs or ASA were identified as having at least one PIP. CONCLUSION: OTC NSAIDs and ASA are widely available and are commonly taken without the knowledge of the prescriber. These medications contribute to the overall risk of bleeding. Review and documentation of OTC NSAIDs and ASA use should be part of all relevant patient encounters when prescribing NSAIDs, antiplatelets and anticoagulants. PMID- 26756893 TI - Efficacy of paediatric anaesthetic trolleys: A call for a basic standard and layout. AB - BACKGROUND: Providing safe anaesthesia to children especially in emergency situations goes hand in hand with instant availability of appropriately sized equipment and monitoring. This is best achieved using a designated paediatric anaesthetic trolley containing essential equipment. Guidance for the contents of such trolleys is neither explicit nor standard. We used a survey and a qualitative enquiry to develop a checklist suitable for standardisation of contents and layout of paediatric anaesthetic trolleys. METHODS: We conducted an observational study of our current practice and paediatric anaesthetic trolleys in a tertiary care hospital. We also performed a qualitative enquiry from experienced paediatric anaesthetists and operating department practitioners.We developed an empirical checklist to ensure the minimum 'essential' equipment is available on these trolleys and implemented a standard layout to facilitate its use. RESULTS: We identified 11 areas in our hospital where anaesthesia is provided to children, each with a designated paediatric anaesthetic trolley. There were considerable deficiencies of items in all areas with no standard pattern or layout. Different types of trolleys contributed to the confusion. In addition, overstocking of inappropriate items hindered its efficient use. CONCLUSION: Standardising the contents and layout of the paediatric anaesthetic trolley is an essential pre-requisite for safer paediatric anaesthetic practice. PMID- 26756894 TI - Evidence-based information leads to reduction in inappropriate drug prescribing: Results from Indian older inpatients. AB - BACKGROUND: Although several guidelines for appropriate prescribing are available, inappropriate drug prescription remains noteworthy problem among older adults. Indian older patients are also not spare from this issue and existing literature indicates a fair level of inappropriate drug use (IDU). OBJECTIVES: Identified potentially IDU and documented their reduction based on provided evidence-based information and also identified possible predictors of IDU in older inpatients. SETTING: Three years prospective study included 1510 inpatients aged 60 years or over, of both sexes. IDU identified using the Modified Updated AGS Beers Criteria 2012. RESULTS: The patients had an average age of 67.10 +/- 0.23 years and on an average were prescribed 9.29 +/- 0.11 medications. Using AGS Beers Criteria 2012, total IDU was found to be 21% (n = 325). Of total 287 patients received only one inappropriate drug whereas 38 patients received two or more inappropriate drug(s). According to first list of criteria long acting benzodiazepines, anticholinergics, nitrofurantoin and digoxin were most common IDU. Prescription of theophylline in insomnia followed by aspirin in gastric ulcer and calcium channel blocker in constipation were listed from second list of criteria. 31% reductions in IDU were observed based on evidence-based information regarding each identified inappropriate drugs. CONCLUSIONS: The findings of this study provide evidence that provision of unbiased evidenced based information is the best possible means for improvement of pharmacotherapy in older patients. PMID- 26756895 TI - Knowledge and perception of off-label drug use amongst prescribing physicians in a tertiary care hospital. AB - INTRODUCTION: Off-label drug use is commonly reported in various disciplines of medicine. Considering the lacunae of studies from prescribers in the Indian subcontinent, the present study was conducted to explore their awareness and views of off-label drug use. METHODS: A validated questionnaire was administered to interns, junior residents and faculty members who were recruited in the present study of various medical and surgical departments of Subharti Medical College, Meerut, India, a tertiary care teaching hospital. Descriptive statistics was used for analyzing the data. RESULTS: A total of 59/85 (69%) stated that they have used a drug in an off-label manner mainly [31/85 (36.5%)] related to indications. Nearly half of the study participants (41/85, 48.2%) considered prescribing an off-label drug illegal and only 25/85 (29.3%) participants felt that they had adequate knowledge regarding the use of drugs in off-label manner. Out of the total 70 participants who answered the question related to informing parents/relatives while prescribing an off label drug, only 39/70 (55.7%) answered affirmative. Out of the remaining 31/70 (44.3%) of participants who did not inform about prescribing an off label drug, 9/31 (29%) felt that it was illegal and more than two-third (24/31, 77%) felt their knowledge on off-label drug use was insufficient. Surprisingly, 74/82 (90.2%) participants felt that a drug approved to be used in adults cannot be used in children for the same indication despite not having any alternative in pediatric age group. CONCLUSION: We found an inadequate knowledge regarding the off-label drug use amongst the prescribers in a tertiary care medical college hospital. Many of the physicians felt such use as illegal and do not inform the patient's relatives about such acts. Considering the legal issues, clearly there exists a need to patch up this lacuna in developing countries like India. PMID- 26756896 TI - Performance assessment of the Thai National Center for Pharmacovigilance. AB - BACKGROUND: The Thai National Pharmacovigilance Center (NPVC) has operated since 1983, but its performance has never been formally assessed. OBJECTIVE: The paper aimed to present the main findings of performance assessment of the Thai NPVC. METHODS: A survey was conducted. Data from January 2011-December 2013 were collected. The performance was assessed through four indicator domains. RESULTS: The NPVC has a clear mission to guide its roles and responsibilities. The center has a well-established structure, adequate budget, qualified personnel, and good IT infrastructure, but it has no in-house IT personnel.Safety surveillance function was considered excellent. The Thai adverse drug reaction database accumulate a number of quality reports. Typically, new signals of traditional or herbal medicines could be generated from the database.The risk management process was well established and carried out. The National Drug Safety Advisory Sub Committee was composed of qualified representatives from related disciplines. Not only do these committee members make safety decisions, but they also provide key safety messages and communicate these to their member audiences.The risk communication function was evaluated to be unsatisfactory. It was not effectively distributed to individual health care professionals. CONCLUSIONS: The overall performance of the Thai NPVC was considerably good. The findings suggested that risk communication should be improved. Moreover, organizational performance should be routinely evaluated. If possible, benchmarking with international pharmacovigilance centers should also be performed. PMID- 26756899 TI - Frameless Stereotactic Ommaya Reservoir Placement: Efficacy and Complication Comparison with Frame-Based Technique. AB - BACKGROUND: Ommaya reservoirs are ventricular access devices used primarily for the administration of intrathecal antineoplastic chemotherapy. In patients with low or normal ventricular volume, stereotaxy can improve accuracy of catheter placement with minimal morbidity. Frameless stereotaxy has become an increasingly popular alternative to frame-based stereotaxy. Relative rates of successful catheter placement between these two techniques are not described in the literature. OBJECTIVES: To compare a large series of frameless to frame-based stereotactic catheter placements for Ommaya reservoirs, with an aim to compare accuracy and complication rate between the two procedures. METHODS: A consecutive series of 41 frame-based and 68 frameless Ommaya reservoir placement procedures performed at our institution from 1998 to 2013 was reviewed. Patient demographics, operative accuracy and complication rates for the two techniques were compared. RESULTS: Characteristics of the two groups were similar in diagnoses, age and other related factors. Comparison of frameless to frame-based stereotactic Ommaya catheter placement did not show significant differences in accuracy of placement, overall morbidity or mortality, or in any subcategory of complications. CONCLUSIONS: These findings suggest that frameless stereotactic Ommaya reservoir placement is as safe and accurate as the frame-based technique. PMID- 26756900 TI - COX-2 inhibitor NS-398 suppresses doxorubicin-induced p53 accumulation through inhibition of ROS-mediated Jnk activation. AB - Cyclooxygenase-2 (COX-2) is one of the isoforms of cyclooxygenase, a rate limiting enzyme in the arachidonic acid cascade. COX-2 protein expression is highly induced by numerous factors and it has been reportedly overexpressed in various human malignancies. Although anti-tumorigenic effects of COX-2 inhibitors have been shown, several lines of evidence suggest that COX-2 inhibitors antagonize the cytotoxicity of chemotherapeutic agents. In this study, we investigated the effect of NS-398, a COX-2 inhibitor, on modulation of doxorubicin (DOX)-induced p53 accumulation. Non-selective and selective COX-2 inhibitors attenuated DOX-induced accumulation of wild type (WT) but not mutant p53. Nutlin-3alpha or MG132 abolished the suppressive effect of a COX-2 inhibitor on DOX-induced p53 increase. Moreover, the DOX-induced increase in p53 protein levels was reduced in COX-2 knockout (KO) mouse embryonic fibroblasts (MEFs) compared to those in WT or COX-1 KO MEFs. DOX-induced accumulation of p53 was attenuated by a specific inhibitor or knockdown of Jun-N-terminal kinase (Jnk). In addition, DOX-induced Jnk activation was decreased in COX-2 KO MEFs or by COX 2 inhibition, suggesting that Jnk stabilizes p53 by a mechanism that involves COX 2. Pre-treatment with a reactive oxygen species (ROS) scavenger, N acetylcysteine, attenuated DOX-induced Jnk activation and subsequent p53 accumulation. Furthermore, the absence or inhibition of COX-2 resulted in suppression of DOX-induced increase in ROS levels. These results suggest that COX 2 activates Jnk through modulation of ROS levels, leading to accumulation of p53. Our study identifies a putative novel cross-talk between COX-2 and p53. (c) 2016 Wiley Periodicals, Inc. PMID- 26756902 TI - Factors Associated With Rates of False-Positive and False-Negative Results From Digital Mammography Screening: An Analysis of Registry Data. AB - BACKGROUND: Women screened with digital mammography may receive false-positive and false-negative results and subsequent imaging and biopsies. How these outcomes vary by age, time since the last screening, and individual risk factors is unclear. OBJECTIVE: To determine factors associated with false-positive and false-negative digital mammography results, additional imaging, and biopsies among a general population of women screened for breast cancer. DESIGN: Analysis of registry data. SETTING: Participating facilities at 5 U.S. Breast Cancer Surveillance Consortium breast imaging registries with linkages to pathology databases and tumor registries. PATIENTS: 405,191 women aged 40 to 89 years screened with digital mammography between 2003 and 2011. A total of 2963 were diagnosed with invasive cancer or ductal carcinoma in situ within 12 months of screening. MEASUREMENTS: Rates of false-positive and false-negative results and recommendations for additional imaging and biopsies from a single screening round; comparisons by age, time since the last screening, and risk factors. RESULTS: Rates of false-positive results (121.2 per 1000 women [95% CI, 105.6 to 138.7]) and recommendations for additional imaging (124.9 per 1000 women [CI, 109.3 to 142.3]) were highest among women aged 40 to 49 years and decreased with increasing age. Rates of false-negative results (1.0 to 1.5 per 1000 women) and recommendations for biopsy (15.6 to 17.5 per 1000 women) did not differ greatly by age. Results did not differ by time since the last screening. False-positive rates were higher for women with risk factors, particularly family history of breast cancer; previous benign breast biopsy result; high breast density; and, for younger women, low body mass index. LIMITATIONS: Confounding by variation in patient-level characteristics and outcomes across registries and regions may have been present. Some factors, such as numbers of first- and second-degree relatives with breast cancer and diagnoses associated with previous benign biopsy results, were not examined. CONCLUSION: False-positive mammography results and additional imaging are common, particularly for younger women and those with risk factors, whereas biopsies occur less often. Rates of false-negative results are low. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality and National Cancer Institute. PMID- 26756901 TI - A Follow-Up of the Multicenter Collaborative Study on HIV-1 Drug Resistance and Tropism Testing Using 454 Ultra Deep Pyrosequencing. AB - BACKGROUND: Ultra deep sequencing is of increasing use not only in research but also in diagnostics. For implementation of ultra deep sequencing assays in clinical laboratories for routine diagnostics, intra- and inter-laboratory testing are of the utmost importance. METHODS: A multicenter study was conducted to validate an updated assay design for 454 Life Sciences' GS FLX Titanium system targeting protease/reverse transcriptase (RTP) and env (V3) regions to identify HIV-1 drug-resistance mutations and determine co-receptor use with high sensitivity. The study included 30 HIV-1 subtype B and 6 subtype non-B samples with viral titers (VT) of 3,940-447,400 copies/mL, two dilution series (52,129 1,340 and 25,130-734 copies/mL), and triplicate samples. Amplicons spanning PR codons 10-99, RT codons 1-251 and the entire V3 region were generated using barcoded primers. Analysis was performed using the GS Amplicon Variant Analyzer and geno2pheno for tropism. For comparison, population sequencing was performed using the ViroSeq HIV-1 genotyping system. RESULTS: The median sequencing depth across the 11 sites was 1,829 reads per position for RTP (IQR 592-3,488) and 2,410 for V3 (IQR 786-3,695). 10 preselected drug resistant variants were measured across sites and showed high inter-laboratory correlation across all sites with data (P<0.001). The triplicate samples of a plasmid mixture confirmed the high inter-laboratory consistency (mean% +/- stdev: 4.6 +/-0.5, 4.8 +/-0.4, 4.9 +/-0.3) and revealed good intra-laboratory consistency (mean% range +/- stdev range: 4.2-5.2 +/- 0.04-0.65). In the two dilutions series, no variants >20% were missed, variants 2-10% were detected at most sites (even at low VT), and variants 1-2% were detected by some sites. All mutations detected by population sequencing were also detected by UDS. CONCLUSIONS: This assay design results in an accurate and reproducible approach to analyze HIV-1 mutant spectra, even at variant frequencies well below those routinely detectable by population sequencing. PMID- 26756903 TI - Hippocampal harms, protection and recovery following regular cannabis use. AB - Shifting policies towards legalisation of cannabis for therapeutic and recreational use raise significant ethical issues for health-care providers seeking evidence-based recommendations. We investigated whether heavy cannabis use is associated with persistent harms to the hippocampus, if exposure to cannabidiol offers protection, and whether recovery occurs with abstinence. To do this, we assessed 111 participants: 74 long-term regular cannabis users (with an average of 15.4 years of use) and 37 non-user healthy controls. Cannabis users included subgroups of participants who were either exposed to Delta9 tetrahydrocannabinol (THC) but not to cannabidiol (CBD) or exposed to both, and former users with sustained abstinence. Participants underwent magnetic resonance imaging from which three measures of hippocampal integrity were assessed: (i) volume; (ii) fractional anisotropy; and (iii) N-acetylaspartate (NAA). Three curve-fitting models across the entire sample were tested for each measure to examine whether cannabis-related hippocampal harms are persistent, can be minimised (protected) by exposure to CBD or recovered through long-term abstinence. These analyses supported a protection and recovery model for hippocampal volume (P=0.003) and NAA (P=0.001). Further pairwise analyses showed that cannabis users had smaller hippocampal volumes relative to controls. Users not exposed to CBD had 11% reduced volumes and 15% lower NAA concentrations. Users exposed to CBD and former users did not differ from controls on any measure. Ongoing cannabis use is associated with harms to brain health, underpinned by chronic exposure to THC. However, such harms are minimised by CBD, and can be recovered with extended periods of abstinence. PMID- 26756905 TI - Disrupted in schizophrenia 1 (DISC1) L100P mutants have impaired activity dependent plasticity in vivo and in vitro. AB - Major neuropsychiatric disorders are genetically complex but share overlapping etiology. Mice mutant for rare, highly penetrant risk variants can be useful in dissecting the molecular mechanisms involved. The gene disrupted in schizophrenia 1 (DISC1) has been associated with increased risk for neuropsychiatric conditions. Mice mutant for Disc1 display morphological, functional and behavioral deficits that are consistent with impairments observed across these disorders. Here we report that Disc1 L100P mutants are less able to reorganize cortical circuitry in response to stimulation in vivo. Molecular analysis reveals that the mutants have a reduced expression of PSD95 and pCREB in visual cortex and fail to adjust expression of such markers in response to altered stimulation. In vitro analysis shows that mutants have impaired functional reorganization of cortical neurons in response to selected forms of neuronal stimulation, but there is no altered basal expression of synaptic markers. These findings suggest that DISC1 has a critical role in the reorganization of cortical plasticity and that this phenotype becomes evident only under challenge, even at early postnatal stages. This result may represent an important etiological mechanism in the emergence of neuropsychiatric disorders. PMID- 26756906 TI - Fate of Ag-NPs in Sewage Sludge after Application on Agricultural Soils. AB - The objective of this work was to investigate the fate of silver nanoparticles (Ag-NPs) in a sludge-amended soil cultivated with monocot (Wheat) and dicot (Rape) crop species. A pot experiment was performed with sludges produced in a pilot wastewater treatment plant containing realistic Ag concentrations (18 and 400 mg kg(-1), 14 mg kg(-1) for the control). Investigations focused on the highest dose treatment. X-ray absorption spectroscopy (XAS) showed that Ag2S was the main species in the sludge and amended soil before and after plant culture. The second most abundant species was an organic and/or amorphous Ag-S phase whose proportion slightly varied (from 24% to 36%) depending on the conditions. Micro and nano X-ray fluorescence (XRF) showed that Ag was preferentially associated with S-rich particles, including organic fragments, of the sludge and amended soils. Ag was distributed as heteroaggregates with soil components (size ranging from <=0.5 to 1-3 MUm) and as diffused zones likely corresponding to sorbed/complexed Ag species. Nano-XRF evidenced the presence of mixed metallic sulfides. Ag was weakly exchangeable and labile. However, micronutrient mobilization by plant roots and organic matter turnover may induce Ag species interconversion eventually leading to Ag release on longer time scales. Together, these data provide valuable information for risk assessment of sewage sludge application on agricultural soils. PMID- 26756904 TI - Behavioral and molecular neuroepigenetic alterations in prenatally stressed mice: relevance for the study of chromatin remodeling properties of antipsychotic drugs. AB - We have recently reported that mice born from dams stressed during pregnancy (PRS mice), in adulthood, have behavioral deficits reminiscent of behaviors observed in schizophrenia (SZ) and bipolar (BP) disorder patients. Furthermore, we have shown that the frontal cortex (FC) and hippocampus of adult PRS mice, like that of postmortem chronic SZ patients, are characterized by increases in DNA methyltransferase 1 (DNMT1), ten-eleven methylcytosine dioxygenase 1 (TET1) and exhibit an enrichment of 5-methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC) at neocortical GABAergic and glutamatergic gene promoters. Here, we show that the behavioral deficits and the increased 5MC and 5HMC at glutamic acid decarboxylase 67 (Gad1), reelin (Reln) and brain-derived neurotrophic factor (Bdnf) promoters and the reduced expression of the messenger RNAs (mRNAs) and proteins corresponding to these genes in FC of adult PRS mice is reversed by treatment with clozapine (5 mg kg(-1) twice a day for 5 days) but not by haloperidol (1 mg kg(-1) twice a day for 5 days). Interestingly, clozapine had no effect on either the behavior, promoter methylation or the expression of these mRNAs and proteins when administered to offspring of nonstressed pregnant mice. Clozapine, but not haloperidol, reduced the elevated levels of DNMT1 and TET1, as well as the elevated levels of DNMT1 binding to Gad1, Reln and Bdnf promoters in PRS mice suggesting that clozapine, unlike haloperidol, may limit DNA methylation by interfering with DNA methylation dynamics. We conclude that the PRS mouse model may be useful preclinically in screening for the potential efficacy of antipsychotic drugs acting on altered epigenetic mechanisms. Furthermore, PRS mice may be invaluable for understanding the etiopathogenesis of SZ and BP disorder and for predicting treatment responses at early stages of the illness allowing for early detection and remedial intervention. PMID- 26756907 TI - Research Progresses in Understanding the Pathophysiology of Moyamoya Disease. AB - BACKGROUND: The pathogenesis of moyamoya disease (MMD) is still unknown. The detection of inflammatory molecules such as cytokines, chemokines and growth factors in MMD patients' biological fluids supports the hypothesis that an abnormal angiogenesis is implicated in MMD pathogenesis. However, it is unclear whether these anomalies are the consequences of the disease or rather causal factors as well as these mechanisms remain insufficient to explain the pathophysiology of MMD. The presence of a family history in about 9-15% of Asian patients, the highly variable incidence rate between different ethnic and sex groups and the age of onset support the role of genetic factors in MMD pathogenesis. However, although some genetic loci have been associated with MMD, few of them have been replicated in independent series. Recently, RNF213 gene was shown to be strongly associated with MMD occurrence with a founder effect in East Asian patients. However, the mechanisms leading from RNF213 mutations to MMD clinical features are still unknown. SUMMARY: The research on pathogenic mechanism of MMD is in its infancy. MMD is probably a complex and heterogeneous disorder, including different phenotypes and genotypes, in which more than a single factor is implicated. KEY MESSAGE: Since the diagnosis of MMD is rapidly increasing worldwide, the development of more efficient stratifying risk systems, including both clinical but also biological drivers became imperative to improve our ability of predict prognosis and to develop mechanism-tailored interventions. PMID- 26756908 TI - Polyhalogenated Indoles from the Red Alga Rhodophyllis membranacea: The First Isolation of Bromo-Chloro-Iodo Secondary Metabolites. AB - An unusual tetrahalogenated indole with the exceptionally rare inclusion of the three halogens bromine, chlorine, and iodine was found using mass spectrometry within a fraction of a semipurified extract obtained from the red alga Rhodophyllis membranacea. We report herein the isolation and structure elucidation, using a combination of NMR spectroscopy and mass spectrometry, of 11 new tetrahalogenated indoles (1-11), including four bromochloroiodoindoles (5-7, 10). Several were evaluated for cytotoxic and antifungal activities against the HL-60 promyelocytic cell line and Saccharomyces cerevisiae, respectively. PMID- 26756910 TI - Summaries for Patients. Screening for Breast Cancer: Recommendations From the U.S. Preventive Services Task Force. PMID- 26756909 TI - Direct sequencing and analysis of the genomes of newly emerging GII.17 norovirus strains in South China. AB - AIMS: This study aims to develop a quick and sensitive method for obtaining GII.17 norovirus genome sequences based on a novel amplification strategy. METHODS AND RESULTS: Based on multiple alignments of GII.17 norovirus genome sequences available in GenBank, a set of primer pairs were first rationally designed, which could amplify six overlapping fragments encompassing the whole genome. Two sequencing primers II.17-Seq1R and II.17-Seq6F were also designed to complement sequences at both ends. The sensitivity of new primers was then evaluated by end-point dilution RT-PCR that was comparable to detection primers G2SKF/G2SKR. In practice, genome sequences of nine Guangzhou GII.17 strains were successfully obtained by the new method in one working day. All genomes comprised 7495 nucleotides with three complete ORFs, and their phylogenetic relationships were verified with other GII norovirus reference strains. CONCLUSIONS: Based on the new amplification strategy, a quick and sensitive method for direct sequencing of GII.17 norovirus genomes was successfully established. SIGNIFICANCE AND IMPACT OF THE STUDY: The newly developed method can be used as an important tool to collect genetic information of GII.17 noroviruses, and new obtained viral genomes in Guangzhou also provide reference data for norovirus research in future. PMID- 26756911 TI - Ultrasound-Guided Thoracic Paravertebral Blockade: A Retrospective Study of the Incidence of Complications. AB - BACKGROUND: The benefits of thoracic paravertebral block (TPVB) have been demonstrated for patients undergoing surgery for breast cancer. However, pleural puncture resulting in pneumothorax is a serious complication associated with traditional approaches using guidance from anatomic landmarks and nerve stimulation and may contribute to the low utilization of this block. An ultrasound-guided technique has the potential to reduce complications by providing direct visualization of the paravertebral space during needle manipulation. We evaluated the complications using a single-injection, transverse, in-plane ultrasound-guided technique for paravertebral blockade in patients undergoing mastectomy with immediate reconstruction for breast cancer treatment or prophylaxis. METHODS: Data from all patients who underwent TPVB between January 1, 2010, and December 3, 2013, at Massachusetts General Hospital was prospectively recorded in a computerized database. All blocks were placed for postoperative analgesia after unilateral or bilateral mastectomy with immediate breast reconstruction. Medical records were retrospectively reviewed for any patient who developed complications including accidental pleural puncture, symptomatic pneumothorax, hypotension, or bradycardia, as well as signs and symptoms of toxicity or effects of local anesthetic outside of the paravertebral space. RESULTS: Eight hundred fifty-six patients underwent a total of 1427 thoracic paravertebral injections (285 unilateral and 571 bilateral TPVB). There were 6 complications (0.70%; 99.2% confidence interval, 0.17%-1.86%) including symptomatic bradycardia and hypotension (n = 3), vasovagal episode (n = 1), and evidence of possible local anesthetic toxicity (n = 2). There was no incidence of suspected accidental pleural puncture or symptomatic pneumothorax identified in our study population. CONCLUSIONS: The routine use of a single-injection, transverse, in-plane ultrasound-guided technique for TPVB in patients undergoing mastectomy with immediate breast reconstruction is associated with very few complications. PMID- 26756912 TI - Clinical Concentrations of Local Anesthetics Bupivacaine and Lidocaine Differentially Inhibit Human Kir2.x Inward Rectifier K+ Channels. AB - BACKGROUND: Inward rectifier K channels of the Kir2.x subfamily are widely expressed in neuronal tissues, controlling neuronal excitability. Previous studies reported that local anesthetics (LAs) do not affect Kir2 channels. However, the effects have not been studied at large concentrations used in regional anesthesia. METHODS: This study used the patch-clamp technique to examine the effects of bupivacaine and lidocaine on Kir2.1, Kir2.2, and Kir2.3 channels expressed in human embryonic kidney 293 cells. RESULTS: When applied extracellularly in whole-cell recordings, both LAs inhibited Kir2.x currents in a voltage-independent manner. Inhibition with bupivacaine was slow and irreversible, whereas that with lidocaine was fast and reversible. Kir2.3 displayed a greater sensitivity to bupivacaine than Kir2.1 and Kir2.2 (50% inhibitory concentrations at approximately 5 minutes, 0.6 vs 8-10 mM), whereas their sensitivities to lidocaine were similar (50% inhibitory concentrations, 1.5 2.7 mM). Increases in the charged/neutral ratio of the LAs at an acidic extracellular pH attenuated their inhibitory effects, and a permanently charged lidocaine derivative QX-314 exhibited no effects when applied extracellularly. Inside-out experiments demonstrated that inhibition of Kir2.1 with cytoplasmic lidocaine and QX-314 was rapid and reversible, whereas that induced by bupivacaine was slow and irreversible. Furthermore, dose-inhibition relations for the charged form of bupivacaine and lidocaine obtained at different cytoplasmic pHs could be approximated by a single relation for each LA. CONCLUSIONS: The results indicate that both LAs at clinical concentrations equilibrated rapidly with the intracellular milieu, differentially inhibiting Kir2.x channel function from the cytoplasmic side. PMID- 26756914 TI - Mn5Si3 Nanoparticles: Synthesis and Size-Induced Ferromagnetism. AB - Mn-based silicides are fascinating due to their exotic spin textures and unique crystal structures, but the low magnetic ordering temperatures and/or small magnetic moments of bulk alloys are major impediments to their use in practical applications. In sharp contrast to bulk Mn5Si3, which is paramagnetic at room temperature and exhibits low-temperature antiferromagnetic ordering, we show ferromagnetic ordering in Mn5Si3 nanoparticles with a high Curie temperature (Tc ~ 590 K). The Mn5Si3 nanoparticles have an average size of 8.6 nm and also exhibit large saturation magnetic polarizations (Js = 10.1 kG at 300 K and 12.4 kG at 3 K) and appreciable magnetocrystalline anisotropy constants (K1 = 6.2 Mergs/cm(3) at 300 K and at 12.8 Mergs/cm(3) at 3 K). The drastic change of the magnetic ordering and properties in the nanoparticles are attributed to low dimensional and quantum-confinement effects, evident from first-principle density functional-theory calculations. PMID- 26756915 TI - Exploration of the importance of geriatric frailty on health-related quality of life. AB - AIM: The ageing of the population is a demographic trend globally. Promoting the health of elderly persons has become a crucial priority. However, knowledge about the relationship between frailty and quality of life (QoL) remains limited. This research aimed to investigate the association between elderly frailty and QoL, and to identify whether frailty or current health status more significantly affects the QoL of elderly persons. METHODS: This research began in 2012, and by the end of the study in April 2013, 375 samples had been collected. Structured questionnaires and the face-to-face questionnaire interviews were used. Multiple linear regression, t-test, and one-way anova were administered. RESULTS: Elderly individuals who were hospitalized performed worse in the physical health QoL domain, whereas those who regularly attended outpatient follow-ups performed worse in the mental health QoL domain. QoL was only partially affected in both groups. All QoL domains were affected in elderly individuals with symptoms of frailty. Age, marital status, and financial status significantly affect health related QoL. CONCLUSION: Geriatric frailty significantly affects general QoL. Early screening of frailty-related conditions among the elderly can prompt early and proper intervention for this population. PMID- 26756913 TI - Lidocaine Inhibits HCN Currents in Rat Spinal Substantia Gelatinosa Neurons. AB - BACKGROUND: Lidocaine, which blocks voltage-gated sodium channels, is widely used in surgical anesthesia and pain management. Recently, it has been proposed that the hyperpolarization-activated cyclic nucleotide (HCN) channel is one of the other novel targets of lidocaine. Substantia gelatinosa in the spinal dorsal horn, which plays key roles in modulating nociceptive information from primary afferents, comprises heterogeneous interneurons that can be electrophysiologically categorized by firing pattern. Our previous study demonstrated that a substantial proportion of substantia gelatinosa neurons reveal the presence of HCN current (Ih); however, the roles of lidocaine and HCN channel expression in different types of substantia gelatinosa neurons remain unclear. METHODS: By using the whole-cell patch-clamp technique, we investigated the effect of lidocaine on Ih in rat substantia gelatinosa neurons of acute dissociated spinal cord slices. RESULTS: We found that lidocaine rapidly decreased the peak Ih amplitude with an IC50 of 80 MUM. The inhibition rate on Ih was not significantly different with a second application of lidocaine in the same neuron. Tetrodotoxin, a sodium channel blocker, did not affect lidocaine's effect on Ih. In addition, lidocaine shifted the half-activation potential of Ih from -109.7 to -114.9 mV and slowed activation. Moreover, the reversal potential of Ih was shifted by -7.5 mV by lidocaine. In the current clamp, lidocaine decreased the resting membrane potential, increased membrane resistance, delayed rebound depolarization latency, and reduced the rebound spike frequency. We further found that approximately 58% of substantia gelatinosa neurons examined expressed Ih, in which most of them were tonically firing. CONCLUSIONS: Our studies demonstrate that lidocaine strongly inhibits Ih in a reversible and concentration-dependent manner in substantia gelatinosa neurons, independent of tetrodotoxin-sensitive sodium channels. Thus, our study provides new insight into the mechanism underlying the central analgesic effect of the systemic administration of lidocaine. PMID- 26756916 TI - Silk fibroin film from golden-yellow Bombyx mori is a biocomposite that contains lutein and promotes axonal growth of primary neurons. AB - The use of doped silk fibroin (SF) films and substrates from Bombyx mori cocoons for green nanotechnology and biomedical applications has been recently highlighted. Cocoons from coloured strains of B. mori, such as Golden-Yellow, contain high levels of pigments that could have a huge potential for the fabrication of SF based biomaterials targeted to photonics, optoelectronics and neuroregenerative medicine. However, the features of extracted and regenerated SF from cocoons of B. mori Golden-Yellow strain have never been reported. Here we provide a chemophysical characterization of regenerated silk fibroin (RSF) fibers, solution, and films obtained from cocoons of a Golden-Yellow strain of B. mori, by SEM, (1) H-NMR, HPLC, FT-IR, Raman and UV-Vis spectroscopy. We found that the extracted solution and films from B. mori Golden-Yellow fibroin displayed typical Raman spectroscopic and optical features of carotenoids. HPLC analyses revealed that lutein was the carotenoid contained in the fiber and RSF biopolymer from yellow cocoons. Notably, primary neurons cultured on yellow SF displayed a threefold higher neurite length than those grown of white SF films. The results we report pave the way to expand the potential use of yellow SF in the field of neuroregenerative medicine and provide green chemistry approaches in biomedicine. PMID- 26756917 TI - New insight into the architecture of oxy-anion pocket in unliganded conformation of GAT domains: A MD-simulation study. AB - Human Guanine Monophosphate Synthetase (hGMPS) converts XMP to GMP, and acts as a bifunctional enzyme with N-terminal "glutaminase" (GAT) and C-terminal "synthetase" domain. The enzyme is identified as a potential target for anti cancer and immunosuppressive therapies. GAT domain of enzyme plays central role in metabolism, and contains conserved catalytic residues Cys104, His190, and Glu192. MD simulation studies on GAT domain suggest that position of oxyanion in unliganded conformation is occupied by one conserved water molecule (W1), which also stabilizes that pocket. This position is occupied by a negatively charged atom of the substrate or ligand in ligand bound crystal structures. In fact, MD simulation study of Ser75 to Val indicates that W1 conserved water molecule is stabilized by Ser75, while Thr152, and His190 also act as anchor residues to maintain appropriate architecture of oxyanion pocket through water mediated H bond interactions. Possibly, four conserved water molecules stabilize oxyanion hole in unliganded state, but they vacate these positions when the enzyme (hGMPS) substrate complex is formed. Thus this study not only reveals functionally important role of conserved water molecules in GAT domain, but also highlights essential role of other non-catalytic residues such as Ser75 and Thr152 in this enzymatic domain. The results from this computational study could be of interest to experimental community and provide a testable hypothesis for experimental validation. Conserved sites of water molecules near and at oxyanion hole highlight structural importance of water molecules and suggest a rethink of the conventional definition of chemical geometry of inhibitor binding site. PMID- 26756919 TI - Iron-Based Metal-Organic Frameworks as Catalysts for Visible Light-Driven Water Oxidation. AB - The development of earth-abundant, active, and stable catalysts is important for solar energy conversion. Metal-organic frameworks (MOFs) have been viewed as a promising class of porous materials, which may have innovative application in photocatalysis. In this paper, three types of Fe-based MOFs and their aminofunctionalized derivatives have been fabricated and systematically studied as water oxidation catalysts (WOCs) for oxygen evolution under visible light irradiation. MIL-101(Fe) possesses a higher current density and earlier onset potential and exhibits excellent visible light-driven oxygen evolution activity than the other Fe-based catalysts. It speeds up the oxygen evolution reaction rate with the higher initial turnover frequencies value of 0.10 s(-1). Our study demonstrates that Fe-based MOFs as efficient WOCs are promising candidates for photocatalytic water oxidation process. PMID- 26756921 TI - Cellular automata model for human articular chondrocytes migration, proliferation and cell death: An in vitro validation. AB - Articular cartilage is characterized by low cell density of only one cell type, chondrocytes, and has limited self-healing properties. When articular cartilage is affected by traumatic injuries, a therapeutic strategy such as autologous chondrocyte implantation is usually proposed for its treatment. This approach requires in vitro chondrocyte expansion to yield high cell number for cell transplantation. To improve the efficiency of this procedure, it is necessary to assess cell dynamics such as migration, proliferation and cell death during culture. Computational models such as cellular automata can be used to simulate cell dynamics in order to enhance the result of cell culture procedures. This methodology has been implemented for several cell types; however, an experimental validation is required for each one. For this reason, in this research a cellular automata model, based on random-walk theory, was devised in order to predict articular chondrocyte behavior in monolayer culture during cell expansion. Results demonstrated that the cellular automata model corresponded to cell dynamics and computed-accurate quantitative results. Moreover, it was possible to observe that cell dynamics depend on weighted probabilities derived from experimental data and cell behavior varies according to the cell culture period. Thus, depending on whether cells were just seeded or proliferated exponentially, culture time probabilities differed in percentages in the CA model. Furthermore, in the experimental assessment a decreased chondrocyte proliferation was observed along with increased passage number. This approach is expected to having other uses as in enhancing articular cartilage therapies based on tissue engineering and regenerative medicine. PMID- 26756918 TI - Genome-Wide Analysis of DNA Methylation and Cigarette Smoking in a Chinese Population. AB - BACKGROUND: Smoking is a risk factor for many human diseases. DNA methylation has been related to smoking, but genome-wide methylation data for smoking in Chinese populations is limited. OBJECTIVES: We aimed to investigate epigenome-wide methylation in relation to smoking in a Chinese population. METHODS: We measured the methylation levels at > 485,000 CpG sites (CpGs) in DNA from leukocytes using a methylation array and conducted a genome-wide meta-analysis of DNA methylation and smoking in a total of 596 Chinese participants. We further evaluated the associations of smoking-related CpGs with internal polycyclic aromatic hydrocarbon (PAH) biomarkers and their correlations with the expression of corresponding genes. RESULTS: We identified 318 CpGs whose methylation levels were associated with smoking at a genome-wide significance level (false discovery rate < 0.05), among which 161 CpGs annotated to 123 genes were not associated with smoking in recent studies of Europeans and African Americans. Of these smoking-related CpGs, methylation levels at 80 CpGs showed significant correlations with the expression of corresponding genes (including RUNX3, IL6R, PTAFR, ANKRD11, CEP135 and CDH23), and methylation at 15 CpGs was significantly associated with urinary 2-hydroxynaphthalene, the most representative internal monohydroxy-PAH biomarker for smoking. CONCLUSION: We identified DNA methylation markers associated with smoking in a Chinese population, including some markers that were also correlated with gene expression. Exposure to naphthalene, a byproduct of tobacco smoke, may contribute to smoking-related methylation. CITATION: Zhu X, Li J, Deng S, Yu K, Liu X, Deng Q, Sun H, Zhang X, He M, Guo H, Chen W, Yuan J, Zhang B, Kuang D, He X, Bai Y, Han X, Liu B, Li X, Yang L, Jiang H, Zhang Y, Hu J, Cheng L, Luo X, Mei W, Zhou Z, Sun S, Zhang L, Liu C, Guo Y, Zhang Z, Hu FB, Liang L, Wu T. 2016. Genome-wide analysis of DNA methylation and cigarette smoking in Chinese. Environ Health Perspect 124:966-973; http://dx.doi.org/10.1289/ehp.1509834. PMID- 26756922 TI - Identification of recombination in the NS1 and VPs genes of parvovirus B19. AB - Human parvovirus B19 (B19V), a member of the genus Erythrovirus of the family Parvoviridae, is a pathogenic virus distributed worldwide in the human population. In this study, we performed phylogenetic and recombination analysis of B19V based on the available nonstructural gene (NS1) and capsid proteins (VPs) genes in GenBank. Results indicated that recombination occurred between genotypes 3 and 1, leading to the recombinant cluster genotype 2. Other three inter genotype recombination events were also discovered. Moreover, our results showed that among the four recombinant events in the present study, all of the major parents belonged to genotype 1, the minor parents were from genotypes 3 or 2, and all of the recombinants belonged to genotype 2. These recombinant events were confirmed by SimPlot Program and phylogenetic analysis. J. Med. Virol. 88:1457 1461, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26756920 TI - Acyclic Cucurbit[n]uril-Type Molecular Container Enables Systemic Delivery of Effective Doses of Albendazole for Treatment of SK-OV-3 Xenograft Tumors. AB - Approximately, 40-70% of active pharmaceutical ingredients (API) are severely limited by their extremely poor aqueous solubility, and consequently, there is a high demand for excipients that can be used to formulate clinically relevant doses of these drug candidates. Here, proof-of-concept studies demonstrate the potential of our recently discovered acyclic cucurbit[n]uril-type molecular container Motor1 (M1) as a solubilizing agent for insoluble drugs. M1 did not induce significant rates of mutations in various Salmonella typhimurium test strains during the Ames test, suggesting low genotoxicity. M1 also has low risk of causing cardiac toxicity in humans since it did not inhibit the human Ether-a go-go-Related Gene channel as tested on transfected CHO cell lines via patch clamp analysis. Albendazole (ABZ) is a widely used antihelminthic agent but that has also shown promising efficacy against cancerous cells in vitro. However, due to its low aqueous solubility (2.7 MUM) and poor pharmacokinetics, ABZ is clinically limited as an anticancer agent. Here we investigated the potential of M1 as a solubilizing excipient for ABZ formulation. A pharmacokinetic study indicated that ABZ escapes the peritoneal cavity resulting in 78% absolute bioavailability, while its active intermediate metabolite, albendazole sulfoxide, achieved 43% absolute bioavailability. The daily dosing of 681 mg/kg M1 complexed with 3.2 mg/kg of ABZ for 14 days did not result in significant weight loss or pathology in Swiss Webster mice. In vivo efficacy studies using this M1.ABZ inclusion complex showed significant decreases in tumor growth rates and increases in survival of mice bearing SK-OV-3 xenograft tumors. In conclusion, we provide substantial new evidence demonstrating that M1 is a safe and efficient excipient that enables in vivo parenteral delivery of poorly water-soluble APIs. PMID- 26756923 TI - Measurement of craniovertebral angle by the Modified Head Posture Spinal Curvature Instrument: A reliability and validity study. AB - The Modified Head Posture Spinal Curvature Instrument (MHPSCI) is an extension of the Head Posture Spinal Curvature Instrument. Two specific modifications were made in the original design by adding a third arm projecting horizontally from the protractor to objectively fix the pivot exactly over the C7 vertebra and the addition of a spirit-level to properly align the instrument. In order to demonstrate reliability and validity, this study was conducted using patients with postural neck pain (N = 65) and healthy subjects (N = 20). All the subjects were working at a selected Information Technology Industry in India and had been recruited using a criterion-based sampling approach. The craniovertebral (CV) angle of each subject was evaluated by two raters consecutively. The measurements were taken by using both MHPSCI and the standard photographic method in a standardized sitting posture for the purpose of establishing criterion-validity of the instrument. The results of this study indicate a good inter-rater reliability (ICC = 0.76; CI = 0.65-0.84) as well as intra-rater reliability (ICC = 0.87; CI = 0.82-0.91) between three successive CV angle measurements (with 2 minutes interval between each measurement) through MHPSCI. While keeping the digital photographic measurement as a standard, this study established that the MHPSCI is a valid tool for measuring the CV angle as shown by non-significant difference (p > 0.01) and high correlation between the two methods (r = 0.79 0.84). This study demonstrates that the MHPSCI is a reliable and valid instrument for measuring CV angle in subjects with or without postural neck pain. PMID- 26756924 TI - Impact of therapy on the development of second malignancies in essential thrombocythemia and polycythemia vera: Are we comfortable about this? PMID- 26756925 TI - Anxiety, depression and fatigue at 5-year review following CNS demyelination. AB - BACKGROUND: Anxiety and depression are common in multiple sclerosis (MS). We evaluated the prevalence and factors associated with anxiety, depression and fatigue at the 5-year review of a longitudinal cohort study following a first clinical diagnosis of CNS demyelination (FCD). METHODS: Cases with a FCD were recruited soon after diagnosis and followed annually thereafter. A variety of environmental, behavioural and clinical covariates were measured at five-year review. Anxiety and depression were measured using the Hospital Anxiety & Depression Scale (HADS), and fatigue by the Fatigue Severity Scale (FSS). RESULTS: Of the 236 cases, 40.2% had clinical anxiety (median HADS-A: 6.0), 16.0% had clinical depression (median HADS-D: 3.0), and 41.3% had clinical fatigue (median FSS: 4.56). The co-occurrence of all three symptoms was 3.76 times greater than expectation. Younger age, higher disability, concussion or other disease diagnosis were independently associated with a higher anxiety score; male sex, higher disability, being unemployed, less physical activity, and antidepressant and/or anxiolytic-sedative medication use were independently associated with a higher depression score. Higher disability, immunomodulatory medication use, other disease diagnosis and anxiolytic-sedative medication use were independently associated with having fatigue, while female sex, higher BMI, having had a concussion, being unemployed and higher disability were associated with a higher fatigue score. CONCLUSION: These results support previous findings of the commonality of anxiety, depression and fatigue in established MS and extend this to post-FCD and early MS cases. The clustering of the three symptoms indicates that they may share common antecedents. PMID- 26756927 TI - Understanding the Impact of Poly(ethylene oxide) on the Assembly of Lignin in Solution toward Improved Carbon Fiber Production. AB - Carbon fiber produced from lignin has recently become an industrial scalable product with applications ranging from thermal insulation to reinforcing automobile bodies. Previous research has shown that mixing 1-2 wt %, of poly(ethylene oxide) (PEO) with the lignin before fiber formation can enhance the properties of the final carbon fibers. The research reported here determines the impact of adding PEO to a lignin solution on its assembly, focusing on the role of the lignin structure on this assembly process. Results indicate the addition of PEO anisotropically directs the self-assembly of the hardwood and softwood lignin by lengthening the cylindrical building blocks that make up the larger global aggregates. On the other hand, results from an annual lignin exhibit a shapeless, more complex structure with a unique dependence on the PEO loading. These results are consistent with improved carbon fibers from solutions of lignin that include PEO, as the local ordering and directed assembly will inhibit the formation of defects during the carbon fiber fabrication process. PMID- 26756926 TI - Effect of trabeculectomy on the accuracy of intraocular lens calculations in patients with open-angle glaucoma. AB - BACKGROUND: The objective of the study is to examine the effect of trabeculectomy on intraocular lens power calculations in patients with open-angle glaucoma (OAG) undergoing cataract surgery. DESIGN: The design is retrospective data analysis. PARTICIPANTS: There are a total of 55 eyes of 55 patients with OAG who had a cataract surgery alone or in combination with trabeculectomy. METHODS: We classified OAG subjects into the following groups based on surgical history: only cataract surgery (OC group), cataract surgery after prior trabeculectomy (CAT group), and cataract surgery performed in combination with trabeculectomy (CCT group). MAIN OUTCOME MEASURES: Differences between actual and predicted postoperative refractive error. RESULTS: Mean error (ME, difference between postoperative and predicted SE) in the CCT group was significantly lower (towards myopia) than that of the OC group (P = 0.008). Additionally, mean absolute error (MAE, absolute value of ME) in the CAT group was significantly greater than in the OC group (P = 0.006). Using linear mixed models, the ME calculated with the SRK II formula was more accurate than the ME predicted by the SRK T formula in the CAT (P = 0.032) and CCT (P = 0.035) groups. CONCLUSIONS: The intraocular lens power prediction accuracy was lower in the CAT and CCT groups than in the OC group. The prediction error was greater in the CAT group than in the OC group, and the direction of the prediction error tended to be towards myopia in the CCT group. The SRK II formula may be more accurate in predicting residual refractive error in the CAT and CCT groups. PMID- 26756928 TI - Comparison of survival outcomes between Expanded Criteria Donor and Standard Criteria Donor kidney transplant recipients: a systematic review and meta analysis. AB - In 2002, the United Network for Organ Sharing proposed increasing the pool of donor kidneys to include Expanded Criteria Donor (ECD). Outside the USA, the ECD definition remains the one used without questioning whether such a graft allocation criterion is valid worldwide. We performed a meta-analysis to quantify the differences between ECD and Standard Criteria Donor (SCD) transplants. We paid particular attention to select studies in which the methodology was appropriate and we took into consideration the geographical area. Thirty-two publications were included. Only five studies, all from the USA, reported confounder-adjusted hazard ratios comparing the survival outcomes between ECD and SCD kidney transplant recipients. These five studies confirmed that ECD recipients seemed to have poorer prognosis. From 29 studies reporting appropriate survival curves, we estimated the 5-year pooled nonadjusted survivals for ECD and SCD recipients. The relative differences between the two groups were lower in Europe than in North America, particularly for death-censored graft failure. It is of primary importance to propose appropriate studies for external validation of the ECD criteria in non-US kidney transplant recipients. PMID- 26756929 TI - Guardians' Knowledge and Husbandry Practices of Feline Environmental Enrichment. AB - Feline environmental enrichment can prevent numerous disorders including anxiety, stress, obesity, and feline idiopathic cystitis. Despite its easy implementation and low cost, it has received little attention. The main goal of this study was to assess guardians' knowledge concerning feline environmental enrichment and husbandry practices. A questionnaire was given to 130 companion animal guardians at the Lisbon Veterinary Faculty's Teaching Hospital. The applications of 22 environmental enrichment measures related to food/water, litter box, and space/entertainment areas were evaluated. The majority of the households studied (74.6%) had a moderately enriched environment. Hygiene-related measures were those most adopted by guardians, while those requiring guardians' commitment or previous awareness were the least implemented. A rating scale was proposed and applied to assess feline domestic environmental quality. PMID- 26756930 TI - Changes in the mean hearing threshold levels in military aircraft maintenance conscripts. AB - Aircraft maintenance crews are constantly exposed to severe aircraft noise. The purpose of this study was to verify whether noise from aircraft adversely affects the hearing threshold levels (HTLs) of aircraft maintenance conscripts during their 2 years of mandatory military service. This study included 3,000 male aircraft maintenance conscripts who work in the military runway area. We measured and analyzed HTLs at 2-4 kHz. The duration of exposure to noise increased with an increase in rank; however, HTLs showed a tendency to decrease. We attributed such contradicting results to the learning effect and adaptation to military service. However, we suspected that sudden deafness in 6 conscripts (0.2%) was due to loud noise in the runway area during military service. The effectiveness of the hearing conservation program for short-term military service personnel could be increased by focusing on preventing sudden deafness and preenlistment baseline audiogram tests. PMID- 26756931 TI - Myelin Basic Protein-Induced Production of Tumor Necrosis Factor-alpha and Interleukin-6, and Presentation of the Immunodominant Peptide MBP85-99 by B Cells from Patients with Relapsing-Remitting Multiple Sclerosis. AB - B cells are involved in driving relapsing-remitting multiple sclerosis (RRMS), as demonstrated by the positive effect of therapeutic B-cell depletion. Aside from producing antibodies, B cells are efficient antigen-presenting and cytokine secreting cells. Diverse polyclonal stimuli have been used to study cytokine production by B cells, but here we used the physiologically relevant self-antigen myelin basic protein (MBP) to stimulate B cells from untreated patients with RRMS and healthy donors. Moreover, we took advantage of the unique ability of the monoclonal antibody MK16 to recognize the immunodominant peptide MBP85-99 presented on HLA-DR15, and used it as a probe to directly study B-cell presentation of self-antigenic peptide. The proportions of B cells producing TNF alpha or IL-6 after stimulation with MBP were higher in RRMS patients than in healthy donors, indicating a pro-inflammatory profile for self-reactive patient B cells. In contrast, polyclonal stimulation with PMA + ionomycin and MBP revealed no difference in cytokine profile between B cells from RRMS patients and healthy donors. Expanded disability status scale (EDSS) as well as multiple sclerosis severity score (MSSS) correlated with reduced ability of B cells to produce IL-10 after stimulation with MBP, indicative of diminished B-cell immune regulatory function in patients with the most severe disease. Moreover, EDSS correlated positively with the frequencies of TNF-alpha, IL-6 and IL-10 producing B cells after polyclonal stimulation. Patient-derived, IL-10-producing B cells presented MBP85-99 poorly, as did IL-6-producing B cells, particulary in the healthy donor group. B cells from MS patients thus present antigen to T cells in a pro inflammatory context. These findings contribute to understanding the therapeutic effects of B-cell depletion in human autoimmune diseases, including MS. PMID- 26756932 TI - Effect of Cigarette Smoking and Passive Smoking on Hearing Impairment: Data from a Population-Based Study. AB - OBJECTIVES: In the present study, we aimed to determine the effect of both active and passive smoking on the prevalence of the hearing impairment and the hearing thresholds in different age groups through the analysis of data collected from the Korea National Health and Nutrition Examination Survey (KNHANES). STUDY DESIGN: Cross-sectional epidemiological study. METHODS: The KNHANES is an ongoing population study that started in 1998. We included a total of 12,935 participants aged >=19 years in the KNHANES, from 2010 to 2012, in the present study. Pure tone audiometric (PTA) testing was conducted and the frequencies tested were 0.5, 1, 2, 3, 4, and 6 kHz. Smoking status was categorized into three groups; current smoking group, passive smoking group and non-smoking group. RESULTS: In the current smoking group, the prevalence of speech-frequency bilateral hearing impairment was increased in ages of 40-69, and the rate of high frequency bilateral hearing impairment was elevated in ages of 30-79. When we investigated the impact of smoking on hearing thresholds, we found that the current smoking group had significantly increased hearing thresholds compared to the passive smoking group and non-smoking groups, across all ages in both speech-relevant and high frequencies. The passive smoking group did not have an elevated prevalence of either speech-frequency bilateral hearing impairment or high frequency bilateral hearing impairment, except in ages of 40s. However, the passive smoking group had higher hearing thresholds than the non-smoking group in the 30s and 40s age groups. CONCLUSION: Current smoking was associated with hearing impairment in both speech-relevant frequency and high frequency across all ages. However, except in the ages of 40s, passive smoking was not related to hearing impairment in either speech-relevant or high frequencies. PMID- 26756933 TI - Mesenchymal Stem Cells Engineered to Secrete Pigment Epithelium-Derived Factor Inhibit Tumor Metastasis and the Formation of Malignant Ascites in a Murine Colorectal Peritoneal Carcinomatosis Model. AB - The therapeutic effects of conventional treatments for advanced colorectal cancer with colorectal peritoneal carcinomatosis (CRPC) and malignant ascites are not very encouraging. Vascular endothelial growth factor-A/vascular permeability factors (VEGF-A/VPF) play key roles in the formation of malignant ascites. In previous work, we demonstrated that pigment epithelium-derived factor (PEDF) antagonized VEGF-A and could repress tumor growth and suppress metastasis in several cancer types. Thus, PEDF may be a therapeutic candidate for treating malignant ascites. Mesenchymal stem cells (MSCs) are promising tools for delivering therapeutic agents in cancer treatment. In the study, MSCs derived from bone marrow were efficiently engineered to secrete human PEDF by adenoviral transduction. Then, intraperitoneal Ad-PEDF-transduced MSCs were analyzed with respect to CRPC and malignant ascites in a CT26 CRPC model. MSCs engineered to secrete PEDF through adenoviral transduction significantly inhibited tumor metastasis and malignant ascites formation in CT26 CRPC mice. Antitumor mechanisms of MSCs-PEDF (MSCs transduced with Ad-PEDF: MOI 500) were associated with inhibiting tumor angiogenesis, inducing apoptosis, and restoring the VEGF A/sFLT-1 ratio in ascites. Moreover, MSC-mediated Ad-PEDF delivery reduced production of adenovirus-neutralizing antibodies, prolonged PEDF expression, and induced MSCs-PEDF migration toward tumor cells. As a conclusion, MSCs engineered to secrete PEDF by adenoviral transduction may be a therapeutic approach for suppressing tumor metastasis and inhibiting malignant ascites production in CRPC. PMID- 26756934 TI - Renal Pseudoaneurysms and Arteriovenous Fistulas as a Complication of Nephron Sparing Partial Nephrectomy: Technical and Functional Outcomes of Patients Treated With Selective Microcoil Embolization During a Ten-Year Period. AB - PURPOSE: The aim of this study was to evaluate the clinical and functional outcomes in patients who underwent selective interventional embolization of renal pseudoaneurysms or arteriovenous fistulas at our center. MATERIALS AND METHODS: Our retrospective analysis included all consecutive patients who received selective transcatheter embolization of renal pseudoaneurysms or arteriovenous fistulas after partial nephrectomy in our department from January, 2003 to September, 2013. The technical and clinical success rate and functional outcome of every procedure was collected and analyzed. Furthermore, the change in renal parenchymal volume before and after embolization was determined in a subgroup. RESULTS: A total of 1425 patients underwent partial nephrectomy at our hospital. Of these, 39 (2.7 %) were identified with a pseudoaneurysm or an arteriovenous fistula after partial nephrectomy. The diagnosis of the vascular lesions was made by means of biphasic CT or CEUS. Technical success by means of selective microcoil embolization was achieved in all 39 patients (100 %). Clinical success, defined as no need for further operation or nephrectomy during follow-up, was achieved in 35 of 39 patients (85.7 %). Renal function, as measured by eGFR before and after the intervention, did not change significantly. However, a mean loss of parenchymal volume of 25.2 % was observed in a subgroup. No major or minor complications were attributable to the embolization procedure. CONCLUSION: Transcatheter embolization is a promising method for treating vascular complications which may occur after partial nephrectomy. We confirm the high success rate of this technique while discussing renal functional outcomes and potential safety aspects. KEY POINTS: Arterial pseudoaneurysms and arteriovenous fistulas are rare but severe complications after partial nephrectomy. Selective microcoil embolization is a safe and effective kidney-preserving procedure for treating these complications. Embolization leads to a significant loss of renal parenchymal volume but not to a loss of renal function. PMID- 26756935 TI - [Not Available]. PMID- 26756936 TI - [Not Available]. PMID- 26756939 TI - Can Mycosporine-Like Amino Acids Act as Multifunctional Compounds in Gymnodinium catenatum (Dinophyceae)? AB - MAAs originating from Gymnodinium catenatum were subjected to H2 O2 oxidation, light and heat. Shinorine and porphyra-334 were the more resistant to all treatments, mycosporine-glycine (MYGL) was the least resistant to oxidation and heat, whereas palythene and M-370 were the least resistant to light. MYGL and M 311 were similarly resistant to photodegradation and oxidation in the dark and low temperature, but M-311 was more resistant to oxidation under light or heat. The ratio M-370/M-365 changed from 29:1 to 6:1 ratio after 240 h of exposure to fluorescent light, indicating that M-365 could represent the M-370 cis-isomer. The role of MAAs as antioxidants and/or osmolytes was evaluated by studying effects of abrupt salinity reduction. Both increases or decreases in concentrations were observed and were dependent on the MAA initial concentration and its chemical structure. The relative increase in MAAs with a known antioxidant capacity (MYGL, palythene) followed an exponential decay trend related to initial concentration. The relative decrease in highly polar MAAs (shinorine, porphyra-334, M-332) with a suspected osmolyte role followed a rise to a maximum with the increase in initial concentration. Whether or not MAAs play a significant role in osmoregulation, their loss can occur upon hypoosmotic shock. PMID- 26756940 TI - Functional Assessment in End-Stage Renal Disease: Enhancing Quality of Life. AB - Why do functional assessments in patients with end-stage renal disease (ESRD) matter? Multiple studies show that new dialysis patients undergo a substantial decline among activities of daily living. Moreover, poor functional status in ESRD patients is associated with early morality. That is why CMS has developed new criteria to assess ESRD patients in regards to their functional, psychologic, and cognitive capabilities. Functional assessments by health providers have been used in field of Rehabilitation Medicine for over 50 years; rehabilitation physicians have found them effective in establishing goals and monitoring improvement. Assessments can provide guidance by identifying the needs and types of intervention most suited for patients. Impairments can be addressed with referrals to physical therapy for gross motor issues, occupational therapy for self-care problems, psychiatry for mental disorders, and neurology for cognitive deficits. The more accurate the assessments over time, the more targeted and effective the therapies become. We believe that the new CMS goals to assess functionality will improve ESRD patient's quality of life, longevity, and long term healthcare costs. PMID- 26756937 TI - The Role of Nicotine in the Effects of Maternal Smoking during Pregnancy on Lung Development and Childhood Respiratory Disease. Implications for Dangers of E Cigarettes. AB - Use of e-cigarettes, especially among the young, is increasing at near exponential rates. This is coupled with a perception that e-cigarettes are safe and with unlimited advertising geared toward vulnerable populations, the groups most likely to smoke or vape during pregnancy. There is now wide appreciation of the dangers of maternal smoking during pregnancy and the lifelong consequences this has on offspring lung function, including the increased risk of childhood wheezing and subsequent asthma. Recent evidence strongly supports that much of the effect of smoking during pregnancy on offspring lung function is mediated by nicotine, making it highly likely that e-cigarette use during pregnancy will have the same harmful effects on offspring lung function and health as do conventional cigarettes. In fact, the evidence for nicotine being the mediator of harm of conventional cigarettes may be most compelling for its effects on lung development. This raises concerns about both the combined use of e-cigarettes plus conventional cigarettes by smokers during pregnancy as well as the use of e cigarettes by e-cigarette-only users who think them safe or by those sufficiently addicted to nicotine to not be able to quit e-cigarette usage during pregnancy. Thus, it is important for health professionals to be aware of the risks of e cigarette usage during pregnancy, particularly as it pertains to offspring respiratory health. PMID- 26756941 TI - Multiphasic Dynamic Computed Tomography Evaluation of Liver Tissue Perfusion Characteristics Using the Dual Maximum Slope Model in Patients With Cirrhosis and Hepatocellular Carcinoma: A Feasibility Study. AB - OBJECTIVE: The aim of this study was to investigate the feasibility of multiphasic dynamic computed tomography (CT) scans in providing liver tissue perfusion characteristics using the dual maximum slope model in patients with liver cirrhosis and hepatocellular carcinoma (HCC). MATERIALS AND METHODS: With institutional review board approval and acquisition of informed consent, we retrospectively analyzed the prospectively collected perfusion CT (PCT) data of 36 patients enrolled in a prospective clinical trial for pretherapeutic assessment of HCC. To obtain perfusion parameters including arterial liver perfusion (ALP), portal venous perfusion (PVP), and the hepatic perfusion index (HPI), 5-phase dynamic CT data sets with triple arterial phases including peak aortic and splenic enhancement information were selected from the PCT data sets. The PCT and 5-phase dynamic CT data sets extracted from the PCT data were analyzed using dedicated perfusion software based on the dual maximum slope model. Comparisons between the perfusion parameters of each method were performed using Wilcoxon signed rank test and intraclass correlation coefficients. RESULTS: The extraction of liver perfusion parameters from 5-phase dynamic CT scans was feasible using the dual maximum slope model, and no significant differences were observed between perfusion parameters obtained from 5-phase dynamic CT and from PCT in the liver parenchyma (ALP, P = 0.137; PVP, P = 0.110; HPI, P = 0.793) and in HCCs (ALP, P = 0.162; HPI, P = 0.131). Regarding intraclass correlation coefficients, excellent agreement was observed between perfusion parameters obtained using 5-phase dynamic CT and from PCT in both the liver parenchyma (ALP, 0.793; PVP, 0.831; HPI, 0.934) and in HCCs (ALP, 0.889; HPI, 0.943). CONCLUSIONS: The extraction of liver perfusion parameters from 5-phase dynamic CT scans was feasible using the dual maximum slope model and provided comparable values to those obtained from PCT. PMID- 26756942 TI - Preexcited Tachycardia: Pacing Maneuvers to Distinguish Retrograde Conduction. PMID- 26756943 TI - Apparent First-Order Liquid-Liquid Transition with Pre-transition Density Anomaly, in Water-Rich Ideal Solutions. AB - The striking increases in response functions observed during supercooling of pure water have been the source of much interest and controversy. Imminent divergences of compressibility etc. unfortunately cannot be confirmed due to pre-emption by ice crystallization. Crystallization can be repressed by addition of second components, but these usually destroy the anomalies of interest. Here we study systems in which protic ionic liquid second components dissolve ideally in water, and ice formation is avoided without destroying the anomalies. We observe a major heat capacity spike during cooling, which is reversed during heating, and is apparently of first order. It occurs just before the glassy state is reached and is preceded by water-like density anomalies. We propose that it is the much discussed liquid-liquid transition previously hidden by crystallization. Fast cooling should allow the important fluctuations/structures to be preserved in the glassy state for leisurely investigation. PMID- 26756944 TI - Three-Dimensional Assembly of Yttrium Oxide Nanosheets into Luminescent Aerogel Monoliths with Outstanding Adsorption Properties. AB - The preparation of macroscopic materials from two-dimensional nanostructures represents a great challenge. Restacking and random aggregation to dense structures during processing prevents the preservation of the two-dimensional morphology of the nanobuilding blocks in the final body. Here we present a facile solution route to ultrathin, crystalline Y2O3 nanosheets, which can be assembled into a 3D network by a simple centrifugation-induced gelation method. The wet gels are converted into aerogel monoliths of macroscopic dimensions via supercritical drying. The as-prepared, fully crystalline Y2O3 aerogels show high surface areas of up to 445 m(2)/g and a very low density of 0.15 g/cm(3), which is only 3% of the bulk density of Y2O3. By doping and co-doping the Y2O3 nanosheets with Eu(3+) and Tb(3+), we successfully fabricated luminescent aerogel monoliths with tunable color emissions from red to green under UV excitation. Moreover, the as-prepared gels and aerogels exhibit excellent adsorption capacities for organic dyes in water without losing their structural integrity. For methyl blue we measured an unmatched adsorption capacity of 8080 mg/g. Finally, the deposition of gold nanoparticles on the nanosheets gave access to Y2O3-Au nanocomposite aerogels, proving that this approach may be used for the synthesis of catalytically active materials. The broad range of properties including low density, high porosity, and large surface area in combination with tunable photoluminescence makes these Y2O3 aerogels a truly multifunctional material with potential applications in optoelectronics, wastewater treatment, and catalysis. PMID- 26756938 TI - Force transmission in epithelial tissues. AB - In epithelial tissues, cells constantly generate and transmit forces between each other. Forces generated by the actomyosin cytoskeleton regulate tissue shape and structure and also provide signals that influence cells' decisions to divide, die, or differentiate. Forces are transmitted across epithelia because cells are mechanically linked through junctional complexes, and forces can propagate through the cell cytoplasm. Here, we review some of the molecular mechanisms responsible for force generation, with a specific focus on the actomyosin cortex and adherens junctions. We then discuss evidence for how these mechanisms promote cell shape changes and force transmission in tissues. PMID- 26756946 TI - Indices of cognitive function measured in rugby union players using a computer based test battery. AB - The purpose of this study was to investigate the intra- and inter-day reliability of cognitive performance using a computer-based test battery in team-sport athletes. Eighteen elite male rugby union players (age: 19 +/- 0.5 years) performed three experimental trials (T1, T2 and T3) of the test battery: T1 and T2 on the same day and T3, on the following day, 24 h later. The test battery comprised of four cognitive tests assessing the cognitive domains of executive function (Groton Maze Learning Task), psychomotor function (Detection Task), vigilance (Identification Task), visual learning and memory (One Card Learning Task). The intraclass correlation coefficients (ICCs) for the Detection Task, the Identification Task and the One Card Learning Task performance variables ranged from 0.75 to 0.92 when comparing T1 to T2 to assess intraday reliability, and 0.76 to 0.83 when comparing T1 and T3 to assess inter-day reliability. The ICCs for the Groton Maze Learning Task intra- and inter-day reliability were 0.67 and 0.57, respectively. We concluded that the Detection Task, the Identification Task and the One Card Learning Task are reliable measures of psychomotor function, vigilance, visual learning and memory in rugby union players. The reliability of the Groton Maze Learning Task is questionable (mean coefficient of variation (CV) = 19.4%) and, therefore, results should be interpreted with caution. PMID- 26756947 TI - In response to: Comparison of methods for the repair of acute tympanic membrane perforations: Silk patch vs. paper patch. PMID- 26756945 TI - Meta-analysis and meta-regression of transcriptomic responses to water stress in Arabidopsis. AB - The large amounts of transcriptome data available for Arabidopsis thaliana make a compelling case for the need to generalize results across studies and extract the most robust and meaningful information possible from them. The results of various studies seeking to identify water stress-responsive genes only partially overlap. The aim of this work was to combine transcriptomic studies in a systematic way that identifies commonalities in response, taking into account variation among studies due to batch effects as well as sampling variation, while also identifying the effect of study-specific variables, such as the method of applying water stress, and the part of the plant the mRNA was extracted from. We used meta-analysis, the quantitative synthesis of independent research results, to summarize expression responses to water stress across studies, and meta regression to model the contribution of covariates that may affect gene expression. We found that some genes with small but consistent differential responses become evident only when results are synthesized across experiments, and are missed in individual studies. We also identified genes with expression responses that are attributable to use of different plant parts and alternative methods for inducing water stress. Our results indicate that meta-analysis and meta-regression provide a powerful approach for identifying a robust gene set that is less sensitive to idiosyncratic results and for quantifying study characteristics that result in contrasting gene expression responses across studies. Combining meta-analysis with individual analyses may contribute to a richer understanding of the biology of water stress responses, and may prove valuable in other gene expression studies. PMID- 26756959 TI - Everolimus-eluting bioresorbable vascular scaffolds versus second generation drug eluting stents for percutaneous treatment of chronic total coronary occlusions: Technical and procedural outcomes from the GHOST-CTO registry. AB - OBJECTIVES: We aimed at comparing the acute performance of bioresorbable scaffolds (BRS) and second-generation drug-eluting stents (DES) for the treatment of chronic total occlusions (CTO). BACKGROUND: There is a lack of knowledge regarding the use of BRS in CTO. METHODS: Key outcomes of interest were technical and procedural success. Technical success was defined as successful stent delivery and implantation, postprocedural residual diameter stenosis <30% within the treated segment, and restoration of thrombolysis in myocardial infarction (TIMI) grade 3 flow. Procedural success was defined as technical success with no in-hospital major adverse cardiac events (MACE). RESULTS: Between May 2013 and May 2014, 32 patients underwent CTO percutaneous coronary intervention (PCI) with the Absorb BRS (Abbott Vascular, Santa Clara, CA) and were compared with a historical control group of 54 patients who had undergone CTO PCI with second generation DES. Baseline characteristics were similar between the BRS and DES groups, with the exception of a larger mean reference vessel diameter in the BRS group (2.92 +/- 0.34 vs 2.50 +/- 0.68; P < 0.001). Technical success was less likely to be achieved in the BRS group compared with the DES group (78.1% vs 96.3%, P = 0.012). Procedural success rates were 78.1% and 94.4% in the BRS and DES group, respectively (P = 0.035). CONCLUSIONS: Compared with second-generation DES for PCI of CTO lesions, BRS were associated with lower rates of technical and procedural success. (c) 2016 Wiley Periodicals, Inc. PMID- 26756960 TI - Proposed pathways to problematic drinking via post-traumatic stress disorder symptoms, emotion dysregulation, and dissociative tendencies following child/adolescent sexual abuse. AB - The relationship between early sexual abuse and college problem drinking was examined using an integration of the self-medication and vulnerability-stress models. Baseline survey data from parti-cipants (N = 213; 135 men and 78 college women) completing a mandated, brief alcohol intervention were utilized. Representative of the self-medication model, post-traumatic stress disorder symptoms mediated the early sexual abuse/problem drinking relationship. Two psychological vulnerability factors-emotion dysregulation and dissociative tendencies-were incorporated into self-medication findings via more advanced mediational models. Results highlighted that problem drinking increased as dissociative tendencies increased, and relations between the vulnerability factors and post-traumatic stress disorder symptoms were in an unexpected direction. PMID- 26756961 TI - Review of receptor modeling methods for source apportionment. AB - Efforts have been made to relate measured concentrations of airborne constituents to their origins for more than 50 years. During this time interval, there have been developments in the measurement technology to gather highly time-resolved, detailed chemical compositional data. Similarly, the improvements in computers have permitted a parallel development of data analysis tools that permit the extraction of information from these data. There is now a substantial capability to provide useful insights into the sources of pollutants and their atmospheric processing that can help inform air quality management options. Efforts have been made to combine receptor and chemical transport models to provide improved apportionments. Tools are available to utilize limited numbers of known profiles with the ambient data to obtain more accurate apportionments for targeted sources. In addition, tools are in place to allow more advanced models to be fitted to the data based on conceptual models of the nature of the sources and the sampling/analytical approach. Each of the approaches has its strengths and weaknesses. However, the field as a whole suffers from a lack of measurements of source emission compositions. There has not been an active effort to develop source profiles for stationary sources for a long time, and with many significant sources built in developing countries, the lack of local profiles is a serious problem in effective source apportionment. The field is now relatively mature in terms of its methods and its ability to adapt to new measurement technologies, so that we can be assured of a high likelihood of extracting the maximal information from the collected data. IMPLICATIONS: Efforts have been made over the past 50 years to use air quality data to estimate the influence of air pollution sources. These methods are now relatively mature and many are readily accessible through publically available software. This review examines the development of receptor models and the current state of the art in extracting source identification and apportionments from ambient air quality data. PMID- 26756962 TI - Development of a 3D cell printed construct considering angiogenesis for liver tissue engineering. AB - Several studies have focused on the regeneration of liver tissue in a two dimensional (2D) planar environment, whereas actual liver tissue is three dimensional (3D). Cell printing technology has been successfully utilized for building 3D structures; however, the poor mechanical properties of cell-laden hydrogels are a major concern. Here, we demonstrate the printing of a 3D cell laden construct and its application to liver tissue engineering using 3D cell printing technology through a multi-head tissue/organ building system. Polycaprolactone (PCL) was used as a framework material because of its excellent mechanical properties. Collagen bioink containing three different types of cells hepatocytes (HCs), human umbilical vein endothelial cells , and human lung fibroblasts--was infused into the canals of a PCL framework to induce the formation of capillary--like networks and liver cell growth. A co-cultured 3D microenvironment of the three types of cells was successfully established and maintained. The vascular formation and functional abilities of HCs (i.e., albumin secretion and urea synthesis) demonstrated that the heterotypic interaction among HCs and nonparenchymal cells increased the survivability and functionality of HCs within the collagen gel. Therefore, our results demonstrate the prospect of using cell printing technology for the creation of heterotypic cellular interaction within a structure for liver tissue engineering. PMID- 26756963 TI - Evaluation of New Palladium Cages as Potential Delivery Systems for the Anticancer Drug Cisplatin. AB - Self-assembled metallocages are very promising drug-delivery systems among supramolecular complexes. Thus, exo-functionalized Pd2 L4 (L=ligand) cages were synthesized and characterized, and the encapsulation of the anticancer drug cisplatin in their cavity has been documented. The antiproliferative effects of the metallocages and their combination with cisplatin were examined in vitro in cancer cell lines, while fluorescence microscopy was used to monitor their uptake. Notably, the hydroxymethyl-functionalized Pd(II) cage encapsulating cisplatin showed improved cytotoxic effect against human ovarian cancer cells compared to free cisplatin. The toxicity of Pd2 L4 cages was evaluated for the first time ex vivo in healthy rat-liver tissues using the precision cut-tissue slices technology, demonstrating in some cases scarce effects on liver viability. These results further highlight the potential of self-assembled Pd2 L4 cages for biological applications. PMID- 26756964 TI - Coil-to-coil physiological noise correlations and their impact on functional MRI time-series signal-to-noise ratio. AB - PURPOSE: Physiological nuisance fluctuations ("physiological noise") are a major contribution to the time-series signal-to-noise ratio (tSNR) of functional imaging. While thermal noise correlations between array coil elements have a well characterized effect on the image Signal to Noise Ratio (SNR0 ), the element-to element covariance matrix of the time-series fluctuations has not yet been analyzed. We examine this effect with a goal of ultimately improving the combination of multichannel array data. THEORY AND METHODS: We extend the theoretical relationship between tSNR and SNR0 to include a time-series noise covariance matrix Psit , distinct from the thermal noise covariance matrix Psi0 , and compare its structure to Psi0 and the signal coupling matrix SSH formed from the signal intensity vectors S. RESULTS: Inclusion of the measured time-series noise covariance matrix into the model relating tSNR and SNR0 improves the fit of experimental multichannel data and is shown to be distinct from Psi0 or SSH . CONCLUSION: Time-series noise covariances in array coils are found to differ from Psi0 and more surprisingly, from the signal coupling matrix SSH . Correct characterization of the time-series noise has implications for the analysis of time-series data and for improving the coil element combination process. Magn Reson Med 76:1708-1719, 2016. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26756965 TI - Discriminant power of socio-demographic characteristics and mood in distinguishing cognitive performance clusters in older individuals: a cross sectional analysis. AB - OBJECTIVES: Identification of predictors of cognitive trajectories has been a matter of concern on aging research. For this reason, it is of relevance to infer cognitive profiles based on rapid screening variables in order to determine which individuals will be more predisposed to cognitive decline. METHOD: In this work, a linear discriminant analysis (LDA) was conducted with socio-demographic variables and mood status as predictors of cognitive profiles, computed in a previous sample, based on different cognitive dimensions. Data were randomly split in two samples. Both samples were representative of the Portuguese population in terms of gender, age and education. The LDA was performed with one sample (n = 506, mean age 65.7 +/- 8.98 years) and tested in the second sample (n = 548, mean age 68.5 +/- 9.3 years). RESULTS: With these variables, we were able to achieve an overall hit rate of 65.9%, which corresponds to a significant increment in comparison to classification by chance. CONCLUSION: Although not ideal, this model may serve as a relevant tool to identify cognitive profiles based on a rapid screening when few variables are available. PMID- 26756966 TI - Broadband Tunable Microlasers Based on Controlled Intramolecular Charge-Transfer Process in Organic Supramolecular Microcrystals. AB - Wavelength tunable micro/nanolasers are indispensable components for various photonic devices. Here, we report broadband tunable microlasers built by incorporating a highly polarized organic intramolecular charge-transfer (ICT) compound with a supramolecular host. The spatial confinement of the ICT dye generates an optimized energy level system that favors controlled population distribution between the locally excited (LE) state and the twisted intramolecular charge-transfer (TICT) state, which is beneficial for significantly broadening the tailorable gain region. As a result, we realized a wide tuning of lasing wavelength in the organic supramolecular microcrystals based on temperature-controlled population transfer from the LE to TICT state. The results will provide a useful enlightenment for the rational design of miniaturized lasers with desired performances. PMID- 26756967 TI - Functionalization of an Antisense Small RNA. AB - In order to explore the possibility of adding new functions to preexisting genes, we considered a framework of riboregulation. We created a new riboregulator consisting of the reverse complement of a known riboregulator. Using computational design, we engineered a cis-repressing 5' untranslated region that can be activated by this new riboregulator. As a result, both RNAs can orthogonally trans-activate translation of their cognate, independent targets. The two riboregulators can also repress each other by antisense interaction, although not symmetrically. Our work highlights that antisense small RNAs can work as regulatory agents beyond the antisense paradigm and that, hence, they could be interfaced with other circuits used in synthetic biology. PMID- 26756968 TI - Treatment to sustain a Th17-type phenotype to prevent skewing toward Treg and to limit premalignant lesion progression to cancer. AB - While immune suppression is a hallmark of head and neck squamous cell carcinoma (HSNCC), the immunological impact of premalignant oral lesions, which often precedes development of HNSCC, is unknown. The present study assessed the changes in splenic and draining lymph node CD4(+) cell populations and their production of select cytokines that occur in mice with carcinogen-induced premalignant oral lesions and the changes that occur as lesions progress to oral cancer. These studies found skewing toward Th1 and Th17-type phenotypes in the spleen and lymph nodes of mice with premalignant oral lesions and a shift to Treg as lesions progress to cancer. Since the role of Th17 cells in the progression from premalignant lesions to cancer is not clear, studies determined the immunological and clinical effect of treating mice bearing premalignant oral lesions with a TGF beta type 1 receptor inhibitor plus IL-23 as an approach to sustain the Th17 phenotype. These studies showed that the treatment approach not only sustained the Th17 phenotype, but also increased distal spleen cell and regional lymph node cell production of other stimulatory/inflammatory mediators and slowed premalignant lesion progression to cancer. PMID- 26756969 TI - MicroRNA-503 promotes angiotensin II-induced cardiac fibrosis by targeting Apelin 13. AB - Cardiac fibrosis is a major cause of heart failure. MicroRNAs (miRs) are important epigenetic regulators of cardiac function and cardiovascular diseases, including cardiac fibrosis. This study aimed to explore the role of miR-503 and its mechanisms in regulating cardiac fibrosis. miR-503 was found up-regulated in the mouse LV tissues subjected to transverse aortic constriction (TAC) and in neonatal cardiac fibroblasts (CFs) cultured with Angiotension II. The role of miR 503 in regulating CF cell proliferation and/or collagen production in mice neonatal CFs were determined using an MTT assay and RT-PCR respectively. Forced expression of miR-503 increased the cellular proliferation and collagen production in mice neonatal CFs. The effects were abrogated by cotransfection with AMO-503 (a specific inhibitor of miR-503). Injection of antagomiR-503 elevated cardiac function and inhibited the expression of connective tissue growth factor (CTGF) and transforming growth factor (TGF)-beta in the TAC mice. Additional analysis revealed that Apelin-13 is a direct target of miR-503, as the overexpression of miR-503 decreased the protein and mRNA expression levels of Apelin-13. In the CFs with pre-treatment of AngII, we transfected AMO-503 into the cells treated with siRNA-APLN. siRNA-APLN abolished the effects of AMO-503 on the production of collagen I and III and the expression of TGF-beta and CTGF. Furthermore, pre-treatment of CFs with Apelin-13 (1-100 nmol/l) inhibited angiotensin II-mediated collagen production and activation of CTGF and TGF-beta. So we conclude that miR-503 promotes cardiac fibrosis via miR-503-Apelin-13-TGF beta-CTGF-collagen production pathway. Thus, miR-503 is a promising therapeutic target for reducing cardiac fibrosis. PMID- 26756970 TI - Myristic acid is associated to low plasma HDL cholesterol levels in a Mediterranean population and increases HDL catabolism by enhancing HDL particles trapping to cell surface proteoglycans in a liver hepatoma cell model. AB - BACKGROUND: HDL-C plasma levels are modulated by dietary fatty acid (FA), but studies investigating dietary supplementation in FA gave contrasting results. Saturated FA increased HDL-C levels only in some studies. Mono-unsaturated FA exerted a slight effect while poly-unsaturated FA mostly increased plasma HDL-C. AIMS: This study presents two aims: i) to investigate the relationship between HDL-C levels and plasma FA composition in a Sicilian population following a "Mediterranean diet", ii) to investigate if FA that resulted correlated with plasma HDL-C levels in the population study and/or very abundant in the plasma were able to affect HDL catabolism in an "in vitro" model of cultured hepatoma cells (HepG2). RESULTS: plasma HDL-C levels in the population correlated negatively with myristic acid (C14:0, beta = -0.24, p < 0.01), oleic acid (C18:1n9, beta = -0.22, p < 0.01) and cis-11-Eicosenoic (C20:1n9, beta = -0.19, p = 0.01) and positively with palmitoleic acid (C16:1, beta = +0.19, p = 0.03). HepG2 cells were conditioned with FA before evaluating HDL binding kinetics, and only C14:0 increased HDL binding by a non-saturable pathway. After removal of heparan sulphate proteoglycans (HSPG) by heparinases HDL binding dropped by 29% only in C14:0 conditioned cells (p < 0.05). C14:0 showed also the highest internalization of HDL-derived cholesteryl esters (CE, +32% p = 0.01 vs. non conditioned cells). CONCLUSIONS: C14:0 was correlated with decreased plasma HDL-C levels in a Mediterranean population. C14:0 might reduce HDL-C levels by increasing HDL trapping to cell surface HSPG and CE stripping from bound HDL. Other mechanisms are to be investigated to explain the effects of other FA on HDL metabolism. PMID- 26756972 TI - Theoretical Studies on Palladium-Mediated Enantioselective C-H Iodination. AB - DFT calculations have been carried out to investigate the reaction mechanism for Pd(II)-mediated enantioselective C-H iodination. Iodination of the aryl ortho C-H bond of benzylamines catalyzed by Pd(II) diacetate complexes in the presence of the L-MPAA ligand experiences three main steps: first, C-H bond activation; second, oxidative addition of iodine on Pd(II) and reductive elimination of iodobenzene; third, catalyst regeneration through ligand exchange. The C-H bond activation is found to be the rate-determining step of the overall iodination due to higher activation energy. The reaction barrier for the formation of iodinated (R)-benzylamine is lower than that of (S)-benzylamine, which confirms the R enantioselectivity in iodination at room temperature. The retainment of the coordination of one acetic acid on Pd(II) and the chelating MPAA ligand during the catalyzed reaction are suggested to give space economy to facilitate the C-H bond activation. The NHTf functional group on the substrate is found to be very important for ortho C-H iodination at ambient condition. Our calculated results are consistent with the experimental observations. PMID- 26756971 TI - Biomarkers for risk stratification in secondary cardiovascular prevention. A role of red blood cell distribution width and calcium score. AB - BACKGROUND: Patients with coronary artery disease (CAD) are considered as high risk in terms of secondary cardiovascular prevention. However, obviously the risk is not homogenous across the whole group. Red blood cell distribution width (RDW) has been recently related to adverse outcomes in patients with atherosclerosis. Calcium score (CaS) may be used for risk stratification in primary prevention. The value of these biomarkers for prediction of cardiovascular outcomes in patients with CAD is unknown. METHODS: The study group comprised 269 consecutive patients with significant stable CAD. The primary endpoint was a composite of death or nonfatal myocardial infarction. RESULTS: Median post-discharge follow up was 43.2 months (IQR39.2-48.6). The primary outcome was observed in 27 patients including 13 deaths and 14 nonfatal myocardial infarction. According to ROC analysis the best cut-off value for RDW for prediction of the primary event was 14% [(AUC) = 0.69; 95%CI:0.63-0.75; p = 0.0002] and for CaS was 603 [(AUC) = 0.66; 95%CI:0.60-0.72; p = 0.001]. According to multivariable Cox regression analysis both RDW>14% (HR 2.6; 95%CI:1.1-5.9) and CaS>603 (HR 2.3; 95%CI:1.1-5.1) were independently correlated to the primary outcome. Subsequently, patients were categorized into three risk subgroups: LOW: CaS <= 603 and RDW <= 14-124(46.1%), MID: either CaS>603 or RDW>14-104(38.7%), and HIGH - CaS>603 and RDW>14-41(15.2%) patients. The respective risk of events according to Kaplan-Meier analysis were 4.03%, 9.62%, and 29.27% (p < 0.0001). CONCLUSIONS: RDW and calcium score may be predictors of future cardiovascular events in patients with significant CAD. They may be useful tools for risk stratification and may indicate patients suitable for more aggressive secondary prevention measures. PMID- 26756973 TI - Climate structures genetic variation across a species' elevation range: a test of range limits hypotheses. AB - Gene flow may influence the formation of species range limits, and yet little is known about the patterns of gene flow with respect to environmental gradients or proximity to range limits. With rapid environmental change, it is especially important to understand patterns of gene flow to inform conservation efforts. Here we investigate the species range of the selfing, annual plant, Mimulus laciniatus, in the California Sierra Nevada. We assessed genetic variation, gene flow, and population abundance across the entire elevation-based climate range. Contrary to expectations, within-population plant density increased towards both climate limits. Mean genetic diversity of edge populations was equivalent to central populations; however, all edge populations exhibited less genetic diversity than neighbouring interior populations. Genetic differentiation was fairly consistent and moderate among all populations, and no directional signals of contemporary gene flow were detected between central and peripheral elevations. Elevation-driven gene flow (isolation by environment), but not isolation by distance, was found across the species range. These findings were the same towards high- and low-elevation range limits and were inconsistent with two common centre-edge hypotheses invoked for the formation of species range limits: (i) decreasing habitat quality and population size; (ii) swamping gene flow from large, central populations. This pattern demonstrates that climate, but not centre-edge dynamics, is an important range-wide factor structuring M. laciniatus populations. To our knowledge, this is the first empirical study to relate environmental patterns of gene flow to range limits hypotheses. Similar investigations across a wide variety of taxa and life histories are needed. PMID- 26756975 TI - Unexpected Formation of Early Late Heterobimetallic Complexes from Transition Metal Frustrated Lewis Pairs. AB - Reaction of transition metal "frustrated" Lewis pair compounds of the type [Cp2Zr(Me)(OC(CF3)2CH2P(t)Bu2)] with the low valent platinum species [Pt(norbornene)3] leads to the unexpected formation of a heterobimetallic species [Cp2Zr{ Pt(Me)}(OC(CF3)2CH2 P(t)Bu2)]. Single crystal X-ray analysis reveals an unusual T-shaped geometry at the platinum center, with a relevant C-Pt-P angle of 163.3(3) degrees . Treatment of this compound with PMe3 yields [Pt(PMe3)4] and regenerates the zirconium precursor. Treatment with [(Et2O)2H][B(C6F5)4] protonates off the methyl ligand to give an ether adduct at platinum. Analogous observations are made with titanium-platinum species. We propose the chemistry is best rationalized as a formal insertion of Pt(0) into a Zr-C or Ti-Cl bond. PMID- 26756974 TI - Nanofiltrated C1-esterase-inhibitor in the prophylactic treatment of bradykinin mediated angioedema. AB - BACKGROUND: Patients suffering from bradykinin-induced angioedema show recurrent swelling of subcutaneous and submucosal structures. Increased bradykinin levels lead to an increase in vascular permeability and edema formation. Current therapy consists of B2 bradykinin receptor antagonists, C1-esterase-inhibitor (C1-INH) concentrate, or the kallikrein inhibitor ecallantide. In most cases the treatment of acute attacks is sufficient. Prophylactic therapy is recommended only in severe cases. C1-INHc has been shown a safe and efficient option. Its effect on the quality of life has not yet been analyzed. STUDY DESIGN AND METHODS: Patients with inadequate disease control despite an "on-demand therapy" including C1-INHc and/or the B2 receptor antagonist icatibant were switched to long-term prophylaxis consisting in an individual dose of intravenous C1-INHc (Cinryze). None of the patients had been previously treated with ecallantide. Disease specific quality-of-life questionnaires and patient records were used for evaluation. Disease control, quality of life, adverse events, and administered dosage per month were compared for 6 months on on-demand therapy and the following 6 months under prophylactic therapy. RESULTS: Data of seven patients with hereditary angioedema (HAE) and one patient with acquired angioedema were evaluated. Prophylactic therapy with Cinryze led to a significant and clinically relevant reduction in the overall attack frequency from 6.7 to 2.3 per month without relevant side effects. The frequency of severe attacks was reduced by 89% and quality of life significantly improved. CONCLUSION: Prophylaxis with Cinryze led to a significantly improved quality of life in our cohort of patients with high-frequency bradykinin-induced angioedema attacks that were not sufficiently treated with on-demand medication. PMID- 26756976 TI - Performances of microbial fuel cells fed with rejected wastewater from BioCH4 and BioH2 processes treating molasses wastewater. AB - An integrated process involving conventional anaerobic digestion and microbial fuel cells (MFCs) has attracted attention recently to produce sustainable energy and to treat wastewater efficiently. To evaluate the possibility of CH4-producing process (BioCH4)-MFC or H2-producing process (BioH2)-MFC integrating systems, the MFC performances were investigated using rejected wastewater from a BioCH4 reactor (RWCH4) or BioH2 reactor (RWH2) treating molasses wastewater. When RWCH4 or RWH2 was fed into a single-chamber MFC reactor (designated as AC-MFCCH4 and AC MFCH2, respectively) at different hydraulic retention times (HRT) of 1-7 d, both MFC systems showed maximum electricity production efficiencies at a HRT of 3 d. In the AC-MFCCH4 reactor, the average current density and average power density were 60.5 mA.m(-2) and 8.8 mW.m(-2), respectively. The AC-MFCH2 reactor generated an average current density of 71.4 mA.m(-2) and an average power density of 12.0 mW.m(-2). The COD removal rates were 45.7% in the AC-MFCCH4 reactor and 90.3% in the AC-MFCH2 reactor. There were no significant differences of the eubacterial community structures between the MFC systems, where Proteobacteria was remarkably dominant in both MFC systems. However, the archaeal community structures were significantly different where Methanothrix (89.3%) was remarkably dominant in the AC-MFCCH4 system, while Methanothrix (52.5%) and Methanosarcina (33.5%) were abundant in the AC-MFCH2 system. These findings demonstrate that the utilization of MFCs after the BioCH4 or BioH2 process is advantageous for energy recovery as well as COD removal from molasses wastewater. PMID- 26756977 TI - Pharmacokinetic and Pharmacodynamic Comparison of Sildenafil-Bosentan and Sildenafil-Ambrisentan Combination Therapies for Pulmonary Hypertension. AB - To elucidate whether the pharmacokinetics (PK) and pharmacodynamics (PD) of sildenafil are influenced differently when it is coadministered with bosentan (S+B) or with ambrisentan (S+A), we evaluated the PK and PD profiles of sildenafil before and after 4-5 weeks of S+A or S+B treatment in patients with pulmonary arterial hypertension. The area under the plasma concentration-time curve of sildenafil was significantly higher in S+A treatment than in S+B treatment (165.8 ng*h/mL vs. 396.8 ng*h/mL, P = 0.018) and the oral clearance of sildenafil was significantly lower after S+A treatment than after S+B treatment (120.6 L/h/kg vs. 50.4 L/h/kg, P = 0.018). In the PD study, incremental shuttle walking distance was superior during treatment with S+A than during treatment with S+B (S+B; 280 m vs. S+A; 340 m, P = 0.042). There were no concerns about safety with either combination therapy regime. PMID- 26756978 TI - Necker cube copying may not be appropriate as an examination of dementia: reanalysis from the Tajiri Project. AB - BACKGROUND: The Necker cube is usually used for evaluating the visuoconstructional ability of patients with mild cognitive impairment (MCI) and dementia. However, the Necker cube is often considered a drawing with a visual illusionary perspective. The purpose of this study was to investigate whether Necker cube copying could detect participants with MCI due to dementia. METHODS: We retrospectively analyzed the database of the 1998 prevalence study that was part of the Tajiri Project (n = 599). Pencil drawings of the Necker cube on A4 sized white paper by non-demented people (Clinical Dementia Rating (CDR) 0 and 0.5, n = 256) were classified into two patterns: non-three-dimension (3-D) and 3 D. Two neuropsychologists assessed Necker cube copying according to the criteria of the classification. After the classification, the database of the 2003 incidence study was used according to the subjects' conversion to dementia. RESULTS: In the prevalence study, among those who made a non-3-D drawing of the Necker cube, there were significantly fewer people in the CDR 0 group than in the CDR 0.5 and CDR 1+ groups; similarly, there were significantly fewer people in the CDR 0.5 group than in the CDR 1 + group (chi(2) = 32.6, P < 0.001; post-hoc tests using chi(2) tests, CDR 0 > CDR 0.5 > CDR 1+, P < 0.001). In the incidence study, among those who made a non-3-D drawing of the Necker cube, there were significantly fewer people in the non-converter group than in the converter group (chi(2) = 19.9, P < 0.001). However, there was no significant difference between the non-converter group (n = 21) and the converter group (n = 21) when age, sex, educational levels, and Mini-Mental State Examination scores were controlled (chi(2) = 0.0, P = 1.000). CONCLUSIONS: Our results suggested that Necker cube copying may evaluate visual illusion as well as visuoconstructional ability. The Necker cube may not be an appropriate test to detect participants with MCI due to dementia. PMID- 26756980 TI - Does Mutual Interference Affect the Feeding Rate of Aphidophagous Coccinellids? A Modeling Perspective. AB - Mutual interference involves direct interactions between individuals of the same species that may alter their foraging success. Larvae of aphidophagous coccinellids typically stay within a patch during their lifetime, displaying remarkable aggregation to their prey. Thus, as larvae are exposed to each other, frequent encounters may affect their foraging success. A study was initiated in order to determine the effect of mutual interference in the coccinellids' feeding rate. One to four 4th larval instars of the fourteen-spotted ladybird beetle Propylea quatuordecimpunctata were exposed for 6 hours into plastic containers with different densities of the black bean aphid, Aphis fabae, on potted Vicia faba plants. The data were used to fit a purely prey-dependent Holling type II model and its alternatives which account for interference competition and have thus far been underutilized, i.e. the Beddington-DeAngelis, the Crowley-Martin and a modified Hassell-Varley model. The Crowley-Martin mechanistic model appeared to be slightly better among the competing models. The results showed that although the feeding rate became approximately independent of predator density at high prey density, some predator dependence in the coccinellid's functional response was observed at the low prey-high predator density combination. It appears that at low prey densities, digestion breaks are negligible so that the predators do waste time interfering with each other, whereas at high prey densities time loss during digestion breaks may fully accommodate the cost of interference, so that the time cost may be negligible. PMID- 26756979 TI - Immunometabolic biomarkers of inflammation in Behcet's disease: relationship with epidemiological profile, disease activity and therapeutic regimens. AB - Behcet's disease (BD) is a systemic inflammatory disease with a still unclear pathogenesis. Although several inflammatory molecules have been studied, current biomarkers are largely insensitive in BD and unable to predict disease progression and response to treatment. Our primary aim was to explore serum levels of soluble CD40 L (sCD40L), soluble intracellular adhesion molecule (sICAM 1), monocyte chemoattractant protein-1 (MCP-1), myeloperoxidase (MPO), leptin, resistin, osteoprotegerin (OPG), soluble type 1 tumour necrosis factor receptor (sTNFR), interleukin (IL)-6 and serum amyloid A (SAA) serum concentration in a cohort of 27 BD patients. The secondary aim was to evaluate potential correlations between the putative circulating biomarkers, demographic profile of patients, the status of disease activity, the specific organ involvement at the time of sample collection and different therapeutic regimens. Serum concentrations of sTNFR (P = 0.008), leptin (P = 0.0011), sCD40L (P < 0.0001) and IL-6 (P = 0.0154) were significantly higher in BD patients than in HC, while no difference was found in MCP-1, MPO and resistin serum levels. Moreover, we observed significantly higher sTNFR serum concentrations in BD patients presenting inactive disease than HC (P = 0.0108). A correlation between sTNFR and age was also found, with higher levels in patients over 40 years than HC (P = 0.0329). Although further research is warranted to elucidate the role of circulating biomarkers, some of that may contribute to the understanding of the physiopathology processes underlying BD activity and damage as well as to provide useful tools for prognostic purposes and a personalized treatment approach. PMID- 26756981 TI - Organ-specific accumulation, transportation, and elimination of methylmercury and inorganic mercury in a low Hg accumulating fish. AB - Low mercury (Hg) concentrations down to several nanograms Hg per gram of wet tissue are documented in certain fish species such as herbivorous fish, and the underlying mechanisms remain speculative. In the present study, bioaccumulation and depuration patterns of inorganic Hg(II) and methylmercury (MeHg) in a herbivorous rabbitfish Siganus canaliculatus were investigated at organ and subcellular levels following waterborne or dietary exposures. The results showed that the efflux rate constants of Hg(II) and MeHg were 0.104 d(-1) and 0.024 d( 1) , respectively, and are probably the highest rate constants recorded in fish thus far. The dietary MeHg assimilation efficiency (68%) was much lower than those in other fish species (~90%). The predominant distribution of MeHg in fish muscle was attributable to negligible elimination of MeHg from muscle (< 0) and efficient elimination of MeHg from gills (0.12 d(-1) ), liver (0.17 d(-1) ), and intestine (0.20 d(-1) ), as well as efficient transportation of MeHg from other organs into muscle. In contrast, Hg(II) was much more slowly distributed into muscle but was efficiently eliminated by the intestine (0.13 d(-1) ). Subcellular distribution indicated that some specific membrane proteins in muscle were the primary binding pools for MeHg, and both metallothionein-like proteins and Hg rich granules were the important components in eliminating both MeHg and Hg(II). Overall, the present study's results suggest that the low tissue Hg concentration in the rabbitfish was partly explained by its unique biokinetics. Environ Toxicol Chem 2016;35:2074-2083. (c) 2016 SETAC. PMID- 26756982 TI - Assessment of tumourigenic potential in long-term cryopreserved human adipose derived stem cells. AB - Cryopreservation represents an efficient way to preserve human mesenchymal stem cells (hMSCs) at early culture/passage, and allows pooling of cells to achieve sufficient cells required for off-the-shelf use in clinical applications, e.g. cell-based therapies and regenerative medicine. To fully apply cryopreserved hMSCs in a clinical setting, it is necessary to evaluate their biosafety, e.g. chromosomal abnormality and tumourigenic potential. To date, many studies have demonstrated that cryopreserved hMSCs display no chromosomal abnormalities. However, the tumourigenic potential of cryopreserved hMSCs has not yet been evaluated. In the present study, we cryopreserved human adipose-derived mesenchymal stem cells (hASCs) for 3 months, using a slow freezing method with various cryoprotective agents (CPAs), followed by assessment of the tumourigenic potential of the cryopreserved hASCs after thawing and subculture. We found that long-term cryopreserved hASCs maintained normal levels of the tumour suppressor markers p53, p21, p16 and pRb, hTERT, telomerase activity and telomere length. Further, we did not observe significant DNA damage or signs of p53 mutation in cryopreserved hASCs. Our findings suggest that long-term cryopreserved hASCs are at low risk of tumourigenesis. These findings aid in establishing the biosafety profile of cryopreserved hASCs, and thus establishing low hazardous risk perception with the use of long-term cryopreserved hASCs for future clinical applications. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26756984 TI - Surgical Correction of Scoliosis in Patients With Duchenne Muscular Dystrophy: 30 Year Experience. AB - BACKGROUND: The natural history of scoliosis in Duchenne muscular dystrophy (DMD) is progressive and debilitating if neglected. The purpose of this study was to evaluate outcomes related to spinal deformity surgery in patients with DMD over a 30-year period. METHODS: This was a single center retrospective study of all operatively treated scoliosis in DMD patients over 30 years. Minimum follow-up was 2 years. Owing to changes in instrumentation over time, patients were divided into 2 groups: Luque or pedicle screws (PS) constructs. Radiographic, perioperative variables, pulmonary function test (preoperatively and postoperatively), and complication data were evaluated. RESULTS: There were 60 subjects (Luque: 47, PS: 13). The Luque group was on average 13 years old, 53 kg, and had 7 years of follow-up. Coronal Cobb was 31+/-12 degrees preoperatively, 16+/-11 degrees at first postoperatively, and 21+/-15 degrees at final follow-up (P<=0.001). Pelvic obliquity was 7+/-6 degrees preoperatively, 5+/-5 degrees at first postoperatively (P=0.43), and 5+/-4 degrees at final follow-up (P=0.77). The majority of this group was fused to L5 (45%) or the sacrum (49%). The PS group was on average 14 years old, 65 kg, and had 4 years of follow-up. Coronal Cobb was 43+/-19 degrees preoperatively, 12+/-9 degrees at first postoperatively (P<=0.001), and 12+/-8 degrees at final follow-up. Pelvic obliquity was 6+/-5 degrees preoperatively, 3+/-3 degrees at first postoperatively (P=0.06), and 2+/ 2 degrees at final follow-up (P=0.053). The majority were fused to the pelvis (92%). Both groups' pulmonary function declined with time. Both groups had high complication rates (Luque 68%; PS group 54%). The Luque group had more implant related complications (26%); the PS group had a higher rate of early postoperative infections (23%). CONCLUSIONS: Over a 30-year period of operative treatment of scoliosis in DMD, both PS constructs and Luque instrumentation improved coronal Cobb. The PS group had improved and maintained pelvic obliquity. Both groups had high complication rates. LEVEL OF EVIDENCE: Level IV-therapeutic. PMID- 26756983 TI - Increased Urinary Cystatin-C Levels Correlate with Reduced Renal Volumes in Neonates with Intrauterine Growth Restriction. AB - BACKGROUND: Exposure to intrauterine growth retardation (IUGR) can have a negative impact on nephrogenesis resulting in limited fetal kidney development and supporting the hypothesis that IUGR represents a risk for renal function and long-term renal disease. Cystatin-C (Cys-C), a strong inhibitor of cysteine proteinases, is freely filtered by the kidney glomerulus and is reabsorbed by the tubules, where it is almost totally catabolized; what remains is subsequently eliminated in urine. In tubular diseases and in hyperfiltration conditions, it seems reasonable to postulate that Cys-C degradation would decrease, and consequently an increase in its urinary elimination would be observed. OBJECTIVES: The aim of this study was to investigate the urinary excretion of Cys C simultaneously with the assessment of renal volumes in adequate for gestational age (AGA) and IUGR neonates in order to identify its clinical value in IUGR. METHODS: Urinary Cys-C levels were measured using the enzyme immunoassay DetectX(r) Human Cystatin C kit in IUGR and AGA neonates. Whole renal and renal cortex volumes were assessed with ultrasounds (Vocal II; Software, GE). RESULTS: Urinary Cys-C levels in IUGR were significantly higher than those found in AGA and were negatively correlated to reduced whole renal and renal cortex volumes. CONCLUSIONS: The increased levels of Cys-C in the urine of neonates with IUGR were significantly associated with reduced renal/renal cortex volumes, suggesting that Cys-C could be taken as a surrogate of nephron mass. It also could be used as an early biochemical marker to identify IUGR neonates at high risk of developing long-term renal disease and to select patients for monitoring during childhood. PMID- 26756986 TI - The Impact of Child Safety Restraint Status and Age in Motor Vehicle Collisions in Predicting Type and Severity of Bone Fractures and Traumatic Injuries. AB - BACKGROUND: Although morbidity and mortality in children increases in motor vehicle collisions (MVC) if child restraints are not used, no data exist correlating specific injuries with proper or improper use of safety restraints or age. The purpose of this study was to evaluate correlations between childhood MVC injuries, age, and restraint status. METHODS: A medical record search for pediatric patients involved in a MVC was conducted at a pediatric hospital (level 1 trauma). Charts were reviewed for demographics and injury-specific information. Patients were grouped by age, restraint use, and injuries. RESULTS: Nine hundred sixty-seven patients <=12 years (average age 6.39 y) were identified. Being properly restrained was most common in all age groups except the 4- to 8-year age group in which being improperly restrained was most common. Unrestrained patients were most commonly found in the 9- to 12-year age group. A statistically significant difference was not observed for orthopaedic injuries among the restraint groups, but internal thoracic injuries, open head wound, and open upper extremity wounds were significantly more common in improperly or unrestrained patients. Improperly restrained infants had a significantly higher rate of intracranial bleeds and abrasions than those properly restrained. Unrestrained and improperly restrained 9- to 12-year olds had significantly more open head, open upper extremity, and vascular injuries. When comparing injury types with age groups, upper extremity fractures, femoral fractures, dislocations, and spinal fractures were found to be significantly higher in older children. CONCLUSIONS: Preventing orthopaedic injuries in older children may be accomplished by changes in regulations or automotive safety equipment. Rear-facing child safety seats could possibly be improved to prevent head trauma in the youngest patients. There is a continued need to reinforce the importance of proper use of child safety devices to parents. Knowledge of the patient's age, along with restraint status, might aid in diagnosis of less obvious MCV injuries. LEVEL OF EVIDENCE: Level III. PMID- 26756985 TI - Cortical Atrophy Related to Tumor Prosthesis in Skeletally Immature Osteosarcoma Patients. AB - BACKGROUND: Cortical atrophy is commonly observed after prosthetic reconstruction for bone sarcomas. However, relevant literature regarding this phenomenon in skeletally immature patients is limited. Therefore, in this study, we evaluated the incidence and patterns of cortical atrophy. We then assessed its predisposing factors. Finally, we analyzed whether cortical atrophy was associated with poor prosthesis survival. METHODS: We retrospectively reviewed 31 stems in 19 skeletally immature osteosarcoma patients who were treated with resection and tumor prosthesis surgery. We measured the cortical thickness using plain radiographs annually. The mean patient age was 11 years (range, 6 to 14 y) and the mean follow-up period was 10 years (range, 2 to 14 y). RESULTS: Cortical atrophy developed in 13 stems, all within 3 years. There were 3 gross types of cortical atrophy: hourglass in 5, sharpening in 4, and shortening atrophy in 4. On multivariate analysis, stem-cortex diameter ratio of >=0.5 and age of less than 10 years were significantly associated with cortical atrophy (P=0.002 and P=0.019, respectively). Cortical atrophy was significantly associated with eventual prosthesis failure (9/13 in the cortical atrophy group vs. 4/18 in the nonatrophy group, P=0.035). CONCLUSIONS: Cortical atrophy is common in the skeletally immature patients with tumor prosthesis and is associated with prosthesis failure. Patients with cortical atrophy should be closely monitored for prosthesis failure and appropriately managed to prevent failures. LEVEL OF EVIDENCE: Level IV-therapeutic study. PMID- 26756987 TI - Sacral Alar Iliac (SAI) Screws Fail 75% Less Frequently Than Iliac Screws in Neuromuscular Scoliosis. AB - BACKGROUND: Despite recent popularity of sacral alar iliac (SAI) screws for fusion to the pelvis for neuromuscular scoliosis, there are little data regarding the failure rate of this technique compared with traditional modes of iliac fixation. Theoretical advantages of the SAI screws are obviating the need for a rod to iliac screw connector and a lower implant profile. The purpose of this study is to determine whether SAI screws have fewer failures than iliac screws in neuromuscular scoliosis. METHODS: Review of neuromuscular patients treated with posterior spinal fusion with pelvic fixation from 2004 to 2012 with minimum 2 year follow-up was conducted. Medical records and imaging studies were reviewed. Patients were divided into 2 groups based on the type of pelvic fixation (SAI or iliac screws), and implant failures were compared between the groups. RESULTS: A total of 101 patients were reviewed, including 55 patients with iliac screws and 46 patients with SAI screws. Implant failures included: disengagement of the rod to iliac screw connector (10%, 10/101), separation of screw head from screw shaft (4%, 4/101), and set screw disengagement (2%, 2/101). The SAI group had a lower implant failure rate (7%, 3/46) compared with the iliac screw group (24%, 13/55) (P=0.031). Rod to iliac screw connectors failed in 18% (10/55) of patients. There were significantly less surgical revisions in the SAI group (2%, 1/46) for pelvic screw prominence compared with the iliac screw group (11%, 6/55) (P=0.027). CONCLUSIONS: SAI screws had a lower rate of implant failure and revision surgery compared with iliac screws. If rod to screw connector failures are excluded, the failure rate of SAI screws of 6.5% (3/46) is similar to that of iliac screws 5.5% (3/55); therefore, the most important advantage of the SAI technique may be obviating the need for a screw to rod connector. LEVEL OF EVIDENCE: Level III. PMID- 26756988 TI - Internet-administered Health-related Quality of Life Questionnaires Compared With Pen and Paper in an Adolescent Scoliosis Population: A Randomized Crossover Study. AB - BACKGROUND: Modern technology puts into question the effectiveness of using pen and paper as a means of collecting information from web-enabled patients. This study aimed to validate and test the reliability of using the Internet as a method of administering health-related quality of life questionnaires in a pediatric spine population. METHODS: A prospective randomized crossover study was conducted. Patients aged 11 to 18 with idiopathic scoliosis were invited to participate, and informed consent was obtained from a scoliosis outpatient clinic setting. Participants were randomized to one of 4 groups determining the method of questionnaire administration [Scoliosis Research Society 30 (SRS-30) and Pediatric Outcomes Data Collection Instrument (PODCI)]. Both questionnaires were completed at 2 separate timepoints and 2 weeks apart to prevent recall bias. Groups included: Paper/Paper, Paper/Internet, Internet/Paper, and Internet/Internet. Paired-samples t tests were used to determine the test-retest reliability of each group. Analysis was stratified for surveys returned within or outside of the allotted 4-week timeframe following enrollment. RESULTS: Of the 96 participants who completed and returned both sets of questionnaires, 26 were allocated to the Paper/Paper group (27%), 20 to the Paper/Internet group (21%), 26 to the Internet/Paper group (27%), and 24 to the Internet/Internet group (25%). The second iteration of questionnaires was returned on time by 69 of the participants (71.2%). Of the late questionnaires, 18 (67%) were paper forms. Overall, no differences were observed between Internet-administered compared with pen and paper-administered questionnaires (P=0.206). No differences were observed within any group individually for either the SRS-30 or PODCI questionnaire. In addition, no significant differences were observed within groups for surveys returned within or outside of the 4-week timeframe. Eighty-four percent of the participants who completed both paper and Internet versions of the questionnaires reported a preference of the Internet. CONCLUSION: Internet administration of both the SRS-30 and PODCI questionnaires is a valid and reliable method of acquiring health-related quality of life information in this population LEVEL OF EVIDENCE:: Level II-therapeutic study. PMID- 26756989 TI - The POSNA-COUR International Scholar Program. Results of the First 7 Years. AB - BACKGROUND: The Pediatric Orthopedic Society of North America (POSNA)-Children's Orthopedics in Underserved Regions (COUR) International Scholar Program was initiated in 2007 to provide educational opportunities for emerging leaders who treat children with orthopaedic conditions in resource-challenged environments worldwide. Financial support is available each year for 4 to 6 orthopaedic surgeons to attend either the POSNA Annual Meeting or the International Pediatric Orthopedic Symposium. The scholars are also encouraged to visit selected centers for observerships during their trip. Since 2007 there have been 41 international scholars who have participated in the program. We wished to assess the impact of the program and to obtain feedback to improve the experience for future participants. METHODS: A 23-question web-based survey was created and sent to 38 past scholars from 22 countries who have participated in the program by July 2013. The responses were gathered online and the data were analyzed for the 24 (62%) respondents from 18 countries who completed the survey. RESULTS: Of the respondents, 16/24 (66%) reported that their current practice is comprised of at least 75% pediatrics. Twelve of 24 (52%) were fellowship trained in pediatric orthopaedics, typically outside of North America. All scholars found the meeting they attended to be very useful and have subsequently made changes to their clinical practice. Nineteen of 24 (82%) did a premeeting or postmeeting observership. Twenty-two of 24 (92%) participants have remained in contact with POSNA members they met at the meeting, with 86% of respondents stating that they have subsequently consulted POSNA members on management of patients. Sixty-two percent of the scholars had a POSNA member visit them following the scholarship and 29% have since returned to visit POSNA members for further clinical observerships. Twenty-one of 24 (91%) have had the opportunity to share the knowledge they gained with others in their region through lectures, surgical demonstrations, and/or clinical training. A common response from the scholars was that the scholarship program was a truly transformative life experience that provided them with an opportunity to receive the highest quality of professional education. The main challenges that these scholars report are lack of available fellowship/subspecialty training in their region, patients' inability to pay, and excessive physician workload. All of the respondents expressed interest in arranging a POSNA cosponsored regional meeting. CONCLUSIONS: Since 2007, the POSNA-COUR international scholar program has been a fruitful resource for orthopaedists practicing in resource-challenged environments worldwide. It has provided unique training for the scholars and has further enabled them to teach others in their region. The program has thus far succeeded in fostering lasting relationships that have led to continued educational exchanges. LEVEL OF EVIDENCE: Level IV-case series. PMID- 26756990 TI - Evidence of pomegranate methanolic extract in antagonizing the endogenous SERM, 27-hydroxycholesterol. AB - The direct relationship between obesity and breast cancer has been elucidated recently with the identification of a cholesterol derivative 27 hydroxycholesterol (27HC), an endogenous SERM that can act through estrogen receptor (ER)-mediated mechanisms. Our recent research shed light on the possible SERM-like property of methanol extract of pericarp of pomegranate (PME) by using human breast (MCF-7, MDA-MB-231), endometrial (HEC-1A), cervical (SiHa, HeLa), ovarian (SKOV3) cancer cell lines, normal breast fibroblasts (MCF-10A) and also by in vivo models (ovariectomized Swiss albino mice). Our findings demonstrated that PME binds to ER and downregulates the Estrogen response elements (ERE) mediated transcription in breast cancer cells without being agonistic in the uterine endometrium and has cardioprotective effects comparable to that of 17 beta-estradiol. This preliminary work indicates the ability of PME to antagonize the activity of 27HC. We hypothesize that PME can compete with 27HC for ERalpha and reduce 27HC-induced proliferation of MCF-7 cells. Relevant estrogen-regulated genes such as pS2, PR and ERalpha were checked to evaluate the ability of PME to abrogate 27HC-induced genes. This study is significant, being the first report describing that bioactive components of the methanolic extract of pericarp of PME, a proven SERM could plausibly compete for 27HC. PMID- 26756991 TI - Results of Renal Transplantation on Alloplastic Arterial Grafts. AB - BACKGROUND: The aim of this retrospective study was to report results of a consecutive series of kidney transplant patients in whom the renal artery was implanted on a prosthetic vascular graft (PVG). METHODS: Between January 2011 and December 2014, 208 deceased donor renal transplantations (68 female, 140 male, mean age 52, SD 16 years) were performed. Medical charts and outpatient clinical records of patients who had undergone renal artery implantation on a PVG were reviewed. Extensive literature research added to our 4 patients further 170 published cases during 1989 and 2015 and was compared with regular transplanted patients. Data on patient characteristics, prior vascular procedures, postoperative and long-term outcome were collected. RESULTS: Patients with transplant renal artery anastomosis on a PVG were 4 years older than the control group. Function of the graft was similar in these patients compared to regular renal transplant patients. Resistance indices assessed in our clinic over the entire follow-up period showed also no significant difference between the 2 groups. Thirty-day mortality was 6% (none in our group), which occurred mostly in combination when renal transplantation and PVG replacement was performed simultaneously. CONCLUSION: Grafting of the renal artery to a PVG is feasible and yields good results, despite the technical difficulties involved. PMID- 26756993 TI - Human Activity Dampens the Benefits of Group Size on Vigilance in Khulan (Equus hemionus) in Western China. AB - Animals receive anti-predator benefits from social behavior. As part of a group, individuals spend less time being vigilant, and vigilance decreases with increasing group size. This phenomenon, called "the many-eyes effect", together with the "encounter dilution effect", is considered among the most important factors determining individual vigilance behavior. However, in addition to group size, other social and environmental factors also influence the degree of vigilance, including disturbance from human activities. In our study, we examined vigilance behavior of Khulans (Equus hemionus) in the Xinjiang Province in western China to test whether and how human disturbance and group size affect vigilance. According to our results, Khulan showed a negative correlation between group size and the percentage time spent vigilant, although this negative correlation depended on the groups' disturbance level. Khulan in the more disturbed area had a dampened benefit from increases in group size, compared to those in the undisturbed core areas. Provision of continuous areas of high quality habitat for Khulans will allow them to form larger undisturbed aggregations and to gain foraging benefits through reduced individual vigilance, as well as anti-predator benefits through increased probability of predator detection. PMID- 26756992 TI - Resuscitating the Dying Autopsy. PMID- 26756994 TI - Use of Lean methodology to improve operating room efficiency in hospitals across the Kingdom of Saudi Arabia. AB - OBJECTIVE: The objective of this study was to assess whether an intervention on process efficiency using the Lean methodology leads to improved utilization of the operating room (OR), as measured by key performance metrics of OR efficiency. DESIGN: A quasi-experimental design was used to test the impact of the intervention by comparing pre-intervention and post-intervention data on five key performance indicators. SETTING: The ORs of 12 hospitals were selected across regions of the Kingdom of Saudi Arabia (KSA). PARTICIPANTS: The participants were patients treated at these hospitals during the study period. INTERVENTION(S): The intervention comprised the following: (i) creation of visual dashboards that enable starting the first case on time; (ii) use of computerized surgical list management; (iii) optimization of time allocation; (iv) development of an operating model with policies and procedures for the pre-anesthesia clinic; and (iv) creation of a governance structure with policies and procedures for day surgeries. MAIN OUTCOME MEASURE(S): The following were the main outcome measures: on-time start for the first case, room turnover times, percent of overrun cases, average weekly procedure volume and OR utilization. RESULTS: The hospital exhibited statistically significant improvements in the following performance metrics: on-time start for the first case, room turnover times and percent of overrun cases. A statistically significant difference in OR utilization or average weekly procedure volumes was not detected. CONCLUSIONS: The implementation of a Lean-based intervention targeting process efficiency applied in ORs across various KSA hospitals resulted in encouraging results on some metrics at some sites, suggesting that the approach has the potential to produce significant benefit in the future. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26756995 TI - The better, the bigger: The effect of graded positive performance feedback on the reward positivity. AB - In this study on skill acquisition in a computerized throwing task, we examined the effect of graded correct-related performance feedback on the reward positivity of the event-related brain potential (ERP). Theories of reinforcement learning predict effects of reward magnitude and expectancy on the reward prediction error. The later is supposed to be reflected in reward positivity, a fronto-central ERP component. A sample of 68 participants learned to throw at a beamer-projected target disk while performance accuracy, displayed as the place of impact of the projectile on the target, served as graded feedback. Effects of performance accuracy in successful trials, hit frequency, and preceding trial performance on reward positivity were analyzed simultaneously on a trial-by-trial basis by means of linear mixed models. In accord with previous findings, reward positivity increased with feedback about more accurate performance. This relationship was not linear, but cubic, with larger impact of feedback towards the end of the accuracy distribution. In line with being a measure of expectancy, the reward positivity decreased with increasing hit frequency and was larger after unsuccessful trials. The effect of hit frequency was more pronounced following successful trials. These results indicate a fast trial-by-trial adaptation of expectation. The results confirm predictions of reinforcement learning theory and extend previous findings on reward magnitude to the area of complex, goal directed skill acquisition. PMID- 26756996 TI - Hepatic miR-126 is a potential plasma biomarker for detection of hepatitis B virus infected hepatocellular carcinoma. AB - Controversies about the origin of circulating miRNAs have encouraged us to identify organ specific circulating miRNAs as disease biomarkers. To identify liver-specific miRNAs for hepatocellular carcinoma (HCC), global expression profiling of miRNAs in liver tissue of HBV-HCC and HBV-control with no or mild fibrosis was evaluated. A total of 40 differentially expressed miRNAs were identified in HCC. Among ten highly altered miRNAs, six miRNAs were successfully validated in tissues, whereas only two miRNAs, miR-126 and miR-142-3p showed increased expression in plasma of HBV-HCC compared to HBV-non-HCC patients. Subsequently, ROC curve analysis revealed that neither miR-126 nor miR-142-3p performed better than AFP in discriminating HCC from non-HCC while combination of each with AFP showed significantly higher efficiency rather than AFP alone (AUC: 0.922, 0.908 vs. 0.88; sensitivity: 0.84, 0.86 vs. 0.82 and specificity: 0.92, 0.94 vs. 0.86 respectively). Interestingly, triple combination of markers (miR 126 + miR-142-3p + AFP) showed no additive effect on efficiency (AUC: 0.925) over the dual combination. Again, the expression of only miR-126 was noticed significantly higher in HBV-HCC patients with low-AFP [<250 ng/ml] compared to either non-HCC or liver cirrhosis (AUC: 0.77, 0.64, respectively). Furthermore, no alteration in expression of mir-126 in HCV-HCC or non-viral-HCC revealed that miR-126 + AFP might be specific to HBV-HCC. To understand the physiological role of these two miRNAs in hepato-carcinogenesis, target genes related to cancer pathways (APAF1, APC2, CDKN2A, IRS1, CRKL, LIFR, EGR2) were verified. Thus, combination of circulating miR-126 + AFP is a promising noninvasive diagnostic biomarker for HBV-HCC and may be useful in the management of HCC patients. PMID- 26756998 TI - Expression of Beclin-1, an autophagy-related marker, in chronic hepatitis and hepatocellular carcinoma and its relation with apoptotic markers. AB - Hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors in worldwide. Multiple precancerous factors, including infection with hepatitis C virus (HCV), have been studied extensively. Autophagy is a highly regulated process, involved in the turnover of damaged organelles. The relationship between apoptosis and autophagy is still a debated topic especially in HCC. This study aimed to investigate the expression of beclin-1 in chronic hepatitis and HCC and its relation with apoptotic markers. The study included the following: 20 chronic HCV hepatitis cases (first group), 35 HCC cases (second group), and 10 normal tissues as control (third group). All were stained for anti-beclin-1, Bcl-2, Bcl XL, and Bax antibodies. A significant positive correlation was found between beclin-1 and Bcl-2 among the first group. While a significant inverse correlation was found between them in the second group. A positive correlation was found between beclin-1 and Bcl-XL expression in the first and the second groups. Also positive significant correlations were identified between beclin-1 and Bax in the first and the second groups. Autophagy and apoptosis in the liver are interrelated processes. The high levels of beclin-1 observed in hepatitis may suggest a central role that may limit liver damage and interact with progression to cancer where beclin-1 later on becomes suppressed in aggressive HCC cases. So defective autophagy synergized with defective apoptosis may facilitate tumor progression. Knowledge of the role of autophagic molecules together with apoptotic markers in HCC could lead to improved treatment efficacy and overall prognosis. PMID- 26756999 TI - A Cross-Sectional Cohort Study of Cerebrovascular Disease and Late Effects After Radiation Therapy for Craniopharyngioma. AB - BACKGROUND: The study objective was to describe radiation-induced vascular abnormalities, stroke prevalence, and stroke risk factors in survivors of childhood craniopharyngioma. PROCEDURE: Twenty survivors of childhood craniopharyngioma who received radiotherapy (RT) were included in the study. A clinical history, quality of life assessment, cognitive functioning assessment, magnetic resonance angiogram or computed tomography angiogram, fasting lipid profile, and fasting glucose or hemoglobin A1c test were obtained. RESULTS: Median age at diagnosis was 10.3 years and median age at time of study was 29.0 years. Vascular abnormalities were detected in six (32%) of 19 patients' angiograms (vascular stenosis, decreased artery size, aneurysm, cavernoma, and small vessel disease). Five (25%) of 20 patients experienced a stroke after RT. Median time since RT was 27.8 versus 9.1 years in patients with versus without vascular abnormalities (P = 0.02). A low level of high-density lipoproteiin (HDL) was present in 100% (5/5) of patients who had a post-RT stroke as compared with 13% (2/15) of patients who did not have any post-RT stroke (P = 0.02). Previous stroke had occurred in 0% (0/5) of patients receiving growth hormone (GH) replacement at the time of study, compared to 40% (6/15) of patients who were not receiving GH replacement (P = 0.09). CONCLUSIONS: Patients with craniopharyngioma treated with RT have a high prevalence of stroke and vascular abnormalities, particularly those with low HDL and longer duration of time since RT. There is a trend to suggest that continual GH replacement may reduce the risk of stroke. These patients should undergo careful monitoring and aggressive modification of stroke risk factors. PMID- 26757000 TI - Greenhouse Gas and Noxious Emissions from Dual Fuel Diesel and Natural Gas Heavy Goods Vehicles. AB - Dual fuel diesel and natural gas heavy goods vehicles (HGVs) operate on a combination of the two fuels simultaneously. By substituting diesel for natural gas, vehicle operators can benefit from reduced fuel costs and as natural gas has a lower CO2 intensity compared to diesel, dual fuel HGVs have the potential to reduce greenhouse gas (GHG) emissions from the freight sector. In this study, energy consumption, greenhouse gas and noxious emissions for five after-market dual fuel configurations of two vehicle platforms are compared relative to their diesel-only baseline values over transient and steady state testing. Over a transient cycle, CO2 emissions are reduced by up to 9%; however, methane (CH4) emissions due to incomplete combustion lead to CO2e emissions that are 50-127% higher than the equivalent diesel vehicle. Oxidation catalysts evaluated on the vehicles at steady state reduced CH4 emissions by at most 15% at exhaust gas temperatures representative of transient conditions. This study highlights that control of CH4 emissions and improved control of in-cylinder CH4 combustion are required to reduce total GHG emissions of dual fuel HGVs relative to diesel vehicles. PMID- 26757001 TI - Bioorthogonal Chemical Reporters for Selective In Situ Probing of Mycomembrane Components in Mycobacteria. AB - The global pathogen Mycobacterium tuberculosis and other species in the suborder Corynebacterineae possess a distinctive outer membrane called the mycomembrane (MM). The MM is composed of mycolic acids, which are either covalently linked to an underlying arabinogalactan layer or incorporated into trehalose glycolipids that associate with the MM non-covalently. These structures are generated through a process called mycolylation, which is central to mycobacterial physiology and pathogenesis and is an important target for tuberculosis drug development. Current approaches to investigating mycolylation rely on arduous analytical methods that occur outside the context of a whole cell. Herein, we describe mycobacteria-specific chemical reporters that can selectively probe either covalent arabinogalactan mycolates or non-covalent trehalose mycolates in live mycobacteria. These probes, in conjunction with bioorthogonal chemistry, enable selective in situ detection of the major MM components. PMID- 26757002 TI - Evaluation of caffeine and the development of necrotizing enterocolitis. AB - OBJECTIVE: To test the association between medical or surgical necrotizing enterocolitis (NEC) and caffeine administration in premature infants. STUDY DESIGN: This single-center, retrospective study evaluated patients admitted to a level 3 neonatal intensive care unit (NICU) over an 18-month period. All patients were evaluated for factors associated with the development of NEC including exposure to caffeine (dosing and duration), gestational age, birth weight, vasoactive medications and maternal illicit drug use. RESULTS: There were 615 subjects included in the study; among these subjects, 7.3% (n = 45) developed NEC (35 subjects receiving caffeine and 10 subjects not receiving caffeine). The administration of caffeine (p = 0.008), birth weight (p = 0.014) and the use of vasopressors (p = 0.033) were associated with the development of NEC. When considering only infants with a birth weight less than 1500 g and less than 32 weeks gestation, the effects of caffeine and vasopressor use remained statistically significant (p = 0.047 and p = 0.045, respectively). The time to development of NEC did not differ statistically between patients receiving caffeine and those not receiving caffeine (p = 0.129). CONCLUSION: A potential association between the administration of caffeine and the development of medical or surgical necrotizing enterocolitis in premature infants exists. Further investigation of dose-dependent effects and loading doses is warranted. PMID- 26757003 TI - Improving neonatal complications with a structured multidisciplinary approach to gestational diabetes mellitus management. AB - BACKGROUND: Gestational Diabetes Mellitus (GDM) is a common condition that affects pregnant women and may result in maternal as well as fetal and neonatal complications. Optimal coordinated management may reduce these complications if applied in team approach following generally accepted international guidelines. METHODS: A retrospective analysis of the neonatal outcomes of GDM mothers who were followed in a tertiary medical center in the United Arab Emirates. The aim of the study was to assess the efficacy of a comprehensive and multidisciplinary GDM program which was applied to a quality improvement project. Clinical neonatal outcome indicators were compared at two time periods, one before the implementation in (2005-2006) and the other was following the initiation of this comprehensive multidisciplinary program in (2011-2012). RESULTS: Follow up results revealed increased caesarian section and admission to neonatal intensive care unit. There was decreased incidence of macrosomia and a significant reduction of neonatal hypoglycemia in the newborn of GDM mothers. Overall rate of neonatal complications showed a significant improvement. CONCLUSIONS: Implementing a structured comprehensive multidisciplinary program to manage GDM women has a positive impact on improving the care and outcomes of neonates. PMID- 26757004 TI - Resting energy expenditure, macronutrient utilization, and body composition in term infants after corrective surgery of major congenital anomalies: A case study. AB - INTRODUCTION: Knowledge on the metabolic changes and nutritional needs during the postsurgical anabolic phase in infants is scarce. This analysis explores the associations of resting energy expenditure (REE) and macronutrient utilization with body composition of full-term infants, during catch-up growth after corrective surgery of major congenital anomalies. METHODS: A cohort of full-term appropriate for-gestational-age neonates subjected to corrective surgery of major congenital anomalies were recruited after gaining weight for at least one week. REE and macronutrient utilization, measured by respiratory quotient (RQ), were assessed by indirect calorimetry using the Deltatrac II Metabolic Monitor (r). Body composition, expressed as fat-free mass (FFM), fat mass (FM) and adiposity defined as percentage of FM (% FM), was measured by air displacement plethysmography using the Pea Pod (r). RESULTS: Four infants were included at 3 to 5 postnatal weeks. Recommended energy and macronutrient intakes for healthy term infants were provided. Through the study, the median (min-max) REE (Kcal/Kg FFM/d) was 70.8 (60.6-96.1) and RQ was 0.99 (0.72-1.20). Steady increases in both body weight and FFM were associated with initial decrease in FM and adiposity followed by their increase. Low RQ preceded decrease in adiposity. CONCLUSION: The marked adiposity depletion, not expected during steady weight gain in the postsurgical period, prompts us to report this finding. The subsequent adiposity catch-up was associated with relatively high REE and RQ, suggesting preferential oxidation of carbohydrates and preservation of lipids for fat storage. PMID- 26757005 TI - Acute kidney injury in ELBW infants (< 750 grams) and its associated risk factors. AB - BACKGROUND: The advancement of neonatology over the past 20 years has allowed a greater number of ELBW infants to survive. However, these advancements have contributed to the increased incidence of acute kidney injury (AKI) seen in this population. Understanding the risk factors for AKI in this population of ELBW infants is imperative for the successful survival of these infants since the morbidity and mortality rates from this disease are increasing. OBJECTIVES: 1) to determine the prevalence of AKI in ELBW (< 750 grams). 2) to compare the mortality rate of ELBW infants (< 750 grams) with and without AKI; and 3) to identify the associated risk factors of AKI in ELBW infants (< 750 grams). METHODS: A retrospective chart review of all infants with AKI as defined by AKIN criterias, admitted to the NICU between 1998 and 2008 was conducted. Case controls were matched for BW, gestational age and date of birth, (SPSS v17.0 software, using Student's t test, X2 test, and Mann-Whitney U test were used for statistical analysis. CONCLUSION: The prevalence rate of ELBW infants (< 750 grams) with AKI admitted at CHMCA NICU from 1998 to 2008 was 26% . The mortality rate of ELBW infants (< 750 grams) with AKI was 54% , compared to 20% in those ELBW infants who did not have AKI. The associated risk factors of AKI in the ELBW infants (< 750 grams) were as follows: presence of maternal placental abruption/bleeding, grade III or IV IVH, PDA, positive culture/s, NEC, use of steroid, nephrotoxic drugs, and longer use of the ventilator and TPN. PMID- 26757006 TI - Genital injuries in neonates following breech presentation. AB - Breech presentation is seen in 3-4% of babies born. Delivering a breech baby through vaginal route is difficult and carries a much higher complication rate than cesarean sections. Breech born babies carry an overall increased risk of maternal morbidity, neonatal mortality, birth asphyxia and birth injuries. Various types of birth injuries to the babies have been reported following breech delivery, but genital injuries are less commonly reported and thus, less anticipated. We report series of five babies with spectrum of genital injuries following breech delivery. These injuries led to significant short and long term morbidity in these babies. Keeping high index of suspicion, an early cesarean section can be an aide in preventing these complications. Once the baby is born, careful examination and early intervention should be done to prevent long term complications. PMID- 26757007 TI - High flow nasal heliox improves work of breathing and attenuates lung injury in a newborn porcine lung injury model. AB - BACKGROUND: High flow nasal cannula (HFNC) has been shown to improve ventilation and oxygenation and reduce work of breathing in newborns with respiratory distress. Heliox, decreases resistance to airflow, reduces the work of breathing, facilitates the distribution of inspired gas, and has been shown to attenuate lung inflammation during the treatment of acute lung injury. HYPOTHESIS: Heliox delivered by HFNC will decrease resistive load, decrease work of breathing, improve ventilation and attenuate lung inflammation during spontaneous breathing following acute lung injury in the newborn pig. METHODS: Spontaneously breathing neonatal pigs received Nitrox or Heliox by HFNC and studied over 4 hrs following oleic acid injury. Gas exchange, pulmonary mechanics and systemic inflammation were measured serially. Lung inflammation biomarkers were assessed at termination. RESULTS: Heliox breathing animals demonstrated lower work of breathing reflected by lower tracheal pressure, phase angle and phase relationship. Ventilation efficiency index was greater compared to Nitrox. Heliox group showed less lung inflammation reflected by lower tissue interleukin-6 and 8. CONCLUSION: High flow nasal Heliox decreased respiratory load, reduced resistive work of breathing indices and attenuated lung inflammatory profile while ventilation was supported at less pressure effort in the presence of acute lung injury. PMID- 26757008 TI - Safety and efficacy of delayed umbilical cord clamping in multiple and singleton premature infants - A quality improvement study. AB - OBJECTIVES: To evaluate the safety and efficacy of a quality improvement (QI) program of delayed umbilical cord clamping (DCC) in multiple and singleton preterm infants born at our center. METHODS: After DCC protocol implementation, compliance and success rate were assessed. Clinical outcomes of selected 150 preterm infants <34 weeks gestation born in 2014 after protocol implementation (Epoch II) were compared to those of preterm infants born in 2013 before protocol implementation (Epoch I). RESULTS: Overall protocol compliance rate was 92% (246/267). DCC was successfully performed in 77% (205/267) after protocol implementation. There were higher multiple births in Epoch II compared to Epoch I (27.3 vs. 15.3% , p < 0.01). At birth, infants in Epoch II had significantly decreased need for intubation in delivery room (23.3 vs. 39.3% , p < 0.01), had higher hematocrit (46.4+/-7.3 vs. 44.0+/-7.1% , p < 0.01) and less metabolic acidosis (base excess -4.1+/-2.7 vs. -5.3+/-4.2 mmol/L, p < 0.01) compared to those born in Epoch I. During hospital stay, fewer infants in Epoch II received rescue surfactant therapy (45.3 vs. 56.7% , p = 0.05), medical treatment for PDA (6.7 vs. 16.6% , p = 0.04%) and red blood cell transfusions (20.7 VS. 32.0% , p < 0.01) compared to Epoch I. CONCLUSIONS: Protocol-guided practice of DCC for 30 seconds can be safely performed in multiple and singleton preterm infants. In addition to higher initial hematocrit, infants in our QI project had lower need for delivery room resuscitation and less metabolic acidosis at birth. We also observed decreased need for rescue surfactant therapy, medical treatment for PDA and red blood cell transfusions after DCC protocol implementation. PMID- 26757009 TI - Assessment of the severity of visible blood in the stool using a cluster of neonatal cases -a quality improvement study. AB - BACKGROUND: Non-availability of an established validated tool to assess and monitor the severity of visible blood in a stool (VBS) specimen over time, prevents effective decision making about discontinuation of contact precautions and hospital discharge. OBJECTIVE: To determine the impact of implementing a VBS investigation, parent apprisal template and Visible Blood in the Stool Assessment Tool (VBS-AT) on standardized reporting and the evaluation of clinical improvement. METHODS: A prospective quality improvement cohort study was conducted in a tertiary, neonatal unit. All infants with isolated VBS without clinical signs, radiological pneumatosis and abnormal laboratory results were included. The template and VBS-AT instrument were implemented at the bedside. Criteria for discontinuation of contact precautions and readiness for discharge home were defined apriori. RESULTS: Eight infants developed VBS during the cluster lasting ten days. Seventy-four (78%) of the 98 episodes were graded by the VBS-AT. Five of the six infants had a maximum VBS grade of 3. The duration of VBS and contact precautions ranged from 4-38 days. All six infants with a VBS grade <=2 for 4 consecutive days did not deteriorate beyond grade >=3 or develop gastrointestinal complications during the ten week period following the end of the cluster. Consistent objective reporting of the severity of VBS and consistent evaluation of infants' progress over time contained the cluster effectively and facilitated discharge of stable infants. CONCLUSIONS: Implementation of a tool to standardize, investigate and objectively monitor the severity of VBS is feasible and improves effectiveness of care at no extra cost. PMID- 26757010 TI - Vitamin K antagonist therapy and liver transplantation: two cases managed without normalizing the international normalized ratio. AB - Guidelines for surgery in patients treated with vitamin K antagonist recommends to correct international normalized ratio (INR), although they do not focus on liver transplantation candidates. We report two patients treated with vitamin K antagonist, monitored by thromboelastometry during liver transplantation. Case 1: basal INR was 3.15. Extem coagulation time was 83 s and maxim clot firmness was 60 mm. The surgical procedure did not show bleeding. Two red blood cells were transfused and no other blood products were administered. Last INR was 3.17. Case 2: basal INR was 2.79. A thrombocytopenia of 58 000/mm was detected. Extem coagulation time was 176 s, and maxim clot firmness was 40 mm. Fibtem maxim clot firmness was 11 mm. The surgical procedure did not show bleeding. No blood product was administered. Last INR was 2.1. Although thromboelastometry did not correlate with INR, monitoring of the coagulation using thromboelastometry in combination with surgery helped to conduct hemostatic corrections. PMID- 26757011 TI - Prospective evaluation of ADAMTS-13 and von Willebrand factor multimers in cardiac surgery. AB - Acquired thrombotic-thrombocytopenic purpura, one of the main representatives of thrombotic microangiopathies (TMAs), is caused by the accumulation of antibodies against ADAMTS-13. Several cases of postoperative TMAs have been observed during the past few years, but the pathogenesis remains unknown. In addition to this, it is unclear whether the use of extracorporeal circulation (ECC) during cardiac surgery has an influence on the occurrence of cardiac surgery-associated TMA. In this study, we investigated the relationship between ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs 13), ADAMTS-13 inhibitor, von Willebrand factor (VWF) and large VWF multimers in cardiac surgery with and without the use of ECC. Blood samples were taken preoperatively, intraoperatively and up to 6 days postoperatively. A total of 47 patients (median age 70 years, 18 women, 29 men) undergoing cardiac surgery were included; cardiac surgery with the use of ECC (cardiopulmonary bypass) was used in 39 patients, and the off-pump coronary artery bypass technique was used in eight patients. TMA was not diagnosed in any of the patients. Cardiac surgery led to a significantly reduced ADAMTS-13 activity (from 67 to 51%, P < 0.001 in the cardiopulmonary bypass group, from 64 to 48%, P = 0.02 in the off-pump coronary artery bypass group) and higher amounts of large VWF multimers. Development of ADAMTS-13 antibodies was not induced by cardiac surgery. Cardiac surgery led to a slight but significant decrease of ADAMTS-13, but this decrease was not associated with TMA. PMID- 26757012 TI - An in-vitro evaluation of direct thrombin inhibitor and factor Xa inhibitor on tissue factor-induced thrombin generation and platelet aggregation: a comparison of dabigatran and rivaroxaban. AB - Dabigatran and rivaroxaban may simultaneously inhibit coagulation and platelet activation. This study aimed to reveal the in-vitro effects of dabigatran and rivaroxaban on thrombin generation and platelet aggregation (PAg) derived via tissue factor (TF) pathway. Citrated blood was obtained from six healthy adults (26-60 years old) and pretreated with increasing concentrations of dabigatran or rivaroxaban. Plasmatic endogenous thrombin potential (ETP) was measured by the calibrated automated thrombogram method. The whole blood PAg was evaluated via a kinetic counting method. TF produced an ETP of 1904.69 +/- 121.42 nmol min and a PAg of 78 +/- 5%. Dabigatran and rivaroxaban concentration-dependently reduced ETP with half-maximal inhibitory concentrations of 460.1 +/- 1.4 and 678.1 +/- 1.4 nmol/l, and inhibited PAg with half-maximal inhibitory concentrations of 119.5 +/- 1.5 and 77.5 +/- 1.6 nmol, respectively. Dabigatran and rivaroxaban significantly inhibit TF-induced hypercoagulation and platelet activation in vitro in a concentration-dependent manner. Rivaroxaban displays stronger inhibition on thrombin generation and PAg than dabigatran. PMID- 26757013 TI - Novel method using rotational thromboelastography analysis for intraoperative management of device patient with heparin-induced thrombocytopenia. AB - Heparin-induced thrombocytopenia (HIT) is a prothrombotic disease in response to previous heparin exposure. Direct thrombin inhibitors are suitable candidates for the prophylaxis of thrombosis in patients with HIT. Currently activated clotting time and activated partial thromboplastin time are used to guide dosing and monitor anticoagulation. These assays provide a measure of clot initiation and only account for a small fraction of the coagulation pathway. In this case study we performed rotational thromboelastography (ROTEM) analysis on a patient with HIT implanted with a continuous-flow CentriMag device for left ventricular support. ROTEM evaluation confirmed a decline in activated clotting time values and provided further information regarding intrinsic and extrinsic clotting times. Monitoring ROTEM parameters aided in the detection of coagulopathies and the decision to administer platelet or fresh frozen plasma products. Utilizing ROTEM can guide clinical decisions in transfusions, particularly in patients with HIT, where platelet and fibrinogen levels can be safely maintained to prevent thrombosis. PMID- 26757014 TI - Thrombotic risk of reduced ADAMTS13 activity in patients with antiphospholipid antibodies. AB - Antiphospholipid syndrome (APS) is an autoimmune disease in which antiphospholipid antibodies (aPLs) are generated. Previous studies show concurrence of APS and thrombotic thrombocytopenic purpura; therefore it is plausible to assume that anti-ADAMTS13 autoantibody is also involved in the pathophysiology of APS. We investigated the clinical significance of ADAMTS13 activity and anti-ADAMTS13 antibody in patients with aPLs. Two hundred and sixteen patients with positive lupus anticoagulant and/or anticardiolipin antibody were included. ADAMTS13 activity and anti-ADAMTS13 antibody were measured using fluorescence resonance energy-transfer technology and ELISA, respectively. Reduced ADAMTS13 activity was observed in 40.3% (87/216) of patients with aPLs. Although 33.8% (73/216) of patients were positive for anti ADAMTS13 antibody, 41 of these 73 patients had normal levels of ADAMTS13 activity. Reduced ADAMTS13 activity was a significant risk factor for thrombotic events. Thrombotic events and age contributed to the reduced level of ADAMTS13 activity. Presence of anti-ADAMTS13 antibody did not show any association with the level of ADAMTS13 activity. Patients with autoimmune diseases tended to show higher levels of anti-ADAMTS13 antibody. Our findings suggest that reduced ADAMTS13 activity is a significant thrombotic risk factor in patients with aPLs irrespective of the presence of anti-ADAMTS13 antibody. Presence of anti-ADAMTS13 antibody is not seen with reduced activity and it tends to be increased in patients with autoimmune diseases. PMID- 26757015 TI - Management of pregnancy in dysfibrinogenemia cases: a dilemma. AB - Dysfibrinogenemia is a very challenging disorder, and there are no firm guidelines on treatment for pregnant patients with dysfibrinogenemia. A 37-year old patient with a history of six unexplained recurrent miscarriages was referred for thrombophilia testing. Elevated procoagulant microparticles were found, for which during her seventh pregnancy anticoagulant therapy was initiated. However, she again miscarried and bled excessively. She was then diagnosed with dysfibrinogenemia. DNA sequence analysis revealed a novel homozygous insertion deletion in exon 7 in FGB. Dysfibrinogenemia is very difficult to diagnose and even after diagnosis, the treatment varies with the patient's symptoms. In this case, anticoagulant therapy failed. With her history of recurrent miscarriages, it is clear that pregnancy without any treatment is not an option. Few reports suggest a combination of intravenous fibrinogen infusions along with anticoagulants in which successful pregnancy outcome was achieved. The present case thus stresses on the need for some treatment guidelines in such cases. PMID- 26757016 TI - Acute myocardial infarction as the initial thrombotic event of thrombotic thrombocytopenic purpura. AB - Acquired thrombotic thrombocytopenic purpura (TTP) is characterized by the coemergence of microangiopathic hemolytic anemia, thrombocytopenia, and thrombosis-mediated ischemic injuries of various organs, such as the central nervous system and kidneys. Acute myocardial infarction (AMI) has also occasionally been reported as a complication with TTP as the secondary thrombotic event; however, its emergence as the initial thrombotic event in TTP is extremely rare. This report describes an 80-year-old male patient with acquired TTP, who was affected by AMI without any clinically apparent damage to other organs or abnormal laboratory findings that would be suggestive of TTP at the first presentation. Although AMI was successfully treated by percutaneous coronary intervention (PCI), the patient developed marked thrombocytopenia with acute kidney injury and hemolytic anemia 5 days after PCI. The patient was diagnosed as having acquired TTP based on decreased ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13) below the level of detection and the presence of the inhibitor against ADAMTS13, and eventually died of multiorgan failure due to TTP despite undergoing repeated plasma exchanges and immunosuppressive therapies, including corticosteroid and rituximab. Although caution is often paid to therapy-related thrombocytopenia or renal damage after PCI, that is, those caused by antiplatelet drugs, heparin, or contrast agents, our report alerts us to the presence of TTP as an extremely rare, but underlying cause for AMI that could be subclinical at the initial presentation. PMID- 26757017 TI - Boosting the coagulation restores haemostasis in ticagrelor-treated mice. AB - Antiplatelet therapy is given to patients with acute coronary syndrome to reduce the risk for thrombotic events, but may increase the risk for bleeding. Ticagrelor was administered intravenously to mice. Cumulative blood loss and bleeding time were measured after cutting 5 mm of the tail, 20 min after the start of ticagrelor infusion. The tail was placed in a hemoglobin-sensitive device measuring light absorbance (abs) over time for 35 min. Activated recombinant human factor VII (rhFVIIa; NovoSeven; NovoNordisk A/S, Bagsvaerd, Denmark) 1 mg/kg (study 1); recombinant human prothrombin (rhFII, MEDI8111) 10 mg/kg (study 2); or vehicle was given intravenously once bleeding had commenced, within 90s after tail cut. Ticagrelor resulted in more than 98% inhibition of ex vivo ADP-induced platelet aggregation. In study 1, the median blood loss in the ticagrelor, vehicle, and rhFVIIa groups were 909, 122, and 397 abs*s, respectively (P < 0.05 for both comparisons, including the ticagrelor group). Similar pattern was seen for bleeding time. The median bleeding time in the ticagrelor, vehicle, and rhFVIIa groups were 2003, 449, and 884s, respectively (P < 0.05 for both comparisons, including the ticagrelor group). In study 2, the median blood loss and bleeding time in the ticagrelor group were 362 abs*s and 1847s. The corresponding numbers for the vehicle and rhFII groups were 71 abs*s and 613s, and 178 abs*s and 701s, respectively (P < 0.05 for comparisons between ticagrelor and vehicle for both blood loss and bleeding time). In mice dosed to complete P2Y12 inhibition, boosting coagulation by administration of rhFVIIa or rhFII within 90s after bleeding initiation can partly reverse ticagrelor-enhanced bleeding. PMID- 26757018 TI - Incremental value of hormonal therapy for deep vein thrombosis prediction: an adjusted Wells score for women. AB - Deep venous thrombosis (DVT) management includes prediction rule evaluation to define standard pretest DVT probabilities in symptomatic patients. The aim of this study was to evaluate the incremental usefulness of hormonal therapy to the Wells prediction rules for DVT in women. We studied women undertaking compressive ultrasound scanning for suspected DVT. We adjusted the Wells score for DVT, taking into account the beta-coefficients of the logistic regression model. Data discrimination was evaluated by the receiver operating characteristic (ROC) curve. The adjusted score calibration was assessed graphically and by the Hosmer Lemeshow test. Reclassification tables and the net reclassification index were used for the adjusted score comparison with the Wells score for DVT. We observed 461 women including 103 DVT events. The mean age was 56 years (+/-21 years). The adjusted logistic regression model included hormonal therapy and six Wells prediction rules for DVT. The adjusted score weights ranged from -4 to 4. Hosmer Lemeshow test showed a nonsignificant P value (0.69) and the calibration graph showed no differences between the expected and the observed values. The area under the ROC curve was 0.92 [95% confidence interval (CI) 0.90-0.95] for the adjusted model and 0.87 (95% CI 0.84-0.91) for the Wells score for DVT (Delong test, P value < 0.01). Net reclassification index for the adjusted score was 0.22 (95% CI 0.11-0.33, P value < 0.01). Our results suggest an incremental usefulness of hormonal therapy as an independent DVT prediction rule in women compared with the Wells score for DVT. The adjusted score must be evaluated in different populations before clinical use. PMID- 26757019 TI - Bioactive Enmein-Type ent-Kaurane Diterpenoids from Isodon phyllostachys. AB - Thirty-two enmein-type ent-kaurane diterpenoids, including 13 new compounds, were isolated from the aerial parts of Isodon phyllostachys. Compounds 1 and 2 are the first examples of 3,20:6,20-diepoxyenmein-type ent-kauranoids, and the structures of these new compounds were established mainly by analyzing NMR and HREIMS data. The absolute configurations of 1 and 8 and the relative configuration of 9 were determined using single-crystal X-ray diffraction. Compounds 11, 15, 20, and 21 were active against five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW-480), with IC50 values ranging from 1.2 to 5.0 MUM. Compounds 3, 11, 15, 17, 20, 21, 25, and 29 strongly inhibited NO production in LPS-stimulated RAW264.7 cells, with IC50 values ranging from 0.74 to 4.93 MUM. PMID- 26757020 TI - Prominent efficiency in skin delivery of resveratrol by novel sucrose oleate microemulsion. AB - OBJECTIVES: To achieve an efficient skin delivery of resveratrol using sucrose fatty acid ester microemulsions and to clarify the mechanism of enhanced penetration. METHODS: Skin delivery of resveratrol using different sucrose fatty acid ester microemulsions was examined in vitro. Vehicle-skin interaction was assessed by applying blank microemulsions to skin. Skin incorporation of microemulsion components was also assessed. KEY FINDINGS: The microemulsion consisting of sucrose oleate (SO), ethanol, isopropyl myristate (IPM) and water (MESO-E) showed a prominent increase in the amount of skin incorporation of resveratrol, which was more than 5-fold higher than those of all microemulsions we previously examined. Using MESO-E, resveratrol was rapidly incorporated into skin and mainly located in the dermis. When applied in the concentration range of 5-55 mm, the amount of skin incorporation of resveratrol increased with the applied concentration up to 30 mm, whereas skin incorporation efficiency was inversely proportional to the concentration. The microemulsion-skin interaction seemed to be involved in the enhanced skin delivery process of resveratrol by MESO-E. Stratum corneum modification due to the penetration of IPM, ethanol and SO is also involved in this interaction. CONCLUSIONS: MESO-E would be a promising vehicle for the efficient skin delivery of resveratrol, especially when applied at a low concentration. PMID- 26757023 TI - Genetic engineering and molecular characterization of yeast strain expressing hybrid human-yeast squalene synthase as a tool for anti-cholesterol drug assessment. AB - AIMS: The main objective of the study is molecular and biological characterization of the human-yeast hybrid squalene synthase (SQS), as a promising target for treatment of hypercholesterolaemia. METHODS AND RESULTS: The human-yeast hybrid SQS, with 67% amino acids, including the catalytic site derived from human enzyme, was expressed in Saccharomyces cerevisiae strain deleted of its own SQS gene. The constructed strain has a decreased level of sterols compared to the control strain. The mevalonate pathway and sterol biosynthesis genes are induced and the level of triacylglycerols is increased. Treatment of the strain with rosuvastatin or zaragozic acid, two mevalonate pathway inhibitors, decreased the amounts of squalene, lanosterol and ergosterol, and up-regulated expression of several genes encoding enzymes responsible for biosynthesis of ergosterol precursors. Conversely, expression of the majority genes implicated in the biosynthesis of other mevalonate pathway end products, ubiquinone and dolichol, was down-regulated. CONCLUSIONS: The S. cerevisiae strain constructed in this study enables to investigate the physiological and molecular effects of inhibitors on cell functioning. SIGNIFICANCE AND IMPACT OF THE STUDY: The yeast strain expressing hybrid SQS with the catalytic core of human enzyme is a convenient tool for efficient screening for novel inhibitors of cholesterol-lowering properties. PMID- 26757022 TI - Comparing Cerebralcare Granule and aspirin for neurological dysfunction in acute stroke in real-life practice. AB - BACKGROUND: Cerebralcare Granule (CG) is a polyherbal Chinese medicine that has been shown to have neuroprotective effects in experimental models of stroke. We compared the efficacy and safety of CG with aspirin in patients with acute stroke. METHODS: For this open-label, controlled trial, we recruited patients with angiographically confirmed strokes and US National Institutes of Health Stroke Scale (NIHSS) scores of 4-22 within 2 weeks of symptom onset; recruitment was performed at 55 sites in China. Patients received CG or aspirin. The primary efficacy end-point was neurological function. Analyses were done by intention to treat. Patients were measured for NIHSS, Montreal Cognitive Assessment, and Mini Mental State Examination scores and Barthel index at baseline and at 4, 8, and 12 weeks after treatment. RESULTS: Between January 2013 and January 2014, we treated 1963 patients with CG and 1288 patients with aspirin. Baseline NIHSS, Mini-Mental State Examination, and Montreal Cognitive Assessment scores were comparable between the two groups. Patients in the CG group had a greater improvement than the aspirin group in terms of NIHSS (P < 0.01) and Barthel index at 4, 8, and 12 weeks. At 12 weeks, patients in the CG group had a greater improvement than the aspirin group in terms of Mini-Mental State Examination (P < 0.01) and Montreal Cognitive Assessment (P < 0.05). Adverse reactions were similar between the two groups. CONCLUSIONS: This large-scale, controlled trial indicated that CG may be a useful treatment in the management of post-stroke patients. PMID- 26757024 TI - Determination of continuous complex refractive index dispersion of biotissue based on internal reflection. PMID- 26757025 TI - Contrast enhancement in microscopy of human thyroid tumors by means of acousto optic adaptive spatial filtering. PMID- 26757021 TI - Supplemental Screening for Breast Cancer in Women With Dense Breasts: A Systematic Review for the U.S. Preventive Services Task Force. AB - BACKGROUND: Screening mammography has lower sensitivity and specificity in women with dense breasts, who experience higher breast cancer risk. PURPOSE: To perform a systematic review of reproducibility of Breast Imaging Reporting and Data System (BI-RADS) density categorization and test performance and clinical outcomes of supplemental screening with breast ultrasonography, magnetic resonance imaging (MRI), and digital breast tomosynthesis (DBT) in women with dense breasts and negative mammography results. DATA SOURCES: MEDLINE, PubMed, EMBASE, and Cochrane database from January 2000 to July 2015. STUDY SELECTION: Studies reporting BI-RADS density reproducibility or supplemental screening results for women with dense breasts. DATA EXTRACTION: Quality assessment and abstraction of 24 studies from 7 countries; 6 studies were good-quality. DATA SYNTHESIS: Three good-quality studies reported reproducibility of BI-RADS density; 13% to 19% of women were recategorized between "dense" and "nondense" at subsequent screening. Two good-quality studies reported that sensitivity of ultrasonography for women with negative mammography results ranged from 80% to 83%; specificity, from 86% to 94%; and positive predictive value (PPV), from 3% to 8%. The sensitivity of MRI ranged from 75% to 100%; specificity, from 78% to 94%; and PPV, from 3% to 33% (3 studies). Rates of additional cancer detection with ultrasonography were 4.4 per 1000 examinations (89% to 93% invasive); recall rates were 14%. Use of MRI detected 3.5 to 28.6 additional cancer cases per 1000 examinations (34% to 86% invasive); recall rates were 12% to 24%. Rates of cancer detection with DBT increased by 1.4 to 2.5 per 1000 examinations compared with mammography alone (3 studies). Recall rates ranged from 7% to 11%, compared with 7% to 17% with mammography alone. No studies examined breast cancer outcomes. LIMITATIONS: Good-quality evidence was sparse. Studies were small and CIs were wide. Definitions of recall were absent or inconsistent. CONCLUSION: Density ratings may be recategorized on serial screening mammography. Supplemental screening of women with dense breasts finds additional breast cancer but increases false-positive results. Use of DBT may reduce recall rates. Effects of supplemental screening on breast cancer outcomes remain unclear. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 26757026 TI - Errata: Temperature-controlled laser-soldering system and its clinical application for bonding skin incisions. PMID- 26757027 TI - Coupling and Stacking Order of ReS2 Atomic Layers Revealed by Ultralow-Frequency Raman Spectroscopy. AB - We investigate the ultralow-frequency Raman response of atomically thin ReS2, a special type of two-dimensional (2D) semiconductors with unique distorted 1T structure. Bilayer and few-layer ReS2 exhibit rich Raman spectra at frequencies below 50 cm(-1), where a panoply of interlayer shear and breathing modes are observed. The emergence of these interlayer phonon modes indicate that the ReS2 layers are coupled and orderly stacked. Whereas the interlayer breathing modes behave similarly to those in other 2D layered crystals, the shear modes exhibit distinctive behavior due to the in-plane lattice distortion. In particular, the two shear modes in bilayer ReS2 are nondegenerate and clearly resolved in the Raman spectrum, in contrast to the doubly degenerate shear modes in other 2D materials. By carrying out comprehensive first-principles calculations, we can account for the frequency and Raman intensity of the interlayer modes and determine the stacking order in bilayer ReS2. PMID- 26757028 TI - Crystal structure of archaeal ketopantoate reductase complexed with coenzyme a and 2-oxopantoate provides structural insights into feedback regulation. AB - Coenzyme A (CoA) plays essential roles in a variety of metabolic pathways in all three domains of life. The biosynthesis pathway of CoA is strictly regulated by feedback inhibition. In bacteria and eukaryotes, pantothenate kinase is the target of feedback inhibition by CoA. Recent biochemical studies have identified ketopantoate reductase (KPR), which catalyzes the NAD(P)H-dependent reduction of 2-oxopantoate to pantoate, as a target of the feedback inhibition by CoA in archaea. However, the mechanism for recognition of CoA by KPR is still unknown. Here we report the crystal structure of KPR from Thermococcus kodakarensis in complex with CoA and 2-oxopantoate. CoA occupies the binding site of NAD(P)H, explaining the competitive inhibition by CoA. Our structure reveals a disulfide bond between CoA and Cys84 that indicates an irreversible inhibition upon binding of CoA. The structure also suggests the cooperative binding of CoA and 2 oxopantoate that triggers a conformational closure and seems to facilitate the disulfide bond formation. Our findings provide novel insights into the mechanism that regulates biosynthesis of CoA in archaea. PMID- 26757029 TI - Integrated process for high conversion and high yield protein PEGylation. AB - Over the past decades, PEGylation has become a powerful technique to increase the in vivo circulation half-life of therapeutic proteins while maintaining their activity. The development of new therapeutic proteins is likely to require further improvement of the PEGylation methods to reach even better selectivity and yield for reduced costs. The intensification of the PEGylation process was investigated through the integration of a chromatographic step in order to increase yield and conversion for the production of mono-PEGylated protein. Lysozyme was used as a model protein to demonstrate the feasibility of such approach. In the integrated reaction/separation process, chromatography was used as fractionation technique in order to isolate and recycle the unreacted protein from the PEGylated products. This allows operating the reactor with short reaction times so as to minimize the production of multi-PEGylated proteins (i.e., conjugated to more than one polymer). That is, the reaction is stopped before the desired product (i.e., the mono-PEGylated protein) can further react, thus leading to limited conversion but high yield. The recycling of the unreacted protein was then considered to drive the protein overall conversion to completion. This approach has great potential to improve processes whose yield is limited by the further reaction of the product leading to undesirable by products. Biotechnol. Bioeng. 2016;113: 1711-1718. (c) 2016 Wiley Periodicals, Inc. PMID- 26757030 TI - Partial least squares model and design of experiments toward the analysis of the metabolome of Jatropha gossypifolia leaves: Extraction and chromatographic fingerprint optimization. AB - A major challenge in metabolomic studies is how to extract and analyze an entire metabolome. So far, no single method was able to clearly complete this task in an efficient and reproducible way. In this work we proposed a sequential strategy for the extraction and chromatographic separation of metabolites from leaves Jatropha gossypifolia using a design of experiments and partial least square model. The effect of 14 different solvents on extraction process was evaluated and an optimized separation condition on liquid chromatography was estimated considering mobile phase composition and analysis time. The initial conditions of extraction using methanol and separation in 30 min between 5 and 100% water/methanol (1:1 v/v) with 0.1% of acetic acid, 20 MUL sample volume, 3.0 mL min(-1) flow rate and 25 degrees C column temperature led to 107 chromatographic peaks. After the optimization strategy using i-propanol/chloroform (1:1 v/v) for extraction, linear gradient elution of 60 min between 5 and 100% water/(acetonitrile/methanol 68:32 v/v with 0.1% of acetic acid), 30 MUL sample volume, 2.0 mL min(-1) flow rate, and 30 degrees C column temperature, we detected 140 chromatographic peaks, 30.84% more peaks compared to initial method. This is a reliable strategy using a limited number of experiments for metabolomics protocols. PMID- 26757031 TI - High-Strength Carbon Nanotube Film from Improving Alignment and Densification. AB - A new method is reported for preparing carbon nanotube (CNT) films. This method involves the continuous production of a hollow cylindrical CNT assembly and its condensation on a winding drum. The alignment and densification of CNTs in the film are improved by controlling the winding rate and imposition of mechanical rolling, respectively. The prepared film has a strength of 9.6 GPa, which is well above those for all other man-made films and fibers. PMID- 26757032 TI - Organized Sports and Unstructured Active Play as Physical Activity Sources in Children From Low-Income, Chicago Households. AB - PURPOSE: This study tested associations of organized sports participation and unstructured active play with overall moderate and vigorous physical activity (MVPA) in low-income children and examined factors associated with participation frequency. METHOD: Research staff visited 88 low-income Chicago households with children ages 6-13 years. MVPA was assessed through 7-day accelerometry. Researchers documented the home availability of physical activity equipment. Caregivers reported on child participation in organized sports and unstructured active play, family support for physical activity, perceived neighborhood safety, and access to neighborhood physical activity venues. RESULTS: Despite similar participation in organized sports and unstructured active play, boys accumulated more MVPA than girls. MVPA was predicted by an interaction between gender and unstructured active play. Boys accumulated 23-45 additional minutes of weekday MVPA and 53-62 additional minutes of weekend MVPA through unstructured active play, with no such associations in girls. Higher reported neighborhood safety and family support for physical activity were associated with engagement in unstructured active play for both genders, and with participation in organized sports for girls. CONCLUSION: Physical activity interventions for low-income, urban children should emphasize unstructured active play, particularly in boys. Fostering family support for physical activity and safe play environments may be critical intervention components. PMID- 26757033 TI - Survey of Intraoperative Bacterial Contamination in Dogs Undergoing Elective Orthopedic Surgery. AB - OBJECTIVE: To investigate the frequency, source, and risk factors of intraoperative (IO) surgeon and patient bacterial contamination during clean orthopedic surgeries, and to investigate the relationship between IO contamination and surgical site infection (SSI) in dogs. STUDY DESIGN: Prospective clinical study. SAMPLE POPULATION: Client-owned dogs undergoing stifle surgery (n = 100). METHODS: IO cultures were taken in each case from surgical foot wrap, peri-incisional skin, surgical gloves, and the surgical team's hands. The environment (operating room [OR] lights, computers, scrub sink faucet, anesthesia gurney, and radiology table) was sampled every 5 months. Bacteria were identified and the contamination of each case was categorized. All gloves from the surgical team were collected and tested for perforations using a water infusion test. Cases were followed for at least 8 weeks to determine the presence or absence of SSI. Perioperative variables were evaluated for association with IO contamination and SSI. RESULTS: Bacterial isolates were yielded from 81% of procedures from 1 or more sources; 58% had positive hand cultures, 46% had positive glove cultures, 23% had positive patient skin cultures, and 12% had positive foot wrap cultures. Staphylococcus spp. was the most commonly recovered bacteria. There was no apparent association between IO contamination and SSI. The highest level of environmental contamination was associated with the scrub sink faucet, followed by the radiology table, anesthesia gurney, and OR computers. The IO glove perforation rate was 18%. CONCLUSION: Clean orthopedic procedures commonly had clinically insignificant bacterial contamination. In our study, bacteria responsible for SSI did not appear to colonize the patient in the OR. PMID- 26757035 TI - Homotaurine Effects on Hippocampal Volume Loss and Episodic Memory in Amnestic Mild Cognitive Impairment. AB - Homotaurine supplementation may have a positive effect on early Alzheimer's disease. Here, we investigated its potential neuroprotective effect on the hippocampus structure and episodic memory performances in amnestic mild cognitive impairment (aMCI). Neuropsychological, clinical, and neuroimaging assessment in 11 treated and 22 untreated patients were performed at baseline and after 1 year. Magnetic resonance data were analyzed using voxel-based morphometry to explore significant differences (Family Wise Error corrected) between the two groups over time. Patients treated with homotaurine showed decreased volume loss in the left and right hippocampal tail, left and right fusiform gyrus, and right inferior temporal cortex which was associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI has a positive effect on hippocampus atrophy and episodic memory loss. Future studies should further clarify the mechanisms of its effects on brain morphometry. PMID- 26757034 TI - Pauses During Autobiographical Discourse Reflect Episodic Memory Processes in Early Alzheimer's Disease. AB - There is a large body of research on discourse production in Alzheimer's disease (AD). Some studies have focused on pause production, revealing that patients make extensive use of pauses during speech. This has been attributed to lexical retrieval difficulties, but pausing may also reflect other forms of cognitive impairment as it increases with cognitive load. The aim of the present study was to analyze autobiographical discourse impairment in AD from a broad perspective, looking at pausing behavior (frequency, duration, and location). Our first objective was to characterize discourse changes in mild cognitive impairment (MCI) due to AD. Our second objective was to determine the cognitive and neuroanatomical correlates of these changes. Fifteen patients with MCI due to AD and 15 matched cognitively normal controls underwent an ecological episodic memory task, a full neuropsychological assessment, and a 3D T1-weighted MRI scans. Autobiographical discourse collected from the ecological episodic memory task was recorded, transcribed, and analyzed, focusing on pausing. Intergroup comparisons showed that although patients did not produce more pauses than controls overall, they did make more between-utterance pauses. The number of these specific pauses was positively correlated with patients' episodic memory performance. Furthermore, neuroimaging analysis showed that, in the patient group, their use was negatively correlated with frontopolar area (BA 10) grey matter density. This region may therefore play an important role in the planning of autobiographical discourse production. These findings demonstrate that pauses in early AD may reflect a compensatory mechanism for improving mental time travel and memory retrieval. PMID- 26757036 TI - Older Adults Taking AT1-Receptor Blockers Exhibit Reduced Cerebral Amyloid Retention. AB - BACKGROUND: Evidence suggests that angiotensin II AT1-receptor blockers (ARBs) may be protective against dementia, and studies in transgenic animals indicate that this may be due to improved amyloid-beta (Abeta) clearance. OBJECTIVE: We investigated whether taking ARBs was associated with an attenuation of age related increases in cerebral Abeta retention, and reduced progression to dementia. METHODS: Eight hundred seventy-one stroke-free and dementia-free older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study underwent baseline lumbar puncture, and a subgroup (n = 124) underwent 12 and 24 month follow-up lumbar puncture. Participants were followed at variable intervals for clinical progression to dementia. Linear mixed models and ANCOVA compared ARBs users with those taking other antihypertensives (O-antiHTN) or no antihypertensives (No-antiHTN) on cerebrospinal fluid (CSF) Abeta and phosphorylated tau (P-tau) levels. Cox regression and chi-square analyses compared groups on progression to dementia. RESULTS: ARBs users exhibited greater vascular risk and lower educational attainment than the No-antiHTN group. Longitudinal analyses indicated higher CSF Abeta and lower P-tau in ARBs users versus other groups. Cross-sectional analyses revealed age-related decreases in CSF Abeta in other groups but not ARBs users. ARBs users were less likely to progress to dementia and showed reduced rate of progression relative to the No antiHTN group. DISCUSSION: Patients taking ARBs showed an attenuation of age related decreases in CSF Abeta, a finding that is consistent with studies done in transgenic animals. These findings may partly explain why ARBs users show reduced progression to dementia despite their lower educational attainment and greater vascular risk burden. PMID- 26757037 TI - Cerebral Small Vessel Disease and Motoric Cognitive Risk Syndrome: Results from the Kerala-Einstein Study. AB - BACKGROUND: The contribution of cerebral small vessel disease to cognitive decline, especially in non-Caucasian populations, is not well established. OBJECTIVE: We examined the relationship between cerebral small vessel disease and motoric cognitive risk syndrome (MCR), a recently described pre-dementia syndrome, in Indian seniors. METHODS: 139 participants (mean age 66.6 +/- 5.4 y, 33.1% female) participating in the Kerala-Einstein study in Southern India were examined in a cross-sectional study. The presence of cerebral small vessel disease (lacunar infarcts and cerebral microbleeds (CMB)) and white matter hyperintensities on MRI was ascertained by raters blinded to clinical information. MCR was defined by the presence of cognitive complaints and slow gait in older adults without dementia or mobility disability. RESULTS: Thirty eight (27.3%) participants met MCR criteria. The overall prevalence of lacunar infarcts and CMB was 49.6% and 9.4% , respectively. Lacunar infarcts in the frontal lobe, but no other brain regions, were associated with MCR even after adjusting for vascular risk factors and presence of white matter hyperintensities (adjusted Odds Ratio (aOR): 4.67, 95% CI: 1.69-12.94). Frontal lacunar infarcts were associated with slow gait (aOR: 3.98, 95% CI: 1.46-10.79) and poor performance on memory test (beta: -1.24, 95% CI: -2.42 to -0.05), but not with cognitive complaints or non-memory tests. No association of CMB was found with MCR, individual MCR criterion or cognitive tests. CONCLUSIONS: Frontal lacunar infarcts are associated with MCR in Indian seniors, perhaps, by contributing to slow gait and poor memory function. PMID- 26757038 TI - Prognostic Significance of Mild Cognitive Impairment Subtypes for Dementia and Mortality: Data from the NEDICES Cohort. AB - BACKGROUND: The predictive value of diverse subtypes of mild cognitive impairment (MCI) for dementia and death is highly variable. OBJECTIVE: To compare the predictive value of several MCI subtypes in progression to dementia and/or mortality in the NEDICES (Neurological Disorders in Central Spain) elderly cohort. METHODS: Retrospect algorithmic MCI subgroups were established in a non dementia baseline NEDICES cohort using Spanish adaptations of the original Mini Mental State Examination (MMSE-37) and Pfeffer's Functional Activities Questionnaire (Pfeffer-11). The presence of MCI was defined according two cognitive criteria: using two cut-offs points on the total MMSE-37 score. Five cognitive domains were used to establish the MCI subtypes. Functional capacity (Pfeffer-11) was preserved or minimally impaired in all MCI participants. The incident dementia diagnoses were established by specialists and the mortality data obtained from Spanish official registries. RESULTS: 3,411 participants without dementia were assessed in 1994-5. The baseline prevalence of MCI varied according to the MCI definition (4.3%-31.8%). The follow-up was a mean of 3.2 years (1997-8). The dementia incidence varied between 14.9 and 71.8 per 1,000/person-years. The dementia conversion rate was increased in almost all MCI subgroups (p > 0.01), and mortality rate was raised only in four MCI subtypes. The amnestic-multi-domain MCI (aMd-MCI) had the best dementia predictive accuracy (highest positive likelihood ratio and highest clinical utility when negative). CONCLUSIONS: Those with aMd-MCI were at greatest risk of progression to dementia, as in other surveys and might be explored with increased attention in MCI research and in dementia preventive trials. PMID- 26757040 TI - The Cytome Assay as a Tool to Investigate the Possible Association Between Exposure to Extremely Low Frequency Magnetic Fields and an Increased Risk for Alzheimer's Disease. AB - Exposure to extremely low frequency magnetic fields (ELF-MF) has been identified as one of the potential environmental risk factors for Alzheimer's disease (AD). However, this is far from being established. So far there is no experimental evidence supporting this alleged association. We have performed an in vitro cytogenetic laboratory investigation to explore the plausibility of such association. Our investigation was based on possible similarities found in cells from AD patients and in cells exposed to ELF-MF. We especially found that 50 Hz ELF-MF increase the frequency of cells with (large) micronuclei and nuclear buds indicating that fields above 50 MUT may induce chromosome instabilities as those found in AD patients. It should be stressed yet that results from the few published experimental studies on ELF-MF and AD are rather reassuring. Thus, our findings certainly do not prove anything. They only suggest that further investigations might be necessary. PMID- 26757039 TI - Distinctive Resting State Network Disruptions Among Alzheimer's Disease, Subcortical Vascular Dementia, and Mixed Dementia Patients. AB - BACKGROUND: Recent advances in resting-state functional MRI have revealed altered functional networks in Alzheimer's disease (AD), especially those of the default mode network (DMN) and central executive network (CEN). However, few studies have evaluated whether small vessel disease (SVD) or combined amyloid and SVD burdens affect the DMN or CEN. OBJECTIVE: The aim of this study was to evaluate whether SVD or combined amyloid and SVD burdens affect the DMN or CEN. METHODS: In this cross-sectional study, we investigated the resting-state functional connectivity within DMN and CEN in 37 Pittsburgh compound-B (PiB)(+) AD, 37 PiB(-) subcortical vascular dementia (SVaD), 13 mixed dementia patients, and 65 normal controls. RESULTS: When the resting-state DMN of PiB(+) AD and PiB(-) SVaD patients were compared, the PiB(+) AD patients displayed lower functional connectivity in the inferior parietal lobule while the PiB(-) SVaD patients displayed lower functional connectivity in the medial frontal and superior frontal gyri. Compared to the PiB(-) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the DMN in the posterior cingulate gyrus. When the resting-state CEN connectivity of PiB(+) AD and PiB(-) SVaD patients were compared, the PiB(-) SVaD patients displayed lower functional connectivity in the anterior insular region. Compared to the PiB(-) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the CEN in the inferior frontal gyrus. CONCLUSIONS: Our findings suggest that in PiB(+) AD and PiB(-) SVaD, there is divergent disruptions in resting-state DMN and CEN. Furthermore, patients with combined amyloid and SVD burdens exhibited more disrupted resting-state DMN and CEN than patients with only amyloid or SVD burden. PMID- 26757043 TI - Safety and Efficacy of Medical Cannabis Oil for Behavioral and Psychological Symptoms of Dementia: An-Open Label, Add-On, Pilot Study. AB - BACKGROUND: Tetrahydrocannabinol (THC) is a potential treatment for Alzheimer's disease (AD). OBJECTIVE: To measure efficacy and safety of medical cannabis oil (MCO) containing THC as an add-on to pharmacotherapy, in relieving behavioral and psychological symptoms of dementia (BPSD). METHODS: Eleven AD patients were recruited to an open label, 4 weeks, prospective trial. RESULTS: Ten patients completed the trial. Significant reduction in CGI severity score (6.5 to 5.7; p < 0.01) and NPI score were recorded (44.4 to 12.8; p < 0.01). NPI domains of significant decrease were: Delusions, agitation/aggression, irritability, apathy, sleep and caregiver distress. CONCLUSION: Adding MCO to AD patients' pharmacotherapy is safe and a promising treatment option. PMID- 26757042 TI - Pain Assessment in Elderly with Behavioral and Psychological Symptoms of Dementia. AB - BACKGROUND: Pain is under-detected and undertreated in people with dementia. The present study investigates the prevalence of pain in people with dementia hospitalized in nursing homes that are members of National Association of Third Age Residences (ANASTE) Calabria, and evaluates the association among pain, mood, and behavioral and psychological symptoms of dementia (BPSD). OBJECTIVE: The aim of this study is to define the prevalence of pain in people with dementia in long term care facilities using scales of self-reporting and observational tools and, particularly, to study the relationship between pain and BPSD. METHODS: A prospective observational study was carried out on 233 patients. Pain assessment was performed using self-reporting tools such as the Numeric Rating Scale (NRS) for patients with slight cognitive impairment or no cognitive impairment and observational tools such as Pain Assessment In Advanced Dementia Scale (PAINAD) for patients with moderate or severe cognitive impairment. Mood was evaluated through the Cornell Scale for Depression in Dementia (CSDD) while behavioral problems were assessed through the Cohen-Mansfield Agitation Inventory (CMAI) and Neuropsychiatric Inventory (NPI). RESULTS: Only 42.5% of patients evaluated by NRS provided a reliable answer; of these, 20.4% reported no pain. The percentage of pain evaluated by PAINAD was 51.8% . Analysis of data showed a statistically significant correlation between diagnosis of pain and depressive symptoms, assessed with CSDD (p = 0.0113), as well as by single items of NPI, such as anxiety (p = 0.0362) and irritability (p = 0.0034), and F1 profile (Aggression) of CMAI (p = 0.01). CONCLUSION: This study confirms that self-report alone is not sufficient to assess pain in elderly people with dementia; the observational tool is a necessary and suitable way of assessing pain in patients with cognitive impairment. If not adequately treated, chronic pain can cause depression, agitation, and aggression in patients with dementia. PMID- 26757041 TI - Chronic Sleep Deprivation Exacerbates Learning-Memory Disability and Alzheimer's Disease-Like Pathologies in AbetaPP(swe)/PS1(DeltaE9) Mice. AB - Recently, there is an increasing concern over the association between sleep disorders and Alzheimer's disease (AD). Clinical observations have reported that chronic sleep deprivation (SD) may serve as a risk factor for AD. However, the pathological evidence for this assumption is still lacking. In the present study, we examined the potential impacts of chronic SD on learning-memory and AD-related pathologies in AbetaPP(swe)/PS1(DeltaE9) transgenic (TG) mice and their wild-type (WT) littermates. Results indicated that mice (both TG and WT) exposed to 2-month SD showed an altered amyloid-beta protein precursor processing, an elevated level of phosphorylated tau protein, and impaired cognitive performance as compared to non-sleep deprivation (NSD) controls. Moreover, the SD-treated TG mice exhibited more amyloid-beta(1-42) production and developed more senile plaques in the cortex and hippocampus than NSD-treated TG mice. In addition, SD caused a striking neuronal mitochondrial damage, caspase cascade activation, and neuronal apoptosis in the hippocampus of both TG and WT mice. More importantly, all these behavioral, neuropathological, and biochemical changes induced by chronic SD were long lasting and were irreversible during a 3-month normal housing condition. Collectively, these results indicate that chronic SD impairs learning and memory, exacerbates AD pathologies, and aggravates the mitochondria-mediated neuronal apoptosis in a long-lasting manner. Our findings provide important experimental evidence to prove that chronic SD is a risk factor for AD. PMID- 26757044 TI - Student-clinician agreement in clinical competence as a predictor of clinical placement performance in Australian undergraduate physiotherapy students. AB - OBJECTIVES: The opportunity for student self-reflection and the accuracy of that reflection are critical to the acquisition of professional competencies. The relationship between student-clinician agreement and clinical performance in physiotherapy students has not yet been investigated. The aim was to determine whether a simple measure of student-clinician agreement assessed midway during a clinical placement predicts final placement score. PARTICIPANTS: 100 undergraduate Monash University Bachelors of Physiotherapy students and their clinical educators. MAIN OUTCOME MEASURES: Assessment of Physiotherapy Practice (APP). METHOD: Clinician and student ratings of student performance across all clinical placements from January 2012-June 2013 at two time-points (midway and final) were entered into a purpose-built, web-based platform, and then averaged across the number of placements undertaken. The relationship between midway student-clinician agreement (student minus clinician APP score) and final APP score (determined by the clinician) was analyzed via forward regression. Sub group comparisons were performed investigating the stability of the relationship across placements. RESULTS: On average, midway agreement was associated with a 0.50 (95% CI -0.67 to -0.33) unit decrease in final placement APP% score. This model was highly statistically significant (p < 0.001) but only explained 24% of the total variance (based on the adjusted r-squared statistic). This relationship was similar in early and late placements. CONCLUSIONS: Student-clinician agreement is related to clinical performance. A midway evaluation may provide an important opportunity to identify students "at risk" of poor clinical outcomes enabling timely implementation of support strategies. Further work is required to improve the predictive accuracy of the proposed model. PMID- 26757045 TI - Randomized dose-response study of subcutaneous immunotherapy with a Dermatophagoides pteronyssinus extract in patients with respiratory allergy. AB - AIM: To evaluate the efficacy of Dermatophagoides pteronyssinus (DPT) subcutaneous immunotherapy in allergic rhinoconjunctivitis patients. PATIENTS & METHODS: This 17-week double-blind study randomized 136 patients (95 evaluable) to five dose groups of DPT depot extract (0.0625-0.75 skin prick test [SPT] units) or placebo, administered in a six updosing schedule. RESULTS: A dose response was observed for clinical efficacy (allergen concentration needed to induce a positive nasal provocation test response from baseline to final visit) and safety (adverse reactions). Local and systemic reactions occurred with 14.8 and 6.4% of administered doses, respectively; a single anaphylactic reaction occurred in each of Groups 3, 4 and 5 (0.3% of doses). CONCLUSION: The risk benefit profile appeared most favorable with a DPT dose of 0.125 SPT units. PMID- 26757046 TI - Initial serum thyroid peroxidase antibodies and long-term outcomes in SREAT. AB - OBJECTIVE: To quantify clinical outcome in patients with steroid-responsive encephalopathy and associated autoimmune thyroiditis (SREAT) after the acute phase and explore potential associations of initial serum thyroid peroxidase antibody titers (TPO-Abs) with outcome. MATERIALS AND METHODS: Retrospective chart review of patients diagnosed with SREAT between 01/2005 and 05/2014 in a tertiary care center and followed in an affiliated autoimmune outpatient clinic. Outcome was quantified using the extended Glasgow Outcome Scale (GOS-E). We calculated Pearson's correlation coefficients to quantify associations with clinical outcome at follow-up. RESULTS: Among 134 patients with encephalopathy of unknown etiology, we identified 13 patients diagnosed with SREAT. In two patients, the diagnosis was revised at subsequent hospitalization (NMDA-R encephalitis and adult-onset Still's disease). The median follow-up time was 11 months, and the median GOS-E was 6 (range 3-8). Higher serum TPO-Ab-titers correlated with more favorable outcomes (Pearson coefficient 0.65, P = 0.03). CONCLUSION: A correlation between TPO-Ab-titers and outcome has not been reported previously and challenges the notion of a mere bystander role of TPO-Abs in SREAT. PMID- 26757047 TI - The ecological and evolutionary stability of interspecific territoriality. AB - Interspecific territoriality may play an important role in structuring ecological communities, but the causes of this widespread form of interference competition remain poorly understood. Here, we investigate the phenotypic, ecological and phylogenetic correlates of interspecific territoriality in wood warblers (Parulidae). Interspecifically territorial species have more recent common ancestors and are more similar phenotypically, and are more likely to hybridise, than sympatric, non-interspecifically territorial species. After phylogenetic corrections, however, similarity in plumage and territorial song are the only significant predictors of interspecific territoriality besides syntopy (fine scale geographic overlap). Our results do not support the long-standing hypothesis that interspecific territoriality occurs only under circumstances in which niche divergence is restricted, which combined with the high incidence of interspecific territoriality in wood warblers (39% of species), suggests that this interspecific interaction is more stable, ecologically and evolutionarily, than commonly assumed. PMID- 26757048 TI - High-Performance Polymer Solar Cells with Zinc Sulfide-Phenanthroline Derivatives as the Hybrid Cathode Interlayers. AB - Environmentally benign hybrid interlayers are prepared by modifying the zinc sulfide (ZnS) with phenanthroline/derivatives and utilized in inverted polymer solar cells (PSCs). Performances of the inverted PSCs are improved enormously by incorporating these hybrid interlayers, as which can effectively improve the energy level alignment, electron mobility, surface morphology, and interfacial contact. Greatly improved power conversion efficiencies (PCEs) of 7.79%, 8.00%, 7.47%, and 7.56% are achieved with these hybrid interlayers ZnS-BCP, ZnS-Bphen, ZnS-Mphen, and ZnS-Phen, respectively, compared to the PCE of 2.99% of the reference ZnS-based device, based on PTB7:PC71BM active layer. Our results demonstrate that hybrid interfacial materials comprising inorganic and organic semiconductor possess promising potential to improve the performance of organic electronic devices, and set an example to develop this novel class of interfacial materials for electronic devices. PMID- 26757049 TI - Volumetric Portal Embolization: A New Concept to Improve Liver Regeneration and Hepatocyte Engraftment. AB - BACKGROUND: Hepatocyte transplantation has been proposed as an alternative to orthotopic liver transplantation to treat metabolic liver diseases. This approach requires preconditioning of the host liver to enhance engraftment of transplanted hepatocytes. Different methods are currently used in preclinical models: partial hepatectomy, portal ligature or embolization, and radiotherapy or chemotherapeutic drugs. However, these methods carry high risks of complications and are problematic for use in clinical practice. Here, we developed an innovative method called volumetric (distal, partial, and random) portal embolization (VPE), which preserves total liver volume. METHODS: Embolization was performed in the portal trunk of C57BL6 adult mice with polyester microspheres, to ensure a bilateral and distal distribution. The repartition of microspheres was studied by angiographic and histological analyses. Liver regeneration was evaluated by Ki67 labeling. Optimal conditions for VPE were determined, and the resulting regeneration was compared with that after partial hepatectomy (70%). Labeled adult hepatocytes were then transplanted, and engraftment was compared between embolized (n = 19) and nonembolized mice (n = 8). Engraftment was assessed in vivo and histologically by tracking labeled cells at day 5. RESULTS: The best volumetric embolization conditions, which resulted in the regeneration of 5% of total liver, were 8 * 10 ten-micron microspheres infused with a 29 G needle directly into the portal trunk at 3.3 MUL/s. In these conditions, transplanted hepatocytes engraftment was significantly higher than that in control conditions (3 vs 0.65%). CONCLUSIONS: The VPE is a new, minimally invasive, and efficient technique to prepare the host liver for cell transplantation. PMID- 26757050 TI - Prevalence of Anti-Hepatitis E Virus Antibodies and First Detection of Hepatitis E Virus in Wild Boar in Slovenia. AB - Hepatitis E is an emerging zoonotic disease caused by hepatitis E virus (HEV). In this study, we investigated HEV presence in a wild boar (Sus scrofa) population of Slovenia. A total of 288 wild boar serum samples were collected throughout the country, and HEV infection was investigated by serology, using enzyme-linked immunosorbent assay (ELISA) and by HEV RNA detection using a real-time PCR assay. Antibodies against HEV were detected in 30.2% (87/288) of animals tested, whereas HEV RNA was detected in only one sample. This is the first evidence of HEV presence in the wild boar population in Slovenia, and these results suggest that these animals are part of the HEV epidemiological cycle in the country. PMID- 26757052 TI - Adjuvant Therapy for Thymic Carcinoma--A Decade of Experience in a Taiwan National Teaching Hospital. AB - BACKGROUND: Thymic carcinomas are rare tumors for which surgical resection is the first treatment of choice. The role of adjuvant treatment after surgery is unknown because of limited available data. The present study evaluated the efficacy of post-surgery adjuvant chemotherapy or radiotherapy in patients with thymic carcinoma. METHODS: To evaluate the role of adjuvant therapy in patients with thymic carcinoma, we retrospectively reviewed the records of patients with thymic carcinoma who were diagnosed and treated between 2004 and 2014. RESULTS: Among 78 patients with thymic carcinoma, 30 patients received surgical resection. Progression-free survival (PFS) and overall survival (OS) were significantly longer among these patients than among patients who received other treatments (PFS: 88.4 months vs 9.1 months, p<0.001; OS: 134.9 months vs 60.9 months; p = 0.003). Patients with stage III thymic carcinoma who received surgery had a longer OS than patients who did not receive surgery (70.1 months vs 23.9 months; p = 0.017, n = 11). Among 47 patients with stage IV carcinoma, 12 patients who received an extended thymothymectomy had a longer PFS than 35 patients who did not receive surgery (18.9 months vs 8.7 months; p = 0.029). Among 30 patients (with stage I- IV carcinoma) who received primary lesion surgery, 19 patients received an R0 resection and 9 patients of the 19 patients received adjuvant radiotherapy. These patients had longer PFS (50.3 months) than 2 patients who received adjuvant chemotherapy (5.9 months) or 4 patients who received concurrent chemoradiotherapy (7.5 months) after surgery (p = 0.003). CONCLUSIONS: Surgical resection should be considered for patients with thymic carcinoma, even for patients with locally advanced or stage IV carcinoma. Adjuvant radiotherapy resulted in a better PFS after R0 resection. PMID- 26757051 TI - Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids. AB - Recombinant adeno-associated virus vectors (rAAV) are being explored as gene delivery vehicles for the treatment of various inherited and acquired disorders. rAAVs are attractive vectors for several reasons: wild-type AAVs are nonpathogenic, and rAAVs can trigger long-term transgene expression even in the absence of genome integration-at least in postmitotic tissues. Moreover, rAAVs have a low immunogenic profile, and the various AAV serotypes and variants display broad but distinct tropisms. One limitation of rAAVs is that their genome packaging capacity is only ~5 kb. For most applications this is not of major concern because the median human protein size is 375 amino acids. Excluding the ITRs, for a protein of typical length, this allows the incorporation of ~3.5 kb of DNA for the promoter, polyadenylation sequence, and other regulatory elements into a single AAV vector. Nonetheless, for certain diseases the packaging limit of AAV does not allow the delivery of a full-length therapeutic protein by a single AAV vector. Hence, approaches to overcome this limitation have become an important area of research for AAV gene therapy. Among the most promising approaches to overcome the limitation imposed by the packaging capacity of AAV is the use of dual-vector approaches, whereby a transgene is split across two separate AAV vectors. Coinfection of a cell with these two rAAVs will then through a variety of mechanisms-result in the transcription of an assembled mRNA that could not be encoded by a single AAV vector because of the DNA packaging limits of AAV. The main purpose of this review is to assess the current literature with respect to dual-AAV-vector design, to highlight the effectiveness of the different methodologies and to briefly discuss future areas of research to improve the efficiency of dual-AAV-vector transduction. PMID- 26757053 TI - Altered Circadian Food Anticipatory Activity Rhythms in PACAP Receptor 1 (PAC1) Deficient Mice. AB - Light signals from intrinsically photosensitive retinal ganglion cells (ipRGCs) entrain the circadian clock and regulate negative masking. Two neurotransmitters, glutamate and Pituitary Adenylate Cyclase Activating Polypeptide (PACAP), found in the ipRGCs transmit light signals to the brain via glutamate receptors and the specific PACAP type 1 (PAC1) receptor. Light entrainment occurs during the twilight zones and has little effect on clock phase during daytime. When nocturnal animals have access to food only for a few hours during the resting phase at daytime, they adapt behavior to the restricted feeding (RF) paradigm and show food anticipatory activity (FAA). A recent study in mice and rats demonstrating that light regulates FAA prompted us to investigate the role of PACAP/PAC1 signaling in the light mediated regulation of FAA. PAC1 receptor knock out (PAC1-/-) and wild type (PAC1+/+) mice placed in running wheels were examined in a full photoperiod (FPP) of 12:12 h light/dark (LD) and a skeleton photoperiod (SPP) 1:11:1:11 h L:DD:L:DD at 300 and 10 lux light intensity. Both PAC1-/- mice and PAC1+/+ littermates entrained to FPP and SPP at both light intensities. However, when placed in RF with access to food for 4-5 h during the subjective day, a significant change in behavior was observed in PAC1-/- mice compared to PAC1+/+ mice. While PAC1-/- mice showed similar FAA as PAC1+/+ animals in FPP at 300 lux, PAC1-/- mice demonstrated an advanced onset of FAA with a nearly 3-fold increase in amplitude compared to PAC1+/+ mice when placed in SPP at 300 lux. The same pattern of FAA was observed at 10 lux during both FPP and SPP. The present study indicates a role of PACAP/PAC1 signaling during light regulated FAA. Most likely, PACAP found in ipRGCs mediating non-image forming light information to the brain is involved. PMID- 26757054 TI - Pseudotyping Serotype 5 Adenovirus with the Fiber from Other Serotypes Uncovers a Key Role of the Fiber Protein in Adenovirus 5-Induced Thrombocytopenia. AB - Adenovirus (Ad) infection in humans is associated with inflammatory responses and thrombocytopenia. Although several studies were conducted in mice models to understand molecular and cellular mechanisms of Ad-induced inflammatory responses, only few of them turned their interest toward the mechanisms of Ad induced thrombocytopenia. Using different depletion methods, the present study ruled out any significant role of spleen, macrophages, and vitamin K-dependent factor in Ad-induced thrombocytopenia. Interestingly, mice displaying thrombocytopenia expressed high levels of cytokines/chemokines after Ad administration. Most importantly, pseudotyping adenovirus with the fiber protein from other serotypes was associated with reduction of both cytokine/chemokine production and thrombocytopenia. Altogether, our results suggest that capsid fiber protein (and more precisely its shaft) of Ad serotype 5 triggers the cytokine production that leads to Ad-induced thrombocytopenia. PMID- 26757055 TI - Organocatalytic Strategy for the Enantioselective Cycloaddition to Trisubstituted Nitroolefins to Create Spirocyclohexene-Oxetane Scaffolds. AB - The first catalytic enantioselective cycloaddition reaction to alpha,beta,beta trisubstituted nitroolefins is reported. For this purpose, nitroolefin oxetanes were employed in the reaction with 2,4-dienals promoted by trienamine catalysis. This methodology provides a facile and efficient strategy for the synthesis of highly functionalized chiral spirocyclohexene-oxetanes with two adjacent tetrasubstituted carbon atoms in high yields and excellent selectivities. This strategy also enabled access to chiral spirocyclohexene-cyclobutanes and azetidines. Additionally, the obtained scaffolds can undergo diverse transformations leading to complex structures with up to four stereocenters, and we demonstrate that the nitro group, under nucleophilic conditions, can be applied for ring-opening of the oxetane. PMID- 26757056 TI - An Unusual Etiology of Infantile Hemoptysis. PMID- 26757057 TI - Stereoselective Self-Aggregation of 31 -Epimerically Pure Amino Analogs of Zinc Bacteriochlorophyll-d in an Aqueous Micelle Solution. AB - Zinc bacteriochlorophyll-d analogs possessing an amino group instead of the original hydroxy group at the C31 position were prepared by chemical modification of naturally occurring chlorophyll-a. The synthetic 31 -epimers were successfully separated by reverse phase HPLC to give diastereomerically pure samples. The stereochemistry of the chiral C31 -center in the separated amines was determined by NMR analysis of their diastereomeric amides as well as by their asymmetric synthesis from authentic stereoisomers. Both the epimers were monomeric in tetrahydrofuran to give sharp electronic absorption bands, while they self aggregated to form chlorosomal oligomers with the redshifted bands in an aqueous Triton X-100 micelle solution (pH = 6.9). The resulting oligomers deaggregated by addition of p-toluenesulfonic acid to give monomeric N-protonated ammonium species. The aggregation and deaggregation were dependent on the 31 stereochemistry, indicating that each epimer produced supramolecularly different self-aggregates. PMID- 26757058 TI - Efficacy of Cryoballoon Pulmonary Vein Isolation in Patients With Persistent Atrial Fibrillation. AB - INTRODUCTION: Cryoballoon PVI has emerged as an alternative to radiofrequency PVI for the treatment of paroxysmal AF. The optimal strategy for patients with persistent AF is unclear as data are limited. METHODS: We analyzed a prospective registry of consecutive patients with persistent AF who underwent Cryoballoon PVI at a single center between 2011 and 2014. Patients were assessed for atrial arrhythmia recurrence after a 3-month blanking period at 6 months, 1 year, and 2 years postprocedure. Recurrence was based on typical symptoms, ECG, or event monitor evidence of AF. Kaplan-Meier analysis was used to estimate arrhythmia free survival. RESULTS: Final analysis included 69 patients who underwent Cryoballoon PVI with a mean age 59.4 +/- 8.1 years, 85.5% male, 53.6% HTN patients, CHA2DS2-VASC score 1.6 +/- 1.2, and LA size 4.5 +/- 0.6 cm. The single procedure atrial arrhythmia recurrence-free rate at 1-year postprocedure after a 3-month blanking period was 59% and 50% at a mean follow-up of 607 days. Of the recurrence-free group, 17% were taking previously ineffective antiarrhythmic medications. In comparing patients with persistent AF duration <1 year versus >1 year, there was a trend toward greater AF recurrence-free rates in the <1 year group (66% vs. 55%, P = 0.09). CONCLUSION: Cryoballoon PVI appears to be an effective initial strategy in treating persistent AF, with an AF recurrence-free rate of 59% at 1 year. PMID- 26757059 TI - How Can We Improve the Quality of Life of Dialysis Patients? AB - As medical advances are made in the care of persons with chronic illnesses including those with end-stage renal disease (ESRD), patients are not only experiencing increasing life expectancy but also bearing the burden of illness and treatment for a longer duration of time. With this in mind, it is increasingly important for health care providers to pay close attention to their individual patient's perceptions of their health, fitness, life satisfaction, and well-being. This assessment of Health-Related Quality of Life (HRQOL) also includes an evaluation of the patient's level of satisfaction with treatment, outcome, and health status, also taking into account their perspective on future prospects. In addition to improving patient-provider communication by helping in the identification and prioritization of problems, it is important to note that high HRQOL has been shown to be associated with better medical outcomes, including reduction in hospitalizations and death. In this review, we outline several validated tools that are used to quantitatively measure HRQOL in the ESRD population and incorporate these instruments in a review of specific, evidence based measures by which we can measurably improve health-related quality of life in dialysis patients. PMID- 26757060 TI - Trophoblast Development in the Murine Preimplantation Embryo. AB - Trophoblast cells of the murine placenta are derived from the trophectoderm (TE) cells of the preimplantation embryo. Establishment of the TE cell lineage is the result of a cell segregation event early in blastomere division. Models of cell lineage segregation suggest it is driven by the internalization of spatial information which induce or inhibit specific signaling pathways. Once segregated, TE cells undergo a differentiation event, resulting in both proliferative and terminally differentiated trophoblast cells. Thus, the development of a healthy, functional placenta relies on the well-choreographed events of trophoblast segregation, proliferation and differentiation. The pre and peri-implantation events that contribute to the development of the four main types of placental trophoblasts are the subject of this review. Identifying the components and promotors of trophoblast development will lead to a more comprehensive understanding of diseases associated with abnormal placentation and recurrent pregnancy loss. PMID- 26757061 TI - Superstructure Formation and Topological Evolution Achieved by Self-Organization of a Highly Adaptive Dynamer. AB - The adaptive property of supramolecular building blocks facilitates noncovalent synthesis of soft materials. While it is still a challenging task, fine-tuning and precise control over topological nanostructures constructed from the self assembly of low-molecular-weight building blocks are an important research direction to investigate the structure-property relationship. Herein, we report controlled self-assembly evolution of a low-molecular-weight building block bearing cholesterol and naphthalene-dicarboximide moieties, showing ultrasensitivity to solvent polarity. In low-polarity solvents (<4), it could form an M-type fiber-constituted organogel (supergel) with high solvent content, columnar molecular packing, and self-healing property. Highly polar solvents (>7.8) favor the formation of P-type helical nanostructures terminated by nanotoroids, having lamellar molecular packing. With a further increase in solvent polarity (up to 9.6), unilamellar and multilamellar vesicles were generated, which could undergo an aggregation-induced fusion process to form branched nanotubes tuned by the concentration. Self-attractive interactions between aggregates were found to be responsible for the formation of superstructures including helix-nanotoroid junctions as well as membrane-fused nanotubes. PMID- 26757062 TI - Morphology and distribution of antennal sensilla of female Phyllotreta striolata (Fabricius) (Coleoptera: Chrysomelidae). AB - Phyllotreta striolata (Fabricius) is an important pest of Brassicaceae in Southeast Asia and North America. Using scanning electron microscopy, we observed the external structure, number, and distribution of the antennal sensilla in P. striolata females to discuss the putative function of these sensilla in host location and oviposition behaviors. The antenna of female P. striolata is filiform, composed of a scape, a pedicel, and a flagellum with 9 flagellomeres. Five types of sensilla were identified, including sensilla cheaetica, sensilla trichodea, Bohm bristles, sensilla auricillica, and sensilla basiconica (five subtypes, SB1-SB2). External structure and distribution of antennal sensilla are compared with data from other insect species. In addition, we discuss the possible functions of antennal sensilla based on their characteristics. PMID- 26757063 TI - Pulmonary tuberculosis: Improving diagnosis and management. AB - Tuberculosis (TB) is a major public health concern worldwide and the world's second most common cause of death from infectious disease after HIV/AIDS. With the emergence of resistant strains of tuberculosis and increase in immunosuppressed patients, clinicians must be familiar with the clinical presentation of this potentially deadly infection. This article reviews the pathology, signs and symptoms, diagnostics, and management of TB, focusing on recent advances in drug therapy for drug-sensitive and drug-resistant forms. A better understanding of TB will help clinicians identify the disease early, reduce transmission, and provide treatment to prevent complications and reduce patient morbidity and mortality. PMID- 26757064 TI - Evaluating scrotal masses. AB - Scrotal complaints can be challenging to diagnose because of overlapping signs and symptoms among various presentations. Failure to properly identify and manage testicular malfunctions such as testicular torsion, testicular cancer, varicocele, and hydrocele may lead to patient infertility, testicle loss, or death. This article describes proper assessment of scrotal masses, recognition of potentially life-threatening testicular conditions, and appropriate diagnostic evaluations for each pathology. PMID- 26757065 TI - Coordination pattern of baseball pitching among young pitchers of various ages and velocity levels. AB - This study compared the whole-body movement coordination of pitching among 72 baseball players of various ages and velocity levels. Participants were classified as senior, junior, and little according to their age, with each group comprising 24 players. The velocity levels of the high-velocity (the top eight) and low-velocity (the lowest eight) groups were classified according to their pitching velocity. During pitching, the coordinates of 15 markers attached to the major joints of the whole-body movement system were collected for analysis. Sixteen kinematic parameters were calculated to compare the groups and velocity levels. Principal component analysis (PCA) was conducted to quantify the coordination pattern of pitching movement. The results were as follows: (1) five position and two velocity parameters significantly differed among the age groups, and two position and one velocity parameters significantly differed between the high- and low-velocity groups. (2) The coordination patterns of pitching movement could be described using three components, of which the eigenvalues and contents varied according to age and velocity level. In conclusion, the senior and junior players showed greater elbow angular velocity, whereas the little players exhibited a wider shoulder angle only at the beginning of pitching. The players with high velocity exhibited higher trunk and shoulder rotation velocity. The variations among groups found using PCA and kinematics parameter analyses were consistent. PMID- 26757066 TI - Systematic evaluation of data-independent acquisition for sensitive and reproducible proteomics-a prototype design for a single injection assay. AB - Data-independent acquisition (DIA)-based proteomics has become increasingly complicated in recent years because of the vast number of workflows described, coupled with a lack of studies indicating a rational framework for selecting effective settings to use. To address this issue and provide a resource for the proteomics community, we compared 12 DIA methods that assay tryptic peptides using various mass-isolation windows. Our findings indicate that the most sensitive single injection LC-DIA method uses 6 m/z isolation windows to analyze the densely populated tryptic peptide range from 450 to 730 m/z, which allowed quantification of 4465 Escherichia coli peptides. In contrast, using the sequential windowed acquisition of all theoretical fragment-ions (SWATH) approach with 26 m/z isolation windows across the entire 400-1200 m/z range, allowed quantification of only 3309 peptides. This reduced sensitivity with 26 m/z windows is caused by an increase in co-eluting compounds with similar precursor values detected in the same tandem MS spectra, which lowers the signal-to-noise of peptide fragment-ion chromatograms and reduces the amount of low abundance peptides that can be quantified from 410 to 920 m/z. Above 920 m/z, more peptides were quantified with 26 m/z windows because of substantial peptide (13) C isotope distributions that parse peptide ions into separate isolation windows. Because reproducible quantification has been a long-standing aim of quantitative proteomics, and is a so-called trait of DIA, we sought to determine whether precursor-level chromatograms used in some methods rather than their fragment level counterparts have similar precision. Our data show that extracted fragment ion chromatograms are the reason DIA provides superior reproducibility. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26757068 TI - Depth profiling of inks in authentic and counterfeit banknotes by electrospray laser desorption ionization/mass spectrometry. AB - Electrospray laser desorption ionization is an ambient ionization technique that generates neutrals via laser desorption and ionizes those neutrals in an electrospray plume and was utilized to characterize inks in different layers of copy paper and banknotes of various currencies. Depth profiling of inks was performed on overlapping color bands on copy paper by repeatedly scanning the line with a pulsed laser beam operated at a fixed energy. The molecules in the ink on a banknote were desorbed by irradiating the banknote surface with a laser beam operated at different energies, with results indicating that different ions were detected at different depths. The analysis of authentic $US100, $100 RMB and $1000 NTD banknotes indicated that ions detected in 'color-shifting' and 'typography' regions were significantly different. Additionally, the abundances of some ions dramatically changed with the depth of the aforementioned regions. This approach was used to distinguish authentic $1000 NTD banknotes from counterfeits. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26757067 TI - Evidence for electron-based ion generation in radio-frequency ionization. AB - Radio-frequency ionization (RFI) is a novel ionization method coupled to mass spectrometry (MS) for analysis of semi-volatile and volatile organic compounds (VOCs). Despite the demonstrated capabilities of RFI MS for VOC analysis in both positive- and negative-ion modes, mechanism of RFI is not completely understood. Improved understanding of the ion generation process in RFI should expand its utility in MS. Here, we studied the possibility of electron emission in RFI using both direct charged particle current measurements and indirect electron detection in a 9.4-T Fourier transform-ion cyclotron resonance (FT-ICR) mass spectrometer. We show that RF-generated electrons can be trapped in the ICR cell and, subsequently, reacted with neutral hexafluorobenzene (C6 F6 ) molecules to generate C6 F6 (?-) . Intensity of observed C6 F6 (?-) species correlated with the number of trapped electrons and decreased as a function of electron quenching period. We also measured the electron attachment rate constant of hexafluorobenzene using a post-RF electron trapping experiment. Measured electron attachment rate constant of hexafluorobenzene (1.19 (+/-0.53) * 10(-9) cm(3) molecule(-1) s(-1) ) for post-RF FT-ICR MS agreed with the previously reported value (1.60 (+/-0.30) * 10(-9) cm(3) molecule(-1) s(-1) ) from low-pressure ICR MS measurements. Experimental results from direct and indirect electron measurements suggest that RFI process involves RF-generated electrons under ultrahigh vacuum conditions. PMID- 26757069 TI - Fragmentation of synthetic cannabinoids with an isopropyl group or a tert-butyl group ionized by electron impact and electrospray. AB - This study described a fragmentation pattern of 21 synthetic cannabinoids with an isopropyl group or a tert-butyl group by electron impact ionization quadrupole mass spectrometry and electrospray ionization time-of-flight mass spectrometry in the positive mode. The compounds were categorized into four types according to substituted group such as a terminal amide and ester. The characteristic fragment ion in each group was obtained. The main common fragment ions for the two ionizations were formed by C-N cleavage of the amide group adjacent to the N hetero rings. Additionally, the fragment ions indicated the difference in the basic structure as well as substituted group, which are useful for estimating the chemical structures of unknown compounds. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26757070 TI - Negative ion electrospray high-resolution tandem mass spectrometry of polyphenols. AB - Representative compounds with a 1,3-dihydroxybenzene substructure belonging to different important polyphenol classes (stilbenes, flavones, isoflavones, flavonols, flavanones, flavanols, phloroglucinols, anthraquinones and bisanthraquinones) were investigated based on detailed high-resolution tandem mass spectrometry measurements with an Orbitrap system under negative ion electrospray conditions. The mass spectral behaviour of these compound classes was compared among each other not only with respect to previously described losses of CO, CH2 CO and C3 O2 but also concerning the loss of CO2 and successive specific fragmentations. Furthermore, some unusual fragmentations such as the loss of a methyl radical during mass spectral decomposition are discussed. The obtained results demonstrate both similarities and differences in their mass spectral fragmentation under MS(n) conditions, allowing a characterization of the corresponding compound type. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26757071 TI - A semi-quantitative approach for the rapid screening and mass profiling of naphthenic acids directly in contaminated aqueous samples. AB - We report the use of a direct sampling, online analytical approach for the determination of acid extractable naphthenic acids in complex aqueous samples, known as condensed phase membrane introduction mass spectrometry (CP-MIMS). The technique employs a capillary hollow fibre semi-permeable membrane probe configured for immersion into a pH adjusted sample. A continuously flowing methanol acceptor phase transfers naphthenic acids to an electrospray ionization source, operated in negative ion mode, whereupon they are analysed by mass spectrometry as [M-H](-) ions. High-resolution mass spectrometry is used to characterize the influence of sample pH on membrane transport of multiple components of complex naphthenic acid mixtures. We demonstrate the use of CP-MIMS for semi-quantitative analysis of real-world samples using selected ion monitoring and full scan mass spectra at unit mass resolution. The technique has also been employed to continuously monitor the temporal evolution in the mass profile and concentrations of individual naphthenic acid isomer classes in heterogeneous solutions during adsorption processes. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26757072 TI - A dopant for improved sensitivity in easy ambient sonic-spray ionization mass spectrometry. AB - Recently, 3-nitrobenzonitrile (3-NBN) has been used to improve sensitivity of sonic-spray ionization mass spectrometry. Easy ambient sonic-spray ionization (EASI) is one of the simplest, gentlest and most used spray-based desorption/ionization ambient techniques, but limited sensitivity has been commonly taken as its major drawback. Herein we investigate the use of 3-NBN as a dopant in EASI-MS for improved sensitivity. Using a few typical EASI samples as test cases, the presence of 10 ppm (ug ml(-1) ) of 3-NBN in the spray solvent showed two to fourfold gains in EASI-MS sensitivity as measured both by total ion current and S/N ratios, accompanied with significant reductions in chemical noise. Sensitivity for DESI using 3-NBN as a dopant also improved and dopant DESI versus dopant EASI sensitivities were compared. The use of solvent dopants seems therefore to be a promising strategy to improve sensitivity for spray-based ambient MS techniques. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26757073 TI - Application of porous metal enrichment probe sampling to single cell analysis using matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS). AB - There is an increasing need for analyzing metabolism in a single cell, which is important to understand the nature of cellular heterogeneity, disease, growth and specialization, etc. However, single cell analysis is often challenging for the traces of samples. In the present study, porous metal enrichment probe sampling combined with matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) has been applied for in situ analysis of live onion epidemic cell. Porous probe, treated by corroding copper wire with HCl, was directly inserted into a single cell to get cell solution. A self-made linear actuator was enough to control the penetration of probe into the target cell accurately. Then samples on the tip of probe were eluted and detected by a commercial MALDI-TOF-MS directly. The formation of porous microstructure on the probe surface increased the adsorptive capacity of cell solution. The sensitivity of porous probe sampling was 6 times higher than uncorroded probes generally. This method provides a sensitive and convenient way for the sampling and detection of single cell solution. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26757075 TI - MALDI ionization mechanisms investigated by comparison of isomers of dihydroxybenzoic acid. AB - Matrix-assisted laser desorption/ionization (MALDI) ion formation mechanisms were investigated by comparison of isomers of dihydroxybenzoic acid (DHB). These exhibit substantially different MALDI performance, the basis for which was not previously understood. Luminescence decay curves are used here to estimate excited electronic state properties relevant for the coupled chemical and physical dynamics (CPCD) model. With these estimates, the CPCD predictions for relative total ion and analyte ion yields are in good agreement with the data for the DHB isomers. Predictions of a thermal equilibrium model were also compared and found to be incompatible with the data. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26757074 TI - A liquid chromatography-tandem mass spectrometry method for the quantitation of actarit in rabbit plasma: application to pharmacokinetics and metabolic stability. AB - Actarit (ATR), 4-acetylaminophenylacetic acid is an orally effective disease modifying anti-rheumatic drug widely prescribed for the treatment of rheumatoid arthritis. The present study demonstrates the first report on a selective and sensitive liquid chromatography-tandem mass spectrometry method for the quantification of ATR in rabbit plasma using p-coumaric acid as an internal standard (IS). Following liquid-liquid extraction, chromatographic separation of the reconstituted samples was achieved isocratically on a Syncronis-C18 column with a mobile phase consisting of aqueous ammonium acetate (10 mM, pH 4)- methanol and acetonitrile mixture (8 : 92, v/v) at a flow rate of 0.6 ml/min. ATR and IS were detected using electrospray ionization operated in negative multiple reaction monitoring mode. The calibration curve was linear (r(2) >= 0.990) over the concentration range of 1-4000 ng/ml with a lower limit of quantitation of 1 ng/ml. The mean extraction recovery of ATR and IS from rabbit plasma was greater than 85%. The method complied well with US Food and Drug Administration guidelines for selectivity, sensitivity, accuracy, precision, matrix effect, dilution integrity, carry-over effect and stability. The method was successfully applied to in vitro metabolic stability (using rabbit liver microsomes) and in vivo pharmacokinetic study after oral administration of ATR at a dose of 10 mg/kg in New Zealand rabbits. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26757093 TI - Drug test results as a predictor of retention among patients using buprenorphine in a comprehensive outpatient treatment program. AB - The study examined the relationship between continued non-medical drug use and treatment retention for patients receiving buprenorphine maintenance treatment in a comprehensive addiction treatment program. The participants were 106 newly admitted patients and 103 continuing patients in treatment for an average of 9.4 months at the start of the study. Retrospective chart reviews were used to determine for each group whether the use of illicit, non-prescribed drugs during a 3-month baseline period was associated with lowered rates of treatment retention over the following 14 months. The New Admissions group was divided into 4 subgroups based on the percentage of urine drug tests that were positive during baseline: 0, 1-33, 34-67, or 68-100%. Because only 16 (15%) of the continuing patients had positive drug tests during baseline, the continuing group was divided into just 2 subgroups-no positives and any positives. Newly admitted patients testing positive for drugs more than 33% of the time were significantly more likely than those with less frequent or no positive tests to withdraw from treatment within 2 months. Continuing patients with at least 1 positive drug test left treatment 6 months sooner, on average, than those with no positive tests and were twice as likely to leave without completing continuing care (87 to 42%). Non prescribed drug use during buprenorphine maintenance treatment is strongly correlated with lowered retention and risk of early treatment termination for new and continuing patients. Actions taken to monitor and reduce drug use during buprenorphine maintenance treatment may improve retention and enhance long-term recovery outcomes. PMID- 26757094 TI - A Semi-Structured MODFLOW-USG Model to Evaluate Local Water Sources to Wells for Decision Support. AB - In order to better represent the configuration of the stream network and simulate local groundwater-surface water interactions, a version of MODFLOW with refined spacing in the topmost layer was applied to a Lake Michigan Basin (LMB) regional groundwater-flow model developed by the U.S. Geological. Regional MODFLOW models commonly use coarse grids over large areas; this coarse spacing precludes model application to local management issues (e.g., surface-water depletion by wells) without recourse to labor-intensive inset models. Implementation of an unstructured formulation within the MODFLOW framework (MODFLOW-USG) allows application of regional models to address local problems. A "semi-structured" approach (uniform lateral spacing within layers, different lateral spacing among layers) was tested using the LMB regional model. The parent 20-layer model with uniform 5000-foot (1524-m) lateral spacing was converted to 4 layers with 500 foot (152-m) spacing in the top glacial (Quaternary) layer, where surface water features are located, overlying coarser resolution layers representing deeper deposits. This semi-structured version of the LMB model reproduces regional flow conditions, whereas the finer resolution in the top layer improves the accuracy of the simulated response of surface water to shallow wells. One application of the semi-structured LMB model is to provide statistical measures of the correlation between modeled inputs and the simulated amount of water that wells derive from local surface water. The relations identified in this paper serve as the basis for metamodels to predict (with uncertainty) surface-water depletion in response to shallow pumping within and potentially beyond the modeled area, see Fienen et al. (2015a). PMID- 26757076 TI - The use of matrix coating assisted by an electric field (MCAEF) to enhance mass spectrometric imaging of human prostate cancer biomarkers. AB - In this work, we combined a newly developed matrix coating technique - matrix coating assisted by an electric field (MCAEF) and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) to enhance the imaging of peptides and proteins in tissue specimens of human prostate cancer. MCAEF increased the signal-to-noise ratios of the detected proteins by a factor of 2 to 5, and 232 signals were detected within the m/z 3500-37500 mass range on a time of-flight mass spectrometer and with the sinapinic acid MALDI matrix. Among these species, three proteins (S100-A9, S100-A10, and S100-A12) were only observed in the cancerous cell region and 14 proteins, including a fragment of mitogen activated protein kinase/extracellular signal-regulated kinase kinase kinase 2, a fragment of cAMP-regulated phosphoprotein 19, 3 apolipoproteins (C-I, A-I, and A II), 2 S100 proteins (A6 and A8), beta-microseminoprotein, tumor protein D52, alpha-1-acid glycoprotein 1, heat shock protein beta-1, prostate-specific antigen, and 2 unidentified large peptides at m/z 5002.2 and 6704.2, showed significantly differential distributions at the p < 0.05 (t-test) level between the cancerous and the noncancerous regions of the tissue. Among these 17 species, the distributions of apolipoprotein C-I, S100-A6, and S100-A8 were verified by immunohistological staining. In summary, this study resulted in the imaging of the largest group of proteins in prostate cancer tissues by MALDI-MS reported thus far, and is the first to show a correlation between S100 proteins and prostate cancer in a MS imaging study. The successful imaging of the three proteins only found in the cancerous tissues, as well as those showing differential expressions demonstrated the potential of MCAEF-MALDI/MS for the in situ detection of potential cancer biomarkers. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26757095 TI - Ceramic tiles with black pigment made from stainless steel plant dust: Physical properties and long-term leaching behavior of heavy metals. AB - Stainless steel plant dust is a hazardous by-product of the stainless steelmaking industry. It contains large amounts of Fe, Cr, and Ni, and can be potentially recycled as a raw material of inorganic black pigment in the ceramic industry to reduce environmental contamination and produce value-added products. In this paper, ceramic tiles prepared with black pigment through recycling of stainless steel plant dust were characterized in terms of physical properties, such as bulk density, water absorption, apparent porosity, and volume shrinkage ratio, as well as the long-term leaching behavior of heavy metals (Cr, Ni, Pb, Cd, and Zn). The results show that good physical properties of ceramic tiles can be obtained with 8% pigments addition, sample preparation pressure of 25 MPa, and sintering at 1200 oC for 30 min. The major controlling leaching mechanism for Cr and Pb from the ceramic tiles is initial surface wash-off, while the leaching behavior of Cd, Ni, and Zn from the stabilized product is mainly controlled by matrix diffusion. The reutilization process is safe and effective to immobilize the heavy metals in the stainless steel plant dust. IMPLICATIONS: Stainless steel plant dust is considered as a hazardous material, and it can be potentially recycled for black pigment preparation in the ceramic industry. This paper provides the characteristics of the ceramic tiles with black pigment through recycling stainless steel plant dust, and the long-term leaching behavior and controlling leaching mechanisms of heavy metals from the ceramic tile. The effectiveness of the treatment process is also evaluated. PMID- 26757096 TI - RoboFish: increased acceptance of interactive robotic fish with realistic eyes and natural motion patterns by live Trinidadian guppies. AB - In recent years, simple biomimetic robots have been increasingly used in biological studies to investigate social behavior, for example collective movement. Nevertheless, a big challenge in developing biomimetic robots is the acceptance of the robotic agents by live animals. In this contribution, we describe our recent advances with regard to the acceptance of our biomimetic RoboFish by live Trinidadian guppies (Poecilia reticulata). We provide a detailed technical description of the RoboFish system and show the effect of different appearance, motion patterns and interaction modes on the acceptance of the artificial fish replica. Our results indicate that realistic eye dummies along with natural motion patterns significantly improve the acceptance level of the RoboFish. Through the interactive behaviors, our system can be adjusted to imitate different individual characteristics of live animals, which further increases the bandwidth of possible applications of our RoboFish for the study of animal behavior. PMID- 26757097 TI - Alcohol Dimer is Requisite to Form an Alkyl Oxonium Ion in the Proton Transfer of a Strong (Photo)Acid to Alcohol. AB - Alcohols, the simplest amphiprotic organic compounds, can exhibit either acidic or basic behavior by donating or accepting a proton. In this study, proton dissociation of a model photoacid in solution is explored by using time-resolved spectroscopy, revealing quantitatively for the first time that alcohol acts as a Bronsted base because of H-bonded cluster formation to enhance the reactivity. The protonated alcohol cluster, the alkyl oxonium ion, can be regarded as a key reaction intermediate in the well-established alcohol dehydration reaction. This finding signifies, as in water, the cooperativity of protic solvent molecules to facilitate nonaqueous acid-base reactions. PMID- 26757098 TI - Trimetallic TriStar Nanostructures: Tuning Electronic and Surface Structures for Enhanced Electrocatalytic Hydrogen Evolution. AB - PtFeCo alloy nanostructures in a TriStar shape with tunable Fe and Co content are developed for the electrocatalytic hydrogen evolution reaction (HER). With electronic and surface structures well-tailored, the PtFeCo nanostructures exhibit dramatically enhanced performance in HER against commercial Pt/C and other Pt-based nanoparticles. PMID- 26757099 TI - Tuning Polyelectrolyte-Surfactant Interactions: Modification of Poly(ethylenimine) with Propylene Oxide and Blocks of Ethylene Oxide. AB - Significantly enhanced adsorption at the air-water interface arises in polyelectrolyte/ionic surfactant mixtures, such as poly(ethylenimine)/sodium dodecyl sulfate (PEI/SDS), down to relatively low surfactant concentrations due to a strong surface interaction between the polyelectrolyte and surfactant. In the region of charge neutralization this can result in precipitation or coacervation and give rise to undesirable properties in many applications. Ethoxylation of the PEI can avoid precipitation, but can also considerably weaken the interaction. Localization of the ethoxylation can overcome these shortcomings. Further manipulation of the polyelectrolyte-surfactant interaction can be achieved by selective ethoxylation and propoxylation of the PEI amine groups. Neutron reflectivity and surface tension data are presented here which show how the polyelectrolyte-surfactant interaction can be manipulated by tuning the PEI structure. Using deuterium labeled surfactant and polymer the neutron reflectivity measurements provide details of the surface composition and structure of the adsorbed layer. The general pattern of behavior is that at low surfactant concentrations there is enhanced surfactant adsorption due to the strong surface interaction; whereas around the region of the SDS critical micellar concentration, cmc, the surface is partially depleted of surfactant in favor bulk aggregate structures. The results presented here show how these characteristic features of the adsorption are affected by the degree of ethoxylation and propoxylation. Increasing the degree of propoxylation enhances the surfactant adsorption, whereas varying the degree of ethoxylation has a less pronounced effect. In the region of surfactant surface depletion increasing both the degree of ethoxylation and propoxylation result in an increased surface depletion. PMID- 26757100 TI - Hypoxia Enhances Direct Reprogramming of Mouse Fibroblasts to Cardiomyocyte-Like Cells. AB - Recent work has shown that mouse and human fibroblasts can be reprogrammed to cardiomyocyte-like cells with a combination of transcription factors. Current research has focused on improving the efficiency and mechanisms for fibroblast reprogramming. Previously, it has been reported that hypoxia enhances fibroblast cell reprogramming to pluripotent stem cells. In this study, we observed that 6 h of hypoxic conditions (2% oxygen) on newborn mouse dermal fibroblasts can improve the efficiency of reprogramming to cardiomyocyte-like cells. Expression of cardiac-related genes and proteins increased at 4 weeks after transfer of three transcription factors (Gata4/Mef2c/Tbx5 [GMT]). However, beating cardiomyocyte cells were not detected. The epigenetic mechanism of hypoxia-induced fibroblast reprogramming to cardiomyocyte cells requires further study. PMID- 26757101 TI - A Remarkable Multitasking Double Spiropyran: Bidirectional Visible-Light Switching of Polymer-Coated Surfaces with Dual Redox and Proton Gating. AB - Smart or functional surfaces that exhibit complex multimodal responsivity, e.g., to light, heat, pH, etc., although highly desirable, require a combination of distinct functional units to achieve each type of response and present a challenge in achieving combinations that can avoid cross-talk between the units, such as excited-state quenching. Compounds that exhibit multiple switching modalities help overcome this challenge and drastically reduce the synthetic cost and complexity. Here we show that a bis-spiropyran photochrome, which is formed through coupling at the indoline 5-position using redox chemistry, exhibits pH gated photochromism, with opening of the spiro moiety by irradiation with UV light and the expected reversion by either heating or irradiation with visible light gated by protonation/deprotonation. Remarkably, when the photochrome is oxidized to its dicationic form, bis-spiropyran(2+), visible light can be used instead of UV light to switch between the spiro and merocyanine forms, with locking and unlocking of each state achieved by protonation/deprotonation. The formation of the bis-spiropyran unit by electrochemical coupling is exploited to generate "smart surfaces", i.e., polymer-modified electrodes, avoiding the need to introduce an ancillary functional group for polymerization and the concomitant potential for cross-talk. The approach taken means not only that the multiresponsive properties of the bis-spiropyran are retained upon immobilization but also that the effective switching rate can be enhanced dramatically. PMID- 26757102 TI - Matrix pencil decomposition of time-resolved proton MRI for robust and improved assessment of pulmonary ventilation and perfusion. AB - PURPOSE: To present an improved and robust method of pulmonary function assessment from time-resolved proton MRI using a matrix pencil (MP) method in combination with a linear least squares analysis. METHODS: Simulations of the signal time course in lung parenchyma were performed to compare the accuracy of Fourier decomposition (FD) and MP methods for the estimation of respiratory and cardiac amplitudes. Series of two-dimensional time-resolved lung images were acquired in healthy volunteers at 1.5 T using ultra-fast steady-state free precession. Qualitative lung ventilation- and perfusion-weighted images as well as a quantitative map of fractional ventilation, perfusion, and blood arrival time were calculated using the proposed MP method and compared with the contemporary FD technique. A region-of-interest analysis was performed on the quantitative data. RESULTS: The signal analysis performed using MP decomposition resulted in reduced variability of the estimated respiratory and cardiac amplitudes in comparison with FD for both simulated and in vivo data. CONCLUSION: MP decomposition provides an automatic, robust, and more accurate estimation of amplitudes of respiratory and cardiac signal modulations in the lung parenchyma than the contemporary FD technique. Magn Reson Med 77:336-342, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26757103 TI - A review on the determination of isotope ratios of boron with mass spectrometry. AB - The present review discusses different mass spectrometric techniques-viz, thermal ionization mass spectrometry (TIMS), inductively coupled plasma mass spectrometry (ICPMS), and secondary ion mass spectrometry (SIMS)-used to determine 11 B/10 B isotope ratio, and concentration of boron required for various applications in earth sciences, marine geochemistry, nuclear technology, environmental, and agriculture sciences, etc. The details of the techniques-P-TIMS, which uses Cs2 BO2+ , N-TIMS, which uses BO2- , and MC-ICPMS, which uses B+ ions for bulk analysis or B- and B+ ions for in situ micro-analysis with SIMS-are highlighted. The capabilities, advantages, limitations, and problems in each mass spectrometric technique are summarized. The results of international interlaboratory comparison experiments conducted at different times are summarized. The certified isotopic reference materials available for boron are also listed. Recent developments in laser ablation (LA) ICPMS and QQQ-ICPMS for solids analysis and MS/MS analysis, respectively, are included. The different aspects of sample preparation and analytical chemistry of boron are summarized. Finally, the future requirements of boron isotope ratios for future applications are also given. Presently, MC-ICPMS provides the best precision and accuracy (0.2 0.40/00) on isotope ratio measurements, whereas N-TIMS holds the potential to analyze smallest amount of boron, but has the issue of bias (+20/00 to 40/00) which needs further investigations. (c) 2016 Wiley Periodicals, Inc. Mass Spec Rev 36:499-519, 2017. PMID- 26757105 TI - Charge Transfer Dynamics between Carbon Nanotubes and Hybrid Organic Metal Halide Perovskite Films. AB - In spite of the rapid rise of metal organic halide perovskites for next generation solar cells, little quantitative information on the electronic structure of interfaces of these materials is available. The present study characterizes the electronic structure of interfaces between semiconducting single walled carbon nanotube (SWCNT) contacts and a prototypical methylammonium lead iodide (MAPbI3) absorber layer. Using photoemission spectroscopy we provide quantitative values for the energy levels at the interface and observe the formation of an interfacial dipole between SWCNTs and perovskite. This process can be ascribed to electron donation from the MAPbI3 to the adjacent SWCNT making the nanotube film n-type at the interface and inducing band bending throughout the SWCNT layer. We then use transient absorbance spectroscopy to correlate this electronic alignment with rapid and efficient photoexcited charge transfer. The results indicate that SWCNT transport and contact layers facilitate rapid charge extraction and suggest avenues for enhancing device performance. PMID- 26757104 TI - Clinical study of a retinoic acid-loaded microneedle patch for seborrheic keratosis or senile lentigo. AB - AIMS: Pigmented lesions such as of seborrheic keratosis and senile lentigo, which are commonly seen on skin of people>50years of age, are considered unattractive and disfiguring because of their negative psychological impact. Drug therapy using all-trans retinoic acid (ATRA) is an attractive option for self-treatment at home. We have developed an ATRA-loaded microneedle patch (ATRA-MN) and confirmed the pharmacological effects of ATRA-MN application in mice. Here, we describe a clinical study to evaluate the safety and efficacy of ATRA-MN in subjects with seborrheic keratosis or senile lentigo. MAIN METHODS: ATRA-MN was applied to the lesion site of each subject for 6h once per week for 4weeks. The skin irritation reaction was scored to assess adverse reactions and blood tests were performed to evaluate the presence of systemic adverse reactions. To assess the treatment effect using ATRA-MN, the desquamation and whitening ability of the investigational skin was observed. KEY FINDINGS: Desquamation of the stratum corneum was observed following four ATRA-MN applications at 1-week intervals, but ATRA-MN applications did not induce severe local or systemic adverse effects. SIGNIFICANCE: These results showed that ATRA-MN treatment is promising as a safe and effective therapy for seborrheic keratosis and senile lentigo. PMID- 26757106 TI - Stress management by autophagy: Implications for chemoresistance. AB - Development of chemoresistance, which limits the efficiency of anticancer agents, has long been a major problem in cancer therapy and urgently needs to be solved to improve clinical outcomes. Factors contributing to chemoresistance are various, but a key factor is the cell's capability for stress management. Autophagy, a favored survival strategy that organisms employ to get over many kinds of stress, is emerging as a crucial player in drug resistance. It has been shown that autophagy facilitates the resistance of tumor cells to anticancer agents, and abrogation of autophagy could be therapeutically beneficial in some cases, suggesting autophagy could be a promising target for cancer treatments. Thus, defining the roles of autophagy in chemoresistance, and the mechanisms involved, will be critical to enhance the efficiency of chemotherapy and develop novel anticancer strategy interventions. PMID- 26757108 TI - A study on 17alpha-ethinylestradiol metabolism in rat and Pleurotus ostreatus. AB - OBJECTIVES: 17alpha-Ethinylestradiol (EE2) is an endocrine disruptor that is an ingredient of oral contraceptives. Here, EE2 metabolism catalyzed by cytochromes P450 (CYP) was studied. Two model organisms, rat and ligninolytic fungus Pleurotus ostreatus, were used. METHODS: To resolve the role of rat and/or fungal CYPs in EE2 oxidation, microsomes were incubated with EE2 and NADPH or cumene hydroperoxide. Using SupersomesTM, we examined which of rat CYPs oxidize EE2. RESULTS: EE2 is effectively degraded by P. ostreatus in vivo. In vitro, EE2 is metabolized by CYPs by the NADPH-dependent and organic hydroperoxide-dependent mechanisms. Rat hepatic microsomes metabolize EE2 in the presence of NADPH to three products; two of them are hydroxylated EE2 derivatives. Using rat SupersomesTM we found that EE2 is hydroxylated by several rat CYPs, among them CYP2C6 and 2C11 are most efficient in 2-hydroxy-EE2 formation, while CYP2A and 3A catalyze EE2 hydroxylation to the second product. On the contrary, the products of the NADPH-dependent hydroxylating reactions were not detected in Pleurotus ostreatus. During the reaction of EE2 in microsomes isolated from rat and P. ostreatus in the presence of the alternate oxidant, cumene hydroperoxide, another metabolite, different from the above mentioned products, is generated. Rat CYP1A1 is the most efficient enzyme catalyzing formation of this EE2 product. CONCLUSION: The results suggest that CYPs play a role in EE2 metabolism in rat and P. ostreatus. To our knowledge this is the first finding describing ligninolythic fungal metabolism of EE2 by CYP in the presence of cumene hydroperoxide. PMID- 26757109 TI - Activity of selected salicylamides against intestinal sulfate-reducing bacteria. AB - OBJECTIVES: The aim of our work was to evaluate effect of selected salicylamides on cell viability of sulfate-reducing bacterium Desulfovibrio piger Vib-7 isolated from the human large intestine, as well as to assess antimicrobial activity and biological properties of these compounds. METHODS: Microbiological, biochemical, biophysical methods, and statistical processing of the results were used. RESULTS: An antimicrobial activity and biological properties of salicylamides against intestinal sulfate-reducing bacteria was studied. Primary in vitro screening of the synthesized selected salicylamides was performed against D. piger Vib-7. Adding 0.37-1.10 umol.L(-1) (N-(4-bromophenyl)-5-chloro-2 hydroxybenzamide, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide, 5 chloro-N-(3,4-dichlorophenyl)-2-hydroxybenzamide, 5-chloro-2-hydroxy-N-(4 nitrophenyl)benzamide and 4-chloro-N-(3,4-dichlorophenyl)-2-hydroxybenzamide) caused decrease in biomass accumulation by 8-53, 64-66, 49-50, 82-90, 43-46% compared to control, respectively. The studied compounds completely inhibited the growth of D. piger Vib-7 under the effect of 30 umol.L(-1). Moreover, addition of the compounds in the culture medium inhibited the process of dissimilation sulfate dose dependently. Treatment with salicylamides led to the bacterial growth inhibition which correlated with the level of inhibition of sulfate reduction. The data on relative survival of D. piger Vib-7 cells and cytotoxicity of salicylamides are consistent to our research in previous series of the biomass accumulation experiments. CONCLUSIONS: A significant cytotoxic activity under the influence of salicylamides was determined. These results are consistent with a data on bacterial growth and inhibition process of dissimilation sulfate. The strongest cytotoxic effect of the derivatives was observed in compounds of 5 chloro-2-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide and 5-chloro-2-hydroxy-N (4-nitrophenyl)benzamide which showed low survival and high toxicity rates. PMID- 26757110 TI - Comparison of the effect of four anaesthetics on haematological profiles, oxidative stress and antioxidant enzymes in barbel (Barbus barbus). AB - OBJECTIVES: Currently, many questions regarding the effect of anaesthetics to fish remain unresolved. Fish species may differ widely in their response to an anaesthetic, the screening of dosages is often necessary. The aim of this study was to compare the effect of tricaine methane sulphonate (MS 222), clove oil, 2 phenoxyethanol and Propiscin on haematological profiles, oxidative stress biomarkers and antioxidant enzymes in barbel (Barbus barbus). DESIGN: The haematological profiles, oxidative stress biomarkers and antioxidant enzymes of barbel were evaluated immediately after a 10 min anaesthesia (MS 222--100 mg.L( 1), clove oil--33 mg.L(-1), 2-phenoxyethanol--0.4 mg.L(-1), Propiscin--1.0 mg.L( 1)), and 24 h after anaesthesia. RESULTS: The 10 min exposure in the recommended concentrations of tested anaesthetics have no significant effect on haematological profiles, levels of thiobarbituric acid reactive substances, and activity of glutathione reductase of barbel. The activity of superoxide dismutase (SOD) was significantly decreased (p<0.01) in the muscle in all experimental groups. The activity of SOD showed a significant decrease (p<0.01) in the liver 24 h after all anaesthetics; however in the gill the activity of SOD was significantly increased (p<0.01) in Propiscin (10 min). The activity of catalase (CAT) was significantly increased (p<0.05) in the muscle 24 h after all anaesthetics. CONCLUSIONS: The observed effects on barbel antioxidant systems may be a defence against oxidative damage. The results of this study suggest that the antioxidant systems of barbel are altered by Propiscin anaesthesia, but are slightly affected by MS 222, clove oil, and 2-phenoxyethanol anaesthesia. PMID- 26757107 TI - Progranulin deficiency leads to severe inflammation, lung injury and cell death in a mouse model of endotoxic shock. AB - Progranulin (PGRN) is a crucial secreted growth factor involved in various kinds of physiologic and disease processes and often has a protective role in inflammatory diseases. This study was designed to investigate the protective effects of PGRN on endotoxic shock in a mouse model of PGRN deficiency. After lipopolysaccharide (LPS) injection to induce endotoxic shock in mice, PGRN levels were induced in wild-type (WT) mice at 6 and 24 hrs. Survival rate analysis, haematoxylin and eosin staining, immunohistochemical staining, enzyme-linked immunosorbent assay and in situ terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick-end labelling assay were used to reveal the susceptibility, lung injury, inflammatory cell infiltration, production of inflammatory mediators and lung cell death in mice after LPS injection. PGRN deficient (Grn(-/-) ) mice were highly susceptible to LPS-induced endotoxic shock, with decreased survival, severe lung injury, increased production of pro inflammatory mediators, and inflammatory cell infiltration and apoptotic death in the lung. Additionally, recombinant PGRN (rPGRN) administration before LPS stimulation ameliorated the survival of and abnormalities in both WT and Grn(-/-) mice. Altogether, these findings indicate that PGRN may be a novel biologic agent with therapeutic potential for endotoxic shock probably by inhibiting LPS-induced systemic and local inflammation in mice for treating endotoxic shock. PMID- 26757111 TI - Concentration of heavy and toxic metals in fish and sediments from the Morava river basin, Czech Republic. AB - OBJECTIVES: The monitoring survey to assess the environmental pollution status of the river Morava--was carried out in 2014. DESIGN: This study presents the concentrations of heavy metals (Hg, Cr, Zn, Pb and Cd) in the water, sediment and muscle tissue of fish from the middle and lower reaches of the Morava river basin (Becva, Drevnice, Hana, Kyjovka and Morava rivers), in the Czech Republic. Atomic absorption spectrometry (AAS) was used for the analysis of toxic metals. European chub (Squalius cephalus) was chosen as a reference fish species for the comparison of monitored localities. RESULTS: Results showed a positive significant correlation between concentration of Hg, Pb, Cd, Cr and Zn in muscles and age of fishes (p<0.05). The contents of the analyzed metals in European chub muscles were low Hg 0.049-0.402, Pb 0.005-0.035, Cd 0.006-0.026, Cr 0.016-0.042 and Zn 5.59-64.31 mg.kg(-1) wet weight basis and did not exceed the values of limits admissible in the Czech Republic. CONCLUSIONS: The contents of the analyzed metals in European chub muscles were low at monitoring sites and did not exceed the values of limits admissible in the Czech Republic. PMID- 26757112 TI - Cytotoxicity of and DNA adduct formation by ellipticine and its micellar form in human leukemia cells in vitro. AB - OBJECTIVES: The improvements of cancer treatment are the major challenge in oncology research. Nanocarriers are one of the promising approaches to selectively target tumor cells, frequently leading to improve drug therapeutic index. Ellipticine is an anticancer agent that functions through multiple mechanisms. Here, the toxic effects of an anticancer drug ellipticine encapsulated in a micellar nanotransporter and free ellipticine on human HL-60 leukemia cells and formation of ellipticine-derived DNA adducts by both forms of the drug in these cells were investigated. METHODS: The toxicity of modified ellipticine on cells was compared to that of free ellipticine using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide cytotoxicity assay. 32P postlabeling was utilized to determine ellipticine-DNA adducts in treated cells. RESULTS: The comparison of efficiencies of free ellipticine and ellipticine micelles [the poly(ethylene oxide)-block-poly(allyl glycidyl ether) block copolymer] to form ellipticine-derived DNA adducts in leukemia HL-60 cells and to act as cytotoxic agent on these cells was performed. Exposure of HL-60 cells to ellipticine in micelles resulted in formation of ellipticine-DNA adducts and caused the cytotoxic effect on these cells. The influence of ellipticine in micelles on HL-60 cells was very similar to that of free ellipticine. The ellipticine half maximal inhibition concentration was determined as 1.3+/-0.3 umol.L(-1) and 1.4+/-0.3 umol.L(-1) for ellipticine and ellipticine in micelles, respectively. Likewise, the levels of ellipticine-DNA adducts generated in HL-60 cells by both forms of ellipticine were analogous. CONCLUSION: The results found in this work demonstrate similar cytotoxicity and DNA-damaging effects of ellipticine and its micellar form on leukemia HL-60 cells in vitro. PMID- 26757113 TI - Degradation rate of praziquantel and fenbendazole in rainbow trout following oral administration. AB - OBJECTIVES: The aim of this study was to evaluate and compare the rate of degradation and elimination of praziquantel and fenbendazole antiparasitics following oral administration to salmonids. In addition, we determine whether the length of the legal withdrawal period is sufficient for complete elimination of antiparasitic residue from the body. The use of these drugs in fish is currently considered off-label and data on degradation are not available for rainbow trout. METHODS: The model species for this experiment was the rainbow trout (Oncorhynchus mykiss) and praziquantel and fenbendazole were chosen for experimental therapy. Both drugs were administered into the gastrointestinal tract using a stomach tube. Concentrations of fenbendazole and praziquantel were established through high performance liquid chromatography-tandem mass spectrometry. RESULTS: Our results show that concentrations of praziquantel and fenbendazole reach their maximum in the body within 24 hours of administration, with concentrations dropping sharply over the following 24 hours. With one exception, when trace amounts of both substances were found in blood plasma, the drugs were completely degraded and eliminated from the body by the end of the experiment (corresponding to 497.6 degree days). CONCLUSIONS: Praziquantel and fenbendazole both show a high rate of degradation and elimination from fish. As both substances were eliminated from the body within the required withdrawal period (i.e. within 500 degree days) they can be safely used based on current knowledge of their therapeutic effect for treating helminth infections. PMID- 26757114 TI - Effect of arsenic and cyanobacterial co-exposure on pathological, haematological and immunological parameters of rainbow trout (Oncorhynchus mykiss). AB - OBJECTIVES: Under environmental conditions, fish are simultaneously exposed to multiple stressors. This study provides new knowledge on the effects of controlled exposure to multiple stressors, namely cyanobacterial biomass and food contaminated with arsenic. METHODS: Rainbow trout were divided into six groups of 25 fish and exposed to different contaminant combinations for 30 days: 1) control group, 2) cyanobacterial biomass, 3 & 4) two groups exposed to arsenic at concentrations of 5 mg.kg(-1) and 50 mg.kg(-1) fish feed, and 5 & 6) two groups exposed to cyanobacterial biomass and arsenic combined. We then evaluated pathological, haematological and immunological parameters at 10, 20 and 30 days after exposure. RESULTS: Marked gross pathological findings were present in groups exposed to arsenic and arsenic/cyanobacteria after 30 days. A strong decrease in haemoglobin concentration was observed in all experimental groups receiving arsenic after 10 days exposure. Total leukocyte count increased markedly in fish exposed to cyanobacterial biomass, and to higher arsenic concentrations by the end of the experiment. Neutrophils decreased significantly at the end of exposure. Similarly, exposure to cyanobacteria and/or arsenic led to suppression of opsonised zymosan particle-induced neutrophil respiratory bursts. CONCLUSIONS: Our results demonstrate that the effects of exposure to toxic cyanobacterial biomass and arsenic on fish are enhanced when the contaminants are combined. In particular, long-term exposure led to disturbances in the white blood-cell count. Modulation of phagocytosis, which is the first line of defence against invading pathogens, suggests that the combined action leads to a decreased ability to control infection. PMID- 26757115 TI - Effect of polymeric nanoparticle poly(ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA) on in vitro luteinizing hormone release from anterior pituitary cells of infantile and adult female rats. AB - OBJECTIVES: Polymeric PEG-b-PLA nanoparticles (NPs) were developed for delivery of poorly water-soluble drugs via blood brain barrier into brain parenchyma. We analyzed neuroendocrine disrupting effects of neonatal exposure of female rats to PEG-b-PLA NPs and diethylstilbestrol (DES) on the function of adenohypophyseal gonadotrophs of infantile or adult rats by examining in vitro luteinizing hormone releasing hormone (LHRH)-induced luteinizing hormone (LH) release. METHODS: Neonatal female Wistar rats were injected intraperitoneally, daily, from postnatal day (PND) 4 to PND7 with PEG-b-PLA NPs (20 mg.kg b.w.(-1)), DES (4 ug.kg b.w.(-1)) or vehicle. At the necropsy day (PND15 in infantile and the first estrus day after PND176 in adult rats), adenohypophyseal cells were isolated by enzymatic digestion, plated in 96-well plates (5*10(4) cells.well(-1)) in serum supplemented medium and left to recover for 96 h. LHRH (10-7 mol.L(-1)) treatment was performed in serum-free medium for 60 min and LH levels in culture media were determined by radioimmunoassay. RESULTS: In all experimental groups, in vitro LHRH treatment significantly stimulated LH release from pituitary cells of infantile but not adult female rats. Neonatal DES treatment increased basal LH secretion from cultured pituitary cells of adult but not infantile rats. In both, infantile and adult rats, neonatal treatment with PEG-b-PLA significantly increased basal and LHRH-induced LH release from pituitary cells compared to corresponding controls and DES-treated group. CONCLUSIONS: Data indicate that neonatal exposure to PEG-b-PLA NPs may alter pituitary LH release, and thereby modify reproductive system development in infantile female rats leading to reproductive dysfunctions in adult age. PMID- 26757116 TI - Effects of acute exposure to deltamethrin and recovery time on common carp (Cyprinus carpio L.). AB - OBJECTIVES: The aim of this study is to evaluate effects of the insecticide Decis Mega (DM; active substance deltamethrin 50 g.L(-1)) on common carp on the basis of haematological profile, oxidative stress, antioxidant enzymes and histopathology. DESIGN: Fish were exposed two concentrations of DM 6.56 MUg.L(-1) (1DM) and 65.6 MUg.L(-1) (2DM) for 96 h. Then the remaining fish were transferred into DM-free water for depuration for another period of 96 h. RESULTS: Exposure to 1DM and 2DM proved effect on enzymatic activity of superoxide dismutase, catalase, glutathione reductase and on oxidative damage of cells in gills, liver and kidney (p<0.05, p<0.01). Exposure to 1DM showed differences (p<0.05, p<0.01) in hematocrit and hemoglobin in blood. Histopathological changes were observed after acute exposure to DM as well as to DM-free water in gills, liver and kidney. CONCLUSION: This study concludes that deltamethrin has influence on the haematological parameters, activity of antioxidant enzymes and caused oxidative damage, and histopathological changes in the fish. However, antioxidant balance in the body was restored after placing the fish in clean water for 4 days, however, this time was not sufficient complete regeneration. PMID- 26757117 TI - Effects of terbuthylazine on early life stages of common carp. AB - OBJECTIVES: The aim of this study was to assess the toxicity of terbuthylazine in different developmental stages of common carp (Cyprinus carpio) on the basis of mortality, early ontogeny, occurrence of morphological anomalies, growth rate, and Fulton's condition factor during and at the conclusion of the test. DESIGN: The toxicity tests were performed on carp according to OECD 210 methodology. The developmental stages of carp were exposed to terbuthylazine at four concentrations, 2.9 (reported environmental concentration in Czech rivers); 70; 1,400; and 3,500 ug.L(-1) for 35 days and compared to carps in a non-treated control group. RESULTS: Terbuthylazine in concentration 1,400 and 3,000 ug.L(-1) caused significant (p<0.01) decrease of mass, total length and delayed in development of carp. Fish exposed to terbuthylazine showed alteration of tubular system of caudal kidney. On the basis of histopathological changes the values of LOEC=2.9 ug.L(-1) terbuthylazine were estimated. CONCLUSIONS: Chronic terbuthylazine exposure of early-life stages of common carp affected their growth rate, early ontogeny and histology. Some of the changes were observed only at higher exposures, but change founded in caudal kidney was affected in fish exposed to the real environmental concentration tested (i.e., 2.9 ug.L(-1)). PMID- 26757118 TI - Evaluation of mercury contamination in dogs using hair analysis. AB - OBJECTIVES: The present work is aimed at assessing the mercury contamination of dogs through the analysis of hair. For the determination of the total mercury in dogs, we chose skin derivatives--hair. The content of total mercury was also measured in the pelleted feed. METHODS: Dogs were divided into two groups. The first group (group A) was fed granular feed containing fish and the second group (group B) granular feed free of fish. A total of 131 hair and granular feed samples were collected. The total mercury in hair and granular feed samples was measured using atomic absorption spectrophotometry on AMA 254. RESULTS: The values of the total mercury content in the hair of dogs had a median value of 0.0375 mg.kg(-1) in group A and of 0.0336 mg.kg(-1) in group B. No statistically significant difference was found between the groups (p>0.05). The median values of the total mercury were 0.0048 mg.kg(-1) in group A and 0.0017 mg.kg(-1) in group B, respectively. A highly statistically significant difference between the groups was found (p<0.01). CONCLUSIONS: No correlation was obtained between the total mercury content in the hair of dogs and granulated feed (rs=0.2069, p>0.05). The reason may be a content of various mercury species in feed samples or a human failure (nonobservance of the prescribed diet). PMID- 26757119 TI - Ferrous and ferric state of cytochromes P450 in intact Escherichia coli cells: a possible role of cytochrome P450-flavodoxin interactions. AB - OBJECTIVES: Cytochromes P450 (CYPs) are heme enzymes oxygenating a broad range of substrates. Their activity is dependent on the presence of a suitable electron donor (eukaryotic NADPH:CYP oxidoreductase or cytochrome b5). The Escherichia naturally contain no CYPs and no NADPH:CYP oxidoreductase, however it was reported that some CYPs heterologously expressed in E. coli may exist in the ferrous form. A small bacterial flavoprotein, flavodoxin is considered to be responsible for reduction some of these CYPs. METHODS: The reduction state of several human CYPs expressed in the intact living E. coli cells was examined. In addition, molecular dynamics and steered molecular dynamics simulations were performed to predict and compare affinity of flavodoxin toward selected CYPs. RESULTS: We determined the reduction state of five human CYPs heterologously expressed in E. coli. The computationally predicted stabilities of CYP-flavodoxin complexes correlate with the percentage of reduced CYPs in bacterial cells. The mean electron transfer distance within optimized complexes was also related to the percentage of reduced CYPs. CONCLUSION: Depending on the resting state, the CYPs heterologously expressed in E. coli could be divided into two groups; CYP2C8, 2C9, 3A4 are in E. coli present mainly in the oxidized form; while CYP1A1, 1A2, 2A6, 2A13, 2B6, 2D6 are found predominantly in the reduced form. We found a significant correlation between the stability of CYP-flavodoxin complexes and the percentage of reduced CYPs in bacteria. Hence, the naturally expressed flavodoxin is probably responsible for reduction of a larger group of human CYPs in bacterial cells. PMID- 26757120 TI - Impact of tacrine and 7-methoxytacrine on gastric myoelectrical activity assessed using electrogastrography in experimental pigs. AB - OBJECTIVES: Tacrine was the first acetylcholinesterase inhibitor approved for therapy of Alzheimer's disease. It has currently been withdrawn in some countries mostly due to the risk of hepatotoxicity and might be replaced by its derivate 7 methoxytacrine (7-MEOTA). The aim of this study was to assess the impact of these two compounds on gastric myoelectrical activity by means of surface cutaneous electrogastrography (EGG). METHODS: Twelve pigs (Sus scrofa f. domestica, weighing 30-35 kg) entered the study. A single dose of tacrine (200 mg i.m., n=6) or 7-MEOTA (200 mg i.m., n=6) was administrated. All EGG recordings were performed under general anaesthesia in the morning after 24 hours of fasting. Basal (30 minutes) and study recordings (150 minutes) were accomplished using an EGG stand (MMS, Enschede, the Netherlands). Results were expressed as dominant frequency of gastric slow waves, power analysis (areas of amplitudes) and power ratio assessment (ratio of the areas of amplitudes after and before study drug administration). RESULTS: Tacrine decreased EGG dominant frequency 10 minutes after its administration (from basal 3.1+/-0.6 to 2.8+/-0.6 cycles per minute; p=0.014). Tacrine induced a non-significant 60-minute increase of the power (with maximal value 493+/-533 MUV2 at 20 minutes) and power ratio (with maximal value 2.04+/-3.4 at 10 minutes). Tacrine caused substantial gastric arrhythmia. 7-MEOTA did not influence dominant frequency of gastric slow waves significantly. 7-MEOTA caused a short-term late increase of the power ratio at 60 minutes (6.3+/-11.2; p=0.003). Blood cholinesterase activity did not correlate with any EGG parameter either after tacrine or 7-MEOTA at any time. CONCLUSIONS: Tacrine and 7-MEOTA have different impacts on EGG. Tacrine decreased dominant frequency and induced long-lasting gastric arrhythmia. 7-MEOTA caused a short-term late increase of the EGG power in experimental pigs. PMID- 26757121 TI - Mixture toxicity of microcystin-LR, paraoxon and bromadiolone in Xenopus laevis embryos. AB - OBJECTIVES: Apart from infections and habitat loss, environmental pollution is another major factor of global decline of amphibians. Using the model of Xenopus laevis embryos, we test the hypothesis that combined exposure of amphibians to natural toxins and anthropogenic pollutants induces more pronounced adverse effects than single exposures. METHODS: Experimental procedures adhered to Frog Embryo Teratogenesis Assay - Xenopus standards (FETAX). Exposure groups included controls, solvent (dimethyl sulfoxide) controls, and embryos exposed for 96 h to single, double and triple action of paraoxon (P), bromadiolone (B), and microcystin-LR (M), added to the FETAX medium at a dose of 300, 350, and 500 MUg.L(-1), respectively. Studied responses of X. laevis embryos included mortality and malformations, head-to-tail length, total antioxidant capacity, lipid peroxidation, and caspase-3 activity. RESULTS: The triple combination induced the highest mortality. Malformations in embryos significantly prevailed only in B-, and B+P-exposure groups. Apart from the single exposure to B, the tested substances and their combinations inhibited the embryonic growth. Triple exposure had the most pronounced effect both on the growth inhibition and total antioxidant capacity. Lipid peroxidation was increased after B+M exposure, while single and combined exposures to B and P had an opposite effect. CONCLUSIONS: This study helps to understand adverse effects of environmental pollution by natural toxins and agrochemicals in amphibians. The results allow for risk assessment of environmental pollution and findings of low concentrations of contaminants in aquatic environments. Further research to address issues such as mixture toxicity to metamorphosing and adult amphibians is necessary. PMID- 26757122 TI - Neonatal withdrawal syndrome and perinatal asphyxia. How to manage the patient? Case Report. AB - The aim of this work is to present the pitfalls of management of newborns with neonatal withdrawal syndrome (NWS) of different forms, which were complicated with the presence of severe perinatal asphyxia. The authors present some case reports of asphyxiated newborns of different gestational age with different forms of NWS. Prenatal and perinatal asphyxia determines the prognosis of future development of newborn. The combination of the asphyxia and NWS is stressful not only for the patient, but also for the physician. The most important step in management of this group of patients is to know the detailed mother's and patient's history and to perform detailed physical investigation. The optimal prenatal, perinatal and postnatal management with good cooperation between gynecologist and neonatologist can improve the quality of newborn's life. Care of newborn requires all the time teamwork. PMID- 26757123 TI - Oxidative stress indices and histopathological effects of the nonsteroidal antiinflammatory drug naproxen in adult zebrafish (Danio rerio). AB - OBJECTIVES: The aim of this study was to investigate the effects of the nonsteroidal antiinflammatory drug naproxen on adult zebrafish (Danio rerio). METHODS: Three months old zebrafish (Danio rerio) were exposed to naproxen at concentrations of 0.001, 0.1 and 5 mg.L(-1). We focused on the changes in oxidative stress indices during and at the end of the experiment and histopathological examination of tissues after a two week long exposure period. RESULTS: We found that a 3 day long exposure to naproxen causes mild oxidative stress and affects detoxification in zebrafish, which is demonstrated by the increased activity of glutathione peroxidase and glutathione S-transferase at 0.001 and 0.1 mg.L(-1) of naproxen, respectively. After a 7 day long exposure to 0.1 and 5 mg.L(-1), more potent effects on enzymes occur. However, these effects are only short lasting. At the end of the experiment, the activities of the target enzymes recover back to homeostatic baseline levels. Except catalase, which is induced only after a two week long exposure to the environmental concentration of naproxen. Despite the fact that naproxen causes mild oxidative stress in zebrafish, exposure to this drug does not result in lipid peroxidation. Histopathological examination revealed obvious changes to the gills and liver even at exposure to the environmental concentration of naproxen. CONCLUSION: This study demonstrates that the environmental concentration of naproxen can slightly influence both the antioxidant defense system and histopathology of non-target fish. PMID- 26757124 TI - Preparation and application of anti-peptide antibodies for detection of orphan cytochromes P450. AB - OBJECTIVES: Cytochromes P450 (CYP) are monooxygenases, which metabolize mostly hydrophobic endogenous and exogenous compounds. CYPs without any clear connection to metabolism are called "orphans". Interestingly, these "orphan" CYPs are over expressed in tumor tissues. Thus, the main aim of the paper is the development of antibodies for immunodetection of these CYPs as potential malignancy markers. METHODS: Unique sequences of CYP2S1 and 2W1 were selected and peptides synthesized. Chickens were immunized with peptides bound to hemocyanin (KLH). The antibodies were isolated from egg yolks and their reactivity was tested by ELISA. Antibodies were further affinity purified on immobilized peptides. Western blots containing CYP2S1 and 2W1 standards were developed with purified antibodies. RESULTS: Using unique peptide immunogens of CYP2S1 and 2W1 the antibodies were developed. As judged from ELISA all chickens produced specific antibodies against the respective peptides. Both affinity purified antibodies against CYP2S1 peptide recognized the CYP2S1 standard on Western blots, but only one of four anti peptide antibodies against CYP2W1 reacted with CYP2W1 standard. The antibodies were used for the detection of CYPs in cancer cell lines and human tissues samples. Although both CYPs were frequently co-expressed in cancer cells, CYP2S1 was solely induced in the cell line BxPC3, while CYP2W1 was predominantly present in cell lines MCF7 and HeLa. Our data show that anti-peptide antibodies are an indispensable tool for detection of homologous CYPs. CONCLUSIONS: The anti peptide antibodies successfully recognized CYP2S1 and 2W1 in the cancer cell lines and tissue samples. PMID- 26757125 TI - Preparation and evaluation of carriers for detection of cholinesterase inhibitors. AB - OBJECTIVES: The aim of the study was to use methods of pharmaceutical technology, and prepare carriers in the form of pellets suitable as a filling of detection tubes for enzymatic detection of cholinesterase inhibitors. The enzymatic detection was based on enzymatic hydrolysis of acetylthiocholine iodide and the subsequent colour reaction of its hydrolysis product with Ellman's reagent. The suitable carriers should be in the form of white, regular and sufficiently mechanically resistant particles of about 1 mm allowing it to capture the enzyme during the impregnation process and ensuring its high activity for enzymatic detection. METHODS: Carriers consisting of microcrystalline cellulose, lactose, povidone, and sodium carboxymethyl cellulose were prepared using extrusion spheronization method under three different drying conditions in either a hot air oven or a microwave oven. Subsequently, the carriers were impregnated with acetylcholinesterase and their size, shape, mechanical resistance, bulk, tapped and pycnometric density, Hausner ratio, intraparticular and total tapped porosity, and activity were measured and recorded. RESULTS: In this procedure, carriers with different physical parameters and different acetylcholinesterase activity were evaluated. It was found that higher acetylcholinesterase activity was associated not only with a higher intraparticular porosity but also with more regular particles characterized by high sphericity and low total tapped porosity. CONCLUSION: This unique finding is important for the preparation of detection tubes based on enzymatic detection which is still irreplaceable especially in the field of detection and analysis of super-toxic cholinesterase inhibitors. PMID- 26757126 TI - Residues of selected antibiotics in the South Moravian Rivers, Czech Republic. AB - OBJECTIVES: The aim of this study was to assess the contamination level of aquatic ecosystems of the Oslava and the Jihlava Rivers, and of the Nove Mlyny Water Reservoir, situated in the South Moravian Region (Czech Republic), by residues of selected veterinary pharmaceuticals. We isolated and determined 10 sulfonamide antibiotics in samples of surface water and bottom sediments using optimized analytical methods. DESIGN: A representative number of sampling sites in the entire basin of selected waters were chosen. Samples were collected particularly near the larger cities in order to assess their possible impact to the aquatic ecosystems. Extraction, pre-concentration and purification of samples were performed using optimized methods of solid phase extraction and pressurized solvent extraction. Final identification and quantification were carried out by high-performance liquid chromatography coupled with diode array detector. RESULTS: The concentration of sulfonamides in water samples were all under the limit of detection. Regarding sediment samples, sulfadimidine was found at most sampling sites; its highest values were recorded in the Jihlava River (up to 979.8 ug.kg(-1) dry matter). Other frequently detected sulfonamides were sulfamethoxazole and sulfamerazine. Most other sulfonamides were under the limit of detection or limit of quantification. CONCLUSIONS: Monitoring of antibiotic residues in the environment, especially in the aquatic ecosystem, is a current topic due to the growing worldwide use in both human and veterinary medicine. According to obtained results, we document the pollution of selected rivers and water reservoir by particular sulfonamides which basically reflects their application in veterinary medicine. PMID- 26757127 TI - Role of dihydromyricetin in cytochrome P450-mediated metabolism and carcinogen activation. AB - OBJECTIVES: Dihydromyricetin (DHM) is a flavonoid, which has been shown to antagonize effects of ethanol intoxication. As a potential pharmacological agent, its biological interactions with enzymes metabolizing foreign compounds should be tested. Thus, the aim of this study was to analyze the influence of DHM on the induction and metabolic activity of selected cytochromes P450 (CYPs). METHODS: After flavonoid administration by oral gavage to stomach the CYP expression at protein and mRNA levels was determined in rat liver and small intestine. The effects of flavonoids on CYP1A1/2, CYP1A2 or CYP2B1/2 enzyme activities in microsomes were measured using marker activities of these enzymes. Flavonoid mediated inhibition of recombinant CYP1A2 was also assayed with luciferin-ME substrate. The flavonoid interaction with aryl hydrocarbon receptor (AhR) was assayed by reporter luciferase activity in Hep2G cells. RESULTS: The value of half maximal inhibitory concentration of DHM for CYP1A1/2, CYP1A2, and CYP2B1 were determined to be 4.1, 14.2, and 98.5 mmol.L(-1), respectively. With the exception of a weak induction of CYP2B1 and CYP1A2 in the middle part of small intestine and in the liver, respectively, DHM did not affect the CYP expression at protein levels. On the contrary, real-time PCR revealed elevated expression of CYP1A1 and CYP1A2 mRNA in proximal part of the small intestine while decreased in the middle part. In the study utilizing the HepG2 cells, DHM showed only an additive effect on the benzo[a]pyrene-mediated activation of Ah receptor. CONCLUSIONS: Dihydromyricetin doesn't significantly interfere with metabolic activity of CYP1A1/2 and CYP2B1 enzymes. PMID- 26757128 TI - The effect of the fluoroquinolone norfloxacin on somatic indices and oxidative stress parameters in early stages of common carp (Cyprinus carpio L.). AB - OBJECTIVES: The aim of this study was to assess the effect of the subchronic exposure of early stages of common carp (Cyprinus carpio L.) to norfloxacin using morphometric data and oxidative stress parameters. METHODS: A subchronic toxicity test was performed on fertilized embryos of common carp according to the OECD Guidelines No. 210. Embryos were exposed to norfloxacin concentrations of 0.0001 (environmental), 0.1, 1.0, 5.0, and 10.0 mg.L(-1) for 34 days. RESULTS: At the end of the test (day 34), significant (p<0.05) stimulation of development was observed in all experimental groups, in contrast to the control. Significantly greater (p<0.01) total body length was also observed in the group exposed to 10.0 mg.L(-1) of norfloxacin compared to the control. A significant increase in the activity of glutathione S-transferase in all carp exposed to norfloxacin concentrations of 0.1 and 1.0 mg.L(-1) (p<0.01), and 5.0 mg.L(-1) (p<0.05) compared to control group was revealed. The activity of glutathione peroxidase was significantly lower (p<0.01) in experimental carp exposed to a norfloxacin concentration of 10.0 mg.L(-1). In experimental carp exposed to a norfloxacin concentration of 0.0001 mg.L(-1), a significant increase (p<0.05) in glutathione reductase activity was found. Significant (p<0.01) decreases in the content of thiobarbituric acid reactive substances in the groups exposed to norfloxacin concentrations of 1.0, 5.0, and 10.0 mg.L(-1) were revealed. CONCLUSION: From the results, we can conclude that norfloxacin has a negative impact on selected biochemical processes related to the production of reactive oxygen species in early-life stages of common carp. PMID- 26757129 TI - The effects of heavy metal ions, phthalates and ochratoxin A on oxidation of carcinogenic aristolochic acid I causing Balkan endemic nephropathy. AB - OBJECTIVES: Balkan endemic nephropathy (BEN) is a chronic progressive fibrosis associated with upper urothelial carcinoma (UUC). Aetiology of BEN is still not fully explained. Although carcinogenic aristolochic acid I (AAI) was proven as the major cause of BEN/UUC, this nephropathy is considered to be multifactorial. Hence, we investigated whether other factors considered as potential causes of BEN [a mycotoxin ochratoxin A (OTA), Cd, Pb, Se and As ions and organic compounds (i.e. phthalates) released from lignite deposits in BEN areas] can influence detoxication of AAI, whose concentrations are crucial for BEN development. METHODS: Oxidation of AAI to 8-hydroxyaristolochic acid I (AAIa) in the presence of Cd, Pb, Se, As ions, dibutylphthalate (DBP), butylbenzylphthalate (BBP), bis(2 ethylhexyl)phthalate (DEHP) and OTA by rat liver microsomes was determined by HPLC. RESULTS: Only OTA, cadmium and selenium ions, and BBP inhibited AAI oxidation by rat liver microsomes. These compounds also inhibited activities of CYP1A1 and/or CYP2C6/11 catalysing AAI demethylation in rat livers. Therefore, these CYP inhibitions can be responsible for a decrease in AAIa formation. When the combined effects of these compounds were investigated, the most efficient inhibition was caused by OTA combined with BBP and selenium ions. CONCLUSION: The results show low effects of BBP, cadmium and selenium ions, and/or their combinations on AAI detoxication. No effects were produced by the other metal ions (Pb, As) and phthalates DBP and DEHP. This finding suggests that they do not influence AAI-mediated BEN development. In contrast, OTA might influence this process, by inhibition of AAI detoxication. PMID- 26757130 TI - Unusual way of suicide by carbon monoxide. Case Report. AB - OBJECTIVES: Authors discuss the case of a suicide of a 29-year-old man caused by carbon monoxide (CO) intoxication. What the authors found interesting was the unusual way of committing suicide that required good technical skills and expert knowledge. METHODS: The level of carboxyhemoglobin (COHb) in the blood of the deceased man was routinely determined by the modified method by Blackmoore (1970), using gas chromatography/thermal conductivity detection. The level of saturation of the hemoglobin by CO in the collected blood sample is determined relatively to the same sample saturated to 100%. RESULTS: In the blood sample of the deceased man the lethal concentration of COHb of 76.5% was determined. Within the following examinations the blood alcohol concentration of 0.05 g.kg(-1) was determined. Further analysis revealed traces of sertraline, its metabolite N desmethylsertraline, omeprazole and caffeine in the liver tissue, traces of N desmethylsertraline, ibuprofen and caffeine in urine sample, and only traces of caffeine in the stomach content and blood samples were proved. To commit suicide the man used a sophisticated double container-system equipped with a timer for controlled generation of CO based on the chemical reaction of concentrated sulphuric acid and formic acid. The used timer was set by an electromechanical timer switch that triggered the fatal reaction of the acids while the man was sleeping. CONCLUSIONS: The authors discuss an unusual case of suicide by CO intoxication rarely seen in the area of forensic medicine and toxicology that is specific due to its sophisticated way of execution. PMID- 26757131 TI - Synthesis and Diels-Alder Reactivity of Substituted [4]Dendralenes. AB - The first synthesis of all five possible monomethylated [4]dendralenes has been achieved via two distinct synthetic strategies. The Diels-Alder chemistry of these new dendralenes (as multidienes) with an electron poor dienophile, N methylmaleimide (NMM), has been studied. Thus, simply upon mixing the dendralene and an excess of dienophile at ambient temperature in a common solvent, sequences of cycloadditions result in the rapid generation of complex multicyclic products. Distinct product distributions are obtained with differently substituted dendralenes, demonstrating that dendralene substitution influences the pathway followed, when a matrix of mechanistic possibilities exists. Dendralene site selectivities are traced to electronic, steric and conformational effects, thereby allowing predictive tools for applications of substituted dendralenes in future synthetic endeavors. PMID- 26757132 TI - Occurrence and distribution of the environmental pollutant antibiotics in Gaoqiao mangrove area, China. AB - Occurrence and distribution of 15 antibiotics belonging to families of sulfonamides, fluoroquinolones, tetracyclines and chloramphenicols were investigated in water and sediment in Gaoqiao mangrove area, China, using LC-MS MS. The influence of tidal level and mangrove vegetation on antibiotic residues were examined. The levels of antibiotics were found to be ranged from 0.15 to 198 ng L(-1) in water and from 0.08 to 849 MUg kg(-1) in sediment. No significant difference in concentrations of 15 different antibiotics from water and sediment samples was observed among the high, middle and low intertidal channel. The residues of SMZ, SMTZ, OFL, NOR, ENR, OXY and FLO were significantly higher in Aegiceras corniculatum assemblage than in Avicennia marina assemblage. Although no significant difference in tested antibiotics was found between the surface and bottom sediment, mangrove vegetation can to some extent reduce the accumulation for SMZ, SMTZ, OFL, NOR, CIP, OXY and TET in sediments relative to corresponding bare mudflats, implying that the environmental pollution from antibiotics may be mitigated by mangrove vegetation. Principal components analysis revealed that the terrestrial input and different habitats directly influenced the occurrence and distribution of antibiotics. PMID- 26757133 TI - A novel A allele with multiple missense mutations in Exon 7 identified in a Chinese individual. PMID- 26757136 TI - Effects of group exercise programmes on quality of life in older adults with mild cognitive impairment: preliminary results from a randomized controlled trial. PMID- 26757134 TI - Genetic and Nongenetic Factors Affecting Clopidogrel Response in the Egyptian Population. AB - Aspirin and clopidogrel are the mainstay oral antiplatelet regimens, yet a substantial number of major adverse cardiac events (MACE) still occur. Herein, we investigated genetic and nongenetic factors associated with clopidogrel response in Egyptians. In all, 190 Egyptians with acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI), treated with clopidogrel (75 mg/day) for at least a month, were genotyped for CYP2C19 *2, *3, *6, *8, *10, and *17, CES1 G143E and ABCB1*6 and *8. These variants along with nongenetic factors were tested for association with the risk of having MACE in clopidogrel-treated patients. CYP2C19 loss-of-function (LOF) alleles carriers had increased risk of MACE vs. noncarriers (odds ratio 2.52; 95% confidence interval 1.23-5.15, P = 0.011). In a logistic regression, CYP2C19 LOF variants (P = 0.011), age (P = 0.032), and body mass index (BMI, P = 0.039) were significantly associated with the incidence of MACE in patients taking clopidogrel. CYP2C19 genetic variants, age, and BMI are potential predictors associated with variability to clopidogrel response in Egyptians. PMID- 26757138 TI - Kinetic Rate Kernels via Hierarchical Liouville-Space Projection Operator Approach. AB - Kinetic rate kernels in general multisite systems are formulated on the basis of a nonperturbative quantum dissipation theory, the hierarchical equations of motion (HEOM) formalism, together with the Nakajima-Zwanzig projection operator technique. The present approach exploits the HEOM-space linear algebra. The quantum non-Markovian site-to-site transfer rate can be faithfully evaluated via projected HEOM dynamics. The developed method is exact, as evident by the comparison to the direct HEOM evaluation results on the population evolution. PMID- 26757137 TI - Enhancement of CO2 Adsorption and Catalytic Properties by Fe-Doping of [Ga2(OH)2(L)] (H4L = Biphenyl-3,3',5,5'-tetracarboxylic Acid), MFM-300(Ga2). AB - Metal-organic frameworks (MOFs) are usually synthesized using a single type of metal ion, and MOFs containing mixtures of different metal ions are of great interest and represent a methodology to enhance and tune materials properties. We report the synthesis of [Ga2(OH)2(L)] (H4L = biphenyl-3,3',5,5'-tetracarboxylic acid), designated as MFM-300(Ga2), (MFM = Manchester Framework Material replacing NOTT designation), by solvothermal reaction of Ga(NO3)3 and H4L in a mixture of DMF, THF, and water containing HCl for 3 days. MFM-300(Ga2) crystallizes in the tetragonal space group I4122, a = b = 15.0174(7) A and c = 11.9111(11) A and is isostructural with the Al(III) analogue MFM-300(Al2) with pores decorated with OH groups bridging Ga(III) centers. The isostructural Fe-doped material [Ga(1.87)Fe(0.13)(OH)2(L)], MFM-300(Ga(1.87)Fe(0.13)), can be prepared under similar conditions to MFM-300(Ga2) via reaction of a homogeneous mixture of Fe(NO3)3 and Ga(NO3)3 with biphenyl-3,3',5,5'-tetracarboxylic acid. An Fe(III) based material [Fe3O(1.5)(OH)(HL)(L)(0.5)(H2O)(3.5)], MFM-310(Fe), was synthesized with Fe(NO3)3 and the same ligand via hydrothermal methods. [MFM 310(Fe)] crystallizes in the orthorhombic space group Pmn21 with a = 10.560(4) A, b = 19.451(8) A, and c = 11.773(5) A and incorporates MU3-oxo-centered trinuclear iron cluster nodes connected by ligands to give a 3D nonporous framework that has a different structure to the MFM-300 series. Thus, Fe-doping can be used to monitor the effects of the heteroatom center within a parent Ga(III) framework without the requirement of synthesizing the isostructural Fe(III) analogue [Fe2(OH)2(L)], MFM-300(Fe2), which we have thus far been unable to prepare. Fe doping of MFM-300(Ga2) affords positive effects on gas adsorption capacities, particularly for CO2 adsorption, whereby MFM-300(Ga(1.87)Fe(0.13)) shows a 49% enhancement of CO2 adsorption capacity in comparison to the homometallic parent material. We thus report herein the highest CO2 uptake (2.86 mmol g(-1) at 273 K at 1 bar) for a Ga-based MOF. The single-crystal X-ray structures of MFM-300(Ga2) solv, MFM-300(Ga2), MFM-300(Ga2).2.35CO2, MFM-300(Ga(1.87)Fe(0.13))-solv, MFM 300(Ga(1.87)Fe(0.13)), and MFM-300(Ga(1.87)Fe(0.13)).2.0CO2 have been determined. Most notably, in situ single-crystal diffraction studies of gas-loaded materials have revealed that Fe-doping has a significant impact on the molecular details for CO2 binding in the pore, with the bridging M-OH hydroxyl groups being preferred binding sites for CO2 within these framework materials. In situ synchrotron IR spectroscopic measurements on CO2 binding with respect to the -OH groups in the pore are consistent with the above structural analyses. In addition, we found that, compared to MFM-300(Ga2), Fe-doped MFM 300(Ga(1.87)Fe(0.13)) shows improved catalytic properties for the ring-opening reaction of styrene oxide, but similar activity for the room-temperature acetylation of benzaldehyde by methanol. The role of Fe-doping in these systems is discussed as a mechanism for enhancing porosity and the structural integrity of the parent material. PMID- 26757135 TI - Natural history collections as windows on evolutionary processes. AB - Natural history collections provide an immense record of biodiversity on Earth. These repositories have traditionally been used to address fundamental questions in biogeography, systematics and conservation. However, they also hold the potential for studying evolution directly. While some of the best direct observations of evolution have come from long-term field studies or from experimental studies in the laboratory, natural history collections are providing new insights into evolutionary change in natural populations. By comparing phenotypic and genotypic changes in populations through time, natural history collections provide a window into evolutionary processes. Recent studies utilizing this approach have revealed some dramatic instances of phenotypic change over short timescales in response to presumably strong selective pressures. In some instances, evolutionary change can be paired with environmental change, providing a context for potential selective forces. Moreover, in a few cases, the genetic basis of phenotypic change is well understood, allowing for insight into adaptive change at multiple levels. These kinds of studies open the door to a wide range of previously intractable questions by enabling the study of evolution through time, analogous to experimental studies in the laboratory, but amenable to a diversity of species over longer timescales in natural populations. PMID- 26757140 TI - Interactions of metal-based engineered nanoparticles with aquatic higher plants: A review of the state of current knowledge. AB - The rising potential for the release of engineered nanoparticles (ENPs) into aquatic environments requires evaluation of risks to protect ecological health. The present review examines knowledge pertaining to the interactions of metal based ENPs with aquatic higher plants, identifies information gaps, and raises considerations for future research to advance knowledge on the subject. The discussion focuses on ENPs' bioaccessibility; uptake, adsorption, translocation, and bioaccumulation; and toxicity effects on aquatic higher plants. An information deficit surrounds the uptake of ENPs and associated dynamics, because the influence of ENP characteristics and water quality conditions has not been well documented. Dissolution appears to be a key mechanism driving bioaccumulation of ENPs, whereas nanoparticulates often adsorb to plant surfaces with minimal internalization. However, few reports document the internalization of ENPs by plants; thus, the role of nanoparticulates' internalization in bioaccumulation and toxicity remains unclear, requiring further investigation. The toxicities of metal-based ENPs mainly have been associated with dissolution as a predominant mechanism, although nano toxicity has also been reported. To advance knowledge in this domain, future investigations need to integrate the influence of ENP characteristics and water physicochemical parameters, as their interplay determines ENP bioaccessibility and influences their risk to health of aquatic higher plants. Furthermore, harmonization of test protocols is recommended for fast tracking the generation of comparable data. Environ Toxicol Chem 2016;35:1677-1694. (c) 2016 SETAC. PMID- 26757139 TI - Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole exome sequencing as a first-line diagnostic test. AB - The current standard of care for diagnosis of severe intellectual disability (ID) and epileptic encephalopathy (EE) results in a diagnostic yield of ~50%. Affected individuals nonetheless undergo multiple clinical evaluations and low-yield laboratory tests often referred to as a 'diagnostic odyssey'. This study was aimed at assessing the utility of clinical whole-exome sequencing (WES) in individuals with undiagnosed and severe forms of ID and EE, and the feasibility of its implementation in routine practice by a small regional genetic center. We performed WES in a cohort of 43 unrelated individuals with undiagnosed ID and/or EE. All individuals had undergone multiple clinical evaluations and diagnostic tests over the years, with no definitive diagnosis. Sequencing data analysis and interpretation were carried out at the local molecular genetics laboratory. The diagnostic rate of WES reached 32.5% (14 out of 43 individuals). Genetic diagnosis had a direct impact on clinical management in four families, including a prenatal diagnostic test in one family. Our data emphasize the clinical utility and feasibility of WES in individuals with undiagnosed forms of ID and EE and highlight the necessity of close collaborations between ordering physicians, molecular geneticists, bioinformaticians and researchers for accurate data interpretation. PMID- 26757141 TI - Functional Comorbidity Index in chronic rhinosinusitis. AB - BACKGROUND: The Functional Comorbidity Index is a promising tool to predict general health status and adjust for comorbidity confounding in outcomes studies of chronic conditions, but it has been tested as a predictor of general health status only in a sleep apnea cohort. We tested it in a chronic rhinosinusitis cohort with 2 objectives: (1) measure the association between the Functional Comorbidity Index (range, 0 to 18) and general health status (SF-36 Physical Component Score and Mental Component Score); and (2) test if the Functional Comorbidity Index is more strongly associated (a better predictor) than the well known Charlson Comorbidity Index (range, 0 to 37) with these SF-36 outcome measures. METHODS: In a cross-sectional study of chronic rhinosinusitis patients, we obtained scores for the Functional Comorbidity Index, Charlson Comorbidity Index, and the SF-36. We calculated Spearman correlations and adjusted coefficients of determination (R(2)) using multiple linear regression, adjusted for demographic covariates. Bootstrapping generated R(2) distributions for statistical comparison. RESULTS: In the cohort (N = 97), the Functional Comorbidity Index scores (mean +/- standard deviation: 2.2 +/- 1.9) were more widely distributed than Charlson Comorbidity Index scores (0.6 +/- 1.2). The Functional Comorbidity Index significantly correlated with the SF-36 Physical Component Score (-0.49, p < 0.001) and Mental Component Score (-0.37, p < 0.001). The Functional Comorbidity Index was a better predictor than the Charlson Comorbidity Index of SF-36 Physical Component Score (R(2) mean +/- standard error: 0.21 +/- 0.09 vs 0.15 +/- 0.05; p < 0.001) and Mental Component Score (0.16 +/- 0.10 vs 0.01 +/- 0.06; p < 0.001). CONCLUSION: The Functional Comorbidity Index is a more robust predictor of general health status than the Charlson Comorbidity Index in chronic rhinosinusitis patients. PMID- 26757143 TI - Surgical Treatment of Isthmic Spondylolisthesis. PMID- 26757142 TI - Real-Time Reverse Transcription PCR Assay for Detection of Senecavirus A in Swine Vesicular Diagnostic Specimens. AB - Senecavirus A (SV-A), formerly, Seneca Valley virus (SVV), has been detected in swine with vesicular lesions and is thought to be associated with swine idiopathic vesicular disease (SIVD), a vesicular disease syndrome that lacks a defined causative agent. The clinical presentation of SIVD resembles that of other more contagious and economically devastating vesicular diseases, such as foot-and-mouth disease (FMD), swine vesicular disease (SVD), and vesicular stomatitis (VS), that typically require immediate rule out diagnostics to lift restrictions on animal quarantine, movement, and trade. This study presents the development of a sensitive, SYBR Green RT-qPCR assay suitable for detection of SV A in diagnostic swine specimens. After testing 50 pigs with clinical signs consistent with vesicular disease, 44 (88%) were found to be positive for SV-A by RT-qPCR as compared to none from a negative cohort of 35 animals without vesicular disease, indicating that the assay is able to successfully detect the virus in an endemic population. SV-A RNA was also detectable at a low level in sera from a subset of pigs that presented with (18%) or without (6%) vesicular signs. In 2015, there has been an increase in the occurrence of SV-A in the US, and over 200 specimens submitted to our laboratory for vesicular investigation have tested positive for the virus using this method. SV-A RNA was detectable in all common types of vesicular specimens including swabs and tissue from hoof lesions, oral and snout epithelium, oral swabs, scabs, and internal organ tissues such as liver and lymph node. Genome sequencing analysis from recent virus isolates was performed to confirm target amplicon specificity and was aligned to previous isolates. PMID- 26757144 TI - Adipose-derived mesenchymal stem cells modulate the immune response in chronic experimental autoimmune encephalomyelitis model. AB - Multiple sclerosis (MS) is an autoimmune inflammatory neurodegenerative disease of the central nervous system (CNS) that disrupts the myelin sheath, leading to dysfunction of the brain and spinal cord. No curative treatment is known for MS. Mesenchymal stem cells, through their immunomodulatory effects, represent a promising therapeutic approach for MS. The aim of this article is to explore the impact of human adipose-derived mesenchymal stem cells (ASCs) on chronic experimental autoimmune encephalomyelitis (EAE) model of MS when injected after a disease entered an irreversible clinical course. Forty-one female albino rats were classified into the following groups: I: control, II: EAE-untreated, III and IV: EAE treated with PBS at 15 and 25 days postimmunization (dpi), respectively, V and VI: EAE treated with ASCs at 15 and 25 dpi, respectively. Intravenous administration of ASCs at 15 or 25 dpi significantly ameliorates the disease course and decreases the immune cell infiltration, vascular congestion and axonal loss of the gray and white matters of cerebral cortex. ASCs treatment induced a Th2 shift of the immune response and downregulation of IL-17 levels. We also found an engraftment of the ASCs into the lymph nodes and the brains up to 25 days after injection. The important finding was that human HLA-G gene was significantly expressed in lymph nodes and brains of rats treated with ASCs. Transplantation of human ASCs has demonstrated striking therapeutic effects and unique immunomodulatory capacities when delivered at the peak or later in the course of the disease in EAE rats. Interestingly, ASCs injection at the peak of EAE had better effects than those injected after disease stabilization. We first determined that the immunomodulatory properties of ASCs in the brain are explained, at least in part, by the ability of ASCs to express HLA-G. PMID- 26757145 TI - Implementing root cause analysis in Iranian hospitals: challenges and benefits. AB - Root cause analysis (RCA) has been widely used for retrospective investigations of patient safety incidents. To increase patient safety competencies, RCA has recently been introduced in Iranian hospitals. The aims of the current study were to explore team members' experiences and perceptions of RCA and to identify the challenges and benefits of using it in Iranian hospitals from their perspective. A qualitative study was conducted consisting of 32 semi-structured interviews with health professionals who participated in the national training programme and were involved in RCA investigations. Data were analysed using the thematic analysis method. The participants encountered a range of obstacles while conducting RCA, including time constraints, a lack of resources, the blame culture and unsupportive colleagues. They stressed the need for further leadership support and cultural change within the Iranian healthcare system to facilitate the application of RCA. RCA was perceived as a beneficial analytical tool that improved patient care, fostered teamwork and communication among staff and promoted safety culture. This study concluded that applying RCA in the Iranian healthcare setting has had a significant impact on improving commitment to safety. However, the general adoption of this method is hindered by the lack of workplace and system supports. To maximize profits from RCA, clinical leaders must assign a high priority to RCA investigations and support RCA team efforts. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26757147 TI - The influence of microemulsion structure on their skin irritation and phototoxicity potential. AB - The purpose of this study was to examine skin irritation and phototoxicity potentials of several microemulsions (ME), all comprising approximately the same percentage of surfactant mixture, but varying oil/water content and consequently inner structure being either droplet-like (o/w ME, o/w ME carbomer, w/o ME and w/o ME white wax) or lamellar (gel-like ME). Two different in vitro methods were used: MTT assay (performed either on reconstructed human epidermis (RHE) or NCTC 2544 cells) and pig ear test. Neither assay revealed the difference among ME with droplet-like structure. Then again, pig ear test and MTT assay performed on RHE indicated that gel-like ME is more irritant compared to other tested ME, whereas no difference among formulations were observed by MTT assay on NCTC 2544 cells. The reasonable explanation is destruction and consequently uniform structure of ME upon dilution that is inevitable for testing on cell cultures. The results of phototoxicity test again indicated the increased potential of gel-like ME to cause adverse effects on skin. It can be concluded that for ME consisting of the same amount of identical surfactants but having different structure the latter represent a crucial factor that determines their dermal toxicity. PMID- 26757146 TI - Neonatal Vaccination: Challenges and Intervention Strategies. AB - BACKGROUND: While vaccines have been tremendously successful in reducing the incidence of serious infectious diseases, newborns remain particularly vulnerable in the first few months of their life to life-threatening infections. A number of challenges exist to neonatal vaccination. However, recent advances in the understanding of neonatal immunology offer insights to overcome many of those challenges. OBJECTIVE: This review will present an overview of the features of neonatal immunity which make vaccination difficult, survey the mechanisms of action of available vaccine adjuvants with respect to the unique features of neonatal immunity, and propose a possible mechanism contributing to the inability of neonates to generate protective immune responses to vaccines. METHODS: We surveyed recent published findings on the challenges to neonatal vaccination and possible intervention strategies including the use of novel vaccine adjuvants to develop efficacious neonatal vaccines. RESULTS: Challenges in the vaccination of neonates include interference from maternal antibody and excessive skewing towards Th2 immunity, which can be counteracted by the use of proper adjuvants. CONCLUSION: Synergistic stimulation of multiple Toll-like receptors by incorporating well-defined agonist-adjuvant combinations to vaccines is a promising strategy to ensure a protective vaccine response in neonates. PMID- 26757149 TI - Micropellet-loaded rods with dose-independent sustained release properties for individual dosing via the Solid Dosage Pen. AB - Individual dosing of medicines is relevant for paediatrics, geriatrics and personalised medicine. The Solid Dosage Pen (SDP) allows for individual dosing by cutting monolithic, tablet-like drug carriers of pre-defined heights. The aim of the present study was to develop micropellet-loaded rods (MPLRs) with dose independent sustained release properties for individual dosing via the Solid Dosage Pen. Therefore, micropellets were successfully layered with carbamazepine and coated with polyvinyl acetate (PVAc) and PVAc/polyvinyl alcohol-polyethylene glycol (PVA-PEG). The tensile strength of the sustained release micropellets (300 450 MUm) was more than two times higher (12.6-17.1 MPa) than pressures occurring during ram-extrusion of the MPLRs (below 5.8 MPa). Due to relative crystallinities above 93% for PVAc and PVA-PEG a low solubility of the coating films within the PEG-matrix was observed. The sustained release micropellets were successfully incorporated into MPLRs. Drug release properties of the pellets maintained after embedding into the matrix. Hence, the MPLRs provided dose independent prolonged drug liberation which was not achieved for drug-loaded rods before. The MPLRs permitted the application of the SDP with a precise drug delivery from individually cut single doses. Storage stability was proven for MPLRs containing PVAc/PVA-PEG coated pellets. In conclusion, the MPLRs combined the advantages of multiparticulate dosage forms with the SDP as a device for individual dosing. PMID- 26757150 TI - 3D printing in pharmaceutics: A new tool for designing customized drug delivery systems. AB - Three-dimensional printing includes a wide variety of manufacturing techniques, which are all based on digitally-controlled depositing of materials (layer-by layer) to create freeform geometries. Therefore, three-dimensional printing processes are commonly associated with freeform fabrication techniques. For years, these methods were extensively used in the field of biomanufacturing (especially for bone and tissue engineering) to produce sophisticated and tailor made scaffolds from patient scans. This paper aims to review the processes that can be used in pharmaceutics, including the parameters to be controlled. In practice, it not straightforward for a formulator to be aware of the various technical advances made in this field, which is gaining more and more interest. Thus, a particular aim of this review is to give an overview on the pragmatic tools, which can be used for designing customized drug delivery systems using 3D printing. PMID- 26757148 TI - Dry powder inhaler formulation of high-payload antibiotic nanoparticle complex intended for bronchiectasis therapy: Spray drying versus spray freeze drying preparation. AB - Inhaled nano-antibiotics have recently emerged as the promising bronchiectasis treatment attributed to the higher and more localized antibiotic exposure generated compared to native antibiotics. Antibiotic nanoparticle complex (or nanoplex in short) prepared by self-assembly complexation with polysaccharides addresses the major drawbacks of existing nano-antibiotics by virtue of its high payload and cost-effective preparation. Herein we developed carrier-free dry powder inhaler (DPI) formulations of ciprofloxacin nanoplex by spray drying (SD) and spray freeze drying (SFD). d-Mannitol and l-leucine were used as the drying adjuvant and aerosol dispersion enhancer, respectively. The DPI formulations were evaluated in vitro in terms of the (1) aerosolization efficiency, (2) aqueous reconstitution, (3) antibiotic release, and (4) antimicrobial activity against respiratory pathogen Pseudomonas aeruginosa. The SFD powders exhibited superior aerosolization efficiency to their SD counterparts in terms of emitted dose (92% versus 66%), fine particle fraction (29% versus 23%), and mass median aerodynamic diameter (3 MUm versus 6 MUm). The superior aerosolization efficiency of the SFD powders was attributed to their large and porous morphology and higher l-leucine content. While the SFD powders exhibited poorer aqueous reconstitution that might jeopardize their mucus penetrating ability, their antibiotic release profile and antimicrobial activity were not adversely affected. PMID- 26757151 TI - Improved Mitochondrial and Methylglyoxal-Related Metabolisms Support Hyperproliferation Induced by 50 Hz Magnetic Field in Neuroblastoma Cells. AB - Extremely low frequency magnetic fields (ELF-MF) are common environmental agents that are suspected to promote later stages of tumorigenesis, especially in brain derived malignancies. Even though ELF magnetic fields have been previously linked to increased proliferation in neuroblastoma cells, no previous work has studied whether ELF-MF exposure may change key biomolecular features, such as anti glycative defence and energy re-programming, both of which are currently considered as crucial factors involved in the phenotype and progression of many malignancies. Our study investigated whether the hyperproliferation that is induced in SH-SY5Y human neuroblastoma cells by a 50 Hz, 1 mT ELF magnetic field is supported by an improved defense towards methylglyoxal (MG), which is an endogenous cancer-static and glycating alpha-oxoaldehyde, and by rewiring of energy metabolism. Our findings show that not only the ELF magnetic field interfered with the biology of neuron-derived malignant cells, by de differentiating further the cellular phenotype and by increasing the proliferative activity, but also triggered cytoprotective mechanisms through the enhancement of the defense against MG, along with a more efficient management of metabolic energy, presumably to support the rapid cell outgrowth. Intriguingly, we also revealed that the MF-induced bioeffects took place after an initial imbalance of the cellular homeostasis, which most likely created a transient unstable milieu. The biochemical pathways and molecular targets revealed in this research could be exploited for future approaches aimed at limiting or suppressing the deleterious effects of ELF magnetic fields. J. Cell. Physiol. 231: 2014-2025, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26757152 TI - Laparoscopic Management of Vaginal Vault Prolapse Recurring after Pelvic Organ Prolapse Surgery. AB - INTRODUCTION: Despite the increasing success of surgery for pelvic organ prolapse, recurrent vaginal vault prolapse is not rare. We present a step-by-step laparoscopic approach with a sacral colpopexy (SC) for treatment of recurrent vault prolapse. MATERIALS AND METHODS: From 2006, 25 women presenting with symptomatic recurrent vault prolapse were prospectively evaluated and treated with laparoscopic SC. This article briefly describes all of the steps that are required to conduct a proper surgery in such cases. RESULTS: After previous abdominal sacropexy, both the dissection of adherences and restoration of normal pelvic anatomy were challenging. As result, the overall operating time was longer in patients who had undergone abdominal sacropexy vs. vaginal route, p = 0.032. No significant peri- or postoperative complications were observed. At a mean follow-up of 41 months, all women presented with less than stage 2 prolapse and high levels of satisfaction. CONCLUSIONS: Despite the need for an intraoperative step-by-step surgical safety checklist, the laparoscopic repair of recurrent vault prolapse is technically feasible, safe and effective. PMID- 26757153 TI - Melatonin's protective effect on the salivary gland against ionized radiation damage in rats. AB - OBJECTIVES: The aim of this study was to examine the effects of melatonin on ionized radiation-induced salivary gland damage using an experimental model. MATERIALS AND METHODS: Thirty-two rats were randomized into four groups: (i) the control group (C, n = 8) that received intraperitoneal (i.p.) 0.9% NaCl; (ii) the melatonin group (M, n = 8) that received i.p. 5 mg/kg melatonin; (iii) the radiotherapy group (RT, n = 8) that underwent irradiation; (iv) the melatonin plus radiotherapy group (M+RT, n = 8) that received i.p. 5 mg/kg of melatonin, followed by irradiation 30 min later; and (v) the radiotherapy plus melatonin group (RT+M, n = 8) that received irradiation followed by i.p. 5 mg/kg of melatonin 30 min later. The medications and irradiation were administered for 5 days and the salivary glands of the rats were excised 10 days later; the histopathological changes in the salivary glands were assessed and biochemical analyses were conducted (tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI)). RESULTS: Regardless of whether melatonin was administered before or after radiotherapy, melatonin decreased the radiation induced parotid and submandibular histological damage. In addition, regardless of whether administration occurred before or after radiotherapy, melatonin decreased oxidative stress markers, such as MDA, TOS, and OSI. On the contrary, levels of antioxidative markers, such as CAT and GPx, were increased by melatonin. CONCLUSIONS: Melatonin may have a significant protective effect on salivary gland damage secondary to ionizing radiation. PMID- 26757154 TI - Between Openness and Privacy in Genomics. PMID- 26757155 TI - Testing Three Species Distribution Modelling Strategies to Define Fish Assemblage Reference Conditions for Stream Bioassessment and Related Applications. AB - Species distribution models are widely used for stream bioassessment, estimating changes in habitat suitability and identifying conservation priorities. We tested the accuracy of three modelling strategies (single species ensemble, multi species response and community classification models) to predict fish assemblages at reference stream segments in coastal subtropical Australia. We aimed to evaluate each modelling strategy for consistency of predictor variable selection; determine which strategy is most suitable for stream bioassessment using fish indicators; and appraise which strategies best match other stream management applications. Five models, one single species ensemble, two multi-species response and two community classification models, were calibrated using fish species presence-absence data from 103 reference sites. Models were evaluated for generality and transferability through space and time using four external reference site datasets. Elevation and catchment slope were consistently identified as key correlates of fish assemblage composition among models. The community classification models had high omission error rates and contributed fewer taxa to the 'expected' component of the taxonomic completeness (O/E50) index than the other strategies. This potentially decreases the model sensitivity for site impact assessment. The ensemble model accurately and precisely modelled O/E50 for the training data, but produced biased predictions for the external datasets. The multi-species response models afforded relatively high accuracy and precision coupled with low bias across external datasets and had lower taxa omission rates than the community classification models. They inherently included rare, but predictable species while excluding species that were poorly modelled among all strategies. We suggest that the multi-species response modelling strategy is most suited to bioassessment using freshwater fish assemblages in our study area. At the species level, the ensemble model exhibited high sensitivity without reductions in specificity, relative to the other models. We suggest that this strategy is well suited to other non-bioassessment stream management applications, e.g., identifying priority areas for species conservation. PMID- 26757156 TI - Systemic Chemotherapy and White Matter Integrity in Tracts Associated with Cognition Among Children With Neurofibromatosis Type 1. AB - BACKGROUND: Children with neurofibromatosis type 1 (NF1) are predisposed to both brain tumors and cognitive deficits. While changes in white matter integrity after multimodal therapy are associated with cognitive dysfunction, the effect of isolated chemotherapy in NF1 is unknown. To determine whether chemotherapy is associated with white matter microstructural changes, we examined diffusion tensor imaging (DTI) in NF1 subjects. PROCEDURE: We reviewed DTI measures in tracts associated with cognition but free from tumor in 24 children with NF1 associated optic pathway gliomas unexposed to surgery or radiation. Twelve age matched pairs were identified based on exposure to chemotherapy. A paired t-test was used to compare fractional anisotropy (FA) in tracts of interest between subjects with and without chemotherapy exposure. RESULTS: On paired t-test, FA was significantly lower in the corpus callosum (P = 0.015) and cerebellothalamic (P = 0.038) tracts of subjects exposed to chemotherapy. There was no effect of age or time from chemotherapy on the difference between groups. In multivariable analysis, FA of these tracts was associated with chemotherapy exposure after adjusting for age, tumor location, and DTI acquisition. In longitudinal measures, FA decreased after chemotherapy exposure while FA increased with age in unexposed subjects. CONCLUSIONS: Exposure to low-intensity chemotherapy in NF1 is associated with changes in white matter microstructure in tracts associated with cognition. Future studies should determine whether these changes are associated with cognitive decline. While chemotherapy may spare cognition relative to radiation and surgery, children with NF1 exposed to chemotherapy may benefit from early cognitive testing to allow for earlier intervention. PMID- 26757157 TI - Polychlorinated Biphenyls (PCBs) in Human Hair and Serum from E-Waste Recycling Workers in Southern China: Concentrations, Chiral Signatures, Correlations, and Source Identification. AB - Hair is increasingly used as a biomarker for human exposure to persistent organic pollutants (POPs). However, the internal and external sources of hair POPs remain a controversial issue. This study analyzed polychlorinated biphenyls (PCBs) in human hair and serum from electronic waste recycling workers. The median concentrations were 894 ng/g and 2868 ng/g lipid in hair and serum, respectively. The PCB concentrations in male and female serum were similar, while concentrations in male hair were significantly lower than in female hair. Significant correlations between the hair and serum PCB levels and congener profiles suggest that air is the predominant PCB source in hair and that hair and blood PCB levels are largely dependent on recent accumulation. The PCB95, 132, and 183 chiral signatures in serum were significantly nonracemic, with mean enantiomer fractions (EFs) of 0.440-0.693. Nevertheless, the hair EFs were essentially racemic (mean EFs = 0.495-0.503). Source apportionment using the Chemical Mass Balance model also indicated primary external PCB sources in human hair from the study area. Air, blood, and indoor dust are responsible for, on average, 64.2%, 27.2%, and 8.79% of the hair PCBs, respectively. This study evidenced that hair is a reliable matrix for monitoring human POP exposure. PMID- 26757158 TI - Reactive Oxygen Species Play an Important Role in the Bactericidal Activity of Quinolone Antibiotics. AB - Recent studies posit that reactive oxygen species (ROS) contribute to the cell lethality of bactericidal antibiotics. However, this conjecture has been challenged and remains controversial. To resolve this controversy, we adopted a strategy that involves DNA polymerase IV (PolIV). The nucleotide pool of the cell gets oxidized by ROS and PolIV incorporates the damaged nucleotides (especially 8oxodGTP) into the genome, which results in death of the bacteria. By using a combination of structural and biochemical tools coupled with growth assays, it was shown that selective perturbation of the 8oxodGTP incorporation activity of PolIV results in considerable enhancement of the survival of bacteria in the presence of the norfloxacin antibiotic. Our studies therefore indicate that ROS induced in bacteria by the presence of antibiotics in the environment contribute significantly to cell lethality. PMID- 26757161 TI - Sprouty-Related Ena/Vasodilator-Stimulated Phosphoprotein Homology 1-Domain Containing Protein-2 Critically Regulates Influenza A Virus-Induced Pneumonia. AB - OBJECTIVES: Influenza A virus causes acute respiratory infections that induce annual epidemics and occasional pandemics. Although a number of studies indicated that the virus-induced intracellular signaling events are important in combating influenza virus infection, the mechanism how specific molecule plays a critical role among various intracellular signaling events remains unknown. Raf/MEK/extracellular signal-regulated kinase cascade is one of the key signaling pathways during influenza virus infection, and the Sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein has recently been identified as a negative regulator of Raf-dependent extracellular signal-regulated kinase activation. Here, we examined the role of Raf/MEK/extracellular signal-regulated kinase cascade through sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein in influenza A viral infection because the expression of sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein was significantly enhanced in human influenza viral-induced pneumonia autopsy samples. DESIGN: Prospective animal trial. SETTING: Research laboratory. SUBJECTS: Wild-type and sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 knockout mice inoculated with influenza A. INTERVENTIONS: Wild-type or sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 knockout mice were infected by intranasal inoculation of influenza A (A/PR/8). An equal volume of phosphate buffered saline was inoculated intranasally into mock-infected mice. MEASUREMENTS AND MAIN RESULTS: Influenza A infection of sprouty-related Ena/vasodilator stimulated phosphoprotein homology 1-domain-containing protein-2 knockout mice led to higher mortality with greater viral load, excessive inflammation, and enhanced cytokine production than wild-type mice. Administration of MEK inhibitor, U0126, improved mortality and reduced both viral load and cytokine levels. Furthermore, bone marrow chimeras indicated that influenza A-induced lung pathology was most severe when sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 expression was lacking in nonimmune cell populations. Furthermore, microarray analysis revealed knockdown of sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain containing protein-2 led to enhanced phosphatidylinositol 3-kinase signaling pathway, resulting that viral clearance was regulated by sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain-containing protein-2 expression through the phosphatidylinositol 3-kinase signaling pathway in murine lung epithelial cells. CONCLUSIONS: These data support an important function of sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1-domain containing protein-2 in controlling influenza virus-induced pneumonia and viral replication. Sprouty-related Ena/vasodilator-stimulated phosphoprotein homology 1 domain-containing protein-2 may be a novel therapeutic target for controlling the immune response against influenza influenza A virus infection. PMID- 26757162 TI - Fentanyl and Midazolam Are Ineffective in Reducing Episodic Intracranial Hypertension in Severe Pediatric Traumatic Brain Injury. AB - OBJECTIVE: To evaluate the clinical effectiveness of bolus-dose fentanyl and midazolam to treat episodic intracranial hypertension in children with severe traumatic brain injury. DESIGN: Retrospective cohort. SETTING: PICU in a university-affiliated children's hospital level I trauma center. PATIENTS: Thirty one children 0-18 years of age with severe traumatic brain injury (Glasgow Coma Scale score of <= 8) who received bolus doses of fentanyl and/or midazolam for treatment of episodic intracranial hypertension. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The area under the curve from high-resolution intracranial pressure-time plots was calculated to represent cumulative intracranial hypertension exposure: area under the curve for intracranial pressure above 20 mm Hg (area under the curve-intracranial hypertension) was calculated in 15-minute epochs before and after administration of fentanyl and/or midazolam for the treatment of episodic intracranial hypertension. Our primary outcome measure, the difference between predrug and postdrug administration epochs (Deltaarea under the curve-intracranial hypertension), was calculated for all occurrences. We examined potential covariates including age, injury severity, mechanism, and time after injury; time after injury correlated with Deltaarea under the curve-intracranial hypertension. In a mixed-effects model, with patient as a random effect, drug/dose combination as a fixed effect, and time after injury as a covariate, intracranial hypertension increased after administration of fentanyl and/or midazolam (overall aggregate mean Deltaarea under the curve intracranial hypertension = +17 mm Hg * min, 95% CI, 0-34 mm Hg * min; p = 0.04). The mean Deltaarea under the curve-intracranial hypertension increased significantly after administration of high-dose fentanyl (p = 0.02), low-dose midazolam (p = 0.006), and high-dose fentanyl plus low-dose midazolam (0.007). Secondary analysis using age-dependent thresholds showed no significant impact on cerebral perfusion pressure deficit (mean Deltaarea under the curve-cerebral perfusion pressure). CONCLUSIONS: Bolus dosing of fentanyl and midazolam fails to reduce the intracranial hypertension burden when administered for episodic intracranial hypertension. Paradoxically, we observed an overall increase in intracranial hypertension burden following drug administration, even after accounting for within-subject effects and time after injury. Future work is needed to confirm these findings in a prospective study design. PMID- 26757163 TI - Nonhematopoietic Peroxisome Proliferator-Activated Receptor-alpha Protects Against Cardiac Injury and Enhances Survival in Experimental Polymicrobial Sepsis. AB - OBJECTIVES: Peroxisome proliferator-activated receptor-alpha is significantly down-regulated in circulating leukocytes from children with sepsis. Peroxisome proliferator-activated receptor-alpha null (Ppara) mice have greater mortality than wild-type mice when subjected to sepsis by cecal ligation and puncture. We sought to characterize the role of peroxisome proliferator-activated receptor alpha in sepsis and to identify the mechanism whereby peroxisome proliferator activated receptor-alpha confers a survival advantage. DESIGN: Prospective randomized preclinical study. SETTING: Laboratory investigation. SUBJECTS: Male C57Bl/6J and Ppara mice (B6.129S4-Ppara/J), aged 12-16 weeks. INTERVENTIONS: Bone marrow chimeric mice were generated and subjected to cecal ligation and puncture. Survival was measured for 7 days. Separate groups of nontransplanted mice underwent cecal ligation and puncture and were euthanized 24 hours later for plasma and tissue analyses. MEASUREMENTS AND MAIN RESULTS: Ppara mice had dramatically reduced survival compared with wild-type mice irrespective of the peroxisome proliferator-activated receptor-alpha status of the bone marrow they received (3% vs 63%; p < 0.0001). No difference in survival was observed between Ppara mice that received wild-type versus Ppara marrow or in wild-type mice receiving wild-type versus Ppara marrow. In septic, nontransplanted mice at 24 hours, Ppara mice had elevated cardiac troponin levels compared with wild-type mice. Cardiac histologic injury scores were greater in Ppara versus wild-type mice. Expression of transcription factors and enzymes related to fatty acid oxidation in the heart were profoundly down-regulated in both wild-type and Ppara mice, but more so in the Ppara mice. CONCLUSIONS: Peroxisome proliferator activated receptor-alpha expression in nonhematopoietic tissues plays a critical role in determining clinical outcome in experimental polymicrobial sepsis and is more important to survival in sepsis than hematopoietic peroxisome proliferator activated receptor-alpha expression. Cardiac injury due to inadequate energy production from fatty acid substrate is a probable mechanism of decreased survival in Ppara mice. These results suggest that altered peroxisome proliferator-activated receptor-alpha-mediated cellular metabolism may play an important role in sepsis-related end-organ injury and dysfunction, especially in the heart. PMID- 26757164 TI - Relationship Between Peak Lactate and Patient Outcome Following High-Risk Gastrointestinal Surgery: Influence of the Nature of Their Surgery: Elective Versus Emergency. AB - OBJECTIVES: The association between hyperlactatemia and adverse outcome in patients admitted to ICUs following gastrointestinal surgery has not been reported. To explore the hypothesis that in a large cohort of gastrointestinal surgical patients, the peak serum lactate (in the first 24 hr) observed in patients admitted to ICU following surgery is associated with unadjusted and severity-adjusted acute hospital mortality and that the strength of association is greater in patients admitted following "emergency" surgery than in patients admitted following "elective" surgery. DESIGN: A retrospective cohort study of all patients who had gastrointestinal surgery and were admitted directly to the ICU between 2008 and 2012. SETTING: Two hundred forty-nine hospitals in the United Kingdom. PATIENTS: One hundred twenty-one thousand nine hundred ninety patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Peak blood lactate in the first 24 hours of admission to critical care, acute hospital mortality, length of stay, and other variables routinely collected within the U.K. Intensive Care National Audit and Research Centre Case Mix Programme database. Elevated blood lactate was associated with increased risk of death and prolonged duration of stay, and the relationship was maintained once adjusted for confounding variables. The positive association between mortality and levels of blood lactate continued down into the "normal range," without evidence of a plateau. There was no difference in the extent to which hyperlactatemia was related to mortality between patients admitted following elective and emergency surgery. CONCLUSIONS: These findings have implications for our understanding of the role of lactate in critically ill patients. PMID- 26757166 TI - Alda-1 Attenuates Lung Ischemia-Reperfusion Injury by Reducing 4-Hydroxy-2 Nonenal in Alveolar Epithelial Cells. AB - OBJECTIVES: Excessive oxidative stress is a main cause of lung ischemia reperfusion injury, which often results in respiratory insufficiency after open heart surgery for a cardiopulmonary bypass. Previous studies demonstrate that the activation of aldehyde dehydrogenase-2 could significantly reduce the oxidative stress mediated by toxic aldehydes and attenuate cardiac and cerebral ischemia reperfusion injury. However, both the involvement of aldehydes and the protective effect of the aldehyde dehydrogenase-2 agonist, Alda-1, in lung ischemia reperfusion injury remain unknown. DESIGN: Prospective laboratory and animal investigation were conducted. SETTING: State Key Laboratory of Cardiovascular Disease. SUBJECTS: Primary human pulmonary alveolar epithelial cells, human pulmonary microvascular endothelial cells, and Sprague-Dawley rats. INTERVENTIONS: A hypoxia/reoxygenation cell-culture model of human pulmonary alveolar epithelial cell, human pulmonary microvascular endothelial cell, and an isolated-perfused lung model were applied to mimic lung ischemia-reperfusion injury. We evaluated the effects of Alda-1 on aldehyde dehydrogenase-2 quantity and activity, on aldehyde levels and pulmonary protection. MEASUREMENTS AND MAIN RESULTS: We have demonstrated that ischemia-reperfusion-induced pulmonary injury concomitantly induced aldehydes accumulation in human pulmonary alveolar epithelial cells and lung tissues, but not in human pulmonary microvascular endothelial cells. Moreover, Alda-1 pretreatment significantly elevated aldehyde dehydrogenase-2 activity, increased surfactant-associated protein C, and attenuated elevation of 4-hydroxy-2-nonenal, apoptosis, intercellular adhesion molecule-1, inflammatory response, and the permeability of pulmonary alveolar capillary barrier, thus alleviated injury. CONCLUSIONS: Our study indicates that the accumulation of 4-hydroxy-2-nonenal plays an important role in lung ischemia reperfusion injury. Alda-1 pretreatment can attenuate lung ischemia-reperfusion injury, possibly through the activation of aldehyde dehydrogenase-2, which in turn removes 4-hydroxy-2-nonenal in human pulmonary alveolar epithelial cells. Alda-1 pretreatment has clinical implications to protect lungs during cardiopulmonary bypass. PMID- 26757165 TI - Complement Factor B Production in Renal Tubular Cells and Its Role in Sodium Transporter Expression During Polymicrobial Sepsis. AB - OBJECTIVES: Toll-like receptors and complement are two components of the innate immunity. Complement factor B is essential for the alternative pathway of complement activation. We have recently reported that complement factor B is significantly up-regulated in the kidney and may contribute to acute tubular injury in an animal model of sepsis. This study investigates the mechanisms responsible for the complement factor B up-regulation and its role in sodium transporter expression in tubular cells during sepsis. DESIGN: Animal study. SETTING: Laboratory investigation. SUBJECTS: C57BL/6 J wild-type, complement factor B(-/-), and Nfkb1(tm1Bal) p50(-/-) mice. INTERVENTIONS: Human proximal tubular cells and mouse tubular epithelial cells were stimulated with Toll-like receptor agonists. Bay 11-7082 was used to block nuclear factor-kappaB pathway. Alternative pathway activation was detected by C3 zymosan deposition. Polymicrobial sepsis was created by cecal ligation and puncture. Sodium transporter gene expression was determined by quantitative reverse transcriptase polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: The agonists for Toll like receptor 4 (lipopolysaccharide) or Toll-like receptor 3 (polyinosinic polycytidylic acid) induced a marked increase in complement factor B expression in human proximal tubular cells and mouse tubular epithelial cells both at gene and protein levels. The Toll-like receptor 1/2 agonist, Pam3cys, induced complement factor B production only in human proximal tubular cells, not in mouse tubular epithelial cells. The Toll-like receptor 9 ligand, CpG oligodeoxynucleotides failed to induce complement factor B production either in human proximal tubular cells or in mouse tubular epithelial cells. Lipopolysaccharide/polyinosinic-polycytidylic acid-induced complement factor B up regulation was blocked by Bay 11-7082, a potent inhibitor of nuclear factor kappaB signaling, and in mouse tubular epithelial cells deficient in p50 subunit of nuclear factor-kappaB. Media from the lipopolysaccharide-treated mouse tubular epithelial cell cultures contained de novo synthesized complement factor B and led to functional alternative pathway activation. In a cecal ligation and puncture model, wild-type septic mice had down-regulated expression of sodium transporters in the kidney compared with the sham. In comparison, complement factor B mice or mice treated with anti-complement factor B displayed preserved levels of Na+/K+ ATPase-alpha1 following sepsis. CONCLUSIONS: 1) Toll-like receptor 3/4 activation is sufficient to induce complement factor B production via nuclear factor-kappaB pathway and to enhance alternative pathway activation in the kidney tubular epithelial cells. 2) Complement factor B may contribute to the down-regulation of certain sodium transporter expression during sepsis. PMID- 26757168 TI - Translating Clinical Evidence-Based Medicine into the Real World: Single-Center Experience with Cabazitaxel in Metastatic Prostate Cancer Patients. AB - BACKGROUND: We studied the efficacy and safety of cabazitaxel in unselected real life patients. PATIENTS AND METHODS: We retrospectively investigated all patients with metastatic prostate cancer (mPC) treated with cabazitaxel 25 mg/m2 i.v. every 3 weeks combined with oral prednisolone (10 mg once daily) after first-line docetaxel chemotherapy. Study issues were to report patient characteristics and cabazitaxel data in terms of tolerance and efficacy. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method. All data were compared with TROPIC results. RESULTS: From 2011 to 2014, 41 patients received cabazitaxel; 15 patients (37%) had a performance status (PS) >=2 versus 7% (p < 0.0001) in TROPIC, and 38 patients (93%) presented a Gleason score >=7 at baseline (vs. 60%; p < 0.0001). All patients had metastatic disease at baseline. Previous therapies were radiotherapy in 17 patients (41 vs. 61%; p = 0.01) and surgery in 24 patients (59 vs. 52%; p = 0.4). The median number of cabazitaxel cycles was 5 (1-10) versus 6 (3-10) in TROPIC. Five patients completed 10 cycles of cabazitaxel (12%) versus 28% in TROPIC (p = 0.03). Toxicities were anemia (12 patients, 29%), diarrhea (9 patients, 22%), nausea (7 patients, 17%), pain (6 patients, 15%), sepsis (4 patients, 10%), neutropenia (3 patients, 7%) and urinary tract infection (1 patient, 2%). The tumor response rate was 19.5 versus 14.4% in TROPIC (nonsignificant). PFS was 4.5 months (95% CI 3.3-6.4) in our analysis and 2.8 months (95% CI 2.4-3.0) in TROPIC. OS was 12.1 months (95% CI 9.2 to not reached) and 15.1 months (95% CI 14.1-16.3), respectively. CONCLUSION: In our unselected mPC patients with poorer baseline clinical conditions and aggressive disease, cabazitaxel seems efficient and not more toxic than in the TROPIC study. PMID- 26757167 TI - Rate of Perihematomal Edema Expansion Predicts Outcome After Intracerebral Hemorrhage. AB - OBJECTIVES: Intracerebral hemorrhage is a devastating disorder with no current treatment. Whether perihematomal edema is an independent predictor of neurologic outcome is controversial. We sought to determine whether perihematomal edema expansion rate predicts outcome after intracerebral hemorrhage. DESIGN: Retrospective cohort study. SETTING: Tertiary medical center. PATIENTS: One hundred thirty-nine consecutive supratentorial spontaneous intracerebral hemorrhage patients 18 years or older admitted between 2000 and 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Intracerebral hemorrhage, intraventricular hemorrhage, and perihematomal edema volumes were measured from CT scans obtained at presentation, 24-hours, and 72-hours postintracerebral hemorrhage. Perihematomal edema expansion rate was the difference between initial and follow-up perihematomal edema volumes divided by the time interval. Logistic regression was performed to evaluate the relationship between 1) perihematomal edema expansion rate at 24 hours and 90-day mortality and 2) perihematomal edema expansion rate at 24 hours and 90-day modified Rankin Scale score. Perihematomal edema expansion rate between admission and 24-hours postintracerebral hemorrhage was a significant predictor of 90-day mortality (odds ratio, 2.97; 95% CI, 1.48 5.99; p = 0.002). This association persisted after adjusting for all components of the intracerebral hemorrhage score (odds ratio, 2.21; 95% CI, 1.05-4.64; p = 0.04). Similarly, higher 24-hour perihematomal edema expansion rate was associated with poorer modified Rankin Scale score in an ordinal shift analysis (odds ratio, 2.40; 95% CI, 1.37-4.21; p = 0.002). The association persisted after adjustment for all intracerebral hemorrhage score components (odds ratio, 2.07; 95% CI, 1.12-3.83; p = 0.02). CONCLUSIONS: Faster perihematomal edema expansion rate 24-hours postintracerebral hemorrhage is associated with worse outcome. Perihematomal edema may represent an attractive translational target for secondary injury after intracerebral hemorrhage. PMID- 26757169 TI - Mitochondrial mutagenesis in BCR-ABL1-expressing cells sensitive and resistant to imatinib. AB - Imatinib revolutionized the treatment of chronic myeloid leukemia (CML) with the expression of the BCR-ABL1 tyrosine kinase, but imatinib resistance is an emerging problem. Imatinib can hinder the inhibitory effects of BCR-ABL1 on mitochondrial apoptotic pathway, so mitochondrial mutagenesis can be important for its action. To explore the mechanisms of imatinib resistance we created a mouse-derived CML model cells consisting of parental 32D cells (P) and cells transfected with the BCR-ABL1 gene (S cells) or its variants with the Y253H or T315I mutations (253 and 315 cells, respectively), conferring resistance to imatinib. A fraction of the S cells was cultured in increasing concentrations of imatinib, acquiring resistance to this drug (AR cells). The 253, 315 and AR cells, in contrast to S cells, displayed resistance to imatinib. We observed that the T315I cells displayed greater extent of H2O2-induced mtDNA damage than their imatinib-sensitive counterparts. No difference in the sensitivity to UV radiation was observed among all the cell lines. A decrease in the extent of H2O2-induced mtDNA damage was observed during a 120-min repair incubation in all cell lines, but it was significant only in imatinib-sensitive and T315I cells. No difference in the copy number of mtDNA and frequency of the 3,867-bp deletion was observed and genotoxic stress induced by H2O2 or UV did not change this relationship. In conclusion, some aspects of mtDNA mutagenesis, including sensitivity to oxidative stress and DNA repair can contribute to imatinib resistance in BCR-ABL1 expressing cells. PMID- 26757170 TI - Screening for Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement. AB - DESCRIPTION: Update of the 2009 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for breast cancer. METHODS: The USPSTF reviewed the evidence on the following: effectiveness of breast cancer screening in reducing breast cancer-specific and all-cause mortality, as well as the incidence of advanced breast cancer and treatment-related morbidity; harms of breast cancer screening; test performance characteristics of digital breast tomosynthesis as a primary screening strategy; and adjunctive screening in women with increased breast density. In addition, the USPSTF reviewed comparative decision models on optimal starting and stopping ages and intervals for screening mammography; how breast density, breast cancer risk, and comorbidity level affect the balance of benefit and harms of screening mammography; and the number of radiation-induced breast cancer cases and deaths associated with different screening mammography strategies over the course of a woman's lifetime. POPULATION: This recommendation applies to asymptomatic women aged 40 years or older who do not have preexisting breast cancer or a previously diagnosed high-risk breast lesion and who are not at high risk for breast cancer because of a known underlying genetic mutation (such as a BRCA1 or BRCA2 gene mutation or other familial breast cancer syndrome) or a history of chest radiation at a young age. RECOMMENDATIONS: The USPSTF recommends biennial screening mammography for women aged 50 to 74 years. (B recommendation) The decision to start screening mammography in women prior to age 50 years should be an individual one. Women who place a higher value on the potential benefit than the potential harms may choose to begin biennial screening between the ages of 40 and 49 years. (C recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening mammography in women aged 75 years or older. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the benefits and harms of digital breast tomosynthesis (DBT) as a primary screening method for breast cancer. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of adjunctive screening for breast cancer using breast ultrasonography, magnetic resonance imaging (MRI), DBT, or other methods in women identified to have dense breasts on an otherwise negative screening mammogram. (I statement). PMID- 26757171 TI - New drug design with covalent modifiers. AB - INTRODUCTION: A major challenge for drug design is the alarming increase in drug resistance, mutations and toxicity. In recent years, covalent drugs have become a promising option to address these problems, due to their significant advantages. These advantages include their ability to target rare, non-conserved residues, shallow binding sites of target proteins and their ability to retain their binding with a receptor for a very long time. AREAS COVERED: This review shows the increasing progress in rational design and virtual screening of covalent drugs and the promising future of accurately predicting effective covalent drugs through in silico screening. EXPERT OPINION: All the current clinically approved covalent drugs were discovered by chance instead of systematic design. There is a promising and commendable effort towards high-throughput screening and the accurate discovery of new covalent inhibitors, which may address the problems of drug resistance and mutation. However, despite the current progression, there is still a need for more rational attention to improve the covalent warhead for improved receptor interaction and selectivity. PMID- 26757172 TI - Rapid eye movement sleep without atonia may help diagnose Lewy body disease in middle-aged and older patients with somatic symptom disorder. AB - BACKGROUND: Lewy body disease (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB), is defined pathologically as degeneration in the central and peripheral nervous system associated with Lewy bodies. Somatic symptom disorder often predates the clinical diagnosis of PD and DLB. It is crucial to make an initial diagnosis of LBD in patients with psychiatric symptoms because administering psychotropic drugs often causes or exacerbates extrapyramidal signs. Given the close association between rapid eye movement (REM) sleep behaviour disorder and LBD, REM sleep without atonia on polysomnography may help to diagnose LBD in middle-aged and older patients with somatic symptom disorder. METHODS: We reviewed the clinical profiles of five patients with an initial diagnosis of somatic symptom disorder who exhibited REM sleep without atonia on polysomnography. There were three men and two women, with a mean age of 68.4 years (range: 55.0-78.0 years). The mean Mini-Mental State Examination score was 26 (range: 22-30). RESULTS: Only two patients had a clinical history of dream-enacting behaviour and fulfilled the clinical criteria for REM sleep behaviour disorder, but clinical conditions in the other three patients corresponded to subclinical REM sleep behaviour disorder. Final clinical diagnoses were made as probable DLB in three patients; two patients did not meet the clinical criteria for PD or DLB. Neurological examinations revealed mild extrapyramidal signs in these two patients, and their scores on the motor component of the Unified Parkinson's Disease Rating Scale were 8 and 5 points, and their Mini-Mental State Examination scores were 30 points. Neither patient exhibited dream-enacting behaviour, but both had constipation. Cardiac 123 I metaiodobenzylguanidine scintigraphy revealed mild increased washout rates. DISCUSSION: REM sleep without atonia may provide an opportunity to identify LBD in patients with somatic symptom disorder, even before they fulfil the clinical criteria for PD or DLB. Continued follow-up will be needed to determine whether these psychiatric patients are in the prodromal stage of PD or DLB. PMID- 26757173 TI - Biotherapeutic agents and vaginal health. AB - Treatment of vaginal infection requires different drugs although the recurrence rate post treatment remains high due to adverse effects on the beneficial microbiota. Thus, there are clear clinical advantages for the use of biotherapeutic agents (prebiotics and/or probiotics) for treating these infections. Pre- and probiotic beneficial effects can be delivered topically or systemically. In general, both approaches have the potential to optimize, maintain and restore the ecology of the vaginal ecosystem. Specific carbohydrates provide a therapeutic approach for controlling infections by stimulating the growth of the indigenous lactobacilli but inhibiting the growth and adhesion of pathogens to the vaginal epithelial cells. Overall, little evidence exists to promote the prevention or treatment of vaginal disease with prebiotic carbohydrates in formulations such as pessaries, creams or douches. However, recent reports have promoted prebiotic applications in ecosystems other than the gut and include the mouth, skin and vagina. This review focuses on the utilization of pre- and probiotics for vaginal health. PMID- 26757174 TI - Redox-Neutral alpha-Amino C-H Functionalization: When the Catalyst Is Also the Nucleophile. AB - A redox-neutral functionalization of cyclic amines that leads to acyclic products is presented. The reaction hinges on generation of transient aryl radical intermediates by catalytic activation with a simple hydrazine. Those aryl radicals subsequently undergo translocation and further oxidation prior to trapping with the same hydrazine, thus resulting in an overall process where the catalyst unusually also acts as the nucleophile. PMID- 26757176 TI - The Stage is Set for a New Trend. PMID- 26757175 TI - Insights into regioselective metabolism of mefenamic acid by cytochrome P450 BM3 mutants through crystallography, docking, molecular dynamics, and free energy calculations. AB - Cytochrome P450 BM3 (CYP102A1) mutant M11 is able to metabolize a wide range of drugs and drug-like compounds. Among these, M11 was recently found to be able to catalyze formation of human metabolites of mefenamic acid and other nonsteroidal anti-inflammatory drugs (NSAIDs). Interestingly, single active-site mutations such as V87I were reported to invert regioselectivity in NSAID hydroxylation. In this work, we combine crystallography and molecular simulation to study the effect of single mutations on binding and regioselective metabolism of mefenamic acid by M11 mutants. The heme domain of the protein mutant M11 was expressed, purified, and crystallized, and its X-ray structure was used as template for modeling. A multistep approach was used that combines molecular docking, molecular dynamics (MD) simulation, and binding free-energy calculations to address protein flexibility. In this way, preferred binding modes that are consistent with oxidation at the experimentally observed sites of metabolism (SOMs) were identified. Whereas docking could not be used to retrospectively predict experimental trends in regioselectivity, we were able to rank binding modes in line with the preferred SOMs of mefenamic acid by M11 and its mutants by including protein flexibility and dynamics in free-energy computation. In addition, we could obtain structural insights into the change in regioselectivity of mefenamic acid hydroxylation due to single active-site mutations. Our findings confirm that use of MD and binding free-energy calculation is useful for studying biocatalysis in those cases in which enzyme binding is a critical event in determining the selective metabolism of a substrate. PMID- 26757179 TI - Evolution of translation initiation sequences using in vitro yeast ribosome display. AB - We report a novel in vitro yeast ribosome display method based on cell-free protein synthesis (CFPS) using linear DNA templates. We demonstrate that our platform can enrich a target gene from a model library by 100-fold per round of selection. We demonstrate the utility of our approach by evolving cap-independent translation initiation (CITI) sequences, which result in a 13-fold increase in CFPS yields after four rounds of selection, and a threefold further increase by placing the beneficial short sequences in tandem. We also show that 12 of the selected CITI sequences permit precise control of gene expression in vitro over a range of up to 80-fold by enhancing translation (and not as cryptic promoters). These 12 sequences are then shown to tune protein expression in vivo, though likely due to a different mechanism. Looking forward, yeast ribosome display holds promise for evolving libraries of proteins and DNA regulatory parts for protein engineering and synthetic biology. Biotechnol. Bioeng. 2016;113: 1777 1786. (c) 2016 Wiley Periodicals, Inc. PMID- 26757180 TI - Idiopathic Canine Laryngeal Paralysis as One Sign of a Diffuse Polyneuropathy: An Observational Study of 90 Cases (2007-2013). AB - OBJECTIVE: To determine survival and incidence of complications in dogs with idiopathic laryngeal paralysis (ILP) and concurrent neurologic signs. STUDY DESIGN: Observational study. ANIMALS: Dogs (n = 90) with ILP. METHODS: Medical records (January 2007-June 2013) of dogs with ILP were reviewed. Neurologic comorbidities, including pelvic limb neurologic abnormalities and esophageal abnormalities were identified. Using medical record information and client interviews, the relationship between these comorbidities and postoperative survival (primary outcome measure) and postoperative complications (secondary outcome measure) was identified. RESULTS: Dogs that had surgical correction of ILP had a 2.6-fold reduction in the hazard of death throughout the study period (HR = 2.6; 95% CI: 1.34-4.84, P = .006). Owner assessed patient quality of life (10-point scale) increased by an average of 4.1 +/- 1.4 units immediately postoperatively, and 4.9 +/- 0.9 units until death or followup compared with preoperative values. Thirty-five of 72 dogs available for followup had evidence of diffuse neurologic comorbidities. Overall complication rate for dogs with neurologic comorbidities was 74%, compared with 32% for dogs without neurologic comorbidities. Presence of any neurologic comorbidity was associated with a significantly greater odds of any complication (OR = 4.04; 95% CI: 1.25-13.90, P = .019) as well as recurring complications (OR = 8.00; 95% CI: 1.49-54.38; P = .015). CONCLUSION: Surgical correction of ILP was positively associated with survival, and dogs with neurologic comorbidities were at greater risk for developing postoperative complications. PMID- 26757181 TI - Children's Neuromotor and Muscle-Functional Attributes - Outstanding Issues. AB - The current understanding of child-adult differences in muscular and neuromotor function will be reviewed while highlighting the gaps in our knowledge and raising research questions that could be addressed in the immediate or near future. Topics include muscle activation, muscle composition, strength attributes, strength- and aerobic-training, neuromotor development, where neuromuscular differences originate from, and the possible interrelationships between motor and cognitive function. The various differences will be discussed on their specific merits, but also as possible manifestations of a common underlying factor which, if true, could provide a more holistic view of child adult functional differences. PMID- 26757183 TI - Ventilatory Response to Hypercapnia Predicts Dementia with Lewy Bodies in Late Onset Major Depressive Disorder. AB - BACKGROUND: Studies have shown that developing major depressive disorder (MDD) at 50 years of age or older can predict dementia. Depression is particularly common in dementia with Lewy bodies (DLB), and occasionally occurs before the onset of extrapyramidal symptoms. Moreover, systemic autonomic dysfunction, including an abnormal ventilatory response to hypercapnia (VRH), is common in patients with DLB. OBJECTIVE: Here, we aimed to determine whether the VRH is useful for distinguishing depression that is predictive of DLB from other types of MDD. METHODS: Participants were 35 consecutive patients with first onset MDD at 50 years or older with bradykinesia. After diagnosing the clinical subtype of MDD according to DSM-IV criteria, each subject underwent a battery of psychological tests, autonomic examinations including VRH, brain magnetic resonance imaging, and 123I-meta-iodobenzylguanidine scintigraphy. RESULTS: Longitudinal follow-up showed that all 18 patients with abnormal VRH results developed DLB, whereas none of the 17 patients with normal VRH results converted to DLB within the study period (sensitivity: 100% , specificity: 100%). Additionally, over half of the DLB converters showed abnormalities on other autonomic examinations. For converters, the most common MDD subtype had psychotic and melancholic features simultaneously. The frequency of hypersensitivity to psychotropics was higher in converters than it was in non-converters. CONCLUSION: In the present study, patients with abnormal VRH results were very likely to develop DLB. Thus, for patients with late-onset MDD accompanied by bradykinesia, the VRH in combination with the clinical subtype of MDD or hypersensitivity to psychotropics may be useful for diagnosing prodromal DLB. PMID- 26757184 TI - Biochemical and Radiological Markers of Alzheimer's Disease Progression. AB - Alzheimer's disease (AD) is a neurodegenerative, inevitably progressive disease with a rate of cognitive, functional, and behavioral decline that varies highly from patient to patient. Although several clinical predictors of AD progression have been identified, to our mind in clinical practice there is a lack of a reliable biomarker that enables one to stratify the risk of deterioration. Identification of biomarkers that allow the monitoring of AD progression could change the way physicians and caregivers make treatment decisions. This review summarizes the results of studies on potential biochemical and radiological markers related to AD progression. PMID- 26757182 TI - Beneficial Effects of an Integrated Psychostimulation Program in Patients with Alzheimer's Disease. AB - BACKGROUND: The existing pharmacological treatments for Alzheimer's disease (AD) can only slow the progression of symptoms or delay admission to long-term care facilities. The beneficial effects of non-drug treatments are poorly studied. OBJECTIVE: To describe the effects of an Integrated Psychostimulation Program (IPP) in patients with mild-moderate AD treated with acetylcholinesterase inhibitors; and to identify factors related to greater benefit of the IPP. METHODS: 206 patients (mean age = 75.9 years; MMSE = 19.6) were evaluated before starting the IPP and 3, 6, 9, and 12 months later. Measures included: Mini-Mental State Examination (MMSE), Cognitive Subscale of Alzheimer's Disease Assessment Scale (ADAS-Cog), Rapid Disability Rating Scale (RDRS-2), and Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: Patients remained cognitively stable (MMSE/ADAS-Cog) for more than 6 months and significantly worsened at 9-month and 12-month follow-ups, without clinically significant functional changes (RDRS-2) or psychiatric symptoms(NPI-Q). The mean annual change on MMSE and ADAS-Cog were 2.06 and 3.56 points, respectively, lower than the annual decline demonstrated previously in similar patients (2.4 and 4.5, respectively). 42.7% of patients maintained or improved global cognitive scores between baseline and 12-month follow-up. The patients who maintained cognitive functions were older than those who did not (77.5 versus 74.7 years). CONCLUSIONS: The IPP may be an effective treatment to maintain cognition, functionality, and psychiatric symptoms in AD patients pharmacologically treated, and older age seems to increase beneficial effects of IPP. PMID- 26757185 TI - Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Cerebral Amyloid Angiopathy Related Inflammation. AB - BACKGROUND: Decreased cerebrospinal fluid (CSF) amyloid-beta 1-40 (Abeta40) and amyloid-beta 1-42 (Abeta42) and increased total and phosphorylated tau (t-tau, p tau) concentrations have been described in cerebral amyloid angiopathy (CAA). OBJECTIVE: Our aim was to analyze these biomarkers in patients with CAA-related inflammation (CAA-I). METHODS: We prospectively recruited nine patients with acute phase CAA-I fulfilling Chung criteria. CSF was analyzed for t-tau, p-tau, Abeta42, and Abeta40. Data were compared to controls (n = 14), patients with Alzheimer's disease (AD, n = 42), CAA (n = 10), and primary angiitis of the central nervous system (PACNS, n = 3). RESULTS: For the CAA-I group, statistically significant differences were: lower Abeta42 (p = 0.00053) compared to the control group; lower t-tau (p = 0.018), p-tau (p < 0.001), and Abeta40 (p < 0.001) compared to AD; lower Abeta42 (p = 0.027) compared to CAA; lower Abeta42 (p = 0.012) compared to PACNS. Nearly significantly lower Abeta40 (p = 0.051) and higher t-tau (p = 0.051) were seen in CAA-I compared to controls. CONCLUSION: CSF biomarkers profile similar to that of CAA was observed in CAA-I (with even lower levels of Abeta42 compared to CAA). Based on our findings, high p-tau seems more specific for AD, whereas low Abeta42 differentiates CAA-I from CAA, PACNS, and controls, and low Abeta40 differentiates CAA-I from AD. PMID- 26757186 TI - Lower Prevalence of Alzheimer's Disease among Tibetans: Association with Religious and Genetic Factors. AB - BACKGROUND: The prevalence of dementia differs among racial groups, the highest prevalence being in Latin America (8.5%) compared to sub-Saharan African regions (2-4%). The most common type of dementia is Alzheimer's disease (AD). OBJECTIVE: To estimate the prevalence of AD in the Qinghai-Tibet plateau and to investigate the related factors. METHODS: This was a cross-sectional, multistage cluster sampling design survey. Data was collected from May 2014 to September 2014 from 4,060 Tibetan aged >60 years. Participants underwent clinical examinations and neuropsychological evaluations. MALDI-TOF was used to test the genotypes of CLU, TFAM, TP53INP1, IGHV1-67, CR1, ApoE, and BIN1. Logistic regression models were used to ascertain the associations with AD. RESULTS: The prevalence of AD among Tibetan individuals aged >60 years was 1.33% (95% CI: 0.98-1.69). The CLU haplotypes AA+GA (odds ratio (OR) = 4.483; 95% CI: 1.069-18.792) of rs2279590 was correlated with AD. The CLU haplotypes GG+GC (OR = 0.184; 95% CI: 0.038-0.888) of rs9331888 and kowtow (OR = 0.203; 95% CI 0.046-0.896) were negatively correlated with AD. CONCLUSION: A low prevalence of AD was found in Tibetans from the Qinghai-Tibet plateau. Multivariate analysis might suggest that regular "mind body" religious meditative activities may be negatively associated with AD in this population, as well as the CLU genotype at rs9331888. PMID- 26757187 TI - Increase of alpha-Secretase ADAM10 in Platelets Along Cognitively Healthy Aging. AB - ADAM10 is one of the key players in ectodomain-shedding of the amyloid-beta protein precursor (AbetaPP). Previous research with postmortem tissue has shown reduced expression and activity of ADAM10 within the central nervous system (CNS) of Alzheimer's disease (AD) patients. Determination of cerebral ADAM10 in living humans is hampered by its transmembrane property; only the physiological AbetaPP cleavage product generated by ADAM10, sAbetaPPalpha, can be assessed in cerebrospinal fluid. Establishment of surrogate markers in easily accessible material therefore is crucial. It has been demonstrated that ADAM10 is expressed in platelets and that platelet amount is decreased in AD patients. Just recently it has been shown that platelet ADAM10 and cognitive performance of AD patients positively correlate. In contrast to AD patients, to our knowledge almost no information has been published regarding ADAM10 expression during normal aging. We investigated ADAM10 amount and activity in platelets of cognitively healthy individuals from three different age groups ranging from 22-85 years. Interestingly, we observed an age-dependent increase in ADAM10 levels and activity in platelets. PMID- 26757189 TI - Familial Presenilin Mutations and Sporadic Alzheimer's Disease Pathology: Is the Assumption of Biochemical Equivalence Justified? AB - Studies of presenilin (PSEN) gene mutations producing early onset Alzheimer's disease (AD) have helped elucidate the pathogenic mechanisms of dementia and guided clinical trials of potential therapeutic interventions. Although familial and sporadic forms of AD share features, it is unclear if the two are precisely equivalent. In addition, PSEN mutations do not all produce a single phenotype, but exhibit substantial variability in clinical manifestations, which are related to the position and chemical nature of their amino acid substitutions as well as ratios of critical molecules such as Abeta40 and Abeta42. These differences complicate the interpretation of critical clinical trial results and their desired extrapolation to sporadic AD treatment. In this perspective, we examine differences between familial AD and sporadic AD as well as attributes shared by these uniquely arising disturbances in brain biochemical homeostasis that culminate in dementia. PMID- 26757188 TI - Association of Butyrylcholinesterase-K Allele and Apolipoprotein E E4 Allele with Cognitive Decline in Dementia with Lewy Bodies and Alzheimer's Disease. AB - BACKGROUND: A common polymorphism of the butyrylcholinesterase gene, the K variant (BCHE-K) is associated with reduced butyrylcholinesterase (BuChE) activity. Insufficient studies exist regarding the frequency and role of BCHE-K in dementias. OBJECTIVE: To determine the association of BCHE-K and APOEE4 with diagnosis and rate of cognitive decline in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) patients. METHODS: Genomic DNA from 368 subjects (108 AD, 174 DLB, and 86 controls) from two routine clinical cohort studies in Norway; DemVest and TronderBrain, were genotyped for BCHE-K and APOEE4. The mild dementia DemVest subjects received annual Mini-Mental State Examination assessments for five years. RESULTS: BCHE-K frequency was lower in DLB (33.9% ; p < 0.01) than in control subjects (51.2%), and was numerically lower in AD as well (38.9% ; p = 0.11). More rapid cognitive decline was associated with the APOEE4 genotype, but not with the BCHE-K genotype. In an exploratory analysis of patients who completed all five follow-up visits, there was greater cognitive decline in BCHE K carriers in the presence of the APOEE4 allele than in the absence of these polymorphisms. CONCLUSION: BCHE-K is associated with a reduced risk for AD and DLB whereas APOEE4 is associated with more rapid cognitive decline. The greater cognitive decline in individuals with both APOEE4 and BCHE-K alleles require prospective confirmation in well-controlled trials. PMID- 26757190 TI - Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment. AB - A randomized trial (VITACOG) in people with mild cognitive impairment (MCI) found that B vitamin treatment to lower homocysteine slowed the rate of cognitive and clinical decline. We have used data from this trial to see whether baseline omega 3 fatty acid status interacts with the effects of B vitamin treatment. 266 participants with MCI aged >=70 years were randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years. Baseline cognitive test performance, clinical dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic acids (omega-3 fatty acids) were measured. Final scores for verbal delayed recall, global cognition, and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in the placebo group were similar across these concentrations. Among those with good omega-3 status, 33% of those on B vitamin treatment had global CDR scores >0 compared with 59% among those on placebo. For all three outcome measures, higher concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic acid appeared less effective. When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD. PMID- 26757191 TI - Dose-Dependent Neuroprotection and Neurotoxicity of Simvastatin through Reduction of Farnesyl Pyrophosphate in Mice Treated with Intracerebroventricular Injection of Abeta 1-42. AB - BACKGROUND: Simvastatin (SV) has been reported to improve dementia and slow progression of Alzheimer's disease (AD), however there are conflicting reports. OBJECTIVE & METHODS: Intracerebroventricular injection of aggregated Abeta1-42 in mice (Abeta1-42-mice) caused spatial cognitive deficits, long-term potentiation (LTP) impairment, and death of hippocampal pyramidal cells. The present study focused on exploring the dose-dependent effects of SV (10-80 mg/kg) on Abeta1-42 impaired spatial memory and the underlying mechanisms. RESULTS: The treatment of Abeta1-42-mice with SV for continuous 15 days could attenuate the spatial cognitive deficits and recover the LTP induction in a "U" type dose-dependent manner. The death of pyramidal cells in Abeta1-42-mice was significantly reduced by the SV-treatment at 20 mg/kg, but not at a dose of 10 or 40 mg/kg, even was aggravated at a dose of 80 mg/kg. Hippocampal NMDA receptor (NMDAr) NR2B phosphorylation (phospho-NR2B) was elevated in Abeta1-42-mice, which was further dose-dependently increased by SV-treatment. Replenishment of isoprenoid farnesyl pyrophosphate (FPP) by applying farnesol (FOH) could abolish the SV-increased phospho-NR2B in Abeta1-42-mice, but had no effect on the Abeta1-42-enhanced phospho-NR2B. NMDAr antagonist blocked the neurotoxicity of Abeta1-42 and SV (80 mg/kg) in Abeta1-42-mice, whereas FOH only inhibited SV (80 mg/kg)-neurotoxicity. The SV-treatment in Abeta1-42-mice corrected the decrease in hippocampal Akt phosphorylation. The PI3K inhibitor abolished the SV (20 mg/kg)-neuroprotection in Abeta1-42-mice. CONCLUSION: SV-treatment in Abeta1-42-mice exerts dose dependent neuroprotection and neurotoxicity by reducing FPP to enhance the phosphorylation of NR2B and Akt. PMID- 26757193 TI - Reversal of LTP-Like Cortical Plasticity in Alzheimer's Disease Patients with Tau Related Faster Clinical Progression. AB - Cerebrospinal fluid (CSF) concentrations of amyloid-beta (Abeta), total tau (t tau), and phosphorylated tau proteins are associated with different clinical progression in Alzheimer's disease (AD). We enrolled forty newly diagnosed AD patients, who underwent lumbar puncture, and carried out a K-means cluster analysis based on CSF biomarkers levels, resulting in two AD patient groups: Cluster 1 showed relatively high levels of Abeta and low levels of tau; Cluster 2 showed relatively low levels of Abeta and high levels of tau. Cortical plasticity was tested using the intermittent and continuous theta burst stimulation (iTBS and cTBS) protocols evoking respectively long-term potentiation (LTP) and depression (LTD). Cholinergic transmission was tested by the short-latency afferent inhibition protocol. Neurophysiological evaluation showed that the two AD groups differed in terms of cortical plasticity: after iTBS, Cluster 2 patients showed a remarkable reversal of LTP toward LTD that was not observed in Cluster 1. LTD and central cholinergic transmission did not differ between groups. Patients were assessed longitudinally with Mini-Mental State Examination at 6, 12, and 18 month follow-ups. Cluster 2 AD had a faster cognitive decline already evident at the 12 month follow-up. High tau CSF levels were associated with LTD-like cortical plasticity and faster clinical progression. These results suggest that more aggressive tau pathology is associated with prominent LTD-like mechanisms of cortical plasticity and faster cognitive decline. PMID- 26757192 TI - Low Prevalence of Mixed Dementia in a Cohort of 2,000 Elderly Patients in a Memory Clinic Setting. AB - BACKGROUND: It is generally assumed that with increasing age, pathology in clinically diagnosed Alzheimer's disease (AD) becomes more mixed, i.e., co existence of amyloid plaques and cerebrovascular pathology. OBJECTIVE: To test the hypothesis of increasing prevalence of mixed dementia in late-onset clinically diagnosed Alzheimer's disease (AD) in a single-center memory clinic population. METHODS: Patients included had diagnoses of AD (n = 832), subjective cognitive impairment (SCI, n = 333), mild cognitive impairment (MCI, n = 492), vascular dementia (VaD, n = 57), other dementia (n = 53), or other diagnosis (n = 233). Prevalence of severe white matter lesions (WML) was defined as a score of 2 or higher on the Fazekas-scale on brain computed tomography to classify AD patients as having mixed dementia. We examined the effect of age on WML using multiple linear regression analysis, and AD patients were compared to SCI to determine the effect of disease on WML. RESULTS: Prevalence of severe WML was 33.6% in AD patients (mixed dementia), 11.4% in SCI, 22.7% in MCI, 75.4% in VaD, 3.8% in other dementia, and 15.5% in other diagnosis. With increasing age there was a significant and similar increase of WML scores in SCI, MCI, AD, other dementia, and other diagnosis, indicating no effect modification by AD. The difference between AD patients and SCI averaged 0.16 on the WML score and difference in percentage severe WML between AD and SCI patients was 15% across all ages. CONCLUSION: We found a low prevalence of mixed dementia. Furthermore, severe WML in AD was largely explained by age rather than effect of disease. PMID- 26757194 TI - Serotonin 2A Receptor Inverse Agonist as a Treatment for Parkinson's Disease Psychosis: A Systematic Review and Meta-analysis of Serotonin 2A Receptor Negative Modulators. AB - BACKGROUND: There is uncertainty about the efficacy and tolerability of serotonin 2A (5-HT2A) receptor negative modulators for Parkinson's disease psychosis (PDP). OBJECTIVE: This is the first meta-analysis of randomized placebo-controlled trials (RCTs) testing negative modulators of the 5-HT2A receptor as a treatment for PDP. METHODS: The primary outcome was the Scale for Assessment of Positive Symptoms (SAPS)-hallucinations (H) and -delusions (D) scores (SAPS-H+D). Other outcome measures were SAPS-H, SAPS-D, the Unified Parkinson's Disease Rating Scale Part II and III (UPDRS-II+III), discontinuation rates, and individual adverse events. RESULTS: Four RCTs were identified that met inclusion criteria, all assessing the 5-HT2A inverse agonist pimavanserin (including 417 drug-treated and 263 placebo-treated PDP patients). Pimavanserin significantly decreased SAPS H+D scores compared to placebo [weighted mean differences (WMD) = -2.26, 95% confidence interval (95% CI) = -3.86 to -0.67, p = 0.005, I2 = 30% , N = 4 studies, n = 502 patients]. Moreover, pimavanserin was superior to placebo for reducing SAPS-H (WMD = -2.15, 95% CI = -3.45 to -0.86, p = 0.001, I2 = 0% , N = 2, n = 237) and SAPS-D scores (WMD = -1.32, 95% CI = -2.32 to -0.32, p = 0.010, I2 = 0% , N = 2, n = 237). Pimavanserin was associated with less orthostatic hypotension than placebo (risk ratio = 0.33, 95% CI = 0.15-0.75, p = 0.008, I2 = 0% , number needed to harm = 17, p = 0.01, N = 3, n = 476). There were no significant differences in rates of all-cause discontinuation, adverse events, and death, UPDRS-II+III scores, and incidences of individual adverse events (other than orthostatic hypotension) between pimavanserin and placebo groups. CONCLUSIONS: Pooled RCT results suggest that pimavanserin is beneficial for the treatment of PDP and is well tolerated. We did not identify other negative modulators of the 5-HT2A receptor for the treatment of PDP. PMID- 26757196 TI - The Elusive Goal of Drug-Free Prisons. AB - BACKGROUND: Although there is a need for well-designed evaluations, international evidence shows that drugs frequently enter prisons and enforcement efforts are said to be linked to adverse events. OBJECTIVES: This study sought to examine drug enforcement within a federal prison system, overseen by the Correctional Service of Canada (CSC), and to detail competing perspectives. METHODS: Three main sources of data were used in this qualitative study: 16 interviews conducted between 2010 and 2012 with former CSC senior officials, former frontline staff, and external stakeholders; CSC research publications and other documents; and transcripts from a relevant House of Commons Standing Committee public study. All texts were coded and compared to examine emergent themes of interest. RESULTS: Six key themes are described as contested effects of enhanced in-prison drug enforcement: (1) continued and creative efforts to bring in drugs; (2) climate of tensions and violence; (3) prisoners switching their drug use; (4) health-related harms; (5) deterrence of visitors; and (6) staff involvement in the in-prison drug trade. CONCLUSIONS/IMPORTANCE: Urgently needed are rigorous evaluations of in-prison drug enforcement, along with closer scrutiny of policy recommendations that uphold the goal of drug-free prisons. Studying similar prison systems as complex risk-managing organizations may offer new information about drug enforcement policy and practice resistance despite detrimental effects. PMID- 26757195 TI - PRNP P39L Variant is a Rare Cause of Frontotemporal Dementia in Italian Population. AB - The missense P39L variant in the prion protein gene (PRNP) has recently been associated with frontotemporal dementia (FTD). Here, we analyzed the presence of the P39L variant in 761 patients with FTD and 719 controls and found a single carrier among patients. The patient was a 67-year-old male, with a positive family history for dementia, who developed apathy, short term memory deficit, and postural instability at 66. Clinical and instrumental workup excluded prion disease. At MRI, bilateral frontal lobe atrophy was present. A diagnosis of FTD was made, with a mainly apathetic phenotype. The PRNP P39L mutation may be an extremely rare cause of FTD (0.13%). PMID- 26757197 TI - Serum HER2 as an adjunct to assess HER2 status for advanced gastric cancer: A prospective multicenter trial (SHERLOCK). AB - BACKGROUND: Intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity of gastric cancer can be an obstacle to accurate HER2 assessment. Serum HER2, concentrations of the HER2 extracellular domain shed into the bloodstream, has a potential to compensate HER2 immunohistochemistry (IHC) but has not been scrutinized in gastric cancer. This study sought to explore the clinical utility of serum HER2 in gastric cancer. METHODS: We performed a prospective multicenter trial (SHERLOCK trial) involving patients with all-stage gastric or gastro-esophageal junction cancer. Serum HER2 was measured using direct chemiluminescence while tissue HER2 status was determined using IHC and fluorescent in situ hybridization. For stage IV cases, concordance between local and central laboratories in tissue HER2 assessment was also evaluated. RESULTS: Of 224 patients enrolled, both tissue HER2 status and serum HER2 levels were successfully determined in 212 patients and 21% (45/212) were tissue HER2 positive. Serum HER2 levels, ranged from 4.5 to 148.0 ng/ml (median 10.3), correlated with tissue HER2 status (p = 0.003). At a cut-off level of 28.0 ng/ml determined by receiver operating characteristics analysis, sensitivity, specificity, positive and negative predictive values of serum HER2 were 22.6%, 100%, 100% and 82.3%, respectively. All nine cases with elevated serum HER2 were tissue HER2-positive stage IV cases. Among 61 stage IV cases, the agreement rate for IHC scoring between the local and the central laboratories was 82% and tissue HER2 judgment was conflicting in five (8.2%) cases. Of these five cases, four were confirmed as false-negative and two of these four patients demonstrated elevated serum HER2. CONCLUSIONS: Serum HER2 levels correlated with tissue HER2 status in gastric cancer. Although the low sensitivity is a drawback, serum HER2 might be a useful adjunct tool to detect tissue HER2 false-negative gastric cancer. PMID- 26757199 TI - Reply to Kelly et al. PMID- 26757200 TI - Preparation of Free-Standing and Flexible Graphene/Ag Nanoparticles/Poly(pyronin Y) Hybrid Paper Electrode for Amperometric Determination of Nitrite. AB - A flexible and free-standing graphene-based hybrid paper was successfully fabricated by successive applications of vacuum filtration and electropolymerization. First, a suspension including graphene oxide (GO) and silver nanoparticles (AgNPs) was prepared, and GO/AgNPs paper was obtained by vacuum-filtration of this suspension through a membrane. This GO/AgNPs paper was transformed to rGO/AgNPs paper by using both chemical reduction with HI and thermal annealing procedures. rGO/AgNPs/poly(PyY) hybrid paper electrode was formed by electropolymerization of Pyronin Y (PyY) on rGO/AgNPs paper electrode from a PyY monomer-containing (pH 1.0) solution. Structural, chemical, and morphological characterization of this hybrid paper was carried out by scanning electron microscopy, X-ray photoelectron spectroscopy, X-ray diffraction, Raman spectroscopy, infrared spectroscopy, UV-vis absorption spectroscopy, four-point probe conductivity measurement, and cyclic voltammetry techniques. Electrooxidation of nitrite on rGO/AgNPs/poly(PyY) hybrid paper electrode has been achieved at 860 mV with a linear range of 0.1-1000 MUM, sensitivity of 13.5 MUAMUM(-1)cm(-2), and a detection limit of 0.012 MUM. Amperometry studies have shown that the hybrid paper electrode is suitable for amperometric determination of nitrite in both standard laboratory samples and real samples. Moreover, this paper electrode selectively detects nitrite even in the presence of 100-fold common ions and exhibits an excellent operational stability and good flexibility. PMID- 26757198 TI - On Efficient and Accurate Calculation of Significance P-Values for Sequence Kernel Association Testing of Variant Set. AB - The objective of this paper is to discuss and develop alternative computational methods to accurately and efficiently calculate significance P-values for the commonly used sequence kernel association test (SKAT) and adaptive sum of SKAT and burden test (SKAT-O) for variant set association. We show that the existing software can lead to either conservative or inflated type I errors. We develop alternative and efficient computational algorithms that quickly compute the SKAT P-value and have well-controlled type I errors. In addition, we derive an alternative and simplified formula for calculating the significance P-value of SKAT-O, which sheds light on the development of efficient and accurate numerical algorithms. We implement the proposed methods in the publicly available R package that can be readily used or adapted to large-scale sequencing studies. Given that more and more large-scale exome and whole genome sequencing or re-sequencing studies are being conducted, the proposed methods are practically very important. We conduct extensive numerical studies to investigate the performance of the proposed methods. We further illustrate their usefulness with application to associations between rare exonic variants and fasting glucose levels in the Atherosclerosis Risk in Communities (ARIC) study. PMID- 26757201 TI - Characteristics of affected third parties and cooperative behavior in social dilemmas. AB - The studies described in this article explore the influence of an under emphasized determinant of cooperative behavior in social dilemmas: affected third parties. Two experiments examined the effect of characteristics of third parties on individual cooperative behavior in social dilemmas, and identified mechanisms associated with these relationships. Study 1 demonstrated that third-party need affects individual cooperative behavior, and tested prosocial motivation and intra-group trust as mediators of this relationship. Study 2 provided further elaboration by demonstrating that individual cooperative behavior was reduced when a needy third party was low on reliability, and by showing that prosocial motivation and intra-group trust mediated this relationship. This research connects the literatures on individual cooperation in social dilemmas and relational job design, and demonstrates why third parties influence individuals' cooperative behavior. PMID- 26757202 TI - Cerebellomedullary Cistern Delivery for AAV-Based Gene Therapy: A Technical Note for Nonhuman Primates. AB - Accessing cerebrospinal fluid (CSF) from the craniocervical junction through the posterior atlanto-occipital membrane via cerebellomedullary injection (also known as cisternal puncture or cisterna magna injection) has become a standard procedure in preclinical studies. Such delivery provides broader coverage to the central and peripheral nervous system unlike local parenchymal delivery alone. As a clinical application, this approach offers a more reliable method for neurological gene replacement delivery in infants, where skull-mounted devices are not indicated. Here we describe a consistent, precise, and safe method for CSF injection with minimal equipment and technical skills. PMID- 26757203 TI - Sentinel Lymph Node in Breast Cancer: Review Article from a Pathologist's Point of View. AB - Breast cancer staging, in particular N-stage changed most significantly due to the advanced technique of sentinel lymph node biopsy two decades ago. Pathologists have more thoroughly examined and scrutinized sentinel lymph node and found increased number of small volume metastases. While pathologists use the strict criteria from the Tumor Lymph Node Metastasis (TNM) Classification, studies have shown poor reproducibility in the application of American Joint Committee on Cancer and International Union Against Cancer/TNM guidelines for sentinel lymph node classification in breast cancer. In this review article, a brief history of TNM with a focus on N-stage is described, followed by innate problems with the guidelines, and why pathologists may have difficulties in assessing lymph node metastases uniformly. Finally, clinical significance of isolated tumor cells, micrometastasis, and macrometastasis is described by reviewing historical retrospective data and significant prospective clinical trials. PMID- 26757204 TI - Electroanatomic Correlates of Depolarization Abnormalities in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. AB - BACKGROUND: Epsilon waves and other depolarization abnormalities in the right precordial leads are thought to represent delayed activation of the right ventricular outflow tract in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, no study has directly correlated cardiac electrical activation with the surface ECG findings in ARVD/C. METHODS AND RESULTS: Thirty ARVD/C patients (mean age 32.7 +/- 11.2 years, 16 men) underwent endocardial and epicardial electroanatomical activation mapping in sinus rhythm. Twelve-lead ECGs were classified into 5 patterns: (1) normal QRS (11 patients); (2) terminal activation delay (TAD) (3 patients); (3) incomplete right bundle branch block (IRBBB) (5 patients); (4) epsilon wave (5 patients); (5) complete right bundle branch block (CRBBB) (6 patients). Timing of local ventricular activation and extent of scar was then correlated with surface QRS. Earliest endocardial and epicardial RV activation occurred on the mid anteroseptal wall in all patients despite the CRBBB pattern on ECG. Total RV activation times increased from normal QRS to prolonged TAD, IRBBB, epsilon wave, and CRBBB, respectively (103.9 +/- 5.6, 116.3 +/- 6.5, 117.8 +/- 2.7, 146.4 +/- 16.3, and 154.3 +/- 6.3, respectively, P < 0.05). The total epicardial scar area (cm(2) ) was similar among the different ECG patterns. Median endocardial scar burden was significantly higher in patients with epsilon waves even compared with patients with CRBBB (34.3 vs. 11.3 cm(2) , P < 0.01). Timing of epsilon wave corresponded to activation of the subtricuspid region in all patients. CONCLUSION: We found that epsilon waves are often associated with severe conduction delay and extensive endocardial scarring in addition to epicardial disease. The timing of epsilon waves on surface ECG correlated with electrical activation of the sub-tricuspid region. PMID- 26757205 TI - The Odocoileus virginianus Femur: Mechanical Behavior and Morphology. AB - Biomechanical research relies heavily on laboratory evaluation and testing with osseous animal structures. While many femora models are currently in use, including those of the European red deer (Cervus elaphus), the Odocoileus virginianus femur remains undocumented, despite its regional abundance in North America. The objective of this study was to compare biomechanical and morphological properties of the Odocoileus virginianus femur with those of the human and commonly used animal models. Sixteen pairs of fresh-frozen cervine femora (10 male, 6 female, aged 2.1 +/- 0.9 years) were used for this study. Axial and torsional stiffnesses (whole bone) were calculated following compression and torsion to failure tests (at rates of 0.1 mm/sec and 0.2 degrees /sec). Lengths, angles, femoral head diameter and position, periosteal and endosteal diaphyseal dimensions, and condylar dimensions were measured. The results show that the cervine femur is closer in length, axial and torsional stiffness, torsional strength, and overall morphology to the human femur than many other commonly used animal femora models; additional morphological measurements are comparable to many other species' femora. The distal bicondylar width of 59.3mm suggests that cervine femora may be excellent models for use in total knee replacement simulations. Furthermore, the cervine femoral head is more ovoid than other commonly-used models for hip research, making it a more suitable model for studies of hip implants. Thus, with further, more application-specific investigations, the cervine femur could be a suitable model for biomechanical research, including the study of ballistic injuries and orthopaedic device development. PMID- 26757206 TI - Total Synthesis of (+/-)-Alstoscholarisine A. AB - The first total synthesis of the neuroactive indole alkaloid (+/-) alstoscholarisine A is reported. The key step of the concise synthesis is an efficient domino sequence that was used to assemble the 2,8 diazabicyclo[3.3.1]nonane core through the formation of two C-N bonds and one C-C bond in a single step. PMID- 26757207 TI - The Triplet State of 6-thio-2'-deoxyguanosine: Intrinsic Properties and Reactivity Toward Molecular Oxygen. AB - Thiopurine prodrugs are currently among the leading treatment options for leukemia, immunosuppression, and arthritis. Patients undergoing long-term thiopurine treatment are at a higher risk of developing sunlight-induced skin cancers than the general population. This side effect originates from the cellular metabolization of thiopurine prodrugs to form 6-thio-2'-deoxyguanosine, which can absorb UVA radiation, populating its reactive triplet state and leading to oxidatively generated damage. However, the photo-oxidation mechanism is not fully understood. In this contribution, the oxidation potential and the adiabatic triplet energy of 6-thio-2'-deoxyguanosine are estimated computationally, whereas the intrinsic rate of triple-state decay and the rate constant for triplet quenching by molecular oxygen are determined using time-resolved spectroscopic techniques. A singlet oxygen quantum yield of 0.24 +/- 0.02 is measured in aqueous solution (0.29 +/- 0.02 in acetonitrile). Its magnitude correlates with the relatively low percentage of triplet-O2 collision events that generate singlet oxygen (SDelta = 37%). This behavior is rationalized as being due to the exergonic driving force for electron transfer between the triplet state of 6-thio 2'-deoxyguanosine and molecular oxygen (DeltaGET = -69.7 kJ mol-1 ), resulting in the formation of a charge-transfer complex that favors nonradiative decay to the ground state over triplet energy transfer. PMID- 26757208 TI - Early Radiation Toxicity from Yttrium-90 Radioembolization for Advanced Hepatocellular Carcinoma. PMID- 26757210 TI - Antifactor Xa Activity for the Management of Anticoagulation during Cardiac Surgery. AB - Background In patients with autoimmune diseases associated with antiphospholipid antibodies, precise management of anticoagulation during extracorporeal circulation (ECC) is complicated. It was the aim of the present study to determine whether antifactor Xa (aXa) activity is useful in guiding heparin therapy during ECC. Methods In 15 patients undergoing cardiac surgery, anticoagulation with unfractionated heparin (UFH) and its reversal with protamine were guided using activated clotting time (ACT) (>400 second during ECC; <=100 second for UFH reversal). For each ACT, the corresponding aXa activity levels were measured. Results A total of 144 blood samples were obtained. ACT and aXa activity were significantly correlated (r = 0.771, p< 0.0001, Spearman rank-order correlation). Using receiver operating characteristic curve (ROC) analyses, the cutoffvalues for aXa activity were 1.14 IU/mL (area under the ROC curve [AUC]: 0.89; inaccuracy rate: 9.4%) to predict ACT > 400 seconds and 0.55 IU/mL (AUC: 0.85; inaccuracy rate: 13.3%) for ACT <= 100 seconds. Conclusion AXa activity is strongly correlated with ACT, and therefore may be feasible for managing anticoagulation with UFH during ECC. PMID- 26757209 TI - Cardiovascular Comorbidities Relate More than Others with Disease Activity in Rheumatoid Arthritis. AB - OBJECTIVES: To explore the influence of comorbidities on clinical outcomes and disease activity in rheumatoid arthritis (RA). METHODS: In patients included in the cross-sectional observational multicenter international study COMORA, demographics, disease characteristics and comorbidities (hypertension, diabetes, hyperlipidemia, renal failure, ischemic heart disease, stroke, cancer, gastro intestinal ulcers, hepatitis, depression, chronic pulmonary disease, obesity) were collected. Multivariable linear regression models explored the relationship between each comorbidity and disease activity measures: 28-swollen joint count (SJC), 28-tender joint count (TJC), erythrocyte sedimentation rate (ESR), patient's and physician's global assessment (PtGA, PhGA), patient reported fatigue and 28-Disease Activity Score (DAS28). Results are expressed as mean difference (MD) adjusted for the main confounders (age, gender, disease characteristics and treatment). RESULTS: A total of 3,920 patients were included: age (mean +/-SD) 56.27 +/-13.03 yrs, female 81.65%, disease duration median 7.08 yrs (IQR 2.97-13.27), DAS28 (mean +/-SD) 3.74 +/- 1.55. Patients with diabetes had more swollen and tender joints and worse PtGA and PhGA (MD +1.06, +0.93, +0.53 and +0.54, respectively). Patients with hyperlipidemia had a lower number of swollen and tender joints, lower ESR and better PtGA and PhGA (MD -0.77, 0.56, -3.56, -0.31 and -0.35, respectively). Patients with history of ischemic heart disease and obese patients had more tender joints (MD +1.27 and +1.07) and higher ESR levels (MD +5.64 and +5.20). DAS28 is influenced exclusively by cardiovascular comorbidities, in particular diabetes, hyperlipidemia, ischemic heart disease and obesity. CONCLUSIONS: Cardiovascular comorbidities relate more than others with disease activity in RA. Diabetes and hyperlipidemia in particular seem associated with higher and lower disease activity respectively influencing almost all considered outcomes, suggesting a special importance of this pattern of comorbidities in disease activity assessment and clinical management. PMID- 26757211 TI - Surgery for Left Ventricular Outflow Tract Obstruction with a Relatively Thin Interventricular Septum. AB - BACKGROUND: To examine the results of myectomy and mitral valve surgery for systolic anterior motion (SAM) of the mitral valve and left ventricular outflow tract obstruction (LVOTO) with a relatively thin interventricular septum. METHODS: The subjects were 12 patients with SAM and LVOTO. Eight had hypertrophic obstructive cardiomyopathy (HOCM) with a mean interventricular septal thickness of 16 mm. Three had sigmoid septum and one had an unknown etiology. For HOCM, isolated extended myectomy was performed when mitral regurgitation was mild (n = 1) and extended myectomy plus mitral valve surgery was performed when mitral regurgitation was more than mild (n = 4) or primary valve etiologies existed (n = 3). Myectomy was performed for the three cases with sigmoid septum. Myectomy plus height reduction of the posterior mitral leaflet was performed for the one case with the unknown etiology of SAM. RESULTS: In the patients with HOCM, the maximum LVOT pressure gradient significantly decreased from 140 +/- 18 to 16 +/- 6 and 3 +/- 3 mm Hg, while mitral regurgitation significantly decreased from 2.3 +/- 0.5 to 0.5 +/- 0.3 and 0.4 +/- 0.2 at pre-op, early post-op, and last follow-up (3 +/ 1 years), respectively. In the other etiologies, the maximum LVOT pressure gradient changed from 56 +/- 15 to 25 +/- 15 and 5 +/- 4 mm Hg; mitral regurgitation changed from 2.0 +/- 0.6 to 1.3 +/- 0.3 and 1.3 +/- 0.8, at pre-op, early post-op, and the last follow-up (3 +/- 2 years), respectively. CONCLUSION: Myectomy with mitral valve surgery is an option for SAM and LVOTO in patients with a relatively thin interventricular septum. PMID- 26757212 TI - Therapeutic Pneumoperitoneum: Relevant or Obsolete in 2015? AB - Background Therapeutic pneumoperitoneum (TP) is one alternative to manage pleural space problems. We describe our technique and experience. Materials and Methods Medical records of all patients who underwent TP from January 1, 2007, to January 1, 2015, were reviewed after Institutional Review Board approval. We report indication, preprocedure pulmonary function tests, volume of insufflated air, time to chest tube removal, and complications. We place a red rubber catheter into the peritoneal space through the diaphragm or a small abdominal incision, insufflate with room air, record volume (liters), intraperitoneal pressure (goal 9-10 mm Hg), and monitor vital signs, airway pressures, and urine output. Results We performed TP in 32 patients. Follow-up was available for 31 patients. Indications were prevention of pleural space problems in bilobectomy patients (n = 11), following decortication for empyema (n = 11), prevention of prolonged air leak (n = 3), prevention of postresection space (n = 4), and spontaneous chylothorax (n = 2). TP was done postoperatively in three patients. Median air volume used was 3.5 L (3-6 L). Time to chest tube removal overall was 7.8 days (3 20 days) and to discharge 10.2 days (4-32 days). No patient developed respiratory failure, renal failure, or required evacuation of TP. Conclusion TP is a simple, safe, and effective technique to manage pleural space problems. Proper patient selection and meticulous technique are imperative for the successful clinical application of TP. We believe that TP is an underutilized tool for the management of pleural space problems and merits wider application in thoracic surgical practice. PMID- 26757213 TI - Can Sericin Prove Useful as a Pleurodesis Agent or Tissue Glue? AB - Background Sericin is a natural, gum-like, macromolecule protein, synthesized from silkworms for the formation of cocoon shells. The aim of the present study is to describe the effects of sericin when used for pleurodesis and/or as tissue glue. Methods Adult, male, 12-week-old Wistar albino rats, weighing 257 to 395 g were used in the present study (n = 12). The animals were randomly divided into two equal groups as the sericin and the control group. After intramuscular administration of the anesthetic agent, the rats were intubated and mechanically ventilated. A left thoracotomy was performed and 30 mg sericin powder was instilled into the thoraxes of the sericin group. The remaining rats were allocated to a sham thoracotomy group. The animals were housed in individual cages, fed ad-libitum, and sacrificed 8 days after. After sacrifice, the left hemithoraxes were removed en bloc and underwent histopathologic examination. Results Masson trichrome staining was applied on the visceral pleura sections of all the animals. Each animal specimen (n = 6, 100%) in the control group showed minimal collagen deposition, while only one rat (16.67%) in the sericin group had minimal collagen deposition. However, in the sericin group, five animals (83.33%) showed dense collagen deposition, fibroblastic activity, and fibrosis. According to the test method, independent t-test, developing fibroblastic activity and fibrosis are statistically significant between the two groups (p < 0.01). There were no foreign-body reactions and no evidence of biological glue on the specimens in the sericin group. The rats in the sericin group had lower inflammatory reactions compared with those in the control group. Emphysema was observed in two rats (33.33%) in the sericin group and in four rats (66.67%) in the control group. Therefore, sericin was found to be associated with an increase in fibroblastic activity and fibrosis in visceral pleura without exerting any adverse effect on the lung parenchyma. Conclusion Sericin is a new and researchable protein for chest diseases and thoracic surgery. To develop an effect of dense collagen deposition, fibroblastic activity, and fibrosis in the visceral pleura, without significant adverse effects, is remarkable. Therefore, sericin may be useful as a pleurodesis agent or natural biological glue in the future. Sericin treatment can add value to the disciplines of pulmonology and thoracic surgery. PMID- 26757215 TI - Cerebrospinal fluid profile and seroprevalence of antiganglioside reactivity in patients with neuralgic amyotrophy. AB - Neuralgic amyotrophy (NA), also known as acute brachial plexitis, is postulated as an autoimmune pathogenesis. In a well-defined cohort of patients with NA, we analyzed the cerebrospinal fluid (CSF) profile and the prevalence of antiganglioside antibodies. Patients with Varicella zoster-associated radiculitis and healthy blood donors served as controls. An abnormal routine laboratory CSF profile was found in 29% of those with NA, mostly showing a disruption of the blood-brain barrier. Antibodies predominantly from the immunoglobulin M (IgM) isotype against at least one human ganglioside were detected in 36% of sera from patients with NA but in only 2% of controls. An NA-specific reactivity pattern was not detected, and there was no significant association with clinical or CSF parameters. This suggests that the seroprevalence of antiganglioside autoantibodies in patients with NA is nonspecific. PMID- 26757214 TI - How mutational epistasis impairs predictability in protein evolution and design. AB - There has been much debate about the extent to which mutational epistasis, that is, the dependence of the outcome of a mutation on the genetic background, constrains evolutionary trajectories. The degree of unpredictability introduced by epistasis, due to the non-additivity of functional effects, strongly hinders the strategies developed in protein design and engineering. While many studies have addressed this issue through systematic characterization of evolutionary trajectories within individual enzymes, the field lacks a consensus view on this matter. In this work, we performed a comprehensive analysis of epistasis by analyzing the mutational effects from nine adaptive trajectories toward new enzymatic functions. We quantified epistasis by comparing the effect of mutations occurring between two genetic backgrounds: the starting enzyme (for example, wild type) and the intermediate variant on which the mutation occurred during the trajectory. We found that most trajectories exhibit positive epistasis, in which the mutational effect is more beneficial when it occurs later in the evolutionary trajectory. Approximately half (49%) of functional mutations were neutral or negative on the wild-type background, but became beneficial at a later stage in the trajectory, indicating that these functional mutations were not predictable from the initial starting point. While some cases of strong epistasis were associated with direct interaction between residues, many others were caused by long-range indirect interactions between mutations. Our work highlights the prevalence of epistasis in enzyme adaptive evolution, in particular positive epistasis, and suggests the necessity of incorporating mutational epistasis in protein engineering and design to create highly efficient catalysts. PMID- 26757217 TI - Reply to Jackson and Cross' Comment on "Exceptionally Long MTBE Plumes of the Past Have Greatly Diminished". PMID- 26757232 TI - The Effect of Gender, Tone, and Sound Location on the Response Behavior of Neogobius melanostomus (Round Goby) and the Possibility of Future Trapping of this Invasive Species in Lake Superior. AB - Neogobius melanostomus (round goby) are a benthic dwelling invasive species of fish in the Great Lakes. This study was done to determine if a tone that mimics the frequency (175 Hz) of mating call of a male round goby would have an effect on male and female response. A testing tank and a simulated trap in front of a speaker at each end were used. Each fish was then placed individually into the small holding box that was in the center of the tank. A video camera was then turned on to record fish movement once the door was opened. Next, the artificial sound was turned on for 1 min (175, 300, 500 Hz, and no sound); 175 Hz mimics the conspecific mating call. This process was done for each frequency for each fish. The individual fish was then allowed to roam for 5 min. The video camera recorded fish location and behavior. From the videos, a continuous measure was collected according to when the fish crossed the center line. The hypothesis, if (N. melanostomus) hears different frequencies of sound projected from a certain location in a fish tank habitat, then the females will be attracted and spend more time on the sound-emitting side of the tank, which mimics the frequency of mating call of a male round goby (175 Hz, 13 pulse), was supported; females spent more time on the sound-emitting side of the tank and males avoided the sound emitting side of the tank, analysis of variance p < 0.012. PMID- 26757233 TI - Parasitic weed management by using strigolactone-degrading fungi. AB - BACKGROUND: Seed germination is a key phase of the parasitic plant life cycle that is stimulated by the secondary metabolites, mainly strigolactones (SLs), secreted by the host roots. Interventions during this stage would be particularly suitable for parasitic weed management practices, as blocking these chemical signals would prevent seed germination and thus parasite attack. Four fungal strains with different ecological functions were considered for their possible ability to metabolise SLs: Fusarium oxysporum and F. solani, biocontrol agents of Phelipanche ramosa; Trichoderma harzianum, a potential biopesticide; Botrytis cinerea, a phytopathogenic fungus. Four different SLs [the natural strigol, 5 deoxystrigol (5DS) and 4-deoxyorobanchol (4DO), and the synthetic analogue GR24] were added to fungal cultures, followed by determination of the SL content by liquid chromatography-tandem mass spectrometry. RESULTS: Differences were observed among microorganisms, treatments and SLs used. T. harzianum and F. oxysporum were the most capable of reducing the SL content; considering the whole set of fungi used, 5DS and 4DO proved to be the most degradable SLs. CONCLUSIONS: Beneficial microscopic fungi could differently be used for biocontrolling parasitic weeds, acting as a 'physiological' barrier, by preventing the germination of their seeds through the ability to biotransform the stimulatory signals. (c) 2016 Society of Chemical Industry. PMID- 26757216 TI - Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures. AB - Recent studies indicate that selective noradrenergic (atomoxetine) and serotonergic (citalopram) reuptake inhibitors may improve response inhibition in selected patients with Parkinson's disease, restoring behavioral performance and brain activity. We reassessed the behavioral efficacy of these drugs in a larger cohort and developed predictive models to identify patient responders. We used a double-blind randomized three-way crossover design to investigate stopping efficiency in 34 patients with idiopathic Parkinson's disease after 40 mg atomoxetine, 30 mg citalopram, or placebo. Diffusion-weighted and functional imaging measured microstructural properties and regional brain activations, respectively. We confirmed that Parkinson's disease impairs response inhibition. Overall, drug effects on response inhibition varied substantially across patients at both behavioral and brain activity levels. We therefore built binary classifiers with leave-one-out cross-validation (LOOCV) to predict patients' responses in terms of improved stopping efficiency. We identified two optimal models: (1) a "clinical" model that predicted the response of an individual patient with 77-79% accuracy for atomoxetine and citalopram, using clinically available information including age, cognitive status, and levodopa equivalent dose, and a simple diffusion-weighted imaging scan; and (2) a "mechanistic" model that explained the behavioral response with 85% accuracy for each drug, using drug-induced changes of brain activations in the striatum and presupplementary motor area from functional imaging. These data support growing evidence for the role of noradrenaline and serotonin in inhibitory control. Although noradrenergic and serotonergic drugs have highly variable effects in patients with Parkinson's disease, the individual patient's response to each drug can be predicted using a pattern of clinical and neuroimaging features. PMID- 26757235 TI - Hydrazine-Assisted Liquid Exfoliation of MoS2 for Catalytic Hydrodeoxygenation of 4-Methylphenol. AB - A simple but effective method to exfoliate bulk MoS2 in a range of solvents is presented for the preparation of colloid flakes consisted of one to a few molecular layers by application of ultrasonic treatment in N2 H4 . Their high yield in solution and exposure of more active surface sites allows the synthesis of corresponding solid catalysts with remarkably high activity in hydrodeoxygenation of 4-methylphenol and this method can also be applied to other two dimensional materials. PMID- 26757234 TI - Correlates of Amount Spent on Marijuana Buds During a Discrete Purchase at Medical Marijuana Dispensaries: Results from a Pilot Study. AB - Marijuana purchasing behaviors vary by the purchaser's individual characteristics; however, little is known about patients' purchasing behaviors when buying from medical marijuana dispensaries (MMDs). Our objective was to explore whether patient characteristics were associated with amount spent during one financial transaction at medical marijuana dispensaries. We conducted a pilot study of four purposively sampled MMD locations in Long Beach, California, in 2012. A total of 132 medical marijuana patients (33 patients per dispensary) participated in an exit survey about their demographic characteristics, conditions for their medical marijuana recommendation, amount spent at the dispensary, and cross-streets of where they lived. The sample reported amounts spent on discrete purchases of marijuana buds averaging $40.82 (ranging from $10 to $255). Multivariate regression analyses indicated average amount spent differed significantly by patient age and condition. An increase in 10 years of age was associated with a 10% higher amount spent. Receiving a recommendation for anxiety and/or sleeping problems or other nonspecified conditions was related to higher discrete purchase amounts than chronic pain. This pilot suggests that variations in patient purchasing behaviors from MMDs exist. These purchase behaviors can provide insight into variations in how patients use dispensaries, consume products, and allocate personal resources. PMID- 26757236 TI - On the Efficiency Limit of Conjugated Polymer:Fullerene-Based Bulk Heterojunction Solar Cells. AB - The power conversion efficiency potential of eight high-performance polymer fullerene blends is investigated. All studied absorbers show the typical organic solar cell losses limiting their performance to ~13%. PMID- 26757237 TI - Particle-by-Particle Charge Analysis of DNA-Modified Nanoparticles Using Tunable Resistive Pulse Sensing. AB - Resistive pulse sensors, RPS, are allowing the transport mechanism of molecules, proteins and even nanoparticles to be characterized as they traverse pores. Previous work using RPS has shown that the size, concentration and zeta potential of the analyte can be measured. Here we use tunable resistive pulse sensing (TRPS) which utilizes a tunable pore to monitor the translocation times of nanoparticles with DNA modified surfaces. We start by demonstrating that the translocation times of particles can be used to infer the zeta potential of known standards and then apply the method to measure the change in zeta potential of DNA modified particles. By measuring the translocation times of DNA modified nanoparticles as a function of packing density, length, structure, and hybridization time, we observe a clear difference in zeta potential using both mean values and population distributions as a function of the DNA structure. We demonstrate the ability to resolve the signals for ssDNA, dsDNA, small changes in base length for nucleotides between 15 and 40 bases long, and even the discrimination between partial and fully complementary target sequences. Such a method has potential and applications in sensors for the monitoring of nanoparticles in both medical and environmental samples. PMID- 26757241 TI - Metal-Free Catalyzed Regioselective Allylic Trifluoromethanesulfonylation of Aromatic Allylic Alcohols with Sodium Trifluoromethanesulfinate. AB - An efficient procedure for the preparation of allylic trifluoromethanesulfones with high regioselectivity from aromatic allylic alcohols/esters and NaSO2CF3 under transition-metal-free conditions is described. A wide range of functional groups were tolerated. This is the first example to realize different types of allylic alcohols, including primary, secondary, and tertiary allylic alcohols, all of which transferred to the corresponding products efficiently in good to excellent yields with readily available and inexpensive NaSO2CF3. The synthetic utility of the method was demonstrated by performing the reaction at gram scale. PMID- 26757240 TI - Increasing the Number of Organs Available to Transplant Is Separate From Ensuring Equitable Distribution of Available Organs: Both Are Important Goals. PMID- 26757239 TI - New Insight into the Structure-Activity Relationships of the Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors UCPH-101 and UCPH-102. AB - In the present study, we made further investigations on the structure-activity requirements of the selective excitatory amino acid transporter 1 (EAAT1) inhibitor, 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8 tetrahydro-4H-chromene-3-carbonitrile (UCPH-101), by exploring 15 different substituents (R(1) ) at the 7-position in combination with eight different substituents (R(2) ) at the 4-position. Among the 63 new analogues synthesized, we identified a number of compounds that unexpectedly displayed inhibitory activities at EAAT1 in light of understanding the structure-activity relationship (SAR) of this inhibitor class extracted from previous studies. Moreover, the nature of the R(1) and R(2) substituents were observed to contribute to the functional properties of the various analogues in additive and non-additive ways. Finally, separation of the four stereoisomers of analogue 14 g (2-amino-4-([1,1' biphenyl]-4-yl)-3-cyano-7-isopropyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene) was carried out, and in agreement with a study of a related scaffold, the R configuration at C4 was found to be mandatory for inhibitory activity, while both the C7 diastereomers were found to be active as EAAT1 inhibitors. A study of the stereochemical stability of the four pure stereoisomers 14 g-A-D showed that epimerization takes places at C7 via a ring-opening, C-C bond rotation, ring closing mechanism. PMID- 26757238 TI - Guidelines for postoperative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS(r)) Society recommendations--Part II. PMID- 26757242 TI - A Mutant of the Bck1 Homolog from Cryphonectria parasitica Resulted in Sectorization with an Impaired Pathogenicity. AB - CpBck1, an ortholog of the cell-wall integrity mitogen-activated protein kinase kinase kinase of Saccharomyces cerevisiae, was cloned and characterized from the chestnut blight fungus Cryphonectria parasitica. The CpBck1-null mutant displayed cell wall integrity-related phenotypic changes such as abnormal cell morphology and wall formation and hypersensitivity to cell wall-disrupting agents. In addition, the mutant showed severely retarded growth without any sign of normal development, such as hyphal differentiation, conidiation, or pigmentation. As the culture proceeded, the mutant colony showed sporadic sectorization. Once sectored, the sectored phenotype of robust mycelial growth without differentiation was stably inherited. Compared with the wild type, both the parental CpBck1-null mutant and the sectored progeny exhibited marked impaired virulence. The present study revealed that a mutation in a signaling pathway component related to cell-wall integrity resulted in sporadic sectorization and these sectored phenotypes were stably inherited, suggesting that this signal transduction pathway is implicated in adaptive genetic changes for sectorization. PMID- 26757243 TI - Strigolactone-Induced Putative Secreted Protein 1 Is Required for the Establishment of Symbiosis by the Arbuscular Mycorrhizal Fungus Rhizophagus irregularis. AB - Arbuscular mycorrhizal (AM) symbiosis is the most widespread association between plants and fungi. To provide novel insights into the molecular mechanisms of AM symbiosis, we screened and investigated genes of the AM fungus Rhizophagus irregularis that contribute to the infection of host plants. R. irregularis genes involved in the infection were explored by RNA-sequencing (RNA-seq) analysis. One of the identified genes was then characterized by a reverse genetic approach using host-induced gene silencing (HIGS), which causes RNA interference in the fungus via the host plant. The RNA-seq analysis revealed that 19 genes are up regulated by both treatment with strigolactone (SL) (a plant symbiotic signal) and symbiosis. Eleven of the 19 genes were predicted to encode secreted proteins and, of these, SL-induced putative secreted protein 1 (SIS1) showed the largest induction under both conditions. In hairy roots of Medicago truncatula, SIS1 expression is knocked down by HIGS, resulting in significant suppression of colonization and formation of stunted arbuscules. These results suggest that SIS1 is a putative secreted protein that is induced in a wide spatiotemporal range including both the presymbiotic and symbiotic stages and that SIS1 positively regulates colonization of host plants by R. irregularis. PMID- 26757244 TI - Mercury correlations among blood, muscle, and hair of northern elephant seals during the breeding and molting fasts. AB - Mercury (Hg) biomonitoring and toxicological risk assessments for marine mammals commonly sample different tissues, making comparisons with toxicity benchmarks and among species and regions difficult. Few studies have examined how life history events, such as fasting, influence the relationship between total Hg (THg) concentrations in different tissues. The authors evaluated the relationships between THg concentrations in blood, muscle, and hair of female and male northern elephant seals (Mirounga angustirostris) at the start and end of the breeding and molting fasts. The relationships between tissues varied among tissue pairs and differed by sampling period and sex. Blood and muscle were generally related at all time periods; however, hair, an inert tissue, did not strongly represent the metabolically active tissues (blood and muscle) at all times of year. The strongest relationships between THg concentrations in hair and those in blood or muscle were observed during periods of active hair growth (end of the molting period) or during time periods when internal body conditions were similar to those when the hair was grown (end of the breeding fast). The results indicate that THg concentrations in blood or muscle can be translated to the other tissue type using the equations developed but that THg concentrations in hair were generally a poor index of internal THg concentrations except during the end of fasting periods. Environ Toxicol Chem 2016;35:2103-2110. (c) 2016 SETAC. PMID- 26757245 TI - Identification of Quantitative Trait Loci for the Phenolic Acid Contents and Their Association with Agronomic Traits in Tibetan Wild Barley. AB - Phenolic acids have been of considerable interest in human nutrition because of their strong antioxidative properties. However, even in a widely grown crop, such as barley, their genetic architecture is still unclear. In this study, genetic control of two main phenolic acids, ferulic acid (FA) and p-coumaric acid (p-CA), and their associations with agronomic traits were investigated among 134 Tibetan wild barley accessions. A genome-wide association study (GWAS) identified three DArT markers (bpb-2723, bpb-7199, and bpb-7273) associated with p-CA content and one marker (bpb-3653) associated with FA content in 2 consecutive years. The contents of the two phenolic acids were positively correlated with some agronomic traits, such as the first internode length, plant height, and some grain color parameters, and negatively correlated with the thousand-grain weight (TGW). This study provides DNA markers for barley breeding programs to improve the contents of phenolic acids. PMID- 26757246 TI - Effectiveness of the Japanese DOLOPLUS-2: a pain assessment scale for patients with moderate-to-severe dementia. AB - BACKGROUND: This study aimed to assess whether the Japanese DOLOPLUS-2 scale could effectively identify pain in elderly individuals with moderate-to-severe dementia. METHODS: This study used a pre-test/post-test design with purposive sampling to select an experimental group and a historical control group. The inclusion criteria were a Functional Assessment Staging score of 5 or 6, a diagnosis of an orthopaedic disease that typically involves pain, the ability to say 'I am currently in pain' (to prevent medication errors), and a total DOLOPLUS 2 scale score >=5 at the first pain assessment. In the experimental group (n = 19), each patient was assessed by the DOLOPLUS-2 scale at 2PM and 9PM each day for 5 days. If a patient's total score was >=5, analgesics were prescribed and the patient was re-assessed approximately 3 hours later. In the control group (n = 20), data were collected from medical records over a 1-year period, and we matched the characteristics of the control group to that of the experimental group. We also reviewed nursing records to determine the number of times analgesics had been administered over the 5 days after the nurses had first recorded that the patient had experienced pain. RESULTS: Among the 19 patients in the experimental group, 15 received pain medication because of a total pain score >=5. Before treatment, their mean DOLOPLUS-2 scale score was 7.5 +/- 3.2, and their score significantly decreased to 2.9 +/- 2.1 (P < 0.001) after treatment. The experimental group also received significantly more treatments with analgesic medication than the control group (chi(2) = 16.033, P < 0.001, phi = 0.641). CONCLUSION: This study's findings suggested that the Japanese DOLOPLUS-2 scale could adequately identify pain in elderly individuals with moderate-to-severe dementia. PMID- 26757247 TI - Development and Implementation of a Quality Improvement Process for Echocardiographic Laboratory Accreditation. AB - We describe our process for quality improvement (QI) for a 3-year accreditation cycle in echocardiography by the Intersocietal Accreditation Commission (IAC) for a large group practice. Echocardiographic laboratory accreditation by the IAC was introduced in 1996, which is not required but could impact reimbursement. To ensure high-quality patient care and community recognition as a facility committed to providing high-quality echocardiographic services, we applied for IAC accreditation in 2010. Currently, there is little published data regarding the IAC process to meet echocardiography standards. We describe our approach for developing a multicampus QI process for echocardiographic laboratory accreditation during the 3-year cycle of accreditation by the IAC. We developed a quarterly review assessing (1) the variability of the interpretations, (2) the quality of the examinations, (3) a correlation of echocardiographic studies with other imaging modalities, (4) the timely completion of reports, (5) procedure volume, (6) maintenance of Continuing Medical Education credits by faculty, and (7) meeting Appropriate Use Criteria. We developed and implemented a multicampus process for QI during the 3-year accreditation cycle by the IAC for Echocardiography. We documented both the process and the achievement of those metrics by the Echocardiography Laboratories at the Ochsner Medical Institutions. We found the QI process using IAC standards to be a continuous educational experience for our Echocardiography Laboratory physicians and staff. We offer our process as an example and guide for other echocardiography laboratories who wish to apply for such accreditation or reaccreditation. PMID- 26757248 TI - The evolution of highly variable immunity genes across a passerine bird radiation. AB - To survive, individuals must be able to recognize and eliminate pathogens. The genes of the major histocompatibility complex (MHC) play an essential role in this process in vertebrates as their diversity affects the repertoire of pathogens that can be recognized by the immune system. Emerging evidence suggests that birds within the parvorder Passerida possess an exceptionally high number of MHC genes. However, this has yet to be directly investigated using a consistent framework, and the question of how this MHC diversity has evolved has not been addressed. We used next-generation sequencing to investigate how MHC class I gene copy number and sequence diversity varies across the Passerida radiation using twelve species chosen to represent the phylogenetic range of this group. Additionally, we performed phylogenetic analyses on this data to identify, for the first time, the evolutionary model that best describes how MHC class I gene diversity has evolved within Passerida. We found evidence of multiple MHC class I genes in every family tested, with an extremely broad range in gene copy number across Passerida. There was a strong phylogenetic signal in MHC gene copy number and diversity, and these traits appear to have evolved through a process of Brownian motion in the species studied, that is following the pattern of genetic drift or fluctuating selection, as opposed to towards a single optimal value or through evolutionary 'bursts'. By characterizing MHC class I gene diversity across Passerida in a systematic framework, this study provides a first step towards understanding this huge variation. PMID- 26757250 TI - Gastrointestinal: Letterer Siwe disease: An uncommon gastrointestinal presentation. PMID- 26757249 TI - Relaxed Chromatin Formation and Weak Suppression of Homologous Pairing by the Testis-Specific Linker Histone H1T. AB - Linker histones bind to nucleosomes and compact polynucleosomes into a higher order chromatin configuration. Somatic and germ cell-specific linker histone subtypes have been identified and may have distinct functions. In this study, we reconstituted polynucleosomes containing human histones H1.2 and H1T, as representative somatic and germ cell-specific linker histones, respectively, and found that H1T forms less compacted chromatin, as compared to H1.2. An in vitro homologous pairing assay revealed that H1T weakly inhibited RAD51/RAD54-mediated homologous pairing in chromatin, although the somatic H1 subtypes, H1.0, H1.1, H1.2, H1.3, H1.4, and H1.5, substantially suppressed it. An in vivo recombination assay revealed that H1T overproduction minimally affected the recombination frequency, but significant suppression was observed when H1.2 was overproduced in human cells. These results suggested that the testis-specific linker histone, H1T, possesses a specific function to produce the chromatin architecture required for proper chromosome regulation, such as homologous recombination. PMID- 26757252 TI - Paired comparison of methylene blue- and amotosalen-treated plasma and cryoprecipitate. AB - BACKGROUND AND OBJECTIVES: Cryoprecipitate is used in the treatment of patients with acquired hypofibrinogenaemia. Studies have not directly compared cryoprecipitate produced following pathogen inactivation (PI) of fresh-frozen plasma (FFP) using different systems. The effects of methylene blue (MB) and amotosalen (AS) PI systems on the quality of FFP and cryoprecipitate were investigated in a paired study. MATERIALS AND METHODS: Seven group A and 7 group O pools of plasma were prepared and split into individual units and rapidly frozen to produce FFP. Units of FFP were thawed and either PI treated with MB or amotosalen, or left untreated (control). Samples of FFP along with the corresponding cryoprecipitate were tested for a range of coagulation factors, thrombin generation (TGT) and rotational thromboelastometry (ROTEM). RESULTS: AS FFP showed a smaller decrease following treatment for most coagulation factors analysed than MB-FFP, except fibrinogen (antigen) and factor VII, partly due to lower volume losses. There was no significant difference between treatment methods for fibrinogen content of cryoprecipitate with treated units meeting current UK specification, or TGT and ROTEM parameters studied. CONCLUSIONS: MB cryo contained a significantly higher content of FVIII and lower content of FXIII when compared to AS-cryo, with no difference in fibrinogen activity. PMID- 26757253 TI - Comparison of the Ultrastructures of Primed and Naive Mouse Embryonic Stem Cells. AB - Culture conditions have been established to maintain the pluripotency of mouse naive and primed embryonic stem cells (ESCs) using human amnion epithelial cells (hAECs) as the feeder layer. In this study, the ultrastructures of mouse primed ESCs grown on hAECs were analyzed by transmission electron microscopy. Consistent with mouse naive ESCs, the undifferentiated mouse primed ESC line ESD-EpiSC [ESC derived epiblast stem cells (EpiSCs)] revealed typical characteristics, including large nuclei, reticulated nucleoli, scanty cytoplasm, and low cytoplasm-to nuclear ratios. Cells had prominent Golgi apparatus and well-developed endoplasmic reticulum. Adjacent cells were tightly in contact with dense junction desmosomes. However, in EpiSC colonies, cell contact was no longer close like naive ESCs, and differentiated cells existed. The differentiated cells had small nucleoli with large cytoplasm, which represented primitive mesenchyme. Phagosomes or apoptotic cells were also common in the cytoplasm of differentiated cells, which suggests a differentiation potential. When exposed to leukemia inhibitory factor (LIF), ESD-EpiSCs could convert to naive-like cells. We further analyzed the ultrastructure of converted EpiSCs (cESCs). As compared to ESD-EpiSCs, cESCs showed similar ultrastructural characteristics as naive ESCs. These findings suggest that ultrastructure could be used to evaluate the pluripotency of ESCs. PMID- 26757251 TI - Genetic variants in ABCG1 are associated with survival of nonsmall-cell lung cancer patients. AB - Cell membrane transporters and metabolic enzymes play a crucial role in the transportation of a wide variety of substrates that maintain homeostasis in biological processes. We explored associations between genetic variants in these genes and survival of nonsmall-cell lung cancer (NSCLC) patients by reanalyzing two datasets from published genome-wide association studies (GWASs). In the discovery by using the GWAS dataset of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, we evaluated associations of 1,245 single nucleotide polymorphisms (SNPs) in genes of four transporter families and two metabolic enzyme families with survival of 1,185 NSCLC patients. We then performed a replication analysis in the Harvard University Lung Cancer study (LCS) with 984 NSCLC patients. Multivariate Cox proportional hazards regression and false discovery rate (FDR) corrections were performed to evaluate the associations. We identified that 21 genotyped SNPs in eight gene regions were significantly associated with survival with FDR <= 0.1 in the discovery dataset. Subsequently, we confirmed six SNPs, which were putative functional, in ABCG1 of the ATP-binding cassette transporter family in the replication dataset. In the pooled analysis, two tagging (at r(2) > 0.8 for linkage disequilibrium with other replicated SNPs)/functional SNPs were independently associated with survival: rs225388 G > A [adjusted hazards ratio (HR) = 1.12, 95% confidence interval (CI) = 1.03-1.20, Ptrend = 4.6 * 10(-3)] and rs225390 A > G (adjusted HR = 1.16, 95% CI = 1.07-1.25, Ptrend = 3.8 * 10(-4) ). Our results indicated that genetic variants of ABCG1 may be predictors of survival of NSCLC patients. PMID- 26757255 TI - Structure, Stability, and Electronic Properties of Dimethyl Sulfoxide and Dimethyl Formammide Clusters Containing Th(4.). AB - By using accurate density functional theory calculations, we have studied the complexes of Th(4+) with dimethyl-sulfoxide (DMSO) and dimethyl-formammide (DMF) molecules. These solvents are prototypes for oxygen-donor organic environments in which the oxygen atom is connected to S and C atom, respectively. Extended structural, energetic, and electronic structure analysis has been performed to provide a complete picture of the physical properties at the basis of the interaction of Th(4+) with the two solvents. By using a cluster grow approach, we have found that, very likely, the first solvation shell contains nine molecules in the case of DMSO, while it contains eight molecules for DMF. The theoretical results shown here are in agreement with experimental data taken from the literature. PMID- 26757256 TI - Stent-assisted coil embolization for the treatment of aneurysm involving a coronary bifurcation. AB - Coronary artery aneurysm (CAA) is an uncommon disease with high risks of complications including rupture and ischemia from embolic events or thrombosis, especially if associated with critical stenosis of the coronary artery. No consensus document or guidelines has been established regarding the optimal therapy for concomitant CAAs and acute coronary syndrome (ACS). Percutaneous catheter-based treatments using only membrane-covered stents have been described; however, only few reports of drug-eluting stent (DES) and coil embolization for CAAs during ACS have been published to date. Therefore, we report a case of coronary artery disease with aneurysm and critical stenosis successfully treated with DES and coil embolization. (c) 2016 Wiley Periodicals, Inc. PMID- 26757254 TI - DMRTA2 (DMRT5) is mutated in a novel cortical brain malformation. AB - Lissencephaly is a phenotypically and genetically heterogeneous group of cortical brain malformations due to abnormal neuronal migration. The identification of many causative genes has increased the understanding of normal brain development. A consanguineous family was ascertained with three siblings affected by a severe prenatal neurodevelopmental disorder characterised by fronto-parietal pachygyria, agenesis of the corpus callosum and progressive severe microcephaly. Autozygosity mapping and exome sequencing identified a homozygous novel single base pair deletion, c.1197delT in DMRTA2, predicted to result in a frameshift variant p.(Pro400Leufs*33). DMRTA2 encodes doublesex and mab-3-related transcription factor a2, a transcription factor key to the development of the dorsal telencephalon. Data from murine and zebrafish knockout models are consistent with the variant of DMTRA2 (DMRT5) as responsible for the cortical brain phenotype. Our study suggests that loss of function of DMRTA2 leads to a novel disorder of cortical development. PMID- 26757258 TI - Phototriggered fibril-like environments arbitrate cell escapes and migration from endothelial monolayers. AB - Cell detachment and migration from the endothelium occurs during vasculogenesis and also in pathological states. Here, we use a novel approach to trigger single cell release from an endothelial monolayer by in-situ opening of adhesive, fibril like environment using light-responsive ligands and scanning lasers. Cell escapes from the monolayer were observed on the fibril-like adhesive tracks with 3-15 MUm width. The frequency of endothelial cell escapes increased monotonically with the fibril width and with the density of the light-activated adhesive ligand. Interestingly, treatment with VEGF induced cohesiveness within the cell layer, preventing cell leaks. When migrating through the tracks, cells presented body lateral reduction and nuclear deformation imposed by the line width and dependent on myosin contractility. Cell migration mode changed from mesenchymal to amoeboid like when the adhesive tracks narrowed (<=5 MUm). Moreover, cell nucleus was shrunk showing packed DNA on lines narrower than the nuclear dimensions in a mechanisms intimately associated with the stress fibers. This platform allows the detailed study of escapes and migratory transitions of cohesive cells, which are relevant processes in development and during diseases such as organ fibrosis and carcinomas. PMID- 26757259 TI - Intravenous administration of brain-targeted stable nucleic acid lipid particles alleviates Machado-Joseph disease neurological phenotype. AB - Others and we showed that RNA interference holds great promise for the treatment of dominantly inherited neurodegenerative disorders such as Machado-Joseph disease (MJD), for which there is no available treatment. However, successful experiments involved intracranial administration of viral vectors and there is a need for a safer and less invasive procedure. In this work, we successfully generated stable nucleic acid lipid particles (SNALPs), incorporating a short peptide derived from rabies virus glycoprotein (RVG-9r) and encapsulating small interfering RNAs (siRNAs), which can target mutant ataxin-3. The developed formulation exhibited important features that make it adequate for systemic administration: high encapsulation efficiency of siRNAs, ability to protect the encapsulated siRNAs, appropriate and homogeneous particle size distribution. Following optimization of the formulation and in vitro validation of its efficacy to silence the MJD-causing protein - mutant ataxin-3 - in neuronal cells, in vivo experiments showed that intravenous administration of RVG-9r-targeted SNALPs efficiently silenced mutant ataxin-3 reducing neuropathology and motor behavior deficits in two mouse models of MJD. To our knowledge, this is the first report showing beneficial impact of a non-viral gene silencing strategy in MJD and the first time that a non-invasive systemic administration proved to be beneficial on a polyglutamine disorder. Our study opens new avenues towards MJD therapy that can also be applied to other neurodegenerative diseases linked to the production of pathogenic proteins. PMID- 26757260 TI - Phase I trial outcomes in older patients with advanced solid tumours. AB - BACKGROUND: This study had two aims: (a) to test the hypothesis that advanced age is associated with lower levels of tolerability and clinical benefit to experimental Phase I trial agents; (b) to assess the validity of the Royal Marsden Hospital (RMH) prognostic score as a patient selection tool in older patients. METHODS: Clinico-pathological characteristics and treatment outcomes of all patients treated consecutively from 2005 to 2009 in phase I trials at the RMH were recorded. All toxicity and clinical outcome data were compared between patients aged below and above 65 years of age. RESULTS: One thousand and four patients were treated in 30 Phase I trials, with 315 (31%) patients aged 65 years and older. Grade 3-5 toxicities (22.8% vs 24.8% (P=0.52)), trial discontinuation (6% vs 4%; P=0.33), and dose interruptions (8.0% vs 8.0% (P=0.96)) were observed at similar rates in patients below and above 65 years of age, respectively. The overall response rate 5.2% vs 4.1%, progression-free survival (PFS) 1.9 vs 3.5 months and clinical benefit rate (CBR) at 6 months 15.2% vs 14.3% were comparable in both groups. To avoid bias due to the potential therapeutic benefit of abiraterone, comparisons were repeated excluding prostate cancer patients with similar results (ORR 4.6% vs 4%, PFS 1.8 vs 3.0 months, CBR at 6 months 13.5% vs 9.5%). Multivariate analysis indicated that the previously identified RMH score (including albumin and lactate dehydrogenase levels) was an accurate predictor of outcome. CONCLUSIONS: Phase I clinical trials should be considered in patients with advanced cancers regardless of age, as older patients who enter these have similar safety and efficacy outcomes as their younger counterparts. The RMH prognostic score can assist in the selection of suitable older patients. PMID- 26757261 TI - E-Cadherin fragments as potential mediators for peritoneal metastasis in advanced epithelial ovarian cancer. AB - BACKGROUND: Peritoneal dissemination and retroperitoneal lymph node involvement are main routes for tumour spread of epithelial ovarian cancer (EOC), possibly determined by the intercellular connecting protein E-Cadherin (E-Cad) and its fragments. METHODS: Tumour tissue of 105 advanced EOC patients was evaluated for protein expression of E-Cad, beta-Catenin and Calpain by western blotting and immunohistochemistry. Expression patterns were compared between tumours with solely intraperitoneal (pT3c, pN0; n=41) and tumours with retroperitoneal metastases (pT1a-3c, pN1; n=64). Lysates of the EOC cell line SKOV3 and tumour tissue from the intraperitoneal group were tested for E-Cad expression following Calpain treatment. RESULTS: E-Cad full-length (E-Cad-FL, 120 kDa) and two major fragments at 85 kDa (E-Cad-85) and 23 kDa (E-Cad-23) were detected by western blotting. E-Cad-85 expression was significantly higher in tumours with solely intraperitoneal metastases and correlated strongly with E-Cad-23 and the protease Calpain. Calpain-mediated cleavage was identified as a potential mechanism to generate E-Cad-85 from E-Cad-FL by treating lysates from SKOV3 cells and tumour tissue with this enzyme. Increased cytoplasmic localisation of beta-Catenin in tumours with high E-Cad-85 expression corroborates that E-Cad-85 loses the binding site for beta-Catenin after fragmentation, enabling tumour cluster formation and peritoneal dissemination. CONCLUSIONS: Calpain-mediated E-Cad fragmentation appears to promote intraperitoneal EOC progression. Understanding these mechanisms might eventually lead to new tailored subtype-specific diagnostic and therapeutic interventions. PMID- 26757262 TI - Gene-environment interaction and risk of breast cancer. AB - Hereditary, genetic factors as well as lifestyle and environmental factors, for example, parity and body mass index, predict breast cancer development. Gene environment interaction studies may help to identify subgroups of women at high risk of breast cancer and can be leveraged to discover new genetic risk factors. A few interesting results in studies including over 30,000 breast cancer cases and healthy controls indicate that such interactions exist. Explorative gene environment interaction studies aiming to identify new genetic or environmental factors are scarce and still underpowered. Gene-environment interactions might be stronger for rare genetic variants, but data are lacking. Ongoing initiatives to genotype larger sample sets in combination with comprehensive epidemiologic databases will provide further opportunities to study gene-environment interactions in breast cancer. However, based on the available evidence, we conclude that associations between the common genetic variants known today and breast cancer risk are only weakly modified by environmental factors, if at all. PMID- 26757263 TI - Perceptions of parents and children, participating in a school-based feeding programme in disadvantaged areas in Greece: a qualitative study. AB - AIM: The aim of this work was to explore parents' and children's attitudes towards healthy eating and the free provision of a daily school meal in underprivileged areas of Greece. METHODS: Twenty focus groups were conducted in 14 schools. Eligible participants were children/adolescents and their parents, who were recipients of a food aid, healthy nutrition school-based programme. Their perceptions towards healthy eating and related barriers, experience of a school feeding programme, other nutrition intervention initiatives were qualitatively evaluated. RESULTS: Most of the parents referred to the Mediterranean diet as a healthy dietary pattern. Nearly all parents were aware of their effect as role models and commented on the benefits of eating together as a family, as well as on the importance of improving their own dietary habits. Parents reported using various methods to promote a healthy diet, as part of their parenting role. They perceived their role as difficult, as they have to deal with children's resistance, financial constraints arising from the current economic crisis in Greece and busy work schedules. All students perceived the school feeding programme as health-promoting, reflecting their parents' perceptions. CONCLUSION: The present findings indicate that although the traditional Mediterranean diet was perceived by the majority of the adults as a health and traditional dietary pattern, parents reported several barriers related to its adoption. In particular, the most common barriers included financial difficulties, limited time for food preparation and children's resistance to consume healthy foods. PMID- 26757265 TI - Sperm chromatin structure assay in prediction of in vitro fertilization outcome. AB - Sperm DNA fragmentation index (DFI) assessed by sperm chromatin structure assay is a valuable tool for prediction of fertility in vivo. Previous studies on DFI as predictor of in vitro fertilization (IVF) outcome, based on relatively small materials, gave contradictory results. The present study examines, in a large cohort, the association between sperm DFI and the outcome of IVF/ICSI procedure. The study is based on 1633 IVF or ICSI cycles performed at the Reproductive Medicine Centre, Skane University Hospital, Malmo, Sweden, between May 2007 and March 2013. DFI values were categorized into four intervals: DFI <= 10% (reference group), 10% < DFI <= 20%, 20% < DFI <= 30%, DFI > 30%. For the three latter intervals, the following outcomes of IVF/ICSI procedures were analyzed in relation to the reference group: fertilization, good quality embryo, pregnancy, miscarriage, and live births. In the standard IVF group, a significant negative association between DFI and fertilization rate was found. When calculated per ovum pick-up (OPU) Odds Ratios (ORs) for at least one good quality embryo (GQE) were significantly lower in the standard IVF group if DFI > 20%. OR for live birth calculated per OPU was significantly lower in standard IVF group if DFI > 20% (OR 0.61; 95% CI: 0.38-0.97; p = 0.04). No such associations were seen in the ICSI group. OR for live birth by ICSI compared to IVF were statistically significantly higher for DFI > 20% (OR 1.7; 95% CI: 1.0-2.9; p = 0.05). OR for miscarriage was significantly increased for DFI > 40% (OR 3.8; 95% CI: 1.2-12; p = 0.02). The results suggest that ICSI might be a preferred method of in vitro treatment in cases with high DFI. Efforts should be made to find options for pharmacologically induced reduction of DFI. The study was based on retrospectively collected data and prospective studies confirming the superiority of ICSI in cases with high DFI are warranted. PMID- 26757264 TI - Functionally graded materials for orthopedic applications - an update on design and manufacturing. AB - Functionally graded materials (FGMs) are innovative materials whose composition and/or microstructure gradually vary in space according to a designed law. As a result, also the properties gradually vary in space, so as to meet specific non homogeneous service requirements without any abrupt interface at the macroscale. FGMs are emerging materials for orthopedic prostheses, since the functional gradient can be adapted to reproduce the local properties of the original bone, which helps to minimize the stress shielding effect and, at the same time, to reduce the shear stress between the implant and the surrounding bone tissue, two critical prerequisites for a longer lifespan of the graft. After a brief introduction to the origin of the FGM concept, the review surveys some representative examples of graded systems which are present in nature and, in particular, in the human body, with a focus on bone tissue. Then the rationale for using FGMs in orthopedic devices is discussed more in detail, taking into account both biological and biomechanical requirements. The core of the paper is dedicated to two fundamental topics, which are essential to benefit from the use of FGMs for orthopedic applications, namely (1) the computational tools for materials design and geometry optimization, and (2) the manufacturing techniques currently available to produce FGM-based grafts. This second part, in its turn, is structured to consider the production of functionally graded coatings (FGCs), of functionally graded 3D parts, and of special devices with a gradient in porosity (functionally graded scaffolds). The inspection of the literature on the argument clearly shows that the integration of design and manufacturing remains a critical step to overpass in order to achieve effective FGM-based implants. PMID- 26757266 TI - Evidence for Decoupled Electron and Proton Transfer in the Electrochemical Oxidation of Ammonia on Pt(100). AB - The two traditional mechanisms of the electrochemical ammonia oxidation consider only concerted proton-electron transfer elementary steps and thus they predict that the rate-potential relationship is independent of the pH on the pH-corrected RHE potential scale. In this letter we show that this is not the case: the increase of the solution pH shifts the onset of the NH3-to-N2 oxidation on Pt(100) to lower potentials and also leads to higher surface concentration of formed NOad before the latter is oxidized to nitrite. Therefore, we present a new mechanism for the ammonia oxidation that incorporates a deprotonation step occurring prior to the electron transfer. The deprotonation step yields a negatively charged surface-adsorbed species that is discharged in a subsequent electron transfer step before the N-N bond formation. The negatively charged species is thus a precursor for the formation of N2 and NO. The new mechanism should be a future guide for computational studies aiming at the identification of intermediates and corresponding activation barriers for the elementary steps. Ammonia oxidation is a new example of a bond-forming reaction on (100) terraces that involves decoupled proton-electron transfer. PMID- 26757257 TI - Towards comprehensive cardiac repair and regeneration after myocardial infarction: Aspects to consider and proteins to deliver. AB - Ischemic heart disease is a leading cause of death worldwide. After the onset of myocardial infarction, many pathological changes take place and progress the disease towards heart failure. Pathologies such as ischemia, inflammation, cardiomyocyte death, ventricular remodeling and dilation, and interstitial fibrosis, develop and involve the signaling of many proteins. Proteins can play important roles in limiting or countering pathological changes after infarction. However, they typically have short half-lives in vivo in their free form and can benefit from the advantages offered by controlled release systems to overcome their challenges. The controlled delivery of an optimal combination of proteins per their physiologic spatiotemporal cues to the infarcted myocardium holds great potential to repair and regenerate the heart. The effectiveness of therapeutic interventions depends on the elucidation of the molecular mechanisms of the cargo proteins and the spatiotemporal control of their release. It is likely that multiple proteins will provide a more comprehensive and functional recovery of the heart in a controlled release strategy. PMID- 26757268 TI - Phospholipid Composition in Synthetic Surfactants Is Important for Tidal Volumes and Alveolar Stability in Surfactant-Treated Preterm Newborn Rabbits. AB - BACKGROUND: The development of synthetic surfactants for the treatment of lung pulmonary diseases has been going on for many years. OBJECTIVES: To investigate the effects of phospholipid mixtures combined with SP-B and SP-C analogues on lung functions in an animal model of respiratory distress syndrome. METHODS: Natural and synthetic phospholipid mixtures with/without SP-B and/or SP-C analogues were instilled in ventilated premature newborn rabbits. Lung functions were evaluated. RESULTS: Treatment with Curosurf or phospholipids from Curosurf combined with SP-B and SP-C analogues gave similar results. Treatment with phospholipids from adult rabbit lungs or liver combined with dipalmitoylphosphatidylcholine (DPPC) and palmitoyloleoylphosphatidylglycerol (POPG) gave tidal volumes (VT) well above physiological levels, but alveolar stability at end-expiration was only achieved when these phospholipids were combined with analogues of SP-B and SP-C. Treatment with egg yolk-PC mixed with DPPC with and without POPG gave small VT, but after addition of both analogues VT was only somewhat lower and lung gas volumes (LGV) similar to those obtained with Curosurf. Substitution of egg yolk-PC (>=99% PC) with 1-palmitoyl-2-oleoyl-sn glycero-3-phosphocholine and 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine, and combining them with DPPC, POPG and 2% each of the SP-B and SP-C analogue gave a completely synthetic surfactant with similar effects on VT and LGV as Curosurf. CONCLUSIONS: Phospholipid composition is important for VT while the SP-B and SP-C analogues increase alveolar stability at end-expiration. Synthetic surfactant consisting of unsaturated and saturated phosphatidylcholines, POPG and the analogues of SP-B and SP-C has similar activity as Curosurf regarding VT and LGV in an animal model using preterm newborn rabbits ventilated without positive end expiratory pressure. PMID- 26757267 TI - Serum Bilirubin Is Inversely Associated with Increased Arterial Stiffness in Men with Pre-Hypertension but Not Normotension. AB - OBJECTIVE: Serum bilirubin level has shown to be inversely associated with coronary atherosclerosis, and may serve as a protective biomarker of coronary artery disease. Serum bilirubin has also been shown to be negatively associated with brachial-ankle pulse wave velocity (baPWV) in men without a history of hypertension, and in men with hypertension. It is unknown whether such associations can be observed in the pre-hypertensive or normotensive population. This study thus aimed to investigate the relationship between serum bilirubin level and increased arterial stiffness in subjects with pre-hypertension and normotension for both genders. METHODS: A cross-sectional sample of 3,399 apparently healthy subjects undergoing a medical check-up at National Cheng Kung University Hospital was enrolled between October 2006 and August 2009, after excluding subjects with serum total bilirubin level greater than 20.52 MUmol/L. Increased arterial stiffness was defined as baPWV of 1,400 cm/s or higher as the dichotomous variable and bilirubin as the continuous variable. RESULTS: Based on multiple linear regression analysis, serum bilirubin level was inversely associated with baPWV in non-hypertensive men (beta = -0.066, p < 0.001) but not in non-hypertensive women. In addition, the inverse relationship between bilirubin level and baPWV was found statistically significant only in pre hypertensive men (beta = -0.110, p < 0.001). Multiple logistic regression analysis showed that serum bilirubin was inversely associated with increased arterial stiffness in men with pre-hypertension (odds ratio = 0.955, 95% confidence interval = 0.916-0.996, p < 0.05) but not normotension after adjustment for other confounding factors. However, the relationship between total bilirubin level and increased arterial stiffness did not reach statistical significance for female subjects with pre-hypertension and normotension. CONCLUSION: Serum bilirubin is inversely associated with increased arterial stiffness in men with pre-hypertension but not normotension. The association between bilirubin level and arterial stiffness was not found significant in women. PMID- 26757269 TI - Contributing factors for menopausal symptoms after surgical staging for endometrial cancer. AB - OBJECTIVE: The aim of the study was to examine contributing factors associated with developing menopausal symptoms after surgical staging in women with endometrial cancer. METHODS: This is a retrospective study examining patients with endometrial cancer who were premenopausal at the time of hysterectomy-based surgical staging including bilateral oophorectomy between January 2000 and October 2013. Cox proportional hazard regression model was used to evaluate demographics, medical comorbidity, liver function tests, tumor factors, and medication history for menopausal symptoms. RESULTS: There were 269 premenopausal women who were eligible. Mean age was 44.5 years, and the majority had endometrioid histology (91.1%), grade 1 tumor (60.2%), and stage I disease (65.8%). Postoperatively, 73 (27.1%) women developed menopausal symptoms, with hot flushes (20.1%) being the most common symptom followed by night sweats (4.1%). On multivariate analysis, younger age was independently associated with increased risk of developing menopausal symptoms (hazard ratio per unit 0.91, 95% CI 0.88-0.94, P < 0.01). In addition, lower albumin level remained an independent predictor for decreased risk of developing menopausal symptoms (hazard ratio per unit 2.16, 95% CI 1.19-3.93, P = 0.012). Lower albumin level was associated with medical comorbidity (hypertension and diabetes mellitus), use of antihypertensive/glycemic agents (angiotensin-converting enzyme inhibitors or receptor blocker, hydrochlorothiazide, sulfonylurea, and insulin), aggressive tumor (high cancer antigen 125 level, nonendometrioid histology, and advanced stage), and abnormal liver function (high alkaline phosphatase level and low total protein level; all, P < 0.05). CONCLUSIONS: Assessing albumin level, medical comorbidity, and medication type for the development of postoperative menopausal symptoms is a valuable step in the preoperative management of women with endometrial cancer. PMID- 26757270 TI - Efficacy and safety of solifenacin succinate tablets versus solifenacin succinate tablets with local estrogen for the treatment of overactive bladder in postmenopausal women--a multicenter, randomized, open-label, controlled comparison study. AB - OBJECTIVE: The aim of the study was to compare the effectiveness and safety of solifenacin succinate tablets alone or combined with local estrogen for overactive bladder treatment in postmenopausal women. METHODS: This multicenter, randomized, open, parallel-controlled clinical trial enrolled 104 women between January 2012 and August 2013. Participants meeting the inclusion criteria were randomized 1:1 to 12 weeks of treatment with group A (solifenacin 5 mg qd + promestriene vaginal capsules intravaginally) or group B (solifenacin 5 mg qd). Before and after 12 weeks of treatment, symptoms (urinary urgency, frequency, and urge incontinence) were analyzed. Our primary outcome was the change from baseline to the end of treatment in the mean number of voids in 24 hours. Quality of life (QoL) was assessed using International Prostate Symptom Score and Overactive Bladder Symptom Score questionnaires and safety according to the incidence of adverse events. The t test or the Mann-Whitney U test was used to compare continuous variables, and the chi(2) test or Fisher's exact test was used to compare categorical variables. RESULTS: The median decreases in the mean number of voids in 24 hours in groups A and B were 5.2. and 4.3, respectively, which were not significantly different. The median decreases in urgency episodes in groups A and B were 2.0 and 2.5, respectively. In addition, the QoL scores significantly changed in both groups (both P < 0.05). The most common adverse event was dry mouth (19.2% in both groups). CONCLUSIONS: Solifenacin with or without local estrogen was effective and safe for overactive bladder treatment in postmenopausal women. The addition of local estrogen improved subjective feelings and QoL. PMID- 26757271 TI - The association of Asn453Ser polymorphism in CYP1B1 gene with selected somatic and biochemical variables in Slovak women of different menopause status. AB - OBJECTIVE: The aim of this study was to determine the relationship between the CYP1B1 Asn453Ser polymorphism and selected somatic and biochemical variables, and atherogenic indices in premenopausal and postmenopausal Slovak women. METHODS: The studied sample consisted of 334 women; 188 premenopausal (mean age 45.73 +/- 3.77 y) and 146 postmenopausal women (mean age 53.51 +/- 4.52 y). The participants were interviewed during their medical examination. They provided a blood sample for biochemical analysis and DNA genotyping. RESULTS: The frequency of rare allele Ser (CYP1B14) was equal to 0.125 in premenopausal and 0.168 in postmenopausal women. The observed genotype frequencies were in the Hardy Weinberg equilibrium. The Asn453Ser genotype showed statistically significant associations with a high-density lipoprotein (HDL-cholesterol) and apolipoprotein A1 levels in postmenopausal women. The mean values of the above mentioned variables were significantly higher in women carrying the Ser/Ser genotype. The general linear model analysis confirmed the results of the additive genetic model in postmenopausal women and demonstrated significant association of the Asn453Ser polymorphism with HDL-cholesterol levels also in premenopausal women (P = 0.041). CONCLUSIONS: This pilot study revealed a significant association of the CYP1B1 Asn453Ser genotypes with the plasma levels of HDL-cholesterol and of apolipoprotein A1 in postmenopausal women and less unequivocal findings in premenopausal women. Because of study limitations, these results need to be examined in a larger study. PMID- 26757273 TI - Lack of a functional response to SERM treatment in ovariectomy-induced vaginal remodeling. PMID- 26757272 TI - Prior hysterectomy and oophorectomy and incident venous thrombosis risk among postmenopausal women: a population-based, case-control study. AB - OBJECTIVE: Hysterectomy and bilateral salpingo-oophorectomy (BSO) are associated with changes in endogenous hormone levels, yet the risk of venous thrombosis (VT) associated with hysterectomy and BSO is incompletely characterized. This study evaluated the risk of incident VT among postmenopausal women associated with combined prior hysterectomy/oophorectomy status and current use of hormone therapy (HT). METHODS: In a case-control study, we identified incident VT cases (n = 1,623) among postmenopausal Group Health Cooperative enrollees without reproductive cancer, defining their "index date" as their VT diagnosis date (1995 2010). Matched controls had not experienced a prior VT (n = 4,480). Multiple logistic regression models estimated adjusted relative risks for VT associated with combinations of prior hysterectomy/oophorectomy status and HT use at the index date. RESULTS: Compared with women with an intact uterus who were not using HT, there was no suggestion of greater VT risk in women with prior hysterectomy without BSO, whether they were (adjusted odds ratio [aOR] = 0.80 [95% CI: 0.57, 1.12]) or were not using HT (aOR = 1.09 [95% CI: 0.89, 1.35]). Women with prior hysterectomy and BSO who were using HT were not at a greater VT risk (OR = 1.00 [95% CI: 0.78, 1.27]), but there was evidence of a 25% greater risk associated with prior hysterectomy with BSO and no current HT use (OR = 1.25 [95% CI: 1.05, 1.49]). CONCLUSIONS: Collectively, these and prior data do not suggest a substantial impact of hysterectomy, with or without BSO, on the risk of VT among postmenopausal women. PMID- 26757275 TI - Human skin: a mirror for estrogen action? PMID- 26757274 TI - Oral contraceptive use and fracture risk around the menopausal transition. AB - OBJECTIVE: The effect of oral contraceptive (OC) use on risk of fracture remains unclear, and use during later reproductive life may be increasing. To determine the association between OC use during later reproductive life and risk of fracture across the menopausal transition, we conducted a population-based case control study in a Pacific Northwest HMO, Group Health Cooperative. METHODS: For the January 2008 to March 2013 interval, 1,204 case women aged 45 to 59 years with incident fractures, and 2,275 control women were enrolled. Potential cases with fracture codes in automated data were adjudicated by electronic health record review. Potential control women without fracture codes were selected concurrently, sampling based on age. Participants received a structured study interview. Using logistic regression, associations between OC use and fracture risk were calculated as odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Participation was 69% for cases and 64% for controls. The study sample was 82% white; mean age was 54 years. The most common fracture site for cases was the wrist/forearm (32%). Adjusted fracture risk did not differ between cases versus controls for OC use in the 10 years before menopause (OR 0.90, 95% CI 0.74, 1.11); for OC use after age 38 (OR 0.94, 95% CI 0.78, 1.14); for duration of use, or for other OC exposures. CONCLUSIONS: The current study does not show an association between fractures near the menopausal transition and OC use in the decade before menopause or after age 38. For women considering OC use at these times, fracture risk does not seem to be either reduced or-reassuringly increased. PMID- 26757278 TI - Regrowth of Broken Hydroxide Flocs: Effect of Added Fluoride. AB - Hydrous oxides of Al(III) and Fe(III) play a large part in environmental processes and in the action of coagulants used in water and wastewater treatment. Aggregates (flocs) of hydroxide precipitates can be rather weak and are easily broken by applied shear. It is usually found that broken flocs do not fully regrow under low-shear conditions, and this could be a serious disadvantage in practical applications. The irreversible nature of floc breakage suggests that some form of specific, chemical interaction between precipitate particles must be at least partly responsible. On the basis of experiments reported here and elsewhere, we propose that hydroxyl bridges between particles play a part. When these are broken, there is a reduction in the number of "active" surface groups that are able to form new bridges. When small amounts of fluoride are added during breakage of Al flocs, there can be significant improvement in floc regrowth, although this depends on a number of factors, especially pH. With Fe flocs, fluoride has no noticeable effect. These results can be explained by the formation of soluble Al-F complexes and some dissolution of the Al(OH)3 precipitate. This creates a new surface with more "active" groups that can form new hydroxyl bridges. PMID- 26757277 TI - Multimodality Treatment May Improve the Survival Rate of Patients with Metastatic Nasopharyngeal Carcinoma with Good Performance Status. AB - The aim of the present study was to evaluate the benefit of chemotherapy, combined with palliative radiotherapy (PRT) and other local treatments to the metastatic sites, for patients with metastatic nasopharyngeal carcinoma (NPC) who had a performance status 0-2. We conducted a retrospective review of available data from 197 biopsy-proven NPC patients who developed metastasis after their initial definitive treatment. These patients were grouped into three categories according to the different treatment paths that were followed: the best supportive care (64 patients), chemotherapy alone (55 patients), and multimodality treatment with chemotherapy combined with PRT and other local treatments to metastatic sites (78 patients). The 2-year metastatic survival rate of patients in the multimodality treatment group was 57.7%, which was significantly better than that of the patients in both the chemotherapy alone group and the best supportive care group (32.7% and 1.6%, respectively). The independent significant factors affecting survival were the disease-free interval prior to the detection of metastatic disease, the number of metastases, the number of chemotherapy cycles and the biological effective dose of PRT. In conclusion, multimodality treatment may improve survival of select patients with recurrent NPC with distant metastases. PMID- 26757276 TI - Intramuscular Artesunate for Severe Malaria in African Children: A Multicenter Randomized Controlled Trial. AB - BACKGROUND: Current artesunate (ARS) regimens for severe malaria are complex. Once daily intramuscular (i.m.) injection for 3 d would be simpler and more appropriate for remote health facilities than the current WHO-recommended regimen of five intravenous (i.v.) or i.m. injections over 4 d. We compared both a three dose i.m. and a three-dose i.v. parenteral ARS regimen with the standard five dose regimen using a non-inferiority design (with non-inferiority margins of 10%). METHODS AND FINDINGS: This randomized controlled trial included children (0.5-10 y) with severe malaria at seven sites in five African countries to assess whether the efficacy of simplified three-dose regimens is non-inferior to a five dose regimen. We randomly allocated 1,047 children to receive a total dose of 12 mg/kg ARS as either a control regimen of five i.m. injections of 2.4 mg/kg (at 0, 12, 24, 48, and 72 h) (n = 348) or three injections of 4 mg/kg (at 0, 24, and 48 h) either i.m. (n = 348) or i.v. (n = 351), both of which were the intervention arms. The primary endpoint was the proportion of children with >= 99% reduction in parasitemia at 24 h from admission values, measured by microscopists who were blinded to the group allocations. Primary analysis was performed on the per protocol population, which was 96% of the intention-to-treat population. Secondary analyses included an analysis of host and parasite genotypes as risks for prolongation of parasite clearance kinetics, measured every 6 h, and a Kaplan Meier analysis to compare parasite clearance kinetics between treatment groups. A post hoc analysis was performed for delayed anemia, defined as hemoglobin <= 7 g/dl 7 d or more after admission. The per-protocol population was 1,002 children (five-dose i.m.: n = 331; three-dose i.m.: n = 338; three-dose i.v.: n = 333); 139 participants were lost to follow-up. In the three-dose i.m. arm, 265/338 (78%) children had a >= 99% reduction in parasitemia at 24 h compared to 263/331 (79%) receiving the five-dose i.m. regimen, showing non-inferiority of the simplified three-dose regimen to the conventional five-dose regimen (95% CI -7, 5; p = 0.02). In the three-dose i.v. arm, 246/333 (74%) children had >= 99% reduction in parasitemia at 24 h; hence, non-inferiority of this regimen to the five-dose control regimen was not shown (95% CI -12, 1; p = 0.24). Delayed parasite clearance was associated with the N86YPfmdr1 genotype. In a post hoc analysis, 192/885 (22%) children developed delayed anemia, an adverse event associated with increased leukocyte counts. There was no observed difference in delayed anemia between treatment arms. A potential limitation of the study is its open-label design, although the primary outcome measures were assessed in a blinded manner. CONCLUSIONS: A simplified three-dose i.m. regimen for severe malaria in African children is non-inferior to the more complex WHO-recommended regimen. Parenteral ARS is associated with a risk of delayed anemia in African children. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201102000277177. PMID- 26757279 TI - Interaction of stromal and microvascular components in keratocystic odontogenic tumors. AB - OBJECTIVE: Little is known about the interaction of stromal components in odontogenic tumors. Thus, the aim of this study was to investigate mast cells (MCs), myofibroblasts, macrophages, and their possible association with angiogenesis and lymphangiogenesis in keratocystic odontogenic tumors (KCOTs). MATERIAL AND METHODS: Thirty cases of KCOTs were included and analyzed by immunohistochemistry for mast cell tryptase, alpha-SMA, CD34, CD163, and D240. For comparative purpose, 15 radicular cysts (CRs) and 7 pericoronal follicles (PFs) were included. RESULTS: There was an increase in MCs for RCs and this difference was significant when they were compared to KCOTS and PFs. A significant increase in the density of MFs was observed for KCOTs when compared to RCs and PFs (P = 0.00). No significant difference in CD163-positive macrophages (P = 0.084) and CD34-positive vessels (P = 0.244) densities was observed between KCOTs, RCs, and PFs, although KCOTs showed a higher density of all proteins. Significant difference in lymphatic vessel density was observed for KCOTs when compared to RCs and PFs (P = 0.00). Positive correlation was observed between mast cell tryptase and CD34 in KCOTs (P = 0.025). CONCLUSIONS: A significant interaction between the MC population and CD34-positive vessels in KCOTs supported the hypothesis that MCs and blood vessels contribute to the stromal scaffold of KCOT. PMID- 26757280 TI - Spread the Word About CHEST in 2016: An Ever-Rising Impact Factor, Content Innovations, Launching a New Partnership With Elsevier, and Protecting the Name and Legacy of the Journal. PMID- 26757281 TI - Asthma-COPD Overlap. PMID- 26757282 TI - Slow and Study: Support for a Randomized Trial of beta-Blockade in Sepsis Associated Atrial Fibrillation. PMID- 26757283 TI - Postoperative Complications in Obesity Hypoventilation Syndrome and Hypercapnic OSA: CO2 Levels Matter! PMID- 26757284 TI - Children With Chronic Wet or Productive Cough--Treatment and Investigations: A Systematic Review. AB - BACKGROUND: Systematic reviews were conducted to examine two related key questions (KQs) in children with chronic (> 4 weeks' duration) wet or productive cough not related to bronchiectasis: KQ1-How effective are antibiotics in improving the resolution of cough? If so, what antibiotic should be used and for how long? KQ2-When should they be referred for further investigations? METHODS: The systematic reviews were undertaken based on the protocol established by selected members of the CHEST expert cough panel. Two authors screened searches and selected and extracted data. The study included systematic reviews, randomized controlled trials (RCTs), cohort (prospective and retrospective) studies, and cross-sectional studies published in English. RESULTS: Data were presented in Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowcharts, and the summaries were tabulated. Fifteen studies were included in KQ1 (three systematic reviews, three RCTs, five prospective studies, and four retrospective studies) and 17 in KQ2 (one RCT, 11 prospective studies, and five retrospective studies). Combining data from the RCTs (KQ1), the number needed to treat for benefit was 3 (95% CI, 2.0-4.3) in achieving cough resolution. In general, findings from prospective and retrospective studies were consistent, but there were minor variations. CONCLUSIONS: There is high-quality evidence that in children aged <= 14 years with chronic (> 4 weeks' duration) wet or productive cough, the use of appropriate antibiotics improves cough resolution. There is also high-quality evidence that when specific cough pointers (eg, digital clubbing) are present in children with wet cough, further investigations (eg, flexible bronchoscopy, chest CT scans, immunity tests) should be conducted. When the wet cough does not improve by 4 weeks of antibiotic treatment, there is moderate-quality evidence that children should be referred to a major center for further investigations to determine whether an underlying lung or other disease is present. PMID- 26757287 TI - Adaptive Support Ventilation From Intubation to Extubation: A Word of Caution. PMID- 26757288 TI - Response. PMID- 26757289 TI - Childhood Asthma: A Narrative Approach. PMID- 26757290 TI - Therapeutic Role of Endoscopic Resection in Typical, Noninvasive, Carcinoid Tumors. PMID- 26757291 TI - Response. PMID- 26757292 TI - Response. PMID- 26757293 TI - Cough Intensity: Is Respiratory Muscle Activation Important and Does It Relate to Symptoms? PMID- 26757294 TI - Response. PMID- 26757295 TI - Nighttime ICU Staffing and Mortality: Still in the Dark. PMID- 26757297 TI - Choice of Imaging Studies in Acutely Ill Pregnant Women. PMID- 26757296 TI - Relationship Between OSA Clinical Phenotypes and CPAP Treatment Outcomes. PMID- 26757298 TI - Lung Density in Extremely Large Healthy Lungs. PMID- 26757299 TI - Lung Transplantation in Gaucher Disease: A Learning Lesson in Trying to Avoid Both Scylla and Charybdis. AB - Gaucher disease (GD), a lysosomal storage disorder, may result in end-stage lung disease. We report successful bilateral lung transplantation in a 49-year-old woman with GD complicated by severe pulmonary hypertension and fibrotic changes in the lungs. Before receiving the lung transplant, the patient was undergoing both enzyme replacement therapy (imiglucerase) and triple pulmonary hypertension treatment (epoprostenol, bosentan, and sildenafil). She had a history of splenectomy, severe bone disease, and renal involvement, all of which were related to GD and considered as relative contraindications for a lung transplantation. In the literature, lung transplantation has been suggested for severe pulmonary involvement in GD but has been reported only once in a child. To our knowledge, until now, no successful procedure has been reported in adults, and no reports deal with the severe potential posttransplantation complications specifically related to GD. PMID- 26757300 TI - A Man in His 60s With Circulatory Collapse. PMID- 26757301 TI - Patient With Slow-Growing Mediastinal Mass Presents With Chest Pain and Dyspnea. AB - A 52-year-old white woman presented with severe pain over the right upper abdomen and nonpleuritic, right-sided, lower chest-wall pain. Her pain had progressively gotten more frequent and severe over the last 5 months. It was also associated with a nonexertional, pressure-like sensation in the central chest. The patient denied any shortness of breath, fevers, cough, or any sputum production. She was taking levothyroxine for hypothyroidism and was a 30-pack-year current smoker; there was no history of drug abuse or occupational exposure. Previous chest radiographs dating back to 5 years consistently showed an elevated right-sided hemidiaphragm without any infiltrates or effusions; cardiomediastinal structures were unremarkable. She had not had a previous workup for these abnormal findings. PMID- 26757302 TI - A 42-Year-Old Woman With Abnormal Chest CT Scan and Chylous Ascites. AB - A 42-year-old white woman presented to the pulmonary clinic for evaluation of abnormal chest imaging. Twenty years prior to presentation, she was noted to have an abnormal chest radiograph during a routine preemployment evaluation. A subsequent bronchoscopy was nondiagnostic. She was followed up with annual imaging, which demonstrated little or no progression of her disease. She remained symptom free throughout this period. A year before her visit to the pulmonary clinic, she developed abdominal discomfort and was found to have ascites. Subsequently, she underwent three paracenteses with analysis revealing chylous fluid. She was a nonsmoker without a history of exposures or travel. PMID- 26757304 TI - An Elderly Man With Dyspnea and Chest Pain. PMID- 26757303 TI - A 26-Year-Old Woman With Systemic Lupus Erythematosus Presenting With Orthopnea and Restrictive Lung Impairment. AB - A 26-year-old white woman diagnosed with systemic lupus erythematosus (SLE) presented with left shoulder pain and a three-pillow orthopnea. Lupus was diagnosed at age 21 years when she developed arthritis, and she has been maintained on prednisone (2.5 mg) and mycophenolate (500 mg bid). In the course of evaluating her new symptoms, imaging revealed a small left pleural effusion with exudative characteristics on a diagnostic thoracentesis, but there was no evidence of infection. Her immunosuppression treatment was increased to 1,000 mg bid of mycophenolate and 20 mg of prednisone. Three months later, she presented to our clinic with worsening six-pillow orthopnea, such that she usually slept with 45 degrees truncal elevation on a recliner at night. She was unable to lie flat. Her dyspnea was worse in the mornings, and she described having to "gasp" for air. PMID- 26757305 TI - An Overlooked Victim of Cannabis: Losing Several Years of Well-being and Inches of Jejunum on the Way to Unravel Her Hyperemesis Enigma. AB - A case report of a severe cannabis hyperemesis syndrome (CHS) is presented, which had worsened during dronabinol administration and was associated with intestinal dysmotility (pseudo-obstruction). Because dronabinol is an isomer of THC (delta-9 tetrahydrocannabinol), the main psychotropic constituent of cannabis, this case provides first direct clinical evidence on the key role of THC in the obscure pathogenesis of CHS. Another peculiarity of this case was that the patient had an odyssey of hospital stays with extensive workups before the patient herself found via Internet the right diagnosis for her cyclic vomiting and abdominal pain. This is typical for CHS, which is often overlooked because physicians refer to the widely known antiemetic properties of cannabis, for example, in cancer chemotherapy but were not always aware of a possible paradoxical emetic reaction of recreational cannabis use. Being pathognomonic of CHS, the patient became symptom-free while abstaining from her cannabis use, meanwhile being in her 12th month of controlled abstinence. PMID- 26757306 TI - Bumetanide to Treat Parkinson Disease: A Report of 4 Cases. AB - Relying on recent experimental data in 2 animal models of Parkinson disease (PD), we have tested the effects of the loop diuretic bumetanide as an add-on treatment to dopaminergic drugs in 4 volunteered patients with PD using the Unified Parkinson's Disease Rating Scale. Bumetanide is a specific antagonist of the chloride importer NKCC1 (sodium/potassium/chloride cotransporter isoform 1) that ameliorates neuronal inhibition by reducing intracellular chloride levels in a variety of pathological conditions. Bumetanide is however not labeled for use in PD. We report an improvement of PD motor symptoms in the 4 patients treated with bumetanide (5 mg/d for 2 months). Bumetanide also improved gait and freezing in 2 of these patients. Our results suggest that bumetanide is well tolerated and call for double-blind, placebo-controlled, randomized trials to confirm the therapeutic efficacy of bumetanide. PMID- 26757308 TI - Drug-Related Eyelid Nystagmus: Two Cases of a Rare Clinical Phenomenon Related to Carbamazepine and Derivatives. AB - BACKGROUND: Eyelid nystagmus is a rare clinical phenomenon described mostly related to brainstem or cerebellum lesions. The mechanism of this phenomenon is incompletely understood. PATIENTS AND METHODS: We report 2 cases of eyelid nystagmus induced by carbamazepine and oxcarbazepine intoxication. CONCLUSIONS: Carbamazepine and derivatives may induce eyelid nystagmus in the setting of acute intoxication. To the best of our knowledge, these are the first cases of drug related eyelid nystagmus. PMID- 26757307 TI - Pharmacogenetics and Treatment Response in Narcolepsy Type 1: Relevance of the Polymorphisms of the Drug Transporter Gene ABCB1. AB - OBJECTIVE: Narcolepsy type 1 (NT1) is a chronic hypersomnia clinically characterized by daytime sleepiness and cataplexy. Narcolepsy type 1 treatments target individual symptoms: wake-promoting agents (eg, modafinil) are effective for sleepiness, antidepressants (eg, venlafaxine) on cataplexy, whereas sodium oxybate on both. Narcolepsy type 1 patients variably respond to modafinil and venlafaxine independently of individual clinical features.Given the potential influence of drug transmembrane transport (glycoprotein-P) on drug response, we explored the relation between genetic polymorphisms in the ABCB1 gene and clinical response to modafinil/venlafaxine in NT1. METHODS: Individual drug response and genotypes were assessed in 107 NT1 patients (males/females, 64/43; mean age, 38 +/- 21 years) treated with modafinil and/or venlafaxine at stable doses for at least 3 months. Minisequencing was performed to detect single nucleotide polymorphisms in ABCB1. Patients with different responses to treatment were contrasted by Fisher exact test and multivariate analysis. RESULTS: The ABCB1 diplotype was significantly associated with clinical response to modafinil, with the CGC-TTT (1236/2677/3435) being more frequent in the modafinil responder versus nonresponder group (P = 0.013). Conversely, no significant associations with clinical response to venlafaxine were found. CONCLUSIONS: The ABCB1 variants modulate therapeutic response to modafinil and may partly explain pharmacoresistance in NT1 patients. PMID- 26757310 TI - Parkinsonism in Patients With Chronic Hepatitis C Treated With Interferons: Case Reports and Review of the Literature. AB - Interferons are a set of cytokines that activate antiviral responses by the body's immune cells and have been a mainstay of treatment of hepatitis C. Well known neuropsychiatric effects of interferons include depression, irritability, and impaired concentration. A condition reported rarely in association with this treatment is parkinsonism. We report 2 patients who developed parkinsonism in conjunction with treatment of hepatitis C with alpha interferons. The first is a 51-year-old man who developed intermittent rest and postural tremor during treatment with pegylated interferon alpha ribavirin, and amantadine, with resolution of the symptoms after completing a 36-week course. Similar tremor recurred 3 years later with progressive parkinsonism, compatible with Parkinson disease (PD). The second patient is a 71-year-old man who developed postural tremor 8 weeks into a regimen of consensus interferon. Tremor resolved at completion of 48 weeks of interferon. Pegylated interferon alpha and ribavirin were started 2 years later because of lack of sustained virologic response. At 24 weeks of treatment, postural tremor returned along with features and a progressive course compatible with PD. Thus, both patients presented here developed (rest and/or postural) tremor during interferon therapy followed by delayed onset of parkinsonism. We identified 10 other cases in the literature of parkinsonism/PD associated with interferon administration. This report reviews the clinical presentation and potential pathophysiological mechanisms and recommends that physicians who prescribe interferon be vigilant for symptoms of PD in their patients. PMID- 26757309 TI - Effect of Ziprasidone Augmentation of Serotonin Reuptake Inhibitors in Treatment Resistant Obsessive-Compulsive Disorder: A 12-Week, Open-Label Uncontrolled Preliminary Study. AB - OBJECTIVES: The present 12-week, open-label uncontrolled trial was aimed to explore the efficacy of ziprasidone add-on pharmacotherapy on clinical symptoms and cognitive functioning in a sample of patients with treatment-resistant obsessive-compulsive disorder receiving serotonin reuptake inhibitors (SRIs). METHODS: After clinical (Yale-Brown Obsessive Compulsive Scale [Y-BOCS], Hamilton Rating Scale for Depression) and neurocognitive (Wisconsin Card Sorting Test, Stroop Colour-Word Test, Trail Making Test) assessments, patients received 80 mg/d of ziprasidone. RESULT: A final sample of 17 patients completed the study. The results obtained indicate that ziprasidone added to stable SRIs treatment appeared to be moderately effective for reducing compulsive symptoms, as evidenced by changes on Y-BOCS compulsion scale score (P = 0.005) at the end of the trial. Only 4 subjects (23.5% of the completers) had a partial response (reduction between 25% and 34% in Y-BOCS total score), whereas none of the patients had a full response (reduction >= 35% in Y-BOCS total score). Regarding cognitive performances, no significant differences were found during the study. CONCLUSIONS: The findings provide evidence that ziprasidone added to ongoing treatment appeared to be mildly effective to improve symptoms in patients with obsessive-compulsive disorder who have failed to respond sufficiently to SRIs. PMID- 26757311 TI - Assessing and Reporting the Adverse Effects of Antipsychotic Medication: A Systematic Review of Clinical Studies, and Prospective, Retrospective, and Cross Sectional Research. AB - OBJECTIVE: Adverse effects (AEs) of antipsychotic medication have important implications for patients and prescribers in terms of well-being, treatment adherence, and quality of life. This review summarizes strategies for collecting and reporting AE data across a representative literature sample to ascertain their rigor and comprehensiveness. METHODS: A PsycINFO search, following preferred reporting items for systematic reviews and meta-analyses statement guidelines, was conducted in English-language journals (1980 to July 2014) using the following search string: (antipsychotic* or neuroleptic*) and (subjective effect or subjective experience or subjective response or subjective mental alterations or subjective tolerability OR subjective well-being or patient perspective or self-rated effects or adverse effects or side effects). Of 7825 articles, 384 were retained that reported quantified results for AEs of typical or atypical antipsychotics among transdiagnostic adult, adolescent, and child populations. Information extracted included: types of AEs reported, how AEs were assessed, assessment duration, assessment of the global impact of antipsychotic consumption on subjective patient wellbeing, and conflict of interest due to industry sponsorship. RESULTS: Neurological, metabolic, and sedation-related cognitive effects were reported more systematically than affective, anticholinergic, autonomic, cutaneous, hormonal, miscellaneous, and nonsedative cognitive effects. The global impact of AEs on patient well-being was poorly assessed. Cross-sectional and prospective research designs yielded more comprehensive data about AE severity and prevalence than clinical or observational retrospective studies. CONCLUSIONS: The detection and classification of AEs can be improved through the use of standardized assessment instruments and consideration of the global impact on subjective patient wellbeing. Observational research can supplement information from clinical trials to improve the ecological validity of AE data. PMID- 26757312 TI - Levodopa and Other Pharmacologic Interventions in Ischemic and Traumatic Optic Neuropathies and Amblyopia. AB - The visual impairment in traumatic and ischemic optic neuropathy and amblyopia may be permanent. Hence, lots of efforts have been focused on neuroprotection. Dopamine is one of the suggested neuroprotective agents. Besides its important role in the brain, dopamine is found in various cell types of the retina, and is claimed to play a neuromodulator and neurotransmitter role there. The dopamine D1 receptor is the most highly expressed subtype of dopamine receptors, and its activation has been shown to be potentially neuroprotective against oxidative stress damage in retinal neurons. Levodopa, a precursor of dopamine, can easily breach the blood-brain and blood-retinal barriers, and exerts effective dopaminergic responses in the brain and retina. This article summarizes and discusses the use of levodopa and other pharmacologic agents in the treatment of 3 groups of visual pathway disorders that primarily involve neuronal systems: ischemic optic neuropathy, traumatic optic neuropathy, and amblyopia. PMID- 26757313 TI - Spontaneous Remission of Ketamine Withdrawal-Related Depression. AB - Ketamine, an antagonist of the N-methyl-D-aspartate receptor, has a rapid antidepressant effect, and its withdrawal may induce depression. However, the duration of depression and possibility of spontaneous remission remain unclear. We describe a male patient with ketamine dependence who developed depressive and anxiety symptoms soon after ketamine withdrawal. His mood symptoms remitted without medication after 1 month. This case suggests that clinicians should be aware that patients receiving ketamine may experience withdrawal symptoms, including depression and anxiety. Further research is required to elucidate the natural course of depression after ketamine withdrawal. PMID- 26757314 TI - A Case of Parkinson Disease With Both Visual Hallucination and Pain Improved by Gabapentin. AB - OBJECTIVES: Visual hallucinations (VHs) and pain are common non-motor symptoms in Parkinson disease (PD). Although dopaminergic dysfunction has traditionally been considered as the principal cause of these symptoms, the detail mechanisms are still unclear. Conventional treatment for VH, decrease of dopamine agonists, and use of antipsychotic medications often lead to an exacerbation of motor symptoms and excessive sedation. Gabapentin (GPT) is an antiepilepsy drug, which affects the glutamic acid neuron system and the gamma-amino butyric acid neuron system. It is also known to have an analgesic effect. Here, we report a case of PD in which GPT improved both VH and pain without any adverse effects. METHODS: This study is a case report. RESULTS: The subject is an 81-year-old Japanese man who was diagnosed with PD at the age of 67 years. His Hoehn and Yahr staging scale was IV. He developed VH of insects and also experienced pain, which is, as he described, caused by these insects invading his body. Despite the general treatments, VH and pain persisted. Moreover, exacerbation of motor symptoms and excessive sedation hindered a further attempt. Gabapentin was administered to ease his pain. After that, not only pain but also VH disappeared without any adverse effects. CONCLUSIONS: The positive outcomes of GPT on VH and pain without any adverse effects may offer us a useful alternative treatment for PD. Further experience and study are needed to prove the efficacy of this agent. PMID- 26757315 TI - Recurrent Bilateral Dislocation of the Temporomandibular Joint Induced by Clonazepam in a Parkinsonian Patient. PMID- 26757317 TI - Use of Ketamine in Barbiturate Coma for Status Epilepticus. AB - OBJECTIVES: We described the use of adjunctive ketamine to terminate seizure activity and decrease the dose and duration of pentobarbital coma in 2 patients with refractory status epilepticus (SE). CASES: A 56-year-old woman (patient 1) developed SE after cardiac arrest, which was refractory to antiepileptic agents and escalating doses of continuous midazolam. Midazolam was replaced with pentobarbital infusion with no significant change in electroencephalography. A continuous ketamine infusion was initiated as an adjunct to pentobarbital. After initiation of ketamine, seizure frequency decreased and sustained burst suppression was achieved. After 48 hours of induced burst suppression, pentobarbital was discontinued followed by ketamine and the patient remained seizure on oral anticonvulsants alone. Meanwhile, a 57-year-old woman (patient 2) with autoimmune encephalitis developed SE, which was refractory to first-line medications. Pentobarbital infusion was initiated with attainment of burst suppression on electroencephalography. Multiple attempts at weaning pentobarbital failed because of recurrence of seizures. To minimize the dose of pentobarbital needed, a continuous ketamine infusion was initiated as an adjunct to pentobarbital with maintenance of burst suppression at much lower doses of pentobarbital than before. Ketamine was continued for 19 days with titration of other antiepileptic therapy, without return of SE. CONCLUSIONS: These cases demonstrate that ketamine may show promise as an adjunct to induced pentobarbital coma for refractory SE. Adjunctive use of ketamine may reduce the dose and duration of pentobarbital required, hence preventing complications associated with barbiturate therapy. Future studies are needed to define the optimal dose, timing, and role of ketamine infusions in the management of refractory SE. PMID- 26757316 TI - Effect of Primidone on Dentate Nucleus gamma-Aminobutyric Acid Concentration in Patients With Essential Tremor. AB - OBJECTIVES: It is not known whether current use of the medication primidone affects brain gamma-aminobutyric acid (GABA) concentrations. This is an important potential confound in studies of the pathophysiology of essential tremor (ET), one of the most common neurological diseases. We compared GABA concentrations in the dentate nucleus in 6 ET patients taking primidone versus 26 ET patients not taking primidone. METHODS: (1)H magnetic resonance spectroscopy was performed using a 3.0-T Siemens Tim Trio scanner. The MEGA-PRESS J-editing sequence was used for GABA detection in 2 cerebellar volumes of interest (left and right) that included the dentate nucleus. RESULTS: The right dentate GABA concentration was similar in the 2 groups (2.21 +/- 0.46 [on primidone] vs 1.93 +/- 0.39 [not on primidone], P = 0.15), as was the left dentate GABA concentration (1.61 +/- 0.35 [on primidone] vs 1.67 +/- 0.34 [not on primidone], P = 0.72). The daily primidone dose was not associated with either right or left dentate GABA concentrations (P = 0.89 and 0.76, respectively). CONCLUSIONS: We did not find a difference in dentate GABA concentrations between 6 ET patients taking daily primidone and 26 ET patients not taking primidone. Furthermore, there was no association between daily primidone dose and dentate GABA concentration. These data suggest that it is not necessary to exclude ET patients on primidone from magnetic resonance spectroscopy studies of dentate GABA concentration, and if assessment of these concentrations was to be developed as a biomarker for ET, primidone usage would not confound interpretation of the results. PMID- 26757319 TI - Alopecia Areata Progression Index, a Scoring System for Evaluating Overall Hair Loss Activity in Alopecia Areata Patients with Pigmented Hair: A Development and Reliability Assessment. AB - BACKGROUND: No scoring systems to evaluate overall hair loss activity in alopecia areata (AA) have been established. OBJECTIVE: We sought to develop a measurement tool (Alopecia Areata Progression Index, AAPI) for the evaluation of overall hair loss activity in AA patients with pigmented hair. METHODS: The scalp surface area was divided into 4 quadrants. In each quadrant, hair loss activity was scored on the basis of the percentage of alopecic area, clinical findings associated with hair loss. The AAPI was measured in 17 patients with different severities of AA. RESULTS: Interobserver and intraobserver reliabilities were assessed by 4 investigators. A significant correlation of the total AAPI was found among the 4 investigators. In addition, intraobserver reliability was excellent, and interobserver reliability was statistically reliable. CONCLUSION: The AAPI seems to represent a system capable of truly quantifying overall hair loss activity in AA patients with different severity, demonstrating trustworthy interobserver and intraobserver reliability. PMID- 26757318 TI - Pilot Study of Massage to Improve Sleep and Fatigue in Hospitalized Adolescents With Cancer. AB - BACKGROUND: Adolescents with cancer experience many troubling symptoms, including sleep disruptions that can affect mood and quality of life. Massage is a safe and popular intervention that has demonstrated efficacy in pediatric and adult patients with cancer. This study aimed to assess the feasibility of conducting a massage intervention to help with sleep in hospitalized adolescent oncology patients. PROCEDURE: Adolescents ages 12-21 with cancer who were expected to be hospitalized for at least four consecutive nights were recruited from the inpatient unit at Children's National Health System and randomized to either massage intervention or a waitlist control. Patients in the intervention group received one massage per night, for two or three nights. Sleep was measured with actigraphy and patient and proxy reported instruments were used to measure fatigue, mood, and anxiety. RESULTS: The majority (78%) of patients approached for the study consented, and almost all patients in the intervention group (94%) received at least one massage, 69% received two, and rates of completion of instruments among adolescents were high demonstrating feasibility. There were trends toward increased night time and overall sleep in the intervention group compared with standard of care, but no differences between groups in the patient reported outcome measures. Participant and parent feedback on the intervention was positive and was the impetus for starting a clinical massage service at the hospital. CONCLUSIONS: Massage for hospitalized adolescents with cancer is feasible, well received, and can potentially improve patients' sleep. A randomized multicenter efficacy study is warranted. PMID- 26757320 TI - Construction of Hetero-Four-Layered Tripalladium(II) Cyclophanes by Transannular pi???pi Interactions. AB - A synthetic strategy for the generation of new molecular species utilizing a provision of nature is presented. Nano-dimensional (23(2)*21(1)*16(1) A3) hetero four-layered trimetallacyclophanes were constructed by proof-of-concept experiments that utilize a suitable combination of pi???pi interactions between the central aromatic rings, tailor-made short/long spacer tridentate donors, and the combined helicity. The behavior of the unprecedented four-layered metallacyclophane system offers a landmark in the development of new molecular systems. PMID- 26757321 TI - The Sagittal Condylar Paths in Edentulous Patients: Analysis with Computerized Axiography. AB - PURPOSE: Published literature on mandibular movements is extensive, but it lacks scientific robustness and is understandably controversial. This preliminary study recorded and assessed characteristic forms and condylar path inclination patterns during mandibular protrusion and opening in completely edentulous subjects. These features facilitate the setting of condylar guidance records on articulators. MATERIALS AND METHODS: A convenience study sample of 60 asymptomatic edentulous patients (aged 58 to 74 years) was provided with new complete dentures. After localizing hinge axis movement, sagittal condylar paths were recorded and analyzed with an electronic axiograph (AXIOCOMP, SAM). RESULTS: Protrusion and opening movement patterns showed completely different characteristics. During protrusive movement, condylar paths showed a sinusoidal pattern (51%), and condylar inclination was low at 1 mm (32.2 degrees) and 2 mm (40.4 degrees). Conversely, during the opening movement, the most frequent pattern found was the classical convex form (57%). Inclinations were higher: 50.8 degrees at 1 mm and 50.7 degrees at 2 mm. CONCLUSIONS: Completely edentulous subjects present radically different sagittal condylar paths when compared with dentate patients. These differences result from alterations in disc-condyle relationships and morphologic changes in bone structure. No link was observed between condylar paths recorded in protrusion and opening movements. Consequently, condylar guidance for articulators should be set using recordings from protrusive movements. PMID- 26757323 TI - Search Strategy to Identify Dental Survival Analysis Articles Indexed in MEDLINE. AB - PURPOSE: Articles reporting survival outcomes (time-to-event outcomes) in patients over time are challenging to identify in the literature. Research shows the words authors use to describe their dental survival analyses vary, and that allocation of medical subject headings by MEDLINE indexers is inconsistent. Together, this undermines accurate article identification. The present study aims to develop and validate a search strategy to identify dental survival analyses indexed in MEDLINE (Ovid). MATERIALS AND METHODS: A gold standard cohort of articles was identified to derive the search terms, and an independent gold standard cohort of articles was identified to test and validate the proposed search strategies. The first cohort included all 6,955 articles published in the 50 dental journals with the highest impact factors in 2008, of which 95 articles were dental survival articles. The second cohort included all 6,514 articles published in the 50 dental journals with the highest impact factors for 2012, of which 148 were dental survival articles. Each cohort was identified by a systematic hand search. Performance parameters of sensitivity, precision, and number needed to read (NNR) for the search strategies were calculated. RESULTS: Sensitive, precise, and optimized search strategies were developed and validated. The performances of the search strategy maximizing sensitivity were 92% sensitivity, 14% precision, and 7.11 NNR; the performances of the strategy maximizing precision were 93% precision, 10% sensitivity, and 1.07 NNR; and the performances of the strategy optimizing the balance between sensitivity and precision were 83% sensitivity, 24% precision, and 4.13 NNR. The methods used to identify search terms were objective, not subjective. The search strategies were validated in an independent group of articles that included different journals and different publication years. CONCLUSIONS: Across the three search strategies, dental survival articles can be identified with sensitivity up to 92%, precision up to 93%, and NNR of less than two articles to identify relevant records. This research has highlighted the impact that variation in reporting and indexing has on article identification and has improved researchers' ability to identify dental survival articles. PMID- 26757322 TI - Loading Variables on Implant-Supported Distal-Extension Removable Partial Dentures: An In Vitro Pilot Study. AB - PURPOSE: The aim of this study was to investigate strain on implants used for adjunctive support of distal extension removable partial dentures. MATERIALS AND METHODS: An implant with strain gauges was used for testing purposes in two positions, parallel and inclined. Three loading scenarios--loading apparatus (LA), artificial teeth via cotton roll (CR), and artificial teeth (UT)--were studied and strains compared via the Kruskal-Wallis test (P=.05). RESULTS: Strain under CR was significantly larger than UT in parallel (P<.05). However, the opposite was observed in inclined. CONCLUSIONS: Strain in parallel was smallest for UT, whereas in inclined it was largest for CR. PMID- 26757324 TI - Oral Health-Related Quality of Life in Different Types of Mandibular Implant Overdentures in Function Longer Than 3 Years. AB - PURPOSE: The aim of this study was to evaluate the oral health-related quality of life (OHRQoL) of patients treated with three different types of mandibular implant overdentures (IOD) after at least 3 years in function. MATERIALS AND METHODS: A total of 122 patients treated with mini implant (50), locator (56), or bar (16) mandibular IODs participated. Modified plaque (PI) and gingival (GI) indices were also assessed. RESULTS: Older patients and patients with mini mandibular IODs were the most satisfied with their OHRQoL. The bar overdenture presented the worst PI and GI results. CONCLUSION: The mini mandibular overdenture patients were assessed with a better OHRQoL than those with bar and locator IODs. PMID- 26757325 TI - Ten-Year Follow-Up of Implant-Supported All-Ceramic Fixed Dental Prostheses: A Randomized, Prospective Clinical Trial. AB - PURPOSE: The aim of this study was to evaluate the long-term clinical performance of and patient satisfaction with implant-supported all-ceramic fixed dental prostheses (FDPs) and to compare two different all-ceramic systems, Denzir (DZ) and In-Ceram Zirconia (InZ). MATERIALS AND METHODS: A total of 18 patients received 25 partial FDPs; 13 DZ, and 12 InZ. RESULTS: Of these patients, 17 attended the 10-year follow-up. None of the restorations had fractured. Fractures of the veneering porcelain were observed in nine patients; two from the InZ group and seven from the DZ group. All FDPs were in use, and all patients were fully satisfied with the treatment. CONCLUSION: Results from this long-term follow-up suggest that implant-supported all-ceramic FDPs are an acceptable treatment alternative. PMID- 26757326 TI - Digitizing the Facebow: A Clinician/Technician Communication Tool. AB - Communication between the clinician and the technician has been an ongoing problem in dentistry. To improve the issue, a dental software application has been developed--the Virtual Facebow App. It is an alternative to the traditional analog facebow, used to orient the maxillary cast in mounting. Comparison data of the two methods indicated that the digitized virtual facebow provided increased efficiency in mounting, increased accuracy in occlusion, and lower cost. Occlusal accuracy, lab time, and total time were statistically significant (P<.05). The virtual facebow provides a novel alternative for cast mounting and another tool for clinician-technician communication. PMID- 26757327 TI - Main Clinical Outcomes of Feldspathic Porcelain and Glass-Ceramic Laminate Veneers: A Systematic Review and Meta-Analysis of Survival and Complication Rates. AB - PURPOSE: The aim of this study was to perform a systematic review and meta analysis based on clinical trials that evaluated the main outcomes of glass ceramic and feldspathic porcelain laminate veneers. MATERIALS AND METHODS: A systematic search was carried out in Cochrane and PubMed databases. From the selected studies, the survival rates for porcelain and glass-ceramic veneers were extracted, as were complication rates of clinical outcomes: debonding, fracture/chipping, secondary caries, endodontic problems, severe marginal discoloration, and influence of incisal coverage and enamel/dentin preparation. The Cochran Q test and the I(2) statistic were used to evaluate heterogeneity. RESULTS: Out of the 899 articles initially identified, 13 were included for analysis. Metaregression analysis showed that the types of ceramics and follow-up periods had no influence on failure rate. The estimated overall cumulative survival rate was 89% (95% CI: 84% to 94%) in a median follow-up period of 9 years. The estimated survival for glass-ceramic was 94% (95% CI: 87% to 100%), and for feldspathic porcelain veneers, 87% (95% CI: 82% to 93%). The meta analysis showed rates for the following events: debonding: 2% (95% CI: 1% to 4%); fracture/chipping: 4% (95% CI: 3% to 6%); secondary caries: 1% (95% CI: 0% to 3%); severe marginal discoloration: 2% (95% CI: 1% to 10%); endodontic problems: 2% (95% CI: 1% to 3%); and incisal coverage odds ratio: 1.25 (95% CI: 0.33 to 4.73). It was not possible to perform meta-analysis of the influence of enamel/dentin preparation on failure rates. CONCLUSION: Glass-ceramic and porcelain laminate veneers have high survival rates. Fracture/ chipping was the most frequent complication, providing evidence that ceramic veneers are a safe treatment option that preserve tooth structure. PMID- 26757328 TI - Analyzing Complete Denture Occlusal Contacts: Accuracy and Reliability. AB - The aim of this study was to investigate the accuracy and reliability of interpreting occlusal markings made by articulating paper on complete dentures intraorally. Clinical teachers at a training hospital interpreted occlusal markings intended for adjustment. Their scores were compared to a control score to determine accuracy. For reliability determination, the observations were repeated. Only between 20% and 30% of observations were found to be both accurate and reliable. Unless the procedure can be standardized, this technique shouldn't be considered appropriate prosthodontics protocol for balancing the occlusion of complete dentures. PMID- 26757330 TI - Application of the Social Appeal Scale to a Selected Spanish Population. AB - PURPOSE: The aim of this study was to validate the Social Appeal Scale (SAS) among the Spanish general population, exploring the underlying dimensions of the construct assessed. MATERIALS AND METHODS: The SAS test was applied to 555 participants between 16 and 75 years of age. The scale is divided into four dimensions: social competence (SC), intellectual ability (IA), psychologic adjustment (PA), and relationship satisfaction (RS). RESULTS: The SAS (12 items) had a Cronbach alpha of .93, and SC had a Cronbach alpha of .83. For IA it was .85, for PA .87, and for RS .84. CONCLUSION: Bearing in mind the limitations of the present study, it may be concluded that the Social Appeal Scale is a valid and reliable instrument to assess social perceptions related to changes in tooth color. PMID- 26757329 TI - Case History Report: Immediate Rehabilitation with a Prefabricated Fibula Flap Following Removal of a Locally Aggressive Maxillary Tumor. AB - The present clinical case history report describes an interdisciplinary treatment protocol that combines maxillary tumor resection with immediate reconstruction to achieve functional rehabilitation. A fibula flap that received four dental implants and a split-thickness graft epithelial layer was prefabricated for a 31 year-old man. The flap was designed so that it could be adapted to fit in different extents of tumor resection. Resection and immediate reconstruction were successfully performed 6 weeks after flap prefabrication, with the final bar retained dental prosthesis delivered 4 weeks later. PMID- 26757331 TI - Effectiveness of Disinfectants on Antimicrobial and Physical Properties of Dental Impression Materials. AB - PURPOSE: The aim of this study was to assess the antimicrobial activity of chemical disinfectants on alginate and silicone impression materials. The effect of chemical disinfectants on the dimensional stability of the impression materials was also assessed. MATERIALS AND METHODS: For the microbiologic assessment, impressions of the maxillary arch were taken from 14 participants, 7 using alginate and 7 using an addition silicone. The impressions were divided into three sections. Each section was subjected to spraying with MD 520 or Minuten or no disinfection (control), respectively. Antimicrobial action of the chemical disinfectants was assessed by measuring microbial counts in trypticase soy agar (TSA) media and expressing the results in colony-forming units/cm2. The surface area of the dental impressions was calculated by scanning a stone cast using computer-aided design/computer-assisted manufacture and analyzing the data using a custom computer program. The dimensional stability of the impression materials after immersion in disinfectants was assessed by measuring the linear displacement of horizontally restrained materials using a traveling microscope. The percent change in length over 3 hours was thus determined. RESULTS: Alginate exhibited a higher microbial count than silicone. MD 520 eliminated all microbes as opposed to Minuten. The bacterial growth after Minuten disinfection was almost twice as much for alginate than for addition silicone impressions. The chemical disinfectants affected the alginate dimensional stability. Minuten reduced the shrinkage sustained by alginate during the first hour of storage. CONCLUSIONS: Alginate harbors three times more microorganisms than silicone impression material. Chemical disinfection by glutaraldehyde-based disinfectant was effective in eliminating all microbial forms for both alginate and silicone without modifying the dimensional stability. Alcohol-based disinfectants, however, reduced the alginate shrinkage during the first 90 minutes of setting. The current studies also propose another method to report the surface area based on accurate estimation by 3D image analysis. PMID- 26757332 TI - Tooth Loss and Prosthetic Treatment in Dependent and Functionally Impaired Individuals with Respect to Age and Gender. AB - PURPOSE: The aim of this study was to compare the prevalence of tooth loss and prosthetic treatments in dependent, functionally impaired individuals with the general population. MATERIALS AND METHODS: Data collected from 250 subjects from a register covering dependent and functionally impaired individuals in Sweden were compared with data from matched controls. The collected variables included number of teeth, tooth loss, and prosthetic treatments in the different jaw regions. RESULTS: The study group had a lower mean number of teeth and a higher proportion of complete tooth loss than the control group. Dentures were more common in the study group, and fixed prostheses, including dental implants, were more common in the control group. Gender-based differences related to tooth loss were also apparent. CONCLUSION: In spite of a well-organized recall system for dental care, differences still existed in tooth loss. The differences were more apparent in older individuals and appeared to be related to general health, functional impairments, and gender. Prosthetic treatment options were unevenly used and only one implant overdenture was found. PMID- 26757333 TI - Photogrammetry Impression Technique: A Case History Report. AB - PURPOSE: The aim of this report is to present photogrammetry as a reliable step in the fabrication of a full-arch immediate rehabilitation. MATERIALS AND METHODS: A 59-year-old man attended the department seeking dental rehabilitation for the sequelae of severe oral health neglect. The mandibular teeth suffered from advanced periodontal disease and the patient wore a maxillary complete denture. An irreversible hydrocolloid impression of the mandibular arch was made, poured in stone, and digitally scanned to create the first stereolithography (STL) file. All teeth with the exception of two retained as landmarks were extracted, and seven implants were placed under local anesthesia and their positions recorded using photogrammetry. Maxillary and mandibular dental arch alginate impressions were made, poured in laboratory stone, and scanned. A provisional restoration was placed 7 hours after surgery using the STL files to determine the best-fit line. RESULTS: Radiographic and clinical follow-up after 1 year showed a favorable evolution of the implants. No screw loosening or other mechanical or biologic complications were observed. CONCLUSION: The case history using the described system suggests certain advantages over conventional techniques. More research is needed to assess the possible benefits associated with photogrammetry when making implant-supported restorations. PMID- 26757334 TI - Angled Screw Channel: An Alternative to Cemented Single-Implant Restorations- Three Clinical Examples. AB - This article presents three cases of single labially tilted implants restored with screw-retained single crowns. Individualized abutments with an angled screw channel were used to avoid an unesthetic vestibular access channel. This individualized abutment allows the dentist and dental technician to use the screw retained restorations where a cemented reconstruction would otherwise have been needed. PMID- 26757335 TI - Mechanical Properties of Abutments: Resin-Bonded Glass Fiber-Reinforced Versus Titanium. AB - PURPOSE: The clinical success and longevity of endosseous implants, after their prosthetic finalization, mainly depends on mechanical factors. Excessive mechanical stress has been shown to cause initial bone loss around implants in the presence of a rigid implant-prosthetic connection. The implant abutments are manufactured with high elastic modulus materials such as titanium, steel, precious alloys, or esthetic ceramics. These materials do not absorb any type of shock from the chewing loads or ensure protection of the bone-implant interface, especially when the esthetic restorative material is ceramic rather than composite resin. MATERIALS AND METHODS: The mechanical resistance to cyclical load was evaluated in a tooth-colored fiber-reinforced abutment prototype (TCFRA) and compared to that of a similarly shaped titanium abutment (TA). Eight TCFRAs and eight TAs were adhesively cemented on as many titanium implants. The swinging the two types of abutments showed during the application of sinusoidal load was also analyzed. RESULTS: In the TA group, fracture and deformation occurred in 12.5% of samples, while debonding occurred in 62.5%. In the TCFRA group, only debonding was present, in 37.5% of samples. In comparison to the TAs, the TCFRAs exhibited greater swinging during the application of sinusoidal load. In the TA group extrusion prevailed, whereas in the TCFRA group intrusion was more frequent. CONCLUSION: TCFRA demonstrated a greater elasticity than did TAs to the flexural load, absorbing part of the transversal load applied on the fixture during the chewing function and thus reducing the stress on the bone-implant interface. PMID- 26757336 TI - The Effect of Compressive Cyclic Loading on the Retention of Cast Single Crowns Cemented to Implant Abutments. AB - PURPOSE: The aim of this study was to evaluate and compare the retention strength of three cements commonly used in implant-supported prostheses before and after compressive cyclic loading. MATERIALS AND METHODS: The working model consisted of five solid abutments, 7 mm in height and with a 6-degree taper, screw retained to five implant analogs secured in a rectangular block of self-curing acrylic. On the abutments, 30 metal Cr-Ni alloy copings were cemented using three luting agents: glass ionomer, resin urethane-based, and compomer cement (n = 10). Two tensile tests were conducted with a universal testing machine, before and after 100,000 cycles of 100 N and 0.72 Hz compressive cyclic loading in a humid environment. RESULTS: Before applying the compressive load, the retention strength of the resin urethane-based cement was slightly higher than that of the compomer cement and 75% greater than the glass-ionomer cement. After compressive loading, the resin urethane-based cement showed the highest percentage of loss of retention (64.45%, compared with 50% for glass-ionomer and compomer cement). However, the glass-ionomer cement showed the lowest mean retentive strength with 50.35 N as opposed to 75.12 N for the compomer cement and 71.25 N for the resin urethane-based. CONCLUSIONS: Compressive cyclic loading significantly influences the retention strength of the luting agents tested. All three cements may favor the retrievability of the crowns. PMID- 26757337 TI - Is There a Correlation Between Tensile Strength and Retrievability of Cemented Implant-Retained Crowns Using Artificial Aging? AB - PURPOSE: The main goal of this in-vitro study was to evaluate whether tensile strength and retrievability of cemented implant-retained crowns correlate when using artificial aging. MATERIALS AND METHODS: A total of 128 crowns were fabricated from a cobalt-chromium alloy for 128 tapered titanium abutments (6 degrees taper, 4.3 mm diameter, 4 mm length, Camlog). The crowns were cemented with glass-ionomer (Ketac Cem, 3M) or resin cements (Multilink Implant, Telio CS Cem [Ivoclar Vivadent], Retrieve [Parkell]). Multilink Implant was used without priming. The experimental groups were subjected to either 37,500 thermal cycles between 5 degrees C and 55 degrees C, 1,200,000 chewing cycles, or a combination of both. Control groups were stored for 10 days in deionized water. The crowns were removed with a universal testing machine or a clinically used removal device (Coronaflex, KaVo). Data were statistically analyzed using nonparametrical tests. RESULTS: Retention values were recorded between 31 N and 362 N. Telio CS Cem showed the lowest retention values, followed by Retrieve, Ketac Cem, and Multilink Implant (P<=.0001). The number of removal attempts with the Coronaflex were not significantly different between the cements (P>.05). Thermal cycling and chewing simulation significantly influenced the retrieval of Retrieve Telio CS Cem, and Ketac Cem specimens (P<=.05). Only for Multilink Implant and Telio CS Cem correlations between removal with the universal testing machine and the Coronaflex could be revealed (P<=.0001). CONCLUSIONS: Ketac Cem and Multilink Implant (without silane) can be used for a semipermanent cementation. Retrieve and Telio CS Cem are recommendable for a temporary cementation. PMID- 26757338 TI - Supplemental Breast Cancer Screening in Women With Dense Breasts Should Be Offered With Simultaneous Collection of Outcomes Data. PMID- 26757340 TI - Indole Based Weapons to Fight Antibiotic Resistance: A Structure-Activity Relationship Study. AB - Antibiotic resistance represents a worldwide concern, especially regarding the outbreak of methicillin-resistant Staphylococcus aureus, a common cause for serious skin and soft tissues infections. A major contributor to Staphylococcus aureus antibiotic resistance is the NorA efflux pump, which is able to extrude selected antibacterial drugs and biocides from the membrane, lowering their effective concentrations. Thus, the inhibition of NorA represents a promising and challenging strategy that would allow recycling of substrate antimicrobial agents. Among NorA inhibitors, the indole scaffold proved particularly effective and suitable for further optimization. In this study, some unexplored modifications on the indole scaffold are proposed. In particular, for the first time, substitutions at the C5 and N1 positions have been designed to give 48 compounds, which were synthesized and tested against norA-overexpressing S. aureus. Among them, 4 compounds have NorA IC50 values lower than 5.0 MUM proving to be good efflux pump inhibitor (EPI) candidates. In addition, preliminary data on their ADME (absorption, distribution, metabolism, and excretion) profile is reported. PMID- 26757339 TI - Cystatin C as a p53-inducible apoptotic mediator that regulates cathepsin L activity. AB - In response to various cellular stresses, p53 is activated and inhibits malignant transformation through the transcriptional regulation of its target genes. However, the full picture of the p53 downstream pathway still remains to be elucidated. Here we identified cystatin C, a major inhibitor of cathepsins, as a novel p53 target. In response to DNA damage, activated p53 induced cystatin C expression through p53 binding sequence in the first intron. We showed that cathepsin L activity was decreased in HCT116 p53(+/+) cells after adriamycin treatment, but not in HCT116 p53(-/-) cells. We also found that knockdown of cystatin C reduced adriamycin-induced caspase-3 activation. Cystatin C expression was significantly downregulated in breast cancer cells with p53 mutations, and decreased cystatin C expression was associated with poor prognosis of breast cancer. Our findings revealed an important role of the p53-cystatin C pathway in human carcinogenesis. PMID- 26757342 TI - Optimization of a cytochrome P450 oxidation system for enhancing protopanaxadiol production in Saccharomyces cerevisiae. AB - Ginsenosides, the major bioactive components of Panax ginseng, are regarded as promising high-value pharmaceutical compounds. In ginseng, ginsenosides are produced from their precursor protopanaxadiol. Recently, an artificial biosynthetic pathway of protopanaxadiol was built in Saccharomyces cerevisiae by introducing a P. ginseng dammarenediol-II synthase, a P. ginseng cytochrome P450 type protopanaxadiol synthase (PPDS), and a Arabidopsis thaliana NADPH-cytochrome P450 reductase (ATR1). In this engineered yeast strain, however, the low metabolic flux through PPDS resulted in a low productivity of protopanaxadiol. Moreover, health of the yeast cells was significantly affected by reactive oxygen species released by the pool coupling between PPDS and ATR1. To overcome the obstacles in protopanaxadiol production, PPDS was modified through transmembrane domain truncation and self-sufficient PPDS-ATR1 fusion construction in this study. The fusion enzymes conferred approximately 4.5-fold increase in catalytic activity, and 71.1% increase in protopanaxadiol production compared with PPDS and ATR1 co-expression. Our in vivo experiment indicated that the engineered yeast carrying fusion protein effectively converted 96.8% of dammarenediol-II into protopanaxadiol. Protopanaxadiol production in a 5 L bioreactor in fed-batch fermentation reached 1436.6 mg/L. Our study not only improved protopanaxadiol production in yeast, but also provided a generic method to improve activities of plant cytochrome P450 monooxygenases. This method is promising to be applied to other P450 systems in yeast. Biotechnol. Bioeng. 2016;113: 1787-1795. (c) 2016 Wiley Periodicals, Inc. PMID- 26757343 TI - Synthesis of Quinoline-Fused 1-Benzazepines through a Mannich-Type Reaction of a C,N-Bisnucleophile Generated from 2-Aminobenzaldehyde and 2-Methylindole. AB - Various quinoline-fused 1-benzazepine derivatives were synthesized using the C,N 1,6-bisnucleophile generated in situ from o-aminobenzaldehyde and 2-methylindole through a Mannich-type reaction. PMID- 26757341 TI - Endolysosomal two-pore channels regulate autophagy in cardiomyocytes. AB - KEY POINTS: Two-pore channels (TPCs) were identified as a novel family of endolysosome-targeted calcium release channels gated by nicotinic acid adenine dinucleotide phosphate, as also as intracellular Na(+) channels able to control endolysosomal fusion, a key process in autophagic flux. Autophagy, an evolutionarily ancient response to cellular stress, has been implicated in the pathogenesis of a wide range of cardiovascular pathologies, including heart failure. We report direct evidence indicating that TPCs are involved in regulating autophagy in cardiomyocytes, and that TPC knockout mice show alterations in the cardiac lysosomal system. TPC downregulation implies a decrease in the viability of cardiomyocytes under starvation conditions. In cardiac tissues from both humans and rats, TPC transcripts and protein levels were higher in females than in males, and correlated negatively with markers of autophagy. We conclude that the endolysosomal channels TPC1 and TPC2 are essential for appropriate basal and induced autophagic flux in cardiomyocytes, and also that they are differentially expressed in male and female hearts. ABSTRACT: Autophagy participates in physiological and pathological remodelling of the heart. The endolysosomal two-pore channels (TPCs), TPC1 and TPC2, have been implicated in the regulation of autophagy. The present study aimed to investigate the role of TPC1 and TPC2 in basal and induced cardiac autophagic activity. In cultured cardiomyocytes, starvation induced a significant increase in TPC1 and TPC2 transcripts and protein levels that paralleled the increase in autophagy identified by increased LC3-II and decreased p62 levels. Small interfering RNA depletion of TPC2 alone or together with TPC1 increased both LC3II and p62 levels under basal conditions and in response to serum starvation, suggesting that, under conditions of severe energy depletion (serum plus glucose starvation), changes in the autophagic flux (as assessed by use of bafilomycin A1) occurred either when TPC1 or TPC2 were downregulated. The knockdown of TPCs diminished cardiomyocyte viability under starvation and simulated ischaemia. Electron micrographs of hearts from TPC1/2 double knockout mice showed that cardiomyocytes contained large numbers of immature lysosomes with diameters significantly smaller than those of wild-type mice. In cardiac tissues from humans and rats, TPC1 and TPC2 transcripts and protein levels were higher in females than in males. Furthermore, transcript levels of TPCs correlated negatively with p62 levels in heart tissues. TPC1 and TPC2 are essential for appropriate basal and induced autophagic flux in cardiomyocytes (i.e. there is a negative effect on cell viability under stress conditions in their absence) and they are differentially expressed in male and female human and murine hearts, where they correlate with markers of autophagy. PMID- 26757345 TI - Teachers' screening estimations of speech-language impairments in primary school children in Nepal. AB - BACKGROUND: The prevalence of speech-language impairments in children have been estimated for several languages, primarily in developed countries. However, prevalence data is lacking for developing countries, such as Nepal. AIMS: (1) To obtain teacher estimates of incidence and overall prevalence of speech-language impairments and its subtypes as a function of gender, age and grade level; and (2) to validate the screening instrument on Nepalese children. METHODOLOGY: The adapted teachers' screening instrument, namely adapted Teachers' Speech and Language Referral Checklist (a-TSLRC), was administered in 2776 (690 and 2086) primary school children aged 5;00-11;11 years (mean = 8;11 years). The screening was conducted at four different points in time, i.e. Incidences I and II, and each incidence consisted of a testing and a retesting phase. Prior to this, teachers were trained in forum meetings, and an information sheet containing an overview of speech-language impairments, and guidelines/criteria for marking the occurrence of speech-language impairments in the TSLRC were disseminated. OUTCOMES & RESULTS: Overall prevalence of speech-language impairments in children was estimated as 8.11%. Specifically, overall speech problems were estimated as 4.68%, and language problems as 8.0%. Additionally, the prevalence by subtypes of speech-language impairments as categorized in the TSLRC were reported to be 2.95% for an articulation/phonological problems, 2.09% for stuttering, 3.42% for a voice problems, 4.97% for a receptive language problems and 7.74% for an expressive language problems. The internal consistency among items was sufficient and a good intra-rater reliability was obtained. CONCLUSIONS & IMPLICATIONS: The study indicates that the overall results of speech-language impairments in children via the adapted in-Nepalese criterion-referenced instrument are supported by international studies. In addition, justifiable reliability and validity was obtained. Therefore, based on these overall evidence, this instrument can be useful for the screening of speech-language impairments in primary school children in Nepal. PMID- 26757346 TI - Scanning Ion Conductance Microscopic Study for Cellular Uptake of Cationic Conjugated Polymer Nanoparticles. AB - Positively charged conjugated polymer nanoparticles (CPNs) are emerging biomaterials exhibiting high levels of cellular entry. High rate of cellular entry efficiency is believed that the amphiphilic CPNs interact efficiently with the negatively charged hydrophobic cellular membranes. For the first time, the cell surface morphological changes of human cervical cancer cells treated with CPNs using a scanning probe microscopy technique, scanning ion conductance microscopy (SICM) are imaged. After 1 h of CPN incubation, distinct changes are observed in cell surface morphology such as interconnected protrusions and pits with sub-micrometer sizes, which are not observed from cells treated with positively charged polyethyleneimine (PEI) under the same treatment conditions. The change on cell surface morphology is quantified by surface roughness ratio, which is increased as CPN concentration increases, while the ratio first increases and then decreases as the incubation time increases. These results suggest that cells respond actively toward CPN with both positive charges on the side chain and the hydrophobicity from rigid aromatic backbone, which leads to subsequent endocytosis. In conclusion, it is demonstrated that SICM is a suitable imaging technique to reveal the dynamic alternations on the cell surface morphology at the early stage of nanoparticles endocytosis with high resolution. PMID- 26757347 TI - A Novel Strategy for Large-Scale Metabolomics Study by Calibrating Gross and Systematic Errors in Gas Chromatography-Mass Spectrometry. AB - Metabolomics is increasingly applied to discover and validate metabolite biomarkers and illuminate biological variations. Combination of multiple analytical batches in large-scale and long-term metabolomics is commonly utilized to generate robust metabolomics data, but gross and systematic errors are often observed. The appropriate calibration methods are required before statistical analyses. Here, we develop a novel correction strategy for large-scale and long term metabolomics study, which could integrate metabolomics data from multiple batches and different instruments by calibrating gross and systematic errors. The gross error calibration method applied various statistical and fitting models of the feature ratios between two adjacent quality control (QC) samples to screen and calibrate outlier variables. Virtual QC of each sample was produced by a linear fitting model of the feature intensities between two neighboring QCs to obtain a correction factor and remove the systematic bias. The suggested method was applied to handle metabolic profiling data of 1197 plant samples in nine batches analyzed by two gas chromatography-mass spectrometry instruments. The method was evaluated by the relative standard deviations of all the detected peaks, the average Pearson correlation coefficients, and Euclidean distance of QCs and non-QC replicates. The results showed the established approach outperforms the commonly used internal standard correction and total intensity signal correction methods, it could be used to integrate the metabolomics data from multiple analytical batches and instruments, and it allows the frequency of QC to one injection of every 20 real samples. The suggested method makes a large amount of metabolomics analysis practicable. PMID- 26757344 TI - Identification of family determining residues in Jumonji-C lysine demethylases: A sequence-based, family wide classification. AB - Histone post-translational modifications play a critical role in the regulation of gene expression. Methylation of lysines at N-terminal tails of histones has been shown to be involved in such regulation. While this modification was long considered to be irreversible, two different classes of enzymes capable of carrying out the demethylation of histone lysines were recently identified: the oxidases, such as LSD1, and the oxygenases (JmjC-containing). Here, a family-wide analysis of the second of these classes is proposed, with over 300 proteins studied at the sequence level. We show that a correlated evolution analysis yields some position/residue pairs which are critical at comparing JmjC sequences and enables the classification of JmjC domains into five families. A few positions appear more frequently among conditions, such as positions 23 (directly C-terminal to the second iron ligand), 24, 252 and 253 (directly N-terminal to a conserved Asn). Implications of family conditions are studied in detail on PHF2, revealing the meaningfulness of the sequence-derived conditions at the structural level. These results should help obtain insights on the diversity of JmjC containing proteins solely by considering some of the amino acids present in their JmjC domain. PMID- 26757348 TI - Enantioseparation of citalopram analogues with sulfated beta-cyclodextrin by capillary electrophoresis. AB - Capillary electrophoresis methods were developed for the enantiomeric separation of 27 citalopram analogues. Sulfated beta-cyclodextrin was the most broadly selective and useful chiral selector. The separations of most of the citalopram analogue compounds reported in this work have not been reported previously. Excellent enantiomeric separations were obtained for 26 out of 27 compounds, and most of the separations were achieved within 10 min. The effects of chemical parameters such as chiral selector types, buffer types, chiral selector and buffer concentrations, buffer pH and organic modifiers on the separation were investigated. The influence of analyte structure on separation also was examined and discussed. PMID- 26757349 TI - A Systematic Review of Intervening to Prevent Driving While Intoxicated: The Problem of Driving While Intoxicated (DWI). AB - BACKGROUND: Driving while intoxicated (DWI) is a significant public health issue. The likelihood someone will intervene to prevent DWI is affected by the characteristics of the individuals and the context of the potential driving scenario. Understanding such contexts may help tailor public health messages to promote intervening from those who are nearby to an intoxicated driver. OBJECTIVE: This systematic review investigates the behavior of those close to an intoxicated driver and factors associated with increasing the likelihood they will intervene in situations where driving while impaired may be likely. The review of the literature is guided by an orienting framework, namely the classic social psychology theory of decision-making proposed by Latane and Darley. RESULTS: Drawing upon this framework, the review examines the extent to which research has focused on factors which influence whether or not an individual identifies a need to intervene and identifies a seriously dangerous situation. In addition, consideration is given to perceived personal responsibility. The final two components of the model are then discussed; the perceived skill an individual who may intervene has (in their ability to intervene) and their actual enactment of the intervening behavior. Conclusions and Importance: Drawing upon such a well considered theoretical framework, this review provides guidance on key components likely to assist in the development of targeted, more effective public education messages and campaigns that dissuade individuals from drinking and then driving. PMID- 26757350 TI - Validation of Maturity Offset in the Fels Longitudinal Study. AB - Sex-specific equations for predicting maturity offset, time before or after peak height velocity (PHV), were evaluated in 63 girls and 74 boys from the Fels Longitudinal Study. Serially measured heights (0.1 cm), sitting heights (0.1 cm), weights (0.1 kg), and estimated leg lengths (0.1 cm) from 8 to 18 years were used. Predicted age at PHV (years) was calculated as the difference between chronological age (CA) and maturity offset. Actual age at PHV for each child was derived with a triple logistic model (Bock-Thissen-du Toit). Mean predicted maturity offset was negative and lowest at 8 years and increased linearly with increasing CA. Predicted ages at PHV increased linearly with CA from 8 to 18 years in girls and from 8 to 13 years in boys; predictions varied within relatively narrow limits from 12 to 15 years and then increased to 18 years in boys. Differences between predicted and actual ages at PHV among youth of contrasting maturity status were significant across the age range in both sexes. Dependence of predicted age at PHV upon CA at prediction and on actual age at PHV limits its utility as an indicator of maturity timing and in sport talent programs. PMID- 26757351 TI - Progressing towards standard outcomes in gestational diabetes Cochrane reviews and randomised trials. AB - Outcomes in gestational diabetes Cochrane protocols and reviews before and after development of 'standard outcomes' by WOMBAT (WOMen and Babies health and well being: Action through Trials) were surveyed. An increase in 'common' outcomes (those prespecified by >=50% of the protocols and reviews) over time was observed (2001-2009: 27 vs 2010-2014: 46). There were discrepancies in outcomes prespecified in reviews and reported by randomised trials. Efforts are needed to develop a core outcome set, to reduce research waste and improve health outcomes. PMID- 26757352 TI - Current Understanding of the Genetic Architecture of Rhegmatogenous Retinal Detachment. AB - Rhegmatogenous retinal detachment (RRD) is a common and potentially blinding surgical retinal disease. While the precise molecular mechanisms leading to RRD are poorly understood, there is an increasing body of literature supporting the role of heritable factors in the pathogenesis of the condition. Much work has been undertaken investigating genes important in syndromic forms of RRD (e.g., Stickler, Wagner Syndrome, etc.) and research pertaining to genetic investigations of idiopathic or non-syndromic RRD has also recently been reported. To date, at least 12 genetic loci have been implicated in the development of syndromes of which RRD is a feature. A recent GWAS identified five loci implicated in the development of idiopathic RRD.This article provides an overview of the genetic mechanisms of both syndromic and idiopathic RRD. The genetics of predisposing conditions, such as myopia and lattice degeneration, are also discussed. PMID- 26757353 TI - Cost-effectiveness of a carcinoembryonic antigen (CEA) based follow-up programme for colorectal cancer (the CEA Watch trial). AB - AIM: The study CEA Watch (Netherlands Trial Register 2182) has shown that an intensified follow-up schedule with more frequent carcinoembryonic antigen (CEA) measurements but fewer outpatient visits detects more curable recurrences compared with the usual follow-up protocol in colorectal cancer (CRC) patients. The aim of the study was to compare the cost and cost-effectiveness between various follow-up programmes. METHOD: In total, 3223 patients with stage I-III CRC were followed between October 2010 and October 2012. Direct medical costs were calculated per patient adding the costs for all visits, CEA measurements and imaging. Productivity losses and travel expenses were calculated using answers from questionnaires. The cost-effectiveness displayed the additional costs per additional patient with recurrent disease and used an incremental cost effectiveness ratio (ICER) to compare them. RESULTS: The mean yearly cost per patient was ?548 in the intensified protocol and ?497 in the control protocol. The ICER was ?94 (95% CI ?76-?157) per cent; to detect one additional patient with a recurrence in the intervention protocol compared with the control protocol would require an additional ?9400. For curable recurrences, the ICER was ?607 (95% CI ?5695-?5728). Annual patient-reported costs were ?509 per year in the intervention protocol and ?488 in the control protocol. CONCLUSION: The current study demonstrates that the direct medical and patient-reported cost of a newly introduced, safe and effective way of CRC follow-up was comparable to that of standard care. The ICER per curable recurrence was considered acceptably low. PMID- 26757354 TI - Representation, Exemplification, and Risk: Resonance of Tobacco Graphic Health Warnings Across Diverse Populations. AB - As countries implement Article 11 of the World Health Organization (WHO) Framework Convention on Tobacco Control, graphic warning labels that use images of people and their body parts to illustrate the consequences of smoking are being added to cigarette packs. According to exemplification theory, these case examples-exemplars-can shape perceptions about risk and may resonate differently among demographic subpopulations. Drawing on data from eight focus groups (N = 63) with smokers and nonsmokers from vulnerable populations, this qualitative study explores whether people considered exemplars in their reactions to and evaluations of U.S. graphic health warning labels initially proposed by the Food and Drug Administration. Participants made reference to prior and concurrent mass media messages and exemplars during the focus groups and used demographic cues in making sense of the images on the warning labels. Participants were particularly sensitive to age of the exemplars and how it might affect label effectiveness and beliefs about smoking. Race and socioeconomic status also were salient for some participants. We recommend that exemplars and exemplification be considered when selecting and evaluating graphic health warnings for tobacco labels and associated media campaigns. PMID- 26757355 TI - Implications of fear of negative evaluation, state anxiety, and implied level of target-dominance on perceptions of personality traits. AB - Fear of negative evaluation (FNE), state anxiety (SA), and dominance have consequences for social functioning. The present study assessed how FNE, SA, and a target's dominance-relevant label are related to perceptions of personality. One hundred seventy-eight participants who scored high or low on FNE underwent a laboratory manipulation of SA, viewed a photograph of a target with a high or low dominance-relevant label, and rated the target on the Big Five personality traits and dominance. FNE and SA were unrelated to perceptions, but the high-dominance label was associated with perceptions of higher dominance, conscientiousness, and openness. In conclusion, judges did use information about others when making initial judgments of personality, but these judgments were not impacted by trait or state psychological distress. PMID- 26757356 TI - Impact of pedometer-based walking on menopausal women's sleep quality: a randomized controlled trial. AB - Objective Sleep disturbances are one of the most common psycho-physiological issues among postmenopausal women. This study was designed to evaluate the impact of walking with a pedometer on the sleep quality of postmenopausal Iranian women. Methods This randomized, controlled trial was conducted on 112 women who were randomly assigned to two groups. The women in the intervention group (n = 56) were asked to walk with a pedometer each day for 12 weeks and to increase their walking distance by 500 steps per week. A sociodemographic instrument and the Pittsburgh Sleep Quality Index were used to collect data. Sleep quality was measured at baseline, 4, 8, and 12 weeks after intervention. The control group (n = 56) did not receive any intervention. Results After 12 weeks, subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction improved to a significantly greater extent in the intervention group than in the control group (p < 0.05). The total sleep quality score was significantly higher in the intervention group than in the control group (0.64 vs. 0.98, p = 0.001). Conclusion This study showed that walking with a pedometer is an easy and cost effective way to improve the quality of sleep among postmenopausal women. Use of this method in public health centers is recommended. PMID- 26757357 TI - The Pleiotropic Effect of Glycodelin-A in Early Pregnancy. AB - Successful pregnancy depends largely on adequate placentation and maternal tolerance of the fetus. Glycodelin-A is a glycoprotein abundant in the decidua during early pregnancy. It plays an important role in placental development and fetomaternal defense. Glycodelin-A interacts by its unique carbohydrate side chains with the cell surface of various cell types in the human fetomaternal interface, particularly the trophoblasts and the immune cells, and modulates their functions and differentiation to permit successful pregnancy. Abnormal levels of glycodelin-A in the endometrium, uterine flushings, and/or maternal serum correlate with unexplained infertility, early pregnancy loss, and recurrent miscarriage. This review integrates recent studies on the role of glycodelin-A in placental development and fetomaternal tolerance in early pregnancy. PMID- 26757358 TI - Strong-Coupled Cobalt Borate Nanosheets/Graphene Hybrid as Electrocatalyst for Water Oxidation Under Both Alkaline and Neutral Conditions. AB - Developing highly active catalysts for the oxygen evolution reaction (OER) is of paramount importance for designing various renewable energy storage and conversion devices. Herein, we report the synthesis of a category of Co-Pi analogue, namely cobalt-based borate (Co-Bi ) ultrathin nanosheets/graphene hybrid by a room-temperature synthesis approach. Benefiting from the high surface active sites exposure yield, enhanced electron transfer capacity, and strong synergetic coupled effect, this Co-Bi NS/G hybrid shows high catalytic activity with current density of 10 mA cm(-2) at overpotential of 290 mV and Tafel slope of 53 mV dec(-1) in alkaline medium. Moreover, Co-Bi NS/G electrocatalysts also exhibit promising performance under neutral conditions, with a low onset potential of 235 mV and high current density of 14.4 mA cm(-2) at 1.8 V, which is the best OER performance among well-developed Co-based OER electrocatalysts to date. Our finding paves a way to develop highly active OER electrocatalysts. PMID- 26757359 TI - NOX2 Activation of Natural Killer T Cells Is Blocked by the Adenosine A2A Receptor to Inhibit Lung Ischemia-Reperfusion Injury. AB - RATIONALE: Ischemia-reperfusion (IR) injury after lung transplantation, which affects both short- and long-term allograft survival, involves activation of NADPH oxidase 2 (NOX2) and activation of invariant natural killer T (iNKT) cells to produce IL-17. Adenosine A2A receptor (A2AR) agonists are known to potently attenuate lung IR injury and IL-17 production. However, mechanisms for iNKT cell activation after IR and A2AR agonist-mediated protection remain unclear. OBJECTIVES: We tested the hypothesis that NOX2 mediates IL-17 production by iNKT cells after IR and that A2AR agonism prevents IR injury by blocking NOX2 activation in iNKT cells. METHODS: An in vivo murine hilar ligation model of IR injury was used, in which left lungs underwent 1 hour of ischemia and 2 hours of reperfusion. MEASUREMENTS AND MAIN RESULTS: Adoptive transfer of iNKT cells from p47(phox-/-) or NOX2(-/-) mice to Jalpha18(-/-) (iNKT cell-deficient) mice significantly attenuated lung IR injury and IL-17 production. Treatment with an A2AR agonist attenuated IR injury and IL-17 production in wild-type (WT) mice and in Jalpha18(-/-) mice reconstituted with WT, but not A2AR(-/-), iNKT cells. Furthermore, the A2AR agonist prevented IL-17 production by murine and human iNKT cells after acute hypoxia-reoxygenation by blocking p47(phox) phosphorylation, a critical step for NOX2 activation. CONCLUSIONS: NOX2 plays a key role in inducing iNKT cell-mediated IL-17 production and subsequent lung injury after IR. A primary mechanism for A2AR agonist-mediated protection entails inhibition of NOX2 in iNKT cells. Therefore, agonism of A2ARs on iNKT cells may be a novel therapeutic strategy to prevent primary graft dysfunction after lung transplantation. PMID- 26757360 TI - Targeting c-MET by LY2801653 for treatment of cholangiocarcinoma. AB - Palliative treatment options for human cholangiocarcinoma (CCC) are quite limited and new therapeutic strategies are of utmost need. c-MET has been shown to be deregulated in many cancers, but the role of c-MET in the carcinogenesis of CCC remains unclear. The main purpose of this study is to evaluate the expression and also to investigate the role of c-MET and its effective inhibition for the treatment of CCC. In this study we investigated the effects of LY2801653, a small molecule inhibitor with potent activity against MET kinase, in human CCC cell lines and in vivo using a xenograft mouse model. We have investigated the role of c-MET and its inhibitory effects on migration, invasion, colony formation, MET downstream targets, and CCC tumor growth. We also analyzed the role of apoptosis and senescence as well as the influence of hypoxia in this context. c-MET and p MET were expressed in 72% and 12.5% of human CCC tissues and in TFK-1, SZ-1 cell lines. MET inhibition was achieved by blocking phosphorylation of MET with LY2801653 and subsequent down regulation of c-MET downstream targets. Treatment showed in a xenograft model potent anti-tumor activity. LY2801653 is an effective inhibitor and suppress the proliferation of CCC cells as well as the growth of xenograft tumors. Therefore, inhibition of c-MET could be a possible alternative approach for the treatment of human CCC. (c) 2016 Wiley Periodicals, Inc. PMID- 26757361 TI - The Involvement of Splicing Factor hnRNP A1 in UVB-induced Alternative Splicing of hdm2. AB - Human homolog double minute 2 (hdm2), an oncoprotein, which binds to tumor suppressor p53 to facilitate its degradation, has been known to contribute to tumorigenesis. Its splicing variants are reported to be highly expressed in many cancers and can be induced by ultraviolet B light (UVB). However, the mechanisms of how UVB radiation induces hdm2 alternative splicing still remain unclear. In this study, we investigated the roles of two common splicing factors, heterogeneous nuclear ribonucleoproteins (hnRNP) A1 and serine/arginine-rich splicing factor 1 (SRSF1), in regulating UVB-induced hdm2 splicing. Our study indicated that while the expression of both hnRNP A1 and SRSF1 are induced, only hnRNP A1 is involved in hdm2 alternative splicing upon UVB irradiation. Overexpression of hnRNP A1 resulted in decrease of full-length hdm2 (hdm2-FL) and increase of hdm2B, one of hdm2 alternate-splicing forms; while down-regulated hnRNP A1 expression led to the decrease of the hdm2-FL and hdm2B in HaCaT cells. Protein-mRNA binding assay confirmed that UVB irradiation could increase the binding of hnRNP A1 to hdm2 pre-mRNA. In conclusion, we elucidated that UVB induces alternative splicing of hdm2 by increasing the expression and the binding of hnRNP A1 to hdm2 full-length mRNA. PMID- 26757364 TI - [Cost-effective medical therapy of hepatitis C employing novel compensation models - pay for cure]. PMID- 26757362 TI - Characterization of Viral Load, Viability and Persistence of Influenza A Virus in Air and on Surfaces of Swine Production Facilities. AB - Indirect transmission of influenza A virus (IAV) in swine is poorly understood and information is lacking on levels of environmental exposure encountered by swine and people during outbreaks of IAV in swine barns. We characterized viral load, viability and persistence of IAV in air and on surfaces during outbreaks in swine barns. IAV was detected in pigs, air and surfaces from five confirmed outbreaks with 48% (47/98) of oral fluid, 38% (32/84) of pen railing and 43% (35/82) of indoor air samples testing positive by IAV RT-PCR. IAV was isolated from air and oral fluids yielding a mixture of subtypes (H1N1, H1N2 and H3N2). Detection of IAV RNA from air was sustained during the outbreaks with maximum levels estimated between 7 and 11 days from reported onset. Our results indicate that during outbreaks of IAV in swine, aerosols and surfaces in barns contain significant levels of IAV potentially representing an exposure hazard to both swine and people. PMID- 26757363 TI - The MTHFR C677T Polymorphism and Risk of Intracerebral Hemorrhage in a Chinese Han Population. AB - BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been speculated to be and extensively investigated as a risk factor for various vascular diseases, including intracerebral hemorrhage (ICH). However, results from published studies regarding the role of C677T polymorphism in ICH risk in Chinese populations were contradictory rather than conclusive. MATERIAL/METHODS: In this study, a total of 180 ICH patients and 180 matched controls of Chinese Han ethnicity were enrolled. The MTHFR C677T polymorphism was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). A meta-analysis was conducted by combining our data with previous relevant studies in Chinese populations. RESULTS: In our case-control study, similar allele frequency (p=0.492) and genotype distribution (p=0.748) of MTHFR C677T polymorphism were detected between ICH patients and controls. Further analysis based on hematoma location did not show a significant association. When combined with previous studies, however, C677T polymorphism was found to be significantly associated with an increased risk for ICH in Chinese populations (recessive model: OR=1.57, 95%CI=1.29-1.91). When focusing on the Han ethnicity, carriers of the TT genotype had an increased risk of ICH (recessive model: OR=1.36, 95%CI=1.05-1.75). CONCLUSIONS: In this case-control study we did not observe that the MTHFR C677T polymorphism was associated with ICH risk in people of Chinese Han ethnicity. However, when combined with previous published studies, a significant association of C677T polymorphism with an increased risk of ICH was detected in Chinese populations, and also in the subgroup analysis focusing on Han ethnicity. PMID- 26757365 TI - A Novel Augmented Reality Navigation System for Endoscopic Sinus and Skull Base Surgery: A Feasibility Study. AB - OBJECTIVE: To verify the reliability and clinical feasibility of a self-developed navigation system based on an augmented reality technique for endoscopic sinus and skull base surgery. MATERIALS AND METHODS: In this study we performed a head phantom and cadaver experiment to determine the display effect and accuracy of our navigational system. We compared cadaver head-based simulated operations, the target registration error, operation time, and National Aeronautics and Space Administration Task Load Index scores of our navigation system to conventional navigation systems. RESULTS: The navigation system developed in this study has a novel display mode capable of fusing endoscopic images to three-dimensional (3-D) virtual images. In the cadaver head experiment, the target registration error was 1.28 +/- 0.45 mm, which met the accepted standards of a navigation system used for nasal endoscopic surgery. Compared with conventional navigation systems, the new system was more effective in terms of operation time and the mental workload of surgeons, which is especially important for less experienced surgeons. CONCLUSION: The self-developed augmented reality navigation system for endoscopic sinus and skull base surgery appears to have advantages that outweigh those of conventional navigation systems. We conclude that this navigational system will provide rhinologists with more intuitive and more detailed imaging information, thus reducing the judgment time and mental workload of surgeons when performing complex sinus and skull base surgeries. Ultimately, this new navigational system has potential to increase the quality of surgeries. In addition, the augmented reality navigational system could be of interest to junior doctors being trained in endoscopic techniques because it could speed up their learning. However, it should be noted that the navigation system serves as an adjunct to a surgeon's skills and knowledge, not as a substitute. PMID- 26757366 TI - Using a second-order differential model to fit data without baselines in protein isothermal chemical denaturation. AB - In vitro protein stability studies are commonly conducted via thermal or chemical denaturation/renaturation of protein. Conventional data analyses on the protein unfolding/(re)folding require well-defined pre- and post-transition baselines to evaluate Gibbs free-energy change associated with the protein unfolding/(re)folding. This evaluation becomes problematic when there is insufficient data for determining the pre- or post-transition baselines. In this study, fitting on such partial data obtained in protein chemical denaturation is established by introducing second-order differential (SOD) analysis to overcome the limitations that the conventional fitting method has. By reducing numbers of the baseline-related fitting parameters, the SOD analysis can successfully fit incomplete chemical denaturation data sets with high agreement to the conventional evaluation on the equivalent completed data, where the conventional fitting fails in analyzing them. This SOD fitting for the abbreviated isothermal chemical denaturation further fulfills data analysis methods on the insufficient data sets conducted in the two prevalent protein stability studies. PMID- 26757367 TI - A proposed dosing algorithm for the individualized dosing of human immunoglobulin in chronic inflammatory neuropathies. AB - Dosing guidelines for immunoglobulin (Ig) treatment in neurological disorders do not consider variations in Ig half-life or between patients. Individualization of therapy could optimize clinical outcomes and help control costs. We developed an algorithm to optimize Ig dose based on patient's response and present this here as an example of how dosing might be individualized in a pharmacokinetically rational way and how this achieves potential dose and cost savings. Patients are "normalized" with no more than two initial doses of 2 g/kg, identifying responders. A third dose is not administered until the patient's condition deteriorates, allowing a "dose interval" to be set. The dose is then reduced until relapse allowing dose optimization. Using this algorithm, we have individualized Ig doses for 71 chronic inflammatory neuropathy patients. The majority of patients had chronic inflammatory demyelinating polyradiculoneuropathy (n = 39) or multifocal motor neuropathy (n = 24). The mean (standard deviation) dose of Ig administered was 1.4 (0.6) g/kg, with a mean dosing interval of 4.3 weeks (median 4 weeks, range 0.5-10). Use of our standardized algorithm has allowed us to quickly optimize Ig dosing. PMID- 26757368 TI - Behavioural and neurofunctional impact of transcranial direct current stimulation on somatosensory learning. AB - We investigated the effect of repeated delivery of anodal transcranial direct current stimulation (tDCS) on somatosensory performance and long-term learning. Over the course of five days, tDCS was applied to the primary somatosensory cortex (S1) by means of neuronavigation employing magnetencephalography (MEG). Compared to its sham application, tDCS promoted tactile learning by reducing the two-point discrimination threshold assessed by the grating orientation task (GOT) primarily by affecting intersessional changes in performance. These results were accompanied by alterations in the neurofunctional organization of the brain, as revealed by functional magnetic resonance imaging conducted prior to the study, at the fifth day of tDCS delivery and four weeks after the last application of tDCS. A decrease in activation at the primary site of anodal tDCS delivery in the left S1 along retention of superior tactile acuity was observed at follow-up four weeks after the application of tDCS. Thus, we demonstrate long-term effects that repeated tDCS imposes on somatosensory functioning. This is the first study to provide insight into the mode of operation of tDCS on the brain's response to long-term perceptual learning, adding an important piece of evidence from the domain of non-invasive brain stimulation to show that functional changes detectable by fMRI in primary sensory cortices participate in perceptual learning. PMID- 26757369 TI - An Overview of Protocols for the Neural Induction of Dental and Oral Stem Cells In Vitro. AB - To date, various adult stem cells have been identified within the oral cavity, including dental pulp stem cells, dental follicle stem cells, stem cells from apical papilla, stem cells from human exfoliated deciduous teeth, periodontal ligament stem cells, and mesenchymal stem cells from the gingiva. All of these possess neurogenic potential due to their common developmental origin from the embryonic neural crest. Besides the relative ease of isolation of these adult stem cells from readily available biological waste routinely produced during dental treatment, these cells also possess the advantage of immune compatibility in autologous transplantation. In recent years, much interest has been focused on the derivation of neural lineages from these adult stem cells for therapeutic applications in the brain, spinal cord, and peripheral nerve regeneration. In addition, there are also promising nontherapeutic applications of stem cell derived neurons in pharmacological and toxicological screening of neuroactive drugs, and for in vitro modeling of neurodevelopmental and neurodegenerative diseases. Hence, this review will critically examine the diverse array of in vitro neural induction protocols that have been devised for dental and oral derived stem cells. These protocols are defined not only by the culture milieu comprising the basal medium plus growth factors, small molecules, and other culture supplements but also by the substrata/surface coatings utilized, the presence of multiple culture stages, the total culture duration, the initial seeding density, and whether the spheroid/neurosphere formation is being utilized to recapitulate the three-dimensional neural differentiation microenvironment that is naturally present physiologically in vivo. PMID- 26757391 TI - Effect of Circadian Rhythm on Clinical and Pathophysiological Conditions and Inflammation. AB - Circadian rhythms have long been known to regulate numerous physiological processes that vary across the diurnal cycle. The circadian clock system also controls various parameters of the immune system and its biological defense functions, allowing an organism to anticipate daily changes in activity and feeding and the associated risk of infection. Inflammation is an immune response triggered in living organisms in response to external stimuli. The risk of sepsis, an excessive inflammatory response, has been shown to have a diurnal variation. On the other hand, inflammatory responses are emerging to be induced by endogenous factors. Recent studies have suggested that chronic inflammation causes chronic diseases including rheumatoid arthritis, allergies, and aging related diseases and that proteins encoded by clock genes affect the development of such chronic inflammatory diseases or increase the severity of their symptoms. Therefore, detailed understanding of circadian rhythm effects on inflammatory responses is expected to lead to new strategies for prevention or treatment of inflammatory diseases. PMID- 26757392 TI - Pathogenesis of Multiple Organ Failure in Sepsis. AB - Sepsis is a severe critical illness syndrome that arises from infectious insults. While the host immune system is generally beneficial, an overshooting and unregulated immune response can cause serious organ tissue injury. During sepsis, systemic hypotension, disturbed perfusion of the microcirculation, and direct tissue-toxicity caused by inflammatory immune reaction can occur and contribute to organ failure. The failure of two or more vital organ systems is termed multi organ dysfunction syndrome (MODS) and resembles a very critical condition associated with high morbidity and mortality. Importantly, no specific treatment strategy exists to efficiently prevent the development of MODS during sepsis. In this review, we aim to identify the relevant molecular immunological pathways involved in the pathogenesis of MODS during sepsis. We believe that a detailed understanding of this mechanism is necessary for the development of new treatment approaches for septic patients. In particular, knowledge of the endogenous regulators keeping the balance between necessary immune system activation to combat infections and prevention of host tissue damage would greatly improve the chances for the development of effective interventions. PMID- 26757393 TI - The Regulation of Endotoxin Tolerance and its Impact on Macrophage Activation. AB - Endotoxin tolerance in macrophages is a key regulatory mechanism to limit the innate immune response to infection or injury. Long considered a state of unresponsiveness to Toll-like receptor activation, tolerance is now recognized as a state of altered responsiveness to infection or injury. Endotoxin tolerance leads to a shift away from a pro-inflammatory response toward a response with key anti-inflammatory and pro-resolution features. Advances in our understanding of Toll-like receptor function have identified a number of molecular mechanisms that promote tolerance, but how these are integrated to achieve gene-specific regulation is an important outstanding question. The potential to harness the mechanisms of endotoxin tolerance to promote the resolution of chronic inflammation warrants the continued investigation of this fundamental feature of innate immunity. This review focuses on the endotoxin tolerant state, our understanding of the underlying molecular mechanisms, and the clinical significance of endotoxin tolerance. PMID- 26757394 TI - The Role of the immunological Synapse Formed by Cytotoxic Lymphocytes in Immunodeficiency and Anti-Tumor immunity. AB - A synapse is a specialized structure that forms when the plasma membrane of two cells come into close contact to facilitate communication and signaling. Cells of the immune system form 'immunological' synapses that have an ordered structure and are essential for immune cell activation, function and homeostasis. Optimal synapse formation is not only critical for the generation of effective immunity against pathogens but is also essential for immune surveillance against cancer and for the prevention of immune disorders. Not surprisingly, defective synapse formation can therefore have severe consequences for human health, culminating in poor immune function leading to immunodeficiency disease or failure to detect and control infected or cancerous cells. Here, we discuss the immunological synapse formed by cytotoxic lymphocytes in both immunodeficiency diseases and anticancer immunity and touch on novel therapies that may alter or enhance synapse formation. PMID- 26757397 TI - Quantitative control of a rotary carbon nanotube motor under temperature stimulus. AB - Since a double-walled carbon nanotube (DWCNT)-based rotary motor driven by a uniform temperature field was proposed in 2014, how to control quantitatively the rotation of the rotor is still an open question. In this work, we present a mathematical relationship between the rotor's speed and interaction energy. Essentially, the increment of interaction energy between the rotor and the stator(s) determines the rotor's rotational speed, whereas the type of radial deviation of an end carbon atom on the stator determines the rotational direction. The rotational speed of the rotor can be specified by adjusting temperature and radial deviation of an end carbon atom on the stator. It is promising for designing a controllable temperature-driven rotary motor based on DWCNTs with length of few nanometers only. PMID- 26757396 TI - Marijuana: A Fifty-Year Personal Addiction Medicine Perspective. AB - As of September 2015, the cultivation, possession, and/or use of marijuana is illegal under U.S. federal law as a Schedule I narcotic; however, it is legal in four states and Washington, D.C. Forty-six states allow some form of medicinal marijuana or decriminalization. Marijuana has been used medicinally for thousands of years; Marijuana's regulation by law enforcement in the U.S., rather than the medical community, led to an almost complete halt to academic and scientific research after the 1930s. The late 1960s saw an upsurge in recreational marijuana use by middle-class youth, the majority of whom experienced minimal adverse effects aside from arrest and attendant legal complications. Since the mid-1990s, the use of medicinal marijuana for certain conditions has gained increasing acceptance. Stronger strains and formulations of marijuana pose a risk to the developing brains of adolescents. Within the addiction medicine community, there is currently no consensus on marijuana. In the East, the feeling is primarily that marijuana continue to be proscribed. In the West, where clinicians must face the realities of medicalization, decriminalization, and/or legalization, as well as widespread recreational use, there is more of a movement to minimize adverse effects, particularly on youth. PMID- 26757398 TI - Investigation into the Sensing Process of High-Performance H2S Sensors Based on Polymer Transistors. AB - Herein a H2S sensor based on a polymer field-effect transistor is reported and the sensor shows high sensitivity, excellent selectivity, fast response, and good operational stability. A concentration as low as 1 ppb H2 is detectable, which is to date the most sensitive H2S sensor based on organic semiconducting film. Thinning the thickness of active layer does not necessarily improve the sensitivity, but rather leads to the reduction of performance if the thickness is too low. Further analysis proposes a mechanism that the changing rate of absorption and desorption of H2S molecules is different when the thickness of active layer varies, indicating the necessity for thickness optimization. PMID- 26757395 TI - Foliar application of microdoses of sucrose to reduce codling moth Cydia pomonella L. (Lepidoptera: Tortricidae) damage to apple trees. AB - BACKGROUND: The effects of foliar applications of microdoses of sucrose to reduce the damage by the codling moth have been reported from nine trials carried in France and Algeria from 2009 to 2014. The activity of sucrose alone was assessed by comparison with an untreated control and some treatments with the Cydia pomonella granulovirus or a chemical insecticide. The addition of sucrose to these different treatments was also investigated. RESULTS: The application of sucrose at 0.01% reduced the means of infested fruits with a value of Abbott's efficacy of 41.0 +/- 10.0%. This involved the induction of resistance by antixenosis to insect egg laying. Indeed, it seems that acceptance of egg laying on leaves treated with sucrose was reduced. The addition of sucrose to thiacloprid improved its efficacy (59.5% +/- 12.8) by 18.4%. However, the sucrose had no added value when associated with C. pomonella granulovirus treatments. CONCLUSION: Foliar applications of microdoses of sucrose every 20 days in commercial orchards can partially protect against the codling moth. Its addition to thiacloprid increases the efficacy in integrated control strategies, contrary to C. pomonella granulovirus treatments. This work opens a route for the development of new biocontrol strategies. (c) 2016 Society of Chemical Industry. PMID- 26757399 TI - Stabilization of Water-in-Water Emulsions by Polysaccharide-Coated Protein Particles. AB - The phase diagram of mixtures of xyloglucan (XG) and amylopectin (AMP) in aqueous solution is presented. Water-in-water emulsions prepared from mixtures in the two phase regime were studied in detail, and the interfacial tension was determined. It is shown that the emulsions can be stabilized by addition of beta lactoglobulin microgels (betaLGm), but only at pH <= 5.0. Excess betaLGm preferentially entered the AMP phase at pH > 5.0 and the XG phase at lower pH. The inversion was caused by adsorption of XG onto betaLGm that started below pH 5.5. It is shown that modification of the surface of particles by coating with polysaccharides is a potential lever to control stabilization of water-in-water emulsions. PMID- 26757400 TI - CANPLAY study: Secular trends in steps/day amongst 5-19year-old Canadians between 2005 and 2014. AB - INTRODUCTION: The Canadian Physical Activity Levels Among Youth (CANPLAY) study collected pedometer data from eight surveys between 2005 and 2014, making it a unique database of objective population physical activity surveillance. The purpose of this study was to describe secular physical activity trends for 5 19year olds. METHODS: Canadian children from nationally representative samples (10,000 recruited, n?5500 per survey) were mailed a pedometer kit, asked to wear the pedometer for 7 consecutive days, log steps daily, then return the log by mail. Weighted medians and prevalence estimates were calculated. Trends were tested by chi(2) test of independence. RESULTS: An overall median of 10,935 steps/day was taken by Canadian children 5-19years of age (n=43,806) across the eight surveys. Steps/day increased between 2005-06 and 2007-08, then decreased in 2012-14. The prevalence of taking sufficient steps/day (defined as >=10,000 steps/day for 5year olds, >=13,000 steps/day for 6-11year-old boys; >=11,000 steps/day for 6-11year-old girls; and >=10,000 steps/day for 12-19year olds;) also increased then decreased over time, whereas the prevalence of accumulating <7000 steps/day generally increased over time. Trends were significant for boys, girls and each age group. DISCUSSION: The CANPLAY surveillance system provided comparable data at multiple time points over 9years. An overall shift in the distribution of steps/day towards a less active lifestyle occurred between 2005 06 and 2012-14 for boys, girls and each age group. This provides evidence that the national policy goal to increase children's steps/day by 2015 has not been met. PMID- 26757401 TI - Predictors of influenza vaccine uptake during the 2009/10 influenza A H1N1v ('swine flu') pandemic: Results from five national surveys in the United Kingdom. AB - OBJECTIVES: To investigate reasons underlying the low uptake of the influenza A H1N1v vaccination in the UK during the 2009/10 pandemic. METHODS: We analysed data from five national telephone surveys conducted in the UK during the latter stages of the pandemic to identify predictors of uptake amongst members of the public offered the vaccine by their primary care physician (n=1320). In addition to demographic variables, participants reported: reasons for declining the vaccination, levels of worry about the risk of catching swine flu, whether too much fuss was being made about the pandemic, whether they or a close friend or relative had had swine flu, how effective they felt the vaccine was, whether they had previously had a seasonal flu vaccination, how well prepared they felt the government was for a pandemic and how satisfied they were with information available about the pandemic. Most participants (n=734, 55.6%) reported being vaccinated against swine flu, compared to 396 who had not been vaccinated and were unlikely to be vaccinated in the future. RESULTS: The main reasons given for declining vaccination were concerns over the vaccine's safety, and being generally healthy. Controlling for demographic variables, risk factors for not being vaccinated were: being female, not having a long-standing infirmity or illness, not having been vaccinated against seasonal flu in previous years, feeling that too much fuss had been made about the pandemic and believing that the vaccine was ineffective. CONCLUSIONS: Interventions that target these factors may be effective in improving uptake in a future pandemic. PMID- 26757402 TI - Bismuth Nanoparticles Embedded in Carbon Spheres as Anode Materials for Sodium/Lithium-Ion Batteries. AB - Sodium-ion batteries (SIBs) are regarded as an attractive alternative to lithium ion batteries (LIBs) for large-scale commercial applications, because of the abundant terrestrial reserves of sodium. Exporting suitable anode materials is the key to the development of SIBs and LIBs. In this contribution, we report on the fabrication of Bi@C microspheres using aerosol spray pyrolysis technique. When used as SIBs anode materials, the Bi@C microsphere delivered a high capacity of 123.5 mAh g(-1) after 100 cycles at 100 mA g(-1) . The rate performance is also impressive (specific capacities of 299, 252, 192, 141, and 90 mAh g(-1) are obtained under current densities of 0.1, 0.2, 0.5, 1, and 2 A g(-1) , respectively). Furthermore, the Bi@C microsphere also proved to be suitable LIB anode materials. The excellent electrochemical performance for both SIBs and LIBs can attributed to the Bi@C microsphere structure with Bi nanoparticles uniformly dispersed in carbon spheres. PMID- 26757403 TI - Fluorescent Detection of 2,4-DNT and 2,4,6-TNT in Aqueous Media by Using Simple Water-Soluble Pyrene Derivatives. AB - Pyrene-containing water-soluble probes for the fluorescent detection of nitroaromatic compounds (NACs), such as explosive components (2,4-DNT and 2,4,6 TNT) and herbicides (2,4-dinitrocresol, 2,4-DNOC), in aqueous media are reported. In the probes, the introduction of surface-active hydrophilic "heads" at the periphery of lipophilic (i.e., hydrophobic) pyrene "tails" resulted in the formation of highly fluorescent micelle-like aggregates/pre-associates in aqueous solutions at concentrations of <=10(-5) m. The enhanced fluorescence quenching of the herein reported architectures is achieved in the presence of ultra-trace amounts of TNT or 2,4-DNT with values of Stern-Volmer quenching constant close to 1*10(5) m(-1) and a detection limit as low as 182 ppb. The most hydrophilic probes demonstrated higher response to 2,4-DNT over TNT. Filter paper test strips impregnated with 1*10(-5) m solutions of the probes were able to detect TNT, 2,4 DNT, and other NACs at levels as low as 50 ppb in water. PMID- 26757405 TI - Silver-Catalyzed, Aldehyde-Induced alpha-C-H Functionalization of Tetrahydroisoquinolines with Concurrent C-P Bond Formation/N-Alkylation. AB - The first facile and efficient silver-catalyzed, aldehyde-induced three-component reaction of N-unprotected tetrahydroisoquinolines, aldehydes, and dialkyl phosphonates has been developed, providing a general one-step approach to structurally diverse C1-phosphonylated THIQs accompanied by concurrent C-P bond formation/N-alkylation with remarkable functional group tolerance and excellent regioselectivity for endo products. PMID- 26757404 TI - Reply to "Increasing the Number of Organs Available to Transplant Is Separate From Ensuring Equitable Distribution of Available Organs: Both Are Important Goals". PMID- 26757407 TI - Sex-specific changes in thyroid gland function and circulating thyroid hormones in nestling American kestrels (Falco sparverius) following embryonic exposure to polybrominated diphenyl ethers by maternal transfer. AB - High concentrations of polybrominated diphenyl ethers (PBDEs) accumulate in predatory birds. Several PBDE congeners are considered thyroid disruptors; however, avian studies are limited. The authors examined circulating thyroid hormones and thyroid gland function of nestling American kestrels (Falco sparverius) at 17 d to 20 d of age, following embryonic exposure by maternal transfer only to environmentally relevant levels of PBDEs (DE-71 technical mixture). Nestlings were exposed to in ovo sum (Sigma) PBDE concentrations of 11 301 +/- 95 ng/g wet weight (high exposure), 289 +/- 33 ng/g wet weight (low exposure), or 3.0 +/- 0.5 ng/g wet weight (controls, background exposure). Statistical comparisons are made to controls of the respective sexes and account for the relatedness of siblings within broods. Circulating concentrations of plasma total thyroxine (TT4 ) and total triiodothyronine (TT3 ) in female nestlings were significantly influenced overall by the exposure to DE-71. Following intramuscular administration of thyroid-stimulating hormone, the temporal response of the thyroid gland in producing and/or releasing TT4 was also significantly affected by the females' exposure to DE-71. The altered availability of T4 for conversion to T3 outside of the gland and/or changes in thyroid-related enzymatic activity may explain the lower TT3 concentrations (baseline, overall) and moderately altered temporal TT3 patterns (p = 0.06) of the treatment females. Controlling for the significant effect on TT3 levels of the delayed hatching of treatment females, baseline TT3 levels were significantly and positively correlated with body mass (10 d, 15 d, 20 d), with PBDE-exposed females generally being smaller and having lower TT3 concentrations. Given that exposure concentrations were environmentally relevant, similar thyroidal changes and associated thyroid-mediated processes relating to growth may also occur in wild female nestlings. Environ Toxicol Chem 2016;35:2084-2091. (c) 2016 SETAC. PMID- 26757408 TI - A case of severe parkinsonism in an elderly person induced by valproic acid. PMID- 26757409 TI - Survivors of childhood leukaemia treated with haematopoietic stem cell transplantation and total body irradiation should undergo screening for diabetes by oral glucose tolerance tests. AB - AIMS: Childhood cancer survivors treated with haematopoietic stem cell transplantation (HSCT) and total body irradiation are at an increased risk of developing diabetes early in life due to insulin resistance and beta-cell dysfunction, but the optimal screening method is unknown. The National Institute for Health and Care Excellence guidelines for community diabetes screening recommend using fasting glucose >= 7 mmol/l and/or HbA1c >= 48 mmol/mol (6.5%) for diagnosis and, fasting glucose 5.5-6.9 mmol/l or HbA1c 42-47 mmol/mol (6 6.5%) to indicate high risk. This study aimed to evaluate the sensitivities of fasting glucose and HbA1c in the diagnosis of diabetes and impaired glucose tolerance in childhood HSCT survivors. METHOD: The patients were 35 (male = 19) HSCT survivors from a single UK centre under follow-up from 2006 to 2013. Patients had a median age (range) of 19.2 (13.1-26.2) years and had been treated for acute lymphoblastic (n = 31) or myeloid (n = 4) leukaemia when aged 7.8 (2.4 16.7) years. The outcome measures were oral glucose tolerance test (OGTT), fasting glucose and HbA1c . RESULTS: OGTT identified 6 patients with diabetes (120-min glucose >= 11.1 mmol/l), 12 with impaired glucose tolerance (120-min glucose 7.8-11.0 mmol/l) and 2 with impaired fasting glucose (>= 7 mmol/l). Fasting glucose >= 7 mmol/l or HbA1c >= 48 mmol/mol identified two of the six patients with diabetes diagnosed on OGTT. Fasting glucose >= 5.5 mmol/l and HbA1c >= 42 mmol/mol identified three and two patients, respectively, with diabetes. Only 1 of 12 patients with impaired glucose tolerance had a fasting glucose >= 5.5 mmol/l and none had HbA1c >= 42 mmol/mol (>= 6%). CONCLUSIONS: The fasting glucose and HbA1c cut-offs used in UK population screening only identified one third of HSCT survivors with diabetes and do not identify those at risk. Diabetes screening in HSCT survivors requires standard OGTTs. PMID- 26757411 TI - Direct Monitoring of the Reaction between Photochemically Generated Nitric Oxide and Mycobacterium tuberculosis Truncated Hemoglobin N Wild Type and Variant Forms: An Assessment of Computational Mechanistic Predictions. AB - The previously reported nitric oxide precursor [Mn(PaPy2Q)NO]ClO4 (1), where (PaPy2QH) is N,N-bis(2-pyridylmethyl)-amine-N-ethyl-2-quinoline-2-carboxamide, was used to investigate the interaction between NO and the protein truncated hemoglobin N (trHbN) from the pathogen Mycobacterium tuberculosis. Oxy-trHbN is exceptionally efficient at converting NO to nitrate, with a reported rate constant of 7.45 * 10(8) M(-1) s(-1) [Ouellet, H., et al. (2002) Proc. Natl. Acad. Sci. U.S.A. 99, 5902] compared to 4 * 10(7) M(-1) s(-1) for oxy-myoglobin [Eich, R. F., et al. (1996) Biochemistry 35, 6976]. This work analyzed the NO dioxygenation kinetics of wild type oxy-trHbN and a set of variants, as well as the nitrosylation kinetics for the reduced (red-trHbN) forms of these proteins. The NO dioxygenation reaction was remarkably insensitive to mutations, even within the active site, while nitrosylation was somewhat more sensitive. Curiously, the most profound change to the rate constant for nitrosylation was effected by deletion of a 12-amino acid dangling N-terminal sequence. The deletion mutant exhibited first-order kinetics with respect to NO but was zero order with respect to protein concentration; by contrast, all other variants exhibited second-order rate constants of >10(8) M(-1) s(-1). trHbN boasts an extensive tunnel system that connects the protein exterior with the active site, which is likely the main contributor to the protein's impressive NO dioxygenation efficiency. The results herein suggest that N-terminal deletion abolishes a large scale conformational motion, in the absence of which NO can still readily enter the tunnel system but is then prevented from binding to the heme for an extended period of time. PMID- 26757406 TI - Fit for the Eye: Aptamers in Ocular Disorders. AB - For any new class of therapeutics, there are certain types of indications that represent a natural fit. For nucleic acid ligands in general, and aptamers in particular, the eye has historically been an attractive site for therapeutic intervention. In this review, we recount the discovery and early development of three aptamers designated for use in ophthalmology, one approved (Macugen), and two in late-stage development (Fovista and Zimura). Every one of these molecules was originally intended for other indications. Key improvements in technology, specifically with regard to libraries used for in vitro selection and subsequent chemical optimization of aptamers, have played an important role in allowing the identification of development candidates with suitable properties. The lessons learned from the selection of these molecules are valuable for informing us about the many remaining opportunities for aptamer-based therapeutics in ophthalmology as well as for identifying additional indications for which aptamers as a class of therapeutics have distinct advantages. PMID- 26757412 TI - Optimization and modeling for the synthesis of sterol esters from deodorizer distillate by lipase-catalyzed esterification. AB - In this paper, cotton seed oil deodorizer distillate (CSODD), was recovered to obtain fatty acid sterol ester (FASE), which is one of the biological activated substances added as human therapeutic to lower cholesterol. Esterification reactions were carried out using Candida rugosa lipase as a catalyst, and the conversion of phytosterol was optimized using response surface methodology. The highest conversion (90.8 +/- 0.4%) was reached at 0.84 wt% enzyme load, 1:25 solvent/CSODD mass ratio, and 44.2 degrees C after 12 H reaction. A kinetic model based on the reaction rate equation was developed to describe the reaction process. The activation energy of the reaction was calculated to be 56.9 kJ/mol and the derived kinetic parameters provided indispensable basics for further study. The optimization and kinetic research of synthesizing FASE from deodorizer distillate provided necessary information for the industrial applications in the near future. Experimental results showed that the proposed process is a promising alternative to recycle sterol esters from vegetable oil deodorizer distillates in a mild, efficient, and environmental friendly method. PMID- 26757410 TI - Physicians' recognition of death in the foreseeable future in patients with intellectual disabilities. AB - BACKGROUND: Physicians are increasingly confronted with people with intellectual disabilities (ID) who are facing life-threatening diseases. We aimed to explore when and based on which information sources and signals physicians recognised that a patient with ID would die in the foreseeable future. Insights may help in identifying patients in need of palliative care. METHOD: In this study, 81 physicians for people with ID and 16 general practitioners completed a retrospective survey about their last case of a patient with ID with a non-sudden death. RESULTS: More than 20% of all physicians foresaw death not until the last week of life. In 30% of all patients, the physician did not discuss the start of the palliative care phase until the last week. The most reported information sources based on which physicians foresaw death were the physicians themselves and professional caregivers. We found 40 different signals that lead to physicians' foreseeing death. These were not only medical signals but also behavioural and physical signals. CONCLUSIONS: Results indicate that the physicians' ability to foresee death is a result of a process of growing awareness in which multiple signals from different information sources converge. This demands continuous multi-disciplinary communication because people involved have their own unique interactions with the patient and can therefore contribute to a growing and timely awareness of patients' death in the future. PMID- 26757415 TI - Clinical News. PMID- 26757414 TI - Attention-dependent sound offset-related brain potentials. AB - When performing sensory tasks, knowing the potentially occurring goal-relevant and irrelevant stimulus events allows the establishment of selective attention sets, which result in enhanced sensory processing of goal-relevant events. In the auditory modality, such enhancements are reflected in the increased amplitude of the N1 ERP elicited by the onsets of task-relevant sounds. It has been recently suggested that ERPs to task-relevant sound offsets are similarly enhanced in a tone-focused state in comparison to a distracted one. The goal of the present study was to explore the influence of attention on ERPs elicited by sound offsets. ERPs elicited by tones in a duration-discrimination task were compared to ERPs elicited by the same tones in not-tone-focused attentional setting. Tone offsets elicited a consistent, attention-dependent biphasic (positive-negative- P1-N1) ERP waveform for tone durations ranging from 150 to 450 ms. The evidence, however, did not support the notion that the offset-related ERPs reflected an offset-specific attention set: The offset-related ERPs elicited in a duration discrimination condition (in which offsets were task relevant) did not significantly differ from those elicited in a pitch-discrimination condition (in which the offsets were task irrelevant). Although an N2 reflecting the processing of offsets in task-related terms contributed to the observed waveform, this contribution was separable from the offset-related P1 and N1. The results demonstrate that when tones are attended, offset-related ERPs may substantially overlap endogenous ERP activity in the postoffset interval irrespective of tone duration, and attention differences may cause ERP differences in such postoffset intervals. PMID- 26757413 TI - Cathepsin L inactivation leads to multimodal inhibition of prostate cancer cell dissemination in a preclinical bone metastasis model. AB - It is estimated that approximately 90% of patients with advanced prostate cancer develop bone metastases; an occurrence that results in a substantial reduction in the quality of life and a drastic worsening of prognosis. The development of novel therapeutic strategies that impair the metastatic process and associated skeletal adversities is therefore critical to improving prostate cancer patient survival. Recognition of the importance of Cathepsin L (CTSL) to metastatic dissemination of cancer cells has led to the development of several CTSL inhibition strategies. The present investigation employed intra-cardiac injection of human PC-3ML prostate cancer cells into nude mice to examine tumor cell dissemination in a preclinical bone metastasis model. CTSL knockdown confirmed the validity of targeting this protease and subsequent intervention studies with the small molecule CTSL inhibitor KGP94 resulted in a significant reduction in metastatic tumor burden in the bone and an improvement in overall survival. CTSL inhibition by KGP94 also led to a significant impairment of tumor initiated angiogenesis. Furthermore, KGP94 treatment decreased osteoclast formation and bone resorptive function, thus, perturbing the reciprocal interactions between tumor cells and osteoclasts within the bone microenvironment which typically result in bone loss and aggressive growth of metastases. These functional effects were accompanied by a significant downregulation of NFkappaB signaling activity and expression of osteoclastogenesis related NFkappaB target genes. Collectively, these data indicate that the CTSL inhibitor KGP94 has the potential to alleviate metastatic disease progression and associated skeletal morbidities and hence may have utility in the treatment of advanced prostate cancer patients. PMID- 26757416 TI - Brexpiprazole for the Treatment of Schizophrenia: A Review of this Novel Serotonin-Dopamine Activity Modulator. AB - Brexpiprazole is an antipsychotic medication and received approval by the U.S. Food and Drug Administration for the treatment of schizophrenia in July 2015. Brexpiprazole acts as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A and at adrenergic alpha1B and alpha2C receptors. Compared with aripiprazole, brexpiprazole is more potent at 5 HT1A receptors and displays less intrinsic activity at D2 receptors. The recommended dose range of brexpiprazole for the treatment of schizophrenia is 2-4 mg/day; the recommended titration schedule is to start with 1 mg/day and increase to 2 mg/day on Day 5 to Day 7, then to 4 mg/day on Day 8. Two positive, 6-week, Phase 3 randomized controlled trials in acute schizophrenia demonstrated superiority of brexpiprazole over placebo. Pooled responder rates were 46% for brexpiprazole 2-4 mg/day vs. 31% for placebo, resulting in a number needed to treat (NNT) of 7. In a 52-week, randomized withdrawal study, significantly fewer patients relapsed in the brexpiprazole group compared with placebo (13.5% vs. 38.5%), resulting in an NNT of 4. The most commonly encountered adverse event (incidence >=4% and at least twice the rate of placebo) is increased weight. Short-term weight gain appears modest (approximately 10% of patients receiving brexpiprazole 1-4 mg/day gained >=7% body weight from baseline, compared with 4% for those randomized to placebo, resulting in a number needed to harm [NNH] of 17); however, more outliers with an increase of >=7% of body weight were evident in open-label, 52-week safety studies. Effects on glucose and lipids were small. Rates of akathisia as an adverse event were 5.5% for the pooled doses of brexpiprazole 1-4 mg/day vs. 4.6% for placebo, yielding an NNH of 112. Minimal effects on prolactin were observed, and no clinically relevant effects on the ECG QTc interval were evident. Brexpiprazole is also approved as an adjunct medication for the treatment of major depressive disorder. Phase 3 trials are ongoing in patients with agitation associated with Alzheimer's disease. PMID- 26757418 TI - Simulation and Experimental on the Solvation Interaction between the GAP Matrix and Insensitive Energetic Plasticizers in Solid Propellants. AB - Multimethods of simulation and experiment have been performed to investigate the interaction between glycidyl azide polymer (GAP) matrix and insensitive energetic plasticizers N-butyl-N-(2-nitroxy-ethyl)nitramine (Bu-NENA) and bis(2,2 dinitropropyl)formal/acetal (BDNPF/A). To start with, the blending energy distribution and Huggins parameters have been calculated, indicating fine miscibility between the GAP matrix and both plasticizers. The solubility parameter and binding energies show better compatibility between Bu-NENA and the GAP matrix than BDNPF/A, owing to stronger interactions. The interaction mechanism includes both hydrogen bonds and van der Waals forces. The low field NMR physical cross-link density and dynamic rheological behaviors imply larger disentanglement effect of Bu-NENA in the GAP matrix. The dynamic mechanical performance of elastomers show lower glass transition temperature of GAP/Bu-NENA blends, as supportive proof of stronger interactions between the GAP matrix and Bu-NENA in comparison with BDNPF/A. PMID- 26757417 TI - Identification of germline alterations in breast cancer predisposition genes among Malaysian breast cancer patients using panel testing. AB - Although an association between protein-truncating variants and breast cancer risk has been established for 11 genes, only alterations in BRCA1, BRCA2, TP53 and PALB2 have been reported in Asian populations. Given that the age of onset of breast cancer is lower in Asians, it is estimated that inherited predisposition to breast cancer may be more significant. To determine the potential utility of panel testing, we investigated the prevalence of germline alterations in 11 established and 4 likely breast cancer genes in a cross-sectional hospital-based cohort of 108 moderate to high-risk breast cancer patients using targeted next generation sequencing. Twenty patients (19%) were identified to carry deleterious mutations, of whom 13 (12%) were in the BRCA1 or BRCA2, 6 (6%) were in five other known breast cancer predisposition genes and 1 patient had a mutation in both BRCA2 and BARD1. Our study shows that BRCA1 and BRCA2 account for the majority of genetic predisposition to breast cancer in our cohort of Asian women. Although mutations in other known breast cancer genes are found, the functional significance and breast cancer risk have not yet been determined, thus limiting the clinical utility of panel testing in Asian populations. PMID- 26757419 TI - Photo-Cross-Linked Scaffold with Kartogenin-Encapsulated Nanoparticles for Cartilage Regeneration. AB - The regeneration of cartilage, an aneural and avascular tissue, is often compromised by its lack of innate abilities to mount a sufficient healing response. Kartogenin (KGN), a small molecular compound, can induce bone marrow derived mesenchymal stem cells (BMSCs) into chondrocytes. The previous in vitro study showed that kartogenin also had a chondrogenesis effect on synovium derived mesenchymal stem cells (SMSCs). Herein, we present the effect of an ultraviolet reactive, rapidly cross-linkable scaffold integrated with kartogenin-loaded nanoparticles using an innovational one-step technology. In vivo studies showed its potential role for cell homing, especially for recruiting the host's endogenous cells, including BMSCs and SMSCs, without cell transplantation. Of note, the regenerated tissues were close to the natural hyaline cartilage based on the histological tests, specific markers analysis, and biomechanical tests. This innovative KGN release system makes the chondrogenesis efficient and persistent. PMID- 26757420 TI - Goose-neck snare-assisted transcatheter ASD closure: A safety procedure for large and complex ASDs. AB - OBJECTIVE: To report on a new technique that increases the safety of percutaneous atrial septal defect (ASD) closure using a goose-neck snare system. BACKGROUND: ASD transcatheter closure is a widespread procedure. However, in some cases, ASDs may be large and with soft rims. In these situation, a potential risk exists for device malposition or embolization. METHODS: When transesophageal echocardiography (TEE) evaluation and balloon sizing showed large defects with floppy rims the chosen Amplatzer device was implanted in a standard way. In large defects with floppy rims, before release a 5-mm goose-neck snare with its 4 Fr catheter was placed across the delivery cable and fixed to catch the screwing mechanism of implanted Amplatzer device. The delivery cable was unscrewed and the device reached its final position without any tension. If the position was considered satisfactory the device was released from the goose-neck snare. RESULTS: Thirteen patients had a snare-assisted ASD transcatheter closure. Median device size was 24 mm (range 14-38 mm). Retrieval or repositioning of the device using the goose-neck snare was performed in four cases: in three patients, because of device malposition after delivery cable release and in one patient, because of unsuitability of closure of a second significant defect. Furthermore, in two subjects with multiple ASDs, a second fenestration looked quite significant with the device still attached to the delivery cable while it appeared smaller after release. CONCLUSIONS: Snare-assisted Amplatzer ASD device placement is a new method for ASD percutaneous closure and adds safety to the procedure. PMID- 26757421 TI - c-Rel and its many roles in cancer: an old story with new twists. AB - When the genes encoding NF-kappaB subunits were first isolated, their homology to the previously identified c-Rel proto-oncogene and its viral homologue v-Rel was clear. This provided the first indication that these transcription factors also had a role in cancer. Because of its homology to v-Rel, which transforms chicken B cells together with the important role c-Rel can have as a regulator of B- and T-cell proliferation, most attention has focussed on its role in B-cell lymphomas, where the REL gene is frequently amplified. However, a growing number of reports now indicate that c-Rel has important functions in many solid tumours, although studies in mice suggest it may not always function as an oncogene. Moreover, c-Rel is a critical regulator of fibrosis, which provides an environment for tumour development in many settings. Overall, c-Rel is emerging as a complex regulator of tumorigenesis, and there is still much to learn about its functions in human malignancies and the response to cancer therapies. PMID- 26757423 TI - Supplemental folic acid in pregnancy and childhood cancer risk. AB - BACKGROUND: We investigated the association between supplemental folic acid in pregnancy and childhood cancer in a nation-wide study of 687 406 live births in Norway, 1999-2010, and 799 children diagnosed later with cancer. METHODS: Adjusted hazard ratios (HRs) compared cancer risk in children by approximated periconceptional folic acid levels (folic acid tablets and multivitamins (0.6 mg), only folic acid (0.4 mg), only multivitamins (0.2 mg)) and cancer risk in unexposed. RESULTS: Any folic acid levels were not associated with leukemia (e.g., high-level folic acid HR 1.25; 95% CI 0.89-1.76, PTrend 0.20), lymphoma (HR 0.96; 95% CI 0.42-2.21, PTrend 0.51), central nervous system tumours (HR 0.68; 95% CI 0.42-1.10, PTrend 0.32), neuroblastoma (HR 1.05; 95% CI 0.53-2.06, PTrend 0.85), Wilms' tumour (HR 1.16; 95% CI 0.52-2.58, PTrend 0.76), or soft tissue tumours (HR 0.77; 95% CI 0.34-1.75, PTrend 0.90). CONCLUSIONS: Folic acid supplementation was not associated with risk of major childhood cancers. PMID- 26757422 TI - Clinical verification of sensitivity to preoperative chemotherapy in cases of androgen receptor-expressing positive breast cancer. AB - BACKGROUND: Triple-negative breast cancer (TNBC) patients testing positive for androgen receptor (AR) expression are thought to be chemotherapy resistant, similar to other hormone receptor-positive breast cancers; however, this has not been substantially validated in the clinic. In this study, we investigated the association between chemotherapy sensitivity and AR expression in patients treated with neoadjuvant chemotherapy (NAC) using standardised chemotherapy criteria and regimens. METHODS: A total of 177 patients with resectable early stage breast cancer were treated with NAC. Oestrogen receptor, progesterone receptor, HER2, Ki67 and AR status were assessed immunohistochemically. RESULTS: Sixty-one patients were diagnosed with TNBC; AR expression was identified in 23 (37.7%), which was significantly less common than that found in non-TNBC patients (103 of 116; 88.8%; P<0.001). The rate of pathological complete response after NAC was significantly lower (P=0.001), and disease recurrence was more common (P=0.008) in patients with AR-positive compared with those with AR-negative TNBC. In TNBC cases, as expected, the non-recurrence period in cases that were negative for AR expression was significantly extended (P=0.006, log-rank). CONCLUSIONS: Androgen receptor expressions may be useful as biomarkers to predict treatment responses to NAC in TNBC. Moreover, induction of a change in subtype to the AR negative phenotype was observed after NAC. PMID- 26757425 TI - Male pattern baldness and risk of colorectal neoplasia. AB - BACKGROUND: Male pattern baldness is positively associated with androgens as well as insulin-like growth factor 1 (IGF-1) and insulin, all of which are implicated in pathogenesis of colorectal neoplasia. METHODS: From 1992 through 2010, we prospectively followed participants in the Health Professionals Follow-Up Study. Hair pattern at age 45 years was assessed at baseline with five image categories (no baldness, frontal-only baldness, frontal-plus-mild-vertex baldness, frontal plus-moderate-vertex baldness, and frontal-plus-severe-vertex baldness). Cancer analysis included 32 782 men and used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Restricted to men who underwent at least one endoscopy over the study period, adenoma analysis included 29 770 men and used logistic regressions for clustered data to estimate odds ratios (ORs) and 95% CIs. RESULTS: Over the mean follow-up of 15.6 years, 710 cases of colorectal cancer (478 for colon, 152 for rectum, and 80 unknown site) developed. Significantly increased risks associated with frontal-only baldness and frontal-plus-mild-vertex baldness relative to no baldness were observed for colon cancer with respective HR being 1.29 (95% CI, 1.03-1.62) and 1.31 (95% CI, 1.01-1.70). Over the 19-year study period, 3526 cases of colorectal adenoma were detected. Evidence for an increased risk of colorectal adenoma relative to no baldness was significant with frontal-only baldness (OR, 1.16; 95% CI, 1.06-1.26) and borderline insignificant with frontal-plus-severe-vertex baldness (OR, 1.14; 95% CI, 0.98-1.33). CONCLUSIONS: Subtypes of male pattern baldness at age 45 years were positively associated with colorectal neoplasia. Future studies are warranted to confirm our results and to determine the predictive value of male pattern baldness to identify those at high risk for colorectal neoplasia. PMID- 26757424 TI - Employment and social benefits up to 10 years after breast cancer diagnosis: a population-based study. AB - BACKGROUND: Little is known about employment outcomes after breast cancer (BC) beyond the first years after treatment. METHODS: Employment outcomes were compared with a general population comparison group (N=91 593) up to 10 years after BC for 26 120 patients, diagnosed before age 55 between 2000-2005, with income and social benefits data from Statistics Netherlands. Treatment effects were studied in 14 916 patients, with information on BC recurrences and new cancer events. RESULTS: BC survivors experienced higher risk of losing paid employment (Hazard Ratio (HR): 1.6, 95% Confidence Interval (95% CI) 1.4-1.8) or any work-related event up to 5-7 years (HR 1.5, 95% CI 1.3-1.6) and of receiving disability benefits up to 10 years after diagnosis (HR 2.0, 95% CI 1.6-2.5), with higher risks for younger patients. Axillary lymph node dissection increased risk of disability benefits (HR 1.5, 95% CI 1.4-1.7) or losing paid employment (HR 1.3, 95% CI 1.2-1.5) during the first 5 years of follow-up. Risk of disability benefits was increased among patients receiving mastectomy and radiotherapy (HR 1.2; 95% CI 1.1-1.3) and after chemotherapy (HR 1.7; 95% CI 1.5-1.9) during the first 5 years after diagnosis. CONCLUSIONS: BC treatment at least partly explains the increased risk of adverse employment outcomes up to 10 years after BC. PMID- 26757426 TI - Effect of Ultrastructure on Changes of Textural Characteristics between Crisp Grass Carp (Ctenopharyngodon Idellus C.Et V) and Grass Carp (Ctenopharyngodon Idellus) Inducing Heating Treatment. AB - The research studies the ultrastructure effect on texture of crisp grass carp (CGC) and grass carp (GC) fillets inducing heating for 15, 25, and 40 min with boiling water. After heating, the hardness, fracturability, springiness, chewiness, resilience, and cohesiveness of CGC were higher than that of raw CGC, whereas the all textural characteristics of heating GC were lower obviously than that of raw GC. The hardness, fracturability, springiness, chewiness, resilience, and cohesiveness of CGC for heating 15 min were higher by 6.3%, 9.0%, 27.0%, 71.8%, 9.4%, and 23.9%, respectively, than that of raw CGC (RCGC). The hardness increasing of CGC flesh with the extension of heating time related closely to more coagulating connective tissue in interstitial spaces, especially relating to smaller muscle fiber diameter and denser muscle fiber density. The more and larger spaces between fiber and fiber with the extension of heating time results in the decrease of cohesiveness and resilience of CGC flesh. For chewiness, the stronger chewiness of cooked CGC associated with more detachment of myofiber myocommata and fiber-fiber. Overall, the results show that the changes of texture characteristics of CGC fillet with extension of heating time correlates positively with the ultrastructure. PMID- 26757427 TI - N-acetylcysteine for non-paracetamol drug-induced liver injury: a systematic review. AB - AIMS: N-acetylcysteine (NAC) may be useful in the management of non-paracetamol drug-induced liver injury (DILI). Our objective was to review systematically evidence for the use of NAC as a therapeutic option for non-paracetamol DILI. METHODS: We searched for randomized controlled trials (RCTs) and prospective cohort studies. We searched several bibliographic databases, grey literature sources, conference proceedings and ongoing trials. Our pre-specified primary outcomes were all cause and DILI related mortality, time to normalization of liver biochemistry and adverse events. Secondary outcomes were proportion receiving liver transplant, time to transplantation, transplant-free survival and hospitalization duration. RESULTS: We identified one RCT of NAC vs. placebo in patients with non-paracetamol acute liver failure. There was no difference in the primary outcomes of overall survival at 3 weeks between NAC [70%, 95% confidence interval (CI) = 60%, 81%, n = 81] and placebo (66%, 95% CI = 56%, 77%, n = 92). NAC significantly improved the secondary outcomes of transplant-free survival compared with placebo: 40% NAC (95% CI = 28%, 51%) vs. 27% placebo (95% CI = 18%, 37%). A subgroup analysis according to aetiology found improved transplant-free survival in patients with non-paracetamol DILI, NAC (58%, n = 19) vs. placebo (27%, n = 26), odds ratio (OR) 0.27 (95% CI = 0.076, 0.942). Overall survival was similar, NAC (79%) vs. placebo (65%);, OR 0.50 (95% CI = 0.13, 1.98). CONCLUSION: Current available evidence is limited and does not allow for any firm conclusions to be made regarding the role of NAC in non-paracetamol DILI. We therefore highlight the need for further research in this area. PMID- 26757428 TI - Preconditioning is hormesis part I: Documentation, dose-response features and mechanistic foundations. AB - This article provides the first extensive documentation of the dose response features of pre- and postconditioning. Pre- and postconditioning studies with rigorous study designs, using multiple doses/concentrations along with refined dose/concentration spacing strategies, often display hormetic dose/concentration response relationships with considerable generality across biological model, inducing (i.e., conditioning) agent, challenging dose treatment, endpoint, and mechanism. Pre- and postconditioning hormesis dose/concentration-response relationships are reported for 154 diverse conditioning agents, affecting more than 550 dose/concentration responses, across a broad range of biological models and endpoints. The quantitative features of the pre- and postconditioning-induced protective responses are modest, typically being 30-60% greater than control values at maximum, findings that are consistent with a large body (>10,000) of hormetic dose/concentration responses not related to pre- and postconditioning. Regardless of the biological model, inducing agent, endpoint or mechanism, the quantitative features of hormetic dose/concentration responses are similar, suggesting that the magnitude of response is a measure of biological plasticity. This paper also provides the first documentation that hormetic effects account for preconditioning induced early (1-3h) and delayed (12-72h) windows of protection. These findings indicate that pre- and postconditioning are specific types of hormesis. PMID- 26757430 TI - Difference in appearance between prone and supine myocardial perfusion images obtained on a high-efficiency cadmium zinc telluride SPECT camera. AB - OBJECTIVE: The recent introduction of high-efficiency solid-state gamma cameras for myocardial perfusion single photon emission computed tomography has enabled lower patient radiation dose, faster imaging, and improved image quality. However, artifacts still complicate interpretation. Prone imaging is a common maneuver to reduce artifacts and increase accuracy for detection of coronary artery disease, but its effect on imaging relative to supine imaging has not been fully characterized in these new systems. METHODS: In this IRB-approved, HIPAA compliant retrospective study, 30 patients were reviewed, who underwent prone and supine imaging on the GE 530c multipinhole cadmium zinc telluride camera under both rest and stress conditions. Informed consent was waived. Perfusion was scored visually by two readers on a five-point scale according to the 17-segment model. Differences were assessed for significance using a multivariate linear effects model and restricted maximum likelihood method. RESULTS: Prone positioning resulted in increased activity in the basal inferior (P<0.001), basal inferolateral (P=0.009), basal inferoseptal (P<0.001), and mid-inferior (P<0.001) segments when taking into account factors such as stress versus rest, perfusion scores of other segments, and reader. CONCLUSION: Prone imaging on the GE 530c camera increases measured tracer activity in the basal inferior, basal inferolateral, basal inferoseptal, and mid-inferior segments. Caution is advised when diagnosing myocardial ischemia in these territories, particularly if clinical data are unavailable. PMID- 26757429 TI - Post-fertilization effect of bilateral primary testicular damage induced by unilateral cryptorchidism in the rat model. AB - Cryptorchidism, a common anomaly of the male genitalia, affects 2-4% of male infants. The post-fertilization effects of unilateral cryptorchidism model in the rat and the effects of antioxidant treatment were investigated. Six-week-old male Wistar rats were randomly separated into four groups. Unilateral cryptorchidism was induced in the right testis of three groups. One group was treated with saline intraperitoneally (i.p.) (Crypto), one group was treated with taurine (500 mg/kg, i.p.; Tau), and another group was treated with sivelestat (15 mg/kg i.p.; Siv). The control group was treated with saline i.p. The treatment was daily for 8 weeks. Five days before sacrifice, mating studies were performed. Body, testicular, and epididymal weights were recorded. Malondialdehyde (MDA) levels in the seminal vesicular fluid (SVF) were measured. Testicular levels of MDA and 8 hydroxy-2'-deoxyguanosine (8-OHdG) were determined bilaterally. TUNEL assay was used to examine DNA fragmentation bilaterally. Histological examination and the Johnsen score were used to evaluate morphological testicular alterations. The Crypto group demonstrated significantly lower right testicular and epididymal weights, significantly increased SVF-MDA levels, testicular MDA and 8-OHdG levels, and the apoptotic score bilaterally compared to the controls. Furthermore, histological evaluation revealed significantly reduced spermatogenesis and mild injury to the cryptorchid testes compared to the control. Treatment with both taurine and sivelestat significantly reduced SVF-MDA levels, testicular MDA, 8-OHdG, and apoptosis bilaterally compared to the Crypto group. Antioxidant treatment was unable to ameliorate spermatogenesis. Newborns delivered by females that mated with Crypto-males had significantly lower body weight compared with the respective animals from the control, Tau and Siv groups. The present study demonstrated that unilateral cryptorchidism-induced testicular damage can significantly affect the contralateral testis as well having further deleterious post-fertilization effect on the development of newborns. Treatment with antioxidants can partially improve the testicular damage bilaterally with beneficial effects for the newborns. PMID- 26757434 TI - Primary Debulking Surgery Versus Neoadjuvant Chemotherapy in Advanced Epithelial Ovarian Cancer: A Propensity-matched Analysis. AB - AIMS: To compare the surgical and survival outcomes of patients undergoing primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT) plus interval debulking surgery (IDS) for advanced epithelial ovarian cancer (EOC). MATERIALS AND METHODS: Consecutive patients managed for advanced EOC since 2009 were matched through a propensity score analysis, defined as the probability of a woman having PDS or NACT plus IDS. RESULTS: The study group consisted of 100 propensity-matched women receiving PDS or NACT plus IDS. Groups resulted homogeneous in terms of baseline characteristics and pathologic findings. Patients undergoing PDS had longer operative time (P=0.032) and more blood loss (P=0.011) than the counterpart receiving NACT. No differences were found in terms of residual disease (P=0.11), as well as in terms of hospitalization, intraoperative, and postoperative complications. The mean progression-free survival was 23.0 and 27.7 months (P=0.67), whereas the overall survival (OS) was 44.5 and 43.2 months (P=0.48) for the PDS and NACT plus IDS group, respectively. Residual disease (P<0.0001) was the only independent predictor of progression free and OS at multivariate analysis. CONCLUSIONS: PDS and NACT plus IDS achieved comparable results in terms of progression-free and OS in patients with advanced EOC. PMID- 26757432 TI - The relationship between EMT, CD44high /EGFRlow phenotype, and treatment response in head and neck cancer cell lines. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) tumors are often therapy resistant and may originate from cancer stem cells or tumor cells with an epithelial-to-mesenchymal transition (EMT) phenotype. The aim of this study was to characterize HNSCC cell lines with regard to EMT profile and to investigate the influence of EMT on the response to treatment. METHODS: mRNA expression of the EMT-associated genes CDH1 (E-cadherin), CDH2 (N-cadherin), FOXC2, TWIST1, VIM (vimentin), and FN1 (fibronectin) was determined using quantitative real-time PCR. Cell morphology and migration were investigated by phase-contrast microscopy and Boyden chamber assay, respectively. The cell surface expression of CD44 and epidermal growth factor receptor (EGFR) was examined by flow cytometry. The response to radiotherapy, cetuximab, and dasatinib was assessed by crystal violet staining. RESULTS: A total of 25 cell lines investigated differed greatly with regard to EMT phenotype. Cell lines with an EMT expression profile showed a mesenchymal morphology and a high migratory capacity. In addition, they exhibited a high cell surface expression of CD44 and a low expression of EGFR, a pattern previously associated with stemness. When the EMT inducer transforming growth factor-beta (TGF-beta) was added to non-EMT cells, changes in treatment responses were observed. Moreover, the expression of TWIST1 was found to correlate with radioresistance. CONCLUSIONS: The data presented in this report suggest that EMT is associated with a CD44high /EGFRlow phenotype and possibly negative impact on radiotherapy response in HNSCC cell lines. PMID- 26757435 TI - Breast Cancer is Common in Women With Ovarian Malignant Mixed Mullerian Tumors. AB - BACKGROUND: Ovarian malignant mixed Mullerian tumors (MMMTs) are uncommon cancers. The purpose of the study was to determine the rate of metachronous or synchronous breast cancer as well as the rate of truncating germline BRCA1 and/or BRCA2 mutations in a series of women with these uncommon tumors. MATERIALS AND METHODS: Records were reviewed to identify all women with MMMTs treated by the gynecologic oncology service. The stage, grade, histology, survival, and rate of coexistent breast cancer were determined. Tumor and/or peripheral blood was tested for BRCA1 and BRCA2 truncating mutations. RESULTS: Twenty-four patients with MMMTs were found. Tumor and paired peripheral blood was available on 20 patients and 4 more patients had only peripheral blood available. Family pedigrees were available on all 24 patients. Fifteen of 24 (62.5%) patients were found to have metachronous or synchronous breast cancers with 9 of 15 (60%) having bilateral breast cancer. No BRCA1 or BRCA2 mutations were found (somatic or germline) in this cohort. CONCLUSIONS: Although an uncommon tumor, MMMTs are often found in women with breast cancer. Despite this finding, BRCA1 or BRCA2 germline mutations are not common in this population. PRECIS: Ovarian MMMTs are frequently found in women with cancer but are not frequently associated with defects in BRCA1 or BRCA2. PMID- 26757431 TI - Placental Microparticles and MicroRNAs in Pregnant Women with Plasmodium falciparum or HIV Infection. AB - BACKGROUND: During pregnancy, syncytiotrophoblast vesicles contribute to maternal tolerance towards the fetus, but also to pathologies such as pre-eclampsia. The aim of the study was to address whether Plasmodium falciparum and HIV infections in pregnancy affect the secretion, microRNA content and function of trophoblast microparticles. METHODS: Microparticles were isolated and characterized from 122 peripheral plasmas of Mozambican pregnant women, malaria- and/or HIV-infected and non-infected. Expression of placenta-related microRNAs in microparticles was analysed by qPCR and the effect of circulating microparticles on dendritic cells assessed by phenotype analysis and cytokine/chemokine measurement. RESULTS: Concentrations of total and trophoblast microparticles detected by flow cytometry were higher in HIV-positive (P = 0.005 and P = 0.030, respectively) compared to non-infected mothers, as well as in women delivering low birthweight newborns (P = 0.032 and P = 0.021, respectively). miR-517c was overexpressed in mothers with placental malaria (P = 0.034), compared to non-infected. Microparticles from HIV positive induced a higher expression of MHCII (P = 0.021) and lower production of MCP1 (P = 0.008) than microparticles from non-infected women. CONCLUSIONS: In summary, alterations in total and trophoblast microparticles associated with malaria and HIV in pregnant women may have an immunopathogenic role. The potential for placental-derived vesicles and microRNAs as biomarkers of adverse outcomes during pregnancy and malaria infection should be confirmed in future studies. PMID- 26757436 TI - Albumin and Neutrophil-Lymphocyte Ratio (NLR) Predict Survival in Patients With Pancreatic Adenocarcinoma Treated With SBRT. AB - PURPOSE: To determine if pretreatment nutritional status and inflammatory markers correlate with survival in patients with locally advanced pancreatic adenocarcinoma treated with stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: We retrospectively reviewed 208 patients with newly diagnosed, locally advanced pancreatic adenocarcinoma treated with SBRT at our institution from 2002 to 2014. Laboratory values were collected before SBRT, including hemoglobin, platelets, albumin, red blood cell, white blood cell, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, and tumor markers CA 19-9 and CEA. Patients were followed every 3 months with computed tomography (CT) and/or positron emission tomography-CT imaging to monitor for local recurrence and overall survival (OS). RESULTS: Median follow-up after SBRT was 7.5 months (interquartile range, 4.6 to 12.0 mo) for all patients. Median OS for patients with NLR>5 compared with NLR<=5 was 6.9 and 8.5 months, respectively (P=0.0057). On univariate analysis, receipt of chemotherapy (P=0.05, hazard ratio [HR]=0.69), increased albumin (P=0.002, HR=0.64), increased red blood cell (P=0.05, HR=0.75), increased lymphocyte count (P=0.002, HR=0.66), decreased CEA (P=0.01, HR=0.96), and NLR<=5 (P=0.01, HR=0.65) correlated with improved OS. On multivariate analysis, higher albumin (P=0.03, HR=0.70), receipt of chemotherapy (P=0.007, HR=0.56), and NLR<=5 (P=0.02, HR=0.66) correlated with better survival. CONCLUSIONS: Preradiotherapy low albumin levels and NLR>5 correlate with decreased survival in patients with locally advanced pancreatic adenocarcinoma treated with SBRT, indicating the prognostic value of systemic inflammatory markers (such as NLR) and a role of nutritional supplementation to improve outcomes in these patients. Further investigation is warranted. PMID- 26757433 TI - Cerebral Correlates of Emotional and Action Appraisals During Visual Processing of Emotional Scenes Depending on Spatial Frequency: A Pilot Study. AB - Visual processing of emotional stimuli critically depends on the type of cognitive appraisal involved. The present fMRI pilot study aimed to investigate the cerebral correlates involved in the visual processing of emotional scenes in two tasks, one emotional, based on the appraisal of personal emotional experience, and the other motivational, based on the appraisal of the tendency to action. Given that the use of spatial frequency information is relatively flexible during the visual processing of emotional stimuli depending on the task's demands, we also explored the effect of the type of spatial frequency in visual stimuli in each task by using emotional scenes filtered in low spatial frequency (LSF) and high spatial frequencies (HSF). Activation was observed in the visual areas of the fusiform gyrus for all emotional scenes in both tasks, and in the amygdala for unpleasant scenes only. The motivational task induced additional activation in frontal motor-related areas (e.g. premotor cortex, SMA) and parietal regions (e.g. superior and inferior parietal lobules). Parietal regions were recruited particularly during the motivational appraisal of approach in response to pleasant scenes. These frontal and parietal activations, respectively, suggest that motor and navigation processes play a specific role in the identification of the tendency to action in the motivational task. Furthermore, activity observed in the motivational task, in response to both pleasant and unpleasant scenes, was significantly greater for HSF than for LSF scenes, suggesting that the tendency to action is driven mainly by the detailed information contained in scenes. Results for the emotional task suggest that spatial frequencies play only a small role in the evaluation of unpleasant and pleasant emotions. Our preliminary study revealed a partial distinction between visual processing of emotional scenes during identification of the tendency to action, and during identification of personal emotional experiences. It also illustrates flexible use of the spatial frequencies contained in scenes depending on their emotional valence and on task demands. PMID- 26757438 TI - A contribution for cost models in biobanking. AB - This paper is a contribution on financial sustainability of hospital biobanks and data warehouses for biospecimens. It aims to discuss new venues for cost models in addition to conventional cost recovery models. It follows the first paper issues on economics of biobanking by Huttin and Liebman, where adaptive platforms where already suggested for biobanks in translational medicine. A case study approach is proposed in order to identify the type of cost drivers that will be needed for optimization of resource allocation in hospital biobanks. It can help the collaboration with designers of ontologies for adaptive platforms, with new data elements on costs and their measurement in different organizational structures. PMID- 26757437 TI - Formulation, Pharmacokinetic, and Efficacy Studies of Mannosylated Self Emulsifying Solid Dispersions of Noscapine. AB - PURPOSE: To formulate hydroxypropyl methylcellulose-stabilized self-emulsifying solid dispersible carriers of noscapine to enhance oral bioavailability. METHODS: Formulation of noscapine (Nos) self-emulsifying solid dispersible microparticles (SESDs) was afforded by emulsification using an optimized formula of Labrafil M1944, Tween-80, and Labrasol followed by spray-drying with hydroxypropyl methylcellulose (HPMC), with and without mannosamine (Mann-Nos_SESDs and Nos_SESDs respectively); self-microemulsifying liquid dispersions (SMEDDs) with and without mannosamine (Mann-Nos_SMEDDs and Nos_SMEDDs respectively) were also prepared. SMEDDs and SESDs were characterized for size, polydispersity, surface charge, entrapment efficiency, in vitro permeability, in vitro release kinetics, and oral pharmacokinetics in Sprague-Dawley rats (10 mg/kg p.o). The antitumor efficacy of Mann-Nos_SESDs on the basis of chemosensitization to cisplatin (2.0 mg/kg, i.v.) was investigated in a chemorefractory lung tumor Nu/Nu mouse model up to a maximal oral dose of 300 mg/kg. RESULTS: The oil/surfactant/co-surfactant mixture of Labrafil M1944, Tween-80, and Labrasol optimized at weight ratios of 62.8:9.30:27.90% produced stable self-microemulsifying dispersions (SMEDDs) at a SMEDD to water ratio of 1-3:7-9 parts by weight. SMEDDs had hydrodynamic diameters between 231 and 246 nm; surface charges ranged from -16.50 to -18.7 mV; and entrapment efficiencies were between 32 and 35%. SESDs ranged in size between 5.84 and 6.60 MUm with surface charges from -10.62 to -12.40 mV and entrapment efficiencies of 30.96+/-4.66 and 32.05+/-3.72% (Nos_SESDs and Mann-Nos_SESDs respectively). Mann-Nos_SESDs exhibited saturating uptake across Caco-2 monolayers (Papp = 4.94+/-0.18 * 10(-6) cm/s), with controlled release of 50% of Nos in 6 hr at pH 6.8 following Higuchi kinetics. Mann-Nos_ SESDs was 40% more bioavailable compared to Nos_SESDs; and was effective in sensitizing H1650 SP cells to Cisplatin in vitro and in an orthotopic lung tumor model of H1650 SP origin. CONCLUSIONS: Mannosylated noscapine self-emulsifying solid dispersions (Mann-Nos_SESDs) are bioavailable and potentiate the antineoplastic effect of cisplatin-based chemotherapy in cisplatin-resistant NSCLC. PMID- 26757439 TI - Nintendo Wii assessment of Hoehn and Yahr score with Parkinson's disease tremor. AB - OBJECTIVE: Diagnosis of Parkinson's Disease (PD) by analyzing the resting tremor were much studied by using different accelerometer based methods, however the quantitative assessment of Hoehn and Yahr Scale (HYS) score with a machine learning based system has not been previously addressed. In this study, we aimed to propose a system to automatically assess the HYS score of patients with PD. METHODS: The system was evaluated and tested on a dataset containing 55 subjects where 35 of them were patients and 20 of them were healthy controls. The resting tremor data were gathered with the 3 axis accelerometer of the Nintendo Wii (Wiimote). The clinical disability of the PD was graded from 1 to 5 by the HYS and tremor was recorded twice from the more affected side in each patient and from the dominant extremity in each control for a 60 seconds period. The HYS scores were learned with Support Vector Machines (SVM) from the features of the tremor data. RESULTS: Thirty-two of the subjects with PD were classified correctly and 18 of the normal subjects were also classified correctly by our system. The system had average 0.89 accuracy rate (Range: 81-100% changing according to grading by HYS). CONCLUSIONS: We compared quantitative measurements of hand tremor in PD patients, with staging of PD based on accelerometer data gathered using the Wii sensor. Our results showed that the machine learning based system with simple features could be helpful for diagnosis of PD and estimate HYS score. We believed that this portable and easy-to-use Wii sensor measure might also be applicable in the continuous monitoring of the resting tremor with small modifications in routine clinical use. PMID- 26757440 TI - Dynamic mitral annular motion after posterior mitral annuloplasty: Use of a strip that is designed for placement in the posterior annulus. AB - BACKGROUND: Most annuloplasty rings and bands used for mitral valve repair restrict annular motion due to their fixation to the posterior annulus, the commissures, and the trigones. OBJECTIVE: Annular motion was evaluated after posterior mitral annuloplasty (PMA) for correction of mitral valve regurgitation (MR) using a strip that is designed for placement in the posterior annulus only, sparing the anterior annulus and both commissural angles. METHODS: Valve annular dynamics were analyzed in 51 patients who underwent PMA for MR. In 37 patients (72.5%), additional associated procedures were performed: new chord placement (n = 35), patch valvuloplasty (n = 4), and posterior leaflet augmentation (n = 12). Patients received serial echocardiographic follow-up. RESULTS: After PMA, the MR grade was nil or mild (0 and 1+) in 47 patients (92.1%), moderate (2+) in 3 patients (5.9%), and moderate to severe (3+) in 1 patient (2.0%). The maximum and minimum septo-lateral dimensions during the cardiac cycle were 21.7 +/- 4.8 mm and 18.1 +/- 4.1 mm (p < 0.0001), respectively, and the change ratios were 19.8 +/- 9.3%. While the septo-lateral dimensions exhibited dynamic changes, the aorto mitral dimensions remained constant throughout the cardiac cycle. CONCLUSIONS: PMA preserves dynamic septo-lateral motion of the mitral valve annulus during the cardiac cycle. PMID- 26757441 TI - Disk hernia and spondylolisthesis diagnosis using biomechanical features and neural network. AB - Artificial neural networks have found applications in various areas of medical diagnosis. The capability of neural networks to learn medical data, mining useful and complex relationships that exist between attributes has earned it a major domain in decision support systems. This paper proposes a fast automatic system for the diagnosis of disk hernia and spondylolisthesis using biomechanical features and neural network. Such systems as described within this work allow the diagnosis of new cases using trained neural networks; patients are classified as either having disk hernia, spondylolisthesis, or normal. Generally, both disk hernia and spondylolisthesis present similar symptoms; hence, diagnosis is prone to inter-misclassification error. This work is significant in that the proposed systems are capable of making fast decisions on such somewhat difficult diagnoses with reasonable accuracies. Feedforward neural network and radial basis function networks are trained on data obtained from a public database. The results obtained within this research are promising and show that neural networks can find applications as efficient and effective expert systems for the diagnosis of disk hernia and spondylolisthesis. PMID- 26757442 TI - Arthroscopic assisted mini-open approach of the hip: Early multicentric experience. AB - BACKGROUND: Surgical treatment of femoroacetabular impingement is becoming accepted worldwide, owing to improvements in clinical results and quality of life. In addition to treatment by surgical dislocation or arthroscopy, arthroscopic assisted mini-open approach was postulated to treat this pathology. OBJECTIVE: The aim of this study was to analyze early results of the first consecutive 72 cases of femoroacetabular impingement treated using the arthroscopic assisted mini-open approach in two different centers by two surgeons trained by a senior surgeon experienced in the technique. METHODS: Seventy-two consecutive cases of femoroacetabular impingement were operated in arthroscopic assisted mini-open approach technique in two different centers. After a mean follow-up time of 15 months (range 6-24 months), the Western Ontario and McMaster Universities Arthritis Index, Hip disability and Osteoarthritis Outcome Score and University of California, Los Angeles activity score, alpha angle and Wiberg angle were obtained. RESULTS: In both centers, all three scores showed significantly better results at follow-up time than preoperatively. The Western Ontario and McMaster Universities Arthritis Index increased from 64.3 to 91.4 (A) and from 68.1 to 89 (B). The Hip disability and Osteoarthritis Outcome Score increased from 59.5 to 94.4 (A) and from 62.1 to 93.8 (B). The University of California, Los Angeles activity score increased from 5.2 to 8.1 (A) and from 5.3 to 8.4 (B). The alpha angle and the Wiberg angle were significantly reduced after osteoplasty. The overall complication rate was low. CONCLUSIONS: Early results of this study show a good clinical and radiological outcome; therefore, the arthroscopic assisted mini-open approach can be used as an alternative in treating femoroacetabular impingement. PMID- 26757443 TI - Does BMI influence clinical outcomes after total knee arthroplasty? AB - INTRODUCTION: Obesity is a common problem in the western European countries. Since the association between obesity and the emergence of gonarthrosis is approved, it is more important to gain reliable information about this patient group. The aim of the present retrospective study is to evaluate clinical outcomes of German obese patients after total knee arthroplasty (TKA). PATIENTS AND METHODS: Between 2001 and 2009 a total of 199 patients with 230 TKA were included in the present study. The collective was divided into four groups in relation to their Body-Mass-Index (BMI); group 1: BMI < 25 kg/m2, n = 24; group 2: BMI 25-30 kg/m2, n = 80, group 3: BMI 30-40 kg/m2, n = 109; group 4: BMI> 40 kg/m2, n = 17. Clinical outcome measurement was scored postoperatively using the knee society score (KSS), hospital for special surgery score (HSS) and the visual analogue scale (VAS). Furthermore complications and subjective patient satisfaction were noted. RESULTS: We did not detect any significant differences in the clinical scores between the BMI-subgroups. However we measured statistically significant worse results in case of infection and instability in all BMI subgroups (p> 0.01). CONCLUSION: While infection and instability may have a negative influence for the clinical outcome, we did not detect any significant correlation between obesity and exiting complications. Obesity has no significant correlation to influence the outcome after TKA implantation negatively. PMID- 26757444 TI - A Mononuclear Co(II) Coordination Complex Locked in a Confined Space and Acting as an Electrochemical Water-Oxidation Catalyst: A "Ship-in-a-Bottle" Approach. AB - Preparing efficient and robust water oxidation catalyst (WOC) with inexpensive materials remains a crucial challenge in artificial photosynthesis and for renewable energy. Existing heterogeneous WOCs are mostly metal oxides/hydroxides immobilized on solid supports. Herein we report a newly synthesized and structurally characterized metal-organic hybrid compound [{Co3 (MU3 OH)(BTB)2(dpe)2} {Co(H2O)4(DMF)2}0.5]n ?n H2O(Co-WOC-1) as an effective and stable water-oxidation electrocatalyst in an alkaline medium. In the crystal structure of Co-WOC-1, a mononuclear Co(II) complex {Co(H2O)4(DMF)2}(2+) is encapsulated in the void space of a 3D framework structure and this translationally rigid complex cation is responsible for a remarkable electrocatalytic WO activity, with a catalytic turnover frequency (TOF) of 0.05 s(-1) at an overpotential of 390 mV (vs. NHE) in 0.1 m KOH along with prolonged stability. This host-guest system can be described as a "ship-in-a-bottle", and is a new class of heterogeneous WOC. PMID- 26757446 TI - Time to Douse the Firestorm Around Breast Cancer Screening. PMID- 26757445 TI - Improved Splenic Function After Hematopoietic Stem Cell Transplant for Sickle Cell Disease. AB - BACKGROUND: Splenic dysfunction is a significant complication of sickle cell disease (SCD). Hematopoietic stem cell transplant (HSCT) is a proven cure for SCD; however, its long-term effect on splenic function is not well characterized. PROCEDURE: We conducted a retrospective cohort study of pediatric patients who had HSCT for SCD at two transplant centers. (99m) Tc liver-spleen (LS) scans were blindly reviewed and classified as demonstrating absent, decreased, or normal splenic uptake. RESULTS: Considering all engrafted nonsplenectomized Hb SS and Sbeta(0) -thalassemia patients with LS scans available, at a median of 2.0 years post-HSCT (range 1.0-9.3 years) eight of 53 (15%) had normal, 40 of 53 (75%) decreased, and five of 53 (9%) absent splenic uptake. More patients had splenic uptake after HSCT: pre-HSCT 14/38 (37%) versus post-HSCT 34/38 (89%), P < 0.0001. Older age at HSCT was associated with worse splenic function post-HSCT (median age at HSCT for absent uptake 16.6 years vs. present uptake 8.0 years, P = 0.030). Extensive chronic GVHD was also more common in patients with absent splenic uptake compared to patients with present uptake (absent 40% vs. present 6%, P = 0.064). CONCLUSIONS: HSCT significantly improves splenic function for most pediatric patients with SCD, but older patient age at time of HSCT and extensive chronic GVHD appear to be risk factors for poor post-HSCT splenic function. PMID- 26757447 TI - Self-assembled biosensor with universal reporter and dual-quenchers for detection of unlabelled nucleic acids. AB - A novel biosensor with universal reporter and dual quenchers was developed for rapid, sensitive, selective, and inexpensive detection of unlabelled nucleic acids. The biosensor is based on a single-strand DNA stem-loop motif with an extended universal reporter-binding region, a G-base rich stem region, and a universal address-binding region. The self-assembly of these stem-loop probes with fluorescence labeled universal reporter and a universal address region conjugated to gold nanoparticles forms the basis of a biosensor for DNA or microRNA targets in solution. The introduction of dual quenchers (G-base quenching and gold surface plasmon resonance-induced quenching) significantly reduces the fluorescence background to as low as 12% of its original fluorescence intensity and hence enhances the detection limit to 0.01 picomoles without signal ampilication. PMID- 26757448 TI - Investigational drugs for autonomic dysfunction in Parkinson's disease. PMID- 26757449 TI - Abnormal movement-related suppression of sensory evoked potentials in upper limb dystonia. AB - BACKGROUND: Gating of sensory evoked potentials (SEPs) around the onset of a voluntary movement is a physiological phenomenon with centripetal and central components, and may reflect sensorimotor integration required for normal movement control. OBJECTIVE: Our objective was the investigation of SEP suppression at the onset of movement and the interaction between SEP suppression and vibration of the limb. METHODS: Fourteen patients with primary focal/segmental dystonia and 17 age-matched healthy volunteers were studied. SEPs were elicited after electrical stimulation of the median nerve at the wrist. Electroencephalograms (EEGs) were recorded over the scalp at three sites according to the International 10-20 System (F3, C3 and P3). SEPs were recorded in four conditions: at rest, at the onset of movement (a self-paced abduction movement of the right thumb), both in the absence and in the presence of vibration of the limb. RESULTS: Repeated measures anova revealed that there was a significant main effect of group [F(1, 11.1) = 0.471, P = 0.002]. Post hoc exploration of this effect revealed it to be due to an absence of SEP suppression at movement onset in patients (mean ratio SEP movement onset/rest 1.15 at F3, 1.13 at C3, 1.01 at P3) compared to controls, who had SEP suppression at movement onset (mean ratio SEP movement onset/rest 0.79 at F3, 0.78 at C3, 0.77 at P3). With vibration, SEP suppression reduced in both patients and controls to a similar extent. CONCLUSION: These results demonstrate abnormal SEP suppression at the onset of movement in patients with primary dystonia, and in addition that vibration of the limb reduces SEP suppression in patients and controls. PMID- 26757451 TI - "A Montrouge"--Rosa La Rouge: Henri de Toulouse-Lautrec. PMID- 26757459 TI - Creating Safe Harbors for Quality Measurement Innovation and Improvement. PMID- 26757460 TI - A PIECE OF MY MIND. Old Soldier, Is It Like This? PMID- 26757461 TI - Expanded Evidence for Frozen Fecal Microbiota Transplantation for Clostridium difficile Infection: A Fresh Take. PMID- 26757462 TI - Bronchoscopic Lung Volume Reduction in COPD: Lessons in Implementing Clinically Based Precision Medicine. PMID- 26757463 TI - Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. AB - IMPORTANCE: Clostridium difficile infection (CDI) is a major burden in health care and community settings. CDI recurrence is of particular concern because of limited treatment options and associated clinical and infection control issues. Fecal microbiota transplantation (FMT) is a promising, but not readily available, intervention. OBJECTIVE: To determine whether frozen-and-thawed (frozen, experimental) FMT is noninferior to fresh (standard) FMT in terms of clinical efficacy among patients with recurrent or refractory CDI and to assess the safety of both types of FMT. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double blind, noninferiority trial enrolling 232 adults with recurrent or refractory CDI, conducted between July 2012 and September 2014 at 6 academic medical centers in Canada. INTERVENTIONS: Patients were randomly allocated to receive frozen (n = 114) or fresh (n = 118) FMT via enema. MAIN OUTCOMES AND MEASURES: The primary outcome measures were clinical resolution of diarrhea without relapse at 13 weeks and adverse events. Noninferiority margin was set at 15%. RESULTS: A total of 219 patients (n = 108 in the frozen FMT group and n = 111 in the fresh FMT group) were included in the modified intention-to-treat (mITT) population and 178 (frozen FMT: n = 91, fresh FMT: n = 87) in the per-protocol population. In the per-protocol population, the proportion of patients with clinical resolution was 83.5% for the frozen FMT group and 85.1% for the fresh FMT group (difference, 1.6% [95% CI, -10.5% to infinity]; P = .01 for noninferiority). In the mITT population the clinical resolution was 75.0% for the frozen FMT group and 70.3% for the fresh FMT group (difference, 4.7% [95% CI, -5.2% to infinity]; P < .001 for noninferiority). There were no differences in the proportion of adverse or serious adverse events between the treatment groups. CONCLUSIONS AND RELEVANCE: Among adults with recurrent or refractory CDI, the use of frozen compared with fresh FMT did not result in worse proportion of clinical resolution of diarrhea. Given the potential advantages of providing frozen FMT, its use is a reasonable option in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01398969. PMID- 26757464 TI - Mental Health Conditions Among Patients Seeking and Undergoing Bariatric Surgery: A Meta-analysis. AB - IMPORTANCE: Bariatric surgery is associated with sustained weight loss and improved physical health status for severely obese individuals. Mental health conditions may be common among patients seeking bariatric surgery; however, the prevalence of these conditions and whether they are associated with postoperative outcomes remains unknown. OBJECTIVE: To determine the prevalence of mental health conditions among bariatric surgery candidates and recipients, to evaluate the association between preoperative mental health conditions and health outcomes following bariatric surgery, and to evaluate the association between surgery and the clinical course of mental health conditions. DATA SOURCES: We searched PubMed, MEDLINE on OVID, and PsycINFO for studies published between January 1988 and November 2015. Study quality was assessed using an adapted tool for risk of bias; quality of evidence was rated based on GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. FINDINGS: We identified 68 publications meeting inclusion criteria: 59 reporting the prevalence of preoperative mental health conditions (65,363 patients) and 27 reporting associations between preoperative mental health conditions and postoperative outcomes (50,182 patients). Among patients seeking and undergoing bariatric surgery, the most common mental health conditions, based on random-effects estimates of prevalence, were depression (19% [95% CI, 14%-25%]) and binge eating disorder (17% [95% CI, 13%-21%]). There was conflicting evidence regarding the association between preoperative mental health conditions and postoperative weight loss. Neither depression nor binge eating disorder was consistently associated with differences in weight outcomes. Bariatric surgery was, however, consistently associated with postoperative decreases in the prevalence of depression (7 studies; 8%-74% decrease) and the severity of depressive symptoms (6 studies; 40%-70% decrease). CONCLUSIONS AND RELEVANCE: Mental health conditions are common among bariatric surgery patients-in particular, depression and binge eating disorder. There is inconsistent evidence regarding the association between preoperative mental health conditions and postoperative weight loss. Moderate-quality evidence supports an association between bariatric surgery and lower rates of depression postoperatively. PMID- 26757467 TI - Constipation: Advances in Diagnosis and Treatment. AB - IMPORTANCE: Chronic constipation accounts for at least 8 million annual visits to health care providers in the United States and is associated with large expenditures for diagnostic testing and prescription and nonprescription laxatives. OBSERVATIONS: Strong evidence for efficacy has been established for stimulant and osmotic laxatives, new intestinal secretogogues, and peripherally restricted MU-opiate receptor antagonists, the latter a major advance in the treatment of opioid-induced constipation (OIC). An algorithm provided to evaluate chronic idiopathic constipation (CIC) that is refractory to available laxatives focuses on the importance of defecation disorders and biofeedback therapies. When used appropriately, available stimulant laxatives such as senna and bisacodyl are both safe and effective when used long-term. There is a paucity of (and a strong desire for) studies that compare inexpensive laxatives with newer agents that work by other mechanisms. CONCLUSIONS AND RELEVANCE: The choice of treatment for CIC and OIC should be based on cost as well as efficacy. The small subgroup of patients who do not respond to currently available laxatives requires further evaluation at experienced centers that are capable of performing studies of defecation and colonic transit. PMID- 26757468 TI - Evaluation and Treatment of Patients With Constipation. PMID- 26757469 TI - Naloxegol (Movantik) for Opioid-Induced Constipation. PMID- 26757466 TI - Lung Volume Reduction Coil Treatment vs Usual Care in Patients With Severe Emphysema: The REVOLENS Randomized Clinical Trial. AB - IMPORTANCE: Therapeutic options for severe emphysema are limited. Lung volume reduction using nitinol coils is a bronchoscopic intervention inducing regional parenchymal volume reduction and restoring lung recoil. OBJECTIVE: To evaluate the efficacy, safety, cost, and cost-effectiveness of nitinol coils in treatment of severe emphysema. DESIGN, SETTING, AND PARTICIPANTS: Multicenter 1:1 randomized superiority trial comparing coils with usual care at 10 university hospitals in France. Enrollment of patients with emphysema occurred from March to October 2013, with 12-month follow-up (last follow-up, December 2014). INTERVENTIONS: Patients randomized to usual care (n = 50) received rehabilitation and bronchodilators with or without inhaled corticosteroids and oxygen; those randomized to bilateral coil treatment (n = 50) received usual care plus additional therapy in which approximately 10 coils per lobe were placed in 2 bilateral lobes in 2 procedures. MAIN OUTCOMES AND MEASURES: The primary outcome was improvement of at least 54 m in the 6-minute walk test at 6 months (1-sided hypothesis test). Secondary outcomes included changes at 6 and 12 months in the 6 minute walk test, lung function, quality of life as assessed by St George's Respiratory Questionnaire (range, 0-100; 0 being the best and 100 being the worst quality of life; minimal clinically important difference, >=4), morbidity, mortality, total cost, and cost-effectiveness. RESULTS: Among 100 patients, 71 men and 29 women (mean age, 62 years) were included. At 6 months, improvement of at least 54 m was observed in 18 patients (36%) in the coil group and 9 patients (18%) in the usual care group, for a between-group difference of 18% (1-sided 95% CI, 4% to infinity; P = .03). Mean between-group differences at 6 and 12 months in the coil and usual care groups were +0.09 L (95% CI, 0.05 L to infinity) (P = .001) and +0.08 L (95% CI, 0.03 L to infinity) (P = .002) for forced expiratory volume in the first second, +21 m (95% CI, -4 m to infinity) (P = .06) and +21 m (95% CI, -5 m to infinity) (P = .12) for 6-minute walk distance, and -13.4 points (95% CI, -8 points to infinity) and -10.6 points (95% CI, -5.8 points to infinity) for St George's Respiratory Questionnaire (1-sided P < .001 for both). Within 12 months, 4 deaths occurred in the coil group and 3 in the usual care group. The mean total 1-year per-patient cost difference between groups was $47,908 (95% CI, $47,879-$48,073) (P < .001); the incremental cost-effectiveness ratio was $782,598 per additional quality-adjusted life-year. CONCLUSIONS AND RELEVANCE: In this preliminary study of patients with severe emphysema followed up for 6 months, bronchoscopic treatment with nitinol coils compared with usual care resulted in improved exercise capacity with high short-term costs. Further investigation is needed to assess durability of benefit and long-term cost implications. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01822795. PMID- 26757470 TI - Global Use of Peripheral Blood vs Bone Marrow as Source of Stem Cells for Allogeneic Transplantation in Patients With Bone Marrow Failure. PMID- 26757465 TI - Multinational Assessment of Accuracy of Equations for Predicting Risk of Kidney Failure: A Meta-analysis. AB - IMPORTANCE: Identifying patients at risk of chronic kidney disease (CKD) progression may facilitate more optimal nephrology care. Kidney failure risk equations, including such factors as age, sex, estimated glomerular filtration rate, and calcium and phosphate concentrations, were previously developed and validated in 2 Canadian cohorts. Validation in other regions and in CKD populations not under the care of a nephrologist is needed. OBJECTIVE: To evaluate the accuracy of the risk equations across different geographic regions and patient populations through individual participant data meta-analysis. DATA SOURCES: Thirty-one cohorts, including 721,357 participants with CKD stages 3 to 5 in more than 30 countries spanning 4 continents, were studied. These cohorts collected data from 1982 through 2014. STUDY SELECTION: Cohorts participating in the CKD Prognosis Consortium with data on end-stage renal disease. DATA EXTRACTION AND SYNTHESIS: Data were obtained and statistical analyses were performed between July 2012 and June 2015. Using the risk factors from the original risk equations, cohort-specific hazard ratios were estimated and combined using random-effects meta-analysis to form new pooled kidney failure risk equations. Original and pooled kidney failure risk equation performance was compared, and the need for regional calibration factors was assessed. MAIN OUTCOMES AND MEASURES: Kidney failure (treatment by dialysis or kidney transplant). RESULTS: During a median follow-up of 4 years of 721,357 participants with CKD, 23,829 cases kidney failure were observed. The original risk equations achieved excellent discrimination (ability to differentiate those who developed kidney failure from those who did not) across all cohorts (overall C statistic, 0.90; 95% CI, 0.89-0.92 at 2 years; C statistic at 5 years, 0.88; 95% CI, 0.86-0.90); discrimination in subgroups by age, race, and diabetes status was similar. There was no improvement with the pooled equations. Calibration (the difference between observed and predicted risk) was adequate in North American cohorts, but the original risk equations overestimated risk in some non-North American cohorts. Addition of a calibration factor that lowered the baseline risk by 32.9% at 2 years and 16.5% at 5 years improved the calibration in 12 of 15 and 10 of 13 non-North American cohorts at 2 and 5 years, respectively (P = .04 and P = .02). CONCLUSIONS AND RELEVANCE: Kidney failure risk equations developed in a Canadian population showed high discrimination and adequate calibration when validated in 31 multinational cohorts. However, in some regions the addition of a calibration factor may be necessary. PMID- 26757471 TI - Tinzaparin vs Warfarin for Acute Venous Thromboembolism. PMID- 26757472 TI - Tinzaparin vs Warfarin for Acute Venous Thromboembolism--Reply. PMID- 26757473 TI - Electronic Health Records as Sources of Research Data. PMID- 26757476 TI - Error in the Figure. PMID- 26757474 TI - Correction of Description of MMR Vaccine Receipt Coding and Minor Errors in MMR Vaccine and Autism Study. PMID- 26757475 TI - Electronic Health Records as Sources of Research Data--Reply. PMID- 26757477 TI - Incorrect Variable Description. PMID- 26757478 TI - Incorrect Author Contributions. PMID- 26757480 TI - The Signs and Symptoms of Impending Death. PMID- 26757481 TI - JAMA PATIENT PAGE. Constipation. PMID- 26757482 TI - Estimation of cotyledon isoflavone abundance by a grey luminance-based model in variously hilum-coloured soybean varieties. AB - BACKGROUND: The nutraceutical uses of soybean (Glycine max L. Merr.) have received increasing attention in recent years, due to the therapeutic effects of high seed isoflavone concentrations against heart disease, cancer and menopausal symptoms. RESULTS: We found a close correlation between seed isoflavone abundance and hilum colour in a set of 17 contrasting soybean varieties. Image analysis of the hilum grey level pattern allowed us to identify a power model which approximates total cotyledon isoflavone concentrations (TCIC) at 65-71% by the normalised modal grey level. Higher TCIC levels were assigned to darker hilum varieties and vice versa within a variety-dependent response. Optimisation of the algorithm required correction for a few specific varieties falling in the intermediate 1.1-1.5 mg g(-1) TCIC range, which were over-estimated by the model, perhaps due to variations in hilar optical properties related to the geometric features of both hilum and seed. CONCLUSION: In view of its easy, low-cost detection, seed hilum colour is a useful phenotypic trait in soybean for rapid evaluation of isoflavone abundance in food uses and for improving specific nutraceutical breeding programmes. (c) 2016 Society of Chemical Industry. PMID- 26757483 TI - Effects of Grafting Density and Film Thickness on the Adhesion of Staphylococcus epidermidis to Poly(2-hydroxy ethyl methacrylate) and Poly(poly(ethylene glycol)methacrylate) Brushes. AB - Thin polymer films that prevent the adhesion of bacteria are of interest as coatings for the development of infection-resistant biomaterials. This study investigates the influence of grafting density and film thickness on the adhesion of Staphylococcus epidermidis to poly(poly(ethylene glycol)methacrylate) (PPEGMA) and poly(2-hydroxyethyl methacrylate) (PHEMA) brushes prepared via surface initiated atom transfer radical polymerization (SI-ATRP). These brushes are compared with poly(ethylene glycol) (PEG) brushes, which are obtained by grafting PEG onto an epoxide-modified substrate. Except for very low grafting densities (rho = 1%), crystal violet staining experiments show that the PHEMA and PPEGMA brushes are equally effective as the PEG-modified surfaces in preventing S. epidermis adhesion and do not reveal any significant variations as a function of film thickness or grafting density. These results indicate that brushes generated by SI-ATRP are an attractive alternative to grafted-onto PEG films for the preparation of surface coatings that resist bacterial adhesion. PMID- 26757484 TI - Effect of Fluorescent Labels on Peptide and Amino Acid Sample Dimensionality in Two Dimensional nLC * MUFFE Separations. AB - Multidimensional separations present a unique opportunity for generating the high peak capacities necessary for the analysis of complex biological mixtures. We have coupled nano liquid chromatography with micro free flow electrophoresis (nLC * MUFFE) to produce high peak capacity separations of peptide and amino acid mixtures. Currently, MUFFE largely relies on laser-induced fluorescence (LIF) detection. We have demonstrated that the choice of fluorescent label significantly affects the fractional coverage and peak capacity of nLC * MUFFE separations of peptides and amino acids. Of the labeling reagents assessed, Chromeo P503 performed the best for nLC * MUFFE separations of peptides. A nLC * MUFFE analysis of a Chromeo P503-labeled BSA tryptic digest produced a 2D separation that made effective use of the available separation space (48%), generating a corrected peak capacity of 521 in a 5 min separation window (104 peaks/min). nLC * MUFFE separations of NBD-F-labeled peptides produced similar fractional coverage and peak capacity, but this reagent was able to react with multiple reaction sites, producing an unnecessarily complex analyte mixture. NBD F performed the best for nLC * MUFFE separations of amino acids. NBD-F-labeled amino acids produced a 2D separation that covered 36% of the available separation space, generating a corrected peak capacity of 95 in a 75 s separation window (76 peaks/min). Chromeo P503 and Alexa Fluor 488-labeled amino acids were not effectively separated in the MUFFE dimension, giving 2D separations with poor fractional coverage and peak capacity. PMID- 26757485 TI - Separation efficiency of free-solution conjugated electrophoresis with drag-tags incorporating a synthetic amino acid. AB - DNA sequencing or separation by conventional capillary electrophoresis with a polymer matrix has some inherent drawbacks, such as the expense of polymer matrix and limitations in sequencing read length. As DNA fragments have a linear charge to-friction ratio in free solution, DNA fragments cannot be separated by size. However, size-based separation of DNA is possible in free-solution conjugate electrophoresis (FSCE) if a "drag-tag" is attached to DNA fragments because the tag breaks the linear charge-to-friction scaling. Although several previous studies have demonstrated the feasibility of DNA separation by free-solution conjugated electrophoresis, generation of a monodisperse drag-tag and identification of a strong, site-specific conjugation method between a DNA fragment and a drag-tag are challenges that still remain. In this study, we demonstrate an efficient FSCE method by conjugating a biologically synthesized elastin-like polypeptide (ELP) and green fluorescent protein (GFP) to DNA fragments. In addition, to produce strong and site-specific conjugation, a methionine residue in drag-tags is replaced with homopropargylglycine (Hpg), which can be conjugated specifically to a DNA fragment with an azide site. PMID- 26757487 TI - Effects of Sport-Specific Training Intensity on Sleep Patterns and Psychomotor Performance in Adolescent Athletes. AB - PURPOSE: Adolescent student-athletes face time constraints due to athletic and scholastic commitments, resulting in habitually shortened nocturnal sleep durations. However, there is a dearth of research on the effects of sleep debt on student-athlete performance. The study aimed to (i) examine the habitual sleep patterns (actigraphy) of high-level student-athletes during a week of training and academic activities, (ii) ascertain the effects of habitual sleep durations experienced by high-level student-athletes on psychomotor performance, and (iii) examine the impact of sport training intensities on the sleep patterns of high level student-athletes that participate in low and high intensity sports. METHODS: Sleep patterns of 29 high-level student-athletes (14.7 +/- 1.3 yrs) were monitored over 7 days. A psychomotor vigilance task was administered on weekdays to ascertain the effects of habitual sleep durations. RESULTS: Weekend total sleep time was longer than weekdays along with a delay in bedtime, and waketimes. Psychomotor vigilance reaction times on Monday were faster than on Thursday and Friday, with reaction times on Tuesday also faster than on Friday. False starts and lapses were greater on Friday compared with Monday. CONCLUSION: There was a negative impact of sleep debt on student-athletes' psychomotor performance. PMID- 26757486 TI - Bullying Perpetration and Victimization as Externalizing and Internalizing Pathways: A Retrospective Study Linking Parenting Styles and Self-Esteem to Depression, Alcohol Use, and Alcohol-Related Problems. AB - BACKGROUND: Emerging research suggests significant positive associations between bullying and substance use behaviors. However, these studies typically focused either on the link between substance use and bullying perpetration or victimization, and few have conceptualized bullying perpetration and/or victimization as mediators. OBJECTIVE: In this study, we simultaneously tested past bullying perpetration and victimization as mediational pathways from retrospective report of parenting styles and global self-esteem to current depressive symptoms, alcohol use, and alcohol-related problems. METHODS: Data were collected from a college sample of 419 drinkers. Mediation effects were conducted using a bias-corrected bootstrap technique within a structural equation modeling framework. RESULTS: Two-path mediation analyses indicated that mother and father authoritativeness were protective against bully victimization and depression through higher self-esteem. Conversely, having a permissive or authoritarian mother was positively linked to bullying perpetration, which in turn, was associated with increased alcohol use, and to a lesser degree, more alcohol-related problems. Mother authoritarianism was associated with alcohol related problems through depressive symptoms. Three-path mediation analyses suggested a trend in which individuals with higher self-esteem were less likely to report alcohol-related problems through lower levels of bullying victimization and depression. CONCLUSIONS/IMPORTANCE: Results suggested that bullying perpetration and victimization may, respectively, serve as externalizing and internalizing pathways through which parenting styles and self-esteem are linked to depression and alcohol-related outcomes. The present study identified multiple modifiable precursors of, and mediational pathways to, alcohol-related problems which could guide the development and implementation of prevention programs targeting problematic alcohol use. PMID- 26757488 TI - Robust nonparametric estimation of monotone regression functions with interval censored observations. AB - Nonparametric estimation of monotone regression functions is a classical problem of practical importance. Robust estimation of monotone regression functions in situations involving interval-censored data is a challenging yet unresolved problem. Herein, we propose a nonparametric estimation method based on the principle of isotonic regression. Using empirical process theory, we show that the proposed estimator is asymptotically consistent under a specific metric. We further conduct a simulation study to evaluate the performance of the estimator in finite sample situations. As an illustration, we use the proposed method to estimate the mean body weight functions in a group of adolescents after they reach pubertal growth spurt. PMID- 26757489 TI - An Unusual Cause of Pseudopapillary Oedema: Hyperphosphatemic Hyperostosis Syndrome. AB - For the first time, we report hyperphosphatemic hyperostosis syndrome as a cause for pseudopapillary oedema in a pediatric case. Clinical findings are presented and discussed with tomographic evaluation (optical coherence tomography and Heidelberg retinal tomography) of optic discs, visual-evoked potentials, and visual fields. PMID- 26757493 TI - Stevens Johnson syndrome-Toxic Epidermal Necrolysis Overlap induced by sulfasalazine treatment: a case report. AB - INTRODUCTION: Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are life-threatening and severe adverse cutaneous drug reactions characterized by epidermal detachment presenting as blisters and areas of denuded skin. SJS, SJS TEN overlap and TEN differ only by their extent of skin detachment. CASE PRESENTATION: We report here the case of a young woman (33- year old) admitted to the dermatological unit for epidermal detachment (at 18% of the body surface area), blisters, red macular and papular lesions, developed 15 days after administration of sulfasalazine. Prior to this, she complained of fever and discomfort upon swallowing. Skin biopsy had shown epidermal necrosis compatible with Stevens Johnson Syndrome and Toxic Epidermal Necrolysis. As the epidermal detachment was between 10% and 30%, she was diagnosed as a Stevens Johnson Syndrome/Toxic Epidermal Necrolysis overlap. The course was favorable 17 days after stopping the drug and starting a symptomatic treatment. CONCLUSION: Practitioners and patients need to be aware of the initial clinical signs of severe cutaneous adverse drug reactions such as fever, influenza-like symptoms, dysphagia or burning eyes. Early discontinuation of medication remains the best way to improve prognosis of patients with Stevens Johnson's Syndrome and Toxic Epidermal Necrolysis. PMID- 26757492 TI - [Medical treatment of endometriosis]. AB - PREREQUISITES: Pathogenesis and pathophysiology of endometriosis, pharmacodynamics of oral contraceptives, progestagens, antiprogestagens, danazol, GnRh agonist and non-steroidal antiinflammatory. PURPOSE OF REVIEW: The aim of this paper is to systematically review the literature evidence of medical treatments for endometriosis and to summarize recently published recommendations. METHODS: Literature and recently published recommendations review via bibliographic research using Pubmed/Medline, Google scholar and Cochrane database. RESULTS: Endometriosis is an estrogen-dependent gynecological disease. Medical treatement of endometriosis induce an estrogen deprivation situation. The Oral contraceptives reduce the rate of postoperative endometrioma recurrence and should be considered an essential part of long-term therapeutic strategies.New agents promise a distinct perspective in endometriosis treatment. CONCLUSIONS: The effectiveness of medical treatmentis well established in the management pelvic pain and infertility associated with endometriosis and constitutes an important alternative or complement to surgery. PMID- 26757491 TI - Sociocultural factors and breast cancer in sub-Saharan Africa: implications for diagnosis and management. AB - The incidence of breast cancer is on the rise in sub-Saharan Africa (SSA) and efforts at early diagnosis have not been very successful because the public has scant knowledge about the disease, a large percentage of breast cancer cases are diagnosed late and mainly rural SSA women's practice of breast self-examination is poor. In this paper, we argue that an examination of the social and cultural contexts of SSA that influence breast cancer diagnosis and management in the region is needed. We discuss the implications of sociocultural factors, such as gender roles and spirituality, on breast cancer diagnosis and management in SSA. PMID- 26757495 TI - [A diagnostic trap simulating pulmonary embolism]. AB - Pulmonary embolism is one of the differential diagnoses of "acute chest" syndromes. We report a clinical case of contained rupture of ascending aortic aneurysm with pulmonary arteries compression, which was presented as pulmonary embolism, and we well review the literature data of this diagnostic trap. PMID- 26757496 TI - Cyclic vomiting syndrome in multisystem mitochondrial disorder. AB - BACKGROUND: Cyclic vomiting syndrome (CVS) is characterized by recurrent episodes of incapacitating nausea or vomiting accompanied by abdominal pain, interspersed with relatively symptom-free intervals that might last from a few weeks to months. There are a number of indications that CVS could be a manifestation of a mitochondrial disorder (MID). AIM: To illustrate how a MID may present with symptoms typical of CVS. CASE: A 31 year old female diagnosed as having CVS since birth had additional features of short stature, deafness, irritable bowel syndrome, cardiomyopathy with myocardial thickening in the absence of arterial hypertension, hepatopathy with steatosis hepatis, myopathy, and polyarthrosis. Her family history was positive for diabetes, short stature, and migraine with a maternal mode of inheritance, frequently found in patients with MIDs. Frequency of CVS episodes decreased with age but other manifestations of the MID became worse over time. Due to the multisystem nature of the disease and the positive family history, a MID was assumed. CONCLUSIONS: Early-onset CVS often improves in adulthood. CVS may be associated with multisystem disease, suggesting the presence of a MID. CVS should be regarded as a manifestation of a MID if typical clinical manifestations of a MID, which cannot be explained by other causes, are present. PMID- 26757494 TI - [Endoscopic treatment of Zenker's diverticulum with soft diverticuloscope: a first Tunisian experience]. AB - INTRODUCTION: Zenker's diverticulum is an acquired hernia from the posterior pharyngeal mucosa developed in the pharyngo-esophageal junction. The gold standard for diagnosis is pharyngo-esophageal barium swallow study. Open surgery with cricopharyngeal myotomy has long been the conventional treatment. Actually, endoscopic treatment is an efficient alternative to resolve the problem with shorter surgery duration and less complication. AIM: We report 3 cases of patients with Zenker's diverticulum treated with endoscopic approach in our department between 2013 and 2014. CASE REPORT: There were three men aged 71, 79 and 62 years admitted to our department with symptomatic Zenker's diverticulum. Predominant symptoms were dysphagia and regurgitation. Diverticulotomy with a flexible endoscope was performed for all patients, using argon plasma coagulation in the first case and a needle-knife in the two others. Hemostatic clips were placed at the end of the procedure. There was no complication in the last two cases. Perforation at the left lateral side of the cervical diverticulum was observed in the first patient solved by diet and antibiotics. We performed a pharyngo-esophageal barium swallow study before and after the intervention in all patients showing significant regression of the diverticulum and we observed a complete regression of clinical symptoms. CONCLUSION: Treatment with endoscopic approach using a flexible endoscope and a diverticuloscope for good exposure of the diverticulum is a safe procedure offering a rapid improvement of symptoms with a lower risk of complications and a shorter duration of hospitalization compared to surgical treatment. PMID- 26757490 TI - A novel sweet potato potyvirus open reading frame (ORF) is expressed via polymerase slippage and suppresses RNA silencing. AB - The single-stranded, positive-sense RNA genome of viruses in the genus Potyvirus encodes a large polyprotein that is cleaved to yield 10 mature proteins. The first three cleavage products are P1, HCpro and P3. An additional short open reading frame (ORF), called pipo, overlaps the P3 region of the polyprotein ORF. Four related potyviruses infecting sweet potato (Ipomoea batatas) are predicted to contain a third ORF, called pispo, which overlaps the 3' third of the P1 region. Recently, pipo has been shown to be expressed via polymerase slippage at a conserved GA6 sequence. Here, we show that pispo is also expressed via polymerase slippage at a GA6 sequence, with higher slippage efficiency (~5%) than at the pipo site (~1%). Transient expression of recombinant P1 or the 'transframe' product, P1N-PISPO, in Nicotiana benthamiana suppressed local RNA silencing (RNAi), but only P1N-PISPO inhibited short-distance movement of the silencing signal. These results reveal that polymerase slippage in potyviruses is not limited to pipo expression, but can be co-opted for the evolution and expression of further novel gene products. PMID- 26757497 TI - Sub-cutaneous histiocytic sarcoma in a child: a case report. AB - BACKGROUND: Histiocytic sarcoma (HS) is a rare hematologic malignancy with morphologic and immunophenotypic evidence of histiocytic differentiation. This tumor follows an aggressive clinical course. CASE PRESENTATION: We report the case of a 14 year-old white girl who presented with a nodular lesion in the thigh, involving the skin and soft tissue. The histologic diagnosis retained was a HS. CONCLUSION: HS is a rare neoplasm that may cause a diagnostic pitfall. Unfortunately, incomplete clinical data and histopathologic disparities in addition to the overall rarity of the neoplasms induced difficulties of management and of full appreciation of their clinical behavior. PMID- 26757498 TI - [Predictive factors of the outcome of smoking cessation among Tunisian women]. AB - BACKGROUND: The spread of smoking among women in Tunisia has reached alarming proportions because of increasing smoker rate, the younger age of smoking initiation and therefore its duration. AIM: Identify predictors of success or failure of smoking cessation, Methods: we conducted a retrospective study (January 2008-June 2011), including 101 female smokers (19.8%) among 510 smokers of both sexes undergoing smoking cessation interventions. Univariate and multivariate analysis between groups of smokers who succeeded and who failed smoking cessation was performed. RESULTS: Average age of our patients was 44 years. The overall success rate at 6 months and 1 year were respectively 24.7 and 18.8%. In univariate analysis, a statistically significant difference in terms of successful weaning was observed in smokers who had a late age of smoking onset (after 20 years) (p=0.03), respiratory or cardiovascular comorbidities associated (p=0.03) and good adhesion to the consultation (p=0.02). In multivariate analysis only the presence of a tobacco-related disease (OR: 4.43, 95% CI [1.29- 15.17], p=0.01) and adherence to the consultation (OR 5.02 95% CI [1.29 -19.39], p=0.01) were significantly associated with a good prognosis for successful weaning at 6 months and one year. A possible but not significantly associated with age of smoking initiation was observed (OR=0.3 95% CI [0.08-1.07], p=0.06). CONCLUSION: Beyond validated smoking cessation and prolonged follow-up, a differential approach, taking into account women specificities, would increase the chances of quitting smoking. PMID- 26757499 TI - [Intestinal parasitosis among non-permanent resident students in Tunisia: a review of 23 years of monitoring in the department of Parasitology-Mycology at the Rabta Hospital of Tunisia]. AB - BACKGROUND: In order to fight digestive parasitism in Tunisia, a national program of surveillance of non-permanent resident students in Tunisia has been found to detect these parasitosis in this target population. OBJECTIVE: To determine the prevalence of intestinal parasitosis among non-permanent resident students in Tunisia, to identify the different parasitic species founded and to show the interest of this screening. METHODS: During a period of 23 years (1990-2012), 7386 parasitological examinations of stools has been made among students essentially from or had visited tropical Africa, Maghreb and Middle-East, at the laboratory of Parasitology-Mycology at the Rabta Hospital of Tunis. RESULTS: The prevalence of intestinal parasitism found was 34.45% (i.e. 2545 infested students). Among the protozoa that have been isolated in the majority of cases (78.75%), amoebae were most frequently found (86.4%) represented mainly by Entamoeba coli and Endolimax nanus in respectively, 25.62 and 23.33% of parasites isolated; while Entamoeba histolytica/dispar, only pathogenic Amoeba was found in 8.05% of the total of parasites isolated. Regarding helminths, found in 21.25% of parasites isolated, Ankylostome was predominant (34.5%) represented by the species of Necator americanus. A single case of Ancylostom duodenale has been isolated. Among the identified parasite species, 38.7% were known parasitic pathogens for humans. CONCLUSIONS: These results note the interest of the control of the non-permanent resident students in Tunisia. The precocious tracking and treatment of affected subjects permits to avoid the introduction and the dissemination of parasites already rare and virulent strains in our country. PMID- 26757500 TI - [Prevalence and associated factors of low birth weight in the provincial hospital of Mohammedia--Morocco]. AB - BACKGROUND: Low birth weight (LBW) constitutes a major public health problem, both in developed than in developing countries, due to its extent and its strong association with childhood morbidity and mortality. OBJECTIVE: to estimate prevalence of low birth weight and determine its related factors in the Prefectoral Hospital in Mohammedia. METHODS: We carried out a cross sectional study from May to July 2012 which concerned 713 newborns and theirs mothers. We collected information about socioeconomic and anthropometric factors and characteristics of pregnancy. A multivariate analysis was performed. RESULTS: Among the 713 studied newborns, 38 had LBW; the prevalence of LBW was 5,3% (95% CI: 3,7%-6,9%). Factors significantly associated with LBW in multivariate analysis were: mother age ( OR 9,27; IC95%:2,15-39,85), prematurity (OR 9,34; IC95%:1,29-67,32), twin pregnancy (OR 195,07; IC 95%:30,38-125,39) and gender of new born (OR 5,26; IC 95%:1,61-17,18). Well-balanced diet (OR 0,12; IC 95%:0,04 0,34) and hours of sleep equal or more than 8 per day (OR 0,20; IC 95%:0,07-0,58) were protector factors. CONCLUSION: Actions of education, screening and treatment of the diseases occurred in the pregnancy are necessary. Facilitating the access of pregnant women to high quality antenatal care, promoting a healthy lifestyle as a balanced diet, fighting against the active and passive smoking and offering a psychological support to the pregnant woman is necessary to reduce the prevalence of LBW and to improve the maternal and child health. PMID- 26757501 TI - [Molecular exploration of the R91W (RPE65 gene) in Tunisian patients with early onset retinal dystrophy and early onset retinitis pigmentosa]. AB - BACKGROUND: Inherited retinal dystrophies are the major causes of blindness and visual impairment. Visual loss is due to neurosensory retinal and pigment epithelium cells degeneration. The most severe were Leber Congenital amaurosis (LCA), juvenile retinitis pigmentosa (RP) and early onset RP. The LCA and juvenile RP are called "Early Onset Retinal Dystrophy" (EORD). OBJECTIVE: Molecular exploration of the R91W (RPE65 gene) in Tunisian patients with Early Onset Retinal Dystrophy and early onset RP. METHODS: All patients underwent a complete ophthalmological and a general examinations. The R91W exploration was performed by direct sequencing of exon 4 of the RPE65 gene and enzyme digestion. RESULTS: Among 47 patients, 13 were from Nabeul. Twenty three had an EROD with a visual loss under the age of 2 years. Twenty four were with early onset RP and had these symptoms between the ages of 4 and 10 years. The best corrected visual acuity ranged from 2/10 to 1/60. Among the explored 94 chromosomes, the R91W (325C>T) allele was identified in heterozygous state in a sibling from Nabeul. The allele frequency was 2.12% (2/94). CONCLUSION: All our patients had severe forms of RP with a decrease in visual acuity and a wide advanced retinal degeneration. The R91W mutation (325C>T) was not the major cause of EORD and early onset RP among Tunisian patients. PMID- 26757502 TI - [The role of general practitioners in the management of cancer patients from the central region of Tunisia: a retrospective study of 215 physicians]. AB - BACKGROUND: General practitioners have a major contribution in cancer prevention and screening. However, their contribution in the treatment plan management and in the post treatment follow-up of cancer patients needs to be clarified. OBJECTIVE: To evaluate the contribution of general practitioners of the public and private sectors in the management of cancer patients during and after the treatment protocol. To analyze the problems they encounter and find the possible solutions. METHOD: A retrospective declarative KAP (Knowledge, Attitudes and Practices) survey was conducted from first September 2010 to 28 February 2011 in the central region of Tunisia among 215 primary care physicians in the public and private sectors. The questionnaire focused on their effective involvement, the role during treatment, follow up and supportive care. RESULTS: Nearly 80% of physicians who participated in the survey were involved in the management of their patients, primarily by ensuring adherence to their treatment (42.9%), in the follow up care after treatment (42.3%) and in palliative care (29%), however the majority has never prescribed opioid drugs (66.5%). Only 46.6% of the physicians announced the diagnosis of cancer to their patients. The questioned doctors deplored the lack of training in oncology (22.8%) and the feeling of being excluded from the management of their patients once they have addressed them to their specialist peers (48.8%). The interviewed physicians expressed their wish to have a further medical training in oncology (79.5%) and to join a structured cancer network (55.8%). CONCLUSION: The majority of interviewed general practitioners of our region were engaged in cancer patients' care. However, gaps were identified especially in palliative care and in prescribing opioid drugs. Promoting continuing education in this field and the establishment of cancer networks will allow extend the scope of general practitioners' intervention in the cancer network. PMID- 26757504 TI - [Early detection of COPD in smoking cessation outpatients]. AB - BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is among the leading causes of chronic morbidity and mortality throughout the world. Potentially, COPD can be prevented by the early detection of COPD, which generally entails spirometry. Physicians in smoking cessation outpatient are in an ideal position to detect early-stage of COPD by the simple examination of the patient. They can also perform spirometry to confirm the diagnosis of COPD. The main objective of this study was to assess the frequency of COPD among smokers in smoking cessation outpatient. Secondary objectives were to Compare two methods for COPD screening, the questionnaire (clinical score) and the mini-electronic spirometer (Neo-6) and to assess the degree of motivation to stop smoking by the announcement of lung age to smokers. METHODS: a prospective cross-sectional study was carried out in four consultations for smoking cessation. Inclusion criteria were male patients aged over 35 years and seen in smoking cessation outpatient. A clinical score was then calculated to detect COPD. This score is based on age, BMI, the quantity of tobacco smoking and the respiratory clinical signs. By establishing this score, we could classify our smokers on consultants with likely COPD if the clinical score>16. Secondly, a measure of the breath with a portable minispirometre "neo6" was performed with quantification of the first second forced expiratory volume (FEV1), forced expiratory volume in 6 seconds (FEV6) and their ratio (FEV1/FEV6). A ratio FEV1/FEV6 less than 0.8 was in favor of an obstructive ventilator defect (DVO). In this case a total body plethysmography was indicated. RESULTS: The sample of the study consisted of 115 male smokers with a mean age of 48+/-12 years old. A low socio-economic level and a low level of education were found respectively in 50.4% and 58% of smokers. Cigarette smoking is the most consumed form of tobacco. A significant clinical score predicting COPD, was found in 54 patients. The measurement of the breath through the Neo-6 found that 23 (20%) smokers had FEV1/FEV6 less than or equal to 0.7 predicting bronchial obstruction and 26 had a ratio between 0.7 and 0.8. plethysmography confirmed the diagnosis of COPD for 27 patients. So the prevalence of COPD in our sample was of 23.48%. The clinical score had a sensibility of 81.48% and a specificity of 63.64 with a negative predictive value of 91.8%. The sensitivity of the Neo 6 (70.37%) is smaller than the clinical score but the specificity is better than 95.94 % of the clinical score. Its negative predictive value was 91.3%. So when VEMS/VEM6 ratio is greater than 0.7, the probability of COPD remains very low. The announcement of the pulmonary patient age is an important parameter for the motivation to stop smoking. CONCLUSION: The combination of a standardized questionnaire to the measure of breath by Neo6 can further optimize COPD screening. PMID- 26757503 TI - [Clinical predictors of high risk bleeding endoscopic lesions in children with hematemesis]. AB - BACKGROUND: Haematemesis is an alarming symptom in children, even if the proportion of normal endoscopies ranges from 10 to 21% and the causes are often benign. The purpose of the study was to identify clinical predictors of endoscopic lesions with high risk of bleeding and to establish a score that predict the presence of these lesions. METHODS: Retrospective study carried in Children's Hospital of Tunis between 1997 and 2006 involved children with haematemesis who underwent Upper gastrointestinal endoscopy. Several clinical parameters were analyzed. Univariate analysis and multivariate logistic regression were performed to identify predictive parameters of endoscopic lesions with high risk of bleeding. A score was developed from the parameters derived from the multivariate analysis. The sensitivity and specificity of the score were determined. RESULTS: Among 2814 endoscopies, 814 were conducted for haematemesis and 489 were selected for the study. 140/489 had lesions with high risk of bleeding. Multivariate logistic regression analysis identified six factors independently associated with high risk bleeding lesions: endoscopy performed within 48 hours (OR=2.2; 95% CI 0.7-6.9), re-bleeding (OR=1.4; 95% CI 0.7-2.5), the importance of the bleeding, mild to severe (OR=1.8; 95% CI 1.1-3), bright red haematemesis (OR=1; 95% CI 0.2-5.8), history of gastrointestinal and liver disease (OR=1.6; 95% CI 1.1-3) and intake of gastro toxic drugs (OR=1.3; 95% CI 0.8-2.3). Then, we established a score. The sensitivity, specificity, positive predictive value and negative predictive value of this score were respectively 79.6%, 32.9%, 34.9% and 78% for a cut off value>0.22. CONCLUSION: The clinical predictive parameters of high risk bleeding lesions identified have not yielded a score with significant sensitivity and specificity. A prospective study should be performed to improve the score. PMID- 26757505 TI - [Emergency department visits for respiratory symptoms in greater Tunisia, 2007 and 2010]. AB - BACKGROUND: Asthma and Chronic Obstructive pulmonary Disease (COPD) are considered as a major public health problem worldwide. They are characterized by a progressive evolution with episodes of exacerbations. OBJECTIVE: The aim of this work was to describe the emergency department visits for asthma and COPD according to sociodemographic characteristics of patients and to assess trends over time. METHODS: We conducted a cross sectional study including all emergency department visits of the Abderrahmane Mami hospital during the period between January, 1st 2007 and the 31th of December 2010. We used a standardized questionnaire to collect age; sex and date of emergency department visits with a primary diagnosis of asthma and COPD exacerbation from the emergency register. Data analyses were performed with SPSS 17.0. RESULTS: A total of 9814 emergency department visits were reported over the period of four years, 6499 (66,2%) for asthma and 3315 (33,8%) for COPD exacerbation. The mean age was 52+/-21 years; it was for asthma and COPD respectively 48+/-21 and 60+/-18 years. Aging was associated with a marked decrease in the prevalence of asthma (from 51.0% to 25.6%) and with a marked increase in the prevalence of COPD (from 6.8% to 47.5%). Men visit most frequently the emergency department for both diseases than women and particularly for COPD where the proportion of men was 75%. The number of visits increased steadily between 2007 and 2010, it peaked in January for asthma and in February for COPD and it was most important on the period from December to May. CONCLUSION: Asthma was most common among emergency department visits than COPD exacerbation, it affects men and women in a nearly same proportions and it is most frequent in young adults aged between 30 and 65 years. COPD exacerbation is most frequent in men aged over 65 years. Our study suggests that there is significant seasonal variation in the emergency department visits for respiratory illness. These findings suggest that greater attention and most adapted studies should be necessary to explain and to identify factors implied in these variations. PMID- 26757506 TI - [First documented cases of systemic lupus erythematosus in Niger]. AB - OBJECTIVE: We describe in this first series of lupus documented in Niger, the epidemiological, diagnostic, therapeutic and prognostic aspects. METHOD: This is a prospective study in internal medicine at the National Hospital of Niamey during 10 years. ACR criteria were used as diagnostic criteria. RESULTS: We identified only 9 cases with a frequency of 0.05 % (7 women, 2 men) with a mean age of 36.7 years [range, (26, 48)]. Frequent manifestations were prolonged fever (8 cases), malar rash (6 cases), arthritis (6 cases), alopecia (5 cases), discoid lupus (3 cases), haematological disorders (7 cases), serositis (4 cases) and renal failure (4 cases). All patients had at least 4 ACR criteria with an average of 6.11 criteria. ANA were positive in 8 patients with an average of 1/568, 68 [extremes (1/1280-1/160)]. The most commonly molecules used were Prednisone, Azathioprine and Hydroxychloroquine. The Mycofenolate Mofetil, Cyclophosphamide and Rituximab were used in a single patient. The outcome was favorable in 8 patients and we deplore the death of one patient. CONCLUSION: Under diagnosis would be the basis of the low prevalence of lupus in Niger. Diagnostic means are necessary for epidemiological studies in order to have more representative data. PMID- 26757507 TI - [The JAK2 mutation in myeloproliferative disorders: A predictive factor of thrombosis]. AB - BACKGROUND: BCR-ABL negative myeloproliferative neoplasms (MPN) include polycythemia Vera (PV), essential thrombocythemia (ET) and primitive myelofibrosis (PMF). the JAK2 V617F mutation has been introduced since 2008 as a major diagnostic criterion on the one hand and on the other hand, it would be linked to increased risk of thrombotic complications. AIM: This study aimed to evaluate the association of JAK2 mutation and thrombotic events in MPN. METHODS: A retrospective study concerning 45 BCR-ABL negative MPN patients (mean age=53 old years, sex ratio=0.8) was conducted. RESULTS: They were classified as PV (22 patients), ET (17 patients), PMF (3 patients) and atypical MPN (3 patients). The JAK2 mutation was found in 64.4% of patients: 72.7% of PV patients, 47% of ET patients and 66.7% of PMF patients. Thrombotic events were recorded in 11 patients (24.4%). Cerebral arteries and portal vein were the most frequent localizations. The JAK2 mutation was an independent risk factor of thrombotic events. CONCLUSION: Consequently, it seems that screening for JAK2 mutation in BCR-ABL negative MPN could play a role in identifying patients at high risk of vascular complications. PMID- 26757508 TI - Cleidocranial dysplasia: family cases. PMID- 26757509 TI - [Bartonella henselae infection revealed by Guillain Barre Syndrome]. PMID- 26757510 TI - [Diagnosis of breast schwannoma on percutaneous breast biopsy]. PMID- 26757511 TI - An incidental finding of a crossed fused renal ectopia. PMID- 26757512 TI - Congenital ichtyosis and hetomegaly: Think about Chanarin Dorfman syndrome. PMID- 26757514 TI - [Delusional parasitosis or Ekbom Syndrome in an elderly hemodialysis patient]. PMID- 26757513 TI - [Reactivation of hepatitis B in a long-term anti-HBS-positive patient after immunosuppressive therapy]. PMID- 26757515 TI - Gynecologic oncology. PMID- 26757516 TI - Infectious disease. PMID- 26757517 TI - Liposuction. PMID- 26757518 TI - Surgical first assistant. PMID- 26757519 TI - Clinical nurse specialist. PMID- 26757520 TI - Urgent care medicine. PMID- 26757521 TI - [Clinical application of dynamic neutralization system in treating multisegmental lumbar degenerative disease]. PMID- 26757522 TI - [Application of Dynesys system combined with posterior lumbar interbody fusion in treating multiple lumbar degenerative disease]. AB - OBJECTIVE: To explore the clinical effects of Dynesys system combined with posterior lumbar interbody fusion (PLIF) in treating multiple lumbar degenerative disease. METHODS: The clinical data of 46 patients with multiple lumbar degenerative diseases treated by Dynesys system combined with PLIF from September 2010 to May 2013 were retrospectively analyzed. There were 17 males and 29 females, aged from 38 to 68 years old with an average of (56.38+/-11.63) years. Operation section was in L2-L5 of 16 patients (6 with fusion of L4,5 and 10 with fusion of L4,5,L5S1) and in L3-S1 of 30 patients (11 with fusion of L5S1 and 19 with fusion of L4,5,L5S1). Patients were followed up for three times: postoperative 3 months, 1 year and final follow-up. Visual analogue scale (VAS) and Oswestry Disability Index (ODI) were used to assess clinical symptoms preoperatively and postoperatively. All patients underwent flexion/extension radiographs examinations before surgery and at final follow-up. Range of motion (ROM) and disc height index (DHI) were recorded. RESULTS: All patients were followed up from 16 to 48 months with the mean of (23.23+/-7.34) months. At third follow-up after operation, ODI and VAS of lumbago and leg pain were significant improved than that of preoperative (P<0.01). DHI of fusion segment was significantly increased than that of preoperative (P<0.05). There was no significant difference in adjacent non-fusion segment between preoperative and postoperative (P>0.05). Postoperative ROM of fusion and non-fusion segments were obviously decreased than that of preoperative. There was no significant difference in ROM of upper adjacent non-fusion segment between 3 months and 1 year after operation (P>0.05), but at final follow-up, the ROM was increased (P<0.05). CONCLUSION: The preliminary clinical results of the Dynesys system combined with PLIF in the treatment of multiple lumbar degenerative diseases are satisfactory. It can be determined in fusion or non-fusion according to the individual needs and can reserve the some intervertebral motion, prevent the early degeneration of adjacent segments. However, its long-term clinical efficacy should be verified with long time. PMID- 26757523 TI - [Clinical application of dynamic neutralization system (K-Rod) in treating multisegmental lumbar degenerative disease]. AB - OBJECTIVE: To evaluate the clinical effects of dynamic neutralization system (K Rod) in treating multisegmental lumbar degenerative disease. METHODS: From October 2011 to October 2013, 20 patients with multisegmental lumbar degenerative disease were treated with dynamic neutralization system (K-Rod). There were 8 males and 12 females with an average age of 45.4 years old (ranged from 31 to 65) and an average course of 3.8 years (ranged from 9 months to 6.25 years). All patients had the history of low back and legs pain. Among them, 10 cases were far lateral lumbar disc herniation, 7 cases were lumbar spinal stenosis, 3 cases were lumbar spondylolisthesis (degree I in 2 cases and degree II in 1 case). Every patient had only one responsible segment which causing the symptom would have to be rigidly fixed during operations, and the adjacent intervertebral disc of the responsible segments at least 1 segment has already obvious degenerated. All patients underwent the operation to relieve compressed nerves and reconstruct spinal stability with K-Rod system (the responsible segments were fixed with interbody fusion, and the adjacent segments were fixed with dynamic stabilization). Visual analogue scale (VAS), Japanese Orthopaedic Association Scores (JOA) and Oswestry Disability Index (ODI) were used to evaluate the clinical effects. Imaging data were used to analyze the range of motion (ROM), intervertebral disc height and intervertebral disc signal (according to modified Pfirrmann grading system) in degenerative adjacent segment. RESULTS: All patients were followed up for more than 1 year, and preoperative symptoms obviously relieved. There were significant differences in VAS, JOA, ODI between preoperative and postoperative (postoperative at 1 week and 1 year) (P<0.05). Radiological examination showed that all responsible segments had already fused, and no looseness, displacement and breakage of internal fixations were found. Postoperative at 1 year, the ROM of adjacent segments were decreased (P<0.05). There was no significant difference in intervertebral disc height between preoperative and postoperative at 1 year (P>0.05). According to modified Pfirrmann grading system to classification for the 25 disks of adjacent segment, 8 disks (32%) got improvement, 15 disks (60%) got no change and 2 disks (8%) got aggravation at 1 year after operation. CONCLUSION: Dynamic neutralization system (K-Rod) combined with interbody fusion could obtain short-term clinical effects in the treatment of multisegmental lumbar degenerative disease. PMID- 26757524 TI - [Correlation study of spinal canal and dural sac dimensions on MRI with therapy of lumbar disc herniation]. AB - OBJECTIVE: To explore the value of spinal canal and dural sac dimensions for the treatment of lumbar disc herniation in MRI. METHODS: The clinical data of 144 patients with single-level lumbar disc herniation underwent nonsurgical or surgical treatment from January 2010 to December 2012 were retrospectively analyzed. There were 91 patients in the nonsurgical group, including 55 males and 36 females, ranging in age from 20 to 68 years old with an average of (43.37+/ 12.48) years; and there were 53 patients in the surgical group, including 28 males and 25 females, ranging in age from 20 to 64 years old with an average of (42.98+/-12.95) years. JOA scores (29 scores) were used to evaluate clinical manifestation (including subjective symptoms, objective findings, limitation of daily activities and bladder function) and outcomes. The parameters related to spinal canal and dural sac dimensions (including spinal canal midsagittal diameter and available diameter, lateral recess width, spinal canal and dural sac cross-sectional area) in the initial axial T2-weighted MRI were measured, and odds ratio of available diameter to midsagittal diameter, odds ratio of lateral recess width to midsagittal diameter and area ratio of dural sac to spinal canal were calculated. Then, the differences of all parameters between two groups, and the correlations with initial JOA scores were analyzed. RESULTS: (1) All patients were followed up from 1 to 3 years with an average of 2.1 years. JOA scores before treatment were 16.27+/-2.96 in nonsurgical group and 12.64+/-3.30 in surgical group, there was statistically significant difference (t=6.319, P<0.01). At final follow-up time, there was no statistically significant difference in JOA scores (25.41+/-2.22 vs 25.76+/-2.29), improvement rate [(72.95+/-12.54)% vs (76.80+/-9.45)%], and the excellent and good rate (84.91% vs 78.02%) between two groups (P>0.05). But, the relapse rate of nonsurgical group was higher than surgical group (14.29% vs 5.67%). (2) Spinal canal midsagittal diameter and available diameter, lateral recess width, spinal canal and dural sac area, the ratio of available diameter to midsagittal diameter, and the ratio of lateral recess width to midsagittal diameter in surgical group were smaller than that of nonsurgical group, but the area ratio of dural sac to spinal canal was larger, and there were statistically significant differences between two groups (P<0.01). (3) The initial JOA scores showed significantly positive correlation with spinal canal midsagittal diameter and available diameter, lateral recess width, and canal and dural sac area (P<0.01); also presented positive correlation with the ratio of available diameter to midsagittal diameter and the ratio of lateral recess width to midsagittal diameter (P<0.05); but there was a significantly negative correlation between initial JOA scores and the area ratio of dural sac to spinal canal. CONCLUSION: Both nonsurgical and surgical treatment of lumbar disc herniation can obtain good effect, but the recurrence rate of non-surgical treatment is higher. Preoperative MRI measurement parameters of spinal canal and dural sac dimensions has certain value for the treatment selection of lumbar disc herniation, but further refinement and validation is still required. PMID- 26757525 TI - [Long-term follow-up of Dynesys system in clinical application for the treatment of multiple lumbar degenerative disease]. AB - OBJECTIVE: To explore the clinical effects of Dynesys system for the treatment of multiple segment lumbar degenerative disease. METHODS: A total of 28 patients with lumbar degenerative disc disease treated with Dynesys system from December 2008 to May 2011 were retrospectively reviewed. There were 16 males and 12 females, aged from 27 to 75 years old with an average of 49.1 years. Thirteen patients with multiple segmental lumbar intervertebral disc protrusion, including L3-L5 in 7 cases, L2-L4 in 1 case and L4-S1 in 5 cases. Fifteen patients with multiple segmental lumbar spinal stenosis, including L3-L5 in 10 cases, L4-L5 in 4 cases and L2-S1 in 1 case. The symptoms of lumbago and (or) intermittent claudication in all patients were treated with conservative treatments for more than 6 months and these methods did not work. Visual analogue scale (VAS) was used to analyze the lumbar and leg pain, imaging data were used to measure the intervertebral space height and intervertebral motion of fixed segment and upper adjacent segment, Oswestry Disability Index (ODI) was used to evaluate the clinical effect. RESULTS: All operations were successful and the patients were followed up from 38 to 65 months with an average 50.6 months. At final follow-up, ODI and VAS of the low back pain and leg pain were (25.10+/-6.52)%, (1.25+/-0.70) points and (1.29+/-0.89) points, respectively and were decreased compared with preoperative (P<0.05). Postoperative intervertebral space heights were increased and intervertebral motions were decreased in fixed segment compared with preoperative (P<0.05). There were no significant differences in intervertebral space heights and intervertebral motions of upper adjacent segment between preoperative and postoperative (P>0.05). CONCLUSION: Dynesys system may obtain long-term clinical curative effect in treating multiple lumbar degenerative disease. It can partially preserve the intervertebral motions of the fixed segments, have little effect on adjacent segments. The long-term clinical effect of Dynesys still need longer time follow-up observation. PMID- 26757526 TI - [Acute onset of intra-spinal osteochondroma in L3,4 segment in a case report and literature review]. PMID- 26757527 TI - [Mini-open trans-spatium intermuscular versus percutaneous short-segment pedicle fixation for the treatment of thoracolumbar mono-segmental vertebral fractures]. AB - OBJECTIVE: To compare the clinical effects and radiographic outcomes of mini-open trans-spatium intermuscular and percutaneous short-segment pedicle fixation in treating thoracolumbar mono-segmental vertebral fractures without neurological deficits. METHODS: From August 2009 and August 2012, 95 patients with thoracolumbar mono-segmental vertebral fractures without neurological deficits were treated with short-segment pedicle fixation through mini-open trans-spatium intermuscular or percutaneous approach. There were 65 males and 30 females, aged from 16 to 60 years old with an average of 42 years. The mini-open trans-spatium intermuscular approach was used in 58 cases (group A) and the percutaneous approach was used in 37 cases (group B). Total incision length, operative time, intraoperative bleeding, fluoroscopy, hospitalization cost were compared between two groups. Visual analog scale (VAS) and radiographic outcomes were compared between two groups. RESULTS: All patients were followed up from 12 to 36 months with an average of 19.6 months. No complications such as incision infection, internal fixation loosening and breakage were found. In group A, fluoroscopy time was short and hospitalization cost was lower than that of group B (P<0.05). But the total incision length in group B was smaller than that of group A (P<0.05). There was no significant differences in operative time, intraoperative bleeding, postoperative VAS and radiographic outcomes between two groups (P>0.05). Postoperative VAS and radiographic outcomes were improved than that of preoperative (P<0.05). CONCLUSION: The mini-open trans-spatium intermuscular and percutaneous short-segment pedicle fixation have similar clinical effects and radiographic outcomes in treating thoracolumbar mono-segmental vertebral fractures without neurological deficits. However, in this study, the mini-open trans-spatium intermuscular approach has a short learning curve and more advantages in hospitalization cost and intraoperative radiation exposure times, and is recommendable. PMID- 26757528 TI - [Clinical characteristics and surgical treatment of ganglioneuroma in spine]. AB - OBJECTIVE: To summarize the clinical manifestation and diagnosis of ganglioneuroma in spine and investigate the clinical effect of surgical treatment. METHODS: The clinical data of 6 patients underwent a surgery for ganglioneuroma in spine from January 2008 to January 2015 were retrospectively analyzed. There were 4 males and 2 females, aged from 2 to 63 years old with an average of 34.6 years. The courses of disease were from 3 days to 17 years. Five patients complicated with superficial hypesthesia in correlative level of tumor, and the muscle strength under tumor plane had decreased at different levels, with the strength of grade II-IV. Two cases complicated with hypermyotonia and positive bilateral Hoffmann's and Babinski sign. Five cases were sporadic lesion in correlative spinal canal and one case complicated with the giant occupying lesion in thoracic cavity. RESULTS: Six operations had been performed including 5 en bloc and 1 subtotal resection. Postoperative pathological results showed tumor cells scattered or fasciculated inserted into Schwann cells in the stroma. In 2 patients complicated with radiculalgia before operation, 1 case was relieved and 1 was invariant after operation. All 4 patients with preoperative dyscinesia in the limbs obtained improvement after operation. All the patients were followed up from 0.3 to 6.8 years with an average of 2.5 years. At the final follow-up, according to ASIA grade, 5 cases were good and 1 case was invariant. During the follow-up, only 1 patient experienced chemoradiation because of merging ganglioneuroblastoma and receiving subtotal resection. No recurrence in other 5 cases. CONCLUSION: Ganglioneuroma is a benign and rare tumors in spine. Clinically, radicular pain and sensory-motor disorders are the main manifestations. Its diagnosis depends on pathological examination. Prognosis of surgical treatment is good. PMID- 26757529 TI - [Treatment of chronic mallet finger deformity with minor bone anchors and palmaris longus tendon graft]. AB - OBJECTIVE: To explore the clinical effects of minor bone anchors and palmaris longus tendon graft in treating chronic mallet fingers deformity. METHODS: From January 2008 to June 2013, 26 patients with chronic mallet fingers deformity were treated with minor bone anchors and palmaris longus tendon graft. There were 18 males and 8 females, aged from 18 to 52 years old with an average of (32.0+/-1.3) years. Among them, 8 cases caused by machine injury, 6 cases by fall injury, 6 cases by sprain from fight, 4 cases by tendon spontaneous rupture, 2 cases by knife trauma. There was no tendon attachment of extensor tendon check in 16 cases, and with 0.3 to 0.5 cm tendon attachment in 10 cases. All patients had the flexion deformity and the disability of dorsiflexion activity. During operation, the distal interphalangeal joint was fixed in 10 degrees to 20 degrees dorsiflexion by a Kirshner wire, the minor bone anchor was used to reconstruct the extensor tendon insertion, the palmaris longus tendon slice was transplanted the decayed area of extensor tendon insertion. Four weeks postoperatively, the Kirshner wire was removed and the plaster external fixation was used, and the patient began function exercises. Postoperative complications were observed and fingers functions were assessed according to Dargan standard. RESULTS: The patients were followed up from 6 to 14 months with an average of (5.0+/-0.3) months. Wound superficial infection occurred in 2 cases, the skin pressure ulcer in 2 cases, joint activities disability in 1 case; these symptoms got improvement after symptomatic treatment. Traumatic arthritis occurred in 2 cases, 1 case was improved after treatment, and 1 case had chronic pain for a long time. No internal fixation loosening or breakage and tendon rupture were found. According to Dargan standard to evaluate the finger function, 17 cases got excellent results, 8 good, and 1 poor. CONCLUSION: It is an effective way to treat the chronic mallet finger deformity using minor bone anchors and palmaris longus tendon graft, and the method has advantages of reliable fixation, easy operation, satisfactory effect and less complication. PMID- 26757530 TI - [Analysis of posterior lumbar interbody fusion (PLIF) in treating lumbar degenerative disease in elderly patients]. AB - OBJECTIVE: To explore the clinical effects of PLIF surgery for elderly patients with lumbar degenerative disease. METHODS: From March 2010 to May 2013, 28 patients with lumbar degenerative disease, aged more than 80 years were treated with PLIF surgery. There were 10 males and 18 females, aged from 80 to 93 years old with an average of (85.44+/-3.66) years. Course of disease was from 3 to 20 years. The operation time, intra-operative blood loss, operation complications were recorded and JOA scores and Macnab criteria were used to evaluate the clinical outcomes. RESULTS: All patients were followed up from 12 to 40 months with an average of 26.5 months. The average operation time was (150.00+/-26.42) min and the average intra-operative blood loss was (373.33+/-99.88) ml. The pre operative JOA score was 12.30+/-2.43, and the corresponding postoperative JOA score at the final follow-up was 24.81+/-2.09 which was much higher than the preoperative one (P<0.01). According to the modified Macnab criteria to evaluate at the final follow-up, 16 patients got an excellent result, 10 good, 2 fair. In the weeks postoperatively, injuries of nerve root happened in 3 cases, superficial wound infection with delayed healing in 3 cases, and tear of the dural sac accompanied with cerebrospinal fluid leakage in 1 case. After long term follow-up, adjacent segment degeneration and the corresponding spinal canal stenosis occurred in 1 case at 34 months after operation. All cases got successful fusion without any displacement of internal fixation and pseudoarthrosis formation. CONCLUSION: With proper cases, fully preoperative preparation, perfect intra-operative manipulation and active treatment after operation, even advanced ages older than 80 years with lumbar degenerative disease could get satisfactory outcomes after PLIF surgery. PMID- 26757531 TI - [Comparison of early clinical effects between Activ C cervical disc replacement and anterior cervical discectomy and fusion for single-level cervical spondylosis]. AB - OBJECTIVE: To compare the early clinical effects of Activ C cervical disc replacement (ACDR) and anterior cervical discectomy and fusion (ACDF) in treating single-level cervical spondylosis. METHODS: The clinical data of 76 patients with single-level cervical spondylosis underwent surgery from July 2009 to September 2012 were retrospectively analyzed. Among them, 28 patients were treated with ACDR (ACDR group), including 18 males and 10 females, aged from 32 to 62 years old with an average of (45.2+/-6.2) years; and 48 patients were treated with ACDF (ACDF group), including 28 males and 20 females, aged from 33 to 60 years old with an average of (45.8+/-6.4) years. Visual analogue scale (VAS), Japanese Orthopedics Association (JOA) score, Short Form-36 (SF-36), imaging data were used to assess the clinical effects after operation. RESULTS: A total of 76 patients were followed up from 6 to 24 months with an average of 13.2 months. VAS of neck pain and brachialgia were improved in all patients after operation (P<0.05), there was no significant difference between two group (P>0.05). Somato score and psycho-score of SF-36 of two groups were obviously increased (P<0.05), ACDR group was better than that of ACDF group (P<0.05). In ACDR group, there was no significant difference in the range of motion of surgical segments and adjacent segments between preoperative and postoperative (P>0.05); heterotopic ossification around the edge of vertebral body occurred in 1 case on the 6th month after operation, no fusion was found on the 1st year after operation. In ACDF group, the adjacent vertebral disease occurred in 1 case and the patient underwent the reoperation. CONCLUSION: Activ C cervical disc replacement can reduce the degeneration of adjacent segments and its early outcomes for the treatment of single-level cervical spondylosis are satisfactory, but the long term effects still need study. PMID- 26757532 TI - [Case-control study on hidden blood loss in perioperative period of femoral intertrochanteric fractures in elderly patients treated with intramedullary nailing]. AB - OBJECTIVE: To analyze the neglected hidden blood loss before and after operations in the elderly patients with intertrochanteric fractures and strengthen the treatment and clinical nursing in the perioperative period in order to ensure clinical effects. METHODS: The clinical data of 99 patients with intertrochanteric fracture treated with intramedullary nailing from January 2010 to January 2014 were retrospectively analyzed (47 males and 52 females). Forty seven cases got blood transfusion supporting and 52 cases were not (blood transfusion group and no-blood transfusion group respectively). According to the Gross equation, the average hemoglobin (Hb) and hematocrit (HCT) were used to analyze blood loss in perioperative period and assess the patients' hidden blood loss situation. RESULTS: There were 22 males and 30 females in blood transfusion group. The average operative time was (62.13+/-4.01) min; intraoperative visible blood loss and postoperative drainage were 215 ml, totally; preoperative Hb was (103.22+/-9.01) g/L and postoperative was (81.13+/-6.20) g/L; preoperative HCT was (96.93+/-3.38) I/L and postoperative was (308.00+/-11.81) I/L. There were 25 males and 22 females in no-blood transfusion group. The average operative time was (60.12+/-3.27) min; intraoperative visible blood loss and postoperative drainage were 196 ml, totally; the average blood transfusion were 621 ml; preoperative Hb was (92.15+/-5.46) g/L and preoperative was (95.20+/-8.93) g/L; preoperative HCT was (96.52+/-3.63) I/L and preoperative was (392.70+/-14.03) I/L. According to the Gross equation, the blood loss of no-blood transfusion group and blood transfusion group in peroperative period were (937.29+/-63.04) ml and (706.43+/-35.02) ml, respectively. The hidden blood loss was dominant. At 1, 3 months after operation, Harris score of blood transfusion group was better than that of no-blood transfusion group, and 12 months after operation, there was no significant difference between two groups. CONCLUSION: The hidden blood loss of intramedullary nailing for intertrochanteric fracture should be emphasized in perioperative period, it can avoid the perioperative complications caused by anemia and affect the prognosis of patients. PMID- 26757533 TI - [Extracellular splitting pattern of mitochondria and the depressant effects of CsA on the process]. AB - OBJECTIVE: To investigate extracellular splitting pattern of mitochondria and the depressant effects of CsA on the process and explore the mechanism of post traumatic SIRS and its therapeutic strategy. METHODS: Ten male SD rats with 60 to 70 days age and 240 to 280 g weight were used for mitochondrial isolation. Freshly isolated mitochondria were randomly divided into two groups, which were cultured in blood plasma with or without CsA respectively for 8 h. COX and MDH were assayed by ELISA every 30 min. Meanwhile, Rat macrophage cell line NR8383 were treated as follows, control (group A): cultivation with normal medium; NR8383+CsA co-culture group (group B): culture medium was supplemented with CsA of 10 mmol/L; NR8383+intact mitochondria co-culture group (group C): culture medium was supplemented with intact mitochondria (mtDNA=5 g/ml); NR8383+intact mitochondria+CsA co-culture group (group D): culture medium was supplemented with intact mitochondria (mtDNA=5 MUg/ml)and CsA of 10 mmol/L; NR8383+disrupted mitochondria co-culture group (group E): culture medium was supplemented with disrupted mitochondria (mtDNA=5 MUg/ml); NR8383+disrupted mitochondria+CsA co culture group (group F): culture medium was supplemented with disrupted mitochondria (mtDNA=5 MUg/ml)and CsA of 10 mmol/L. TNF-alpha and IL-6 concentrations in supernatant were assessed at 1, 3, 5 h after culture. RESULTS: In the mitochondria plasma cultures, MDH and COX levels were increased with the time and peaked at about 3 h and 3.5 h; CsA can delay the appearance of peak to 4.5 h. Among different treated groups,there was no significant difference in TNF alpha and IL-6 between group A and group B; there was significant difference in TNF-alpha and IL-6 other groups. After 1 h culture, compared with group C, no significant difference of TNF-alpha and IL-6 was observed in group D, while TNF alpha and IL-6 were significant higher in group E; after 3 h culture, compared with group C, TNF-alpha and IL-6 were significantly lower in group D, while TNF alpha and IL-6 were significantly higher in group E; after 5 h culture, compared with group C, TNF-alpha and IL-6 were significantly lower in group D, while no significant difference of TNF-alpha and IL-6 were observed in group E. At each time point, there was no significant difference in TNF-alpha and IL-6 between group F and group E. CONCLUSION: Mitochondria can split in serum with time, which will further activate macrophages. CsA has depressant effect to mitochondrial splitting on the process and will therefore inhibit the activation of macrophages. PMID- 26757535 TI - [Minimal invasion and closed reduction with external fixation for elderly femoral intertrochanteric fracture]. AB - OBJECTIVE: To evaluate the clinical effects of minimal invasion and closed reduction with external fixation in treating elderly femoral intertrochanteric fracture. METHODS: From August 2007 and September 2013, 43 patients with elderly femoral intertrochanteric fracture were treated by minimal invasion and closed reduction with external fixation. There were 26 males and 17 females with an average age of 78 years old ranging from 68 to 92 years. Durations from injury to operation ranged from 1 to 8 days with an average of 3 days. According to AO classification, there were 22 cases with type A1, 15 with type A2, 6 with type A3. The time of bone healing were observed after operation and the clinical effects were evaluated by Harris scoring standard. RESULTS: All patients were followed up from 10 to 18 months with an average of 13 months. The incisions obtained one-stage healing after removal of external fixation. All the fractures were healed and the mean healing time was 16 weeks (ranged, 12 to 18 weeks). Two patiens complicated with the thread needle loosening in the femoral trochanteric, 2 cases with the hip varus deformity and 1 case with the delayed union. No bone nonunion, external fixer breakage, blood vessel or nerve damage were found. According to the Harris scoring standard,the average Harris score of hip joint function was 85.89+/-7.36, and 18 cases got excellent results, 19 good. CONCLUSION: Minimal invasion and closed reduction with external fixation can obtain satisfactory results in treating elderly femoral intertrochanteric fractures. It is a simple and effective method for elderly patients who cannot tolerate anesthesia and surgery trauma. PMID- 26757534 TI - [Effectiveness of manipulative reduction combined with minimally invasive surgery in the treatment of osteoporotic vertebral compression fracture: a meta analysis]. AB - OBJECTIVE: To evaluate the clinical efficacy of manipulative reduction combined with percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP) in treating osteoporotic vertebral compression fracture (OVCF) using meta-analysis method, in order to provide a reference for clinical treatment. METHODS: A systematic computer-based search (from January 1987 to April 2014) from CNKI, Wanfang database, Web of Science and PubMed were performed for the collection of controlled clinical researches on manipulative reduction combined with PVP or PKP in treating OVCF. The quality of selected researches was evaluated. Meta-analysis was adopted to evaluate visual analog scale, Cobb angle, anterior height ratio of the injured vertebra. RESULTS: A total of 7 researches of 410 patients were included in the present analysis, there were 5 RCTs and 2 non-RCTs and all come from China. Manipulative reduction combined with PVP could got better improvement in Cobb angle (WMD=-7.35; 95%CI: -12.15, -2.54) and anterior height ratio of the injured vertebra (P<0.01) than simple PVP, but no significant difference was found in improvement of visual analog scale (WMD=-0.01; 95%CI: -0.45, 0.42). There were no significant differences in the improvement of visual analog scale, Cobb angle, anterior height ratio of the injured vertebra between manipulative reduction combined with PKP and simple PKP (P>0.05). CONCLUSION: Compared with simple PVP, manipulative reduction combined with PVP may result in more clinical efficacy on the improvement of Cobb angle and anterior ratio of the injured vertebra. And compared with simple PKP, manipulative reduction combined with PKP has no obvious advantages on the improvement of visual analog scale, Cobb angle, anterior height ratio of the injured vertebra. However, the number and quality of the literatures, may resulted in the effect of mistrust, so more large sample and high-quality RCTs are needed in future. PMID- 26757536 TI - [Application of cross-leg soleus muscle flap transplantation to treat the soft tissue defect in contralateral leg]. AB - OBJECTIVE: To summarize the clinical application results of the repair soft tissue defect in contralateral leg with a cross-leg soleus muscle flap pedicle transplantation. METHODS: From January 2008 to January 2013, 8 patients with soft tissue defect in lower leg underwent reconstruction with a cross-leg soleus muscle flap pedicle transplantation (without microvascular anastomoses). There were 7 males and 1 female, aged from 20 to 49 years old with an average of 31.8 years. The operative time after injury was from 2 to 8 weeks with the mean of 46 days. The soleus muscle flap was transposed across to the contralateral leg defect area, then immediate to perform the coverage of the muscle flaps by a meshed split-thickness skin graft. The donor site was closed directly. RESULTS: All the muscle flaps had survived completely. In one case, recipient area edge had a less exudate from drainage hole everyday, the incision spontaneously was healed after 2 week's changing dressing. Follow-up period ranged form 1.5 to 4 years with an average of 2.5 years postoperatively. The tibia and fibula fractures were healed well. A good contour was achieved at the recipient area. According to LEM standard, 2 cases got excellent results, 5 good and 1 fair. CONCLUSION: Soleus flap pedicle transplantation is very suitable to repair the soft tissue defect of the injuried leg only one main blood vessel, and can reduce the damage of donor area. PMID- 26757538 TI - [Treatment of the injury of the plantar plate on the second metatarsophalangeal joint with dorsal approach and Weil osteotomy]. AB - OBJECTIVE: To evaluate the clinical results of dorsal approach and Weil osteotomy in treating the injury of the plantar plate in second metatarsophalangeal joint. METHODS: Eight feet with plantar plate tear in five cases were treated by plantar plate repairment through dorsal approach and Weil osteotomy from June 2012 to December 2013. The mean age of the patients was 52 years old. All the patients were followed up for 6 to 12 months. American Orthopaedic Foot and Ankle Society (AOFAS) and visual analogue scale (VAS) were used to evaluate the clinical effect. RESULTS: The second metatarsophalangeal joint stability recovered and the pain released in all patients. Postoperative VAS was lower and AOFAS was higher than preoperative. CONCLUSION: Combined dorsal approach and Weil osteotomy can effectively release the pian of plantar plate, stabilize the metatarsophalangeal joint, decrease the incidence rate of postoperative subluxation and anchylosis in treating plantar plate tears in the second metatarsophalangeal joint. PMID- 26757537 TI - [Treatment of fresh subtrochanteric fracture combined with old femoral neck fracture with hemiarthoplasty through anterolateral approach]. AB - OBJECTIVE: To explore the clinical effects of one-stage hemiarthroplasty in treating fresh subtrochanteric fracture combined with old femoral neck fracture. METHODS: From October 2003 to October 2013, 7 patients with fresh subtrochanteric fracture and old femoral neck fracture were treated with hemiarthroplasty in one stage. There were 5 males and 2 females, aged from 69 to 80 years old with an average of 74.5 years. According to the Garden classification, 2 cases were type IV and 5 cases were type V. According to the A0 classification of subtrochanteric fracture, all cases were type A1 (long oblique femoral subtrochanteric fractures). Biological coating long handle femoral prosthesis was used in the patients. The hip joint functions were assessed according to Charnley scoring system after all hemiarthroplasty. RESULTS: Seven patients were followed up from 12 to 24 months with an average of 18 months. There were 1 case with urinary system infection and 1 case with deep venous thrombosis. Of all, 5 cases recovered the walk ability at 6 months after operation and 2 cases could walk with the help of the crutch at 1 year after operation. According to Charnley scoring system to assess the hip joint function, the total Charnley scores reached 15.0+/-2.5, and 4 cases got an excellent results, 2 good, 1 fair. CONCLUSION: Arthroplasty through anterolateral approach can obtain satisfactory clinical effects in treating fresh subtrochanteric fracture combined with old femoral neck fracture, it has advantages of good joint stability, little pain, less complication, quickly recover, early activities on fields. PMID- 26757539 TI - [Update on prevention of epidural adhesion after lumbar laminectomy]. AB - Postoperative epidural adhesion is one of the most common causes of failed back surgery syndrome (FBSS), which can lead to back and leg pain or neurological deficit. Prevention of epidural adhesion after laminectomy is critical for improving the outcomes of lumbar surgery. The main origins of epidural fibrosis are raw surface of erector muscles and rupture fibers of intervertebral disc. The main current preventive methods for epidural adhesion include the usage of implants, chemicals and low dose radiation. However, most of them are still in experiment period. There are still controversies on the clinic usage of autograft free fat, ADCON-L, and Mitomycin C (MMC). The optimal implants are characteristics of better biocompatibility, degradable absorption and capability of existing for a certain period in body. The optimal medicine should have good effect on anti-desmoplasia, less side effects and long half-life. Besides, the combination of biodegradable medical film and drug and the mixture of two or more medical films are also the research frontlines of epidural adhesion. Further researches are required to explore new materials and drugs with stable and most favorable effect in preventing epidural adhesion. PMID- 26757540 TI - [Progress on treatment of transverse patella fractures with tension band fixation]. AB - Transverse fracture is the most common in patella fracture and tension band fixation is one of the most effective methods. Surgical wire tension band technique is simple, the use of materials is also simple, but it is not strong and difficult to promote. Kirschner tension band technique can get satisfactory reduction with reliable fixation, but it is easy to complicate with steel wire breakage and Kirschner loosening. Screw tension band technique inherits the traditional advantages of simple manipulation and reliable fixation, also overcomes the disadvantages of early activity limitations caused soft tissue irritation of tension band around knee, the slippage and breakage of internal fixation, and the technique can be popularized generally. PMID- 26757541 TI - [A review of drug metabolism under hypoxia environment at high altitude]. AB - The special environmental features of high altitude, such as hypobaric hypoxia, low temperature, arid, high solar radiation, variable climate and geochemical anomaly, cause great effects on human physiology and health. It will provide valuable references and new ideas to study drug's metabolism in special environment of high altitude hypoxia, and give the guidance to clinical reasonable medication, avoiding adverse reactions and personalized medicine in plateau areas. This article reviewed the effect of high altitude hypoxia on drug metabolism, elaborated metabolic characteristics of some drugs and the activity and expression of drug metabolism enzymes under hypoxia environment at high altitude, and discussed related mechanism. PMID- 26757542 TI - [Recent advances in the study of Nrf2 and inflammatory respiratory diseases]. AB - Nuclear factor-erythroid 2 related factor 2 (Nrf2) is an ubiquitous and important transcription factor. It regulates antioxidant response elements (AREs)-mediated expression of antioxidant enzyme and cytoprotective proteins. A large body of research showed that Nrf2-Keap1 (Kelch-like ECH-associated protein 1, Keap 1)-ARE signaling pathway is involved in the endogenous antioxidant defense mechanisms. Nrf2 increases the expression of a number of cytoprotective genes, protects cells and tissues from the injury of a variety of toxicants and carcinogens. As a result, Nrf2 enhances the expression of glutathione and antioxidants such as superoxide dismutase and glutathione S-transferase, and subsequently scavenging free radicals. Air pollution especially from PM2.5 particles, is associated with an increasing morbidity of inflammatory pulmonary diseases and their deterioration. More and more studies demonstrated that Nrf2 was a novel signaling molecule in the modulation of inflammatory responses in these inflammatory respiratory diseases, such as asthma, acute lung injury (ALI) and COPD. Therefore, Nrf2 targeting might be a therapeutic target, which will provide clinical benefit by reducing both oxidative stress and inflammation in asthma, acute lung injury (ALI) and COPD. This review focused on the relationship between Nrf2 and inflammatory respiratory diseases and oxidative stress. PMID- 26757543 TI - [Progress in the study of HIV capsid structure and drug discovery]. AB - The HIV-1 capsid protein plays a crucial role in viral infectivity, assembling into a fullerene cone that encloses the viral RNA and it has gained attention as a promising therapeutic target. Research has been focused on the spatial structures of capsid proteins in recent years, and peptides and small molecules targeting capsid have been discovered. In this article, it summarizes the structure information of capsid protein, analyzes and compares the binding information of different peptides and small molecules targeting capsid. At the same time we give the perspective to the future drug discovery based on the protein-protein interaction during the maturation process. PMID- 26757544 TI - [Gray relational analysis for the effect of nano-drug features on drug absorption]. AB - Gray relational analysis is employed to analyze the effects of nano-drug features on phagocytosis of macrophages, including zeta potential, shape factor and scale size of drug particle, the correlation among such factors and macrophage cell is calculated. The results showed that the internalization processe is affected significantly by the zeta potential of the drug in the process of phagocytosis of macrophages, followed by the impact particle shape, and the effect of particle scale behaves relatively small. PMID- 26757545 TI - [Mechanisms of the role of fibroblast growth factor 21 in attenuating insulin resistance]. AB - This study is to evaluate the therapeutic effect of fibroblast growth factor 21 (FGF21) on type 2 diabetic mice model and to provide mechanistic insights into its therapeutic effect. Type 2 diabetic animal model was established with high calorie fat diet and low dose streptozotocin (STZ) injection. Mice were then randomized into 5 groups: model control, FGF21 0.25 and 0.05 MUmol x kg(-1) x d( 1) groups, insulin treatment group. Ten age-matched normal KM mouse administered with saline were used as normal controls. Serum glucose, insulin, lipid products and the change of serum and liver tissue inflammation factor levels between five groups of mouse were determined. The results showed that blood glucose, insulin, free fatty acids (FFAs), triglycerides, and inflammatory factor average FGF-21 of type 2 diabetes model group and normal control group were significantly higher (P < 0.01), while compared with insulin group, no difference was significant. Average blood glucose, insulin, blood lipid and inflammatory factor of FGF-21 treatment group compared with type 2 diabetes group was significantly lower (P < 0.01) and insulin group has no difference with the model control group. The results of OGTT and HOMA-IR showed that insulin resistance state was significantly relieved in a dose-dependent manner. Thus, this study demonstrates that FGF-21 significantly remits type 2 diabetic mice model's insulin resistance state and participates in the regulation of inflammatory factor levels and type 2 diabetes metabolic disorders. PMID- 26757546 TI - [Inhibitory effects and mechanisms of snake venom tripeptide pENW on platelet adhesion]. AB - This study was designed to investigate inhibitory effects and possible mechanisms of snake venom tripeptide (pENW) on platelet adhesion in order to promote the development of a novel anti-platelet therapy. To study the inhibitory effects of pENW on platelet adhesion, washed platelets pre-incubated with pENW (116.5-466.2 MUmol x L(-1)) were used to test the ability of platelet adhesion to fibrinogen. Effect of pENW on fibrin clot retraction was also tested. Effect of pENW on platelets viability was tested by MTT assay. Effect of pENW on reactive-oxygen species (ROS) levels of platelet was studied by flow cytometry assay. Calcium mobilization in Fura-2/AM-loaded platelets was monitored with a spectrofluorimeter. Cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP), thromboxane A2 (determined as its metabolite thromboxane B2) were measured using enzyme immunoassay kits. Akt, ERK and p38 phosphorylation were tested by Western blot. The results showed that pENW inhibited platelet adhesion and fibrin clot retraction in a concentration-dependent manner without cytotoxicity. Intracellular cGMP and cAMP in both resting and thrombin-activated platelets were increased by pENW. In addition, pENW attenuated intracellular Ca2+ mobilization and TXA2 production in platelets stimulated by thrombin. As shown by Western blot assay, Akt, ERK and p38 phosphorylation in thrombin-induced platelet were attenuated by pENW. However, inhibitory effects of pENW had nothing to do with ROS. Thus, pENW exhibited a significant inhibition on platelet adhesion to fibrinogen, which means pENW could block the first step of thrombosis as while as retard the more stable clot formation. The mechanisms of pENW on inhibition platelet adhesion might be related to instant regulations, such as protein kinases. PMID- 26757547 TI - [Development of HTS model on SERT inhibitors combined biological screening model with HTVS]. AB - In order to improve the efficiency of drug screening on serotonin transporter (SERT) inhibitors, a high-throughput screening (HTS) model is established in RBL 2H3 cells. The RBL-2H3 cells are very similar to the serotonin genetic neuro, in modulation of post-receptor mechanisms and transduction pathway of SERT reactivated. Depending on a fluorescence substrate ASP+ used in detection method of inhibitor rates, it's convenient, quick, accurate and effective, not making the environmental biohazard compared with radioactive experiments. Furthermore, biological screening model combined with computer aided virtual screening technique describing high-throughput virtual screening (HTVS). Bayesian classification method and molecular fingerprint similarity were applied to virtual screening technique, for screening compounds in compound library. Some compounds have been found, and then validated further by biological screening model. Combination of HTS and HTVS improves the efficiency of screening SERT inhibitors. PMID- 26757548 TI - [The evaluation of efflux transporter model based on RNA interference technology in vitro]. AB - In the present study, the specifically knockdown models of P-gp or MRP2 were constructed by using a series of chemically synthesized small interfering RNA (siRNA) in vitro. The expression of P-gp and MRP2 was measured by real-time PCR and Western blot, and the function was evaluated by applying P-gp and MRP2 substrate, rhodamine and methotrexate. The results showed that MRP2 siRNA-3 or P gp siRNA-2 significantly decreased the mRNA expression of MRP2 or P-gp, the inhibition ratio was 68% or 84%; MRP2 siRNA-3 or P-gp siRNA-2 at a dose of 80 nmol x L(-1) significantly reduced the protein expression of MRP2 or P-gp at 48 h after treatment, the inhibition ratio was 62% or 70%. Meanwhile, other transporters were not influenced by siRNA. When pretreatment with MRP2 siRNA-3 or P-gp siRNA-2, the efflux of methotrexate or rhodamine decreased significantly and the intra-cellular concentration increased. The results suggested that chemically synthesized siRNA could significantly inhibit the expression and function of MRP2 and P-gp, and the model of RNAi in vitro could be used to evaluate the role of efflux transporters in transportation of drugs. PMID- 26757549 TI - [Effect of chrysin on expression of NOX4 and NF-kappaB in right ventricle of monocrotaline-induced pulmonary arterial hypertension of rats]. AB - The aim of the present study is to investigate the protective effect of chrysin (5,7-dihydroxyflavone) on right ventricular remodeling in a rat model of monocrotaline-induced pulmonary arterial hypertension (PAH). PAH rats were induced by a single injection of monocrotaline (60 mg x kg(-1), sc) and were administered with chrysin (50 or 100 mg x kg(-1) x d(-1)) for 4 weeks. At the end of experiment, the right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) were monitored via the right jugular vein catheterization into the right ventricle. Right ventricle (RV) to left ventricle (LV) + septum (S) and RV to tibial length were calculated. Right ventricular morphological change was observed by HE staining. Masson's trichrome stain was used to demonstrate collagen deposition. The total antioxidative capacity (T-AOC) and malondialdehyde (MDA) levels in right ventricle were determined according to the manufacturer's instructions. The expressions of collagen I, collagen III, NADPH oxidase 4 (NOX4) and nuclear factor-kappa B (NF-kappaB) were analyzed by immunohistochemisty, qPCR and (or) Western blot. The results showed that chrysin treatment for 4 weeks attenuated RVSP, mPAP and right ventricular remodeling index (RV/LV+S and RV/Tibial length) of PAH rats induced by monocrotaline. Furthermore, monocrotaline-induced right ventricular collagen accumulation and collagen I and collagen III expression were both significantly suppressed by chrysin. The expressions of NOX4, NF-kappaB and MDA contents were obviously decreased, while the T-AOC was significantly increased in right ventricule from PAH rats with chrysin treatment. These results suggest that chrysin ameliorates right ventricular remodeling of PAH induced by monocrotaline in rats through its down-regulating of NOX4 expression and antioxidant activity, and inhibiting NF kappaB expression and collagen accumulation. PMID- 26757550 TI - [Interaction of anti-thrombotic and anti-inflammatory activities of commonly used traditional Chinese medicine for promoting blood circulation and removing blood stasis revealed by network pharmacology analysis]. AB - Chinese traditional patent medicine for promoting blood circulation and removing blood stasis(PBCRBS) originated from traditional Chinese medicine theory and had approved efficacy and safety standards. However, its compatibility regularity and anti-thrombotic mechanism is not clear. To analyze the compatibility regularity and anti-thrombotic mechanism of Chinese traditional patent medicine for PBCRBS, a statistical and bioinformatics analysis was carried out using traditional Chinese medicine inheritance support system (TICMISS, V2.0) and ingenuity pathway analysis (IPA). The compatibility regularity analysis shows that the most commonly used herb combinations are Danshen (Salvia miltiorrhiza Bge.), Chuanxiong (Ligusticum chuanxiong Hort.) and Honghua (Carthamustinctorius L.). The anti-thrombotic mechanism analysis reveals that 25 ingredients have an effect on 29 thrombosis related molecules which 23 molecules are related to inflammation response. Furthermore, there are 5 inflammation molecules (NOS2, PTGS2, IL6, TNF, IL1beta) served as major targets. At the same time, Danshen, Chuangxiong and Honghua mainly used as sovereign herb or minister herb in the application of cardiovascular and cerebrovascular diseases. Therefore, Chinese traditional patent medicine for PBCRBS probably has an effect on anti-thrombotic activity through inhibiting the inflammatory response. In summary, the most commonly used herb combinations of Chinese traditional patent medicine for PBCRBS are Danshen, Chuanxiong and Honghua. Inhibiting inflammatory response, especially inflammation related molecules (NOS2, PTGS2, IL6, TNF and IL1beta), is probably a new starting point to clarify the anti-thrombotic mechanism of Chinese patent medicine for PBCRBS. PMID- 26757551 TI - [Pharmacokinetics of salvianolic acid A after single intravenous administration in Rhesus monkey]. AB - Salvianolic acid A (Sal A) is one of the most effective compounds isolated from the root of Salvia miltiorrhiza. Up to now, several studies regarding the pharmacokinetic profiles of Sal A have been reported, however there is no such study reported in monkeys, the species which is more similar to human. The aim of this study is to develop a LC-MS method for the determination of Sal A in monkey plasma and apply it to the pharmacokinetic studies of monkeys. After single intravenous administration of Sal A, the plasma concentration-time curves were observed and the main pharmacokinetic parameters were calculated. The plasma concentration at 2 min (C2 (min)) values were (28.343 +/- 6.426), (45.679 +/- 12.301) and (113.293 +/- 24.360) mg x L(-1) for Rhesus monkeys treated with Sal A at 2.5, 5 and 10 mg x kg(-1). The area under the concentration-time curve (AUC(0 infinity)) values were (3.316 +/- 0.871), (5.754 +/- 2.150) and (13.761 +/- 2.825) MUg x L(-1) x h, respectively. Furthermore, this method was improved and applied to the simultaneous determination of Sal A, Sal B and Sal C, which provided useful information for preclinical studies and clinical trials of Sal A, Sal B and Sal C. PMID- 26757552 TI - [Design, synthesis and pharmacological investigation of isoindoline derivatives as 5-HT/NE double reuptake inhibitors]. AB - A series of isoindoline derivatives were designed, synthesized, and evaluated for their double inhibitory activities. All of them were new compounds, and their structures were confirmed by 1H NMR and HR-MS. Preliminary in vitro pharmacological tests showed that all compounds exhibited 5-HT or NE reuptake inhibition activity. Among the tested compounds, compound I-3 exhibited potent inhibitory activity against 5-HT and NE reuptake in vitro, and exhibited potent antidepressant activity in vivo. These compounds designed can be further optimized for finding more potent 5-HT/NE dual reuptake inhibitors and antidepressant candidates as well. PMID- 26757553 TI - [Sesquiterpenoids from gorgonian Muriceides collaris]. AB - Seven guaiane-type sesquiterpenoids, a new compound 6-formyl-5-isopropyl-3 hydroxymethyl-7-methyl-1H-indene (1), a new natural product 5-isopropyl-3, 7 dimethyl-1H-indene-1-one (2), along with five known compounds: guaiazulene (3), 4 formyl-7-isopropyl-10-methylazulene (4), sesquiterpene ketolactone (5), alismoxide (6) and guaia-1 (5), 6-diene (7), were isolated from gorgonian Muriceides collaris collected in South China Sea. Their structures were elucidated on the basis of extensive spectroscopic analysis [MS, IR, 1H NMR, 13C NMR (DEPT), HMQC, HMBC, NOESY] and by comparison of the spectral data with those of the literatures. PMID- 26757554 TI - [Construction of the quantitative structure retention relationship of cefdinir related substances]. AB - The molecular descriptors of impurities with known structure in cefdinir were calculated, selected and associated with the chromatographic retention behavior to establish a model. This quantitative structure retention relationships (QSRR) model for the related substances of cefdinir was established under specific chromatographic condition and verified by other impurities. 12 molecular descriptors were used to establish the QSRR model, F_AFRBWF, Blbn_J, SsCH3, SssCH2, SsNH2, SssNH, SssS, SHdCH2, EEM_AFc, EEM_AFpl, EEM_XFpl and Pi_MaxQ. The relativity between true values and predictions in QSRR of cefdinir is R2 = 0.9836 (n = 18), DeltaRRT is no more than 0.154, as 10.17% in RRT. The results indicate that the QSRR model for the related substances of cefdinir can be used to evaluate the analysis methods for related substances and predict the chromatographic behavior of new impurities, which will provide a new way for the evaluation of the effectiveness for drug quality control. PMID- 26757555 TI - [Determination of the interaction kinetics between meloxicam and beta cyclodextrin using the quantitative high-performance affinity chromatography coupled with mass spectrometry]. AB - The association rate constant and dissociation rate constant are important parameters of the drug-cyclodextrin supermolecule systems, which determine the dissociation of drugs from the complex and the further in vivo absorption of drugs. However, the current studies of drug-cyclodextrin interactions mostly focus on the thermodynamic parameter of equilibrium constants (K). In this paper, a method based on quantitative high performance affinity chromatography coupled with mass spectrometry was developed to determine the apparent dissociation rate constant (k(off,app)) of drug-cyclodextrin supermolecule systems. This method was employed to measure the k(off,app) of meloxicam and acetaminophen. Firstly, chromatographic peaks of drugs and non-retained solute (uracil) on beta cyclodextrin column at different flow rates were acquired, and the retention time and variance values were obtained via the fitting the peaks. Then, the plate heights of drugs (H(R)) and uracil (H(M,C)) were calculated. The plate height of theoretical non-retained solute (H(M,T)) was calculated based on the differences of diffusion coefficient and the stagnant mobile phase mass transfer between drugs and uracil. Finally, the k(off,app) was calculated from the slope of the regression equation between (H(R)-H(M,T)) and uk/(1+k)2, (0.13 +/- 0.00) s(-1) and (4.83 +/- 0.10) s(-1) for meloxicam and acetaminophen (control drug), respectively. In addition, the apparent association rate constant (k(on,app)) was also calculated through the product of K (12.53 L x mol(-1)) and k(off,app). In summary, it has been proved that the method established in our study was simple, efficiently fast and reproducible for investigation on the kinetics of drug cyclodextrin interactions. PMID- 26757556 TI - [Preparation and evaluation of doxorubicin hydrochloride liposomes modified by poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate]. AB - In this study, the buffering capacity of amphiphilic pH-sensitivity copolymer poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate (PEOZ-CHMC) was evaluated. The ammonium sulfate gradient method was used to prepare doxorubicin hydrochloride (DOX x HCl)-loaded liposomes (DOX-L), and then the post-insertion method was used to prepare PEOZ-CHMC and polyethylene glycol-distearoyl phosphatidyl ethanolamine (PEG-DSPE) modified DOX x HCl-loaded liposomes (PEOZ DOX-L and PEG-DOX-L). The physico-chemical properties, in vitro drugs release behavior, cellular toxicity and intracellular delivery of liposomes were evaluated, separately. The results showed that PEOZ-CHMC has a satisfactory buffering capacity. The sephadex G-50 column centrifugation method and dynamic light scattering were used to determine the encapsulation efficiency (EE) and particle size of liposomes. The EE and particle size of DOX-L were (97.3 +/- 1.4) % and 120 nm, respectively, and the addition of PEOZ-CHMC or PEG-DSPE had no influence on EE and particle size. The zeta potentials of three kinds of liposomes were negative. The release behavior of various DOX liposomes in vitro was investigated by dialysis method. In phosphate buffer solution (PBS) at pH 7.4, DOX x HCl was released from PEOZ-DOX-L in a sustained manner. While in PBS at pH 5.0, the release rate of DOX x HCl from PEOZ-DOX-L increased significantly, which suggested DOX x HCl was released from PEOZ-DOX-L in a pH-dependent manner. The intracellular delivery of liposomes was investigated by confocal laser scanning microscopy (CLSM). The CLSM images indicated that PEOZ-DOX-L showed efficient intracellular trafficking including endosomal escape and release DOX x HCl into nucleus, as well as the DOX-L and PEG-DOX-L had no this effect. The cytotoxicity of liposomes against MCF-7 cells was detected by using MTT assay. The results showed that antiproliferative effects of PEOZ-DOX-L enhanced with pH value decreased, whereas DOX-L and PEG-DOX-L did not have any significant difference in inhibitions at different pH conditions. Therefore, the problems of the inhibition of cellular uptake of liposomes and the failed endosomal escape of pH-sensitive liposomes by PEG chain can be overcome by the pH-sensitive liposomes constructed by PEOZ-CHMC. PMID- 26757557 TI - [Preparation of budesonide sustained-release dry powder for inhalation and influence of lactose content]. AB - Using high pressure homogenization method combined with spray-drying, budesonide loaded chitosan microparticles were prepared and the in vitro release profile was investigated. The microparticles were then blended with lactose using a vortex mixer, influence of mixing speed, mixing time on drug recovery rate and content homogeneity were investigated. Meanwhile, influence of lactose content on drug recovery rate, content homogeneity, powder flowability and in vitro deposition were studied. It turned out that budesonide was released from the microparicles in a sustained manner, with fine particle fraction as high as 46.0%, but the powder flowability was poor. After blending with 10 times of lactose, the drug recovery rate was 96.5%, with relative standard deviation of drug content 2.5%, and fine particle fraction of the formulation increased to 59.6% with good flowability. It's demonstrated that using a vortex mixer, budesonide sustained release dry powder for inhalation with good recovery and content homogeneity could be prepared, the formulation had good flowability and was suitable for pulmonary inhaling. PMID- 26757558 TI - [Molecular cloning and characterization of four small GTPase genes from medicinal fungus Polyporus umbellatus]. AB - Four small GTPase genes which may be relative to sclerotial development were firstly cloned from medicinal fungus Polyporus umbellatus using rapid amplification of cDNA end PCR (RACE) method. The results showed that full-length cDNA of PuRhoA was 698 bp contained 585 bp ORF, which was predicted to encode a 194 amino acid protein with a molecular weight of 21.75 kD with an isoelectric point (pI) of 6.44; the full length cDNA of PuRhoA2 was 837 bp in length and encoded a 194 amino acid protein with a molecular weight of 21.75 kD and an isoelectric point (pI) of 6.33; the full length cDNA of Puypt1 was 896 bp in length and encoded a 204-aa protein with a molecular weight of 22.556 kD and an isoelectric point (pI) of 5.75; the full length cDNA of PuRas was 803 bp in length and encoded a 212-aa protein with a molecular weight of 23.821 kD and an isoelectric point (pI) of 5.2. There are fani acyl transferase enzyme catalytic site and myrcene-transferase enzyme catalytic site in PuRhoA1 while the PuRhoA2 only possess myrcene-transferase enzyme catalytic site. Puypt1 contains the Rab1 Ypt1 conserved domain of small GTPase family and PuRas contains the fani acyl transferase enzyme catalytic site. According to the phylogenetic analysis all these four small GTPase clustered with basidiomycete group. Quantitative real time PCR analysis revealed that Puypt1, PuRas and PuRhoA1 transcripts were significantly higher in the beginning of sclerotial formation than that in the mycelia, whereas the transcripts levels of PuRhoA2 gene were particularly lower in sclerotia than that in mycelia, suggesting that these four genes might be involved in P umbellatus selerotial development. PMID- 26757559 TI - [Effects of SUMO specific protease 1 on hPXR-mediated P-gp gene expression]. AB - The study aimed to investigate the effects of small ubiquitin-related modifier (SUMO) specific protease 1 (SENP1) on human PXR-mediated MDR1 transcriptional activity and mRNA expression. Empty vector and expression plasmids, including PXR, SENP1 and SENP1 mutant (SENP1m) were transiently transfected into HepG2 and LS174T cells using Lipo2000. Transcriptional activity was detected by dual luciferase reporter gene assay, and mRNA level was measured using real-time polymerase chain reaction. The results showed that SENP1 could remarkably reduce the rifampicin (RIF)-induced MDR1 reporter activity and mRNA level in hPXR over expressed HepG2 and LS174T cells (P < 0.05), whereas adding SENP1m restored the RIF-induced increases (P < 0.05). These results indicated that SENP1 could repress the RIF-induced hPXR-mediated MDR1 transcriptional activity and mRNA expression. PMID- 26757560 TI - Pregnancy Prevention and Termination of Pregnancy in Adolescence: Facts, Ethics, Law and Politics. AB - We present an overview of the current sexual behavior of adolescents in Israel, including the related social and moral issues, and compare it to that in Western countries. An important factor is the existence of liberal versus conservative views regarding the use of contraception and termination of pregnancy in these young subjects. We describe the current situation where in most cases the medical providers do not provide adequate contraceptive advice to adolescent girls, resulting ultimately in a high rate of unintended pregnancy. In our opinion, it is essential to make effective contraception more accessible to this vulnerable group. PMID- 26757561 TI - Atrial Tachycardia in Patients with Cryptogenic Stroke: Is there a Need For Anticoagulation? AB - BACKGROUND: Brief episodes of atrial tachycardia are a common finding in the Holter monitor recordings of elderly patients. Episodes of atrial tachycardia may convert to atrial fibrillation. Current guidelines do not recommend anti coagulant therapy in patients with atrial tachycardia and risk factors for embolism. OBJECTIVES: To assess the incidence of atrial tachycardia in a 24 hour Holter monitor recording of patients admitted to hospital with ischemic stroke. METHODS: The patient cohort included two groups: 134 patients admitted with a diagnosis of ischemic stroke (the study group), and 68 consecutive patients with a diagnosis of syncope (the control group). Both groups used a Holter monitor. RESULTS: There was no difference in the incidence of atrial tachycardia runs between the groups. Patients who suffered a stroke were more likely to be hypertensive (P < 0.05) and more likely to have a CHA2DS2-VASc score of >= 3 (P = 0.05). CONCLUSIONS: Atrial tachycardia as recorded on a Holter monitor was not more prevalent in patients presenting with ischemic stroke. The occurrence of atrial tachycardia is not an indication for systemic anticoagulation. PMID- 26757562 TI - Apparent Life-Threatening Events: Patients' Health Status at 5 Years of Age. AB - BACKGROUND: The long-term significance of apparent life-threatening events (ALTE) has not been thoroughly studied. OBJECTIVES: To evaluate, at age 5 years, the health status of consecutive children diagnosed with ALTE in infancy. METHODS: Based on the diagnostic workup, patients were classified into two groups: a 'broad' evaluation group (at least one test/procedure related to each of the five main causes: infectious, metabolic, cardiopulmonary, gastroenterological, neurological), and a 'narrow' workup group whose evaluation did not cover all five domains. Health status around age 5 was obtained from hospital records, community clinics and parents/caregivers. RESULTS: We identified 132 children with ALTE. Choking (49.2%) was the most common description, followed by apnea (13.6%), suspected seizure (12.9%), cyanosis (12.1%), breath-holding spell (8.3%), and pallor (3.8%). A broad diagnostic workup was performed in 62.1% of the infants, and a narrow workup in 37.9%. At age 5 years, 56.8% of the children were healthy; 27.3% reported chronic conditions unrelated to ALTE. Twenty-one children (15.9%) had unrelated neurodevelopmental conditions, mostly attention deficit disorder. One of the 132 ALTE patients relapsed and was eventually diagnosed with epilepsy. CONCLUSIONS: A single episode of ALTE in infancy was neither predictive of nor associated with chronic systemic or neurological disease at age 5 years. PMID- 26757563 TI - Role of Plain Abdominal Radiographs in the Evaluation of Patients with Non Traumatic Abdominal Pain. AB - BACKGROUND: Plain abdominal radiographs are still performed as a first imaging examination to evaluate abdominal pain in the emergency department (ED), despite uncertainty regarding their utility. OBJECTIVES: To describe the frequency and outcomes of the use of plain abdominal radiographs in the diagnosis of patients presenting with acute non-traumatic abdominal pain in the ED of a medical center. METHODS: We retrospectively reviewed the records of patients presenting to the ED with acute abdominal pain during a 6 month period. Further imaging (computed tomography, ultrasonography), when performed, was compared with the abdominal radiography. RESULTS: Of 573 consecutive patients, 300 (52%) underwent abdominal radiography. Findings were normal in 88% (n = 264), non-specific in 7.3% (n = 22), and abnormal in 4.7% (n = 14). For those with normal results, no further imaging was ordered for 43% (114/264). Of the 57% (150/264) who had follow-up imaging, 65% (98/150) showed abnormal findings. In 9 (3%) of the 300 patients, abdominal radiography identified bowel perforations and obstructions, and treatment was provided without the need for further radiologic examination. CONCLUSIONS: The use of plain abdominal radiography is still common despite the high rate of false positive results. Efforts are needed to decrease the indiscriminate use of radiography in patients presenting with abdominal symptoms. PMID- 26757564 TI - Endothelial Function Assessment in Patients with Erectile Dysfunction. AB - BACKGROUND: Erectile dysfunction (ED), a common problem in males of all ages, can be of organic, psychogenic or combined etiology. Organic ED is mainly caused by vascular and neurological disorders. One of the available tests for differentiating organic from inorganic ED is measuring penile tumescence and rigidity during the REM phase of sleep. However, this test lacks the ability to differentiate between a vascular and non-vascular cause of organic ED. OBJECTIVES: To compare the results of the EndoPAT test and the nocturnal penile tumescence (NPT) test in patients with erectile dysfunction. METHODS: Twenty patients with ED were recruited for the study. Each participant was evaluated by the SHIM score, RigiScan during polysomnography, and two EndoPAT tests (at the beginning and end of the study). RESULTS: Seventeen patients had a SHIM score 21; 4 of them had organic ED with a mean EndoPAT score of 1.49, significantly lower than the 1.93 mean EndoPAT score of the 11 patients in the psychogenic ED group (P = 0.047). Two participants had a neurological impairment (spinal trauma and herniated disk). The average SHIM score in the vascular organic group was 6.25 points as compared to 11.69 for the psychogenic group (P = 0.027). The positive predictive value was 43% and the negative predictive value 90%. CONCLUSIONS: EndoPAT could be helpful in excluding organic ED. PMID- 26757565 TI - Primary Ovarian Pregnancy: 43 Years Experience in a Single Institute and still a Medical Challenge. AB - BACKGROUND: Despite awareness regarding tubal pregnancy, ovarian pregnancy still remains a diagnostic challenge. The correct diagnosis is most frequently made intraoperatively and requires histopathologic confirmation. Therefore, additional diagnostic measurements are needed for earlier and more accurate detection of ovarian pregnancies which will allow more rapid and efficient treatment. OBJECTIVES: To assess the time trends, clinical manifestations, surgical management and post-procedure outcome of 46 primary ovarian pregnancies in a single institution during three time periods. METHODS: In this retrospective study we compared 20 patients with primary ovarian pregnancy during the years 1971- 1989 (first period), 19 patients in 1990-2001 (second period) and 7 patients in 2002-2013 (third period). In all cases the pathology examination confirmed primary ovarian pregnancy. RESULTS: The number of tubal ectopic pregnancies almost doubled, from 637 in the first period to 1279 in the third period (P < 0.001). However, there was a significant fall in the number of ovarian ectopic pregnancies, from 20 cases in the first period to 7 cases in the third (P = 0.009). A significant difference was noted when we compared the postoperative hospitalization time (4.06 +/- 1.4 vs. 2.0 +/- 0.6 days respectively, P = 0.001) in the second versus the third time period. CONCLUSIONS: Ovarian pregnancy continues to be a diagnostic challenge, associated with a high rate of circulatory collapse, hemoperitoneum and requirements for blood transfusions, all leading to longer hospitalization. PMID- 26757566 TI - Visual Analogue Scales of Pain, Fatigue and Function in Patients with Various Rheumatic Disorders Receiving Standard Care. AB - BACKGROUND: Pain, fatigue and functional disability are common key outcomes in most rheumatologic disorders. While many studies have assessed the outcomes of specific disease states, few have compared the outcomes of various rheumatic diseases. OBJECTIVES: To assess how the intensity and rating of pain, fatigue and functional disability vary among groups of patients with various rheumatic disorders receiving standard care. METHODS: In a cross-sectional study conducted in a hospital-based rheumatology unit, standard clinical and laboratory data were obtained and all patients filled out questionnaires on pain, fatigue and daily function. The analysis concentrated on visual analogue scales (VAS) using specific statistical methods. RESULTS: A total of 618 visits of 383 patients with inflammatory as well as non-inflammatory rheumatic disorders were analyzed. Fibromyalgia patients had significantly higher VAS scores compared to all other groups. On the other hand, patients with polymyalgia rheumatica demonstrated significantly lower VAS scores compared to all other groups of patients. Patients with psoriatic arthritis also demonstrated relatively low VAS scores. VAS scores were lower in patients with inflammatory disorders as compared to patients with non-inflammatory disorders. CONCLUSIONS: Our results suggest a spectrum of outcome intensity in various rheumatic disorders receiving standard care, ranging from fibromyalgia patients who report distinctive severity to patients with inflammatory disorders who are doing relatively well as compared to patients with non-inflammatory disorders. The findings emphasize the need to explore the underlying mechanisms of pain and fatigue in patients with non-inflammatory rheumatic disorders. PMID- 26757567 TI - Meningitis and Meningoencephalitis among Israel Defense Force Soldiers: 20 Years Experience at the Hadassah Medical Centers. AB - BACKGROUND: Meningitis and meningoencephalitis pose major risks of morbidity and mortality. OBJECTIVES: To describe 20 years of experience treating infections of the central nervous system in Israel Defense Force (IDF) soldiers, including the common presentations, pathogens and sequelae, and to identify risk groups among soldiers. METHODS: All soldiers who were admitted to the Hadassah University Medical Center (both campuses: Ein Kerem and Mt. Scopus) due to meningitis and meningoencephalitis from January 1993 to January 2014 were included in this retrospective study. Clinical, laboratory and radiologic data were reviewed from their hospital and army medical corps files. Attention was given to patients' military job description, i.e., combat vs. non-combat soldier, soldiers in training, and medical personnel. RESULTS: We identified 97 cases of suspected meningitis or meningoencephalitis. Six were mistakenly filed and these patients were found to have other disorders. Four soldiers were diagnosed with epidural abscess and five with meningitis due to non-infectious in flammatory diseases. Eighty-two soldiers in active and reserve duty had infectious meningitis or meningoencephalitis. Of these, 46 (56.1%) were combat soldiers and 31 (37.8%) non combat; 20 (29.2%) were soldiers in training, 10 (12.2%) were training staff and 8 (9.8%) were medical staff. The main pathogens were enteroviruses, Epstein-Barr virus an d Neisseria meningitidis. CONCLUSIONS: In our series, soldiers in training, combat soldiers and medical personnel had meningitis and meningoencephalitis more than other soldiers. Enteroviruses are highly infectious pathogens and can cause outbreaks. N. meningitidis among IDF soldiers is still a concern. Early and aggressive treatment with steroids should be considered especially in robust meningoencephalitis cases. PMID- 26757568 TI - Adenocarcinoma of the Gallbladder: Incidental Finding in Patients following Laparoscopic Sleeve Gastrectomy and Cholecystectomy. AB - BACKGROUND: Gallbladder (GB) cancer is rare. Most cases are incidentally found in specimens after a cholecystectomy. Cholelithiasis is almost always present when this diagnosis is made. Obesity is a known risk factor for gallstone formation and thus may be related to GB cancer. OBJECTIVES: To highlight the importance of evaluating the gallbladder before surgery, resecting the gallbladder whenever required, and screening the resected tissue for malignancy. METHODS: We retrospectively searched a prospectively maintained database of all bariatric procedures during the last 8 years for cases of concomitant laparoscopic sleeve gastrectomy (LSG) and laparoscopic cholecystectomy (LC). Pathologic reports of the gallbladders were reviewed. Demographic data and perioperative parameters were documented. RESULTS: Of 2708 patients reviewed, 1721 (63.55%) were females and 987 (36.45%) males. Excluded were 145 (5.35%) who had a previous cholecystectomy. Of the remaining 2563, 180 (7.02%) had symptomatic gallbladder disease and underwent LSG with LC. Of these, two females (BMI 53 kg/m2 and 47 kg/m2, both age 60) were found by histological examination to have adenocarcinoma in their GB specimens (1.11%). Both were reoperated, which included partial hepatectomy of the GB bed, resection of the cystic stump, lymph node dissection, and resection of the port sites. One patient is doing well, with no evidence of disease at a postoperative follow-up of 4 years. The second patient had recurrent disease with peritoneal spread and ascites 20 months post-surgery and died 18 months later. CONCLUSIONS: GB cancer is a rare finding in cholecystectomy specimens. The incidence of this entity might be higher in obese older females owing to the higher incidence of cholelithiasis in these patients. PMID- 26757569 TI - Hepatitis C Virus in Children: Deferring Treatment in Expectation of Direct Acting Antiviral Agents. AB - The major route of hepatitis C virus (HCV) infection in the pediatric age group is vertical, with infection occurring in up to 5% of infants born to mothers positive for HCV-RNA. The natural course of pediatric HCV infection is characterized by a high rate of spontaneous clearance, an asymptomatic clinical course, and normal or mild histologic changes. Cirrhosis is reported in 1-2% of children, and progression to severe chronic liver disease and HCC occurs 20-30 years after infection. Treatment with pegylated interferon (Peg-IFN) + ribavirin results in a sustained viral response (SVR) reaching 100% in children with HCV genotypes 2 or 3 but only 45-55% in those infected with genotypes 1 or 4. Treatment is associated with adverse effects ranging from flu-like symptoms, myalgia, anemia and thrombocytopenia, to less commonly observed thyroid-related symptoms, alopecia, neuropsychiatric manifestations and possible long-term effects on growth. Ongoing trials with direct-acting antiviral agents in adults show promising results with treatment regimens of shorter duration and high tolerance. The next few years will likely see these advances introduced to the pediatric population as well. In the meantime, in children with HCV an expectant approach is advocated and treatment should be offered only to those at high risk for more severe, progressive disease. PMID- 26757570 TI - Lymphoma of the Right Atrium and Ventricle. PMID- 26757571 TI - Q Fever Manifested as Acalculous Cholecystitis. PMID- 26757572 TI - Coronary Computed Tomography for Diagnosis of Traumatic Coronary Dissection. PMID- 26757573 TI - Extremely Low Birth Weight Infant Born with Extensive Abdominal Cutis Aplasia. PMID- 26757574 TI - Prolonged Adrenal Suppression after Adrenalectomy for Subclinical Hypercortisolism. PMID- 26757575 TI - Melioidosis of the Skin in an Israeli Traveler Returning from Thailand. PMID- 26757576 TI - Gout. PMID- 26757577 TI - [Ten years of networking days for Swiss equine research]. PMID- 26757578 TI - [Ban on wooing an employee away--what is permissible, what not?]. PMID- 26757580 TI - [Third Swiss veterinary seminar: a rendezvous in Basel]. PMID- 26757579 TI - [Small ruminant seminar 2015]. PMID- 26757581 TI - [Workshop on strategies against antibiotic resistance. Great unity about the subject matter, uncertainty about setting of priorities]. PMID- 26757582 TI - [Development of a real-time RT-PCR for detection of equine influenza virus]. AB - Equine influenza is a highly contagious respiratory disease in horses caused by influenza A viruses. In this work a real-time RT-PCR for fast and sensitive diagnosis of equine influenza viruses (EIV) targeting a highly conserved region of the matrix gene was developed. In addition two RT-PCR methods for the amplification of large parts of the matrix- and HA gene were adapted for molecular-epidemiological characterization of viruses. The primers of the real time RT-PCR had homologies of 99.4% to EIV- and 97.7% to all influenza A viral sequences, whereas the minor groove binder (MGB) probe showed homologies of 99.3% and 99.6%, respectively. These high values allow application of the assay for influenza viruses in other species. Using 20 equine, 11 porcine and 2 avian samples, diagnostic suitability of the assay was confirmed. High specificity for influenza viruses was shown both experimentally and by software simulation. The assay analytical sensitivity was at 10(2)-10(3) copies of RNA and 10(0)-10(1) copies of DNA, respectively. This allows virus detection also in circumstances of minor viral shedding. All amplified EIV sequences were classified phylogenetically within the known lineages. PMID- 26757584 TI - [In the poultry field much knowledge of the subject is available]. PMID- 26757583 TI - [Ulcerative colitis and proctitis in two Swiss Braunvieh cows]. AB - Two Swiss Braunvieh cows were referred to our clinic because of narrowing of the rectum and difficult rectal examination attributable to restricted arm movement within the pelvic cavity. Cow 1 also had perforation of the cranial rectum and cow 2 had multiple small funnel-shaped depressions in the rectal mucosa. Both cows had ultrasonographic evidence of peritonitis with thickening of the intestinal wall and fibrin and fluid accumulation in the abdominal cavity. A diagnosis of peritonitis was made in both cows, most likely caused by rectal perforation; they were euthanized and a post-mortem examination was carried out. Both cows had proctitis and ulcerative colitis with three or four perforated ulcers which were associated with fibrinopurulent peritonitis. The final diagnosis was ulcerative colitis and proctitis of unknown aetiology. Infectious causes of colitis and proctitis, including bovine viral diarrhoea, adenovirus infection and salmonellosis, and trauma and poisoning were ruled out. PMID- 26757585 TI - [Module book for veterinarians]. PMID- 26757586 TI - [Pull on a rope together--for the well-being of our profession]. PMID- 26757587 TI - [Noise from fireworks and animal wellbeing]. PMID- 26757588 TI - [Pension funds in the real and ideal world]. PMID- 26757589 TI - [Must the veterinarian reimburse for an animal protection offense punishment or report?]. PMID- 26757590 TI - [Diagnosis and therapy of retained fetal membranes, puerperal metritis and clinical endometritis in cattle: Results of the Online-survey among Swiss practitioners. I Retained fetal membranes]. AB - The aim of this study was to obtain the diagnostic and therapeutic approach among Swiss practitioners in cows with retained fetal membranes (RFM) (part 1). All members of the Association for ruminant health were contacted per email via the newsletter. The survey was completed by 128 veterinarians, partially responded by 140 veterinarians. The manual removal of the fetal membranes is practiced by 129 of the responding veterinarians. Cows with/without fever are treated usually with intrauterine antibiotics. Cows with RFM with/without fever are most commonly treated parenterally with tetracycline or penicillin. The use of cephalosporins and quinolones in cows with fever is more common than in cows without fever. With the present results of the survey veterinarians should critically question the supposed benefits of the manual removal of the placenta and the use of antibiotics in cows with RFM. PMID- 26757591 TI - [Diagnosis and therapy of retained fetal membranes, puerperal metritis and clinical endometritis in cattle: Results of the Online-survey among Swiss practitioners. II. Puerperal metritis and clinical endometritis]. AB - The aim of the study was to obtain the diagnostic and therapeutic approach among Swiss practitioners in cows with puerperal metritis and clinical endometritis (part 2). All members of the Association for ruminant health were contacted per email via the newsletter. The survey was completed by 128 veterinarians, partially responded by 140 veterinarians. The following main symptoms of puerperal metritis were stated by the practitioners: purulent vaginal discharge, fever and reduced appetite. A vaginal and rectal examination was performed to diagnose the disease. Usually, an intrauterine treatment with tetracycline or cefapirin was done. Parenteral administration of tetracycline or penicillin was often combined with PGF(2alpha), NSAIDS or cortisone. Clinical endometritis was also diagnosed by vaginal and rectal examination and the main symptom indicated was purulent vaginal discharge. The therapy consisted of the administration of PGF(2alpha), uterine infusions predominantly with cefapirin, and rarely with parenteral administration of antibiotics. Further diagnostic tools were not used and normally cows were not rechecked. The success of the therapy of puerperal metritis and clinical endometritis was judged to be satisfactory to excellent. PMID- 26757592 TI - [Sonographic findings in two miniature goats with metastatic bile duct carcinoma]. AB - This case study describes 2 miniature goats with metastatic bile duct carcinoma. The main clinical sign was a pear-shaped abdomen due to abdominal distension in case 1 and stranguria and pollakiuria in case 2. Liver enzyme activity was markedly elevated in both goats, and ultrasonographic examination showed multiple round echoic structures that were partly surrounded by a hypoechoic zone. A tentative diagnosis of liver tumour was made based on the sonographic findings, and a final diagnosis of intrahepatic bile duct carcinoma was made post mortem. PMID- 26757593 TI - Chronic Achilles tendon rupture augmented by transposition of the fibularis brevis and fibularis longus muscles. AB - A 1 year and 8 months old castrated male Pyrenean mountain dog was presented with an Achilles tendon rupture at least 5 weeks old. The defect between the two tendon ends was 2 cm in full extension of the tarsal joint. A new technique was successfully applied; a transposition and tenodesis of the fibularis brevis and fibularis longus muscles, combined with a 3 loop pulley suture and a tensor fascia lata graft. A transarticular external fixator was used for the first 3.5 weeks after surgery and a splint for the two following weeks. A 3 years follow-up shows the dog walking without any lameness. PMID- 26757594 TI - Implications of mesenchymal stem cells in regenerative medicine. AB - Mesenchymal stem cells (MSCs) are a population of multipotent progenitors which reside in bone marrow, fat, and some other tissues and can be isolated from various adult and fetal tissues. Self-renewal potential and multipotency are MSC's hallmarks. They have the capacity of proliferation and differentiation into a variety of cell lineages like osteoblasts, condrocytes, adipocytes, fibroblasts, cardiomyocytes. MSCs can be identified by expression of some surface molecules like CD73, CD90, CD105, and lack of hematopoietic specific markers including CD34, CD45, and HLA-DR. They are hopeful tools for regenerative medicine for repairing injured tissues. Many studies have focused on two significant features of MSC therapy: (I) systemically administered MSCs home to sites of ischemia or injury, and (II) MSCs can modulate T-cell-mediated immunological responses. MSCs express chemokine receptors and ligands involved in cells migration and homing process. MSCs induce immunomedulatory effects on the innate (dendritic cells, monocyte, natural killer cells, and neutrophils) and the adaptive immune system cells (T helper-1, cytotoxic T lymphocyte, and B lymphocyte) by secreting soluble factors like TGF-beta, IL-10, IDO, PGE-2, sHLA G5, or by cell-cell interaction. In this review, we discuss the main applications of mesenchymal stem in Regenerative Medicine and known mechanisms of homing and Immunomodulation of MSCs. PMID- 26757595 TI - Structural brain indices and executive functioning in multiple sclerosis: A review. AB - Multiple sclerosis (MS) is a neurological disease characterized by lesion-induced white matter deterioration. Brain atrophy and damage to normal appearing white matter (NAWM) and normal appearing gray matter (NAGM) have also been identified as consequences of MS. Neuroimaging has played an integral role in investigating the effects of white and gray matter damage across the three primary clinical phenotypes of the disease-primary progressive (PPMS), relapsing remitting (RRMS), and secondary progressive (SPMS) MS. Both conventional (e.g., T1-weighted imaged) and nonconventional (e.g., diffusion tensor imaging) neuroimaging methods have yielded important information regarding the structural integrity of the brain during the course of the disease. Moreover, it has provided the opportunity to explore the relationship between structural brain indices and cognitive functioning, such as executive functioning, in MS. In this paper, we provide a brief overview of executive functioning in MS, a general review of how structural damage presents in MS by way of sclerotic lesions, atrophy, and microstructural white matter damage, and, finally, how structural brain damage relates to executive dysfunction. PMID- 26757596 TI - Microbial production of poly(lactate-co-3-hydroxybutyrate) from hybrid Miscanthus derived sugars. AB - P[(R)-lactate-co-(R)-3-hydroxybutyrate] [P(LA-co-3HB)] was produced in engineered Escherichia coli using lignocellulose-derived hydrolysates from Miscanthus * giganteus (hybrid Miscanthus) and rice straw. Hybrid Miscanthus-derived hydrolysate exhibited no negative effect on polymer production, LA fraction, and molecular weight of the polymer, whereas rice straw-derived hydrolysate reduced LA fraction. These results revealed that P(LA-co-3HB) was successfully produced from hybrid Miscanthus-derived sugars. PMID- 26757597 TI - Self-managed oral anticoagulant therapy: a call for implementation. PMID- 26757598 TI - Association of DENND1A Gene Polymorphisms with Polycystic Ovary Syndrome: A Meta Analysis. AB - OBJECTIVE: The rs2479106 and rs10818854 polymorphisms in the DENND1A gene have been reported to be extensively associated with risk of polycystic ovary syndrome (PCOS). However, the results from these studies remained inconclusive and conflicting. To detect a true association of rs2479106 and rs10818854 polymorphisms with PCOS risk, a single study may be underpowered, particularly for those studies with inadequate sample size. Therefore, we performed a meta analysis of all available studies to explore this association. METHODS: All studies published up to March 2015 on the association were identified by searching electronic databases PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure. Studies containing available genotype frequencies of those 2 polymorphisms were chosen, and the odds ratios and associated 95% confidence intervals were calculated using fixed- or random- effects models. RESULTS: A total of 8 studies about s2479106 polymorphism (8185 cases and 28675 controls) and 5 studies about rs10818854 polymorphism (6638 cases and 27443 controls) met the inclusion criteria for the meta-analysis. Overall, significant increase of PCOS risk was found between DENND1A-rs10818854 and PCOS susceptibility. In addition, we also found an increased risk of PCOS in rs2479106 allele model, heterozygote variant genetic model, and dominant genetic model. CONCLUSION: This meta-analysis suggested that rs2479106 and rs10818854 polymorphisms in the DENND1A gene were associated with increased risk of PCOS. To validate the association between these polymorphisms and PCOS susceptibility, further large and well-designed studies are needed. PMID- 26757599 TI - Enhanced TRAP-induced platelet aggregation with dabigatran - Clinical perspective. PMID- 26757600 TI - Analysis of dendritic cell subpopulations in follicular lymphoma with respect to the tumor immune microenvironment. AB - The immune cell composition of the follicular lymphoma (FL) tumor microenvironment is increasingly recognized as an important determinant for clinical outcome. Here, we explored frequency and distribution of dendritic cell (DC) subtypes in relation to regulatory T cells (Treg) by immunohistochemistry in lymph node biopsies from patients with de novo FL. We found that neoplastic follicles contained lower DC and higher Treg frequencies than hyperplastic follicles in control lymph nodes. Treg numbers particularly correlated with the subset of conventional CD11c(+ )DCs. Additionally, both a high intra- to interfollicular ratio of CD11c(+ )DCs and increased intrafollicular Treg frequencies were associated with decreased overall survival. This suggests that functional interactions between these cells may be relevant for FL progression/recurrence. The presence of CD11c(+ )DCs in the tumor microenvironment may assist tumor infiltration by Tregs, thus contributing to the suppression of an otherwise beneficial T-cell-dominated FL microenvironment. PMID- 26757608 TI - Rhythmic electrographic discharges during deep hypothermic circulatory arrest. AB - OBJECTIVE: The main objective of this study is to examine the prevalence and timing of rhythmic electrographic discharges and periodic sharp transients during aortic arch repair surgeries using DHCA as detected by continuous intraoperative encephalogram (EEG) and correlate it with outcome. METHODS: Electronic medical records and the intraoperative EEGs of 32 patients who underwent aortic arch reconstruction with DHCA were reviewed. Preoperative patient characteristics, intraoperative data, and postoperative outcomes were examined. EEGs were graded based on the frequency of sharp transients (grade 0-2) and/or the presence of rhythmic electrographic discharges (grade 3). RESULTS: Periodic sharp transients were seen in 30/32 cases. Grade 1 and grade 2 activations were more prominent during cooling at nasopharyngeal temperature of 23.9+/-4.01 degrees C (mean+/ SDV). Rhythmic electrographic discharges occurred in seven patients and were exclusively seen during cooling at nasopharyngeal temperatures below 28 degrees C except in one case during rewarming at nasopharyngeal temperatures of 22 degrees C. No patient with rhythmic discharges developed postoperative clinical neurologic deficit or seizures. CONCLUSIONS: Periodic sharp transients occurred in almost all cases during induction of deep hypothermia. This activity was not associated with postoperative neurologic deficit. SIGNIFICANCE: Clinical neurophysiologists, technicians and surgeons need to be aware that low amplitude periodic sharp transients and rhythmic electrographic discharges are common during DHCA, yet have no apparent clinical significance. PMID- 26757610 TI - Scalable topographies to support proliferation and Oct4 expression by human induced pluripotent stem cells. AB - It is well established that topographical features modulate cell behaviour, including cell morphology, proliferation and differentiation. To define the effects of topography on human induced pluripotent stem cells (iPSC), we plated cells on a topographical library containing over 1000 different features in medium lacking animal products (xeno-free). Using high content imaging, we determined the effect of each topography on cell proliferation and expression of the pluripotency marker Oct4 24 h after seeding. Features that maintained Oct4 expression also supported proliferation and cell-cell adhesion at 24 h, and by 4 days colonies of Oct4-positive, Sox2-positive cells had formed. Computational analysis revealed that small feature size was the most important determinant of pluripotency, followed by high wave number and high feature density. Using this information we correctly predicted whether any given topography within our library would support the pluripotent state at 24 h. This approach not only facilitates the design of substrates for optimal human iPSC expansion, but also, potentially, identification of topographies with other desirable characteristics, such as promoting differentiation. PMID- 26757611 TI - New neo-clerodane diterpenoids from Scutellaria strigillosa with cytotoxic activities. AB - Two new neo-clerodane diterpenoids, named scutestrigillosins D and E (1 and 2), were isolated from the whole plant Scutellaria strigillosa. Their structures were established on the basis of detailed physical data analyses. In vitro, two new compounds exhibited cytotoxic activities against four tumor cell lines (HONE-1, P 388, MCF7, and HT29), and gave IC50 values in the range of 3.4-8.9 MUMU. PMID- 26757609 TI - Screening of HHEX Mutations in Chinese Children with Thyroid Dysgenesis. AB - OBJECTIVE: Congenital hypothyroidism (CH) is a frequent neonatal endocrine disease with an incidence of about 1:2500 worldwide. Although thyroid dysgenesis (TD) is the most frequent cause of CH cases, its pathogenesis remains unclear. The aim of this study was to screen the hematopoietically-expressedhomeobox gene (HHEX) mutations in Chinese children with TD. METHODS: Genomic deoxyribonucleic acid was extracted from peripheral blood leukocytes in 234 TD patients from Shandong Province. Mutations in all exons and nearby introns of HHEX were analyzed by direct sequencing after polymerase chain reaction amplification. RESULTS: Sequencing analysis of HHEX indicated that no causative mutations were present in the coding regionof the TD patients. However, a genetic variant (IVS2+ 127 G/T, 10.26%) was observed in the intron 2 in HHEX. CONCLUSION: Our results indicate that the frequency of HHEX mutation is very low and may not be the main causative factor in Chinese TD patients. However, these results need to be replicated using larger datasets collected from different populations. PMID- 26757612 TI - Serial Quantitative Computed Tomography Perfusion in Aneurysmal Subarachnoid Hemorrhage. AB - PURPOSE: Computed tomography perfusion (CTP) has been performed to predict which patients with aneurysmal subarachnoid hemorrhage are at risk of developing delayed cerebral ischemia (DCI). Patients with severe arterial narrowing may have significant reduction in perfusion. However, many patients have less severe arterial narrowing. There is a paucity of literature evaluating perfusion changes which occur with mild to moderate narrowing. The purpose of our study was to investigate serial whole-brain CTP/computed tomography angiography in aneurysm related subarachnoid hemorrhage (aSAH) patients with mild to moderate angiographic narrowing. METHODS: We retrospectively studied 18 aSAH patients who had baseline and follow-up whole-brain CTP/computed tomography angiography. Thirty-one regions of interest/hemisphere at six levels were grouped by vascular territory. Arterial diameters were measured at the circle of Willis. The correlation between arterial diameter and change in CTP values, change in CTP in with and without DCI, and response to intra-arterial vasodilator therapy in DCI patients was evaluated. RESULTS: There was correlation among the overall average cerebral blood flow (CBF; R=0.49, p<0.04), mean transit time (R=-0.48, p=0.04), and angiographic narrowing. In individual arterial territories, there was correlation between changes in CBF and arterial diameter in the middle cerebral artery (R=0.53, p=0.03), posterior cerebral artery (R=0.5, p=0.03), and anterior cerebral artery (R=0.54, p=0.02) territories. Prolonged mean transit time was correlated with arterial diameter narrowing in the middle cerebral artery territory (R=0.52, p=0.03). Patients with DCI tended to have serial worsening of CBF compared with those without DCI (p=0.055). CONCLUSIONS: Our preliminary study demonstrates there is a correlation between mild to moderate angiographic narrowing and serial changes in perfusion in patients with aSAH. Patients developing DCI tended to have progressively worsening CBF compared with those not developing DCI. PMID- 26757614 TI - Evaluation of genotoxic and antigenotoxic effects of boron by the somatic mutation and recombination test (SMART) on Drosophila. AB - OBJECTIVE: In this study, different concentrations of boron have been evaluated for genotoxic and antigenotoxic properties by using the somatic mutation and recombination test (SMART) on Drosophila melanogaster. STUDY DESIGN: The treatment concentrations were chosen to a pretest. Third-instar larvae trans heterozygous for two genetic markers, multiple wing hair (mwh) and flare (flr3), were treated at different concentrations (0.1, 5, 10, 20, and 40 mg/mL) of boron. In addition to investigating antigenotoxic effects, the same boron concentrations were co-administered with 0.1 mM Ethyl Methane Sulfonate (EMS). Distilled water was used as a negative control; 0.1 mM of EMS was used as a positive control. For the chronic feeding study, small plastic vials were prepared with 1.5 g of dry Drosophila Instant Medium and 5 mL of the respective test solution. Hundreds of trans-heterozygous larvae were embedded into this medium. Feeding ended with pupation of the surviving larvae. After metamorphosis, all surviving flies were collected and stored in a 70% ethanol solution. Preparation and microscopic analyses of wing were made after the treatment. Then the observed mutations were classified according to size and type of mutation per wing. RESULTS: Results indicated that there is no significant genotoxic effect with all of the boron concentrations. In addition, the antigenotoxic activities of boron against EMS were tested. Results indicated that all boron concentrations (0.1, 5, 10, 20 and 40 mg/mL) were able to abolish the genotoxic effects induced by the EMS. CONCLUSION: It is suggested that the observed effects can be linked to the antioxidant properties of boron. Moreover, these in vivo results will contribute to the antigenotoxicity database of boron. PMID- 26757615 TI - Paroxysmal Atrial Fibrillation and Brain Freeze: A Case of Recurrent Co-Incident Precipitation From a Frozen Beverage. AB - BACKGROUND: Episodes of paroxysmal atrial fibrillation may be precipitated by the rapid ingestion of ice-cold foods and beverages. This condition has received little research attention, and its true prevalence is poorly described. Treating physicians may not identify cold ingestion as a causal factor of paroxysmal atrial fibrillation, thus compromising both history taking and patient education. CASE REPORT: We report a case of a healthy young-adult man who drank a slushed ice beverage that immediately induced atrial fibrillation and a brain freeze headache simultaneously. This occurred on two separate occasions, years apart. During both episodes, the acute brain freeze self-resolved quickly, but the new onset palpitations occasioned a visit to the emergency department for diagnosis and treatment. The emergency physicians failed to make the causal link between the cold drink and the atrial dysrhythmia. Though the brain freeze headache and paroxysmal atrial fibrillation were both precipitated by rapid ingestion of an ice-cold beverage, the mediating mechanisms are distinct. We review these two cold-induced conditions, their prevalence, and their probable mechanisms. CONCLUSIONS: The recurrent simultaneous occurrence of brain-freeze headache with paroxysmal atrial fibrillation identifies the ingestion of a frozen beverage as the precipitant of the atrial dysrhythmia. Increasing physician awareness of cold ingestion as a cause of paroxysmal atrial fibrillation will improve history taking and patient education. PMID- 26757617 TI - A systematic molecular dynamics approach to the structural characterization of amyloid aggregation propensity of beta2-microglobulin mutant D76N. AB - Beta-2 microglobulin (beta2m) is an amyloidogenic protein belongs to the immunoglobulin superfamily, responsible for the dialysis-related amyloidosis (DRA). Misfolding of beta2m is a prerequisite to the formation of systemic amyloidosis that has an effect on the structure and function of the affected organ. The aim of our present study is to intensively explore the structural characterization of amyloid aggregation propensity of recently identified natural mutation D76N by applying the classical molecular dynamics (MD) approach. The MD result revealed that mutant D76N exhibited a wide variation in the evolutionarily conserved secondary structure profile. Due to an unsatisfied position of main chain donor/acceptor atoms that unable to form essential hydrogen bonds resulted to cause misfolding of mutant D76N by disrupting the local folding of beta strands and turn region. Analysis of time evolution of various structural properties, especially those of the functionally important residues: aggregation determining, initiating, and gatekeeper residues gave some possible insights into the structural characteristics of the disease mutant D76N. In a nutshell, compared to the wild-type beta2m, aggregation promoting propensity of mutant D76N has established a long beta-strand D owing to an inward movement of residue, Asp(53). Besides, aggregation forming characteristic of the DE loop in mutant D76N showed greater flexibility along the first principal eigenvector that favored to enhance an unusual conformational dynamics may lead toward self aggregation and amyloid fibrils. PMID- 26757618 TI - Study of the Formation of the First Aromatic Rings in the Pyrolysis of Cyclopentene. AB - The thermal decomposition of cyclopentene was studied in a jet-stirred reactor operated at constant pressure and temperature to provide new experimental information about the formation of the first aromatic rings from cyclic C5 species. Experiments were carried out at a residence time of 1 s, a pressure of 106.7 kPa, temperatures ranging from 773 to 1073 K and under diluted conditions (cyclopentene inlet mole fraction of 0.04). Species were quantified using three analytical methods: gas chromatography, synchrotron vacuum ultraviolet photoionization mass spectrometry (SVUV-PIMS), and single photon laser ionization mass spectrometry (SPI-MS). Several species could be quantified using both methods allowing comparison of experimental data obtained with the three apparatuses. Discrepancies observed in mole fraction profiles of some large aromatics suggest that the direct sampling in the gas phase (with a molecular beam or a capillary tube) provide more reliable results. The main reaction products are 1,3-cyclopentadiene and hydrogen. The formation of many unsaturated C2-C6 olefins, diolefins and alkynes was also observed but in smaller amounts. Benzene, toluene, styrene, indene, and naphthalene were detected from 923 K. SVUV PIMS data allowed the identification of another C6H6 isomer which is 1,5-hexadien 3-yne rather than fulvene. The quantification of the cyclopentadienyl radical was obtained from SVUV-PIMS and SPI-MS data with some uncertainty induced by the possible contribution to the signal for m/z 65 of a fragment from the decomposition of a larger ion. This is the first time that a radical is quantified in a jet-stirred reactor using non-optical techniques. SPI-MS analyses allowed the detection of species likely being combination products of allyl and cyclopentadienyl radicals. A model was developed for the pyrolysis of cyclopentene. This model includes routes of formation of aromatics from the cyclopentadienyl radical. The comparison of experimental and computed data is overall satisfactory for primary reaction products whereas discrepancies are still observed for aromatics. PMID- 26757613 TI - Long-term efficacy and safety of etravirine-containing regimens in a real-life cohort of treatment-experienced HIV-1-infected patients. AB - OBJECTIVES: Etravirine (ETR) was approved in France in September 2008 and is used in combination with a boosted protease inhibitor (bPI) and other anti-retrovirals (ART) in HIV-infected pre-treated patients. This study aimed to report in a real life setting the efficacy and tolerability of ETR-based regimens and factors associated with virological response. METHODS: The study population included all treatment-experienced patients who initiated an ETR-based regimen between September 2008 and July 2013 from the French Dat'AIDS cohort. Analyses were performed in ART-experienced patients starting ETR after virological failure (VF) or as a maintenance therapy (MT), with or without bPI. RESULTS: A total of 2006 patients (VF, n = 1014 (51%); MT, n = 992 (49%)) were included. At M12, the proportion of patients with HIV RNA < 50 copies/ml was 71.7% (72.0% and 71.1% with or without bPI) in the VF group and 90.5% (85.0% and 92.3% with or without bPI) in the MT group, without significant differences regarding the use of bPI. ETR was discontinued in 8.8% of patients for adverse events in 23.9% of cases (21.5% in VF, 29.5% in MT), treatment failure in 15.2% (16.2% in VF, 7.4% in MT) or simplification in 5.4% (4.6% in VF, 7.4% in MT). In the VF group, factors associated with virological response were a longer duration of HIV infection (OR = 2.7; p < 0.001) and baseline HIV RNA < 5 log10 copies/mL (OR = 2.1; p = 0.002). CONCLUSION: This study shows that in ART-experienced patients ETR is well tolerated with a high efficacy when combined with other active drugs, even when the regimen does not include a bPI. PMID- 26757616 TI - Remote and reversible inhibition of neurons and circuits by small molecule induced potassium channel stabilization. AB - Manipulating the function of neurons and circuits that translate electrical and chemical signals into behavior represents a major challenges in neuroscience. In addition to optogenetic methods using light-activatable channels, pharmacogenetic methods with ligand induced modulation of cell signaling and excitability have been developed. However, they are largely based on ectopic expression of exogenous or chimera proteins. Now, we describe the remote and reversible expression of a Kir2.1 type potassium channel using the chemogenetic technique of small molecule induced protein stabilization. Based on shield1-mediated shedding of a destabilizing domain fused to a protein of interest and inhibition of protein degradation, this principle has been adopted for biomedicine, but not in neuroscience so far. Here, we apply this chemogenetic approach in brain research for the first time in order to control a potassium channel in a remote and reversible manner. We could show that shield1-mediated ectopic Kir2.1 stabilization induces neuronal silencing in vitro and in vivo in the mouse brain. We also validated this novel pharmacogenetic method in different neurobehavioral paradigms.The DD-Kir2.1 may complement the existing portfolio of pharmaco- and optogenetic techniques for specific neuron manipulation, but it may also provide an example for future applications of this principle in neuroscience research. PMID- 26757619 TI - Effect of estrodiol on leptin receptors expression in regulating fat distribution and adipocyte genesis. AB - OBJECTIVE: To examine how estradiol influence fat distribution and adipocyte genesis through regulating leptin function. DESIGN AND METHODS: We randomized female SD rats into ovariectomy and sham group. After 14 weeks, we examined leptin receptor expression in perigenital, mesenteric and subcutaneous adipose tissues and leptin in serum. We further introduced mesenchymal stem cells (MSCs) to figure out the effect of 17-beta estradiol on expression of leptin receptors (OBRb and OBRa), leptin and PPARgamma2. RESULTS: Weight and Lee's index was both significantly higher in ovariectomized group than sham group (p < 0.001). The interaction of serum E2 and leptin was negatively correlated with body weight. Expression of leptin receptor protein was extremely upregulated in ovariectomized group in perigenital and mesenteric fat. Both estradiol and leptin upregulated mRNA expression of OBRb, and created a dose-dependent decreasing manner in MSCs. Higher doses of estradiol (10(-7)-10(-5) M) inhibited adipogenic markers mRNA expression of leptin and PPARgamma2, but low doses promoted leptin expression. CONCLUSIONS: In ovariectomized rats, low level of serum estradiol may change body composition and promote adipocyte genesis through affecting leptin function. PMID- 26757620 TI - Self-assembled nanomaterials for photoacoustic imaging. AB - In recent years, extensive endeavors have been paid to construct functional self assembled nanomaterials for various applications such as catalysis, separation, energy and biomedicines. To date, different strategies have been developed for preparing nanomaterials with diversified structures and functionalities via fine tuning of self-assembled building blocks. In terms of biomedical applications, bioimaging technologies are urgently calling for high-efficient probes/contrast agents for high-performance bioimaging. Photoacoustic (PA) imaging is an emerging whole-body imaging modality offering high spatial resolution, deep penetration and high contrast in vivo. The self-assembled nanomaterials show high stability in vivo, specific tolerance to sterilization and prolonged half-life stability and desirable targeting properties, which is a kind of promising PA contrast agents for biomedical imaging. Herein, we focus on summarizing recent advances in smart self-assembled nanomaterials with NIR absorption as PA contrast agents for biomedical imaging. According to the preparation strategy of the contrast agents, the self-assembled nanomaterials are categorized into two groups, i.e., the ex situ and in situ self-assembled nanomaterials. The driving forces, assembly modes and regulation of PA properties of self-assembled nanomaterials and their applications for long-term imaging, enzyme activity detection and aggregation induced retention (AIR) effect for diagnosis and therapy are emphasized. Finally, we conclude with an outlook towards future developments of self-assembled nanomaterials for PA imaging. PMID- 26757622 TI - [Controversies over the potential malignant nature of oral lichen planus: a pathological view]. PMID- 26757621 TI - Relationship between uterine biopsy score, endometrial infection and inflammation in the mare. AB - OBJECTIVE: Endometrial biopsy score is an accepted marker of uterine health and predicted fertility, and it has been suggested that endometrial alternations are correlated with susceptibility to persistent infectious endometritis. The objective of this study was to investigate associations of endometrial biopsy score with: 1) presence of polymorphonuclear cells (PMNs) in the epithelium and stratum compactum in histopathology; 2) presence of PMNs in cytology and 3) presence of infection in microbiology. MATERIALS AND METHODS: The material for examination was collected from 69 mares suspected for subclinical endometritis (bred three or more times unsuccessfully in the same breeding season) and from 15 maiden mares. Samples were collected by endometrial biopsy and cytobrush technique. RESULTS: Endometrial alterations (biopsy score IIA, IIB, III) were found in 64 of 82 mares (78%). There was an increase in PMN occurrence for grades IIA, IIB and III. When comparing grades and PMNs infiltration, we observed statistically significant differences between grades I and IIA (p = 0.222) and grades I and IIB (p = 0.042) in samples collected by endometrial biopsy. Statistically significant differences were found in microbiological examination (biopsy p = 0.036; cytobrush p = 0.189), cytological examination (biopsy p = 0.040; cytobrush p = 0.079) and PMN infiltration (p = 0.042) between mares with biopsy scores I and IIB. Furthermore, the highest percentage of infected mares was in grade IIA and IIB, and we found statistically significant differences between grades I and IIA (p = 0.043), and grades I and IIB (p = 0.036) in biopsy samples. We observed a tendency to higher prevalence of endometrial infection in mares with biopsy score IIA, IIB and III than with biopsy score I in samples collected using cytobrush technique. However, there were no statistical significant differences. CONCLUSION: Degenerative endometrial changes can predispose to uterine infection and inflammation. Our study shows that mares with endometrial score I are less predisposed to infection than mares with category IIA, IIB and III. Endometrial biopsy is a reliable diagnostic tool. PMID- 26757623 TI - [Diagnosis of intractable cases of oral mucosal diseases]. PMID- 26757624 TI - [Expression of soluble programmed death-1, soluble programmed death ligand 1 proteins and immune status in patients with oral lichen planus]. AB - OBJECTIVE: To investigate the possible role and significance of soluble programmed death-1 (sPD-1)/soluble programmed death ligand 1 (sPD-L1) in the pathogenesis of oral lichen planus (OLP). METHODS: Thirty-six patients with OLP (20 cases of reticular OLP and 16 cases of erosive OLP) were enrolled in this study, and 18 healthy people served as controls. Lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, CD16+ + 56+) were examined by flow cytometric analysis and humoral immunity indexes (IgG, IgA, IgM, C3, C4) tested by nephelometry immunoassay. The levels of sPD-1 and sPD-L1 proteins in serum of patients with OLP were determined by enzyme-linked immunosorbent assay. The correlations between the level of sPD 1, sPD-L1 proteins and the immune status and clinical characteristics of patients with OLP were analyzed by SPSS 19.0. RESULTS: CD3+, CD4+, CD8+, CD16+ + 56+ in patients with OLP were decreased compared with the normal value, while CD19+ in patients with OLP was increased compared with the normal value (P < 0.05). C3 and C4 in patients with OLP were decreased compared with the normal value, but IgM in patients with OLP was increased (P < 0.05). The levels of sPD-1 and sPD-L1 proteins in patients with OLP were significantly higher than that in control group [26.10(8.81, 40.00) ng/L vs 17.65(0.00, 26.10) ng/L, 29.53(21.47, 36.76) ng/L vs 22.79(1.19, 28.29) ng/L] (P < 0.05), but the expression of sPD-1 and sPD L1 was not related with clinical characteristics of OLP. There were negative correlations between the levels of sPD-1 protein and CD4+ T cells or CD16+ + 56+ cells (r1 = -0.378, P1 = 0.007; r2 = -0.365, P2 = 0.009), while there was a positive correlation between the levels of sPD-1 and CD19+ B cells (r = 0.482, P = 0.000). There was a negative correlation between sPD-L1 expression level and CD4+ and a positive correlation between sPD-L1 expression level and IgG (r1 = 0.286, P1 = 0.044; r2 = 0.365, P2= 0.029). CONCLUSIONS: In patients with OLP, the cellular immune function is low with humoral immunity function disorder. PD-1/PD L1 signaling pathway, which might be influenced by the involvement of sPD-1 and sPD-L1 proteins in a certain extent, may play an important role in the immune pathogenesis of OLP. PMID- 26757625 TI - [A case of multiple endocrine neoplasia type 2B]. PMID- 26757626 TI - [The research advancement in treatment of radiation oral mucositis]. PMID- 26757627 TI - [A new three-dimensional scale in the evaluation of the secondary alveolar bone grafting]. AB - OBJECTIVE: To propose a new three-dimensional method or grading scale in the evaluation of the secondary alveolar bone grafting, thus modifying the Bergland grading scale. METHODS: A total of 40 patients (26 male, 14 female) with unilateral cleft lip and palate (UCLP), who underwent secondary alveolar bone grafting at least 3 months ago, were enrolled. Regional cone-beam CT (CBCT) scans were taken to evaluate the height and thickness of the postoperative bone bridges. A new three-dimensional grafting scale was established, including four grades respectively in alveolar height and thickness. RESULTS: According to the new three-dimensional scale in this study, 15 grafted sites were rated grade T-I or T-II in the alveolar thickness among 18 sites of grade H-I in height, and 10 among 15 of grade H-II in height. Therefore, 25 grafted sites were considered as clinical success in the alveolar thickness (grade T-I or T-II) among 33 sites with clinical success in alveolar height (grade H-I and H-II). There were 24% of 33 sites with clinical success in height, which were considered as clinical failure in the alveolar thickness. CONCLUSIONS: It is necessary to establish a new three-dimensional method or grading scale for evaluating the secondary alveolar bone grafting. The three-dimensional scale can take comprehensive view of the bone-grafted alveolar clefts and thus modify the Bergland grading scale. PMID- 26757628 TI - [Correlation analysis of hearing level and soft palate movement after palatoplasty]. AB - OBJECTIVE: To explore the relationship between hearing level and soft palate movement after palatoplasty and to verify the importance of recovery of soft palate movement function for improving the middle ear function as well as reducing the hearing loss. METHODS: A total of 64 non-syndromic cleft palate patients were selected and the lateral cephalometric radiographs were taken. The patients hearing level was evaluated by the pure tone hearing threshold examination. This study also analyzed the correlation between hearing threshold of the patients after palatoplasty and the soft palate elevation angle and velopharyngeal rate respectively. RESULTS: Kendall correlation analysis revealed that the correlation coefficient between hearing threshold and the soft palate elevation angle after palatoplasty was -0.339 (r = -0.339, P < 0.01).The correlation showed a negative correlation. The hearing threshold decreased as the soft palate elevation angle increased. After palatoplasty, the correlation coefficient between the hearing threshold and the rate of velopharyngeal closure was -0.277 (r = -0.277, P < 0.01). The correlation showed a negative correlation. While, The hearing threshold decreased with the increase of velopharyngeal closure rate. The hearing threshold was correlated with soft palate elevation angle and velpharyngeal closure rate. CONCLUSIONS: The movement of soft palate and velopharyngeal closure function after palatoplasty both have impact on patient hearing level. In terms of the influence level, the movement of soft palate has a higher level of impact on patient hearing level than velopharygeal closure function. PMID- 26757629 TI - [Whether free anterolateral thigh flaps are suitable for the elderly patients with oral cancer]. AB - OBJECTIVE: To identify the factors that were predictive of outcome and to determine the effect of age on perioperative complications. METHODS: Reviewed the records of 1 100 consecutive patients who underwent anterolateral thigh flap free flap transfers for oral and maxillofacial cancer surgery defects between February 2002 and March 2013. All patients were divided into two groups: A group (< 60 years old) and B group (>= 60 years old). Postoperative complications were analyzed from all patients. RESULTS: There were 781 cases in A group and 319 in B group. The overall success rate was 97.2% (1 100/1 132) [97.3% (781/803) in A group, 97.0% (319/329) in B group, P > 0.05]. The overall complication rate was 27.5% (302/1 100) [25.9% (202/781) in A group, 31.3% (100/319) in B group, P = 0.064]. Multivariate Cox regression analyses revealed that American Society of Anesthesiologists (ASA) status (P < 0.001), operation time (P = 0.021) and comorbidity (P = 0.002) were the independent factor for the complication of patients. However, age (P > 0.05) was not an independent factor for the complication of patients. CONCLUSIONS: Oral and maxillofacial reconstruction using anterolateral thigh flap free flaps in elderly patients can achieve similar outcomes as in younger patients. Controlling operative time is very important in reducing post-operative complications and improving the results of surgery. PMID- 26757630 TI - [Study on the difference of corresponding age at cervical vertebral maturation stages among different skeletal malocclusions]. AB - OBJECTIVE: To compare the difference of corresponding age at cervical vertebral maturation (CVM) stages among different skeletal malocclusions and provide clinic guideline on optimal treatment timing for skeletal malocclusion. METHODS: Based on ANB angle, 2 575 cephalograms collected from Department of Orthodontics, Peking University School and Hospital of Stomatology from May, 2006 to November, 2014 were classified into skeletal Class I (ANB 0 degrees ~5 degrees , 1 317 subjects), Class II (ANB > 5 degrees , 685 subjects) and Class III (ANB < 0 degrees , 573 subjects) groups. CVM stages were evaluated with the modified version of CVM method. Independent sample t test was performed to analyze the difference of age at different CVM stages among various skeletal groups. RESULTS: Significant gender difference of age was found at CS3 to CS6 for skeletal Class I group (P < 0.05), at CS5 and CS6 for skeletal Class II group (P < 0.05), and at CS3 and CS5 for skeletal Class III group (P < 0.05). At CS3 stage, the average age of male in skeletal Class II and skeletal Class III groups was (11.6 +/- 1.5) years old and (10.3 +/- 1.9) years old, respectively; the average age of females in those two groups was (11.7 +/- 1.3) years old and (9.3 +/- 1.5) years old, respectively, and significant difference was found in both comparisons (P < 0.05). Compared average age at CS5 and CS6 between skeletal Class II and skeletal Class III groups [the ages of male was (15.1 +/- 1.7) and (16.8 +/- 1.6) years old, the ages of male was (14.6 +/- 1.2) and (15.7 +/- 2.5) years old], significant difference was also found (P < 0.05). CONCLUSIONS: Significant gender differences were found when evaluated CVM stage and age in skeletal Class I, II and III groups. Significant differences of age at different CVM stage was noted when skeletal Class II was compared with skeletal Class III groups. PMID- 26757631 TI - [Cone-beam computed tomography evaluation of upper airway change in skeletal Class III patients after orthodontic-mandibular setback surgery]. AB - OBJECTIVE: To evaluate the short-term and long-term effects of pharyngeal airway in mandibular prognathism patients after the combined orthodontic and orthognathic treatment. METHODS: The sample included 28 skeletal Class III patients (13 males, 15 females) who had undergone mandibular setback surgery and orthodontic treatment. Cone-beam CT was taken one week before treatment (T0), 6 months (T1) and 3 years after surgery (T2). Raw data were reconstructed into three-dimensional model. Sagittal and transversal measurements, cross sectional areas, partial and total volumes were computed. RESULTS: Six months after surgery, oropharyngeal volume [(9 021 +/- 4 263) mm3], hypopharyngeal volume [(9 236 +/- 5 963) mm3] and total volume [(28 619 +/- 9 854) mm3] decreased significantly (P < 0.05). Three years after surgery, only sagittal diameters [(15.9 +/- 3.5) mm] and cross sectional areas [(996 +/- 398) mm2] in the first cervical vertebra plane came back to the original levels (P > 0.05). CONCLUSIONS: The pharyngeal airway space decreased after orthodontic-orthognathic therapy in the short term and it increased in some areas in the long term. PMID- 26757632 TI - [Interleukin-17 expression induced by orthodontic force in periodontal ligament in different periodontal condition]. AB - OBJECTIVE: To investigate interleukin (IL)-17 expression induced by orthodontic force in periodontal ligament under different periodontal conditions. METHODS: Seventy-seven male SD rats were divided randomly into 5 groups: healthy movement group (HM), active periodontitis movement group (PM) recovery periodontitis movement group (RM), positive control group (PC) and normal control group (NC). Active periodontitis was set up by means of ligature + susceptible bacteria + suger water in PM, PC and RM groups. This stimulating factor was removed in RM group. NiTi spring was used to apply 0.49 N mesial force to move upper first molar of the rats in HM, PM and RM groups. HM, PM and RM group rats were sacrificed on day 3 (d3), day 7 (d7) and day 14 (d14). Expression changes of IL 17 in periodontal tissue in each group were measured using immunohistochemical stain and real time fluorescence quantitative PCR. RESULTS: IL-17 expression in periodontal ligament showed more positively in PM and RM groups compared with NC, PC and HM groups. No difference was found in the expression of IL-17 mRNA in NC (1.00 +/- 0.00) (P > 0.05), except in HM d14 (1.00 +/- 0.07) and RM d14 (1.19 +/- 0.15). Higher expression of IL-17 mRNA (P < 0.05) was found in other groups. The expression of IL-17 mRNA in RM d3 and d7 increased more than that in HM group in the same period (P < 0.05) and it decreased significantly (P < 0.05) compared with that in PM groups in the same period. CONCLUSIONS: IL-17 was involved in the regulation of orthodontic tooth movement in different periodontal conditions. Orthodontic force caused limited increase of IL-17 mRNA expression in recovery phase of periodontitis at early stage, then back to normal. However, in active inflammatory periodontal tissue, orthodontic force kept IL-17 mRNA at high level. PMID- 26757633 TI - [A clinical study on the treatment of mucocele by bleomyin A5 combined with phosphorus-32 colloid]. AB - OBJECTIVE: To evaluate the effect of bleomyin A5 combined with phosphorus-32 colloid in the treatment of mucocele. METHODS: A total of 214 patients divided into three groups, bleomyin A5 (50 cases), phosphorus-32 colloid (50 cases) and bleomyin A5 combined with phosphorus-32 colloid (114 cases). RESULTS: The efficacy of bleomyin A5 group, phosphorus-32 colloid group, and bleomyin A5 combined with phosphorus-32 colloid group was 84% (42/50), 82% (41/50) and 98% (112/114), respectively. There were significant difference in efficacy among the three groups (P < 0.05). The phosphorus-32 colloid group and the bleomyin A5 group had no significant difference in efficacy (P > 0.05). CONCLUSIONS: The independent use of bleomyin A5 and phosphorus-32 colloid is effective, but the combined use of the two methods is more effective. PMID- 26757634 TI - [A case of congenital trilobe tongue associated with cleft palate and ectopic salivary gland]. PMID- 26757635 TI - [Expression of Na(+)/Ca(2+) exchanger channel protein in human odontoblasts and nervous tissue of dental pulp]. AB - OBJECTIVE: To investigate the expression of Na(+)/Ca(2+) exchanger 1 (NCX1) channel protein in human odontoblasts (OD) and nervous tissue of dental pulp. METHODS: Twenty intact and healthy third molars extracted for orthodontic purpose were collected. The OD layer and nervous tissue were determined by dentin sialophosphoproteins (DSPP) antibody staining and modified Bielschowsky silver staining respectivelly. The immunohistochemical method was used to detect the expressions of NCX1 protein in human dental pulp tissue. The difference of expression of NCX1 in human OD at different part of dental pulp was statistically analyzed using Image Pro Plus and SPSS software. RESULTS: NCX1 channel protein was mainly expressed on the cell body of OD, and nervous tissue of dental pulp. The expression level of NCX1 on the OD of crown pulp was higher (A = 0.146 +/- 0.021) than that on the upper part of root pulp (A = 0.120 +/- 0.034), but the expression difference was not significant (P > 0.05). CONCLUSIONS: NCX1 channel protein was expressed on human OD and nervous tissue in dental pulp. PMID- 26757636 TI - [A pilot study of root position in orthodontic diagnosis model set-up]. AB - OBJECTIVE: To investigate the importance of root information in diagnosis set-up by constructing three-dimensional (3D) digital models with individual anatomic roots. METHODS: Pretreatment cone-beam CT (CBCT) and laser scanning data were collected from two patients (extraction and non-extraction each) with skeletal Class I malocclusion. Threshold segmentation of the CBCT was performed to generate a 3D digital model which has individually isolated tooth. This model and the scan model were superimposed to generate an integrated model (Mo) composed of high-resolution surface scan crowns sutured to the CBCT roots. Pretreatment dentition plaster model were made into set-up model. The diagnosis model set-up was performed successively by three orthodontists and one senior orthodontic technician. Set-up model scan of each patient after tooth alignment was obtained. The isolated composite teeth were individually superimposed onto the set-up model surface scan to creat set-up model (Ma, Mb, Mc, Md) containing root position. These isolated composite teeth were also superimposed onto the posttreatment surface scan depicting the posttreatment model (M). In order to observe whether diagnosis model set-up would cause exposure of the root, Ma-Md were compared with Mo, which showed the true positions of alveolus. In order to validate the accuracy of the expected root position setup, Ma-Md were compared with the true root position represented by M. Color displacement maps generated to measure the discrepancies of root positions. RESULTS: Nonparallel and exposure of the root was found in all setup models. Color displacement maps through molar superimpositions showed maximum differences of 8.79 mm for the maxillary teeth and 9.96 mm for the mandibular teeth. CONCLUSIONS: Diagnosis model set-up based only on crown can not absolutely ensure the good alignment of roots without root exposure. It is necessary to construct the integrated model including root for diagnosis during tooth arrangement process. PMID- 26757637 TI - [Aging of silorane- and methacrylate-based composite resins: effects on color and translucency]. AB - OBJECTIVE: To evaluate the color stability and translucency of silorane-based low shrinkage composite after in vitro aging procedures of thermal cycling and water storage respectively, and to compare with those of conventional methacrylate based posterior composite. METHODS: Three light-cured composite resins, dimethacrylate-based composite A (FiltekTM Z350), B (FiltekTM P60) and silorane based composite C (FiltekTM P90), were tested in this study. Ten specimens (10 mm in diameter, 1 mm in height) of each composite were prepared. The ten specimens in each group were then divided into two subgroups (n = 5). One subgroup underwent thermal cycling [(5.0 +/- 0.5)~(55.0 +/- 1.0) degrees C, 10 000 cycles] and the other was stored in 37 C degrees distilled water for 180 days. With a spectrophotometer, the CIE L * a * b * parameters of the specimens were tested before and after artificial aging against white, medium grey and black backgrounds, respectively. ?E, TP and ?TP were calculated and data were analyzed using independent-samples t test and partial analysis (P < 0.05). RESULTS: With regard to color stability, silorane-based composite showed color alteration above the clinically acceptable levels (?E > 3.3), and also showed higher ?E with a statistically significant difference in comparison with the other composites (B and C) (P < 0.05) after artificial aging. With regard to translucency, composite C showed more alteration compared with composite B (P < 0.05) after thermal cycling. CONCLUSIONS: It may be concluded that the silorane-based composite underwent greater alteration with regard to color stability and translucency. PMID- 26757639 TI - Freedom in a pill? PMID- 26757640 TI - [Re: Circumcision of boys]. PMID- 26757641 TI - [Re: Circumcision of boys]. PMID- 26757638 TI - A Signaling Lipid Associated with Alzheimer's Disease Promotes Mitochondrial Dysfunction. AB - Fundamental changes in the composition and distribution of lipids within the brain are believed to contribute to the cognitive decline associated with Alzheimer's disease (AD). The mechanisms by which these changes in lipid composition affect cellular function and ultimately cognition are not well understood. Although "candidate gene" approaches can provide insight into the effects of dysregulated lipid metabolism they require a preexisting understanding of the molecular targets of individual lipid species. In this report we combine unbiased gene expression profiling with a genome-wide chemogenomic screen to identify the mitochondria as an important downstream target of PC(O-16:0/2:0), a neurotoxic lipid species elevated in AD. Further examination revealed that PC(O 16:0/2:0) similarly promotes a global increase in ceramide accumulation in human neurons which was associated with mitochondrial-derived reactive oxygen species (ROS) and toxicity. These findings suggest that PC(O-16:0/2:0)-dependent mitochondrial dysfunction may be an underlying contributing factor to the ROS production associated with AD. PMID- 26757642 TI - [Re: Circumcision of boys]. PMID- 26757643 TI - [Re: Circumcision of boys]. PMID- 26757644 TI - [Re: Circumcision of boys]. PMID- 26757645 TI - [M. Bretthauer & E. Hem reply]. PMID- 26757646 TI - [Re: A call to anonymous sperm donors]. PMID- 26757647 TI - [G.I. Elgjo replies]. PMID- 26757648 TI - [Re: An illogical and unfortunate side effect concept]. PMID- 26757649 TI - [L. Slordal & T. Christoffersen reply]. PMID- 26757650 TI - [Re: When the Earth is our patient]. PMID- 26757651 TI - Proton pump inhibitors and gastric cancer. PMID- 26757652 TI - [Smoking, risk--and straight legs]. PMID- 26757653 TI - [Ad validity to deceased physicians' requisitions]. PMID- 26757654 TI - [Does the core journal need to contain information on whether patients are divorced?]. PMID- 26757655 TI - [Not Available]. PMID- 26757656 TI - Norwegian patients with colon cancer start their adjuvant therapy too late. AB - BACKGROUND: For patients with colon cancer who are to receive adjuvant chemotherapy according to national guidelines, such therapy must be initiated no more than 4-6 weeks after the surgical intervention. We wished to investigate whether these guidelines are being complied with. We also wished to see whether the type of surgery (open or laparoscopic) had any effect on the time elapsing before initiation of adjuvant therapy. MATERIAL AND METHOD: The material includes 1,132 patients who had undergone surgery for colon cancer in the period 2008-2013 and who received adjuvant chemotherapy. Surgical treatment and adjuvant chemotherapy are defined through diagnosis and procedural codes in the Norwegian Patient Register for the period 2008-2013. RESULTS: On average, 44.7 days passed after the surgical intervention before the patients commenced their adjuvant chemotherapy. For 49% of the patients, the adjuvant therapy was not initiated within the six-week deadline. Patients who had undergone laparoscopic surgery were hospitalised for shorter periods (6.5 days versus 10.7 days) and had fewer complications (7.6% versus 16.4%) when compared to patients who had undergone open surgery, yet still failed to start their adjuvant therapy correspondingly earlier. INTERPRETATION: Measures should be taken to improve quality, thus ensuring that the guidelines are complied with and that patients start their required adjuvant therapy earlier. For those who have undergone laparoscopic surgery, it ought to be simple to reap the gains from shorter hospitalisation periods and fewer complications in the form of a more rapid initiation of adjuvant therapy. PMID- 26757657 TI - [Contraception for women taking antiepileptic drugs]. AB - Most women of fertile age want safe contraception. This is especially important for women with epilepsy, as some antiepileptic drugs may have harmful effects on the foetus. When hormonal contraception is combined with antiepileptic drugs, it is essential to be aware that certain antiepileptic drugs may reduce the efficacy of hormonal contraceptives and vice versa, which may result in a reduced effect for both drugs. Non-hormonal contraception, such as the copper coil and barrier methods may, however, be used safely in this patient group. PMID- 26757658 TI - [What causes febrile convulsions?]. AB - Febrile convulsions affect 2-5% of children in the age group from 6 months to 5 years. The convulsions seldom have negative consequences for the child's development, but may in rare cases constitute a debut symptom of epilepsy. PMID- 26757659 TI - [Primum non dosere]. PMID- 26757660 TI - [A woman in her 80s with reduced general condition and hypercalcemia]. PMID- 26757661 TI - [Premature infants and treatment boundaries]. PMID- 26757662 TI - [The appendix, the hip and the stroke]. PMID- 26757664 TI - [Not Available]. PMID- 26757666 TI - [Not Available]. PMID- 26757663 TI - [Obesity in new Norwegian]. PMID- 26757667 TI - [Not Available]. PMID- 26757669 TI - [Not Available]. PMID- 26757668 TI - [Not Available]. PMID- 26757670 TI - [Not Available]. PMID- 26757671 TI - [Not Available]. PMID- 26757676 TI - Bacterial flagellar motility on hydrated rough surfaces controlled by aqueous film thickness and connectedness. AB - Recent studies have shown that rates of bacterial dispersion in soils are controlled by hydration conditions that define size and connectivity of the retained aqueous phase. Despite the ecological implications of such constraints, microscale observations of this phenomenon remain scarce. Here, we quantified aqueous film characteristics and bacterial flagellated motility in response to systematic variations in microhydrological conditions on porous ceramic surfaces that mimic unsaturated soils. We directly measured aqueous film thickness and documented its microscale heterogeneity. Flagellar motility was controlled by surface hydration conditions, as cell velocity decreased and dispersion practically ceased at water potentials exceeding -2 kPa (resulting in thinner and disconnected liquid films). The fragmentation of aquatic habitats was delineated indirectly through bacterial dispersal distances within connected aqueous clusters. We documented bacterial dispersal radii ranging from 100 to 10 MUm as the water potential varied from 0 to -7 kPa, respectively. The observed decrease of flagellated velocity and dispersal ranges at lower matric potentials were in good agreement with mechanistic model predictions. Hydration-restricted habitats thus play significant role in bacterial motility and dispersal, which has potentially important impact on soil microbial ecology and diversity. PMID- 26757675 TI - Superlattice-based thin-film thermoelectric modules with high cooling fluxes. AB - In present-day high-performance electronic components, the generated heat loads result in unacceptably high junction temperatures and reduced component lifetimes. Thermoelectric modules can, in principle, enhance heat removal and reduce the temperatures of such electronic devices. However, state-of-the-art bulk thermoelectric modules have a maximum cooling flux qmax of only about 10 W cm(-2), while state-of-the art commercial thin-film modules have a qmax <100 W cm(-2). Such flux values are insufficient for thermal management of modern high power devices. Here we show that cooling fluxes of 258 W cm(-2) can be achieved in thin-film Bi2Te3-based superlattice thermoelectric modules. These devices utilize a p-type Sb2Te3/Bi2Te3 superlattice and n-type delta-doped Bi2Te3-xSex, both of which are grown heteroepitaxially using metalorganic chemical vapour deposition. We anticipate that the demonstration of these high-cooling-flux modules will have far-reaching impacts in diverse applications, such as advanced computer processors, radio-frequency power devices, quantum cascade lasers and DNA micro-arrays. PMID- 26757677 TI - The Mesoscopic Electrochemistry of Molecular Junctions. AB - Within the context of an electron dynamic (time-dependent) perspective and a voltage driving force acting to redistribute electrons between metallic and addressable molecular states, we define here the associated electron admittance and conductance. We specifically present a mesoscopic approach to resolving the electron transfer rate associated with the electrochemistry of a redox active film tethered to metallic leads and immersed in electrolyte. The methodology is centred on aligning the lifetime of the process of electron exchange with associated resistance and capacitance quantities. Notably, however, these are no longer those empirically known as charge transfer resistance and pseudo capacitance, but are those derived instead from a consideration of the quantum states contained in molecular films and their accessibility through a scattering region existing between them and the metallic probe. The averaged lifetime (taur) associated with the redox site occupancy is specifically dependent on scattering associated with the quantum channels linking them to the underlying metallic continuum and associated with both a quantum resistance (Rq) and an electrochemical (redox) capacitance (Cr). These are related to electron transfer rate through k = 1/taur = (RqCr)(-1). The proposed mesoscopic approach is consistent with Marcus's (electron transfer rate) theory and experimental measurements obtained by capacitance spectroscopy. PMID- 26757674 TI - Interaction of RNA with a C-terminal fragment of the amyotrophic lateral sclerosis-associated TDP43 reduces cytotoxicity. AB - A hallmark of amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, is formation of inclusion bodies (IBs) from misfolded proteins in neuronal cells. TAR RNA/DNA-binding protein 43 kDa (TDP43) is an ALS causative protein forming IBs in ALS patients. The relation between localization of the IBs and neurotoxicity remains largely unknown. We characterized aggregation of fluorescently tagged TDP43 and its carboxyl-terminal fragments (CTFs) by analytical fluorescence imaging techniques. Quantitative time-lapse analysis in individual live cells showed that fluorescent-protein-tagged TDP43 was cleaved and a 35 kDa TDP43 CTF (TDP35) formed ubiquitin (Ub)-negative cytoplasmic IBs. Although TDP35 formed mildly toxic Ub-negative IBs in the cytoplasm, TDP25, another type of a TDP43 CTF, efficiently formed sufficiently toxic Ub-positive IBs. One- or two-color fluorescence correlation spectroscopy (FCS/FCCS) revealed that coaggregation of TDP25 with TDP43 was initiated by depletion of the RNA that binds to TDP25. Moreover, nuclear localization tagging TDP25 reduced the rate of neuronal cell death. These observations point to the need to elucidate the novel sequestration mechanism and details of the toxicity of the misfolded and aggregation-prone TDP43 CTFs (as well as the RNA binding and nuclear retention) in order to identify possible preventive interventions against ALS. PMID- 26757678 TI - 1,2,3,4-Bis(p-methylbenzylidene sorbitol) accelerates crystallization and improves hole mobility of poly(3-hexylthiophene). AB - The addition of 1,2,3,4-bis(p-methylbenzylidene sorbitol) (MDBS) does not change the nucleation mechanism or the crystal form of poly(3-hexylthiophene) (P3HT), but its presence increases the crystallization temperature (T c) of P3HT, decreases the crystallization half-time (t 1/2) and accelerates P3HT crystallization, which indicates that MDBS is an effective nucleating agent for P3HT. An acceleration of P3HT crystallization by the addition of MDBS decreases the crystalline size and crystallinity of P3HT, and enhances the connectivity between ordered regions of P3HT, leading to the hole mobility rising from 1.99 * 10(-6) to 7.57 * 10(-5) cm(2) V(-1)s(-1) in P3HT:PCBM blend based hole-only devices with sandwich configurations. Our results suggest that accelerating P3HT crystallization by adding a nucleating agent might be an important factor to improve the hole mobility and balance the electron and hole mobility in a photovoltaic blend. PMID- 26757679 TI - Total synthesis and stereochemical revision of xiamenmycin A. AB - The relative and absolute configurations of xiamenmycin A, a benzopyran compound isolated from Streptomyces xiamenensis 318 with a highly potent anti-fibrotic activity, have been characterized through the total synthesis. The key steps include the construction of the 3-chromanol moiety via Sharpless epoxidation followed by regio- and diastereo-selective cyclization and introduction of the threonine moiety at a later stage via Pd-catalysed aminocarbonylation in a one pot procedure. The stereochemical assignment of natural xiamenmycin A has been accordingly revised to be 2R, 3S, 3'S, 4'R. PMID- 26757680 TI - Fractal density and singularity analysis of heat flow over ocean ridges. AB - Peak heat flow occurs at mid-ocean ridges and decreases with the age of the oceanic lithosphere. Several plate models, including the Parsons and Sclater (PSM) model, Global Depth and Heat (GDH1) model and Constant Heat flow Applied on the Bottom Lithospheric Isotherm (CHABLIS) model, have been used to predict heat flow in the ocean lithosphere. The discrepancy between the predicted and measured heat flow in the younger lithosphere (i.e. younger than 55 Myr) influenced by local hydrothermal circulation has been used to estimate hydrothermal heat flux and investigate hydrothermal processes. We can modify the cooling models by substituting the ordinary mass density of lithosphere by fractal density with singularity. This new model provides a modified solution to fit the observed heat flow data used in other models in the literature throughout the age range. This model significantly improves the results for prediction of heat flow that were obtained using the PSM, GDH1 and CHABLIS models. Furthermore, the heat flow model does not exhibit special characteristics around any particular age of lithosphere. This raises a fundamental question about the existence of a "sealing" age and accordingly the hydrothermal flux estimation based on the cooling models. PMID- 26757681 TI - Maternal effects on offspring stress physiology in wild chimpanzees. AB - Early life experiences are known to influence hypothalamic-pituitary-adrenal (HPA) axis development, which can impact health outcomes through the individual's ability to mount appropriate physiological reactions to stressors. In primates, these early experiences are most often mediated through the mother and can include the physiological environment experienced during gestation. Here, we investigate stress physiology of dependent offspring in wild chimpanzees for the first time and examine whether differences in maternal stress physiology are related to differences in offspring stress physiology. Specifically, we explore the relationship between maternal rank and maternal fecal glucocorticoid metabolite (FGM) concentration during pregnancy and early lactation (first 6 months post-partum) and examine whether differences based on maternal rank are associated with dependent offspring FGM concentrations. We found that low-ranking females exhibited significantly higher FGM concentrations during pregnancy than during the first 6 months of lactation. Furthermore, during pregnancy, low ranking females experienced significantly higher FGM concentrations than high ranking females. As for dependent offspring, we found that male offspring of low ranking mothers experienced stronger decreases in FGM concentrations as they aged compared to males with high-ranking mothers or their dependent female counterparts. Together, these results suggest that maternal rank and FGM concentrations experienced during gestation are related to offspring stress physiology and that this relationship is particularly pronounced in males compared to females. Importantly, this study provides the first evidence for maternal effects on the development of offspring HPA function in wild chimpanzees, which likely relates to subsequent health and fitness outcomes. Am. J. Primatol. 80:e22525, 2018. (c) 2016 Wiley Periodicals, Inc. PMID- 26757682 TI - Noise-induced hearing loss in bus and truck drivers in Mazandaran province, 2011. AB - BACKGROUND AND PURPOSE: Noise-induced hearing loss (NIHL) is among the most prevalent and preventable work-related disorders. This study was conducted to evaluate the prevalence and severity of NIHL in bus and truck drivers of Mazandaran province in north Iran. MATERIALS AND METHODS: In a cross-sectional descriptive study, 2283 drivers were examined clinically and para-clinically, including measuring their fasting blood sugar, triglyceride and cholesterol levels. All participants were evaluated for the air and bone thresholds of both ears. Twenty-three individuals were excluded from the study because of conductive hearing loss. Data from 2260 drivers were analyzed using SPSS version 18. RESULTS: Of the drivers, 37.5% had hearing loss in the right ear and 41.8% of the drivers had hearing loss in the left ear in one or more frequencies of sound. Hearing loss was significantly more frequent in the left ear and in 6000 Hz followed by 4000 Hz. CONCLUSION: Our study showed that the prevalence and severity of NIHL is high in drivers of Mazandaran province. There was a correlation between hearing loss and age and driving work history. We recommend considering hearing conservation programs more seriously. PMID- 26757697 TI - Structure and reactivity with oxygen of Pr2NiO(4+delta): an in situ synchrotron X ray powder diffraction study. AB - The promising SOFC cathode material Pr2NiO(4.22) has been studied in situ under a pure oxygen atmosphere from 25 to 950 degrees C by high resolution synchrotron X ray powder diffraction. At room temperature (RT) delta = 0.22(1), the average crystal structure turns out to be monoclinic. The subtle monoclinic distortion (gamma = 90.066(1) degrees at RT), retained up to 460 degrees C, is interpreted in terms of specific tilt schemes of the NiO6 octahedra. It is also shown that Pr2NiO(4.22) is incommensurately structurally modulated already at room temperature, in the same manner as the homologous cobaltate La2CoO(4.14). The phase transition to the High Temperature Tetragonal (HTT) phase was completed at 480 degrees C without any evidence for the Low Temperature Orthorhombic (LTO) phase allowing clarifying the phase diagram of this K2NiF4-type ternary oxide. Moreover, it turns out that above 800 degrees C, the HTT phase transforms reversibly into two coexisting isomorphous tetragonal phases. The incommensurate modulation subsists up to 950 degrees C, although modified concomitantly with the two abovementioned phase transformations. In addition, the role of kinetics on the decomposition process is highlighted through thermo-gravimetric analyses. PMID- 26757698 TI - Ectopic prostatic tissue in mature cystic teratoma of the ovary, a case report and review of the literature. PMID- 26757699 TI - The effects of polysaccharides from the root of Angelica sinensis on tumor growth and iron metabolism in H22-bearing mice. AB - The crude polysaccharide was obtained from the root of Angelica sinensis (AS) to investigate its effect on tumor growth and iron metabolism in H22-bearing mice. In our study, we showed that Angelica sinensis polysaccharide (ASP) was mainly composed of arabinose, glucose and galactose in a molar ratio of 1:1:1.75, with a molecular weight of 80,900 Da and a sugar content of 88.0%. Animal experimental results revealed that three doses of ASP all had anti-tumor effects with inhibition ratios of 27.11%, 31.65% and 37.05%. With respect to iron metabolism, the mean levels of serum hepcidin, interleukin-6 (IL-6), ferritin, transferrin (Tf), transferrin receptor 1 (TfR1) and transferrin receptor 2 (TfR2) in H22 bearing mice were promoted, and serum iron concentration decreased significantly. After treatment with ASP, these iron-related indicators recovered in different degrees. The findings suggested that the anti-tumor activity of ASP may be affected by its regulation on iron metabolism in H22-bearing mice. PMID- 26757700 TI - A mitochondria-targeted fluorescent probe for ratiometric detection of endogenous sulfur dioxide derivatives in cancer cells. AB - A new mitochondria-targeted fluorescent probe HCy-D, constructed by dansyl and hemicyanine fluorophores, for SO2 derivatives (HSO3(-)/SO3(2-)) was presented. This probe was designed based on a new FRET platform. HCy-D showed a ratiometric, sensitive and rapid response to HSO3(-)/SO3(2-). Importantly, HCy-D was successfully used for fluorescence imaging of endogenous bisulfite in HepG2 cells, which may benefit cancer diagnosis by discriminating liver cancer cells from normal liver cells. PMID- 26757702 TI - Invasive plants have different effects on trophic structure of green and brown food webs in terrestrial ecosystems: a meta-analysis. AB - Although invasive plants are a major source of terrestrial ecosystem degradation worldwide, it remains unclear which trophic levels above the base of the food web are most vulnerable to plant invasions. We performed a meta-analysis of 38 independent studies from 32 papers to examine how invasive plants alter major groupings of primary and secondary consumers in three globally distributed ecosystems: wetlands, woodlands and grasslands. Within each ecosystem we examined if green (grazing) food webs are more sensitive to plant invasions compared to brown (detrital) food webs. Invasive plants have strong negative effects on primary consumers (detritivores, bacterivores, fungivores, and/or herbivores) in woodlands and wetlands, which become less abundant in both green and brown food webs in woodlands and green webs in wetlands. Plant invasions increased abundances of secondary consumers (predators and/or parasitoids) only in woodland brown food webs and green webs in wetlands. Effects of invasive plants on grazing and detrital food webs clearly differed between ecosystems. Overall, invasive plants had the most pronounced effects on the trophic structure of wetlands and woodlands, but caused no detectable changes to grassland trophic structure. PMID- 26757704 TI - Early childhood development in Rwanda: a policy analysis of the human rights legal framework. AB - BACKGROUND: Early childhood development (ECD) is a critical period that continues to impact human health and productivity throughout the lifetime. Failing to provide policies and programs that support optimal developmental attainment when such services are financially and logistically feasible can result in negative population health, education and economic consequences that might otherwise be avoided. Rwanda, with its commitment to rights-based policy and program planning, serves as a case study for examination of the national, regional, and global human rights legal frameworks that inform ECD service delivery. DISCUSSION: In this essay, we summarize key causes and consequences of the loss of early developmental potential and how this relates to the human rights legal framework in Rwanda. We contend that sub-optimal early developmental attainment constitutes a violation of individuals' rights to health, education, and economic prosperity. These rights are widely recognized in global, regional and national human rights instruments, and are guaranteed by Rwanda's constitution. Recent policy implementation by several Rwandan ministries has increased access to health and social services that promote achievement of full developmental potential. These ECD-centric activities are characterized by an integrated approach to strengthening the services provided by several public sectors. Combining population level activities with those at the local level, led by local community health workers and women's councils, can bolster community education and ensure uptake of ECD services. CONCLUSIONS: Realization of the human rights to health, education, and economic prosperity requires and benefits from attention to the period of ECD, as early childhood has the potential to be an opportunity for expedient intervention or the first case of human rights neglect in a lifetime of rights violations. Efforts to improve ECD services and outcomes at the population level require multisector collaboration at the highest echelons of government, as well as local education and participation at the community level. PMID- 26757701 TI - The leukocyte-stiffening property of plasma in early acute respiratory distress syndrome (ARDS) revealed by a microfluidic single-cell study: the role of cytokines and protection with antibodies. AB - BACKGROUND: Leukocyte-mediated pulmonary inflammation is a key pathophysiological mechanism involved in acute respiratory distress syndrome (ARDS). Massive sequestration of leukocytes in the pulmonary microvasculature is a major triggering event of the syndrome. We therefore investigated the potential role of leukocyte stiffness and adhesiveness in the sequestration of leukocytes in microvessels. METHODS: This study was based on in vitro microfluidic assays using patient sera. Cell stiffness was assessed by measuring the entry time (ET) of a single cell into a microchannel with a 6 * 9-MUm cross-section under a constant pressure drop (DeltaP = 160 Pa). Primary neutrophils and monocytes, as well as the monocytic THP-1 cell line, were used. Cellular adhesiveness to human umbilical vein endothelial cells was examined using the laminar flow chamber method. We compared the properties of cells incubated with the sera of healthy volunteers (n = 5), patients presenting with acute cardiogenic pulmonary edema (ACPE; n = 6), and patients with ARDS (n = 22), of whom 13 were classified as having moderate to severe disease and the remaining 9 as having mild disease. RESULTS: Rapid and strong stiffening of primary neutrophils and monocytes was induced within 30 minutes (mean ET >50 seconds) by sera from the ARDS group compared with both the healthy subjects and the ACPE groups (mean ET <1 second) (p < 0.05). Systematic measurements with the THP-1 cell line allowed for the establishment of a strong correlation between stiffening and the severity of respiratory status (mean ET 0.82 +/- 0.08 seconds for healthy subjects, 1.6 +/- 1.0 seconds for ACPE groups, 10.5 +/- 6.1 seconds for mild ARDS, and 20.0 +/- 8.1 seconds for moderate to severe ARDS; p < 0.05). Stiffening correlated with the cytokines interleukin IL-1beta, IL-8, tumor necrosis factor TNF-alpha, and IL-10 but not with interferon-gamma, transforming growth factor-beta, IL-6, or IL-17. Strong stiffening was induced by IL-1beta, IL-8, and TNF-alpha but not by IL-10, and incubations with sera and blocking antibodies against IL-1beta, IL-8, or TNF alpha significantly diminished the stiffening effect of serum. In contrast, the measurements of integrin expression (CD11b, CD11a, CD18, CD49d) and leukocyte endothelium adhesion showed a weak and slow response after incubation with the sera of patients with ARDS (several hours), suggesting a lesser role of leukocyte adhesiveness compared with leukocyte stiffness in early ARDS. CONCLUSIONS: The leukocyte stiffening induced by cytokines in the sera of patients might play a role in the sequestration of leukocytes in the lung capillary beds during early ARDS. The inhibition of leukocyte stiffening with blocking antibodies might inspire future therapeutic strategies. PMID- 26757705 TI - County-level heat vulnerability of urban and rural residents in Tibet, China. AB - BACKGROUND: Tibet is especially vulnerable to climate change due to the relatively rapid rise of temperature over past decades. The effects on mortality and morbidity of extreme heat in Tibet have been examined in previous studies; no heat adaptation initiatives have yet been implemented. We estimated heat vulnerability of urban and rural populations in 73 Tibetan counties and identified potential areas for public health intervention and further research. METHODS: According to data availability and vulnerability factors identified previously in Tibet and elsewhere, we selected 10 variables related to advanced age, low income, illiteracy, physical and mental disability, small living spaces and living alone. We separately created and mapped county-level cumulative heat vulnerability indices for urban and rural residents by summing up factor scores produced by a principal components analysis (PCA). RESULTS: For both study populations, PCA yielded four factors with similar structure. The components for rural and urban residents explained 76.5 % and 77.7 % respectively of the variability in the original vulnerability variables. We found spatial variability of heat vulnerability across counties, with generally higher vulnerability in high-altitude counties. Although we observed similar median values and ranges of the cumulative heat vulnerability index values among urban and rural residents overall, the pattern varied strongly from one county to another. CONCLUSIONS: We have developed a measure of population vulnerability to high temperatures in Tibet. These are preliminary findings, but they may assist targeted adaptation plans in response to future rapid warming in Tibet. PMID- 26757703 TI - Metatranscriptomic analysis of diverse microbial communities reveals core metabolic pathways and microbiome-specific functionality. AB - BACKGROUND: Metatranscriptomics is emerging as a powerful technology for the functional characterization of complex microbial communities (microbiomes). Use of unbiased RNA-sequencing can reveal both the taxonomic composition and active biochemical functions of a complex microbial community. However, the lack of established reference genomes, computational tools and pipelines make analysis and interpretation of these datasets challenging. Systematic studies that compare data across microbiomes are needed to demonstrate the ability of such pipelines to deliver biologically meaningful insights on microbiome function. RESULTS: Here, we apply a standardized analytical pipeline to perform a comparative analysis of metatranscriptomic data from diverse microbial communities derived from mouse large intestine, cow rumen, kimchi culture, deep-sea thermal vent and permafrost. Sequence similarity searches allowed annotation of 19 to 76% of putative messenger RNA (mRNA) reads, with the highest frequency in the kimchi dataset due to its relatively low complexity and availability of closely related reference genomes. Metatranscriptomic datasets exhibited distinct taxonomic and functional signatures. From a metabolic perspective, we identified a common core of enzymes involved in amino acid, energy and nucleotide metabolism and also identified microbiome-specific pathways such as phosphonate metabolism (deep sea) and glycan degradation pathways (cow rumen). Integrating taxonomic and functional annotations within a novel visualization framework revealed the contribution of different taxa to metabolic pathways, allowing the identification of taxa that contribute unique functions. CONCLUSIONS: The application of a single, standard pipeline confirms that the rich taxonomic and functional diversity observed across microbiomes is not simply an artefact of different analysis pipelines but instead reflects distinct environmental influences. At the same time, our findings show how microbiome complexity and availability of reference genomes can impact comprehensive annotation of metatranscriptomes. Consequently, beyond the application of standardized pipelines, additional caution must be taken when interpreting their output and performing downstream, microbiome-specific, analyses. The pipeline used in these analyses along with a tutorial has been made freely available for download from our project website: http://www.compsysbio.org/microbiome . PMID- 26757706 TI - Worse Neurological State During Acute Ischemic Stroke is Associated with a Decrease in Serum Albumin Levels. AB - High serum albumin levels during ischemic stroke (IS) decrease the risk of a poor outcome. This study aimed to determine whether serum albumin levels within the first days after IS correlate with radiological and biochemical markers of brain tissue damage. Fifty-six IS patients were enrolled into the study. Neurological examinations were based on the National Institute of Health Stroke Scale. Serum albumin levels and S100BB were evaluated using commercially available ELISA kits. The albumin decrease index (ADI) was calculated as the difference between serum albumin levels measured on days 1 and 10 of IS. All parameters were estimated on the 1st, 3rd, 5th, and 10th days of IS, and the volume of ischemic focus was measured on the 10th day. Mean serum albumin levels were decreased during acute IS. There were correlations between the ADI and mean S100BB serum levels (r = 0.36, p < 0.05), the volume of ischemic focus (r = 0.39, p < 0.05), and the patients' neurological state when measured on day 10 of IS (r = 0.59, p < 0.001). A decrease in serum albumin levels during the acute phase of IS corresponds to a worse neurological state as a result of a large ischemic focus with intense catabolic processes. PMID- 26757707 TI - Undiagnosed Stanford type A aortic dissection: a rare survival report. AB - Acute aortic dissection is a life-threatening conditions with a high mortality rate within the first 24 h since presentation, if left untreated. Nevertheless the setting may be chronic and stable. We present a rare case of a misdiagnosed and unoperated Stanford type A aortic dissection in a 78-year old woman with stable computed tomography features at the second year of clinical follow-up. PMID- 26757708 TI - Detection of radiotherapy-induced myocardial changes by ultrasound tissue characterisation in patients with breast cancer. AB - Radiotherapy (RT) in the thoracic region is associated with an increased risk of late cardiovascular morbidity and mortality. Ultrasonic tissue characterisation (UTC) is a non-invasive method of identifying changes in myocardial tissue, such as increased fibrosis. The aim of this study was to assess whether UTC can detect early RT-induced myocardial alterations. Seventy-eight eligible patients with early stage breast cancer were evaluated before and immediately after RT. Twenty patients had right-sided and 58 left-sided breast cancer. None received chemotherapy. A comprehensive echocardiographic examination included 3D measurements and UTC of the right ventricular (RV) free wall, ventricular septum and left ventricular (LV) posterior wall. Integrated backscatter calibration was done for the pericardium (cpIBS) and LV cavity (ccIBS). RT for left-sided breast cancer was associated with increased echodensity in the UTC analysis. RV free wall and ventricular septum cpIBS increased from -15.0 +/- 7.3 to -13.7 +/- 7.9 dB (p = 0.079) and from -18.2 +/- 5.1 to -16.0 +/- 6.4 dB (p = 0.002), respectively. Likewise, ccIBS in the RV free wall increased from 20.4 +/- 5.9 to 22.1 +/- 5.6 dB (p = 0.046), and in the LV septum from 17.3 +/- 5.2 to 19.8 +/- 5.5 dB (p < 0.001). In 3D echocardiography, LV mass increased from 102 +/- 18 to 107 +/- 18 g (p = 0.005). Patients receiving RT for right-sided breast cancer did not display these changes. Left-sided RT increased myocardial echodensity, particularly in the structures receiving the highest radiation dose. Considering the progressive nature of the RT induced damage, these early changes may help us with individual risk stratification and serve as a tool for screening. PMID- 26757709 TI - Simulated increased soft tissue thickness artefactually decreases trabecular bone score: a phantom study. AB - BACKGROUND: Trabecular bone score (TBS), which has been proposed to be used in complementary with bone mineral density (BMD) to improve the assessment of fracture risk, is negatively associated with body mass index (BMI). The effect of soft tissue, which is expected to be thicker in subjects with high BMI, on TBS was studied using three scan types: Hologic with fast array mode (Hfa), Hologic with high definition mode (Hhd), and GE-Lunar iDXA. METHODS: A spine phantom provided by Hologic for routine quality control procedure was scanned using three scan types: Hfa, Hhd, and iDXA. The phantom was scanned with an overlying soft tissue equivalent material (bolus used in radiotherapy) of 0 (without), 1, 2.5, 3.5, 5 and 7.5 cm thick. For each setting, 30 acquisitions were performed in the same way as for the quality control procedure. TBS was calculated using TBS iNsight(r) software version 2.1 on the same regions of interest as those used for lumbar spine BMD. RESULTS: Mean +/- SD TBS of the phantom (without overlying soft tissue) were 1.379 +/- 0.018, 1.430 +/- 0.009, and 1.423 +/- 0.005 using Hfa, Hhd, and iDXA, respectively. A one-way repeated measures ANOVA showed that there were statistically differences in TBS due to different thicknesses of soft tissue equivalent materials for all three scan types (p < 0.001). A Tukey post-hoc test revealed that the decrease in TBS was statistically significant (p < 0.001) when the soft tissue thickness was 1 cm (-0.0246 +/- 0.0044, -0.0319 +/- 0.0036, and 0.0552 +/- 0.0015 for Hfa, Hhd, and iDXA, respectively). Although to a lesser degree, the effects were also statistically significant for BMD (p < 0.05): an increase for Hfa and Hhd but a decrease for iDXA. However, these changes did not exceed the least significant change (LSC) derived from patients. CONCLUSIONS: Increased soft tissue thickness results in lower TBS value. Although BMD is also affected, it is unlikely to pose a clinical problem because the change is unlikely to exceed the patient-derived LSC. PMID- 26757710 TI - Headache in Intracranial and Cervical Artery Dissections. AB - Dissection refers to a tear in the wall of an artery, with the two main types being intracranial or extracranial. Dissections tend to occur most commonly in the young, sometimes secondary to trauma involving the neck. To confirm a dissection, some type of vessel imaging is necessary, including magnetic resonance angiography (MRA), computed tomography angiography (CTA), or angiography. The most common presentation of a dissection (especially extracranial) is pain, usually head and neck pain along with a Horner's syndrome. Patients may also present with ischemic symptoms, including transient ischemic attack (TIA) or stroke, which may also be a complication of a dissection. Although headache is a common presentation, there is little research into phenotype or long-term outcomes. There are a number of case reports detailing the phenotypes of headaches that may be present in dissection, including a migraine like or hemicrania-like headache. Dissections are usually treated with some type of anti-platelet or anti-coagulation, although there are only a few randomized controlled trials. In a new acute headache, dissection is an important diagnosis to keep in mind. PMID- 26757711 TI - Lifestyle Factors and Migraine in Childhood. AB - Migraine is one of the most common pain symptoms in children. Indeed, a high percentage of adult migraine patients report to have suffered from recurrent headache during the childhood. In particular, children could experience the so called childhood periodic syndromes (such as cyclic vomiting, abdominal migraine, and benign paroxysmal vertigo) that have been usually considered precursors of migraine or they could develop overt migraine headaches. However, typical cohort of migraine symptoms could be absent and children could not achieve all clinical features necessary for a migraine attack diagnosis according to classification criteria. Nevertheless, migraine is characterized also in childhood by a significant negative impact on the quality of life and a high risk of developing chronic and persistent headache in adulthood. Several studies have emphasized the role of different risk factors for migraine in children. Among these, obesity and overweight, particular food or the regular consumption of alcohol or caffeine, dysfunctional family situation, low level of physical activity, physical or emotional abuse, bullying by peers, unfair treatment in school, and insufficient leisure time seem to be strictly related to migraine onset or progression. Consequently, both identification and avoidance of triggers seem to be mandatory in children with migraine and could represent an alternative approach to the treatment of migraine abstaining from pharmacologic therapies. PMID- 26757713 TI - The analysis of factors affecting municipal employees' willingness to report to work during an influenza pandemic by means of the extended parallel process model (EPPM). AB - BACKGROUND: The management of pandemics with highly infectious diseases in modern urban habitats depends largely on the maintenance of public services. Understanding the factors that influence municipal employees' willingness to come to work during a pandemic is therefore a basic requirement for adequate public health preparedness. In this study the extended parallel process model (EPPM) is applied to investigate how the readiness of municipal employees to report to work during an influenza pandemic (IP) is affected by individual attitudes and environmental conditions. METHODS: 1.566 employees of a major German city participated in a cross-sectional online survey. The questions of the survey covered the dimensions of risk perception, role competence, self-efficacy, role importance, sense of duty, and willingness to report to work in the case of an IP. Data were analysed by means of path analyses. RESULTS: Data suggest that up to 20% of the public service workers were not willing to come to work during an IP. Willingness to report to work was increased by the perception of a high working role competence, a high assessment of role importance, high self-efficacy expectations, and a high sense of duty. Negative effects on willingness to report to work were identified as the perception of a high risk to become infected at work and the perceived risk to infect family members. The decomposition of direct and indirect effects provided important insights into the interrelationships between model variables. CONCLUSIONS: Measures to increase municipal workers' willingness to report to work in case of an infectious pandemic should include communication strategies to inform employees clearly about their particular tasks during such critical events and training exercises to increase their confidence in their competences and skills to fulfil these tasks. PMID- 26757712 TI - The CII-specific autoimmune T-cell response develops in the presence of FTY720 but is regulated by enhanced Treg cells that inhibit the development of autoimmune arthritis. AB - BACKGROUND: Fingolimod (FTY720) is an immunomodulating drug that inhibits sphingosine-1-phosphate binding and blocks T-cell egress from lymph nodes. We analyzed the effect of FTY720 on the autoimmune T- and B-cell response in autoimmune arthritis and studied the mechanisms by which it alters the function of T cells. METHODS: Human leukocyte antigen (HLA)-DR1 humanized mice were immunized with type II collagen (CII) and treated with FTY720 three times per week for 3 weeks. Arthritis was evaluated and autoimmune T- and B-cell responses were measured using proliferation assays, enzyme-linked immunosorbent assays, HLA DR tetramers, and flow cytometry. The functional capacity of regulatory T (Treg) cells from FTY720-treated mice was measured using an in vitro suppression assay, and the role of Treg cells in inhibiting arthritis in FTY720-treated mice was evaluated using mice treated with anti-CD25 to deplete Treg cells. RESULTS: Treatment with FTY720 delayed the onset of arthritis and significantly reduced disease incidence. FTY720 did not prevent the generation of a CII-specific autoimmune T-cell response in vivo. However, as the treatment continued, these T cells became unresponsive to restimulation with antigen in vitro, and this anergic state was reversed by addition of interleukin 2. Measurements of CD4(+)CD25(+)Foxp3(+) cells in the lymph nodes revealed that the ratio of Treg to helper T (Th) cells increased twofold in the FTY720-treated mice, and in vitro assays indicated that the regulatory function of these cells was enhanced. That FTY720 stimulation of Treg cells played a major role in arthritis inhibition was demonstrated by a loss of disease inhibition and restitution of the T-cell proliferative function after in vivo depletion of the Treg cells. CONCLUSIONS: While FTY720 affects the recirculation of lymphocytes, its ability to inhibit the development of autoimmune arthritis involves several mechanisms, including the enhancement of Treg cell function by increasing the Treg/Th ratio and increased regulatory function on a per-cell basis. FTY720 did not inhibit the development of the autoimmune T-cell response, but disease inhibition appeared to be mediated by Treg cell-mediated suppression of the CII-specific T cells. These data suggest that specific targeting of Treg cells with FTY720 may be a novel therapy for autoimmunity. PMID- 26757715 TI - Learning to Take Informed Consent: On a Project for German Medical Students: Reply. PMID- 26757714 TI - Translational Stroke Research on Blood-Brain Barrier Damage: Challenges, Perspectives, and Goals. PMID- 26757716 TI - Measuring Outcomes of Laparoscopic Anti-reflux Surgery: Quality of Life Versus Symptom Scores? AB - INTRODUCTION: Outcome following fundoplication for gastroesophageal reflux can be measured using objective tests, symptom scores and quality of life (QoL) measures. Which is best and how these assessments correlate is uncertain. To determine the utility of assessment measures we compared a general QoL measure (SF-36) and a disease-specific measure (GERD-hr-QoL) with symptom and satisfaction scores in individuals following fundoplication. METHODS: 329 individuals underwent fundoplication between 2000 and 2015 in 2 centres in Australia and the Netherlands. Patients were assessed before and 3, 12 and 24 months after surgery using 10-point Likert scales to assess heartburn and satisfaction, the SF-36 questionnaire and the GERD-hr-QoL questionnaire. SF-36 scores were converted into component scores: Physical Component Scale (PCS) score and Mental Component Scale (MCS) score. Correlations between QoL measures and clinical outcomes were determined. RESULTS: Surgery relieved heartburn (7.0 vs. 0.0 median, P < 0.001) and patients were highly satisfied with the outcome (median 9.0). PCS and MCS scores improved after surgery (PCS 40.9 vs. 46.0, P < 0.001; MCS 47.6 vs. 50.3, P = 0.027). GERD-hr-QoL scores also improved after surgery (15.7 vs. 3.7, P < 0.001). Correlations between PCS and MCS scores versus heartburn and satisfaction scores were generally weak or absent. However, correlations between GERD-hr-QoL versus heartburn and satisfaction scores were moderate to strong. CONCLUSION: Despite improvements in scores, the SF-36 correlated poorly with clinical outcome measures, and its use to measure outcome following fundoplication is questioned. However, the GERD-hr-QoL correlated well with the symptom scores, suggesting this disease-specific QoL measure is a better tool for assessing anti-reflux surgery outcome. PMID- 26757717 TI - Long-Term Outcome of Follicular Thyroid Carcinoma in Patients Undergoing Surgical Intervention for Skeletal Metastases. AB - BACKGROUND: A large proportion of follicular thyroid carcinoma (FTC) patients in developing countries present with overt skeletal metastases (SM). These patients often require surgical interventions for prevention of morbidity, palliation of symptoms, and facilitation of radioiodine therapy (RAIT). Scarce literature is available about the long-term outcome of such patients. The aim of this study was to evaluate the long-term outcome of FTC patients undergoing surgical intervention for SM. METHODS: We retrospectively reviewed the data of FTC patients with SM (January 1990-December 2011). Out of 91 patients with SM, 32 had surgical interventions for SM. All had total thyroidectomy performed. RESULTS: The mean age of the patients was 48.5 years (M:F = 1:2). Majority (93.7%) had synchronous metastases and 22% had multiple SM. The surgical interventions for SM included: laminectomy (50%), resection of skull metastases (18.8%), resection of manubrium sterni (18.8%), partial clavicle excision (9.4%), and hemimandibulectomy (3.1%). The main intents were palliation (50%) and facilitation of RAIT (37.5%). 84% patients received RAIT. Median follow-up was 52 months (mean = 50 +/- 37). Five- (56 vs 63%) and 10-year (28 vs 23%) overall survival (OS) did not differ significantly (p = 0.968) from those not having interventions for SM. On univariate analysis tumor invasion (p = 0.006) and synchronous presentation of SM (p = 0.043) were significant risk factors for OS, whereas on multivariate analysis tumor invasion (p = 0.006) was significant. CONCLUSIONS: Surgical interventions directed at SM in FTC patients with overt multiple SM might not result in improve OS. However, considering reasonable long term survival, interventions should be considered for desired palliation and preservation of body function. PMID- 26757718 TI - Significance of R1 Resection for Advanced Colorectal Liver Metastases in the Era of Modern Effective Chemotherapy. AB - BACKGROUND: The prognosis impact of positive margins after resection of colorectal liver metastases (CLM) in patients treated with modern effective chemotherapy has not been elucidated. The objective was to compare oncologic outcomes after R0 and R1 resections in the era of modern effective chemotherapy. METHODS: Between 1999 and 2010, all consecutive patients undergoing liver resection for CLM were analyzed retrospectively. Patients with extrahepatic metastases, macroscopic residual tumor, treated with combined radiofrequency, or not treated with chemotherapy were excluded. Survival and recurrence after R0 (tumor-free margin >0 mm) and R1 resections were analyzed. RESULTS: Among 466 patients undergoing hepatectomy for CLM, 191 were eligible. Of them, 164 (86 %) received preoperative chemotherapy and 105 (55 %) received postoperative chemotherapy. R1 resection (10 %) was comparable in patients treated or not by preoperative chemotherapy. R1 status was associated with more intrahepatic recurrences. Overall survival (OS) (44 vs. 61 %; p = 0.047) and disease-free survival (DFS) (8 vs. 26 %; p = 0.082) were lower in patients after R1 compared to R0 resection (32 months of median follow-up). Preoperative chemotherapy and major hepatectomy were prognostic factors of survival, whereas postoperative chemotherapy was a protective factor from recurrences. In patients treated with preoperative chemotherapy, OS and DFS were similar between R1 and R0 resections (40 vs. 55 %, p = 0.104 and 9 vs. 22 %, p = 0.174, respectively). CONCLUSION: In the era of modern effective chemotherapy, R1 resection leads to more intrahepatic recurrences but did not affect OS in selected patient responders to neoadjuvant chemotherapy. Postoperative chemotherapy protects from recurrences whatever the margin resection status. PMID- 26757719 TI - Oncological, functional and perioperative outcomes in transplant patients after radical prostatectomy. AB - PURPOSE: Oncological surgery in immunosuppressed patients with solid organ transplantation (Tx) is challenging. These patients are thought to have higher postoperative morbidity and an increased rate of tumour progression. The aim of the present study was to analyse oncological, functional and perioperative outcomes in Tx patients following radical prostatectomy (RP). MATERIALS AND METHODS: Between 1996 and 2014, 30 patients diagnosed with prostate cancer underwent RP at our institution following Tx (kidney: n = 20, heart: n = 5, liver: n = 5). Functional, oncological and perioperative follow-ups were analysed. Postoperative complications were assessed using the Clavien-Dindo classification. RESULTS: Median follow-up was 45 months. Median PSA was 5.3 ng/ml. Intraoperative blood loss was 600 ml at a median operating time of 180 min. Surgery in kidney Tx patients was technically feasible. Major complications occurred in 3 patients (ureteral injury, lymphocele and haematoma). Histological evaluation revealed n = 18 <=pT2 tumours (60.0 %), n = 7 pT3a tumours (23.3 %) and n = 5 >=pT3b tumours (16.7 %). Continence rate 12 months after surgery, defined as no or one safety pad use, was 73.3 %, while 93.3 % of the patients used <=2 pads/24 h. After the median follow-up of 45 months, BCR-free survival was 69.0 %. In recurrent men, there was suspicion of metastasis in one patient. No cancer-specific death was observed. Five-year overall survival was 94.4 %. CONCLUSION: The complication rate in patients with solid organ transplantation after RP was low. While histopathological evaluation revealed disease characteristics comparable to non-transplant patients from current RP series, postoperative continence was worse. Immunosuppressive therapy does not seem to lead to an increased rate of tumour progression. PMID- 26757720 TI - Assessment of Adherence to Prescribed Therapy in Patients with Chronic Hepatitis B. AB - INTRODUCTION: Evidence shows that treatment for hepatitis B virus (HBV) can suppress viral load. Among the factors directly linked to therapeutic success is adherence to the treatment. Several instruments to assess adherence are available, but they are not validated for use in chronic hepatitis B. The purpose of this paper was to adapt and validate the "Assessment of Adherence to Antiretroviral Therapy Questionnaire-HIV" (CEAT-VIH) for patients with chronic hepatitis B (referred to herein as CEAT-HBV). METHODS: The validity of the adapted questionnaire evidence was established through concurrent, criterion, and construct validities. RESULTS: We found negative and significant correlation between the domain "degree of compliance to antiviral therapy" assessed by CEAT HBV and the Morisky test (r = -0.62, P < 0.001) and between the domain "barriers to adherence" and HBV viral load (r = -0.42, P < 0.001). In terms of the construct's discriminative capacity, scores greater than or equal to 80 detected antiviral therapy success, which are necessary for the prediction of an undetectable HBV viral load. Thus, a cutoff value of 80.5 was set with a value of 81% for sensitivity and 67% for specificity. CONCLUSION: The CEAT-HBV identified 43% (n = 79) non-adherent patients and was shown to be a useful tool in clinical practice. PMID- 26757722 TI - Parents of children with psychopathology: psychiatric problems and the association with their child's problems. AB - Knowledge is lacking regarding current psychopathology in parents whose children are evaluated in a psychiatric outpatient clinic. This especially accounts for fathers. We provide insight into the prevalence rates of parental psychopathology and the association with their offspring psychopathology by analyzing data on psychiatric problems collected in 701 mothers and 530 fathers of 757 referred children. Prevalence rates of parental psychopathology were based on (sub)clinical scores on the adult self report. Parent-offspring associations were investigated in multivariate analyses taking into account co-morbidity. Around 20 % of the parents had a (sub)clinical score on internalizing problems and around 10 % on attention deficit hyperactivity (ADH) problems. Prevalence rates did not differ between mothers and fathers. Parent-offspring associations did not differ between girls and boys. Maternal anxiety was associated with all offspring problem scores. In addition, maternal ADH problems were associated with offspring ADH problems. Paternal anxiety and ADH problems scores were specifically associated with offspring internalizing and externalizing problem scores, respectively. Associations with offspring psychopathology were of similar magnitude for mothers and fathers and were not influenced by spousal resemblance. Our study shows that both fathers and mothers are at increased risk for psychiatric problems at the time of a child's evaluation and that their problems are equally associated with their offspring problems. The results emphasize the need to screen mothers as well as fathers for psychiatric problems. Specific treatment programs should be developed for these families in especially high need. PMID- 26757724 TI - Different distribution patterns of ten virulence genes in Legionella reference strains and strains isolated from environmental water and patients. AB - Virulence genes are distinct regions of DNA which are present in the genome of pathogenic bacteria and absent in nonpathogenic strains of the same or related species. Virulence genes are frequently associated with bacterial pathogenicity in genus Legionella. In the present study, an assay was performed to detect ten virulence genes, including iraA, iraB, lvrA, lvrB, lvhD, cpxR, cpxA, dotA, icmC and icmD in different pathogenicity islands of 47 Legionella reference strains, 235 environmental strains isolated from water, and 4 clinical strains isolated from the lung tissue of pneumonia patients. The distribution frequencies of these genes in reference or/and environmental L. pneumophila strains were much higher than those in reference non-L. pneumophila or/and environmental non-L. pneumophila strains, respectively. L. pneumophila clinical strains also maintained higher frequencies of these genes compared to four other types of Legionella strains. Distribution frequencies of these genes in reference L. pneumophila strains were similar to those in environmental L. pneumophila strains. In contrast, environmental non-L. pneumophila maintained higher frequencies of these genes compared to those found in reference non-L. pneumophila strains. This study illustrates the association of virulence genes with Legionella pathogenicity and reveals the possible virulence evolution of non L. pneumophia strains isolated from environmental water. PMID- 26757723 TI - Microbacterium horti sp. nov., a bacterium isolated from Cucurbita maxima cultivating soil. AB - A novel bacterial strain THG-SL1(T) was isolated from a soil sample of Cucurbita maxima garden and was characterized by using a polyphasic approach. Cells were Gram-reaction-positive, non-motile and rod-shaped. The strain was aerobic, catalase positive and weakly positive for oxidase. Phylogenetic analysis based on 16S rRNA gene sequence analysis but it shared highest similarity with Microbacterium ginsengisoli KCTC 19189(T) (96.6 %), indicating that strain THG SL1(T) belongs to the genus Microbacterium. The DNA G + C content of the isolate was 68.9 mol %. The major fatty acids were anteiso-C15: 0 (39.7 %), anteiso-C17: 0 (24.4 %) and iso-C16: 0 (18.5 %). The major polar lipids of strain THG-SL1(T) were phosphatidylglycerol (PG) and an unidentified glycolipid (GL). The predominant respiratory isoprenoid quinones were menaquinone-11 and menaquinone 12. The diamino acid in the cell-wall peptidoglycan was ornithine. Based on the results of polyphasic characterization, strain THG-SL1(T) represented a novel species within the genus Microbacterium, for which the name Microbacterium horti sp. nov. is proposed. The type strain is THG-SL1(T) (=KACC 18286(T)=CCTCC AB 2015117(T)). PMID- 26757721 TI - Salicylic acid treatment and expression of an RNA-dependent RNA polymerase 1 transgene inhibit lethal symptoms and meristem invasion during tobacco mosaic virus infection in Nicotiana benthamiana. AB - BACKGROUND: Host RNA-dependent RNA polymerases (RDRs) 1 and 6 contribute to antiviral RNA silencing in plants. RDR6 is constitutively expressed and was previously shown to limit invasion of Nicotiana benthamiana meristem tissue by potato virus X and thereby inhibit disease development. RDR1 is inducible by salicylic acid (SA) and several other phytohormones. But although it contributes to basal resistance to tobacco mosaic virus (TMV) it is dispensable for SA induced resistance in inoculated leaves. The laboratory accession of N. benthamiana is a natural rdr1 mutant and highly susceptible to TMV. However, TMV induced symptoms are ameliorated in transgenic plants expressing Medicago truncatula RDR1. RESULTS: In MtRDR1-transgenic N. benthamiana plants the spread of TMV expressing the green fluorescent protein (TMV.GFP) into upper, non inoculated, leaves was not inhibited. However, in these plants exclusion of TMV.GFP from the apical meristem and adjacent stem tissue was greater than in control plants and this exclusion effect was enhanced by SA. TMV normally kills N. benthamiana plants but although MtRDR1-transgenic plants initially displayed virus-induced necrosis they subsequently recovered. Recovery from disease was markedly enhanced by SA treatment in MtRDR1-transgenic plants whereas in control plants SA delayed but did not prevent systemic necrosis and death. Following SA treatment of MtRDR1-transgenic plants, extractable RDR enzyme activity was increased and Western blot analysis of RDR extracts revealed a band cross reacting with an antibody raised against MtRDR1. Expression of MtRDR1 in the transgenic N. benthamiana plants was driven by a constitutive 35S promoter derived from cauliflower mosaic virus, confirmed to be non-responsive to SA. This suggests that the effects of SA on MtRDR1 are exerted at a post-transcriptional level. CONCLUSIONS: MtRDR1 inhibits severe symptom development by limiting spread of virus into the growing tips of infected plants. Thus, RDR1 may act in a similar fashion to RDR6. MtRDR1 and SA acted additively to further promote recovery from disease symptoms in MtRDR1-transgenic plants. Thus it is possible that SA promotes MtRDR1 activity and/or stability through post-transcriptional effects. PMID- 26757725 TI - From Exceptional to Liminal Subjects: Reconciling Tensions in the Politics of Tuberculosis and Migration. AB - Controlling the movement of potentially infectious bodies has been central to Australian immigration law. Nowhere is this more evident than in relation to tuberculosis (TB), which is named as a ground for refusal of a visa in the Australian context. In this paper, I critically examine the "will to knowledge" that this gives rise to. Drawing on a critical analysis of texts, including interviews with migrants diagnosed with TB and healthcare professionals engaged in their care (n=19), I argue that this focus on border policing, rather than resettlement and the broader social determinants of health that drive current rates of TB, paradoxically renders migrants diagnosed with TB as liminal subjects in the post-arrival phase. This raises ethical issues about who "matters," as well as dilemmas about what constitutes adequate care for the "Other," both of which go to the heart of the political economy of migration. PMID- 26757727 TI - Involvement of oxidative stress in tri-ortho-cresyl phosphate-induced liver injury in male mice. AB - Tri-ortho-cresyl phosphate (TOCP) has been widely used as plasticizers, plastic softeners, and flame retardants in industry and reported to have delayed neurotoxicity and reproductive toxicology in animals. However, it remains to be elusive whether TOCP induces liver injury. In this study, male mice were orally administered different concentrations of TOCP (100, 200, or 400 mg/kg/day) for 28 days. Histological examination showed that TOCP led to serious hepatocellular injury. In addition, administration of TOCP induced a marked elevation in the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in mice. The content of malondialdehyde (MDA) was increased significantly in the liver after the mice were treated with TOCP; while there was a dramatic decrease in the content of glutathione (GSH) and the activities of antioxidative enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX). TOCP inhibited viability of mouse liver cancer Hepa 1-6 cells in a dose-dependent manner. Meanwhile, TOCP significantly increased MDA content and inhibited GSH content and the activities of SOD and GSH-PX in the cells, respectively. Oxidative stress dramatically inhibited viability of Hepa 1-6 cells; while inhibition of oxidative stress by N-acetyl-l-cysteine could rescue the cell viability inhibited by TOCP to a certain extent. In summary, oxidative stress might be involved in TOCP induced hepatocellular injury in male mice. PMID- 26757726 TI - Cyclic AMP is a key regulator of M1 to M2a phenotypic conversion of microglia in the presence of Th2 cytokines. AB - BACKGROUND: Microglia and macrophages play a central role in neuroinflammation. Pro-inflammatory cytokines trigger their conversion to a classically activated (M1) phenotype, sustaining inflammation and producing a cytotoxic environment. Conversely, anti-inflammatory cytokines polarize the cells towards an alternatively activated (M2), tissue reparative phenotype. Elucidation of the signal transduction pathways involved in M1 to M2 phenotypic conversion may provide insight into how the innate immune response can be harnessed during distinct phases of disease or injury to mediate neuroprotection and neurorepair. METHODS: Microglial cells (cell line and primary) were subjected to combined cyclic adenosine monophosphate (cyclic AMP) and IL-4, or either alone, in the presence of pro-inflammatory mediators, lipopolysaccharide (LPS), or tumor necrosis factor-alpha (TNF-alpha). Their effects on the expression of characteristic markers for M1 and M2 microglia were assessed. Similarly, the M1 and M2 phenotypes of microglia and macrophages within the lesion site were then evaluated following a contusive spinal cord injury (SCI) to the thoracic (T8) spinal cord of rats and mice when the agents were administered systemically. RESULTS: It was demonstrated that cyclic AMP functions synergistically with IL-4 to promote M1 to M2 conversion of microglia in culture. The combination of cyclic AMP and IL-4, but neither alone, induced an Arg-1(+)/iNOS(-)cell phenotype with concomitant expression of other M2-specific markers including TG2 and RELM-alpha. M2-converted microglia showed ameliorated production of pro-inflammatory cytokines (TNF-alpha and IP-10) and reactive oxygen species, with no alteration in phagocytic properties. M2a conversion required protein kinase A (PKA), but not the exchange protein directly activated by cyclic AMP (EPAC). Systemic delivery of cyclic AMP and IL-4 after experimental SCI also promoted a significant M1 to M2a phenotypic change in microglia and macrophage population dynamics in the lesion. CONCLUSIONS: Using primary microglia, microglial cell lines, and experimental models of CNS injury, we demonstrate that cyclic AMP levels are a critical determinant in M1-M2 polarization. High levels of cyclic AMP promoted an Arg-1(+) M2a phenotype when microglia were activated with pro-inflammatory stimuli and Th2 cytokines. Th2 cytokines or cyclic AMP independently did not promote these changes. Phenotypic conversion of microglia provides a powerful new therapeutic approach for altering the balance of cytotoxic to reparative microglia in a diversity of neurological diseases and injury. PMID- 26757728 TI - The efficacy of a Mindfulness Based Intervention for depressive symptoms in patients with Multiple Sclerosis and their caregivers: study protocol for a randomized controlled clinical trial. AB - BACKGROUND: Multiple Sclerosis has a great impact on psychological functioning of patients and can be associated with various mental health disorders and symptoms. The most prevalent one is depression, which ranges from 15 to 47%. Mindfulness Based Interventions are a relatively brief and cost-effective program that has been studied in patients with several chronic diseases and recently also in patients with Multiple Sclerosis. Mindfulness Based Interventions are based on the assumption that a non-judgmental awareness and acceptance of one's moment-to moment experience can have a positive effect on the adaptation to the disease, reducing the psychological burden and improving patients' quality of life. Several studies concluded that Mindfulness Based Interventions can be beneficial in terms of improving both psychological and psychical aspects of Multiple Sclerosis, but none of them compared the intervention with an active control group. The primary objective of the study is to evaluate the efficacy of a group based Mindfulness Based Intervention on depressive symptoms in patients with Multiple Sclerosis, as compared with an active control group. METHODS: The study design is a randomized controlled clinical trial. Eighty-eight patients with Multiple Sclerosis and depressive symptoms will be recruited and randomized to either Mindfulness Based Intervention or an active control group. The latter is designed to control for non-specific elements of the intervention and it comprises psycho-education and relaxation techniques. The primary outcome is the reduction of depressive symptoms as measured via the Beck Depressive Inventory II. Secondary outcome measures are level of quality of life, anxiety, perceived stress, illness perception, fatigue and quality of interpersonal relationship. Outcomes will be assessed at baseline, after treatment and 6 months after the end of the treatment. Caregivers will participate in groups together with patients. DISCUSSION: As far as we know this trial will be the first randomized controlled trial testing the efficacy of group-based Mindfulness Based Intervention for patients with Multiple Sclerosis with a comparison with an active control group with a specific focus on depressive symptoms. TRIAL REGISTRATION: NCT02611401. PMID- 26757729 TI - [Prehospital assessment of injury type and severity in severely injured patients by emergency physicians : An analysis of the TraumaRegister DGU(r)]. AB - BACKGROUND: Prehospital assessment of injury type and severity by emergency medical services physicians impacts treatment including appropriate destination hospital selection, especially in (potentially) life-threatening cases. Injuries which are underestimated or overlooked by the emergency physician can delay adequate therapy and thus significantly influence the overall outcome. The current study used data from the TraumaRegister DGU(r) to evaluate the reliability of prehospital injury assessments made by emergency physicians. MATERIAL AND METHODS: Data of 30,777 patients from the TraumaRegister DGU(r) between 1993 and 2009 were retrospectively evaluated. Using the abbreviated injury scale (AIS), subjective prehospital assessments of injury severity by emergency physicians were correlated with objectively identified injuries diagnosed after admission to hospital. For this evaluation, prehospital injury assessments rated moderate or severe by the emergency physician as well as injuries diagnosed in hospital with an AIS score >=3 points were deemed relevant. RESULTS: The 30,777 patients with an injury severity score (ISS) >= 9 suffered a total of 202,496 injuries and of these 26 % (51,839 out of 202,496) were considered relevant with an AIS >=3 points. The most frequent relevant injuries were to the head (47 %) and chest (46 %). Of the 51,839 relevant injuries, the prehospital assessment by the emergency physician was accurate for 71 % and in 29 % of the cases relevant injuries were underestimated. Relevant injuries were unrecognized or underestimated in prehospital assessments for almost 1 out of every 7 cases of head trauma, almost 1 out of every 3 thoracic trauma and almost 1 out of every 2 abdominal and pelvic trauma. CONCLUSION: The assessment of injury severity by emergency medical services physicians based on physical examination at the scene of the trauma is not very reliable. Thus, mechanisms of injury and overall presentation as well as identifiable injuries and vital parameters should be recognized by the emergency physician when considering treatment strategies and choice of appropriate destination hospital. The patient should be re-evaluated in a priority-oriented manner at the latest on arrival in the trauma room to avoid the consequences of unrecognized or underestimated injuries. PMID- 26757730 TI - Improvement of Parameter Estimations in Tumor Growth Inhibition Models on Xenografted Animals: a Novel Method to Handle the Interval Censoring Caused by Measurement of Smaller Tumors. AB - The purpose of this study was to explore the interval censoring induced by caliper measurements on smaller tumors during tumor growth experiments in preclinical studies and to show its impact on parameter estimations. A new approach, the so-called interval-M3 method, is proposed to specifically handle this type of data. Thereby, the interval-M3 method was challenged with different methods (including classical methods for handling below quantification limit values) using Stochastic Simulation and Estimation process to take into account the censoring. In this way, 1000 datasets were simulated under the design of a typical of tumor growth study in xenografted mice, and then, each method was used for parameter estimation on the simulated datasets. Relative bias and relative root mean square error (relative RMSE) were consequently computed for comparison purpose. By not considering the censoring, parameter estimations appeared to be biased and particularly the cytotoxic effect parameter, k 2 , which is the parameter of interest to characterize the efficacy of a compound in oncology. The best performance was noted with the interval-M3 method which properly takes into account the interval censoring induced by caliper measurement, giving overall unbiased estimations for all parameters and especially for the antitumor effect parameter (relative bias = 0.49%, and relative RMSE = 4.06%). PMID- 26757731 TI - Secondary Metabolome Variability and Inducible Chemical Defenses in the Mediterranean Sponge Aplysina cavernicola. AB - Secondary metabolites play a crucial role in marine invertebrate chemical ecology. Thus, it is of great importance to understand factors regulating their production and sources of variability. This work aimed to study the variability of the bromotyrosine derivatives in the Mediterranean sponge Aplysina cavernicola, and also to better understand how biotic (reproductive state) and abiotic factors (seawater temperature) could partly explain this variability. Results showed that the A. cavernicola reproductive cycle has little effect on the variability of the sponges' secondary metabolism, whereas water temperature has a significant influence on the production level of secondary metabolites. Temporal variability analysis of the sponge methanolic extracts showed that bioactivity variability was related to the presence of the minor secondary metabolite dienone, which accounted for 50 % of the bioactivity observed. Further bioassays coupled to HPLC extract fractionation confirmed that dienone was the only compound from Aplysina alkaloids to display a strong bioactivity. Both dienone production and bioactivity showed a notable increase in October 2008, after a late-summer warming episode, indicating that A. cavernicola might be able to induce chemical changes to cope with environmental stressors. PMID- 26757734 TI - Old technique revisited with surgical innovation: complicated Mallory-Weiss tear with bleeding gastric ulcer exclusion. AB - Mallory-Weiss tears (MWTs) rarely require surgical intervention. A 60-year-old female presented with massive hematemesis secondary to MWT and gastric ulceration. After failure of endoscopic management, an operative approach was embarked on, with a direct surgical hemostasis of the Mallory-Weiss tear and exclusion of the gastric ulcer. This exclusion strategy may be applicable for other patients with uncontrolled upper gastrointestinal bleeding in whom a simple repair would be difficult. PMID- 26757732 TI - CAPG and GIPC1: Breast Cancer Biomarkers for Bone Metastasis Development and Treatment. AB - BACKGROUND: Bone is the predominant site of metastasis from breast cancer, and recent trials have demonstrated that adjuvant bisphosphonate therapy can reduce bone metastasis development and improve survival. There is an unmet need for prognostic and predictive biomarkers so that therapy can be appropriately targeted. METHODS: Potential biomarkers for bone metastasis were identified using proteomic comparison of bone-metastatic, lung-metastatic, and nonmetastatic variants of human breast cancer MDA-MB-231 cells. Clinical validation was performed using immunohistochemical staining of tumor tissue microarrays from patients in a large randomized trial of adjuvant zoledronic acid (zoledronate) (AZURE-ISRCTN79831382). We used Cox proportional hazards regression, the Kaplan Meier estimate of the survival function, and the log-rank test to investigate associations between protein expression, clinical variables, and time to distant recurrence events. All statistical tests were two-sided. RESULTS: Two novel biomarker candidates, macrophage-capping protein (CAPG) and PDZ domain-containing protein GIPC1 (GIPC1), were identified for clinical validation. Cox regression analysis of AZURE training and validation sets showed that control patients (no zoledronate) were more likely to develop first distant recurrence in bone (hazard ratio [HR] = 4.5, 95% confidence interval [CI] = 2.1 to 9.8, P < .001) and die (HR for overall survival = 1.8, 95% CI = 1.01 to 3.24, P = .045) if both proteins were highly expressed in the primary tumor. In patients with high expression of both proteins, zoledronate had a substantial effect, leading to 10-fold hazard ratio reduction (compared with control) for first distant recurrence in bone (P = .008). CONCLUSIONS: The composite biomarker, CAPG and GIPC1 in primary breast tumors, predicted disease outcomes and benefit from zoledronate and may facilitate patient selection for adjuvant bisphosphonate treatment. PMID- 26757733 TI - Cotton S-adenosylmethionine decarboxylase-mediated spermine biosynthesis is required for salicylic acid- and leucine-correlated signaling in the defense response to Verticillium dahliae. AB - MAIN CONCLUSION: Cotton S-adenosylmethionine decarboxylase-, rather than spermine synthase-, mediated spermine biosynthesis is required for salicylic acid- and leucine-correlated signaling in the defense response to Verticillium dahliae. Spermine (Spm) signaling is correlated with plant resistance to the fungal pathogen Verticillium dahliae. We identified genes for key rate-limiting enzymes in the biosynthesis of Spm, namely S-adenosylmethionine decarboxylase (GhSAMDC) and Spm synthase (GhSPMS). These were found by screening suppression subtractive hybridization and cDNA libraries of cotton (Gossypium) species tolerant to Verticillium wilt. Both were induced early and strongly by inoculation with V. dahliae and application of plant hormones. Silencing of GhSPMS or GhSAMDC in cotton leaves led to a significant accumulation of upstream substrates and, ultimately, enhanced plant susceptibility to Verticillium infection. Exogenous supplementation of Spm to the silenced cotton plants improved resistance. When compared with the wild type (WT), constitutive expression of GhSAMDC in Arabidopsis thaliana was associated with greater Verticillium wilt resistance and higher accumulations of Spm, salicylic acid, and leucine during the infection period. By contrast, transgenic Arabidopsis plants that over-expressed GhSPMS were unexpectedly more susceptible than the WT to V. dahliae and they also had impaired levels of putrescine (Put) and salicylic acid (SA). The susceptibility exhibited in GhSPMS-overexpressing Arabidopsis plants was partially reversed by the exogenous supply of Put or SA. In addition, the responsiveness of those two transgenic Arabidopsis lines to V. dahliae was associated with an alteration in transcripts of genes involved in plant resistance to epidermal penetrations and amino acid signaling. Together, these results suggest that GhSAMDC-, rather than GhSPMS-, mediated spermine biosynthesis contributes to plant resistance against V. dahliae through SA- and leucine-correlated signaling. PMID- 26757737 TI - Genomic characterization of primary central nervous system lymphoma. AB - Primary central nervous system lymphoma (PCNSL) is a rare malignancy confined to the central nervous system (CNS), and majority of PCNSL is pathologically classified as diffuse large B-cell lymphoma (DLBCL). We have now performed whole exome sequencing for 41 tumor tissues of DLBCL-type PCNSL and paired normal specimens and also RNA-sequencing for 30 tumors, revealing a very high frequency of nonsynonymous somatic mutations in PIM1 (100 %), BTG2 (92.7 %), and MYD88 (85.4 %). Many genes in the NF-kappaB pathway are concurrently mutated within the same tumors. Further, focal deletion or somatic mutations in the HLA genes are associated with poor prognosis. Copy number amplification and overexpression of genes at chromosome 7q35 were both found to predict short progression-free survival as well. Oncogenic mutations in GRB2 were also detected, the effects of which in cultured cells were attenuated by inhibitors of the downstream kinases MAP2K1 and MAP2K2. Individuals with tumors positive for MYD88 mutations also harbored the same mutations at a low frequency in peripheral blood mononuclear cells, suggesting that MYD88 mutation-positive precancerous cells originate outside of the CNS and develop into lymphoma after additional genetic hits that confer adaptation to the CNS environment. PMID- 26757740 TI - Strong support for strike sends clear message to government, says BMA. PMID- 26757735 TI - Tenogenic induction of equine mesenchymal stem cells by means of growth factors and low-level laser technology. AB - Tendons regenerate poorly due to a dense extracellular matrix and low cellularity. Cellular therapies aim to improve tendon repair using mesenchymal stem cells and tenocytes; however, a current limitation is the low proliferative potential of tenocytes in cases of severe trauma. The purpose of this study was to develop a method useful in veterinary medicine to improve the differentiation of Peripheral Blood equine mesenchymal stem cells (PB-MSCs) into tenocytes. PB MSCs were used to study the effects of the addition of some growth factors (GFs) as TGFbeta3 (transforming growth factor), EGF2 (Epidermal growth factor), bFGF2 (Fibroblast growth factor) and IGF-1 (insulin-like growth factor) in presence or without Low Level Laser Technology (LLLT) on the mRNA expression levels of genes important in the tenogenic induction as Early Growth Response Protein-1 (EGR1), Tenascin (TNC) and Decorin (DCN). The singular addition of GFs did not show any influence on the mRNA expression of tenogenic genes whereas the specific combinations that arrested cell proliferation in favour of differentiation were the following: bFGF2 + TGFbeta3 and bFGF2 + TGFbeta3 + LLLT. Indeed, the supplement of bFGF2 and TGFbeta3 significantly upregulated the expression of Early Growth Response Protein-1 and Decorin, while the use of LLLT induced a significant increase of Tenascin C levels. In conclusion, the present study might furnish significant suggestions for developing an efficient approach for tenocyte induction since the external administration of bFGF2 and TGFbeta3, along with LLLT, influences the differentiation of PB-MSCs towards the tenogenic fate. PMID- 26757738 TI - Long-Term Serial Follow-Up of Pulmonary Artery Size and Wall Shear Stress in Fontan Patients. AB - Pulmonary arterial (PA) flow is abnormal after the Fontan operation and is marked by a lack of pulsatility. We assessed the effects of this abnormal flow on the size and function of the PA's in Fontan patients in long-term serial follow-up. Twenty-three Fontan patients with serial follow-up were included. Median age was 11.1 (9.5-16.0) years at baseline and 15.5 (12.5-22.7) years at follow-up. Median follow-up duration was 4.4 (4.0-5.8) years. Flow and size of the left pulmonary artery were determined using phase-contrast MRI. From this wall shear stress (WSS), distensibility and pulsatility were determined. A group of healthy peers was included for reference. Flow and pulsatility were significantly lower in patients than in controls (p < 0.001). Mean area was comparable in patients and controls, but distensibility was significantly higher in controls (p < 0.001). Mean and peak WSS were significantly lower in Fontan patients (p < 0.001). Between baseline and follow-up, there was a significant increase in normalized flow (15.1 (14.3-19.1) to 18.7 (14.0-22.6) ml/s/m(2), p = 0.023). Area, pulsatility, distensibility and WSS did not change, but there was a trend toward a lower mean WSS (p = 0.068). Multivariable regression analysis showed that flow, area and age were important predictors for WSS. WSS in Fontan patients is decreased compared to healthy controls and tends to decrease further with age. Pulsatility and distensibility are significantly lower compared to healthy controls. Pulmonary artery size, however, is not significantly different from healthy controls and long-term growth after Fontan operation is proportionate to body size. PMID- 26757739 TI - Aromatase inhibitor associated arthralgia: the importance of oncology provider patient communication about side effects and potential management through physical activity. AB - PURPOSE: Breast cancer survivors on aromatase inhibitors (AI) often experience side effects of joint pain, stiffness, or achiness (arthralgia). This study presents findings from a qualitative study of survivors on an AI regarding their knowledge of potential joint pain side effects and how both AI side effects and their management through moderate physical activity could be discussed during routine visits with their oncology provider. METHODS: Qualitative data from semi structured interviews were content analyzed for emergent themes. Descriptive statistics summarize sample characteristics. RESULTS: Our sample included 36 survivors, mean age of 67 (range 46-87); 86 % Caucasian and 70 % had education beyond high school. AI experience are as follows: 64 % anastrozole/Arimidex, 48 % letrozole/Femara, and 31 % exemestane/Aromasin. Participants expressed interest in having more information about potential joint pain side effects when the AI was prescribed so they could understand their joint symptoms when they appeared or intensified. They were relieved to learn that their joint symptoms were not unusual or "in their head." Participants would have been especially motivated to try walking as a way to manage their joint pain if physical activity had been recommended by their oncologist. CONCLUSIONS: Breast cancer survivors who are prescribed an AI as part of their adjuvant treatment want ongoing communication with their oncology provider about the potential for joint pain side effects and how these symptoms may be managed through regular physical activity. The prescription of an AI presents a "teachable moment" for oncologists to recommend and encourage their patients to engage in regular physical activity. PMID- 26757741 TI - Impact of Vitamin D Status on Cardiometabolic Complications among Children and Adolescents with Type 1 Diabetes Mellitus. AB - OBJECTIVE: There is an ongoing interest in the relationship between vitamin D status and diabetes control and complications. However, data from Saudi Arabia are limited. To determine the impact of vitamin D status on glycemic control and cardiometabolic complications of children and adolescents with type 1 diabetes mellitus (T1DM) attending a tertiary care diabetes clinic in Saudi Arabia. METHODS: Demographic, clinical, and laboratory data of 301 children and adolescent subjects with T1DM (53.5% females) of a mean age of 13.9 years attending King Abdulaziz Medical City-Jeddah during 2010-2013 were retrospectively collected. Relationships between vitamin D status and frequency of hypoglycemia, hemoglobin A1c (HbA1c) level, body mass index (BMI), blood pressure, and lipid profile were evaluated. RESULTS: The mean duration of diabetes was 7.7+/-3.7 years. Mean BMI value was 21.1+/-4.5 kg/m2 and HbA1c was 9.6+/-1.9% in both genders. Only 26.2% of the patients had a satisfactory HbA1c level. The mean level of 25-hydroxyvitamin D [25(OH)D] was 35.15 and that of cholesterol was 4.75. Vitamin D deficiency [25(OH)D<=37.5 nmol/L] was detected in 63.6% of the male and 67.7% of the female subjects. In males, it was inversely associated with frequency of hypoglycemia (p<0.01), BMI (p<0.05), diastolic blood pressure (p<0.05), and triglyceride levels (p<0.01), while in females, it was inversely associated with current age (p<0.05), age at diagnosis (p<0.01), and triglyceride levels (p<0.01). No significant correlation between HbA1c and vitamin D deficiency was observed. CONCLUSION: Vitamin D deficiency was highly prevalent in our study sample and was found to be associated with frequency of hypoglycemic episodes and with adverse cardiometabolic control. PMID- 26757742 TI - Delayed Adrenarche may be an Additional Feature of Immunoglobulin Super Family Member 1 Deficiency Syndrome. AB - Immunoglobulin super family member 1 (IGSF1) deficiency syndrome is characterized by central hypothyroidism, delayed surge in testosterone during puberty, macro orchidism, and in some cases, hypoprolactinemia and/or transient growth hormone (GH) deficiency. Our patient was a 19-year-old male adolescent who had been treated since the age of 9 years with GH and thyroxine for an idiopathic combined GH, thyroid-stimulating hormone (TSH), and prolactin (PRL) deficiency. His GH deficiency proved to be transient, but deficiencies of TSH and PRL persisted, and he had developed macro-orchidism since the end of puberty. Brain magnetic resonance imaging and PROP1 and POU1F1 sequencing were normal. A disharmonious puberty (delayed genital and pubic hair development, bone maturation, and pubertal growth spurt, despite normal testicular growth) was observed as well as a delayed adrenarche, as reflected by very low dehydroepiandrosterone sulfate and delayed pubarche. Direct sequencing of the IGSF1 gene revealed a novel hemizygous mutation, c.3127T>C, p.Cys1043Arg. Pathogenicity of the mutation was demonstrated in vitro. Male children with an idiopathic combined GH, PRL, and TSH deficiency, showing persistent central hypothyroidism but transient GH deficiency upon retesting at adult height, should be screened for mutations in the IGSF1 gene, especially when macro-orchidism and/or hypoprolactinemia are present. We suspect that delayed adrenarche, as a consequence of PRL deficiency, might be part of the clinical phenotype of patients with IGSF1 deficiency. PMID- 26757743 TI - Rational design and interaction studies of combilexins towards duplex DNA. AB - DNA, which is the genetic material, plays a predominant role in all living organisms. Alterations in the structure and function of this genetic material correlate with complex diseases such as cancer. A number of anticancer drugs exert their action by binding to DNA. Although DNA binding compounds exert genotoxicity, there is a high demand for novel DNA binding molecules because they can be further developed into anticancer drugs. In the present study, the mode of interaction of two compounds, 2,4-D and tacrine, has been determined to be minor groove binding and intercalation, respectively. Subsequently, from their binding modes, novel combilexin molecules were designed using computational tools and their mode of binding and affinities towards DNA were determined through a series of molecular modeling experiments such as molecular docking, molecular dynamics and binding free energy calculations. The entire study focuses on the potential effects of combilexins compared to intercalators and minor groove binders. The combilexins deduced from the current study may be considered as lead compounds for the development of better anticancer drugs. PMID- 26757745 TI - Ancillary ligand-free copper catalysed hydrohydrazination of terminal alkynes with NH2NH2. AB - An efficient and selective Cu-catalysed hydrohydrazination of terminal alkynes with parent hydrazine is reported. The methodology tolerates a broad range of functional groups, allows for the synthesis of symmetrical and unsymmetrical azines, and can be extended to hydrazine derivatives and amines. PMID- 26757744 TI - Aberrant Maspin mRNA Expression is Associated with Clinical Outcome in Patients with Pulmonary Adenocarcinoma. AB - BACKGROUND: The aim of this study was to investigate the expression level of maspin mRNA in pulmonary adenocarcinoma and to clarify its clinical significance in prediction of prognosis. MATERIAL/METHODS: RNA was extracted from formalin fixed paraffin-embedded (FFPE) tumor tissue blocks of 30 pairs of pulmonary adenocarcinoma (AC) tissues and adjacent noncancerous tissues (ANT) and in another 81 AC tissues. Expression of maspin mRNA was tested by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and the potential relationship between maspin mRNA expression and clinic pathological features of AC patients was analyzed. RESULTS: The expression of maspin mRNA was upregulated in AC samples compared with the ANT (p<0.001). Patients at advanced clinical stage (III) and patients with lymphatic metastasis showed higher maspin mRNA expression level than those in early-stage patients (I and II) (p=0.038) or with non-lymphatic metastasis (p=0.034). The Kaplan-Meier survival curves indicated that disease-free survival (DFS) was significantly worse in high maspin mRNA expression AC patients (p=0.007). Furthermore, multivariate analysis revealed that the expression of maspin mRNA was an independent prognostic marker for AC (p=0.040). CONCLUSIONS: Our study reveals that maspin mRNA was significantly up regulated in tissues of AC patients. Maspin mRNA may be useful as a new marker of prognosis in AC. PMID- 26757746 TI - Actively targeted gold nanoparticles as novel radiosensitizer agents: an in vivo head and neck cancer model. AB - A major problem in the treatment of head and neck cancer today is the resistance of tumors to traditional radiation therapy, which results in 40% local failure, despite aggressive treatment. The main objective of this study was to develop a technique which will overcome tumor radioresistance by increasing the radiation absorbed in the tumor using cetuximab targeted gold nanoparticles (GNPs), in clinically relevant energies and radiation dosage. In addition, we have investigated the biological mechanisms underlying tumor shrinkage and the in vivo toxicity of GNP. The results showed that targeted GNP enhanced the radiation effect and had a significant impact on tumor growth (P < 0.001). The mechanism of radiation enhancement was found to be related to earlier and greater apoptosis (TUNEL assay), angiogenesis inhibition (by CD34 level) and diminished repair mechanism (PCNA staining). Additionally, GNPs have been proven to be safe as no evidence of toxicity has been observed. PMID- 26757747 TI - Anticitrullinated protein antibodies and rheumatoid factor are associated with increased mortality but with different causes of death in patients with rheumatoid arthritis: a longitudinal study in three European cohorts. AB - OBJECTIVE: Patients with rheumatoid arthritis (RA)-related autoantibodies have an increased mortality rate. Different autoantibodies are frequently co-occurring and it is unclear which autoantibodies associate with increased mortality. In addition, association with different causes of death is thus far unexplored. Both questions were addressed in three early RA populations. METHODS: 2331 patients with early RA included in Better Anti-Rheumatic Farmaco-Therapy cohort (BARFOT) (n=805), Norfolk Arthritis Register (NOAR) (n=678) and Leiden Early Arthritis Clinic cohort (EAC) (n=848) were studied. The presence of anticitrullinated protein antibodies (ACPA), rheumatoid factor (RF) and anticarbamylated protein (anti-CarP) antibodies was studied in relation to all-cause and cause-specific mortality, obtained from national death registers. Cox proportional hazards regression models (adjusted for age, sex, smoking and inclusion year) were constructed per cohort; data were combined in inverse-weighted meta-analyses. RESULTS: During 26 300 person-years of observation, 29% of BARFOT patients, 30% of NOAR and 18% of EAC patients died, corresponding to mortality rates of 24.9, 21.0 and 20.8 per 1000 person-years. The HR for all-cause mortality (95% CI) was 1.48 (1.22 to 1.79) for ACPA, 1.47 (1.22 to 1.78) for RF and 1.33 (1.11 to 1.60) for anti-CarP. When including all three antibodies in one model, RF was associated with all-cause mortality independent of other autoantibodies, HR 1.30 (1.04 to 1.63). When subsequently stratifying for death cause, ACPA positivity associated with increased cardiovascular death, HR 1.52 (1.04 to 2.21), and RF with increased neoplasm-related death, HR 1.64 (1.02 to 2.62), and respiratory disease-related death, HR 1.71 (1.01 to 2.88). CONCLUSIONS: The presence of RF in patients with RA associates with an increased overall mortality rate. Cause specific mortality rates differed between autoantibodies: ACPA associates with increased cardiovascular death and RF with death related to neoplasm and respiratory disease. PMID- 26757748 TI - Towards personalised treatment in primary Sjogren's syndrome: baseline parotid histopathology predicts responsiveness to rituximab treatment. AB - OBJECTIVES: The aims of this study were (1) to assess the effect of rituximab (RTX; anti-CD20) treatment in patients with primary Sjogren's syndrome (pSS) based on sequential parotid biopsies obtained in a placebo-controlled, randomised clinical trial, and (2) to assess the prognostic value of the histological characteristics of parotid gland tissue with regard to responsiveness to RTX treatment. METHODS: In a double-blinded, placebo-controlled trial, sequential parotid gland biopsies were taken from 20 RTX-treated and 10 placebo-treated patients with pSS, at baseline and 12 weeks after treatment. The relative amount of lymphocytic infiltrate (stained for CD45), absolute number of T cells and B cells per mm2 parenchyma (stained for CD3 and CD20, respectively), focus score, number of germinal centres and of lymphoepithelial lesions per mm2 in parotid gland parenchyma were assessed. Histopathological data were compared between clinical responders (decrease in European League Against Rheumatism Sjogren's Syndrome Disease Activity Index (ESSDAI) score of >=3 at 12 weeks compared with baseline) and non-responders (change in ESSDAI<3) to RTX treatment. RESULTS: In RTX-treated patients, a significant reduction in the number of CD20+ B cells/mm2 parenchyma was observed, while no such reduction was observed in placebo-treated patients. The number of CD3+ T cells/mm2 in parenchyma did not change in either group. Furthermore, the number and the severity of lymphoepithelial lesions/mm2 and number of germinal centres/mm2 was significantly reduced in RTX-treated patients, but did not change in placebo-treated patients. When comparing the pretreatment characteristics of clinical responders with non-responders, the median number of CD20+ B cells/mm2 parenchyma at baseline was significantly higher in responders (1871 vs 353 cells/mm2, p<0.05). Other histopathological baseline characteristics were not predictive for response to RTX treatment. CONCLUSIONS: RTX treatment in pSS leads to a major reduction of lymphocytic infiltration and to fewer B cells, germinal centres and lymphoepithelial lesions in parotid gland parenchyma. A high pretreatment number of CD20+ B cells/mm2 parotid gland parenchyma predicts better responsiveness of patients with pSS to RTX treatment. Pretreatment parotid gland histopathological characteristics could therefore contribute to a more personalised treatment approach to pSS. PMID- 26757749 TI - Transitions to different patterns of interstitial lung disease in scleroderma with and without treatment. AB - OBJECTIVES: The aim is to investigate whether the 12-month quantitative changes in high-resolution CT (HRCT) measures of interstitial lung disease (ILD) are different, and to understand how they change, in patients with scleroderma related ILD who receive drug therapy versus placebo. METHODS: HRCT images were acquired at baseline and at 12 months in 83 participants in Scleroderma Lung Study I, a clinical trial comparing treatment with oral cyclophosphamide versus placebo. A computer-aided model was used to quantify the extent of fibrotic reticulation, ground glass and honeycomb patterns and quantitative ILD (QILD: sum of these patterns) in the whole lung and the lung zone (upper, middle or lower) of maximal disease involvement. RESULTS: Mean QILD score decreased by 3.9% in the cyclophosphamide group while increasing by 4.2% in the placebo group in the most severe zone (p=0.01) and decreased by 3.2% in the cyclophosphamide group while increasing by 2.2% in the placebo group in the whole lung (p=0.03). Transitional probabilities demonstrated greater changes from a fibrotic to either a ground glass or normal pattern in the cyclophosphamide group and the reverse in the placebo group. CONCLUSIONS: Changes in quantitative HRCT measures of ILD provide a sensitive indication of disease progression and response to treatment. TRIAL REGISTRATION NUMBER: NCT00004563; Post-results. PMID- 26757750 TI - Does b1000-b0 Mismatch Challenge Diffusion-Weighted Imaging-Fluid Attenuated Inversion Recovery Mismatch in Stroke? AB - BACKGROUND AND PURPOSE: Our aim was to explore whether the mismatch in lesion visibility between b1000 and b0 images is an alternative to mismatch between diffusion-weighted imaging and fluid-attenuated inversion recovery imaging as a surrogate marker of stroke age. METHODS: We analyzed patients from the European multicenter I-KNOW database. Independent readers assessed the visibility of ischemic lesions of the anterior circulation on b0 and fluid-attenuated inversion recovery imaging images. The signal-intensity ratio for b0 and fluid-attenuated inversion recovery imaging images was also measured from the segmented stroke lesion volume on b1000 images. RESULTS: This study included 112 patients (68 men; mean age, 67.4 years) with stroke onset within (n=85) or longer than (n=27) 4.5 hours. b1000-b0 mismatch identified patients within 4.5 hours of stroke onset with moderate sensitivity (72.9%; 95% confidence interval [CI], 63.5-82.4) and specificity (70.4%; 95% CI, 53.2-87.6), high positive predictive value (88.6%; 95% CI, 81.1-96.0), and low negative predictive value (45.2%; 95% CI, 30.2-60.3). Global comparison of b1000-b0 mismatch with diffusion-weighted imaging-fluid attenuated inversion recovery imaging mismatch (considered the imaging gold standard) indicated high sensitivity (85.9%; 95% CI, 78.2-93.6), specificity (91.2%; 95% CI, 76.3-98.1), and positive predictive value (96.7%; 95% CI, 88.0 99.1) and moderate negative predictive value (73.8%; 95% CI, 60.5-87.1) of this new approach. b0 signal-intensity ratio (r=0.251; 95% CI, 0.069-0.417; P=0.008) was significantly although weakly correlated with delay between stroke onset and magnetic resonance imaging. CONCLUSIONS: b1000-b0 mismatch may identify patients with ischemic stroke of the within 4.5 hours of onset with high positive predictive value, perhaps constituting an alternative imaging tissue clock. PMID- 26757751 TI - Cortical Sparing in Preterm Ischemic Arterial Stroke. AB - BACKGROUND AND PURPOSE: Residual injury after perinatal arterial ischemic stroke in the middle cerebral artery territory usually involves the loss of cortical gray matter and subcortical white matter. In this article, we describe a different pattern of residual injury after middle cerebral artery stroke in preterm-born infants, in which the cortex is spared. METHODS: Magnetic resonance imaging scans of 40 infants (12 preterm and 28 full-term infants) with a large middle cerebral artery stroke were reviewed and correlated with outcome. RESULTS: Complete sparing of the cortex with cavitation of the underlying white matter was observed in 3 preterm infants, and partial sparing was noted in another 4 late preterm-born infants. One full-term infant had partial cortical sparing, and all others showed no sparing. Overall, 86% developed a hemiplegia and 30% had a developmental quotient below 85, but this did not vary between the different types of cortical injury. CONCLUSIONS: The pattern of cortical injury after middle cerebral artery stroke changes with gestational age and may be related to maturational changes of the vascular system. Outcome did not vary between the different patterns of cortical injury. PMID- 26757753 TI - The Hammer: Something to Ignore. PMID- 26757752 TI - History of the Letzte Wiese/Last Meadow Concept of Brain Ischemia. PMID- 26757755 TI - Early Intervention in First Episode Psychosis: A Service User's Experience. PMID- 26757756 TI - [The concept and clinical technique of minimally invasive dentistry]. PMID- 26757757 TI - [Clinical application and development of ultrathin porcelain veneer technology]. PMID- 26757754 TI - Self-Disorders and Clinical High Risk for Psychosis: An Empirical Study in Help Seeking Youth Attending Community Mental Health Facilities. AB - Anomalous subjective experiences involving an alteration of the basic sense of self (ie, Self-disorder [SD]) are emerging as a core marker of schizophrenia spectrum disorders with potential impact on current early detection strategies as well. In this study, we wished to field-test the prevalence of SD in a clinical sample of adolescent/young adult help-seekers at putative risk for psychosis attending standard community mental health facilities in Italy. Participants (n = 47), aged between 14 and 25, underwent extensive psychopathological evaluations with current semi-structured tools to assess Clinical High Risk (CHR) state (ie, Structured Interview for Prodromal Syndromes/Scale of Prodromal Symptoms [SIPS/SOPS], Schizophrenia Proneness Instrument-Adult/Child and Youth [SPI A/CY]). SD aggregated in CHR subjects as compared to the non-CHR and revealed substantial association with sub-psychotic symptoms (SIPS), subjective experience of cognitive and cognitive-perceptual vulnerability (basic symptoms) and functional level (Global Assessment of functioning). Moreover, a combination of the 2 approaches (ie, CHR plus SD) enabled further "closing-in" on a subgroup of CHR with lower global functioning. The results confirm SD's relevance for the early profiling of youths at potential high risk for psychosis. PMID- 26757758 TI - [A retrospective study of 1 009 patients with oral and maxillofacial fresh trauma]. AB - OBJECTIVE: To analyze the epidemiological characters of fresh maxillofacial fractures in hospitalized patients by the retrospective study. METHODS: From Jan. 2008 to Dec. 2013, a total of 1 009 patients with fresh maxillofacial fractures treated at Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology were investigated. The data were statistically analyzed by SPSS 21.0. RESULTS: The male and female ratio was 2.94:1 and 33.5% of the patients aged from 20 to 30 years. The most common cause of the fresh fracture was road traffic accidents (424 cases, 42.0%), followed by tumblings (250 cases, 24.8%) and violence (128 cases, 12.7%). The number of new fracture was increasing gradually in recent years. The patients were at peak of 20-29 years old. The mandibular fracture was the most frequently seen (536 cases, 53.1%), followed by zygomatic complex fractures (233 cases, 23.1%). The simple maxillary fracture was rare and usually combined with other fractures. Infraorbital nerve injury was the most common one in nerve injuries (144 cases). The most common associated injury was extremity injuries (77 cases), followed by thoracic injury (65 cases) and craniocerebral injury (57 cases). Associated injuries were mostly caused by car accidents (127 sites), followed by fall (32 sites). Logictic regression analysis showed that fall and tumbling were risk factors of mandibular and condylar fracture (OR > 1, P < 0.05), while age was a protective factor (OR > 1, P < 0.05). CONCLUSIONS: Oral and maxillofacial fresh fractures most commonly occurred in young people, and the most common cause of fractures was road traffic accidents. Infraorbital nerve was involved frequently. The most common associated injuries was extremity injuries. PMID- 26757759 TI - [Dentoalveolar compensation in skeletal Class III patients treated with orthognathic surgery]. AB - OBJECTIVE: To investigate the compensation of the upper and lower incisors in skeletal Class III patients treated with orthodontic-surgical approach. METHODS: The samples consisted of 54 skeletal Class III patients treated with orthodontic surgical approach from November 2011 to January 2015. Lateral cephalograms were taken before treatment. The differences between the samples and the norms from Peking University normal occlusion sample library were assessed using independent sample t test. Correlation analyses were performed to find associations between skeletal and dental parameters. According to skeletal anteroposterior discrepancy/vertical type (ANB/SN-MP), the samples were allocated into group A (ANB < -4 degrees , SN-MP <= 37.7 degrees , n = 11), group B (ANB >= -4 degrees , SN-MP <= 37.7 degrees , n = 16), group C (ANB < -4 degrees , SN-MP > 37.7 degrees , n = 14), and group D (ANB >= -4 degrees , SN-MP > 37.7 degrees , n = 13). After measurement of variables, one-way ANOVA with SNK multiple comparison test were performed. RESULTS: The maxillary incisors were more proclined and the mandibular incisors more retroclined in skeletal Class III patients compared with norm values (P < 0.01). Both skeletal anteroposterior discrepancy and vertical type were correlated with the position of upper and lower incisors (P < 0.01). According to skeletal anteroposterior discrepancy/vertical type, no significant differences were found in the upper incisors' inclination among the four groups, while patients in group A and group D exhibited significant difference in lower incisor compensation. CONCLUSIONS: Different skeletal anteroposterior discrepancy/vertical type resulted in varied incisors' compensation. Therefore, decompensation should be treated differently. PMID- 26757760 TI - [Expressions of interleukin-21 and interleukin-22 in Kimura's disease]. AB - OBJECTIVE: To investigate the expressions of interleukin (IL)-21 (IL-21) and IL 22 in patients with Kimura's disease (KD). METHODS: Expressions of IL-21 and IL 22 were examined immunohistochemically in 36 patients with KD and 7 normal controls. The integral absorbance (IA) of the two groups was compared. Meanwhile, clinical data were reviewed. RESULTS: The IA of IL-21 [M(Q): 1 373 418 (1 800 926)] and IL-22 [M(Q): 462 086(484 672)] in KD was significantly higher than those in normal controls [M(Q): 70 445(44 658), 51 599(71 241), P < 0.05]. The overexpression of IL-21 was significantly associated with pruritus (Z = -1.993, P < 0.05). Moreover, IL-21 was identified for disease recurrence (Z = -2.303, P < 0.05). There was a significant association between the expression of IL-22 and the number of affected sites (Z = -1.979, P < 0.05). In addition, IL-22 was significantly higher in the high-eosinophils group than in the low-eosinophils group (Z = -2.025, P < 0.05). There was no association between IL-21, IL-22 and age, gender, laterality, maximum size. CONCLUSIONS: IL-21 and IL-22 may be involved in the pathogenesis of KD. PMID- 26757761 TI - [Effect of zoledronic acid on cell proliferation and apoptosis of human periodontal fibroblasts]. AB - OBJECTIVE: To observe the effect of different concentrations of zoledronic acid on human gingival fibroblast (HGF) cells proliferation and apoptosis, and to investigate the mechanism of bisphosphonate-related osteonecrosis of the jaw (BRONJ) caused by zoledronic acid. METHODS: Different concentrations (0, 0.5, l.0, 5.0, 10.0 umol/L) of zoledronic acid acted on the HGF. After 24 hours, flow cytometry was used to detect the rate of apoptosis and methyl thiazolyl terazolium (MTT) assay used to observe the proliferation of HGF. The effect of different concentrations of zoledronic acid on cell proliferation was examined by proliferation test on day 2, 4 and 7. RESULTS: Flow cytometry showed that when the concentration of zoledronic acid was 0, 0.5, 1.0, 5.0, 10.0 umol/L, the apoptosis rate was (0.67 +/- 0.50)%, (2.13 +/- 0.21)%, (3.27 +/- 0.23)%, (4.17 +/ 0.35)%, (9.87 +/- 1.79)% respectively. The difference in HGF cells between control group and zoledronic acid groups was significant (P < 0.05) at three concentrations of zoledronic acid (1.0, 5.0, 10.0 umol/L). The cell proliferation test showed an concentration-time dependent effect. With increase of concentration and time, the cell proliferation was significantly inhibited. There was significant difference in absorbance value among the different concentration groups (P < 0.05). CONCLUSIONS: Zoledronic acid can inhibit HGF proliferation and promote its apoptosis. PMID- 26757762 TI - [Preliminary study on treatment of mandibular osteoradionecrosis by autologous bone marrow mesenchymal stem cells in miniature pigs]. AB - OBJECTIVE: To investigate the treatment effect of mandibular osteoradionecrosis (ORN) by autologous bone marrow mesenchymal stem cells (BMMSC) in miniature pigs. METHODS: Six miniature pigs with mandibular ORN (25 Gy) were used. BMMSC were separated and cultured in vitro and then implanted on to the premolded hydroxyapatite-tricalcium phosphate (HA-TCP). The BMMSC-HA-TCP complexes were implanted into the defective area of mandibular ORN in 4 animals. Implantation of only HA-TCP in 2 animals served as control. Gross observation, spiral CT, coronary CT and histopathologic examination were carried out. RESULTS: Fistula disappeared in animals with BMMSC-HA-TCP complexes 3 months after implantation, while fistula was found in controls. Spiral CT analysis showed that cortical bone repair were found 4 months after BMMSC-HA-TCP complexes implantation, while bone damage (cortical and cancellous bone fracture) increased in controls. Histopathologic examination revealed that 4 months later after BMMSC-HA-TCP complexes implantation, new bone formation and bone cells could be observed, but there was a large number of fibrous tissue and no new bone in controls. CONCLUSIONS: Transplantation of autologous BMMSC with HA-TCP may have therapeutic effect in the treatment of mandibular ORN. PMID- 26757763 TI - [Effect of different proportions of bone marrow mesenchymal stem cells and endothelial cells on osteogenesis]. AB - OBJECTIVE: To evaluate the effect of co-culture system of bone marrow mesenchymal stem cells (BMSC) and vascular endothelial cells (EC) on osteogenesis. METHODS: BMSC were isolated by whole bone marrow centrifugal adherent method. Then BMSC were induced into EC with induced medium. Co-culture system in different proportions of BMSC and EC (10:0, 10:1, 8:2, 7:3, 5:5, 3:7, 2:8, 1:10, 0:10) were further evaluated. The cell growth level of BMSC was examined. The CD44 expression of BMSC and von willebrand factor (vWF) expression of vascular EC were examined by immunofluorescence. Furthermore, calcium nodules exhibited by alizarin red staining, alkaline phosphatase activity, and the expression of osteogenic genes by reverse transcription-quantitative PCR (RT-qPCR) were observed to validate the osteogenesis of co-culture system. RESULTS: The growth curve of P3 passage of BMSC demonstrated the doubling time of BMSC was 39.9 h. The positive specific markers of BMSC and EC showed efficient induction. Although the calcium nodules ratio of the co-culture [group 7:3 (19.0 +/- 3.0) and group 5:5 (20.8 +/- 2.9)] was not significantly different (P > 0.05), but higher than that of other co-culture groups with a significant difference (P < 0.01). Alkaline phosphatase activity was increased with prolonged induction of osteogenic medium. While alkaline phosphatase activity of group 10:0 (16.84 +/- 0.82), group 10:1 (15.86 +/- 3.10), group 8:2 (16.37 +/- 1.33), group 7:3 (17.99 +/- 1.98), and group 5:5 (17.49 +/- 0.87) did not show significant difference after osteogenic induction for 7 days (P > 0.05), but significantly higher than that of other co-culture groups (P < 0.05). The co-culture ratio of 7:3 (33.74 +/ 0.99) was slightly higher than that of 5:5 (31.09 +/- 0.87), but significantly higher than that of other groups (P < 0.01). Moreover, the osteocalcin (OCN) and runt-related transcription factor 2 (RUNX2) expression of group 7:3 was significantly higher than that of other groups. CONCLUSIONS: The EC that derived from BMSC can promote the BMSC differentiate into osteoblasts. The co-culture system of BMSC and EC with the ratio of 7:3 increases the alkaline phosphatase activity and facilitates the expression of osteogenic genes. PMID- 26757764 TI - [Effect of SiO2-ZrO2slurry coating on surface performance of zirconia ceramic]. AB - OBJECTIVE: To evaluate the effect of SiO2-ZrO2slurry coating on surface performance of zirconia ceramic. METHODS: Seventy pre-sintered zirconia discs were randomly divided into seven groups with 10 discs per group. Sample discs in each group received one of the following seven different surface treatments, namely, sintered (group AS), sand blasting after sintered (group SB), coated with slurry of mole ratio of SiO2to ZrO22:1 (group 2SiO2-1ZrO2), coated with slurry of mole ratio of SiO2to ZrO21:1 (group 1SiO2-1ZrO2), coated with slurry of mole ratio of SiO2to ZrO21:2 (group 1SiO2-2ZrO2), coated with slurry of mole ratio of SiO2to ZrO21:3 (group 1SiO2-3ZrO2), coated with slurry of mole ratio of SiO2to ZrO21:4 (group 1SiO2-4ZrO2). Profilometer, X-ray diffractometer (XRD), energy dispersive spectrometer, scanning electron microscopy (SEM) were used to analyze surface performance. RESULTS: The surface roughness of the discs in group AS was lower than those in the other groups [(0.33 +/- 0.03) um] (P < 0.05), there was no statistically significant difference (P > 0.05) among group 2SiO2-1ZrO2[(3.85 +/- 0.38) um], group 1SiO2-1ZrO2[(3.78 +/- 0.56) um] and group 1SiO2-2ZrO2[(4.06 +/- 0.48) um], and no difference (P > 0.05) was observed between group 1SiO2 3ZrO2[(1.02 +/- 0.09) um] and group 1SiO2-4ZrO2[(1.53 +/- 0.23) um] either. However, surface roughness in all coating groups was higher than those in group SB [(0.86 +/- 0.05) um] (P < 0.05). According to the XRD pattern, group AS and all coating groups consisted of 100% tetragonal airconia and monoclinic zirconia was detected at surface of group SB. Contents of surface silicon of coating groups increased significantly, however, no silicon was detected at sample surface of group AS and group SB. SEM showed that zirconia grains of coating exposed since part of silicon was etched by hydrofluoric acid, a three dimensional network of intergrain nano-spaces was created. CONCLUSIONS: SiO2 ZrO2slurry coating could make surface of zirconia rough and increase Si content without creating monoclinic zirconia. PMID- 26757766 TI - [Micro-precision in prosthetic treatment: from macro to micro]. PMID- 26757765 TI - [Aesthetic outcome of implant-supported restoration of unilateral missing maxillary central incisor using guided bone regeneration and connective tissue graft procedures]. PMID- 26757767 TI - [Bioinformatic resources of oral hereditary diseases]. PMID- 26757768 TI - [Prognostic significance of positive lymph node ratio in oral squamous cell carcinoma]. PMID- 26757769 TI - [The influence of insertion torque on osseointegration]. PMID- 26757770 TI - [Full-bony impaction of deciduous maxillary and mandibular molars combined with posterior open bite]. PMID- 26757774 TI - Current challenges in endovascular therapy for thoracic aneurysms. AB - Surgical treatment of thoracic aortic aneurysms can be associated with high mortality and complication rates, resulting in prolonged hospital stay. Endovascular techniques for treating thoracic aortic disease have been rapidly embraced, showing limited mortality and major adverse events. Its wide availability and relative ease of application has changed and extended management options for thoracic aortic disease, including inpatients deemed unsuitable for open surgery. Rapid technical evolution has allowed it to be applied to even hostile anatomy and complex cases. However, as it is still a young technology, many unknowns remain, including long-term outcomes with respect to conservative treatment and open surgical repair. PMID- 26757771 TI - Local Anesthetics and Antipsychotic Phenothiazines Interact Nonspecifically with Membranes and Inhibit Hexose Transporters in Yeast. AB - Action mechanisms of anesthetics remain unclear because of difficulty in explaining how structurally different anesthetics cause similar effects. In Saccharomyces cerevisiae, local anesthetics and antipsychotic phenothiazines induced responses similar to those caused by glucose starvation, and they eventually inhibited cell growth. These drugs inhibited glucose uptake, but additional glucose conferred resistance to their effects; hence, the primary action of the drugs is to cause glucose starvation. In hxt(0) strains with all hexose transporter (HXT) genes deleted, a strain harboring a single copy of HXT1 (HXT1s) was more sensitive to tetracaine than a strain harboring multiple copies (HXT1m), which indicates that quantitative reduction of HXT1 increases tetracaine sensitivity. However, additional glucose rather than the overexpression of HXT1/2 conferred tetracaine resistance to wild-type yeast; therefore, Hxts that actively transport hexoses apparently confer tetracaine resistance. Additional glucose alleviated sensitivity to local anesthetics and phenothiazines in the HXT1m strain but not the HXT1s strain; thus, the glucose-induced effects required a certain amount of Hxt1. At low concentrations, fluorescent phenothiazines were distributed in various membranes. At higher concentrations, they destroyed the membranes and thereby delocalized Hxt1-GFP from the plasma membrane, similar to local anesthetics. These results suggest that the aforementioned drugs affect various membrane targets via nonspecific interactions with membranes. However, the drugs preferentially inhibit the function of abundant Hxts, resulting in glucose starvation. When Hxts are scarce, this preference is lost, thereby mitigating the alleviation by additional glucose. These results provide a mechanism that explains how different compounds induce similar effects based on lipid theory. PMID- 26757773 TI - Polyelectrolyte complexes: mechanisms, critical experimental aspects, and applications. AB - The polyelectrolyte complexes (PECs) are versatile formulations formed by electrostatic interactions between oppositely charged biopolymers. PECs have been investigated widely by the researchers to explore the virtues of this formulation viz. high biocompatibility, excellent biodegradability, low toxicity, cost effective, environment-friendly, and energy-efficient production. The prime object of the present review is to present the prominent features of PECs including mechanism of PEC formation, structural models of PECs, interactions involved in PEC formation, steps involved in PEC fabrication, factors affecting the formation of PECs and applications of PECs. The patents pertaining to PECs have briefly been tabulated as well. PMID- 26757775 TI - Geranylgeraniol enhances testosterone production via the cAMP/protein kinase A pathway in testis-derived I-10 tumor cells. AB - Testosterone levels in men decrease with age; this decline has been linked to various diseases and can shorten life expectancy. Geranylgeraniol (GGOH) is an isoprenoid found in plants that plays an important role in several biological processes; however, its role in steroidogenesis is unknown. Here, we report that GGOH enhances the production of testosterone and its precursor progesterone in testis-derived I-10 tumor cells. GGOH induced protein kinase A (PKA) activity and increased cAMP levels and was found to regulate cAMP/PKA signaling by activating adenylate cyclase without altering phosphodiesterase activity. GGOH also stimulated mRNA and protein levels of steroidogenic acute regulatory protein, a downstream effector in the cAMP/PKA pathway. These results demonstrate that GGOH enhances steroidogenesis in testis-derived cells by modulating cAMP/PKA signaling. Our findings have potential applications for the development of therapeutics that increase testosterone levels in aging men. PMID- 26757772 TI - Germline Stem Cell Differentiation Entails Regional Control of Cell Fate Regulator GLD-1 in Caenorhabditis elegans. AB - Germline stem cell differentiation in Caenorhabditis elegans is controlled by glp 1 Notch signaling. Cell fate regulator GLD-1 is sufficient to induce meiotic entry and expressed at a high level during meiotic prophase, inhibiting mitotic gene activity. glp-1 signaling and other regulators control GLD-1 levels post transcriptionally (low in stem cells, high in meiotic prophase), but many aspects of GLD-1 regulation are uncharacterized, including the link between glp-1 mediated transcriptional control and post-transcriptional GLD-1 regulation. We established a sensitive assay to quantify GLD-1 levels across an ~35-cell diameter field, where distal germline stem cells differentiate proximally into meiotic prophase cells in the adult C. elegans hermaphrodite, and applied the approach to mutants in known or proposed GLD-1 regulators. In wild-type GLD-1 levels elevated ~20-fold in a sigmoidal pattern. We found that two direct transcriptional targets of glp-1 signaling, lst-1 and sygl-1, were individually required for repression of GLD-1. We determined that lst-1 and sygl-1 act in the same genetic pathway as known GLD-1 translational repressor fbf-1, while lst-1 also acts in parallel to fbf-1, linking glp-1-mediated transcriptional control and post-transcriptional GLD-1 repression. Additionally, we estimated the position in wild-type gonads where germ cells irreversibly commit to meiotic development based on GLD-1 levels in worms where glp-1 activity was manipulated to cause an irreversible fate switch. Analysis of known repressors and activators, as well as modeling the sigmoidal accumulation pattern, indicated that regulation of GLD-1 levels is largely regional, which we integrated with the current view of germline stem cell differentiation. PMID- 26757776 TI - Quantification of selected antidepressants and antipsychotics in clinical samples using chromatographic methods combined with mass spectrometry: A review (2006 2015). AB - BACKGROUND: Psychiatric disorders contribute significantly to worldwide morbidity and mortality. In the case of depression and schizophrenia, effective drug therapy is available but 30-50% of patients do not respond sufficiently to the initial treatment regimen. Apart from the development of new molecules, it is desirable to optimize treatment outcomes with agents that are currently available. Therapeutic drug monitoring (TDM) is a suitable and widely accepted approach for improving the efficacy and safety of these drugs. METHODS: A review of the relevant literature published between 2006 and January 2015. RESULTS AND CONCLUSIONS: This review describes major advances and drawbacks in the field of chromatography coupled with single or tandem mass spectrometry (LC-MS, LC-MS/MS and GC/MS) of selected antidepressants (agomelatine, vilazodone) and antipsychotics (iloperidone, asenapine, amisulpride, aripiprazole, melperone, zotepine, ziprasidone). The high specificity in combination with high sensitivity makes these techniques an attractive complementary method to traditional procedures used in routine practice for TDM. PMID- 26757777 TI - Prevalence and correlates of cognitive asymmetry in a large sample of Alzheimer's disease patients. AB - Previous research has suggested that a significant minority of patients with Alzheimer's disease (AD) exhibit asymmetric cognitive profiles (greater verbal than visuospatial impairment or vice versa) and that these patient subgroups may differ in demographic and other characteristics. Prior studies have been relatively small, and this investigation sought to examine correlates of asymmetry in a large patient sample (N = 438). Patients were classified into the following cognitive profile groups: low verbal, symmetric, and low visuospatial. Consistent with past research, 28.3% of participants were classified as having asymmetric cognitive profiles, with more participants in the low visuospatial subgroup. Low visuospatial participants were younger than members of the other subgroups, and low verbal participants performed worse on a measure estimating premorbid verbal intelligence. Findings regarding apolipoprotein E (ApoE) epsilon4 genotype were equivocal, although results provided some evidence for an effect of the E4 allele on cognitive asymmetry. These results suggest systematic differences between neuropsychological asymmetry profiles that support the possibility of distinct subgroups of the disease. PMID- 26757778 TI - Cytisine-type alkaloids and flavonoids from the rhizomes of Sophora tonkinensis. AB - A new cytisine-type alkaloid, (-)-N-hexanoylcytisine (1), and a new isoflavan, (3S, 4R)-4-hydroxy-7,4'-dimethoxyisoflavan 3'-O-beta-d-glucopyranoside (2), along with 10 known compounds, were isolated from the rhizomes of Sophora tonkinensis. Their structures were determined by spectroscopic methods, chemical evidence, and ECD data analysis. All of the isolates were evaluated for their cytotoxic activities against four human tumor cell lines. PMID- 26757779 TI - Self-determination among community-dwelling older persons: explanatory factors. AB - BACKGROUND: Although it is acknowledged that exercising self-determination in daily activities affects older people's health and well-being, few studies have focused on the explanatory factors for self-determination in daily life. OBJECTIVE: To investigate explanatory factors for self-determination in the context of community-dwelling older persons. METHOD: This cross-sectional study combined two sets of data that included community-dwelling persons 80 years and older (n = 456). A bivariate logistic regression was performed to analyse the association of self-determination and a set of explanatory factors. RESULTS: The final bivariate logistic regression model revealed five explanatory factors that were significantly associated with perceiving reduced self-determination: high education (OR = 2.83), frailty (OR = 2.70), poor self-rated health (OR = 2.54), dissatisfaction with physical health (OR = 6.50), and receiving help from public homecare service (OR = 2.46). CONCLUSION: Several explanatory factors related to the ageing body and environmental aspects were associated with reduced self determination. To help older people maintain self-determination, healthcare professionals should consider using a person-centred and capability approach to care. PMID- 26757781 TI - Argemone oil induces genotoxicity in mice. AB - CONTEXT: Argemone mexicana L. is native to Mexico and the plant extracts are used in traditional medicine in India and South American countries. Argemone oil (AO) is a common adulterant of mustard oil in India and causes serious pathophysiological consequences leading to outbreaks of epidemic dropsy among consumers. In vivo cytogenetic studies on the toxicological effects of AO and its component alkaloids are limited. OBJECTIVE: The present study was undertaken to evaluate the safety of AO by assessment of their in vivo genotoxic potential in bone marrow cells of mice. MATERIALS AND METHODS: AO mixed in corn oil in the proportions of 0.01, 0.1, and 1 ml AO/kg body weight in a total volume of 10 ml/kg body weight and a single undiluted dose of AO (10 ml/kg body weight) were administered intraperitoneally in separate groups of male Swiss Albino mice for 24 h. In addition, a single concentration of sanguinarine (SG) (50 mg/kg body weight) was also administered. Genotoxicity was evaluated by chromosome aberration (CA) and sister chromatid exchange (SCE) tests. Bromodeoxyuridine (BrdU) differential technique was used to study the effect on cell replication by the calculation of average generation time (AGT). RESULTS: The minimum effective concentrations that produced significant frequencies of CA and SCE were 0.1 and 0.01 ml/kg, respectively. AO and SG induced an insignificant increase of AGT indicating that they are non-cytotoxic in the concentrations tested. DISCUSSION AND CONCLUSION: Our results confirm that AO is genotoxic even at low concentrations and its usage should be checked. PMID- 26757780 TI - SOX11 and HIG-2 are cross-regulated and affect growth in mantle cell lymphoma. AB - The transcriptional factor SOX11 is a disease-defining antigen in mantle cell lymphoma (MCL) and absent in most non-malignant tissues. To explore the role of SOX11-related cell signaling, and potentially take benefit from these for targeted therapy, associated networks and proteins need to be defined. In this study, we used an inducible SOX11 knock-down system followed by gene expression analysis to identify co-regulated genes and associated signaling pathways. A limited number (n = 27) of significantly co-regulated genes were identified, including SETMAR, HIG-2, and CD24. Further analysis confirmed co-regulation of SOX11 with HIG-2 and CD24 at the protein level. Of major interest, knock-down of HIG-2 reduced SOX11 levels and increased proliferation, the proteins are thus cross-regulated. HIG-2 was localized at the plasma cell membrane in both cell lines and primary MCL cells, and could potentially be of interest for targeted therapy. PMID- 26757782 TI - Fetal Anemia and Hydrops Fetalis Associated with Homozygous Hb Constant Spring (HBA2: c.427T > C). AB - Hb Constant Spring (Hb CS, HBA2: c.427T > C) is a common nondeletional alpha thalassemia (alpha-thal) that results from a nucleotide substitution at the termination codon of the alpha2-globin gene. Homozygosity for Hb CS (alpha(CS)alpha/alpha(CS)alpha) is relatively rare, and generally characterized with mild hemolytic anemia, jaundice, and splenomegaly. In this report we present a fetus with cardiomegaly, pericardial effusion, enlarged placenta and increased middle cerebral artery-peak systolic velocity (MCA-PSV) at 24 weeks' gestation. Fetal blood sampling revealed the severe anemia [hemoglobin (Hb) level being 4.8 g/dL] and Hb H (beta4) disease-like hematological findings with Hb Bart's (gamma4) level of 17.9%. DNA sequencing of the alpha-globin genes found that both partners were Hb CS carriers and the fetus was an Hb CS homozygote. Therefore, this was a rare case of homozygous Hb CS which demonstrated an unusual and serious anemia and hydrops fetalis in utero. PMID- 26757783 TI - Synthesis, radiolabeling with fluorine-18 and preliminary in vivo evaluation of a heparan sulphate mimetic as potent angiogenesis and heparanase inhibitor for cancer applications. AB - Heparan Sulfate (HS) mimetics are able to block crucial interactions of the components of the extracellular matrix in angiogenic processes and as such, represent a valuable class of original candidates for cancer therapy. Here we first report the synthesis and in vitro angiogenic inhibition properties of a conjugated, novel and rationally-designed octasaccharide-based HS mimetic. We also herein report its labeling with fluorine-18 and present the preliminary in vivo Positron Emission Tomography imaging data in rats. This constitutes one of the rare examples of labeling and in vivo evaluation of a synthetic, polysaccharide-based, macromolecule. PMID- 26757784 TI - Occurrence of Brachyspira hyodysenteriae in multiplier pig herds in Switzerland. AB - OBJECTIVE: This research was aimed to determine the occurrence of Brachyspira (B.) hyodysenteriae in Swiss multiplier pig herds. MATERIALS AND METHODS: In a pilot study a direct real-time polymerase chain reaction (PCR) method for B. hyodysenteriae was compared to culture followed by PCR on 106 samples from three herds. Subsequently 40 multiplier herds were epidemiologically characterized and analysed for the presence of B. hyodysenteriae using direct PCR on 1412 rectal swabs. For external validation 20 swabs obtained from two positive conventional herds were analysed. RESULTS: The comparison of direct PCR with culture followed by PCR resulted in a moderate agreement (kappa index: 0.58). In the two conventional herds, 35% of the samples (7/20) tested positive. Samples from 39 multipliers tested negative. In one multiplier herd, 25% (9/36) of the samples tested PCR positive. Risk factors in the multiplier herd may have been rodents or birds, but not pig purchase. CONCLUSION AND CLINICAL RELEVANCE: B. hyodysenteriae have been detected in a Swiss multiplier herd, which underlines the threat of potential spread by replacement pigs. Consequently, a Brachyspira monitoring programme was established for Swiss multiplier herds. PMID- 26757785 TI - Association between psychosocial, organizational and personal factors and prevalence of musculoskeletal disorders in office workers. AB - The purpose of this study was to investigate the relationship between organizational and personal (individual) factors with the prevalence of musculoskeletal disorders (MSDs) in office workers of the Iranian Gas Transmission Company. The participants rated two questionnaires - the standardized Nordic Musculoskeletal Questionnaire to measure the prevalence of MSDs, and the Veterans Healthcare Administration All Employee Survey questionnaire (2004 version) - to measure psychosocial, organizational and individual aspects of job satisfaction and workplace climate. The highest prevalence of MSDs was found in the lower back (49.7%) and neck (49.0%) regions. Results of the logistic regression models showed that some psychosocial and organizational factors and also some individual factors were associated with prevalence of MSDs (p < 0.05).These findings illustrate the need to consider all elements of the work system as a whole in future studies and in organizational planning. PMID- 26757786 TI - Temporal trends in the treatment and outcomes of elderly patients with acute coronary syndrome. AB - AIMS: To determine whether treatment and outcomes of older acute coronary syndrome (ACS) patients changed over time. METHODS AND RESULTS: We analysed the use of guideline-recommended therapies and in-hospital outcomes of 13 662 ACS patients >=70 years enrolled in the prospective Acute Myocardial Infarction in Switzerland (AMIS) cohort between 2001 and 2012 according to 4-year periods (2001 2004, 2005-2008, and 2009-2012). Between first and last 4-year period, percutaneous coronary intervention (PCI) use increased from 43.8 to 69.6% of older ACS patients ( ITALIC! P < 0.001). Use of guideline-recommended drugs as well increased. At the same time, in-hospital mortality of the overall population decreased from 11.6% in the first to 10.0% in the last 4-year period ( ITALIC! P = 0.020), and in-hospital major adverse cardiac and cerebrovascular events from 14.4 to 11.3% ( ITALIC! P < 0.001). Percutaneous coronary intervention was used in increasingly older and co-morbid patients over time (mean age of patients treated with PCI 76.2 years in 2001-2004 and 78.1 years in 2009-2012, ITALIC! P < 0.001; Charlson score >=2 was found for 27.6% of patients treated with PCI in 2001-2004 and for 32.1% in 2009-2012, ITALIC! P = 0.003). Percutaneous coronary intervention use was associated with similar odds ratios (ORs) of in-hospital mortality over time (adjusted OR 0.29, 95% confidence interval, CI, 0.22-0.40, in 2001-2004; and, adjusted OR 0.26, 95% CI 0.20-0.35, in 2009-2012). CONCLUSION: Use of guideline-recommended therapies for ACS increased and in-hospital outcomes improved over the observed 12-year period. Though PCI was used in increasingly older and co-morbid patients, PCI use was associated with similar ORs of in hospital mortality over time. This study suggests that increasing use of guideline-recommended therapies was appropriate. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01305785. PMID- 26757790 TI - Synthesis and reactivity of fluorenyl-tethered N-heterocyclic stannylenes. AB - A fluorenyl (Fl) tethered diamine was synthesised by nucleophilic substitution of (bromoethyl)fluorene with a diisopropylphenyl (Dipp) substituted diamine to give FlC2H4N(H)C2H4N(H)Dipp (1a) in good yield (85%). Lithiation of 1a with n-BuLi proceeded with coordination of the Li cation to the aromatic fluorenide ring (2), and with subsequent equivalents of n-BuLi, the secondary amines were then sequentially deprotonated. A fluorenyl-tethered N-heterocyclic stannylene (NHSn) was synthesised from the reaction of 1a with SnN''2 {N'' = N(SiMe3)2} as a neutral dimeric species (5), and this was deprotonated with LiN'' to give the corresponding dianionic fluorenide-tethered NHSn (6). Reactions of [{Rh(cod)(MU Cl)}2] with the mono-deprotonated ligand 2 led to the formation of a mixed-donor amide-amine Rh(i) compound (7), whereas reactions with the anionic NHSn 6 led to a Rh-fluorenyl complex of low stability with an uncoordinated pendent NHSn arm, which X-ray crystallography showed to be dimeric in the solid state. PMID- 26757787 TI - Mechanisms of stent thrombosis analysed by optical coherence tomography: insights from the national PESTO French registry. AB - AIMS: Angiography has limited value for identifying the causes of stent thrombosis (ST). We studied a large cohort of patients by optical coherence tomography (OCT) to explore ST characteristics and mechanisms. METHODS AND RESULTS: A prospective multicentre registry was screened for patients with confirmed ST. Optical coherence tomography was performed after initial intervention to the culprit lesion (in 69% of cases in a deferred procedure). Stent thrombosis was classified as acute (AST), sub-acute (SAST), late (LST), and very late (VLST). Optical coherence tomography records were analysed in a central core lab. The analysis included 120 subjects aged 61.7 [51.4-70.7]; 89% male. Very late ST was the clinical presentation in 75%, LST in 6%, SAST in 15%, and AST in 4% of patients. Bare metal stents (BMS) were used in 39%, drug-eluting stents (DES) in 59% and bioresorbable vascular scaffolds in 2% of the cases. Optical coherence tomography identified an underlying morphological abnormality in 97% of cases, including struts malapposition (34%), neoatherosclerotic lesions (22%), major stent underexpansion (11%), coronary evagination (8%), isolated uncovered struts (8%), edge-related disease progression (8%), and neointimal hyperplasia (4%). Ruptured neoatherosclerotic lesions were more frequent with BMS than with DES (36 vs. 14%, P = 0.005), whereas coronary evaginations were more frequent with DES than with BMS (12 vs. 2%, P = 0.04). LST + VLST were mainly related to malapposition (31%) and neoatherosclerosis (28%), while prominent mechanisms for AST + SAST were malapposition (48%) and underexpansion (26%). CONCLUSION: In patients with confirmed ST, OCT imaging identified an underlying morphological abnormality in 97% of cases. PMID- 26757789 TI - Clinical outcomes of patients with hypothyroidism undergoing percutaneous coronary intervention. AB - AIMS: The aim of this study was to investigate the association between hypothyroidism and major adverse cardiovascular and cerebral events (MACCE) in patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: Two thousand four hundred and thirty patients who underwent PCI were included. Subjects were divided into two groups: hypothyroidism (n = 686) defined either as a history of hypothyroidism or thyroid-stimulating hormone (TSH) >=5.0 mU/mL, and euthyroidism (n = 1744) defined as no history of hypothyroidism and/or 0.3 mU/mL <= TSH < 5.0 mU/mL. Patients with hypothyroidism were further categorized as untreated (n = 193), or those taking thyroid replacement therapy (TRT) with adequate replacement (0.3 mU/mL <= TSH < 5.0 mU/mL, n = 175) or inadequate replacement (TSH >= 5.0 mU/mL, n = 318). Adjusted hazard ratios (HRs) were calculated using Cox proportional hazards models. Median follow-up was 3.0 years (interquartile range, 0.5-7.0). After adjustment for covariates, the risk of MACCE and its constituent parts was higher in patients with hypothyroidism compared with those with euthyroidism (MACCE: HR: 1.28, P = 0.0001; myocardial infarction (MI): HR: 1.25, P = 0.037; heart failure: HR: 1.46, P = 0.004; revascularization: HR: 1.26, P = 0.0008; stroke: HR: 1.62, P = 0.04). Compared with untreated patients or those with inadequate replacement, adequately treated hypothyroid patients had a lower risk of MACCE (HR: 0.69, P = 0.005; HR: 0.78, P = 0.045), cardiac death (HR: 0.43, P = 0.008), MI (HR: 0.50, P = 0.0004; HR: 0.60, P = 0.02), and heart failure (HR: 0.50, P = 0.02; HR: 0.52, P = 0.017). CONCLUSION: Hypothyroidism is associated with a higher incidence of MACCE compared with euthyroidism in patients undergoing PCI. Maintaining adequate control on TRT is beneficial in preventing MACCE. PMID- 26757788 TI - Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9): a randomized, placebo-controlled Phase 2 study. AB - AIMS: The objective of this study was to evaluate the efficacy, safety, and tolerability of LY3015014 (LY), a neutralizing antibody of proprotein convertase subtilisin/kexin type 9 (PCSK9), administered every 4 or 8 weeks in patients with primary hypercholesterolaemia, when added to a background of standard-of-care lipid-lowering therapy, including statins. METHODS AND RESULTS: Double-blind, placebo-controlled trial randomized 527 patients with primary hypercholesterolaemia from June 2013 to January 2014 at 61 community and academic centres in North America, Europe, and Japan. Patients were randomized to subcutaneous injections of LY 20, 120, or 300 mg every 4 weeks (Q4W); 100 or 300 mg every 8 weeks (Q8W) alternating with placebo Q4W; or placebo Q4W. The primary endpoint was percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) by beta quantification at Week 16. The mean baseline LDL-C by beta quantification was 136.3 (SD, 45.0)mg/dL. LY3015014 dose-dependently decreased LDL-C, with a maximal reduction of 50.5% with 300 mg LY Q4W and 37.1% with 300 mg LY Q8W compared with a 7.6% increase with placebo maintained at the end of the dosing interval. There were no treatment-related serious adverse events (AEs). The most common AE terms (>10% of any treatment group) reported more frequently with LY compared with placebo were injection site (IS) pain and IS erythema. No liver or muscle safety issues emerged. CONCLUSIONS: LY3015014 dosed every 4 or 8 weeks, resulted in robust and durable reductions in LDL-C. No clinically relevant safety issues emerged with the administration of LY. The long term effects on cardiovascular outcomes require further investigation. PMID- 26757791 TI - Fluence-based dosimetry of proton and heavier ion beams using single track detectors. AB - Due to their superior spatial resolution, small and biocompatible fluorescent nuclear track detectors (FNTDs) open up the possibility of characterizing swift heavy charged particle fields on a single track level. Permanently stored spectroscopic information such as energy deposition and particle field composition is of particular importance in heavy ion radiotherapy, since radiation quality is one of the decisive predictors for clinical outcome. Findings presented within this paper aim towards single track reconstruction and fluence-based dosimetry of proton and heavier ion fields. Three-dimensional information on individual ion trajectories through the detector volume is obtained using fully automated image processing software. Angular distributions of multidirectional fields can be measured accurately within +/-2 degrees uncertainty. This translates into less than 5% overall fluence deviation from the chosen irradiation reference. The combination of single ion tracking with an improved energy loss calibration curve based on 90 FNTD irradiations with protons as well as helium, carbon and oxygen ions enables spectroscopic analysis of a detector irradiated in Bragg peak proximity of a 270 MeV u(-1) carbon ion field. Fluence-based dosimetry results agree with treatment planning software reference. PMID- 26757792 TI - Twin pregnancy in the congenital malformed uterus. AB - The frequency and outcome of twin pregnancies in women with uterine malformation were studied. The cohort comprised 13 (4.9%) women with twin pregnancy found among 263 women. They had 483 deliveries, 13 of them twins (2.7%; 95% CI 1.6 4.6%). Among 38 patients with unicornuate uterus 5 (6.8%) out of 74 deliveries were twins, 39 women with didelphic uterus 2 (3.2%) out of 62 deliveries and 147 women with septate or subseptate uterus 6 (2.3%) out of 264 deliveries were twins. The mean duration of gestation was 249 days (range 190-268 days), 5 (38%) out of 13 deliveries were premature, 25 out of 26 newborns were alive. Mean durations of gestation and mean weights of newborns did not differ when 7 cases with unicornuate or didelphic uterus were compared to 6 cases with complete or partial uterine septum. A congenital malformed uterus can bear twin pregnancy without severe complications apart from prematurity. PMID- 26757793 TI - Impact of increasing fruit and vegetables and flavonoid intake on the human gut microbiota. AB - Epidemiological studies have shown protective effects of fruits and vegetables (F&V) in lowering the risk of developing cardiovascular diseases (CVD) and cancers. Plant-derived dietary fibre (non-digestible polysaccharides) and/or flavonoids may mediate the observed protective effects particularly through their interaction with the gut microbiota. The aim of this study was to assess the impact of fruit and vegetable (F&V) intake on gut microbiota, with an emphasis on the role of flavonoids, and further to explore relationships between microbiota and factors associated with CVD risk. In the study, a parallel design with 3 study groups, participants in the two intervention groups representing high flavonoid (HF) and low flavonoid (LF) intakes were asked to increase their daily F&V intake by 2, 4 and 6 portions for a duration of 6 weeks each, while a third (control) group continued with their habitual diet. Faecal samples were collected at baseline and after each dose from 122 subjects. Faecal bacteria enumeration was performed by fluorescence in situ hybridisation (FISH). Correlations of dietary components, flavonoid intake and markers of CVD with bacterial numbers were also performed. A significant dose X treatment interaction was only found for Clostidium leptum-Ruminococcus bromii/flavefaciens with a significant increase after intake of 6 additional portions in the LF group. Correlation analysis of the data from all 122 subjects independent from dietary intervention indicated an inhibitory role of F&V intake, flavonoid content and sugars against the growth of potentially pathogenic clostridia. Additionally, we observed associations between certain bacterial populations and CVD risk factors including plasma TNF-alpha, plasma lipids and BMI/waist circumference. PMID- 26757794 TI - Edge-rich and dopant-free graphene as a highly efficient metal-free electrocatalyst for the oxygen reduction reaction. AB - For the first time, we developed edge-rich and dopant-free graphene as a highly efficient ORR electrocatalyst. Electrochemical analysis revealed that the as obtained edge-rich graphene showed excellent ORR activity through a one-step and four-electron pathway. With a similar strategy, edge-rich carbon nanotubes and graphite can also be obtained with enhanced ORR activity. This work confirms the important role of edge carbon in efficient ORR electrocatalysis without interruption by any other dopants. PMID- 26757795 TI - Flower-like Copper Cobaltite Nanosheets on Graphite Paper as High-Performance Supercapacitor Electrodes and Enzymeless Glucose Sensors. AB - Flower-like copper cobaltite (CuCo2O4) nanosheets anchored on graphite paper have been synthesized using a facile hydrothermal method followed by a postannealing treatment. Supercapacitor electrodes employing CuCo2O4 nanosheets exhibit an enhanced capacitance of 1131 F g(-1) at a current density of 1 A g(-1) compared with previously reported supercapacitor electrodes. The CuCo2O4 electrode delivers a specific capacitance of up to 409 F g(-1) at a current density of as high as 50 A g(-1), and a good long-term cycling stability, with 79.7% of its specific capacitance retained after 5000 cycles at 10 A g(-1). Furthermore, the as-prepared CuCo2O4 nanosheets on graphite paper can be fabricated as electrodes and used as enzymeless glucose sensors, which exhibit good sensitivity (3.625 MUA MUM(-1) cm(-2)) and an extraordinary linear response ranging up to 320 MUM with a low detection limit (5 MUM). PMID- 26757796 TI - Gender and Age Determinants of Psychogenic Movement Disorders: A Clinical Profile of 73 Patients. AB - BACKGROUND: Psychogenic movement disorders (PMD) is a group of disorders that cannot be attributed to any structural or biochemical abnormality, but has an underlying psychiatric illness. The profile of PMD varies according to country and socioeconomic factors. METHODS: The present study reports the clinical profile of patients with PMD from India. Seventy-three patients with documented or clinically established PMD were seen over a period of 14 years with detailed neurological and psychiatric examinations. RESULTS: The mean age at presentation was 29.1+/-15.1 years (women, 51%). Approximately 30% were <=18 years of age (boys, 63.6%). The onset of symptoms was abrupt in 61.6% and the initial body part most often affected was right upper limb (adults, 29.4%; children, 31.8%). Tremor was observed in 31.4% of adults and 9% of children, whereas myoclonus was more common in children (36.4%). Tremors were more often seen in women (42.3%) than in men (20%), whereas myoclonus was almost equally prevalent in girls (37.5%) and boys (35.7%). Depression was the most common psychiatric comorbidity (men, 16%; women, 15.4%). About 42.5% required hospital admission and 57.5% had significant reduction or complete cessation of PMD after counseling, antidepressants, and/ or placebo. CONCLUSIONS: PMD was equally prevalent among women and men. Tremor was most often observed in adults, whereas myoclonus was most often observed in children. Electrophysiology and placebo were useful supplementary tools for diagnosing PMD. PMID- 26757798 TI - Ethics, genetic testing, and athletic talent: children's best interests, and the right to an open (athletic) future. AB - In this paper we discuss the ethics of genetics-based talent identification programs in sports. We discuss the validity and reliability of the tests and the claims made by direct to consumer companies, before presenting a range of ethical issues concerning child-parent/guardian relations raised by these tests, which we frame in terms of parental/guardian duties, children's rights, and best interests. We argue that greater ethical emphasis needs to be put on the parental decision on the wellbeing on the child going forward, not on ex post justifications on the basis of good and bad consequences. Best interests decisions made by a third party seem to comprise both subjective and objective elements, but only a holistic approach can do justice to these questions by addressing the wellbeing of the child in a temporal manner and taking into account the child's perspective on its wellbeing. Such decisions must address wider questions of what a good (sports)parent ought do to help the child flourish and how to balance the future-adult focus necessary to nurture talent with the wellbeing of the child in the present. We conclude that current genetic tests for "talent" do not predict aptitude or success to any significant degree and are therefore only marginally pertinent for talent identification. Claims that go beyond current science are culpable and attempt to exploit widespread but naive perceptions of the efficacy of genetics information to predict athletic futures. Sports physicians and health care professionals involved in sport medicine should therefore discourage the use of these tests. PMID- 26757797 TI - Mitochondrial polymerase gamma dysfunction and aging cause cardiac nuclear DNA methylation changes. AB - Cardiomyopathy (CM) is an intrinsic weakening of myocardium with contractile dysfunction and congestive heart failure (CHF). CHF has been postulated to result from decreased mitochondrial energy production and oxidative stress. Effects of decreased mitochondrial oxygen consumption also can accelerate with aging. We previously showed DNA methylation changes in human hearts with CM. This was associated with mitochondrial DNA depletion, being another molecular marker of CM. We examined the relationship between mitochondrial dysfunction and cardiac epigenetic DNA methylation changes in both young and old mice. We used genetically engineered C57Bl/6 mice transgenic for a cardiac-specific mutant of the mitochondrial polymerase-gamma (termed Y955C). Y955C mice undergo left ventricular hypertrophy (LVH) at a young age (~ 94 days old), and LVH decompensated to CHF at old age (~ 255 days old). Results found 95 genes differentially expressed as a result of Y955C expression, while 4,452 genes were differentially expressed as a result of aging hearts. Moreover, cardiac DNA methylation patterns differed between Y955C (4,506 peaks with 68.5% hypomethylation) and aged hearts (73,286 peaks with 80.2% hypomethylated). Correlatively, of the 95 Y955C-dependent differentially expressed genes, 30 genes (31.6%) also displayed differential DNA methylation; in the 4,452 age-dependent differentially expressed genes, 342 genes (7.7%) displayed associated DNA methylation changes. Both Y955C and aging demonstrated significant enrichment of CACGTG-associated E-box motifs in differentially methylated regions. Cardiac mitochondrial polymerase dysfunction alters nuclear DNA methylation. Furthermore, aging causes a robust change in cardiac DNA methylation that is partially associated with mitochondrial polymerase dysfunction. PMID- 26757799 TI - Association of ACTN3 R577X but not ACE I/D gene variants with elite rugby union player status and playing position. AB - We aimed to quantify the ACE I/D and ACTN3 R577X (rs1815739) genetic variants in elite rugby athletes (rugby union and league) and compare genotype frequencies to controls and between playing positions. The rugby athlete cohort consisted of 507 Caucasian men, including 431 rugby union athletes that for some analyses were divided into backs and forwards and into specific positional groups: front five, back row, half backs, centers, and back three. Controls were 710 Caucasian men and women. Real-time PCR of genomic DNA was used to determine genotypes using TaqMan probes and groups were compared using chi(2) and odds ratio (OR) statistics. Correction of P values for multiple comparisons was according to Benjamini-Hochberg. There was no difference in ACE I/D genotype between groups. ACTN3 XX genotype tended to be underrepresented in rugby union backs (15.7%) compared with forwards (24.8%, P = 0.06). Interestingly, the 69 back three players (wings and full backs) in rugby union included only six XX genotype individuals (8.7%), with the R allele more common in the back three (68.8%) than controls (58.0%; chi(2) = 6.672, P = 0.04; OR = 1.60) and forwards (47.5%; chi(2) = 11.768, P = 0.01; OR = 2.00). Association of ACTN3 R577X with playing position in elite rugby union athletes suggests inherited fatigue resistance is more prevalent in forwards, while inherited sprint ability is more prevalent in backs, especially wings and full backs. These results also demonstrate the advantage of focusing genetic studies on a large cohort within a single sport, especially when intrasport positional differences exist, instead of combining several sports with varied demands and athlete characteristics. PMID- 26757800 TI - Blood transcriptional signature of recombinant human erythropoietin administration and implications for antidoping strategies. AB - Recombinant human erythropoietin (rHuEPO) is frequently abused by athletes as a performance-enhancing drug, despite being prohibited by the World Anti-Doping Agency. Although the methods to detect blood doping, including rHuEPO injections, have improved in recent years, they remain imperfect. In a proof-of-principle study, we identified, replicated, and validated the whole blood transcriptional signature of rHuEPO in endurance-trained Caucasian males at sea level (n = 18) and Kenyan endurance runners at moderate altitude (n = 20), all of whom received rHuEPO injections for 4 wk. Transcriptional profiling shows that hundreds of transcripts were altered by rHuEPO in both cohorts. The main regulated expression pattern, observed in all participants, was characterized by a "rebound" effect with a profound upregulation during rHuEPO and a subsequent downregulation up to 4 wk postadministration. The functions of the identified genes were mainly related to the functional and structural properties of the red blood cell. Of the genes identified to be differentially expressed during and post-rHuEPO, we further confirmed a whole blood 34-transcript signature that can distinguish between samples collected pre-, during, and post-rHuEPO administration. By providing biomarkers that can reveal rHuEPO use, our findings represent an advance in the development of new methods for the detection of blood doping. PMID- 26757801 TI - Sports genetics moving forward: lessons learned from medical research. AB - Sports genetics can take advantage of lessons learned from human disease genetics. By righting past mistakes and increasing scientific rigor, we can magnify the breadth and depth of knowledge in the field. We present an outline of challenges facing sports genetics in the light of experiences from medical research. Sports performance is complex, resulting from a combination of a wide variety of different traits and attributes. Improving sports genetics will foremost require analyses based on detailed phenotyping. To find widely valid, reproducible common variants associated with athletic phenotypes, study sample sizes must be dramatically increased. One paradox is that in order to confirm relevance, replications in specific populations must be undertaken. Family studies of athletes may facilitate the discovery of rare variants with large effects on athletic phenotypes. The complexity of the human genome, combined with the complexity of athletic phenotypes, will require additional metadata and biological validation to identify a comprehensive set of genes involved. Analysis of personal genetic and multiomic profiles contribute to our conceptualization of precision medicine; the same will be the case in precision sports science. In the refinement of sports genetics it is essential to evaluate similarities and differences between sexes and among ethnicities. Sports genetics to date have been hampered by small sample sizes and biased methodology, which can lead to erroneous associations and overestimation of effect sizes. Consequently, currently available genetic tests based on these inherently limited data cannot predict athletic performance with any accuracy. PMID- 26757803 TI - Crystal structure of the mouse hepatitis virus ns2 phosphodiesterase domain that antagonizes RNase L activation. AB - Prior studies have demonstrated that the mouse hepatitis virus (MHV) A59 strain ns2 protein is a member of the 2H phosphoesterase family and exhibits 2',5' phosphodiesterase (PDE) activity. During the IFN antiviral response, ns2 cleaves 2',5'-oligoadenylate (2-5A), a key mediator of RNase L activation, thereby subverting the activation of RNase L and evading host innate immunity. However, the mechanism of 2-5A cleavage by ns2 remains unclear. Here, we present the crystal structure of the MHV ns2 PDE domain and demonstrate a PDE fold similar to that of the cellular protein, a kinase anchoring protein 7 central domain (AKAP7(CD)) and rotavirus VP3 carboxy-terminal domain. The structure displays a pair of strictly conserved HxT/Sx motifs and forms a deep, positively charged catalytic groove with beta-sheets and an arginine-containing loop. These findings provide insight into the structural basis for 2-5A binding of MHV ns2. PMID- 26757806 TI - SOUNDS OF MOLECULAR BIOLOGY. AB - Engineers and biologists are using sound to mix fluids, move cells, and dispense liquids. Nathan Blow looks at how acoustic science is changing molecular biology and high-throughput screening. PMID- 26757802 TI - Peptide affinity analysis of proteins that bind to an unstructured NH2-terminal region of the osmoprotective transcription factor NFAT5. AB - NFAT5 is an osmoregulated transcription factor that particularly increases expression of genes involved in protection against hypertonicity. Transcription factors often contain unstructured regions that bind co-regulatory proteins that are crucial for their function. The NH2-terminal region of NFAT5 contains regions predicted to be intrinsically disordered. We used peptide aptamer-based affinity chromatography coupled with mass spectrometry to identify protein preys pulled down by one or more overlapping 20 amino acid peptide baits within a predicted NH2-terminal unstructured region of NFAT5. We identify a total of 467 unique protein preys that associate with at least one NH2-terminal peptide bait from NFAT5 in either cytoplasmic or nuclear extracts from HEK293 cells treated with elevated, normal, or reduced NaCl concentrations. Different sets of proteins are pulled down from nuclear vs. cytoplasmic extracts. We used GeneCards to ascertain known functions of the protein preys. The protein preys include many that were previously known, but also many novel ones. Consideration of the novel ones suggests many aspects of NFAT5 regulation, interaction and function that were not previously appreciated, for example, hypertonicity inhibits NFAT5 by sumoylating it and the NFAT5 protein preys include components of the CHTOP complex that desumoylate proteins, an action that should contribute to activation of NFAT5. PMID- 26757804 TI - Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis. AB - BACKGROUND: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9 7.1; I(2)R, 0.2%). CONCLUSIONS: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy. PMID- 26757805 TI - Vitamin D status predicts reproductive fitness in a wild sheep population. AB - Vitamin D deficiency has been associated with the development of many human diseases, and with poor reproductive performance in laboratory rodents. We currently have no idea how natural selection directly acts on variation in vitamin D metabolism due to a total lack of studies in wild animals. Here, we measured serum 25 hydroxyvitamin D (25(OH)D) concentrations in female Soay sheep that were part of a long-term field study on St Kilda. We found that total 25(OH)D was strongly influenced by age, and that light coloured sheep had higher 25(OH)D3 (but not 25(OH)D2) concentrations than dark sheep. The coat colour polymorphism in Soay sheep is controlled by a single locus, suggesting vitamin D status is heritable in this population. We also observed a very strong relationship between total 25(OH)D concentrations in summer and a ewe's fecundity the following spring. This resulted in a positive association between total 25(OH)D and the number of lambs produced that survived their first year of life, an important component of female reproductive fitness. Our study provides the first insight into naturally-occurring variation in vitamin D metabolites, and offers the first evidence that vitamin D status is both heritable and under natural selection in the wild. PMID- 26757809 TI - Development of single-tube nested real-time PCR assays with long internally quenched probes for detection of norovirus genogroup II. AB - The high sequence variation of RNA viruses necessitates use of degenerate primers and probes or multiple primers and probes in molecular diagnostic assays. We showed previously that PCR amplification in two rounds, first with long target specific primers and then with short generic primers, followed by detection using long probes, can tolerate sequence variation. Here we demonstrate that long primers and probes of up to 56 nucleotides can also be applied in real-time PCR for the detection of norovirus genogroup II with improved sensitivity. Probe design (method of incorporating quenchers, use of Zen internal quencher or traditional quenchers) greatly affects the sensitivity of the real-time PCR assays. PMID- 26757808 TI - Simple horizontal magnetic tweezers for micromanipulation of single DNA molecules and DNA-protein complexes. AB - We report the development of a simple-to-implement magnetic force transducer that can apply a wide range of piconewton (pN) scale forces on single DNA molecules and DNA-protein complexes in the horizontal plane. The resulting low-noise force extension data enable very high-resolution detection of changes in the DNA tether's extension: ~0.05 pN in force and <10 nm change in extension. We have also verified that we can manipulate DNA in near equilibrium conditions through the wide range of forces by ramping the force from low to high and back again, and observing minimal hysteresis in the molecule's force response. Using a calibration technique based on Stokes' drag law, we have confirmed our force measurements from DNA force-extension experiments obtained using the fluctuation dissipation theorem applied to transverse fluctuations of the magnetic microsphere. We present data on the force-distance characteristics of a DNA molecule complexed with histones. The results illustrate how the tweezers can be used to study DNA binding proteins at the single molecule level. PMID- 26757807 TI - Efficient transgenesis mediated by pigmentation rescue in zebrafish. AB - The zebrafish represents a revolutionary tool in large-scale genetic and small molecule screens for gene and drug discovery. Transgenic zebrafish are often utilized in these screens. Many transgenic fish lines are maintained in the heterozygous state due to the lethality associated with homozygosity; thus, their progeny must be sorted to ensure a population expressing the transgene of interest for use in screens. Sorting transgenic embryos under a fluorescence microscope is very labor-intensive and demands fine-tuned motor skills. Here we report an efficient transgenic method of utilizing pigmentation rescue of nacre mutant fish for accurate naked-eye identification of both mosaic founders and stable transgenic zebrafish. This was accomplished by co-injecting two constructs with the I-SceI meganuclease enzyme into pigmentless nacre embryos: I-SceI mitfa:mitfa-I-SceI to rescue the pigmentation and I-SceI-zpromoter:gene-of interest-I-SceI to express the gene of interest under a zebrafish promoter (zpromoter). Pigmentation rescue reliably predicted transgene integration. Compared with other transgenic techniques, our approach significantly increases the overall percentage of founders and facilitates accurate naked-eye identification of stable transgenic fish, greatly reducing laborious fluorescence microscope sorting and PCR genotyping. Thus, this approach is ideal for generating transgenic fish for large-scale screens. PMID- 26757810 TI - A new approach to follow a single extracellular vesicle-cell interaction using optical tweezers. AB - Extracellular vesicles (EVs) are spherical membrane structures released by most cells. These highly conserved mediators of intercellular communication carry proteins, lipids, and nucleic acids, and transfer these cellular components between cells by different mechanisms, such as endocytosis, macropinocytosis, or fusion. However, the temporal and spatial dynamics of vesicle-cell interactions still remain largely unexplored. Here we used optical tweezers to drive single EVs produced by microglial cells onto the surface of astrocytes or microglia in primary culture. By visualizing single EV-cell contacts, we observed that microglial vesicles displayed different motilities on the surface of astrocytes compared with microglia. After contact, EVs positioned on astrocytes displayed some minor oscillatory motion around the point of adhesion, while vesicles dragged to microglia displayed quite regular directional movement on the plasma membrane. Both the adhesion and motion of vesicles on glial cells were strongly reduced by cloaking phosphatidylserine (PS) residues, which are externalized on the vesicle membrane and act as determinants for vesicle recognition by target cells. These data identify optical manipulation as a powerful tool to monitor in vitro vesicle-cell dynamics with high temporal and spatial resolution and to determine in a quantitative manner the contribution of surface receptors/extracellular protein ligands to the contact. PMID- 26757811 TI - A simple, low-cost staining method for rapid-throughput analysis of tumor spheroids. AB - Tumor spheroids are becoming an important tool for the investigation of cancer stem cell (CSC) function in tumors; thus, low-cost and high-throughput methods for drug screening of tumor spheroids are needed. Using neurospheres as non adherent three-dimensional (3-D) cultures, we developed a simple, low-cost acridine orange (AO)-based method that allows for rapid analysis of live neurospheres by fluorescence microscopy in a 96-well format. This assay measures the cross-section area of a spheroid, which corresponds to cell viability. Our novel method allows rapid screening of a panel of anti-proliferative drugs to assess inhibitory effects on the growth of cancer stem cells in 3-D cultures. PMID- 26757812 TI - Method for collecting mouse milk without exogenous oxytocin stimulation. AB - It has been reported that breast-feeding more than 6 months strongly decreases the risk of allergy, diabetes, obesity, and hypertension in humans. In order to understand the mechanisms responsible for this benefit, it is important to evaluate precisely the composition of maternal milk, especially in response to environmental cues. Mouse models offer a unique opportunity to study the impact of maternal milk composition on the development and health of offspring. Oxytocin injection of the dam is usually used to stimulate milk ejection; however, exogenous oxytocin might have deleterious effects under some experimental conditions by modifying milk content as well as the physiology and behavior of the dam. Taking advantage of the natural stimulation of the mammary gland that occurs after the reunion of a dam that has been separated from her pups, we developed a new procedure to collect mouse milk without the injection of oxytocin. This method is easy to use, low-cost ,and non-invasive. Moreover, it provides a sufficient amount of milk for use in a wide range of biological analyses. PMID- 26757814 TI - YAP Nuclear Localization in the Absence of Cell-Cell Contact Is Mediated by a Filamentous Actin-dependent, Myosin II- and Phospho-YAP-independent Pathway during Extracellular Matrix Mechanosensing. AB - Cell-cell contact inhibition and the mechanical environment of cells have both been shown to regulate YAP nuclear localization to modulate cell proliferation. Changes in cellular contractility by genetic, pharmacological, and matrix stiffness perturbations regulate YAP nuclear localization. However, because contractility and F-actin organization are interconnected cytoskeletal properties, it remains unclear which of these distinctly regulates YAP localization. Here we show that in the absence of cell-cell contact, actomyosin contractility suppresses YAP phosphorylation at Ser(112), however, neither loss of contractility nor increase in YAP phosphorylation is sufficient for its nuclear exclusion. We find that actin cytoskeletal integrity is essential for YAP nuclear localization, and can override phosphoregulation or contractility mediated regulation of YAP nuclear localization. This actin-mediated regulation is conserved during mechanotransduction, as substrate compliance increased YAP phosphorylation and reduced cytoskeletal integrity leading to nuclear exclusion of both YAP and Ser(P)(112)-YAP. These data provide evidence for two actin mediated pathways for YAP regulation; one in which actomyosin contractility regulates YAP phosphorylation, and a second that involves cytoskeletal integrity mediated regulation of YAP nuclear localization independent of contractility. We suggest that in non-contact inhibited cells, this latter mechanism may be important in low stiffness regimes, such as may be encountered in physiological environments. PMID- 26757813 TI - Widely tunable two-colour seeded free-electron laser source for resonant-pump resonant-probe magnetic scattering. AB - The advent of free-electron laser (FEL) sources delivering two synchronized pulses of different wavelengths (or colours) has made available a whole range of novel pump-probe experiments. This communication describes a major step forward using a new configuration of the FERMI FEL-seeded source to deliver two pulses with different wavelengths, each tunable independently over a broad spectral range with adjustable time delay. The FEL scheme makes use of two seed laser beams of different wavelengths and of a split radiator section to generate two extreme ultraviolet pulses from distinct portions of the same electron bunch. The tunability range of this new two-colour source meets the requirements of double resonant FEL pump/FEL probe time-resolved studies. We demonstrate its performance in a proof-of-principle magnetic scattering experiment in Fe-Ni compounds, by tuning the FEL wavelengths to the Fe and Ni 3p resonances. PMID- 26757815 TI - A Novel Nectin-mediated Cell Adhesion Apparatus That Is Implicated in Prolactin Receptor Signaling for Mammary Gland Development. AB - Mammary gland development is induced by the actions of various hormones to form a structure consisting of collecting ducts and milk-secreting alveoli, which comprise two types of epithelial cells known as luminal and basal cells. These cells adhere to each other by cell adhesion apparatuses whose roles in hormone dependent mammary gland development remain largely unknown. Here we identified a novel cell adhesion apparatus at the boundary between the luminal and basal cells in addition to desmosomes. This apparatus was formed by the trans-interaction between the cell adhesion molecules nectin-4 and nectin-1, which were expressed in the luminal and basal cells, respectively. Nectin-4 of this apparatus further cis-interacted with the prolactin receptor in the luminal cells to enhance the prolactin-induced prolactin receptor signaling for alveolar development with lactogenic differentiation. Thus, a novel nectin-mediated cell adhesion apparatus regulates the prolactin receptor signaling for mammary gland development. PMID- 26757817 TI - Transcription Factors and DNA Repair Enzymes Compete for Damaged Promoter Sites. AB - Transcriptional regulation is a tightly regulated, vital process. The transcription factor cyclic AMP-response element-binding protein 1 (CREB1) controls ~25% of the mammalian transcriptome by binding the CREB1 binding site consensus sequence (CRE) sequence (TGACGTCA). DNA lesions within CRE modulate CREB1 binding negatively and positively. Because appropriate DNA lesions also interact with base excision repair proteins, we investigated whether CREB1 and repair glycosylases compete with each other. We incubated 39-mer CRE-containing double-stranded oligonucleotides with recombinant CREB1 alone or with UNG2 or OGG1, followed by EMSA. The CpG islet within CRE was modified to contain a G/U or 8-oxoG ( degrees G)/C mispair. OGG1 and CREB1 reversibly competed for CRE containing an degrees G/C pair. Also, OGG1 blocked CREB1 from dimerizing by 69%, even when total CREB1 binding was reduced only by 20-30%. In contrast, bound CREB1 completely prevented access to G/U-containing CRE by UNG2 and, therefore, to base excision repair, whereas UNG2 exposure prevented CREB1 binding. CREB1 dimerization was unaffected by UNG2 when CREB1 bound to CRE, but was greatly reduced by prior UNG2 exposure. To explore physiological relevance, we microinjected zebrafish embryos with the same oligonucleotides, as a sink for endogenous CREB1. As predicted, microinjection with unmodified or lesion containing CRE, but not scrambled CRE or scrambled CRE with a G/U mispair, resulted in increased embryo death. However, only the G/U mispair in native CRE resulted in substantial developmental abnormalities, thus confirming the danger of unrepaired G/U mispairs in promoters. In summary, CREB1 and DNA glycosylases compete for damaged CRE in vitro and in vivo, thus blocking DNA repair and resulting in transcriptional misregulation leading to abnormal development. PMID- 26757816 TI - Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet alpha Cells to Promote Glucose Homeostasis. AB - The physiological role of the TGR5 receptor in the pancreas is not fully understood. We previously showed that activation of TGR5 in pancreatic beta cells by bile acids induces insulin secretion. Glucagon released from pancreatic alpha cells and glucagon-like peptide 1 (GLP-1) released from intestinal L cells regulate insulin secretion. Both glucagon and GLP-1 are derived from alternate splicing of a common precursor, proglucagon by PC2 and PC1, respectively. We investigated whether TGR5 activation in pancreatic alpha cells enhances hyperglycemia-induced PC1 expression thereby releasing GLP-1, which in turn increases beta cell mass and function in a paracrine manner. TGR5 activation augmented a hyperglycemia-induced switch from glucagon to GLP-1 synthesis in human and mouse islet alpha cells by GS/cAMP/PKA/cAMP-response element-binding protein-dependent activation of PC1. Furthermore, TGR5-induced GLP-1 release from alpha cells was via an Epac-mediated PKA-independent mechanism. Administration of the TGR5 agonist, INT-777, to db/db mice attenuated the increase in body weight and improved glucose tolerance and insulin sensitivity. INT-777 augmented PC1 expression in alpha cells and stimulated GLP-1 release from islets of db/db mice compared with control. INT-777 also increased pancreatic beta cell proliferation and insulin synthesis. The effect of TGR5-mediated GLP-1 from alpha cells on insulin release from islets could be blocked by GLP-1 receptor antagonist. These results suggest that TGR5 activation mediates cross-talk between alpha and beta cells by switching from glucagon to GLP-1 to restore beta cell mass and function under hyperglycemic conditions. Thus, INT-777-mediated TGR5 activation could be leveraged as a novel way to treat type 2 diabetes mellitus. PMID- 26757818 TI - Requirement of Neuronal Ribosome Synthesis for Growth and Maintenance of the Dendritic Tree. AB - The nucleolus serves as a principal site of ribosome biogenesis but is also implicated in various non-ribosomal functions, including negative regulation of the pro-apoptotic transcription factor p53. Although disruption of the nucleolus may trigger the p53-dependent neuronal death, neurotoxic consequences of a selective impairment of ribosome production are unclear. Here, we report that in rat forebrain neuronal maturation is associated with a remarkable expansion of ribosomes despite postnatal down-regulation of ribosomal biogenesis. In cultured rat hippocampal neurons, inhibition of the latter process by knockdowns of ribosomal proteins S6, S14, or L4 reduced ribosome content without disrupting nucleolar integrity, cell survival, and signaling responses to the neurotrophin brain-derived neurotrophic factor. Moreover, reduced general protein synthesis and/or formation of RNA stress granules suggested diminished ribosome recruitment to at least some mRNAs. Such a translational insufficiency was accompanied by impairment of brain-derived neurotrophic factor-mediated dendritic growth. Finally, RNA stress granules and smaller dendritic trees were also observed when ribosomal proteins were depleted from neurons with established dendrites. Thus, a robust ribosomal apparatus is required to carry out protein synthesis that supports dendritic growth and maintenance. Consequently, deficits of ribosomal biogenesis may disturb neurodevelopment by reducing neuronal connectivity. Finally, as stress granule formation and dendritic loss occur early in neurodegenerative diseases, disrupted homeostasis of ribosomes may initiate and/or amplify neurodegeneration-associated disconnection of neuronal circuitries. PMID- 26757819 TI - Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate. AB - Bone degenerative pathologies like osteoporosis may be initiated by age-related shifts in anabolic and catabolic responses that control bone homeostasis. Here we show that sulforaphane (SFN), a naturally occurring isothiocyanate, promotes osteoblast differentiation by epigenetic mechanisms. SFN enhances active DNA demethylation viaTet1andTet2and promotes preosteoblast differentiation by enhancing extracellular matrix mineralization and the expression of osteoblastic markers (Runx2,Col1a1,Bglap2,Sp7,Atf4, andAlpl). SFN decreases the expression of the osteoclast activator receptor activator of nuclear factor-kappaB ligand (RANKL) in osteocytes and mouse calvarial explants and preferentially induces apoptosis in preosteoclastic cells via up-regulation of theTet1/Fas/Caspase 8 and Caspase 3/7 pathway. These mechanistic effects correlate with higher bone volume (~20%) in both normal and ovariectomized mice treated with SFN for 5 weeks compared with untreated mice as determined by microcomputed tomography. This effect is due to a higher trabecular number in these mice. Importantly, no shifts in mineral density distribution are observed upon SFN treatment as measured by quantitative backscattered electron imaging. Our data indicate that the food derived compound SFN epigenetically stimulates osteoblast activity and diminishes osteoclast bone resorption, shifting the balance of bone homeostasis and favoring bone acquisition and/or mitigation of bone resorptionin vivo Thus, SFN is a member of a new class of epigenetic compounds that could be considered for novel strategies to counteract osteoporosis. PMID- 26757820 TI - Soluble Oligomers of the Pore-forming Toxin Cytolysin A from Escherichia coli Are Off-pathway Products of Pore Assembly. AB - The alpha-pore-forming toxin Cytolysin A (ClyA) is responsible for the hemolytic activity of various Escherichia coli and Salmonella enterica strains. Soluble ClyA monomers spontaneously assemble into annular dodecameric pore complexes upon contact with membranes or detergent. At ClyA monomer concentrations above ~100 nm, the rate-limiting step in detergent- or membrane- induced pore assembly is the unimolecular reaction from the monomer to the assembly-competent protomer, which then oligomerizes rapidly to active pore complexes. In the absence of detergent, ClyA slowly forms soluble oligomers. Here we show that soluble ClyA oligomers cannot form dodecameric pore complexes after the addition of detergent and are hemolytically inactive. In addition, we demonstrate that the natural cysteine pair Cys-87/Cys-285 of ClyA forms a disulfide bond under oxidizing conditions and that both the oxidized and reduced ClyA monomers assemble to active pores via the same pathway in the presence of detergent, in which an unstructured, monomeric intermediate is transiently populated. The results show that the oxidized ClyA monomer assembles to pore complexes about one order of magnitude faster than the reduced monomer because the unstructured intermediate of oxidized ClyA is less stable and dissolves more rapidly than the reduced intermediate. Moreover, we show that oxidized ClyA forms soluble, inactive oligomers in the absence of detergent much faster than the reduced monomer, providing an explanation for several contradictory reports in which oxidized ClyA had been described as inactive. PMID- 26757821 TI - Novel Features of Eukaryotic Photosystem II Revealed by Its Crystal Structure Analysis from a Red Alga. AB - Photosystem II (PSII) catalyzes light-induced water splitting, leading to the evolution of molecular oxygen indispensible for life on the earth. The crystal structure of PSII from cyanobacteria has been solved at an atomic level, but the structure of eukaryotic PSII has not been analyzed. Because eukaryotic PSII possesses additional subunits not found in cyanobacterial PSII, it is important to solve the structure of eukaryotic PSII to elucidate their detailed functions, as well as evolutionary relationships. Here we report the structure of PSII from a red alga Cyanidium caldarium at 2.76 A resolution, which revealed the structure and interaction sites of PsbQ', a unique, fourth extrinsic protein required for stabilizing the oxygen-evolving complex in the lumenal surface of PSII. The PsbQ' subunit was found to be located underneath CP43 in the vicinity of PsbV, and its structure is characterized by a bundle of four up-down helices arranged in a similar way to those of cyanobacterial and higher plant PsbQ, although helices I and II of PsbQ' were kinked relative to its higher plant counterpart because of its interactions with CP43. Furthermore, two novel transmembrane helices were found in the red algal PSII that are not present in cyanobacterial PSII; one of these helices may correspond to PsbW found only in eukaryotic PSII. The present results represent the first crystal structure of PSII from eukaryotic oxygenic organisms, which were discussed in comparison with the structure of cyanobacterial PSII. PMID- 26757823 TI - Molecular markers for tolerance of European ash (Fraxinus excelsior) to dieback disease identified using Associative Transcriptomics. AB - Tree disease epidemics are a global problem, impacting food security, biodiversity and national economies. The potential for conservation and breeding in trees is hampered by complex genomes and long lifecycles, with most species lacking genomic resources. The European Ash tree Fraxinus excelsior is being devastated by the fungal pathogen Hymenoscyphus fraxineus, which causes ash dieback disease. Taking this system as an example and utilizing Associative Transcriptomics for the first time in a plant pathology study, we discovered gene sequence and gene expression variants across a genetic diversity panel scored for disease symptoms and identified markers strongly associated with canopy damage in infected trees. Using these markers we predicted phenotypes in a test panel of unrelated trees, successfully identifying individuals with a low level of susceptibility to the disease. Co-expression analysis suggested that pre-priming of defence responses may underlie reduced susceptibility to ash dieback. PMID- 26757822 TI - The Deubiquitinase Inhibitor PR-619 Sensitizes Normal Human Fibroblasts to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-mediated Cell Death. AB - TNF-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapy that selectively targets cancer cell death while non-malignant cells remain viable. Using a panel of normal human fibroblasts, we characterized molecular differences in human foreskin fibroblasts and WI-38 TRAIL-resistant cells and marginally sensitive MRC-5 cells compared with TRAIL-sensitive human lung and colon cancer cells. We identified decreased caspase-8 protein expression and protein stability in normal fibroblasts compared with cancer cells. Additionally, normal fibroblasts had incomplete TRAIL-induced caspase-8 activation compared with cancer cells. We found that normal fibroblasts lack the ubiquitin modification of caspase-8 required for complete caspase-8 activation. Treatment with the deubiquitinase inhibitor PR-619 increased caspase-8 ubiquitination and caspase-8 enzymatic activity and sensitized normal fibroblasts to TRAIL-mediated apoptosis. Therefore, posttranslational regulation of caspase-8 confers resistance to TRAIL induced cell death in normal cells through blockade of initiation of the extrinsic cell death pathway. PMID- 26757824 TI - Pterisolic Acid B is a Nrf2 Activator by Targeting C171 within Keap1-BTB Domain. AB - The use of chemoprotective agents to minimize the side effects of the chemotherapy, primarily via activation of the Nrf2 pathway, is an emerging research field, which has attracted broad attention from both academia and pharmaceutical industry. Through high-throughput chemical screens we have disclosed that pterisolic acid B (J19), a naturally occuring diterpenoid, is an effective Nrf2 activator. We have also identified a more potent natural product analogue J19-1 by semisynthesis and the subsequent biochemical evaluations revealed that J19-1 activates the Nrf2 pathway by covalently modifying Cys171 of keap1, which inhibits Nrf2 degradation mediated by Keap1-Cul3 complexes. Ultimately, we have demonstrated that J19-1 shows significant cytoprotective effect against cisplatin-induced cytotoxicity in HKC cells. PMID- 26757825 TI - Down regulated lncRNA MEG3 eliminates mycobacteria in macrophages via autophagy. AB - Small non-coding RNA play a major part in host response to bacterial agents. However, the role of long non-coding RNA (lncRNA) in this context remains unknown. LncRNA regulate gene expression by acting e.g. as transcriptional coactivators, RNA decoys or microRNA sponges. They control development, differentiation and cellular processes such as autophagy in disease conditions. Here, we provide an insight into the role of lncRNA in mycobacterial infections. Human macrophages were infected with Mycobacterium bovis BCG and lncRNA expression was studied early post infection. For this purpose, lncRNA with known immune related functions were preselected and a lncRNA specific RT-qPCR protocol was established. In addition to expression-based prediction of lncRNA function, we assessed strategies for thorough normalisation of lncRNA. Arrayed quantification showed infection-dependent repression of several lncRNA including MEG3. Pathway analysis linked MEG3 to mTOR and PI3K-AKT signalling pointing to regulation of autophagy. Accordingly, IFN-gamma induced autophagy in infected macrophages resulted in sustained MEG3 down regulation and lack of IFN-gamma allowed for counter regulation of MEG3 by viable M. bovis BCG. Knockdown of MEG3 in macrophages resulted in induction of autophagy and enhanced eradication of intracellular M. bovis BCG. PMID- 26757827 TI - Surface passivation of semiconducting oxides by self-assembled nanoparticles. AB - Physiochemical interactions which occur at the surfaces of oxide materials can significantly impair their performance in many device applications. As a result, surface passivation of oxide materials has been attempted via several deposition methods and with a number of different inert materials. Here, we demonstrate a novel approach to passivate the surface of a versatile semiconducting oxide, zinc oxide (ZnO), evoking a self-assembly methodology. This is achieved via thermodynamic phase transformation, to passivate the surface of ZnO thin films with BeO nanoparticles. Our unique approach involves the use of Be(x)Zn(1-x)O (BZO) alloy as a starting material that ultimately yields the required coverage of secondary phase BeO nanoparticles, and prevents thermally-induced lattice dissociation and defect-mediated chemisorption, which are undesirable features observed at the surface of undoped ZnO. This approach to surface passivation will allow the use of semiconducting oxides in a variety of different electronic applications, while maintaining the inherent properties of the materials. PMID- 26757826 TI - Productive Entry of Foot-and-Mouth Disease Virus via Macropinocytosis Independent of Phosphatidylinositol 3-Kinase. AB - Virus entry is an attractive target for therapeutic intervention. Here, using a combination of electron microscopy, immunofluorescence assay, siRNA interference, specific pharmacological inhibitors, and dominant negative mutation, we demonstrated that the entry of foot-and-mouth disease virus (FMDV) triggered a substantial amount of plasma membrane ruffling. We also found that the internalization of FMDV induced a robust increase in fluid-phase uptake, and virions internalized within macropinosomes colocalized with phase uptake marker dextran. During this stage, the Rac1-Pak1 signaling pathway was activated. After specific inhibition on actin, Na(+)/H(+) exchanger, receptor tyrosine kinase, Rac1, Pak1, myosin II, and protein kinase C, the entry and infection of FMDV significantly decreased. However, inhibition of phosphatidylinositol 3-kinase (PI3K) did not reduce FMDV internalization but increased the viral entry and infection to a certain extent, implying that FMDV entry did not require PI3K activity. Results showed that internalization of FMDV exhibited the main hallmarks of macropinocytosis. Moreover, intracellular trafficking of FMDV involves EEA1/Rab5-positive vesicles. The present study demonstrated macropinocytosis as another endocytic pathway apart from the clathrin-mediated pathway. The findings greatly expand our understanding of the molecular mechanisms of FMDV entry into cells, as well as provide potential insights into the entry mechanisms of other picornaviruses. PMID- 26757828 TI - Coexistence of Kabuki Syndrome and Autoimmune Thyroiditis. PMID- 26757829 TI - Static and dynamic electronic characterization of organic monolayers grafted on a silicon surface. AB - Organic layers chemically grafted on silicon offer excellent interfaces that may open up the way for new organic-inorganic hybrid nanoelectronic devices. However, technological achievements rely on the precise electronic characterization of such organic layers. We have prepared ordered grafted organic monolayers (GOMs) on Si(111), sometimes termed self-assembled monolayers (SAMs), by a hydrosilylation reaction with either a 7-carbon or an 11-carbon alkyl chain, with further modification to obtain amine-terminated surfaces. X-ray photoelectron spectroscopy (XPS) is used to determine the band bending (~ 0.3 eV), and ultraviolet photoelectron spectroscopy (UPS) to measure the work function (~ 3.4 eV) and the HOMO edge. Scanning tunneling microscopy (STM) confirms that the GOM surface is clean and smooth. Finally, conductive AFM is used to measure electron transport through the monolayer and to identify transition between the tunneling and the field emission regimes. These organic monolayers offer a promising alternative to silicon dioxide thin films for fabricating metal-insulator semiconductor (MIS) junctions. We show that gold nanoparticles can be covalently attached to mimic metallic nano-electrodes and that the electrical quality of the GOMs is completely preserved in the process. PMID- 26757830 TI - An immunochemical approach to detect oxidized protein tyrosine phosphatases using a selective C-nucleophile tag. AB - Protein tyrosine phosphatases are crucial regulators of signal transduction and function as antagonists towards protein tyrosine kinases to control reversible tyrosine phosphorylation, thereby regulating fundamental physiological processes. Growing evidence has supported the notion that reversible oxidative inactivation of the catalytic cysteine residue in protein tyrosine phosphatases serves as an oxidative post-translational modification that regulates its activity to influence downstream signaling by promoting phosphorylation and induction of the signaling cascade. The oxidation of cysteine to the sulfenic acid is often transient and difficult to detect, thus making it problematic in understanding the role that this oxidative post-translational modification plays in redox biology and pathogenesis. Several methods to detect cysteine oxidation in biological systems have been developed, though targeted approaches to directly detect oxidized phosphatases are still lacking. Herein we describe the development of a novel immunochemical approach to directly profile oxidized phosphatases. This immunochemical approach consists of an antibody designed to recognize the conserved sequence of the PTP active site (VHCDMDSAG) harboring the catalytic cysteine modified with dimedone (CDMD), a nucleophile that chemoselectively reacts with cysteine sulfenic acids to form a stable thioether adduct. Additionally, we provide biochemical and mass spectrometry workflows to be used in conjugation with this newly developed immunochemical approach to assist in the identification and quantification of basal and oxidized phosphatases. PMID- 26757831 TI - Long-term Outcome after Robotic-assisted Gastroplication in Adolescents: Hunger Hormone and Food Preference Changes Two Case Reports. AB - Weight loss surgery (WLS) is efficacious for long-term weight reduction and decreases overall mortality in severely obese patients. The mechanisms implicated in long-term weight loss are not fully understood. Proposed mechanisms include changes in gut hormones and brain regulation of appetite and satiety. We aimed to investigate the long-term ghrelin and leptin profiles and changes in food preference and eating behavior after WLS in adolescent patients. Two obese females aged 15 years and 14 4/12 years, who did not respond to lifestyle changes, including dietary intervention and physical exercise in combination with medical therapy, underwent robotic-assisted gastroplication. Anthropometric measurements, food habits and eating behavior, as well as metabolic and hormonal changes during long-term post-surgical follow-up were monitored. Long-term weight reduction was obtained in both patients, with a significant decrease in waist circumference. Resting energy expenditure showed a decrease over time, with a respiratory quotient that increased showing a shift from oxidation of a high-fat diet before surgery to oxidation of a mixed diet two and three years later. Both subjects improved their eating habits and lifestyle. Co-morbidity resolution was also noted. Increased pre-prandial ghrelin levels as well as higher post-prandial ghrelin and a leptin drop compared with pre-surgery values were observed in both patients. Persistent weight loss after gastroplication is associated with a favorable change in gut hormones and food preferences. The role of hormonal and sensory components in long-term results seems crucial. Particularly in adolescent patients, a multidisciplinary approach and continuous nutritional care is mandatory for weight maintenance and consolidation of changes. PMID- 26757832 TI - Maternal diet during pregnancy and lactation and cow's milk allergy in offspring. AB - BACKGROUND/OBJECTIVES: Diet during pregnancy and lactation may have a role in the development of allergic diseases. There are few human studies on the topic, especially focusing on food allergies. We sought to study the associations between maternal diet during pregnancy and lactation and cow's milk allergy (CMA) in offspring. SUBJECTS/METHODS: A population-based birth cohort with human leukocyte antigen-conferred susceptibility to type 1 diabetes was recruited in Finland between 1997 and 2004 (n=6288). Maternal diet during pregnancy and lactation was assessed by a validated, 181-item semi-quantitative food frequency questionnaire. Register-based information on diagnosed CMA was obtained from the Social Insurance Institution and completed with parental reports. The associations between maternal food consumption and CMA were assessed using logistic regression, comparing the highest and the lowest quarters to the middle half of consumption. RESULTS: Consumption of milk products in the highest quarter during pregnancy was associated with a lower risk of CMA in offspring (odds ratio (OR) 0.56, 95% confidence interval (CI) 0.37-0.86; P<0.01). When stratified by maternal allergic rhinitis and asthma, there was evidence of an inverse association between high use of milk products and CMA in offspring of non allergic mothers (OR 0.30, 95% CI 0.13-0.69, P<0.001). Cord blood IgA correlated positively with the consumption of milk products during pregnancy, indicating exposure to CMA and activation of antigen-specific immunity in the infant during pregnancy. CONCLUSIONS: High maternal consumption of milk products during pregnancy may protect children from developing CMA, especially in offspring of non-allergic mothers. PMID- 26757834 TI - The effect of vitamin D on thyroid autoimmunity in non-lactating women with postpartum thyroiditis. AB - The study included 38 non-lactating l-thyroxine-treated women with postpartum thyroiditis (PPT) and 21 matched healthy postpartum women. Women with vitamin D deficiency were treated with oral vitamin D (4000 IU daily), whereas women with vitamin D insufficiency and women with normal 25-hydroxy vitamin levels were either treated with vitamin D (2000 IU daily) or left untreated. Serum hormone levels and thyroid antibody titers were measured at the beginning of the study and 3 months later. 25-hydroxy vitamin D levels were lower in women with PPT than in healthy women. Thyroid peroxidase and thyroglobulin antibody titers inversely correlated with vitamin D status. Apart from increasing serum levels of 25 hydroxy vitamin D and decreasing serum levels of parathyroid hormone, vitamin D reduced titers of thyroid peroxidase antibodies and this effect was stronger in women with vitamin D deficiency. The study's results suggest that vitamin D supplementation may bring benefits to l-thyroxine-treated women with PPT. PMID- 26757833 TI - Equivalence of afternoon spot and 24-h urinary hydration biomarkers in free living healthy adults. AB - BACKGROUND/OBJECTIVES: Urinary biomarkers of hydration (urine osmolality, UOsm; urine specific gravity, USG) follow circadian variations. For individuals, researchers and health-care professionals, there is value in identifying time frames during which spot values of UOsm and USG are representative of 24-h values in healthy young adults. SUBJECTS/METHODS: Eighty-two free-living adults (22.3+/ 2.9 years, 22.2+/-1.5 kg/m(2)) collected individual urine voids over a 24-h period. UOsm and USG were measured on each void and on the pooled 24-h sample. To determine the time of day when a spot sample was likely to be equivalent to the 24-h value, daytime voids were binned by time and equivalence was tested for each 2-h window. Equivalence was a priori defined as being within 100 mOsm/kg (UOsm) and within 0.003 units (USG) of 24-h values. RESULTS: For both UOsm and USG, voids between 1400 and 2000 hours produced values that were equivalent to the 24 h sample, whereas earlier voids tended to overestimate 24-h UOsm and USG. For windows 1401-1600 hours, 1601-1800 hours and 1801-2000 hours, the mean difference (95% confidence interval) between spot and 24-h UOsm (mOsm/kg) was -25 (-72; 22), 28 (-35; 92) and 12 (-41; 66), respectively, whereas for USG the difference was 0.0014 (-0.0028; -0.0001), 0.0001 (-0.0017; 0.0019) and 0.0005 (-0.0018; 0.0009), respectively. CONCLUSIONS: In free-living healthy French adults, 24-h urine concentration can be approximated from a mid- to late-afternoon spot urine sample. This finding suggests that an afternoon sample may be an accurate and practical tool for hydration monitoring, useful to individuals and health-care practitioners. PMID- 26757835 TI - Effects of dietary saturated and n-6 polyunsaturated fatty acids on the incorporation of long-chain n-3 polyunsaturated fatty acids into blood lipids. AB - BACKGROUND/OBJECTIVES: Omega-3 polyunsaturated fatty acids (n-3PUFA) are better absorbed when they are combined with high-fat meals. However, the role of different dietary fats in modulating the incorporation of n-3PUFA in blood lipids in humans has not been previously explored. Omega-6 polyunsaturated fatty acids (n-6PUFA) are known to compete with n-3PUFA in the metabolic pathways and for the incorporation into phospholipids, whereas saturated fats (SFA) may enhance n 3PUFA incorporation into tissues. SUBJECTS/METHODS: In a randomized parallel design trial, we aimed to investigate the long-term effects of n-3PUFA supplementation in subjects consuming a diet enriched with either SFA or n-6PUFA on fatty acid incorporation into plasma and erythrocytes and on blood lipid profiles (total cholesterol, low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglycerides). RESULTS: Dietary supplementation with n-3PUFA co-administered with SFA for 6 weeks resulted in a significant rise in total cholesterol (0.46+/-0.60 mmol/L; P=0.020) and LDL-C (0.48+/-0.48 mmol/L; P=0.011) in comparison with combination with n-6PUFA. The diet enriched with SFA also induced a greater increase in eicosapentaenoic acid (2.07+/-0.79 vs 1.15+/-0.53; P=0.004), a smaller decrease in docosapentaenoic acid (-0.12+/-0.23 vs -0.30+/-0.20; P=0.034) and a similar increase in docosahexaenoic acid (3.85+/-1.14 vs 3.10+/-1.07; P=0.128) percentage in plasma compared with the diet enriched with n-6PUFA. A similar effect was seen in erythrocytes. N-3PUFA supplementation resulted in similar changes in HDL-C and triglyceride levels. CONCLUSIONS: The results suggest that dietary substitution of SFA with n-6PUFA, despite maintaining low levels of circulating cholesterol, hinders n-3PUFA incorporation into plasma and tissue lipids. PMID- 26757837 TI - Seasonality of food groups and total energy intake: a systematic review and meta analysis. AB - BACKGROUND/OBJECTIVES: The aim of this systematic review and meta-analysis was to assess the effect of season on food intake from selected food groups and on energy intake in adults. SUBJECTS/METHODS: The search process was based on selecting publications listed in the following: Medline, Scopus, Web of Science, Embase and Agris. Food frequency questionnaires, 24-h dietary recalls and food records as methods for assessment of dietary intake were used to assess changes in the consumption of 11 food groups and of energy intake across seasons. A meta analysis was performed. RESULTS: Twenty-six studies were included. Articles were divided into those reporting data on four seasons (winter, spring, summer and autumn) or on two seasons (pre-and post-harvest). Four of the studies could be utilized for meta-analysis describing changes in food consumption across four season scheme: from winter to spring fruits decreased, whereas vegetables, eggs and alcoholic beverages increased; from spring to summer vegetable consumption further increased and cereals decreased; from summer to autumn fruits and cereals increased and vegetables, meat, eggs and alcoholic beverages decreased; from autumn to winter cereals decreased. A significant association was also found between energy intake and season, for 13 studies reporting energy intake across four seasons (favors winter) and for eight studies across pre- and post-harvest seasons (favors post-harvest). CONCLUSIONS: The winter or the post-harvest season is associated with increased energy intake. The intake of fruits, vegetables, eggs, meat, cereals and alcoholic beverages is following a seasonal consumption pattern and at least for these foods season is determinant of intake. PMID- 26757838 TI - The effects of nutritional interventions on recurrence in survivors of colorectal adenomas and cancer: a systematic review of randomised controlled trials. AB - BACKGROUND/OBJECTIVES: Nutrition and dietary supplementation may modulate outcomes in colorectal cancer (CRC) survivors. However, no recent systematic review has focused on randomised controlled trials (RCTs). The aim of this systematic review was to examine the effects of nutritional RCTs in survivors of colorectal adenomas and cancer. SUBJECTS/METHODS: Medline, Embase, Scopus, Web of Science and the Cochrane Library were searched to identify research between April 2006 and January 2014. The primary outcomes were colorectal adenoma and cancer recurrence. Each included study was assessed for risk of bias. A meta-analysis using a random-effects model was performed, in which two or more RCTs investigated the same dietary intervention. RESULTS: Eight completed RCTs, all in colorectal adenoma survivors, were identified, with four investigating the effect of folic acid. A meta-analysis of the four folic acid RCTs showed no statistically significant effect of folic acid on colorectal adenoma recurrence (relative risks=0.93; 95% confidence interval: 0.69, 1.25). The impact of the remaining completed RCTs, investigating antioxidant supplementation, green tea extract, prebiotic fibre and phytooestrogens/insoluble fibre, could not be reliably estimated because of the limited number and heterogeneity of the interventions. In addition, three heterogeneous ongoing RCTs were identified, investigating green tea (n=1) and eicosapentaenoic acid (n=1) in colorectal adenoma survivors and dietary modifications (n=1) in CRC survivors in remission. CONCLUSIONS: Overall, this systematic review highlights the need for further research, especially in CRC survivors, as we identified no completed and only one ongoing RCT in this population. PMID- 26757836 TI - Whole-blood fatty acids and inflammation in European children: the IDEFICS Study. AB - BACKGROUND/OBJECTIVES: Fatty acids are hypothesized to influence cardiovascular disease risk because of their effect on inflammation. The aim of this study is to assess the relationship between whole-blood fatty acids (WBFAs) and high sensitivity C-reactive protein (hs-CRP) in European children. SUBJECTS/METHODS: A total of 1401 subjects (697 boys and 704 girls) aged between 2 and 9 years from the IDEFICS (Identification and prevention of Dietary- and lifestyle-induced health EFfects in Children and infantS) study were measured in this cross sectional analysis. The sample was divided into three categories of hs-CRP. Associations between WBFA and hs-CRP were assessed by logistic regression models adjusting for body mass index (BMI), country, age, breastfeeding, mother's education and hours of physical activity. RESULTS: Linoleic acid (LA) (P=0.013, 95% confidence interval (CI): 0.822-0.977) and sum of n-6 WBFA (P=0.029, 95% CI: 0.866-0.992) concentrations were associated with lower concentrations of hs-CRP in boys. In girls, a high ratio of eicosapentaenoic acid (EPA)/arachidonic acid (AA) was associated (P=0.018, 95% CI: 0.892-0.989) with lower hs-CRP concentrations. In contrast, sum of blood n-6 highly unsaturated fatty acids (P=0.012, 95% CI: 1.031-1.284), AA (P=0.007, 95% CI: 1.053-1.395) and AA/LA ratio (P=0.005, 95% CI: 1.102-1.703) were associated (P<0.05) with higher concentrations of hs-CRP in girls. CONCLUSIONS: The n-6 WBFAs (sum of n-6 FA and LA) were associated with lower hs-CRP in boys and with higher hs-CRP in girls (AA, sum of n-6 highly unsaturated and AA/LA ratio). More studies are needed to identify the optimal levels of WBFAs to avoid low-grade inflammation in children considering the differences by sex and BMI. PMID- 26757842 TI - Electron beam controlled covalent attachment of small organic molecules to graphene. AB - The electron beam induced functionalization of graphene through the formation of covalent bonds between free radicals of polyaromatic molecules and C=C bonds of pristine graphene surface has been explored using first principles calculations and high-resolution transmission electron microscopy. We show that the energetically strongest attachment of the radicals occurs along the armchair direction in graphene to carbon atoms residing in different graphene sub lattices. The radicals tend to assume vertical position on graphene substrate irrespective of direction of the bonding and the initial configuration. The "standing up" molecules, covalently anchored to graphene, exhibit two types of oscillatory motion--bending and twisting--caused by the presence of acoustic phonons in graphene and dispersion attraction to the substrate. The theoretically derived mechanisms are confirmed by near atomic resolution imaging of individual perchlorocoronene (C24Cl12) molecules on graphene. Our results facilitate the understanding of controlled functionalization of graphene employing electron irradiation as well as mechanisms of attachment of impurities via the processing of graphene nanoelectronic devices by electron beam lithography. PMID- 26757839 TI - (13)C mixed triglyceride breath testing using infrared spectrometry: comparison of two devices in early infancy. AB - BACKGROUND/OBJECTIVES: The (13)C mixed triglyceride (MTG) breath test has been proposed for the non-invasive assessment of fat digestion and absorption. To evaluate whether reference values for the adequacy of fat absorption, set in the non-dispersive infrared spectrometry (NDIRS) system software proposed for healthy children and adults using the (13)C MTG breath test, are also applicable to infants of <5 months of age. SUBJECTS/METHODS: (13)C MTG breath testing with the NDIRS technique was performed in 54 healthy infants <5 months of age (38 breast fed, 16 formula-fed) and six infants diagnosed with cystic fibrosis (CF) using two NDIRS devices, IRIS and FANci2. RESULTS: The IRIS results were slightly higher compared with those assessed by the FANci2 device. The minimum cutoff value for pancreatic sufficiency (PS) is set as a cumulative percentage dose of (13)C recovered (cPDR) after 5 h of 13.0%. Pancreatic function status of six CF infants, three with PS and three with pancreatic insufficiency (PI), according to the 72 h-faecal fat balance test could be correctly determined with the (13)C MTG breath test using two NDIRS techniques. However, if these reference values had been used to determine pancreatic function status in healthy infants, 26 out of 54 infants would have been misclassified as pancreatic insufficient. CONCLUSIONS: Although the (13)C MTG breath test with the MS technique has the potential to be a suitable assessment of fat absorption in infants, the technique of NDIRS appears too insensitive in an infant population group. PMID- 26757840 TI - Support for the Microgenderome: Associations in a Human Clinical Population. AB - The 'microgenderome' provides a paradigm shift that highlights the role of sex differences in the host-microbiota interaction relevant for autoimmune and neuro immune conditions. Analysis of cross-sectional self-report and faecal microbial data from 274 patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) suggests that commensal gut microorganisms may play both protective and deleterious roles in symptom expression. Results revealed significant sex specific interactions between Firmicutes (Clostridium, Streptococcus, Lactobacillus and Enterococcus) and ME/CFS symptoms (including neurological, immune and mood symptoms), regardless of compositional similarity in microbial levels across the sexes. Extending animal studies, we provide support for the microgenderome in a human clinical population. Applied and mechanistic research needs to consider sex-interactions when examining the composition and function of human microbiota. PMID- 26757847 TI - RNA recombination in Hepatitis delta virus: Identification of a novel naturally occurring recombinant. AB - BACKGROUND/PURPOSE: Hepatitis delta virus (HDV) is the only animal RNA virus that has an unbranched rod-like genome with ribozyme activity. It replicates in the nucleus by host RNA polymerase via a rolling circle mechanism. Similar to many RNA viruses encoding their own RNA-dependent RNA polymerases, homologous recombination of HDV occurs in mixed-genotype infections and in cultured cells cotransfected with two HDV sequences, as demonstrated by molecular analyses. METHODS: Among 237 published complete genomic sequences, 34 sequences were reported from the small and isolated Miyako Island, Japan, and belonged to the Asia-specific genotypes, HDV-2 and HDV-4 (the majority of them belonged to the known Miyako Island-specific subgroup, HDV-4M). We investigated the presence of naturally occurring HDV recombinant in Miyako Island using phylogenetic and recombination analyses. RESULTS: We identified a two-switch HDV-4/4M intersubtype recombinant with an unbranched rod-like RNA genome. CONCLUSION: Our data suggest that RNA recombination plays an important role in the rapid evolution of HDV, allowing the production of new HDV strains with correct genomic structures. PMID- 26757848 TI - Comparative assessment of humoral immune responses of aluminum hydroxide and oil emulsion adjuvants in Influenza (H9N2) and Newcastle inactive vaccines to chickens. AB - Context Adjuvants are compounds used in the preparation of inactive vaccines to enhance the immune response. Aluminum hydroxide (alum) is one of the first compounds approved by the Food and Drug Administration, which is used as adjuvants in vaccine products for humans. Montanide ISA 70 is an oil-emulsion adjuvant and is used in poultry inactive vaccines. Objective In this study, the effects of alum adjuvant on the efficiency and induction of immune response in inactive vaccines of Influenza and Newcastle are compared with those of ISA 70. Materials and methods Six groups of 7-d-old specific-pathogen-free chickens were inoculated with 0.3 ml of the prepared vaccines via the subcutaneous route in the neck. Immune response in each group after 7, 14, 21, 31, 41, and 45 d was evaluated using the technique of hemagglutination inhibition. Results The results were compared using SPSS software. Results showed that vaccines containing adjuvant ISA 70 depicted a higher increase in the immune response and adjuvant of 20% alum is similar to adjuvant of ISA 70 in boosting the immune system. There was no statistically significant difference between 10% and 20% alum, but these adjuvants are visibly different from ISA 70. Conclusion In conclusion, alum can be used as an easily accessible, harmless, and effective adjuvant; however, to increase the immune period using the inactive vaccines for poultry, more research would be necessary. PMID- 26757856 TI - Durable and scalable icephobic surfaces: similarities and distinctions from superhydrophobic surfaces. AB - Formation, adhesion, and accumulation of ice, snow, frost, glaze, rime, or their mixtures can cause severe problems for solar panels, wind turbines, aircrafts, heat pumps, power lines, telecommunication equipment, and submarines. These problems can decrease efficiency in power generation, increase energy consumption, result in mechanical and/or electrical failure, and generate safety hazards. To address these issues, the fundamentals of interfaces between liquids and surfaces at low temperatures have been extensively studied. This has lead to development of so called "icephobic" surfaces, which possess a number of overlapping, yet distinctive, characteristics from superhydrophobic surfaces. Less attention has been given to distinguishing differences between formation and adhesion of ice, snow, glaze, rime, and frost or to developing a clear definition for icephobic, or more correctly pagophobic, surfaces. In this review, we strive to clarify these differences and distinctions, while providing a comprehensive definition of icephobicity. We classify different canonical families of icephobic (pagophobic) surfaces providing a review of those with potential for scalable and robust development. PMID- 26757850 TI - Ozone Gas as a Benign Sterilization Treatment for PLGA Nanofiber Scaffolds. AB - The use of electrospun nanofibers for tissue engineering and regenerative medicine applications is a growing trend as they provide improved support for cell proliferation and survival due, in part, to their morphology mimicking that of the extracellular matrix. Sterilization is a critical step in the fabrication process of implantable biomaterial scaffolds for clinical use, but many of the existing methods used to date can negatively affect scaffold properties and performance. Poly(lactic-co-glycolic acid) (PLGA) has been widely used as a biodegradable polymer for 3D scaffolds and can be significantly affected by current sterilization techniques. The aim of this study was to investigate pulsed ozone gas as an alternative method for sterilizing PLGA nanofibers. The morphology, mechanical properties, physicochemical properties, and response of cells to PLGA nanofiber scaffolds were assessed following different degrees of ozone gas sterilization. This treatment killed Geobacillus stearothermophilus spores, the most common biological indicator used for validation of sterilization processes. In addition, the method preserved all of the characteristics of nonsterilized PLGA nanofibers at all degrees of sterilization tested. These findings suggest that ozone gas can be applied as an alternative method for sterilizing electrospun PLGA nanofiber scaffolds without detrimental effects. PMID- 26757849 TI - An Overview of Fractional Exhaled Nitric Oxide and Children with Asthma. AB - Asthma is the most common pediatric chronic disease and is characterized by lung inflammation. Fractional exhaled nitric oxide (FeNO) is thought to reflect the presence of eosinophilic airway inflammation, and is an easy, non-invasive test that has held promise in providing additional objective data. However, not all studies have shown a clinical benefit in the use of FeNO to guide management of asthma in children. This review will describe the results of the most recent studies examining the use of FeNO in the diagnosis and treatment of asthma in infants, preschool-aged children and in school-aged children. It will aid the clinician in providing a clinical context in which FeNO may be most useful in treating pediatric asthma. PMID- 26757857 TI - Choice of crystal surface finishing for a dual-ended readout depth-of-interaction (DOI) detector. AB - The objective of this study was to choose the crystal surface finishing for a dual-ended readout (DER) DOI detector. Through Monte Carlo simulations and experimental studies, we evaluated 4 crystal surface finishing options as combinations of crystal surface polishing (diffuse or specular) and reflector (diffuse or specular) options on a DER detector. We also tested one linear and one logarithm DOI calculation algorithm. The figures of merit used were DOI resolution, DOI positioning error, and energy resolution. Both the simulation and experimental results show that (1) choosing a diffuse type in either surface polishing or reflector would improve DOI resolution but degrade energy resolution; (2) crystal surface finishing with a diffuse polishing combined with a specular reflector appears a favorable candidate with a good balance of DOI and energy resolution; and (3) the linear and logarithm DOI calculation algorithms show overall comparable DOI error, and the linear algorithm was better for photon interactions near the ends of the crystal while the logarithm algorithm was better near the center. These results provide useful guidance in DER DOI detector design in choosing the crystal surface finishing and DOI calculation methods. PMID- 26757858 TI - Synthesis and antitumor activity evaluation of lamiridosin A derivatives. AB - A series of lamiridosin A derivatives were synthesized through simple procedures. Their antitumor activities were evaluated against EC9706, MGC803, and B16 cell lines in vitro. Several compounds showed potent antitumor activity, especially compound 10, with IC50 value of 2.36 MUmol/L against MGC803 cell lines, is more potent than marketed positive drug 5-fluorouridine (5-FU). PMID- 26757859 TI - Occupational life trajectories in the context of chronic pain and immigration. AB - BACKGROUND: Persons with chronic pain report a range of occupational problems. The specific health needs of immigrants are judged to be poorly understood, and health systems are not prepared to respond adequately. Being an immigrant is regarded as a risk factor for the progression of chronic widespread pain into a state of disability. OBJECTIVES: To explore occupational life trajectories among immigrant women with chronic pain. MATERIAL AND METHODS: A qualitative content analysis was used to capture the latent meaning of experiences in individual interviews of eight women with immigrant background and chronic pain. RESULTS: An overarching theme, 'making the best of a conditional situation', representing the women's occupational life trajectories, covers the content of two categories: 'being controlled', including affected self-perception, social relations, and future prospects, and 'trying to deal with challenges', comprising a focus on resources, having trust in one's own judgements and getting help from others. CONCLUSION AND SIGNIFICANCE: The experiences demonstrate an occupational life controlled by internal and external factors and may be understood as a disrupted occupational life trajectory. This knowledge may be helpful to occupational therapists supporting immigrant women's attempts to regain a structured life despite the constant presence of pain. PMID- 26757855 TI - Traumatic Brain Injury Causes Endothelial Dysfunction in the Systemic Microcirculation through Arginase-1-Dependent Uncoupling of Endothelial Nitric Oxide Synthase. AB - Endothelial dysfunction is a hallmark of many chronic diseases, including diabetes and long-term hypertension. We show that acute traumatic brain injury (TBI) leads to endothelial dysfunction in rat mesenteric arteries. Endothelial dependent dilation was greatly diminished 24 h after TBI because of impaired nitric oxide (NO) production. The activity of arginase, which competes with endothelial NO synthase (eNOS) for the common substrate l-arginine, were also significantly increased in arteries, suggesting that arginase-mediated depletion of l-arginine underlies diminished NO production. Consistent with this, substrate restoration by exogenous application of l-arginine or inhibition of arginase recovered endothelial function. Moreover, evidence for increased reactive oxygen species production, a consequence of l-arginine starvation-dependent eNOS uncoupling, was detected in endothelium and plasma. Collectively, our findings demonstrate endothelial dysfunction in a remote vascular bed after TBI, manifesting as impaired endothelial-dependent vasodilation, with increased arginase activity, decreased generation of NO, and increased O2- production. We conclude that blood vessels have a "molecular memory" of neurotrauma, 24 h after injury, because of functional changes in vascular endothelial cells; these effects are pertinent to understanding the systemic inflammatory response that occurs after TBI even in the absence of polytrauma. PMID- 26757860 TI - [Effect of VKORC1 and CYP2C9 variants on dosage of oral anticoagulants in Chilean individuals]. AB - BACKGROUND: The dose of oral anticoagulants (OAC) shows great variability among patients. Pharmacogenetic studies have shown that common variants in genes CYP2C9 (*2 and *3) and VKORC1 (-1639G>A) are associated with lower requirements of OAC. AIM: To study the association between average maintenance doses of oral anticoagulant therapy required to maintain a stable INR and CYP2C9 and VKORC1 gene variants in Chilean adults. MATERIAL AND METHODS: Prospective study of patients on anticoagulant treatment and with a stable international normalized ratio (INR) for prothrombin time for at least three months. Patients were classified as having high or low acenocoumarol or warfarin requirements. Peripheral blood DNA genotyping was performed by polymerase chain reaction and restriction fragment polymorphism or sequencing and electrophoresis. RESULTS: The study included 185 patients, 125 on acenocoumarol and 60 on warfarin. Patients with VKORC1-1639A allele were more likely to require lower doses of both drugs than patients with the G allele (Odds ratio [OR] for acenocoumarol 9.06, and OR for warfarin = 18.7). There was no association between CYP2C9*2 and*3 and acenocoumarol or warfarin requirements. CONCLUSIONS: There is an association between VKORC1-1639A variant and anticoagulant doses. PMID- 26757861 TI - [Association between genotype and allele frequencies of CYP2A6*12 and rs16969968 in CHRNA5 variants with smoking and body mass index in young subjects from Northeast Mexico]. AB - BACKGROUND: Several studies have reported that variants rs16969968 G>A of the CHRNA5 gene and CYP2A6*12 of the CYP2A6 gene are associated with smoking and smoking refusal, respectively. In addition, some studies report that a higher cigarette consumption is associated with low body mass index (BMI). AIM: To analyze the allele and genotypic frequencies of these variants and their impact on smoking and BMI. MATERIAL AND METHODS: A blood sample was obtained and a survey about smoking habits was answered by 319 university students aged 18 to 35 years (127 women, 171 smokers), living in Northeastern Mexico. Genetic variants were studied by polymerase chain reaction/restriction fragment length polymorphism and their frequencies were associated with smoking and BMI. RESULTS: No associations were found between the analyzed variants and smoking in the study groups. However, there was an association among non-smoking subjects between the A allele of rs16969968 and high a BMI (p < 0.01). CONCLUSIONS: This last variant may be involved in food-addiction disorders. PMID- 26757863 TI - [Learning during the early clinical years takes more than good study habits: Perceptions of students and teachers]. AB - BACKGROUND: Teaching methods of the undergraduate medical curriculum change considerably from the first years to clinical training. Clinical learning occurs in complex and varied scenarios while caring for patients. Students have to adapt their learning approaches and strategies to be able to integrate theory and clinical practice and become experiential learners. AIM: To identify the strategies used by medical students to learn during the initial clinical years, as reported by students themselves and by their clinical tutors. MATERIAL AND METHODS: We performed eight focus group discussions with 54 students enrolled in years three to six and we interviewed eight clinical tutors. Both focus group discussions and interviews were audio recorded, transcribed and analyzed according to Grounded Theory. RESULTS: Four main themes were identified in the discourse of both students and tutors: Strategies oriented to theoretical learning, strategies oriented to experiential learning, strategies for integrating theory and practice and strategies oriented to evaluation. The mentioning of individual differences was present across the reports of both students and tutors. CONCLUSIONS: Students use a rich variety of strategies to face the challenges of clinical learning. Both students and tutors recognize that the learning approaches and strategies vary according the nature of the task and individual differences. The responses of students bring particular knowledge of the approaches used for the theoretical and practical integration and delve into the social dimension of learning. PMID- 26757862 TI - [Spirometric values in healthy Chilean children and adolescents]. AB - BACKGROUND: Spirometric flow and volume measurement are essential to evaluate patients with pulmonary disease. In Chile, several reference equations are used. AIM: To measure flow and expiratory volumes in healthy children and adolescents and compare their results with theoretical values according to Knudson, Quanjer, Gutierrez and NANHES III. SUBJECTS AND METHODS: Spirometries were performed according to international standards in 1589 healthy children and adolescents aged 6 to 18 years (861 females) who lived in Santiago, Chile. RESULTS: The obtained values for forced vital capacity, expiratory volume in one second, peak expiratory flow, were significantly higher than those calculated according to the above mentioned standards (p < 0.0001) with differences up to 18.7%. We constructed reference formulas for ages ranging from 6 to 18 years, separated by gender, using age, weight and height as independent variables. The latter had the greater influence on formula construction. CONCLUSIONS: The use of these new local formulas with allow the correct interpretation of spirometric results obtained in Chilean children and adolescents. PMID- 26757864 TI - [A survey about the criteria for the indication of a gastrostomy in patients with advanced dementia]. AB - BACKGROUND: Decision making concerning patients with advanced dementia is complicated. The indication of a gastrostomy is among these hard decisions, especially considering that there is no consensus about its real benefit. AIM: To explore the criteria used by Chilean physicians to indicate a gastrostomy in patients with advanced dementia. MATERIAL AND METHODS: A questionnaire about the decision making to indicate a gastrostomy was delivered to 72 physicians working in public and private hospitals. RESULTS: The survey was answered by 43 physicians. Fifty one percent had indicated a gastrostomy to patients with advanced dementia in the last year, 79% believed that gastrostomy reduces the risk of aspiration pneumonia, 50% thought that gastrostomy helps in bed sore healing and 74% believed that gastrostomy improves survival. CONCLUSIONS: The majority of physicians who answered the survey think that gastrostomy will improve the health status of patients with advanced dementia. PMID- 26757866 TI - [An organ allocating system for transplantation that does not consider donor and recipient ages is not fair]. AB - BACKGROUND: Kidney transplantation is the best treatment for end stage kidney disease. The allograft allocation system considers immunological factors and time in waiting list, but not the age of donors or recipients, in spite that both have prognostic relevance. AIM: To study the fairness of the allograft allocation system considering the age of donors and recipients. MATERIAL AND METHODS: Based in the age distribution of donors and waiting list of patients for kidney transplantation, we constructed probability functions for receiving a graft as an allocation system based on age changes from a strict to a more lax criteria. Finally, we compared our model with the real transplants performed during 2012. RESULTS: The probability distribution for receiving a kidney transplantation is displaced to the right compared with the age distribution of graft donors. This gap increases as the procuring hospitals enlist progressively older graft candidates without accepting older donors in parallel. An allocation system that maintains age parity between donors and recipients is fairer that other that allows lax criteria for the same allocation. This phenomenon is attenuated if the procurement acceptance criterion allows older donors. CONCLUSIONS: It is necessary to reduce the gap between donor and recipient ages for kidney transplantation to improve the fairness of the graft allocation system. PMID- 26757865 TI - [Levels of physical activity among colombian university students]. AB - BACKGROUND: Physical inactivity is an important risk factor for chronic diseases in Western societies. AIM: To determine the sociodemographic and motivational factors associated with physical activity in college students. MATERIAL AND METHODS: The International Physical Activity Questionnaire (IPAQ) -short form- and the "motives for physical activities measure-revised" (MPAM-R) questionnaire were applied to 900 university students aged 20 +/- 3 years (60% women). The frequency, level and motivations for engaging in physical activity and associated demographic factors were analyzed. RESULTS: Twenty two percent of students were classified as having a high level of physical activity, 54.8% had a low level and 13.9% were considered inactive. According to MET consumption, 68.9% of students are inactive and only 16.8% of students classified as very active. Ninety two percent of active students performed physical activity for health reasons. A significant association between gender and social motivation was observed. CONCLUSIONS: A high prevalence of physical inactivity was found in these students. Males showed higher levels of physical activity than females. PMID- 26757867 TI - [Follow-up of patients with good exercise capacity in stress test with myocardial single-photon emission computed tomography (SPECT)]. AB - BACKGROUND: The evaluation of coronary artery disease (CAD) can be performed with stress test and myocardial SPECT tomography. AIM: To assess the predictive value of myocardial SPECT using stress test for cardiovascular events in patients with good exercise capacity. MATERIAL AND METHODS: We included 102 males aged 56 +/- 10 years and 19 females aged 52 +/- 10 years, all able to achieve 10 METs and >= 85% of the theoretical maximum heart rate and at least 8 min in their stress test with gated 99mTc-sestamibi SPECT. Eighty two percent of patients were followed clinically for 33 +/- 17 months. RESULTS: Sixty seven percent of patients were studied for CAD screening and the rest for known disease assessment. Treadmill stress test was negative in 75.4%; 37% of patients with moderate to severe Duke Score presented ischemia. Normal myocardial perfusion SPECT was observed in 70.2%. Reversible defects appeared in 24.8% of cases, which were of moderate or severe degree (> 10% left ventricular extension) in 56.6%. Only seven cases had coronary events after the SPECT. Two major (myocardial infarction and emergency coronary revascularization) and 5 minor events (elective revascularization) ere observed in the follow-up. In a multivariate analysis, SPECT ischemia was the only statistically significant parameter that increased the probability of having a major or minor event. CONCLUSIONS: Nearly a quarter of our patients with good exercise capacity demonstrated reversible defects in their myocardial perfusion SPECT. In the intermediate-term follow-up, a low rate of cardiac events was observed, being the isotopic ischemia the only significant predictive parameter. PMID- 26757868 TI - [Higher physical activity levels are associated with lower prevalence of cardiovascular risk factors in Chile]. AB - BACKGROUND: Little is known about the relationship between physical activity (PA) and cardiovascular risk factors in the Chilean population. AIM: To investigate the association between different levels and intensities of PA and the prevalence of cardiovascular (CV) risk factors in Chilean adults. MATERIAL AND METHODS: Data from the National Health Survey 2009-10 including 5157 participants, provided by the Epidemiology Department of the Ministry of Health, was analyzed in this study. The prevalence of type 2 diabetes mellitus, hypertension, metabolic syndrome and dyslipidemia were determined using international criteria. PA levels were determined using the Global Physical Activity Questionnaire (GPAQ v2) and different levels of PA were derived from it (transport-related, moderate and vigorous PA). Quartiles of PA were determined to investigate the association between PA and cardiovascular risk factors. RESULTS: Twenty three percent of women and 17.1% of men did not meet the PA recommendation (>= 600 METs.min.week 1). When prevalence of CV risk factors were compared between inactive individuals (< 600 METs.min.week-1) and active individuals (>= 9500 METs.min.week-1) a significantly lower prevalence of diabetes mellitus (6.2% and 10%), hypertension (18.0% and 12.4%) and metabolic syndrome (8.9% and 12.1%) for women and men, respectively, was found in the active participants. Similar results were found for high versus low transport-related PA. CONCLUSIONS: Increasing levels of PA are associated with a significantly lower frequency of cardiovascular risk factors in Chilean adults. PMID- 26757869 TI - [Ebola: characterization, history and cutaneous manifestations]. AB - Ebola virus (EV) is one of the most virulent human pathogens. Fruits bats are its natural reservoir, the transmission to humans is across wild animals (especially primates) and the propagation in human populations is through bodily fluid contact. The actual outbreak started in December 2013 and crossed continental borders. Up to now, there are 17,145 suspected and confirmed cases with 6,070 deaths, resulting a total case fatality rate of 35%. Clinical manifestations can be divided in 3 phases. In phase I, symptoms are similar to flu, which may appear in a range of 2 to 21 days. In phase II which occurs in over 50% of cases, visceral symptoms and mucocutaneous manifestations appear within 4 and 5 days of the onset of symptoms. The main symptoms are a macular or maculopapular non pruritic rash, desquamation and mucosal involvement of eyes, mouth and pharynx. In phase III, recovery or death occurs. The diagnosis is made on clinical grounds, epidemiological suspicion and a positive polymerase chain reaction (PCR) test. The treatment is supportive. If there is a suspected case, it should be notified immediately and all relevant safety measures should be instituted. PMID- 26757870 TI - [Sezary syndrome treated with extracorporeal photopheresis: Report of one case]. AB - Sezary syndrome (SS) is an unusually aggressive T- cell lymphoma characterized by the triad of erythroderma, the presence of more than 1,000 Sezary cells in peripheral blood and lymphadenopathies. It is accompanied by generalized pruritus and poor quality of life. The management of SS depends on its stage, patient comorbidities, and treatment availability. Extracorporeal photopheresis (ECP) is the first line of treatment for patients with T-cell lymphomas in stage IVA1, IVA2 or SS. This treatment comprises three phases: leukapheresis, photoactivation and subsequent reinfusion of lymphocytes. As it is an immunomodulatory therapy it does not produce generalized immunosuppression. We report a 76 year-old male with SS stage IIIb initially treated with 12 sessions of ultraviolet phototherapy without response. After 10 well-tolerated sessions of ECP, itching and skin lesions eventually disappeared. PMID- 26757871 TI - [Assessment of psychometric properties of the academic involvement questionnaire, expectations version]. AB - BACKGROUND: Academic Involvement Questionnaire, Expectations version (CIA-A), assesses the expectations of involvement in studies. It is a relevant predictor of student success. However, the evidence of its validity and reliability in Chile is low, and in the case of Medical students, there is no evidence at all. AIM: To evaluate the factorial structure and internal consistency of the CIA-A in Chilean Medical school freshmen. MATERIAL AND METHODS: The survey was applied to 340 Medicine freshmen, chosen by non-probability quota sampling. They answered a back-translated version of CIA-A from Portuguese to Spanish, plus a sociodemographic questionnaire. For psychometric analysis of the CIA-A, an exploratory factor analysis was carried on, the reliability of the factors was calculated, a descriptive analysis was conducted and their correlation was assessed. RESULTS: Five factors were identified: vocational, institutional and social involvement, use of resources and student participation. Their reliabilities ranged between Cronbach's alpha values of 0.71 to 0.87. Factors also showed statistically significant correlations between each other. CONCLUSIONS: Identified factor structure is theoretically consistent with the structure of original version. It just disagrees in one factor. In addition, the factors' internal consistency were adequate for using them in research. This supports the construct validity and reliability of the CIA-A to assess involvement expectations in medical school freshmen. PMID- 26757872 TI - [Adequacy of nutritionist (dietician) resources in Chilean public hospitals]. AB - BACKGROUND: Human resource deficit is an important management problem in Chilean public hospitals. AIM: To analyze the adequacy of Nutritionist (Dietician) resources in public hospitals. MATERIAL AND METHODS: A questionnaire about Nutritionist resources was sent to head Nutritionists of all public Chilean hospitals, asking about the number of Nutritionists per service, number of hospital beds and number of daily rations served. Results were analyzed based on the Technical Guideline about Nutritional and Feeding Services of public hospitals issued by the Chilean Ministry of Health in 2005. RESULTS: According to the guideline, there should be 1,396 nutritionists working in public hospitals and the results of the survey showed that there were only 603 professionals with a 57% deficit. CONCLUSIONS: There is a huge gap between the amount of Nutritionists (Dieticians) required and those effectively working in public hospitals. PMID- 26757873 TI - [An ethical and medical perspective on the voluntary termination of pregnancy]. AB - "Voluntary termination of pregnancy" can refer to actions intended to make a delivery easier, to provide medical care to the fetus, or to protect the life or health of the mother. All of these are proper medical actions and are by definition voluntary. In other cases, the expression denotes a termination of pregnancy before the embryo or fetus is viable, leading to the death of the latter. This action is constitutive of abortion under current Chilean law. The product of conception living being, who develops in the womb during pregnancy, is an individual, both in the sense that it is different from its mother and father, and in that it is a biological individual. For these reasons, such living being constitutes another patient in itself. The free and voluntary medical action of health care professionals is geared toward disease prevention or health recovery and medical terminations of pregnancy, as distinguished from abortion, are not criminalized in our country. Therefore, the idea of legalizing abortive terminations of pregnancy so that they become "legitimate health care services" is a call to the medical community, which should engage in a debate about the meaning and consequences of an eventual mandate of the State that would be at odds with the Hippocratic tradition. A woman can feel that her health is at risk due to her pregnancy, and she certainly has the right to request medical help. Health professionals should care both at the medical and emotional level for all those who require their services, especially when such persons are undergoing situations of vulnerability and distress. When requested to perform an abortion, the physician faces dilemmas that should be addressed in line with the present state of the medical art. PMID- 26757874 TI - [Fatal toxic leukoencephalopathy associated with consumption of pasta base of cocaine: Report of three cases]. AB - The prevalence of drug-associated toxic encephalopathy is unknown, but it is an uncommon condition. Toxic leukoencephalopathy was described associated with heroin consumption, it has been less commonly described with the use of cocaine and there are no reports of its association with consumption pasta base of cocaine (PBC). We report two females aged 31 years and a male aged 19 years, consumers of PBC who developed a fatal toxic leukoencephalopathy. They initiated their disease with severe and persistent headache, sequential focal neurologic deficits and a progressive impairment of consciousness that culminated with their death. Laboratory parameters such as blood count, cerebrospinal fluid analyses or infectious biological indices were normal. MRI showed multifocal lesions in brain white matter of both hemispheres confirming the leukoencephalopathy. There was no response to the use of methylprednisolone. PMID- 26757875 TI - [Isolated factor X deficiency in chronic myelomonocytic leukemia: Report of one case]. AB - Bleeding disorders are commonly associated with hemato-oncologic diseases. We report a 68 years old male with a chronic myelomonocytic leukemia derived from a long lasting mielodysplastic syndrome that did not respond to treatment with Azacitidine. The patient was hospitalized due to tonic clonic seizures. A CAT scan showed a hematoma in the frontal lobe. A new assessment of hemostasis revealed an isolated deficiency of Factor X. We speculate that this deficit could be secondary to consumption due to the chronic Myelomonocytic Leukemia. PMID- 26757876 TI - [Gender perspective and vulnerability in health: when do we start to involve men?]. PMID- 26757877 TI - [A new imaging diagnostic tool by magnetic resonance in Parkinson's Disease: Visualization of Nigrosome 1]. PMID- 26757878 TI - An iron(ii) hydride complex of a ligand with two adjacent beta-diketiminate binding sites and its reactivity. AB - After lithiation of PYR-H2 (PYR = [(NC(Me)C(H)C(Me)NC6H3(iPr)2)2(C5H3N)](2-)) - the precursor of an expanded beta-diketiminato ligand system with two binding pockets - with KN(TMS)2 the reaction of the resulting potassium salt with FeBr2 led to a dinuclear iron(ii) bromide complex [(PYR)Fe(MU-Br)2Fe] (1). Through treatment with KHBEt3 the bromide ligands could be replaced by hydrides to yield [PYR)Fe2(MU-H)2] (2), a distorted analogue of known beta-diketiminato iron hydride complexes, as evidenced by NMR, Mobetabauer and X-ray absorption spectroscopy, as well as by its reactivity: for instance, 2 reacts with the proton source lutidinium triflate via protonation of the hydride ligands to form an iron(ii) product [(PYR)Fe2(OTf)2] (4), while CO2 inserts into the Fe-H bonds generating the formate complex [(PYR)Fe2(MU-HCOO)2] (5); in the presence of traces of water partial hydrolysis occurs so that [(PYR)Fe2(MU-OH)(MU-HCOO)] (6) is isolated. Altogether, the iron(ii) chemistry supported by the PYR(2-) ligand is distinctly different from the one of nickel(ii), where both, the arrangement of the two binding pockets and the additional pyridyl donor led to diverging features as compared with the corresponding system based on the parent beta diketiminato ligand. PMID- 26757879 TI - Hyperthermia using nanoparticles--Promises and pitfalls. AB - An ever-increasing body of literature affirms the physical and biological basis for sensitisation of tumours to conventional therapies such as chemotherapy and radiation therapy by mild temperature hyperthermia. This knowledge has fuelled the efforts to attain, maintain, measure and monitor temperature via technological advances. A relatively new entrant in the field of hyperthermia is nanotechnology which capitalises on locally injected or systemically administered nanoparticles that are activated by extrinsic energy sources to generate heat. This review describes the kinds of nanoparticles available for hyperthermia generation, their activation sources, their characteristics, and the unique opportunities and challenges with nanoparticle-mediated hyperthermia. PMID- 26757881 TI - Inflammatory profiles in canine intervertebral disc degeneration. AB - BACKGROUND: Intervertebral disc (IVD) disease is a common spinal disorder in dogs and degeneration and inflammation are significant components of the pathological cascade. Only limited studies have studied the cytokine and chemokine profiles in IVD degeneration in dogs, and mainly focused on gene expression. A better understanding is needed in order to develop biological therapies that address both pain and degeneration in IVD disease. Therefore, in this study, we determined the levels of prostaglandin E2 (PGE2), cytokines, chemokines, and matrix components in IVDs from chondrodystrophic (CD) and non-chondrodystrophic (NCD) dogs with and without clinical signs of IVD disease, and correlated these to degeneration grade (according to Pfirrmann), or herniation type (according to Hansen). In addition, we investigated cyclooxygenase 2 (COX-2) expression and signs of inflammation in histological IVD samples of CD and NCD dogs. RESULTS: PGE2 levels were significantly higher in the nucleus pulposus (NP) of degenerated IVDs compared with non-degenerated IVDs, and in herniated IVDs from NCD dogs compared with non-herniated IVDs of NCD dogs. COX-2 expression in the NP and annulus fibrosus (AF), and proliferation of fibroblasts and numbers of macrophages in the AF significantly increased with increased degeneration grade. GAG content did not significantly change with degeneration grade or herniation type. Cytokines interleukin (IL)-2, IL-6, IL-7, IL-8, IL-10, IL-15, IL-18, immune protein (IP)-10, tumor necrosis factor (TNF)-alpha, and granulocyte macrophage colony-stimulating factor (GM-CSF) were not detectable in the samples. Chemokine (C-C) motif ligand (CCL)2 levels in the NP from extruded samples were significantly higher compared with the AF of these samples and the NP from protrusion samples. CONCLUSIONS: PGE2 levels and CCL2 levels in degenerated and herniated IVDs were significantly higher compared with non-degenerated and non herniated IVDs. COX-2 expression in the NP and AF and reactive changes in the AF increased with advancing degeneration stages. Although macrophages invaded the AF as degeneration progressed, the production of inflammatory mediators seemed most pronounced in degenerated NP tissue. Future studies are needed to investigate if inhibition of PGE2 levels in degenerated IVDs provides effective analgesia and exerts a protective role in the process of IVD degeneration and the development of IVD disease. PMID- 26757880 TI - Antitumor activity of Cetuximab in combination with Ixabepilone on triple negative breast cancer stem cells. AB - BACKGROUND: Developing novel strategies against treatment-resistant triple negative breast cancer (TNBC) cells remains a significant challenge. The ErbB family, including epidermal growth factor receptor (EGFR), plays key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSC) which are believed to be responsible for tumor initiation and maintenance. Ixabepilone is a new generation microtubule stabilizing agent, which has been expected to be more efficacious than conventional taxanes. Here we aim to investigate whether the EGFR monoclonal antibody Cetuximab, in combination with Ixabepilone, is more effective in eliminating CSC populations compared to chemotherapy alone in TNBC. METHODS: Representative TNBC cell lines (MDA-MB-231 and SUM159) were used to evaluate breast CSC populations. We used fluorescence-activated cell sorter analysis (CD44(+) and CD24(-/low), or Aldefluor(+)) and a self-renewal assay called mammosphere formation efficiency (MSFE) to measure CSC population size after treatment with Cetuximab, or Cetuximab plus Ixabepilone in vitro. RESULTS: Although there was no significant decrease in cell viability, Cetuximab reduced MSFE and the CSC population in breast cancer cells in vitro and in vivo through inhibition of autophagy. Also, SUM159 and MDA-MB-231 orthotopic tumors demonstrated partial response to Centuximab or Ixabepilone monotherapy; however, the effect of the combination treatment was significant only in SUM159 tumors (p <0.0001), when compared to Ixabepilone alone. CONCLUSIONS: Overall, our findings demonstrate that EGFR-targeted therapy by Cetuximab effectively reduces the CSC population in TNBC tumors. However, combination therapy with Ixabepilone may be effective only in a small subset of TNBCs, warranting further investigation of alternative approaches to target multiple pathways for TNBC treatment. PMID- 26757882 TI - Farewell to GBM-O: Genomic and transcriptomic profiling of glioblastoma with oligodendroglioma component reveals distinct molecular subgroups. AB - INTRODUCTION: Glioblastoma with oligodendroglioma component (GBM-O) was recognized as a histologic pattern of glioblastoma (GBM) by the World Health Organization (WHO) in 2007 and is distinguished by the presence of oligodendroglioma-like differentiation. To better understand the genetic underpinnings of this morphologic entity, we performed a genome-wide, integrated copy number, mutational and transcriptomic analysis of eight (seven primary, primary secondary) cases. RESULTS: Three GBM-O samples had IDH1 (p.R132H) mutations; two of these also demonstrated 1p/19q co-deletion and had a proneural transcriptional profile, a molecular signature characteristic of oligodendroglioma. The additional IDH1 mutant tumor lacked 1p/19q co-deletion, harbored a TP53 mutation, and overall, demonstrated features most consistent with IDH mutant (secondary) GBM. Finally, five tumors were IDH wild-type (IDHwt) and had chromosome seven gains, chromosome 10 losses, and homozygous 9p deletions (CDKN2A), alterations typical of IDHwt (primary) GBM. IDHwt GBM-Os also demonstrated EGFR and PDGFRA amplifications, which correlated with classical and proneural expression subtypes, respectively. CONCLUSIONS: Our findings demonstrate that GBM-O is composed of three discrete molecular subgroups with characteristic mutations, copy number alterations and gene expression patterns. Despite displaying areas that morphologically resemble oligodendroglioma, the current results indicate that morphologically defined GBM-O does not correspond to a particular genetic signature, but rather represents a collection of genetically dissimilar entities. Ancillary testing, especially for IDH and 1p/19q, should be used for determining these molecular subtypes. PMID- 26757884 TI - Rhodium-catalyzed annulation of arenes with alkynes through weak chelation assisted C-H activation. AB - The purpose of this article is to give a brief review of weak chelation assistance as a powerful means for the rhodium-catalyzed annulation of arenes with alkynes. The use of commonly occurring functional groups (e.g., ketones, aldehydes, carboxylic acids and alcohols) as the directing groups enriches the versatility of auxiliary ligands and extends the scope of products. This short article offers an overview on emerging procedures, highlights their advantages and limitations, and covers the latest progress in the rapid synthesis of organic functional materials and natural products. PMID- 26757883 TI - Effects of piceatannol and pterostilbene against beta-amyloid-induced apoptosis on the PI3K/Akt/Bad signaling pathway in PC12 cells. AB - Neuron apoptosis induced by beta-amyloid (Abeta) is an important precipitating factor in the pathogenesis of Alzheimer's disease (AD). In the present study, the effects of piceatannol (PT) and pterostilbene (PS) against Abeta-induced apoptosis in PC12 cells were evaluated. PT and PS both showed observable anti apoptosis activity. Increased cell viability, decreased apoptosis rate and declining intracellular ROS were observed after PT and PS treatment. For the signaling pathway, PT significantly promoted phosphorylation of Akt and Bad, further suppressed Bcl-2/Bax expression and inhibited cleavage of caspase-9, caspase-3 and PARP. PS promoted phosphorylation of Akt without affecting the other factors. The experimental results, for the first time, unambiguously suggested that PT showed a comprehensive protective effect against Abeta-induced apoptosis in PC12 cells via a novel PI3K/Akt/Bad signaling pathway and downstream mitochondria-mediated and caspase-dependent signaling pathway. Unlike PT, PS inhibited apoptosis against Abeta through a different PI3K/Akt signaling pathway in which the downstream targets need to be further investigated. The results also provide the basis for dietary intervention involved in the prevention and adjunctive therapy of AD. PMID- 26757886 TI - Income Inequities in Health Care Utilization among Adults Aged 50 and Older. AB - Equitable access to and utilization of health services is a primary goal for many health care systems, particularly in countries with universal publicly funded systems. Despite concerns regarding potentially adverse implications of the 1990s' health care policy and other reforms, whether and how income inequalities in service utilization changed remains unclear. This study addressed the impact of income on physician and hospital utilization from 1992-2002 among adults aged 50 and older in British Columbia. Those with lower incomes were found less likely to access general practitioner and specialist services but more likely to access hospital services. Income-related disparities in physician care increased over time; hospital care declined. Volume of GP and hospital care was inversely associated with income; these differences increased regarding GP services only. Findings of declines in hospital-care access, accompanied by increasing income related disparities in physician-services access, show that inequities are increasing within Canada's health care system. PMID- 26757885 TI - Porous Organic Cages for Sulfur Hexafluoride Separation. AB - A series of porous organic cages is examined for the selective adsorption of sulfur hexafluoride (SF6) over nitrogen. Despite lacking any metal sites, a porous cage, CC3, shows the highest SF6/N2 selectivity reported for any material at ambient temperature and pressure, which translates to real separations in a gas breakthrough column. The SF6 uptake of these materials is considerably higher than would be expected from the static pore structures. The location of SF6 within these materials is elucidated by X-ray crystallography, and it is shown that cooperative diffusion and structural rearrangements in these molecular crystals can rationalize their superior SF6/N2 selectivity. PMID- 26757887 TI - Pregnancy outcome after oocyte donation in patients with Turner's syndrome: Clinical experience and management. AB - Turner's syndrome (TS) is a chromosomal defect with partial or total absence of the X chromosome. Our objective is to report our experience in Greece with patients suffering from TS and trying to conceive; therefore, we present four patients with TS, who underwent In vitro fertilization (ICSI) with donor oocytes in order to get pregnant. Three out of four patients managed to conceive and bring pregnancy to completion. It was shown that patients diagnosed in childhood or adolescence with TS have the possibility to undergo hormone replacement therapy (HRT) and thus, secondary sexual characteristics as well as uterus of almost normal size can develop. Assisted reproduction techniques (ART), predominantly with donated oocytes, could give these patients the possibility to have children. PMID- 26757888 TI - Activation of the polycomb repressive complex pathway in the bone marrow resident cells of diffuse large B-cell lymphoma patients. AB - The present study investigated the activation of polycomb repressive complex 2 (PRC2) pathway proteins in the resident cells within the bone marrow hematopoietic microenvironment of diffuse large B-cell lymphoma (DLBCL) patients. PRC2 proteins (enhancer of zeste homolog 2, suppressor of zeste 12 homolog, and embryonic ectoderm development), histone methylation mark (H3K27me3), and c-MYC activation were evaluated in pretreatment bone marrow from 208 DLBLC patients. Positive expression of the PRC2, H3K27me3, and c-MYC in the bone marrow resident cells was more frequent in cases with bone marrow involvement of tumor. The expression among PRC2, H3K27me3 mark, and c-MYC was closely correlated. Positive PRC2 expression in bone marrow resident cells was significantly associated with inferior progression-free survival (PFS) and overall survival (OS) and determined to be an independent prognostic factor of inferior PFS and OS. In conclusion, the PRC pathway was frequently activated in bone marrow resident cells of DLBCL patients, and PRC activation was tumor-related and associated with poor clinical outcomes. PMID- 26757889 TI - Gloves against mineral oils and mechanical hazards: composites of carboxylated acrylonitrile-butadiene rubber latex. AB - Resistance to permeation of noxious chemical substances should be accompanied by resistance to mechanical factors because the glove material may be torn, cut or punctured in the workplace. This study reports on glove materials, protecting against mineral oils and mechanical hazards, made of carboxylated acrylonitrile butadiene rubber (XNBR) latex. The obtained materials were characterized by a very high resistance of the produced materials to oil permeation (breakthrough time > 480 min). The mechanical properties, and especially tear resistance, of the studied materials were improved after the addition of modified bentonite (nanofiller) to the XNBR latex mixture. The nanocomposite meets the requirements in terms of parameters characterizing tear, abrasion, cut and puncture resistance. Therefore, the developed material may be used for the production of multifunctional protective gloves. PMID- 26757890 TI - Crystal-Size Effects on Carbon Dioxide Capture of a Covalently Alkylamine Tethered Metal-Organic Framework Constructed by a One-Step Self-Assembly. AB - To enhance the carbon dioxide (CO2) uptake of metal-organic frameworks (MOFs), amine functionalization of their pore surfaces has been studied extensively. In general, amine-functionalized MOFs have been synthesized via post-synthetic modifications. Herein, we introduce a one-step construction of a MOF ([(NiLethylamine)(BPDC)] = MOFNH2; [NiLethylamine](2+) = [Ni(C12H32N8)](2+); BPDC(2-) = 4,4'-biphenyldicarboxylate) possessing covalently tethered alkylamine groups without post-synthetic modification. Two-amine groups per metal centre were introduced by this method. MOFNH2 showed enhanced CO2 uptake at elevated temperatures, attributed to active chemical interactions between the amine groups and the CO2 molecules. Due to the narrow channels of MOFNH2, the accessibility to the channel of CO2 is the limiting factor in its sorption behaviour. In this context, only crystal size reduction of MOFNH2 led to much faster and greater CO2 uptake at low pressures. PMID- 26757891 TI - Risk factors of adjacent vertebral collapse after percutaneous vertebroplasty for osteoporotic vertebral fracture in postmenopausal women. AB - BACKGROUND: Recently percutaneous vertebroplasty (PVP) was frequently performed for treatment of osteoporotic vertebral fractures (VFs). It is widely accepted that new compression fractures tend to occur adjacent to the vertebral bodies, typically within a month after PVP. To determine the risk factors among several potential predictors for de novo VFs following PVP in patients with osteoporosis. METHODS: We retrospectively screened the clinical results of 88 patients who had been treated by PVP. Fifteen cases were excluded due to non-union. Of the remaining 73 patients, 19 (26.0%) later returned with pain due to a new vertebral compression fracture. One patient with a non-adjacent fracture and 2 patients with adjacent factures occurring 3 months later were excluded from the study. The 9 male patients were excluded to avoid gender bias. Ultimately, we divided the 61 remaining postmenopausal female patients (mean age: 78.9 years) into the collapse group (14 patients) who had experienced adjacent vertebral collapse after PVP and the non-collapse group (47 patients) who had not. Logistic regression analysis was performed to identify the risk factors for new VFs after PVP. RESULTS: All 14 cases of adjacent VF occurred within the first month after surgery. The collapse group had significantly advanced age, higher urinary N-terminal cross-linking telopeptide of type I collagen, and lower lumbar and hip bone mineral density (BMD) scores as compared with the non-collapse group. The odds ratios for age, lumbar, total hip, femoral neck, and trochanteric BMD were 4.5, 8.2, 4.5, 7.2, and 9.6, respectively. Positive likelihood ratios suggested that age more than 85 years, lumbar BMD less than 0.700 [-2.6SD], total hip BMD less than 0.700 [ 1.8SD], neck BMD less than 0.600 [-2.1], and trochanter BMD less than 0.600 conferred an elevated risk of adjacent VF. CONCLUSIONS: Our study revealed that advanced age and decreased lumbar and hip BMD scores most strongly indicated a risk of adjacent VF following PVP. PMID- 26757892 TI - Two-Photon Excitation STED Microscopy with Time-Gated Detection. AB - We report on a novel two-photon excitation stimulated emission depletion (2PE STED) microscope based on time-gated detection. The time-gated detection allows for the effective silencing of the fluorophores using moderate stimulated emission beam intensity. This opens the possibility of implementing an efficient 2PE-STED microscope with a stimulated emission beam running in a continuous-wave. The continuous-wave stimulated emission beam tempers the laser architecture's complexity and cost, but the time-gated detection degrades the signal-to-noise ratio (SNR) and signal-to-background ratio (SBR) of the image. We recover the SNR and the SBR through a multi-image deconvolution algorithm. Indeed, the algorithm simultaneously reassigns early-photons (normally discarded by the time-gated detection) to their original positions and removes the background induced by the stimulated emission beam. We exemplify the benefits of this implementation by imaging sub-cellular structures. Finally, we discuss of the extension of this algorithm to future all-pulsed 2PE-STED implementationd based on time-gated detection and a nanosecond laser source. PMID- 26757893 TI - Factors associated with incomplete childhood immunization in Arbegona district, southern Ethiopia: a case--control study. AB - BACKGROUND: The prevention of child mortality through immunization is one of the most cost-effective and widely applied public health interventions. In Ethiopia, the Expanded Program on Immunization (EPI) schedule is rarely completed as planned and the full immunization rate is only 24%. The objective of this study was to identify determinant factors of incomplete childhood immunization in Arbegona district, Sidama zone, southern Ethiopia. METHODS: A community based unmatched case-control study was undertaken among randomly selected children aged 12 to 23 months and with a total sample size of 548 (183 cases and 365 controls). A multi-stage sampling technique was used to get representative cases and controls. Data was collected using a structured questionnaire and analyzed using SPSS version 16 statistical software. Bivariate and multiple logistic regression analyses were done to identify independent factors for incomplete immunization status of children. Qualitative data were also generated and analyzed using thematic framework. RESULTS: The incomplete immunization status of children was significantly associated with young mothers (AOR = 9.54; 95% CI = 5.03, 18.09), being born second to fourth (AOR = 3.64; 95% CI = 1.63, 8.14) and being born fifth or later in the family (AOR = 5.27; 95% CI = 2.20, 12.64) as compared to being born first, a mother's lack of knowledge about immunization benefits (AOR = 5.51; 95% CI = 1.52, 19.94) and a mother's negative perception of vaccine side effects (AOR = 1.92; 95% CI = 1.01, 3.70). The qualitative finding revealed that the migration of mothers and unavailability of vaccines on appointed immunization dates were the major reasons for partial immunization of children. CONCLUSION: To reduce the number of children with incomplete immunization status, the Arbegona district needs to consider specific planning for mothers with these risk profiles. A focus on strengthening health communication activities to raise immunization awareness and address concerns of vaccine side effects at community level is also needed. This could be achieved through integrating the immunization service to other elements of primary health care. PMID- 26757894 TI - Experimental blunt chest trauma--cardiorespiratory effects of different mechanical ventilation strategies with high positive end-expiratory pressure: a randomized controlled study. AB - BACKGROUND: Uncertainty persists regarding the optimal ventilatory strategy in trauma patients developing acute respiratory distress syndrome (ARDS). This work aims to assess the effects of two mechanical ventilation strategies with high positive end-expiratory pressure (PEEP) in experimental ARDS following blunt chest trauma. METHODS: Twenty-six juvenile pigs were anesthetized, tracheotomized and mechanically ventilated. A contusion was applied to the right chest using a bolt-shot device. Ninety minutes after contusion, animals were randomized to two different ventilation modes, applied for 24 h: Twelve pigs received conventional pressure-controlled ventilation with moderately low tidal volumes (VT, 8 ml/kg) and empirically chosen high external PEEP (16 cmH2O) and are referred to as the HP-CMV-group. The other group (n = 14) underwent high-frequency inverse-ratio pressure-controlled ventilation (HFPPV) involving respiratory rate of 65 breaths . min(-1), inspiratory-to-expiratory-ratio 2:1, development of intrinsic PEEP and recruitment maneuvers, compatible with the rationale of the Open Lung Concept. Hemodynamics, gas exchange and respiratory mechanics were monitored during 24 h. Computed tomography and histology were analyzed in subgroups. RESULTS: Comparing changes which occurred from randomization (90 min after chest trauma) over the 24 h treatment period, groups differed statistically significantly (all P values for group effect <0.001, General Linear Model analysis) for the following parameters (values are mean +/- SD for randomization vs. 24-h): PaO2 (100% O2) (HFPPV 186 +/ 82 vs. 450 +/- 59 mmHg; HP-CMV 249 +/- 73 vs. 243 +/- 81 mmHg), venous admixture (HFPPV 34 +/- 9.8 vs. 11.2 +/- 3.7%; HP-CMV 33.9 +/- 10.5 vs. 21.8 +/- 7.2%), PaCO2 (HFPPV 46.9 +/- 6.8 vs. 33.1 +/- 2.4 mmHg; HP-CMV 46.3 +/- 11.9 vs. 59.7 +/ 18.3 mmHg) and normally aerated lung mass (HFPPV 42.8 +/- 11.8 vs. 74.6 +/- 10.0 %; HP-CMV 40.7 +/- 8.6 vs. 53.4 +/- 11.6%). Improvements occurring after recruitment in the HFPPV-group persisted throughout the study. Peak airway pressure and VT did not differ significantly. HFPPV animals had lower atelectasis and inflammation scores in gravity-dependent lung areas. CONCLUSIONS: In this model of ARDS following unilateral blunt chest trauma, HFPPV ventilation improved respiratory function and fulfilled relevant ventilation endpoints for trauma patients, i.e. restoration of oxygenation and lung aeration while avoiding hypercapnia and respiratory acidosis. PMID- 26757895 TI - Large molecular systems landscape uncovers T cell trapping in human skin cancer. AB - Immune surveillance of tumour cells is an important function of CD8 T lymphocytes, which has failed in cancer for reasons still unknown in many respect but mainly related to cellular processes in the tumour microenvironment. Applying imaging cycler microscopy to analyse the immune contexture in a human skin cancer we could identify and map 7,000 distinct cell surface-associated multi-protein assemblies. The resulting combinatorial geometry-based high-functional resolution led to discovery of a mechanism of T cell trapping in the epidermis, which involves SPIKE, a network of suprabasal keratinocyte projections piercing and interconnecting CD8 T cells. It appears initiated by clusters of infrabasal T and dendritic cells connected via cell projections across a fractured basal lamina to suprabasal keratinocytes and T lymphocytes. PMID- 26757897 TI - The incidence and morphology of Monckeberg's medial calcification in banked vascular segments from a monocentric donor population. AB - Little is known about the real incidence and the clinical relevance of the enigmatic Monckeberg's medial calcification in the patency of the femoral artery allograft. Here we present a retrospective study on 143 multiorgan donors (mean age 38 years, range 14-59 years), to describe the incidence and the morphological features of vascular calcifications in banked femoral arteries suitable for clinical use. In the present series, focal vascular calcifications were present in 36 (25 %) cases, 23 cases localized in the intima, 7 in the media, and 6 were mixed. No correlation was found between the incidence of calcifications and the classical cardiovascular clinical risk factors (n = 9); only hypertension correlated with the medial localization, but not with the incidence, of the calcification (P = 0.017). While the macroscopic exclusion criteria of vascular grafts include atheromatous and not-atheromatous lesions, we ignore the actual impact of Monckeberg's medial calcification on vessel transplantation and allograft life. In our opinion this is a very important topic, since when the histological criteria for Monckeberg's calcification diagnosis are used, 25 % of our young donors population was affected. Whether Monckeberg's medial calcification is a stable arterial condition, apparently underestimated in the general population, or a dynamic process evolving with age and atherosclerosis, or a banking-related vascular alteration, still remain an open issue deserving further studies with subjects of different ages. PMID- 26757896 TI - The effect of nucleus basalis magnocellularis deep brain stimulation on memory function in a rat model of dementia. AB - BACKGROUND: Deep brain stimulation has recently been considered a potential therapy in improving memory function. It has been shown that a change of neurotransmitters has an effect on memory function. However, much about the exact underlying neural mechanism is not yet completely understood. We therefore examined changes in neurotransmitter systems and spatial memory caused by stimulation of nucleus basalis magnocellularis in a rat model of dementia. METHODS: We divided rats into four groups: Normal, Lesion, Implantation, and Stimulation. We used 192 IgG-saporin for degeneration of basal forebrain cholinergic neuron related with learning and memory and it was injected into all rats except for the normal group. An electrode was ipsilaterally inserted in the nucleus basalis magnocellularis of all rats of the implantation and stimulation group, and the stimulation group received the electrical stimulation. Features were verified by the Morris water maze, immunochemistry and western blotting. RESULTS: All groups showed similar performances during Morris water maze training. During the probe trial, performance of the lesion and implantation group decreased. However, the stimulation group showed an equivalent performance to the normal group. In the lesion and implantation group, expression of glutamate acid decarboxylase65&67 decreased in the medial prefrontal cortex and expression of glutamate transporters increased in the medial prefrontal cortex and hippocampus. However, expression of the stimulation group showed similar levels as the normal group. CONCLUSION: The results suggest that nucleus basalis magnocellularis stimulation enhances consolidation and retrieval of visuospatial memory related to changes of glutamate acid decarboxylase65&67 and glutamate transporter. PMID- 26757898 TI - Development of Tablet Formulation of Amorphous Solid Dispersions Prepared by Hot Melt Extrusion Using Quality by Design Approach. AB - The objective of the study was to identify the extragranular component requirements (level and type of excipients) to develop an immediate release tablet of solid dispersions prepared by hot melt extrusion (HME) process using commonly used HME polymers. Solid dispersions of compound X were prepared using polyvinyl pyrrolidone co-vinyl acetate 64 (PVP VA64), Soluplus, and hypromellose acetate succinate (HPMCAS-LF) polymers in 1:2 ratio by HME through 18 mm extruder. A mixture design was employed to study effect of type of polymer, filler (microcrystalline cellulose (MCC), lactose, and dicalcium phosphate anhydrous (DCPA)), and disintegrant (Crospovidone, croscarmellose sodium, and sodium starch glycolate (SSG)) as well as level of extrudates, filler, and disintegrant on tablet properties such as disintegration time (DT), tensile strength (TS), compactibility, and dissolution. Higher extrudate level resulted in longer DT and lower TS so 60-70% was the maximum amount of acceptable extrudate level in tablets. Fast disintegration was achieved with HPMCAS containing tablets, whereas Soluplus- and PVP VA64-containing tablets had higher TS. Crospovidone and croscarmellose sodium were more suitable disintegrant than SSG to achieve short DT, and MCC was a suitable filler to prepare tablets with acceptable TS for each studied HME polymer. The influence of extragranular components on dissolution from tablets should be carefully evaluated while finalizing tablet composition, as it varies for each HME polymer. The developed statistical models identified suitable level of fillers and disintegrants for each studied HME polymer to achieve tablets with rapid DT (<15 min) and acceptable TS (>=1 MPa at 10-15% tablet porosity), and their predictivity was confirmed by conducting internal and external validation studies. PMID- 26757899 TI - Aligning the unalignable: bacteriophage whole genome alignments. AB - BACKGROUND: In recent years, many studies focused on the description and comparison of large sets of related bacteriophage genomes. Due to the peculiar mosaic structure of these genomes, few informative approaches for comparing whole genomes exist: dot plots diagrams give a mostly qualitative assessment of the similarity/dissimilarity between two or more genomes, and clustering techniques are used to classify genomes. Multiple alignments are conspicuously absent from this scene. Indeed, whole genome aligners interpret lack of similarity between sequences as an indication of rearrangements, insertions, or losses. This behavior makes them ill-prepared to align bacteriophage genomes, where even closely related strains can accomplish the same biological function with highly dissimilar sequences. RESULTS: In this paper, we propose a multiple alignment strategy that exploits functional collinearity shared by related strains of bacteriophages, and uses partial orders to capture mosaicism of sets of genomes. As classical alignments do, the computed alignments can be used to predict that genes have the same biological function, even in the absence of detectable similarity. The Alpha aligner implements these ideas in visual interactive displays, and is used to compute several examples of alignments of Staphylococcus aureus and Mycobacterium bacteriophages, involving up to 29 genomes. Using these datasets, we prove that Alpha alignments are at least as good as those computed by standard aligners. Comparison with the progressive Mauve aligner - which implements a partial order strategy, but whose alignments are linearized - shows a greatly improved interactive graphic display, while avoiding misalignments. CONCLUSIONS: Multiple alignments of whole bacteriophage genomes work, and will become an important conceptual and visual tool in comparative genomics of sets of related strains. A python implementation of Alpha, along with installation instructions for Ubuntu and OSX, is available on bitbucket (https://bitbucket.org/thekswenson/alpha). PMID- 26757900 TI - Exosomes derived from atorvastatin-modified bone marrow dendritic cells ameliorate experimental autoimmune myasthenia gravis by up-regulated levels of IDO/Treg and partly dependent on FasL/Fas pathway. AB - BACKGROUND: Previously, we have demonstrated that spleen-derived dendritic cells (DCs) modified with atorvastatin suppressed immune responses of experimental autoimmune myasthenia gravis (EAMG). However, the effects of exosomes derived from atorvastatin-modified bone marrow DCs (BMDCs) (statin-Dex) on EAMG are still unknown. METHODS: Immunophenotypical characterization of exosomes from atorvastatin- and dimethylsulfoxide (DMSO)-modified BMDCs was performed by electron microscopy, flow cytometry, and western blotting. In order to investigate whether statin-DCs-derived exosomes (Dex) could induce immune tolerance in EAMG, we administrated statin-Dex, control-Dex, or phosphate buffered saline (PBS) into EAMG rats via tail vein injection. The tracking of injected Dex and the effect of statin-Dex injection on endogenous DCs were performed by immunofluorescence and flow cytometry, respectively. The number of Foxp3(+) cells in thymuses was examined using immunocytochemistry. Treg cells, cytokine secretion, lymphocyte proliferation, cell viability and apoptosis, and the levels of autoantibody were also carried out to evaluate the effect of statin Dex on EAMG rats. To further investigate the involvement of FasL/Fas in statin Dex-induced apoptosis, the underlying mechanisms were studied by FasL neutralization assays. RESULTS: Our data showed that the systemic injection of statin-Dex suppressed the clinical symptoms of EAMG rats. These statin-Dex had immune regulation functions in immune organs, such as the spleen, thymus, and popliteal and inguinal lymph nodes. Furthermore, statin-Dex exerted their immunomodulatory effects in vivo by decreasing the expression of CD80, CD86, and MHC class II on endogenous DCs. Importantly, the therapeutic effects of statin Dex on EAMG rats were associated with up-regulated levels of indoleamine 2,3 dioxygenase (IDO)/Treg and partly dependent on FasL/Fas pathway, which finally resulted in decreased synthesis of anti-R97-116 IgG, IgG2a, and IgG2b antibodies. CONCLUSIONS: Our data suggest that atorvastatin-induced immature BMDCs are able to secrete tolerogenic Dex, which are involved in the suppression of immune responses in EAMG rats. Importantly, our study provides a novel cell-free approach for the treatment of autoimmune diseases. PMID- 26757901 TI - Diagnosis and management of splenic injury following colonoscopy: algorithm and case series. AB - BACKGROUND: Splenic injury following colonoscopy is a rare yet life-threatening complication. These injuries are often associated with delayed diagnosis and may require invasive intervention. We sought to study the emergent presentation associated with splenic injury post-colonoscopy and to suggest a new treatment algorithm. METHODS: Six cases of splenic injury following colonoscopy were collected from three medical centers. Data regarding patient medical history, clinical presentation, laboratory and imaging findings and clinical management were recorded. A systematic PubMed/MEDLINE search was performed. Non-English language publications and publications dating earlier than 2010 were excluded. An emergency department trauma-based management algorithm was designed according to the identified publications and review of the available trauma literature. RESULTS: The mean age was 65.3 years and the male-to-female ratio was 1:5. Five of the cases presented within 24 h of the colonoscopy complaining of severe abdominal pain. Hemodynamic instability was noted in four patients who presented with tachycardia (105-130), hypotension and/or a rapid drop in hemoglobin levels. All of the patients underwent initial resuscitation and a computerized abdominal tomography scan. Four of them required emergent splenectomy. No mortality or major morbidity was reported following the hospitalization. CONCLUSIONS: Although very rare, splenic injury during colonoscopy is an acute, severe and possible fatal complication. Patients may present with a rapid clinical deterioration and hemodynamic instability. Physicians should be familiar with the practical management of this surgical emergency and the treatment options available. PMID- 26757902 TI - Salud es Vida: a Cervical Cancer Screening Intervention for Rural Latina Immigrant Women. AB - This study examined the feasibility and efficacy of Salud es Vida-a promotora led, Spanish language educational group session on cervical cancer screening (Pap tests)-self-efficacy (belief in ability to schedule and complete a Pap test), and knowledge among immigrant Hispanic/Latina women from farmworker backgrounds. These women are disproportionately burdened with cervical cancer, with mortality rates significantly higher than non-Hispanic whites. The two-arm, quasi experimental study was conducted in four rural counties of Southeast Georgia in 2014-2015. Hispanic/Latina immigrant women aged 21-65 years and overdue for a Pap test were included as intervention (N = 38) and control (N = 52) group participants. The intervention was developed in partnership with a group of promotoras to create the toolkit of materials which includes a curriculum guide, a brochure, a flipchart, a short animated video, and in-class activities. Twelve (32 %) intervention group participants received the Pap test compared to 10 (19 %) control group participants (p = 0.178). The intervention group scored significantly higher on both cervical cancer knowledge recall and retention than the control group (p < 0.001). While there was no statistically significant difference in cervical cancer screening self-efficacy scores between the group participants, both groups scored higher at follow-up, adjusting for the baseline scores. The group intervention approach was associated with increased cervical cancer knowledge but not uptake of Pap test. More intensive interventions using patient navigation approaches or promotoras who actively follow participants or conducting one-on-one rather than group sessions may be needed to achieve improved screening outcomes with this population. PMID- 26757903 TI - Rationale and Early Experience with Prophylactic Placement of Mesh to Prevent Parastomal Hernia Formation after Ileal Conduit Urinary Diversion and Cystectomy for Bladder Cancer. AB - Parastomal hernias (PH) represent a clinically significant problem for many patients after radical cystectomy and ileal conduit diversion. The prevalence may be as high as 60% and in some series, up to 30% of patients require surgical intervention due to the complications of pain, poor fit of an ostomy appliance, leakage, urinary obstruction, and bowel obstruction or strangulation. Due to the potential morbidity associated with PH repair, there have been efforts to prevent PH development at the time of the index surgery. Four randomized trials of prophylactic mesh placement at the time of colostomy and ileostomy stoma formation have demonstrated significant reductions in PH rates with acceptably low complication rates. In this review, we describe the clinical and radiographic definitions of PH, the clinical impact and risk factors behind its development, and the rationale behind prophylactic mesh placement for patients undergoing ileal conduit urinary diversion. Additionally, we report our experience with prophylactic mesh placed at radical cystectomy at our institution. PMID- 26757904 TI - Pelvic Floor Muscle Training: Underutilization in the USA. AB - Pelvic floor disorders are highly prevalent in women of all ages and can greatly impair quality of life. Pelvic floor muscle training (PFMT) is a viable treatment option for several pelvic floor conditions including urinary incontinence and pelvic organ prolapse. PFMT is a program of therapy initiated by an experienced clinician (e.g., women's health or urology nurse practitioner (NP), physical therapist (PT)) that involves exercises for women with stress urinary incontinence (UI) and exercises combined with behavioral or conservative treatments (lifestyle changes, bladder training with urge suppression) for women with urgency or mixed UI. These exercise programs are more comprehensive than simple Kegel exercises. Despite evidence-based research indicating the efficacy and cost-effectiveness for treatment of urinary incontinence, PFMT is not commonly used as a first-line treatment in clinical practice in the USA (Abrams et al., 2012). This article will review PFMT for the treatment of UI and pelvic organ prolapse (POP) and theorize how this conservative therapy can be utilized more effectively in the USA. PMID- 26757905 TI - Role of Sonic Hedgehog (Shh) Signaling in Bladder Cancer Stemness and Tumorigenesis. AB - Sonic hedgehog (Shh) signaling pathway has emerged as a critical component of bladder development, cancer initiation, and progression. While the role of Shh signaling in bladder development is well documented, its role in bladder cancer progression is uncertain. Additionally, epithelial-to-mesenchymal transition (EMT) has been identified to promote bladder cancer progression in the initial stages and also contribute to drug resistance in the later stage and ultimately metastasis. We speculate that epithelial-to-mesenchymal transitions (EMT) and Shh fuel the carcinogenesis process. This review presents the most recent studies focusing on the role of Shh signaling in bladder cancer progression. PMID- 26757906 TI - Prognostic Genetic Signatures in Upper Tract Urothelial Carcinoma. AB - Urothelial carcinoma is a highly heterogeneous disease that can arise throughout the entire urothelial lining from the renal pelvis to the proximal urethra. Upper tract urothelial carcinoma (UTUC) is rare, and while it shares many similarities with urothelial carcinoma of bladder (UCB), there are also significant differences between UTUC and UCB regarding clinical management and outcomes. No major advances have been made recently in the development of new systemic therapies for urothelial carcinoma, partly due to the lack of understanding of underlying molecular pathogenetic mechanisms. In the past decade, the emergence of next-generation sequencing has greatly enabled genomic characterization of tumor samples. Researchers are currently exploring a personalized approach to augment traditional clinical decision-making based on genetic alterations. In the present review, we summarize current genomic advances in UTUC and discuss the potential implications of these developments for developing prognostic and predictive biomarkers. PMID- 26757907 TI - Integrating Social Media into Urologic Health care: What Can We Learn from Other Disciplines? AB - Social media (SoMe) have become an integral part in many aspects of personal and professional life. With current uptake rates of 50-70% among urologists, SoMe platforms merit huge potential for dissemination of information and professional exchange among stakeholders in urology. Application of SoMe includes conference conversations via tweet chats, health education via YouTube videos, and Twitter online journal clubs. In addition, a number of urology journals have embraced SoMe to allow rapid dissemination of their content and engagement with their readers. Guidance for the appropriate use of SoMe is provided to urologists by several organizations. Besides urology, other disciplines have adopted SoMe for a variety of areas: continuing professional development, awareness of rare diseases, recruitment of study participants, patient education and support, and publicizing research. Openness to new approaches is the basic prerequisite for a transfer of successful concepts embraced by other specialties, to the field of urology. PMID- 26757908 TI - Adipose Tissue-Derived Stem Cells for the Treatment of Erectile Dysfunction. AB - Although a spectrum of options is available for erectile dysfunction (ED) treatment, ED in diabetics, post-prostatectomy patients, and those with Peyronie's disease (PD) may be more severe in degree and less likely to respond to conventional medical therapies. Unfortunately, there have been limited breakthroughs in therapeutic options for severe ED during the past decade. However, one of the more fascinating strategies in preclinical development to treat ED is stem cell transplantation. Depending on the cell type, recent research has demonstrated that with transplantation, these stem cells can exert a paracrine effect on surrounding penile tissues and differentiate into smooth muscle, endothelium, and neurons. Adipose tissue-derived stem cells (ADSCs) have become a valuable resource because of their abundance and ease of isolation. It is evident that ADSCs may provide a realistic, therapeutic modality for the treatment of ED. In this review, we will cover the literature that has evaluated ADSCs in the treatment of ED. PMID- 26757909 TI - An Attractant of the Aphidophagous Gall Midge Aphidoletes aphidimyza From Honeydew of Aphis gossypii. AB - Many natural enemies of insects use honeydew as a volatile cue to locate hosts or prey, as an oviposition stimulant, and as an arrestant for foraging. The aphidophagous gall midge Aphidoletes aphidimyza (Rondani) (Diptera: Cecidomyiidae) has predacious larval stages and can be used to control aphid populations, especially in greenhouses. Previous studies have shown that the honeydew, excreted by the aphid Myzus persicae, attracts A. aphidimyza, but the crucial attractants have not been identified. Using an olfactometer, we studied behavioral responses of female A. aphidimyza to volatiles emitted from honeydew excreted by the aphid Aphis gossypii on eggplants. The volatiles attracted female midges and induced oviposition. Moreover, using gas chromatography coupled with mass spectrometry (GC/MS), we identified phenylacetaldehyde as the attractant compound in the honeydew, although it did not induce oviposition in olfactometer experiments. PMID- 26757910 TI - Delayed Recurrence of Type 1A Endoleak with Aortic Rupture and Hemorrhage After Endovascular Aneurysm Sealing (EVAS). PMID- 26757911 TI - Dislodgement of the MGuard Prime MicroNetTM During Primary PCI. PMID- 26757912 TI - Comparison of Balloon-Occluded Retrograde Transvenous Obliteration (BRTO) Using Ethanolamine Oleate (EO), BRTO Using Sodium Tetradecyl Sulfate (STS) Foam and Vascular Plug-Assisted Retrograde Transvenous Obliteration (PARTO). AB - PURPOSE: To compare the clinical outcomes of balloon-occluded retrograde transvenous obliteration (BRTO) using ethanolamine oleate (EO), BRTO using sodium tetradecyl sulfate (STS) foam, and vascular plug-assisted retrograde transvenous obliteration (PARTO). MATERIALS AND METHODS: From April 2004 to February 2015, ninety-five patients underwent retrograde transvenous obliteration for gastric varices were analyzed retrospectively. BRTO with EO was performed in 49 patients, BRTO with STS foam in 25, and PARTO in 21. Among them, we obtained follow-up data in 70 patients. Recurrence of gastric varices was evaluated by follow-up endoscopy or CT. Medical records were reviewed for the clinical efficacy. Statistical analyses were performed by Kaplan-Meier method, Chi-square, Fisher's, and Kruskal-Wallis tests. RESULTS: Technical and clinical success was 94.7 %. As major complications, a hemoglobinuria and a death due to disseminated intravascular coagulation (DIC) were occurred in two patients with BRTO using EO. Recurrence occurred more frequently in PARTO group (P < 0.05). Recurrence occurred in three patients in BRTO using EO group and four patients in PARTO group with 3.2 and 32.8 % of each expected 1-year recurrence rates. There was no recurrence in BRTO using STS group. Abdominal pain occurred more frequently in BRTO using EO than BRTO using STS foam and PARTO (P < 0.05). Procedure time of PARTO was shorter than two conventional BRTOs (P < 0.05). CONCLUSIONS: BRTO using STS foam or PARTO is better than BRTO using EO for treatment of gastric varices in terms of complication or procedure time. However, PARTO showed frequent recurrence of gastric varices during the long-term follow-up rather than BRTO. PMID- 26757913 TI - The stacking interactions of bipyridine complexes: the influence of the metal ion type on the strength of interactions. AB - The strength of the stacking interactions in the bipy complexes of nickel, palladium, and platinum, [M(CN)2 bipy]2 (M = Ni, Pd, Pt), was calculated using the omegaB97xD/def2-TZVP method. The results show that for all considered geometries, interactions are the strongest for platinum, and weakest for nickel complexes, as a result of higher dispersion contributions of platinum over the palladium and nickel complexes. It was also shown that strength of interactions considerably rises with an increase of the stacking overlap area. As a consequence of the favorable electrostatic term, the strength of interactions also rises when metal atom and cyano ligands are involved in the overlap with bipy ligand. The strongest interaction was calculated in the platinum complex, for the geometry that has overlap of metal and cyano ligands with bipy ligand with an energy of -39.80 kcal mol(-1). The energies for similar geometries of palladium and nickel complexes are -34.60 and -32.45 kcal mol(-1). These energies, remarkably, exceed the strength of the stacking interactions between organic aromatic molecules. These results can be of importance in all systems with stacking interactions, from materials to biomolecules. PMID- 26757914 TI - Improving the iterative Linear Interaction Energy approach using automated recognition of configurational transitions. AB - Recently an iterative method was proposed to enhance the accuracy and efficiency of ligand-protein binding affinity prediction through linear interaction energy (LIE) theory. For ligand binding to flexible Cytochrome P450s (CYPs), this method was shown to decrease the root-mean-square error and standard deviation of error prediction by combining interaction energies of simulations starting from different conformations. Thereby, different parts of protein-ligand conformational space are sampled in parallel simulations. The iterative LIE framework relies on the assumption that separate simulations explore different local parts of phase space, and do not show transitions to other parts of configurational space that are already covered in parallel simulations. In this work, a method is proposed to (automatically) detect such transitions during the simulations that are performed to construct LIE models and to predict binding affinities. Using noise-canceling techniques and splines to fit time series of the raw data for the interaction energies, transitions during simulation between different parts of phase space are identified. Boolean selection criteria are then applied to determine which parts of the interaction energy trajectories are to be used as input for the LIE calculations. Here we show that this filtering approach benefits the predictive quality of our previous CYP 2D6 aryloxypropanolamine LIE model. In addition, an analysis is performed of the gain in computational efficiency that can be obtained from monitoring simulations using the proposed filtering method and by prematurely terminating simulations accordingly. PMID- 26757915 TI - Iron depletion strategy for targeted cancer therapy: utilizing the dual roles of neutrophil gelatinase-associated lipocalin protein. AB - Decreasing iron uptake and increasing iron efflux may result in cell death by oxidative inactivation of vital enzymes. Applying the dual function of neutrophil gelatinase-associated lipocalin (NGAL) could achieve the goal of iron depletion in the cancer cells. Tyr106, Lys125 or Lys134 was the key binding site for NGAL protein to sequester iron-chelating siderophores. In this study, we employed all bioactive peptides in peptide databank to dock with the siderophore-binding sites of NGAL protein by virtual screening. In addition, we performed molecular dynamics (MD) simulation to observe the molecular character and structural variation of ligand-protein interaction. Glu-Glu-Lys-Glu (EEKE), Glu-Glu-Asp-Cys Lys (EEDCK), and Gly-Glu-Glu-Cys-Asp (GEECD) were selected preliminarily by rigorous scoring functions for further investigation. GEECD was excluded due to higher binding total energy than the others. Moreover, we also excluded EEKE due to larger influence to the stability of binding residues by the information of root mean square fluctuation (RMSF) and principal component analysis (PCA). Thus, we suggested that EEDCK was the potential bioactive peptide which had been proved to inhibit malignant cells for targeted cancer therapy. Graphical Abstract Perspective drug design of occupying the siderophore-binding sites of NGAL outside the cell temporarily by a potential short peptide until NGAL enters into the cell, and releasing the siderophore-binding sites inside the cell. PMID- 26757916 TI - New insights into the regulation of innate immunity by caspase-8. AB - Caspase-8 is required for extrinsic apoptosis, but is also central for preventing a pro-inflammatory receptor interacting protein kinase (RIPK) 3-mixed lineage kinase domain-like (MLKL)-dependent cell death pathway termed necroptosis. Despite these critical cellular functions, the impact of capase-8 deletion in the myeloid cell lineage, which forms the basis for innate immune responses, has remained unclear. In a recent article in Arthritis Research & Therapy, Cuda et al. report that myeloid cell-restricted caspase-8 loss leads to a very mild RIPK3 dependent inflammatory phenotype. The presented results suggest that inflammation does not arise exclusively because of RIPK3-mediated necroptotic death but that, in the absence of caspase-8, RIPK1 and RIPK3 enhance microbiome-driven Toll-like receptor-induced pro-inflammatory cytokine production. PMID- 26757917 TI - Is Bariatric Surgery Effective in Reducing Comorbidities and Drug Costs? Reply to Letter to the Editor. PMID- 26757918 TI - Bariatric Surgery and Liver Cancer in a Consortium of Academic Medical Centers. AB - Obesity is implicated as an important factor in the rising incidence of liver cancer in the USA. Bariatric surgery is increasingly used for treating morbid obesity and comorbidities. Using administrative data from UHC, a consortium of academic medical centers in the USA, we compared the prevalence of liver cancer among admissions with and without a history of bariatric surgery within a 3-year period. Admissions with a history of bariatric surgery had a 61 % lower prevalence of liver cancer compared to those without a history of bariatric surgery (prevalence ratio 0.39, 95 % confidence interval 0.35-0.44), and these inverse associations persisted within strata of sex, race, and ethnicity. This hospital administrative record-based analysis suggests that bariatric surgery could play a role in liver cancer prevention. PMID- 26757919 TI - Laparoscopic Sleeve Gastrectomy for Morbid Obesity in 3003 Patients: Results at a High-Volume Bariatric Center. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is gaining wide acceptance as a single surgical treatment for obesity. The reported morbidity and mortality rates are low. We herein report the results of LSG performed in a high-volume center by an experienced team. METHODS: Retrospective analysis of a prospectively maintained database of all bariatric surgery (BS) was performed between May 2006 and December 2014. Data inspected included operative time, length of hospital stay (LOS), comorbidity resolution, re-operation, percent excess weight loss (%EWL), and 30-day morbidity and mortality. RESULTS: In the study period, 3003 patients underwent BS (1901 (63 %) female). Mean age and body mass index (BMI) were 43 years (range 14-73) and 42.8 kg/m(2) (range 35-73), respectively. %EWL at 1 year was 72 % (n = 937; 57 % follow-up rate). There was 1 perioperative mortality due to bleeding (0.03 %). Comorbidity improvement and resolution were 98 % for obstructive sleep apnea, 79 % for diabetes mellitus, 87 % for dyslipidemia, and 85 % for hypertension. Mean operative time and LOS were 50 min (range 32-94) and 2.2 days (range 1-38), respectively. Of the patients, 132 had complications (4.4 %), 25 leaks (0.83 %), 63 bleeding (2.1 %), 1 intra-abdominal abscesses (0.03 %), 3 sleeve strictures (0.1 %), 2 mesenteric vein thromboses (0.06 %), 10 trocar site hernias (0.3 %), and 78 symptomatic cholelithiasis (2.6 %). Re-operation was needed in 13 patients (0.43 %). CONCLUSION: In a high-volume center with an experienced team, LSG can be performed with low morbidity and mortality. PMID- 26757920 TI - Mesenteric Defect Closure Decreases the Incidence of Internal Hernias Following Laparoscopic Roux-En-Y Gastric Bypass: a Retrospective Cohort Study. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is one of the most effective bariatric procedures. Internal hernia (IH) is the commonest long-term complication seen after LRYGB. We analyzed the impact of closure of mesenteric defect at primary surgery on the incidence of IH. We also studied the effectiveness of pre-operative abdominal contrast-enhanced computerized tomography (CECT) in diagnosing IH. METHODS: This is a retrospective cohort study in which we analyzed prospectively the collected data of all patients who underwent LRYGB from 2005 to 2014. All patients post-LRYGB presenting with unexplained abdominal pain with a suspicion of IH were subjected to a CECT abdomen, in which we looked specifically for "whirlpool" sign and "clustering of bowel loops." All patients underwent diagnostic laparoscopy. We compared the incidence of IH in those who did not undergo mesenteric defect closure (2005 2008, i.e., group A) with those who had the mesenteric defects closed during primary surgery (2009-2014, i.e., group B). We also calculated the sensitivity of abdominal CECT in diagnosing IH pre-operatively. RESULTS: Among patients who did not undergo closure of any mesenteric defect (group A 2005-2009), 21/600 (3.5 %) developed IH, while 17/976 (1.7 %) patients who underwent mesenteric defect closure (group B 2009-2014) developed IH (p = 0.027). Pre-operative CECT abdomen confirmed the diagnosis of IH in 47.5 % (19/40 patients). CONCLUSIONS: Closing of mesenteric defects after laparoscopic gastric bypass seems to be related to a lower incidence of internal hernia in the follow up. As the sensitivity of abdominal CECT is low, laparoscopic exploration is recommended based on clinical suspicion. PMID- 26757921 TI - Changing Epidemiology of Bariatric Surgery in the UK: Cohort Study Using Primary Care Electronic Health Records. AB - BACKGROUND: This study aimed to use primary care electronic health records to evaluate the epidemiology of bariatric surgery in the UK. METHODS: A cohort comprising all obese patients with a bariatric surgical procedure was drawn from the Clinical Practice Research Datalink (CPRD). Rates of bariatric surgery were estimated using the registered CPRD population as denominator. RESULTS: There were 3039 adult obese patients with first bariatric surgery procedures between 2002 and 2014, including laparoscopic adjustable gastric banding (LAGB), 1297; gastric bypass (GBP), 1265; and sleeve gastrectomy (SG), 477. Annual procedures increased from one in 2002 to a maximum of 525 in 2010. Intervention rates were greatest among those aged 35-54, with a peak of 37 procedures per 100,000 population per year in women and 10 per 100,000 per year in men. The mean age and body mass index of participants increased, as did the proportion of men and proportion with diabetes. Between 2002 and 2006, LAGB accounted for >90 % of procedures; in 2014, GBP accounted for 52 % and SG 26 %. Among patients initially receiving LAGB, the rate of band removal was 1.6 (95 % confidence interval 1.3 2.0) per 100 patient years; the rate of a second procedure of a different type was 1.2 (0.9-1.5) per 100 patient years. CONCLUSIONS: Numbers of bariatric surgical procedures have increased with increasing use of GBP and SG. Rates of bariatric surgery per 100,000 population remain low and provide evidence of limited access to bariatric surgical procedures in relation to need. PMID- 26757922 TI - Postoperative Follow-up After Bariatric Surgery: Effect on Weight Loss. AB - While adherence to long-term follow-up after bariatric surgery is a mandate for center of excellence certification, the effect of attrition on weight loss is not well understood. The aim of this study was to assess the effect of postoperative follow-up on 12-month weight loss using the Bariatric Outcomes Longitudinal Database (BOLD) dataset. Patients with complete follow-up (3, 6, and 12 months) were compared to patients who had one or more prior missed visits. There were 51,081 patients with 12-month follow-up data available. After controlling for baseline characteristics, complete follow-up was independently associated with excess weight loss >=50%, and total weight loss >=30%. Adherence to postoperative follow-up is independently associated with improved 12-month weight loss after bariatric surgery. Bariatric programs should strive to achieve complete follow-up for all patients. PMID- 26757923 TI - Erratum to: Letter to the Editor: Minimizing the Access Trauma of Laparoscopic Sleeve Gastrectomy: the Transoral Specimen Extraction Technique. PMID- 26757924 TI - Glucose Profiles in Pregnant Women After a Gastric Bypass : Findings from Continuous Glucose Monitoring. AB - BACKGROUND: The diagnosis of gestational diabetes mellitus (GDM) usually requires an oral glucose tolerance test, but this procedure seems inappropriate after gastric bypass surgery (Roux-en-Y gastric bypass (RYGB)) due to specific altered glycemic responses. We aimed here at describing continuous glucose monitoring (CGM) profile of pregnant women after RYGB. METHODS: CGM was performed in 35 consecutive pregnant women after RYGB at 26.2 +/- 5 weeks of gestation. RESULTS: After RYGB, pregnant women display high postprandial interstitial glucose (IG) peaks and low IG before and 2 h after meals. The postprandial IG peak is reached early, within 54 +/- 9 min. The maximum IG values reach 205 mg/dl, and the percentage of time above 140 mg/dl (6.6 +/- 7 %) is similar to what is described in GDM women. CONCLUSIONS: This study is the first to describe CGM profile in pregnant women after RYGB. CGM features are similar to those of non-pregnant post RYGB patients, characterized by wide and rapid changes in postprandial IG, and high exposure to hyperglycemia. The exposure to hyperglycemia is similar to what is reported in GDM although the time to postprandial peak is shorter. CGM could be an additional useful approach to screen for glucose intolerance during pregnancy after RYGB. PMID- 26757926 TI - Surface and structural effects of pitch and time on global melodic expectancies. AB - We investigated how the surface and structural information of pitch and time in melodies contribute to the perceived expectancy of melodic segments. The contour (pitch surface), tonality (pitch structure), rhythm (time surface) and metre (time structure) were preserved or altered in factorial fashion, either for the full length of a melody (Full condition) or only its last phrase (Last condition). Participants (N = 24) with a range of musical training received instructions to rate how expected the second portion of a melody was, having heard its first part. Additionally, instructions varied across blocks to attend selectively to pitch, time, or both. Expectancy ratings for the Last condition were lower than for the Full condition, indicating that ratings truly reflected expectancy (rather than overall goodness, which would predict the opposite). Interestingly, tonality and rhythm contributed to global expectancy ratings, but not contour or metre. Furthermore, listeners were unable to ignore entirely either dimension, but successfully attenuated their influence in accordance with instructions. These findings offer a unique insight into music perception by testing expectancies of melody segments (beyond single-note continuations), factorially varying both the surface and structure of pitch and time, and using a selective attention manipulation. PMID- 26757925 TI - Prognostic significance of stem cell marker CD133 determined by promoter methylation but not by immunohistochemical expression in malignant gliomas. AB - CD133 has played a pivotal role in the identification and isolation of brain tumor stem cells. The correlation between CD133 expression in tumor tissues with patients survival is still controversial. CD133 expression is determinated by methylation status of the promoter region 1-3. Aberrant methylation of CD133 was observed in glioblastoma. To date, a direct link between CD133 methylation and patient outcome has not been established.To address this question, we studied CD133 expression and promoter methylation in a series of 170 gliomas of various grade and histology, and investigated the correlation of CD133 expression and promoter methylation with patient outcome.We detected five CD133 promoter methylation patterns in 170 glioma samples: methylation only (M+, U-), unmethylation only (M-, U+), both methylation and unmethylation equally (M+, U+), high methylation and low unmethylation (M+, Ul), and low methylation and high unmethylation (Ml, U+). By multivariate survival analysis, we found CD133 promoter methylation status was significant (P < 0.01) prognostic factors for adverse progression-free survival and overall survival independent of tumor grade, extent of resection, or patient age. CD133 immunostaining showed considerable variability among tumors. While, there was lack of correlation between CD133 protein expression and patient's survival. Furthermore, no correlation between CD133 protein expression and CD133 promoter methylation status was observed (Kw = -0.165).CD133 promoter methylation status in glioma is closely correlated with patient survival, which suggest CD133 promoter methylaiton pattern is a promising tool for diagnostic purposes. PMID- 26757927 TI - Evodiamine induces apoptosis and enhances apoptotic effects of erlotinib in wild type EGFR NSCLC cells via S6K1-mediated Mcl-1 inhibition. AB - Erlotinib is effective in NSCLC patients with known drug-sensitizing EGFR mutations, but its clinical efficacy in patients with wild-type EGFR or acquired resistance to erlotinib remains modest. Evodiamine is a chemical extracted from the Evodia rutaecarpa (Juss.) Benth, we showed that evodiamine could induce anti proliferation and apoptosis in four wild-type EGFR NSCLC cell lines, and combining evodiamine with erlotinib might successfully inhibit cell proliferation and survival in wild-type EGFR NSCLC cells, characterized as erlotinib-resistant. In addition, evodiamine plus erlotinib significantly increased the apoptotic rate of NSCLC cells, as compared to single agent treatment alone. Further investigation of the mechanism underlying these effects revealed that evodiamine plus erlotinib might downregulate Mcl-1 expression through the mTOR/S6K1 control of its translation. Thus, our study has revealed evodiamine as a pertinent sensitizer to erlotinib and the strategy of combining erlotinib with evodiamine appears to be an attractive option for reversing resistance to erlotinib. PMID- 26757929 TI - Light triggers habitat choice of eyeless subterranean but not of eyed surface amphipods. AB - Boundaries of species distributions are the result of colonization-extinction processes. Survival on the boundary depends on how well individuals discriminate optimal from suboptimal habitat patches. Such behaviour is called habitat choice and was only rarely applied to macroecology, although it links species ecological niche and species distribution. Surface and subterranean aquatic species are spatially strongly segregated, even in the absence of physical barriers. We explored whether a behavioural response to light functions as a habitat choice mechanism that could explain species turnover between surface and subterranean aquatic ecosystems. In a controlled laboratory experiment, we studied the behavioural response to light of ten pairs of surface and subterranean amphipods that permanently co-occur in springs. Surface species showed a weak photophobic, photoneutral, and in one case, photophilic response, whereas all subterranean species showed a strong photophobic response. Eyeless subterranean but not eyed surface amphipods appear to orient themselves with light cues. On a local scale, this difference possibly diminishes harmful interactions between the co-occurring amphipods, whereas on a regional scale, photophobia could explain limited dispersal and a high degree of endemism observed among subterranean species. PMID- 26757930 TI - Novel biodiversity baselines outpace models of fish distribution in Arctic waters. AB - During a recent marine biological expedition to the Northeast Greenland shelf break (latitudes 74-77 degrees N), we made the first discovery of Atlantic cod (Gadus morhua), beaked redfish (Sebastes mentella) and capelin (Mallotus villosus). Our novel observations shift the distribution range of Atlantic cod >1000 km further north in East Greenland waters. In light of climate change, we discuss physical forcing and putative connections between the faunas of the Northeast Greenland shelf and the Barents Sea. We emphasise the importance of using real data in spread scenarios for understudied Arctic seas. PMID- 26757931 TI - Inter-rater reliability and generalizability of patient note scores using a scoring rubric based on the USMLE Step-2 CS format. AB - Recent changes to the patient note (PN) format of the United States Medical Licensing Examination have challenged medical schools to improve the instruction and assessment of students taking the Step-2 clinical skills examination. The purpose of this study was to gather validity evidence regarding response process and internal structure, focusing on inter-rater reliability and generalizability, to determine whether a locally-developed PN scoring rubric and scoring guidelines could yield reproducible PN scores. A randomly selected subsample of historical data (post-encounter PN from 55 of 177 medical students) was rescored by six trained faculty raters in November-December 2014. Inter-rater reliability (% exact agreement and kappa) was calculated for five standardized patient cases administered in a local graduation competency examination. Generalizability studies were conducted to examine the overall reliability. Qualitative data were collected through surveys and a rater-debriefing meeting. The overall inter-rater reliability (weighted kappa) was .79 (Documentation = .63, Differential Diagnosis = .90, Justification = .48, and Workup = .54). The majority of score variance was due to case specificity (13 %) and case-task specificity (31 %), indicating differences in student performance by case and by case-task interactions. Variance associated with raters and its interactions were modest (<5 %). Raters felt that justification was the most difficult task to score and that having case and level-specific scoring guidelines during training was most helpful for calibration. The overall inter-rater reliability indicates high level of confidence in the consistency of note scores. Designs for scoring notes may optimize reliability by balancing the number of raters and cases. PMID- 26757928 TI - Methylation-dependent regulation of HIF-1alpha stability restricts retinal and tumour angiogenesis. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) mediates hypoxic responses and regulates gene expression involved in angiogenesis, invasion and metabolism. Among the various HIF-1alpha posttranslational modifications, HIF-1alpha methylation and its physiological role have not yet been elucidated. Here we show that HIF-1alpha is methylated by SET7/9 methyltransferase, and that lysine specific demethylase 1 reverses its methylation. The functional consequence of HIF-1alpha methylation is the modulation of HIF-1alpha stability primarily in the nucleus, independent of its proline hydroxylation, during long-term hypoxic and normoxic conditions. Knock-in mice bearing a methylation-defective Hif1a(KA/KA) allele exhibit enhanced retinal angiogenesis and tumour vascularization via HIF 1alpha stabilization. Importantly, S28Y and R30Q mutations of HIF-1alpha, found in human cancers, are involved in the altered HIF-1alpha stability. Together, these results demonstrate a role for HIF-1alpha methylation in regulating protein stability, thereby modulating biological output including retinal and tumour angiogenesis, with therapeutic implications in human cancer. PMID- 26757932 TI - Refraction data survey: 2nd generation correlation of myopia. AB - The objective herein is to provide refraction data, myopia progression rate, prevalence, and 1st and 2nd generation correlations, relevant to whether myopia is random or inherited. First- and second-generation ocular refraction data are assembled from N = 34 families, average of 2.8 children per family. From this group, data are available from N = 165 subjects. Inter-generation regressions are performed on all the data sets, including correlation coefficient r, and myopia prevalence [%]. Prevalence of myopia is [M] = 38.5 %. Prevalence of high myopes with |R| >6 D is [M-] = 20.5 %. Average refraction is = -1.84 D +/- 3.22 (N = 165). For the high myopes, |R| >6 D, prevalence for the parents is [M-] = 25 %, for the 2nd generation [M-] = 16.5 %. Average myopia level for the high myopes, both generations, is = -7.52 D +/- 1.31 D (N = 33). Regression parameters are calculated for all the data sets, yielding correlation coefficients in the range r = 0.48-0.72 for some groups of myopes and high myopes, fathers to daughters, and mothers to sons. Also of interest, some categories show essentially no correlation, -0.20 < r < 0.20, indicating that the refractive errors occur randomly. Time series results show myopia diopter rates = -0.50 D/year. PMID- 26757933 TI - Results of pterygium excision adjunct with conjunctival autograft transplantation for primary pterygium by ophthalmology trainees. AB - To evaluate the results of pterygium excision with conjunctival autograft transplantation for primary pterygium performed by trainee ophthalmologists. Design Prospective interventional case series. Setting A tertiary eye care center in northern Thailand. Participants Patients with primary pterygium recruited from July 2011 to August 2012. Intervention In all cases, the affected eye underwent pterygium excision followed by a superior conjunctival autograft carried out by trainee ophthalmologists. Main outcome measure The recurrence of pterygium and other post-operative complications. Results Sixty-two eyes from 54 patients were studied. There were 36 females (66.7 %) and 18 males (33.3 %). The mean age of the patients was 54.5 (+/-9.8) years with the mean corneal invasion measured at 3.3(+/-0.8) mm. Pterygium morphologies of Grade 1, Grade 2, and Grade 3 were 33.9, 48.4, and 17.7 %, respectively, with the mean follow-up time of 17.3 (+/ 7.9) months. Pterygium recurred in the cornea of six eyes (9.7 %). All recurrences occurred within 6-month post-operation. Other post-operative complications included conjunctival recurrence (4.8 %), graft retraction (3.2 %), conjunctival cyst (3.2 %), and increased intraocular pressure (1.6 %). The recurrence of pterygium was not associated with the patient age (p = 0.72), occupation (p = 0.23), sun exposure time (p = 0.18), pterygium duration (p = 0.22), pterygium size (p = 0.67), or pterygium morphology (p = 0.85). Conclusion The recurrence rate and post-operative complications of pterygium excision with conjunctival autograft performed by trainee ophthalmologists were within acceptable limits. All recurrence occurred within 6 months after surgery. PMID- 26757934 TI - A very rare case of eyelid metastasis originating from lung adenocarcinoma. AB - PURPOSE: To report a very rare eyelid mass confirmed to be a metastasis from lung adenocarcinoma. METHODS: A 68-year-old man had a two-month history of a large nodule in the right upper eyelid. He was a known case of lung adenocarcinoma since 2 years without a history of systemic metastasis. He underwent further investigations including orbital imaging and biopsy of the lesion. RESULTS: Biopsy and immunohistochemical evaluations of the eyelid lesion revealed a moderate to poorly differentiated adenocarcinoma, a similar histology to the lung lesion. CONCLUSIONS: Metastatic involvement of the eyelids is rarely seen; specifically, those associated with lung adenocarcinoma as the source have been reported extremely rare. Eyelid metastases present with various and non-specific clinical features, and therefore biopsy of suspicious or recurrent lesions is highly recommended to rule out such malignant processes. PMID- 26757935 TI - Comparative effect of topical diclofenac and topical dexamethasone on anterior chamber flare and postoperative pain following rhegmatogenous retinal detachment surgery. AB - The purpose of this study is to compare the effect of topical diclofenac and topical dexamethasone on anterior chamber flare and postoperative pain following rhegmatogenous retinal detachment (RRD) surgery. This prospective study included 40 eyes of 40 patients treated for RRD. Twenty-eight patients underwent scleral buckling and 12 patients underwent 20-gauge pars plana vitrectomy (PPV). For each surgical procedure, patients were postoperatively randomly divided into two groups: the first group received topical dexamethasone phosphate 0.1 % four times daily for 28 days; the second group received topical diclofenac sodium 0.1 % three times daily for 28 days. The inflammatory reaction in the anterior chamber was measured with laser flare photometry preoperatively and 1, 7, 14, 28, and 90 days postoperatively. Pain level was evaluated with Scott's visual analog scale at day 1, 7, 14, and 28 postoperatively. For patients treated with scleral buckling, there was no significant difference between the two groups regarding mean aqueous flare at day 1 (p = 0.096), day 7 (p = 0.435), day 14 (p = 0.510), day 28 (p = 0.583), and day 90 (p = 0.423). The group who received diclofenac had significantly lower pain score at days 7, 14, and 28 (p = 0.048, p = 0.017, and p = 0.028, respectively). For patients treated with PPV, there was no significant difference between the two groups regarding mean aqueous flare at day 1 (p = 0.400), day 7 (p = 0.728), day 14 (p = 0.843), day 28 (p = 0.939), and day 90 (p = 0.568). Patients who received diclofenac had significantly lower pain score at days 7, 14, and 28 (p = 0.032, p = 0.030, and p = 0.023, respectively). Topical diclofenac seems to be as potent as topical dexamethasone in managing postoperative inflammatory response induced by surgery for RRD with better analgesic effect. Both of them are consequences of blood-aqueous barrier and blood-retinal barrier breakdown. PMID- 26757937 TI - Response to "the causes worsening sleep quality". PMID- 26757936 TI - Systematic review of reduced therapy regimens for children with low risk febrile neutropenia. AB - PURPOSE: Reduced intensity therapy for children with low-risk febrile neutropenia may provide benefits to both patients and the health service. We have explored the safety of these regimens and the effect of timing of discharge. METHODS: Multiple electronic databases, conference abstracts and reference lists were searched. Randomised controlled trials (RCT) and prospective observational cohorts examining the location of therapy and/or the route of administration of antibiotics in people younger than 18 years who developed low-risk febrile neutropenia following treatment for cancer were included. Meta-analysis using a random effects model was conducted. I (2) assessed statistical heterogeneity not due to chance. REGISTRATION: PROSPERO (CRD42014005817). RESULTS: Thirty-seven studies involving 3205 episodes of febrile neutropenia were included; 13 RCTs and 24 prospective observational cohorts. Four safety events (two deaths, two intensive care admissions) occurred. In the RCTs, the odds ratio for treatment failure (persistence, worsening or recurrence of fever/infecting organisms, antibiotic modification, new infections, re-admission, admission to critical care or death) with outpatient treatment was 0.98 (95% confidence interval (95%CI) 0.44-2.19, I (2) = 0 %) and with oral treatment was 1.05 (95%CI 0.74-1.48, I (2) = 0 %). The estimated risk of failure using outpatient therapy from all prospective data pooled was 11.2 % (95%CI 9.7-12.8 %, I (2) = 77.2 %) and using oral antibiotics was 10.5 % (95%CI 8.9-12.3 %, I (2) = 78.3 %). The risk of failure was higher when reduced intensity therapies were used immediately after assessment, with lower rates when these were introduced after 48 hours. CONCLUSIONS: Reduced intensity therapy for specified groups is safe with low rates of treatment failure. Services should consider how these can be acceptably implemented. PMID- 26757938 TI - A novel, clinically relevant use of a piglet model to study the effects of anesthetics on the developing brain. AB - BACKGROUND: Anesthesia-induced neurotoxicity research in the developing brain must rely upon an unimpeachable animal model and a standardized treatment approach. In this manner, identification of mechanisms of action may be undertaken. The goal of this study was to develop a novel, clinically relevant, translational way to use a piglet model to investigate anesthesia effects on the developing brain. METHODS: 29 newborn piglets were assigned to either: (1) control (no intervention, n = 10); (2) lipopolysaccharide (LPS; positive inflammatory control, n = 9); or (3) isoflurane anesthesia (n = 10). Positive inflammatory control animals were given 100 mcg/kg LPS from Escherichia coli intraperitoneally (IP) on the same day as those receiving isoflurane. Isoflurane was administered for 3 h while care was taken to ensure human perioperative conditions. To establish a clinical scenario, each animal was intubated and monitored with pulse oximetry, invasive and non-invasive blood pressure, electrocardiogram, temperature, end-tidal CO2, anesthetic concentration, and iSTAT blood analysis. All animals were sacrificed after 48 h using transcardiac perfusion of ice-cold, heparinized phosphate buffered saline (PBS) followed by 4 % paraformaldehyde (PFA). Brains were collected and histopathological analysis focused on the entorhinal cortex looking for degenerative changes due to its critical role in learning and memory. Reliable identification of entorhinal cortex was achieved by using colored ink on the surface of the brains, which was then cross-referenced with microscopic anatomy. Hematoxylin & eosin-stained high power fields was used to quantify cells. ImageJTM (National Institutes of Health, Bethesda, MD, USA) was used to count absolute number of progenitor glial cells (PGC) and number of PGCs per cluster. Immunohistochemistry was also utilized to ensure positive identification of cellular structures. RESULTS: Histopathological sections of 28 brains were analyzed. One animal in the LPS group died shortly after administration, presumably from inadvertent intravascular injection. There was an acute basal ganglia ischemic infarct in one isoflurane-treated animal. A large number of small, round nucleated cells were seen throughout layer II of the entorhinal cortex in all animals. These cells were identified as PGCs using immunohistochemistry and light microscopy. Although there was no difference in the absolute number of PGCs between the groups, animals given isoflurane or LPS demonstrated a significant increase in cells forming 'clusters' in the entorhinal cortex. An apparent change in the pattern of doublecortin labeling also suggests changes in neuronal precursors and undifferentiated neurons. CONCLUSIONS: This study represents the first novel use of a clinically relevant neonatal piglet model to study anesthesia effects on the developing brain. LPS induces neuroinflammation, and this is a potential mechanism for LPS and perhaps isoflurane in causing a change in progenitor cell distribution. We postulate that the isoflurane-induced change in glial progenitor cell distribution could have important implications for cell differentiation, maturation and neural circuit behavior in the rapidly developing brain. PMID- 26757939 TI - Two-stage revision arthroplasty for periprosthetic joint infections: What is the value of cultures and white cell count in synovial fluid and CRP in serum before second stage reimplantation? AB - INTRODUCTION: Besides CRP in serum, white cell counts and cultures of synovial fluid are routinely used to detect periprosthetic joint infections. But the sensitivities of these parameters do vary from 12 to 100 %. In two stage revision arthroplasty before the second stage surgeons have to decide if reimplantation is justified. Therefore, we investigated the value of cultures and white cell count from the synovial fluid with a polymethyl methacrylate spacer in place and CRP in serum before reimplantation to detect persistent infection in a standardized setting. METHODS: 115 patients with a two-stage revision hip or knee arthroplasty were included in this study. All patients had an antibiotic loaded polymethylmethacrylate spacer. Retrospectively synovial cultures, white blood count in synovial fluid and CRP in serum were assessed before reimplantation. RESULTS: The sensitivity of the synovial cultures was 5 % (95 % CI 0.13-24.87), with a specificity of 99 % (95 % CI 94.27-99.97). For white blood count in synovial fluid the sensitivity was 31.3 %, specificity was 39.1 %. Sensitivity for CRP in serum was 42.10 %, specificity was 84.21 %. CONCLUSION: Cultures from synovial fluid and white blood count in synovial fluid and CRP seem to be uncertain parameters to exclude persistent infection. We do not recommend joint aspiration before reimplantation anymore. Further research is necessary to find other markers to confirm or exclude persistent infection. PMID- 26757940 TI - Erratum to: Accuracy of Blood Pressure-to-Height Ratio to Define Elevated Blood Pressure in Children and Adolescents: The CASPIAN-IV Study. PMID- 26757941 TI - Isolation of a novel H3N2 influenza virus containing a gene of H9N2 avian influenza in a dog in South Korea in 2015. AB - We isolated a serotype H3N2 influenza virus from a dog with severe respiratory distress in an animal clinic in South Korea in 2015 and characterized the sequences of its eight genes. The following seven genes were derived from canine influenza virus: PB2, PB1, HA, NP, NA, M, and NS. However, the PA gene was derived from avian H9N2 influenza virus that is circulating in poultry in Korea. These findings suggest that the continued surveillance of the influenza virus in dogs is warranted because humans have close contact with dogs, which may promote viral transmission. PMID- 26757942 TI - Genomic characterization of Salmonella bacteriophages isolated from India. AB - Salmonella are a medically important Gram-negative foodborne pathogen. Genomic diversity of Salmonella is increasingly studied but at the same time, we have limited knowledge of Salmonella phage diversity. In this study, we have isolated Salmonella phages from sewage and river water. Genomic characterization of 12 Salmonella phages was carried out using next-generation sequencing platform. Newly sequenced phages were classified based on amino acid sequence phylogenetic analysis. In newly sequenced phages, several virulence genes, DNA metabolism genes, tRNA genes, antibiotic resistance genes and genes not having known role in the life cycle of phages were identified. Annotations of newly sequenced phage genome showed the presence of polymyxin-b resistance gene and penicillin binding protein. Annotation identified number of genes which are involved in DNA metabolism. Results suggest that most of the phages having G + C content different than their host possess DNA metabolism genes. The presence of tRNAs in the genome of Salmonella_phage38-India was identified; however, we did not observe any correlation between tRNA genes and overall codon usage in the phage genome. It is suggested that the phage-encoded tRNAs may increase fitness of phages. In summary, we isolated novel Salmonella phages, determined full genome sequences and provided phylogenetic analysis-based classification. PMID- 26757943 TI - Molecular identification of a novel victorivirus from the phytopathogenic fungus Nigrospora oryzae. AB - Nigrospora oryzae is a worldwide phytopathogenic fungus that can infect many plant host species. In this study, complete sequence of a novel mycovirus from N. oryzae was reported. The viral genome is 5100 base pairs in length and possesses two overlapping open reading frames (ORFs). The two ORFs potentially encode proteins that showed significant similarity to the capsid protein and RNA dependent RNA polymerase, in the family Totiviridae, respectively. Phylogenetic tree showed that this novel mycovirus is a new member of the genus Victorivirus in the family Totiviridae. We here designated the virus as Nigrospora oryzae victorivirus 1 (NoRV1), the first putative victorivirus identified in N. oryzae. PMID- 26757944 TI - Thermodynamics of Pb(ii) and Zn(ii) binding to MT-3, a neurologically important metallothionein. AB - Isothermal titration calorimetry (ITC) was used to quantify the thermodynamics of Pb(2+) and Zn(2+) binding to metallothionein-3 (MT-3). Pb(2+) binds to zinc replete Zn7MT-3 displacing each zinc ion with a similar change in free energy (DeltaG) and enthalpy (DeltaH). EDTA chelation measurements of Zn7MT-3 and Pb7MT 3 reveal that both metal ions are extracted in a tri-phasic process, indicating that they bind to the protein in three populations with different binding thermodynamics. Metal binding is entropically favoured, with an enthalpic penalty that reflects the enthalpic cost of cysteine deprotonation accompanying thiolate ligation of the metal ions. These data indicate that Pb(2+) binding to both apo MT-3 and Zn7MT-3 is thermodynamically favourable, and implicate MT-3 in neuronal lead biochemistry. PMID- 26757945 TI - Single-crystalline ZnO sheet Source-Gated Transistors. AB - Due to their fabrication simplicity, fully compatible with low-cost large-area device assembly strategies, source-gated transistors (SGTs) have received significant research attention in the area of high-performance electronics over large area low-cost substrates. While usually based on either amorphous or polycrystalline silicon (alpha-Si and poly-Si, respectively) thin-film technologies, the present work demonstrate the assembly of SGTs based on single crystalline ZnO sheet (ZS) with asymmetric ohmic drain and Schottky source contacts. Electrical transport studies of the fabricated devices show excellent field-effect transport behaviour with abrupt drain current saturation (IDS(SAT)) at low drain voltages well below 2 V, even at very large gate voltages. The performance of a ZS based SGT is compared with a similar device with ohmic source contacts. The ZS SGT is found to exhibit much higher intrinsic gain, comparable on/off ratio and low off currents in the sub-picoamp range. This approach of device assembly may form the technological basis for highly efficient low-power analog and digital electronics using ZnO and/or other semiconducting nanomaterial. PMID- 26757946 TI - Reply; Testotoxicosis: Report of Two Cases, One with a Novel Mutation in LHCGR Gene. PMID- 26757947 TI - Metal adatoms generated by the co-play of melamine assembly and subsequent CO adsorption. AB - Molecular self-assembly films are expected to tailor the surface process by the periodic nanostructures and add-on functional groups. In this work, a molecular network of melamine with featured pores of subnanometer size is prepared on the Au(111) surface, and is found to be able to trap the gold adatoms and concomitant single vacancies generated under the impingement of CO molecules at room temperature. DFT calculations suggest that the strong CO-Au adatom interaction as well as the high adhesion of the Au adatom inside the melamine pore could well be the driving force behind such process. This study not only sheds light onto the interactions between gasses and the metal surface that is covered by molecular self-assembly films, but also provides a novel route to manipulate the monoatomic surface species which is of catalytic interest. PMID- 26757948 TI - An Adolescent Boy with Comorbid Anorexia Nervosa and Hashimoto Thyroiditis. AB - Low triiodothyronine syndrome is a physiological adaptation encountered in anorexia nervosa (AN) and generally improves with sufficient weight gain. However, when a primary thyroid pathology accompanies AN, both the evaluation of thyroid hormone levels and the management of the co-morbid disease become more challenging. Hashimoto thyroiditis could complicate the management of AN by causing hyper- or hypothyroidism. AN could also negatively affect the treatment of Hashimoto thyroiditis by altering body weight and metabolic rate, as well as by causing drug non-compliance. We present the case of a 15-year-old boy with comorbid AN restrictive sub-type and Hashimoto thyroiditis. In this case report, we aimed to draw attention to the challenges that could be encountered in the diagnosis, treatment, and follow-up of patients with AN when accompanied by Hashimoto thyroiditis. PMID- 26757949 TI - CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction. AB - The endocannabinoid system can modulate energy homeostasis by regulating feeding behaviour as well as peripheral energy storage and utilization. Importantly, many of its metabolic actions are mediated through the cannabinoid type 1 receptor (CB1R), whose hyperactivation is associated with obesity and impaired metabolic function. Herein, we explored the effects of administering rimonabant, a selective CB1R inverse agonist, upon key metabolic parameters in young (4 month old) and aged (17 month old) adult male C57BL/6 mice. Daily treatment with rimonabant for 14 days transiently reduced food intake in young and aged mice; however, the anorectic response was more profound in aged animals, coinciding with a substantive loss in body fat mass. Notably, reduced insulin sensitivity in aged skeletal muscle and liver concurred with increased CB1R mRNA abundance. Strikingly, rimonabant was shown to improve glucose tolerance and enhance skeletal muscle and liver insulin sensitivity in aged, but not young, adult mice. Moreover, rimonabant-mediated insulin sensitization in aged adipose tissue coincided with amelioration of low-grade inflammation and repressed lipogenic gene expression. Collectively, our findings indicate a key role for CB1R in aging related insulin resistance and metabolic dysfunction and highlight CB1R blockade as a potential strategy for combating metabolic disorders associated with aging. PMID- 26757950 TI - Sublethal Dosage of Imidacloprid Reduces the Microglomerular Density of Honey Bee Mushroom Bodies. AB - The dramatic loss of honey bees is a major concern worldwide. Previous studies have indicated that neonicotinoid insecticides cause behavioural abnormalities and have proven that exposure to sublethal doses of imidacloprid during the larval stage decreases the olfactory learning ability of adults. The present study shows the effect of sublethal doses of imidacloprid on the neural development of the honey bee brain by immunolabelling synaptic units in the calyces of mushroom bodies. We found that the density of the synaptic units in the region of the calyces, which are responsible for olfactory and visual functions, decreased after being exposed to a sublethal dose of imidacloprid. This not only links a decrease in olfactory learning ability to abnormal neural connectivity but also provides evidence that imidacloprid damages the development of the nervous system in regions responsible for both olfaction and vision during the larval stage of the honey bee. PMID- 26757952 TI - Comments on 'Twenty-five years of confirmatory adaptive designs: opportunities and pitfalls'. PMID- 26757951 TI - Cytokine levels contribute to the pathogenesis of minimal hepatic encephalopathy in patients with hepatocellular carcinoma via STAT3 activation. AB - Hepatocellular carcinoma (HCC) patients were grouped according to the degree of encephalopathy, with healthy volunteers as controls. We investigated clinical presentation, protein and mRNA expression of 14 cytokines, and activation of six STAT proteins, the downstream signaling mediators. Levels of all 14 cytokines were significantly elevated in HCC patients with clinical hepatic encephalopathy. Statistical analysis showed that levels of IL-1beta, IL-6, IFNgamma, IL-17alpha, IFNlambda2 and IFNlambda3 were correlated with minimal hepatic encephalopathy (MHE). Multivariate regression analysis identified serum IL-6, IFNlambda3 and IL 17alpha as independent risk factors for MHE. Increased mRNA levels of IL-6 and IFNgamma were associated with MHE. Among the STAT proteins examined, only STAT3 was elevated in MHE. Treatment with a STAT3 inhibitor protected neurons from cytokine-induced apoptosis in vitro. In conclusion, this study identified potential biomarkers for MHE in HCC. The cytokines investigated may induce neural apoptosis via STAT3 in the pathogenesis of MHE in HCC. PMID- 26757953 TI - An objective re-evaluation of adaptive sample size re-estimation: commentary on 'Twenty-five years of confirmatory adaptive designs'. AB - Over the past 25 years, adaptive designs have gradually gained acceptance and are being used with increasing frequency in confirmatory clinical trials. Recent surveys of submissions to the regulatory agencies reveal that the most popular type of adaptation is unblinded sample size re-estimation. Concerns have nevertheless been raised that this type of adaptation is inefficient.We intend to show in our discussion that such concerns are greatly exaggerated in any practical setting and that the advantages of adaptive sample size re-estimation usually outweigh any minor loss of efficiency. PMID- 26757954 TI - Comments on 'Twenty-five years of confirmatory adaptive designs: opportunities and pitfalls'. PMID- 26757955 TI - Comments on 'Twenty-five Years of Confirmatory Adaptive Designs: Opportunities and Pitfalls'. PMID- 26757956 TI - Authors' response to comments. PMID- 26757957 TI - Comments on 'A comparative study of adaptive dose-finding designs for phase I oncology trials of combination therapies'. PMID- 26757958 TI - Authors' Reply. PMID- 26757960 TI - Valuing inter-sectoral costs and benefits of interventions in the healthcare sector: methods for obtaining unit prices. AB - INTRODUCTION: There is a lack of knowledge about methods for valuing health intervention-related costs and monetary benefits in the education and criminal justice sectors, also known as 'inter-sectoral costs and benefits' (ICBs). The objective of this study was to develop methods for obtaining unit prices for the valuation of ICBs. METHODS: By conducting an exploratory literature study and expert interviews, several generic methods were developed. The methods' feasibility was assessed through application in the Netherlands. Results were validated in an expert meeting, which was attended by policy makers, public health experts, health economists and HTA-experts, and discussed at several international conferences and symposia. RESULTS: The study resulted in four methods, including the opportunity cost method (A) and valuation using available unit prices (B), self-constructed unit prices (C) or hourly labor costs (D). DISCUSSION: The methods developed can be used internationally and are valuable for the broad international field of HTA. PMID- 26757962 TI - [It's time to expand pediatric kidney transplantation in China]. PMID- 26757961 TI - [Solve the problem of kidney disease in children with the concept of evidence based medicine]. PMID- 26757959 TI - alpha-Synuclein and huntingtin exon 1 amyloid fibrils bind laterally to the cellular membrane. AB - Fibrillar aggregates involved in neurodegenerative diseases have the ability to spread from one cell to another in a prion-like manner. The underlying molecular mechanisms, in particular the binding mode of the fibrils to cell membranes, are poorly understood. In this work we decipher the modality by which aggregates bind to the cellular membrane, one of the obligatory steps of the propagation cycle. By characterizing the binding properties of aggregates made of alpha-synuclein or huntingtin exon 1 protein displaying similar composition and structure but different lengths to mammalian cells we demonstrate that in both cases aggregates bind laterally to the cellular membrane, with aggregates extremities displaying little or no role in membrane binding. Lateral binding to artificial liposomes was also observed by transmission electron microscopy. In addition we show that although alpha-synuclein and huntingtin exon 1 fibrils bind both laterally to the cellular membrane, their mechanisms of interaction differ. Our findings have important implications for the development of future therapeutic tools that aim to block protein aggregates propagation in the brain. PMID- 26757963 TI - [Application of pharmacometrics in personalized therapy in children]. PMID- 26757964 TI - [Chinese expert consensus of pediatric therapeutic drug monitoring]. PMID- 26757965 TI - [Analysis on factors relevant to operation success rate of internal arteriovenous fistula used in pediatric patients with end stage renal disease]. AB - OBJECTIVE: To analyze the factors relevant to success rate of arteriovenous fistula (AVF) plasty in children who need maintenance hemodialysis and to provide predictor of the success of operation. METHOD: Totally 62 patients who had arteriovenous fistula plasty operation for maintenance of hemodialysis in our hospital treated during June 2007 to April 2014 were enrolled into this study, 41 were male, and 21 female, median age of surgery was 11 years and 9 months (age range was 5 y 8 m to 16 y 2 m). The proportions of primary diseases were: chronic glomerulonephritis 29% (18), kidney abnormality and dysplasia 27% (17). These 62 cases were divided into 2 groups: the success group and the failure group according to whether there were tremble and vascular murmur on the surgery site 1 week after the surgery. Factors like sex, choice of operation side, choice of operation vessel, anesthesia, urine protein, model of vascular suture line, age of surgery, inner diameter of anastomotic stoma, hemoglobin (Hb), platelet (Plt), hematocrit (Hct), coagulation function (prothrombin time, PT, fibrinogen, Fib, activated partial thromboplastin time, APTT), creatinine (Scr), Ca2+, left ventricular ejection fraction (LVEF), blood pressure (before, during and after surgery) were collected retrospectively. Student's t test and chi-square tests were used to analyze the differences of the factors between 2 groups. Those factors which were statistically significant in t test and chi-square test were taken into multi factor logistic regression analysis. RESULT: (1) Average time interval from final diagnosis of ESRD to surgery was 30.8 days. (2) Relevant factors of operation success rate: anesthesia (chi2 = 5.531, P=0.026), preoperative serum cholesterol (CHO) (t=-2.069, P=0.043), mean systolic blood pressure in the afternoon before operation (t=2.154, P=0.042), systolic blood pressure when the operation was finished (t=2.199, P=0.032) were related to the success rate of AVF operation in the t test and chi-square test. Multi factors logistic regression analysis showed systolic blood pressure measured when the operation was finished was a dependent protective factor of the surgery (OR=0.962, P=0.040, 95% CI=0.926-0.998). When the systolic blood pressure at the end of operation elevated 1 mmHg (1 mmHg=0.133 kPa), the failure rate of the surgery would be 0.962 times. CONCLUSION: The time interval from final diagnosis of ESRD to surgery was 30.8 days, it was much shorter than 6-12 months which was suggested by 2006 NKF-KDOQI vascular access guideline. As dependent protective factor of success rate, the systolic blood pressure at the end of operation was suggested to be the predictor of successful operation. And the higher systolic blood pressure at the end of operation may increase the success rate of operation. PMID- 26757966 TI - [Etiological analysis of 264 cases with chronic kidney disease stage 2 to 5 in children]. AB - OBJECTIVE: To study and summarize the etiology of children patients with chronic kidney disease (CKD) stage 2 to 5 seen in Children's Hospital of Fudan University from Jan. 2004 to Dec. 2013. METHOD: By complying with the NKF-K/DOQI guidelines, we collected data of 264 cases of children patients with CKD stage 2-5 from Jan. 2004 to Dec. 2013 in the medical record system of Children's Hospital of Fudan University. And we retrospectively analyzed their age and CKD stage at first diagnosis, primary diseases, complications, etc. RESULT: In the collected 264 cases, 52 cases (19.7%) were diagnosed at stage 2, 67 (25.4%) at stage 3, 52 (19.7%) at stage 4 and 93 (35.2%) at stage 5. For disease causes, 116 cases (43.9%) had congenital anomalies of the kidney and urinary tract (CAKUT), 61 cases (23.1%) had glomerular disease, 15 (5.7%) had hereditary kidney disease, 14 (5.3%) had other diseases and in 58 cases (22.0%) the causes of disease were unknown. In the group with age between 0 and 3.0 and 3.1 and 6.0 years, 57.1% (24 cases) and 60.0% (30 cases) had primary disease with CAKUT. In the group with age older than 10 years, 49.2% (30 cases) had primary disease with glomerular disease and 32.0% (32 cases) with unknown causes. CONCLUSION: The major cause of CKD stage 2-5 in children in our hospital during the last ten years was CAKUT (43.9%), followed by glomerular disease (23.1%). The primary diseases of CKD were significantly different between the 2 age groups. CAKUT was more common in infants and preschool children while for adolescents, glomerular disease was the major cause. PMID- 26757967 TI - [Retrospective study of primary IgA nephropathy with crescent formation and/or rapidly progressive glomerulonephritis in children]. AB - OBJECTIVE: IgA nephropathy is the most common type of glomerulonephritis in the world. Its clinical and pathological manifestations vary. A few of the patients with IgA nephropathy present with rapidly progressive glomerulonephritis (RPGN) and/or crescent formation. Their conditions are serious and acute, but there are few reports on their characteristics, treatment and outcome. This study aimed to analyze the clinicalopathological features, treatment and prognosis of primary IgA nephropathy in children, to provide a reference for clinical diagnosis and treatment. METHOD: A retrospective study was conducted in children with primary IgA nephropathy with crescent formation and/or rapidly progressive glomerulonephritis admitted to our department from 2000 to 2014. The patients meeting the inclusion and exclusion criteria were included. Patients were divided into RPGN group and non-RPGN group according to the clinical manifestations, crescent formation group and non-crescent group, crescentic IgA nephropathy group and non-crescentic IgA nephropathy group according to renal biopsy. Their clinical manifestations and pathological features, treatment and prognosis were compared. RESULT: A total of 265 patients were recruited, 10 patients (3.8%) had RPGN, 151 patients (57.0%) had crescent formation, 19 cases (7.2%) showed crescentic IgA nephropathy.Compared with non-RPGN group, RPGN group showed more gross hematuria, higher serum creatinine, lower creatinine clearance correction at biopsy and follow-up, and more crescentic IgA nephropathy (P<0.05). The percent of patients who received methylprednisolone pulse and blood purification therapy in RPGN group is higher than that of non-RPGN group (P<0.05). Compared with non-crescent group, crescent formation group showed more gross hematuria at biopsy and follow-up, higher serum creatinine at biopsy, lower creatinine clearance correction, more 24-hour urinary protein at biopsy and higher serum creatinine at follow-up (P<0.05). The percentage of patients received more methylprednisolone pulse, oral steroids, cyclophosphamide pulse in crescent formation group was higher than that of non-crescent group (P<0.05). Compared with non-crescentic IgA nephropathy group, crescentic IgA nephropathy group showed more RPGN percent, higher serum creatinine, more 24-hour urinary protein at biopsy (P<0.05). The percentage of patients who received more methylprednisolone pulse and blood purification therapy in crescentic IgA nephropathy group was more than non-crescentic IgA nephropathy group (P<0.05). At follow-up, 20.0% of the patients with RPGN and crescent nephritis returned to normal renal function and the percent of crescent glomerulonephritis but not RPGN was 71.4%, RPGN but not crescent glomerulonephritis was 80.0%, crescent formation but not crescent nephritis was 87.5%. CONCLUSION: In primary IgA nephropathy with crescent formation and/or rapidly progressive glomerulonephritis, the patients with both RPGN and crescentic IgA nephropathy showed the worst clinical manifestations, its prognosis was worst while the patients with crescent formation showed the mildest clinical manifestations and best prognosis. PMID- 26757968 TI - [Epidemiological surveillance of hand, foot and mouth disease in Shanghai, 2010 2014]. AB - OBJECTIVE: To understand the epidemiological profiles of hand, foot and mouth disease (HFMD) and the major enteroviruses causing the epidemics of HFMD in Shanghai from 2010 to 2014. METHOD: The city-wide surveillance data between 2010 and 2014 were used to analyze the epidemiologic characteristics of the HFMD outbreaks in Shanghai. The annual incidence of HFMD was estimated based on the 2010 Shanghai Census data. RESULT: From 2010 to 2014, the reported HFMD cases were 41 080, 37 323, 51 172, 42 198, and 65 018, respectively; the severe cases (case-severity ratio) were 469 (1.14%), 456 (1.22%), 318 (0.62%), 104 (0.25%) and 248 (0.38%), respectively. Based on Shanghai census data by the end of 2010, the attack rates of HFMD in Shanghai were 0.16%-0.28% in the entire population. In terms of the proportion of HFMD cases and severe cases in the specific population, male accounted for 59.62%-61.48% and 62.26%-73.08%, migrant population accounted for 51.86%-62.40% and 72.01%-80.38%; children aged 1.0-1.9 years comprised the highest proportion, up to 22.70%-27.00% and 32.08%-36.40%. HFMD peaked from April to July, in parallel with the peak circulation of enterovirus (EV) 71, and a small peak usually occurred in autumn and winter. All the critically severe and fatal cases were caused by EV71. The detection rates of EV71 and Coxsackievirus A (CA) 16 were 73.08%-88.09% and 1.12%-2.90% in severe HFMD cases, 19.75%-48.74% and 2.02%-23.69% in uncomplicated inpatients, and 16.78%-40.08% and 8.36%-33.39% in mild community cases, respectively. The detection rates of CA6 and CA10 in the mild community cases in 2014 were 18.38% and 1.43%, respectively. In 2013 non-EV71 and non-CA16 enteroviruses comprised 74.86% in the community cases. CONCLUSION: The annual HFMD outbreaks occurred in Shanghai during 2010-2014. Children under 5 years of age, migrant population and male were the major susceptible population. EV71 and CA16 were the predominant pathogens causing the epidemics of HFMD except in 2013, and CA6 was prevalent in the community cases in 2014. The major peak season of HFMD usually overlapped with the peak of EV71 circulation and the majority of severe HFMD cases were associated with EV71 infection. PMID- 26757969 TI - [Clinical analysis of 247 children with whooping cough and the risk factors of severe cases]. AB - OBJECTIVE: To summarize the clinical characteristics of whooping cough in children and analyze the risk factors for severe whooping cough. METHOD: A retrospective analysis was made on the clinical data of 247 children with whooping cough in Children's Hospital of Chongqing Medical University between Jan 2013 and Dec 2014. Of these patients, 126 were male, 121 were female, the median age was 3.1 months (23 days-4 years and eight months old). The patients were divided into two groups, group 1 had infants less than 3 months of age (n=120) and group 2 had infants and young children older than 3 months (n=127) according to their age. On the other hand, the patients were also divided into two groups according to vaccination status: vaccinated group (received diphtheria toxoid, tetanus toxoid, and acellular pertussis, DTP) (n=31) and unvaccinated group (n=188). Pure Bordetella pertussis infection was seen in 106 cases, and 141 cases had mixed infection. Severe disease was seen in 13 cases, and the other 234 cases had the modest disease. Clinical data were retrospectively analyzed and compared. RESULT: (1) Bordetella pertussis was identified in 57/680 cases (8.4%) in 2013, and 190/1 856 cases (10.2%) in 2014. The disease could be seen throughout the year, but 182 cases (73.7%) occurred in summer or autumn; 202 cases (81.8%) were less than 6 months. (2) Paroxysmal cough was seen in 238 cases (96.4%) , 61 cases (24.7%) had inspiratory whoop. Infants in group 1 often had episodes of cyanosis, apnea and suffocation (chi2 = 19.999, 12.081, 6.508, P<0.05), persistent cough was often seen in group 2 (chi2 = 9.885, P<0.05). Complications such as severe pneumonia, pulmonary consolidation and encephalopathy were more common in the group 1 than in group 2 (chi2 = 17.340, 6.080, 11.030, 23.545, P<0.05). (3) The length of stay of group 1, and of unvaccinated group was significantly longer than that of group 2 and of vaccinated group (t=19.331, 26.741, P<0.05). (4) Leukocytosis was found in 224 cases (90.7%), 182 cases (73.7%) had predominant lymphocytosis. White blood cell in group 1, unvaccinated group and severe disease group was higher than the corresponding group (t=11.075,13.739,3.469, P<0.05). (5) Patients who had a history of exposure, fever, leukocytosis and pulmonary consolidation or atelectasis on chest imaging were prone to develop into severe pertussis (OR=4.521, 4.900, 1.085, 4.792, 50.400; P<0.05). A total of 244 cases (98.8%) recovered, 3 cases (1.2%) died, they were less than 3 months old and unvaccinated. CONCLUSION: The number of cases with whooping cough in Chongqing area tends to be rising. The disease occurred mostly in summer and fall. Infants less than 3 months old, unvaccinated with DTP had high susceptibility to pertussis, often had a severe clinical presentation and severe complications, had a high mortality rate. PMID- 26757970 TI - [Evaluation of treatment and management of Kawasaki coronary artery disease based on clinical severity classification]. AB - OBJECTIVE: To evaluate the efficacy and safety of evaluation,treatment and follow up of Kawasaki coronary artery disease based on the clinical severity classification. METHOD: This study evaluated 52 patients admitted to the Children's Hospital of Fudan University between July 2005 and December 2013 who were diagnosed with Kawasaki Disease with coronary artery disease.Inclusion criteria were a disease course of more than two months, initial echocardiography showing severity of grade IV and above, and confirmation of disease severity by angiography. Of those studies, 44 were male and eight were female, aged 6 to 142 (average 41) months. Treatment was planned according to protocols in "Suggestions for Management of Kawasaki Coronary Artery Disease" with follow-up. Those patients with grade IV and above confirmed by angiogram were given oral low-dose asprin and warfarin, and those with grade Vb were given coronary artery bypass grafting (CABG) after comprehensive evaluation. Analysis was carried out for diagnosis, treatment, complications, and results of follow-up. RESULT: (1) Satisfied images were shown by the angiography of all 52 cases. Forty five patients (86%) had giant aneurysm or multiple aneurysms, with thrombosis found in 10 of 45 patients (22%). Coronary artery lesions occurred in 138 coronary branches, and more common in left anterior descending branch (47 branches, with incidence 34%) and right coronary artery (48 branches, with incidence 35%). There were no complications during or after angiography. (2) After angiography, 49 patients remained at grade IV or above, and three improved to grade III. Ultimately, clinical severities of coronary artery disease included three patients at grade III, 31 patients at grade IV, nine patients at grade Va, and nine patients at grade Vb. (3) Thirty-eight patients were properly using aspirin and warfarin, and two patients with severely elevated international normalized ratio (INR) levels presented with knee joint and gastric hemorrhage, both of which were treated successfully.Patients with INR levels between 1.5 and 2.5 did not show signs of hemorrhage. (4) In follow-up visits between 6 months and 8 years, one patient had representation of thrombosis on angiography, but did not lead to coronary stenosis; four patients were improved from grade IV to either grade III or II. The remaining showed no new thrombotic formation or stenosis. (5) Of the nine grade Vb patients, five underwent coronary artery bypass grafting. The youngest of these patients, a 22 months old girl, died intraoperatively. The remaining four recovered postoperatively and were followed up for 8 to 90 months. One patient had a preoperative left ventricular ejection fraction (LVEF) of only 32.8%, with LVEF remaining abnormal post-CABG, between 35% and 44%. The remaining three patients had normal heart size, cardiac function, and electrocardiogram.Of the other four grade Vb patients, two were contraindicated for surgery due to severe heart failure and loss of myocardial activity. Two other cases are being followed up closely due to their young age of 9 months. CONCLUSION: Coronary angiography is safe and efficacious in children, and even in infants.It is the current gold standard tool for grading Kawasaki coronary artery disease. Proper anticoagulation therapy can markedly decrease the incidence of coronary artery occlusion in patients with Kawasaki coronary artery disease. Safe ranges of corrected INR should be between 1.5 and 2.5 after taking warfarin. CABG is an effective treatment for severe coronary artery disease with myocardial ischemia. PMID- 26757971 TI - [A voxel-based morphometric study on change of gray matter structures in cerebral palsy]. AB - OBJECTIVE: To measure gray matter volume of whole brain with voxel-based morphometry (VBM) method and to study brain structures associated with gross motor function. METHOD: Forty children with cerebral palsy were recruited in the authors' hospital from Oct. 2012 to Dec. 2013 (26 male, 14 female cases, average age (3.6 +/- 2.0) years ). Gross motor function classification system (GMFCS) for children was used to obtain their motor function. The whole-brain three dimensional magnetic resonance imaging (MRI) was performed on a 3.0 T MRI scanner. The data were segmented by VBM 5, and the whole brain volumes of gray matter, white matter and cerebospinal fluid were produced. Correlation analysis was used to analyze the correlation of GMFCS with whole brain volumes using SPM 5 in Matalab 7.1. RESULT: The volume in left meditemporal gyrus (Z=3.57) and inferior temporal gyrus (Z=3.40), right thalamus and pallidum (Z=3.36), left thalamus and pallidum (Z=2.76), left supramarginal gyrus (Z=3.14), left precuneus gyrus (Z=3.00), right dorsolateral superior frontal gyrus (Z=3.08), right superior and medial occipital gyrus (Z=2.84) significantly increased as aggravation of gross motor dysfunction. The volume of the left medial orbitofrontal lobe and anterior cingulate (Z=3.28,3.02), left medial superior frontal gyrus (Z=3.19), left caudate (Z=3.04, 2.94, 2.92), left cerebellum (Z=2.94), right cerebellum (Z=2.97), left parahippocampal (Z=3.94), right parahippocampal (Z=3.43, 3.00), left insula (Z=3.50), right insula (Z=3.41, 3.80), left lingual (Z=3.37), right lingual (Z=3.30), left post cingulum (Z=2.73), left midioccipital gyrus (Z=2.92) and right miditemporal gyrus (Z=3.05) significantly reduced as the aggravation of gross motor dysfunction (P all<0.005). CONCLUSION: GMFCS in children with cerebral palsy is related to abnormalities of brain gray matter structure for motor, emotion, memory and default model network when examined with VBM method. PMID- 26757972 TI - [Clinical characteristics, prognosis and genetic susceptibility of herpes simplex encephalitis in children]. AB - OBJECTIVE: To summarize the clinical characteristics and long-term prognosis of herpes simplex virus encephalitis (HSE) in childhood and to analyze genotype of UNC93B1 and TLR3. METHOD: Data of a total of 30 HSE patients admitted to Beijing Children's Hospital from January 2008 to September 2013 were retrospectively analyzed, the data included clinical manifestations, physical sign, auxiliary examination, therapy and long-term clinical prognosis. The family history obtained during follow-up visit was also analyzed for genetic predisposition. With parents' agreement, the blood specimens of patients were collected in EDTA anticoagulant tubes, the first 2 genetic etiologies UNC93B1 and TLR3 were sequenced, and the genetic susceptibility to HSE in childhood was summarized. RESULT: (1) All the 30 patients (100%) had fever, 28 (93%) had seizure, 25 (83%) had altered state of consciousness, only 11 (37%) had personality changes, and in 8 (73%) appeared at or after 2 weeks of onset . (2) During the long-term follow up, 2 (7%) patients died after discharge, 23 patients (82%) had neurological sequelae, 13 patients (57%) had moderate, severe disability and vegetative state. (3) After sequencing of UNC93B1, and TLR3, one patient was found homozygous for a single-nucleotide substitution at position C.414C>G in exon 4 of UNC93B1 which affected the expression of UNC93B1, and may block or decrease the production of interferon. (4) Six single nucleotide polymorphisms (SNPs) were found in this study, their genotype frequency and gene frequency of Chinese were respectively searched in Genomes Project in NCBI and defined 1 000 genomes group. The genotype frequency of UNC93B1 rs7149 between 1 000 genomes group and HSE group was significantly different (chi2 = 55.37, P<0.05). The frequency of CC type and C type was higher in HSE group, both of them had significant difference (chi2 = 93.90, P<0.05, OR=61.563; chi2 = 134.40, P<0.05, OR=12.491). CONCLUSION: HSE lacks specific clinical manifestations, the long-term prognosis is poor. One HSE patient carrying a heterozygous mutation in UNC93B1 which may lead to the susceptibility to HSE and had harmful effect on long-term prognosis. The SNP UNC93B1 rs7149 may also have relationship with susceptibility to HSE and the children carrying CC genotype or C gene in this gene site maybe more susceptible to HSE. PMID- 26757973 TI - [Detection and clinical analysis of acute lower respiratory tract infection with human coronaviruses in children in Beijing area 2007-2015]. AB - OBJECTIVE: To investigate human coronaviruses (HCoVs) infection in children with acute lower respiratory tract infection(ALRTI)and to explore the clinical features of ALRTI caused by HCoVs in children. METHOD: Totally 4 371 children with clinical diagnosis of ALRTI during the period from March 2007 to February 2015 seen in Beijing Children's Hospital were recruited into this study. Patients were divided into 4 groups by age, including 1 890 cases in < 1 year group, 788 cases in 1-3 years group, 553 cases in 3-6 years group, 1140 cases in >=6 years group. One nasopharyngeal aspirate specimen was collected from each patient. RT PCR methods were applied to detect 9 common respiratory viruses including HCoVs (including HCoV-OC43, HCoV-229E, HCoV-NL63 and HCoV-HKU1), respiratory syncytial virus (RSV) and so on. Clinical features of ALRTI with single HCoVs infection were analyzed and compared with hospitalized ALRTI cases with single RSV infection in the same period. RESULT: (1) Totally 2 895 cases were positive for at least one virus in this study in 4 371 ALRTI patients (positive rate 66.23%), in which 147 cases were positive for HCoVs infection (positive rate 3.36%). (2) Positive rates of HCoVs in each year from 2007 to 2014 were 6.11%, 3.79%, 4.69%, 4.31%, 2.38% 2.10%, 0.77% and 2.65%, respectively. The mean positive rates of HCoVs for each month from January to December were 2.53%, 2.12%, 3.63%, 6.68%, 1.53%, 3.77%, 3.92%, 3.00%, 2.15%, 5.26%, 3.01% and 2.80%. (3) Detection results of each subtypes of HCoVs in total 4 371 pediatric ALRTI patients were: 48 cases positive for HCoV-OC43(1.10%), 32 cases positive for HCoV-229E(0.73%), 25 cases positive for HCoV-NL63 (0.57%), 27 cases positive for HCoV-HKU1 (0.62%). (4) Positive rates of HCoVs infection in <1 year group, 1-3 years group, 3-6 years group and >= 6 years group were 4.13%, 5.08%, 2.71% and 1.23%, respectively. There were significant differences in positive rates of HCoV among groups (chi2 = 27.218, P<0.01). (5) There were 16 hospitalized cases with single infection of HCoVs in this study, of which 12 cases were diagnosed as bronchopneumonia, 3 cases developed acute laryngeal obstruction, 2 cases had acute bronchial asthma attack. Common clinical manifestations included cough (14 cases), gasping (13 cases), dyspnea (9 cases), fever (6 cases), hoarseness (4 cases), laryngeal stridor (4 cases) and abnormality on chest X-ray (including fuzzy lung texture, patchy shadow and consolidation) (12 cases). (6) There were no significant differences in the incidence of clinical manifestations (including cough, gasping, dyspnea, fever and abnormality on chest X-ray), complications (including respiratory failure, myocardial damage, and acute bronchial asthma attack) and mechanical ventilation between hospitalized ALRTI patients with single HCoV infection and 193 patients with single RSV infection in the same period. CONCLUSION: HCoVs are pathogens of ALRTI in children, The overall positive rate of HCoVs was 3.36% in this study. The clinical manifestations and severity of ALRTI caused by single HCoVs was comparable to that of ALRTI with single RSV infection in children. PMID- 26757974 TI - [A case of autosomal recessive Alport syndrome with nephrotic syndrome as initial symptom]. PMID- 26757976 TI - [The application of B-type natriuretic peptide and N-terminal pro B-type natriuretic peptide in preterm infants with patent ductus arteriosus]. PMID- 26757975 TI - [Progress in diagnosis and treatment of tubular interstitial nephritis-uveitis syndrome]. PMID- 26757977 TI - Chemically doped fluorescent carbon and graphene quantum dots for bioimaging, sensor, catalytic and photoelectronic applications. AB - Doping fluorescent carbon dots (DFCDs) with heteroatoms have recently become of great interest compared to traditional fluorescent materials because it provides a feasible and new way to tune the intrinsic properties of carbon quantum dots (CQDs) and graphene quantum dots (GQDs) to achieve new applications for them in different fields. Since the first report on nitrogen (N) doped GQDs in 2012, more effort is being focused on exploring different procedures for making new types of DFCDs with different heteroatoms. This mini review will summarize recent research progress on DFCDs. It first reviews various doping categories achieved up to now, looking back on the synthesis method and comparing the differences in synthesis approaches between the DFCDs and the undoped ones. Then it focuses on the advances on how the doping affects the optical properties, especially DFCDs doped with N, which have been investigated the most. Finally, different applications of DFCDs involving bio-imaging, sensing, catalysis and photoelectronic devices will be discussed. This review will give new insights into how to use different synthetic methods for tuning the structure of DFCDs, understanding the correlation between the doping and properties, and achieving new applications. PMID- 26757978 TI - In vitro effects of recombinant adenovirus-mediated bone morphogenetic protein 2/vascular endothelial growth factor 165 on osteogenic differentiation of bone marrow mesenchymal stem cells. AB - Mouse bone marrow mesenchymal stem cells C3H10T1/2 were divided into Ad-BMP2 (bone morphogenetic protein 2) group, Ad-VEGF165 (vascular endothelial growth factor 165) group, Ad-VEGF165 + Ad-BMP2 group, empty adenovirus group and control group. BMP2 and VEGF165 were highly co-expressed in Ad-VEGF165 + Ad-BMP2 group. Ad-BMP2 and Ad-VEGF165 + Ad-BMP2 groups, especially the latter (P < 0.05), had significantly higher expression levels of osteocalcin, osteoprotegerin, and osteopontin mRNA and OPN protein (P < 0.05). Ad-VEGF165 + Ad-BMP2 group had highest alkaline phosphatase (ALP) activity, strongest ALP staining and most calcium salt deposits (P < 0.05). Combining VEGF165 obviously enhanced the inducing effects of BMP2 on osteogenic differentiation capacity of C3H10T1/2 cells. PMID- 26757979 TI - Care partner dyad strategies to support participation in community mobility. AB - BACKGROUND: Factors supporting continued community mobility for older adults warrant attention due to the relationship between mobility, health, and social participation. Although community mobility is typically considered from the perspective of individual functional abilities, care partnerships represent a situation in which maintaining community mobility has implications for the well being of all members. AIM: The aim of this research was to explore and describe strategies used by older adult care partner dyads to support and maintain participation in community mobility. METHODS: Ethnographic case studies of three care partner dyads were conducted using in-depth interviews, participant observation, photographs, and reciprocal data analysis. An inductive, constant comparative data analysis resulted in thematic descriptions of strategies employed by the care partner dyads. RESULTS: Three strategies were identified in collaboration with care partners: (i) Acting in accordance with the values of the relationship, (ii) Finding and using available assistive technology and (iii) Relying on social networks. CONCLUSION AND SIGNIFICANCE: Strategies identified by participants were more relational than procedural in nature, indicating the need for occupational therapists working with care partner dyads to consider historical routines, social connectedness, and needs of the care partnership in addition to functional abilities of the care recipient when addressing community mobility. PMID- 26757980 TI - Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia. AB - Noonan syndrome is a heterogeneous autosomal dominant disorder caused by mutations in at least eight genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 (Ras-like without CAAX 1) has been shown to be involved in the pathogenesis of some patients. We report a series of 44 patients from 30 pedigrees (including nine multiplex families) with mutations in RIT1. These patients display a typical Noonan gestalt and facial phenotype. Among the probands, 8.7% showed postnatal growth retardation, 90% had congenital heart defects, 36% had hypertrophic cardiomyopathy (a lower incidence compared with previous report), 50% displayed speech delay and 52% had learning difficulties, but only 22% required special education. None had major skin anomalies. One child died perinatally of juvenile myelomonocytic leukemia. Compared with the canonical Noonan phenotype linked to PTPN11 mutations, patients with RIT1 mutations appear to be less severely growth retarded and more frequently affected by cardiomyopathy. Based on our experience, we estimate that RIT1 could be the cause of 5% of Noonan syndrome patients. Because mutations found constitutionally in Noonan syndrome are also found in several tumors in adulthood, we evaluated the potential contribution of RIT1 to leukemogenesis in Noonan syndrome. We screened 192 pediatric cases of acute lymphoblastic leukemias (96 B-ALL and 96 T-ALL) and 110 cases of juvenile myelomonocytic leukemias (JMML), but detected no variation in these tumoral samples, suggesting that Noonan patients with germline RIT1 mutations are not at high risk to developing JMML or ALL, and that RIT1 has at most a marginal role in these sporadic malignancies. PMID- 26757981 TI - De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila. AB - Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification. PMID- 26757983 TI - Genomic complexity of urothelial bladder cancer revealed in urinary cfDNA. AB - Urothelial bladder cancers (UBCs) have heterogeneous clinical characteristics that are mirrored in their diverse genomic profiles. Genomic profiling of UBCs has the potential to benefit routine clinical practice by providing prognostic utility above and beyond conventional clinicopathological factors, and allowing for prediction and surveillance of treatment responses. Urinary DNAs representative of the tumour genome provide a promising resource as a liquid biopsy for non-invasive genomic profiling of UBCs. We compared the genomic profiles of urinary cellular DNA and cell-free DNA (cfDNA) from the urine with matched diagnostic formalin-fixed paraffin-embedded tumour DNAs for 23 well characterised UBC patients. Our data show urinary DNAs to be highly representative of patient tumours, allowing for detection of recurrent clinically actionable genomic aberrations. Furthermore, a greater aberrant load (indicative of tumour genome) was observed in cfDNA over cellular DNA (P<0.001), resulting in a higher analytical sensitivity for detection of clinically actionable genomic aberrations (P<0.04) when using cfDNA. Thus, cfDNA extracted from the urine of UBC patients has a higher tumour genome burden and allows greater detection of key genomic biomarkers (90%) than cellular DNA from urine (61%) and provides a promising resource for robust whole-genome tumour profiling of UBC with potential to influence clinical decisions without invasive patient interventions. PMID- 26757985 TI - A Prospective Study of Ripple Mapping in Atrial Tachycardias: A Novel Approach to Interpreting Activation in Low-Voltage Areas. AB - BACKGROUND: Post ablation atrial tachycardias are characterized by low-voltage signals that challenge current mapping methods. Ripple mapping (RM) displays every electrogram deflection as a bar moving from the cardiac surface, resulting in the impression of propagating wavefronts when a series of bars move consecutively. RM displays fractionated signals in their entirety thereby helping to identify propagating activation in low-voltage areas from nonconducting tissue. We prospectively used RM to study tachycardia activation in the previously ablated left atrium. METHODS AND RESULTS: Patients referred for atrial tachycardia ablation underwent dense electroanatomic point collection using CARTO3v4. RM was played over a bipolar voltage map and used to determine the voltage "activation threshold" that differentiated functional low voltage from nonconducting areas for each map. Ablation was guided by RM, but operators could perform entrainment or review the isochronal activation map for diagnostic uncertainty. Twenty patients were studied. Median RM determined activation threshold was 0.3 mV (0.19-0.33), with nonconducting tissue covering 33+/-9% of the mapped surface. All tachycardias crossed an isthmus (median, 0.52 mV, 13 mm) bordered by nonconducting tissue (70%) or had a breakout source (median, 0.35 mV) moving away from nonconducting tissue (30%). In reentrant circuits (14/20) the path length was measured (87-202 mm), with 9 of 14 also supporting a bystander circuit (path lengths, 147-234 mm). In breakout tachycardias, splitting of wavefronts resulted in 2 to 4 incomplete circuits. RM-guided ablation interrupted the tachycardia in 19 of 20 cases with the first ablation set. CONCLUSIONS: RM helps to define activation through low-voltage regions and aids ablation of atrial tachycardias. PMID- 26757984 TI - On the Utility of ToxCastTM and ToxPi as Methods for Identifying New Obesogens. AB - BACKGROUND: In ToxCastTM Phase I, the U.S. EPA commissioned screening of 320 pesticides, herbicides, fungicides, and other chemicals in a series of high throughput assays. The agency also developed a toxicological prioritization tool, ToxPi, to facilitate using ToxCastTM assays to predict biological function. OBJECTIVES: We asked whether top-scoring PPARgamma activators identified in ToxCastTM Phase I were genuine PPARgamma activators and inducers of adipogenesis. Next, we identified ToxCastTM assays that should predict adipogenesis, developed an adipogenesis ToxPi, and asked how well the ToxPi predicted adipogenic activity. METHODS: We used transient transfection to test the ability of ToxCastTM chemicals to modulate PPARgamma and RXRalpha, and differentiation assays employing 3T3-L1 preadipocytes and mouse bone marrow-derived mesenchymal stem cells (mBMSCs) to evaluate the adipogenic capacity of ToxCastTM chemicals. RESULTS: Only 5/21 of the top scoring ToxCastTM PPARgamma activators were activators in our assays, 3 were PPARgamma antagonists, the remainder were inactive. The bona fide PPARgamma activators we identified induced adipogenesis in 3T3-L1 cells and mBMSCs. Only 7 of the 17 chemicals predicted to be active by the ToxPi promoted adipogenesis, 1 inhibited adipogenesis, and 2 of the 7 predicted negatives were also adipogenic. Of these 9 adipogenic chemicals, 3 activated PPARgamma, and 1 activated RXRalpha. CONCLUSIONS: ToxCastTM PPARgamma and RXRalpha assays do not correlate well with laboratory measurements of PPARgamma and RXRalpha activity. The adipogenesis ToxPi performed poorly, perhaps due to the performance of ToxCastTM assays. We observed a modest predictive value of ToxCastTM for PPARgamma and RXRalpha activation and adipogenesis and it is likely that many obesogenic chemicals remain to be identified. CITATION: Janesick AS, Dimastrogiovanni G, Vanek L, Boulos C, Chamorro-Garcia R, Tang W, Blumberg B. 2016. On the utility of ToxCastTM and ToxPi as methods for identifying new obesogens. Environ Health Perspect 124:1214-1226; http://dx.doi.org/10.1289/ehp.1510352. PMID- 26757987 TI - Increasing the HIFU ablation rate through an MRI-guided sonication strategy using shock waves: feasibility in the in vivo porcine liver. AB - This study investigated whether an MR-guided pulsed HIFU ablation strategy could be implemented under clinical conditions, using a transducer designed for uterine fibroid ablation, to obtain an ablation rate that is sufficiently high for clinical abdominal HIFU therapy in highly perfused organs. A pulsed HIFU ablation strategy, aimed at increasing the energy absorption in the HIFU focal area by local shock wave formation in the non-linear pressure regime, was compared to an energy-equivalent continuous wave sonication strategy in the linear pressure regime. Both ablation strategies were used for transcutaneous sonication of pre defined treatment cells in the livers of 5 pigs in vivo. Temperature evolution in both the target area as well as the pre-focal muscle layer was monitored simultaneously using MR thermometry. Local energy absorption and thermal dose volumes were shown to be increased using the pulsed ablation strategy, while preserving healthy tissue in the near field of the acoustic beam. Respiratory motion compensation of both acoustic energy delivery and MR thermometry was applied through gating based on MR navigator echoes. Histopathology showed that confluent vacuolated thermal lesions were created when the pulsed ablation strategy was used. Additionally, it was shown that the heat sink effect caused by the presence of larger vessels could be overcome. The pulsed HIFU ablation strategy achieved an ablation rate of approximately 4 ml per hour in the in vivo porcine liver, without causing undesired damage to healthy tissues in the near field. PMID- 26757982 TI - Rare variant associations with waist-to-hip ratio in European-American and African-American women from the NHLBI-Exome Sequencing Project. AB - Waist-to-hip ratio (WHR), a relative comparison of waist and hip circumferences, is an easily accessible measurement of body fat distribution, in particular central abdominal fat. A high WHR indicates more intra-abdominal fat deposition and is an established risk factor for cardiovascular disease and type 2 diabetes. Recent genome-wide association studies have identified numerous common genetic loci influencing WHR, but the contributions of rare variants have not been previously reported. We investigated rare variant associations with WHR in 1510 European-American and 1186 African-American women from the National Heart, Lung, and Blood Institute-Exome Sequencing Project. Association analysis was performed on the gene level using several rare variant association methods. The strongest association was observed for rare variants in IKBKB (P=4.0 * 10(-8)) in European Americans, where rare variants in this gene are predicted to decrease WHRs. The activation of the IKBKB gene is involved in inflammatory processes and insulin resistance, which may affect normal food intake and body weight and shape. Meanwhile, aggregation of rare variants in COBLL1, previously found to harbor common variants associated with WHR and fasting insulin, were nominally associated (P=2.23 * 10(-4)) with higher WHR in European-Americans. However, these significant results are not shared between African-Americans and European Americans that may be due to differences in the allelic architecture of the two populations and the small sample sizes. Our study indicates that the combined effect of rare variants contribute to the inter-individual variation in fat distribution through the regulation of insulin response. PMID- 26757986 TI - "It pains me because as a woman you have to breastfeed your baby": decision making about infant feeding among African women living with HIV in the UK. AB - OBJECTIVES: UK guidance advises HIV-positive women to abstain from breast feeding. Although this eliminates the risk of postnatal vertical transmission of HIV, the impact of replacement feeding on mothers is often overlooked. This qualitative study examines, for the first time in the UK, decision-making about infant feeding among African women living with HIV. METHODS: Between 2010 and 2011, we conducted semistructured interviews with 23 HIV-positive African women who were pregnant or had recently given birth. We recruited participants from three HIV antenatal clinics in London. RESULTS: Women highlighted the cultural importance of breast feeding in African communities and the social pressure to breast feed, also describing fears that replacement feeding would signify their HIV status. Participants had significant concerns about physical and psychological effects of replacement feeding on their child and felt their identity as good mothers was compromised by not breast feeding. However, almost all chose to refrain from breast feeding, driven by the desire to minimise vertical transmission risk. Participants' resilience was strengthened by financial assistance with replacement feeding, examples of healthy formula-fed children and support from partners, family, peers and professionals. CONCLUSIONS: The decision to avoid breast feeding came at considerable emotional cost to participants. Professionals should be aware of the difficulties encountered by HIV-positive women in refraining from breast feeding, especially those from migrant African communities where breast feeding is culturally normative. Appropriate financial and emotional support increases women's capacity to adhere to their infant-feeding decisions and may reduce the emotional impact. PMID- 26757989 TI - C-reactive protein point-of-care testing in acutely ill children: a mixed methods study in primary care. AB - BACKGROUND: Point-of-care C-reactive protein (CRP) testing of adults with acute respiratory infection in primary care reduces antibiotic prescribing by 22%. The acceptability and impact of CRP testing in children is unknown OBJECTIVE: To determine the acceptability and impact of CRP testing in acutely ill children. DESIGN: Mixed methods study comprising an observational cohort with a nested randomised controlled trial and embedded qualitative study. SUBJECTS AND SETTING: Children presenting with an acute illness to general practice out-of-hours services; children with a temperature >=38 degrees C were randomised in the nested trial; parents and clinical staff were invited to the qualitative study. MAIN OUTCOMES: Informed consent rates; parental and staff views on testing. RESULTS: Consent to involvement in the study was obtained for 200/297 children (67.3%, 95% CI 61.7% to 72.6%); the finger-prick test might have been a contributory factor for 63 of the 97 children declining participation but it was cited as a definite factor in only 10 cases. None of the parents or staff raised concerns about the acceptability of testing, describing the pain caused as minor and transient. General practitioner views on the utility of the CRP test were inconsistent. CONCLUSIONS: CRP point-of-care testing in children is feasible in primary care and is likely to be acceptable. However, it will not reduce antibiotic prescribing and hospital referrals until general practitioners accept its diagnostic value in children. TRIAL REGISTRATION NUMBER: ISRCTN 69736109. PMID- 26757988 TI - A Prospective Study of Back Pain and Risk of Falls Among Older Community-dwelling Women. AB - BACKGROUND: Back pain and falls are common health conditions among older U.S. women. The extent to which back pain is an independent risk factor for falls has not been established. METHODS: We conducted a prospective study among 6,841 community-dwelling U.S. women at least 65 years of age from the Study of Osteoporotic Fractures (SOF). Baseline questionnaires inquired about any back pain, pain severity, and frequency in the past year. During 1 year of follow-up, falls were summed from self-reports obtained every 4 months. Two outcomes were studied: recurrent falls (>=2 falls) and any fall (>=1 fall). Associations of back pain and each fall outcome were estimated with risk ratios (RRs) and 95% confidence intervals (CIs) from multivariable log-binomial regression. Adjustments were made for age, education, smoking status, fainting history, hip pain, stroke history, vertebral fracture, and Geriatric Depression Scale. RESULTS: Most (61%) women reported any back pain. During follow-up, 10% had recurrent falls and 26% fell at least once. Any back pain relative to no back pain was associated with a 50% increased risk of recurrent falls (multivariable RR = 1.5, 95% CI: 1.3, 1.8). Multivariable RRs for recurrent falls were significantly elevated for all back pain symptoms, ranging from 1.4 (95% CI: 1.1, 1.8) for mild back pain to 1.8 (95% CI: 1.4, 2.3) for activity-limiting back pain. RRs of any fall were also significantly increased albeit smaller than those for recurrent falls. CONCLUSIONS: Older community-dwelling women with a recent history of back pain are at increased risk for falls. PMID- 26757992 TI - An S4-symmetric mixed-valent decacopper cage comprised of [Cu(II)(L-S2N2)] complexes bridged by Cu(I)(MeCN)n (n = 1 or 2) cations. AB - Oxidative addition of 1,2,11,12-tetrathia-5,8,15,19-tetra(N methylamino)cycloicosane, the bis(disulfide) form of N,N'-dimethyl-N,N'-bis(2 mercaptoethyl)ethylenediamine (L-N2S2) to [Cu(MeCN)4][BF4] (2.5 eq.) in MeCN produces good yields of the decacopper cage compound [(Cu(II)(L-N2S2))4(MU2 Cu(I)(MeCN)2)2(MU3-Cu(I)(MeCN))4][BF4]6.2.25MeCN, [1][BF4]6.2.25MeCN. This mixed valent hexacation shows idealized S4 point group symmetry and is composed of four [Cu(II)(L-N2S2] centers held in distorted four-coordinate environments and joined by MU2-Cu(I)(MeCN)2/MU3-Cu(I)(MeCN) ions that bridge their thiolate sulfur atoms. Each four-coordinate [Cu(II)(L-N2S2)] center is related to the other three by successive executions of the S4 operation. A dark violet color is observed for [1](6+) and attributed to a combination of metal-to-ligand (S), ligand (S)-to metal, and, at lower energy, intermetal charge transfer transitions, as found for Cu5 cage compounds with a compositional relationship to [1](6+). PMID- 26757990 TI - Nitrogen Use Efficiency Is Mediated by Vacuolar Nitrate Sequestration Capacity in Roots of Brassica napus. AB - Enhancing nitrogen use efficiency (NUE) in crop plants is an important breeding target to reduce excessive use of chemical fertilizers, with substantial benefits to farmers and the environment. In Arabidopsis (Arabidopsis thaliana), allocation of more NO3 (-) to shoots was associated with higher NUE; however, the commonality of this process across plant species have not been sufficiently studied. Two Brassica napus genotypes were identified with high and low NUE. We found that activities of V-ATPase and V-PPase, the two tonoplast proton-pumps, were significantly lower in roots of the high-NUE genotype (Xiangyou15) than in the low-NUE genotype (814); and consequently, less vacuolar NO3 (-) was retained in roots of Xiangyou15. Moreover, NO3 (-) concentration in xylem sap, [(15)N] shoot:root (S:R) and [NO3 (-)] S:R ratios were significantly higher in Xiangyou15. BnNRT1.5 expression was higher in roots of Xiangyou15 compared with 814, while BnNRT1.8 expression was lower. In both B. napus treated with proton pump inhibitors or Arabidopsis mutants impaired in proton pump activity, vacuolar sequestration capacity (VSC) of NO3 (-) in roots substantially decreased. Expression of NRT1.5 was up-regulated, but NRT1.8 was down-regulated, driving greater NO3 (-) long-distance transport from roots to shoots. NUE in Arabidopsis mutants impaired in proton pumps was also significantly higher than in the wild type col-0. Taken together, these data suggest that decrease in VSC of NO3 (-) in roots will enhance transport to shoot and essentially contribute to higher NUE by promoting NO3 (-) allocation to aerial parts, likely through coordinated regulation of NRT1.5 and NRT1.8. PMID- 26757991 TI - Early and gender-specific differences in spinal cord mitochondrial function and oxidative stress markers in a mouse model of ALS. AB - INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a gender bias towards major prevalence in male individuals. Several data suggest the involvement of oxidative stress and mitochondrial dysfunction in its pathogenesis, though differences between genders have not been evaluated. For this reason, we analysed features of mitochondrial oxidative metabolism, as well as mitochondrial chain complex enzyme activities and protein expression, lipid profile, and protein oxidative stress markers, in the Cu,Zn superoxide dismutase with the G93A mutation (hSOD1-G93A)- transgenic mice and Neuro2A(N2A) cells overexpressing hSOD1-G93A. RESULTS AND CONCLUSIONS: Our results show that overexpression of hSOD1-G93A in transgenic mice decreased efficiency of mitochondrial oxidative phosphorylation, located at complex I, revealing a temporal delay in females with respect to males associated with a parallel increase in selected markers of protein oxidative damage. Further, females exhibit a fatty acid profile with higher levels of docosahexaenoic acid at 30 days. Mechanistic studies showed that hSOD1-G93A overexpression in N2A cells reduced complex I function, a defect prevented by 17beta-estradiol pretreatment. In conclusion, ALS-associated SOD1 mutation leads to delayed mitochondrial dysfunction in female mice in comparison with males, in part attributable to the higher oestrogen levels of the former. This study is important in the effort to further understanding of whether different degrees of spinal cord mitochondrial dysfunction could be disease modifiers in ALS. PMID- 26757993 TI - The Influence of Hand Location and Force Direction on Shoulder Muscular Activity in Females During Nonsagittal Multidirectional Overhead Exertions. AB - OBJECTIVE: We examined interactions of overhead work location and direction of force application on shoulder muscular activity. BACKGROUND: Overhead work tasks are common occupational stressors. Previous research has quantified influences of overhead work spatial placement and different force application directions but typically separately or exclusively for tasks done in the median plane. METHOD: Twenty female participants exerted 40 N of force in six directions (forward/backward, upward/downward, left/right) 150 cm off the floor while seated. An asymmetric pattern of 14 work locations spaced 15 cm centered directly overhead were evaluated. RESULTS: Force direction and work location strongly influenced mean muscle activity (F = 559, p < .01). Interaction effects existed between force direction and hand location in the transverse plane (F = 21, p < .01), with increases as high as 49% in normalized mean muscle activity. CONCLUSION: Backward exertions produced the highest mean overall muscle activity across hand force directions, exceeding 30% maximum voluntary isometric exertion (MVE) across work locations, with higher activation of anterior deltoid, biceps, infraspinatus, supraspinatus, and upper and lower trapezius. Downward exertions had the lowest mean overall activity, with <10% MVE across work locations. Altered (up to 47%) muscular activity occurred as exertions moved laterally from the origin, and increasingly forward hand positions generally yielded decreased mean overall activity for most force directions. APPLICATION: This study provides previously unavailable submaximal shoulder muscular activity data for a wide range of overhead tasks. As such, it enables novel work design considerations that include modifying existing overhead elements to reduce or redistribute associated muscular demands. PMID- 26757995 TI - Social determinants and inequalities in tuberculosis incidence in Latin America and the Caribbean. AB - OBJECTIVE: To identify key social determinants of tuberculosis (TB) incidence among countries in Latin America and the Caribbean (LAC), a geographic area regarded as one of the most socioeconomically unequal in the world METHODS: An ecological study was conducted at the country level. Data were obtained from several institutional-based sources. Random-effects regression modeling was used to explore the relationship between several social determinants indicators and TB incidence rates in 20 LAC countries in 1995-2012. Standard gap and gradient metrics of social inequality in TB incidence among countries in 2000, 2005, and 2010 were then calculated. RESULTS: TB incidence rate trends were significantly associated with health expenditure per capita and access to improved sanitation facilities, as well as with life expectancy at birth and TB detection rate, after adjusting for other socioeconomic, demographic, and health services variables. Absolute and relative inequality in TB incidence remained mostly unchanged: countries at the bottom 20% of both health expenditure and sanitation coverage distributions concentrated up to 40% of all TB incident cases, despite a considerable decline in the overall TB incidence mean rate during the period assessed. CONCLUSIONS: Along with the intensity of TB control (reflected by TB detection rate), both access to sanitation (as a proxy of quality of living conditions) and health expenditure per capita (either as an indicator of the level of resources and/or commitment to health care) appear to be key determinants of TB incidence trends in LAC countries. Inequalities in both health expenditure per capita and access to sanitation seem to define profound and persistent inverse gradients in TB incidence among LAC countries. PMID- 26757994 TI - Increased Synthesis of Liver Erythropoietin with CKD. AB - Anemia of CKD seems to be related to impaired production of renal erythropoietin (Epo). The glycosylation pattern of Epo depends on the synthesizing cell and thus, can indicate its origin. We hypothesized that synthesis of Epo from nonkidney cells increases to compensate for insufficient renal Epo production during CKD. We determined plasma Epo levels and Epo glycosylation patterns in 33 patients with CKD before undergoing dialysis and nine patients with CKD undergoing dialysis. We compared these values with values obtained in healthy volunteers and other controls. Although patients with CKD before undergoing dialysis had median (interquartile range) Epo levels higher than those of healthy controls (13.8 IU/L; interquartile range, 10.0-20.7 IU/L versus 8.4 IU/L; interquartile range, 7.6-9.0 IU/L; P<0.01), these patients were moderately anemic (mean+/-SD; hemoglobin =118+/-17 g/L). Detected as the percentage of migrated isoforms (PMI), Epo glycosylation in patients with CKD before undergoing dialysis (PMI=36.1+/-11.7%) differed from that in healthy controls (PMI=9.2+/-3.8%; P<0.01) but not from that in umbilical cord plasma (PMI=53.9+/-10.6%; P>0.05), which contains mainly liver-derived Epo. Furthermore, glycosylation modification correlated with eGFR loss. These results suggest that patients with CKD maintain persistent Epo synthesis despite declining renal function, and this maintenance may result in part from increased liver Epo synthesis. PMID- 26757996 TI - [The epidemiological advantage of preferential targeting of tuberculosis control at the poor]. AB - Tuberculosis (TB) remains disproportionately concentrated among the poor, yet known determinants of TB reactivation may fail to explain observed disparities in disease rates according to wealth. Reviewing data on TB disparities in India and the wealth distribution of known TB risk factors, we describe how social mixing patterns could be contributing to TB disparities. Wealth-assortative mixing, whereby individuals are more likely to be in contact with others from similar socio-economic backgrounds, amplifies smaller differences in risk of TB, resulting in large population-level disparities. As disparities and assortativeness increase, TB becomes more difficult to control, an effect that is obscured by looking at population averages of epidemiological parameters, such as case detection rates. We illustrate how TB control efforts may benefit from preferential targeting toward the poor. In India, an equivalent-scale intervention could have a substantially greater impact if targeted at those living below the poverty line than with a population-wide strategy. In addition to potential efficiencies in targeting higher-risk populations, TB control efforts would lead to a greater reduction in secondary TB cases per primary case diagnosed if they were preferentially targeted at the poor. We highlight the need to collect programmatic data on TB disparities and explicitly incorporate equity considerations into TB control plans. PMID- 26757997 TI - [Common mental disorders and use of psychotropic medications in women consulting at primary care units in a Brazilian urban area]. AB - OBJECTIVE: To investigate the prevalence of common mental disorders (CMD) in women consulting at primary health care units in a Brazilian urban area, as well as to determine the impact of CMD on quality of life (QoL), the association of sociodemographic factors with CMD and QoL, and the prevalence and pattern of psychotropic medication use in the study sample. METHODS: In this quantitative, cross-sectional, correlational-descriptive study, a stratified sample of 365 women was interviewed between May 2012 and January 2013 in five primary health care units in Brazil. Data were collected using sociodemographic and drug use questionnaires. The self-reporting questionnaire (SRQ-20) was used to estimate the prevalence of CMD; and the World Health Organization Quality of Life (WHOQOL) bref instrument was used to assess quality of life. To evaluate the impact of CMD on QoL, the t test and linear regression models were employed. The chi-square test was used to verify associations between CMD and sociodemographic variables. Descriptive analysis was used for psychotropic drug use. RESULTS: The prevalence of CMD was 44.1%. The prevalence of psychotropic medication use was 27.1%. Only 5.6% of participants had a psychiatric diagnosis recorded in their medical chart. Psychotropic drugs were used by 41.6% of participants with CMD according to the SRQ-20 and by 15.7% of those without CMD. There was no association between CMD and sociodemographic variables, but CMD and QoL were significantly associated. Women with CMD had the worst QoL, without impact of sociodemographic variables. CONCLUSIONS: Further attention should be given to the pattern of psychotropic medication use and prescription in primary care settings. Women with CMD had functional impairment, as shown by significantly lower QoL scores. The fact that sociodemographic factors did not impact the present results seems to support the notion of a different basis for CMD in women. PMID- 26757998 TI - Prevalence of metabolic syndrome in Central America: a cross-sectional population based study. AB - OBJECTIVE: To report the prevalence of metabolic syndrome (MetS) as found by the Central American Diabetes Initiative (CAMDI) study for five major Central American populations: Belize (national); Costa Rica (San Jose); Guatemala (Guatemala City); Honduras (Tegucigalpa); and Nicaragua (Managua). METHODS: Study data on 6 185 adults aged 20 years or older with anthropometric and laboratory determination of MetS from population-based surveys were analyzed. Overall, the survey response rate was 82.0%. MetS prevalence was determined according to criteria from the Adult Treatment Panel III of the National Cholesterol Education Program. The study's protocol was reviewed and approved by the bioethical committee of each country studied. RESULTS: The overall standardized prevalence of MetS in the Central American region was 30.3% (95% confidence interval (CI): 27.1-33.4). There was wide variability by gender and work conditions, with higher prevalence among females and unpaid workers. The standardized percentage of the population free of any component of MetS was lowest in Costa Rica (9.0%; CI: 6.5 11.4) and highest in Honduras (21.1%; CI: 16.4-25.9). CONCLUSIONS: Overall prevalence of MetS in Central America is high. Strengthening surveillance of chronic diseases and establishing effective programs for preventing cardiovascular diseases might reduce the risk of MetS in Central America. PMID- 26757999 TI - [Factors associated with contacting HIV/AIDS associations in Ecuador: results of a community study]. AB - OBJECTIVE: To describe the profile of people living with HIV/AIDS (PLHA) who contact HIV/AIDS associations in Ecuador and to identify the factors related to that contact. METHODS: In 2011, a cross-sectional community study was conducted in two hospitals in Guayaquil. Based on a 125-question survey administered to 300 adult PLHA, a weighted multivariate regression analysis was performed to identify the factors related to contact with an association RESULTS: Of the 300 participants, 34 (11.3%) were in contact with an association. Being over the age of 35, scoring high on the self-efficacy scale, having suffered serious social consequences after disclosing their HIV status, being able to talk to friends about living with HIV, expressing the need to talk about living with HIV with a health professional, and scoring low on the index of the HIV status disclosure control effort were related to that contact. CONCLUSIONS: The characteristics of the PLHA in contact with an association were: being over the age of 35, having suffered serious social consequences following disclosure of seropositivity, and feeling that their psychosocial needs were not being met by the health system in terms of the services provided. These people more easily managed their HIV status in their social milieu and displayed a greater ability to talk to friends about their seropositivity. This information is useful for community actors to maintain and support mobilization on HIV in Ecuador. PMID- 26758000 TI - Cesarean sections in Brazil: will they ever stop increasing? AB - OBJECTIVE: To describe trends, geographic distribution, and risk factors for cesarean deliveries in Brazil in 2000-2011, and to determine if efforts to curtail rates have had a measurable impact. METHODS: This was an observational study using nationwide information from the Department of Informatics of the Unified Health System (DATASUS). Individual level analyses were based on data regarding maternal education, age, parity, and skin color. Ecological analyses at the level of 431 health districts investigated the relationships with health facility density and poverty level. RESULTS: Cesarean rates increased markedly, from 37.9% in 2000 to 53.9% in 2011. Preliminary results from 2012 showed a rate of 55.8%, with the richest geographic areas showing the highest rates. Rates at the municipal level varied from 9%-96%. Cesareans were more common in women with higher education, white skin color, older age, and in primi- paras. In the ecological analyses, the number of health facilities per 1 000 population was strongly and positively correlated with cesarean rates, with an increase of 16.1 percentage points (95% Confidence Interval [95%CI] = 4.3-17.8) for each facility. An increase of 1 percentage point in the poverty rate was associated with a decline of 0.5 percentage point in cesarean rates (95%CI = 0.5-0.6). CONCLUSIONS: The strong associations with maternal education and health facility density suggest that the vast majority of cesareans are not medically indicated. A number of policies and programs have been launched to counteract this trend, but have had virtually no impact. PMID- 26758001 TI - Socioeconomic and lifestyle factors associated with chronic conditions among older adults in Ecuador. AB - OBJECTIVE: To explore socioeconomic and lifestyle factors associated with the prevalence of self-reported chronic conditions among older adults in Ecuador. METHODS: The sample was drawn from the nationally representative observational cross-sectional data of the Health, Well-Being, and Aging survey conducted in Ecuador in 2009. Logistic regression models were used to explore the association between socioeconomic and lifestyle factors and the prevalence of selected chronic conditions. RESULTS: Older women in Ecuador are more likely than men to have been previously diagnosed with diabetes, heart disease, high blood pressure, and arthritis. Results suggest no difference by education or health insurance on number and type of self-reported chronic conditions. However, older adults who resided in the coastal area were more likely to report having diabetes, heart disease, high blood pressure, and stroke than those in the highlands. Living in rural areas was associated with lower odds of having diabetes and high blood pressure. Compared to white older adults, indigenous older adults were less likely to report having high blood pressure, but more likely to report having arthritis. CONCLUSIONS: Older age in Ecuador is marked by low educational levels and poverty. Female gender and living in coastal areas were associated with higher risks of self-reported chronic conditions. PMID- 26758002 TI - Technology transfer for the implementation of a clinical trials network on drug abuse and mental health treatment in Mexico. AB - Low- and middle-income countries (LMIC) lack the research infrastructure and capacity to conduct rigorous substance abuse and mental health effectiveness clinical trials to guide clinical practice. A partnership between the Florida Node Alliance of the United States National Drug Abuse Treatment Clinical Trials Network and the National Institute of Psychiatry in Mexico was established in 2011 to improve substance abuse practice in Mexico. The purpose of this partnership was to develop a Mexican national clinical trials network of substance abuse researchers and providers capable of implementing effectiveness randomized clinical trials in community-based settings. A technology transfer model was implemented and ran from 2011-2013. The Florida Node Alliance shared the "know how" for the development of the research infrastructure to implement randomized clinical trials in community programs through core and specific training modules, role-specific coaching, pairings, modeling, monitoring, and feedback. The technology transfer process was bi-directional in nature in that it was informed by feedback on feasibility and cultural appropriateness for the context in which practices were implemented. The Institute, in turn, led the effort to create the national network of researchers and practitioners in Mexico and the implementation of the first trial. A collaborative model of technology transfer was useful in creating a Mexican researcher-provider network that is capable of changing national practice in substance abuse research and treatment. Key considerations for transnational technology transfer are presented. PMID- 26758004 TI - A systems approach to understanding and improving health systems. AB - Health systems face the challenge of helping to improve health conditions. They occupy a priority place in middle- and lower-income countries, since the absence or fragility of health systems adversely impacts expected health outcomes. Thus, due to the direct relationship between programs and systems, the absence or weakness of either will result in a consequent deficiency in public health and the very execution of the programs. In the same vein, weakened health systems are one of the main bottlenecks to attaining the Millennium Development Goals. Systems thinking is one of the "four revolutions in progress" that are helping to transform health and health care systems. Within that framework, this article identifies conceptual and operational elements of systems applicable to health systems that contribute to overcoming the obstacles and inertia that hinder health activities and outcomes. It discusses relevant concepts characteristic of systems thinking, such as structural variables and dynamic complexity, the relationship between programs and health systems, and the monitoring and evaluation function, together with the role of innovation and systems integration as high-priority elements. This will aid in the development of designs that also stress the context of the components that guide management, identifying processes and outcomes in a health management continuum. PMID- 26758003 TI - Developmental neurotoxicity: methylmercury and prenatal exposure protection in the context of the Minamata Convention. AB - Mercury is a global pollutant of public environmental health concern due to its long-range atmospheric distribution, environmental distribution, and neurotoxic effects. Following biological methylation, methylmercury (MeHg) can be un-evenly bioaccumulated within aquatic food chains. Fish consumption can be a significant route of human exposure to MeHg. MeHg exposure in the prenatal stage, at relatively low levels, has recently been established as harmful during neurological development, potentially leading to intellectual disability. The Minamata Convention on Mercury is a global agreement, currently under ratification, to protect human health and the environment from anthropogenic emissions and releases of mercury and mercury compounds. The resolution regarding the role of the World Health Organization and ministries of health in the implementation of the Convention includes protection of human health from critical exposures to MeHg. Riverside populations living in areas with artisanal small-scale gold mining, and relying heavily on fish consumption, have been identified as the most vulnerable population in terms of MeHg exposure and developmental neurotoxicity. This article focuses on the proper design and dissemination of fish advisories within the context of implementation of the Convention. PMID- 26758005 TI - National kidney dialysis and transplant registries in Latin America: how to implement and improve them. AB - The Strategic Plan of the Pan American Health Organization, 2014-2019, Championing Health: Sustainable Development and Equityrecognizes that "Chronic kidney disease, caused mainly by complications of diabetes and hypertension, has increased in the Region." This Plan includes the first concrete goal on chronic kidney disease: to achieve a prevalence rate for renal replacement therapy of at least 700 patients per million population by 2019. National dialysis and transplant registries (DTR) are a useful tool for epidemiological research, health care planning, and quality improvement. Their success depends on the quality of their data and quality control procedures. This article describes the current situation of national DTRs in the Region and the content of their information and health indicators, and it offers recommendations for creating and maintaining them. It points to their heterogeneity or absence in some countries, in line with the inequities that patients face in access to renal replacement therapy. The complete lack of information in Caribbean countries prevents their inclusion in this communication, which requires immediate attention. PMID- 26758020 TI - Oscillatory elastic instabilities in an extensional viscoelastic flow. AB - Dilute polymer solutions are known to exhibit purely elastic instabilities even when the fluid inertia is negligible. Here we report the quantitative evidence of two consecutive oscillatory elastic instabilities in an elongation flow of a dilute polymer solution as realized in a T-junction geometry with a long recirculating cavity. The main result reported here is the observation and characterization of the first transition as a forward Hopf bifurcation resulted in a uniformly oscillating state due to breaking of time translational invariance. This unexpected finding is in contrast with previous experiments and numerical simulations performed in similar ranges of the Wi and Re numbers, where the forward fork-bifurcation into a steady asymmetric flow due to the broken spatial inversion symmetry was reported. We discuss the plausible discrepancy between our findings and previous studies that could be attributed to the long recirculating cavity, where the length of the recirculating cavity plays a crucial role in the breaking of time translational invariance instead of the spatial inversion. The second transition is manifested via time aperiodic transverse fluctuations of the interface between the dyed and undyed fluid streams at the channel junction and advected downstream by the mean flow. Both instabilities are characterized by fluid discharge-rate and simultaneous imaging of the interface between the dyed and undyed fluid streams in the outflow channel. PMID- 26758018 TI - Using global transcription machinery engineering (gTME) to improve ethanol tolerance of Zymomonas mobilis. AB - BACKGROUND: With the increasing global crude oil crisis and resulting environmental concerns, the production of biofuels from renewable resources has become increasingly important. One of the major challenges faced during the process of biofuel production is the low tolerance of the microbial host towards increasing biofuel concentrations. RESULTS: Here, we demonstrate that the ethanol tolerance of Zymomonas mobilis can be greatly enhanced through the random mutagenesis of global transcription factor RpoD protein, (sigma(70)). Using an enrichment screening, four mutants with elevated ethanol tolerance were isolated from error-prone PCR libraries. All mutants showed significant growth improvement in the presence of ethanol stress when compared to the control strain. After an ethanol (9 %) stress exposure lasting 22 h, the rate of glucose consumption was approximately 1.77, 1.78 and 1.39 g L(-1) h(-1) in the best ethanol-tolerant strain ZM4-mrpoD4, its rebuilt mutant strain ZM4-imrpoD and the control strain, respectively. Our results indicated that both ZM4-mrpoD4 and ZM4-imrpoD consumed glucose at a faster rate after the initial 9 % (v/v) ethanol stress, as nearly 0.64 % of the initial glucose remained after 54 h incubation versus approximately 5.43 % for the control strain. At 9 % ethanol stress, the net ethanol productions by ZM4-mrpoD4 and ZM4-imrpoD during the 30-54 h were 13.0-14.1 g/l versus only 6.6-7.7 g/l for the control strain. The pyruvate decarboxylase activity of ZM4 mrpoD4 was 62.23 and 68.42 U/g at 24 and 48 h, respectively, which were 2.6 and 1.6 times higher than the control strain. After 24 and 48 h of 9 % ethanol stress, the alcohol dehydrogenase activities of ZM4-mrpoD4 were also augmented, showing an approximate 1.4 and 1.3 times increase, respectively, when compared to the control strain. Subsequent quantitative real-time PCR analysis under these stress conditions revealed that the relative expression of pdc in cultured (6 and 24 h) ZM4-mrpoD4 increased by 9.0- and 12.7-fold when compared to control strain. CONCLUSIONS: Collectively, these results demonstrate that the RpoD mutation can enhance ethanol tolerance in Z. mobilis. Our results also suggested that RpoD may play an important role in resisting high ethanol concentration in Z. mobilis and manipulating RpoD via global transcription machinery engineering (gTME) can provide an alternative and useful approach for strain improvement for complex phenotypes. PMID- 26758019 TI - Breast primary epithelial cells that escape p16-dependent stasis enter a telomere driven crisis state. AB - Breast cancer is the most common malignant disease in women, but some basic questions remain in breast cancer biology. To answer these, several cell models were developed. Recently, the use of improved cell-culture conditions has enabled the development of a new primary cell model with certain luminal characteristics. This model is relevant because, after the introduction of a specific set of genetic elements, the transformed cells yielded tumors resembling human adenocarcinomas in mice. The use of improved cell-culture conditions supporting the growth of these breast primary epithelial cells was expected to delay or eliminate stress-induced senescence and lead to the propagation of normal cells. However, no studies have been carried out to investigate these points. Propagation of breast primary epithelial cells was performed in WIT medium on Primaria plates. Immunofluorescence, western blot and qRT-PCR were used to detect molecular markers, and to determine the integrity of DNA damage-response pathways. Promoter methylation of p16 (INK4a) was assessed by pyrosequencing. In order to obtain a dynamic picture of chromosome instability over time in culture, we applied FISH methodologies. To better link chromosome instability with excessive telomere attrition, we introduced the telomerase reverse transcriptase human gene using a lentiviral vector. We report here that breast primary epithelial cells propagated in vitro with WIT medium on Primaria plates express some luminal characteristics, but not a complete luminal lineage phenotype. They undergo a p16-dependent stress-induced senescence (stasis), and the cells that escape stasis finally enter a crisis state with rampant chromosome instability. Chromosome instability in these cells is driven by excessive telomere attrition, as distributions of chromosomes involved in aberrations correlate with the profiles of telomere signal-free ends. Importantly, ectopic expression of the human TERT gene rescued their chromosomal instability phenotype. Essentially, our data show that contrary to what was previously suggested, improved culture conditions to propagate in vitro mammary epithelial cells with some luminal characteristics do not prevent stress-induced senescence. This barrier is overcome by spontaneous methylation of the p16 (INK4a) promoter, allowing the proliferation of cells with telomere dysfunction and ensuing chromosome instability. PMID- 26758021 TI - 3-Trifluoromethyl-3-aryldiazirine photolabels with enhanced ambient light stability. AB - Ambient light stable 3-trifluoromethyl-3-aryldiazirine photolabels are developed via stabilization of the strained three membered diazirine ring by replacing the phenyl ring with electron withdrawing heterocyclic rings. Photolabeling studies reveal that these ambient light stable photolabels are equally efficient in photolabeling target proteins as the traditional 3-trifluoromethyl-3 phenyldiazirine and found to significantly increase the aqueous solubility of the photoaffinity labels. PMID- 26758024 TI - Association mapping of germinability and seedling vigor in sorghum under controlled low-temperature conditions. AB - Sorghum is one of the world's most important food, feed, and fiber crops as well as a potential feedstock for lignocellulosic bioenergy. Early-season planting extends sorghum's growing season and increases yield in temperate regions. However, sorghum's sensitivity to low soil temperatures adversely impacts seed germination. In this study, we evaluated the 242 accessions of the ICRISAT sorghum mini core collection for seed germination and seedling vigor at 12 degrees C as a measure of cold tolerance. Genome-wide association analysis was performed with approximately 162,177 single nucleotide polymorphism markers. Only one marker locus (Locus 7-2) was significantly associated with low-temperature germination and none with vigor. The linkage of Locus 7-2 to low-temperature germination was supported by four lines of evidence: strong association in three independent experiments, co-localization with previously mapped cold tolerance quantitative trait loci (QTL) in sorghum, a candidate gene that increases cold tolerance and germination rate when its wheat homolog is overexpressed in tobacco, and its syntenic region in rice co-localized with two cold tolerance QTL in rice. This locus may be useful in developing tools for molecular breeding of sorghums with improved low-temperature germinability. PMID- 26758023 TI - The Neurochemical and Microstructural Changes in the Brain of Systemic Lupus Erythematosus Patients: A Multimodal MRI Study. AB - The diagnosis and pathology of neuropsychiatric systemic lupus erythematosus (NPSLE) remains challenging. Herein, we used multimodal imaging to assess anatomical and functional changes in brains of SLE patients instead of a single MRI approach generally used in previous studies. Twenty-two NPSLE patients, 21 non-NPSLE patients and 20 healthy controls (HCs) underwent 3.0 T MRI with multivoxel magnetic resonance spectroscopy, T1-weighted volumetric images for voxel based morphometry (VBM) and diffusional kurtosis imaging (DKI) scans. While there were findings in other basal ganglia regions, the most consistent findings were observed in the posterior cingulate gyrus (PCG). The reduction of multiple metabolite concentration was observed in the PCG in the two patient groups, and the NPSLE patients were more prominent. The two patient groups displayed lower diffusional kurtosis (MK) values in the bilateral PCG compared with HCs (p < 0.01) as assessed by DKI. Grey matter reduction in the PCG was observed in the NPSLE group using VBM. Positive correlations among cognitive function scores and imaging metrics in bilateral PCG were detected. Multimodal imaging is useful for evaluating SLE subjects and potentially determining disease pathology. Impairments of cognitive function in SLE patients may be interpreted by metabolic and microstructural changes in the PCG. PMID- 26758027 TI - Determining eyeball surface area directly exposed to the effects of external factors. AB - This article discusses determining the surface area of eyeballs of men and women exposed to the direct effects of external factors in the working environment. For one eye, the mean surface is 172-182 mm(2). The determined surface area can be used in formulas for calculating the exposure of eyeballs to harmful chemical substances in workplace air. PMID- 26758025 TI - Incidence of peripheral arterial disease in the ARTPER population cohort after 5 years of follow-up. AB - BACKGROUND: To know the epidemiology (prevalence, incidence, progression and morbidity and mortality associated) of peripheral artery disease in general population and the factors associated with this progression is essential to know the evolution of atherosclerosis and develop preventive strategies. The aim of the study was to determine the incidence of PAD after 5 years of follow-up population-based cohort ARTPER, and the evolution of Ankle brachial Index (ABI) in this period. METHODS: Peripheral artery disease incidence analysis after 5 years of follow-up of 3786 subjects > 50 years old. Peripheral artery disease incident when the second cross section Ankle brachial Index was <0.9 in any of the lower limbs, with normal baseline (0.9 to 1.4). RESULTS: Between 2012 and 2013 2762 individuals (77% participation) were re-examined . Finally analyzed 2256 subjects (after excluding pathological Ankle brachial Index) followed for 4.9 years (range 3.8 to 5.8 years), totalling 11,106 person-years. Peripheral artery disease 95 new cases were detected, representing an incidence of 4.3% at 5 years and 8.6 per 1000 person-years (95% CI 6.9 to 10.5) being higher in men (10.2, 95% CI 7.4 to 13.5) than in women (7.5, 95% CI 5.5 to 9.9). Linear correlation between the baseline Ankle brachial Index and the second cross section was low (r = 0.23). CONCLUSIONS: The incidence of peripheral artery disease in ARTPER cohort was 8.6 cases per 1000 person-years, being higher in men, especially <65 years. The correlation between two measures Ankle brachial Index after 5 years of follow-up was low. One might consider whether Ankle brachial Index repeated measures could improve the correlation. PMID- 26758026 TI - Motor imagery training for children with developmental coordination disorder- study protocol for a randomized controlled trial. AB - BACKGROUND: Previous studies have shown that the predictive control of movements is impaired in children with Developmental Coordination Disorder (DCD), most likely due to a deficit in the internal modeling of movements. Motor imagery paradigms have been used to test this internal modeling deficit. The aim of the present study is to examine whether a training focused on the mental imagery of motor skills, can help to improve the motor abilities of children with DCD. METHODS/DESIGN: A pre-post design will be used to examine the motor performance, motor imagery and motor planning abilities before and after a training of 9 weeks. Two groups will be included in this study (1) one receiving motor imagery (MI) training focused on the forward modeling of purposive actions, (2) one receiving Cognitive Orientation to daily Occupational Performance (CO-OP) training focused on identifying effective cognitive strategies that will increase motor competence. MI training will be given with the use of instruction videos of the motor skill that will be trained. Both groups will participate in 9 individual sessions of 45 min (once a week) with a paediatric physical or occupational therapist, added with homework sessions. Inclusion criteria are: (1) aged 7-12 years, (2) meeting the DSM-V criteria for DCD (motor performance substantially low (score on the m-ABC <= 16th percentile) and motor problems that interfere with daily life (DCDQ, and request for help at a paediatric physical or occupational therapist)). Exclusion criteria are IQ < 70 and other medical conditions causing the motor impairment. DISCUSSION: The results of this study will help to make treatment protocols for children with DCD more evidence-based. This study will increase our knowledge about the efficacy of both the MI training and CO-OP training, and both children with DCD and therapists will benefit from this knowledge. TRIAL REGISTRATION: www.trialregister.nl/NTR5471. PMID- 26758029 TI - LGBT organisation successfully advocated for ban on tobacco promotions in San Jose, California. PMID- 26758028 TI - SMAD4 is Involved in the Development of Endotoxin Tolerance in Microglia. AB - Initial exposure of macrophages to LPS induces hyporesponsiveness to a second challenge with LPS, a phenomenon termed LPS tolerance. Smad4 plays important roles in the induction of LPS tolerance. However, the function of Smad4 in microglia remains unknown. Here we show that expression of Smad4 was highly up regulated in LPS-tolerized mouse cerebral cortex. Smad4 was mostly colocalized with microglia, rarely with neurons. Using a microglia cell line, BV2, we find that LPS activates endogenous Smad4, inducing its migration into the nucleus and increasing its expression. Smad4 significantly suppressed TLR-triggered production of proinflammatory cytokines (IL-6), increased anti-inflammatory cytokine in LPS-tolerized microglia. Moreover, IL-6 concentrations in culture supernatants after second LPS challenge are higher in SMAD4 small interfering RNA (siRNA) BV2 cells than control siRNA BV2 cells, indicating failure to induce tolerance in absence of Smad4 signaling. In our study, we conclude that both in vivo and in vitro, Smad4 signaling is required for maximal induction of endotoxin tolerance. PMID- 26758030 TI - YouTube as a source of quit smoking information for people living with mental illness. AB - BACKGROUND: YouTube is the most popular video sharing website, and is increasingly used to broadcast health information including smoking cessation advice. This study examines the quality and quantity of YouTube quit smoking videos targeted at people living with mental illness (MI). METHODS: We systematically searched YouTube using selected relevant search terms. The first 50 videos obtained for each search term were screened for relevance and further videos screened through snowball sampling. Forty unique, English language videos focussing on people with MI were included in the assessment and evaluated for general video characteristics, themes, format, targeted smoking cessation and harm reduction information. RESULTS: Most videos either discussed the problem of high smoking rates among people with MI (n=12) or smoking cessation programmes and policies at an institutional level (n=13). Only nine videos were aimed at providing quit smoking advice to this population. One video recommended higher doses of nicotine replacement therapy (NRT) for people with MI while six videos referred to possible changes in medication dosage on quitting smoking. Four videos suggested cutting down smoking for harm reduction. CONCLUSIONS: Very few YouTube videos specifically focus on the problem of high smoking rates among people with MI and even fewer provide targeted smoking cessation and harm reduction advice for this priority population. There is a need to develop comprehensive, evidence based, quit smoking video resources for smokers with a MI. PMID- 26758033 TI - Novel non-ionic surfactant proniosomes for transdermal delivery of lacidipine: optimization using 2(3) factorial design and in vivo evaluation in rabbits. AB - CONTEXT: Proniosomes offer a versatile vesicle drug delivery concept with potential for delivery of drugs via transdermal route. OBJECTIVES: To develop proniosomal gel using cremophor RH 40 as non-ionic surfactant containing the antihypertensive drug lacidipine for transdermal delivery so as to avoid its extensive first pass metabolism and to improve its permeation through the skin. MATERIALS AND METHODS: Proniosomes containing 1% lacidipine were prepared by the coacervation phase separation method, characterized, and optimized using a 2(3) full factorial design to define the optimum conditions to produce proniosomes with high entrapment efficiency, minimal vesicle size, and high-percentage release efficiency. The amount of cholesterol (X1), the amount of soya lecithin (X2), and the amount of cremophor RH 40 (X3) were selected as three independent variables. RESULTS AND DISCUSSION: The system F4 was found to fulfill the maximum requisite of an optimum system because it had minimum vesicle size, maximum EE, maximum release efficiency, and maximum desirability. The optimized system (F4) was then converted to proniosomal gel using carbopol 940 (1% w/w). In vitro permeation through excised rabbit skin study revealed higher flux (6.48 +/- 0.45) for lacidipine from the optimized proniosomal gel when compared with the corresponding emulgel (3.04 +/- 0.13) mg/cm(2)/h. The optimized formulation was evaluated for its bioavailability compared with commercial product. Statistical analysis revealed significant increase in AUC (0 - alpha) 464.17 +/- 113.15 ng h/ml compared with 209.02 +/- 47.35 ng h/ml for commercial tablet. Skin irritancy and histopathological investigation of rat skin revealed its safety. CONCLUSIONS: Cremophor RH 40 proniosomal gel could be considered as very promising nanocarriers for transdermal delivery of lacidipine. PMID- 26758031 TI - PTESFinder: a computational method to identify post-transcriptional exon shuffling (PTES) events. AB - BACKGROUND: Transcripts, which have been subject to Post-transcriptional exon shuffling (PTES), have an exon order inconsistent with the underlying genomic sequence. These have been identified in a wide variety of tissues and cell types from many eukaryotes, and are now known to be mostly circular, cytoplasmic, and non-coding. Although there is no uniformly ascribed function, several have been shown to be involved in gene regulation. Accurate identification of these transcripts can, however, be difficult due to artefacts from a wide variety of sources. RESULTS: Here, we present a computational method, PTESFinder, to identify these transcripts from high throughput RNAseq data. Uniquely, it systematically excludes potential artefacts emanating from pseudogenes, segmental duplications, and template switching, and outputs both PTES and canonical exon junction counts to facilitate comparative analyses. In comparison with four existing methods, PTESFinder achieves highest specificity and comparable sensitivity at a variety of read depths. PTESFinder also identifies between 13 % and 41.6 % more structures, compared to publicly available methods recently used to identify human circular RNAs. CONCLUSIONS: With high sensitivity and specificity, user-adjustable filters that target known sources of false positives, and tailored output to facilitate comparison of transcript levels, PTESFinder will facilitate the discovery and analysis of these poorly understood transcripts. PMID- 26758032 TI - Prognostic Importance of Lesion Location on Functional Outcome in Patients with Cerebellar Ischemic Stroke: a Prospective Pilot Study. AB - To date, few studies focused on prediction of functional recovery after cerebellar stroke. The main aim of this prospective pilot study was to determine the association between cerebellar lesion location and functional outcome in adults with acute cerebellar infarction. We examined 14 patients with first-ever unilateral cerebellar ischemic stroke within 7 days and at 90 days from the onset of stroke by means of the International Cooperative Ataxia Rating Scale. Cerebellar lesions were traced from magnetic resonance imaging performed within 72 h since stroke and region of interest were generated. The association between the International Cooperative Ataxia Rating Scale score and lesion location was determined with the voxel-based lesion-symptom mapping methods implemented in the MRIcro software. Colored lesion-symptom maps representing the z statistics were generated and overlaid onto the MNI-ICBM 152 linear probabilistic atlas of the human brain and the Johns Hopkins University white matter templates. Our results documented that injuries to the V, VI, VIIA Crus I, VIIA Crus II, VIIB, VIIIA, and VIIIB lobules and the middle cerebellar peduncle are significantly associated with the International Cooperative Ataxia Rating Scale (ICARS) score at 1 week after the onset of stroke. Furthermore, we found that injuries to the VI, VIIA Crus I, VIIA Crus II, VIIB, VIIIA, and VIIIB lobules, the dentate nucleus, and the middle cerebellar peduncle are significantly associated with the ICARS score at 3 months since the cerebellar stroke onset. The findings of this pilot study might improve prognostic accuracy of functional outcome in patients with acute cerebellar infarction. PMID- 26758034 TI - Women's communication self-efficacy and expectations of primary male partners' cooperation in sexually transmitted infection treatment in Ho Chi Minh City, Vietnam: a cross-sectional study. AB - BACKGROUND: Effective control of sexually transmitted infections (STIs) depends on affected patients notifying their sexual partners, and partners following through with screening and treatment. Our study assessed high-risk-STI women's confidence in STI-diagnosis-related communications with their primary male partners in Ho Chi Minh City, Vietnam, and determined associated characteristics of the women and their partners. METHODS: We employed convenience and snowball sampling in a clinic-based setting to recruit 126 women from August to October 2013. All data were obtained from women's self-report. RESULTS: The proportions of participants who were "slightly confident" or "very confident" that they could disclose their STI positivity to partners, ask partners to have an STI examination or treatment, and give partners bacterial-STI medications were 70.3%, 62.1%, and 69.0%, respectively. The proportions who perceived that their partners would be "very likely" to have an STI examination and to take STI medications were 16.2% and 38.8%, respectively. Significantly lower self-efficacy was observed in women who had a lower education level, who had ever traded sex, or whose primary partners were not husbands or fiances. CONCLUSIONS: Our results suggest potential for piloting STI-partner-targeted interventions. To be effective, these programs should improve women's self-efficacy and primary partners' cooperation with screening and treatment. PMID- 26758036 TI - Is CEM43 still a relevant thermal dose parameter for hyperthermia treatment monitoring? AB - CEM43 has its roots in the direct cytotoxic effect of heat, whereby the amount of cell death depends on the temperature and exposure time. CEM43 is a normalising method to convert the various time-temperature exposures applied into an equivalent exposure time expressed as minutes at the reference temperature of 43 degrees C. The CEM43 concept also holds a number of weaknesses, however. When used to predict treatment efficacy of combined radiotherapy plus hyperthermia, CEM43 does not include the effect of sensitisation by enhanced oxygenation, variation in interval time and the effect of multiple fractions. Further, it does not include the effect of increased perfusion at the lower thermal dose - and the occurrence of stasis at the higher thermal dose. Overall, studies towards a thermal dose-effect relationship in radiotherapy plus hyperthermia present a diffuse message without a definitive conclusion. However, prospective studies and studies with large patient numbers did report significant thermal dose-effect relationships and provide a good reason to continue research in the CEM43 model. Such research would be best performed in homogeneous patient groups with a single pathology and a low variation in tumour size and heterogeneity. Further, high quality thermometry, strict treatment schedules with fixed intervals and preferably homogenous heating are important requirements to enhance the probability of detecting a thermal dose-effect relationship. The slowly growing availability of hybrid MR hyperthermia systems should be a strong stimulus to expand these studies with the inclusion of measuring thermal dose-dependent blood flow and oxygen changes in the tumour and normal tissues. PMID- 26758035 TI - General Movements in preterm infants undergoing craniosacral therapy: a randomised controlled pilot-trial. AB - BACKGROUND: The objective of this study was to investigate neurological short term effects of craniosacral therapy as an ideal form of osteopathic manipulative treatment (OMT) due to the soft kinaesthetic stimulation. METHODS: Included were 30 preterm infants, with a gestational age between 25 and 33 weeks, who were admitted to the neonatal intensive care unit of the University Hospital of Graz, Austria. The infants were randomized either into the intervention group (IG) which received standardised craniosacral therapy, or the control group (CG) which received standard care. To guarantee that only preterm infants with subsequent normal neurodevelopment were included, follow up was done regularly at the corrected age (= actual age in weeks minus weeks premature) of 12 and 24 months. After 2 years 5 infants had to be excluded (IG; n = 12; CG: n = 13). General Movements (GMs) are part of the spontaneous movement repertoire and are present from early fetal life onwards until the end of the first half year of life. To evaluate the immediate result of such an intervention, we selected the General Movement Assessment (GMA) as an appropriate tool. Besides the global GMA (primary outcome) we used as detailed GMA, the General Movement Optimality Score (GMOS- secondary outcome), based on Prechtl's optimality concept. To analyse GMOS (secondary outcome) a linear mixed model with fixed effects for session, time point (time point refers to the comparisons of the measurements before vs. after each session) and intervention (IG vs. CG), random effect for individual children and a first order autoregressive covariance structure was used for calculation of significant differences between groups and interactions. Following interaction terms were included in the model: session*time point, session*intervention, time point*intervention and session*time point*intervention. Exploratory post hoc analyses (interaction: session*time point*intervention) were performed to determine group differences for all twelve measurement (before and after all 6 sessions) separately. RESULTS: Between groups no difference in the global GMA (primary outcome) could be observed. The GMOS (secondary outcome) did not change from session to session (main effect session: p = 0.262) in the IG or the CG. Furthermore no differences between IG and CG (main effect group: p = 0.361) and no interaction of time*session could be observed (p = 0.658). Post hoc analysis showed a trend toward higher values before (p = 0.085) and after (p = 0.075) the first session in CG compared to IG. At all other time points GMOS were not significantly different between groups. CONCLUSION: We were able to indicate that a group of "healthy" preterm infants undergoing an intervention with craniosacral therapy (IG) showed no significant changes in GMs compared to preterm infants without intervention (CG). In view of the fact that the global GMA (primary outcome) showed no difference between groups and the GMOS (detailed GMA-secondary outcome) did not deteriorate in the IG, craniosacral therapy seems to be safe in preterm infants. TRIAL REGISTRATION: German Clinical Trials Register DRKS00004258 . PMID- 26758037 TI - Validation of a Sampling Method to Collect Exposure Data for Central-Line Associated Bloodstream Infections. AB - OBJECTIVE: Surveillance of central-line-associated bloodstream infections requires the labor-intensive counting of central-line days (CLDs). This workload could be reduced by sampling. Our objective was to evaluate the accuracy of various sampling strategies in the estimation of CLDs in intensive care units (ICUs) and to establish a set of rules to identify optimal sampling strategies depending on ICU characteristics. DESIGN: Analyses of existing data collected according to the European protocol for patient-based surveillance of ICU-acquired infections in Belgium between 2004 and 2012. SETTING AND PARTICIPANTS: CLD data were reported by 56 ICUs in 39 hospitals during 364 trimesters. METHODS: We compared estimated CLD data obtained from weekly and monthly sampling schemes with the observed exhaustive CLD data over the trimester by assessing the CLD percentage error (ie, observed CLDs - estimated CLDs/observed CLDs). We identified predictors of improved accuracy using linear mixed models. RESULTS: When sampling once per week or 3 times per month, 80% of ICU trimesters had a CLD percentage error within 10%. When sampling twice per week, this was >90% of ICU trimesters. Sampling on Tuesdays provided the best estimations. In the linear mixed model, the observed CLD count was the best predictor for a smaller percentage error. The following sampling strategies provided an estimate within 10% of the actual CLD for 97% of the ICU trimesters with 90% confidence: 3 times per month in an ICU with >650 CLDs per trimester or each Tuesday in an ICU with >480 CLDs per trimester. CONCLUSION: Sampling of CLDs provides an acceptable alternative to daily collection of CLD data. PMID- 26758038 TI - Reorienting adolescent sexual and reproductive health research: reflections from an international conference. AB - On December 4th 2014, the International Centre for Reproductive Health (ICRH) at Ghent University organized an international conference on adolescent sexual and reproductive health (ASRH) and well-being. This viewpoint highlights two key messages of the conference--(1) ASRH promotion is broadening on different levels and (2) this broadening has important implications for research and interventions -that can guide this research field into the next decade. Adolescent sexuality has long been equated with risk and danger. However, throughout the presentations, it became clear that ASRH and related promotion efforts are broadening on different levels: from risk to well-being, from targeted and individual to comprehensive and structural, from knowledge transfer to innovative tools. However, indicators to measure adolescent sexuality that should accompany this broadening trend, are lacking. While public health related indicators (HIV/STIs, pregnancies) and their behavioral proxies (e.g., condom use, number of partners) are well developed and documented, there is a lack of consensus on indicators for the broader construct of adolescent sexuality, including sexual well-being and aspects of positive sexuality. Furthermore, the debate during the conference clearly indicated that experimental designs may not be the only appropriate study design to measure effectiveness of comprehensive, context specific and long-term ASRH programmes, and that alternatives need to be identified and applied. Presenters at the conference clearly expressed the need to develop validated tools to measure different sub-constructs of adolescent sexuality and environmental factors. There was a plea to combine (quasi )experimental effectiveness studies with evaluations of the development and implementation of ASRH promotion initiatives. PMID- 26758039 TI - Comparison of steroid-pulse therapy and combined with mizoribine in IgA nephropathy: a randomized controlled trial. AB - BACKGROUND: The significance of immunosuppressants as an adjunct treatment with corticosteroids for IgA nephropathy (IgAN) has not been well demonstrated. This study was performed to compare two treatment regimens, steroid-pulse therapy or combined with mizoribine (MZR) in progressive IgAN. METHODS: Study design was a prospective randomized controlled trial of 40 patients with moderate to severe glomerular injuries who were randomly administered either pulse methylprednisolone followed by a 25-month course of oral prednisolone (P group, n = 20) or in combination with MZR (150 mg/day for 24 months, M + P group, n = 20). The primary endpoint was a reduction of proteinuria by >=50 % of the baseline value. Secondary endpoints were increased serum creatinine (Cr) by >=50 %, or a decrease in estimated glomerular filtration rate by <=50 %. RESULTS: Twenty-five months after the initiation of treatment, urinary protein excretion significantly declined from the median of 0.98 to 0.17 g/gCr in the P group (P < 0.05) and from 1.01 to 0.38 g/gCr in the M + P group (P < 0.05). There was no statistical difference in the serial changes of proteinuria between two groups (P = 0.81). All patients reached the primary endpoint, and the cumulative incidence of the reduction of proteinuria was not significantly different (P = 0.76). No patient reached the secondary endpoint during the 25 months of treatment. CONCLUSIONS: Both therapeutic regimens significantly reduced the levels of proteinuria. We could not find the additional effect of MZR in combination with steroid-pulses in this small-scale controlled trial. Steroid-pulse therapy with a 25-month course of oral steroids seems to be effective for progressive IgAN. PMID- 26758040 TI - An efficient full-length cDNA amplification strategy based on bioinformatics technology and multiplexed PCR methods. AB - A novel strategy for amplification full-length cDNA and promoter sequences has been developed using bioinformatics technology and multiplexed PCR methods in this study. The amplification of 3' ends of cDNA is performed according to the modified classic 3' RACE techniques, therein the more efficient and effective oligo(dT)-anchor primer with hairpin structure is specially designed. For the amplification of 5' ends of cDNA, two or three-round TAIL-PCR or touch-down PCR using arbitrary degenerate (AD) and sequence-specific reverse (SPR) primers is performed until the 5' sequence of multi-assembled fragment reaches the exon1 region identified by aligning this fragment to reference genome database. Then another TAIL-PCR or touch-down PCR using genomic DNA as template is conducted to obtain the remaining 5' and promoter sequences. The 5' end sites of cDNA are predicted by aligning finally assembled fragment to homologous reference genes of other species, and screening the relative locations of common characteristic cis elements in silico on promoter. The putative 5' ends are further validated by primers corresponding to these predicted sites in cDNAs. This method is suitable for researchers to isolate limited full-length cDNA sequences due to its operability, inexpensiveness, efficiency and speediness. PMID- 26758041 TI - Myelodysplastic syndrome macrophages have aberrant iron storage and heme oxygenase-1 expression. AB - Iron overload and transfusion dependance portend poor risk in myelodysplastic syndromes (MDS); bone marrow macrophages store iron and limit oxidative damage through heme oxygenase-1 (HO1). We assessed iron stores and macrophage HO1 expression in MDS using image analysis of intact diagnostic bone marrow biopsies and qualitative scoring of marrow aspirate iron among 129 cytopenic patients, 67 with MDS and 62 similarly aged patients with benign cytopenias. Using double immunofluorescence and sequential iron and immunohistochemistry staining, we showed that marrow iron colocalizes with HO1 and H-ferritin to CD163 + macrophages. Marrow iron was elevated in MDS independent of transfusion status, a finding of potential utility in distinguishing benign cytopenia from MDS. Among MDS patients only, CD163 + macrophage density and HO1 and H-ferritin expression by CD163 + macrophages increased in tandem with marrow iron. High HO1 was significantly associated with shorter overall survival among MDS patients independent of IPSSR and history of transfusion. PMID- 26758042 TI - Unveiling Spatial Epidemiology of HIV with Mobile Phone Data. AB - An increasing amount of geo-referenced mobile phone data enables the identification of behavioral patterns, habits and movements of people. With this data, we can extract the knowledge potentially useful for many applications including the one tackled in this study - understanding spatial variation of epidemics. We explored the datasets collected by a cell phone service provider and linked them to spatial HIV prevalence rates estimated from publicly available surveys. For that purpose, 224 features were extracted from mobility and connectivity traces and related to the level of HIV epidemic in 50 Ivory Coast departments. By means of regression models, we evaluated predictive ability of extracted features. Several models predicted HIV prevalence that are highly correlated (>0.7) with actual values. Through contribution analysis we identified key elements that correlate with the rate of infections and could serve as a proxy for epidemic monitoring. Our findings indicate that night connectivity and activity, spatial area covered by users and overall migrations are strongly linked to HIV. By visualizing the communication and mobility flows, we strived to explain the spatial structure of epidemics. We discovered that strong ties and hubs in communication and mobility align with HIV hot spots. PMID- 26758043 TI - Extrusion of barley and oat influence the fecal microbiota and SCFA profile of growing pigs. AB - The effect of extrusion of barley and oat on the fecal microbiota and the formation of SCFA was evaluated using growing pigs as model system. The pigs were fed a diet containing either whole grain barley (BU), oat groat (OU), or their respective extruded samples (BE and OE). 454 pyrosequencing showed that the fecal microbiota of growing pigs was affected by both extrusion and grain type. Extruded grain resulted in lower bacterial diversity and enrichment in operational taxonomic units (OTUs) affiliated with members of the Streptococcus, Blautia and Bulleidia genera, while untreated grain showed enrichment in OTUs affiliated with members of the Bifidobacterium and Lactobacillus genera, and the butyrate-producing bacteria Butyricicoccus, Roseburia, Coprococcus and Pseudobutyrivibrio. Untreated grain resulted in a significant increase of n butyric, i-valeric and n-valeric acid, which correlated with an increase of Bifidobacterium and Lactobacillus. This is the first study showing that cereal extrusion affects the microbiota composition and diversity towards a state generally thought to be less beneficial for health, as well as less amounts of beneficial butyric acid. PMID- 26758044 TI - Prosthetic valve choice in middle-aged patients: guidelines and other guiding principles. PMID- 26758045 TI - Reply to White and Balasubramanian. PMID- 26758046 TI - Using the radial artery for coronary revascularization after radial puncture. PMID- 26758047 TI - Assessment of Breast Cancer Risk and Belief in Breast Cancer Screening Among the Primary Healthcare Nurses. AB - Breast cancer is the most frequently diagnosed cancer in women. Early detection of breast cancer is known to increase survival rates significantly after diagnosis. This research was carried out to determine the level of breast cancer risk among primary healthcare nurses and their belief in breast cancer screening. In this descriptive research, the data were collected in face-to-face interviews with the participants. The researchers contacted all primary healthcare nurses currently working in the province. The data collection tools included a questionnaire form on sociodemographic characteristics, breast cancer risk assessment form, and Champion's Health Belief Model Scale (CHBMS) for breast cancer screening. In data analysis, descriptive statistics, t test, and analysis of variance (ANOVA) were used. The mean age of nurses was 35 +/- 3.6. The mean score for the breast cancer risk assessment form was calculated as 82.9 +/- 18.7. The subscale scores for the CHBMS for breast cancer screening were as follows: susceptibility 7.3 +/- 1.8, seriousness 19.5 +/- 4.1, benefits of breast self exam 15.5 +/- 2.6, barriers to breast self-exam 15.1 +/- 2.8, self-efficacy 40.3 +/- 7.0, and motivation 19.5 +/- 4.1. The risk of breast cancer was found to be low in the study group. The analysis of the subscale scores for the CHBMS for breast cancer screening revealed that nurses had a below-average susceptibility perception, a somewhat lower perception of seriousness, an above-average mean score for perceived benefits, a moderate barrier perception, a relatively high perceived self-efficacy, and motivation above average. PMID- 26758049 TI - Comparison of the predictive value of plateletcrit with various other blood parameters in gestational diabetes development. AB - Gestational diabetes is the most encountered metabolic disease in pregnancy and affects both the mother and fetus adversely. Low-grade subchronic inflammation is associated with gestational diabetes development. Platelets (PLT) play role in blood coagulation and inflammatory process. We aimed to compare the various platelet indices in patients with GDM and healthy pregnant controls and to determine whether PLT indices are useful in Gestational diabetes diagnosis. The present study was performed at the Zonguldak Bulent Ecevit University, School of Medicine, Department of Obstetrics and Gynecology. Statistically significant relationships with plateletcrit, mean platelet volume, and platelet distribution width and patients with GDM were found (p < 0.001). Plateletcrit had higher sensitivity and specificity than other platelet indices. Although plateletcrit is a largely unknown or an underestimated parameter in complete blood count, it gives more precise information than platelet count and mean platelet volume. Platelet-related indices and their determination are inexpensive and routinely ordered markers, the significance of which is often ignored. They may be useful in screening for gestational diabetes as an adjunct to oral glucose tolerance test. PMID- 26758048 TI - Mass Spectrometry-Based Quantitative Strategies for Assessing the Biological Consequences and Repair of DNA Adducts. AB - The genetic integrity of living organisms is constantly threatened by environmental and endogenous sources of DNA damaging agents that can induce a plethora of chemically modified DNA lesions. Unrepaired DNA lesions may elicit cytotoxic and mutagenic effects and contribute to the development of human diseases including cancer and neurodegeneration. Understanding the deleterious outcomes of DNA damage necessitates the investigation about the effects of DNA adducts on the efficiency and fidelity of DNA replication and transcription. Conventional methods for measuring lesion-induced replicative or transcriptional alterations often require time-consuming colony screening and DNA sequencing procedures. Recently, a series of mass spectrometry (MS)-based strategies have been developed in our laboratory as an efficient platform for qualitative and quantitative analyses of the changes in genetic information induced by DNA adducts during DNA replication and transcription. During the past few years, we have successfully used these MS-based methods for assessing the replicative or transcriptional blocking and miscoding properties of more than 30 distinct DNA adducts. When combined with genetic manipulation, these methods have also been successfully employed for revealing the roles of various DNA repair proteins or translesion synthesis DNA polymerases (Pols) in modulating the adverse effects of DNA lesions on transcription or replication in mammalian and bacterial cells. For instance, we found that Escherichia coli Pol IV and its mammalian ortholog (i.e., Pol kappa) are required for error-free bypass of N(2)-(1-carboxyethyl)-2' deoxyguanosine (N(2)-CEdG) in cells. We also found that the N(2)-CEdG lesions strongly inhibit DNA transcription and they are repaired by transcription-coupled nucleotide excision repair in mammalian cells. In this Account, we focus on the development of MS-based approaches for determining the effects of DNA adducts on DNA replication and transcription, where liquid chromatography-tandem mass spectrometry is employed for the identification, and sometimes quantification, of the progeny products arising from the replication or transcription of lesion bearing DNA substrates in vitro and in mammalian cells. We also highlight their applications to lesion bypass, mutagenesis, and repair studies of three representative types of DNA lesions, that is, the methylglyoxal-induced N(2) CEdG, oxidatively induced 8,5'-cyclopurine-2'-deoxynucleosides, and regioisomeric alkylated thymidine lesions. Specially, we discuss the similar and distinct effects of the minor-groove DNA lesions including N(2)-CEdG and O(2)-alkylated thymidine lesions, as well as the major-groove O(4)-alkylated thymidine lesions on DNA replication and transcription machinery. For example, we found that the addition of an alkyl group to the O(4) position of thymine may facilitate its preferential pairing with guanine and thus induce exclusively the misincorporation of guanine nucleotide opposite the lesion, whereas alkylation of thymine at the O(2) position may render the nucleobase unfavorable in pairing with any of the canonical nucleobases and thus exhibit promiscuous miscoding properties during DNA replication and transcription. The MS-based strategies described herein should be generally applicable for quantitative measurement of the biological consequences and repair of other DNA lesions in vitro and in cells. PMID- 26758051 TI - Editorial 2016. PMID- 26758050 TI - Diagnosis of a C3 segmental type of vertebral artery by magnetic resonance angiography: report of two cases. AB - We report two cases in which the vertebral artery (VA) entered the spinal canal via the intervertebral foramen at the C2-C3 disc level, an extremely rare variation regarded as a C3 segmental type of VA, that we diagnosed by magnetic resonance angiography. The C2 segmental type of VA, in which the VA enters the spinal canal via the C1-C2 intervertebral space, is relatively common. It is important to identify these variations before surgery of the craniovertebral junction or interventional procedures to prevent complications. PMID- 26758052 TI - Replaced common hepatic artery from the superior mesenteric artery: multidetector computed tomography (MDCT) classification focused on pancreatic penetration and the course of travel. AB - PURPOSE: We categorize the subtypes of the replaced common hepatic artery (RCHA) and evaluate the clinical implications. METHODS: Thirty-four cases of the RCHA were evaluated retrospectively using multidetector computed tomography. We categorized them into the three RCHA subtypes according to pancreatic penetration and the passing routes. The distance between the orifice of the superior mesenteric artery (SMA) and RCHA bifurcation (D SMA-RCHA) was measured using advanced 3D imaging software. Analysis of variance was used to evaluate the difference in D SMA-RCHA according to the RCHA subtype. RESULTS: Type A (n = 17, 50 %) referred to RCHA penetrating the pancreatic parenchyma, all crossing the dorsal aspect of the superior mesenteric vein (SMV). Among them, three cases were accompanied by the circumportal pancreas. Type B (n = 10, 29 %) referred to RCHA without penetration of the pancreatic parenchyma and crossing of the dorsal aspect of the main portal vein (MPV) or SMV. Type C (n = 7, 21 %) referred to RCHA without penetration of the pancreas parenchyma and crossing of the ventral aspect of the MPV or SMV. The mean D SMA-RCHA of each subtype was as follows: type A, 3.13 cm [95 % confidence interval (CI) 2.70-3.57]; type B, 2.04 cm [95 % CI 1.40-2.68]; and type C, 2.14 cm [95 % CI 2.23-2.92]. The D SMA-RCHA of the penetrating pancreatic parenchyma of the RCHA was significantly longer than that of the non-penetrating pancreatic parenchyma (P = 0.007). CONCLUSION: Half of RCHA show penetrating the pancreatic parenchyma, which was categorized as type A, and this type A takes off from the SMA more distally than RCHA without intrapancreatic penetration. PMID- 26758053 TI - Percutaneous Mechanical Circulatory Support for Cardiogenic Shock. AB - OPINION STATEMENT: The use of percutaneous, non-durable mechanical circulatory support (MCS) for cardiogenic shock (CS) is growing; however, large, randomized clinical trials confirming benefit in this population do not exist. Guidelines and recommendations regarding optimal timing for MCS implementation, patient selection, device selection, and post-implantation management are beginning to emerge. A better understanding of (1) the distinct hemodynamic effects of each device option, (2) the need for early implementation of the appropriate device option for a particular clinical scenario, (3) the definition of non-salvageable CS to help clinicians know when to say "no" to non-durable MCS, and (4) best practices to monitor, wean, and optimize metabolic parameters while using non durable MCS are required to continue improving clinical outcomes for patients with CS. PMID- 26758054 TI - A New Fluorescent Sensor Based on Bisindolizine Derivative. AB - A fluorescent sensor based on 1,2,1',2'- Tetra(methoxycarbonyl)- 3,3'- bis(p methylbenzoyl)- 7,7'-bisindolizine (MBI) showing excellent selectivity towards Fe(3+) ions was developed. Under optimized experimental conditions, the fluorescence intensity of 1,2,1',2'- Tetramethoxycarbonyl- 3,3'- bis(p methylbenzoyl)- 7,7'-bisindolizine was quenched linearly by Fe(3+) ions in the range of 2.00 * 10(-2) to 4.76 * 10(-3) M. The limit of detection was found to be 3.17 * 10(-3) M. The mechanism for quenching was investigated. The developed sensor was applied for the determination of Fe(3+) in pharmaceutical samples. PMID- 26758055 TI - Bis(Naphthalimide-Piperazine)-Based Off-On Fluorescent Probe for Acids. AB - A bis(naphthalimide-piperazine) derivative (1) was synthesized as a pH-sensitive Off-On fluorescent probe. Operation mechanism of 1 is based on photo-induced electron transfer (PET) and its pH-dependent optical changes were investigated by using absorption and fluorescence spectroscopy. In the pH range of 11-4.5, this probe undergoes PET process from the piperazine to the naphthalimide moiety, leading to a fluorescence quenching. However, in the pH range of 4.5-1, the PET is inhibited to give a fluorescence enhancement. Moreover, the fluorescence 'turn on' response of 1 is highly selective for protons (H(+)) over other metal cations, biomolecules and it shows a good reversibility between acidic and basic conditions. Graphical Abstract ?. PMID- 26758056 TI - Veno-arterial extracorporeal membrane oxygenation for Streptococcus pyogenes toxic shock syndrome in pregnancy. AB - Streptococcal toxic shock syndrome (STSS), an invasive Streptococcus pyogenes (Group A streptococcus) infection with hypotension and multiple organ failure, is quite rare in pregnancy but is characterized by rapid disease progression and high fatality rates. We present a case of STSS with infection-induced cardiac dysfunction in a pregnant woman who was treated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO). A 24-year-old multiparous woman in the third trimester had early symptoms of high fever and diarrhea 1 day prior to admission to the hospital emergency department. On admission, she had multiple organ failure including circulatory failure. Due to fetal distress, emergency Cesarean section was carried out and transferred to intensive care units. She had refractory circulatory failure with depressed myocardial contractility with progressive multiple organ failure, despite receiving significant hemodynamic supports including high-dose catecholamine. Thus, VA-ECMO was initiated 18 h after intensive care unit admission. Consequently, ECMO provided extra time to recover from infection and myocardial depression. She was successfully weaned from VA-ECMO on day 7 and was discharged home on day 53. VA-ECMO can be a therapeutic option for refractory circulatory failure with significant myocardial depression in STSS. PMID- 26758057 TI - Minimal change in children's lifestyle behaviours and adiposity following a home based obesity intervention: results from a pilot study. AB - BACKGROUND/METHODS: Families of overweight and obese children require support to make sustainable lifestyle changes to improve their child's diet and activity behaviours and in turn weight status. The aim of this pre-post intervention pilot study was to evaluate the feasibility of an individualised home-based intervention for treatment seeking overweight/obese 4-12 year olds and their caregivers. Baseline measures were used to develop a family-specific intervention to improve the quality of the home environment. The intervention was delivered as individualised written recommendations and resources plus phone call and home visit support. Baseline measures were repeated approximately 6 months later. RESULTS: Complete data for 24 children was available. Parents reported that 43% of intervention recommendations were implemented 'very much'. Some descriptive changes were observed in the home environment, most commonly including fruit and vegetables in their child's lunchbox, not providing food treats, and restricting children's access to chips/savoury snack biscuits. At the group level, minimal change was detected in children's diet and activity behaviours or weight status (all p > 0.05). CONCLUSION: The study findings did not support intervention feasibility in its current form. Future interventions should target the family food and activity environment, but also utilise an approach to address the complex social circumstances which limit parent's ability to prioritise healthy family lifestyle behaviours. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) 3/12/2014. http://www.ANZCTR.org.au. ACTRN12614001264673. PMID- 26758058 TI - A significant subgroup of resectable gallbladder cancer patients has an HER2 positive status. AB - Gallbladder cancer (GBC) has a poor prognosis, and new targeted therapeutic options are needed. We investigated the human epidermal growth factor receptor 2 (HER2) status and its clinicopathological significance in a large cohort of GBC patients. We assessed HER2 expression in a consecutive series of 211 GBC cases by immunohistochemistry (IHC), paying particular attention to intratumoral heterogeneity. HER2 gene amplification was analyzed by dual-color fluorescence in situ hybridization (FISH). An HER2 positive status was called when the IHC score was 3+ or when the IHC score was 2+, and FISH was positive. Correlations were analyzed between HER2 status and clinicopathological parameters including survival. The HER2 IHC score was 0 in 144 (68.2%), 1+ in 28 (13.3%), 2+ in 14 (6.6%), and 3+ in 25 cases (11.8%). In 20/39 (51%) of the IHC 2+ and 3+ cases, the staining pattern was heterogeneous. In HER2 IHC score 2+ and 3+ cases, HER2 FISH was positive in 83% (10/12) and 96% (24/25), respectively. Altogether, 35/211 cases (16.6%) were HER2 positive. There was no significant association between HER2 status and clinicopathological variables or survival. We identified a significant subgroup of HER2-positive GBC cases, for whom a clinical trial with anti-HER2 therapy might be considered. PMID- 26758059 TI - The effects of antiepileptic drugs on the growth of glioblastoma cell lines. AB - To determine the effects of antiepileptic drug compounds on glioblastoma cellular growth, we exposed glioblastoma cell lines to select antiepileptic drugs. The effects of selected antiepileptic drugs on glioblastoma cells were measured by MTT assay. For compounds showing significant inhibition, cell cycle analysis was performed. Statistical analysis was performed using SPSS. The antiepileptic compounds selected for screening included carbamazepine, ethosuximide, gabapentin, lamotrigine, levetiracetam, magnesium sulfate, oxcarbazepine, phenytoin, primidone, tiagabine, topiramate, valproic acid, and vigabatrin. Dexamethasone and temozolomide were used as a negative and positive control respectively. Our results showed temozolomide and oxcarbazepine significantly inhibited glioblastoma cell growth and reached IC50 at therapeutic concentrations. The other antiepileptic drugs screened were unable to reach IC50 at therapeutic concentrations. The metabolites of oxcarbazepine were also unable to reach IC50. Dexamethasone, ethosuximide, levetiracetam, and vigabatrin showed some growth enhancement though they did not reach statistical significance. The growth enhancement effects of ethosuximide, levetiracetam, and vigabatrin found in the study may indicate that these compounds should not be used for prophylaxis or short term treatment of epilepsy in glioblastoma. While valproic acid and oxcarbazepine were effective, the required dose of valproic acid was far above that used for the treatment of epilepsy and the metabolites of oxcarbazepine failed to reach significant growth inhibition ruling out the use of oral oxcarbazepine or valproic acid as monotherapy in glioblastoma. The possibility of using these compounds as local treatment is a future area of study. PMID- 26758060 TI - Association between hemoglobin levels and clinical outcomes in adult patients after in-hospital cardiac arrest: a retrospective cohort study. AB - In addition to cardiac output, oxygen delivery is determined by the amount of oxygen carried by hemoglobin, which is estimated by the product of hemoglobin level and peripheral hemoglobin oxygen saturation (SpO2). Optimal hemoglobin concentration for post-cardiac arrest syndrome (PCAS) has not yet been investigated thoroughly. We conducted a retrospective observational study in a single medical center. We included adult patients between 2006 and 2012 who experienced in-hospital cardiac arrest, and achieved sustained return of spontaneous circulation (ROSC). We used multivariable logistic regression analysis to identify factors associated with favorable neurological status at hospital discharge, defined as a score of 1 or 2 on the Cerebral Performance Category scale. Minimum hemoglobin concentration and SpO2 during the initial 24 h after ROSC were used for analysis. Anemia was defined by the World Health Organization criteria as a hemoglobin concentration <12 g/dL in women and <13 g/dL in men. Of the 426 patients included in our analysis, 387 patients (90.8 %) met the criteria for anemia. The mean minimum hemoglobin concentration among all the patients was 9.2 g/dL. The product of hemoglobin * SpO2 was correlated with a favorable neurological outcome (odds ratio 1.003, 95 % confidence interval 1.002 1.004). According to recommended SpO2 by resuscitation guidelines (94-98 %), we calculated the corresponding range of minimum required hemoglobin concentration to be 8.6-9.0 g/dL for a favorable neurological outcome. Anemia common among PCAS patients. Neurological outcome in PCAS might be correlated with hemoglobin concentration following resuscitation. PMID- 26758061 TI - The dangerous link between childhood and adulthood predictors of obesity and metabolic syndrome. AB - The purpose of this review is to evaluate whether some risk factors in childhood work as significant predictors of the development of obesity and the metabolic syndrome in adulthood. These factors include exposures to risk factors in the prenatal period, infancy and early childhood, as well as other socio-demographic variables. We searched articles of interest in PubMed using the following terms: 'predictors AND obesity OR Metabolic syndrome AND (children OR adolescents) AND (dyslipidemia OR type 2 diabetes OR atherosclerosis OR hypertension OR hypercholesterolemia OR cardiovascular disease)' AND genetic OR epigenetic. Maternal age, smoking and weight gain during pregnancy, parental body mass index, birth weight, childhood growth patterns (early rapid growth and early adiposity rebound), childhood obesity and the parents' employment have a role in early life. Furthermore, urbanization, unhealthy diets, increasingly sedentary lifestyles and genetic/epigenetic variants play a role in the persistence of obesity in adulthood. Health promotion programs/agencies should consider these factors as reasonable targets to reduce the risk of adult obesity. Moreover, it should be a clinical priority to correctly identify obese children who are already affected by metabolic comorbidities. PMID- 26758062 TI - Mass gathering medicine: event factors predicting patient presentation rates. AB - This study was conducted to identify the event characteristics of mass gatherings that predict patient presentation rates held in a southeastern US university community. We conducted a retrospective review of all event-based emergency medical services (EMS) records from mass gathering patient presentations over an approximate 23 month period, from October 24, 2009 to August 27, 2011. All patrons seen by EMS were included. Event characteristics included: crowd size, venue percentage filled seating, venue location (inside/outside), venue boundaries (bounded/unbounded), presence of free water (i.e., without cost), presence of alcohol, average heat index, presence of climate control (i.e., air conditioning), and event category (football, concerts, public exhibitions, non football athletic events). We identified 79 mass gathering events, for a total of 670 patient presentations. The cumulative patron attendance was 917,307 persons. The patient presentation rate (PPR) for each event was calculated as the number of patient presentations per 10,000 patrons in attendance. Overdispersed Poisson regression was used to relate this rate to the event characteristics while controlling for crowd size. In univariate analyses, increased rates of patient presentations were strongly associated with outside venues [rate ratio (RR) = 3.002, p < 0.001], unbounded venues (RR = 2.839, p = 0.001), absence of free water (RR = 1.708, p = 0.036), absence of climate control (RR = 3.028, p < 0.001), and a higher heat index (RR = 1.211 per 10-unit heat index increase, p = 0.003). The presence of alcohol was not significantly associated with the PPR. Football events had the highest PPR, followed sequentially by public exhibitions, concerts, and non-football athletic events. In multivariate models, the strong predictors from the univariate analyses retained their predictive significance for the PPR, together with heat index and percent seating. In the setting of mass event medical care, we note that several factors are strongly associated with an increased patient census, including outside (external) or unbounded venues, the absence of fee water (i.e., without cost), no climate control, percent (occupied) seating, and increasing heat index. Although the presence of alcohol is noted to increase patient needs, it does not do so significantly. Regarding event type, collegiate football games have the highest patient census among the range of other events studied. These findings should be considered during the process of EMS resource planning for mass gatherings. PMID- 26758063 TI - Upregulation of CD19+CD24(hi)CD38(hi) regulatory B cells is associated with a reduced risk of acute lung injury in elderly pneumonia patients. AB - Acute lung injury (ALI) is a common complication in elderly pneumonia patients who have a rapid progression, and is accompanied by a high mortality rate. Because the treatment options of ALI are limited to supportive care, identifying pneumonia patients who are at higher risk of ALI development is the emphasis of many studies. Here, we approach this problem from an immunological perspective by examining CD19(+)CD24(hi)CD38(hi) B cells, an important participant in acute and chronic inflammation. We find that elderly pneumonia patients have elevated CD19(+)CD24(hi)CD38(hi) B cell frequency compared to healthy individuals. This B cell population may express a higher level of IL-10, which has been was shown to suppress CD4(+) T cell-mediated proinflammatory cytokine interferon gamma (IFNg) and tumor necrosis factor alpha (TNFa) production, through an IL-10-dependent mechanism. We also observe that the frequency of CD19(+)CD24(hi)CD38(hi) B cell is positively correlated with the frequency of CD4(+)CD25(+)Foxp3(+)Tregs in peripheral blood. Moreover, consistent with CD19(+)CD24(hi)CD38(hi) B cell's anti inflammatory role, we find that pneumonia patients who later developed ALI have reduced level of CD19(+)CD24(hi)CD38(hi) B cells. Together, our results demonstrated that CD19(+)CD24(hi)CD38(hi) B cells in pneumonia patients possess regulatory function in vivo, and are associated with a reduced ALI risk. PMID- 26758064 TI - Recombinant HAP Phytase of the Thermophilic Mold Sporotrichum thermophile: Expression of the Codon-Optimized Phytase Gene in Pichia pastoris and Applications. AB - The codon-optimized phytase gene of the thermophilic mold Sporotrichum thermophile (St-Phy) was expressed in Pichia pastoris. The recombinant P. pastoris harboring the phytase gene (rSt-Phy) yielded a high titer of extracellular phytase (480 +/- 23 U/mL) on induction with methanol. The recombinant phytase production was ~40-fold higher than that of the native fungal strain. The purified recombinant phytase (rSt-Phy) has the molecular mass of 70 kDa on SDS-PAGE, with K m and V max (calcium phytate), k cat and k cat/K m values of 0.147 mM and 183 nmol/mg s, 1.3 * 10(3)/s and 8.84 * 10(6)/M s, respectively. Mg(2+) and Ba(2+) display a slight stimulatory effect, while other cations tested exert inhibitory action on phytase. The enzyme is inhibited by chaotropic agents (guanidinium hydrochloride, potassium iodide, and urea), Woodward's reagent K and 2,3-bunatedione, but resistant to both pepsin and trypsin. The rSt-Phy is useful in the dephytinization of broiler feeds efficiently in simulated gut conditions of chick leading to the liberation of soluble inorganic phosphate with concomitant mitigation in antinutrient effects of phytates. The addition of vanadate makes it a potential candidate for generating haloperoxidase, which has several applications. PMID- 26758065 TI - Stress resilience and subsequent risk of type 2 diabetes in 1.5 million young men. AB - AIMS/HYPOTHESIS: Psychosocial stress in adulthood is associated with a higher risk of type 2 diabetes, possibly mediated by behavioural and physiological factors. However, it is unknown whether low stress resilience earlier in life is related to subsequent development of type 2 diabetes. We examined whether low stress resilience in late adolescence is associated with an increased risk of type 2 diabetes in adulthood. METHODS: We conducted a national cohort study of all 1,534,425 military conscripts in Sweden during 1969-1997 (97-98% of all 18 year-old men nationwide each year) without prior diagnosis of diabetes, who underwent standardised psychological assessment for stress resilience (on a scale of 1-9) and were followed up for type 2 diabetes identified from outpatient and inpatient diagnoses during 1987-2012 (maximum attained age 62 years). RESULTS: There were 34,008 men diagnosed with type 2 diabetes in 39.4 million person-years of follow-up. Low stress resilience was associated with an increased risk of developing type 2 diabetes after adjusting for BMI, family history of diabetes, and individual and neighbourhood socioeconomic factors (HR for lowest vs highest quintile: 1.51; 95% CI 1.46, 1.57; p < 0.0001), including a strong linear trend across the full range of stress resilience (p trend < 0.0001). This association did not vary by BMI level, family history of diabetes or socioeconomic factors. CONCLUSIONS/INTERPRETATION: These findings suggest that low stress resilience may play an important long-term role in aetiological pathways for type 2 diabetes. Further elucidation of the underlying causal factors may help inform more effective preventive interventions across the lifespan. PMID- 26758067 TI - Human islet cells are killed by BID-independent mechanisms in response to FAS ligand. AB - Cell death via FAS/CD95 can occur either by activation of caspases alone (extrinsic) or by activation of mitochondrial death signalling (intrinsic) depending on the cell type. The BH3-only protein BID is activated in the BCL-2 regulated or mitochondrial apoptosis pathway and acts as a switch between the extrinsic and intrinsic cell death pathways. We have previously demonstrated that islets from BID-deficient mice are protected from FAS ligand-mediated apoptosis in vitro. However, it is not yet known if BID plays a similar role in human beta cell death. We therefore aimed to test the role of BID in human islet cell apoptosis immediately after isolation from human cadaver donors, as well as after de-differentiation in vitro. Freshly isolated human islets or 10-12 day cultured human islet cells exhibited BID transcript knockdown after BID siRNA transfection, however they were not protected from FAS ligand-mediated cell death in vitro as determined by DNA fragmentation analysis using flow cytometry. On the other hand, the same cells transfected with siRNA for FAS-associated via death domain (FADD), a molecule in the extrinsic cell death pathway upstream of BID, showed significant reduction in cell death. De-differentiated islets (human islet derived progenitor cells) also demonstrated similar results with no difference in cell death after BID knockdown as compared to scramble siRNA transfections. Our results indicate that BID-independent pathways are responsible for FAS-dependent human islet cell death. These results are different from those observed in mouse islets and therefore demonstrate potentially alternate pathways of FAS ligand induced cell death in human and mouse islet cells. PMID- 26758066 TI - Pharmacological reports about gastroprotective effects of methanolic extract from leaves of Solidago chilensis (Brazilian arnica) and its components quercitrin and afzelin in rodents. AB - Solidago chilensis Meyenmost (Asteraceae), popularly known as "Brazilian arnica" or "arnica-do-campo," is widely used in the folk medicine to treat gastric disorders. Based on this, the gastroprotective activity of S. chilensis methanolic extract was investigated. Besides, a phytochemical study allowed isolation of two flavonoids (quercitrin and afzelin). The gastroprotective effects were investigated in acute gastric ulcer models, and the antisecretory activity was assessed in vivo and in vitro. The adhered mucus levels, reduced glutathione (GSH) content and myeloperoxidase (MPO) activity were quantified in ulcerated tissues. The contribution of isolated compounds in extract effects was evaluated, and its doses were calculated according to its yield. To evaluate the in vivo healing properties of S. chilensis methanolic extract, a chronic gastric ulcer was induced in mice by 10 % acetic acid. Evaluation of tumor necrosis factor (TNF) levels was also performed at the site of the acetic acid-induced gastric ulcer. In parallel, effects on cell viability and cell proliferation of fibroblasts (L929 cells) were determined by in vitro trials. Firstly, the S. chilensis methanolic extract (100 or 300 mg/kg) reduced the ulcer area induced by ethanol/HCl in mice when compared to the vehicle group. Moreover, the S. chilensis extract (300 mg/kg) prevented the mucus depletion, the increase in MPO activity and the decrease in the GSH levels in the ulcerated gastric tissue. The S. chilensis extract also was able to decrease the indomethacin-induced gastric ulcer in rats at a dose of 100 mg/kg. The antisecretory effect of the extract (100 mg/kg, intraduodenal (i.d.)) was confirmed by the reduction in the volume and acidity in parallel to an increase in the pH of gastric content. In addition, quercitrin (1.38 mg/kg, but not 0.46 mg/kg) and afzelin (0.026 and 0.078 mg/kg) decreased the ethanol/HCl-induced gastric ulcer. In this model, quercitrin (1.38 mg/kg) prevented the depletion of gastric GSH content and both quercitrin (1.38 mg/kg) and afzelin (0.078 mg/kg) reduced the MPO activity. These compounds also inhibited the H(+),K(+)-ATPase activity at a concentration of 1-100 MUg/ml. In addition, the participation of quercitrin and afzelin in these effects also was confirmed. Furthermore, after 4 days of the treatment, an oral administration of S. chilensis methanolic extract (100 mg/kg) reduced the area of the gastric ulcer induced by acetic acid and the regeneration of the gastric mucosa was accompanied by a reduction in gastric TNF levels. The healing properties of the extract also were confirmed by enhancement of proliferation and coverage of scratched wounds in a fibroblast monolayer. Together, our results confirmed the gastroprotective effect of S. chilensis methanolic extract as well as its gastric healing potential and provided some support to the traditional use of S. chilensis for prevention and treatment of gastric lesions in complementation to its known anti inflammatory properties. PMID- 26758069 TI - The importance of employing power analysis and the accurate statistical method when designing a study. PMID- 26758070 TI - LOXL1 gene analysis in Turkish patients with exfoliation glaucoma. AB - The purpose of this study is to evaluate whole lysyl oxidase like 1 (LOXL1) gene by sequence analysis in Turkish patients with exfoliation glaucoma (XFG). A total of 48 (35 male, 13 female) patients with XFG were enrolled. Besides routine ophthalmological examination, peripapillary retinal nerve fibre layer (RNFL) analysis with optic coherence tomography was performed. Blood samples of 2 ml with EDTA were obtained and sent to Medical Genetics Department, Molecular Genetics Laboratory for LOXL1 polymorphism (PCR and agarose gel imaging) analysis. The role of the detected changes on disease severity was evaluated. No LOXL1 gene mutations in any of the patients were detected. Three types of single nucleotide polymorphisms (SNPs) including R141L(rs1048661), A320A(rs41435250), and F184F were detected in 17 (35.3 %) patients. When compared, SNP-positive patients had thinner RNFL than SNP-negative patients (64.5 +/- 17.6 and 66.1 +/- 20.4 u, respectively), and SNP-positive patients had higher cupping/disc ratio than SNP-negative patients (0.76 +/- 0.2 and 0.70 +/- 0.3, respectively). However, both values were not statistically significant (p = 0.966 and p = 0.539, respectively). When compared, R141L-positive patients had significantly thinner cornea thickness (516.11 +/- 30.3 u) than R141L-negative patients (556.69 +/- 27.2 u) (p = 0.004). There was not any statistical significant difference in the means of age, gender, BCVA, MD, PSD, IOP, number of hypotensive agents, and percent of glaucoma surgery (p > 0.05). In this study group of Turkish population, no LOXL1 mutations were found. No associations between the defined SNPs (A320A, R141L and F184F) and the severity of the disease were detected. PMID- 26758071 TI - Comparison between visual field defect in pigmentary glaucoma and primary open angle glaucoma. AB - To compare visual field defect patterns between pigmentary glaucoma and primary open-angle glaucoma. Retrospective, comparative study. Patients with diagnosis of primary open-angle glaucoma (POAG) and pigmentary glaucoma (PG) in mild to moderate stages were enrolled in this study. Each of the 52 point locations in total and pattern deviation plot (excluding 2 points adjacent to blind spot) of 24-2 Humphrey visual field as well as six predetermined sectors were compared using SPSS software version 20. Comparisons between 2 groups were performed with the Student t test for continuous variables and the Chi-square test for categorical variables. Thirty-eight eyes of 24 patients with a mean age of 66.26 +/- 11 years (range 48-81 years) in the POAG group and 36 eyes of 22 patients with a mean age of 50.52 +/- 11 years (range 36-69 years) in the PG group were studied. (P = 0.00). More deviation was detected in points 1, 3, 4, and 32 in total deviation (P = 0.03, P = 0.015, P = 0.018, P = 0.023) and in points 3, 4, and 32 in pattern deviation (P = 0.015, P = 0.049, P = 0.030) in the POAG group, which are the temporal parts of the field. It seems that the temporal area of the visual field in primary open-angle glaucoma is more susceptible to damage in comparison with pigmentary glaucoma. PMID- 26758068 TI - Structural basis of RNA recognition and dimerization by the STAR proteins T-STAR and Sam68. AB - Sam68 and T-STAR are members of the STAR family of proteins that directly link signal transduction with post-transcriptional gene regulation. Sam68 controls the alternative splicing of many oncogenic proteins. T-STAR is a tissue-specific paralogue that regulates the alternative splicing of neuronal pre-mRNAs. STAR proteins differ from most splicing factors, in that they contain a single RNA binding domain. Their specificity of RNA recognition is thought to arise from their property to homodimerize, but how dimerization influences their function remains unknown. Here, we establish at atomic resolution how T-STAR and Sam68 bind to RNA, revealing an unexpected mode of dimerization different from other members of the STAR family. We further demonstrate that this unique dimerization interface is crucial for their biological activity in splicing regulation, and suggest that the increased RNA affinity through dimer formation is a crucial parameter enabling these proteins to select their functional targets within the transcriptome. PMID- 26758073 TI - Comparison of remifentanil EC50 for facilitating i-gel and laryngeal mask airway insertion with propofol anesthesia. AB - OBJECTIVE: Each supraglottic airway requires different anesthetic depth because it has a specific structure and different compressive force in the oropharyngeal cavity. We designed the study to compare the effect-site concentration (Ce) of remifentanil in 50 % of patients (EC50) for successful insertion of the i-gel second-generation supraglottic airway device with that for laryngeal mask airway (LMA) insertion during target-controlled infusion (TCI) of propofol. METHODS: Forty-one female patients were randomized to the i-gel group (n = 20) or the LMA group (n = 21). Anesthesia was induced with propofol Ce of 5 MUg/ml and the predetermined remifentanil Ce, and the i-gel or LMA was inserted 5 min later. The remifentanil Ce was estimated by modified Dixon's up-and-down method (initial concentration: 3.0 ng/ml, step size: 0.5 ng/ml). The patient's response to device insertion was classified as either "success (no movement)" or "failure (movement)". RESULTS: Using the Dixon's up-and-down method, EC50 of remifentanil Ce for the i-gel (1.58 +/- 0.41 ng/ml) was significantly lower than that for LMA (2.25 +/- 0.55 ng/ml) (p = 0.038). Using isotonic regression, EC50 (83 % CI) of remifentanil in the i-gel group [1.50 (1.37-1.80) ng/ml] was statistically lower than that in the LMA group [2.00 (1.82-2.34) ng/ml]. EC95 (95 % CI) of remifentanil in the i-gel group [2.38 (1.48-2.50) ng/ml] was statistically lower than that in the LMA group [3.35 (2.58-3.48) ng/ml]. CONCLUSIONS: We found that EC50 of remifentanil Ce for i-gel insertion (1.58 ng/ml) was significantly lower than that for LMA insertion (2.25 ng/ml) in female patients during propofol TCI without neuromuscular blockade. PMID- 26758075 TI - Inhibition of human DNA topoisomerase IB by nonmutagenic ruthenium(II)-based compounds with antitumoral activity. AB - Herein we synthesized two new ruthenium(II) compounds [Ru(pySH)(bipy)(dppb)]PF6 (1) and [Ru(HSpym)(bipy)(dppb)]PF6 (2) that are analogs to an antitumor agent recently described, [Ru(SpymMe2)(bipy)(dppb)]PF6 (3), where [(Spy) = 2 mercaptopyridine anion; (Spym) = 2-mercaptopyrimidine anion and (SpymMe2) = 4,6 dimethyl-2-mercaptopyrimidine anion]. In vitro cell culture experiments revealed significant anti-proliferative activity for 1-3 against HepG2 and MDA-MB-231 tumor cells, higher than the standard anti-cancer drugs doxorubicin and cisplatin. No mutagenicity is detected when compounds are evaluated by cytokinesis-blocked micronucleus cytome and Ames test in the presence and absence of S9 metabolic activation from rat liver. Interaction studies show that compounds 1-3 can bind to DNA through electrostatic interactions and to albumin through hydrophobic interactions. The three compounds are able to inhibit the DNA supercoiled relaxation mediated by human topoisomerase IB (Top1). Compound 3 is the most efficient Top1 inhibitor and the inhibitory effect is enhanced upon pre incubation with the enzyme. Analysis of different steps of Top1 catalytic cycle indicates that 3 inhibits the cleavage reaction impeding the binding of the enzyme to DNA and slows down the religation reaction. Molecular docking shows that 3 preferentially binds closer to the residues of the active site when Top1 is free and lies on the DNA groove downstream of the cleavage site in the Top1 DNA complex. Thus, 3 can be considered in further studies for a possible use as an anticancer agent. PMID- 26758074 TI - Anesthetic management of nonintubated video-assisted thoracoscopic surgery using epidural anesthesia and dexmedetomidine in three patients with severe respiratory dysfunction. AB - Nonintubated video-assisted thoracoscopic surgery (VATS) has been reported to be safe and feasible for patients with various thoracic diseases, including those who have respiratory dysfunction. In nonintubated VATS, it is important to maintain spontaneous respiration and to obtain a satisfactory operating field through adequate collapse of the lung by surgical pneumothorax. Therefore, we need to minimize the patient's physical and psychological discomfort by using regional anesthesia and sedation. If analgesia and sedation are inadequate, conversion to intubated general anesthesia may be required. Dexmedetomidine (DEX) is a highly selective alpha2-adrenoceptor agonist that provides anxiolysis and cooperative sedation without respiratory depression. It seems to be a suitable sedative for nonintubated VATS, especially in high-risk patients for intubated general anesthesia, but there have been no report about its use combined with epidural anesthesia in nonintubated VATS for adult patients. Here, we report three patients with severe respiratory dysfunction who underwent nonintubated VATS for pneumothorax using epidural anesthesia and DEX. In all three patients, DEX infusion was started after placement of an epidural catheter and was titrated to achieve mild sedation, while maintaining communicability and cooperation. This seems to be a promising strategy for nonintubated VATS in patients with respiratory dysfunction, as well as patients with normal respiratory function. PMID- 26758072 TI - Remifentanil: applications in neonates. AB - Remifentanil is a synthetic opioid derivative that was introduced into clinical practice in the United States in 1996. The unique modification of its chemical structure to include a methyl-ester ring allows its hydrolysis by non-specific plasma and tissue esterases. This molecular configuration results in its rapid metabolism thereby providing a rapid onset, easy titration by continuous infusion, and a short context-sensitive half-life with rapid elimination. These principles are stable and consistent across all age groups regardless of the infusion characteristics. Owing to these pharmacokinetic characteristics, it is an effective agent in the neonatal population allowing the provision of intense analgesia and anesthesia with a rapid recovery profile in various clinical scenarios. Here, we review the pharmacokinetics of remifentanil in neonates, discuss its clinical applications including intraoperative administration for anesthetic care, unique applications for procedural sedation including endotracheal intubation, and its potential use for sedation in the Intensive Care Unit setting during mechanical ventilation. PMID- 26758076 TI - Levels of maternal care in dogs affect adult offspring temperament. AB - Dog puppies are born in a state of large neural immaturity; therefore, the nervous system is sensitive to environmental influences early in life. In primates and rodents, early experiences, such as maternal care, have been shown to have profound and lasting effects on the later behaviour and physiology of offspring. We hypothesised that this would also be the case for dogs with important implications for the breeding of working dogs. In the present study, variation in the mother-offspring interactions of German Shepherd dogs within the Swedish breeding program for military working dogs was studied by video recording 22 mothers with their litters during the first three weeks postpartum. The aim was to classify mothers with respect to their level of maternal care and to investigate the effect of this care on pup behaviour in a standardised temperament test carried out at approximately 18 months of age. The results show that females differed consistently in their level of maternal care, which significantly affected the adult behaviour of the offspring, mainly with respect to behaviours classified as Physical and Social Engagement, as well as Aggression. Taking maternal quality into account in breeding programs may therefore improve the process of selecting working dogs. PMID- 26758077 TI - Controversies in Establishing Biosimilarity: Extrapolation of Indications and Global Labeling Practices. AB - The principles of establishing biosimilarity are to demonstrate structural and functional similarity to a reference product using the most discriminatory analytical methods. There is still considerable controversy on the scientific basis for extrapolation of indications for biosimilars, which has been strengthened by diverging global regulatory decision making. Closely related to the question of extrapolation is the question of how to communicate the evidence base for authorizing biosimilars to healthcare professionals. In this paper we will consider some of the discussions around extrapolation of indications and the implications of decisions of various regulatory agencies in the world regarding the authorization and labeling of biosimilars. PMID- 26758078 TI - Hysterectomy for placenta accreta; methods for gross and microscopic pathology examination. AB - PURPOSE: Placenta accreta is an abnormal adherence of the placenta to the uterine wall. As the incidence of placenta accreta continues to rise, it has been useful to develop standard protocols for the diagnosis and management of affected patients. Pathologists have the opportunity to take an active role in evaluating these resource intensive protocols. METHODS: We describe methods of gross dissection, microscopic examination and reporting of hysterectomy specimens containing placenta accreta. RESULTS: This protocol facilitates retrospective correlation with surgical and radiographic findings as well as standardized tissue sampling for potential research. CONCLUSIONS: Through regular review of such quality measures pathologists can give feedback on the quality of surgical planning and use of imaging. PMID- 26758080 TI - Transcription of densovirus endogenous sequences in the Myzus persicae genome. AB - Integration of non-retroviral sequences in the genome of different organisms has been observed and, in some cases, a relationship of these integrations with immunity has been established. The genome of the green peach aphid, Myzus persicae (clone G006), was screened for densovirus-like sequence (DLS) integrations. A total of 21 DLSs localized on 10 scaffolds were retrieved that mostly shared sequence identity with two aphid-infecting viruses, Myzus persicae densovirus (MpDNV) and Dysaphis plantaginea densovirus (DplDNV). In some cases, uninterrupted potential ORFs corresponding to non-structural viral proteins or capsid proteins were found within DLSs identified in the aphid genome. In particular, one scaffold harboured a complete virus-like genome, while another scaffold contained two virus-like genomes in reverse orientation. Remarkably, transcription of some of these ORFs was observed in M. persicae, suggesting a biological effect of these viral integrations. In contrast to most of the other densoviruses identified so far that induce acute host infection, it has been reported previously that MpDNV has only a minor effect on M. persicae fitness, while DplDNV can even have a beneficial effect on its aphid host. This suggests that DLS integration in the M. persicae genome may be responsible for the latency of MpDNV infection in the aphid host. PMID- 26758082 TI - Cyclodextrin induced controlled delivery of a biological photosensitizer from a nanocarrier to DNA. AB - In this article, we have addressed to a demanding physicochemical aspect of therapeutic and drug research. We have reported a simple yet prospective technique that can be exploited for the controlled delivery of drugs and/or bioactive small molecules to the most relevant biomolecular target DNA. Exploiting various steady state and time resolved spectroscopic techniques together with the DNA helix melting study, we have shown that a biologically significant photosensitizer, namely, phenosafranin (PSF), can be quantitatively transferred to the DNA from the micellar nanocarrier made up of sodium tetradecyl sulfate (STS) using the external stimulant beta-cyclodextrin (beta-CD). The complexation property of beta-CD with the nanocarrier (STS) has been utilized for the controlled release of the probe from the micelle to the DNA. Non-toxicity of the stimulant and the noninvasive nature of the carrier towards the target are expected to add to the suitability of this approach from a clinical perspective. PMID- 26758079 TI - Understanding the obstacle of incompatibility at residue 156 within HLA-B*35 subtypes. AB - Defining permissive and non-permissive mismatches for transplantation is a demanding challenge. Single mismatches at amino acid (AA) position 156 of human leucocyte antigen (HLA) class I have been described to alter the peptide motif, repertoire, or mode of peptide loading through differential interaction with the peptide-loading complex. Hence, a single mismatch can tip the balance and trigger an immunological reaction. HLA-B*35 subtypes have been described to evade the loading complex, 156 mismatch distinguishing B*35:01 and B*35:08 changes the binding groove sufficiently to alter the sequence features of the selected peptide repertoire. To understand the functional influences of residue 156 in B*35 variants, we analyzed the peptide binding profiles of HLA-B*35:01(156Leu), B*35:08(156Arg) and B*35:62(156Trp). The glycoprotein tapasin represents a target for immune evasions and functions within the multimeric peptide-loading complex to stabilize empty class I molecules and promote acquisition of high-affinity peptides. All three B*35 subtypes showed a tapasin-independent mode of peptide acquisition. HLA-B*35-restricted peptides of low- and high-binding affinities were recovered in the presence and absence of tapasin and subsequently sequenced utilizing mass spectrometry. The peptides derived from B*35 variants differ substantially in their features dependent on their mode of recruitment; all peptides were preferentially anchored by Pro at p2 and Tyr, Phe, Leu, or Lys at pOmega. However, the Trp at residue 156 altered the p2 motif to an Ala and restricted the pOmega to a Trp. Our results highlight the importance of understanding the impact of key micropolymorphism and how a single AA mismatch orchestrates the neighboring AAs. PMID- 26758084 TI - Investigation of SHOX Gene Mutations in Turkish Patients with Idiopathic Short Stature. AB - OBJECTIVE: The frequency of mutations in the short stature homeobox (SHOX) gene in patients with idiopathic short stature (ISS) ranges widely, depending mostly on the mutation detection technique and inclusion criteria. We present phenotypic and genotypic data on 38 Turkish patients with ISS and the distinctive features of 1 patient with a SHOX deletion. METHODS: Microsatellite markers (MSMs) DXYS10092 (GA repeats) and DXYS10093 (CT repeats) were used to select patients for fluorescent in situ hybridisation (FISH) analysis and to screen for deletions in the SHOX gene. The FISH analysis was applied to patients homozygous for at least one MSM. A Sanger sequencing analysis was performed on patients with no deletions according to FISH to investigate point mutations in the SHOX gene. RESULTS: One patient (2.6%) had a SHOX mutation. CONCLUSION: Although the number of cases was limited and the mutation analysis techniques we used cannot detect all mutations, our findings emphasize the importance of the difference in arm span and height when selecting patients for SHOX gene testing. PMID- 26758085 TI - Mutations in the 'Fingers' subdomain of the deubiquitinase USP1 modulate its function and activity. AB - Ubiquitin-specific protease (USP)1 is a member of the USP family of deubiquitinating enzymes. Efficient USP1 activity requires binding to its cofactor USP1-associated factor 1 (UAF1), and the USP1-UAF1 deubiquitinase complex has important roles in regulating DNA damage-related processes. USPs show common folding of their catalytic domain, with three subdomains termed Thumb, Palm, and Fingers. The Fingers subdomain appears to be the primary site for ubiquitin binding. In USP1, the Fingers subdomain also mediates its interaction with UAF1, and thus represents a crucial, but poorly characterized, motif in USP1. To explore the role of USP1-UAF1 in ubiquitin-dependent nuclear processes, we tested the effect of modulating USP1-UAF1 activity on the level and/or localization of conjugated ubiquitin and the DNA damage-related proteins phosphorylated histone H2AX, Lys56-acetylated histone H3, and p53-binding protein 1 (53BP1). Small interfering RNA-mediated USP1 knockdown or treatment with the novel USP1-UAF1 inhibitor ML323 increased the recruitment of conjugated ubiquitin and 53BP1 into nuclear foci. Strikingly, ectopic coexpression of USP1 and UAF1 depleted conjugated ubiquitin in the nucleus and blocked the recruitment of 53BP1 to DNA damage foci. In a direct comparison with other overexpressed USPs, USP1 UAF1 behaved as a relatively promiscuous deubiquitinase. Experimental and cancer related mutations in the USP1 The Fingers subdomain abrogated substrate deubiquitination without interfering with other USP1 activities, such as UAF1 binding or autocleavage. These results provide new insights into the function and regulation of the USP1-UAF1 complex. PMID- 26758087 TI - Electrical current through individual pairs of phosphorus donor atoms and silicon dangling bonds. AB - Nuclear spins of phosphorus [P] donor atoms in crystalline silicon are among the most coherent qubits found in nature. For their utilization in scalable quantum computers, distinct donor electron wavefunctions must be controlled and probed through electrical coupling by application of either highly localized electric fields or spin-selective currents. Due to the strong modulation of the P-donor wavefunction by the silicon lattice, such electrical coupling requires atomic spatial accuracy. Here, the spatially controlled application of electrical current through individual pairs of phosphorus donor electron states in crystalline silicon and silicon dangling bond states at the crystalline silicon (100) surface is demonstrated using a high-resolution scanning probe microscope operated under ultra-high vacuum and at a temperature of 4.3 K. The observed pairs of electron states display qualitatively reproducible current-voltage characteristics with a monotonous increase and intermediate current plateaus. PMID- 26758086 TI - SALO, a novel classical pathway complement inhibitor from saliva of the sand fly Lutzomyia longipalpis. AB - Blood-feeding insects inject potent salivary components including complement inhibitors into their host's skin to acquire a blood meal. Sand fly saliva was shown to inhibit the classical pathway of complement; however, the molecular identity of the inhibitor remains unknown. Here, we identified SALO as the classical pathway complement inhibitor. SALO, an 11 kDa protein, has no homology to proteins of any other organism apart from New World sand flies. rSALO anti complement activity has the same chromatographic properties as the Lu. longipalpis salivary gland homogenate (SGH)counterparts and anti-rSALO antibodies blocked the classical pathway complement activity of rSALO and SGH. Both rSALO and SGH inhibited C4b deposition and cleavage of C4. rSALO, however, did not inhibit the protease activity of C1s nor the enzymatic activity of factor Xa, uPA, thrombin, kallikrein, trypsin and plasmin. Importantly, rSALO did not inhibit the alternative or the lectin pathway of complement. In conclusion our data shows that SALO is a specific classical pathway complement inhibitor present in the saliva of Lu. longipalpis. Importantly, due to its small size and specificity, SALO may offer a therapeutic alternative for complement classical pathway-mediated pathogenic effects in human diseases. PMID- 26758089 TI - Transepidermal Water Loss in Neonates: Baseline Values Using a Closed-Chamber System. AB - BACKGROUND: Transepidermal water loss (TEWL) is the normal, constitutive loss of water vapor from the skin in the absence of sweat gland activity. It is regarded as one of the most important parameters for characterizing skin barrier function, and the values are dependent on multiple variables. The objective of this study was to evaluate TEWL in neonates using a closed- chamber system, and determine if there is a variation of TEWL with the mode of delivery, pre-term birth, low birthweight or phototherapy. METHODS: This prospective study was conducted in 104 healthy neonates, 30 neonates in the Neonatal Intensive Care Unit (NICU) and 40 adults using a noninvasive, closed- chamber system (VapoMeterTM). RESULTS: A statistically significant difference in TEWL was noted between newborns and adults. No remarkable difference in TEWL was seen between boys or men and girls or women or those born via normal vaginal birth and caesarean section, but TEWL was significantly higher in preterm and low birthweight neonates. Significantly higher TEWL was noted from the antecubital fossa of the neonates who received phototherapy when compared with six other sites. CONCLUSIONS: The closed- chamber system is an acceptable alternative to the more widely used open-chamber system. The higher mean TEWL in neonates suggests that the epidermal barrier is still adapting to extrauterine life, making newborn skin more sensitive and requiring appropriate, age adapted care. PMID- 26758090 TI - Effectiveness of Intralesional Triamcinolone in the Treatment of Keloids in Children. AB - BACKGROUND: The current treatment of keloids includes surgery, intralesional steroids, and radiotherapy, among others. Radiotherapy is not recommended in children due to its effects on growing tissues. Our aim was to study intralesional triamcinilone therapy of keloids in children and analyze the impact of body location, age of the lesion, and etiology of the keloid on clinical response. METHODS: We conducted a prospective clinical trial with patients 1 to 14 years of age evaluated for keloid treatment. A soft tissue ultrasound was performed to measure the keloid volume, prior to intralesional infiltration with triamcinolone acetonide. A posttreatment ultrasound quantified the volume differences attributed to therapy. For the analysis, Mann-Whitney/Wilcoxon test for paired samples and a multiple regression analysis were performed. RESULTS: Twenty-one patients with a total of 25 keloids were enrolled, with a median age of 12 years (range 6-14 yrs). The initial lesional volume was 1.25 cc (range 0.2 6.3 cc) and the final volume was 0.2 cc (range 0.0-1.53 cc), corresponding to 82.7% of size reduction (p < 0.001). Regarding the relationships between response and body location, etiology and age of the lesion, the multiple regression analyses obtained p-values of 0.46, 0.16, and 0.87, respectively. One patient failed to improve. Average follow-up was 30 months. CONCLUSIONS: Triamcinolone acetonide is highly effective for the treatment of pediatric keloids. There is no relationship between clinical response and the factors evaluated, such as lesion location, etiology and age of the keloid. PMID- 26758088 TI - Metabolic traits of an uncultured archaeal lineage--MSBL1--from brine pools of the Red Sea. AB - The candidate Division MSBL1 (Mediterranean Sea Brine Lakes 1) comprises a monophyletic group of uncultured archaea found in different hypersaline environments. Previous studies propose methanogenesis as the main metabolism. Here, we describe a metabolic reconstruction of MSBL1 based on 32 single-cell amplified genomes from Brine Pools of the Red Sea (Atlantis II, Discovery, Nereus, Erba and Kebrit). Phylogeny based on rRNA genes as well as conserved single copy genes delineates the group as a putative novel lineage of archaea. Our analysis shows that MSBL1 may ferment glucose via the Embden-Meyerhof-Parnas pathway. However, in the absence of organic carbon, carbon dioxide may be fixed via the ribulose bisphosphate carboxylase, Wood-Ljungdahl pathway or reductive TCA cycle. Therefore, based on the occurrence of genes for glycolysis, absence of the core genes found in genomes of all sequenced methanogens and the phylogenetic position, we hypothesize that the MSBL1 are not methanogens, but probably sugar fermenting organisms capable of autotrophic growth. Such a mixotrophic lifestyle would confer survival advantage (or possibly provide a unique narrow niche) when glucose and other fermentable sugars are not available. PMID- 26758092 TI - Patient Perspectives: Atopic dermatitis (eczema). PMID- 26758091 TI - "Mint" Condition: Contact Dermatitis in an Adolescent Numismatist. AB - Allergic contact dermatitis (ACD) is common in children and adolescents. A history of persistent rash despite appropriate treatment should raise suspicion of ACD. We present the case of a 16-year-old boy with chronic dermatitis suspected of being a possible nickel allergy. He and his mother denied known common exposures. Patch testing confirmed allergies to multiple metals and several preservatives. A detailed social history revealed that the patient was an avid coin collector. Information about hobbies and activities should be elicited in any patient in whom ACD is suspected to determine exposures they may not initially have considered relevant. This case highlights the importance of pre- and posttest counseling and exposure history. PMID- 26758093 TI - Pediatric Dermatology Photoquiz: An Ulcerated Nodule on the Abdomen of a Child. Eccrine poroma. PMID- 26758094 TI - Pediatric Dermatology Photoquiz: A 9-Year Old Girl with Papules on Her Hands. Papular umbilicated granuloma annulare. PMID- 26758095 TI - Pediatric Dermatology Photoquiz: Multiple Papules on the Mucosal Surfaces of a 17 Year-Old Boy. Focal epithelial hyperplasia (Heck's disease). PMID- 26758096 TI - Pediatric Dermatology Photoquiz: Refractory Purulent Paronychia in a Young Girl. Paronychial cutaneous leishmaniasis. PMID- 26758097 TI - Pediatric Dermatology Photoquiz: Persistent Lesion of the Thumbnail of a 3-Year Old Boy. Lichen striatus. PMID- 26758098 TI - Pediatric Dermatology Photoquiz: Multiple Erythematous Papules on the Back. Recurrent pyogenic granulomas with satellitosis. PMID- 26758099 TI - Parathyroid Hormone: An Overlooked Variable in Atopic Dermatitis and Vitamin D Research. PMID- 26758100 TI - Childhood Pemphigus Foliaceus with Exclusive Immunoglobulin G Autoantibodies to Desmocollins. AB - Pemphigus refers to a group of potentially fatal blistering skin diseases that are often due to the deleterious effects of autoantibodies directed against desmosomal antigens. Although desmogleins have been mainly implicated as autoantigens in pemphigus, a steadily growing body of evidence suggests that other desmosomal proteins may be causally involved as well. Antibodies directed against desmocollin-3 have been shown to play a direct role in the pathogenesis of several types of pemphigus. Here we describe the case of a child with localized pemphigus foliaceus and immunoglobulin G (IgG) reactivity exclusively directed to desmocollins. The present report suggests that autoantibodies against nondesmoglein antigens may play a role in the pathogenesis of superficial pemphigus, in addition to pemphigus vulgaris, paraneoplastic pemphigus, and IgA pemphigus. PMID- 26758101 TI - Adolescent "Saxophone Penis" Secondary to Crohn's Disease: Misdiagnosed as Being Posttraumatic. AB - We describe a patient with a "saxophone penis" mistakenly diagnosed as having posttraumatic changes. A careful history and attention to blood tests at presentation may have alerted clinicians that there was a nontraumatic cause for our patient's disease. It is essential that clinicians consider "metastatic" anogenital Crohn's disease as a possible cause of "saxophone penis". PMID- 26758103 TI - [History and future perspectives of pediatric neurology in China]. PMID- 26758102 TI - Rhabdomyomatous Mesenchymal Hamartoma: A Deep Subcutaneous Lesion in the Sternoclavicular Area. AB - Cutaneous rhabdomyomatous mesenchymal hamartoma (RMH) is a rare benign tumor composed of two or more types of mesenchymal-derived cells. RMHs are generally sporadic and independent, but they can be associated with congenital abnormalities. We report a subcutaneous case of RMH in the sternoclavicular area with two recurrences after complete surgical excision. The course is variable and can range from spontaneous resolution to repeated recurrences. PMID- 26758104 TI - [Challenges and developments in diagnosis of mitochondrial diseases in children]. PMID- 26758105 TI - [Enhancing communication and cooperation is the key to the improvement of prenatal diagnosis of congenital heart disease]. PMID- 26758106 TI - [Chinese expert consensus for the diagnosis and treatment of fetal congenital heart disease]. PMID- 26758107 TI - [Initial monotherapy of newly diagnosed pediatric epilepsy: expert consensus]. PMID- 26758108 TI - [Interpretation of the expert consensus of initial monotherapy of newly diagnosed pediatric epilepsy]. PMID- 26758110 TI - [Diagnosis of mitochondrial disorders in children with next generation sequencing]. AB - OBJECTIVE: To explore the application value of next generation sequencing (NGS) in the diagnosis of mitochondrial disorders. METHOD: According to mitochondrial disease criteria, genomic DNA was extracted using standard procedure from peripheral venous blood of patients with suspected mitochondrial disease collected from neurological department of Beijing Children's Hospital Affiliated to Capital Medical University between October 2012 and February 2014. Targeted NGS to capture and sequence the entire mtDNA and exons of the 1 000 nuclear genes related to mitochondrial structure and function. Clinical data were collected from patients diagnosed at a molecular level, then clinical features and the relationship between genotype and phenotype were analyzed. RESULT: Mutation was detected in 21 of 70 patients with suspected mitochondrial disease, in whom 10 harbored mtDNA mutation, while 11 nuclear DNA (nDNA) mutation. In 21 patients, 1 was diagnosed congenital myasthenic syndrome with episodic apnea due to CHAT gene p.I187T homozygous mutation, and 20 were diagnosed mitochondrial disease, in which 10 were Leigh syndrome, 4 were mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes syndrome, 3 were Leber hereditary optic neuropathy (LHON) and LHON plus, 2 were mitochondrial DNA depletion syndrome and 1 was unknown. All the mtDNA mutations were point mutations, which contained A3243G, G3460A, G11778A, T14484C, T14502C and T14487C. Ten mitochondrial disease patients harbored homozygous or compound heterozygous mutations in 5 genes previously shown to cause disease: SURF1, PDHA1, NDUFV1, SUCLA2 and SUCLG1, which had 14 mutations, and 7 of the 14 mutations have not been reported. CONCLUSION: NGS has a certain application value in the diagnosis of mitochondrial diseases, especially in Leigh syndrome atypical mitochondrial syndrome and rare mitochondrial disorders. PMID- 26758109 TI - [Application of targeted capture technology and next generation sequencing in molecular diagnosis of inherited myopathy]. AB - OBJECTIVE: To elucidate the usefulness of next generation sequencing for diagnosis of inherited myopathy, and to analyze the relevance between clinical phenotype and genotype in inherited myopathy. METHOD: Related genes were selected for SureSelect target enrichment system kit (Panel Version 1 and Panel Version 2). A total of 134 patients who were diagnosed as inherited myopathy clinically underwent next generation sequencing in Department of Pediatrics, Peking University First Hospital from January 2013 to June 2014. Clinical information and gene detection result of the patients were collected and analyzed. RESULT: Seventy-seven of 134 patients (89 males and 45 females, visiting ages from 6 month-old to 26-year-old, average visiting age was 6 years and 1 month) underwent next generation sequencing by Panel Version 1 in 2013, and 57 patients underwent next generation sequencing by Panel Version 2 in 2014. The gene detection revealed that 74 patients had pathogenic gene mutations, and the positive rate of genetic diagnosis was 55.22%. One patient was diagnosed as metabolic myopathy. Five patients were diagnosed as congenital myopathy; 68 were diagnosed as muscular dystrophy, including 22 with congenital muscular dystrophy 1A (MDC1A), 11 with Ullrich congenital muscular dystrophy (UCMD), 6 with Bethlem myopathy (BM), 12 with Duchenne muscular dystrophy (DMD) caused by point mutations in DMD gene, 5 with LMNA-related congenital muscular dystrophy (L-CMD), 1 with Emery Dreifuss muscular dystrophy (EDMD), 7 with alpha-dystroglycanopathy (alpha-DG) patients, and 4 with limb-girdle muscular dystrophy (LGMD) patients. CONCLUSION: Next generation sequencing plays an important role in diagnosis of inherited myopathy. Clinical and biological information analysis was essential for screening pathogenic gene of inherited myopathy. PMID- 26758111 TI - [Cognitive profile of children with newly onset benign epilepsy with centro temporal spikes before treatment:a study of computerized cognitive testing in epilepsy]. AB - OBJECTIVE: Benign epilepsy with centro-temporal spikes (BECTs) is a common idiopathic partial epileptic syndrome in childhood, which often affect the pre school and school-age children and a considerable proportion have comorbidity including lower academic achievement and cognitive impairment. Few studies involved the psychocognitive assessment in such a drug-treatable epileptic syndrome especially in the newly diagnosed and medications-naive group. This study aimed to investigate the cognitive characteristics of children with newly onset BECTs before treatment. METHOD: Forty-one outpatients with newly diagnosed BECTs who visited the Clinic during the periods from October 2012 to May 2014 before the medications against epilepsy and 41 healthy controls recruited from regular school in Beijing during the period from July 2013 to March 2014, who matched in age and gender underwent battery testing by computerized cognitive testing in epilepsy (CCTE). The BECTs group included 41 children, 20 boys and 21 girls, mean age (8.2 +/- 1.7) years, the age of onset of epilepsy 4.5-11.5 years (the age of onset <8 years in 25 cases, >= 8 years in 16 cases). The cognitive characteristics and associated factors were analyzed. The primary data including correct answer numbers and reaction times were analyzed by independent sample t test between the two groups of children with BECTs and healthy controls based on SPSS 18.0 statistical software. RESULT: Raw data of 9 tasks' scores collected from BECTs and healthy control children were continuous variables in accordance with normal distribution. BECTs children performed significantly worse than controls in choice reaction time ((618+158) vs. (524+254) ms), three-dimensional mental rotation (11 +/- 10 vs. 18 +/- 12) and visual tracing (10 +/- 6 vs.15 +/- 6), t=2.01, 3.03 and 3.47, P<0.05, <0.01 and <0.001, respectively.While other 6 tasks showed no significant difference between the two groups (P>0.05 for all comparisons). BECTs boys performed significantly worse than girls on simple substraction tasks compared with standard nine score ((4.7 +/- 1.5) vs. (5.6 +/- 1.2), t=-2.24, P<0.05). Other 8 tasks showed no significant difference between boys and girls (P>0.05 for all comparisons). Other 9 tasks showed no significant differences between the two groups of BECTs children whose age of onset was before 8 years and those who started seizure >= 8 years (P all >0.05). The standard nine scores of simple substraction from the three BECTs groups of dominance sides of spikes and waves during NREM showed significant difference (P<0.05). BECTs children with bilateral discharges performed significantly worse than the other two groups dominantly right or left discharges (4.7 +/- 1.2 vs. 6.0 +/- 1.2 vs. 4.9 +/- 1.4, P all <0.05). There was no significant difference between the two groups with right and left side dominance discharges (P>0.05). Other 8 tasks showed no significant differences among the three groups (P>0.05 for all comparisons). CONCLUSION: Although EEG discharges index below 50% during NREM period, while newly diagnosed BECTs children before treatment with medications against epilepsy performed poorer on tasks of choice reaction time, three-dimensional mental rotation, and visual tracing. The two factors of male and bilateral discharges during NREM period correlate with dysfunction of simple subtraction, the mechanism needs further study and the cognitive function of epilepsy children should be evaluated and followed up, in order to provide psychologic baseline data for persistent cognitive disturbance. PMID- 26758112 TI - [Clinical effect of atomoxetine hydrochloride in 66 children with narcolepsy]. AB - OBJECTIVE: To observe the efficacy and safety of atomoxetine hydrochloride in children with narcolepsy. METHOD: Totally 66 patients with narcolepsy who were conformed international classification of sleep disturbances (ICSD-2) diagnostic criteria treated with atomoxetine hydrochloride seen from November 2010 to December 2014 were enrolled into this study, 42 of them were male and 24 female, mean age of onset was 7.5 years (3.75-13.00 years), mean duration before diagnosis was 1.75 years (0.25-5.00 years). Complete blood count, liver and kidney function, multiple sleep latency test (MSLT), polysomnography (PGS), neuroimaging and electroencephalography (EEG) were performed for each patient. For some of the children HLA-DR2 gene and serum markers of infection were tested. The 66 cases were followed up from 2 to 49 months (average 18 months) to observe the clinical efficacy and adverse reactions. RESULTS: In 62 cases excessive daytime sleepiness was improved, in 11 cases (16.7%) it was controlled (16.7%), in 29 cases (43.9%) the treatment was obviously effective and in 22 (33.3%) it was effective; cataplexy occurred in 54 cases, in 18 (33.3%) it was controlled, in 19 (35.2%) the treatment was obviously effective and in 10 (18.5%) effective; night sleep disorders existed in 55 cases, in 47 cases it was improved, in 14 (25.5%) it was controlled, in 20 (36.4%) the treatment was obviously effective and in 13 (23.6%) effective; hypnagogic or hypnopompic hallucination was present in 13 cases, in only 4 these symptoms were controlled. Sleep paralysis existed in 4 cases, it was controlled in only 1 case. In 18 cases attention and learning efficiency improved.Anorexia occurred in 18 cases, mood disorder in 5 cases, depression in 2 cases, nocturia, muscle tremors, involuntary tongue movement each occurred in 1 case. P-R interval prolongation and atrial premature contraction were found in 1 case. CONCLUSION: Atomoxetine hydrochloride showed good effects in patients with narcolepsy on excessive daytime sleepiness, cataplexy and night sleep disorders, the effects on hallucinations and sleep paralysis were not significant. Adverse reactions were slight, anorexia and mood disorder were common. As a non-central nervous system stimulant, atomoxetine hydrochloride does not induce drug dependence and has no prescription limits; it has good tolerability, safety and effectiveness, it can be a good alternative in treatment of children with narcolepsy. PMID- 26758113 TI - [Analysis of the drug resistance and the integron resistance gene cassette's characteristics of Shigella flexneri]. AB - OBJECTIVE: To investigate the correlation between Shigella flexneri multi-drug resistance and drug resistance gene cassette of integrons. METHOD: All 79 strains of Shigella flexneri were isolated from the feces of children ranged in age from 6 months to 14 years in some hospitals of Jinan, between May 2009 and April 2012.The resistance was detected by Kirby Bauer agar diffusion method, 1, 2 and 3 integron gene was amplified by PCR, the variable region of positive strains treated with enzyme digestion and determined by Series Analysis. RESULT: Among 79 Shigella flexneri strains, the resistance rate was 91% (72/79) to ampicillin, chloramphenicol, tetracycline, streptomycin, 70% (55/79) to sulfamethoxazole/trimethoprim, 30% (24/79), 23% (18/79), 33% (26/79) and 32% (25/79) to cefotaxime, ceftazidime, ciprofloxacin and levofloxacin.All 79 strains were susceptible to cefoxitin, imipenem, cefoperazone/sulbactam. The common drug resistance pattern is ampicillin tetracycline-chloramphenicol-streptomycin, accounted for 91% (72/79); 91% (72/79) strains carried integrons of class 1, 86% (68/79) strains carried integrons of class 2, No intI3 was detected. The resistance to ampicillin, streptomycin, tetracycline, chloramphenicol of atypical class 1 integron positive strains was significantly higher than the negative strains (chi2 = 35.96, P<0.01). The sequencing results:dfrV was detected in class 1 integron variable regions of 9 strains, dfrA17-aadA5 in 2 strains, blaOXA-30 aadA1 in 70 strains, 2 strains were not detected resistance gene cassette, all resistance gene cassettes were dfrA1-sat1-aadA1 in class 2 integron variable regions. CONCLUSION: The muti-drug resistance of Shigella flexneri in Jinan was closely associated with integrons. PMID- 26758114 TI - [Trisomy 21 syndrome associated interstitial lung disease: a case report]. AB - OBJECTIVE: To study the pathology, imaging and clinical features of a child with trisomy 21 syndrome associated interstitial lung disease. METHOD: Data of a case with trisomy 21 syndrome associated interstitial lung disease confirmed by lung imaging and pathology were collected, analyzed and the related reports in literature were reviewed. RESULT: The patient was a one year and 7 months old boy who suffered from severe pneumonia and recurrent infection during his hospital stay. When his disease was stable, he did not have shortness of breath and cyanosis, but a chest computed tomography (CT) showed ground-glass opacity, regional emphysema, band-like change in lung parenchyma, which indicated interstitial lung diseases. Unequal air inflation in bilateral lungs and diffuse over-distension of peripheral air spaces in lung surface were seen through thoracoscope. Pathological examination indicated that alveolar, alveolar ducts and alveolar sac were enlarged, alveolar septa was expanded. There were two reports in lung pathology of trisomy 21 syndrome, alveolar growth abnormalities was seen in 86%-88% cases. The multiple subpleural cysts in chest CT was characteristic. Clinically, trisomy 21 syndrome had high morbidity of respiratory tract infection and progress to respiratory failure frequently. Prolonged postoperative desaturation was constant which required long duration of respiratory support. CONCLUSION: Trisomy 21 syndrome associated alveolar growth abnormalities were confirmed, which manifest as alveolar simplification in pathology and interstitial lung diseases in imaging. The risk of respiratory failure in these cases caused by infection and surgery should be considered. PMID- 26758115 TI - [Interventional treatment of post-biopsy renal artery pseudoaneurysm in a child: case report and literature review]. AB - OBJECTIVE: To investigate the characteristics,diagnosis and therapy of post biopsy renal artery pseudoaneurysm in children and to study the clinical value of arterial embolization for traumatic renal hemorrhage when conservative treatment failed. METHOD: Data were compiled from medical records of a child in whom renal artery pseudoaneurysm occurred after biopsy in the Provincial Hospital Affiliated to Shandong University , and the related literature was reviewed to analyze the diagnosis and treatment of such pseudoaneurysm. RESULT: A 13-year-old boy had gross hematuria, aggravated dysuria and decreased hemoglobin 10 days after percutaneous renal biopsy. Hb decreased from 110 g/L on the first day after admission to 92 g/L on the 4th day, 83 g/L on the 7th day and the minimum to 74 g/L at the 8th day after admission. Ultrasound showed solid echogenic mass in the right renal pelvis as well as the bladder. Color Doppler ultrasound shows the red and blue rotation of blood flow in the polar capsule under the right kidney. Contrast-enhanced CT in the arterial phase showed a 0.5 cm sized renal mass with a strongly enhanced dot in the lower pole of the right kidney, suggesting a renal artery pseudoaneurysm. Haemostatic, supplement of red blood cells and blood volume and other integrative treatment of hematuria were applied for seven days, but his gross hematuria continued to be worsened. He was diagnosed as pseudoaneurysm by digital subtraction angiography (DSA) on the 19th day after renal biopsy. Superselective renal artery embolization using micro-coils and gelatin sponge particles was performed, and the blood clots were cleaned under cystoscope. Macro-haematuria and dysuria disappeared after the interventional treatment. Retrieval of reports on post-biopsy renal artery pseudoaneurysm in children by using "pseudoaneurysm, child" as the search term showed report of one case from the Chinese CNKI database and 3 cases from the PubMed database. The underlying disease was Henoch-Schonlein purpura nephritis in 3 cases and Sneedon syndrome in 1 case; clinical manifestation of gross haematuria was present in 4 cases, lumbago or pain at the site of the puncture in 2 cases, dysuria in 1 case, and fever in 2 cases. CONCLUSION: The post-biopsy renal artery pseudoaneurysm in children is often manifested as gross hematuria, lumbago, pain at the site of the puncture, fever and dysuria, DSA can be used for definite diagnosis and the interventional treatment is effective. PMID- 26758116 TI - [Effectiveness of methylprednisolone in treatment of children with refractory Mycoplasma pneumoniae pneumonia and its relationship with bronchoalveolar lavage cytokine levels]. AB - OBJECTIVE: To investigate cytokine level in bronchoalveolar lavage fluid (BALF) in children with refractory Mycoplasma pneumoniae pneumonia (RMPP) and the effects of methylprednisolone on RMPP. METHOD: Sixty cases with RMPP and 20 cases with bronchial foreign body with no respiratory tract infection as control group hospitalized in Department of Pulmonary Diseases, the Children's Hospital Affiliated to Medical School of Zhejiang University from February 2012 to February 2013 were enrolled. The RMPP patients were divided into two groups randomly (30 cases in each). Steroid group were given methylprednisolone 2 mg/(kg.d) intravenously for 3 days, and the cases in non steroid group were not given steroid therapy. Patients whose fever relieved after steroid treatment were classified as defervesced group while the others were classified as non defervesced group. Each patient was examined with fiberoptic bronchoscopy and bronchoalveolar lavage 3 days after admission and cytokine level in BALF of each patient was detected. RESULT: (1) In steroid group, the proportion of patients whose fever disappeared within 3 days after steroid therapy was 9/30 cases (30%), and in non steroid group no one responded within 3 days after medication, showing statistically significant difference (chi2 = 14.073, P=0.002), at the same time, the duration of cough in steroid group was significantly shorter than that in non steroid group (5.1 d vs. 7.0 d, t=-2.276, P=0.027). The total fever time of steroid group was 4.7 days, which as compaired with non steroid group (6.7 days) was shorter, but the difference was not significant (t=-1.351, P=0.134). (2) IL-1 beta, IL-4, IL-6, IL-8, IL-10, IFN-gamma in BALF of steroid group and non steroid group were both significantly higher than that of control group. But the same comparison between steroid group and non steroid group showed no significant difference. (3) In steroid group, IL-2 and IL-8 in BALF of patient whose fever disappeared after steroid therapy were both significantly lower than that of patients who still had fever (t=2.771, 2.054, P=0.010, 0.049) , but no significant difference was found between the two groups in BALF IL-1 beta, IL-4, IL-6, IL-10, IFN-gamma levels (P>0.05). CONCLUSION: (1) Three days of 2 mg/(kg.d) methylprednisolone therapy had the antipyretic effect in children with RMPP, and could shorten the length of cough. (2) Incresed BALF IL-1 beta, IL-4, IL-6, IL-8, IL-10, IFN-gamma levels were observed in RMPP and high level of BALF IL-2 and IL 8 might have some relevance with persistent fever of RMPP in children. PMID- 26758117 TI - [Clinical features of protracted bacterial bronchitis in children]. AB - OBJECTIVE: To analyze the clinical characteristics of protracted bacterial bronchitis (PBB) in children. METHOD: The clinical data of patients seen from October, 2010 to March, 2014 in Department of Respiratory Diseases of our hospital were retrospectively analyzed. Inclusion criteria were over 4 weeks cough, receiving fiberoptic bronchoscopy, positive bacterial culture and (or) the increased percentage of neutral granulocytes in bronchoalveolar lavage fluid (BALF). RESULT: Twenty eight patients were involved, 26 were male (93%) and two were female (7%). The median age of patients was 8.5 months. The median duration of cough was four weeks. The average length of hospital stay was (8.3 +/- 3.9)days. The main clinical feature was wet cough in 28 cases, wet cough with wheezing was seen in 21 cases. The wet cough phase distribution was irregular in 21 cases. The crackles with wheeze (in 21 cases) was main signs of PBB. The percentage of CD3- CD16+ 56+ cells increased in peripheral blood. The fiberoptic bronchoscopic manifestations of PBB were luminal mucosal edema. Eleven patients also had airway malacia. The neutrophil median in BALF was 0.2. The positive rate of bacterial culture of BALF was 36%. The main bacteria were Streptococcus pneumoniae (50%) and Haemophilus influenzae (30%). The main treatment for PBB patients included amoxycillin/clavulanate potassium and second-generation cephalosporins. The average duration of treatment was (17.3 +/- 3.2)days, the prognosis was good. CONCLUSION: PBB is common in male infants. Persistent wet cough with wheezing was the main characteristic of PBB. PBB is commonly accompanied by immune dysfunction and airway malacia, and the pathogens were Streptococcus pneumoniae and Haemophilus influenzae. PMID- 26758118 TI - [One case of early-onset epileptic encephalopathy caused by KCNQ2 gene nonsense mutation]. PMID- 26758119 TI - [Kaposiform hemangioendothelioma in a neonate associated with Kasabach-Merritt phenomenon: case report]. PMID- 26758121 TI - [Apnea and hyperbilirubinemia infants]. PMID- 26758120 TI - [Progress of MECP2 duplication syndrome]. PMID- 26758122 TI - This is what excellent care homes look like. AB - Read the national press and you could be forgiven for thinking that care homes are depressing places where older people go to die in grim surroundings. While criticism of some care homes is justified, in reality there are many others where staff deliver excellent care without receiving recognition. Nursing Standard seeks to redress this balance by showcasing a home that has been adjudged excellent by the Care Quality Commission (CQC). PMID- 26758125 TI - College highlights the crucial role of matrons. AB - The number of NHS matrons working in England has fallen from 6,338 in 2010 to 5,133 in just five years. PMID- 26758123 TI - Thousands show their solidarity in the battle to save bursaries. AB - Crowds of protesters who marched on Downing Street have vowed to escalate their campaign against the threat to bursaries by walking out for an hour during one of the forthcoming junior doctors' strikes. PMID- 26758126 TI - Call for exposure of research on safe staffing. AB - A safe staffing campaigner has criticised the time it is taking to decide whether information on nurse numbers in England should be made public. PMID- 26758127 TI - Overseas recruitment under review as demand continues to increase. AB - The reliance the NHS has on foreign workers has been highlighted by a survey of English trusts that shows six out of ten nurses to be recruited next year will come from outside the European Economic Area (EEA). PMID- 26758129 TI - Community welcomes chief nurse. AB - England's chief nursing officer Jane Cummings met community nurses last week to hear how they help people with learning disabilities and mental health issues to live independently. PMID- 26758128 TI - More than 10,000 empty nursing posts among NHS trusts in London. AB - Almost one in five nursing posts in London is vacant, according to research that reveals a 'critical' shortage of staff in the capital. PMID- 26758130 TI - Poor pay forcing Northern Ireland nurses to moonlight across the UK. AB - RCN leaders in Northern Ireland will decide this week whether to ballot members on industrial action over pay. PMID- 26758134 TI - Tool will identify fatigue in carers. AB - A screening tool has been developed that will allow nurses to identify when unpaid carers are exhausted, feeling overwhelmed and in need of respite care or other support. PMID- 26758135 TI - Is the nursing associate role an innovation or a step backwards? AB - A new support role is designed to open up the profession, but some say it will undermine nurses and assistant practitioners. Petra Kendall-Raynor reports. PMID- 26758142 TI - Discharge planning. PMID- 26758143 TI - Changing the realities of poverty in pregnancy. AB - Pregnant women from disadvantaged, vulnerable or excluded groups are more likely to have poorer maternal and neonatal outcomes. In Bradford, a three-year pilot project is targeting pregnant women in some of the poorest areas to improve the health of mothers and babies. PMID- 26758144 TI - So you want to meet Elvis? AB - Eden House care home in County Durham, part of Helen McArdle Care, was rated 'outstanding' by the Care Quality Commission after one of its new unannounced inspections. Residents have a nail bar and hair salon and are served restaurant style meals at the home. Set amid landscaped gardens, it prides itself on meeting the expectations of its 53 residents. PMID- 26758145 TI - Towards a better understanding. AB - A new website from Alzheimer's Research UK aims to help young children, juniors and teenagers to understand dementia and the changes it can cause to a loved one's behaviour. The site also assists nurses to answer children's questions about the condition. PMID- 26758158 TI - Better management, not more money, should be the new mantra. PMID- 26758159 TI - Funding cuts will be felt in perinatal mental health care. PMID- 26758160 TI - Without a scientific process, the NHS will never get the workforce it needs. PMID- 26758161 TI - Senior nurses be aware: cynicism saps colleagues' enthusiasm. PMID- 26758162 TI - Turn our backs on the doctors and we should expect to be next. PMID- 26758163 TI - Employing more nurses is the only way to ensure patient safety. PMID- 26758166 TI - How to perform first aid. AB - RATIONALE AND KEY POINTS: This article aims to help nurses to perform first aid in a safe, effective and patient-centred manner. First aid comprises a series of simple, potentially life-saving steps that an individual can perform with minimal equipment. Although it is not a legal requirement to respond to an emergency situation outside of work, nurses have a professional duty to respond and provide care within the limits of their competency. First aid is the provision of immediate medical assistance to an ill or injured person until definitive medical treatment can be accessed. First aid can save lives and it is essential that nurses understand the basic principles. REFLECTIVE ACTIVITY: Clinical skills articles can help update your practice and ensure it remains evidence based. Apply this article to your practice. Reflect on and write a short account of: 1. Your skill in performing first aid and any areas where you may need to extend your knowledge. 2. How reading this article will change your practice. Subscribers can upload their reflective accounts at: rcni.com/portfolio . PMID- 26758167 TI - Applying for ethical approval for research: the main issues. AB - The need to obtain research ethical approval is common to all research involving human participants. This approval must be obtained before research participants can be approached and before data collection can begin. The process of ethical review is one way that research participants can be confident that possible risks have been considered, minimised and deemed acceptable. This article outlines some of the main issues researchers should consider when planning an application for research ethical approval by answering the following six questions: 'Do I need research ethical approval?', 'How many applications will I need to make?', 'Where should I apply for research ethical approval?', 'What do I need to include in my application?', 'What do research ethics committees look for?' and 'What other approvals might I need?' Answering these questions will enable researchers to navigate the ethical review process. PMID- 26758168 TI - Evaluation of a PICC care training programme. AB - An integrated care organisation requires a flexible workforce with a variable skill mix in all care settings. Organisations should ensure that education and training are maintained to support safe, high quality care that provides value for money, promotes flexibility, and increases workforce participation in achieving organisation objectives and the expansion of services. Peripherally inserted central catheter (PICC) care was identified as a challenging area for the nursing workforce in acute care and community services, following the integration and service enlargement of the Whittington Health NHS Trust. This article describes the evaluation of a new PICC care training programme that was developed and implemented to increase knowledge and awareness. The evaluation provides the clinical education team with information to help identify additional training needs to facilitate the integration of care. PMID- 26758169 TI - Management and treatment options for patients with open abdomen. AB - Abdominal sepsis and trauma are the main indications for open abdomen. However, there is no robust evidence that open abdomen is better than closed in these cases. When using open abdomen, treatment goals are to control the source of infection, protect the bowel from damage, minimise adhesions between the bowel and abdominal wall, facilitate nursing care and allow permanent closure of the wound by bringing the fascial edges closer. Several temporary abdominal closure techniques exist, but are associated with high mortality and morbidity rates. There is no evidence that any specific temporary abdominal closure technique is better than others; however, negative pressure wound therapy appears to be a popular method of management of open abdomen. PMID- 26758170 TI - Patient-centred care. AB - A CPD article enhanced Robin Hooks' understanding of the importance of communication and how care is delivered. PMID- 26758171 TI - Sun, fun and nursing. AB - Whether you aim to start a new life and career or want to enjoy a short working holiday, Australia is an attractive option for many nurses. Erin Dean reports. PMID- 26758172 TI - A Cinderella service no more? AB - Care homes offer unique clinical and management opportunities for ambitious nurses and will provide the leaders of the future, says Care UK's Pauline Houchin. PMID- 26758174 TI - Student life--your fellows need you. AB - Medic to Medic is a UK-based charity that sponsors disadvantaged students training to be healthcare professionals in Malawi and Uganda. PMID- 26758175 TI - Effect of magnetic field strength on the alignment of alpha''-Fe16N2 nanoparticle films. AB - Aligning the magnetic orientation is one strategy to improve the magnetic performance of magnetic materials. In this study, well-dispersed single-domain core-shell alpha''-Fe16N2/Al2O3 nanoparticles (NPs) were aligned by vertically applying magnetic fields with various strengths to a Si wafer substrate followed by fixation with resin. X-ray diffraction indicated that the alignment of the easy c-axis of the alpha''-Fe16N2 crystal and the magnetic orientation of the NPs depended upon the applied magnetic field. Magnetic analysis demonstrated that increasing the magnetic field strength resulted in hysteresis loops approaching a rectangular form, implying a higher magnetic coercivity, remanence, and maximum energy product. The same tendency was also observed when a horizontal magnetic field was applied. The fixation of the easy c-axis alignment of each nanoparticle caused by Brownian rotation under the magnetic field, instead of Neel rotation, was the reason for the enhancement in the magnetic performance. These results on the alignment of the magnetic orientation of alpha''-Fe16N2 NPs suggest the practical application of high-performance permanent bulk magnets from well dispersed single-domain alpha''-Fe16N2/Al2O3 NPs. PMID- 26758176 TI - The role of TF- and Tn-antigens in breast cancer metastasis. AB - Almost 40 years ago, researchers found out that the Thomsen-Friedenreich (TF) and the Thomsen nouvelle (Tn) antigens could be detected in carcinoma, but not in healthy tissue. A short time after that it became clear that TF and Tn are precursor molecules of the MN-blood group antigens. In normal tissue TF and Tn are coated by glycosyl structures, thereby forming the glycoproteins which are known to account for the MN-blood group, but in malignant tissue these molecules are uncovered.TF, which has an additional Galectin-residue compared to Tn, is correlated with a more favourable prognosis for patients. On the contrary, patients with Tn-bearing tissues have a worse prognosis for overall and progression-free survival. It is known that TF and Tn are involved in the adhesion of tumour cells to the endothelium via a mechanism recruiting Galectin-3 and MUC-1, which is the first step in metastasis formation. Furthermore, it became clear that this pathway can be blocked by a growing number of molecules, thereby creating ways of therapeutical intervention. PMID- 26758177 TI - The Influence of Organizational Systems on Information Exchange in Long-Term Care Facilities: An Institutional Ethnography. AB - Person-centered care is heavily dependent on effective information exchange among health care team members. We explored the organizational systems that influence resident care attendants' (RCAs) access to care information in long-term care (LTC) settings. We conducted an institutional ethnography in three LTC facilities. Investigative methods included naturalistic observations, in-depth interviews, and textual analysis. Practical access to texts containing individualized care-related information (e.g., care plans) was dependent on job classification. Regulated health care professionals accessed these texts daily. RCAs lacked practical access to these texts and primarily received and shared information orally. Microsystems of care, based on information exchange formats, emerged. Organizational systems mandated written exchange of information and did not formally support an oral exchange. Thus, oral information exchanges were largely dependent on the quality of workplace relationships. Formal systems are needed to support structured oral information exchange within and between the microsystems of care found in LTC. PMID- 26758178 TI - Postprimary Tuberculosis and Macrophage Necrosis: Is There a Big ConNECtion? AB - Adult or postprimary tuberculosis (TB) accounts for most TB cases. Its hallmark is pulmonary cavitation, which occurs as a result of necrosis in the lung in individuals with tuberculous pneumonia. Postprimary TB has previously been known to be associated with vascular thrombosis and delayed-type hypersensitivity, but their roles in pulmonary cavitation are unclear. A necrosis-associated extracellular cluster (NEC) refers to a cluster of drug-tolerant Mycobacterium tuberculosis attached to lysed host materials and is proposed to contribute to granulomatous TB. Here we suggest that NECs, perhaps due to big size, produce a distinct host response leading to postprimary TB. We propose that vascular thrombosis and pneumonia arise from NEC and that these processes are promoted by inflammatory cytokines produced from cell-mediated delayed-type hypersensitivity, such as interleukin-17 and gamma interferon, eventually triggering necrosis in the lung and causing cavitation. According to this view, targeting NEC represents a necessary strategy to control adult TB. PMID- 26758179 TI - The Human Disease-Associated Abeta Amyloid Core Sequence Forms Functional Amyloids in a Fungal Adhesin. AB - There is increasing evidence that many amyloids in living cells have physiological functions. On the surfaces of fungal cells, amyloid core sequences in adhesins can aggregate into 100- to 1,000-nm-wide patches to form high-avidity adhesion nanodomains on the cell surface. The nanodomains form through interactions that have amyloid-like properties: binding of amyloid dyes, perturbation by antiamyloid agents, and interaction with homologous sequences. To test whether these functional interactions are mediated by typical amyloid interactions, we substituted an amyloid core sequence, LVFFA, from human Abeta protein for the native sequence IVIVA in the 1,419-residue Candida albicans adhesin Als5p. The chimeric protein formed cell surface nanodomains and mediated cellular aggregation. The native sequence and chimeric adhesins responded similarly to the amyloid dye thioflavin T and to amyloid perturbants. However, unlike the native protein, the nanodomains formed by the chimeric protein were not force activated and formed less-robust aggregates under flow. These results showed the similarity of amyloid interactions in the amyloid core sequences of native Als5p and Abeta, but they also highlighted emergent properties of the native sequence. Also, a peptide composed of the Abeta amyloid sequence flanked by amino acids from the adhesin formed two-dimensional sheets with sizes similar to the cell surface patches of the adhesins. These results inform an initial model for the structure of fungal cell surface amyloid nanodomains. IMPORTANCE: Protein amyloid aggregates are markers of neurodegenerative diseases such as Alzheimer's and Parkinsonism. Nevertheless, there are also functional amyloids, including biofilm-associated amyloids in bacteria and fungi. In fungi, glycoprotein adhesins aggregate into cell surface patches through amyloid-like interactions, and the adhesin clustering strengthens cell-cell binding. These fungal surface amyloid nanodomains mediate biofilm persistence under flow, and they also moderate host inflammatory responses in fungal infections. To determine whether the amyloid-like properties of fungal surface nanodomains are sequence specific, we ask whether a disease-associated amyloid core sequence has properties equivalent to those of the native sequence in a fungal adhesin. A chimeric adhesin with an amyloid sequence from the Alzheimer's disease protein Abeta instead of its native sequence effectively clustered the adhesins on the cell surface, but it showed a different response to hydrodynamic shear. These results begin an analysis of the sequence dependence for newly discovered activities for fungal surface amyloid nanodomains. PMID- 26758181 TI - Nascent Genomic Evolution and Allopatric Speciation of Myroides profundi D25 in Its Transition from Land to Ocean. AB - A large amount of bacterial biomass is transferred from land to ocean annually. Most transferred bacteria should not survive, but undoubtedly some do. It is unclear what mechanisms these bacteria use in order to survive and even thrive in a new marine environment. Myroides profundi D25(T), a member of the Bacteroidetes phylum, was isolated from deep-sea sediment of the southern Okinawa Trough near the China mainland and had high genomic sequence identity to and synteny with the human opportunistic pathogen Myroides odoratimimus. Phylogenetic and physiological analyses suggested that M. profundi recently transitioned from land to the ocean. This provided an opportunity to explore how a bacterial genome evolved to survive in a novel environment. Changes in the transcriptome were evaluated when both species were cultured under low-salinity conditions and then transferred to high-salinity conditions. Comparative genomic and transcriptomic analyses showed that M. profundi altered transcription regulation in the early stages of survival. In these stages, vertically inherited genes played a key role in the survival of M. profundi. The contribution of M. profundi unique genes, some possibly acquired by horizontal gene transfer (HGT), appeared relatively small, and expression levels of unique genes were diminished under the high salinity conditions. We postulate that HGT genes might play an important role in longer-term adaptation. These results suggested that some human pathogens might have the ability to survive in and adapt to the marine environment, which may have important implications for public health control in coastal regions. IMPORTANCE: Horizontal gene transfer (HGT) is considered to be important for bacteria to adapt to a different microhabitat. However, our results showed that vertically inherited genes might play more important roles than HGT genes in the nascent adaptation to the marine environment in the bacterium Myroides profundi, which has recently been transferred from land to ocean. M. profundi unique genes had low expression levels and were less regulated under high-salinity conditions, indicating that the contribution of HGT genes to survival of this bacterium under marine high-salinity conditions was limited. In the early adaptation stages, M. profundi apparently survived and adapted mainly by regulating the expression of inherited core genes. These results may explain in part why human pathogens can easily be detected in marine environments. PMID- 26758180 TI - Analysis of the Protein Kinase A-Regulated Proteome of Cryptococcus neoformans Identifies a Role for the Ubiquitin-Proteasome Pathway in Capsule Formation. AB - The opportunistic fungal pathogen Cryptococcus neoformans causes life-threatening meningitis in immunocompromised individuals. The expression of virulence factors, including capsule and melanin, is in part regulated by the cyclic-AMP/protein kinase A (cAMP/PKA) signal transduction pathway. In this study, we investigated the influence of PKA on the composition of the intracellular proteome to obtain a comprehensive understanding of the regulation that underpins virulence. Through quantitative proteomics, enrichment and bioinformatic analyses, and an interactome study, we uncovered a pattern of PKA regulation for proteins associated with translation, the proteasome, metabolism, amino acid biosynthesis, and virulence-related functions. PKA regulation of the ubiquitin-proteasome pathway in C. neoformans showed a striking parallel with connections between PKA and protein degradation in chronic neurodegenerative disorders and other human diseases. Further investigation of proteasome function with the inhibitor bortezomib revealed an impact on capsule production as well as hypersusceptibility for strains with altered expression or activity of PKA. Parallel studies with tunicamycin also linked endoplasmic reticulum stress with capsule production and PKA. Taken together, the data suggest a model whereby expression of PKA regulatory and catalytic subunits and the activation of PKA influence proteostasis and the function of the endoplasmic reticulum to control the elaboration of the polysaccharide capsule. Overall, this study revealed both broad and conserved influences of the cAMP/PKA pathway on the proteome and identified proteostasis as a potential therapeutic target for the treatment of cryptococcosis. IMPORTANCE: Fungi cause life-threatening diseases, but very few drugs are available to effectively treat fungal infections. The pathogenic fungus Cryptococcus neoformans causes a substantial global burden of life-threatening meningitis in patients suffering from HIV/AIDS. An understanding of the mechanisms by which fungi deploy virulence factors to cause disease is critical for developing new therapeutic approaches. We employed a quantitative proteomic approach to define the changes in the protein complement that occur upon modulating the cAMP signaling pathway that regulates virulence in C. neoformans. This approach identified a conserved role for cAMP signaling in the regulation of the ubiquitin-proteasome pathway and revealed a link between this pathway and elaboration of a major virulence determinant, the polysaccharide capsule. Targeting the ubiquitin-proteasome pathway opens new therapeutic options for the treatment of cryptococcosis. PMID- 26758182 TI - Molecular and Structural Analysis of the Helicobacter pylori cag Type IV Secretion System Core Complex. AB - Bacterial type IV secretion systems (T4SSs) can function to export or import DNA, and can deliver effector proteins into a wide range of target cells. Relatively little is known about the structural organization of T4SSs that secrete effector proteins. In this report, we describe the isolation and analysis of a membrane spanning core complex from the Helicobacter pylori cag T4SS, which has an important role in the pathogenesis of gastric cancer. We show that this complex contains five H. pylori proteins, CagM, CagT, Cag3, CagX, and CagY, each of which is required for cag T4SS activity. CagX and CagY are orthologous to the VirB9 and VirB10 components of T4SSs in other bacterial species, and the other three Cag proteins are unique to H. pylori. Negative stain single-particle electron microscopy revealed complexes 41 nm in diameter, characterized by a 19-nm diameter central ring linked to an outer ring by spoke-like linkers. Incomplete complexes formed by Deltacag3 or DeltacagT mutants retain the 19-nm-diameter ring but lack an organized outer ring. Immunogold labeling studies confirm that Cag3 is a peripheral component of the complex. The cag T4SS core complex has an overall diameter and structural organization that differ considerably from the corresponding features of conjugative T4SSs. These results highlight specialized features of the H. pylori cag T4SS that are optimized for function in the human gastric mucosal environment. IMPORTANCE: Type IV secretion systems (T4SSs) are versatile macromolecular machines that are present in many bacterial species. In this study, we investigated a T4SS found in the bacterium Helicobacter pylori. H. pylori is an important cause of stomach cancer, and the H. pylori T4SS contributes to cancer pathogenesis by mediating entry of CagA (an effector protein regarded as a "bacterial oncoprotein") into gastric epithelial cells. We isolated and analyzed the membrane-spanning core complex of the H. pylori T4SS and showed that it contains unique proteins unrelated to components of T4SSs in other bacterial species. These results constitute the first structural analysis of the core complex from this important secretion system. PMID- 26758184 TI - Targeting Autophagy in Dendritic Cells as a Mechanism to Limit Immunopathogenesis in Herpetic Stromal Keratitis. AB - In a recent mBio article, Y. Jiang, X. Yin, P. M. Stuart, and D. A. Lieb [mBio 6(6):e01426-15, 2015, doi:10.1128/mBio.01426-15] presented an elegant set of experiments that utilized a transgenic, knockout strain of mice whose dendritic cells (DCs) are incapable of undergoing autophagy, to dissect out the aspects of the chronic inflammatory response following viral infection of corneal epithelial cells. The authors' results provide a potential proof of concept that the DC autophagy pathway may be a valid target for therapeutic drug design in certain inflammatory pathologies. PMID- 26758183 TI - Herpesviral ICP0 Protein Promotes Two Waves of Heterochromatin Removal on an Early Viral Promoter during Lytic Infection. AB - Herpesviruses must contend with host cell epigenetic silencing responses acting on their genomes upon entry into the host cell nucleus. In this study, we confirmed that unchromatinized herpes simplex virus 1 (HSV-1) genomes enter primary human foreskin fibroblasts and are rapidly subjected to assembly of nucleosomes and association with repressive heterochromatin modifications such as histone 3 (H3) lysine 9-trimethylation (H3K9me3) and lysine 27-trimethylation (H3K27me3) during the first 1 to 2 h postinfection. Kinetic analysis of the modulation of nucleosomes and heterochromatin modifications over the course of lytic infection demonstrates a progressive removal that coincided with initiation of viral gene expression. We obtained evidence for three phases of heterochromatin removal from an early gene promoter: an initial removal of histones and heterochromatin not dependent on ICP0, a second ICP0-dependent round of removal of H3K9me3 that is independent of viral DNA synthesis, and a third phase of H3K27me3 removal that is dependent on ICP0 and viral DNA synthesis. The presence of ICP0 in transfected cells is also sufficient to promote removal of histones and H3K9me3 modifications of cotransfected genes. Overall, these results show that ICP0 promotes histone removal, a reduction of H3K9me3 modifications, and a later indirect reduction of H3K27me3 modifications following viral early gene expression and DNA synthesis. Therefore, HSV ICP0 promotes the reversal of host epigenetic silencing mechanisms by several mechanisms. IMPORTANCE: The human pathogen herpes simplex virus (HSV) has evolved multiple strategies to counteract host-mediated epigenetic silencing during productive infection. However, the mechanisms by which viral and cellular effectors contribute to these processes are not well defined. The results from this study demonstrate that HSV counteracts host epigenetic repression in a dynamic stepwise process to remove histone 3 (H3) and subsequently target specific heterochromatin modifications in two distinct waves. This provides the first evidence of a stepwise reversal of host epigenetic silencing by viral proteins. This work also suggests that targets capable of disrupting the kinetics of epigenetic regulation could serve as potential antiviral therapeutic agents. PMID- 26758186 TI - Diversity and homogeneity of oral microbiota in healthy Korean pre-school children using pyrosequencing. AB - Objectives The purpose of this study was designed to identify the oral microbiota in healthy Korean pre-school children using pyrosequencing. Materials and methods Dental plaque samples were obtained form 10 caries-free pre-school children. The samples were analysed using pyrosequencing. Results The pyrosequencing analysis revealed that, at the phylum level, Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria and Fusobacteria showed high abundance. Also, predominant genera were identified as core microbiome, such as Streptococcus, Neisseria, Capnocytophaga, Haemophilus and Veilonella. Conclusions The diversity and homogeneity was shown in the dental plaque microbiota in healthy Korean pre school children. PMID- 26758185 TI - Small Intestine Bacterial Overgrowth and Environmental Enteropathy in Bangladeshi Children. AB - Recent studies suggest small intestine bacterial overgrowth (SIBO) is common among developing world children. SIBO's pathogenesis and effect in the developing world are unclear. Our objective was to determine the prevalence of SIBO in Bangladeshi children and its association with malnutrition. Secondary objectives included determination of SIBO's association with sanitation, diarrheal disease, and environmental enteropathy. We performed a cross-sectional analysis of 90 Bangladeshi 2-year-olds monitored since birth from an impoverished neighborhood. SIBO was diagnosed via glucose hydrogen breath testing, with a cutoff of a 12-ppm increase over baseline used for SIBO positivity. Multivariable logistic regression was performed to investigate SIBO predictors. Differences in concomitant inflammation and permeability between SIBO-positive and -negative children were compared with multiple comparison adjustment. A total of 16.7% (15/90) of the children had SIBO. The strongest predictors of SIBO were decreased length-for-age Z score since birth (odds ratio [OR], 0.13; 95% confidence interval [CI], 0.03 to 0.60) and an open sewer outside the home (OR, 4.78; 95% CI, 1.06 to 21.62). Recent or frequent diarrheal disease did not predict SIBO. The markers of intestinal inflammation fecal Reg 1beta (116.8 versus 65.6 ug/ml; P = 0.02) and fecal calprotectin (1,834.6 versus 766.7 ug/g; P = 0.004) were elevated in SIBO-positive children. Measures of intestinal permeability and systemic inflammation did not differ between the groups. These findings suggest linear growth faltering and poor sanitation are associated with SIBO independently of recent or frequent diarrheal disease. SIBO is associated with intestinal inflammation but not increased permeability or systemic inflammation. IMPORTANCE: A total of 165 million children worldwide are considered stunted, which is associated with increased risk of death prior to age 5 years and cognitive disability. Stunting has, in part, been attributed to the presence of environmental enteropathy. Environmental enteropathy is a poorly understood condition leading to chronic intestinal inflammation. It has been postulated that small intestine bacterial overgrowth contributes to the pathogenesis of environmental enteropathy as overgrowth has been associated with intestinal inflammation and micronutrient malabsorption when it develops in other clinical contexts. This study confirms the finding that overgrowth occurs at high rates in the developing world. This is the first study to show that overgrowth is associated with intestinal inflammation and linear growth delay in this setting and is the first to examine why children with no known gastrointestinal dysfunction develop overgrowth from the developing world environment. PMID- 26758187 TI - Do hatchery-reared sea urchins pose a threat to genetic diversity in wild populations? AB - In salmonids, the release of hatchery-reared fish has been shown to cause irreversible genetic impacts on wild populations. However, although responsible practices for producing and releasing genetically diverse, hatchery-reared juveniles have been published widely, they are rarely implemented. Here, we investigated genetic differences between wild and early-generation hatchery reared populations of the purple sea urchin Paracentrotus lividus (a commercially important species in Europe) to assess whether hatcheries were able to maintain natural levels of genetic diversity. To test the hypothesis that hatchery rearing would cause bottleneck effects (that is, a substantial reduction in genetic diversity and differentiation from wild populations), we compared the levels and patterns of genetic variation between two hatcheries and four nearby wild populations, using samples from both Spain and Ireland. We found that hatchery reared populations were less diverse and had diverged significantly from the wild populations, with a very small effective population size and a high degree of relatedness between individuals. These results raise a number of concerns about the genetic impacts of their release into wild populations, particularly when such a degree of differentiation can occur in a single generation of hatchery rearing. Consequently, we suggest that caution should be taken when using hatchery-reared individuals to augment fisheries, even for marine species with high dispersal capacity, and we provide some recommendations to improve hatchery rearing and release practices. Our results further highlight the need to consider the genetic risks of releasing hatchery-reared juveniles into the wild during the establishment of restocking, stock enhancement and sea ranching programs. PMID- 26758188 TI - The fate of W chromosomes in hybrids between wild silkmoths, Samia cynthia ssp.: no role in sex determination and reproduction. AB - Moths and butterflies (Lepidoptera) have sex chromosome systems with female heterogamety (WZ/ZZ or derived variants). The maternally inherited W chromosome is known to determine female sex in the silkworm, Bombyx mori. However, little is known about the role of W chromosome in other lepidopteran species. Here we describe two forms of the W chromosome, W and neo-W, that are transmitted to both sexes in offspring of hybrids from reciprocal crosses between subspecies of wild silkmoths, Samia cynthia. We performed crosses between S. c. pryeri (2n=28, WZ/ZZ) and S. c. walkeri (2n=26, neo-Wneo-Z/neo-Zneo-Z) and examined fitness and sex chromosome constitution in their hybrids. The F1 hybrids of both reciprocal crosses had reduced fertility. Fluorescence in situ hybridization revealed not only the expected sex chromosome constitutions in the backcross and F2 hybrids of both sexes but also females without the W (or neo-W) chromosome and males carrying the W (or neo-W) chromosome. Furthermore, crosses between the F2 hybrids revealed no association between the presence or absence of W (or neo-W) chromosome and variations in the hatchability of their eggs. Our results clearly suggest that the W (or neo-W) chromosome of S. cynthia ssp. plays no role in sex determination and reproduction, and thus does not contribute to the formation of reproductive barriers between different subspecies. PMID- 26758189 TI - QTL mapping of temperature sensitivity reveals candidate genes for thermal adaptation and growth morphology in the plant pathogenic fungus Zymoseptoria tritici. AB - Different thermal environments impose strong, differential selection on populations, leading to local adaptation, but the genetic basis of thermal adaptation is poorly understood. We used quantitative trait locus (QTL) mapping in the fungal wheat pathogen Zymoseptoria tritici to study the genetic architecture of thermal adaptation and identify candidate genes. Four wild-type strains originating from the same thermal environment were crossed to generate two mapping populations with 263 (cross 1) and 261 (cross 2) progeny. Restriction site-associated DNA sequencing was used to genotype 9745 (cross 1) and 7333 (cross 2) single-nucleotide polymorphism markers segregating within the mapping population. Temperature sensitivity was assessed using digital image analysis of colonies growing at two different temperatures. We identified four QTLs for temperature sensitivity, with unique QTLs found in each cross. One QTL had a logarithm of odds score >11 and contained only six candidate genes, including PBS2, encoding a mitogen-activated protein kinase kinase associated with low temperature tolerance in Saccharomyces cerevisiae. This and other QTLs showed evidence for pleiotropy among growth rate, melanization and growth morphology, suggesting that many traits can be correlated with thermal adaptation in fungi. Higher temperatures were highly correlated with a shift to filamentous growth among the progeny in both crosses. We show that thermal adaptation has a complex genetic architecture, with natural populations of Z. tritici harboring significant genetic variation for this trait. We conclude that Z. tritici populations have the potential to adapt rapidly to climate change and expand into new climatic zones. PMID- 26758190 TI - MiR-125a regulates chemo-sensitivity to gemcitabine in human pancreatic cancer cells through targeting A20. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly human malignant diseases and the sixth leading cause of cancer-related deaths in China. Gemcitabine is the only first-line chemotherapeutic agent used for the palliative treatment of patients with PDAC, but chemo-resistance limits their efficacy. Here, we showed that miR-125a was up-regulated in chemo-resistant SW1990GZ cells when compared with SW1990 cells. Over-expression of miR-125a increased the chemo resistance to gemcitabine in SW1990 cells, while down-regulation of miR-125a in SW1990GZ cells increased chemo-sensitivity to gemcitabine. By using bioinformatics analysis tool (Targetscan), the 3' untranslated region (3'UTR) of A20 gene was found to be a target of miR-125a. Luciferase reporter assay further confirmed that A20 3'UTR is a direct target of miR-125a. Over-expression of A20 in SW1990 cells increased chemo-sensitivity to gemcitabine, while knockdown of A20 in SW1990 cells promoted the chemo-resistance to gemcitabine. Finally, the expression level of miR-125a in pancreatic cancer tissues from chemo-sensitive patients was significantly lower than that from chemo-resistant patients, and was inversely correlated with the A20 mRNA levels. In conclusion, our results suggest that miR-125a promotes chemo-resistance to gemcitabine in pancreatic cells through targeting A20, which may provide novel therapeutic targets or molecular biomarkers for cancer therapy and improve tumor diagnosis or predictions of therapeutic responses. PMID- 26758191 TI - Transforming growth factor-beta increases breast cancer stem cell population partially through upregulating PMEPA1 expression. AB - The prostate transmembrane protein, androgen-induced 1 (PMEPA1) has been previously shown to promote solid malignancies in a variety of cancers, but the role and mechanisms of PMEPA1 in breast cancer has not been fully addressed. Here, we found that PMEPA1 was upregulated in breast cancer cell lines as well as in a set of clinical invasive breast ductal carcinomas. Interestingly, depletion of PMEPA1 decreased breast cancer stem cell (CSC)-enriched populations, while ectopic overexpression of PMEPA1 increased breast CSC-enriched populations. Furthermore, transforming growth factor-beta (TGF-beta) treatment was also found to upregulate PMEPA1 expression and the CSC-enriched populations in triple negative breast cancer cell lines. TGF-beta-induced PMEPA1 expression partially contributed to TGF-beta-induced breast CSC maintenance. These findings suggest that TGF-beta-PMEPA1 axis might provide new diagnosis and therapeutic targets for breast cancer treatment. PMID- 26758192 TI - Triticumoside induces apoptosis via caspase-dependent mitochondrial pathway and inhibits migration through downregulation of MMP2/9 in human lung cancer cells. AB - Non-small cell lung cancer (NSCLC) is the major cancer-related death worldwide with only 14% five-year survival rate. Triticumoside, a phenolic compound present in Triticum aestivum sprout extract, has been recognized to have antiobesity and anti-inflammatory effects. However, the effect of triticumoside on cancer cell proliferation and migration has not been studied. In order to elucidate whether triticumoside exhibits an anticancer effect, cells were incubated with different doses of triticumoside, and apoptosis was assessed by observing cell viability, cellular morphological changes, and annexin-V-fluorescein isothiocyanate/propidium iodide staining. Cell cycle analysis, western blotting, wound healing assay, and quantitative-polymerase chain reaction were also performed. Triticumoside exhibited marked cytotoxicity in the cells in dose- and time-dependent manner. Triticumoside caused morphological changes, including cellular rounding, nuclear condensation, and shrinkage. Likewise, triticumoside enhanced the sub-G1 proportion of cells. Additionally, triticumoside regulated expression of apoptosis-associated proteins, such as B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X, and procaspase-3/9. Triticumoside also inhibited migration of the cells through downregulation of matrix metalloproteinase-2/9 (MMP2/9). Collectively, these results suggest that triticumoside induces apoptosis through caspase-dependent mitochondrial pathway and suppresses migration via inhibition of MMP2/9 in NSCLC A549 cells. PMID- 26758193 TI - Quantifying the 3 Biases That Lead to Unintentional Overestimation of the Blood Pressure-Lowering Effect of Renal Denervation. AB - BACKGROUND: Studies of renal denervation report disparate results. Meta-analysis by trial design may allow quantitative estimation of sources and magnitude of biases in denervation studies. METHODS AND RESULTS: One hundred forty nonrandomized, 6 randomized open-label, and 2 randomized blinded studies were analyzed for 2 outcomes: (1) blood pressure changes for nonrandomized, open-label randomized, and blinded studies; and (2) quantification of 3 biases potentially contributing to apparent antihypertensive effects: (a) regression to the mean, (b) asymmetrical data handling, and (c) true blood pressure drops caused by something other than the tested therapy (confounding). Nonrandomized studies and open-label randomized trials reported large reductions in office blood pressure of 23.6 mm Hg (95% confidence interval [CI], 22.0 to 25.3) and 29.1 mm Hg (95% CI, 25.2 to 33.1 mm Hg), respectively. They reported smaller reductions in ambulatory blood pressures (11.2 mm Hg; 95% CI, 10.0 to 12.4). The blinded trials found no significant reduction in blood pressure (2.9 mm Hg; 95% CI, -0.4 to 6.3). Analyses of these data indicate the magnitude of the 3 potential sources of bias to be regression to the mean, -1.01 mm Hg (95% CI, 4.24 to -6.27); asymmetrical data handling, -10.8 mm Hg (95% CI, -8.77 to -12.87); and confounding, -8.3 mm Hg (95% CI, -4.73 to -11.83). CONCLUSIONS: Increasingly bias resistant trial designs report effect sizes of decreasing magnitude. This disparity may be caused by asymmetrical data handling and confounding (eg, increased drug adherence). If these differences are caused by trial design and not by some other differences in patients or procedures, which happen to match the trial design, then randomization alone is not enough: blinding is also needed. This has broad implications across trials of medications and devices. PMID- 26758194 TI - Physical and Mental Health Consequences of War-related Stressors Among Older Adults: An Analysis of Posttraumatic Stress Disorder and Arthritis in Northern Vietnamese War Survivors. AB - Objectives: We examine the impacts of trauma exposures and family stressors associated with the Vietnam War on musculoskeletal health and posttraumatic stress disorder (PTSD) outcomes in elderly Vietnamese who were widely impacted by the war as young adults. Noting that wars' impacts extend beyond male veterans in most survivor populations, we give attention to male and female war survivors placed in a variety of roles vis-a-vis the war. Method: Utilizing data from the 2010 Vietnam Health and Aging Pilot Study (N = 405), we use logistic and Poisson regression models to estimate the effect of wartime trauma exposures and family stressors on disabling arthritis and PTSD symptoms in male and female northern Vietnamese adults aged 55 and older. Results: The odds of experiencing recent PTSD symptoms are greater in respondents who report involvement in killing/causing severe injury and who observed war atrocities. In women, PTSD is positively correlated with war era child death and spousal separation. Arthritis also exhibits a significant, positive association with killing/causing severe injury. Discussion: Our study provides insights into the burden of conflict upon health among populations of the global south that survived war and are now entering older adulthood. The pattern of results, indicating greatest suffering among those who inflicted or failed to prevent bodily harm or loss of life, is consistent with the concept of moral injury. PMID- 26758195 TI - Genomic profiling of lower-grade gliomas uncovers cohesive disease groups: implications for diagnosis and treatment. AB - Lower-grade gliomas (including low- and intermediate-grade gliomas, World Health Organization grades II and III) are diffusely infiltrative neoplasms that arise most often in the cerebral hemispheres of adults and have traditionally been classified based on their presumed histogenesis as astrocytomas, oligodendrogliomas, or oligoastrocytomas. Although the histopathologic classification of lower-grade glioma has been the accepted standard for nearly a century, it suffers from high intra- and inter-observer variability and does not adequately predict clinical outcomes. Based on integrated analysis of multiplatform genomic data from The Cancer Genome Atlas, lower-grade gliomas have been found to segregate into three cohesive, clinically relevant molecular classes. Molecular classes were closely aligned with the status of isocitrate dehydrogenase (IDH) mutations, tumor protein 53 mutations and the co-deletion of chromosome arms 1p and 19q, but were not closely aligned with histologic classes. These findings emphasize the potential for improved definition of clinically relevant disease subsets using integrated molecular approaches and highlight the importance of biomarkers for brain tumor classification. PMID- 26758196 TI - Metabolic engineering of Clostridium cellulolyticum for the production of n butanol from crystalline cellulose. AB - BACKGROUND: Sustainable alternatives for the production of fuels and chemicals are needed to reduce our dependency on fossil resources and to avoid the negative impact of their excessive use on the global climate. Lignocellulosic feedstock from agricultural residues, energy crops and municipal solid waste provides an abundant and carbon-neutral alternative, but it is recalcitrant towards microbial degradation and must therefore undergo extensive pretreatment to release the monomeric sugar units used by biofuel-producing microbes. These pretreatment steps can be reduced by using microbes such as Clostridium cellulolyticum that naturally digest lignocellulose, but this limits the range of biofuels that can be produced. We therefore developed a metabolic engineering approach in C. cellulolyticum to expand its natural product spectrum and to fine tune the engineered metabolic pathways. RESULTS: Here we report the metabolic engineering of C. cellulolyticum to produce n-butanol, a next-generation biofuel and important chemical feedstock, directly from crystalline cellulose. We introduced the CoA-dependent pathway for n-butanol synthesis from C. acetobutylicum and measured the expression of functional enzymes (using targeted proteomics) and the abundance of metabolic intermediates (by LC-MS/MS) to identify potential bottlenecks in the n-butanol biosynthesis pathway. We achieved yields of 40 and 120 mg/L n-butanol from cellobiose and crystalline cellulose, respectively, after cultivating the bacteria for 6 and 20 days. CONCLUSION: The analysis of enzyme activities and key intracellular metabolites provides a robust framework to determine the metabolic flux through heterologous pathways in C. cellulolyticum, allowing further improvements by fine tuning individual steps to improve the yields of n-butanol. PMID- 26758197 TI - Validation of Omron HBP-1300 professional blood pressure monitor based on auscultation in children and adults. AB - BACKGROUnD: To determine whether the professional Omron HBP-1300 blood pressure (BP) monitor meets American Association for the Advancement of Medical Instrumentation (AAMI) accuracy standards in Chinese children and adults. METHOD: According to the AAMI protocol, simultaneous auscultatory measurements by two observers using a mercury manometer were obtained in participants using the Omron HBP-1300. Triple measurements were obtained after a minimum 5-min rest with a 1 min interval between adjacent measurements. RESULTS: A total of 85 participants submitted to 255 doctor-measured BP and 255 successful professional monitor readings. The initial auscultation systolic BP was <100 mmHg in 25 participants (29.4%), 100-160 mmHg in 53 participants (62.4%), and >160 mmHg in seven participants (8.2%). All of the simultaneous measurements agreed to within +/- 10 mmHg, while 95% agreed to within +/- 4 mmHg for both systolic and diastolic BP, and the consistency between two observers was satisfactory. The difference between the devices was -1.3 +/- 3.6 mmHg for systolic BP and 0.7 +/- 3.8 mmHg for diastolic BP and by AAMI method 1, which met this guideline. The average difference between two devices by AAMI method 2 was 1.4 +/- 3.2 mmHg for systolic BP and 1.0 +/- 3.9 mmHg for diastolic BP, which met this guideline. CONCLUSION: The professional BP monitor Omron HBP-1300 is desirable for measuring the BP for Chinese children and adults. PMID- 26758198 TI - Lgr5 expression is a valuable prognostic factor for colorectal cancer: evidence from a meta-analysis. AB - BACKGROUND: Lgr5 has recently been identified as a reliable biomarker of cancer stem cells (CSCs) in colorectal cancer (CRC); however, its prognostic value is still controversial. METHODS: We searched PubMed, Web of Science, and Wanfang databases with identical strategies to retrieve articles. We evaluated the impact of Lgr5 expression on survival of CRC patients through meta-analysis. RESULTS: A total of 12 studies comprising 2600 patients revealed that Lgr5 overexpression was negatively associated with overall survival (OS) (HR = 1.73, 95% CI: 1.28 2.33; P = 0.00) and disease free survival (DFS) (HR = 2.89, 95% CI: 1.89-4.44; P = 0.000) in CRC patients. Subgroup analysis suggested that Lgr5 overexpression was significantly associated with worse OS in subgroups with IHC as the method of Lgr5 assessment (HR = 2.01, 95% CI: 1.39-2.89; P = 0.001), patients from Asia (HR = 1.81, 95% CI: 1.27-2.58; P = 0.000), and NOS scores greater than 6 (HR = 2.12, 95% CI: 1.41-3.19; P = 0.000). Furthermore, sensitivity analysis showed that the estimated HR ranged from 1.6 to 1.86 upon excluding one study sequentially from each analysis. In addition, Lgr5 overexpression was significantly associated with deep invasion of CRC (OR = 0.39, 95% CI: 0.17-0.87; P = 0.002), lymphnode metastasis (OR = 0.45, 95% CI: 0.26-0.76; P = 0.003), distant metastasis (OR = 0.37, 95% CI: 0.22-0.62; P = 0.000), and AJCC stage (OR = 0.35, 95% CI: 0.15 0.78; P = 0.01). However, Lgr5 overexpression was not correlated with tumor grade (OR = 0.75 95% CI: 0.37-1.54; P = 0.433). CONCLUSIONS: This study shows that Lgr5 can be a valuable and reliable prognostic factor of colorectal cancer progression. PMID- 26758201 TI - BDNF in sleep, insomnia, and sleep deprivation. AB - The protein brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors involved in plasticity of neurons in several brain regions. There are numerous evidence that BDNF expression is decreased by experiencing psychological stress and that, accordingly, a lack of neurotrophic support causes major depression. Furthermore, disruption in sleep homeostatic processes results in higher stress vulnerability and is often associated with stress-related mental disorders. Recently, we reported, for the first time, a relationship between BDNF and insomnia and sleep deprivation (SD). Using a biphasic stress model as explanation approach, we discuss here the hypothesis that chronic stress might induce a deregulation of the hypothalamic pituitary-adrenal system. In the long-term it leads to sleep disturbance and depression as well as decreased BDNF levels, whereas acute stress like SD can be used as therapeutic intervention in some insomniac or depressed patients as compensatory process to normalize BDNF levels. Indeed, partial SD (PSD) induced a fast increase in BDNF serum levels within hours after PSD which is similar to effects seen after ketamine infusion, another fast-acting antidepressant intervention, while traditional antidepressants are characterized by a major delay until treatment response as well as delayed BDNF level increase. Key messages Brain-derived neurotrophic factor (BDNF) plays a key role in the pathophysiology of stress-related mood disorders. The interplay of stress and sleep impacts on BDNF level. Partial sleep deprivation (PSD) shows a fast action on BDNF level increase. PMID- 26758199 TI - IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation. AB - BACKGROUND: The role of cytokines in establishing specific transcriptional programmes in innate immune cells has long been recognized. However, little is known about how these extracellular factors instruct innate immune cell epigenomes to engage specific differentiation states. Human monocytes differentiate under inflammatory conditions into effector cells with non redundant functions, such as dendritic cells and macrophages. In this context, interleukin 4 (IL-4) and granulocyte macrophage colony-stimulating factor (GM CSF) drive dendritic cell differentiation, whereas GM-CSF alone leads to macrophage differentiation. RESULTS: Here, we investigate the role of IL-4 in directing functionally relevant dendritic-cell-specific DNA methylation changes. A comparison of DNA methylome dynamics during differentiation from human monocytes to dendritic cells and macrophages identified gene sets undergoing dendritic-cell-specific or macrophage-specific demethylation. Demethylation is TET2-dependent and is essential for acquiring proper dendritic cell and macrophage identity. Most importantly, activation of the JAK3-STAT6 pathway, downstream of IL-4, is required for the acquisition of the dendritic-cell specific demethylation and expression signature, following STAT6 binding. A constitutively activated form of STAT6 is able to bypass IL-4 upstream signalling and instruct dendritic-cell-specific functional DNA methylation changes. CONCLUSIONS: Our study is the first description of a cytokine-mediated sequence of events leading to direct gene-specific demethylation in innate immune cell differentiation. PMID- 26758200 TI - Highly distinct chromosomal structures in cowpea (Vigna unguiculata), as revealed by molecular cytogenetic analysis. AB - Cowpea (Vigna unguiculata (L.) Walp) is an important legume, particularly in developing countries. However, little is known about its genome or chromosome structure. We used molecular cytogenetics to characterize the structure of pachytene chromosomes to advance our knowledge of chromosome and genome organization of cowpea. Our data showed that cowpea has highly distinct chromosomal structures that are cytologically visible as brightly DAPI-stained heterochromatic regions. Analysis of the repetitive fraction of the cowpea genome present at centromeric and pericentromeric regions confirmed that two retrotransposons are major components of pericentromeric regions and that a 455 bp tandem repeat is found at seven out of 11 centromere pairs in cowpea. These repeats likely evolved after the divergence of cowpea from common bean and form chromosomal structure unique to cowpea. The integration of cowpea genetic and physical chromosome maps reveals potential regions of suppressed recombination due to condensed heterochromatin and a lack of pairing in a few chromosomal termini. This study provides fundamental knowledge on cowpea chromosome structure and molecular cytogenetics tools for further chromosome studies. PMID- 26758202 TI - Lacrimal gland abscess presenting with preseptal cellulitis depicted on CT. AB - BACKGROUND: Pyogenic lacrimal gland abscesses are uncommon and thus may not be immediately clinically recognized without a high index of suspicion. FINDINGS: We present two patients with preseptal cellulitis and characteristic low-attenuation fluid collections in the lacrimal glands demonstrated on computed tomography (CT). CONCLUSIONS: Lacrimal gland abscesses should be considered when dacryoadenitis is refractory to medical treatment. Indeed, these cases highlight the value of prompt recognition of lacrimal abscess through ophthalmologic referral and the use of diagnostic imaging. Both patients were successfully treated via incision and drainage. PMID- 26758203 TI - Endophthalmitis following intravitreal injection of anti-VEGF agents: long-term outcomes and the identification of unusual micro-organisms. AB - BACKGROUND: While the development of targeted molecular therapy to inhibit vascular endothelial growth factor (VEGF) has revolutionized the treatment and visual prognosis of highly prevalent retinal diseases such as diabetic retinopathy and age-related macular degeneration, each intravitreal injection of these agents carries a small risk of endophthalmitis which can be visually devastating. In the absence of specific guidelines, current management of post injection endophthalmitis is typically extrapolated from data regarding endophthalmitis occurring after cataract surgery despite potential differences in pathogenic organisms and clinical course. Here, we assess the contribution of intravitreal injections of anti-VEGF agents to all cases of endophthalmitis at our tertiary care referral center and characterize the clinical outcomes and microbial pathogens associated with post-injection endophthalmitis in order to inform management of this serious iatrogenic condition. RESULTS: During the 7 year study period analyzed, 199 cases of endophthalmitis were identified using billing records. Of these, the most common etiology was post-surgical, accounting for 62 cases (31.2 %), with bleb-associated, endogenous, and corneal ulcer related infections representing the next most frequent causes, comprising 15.6 % (31/199), 13.1 % (26/199), and 13.6 % (27/199) of all cases, respectively. Intravitreal injections of anti-VEGF agents represented 8.5 % of endophthalmitis (17/199 cases). Intraocular cultures yielded positive results in 75 % of post injection cases, with the majority associated with coagulase-negative Staphylococcus. Consistent with prior literature, a case of Strep viridans displayed more rapid onset and progression. We also report the first association of Enterobacter cloacae and Lactococcus garvieae with post-injection endophthalmitis. While all but one patient were treated with initial vitreous tap and intravitreal injection of antibiotics, both patients with these rare organisms exhibited persistent vitritis requiring subsequent vitrectomy. Long term outcomes of post-injection endophthalmitis indicated visual recovery to baseline levels, even with resumption of anti-VEGF agents following resolution of the acute infection. CONCLUSIONS: Acute endophthalmitis following intravitreal injections of anti-VEGF agents is an uncommon but potentially devastating complication which may be managed effectively with vitreous tap and injection of intravitreal antibiotics. However, persistent vitritis requiring subsequent vitrectomy should raise suspicion for unusual pathogens. PMID- 26758204 TI - Overweight and obesity among women: analysis of demographic and health survey data from 32 Sub-Saharan African Countries. AB - BACKGROUND: Overweight and obesity are risk factors for many chronic diseases globally. However, the extent of the problem in low-income countries like Sub Saharan Africa is unclear. We assessed the magnitude and disparity of both phenomena by place of residence, level of education and wealth quintile using cross-sectional data from 32 countries. METHODS: Demographic and Health Survey (DHS) data collected in 32 Sub-Saharan African countries between January 2005 and December 2013 were used. A total of 250651 women (aged 15-49 years) were analyzed. Trained personnel using a standardized procedure measured body weight and height. Body mass index (BMI) was calculated by dividing body weight by height squared. Prevalence of overweight (25.0-29.9 kg/m(2)) and obesity (>= 30.0 kg/m(2)) were estimated for each country. Analysis of the relationships of overweight and obesity with place of residence, education and wealth index were carried out using logistic regression. RESULTS: The pooled prevalence of overweight for the region was 15.9% (95% CI, 15.7-16.0) with the lowest in Madagascar 5.6% (95% CI, 5.1-6.1) and the highest in Swaziland 27.7% (95% CI, 26.4-29.0). Similarly, the prevalence of obesity was also lowest in Madagascar 1.1% (95% CI, 0.9-1.4) and highest in Swaziland 23.0 (95% CI, 21.8-24.2). The women in urban residence and those who were classified as rich, with respect to the quintile of the wealth index, had higher likelihood of overweight and obesity. In the pooled results, high education was significantly associated with overweight and obesity. CONCLUSIONS: The prevalence of overweight and obesity varied highly between the countries and wealth index (rich vs. poor) was found to be the strongest predictor in most of the countries. Interventions that will address the socio-cultural barriers to maintaining healthy body size can contribute to curbing the overweight and obesity epidemic in Africa. PMID- 26758206 TI - The 2015 Static-99R: Alternative Recidivism Tables for High-Risk Offenders. AB - The Static-99R is an actuarial scale that is commonly used to assess the recidivism risk of male sex offenders. Hanson, Thornton, Helmus, and Babchishin recently revised the Static-99R norms based on revised analyses that excluded the large Bridgewater sample. As a result, the sample size of the high risk/high need (HR/HN) group was reduced substantially, which increased the confidence intervals around the predicted recidivism rates. This study provides alternative 5- and 10 year recidivism rates based on logistic regression analyses of the entire 2009 Static-99R HR/HN group that includes the Bridgewater sample. These rates fit the observed 2009 data well and have smaller confidence intervals. We propose that using alternative sexual recidivism rates from the 2009 HR/HN group is a viable option for assessing sexually violent person (SVP) and other high-risk offenders. PMID- 26758205 TI - Cholesteryl Ester Transfer Protein (CETP) expression does not affect glucose homeostasis and insulin secretion: studies in human CETP transgenic mice. AB - BACKGROUND: Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates the exchange of triglycerides for esterified cholesterol between HDL and apoB-lipoproteins. Previous studies suggest that CETP may modify glucose metabolism in patients or cultured cells. In this study, we tested if stable CETP expression would impair glucose metabolism. METHODS: We used human CETP transgenic mice and non-transgenic littermate controls (NTg), fed with control or high fat diet, as well as in dyslipidemic background and aging conditions. Assays included glucose and insulin tolerance tests, isolated islets insulin secretion, tissue glucose uptake and adipose tissue GLUT mRNA expression. RESULTS: CETP expression did not modify glucose or insulin tolerance in all tested conditions such as chow and high fat diet, adult and aged mice, normo and dyslipidemic backgrounds. Fasting and fed state plasma levels of insulin were not differ in CETP and NTg mice. Direct measurements of isolated pancreatic islet insulin secretion rates induced by glucose (11, 16.7 or 22 mM), KCl (40 mM), and leucine (10 mM) were similar in NTg and CETP mice, indicating that CETP expression did not affect beta-cell function in vivo and ex vivo. Glucose uptake by insulin target tissues, measured in vivo using (3)H-2-deoxyglucose, showed that CETP expression had no effect on the glucose uptake in liver, muscle, perigonadal, perirenal, subcutaneous and brown adipose tissues. Accordingly, GLUT1 and GLUT4 mRNA in adipose tissue were not affected by CETP. CONCLUSIONS: In summary, by comparing the in vivo all-or-nothing CETP expressing mouse models, we demonstrated that CETP per se has no impact on the glucose tolerance and tissue uptake, global insulin sensitivity and beta cell insulin secretion rates. PMID- 26758207 TI - A Test of an Integrative Model Using Social Factors and Personality Traits: Prediction on the Delinquency of South Korean Youth. AB - To more fully comprehend juvenile delinquency, it is necessary to take an integrative approach, with consideration of both personality traits of social risk factors. Many scholars argue the necessity and strength of integrative approach on the ground that juvenile delinquency is an outcome of interplay of individual and social factors. The present study examines the general applicability of an integrative model of personal traits and social risk factors to youth delinquency in the South Korean context. The empirical results show that the delinquency predictors in the current South Korean sample are closely aligned to Loeber and Farrington's theoretical propositions and that found in Western nations. Perhaps this is because South Korea has undergone rapid Westernization for the last decades. Because the correlates in this sample and Western theoretical propositions and studies overlap, an integrative model of personality trait and social risk factors is indeed generally applicable to South Korea. This finding also depicts the extent of Westernization in the South Korean society at least among adolescents. Limitations of the present study and directions for the future study are discussed. PMID- 26758209 TI - Menstrual Characteristics of Pubertal Girls: A Questionnaire-Based Study in Turkey. AB - OBJECTIVE: Clinicians should show an awareness on the menstrual characteristics of adolescent girls which may differ from adults in some aspects. To define menstrual cycle features among high school girls residing in a city center in southeastern Turkey. METHODS: A cross-sectional survey was conducted on 1256 girls attending a high school located in the city center of Elazig, Turkey. Data from 879 girls (median age, 16.2 years; range, 13.6-19.2 years) who agreed to participate in the study and had started to menstruate were evaluated. RESULTS: Mean age at menarche was 12.7+/-1.3 years (range, 8.2-17.3 years). The mean cycle duration was 28.7+/-4.4 days, and the mean menstrual flow lasted 5.9+/-1.3 days. Severe, moderate, and mild dysmenorrhea was reported in 29%, 43%, and 28% of the girls, respectively, and 52% used analgesics for dysmenorrhea. A total of 34% of the girls defined their menstrual cycle as irregular, and 32% reported school absenteeism due to menstruation-associated complaints (pain and/or heavy bleeding). Menstrual bleeding affected attendance to classes and other school activities, daily work, social, family, and friend relationships, as well as sports/exercise activities in 43%, 49%, 58%, 48%, 44%, and 60% of the participants, respectively. In total, 30% of the responders had a problem with menstruation, and 12% and 17% of these stated that they consulted a primary care physician or specialist, respectively. CONCLUSION: Dysmenorrhea was found to be common in adolescent Turkish girls and to affect daily life in approximately half of the girls. PMID- 26758210 TI - Corrigendum to "Undergraduate nursing students' performance in recognising and responding to sudden patient deterioration in high psychological fidelity simulated environments: An Australian multi-centre study" [Nurse Educ. Today 34(5) (May 2014) 691-696]. PMID- 26758208 TI - The role of neural connexins in HeLa cell mobility and intercellular communication through tunneling tubes. AB - BACKGROUND: Membranous tunneling tubes (TTs) are a recently discovered new form of communication between remote cells allowing their electrical synchronization, migration, and transfer of cellular materials. TTs have been identified in the brain and share similarities with neuronal processes. TTs can be open-ended, close-ended or contain functional gap junctions at the membrane interface. Gap junctions are formed of two unapposed hemichannels composed of six connexin (Cx) subunits. There are evidences that Cxs also play channel-independent role in cell adhesion, migration, division, differentiation, formation of neuronal networks and tumorigenicity. These properties of Cxs and TTs may synergetically determine the cellular and intercellular processes. Therefore, we examined the impact of Cxs expressed in the nervous system (Cx36, Cx40, Cx43, Cx45, and Cx47) on: 1) cell mobility; 2) formation and properties of TTs; and 3) transfer of siRNA between remote cells through TTs. RESULTS: We have identified two types of TTs between HeLa cells: F-actin rich only and containing F-actin and alpha-tubulin. The morphology of TTs was not influenced by expression of examined connexins; however, Cx36-EGFP-expressing cells formed more TTs while cells expressing Cx43 EGFP, Cx45, and Cx47 formed fewer TTs between each other compared with wt and Cx40-CFP-expressing cells. Also, Cx36-EGFP and Cx40-CFP-expressing HeLa cells were more mobile compared with wt and other Cxs-expressing cells. TTs containing Cx40-CFP, Cx43-EGFP, or Cx47 gap junctions were capable of transmitting double stranded small interfering RNA; however, Cx36-EGFP and Cx45 were not permeable to it. In addition, we show that Cx43-EGFP-expressing HeLa cells and laryngeal squamous cell carcinoma cells can couple to the mesenchymal stem cells through TTs. CONCLUSIONS: Different Cxs may modulate the mobility of cells and formation of TTs in an opposite manner; siRNA transfer through the GJ-containing TTs is Cx isoform-dependent. PMID- 26758211 TI - Effect of acustimulation on nausea and vomiting and on hyperemesis in pregnancy: a systematic review of Western and Chinese literature. AB - BACKGROUND: Nausea and vomiting in pregnancy (NVP) and hyperemesis gravidarum (HG) have a significant impact on quality of life. Medication to relieve symptoms of NVP and HG are available but pregnant women and their caregivers have been concerned about the teratogenic effect, side effects and poor efficacy. The aim of this review was to investigate if there is any clinical evidence for the efficacy of acustimulation in the treatment of NVP or HG. METHODS: A systematic review of randomized controlled trials (RCTs), including both English and Chinese databases was conducted to assess the efficacy of various techniques of acustimulation for NVP and HG. The methodological quality of the studies was assessed using the Cochrane's risks of bias tool. Revised STRICTA (2010) criteria were used to appraise acustimulation procedures. Pooled relative risks (RRp) and standard mean deviations (SMD) with 95% confidence intervals (CI) were calculated from the data provided by the investigators of the original trials. RESULTS: Twenty-nine trials including 3519 patients met the inclusion criteria. Twenty trials could be included in statistical pooling. The overall effect of different acustimulation techniques shows a significant reduction for the combined outcome for NVP or HG in pregnancy as a dichotomous variable (RRp 1.73, 95% CI 1.43 to 2.08). Studies with continuous outcome measures for nausea, vomiting and the combined outcome did not show any evidence for relieving symptoms of NVP and HG (SMD -0.12, 95% CI -0.35 to 0.12). CONCLUSIONS: Although there is some evidence for an effect of acustimulation on nausea and vomiting or hyperemesis in pregnancy, results are not conclusive. Future clinical trials with a rigorous design and large sample sizes should be conducted to evaluate the efficacy and safety of these interventions for NVP and HG. PMID- 26758212 TI - Coordinate actions of innate immune responses oppose those of the adaptive immune system during Salmonella infection of mice. AB - The immune system enacts a coordinated response when faced with complex environmental and pathogenic perturbations. We used the heterogeneous responses of mice to persistent Salmonella infection to model system-wide coordination of the immune response to bacterial burden. We hypothesized that the variability in outcomes of bacterial growth and immune response across genetically identical mice could be used to identify immune elements that serve as integrators enabling co-regulation and interconnectedness of the innate and adaptive immune systems. Correlation analysis of immune response variation to Salmonella infection linked bacterial load with at least four discrete, interacting functional immune response "cassettes." One of these, the innate cassette, in the chronically infected mice included features of the innate immune system, systemic neutrophilia, and high serum concentrations of the proinflammatory cytokine interleukin-6. Compared with mice with a moderate bacterial load, mice with the highest bacterial burden exhibited high activity of this innate cassette, which was associated with a dampened activity of the adaptive T cell cassette-with fewer plasma cells and CD4(+) T helper 1 cells and increased numbers of regulatory T cells-and with a dampened activity of the cytokine signaling cassette. System-wide manipulation of neutrophil numbers revealed that neutrophils regulated signal transducer and activator of transcription (STAT) signaling in B cells during infection. Thus, a network-level approach demonstrated unappreciated interconnections that balanced innate and adaptive immune responses during the dynamic course of disease and identified signals associated with pathogen transmission status, as well as a regulatory role for neutrophils in cytokine signaling. PMID- 26758214 TI - Astroglial networks promote neuronal coordination. AB - Astrocytes interact with neurons to regulate network activity. Although the gap junction subunits connexin 30 and connexin 43 mediate the formation of extensive astroglial networks that cover large functional neuronal territories, their role in neuronal synchronization remains unknown. Using connexin 30- and connexin 43 deficient mice, we showed that astroglial networks promoted sustained population bursts in hippocampal slices by setting the basal active state of neurons. Astroglial networks limited excessive neuronal depolarization induced by spontaneous synaptic activity, increased neuronal release probability, and favored the recruitment of neurons during bursting, thus promoting the coordinated activation of neuronal networks. In vivo, this sustained neuronal coordination translated into increased severity of acutely evoked epileptiform events and convulsive behavior. These results revealed that connexin-mediated astroglial networks synchronize bursting of neuronal assemblies, which can exacerbate pathological network activity and associated behavior. Our data thus provide molecular and biophysical evidence predicting selective astroglial gap junction inhibitors as anticonvulsive drugs. PMID- 26758216 TI - [Inequalities in health: definitions, concepts, and theories]. AB - Individuals from different backgrounds, social groups, and countries enjoy different levels of health. This article defines and distinguishes between unavoidable health inequalities and unjust and preventable health inequities. We describe the dimensions along which health inequalities are commonly examined, including across the global population, between countries or states, and within geographies, by socially relevant groupings such as race/ethnicity, gender, education, caste, income, occupation, and more. Different theories attempt to explain group-level differences in health, including psychosocial, material deprivation, health behavior, environmental, and selection explanations. Concepts of relative versus absolute; dose response versus threshold; composition versus context; place versus space; the life course perspective on health; causal pathways to health; conditional health effects; and group-level versus individual differences are vital in understanding health inequalities. We close by reflecting on what conditions make health inequalities unjust, and to consider the merits of policies that prioritize the elimination of health disparities versus those that focus on raising the overall standard of health in a population. PMID- 26758217 TI - [Social cohesion as a basis for health-equity- oriented public policies: reflections from the EUROsociAL program]. AB - EUROsociAL is a European Union program for social cohesion in Latin America. The main objective of this essay is to present the conceptual elements underpinning the activities of the EUROsociAL program in the health thematic area, with special attention to their equity aspects. It considers the concepts of social cohesion, equity in health, and the relationship between the two in EUROsociAL, and addresses monitoring of equity in health as a basis of action toward improvement focusing on social determinants of health. PMID- 26758213 TI - Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia. AB - Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) can form multiprotein complexes (heteromers), which can alter the pharmacology and functions of the constituent receptors. Previous findings demonstrated that the Gq/11-coupled serotonin 5-HT2A receptor and the Gi/o coupled metabotropic glutamate 2 (mGlu2) receptor-GPCRs that are involved in signaling alterations associated with psychosis-assemble into a heteromeric complex in the mammalian brain. In single-cell experiments with various mutant versions of the mGlu2 receptor, we showed that stimulation of cells expressing mGlu2-5-HT2A heteromers with an mGlu2 agonist led to activation of Gq/11 proteins by the 5-HT2A receptors. For this crosstalk to occur, one of the mGlu2 subunits had to couple to Gi/o proteins, and we determined the relative location of the Gi/o-contacting subunit within the mGlu2 homodimer of the heteromeric complex. Additionally, mGlu2-dependent activation of Gq/11, but not Gi/o, was reduced in the frontal cortex of 5-HT2A knockout mice and was reduced in the frontal cortex of postmortem brains from schizophrenic patients. These findings offer structural insights into this important target in molecular psychiatry. PMID- 26758215 TI - Copper(ii) mixed-ligand polypyridyl complexes with doxycycline - structures and biological evaluation. AB - Mixed-ligand Cu(ii) complexes of the type [Cu(doxycycline)(L)(H2O)2](NO3)2, where doxycycline = [4-(dimethylamino)-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo 1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide] and L = 2,2'-bipyridine (bpy, 1), 1,10-phenanthroline (phen, 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 3) and dipyrido[3,2-a:2',3'-c]phenazine (dppz, 4) have been synthesised and characterised by structural, analytical, and spectral methods. The single-crystal X-ray structures of 1 and 2 exhibited two different geometries, distorted square pyramidal and octahedral respectively as well as different coordination modes of doxycycline. Complexes 2-4 exhibit prominent plasmid DNA cleavage at significantly low concentrations probably by an oxidative mechanism. Matrix Metalloproteinase (MMP-2) inhibition studies revealed that all complexes inhibit MMP-2 similar to doxycycline which is a well-known MMP inhibitor with 3 being the most potent. IC50 values of doxycycline and 1-4 against MCF-7 (human breast cancer) and HeLa cell lines were almost equal in which 3 showed the highest efficiency (IC50 = 0.46 +/- 0.05 MUM), being consistent with its increased MMP inhibition potency. The antimalarial activities of these complexes against the chloroquine-sensitive Plasmodium falciparum NF54 and chloroquine-resistant Plasmodium falciparum Dd2 strains reveal that complex 3 exhibited a higher activity than artesunate drug against the chloroquine-resistant Dd2 strain. PMID- 26758218 TI - The association of nutrition behaviors and physical activity with general and central obesity in Caribbean undergraduate students. AB - OBJECTIVE: To quantify the prevalence of obesity and obesity-related factors in a crosssectional, observational study of Caribbean students using the results of three recent surveys of health behavior among undergraduates in Barbados, Grenada, and Jamaica. METHODS: A total of1 578 Caribbean undergraduate students from Barbados, Grenada, and Jamaica (ages 18-30 years) completed questionnaires and had physical measurements recorded. Multivariable logistic regression was used to estimate odds ratios (ORs) for the association of nutrition behaviors with prevalence of obesity (body mass index > 30 kg/m2 ); elevated waist-to height ratio (W/ht) (> 0.50); and high waist circumference (WC) (> 88 cm in females, > 102 cm in males). Models were adjusted for age, year in university, socioeconomic status, and sex. RESULTS: There was a higher prevalence of obesity (13% versus 10%), high WC (21% versus 7%), and high W/ht (35% versus 25%) in females relative to males. Compared to females, males had reduced odds of obesity (OR 0.46), high WC (OR 0.22), and high W/ht (OR 0.61) (P < 0.05 for all). Both females (46%) and males (24%) reported high levels of physical inactivity. Fruit and vegetable consumption was low (approximately two servings per day). Many students reported avoiding fatty foods (40%); this behavior was associated with high W/ht (OR 1.68), obesity (OR 1.90), and high WC (OR 1.82) (P < 0.05 for all). Irregular breakfast consumption, age, and year of study were also positively associated with obesity. Physical activity was not significantly associated with any obesity measure. CONCLUSIONS: There was a low prevalence of healthy behaviors and a high prevalence of obesity in this sample of Caribbean young adults. PMID- 26758219 TI - [Use of a bayesian approach to rate estimation and projection]. AB - OBJECTIVE: Apply and assess a Bayesian approach to projecting cancer mortality rates by fitting age-period-cohort (APC) models. METHODS: The Bayesian estimation method was applied to bladder cancer mortality data in Argentina. A second-order autoregressive model was adopted for a priori specification of APC model coefficients. The estimates obtained were compared with all available information and excluding age groups with low mortality, to assess behavior of the approach in light of scattered data. Mortality was projected for two successive periods following the ones observed. RESULTS: Robustness of the method was verified, which avoids excluding age groups with null or low mortality. Observed rates all fall within the credibility bands and confirm the model's goodness of fit. An overall downward trend in bladder cancer mortality was observed. Estimates and projections of these rates are more precise in age groups that have greater incidence of mortality. CONCLUSIONS: The Bayesian formulation used herein makes it possible to reduce random variation between adjacent estimates by specifying that the effects of each scale depend on the immediately preceding ones. It was demonstrated that the approach has the capacity to handle low frequencies and obtain reliable mortality estimates, as well as precise projections, without the need for making additional assumptions, as happens in classical APC model fitting. PMID- 26758220 TI - Diphtheria in the Dominican Republic: reduction of cases following a large outbreak. AB - OBJECTIVE: To describe the most recent outbreak of diphtheria in the Dominican Republic and the disease's occurrence and vaccination coverage in 2004-2013. METHODS: Clinical data of diphtheria cases that occurred in 2004 and that met the study's case definition were reviewed along with socioeconomic and epidemiological information from the cases' families. Univariate and multivariate analyses were performed to assess risk factors for fatal diphtheria. Routine surveillance and vaccination coverage data are presented. RESULTS: From January 2004-April 2005, a total of 145 diphtheria cases were reported; 80 (66%) of the 122 cases reported in 2004 met the case definition; 26 were fatal (case-fatality rate: 32.5%). Incidence was highest in the group 1-4 years of age at 5.3 per 100 000; 62.5% were male. Of the 80 cases, 61 (76%) where hospitalized in Hospital A, 17 in Hospital B, and 2 in two other hospitals. Earlier onset (first half of 2004), birth order, and tracheotomy were associated with fatal diphtheria (P < 0.05); cases in Hospital A were also more likely to be fatal (P = 0.066). The average annual diphtheria incidence was 4.91 cases/1 million people in 2000-2003, climbed to 8.8 cases per million in 2004-2005, and dropped to 0.38 in 2006-2014; no diphtheria cases have been reported since 2011. DTP3 vaccination coverage ranged from 72%-81% in 2000-2004 and from 81%-89% in 2005-2013. CONCLUSIONS: The 2004-2005 diphtheria outbreak in the Dominican Republic resulted in important and avoidable morbidity and mortality. Annual cases declined and no cases have been reported in recent years. Maintaining high vaccination coverage and diligent surveillance are crucial to preventing diphtheria outbreaks and controlling the disease. PMID- 26758221 TI - [Epidemiological situation of malaria in the brazilian amazon region, 2003 to 2012]. AB - OBJECTIVE: To describe the epidemiological status of malaria in the Brazilian Amazon region between 2003 and 2012. METHODS: The present retrospective ecological study employed data from the Brazilian Epidemiological Surveillance and Malaria Communication System (SIVEP-Malaria/SVS/MS), Hospital Admissions System (SIH/DATASUS/MS), and Mortality Information System (SIM). For each year, the percentage of Plasmodium falciparum cases, the number of admissions, and deaths and lethality due to malaria were determined. The distribution of P. falciparum cases in each state was also described. Data from 2012 were compared to data from 2005, when the Amazon region recorded a peak number of cases, and with data from 2011. RESULTS: In 2012, 241 806 malaria cases were recorded in the region, a reduction of 60.1% vs. 2005 and of 9.1% vs. 2011. Between 2003 and 2005, there was an increase of 48.3% in the number of cases, with 606 069 recorded cases in 2005. Since 2006, a declining trend in number of cases has been observed, especially for P. falciparum, with 155 169 cases notified in 2005 vs. 35 385 in 2012 (reduction of 77.2%). Between 2005 and 2012, the number of malaria hospital admissions (74,6%) and deaths (54,4%) was also reduced. CONCLUSIONS: Despite a decline in the number of malaria cases, the possible emergence of drug resistant parasites and the lower frequency of P. falciparum indicate the need to adopt new surveillance strategies, more sensitive tools, and integrated vector management to achive a bold, but not impossible, goal: the elimination of P. falciparum. PMID- 26758222 TI - [Assaults on professionals in healthcare settings]. AB - OBJECTIVE: Determine the frequency of assaults on health workers and characterize aspects that deepen understanding and development of prevention strategies. METHODS: A voluntary and confidential electronic survey was conducted through the IntraMed website, a social network of health professionals. Frequency of verbal and physical assaults was analyzed along with their association with demographic variables, occupation, career, specialty, potential consequences, perception of insecurity in the workplace, and proposals to reduce them. RESULTS: A total of 19 967 surveys were analyzed, of which 13 323 (66.7%) described assaults. Assaults were physical in 11.3% of cases, and 73.4% occurred in public institutions, mainly in emergency areas. Delay in care and lack of resources were the most frequent triggers. Alcohol or drug intoxication was reported in 13.8% of aggressors, altered mental status from another cause or psychiatric illness in 13.9%, and no detected impairment of mental faculties in 63%. Of professionals attacked, 16.9% reported sequelae, 7.9% of which were physical, and 28% were temporarily unable to work. Insecurity in the workplace was described by 46.6% of respondents, who suggested various measures to reduce it, chief among them, community education CONCLUSIONS: Verbal and physical violence toward health workers was frequent, resulting in work-related, mental, and even physical sequelae. This study contributes information that could be used to develop strategies aimed at prevention and control of assaults. PMID- 26758223 TI - Effects of tobacco control policies on smoking prevalence and tobacco attributable deaths in Mexico: the SimSmoke model. AB - OBJECTIVE: To examine how policies adopted in Mexico in response to the Framework Convention on Tobacco Control affected smoking prevalence and smoking attributable deaths. METHODS: The SimSmoke simulation model of tobacco control policy is applied to Mexico. This discrete time, first-order Markov model uses data on population size, smoking rates and tobacco control policy for Mexico. It assesses, individually and jointly, the effects of seven types of policies: cigarette taxes, smoke-free air laws, mass media campaigns, advertising bans, warning labels, cessation treatment, and youth tobacco access policies. RESULTS: The Mexico SimSmoke model estimates that smoking rates have been reduced by about 30% as a result of policies implemented since 2002, and that the number of smoking-attributable deaths will have been reduced by about 826 000 by 2053. Increases in cigarette prices are responsible for over 60% of the reductions, but health warnings, smoke-free air laws, marketing restrictions and cessation treatments also play important roles. CONCLUSIONS: Mexico has shown steady progress towards reducing smoking prevalence in a short period of time, as have other Latin American countries, such as Brazil, Panama and Uruguay. Tobacco control policies play an important role in continued efforts to reduce tobacco use and associated deaths in Mexico. PMID- 26758224 TI - [Burden of salmonellosis and shigellosis in four departments of Guatemala, 2010]. AB - OBJECTIVE: Estimate the burden of disease from Salmonella spp. and Shigella spp. in four departments of Guatemala in 2010. METHODS: Burden of disease study based on document analysis of published population surveys, laboratory files, and surveillance data from the Health Management Information System (SIGSA) in four departments of Guatemala: Huehuetenango, Jutiapa, Quetzaltenango, and Santa Rosa, in 2010. Information was supplemented by a laboratory survey. Burden of disease was estimated using methodology adapted by the World Health Organization from the United States Centers for Disease Control and Prevention. RESULTS: Surveillance data yielded 72 salmonellosis and 172 shigellosis cases. According to population surveys, the percentage of the population that consults health services for diarrhea is 64.7% (95% CI: 60.6%-68.7%) in Quetzaltenango and 61.0% (95% CI: 56.0%-66.0%) in Santa Rosa. In the 115 laboratories that answered the survey (72.8% response rate), 6 051 suspected samples were collected for stool culture and 3 290 for hemoculture; 39.4% and 100.0% of them were processed, respectively. In all, 85 Salmonella spp. and 113 Shigella spp. strains were isolated. For each reported case of salmonellosis and shigellosis, it was estimated that 40 cases are not reported in Quetzaltenango, 55 in Huehuetenango, 345 in Santa Rosa, and 466 in Jutiapa. Estimated burden of disease ranged from 5 to 2 230 cases per 100 000 population for salmonellosis and from 60 to 1 195 cases per 100 000 population for shigellosis. CONCLUSIONS: Salmonellosis and shigellosis are a major public health problem in the departments studied and in Guatemala. Burden of disease from these pathogens is higher than that reported by SIGSA. PMID- 26758225 TI - [Blood regulation in Brazil: contextualization for improvement]. AB - The use of blood products as essential medicines and the recognition of the high risk associated with blood transfusions require governments to take regulatory action with a focus on quality and safety. In this scenario, regulatory agencies play an essential role in socially advancing the guarantee that blood components will be produced according to current operating rules. Thus, in the effort to manage sanitary risks involved in the processing and use of blood, the Brazilian regulatory model, based on the construction of a national blood policy overseen by the State, has undergone conceptual improvement and review of the tools employed to achieve its goals. With the inclusion of good manufacturing practices as part of the Brazilian norms, as recommended by the World Health Organization, the country has moved forward in its view of blood facilities as manufacturing centers producing blood-derived biologics for therapeutic applications. It has also strengthened the need to develop safety mechanisms for blood donors and recipients. The development of a State-coordinated national blood policy and the institution of a national surveillance system with legitimate power of inspection are essential elements used in Brazil to guarantee the amount, quality, safety, and timeliness of blood supply to the population. The present article aims to discuss the present context of the blood regulatory model in Brazil so as to identify the challenges for improvement of this model. PMID- 26758226 TI - Food and beverage industries' participation in health scientific events: considerations on conflicts of interest. AB - Several sectors of the industry (pharmaceutical, food, and other) often occupy a prominent position in scientific meetings on health. The aim of this article is to discuss the participation of food and beverage industries (Big Food and Big Soda) in events organized by scientific institutions in health and nutrition, highlighting potential conflicts of interest in such partnerships. As an example, the authors report the case of a Brazilian national event organized by a nutrition scientific association in 2011. Focused on the theme "Evidence-based Nutrition," the event's scientific program was largely influenced by corporate sponsors. For example, a symposium at this congress was organized by a beverage company known worldwide for its sugar-sweetened products and classified as the "diamond sponsor" of the event. While debating the adoption of healthy lifestyles in the current scenario of rising occurrence of obesity, the rationale for health promotion was reduced to providing information that would motivate rational individual choices, thus ignoring any political, economic, cultural, marketing, and social factors involved in the global process of nutrition transition. The authors conclude that conflicts of interest are present in the participation of food and beverage industries in health scientific events. The industries' strategy attempts to grant legitimacy to the production and marketing of their products through an association with adequate health practices. Health professionals and policy-makers should reflect on such partnerships because their main purpose is to generate profit, not the promotion of public health. PMID- 26758227 TI - Sustaining a hygiene education intervention to prevent and control geohelminth infections at schools in the Peruvian Amazon. AB - The World Health Organization currently recommends that school-based deworming programs include health hygiene education as a complementary measure. However, the sustainability and long-term impact of such hygiene education had yet to be assessed. In July 2012, this cross-sectional study was conducted in 18 primary schools in the Peruvian Amazon to gauge continuing adherence to a health hygiene education intervention introduced 2 years earlier to reduce soil-transmitted helminth infections. Due in large part to high teacher turn-over, only 9 of 47 (19.1%) teachers were still implementing the intervention. Health hygiene education interventions must, therefore, be designed to ensure sustainability in order to contribute to the overall effectiveness of school-based deworming programs. PMID- 26758228 TI - Streaming potential-modulated capillary filling dynamics of immiscible fluids. AB - The pressure driven transport of two immiscible electrolytes in a narrow channel with prescribed surface potential (zeta potential) is considered under the influence of a flow-induced electric field. The latter consideration is non trivially and fundamentally different from the problem of electric field-driven motion (electroosmosis) of two immiscible electrolytes in a channel in a sense that in the former case, the genesis of the induced electric field, termed as streaming potential, is the advection of ions in the absence of any external electric field. As the flow occurs, one fluid displaces the other. Consequently, in cases where the conductivities of the two fluids differ, imbibition dynamically alters the net conductivity of the channel. We emphasize, through numerical simulations, that the alteration in the net conductivity has a significant impact on the contact line dynamics and the concomitant induced streaming potential. The results presented herein are expected to shed light on multiphase electrokinetics devices. PMID- 26758229 TI - Suppression for lung metastasis by depletion of collagen I and lysyl oxidase via losartan assisted with paclitaxel-loaded pH-sensitive liposomes in breast cancer. AB - Tumor metastasis would seriously impair the efficacy of chemotherapy. Our previous studies showed losartan combined with paclitaxel-loaded pH-sensitive cleavable liposomes (PTX-Cl-Lip) facilitated paclitaxel accumulation and led to enhanced antitumor efficacy in 4T1 bearing mice. Since losartan could inhibit the level of collagen I which was related to tumor metastasis, this strategy was further applied to suppress tumor metastasis this time. Our in vivo anti metastatic study manifested losartan could lower the colonies occupied in lungs by 76.4% compared with that of saline group. When losartan and PTX-Cl-Lip were combined, anti-metastatic efficiency reached to 88.2%, which was the best among all the groups. In vitro 3D tumor spheroids studies proved losartan could significantly suppress the invasion of tumor cells. Losartan plus PTX-Cl-Lip could further weaken the metastasis of tumor cells. Mechanism study showed the declination of collagen I level via losartan was caused by inhibition of active transforming growth factor-beta1. Western-blot study showed losartan could decrease the level of lysyl oxidase, then inhibit the cross-linking of collagen I, finally weakened the cell signaling transmit via integrin and the metastasis of tumor cells was restrained. All above studies illustrated this combined tactic could achieve favorable effect on suppression of lung tumor metastasis. PMID- 26758231 TI - A T-shaped triazatruxene probe for the naked-eye detection of HCl gas with high sensitivity and selectivity. AB - A T-shaped Schiff-base triazatruxene derivative (TATNFF) was designed, synthesized, and explored as a sensitive probe to detect HCl gas by the naked eye. The remarkable color change of TATNFF with turn-on behavior in the presence of a trace amount of HCl gas was obviously observed by the naked eye, which opens up a new strategy to explore a novel set of smart responsive materials for sensing applications. PMID- 26758230 TI - Environmental assessment of freshwater ecosystems of the Sava River watershed and Cerknisko Lake, Slovenia, using the bioindicator species Fontinalis antipyretica: insights from stable isotopes and selected elements. AB - Ten locations in the Notranjska region, Slovenia, with different land use in the catchment (town, village and agricultural areas), including reference points with different geological composition considered as unpolluted sites, were sampled for water and aquatic moss to evaluate environmental assessment in fresh water systems of the Sava River watershed. Samples of fresh water and Fontinalis antipyretica were taken in all four seasons during the years 2010 and 2012. The water chemistry of the investigated locations was dominated by [Formula: see text], while concentrations of [Formula: see text] seasonally ranged from 2.1 to 6.4 mg L(-1) and at one of the reference sites did not exceed 1.3 mg L(-1). delta(13)CDIC values seasonally ranged from -13.3 to -8.1 0/00 and indicated waters dominated by degradation of organic matter and dissolution of carbonates. delta(13)Cplant values of F. antipyretica seasonally ranged from -45 to -32.9 0/00 and of delta(15)Nplant from -0.2 to 6.5 0/00. The higher delta(15)N value of 6.5 0/00 found in F. antipyretica was related to agricultural activity in the watershed. The content of minor and trace elements in F. antipyretica ranged from 4-38 ug g(-1) for Ni, 17-105 ug g(-1) for Zn, 2-28 ug g(-1) for Pb, 0.26-1.95 ug g(-1) for Cd, 4-27 ug g(-1) for Cu, 4-49 ug g(-1) for Cr, 1-6 ug g(-1) for As and 0.33-3.24 ug g(-1) for Se. The most polluted watershed was the Psata stream (agricultural area, cattle farm with the highest concentration of nitrate in water) also with highest values for Ni, Cr, Pb, Zn and As. PMID- 26758232 TI - Direct reconstruction of the source intensity distribution of a clinical linear accelerator using a maximum likelihood expectation maximization algorithm. AB - Direct determination of the source intensity distribution of clinical linear accelerators is still a challenging problem for small field beam modeling. Current techniques most often involve special equipment and are difficult to implement in the clinic. In this work we present a maximum-likelihood expectation maximization (MLEM) approach to the source reconstruction problem utilizing small fields and a simple experimental set-up. The MLEM algorithm iteratively ray traces photons from the source plane to the exit plane and extracts corrections based on photon fluence profile measurements. The photon fluence profiles were determined by dose profile film measurements in air using a high density thin foil as build-up material and an appropriate point spread function (PSF). The effect of other beam parameters and scatter sources was minimized by using the smallest field size ([Formula: see text] cm(2)). The source occlusion effect was reproduced by estimating the position of the collimating jaws during this process. The method was first benchmarked against simulations for a range of typical accelerator source sizes. The sources were reconstructed with an accuracy better than 0.12 mm in the full width at half maximum (FWHM) to the respective electron sources incident on the target. The estimated jaw positions agreed within 0.2 mm with the expected values. The reconstruction technique was also tested against measurements on a Varian Novalis Tx linear accelerator and compared to a previously commissioned Monte Carlo model. The reconstructed FWHM of the source agreed within 0.03 mm and 0.11 mm to the commissioned electron source in the crossplane and inplane orientations respectively. The impact of the jaw positioning, experimental and PSF uncertainties on the reconstructed source distribution was evaluated with the former presenting the dominant effect. PMID- 26758235 TI - Temperature based Restricted Boltzmann Machines. AB - Restricted Boltzmann machines (RBMs), which apply graphical models to learning probability distribution over a set of inputs, have attracted much attention recently since being proposed as building blocks of multi-layer learning systems called deep belief networks (DBNs). Note that temperature is a key factor of the Boltzmann distribution that RBMs originate from. However, none of existing schemes have considered the impact of temperature in the graphical model of DBNs. In this work, we propose temperature based restricted Boltzmann machines (TRBMs) which reveals that temperature is an essential parameter controlling the selectivity of the firing neurons in the hidden layers. We theoretically prove that the effect of temperature can be adjusted by setting the parameter of the sharpness of the logistic function in the proposed TRBMs. The performance of RBMs can be improved by adjusting the temperature parameter of TRBMs. This work provides a comprehensive insights into the deep belief networks and deep learning architectures from a physical point of view. PMID- 26758241 TI - Lipidomics Biomarkers of Diet-Induced Hyperlipidemia and Its Treatment with Poria cocos. AB - Hyperlipidemia is a major cause of atherosclerotic cardiovascular disease. Poria cocos (PC) is a medicinal product widely used in Asia. This study was undertaken to define the alterations of lipid metabolites in rats fed a high-fat diet to induce hyperlipidemia and to explore efficacy and mechanism of action of PC in the treatment of diet-induced hyperlipidemia. Plasma samples were then analyzed using UPLC-HDMS. The untreated rats fed a high-fat diet exhibited significant elevation of plasma triglyceride and total and low-density lipoprotein (LDL) cholesterol concentrations. This was associated with marked changes in plasma concentrations of seven fatty acids (palmitic acid, hexadecenoic acid, hexanoylcarnitine, tetracosahexaenoic acid, cervonoyl ethanolamide, 3 hydroxytetradecanoic acid, and 5,6-DHET) and five sterols [cholesterol ester (18:2), cholesterol, hydroxytestosterone, 19-hydroxydeoxycorticosterone, and cholic acid]. These changes represented disorders of biosynthesis and metabolism of the primary bile acids, steroids, and fatty acids and mitochondrial fatty acid elongation pathways in diet-induced hyperlipidemia. Treatment with PC resulted in significant improvements of hyperlipidemia and the associated abnormalities of the lipid metabolites. PMID- 26758242 TI - Identification of infusion strategy for achieving repeatable nanoparticle distribution and quantification of thermal dosage using micro-CT Hounsfield unit in magnetic nanoparticle hyperthermia. AB - OBJECTIVES: The objective of this study was to identify an injection strategy leading to repeatable nanoparticle deposition patterns in tumours and to quantify volumetric heat generation rate distribution based on micro-CT Hounsfield unit (HU) in magnetic nanoparticle hyperthermia. METHODS: In vivo animal experiments were performed on graft prostatic cancer (PC3) tumours in immunodeficient mice to investigate whether lowering ferrofluid infusion rate improves control of the distribution of magnetic nanoparticles in tumour tissue. Nanoparticle distribution volume obtained from micro-CT scan was used to evaluate spreading of the nanoparticles from the injection site in tumours. Heating experiments were performed to quantify relationships among micro-CT HU values, local nanoparticle concentrations in the tumours, and the ferrofluid-induced volumetric heat generation rate (q(MNH)) when nanoparticles were subject to an alternating magnetic field. RESULTS: An infusion rate of 3 uL/min was identified to result in the most repeatable nanoparticle distribution in PC3 tumours. Linear relationships have been obtained to first convert micro-CT greyscale values to HU values, then to local nanoparticle concentrations, and finally to nanoparticle induced q(MNH) values. The total energy deposition rate in tumours was calculated and the observed similarity in total energy deposition rates in all three infusion rate groups suggests improvement in minimising nanoparticle leakage from the tumours. The results of this study demonstrate that micro-CT generated q(MNH) distribution and tumour physical models improve predicting capability of heat transfer simulation for designing reliable treatment protocols using magnetic nanoparticle hyperthermia. PMID- 26758243 TI - Do preoperative serum vascular endothelial growth factor and migration-inhibitory factor predict the nature of the adnexal masses? A prospective-controlled trial. AB - The aim of this study was to identify the role of preoperative serum vascular endothelial growth factor (VEGF) and migration inhibitor factor (MIF) in differentiation of benign and malignant adnexal masses, as well as the relationship between prognostic factors and VEGF and MIF in ovarian cancer patients. This prospective study included 41 patients who were admitted between November 2010 and March 2012. In the malignant group, there were 21 patients, and remaining 20 had benign adnexal masses. Age, CA125 levels, grade, stage, presence of ascites and the degree of cytoreduction performed were noted. There was no significant difference between two groups in preoperative serum VEGF and MIF levels (p = 0.118 and p = 0.297, respectively). CA125 levels were significantly higher in the malignant group (p < 0.0001). There was no significant difference for VEGF and MIF between the groups evaluated for tumour grade, stage, presence of ascites and degree of cytoreduction performed in the malignant group. Preoperative serum, VEGF and MIF levels are not suitable for the differentiation of malignant and benign adnexal masses, and they do not correlate with the prognostic factors of ovarian cancer in this cohort of patients. PMID- 26758244 TI - Administrative data is as good as medical chart review for comorbidity ascertainment in patients with infections in Singapore. AB - The Charlson comorbidity index (CCI) is widely used for control of confounding from comorbidities in epidemiological studies. International Classification of Diseases (ICD)-coded diagnoses from administrative hospital databases is potentially an efficient way of deriving CCI. However, no studies have evaluated its validity in infectious disease research. We aim to compare CCI derived from administrative data and medical record review in predicting mortality in patients with infections. We conducted a cross-sectional study on 199 inpatients. Correlation analyses were used to compare comorbidity scores from ICD-coded administrative databases and medical record review. Multivariable regression models were constructed and compared for discriminatory power for 30-day in hospital mortality. Overall agreement was fair [weighted kappa 0.33, 95% confidence interval (CI) 0.23-0.43]. Kappa coefficient ranged from 0.17 (95% CI 0.01-0.36) for myocardial infarction to 0.85 (95% CI 0.59-1.00) for connective tissue disease. Administrative data-derived CCI was predictive of CCI ?5 from medical record review, controlling for age, gender, resident status, ward class, clinical speciality, illness severity, and infection source (C = 0.773). Using the multivariable model comprising age, gender, resident status, ward class, clinical speciality, illness severity, and infection source to predict 30-day in hospital mortality, administrative data-derived CCI (C = 0.729) provided a similar C statistic as medical record review (C = 0.717, P = 0.8548). In conclusion, administrative data-derived CCI can be used for assessing comorbidities and confounding control in infectious disease research. PMID- 26758247 TI - Performances of survival, feeding behavior, and gene expression in aphids reveal their different fitness to host alteration. AB - Insect populations feeding on different plant species are under selection pressure to adapt to these differences. A study integrating elements of the ecology, behavior, and gene expression of aphids on different host plants has not yet been well-explored. The present study explores the relationship between host fitness and survival, feeding behavior, and salivary gland gene expression of a pea (Pisum sativum) host race of Acyrthosiphon pisum feeding on a common host Vicia faba and on three genetically-related hosts (Vicia villosa, Medicago truncatula, and Medicago sativa). Life table data indicated that aphids on non favored hosts exhibited small size, low reproduction rate, slow population increase and individual development, and long lifespan. Electrical penetration graph results showed that the aphids spent significantly less time in passive ingestion of phloem sap on all non-preferred host plants before acclimation. After a period of acclimation on M. truncatula and V. villosa, pea host race individuals showed improved feeding behavior. No individuals of the pea host race completed its life history on M. sativa. Interestingly, the number of host specific differentially-expressed salivary gland genes was negatively correlated with the fitness of aphids on this host plant. This study provided important cues in host plant specialization in aphids. PMID- 26758246 TI - Failure of Standard Training Sets in the Analysis of Fast-Scan Cyclic Voltammetry Data. AB - The use of principal component regression, a multivariate calibration method, in the analysis of in vivo fast-scan cyclic voltammetry data allows for separation of overlapping signal contributions, permitting evaluation of the temporal dynamics of multiple neurotransmitters simultaneously. To accomplish this, the technique relies on information about current-concentration relationships across the scan-potential window gained from analysis of training sets. The ability of the constructed models to resolve analytes depends critically on the quality of these data. Recently, the use of standard training sets obtained under conditions other than those of the experimental data collection (e.g., with different electrodes, animals, or equipment) has been reported. This study evaluates the analyte resolution capabilities of models constructed using this approach from both a theoretical and experimental viewpoint. A detailed discussion of the theory of principal component regression is provided to inform this discussion. The findings demonstrate that the use of standard training sets leads to misassignment of the current-concentration relationships across the scan potential window. This directly results in poor analyte resolution and, consequently, inaccurate quantitation, which may lead to erroneous conclusions being drawn from experimental data. Thus, it is strongly advocated that training sets be obtained under the experimental conditions to allow for accurate data analysis. PMID- 26758248 TI - Human regulatory T cells suppress proliferation of B lymphoma cells. AB - Activated regulatory T cells (Tregs) suppress proliferation and differentiation of normal B cells. In our study, allogeneic polyclonal CD4 (+) CD25 (+) Tregs and CD4 (+) CD25 (+) CD127(lo)Tregs expanded in vitro in the presence of rapamycin and low dose IL-2 suppressed proliferation of 11 out of 12 established lymphoma B cell lines. The effect of expanded CD4 (+) CD25 (+) Tregs on survival of freshly isolated lymphoma B cells maintained in culture with soluble multimeric CD40L and IL-4 was variable across lymphoma entities. The survival of freshly isolated follicular lymphoma cells usually decreased in cocultures with CD4 (+) CD25 (+) Tregs. Treg effect on chronic lymphocytic leukemia/small lymphocytic lymphoma cells ranged from suppression to help in individual patients. CD4 (+) CD25 (+) Tregs or CD4 (+) CD25 (+) CD127(lo)Tregs expanded ex vivo with rapamycin could be used to suppress regrowth of residual lymphoma after autologous hematopoietic cell transplantation (HCT), and to counteract both graft-versus-host disease and lymphoma re-growth after allogeneic HCT in select patients with lymphoma susceptible to the regulation by Tregs. PMID- 26758245 TI - Abnormally activated one-carbon metabolic pathway is associated with mtDNA hypermethylation and mitochondrial malfunction in the oocytes of polycystic gilt ovaries. AB - Polycystic ovarian syndrome (PCOS) is associated with hyperhomocysteinemia and polycystic ovaries (PCO) usually produce oocytes of poor quality. However, the intracellular mechanism linking hyperhomocysteinemia and oocyte quality remains elusive. In this study, the quality of the oocytes isolated from healthy and polycystic gilt ovaries was evaluated in vitro in association with one-carbon metabolism, mitochondrial DNA (mtDNA) methylation, and mitochondrial function. PCO oocytes demonstrated impaired polar body extrusion, and significantly decreased cleavage and blastocyst rates. The mitochondrial distribution was disrupted in PCO oocytes, together with decreased mitochondrial membrane potential and deformed mitochondrial structure. The mtDNA copy number and the expression of mtDNA-encoded genes were significantly lower in PCO oocytes. Homocysteine concentration in follicular fluid was significantly higher in PCO group, which was associated with significantly up-regulated one-carbon metabolic enzymes betaine homocysteine methyltransferase (BHMT), glycine N methyltransferase (GNMT) and the DNA methyltransferase DNMT1. Moreover, mtDNA sequences coding for 12S, 16S rRNA and ND4, as well as the D-loop region were significantly hypermethylated in PCO oocytes. These results indicate that an abnormal activation of one-carbon metabolism and hypermethylation of mtDNA may contribute, largely, to the mitochondrial malfunction and decreased quality of PCO-derived oocytes in gilts. PMID- 26758249 TI - Postnatal Foot Length to Determine Gestational Age: A Pilot Study. AB - Gestational age is a critical factor in the management, decision-making, prognostication and follow-up of newborn infants. It is also essential for research and epidemiology. In the absence of an early assessment of fetal gestation by abdominal ultrasound, many neonatal units in developing countries determine gestational age by neonatal scores and last menstrual period-both of which are highly inaccurate. The aim of this pilot study was to determine whether postnatal foot length measurement could accurately determine gestational age in a specified South African hospitalized neonatal population. Foot length was measured with a plastic Verniere's caliper. Foot length was shown to correlate well with gestational age (r = 0.919,p < 0.001). Intra-observer and inter observer variability of foot length measurements was low. Foot length can therefore be used with high accuracy to determine the gestational age in a population where there is poor access to or utilization of antenatal sonar. PMID- 26758250 TI - Hepatic Abscesses in Preterm Infants: Report of Three Cases and Review of the Literature. AB - PURPOSE: Hepatic abscess is a rare but potentially fatal entity in neonates. The aim of this study was to provide valuable data for diagnosis, management and prevention of hepatic abscess in preterm infants. METHODS: A retrospective chart review was made for patients diagnosed with hepatic abscesses between 2012 and 2015. Methods included clinical and radiological review of records and evaluation of potential risk factors. RESULTS: A total of three infants with hepatic abscesses were identified. All of them had low birth weight and low gestational age. Predisposing factors included prematurity, late sepsis, umbilical catheterization, necrotizing enterocolitis and previous antibiotic therapy. Isolated organisms from blood included Staphylococcus spp. in two cases and Pseudomonas spp. in one case. To the best of our knowledge, this is the first preterm case of hepatic abscess caused by Pseudomonas aeruginosa in the literature. All patients responded well to antibiotic therapy alone, and no interventional drainage was required. CONCLUSION: We suggest evaluating all preterm neonates who have severe sepsis and/or necrotizing enterocolitis signs and who do not respond to prolonged antibiotic therapy with detailed abdominal ultrasound for possible hepatic abscesses as early diagnosis, and treatment favors prognosis. PMID- 26758253 TI - Commentary: Legacy of the Commission on Research Integrity. AB - 20 years ago, the Report of the Commission on Research Integrity (also known as the Ryan Commission after its chair) was submitted to the Secretary of the Department of Health and Human Services and to House and Senate Committees. As directed in enabling legislation, the Commission had provided recommendations on a new definition of research misconduct, oversight of scientific practices, and development of a regulation to protect whistleblowers. Reflecting the ethos of the time, the Commission recommended that institutions receiving Public Health Service research funding should provide oversight of all but the most egregious misconduct. The suggested definition of research misconduct was organized around misappropriation, interference and misrepresentation, which would have addressed collaborative/authorship disputes and sabotage in scientific laboratories, both of which remain unaddressed in current policy. The Commission also recommended the Whistleblower Bill of Rights and Responsibilities which would have authorized remedies for whistleblowers who experienced retaliation and sanctions against retaliators. Response from the scientific community was highly critical, and none of the Commission's recommendations was accepted. No new body has examined issues within the Commission's charge, there has been no significant Congressional or public pressure to do so, institutions have not been able to sustain standards that would have avoided current concerns about bias and irreproducibility in research, and there is still no entity in science capable of addressing issues assigned to the Commission and other urgent issues. PMID- 26758252 TI - Onco-miR-24 regulates cell growth and apoptosis by targeting BCL2L11 in gastric cancer. AB - Gastric cancer is one of the most common malignancies worldwide; however, the molecular mechanism in tumorigenesis still needs exploration. BCL2L11 belongs to the BCL-2 family, and acts as a central regulator of the intrinsic apoptotic cascade and mediates cell apoptosis. Although miRNAs have been reported to be involved in each stage of cancer development, the role of miR-24 in GC has not been reported yet. In the present study, miR-24 was found to be up-regulated while the expression of BCL2L11 was inhibited in tumor tissues of GC. Studies from both in vitro and in vivo shown that miR-24 regulates BCL2L11 expression by directly binding with 3'UTR of mRNA, thus promoting cell growth, migration while inhibiting cell apoptosis. Therefore, miR-24 is a novel onco-miRNA that can be potential drug targets for future clinical use. PMID- 26758255 TI - "Be Prepared if I Bring It Up:" Patients' Perceptions of the Utility of Religious and Spiritual Discussion During Genetic Counseling. AB - As debates continue about the relevance of religion to health care, research is needed to guide decisions about whether genetic counselors (GCs) should routinely address religious and/or spiritual (R/S) issues with their patients. We conducted an online survey to gauge patient perspectives on this issue. Among the 70 respondents, frequencies of closed-ended responses and thematic analyses of open ended responses revealed multiple patient concerns related to R/S discussions with GCs. Although 60 respondents reported being R/S, only a small minority would want to discuss R/S issues if it meant less time discussing medical information. Most respondents also expressed opinions that: 1) genetic counseling should be about science; 2) GCs are not qualified to discuss R/S issues; 3) other outlets are available to meet the needs of patients who want R/S counseling; and/or 4) R/S discussions are more likely to be acceptable if patients broach the topic or in specific circumstances (e.g., when patients are facing end-of life issues). Overall, responses suggest routine or comprehensive R/S assessments or discussions are not necessary and that GCs would be best equipped to help all their patients if they were prepared to listen, be supportive, and make referrals when R/S issues arise in clinic. PMID- 26758251 TI - Morphometric analysis of inflammation in bronchial biopsies following exposure to inhaled diesel exhaust and allergen challenge in atopic subjects. AB - BACKGROUND: Allergen exposure and air pollution are two risk factors for asthma development and airway inflammation that have been examined extensively in isolation. The impact of combined allergen and diesel exhaust exposure has received considerably less attention. Diesel exhaust (DE) is a major contributor to ambient particulate matter (PM) air pollution, which can act as an adjuvant to immune responses and augment allergic inflammation. We aimed to clarify whether DE increases allergen-induced inflammation and cellular immune response in the airways of atopic human subjects. METHODS: Twelve atopic subjects were exposed to DE 300 MUg.m(-3) or filtered air for 2 h in a blinded crossover study design with a four-week washout period between arms. One hour following either filtered air or DE exposure, subjects were exposed to allergen or saline (vehicle control) via segmental challenge. Forty-eight hours post-allergen or control exposure, bronchial biopsies were collected. The study design generated 4 different conditions: filtered air + saline (FAS), DE + saline (DES), filtered air + allergen (FAA) and DE + allergen (DEA). Biopsies sections were immunostained for tryptase, eosinophil cationic protein (ECP), neutrophil elastase (NE), CD138, CD4 and interleukin (IL)-4. The percent positivity of positive cells were quantified in the bronchial submucosa. RESULTS: The percent positivity for tryptase expression and ECP expression remained unchanged in the bronchial submucosa in all conditions. CD4 % positive staining in DEA (0.311 +/- 0.060) was elevated relative to FAS (0.087 +/- 0.018; p = 0.035). IL-4% positive staining in DEA (0.548 +/- 0.143) was elevated relative to FAS (0.127 +/- 0.062; p = 0.034). CD138 % positive staining in DEA (0.120 +/- 0.031) was elevated relative to FAS (0.017 +/- 0.006; p = 0.015), DES (0.044 +/- 0.024; p = 0.040), and FAA (0.044 +/ 0.008; p = 0.037). CD138% positive staining in FAA (0.044 +/- 0.008) was elevated relative to FAS (0.017 +/- 0.006; p = 0.049). NE percent positive staining in DEA (0.224 +/- 0.047) was elevated relative to FAS (0.045 +/- 0.014; p = 0.031). CONCLUSIONS: In vivo allergen and DE co-exposure results in elevated CD4, IL-4, CD138 and NE in the respiratory submucosa of atopic subjects, while eosinophils and mast cells are not changed. TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01792232. PMID- 26758254 TI - Genetic Testing and Post-Testing Decision Making among BRCA-Positive Mutation Women: A Psychosocial Approach. AB - Through an analysis of an online survey of women who tested positive for the BRCA genetic mutation for breast cancer, this research uses a social constructionist and feminist standpoint lens to understand the decision-making process that leads BRCA-positive women to choose genetic testing. Additionally, this research examines how they socially construct and understand their risk for developing breast cancer, as well as which treatment options they undergo post-testing. BRCA positive women re-frame their statistical medical risk for developing cancer and their post-testing treatment choices through a broad psychosocial context of engagement that also includes their social networks. Important psychosocial factors drive women's medical decisions, such as individual feelings of guilt and vulnerability, and the degree of perceived social support. Women who felt guilty and fearful that they might pass the BRCA gene to their children were more likely to undergo risk reducing surgery. Women with at least one daughter and women without children were more inclined toward the risk reducing surgery compared to those with only sons. These psychosocial factors and social network engagements serve as a "nexus of decision making" that does not, for the most part, mirror the medical assessments of statistical odds for hereditary cancer development, nor the specific treatment protocols outlined by the medical establishment. PMID- 26758256 TI - Sensorless cardiac phase detection for synchronized control of ventricular assist devices using nonlinear kernel regression model. AB - Recently, driving methods for synchronizing ventricular assist devices (VADs) with heart rhythm of patients suffering from severe heart failure have been receiving attention. Most of the conventional methods require implanting a sensor for measurement of a signal, such as electrocardiogram, to achieve synchronization. In general, implanting sensors into the cardiovascular system of the patients is undesirable in clinical situations. The objective of this study was to extract the heartbeat component without any additional sensors, and to synchronize the rotational speed of the VAD with this component. Although signals from the VAD such as the consumption current and the rotational speed are affected by heartbeat, these raw signals cannot be utilized directly in the heartbeat synchronization control methods because they are changed by not only the effect of heartbeat but also the change in the rotational speed itself. In this study, a nonlinear kernel regression model was adopted to estimate the instantaneous rotational speed from the raw signals. The heartbeat component was extracted by computing the estimation error of the model with parameters determined by using the signals when there was no effect of heartbeat. Validations were conducted on a mock circulatory system, and the heartbeat component was extracted well by the proposed method. Also, heartbeat synchronization control was achieved without any additional sensors in the test environment. PMID- 26758257 TI - Models of antenatal care to reduce and prevent preterm birth: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the effectiveness of models of antenatal care designed to prevent and reduce preterm birth (PTB) in pregnant women. METHODS: We conducted a search of seven electronic databases and reference lists of retrieved studies to identify trials from inception up to July 2014 where pregnant women, regardless of risk factors for pregnancy complications, were randomly allocated to receive an alternative model of antenatal care or routine care. We pooled risks of PTB to determine the effect of alternative care models in all pregnant women. We also assessed secondary maternal and infant outcomes, women's satisfaction and economic outcomes. RESULTS: 15 trials involving 22,437 women were included. Pregnant women in alternative care models were less likely to experience PTB (risk ratio 0.84, 95% CI 0.74 to 0.96). The subgroup of women randomised to midwife-led continuity models of antenatal care were less likely to experience PTB (0.78, 0.66 to 0.91) but there was no significant difference between this group and women allocated to specialised care (0.92, 0.76 to 1.12) (interaction test for subgroup differences p=0.20). Overall low-risk women in alternative care models were less likely to have PTB (0.74, 0.59 to 0.93), but this effect was not significantly different from that in mixed-risk populations (0.91, 0.79 to 1.05) (subgroup p=0.13). CONCLUSIONS: Alternative models of antenatal care for all pregnant women are effective in reducing PTB compared with routine care, but no firm conclusions could be drawn regarding the relative benefits of the two models. Future research should evaluate the impact of antenatal care models which include more recent interventions and predictive tests, and which also offer continuity of care by midwives throughout pregnancy. PROSPERO REGISTRATION NUMBER: CRD42014007116. PMID- 26758258 TI - Code Blue: methodology for a qualitative study of teamwork during simulated cardiac arrest. AB - INTRODUCTION: In-hospital cardiac arrest (IHCA) is a particularly vexing entity from the perspective of preparedness, as it is neither common nor truly rare. Survival from IHCA requires the coordinated efforts of multiple providers with different skill sets who may have little prior experience working together. Survival rates have remained low despite advances in therapy, suggesting that human factors may be at play. METHODS AND ANALYSIS: This qualitative study uses a quasiethnographic data collection approach combining focus group interviews with providers involved in IHCA resuscitation as well as analysis of video recordings from in situ-simulated cardiac arrest events. Using grounded theory-based analysis, we intend to understand the organisational, interpersonal, cognitive and behavioural dimensions of IHCA resuscitation, and to build a descriptive model of code team functioning. ETHICS AND DISSEMINATION: This ongoing study has been approved by the IRB at UC Davis Medical Center. RESULTS: The results will be disseminated in a subsequent manuscript. PMID- 26758259 TI - Global dietary quality, undernutrition and non-communicable disease: a longitudinal modelling study. AB - OBJECTIVES: To determine the relationship between global dietary energy availability and dietary quality, and nutrition-related health outcomes. DESIGN: A worldwide longitudinal modelling study using country-level data. Data on total dietary energy availability and dietary energy from 10 distinct food groups (as a proxy for dietary quality) were obtained from the FAO Food Balance Sheets database. Indicators of development were abstracted from the World Bank's World Development Indicators database. Data on nutrition and health outcomes were taken from the WHO mortality database and major cross-country analyses. We investigated associations of energy availability from food groups and health and nutrition outcomes in the combined data set using mixed effects models, while adjusting for measures of development. POPULATION: 124 countries over the period 1980-2009. MAIN OUTCOME MEASURES: Prevalence of stunting in children under 5 years and mortality rate from ischaemic heart disease (IHD) in adults aged 55+ years. RESULTS: From 1980 to 2009, global dietary energy availability increased, and rates of child stunting and adult IHD mortality declined. After adjustment for measures of development, increased total dietary energy availability was significantly associated with reduced stunting rates (-0.84% per 100 kcal increase in energy, 95% CI -0.97 to -0.72) and non-significantly associated with increased IHD mortality rates (by 4.2 deaths per 100,000/100 kcal increase, 95% CI -1.85 to 10.2). Further analysis demonstrated that the changing availability of energy from food groups (particularly fruit, vegetables, starchy roots, meat, dairy and sugar) was important in explaining the associations with health outcomes. CONCLUSIONS: Our study has demonstrated that by combining large, publicly available data sets, important patterns underlying trends in diet related health can be uncovered. These associations remain even after accounting for measures of development over a 30-year period. Further work and joined-up multisectoral thinking will be required to translate these patterns into policies that can improve nutrition and health outcomes globally. PMID- 26758261 TI - Determinants of never having tested for HIV among MSM in the Netherlands. AB - OBJECTIVES: Men who have sex with men (MSM) who are unaware of their HIV infection are more likely to infect others, and unable to receive treatment. Therefore, we aimed to identify the proportion and characteristics of Dutch MSM who never tested for HIV. METHODS: In 2010, the European MSM Internet Survey (EMIS) recruited 174,209 men from 38 countries through an anonymous online questionnaire in 25 languages. We analysed data from participants living in the Netherlands (N=3787). The outcome we investigated was having never (lifetime) been tested for HIV. RESULTS: A total of 770 MSM (20.4%) had never been tested for HIV. In multivariate regression analyses, not being from Amsterdam (adjusted OR, aOR 1.54, CI 1.17 to 2.03), with low education (aOR 1.28, CI 1.04 to 1.57) and low knowledge on HIV-testing (aOR 2.23, CI 1.37 to 3.64) were significantly associated with never having tested. Lower sexual risk (including having fewer sexual partners (aOR 2.19, CI 1.57 to 3.04) and no anal intercourse (aOR 5.99, CI 3.04 to 11.77)), and less social engagement (including being less out (aOR 1.93, CI 1.55 to 2.40)) were also associated with having never been tested. Additionally, 36.1% of MSM who never tested for HIV reported high-risk sexual behaviour that may have put them at HIV risk. CONCLUSIONS: MSM make their own risk assessments that inform their choices about HIV-testing. Nevertheless, MSM who were never tested may have been at risk for HIV, and remain important to target for HIV interventions. PMID- 26758260 TI - Protocol for a prospective, longitudinal, cohort study of postconcussive symptoms in children: the Take C.A.Re (Concussion Assessment and Recovery Research) study. AB - INTRODUCTION: A substantial minority of children who sustain a concussion suffer prolonged postconcussive symptoms. These symptoms can persist for more than 1 month postinjury and include physical, cognitive, behavioural and emotional changes. Those affected can develop significant disability, diminishing their quality of life. The precise prevalence of postconcussive symptoms following child concussion is unclear, with heterogeneous and at times conflicting results published regarding factors that predict children at risk for developing long lasting postconcussive symptoms. The aim of the Take C.A.Re (Concussion Assessment and Recovery Research) study is to provide an in-depth multidimensional description of the postconcussive recovery trajectories from a physical, neurocognitive and psychosocial perspective in the 3 months following concussion, with a focus on the early postconcussive period, and identification of factors associated with prolonged recovery. METHODS AND ANALYSIS: Take C.A.Re is a prospective, longitudinal study at a tertiary children's hospital, recruiting and assessing patients aged 5-<18 years who present to the emergency department with a concussion and following them at 1-4 days, 2 weeks, 1 month and 3 months postinjury. Multiple domains are assessed: postconcussive symptoms, balance and coordination, neurocognition, behaviour, quality of life, fatigue, post-traumatic stress symptoms, parental distress and family burden. 'Delayed recovery' is operationalised as the presence of >= 3 symptoms on the Post Concussive Symptoms Inventory rated as worse compared with baseline. Main analyses comprise analysis of variance (recovery trajectories, delayed vs normal recovery groups) and regression analyses of predictors of recovery (preinjury, acute and family factors). ETHICS AND DISSEMINATION: Ethical approval has been obtained through the Royal Children's Hospital Melbourne Human Research Ethics Committee (33122). We aim to disseminate the findings through international conferences, international peer-reviewed journals and social media. TRIAL REGISTRATION NUMBER: ACTRN12615000316505. PMID- 26758262 TI - Association study of TREM2 polymorphism rs75932628 with leucoaraiosis or Parkinson's disease in the Han Chinese population. AB - OBJECTIVES: The previously reported functional mutation rs75932628-T (p.R47H) in the triggering receptor expressed on myeloid cells 2 (TREM2) is a genetic risk factor for Alzheimer's disease, Parkinson's disease (PD) and frontotemporal dementia, in European populations. This study aims to assess the genetic association of the variant rs75932628-T with PD and leucoaraiosis (LA) in a Han Chinese population. SETTING: This population-based study was conducted in China by Xiamen University and its affiliated hospital. PARTICIPANTS: 308 patients with LA, 342 patients with PD and 198 healthy blood donors were recruited from the First Affiliated Hospital of Xiamen University. OUTCOME MEASURES: Genotyping was performed by molecular beacon real-time PCR and Sanger sequencing. RESULTS: None of our participants carried the rs75932628-T mutation. CONCLUSIONS: Our results corroborate and extend previous findings, concluding that the variant rs75932628 T (p.R47H) in TREM2 is not a risk factor for LA or PD in the Han Chinese population. PMID- 26758263 TI - Exploring general practitioners' views and experiences on suicide risk assessment and management of young people in primary care: a qualitative study in the UK. AB - OBJECTIVE: To explore general practitioner (GP) views and experiences of assessing, communicating with and managing suicidal young people with the aim of co-producing an educational intervention on youth suicide prevention tailored to GPs' perceived needs. DESIGN: Qualitative focus group study using framework analysis. SETTING: 5 inner city general practices in Nottingham. PARTICIPANTS: 28 GPs took part (9 males) with mean age of 37 years. The median number of years of professional experience was 13. Participants were recruited through convenience sampling based on accessibility, interest in the study and willingness to participate. RESULTS: 3 themes emerged from the data in relation to GP's attitudes and beliefs towards suicide; the challenges GPs experience when it comes to the assessment and management of suicide risk in young people; and optimal ways of addressing some of these challenges through the provision of specialist education and training targeting GPs' knowledge and clinical skills in this field. CONCLUSIONS: The findings revealed wide variations in the understanding and operationalisation of risk among GPs, which has subsequent implications to how GPs perceive risk should be assessed. GP education on suicide risk assessment and management in youth should promote a holistic understanding and assessment of risk and its individual, social and contextual influences. PMID- 26758264 TI - Preoperative prediction of potentially preventable morbidity after fast-track hip and knee arthroplasty: a detailed descriptive cohort study. AB - OBJECTIVES: Construction of a simple preoperative risk score for patients in high risk of potentially preventable 'medical' complications. Secondary objectives were to construct simple preoperative risk scores for 'severe medical', 'surgical' and 'total' potentially preventable complications. DESIGN: Prospective observational study. SETTING: Elective primary unilateral total hip and knee arthroplasty with prospectively collected preoperative patient characteristics; similar standardised fast-track protocols; evaluation of complications through discharge and medical records; and complete 90 days follow-up through nationwide databases. PARTICIPANTS: 8373 consecutive unselected total hip arthroplasty (THA) and knee arthroplasty from January 2010 to November 2012. RESULTS: There were 557 procedures (6.4%) followed by potentially preventable complications resulting in hospitalisation >4 days or readmission. Of 22 preoperative characteristics, 7 were associated with 379 (4.2%) potentially preventable 'medical' complications. Patients with >= 2 of the following, age >= 80 years, anticoagulant therapy, pulmonary disease, pharmacologically treated psychiatric disorder, anaemia and walking aids, composed 19.1% of the procedures; 55.7% constituted potentially preventable 'medical' complications that were mainly falls, mobilisation issues, pneumonias and cardiac arrhythmias. The number needed to be treated for a hypothetical intervention leading to 25% reduction in potentially preventable 'medical' complications was 34. THA, use of walking aids and cardiac disease were associated with 189 (2.2%) 'surgical' complications, but no clinically relevant preoperative prediction was possible. CONCLUSIONS: Preoperative identification of patients at high risk of preventable 'medical', but not 'surgical', complications is statistically possible. However, clinical relevance is limited. Future risk indices should differ between 'medical' and 'surgical' complications, and also consider 'preventability' of these. TRIAL REGISTRATION NUMBER: NCT01515670. PMID- 26758265 TI - Cost-effectiveness analysis of arthroscopic surgery compared with non-operative management for osteoarthritis of the knee. AB - OBJECTIVE: To determine the cost-effectiveness of arthroscopic surgery in addition to non-operative treatments compared with non-operative treatments alone in patients with knee osteoarthritis (OA). DESIGN, SETTING AND PARTICIPANTS: We conducted an economic evaluation alongside a single-centre, randomised trial among patients with symptomatic, radiographic knee OA (KL grade >= 2). INTERVENTIONS: Patients received arthroscopic debridement and partial resection of degenerative knee tissues in addition to optimised non-operative therapy, or optimised non-operative therapy only. MAIN OUTCOME MEASURES: Direct and indirect costs were collected prospectively over the 2-year study period. The effectiveness outcomes were the Western Ontario McMaster Osteoarthritis Index (WOMAC) and quality-adjusted life years (QALYs). Cost-effectiveness was estimated using the net benefit regression framework considering a range of willingness-to pay values from the Canadian public payer and societal perspectives. We calculated incremental cost-effectiveness ratios and conducted sensitivity analyses using the extremes of the 95% CIs surrounding mean differences in effect between groups. RESULTS: 168 patients were included. Patients allocated to arthroscopy received partial resection and debridement of degenerative meniscal tears (81%) and/or articular cartilage (97%). There were no significant differences between groups in use of non-operative treatments. The incremental net benefit was negative for all willingness-to-pay values. Uncertainty estimates suggest that even if willing to pay $400,000 to achieve a clinically important improvement in WOMAC score, or >=$50,000 for an additional QALY, there is <20% probability that the addition of arthroscopy is cost-effective compared with non operative therapies only. Our sensitivity analysis suggests that even when assuming the largest treatment effect, the addition of arthroscopic surgery is not economically attractive compared with non-operative treatments only. CONCLUSIONS: Arthroscopic debridement of degenerative articular cartilage and resection of degenerative meniscal tears in addition to non-operative treatments for knee OA is not an economically attractive treatment option compared with non operative treatment only, regardless of willingness-to-pay value. TRIAL REGISTRATION NUMBER: NCT00158431. PMID- 26758266 TI - Influence of pre-existing inflammation on the outcome of acute coronary syndrome: a cross-sectional study. AB - OBJECTIVES: Inflammation is a well-established risk factor for the development of coronary artery disease (CAD) and acute coronary syndrome (ACS). However, less is known about its influence on the outcome of ACS. The aim of this study was to determine if blood biomarkers of inflammation were associated specifically with acute myocardial infarction (MI) or unstable angina (UA) in patients with ACS. DESIGN: Cross-sectional study. SETTING: Patients admitted to the coronary care unit, via the emergency room, at a central county hospital over a 4-year period (1992-1996). PARTICIPANTS: In a substudy of Carlscrona Heart Attack Prognosis Study (CHAPS) of 5292 patients admitted to the coronary care unit, we identified 908 patients aged 30-74 years, who at discharge had received the diagnosis of either MI (527) or UA (381). MAIN OUTCOME MEASURES: MI or UA, based on the diagnosis set at discharge from hospital. RESULTS: When adjusted for smoking, age, sex and duration of chest pain, concentrations of plasma biomarkers of inflammation (high-sensitivity C reactive protein>2 mg/L (OR=1.40 (1.00 to 1.96) and fibrinogen (p for trend=0.035)) analysed at admission were found to be associated with MI over UA, in an event of ACS. A strong significant association with MI over UA was found for blood cell markers of inflammation, that is, counts of neutrophils (p for trend<0.001), monocytes (p for trend<0.001) and thrombocytes (p for trend=0.021), while lymphocyte count showed no association. Interestingly, eosinophil count (p for trend=0.003) was found to be significantly lower in patients with MI compared to those with UA. CONCLUSIONS: Our results show that, in patients with ACS, the blood cell profile and degree of inflammation at admission was associated with the outcome. Furthermore, our data suggest that a pre-existing low-grade inflammation may dispose towards MI over UA. PMID- 26758267 TI - Towards a 'patient-centred' operationalisation of the new dynamic concept of health: a mixed methods study. AB - OBJECTIVE: To evaluate among stakeholders the support for the new, dynamic concept of health, as published in 2011: 'Health as the ability to adapt and to self-manage', and to elaborate perceived indicators of health in order to make the concept measurable. DESIGN: A mixed methods study: a qualitative first step with interviews and focus groups, followed by a quantitative survey. PARTICIPANTS: Representatives of seven healthcare stakeholder domains, for example, healthcare providers, patients with a chronic condition and policymakers. The qualitative study involved 140 stakeholders; the survey 1938 participants. RESULTS: The new concept was appreciated, as it addresses people as more than their illness and focuses on strengths rather than weaknesses. Caution is needed as the concept requires substantial personal input of which not everyone is capable. The qualitative study identified 556 health indicators, categorised into six dimensions: bodily functions, mental functions and perception, spiritual/existential dimension, quality of life, social and societal participation, and daily functioning, with 32 underlying aspects. The quantitative study showed all stakeholder groups considering bodily functions to represent health, whereas for other dimensions there were significant differences between groups. Patients considered all six dimensions almost equally important, thus preferring a broad concept of health, whereas physicians assessed health more narrowly and biomedically. In the qualitative study, 78% of respondents considered their health indicators to represent the concept. CONCLUSIONS: To prevent confusion with health as 'absence of disease', we propose the use of the term 'positive health' for the broad perception of health with six dimensions, as preferred by patients. This broad perception deserves attention by healthcare providers as it may support shared decision-making in medical practice. For policymakers, the broad perception of 'positive health' is valuable as it bridges the gap between healthcare and the social domain, and by that it may demedicalise societal problems. PMID- 26758268 TI - Heat shock protein 60 affects behavioral improvement in a rat model of Parkinson's disease grafted with human umbilical cord mesenchymal stem cell derived dopaminergic-like neurons. AB - Parkinson's disease (PD) is a neurodegenerative disorder that is caused by a loss of dopaminergic (DAergic) neurons in mesencephalic substantia nigra (SN). Human umbilical cord mesenchymal stem cells (hUC-MSCs) are capable of self-renewal and differentiation into multiple cell lineages, including DAergic neurons. Thus, hUC MSCs could be a promising alternative to compensate for the loss of DAergic neurons in PD. In the current study, hUC-MSCs and hUC-MSCs-derived DAergic-like neurons were transplanted into the striatum and SN of a rat model of PD that is induced by 6-hydroxydopamine (6-OHDA). We evaluated their therapeutic effects on improving rotation behavior in the rat and on modulating the level of heat shock protein 60 (Hsp60) expression in the brain. After transplantation, an amelioration of rotation behavior was observed in rats that underwent cell grafting, and hUC-MSCs-derived DAergic-like neurons were superior to hUC-MSCs at inducing behavioral improvement. Western blot and immunohistochemistry analysis indicated significantly elevated levels of Hsp60 in cell-grafted rats compared to 6-OHDA-lesioned (PD) rats. These results demonstrate that hUC-MSCs-based cell transplantation is potential therapeutic treatment for PD, and hUC-MSCs-derived DAergic-like neurons appear to be favorable candidates for cell replacement therapy in PD. Finally, Hsp60 could be involved in a mechanism of behavioral recovery. PMID- 26758269 TI - Tumor lysis syndrome in the era of novel and targeted agents in patients with hematologic malignancies: a systematic review. AB - Effective new treatments are now available for patients with hematologic malignancies. However, their propensity to cause tumor lysis syndrome (TLS) has not been systematically examined. A literature search identified published Phase I-III clinical trials of monoclonal antibodies (otlertuzumab, brentuximab, obinutuzumab, ibritumomab, ofatumumab); tyrosine kinase inhibitors (alvocidib [flavopiridol], dinaciclib, ibrutinib, nilotinib, dasatinib, idelalisib, venetoclax [ABT-199]); proteasome inhibitors (oprozomib, carfilzomib); chimeric antigen receptor (CAR) T cells; and the proapoptotic agent lenalidomide. Abstracts from major congresses were also reviewed. Idelalisib and ofatumumab had no reported TLS. TLS incidence was <=5 % with brentuximab vedotin (for anaplastic large-cell lymphoma), carfilzomib and lenalidomide (for multiple myeloma), dasatinib (for acute lymphoblastic leukemia), and oprozomib (for various hematologic malignancies). TLS incidences were 8.3 and 8.9 % in two trials of venetoclax (for chronic lymphocytic leukemia [CLL]) and 10 % in trials of CAR T cells (for B-cell malignancies) and obinutuzumab (for non-Hodgkin lymphoma). TLS rates of 15 % with dinaciclib and 42 and 53 % with alvocidib (with sequential cytarabine and mitoxantrone) were seen in trials of acute leukemias. TLS mitigation was employed routinely in clinical trials of alvocidib and lenalidomide. However, TLS mitigation strategies were not mentioned or stated only in general terms for many studies of other agents. The risk of TLS persists in the current era of novel and targeted therapy for hematologic malignancies and was seen to some extent with most agents. Our findings underscore the importance of continued awareness, risk assessment, and prevention to reduce this serious potential complication of effective anticancer therapy. PMID- 26758271 TI - Constitutional pericentric inversion of chromosome 9 has no impact on survival in chronic myelogenous leukemia. PMID- 26758270 TI - Reprogramming of human peripheral blood monocytes to erythroid lineage by blocking of the PU-1 gene expression. AB - In hematopoietic system development, PU.1 and GATA-1 as lineage-specific transcription factors (TF) are expressed in common myeloid progenitors. The cross antagonism between them ascertains gene expression programs of monocytic and erythroid cells, respectively. This concept in transdifferentiation approaches has not been well considered yet, especially in intralineage conversion systems. To demonstrate whether PU.1 suppression induces monocyte lineage conversion into red blood cells, a combination of three PU.1-specific siRNAs was implemented to knock down PU.1 gene expression and generate the balance in favor of GATA-1 expression to induce erythroid differentiation. For this purpose, monocytes were isolated from human peripheral blood and transfected by PU.1 siRNAs. In transfected monocytes, the rate of PU.1 expression in mRNA level was significantly decreased until 0.38 +/- 0.118 when compared to untreated monocytes at 72 h (p value <=0.05) which resulted in significant overexpression of GATA1 of 16.1 +/- 0.343-fold compared to the untreated group (p value <=0.01). Subsequently, overexpression of hemoglobin (alpha 13.26 +/- 1.34-fold; p value<=0.0001) and beta-globin (37.55 +/- 16.56-fold; p value<=0.0001) was observed when compared to control groups. The results of western immunoblotting confirm those findings too. While, reduced expression of monocyte, CD14 gene, was observed in qRT-PCR and flow cytometry results. Our results suggest that manipulating the ratio of the two TFs in bifurcation differentiation pathways via applying siRNA technology can possibly change the cells' fate as a safe way for therapeutics application. PMID- 26758272 TI - Evaluating the sensitivity of EQ-5D in a sample of patients with type 2 diabetes mellitus in two tertiary health care facilities in Nigeria. AB - BACKGROUND: The EQ-5D instrument is arguably the most well-known and commonly used generic measure of health status internationally. Although the instrument has been employed in outcomes studies of diabetes mellitus in many countries, it has not yet been used in Nigeria. OBJECTIVE: This study was carried out to assess the sensitivity of the EQ-5D instrument in a sample of Nigerian patients with type 2 diabetes mellitus (T2DM). METHODS: A cross-sectional study was conducted using the EQ-5D instrument to assess the self-reported quality of life of patients with T2DM attending two tertiary healthcare facilities in south eastern Nigeria consenting patients completed the questionnaire while waiting to see a doctor. A priori hypotheses were examined using multiple regression analysis to model the relationship between the dependent variables (EQ VAS and EQ-5D Index) and hypothesized independent variables. RESULTS: A total of 226 patients with T2DM participated in the study. The average age of participants was 57 years (standard deviation 10 years) and 61.1% were male. The EQ VAS score and EQ-5D index averaged 66.19 (standard deviation 15.42) and 0.78 (standard deviation 0.21) respectively. Number of diabetic complications, number of co-morbidities, patient's age and being educated predicted EQ VAS score by -6.76, -6.15, -0.22, and 4.51 respectively. Also, number of diabetic complications, number of co morbidities, patient's age and being educated predicted EQ-5D index by -0.12, 0.07, -0.003, and 0.06 respectively.. CONCLUSION: Our findings indicate that the EQ-5D could adequately capture the burden of type 2 diabetes and related complications among Nigerian patients. PMID- 26758273 TI - Lancisi sign: giant C-V waves of tricuspid regurgitation. PMID- 26758275 TI - Primary gastric tumors in infants and children: 15 cases of 20-year report. AB - PURPOSE: Primary gastric tumors in infants and children are rare, and their diagnosis and treatment have not been standardized to date. The objective of the present retrospective study was to analyze the clinical characteristics of these tumors and explore possible improvements in their diagnosis and treatment. METHODS: The study included 15 children with a diagnosis of primary gastric tumor confirmed by pathology. Clinical manifestations, diagnostic methods and treatment were analyzed retrospectively, and postoperative conditions were assessed in follow-up evaluations. RESULTS: There were nine boys and six girls aged 8 months to 13 years. The main presenting symptoms were abdominal pain, melena, fever of undetermined origin and pallor. Children were assessed by ultrasound, CT and upper gastrointestinal barium meal or gastroscopy and showed abdominal blockage or polypoid space-occupying lesions. All patients underwent surgery as initial treatment, and four patients received postoperative chemotherapy. During the follow-up period from 3 to 92 months, four cases were lost, one patient died of metastatic disease, two patients showed recurrence, and the remaining patients were alive without recurrence or progression. CONCLUSIONS: Owing to the atypical and often asymptomatic presentation of primary gastric tumors, careful evaluation using imaging modalities is critical in suspicious cases. Most primary gastric tumors in infants and children are benign or borderline. The prognosis, except in gastric carcinoma, is excellent with close follow-up when complete resection is achieved. PMID- 26758274 TI - Crystal structure of the N-myristoylated lipopeptide-bound MHC class I complex. AB - The covalent conjugation of a 14-carbon saturated fatty acid (myristic acid) to the amino-terminal glycine residue is critical for some viral proteins to function. This protein lipidation modification, termed N-myristoylation, is targeted by host cytotoxic T lymphocytes (CTLs) that specifically recognize N myristoylated short peptides; however, the molecular mechanisms underlying lipopeptide antigen (Ag) presentation remain elusive. Here we show that a primate major histocompatibility complex (MHC) class I-encoded protein is capable of binding N-myristoylated 5-mer peptides and presenting them to specific CTLs. A high-resolution X-ray crystallographic analysis of the MHC class I:lipopeptide complex reveals an Ag-binding groove that is elaborately constructed to bind N myristoylated short peptides rather than prototypic 9-mer peptides. The identification of lipopeptide-specific, MHC class I-restricted CTLs indicates that the widely accepted concept of MHC class I-mediated presentation of long peptides to CTLs may need some modifications to incorporate a novel MHC class I function of lipopeptide Ag presentation. PMID- 26758276 TI - Development of an oncological-multidimensional prognostic index (Onco-MPI) for mortality prediction in older cancer patients. AB - PURPOSE: A multidimensional prognostic index (MPI) based on a comprehensive geriatric assessment (CGA) has been developed and validated in independent cohorts of older patients demonstrating good accuracy in predicting one-year mortality. The aim of this study was to develop a cancer-specific modified MPI (Onco-MPI) for mortality prediction in older cancer patients. METHODS: We enrolled 658 new cancer subjects >=70 years (mean age 77.1 years, 433 females, 65.8 %) attending oncological outpatient services from September 2004 to June 2011. The Onco-MPI was calculated according to a validated algorithm as a weighted linear combination of the following CGA domains: age, sex, basal and instrumental activities of daily living, Eastern Cooperative Oncology Group performance status, mini-mental state examination, body mass index, Cumulative Illness Rating Scale, number of drugs and the presence of caregiver. Cancer sites (breast 46.5 %, colorectal 21.3 %, lung 6.4 %, prostate 5.5 %, urinary tract 5.0 %, other 15.3 %) and cancer stages (I 37 %, II 22 %, III 19 %, IV 22 %) were also included in the model. All-cause mortality was recorded. Three grades of severity of the Onco-MPI score (low risk: 0.0-0.46, medium risk: 0.47-0.63, high risk: 0.64-1.0) were calculated using RECPAM method. Discriminatory power and calibration were assessed by estimating survival C-indices, along with 95 % confidence interval (CI) and the survival-based Hosmer-Lemeshow (HL) measures. RESULTS: One-year mortality incidence rate was 17.4 %. A significant difference in mortality rates was observed in Onco-MPI low risk compared to medium- and high risk patients (2.1 vs. 17.7 vs. 80.8 %, p < 0.0001). The discriminatory power of one-year mortality prediction of the Onco-MPI was very good (survival C-index 0.87, 95 % CI 0.84-0.90) with an excellent calibration (HL p value 0.854). CONCLUSION: Onco-MPI appears to be a highly accurate and well-calibrated predictive tool for one-year mortality in older cancer patients that can be useful for clinical decision making in this age group. PMID- 26758277 TI - Brain-Derived Neurotrophic Factor Knockdown Blocks the Angiogenic and Protective Effects of Angiotensin Modulation After Experimental Stroke. AB - Angiotensin type 1 receptor blockers (ARBs) have been shown to be neuroprotective and neurorestorative in experimental stroke. The mechanisms proposed include anti inflammatory, antiapoptotic effects, as well as stimulation of endogenous trophic factors leading to angiogenesis and neuroplasticity. We aimed to investigate the involvement of the neurotrophin, brain-derived neurotrophic factor (BDNF), in ARB mediated functional recovery after stroke. To achieve this aim, Wistar rats received bilateral intracerebroventricular (ICV) injections of short hairpin RNA (shRNA) lentiviral particles or nontargeting control (NTC) vector, to knock down BDNF in both hemispheres. After 14 days, rats were subjected to 90-min middle cerebral artery occlusion (MCAO) and received the ARB, candesartan, 1 mg/kg, or saline IV at reperfusion (one dose), then followed for another 14 days using a battery of behavioral tests. BDNF protein expression was successfully reduced by about 70 % in both hemispheres at 14 days after bilateral shRNA lentiviral particle injection. The NTC group that received candesartan showed better functional outcome as well as increased vascular density and synaptogenesis as compared to saline treatment. BDNF knockdown abrogated the beneficial effects of candesartan on neurobehavioral outcome, vascular density, and synaptogenesis. In conclusion, BDNF is directly involved in candesartan-mediated functional recovery, angiogenesis, and synaptogenesis. PMID- 26758279 TI - [Refractive changes in triple Descemet membrane endothelial keratoplasty]. AB - BACKGROUND: A hyperopic shift, i.e. a shift of refraction in the direction of plus values, in Descemet membrane endothelial keratoplasty (DMEK) is a well-known phenomenon. Because of the need to select an appropriate intraocular lens power this becomes particularly relevant in triple DMEK, which is a combination of DMEK and cataract surgery. OBJECTIVES: In this study the refractive changes induced by triple DMEK were evaluated. The underlying mechanisms were classified based on corneal topographical data. MATERIAL AND METHODS: The study involved a retrospective evaluation of 29 eyes from 26 patients who underwent triple DMEK. The preoperative and postoperative refractions were compared with the initially desired target refraction. Calculations concerning refractive power were performed using corneal topographical data and the Gullstrand formula. RESULTS: On average a hyperopic shift was observed. The operation led to steepening of the posterior corneal surface and flattening of the anterior corneal surface. Both resulted in a reduction of corneal refractive power but changes of the posterior corneal surface were identified as the most important factor. Those patients in whom both eyes had been operated on, showed very similar postoperative topography for both eyes, irrespective of the preoperative values. CONCLUSION: The observed hyperopic shift was a mean value. A prediction of refraction in the individual cases by means of the available parameters was not possible. In general, the selection of an intraocular lens with a stronger myopic target refraction than that for standard cataract surgery is recommended. PMID- 26758280 TI - [Psychosomatic aspects of dry eye syndrome]. AB - BACKGROUND: Patients with dry eye syndrome are known to suffer from anxiety and depression. OBJECTIVES: Analysis of psychological disorders in therapy-resistant dry eye syndrome. MATERIAL AND METHODS: A retrospective analysis of the training for interactive psychiatric screening (TRIPS) questionnaire from 110 patients with therapy-resistant dry eye syndrome was carried out. The results of the questionnaire allow the diagnosis of psychological disorders and vegetative disorders. Patients were divided into groups with anxiety, depression, mixed diagnoses, vegetative disorders and no diagnosis. A sicca score was used for assessment of dryness comprising the Schirmer test, measurement of tear meniscus, break up time, lipid layer thickness, the use of fluorescein and rose bengal staining tests and the subjective visual analogue scale. The diagnosis of dry eye syndrome was compared with the psychological disorders of anxiety and depression. RESULTS: Of the patients 52.7 % had psychological disorders with anxiety in 21.8 %, depression in 15.3 %, mixed diagnoses in 14.5 %, dystonia in 25.4 % and in 22.7 % no psychological disorders were diagnosed. General anxiety was frequent and panic disorders were often associated with other kinds of anxiety. Severe depression, such as bipolar disorder was rare. Dry eye scores were highest in the mixed group (0.59), and lowest in the group with mild anxiety (0.38). No single sicca phase disorder could be correlated with any of the psychological diagnoses. CONCLUSION: Patients with therapy-resistant dry eye syndrome often suffer from anxiety and depression. The psychological stress acts on the nervous system to suppress lacrimal gland function. Further investigation of the correlation between the lacrimal tear film phase and psychological disorders is recommended. Knowledge of personality disorders may allow psychological support that would improve the treatment options for dry eye syndrome. PMID- 26758278 TI - Non-Ceruloplasmin Copper Distincts Subtypes in Alzheimer's Disease: a Genetic Study of ATP7B Frequency. AB - Meta-analyses show that serum copper non-bound-to-ceruloplasmin (non-Cp-Cu) is higher in patients with Alzheimer's disease (AD). ATP7B gene variants associate with AD, modulating the size of non-Cp-Cu pool. However, a dedicated genetic study comparing AD patients after stratification for a copper biomarker to demonstrate the existence of a copper subtype of AD has not yet been carried out. An independent patient sample of 287 AD patients was assessed for non-Cp-Cu serum concentrations, rs1801243, rs1061472, and rs732774 ATP7B genetic variants and the APOE4 genotype. Patients were stratified into two groups based on a non-Cp-Cu cutoff (1.9 MUM). Single-locus and haplotype-group analyses were performed to define their frequencies in dependence of the non-Cp-Cu group. The two AD subgroups did not differ regarding age, sex, MMSE score, or APOE4 frequency allele, while they did differ regarding non-Cp-Cu concentrations in serum, allele, genotype, and haplotype frequencies of rs1061472 A > G and rs732774 C > T after multiple testing corrections. AD patients with a GG genotype had a 1.76 fold higher risk of having a non-Cp-Cu higher than 1.9 MUmol/L (p = 0.029), and those with a TT genotype for rs732774 C > T of 1.8-fold (p = 0.018). After 100,000 permutations for multiple testing corrections, the haplotype containing the AC alleles appeared more frequently in AD patients with normal non-Cp-Cu [43 vs. 33 %; Pm = 0.03], while the haplotype containing the GT risk alleles appeared more frequently in the higher non-Cp-Cu AD (66 vs. 55 %; Pm = 0.01). Genetic heterogeneity sustains a copper AD metabolic subtype; non-Cp-Cu is a marker of this copper AD. PMID- 26758281 TI - Effects of the potential lithium-mimetic, ebselen, on brain neurochemistry: a magnetic resonance spectroscopy study at 7 tesla. AB - RATIONALE: Lithium is an effective treatment for bipolar disorder, but safety issues complicate its clinical use. The antioxidant drug, ebselen, may be a possible lithium-mimetic based on its ability to inhibit inositol monophosphatase (IMPase), an action which it shares with lithium. OBJECTIVES: Our primary aim was to determine whether ebselen lowered levels of inositol in the human brain. We also assessed the effect of ebselen on other brain neurometabolites, including glutathione, glutamate, glutamine, and glutamate + glutamine (Glx) METHODS: Twenty healthy volunteers were tested on two occasions receiving either ebselen (3600 mg over 24 h) or identical placebo in a double-blind, random-order, crossover design. Two hours after the final dose of ebselen/placebo, participants underwent proton magnetic resonance spectroscopy ((1)H MRS) at 7 tesla (T) with voxels placed in the anterior cingulate and occipital cortex. Neurometabolite levels were calculated using an unsuppressed water signal as a reference and corrected for individual cerebrospinal fluid content in the voxel. RESULTS: Ebselen produced no effect on neurometabolite levels in the occipital cortex. In the anterior cingulate cortex, ebselen lowered concentrations of inositol (p = 0.028, Cohen's d = 0.60) as well as those of glutathione (p = 0.033, d = 0.58), glutamine (p = 0.024, d = 0.62), glutamate (p = 0.01, d = 0.73), and Glx (p = 0.001, d = 1.0). CONCLUSIONS: The study suggests that ebselen produces a functional inhibition of IMPase in the human brain. The effect of ebselen to lower glutamate is consistent with its reported ability to inhibit the enzyme, glutaminase. Ebselen may have potential as a repurposed treatment for bipolar disorder. PMID- 26758283 TI - Differential effects of vilazodone versus citalopram and paroxetine on sexual behaviors and serotonin transporter and receptors in male rats. AB - RATIONALE: Sexual side effects are commonly associated with selective serotonin reuptake inhibitor (SSRI) treatment. Some evidence suggest that activation of 5 HT1A receptors attenuates SSRI-induced sexual dysfunction. OBJECTIVE: This study in male rats compared the effects of vilazodone, an antidepressant with SSRI and 5-HT1A receptor partial agonist activity, with other prototypical SSRIs (citalopram and paroxetine) on sexual behaviors and 5-HT receptors (5-HT1A and 5 HT2A) and transporter (5-HTT) levels in select forebrain regions of the limbic system using quantitative autoradiography. METHODS: Rats received vilazodone (1, 3, and 10 mg/kg), citalopram (10 and 30 mg/kg), or paroxetine (10 mg/kg) treatment for 14 days. Sexual behaviors (frequency and latency of mounts, intromissions, and ejaculations) were measured in the presence of an estrous female rat on days 1 (acute), 7 (subchronic), and 14 (chronic). RESULTS: Vilazodone-treated rats exhibited no sexual dysfunction compared with controls; in contrast, the citalopram- and paroxetine-treated rats exhibited impaired copulatory and ejaculatory behaviors after subchronic and chronic treatments. Chronic vilazodone treatment markedly decreased 5-HT1A receptor levels in cortical and hippocampal regions, while the SSRIs increased levels of this receptor in similar regions. All chronic treatments reduced 5-HTT levels across the forebrain; however, the magnitude of the decrease was considerably smaller for vilazodone than for the SSRIs. CONCLUSIONS: The current studies showed that chronic treatment with vilazodone, in contrast to citalopram and paroxetine, was not associated with diminished sexual behaviors in male rats, which may be related to the differential effects of vilazodone on 5-HT1A receptor and 5-HTT levels relative to conventional SSRIs. PMID- 26758285 TI - Roles of Escherichia coli ZinT in cobalt, mercury and cadmium resistance and structural insights into the metal binding mechanism. AB - Escherichia coli ZinT is a metal binding protein involved in zinc homeostasis, with additional putative functions in the resistance against other metals. Herein, a method was designed and implemented to evaluate from a structural and functional viewpoint metal binding to E. coli ZinT in 96-well microtiter plates. The isolated ZinT was mixed with several metal ions and their binding ability was determined by differential scanning fluorimetry. From the positive hits, six metal ions were evaluated in terms of their toxicity towards an E. coli strain depleted of ZinT (DeltazinT) using as control a strain deleted in the galT gene (DeltagalT). The different sensitivities of each strain to the tested metals revealed novel roles of ZinT in the resistance to cobalt, cadmium and mercury. This approach provides a valuable and reliable platform for the analysis of metal binding and its functional implications, extendable to other metal binding proteins. In combination with the developed platform, structural studies were performed with ZinT, with the zinc-loaded crystallographic structure being obtained at 1.79 A resolution. Besides the canonical zinc-binding site located near the N-terminus, the herein reported dimeric ZinT structure unravelled extra zinc binding sites that support its role in metal loading and/or transport. Altogether, the designed experimental platform allowed revealing new roles for the ZinT protein in microbial resistance to heavy metal toxicity, as well as structural insights into the ZinT metal binding mechanism. PMID- 26758284 TI - The novel ketamine analog methoxetamine produces dissociative-like behavioral effects in rodents. AB - RATIONALE: Methoxetamine (MXE) is a ketamine analog sold online that has been subject to widespread abuse for its dissociative and hallucinogenic effects. Previous studies have shown that MXE has high affinity for the phencyclidine (PCP) binding site located within the channel pore of the NMDA receptor (NMDAR), but little is known about its behavioral effects. Dissociative anesthetics such as ketamine and PCP produce a characteristic behavioral profile in rats that includes locomotor hyperactivity and disruption of prepulse inhibition (PPI) of acoustic startle. METHODS: The goal of the present investigation was to determine whether MXE produces PCP-like effects in Sprague-Dawley rats using the PPI paradigm and the behavioral pattern monitor (BPM), which enables analyses of patterns of locomotor activity and investigatory behavior. PPI studies were conducted with several other uncompetitive NMDAR antagonists that produce dissociative effects in humans, including PCP, the S-(+) and R-(-) isomers of ketamine, and N-allylnormetazocine (NANM; SKF-10,047). RESULTS: MXE disrupted PPI when administered at 3 and 10 mg/kg SC. The rank order of potency of MXE and the other test compounds in the PPI paradigm (PCP > MXE > S-(+)-ketamine > NANM > R-( )-ketamine) parallels their affinities for the PCP binding site reported in the literature. When tested in the BPM, 10 mg/kg MXE induced locomotor hyperactivity, reduced the number of rearings, increased the roughness of locomotor paths, and produced perseverative patterns of locomotion. Administration of PCP (2.25 and 6.75 mg/kg, SC) produced a similar profile of effects in the BPM. CONCLUSIONS: These results indicate that MXE produces a behavioral profile similar to that of other psychotomimetic uncompetitive NMDAR antagonists. Our findings support the classification of MXE as a dissociative drug and suggest that it likely has effects and abuse potential similar to that of PCP and ketamine. PMID- 26758287 TI - Unravelling the hydrogen absorption process in Pd overlayers on a Au(111) surface. AB - The hydrogen absorption into overlayers of Pd deposited on Au(111) has been investigated by density functional theory (DFT). Hydrogen concentrations, absorption environments, and geometrical and electronic effects have been analyzed, seeking for a better understanding of the general principles governing the process and the effect of foreign supports. The results show that the absorption is more favored than in pure Pd leading to lower absorption energies and less repulsive interactions due to the surface expansion induced by the gold larger lattice constant. Our findings also suggest that the hydrogen absorption process is more favorable for a less number of Pd overlayers. This situation changes gradually until the substrate influence is no longer detected and the pure palladium nature appears. An entangled combination of repulsive forces, strain effect, structural ordering and chemical affinity has been found. The kinetics of hydrogen absorption has been studied as well. Two cases were explored: (1) the absorption of an adsorbed hydrogen atom and (2) the bond breaking and penetration of a H2 molecule. PMID- 26758286 TI - Ectopic expression of R3 MYB transcription factor gene OsTCL1 in Arabidopsis, but not rice, affects trichome and root hair formation. AB - In Arabidopsis, a MYB-bHLH-WD40 (MBW) transcriptional activator complex activates the homeodomain protein gene GLABRA2 (GL2), leading to the promotion of trichome formation and inhibition of root hair formation. The same MBW complex also activates single-repeat R3 MYB genes. R3 MYBs in turn, play a negative feedback role by competing with R2R3 MYB proteins for binding bHLH proteins, thus blocking the formation of the MBW complex. By BLASTing the rice (Oryza sativa) protein database using the entire amino acid sequence of Arabidopsis R3 MYB transcription factor TRICHOMELESS1 (TCL1), we found that there are two genes in rice genome encoding R3 MYB transcription factors, namely Oryza sativa TRICHOMELESS1 (OsTCL1) and OsTCL2. Expressing OsTCL1 in Arabidopsis inhibited trichome formation and promoted root hair formation, and OsTCL1 interacted with GL3 when tested in Arabidopsis protoplasts. Consistent with these observations, expression levels of GL2, R2R3 MYB transcription factor gene GLABRA1 (GL1) and several R3 MYB genes were greatly reduced, indicating that OsTCL1 is functional R3 MYB. However, trichome and root hair formation in transgenic rice plants overexpressing OsTCL1 remained largely unchanged, and elevated expression of OsGL2 was observed in the transgenic rice plants, indicating that rice may use different mechanisms to regulate trichome formation. PMID- 26758289 TI - 'Atlas shrugged': congenital lateral angular irreducible atlantoaxial dislocation: a case series of complex variant and its management. AB - PURPOSE: The commonly described congenital atlanto-axial dislocation and Basilar Invagination is antero-posterior or rotational or vertical plane. However, congenital dislocation in lateral plane has received scant attention. The purpose of this manuscript is to describe this unusual entity and discuss its management. MATERIALS AND METHODS: The clinic-radiological feature of seven patients with congenital lateral angular AAD (CLAAAD) were studied and managed. The unilateral C1 facet had subluxed lateral to C2-3 complex. The C1 and C2 facets were drilled comprehensively and repositioned with distraction, placement of metallic spacers and facet manipulation after insertion of screws. The post operative outcome was studied. RESULTS: The presentation is usually with neck tilt (progressive in 3) and/or progressive spastic quadriparesis. The mean C1-2 tilt was 25.2 degrees . C1 was bifid in six patients. C1 lateral mass was assimilated with occipital condyle on dislocated side in and the other side was normal (6 patients). The dislocated C1-2 joint was abnormally oblique as compared to contralateral side. The relationship of occiput and C1 was normal. Correction of dislocation and lateral tilt was achieved in all patients with subsequent correction of neck tilt and deficits. One patient required reoperation. CONCLUSIONS: The acute angulation of joint on one side and near normal on other side leads to differential vertical movement, further accentuated by splaying of bifid C1. The entity is seen in young patients and often present with neck tilt and spastic quadriparesis. Management requires reshaping the joints and facet manipulation. If the reshaping is inappropriate, the joint is likely to redislocate before fusion occurs. PMID- 26758282 TI - Mad men, women and steroid cocktails: a review of the impact of sex and other factors on anabolic androgenic steroids effects on affective behaviors. AB - RATIONALE: For several decades, elite athletes and a growing number of recreational consumers have used anabolic androgenic steroids (AAS) as performance enhancing drugs. Despite mounting evidence that illicit use of these synthetic steroids has detrimental effects on affective states, information available on sex-specific actions of these drugs is lacking. OBJECTIVES: The focus of this review is to assess information to date on the importance of sex and its interaction with other environmental factors on affective behaviors, with an emphasis on data derived from non-human studies. METHODS: The PubMed database was searched for relevant studies in both sexes. RESULTS: Studies examining AAS use in females are limited, reflecting the lower prevalence of use in this sex. Data, however, indicate significant sex-specific differences in AAS effects on anxiety-like and aggressive behaviors, interactions with other drugs of abuse, and the interplay of AAS with other environmental factors such as diet and exercise. CONCLUSIONS: Current methods for assessing AAS use have limitations that suggest biases of both under- and over-reporting, which may be amplified for females who are poorly represented in self-report studies of human subjects and are rarely used in animal studies. Data from animal literature suggest that there are significant sex-specific differences in the impact of AAS on aggression, anxiety, and concomitant use of other abused substances. These results have relevance for human females who take these drugs as performance-enhancing substances and for transgender XX individuals who may illicitly self-administer AAS as they transition to a male gender identity. PMID- 26758288 TI - Where Do Epigenetics and Developmental Origins Take the Field of Developmental Psychopathology? AB - The time is ripe for upgrading or rethinking the assumed paradigms for how we study developmental psychopathology. The classic transactional models appear robust but need specification in terms of biological and psychosocial processes. That specification is increasingly tractable due to developments in genetics, epigenetics, the measurement of psychosocial processes, and theory and data on developmental origins of health and disease. This essay offers a high-level view of where the field has been and where it may be going in regard to nosology and conceptions of etiology. Remarks seek to consider rapidly evolving contexts not only for children, but also for the science itself due to progress in our field and in neighboring fields. Illustrations are provided as to how syndromal nosology can be enriched and advanced by careful integration with biologically relevant behavioral dimensions and application of quantitative methods. It is concluded that a revised, forward-looking, transactional model of abnormal child psychology will incorporate prenatal and postnatal developmental programming, epigenetic mechanisms and their associated genotype x environment interactions, and inflammatory processes as a potential common mediator influencing numerous health and mental health conditions. PMID- 26758290 TI - Teriflunomide in Patients with Relapsing-Remitting Forms of Multiple Sclerosis. AB - Teriflunomide is a once-daily oral agent that has been licensed in the EU since August 2013 for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS). More recently (September 2014), the EU summary of product characteristics (SmPC) was updated to include data from patients with a first clinical demyelinating event. This review examines the EU SmPC for teriflunomide, with reference to key clinical and safety outcomes and practical considerations for prescribing physicians. In two phase III trials (TEMSO and TOWER) in patients with relapsing forms of MS, teriflunomide 14 mg significantly reduced the annualized relapse rate and the risk of confirmed disability progression sustained for at least 12 weeks. Magnetic resonance imaging (MRI) total lesion volume, gadolinium-enhancing lesions, and unique active lesions were reduced with teriflunomide treatment in TEMSO. In the TOPIC study, in patients with a first clinical demyelinating event, teriflunomide treatment significantly reduced the time to a second clinical episode (relapse). Across the clinical studies, teriflunomide was generally well tolerated; adverse events reported in >= 10% of teriflunomide-treated patients were diarrhea, nausea, increased alanine aminotransferase, and alopecia. Data from the clinical development program support the use of teriflunomide in a broad spectrum of patients with RRMS. PMID- 26758291 TI - Pathologic features of metastatic lymph nodes identified from prophylactic central neck dissection in patients with papillary thyroid carcinoma. AB - The importance of pathologic features of metastatic lymph nodes (LNs), such as size, number, and extranodal extension, has been recently emphasized in patients with papillary thyroid carcinoma (PTC). We evaluated the characteristics of metastatic LNs identified after prophylactic central neck dissection (CND) in patients with PTC. We performed a retrospective review of 1,046 patients who underwent unilateral or bilateral thyroidectomy with ipsilateral prophylactic CND. We reviewed the characteristics of the metastatic LNs and analyzed their correlation to the clinicopathologic characteristics of the primary tumor. Cervical LN metastasis after prophylactic CND was identified in 280 out of 1046 patients (26.8 %). The size of metastatic foci (>=2 mm) was independently correlated with primary tumor size (>=1 cm) (p = 0.016, OR = 1.88). Primary tumor size (>=1 cm) was also correlated to the number of metastatic LNs (>=5) (p = 0.004, OR = 3.14) and extranodal extension (p = 0.021, OR = 2.41) in univariate analysis. The size of the primary tumor affects pathologic features of subclinical LN metastasis in patients with PTC. Patients with primary tumors >=1 cm have an increased risk of larger LN metastases (>=2 mm), an increased number of LN metastases (>=5), and a higher incidence of ENE, which should be considered in decision for prophylactic CND. PMID- 26758293 TI - Genetic linkage of capsid protein-encoding RNA segments in group A equine rotaviruses. AB - Rotavirus virions are formed by three concentric protein layers that enclose the 11 dsRNA genome segments and the viral proteins VP1 and VP3. Interactions amongst the capsid proteins (VP2, VP6, VP7 and VP4) have been described to play a major role in viral fitness, whilst restricting the reassortment of the genomic segments during co-infection with different rotavirus strains. In this work we describe and characterize the linkage between VP6 and VP7 proteins based on structural and genomic analyses of group A rotavirus strains circulating in Argentinean horses. Strains with the VP7 genotype G3 showed a strong association with the VP6 genotype I6, whilst strains with G14 were associated with the I2 genotype. Most of the differences on the VP6 and VP7 proteins were observed in interactive regions between the two proteins, suggesting that VP6 : VP7 interactions may drive the co-evolution and co-segregation of their respective gene segments. PMID- 26758294 TI - Biotechnology of riboflavin. AB - Riboflavin (vitamin B2) production has shifted from chemical synthesis to exclusive biotechnological synthesis in less than 15 years. The underlying extraordinary achievement in metabolic engineering and bioprocess engineering is reviewed in this article with regard to the two most important industrial producers Bacillus subtilis and Ashbya gossypii. The respective biosynthetic routes and modifications are discussed, and also the regulation of riboflavin synthesis. As the terminal biosynthesis of riboflavin starts from the two precursors, ribulose 5-phosphate and guanosine triphosphate (GTP), both strains have been optimized for an improved flux through the pentose phosphate pathway as well as the purine biosynthetic pathway. Specific targets for improvement of A. gossypii were the increase of the glycine pool and the increase of carbon flow through the glyoxylic shunt. In B. subtilis, research interest, amongst others, has focused on gluconeogenesis and overexpression of the rib operon. In addition, insight into large-scale production of vitamin B2 is given, as well as future prospects and possible developments. PMID- 26758292 TI - Band limited chirp stimulation in vestibular evoked myogenic potentials. AB - Air conducted vestibular evoked myogenic potentials (VEMP) can be elicited by various low frequency and intense sound stimuli, mainly clicks or short tone bursts (STB). Chirp stimuli are increasingly used in diagnostic audiological evaluations as an effective means to obtain acoustically evoked responses in narrowed or extended frequency ranges. We hypothesized in this study that band limited chirp stimulation, which covers the main sensitivity range of sound sensitive otolithic afferents (around 500 Hz), might be useful for application in cervical and ocular VEMP to air conduction. For this purpose we designed a chirp stimulus ranging 250-1000 Hz (up chirp). The chirp stimulus was delivered with a stimulus intensity of 100 dB nHL in normal subjects (n = 10) and patients with otolith involvement (vestibular neuritis) (n = 6). Amplitudes of the designed chirp ("CW-VEMP-chirp, 250-1000 Hz") were compared with amplitudes of VEMPs evoked by click stimuli (0.1 ms) and a short tone burst (STB, 1-2-1, 8 ms, 500 Hz). CVEMPs and oVEMPs were detectable in 9 of 10 normal individuals. Statistical evaluation in healthy patients revealed significantly larger cVEMP and oVEMP amplitudes for CW-VEMP-chirp (250-1000 Hz) stimuli. CVEMP amplitudes evoked by CW VEMP-chirp (250-1000 Hz) showed a high stability in comparison with click and STB stimulation. CW-VEMP-chirp (250-1000 Hz) showed abnormal cVEMP and oVEMP amplitudes in patients with vestibular neuritis, with the same properties as click and STB stimulated VEMPs. We conclude that the designed CW-VEMP-chirp (250 1000 Hz) is an effective stimulus which can be further used in VEMP diagnostic. Since a chirp stimulus can be easily varied in its properties, in particular with regard to frequency, this might be a promising tool for further investigations. PMID- 26758295 TI - Influence of surface charge, binding site residues and glycosylation on Thielavia terrestris cutinase biochemical characteristics. AB - Cutinases are esterases of industrial importance for applications in recycling and surface modification of polyesters. The cutinase from Thielavia terrestris (TtC) is distinct in terms of its ability to retain its stability and activity in acidic pH. Stability and activity in acidic pHs are desirable for esterases as the pH of the reaction tends to go down with the generation of acid. The pH stability and activity are governed by the charged state of the residues involved in catalysis or in substrate binding. In this study, we performed the detailed structural and biochemical characterization of TtC coupled with surface charge analysis to understand its acidic tolerance. The stability of TtC in acidic pH was rationalized by evaluating the contribution of charge interactions to the Gibbs free energy of unfolding at varying pHs. The activity of TtC was found to be limited by substrate binding affinity, which is a function of the surface charge. Additionally, the presence of glycosylation affects the biochemical characteristics of TtC owing to steric interactions with residues involved in substrate binding. PMID- 26758297 TI - New PhiBT1 site-specific integrative vectors with neutral phenotype in Streptomyces. AB - Integrative plasmids are one of the best options to introduce genes in low copy and in a stable form into bacteria. The PhiC31-derived plasmids constitute the most common integrative vectors used in Streptomyces. They integrate at different positions (attB and pseudo-attB sites) generating different mutations. The less common PhiBT1-derived vectors integrate at the unique attB site localized in the SCO4848 gene (S. coelicolor genome) or their orthologues in other streptomycetes. This work demonstrates that disruption of SCO4848 generates a delay in spore germination. SCO4848 is co-transcribed with SCO4849, and the spore germination phenotype is complemented by SCO4849. Plasmids pNG1-4 were created by modifying the PhiBT1 integrative vector pMS82 by introducing a copy of SCO4849 under the control of the promoter region of SCO4848. pNG2 and pNG4 also included a copy of the P ermE * in order to facilitate gene overexpression. pNG3 and pNG4 harboured a copy of the bla gene (ampicillin resistance) to facilitate selection in E. coli. pNG1-4 are the only integrative vectors designed to produce a neutral phenotype when they are integrated into the Streptomyces genome. The experimental approach developed in this work can be applied to create phenotypically neutral integrative plasmids in other bacteria. PMID- 26758296 TI - Bioreactors for high cell density and continuous multi-stage cultivations: options for process intensification in cell culture-based viral vaccine production. AB - With an increasing demand for efficacious, safe, and affordable vaccines for human and animal use, process intensification in cell culture-based viral vaccine production demands advanced process strategies to overcome the limitations of conventional batch cultivations. However, the use of fed-batch, perfusion, or continuous modes to drive processes at high cell density (HCD) and overextended operating times has so far been little explored in large-scale viral vaccine manufacturing. Also, possible reductions in cell-specific virus yields for HCD cultivations have been reported frequently. Taking into account that vaccine production is one of the most heavily regulated industries in the pharmaceutical sector with tough margins to meet, it is understandable that process intensification is being considered by both academia and industry as a next step toward more efficient viral vaccine production processes only recently. Compared to conventional batch processes, fed-batch and perfusion strategies could result in ten to a hundred times higher product yields. Both cultivation strategies can be implemented to achieve cell concentrations exceeding 10(7) cells/mL or even 10(8) cells/mL, while keeping low levels of metabolites that potentially inhibit cell growth and virus replication. The trend towards HCD processes is supported by development of GMP-compliant cultivation platforms, i.e., acoustic settlers, hollow fiber bioreactors, and hollow fiber-based perfusion systems including tangential flow filtration (TFF) or alternating tangential flow (ATF) technologies. In this review, these process modes are discussed in detail and compared with conventional batch processes based on productivity indicators such as space-time yield, cell concentration, and product titers. In addition, options for the production of viral vaccines in continuous multi-stage bioreactors such as two- and three-stage systems are addressed. While such systems have shown similar virus titers compared to batch cultivations, keeping high yields for extended production times is still a challenge. Overall, we demonstrate that process intensification of cell culture-based viral vaccine production can be realized by the consequent application of fed-batch, perfusion, and continuous systems with a significant increase in productivity. The potential for even further improvements is high, considering recent developments in establishment of new (designer) cell lines, better characterization of host cell metabolism, advances in media design, and the use of mathematical models as a tool for process optimization and control. PMID- 26758298 TI - The gastrointestinal tract microbiota of the Japanese quail, Coturnix japonica. AB - Microbiota in the gastrointestinal tract (GIT) plays an essential role in the health and well-being of the host. With the exception of chickens, this area has been poorly studied within birds. The avian GIT harbours unique microbial communities. Birds require rapid energy bursts to enable energy-intensive flying. The passage time of feed through the avian GIT is only 2-3.5 h, and thus requires the presence of microbiota that is extremely efficient in energy extraction. This investigation has used high-throughput 16S rRNA gene sequencing to explore the GIT microbiota of the flighted bird, the Japanese quail (Coturnix japonica). We are reporting, for the first time, the diversity of bacterial phylotypes inhabiting all major sections of the quail GIT including mouth, esophagus, crop, proventriculus, gizzard, duodenum, ileum, cecum, large intestine and feces. Nine phyla of bacteria were found in the quail GIT; however, their distribution varied significantly between GIT sections. Cecal microbiota was the most highly differentiated from all the other communities and showed highest richness at an OTU level but lowest richness at all other taxonomic levels being comprised of only 15 of total 57 families in the quail GIT. Differences were observed in the presence and absence of specific phylotypes between sexes in most sections. PMID- 26758299 TI - Genetic and biochemical characterization of genes involved in hyaluronic acid synthesis in Streptococcus zooepidemicus. AB - The biosynthetic pathway for hyaluronic acid (HA) has been proposed; however, a thorough genetic and functional analysis is required to further elucidate the roles of genes involved in HA production. Previously, we developed a markerless gene-deletion system for Streptococcus zooepidemicus and confirmed that hasA is essential for HA synthesis. Here, we constructed a comprehensive set of deletion mutants and investigated the roles of ten additional predicted genes in the HA synthetic pathway. Phenotypic assays revealed that all ten genes play a role in cell growth and/or HA synthesis. As expected, the deletion of hasA or hasB abolished HA production with little effect on growth, while the deletion of genes that are also required for peptidoglycan biosynthesis (hasE, glmM, and glmS) significantly reduced cell growth and HA production. Either of the glmU homologues (hasD and gcaD) was sufficient for optimal growth and the mucoid phenotype, while no double mutant could be isolated. Of the two UDP-glucose pyrophosphorylase (UGPase) paralogues, the operon-encoded hasC1 was responsible for 65 % of the activity, while hasC2 was responsible for the remaining 35 %. The deletion of hasC1 had no effect on cell growth and caused only a moderate decrease in the UDP-glucose level and HA production. The deletion of both hasC1 and hasC2 resulted in a severe growth defect and negligible UDP-glucose accumulation, HA production, and pyrophosphorylase activity. Of the two phosphoglucomutase paralogues, pgm1 and pgm2, the former is responsible for around 10 % of activity, while the latter is responsible for 90 %. The deletion of pgm1 showed no apparent effect on HA synthesis and growth, while the deletion of pgm2 resulted in the abolishment of HA synthesis and a significantly slower growth. These results should guide the metabolic engineering of S. zooepidemicus to improve HA productivity and quality. PMID- 26758300 TI - Utilization of protein-rich residues in biotechnological processes. AB - A drawback of biotechnological processes, where microorganisms convert biomass constituents, such as starch, cellulose, hemicelluloses, lipids, and proteins, into wanted products, is the economic feasibility. Particularly the cost of nitrogen sources in biotechnological processes can make up a large fraction of total process expenses. To further develop the bioeconomy, it is of considerable interest to substitute cost-intensive by inexpensive nitrogen sources. The aim of this mini-review was to provide a comprehensive insight of utilization methods of protein-rich residues, such as fish waste, green biomass, hairs, and food waste. The methods described include (i) production of enzymes, (ii) recovery of bioactive compounds, and/or (iii) usage as nitrogen source for microorganisms in biotechnological processes. In this aspect, the utilization of protein-rich residues, which are conventionally considered as waste, allows the development of value-adding processes for the production of bioactive compounds, biomolecules, chemicals, and materials. PMID- 26758302 TI - Source apportionment of indoor PM10 in Elderly Care Centre. AB - Source contribution to atmospheric particulate matter (PM) has been exhaustively modelled. However, people spend most of their time indoors where this approach is less explored. This evidence worsens considering elders living in Elderly Care Centres, since they are more susceptible. The present study aims to investigate the PM composition and sources influencing elderly exposure. Two 2-week sampling campaigns were conducted-one during early fall (warm phase) and another throughout the winter (cold phase). PM10 were collected with two TCR-Tecora((r)) samplers that were located in an Elderly Care Centre living room and in the correspondent outdoor. Chemical analysis of the particles was performed by neutron activation analysis for element characterization, by ion chromatography for the determination of water soluble ions and by a thermal optical technique for the measurement of organic and elemental carbon. Statistical analysis showed that there were no statistical differences between seasons and environments. The sum of the indoor PM10 components measured in this work explained 57 and 53 % of the total PM10 mass measured by gravimetry in warm and cold campaigns, respectively. Outdoor PM10 concentrations were significantly higher during the day than night (p value < 0.05), as well as Ca(2+), Fe, Sb and Zn. The contribution of indoor and outdoor sources was assessed by principal component analysis and showed the importance of the highways and the airport located less than 500 m from the Elderly Care Centre for both indoor and outdoor air quality. PMID- 26758301 TI - Influence of dioxin exposure upon levels of prostate-specific antigen and steroid hormones in Vietnamese men. AB - Most studies on the relationship between Agent Orange and prostate cancer have focused on US veterans of the Vietnam War. There have been few studies focusing on the relationship between levels of prostate-specific antigen (PSA) and dioxins or steroid hormones in Vietnamese men. In 2009-2011, we collected blood samples from 97 men who had resided in a "dioxin hotspot" and 85 men from a non-sprayed region in Vietnam. Then levels of PSA, dioxins, and steroid hormones were analyzed. Levels of most dioxins, furans, and non-ortho polychlorinated biphenyls were higher in the hotspot than those in the non-sprayed region. Levels of testosterone, dehydroepiandrosterone, and estradiol differed significantly between the hotspot and the non-sprayed region, but there were no correlations between levels of PSA and steroid hormones and dioxins in either of the two regions. Our findings suggest that PSA levels in Vietnamese men are not associated with levels of dioxin or steroid hormones in these two regions. PMID- 26758303 TI - Use of flue gas desulfurization gypsum for leaching Cd and Pb in reclaimed tidal flat soil. AB - A soil column leaching experiment was conducted to eliminate heavy metals from reclaimed tidal flat soil. Flue gas desulfurization (FGD) gypsum was used for leaching. The highest removal rates of Cd and Pb in the upper soil layers (0-30 cm) were 52.7 and 30.5 %, respectively. Most of the exchangeable and carbonate bound Cd and Pb were removed. The optimum FGD gypsum application rate was 7.05 kg.m(-2), and the optimum leaching water amount for the application was 217.74 L.m(-2). The application of FGD gypsum (two times) and the extension of the leaching interval time to 20 days increased the heavy metal removal rate in the upper soil layers. The heavy metals desorbed from the upper soil layers were re adsorbed and fixed in the 30-70 cm soil layers. PMID- 26758304 TI - Land use and soil type determine the presence of the pathogen Burkholderia pseudomallei in tropical rivers. AB - Burkholderia pseudomallei is the bacterium that causes melioidosis in humans. While B. pseudomallei is known to be endemic in South East Asia (SEA), the occurrence of the disease in other parts of the tropics points towards a potentially large global distribution. We investigated the environmental factors that influence the presence (and absence) of B. pseudomallei in a tropical watershed in SEA. Our main objective was to determine whether there is a link between the presence of the organism in the hydrographic network and the upstream soil and land-use type. The presence of B. pseudomallei was determined using a specific quantitative real-time PCR assay following enrichment culture. Land use, soil, geomorphology, and environmental data were then analyzed using partial least squares discriminant analysis (PLSDA) to compare the B. pseudomallei positive and negative sites. Soil type in the surrounding catchment and turbidity had a strong positive influence on the presence (acrisols and luvisols) or absence (ferralsols) of B. pseudomallei. Given the strong apparent links between soil characteristics, water turbidity, and the presence/absence of B. pseudomallei, actions to raise public awareness about factors increasing the risk of exposure should be undertaken in order to reduce the incidence of melioidosis in regions of endemicity. PMID- 26758305 TI - A comparison of metal distribution in surface dust and soil among super city, town, and rural area. AB - One super city leading and supported by surrounding smaller cities, towns, and countries is a typical regional development pattern in China. To study the metal enrichment differences in environment among these regions, 91 urban surface dust and rural surface soil samples were collected from Beijing center (BJC), Miyun town (MYT), and Miyun county (MYC). Cu and Sb concentrations in urban surface dust of BJC were much higher than the less crowded MYT which stood out as a good indicator for brake system wear. Cd, Cu, Hg, Pb, Sb, and Zn concentrations in urban surface dust were 1.48, 1.57, 2.73, 1.58, 6.20, and 1.98 times higher than rural surface soils on average, respectively. Aerosol sedimentation was shown to mainly contribute to Cd and Pb in urban surface dust in parks and forest soils. Hospitals and clinics were found to contribute much Hg to the surrounding environment. PMID- 26758306 TI - Sex steroid imbalances in the muricid Stramonita haemastoma from TBT contaminated sites. AB - Imposex incidence, organotin tissue levels, and sex steroid (free and esterified testosterone and estradiol) levels were assessed in Stramonita haemastoma from Babitonga Bay (Santa Catarina State, Southern Brazil). The imposex levels showed a reduction when compared to a previous evaluation performed in the same area. In spite of that, the detected imposex incidence indicated the occurrence of tributyltin (TBT) inputs that were still able to produce endocrine disruption in local gastropods. In addition, a high level of organotins was observed in tissues of imposexed females. These females also showed a hormonal imbalance, especially in the total testosterone/total estradiol ratio. These findings obtained under realistic field conditions suggest that the steroid pathway could be responsible by the imposex induction after exposure to TBT. In this case, measurements of sex steroid levels can be an additional evidence for monitoring sites and impose affected gastropod populations. PMID- 26758307 TI - Heavy metals in estuarine surface sediments of the Hai River Basin, variation characteristics, chemical speciation and ecological risk. AB - The Hai River Basin (HRB) is considered to be one of the most polluted areas in China due to the high regional population density and rapid economic development. The estuaries of the HRB, which receive pollutants from terrestrial rivers, may subsequently suffer potential pollution and result in ecological risk of heavy metals. Six heavy metals (Cd, Cr, Cu, Ni, Pb, and Zn) were measured in estuarine surface sediments from 10 estuaries of the HRB to investigate their variation characteristics and ecological risks. The spatial difference of Cr, Ni, Pb, and Zn in sediments was higher than that of the rest two elements. The Yongdingxin Estuary (YDX) and Ziyaxin Estuary (ZYX) in the Northern Hai River System (NHRS) were the most severe in terms of heavy metal contamination. According to the Risk Assessment Code (RAC) classification, Cd associated with the exchangeable and carbonate fraction (the average of 21.3 %) indicated medium risk to high risk. More than 50 % of Cr, Cu, Ni, and Zn on average were associated with the residual fraction. Based on the sum of the first three fractions (exchangeable and carbonate + reducible + oxidizable), the mobility order of these heavy metals was Cd >Pb > Zn ~ Cu > Ni > Cr. Compared to the background values of cinnamon soil, the potential ecological risk index (RI) values ranged from 25.6 to 168, with an average of 91.2, indicating a low ecological risk in estuarine sites of the HRB. Cd and Pb were the dominant contributors to the toxic-response factor (45.8 and 25.5 %, respectively). The results give insight into the different control measures pertaining to heavy metal pollution and risk for both relatively clean estuaries and urban seriously polluted areas, respectively, for the formation of protect strategies of aquatic environment in the HRB. PMID- 26758308 TI - Trends and variability in blood lead concentrations among US children and adolescents. AB - Using data from the National Health and Nutrition Examination Survey for the period 2003-2012, the objective of this study was to evaluate trends in blood lead levels (BLL) among children aged 1-5 and 6-11 years and smoker and nonsmoker adolescents aged 12-19 years. Regression models with log10 transformed values of BLLs as dependent variable were fitted to evaluate how gender, race/ethnicity, smoking, and exposure to secondhand smoke at home affect BLLs. Irrespective of age, gender, and race/ethnicity, BLLs declined over the study period (p <= 0.01). Overall, adjusted BLLs declined by 0.00114 MUg/dL for every 2 years. Children aged 1-5 years had about 50 % higher BLLs than smoker adolescents, about 75 % higher BLLs than nonsmoker adolescents, and about 45 % higher BLLs than children aged 6-11 years. While overall, children aged 1-5 years with BLL >= 5 MUg/dL made up 3.24 %, 7.8 % non-Hispanic Black children aged 1-5 years had BLL >= 5 MUg/dL. Males were found to have higher adjusted BLLs than females, and non-Hispanic Blacks were found to have higher adjusted BLLs than non-Hispanic Whites. Higher poverty income ratio was associated with lower adjusted BLLs (beta = -0.02916, p < 0.01). Children living in owner-occupied homes had lower adjusted BLLs than children living in renter-occupied homes. BLLs increased with increase in number of smokers smoking inside the home (beta = 0.02496, p = 0.02). In conclusion, while BLLs have declined for all age groups, genders, and races/ethnicities, certain races/ethnicities like non-Hispanic Blacks continue to have substantially higher BLLs than non-Hispanic Whites. PMID- 26758314 TI - Stiffness in vortex-like structures due to chirality-domains within a coupled helical rare-earth superlattice. AB - Vortex domain walls poses chirality or 'handedness' which can be exploited to act as memory units by changing their polarity with electric field or driving/manupulating the vortex itself by electric currents in multiferroics. Recently, domain walls formed by one dimensional array of vortex-like structures have been theoretically predicted to exist in disordered rare-earth helical magnets with topological defects. Here, in this report, we have used a combination of two rare-earth metals, e.g. superlattice that leads to long range magnetic order despite their competing anisotropies along the out-of-plane (Er) and in-plane (Tb) directions. Probing the vertically correlated magnetic structures by off-specular polarized neutron scattering we confirm the existence of such magnetic vortex-like domains associated with magnetic helical ordering within the Er layers. The vortex-like structures are predicted to have opposite chirality, side-by-side, and are fairly unaffected by the introduction of magnetic ordering between the interfacial Tb layers and also with the increase in magnetic field which is a direct consequence of screening of the vorticity in the system due to a helical background. Overall, the stability of these vortices over a wide range of temperatures, fields and interfacial coupling, opens up the opportunity for fundamental chiral spintronics in unconventional systems. PMID- 26758313 TI - Evaluation of Periaortic Adiposity and Metabolic Disorders in Obese Children. AB - OBJECTIVE: To evaluate the relationship between periaortic fat thickness (PAFT) and parameters involved in the development of metabolic complications of the cardiovascular system in obese children and to assess the usefulness of echocardiographic measurements of PAFT in correlation with cardiovascular risk factors. METHODS: The study was conducted with 263 obese and 100 healthy children and adolescents. PAFT was measured with echocardiography method which was recently performed in obese children and adolescents. RESULTS: PAFT was significantly higher in the obese group (0.258+/-0.031 mm) than in the control group (0.137+/-0.032 mm) (p<0.001). In multivariable regression analysis, body mass index-standard deviation score and total body fat were predictors of PAFT. The area under the receiver operating characteristic curve was 0.989 and was quite significant at p<0.001. PAFT above 0.179 mm was determined as the cut-off value in obese children and adolescents (sensitivity=1, specificity=0.97). CONCLUSION: The measurement of PAFT in obese children and adolescents may be a good method to reveal the presence of early cardiovascular risk. PMID- 26758316 TI - [Myelodysplastic syndromes in children:challenge and hope]. PMID- 26758315 TI - Silymarin alleviates hepatic oxidative stress and protects against metabolic disorders in high-fat diet-fed mice. AB - Silymarin is a potent antioxidant medicine and has been widely used for the treatment of liver diseases over 30 years. Recent studies suggest that silymarin may benefit patients with glucose intolerance. However, the mechanism underlying the action of silymarin is not clarified. The aim of this work was to assess the impact of silymarin on glucose intolerance in high-fat diet (HFD)-fed mice, and explore the potential therapeutic mechanisms. C57BL/6 mice were fed with HFD for 12 weeks, randomized, and treated orally with vehicle saline or silymarin (30 mg/kg) daily for 30 days. We found that silymarin significantly improved HFD induced body weight gain, glucose intolerance, and insulin resistance in mice. Silymarin treatment reduced HFD-increased oxidative stress indicators (reactive oxygen species, lipid peroxidation, protein oxidation) and restored HFD-down regulated activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) in the plasma and/or liver of the HFD-fed mice. Furthermore, silymarin decreased HFD-up-regulated hepatic NADPH oxidase expression and NF-kappaB activation in mice. Additionally, silymarin treatment mitigated HFD-increased plasma IL-1beta, TNF-alpha levels, and HFD-enhanced hepatic NO, TLR4, and iNOS expression in mice. These novel data indicate that silymarin has potent anti-diabetic actions through alleviating oxidative stress and inflammatory response, partially by inhibiting hepatic NADPH oxidase expression and the NF-kappaB signaling. PMID- 26758317 TI - [Chinese experts consensus statement on diagnosis and treatment of myelodysplastic syndromes in children, 2015]. PMID- 26758318 TI - [Treatment of Gaucher disease with allogeneic hematopoietic stem cell transplantation: report of three cases and review of literatures]. AB - OBJECTIVE: To explore the efficacy of unrelated umbilical cord blood transplantation (UCBT) in the treatment of Gaucher disease. METHOD: The clinical characteristics of three children with Gaucher disease underwent UCBT in our hospital between April 2013 and September 2014 were retrospectively analyzed. Literature on allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of Gaucher disease was searched at Wanfang and Pubmed databases between 1983 and 2015 and was reviewed and summaried. RESULT: Three children with Gaucher disease, all were female, received UCBT. These patients' age at receiving transplantation was 3.8 years, 7.1 years and 2.6 years, respectively. The second case received the second transplantation. The first and third case received splenectomy before UCBT. The pretreatment regimen was busulfan (Bu)/fludarabine (Flu)/cyclophosphamide (CTX)/antithymocyte globulin (ATG), and for the patient received the second transplantation melphalan was added to the myeloablative conditioning regimen of Bu/Flu/CTX/ATG. Cyclosporine and mycophenolate mofetil (MMF) wee used for prophylaxis of acute graft versus host disease (aGVHD). The dose of cord blood stem cell nucleated cell counts was 9.7 * 107 /kg,11.9 * 107 /kg and 7.6 * 107/kg respectively. The dose of cord blood stem cell CD34+ cell counts was 5.4 * 105/kg , 3.5 * 105/kg and 3.2 * 105/kg respectively. The day of granulocytes exceeding 0.5 * 109/L was day 11, 12 and 19 after transplantation, respectively. The day of platelets exceeding 20 * 109/L was day 14, 33 and 74 after transplantation, respectively. At one month after transplantation the rate of chimerism was over 95% and all patients got donor complete chimerism. The level of beta-glucocerebrosidase recovered to normal at one month after transplantation. During transplantation, all patients developed cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia. In case 1 immune thrombocytopenia occurred at five month after transplantation unresponding to steroids and mesenchymal stem cells infusion was administered and his platelet in routine blood test recovered to normal. But the patient died because she was infected with varicella-zoster virus out of hospital at nine month after transplantation and the level of beta-glucocerebrosidase was normal before death and chronic GVHD (cGVHD) was not found. The case 2 is now in 19th month after transplantation and his level of beta-glucocerebrosidase was normal. cGVHD was not found. The patient is currently free of disease. The case 3 was in 9th month after transplantation and his level of beta-glucocerebrosidase was normal. cGVHD was found at 112 day after transplantation and was localized and could be controlled by hormonal therapy. The patient is currently free of disease. Three patients' size of liver was significantly reduced after their level of beta-glucocerebrosidase ecovered. There were 50 cases with Gaucher disease who were treated with allo-HSCT in the literature and none of them were reported from China. Disease-free survival rate of patients treated with allo-HSCT for Gaucher disease was 85%. In all reports, there were 31 cases who had information of typing of Gaucher disease, of whom 22 cases had type 1 and 9 cases had type 3. Twenty-nine cases had information of survival, of whom 24 cases survived and 5 cases died of infection. Fifteen cases had data of engraftment, 2 of whom had graft failure and one had late graft failure.Glucocerebrosidase recovered to normal in 25 of 31 cases who had relevant data, in one of whom with late graft failure the enzyme recovered to normal 3 month after transplantation, but his enzyme decreased to the initial level 9 month after transplantation. Along with enzyme level's recovery to normal, in a part of cases bone pain and hepatomegaly were relieved and growth delay was improved. CONCLUSION: The unrelated UCBT may be a form of treatment that offers the potential of permanent cure and a procedure with possible long-term benefits in patients with Gaucher disease. PMID- 26758320 TI - [Significance of soluble CD163 and soluble CD25 in diagnosis and treatment of children with hemophagocytic lymphohistiocytosis]. AB - OBJECTIVE: To explore significance of serum soluble CD163(sCD163) and soluble CD25(sCD25) in diagnosis and guiding treatment of children with hemophagocytic lymphohistiocytosis (HLH). METHOD: Data of 42 cases of children with HLH, 32 cases of non-HLH children with infection presented to First Affiliated Hospital of Zhengzhou University pediatric clinic and ward were collected from December 2013 to December 2014. Twenty-four healthy children were enrolled into a normal control group in the same period.Peripheral venous blood specimens (3 ml) were taken from the children with HLH after fasting before treatment, two weeks after treatment and eight weeks after treatment.Peripheral venous blood specimens (3 ml) were also taken from children of non-HLH infected group and normal control group after fasting at the initial visit. Serum sCD163 and sCD25 levels in the peripheral blood in three groups were determined by ELISA. According to cause of disease, children with HLH were divided into infection-related HLH, tumor-related HLH, primary HLH and others; relationship between serum sCD163 and sCD25 level and cause of disease was analyzed. RESULT: Serum sCD163 of HLH group ((6 094 +/- 2 769) ug/L) and serum sCD163 of non-HLH infection group ((2 174 +/- 950) ug/L) were significantly higher than that of normal control group ((777 +/- 256) ug/L), F=71.396, P<0.05), and the differences among groups were statistically significant (P<0.05); serum sCD25 of HLH group ((41 963 +/- 31 821) ng/L) and serum sCD25 of non-HLH infection group ((6 700 +/- 4 105) ng/L) were significantly higher than that of normal control group ((2 440 +/- 1 870) ng/L, F=37.513, P<0.05).There was no statistically significant difference between the non-HLH infection group with the normal control group (P>0.05), and the difference between the remaining groups was statistically significant (P<0.05). And serum sCD163 and sCD25 level of HLH group had a positive linear correlation, and Pearson correlation coefficient r=0.742 (t=7.000, P<0.05). The difference of serum sCD163 and sCD25 level among the different cause of disease in HLH group was significant (P<0.05).Pairwise comparison showed that serum sCD163 and sCD25 level of tumor-associated HLH group significantly increased as compared with infection-associated HLH group (P<0.05), but the difference was not statistically significant between the other groups (all P>0.05). Serum sCD163 and sCD25 level of HLH group before treatment, 2 weeks and 8 weeks after treatment showed a statistically significant tendency of decrease (P<0.05). Seen from the ROC curve, when sCD163 cut-off point was 2 359.08 ug/L, the diagnostic sensitivity was 83.3%, and specificity was 83.9%.When sCD25 cut-off point was 14 901.024 ng/L, the diagnosis sensitivity was 76.2%, and specificity was 98.2%. CONCLUSION: Serum sCD163 and sCD25 levels may be used for diagnosis of HLH.Dynamically monitoring of serum sCD163 and sCD25 level can help to determine deterioration of HLH and guide treatment. PMID- 26758319 TI - [Molecular diagnosis and hematopoietic stem cell transplantation in 17 children with inherited bone marrow failure syndrome]. AB - OBJECTIVE: To enrich our national database with data of rare diseases by analyzing molecular diagnosis and hematopoietic stem cell transplantation (HSCT) in children with inherited bone marrow failure syndromes (IBMFS). METHOD: Next generation sequencing (NGS)-based genetic diagnosis panel was applied for the clinical diagnosis and management of IBMFS. Retrospective analysis was performed on clinical and genetic data of 17 consecutive children who received HSCT over a long time interval (November. 2005-June 2015). RESULT: Three patients were diagnosed only by clinical manifestation before 2012. After that NGS-based genetic diagnosis panel was used to identify IBMFS-related genes in 12/14.IBMFS patients (except two Diamond-Blackfan anemia (DBA) patients). Two Fanconi anemia (FA) patients were confirmed to be new variations through family-genotype analysis and 3 families accepted prenatal diagnosis to avoid birth of affected fetuses. Seventeen IBMFS patients (10 FA,5 DBA and 2 dyskeratosis congenital (DKC)) were treated with HSCT from matched sibling donors (n=2), matched unrelated donors (n=8) or mismatched unrelated donors (n=7). The source of stem cells for transplantation included peripheral blood (n=12) and cord blood (n=5). With regard to the conditioning regimens, FA and DKC patients received fludarabine-based reduced intensity conditioning, while DBA patients received classical busulfan-based myeloablative conditioning. Median age at the time of HSCT was 36 months (7-156 months). The number of infused mononuclear cells and CD34+ cells was (10.6 +/- 6.7) * 108 and (5.9 +/- 7.0) * 106 per kilogram of recipient body weight, respectively. The median number of days to neutrophil recovery was 13 days after HSCT (range: 10-19 days). Platelet recovery was faster in the PBSCT group than in the CBT group ((16.3 +/- 6.0) days vs. (30.0 +/- 17.1) days,t=-2.487,P=0.026). During a median follow-up of 17 months (range: 2-114 months), except one FA patient who was transplanted with HLA-matched unrelated cord blood (CB) died from pneumonia and heart failure because of engraftment failure, other 16 children are alive after the successful HSCT. The failure-free survival rate of the patients three years after HSCT was 94%. CONCLUSION: NGS based molecular diagnosis technology and effective HSCT have significantly facilitated the treatment of children with IBMFS in our country, and our national database about this rare disease is to be further exploited. PMID- 26758321 TI - [Predictive value of hour-specific transcutaneous bilirubin nomogram for neonatal hyperbilirubinemia: a national multicenter study]. AB - OBJECTIVE: To assess the predictive value of hour-specific transcutaneous bilirubin (TcB) nomogram for subsequent neonatal hyperbilirubinemia. METHOD: Thirteen tertiary class-A hospitals (including two hospitals respectively in the northeastern, northern, eastern, south, northwest, southwestern regions of China, and one in central region) participated in this multicenter study between January 1 and December 31, 2013. All TcB measurements were obtained from healthy term and near-term newborns (gestational age >= 35 weeks, birth weight >= 2 000 g) by the JM-103 bilirubinometer between 0 and 168 postnatal hours.Developed an hour specific TcB bilirubin nomogram with these data.Newborns were divided into 4 groups based on the predischarge bilirubin "risk zone" (<= P40, >P40-P75, >P75 P95, and > P95 as low, low-intermediate, high-intermediate and high risk zones on the hour-specific bilirubin nomogram) to predict subsequent hyperbilirubinemia.Selected bilirubin measurements of three time quantums (25-48 h, 49-72 h, 73-96 h) as a predictor for the respective danger zone, and adopted ROC curve to assess the predictive ability of the TcB nomogram. RESULT: Data from 19 601 healthy term and near-term newborns, and 2 673 cases with neonatal hyperbilirubinemia were collected. The prevalence was 13.6%. The P40, P75, and P95 peak percentile value of the hour-specific TcB nomogram was 167, 206, 253 umol/L, respectively. The rate of rise in TcB was highest during the first 24 h of age, and the 95(th) percentile curve was faster than the P40 and P75 percentile curves. The areas under the ROC curves of 25-48 h, 49-72 h and 73-96 h were respectively 0.752 0, 0.834 4, 0.856 1. During 25-48 h, 49-72 h and 73-96 h after birth, the TcB before discharge were in the high-risk zone, its prevalence was 49.4%, 67.3%, 80.4%, its likelihood ratio was 6.20, 13.0, and 27.8, respectively. CONCLUSION: The constructed TcB nomogram shows a good predictivity for hyperbilirubinemia. PMID- 26758322 TI - [ATP1A3 gene mutations in patients with alternating hemiplegia of childhood]. AB - OBJECTIVE: To analyze the ATP1A3 mutations in patients with alternating hemiplegia of childhood (AHC) and recognize its value in diagnosing atypical cases. METHOD: Data of all AHC patients seen at Peking University First Hospital from August 2005 to November 2014 were prospectively collected. Clinical information of the AHC patients and their family members were collected and analyzed. Genomic DNAs were extracted from their peripheral blood. Mutations in ATP1A3 were screened by Sanger sequencing after PCR. RESULT: A total of 78 AHC patients were recruited, including 50 males and 28 females. Only three patients had family history of AHC. The first family case had affected mother with AHC; the second family case was the older one of a monozygotic male twins with AHC but their parents were normal; the third family case had a sister with AHC but their parents were normal. The age of onset ranged from six hours to eight years and six months (median: 4 months). According to the Aicardi's clinical diagnostic criteria, 72 patients were considered as typical AHC cases and the other six patients were considered as atypical AHC cases for their age of onset was older than 18 months. Twenty-seven different missense ATP1A3 mutations were detected in 71 (91.0%, 71/78) patients with AHC, including 66 typical and 5 atypical cases. 11 novel ATP1A3 mutations were first reported. ATP1A3 mutations were identified in the three AHC cases with family history. Parental analysis verified that the ATP1A3 mutation of 63 patients (95.5%, 63/66) were de novo origin except lack of five unavailable maternal or paternal genomic DNA. Mutation D801N was found in 20 cases (28.2%), and E815K in 12 cases (16.9%). In the six atypical AHC patients, ATP1A3 mutations were detected in five of them. CONCLUSION: ATP1A3 was the major causative gene of AHC, and mutations were identified as de novo mostly. ATP1A3 mutations in AHC had mutational hotspot, and the most common mutations were D801N and E815K. ATP1A3 mutation screening is helpful for the genetic and definite diagnosis of the atypical AHC cases. PMID- 26758323 TI - [A new method for adult height prediction in girls with idiopathic central precocious puberty treated with gonadotropin releasing hormone agonist]. AB - OBJECTIVE: To develop a new method for predicting adult height (PAH) based on the theory of Bayley-Pinneau and to evaluate the feasibility of this method in predicting adult height of girls with idiopathic central precocious puberty (ICPP) who were treated with gonadotropin releasing hormone agonist (GnRHa). METHOD: (1) The new method for PAH, i.e. PAH = Height/percentage of adult height for bone age, was established according to the theory of Bayley-Pinneau and the data from the national growth survey of children in the nine cities of China in the year 2005. (2) Data from seventeen female patients with ICPP received GnRHa treatment and achieved final adult height (FAH) were collected. Before and during the treatment, PAH was calculated by the method of Bayley-Pinneau and the new method. RESULT: The mean FAH(cm) of the 17 patients with ICPP was 159.81 +/- 4.95. The PAH (cm), before and after treatment for 1, 2 and 3 years, were 156.53 +/- 3.63, 157.71 +/- 3.62, 158.60 +/- 3.50, 161.46 +/- 4.50 and 161.56 +/- 3.77, 161.68 +/- 3.44, 162.04 +/- 4.42, 163.13 +/- 2.36 respectively by using the new method (PAH-D) and Bayley-Pinneau method(PAH-BP). The mean value of (PAH-D-FAH) and (PAH-BP-FAH) were -1.96 cm and 1.48 cm. However, the 95% confidence interval was (-3.82 cm to -0.11 cm), (-1.60 cm to 4.55 cm) for (PAH-D-FAH) and (PAH-BP FAH). There was no significant difference between the values obtained before and after treatment in terms of PAH by use of Bayley-Pinneau method. By the new method, however, the results showed that the PAH increased and improved further with prolonged treatment periods. And at the end of treatment, there was no significant difference between PAH and FAH. The correlation coefficient was 0.93. Regression analysis showed that the trend line was in parallel with baseline data. CONCLUSION: The new method we established could predict better the final heights of girls with CPP who were treated with GnRHa. PMID- 26758324 TI - [Clinical value of portable sleep testing in children with obstructive sleep apnea syndrome]. AB - OBJECTIVE: To determine the clinical value of portable sleep testing by Watch-PAT (PAT) in children with obstructive sleep apnea syndrome (OSAS). METHOD: Fifty cases of snoring children aged 3-11 years were randomly selected to undergo the polysomnography (PSG) and PAT simultaneously at the same night. The consistency of sleep parameters in OSAS and non - OSAS children were compared with PSG as reference standard, and ROC curve analysis was performed to assess the sensitivity and specificity in the diagnosis of OSAS with PAT portable sleep monitor. RESULT: Fourteen cases were diagnosed as OSAS in 6-11 years group by PAT and PSG. But in 3-5 years group, only six children were diagnosed as OSAS, there was significant difference between PAT and PSG (P < 0.05). Among those 6-11 years old children, compared with non-OSAS, PAT study showed that III+IV stage sleep ((30.5 +/- 2.4)% vs. (38.2 +/- 2.3)%, chi(2)=4.31, P<0.05), REM sleep duration ((8.9 +/- 2.5)% vs. (18.3 +/- 2.1)%, chi2 =4.31, P<0.05), TST ((458 +/- 78) min vs. (522 +/- 56) min, t=4.85, P<0.05) and sleep efficiency ((83.5 +/- 3.1)% vs. (93.5 +/- 3.5)%, t=3.75, P<0.05) decreased, I+II stage sleep ((61.5 +/- 4.4)% vs. (44.1 +/- 3.5)%, chi2 =6.07, P<0.05), arousal index ((29.5 +/- 8.2)/h vs. (10.6 +/- 5.6)/h, t=3.70, P<0.05), AHI ((7.6 +/- 5.3)/h vs. (2.1 +/- 2.0)/h, t=2.40, P<0.05), RDI((18.2 +/- 5.1)/h vs. (6.5 +/- 3.9)/h, t=3.85, P<0.05) increased in OSAS children. Furthermore, the total sleep time (TST) ((458 +/- 78) min vs. (430 +/- 76) min, t=2.90, P<0.05) and sleep efficiency ((83.5 +/- 3.1) % vs. (81.9 +/- 4.3) %, t=2.45, P<0.05) were higher by PAT than scored by PSG. ROC curve analysis showed the best threshold selection of AHI 5.0, the sensitivity was 0.952, the specificity was 0.858. AHI 7.0, the sensitivity was 0.968, the specificity was 0.985. AHI 10, the sensitivity was 0.985 and the specificity was 0.99, but AHI 1.0, the sensitivity was 0.852 and the specificity was 0.785. CONCLUSION: PAT can be used at home in school age children due to the high consistency with PSG and the high compliance. PMID- 26758325 TI - [Analysis of the clinical characteristics of Kartagener syndrome in Chinese and foreign children]. AB - OBJECTIVE: To analyze the clinical characteristic of Kartagener syndrome in Chinese and foreign children. METHOD: Four cases of Kartagener syndrome diagnosed in our hospital were analyzed with literature review. The differences between Chinese and foreign children in clinical manifestations and diagnosis were compared. RESULT: All of the cases had the following clinical manifestations: recurrent productive cough, nasosinusitis, dextrocardia, total situs inversus and bronchiectasia. Situs inversus of the airway structure was visible under the bronchoscope, and electron microscopy of the respiratory mucosa showed an abnormal ciliary ultrastructure. By using "Kartagener syndrome" and "child" as the key words, reports on 55 Chinese cases and 61 foreign cases in children were retrieved from CNKI and PubMed databases. The average age of diagnosis was 9.16 +/- 3.67 years in China, which was significantly later than 7.07 +/- 4.92 years in foreign countries (t=2.642, P<0.01). The main clinical manifestations were recurrent productive cough, nasosinusitis or rhinopolyp, recurrent pulmonary infection, recurrent wheezing and otitis media. Sinus imaging showed maxillary sinusitis. Dextrocardia, total situs inversus and bronchiectasia were found on thoracic and abdominal CT. The ciliary ultrastructural analysis showed shorter and missing dynein arm (6/6 cases in China and 25/27 cases in foreign) . CONCLUSION: The clinical manifestations are recurrent upper and lower respiratory tract infection combined with dextrocardia or other situs inversus in both China and other countries. The diagnosis abroad relied more on abnormal ciliary ultrastructure observed under electron microscopy, but in China mainly relied on its typical clinical manifestations. PMID- 26758326 TI - [Clinical and genetic features of Schwartz-Jampel syndrome in a Chinese child: case report and literature review]. AB - OBJECTIVE: To investigate the clinical and genetic features of a Chinese girl with Schwartz-Jampel syndrome (SJS). METHOD: To analyze the clinical and genetic data of a girl with Schwartz-Jampel syndrome who was sent to neurology outpatient department of Beijing Children's Hospital in Auguest of 2010. Reports on Schwartz Jampel syndrome published until July of 2015 were searched and the clinical and genetic characteristics of reported cases were summarized. RESULT: At 8 months after birth, the girl showed myotonia; at 1 year old when she was walking alone she had myotonia of lower limbs, both feet evaginated, walked slowly and was prone to fall. At 2 years of age, she could not climb up stairs, at 3 years she could not jump continuously. At 3 years and 7 months of age when the girl was taken to neurology outpatient department, on examination, she had a dull facial expression, rigid lips and could not fully open her mouth, a micromandible, low set and prominent ears, systemic muscle rigidity, there were muscular nodes formation on the limbs and gait stiffness. She had high level of creatine kinase and atlanto-axial joint subluxation on cervical CT reconstruction. She also had spontaneous myotonia-like discharges on needle electromyography (NEMG). X-ray of limbs showed metaphyseal dysplasia. The patient was treated with neurologic rehabilitation and carbamazepine. The myotonia at the last follow-up at her 8 years of age was the same as at the onset. On her HSPG2 gene, two novel heterozygous mutations c.10776delT on exon 78 and c.5702-5G>A on intron 45 were found. c.10776delT resulted in the amino acid change on p.Ala3592fsX6 and c.5702 5G>A maybe changed protein splicing. No reports were found among Chinese journals, while 7 reports were found in English literature. The total 34 mutations were known in reviewed reports, which included eleven deletion or insertion, twelve splice site, eight missense, and three nonsense mutations. Four patients had a single mutation. No definite genotype-phenotype correlation was identified. CONCLUSION: Schwartz-Jampel syndrome is a rare autosomal-recessive hereditary disease appears to be slowly progressive, in which distinctive clinical features were induced by HSPG2 gene mutation. We reported the c.10776delT on exon 78 and c.5702-5G>A on intron 45 which were not reported previously. This is the first report of Schwartz-Jampel syndrome of which genetic mutations was identified in a Chinese child. PMID- 26758327 TI - [A case of recurrent bleeding disease caused by alpha1 antitrypsin gene Pittsburgh mutation]. PMID- 26758328 TI - [A case of Lowe syndrome]. PMID- 26758329 TI - [Congenital peribronchial myofibroblastic tumor: a case report]. PMID- 26758330 TI - [A case of neonatal abstinence syndrome combined with retinopathy of premature]. PMID- 26758331 TI - [No.139: recurrent fever and splenomegaly for 9 months, oliguresis for 3 days]. PMID- 26758332 TI - [No.140: recurrent cough for two months,fever and shortness of breath for 16 days]. PMID- 26758333 TI - [The progress of clinical application of fractional exhaled nitric oxide testing in children 5 years and younger]. PMID- 26758334 TI - [Stem cell therapy in bronchopulmonary dysplasia]. PMID- 26758335 TI - Salt: a matter of balance. PMID- 26758336 TI - Charge trap memory based on few-layer black phosphorus. AB - Atomically thin layered two-dimensional materials, including transition-metal dichalcogenide (TMDC) and black phosphorus (BP), have been receiving much attention, because of their promising physical properties and potential applications in flexible and transparent electronic devices. Here, for the first time we show nonvolatile charge-trap memory devices, based on field-effect transistors with large hysteresis, consisting of a few-layer black phosphorus channel and a three dimensional (3D) Al2O3/HfO2/Al2O3 charge-trap gate stack. An unprecedented memory window exceeding 12 V is observed, due to the extraordinary trapping ability of the high-k HfO2. The device shows a high endurance of over 120 cycles and a stable retention of ~30% charge loss after 10 years, even lower than the reported MoS2 flash memory. The high program/erase current ratio, large memory window, stable retention and high on/off current ratio, provide a promising route towards flexible and transparent memory devices utilising atomically thin two-dimensional materials. The combination of 2D materials with traditional high-k charge-trap gate stacks opens up an exciting field of nonvolatile memory devices. PMID- 26758338 TI - [Family resilience and family therapy]. PMID- 26758339 TI - [Focus on Siblings of Children with Chronic Illness or Disability - A Family Oriented Counselling Program]. AB - In the psychosocial support of families with a chronically ill or disabled child siblings are increasingly addressed as a target group for prevention and rehabilitation projects intending to reduce the risk for adverse health consequences. The following article presents a childfocused approach to family counselling as a short-term intervention. Ten flexibly applicable counselling core points covering commonly reported problems of affected siblings and their families are available - including the communication about the disease within the family or the expression of the sibling's feelings and needs. For this purpose an approach in specific counselling sessions has been determined which is used similarly by adept child and youth psychotherapists. The counselling approach is founded theoretically. Furthermore, the counselling approach provides guidance for the structured approach in the diagnosis of potential difficulties, the choice of core points and setting, the closure of counseling sessions as well as the recommendation of additional programs. PMID- 26758340 TI - [Family Climate, Parental Partner Relationships and Symptom Formation in Children - Mentalisation- Based Family Therapy for Childhood Headache]. AB - The emotional family climate is considered both an effective risk and protective factor for child development. Factors such as negative experiences parents made during their childhood or adolescence, which can reoccur as intergenerational transmission, a low partnership quality and a high level of conflict seem to be particularly relevant for the quality of the emotional family climate. Consequently, the relationship between partners, as the core relation within families, is particularly important for the family climate and subsequently for the development of the child. For this reason, problems in parent relationships should receive special attention in family therapeutic interventions. Mentalisation-based family therapy (MBF-T) offers promising approaches in this context. The key principles of mentalisation are introduced and the links between family and mentalisation are presented, followed by information on the history, objectives and the procedures of MBF-T. A case study of a family therapy, in which a child suffers from chronic headache, illustrates the connection and interrelation between family climate, family conflicts and the parental relationship, and it will further show the importance of mentalisation-based elements for therapeutic treatments. PMID- 26758341 TI - [The Family Questionnaire (FB-K) - A Short Version of the General Family Questionnaire and its Reliability and Validity]. AB - A standardized assessment of a family system plays a crucial role in family therapy research and diagnostic, as well as in a family therapy itself. A 14-item short version of the General Family Questionnaire (FB-K) was designed to get a tool for assessing family functionality that is low time-consuming. METHOD: The short version was developed by factor analysis from the long version FA-A. The quality criteria of the family questionnaire were verified in a control sample of 208 high-risk families four months after the birth of their child. The new family questionnaire demonstrates a very good reliability and a satisfactory 8-months stability. The concurrent validity with the FACES scale "cohesion" is assured. Regarding the construct validity a positive correlation to the feeling of coherence was found. The family questionnaire shows a negative correlation to the maternal postnatal depressive symptoms, the degree of maternal stress burden, the dysfunctionality of the mother-child-relationship and impaired bonding. The values taken from a norm sample with infants are higher by trend and in the sample with children under 18 do not deviate from the values of the risk sample. FB-K covers two aspects of family functioning, the bond between family members and their willingness to communicate. The internal consistency of FB-K is excellent, the criterion and the construct validity are good. PMID- 26758342 TI - [Involvement of Turkish Immigrant Fathers Elevates Children's Well-Being]. AB - This study examined paternal involvement in parenting, the association between parents' perception of mutual support, and the relation to their children's well being before (t1) and after the transition to first grade (t2). Participants were first and second generation immigrant families from Turkey (n = 134). In addition, German families (n = 45) were included for the comparison of paternal involvement. The percentage of highly involved fathers was higher in the German sub-sample (54 %) than in the Turkish sub-sample (38 %), but we found no influence of parents' education, household income, employment status, or children's gender. First generation fathers were more likely to be highly involved than second generation fathers. Analyses of the longitudinal data revealed that mothers with highly involved fathers were more likely to report higher marital support. This pattern was less clear for fathers. Children with highly involved fathers reported significantly higher well-being at t1. For t2, a moderator analysis revealed a positive effect on children's well-being only for those fathers who were both highly involved and reported the highest fathering self-efficacy. Among other variables, we controlled for children's well-being at t1, their health status, fathers' work hours and mothers' marital satisfaction. PMID- 26758346 TI - Gastrointestinal: Reptilian skin-like appearance of the colon. PMID- 26758347 TI - Field-induced magnetic instability and quantum criticality in the antiferromagnet CeCu2Ge2. AB - The magnetic quantum criticality in strongly correlated electron systems has been considered to be closely related with the occurrence of unconventional superconductivity. Control parameters such as magnetic field, pressure or chemical doping are frequently used to externally tune the quantum phase transition for a deeper understanding. Here we report the research of a field induced quantum phase transition using conventional bulk physical property measurements in the archetypal antiferromagnet CeCu2Ge2, which becomes superconductive under a pressure of about 10 GPa with Tc ~ 0.64 K. We offer strong evidence that short-range dynamic correlations start appearing above a magnetic field of about 5 T. Our demonstrations of the magnetic instability and the field-induced quantum phase transition are crucial for the quantum criticality, which may open a new route in experimental investigations of the quantum phase transition in heavy-fermion systems. PMID- 26758348 TI - Sleep bruxism: an updated review of an old problem. AB - Objective To provide an update on what is known about bruxism and some of the major clinical highlights derived from new insights into this old problem in dentistry. Materials and methods A selective, non-systematic but critical review of the available scientific literature was performed. Results There are two main different types of bruxism, which are related to different circadian periods (sleep and awake bruxism) that may differ in terms of pathophysiology, but they share some common signs and symptoms. Approximately one out of 10 adult individuals may suffer from bruxism, but not all bruxers may need treatment. Bruxism is complicated to diagnose in the clinic and self-report of bruxism may not necessarily reflect the true presence of jaw muscle activity. Better understanding has been acquired of bruxism relationships with sleep stages, arousal responses and autonomic function with the help of polysomnography and controlled sleep studies. Meanwhile, there is still much more to learn about awake bruxism. With the available scientific knowledge it is possible to systematically assess the effects of bruxism and its potential risk factors for oral and general health. Moreover, we can be aware of the realistic possibilities to manage/treat the patient suffering from bruxism. Conclusion Bruxism is a parafunctional activity involving the masticatory muscles and probably it is as old as human mankind. Different ways have been proposed to define, diagnose, assess the impact and consequences, understand the pathophysiology and treat or manage bruxism. Despite the vast research efforts made in this field, there are still significant gaps in our knowledge. PMID- 26758350 TI - Combining experimental evolution with next-generation sequencing: a powerful tool to study adaptation from standing genetic variation. PMID- 26758349 TI - Visual attention modulates the asymmetric influence of each cerebral hemisphere on spatial perception. AB - Although the allocation of brain functions across the two cerebral hemispheres has aroused public interest over the past century, asymmetric interhemispheric cooperation under attentional modulation has been scarcely investigated. An example of interhemispheric cooperation is visual spatial perception. During this process, visual information from each hemisphere is integrated because each half of the visual field predominantly projects to the contralateral visual cortex. Both egocentric and allocentric coordinates can be employed for visual spatial representation, but they activate different areas in primate cerebral hemispheres. Recent studies have determined that egocentric representation affects the reaction time of allocentric perception; furthermore, this influence is asymmetric between the two visual hemifields. The egocentric-allocentric incompatibility effect and its asymmetry between the two hemispheres can produce this phenomenon. Using an allocentric position judgment task, we found that this incompatibility effect was reduced, and its asymmetry was eliminated on an attentional task rather than a neutral task. Visual attention might activate cortical areas that process conflicting information, such as the anterior cingulate cortex, and balance the asymmetry between the two hemispheres. Attention may enhance and balance this interhemispheric cooperation because this imbalance may also be caused by the asymmetric cooperation of each hemisphere in spatial perception. PMID- 26758351 TI - [Education for patients with fibromyalgia. A systematic review of randomised clinical trials]. AB - AIM: To analyse the effectiveness of education about pain, quality of life and functionality in patients with fibromyalgia. SUBJECTS AND METHODS: The search for articles was carried out in electronic databases. Eligibility criteria were: controlled randomised clinical trials (RCT), published in English and Spanish, that had been conducted on patients with fibromyalgia, in which the therapeutic procedure was based on patient education. Two independent reviewers analysed the methodological quality using the PEDro scale. RESULTS: Five RCT were selected, of which four offered good methodological quality. In three of the studies, patient education, in combination with another intervention based on therapeutic exercise, improved the outcomes in the variables assessing pain and quality of life as compared with the same procedures performed separately. Moreover, an RCT with a high quality methodology showed that patient education activated inhibitory neural pathways capable of lowering the level of pain. The quantitative analysis yields strong-moderate evidence that patient education, in combination with other therapeutic exercise procedures, offers positive results in the variables pain, quality of life and functionality. CONCLUSIONS: Patient education in itself has not proved to be effective for pain, quality of life or functionality in patients with fibromyalgia. There is strong evidence, however, of the effectiveness of combining patient education with exercise and active strategies for coping with pain, quality of life and functionality in the short, medium and long term in patients with fibromyalgia. PMID- 26758353 TI - Infratentorial angioleiomyoma: case report and review of the literature. AB - INTRODUCTION: Intracranial angioleiomyomas are extremely rare lesions. Only 22 intracranial angioleiomyomas have been described in the literature and only three were infratentorial. CASE REPORT: We report a case of an infratentorial angioleiomyoma in a 43 year-old-man, who underwent a brain computer tomography because of hearing loss. The MRI showed a 1.4 cm tumor, initially described as a meningioma, with progressive enhancement after gadolinium injection, an augmented apparent diffusion coefficient and a generalized metabolite decreased in the spectroscopy. The lesion was surgically removed through a suboccipital approach with a good evolution and without postoperative complications. In the immunohistological study, the lesion was mainly composed of multiple vessels and the immunohistochemistry was positive for actin and caldesmon. Two years after surgery, no recurrence has been found in the MRI. CONCLUSION: Angioleiomyomas diagnostic may be complex, but some radiological features could help in the differential diagnostic. Angioleiomyomas are benign tumors associated with favorable outcomes after total resection, that in our case, did not show a significant bleeding risk. PMID- 26758355 TI - [XIII Annual Meeting of the Madrid Society of Neurology. Communications]. PMID- 26758352 TI - [The importance of sleep problems in children with headache and other neurodevelopmental disorders in neuropaediatric services]. AB - INTRODUCTION: Sleep disorders are common in children with neurological disorders. The aim of this study is to know the opinion of neuropediatricians and the prevalence of these disturbances in Spain. PATIENTS AND METHODS: Multicenter cross-sectional study (12 Spanish hospitals, 15 researchers). BEARS survey was collected in three groups: A (2-5 years), (6-12 years), and C (> 12 years). The opinion of neuropediatricians was also collected. RESULTS: 939 questionnaires were filled. The main results in groups B and C were ADHD (32.4% and 30.1% respectively) and headache (25.1% and 27.6% respectively), whereas in group A neurodevelopmental disorders (32.4%) and epilepsy (21.4%) were the main diagnoses. Disturbances in at least one area of sleep were found in 92% of children in group A (n = 209, mean 3 years), 64.2% in group B (n = 534, mean 9.4 years) and 58.2% in group C (n = 196, mean 13.7 years). Sixty-one surveys were answered by neuropediatricians (16.75% of the total sent), estimating that less than a quarter of the patients (24.5%) suffered. Even, up to 23% of doctors claimed that the prevalence of sleep disorders was < 10%. CONCLUSIONS: 58-92% of parents-patients under follow up at a neuropediatrician office in Spain have some degree of disturbed sleep. Although most neurologists emphasize the importance of an early diagnosis and treatment of sleep disorders in children with neurological disorders, its frequency is often underestimated (risk of underdiagnosis). PMID- 26758354 TI - [Memory assessment by means of virtual reality: its present and future]. AB - The human memory is a complex cognitive system whose close relationship with executive functions implies that, in many occasions, a mnemonic deficit comprises difficulties to operate with correctly stored contents. Traditional memory tests, more focused in the information storage than in its processing, may be poorly sensitive both to subjects' daily life functioning and to changes originated by rehabilitation programs. In memory assessment, there is plenty evidence with regards to the need of improving it by means of tests which offer a higher ecological validity, with information that may be presented in various sensorial modalities and produced in a simultaneous way. Virtual reality reproduces three dimensional environments with which the patient interacts in a dynamic way, with a sense of immersion in the environment similar to the presence and exposure to a real environment, and in which presentation of such stimuli, distractors and other variables may be systematically controlled. The current review aims to go deeply into the trajectory of neuropsychological assessment of memory based in virtual reality environments, making a tour through existing tests designed for assessing learning, prospective, episodic and spatial memory, as well as the most recent attempts to perform a comprehensive evaluation of all memory components. PMID- 26758356 TI - [Massive open online courses and mental health: an opportunity to approach to a global health problem]. PMID- 26758357 TI - [Severe infection by Pneumocystis jirovecii in infants with West's syndrome treated with intramuscular adrenocorticotropic hormone]. PMID- 26758358 TI - [Classification of structural lesions in magnetic resonance imaging. Surgical implications in drug-resistant epilepsy patients]. PMID- 26758359 TI - [Classification of structural lesions in magnetic resonance imaging. Surgical implications in drug-resistant epilepsy patients. Reply]. PMID- 26758360 TI - [Estimation of the jugular venous pressure]. AB - Estimation of jugular venous pressure (JVP) is valuable for the differentiation between dyspnoea of cardiac or pulmonary origin, and for determining the cause of oedema. JVP assessments are useful for evaluation of treatment of right ventricular failure. The correlation between non-invasive JVP and invasive measurement of the central venous pressure (CVP) is remarkably better than previously reported. Correlation between JVP - determined via the external jugular vein - and CVP is excellent when the outcomes are categorised into low, normal and elevated pressure. Optimal measurement configurations include: extended expiration (without Valsalva manoeuvre), and during ventricular diastole. In the literature, these measurement configurations concerning the respiratory cycle and cardiac cycle have not been applied uniformly. To investigate in detail the correlation between JVP and CVP, the methods need to be standardized, and tests performed simultaneously and correctly. PMID- 26758361 TI - [Outcomes of in-hospital resuscitation]. AB - To make an advanced decision about resuscitation it is important to know what its outcomes are. In-hospital resuscitation cannot always be compared with out-of hospital resuscitation; furthermore, outcomes of in-hospital resuscitation vary between hospital wards and patient populations. Age plays a role in the outcome of a resuscitation procedure. However, older patients who leave hospital alive have a reasonable prognosis as far as survival and neurological function are concerned. Data on quality of life and self-reliance after resuscitation are scarce or non-existent. Comorbidities and ADL status also contribute to the outcome of resuscitation, independent of age. One of the goals of Emergency Intervention Systems is to limit the number of in-hospital resuscitations. Although these systems are probably successful at this point, this cannot be demonstrated in all studies. Much of our knowledge about in-hospital resuscitation is based solely on American research. PMID- 26758362 TI - [Birds, mosquitoes and West Nile virus: little risk of West Nile fever in the Netherlands]. AB - Due to increased incidence of West Nile fever (WNF) in Europe and the rapid spread of West Nile virus (WNV) in the US, it is commonly thought that it will only be a matter of time before WNV reaches the Netherlands. However, assessing whether WNV is really a threat to the Dutch population is challenging, due to the numerous factors affecting transmission of the virus. Some of these factors are known to limit the risk of WNF in the Netherlands. This risk is determined by the interaction between the pathogen (WNV), the vectors (Culex mosquitoes), the reservoirs (birds) and the exposure of humans to infected mosquitoes. In this paper, we discuss the factors influencing introduction, establishment and spread of WNV in the Netherlands. The probability that each of these three phases will occur in the Netherlands is currently relatively small, as is the risk of WNF infection in humans in the Netherlands. PMID- 26758363 TI - Depression or anxiety and all-cause mortality in adults with atrial fibrillation- A cohort study in Swedish primary care. AB - OBJECTIVE: Our aim was to study depression and anxiety in atrial fibrillation (AF) patients as risk factors for all-cause mortality in a primary care setting. METHODS: The study population included adults (n = 12 283) of 45 years and older diagnosed with AF in 75 primary care centres in Sweden. The association between depression or anxiety and all-cause mortality was explored using Cox regression analysis, with hazard ratios (HRs) and 95% confidence intervals (95% CIs). Analyses were conducted in men and women, adjusted for age, educational level, marital status, neighborhood socio-economic status (SES), change of neighborhood status and anxiety or depression, respectively, and cardiovascular co morbidities. As a secondary analysis, background factors and their association with depression or anxiety were explored. RESULTS: The risk of all-cause mortality was higher among men with depression compared to their counterparts without depression even after full adjustment (HR = 1.28, 95% CI 1.08-1.53). For anxiety among men and anxiety or depression among women with AF, no associations were found. Cerebrovascular disease was more common among depressed AF patients. CONCLUSIONS: Increased awareness of the higher mortality among men with AF and subsequent depression is called for. We suggest a tight follow-up and treatment of both ailments in clinical practice. PMID- 26758364 TI - Histone Deacetylase 1 Regulates the Expression of Progesterone Receptor A During Human Parturition by Occupying the Progesterone Receptor A Promoter. AB - The functional withdrawal of progesterone is mediated by the enhanced expression ratio of the 2 progesterone receptor (PR) isoforms, PRA and PRB, and causes the pregnant human myometrium to switch from a quiet state to a state of excitation contraction and subsequent laboring. However, the precise mechanisms responsible for alterations in PRA and PRB expression during human parturition have yet to be resolved. In the present study, we report that PRA expression was increased in myometrium samples during labor (P < .001), concomitant with reduced expression of histone deacetylase 1 (HDAC1; P < .01). These results were further confirmed in the laboratory using cultured primary myometrial cells to investigate the effects of HDAC1 knockdown or overexpression. Finally, we verified that HDAC1 downregulated PRA expression by binding to the promoter region of PRA as confirmed by chromatin immunoprecipitation assays (P < .01) and real-time polymerase chain reaction (P < .001). Therefore, the present study not only demonstrates the epigenetic mechanisms underlying human labor but also provides a potential clinical strategy with which to intervene and prevent labor disorders. PMID- 26758366 TI - Should junior doctors strike? AB - An impasse in negotiations between the Department of Health (DoH) and the British Medical Association in November this year led to an overwhelming vote for industrial action (IA) by junior doctors. At the time of writing, a last minute concession by DoH led to a deferment of IA to allow further negotiations mediated by the Advisory, Conciliation and Arbitration Service. However, IA by junior doctors remains a possibility if these negotiations stall again. Would the proposed action be ethically justifiable? Furthermore, is IA by doctors ever ethically defendable? Building on previous work, we explore important ethical considerations for doctors considering IA. The primary moral objection to doctors striking is often claimed to be risk of harm to patients. Other common arguments against IA by doctors include breaching their vocational responsibilities and possible damage to their relationship with patients and the public in general. These positions are in turn countered by claims of a greater long-term good and the legal and moral rights of employees to strike. Absolute restrictions appear to be hard to justify in the modern context, as does an unrestricted right to IA. We review these arguments, find that some common moral objections to doctors striking may be less relevant to the current situation, that a stronger contemporary objection to IA might be from a position of social justice and suggest criteria for ethically permissible doctor IA. PMID- 26758365 TI - Comparative Effectiveness of Implantable Cardioverter Defibrillators for Primary Prevention in Women. AB - BACKGROUND: Clinical trials of implantable cardioverter defibrillators (ICDs) for primary prevention enrolled a limited number of women. We sought to examine clinical practice data to compare survival rates among women with heart failure with or without a primary prevention ICD. METHODS AND RESULTS: We linked data from 264 US hospitals included in the Get With The Guidelines for Heart Failure registry with data from the Centers for Medicare and Medicaid Services. From these sources, we propensity score matched 430 women with heart failure who received a primary prevention ICD to 430 women who did not; we further adjusted using a Cox proportional hazards model. Median follow-up was 3.4 and 3.0 years. For comparison, we matched 859 men receiving an ICD with 859 who did not; median follow-up was 3.9 versus 2.9 years. In the matched cohorts, an ICD was associated with similarly better survival in women (hazard ratio, 0.78; 95% confidence interval, 0.66-0.92; P=0.003) and men (hazard ratio, 0.76; 95% confidence interval, 0.67-0.87 P<0.001). There was no interaction between sex and presence of an ICD with respect to survival (P=0.79). CONCLUSIONS: Among patients with heart failure with reduced left ventricular ejection fraction, a primary prevention ICD was associated with a significant survival advantage among women and among men. These findings support guideline-directed use of primary prevention ICDs in eligible patients. PMID- 26758367 TI - Comparison of the Psychometric Properties of the "Word" and "Picture" Versions of the Free and Cued Selective Reminding Test in a Spanish-Speaking Cohort of Patients with Mild Alzheimer's Disease and Cognitively Healthy Controls. AB - The aim of this study was to compare the psychometric properties of the "Word" and "Picture" versions of the Spanish FCSRT across the same sample of mild Alzheimer disease (AD) patients and controls. Mild AD patients (N = 50, 27 CDR = 0.5; 23 CDR = 1) and controls (N = 42, CDR = 0) were assessed with an extensive clinical and neuropsychological evaluation. Psychometric characteristics for both versions of the FCSRT were compared. Free recall (FR) and total recall (TR) across both versions of the FCSRT showed areas under the curve >0.9 and did not significantly differ between them. The scores of both versions were well correlated, although the scores for the Picture version were greater than those for the Word version, particularly for the TR scores of the mild AD group. Both versions of the FCSRT showed an appropriate accuracy to distinguish mild AD patients and controls. Visual cues were easier to recall than verbal cues, especially in the memory impaired patients. PMID- 26758369 TI - Expanded Access Programme: looking for a common definition. AB - Therapeutic use of an unauthorised drug (or of an authorised drug for an unauthorised indication) for patients with a life-threating disease is permitted outside a clinical trial as an Expanded Access Programme (EAP).The regulations regarding EAPs is not the same all over the world. For example, the recommendation of the European Medicines Agency (EMA) in EU countries also includes within EAPs patients who have been treated in a clinical trial and who wish to continue the treatment. Nevertheless, the patients treated in a clinical trial could have the option of continuing treatment for an extended period in an Open-label Extension study, aimed to generate long-term data on efficacy, safety, tolerability and administration.The aims of this paper - based on the difficulties and incoherence encountered by an Italian Ethic Committee (EC) during the authorisation process of EAPs - are: understanding the origin of this misclassification by analysing differences and similarities among USA, European and Italian regulations concerning EAPs; and showing difficulties in classifying international study protocols as a consequence of the lack of harmonisation of definitions.We performed a critical review of the current USA, European and Italian regulations and we analysed some practical cases by retrieving protocols from Clinicaltrials.gov and the Italian Clinical Trials Registry (OsSC) containing in the title the keywords 'Expanded Access Programme', "'Expanded Access', 'Open-label Extension study' or 'Early Access'.We observed that the Food and Drug Administration ( FDA) definition of EAP is very clear while the EMA definition is similar to that of an Open-label Extension study. This lack of a clear definition generates misclassification and it is possible to find an EAP with an efficacy or safety endpoint; or an EAP managed as a clinical trial; or an EAP classified in Clinical Trials Registries as a phase II, III or IV clinical trial.The internationalisation of the studies requires a harmonisation on a global level of legislation and definitions to eliminate misclassification of protocols. For this reason, the authors suggest that: a) the EMA definition should be harmonised with the FDA definition of EAPs, b) European regulation, even if optional, should be adopted in a compulsory way by national regulations. Moreover, separate registries for both EAPs and clinical trials should be organised. PMID- 26758368 TI - Markedly improving asymmetric oxidation of 1-(4-methoxyphenyl) ethanol with Acetobacter sp. CCTCC M209061 cells by adding deep eutectic solvent in a two phase system. AB - BACKGROUND: Enantiopure (S)-1-(4-methoxyphenyl) ethanol {(S)-MOPE} can be employed as an important synthon for the synthesis of cycloalkyl [b] indoles with the treatment function for general allergic response. To date, the biocatalytic resolution of racemic MOPE through asymmetric oxidation in the biphasic system has remained largely unexplored. Additionally, deep eutectic solvents (DESs), as a new class of promising green solvents, have recently gained increasing attention in biocatalysis for their excellent properties and many successful examples in biocatalytic processes. In this study, the biocatalytic asymmetric oxidation of MOPE to get (S)-MOPE using Acetobacter sp. CCTCC M209061 cells was investigated in different two-phase systems, and adding DES in a biphasic system was also explored to further improve the reaction efficiency of the biocatalytic oxidation. RESULTS: Of all the examined water-immiscible organic solvents and ionic liquids (ILs), 1-butyl-3-methylimidazolium hexafluorophoshpate ([C4MIM][PF6]) afforded the best results, and consequently was selected as the second phase of a two-phase system for the asymmetric oxidation of MOPE with immobilized Acetobacter sp. CCTCC M209061 cells. For the reaction performed in the [C4MIM][PF6]/buffer biphasic system, under the optimized conditions, the initial reaction rate, the maximum conversion and the residual substrate e.e. recorded 97.8 MUmol/min, 50.5 and >99.9 % after 10 h reaction. Furthermore, adding the DES [ChCl][Gly] (10 %, v/v) to the aqueous phase, the efficiency of the biocatalytic oxidation was rose markedly. The optimal substrate concentration and the initial reaction rate were significantly increased to 80 mmol/L and 124.0 MUmol/min, respectively, and the reaction time was shortened to 7 h with 51.3 % conversion. The immobilized cell still retained over 72 % of its initial activity after 9 batches of successive reuse in the [C4MIM][PF6]/[ChCl][Gly]-containing buffer system. Additionally, the efficient biocatalytic process was feasible up to a 500-mL preparative scale. CONCLUSION: The biocatalytic asymmetric oxidation of MOPE with Acetobacter sp. CCTCC M209061 cells was successfully conducted in the [C4MIM][PF6]-containing biphasic system with high conversion and enantioselectivity, and the reaction efficiency was further enhanced by adding [ChCl][Gly] to the reaction system. The efficient biocatalytic process was promising for the preparation of enantiopure (S)-MOPE. PMID- 26758371 TI - Health-Related Quality of Life and Metabolic Control in Children and Adolescents with Type 1 Diabetes Mellitus. AB - OBJECTIVE: The burdens imposed on a child and his/her parents by a diagnosis of type 1 diabetes mellitus (T1DM) adversely affect their health-related quality of life (HRQoL). HRQoL is important for prognosis and is related to metabolic control. To evaluate the HRQoL of Turkish children and adolescents with T1DM and to assess the correlation of HRQoL subscales (including physical and psychosocial health) with metabolic control, and particularly with hypo- and hyperglycaemic episodes. METHODS: This cross-sectional study included 70 participants with T1DM aged between 8 and 18 years (study group) and 72 healthy controls who were matched to the study group in terms of age, gender, and sociodemographic characteristics (control group), and their parents. HRQoL was determined by the Pediatric Quality of Life Inventory. As an indicator of metabolic control, the most recent hemoglobin A1c (HbA1c) levels were obtained and the number of hypo- and hyperglycaemic episodes over the past one month were checked. RESULTS: The study group had similar HRQoL scores for children's self-reports and parents' proxy-reports to the control group apart from a decreasing psychosocial health score for parents' proxy-reports in the study group. Although HbA1c level was not related to HRQoL scores, lower number of hypo- and hyperglycaemic episodes were associated with an increase in psychosocial health scores and physical health scores as well as an increase in the total score for parents' proxy-reports. CONCLUSION: Although there was no correlation between metabolic control and HRQoL in children's self-reports, the improving HRQoL levels in parents' proxy-reports were associated with good metabolic control. PMID- 26758372 TI - Hyperhomocysteinemia is associated with decreased apolipoprotein AI levels in normal healthy people. AB - BACKGROUND: Hyperhomocysteinemia (HHcy) is an independent risk factor for various cardiovascular diseases. Animal studies have shown that homocysteine (Hcy) inhibits hepatic expression of apolipoprotein AI (apoAI). Our recent clinical study showed that increased plasma Hcy levels were associated with decreased apoAI levels in patients with impaired glucose tolerance. In this study, we assessed a potential association between Hcy and apoAI levels in normal healthy people. METHODS: A total of 1768 normal healthy individuals were divided into two groups: the control group (subjects without HHcy) and the HHcy group (subjects with HHcy). RESULTS: HHcy subjects exhibited significantly lower high-density lipoprotein cholesterol (HDL-C) and apoAI levels than the control group (HDL-C: 1.18 +/- 0.25 vs. 1.29 +/- 0.32 mmol/L; apoAI: 1.38 +/- 0.19 vs. 1.47 +/- 0.25 g/L; all P < 0.01). Plasma Hcy levels were negatively associated with HDL-C and apoAI levels after adjustments for age, BMI and TG (HDL-C: r = -0.10; apoAI: r = 0.11; all P < 0.05). Multivariate regression analysis showed that the plasma Hcy levels were an independent influencing factor for apoAI (beta = -0.065, P < 0.05). CONCLUSIONS: Increased plasma Hcy levels were associated with decreased apoAI levels in normal healthy people, and the inhibition of apoAI synthesis might be a mechanism through which Hcy is linked with the development of atherosclerosis in HHcy subjects. PMID- 26758373 TI - Plasma fatty acid biomarkers are associated with gait speed in community-dwelling older adults: The Three-City-Bordeaux study. AB - BACKGROUND & AIMS: Nutritional factors, such as fatty acids (FA), could modulate physical performance in the elderly. In particular, the opposite properties of long-chain n-3 and n-6 polyunsaturated FAs (LC PUFAs) could impact muscle function. We aimed to assess the cross-sectional association between plasma FAs and gait speed in French elderly community-dwellers. METHODS: Elderly participants from the Bordeaux centre of the Three-City Study were included. The proportion of 12 FAs, and gait speed (m/s) were measured concomitantly at enrollment. Low gait speed (LGS) was defined as below the first quartile of gait speed. FA patterns were derived from the 12 individual FAs using principal component analysis. Multivariate logistic regression models were used and odds ratios (OR) were expressed per one additional standard-deviation unit of each plasma FA or per one additional unit of pattern score. RESULTS: Among 982 participants, 239 (24.3%) had a low gait speed (<0.63 m/s) at baseline. Regarding individually each FA, a higher proportion of eicosapentaenoic acid (EPA) and of docosahexaenoic acid (DHA) were associated with lower odds of LGS (OR = 0.76; 95% CI: 0.63-0.93 and OR = 0.79; 95% CI: 0.67-0.95 respectively). Conversely, a higher arachidonic acid (AA):(EPA + DHA) ratio was associated with higher odds of LGS. Three main FA patterns were identified. A higher score on the FA pattern characterized by higher proportions of LC n-3 PUFAs was associated with lower odds of LGS (OR = 0.78; 95% CI: 0.67-0.90). CONCLUSIONS: A FA pattern mainly driven by high plasma concentrations of LC n-3 PUFAs is cross-sectionally associated with higher gait speed in community-dwelling older adults, while a higher AA:(EPA + DHA) ratio is associated with lower gait speed. These findings suggest a potential protective effect of n-3 PUFA on physical performance decline. PMID- 26758370 TI - GENESIS: a French national resource to study the missing heritability of breast cancer. AB - BACKGROUND: Less than 20% of familial breast cancer patients who undergo genetic testing for BRCA1 and BRCA2 carry a pathogenic mutation in one of these two genes. The GENESIS (GENE SISter) study was designed to identify new breast cancer susceptibility genes in women attending cancer genetics clinics and with no BRCA1/2 mutation. METHODS: The study involved the French national network of family cancer clinics. It was based on enrichment in genetic factors of the recruited population through case selection relying on familial criteria, but also on the consideration of environmental factors and endophenotypes like mammary density or tumor characteristics to assess potential genetic heterogeneity. One of the initial aims of GENESIS was to recruit affected sibpairs. Siblings were eligible when index cases and at least one affected sister were diagnosed with infiltrating mammary or ductal adenocarcinoma, with no BRCA1/2 mutation. In addition, unrelated controls and unaffected sisters were recruited. The enrolment of patients, their relatives and their controls, the collection of the clinical, epidemiological, familial and biological data were centralized by a coordinating center. RESULTS: Inclusion of participants started in February 2007 and ended in December 2013. A total of 1721 index cases, 826 affected sisters, 599 unaffected sisters and 1419 controls were included. 98% of participants completed the epidemiological questionnaire, 97% provided a blood sample, and 76% were able to provide mammograms. Index cases were on average 59 years old at inclusion, were born in 1950, and were 49.7 years of age at breast cancer diagnosis. The mean age at diagnosis of affected sisters was slightly higher (51.4 years). The representativeness of the control group was verified. CONCLUSIONS: The size of the study, the availability of biological specimens and the clinical data collection together with the detailed and complete epidemiological questionnaire make this a unique national resource for investigation of the missing heritability of breast cancer, by taking into account environmental and life style factors and stratifying data on endophenotypes to decrease genetic heterogeneity. PMID- 26758374 TI - Effect of parenteral infusion of fish oil-based lipid emulsion on systemic inflammatory cytokines and lung eicosanoid levels in experimental acute pancreatitis. AB - : Parenteral fish oil lipid emulsion (FOLE) might mitigate inflammation after injury. Acute pancreatitis (AP) can occur following major surgery and is characterized by tissue and systemic release of inflammatory mediators that contributes to the systemic inflammatory response syndrome and multiple organ failure. AIM: We evaluated the effect of short-term FOLE infusion before experimental induction of AP on systemic cytokine and lung eicosanoid profiles. METHODS: Lewis rats (n = 72) received parenteral infusion of FOLE (FO group) or saline (SS group), or remained without parenteral infusion (CG group) for 48 h. Thereafter, AP was induced by retrograde injection of sodium taurocholate into the pancreatic duct. Animals were sacrificed after 2, 12 and 24 h. Blood and lung samples were collected to assess serum inflammatory cytokines (Luminex) and tissue eicosanoids (ELISA), respectively. RESULTS: Serum TNF-alpha increased over time and serum IL-10 decreased from 12 to 24 h in CG group. In SS group serum TNF alpha increased from 12 to 24 h (p = 0.039) and serum IL-10 decreased over time. Both CG and SS groups exhibited increased IL-6/IL-10 ratio (p = 0.040). From 12 to 24 h animals from FO group showed decreased serum IL-1 (p < 0.001), IL-4 (p < 0.002) and IL-6 (p = 0.050), and a trend towards increased IL-10 (p = 0.060). All experimental groups showed a trend towards increased PGE2 and decreased LTB4 in the lung at 24 compared with 12 h CONCLUSION: Parenteral infusion of FOLE for 48 h before the induction of experimental AP appears to favorably influence the cytokine response without affecting lung eicosanoids at the time points measured. The use of FOLE to prevent and treat AP following major surgery needs to be further explored. PMID- 26758375 TI - Long-term prognostic value of stress myocardial perfusion imaging and coronary computed tomography angiography: A meta-analysis. AB - BACKGROUND: We conducted a meta-analysis to compare the long-term prognostic value of stress single-photon emission computed tomography myocardial perfusion imaging (MPI) and coronary computed tomography angiography (CCTA) for adverse cardiovascular events in subjects with suspected or known coronary artery disease. METHODS AND RESULTS: We searched PubMed, Cochrane, Web of Science, and Scopus database between January 2000 and December 2014 for stress MPI and CCTA studies that followed up >= 100 subjects for >= 2.5 years and provided the unadjusted and/or adjusted hazard ratio (HR) at Cox regression analysis. Summary risk estimates for abnormal perfusion at MPI or >= 50% coronary stenosis at CCTA were derived in random effect regression analysis, and causes of heterogeneity were determined in meta-regression analysis. We identified 21 eligible articles (10 MPI and 11 CCTA) including 25,258 participants (13,484 in MPI and 11,774 in CCTA studies) with suspected or known coronary artery disease. Among the included publications, 8 MPI and 8 CCTA studies reported the HR for the occurrence of hard events (death and nonfatal myocardial infarction). The pooled HR was comparable for MPI and CCTA studies. The HR for the occurrence of a combined endpoint including revascularization as event was reported in 4 MPI and 6 CCTA studies. The pooled HR was higher for CCTA compared to MPI (P < .05) also when only MPI and CCTA studies with limited representation of prior CAD were considered. CONCLUSIONS: The long-term prognostic value of MPI and CCTA for the occurrence of hard events is similar. However, the association between event-free survival and CCTA is higher than MPI when coronary revascularization is included in the endpoint. PMID- 26758376 TI - Comparative analysis of iterative reconstruction algorithms with resolution recovery and time of flight modeling for 18F-FDG cardiac PET: A multi-center phantom study. AB - BACKGROUND: The purpose of this study was to evaluate the image quality in cardiac 18F-FDG PET using the time of flight (TOF) and/or point spread function (PSF) modeling in the iterative reconstruction (IR). METHODS: Three scanners and an anthropomorphic cardiac phantom with an insert simulating a transmural defect (TD) were used. Two sets of scans (with/without TD) were acquired, and four reconstruction schemes were considered: (1) IR; (2) IR + PSF, (3) IR + TOF, and (4) IR + TOF + PSF. LV wall thickness (FWHM), contrast between LV wall and inner chamber (C IC), and TD contrast in LV wall (C TD) were evaluated. RESULTS: Tests of the reconstruction protocols showed a decrease in FWHM from IR (13 mm) to IR + PSF (11 mm); an increase in the C IC from IR (65%) to IR + PSF (71%) and from IR + TOF (72%) to IR + TOF + PSF (77%); and an increase in the C TD from IR + PSF (72%) to IR + TOF (75%) and to IR + TOF + PSF (77%). Tests of the scanner/software combinations showed a decrease in FWHM from Gemini_TF (13 mm) to Biograph_mCT (12 mm) and to Discovery_690 (11 mm); an increase in the C IC from Gemini_TF (65%) to Biograph_mCT (73%) and to Discovery_690 (75%); and an increase in the C TD from Gemini_TF/Biograph_mCT (72%) to Discovery_690 (77%). CONCLUSION: The introduction of TOF and PSF increases image quality in cardiac 18F-FDG PET. The scanner/software combinations exhibit different performances, which should be taken into consideration when making cross comparisons. PMID- 26758377 TI - Formoterol as reliever medication in asthma: a post-hoc analysis of the subgroup of the RELIEF study in East Asia. AB - BACKGROUND: As-needed formoterol can effectively relieve asthma symptoms. Since budesonide/formoterol is available as maintenance and reliever therapy in Asia, formoterol is now being used as-needed, but always with concomitant inhaled corticosteroids. The objective of this analysis was to assess the safety and efficacy of formoterol therapy in patients in East Asia (China, Indonesia, Korea, the Philippines and Singapore) with asthma. METHODS: Post-hoc analyses of data from the East Asian population of the RELIEF (REal LIfe EFfectiveness of Oxis(r) Turbuhaler(r) as-needed in asthmatic patients; study identification code: SD-037 0699) study were performed. RESULTS: This sub-group comprised 2834 randomised patients (formoterol n = 1418; salbutamol n = 1416) with mean age 35 years; 50.7% were male. 2678 patients completed the study. There was no significant difference in the total number of adverse events (AEs) reported in the formoterol and salbutamol groups (21.3% vs 20.9% of patients; p = 0.813), nor in the total number of serious AEs and/or discontinuations due to AEs (4.6% vs 5.5%, respectively; p = 0.323). Compared with salbutamol, formoterol was associated with a significantly longer time to first exacerbation (hazard ratio 0.86; p = 0.023) and a 14% reduction in the risk of any exacerbation (p < 0.05). Relative to salbutamol, mean adjusted reliever medication use throughout the study was significantly lower in the formoterol group (p = 0.017) and the risk of increased asthma medication use was 20% lower with formoterol (p = 0.005). CONCLUSIONS: Among patients with asthma in East Asia, as-needed formoterol and salbutamol had similar safety profiles but, compared with salbutamol, formoterol reduced the risk of exacerbations, increased the time to first exacerbation and reduced the need for reliever medication. PMID- 26758379 TI - The polyoxo-22-palladate(ii), [Na2PdO12(As(V)O4)15(As(V)O3OH)](25-) . AB - The polyoxo-22-palladate [Na2PdO12(As(V)O4)15(As(V)O3OH)](25-) (1), which represents a novel polyoxo-noble-metalate structural type, was synthesized by reaction of Pd(2+) and AsO4(3-) ions in aqueous solution. Polyanion 1 comprises two {NaPd11} units linked by two arsenate bridges, and hence represents the first example of a defect, monolacunary {Pd11} polyoxopalladate nanocube with arsenate capping groups. The title polyanion was characterized in the solid state as well as by theoretical calculations. PMID- 26758378 TI - Replication analysis of genetic association of the NCAN-CILP2 region with plasma lipid levels and non-alcoholic fatty liver disease in Asian and Pacific ethnic groups. AB - BACKGROUND: The Neurocan-cartilage intermediate layer protein 2 (NCAN-CILP2) region forms a tight linkage disequilibrium (LD) block and is associated with plasma lipid levels and non-alcoholic fatty liver disease (NAFLD) in individuals of European descent but not in the Malay and Japanese ethnic groups. Recent genome-wide resequence studies identified a missense single-nucleotide polymorphism (SNP) (rs58542926) of the transmembrane 6 superfamily member 2 (TM6SF2) gene in the NCAN-CILP2 region related to hepatic triglyceride content. This study aims to analyze the influences of SNPs in this region on NAFLD and plasma lipid levels in the Asian and Pacific ethnic groups and to reveal the reasons behind positive and negative genetic associations dependent on ethnicity. METHODS: Samples and characteristic data were collected from 3,013 Japanese, 119 Palauan, 947 Mongolian, 212 Thai and 401 Chinese people. Hepatic sonography data was obtained from the Japanese individuals. Genotyping data of five SNPs, rs58542926, rs735273, rs1009136, rs1858999, and rs16996148, were used to verify the effect on serum lipid levels by multiple linear regression, and the association with NAFLD in the Japanese population was examined by logistic regression analysis. RESULTS: rs58542926 showed significant association with the plasma triglyceride (TG) level in Japanese (P = 0.0009, effect size = 9.5 (+/- 3.25) mg/dl/allele) and Thai (P = 0.0008, effect size = 31.6 (+/- 11.7) mg/dl/allele) study subjects. In Mongolian individuals, there was a significant association of rs58542926 with total cholesterol level (P = 0.0003, 11.7 (+/- 3.2) mg/dl/allele) but not with TG level. In multiple comparisons in Chinese individuals, rs58542926 was weakly (P = 0.022) associated with TG levels, although the threshold for statistical significance was not reached. In Palauan individuals, there was no significant association with the studied SNPs. rs58542926 also showed significant association with Japanese NAFLD. The minor allele (t) increased NAFLD risk (OR 1.682, 95 % CI 1.289-2.196, p value 0.00013). CONCLUSION: This study confirmed the genetic association of missense SNP of TM6SF2, rs58542926, with plasma lipid levels in multiple East Asian ethnic groups and with NAFLD in Japanese individuals. PMID- 26758380 TI - Sugar Consumption and Changes in Dental Caries from Childhood to Adolescence. AB - There are no prospective studies investigating the effects of sugar-related feeding practices on changes in dental caries from early childhood to young adulthood. The aim of this study was to assess whether sugar-related feeding practices affect dental caries between the ages of 6 and 18 y. This birth cohort study was initiated in 1993 in Pelotas, Brazil. There were 3 dental clinical assessments; at ages 6 y (n = 359), 12 y (n = 339), and 18 y (n = 307). Sugar related feeding practices were assessed at ages 4, 15, and 18 y. Covariates included sex and life course variables, such as family income, breast-feeding, mother's education, regularity of dental visit, and child's toothbrushing habits. Group-based trajectory analysis was performed to characterize trajectories of time-varying independent variables that had at least 3 time points. We fitted a generalized linear mixed model assuming negative binomial distribution with log link function on 3-time repeated dental caries assessments. One in 5 participants was classified as "high" sugar consumers, and nearly 40% were "upward consumers." "Low consumers" accounted for >40% of the sample. High and upward sugar consumers had higher dental caries prevalence and mean DMFT in all cohort waves when compared with low sugar consumers. Caries occurred at a relatively constant rate over the period of study, but in all sugar consumption groups, the increment of dental caries was slightly higher between ages 6 and 12 y than between 12 and 18 y. Adjusted analysis showed that dental caries increment ratio between ages 6 and 18 y was 20% and 66% higher in upward and high sugar consumer groups as compared with low consumers. The higher the sugar consumption along the life course, the higher the dental caries increment. Even the low level of sugar consumption was related to dental caries, despite the use of fluoride. PMID- 26758381 TI - Longitudinal Multilevel Modeling of Facial Pain, Muscle Tension, and Stress. AB - The role of masticatory muscle activation on pain in temporomandibular muscle and joint disorders (TMJD) is controversial. This single-group, prospective panel study examined the relationships among masticatory muscle tension, emotional distress, and TMJD pain in a sample of 7,023 observations obtained from 171 individuals using longitudinal multilevel modeling. Three main hypotheses were tested. The first posited that emotional distress and muscle tension directly influenced pain (hypothesis 1a: Distress -> TMJD Pain; hypothesis 1b: Muscle Tension -> TMJD Pain). The second posited that emotional distress directly influenced muscle tension (Distress -> Muscle Tension), and the third posited that the effect of emotional distress on pain was mediated by muscle tension (Distress -> Muscle Tension -> TMJD pain). We also examined the fit of the data to possible alternative models. All the data used in this study were collected via an experience sampling methodology. The fit of the preferred models was better than that of the alternative models, with the preferred models explaining large proportions of the data, especially for level 2 variance (hypothesis 1a = 41% variance; hypothesis 1b = 69% variance; hypothesis 2 = 48% variance). In the mediation model, the addition of muscle tension to the model reduced the impact of emotional distress. The findings support a causal role for masticatory muscle tension in TMJD pain. Clinically, the results suggest that addressing tension and other oral parafunctions in those diagnosed with TMJDs should be an important part of the conservative, noninvasive care of individuals diagnosed with the myofascial pain or arthralgia of TMJD. PMID- 26758382 TI - Steric stabilization of nanoparticles with grafted low molecular weight ligands in highly concentrated brines including divalent ions. AB - Whereas numerous studies of stabilization of nanoparticles (NPs) in electrolytes have examined biological fluids, the interest has grown recently in media with much higher ionic strengths including seawater and brines relevant to environmental science and subsurface oil and gas reservoirs. Given that electrostatic repulsion is limited at extremely high ionic strengths due to charge screening, we have identified ligands that are well solvated in concentrated brine containing divalent cations and thus provide steric stabilization of silica nanoparticles. Specifically, the hydrodynamic diameter of silica nanoparticles with grafted low molecular weight ligands, a diol ether, [3 (2,3-dihydroxypropoxy)propyl]-trimethoxysilane, and a zwitterionic sulfobetaine, 3-([dimethyl(3-trimethoxysilyl)propyl]ammonio)propane-1-sulfonate, is shown with dynamic light scattering to remain essentially constant, indicating lack of aggregation, at room temperature and up to 80 degrees C for over 30 days. An extended DLVO model signifies that steric stabilization is strongly dominant against van der Waals attraction for ~10 nm particles given that these ligands are well solvated even in highly concentrated brine. In contrast, polyethylene glycol oligomers do not provide steric stabilization at elevated temperatures, even at conditions where the ligands are soluble, indicating complicating factors including bridging of the ether oxygens by divalent cations. PMID- 26758384 TI - Chemical constituents of Eugenia catharinae and their antioxidant activity. AB - Nine compounds were isolated from the leaves of Eugenia catharinae, namely monomethyl olivetol (1), beta-sitosterol (2), stigmasterol (3), uvaol (4), erythrodiol (5), rotundic acid (6), quercetin (7), catechin (8) and myricitrin (9). The structures of 1-9 were established through analysis of their spectroscopic (1H and 13C NMR) and spectrometric (MS) data. Compounds 1 and 6 are reported the first time in the Eugenia genus. In addition, these data were compared with those reported in the literature. The antioxidant activity of plant samples and compounds was measured using the DPPH radical scavenging assay. Flavonoids 7, 8, 9 and the ethanolic extract showed the best results, with IC50 values of 20.94 MUM, 44.20 MUM, 30.01 MUM and 58.82 MUg/mL, respectively. PMID- 26758383 TI - Parental beliefs and practice of spiritual methods for their sick children at a tertiary care hospital of Pakistan- a cross sectional questionnaire study. AB - BACKGROUND: Complementary and alternative medicine (CAM) comprises a variety of health care systems, practices, and products that are not usually thought to be part of allopathic medicine. This study investigated the parental beliefs and practices for use of spiritual methods in the treatment and early recovery of their children. METHODS: We performed a cross-sectional, descriptive study with convenience sampling of parents/caregivers of sick children who were admitted to the Children's Hospital in Multan. A trained interviewer collected the data. RESULTS: A total of 1280 forms were analyzed. The majority of respondents were mothers (1053, 82.4%), they resided in Multan (817, 63.8%), and were not educated (754, 58.9%). A total of 420 (32.8%) respondents had a low socioeconomic background, 601 (47%) were middle class, and 259 (20.2%) were upper class. Grandmothers/mothers advised spiritual methods in the majority of respondents (605, 85.9%). The parents used a variety of spiritual methods in 704 (55%) children. Economic status and education showed an inverse relation with the use of CAM. A total of 809 (63.2%) respondents believed that only a drug would heal the disease, while 575 (44.9%) believed that spiritual methods have a 25%-50% role in healing. A total of 1269 (99.1%) respondents believed that allopathic drugs are needed for healing, while only 0.9% considered otherwise. CONCLUSION: The majority of people believe that CAM is a contributory factor towards healing and does not interfere with allopathic treatment. PMID- 26758385 TI - A new technique for mixed-type pectus carinatum: modified Onen method. AB - We modified the Onen method for pectus carinatum repair and used a vertical incision instead of a transverse incision. The most important advantage gained by the vertical incision is that we can switch to the Ravitch method without needing an additional incision, by elongating the existing incision in patients in whom a pectus bar cannot be placed. We successfully performed the modified Onen technique in a 16-year-old boy with a mixed-type pectus carinatum deformity. PMID- 26758386 TI - A supervised texton based approach for automatic segmentation and measurement of the fetal head and femur in 2D ultrasound images. AB - This paper presents a supervised texton based approach for the accurate segmentation and measurement of ultrasound fetal head (BPD, OFD, HC) and femur (FL). The method consists of several steps. First, a non-linear diffusion technique is utilized to reduce the speckle noise. Then, based on the assumption that cross sectional intensity profiles of skull and femur can be approximated by Gaussian-like curves, a multi-scale and multi-orientation filter bank is designed to extract texton features specific to ultrasound fetal anatomic structure. The extracted texton cues, together with multi-scale local brightness, are then built into a unified framework for boundary detection of ultrasound fetal head and femur. Finally, for fetal head, a direct least square ellipse fitting method is used to construct a closed head contour, whilst, for fetal femur a closed contour is produced by connecting the detected femur boundaries. The presented method is demonstrated to be promising for clinical applications. Overall the evaluation results of fetal head segmentation and measurement from our method are comparable with the inter-observer difference of experts, with the best average precision of 96.85%, the maximum symmetric contour distance (MSD) of 1.46 mm, average symmetric contour distance (ASD) of 0.53 mm; while for fetal femur, the overall performance of our method is better than the inter-observer difference of experts, with the average precision of 84.37%, MSD of 2.72 mm and ASD of 0.31 mm. PMID- 26758387 TI - Upgrading ethanol to 1-butanol with a homogeneous air-stable ruthenium catalyst. AB - An amide-derived N,N,N-Ru(ii) complex catalyzes the conversion of EtOH to 1-BuOH with high activity. Conversion to alcohol upgraded products exceeds 250 turnovers per hour (>50% conversion) with 0.1 mol% catalyst loading. In addition to high activity for ethanol upgrading, catalytic reactions can be set up under ambient conditions with no loss in activity. PMID- 26758401 TI - Dipeptidyl Peptidase IV-Inhibitory Peptides Derived from Silver Carp (Hypophthalmichthys molitrix Val.) Proteins. AB - The dipeptidyl peptidase IV (DPP-IV)-inhibitory bioactivity of silver carp protein (SCP) hydrolysates were investigated, and their containing efficacious DPP-IV-inhibitory peptides were explored by in silico hydrolysis analysis, peptide separation combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) identification, and chemical synthesis. SCP hydrolysates generated by six proteases all showed efficient DPP-IV-inhibitory activities, and Neutrase generated hydrolysates had the greatest DPP-IV inhibition (IC50 of 1.12 mg/mL). In silico Neutrase hydrolysis revealed hundreds of fragments released from myosin, actin, and collagen of SCPs, which include different Pro-motif peptides but only three reported peptidic DPP-IV inhibitors with moderate or weak bioactivity. In addition, three new DPP-IV-inhibitory peptides were identified using LC-MS/MS; in particular, LPIIDI and APGPAGP showed high DPP-IV-inhibitory activity with IC50 of 105.44 and 229.14 MUM, respectively, and behaved in competitive/non-competitive mixed-type DPP-IV inhibition mode. The results indicate that the SCP-derived DPP-IV-inhibitory peptides could be potential functional ingredients in the diabetic diet. PMID- 26758390 TI - Quantification of the Metabolic State in Cell-Model of Parkinson's Disease by Fluorescence Lifetime Imaging Microscopy. AB - Intracellular endogenous fluorescent co-enzymes, reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD), play a pivotal role in cellular metabolism; quantitative assessment of their presence in living cells can be exploited to monitor cellular energetics in Parkinson's disease (PD), a neurodegenerative disorder. Here, we applied two-photon fluorescence lifetime imaging microscopy (2P-FLIM) to noninvasively measure the fluorescence lifetime components of NADH and FAD, and their relative contributions in MPP(+) (1-methyl 4-phenylpyridinium) treated neuronal cells, derived from PC12 cells treated with nerve growth factor (NGF), to mimic PD conditions. A systematic FLIM data analysis showed a statistically significant (p < 0.001) decrease in the fluorescence lifetime of both free and protein-bound NADH, as well as free and protein-bound FAD in MPP(+) treated cells. On the relative contributions of the free and protein-bound NADH and FAD to the life time, however, both the free NADH contribution and the corresponding protein-bound FAD contribution increase significantly (p < 0.001) in MPP(+) treated cells, compared to control cells. These results, which indicate a shift in energy production in the MPP(+) treated cells from oxidative phosphorylation towards anaerobic glycolysis, can potentially be used as cellular metabolic metrics to assess the condition of PD at the cellular level. PMID- 26758402 TI - Variation of topical application to skin under good clinical practice (GCP): A "best performance" scenario. AB - INTRODUCTION: Application of topical products by individuals is inherently variable and accurate dosing can be difficult to control. Variation of the dose used under optimal conditions in drug trials is unknown. METHODS: This trial was part of a double-blind, randomized, placebo-controlled good clinical practice (GCP) study designed to investigate the local tolerability and safety on healthy skin of captopril 1% ointment versus a placebo ointment. Volunteers were instructed to apply an even layer of test ointment on a 51 cm(2) test area on the arm twice daily over a 3-week period. At weekly follow-up visits, tubes were weighed and adherence to treatment checked. RESULTS: Of the 37 recruited volunteers, 36 (17 women, 19 men) completed the study. Their mean age was 24 (18 35) years. A 13.6-fold difference in the applied amount was found ranging from 1.26 mg/cm(2) to 17.19 mg/cm(2) per application at week 4, with median 5.60 mg/cm(2) applied versus 2 mg/cm(2) (standard for good application) resulting in a 2.8-fold over-dosage. CONCLUSION: There was a major variation of test ointment application studied under GCP conditions with adherent participants. In dermatological practice, the variation is assumed to be even higher. This should be taken into account in clinical trials, especially dose-finding studies typically operating with 3-5-fold increments. PMID- 26758403 TI - DNA methylation analysis in constitutional disorders: Clinical implications of the epigenome. AB - Genomic, chromosomal, and gene-specific changes in the DNA sequence underpin both phenotypic variations in populations as well as disease associations, and the application of genomic technologies for the identification of constitutional (inherited) or somatic (acquired) alterations in DNA sequence forms a cornerstone of clinical and molecular genetics. In addition to the disruption of primary DNA sequence, the modulation of DNA function by epigenetic phenomena, in particular by DNA methylation, has long been known to play a role in the regulation of gene expression and consequent pathogenesis. However, these epigenetic factors have been identified only in a handful of pediatric conditions, including imprinting disorders. Technological advances in the past decade that have revolutionized clinical genomics are now rapidly being applied to the emerging discipline of clinical epigenomics. Here, we present an overview of epigenetic mechanisms with a focus on DNA modifications, including the molecular mechanisms of DNA methylation and subtypes of DNA modifications, and we describe the classic and emerging genomic technologies that are being applied to this study. This review focuses primarily on constitutional epigenomic conditions associated with a spectrum of developmental and intellectual disabilities. Epigenomic disorders are discussed in the context of global genomic disorders, imprinting disorders, and single gene disorders. We include a section focused on integration of genetic and epigenetic mechanisms together with their effect on clinical phenotypes. Finally, we summarize emerging epigenomic technologies and their impact on diagnostic aspects of constitutional genetic and epigenetic disorders. PMID- 26758404 TI - Effectiveness of a programme to reduce the burden of catheter-related bloodstream infections in a tertiary hospital. AB - The objective of this study was to assess the effectiveness of a catheter-related bloodstream infection (CR BSI) reduction programme and healthcare workers' compliance with recommendations. A 3-year surveillance programme of CR BSIs in all hospital settings was implemented. As part of the programme, there was a direct observation of insertion and maintenance of central venous catheters (CVCs) to determine performance. A total of 38 education courses were held over the study period and feedback reports with the results of surveillance and recommendations were delivered to healthcare workers every 6 months. A total of 6722 short-term CVCs were inserted in 4982 patients for 58 763 catheter-days. Improvements of compliance with hand hygiene was verified at the insertion (87.1 100%, P < 0.001) and maintenance (51.1-72.1%, P = 0.029) of CVCs; and the use of chlorhexidine for skin disinfection was implemented at insertion (35.7-65.4%, P < 0.001) and maintenance (33.3-45.9%, P < 0.197) of CVCs. There were 266 CR BSI incidents recorded with an annual incidence density of 5.75/1000 catheter-days in the first year, 4.38 in the second year [rate ratio (RR) 0.76, 95% confidence interval (CI) 0.57-1.01] and 3.46 in the third year (RR 0.60, 95% CI 0.44-0.81). The education programme clearly improved compliance with recommendations for CVC handling, and was effective in reducing the burden of CR BSIs. PMID- 26758406 TI - Cardiac remodelling and function with primary mitral valve insufficiency studied by magnetic resonance imaging. AB - AIMS: Evaluation of patients with primary mitral valve insufficiency (MI) is best supported by quantitative measures. Cardiovascular magnetic resonance imaging (CMR) offers flow and cardiac chamber volume quantification. We studied cardiac remodelling with CMR to determine MI regurgitation volumes (MIVol) related to severe MI. METHODS AND RESULTS: In total, 24, 20, and 28 patients determined to have mild, moderate, and severe primary MI, respectively, were studied. Combining cine stacks with phase-contrast velocity mapping across the ascending aorta, CMR determined MIVol was reproducibly obtained as the difference between left ventricular (LV) stroke volume and aortic forward flow (Aoflow). With increasing MI severity, MIVol, left heart volumes, and pulmonary venous diameters increased (P < 0.01). Severe MI with LV end-systolic diameter of 40 mm was signified by MIVol >40 mL, MI regurgitant fraction >0.30, LV end-diastolic volume (LVEDV(i)) >108 mL m(-2), and a total left heart volume >188 mL m(-2) with dilated pulmonary veins and a LVEDV/right ventricular EDV ratio >1.2. In severe MI, LV ejection fraction was unaffected, but the Aoflow and the peak ejection rate indexed to LVEDV were lowered (P < 0.05). In surgical patients, the MIVol correlated to the decrease in LV dimension after valve surgery (P < 0.02). CONCLUSION: CMR provides a reproducible quantitative technique for evaluation of MI, as MIVol and cardiac chamber volumes can be held against diagnostic cut-off values. The Aoflow and peak ejection rate indexed to LVEDV may reveal early LV systolic dysfunction in patients with severe MI. Severe MI is related to lower MI regurgitation volume and fraction than previously believed. PMID- 26758405 TI - Venturing in coral larval chimerism: a compact functional domain with fostered genotypic diversity. AB - The globally distributed coral species Pocillopora damicornis is known to release either sexual or asexual derived planula-larvae in various reef locations. Using microsatellite loci as markers, we documented the release of asexually derived chimeric larvae (CL), originating from mosaicked maternal colonies that were also chimeras, at Thai and Philippines reefs. The CL, each presenting different combinations of maternal genotypic constituents, create genetically-complex sets of asexual propagules. This novel mode of inheritance in corals challenges classical postulations of sexual/asexual reproduction traits, as asexual derived CL represent an alliance between genotypes that significantly sways the recruits' absolute fitness. This type of inherited chimerism, while enhancing intra-entity genetic heterogeneity, is an evolutionary tactic used to increase genetic heterogeneity, primarily in new areas colonized by a limited number of larvae. Chimerism may also facilitate combat global change impacts by exhibiting adjustable genomic combinations of within-chimera traits that could withstand alterable environmental pressures, helping Pocillopora become a successful cosmopolitan species. PMID- 26758408 TI - Giant left atrial appendage aneurysm in association with tricuspid atresia. PMID- 26758407 TI - Ten-year longitudinal change in aortic stiffness assessed by cardiac MRI in the second half of the human lifespan: the multi-ethnic study of atherosclerosis. AB - AIMS: Longitudinal determinants of aortic stiffness (AS) measured by magnetic resonance imaging (MRI) have not been assessed in a large community-based population. Our aim was to examine the determinants of change in thoracic AS over 10 years of follow-up in a multi-ethnic population of individuals 45 years of age and older measured by MRI. METHODS AND RESULTS: We studied 1160 participants (mean age = 60 +/- 9 years at baseline, 45% male) with aortic MRI at both the MESA Year 0 and Year 10 examinations. Ascending and descending aorta distensibility (AAD/DAD) and aortic arch pulse-wave velocity (PWV) were measured using MRI. Determinants of the change in AS parameters over 10 years were assessed using linear regression adjusted for baseline values, demographic variables, baseline risk factors and change in risk factors, and chronic risk exposure. AAD and DAD decreased slightly (5% decrease in median for AAD: 1.33 1.26 mmHg(-1) . 10(-3), P = 0.008; 5% decrease in median for DAD: 1.73-1.64 mmHg( 1) . 10(-3), P < 0.001), and PWV increased over 10 years (18% increase in median: 6.8-8.0 m/s P < 0.001). Baseline age was related to a reduction in AAD and DAD and an increase in PWV throughout the follow-up period. Baseline and change in mean blood pressure and continued smoking were associated with a reduction in AAD and an increase in PWV. Furthermore, baseline heart rate was also related to a reduction in AAD and DAD. Blood pressure normalization was related to less aortic stiffening throughout the follow-up period. CONCLUSIONS: In our longitudinal, community-based cohort study of adult individuals aged 45 years or greater, greater mean blood pressure and a history of smoking history were associated with increased aortic stiffening over 10 years as assessed by MRI. PMID- 26758409 TI - Lipoprotein(a) is a risk factor for aortic and mitral valvular stenosis in peripheral arterial disease. AB - AIMS: Lipoprotein(a) (Lp(a)) levels have been associated with aortic valvular calcification and stenosis. The prevalence and risk factors, including Lp(a) level, for valvular heart disease (VHD) were investigated in patients with peripheral arterial disease (PAD). METHODS AND RESULTS: Echocardiography was performed in 861 patients with PAD to detect abnormal cardiac findings. Relationships between VHD and risk factors were analysed. The prevalence of VHD was 43.6%, and the prevalences of aortic valve regurgitation (AR), mitral valve regurgitation (MR), aortic valve stenosis (AS), mitral valve stenosis (MS), and tricuspid regurgitation (TR) were 26.8, 19.7, 5.9, 1.3, and 9.4%, respectively. In stepwise multiple regression analysis, severity of AR was related to age, albumin, and estimated glomerular filtration rate (eGFR); MR was related to eGFR and age; AS was related to eGFR, Lp(a), and age; MS was related to Lp(a) and female gender; and TR was related to age, body mass index, and total cholesterol (all P < 0.05). Lp(a) level was higher in patients with AS compared with those without AS [34.0 (16.7-50.0) vs. 20.0 (11.0-35.0) mg/dL, P = 0.002], in patients with MS compared with those without MS [37.0 (21.5-77.3) vs. 21.0 (11.0-35.0), P = 0.037], and in patients with AS and/or MS compared with those without AS and MS [34.0 (17.3-50.0) vs. 20.0 (11.0-35.0), P = 0.001]. Lp(a) levels were related to low-density lipoprotein cholesterol and high-sensitivity C-reactive protein levels (P = 0.004). CONCLUSIONS: The high prevalence of VHD is found, especially in AR and MR, and the Lp(a) level is associated with increased risks of AS and MS in patients with PAD. PMID- 26758410 TI - Relationship between mitral annulus function and mitral regurgitation severity and left atrial remodelling in patients with primary mitral regurgitation. AB - AIMS: To explore the relationship between the mitral annular (MA) remodelling and dysfunction, mitral regurgitation (MR) severity, left ventricular (LV) and atrial (LA) size and function in patients with organic MR (OMR). METHODS AND RESULTS: A total of 52 patients (57 +/- 15 years, 31 men) with mild to severe OMR and 52 controls underwent 3D transthoracic echocardiography acquisitions of the mitral valve (MV), LA, and LV. MA geometry and dynamics, LV and LA volumes, LV ejection fraction (LVEF) and emptying fractions (LAEF) were assessed using dedicated software packages. LA and LV myocardial deformations were assessed using 2D speckle-tracking echocardiography. OMR patients presented larger and more spherical MA than controls during the entire systole (P < 0.001). Although the MA non-planarity at early-systole was similar between OMR and controls (157 +/- 13 degrees vs. 153 +/- 12 degrees , P = NS), the MA became flatter from mid- to end systole (153 +/- 12 vs. 146 +/- 10 degrees and 157 +/- 12 vs. 147 +/- 8 degrees , P < 0.01) in OMR. MA area fractional change was lower in patients with OMR (22 +/- 5% vs. 28 +/- 5%, P < 0.001), and correlated with the MR orifice and volume (r = -0.52 and r = -0.55). MA fractional area change correlated with LA minimum and maximum volumes (r = 0.77 and r = 0.70), total and active LAEF (r = 0.72 and r = 0.76), and LA negative strain and strain rate (r = 0.52 and r = 0.57), but not with the LVEF or LV global longitudinal strain. In a multivariate regression model using LAEF and LVEF, solely active LAEF correlated with the MA fractional area change (beta = 0.51, P = 0.005). CONCLUSION: In patients with OMR, MA reduced function correlates with the MR severity and the LA size and function, but not with the LV function. PMID- 26758411 TI - Calcium distribution patterns of the aortic valve as a risk factor for the need of permanent pacemaker implantation after transcatheter aortic valve implantation. AB - AIMS: New-onset conduction disturbances still represent a considerable problem after transcatheter aortic valve implantation (TAVI). The aim of this study was to identify calcification patterns with an elevated risk for permanent pacemaker implantation (PPI) after TAVI and investigate underlying mechanisms in an ex vivo setting. METHODS AND RESULTS: One hundred and sixty-two patients who underwent TAVI with the Edwards SAPIEN XT(r) or Medtronic CoreValve(r) at our institution were analysed. The calcium load of the device landing zone was quantified with 3mensio(r), and calcium patterns with an elevated risk for PPI were identified. Ex vivo simulations of balloon valvuloplasty were performed in 3D-printed silicone annuli of patients matching the identified risk profile. Patients with a calcium load of the left coronary cusp (LCC) above 209 mm3 had a higher rate of PPI than patients below this threshold (16.7 vs. 2.6%, P = 0.003). Multivariate regression revealed pre-existing right bundle branch block (RBBB) and increased LCC calcification as independent predictors for PPI. Simulation of the TAVI procedure in a silicone annulus revealed an off-centreline shift of the valvuloplasty balloon and transcatheter heart valve away from the LCC towards the commissure between right- and non-coronary cusp. CONCLUSION: Pre-existing RBBB and elevated LCC calcification were identified as independent predictors for PPI. These two risk factors enabled us to distinguish between patients according to their risk for PPI after TAVI. Ex vivo simulations suggested an off-centreline shift of the balloon as a possible explanation. PMID- 26758413 TI - Editorial: Effects of Aging on Circadian and Sleep Timing. PMID- 26758412 TI - Normal values of left ventricular mass and cardiac chamber volumes assessed by 320-detector computed tomography angiography in the Copenhagen General Population Study. AB - AIMS: Normal values of left ventricular mass (LVM) and cardiac chamber sizes are prerequisites for the diagnosis of individuals with heart disease. LVM and cardiac chamber sizes may be recorded during cardiac computed tomography angiography (CCTA), and thus modality specific normal values are needed. METHODS AND RESULTS: We studied 569 healthy subjects undergoing 320-detector CCTA as a part of the Copenhagen General Population Study. LVM as well as ventricular and atrial volumes was assessed with semi-automated software stratified by gender and age decades and indexed by body surface area (BSA). Mean age was 55 (range: 40 84) years, and 188 (33%) were men. BSA-indexed 97.5th percentile cut-off values: LVM = 80 and 65 gr/m(2), left ventricular volume = 97 and 83 mL/m(2), right ventricular volume = 120 and 102 mL/m(2), left atrial volume = 60 and 57 mL/m(2), and right atrial volume = 85 and 73 mL/m(2) for men and women, respectively. Men had greater absolute and indexed LVM and chamber volumes than women. For both genders, indexed ventricular volumes declined, whereas indexed atrial volumes increased in advancing age groups. For men, indexed LVM declined in advancing age groups. In multivariate analyses, gender, BSA, systolic blood pressure, and hard physical activity accounted for 63% of variance in LVM. CONCLUSION: In this cross sectional general population study, men have greater indexed LVM and chamber volumes than women, and cardiac indexed volumes vary between age groups in both genders. These findings demonstrate the need for age- and gender-specific normal values for clinical diagnostic purposes. PMID- 26758414 TI - Erratum. AB - The authors have modified few sentences and figures in the article entitled as "Age-related decrease of sirtuin 2 protein in human peripheral blood mononuclear cells" published in the journal "Current Aging Science" Vol. 8, Issue no. 3. The correct sentences and figures are as follows: METHODS SECTION "The healthy control group consisted of 91 volunteers (aged 20 to 58 years old, male: 46 cases, female: 45 cases). Exclusion criteria were immune disorders, diabetes, metabolic diseases or malignant diseases." RESULTS SECTION An inverse correlation between the SIRT2 level and donor age was observed (Fig. 1, r= -0.28). Noteworthy, concentrations of SIRT2 in PBMCs, which were analyzed by ELISA, also showed an inverse correlation with donor age (Fig. 2, r= -0.25). PMID- 26758415 TI - Biexciton Emission from Edges and Grain Boundaries of Triangular WS2 Monolayers. AB - Monolayer tungsten disulfides (WS2) constitute a high quantum yield two dimensional (2D) system, and can be synthesized on a large area using chemical vapor deposition (CVD), suggesting promising nanophotonics applications. However, spatially nonuniform photoluminescence (PL) intensities and peak wavelengths observed in single WS2 grains have puzzled researchers, with the origins of variation in relative contributions of excitons, trions, and biexcitons to the PL emission not well understood. Here, we present nanoscale PL and Raman spectroscopy images of triangular CVD-grown WS2 monolayers of different sizes, with these images obtained under different temperatures and values of excitation power. Intense PL emissions were observed around the edges of individual WS2 grains and the grain boundaries between partly merged WS2 grains. The predominant origin of the main PL emission from these regions changed from neutral excitons to trions and biexcitons with increasing laser excitation power, with biexcitons completely dominating the PL emission for the high-power condition. The intense PL emission and the preferential formation of biexcitons in the edges and grain boundaries of monolayer WS2 were attributed to larger population of charge carriers caused by the excessive incorporation of growth promoters during the CVD, suggesting positive roles of excessive carriers in the PL efficiency of TMD monolayers. Our comprehensive nanoscale spectroscopic investigation sheds light on the dynamic competition between exciton complexes occurring in monolayer WS2, suggesting a rich variety of ways to engineer new nanophotonic functions using 2D transition metal dichalcogenide monolayers. PMID- 26758416 TI - Parity and All-cause Mortality in Women and Men: A Dose-Response Meta-Analysis of Cohort Studies. AB - To quantitatively assess the association between parity and all-cause mortality, we conducted a meta-analysis of cohort studies. Relevant reports were identified from PubMed and Embase databases. Cohort studies with relative risks (RRs) and 95% confidence intervals (CIs) of all-cause mortality in three or more categories of parity were eligible. Eighteen articles with 2,813,418 participants were included. Results showed that participants with no live birth had higher risk of all-cause mortality (RR= 1.19, 95% CI = 1.03-1.38; I(2) = 96.7%, P < 0.001) compared with participants with one or more live births. Nonlinear dose-response association was found between parity and all-cause mortality (P for non-linearity < 0.0001). Our findings suggest that moderate-level parity is inversely associated with all-cause mortality. PMID- 26758417 TI - N-(3-oxo-acyl) homoserine lactone inhibits tumor growth independent of Bcl-2 proteins. AB - Pseudomonas aeruginosa produces N-(3-oxododecanoyl)-homoserine lactone (C12) as a quorum-sensing molecule for bacterial communication. C12 has also been reported to induce apoptosis in various types of tumor cells. However, the detailed molecular mechanism of C12-triggerred tumor cell apoptosis is still unclear. In addition, it is completely unknown whether C12 possesses any potential therapeutic effects in vivo. Our data indicate that, unlike most apoptotic inducers, C12 evokes a novel form of apoptosis in tumor cells through inducing mitochondrial membrane permeabilization independent of both pro- and anti apoptotic Bcl-2 proteins. Importantly, C12 inhibits tumor growth in animals regardless of either pro- or anti-apoptotic Bcl-2 proteins. Furthermore, opposite to conventional chemotherapeutics, C12 requires paraoxonase 2 (PON2) to exert its cytotoxicity on tumor cells in vitro and its inhibitory effects on tumor growth in vivo. Overall, our results demonstrate that C12 inhibits tumor growth independent of both pro- and anti-apoptotic Bcl-2 proteins, and through inducing unique apoptotic signaling mediated by PON2 in tumor cells. PMID- 26758420 TI - Activated hepatic stellate cells promote liver cancer by induction of myeloid derived suppressor cells through cyclooxygenase-2. AB - Hepatic stellate cells (HSCs) are critical mediators of immunosuppression and the pathogenesis of hepatocellular carcinoma (HCC). Our previous work indicates that HSCs promote HCC progression by enhancing immunosuppressive cell populations including myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). MDSCs are induced by inflammatory cytokines (e.g., prostaglandins) and are important in immune suppression. However, how HSCs mediate expansion of MDSCs is uncertain. Thus, we studied activated HSCs that could induce MDSCs from bone marrow cells and noted that HSC-induced MDSCs up-regulated immunosuppressive activity via iNOS, Arg-1, and IL-4Ralpha. After treating cells with a COX-2 inhibitor or an EP4 antagonist, we established that HSC-induced MDSC accumulation was mediated by the COX2-PGE2-EP4 signaling. Furthermore, in vivo animal studies confirmed that inhibition of HSC-derived PGE2 could inhibit HSC-induced MDSC accumulation and HCC growth. Thus, our data show that HSCs are required for MDSC accumulation mediated by the COX2-PGE2-EP4 pathway, and these data are the first to link HSC and MDSC subsets in HCC immune microenvironment and provide a rationale for targeting PGE2 signaling for HCC therapy. PMID- 26758418 TI - EM23, a natural sesquiterpene lactone, targets thioredoxin reductase to activate JNK and cell death pathways in human cervical cancer cells. AB - Sesquiterpene lactones (SLs) are the active constituents of a variety of medicinal plants and found to have potential anticancer activities. However, the intracellular molecular targets of SLs and the underlying molecular mechanisms have not been well elucidated. In this study, we observed that EM23, a natural SL, exhibited anti-cancer activity in human cervical cancer cell lines by inducing apoptosis as indicated by caspase 3 activation, XIAP downregulation and mitochondrial dysfunction. Mechanistic studies indicated that EM23-induced apoptosis was mediated by reactive oxygen species (ROS) and the knockdown of thioredoxin (Trx) or thioredoxin reductase (TrxR) resulted in a reduction in apoptosis. EM23 attenuated TrxR activity by alkylation of C-terminal redox-active site Sec498 of TrxR and inhibited the expression levels of Trx/TrxR to facilitate ROS accumulation. Furthermore, inhibition of Trx/TrxR system resulted in the dissociation of ASK1 from Trx and the downstream activation of JNK. Pretreatment with ASK1/JNK inhibitors partially rescued cells from EM23-induced apoptosis. Additionally, EM23 inhibited Akt/mTOR pathway and induced autophagy, which was observed to be proapoptotic and mediated by ROS. Together, these results reveal a potential molecular mechanism for the apoptotic induction observed with SL compound EM23, and emphasize its putative role as a therapeutic agent for human cervical cancer. PMID- 26758419 TI - Down-regulation of C12orf59 is associated with a poor prognosis and VHL mutations in renal cell carcinoma. AB - C12orf59 is newly identified gene in kidney. However, the relation of C12orf59 expression and clinic features is unknown. Here, our study showed that C12orf59 was broadly expressed in normal human tissues with high expression levels in kidney while its expression is beyond detectable in a panel of cancer cell lines. C12orf59 expression in RCC was significantly decreased compared with corresponding adjacent noncancerous tissues (P < 0.01). The decreased C12orf59 expression was correlated with lymph node status (P < 0.05), distant metastases (P < 0.05), poor survival (P < 0.001) (HR 3.00; 95% CI, 1.29-7.53), VHL non-sense mutations or frame-shift mutations (P < 0.01), and UMPP gene non-sense mutations or frame-shift mutations (P = 0.01). Thus, we propose that the decreased C12orf59 expression status is a prognostic biomarker of ccRCC and cooperates with the loss of VHL all the while promoting renal carcinogenesis. PMID- 26758421 TI - Bufalin enhances antitumor effect of paclitaxel on cervical tumorigenesis via inhibiting the integrin alpha2/beta5/FAK signaling pathway. AB - While Bufalin restrains primary tumorigenesis, the role of Bufalin in cervical cancer remains unclear. Here, we show that Bufalin can inhibit cervical cancer cell proliferation, block cell cycle in G2/M phase, induce cellular apoptosis and reduce cell metastasis through stimulation of p21(waf/cip1), p27(cip/kip), Bax and E-cadherin, and suppression of cyclin A, cyclin B1, CDK2, Bcl-2, Bcl-xl, MMP9 and SNAIL1. Further study suggests that Bufalin has no apparent damage to human normal cervical cells at the low concentration (<20nM), but increases the chemotherapeutic efficacy of paclitaxel. Mechanistic study reveals that Bufalin suppresses the integrin alpha2/FAK/AKT1/ GSK3beta signaling. Finally, in vivo studies show that Bufalin blocks the Siha-induced xenograft tumor growth without detectable toxicity in the animals at the therapeutic doses, and the combination treatment of Bufalin and paclitaxel more efficiently inhibits xenograft tumor growth. Thus, Bufalin may be developed as a potential therapeutic agent to treat cervical cancer. PMID- 26758422 TI - A phase II study of belinostat (PXD101) in relapsed and refractory aggressive B cell lymphomas: SWOG S0520. AB - Recent advances in diffuse large B-cell lymphomas (DLBCL) have underscored the importance of tumor microenvironment in escaping host anti-tumor responses. One mechanism is loss of major histocompatibility Class II antigens (MHCII) associated with decreased tumor infiltrating T lymphocytes (TIL) and poor survival. Transcription of MHCII is controlled by CIITA which in turn is regulated by histone acetylation. In this study, we hypothesized that HDAC inhibition with belinostat increases MHCII, CIITA expression, TIL and improves patient outcomes. Primary objective was evaluation of toxicity and response. Twenty-two patients were enrolled for the study. Belinostat was well tolerated with mild toxicity. Two partial responses were observed at 5, 13 months after registration for an overall response rate (ORR) (95% CI) of 10.5% (1.3-33.1%), and three patients had stable disease for 4.7, 42.3+, and 68.4 + months with minimum 3-year follow-up. Included correlative studies support the hypothesis and serve as the basis for SWOG S0806 combining vorinostat with R-CHOP. PMID- 26758425 TI - Coupling curvature-dependent and shear stress-stimulated neotissue growth in dynamic bioreactor cultures: a 3D computational model of a complete scaffold. AB - The main challenge in tissue engineering consists in understanding and controlling the growth process of in vitro cultured neotissues toward obtaining functional tissues. Computational models can provide crucial information on appropriate bioreactor and scaffold design but also on the bioprocess environment and culture conditions. In this study, the development of a 3D model using the level set method to capture the growth of a microporous neotissue domain in a dynamic culture environment (perfusion bioreactor) was pursued. In our model, neotissue growth velocity was influenced by scaffold geometry as well as by flow- induced shear stresses. The neotissue was modeled as a homogenous porous medium with a given permeability, and the Brinkman equation was used to calculate the flow profile in both neotissue and void space. Neotissue growth was modeled until the scaffold void volume was filled, thus capturing already established experimental observations, in particular the differences between scaffold filling under different flow regimes. This tool is envisaged as a scaffold shape and bioprocess optimization tool with predictive capacities. It will allow controlling fluid flow during long-term culture, whereby neotissue growth alters flow patterns, in order to provide shear stress profiles and magnitudes across the whole scaffold volume influencing, in turn, the neotissue growth. PMID- 26758423 TI - Adipose-derived stem cells increase angiogenesis through matrix metalloproteinase dependent collagen remodeling. AB - Adipose-derived stem cells (ASCs) are key regulators of new blood vessel formation and widely investigated for their role in tissue regeneration and tumorigenesis. However, the cellular and molecular mechanisms through which ASCs regulate angiogenesis are not well understood. Here, it was our goal to test the functional contribution of ASC-mediated extracellular matrix (ECM) remodeling on endothelial cell invasion. To isolate the effect of ECM-remodeling, ASCs were embedded within 3-D collagen type I hydrogels and pre-cultured for 7 days; controls were not pre-cultured. A confluent monolayer of human umbilical vein endothelial cells (HUVECs) was seeded on top and its invasion into the underlying hydrogel was analyzed. Without pre-culture, ASCs inhibited vascular sprouting by stabilizing the endothelium. In contrast, 7 day pre-culture of ASCs drastically increased invasion by HUVECs. This effect was largely mediated by proteolytic ECM degradation by ASC-derived matrix metalloproteinases (MMPs) rather than vascular endothelial growth factor (VEGF), as our results indicated that blockade of MMPs, but not VEGF, inhibited endothelial sprouting. Collectively, these data suggest that the angiogenic capability of ASCs is modulated by their proteolytic remodeling of the ECM, opening new avenues for pro- and anti-angiogenic therapies. PMID- 26758424 TI - A Drosophila RNAi library modulates Hippo pathway-dependent tissue growth. AB - Libraries of transgenic Drosophila melanogaster carrying RNA interference (RNAi) constructs have been used extensively to perform large-scale functional genetic screens in vivo. For example, RNAi screens have facilitated the discovery of multiple components of the Hippo pathway, an evolutionarily conserved growth regulatory network. Here we investigate an important technical limitation with the widely used VDRC KK RNAi collection. We find that approximately 25% of VDRC KK RNAi lines cause false-positive enhancement of the Hippo pathway, owing to ectopic expression of the Tiptop transcription factor. Of relevance to the broader Drosophila community, ectopic tiptop (tio) expression can also cause organ malformations and mask phenotypes such as organ overgrowth. To enhance the use of the VDRC KK RNAi library, we have generated a D. melanogaster strain that will allow researchers to test, in a single cross, whether their genetic screen of interest will be affected by ectopic tio expression. PMID- 26758426 TI - A study on the clinical outcomes of patients with revision surgery for adjacent segment disease after 10-year's anterior cervical spine surgery. AB - BACKGROUND: The purpose of this study was to investigate the clinical outcomes of anterior cervical discectomy and fusion (ACDF) or anterior cervical corpectomy and fusion (ACCF) as a revision surgery for adjacent segment disease (ASD) after primary surgery. METHODS: There were 35 patients who underwent anterior cervical spine surgery for symptomatic recurrent radicular or myelopathic symptoms from ASD. According to the ASD involved levels superior or inferior to the previous operated level, patients were divided into two groups: superior and inferior groups. The patients were also grouped into ACDF and ACCF groups by who received ACDF or ACCF as revision surgery for ASD. Clinical evaluations were performed preoperatively and repeated at 2 years after operation. RESULTS: In this study, a total of 35 patients with a minimum of 2 years of follow-up data were available for analysis. There were 20 patients in the superior group and 15 patients in the inferior group according to the ASD developed at levels. Of these 35 patients, according to the treatment method, 12 patients were in the ACCF group and 23 patients were in the ACDF group. The Japanese Orthopaedic Association (JOA), Neck Disability Index (NDI), and visual analogue scale (VAS) on arm pain and neck pain scores demonstrated significant improvement compared to the preoperative scores in both groups (superior and inferior groups or ACDF and ACCF groups) (P < 0.05). However, there was no difference between the two groups (superior and inferior groups or ACDF and ACCF groups) (P > 0.05). CONCLUSIONS: According to our study, both superior and inferior adjacent-level groups together with ACDF and ACCF groups maintained favorable clinical results on patients who underwent one-level ACDF for symptomatic new radicular or myelopathic symptoms. PMID- 26758427 TI - Circulating serum levels of angiopoietin-1 and angiopoietin-2 in nasopharynx and larynx carcinoma patients. AB - We aimed to determine the serum levels of angiogenic factors, namely angiopoietins, in nasopharyngeal and laryngeal carcinoma patients. We also aimed to seek the relation of these molecules with tumor grade and their utility as diagnostic biomarkers. We evaluated angiopoietin 1 and 2 levels innasopharynx and larynx cancer patients before treatment. Angiopoietin 2 levels were significantly elevated in larynx carcinoma patients and tended to be elevated in nasopharynx cancer patients compared with healthy controls. However, angiopoietin 1 levels were similar in cancer patients and controls. Angiopoietin 1 levels were significantly higher in nasopharyngeal cancer patients with advanced stages compared to earlier stages. On the other hand, angiopoietin 2 levels were similar in advanced and earlier stage cancer patients. PMID- 26758429 TI - Erratum to: Abstract supplement The 42nd Congress of the International Society of Oncology and Biomarkers "ONOCOLOGY IN THE BIOMARKER ERA: Biology - Diagnostics - Therapy" ISOBM 2015 : October 3-7, 2015, Zakopane, POLAND. PMID- 26758428 TI - CASP 3 genetic polymorphisms and risk of Hepatocellular carcinoma: a case-control study in a Chinese population. AB - Caspase (CASP) 3 is an important caspase in the apoptosis pathway and plays an important role in the development and progression of cancer. We hypothesized that genetic variants in CASP 3 may modify individual susceptibility to hepatocellular carcinoma (HCC). Five hundred HCC cases in West China Hospital were selected, and 500 healthy cases with the same gender, age (+/-5 years), and residence place were selected as control group, with proportion of 1:1. The matrix-assisted laser desorption ionization time-of-flight mass spectrometry method was performed to detect these polymorphisms. Among the 500 cases and 500 controls with DNA samples, the genotyping was successful for the CASP3 polymorphisms (rs6948, rs1049216, and rs12108497) in 486 HCC cases and 495 controls, which were included in the final analyses.The results showed that the genotype frequencies of the CASP3 did not differ significantly between the HCC patients and the control group (P > 0.05). However, when stratifying by age, sex, smoking, drinking, HBV carrier status, and family history of cancer, we found that the variant genotypes (CT + TT) of the CASP3 rs12108497 were associated with a significant increased risk of HCC among smoking individuals (adjusted OR = 2.31, 95 % CI = 1.11-4.79). No significant association was observed between the other two polymorphisms of the CASP3 gene and risk of HCC in any stratification analysis. These results suggest that the CASP3 rs12108497 polymorphism may play a role in the development of HCC among smoking individuals in the Chinese population. PMID- 26758430 TI - MicroRNA-340 inhibits the migration, invasion, and metastasis of breast cancer cells by targeting Wnt pathway. AB - MicroRNAs (miRNAs) play a key role in tumor metastasis based on their capacity to regulate the expression of tumor-related genes. Over-expression of key genes such as c-MYC and CTNNB1 (encoding beta-catenin) in Wnt/beta-catenin-dependent and ROCK1 in Wnt/beta-catenin-independent signaling pathways (Rho/Rho-associated kinase (ROCK) signaling pathway) has already been identified as the hallmarks of many tumors, and their role in breast cancer has also been investigated and confirmed. miR-340 characterization as an onco-suppressor miRNA has been previously reported. However, the mechanism by which it inhibits metastasis has not been completely elucidated. Quantitative real-time PCR (qPCR), Western blot, and luciferase assays were used to confirm the effect of miR-340 on the 3' untranslated region (UTR) of the target genes. Lentiviral particles containing miR-340 were also used to evaluate the effect of miR-340 restoration on cell proliferation, migration, and invasion in vitro in the invasive MDA-MB-231 cell line. By applying bioinformatic approaches for the prediction of miRNAs targeting 3'-UTRs of CTNNB1, c-MYC, and ROCK1, we found out that miR-340 could dramatically down-regulate metastasis by targeting Wnt signaling in breast cancer cells. In the current study, analyzing miR-340 by reverse transcription quantitative PCR (RT-qPCR) in MDA-MB-231 showed that it was remarkably down-regulated in the metastatic breast cancer cell line. We found that restoration of miR-340 in the invasive breast cancer cell line, MDA-MB-231, suppresses the expression of the target genes' messenger RNA (mRNA) and protein and, as a result, inhibits tumor cell invasion and metastasis. Our findings highlight the ability of bioinformatic approaches to find miRNAs targeting specific genes. By bioinformatic analysis, we confirmed the important role of miR-340 as a pivotal regulator of breast cancer metastasis in targeting previously validated (ROCK1) and potentially novel genes, i.e., (CTNNB1 and c-MYC). PMID- 26758431 TI - miR-421 is a diagnostic and prognostic marker in patients with osteosarcoma. AB - MicroRNAs (miRNAs) are a new class of prognostic and diagnostic biomarkers for many cancers. Recent studies have shown that miRNAs are highly stable in plasma/serum. The aim of this study was to investigate the role of miR-421 in osteosarcoma. We found that the serum expression levels of miR-421 were significantly higher in osteosarcoma patients than those in healthy volunteers. Moreover, miR-421 expression was significantly higher in osteosarcoma tissues compared with that in the adjacent normal tissues. Meanwhile, the expression of miR-421 was upregulated in 90 % (36/40) osteosarcoma tissues compared to non tumor tissues. More importantly, the expression levels of miR-421 in osteosarcoma tissues were correlated with those in patients' serum. In addition, patients with high miR-421 expression had shorter overall survival (OS) than those with low expressions. We also found that overexpression of miR-421 promoted osteosarcoma cell line MG-63 proliferation, migration, and invasion. In conclusion, miR-421 expression levels were upregulated in osteosarcoma tissue and serum and it may be a useful marker for diagnosis of osteosarcoma. PMID- 26758434 TI - A premature proposal for new liver cancer seromarkers. PMID- 26758433 TI - miR-143 inhibits tumor progression by targeting FAM83F in esophageal squamous cell carcinoma. AB - Family with sequence similarity 83 (FAM83) members play important roles in carcinogenesis and tumor progression in several tumor types. However, the mechanism by which cancer cells regulate FAM83F still remains unclear. In this study, we found that the FAM84F protein and messenger RNA (mRNA) levels were consistently upregulated in esophageal squamous cell carcinoma (ESCC) tissues, which suggests that a post-transcriptional mechanism may be involved in the regulation of FAM83F. Since microRNAs (miRNAs) are powerful post-transcriptional regulators of gene expression, we performed bioinformatic analyses to search for miRNAs that could potentially target FAM83F. We identified the specific targeting site of miR-143 in the 3'-untranslated region (3'-UTR) of FAM83F and confirmed the inverse correlation between the levels of miR-143 and FAM83F protein and mRNA in ESCC tissue samples. By overexpressing or silencing miR-143 in ESCC cells, we experimentally validated that miR-143 directly binds to the 3'-UTR of the FAM83F transcript and degrades the FAM83F mRNA to regulate FAM83F expression. Furthermore, the biological consequences that miR-143 mediated by targeting FAM83F were examined using in vitro cell proliferation, apoptosis, migration, and invasion assays. We demonstrate that miR-143 exerted a tumor-suppressing effect by inhibiting the proliferation, migration, and invasion and inducing G1/G0 phase arrest of ESCC cells via the negative regulation of FAM83F expression. Taken together, our findings provide important evidence which supports the role of miR 143 as a tumor suppressor in ESCC via the inhibition of FAM83F expression. PMID- 26758432 TI - Phenotype of circulating tumor cell: face-off between epithelial and mesenchymal masks. AB - Most patients with cancers died of distant metastasis. It is always difficult to find cancer metastasis in early time, let alone to prevent or cure it. Currently, oncologists place high hopes on circulating tumor cell (CTC), which, compared to current imaging methods, is found more sensitive for early metastasis. Recently, techniques for CTC enrichment and identification are developing quickly. However, there are great challenges in the clinical interpretation of CTC assessments. Increasing studies have shown the heterogeneity of CTCs, which may play different roles in cancer metastasis. Epithelial-mesenchymal transition is not only the main mechanism of the cancer cells invading the circulation system but also a distinguished characteristic of CTCs. Investigators are trying to differentiate specific subgroups of CTCs that are truly responsible for cancer metastasis. Here, we reviewed the current evidences on epithelial-mesenchymal transition of CTCs from perspectives of enrichment methods, biology, and its subgroups. PMID- 26758435 TI - A retrospective study of patients with adult-onset Still's disease: is pericarditis a possible predictor for biological disease-modifying anti-rheumatic drugs need? AB - The aims of this study were to look for clinical or serological markers able to predict the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) in patients with adult-onset Still's disease (AOSD) and to evaluate the efficacy and safety of bDMARDs in AOSD. In a single-center retrospective study, 39 patients with AOSD were divided into two groups according to whether they were ever treated with bDMARDs or not. Literature was searched for articles dealing with possible predictors of the use of bDMARDs in AOSD. Among the 18 AOSD patients who received at least one bDMARD, the prevalence of pericarditis was higher than that in the other patients [p = 0.014, odds ratio (OR) = 13.4, 95 % confidence interval (CI) = 1.45 to 122]. Literature search retrieved another paper dealing with predictors of bDMARDs need in AOSD: the analysis pooling data from our series and this previous report confirmed pericarditis at disease onset as a predictor of bDMARDs need (p = 0.028, OR = 3.62, 95 % CI = 1.22 to 10.7). A complete remission was observed in 17 out of 18 patients treated with bDMARDs, allowing withdrawal or tapering of corticosteroid therapy (p < 0.001), but because of inefficacy or adverse events, some patients received more than one bDMARD during the course of the disease and 31 different trials of bDMARDs were needed. Pericarditis at disease onset may be a predictor of bDMARDs need in AOSD. These drugs have a good efficacy and safety profile and should be considered for patients not responding to conventional therapy. PMID- 26758436 TI - A population-based study on the association between rheumatoid arthritis and voice problems. AB - The objective of this study was to investigate whether rheumatoid arthritis increases the frequency of organic laryngeal lesions and the subjective voice complaint rate in those with no organic laryngeal lesion. We performed a cross sectional study using the data from 19,368 participants (418 rheumatoid arthritis patients and 18,950 controls) of the 2008-2011 Korea National Health and Nutrition Examination Survey. The associations between rheumatoid arthritis and organic laryngeal lesions/subjective voice complaints were analyzed using simple/multiple logistic regression analysis with complex sample adjusting for confounding factors, including age, sex, smoking status, stress level, and body mass index, which could provoke voice problems. Vocal nodules, vocal polyp, and vocal palsy were not associated with rheumatoid arthritis in a multiple regression analysis, and only laryngitis showed a positive association (adjusted odds ratio, 1.59; 95 % confidence interval, 1.01-2.52; P = 0.047). Rheumatoid arthritis was associated with subjective voice discomfort in a simple regression analysis, but not in a multiple regression analysis. Participants with rheumatoid arthritis were older, more often female, and had higher stress levels than those without rheumatoid arthritis. These factors were associated with subjective voice complaints in both simple and multiple regression analyses. Rheumatoid arthritis was not associated with organic laryngeal diseases except laryngitis. Rheumatoid arthritis did not increase the odds ratio for subjective voice complaints. Voice problems in participants with rheumatoid arthritis originated from the characteristics of the rheumatoid arthritis group (higher mean age, female sex, and stress level) rather than rheumatoid arthritis itself. PMID- 26758437 TI - Association of serum KL-6 levels with interstitial lung disease in patients with connective tissue disease: a cross-sectional study. AB - It was aimed to evaluate KL-6 glycoprotein levels to determine if it may be a diagnostic marker for the connective tissue diseases (CTDs) predicting CTD related interstitial lung diseases (ILDs) (CTD-ILD) development and to examine if there was a difference between patients and healthy controls. The study included 113 patients with CTD (45 CTD without lung involvement, 68 CTD-ILD) and 45 healthy control subjects. KL-6 glycoprotein levels were analyzed with ELISA in patients and the control group. The relationship between KL-6 glycoprotein levels and CTD-ILD was assessed. In the comparison of all the groups in the study, significantly higher levels of KL-6 were determined in the CTD-ILD group than in either the CTD without pulmonary involvement group or the healthy control group (p < 0.008 and p < 0.001, respectively). There was no statistically significant difference between the KL-6 levels in the healthy control group and the CTD without pulmonary involvement group (p = 0.289). The KL-6 levels did not differ significantly according to the connective tissue diseases in the diagnostic groups (systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, mixed connective tissue disease, scleroderma, polymyositis/ dermatomyositis). In the healthy control group, there was a statistically significant difference between KL-6 levels in smokers and non-smokers. Smokers had significantly higher serum KL-6 levels compared with non-smokers (p < 0.05). There was no statistically significant difference between smoking status (pack-year) and serum KL-6 levels. There was no statistically significant correlation between serum KL 6 levels and time since diagnosis of CTD and CTD-ILD. The level of KL-6 as a predictive factor could be used to identify the clinical development of ILD before it is detected on imaging modality. Further prospective clinical studies are needed to define whether levels of KL-6 might have prognostic value or might predict progressive ILD. PMID- 26758439 TI - Dieting Habits of Men. AB - There is little research involving the US male population regarding weight control and behavior that may affect weight status. Gender-specific weight control programs for men aren't the standard. Our study objectives were to survey dieting and health habits of an adult male employee population and to determine if the population would be interested in gender-specific programming. Demographics, weight-control practices and interest in gender-specific weight control programs were examined cross sectionally. A 50-question web-based survey was posted via email from October 2-30, 2014 to male employees at a Mid-Atlantic university. Statistical analyses included frequencies, means and percentages. Chi square and t tests were conducted. The 254 participants were ages 18-65+ years, predominantly white, college educated with annual incomes above $50,000. Sources of nutrition knowledge ranged from a high of web sites (65 %) to a low of registered dietitians (9 %). Macronutrient restrictions reported for dieting were carbohydrates 77 %, fats 40 % and protein 19 %. The >30 age group was more likely to have: decreased amount of food intake P = .001), reducing overall calories (P = .047), skipping meals (P = .006) or trying commercial programs (P = .011). There was nothing of significance for those <30. Among all respondents, interest in gender-specific programs was compared with these variables: current weight satisfaction (P = .032), education (P = .008), income (P = . 006) and BMI (P = .004). Men who were dissatisfied with their weight were most likely to be interested in a gender-specific weight control program, especially those over age 30 years. Further research should address whether offering male-specific diet programs would offer incentive and motivation for males to lose and maintain weight loss. PMID- 26758438 TI - Evaluation of the effects of different supplementation on oxidative status in patients with rheumatoid arthritis. AB - Rheumatoid arthritis is a chronic inflammatory disease. Reactive oxygen species have been considered as aggravating factors for autoimmune diseases. Fatty acids had been linked in reduction of various diseases by augment of their antioxidant potential and antiinflammatory mechanisms. The aim of this study was to assess the oxidative status in patients with rheumatoid arthritis who used concentrated fish oil only or concentrated fish oil in combination with evening primrose oil in a period of 3 months. Subjects were divided into three groups. The group I consists of patients who had been taking only their regular rheumatologic therapy; group II, patients who had been taking concentrated fish oil; and group III, patients who had been taking concentrated fish oil and evening primrose oil. Peripheral blood samples were used for all the assays. We assessed the following oxidative stress markers: index of lipid peroxidation (thiobarbituric acid reactive substances (TBARS)), hydrogen peroxide (H2O2), superoxide anion radical (O2 (-)), nitric oxide (NO), superoxide dismutase activity (SOD), catalase activity (CAT), and glutathione levels (GSH) in erythrocytes. There were no statistically significant changes for any of the oxidative stress parameters in group I. In group II, levels of TBARS, NO2 (-), and GSH were increased, while levels of H2O2 decreased. Increased values of TBARS, NO2 (-), and SOD were found in group III. Our findings indicate that intakes of fish oil and evening primrose oil may be of importance in mitigation of inflammation, disease activity, and oxidative stress biomarkers, through increased activities of antioxidant enzymes. PMID- 26758440 TI - CORR Insights(r): How Do Hindfoot Fusions Affect Ankle Biomechanics: A Cadaver Model. PMID- 26758441 TI - CORR Insights((r)): Reamed Intramedullary Nailing has an Adverse Effect on Bone Regeneration During the Distraction Phase in Tibial Lengthening. PMID- 26758442 TI - Nicolaes Tulp: The Overshadowed Subject in The Anatomy Lesson of Dr. Nicolaes Tulp. PMID- 26758443 TI - CORR Insights((r)): Does Sclerostin Depletion Stimulate Fracture Healing in a Mouse Model? PMID- 26758444 TI - Catalytic Role of Manganese Oxides in Prebiotic Nucleobases Synthesis from Formamide. AB - Origin of life processes might have begun with the formation of important biomonomers, such as amino acids and nucleotides, from simple molecules present in the prebiotic environment and their subsequent condensation to biopolymers. While studying the prebiotic synthesis of naturally occurring purine and pyrimidine derivatives from formamide, the manganese oxides demonstrated not only good binding for formamide but demonstrated novel catalytic activity. A novel one pot manganese oxide catalyzed synthesis of pyrimidine nucleobases like thymine is reported along with the formation of other nucleobases like purine, 9 (hydroxyacetyl) purine, cytosine, 4(3 H)-pyrimidinone and adenine in acceptable amounts. The work reported is significant in the sense that the synthesis of thymine has exhibited difficulties especially under one pot conditions and also such has been reported only under the catalytic activity of TiO2. The lower oxides of manganese were reported to show higher potential as catalysts and their existence were favored by the reducing atmospheric conditions prevalent on early Earth; thereby confirming the hypothesis that mineral having metals in reduced form might have been more active during the course of chemical evolution. Our results further confirm the role of formamide as a probable precursor for the formation of purine and pyrimidine bases during the course of chemical evolution and origin of life. PMID- 26758445 TI - Novel anti-infective potential of salvianolic acid B against human serious pathogen Neisseria meningitidis. AB - BACKGROUND: Epidemics of meningococcal meningitis cause significant health problems especially in Sub-Saharan Africa. Novel anti-infective candidates are needed. In modern anti-adhesion therapy initial attachment of bacteria to host cells is prevented. Our unique studies have revealed anti-adhesive candidates from natural products, namely milk and berries, against Neisseria meningitidis adhesion. In the present study against N. meningitidis adhesion, a novel binding inhibitor was found; salvianolic acid B (SA-B), a polyphenol from the radix Salviae miltiorrhizae, an important part of Chinese folk medicine. METHODS: In order to test inhibition of meningococcal pili binding and anti-adhesion activity of SA-B, bovine thyroglobulin, a reference glycoprotein for meningococcal receptor was used in a microtiter plate assay. Inhibitory activity was tested by using serial dilutions of SA-B extracts of 98 and 70% purity. Results were confirmed in a HEC-1B cell dot assay and antimicrobial activity was measured by using a microbroth dilution assay. RESULTS: Almost total (93%) inhibition of pili binding, anti-adhesion, was achieved with the 70% extract of SA-B at the concentration of 0.3 mg/mL in the bovine thyroglobulin reference model. 50% binding inhibition activity was achieved with 0.6 ug/mL of the SA-B extract. Total inhibition of the pili binding to HEC-1B cells was found at the tested concentration of 0.5 mg/mL. The 98% pure SA-B resulted in weaker inhibition. At the concentration of 0.3 mg/mL 78% inhibition was achieved in the thyroglobulin model. For 50% inhibition 2.4 MUg/mL of pure SA-B was needed. The difference between the binding inhibition activities (70 and 98% pure SA-B) was statistically significant (P = 0.03). Antimicrobial activity of 70% SA-B, when investigated against N. meningitidis, was detected only in relatively high concentrations. CONCLUSIONS: Our results indicate that plant SA-B may prevent meningococcal infections by inhibiting meningococcal binding and may thus have an impact on the amount of nasopharyngeal carriers of N. meningitidis. This may prevent the spreading of meningococcal infections between humans. One could conclude that SA-B and its source dried radix S. miltiorrhizae, which is an important part of Chinese folk medicine, could be valuable candidates for further research in meningococcal disease prevention. PMID- 26758447 TI - A new Eimeria species (Protozoa: Eimeriidae) from caribou in Ameralik, West Greenland. AB - Fecal samples of 11 calves shot in the Ameralik area, West Greenland, in August September 2014 were examined for coccidian parasites. The calves belonged to a population of interbreeding indigenous caribou Rangifer tarandus groenlandicus and feral semi-domestic Norwegian reindeer Rangifer tarandus tarandus. Two coccidian species were found: Eimeria rangiferis and a coccidium that was identified and described as a new species. The latter's sporulated oocyst is spherical or slightly subspherical. Average size is 25.6 * 24.8 MUm. The oocyst has two distinct walls. Wall thickness is ~1.4 MUm. The unicolored outer wall is brown, the inner wall is dark gray. The oocysts contain a small polar granule but are devoid of a microphyle. The oocysts enclose four ovoid-shaped sporocysts with a rounded end opposite to the Stieda body. The average size of sporocysts is 15.2 * 7.8 MUm. Sporocysts contain a granular sporocyst residuum that forms a spherical cluster between the sporocysts, one large refractile body is present in each sporozoite. The spherical form easily distinguishes oocysts of the new species from the seven previously described eimerid species in R. tarandus. This is the first eimerid described as a new species to the sciences from caribou in the Nearctic. PMID- 26758446 TI - Hypolipidemic Effects of Phospholipids (PL) Containing n-3 Polyunsaturated Fatty Acids (PUFA) Are Not Dependent on Esterification of n-3 PUFA to PL. AB - Phospholipids (PL) containing n-3 polyunsaturated fatty acids (PUFA) have beneficial effects of maintaining and promoting health compared with triacylglycerols (TAG) containing n-3 PUFA or general PL. This study evaluated the effects of dietary PL containing n-3 PUFA and elucidated the effects of the glycerophosphate structure and n-3 PUFA on fatty acid (FA) metabolism in rats. Rats were fed a basal diet containing soybean oil alone, TAG containing n-3 PUFA (1.8%), soybean PL (2.7%), PL containing n-3 PUFA (2.7%), or TAG containing n-3 PUFA (1.8%) + soybean PL (2.7%). The present n-3 PUFA-supplemented diets had similar FA compositions, and the PL diets had similar PL compositions. TAG containing n-3 PUFA reduced serum TAG contents, but did not affect serum cholesterol contents compared with soybean oil alone. PL diets containing n-3 PUFA and the combination of TAG containing n-3 PUFA and soybean PL resulted in decreased serum and liver TAG contents compared with the diet containing soybean oil alone, reflecting enhanced liver FA beta-oxidation. The results of this study show that TAG containing n-3 PUFA with added soybean PL affects serum and liver TAG and cholesterol contents to a similar degree as PL containing n-3 PUFA. TAG containing n-3 PUFA and soybean PL are widely used as functional food ingredients and pharmaceutical constituents and are inexpensive compared with PL containing n 3 PUFA. Therefore, the combination of TAG containing n-3 PUFA and soybean PL has potential as a useful and inexpensive component of functional foods. PMID- 26758448 TI - Predominance of Giardia lamblia assemblage A among iron deficiency anaemic pre school Egyptian children. AB - Intestinal parasites and nutritional deficiency can coexist and influence each other. This study aimed to clarify the association between Giardia genotypes and presence of iron deficiency anaemia (IDA) among pre-school Egyptian children. Two groups (IDA and non-anaemic) of giardiasis children (44/group) were selected according to their recovery response after treatment of giardiasis. Each group included 24 and 20 gastrointestinal symptomatic and asymptomatic, respectively. Giardia human genotypes were performed by intergenic spacer (IGS) gene based polymerase chain reaction (PCR) with high-resolution melting curve (HRM). PCR/HRM proved that Tms of assemblage A and B ranged from 79.31 +/- 0.29 to 84.77 +/- 0.31. In IDA patients, assemblages A and B were found among 40/44 (90.9 %) and 4/44 (9.1 %), respectively, while in non-anaemic patients, assemblages A and B were found in 10/44 (22.7 %) and 32/44 (72.7 %), respectively, beside two (4.6 %) cases had mixed infection. The difference was statistically significant. No significant relation was found between symptomatic or asymptomatic assemblages and IDA as assemblage A was found in 21/24 (87.5 %) and 19/20 (95 %) of symptomatic and asymptomatic, respectively, while 3/24 (12.5 %) and 1/20 (5 %) of assemblage B were symptomatic was asymptomatic, respectively. A significant relation was found between assemblage A subtypes distribution among IDA patients as AI and AII were detected on 23 (52.3 %) and 16 (36.4 %) of patients, respectively, while one case (2.3 %) had mixed infection. In conclusion, assemblage A is predominant among IDA giardiasis children suggesting its role in enhancing the occurrence of IDA while B has a protective role. PMID- 26758449 TI - First report of Cryptosporidium species in farmed and wild buffalo from the Northern Territory, Australia. AB - A molecular epidemiological survey of Cryptosporidium from water buffalo (Bubalus bubalis) in the Northern Territory in Australia was conducted. Fecal samples were collected from adult farmed (n = 50) and wild buffalo (n = 50) and screened using an 18S quantitative PCR (qPCR). Positives were typed by sequence analysis of 18S nested PCR products. The qPCR prevalence of Cryptosporidium species in farmed and wild buffalo was 30 and 12 %, respectively. Sequence analysis identified two species: C. parvum and C. bovis, with C. parvum accounting for ~80 % of positives typed from the farmed buffalo fecal samples compared to 50 % for wild buffalo. Subtyping at the 60 kDa glycoprotein (gp60) locus identified C. parvum subtypes IIdA19G1 (n = 4) and IIdA15G1 (n = 1) in the farmed buffalo and IIaA18G3R1 (n = 2) in the wild buffalo. The presence of C. parvum, which commonly infects humans, suggests that water buffaloes may contribute to contamination of rivers and waterways with human infectious Cryptosporidium oocysts, and further research on the epidemiology of Cryptosporidium in buffalo populations in Australia is required. PMID- 26758450 TI - Insecticide resistance and its molecular basis in urban insect pests. AB - Insecticide resistance is one of the most important evolutionary phenomena for researchers. Overuse of chemicals has induced resistance in insect pests that ultimately has led to the collapse of disease control programs in many countries. The erroneous and inappropriate management of insect vectors has resulted in dissemination of many vector-borne diseases like dengue, malaria, diarrhea, leishmaniasis, and many others. In most cases, the emergence of new diseases and the revival of old ones can be related with ecological changes that have favored rapid growth of vector densities. Understanding molecular mechanisms in resistant strains can assist in the development of management programs to control the development and spread of resistant insect populations. The dominant, recessive, and co-dominant forms of genes encoding resistance can be investigated, and furthermore, resistance development can be addressed either by the release of susceptible strains or timely insecticide rotation. The present review discusses the resistance level in all important insect vectors of human diseases; the molecular basis of evolvement of resistance has also been discussed. PMID- 26758451 TI - Unique marine derived cyanobacterial biosynthetic genes for chemical diversity. AB - Cyanobacteria are a prolific source of structurally unique and biologically active natural products that derive from intriguing biochemical pathways. Advancements in genome sequencing have accelerated the identification of unique modular biosynthetic gene clusters in cyanobacteria and reveal a wealth of unusual enzymatic reactions involved in their construction. This article examines several interesting mechanistic transformations involved in cyanobacterial secondary metabolite biosynthesis with a particular focus on marine derived modular polyketide synthases (PKS), nonribosomal peptide synthetases (NRPS) and combinations thereof to form hybrid natural products. Further, we focus on the cyanobacterial genus Moorea and the co-evolution of its enzyme cassettes that create metabolic diversity. Progress in the development of heterologous expression systems for cyanobacterial gene clusters along with chemoenzymatic synthesis makes it possible to create new analogs. Additionally, phylum-wide genome sequencing projects have enhanced the discovery rate of new natural products and their distinctive enzymatic reactions. Summarizing, cyanobacterial biosynthetic gene clusters encode for a large toolbox of novel enzymes that catalyze unique chemical reactions, some of which may be useful in synthetic biology. PMID- 26758453 TI - Prediction of topological phase transition in X2-SiGe monolayers. AB - Quantum spin Hall (QSH) insulators exhibit a bulk insulting gap and metallic edge states characterized by nontrivial topology. Here, we used first-principles calculations to investigate the electronic and topological properties of halogenated silicon germanide (X2-SiGe, with X = F, Cl, and Br) monolayers, which we found to be trivial semiconductors with energy band gaps ranging from 500 meV to 900 meV. Interestingly, we found that under 8% strain, X2-SiGe monolayers behave as QSH insulators with global band gaps between 53 meV and 123 meV. The underlying mechanism of the topological phase transition is the strain-induced s p band inversion. The nontrivial topological features for the strained X2-SiGe monolayers were further confirmed by the presence of topologically protected edge states that form a single Dirac cone in the middle of the bulk band gaps. Therefore, our results reveal that this new family of QSH insulators is promising for room temperature applications in spintronics and quantum computation devices. PMID- 26758452 TI - Uncoupling shear and uniaxial elastic moduli of semiflexible biopolymer networks: compression-softening and stretch-stiffening. AB - Gels formed by semiflexible filaments such as most biopolymers exhibit non-linear behavior in their response to shear deformation, e.g., with a pronounced strain stiffening and negative normal stress. These negative normal stresses suggest that networks would collapse axially when subject to shear stress. This coupling of axial and shear deformations can have particularly important consequences for extracellular matrices and collagenous tissues. Although measurements of uniaxial moduli have been made on biopolymer gels, these have not directly been related to the shear response. Here, we report measurements and simulations of axial and shear stresses exerted by a range of hydrogels subjected to simultaneous uniaxial and shear strains. These studies show that, in contrast to volume-conserving linearly elastic hydrogels, the Young's moduli of networks formed by the biopolymers are not proportional to their shear moduli and both shear and uniaxial moduli are strongly affected by even modest degrees of uniaxial strain. PMID- 26758455 TI - Adaptation to Parental Gender Transition: Stress and Resilience Among Transgender Parents. AB - Little is known about transgender parents and how they have negotiated their gender transition, referred to here as Parental Gender Transition (PGT), and subsequent stressors. This study addressed this gap using an adapted version of the ABC-X model and Family Stress Theory. The family functioning of 73 transgender parents (72.2 % born male, 25.0 % born female, and 2.8 % other, e.g., intersex), who transitioned after they had children, was examined in regard to the potential stresses associated with PGT (impact of disclosure, stigma, and boundary ambiguity), resources available to transitioning parents (social support and coping), and perception (sense of coherence and perceptions of PGT). Hierarchical multiple regression and path analysis were then conducted to determine if resources and perception altered the relationship between stress and family functioning. Findings from these transgender parents indicated an ameliorating role of sense of coherence, or the perception that they can handle the situation, on the relationship between stigma and family functioning, but not between boundary ambiguity, or confusion regarding who is in the family system, and family functioning. This suggests one avenue for professionals to intervene and help families through PGT. However, it also indicates the need for further research to determine ways to mitigate the impact of boundary ambiguity on family functioning. PMID- 26758456 TI - Concordance of Demographic Characteristics, Sexual Behaviors, and Relationship Attributes Among Sex Dyads of Black and White Men Who Have Sex with Men. AB - Differences in individual behaviors have failed to explain racial disparities between Black and White men who have sex with men (MSM). However, reporting of behaviors and partner characteristics are assumed to be non-differentially reported by race. From 314 participants, this study used the two-sided data-where sexual partners provide information on each other and their relationship-of 127 dyads of Black and White MSM from Atlanta, GA, to assess the reliability of partner-reported demographic characteristics and the concordance of sexual behaviors and partnership attributes by race. We compared proportions of concordance by race using a modified kappa (K m) to assess chance-corrected agreement. The median difference in age between self- and partner-reports was 0 (0-1) years. Compared to self-reports, 97 % of the partners of Black participants and 96 % of the partners of White participants correctly classified their race. We observed poor agreement on pre-sexual discussion (K m = 0.18) and being in an ongoing relationship (K m = 0.13), with no differences by race (p = 0.11). Although not statistically significant, Black MSM dyads had lower levels of concordance for unprotected anal intercourse in the previous 12 months (68 %) compared to White dyads (90 %), with fair agreement among Black dyads (K m = 0.26). Measures of partner-reported age and race are likely accurate; however, certain self-reported sexual behaviors and partnership attributes may be unreliable and differentially reported by race. Our findings highlight the need to assess the validity of measures used to estimate HIV transmission and inform racial disparities research. PMID- 26758454 TI - IGF-1-Involved Negative Feedback of NR2B NMDA Subunits Protects Cultured Hippocampal Neurons Against NMDA-Induced Excitotoxicity. AB - Insulin-like growth factor 1 (IGF-1) is a multifunctional protein involved in neuronal polarity and axonal guidance. In our previous study, it was discovered that IGF-1 alleviated 50-MUM NMDA-induced excitotoxicity against neuronal autophagy via depression of NR2B p-Ser1303 activation. However, it was found that NMDA at a higher dose did not cause neuronal autophagy. And, the performance of IGF-1 under severe excitotoxicity still needs to be clarified. In this study, we observed that IGF-1 can salvage the hippocampal neurons in an autophagy independent manner after 150-MUM NMDA exposure using thiazolyl blue tetrazolium bromide (MTT), lactate dehydrogenase (LDH), Western blot assay, and transmission electron microscopy. In addition, over-activation of post-synaptic NMDARs was found with the whole-cell patch clamp recording method. In order to explore whether there is a positive feedback way for post-synaptic NMDARs and the different pathway caused by 150 MUM NMDA, the phosphorylation level of Fyn and the phosphorylation site of NR2B were investigated. It was observed that NR2B p Tyr1472 was increased by the activation of Fyn after 150-MUM NMDA exposure. When the neutralizing antibody against NR2B p-Ser1303 was added into the medium, both the activations of Fyn and NR2B p-Tyr1472 were blocked, suggesting NR2B p-Ser1303 may be the initial step of NMDA-induced excitotoxicity. In addition, since IGF-1 can block the initial step of NR2B activation, its effect is concluded to continue with the development of excitotoxicity. Overall, this study strongly indicates that the relationship between different phosphorylation sites of NR2B should be laid more emphasis on, which may be a vital target for the NR2B involved excitotoxicity. PMID- 26758457 TI - Extracellular Polymeric Substances of Aphanizomenon flos-aquae (EPS-A) Induced Apoptosis in Astrocytes of Zebrafish. AB - In this study, extracellular polymeric substances of Aphanizomenon flos-aquae (EPS-A) were investigated in order to explore their effect on astrocytes of zebrafish and potential risk for environment. Astrocytes were treated with varying concentrations of EPS-A, the results showed that EPS-A inhibited astrocytes growth in a dose-and time-dependent manner. With the concentrations of EPS-A increasing, the adherent ability of astrocytes decreased and the number of astrocytes floating in the culture medium increased. When treated with 2.35 ug/mL EPS-A, EPS-A induced cell cycle arrest and made the collapse of mitochondrial membrane potential and then led to astrocytes apoptosis. The results suggested that EPS-A could pose a threat to zebrafish and represent risk for environment, so regularly monitoring the presence of EPS-A was very important in nutrient-rich freshwaters when A. flos-aquae blooms broke out. PMID- 26758458 TI - Effects of Barium Chloride Exposure on Hormones and Genes of the Hypothalamic Pituitary-Gonad Axis, and Reproduction of Zebrafish (Danio rerio). AB - Adult zebrafish pairs were exposed to sub-lethal concentrations of BaCl2 for 21 days, and the effects on reproduction, sex steroid hormones, and transcription of the genes belonging to the hypothalamic-pituitary-gonad (HPG) axis were investigated. The adverse effects on performances of F1 generation were further examined with or without subsequent exposure to BaCl2. Egg production was significantly decreased, and parental exposure to BaCl2 resulted in lesser rates of hatching. In males, exposure to BaCl2 resulted in greater concentrations of E2 along with greater mRNA expression of cyp19a. The results demonstrated that BaCl2 could modulate gene transcriptions and hormone production of the HPG axis in a sex-dependent way, which could cause adverse effects on reproduction and the development of offspring. PMID- 26758459 TI - Dehydroepiandrosterone (DHEA) supplementation results in supraphysiologic DHEA-S serum levels and progesterone assay interference that may impact clinical management in IVF. AB - PURPOSE: Dehydroepiandrosterone (DHEA) is often prescribed for poor responders in IVF in an effort to improve response to ovarian stimulation. The effect of DHEA supplementation and resultant supraphysiologic DHEA-S serum levels on sex steroid assays has not been evaluated in this population. This study seeks to determine the relationship between DHEA supplementation and progesterone measurements to characterize the degree of interference with particular immunoassays. METHODS: Characterization was accomplished in two phases. First, DHEA-S standard control reagents with no progesterone present were assayed for both DHEA-S and progesterone levels. Second, serum pools from 60 unique IVF patients' serum were used to create six pooled serum samples: three from patients on DHEA supplementation and three from patients not on DHEA supplementation. The three pools were composed of patients whose serum fell into low, medium, and high progesterone ranges. Baseline DHEA-S and progesterone were measured, and the mean level of DHEA-S in the mid-range progesterone pool was used as the mid-point for addition of DHEA-S standard to the serum pools from patients without DHEA supplementation. Progesterone from these pools was then measured on three commercially available immunoassay systems. RESULTS: The first experiment revealed a linear increase in progesterone when analyzing the DHEA-S standard ranging from 0.5 ng/mL in the blank control (no DHEA-S) to up to 2.0 ng/mL in the high control (DHEA-S >700 MUg/mL), indicating that the DHEA-S cross-reacts with the progesterone assays. In the second experiment, patients' serum DHEA-S and progesterone were measured from pooled serum samples of those taking DHEA and those not taking DHEA. Adding DHEA-S to the pooled serum of those not taking DHEA resulted in a linear increase in progesterone levels on two of three commercially available immunoassays (p < 0.05). CONCLUSIONS: DHEA-S can interfere with standard progesterone immunoassays used in clinical ART programs, and thus serum progesterone levels in IVF patients on DHEA supplementation may not reflect truly bioactive progesterone. PMID- 26758460 TI - Variability in follicular fluid high density lipoprotein particle components measured in ipsilateral follicles. AB - PURPOSE: The purpose of this study was to examine the biological variability of follicular fluid (FF) high density lipoprotein (HDL) particle components measured in ipsilateral ovarian follicles. METHODS: We collected FF from two ipsilateral follicles among six women undergoing in vitro fertilization (IVF). We measured concentrations of 19 FF HDL particle components, including HDL cholesterol, free cholesterol, four cholesteryl esters, phospholipids, triglycerides, paraoxonase and arylesterase activities, apolipoproteins A-1 and A-2 (ApoA-1 and ApoA-2), and seven lipophilic micronutrients, by automated analysis and with high-performance liquid chromatography. We assessed biological variability using two-stage nested analysis of variance and compared values with those previously published for contralateral follicles. RESULTS: For most FF HDL analytes, there was little variability between follicles relative to the variability between women (i.e., %sigma(2) F:%sigma(2) B <0.5). Intraclass correlation coefficients were >0.80 for HDL cholesterol (0.82), phospholipids (0.89), paraoxonase (0.96), and arylesterase (0.91) activities, ApoA-1 (0.89), and ApoA-2 (0.90), and single specimen collections were required to estimate the subject-specific mean, demonstrating sufficient reliability for use as biomarkers of the follicular microenvironment in epidemiologic and clinical studies. CONCLUSIONS: These preliminary results raise the possibility for tighter regulation of HDL in follicles within the same ovary vs. between ovaries. Thus, collection of a single FF specimen may be sufficient to estimate HDL particle components concentrations within a single ovary. However, our results should be interpreted with caution as the analysis was based on a small sample. PMID- 26758461 TI - Effect of cryopreservation on the properties of human endometrial stromal cells used in embryo co-culture systems. AB - PURPOSE: Along with comparative investigation of the decidualization potential and IL-6 secretion by fresh and frozen ESCs, we also aimed to evaluate the effectiveness of co-culture systems based on fresh or frozen ESCs in terms of clinical pregnancy rates. METHODS: Outcome analysis of a total of 215 IVF cycles with co-culture with fresh or frozen ESCs was performed. Endometrial tissue was obtained from 17 healthy donors. Concentrations of secreted prolactin, IGFBP-1, and IL-6 in conditioned media from cultured fresh and frozen ESCs (decidualized or not) were measured using ELISA or ECLIA. RESULTS: Embryo co-culture with frozen ESCs resulted in a much lower pregnancy rate compared to the alternative system using fresh ESCs. Furthermore, cultivated frozen ESCs showed considerably decreased release of prolactin, IGFBP-1, and IL-6 compared to fresh ESCs, indicating that cryopreservation negatively affects their decidualization potential and cytokine production. CONCLUSIONS: Altogether, this data illustrates the need for optimization and improvement of the existing autologous endometrial co-culture systems. PMID- 26758462 TI - Understanding and Overcoming the Sticking Point in Resistance Exercise. AB - In the context of resistance training the so-called "sticking point" is commonly understood as the position in a lift in which a disproportionately large increase in the difficulty to continue the lift is experienced. If the lift is taken to the point of momentary muscular failure, the sticking point is usually where the failure occurs. Hence the sticking point is associated with an increased chance of exercise form deterioration or breakdown. Understanding the mechanisms that lead to the occurrence of sticking points as well as different training strategies that can be used to overcome them is important to strength practitioners (trainees and coaches alike) and instrumental for the avoidance of injury and continued progress. In this article we survey and consolidate the body of existing research on the topic: we discuss different definitions of the sticking point adopted in the literature and propose a more precise definition, describe different muscular and biomechanical aspects that give rise to sticking points, and review the effectiveness of different training modalities used to address them. PMID- 26758463 TI - Distinct vestibular phenotypes in DFNA9 families with COCH variants. AB - Mutations of COCH can cause hearing loss and less frequently vestibular symptoms. However, vestibular phenotypes, especially in terms of the location of specific variants are not well documented yet. In this study, a retrospective and prospective cohort survey was performed in two tertiary referral hospitals to demonstrate vestibular phenotypes of DFNA9 subjects with a focus on the relationship with the location of COCH mutations. Two DFNA9 subjects were recruited from the previously collected cohort, each segregating p.G38D and p.C162Y of the COCH gene. Another two DFNA9 families were newly detected by targeted resequencing of known 129 deafness genes (TRS-129). These two families segregated the p.G38D variant of the COCH gene as the causative mutation, making p.G38D the most frequent COCH mutation in our Korean cohorts. Regarding the detailed clinical phenotype of the four DFNA9 families with documented vestibular phenotypes, we were able to classify them into two groups: one (p.C162Y variant) with a Meniere's disease (MD)-like phenotype and the other three (p.G38D variant) with significant bilateral vestibular loss without any definite MD symptoms. Distinct vestibular phenotypes depending on the location of COCH mutations were demonstrated, and this study correlates a genotype of p.G38D in COCH to the phenotype of bilateral total vestibular loss, therefore expanding the vestibular phenotypic spectrum of DFNA9 to range from bilateral vestibular loss without episodic vertigo to MD-like features with devastating episodic vertigo. In addition, the p.G38D variant of the COCH gene is suggested to be a frequent cause of progressive audiovestibular dysfunction in Koreans eventually requiring cochlear implantation. PMID- 26758464 TI - Lateralization of horizontal semicircular canal canalolithiasis and cupulopathy using bow and lean test and head-roll test. AB - Accurate lateralization is important to improve treatment outcomes in horizontal semicircular canal (HSCC) benign paroxysmal positional vertigo (BPPV). To determine the involved side in HSCC-BPPV, the intensity of nystagmus has been compared in a head-roll test (HRT) and the direction of nystagmus was evaluated in a bow and lean test (BLT). The aim of this study is to compare the results of a BLT with those of a HRT for lateralization of HSCC-canalolithiasis and cupulopathy (heavy cupula and light cupula), and evaluate treatment outcomes in patients with HSCC-canalolithiasis. We conducted retrospective case reviews in 66 patients with HSCC-canalolithiasis and 63 patients with HSCC-cupulopathy. The affected side was identified as the direction of bowing nystagmus on BLT in 55 % (36 of 66) of patients with canalolithiasis, which was concordant with the HRT result in 67 % (24 of 36) of cases (concordant group). Lateralization was determined by comparison of nystagmus intensity during HRT in 30 patients who did not show bowing or leaning nystagmus. The remission rate after the first treatment was 71 % (17 of 24) in the concordant group and 45 % (5 of 11) in the discordant group. Both bowing and leaning nystagmus were observed in all patients with cupulopathy, and the side of the null plane was identified as the affected side. In conclusion, bowing and/or leaning nystagmus were observed in only 55 % of patients with HSCC-canalolithiasis, and the first treatment based on the result of BLT alone was effective in only 45 % of the patients in whom the BLT and HRT were discordant, which may suggest that the usefulness of BLT in lateralizing the HSCC-canalolithiasis may be limited. PMID- 26758465 TI - Neutrophil to lymphocyte ratio in allergic rhinitis. PMID- 26758467 TI - Experience of providing palliative care in critical care settings. AB - BACKGROUND: Changing demographics and medical advances have led to an increased demand for beds in critical care units. Patients in critical care are at risk of physical and psychosocial suffering. The goal of palliative care is to achieve the best quality of life for patients and families irrespective of diagnosis or location of care. The delivery of high-quality end-of-life care in critical care units can be challenging. OBJECTIVES: Our aim was to (1) identify patient characteristics and timing of referral to Hospital Palliative Care Team (HPCT) since admission to critical care unit; (2) assess the impact of HPCT on patient care and location of death; (3) describe challenges of providing input in this setting by HPCT. METHODS: We retrospectively reviewed all referrals to HPCT from critical care units of a large teaching hospital over a 6-year period. Data were extracted from an electronic database storing details of all patient referrals and contacts. RESULTS: As a proportion of all referrals to HPCT, those from critical care rose from 1.7% to 3.17%. The proportion of patients with non malignant diagnoses referred has risen from 29% to 39%. Of total referrals, 96/144 (66.6%) patients died within the same episode of care. 65% of these died within 1 week. 51% of patients died on critical care. We also describe challenges encountered and impact of the HPCT on patient care. CONCLUSIONS: The HPCT provide an important contribution to patients in critical care, through symptom control, family support, continuity of care and in end-of-life care. On the basis of our review, the challenge is to move from a sequential model of care to a more integrated approach. PMID- 26758468 TI - What is known about heart failure in sub-Saharan Africa: a scoping review of the English literature. AB - We systematically reviewed and summarised existing knowledge on heart failure in sub-Saharan Africa (SSA). We searched the following databases Web of Science, EMBASE, Ovid MEDLINE, PsychINFO, Global Health, CINAHL and African Journals Online using a combination of key words: heart failure or congestive heart failure or cardiac failure. We limited our search to studies conducted in SSA and articles published 2000-2014. Twenty-seven articles met our inclusion criteria and all were quantitative studies. Existing knowledge is focused on 3 key areas: (1) epidemiology of heart failure, (2) psychological burden of heart failure, and (3) patient knowledge and compliance to treatment. SSA would benefit from longitudinal qualitative research on the experience of living with heart failure. PMID- 26758466 TI - In silico analyses of antigenicity and surface structure variation of an emerging porcine circovirus genotype 2b mutant, prevalent in southern China from 2013 to 2015. AB - Porcine circovirus type 2 (PCV2) is the pivotal pathogen causing porcine circovirus-associated diseases. In this study, 62 PCV2 isolates were identified from seven farms in southern China from 2013 to 2015 and phylogenetic trees were reconstructed based on whole-genome sequences or the cap gene. In this investigation, PCV2b was the main genotype in circulation throughout these farms. Furthermore, an emerging mutant (PCV2b-1C), isolated from PCV2-vaccinated farms, was the predominant strain prevalent on these farms. In addition, we isolated a new cluster that may represent evolution of the virus through recombination of PCV2b-1A/1B and PCV2b-1C. Finally, we discuss evidence that antigenicity and surface structure variation of the capsid resulted from mutation of the C terminal loop (Loop CT) of the PCV2b-1C Cap in silico. PMID- 26758469 TI - Comparison of informal caregiver and named nurse assessment of symptoms in elderly patients dying in hospital using the palliative outcome scale. AB - OBJECTIVES: A prospective study of symptom assessments made by a healthcare professional (HCP; named nurse) and an informal caregiver (ICG) compared with that of the patient with a terminal diagnosis. To look at the validity of HCP and ICG as proxies, which symptoms they can reliably assess, and to determine who is the better proxy between HCP and ICG. METHODS: A total of 50 triads of patient (>65 years) in the terminal phase, ICG and named nurse on medical wards of an acute general hospital. Assessments were made using the patient and caregiver versions of the palliative outcome scale (POS), all taken within a 24 h period. Agreement between patient-rated, ICG-rated and HCP-rated POS and POS for symptoms (POS-S) was measured using weighted-kappa statistics. Demographic and clinical data on each group of participants were collected. RESULTS: ICG assessments have higher agreement with those of the patient than HCP. Better agreement in both groups was found for physical symptoms, and best agreement was for pain. The worst agreements were for psychological symptoms, such as anxiety and depression, and for satisfaction with information given. Psychological symptoms are overestimated by both ICG and HCP. CONCLUSIONS: ICGs are more reliable proxies than HCPs. A trend for overestimation of symptoms was found in both groups which may lead to undervaluation of the quality of life by proxy and overtreatment of symptoms. This highlights the need to always use the patient report when possible, and to be aware of the potential flaws in proxy assessment. Reasons for overestimation by proxies deserve further research. PMID- 26758471 TI - Observation of giant Goos-Hanchen and angular shifts at designed metasurfaces. AB - Metasurfaces with sub-wavelength features are useful in modulating the phase, amplitude or polarization of electromagnetic fields. While several applications are reported for light manipulation and control, the sharp phase changes would be useful in enhancing the beam shifts at reflection from a metasurface. In designed periodic patterns on metal film, at surface plasmon resonance, we demonstrate Goos-Hanchen shift of the order of 70 times the incident wavelength and the angular shifts of several hundred microradians. We have designed the patterns using rigorous coupled wave analysis (RCWA) together with S-matrices and have used a complete vector theory to calculate the shifts as well as demonstrate a versatile experimental setup to directly measure the shifts. The giant shifts demonstrated could prove to be useful in enhancing the sensitivity of experiments ranging from atomic force microscopy to gravitational wave detection. PMID- 26758472 TI - The utility of faecal calprotectin to predict post-operative recurrence in Crohns disease. AB - OBJECTIVE: Endoscopic recurrence in Crohns disease occurs in up to 80% of patients during the first year after surgery. Due to this, these patients need close monitoring. Faecal calprotectin has been proposed to be used as a non invasive marker to monitor inflammatory activity. Up to now the use of faecal markers in endoscopic recurrence has been scarcely studied and with contradictory results. MATERIAL AND METHODS: This was a cross-sectional observational study of diagnostic validity. It included all patients with Crohns disease (CD) and ileocolic resection retrospectively who had had an ileocolonoscopy and a determination of faecal calprotectin before this colonoscopy, from 2007 to 2015. RESULTS: Ninety-seven patients were included. We observed that the mean value of faecal calprotectin increased as the Rutgeerts score increased. The variable of that most statistical significance obtained in bivariate analysis was faecal calprotectin (p < 0.0001). Area under curve (AUC) of faecal calprotectin in endoscopic recurrence was 0.74 (95% CI: 0.644-0.842), and an optimal cut-off of 60 mcrgr/gr, obtained a score of 0.45 using Youden test. This indicated that calprotectin would have 88% Sensitivity and 58% Specificity in detecting any recurrence, the NPV was approximately 83,9%. None of the other variables studied had a significant correlation. CONCLUSION: Faecal calprotectin predicts endoscopic recurrence in CD patients who have gone through surgery, however the cut-off point is still a problem so we cannot recommend calprotectin as a substitute of colonoscopy for CD monitoring and treatment adjustment. PMID- 26758473 TI - Aqueous phase preparation of ultrasmall MoSe2 nanodots for efficient photothermal therapy of cancer cells. AB - Photothermal therapy (PTT) is a promising cancer treatment with both high effectiveness and fewer side effects. However, an ideal PTT agent not only needs strong absorption of near-infrared (NIR) light and high photothermal conversion efficiency, but also needs good biocompatibility, stability, and small size, which makes the design and preparation of a novel PTT agent a great challenge. In this work, we developed an ultrasonication-assisted liquid exfoliation method for the direct preparation of ultrasmall (2-3 nm) MoSe2 nanodots (NDs) in aqueous solution and demonstrated their superior properties as a PTT agent. The as prepared MoSe2 NDs have strong absorption of NIR light and high photothermal conversion efficiency of about 46.5%. In vitro cellular experiments demonstrate that MoSe2 NDs have negligible cytotoxicity and can efficiently kill HeLa cells (human cervical cell line) under NIR laser (785 nm) irradiation. PMID- 26758474 TI - White phosphorus activation by a Th(III) complex. AB - [Th(Cp'')3] (Cp'' = {C5H3(SiMe3)2-1,3}) activates P4 to give [{Th(Cp'')3}2(MU eta(1):eta(1)-P4)] (1), which has an unprecedented cyclo-P4 binding mode. DFT studies were performed on a model of 1 to probe the bonding in this system. PMID- 26758475 TI - A study of a novel coprocessed dry binder composed of alpha-lactose monohydrate, microcrystalline cellulose and corn starch. AB - This paper deals with a study of the novel coprocessed dry binder Combilac(r), which contains 70% of alpha-lactose monohydrate, 20% of microcrystalline cellulose and 10% of native corn starch. These tests include flow properties, compressibility, lubricant sensitivity, tensile strength and disintegration time of tablets. Compressibility is evaluated by means of the energy profile of compression process, test of stress relaxation and tablet strength. The above mentioned parameters are also evaluated in the physical mixture of alpha-lactose monohydrate, microcrystalline cellulose and native corn starch and compared with Combilac. Combilac shows much better flowability than the physical mixture of the used dry binders. Its compressibility is better, tablets possess a higher tensile strength. Neither Combilac, nor the physical mixture can be compressed without lubricants due to high friction and sticking to the matrix. Combilac has a higher lubricant sensitivity than the physical mixture of the dry binders. Disintegration time of Combilac tablets is comparable with the disintegration time of tablets made from the physical mixture. PMID- 26758476 TI - Carers' and service users' experiences of early intervention in psychosis services: implications for care partnerships. AB - AIM: To explore carers' and service users' experiences of UK Early Intervention Services following referral for first-episode psychosis. METHODS: Thirty-two semi structured interviews (16 interviews with service users and 16 corresponding interviews with their carers) were completed and analysed. RESULTS: Carers spoke retrospectively and prospectively by framing their accounts into the periods before and since their engagement with Early Intervention Services. Desperation was evident as emotive experiences were recalled prior to referral. Relief then emerged as carers described support and engagement with key workers. Hope and optimism for the service user's prognosis and life trajectory were also expressed.Service users described similar positive experiences of Early Intervention Services and the support and insight they had gained through their relationships with key workers. They were however less focused on accounts of desperation and relief and more immersed in their current understanding and attempts to normalize their experiences of first-episode psychosis. Prognosis and future trajectories were only discussed tentatively. CONCLUSION: Communication and 'partnerships' with service users and carers are essential for effective service engagement, delivery of care and the reduction in relapse following first episode psychosis. This study highlights how key workers from Early Intervention Services are appropriately valued and situated to develop such relationships. Findings also reveal that service users' and carers' focus and expectations of recovery vary during the early stages of engagement with services. How key workers manage awareness and communication around such differing expectations is a crucial consideration for maintaining the 'partnerships' necessary for effective service provision. PMID- 26758479 TI - Higher-Order Personality Factors Of The ISI. AB - To determine the higher order factors defined by scales of the Interpersonal Style Inventory (ISI), data from two male samples and from one female sample were separately analyzed. Intercorrelations of 14 of the scales were analyzed by the method of principal axes. The five rotated factors established were highly similar across samples. They were interpreted as Socialized vs. Unsocialized, Interpersonally Involved vs. Withdrawn, Autonomous vs. Conforming, Controlled vs. Spontaneous, and Stable vs. Anxious. The findings are compared to constructs established in the PRF and 16 PF. PMID- 26758478 TI - How are qualitative methods used in diabetes research? A 30-year systematic review. AB - We aimed to describe how qualitative methods are used in global research on diabetes and identify opportunities whereby qualitative methods could further benefit our understanding of the human experience of diabetes and interventions to address it. We conducted a systematic review of National Library of Medicine, EMBASE, and Web of Science electronic databases to identify original research articles that used qualitative methods to study diabetes between 1980 and 2011. We identified 554 eligible articles and categorised these by geographic region, year of publication, study population, study design, research question, qualitative data collection methods, and journal type. Results show low use of qualitative methods in diabetes research over the past 30 years. The majority of articles (75%) reported using substantive qualitative research, while mixed methods research has remained underutilised. Eighty-five per cent of articles reported studies conducted in North America or Europe, with few studies in developing countries. Most articles reported recruiting clinic-based populations (58%). Over half (54%) of research questions focused on patient experience and 24% on diabetes management. Qualitative methods can provide important insights about socio-cultural aspects of disease to improve disease management. However, they remain underutilised for understanding the diabetes experience, especially in Africa and Asia and amongst non-clinic populations. PMID- 26758480 TI - The Construct Validity Of The Affective, Behavioral, And Cognitive Components Of Attitude By Analysis Of Covariance Structures. AB - Using the analysis of covariance structures methodology, the construct validity of the tripartite classification of attitudes is investigated. Convergent and discriminant validity were achieved for the reanalysis of Ostrom's (1969) data examining attitudes toward the church, while convergent, but not discriminant, validity was attained for the reanalysis of Kothandapani's (1971) data investigating attitudes toward birth control. Reasons for the difference in findings are examined including an analysis of measurement error, methods variance, and trait variance. The results are interpreted from a cognitive consistency and learning theory perspective. PMID- 26758477 TI - Sex differences in the effect of HbA1c-defined diabetes on a wide range of cardiovascular disease risk factors. AB - OBJECTIVE: Sex differences in the association of HbA1c and cardiovascular disease (CVD) risk remain controversial. We examined CVD risk profile in both HbA1c defined diabetic and nondiabetic men and women. METHODS: We conducted a cross sectional analysis of 7139 Chinese adults using data from the China Health and Nutrition Survey 2009. RESULTS: HbA1c-defined nondiabetic men have a more favorable CVD risk profile than female counterparts. However, HbA1c-defined diabetic men have higher levels of triglyceride, low-density lipoprotein (LDL) cholesterol, and triglyceride/high-density lipoprotein (HDL)-cholesterol and lower levels of HDL-cholesterol, be more visceral obese as indicated by visceral adiposity index (VAI) and lipid accumulation product (LAP), and more insulin resistant as assessed by the triglycerides and glucose index (TyG) than HbA1c defined diabetic women. Furthermore, HbA1c-defined diabetic men showed greater relative differences in ferritin than diabetic women when compared with their nondiabetic counterparts. Statistically significant sex by HbA1c-defined diabetes status interactions were observed for triglyceride, LDL-cholesterol, HDL cholesterol, triglyceride/HDL cholesterol, VAI, LAP, TyG, and ferritin (all ps < 0.05). Consideration of VAI or homeostasis model assessment of insulin resistance or both failed to eliminate the sex differences in the associations between diabetes and these CVD risk factors. CONCLUSIONS: Men who progressed from HbA1c defined nondiabetes to HbA1c-defined diabetes have greater metabolic deteriorations and put on more visceral adiposity than women. Key messages HbA1c defined nondiabetic men have a more favorable CVD risk profile than female counterparts. Men have to undergo a greater metabolic deterioration to develop HbA1c-defined diabetes than do women. Men have to put on more visceral adiposity to develop HbA1c-defined diabetes than do women. PMID- 26758482 TI - Factor Analysis of Active Avoidance and Operant Discrimination Learning in Mice. PMID- 26758483 TI - An Empirical Demonstration Of The Factor Differentiation Hypothesis. AB - The factor differentiation hypothesis suggests that the factor structure of a set of tests tends to differentiate over time, becoming more complex and articulated. Three hundred seventy-one naval recruits were assigned to one of three groups: a control group and two experimental groups who received training on a spatial visualization test. Confirmatory factor analyses demonstrated that the experimental groups had more differentiated factor structures for a battery of spatial tests, confirming the hypothesis that environmental manipulations can induce factor differentiation. PMID- 26758481 TI - Comparative Cluster Analysis Of Patterns Of Vocational Interest. AB - Published data on the Strong Vocational Interest Blank profiles of 113 occupational groups are analyzed by three different clustering procedures: (a) Hierarchical grouping of standard scores, (b) Hierarchical grouping of orthonormal factor scores and, (c) NORMIX analysis assuming equal covariance matrices for each group. It is shown that the NORMIX solution differs from the other solutions in a psychologically meaningful way. PMID- 26758484 TI - Econometric Modeling Of Individual And Social Multi-Attribute Utility Functions. AB - Econometric techniques for estimating the parameters of individual and composite (group) multi-attribute utility (MAU) models are discussed. These techniques permit measurement of intra- and inter-individual heterogeneity with regard to the importance ascribed to the model attributes. Using data from an experimental task in a simulated university environment, which involved developing criteria for evaluating faculty teaching performance, it is shown that the usual method of ordinary least squares (OLS) can be inaccurate and information restrictive. Implications for design and staffing as well as optimization and implementation of organizational and societal decisions are discussed. PMID- 26758485 TI - The Orthotran Solution. AB - A computational algorithm, the orthotran solution, is developed for determining oblique factor analytic solutions utilizing orthogonal transformation matrices. Using a simple structure criterion orthotran solutions are determined for 17 illustrative data sets and compared with their subjective solutions. The orthotran solution defines transformation solutions that are relatively congruent with the subjective solutions, thereby suggesting that it has considerable data generalizability. PMID- 26758486 TI - An enantioselective three-component reaction of diazoacetates with indoles and enals by iridium/iminium co-catalysis. AB - The first example of chiral secondary amine and iridium(i) co-catalyzed enantioselective three-component reaction of aryldiazoacetates, indoles and enals was rationally designed and developed to afford 3-substituted indole derivatives in good yields and with moderate diastereoselectivity as well as excellent enantioselectivity. This reaction is proposed to proceed through the enantioselective trapping of iridium(I)-associated zwitterionic intermediates via selective 1,4-addtition to the chiral amine activated enals. PMID- 26758487 TI - Quantitative analysis of intrinsic and extrinsic factors in the aggregation mechanism of Alzheimer-associated Abeta-peptide. AB - Disease related mutations and environmental factors are key determinants of the aggregation mechanism of the amyloid-beta peptide implicated in Alzheimer's disease. Here we present an approach to investigate these factors through acquisition of highly reproducible data and global kinetic analysis to determine the mechanistic influence of intrinsic and extrinsic factors on the Abeta aggregation network. This allows us to translate the shift in macroscopic aggregation behaviour into effects on the individual underlying microscopic steps. We apply this work-flow to the disease-associated Abeta42-A2V variant, and to a variation in pH as examples of an intrinsic and an extrinsic perturbation. In both cases, our data reveal a shift towards a mechanism in which a larger fraction of the reactive flux goes via a pathway that generates potentially toxic oligomeric species in a fibril-catalyzed reaction. This is in agreement with the finding that Abeta42-A2V leads to early-onset Alzheimer's disease and enhances neurotoxicity. PMID- 26758488 TI - Growth Hormone Deficiency in a Child with Neurofibromatosis-Noonan Syndrome. AB - Neurofibromatosis-Noonan syndrome (NFNS) is a distinct entity which shows the features of both NF1 (neurofibromatosis 1) and Noonan syndrome (NS). While growth hormone deficiency (GHD) has been relatively frequently identified in NF1 and NS patients, there is limited experience in NFNS cases. The literature includes only one case report of a NFNS patient having GHD and that report primarily focuses on the dermatological lesions that accompany the syndrome and not on growth hormone (GH) treatment. Here, we present a 13-year-old girl who had clinical features of NFNS with a mutation in the NF1 gene. The case is the first NFNS patient reported in the literature who was diagnosed to have GHD and who received GH treatment until reaching final height. The findings in this patient show that short stature is a feature of NFNS and can be caused by GHD. Patients with NFNS who show poor growth should be evaluated for GHD. PMID- 26758489 TI - Distribution of PASTA domains in penicillin-binding proteins and serine/threonine kinases of Actinobacteria. AB - PASTA domains (penicillin-binding protein and serine/threonine kinase-associated domains) have been identified in penicillin-binding proteins and serine/threonine kinases of Gram-positive Firmicutes and Actinobacteria. They are believed to bind beta-lactam antibiotics, and be involved in peptidoglycan metabolism, although their biological function is not definitively clarified. Actinobacteria, especially Streptomyces species, are distinct in that they undergo complex cellular differentiation and produce various antibiotics including beta-lactams. This review focuses on the distribution of PASTA domains in penicillin-binding proteins and serine/threonine kinases in Actinobacteria. In Actinobacteria, PASTA domains are detectable exclusively in class A but not in class B penicillin binding proteins, in sharp contrast to the cases in other bacteria. In penicillin binding proteins, PASTA domains distribute independently from taxonomy with some distribution bias. Particularly interesting thing is that no Streptomyces species have penicillin-binding protein with PASTA domains. Protein kinases in Actinobacteria possess 0 to 5 PASTA domains in their molecules. Protein kinases in Streptomyces can be classified into three groups: no PASTA domain, 1 PASTA domain and 4 PASTA domain-containing groups. The 4 PASTA domain-containing groups can be further divided into two subgroups. The serine/threonine kinases in different groups may perform different functions. The pocket region in one of these subgroup is more dense and extended, thus it may be involved in binding of ligands like beta-lactams more efficiently. PMID- 26758490 TI - AN483, a new anti-MRSA compound from Streptomyces sp. PMID- 26758491 TI - Euvesperins A and B, new circumventors of arbekacin resistance in MRSA, produced by Metarhizium sp. FKI-7236. PMID- 26758494 TI - Aureosurfactin and 3-deoxyaureosurfactin, novel biosurfactants produced by Aureobasidium pullulans L3-GPY. PMID- 26758492 TI - Iminimycin A, the new iminium metabolite produced by Streptomyces griseus OS 3601. AB - A new natural product, designated iminimycin A, was isolated from the cultured broth of a streptomycin-producing microbial strain, Streptomyces griseus OS-3601, via a physicochemical screening method using HP-20, silica gel and ODS column chromatographies and subsequent preparative HPLC. Iminimycin A is an indolizidine alkaloid, containing of an unusual iminium group and a cyclopropane ring with a triene side chain. The absolute configuration of iminimycin A was elucidated by NMR studies and electronic circular dichroism analysis. Iminimycin A shows anti bacterial activity against Bacillus subtilis, Kocuria rhizophila and Xanthomonas campestris pv. orizae, and cytotoxic activity against HeLa S3 and Jurkat cells with IC50 values of 43 and 36 MUM, respectively. PMID- 26758495 TI - Synthesis and antibacterial activity of novel lincomycin derivatives. I. Enhancement of antibacterial activities by introduction of substituted azetidines. AB - The synthesis and antibacterial activity of (7S)-7-sulfur-azetidin-3-yl lincomycin derivatives are described. Modification was achieved by a simple reaction of (7R)-7-O-methanesulfonyllincomycin and the corresponding substituted azetidine-2-thiol. Several compounds first showed moderate antibacterial activity against Streptococcus pneumoniae and Streptococcus pyogenes with erm gene as lincomycin derivatives. PMID- 26758493 TI - Proline-based phosphoramidite reagents for the reductive ligation of S nitrosothiols. AB - S-Nitrosothiols (RSNOs) have many biological implications but are rarely used in organic synthesis. In this work we report the development of proline-based phosphoramidite substrates that can effectively convert RSNOs to proline-based sulfenamides through a reductive ligation process. A unique property of this method is that the phosphine oxide moiety on the ligation products can be readily removed under acidic conditions. In conjugation with the facile preparation of RSNOs from the corresponding thiols (RSHs), this method provides a new way to prepare proline-based sulfenamides from simple thiol starting materials. PMID- 26758496 TI - 4D cone-beam CT reconstruction using multi-organ meshes for sliding motion modeling. AB - A simultaneous motion estimation and image reconstruction (SMEIR) strategy was proposed for 4D cone-beam CT (4D-CBCT) reconstruction and showed excellent results in both phantom and lung cancer patient studies. In the original SMEIR algorithm, the deformation vector field (DVF) was defined on voxel grid and estimated by enforcing a global smoothness regularization term on the motion fields. The objective of this work is to improve the computation efficiency and motion estimation accuracy of SMEIR for 4D-CBCT through developing a multi-organ meshing model. Feature-based adaptive meshes were generated to reduce the number of unknowns in the DVF estimation and accurately capture the organ shapes and motion. Additionally, the discontinuity in the motion fields between different organs during respiration was explicitly considered in the multi-organ mesh model. This will help with the accurate visualization and motion estimation of the tumor on the organ boundaries in 4D-CBCT. To further improve the computational efficiency, a GPU-based parallel implementation was designed. The performance of the proposed algorithm was evaluated on a synthetic sliding motion phantom, a 4D NCAT phantom, and four lung cancer patients. The proposed multi organ mesh based strategy outperformed the conventional Feldkamp-Davis-Kress, iterative total variation minimization, original SMEIR and single meshing method based on both qualitative and quantitative evaluations. PMID- 26758500 TI - Tough dual nanocomposite hydrogels with inorganic hybrid crosslinking. AB - A dual nanocomposite hydrogel with inorganic hybrid crosslinking was fabricated through a simultaneous sol-gel technique and free radical polymerization. Due to the multi-strengthening mechanism of the dual nanocomposite, the hydrogel was super tough and strong with a compressive stress of 32.00 MPa without rupture even at 100% strain, while it exhibited excellent fatigue resistant properties. PMID- 26758497 TI - Relationship between Neck Circumference and Non-Alcoholic Fatty Liver Disease in Childhood Obesity. AB - OBJECTIVE: The aim of this study was to establish the association between anthropometric parameters and non-alcoholic fatty liver disease (NAFLD) and to determine the most reliable measurement as a parameter in predicting NAFLD. METHODS: Two-hundred fifty-three obese children of ages 10 to 18 years were enrolled in this study. Anthropometric data and metabolic parameters such as fasting blood glucose, insulin and lipid levels, were measured. Liver function tests were assessed. NAFLD was determined by ultrasound. RESULTS: Most metabolic parameters and anthropometric indices were significantly higher in children with NAFLD. A univariate logistic regression analysis was performed, taking NAFLD status as the dependent variable and anthropometric parameters as the independent variables. NAFLD was affected significantly by the anthropometric values. The multiple logistic regression analysis showed that neck circumference (NC) was the only parameter which determined the risk in both genders. Each 1 cm increase in the NC increased the risk of NAFLD 1.544-fold (p<0.001, 95% confidence interval (CI): 1.357-2.214) in the boys and 1.733-fold (p=0.001, 95% CI: 1.185-2.012) in the girls. Receiver operating characteristic analysis was performed to compare the reliability of anthropometric measurements. NC was observed to be a better indicator. CONCLUSION: Measurement of the NC was shown to be associated with NAFLD in children. We suggest the use of NC as a novel, simple, practical, and reliable anthropometric index in predicting children at risk for NAFLD. PMID- 26758498 TI - Linezolid versus vancomycin for skin and soft tissue infections. AB - BACKGROUND: The morbidity and treatment costs associated with skin and soft tissue infections (SSTIs) are high. Linezolid and vancomycin are antibiotics that are commonly used in treating skin and soft-tissue infections, specifically those infections due to methicillin-resistant Staphylococcus aureus (MRSA). OBJECTIVES: To compare the effects and safety of linezolid and vancomycin for treating people with SSTIs. SEARCH METHODS: For this first update of this review we conducted searches of the following databases: Cochrane Wounds Group Specialised Register (searched 24 March 2015; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. We also contacted manufacturers for details of unpublished and ongoing trials. We scrutinised citations within all obtained trials and major review articles to identify any additional trials. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing linezolid with vancomycin in the treatment of SSTIs. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed risk of bias and extracted data. The primary outcomes were clinical cure, microbiological cure, and SSTI-related and treatment-related mortality. We performed subgroup analyses according to age, and whether the infection was due to MRSA. MAIN RESULTS: No new trials were identified for this first update. We included nine RCTs (3144 participants). Linezolid was associated with a significantly better clinical (RR 1.09, 95% CI 1.03 to 1.16) and microbiological cure rate in adults (RR 1.08, 95% CI 1.01 to 1.16). For those infections due to MRSA, linezolid was significantly more effective than vancomycin in clinical (RR 1.09, 95% CI 1.03 to 1.17) and microbiological cure rates (RR 1.17, 95% CI 1.04 to 1.32). No RCT reported SSTI-related and treatment-related mortality. There was no significant difference in all-cause mortality between linezolid and vancomycin (RR 1.44, 95% CI 0.75 to 2.80). There were fewer incidents of red man syndrome (RR 0.04, 95% CI 0.01 to 0.29), pruritus (RR 0.36, 95% CI 0.17 to 0.75) and rash (RR 0.27, 95% CI 0.12 to 0.58) in the linezolid group compared with vancomycin, however, more people reported thrombocytopenia (RR 13.06, 95% CI 1.72 to 99.22), and nausea (RR 2.45, 95% CI 1.52 to 3.94) when treated with linezolid. It seems, from the available data, that length of stay in hospital was shorter for those in the linezolid group than the vancomycin group. The daily cost of outpatient therapy was less with oral linezolid than with intravenous vancomycin. Although inpatient treatment with linezolid cost more than inpatient treatment with vancomycin per day, the median length of hospital stay was three days shorter with linezolid. Thus, total hospital charges per patient were less with linezolid treatment than with vancomycin treatment. AUTHORS' CONCLUSIONS: Linezolid seems to be more effective than vancomycin for treating people with SSTIs, including SSTIs caused by MRSA. The available evidence is at high risk of bias and is based on studies that were supported by the pharmaceutical company that makes linezolid. Further well-designed, independently-funded, RCTs are needed to confirm the available evidence. PMID- 26758499 TI - Dietary fibre for the primary prevention of cardiovascular disease. AB - BACKGROUND: The prevention of cardiovascular disease (CVD) is a key public health priority. A number of dietary factors have been associated with modifying CVD risk factors. One such factor is dietary fibre which may have a beneficial association with CVD risk factors. There is a need to review the current evidence from randomised controlled trials (RCTs) in this area. OBJECTIVES: The primary objective of this systematic review was to determine the effectiveness of dietary fibre for the primary prevention of CVD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, Ovid MEDLINE (1946 to January 2015), Ovid EMBASE (1947 to January 2015) and Science Citation Index Expanded (1970 to January 2015) as well as two clinical trial registers in January 2015. We also checked reference lists of relevant articles. No language restrictions were applied. SELECTION CRITERIA: We selected RCTs that assessed the effects of dietary fibre compared with no intervention or a minimal intervention on CVD and related risk factors. Participants included adults who are at risk of CVD or those from the general population. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, extracted data and assessed risk of bias; a third author checked any differences. A different author checked analyses. MAIN RESULTS: We included 23 RCTs (1513 participants randomised) examining the effect of dietary fibre. The risk of bias was unclear for most studies and studies had small sample sizes. Few studies had an intervention duration of longer than 12 weeks. There was a wide variety of fibre sources used, with little similarity between groups in the choice of intervention.None of the studies reported on mortality (total or cardiovascular) or cardiovascular events. Results on lipids suggest there is a significant beneficial effect of increased fibre on total cholesterol levels (17 trials (20 comparisons), 1067 participants randomised, mean difference -0.23 mmol/L, 95% CI -0.40 to -0.06), and LDL cholesterol levels (mean difference -0.14 mmol/L, 95% CI -0.22 to -0.06) but not on triglyceride levels (mean difference 0.00 mmol/L, 95% CI -0.04 to 0.05), and there was a very small but statistically significant decrease rather than increase in HDL levels with increased fibre intake (mean difference -0.03 mmol/L, 95% CI -0.06 to -0.01). Fewer studies (10 trials, 661 participants randomised) reported blood pressure outcomes where there is a significant effect of increased fibre consumption on diastolic blood pressure (mean difference -1.77 mmHg, 95% CI -2.61 to -0.92) whilst there is a reduction in systolic blood pressure with fibre but this does not reach statistical significance (mean difference -1.92 mmHg, 95% CI -4.02 to 0.19). There did not appear to be any subgroup effects by the nature of the type of intervention (fibre supplements or provision of foods/advice to increase fibre consumption) or the type of fibre (soluble/insoluble) although the number of studies contributing to each subgroup were small. All analyses need to be viewed with caution given the risks of bias observed for total cholesterol and the statistical heterogeneity observed for systolic blood pressure. Adverse events, where reported, appeared to mostly reflect mild to moderate gastrointestinal side-effects and these were generally reported more in the fibre intervention groups than the control groups. AUTHORS' CONCLUSIONS: Studies were short term and therefore did not report on our primary outcomes, CVD clinical events. The pooled analyses for CVD risk factors suggest reductions in total cholesterol and LDL cholesterol with increased fibre intake, and reductions in diastolic blood pressure. There were no obvious effects of subgroup analyses by type of intervention or fibre type but the number of studies included in each of these analyses were small. Risk of bias was unclear in the majority of studies and high for some quality domains so results need to be interpreted cautiously. There is a need for longer term, well-conducted RCTs to determine the effects of fibre type (soluble versus insoluble) and administration (supplements versus foods) on CVD events and risk factors for the primary prevention of CVD. PMID- 26758501 TI - Three-year efficacy and safety of tenofovir in nucleos(t)ide analog-naive and nucleos(t)ide analog-experienced chronic hepatitis B patients. AB - BACKGROUND AND AIMS: This study compared the efficacy and safety of tenofovir disoproxil fumarate (TDF) up to 3 years of innucleos(t)ide analog (NA)-naive and NA-experienced chronic hepatitis B (CHB) patients. METHODS: Tenofovir disoproxil fumarate-treated NA-naive and NA-experienced CHB patients were retrospectively analyzed. RESULTS: After 3 years of TDF therapy, 97.7%, 71%, and 45.5% NA-naive patients achieved a virological response, alanine aminotransferase normalization, and hepatitis B e antigen seroconversion, respectively. Compared with NA-naive patients, NA-experienced patients without drug resistance and infected with lamivudine/telbivudine-resistant mutants showed similar results. In contrast, patients previously infected with adefovir-resistant mutants and with a suboptimal entecavir response showed significantly lower rates of virological response and hepatitis B e antigen loss/seroconverion than NA-naive patients. Mean estimated glomerular filtration rate markedly reduced within 12 months of TDF therapy; however, it did not decrease significantly during 12-36 months of treatment. Diabetes mellitus was an independent predictor of a >= 0.5 mg/dL increase above baseline in serum creatinine level, and age, hypertension, diabetes mellitus, and baseline creatinine level were independent factors for > 20% decline in estimated glomerular filtration rate from baseline. Liver stiffness measurements improved significantly, but bone mineral density did not change significantly during treatment. Hepatocellular carcinoma incidence was low at 36 months. Age of > 60 years, cirrhosis, a low baseline platelet count and a high alpha-fetoprotein level at 12 months were significant predictors of hepatocellular carcinoma development. CONCLUSIONS: Tenofovir disoproxil fumarate is effective and safe for NA-naive and NA-experienced CHB patients and should be used cautiously in patients with comorbidities because of a renal dysfunction risk. PMID- 26758503 TI - Atomic-Scale Imaging of the Surface Dipole Distribution of Stepped Surfaces. AB - Stepped well-ordered semiconductor surfaces are important as nanotemplates for the fabrication of 1D nanostructures. Therefore, a detailed understanding of the underlying stepped substrates is crucial for advances in this field. Although measurements of step edges are challenging for scanning force microscopy (SFM), here we present simultaneous atomically resolved SFM and Kelvin probe force microscopy (KPFM) images of a silicon vicinal surface. We find that the local contact potential difference is large at the bottom of the steps and at the restatoms on the terraces, whereas it drops at the upper part of the steps and at the adatoms on the terraces. For the interpretation of the data we performed density functional theory (DFT) calculations of the surface dipole distribution. The DFT images accurately reproduce the experiments even without including the tip in the calculations. This underlines that the high-resolution KPFM images are closely related to intrinsic properties of the surface and not only to tip surface interactions. PMID- 26758502 TI - Fish oil supplementation from 9 to 18 months of age affects the insulin-like growth factor axis in a sex-specific manner in Danish infants. AB - Several studies have investigated the effects of fish oil (FO) on infant growth, but little is known about the effects of FO and sex on insulin-like growth factor 1 (IGF-1), the main regulator of growth in childhood. We explored whether FO v. sunflower oil (SO) supplementation from 9 to 18 months of age affected IGF-1 and its binding protein-3 (IGFBP-3) and whether the potential effects were sex specific. Danish infants (n 115) were randomly allocated to 5 ml/d FO (1.2 g/d n 3 long-chain PUFA (n-3 LCPUFA)) or SO. We measured growth, IGF-1, IGFBP-3 and erythrocyte EPA, a biomarker of n-3 LCPUFA intake and status, at 9 and 18 months. Erythrocyte EPA increased strongly with FO compared with SO (P<0.001). There were no effects of FO compared with SO on IGF-1 in the total population, but a sex * group interaction (P=0.02). Baseline-adjusted IGF-1 at 18 months was 11.1 ug/l (95% CI 0.4, 21.8; P=0.04) higher after FO compared with SO supplementation among boys only. The sex * group interaction was borderline significant in the model of IGFBP-3 (P=0.09), with lower IGFBP-3 with FO compared with SO among girls only (P=0.03). The results were supported by sex-specific dose-response associations between changes in erythrocyte EPA and changes in IGF-1 and IGFBP-3 (both P<0.03). Moreover, IGF-1 was sex specifically associated with BMI and length. In conclusion, FO compared with SO resulted in higher IGF-1 among boys and lower IGFBP-3 among girls. The potential long-term implications for growth and body composition should be investigated further. PMID- 26758504 TI - Food addiction as a new piece of the obesity framework. PMID- 26758506 TI - Assessing posttraumatic stress disorder in children with mild to borderline intellectual disabilities. AB - BACKGROUND: Evidence suggests that children with mild to borderline intellectual disabilities (MBID; IQ 50-85) have an elevated risk for both being exposed to potentially traumatic events and developing a posttraumatic stress disorder (PTSD). In this target group, PTSD often remains undiscovered due to a lack of diagnostic instruments. Valid instruments for the assessment of PTSD in children with MBID are therefore needed. OBJECTIVE: The aim of the current study was to validate the adapted PTSD section of the Anxiety Disorders Interview Schedule for Children (ADIS-C) for the assessment of PTSD in children with MBID according to DSM-IV-TR and DSM-5 criteria. METHOD: Eighty children (aged 6-18 years) with MBID who were referred to an outpatient psychiatric service and their primary caregivers were interviewed using the adapted ADIS-C. RESULTS: The adapted ADIS-C PTSD section has excellent interrater reliability and good convergent validity. PTSD symptoms described spontaneously by children with MBID and their caregivers closely matched those included in the DSM-IV-TR and DSM-5. Many of the children who met Criterion A did not meet PTSD symptom criteria. Conversely, children meeting the full PTSD criteria were more likely than other children with MBID to have been exposed to at least one traumatic event meeting Criterion A and to a higher total number of potentially traumatic events. CONCLUSIONS: The results support the reliability and validity of the adapted ADIS-C PTSD section for assessing PTSD in children with MBID. The use of this clinical interview helps to improve detection of PTSD and subsequent access to trauma-focused interventions for this at risk target group. PMID- 26758505 TI - Bispecific Antibody Affords Complete Post-Exposure Protection of Mice from Both Ebola (Zaire) and Sudan Viruses. AB - Filoviruses (Ebola and Marburg) cause severe hemorrhagic fever. There are five species of ebolavirus; among these, the Ebola (Zaire) and Sudan viruses (EBOV and SUDV, respectively) are highly pathogenic and have both caused recurring, large outbreaks. However, the EBOV and SUDV glycoprotein (GP) sequences are 45% divergent and thus antigenically distinct. Few antibodies with cross-neutralizing properties have been described to date. We used antibody engineering to develop novel bispecific antibodies (Bis-mAbs) that are cross-reactive toward base epitopes on GP from EBOV and SUDV. These Bis-mAbs exhibit potent neutralization against EBOV and SUDV GP pseudotyped viruses as well as authentic pathogens, and confer a high degree (in one case 100%) post-exposure protection of mice from both viruses. Our studies show that a single agent that targets the GP base epitopes is sufficient for protection in mice; such agents could be included in panfilovirus therapeutic antibody cocktails. PMID- 26758507 TI - The extent of the raphe in bicuspid aortic valves is associated with aortic regurgitation and aortic root dilatation. AB - BACKGROUND: The clinical course of bicuspid aortic valves (BAVs) is variable. Data on predictors of aortopathy and valvular dysfunction mainly focus on valve morphology. AIM: To determine whether the presence and extent of the raphe (fusion site of valve leaflets) is associated with the degree of aortopathy and valvular dysfunction in patients with isolated BAV and associated aortic coarctation (CoA). METHODS: Valve morphology and aortic dimensions of 255 BAV patients were evaluated retrospectively by echocardiography. RESULTS: BAVs with a complete raphe had a significantly higher prevalence of valve dysfunction (especially aortic regurgitation) than BAVs with incomplete raphes (82.9 vs. 66.7 %, p = 0.01). Type 1A BAVs (fusion of right and left coronary leaflets) and complete raphe had larger aortic sinus diameters compared with the rest of the population (37.74 vs. 36.01, p = 0.031). Patients with CoA and type 1A BAV had significantly less valve regurgitation (13.6 vs. 55.8 %, p < 0.001) and smaller diameters of the ascending aorta (33.7 vs. 37.8 mm, p < 0.001) and aortic arch (25.8 vs. 30.2 mm, p < 0.001) than patients with isolated BAV. CONCLUSIONS: Type 1A BAV with complete raphe is associated with more aortic regurgitation and root dilatation. The majority of CoA patients have incomplete raphes, associated with smaller aortic root diameters and less valve regurgitation. PMID- 26758508 TI - Novel polymorphisms in caspase-8 are associated with breast cancer risk in the California Teachers Study. AB - BACKGROUND: The ability of tamoxifen and raloxifene to decrease breast cancer risk varies among different breast cancer subtypes. It is important to determine one's subtype-specific breast cancer risk when considering chemoprevention. A number of single nucleotide polymorphisms (SNPs), including one in caspase-8 (CASP8), have been previously associated with risk of developing breast cancer. Because caspase-8 is an important protein involved in receptor-mediated apoptosis whose activity is affected by estrogen, we hypothesized that additional SNPs in CASP8 could be associated with breast cancer risk, perhaps in a subtype-specific manner. METHODS: Twelve tagging SNPs of CASP8 were analyzed in a nested case control study (1,353 cases and 1,384 controls) of non-Hispanic white women participating in the California Teachers Study. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each SNP using all, estrogen receptor (ER)-positive, ER-negative, human epidermal growth factor receptor 2 (HER2)-positive, and HER2-negative breast cancers as separate outcomes. RESULTS: Several SNPs were associated with all, ER-positive, and HER2-positive breast cancers; however, after correcting for multiple comparisons (i.e., p < 0.0008), only rs2293554 was statistically significantly associated with HER2-positive breast cancer (OR = 1.98, 95% CI 1.34-2.92, uncorrected p = 0.0005). CONCLUSIONS: While our results for CASP8 SNPs should be validated in other cohorts with subtype-specific information, we conclude that some SNPs in CASP8 are associated with subtype-specific breast cancer risk. This study contributes to our understanding of CASP8 SNPs and breast cancer risk by subtype. PMID- 26758509 TI - A European multi-language initiative to make the general population aware of independent clinical research: the European Communication on Research Awareness Need project. AB - BACKGROUND: The ECRAN (European Communication on Research Awareness Needs) project was initiated in 2012, with support from the European Commission, to improve public knowledge about the importance of independent, multinational, clinical trials in Europe. METHODS: Participants in the ECRAN consortium included clinicians and methodologists directly involved in clinical trials; researchers working in partnership with the public and patients; representatives of patients; and experts in science communication. We searched for, and evaluated, relevant existing materials and developed additional materials and tools, making them freely available under a Creative Commons licence. RESULTS: The principal communication materials developed were: 1. A website ( http://ecranproject.eu ) in six languages, including a Media centre section to help journalists to disseminate information about the ECRAN project 2. An animated film about clinical trials, dubbed in the 23 official languages of the European Community, and an interactive tutorial 3. An inventory of resources, available in 23 languages, searchable by topic, author, and media type 4. Two educational games for young people, developed in six languages 5. Testing Treatments interactive in a dozen languages, including five official European Community languages 6. An interactive tutorial slide presentation testing viewers' knowledge about clinical trials CONCLUSIONS: Over a 2-year project, our multidisciplinary and multinational consortium was able to produce, and make freely available in many languages, new materials to promote public knowledge about the importance of independent and international clinical trials. Sustained funding for the ECRAN information platform could help to promote successful recruitment to independent clinical trials supported through the European Clinical Research Infrastructure Network. PMID- 26758510 TI - Treatment patterns, resource use and costs of idiopathic pulmonary fibrosis in Spain--results of a Delphi Panel. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a form of chronic fibrosing interstitial pneumonia characterized by progressive worsening of dyspnea and lung function, with a poor prognosis. The objective of this study was to determine treatment patterns, resource use and costs of managing Spanish patients with IPF. METHODS: A three-round Delphi consensus panel of 15 clinical experts was held between December 2012 and June 2013 using questionnaires to describe the management of patients with IPF. A cost analysis based on Delphi panel estimates was made from the Spanish National Health System (NHS) perspective, including the direct costs of IPF diagnosis and management. Unit costs were applied to Delphi panel estimates of health resource use. Univariate sensitivity analyses were made to evaluate uncertainties in parameters. RESULTS: The Delphi panel estimated that 20, 60 and 20% of IPF patients presented with stable disease, slow and rapid disease progression, respectively. The estimated annual cost per patient with stable disease, slow and rapid disease progression was ?11,484, ?20,978 and ?57,759, respectively. This corresponds to a weighted average annual cost of ?26,435 with itemized costs of ?1,184 (4.5), ?7,147 (27.0), ?5,950 (22.5), ?11,666 (44.1) and ?488 (1.9%) for the diagnosis of IPF, treatment, monitoring, management of acute exacerbations and end-of-life care, respectively. The parameter that varied the annual cost per patient the most was resource use associated with acute exacerbations. CONCLUSIONS: The management of patients with IPF in Spain, especially patients with rapid disease progression, has a high economic impact on the NHS. PMID- 26758511 TI - Association of complete blood cell counts with metabolic syndrome in an elderly population. AB - BACKGROUND: Metabolic syndrome's (MetS) role in predicting cardiovascular diseases and diabetes has been confirmed in many large cohort studies. Nontraditionally, hematogram components are significantly related to MetS in many different age groups. However, little is known about its role among the elderly. METHODS: We enrolled 18,907 subjects over the age of 65 years who underwent regular health examinations. They were divided into three groups according to age: young old (YO: >= 65 and < 74 years old), old old (OO: >= 75 and < 84 years old), and oldest old (ODO: >= 85 years old). The MetS components were determined, and correlations between MetS and hematogram components were evaluated using Pearson and multivariate linear regression analyses. The hematogram components were the independent variables evaluated separately against the dependent variable (MetS components). RESULTS: While SBP and HDL-C increased, most other MetS and hematogram parameters decreased in men with age. Fewer significant differences were noted among the women. In the YO and OO groups for both genders, the subjects with MetS had higher WBC and Hb. None of the hematogram components were different for subjects with or without MetS in the ODO group. Multiple regression results show that most of the relationships between hematogram and MetS components disappeared in the ODO groups. The WBC levels were mainly correlated with WC and TG. At the same time, Hb was associated with BP, FPG, and LDL-C. Compared to WBC and Hb, PLT was least related to MetS, except in the cases of LDL-C and TG. Among the MetS components, BMI, LDL-C, and TG were consistently related to all the hematogram components in YO and OO men. However, only TG had the same consistency among YO and OO women. CONCLUSIONS: This study's three major findings are as follows: WBC and Hb are associated with MetS, even among the YO and OO groups, regardless of gender; among the three hematogram components, Hb had the strongest and PLT had the weakest correlation with MetS; and TG is not the only component with relatively higher r values, and it is related to all hematogram components. PMID- 26758512 TI - Psychometric characteristics of the Functional Assessment of Cancer Therapy General when applied to Brazilian cancer patients: a cross-cultural adaptation and validation. AB - BACKGROUND: The psychometric properties of an instrument should be evaluated routinely when using different samples. This study evaluated the psychometric properties of the Functional Assessment of Cancer Therapy-General (FACT-G) when applied to a sample of Brazilian cancer patients. METHODS: The face, content, and construct (factorial, convergent, and discriminant) validities of the FACT-G were estimated. Confirmatory factor analysis (CFA) was conducted the ratio chi-square by degrees of freedom (chi (2)/df), the comparative fit index (CFI), the Tucker Lewis index (TLI), and the root mean square error of approximation (RMSEA) as indices. The invariance of the best model was assessed with multi-group analysis using the difference of chi-squares method (Deltachi(2)). Convergent validity was assessed using Average Variance Extracted (AVE) and discriminant validity was determined via correlational analysis. Internal consistency was assessed using the Cronbach's alpha (alpha) coefficient, and the Composite Reliability (CR) was estimated. RESULTS: A total of 975 cancer patients participated in the study, with a mean age of 53.3 (SD = 13.0) years. Of these participants, 61.5 % were women. In CFA, five correlations between errors were included to fit the FACT-G to the sample (chi (2)/df = 8.611, CFI = .913, TLI = .902, RMSEA = .088). The model did not indicate invariant independent samples (Deltachi(2): MU: p < .001, i: p < .958, Cov: p < .001, Res: p < .001). While there was adequate convergent validity for the physical well-being (AVE = .54) and social and family Well-being factors (AVE = .55), there was low convergent validity for the other factors. Reliability was adequate (CR = .76-.89 and alpha = .71-.82). Functional well being, emotional well-being, and physical well-being were the factors that demonstrated a strong contribution to patients' health-related quality of life (beta = -.99, .88, and .64, respectively). CONCLUSION: The FACT-G was found to be a valid and reliable assessment of health-related quality of life in a Brazilian sample of patients with cancer. PMID- 26758513 TI - CANEapp: a user-friendly application for automated next generation transcriptomic data analysis. AB - BACKGROUND: Next generation sequencing (NGS) technologies are indispensable for molecular biology research, but data analysis represents the bottleneck in their application. Users need to be familiar with computer terminal commands, the Linux environment, and various software tools and scripts. Analysis workflows have to be optimized and experimentally validated to extract biologically meaningful data. Moreover, as larger datasets are being generated, their analysis requires use of high-performance servers. RESULTS: To address these needs, we developed CANEapp (application for Comprehensive automated Analysis of Next-generation sequencing Experiments), a unique suite that combines a Graphical User Interface (GUI) and an automated server-side analysis pipeline that is platform independent, making it suitable for any server architecture. The GUI runs on a PC or Mac and seamlessly connects to the server to provide full GUI control of RNA sequencing (RNA-seq) project analysis. The server-side analysis pipeline contains a framework that is implemented on a Linux server through completely automated installation of software components and reference files. Analysis with CANEapp is also fully automated and performs differential gene expression analysis and novel noncoding RNA discovery through alternative workflows (Cuffdiff and R packages edgeR and DESeq2). We compared CANEapp to other similar tools, and it significantly improves on previous developments. We experimentally validated CANEapp's performance by applying it to data derived from different experimental paradigms and confirming the results with quantitative real-time PCR (qRT-PCR). CANEapp adapts to any server architecture by effectively using available resources and thus handles large amounts of data efficiently. CANEapp performance has been experimentally validated on various biological datasets. CANEapp is available free of charge at http://psychiatry.med.miami.edu/research/laboratory of-translational-rna-genomics/CANE-app . CONCLUSIONS: We believe that CANEapp will serve both biologists with no computational experience and bioinformaticians as a simple, timesaving but accurate and powerful tool to analyze large RNA-seq datasets and will provide foundations for future development of integrated and automated high-throughput genomics data analysis tools. Due to its inherently standardized pipeline and combination of automated analysis and platform independence, CANEapp is an ideal for large-scale collaborative RNA-seq projects between different institutions and research groups. PMID- 26758514 TI - Radix puerariae extracts ameliorate paraquat-induced pulmonary fibrosis by attenuating follistatin-like 1 and nuclear factor erythroid 2p45-related factor-2 signalling pathways through downregulation of miRNA-21 expression. AB - BACKGROUND: Puerarin, extracted from Radix puerariae, was reported to ameliorate airway inflammation, lung injury and lung fibrosis induced by paraquat (PQ) in mice. However, effects of Radix puerariae extracts (RPEs) on lung fibrosis or signalling pathways in PQ-induced lung injury have not been well studied. Therefore, the goals of our study were to investigate whether Radix puerariae extracts are antifibrotic in a paraquat (PQ) induced lung fibrosis model in mice and to propose possible mechanisms of action of the RPE effects. METHODS: We used a long-term exposure model of PQ-induced lung fibrosis in mice to evaluate effects of antioxidant-containing RPE. We examined effects of miR-21 on follistatin-like 1 (Fstl 1) pathways and oxidative stress in the lung. Gene expression levels of miR-21, Fstl 1, transforming growth factor-beta1 (TGF beta1), connective tissue growth factor (CTGF), collagen-1 and collagen III were measured by real-time PCR. Protein expression levels of Fstl 1(FSTL1), heme oxygenase-1 (HO-1), nuclear factor erythroid 2p45-related factor-2 (Nrf2), Smad2/3, p38MAPK, nuclear factor-kappaB 65 (NF-kappaB65), and matrix metalloproteinase-9 were detected by western blotting. FSTL1 andalpha-smooth muscle actin (alpha-SMA) in lung tissue were detected by immunohistochemistry. Malondialdehyde, superoxide dismutase (SOD), reduced (GSH) and oxidised (GSSH) glutathione and reactive oxygen species levels, hydroxyproline and total lung collagen were also determined. RESULTS: Long-term challenge with PQ enhanced miRNA-21 (miR-21), Fstl 1 pathways, oxidative stress and development of fibrotic features in the lungs. RPE reduced features of lung fibrosis by blocking Fstl 1 pathways and oxidative stress through decreased miR-21 expression. This was accompanied by suppression of CTGF, TGF-beta1, vascular endothelial growth factor, collagen I, and collagen III. In addition, PQ-induced activation of NF kappaB, Nrf2 and alpha-SMA were enhanced by puerarin. We also found that puerarin increased HO-1, SOD and GSH levels. CONCLUSIONS: These findings demonstrated that RPEs blocked PQ-induced Fstl 1 pathways and oxidative stress by inhibiting miR-21 expression, leading to attenuation of PQ-induced lung fibrosis. PMID- 26758515 TI - Parathyroidectomy Associates with Reduced Mortality in Taiwanese Dialysis Patients with Hyperparathyroidism: Evidence for the Controversy of Current Guidelines. AB - Parathyroidectomy is recommended by the clinical guidelines for dialysis patients with unremitting secondary hyperparathyroidism (SHPT). However, the survival advantage of parathyroidectomy is debated because of the selection bias in previous studies. To minimize potential bias in the present nationwide cohort study, we enrolled only dialysis patients who had undergone radionuclide parathyroid scanning to ensure all patients had severe SHPT. The parathyroidectomized patients were matched with the controls based on propensity score for parathyroidectomy. Mortality hazard was estimated using multivariate Cox proportional hazard models adjusting for comorbidities before scanning (model 1) or over the whole study period (model 2). Our results showed that among the 2786 enrolled patients, 1707 underwent parathyroidectomy, and the other 1079 were controls. The crude mortality rates were lower in the parathyroidectomized patients than in the controls. In adjusted analyses for the population matched on propensity score, parathyroidectomy was associated with a significant 20% to 25% lower risk for all-cause mortality (model 1: hazard ratio 0.76, 95% confidence interval 0.61 to 0.94; model 2: hazard ratio 0.80, 95% confidence internal 0.64 to 0.98). We concluded that parathyroidectomy was associated with a reduced long term mortality risk in dialysis patients with severe SHPT. PMID- 26758517 TI - Words of Wisdom. Re: Risk Group and Death From Prostate Cancer: Implications for Active Surveillance in Men with Favorable Intermediate-risk Prostate Cancer. PMID- 26758516 TI - Evaluating Phylostratigraphic Evidence for Widespread De Novo Gene Birth in Genome Evolution. AB - The source of genetic novelty is an area of wide interest and intense investigation. Although gene duplication is conventionally thought to dominate the production of new genes, this view was recently challenged by a proposal of widespread de novo gene origination in eukaryotic evolution. Specifically, distributions of various gene properties such as coding sequence length, expression level, codon usage, and probability of being subject to purifying selection among groups of genes with different estimated ages were reported to support a model in which new protein-coding proto-genes arise from noncoding DNA and gradually integrate into cellular networks. Here we show that the genomic patterns asserted to support widespread de novo gene origination are largely attributable to biases in gene age estimation by phylostratigraphy, because such patterns are also observed in phylostratigraphic analysis of simulated genes bearing identical ages. Furthermore, there is no evidence of purifying selection on very young de novo genes previously claimed to show such signals. Together, these findings are consistent with the prevailing view that de novo gene birth is a relatively minor contributor to new genes in genome evolution. They also illustrate the danger of using phylostratigraphy in the study of new gene origination without considering its inherent bias. PMID- 26758518 TI - Words of Wisdom. Re: Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial. PMID- 26758519 TI - Words of Wisdom. Re: Androgen Deprivation With or Without Radiation Therapy for Clinically Node-Positive Prostate Cancer. PMID- 26758520 TI - Words of Wisdom. Re: The Use of Early Postoperative Prostate-specific Antigen to Stratify Risk in Patients with Positive Surgical Margins After Radical Prostatectomy. PMID- 26758521 TI - Words of Wisdom. Re: Vinflunine in Routine Clinical Practice for the Treatment of Advanced or Metastatic Urothelial Cell Carcinoma--Data from a Prospective, Multicenter Experience. PMID- 26758522 TI - Words of Wisdom. Re: Use of Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction and Risk of Malignant Melanoma. PMID- 26758523 TI - Incidence and severity of pseudohyperkalemia in chronic lymphocytic leukemia: a longitudinal analysis. PMID- 26758524 TI - Sensitive Detection of Organophosphorus Pesticides in Medicinal Plants Using Ultrasound-Assisted Dispersive Liquid-Liquid Microextraction Combined with Sweeping Micellar Electrokinetic Chromatography. AB - A simple, rapid, and sensitive method using ultrasound-assisted dispersive liquid liquid microextraction (UA-DLLME) combined with sweeping micellar electrokinetic chromatography (sweeping-MEKC) has been developed for the determination of nine organophosphorus pesticides (chlorfenvinphos, parathion, quinalphos, fenitrothion, azinphos-ethyl, parathion-methyl, fensulfothion, methidathion, and paraoxon). The important parameters that affect the UA-DLLME and sweeping efficiency were investigated. Under the optimized conditions, the proposed method provided 779.0-6203.5-fold enrichment of the nine pesticides compared to the normal MEKC method. The limits of detection ranged from 0.002 to 0.008 mg kg(-1). The relative standard deviations of the peak area ranged from 1.2 to 6.5%, indicating the good repeatability of the method. Finally, the developed UA-DLLME sweeping-MEKC method has been successfully applied to the analysis of the investigated pesticides in several medicinal plants, including Lycium chinense, Dioscorea opposite, Codonopsis pilosula, and Panax ginseng, indicating that this method is suitable for the determination of trace pesticide residues in real samples with complex matrices. PMID- 26758526 TI - The China longitudinal ageing study: overview of the demographic, psychosocial and cognitive data of the Shanghai sample. AB - BACKGROUND: China's ageing population will lead to increased neurodegenerative illness and age-related mental health problems. AIMS: The Chinese Longitudinal Ageing Study has been developed to better understand the impact of ageing on cognition and mental health. An overview of the sample, major diagnoses and results of the first wave of data collection is presented. METHOD: One thousand and sixty-eight elderly Chinese (42.2% male), mean age of 72.8 years (SD = 8.5) completed a comprehensive cognitive, psychosocial and mental health assessment. RESULTS: Mean MMSE score was 24.73 (SD = 6.17). Primary generalised anxiety was detected in 0.4% of the sample. Sub-clinical depression and depressive disorder were diagnosed in 1.7% and 2.4% of the sample, respectively. Most (84.5%) reported subjective memory decline, however 66.5% had no cognitive impairment. Mild Cognitive Impairment (MCI) was detected in 25%, Alzheimer's disease (AD) in 4.7%, vascular dementia in 2.5%, and mixed dementia in 1.3%. Cognition was worse in those 85+ years, but affective disorder rates were not. CONCLUSION: Higher rates of dementia were detected than previously reported in China. Normative data is presented for common cognitive and mental health assessment and screening tasks in a Chinese population. This suggests that the true incidence of dementia has been underestimated, and requires further investigation. PMID- 26758528 TI - Statement of Retraction. PMID- 26758529 TI - Exploration of Microplasma Probe Desorption/Ionization Mass Spectrometry (MPPDI MS) for Biologically Related Analysis. AB - To expand the applications of glow discharge microplasma into biological analysis, an innovative ambient ion source for mass spectrometry, microplasma probe desorption/ionization mass spectrometry (MPPDI-MS), has been developed and demonstrated. Electrodes and a sampling tube were creatively combined using a stainless steel syringe needle, and efficient methods of introduction for biological samples in solid, liquid, and gaseous phases like phospholipid and amino acids were specially designed. Based on the active species generated by glow discharge plasma, simplified protonated spectra were obtained without extra solvent spray assistance. The method is easy to operate and versatile and especially has the ability to distinguish the isomeric compounds of ketone and aldehyde. Quantitative results of this method for different biological samples in different phases were also performed well. It was proved that with further improvement, this sensitive and selective analysis using MPPDI-MS with minimal invasiveness will be an ingenious tool in disease diagnosis and single-cell detections in the future. PMID- 26758525 TI - Stochastic expression of a multiple antibiotic resistance activator confers transient resistance in single cells. AB - Transient resistance can allow microorganisms to temporarily survive lethal concentrations of antibiotics. This can be accomplished through stochastic mechanisms, where individual cells within a population display diverse phenotypes to hedge against the appearance of an antibiotic. To date, research on transient stochastic resistance has focused primarily on mechanisms where a subpopulation of cells enters a dormant, drug-tolerant state. However, a fundamental question is whether stochastic gene expression can also generate variable resistance levels among growing cells in a population. We hypothesized that stochastic expression of antibiotic-inducible resistance mechanisms might play such a role. To investigate this, we focused on a prototypical example of such a system: the multiple antibiotic resistance activator MarA. Previous studies have shown that induction of MarA can lead to a multidrug resistant phenotype at the population level. We asked whether MarA expression also has a stochastic component, even when uninduced. Time lapse microscopy showed that isogenic cells express heterogeneous, dynamic levels of MarA, which were correlated with transient antibiotic survival. This finding has important clinical implications, as stochastic expression of resistance genes may be widespread, allowing populations to hedge against the sudden appearance of an antibiotic. PMID- 26758527 TI - Using On-scene EMS Responders' Assessment and Electronic Patient Care Records to Evaluate the Suitability of EMD-triaged, Low-acuity Calls for Secondary Nurse Triage in 911 Centers. AB - INTRODUCTION: Using the Medical Priority Dispatch System (MPDS) - a systematic 911 triage process - to identify a large subset of low-acuity patients for secondary nurse triage in the 911 center is a largely unstudied practice in North America. This study examines the ALPHA-level subset of low-acuity patients in the MPDS to determine the suitability of these patients for secondary triage by evaluating vital signs and necessity of lights-and-siren transport, as determined by attending Emergency Medical Services (EMS) ambulance crews. OBJECTIVES: The primary objective of this study was to determine the clinical status of MPDS ALPHA-level (low-acuity) patients, as determined by on-scene EMS crews' patient care records, in two US agencies. A secondary objective was to determine which ALPHA-level codes are suitable candidates for secondary triage by a trained Emergency Communication Nurse (ECN). METHODS: In this retrospective study, one full year (2013) of both dispatch data and EMS patient records data, associated with all calls coded at the ALPHA-level (low-acuity) in the dispatch protocol, were collected. The primary outcome measure was the number and percentage of ALPHA-level codes categorized as low-acuity, moderate-acuity, high-acuity, and critical using four common vital signs to assign these categories: systolic blood pressure (SBP), pulse rate (PR), oxygen saturation (SpO2), and Glasgow Coma Score (GCS). Vital sign data were obtained from ambulance crew electronic patient care records (ePCRs). The secondary endpoint was the number and percentage of ALPHA level codes that received a "hot" (lights-and-siren) transport. RESULTS: Out of 19,300 cases, 16,763 (86.9%) were included in the final analysis, after excluding cases from health care providers and those with missing data. Of those, 89% of all cases did not have even one vital sign indicator of unstable patient status (high or critical vital sign). Of all cases, only 1.1% were transported lights and-siren. CONCLUSION: With the exception of the low-acuity, ALPHA-level seizure cases, the ALPHA-level patients are suitable to transfer for secondary triage in a best-practices, accredited, emergency medical dispatch center that utilizes the MPDS at very high compliance rates. The secondary nurse triage process should identify the few at-risk patients that exist in the low-acuity calls. PMID- 26758530 TI - Localized crystallization in shear bands of a metallic glass. AB - Stress-induced viscous flow is the characteristic of atomic movements during plastic deformation of metallic glasses in the absence of substantial temperature increase, which suggests that stress state plays an important role in mechanically induced crystallization in a metallic glass. However, it is poorly understood. Here, we report on the stress-induced localized crystallization in individual shear bands of Zr60Al15Ni25 metallic glass subjected to cold rolling. We find that crystallization in individual shear bands preferentially occurs in the regions neighboring the amorphous matrix, where the materials are subjected to compressive stresses demonstrated by our finite element simulations. Our results provide direct evidence that the mechanically induced crystallization kinetics is closely related with the stress state. The crystallization kinetics under compressive and tensile stresses are interpreted within the frameworks of potential energy landscape and classical nucleation theory, which reduces the role of stress state in mechanically induced crystallization in a metallic glass. PMID- 26758531 TI - Are elderly patients' opinions sought before admission to an intensive care unit? Results of the ICE-CUB study. AB - BACKGROUND: demand for intensive care of the very elderly is growing, but few studies report inclusion of their opinions in the admission decision-making process. Whether or not to refer a very elderly patient to intensive care unit is a difficult decision that should take into account individual wishes, out of respect for the patient's decision-making autonomy. METHODS: in 15 emergency departments, patients over 80 years old who had a potential indication for admission to intensive care, and that were capable of expressing their opinion were included. Frequency of opinions sought before referral decision and individual and organisational factors associated were recorded and analysed. RESULTS: a total of 2,115 patients were included. Only 270 (12.7%) of them were asked for their opinion, and there were marked variations between study centres (minimum: 1.1% and maximum: 53.6%). A history of dementia reduced the probability of a patient being asked for his or her opinion (OR 0.47, 95% CI: 0.25-0.83). Patients' opinion was most often sought when their functional autonomy was conserved (OR 2.10, 95% CI: 1.39-3.21) and when a relative had been questioned (OR 5.46, 95% CI: 3.8-7.88). Older attending physicians were less likely to ask for the patient's opinion (older physician versus younger physician, OR 0.48, 95% CI: 0.35-0.66). CONCLUSIONS: elderly patients are therefore rarely asked for their opinion prior to intensive care admission. Our results indicate that respect of the decision-making autonomy of elderly subjects in the admission process to an intensive care unit should be reinforced. PMID- 26758532 TI - Effect of discontinuation of antihypertensive medication on orthostatic hypotension in older persons with mild cognitive impairment: the DANTE Study Leiden. AB - BACKGROUND: the relationship between antihypertensive medication and orthostatic hypotension in older persons remains ambiguous, due to conflicting observational evidence and lack of data of clinical trials. OBJECTIVE: to assess the effect of discontinuation of antihypertensive medication on orthostatic hypotension in older persons with mild cognitive impairment. METHODS: a total of 162 participants with orthostatic hypotension were selected from the Discontinuation of Antihypertensive Treatment in Elderly people (DANTE) Study. This randomised clinical trial included community-dwelling participants aged >=75 years, with mild cognitive impairment, using antihypertensive medication and without serious cardiovascular disease. Participants were randomised to discontinuation or continuation of antihypertensive treatment (ratio 1:1). Orthostatic hypotension was defined as a drop of at least 20 mmHg in systolic blood pressure and/or 10 mmHg in diastolic blood pressure on standing from a seated position. Outcome was the absence of orthostatic hypotension at 4-month follow-up. Relative risks (RR) were calculated by intention-to-treat and per-protocol analyses. RESULTS: at follow-up, according to intention-to-treat analyses, of the 86 persons assigned to discontinuation of antihypertensive medication, 43 (50%) were free from orthostatic hypotension, compared with 29 (38%) of the 76 persons assigned to continuation of medication [RR 1.31 (95% confidence interval (CI) 0.92-1.87); P = 0.13]. Per-protocol analysis showed that recovery from orthostatic hypotension was significantly higher in persons who completely discontinued all antihypertensive medication (61%) compared with the continuation group (38%) [RR 1.60 (95% CI 1.10-2.31); P = 0.01]. CONCLUSION: in older persons with mild cognitive impairment and orthostatic hypotension receiving antihypertensive medication, discontinuation of antihypertensive medication may increase the probability of recovery from orthostatic hypotension. PMID- 26758533 TI - Anticancer Potential and Molecular Targets of Pristimerin: A Mini- Review. AB - Pristimerin, a natural triterpenoid isolated form Celastrus and Maytenus spp, has been shown to possess a variety of biological and pharmacological effects. Recently, pristimerin has attracted more attention, especially for its potential anticancer activities. The anticancer activities of pristimerin have been illustrated in various cancer cell lines and animal models. It has been found to inhibit in vitro and in vivo proliferation, survival, angiogenesis and metastasis of tumor cells. These activities have been attributed to its modulation of various molecular targets such as cyclins, apoptosis- related proteins, proteasome activity, reactive oxygen species, as well as NF-kB, AKT/mTOR and MAPK/ERK pathways. This mini-review discussed the cellular impact and animal studies of pristimerin treatment, with more attention on the various molecular targets of pristimerin. PMID- 26758534 TI - RBM15 Functions in Blood Diseases. AB - RBM15, an RNA-binding protein, plays important roles in the growth and apoptosis of cells, especially blood cells through regulating multiple signal pathways such as Notch and Wnt. An increasing body of evidence has suggested that RBM15 may play a key function on the development of various blood diseases, such as acute/chronic myeloid leukemia and kaposi's sarcoma. In this review, we will focus on the progress of the association between RBM15 and its related blood diseases. PMID- 26758535 TI - Iris autofluorescence in Fuchs' heterochromic uveitis. AB - AIMS: To explore the characteristic autofluorescence patterns of iris depigmentation in eyes diagnosed with Fuchs' heterochromic uveitis (FHU). METHODS: Near-infrared autofluorescence images and colour images of iris were taken in 21 eyes of 21 patients with FHU, 30 eyes of 15 normal subjects, 30 eyes of 15 normal age-related iris atrophy and 33 eyes of 20 patients with uveitis other than FHU. The confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph 2, HRA2) was used for melanin-related autofluorescence imaging. The indocyanine green angiography mode of HRA2 was applied for near-infrared laser imaging, and the wavelength of the excitation laser was 795 nm. Iris colour images were also taken with the slit lamp. RESULTS: In normal iris, moderately intense autofluorescence was noted for the pigment ruff at the pupillary border, the crests in the pupillary zone and the collarette; and there was mild autofluorescence in the ciliary zone. In eyes with age-related iris atrophy and uveitis, much less autofluorescence was seen than the healthy normal irides. In eyes with FHU, there was moderate but discontinuous autofluorescence in the pigment ruff, a petaloid pattern of autofluorescence in the pupillary zone, moderate autofluorescence in the collarette and reticular pattern of autofluorescence in the ciliary zone. CONCLUSIONS: Characteristic autofluorescence patterns appeared in eyes diagnosed with FHU. Near-infrared autofluorescence is a promising objective technique to document the iris changes in FHU. PMID- 26758537 TI - Medial transposition of split lateral rectus augmented with fixation sutures in cases of complete third nerve palsy. AB - Surgical management of complete third nerve paralysis is a challenge. While several techniques have been described over the years, they result in less than satisfactory outcomes with residual deviations in primary gaze or postoperative drifts. One of the described techniques for management of oculomotor palsy has been medial transposition of the lateral rectus muscle which provides a good surgical alternative but often can result in undercorrection. We describe a modification of the existing technique of medial transposition of the split lateral rectus by force augmentation through the use of equatorial fixation sutures resulting in an improved outcome in primary gaze alignment. The modified technique involves splitting of the lateral rectus into two halves followed by transposing the superior half from below the superior oblique and superior rectus and inferior half from below the inferior oblique and inferior rectus to attach them at the superior and inferior edge of the medial rectus insertion, respectively. This is followed by placing non-absorbable sutures to fix each split belly of the transposed muscles to the sclera at the equator adjacent to the medial rectus such that the split muscles lie nearly parallel to the medial rectus till the equator before reflecting away. These sutures augment the force of the transposed muscles by redirecting the force vectors in the direction of action of the medial rectus. Satisfactory postoperative primary gaze alignment was achieved in three cases of complete third nerve paralysis. PMID- 26758536 TI - The SPARCS: a novel assessment of contrast sensitivity and its reliability in patients with corrected refractive error. AB - PURPOSE: To explore the reliability of the Spaeth/Richman Contrast Sensitivity (SPARCS) test and to assess the contrast sensitivity (CS) distribution among subjects with various refractive errors. METHODS: Cross-sectional study. Ninety three individuals (182 eyes) with varying amounts of refractive error were included in this study and divided into six groups according to their spherical equivalent. CS was evaluated using Pelli-Robson (PR) and SPARCS assessments. Each eye was tested twice with both measurements. Outcomes included the correlations of PR and SPARCS scores, the test-retest agreement of the two measurements and the limits of agreement between tests of CS measurements. The distribution of CS among the six groups was compared. RESULTS: Pearson correlation analysis showed statistically significant correlations between SPARCS and PR scores (p<0.001). Reliability analysis showed that SPARCS had better test-retest agreement than PR, with SPARCS exhibiting a higher intraclass coefficient (ICC=0.635). Bland-Altman plots showed that the mean difference of measurements was close to 0 for both CS measurements. Among the six refractive groups, there were no significant differences in CS scores with either measurement. CONCLUSIONS: SPARCS appears to be a reliable assessment for CS. The difference in CS among myopes, emmetropes and hyperopes wearing their habitual correction was statistically insignificant in this study. CLINICAL TRIAL NUMBER: NCT01300949, post results. PMID- 26758538 TI - Monitoring iCCM: a feasibility study of the indicator guide for monitoring and evaluating integrated community case management. AB - Most countries in sub-Saharan Africa have now adopted integrated community case management (iCCM) of common childhood illnesses as a strategy to improve child health. In March 2014, the iCCM Task Force published an Indicator Guide for Monitoring and Evaluating iCCM: a 'menu' of recommended indicators with globally agreed definitions and methodology, to guide countries in developing robust iCCM monitoring systems. The Indicator Guide was conceived as an evolving document that would incorporate collective experience and learning as iCCM programmes themselves evolve. This article presents findings from two studies that examined the feasibility of collecting the Indicator Guide's 18 routine monitoring indicators with the iCCM monitoring systems that countries currently have in place. We reviewed iCCM monitoring tools, protocols and reports from a purposive sample of 10 countries in sub-Saharan Africa. We developed a scorecard system to assess which of the Indicator Guide's 18 routine monitoring indicators could be calculated with the given monitoring tools, and at which level of the health system the relevant information would be available. We found that the data needed to calculate many of the Indicator Guide's routine monitoring indicators are already being collected through existing monitoring systems, although much of these data are only available at health facility level and not aggregated to district or national levels. Our results highlight challenge of using supervision checklists as a data source, and the need for countries to maintain accurate deployment data for CHWs and CHW supervisors. We suggest that some of the recommended indicators need revising. Routine monitoring will be more feasible, effective and efficient if iCCM programmes focus on a smaller set of high-value indicators that are easy to measure, reliably interpreted and useful both for global and national stakeholders and for frontline health workers themselves. PMID- 26758539 TI - The emergence of the vertical birth in Ecuador: an analysis of agenda setting and policy windows for intercultural health. AB - Maternal mortality continues to claim the lives of thousands of women in Latin America despite the availability of effective treatments to avert maternal death. In the past, efforts to acknowledge cultural diversity in birth practices had not been clearly integrated into policy. However, in Otavalo (Ecuador) a local hospital pioneered the implementation of the 'Vertical Birth'-a practical manifestation of an intercultural health policy aimed at increasing indigenous women's access to maternity care. Drawing on agenda-setting theory, this qualitative research explores how the vertical birth practice made it onto the local policy agenda and the processes that allowed actors to seize a window of opportunity allowing the vertical birth practice to emerge. Our results show that the processes that brought about the vertical birth practice took place over a prolonged period of time and resulted from the interplay between various factors. Firstly, a maternal health policy community involving indigenous actors played a key role in identifying maternal mortality as a policy problem, defining its causes and framing it as an indigenous rights issue. Secondly, previous initiatives to address maternal mortality provided a wealth of experience that gave these actors the knowledge and experience to formulate a feasible policy solution and consolidate support from powerful actors. Thirdly, the election of a new government that had incorporated the demands of the indigenous movement opened up a window of opportunity to push intercultural health policies such as the vertical birth. We conclude that the socioeconomic and political changes at both national and local level allowed the meaningful participation of indigenous actors that made a critical contribution to the emergence of the vertical birth practice. These findings can help us advance our knowledge of strategies to set the agenda for intercultural maternal health policy and inform future policy in similar settings. Our results also show that Kingdon's model was useful in explaining how the VB practice emerged but also that it needs modifications when applied to low and middle income countries. PMID- 26758540 TI - Investigating the remuneration of health workers in the DR Congo: implications for the health workforce and the health system in a fragile setting. AB - The financial remuneration of health workers (HWs) is a key concern to address human resources for health challenges. In low-income settings, the exploration of the sources of income available to HWs, their determinants and the livelihoods strategies that those remunerations entail are essential to gain a better understanding of the motivation of the workers and the effects on their performance and on service provision. This is even more relevant in a setting such as the DR Congo, characterized by the inability of the state to provide public services via a well-supported and financed public workforce. Based on a quantitative survey of 1771 HWs in four provinces of the DR Congo, this article looks at the level and the relative importance of each revenue. It finds that Congolese HWs earn their living from a variety of sources and enact different strategies for their financial survival. The main income is represented by the share of user fees for those employed in facilities, and per diems and top-ups from external agencies for those in Health Zone Management Teams (in both cases, with the exception of doctors), while governmental allowances are less relevant. The determinants at individual and facility level of the total income are also modelled, revealing that the distribution of most revenues systematically favours those working in already favourable conditions (urban facilities, administrative positions and positions of authority within facilities). This may impact negatively on the motivation and performance of HWs and on their distribution patters. Finally, our analysis highlights that, as health financing and health workforce reforms modify the livelihood opportunities of HWs, their design and implementation go beyond technical aspects and are unavoidably political. A better consideration of these issues is necessary to propose contextually grounded and politically savvy approaches to reform in the DR Congo. PMID- 26758541 TI - Will sacubitril-valsartan diminish the clinical utility of B-type natriuretic peptide testing in acute cardiac care? AB - Since the approval of sacubitril-valsartan for the treatment of chronic heart failure with reduced ejection fraction, a commonly raised suspicion is that a wider clinical use of this new drug may diminish the clinical utility of B-type natriuretic peptide testing as sacubitril may interfere with B-type natriuretic peptide clearance. In this education paper we critically assess this hypothesis based on the pathophysiology of the natriuretic peptide system and the limited published data on the effects of neprilysin inhibition on natriuretic peptide plasma concentrations in humans. As the main clinical application of B-type natriuretic peptide testing in acute cardiac care is and will be the rapid rule out of suspected acute heart failure there is no significant impairment to be expected for B-type natriuretic peptide testing in the acute setting. However, monitoring of chronic heart failure patients on sacubitril-valsartan treatment with B-type natriuretic peptide testing may be impaired. In contrast to N terminal-proBNP, the current concept that the lower the B-type natriuretic peptide result in chronic heart failure patients, the better the prognosis during treatment monitoring, may no longer be true. PMID- 26758542 TI - Impact of residual platelet reactivity on reperfusion in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - AIM: Whether high platelet reactivity (HPR) immediately after diagnostic angiography is associated with worse coronary reperfusion prior to and after primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) is unknown. This study aimed to assess the impact of P2Y12-mediated HPR on angiographic outcomes in patients with STEMI undergoing PPCI. METHODS: STEMI patients undergoing PPCI and pretreated with a P2Y12 receptor antagonist underwent platelet function testing with the VerifyNowTM assay at the time of angiography. Light transmission aggregometry (LTA) was performed in a subgroup. HPR was defined according to expert consensus definitions. Pre-PCI coronary patency, thrombotic burden and indices of impaired post-PCI reperfusion were compared between HPR and non-HPR patients. RESULTS: Among 164 patients, the prevalence of VerifyNowTM-derived HPR was 71.3% at a median (interquartile range (IQR)) of 55 (40-75) minutes after a P2Y12 inhibitor loading dose. Compared with non-HPR patients, those with HPR had significantly lower rates of pre-PCI Thrombolysis in Myocardial Infarction (TIMI) flow grades 2 or 3 (51.1% vs. 32.5%, p = 0.04), higher rates of thrombus score (TS) grade 3/4 (29.8% vs. 52.1%, p = 0.015) and 4 (14.9% vs. 32.5%, p = 0.037) and lower median (IQR) corrected TIMI frame count (cTFC; 23.2 (15.8-32.5) vs. 26.0 (21.0-35.0), p = 0.02), respectively. These findings were consistent using LTA-based data. HPR and TS grade 4 were predictors of higher cTFC. CONCLUSIONS: In patients with STEMI undergoing PPCI pretreated with P2Y12 receptor inhibitors, pre-PPCI HPR was found to be associated with lower pre-PCI coronary patency, higher thrombotic burden and a worse index of post-PCI coronary reperfusion. PMID- 26758543 TI - Editor's Choice-Medically managed patients with non-ST-elevation acute myocardial infarction have heterogeneous outcomes, based on performance of angiography and extent of coronary artery disease. AB - BACKGROUND: Medically managed individuals represent a high-risk group among patients with non-ST-elevation acute myocardial infarction (NSTE-AMI). We hypothesized that prognosis in this group is heterogeneous, depending on whether medical management was decided with or without coronary angiography (CAG). METHODS: Using data from the French Registry of Acute ST-Elevation or Non-ST Elevation Myocardial Infarction (FAST-MI), we analysed data from 798 patients with NSTE-AMI who were medically managed (i.e. without revascularization during the index hospitalization). Patients were categorized according to the performance of CAG and, if performed, to the extent of coronary artery disease (CAD). RESULTS: There were marked differences in baseline demographics, according to whether CAG was performed and to the extent of CAD. While the overall mortality rate at five years was high (56.2%), it differed greatly between groups, with patients who did not undergo CAG having a higher mortality rate (77.4%) than patients who underwent CAG (36.7%, p<0.001), and a higher mortality rate even than patients with multivessel CAD (54.2%, p<0.001). By multivariable analysis, non-performance of CAG was an independent predictor of all-cause mortality among medically managed NSTE-AMI patients (adjusted hazard ratios (95% confidence intervals) 3.19 (1.79-5.67) at 30 days, 2.28 (1.60-3.26) at one year, and 1.63 (1.28-2.07) at five years; all p<0.001). CONCLUSION: Medically managed patients with NSTE-AMI are a heterogeneous group in terms of baseline characteristics and outcomes. The highest risk patients are those who do not undergo CAG. Non-performance of CAG is a strong predictor of death. (FAST-MI, NCT00673036). PMID- 26758545 TI - In need of good neighbours: transcription factors require local DNA hypomethylation for target binding. PMID- 26758548 TI - A T-type method for characterization of the thermoelectric performance of an individual free-standing single crystal Bi2S3 nanowire. AB - A comprehensive method to evaluate the thermoelectric performance of one dimensional nanostructures, called the T-type method, has been first developed. The thermoelectric properties, including the Seebeck coefficient, thermal conductivity and electrical conductivity, of an individual free-standing single crystal Bi2S3 nanowire have been first characterized by applying the T-type method. The determined figure of merit is far less than the reported values of nanostructured bulk Bi2S3 samples, and the mechanism is that the Seebeck coefficient is nearly zero in the temperature range of 300-420 K and changes its sign at 320 K. PMID- 26758547 TI - Performing selections under dynamic conditions for synthetic biology applications. AB - As the design of synthetic circuits and metabolic networks becomes more complex it is often difficult to know a priori which parameters and design choices will result in a desired phenotype. To counter this, rational design can be complemented by library-based approaches where diversity is introduced and then coupled with screening or selection methods. Here, we used a model of competitive growth to show that selection can rapidly identify library variants with near optimal phenotypes. Many synthetic biology applications require phenotypes that balance multiple objectives, such as responding to more than one chemical signal. In addition, desired traits may be time-dependent, for example changing with the growth phase. By applying dynamic inputs to the selection, we show that it is possible to select for traits that satisfy multiple goals. Furthermore, we demonstrate that the underlying diversity in a library is heavily influenced by the initial circuit design. Overall, our findings argue that rational synthetic circuit design, coupled with diversity generation and dynamic selection are powerful tools for many synthetic biology applications. PMID- 26758546 TI - Microtubule-binding protein doublecortin-like kinase 1 (DCLK1) guides kinesin-3 mediated cargo transport to dendrites. AB - In neurons, the polarized distribution of vesicles and other cellular materials is established through molecular motors that steer selective transport between axons and dendrites. It is currently unclear whether interactions between kinesin motors and microtubule-binding proteins can steer polarized transport. By screening all 45 kinesin family members, we systematically addressed which kinesin motors can translocate cargo in living cells and drive polarized transport in hippocampal neurons. While the majority of kinesin motors transport cargo selectively into axons, we identified five members of the kinesin-3 (KIF1) and kinesin-4 (KIF21) subfamily that can also target dendrites. We found that microtubule-binding protein doublecortin-like kinase 1 (DCLK1) labels a subset of dendritic microtubules and is required for KIF1-dependent dense-core vesicles (DCVs) trafficking into dendrites and dendrite development. Our study demonstrates that microtubule-binding proteins can provide local signals for specific kinesin motors to drive polarized cargo transport. PMID- 26758550 TI - Activity of the CD40 antagonistic antibody lucatumumab - insights from CLL-niche mimicking xenografts and fludarabine combinations. PMID- 26758549 TI - Enhanced electronic properties in mesoporous TiO2 via lithium doping for high efficiency perovskite solar cells. AB - Perovskite solar cells are one of the most promising photovoltaic technologies with their extraordinary progress in efficiency and the simple processes required to produce them. However, the frequent presence of a pronounced hysteresis in the current voltage characteristic of these devices arises concerns on the intrinsic stability of organo-metal halides, challenging the reliability of technology itself. Here, we show that n-doping of mesoporous TiO2 is accomplished by facile post treatment of the films with lithium salts. We demonstrate that the Li-doped TiO2 electrodes exhibit superior electronic properties, by reducing electronic trap states enabling faster electron transport. Perovskite solar cells prepared using the Li-doped films as scaffold to host the CH3NH3PbI3 light harvester produce substantially higher performances compared with undoped electrodes, improving the power conversion efficiency from 17 to over 19% with negligible hysteretic behaviour (lower than 0.3%). PMID- 26758552 TI - InGaN/Dilute-As GaNAs Interface Quantum Well for Red Emitters. AB - The design of InGaN/dilute-As GaNAs interface quantum well (QW) leads to significant redshift in the transition wavelength with improvement in electron hole wave function overlap and spontaneous emission rate as compared to that of the conventional In0.2Ga0.8N QW. By using self-consistent six-band k.p band formalism, the nitride active region consisting of 30 A In0.2Ga0.8N and 10 A GaN0.95As0.05 interface QW leads to 623.52 nm emission wavelength in the red spectral regime. The utilization of 30 A In0.2Ga0.8N/10 A GaN0.95As0.05 interface QW also leads to 8.5 times enhancement of spontaneous emission rate attributed by the improvement in electron-hole wavefunction overlap, as compared to that of conventional 30 A In0.35Ga0.65N QW for red spectral regime. In addition, the transition wavelength of the interface QW is relatively unaffected by the thickness of the dilute-As GaNAs interface layer (beyond 10 A). The analysis indicates the potential of using interface QW concept in nitride-based light emitting diodes for long wavelength emission. PMID- 26758551 TI - Association between serum levels of high sensitive C-reactive protein and inflammation activity in chronic gastritis patients. AB - BACKGROUND: Gastritis is an important premalignant lesion and recent studies suggested a production of inflammatory cytokine-like C-reactive protein during gastritis. This study aimed to determine any relationship between high sensitive C-reactive protein (hs-CRP) and inflammation activity among patients with gastritis. METHODS: Demographic and clinical variables of participants were collected by a validated questionnaire. Using histology of the gastric mucosa, Helicobacter pylori status was investigated and serum concentrations of hs-CRP were measured among dyspeptic patients. Correlation between hs-CRP serum levels and inflammation activities was evaluated by logistic regression analysis. The relation between active inflammation and other variables was evaluated by logic link function model. RESULTS: Totally 239 patients (56.6% female) were analysed. The prevalence of mild, moderate and severe inflammation activities was 66.5%, 23.8% and 9.6% respectively. Mean +/- SD of hs-CRP among men and women were 2.85 +/- 2.84 mg/dl and 2.80 +/- 4.80 mg/dl (p = 0.047) respectively. Mean +/- SD of hs-CRP among patients with H. pylori infection, gland atrophy, metaplasia and dysplasia were 2.83 +/- 3.80 mg/dl, 3.52 +/- 5.1 mg/dl, 2.22 +/- 2.3 mg/dl and 5.3 +/- 5.04 mg/dl respectively. Relationship between hs-CRP and inflammation activities (p < 0.01) was significant. A significant relationship between dysplasia and hs-CRP (p < 0.04) was revealed. A significant relationship between age and hs-CRP was detected (p < 0.05). CONCLUSION: Although serum hs-CRP is not a specific biomarker for gastritis, elevated hs-CRP levels may be considered as a predictive marker of changes in gastric mucosa and a promising therapeutic target for patients with gastritis. PMID- 26758553 TI - Kinetically controlled synthesis of Au102(SPh)44 nanoclusters and catalytic application. AB - We here explore a kinetically controlled synthetic protocol for preparing solvent solvable Au102(SPh)44 nanoclusters which are isolated from polydispersed gold nanoclusters by solvent extraction and size exclusion chromatography (SEC). The as-obtained Au102(SPh)44 nanoclusters are determined by matrix-assisted laser desorption ionization (MALDI) and electrospray ionization (ESI) mass spectrometry, in conjunction with UV-vis spectroscopy and thermogravimetric analysis (TGA). However, Au99(SPh)42, instead of Au102(SPh)44, is yielded when the polydispersed gold nanoclusters are etched in the presence of excess thiophenol under thermal conditions (e.g., 80 degrees C). Interestingly, the Au102(SPh)44 nanoclusters also can convert to Au99(SPh)42 with equivalent thiophenol ligands, evidenced by the analyses of UV-vis and MALDI mass spectrometry. Finally, the TiO2-supported Au102(SPh)44 nanocluster catalyst is investigated in the selective oxidation of sulfides into sulfoxides by the PhIO oxidant and gives rise to high catalytic activity (e.g., 80-99% conversion of R-S R' sulfides with 96-99% selectivity for R-S([double bond, length as m-dash]O)-R' sulfoxides). The Au102(SPh)44/TiO2 catalyst also shows excellent recyclability in the sulfoxidation process. PMID- 26758544 TI - Astrocytes as secretory cells of the central nervous system: idiosyncrasies of vesicular secretion. AB - Astrocytes are housekeepers of the central nervous system (CNS) and are important for CNS development, homeostasis and defence. They communicate with neurones and other glial cells through the release of signalling molecules. Astrocytes secrete a wide array of classic neurotransmitters, neuromodulators and hormones, as well as metabolic, trophic and plastic factors, all of which contribute to the gliocrine system. The release of neuroactive substances from astrocytes occurs through several distinct pathways that include diffusion through plasmalemmal channels, translocation by multiple transporters and regulated exocytosis. As in other eukaryotic cells, exocytotic secretion from astrocytes involves divergent secretory organelles (synaptic-like microvesicles, dense-core vesicles, lysosomes, exosomes and ectosomes), which differ in size, origin, cargo, membrane composition, dynamics and functions. In this review, we summarize the features and functions of secretory organelles in astrocytes. We focus on the biogenesis and trafficking of secretory organelles and on the regulation of the exocytotic secretory system in the context of healthy and diseased astrocytes. PMID- 26758555 TI - Cyclometalated titanium and zirconium complexes stabilised by a new silylmethylene-linked tetradentate triamidophosphine. AB - The silylmethylene-linked triamidophosphine P(CH2SiMe2NHPh)3 was isolated in form of its tri-lithium salt Li3[P(CH2SiMe2NPh)3].2.5Et2O (1.2.5Et2O) and employed for the synthesis of titanium and zirconium complexes. Starting from 1.2.5Et2O, the chlorido complexes [kappa(4)-N,N,N,P-PN3]MCl (4-M, M = Ti, Zr) were prepared and examined with respect to alkylation. Upon reaction of 4-Ti with (trimethylsilyl)methyl lithium, intra-ligand cyclometalation at one of the ortho N-phenyl positions was observed and the resulting thermally stable titanazetidine [kappa(5)-N,N,N,P,C-N2P(NC)]Ti (5-Ti) isolated. Similarly, the related zirconazetidine [kappa(5)-N,N,N,P,C-N2P(NC)]Zr(THF) (5-Zr) was isolated upon reaction of 4-Zr with Bn2Mg(THF)2. Using LiCH2PMe2 as alkyl transfer reagent, both complexes 4-M were converted to the corresponding phosphametallacyclopropanes [kappa(4)-N,N,N,P-PN3]M(kappa(2)-C,P-CH2PMe2) (7-M, M = Ti, Zr). Upon gentle heating, complexes 7-M were cleanly converted to the cyclometalated species 5-M and trimethylphosphine. These results are discussed in the context of related amidophosphine and triamidoamine complexes. PMID- 26758554 TI - Joint Effects of Intraocular Pressure and Myopia on Risk of Primary Open-Angle Glaucoma: The Singapore Epidemiology of Eye Diseases Study. AB - We examined the joint effects of intraocular pressure (IOP) and myopia on the risk of primary open angle glaucoma (POAG) in a multi-ethnic Asian population. A total of 9,422 participants (18,469 eyes) in the Singapore Epidemiology of Eye Diseases Study were included. Of them, 213 subjects (273 eyes) had POAG. All participants underwent standardised examinations. The independent and joint effects of IOP and myopia on POAG were examined using logistic regression models. Generalised estimating equation models were used to account for correlation between eyes. Higher IOP, longer axial length, and more negative spherical equivalent were independently associated with POAG, after adjusting for relevant covariates (all P <= 0.005). Significant interaction between IOP and myopia on POAG was observed (P interaction = 0.025). Eyes with moderate-to-high myopia (< 3.0 dioptres) with high IOP (>=20 mmHg) were 4.27 times (95% CI, 2.10-8.69) likely to have POAG, compared to eyes without myopia (>-0.5 dioptres) and with IOP <20 mmHg. Eyes with AL of >=25.5 mm and high IOP (>=20 mmHg) were 16.22 times (95% CI, 7.73 to 34.03) likely to have POAG, compared to eyes with shorter AL (<23.5 mm) and lower IOP (<20 mmHg). These findings may provide additional insights into the pathophysiology of POAG and are particularly relevant for Asian populations. PMID- 26758556 TI - In vivo and in vitro taste masking of ofloxacin and sustained release by forming interpenetrating polymer network beads. AB - Drug-resin complexes (DRCs) of ofloxacin and ion-exchange resins (IERs) were prepared in different ratios of drug/IERs, that is, 1:1, 1:2 and 1:4 (w/w) and investigated for taste masking by in vivo and in vitro release studies. Human volunteers graded AD1:4 (DRC) as tasteless with an average value of 0.3 +/- 0.03 and in vitro study showed that AD 1:4 released only 1.70 +/- 0.86% of drug at salivary pH within 30s. Fourier transform infrared spectroscopy (FTIR), powder X ray diffraction (P-XRD) and differential scanning calorimetry (DSC) studies of AD 1:4 showed the change in the morphology of the drug, that is, from crystalline phase to amorphous phase during complex formation. The release of drug from AD 1:4 was completed within 30 min at gastric pH 1.2 and to extend the release time of drug at gastric pH, it was entrapped with different biopolymers, such as sodium alginate (SA) and sodium carboxymethyl cellulose (SCMC), in the presence of ferric chloride and glutaraldehyde (GA) to form interpenetrating polymer network (IPN) beads. FTIR studies revealed that IPN beads were crosslinked with Fe3+ and GA. The release of drug at gastric and intestinal pH was 14.53 +/- 1.52% and 65.86 +/- 1.29%, respectively, for a contact time of 10 h. The kinetics release study shows fickian diffusion for ionically crosslinked beads and zero order release for GA crosslinking beads. PMID- 26758557 TI - MACC1 Induces Tumor Progression in Transgenic Mice and Colorectal Cancer Patients via Increased Pluripotency Markers Nanog and Oct4. AB - PURPOSE: We have previously identified the gene MACC1 as a strong prognostic biomarker for colorectal cancer metastasis and patient survival. Here, we report for the first time the generation of transgenic mouse models for MACC1. EXPERIMENTAL DESIGN: We generated mice with transgenic overexpression of MACC1 in the intestine driven by the villin promoter (vil-MACC1) and crossed them with Apc(Min) mice (vil-MACC1/Apc(Min)). RESULTS: vil-MACC1/Apc(Min) mice significantly increased the total number of tumors (P = 0.0056). This was particularly apparent in large tumors (>=3-mm diameter; P = 0.0024). A detailed histopathologic analysis of these lesions demonstrated that the tumors from the vil-MACC1/Apc(Min) mice had a more invasive phenotype and, consequently, showed a significantly reduced survival time than Apc(Min) mice (P = 0.03). Molecular analysis revealed an increased Wnt and pluripotency signaling in the tumors of vil-MACC1/Apc(Min) mice. Specifically, we observed a prominent upregulation of the pluripotency markers Oct4 and Nanog in these tumors compared with Apc(Min) controls. Finally, we could also validate that Oct4 and Nanog are regulated by MACC1 in vitro and strongly correlate with MACC1 levels in a cohort of 60 tumors of colorectal cancer patients (r = 0.7005 and r = 0.6808, respectively; P > 0.0001 and P > 0.0002, respectively). CONCLUSIONS: We provide proof of principle that MACC1-induced tumor progression in colorectal cancer acts, at least in part, via the newly discovered MACC1/Nanog/Oct4 axis. These findings might have important implications for the design of novel therapeutic intervention strategies to restrict tumor progression. Clin Cancer Res; 22(11); 2812-24. (c)2016 AACR. PMID- 26758558 TI - Integrated Analysis of PTEN and p4EBP1 Protein Expression as Predictors for pCR in HER2-Positive Breast Cancer. AB - BACKGROUND: The PI3K/AKT pathway and phosphatase and tensin homolog (PTEN) aberrations are common in breast cancer. We investigated the correlation between phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), PTEN, p4EBP1 (phosphorylated E4 binding protein 1), and pathologic complete response (pCR) in patients receiving neoadjuvant therapy. EXPERIMENTAL DESIGN: We retrospectively evaluated PIK3CA, PTEN, and p4EBP1 protein expression in centrally HER2-positive patients (n = 181) who received epirubicin cyclophosphamide/trastuzumab followed by docetaxel/trastuzumab alone or concomitant/followed by capecitabine within the GeparQuattro study. PTEN was assessed using the automated quantitative immunofluorescence analysis and was analyzed as a dichotomic variable. p4EBP1 was assessed by immunohistochemistry and used as a continuous and dichotomic variable. RESULTS: p4EBP1 was available from 137, PTEN from 108, and PIK3CA genotype from 83 patients. Overall, the pCR rate in PTEN-low tumors was 27.6%, and in PTEN-high tumors, it was 57.1% (P = 0.010). pCR rates were not statistically different between PIK3CA wild-type and mutant (35% vs. 22%) or p4EBP1 IRS <= 4 and IRS > 4 (39% vs. 33%). pCR rate was 57.1% (8/14) in PTEN-high/PIK3CA wild-type and decreased to 15.4% in PTEN low/PIK3CA-mutant tumors (P = 0.023). In multivariable analysis adjusted for baseline parameters, PTEN independently predicted pCR in the following cohorts: overall [OR, 7.54; 95% confidence interval (CI), 2.03-28.06; P = 0.003], PIK3CA wild-type (OR, 23.81; 95% CI, 1.75-324.05; P = 0.017), p4EBP1 IRS > 4 (OR, 11.53; 95% CI, 1.84-72.24; P = 0.009), and hormone receptor-positive (OR, 40.91; 95% CI, 2.93-570.44; P = 0.006). p4EBP1 was independently predictive for pCR in PIK3CA wild-type tumors (OR, 0.14; 95% CI, 0.03-0.78; P = 0.025). CONCLUSIONS: The study showed the potential role of PIK3CA genotype, PTEN, and p4EBP in predicting pCR after anthracycline-taxane-based chemotherapy and anti-HER2 treatment. Clin Cancer Res; 22(11); 2675-83. (c)2016 AACR. PMID- 26758559 TI - Focusing on Core Patient-Reported Outcomes in Cancer Clinical Trials: Symptomatic Adverse Events, Physical Function, and Disease-Related Symptoms. AB - Cancer clinical trials have relied on overall survival and measures of tumor growth or reduction to assess the efficacy of a drug. However, benefits are often accompanied by significant symptomatic toxicities. The degree to which a therapy improves disease symptoms and introduces symptomatic toxicity affects how patients function in their daily lives. These concepts are important contributors to health-related quality of life (HRQOL). In this article, we discuss patient reported outcome (PRO) assessment in cancer trials and challenges relying solely on static multi-item HRQOL instruments. We propose focusing on three separate measures of well-defined concepts: symptomatic adverse events, physical function, and disease-related symptoms, which are key contributors to the effect of a therapy on HRQOL. Separate measures of these three concepts may facilitate the incorporation of emerging contemporary instruments that can tailor the PRO assessment strategy to different trial contexts. Irrespective of the PRO measures used, continued improvement in trial design and conduct is crucial to decrease missing data and optimize the quality of PRO information. International stakeholder collaboration and continued research into optimal practices for PRO and other clinical outcome assessments are necessary to advance a common framework for generating and reporting rigorous patient-centered data from cancer clinical trials. PMID- 26758561 TI - Diversity and evolution of avian influenza viruses in live poultry markets, free range poultry and wild wetland birds in China. AB - The wide circulation of novel avian influenza viruses (AIVs) highlights the risk of pandemic influenza emergence in China. To investigate the prevalence and genetic diversity of AIVs in different ecological contexts, we surveyed AIVs in live poultry markets (LPMs), free-range poultry and the wetland habitats of wild birds in Zhejiang and Hubei provinces. Notably, LPMs contained the highest frequency of AIV infection, and the greatest number of subtypes (n = 9) and subtype co-infections (n = 14), as well as frequent reassortment, suggesting that they play an active role in fuelling AIV transmission. AIV-positive samples were also identified in wild birds in both provinces and free-range poultry in one sampling site close to a wetland region in Hubei. H9N2, H7N9 and H5N1 were the most commonly sampled subtypes in the LPMs from Zhejiang, whilst H5N6 and H9N2 were the dominant subtypes in the LPMs from Hubei. Phylogenetic analyses of the whole-genome sequences of 43 AIVs revealed that three reassortant H5 subtypes were circulating in LMPs in both geographical regions. Notably, the viruses sampled from the wetland regions and free-range poultry contained complex reassortants, for which the origins of some segments were unclear. Overall, our study highlights the extent of AIV genetic diversity in two highly populated parts of central and south-eastern China, particularly in LPMs, and emphasizes the need for continual surveillance. PMID- 26758560 TI - Circulating Cell-Free Tumor DNA Analysis of 50 Genes by Next-Generation Sequencing in the Prospective MOSCATO Trial. AB - PURPOSE: Liquid biopsies based on circulating cell-free DNA (cfDNA) analysis are described as surrogate samples for molecular analysis. We evaluated the concordance between tumor DNA (tDNA) and cfDNA analysis on a large cohort of patients with advanced or metastatic solid tumor, eligible for phase I trial and with good performance status, enrolled in MOSCATO 01 trial (clinical trial NCT01566019). EXPERIMENTAL DESIGN: Blood samples were collected at inclusion and cfDNA was extracted from plasma for 334 patients. Hotspot mutations were screened using next-generation sequencing for 50 cancer genes. RESULTS: Among the 283 patients with tDNA-cfDNA pairs, 121 had mutation in both, 99 in tumor only, 5 in cfDNA only, and for 58 patients no mutation was detected, leading to a 55.0% estimated sensitivity [95% confidence interval (CI), 48.4%-61.6%] at the patient level. Among the 220 patients with mutations in tDNA, the sensitivity of cfDNA analysis was significantly linked to the number of metastatic sites, albumin level, tumor type, and number of lines of treatment. A sensitivity prediction score could be derived from clinical parameters. Sensitivity is 83% in patients with a high score (>=8). In addition, we analyzed cfDNA for 51 patients without available tissue sample. Mutations were detected for 22 patients, including 19 oncogenic variants and 8 actionable mutations. CONCLUSIONS: Detection of somatic mutations in cfDNA is feasible for prescreening phase I candidates with a satisfactory specificity; overall sensitivity can be improved by a sensitivity score allowing to select patients for whom cfDNA constitutes a reliable noninvasive surrogate to screen mutations. Clin Cancer Res; 22(12); 2960-8. (c)2016 AACR. PMID- 26758562 TI - Proteus syndrome: evaluation of the immunological profile. AB - Proteus syndrome (PS) is an extremely rare and complex disease characterized by malformations and overgrowth of different tissues. Prognosis of affected patients may be complicated by premature death, mostly due to pulmonary embolism and respiratory failure. To date, immunological data in Proteus syndrome are scarse.We report on the novel immunologic findings of a 15 years old girl affected with PS. Detailed T and B cell evaluation revealed maturational alterations for both subsets and functional hyperactivation for the latter. Such findings have not been reported previously in PS and may be the spy of more complex immune abnormalities in this syndrome. PMID- 26758563 TI - Effect of the SGLT2 Inhibitor Dapagliflozin on Potassium Levels in Patients with Type 2 Diabetes Mellitus: A Pooled Analysis. AB - INTRODUCTION: Hyperkalemia risk is increased in diabetes, particularly in patients with renal impairment or those receiving angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) or potassium-sparing diuretics. Conversely, other diuretics can increase hypokalemia risk. We assessed the effects of the sodium glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on serum potassium levels in a pooled analysis of clinical trials in patients with type 2 diabetes mellitus (T2DM). METHODS: Fourteen randomized, placebo-controlled, double-blind T2DM studies were analyzed: pooled data from 13 studies of <=24 weeks' duration (dapagliflozin 10 mg, N = 2360; placebo, N = 2295); and one 52-week moderate renal impairment study in patients with baseline eGFR >=30 to <60 mL/min/1.73 m(2) (dapagliflozin 10 mg, N = 85; placebo, N = 84). Central laboratory serum potassium levels were determined at each study visit. RESULTS: No clinically relevant mean changes from baseline in serum potassium <=24 weeks were reported for dapagliflozin 10 mg [-0.05 mmol/L; 95% confidence interval (CI) -0.07, -0.03] versus placebo (-0.02 mmol/L; 95% CI -0.04, 0.00) in the pooled population or in the renal impairment study (-0.03 mmol/L; 95% CI 0.14, 0.08 vs. -0.02 mmol/L; 95% CI -0.13, 0.09, respectively). The incidence rate ratio for serum potassium >=5.5 mmol/L over 24 weeks for dapagliflozin 10 mg versus placebo was 0.90 (95% CI 0.74, 1.10) in the pooled population; with no increased risk in patients receiving ARBs/ACE inhibitors, or potassium-sparing diuretics, or in those with moderate renal impairment. Slightly more patients receiving dapagliflozin 10 mg had serum potassium <=3.5 mmol/L versus placebo (5.2% vs. 3.6%); however, no instances of serum potassium <=2.5 mmol/L were reported. CONCLUSION: Dapagliflozin is not associated with an increased risk of hyperkalemia or severe hypokalemia in patients with T2DM. FUNDING: Bristol-Myers Squibb and AstraZeneca. PMID- 26758565 TI - Clean water, sanitation and diarrhoea in Indonesia: Effects of household and community factors. AB - Diarrhoea is an important health issue in low- and middle-income countries, including Indonesia. We applied a multilevel regression analysis on the Indonesian Demographic and Health Survey to examine the effects of drinking water and sanitation facilities at the household and community level on diarrhoea prevalence among children under five (n = 33,339). The role of the circumstances was explored by studying interactions between the water and sanitation variables and other risk factors. Diarrhoea prevalence was reported by 4820 (14.4%) children, who on average were younger, poorer and were living in a poorer environment. At the household level, piped water was significantly associated with diarrhoea prevalence (OR = 0.797, 95% CI: 0.692-0.918), improved sanitation had no direct effect (OR = 0.992, 95% CI: 0.899-1.096) and water treatment was not related to diarrhoea incidence (OR = 1.106, 95% CI: 0.994-1.232). At the community level, improved water coverage had no direct effect (OR = 1.002, 95% CI: 0.950-1.057) but improved sanitation coverage was associated with lower diarrhoea prevalence (OR = 0.917, 95% CI: 0.843-0.998). Our interaction analysis showed that the protective effects of better sanitation at the community level were increased by better drinking water at the community level. This illustrates the importance of improving both drinking water and sanitation simultaneously. PMID- 26758566 TI - Erratum to: Sex and age effects on cardiovascular autonomic function in healthy adults. PMID- 26758564 TI - CD68+ cell count, early evaluation with PET and plasma TARC levels predict response in Hodgkin lymphoma. AB - Early response evaluation with [(18) F]fluordeoxyglucose (FDG) positron emission tomography after 2 cycles of chemotherapy (interim PET) has been indicated as the strongest predictor for outcome in classical Hodgkin lymphoma (HL). We studied the prognostic role of the number of tumor-infiltrating CD68+ cells and of the plasma levels of TARC (thymus and activation-regulated chemokine) in the context of interim PET in 102 patients with classical HL treated with Adriamycin, Bleomycin, Vinblastine, Dacarbazine (ABVD). After 2 ABVD cycles, interim PET according to Deauville criteria was negative (score 0-3) in 85 patients and positive (score 4-5) in 15 patients (2 patients technically not evaluable). TARC levels were elevated in 89% of patients at diagnosis, and decreased after 2 cycles in 82% of patients. Persistently elevated TARC levels in 18% of patients were significantly associated with a positive PET result (P = 0.007). Strong predictors for progression-free survival (PFS) were a negative interim PET (85% vs. 28%, P < 0.0001) and CD68+ cell counts <5% (89% vs. 67%, P = 0.006), while TARC levels at diagnosis and at interim evaluation had no prognostic role. In multivariate analysis, interim PET, CD68+ cell counts and presence of B-symptoms were independently associated with PFS. We conclude that although TARC levels are a biomarker for early response evaluation, they cannot substitute for interim PET as outcome predictor in HL. The evaluation of CD68 counts and B-symptoms at diagnosis may help to identify low-risk patients regardless positive interim PET. PMID- 26758567 TI - Cardiovascular disease risks in adult Native and Mexican Americans with a history of alcohol use disorders: association with cardiovascular autonomic control. AB - Hypertension and obesity are serious health problems that have been associated with an increased risk of cardiovascular disease (CVD). We recently showed a relationship between hypertension, obesity and cardiovagal control in a sample of Native and Mexican Americans at high risk of alcohol use disorders (AUD). While studies have shown that Native and Mexican Americans exhibit high rates of AUD, the consequences of AUD on CVD risk factors and their relationship with cardiovascular autonomic control is not well understood in these ethnic groups. This study investigated whether an association could be demonstrated between cardiovascular autonomic control and several CVD risk factors in Native and Mexican American men and women (n = 228) who are literate in English and are residing legally in San Diego County. Participants with lifetime history of AUD showed higher rates of systolic and diastolic hypertension and obesity than participants without lifetime AUD. Lifetime AUD was significantly associated with reduced HR response to deep breathing (HRDB) measure of cardiovagal control, higher current drinking quantity, and obesity. Reduced HRDB was also associated with increased systolic pre-hypertension or hypertension (pre-/hypertension) and with higher diastolic blood pressure in a linear regression model that included several diagnostic and demographic variables. HRDB and time- and frequency-domain measures of cardiovagal control were significantly reduced in participants with diastolic pre-/hypertension. These data suggest that lower cardiovagal control may play a role in the prevalence of systolic and diastolic pre-/hypertension in a community sample with a history of alcohol and substance use disorders. PMID- 26758568 TI - Microbial community profiling shows dysbiosis in the lesional skin of Vitiligo subjects. AB - Healthy human skin harbours a diverse array of microbes that comprise the skin microbiome. Commensal bacteria constitute an important component of resident microbiome and are intricately linked to skin health. Recent studies describe an association between altered skin microbial community and epidemiology of diseases, like psoriasis, atopic dermatitis etc. In this study, we compare the differences in bacterial community of lesional and non-lesional skin of vitiligo subjects. Our study reveals dysbiosis in the diversity of microbial community structure in lesional skin of vitiligo subjects. Although individual specific signature is dominant over the vitiligo-specific microbiota, a clear decrease in taxonomic richness and evenness can be noted in lesional patches. Investigation of community specific correlation networks reveals distinctive pattern of interactions between resident bacterial populations of the two sites (lesional and non-lesional). While Actinobacterial species constitute the central regulatory nodes (w.r.t. degree of interaction) in non-lesional skin, species belonging to Firmicutes dominate on lesional sites. We propose that the changes in taxonomic characteristics of vitiligo lesions, as revealed by our study, could play a crucial role in altering the maintenance and severity of disease. Future studies would elucidate mechanistic relevance of these microbial dynamics that can provide new avenues for therapeutic interventions. PMID- 26758570 TI - Minimizing the magnetic field effect in MR-linac specific QA-tests: the use of electron dense materials. AB - To address the quality assurance (QA) of a MR-linac which is an MRI combined with a linear accelerator (linac), the traditional linac QA-tests need to be redesigned, since the presence of the static magnetic field in the MR-linac alters the electron trajectory. The latter causes the asymmetry in the dose kernel which is introduced by the magnetic field and hinders accurate geometrical QA-tests for the MR-linac. We introduced the use of electron dense materials (e.g. copper) to reduce the size of the dose kernel and thereby the magnetic field effect on the dose deposition. Two examples of QA-tests are presented in which the geometrical accuracy of the MR-linac was addressed; beam profile and star-shot measurements. The introduced setup was compared with a reference setup and both were tested on a conventional and the MR-linac. The results showed that the symmetry of the recorded beam profile was restored in presence of the copper material and that the isocenter size of the MR-linac can be determined accurately with the introduced star-shot setup. The use of electron dense materials is not limited to the presented QA-tests but has a broad application for beam-specific QA-tests in presence of a magnetic field. PMID- 26758572 TI - Cascade Pd(II)-catalyzed Wacker lactonization-Heck reaction: rapid assembly of spiranoid lactones. AB - An unprecedented Pd-catalyzed cascade Wacker-Heck lactonization-cyclization sequence is reported. The process provides a facile approach to bi- and tricyclic spiranoid lactones in good yields. The reaction shows general substrate scope and a broad functional group tolerability. In addition, a rare 4-exo trig Heck-type cyclization is demonstrated. PMID- 26758571 TI - Gonadotropin-Releasing Hormone Analogue Treatment in Females with Moderately Early Puberty: No Effect on Final Height. AB - OBJECTIVE: To investigate the effects of treatment with gonadotropin-releasing hormone analog (GnRHa) on final height in girls who experienced moderately early puberty with symptoms beginning at 7-8.5 years of age. METHODS: Female cases diagnosed with moderately early puberty which had started between ages 7 to 8.5 years were included in the study. In the treatment groups, all cases with a bone age <=10.5 years constituted group 1 (n=18) and those with a bone age >10.5 years constituted group 2 (n=23). The 8 patients for which treatment approval could not be obtained constituted group 3. The 49 cases in all three groups were observed until they reached their final height. RESULTS: Target height, target height standard deviation score (SDS), final height, and final height SDS values were similar in all 3 groups. Final height showed a significant positive correlation with target height (p=0.000, r=0.54) and height at diagnosis (p=0.003, r=0.467) in all groups. Linear regression analysis revealed that a 1 cm longer height at diagnosis increased the final height 0.213 fold, and a 1 cm longer target height at diagnosis increased the final height 0.459 fold. CONCLUSION: We found that GnRHa did not make a positive contribution to final height in cases of moderately early puberty. PMID- 26758569 TI - Stochastic modeling of near-field exposure to parabens in personal care products. AB - Exposure assessment is a key step in determining risks to chemicals in consumer goods, including personal care products (PCPs). Exposure models can be used to estimate exposures to chemicals in the absence of biomonitoring data and as tools in chemical risk prioritization and screening. We apply a PCP exposure model based on the product intake fraction (PiF), which is defined as the fraction of chemical in a product that is taken in by the exposed population, to estimate chemical intake based on physicochemical properties and PCP usage characteristics. The PiF can be used to estimate route and pathway-specific exposures during both the use and disposal stages of a product. As a case study, we stochastically quantified population level exposures to parabens in PCPs, and compared estimates with biomarker values. We estimated exposure based on the usage of PCPs in the female US population, taking into account population variability, product usage characteristics, paraben occurrence in PCPs and the PiF. Intakes were converted to urine levels and compared with National Health and Nutrition Examination Survey (NHANES) biomonitoring data. Results suggest that for parabens, chemical exposure during product use is substantially larger than environmentally mediated exposure after product disposal. Modeled urine concentrations reflect well the NHANES variation of three orders of magnitude across parabens for the 50th, 75th, 90th, and 95th percentiles and were generally in good agreement with measurements, when taking uncertainty into account. This study presents an approach to estimate multi-pathway exposure to chemicals in PCPs and can be used as a tool within exposure-based screening of chemicals as well in higher tier exposure estimates. PMID- 26758573 TI - A hypothetical hierarchical mechanism of the self-assembly of the Escherichia coli RNA polymerase sigma(70) subunit. AB - Diverse morphology of aggregates of amyloidogenic proteins has been attracting much attention in the last few years, and there is still no complete understanding of the relationships between various types of aggregates. In this work, we propose the model, which universally explains the formation of morphologically different (wormlike and rodlike) aggregates on the example of a sigma(70) subunit of RNA polymerase, which has been recently shown to form amyloid fibrils. Aggregates were studied using AFM in solution and depolarized dynamic light scattering. The obtained results demonstrate comparably low Young's moduli of the wormlike structures (7.8-12.3 MPa) indicating less structured aggregation of monomeric proteins than that typical for beta-sheet formation. To shed light on the molecular interaction of the protein during the aggregation, early stages of fibrillization of the sigma(70) subunit were modeled using all atom molecular dynamics. Simulations have shown that the sigma(70) subunit is able to form quasi-symmetric extended dimers, which may further interact with each other and grow linearly. The proposed general model explains different pathways of sigma(70) subunit aggregation and may be valid for other amyloid proteins. PMID- 26758574 TI - Effect of cinnamon, cardamom, saffron and ginger consumption on blood pressure and a marker of endothelial function in patients with type 2 diabetes mellitus: A randomized controlled clinical trial. AB - Herbal medicines with high amounts of phytochemicals have been shown to have beneficial effects on blood pressure (BP), endothelial function and anthropometric measures. This study aimed to determine the effect of herbal treatment on BP, endothelial function and anthropometric measures in patients with type 2 diabetes mellitus (T2DM). This clinical trial included 204 T2DM patients randomly assigned to four intervention groups receiving 3 g cinnamon, 3 g cardamom, 1 g saffron or 3 g ginger with three glasses of black tea, and one control group consuming only three glasses of tea without any herbals, for 8 weeks. Intercellular adhesion molecule-1 (ICAM-1), systolic and diastolic BP and anthropometric measures were collected at baseline and after 8 weeks. No significant difference was found between various medicinal plants in terms of influencing BP, serum soluble (s)ICAM-1 concentrations and anthropometric measures. However, in within-group comparison saffron and ginger intakes significantly reduced sICAM-1 concentrations (340.9 +/- 14.4 vs 339.69 +/- 14.4 ng/ml, p = 0.01, and 391.78 +/- 16.0 vs 390.97 +/- 15.8 ng/ml, p = 0.009, respectively) and ginger intake affected systolic BP (143.06 +/- 0.2 vs 142.07 +/ 0.2 mmHg, p = 0.02). Although administration of these herbal medicines as supplementary remedies could affect BP and sICAM-1 concentrations, there was no significant difference between the plants in terms of influencing anthropometric measures, BP and endothelial function. PMID- 26758576 TI - Intensive versus conventional glycaemic control for treating diabetic foot ulcers. AB - BACKGROUND: The estimated likelihood of lower limb amputation is 10 to 30 times higher amongst people with diabetes compared to those without diabetes. Of all non-traumatic amputations in people with diabetes, 85% are preceded by a foot ulcer. Foot ulceration associated with diabetes (diabetic foot ulcers) is caused by the interplay of several factors, most notably diabetic peripheral neuropathy (DPN), peripheral arterial disease (PAD) and changes in foot structure. These factors have been linked to chronic hyperglycaemia (high levels of glucose in the blood) and the altered metabolic state of diabetes. Control of hyperglycaemia may be important in the healing of ulcers. OBJECTIVES: To assess the effects of intensive glycaemic control compared to conventional control on the outcome of foot ulcers in people with type 1 and type 2 diabetes. SEARCH METHODS: In December 2015 we searched: The Cochrane Wounds Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; EBSCO CINAHL; Elsevier SCOPUS; ISI Web of Knowledge Web of Science; BioMed Central and LILACS. We also searched clinical trial databases, pharmaceutical trial databases and current international and national clinical guidelines on diabetes foot management for relevant published, non-published, ongoing and terminated clinical trials. There were no restrictions based on language or date of publication or study setting. SELECTION CRITERIA: Published, unpublished and ongoing randomised controlled trials (RCTs) were considered for inclusion where they investigated the effects of intensive glycaemic control on the outcome of active foot ulcers in people with diabetes. Non randomised and quasi-randomised trials were excluded. In order to be included the trial had to have: 1) attempted to maintain or control blood glucose levels and measured changes in markers of glycaemic control (HbA1c or fasting, random, mean, home capillary or urine glucose), and 2) documented the effect of these interventions on active foot ulcer outcomes. Glycaemic interventions included subcutaneous insulin administration, continuous insulin infusion, oral anti-diabetes agents, lifestyle interventions or a combination of these interventions. The definition of the interventional (intensive) group was that it should have a lower glycaemic target than the comparison (conventional) group. DATA COLLECTION AND ANALYSIS: All review authors independently evaluated the papers identified by the search strategy against the inclusion criteria. Two review authors then independently reviewed all potential full-text articles and trials registry results for inclusion. MAIN RESULTS: We only identified one trial that met the inclusion criteria but this trial did not have any results so we could not perform the planned subgroup and sensitivity analyses in the absence of data. Two ongoing trials were identified which may provide data for analyses in a later version of this review. The completion date of these trials is currently unknown. AUTHORS' CONCLUSIONS: The current review failed to find any completed randomised clinical trials with results. Therefore we are unable to conclude whether intensive glycaemic control when compared to conventional glycaemic control has a positive or detrimental effect on the treatment of foot ulcers in people with diabetes. Previous evidence has however highlighted a reduction in risk of limb amputation (from various causes) in people with type 2 diabetes with intensive glycaemic control. Whether this applies to people with foot ulcers in particular is unknown. The exact role that intensive glycaemic control has in treating foot ulcers in multidisciplinary care (alongside other interventions targeted at treating foot ulcers) requires further investigation. PMID- 26758575 TI - Maternal Obesity and its Short- and Long-Term Maternal and Infantile Effects. AB - Obesity, in childhood or in adulthood, remains to be a global health problem. The worldwide prevalence of obesity has increased in the last few decades, and consequently, the women of our time suffer more gestational problems than women in the past. The prevalence of obesity is greater in older women than in younger ones and in women with low educational level than in their counterparts with a higher level of education. Maternal obesity during pregnancy may increase congenital malformations and neonatal morbidity and mortality. Maternal obesity is associated with a decreased intention to breastfeed, decreased initiation of breastfeeding, and decreased duration of breastfeeding. We discuss the current epidemiological evidence for the association of maternal obesity with congenital structural neural tube and cardiac defects, fetal macrosomia that predisposes infants to birth injuries and to problems with physiological and metabolic transition, as well as potential for long-term complications secondary to prenatal and neonatal programming effects compounded by a reduction in sustained breastfeeding. PMID- 26758578 TI - Screening Cuts Ovarian Cancer Mortality. AB - Based on a study that began in 2001, researchers have concluded that ovarian cancer screening increases survival. Disease-related mortality was 20% lower among women who received multimodal screening-annual testing of CA125 blood levels and, if CA125 was abnormal, additional CA125 tests and perhaps transvaginal ultrasound-than among those who weren't screened. When researchers factored in the delayed benefits of screening, the mortality reduction was 22%. PMID- 26758577 TI - Molybdate transporter ModABC is important for Pseudomonas aeruginosa chronic lung infection. AB - BACKGROUND: Mechanisms underlying the success of Pseudomonas aeruginosa in chronic lung infection among cystic fibrosis (CF) patients are poorly defined. The modA gene was previously linked to in vivo competitiveness of P. aeruginosa by a genetic screening in the rat lung. This gene encodes a subunit of transporter ModABC, which is responsible for extracellular uptake of molybdate. This compound is essential for molybdoenzymes, including nitrate reductases. Since anaerobic growth conditions are known to occur during CF chronic lung infection, inactivation of a molybdate transporter could inhibit proliferation through the inactivation of denitrification enzymes. Hence, we performed phenotypic characterization of a modA mutant strain obtained by signature-tagged mutagenesis (STM_modA) and assessed its virulence in vivo with two host models. RESULTS: The STM_modA mutant was in fact defective for anaerobic growth and unable to use nitrates in the growth medium for anaerobic respiration. Bacterial growth and nitrate usage were restored when the medium was supplemented with molybdate. Most significantly, the mutant strain showed reduced virulence compared to wild-type strain PAO1 according to a competitive index in the rat model of chronic lung infection and a predation assay with Dictyostelium discoideum amoebae. As the latter took place in aerobic conditions, the in vivo impact of the mutation in modA appears to extend beyond its effect on anaerobic growth. CONCLUSIONS: These results support the modABC-encoded transporter as important for the pathogenesis of P. aeruginosa, and suggest that enzymatic machinery implicated in anaerobic growth during chronic lung infection in CF merits further investigation as a potential target for therapeutic intervention. PMID- 26758580 TI - "Academic racism" and the neglected scholarship of the anatomist M. Wharton Young, MD, PhD (1904-1986). AB - Moses Wharton Young, MD, PhD (1904-1986), was an African American Professor of Neuroanatomy at Howard University College of Medicine from 1934 to 1973, during which time he authored about 100 publications on topics that included baldness, asthma, glaucoma, and, most importantly, the structure and function of the inner ear and the pathophysiology of blast injuries. Much of Young's research was ignored during his lifetime, raising the question whether this professional neglect was an instance of "academic racism." PMID- 26758581 TI - A white horse in the desert: The life of Dr Thomas Somerville (1887-1941). AB - This article details the remarkable life of Dr Thomas Somerville, who qualified both as a veterinary surgeon and medical practitioner, served in two world wars and was recommended for the nation's highest award for gallantry. In doing so, it records the life of a man whose repeated gallantry on the battlefield has been overlooked. PMID- 26758582 TI - Josef Hammar (1868-1927) - a Swedish physician in the Anglo-Boer War (1899-1902). AB - It is well-known that the Anglo-Boer War attracted support and sympathy for the Boer cause from all over Europe. One topic that has not received much scholarly attention, however, is the contribution of Scandinavian medical doctors and nurses in the conflict. One of them was the Swedish surgeon Josef Hammar. This article argues that his participation was for both idealistic and pragmatic reasons. Further, it presents new sources for understanding the day-to-day work in military medicine in the Boer war from an outside perspective and discusses the issue of medical neutrality in a conflict that has been called the rehearsal for the First World War. PMID- 26758579 TI - An Investigation into Suicides Among Bhutanese Refugees Resettled in the United States Between 2008 and 2011. AB - An increase of Bhutanese refugee suicides were reported in the US between 2009 and 2012. This investigation examined these reported suicides in depth to gain a better understanding of factors associated with suicide within this population. The study employed 14 psychological autopsies to elicit underlying motivations and circumstances for self-inflicted death and to identify potential future avenues for prevention and intervention among refugee communities. Disappointment with current (un)employment, lack of resettlement services and social support, and frustrations with separation from family were believed to contribute to suicidal acts. Suicide within refugee populations may be connected with experiences of family withdrawal, integration difficulties, and perceived lack of care. It is important to assess the effectiveness of improving refugee services on the mental health of migrants. More research is needed in order to better understand, and respond to, suicide in resettled populations. PMID- 26758583 TI - Alphons Mermann (1852-1908): hiccups, hygiene and Hebammen. AB - German gynecologist Alphons Mermann (1852-1908) is best known for establishing the Luisenheim Woechnerinnenasyl (lying-in asylum) at the end of the 19th century in Mannheim. The Luisenheim, owing its name to HRH the Grand Duchess Luise of Baden (1838-1923), was a significant step forward in the provision of a safe delivery environment for mothers of modest means. During his life, Mermann used his position as the Luisenheim's director to promote both the training of midwives and a strict maintenance of asepsis in the hospital. Historically, he has been viewed as the first physician to describe fetal hiccups in a peer reviewed scientific publication, although the phenomena were described nearly two centuries before his account. This short work explores the life, family and contributions of Dr Mermann. PMID- 26758584 TI - William Cookesley, William Hunter and the first patient to survive removal of the appendix in 1731 - A case history with 31 years' follow up. AB - William Cookesley, a surgeon in Devon, England, successfully operated on a patient with an Amyand hernia in 1731, incidentally excising the appendix. His patient is the earliest documented to have survived appendicectomy. This was confirmed by a post mortem examination 31 years later. Part of the remaining bowel was preserved by William Hunter and this specimen remains in the Hunterian Museum in Glasgow. PMID- 26758585 TI - Treatment patterns in COPD patients newly diagnosed in primary care. A population based study. AB - INTRODUCTION: Treatment for COPD is tailored based on clinical characteristics and severity. However, prescription patterns in COPD patients newly diagnosed in primary care may differ from guideline recommendations. METHOD: We performed an epidemiological study with data obtained from the Information System for the Development in Research in Primary Care (SIDIAP), a population database that contains information of 5.8 million inhabitants (80% of the population of Catalonia). Patients newly diagnosed with COPD from 2007 to 2012 were identified and information about the initial treatment patterns was collected. The initial treatment was also described by phenotype and severity. RESULTS: During the study period 41,492 patients were newly diagnosed with COPD. Patients were classified as non exacerbators (28,552 patients, 69%), asthma-COPD overlap syndrome (ACOS) (2152 patients, 5.2%) and frequent exacerbators (10,888 patients, 27.6%). Among the patients in whom FEV1 was available, 13.9% were GOLD stage 1, 55.2% stage 2, 26% stage 3 and 4.8% stage 4. Globally, the most frequently prescribed treatment patterns were short-acting bronchodilators (SABD) in monotherapy (17.7%), long acting beta-2 agonists (LABA) + inhaled corticosteroids (ICS) (17.3%) and triple therapy (12.2%). The frequency of patients treated with a SABD increased from 15.9% to 19.5% during the study period, while the number of untreated patients decreased from 24.4% to 15.1%. Up to 45.2% of patients were initially treated with ICS, which were frequently prescribed in the ACOS (69.2%) and in the exacerbator phenotype patients (52.4%) while ICS use has decreased from 43.8% in 2007 to 35.8% in 2012 in non exacerbator patients. Up to 13.6% and 14.8% of GOLD 4 patients received no treatment or only SABD after diagnosis. CONCLUSIONS: Initial treatment patterns in newly diagnosed COPD patients often do no comply with guidelines. The use of ICS is excessive but has decreased mainly in non exacerbator patients. Many COPD patients still remain untreated after diagnosis, although this has decreased. Some GOLD 4 patients are still receiving SABD or no treatment at all after diagnosis. PMID- 26758586 TI - Meta-analysis of published efficacy and safety data for docetaxel in second-line treatment of patients with advanced non-small-cell lung cancer. AB - PURPOSE: To gain a better understanding of the impact of dose and other prognostic factors on safety and efficacy of docetaxel in second-line non-small cell lung cancer patients. METHODS: A model-based meta-analysis (MBMA) of a published docetaxel monotherapy data in 6085 second-line non-small-cell lung cancer patients from 46 trials was conducted. RESULTS: The logit of grade 3/4 neutropenia incidence was a linear function of dose, with a 5% increase in the odds of neutropenia per mg/m(2) increase in dose [odds ratio (OR) 1.05, 95% confidence interval (CI) 1.04-1.06], and a Japanese study effect (OR 17.1, 95% CI 6.05-48.4). The logit of overall response rate (ORR) was a linear function of cumulative dose (0.4% increase in the odds of response per mg/m(2) increase; OR 1.004, 95% CI 1.001-1.008) and median population age (OR 1.08 per year, 95% CI 1.02-1.15). A Japanese study effect was identified for overall survival (OS) in addition to prognostic factors identified by a previous meta-analysis. CONCLUSIONS: This current MBMA identified docetaxel dose-response relationships for both neutropenia and ORR, an effect of age on ORR, and Japanese study effects on both neutropenia and OS. PMID- 26758587 TI - Prevalence and factors related to smoking and smoking cessation 6 months following a cancer diagnosis: a population-based study. AB - PURPOSE: Limited research has examined smoking amongst recent cancer survivors or the relative contribution of factors on smoking behaviour. This study aimed to describe amongst recent Australian cancer survivors (i) prevalence of smoking by cancer type, (ii) characteristics associated with continued smoking following diagnosis, (iii) intention to quit among those who continue to smoke and (iv) characteristics associated with quitting following diagnosis. METHOD: Cross sectional data were analysed from 1299 cancer survivors diagnosed with their first primary cancer recruited from two Australian cancer registries in Australia between 2006 and 2008. RESULTS: Of participants, 8.6 % reported current smoking. Participants who were younger and single or widowed reported higher odds of current smoking. Participants who had a certificate/diploma or tertiary education reported lower odds of smoking. Among current smokers, 53 % intended to quit in the future. Lung cancer survivors reported more than four times the odds of quitting smoking since diagnosis compared to other cancer types. CONCLUSION: Of recent Australian cancer survivors who were smokers, 14% reported that they never expected to quit smoking [corrected]. IMPLICATIONS FOR CANCER SURVIVORS: Smoking following a cancer diagnosis is associated with increased risk of mortality and further morbidity. There is a need to target cessation efforts towards survivors who are younger, without a partner and with a low level of education. PMID- 26758589 TI - Exploring the Effects of Subfreezing Temperature and Salt Concentration on Ice Growth Inhibition of Antarctic Gram-Negative Bacterium Marinomonas Primoryensis Using Coarse-Grained Simulation. AB - The aim of this work is to study the freezing process of water molecules surrounding Antarctic Gram-negative bacterium Marinomonas primoryensis antifreeze protein (MpAFP) and the MpAFP interactions to the surface of ice crystals under various marine environments (at different NaCl concentrations of 0.3, 0.6, and 0.8 mol/l). Our result indicates that activating temperature region of MpAFPs reduced as NaCl concentration increased. Specifically, MpAFP was activated and functioned at 0.6 mol/l with temperatures equal or larger 278 K, and at 0.8 mol/l with temperatures equal or larger 270 K. Additionally, MpAFP was inhibited by ice crystal network from 268 to 274 K and solid-liquid hybrid from 276 to 282 K at 0.3 mol/l concentration. Our results shed lights on structural dynamics of MpAFP among different marine environments. PMID- 26758588 TI - Loci and candidate gene identification for resistance to Phytophthora sojae via association analysis in soybean [Glycine max (L.) Merr]. AB - Phytophthora sojae is an oomycete soil-borne plant pathogen that causes the serious disease Phytophthora root rot in soybean, leading to great loss of soybean production every year. Understanding the genetic basis of this plant pathogen interaction is important to improve soybean disease resistance. To discover genes or QTLs underlying naturally occurring variations in soybean P.sojae resistance, we performed a genome-wide association study using 59,845 single-nucleotide polymorphisms identified from re-sequencing of 279 accessions from Yangtze-Huai soybean breeding germplasm. We used two models for association analysis. The same strong peak was detected by both two models on chromosome 13. Within the 500-kb flanking regions, three candidate genes (Glyma13g32980, Glyma13g33900, Glyma13g33512) had SNPs in their exon regions. Four other genes were located in this region, two of which contained a leucine-rich repeat domain, which is an important characteristic of R genes in plants. These candidate genes could be potentially useful for improving the resistance of cultivated soybean to P.sojae in future soybean breeding. PMID- 26758591 TI - Impact of aldo-keto reductase family 1 member B10 on the risk of hepatitis C virus-related hepatocellular carcinoma. AB - BACKGROUND AND AIM: Aldo-keto reductase family 1 member B10 (AKR1B10), a cancer related oxidoreductase, was recently reported to be upregulated in some chronic liver diseases. However, its relevance in hepatocellular carcinoma (HCC) development is not fully assessed, especially in patients with chronic hepatitis C virus (HCV) infection. METHODS: Aldo-keto reductase family 1 member B10 expression in the liver of 550 patients with chronic HCV infection was immunohistochemically assessed and quantified. A multivariate Cox model was used to estimate the hazard ratios (HRs) of AKR1B10 expression for HCC development, and the cumulative incidence of HCC was evaluated using the Kaplan-Meier method. RESULTS: Aldo-keto reductase family 1 member B10 expression in the patients ranged from 0% to 80%. During the median follow-up of 3.2 years, 43 of 550 patients developed HCC. Multivariate analysis demonstrated that high AKR1B10 expression (>=6%) was an independent risk factor for HCC (HR, 6.43; 95% confidence interval, 2.90-14.25; P < 0.001). The 5-year cumulative incidences of HCC were 22.8% and 2.2% in patients with high and low AKR1B10 expression, respectively (P < 0.001). In subgroup analyses, the effects of high AKR1B10 expression on HCC development risk were significant over strata. In particular, HRs attributed to high AKR1B10 expression were significant in the subgroups that had been considered at a lower risk of HCC, such as in patients with younger age and mild hepatic fibrosis or those who achieved sustained virological response after interferon therapy. CONCLUSION: Various degrees of AKR1B10 upregulation in the liver were observed in patients with chronic HCV infection, and high AKR1B10 expression could be a novel predictor of HCC. PMID- 26758590 TI - A Simple and Improved Active Loading Method to Efficiently Encapsulate Staurosporine into Lipid-Based Nanoparticles for Enhanced Therapy of Multidrug Resistant Cancer. AB - PURPOSE: This study was aimed at developing a new active loading method to stably encapsulate staurosporine (STS), a water insoluble drug, into lipid-based nanoparticles (LNPs) for drug targeting to tumors. METHODS: A limited amount of DMSO was included during the active loading process to prevent precipitation and facilitate the loading of insoluble STS into the aqueous core of a LNP. The drug loading kinetics under various conditions was studied and the STS-LNPs were characterized by size, drug-to-lipid ratio, drug release kinetics and in vitro potency. The antitumor efficacy of the STS-LNPs was compared with free STS in a mouse model. RESULTS: The drug loading efficiency reached 100% within 15 min of incubation at a drug-to-lipid ratio of 0.31 (mol) via an ammonium gradient. STS formed nano-aggregates inside the aqueous core of the LNPs and was stably retained upon storage and in the presence of serum. A 3-fold higher dose of the STS-LNPs could be tolerated by BALB/c mice compared with free STS, leading to nearly complete growth inhibition of a multidrug resistant breast tumor, while free STS only exhibited moderate activity. CONCLUSION: This simple and efficient drug loading method produced a stable LNP formulation for STS that was effective for cancer treatment. PMID- 26758593 TI - Sesame fractions and lipid profiles: a systematic review and meta-analysis of controlled trials. AB - Increased plasma lipid profiles are among the most important risk factors of CHD and stroke. Sesame contains considerable amounts of vitamin E, MUFA, fibre and lignans, which are thought to be associated with its plasma lipid-lowering properties. This study aimed to systematically review the evidence and identify the effects of sesame consumption on blood lipid profiles using a meta-analysis of controlled trials. PubMed, CINAHL and Cochrane Library databases were searched (from 1960 to May 2015). A total of ten controlled trials were identified based on the eligibility criteria. Both the Cochrane Collaboration tool and the Rosendal scale were used to assess the risk of bias of the included studies. The meta-analysis results showed that consumption of sesame did not significantly change the concentrations of total blood cholesterol (-0.32 mmol/l; 95% CI -0.75, 0.11; P=0.14, I(2)=96%), LDL-cholesterol (-0.15 mmol/l; 95% CI -0.50, 0.19; P=0.39, I(2)=96%) or HDL-cholesterol (0.01 mmol/l; 95% CI -0.00, 0.02; P=0.16, I(2)=0%). However, a significant reduction was observed in serum TAG levels ( 0.24 mmol/l; 95% CI -0.32, -0.15; P<0.001, I(2)=84%) after consumption of sesame. It was concluded that sesame consumption can significantly reduce blood TAG levels but there is insufficient evidence to support its hypocholesterolaemic effects. Further studies are required to determine the potential effect of sesame consumption on lipid profiles and cardiovascular risk factors. PMID- 26758594 TI - Development of diamond-lanthanide metal oxide affinity composites for the selective capture of endogenous serum phosphopeptides. AB - Development of affinity materials for the selective enrichment of phosphopeptides has attracted attention during the last decade. In this work, diamond-lanthanum oxide and diamond-samarium oxide composites have been fabricated via the hydrothermal method. The composites are characterized by scanning electron microscopy (SEM), energy dispersive X-Ray spectroscopy (EDAX), and atomic force microscopy (AFM). The analyses confirm the size and composition of the nanocomposites. They have been applied to selectively capture phosphorylated peptides from standard proteins (beta-casein and BSA). Selectivity is calculated as 1:3000 and 1:1500 while sensitivity down to 1 and 20 fmol for diamond lanthanum oxide and diamond-samarium oxide nanocomposites, respectively. Enrichment efficiency has also been evaluated for non-fat milk digest where 18 phosphopeptides are enriched. Total of 213 and 187 phosphopeptides are captured from tryptic digest of HeLa cells extracted proteins by diamond-lanthanum oxide and diamond-samarium oxide, respectively. Finally, human serum, without any pre treatment, is applied and nanocomposites capture the endogenous serum phosphopeptides. PMID- 26758592 TI - Advances in the management of HIV/HCV coinfection. AB - HCV coinfection has emerged as a major cause of non-AIDS-related morbidity and mortality in HIV-positive patients. As a consequence of the availability of modern combined antiretroviral therapy regimens, for optimally managed HIV/HCV coinfected patients, the rates of liver fibrosis progression and the risk of liver-related events are increasingly similar to those of HCV-monoinfected patients. Moreover, our understanding of modulators of liver disease progression has greatly improved. In addition to immune status, endocrine, metabolic, genetic and viral factors are closely interrelated and might be important determinants of liver disease progression. In the last decade, a variety of serologic and radiographic tests for noninvasive liver disease staging have been extensively validated and are commonly used in HIV/HCV-coinfected patients. Sustained virologic response prevents end-stage liver disease, hepatocellular carcinoma, and death, with an even greater effect size in HIV-positive compared to HIV negative patients. As interferon-free regimens achieve comparable rates of sustained virologic response in HIV-negative and HIV-positive patients, HIV/HCV coinfected patients should from now on be referred to as a special, rather than a difficult-to-treat, population. Our comprehensive review covers all relevant aspects of HIV/HCV coinfection. Beginning with the changing epidemiology, it also provides new insights into the natural history of this condition and gives an overview on non-invasive techniques for the staging of liver disease. Furthermore, it outlines current recommendations for the treatment of acute hepatitis C and summarizes the unprecedented advances in the field of chronic hepatitis C therapy. PMID- 26758595 TI - Development of redox-sensitive red fluorescent proteins for imaging redox dynamics in cellular compartments. AB - We recently reported a redox-sensitive red fluorescent protein, rxRFP1, which is one of the first genetically encoded red-fluorescent probes for general redox states in living cells. As individual cellular compartments have different basal redox potentials, we hereby describe a group of rxRFP1 mutants, showing different midpoint redox potentials for detection of redox dynamics in various subcellular domains, such as mitochondria, the cell nucleus, and endoplasmic reticulum (ER). When these redox probes were expressed and subcellularly localized in human embryonic kidney (HEK) 293 T cells, they responded to membrane-permeable oxidants and reductants. In addition, a mitochondrially localized rxRFP1 mutant, Mito rxRFP1.1, was used to detect mitochondrial oxidative stress induced by doxorubicin-a widely used cancer chemotherapy drug. Our work has expanded the fluorescent protein toolkit with new research tools for studying compartmentalized redox dynamics and oxidative stress under various pathophysiological conditions. PMID- 26758596 TI - Screening of additives in plastics with high resolution time-of-flight mass spectrometry and different ionization sources: direct probe injection (DIP)-APCI, LC-APCI, and LC-ion booster ESI. AB - Plastics are complex mixtures consisting of a polymer and additives with different physico-chemical properties. We developed a broad screening method to elucidate the nature of compounds present in plastics used in electrical/electronic equipment commonly found at homes (e.g., electrical adaptors, computer casings, heaters). The analysis was done by (a) solvent extraction followed by liquid chromatography coupled to high accuracy/resolution time-of-flight mass spectrometry (TOFMS) with different ionization sources or (b) direct analysis of the solid by ambient mass spectrometry high accuracy/resolution TOFMS. The different ionization methods showed different selectivity and sensitivity for the different compound classes and were complementary. A variety of antioxidants, phthalates, UV filters, and flame retardants were found in most samples. Furthermore, some recently reported impurities or degradation products derived from flame retardants were identified, such as hydroxylated triphenyl phosphate and tetrabromobisphenol A monoglycidyl ether. PMID- 26758597 TI - A new selective fluorene-based fluorescent internal charge transfer (ICT) sensor for sugar alcohols in aqueous solution. AB - Sugar alcohols, such as sorbitol, are commonly used as a replacement for sucrose in the food industry, applied as starting material for vitamin C synthesis, and involved as one of the causative factors in diabetic complications. Therefore, their detection and quantification in aqueous solution are necessary. The reversible covalent interactions between boronic acids and diols are the basis of efficient methods for the detection of saccharides. Herein, we report a new internal charge transfer (ICT) fluorene-based fluorescent boronic acid sensor (1) 2-[(9,9-dimethyl-9H-fluoren-2-yl-amino)methyl] phenyl boronic acid that shows significant fluorescence changes upon addition of saccharides. The boronic acid has high affinity (K a = 1107.9 M(-1)) and selectivity for sorbitol at pH = 8.31. It showed a linear response toward sorbitol in the concentration range from 1.0 * 10(-5) to 6.0 * 10(-4) mol L(-1) with the detection limit of 7.04 * 10(-6) mol L( 1). Sensor 1 was used to detect sorbitol in real samples with good recovery. PMID- 26758598 TI - Screening enoxaparin tetrasaccharide SEC fractions for 3-O-sulfo-N sulfoglucosamine residues using [(1)H,(15)N] HSQC NMR. AB - Heparin and heparan sulfate (HS) are important in mediating a variety of biological processes through binding to myriad different proteins. Specific structural elements along the polysaccharide chains are essential for high affinity protein binding, such as the 3-O-sulfated N-sulfoglucosamine (GlcNS3S) residue, a relatively rare modification essential for heparin's anticoagulant activity. The isolation of 3-O-sulfated oligosaccharides from complex mixtures is challenging because of their low abundance. Although methods such as affinity chromatography are useful in isolating oligosaccharides that bind specific proteins with high affinity, other important 3-O-sulfated oligosaccharides may easily be overlooked. Screening preparative-scale size-exclusion chromatography (SEC) fractions of heparin or HS digests using [(1)H,(15)N] HSQC NMR allows the identification of fractions containing 3-O-sulfated oligosaccharides through the unique (1)H and (15)N chemical shifts of the GlcNS3S residue. Those SEC fractions containing 3-O-sulfated oligosaccharides can then be isolated using strong anion exchange (SAX)-HPLC. Compared with the results obtained by pooling the fractions comprising a given SEC peak, SAX-HPLC analysis of individual SEC fractions produces a less complicated chromatogram in which the 3-O-sulfated oligosaccharides are enriched relative to more abundant components. The utility of this approach is demonstrated for tetrasaccharide SEC fractions of the low molecular weight heparin drug enoxaparin facilitating the isolation and characterization of an unsaturated 3-O-sulfated tetrasaccharide containing a portion of the antithrombin-III binding sequence. PMID- 26758599 TI - Recent advances in the determination of tocopherols in biological fluids: from sample pretreatment and liquid chromatography to clinical studies. AB - Vitamin E comprises eight related compounds: alpha-, beta-, gamma-, delta tocopherols and alpha-, beta-, gamma-, delta-tocotrienols. In the past, alpha tocopherol has been the isomer that was studied most, and its anti-inflammatory and anti-proliferative effects have been described. Therefore, many prevention trials have investigated the effect of alpha-tocopherol on human health. Current research studies have also defined the important roles of other tocopherols, such as anti-inflammatory, anti-proliferative and cancer preventative effects. Knowledge of the individual tocopherols could help to understand their roles in various metabolic pathways. This review summarizes the recent trends in sample pretreatment, liquid chromatography and selected applications of the determination of tocopherols in various biological materials. The relationship between tocopherol isomers and serious diseases is also described. Graphical Abstract Article structure. PMID- 26758600 TI - Development of a method based on ultra high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry for studying the in vitro metabolism of phosphorothioate oligonucleotides. AB - Ultra high performance liquid chromatography hyphenated with quadrupole time-of flight mass spectrometry was used to determine the products of the in vitro metabolism of phosphorothioate oligonucleotides. These compounds may be used during antisense therapy as synthetic fragments of genes. For this reason, both a sample preparation method and a qualification method were developed during this study. Liquid-liquid extraction, protein or oligonucleotide precipitation, and solid-phase extraction were tested and compared in order to select the method that yielded the highest recoveries. Ion pair chromatography was used for separation while mass spectrometry was applied for metabolite identification. The influence of the type of ion pair reagent used on the resolution and sensitivity was investigated. Results indicated that a mixture of 1,1,1,3,3,3-hexafluoro-2 propanol, N,N-dimethylbutylamine, and methanol was the best mobile phase for maximizing both of these parameters. The developed method was applied to investigate the compounds that form during the incubation of phosphorothioate oligonucleotides with human liver microsomes. Metabolites with short sequences were created after 8 hours, while oligonucleotides constructed from a large number of nucleotide units were obtained after 12 hours of incubation. Moreover, regardless of the length of the polynucleotide chain, metabolites were produced by the same mechanism: enzymatic cleavage at the 3' end of the sequence. PMID- 26758602 TI - Nanoparticle chains as electrochemical sensors and electrodes. AB - With the advances in the field of nanotechnology, significant progress is being achieved in fabrication of nanoscale electrodes (nanoelectrodes) and using their properties for applications in multiple fields. Compared with conventional macroscale electrodes, nanoelectrodes offer many advantages that arise from their limited size. Self-assembled chains of metal nanoparticles in particular have drawn interest for fabrication of nanoelectrodes because of their unique electrical properties and geometric morphology. This article discusses the fabrication methods and potential applications of nanoparticle chains as nanoelectrodes in electrochemical systems and also as conductometric sensors. The challenges for such systems are also summarized. PMID- 26758601 TI - The use of generic surrogate peptides for the quantitative analysis of human immunoglobulin G1 in pre-clinical species with high-resolution mass spectrometry. AB - In the present study, the application of a liquid chromatography high-resolution mass spectrometry (LC-HRMS) analytical assay for the quantitative analysis of a recombinant human immunoglobulin G1 (hIgG1) in rat serum is reported using three generic peptides GPSVFPLAPSSK (GPS), TTPPVLDSDGSFFLYSK (TTP), and VVSVLTVLHQDWLNGK (VVS). Moreover, the deamidation site of a fourth peptide FNWYVDGVEVHNAK (FNW) was identified and further excluded from the assay evaluation due to the inaccuracy of the quantitative results. The rat serum samples were spiked with a fully labeled hIgG1 as internal standard (ISTD). The digestion with trypsin was performed onto the pellet prior to peptide analysis by LC-HRMS using a quadrupole time of flight (QTOF) mass analyzer operating in selected reaction monitoring (SRM) mode with enhanced duty cycles (EDC). The assay linearity for the three investigated peptides was established for a hIgG1 (hIgG1A) from 1.00 to 1000 MUg mL(-1) with a mean coefficient of determination (R (2)) higher than 0.9868. The inter-day accuracy and precision obtained in rat serum over 3 days were <=11.4 and <=10.5%, respectively. Short-term stability on the auto-sampler at 6 degrees C for 30 h, at RT for 48 h, and a 100-fold dilution factor were demonstrated. In addition, QC samples prepared in cynomolgus monkey serum and measured with the present method met the acceptance criteria of +/-20.0 and <=20.0% for all three peptides regarding accuracy and precision, respectively. The LC-HRMS method was applied to the analysis of samples from five individual cynomolgus monkeys dosed with a second hIgG1 (hIgG1B) and consistent data were obtained compared to the LC-MS/MS method (conventional triple quadrupole (QqQ) mass analyzer operating in SRM). The present data demonstrate that LC-HRMS can be used for the quantitative analysis of hIgG1 in both species and that quantification is not only limited to classical QqQ instruments. PMID- 26758603 TI - Biological research into aging: from cells to clinic. PMID- 26758605 TI - Charge Recombination Control for High Efficiency Quantum Dot Sensitized Solar Cells. AB - Benefiting from the unique excellent optoelectronic properties of quantum dot light absorbers, quantum dot sensitized solar cell (QDSCs) are a promising candidate for the low-cost third-generation solar cells. Over the past few years, the power conversion efficiency (PCE) of QDSCs presents a rapid evolution from less than 1% to beyond 8%. Charge recombination is regarded as one of the most significant factors in limiting the photovoltaic performance of QDSCs. A significant improvement in the PCE of QDSCs has been obtained by charge recombination control. Some effective routes to suppress charge recombination processes, such as adopting preprepared high-quality QD sensitizers, tailoring the electronic properties of QDs, and interface engineering with the use of organic or inorganic thin layer overcoating the sensitized photoanode have been overviewed in this perspective. Also, the possible accesses to better performance (higher efficiency and stability) of the QDSCs have been proposed on the basis of achievements obtained previously. PMID- 26758604 TI - Intravertebral vacuum cleft sign: a cause of vertebral cold defect on bone scan. AB - A 67-year-old female presented with an acute compression fracture with an intravertebral vacuum cleft (IVC) sign of the T12 vertebra. Her bone scan demonstrated a cold defect of the fractured vertebra. Although the IVC sign is related to vertebral osteonecrosis, to the best of our knowledge, a cold defect on a bone scan has not been reported in an acute compression fracture with an IVC sign. In this case review, various imaging findings of osteonecrotic compression fractures are discussed along with a review of the current literature. PMID- 26758607 TI - Analysis and Sources of Polycyclic Aromatic Hydrocarbons in Soil and Plant Samples of a Coal Mining Area in Nigeria. AB - This study analysed coal, plant and soil samples collected from the vicinity of Okobo coal mine in Nigeria for Polycyclic aromatic hydrocarbons (PAHs) and evaluated the sources of the PAH contamination in the environmental samples. The environmental samples were extracted by sonication using a ternary solvent system and analysed for 16 PAHs by gas chromatography-mass spectrometry (GC-MS). The results of the analysis of the samples identified some of the target PAHs. The ranges of total concentrations (in mg/kg) of PAHs in the coal, plant and soil samples were, 0.00-0.04, 0.00-0.16 and 0.00-0.01 respectively. The evaluation of the results of the PAH analysis of the environmental samples using diagnostic ratios revealed that the PAHs in the soil samples were mainly of petrogenic origin, while those in plant samples indicated mixture of petrogenic and pyrolytic origins. PMID- 26758606 TI - Purification and biochemical characterization of glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase and glutathione reductase from rat lung and inhibition effects of some antibiotics. AB - G6PD, 6PGD and GR have been purified separately in the single step from rat lung using 2', 5'-ADP Sepharose 4B affinity chromatography. The purified enzymes showed a single band on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The molecular weights of the enzymes were estimated to be 134 kDa for G6PD, 107 kDa for 6PGD and 121 kDa for GR by Sephadex G-150 gel filtration chromatography, and the subunit molecular weights was respectively found to be 66, 52 and 63 kDa by SDS-PAGE. Optimum pH, stable pH, optimum ionic strength, optimum temperature, KM and Vmax values for substrates were determined. Product inhibition studies were also performed. The enzymes were inhibited by levofloxacin, furosemide, ceftazidime, cefuroxime and gentamicin as in vitro with IC50 values in the range of 0.07-30.13 mM. In vivo studies demonstrated that lung GR was inhibited by furosemide and lung 6PGD was inhibited by levofloxacin. PMID- 26758609 TI - Comparison of the clinical and radiologic outcomes obtained with single- versus two-level anterior cervical decompression and fusion using stand-alone PEEK cages filled with allograft. AB - BACKGROUND: Although anterior cervical decompression and fusion with a stand alone cage (ACDF-SAC) is accepted as a suitable procedure, the outcomes of the multi-level procedure remain controversial. The aim of this study is to compare the clinical and radiologic outcomes achieved with single versus two-level ACDF SAC along with identification of the factors that contribute to loss in mean disc height (MDH) and change in cervical lordotic angle (CLA). METHODS: A total of 109 consecutive patients who underwent ACDF-SAC for degenerative spondylosis were reviewed. Patients were divided into two groups according to surgical level (group A, single; group B, two) and were followed for at least 1 year. Clinical outcomes were evaluated using the visual analog scale (VAS) and Robinson's criteria. The fusion and subsidence rates, MDH, CLA, anterior, and posterior vertebral body height of the fused segments (AVBH, PVBH) were measured retrospectively from plain radiographs. RESULTS: Clinical outcomes were similar in both groups, in terms of decreasing VAS score and a grade higher than "good" by Robinson's criteria. The fusion and subsidence rates for each group were found to be 92.2, 91.1, 14.1, and 20.0 %, respectively. The MDH (mm) increased by 1.44 +/- 0.96 in group A, 1.57 +/- 0.79 and 1.66 +/- 0.69 for each surgical level in group B over the 12 postoperative months. The CLA ( degrees ) decreased by 1.70 +/- 4.04 and 0.75 +/- 6.12 over the 12 postoperative months from its presurgery value, the rate of kyphosis >5 degrees was 26.6 and 22.2 % for each group. All compared values were not significantly different between the two groups. Correlation analysis revealed that the AVBH/PVBH ratio exhibited a positive correlation with CLA change in both groups (r = 0.368, 0.397; p = 0.018, 0.040). CONCLUSIONS: The overall outcomes achieved with two-level ACDF-SAC were similar to those achieved with single-level ones. In addition, the AVBH/PVBH ratio might be a predictable marker for a postoperative kyphosis. PMID- 26758610 TI - Molecular, behavioral, and performance responses of juvenile largemouth bass acclimated to an elevated carbon dioxide environment. AB - Aquatic hypercarbia, either naturally occurring or anthropogenically induced, can have extensive impacts on aquatic environments and resident organisms. While the impact of acute hypercarbia exposure on the behavior and physiology of fishes has been well studied, relatively little work has examined the physiological impact and acclimation capacity of fishes to chronic hypercarbia. To better understand the impacts of prolonged hypercarbia exposure, largemouth bass were held at ambient CO2 (13 mg L(-1)) and elevated CO2 (31 mg L(-1); ~ 21,000 uatm) for 58 days. Following this acclimation period, fish were subjected to three separate, yet complementary, experiments: (1) acute hypercarbia challenge of 120 mg L(-1) CO2 for 1 h to quantify physiological and molecular responses; (2) hypercarbia avoidance challenge to compare CO2 agitation and avoidance responses; and (3) swim performance challenge to quantify burst swimming performance. Acclimation to 31 mg L(-1) CO2 resulted in a significant constitutive upregulation of c-fos expression in erythrocytes, combined with significant constitutive expression of hsp70 in both gill and erythrocytes, relative to controls. Largemouth bass acclimated to elevated CO2 also had a reduced glucose response (relative to controls) following an acute CO2 exposure, indicating a reduced stress response to CO2 stressors. In addition, largemouth bass acclimated to elevated CO2 conditions required 50 % higher CO2 concentrations to illicit agitation behaviors and displayed prolonged burst swimming abilities in high CO2 environments relative to controls. Together, results demonstrate that largemouth bass exposed to chronic hypercarbia may possess a physiological advantage during periods of elevated CO2 relative to naive fish, which may permit increased performance in hypercarbia. PMID- 26758612 TI - Biobanking human embryonic stem cell lines: policy, ethics and efficiency. AB - Stem cell banks curating and distributing human embryonic stem cells have been established in a number of countries and by a number of private institutions. This paper identifies and critically discusses a number of arguments that are used to justify the importance of such banks in policy discussions relating to their establishment or maintenance. It is argued (1) that 'ethical arguments' are often more important in the establishment phase and 'efficiency arguments' more important in the maintenance phase, and (2) that arguments relating to the interests of embryo and gamete donors are curiously absent from the particular stem cell banking policy discourse. This to some extent artificially isolates this discourse from the broader discussions about the flows of reproductive materials and tissues in modern society, and such isolation may lead to the interests of important actors being ignored in the policy making process. PMID- 26758613 TI - Promising waste: biobanking, embryo research, and infrastructures of ethical efficiency. AB - Biobanks are custodial institutions that enhance the utility and value of biological materials by collecting and curating them. Their custodial functions tend to include ethical oversight and governance. This paper explores how biobanks increase the value of biological materials by standardizing routines of governance in order to engender "ethical efficiency." Focusing in particular upon banking of human embryos for research, the article offers an historical account of how human embryos came to be "waste" available for use by researchers in the US. It offers a case study of a human embryo biobank and the practices of ethical governance that the biobank employs to capture this waste and convert it into a valuable resource for research use. The article draws attention to the ways biobanks' emphasis on efficiency and resolving problems of ethical governance up front codifies otherwise contested normative relationships and authorizes uses of human biological materials that some see as ethically problematic, even as it eliminates institutionalized mechanisms of reflection in which such problems would otherwise be acknowledged and confronted. PMID- 26758614 TI - Medical student plagiarism in problem-based learning courses. PMID- 26758611 TI - Endothelial cell dysfunction and cardiac hypertrophy in the STOX1 model of preeclampsia. AB - Preeclampsia is a disease of pregnancy involving systemic endothelial dysfunction. However, cardiovascular consequences of preeclampsia are difficult to analyze in humans. The objective of the present study is to evaluate the cardiovascular dysfunction induced by preeclampsia by examining the endothelium of mice suffering of severe preeclampsia induced by STOX1 overexpression. Using Next Generation Sequencing on endothelial cells of mice carrying either transgenic or control embryos, we discovered significant alterations of gene networks involved in inflammation, cell cycle, and cardiac hypertrophy. In addition, the heart of the preeclamptic mice revealed cardiac hypertrophy associated with histological anomalies. Bioinformatics comparison of the networks of modified genes in the endothelial cells of the preeclamptic mice and HUVECs exposed to plasma from preeclamptic women identified striking similarities. The cardiovascular alterations in the pregnant mice are comparable to those endured by the cardiovascular system of preeclamptic women. The STOX1 mice could help to better understand the endothelial dysfunction in the context of preeclampsia, and guide the search for efficient therapies able to protect the maternal endothelium during the disease and its aftermath. PMID- 26758615 TI - Influence of the indirect restoration design on the fracture resistance: a finite element study. AB - OBJECTIVES: To establish a three-dimensional (3D) finite element (FE) model of a maxillary first premolar and to evaluate the stress generated on the tooth (dentine) and on the indirect composite resin restorations by occlusal forces. METHODS: An embedded intact maxillary first premolar tooth was sliced serially and scanned digitally parallel to the occlusal surface. The 64 images were assembled in a 3D FE mesh and exported to generate a 3D solid tooth model. Simulated, adhesively cemented indirect mesial-occlusal-distal (MOD) inlays of 2 mm (I1), 3 mm (I2) and 4 mm (I3) in width, and MOD onlays with occlusal cusp coverage of 2 mm (O1) and 3 mm (O2) in depth were created. The peak von Mises stress values in the five tooth models resulting from static vertical and oblique occlusal forces (300 N) were evaluated using Patran FE software. RESULTS: The peak stress values generated by vertical occlusal force generated in dentine of I1, I2, I3, O1 and O2 restoration were 67, 32, 29, 38 and 27 MPa, respectively, and those generated by oblique occlusal force were 52, 114, 168, 54 and 55 MPa, respectively. The peak von Mises stress values in I1, I2, I3, O1 and O2 restoration subjected to oblique occlusal loading were 79, 120, 1740, 1400 and 1170 MPa, respectively. CONCLUSION: A 3D FE model of a maxillary first premolar was established. Simulated cemented composite resin onlay markedly reduces occlusal stress in the underlying dentine of large MOD preparation. Oblique occlusal force imparts substantially higher stress to large composite resin inlay than to the adjacent dentine. PMID- 26758616 TI - Acute and chronic sensitivity, avoidance behavior and sensitive life stages of bullfrog tadpoles exposed to the biopesticide abamectin. AB - As compared to other aquatic organism groups, relatively few studies have been conducted so far evaluating the toxicity of pesticides to amphibians. This may at least partly be due to the fact that regulations for registering pesticides usually do not require testing amphibians. The sensitivity of amphibians is generally considered to be covered by that based on toxicity tests with other aquatic organisms (e.g. fish) although the impact of a pesticide on amphibians may be very different. In the present study, acute and chronic laboratory tests were conducted to evaluate the acute and chronic toxicity of abamectin (as Vertimec((r)) 18EC) to bullfrog (Lithobates catesbeianus) tadpoles. Acute tests were conducted at two tadpole stages (Gosner stage 21G and 25G) and avoidance tests were also conducted with stage Gosner stage 21G tadpoles. Calculated acute toxicity values were greater than those reported for standard fish test species, hence supporting the use of fish toxicity data as surrogates for amphibians in acute risk assessments. Given the limited number and extent of available amphibian toxicity studies, however, research needs to increase our understanding of pesticide toxicity to amphibians are discussed. PMID- 26758617 TI - Chemical composition, aroma evaluation, and inhibitory activity towards acetylcholinesterase of essential oils from Gynura bicolor DC. AB - The compositions of the essential oils obtained from leaves and stems of Gynura bicolor DC. were analyzed by GC-MS. One hundred eight components of these oils were identified. (E)-beta-caryophyllene (31.42 %), alpha-pinene (17.11 %), and bicyclogermacrene (8.09 %) were found to be the main components of the leaf oil, while alpha-pinene (61.42 %), beta-pinene (14.39 %), and myrcene (5.10 %) were the major constituents of the stem oil. We found 73 previously unidentified components in these oils from G. bicolor. The oils were also subjected to odor evaluation. Eleven and 12 aroma-active compounds were detected in the leaf and stem oils, respectively. The abilities of these oils to inhibit acetylcholinesterase (AChE) activity were determined. The sesquiterpenoids in the oils were found to inhibit AChE activity more strongly than the monoterpenoids in the oils did. It was suggested that the three main components in each essential oil act synergistically against AChE activity. These results show that the essential oils obtained from G. bicolor are a good dietary source of AChE activity inhibition. PMID- 26758618 TI - Two new prenylflavonoids from Epimedii Herba and their inhibitory effects on advanced glycation end-products. AB - Because inhibitors of advanced glycation end-products (AGEs), for example pyridoxamine, significantly inhibit the development of retinopathy and neuropathy in rats with streptozotocin-induced diabetes, treatment with AGE inhibitors is believed to be a potential strategy for the prevention of lifestyle-related diseases such as diabetic complications. In the present study, the MeOH extract of Epimedii Herba (EH; aerial parts of Epimedium spp.) was found to inhibit the formation of N (epsilon) -(carboxymethyl)lysine (CML) and N (omega) (carboxymethyl)arginine (CMA) during incubation of collagen-derived gelatin with ribose. Furthermore, compounds with inhibitory effects against CML and CMA formation were isolated from EH. Two new prenylflavonoids (compounds 1 and 2) and two known compounds (3 and 4) were found to significantly inhibit the formation of both CML and CMA; compound 4 (epimedokoreanin B) had the strongest inhibitory effect of the isolated compounds. These data suggest that epimedokoreanin B could prevent clinical complications of diabetes by inhibiting AGEs. PMID- 26758619 TI - Hammerhead Ribozymes in Archaeal Genomes: A Computational Hunt. AB - Hammerhead ribozymes (HHRs) are small self-cleaving RNAs, first discovered in viroids and satellite RNAs of plant viruses. They are composed of a catalytic core of conserved nucleotides flanked by three helices. More recently, hammerhead encoding sequences have been identified in the genomes of many eukaryotes, prokaryotes and other non-viral species regulating various functions. In this study we have explored the Archaeal domain to identify HHRs using three different bioinformatics approach. Our study reveals four putative hits of HHRs type I and type II in the group Thaumarchaeota and Euryarchaeota in the Archaeal domain, one of which is the instance of HHR 1 in C. symbiosum A, already identified in a previous study. These HHRs are very similar to those previously described in terms of the conservation of their catalytic core. Based on 3-D structure analysis and free energy, these instances were concluded as putative HHRs. Our findings reveal that the catalytic core contains the conserved motifs that are essential for cleavage activity, but there are some instances in which compensatory core variations are present. However, no instances of HHRs have been found in Crenarchaeota. This study reveals a very scarce presence of HHRs in Archaea which suggests the involvement of other ncRNA elements in gene regulatory system like RNase P which are abundantly found in the Archaeal domain. PMID- 26758621 TI - Is family integrated care in neonatal intensive care units feasible and good for preterm infants in China: study protocol for a cluster randomized controlled trial. AB - BACKGROUND: By changing the paradigm of neonatal intensive care and integrating parents into the care team, the 'family integrated care' (FICare) model developed in Canada ensures that infants receive more consistent care and parents are better able to care for their infants within the neonatal intensive care unit (NICU) and at home. However, Chinese health policy dictates that parents are not allowed into the NICU during their infant's stay, which inhibits this type of parent-infant interaction and may affect infant outcomes. This project aims to demonstrate that allowing parents to care for their newborn infants in the NICU improves the medical outcomes of infants. METHODS/DESIGN: This cluster randomized controlled trial will evaluate the feasibility and efficacy of FICare in six Chinese tertiary-level NICUs in China - three 'intervention' and three 'control' NICUs. The study steps are: (1) planning and preparation; (2) staff recruitment and training; (3) pilot study in two centers; (4) interim analysis and confirmation of sample size for main study; (5) implementation of main study; (6) data analysis and preparation and publication of study reports. The primary outcome measure is duration of hospital stay from admission to discharge. Secondary outcome measures are: (1) clinical outcomes, such as nosocomial infection, (2) weight gain, (3) breastfeeding, (4) time to full feed, and (5) maternal stress. DISCUSSION: This study will assess the feasibility and cost effectiveness of FICare in China. By establishing that FICare is a practical model of NICU care for stable preterm infants in China, this project will have a significant impact on health outcomes, medical practice and policy, and the cost of medical care. The approach used in this project could be transferable to many other areas of medical care, such as pediatrics, chronic care, and geriatrics. Data in this project can be used to inform health policy in NICUs across China so that parents are allowed to enter the NICU and be at their infant's bedside during the baby's hospitalization, and modifying the design of NICUs in China to facilitate the participation of parents in caring for their newborns. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TRC-14004736. PMID- 26758620 TI - CD133+ liver cancer stem cells resist interferon-gamma-induced autophagy. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most fatal malignancies worldwide, and CD133 is a popular cancer stem cell (CSC) marker for HCC. CD133(+) CSCs have been reported to resist conventional chemo- and radiotherapy, but little is known about their response to immune surveillance. Interferon-gamma (IFN-gamma) is one of key cytokines that the immune system produce to eradicate cancer cells, so we investigated the function of IFN-gamma on CD133+ HCC CSCs in this study. METHODS: The response of CD133(+) cells to IFN-gamma was performed with functional assays (cell proliferation assay and tumor formation in nude mice), flow cytometry, immunofluorescence staining and RNA interference. RESULTS: We found that IFN-gamma inhibited the proliferation of cell lines with low percentage of CD133(+) cells (wild-type human cells, BEL7402, QGY7701) but it did not affect the proliferation of cell lines with high percentage of CD133(+) cells (wild-type human cells, Huh7, PLC8024) in vivo and in vitro (nude mice). Flow cytometry analysis demonstrated that the percentage of CD133+ cells increased after IFN-gamma treatment of low CD133(+) cell lines. Furthermore, IFN-gamma induced the autophagy of low CD133(+) cell lines to decrease proliferation. CONCLUSION: CD133(+) HCC CSCs resisted IFN-gamma-induced autophagy, which might also be a mechanism through which CSCs resist immune eradication. PMID- 26758622 TI - Transient symptomatic hyperglycaemia secondary to inhaled fluticasone propionate in a young child. AB - BACKGROUND: Inhaled corticosteroids (ICSs) are currently used to prevent and treat asthma and recurrent wheezing attacks in children. Fluticasone propionate (FP) is one of the most commonly prescribed ICSs because it is considered effective and well tolerated. CASE PRESENTATION: A male infant of approximately 1 year of age, who was born to parents without relevant clinical problems or family histories including diabetes, was brought to our attention for recurrent wheezing. When he was approximately 2 years old, a regular daily inhaled treatment with FP given using a spacer was prescribed. With this therapy, the child obtained good control of his symptoms with no further recurrences, but after approximately 2 months of treatment he was admitted to the emergency room because he was whining and agitated and exhibited increased diuresis and water intake. Laboratory tests revealed hyperglycaemia (181 mg/dL), mild glycosuria, blood alkalosis (pH 7.49), a bicarbonate level of 31 mmol/L, a pCO2 level of 39 mmHg, a serum sodium level of 135 mEq/L and a serum potassium level of 3.5 mEq/L. The parents confirmed that the recommended dose of FP had been administered with no increase in the amount of drug. The child was immediately treated with endovenous infusion of physiological saline for 24 h, and his glycaemic levels as well as venous blood gas analysis returned to normal, with an absence of glucose in the urine. Oral glucose tolerance test results and glycated haemoglobin levels were normal. Monitoring of blood glucose levels before and after meals for three consecutive days did not reveal any further increase above normal levels. He was discharged with a diagnosis of transient symptomatic hyperglycaemia during ICS therapy and the suggestion to replace his inhaled FP therapy with oral montelukast. Montelukast was continued for 6 months; during this time, the child did not present any other hyperglycaemia episodes. CONCLUSIONS: Although there is no evidence of causation, this case report represents an interesting and unusual description of paediatric transient symptomatic hyperglycaemia after treatment with inhaled FP and highlights the importance of considering this potential adverse event and the necessity of informing parents of the possible clinically relevant risks associated with this drug. PMID- 26758624 TI - Socioeconomic health disparities revisited: coping flexibility enhances health related quality of life for individuals low in socioeconomic status. AB - BACKGROUND: Previous research has generally indicated that disadvantaged socioeconomic groups tend to experience poor health-related quality of life (HRQoL). In an effort to extend the literature, this study proposes that coping flexibility is a stress buffer that mitigates the adverse effects of low socioeconomic status (SES). METHODS: The participants comprised 150 Indians (53 % women; mean age = 36.38 years) from high, medium and low socioeconomic groups. Their levels of perceived stress, coping flexibility, subjective SES and HRQoL were assessed individually through household interviews. RESULTS: The findings provide support for the hypothesised moderating role of coping flexibility between subjective SES and HRQoL (p < 0.001). In the low SES group, participants higher in coping flexibility reported significantly better HRQoL than those lower in coping flexibility. Moreover, coping flexibility moderated the association between perceived stress and HRQoL (p = 0.001). Of the participants who experienced higher levels of stress, those higher in coping flexibility reported better HRQoL than those lower in coping flexibility. CONCLUSIONS: This study enriches the literature by revealing the beneficial role of coping flexibility on HRQoL among individuals low in SES. These new findings highlight the potential importance of psychological interventions that strengthen the flexible coping skills of socioeconomically disadvantaged groups. PMID- 26758625 TI - A Fluctuating State in the Framework Compounds (Ba,Sr)Al2O4. AB - The structural fluctuation in hexagonal Ba(1-x)Sr(x)Al2O4 with a corner-sharing AlO4 tetrahedral network was characterized at various temperatures using transmission electron microscopy experiments. For x <= 0.05, soft modes of q ~ (1/2, 1/2, 0) and equivalent wave vectors condense at a transition temperature (TC) and form a superstructure with a cell volume of 2a * 2b * c. However, TC is largely suppressed by Sr-substitution, and disappears for x >= 0.1. Furthermore, the q ~ (1/2, 1/2, 0) soft mode deviates from the commensurate value as temperature decreases and survives in nanoscaled regions below ~200 K. These results strongly suggest the presence of a new quantum criticality induced by the soft mode. Two distinct soft modes were observed as honeycomb-type diffuse scatterings in the high-temperature region up to 800 K. This intrinsic structural instability is a unique characteristic of the framework compound and is responsible for this unusually fluctuating state. PMID- 26758623 TI - Years of life lost due to lower extremity injury in association with dementia, and care need: a 6-year follow-up population-based study using a multi-state approach among German elderly. AB - BACKGROUND: Dementia and care need are challenging aging populations worldwide. Lower extremity injury (LEI) in the elderly makes matters worse. Using a multi state approach, we express the effect of LEI on dementia, care need, and mortality in terms of remaining life expectancy at age 75 (rLE) and years of life lost (YLL). METHODS: A population-based random sample of beneficiaries aged 75-95 years was drawn from the largest public health insurer in Germany in 2004 and followed until 2010 (N 62,103; Mean Age +/- SD 81.5 +/- 4.8 years; Female 71.2%). We defined a five-state model (Healthy, Dementia, Care, Dementia & Care, Dead), and calculated transition-specific hazard ratios of LEI using Cox regression. The transition probabilities as well as the YLL due to LEI were estimated. RESULTS: LEI significantly increased the risk for each transition, with a maximum risk for the transition from Healthy to Care (HR: 1.70, 95% CI: 1.63-1.77) and a minimum risk for the transition from Care to Dead (HR: 1.16, 95% CI: 1.10-1.22). If the elderly had LEI-history, their age-specific mortality was generally higher and their probabilities of transient states peaked at younger ages. At age 75, initially dementia-free and care-independent elderly experiencing LEI lost about 2 years of life, of which more than 90% were life years free of dementia or care need. Dementia patients lost about one and a half year, more than 60% were free of long-term care need. CONCLUSIONS: LEI not only casts a large health burden on care need, but is also associated with cognitive decline and shortened rLE. LEI plus dementia extend the relative life time in need of care, despite generally shortening rLE. Using the composite measure YLL may help to better convey these results to the elderly, families, and health professionals. This may strengthen preventive measures as well as improve timely and rehabilitative treatment of LEI, not only in cognitive and physically intact elderly. PMID- 26758626 TI - Transcriptome profiling of Kentucky bluegrass (Poa pratensis L.) accessions in response to salt stress. AB - BACKGROUND: Kentucky bluegrass (Poa pratensis L.) is a prominent turfgrass in the cool-season regions, but it is sensitive to salt stress. Previously, a relatively salt tolerant Kentucky bluegrass accession was identified that maintained green colour under consistent salt applications. In this study, a transcriptome study between the tolerant (PI 372742) accession and a salt susceptible (PI 368233) accession was conducted, under control and salt treatments, and in shoot and root tissues. RESULTS: Sample replicates grouped tightly by tissue and treatment, and fewer differentially expressed transcripts were detected in the tolerant PI 372742 samples compared to the susceptible PI 368233 samples, and in root tissues compared to shoot tissues. A de novo assembly resulted in 388,764 transcripts, with 36,587 detected as differentially expressed. Approximately 75 % of transcripts had homology based annotations, with several differences in GO terms enriched between the PI 368233 and PI 372742 samples. Gene expression profiling identified salt-responsive gene families that were consistently down-regulated in PI 372742 and unlikely to contribute to salt tolerance in Kentucky bluegrass. Gene expression profiling also identified sets of transcripts relating to transcription factors, ion and water transport genes, and oxidation-reduction process genes with likely roles in salt tolerance. CONCLUSIONS: The transcript assembly represents the first such assembly in the highly polyploidy, facultative apomictic Kentucky bluegrass. The transcripts identified provide genetic information on how this plant responds to and tolerates salt stress in both shoot and root tissues, and can be used for further genetic testing and introgression. PMID- 26758627 TI - Education and practice gaps on atrial fibrillation and anticoagulation: a survey of cardiovascular nurses. AB - BACKGROUND: Patients' knowledge of their atrial fibrillation (AF) and anticoagulation therapy are determinants of the efficacy of thromboprophylaxis. Nurses may be well placed to provide counselling and education to patients on all aspects of anticoagulation, including self-management. It is important that nurses are well informed to provide optimal education to patients. Current practice and knowledge of cardiovascular nurses on AF and anticoagulation in the Australian and New Zealand (ANZ) context is not well reported. This study aimed to; 1) Explore the nurse's role in clinical decision making in anticoagulation in the setting of AF; 2) Describe perceived barriers and enablers to anticoagulation in AF; 3) Investigate practice patterns in the management of anticoagulation in the ANZ setting; 4) Assess cardiovascular nurses' knowledge of anticoagulation. METHODS: A paper-based survey on current practices and knowledge of AF and anticoagulation was distributed during the Australian Cardiovascular Nursing College (ACNC) Annual Scientific Meeting, February 2014. This survey was also emailed to Cardiovascular Trials Nurses throughout New South Wales, Australia and nursing members of the Cardiac Society of Australia and New Zealand (CSANZ). RESULTS: There were 41/73 (56%) respondents to the paper-based survey. A further 14 surveys were completed online via nurse members of the CSANZ, and via an investigator developed NSW cardiovascular trials nurse email distribution list. A total of 55 surveys were completed and included in analyses. Prior education levels on AF, stroke risk, anticoagulation and health behaviour modification were mixed. The CHA2DS2VASc and HAS-BLED risk stratification tools were reported to be underused by this group of clinicians. Reported key barriers to anticoagulation included; fears of patients falling, fears of poor adherence to medication taking and routine monitoring. Patient self-monitoring and self-management were reported as underutilised. ANZ cardiovascular nurses reported their key role to be counselling and advising patients on therapy regimens. Anticoagulant-drug interaction knowledge was generally poor. CONCLUSION: This study identified poor knowledge and practice in the areas of AF and anticoagulation. There is scope for improvement for cardiovascular nurses in ANZ in relation to AF and anticoagulation knowledge and practice. PMID- 26758628 TI - A Comprehensive Review on the Chemotherapeutic Potential of Piceatannol for Cancer Treatment, with Mechanistic Insights. AB - Cancer is a diverse class of diseases characterized by uncontrolled cell growth that constitutes the greatest cause of mortality and morbidity worldwide. Despite steady progress, the treatment modalities of cancer are still insufficient. Several new concepts have emerged for therapeutic intervention in malignant diseases with the goal of identifying specific targets and overcoming resistance against current cytotoxic therapies. Many studies have reported the remarkable and significant properties of dietary plant polyphenols such as curcumin, resveratrol, flavopiridol, indirubin, magnolol, piceatannol, parthenolide, epigallocatechin gallate, and cucurbitacin as anticancer agents known for their pleiotropic effects on cancer, immune cells, and inflammation. Piceatannol, an analogue and metabolite of resveratrol, is a natural stilbene commonly found in grape skins and wine. Compared to resveratrol, this molecule exhibits superior bioactivities as an inhibitor of COX-1/2 and the CSN-associated kinase. Piceatannol is thought to be a potent natural compound with many therapeutic effects, such as the prevention of hypercholesterolemia, arrhythmia, atherosclerosis, angiogenesis, and cardiovascular diseases. It also demonstrates vasorelaxation, antioxidant, and anticancer activities. This comprehensive review summarizes the current data regarding the mechanisms of action of piceatannol, its chemopreventive properties, and its possible therapeutic potential against various types of human cancer. PMID- 26758644 TI - "I used to think that they were all abnormal. And I was the normal one": conceptualizing mental health and mental health treatment under Improving Access to Psychological Therapies (IAPT). AB - BACKGROUND: Improving Access to Psychological Therapies (IAPT) was introduced in the United Kingdom in 2006 to provide more effective and efficient services to people experiencing mild to moderate mental ill health. The model represents a paradigm shift in how we provide psychological care to large populations. AIMS: We wanted to document how the IAPT program impacted on patients' understanding of their mental health, and mental health treatment. METHODS: We used Foucauldian Discourse Analysis to analyze six semi-structured research interviews with patients from one IAPT service in a major UK city. RESULTS: Participants constructed their mental health problems as individual pathologies. Constructions of mental health and of treatment evidenced the privileging of personal responsibility and social productivity over dependency on others and the state. CONCLUSIONS: Services are functioning well for some. The role of IAPT in pathologizing those who are dependent on people and services requires further commentary and action. PMID- 26758643 TI - Texture analysis in gel electrophoresis images using an integrative kernel-based approach. AB - Texture information could be used in proteomics to improve the quality of the image analysis of proteins separated on a gel. In order to evaluate the best technique to identify relevant textures, we use several different kernel-based machine learning techniques to classify proteins in 2-DE images into spot and noise. We evaluate the classification accuracy of each of these techniques with proteins extracted from ten 2-DE images of different types of tissues and different experimental conditions. We found that the best classification model was FSMKL, a data integration method using multiple kernel learning, which achieved AUROC values above 95% while using a reduced number of features. This technique allows us to increment the interpretability of the complex combinations of textures and to weight the importance of each particular feature in the final model. In particular the Inverse Difference Moment exhibited the highest discriminating power. A higher value can be associated with an homogeneous structure as this feature describes the homogeneity; the larger the value, the more symmetric. The final model is performed by the combination of different groups of textural features. Here we demonstrated the feasibility of combining different groups of textures in 2-DE image analysis for spot detection. PMID- 26758645 TI - Folate deficiency and DNA-methyltransferase inhibition modulate G-quadruplex frequency. AB - G-quadruplexes (G4) are highly stable tetra-stranded DNA secondary structures known to mediate gene regulation and to trigger genomic instability events during replication. G4 structural stability can be affected by DNA methylation and oxidation modifications; thus nutrients such as folate that have the ability to alter these processes could potentially modify the genomic occurrence of G4 elements. Hela cells were cultured in a range of folate concentrations or in the presence or absence of 5-aza-2'-deoxycytidine, a DNA-methyltransferase inhibitor. G4 structures were then quantified by immunofluorescence using an automated quantitative imaging system. G4 frequency in Hela cells and nuclei area mean were increased in 20nM folate medium compared with 2000nM folate, as well as in the presence of 5-aza-2'-deoxycytidine when compared to cells non-exposed to 5-aza-2' deoxycytidine. These changes were exacerbated when pyridostatin, a G4 stabilising ligand, was added to the culture medium. G4 intensity in Hela cells cultured in deficient folate condition with pyridostatin was highly correlated with DNA damage as measured by gammaH2AX immunofluorescence (r = 0.71). This study showed for the first time that cellular G4 balance is modifiable by low folate concentrations and that these changes may occur as a consequence of DNA hypomethylation. Although the exact mechanism by which these changes occur is unclear, these findings establish the possibility that nutrients could be utilised as a tool for sustaining genome integrity by modifying G4 frequency at a cellular level. PMID- 26758646 TI - Long-term conditions, self-management and systems of support: an exploration of health beliefs and practices within the Sikh community, Birmingham, UK. AB - OBJECTIVE: The global prevalence of non-communicable diseases (NCDs), such as diabetes mellitus and coronary heart disease, continues to rise. Internationally, people of South Asian origin (i.e. by birth or heritage) are much more likely to develop and live with NCDs compared to the general population. The South Asian diaspora population is highly heterogeneous, varying by socioeconomic status, migration history, religion and ethnicity. This article reports the findings of a study to explore the types of support accessed by Punjabi Sikhs living in Birmingham and the Black Country, UK, who were living with NCDs. DESIGN: The study sought to develop a greater understanding of past experiences of accessing support and the importance of relationships in the mobilisation of resources for self-management. It was nested within a larger programme of research which explored attitudes to prevention of chronic diseases in local communities in the region. Seventeen Punjabi Sikh men and women were recruited through purposive sampling. Narrative interviews were conducted and analysed by the research team. Sociological theories on systems of support and social relations were consulted to inform the interpretation of data. RESULTS: The study findings suggest that participants interpreted chronic disease self-management in relation to four primary systems of support: health services for disease management; multiple sources of care, including traditional Indian medicines and the Internet, for symptom management; community groups for lifestyle management; and the family for emotional and physical care. Within these systems of support, participants identified barriers and facilitators to the maintenance of a healthy lifestyle. We focus on intra-group diversity; exploring the intersection of views and experiences by age, gender, generation and caste. CONCLUSION: The findings have implications for the design and delivery of primary care and community services which support the prevention and management of NCDs in an increasingly diverse population. PMID- 26758647 TI - Photoluminescence Studies of Both the Neutral and Negatively Charged Nitrogen Vacancy Center in Diamond. AB - In this study low temperature micro-photoluminescence technology was employed to investigate effects of the irradiation and nitrogen concentration on nitrogen vacancy (NV) luminescence, with the photochromic and vibronic properties of the NV defects. Results showed that the NV luminescence was weakened due to recombination of self-interstitials created by electron irradiation in diamond and the vacancies within the structure of NV centers. For very pure diamond, the vacancies migrated the long distance to get trapped by N atoms only after sufficient high temperature annealing. As with the increase in nitrogen content, the migration distance of vacancies got smaller. The nitrogen also favored the formation of negatively charged NV centers with the donating electrons. Under the high-energy ultraviolet laser excitation, the photochromic property of the NV- center was also observed, though it was not stable. Besides, the NV centers showed very strong broad sidebands, and the vibrations involved one phonon with energy of ~42 meV and another with ~67 meV energy. PMID- 26758648 TI - Digitizing Gold Nanoparticle-Based Colorimetric Assay by Imaging and Counting Single Nanoparticles. AB - Gold colloid changes its color when the internanoparticle distance changes. On the basis of analyte-induced aggregation or disaggregation behavior of gold nanoparticles (AuNPs), versatile colorimetric assays have been developed for measuring various kinds of analytes including proteins, DNA, small molecules, and ions. Traditional read-out signals, which are usually measured by a spectrometer or naked eyes, are based on the averaged extinction properties of a bulk solution containing billions of nanoparticles. Averaged extinction property of a large amount of nanoparticles diminished the contribution from rare events when the analyte concentration was low, thus resulting in limited detection sensitivity. Instead of measuring the averaged optical property from bulk colloid, in the present work, we proposed a digital counterpart of the colorimetric assay by imaging and counting individual AuNPs. This method quantified the analyte concentration with the number percentage of large-sized AuNPs aggregates, which were digitally counted with surface plasmon resonance microscopy (SPRM), a plasmonic imaging technique recently developed by us and other groups. SPRM was able to identify rare AuNPs aggregates despite their small population and greatly improved the detection sensitivity as demonstrated by two model systems based on analyte-induced aggregation and disaggregation, respectively. Furthermore, besides plasmonic AuNPs, SPRM is also suitable for imaging and counting nonplasmonic nanomaterials such as silica and metal oxide with poor extinction properties. It is thus anticipated that the present digitized assay holds a great potential for expanding the colorimetric assay to broad categories of nonplasmonic nanoparticles. PMID- 26758649 TI - A graphene oxide/amidoxime hydrogel for enhanced uranium capture. AB - The efficient development of selective materials for the recovery of uranium from nuclear waste and seawater is necessary for their potential application in nuclear fuel and the mitigation of nuclear pollution. In this work, a graphene oxide/amidoxime hydrogel (AGH) exhibits a promising adsorption performance for uranium from various aqueous solutions, including simulated seawater. We show high adsorption capacities (Qm = 398.4 mg g(-1)) and high % removals at ppm or ppb levels in aqueous solutions for uranium species. In the presence of high concentrations of competitive ions such as Mg(2+), Ca(2+), Ba(2+) and Sr(2+), AGH displays an enhanced selectivity for uranium. For low uranium concentrations in simulated seawater, AGH binds uranium efficiently and selectively. The results presented here reveal that the AGH is a potential adsorbent for remediating nuclear industrial effluent and adsorbing uranium from seawater. PMID- 26758650 TI - Summer mortalities and detection of ostreid herpesvirus microvariant in Pacific oyster Crassostrea gigas in Sweden and Norway. AB - The Pacific oyster Crassostrea gigas has recently expanded its range in Scandinavia. The expansion is presumably a result of northwards larval drift. Massive settlements were recorded in many areas along the Swedish west coast and southern Norway in 2013 and 2014. After the spawning season in 2014, the temperature of the surface water peaked at 24-26 degrees C. After this period, high and sudden mortalities occurred in a Swedish hatchery and in wild populations along the Swedish west coast and south coast of Norway. Surveys and collected data showed that mortalities mainly occurred during 3 wk in September. All size classes were affected, and affected populations displayed a patchy distribution with heavily affected and unaffected populations in close proximity. Flat oysters Ostrea edulis and blue mussels Mytilus edulis were unaffected. Ostreid herpesvirus (OsHV) was detected in moribund Pacific oyster spat as well as in surviving adults. The virus was identified as OsHV-1 MUvar. This is the first detection of this variant in Scandinavia, showing that OsHV-1 MUvar is present in areas with recent establishments of Pacific oysters, and where there is no aquaculture of this species. PMID- 26758651 TI - Germ-free sea bass Dicentrarchus labrax larval model: a valuable tool in the study of host-microbe interactions. AB - A thorough understanding of host-microbe interactions is crucial for more efficient disease management in the marine larviculture industry. As demonstrated in terrestrial animal research, gnotobiotic systems (involving animals cultured in germ-free conditions or inoculated with known microorganisms) are excellent tools to extend our understanding of the mechanisms involved in host-microbe interactions and allow the evaluation of new treatments for diseases. In this study, we introduce a germ-free European sea bass Dicentrarchus labrax larval model, independent of the continuous addition of antimicrobial agents. This model has an experimental set-up that allows addition of live feed to the larvae without compromising the germ-free status. This model will facilitate and render aquaculture research more effective in terms of mitigation fish larval diseases. PMID- 26758652 TI - Sublethal concentrations of ichthyotoxic alga Prymnesium parvum affect rainbow trout susceptibility to viral haemorrhagic septicaemia virus. AB - Ichthyotoxic algal blooms are normally considered a threat to maricultured fish only when blooms reach lethal cell concentrations. The degree to which sublethal algal concentrations challenge the health of the fish during blooms is practically unknown. In this study, we analysed whether sublethal concentrations of the ichthyotoxic alga Prymnesium parvum affect the susceptibility of rainbow trout Oncorhynchus mykiss to viral haemorrhagic septicaemia virus (VHSV). During exposure to sublethal algal concentrations, the fish increased production of mucus on their gills. When fish were exposed to the algae for 12 h prior to the addition of virus, a marginal decrease in the susceptibility to VHSV was observed compared to fish exposed to VHSV without algae. If virus and algae were added simultaneously, inclusion of the algae increased mortality by 50% compared to fish exposed to virus only, depending on the experimental setup. We concluded that depending on the local exposure conditions, sublethal concentrations of P. parvum could affect susceptibility of fish to infectious agents such as VHSV. PMID- 26758653 TI - Development of monoclonal antibodies against polar filaments and spore valves of Myxobolus honghuensis (Myxosporea: Bivalvulida). AB - Myxobolus honghuensis infects the pharynx of allogynogenetic gibel carp Carassius auratus gibelio (Bloch) and can cause high mortality. Only morphology-based diagnostic methods are currently available for clinical samples, but these methods are laborious and have low efficiency of detection. To overcome this problem, we designed a more sensitive diagnostic method. Two monoclonal antibodies (MAbs 1C7 and 3B7) were prepared by immunizing mice with soluble protein from sonicated M. honghuensis spores. Immunofluorescence analysis revealed that MAb 1C7 specifically reacts with polar filaments from spores, whereas MAb 3B7 identified protein localized on the spore valves. The isotypes of MAb 1C7 and MAb 3B7 were IgM and IgG1, respectively. Results of Western blot analysis revealed that MAb 1C7 recognized 2 prominent protein bands with molecular weights of 130 and 180 kDa, while MAb 3B7 recognized a protein band of 28 kDa. Thus, in this study we have developed 2 MAbs that have the potential for efficient detection of M. honghuensis. Moreover, identification of MAb 1C7 and MAb 3B7 allows for further studies of the functions and biochemical composition of polar filament and spore surface antigens. PMID- 26758654 TI - Genotoxic effects and gene expression changes in larval zebrafish after exposure to ZnCl2 and ZnO nanoparticles. AB - Engineered nanoparticles (NPs) can potentially generate adverse effects at the tissue, organ, cellular, subcellular, DNA, and protein levels due to their unique physico-chemical properties. Dissoluble NPs (e.g. nZnO) can be toxic in aquatic organisms. We compared effects of nZnO and corresponding concentrations of released Zn(II) by water-soluble ZnCl(2) on larval zebrafish Danio rerio (72 h post fertilization) by analyzing changes in expression levels of stress-related genes (p53, rad51, mt2) by qRT-PCR. Additionally, genotoxicity of nZnO and Zn(II) was assessed. The lethal concentrations for 50% mortality (LC(50)) in larval zebrafish exposed for 96 h to 0 to 70 mg l(-1) nZnO and Zn(II) were 21.37 +/- 1.81 mg l(-1) (95% CI) and 4.66 +/- 0.11 mg l(-1), respectively. A concentration dependent increase in DNA strand breaks was detected in cells from larvae exposed (96 h) to nZnO and Zn(II). DNA damage was higher in Zn(II)- than nZnO-exposed larvae. Induction of stress-related genes in larvae was complex and was not directly related to nZnO and Zn(II) concentrations, although there was significant induction in the mt2 gene of larvae exposed to Zn(II) and nZnO relative to controls. mt2 induction of 20.5 +/- 1.9-fold and 2.5 +/- 0.8-fold change (mean +/- SEM) was observed in larvae at the highest Zn(II) and nZnO concentrations (3 and 6 mg l(-1)), respectively. The results suggest that toxicity associated with nZnO is primarily due to the release of Zn(II). PMID- 26758655 TI - Initial characterization of novel beaked whale morbillivirus in Hawaiian cetaceans. AB - Cetacean morbillivirus (CeMV) is a causative factor in epizootics that have resulted in thousands of deaths throughout the Atlantic and Mediterranean since 1987, but less is known of its presence and significance in the Pacific. The first case of CeMV reported in Hawai'i was in a Longman's beaked whale that stranded in 2010. The initial CeMV sequence from this individual indicated the possibility of a novel strain. To address this, archived samples from cetaceans that stranded in Hawai'i between 1997 and 2014 were screened for CeMV. The beaked whale morbillivirus (BWMV) was detected in 15 individuals representing 12 different species (24% of Code 1 and 2 stranded cetaceans). The earliest detected case was a humpback whale that stranded in 1998. Sequence comparisons of a 2.2 kb sequence spanning the phosphoprotein (P) and nucleocapsid (N) genes strongly suggest that the BWMV represents a novel strain of CeMV present in Hawai'i and the Central Pacific. In contrast to recently reported isolates from Brazil and Australia that may represent a distinct clade, BWMV appears to be more closely related to known strains of CeMV (dolphin morbillivirus; porpoise morbillivirus; and pilot whale morbillivirus). Detection rates with repeat sampling of positive lymph nodes were between 2 and 61%, illustrating the extreme heterogeneity that can occur in affected tissues. Taken together, these results suggest that BWMV may be common and established in Hawaiian cetacean populations. BWMV will be important for understanding CeMV and health threats in the relatively understudied cetaceans of the Pacific. PMID- 26758656 TI - Lacaziosis-like disease in Tursiops truncatus from Brazil: a histopathological and immunohistochemical approach. AB - Cetacean lacaziosis-like disease or lobomycosis-like disease (LLD) is a chronic skin condition caused by a non-cultivable yeast of the order Onygenales, which also includes Lacazia loboi, as well as Paracoccidioides brasiliensis and P. lutzii, respectively responsible for lacaziosis and paracoccidioidomycosis in humans. Complete identification and phylogenetic classification of the LLD etiological agent still needs to be elucidated, but preliminary phylogenetic analyses have shown a closer relationship of the LLD agent to Paracoccidioides spp. than to L. loboi. Cases of LLD in South American cetaceans based on photographic identification have been reported; however, to date, only 3 histologically confirmed cases of LLD have been described. We evaluated multiple tissue samples from 4 Tursiops truncatus stranded in the states of Santa Catarina (n = 3) and Rio Grande do Sul (n = 1), southern Brazil. Macroscopically, all animals presented lesions consistent with LLD. Hematoxylin-eosin, periodic acid Schiff, Grocott's methenamine silver, and Mayer's mucicarmin stains were used for histological evaluation. Microscopically, numerous refractile yeasts (4-9 um in diameter) were observed in skin samples (4/4), and for the first time in dolphins, also in a skeletal muscle abscess (1/4). Immunohistochemistry using anti-P. brasiliensis glycoprotein gp43 as a primary antibody, which is known to cross-react with L. loboi and the LLD agent, was performed and results were positive in all 4 cases. We describe 3 new cases of LLD in cetaceans based on histopathology and immunohistochemistry. This is the first report of LLD in the muscle of cetaceans. PMID- 26758657 TI - Fluorescent microbead-based immunoassay for anti-Erysipelothrix rhusiopathiae antibody detection in cetaceans. AB - A fluorescent microbead-based immunoassay (FMIA) for detection of anti Erysipelothrix rhusiopathiae antibodies in pigs was adapted for use in cetaceans. The FMIA was validated and adjusted using serum samples from 10 vaccinated captive bottlenose dolphins Tursiops truncatus collected between 1 and 13 mo after immunization. The technique was then used to analyze specimens from 15 free ranging cetaceans stranded alive on the Valencian Mediterranean coast between 2006 and 2014: 11 striped dolphins Stenella coeruleoalba, 3 Risso's dolphins Grampus griseus and 1 bottlenose dolphin Tursiops truncatus. One of these wild animals was confirmed to have died from E. rhusiopathiae septicemia, but no anti E. rhusiopathiae antibodies were detected in its serum, pericardial fluid or milk samples. Another free-ranging individual, which lacked any signs or lesions that might be indicative of E. rhusiopathiae infection, showed high fluorescence intensity similar to that measured in captive dolphins at 6-13 mo after vaccination. These results suggest that this animal underwent an E. rhusiopathiae infection several months before stranding. The findings in the present study suggest that FMIA can be useful for detecting anti-E. rhusiopathiae antibodies in cetaceans, and its application to free-ranging animals is particularly interesting because of the great value of these specimens. Furthermore, the FMIA can be multiplexed to allow the determination of up to 100 analytes per sample in a single well, thereby reducing the cost, time and sample volume needed. PMID- 26758658 TI - Physiological responses of Brazilian amphibians to an enzootic infection of the chytrid fungus Batrachochytrium dendrobatidis. AB - Pathophysiological effects of clinical chytridiomycosis in amphibians include disorders of cutaneous osmoregulation and disruption of the ability to rehydrate, which can lead to decreased host fitness or mortality. Less attention has been given to physiological responses of hosts where enzootic infections of Batrachochytrium dendrobatidis (Bd) do not cause apparent population declines in the wild. Here, we experimentally tested whether an enzootic strain of Bd causes significant mortality and alters host water balance (evaporative water loss, EWL; skin resistance, R(s); and water uptake, WU) in individuals of 3 Brazilian amphibian species (Dendropsophus minutus, n = 19; Ischnocnema parva, n = 17; Brachycephalus pitanga, n = 15). Infections with enzootic Bd caused no significant mortality, but we found an increase in R(s) in 1 host species concomitant with a reduction in EWL. These results suggest that enzootic Bd infections can indeed cause sub-lethal effects that could lead to reduction of host fitness in Brazilian frogs and that these effects vary among species. Thus, our findings underscore the need for further assessment of physiological responses to Bd infections in different host species, even in cases of sub clinical chytridiomycosis and long-term enzootic infections in natural populations. PMID- 26758659 TI - Virus-associated papillomatous skin lesions in a giant guitarfish Rhynchobatus djiddensis: a case report. AB - Although elasmobranch species are increasingly displayed in public aquaria, knowledge of disease in wild and captive elasmobranchs, as well as the agents involved, remains limited, and descriptions are often incomplete. This report describes papillomatous skin lesions in a juvenile giant guitarfish Rhynchobatus djiddensis associated with intranuclear viral particles. Skin biopsies were collected from multiple, friable, raised, villonodular skin lesions affecting pigmented and non-pigmented skin of the caudal fin and ventrum, respectively. Microscopic examination revealed papillary proliferation of the epidermis, with widespread marked karyomegaly of squamous epithelial cells. In approximately 75% of nuclei, chromatin was marginated by one to multiple, large, amphophilic inclusions. Large numbers of unencapsulated, 75 nm, icosahedral viral particles were observed to form large arrays in affected nuclei using transmission electron microscopy. Based on intranuclear location, particle size and morphology, a consensus nested-PCR for adenovirus polymerase was attempted. However, no adenoviral gene sequence was amplified. The nature of the involved virus remains unknown and an ongoing area of investigation. Lesions regressed completely over a 6 mo period, during which time the animal showed no signs of systemic illness, and there has been no recrudescence for 6 mo following resolution. Two cohorts of similar age and in close contact with the case animal were unaffected. PMID- 26758660 TI - Microfluidics and microbial engineering. AB - The combination of microbial engineering and microfluidics is synergistic in nature. For example, microfluidics is benefiting from the outcome of microbial engineering and many reported point-of-care microfluidic devices employ engineered microbes as functional parts for the microsystems. In addition, microbial engineering is facilitated by various microfluidic techniques, due to their inherent strength in high-throughput screening and miniaturization. In this review article, we firstly examine the applications of engineered microbes for toxicity detection, biosensing, and motion generation in microfluidic platforms. Secondly, we look into how microfluidic technologies facilitate the upstream and downstream processes of microbial engineering, including DNA recombination, transformation, target microbe selection, mutant characterization, and microbial function analysis. Thirdly, we highlight an emerging concept in microbial engineering, namely, microbial consortium engineering, where the behavior of a multicultural microbial community rather than that of a single cell/species is delineated. Integrating the disciplines of microfluidics and microbial engineering opens up many new opportunities, for example in diagnostics, engineering of microbial motors, development of portable devices for genetics, high throughput characterization of genetic mutants, isolation and identification of rare/unculturable microbial species, single-cell analysis with high spatio temporal resolution, and exploration of natural microbial communities. PMID- 26758661 TI - Crystallization of a perovskite film for higher performance solar cells by controlling water concentration in methyl ammonium iodide precursor solution. AB - An optimal small amount of water added into methyl ammonium iodide (MAI) solution in isopropyl alcohol (IPA) helps perovskite crystallization and leads to larger grain size from sequential deposition of perovskite films. The concentration of water was varied from 1% to 7% (vol% of IPA) in MAI solution and optical absorption, crystallization, morphology of perovskite films and their photovoltaic performance were studied in perovskite solar cells. 5% by volume was found to lead to preferential crystallization in the (110) plane with grain size about three times that of perovskite films prepared without adding water into the MAI solution. The optimal water concentration of 5% by volume in the MAI solution led to average perovskite grain size of ~600 nm and solar cell efficiency of 12.42% at forward scan with a rate of 0.5 V s(-1). Device performance decreases after increasing water concentration beyond 5% in the MAI solution due to formation of the PbI2 phase. Transient photocurrent and photovoltage measurements show the shortest charge transport time at 0.99 MUs and the longest charge carrier life time at 13.6 MUs for perovskite films prepared from 5% water in MAI solution, which improved perovskite solar cell efficiency from 9.04% to 12.42%. PMID- 26758663 TI - The Hippo Pathway as Drug Targets in Cancer Therapy and Regenerative Medicine. AB - Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ) co-operate with numerous transcription factors to regulate gene transcriptions. YAP1 and TAZ are negatively regulated by the tumor suppressive Hippo pathway. In human cancers, the Hippo pathway is frequently deregulated and YAP1 and TAZ escape the inhibition by the Hippo pathway. The upregulation of YAP1 and TAZ induces epithelial-mesenchymal transition and increases drug resistance in cancer cells. TAZ is implicated in cancer stemness. In consequence cancers with hyperactive YAP1 and TAZ are associated with poor clinical prognosis. Inhibitors of YAP1 and TAZ are reasoned to be beneficial in cancer therapy. On the other hand, since YAP1 and TAZ play important roles in the regulation of various tissue stem cells and in tissue repair, activators of YAP1 and TAZ are useful in the regenerative medicine. We discuss the potential application of inhibitors and activators of YAP1 and TAZ in human diseases and review the progress of drug screenings to search for them. PMID- 26758664 TI - Characterization and Management of Cutaneous Side Effects Related to the Immunosuppressive Treatment in Solid Organ Recipients. AB - Patients who underwent solid organ transplantation frequently suffer from different skin diseases, as consequence of the immunosuppressive treatment. Specific cutaneous side effects such as acne, hypertricosis or other pilosebaceous unit disorders, gingival hyperplasia, purpura or teleangiectasies are commonly associated to immunosuppressive medications. The majority of these conditions are benign, but the aesthetic concern may affect the patient is quality of life and reduce the adherence to the therapy. Moreover, solid organ transplant recipients frequently develop skin infections, as an indirect consequence of the immunosuppressive regimens. Herpes virus reactivation is more common few months after transplantation, whereas when the immunosuppression is reduced, the skin infections are mainly represented by human papilloma virus infections and localized mycosis. Bacterial infections are relatively rare. Long term consequences of the immunosuppressive therapy are represented by development of precancerosis and skin cancers, with a risk that enhances over the time and a significant impact on patient survival. The aim of this paper is to provide an overview of the data published in the recent literature about this topic, in order to characterize the main skin disorders associated to the use of immunosuppressive drugs in solid organ recipients, giving information about their risk, epidemiology, clinical manifestations and management. PMID- 26758662 TI - Ethanol Disinhibits Dorsolateral Striatal Medium Spiny Neurons Through Activation of A Presynaptic Delta Opioid Receptor. AB - The dorsolateral striatum mediates habit formation, which is expedited by exposure to alcohol. Across species, alcohol exposure disinhibits the DLS by dampening GABAergic transmission onto this structure's principal medium spiny projection neurons (MSNs), providing a potential mechanistic basis for habitual alcohol drinking. However, the molecular and circuit components underlying this disinhibition remain unknown. To examine this, we used a combination of whole cell patch-clamp recordings and optogenetics to demonstrate that ethanol potently depresses both MSN- and fast-spiking interneuron (FSI)-MSN GABAergic synaptic transmission in the DLS. Concentrating on the powerfully inhibitory FSI-MSN synapse, we further show that acute exposure of ethanol (50 mM) to striatal slices activates delta opioid receptors that reside on FSI axon terminals and negatively couple to adenylyl cyclase to induce a long-term depression of GABA release onto both direct and indirect pathway MSNs. These findings elucidate a mechanism through which ethanol may globally disinhibit the DLS. PMID- 26758665 TI - Pazopanib in Renal Cell Carcinoma Dialysis Patients: A Mini-Review and a Case Report. AB - BACKGROUND: Sporadic data are available about pazopanib use in patients with metastatic renal cell carcinoma (mRCC) undergoing dialysis and no systematic review has been previously performed about this issue. OBJECTIVE: The objective of the present mini-review is to provide an overview of clinical outcomes of pazopanib in this population, in order to support the clinical oncologist for the treatment choice and management. RESULTS: All the literature ever published about mRCC dialysis patients receiving pazopanib, until August 2015, was evaluated: only two case series emerged from our search and one more patient from our department was also included, with a total of 11 mRCC dialysis patients overall. Moreover, we described our case of intrapatient dose titration of pazopanib during dialysis. CONCLUSION: The continued treatment schedule, the short half life, the predominantly hepatic metabolism, the wide possibility of dose modulation, the favorable tolerability profile and the similar efficacy respect to sunitinib represent factors in favor of pazopanib as first line mRCC treatment in dialysis patients. The knowledge and the good management of toxicity during pazopanib treatment can lead, also in dialysis patients, to the best and longest application of the drug, taking into account the concept of a dose escalation guided by toxicity as a marker of efficacy. The review, together with our single case report, confirmed the efficacy, the good tolerability and the maneuverability of pazopanib treatment in mRCC patients undergoing dialysis. PMID- 26758666 TI - Current Targets for Primary Sclerosing Cholangitis. AB - Primary sclerosing cholangitis (PSC) is a biliary disease characterized by liver inflammation and death of cholangiocytes which, in turn, drive to fibrosis, cirrhosis and functional alterations of the liver. PSC is also associated with an increased risk of developing cholangiocarcinoma. To date, the etiopathogenesis of PSC is still not completely understood, although a genetic predisposition in association to environmental factors contribute to immune-mediated liver damage. The lack of such knowledge is responsible for the failure of most available therapies. At this time, many studies are evaluating potential approaches that could have a positive impact on the progression of the disease. This review aims to provide a summary of present and past therapeutic approaches for PSC. PMID- 26758667 TI - Natural Polyphenols and their Synthetic Analogs as Emerging Anticancer Agents. AB - Polyphenols are a structural class of natural and synthetic organic chemicals which contain phenol units. Numerous epidemiological, preclinical and clinical studies have strongly supported their benefical effects for human health. Polyphenols group include molecules of utterly different complexity grades, ranging from simple molecules to highly polymerized structures. They are classified into: Phenolic acids, Flavonoids, Lignans and the less common Stilbenes. This work first intends to review the current studies on classification, chemical composition and metabolism of polyphenols. Then, we have reported cancer preventive and treatment effects of polyphenols, especially focused in the green tea polyphenol (GTP) (-)-Epigallocatechin-3-gallate (EGCG). Polyphenols such as EGCG and their synthetic analogs interfere in carcinogenesis by modulating and regulating multiple signaling pathways and transcription factors, membrane-associated receptor tyrosine kinases (RTKs), fatty acid metabolism and lipid rafts or methylation together with other emerging targets such as proteasome, telomerase and cancer stem cells. Here, we have reviewed several potential molecular targets of polyphenols (mainly EGCG and EGCG analogs) and their anticancer effects in cellular and animal models of different human carcinomas and we have also listed Phases I and II clinical trials conducted to study the antitumor properties of GTPs. PMID- 26758668 TI - The Emerging Role of the Cannabinoid Receptor Family in Peripheral and Neuro immune Interactions. AB - The classical endogenous cannabinoid (CB) system is composed of the endocannabinoid signalling molecules, 2-arachidonoyl glycerol (2-AG) and anandamide (AEA) and their G-protein coupled receptors (GPCR), CB1 and CB2 which together constitutes the endocannabinoid system (ECS). However, putative, novel lipid-sensing CB receptors have recently been identified, including the orphan GPR55 and GPR18 receptors that are regulated by cannabinoid-like molecules and interact with CB system. CB receptors and associated orphan GPCRs are expressed at high levels in the immune and/or central nervous systems (CNS) and regulate a number of neurophysiological processes, including key events involved in neuroinflammation. As such, these receptors have been identified as emerging therapeutic targets for a number of brain disorders in which neuroinflammation is a key feature, including multiple sclerosis (MS) and Alzheimer's disease (AD). This review will consider the role of the wider cannabinoid receptor superfamily in mediating immune function with a focus on the immune processes that contribute to neuroinflammatory conditions. PMID- 26758669 TI - Structure-Based Drug Discovery Accelerated by Many-Core Devices. AB - Computer-aided design is one of the critical components of modern drug discovery. Drug development is routinely streamlined using computational approaches to improve hit identification and lead selection, enhance bioavailability, and reduce toxicity. A mounting body of genomic knowledge accumulated during the last decade or so presents great opportunities for pharmaceutical research. However, new challenges also arose because processing this large volume of data demands unprecedented computing resources. On the other hand, the state-of-the-art heterogeneous systems deliver petaflops of peak performance to accelerate scientific discovery. In this communication, we review modern parallel accelerator architectures, mainly focusing on Intel Xeon Phi many-core devices. Xeon Phi is a relatively new platform that features tens of computing cores with hundreds of threads offering massively parallel capabilities for a broad range of application. We also discuss common parallel programming frameworks targeted to this accelerator, including OpenMP, OpenCL, MPI and HPX. Recent advances in code development for many-core devices are described to demonstrate the advantages of heterogeneous implementations over the traditional, serial computing. Finally, we highlight selected algorithms, eFindSite, a ligand binding site predictor, a force field for bio-molecular simulations, and BUDE, a structure-based virtual screening engine, to demonstrate how modern drug discovery is accelerated by heterogeneous systems equipped with parallel computing devices. PMID- 26758670 TI - Recent Advances in Protein-Protein Docking. AB - Protein-protein interactions (PPIs) play important roles in a variety of biological processes, and many PPIs have been regarded as biologically compelling targets for drug discovery. Extensive efforts have been made to develop feasible proteinprotein docking approaches to study PPIs in silico. Most of these approaches are composed of two stages: sampling and scoring. Sampling is used to generate a number of plausible protein-protein binding conformations and scoring can rank all those conformations. Due to large and flexible binding interface of PPI, determination of the near native structures is computationally expensive, and therefore computational efficiency is the most challenging issue in protein protein docking. Here, we have reviewed the basic concepts and implementations of the sampling, scoring and acceleration algorithms in some established docking programs, and the limitations of these algorithms have been discussed. Then, some suggestions to the future directions for sampling, scoring and acceleration algorithms have been proposed. This review is expected to provide a better understanding of protein-protein docking and give some clues for the optimization and improvement of available approaches. PMID- 26758671 TI - AMPK As A Target in Rare Diseases. AB - The AMP-activated protein kinase (AMPK) has emerged as an important sensor of signals that control cellular energy balance in all eukaryotes. AMPK is also involved in fatty acid oxidation, glucose transport, antioxidant defense, mitochondrial biogenesis and the modulation of inflammatory processes. The numerous roles of AMPK in cell physiological and pathological states justified the notable increase in the number of publications in previous years, with almost 1500 scientific articles relative to this kinase in 2014. Due to its role in maintaining energy balance, a dysfunction in AMPK signalling pathway may result in perturbations at the systemic level that contribute to the development of many disease conditions. Among them, more than 7000 poorly-known rare diseases are particularly of social and scientific interest because they are usually chronically debilitating or even lifethreatening and lack effective and safe treatment. Several authors have demonstrated AMPK alterations and the beneficial effect of treatments with drugs regulating AMPK activity in some of these low prevalence pathologies. Among these rare diseases in which AMPK can play an important pathological role are mitochondrial disorders, muscular dystrophies, cardiovascular diseases, neurodegenerative pathologies, or even some types of cancer for the importance of AMPK as a suppressor of cell proliferation. This review focuses on current knowledge about the pathophysiological roles of AMPK and future approaches as therapeutic targeting in rare diseases. PMID- 26758672 TI - Fractionated stem cell infusions for patients with plasma cell myeloma undergoing autologous hematopoietic cell transplantation. AB - We conducted a phase II trial investigating the impact of fractionated hematopoietic cell infusions on engraftment kinetics and symptom burden in patients with plasma cell myeloma (PCM) undergoing autologous hematopoietic cell transplant (AHCT). We hypothesized that multiple hematopoietic cell infusions would reduce duration of neutropenia and enhance immune recovery resulting in a better tolerated procedure. Twenty-six patients received high-dose melphalan followed by multiple cell infusions (Days 0, +2, +4, +6) and were compared to PCM patients (N = 77) who received high-dose melphalan and a single infusion (Day 0) (concurrent control group). The primary endpoint was number of days with ANC <500K/mcL. Symptom burden was assessed using the MSK-modified MD Anderson Symptom Inventory. Median duration of neutropenia was similar in study (4 days, range 3 5) and control patients (4 days, range 3-9) (p = 0.654). There was no significant difference in the number of red cell or platelet transfusions, days of fever, diarrhea, antibiotics, number of documented infections, or length of admission. Symptom burden surveys showed that AHCT was well-tolerated in both study and control patients. We conclude that fractionated stem cell infusions following high-dose melphalan do not enhance engraftment kinetics or significantly alter patients' clinical course following AHCT in PCM. PMID- 26758674 TI - Ultrafast structural flattening motion in photoinduced excited state dynamics of a bis(diimine) copper(I) complex. AB - The ultrafast photoinduced structural change dynamics of a prototypical Cu(I) complex, namely, [Cu(dmp)2](+) (dmp = 2,9-dimethyl-1,10-phenanthroline), is investigated based on the theoretical analysis of static and dynamical calculations at the all-atomic level. This work mainly focuses on the intriguing structural flattening features of [Cu(dmp)2](+) occurring in the metal-to-ligand charge transfer singlet excited state ((1)MLCT) on the sub-picosecond timescale. Our estimated time constant (~ 675 fs) of this "flattening" motion is in good agreement with recent experimental values. The full-dimensional excited-state nonadiabatic dynamic simulation provides a direct view of the ultrafast photoinduced events of [Cu(dmp)2](+), especially, the structural flattening mechanism on the S1 state. Several molecular motions (such as Cu-N stretching, the motion of the substituted groups etc.) with distinguishable time scales are involved in the flattening dynamics. The Fourier transformation of the time dependent oscillation of the Cu-N bond and the N-Cu-N bond angle provides consistent conclusions with the experimental spectrum analysis. These dynamics details imply that various nuclear motions are strongly coupled in the high dimensional excited-state potential energy surface responsible for the geometrical evolution of [Cu(dmp)2](+). This work provides us a unique fundamental understanding of the ultrafast photoinduced excited-state nonadiabatic process of Cu(I) complexes and their derivatives, which should have potential impacts on various research fields, such as photo-catalysts, dye sensitized solar cells (DSSCs), and organic light emitting diodes (OLEDs). PMID- 26758673 TI - The training-injury prevention paradox: should athletes be training smarter and harder? AB - BACKGROUND: There is dogma that higher training load causes higher injury rates. However, there is also evidence that training has a protective effect against injury. For example, team sport athletes who performed more than 18 weeks of training before sustaining their initial injuries were at reduced risk of sustaining a subsequent injury, while high chronic workloads have been shown to decrease the risk of injury. Second, across a wide range of sports, well developed physical qualities are associated with a reduced risk of injury. Clearly, for athletes to develop the physical capacities required to provide a protective effect against injury, they must be prepared to train hard. Finally, there is also evidence that under-training may increase injury risk. Collectively, these results emphasise that reductions in workloads may not always be the best approach to protect against injury. MAIN THESIS: This paper describes the 'Training-Injury Prevention Paradox' model; a phenomenon whereby athletes accustomed to high training loads have fewer injuries than athletes training at lower workloads. The Model is based on evidence that non-contact injuries are not caused by training per se, but more likely by an inappropriate training programme. Excessive and rapid increases in training loads are likely responsible for a large proportion of non-contact, soft-tissue injuries. If training load is an important determinant of injury, it must be accurately measured up to twice daily and over periods of weeks and months (a season). This paper outlines ways of monitoring training load ('internal' and 'external' loads) and suggests capturing both recent ('acute') training loads and more medium-term ('chronic') training loads to best capture the player's training burden. I describe the critical variable-acute:chronic workload ratio-as a best practice predictor of training-related injuries. This provides the foundation for interventions to reduce players risk, and thus, time-loss injuries. SUMMARY: The appropriately graded prescription of high training loads should improve players' fitness, which in turn may protect against injury, ultimately leading to (1) greater physical outputs and resilience in competition, and (2) a greater proportion of the squad available for selection each week. PMID- 26758675 TI - Aging and the Effects of Exploratory Behavior on Spatial Memory. AB - The present research examined the effect of encoding from multiple viewpoints on scene recall in a group of younger (18-22 years) and older (65-80 years) adults. Participants completed a visual search task, during which they were given the opportunity to examine a room using two sets of windows that partitioned the room differently. Their choice of window set was recorded, to determine whether an association between these choices and spatial memory performance existed. Subsequently, participants were tested for spatial memory of the domain in which the search task was completed. Relative to younger adults, older adults demonstrated an increased tendency to use a single set of windows as well as decreased spatial memory for the domain. Window-set usage was associated with spatial memory, such that older adults who relied more heavily on a single set of windows also had better performance on the spatial memory task. These findings suggest that, in older adults, moderation in exploratory behavior may have a positive effect on memory for the domain of exploration. PMID- 26758676 TI - Exercise capacity and biological age. PMID- 26758678 TI - Control of the composition of Pt-Ni electrocatalysts in surfactant-free synthesis using neat N-formylpiperidine. AB - This paper describes the facile and surfactant-free synthesis of faceted Pt-Ni alloy nanoparticle electrocatalysts using neat N-formylpiperidine as a new type of solvent. Unlike the widely-used colloidal synthesis based on long-carbon chain surfactants, nanoparticles made in neat N-formylpiperidine possess a directly accessible surface for electrocatalytic reactions, making it a very attractive alternative solvent. The area-specific oxygen reduction reaction (ORR) activity is much higher than the commercial Pt/C catalyst reference and reaches a maximum of 1.12 mA cm(-2) for the Pt-Ni alloy nanoparticles. We observed that the freshly formed Pt-Ni alloy could have controllable bulk and near surface compositions under the same initial reaction conditions and precursor ratio. The change in the composition could be attributed to the effect of CO on the formation of uniform nuclei at the initial stage, and a different deposition rate between Pt and Ni metals during the growth. The well-defined Pt-Ni nanoparticle catalysts show strong composition-dependent catalytic behavior in ORR, highlighting the important role of controlling the growth kinetics in the preparation of active Pt Ni ORR catalysts. PMID- 26758677 TI - Inflammatory response to surgical trauma in patients with minilaparotomy cholecystectomy versus laparoscopic cholecystectomy: a randomised multicentre study. AB - OBJECTIVE: The aim of the study was to evaluate the inflammatory response to surgical trauma in minilaparotomy cholecystectomy (MC) compared to laparoscopic cholecystectomy (LC). Assessment of inflammatory response to surgical trauma in MC has not been addressed properly. Therefore, we investigated five interleukins (IL) and C-reactive protein (CRP) in MC versus LC group in a prospective randomised trial. METHODS: Initially, 106 patients with non-complicated symptomatic gallstone disease were randomised into MC (n = 56) or LC (n = 50) groups. Plasma levels of five interleukins (IL-1beta, IL-1ra, IL-6, IL-8, IL-10) and hs-CRP were measured at three time points; before operation (PRE), immediately after operation (POP1) and six hours after operation (POP2). The primary end-point of the study was to compare the plasma levels of five interleukins and CRP in LC versus MC group. RESULTS: The demographic variables and the surgical data were similar in the study groups. The patients in the MC group had higher elevation of the CRP mean values post-operatively (p = 0.01). However, the patients in the MC group had higher elevation of the IL-1ra mean values post-operatively, the mean pre-/post-operative IL-1ra values being 299/614 pg/ml in the MC group versus 379/439 pg/ml in the LC group (p = 0.003). There was no statistical significance in IL-6 mean values between the MC and LC groups pre- and post-operatively (POP1). However, the patients in the MC group had higher IL 6 mean values six hours post-operatively (POP2), the mean IL-6 values being 27.6 pg/ml in the MC group versus 14.8 pg/ml in the LC group (p = 0.037). In addition, the patients in the MC group had higher elevation of the IL-6 mean values post operatively, the mean pre-/post-operative IL-6 values being 4.1/27.6 pg/ml in the MC group versus 3.8/14.8 pg/ml in the LC group (p = 0.04). There was no statistical significance in IL-8, IL-10, and IL-1beta mean values between the MC and LC groups pre- and post-operatively. CONCLUSION: Our results suggest that the inflammatory response in MC versus LC groups was similar based on the IL-8, IL 10, and IL-1beta values. A new finding with possible clinical relevance in the present work is higher relative elevation of the IL-1ra and IL-6 mean values post operatively in the MC group. PMID- 26758679 TI - Exposure to Polycyclic Aromatic Hydrocarbons, Plasma Cytokines, and Heart Rate Variability. AB - Epidemiological studies have suggested associations between polycyclic aromatic hydrocarbons (PAHs) and heart rate variability (HRV). However, the roles of plasma cytokines in these associations are limited. In discovery stage of this study, we used Human Cytokine Antibody Arrays to examine differences in the concentrations of 280 plasma cytokines between 8 coke-oven workers and 16 community residents. We identified 19 cytokines with significant different expression (fold change >=2 or <=-2, and q-value <5%) between exposed workers and controls. 4 cytokines were selected to validate in 489 coke-oven workers by enzyme-linked immunosorbent assays in validation stage. We found OH-PAHs were inversely associated with brain-derived neurotrophic factor (BDNF) (p < 0.05), and interquartile range (IQR) increases in OH-PAHs were associated with >16% BDNF decreases. Additionally, OH-PAHs were positively associated with activated leukocyte cell adhesion molecule (ALCAM) and C-reactive protein (CRP) (p < 0.05), and IQR increases in OH-PAHs were associated with >20% increases in CRP. We also found significant associations between these cytokines and HRV (p < 0.05), and IQR increases in BDNF and CRP were associated with >8% decreases in HRV. Our results indicated PAH exposure was associated with plasma cytokines, and higher cytokines were associated with decreased HRV, but additional human and potential mechanistic studies are needed. PMID- 26758681 TI - Liquid-induced colour change in a beetle: the concept of a photonic cell. AB - The structural colour of male Hoplia coerulea beetles is notable for changing from blue to green upon contact with water. In fact, reversible changes in both colour and fluorescence are induced in this beetle by various liquids, although the mechanism has never been fully explained. Changes enacted by water are much faster than those by ethanol, in spite of ethanol's more rapid spread across the elytral surface. Moreover, the beetle's photonic structure is enclosed by a thin scale envelope preventing direct contact with the liquid. Here, we note the presence of sodium, potassium and calcium salts in the scale material that mediate the penetration of liquid through putative micropores. The result leads to the novel concept of a "photonic cell": namely, a biocompatible photonic structure that is encased by a permeable envelope which mediates liquid-induced colour changes in that photonic structure. Engineered photonic cells dispersed in culture media could revolutionize the monitoring of cell-metabolism. PMID- 26758680 TI - Somatically mutated ABL1 is an actionable and essential NSCLC survival gene. AB - The lack of actionable mutations in patients with non-small cell lung cancer (NSCLC) presents a significant hurdle in the design of targeted therapies for this disease. Here, we identify somatically mutated ABL1 as a genetic dependency that is required to maintain NSCLC cell survival. We demonstrate that NSCLC cells with ABL1 mutations are sensitive to ABL inhibitors and we verify that the drug induced effects on cell viability are specific to pharmacological inhibition of the ABL1 kinase. Furthermore, we confirm that imatinib suppresses lung tumor growth in vivo, specifically in lung cancer cells harboring a gain-of-function (GOF) mutation in ABL1. Consistent with structural modeling, we demonstrate that mutations in ABL1 identified in primary NSCLC tumors and a lung cancer cell line increase downstream pathway activation compared to wild-type ABL1. Finally, we observe that the ABL1 cancer mutants display an increased cytosolic localization, which is associated with the oncogenic properties of the ABL1 kinase. In summary, our results suggest that NSCLC patients with ABL1 mutations could be stratified for treatment with imatinib in combination with other therapies. PMID- 26758682 TI - CuAAC click reactions for the design of multifunctional luminescent ruthenium complexes. AB - CuAAC (Cu(i) catalyzed azide-alkyne cycloaddition) click chemistry has emerged as a versatile tool in the development of photoactive ruthenium complexes with multilateral potential applicability. In this contribution we discuss possible synthetic approaches towards CuAAC reactions with ruthenium(ii) polypyridine complexes and their differences with respect to possible applications. We focus on two main application possibilities of the click-coupled ruthenium assemblies. New results within the development of ruthenium based photosensitizers for the field of renewable energy supply, i.e. DSSCs (dye-sensitized solar cells) and artificial photocatalysis for the production of hydrogen, or for anticancer photodynamic therapeutic applications are reviewed. PMID- 26758683 TI - Is current medical education adequately preparing future physicians to manage concussion: an initial evaluation. AB - OBJECTIVES: In 2010, there were 2.5 million hospitalizations, emergency room visits, or deaths associated with concussions in the United States.[1] Knowledge deficits exist among physicians regarding concussion management, which can lead to severe repercussions, including poor patient outcomes, poor patient satisfaction, and potential medical-legal issues. While concussion is a prevalent condition evaluated in the medical field, medical students continue to have a knowledge deficit regarding concussion diagnosis, prognosis, medical management, and return to play guidelines. METHODS: Medical students from a mid-western medical school completed a survey on concussion diagnosis, prognosis, medical management, and return to play guidelines. RESULTS: The response rate was 40%. The data suggests that the vast majority of medical students are able to define concussion; however, most reported never having a lecture dedicated to concussion during medical school and also lacked clinical experience with acute concussion and post-concussive syndrome. There are clear areas of deficiency as noted by the inability of students to correctly identify symptoms and appropriate management of concussion. CONCLUSION: The current study indicates that at an individual, mid western, top 50 medical school, current medical trainees may not be adequately educated to identify and manage concussion. Future research is warranted to determine the optimal guidelines to educate future physicians as it pertains to concussion diagnosis, management, prognosis, and return to play guidelines. PMID- 26758684 TI - Transcriptional regulation of FoxO3 gene by glucocorticoids in murine myotubes. AB - Glucocorticoids and FoxO3 exert similar metabolic effects in skeletal muscle. FoxO3 gene expression was increased by dexamethasone (Dex), a synthetic glucocorticoid, both in vitro and in vivo. In C2C12 myotubes the increased expression is due to, at least in part, the elevated rate of FoxO3 gene transcription. In the mouse FoxO3 gene, we identified three glucocorticoid receptor (GR) binding regions (GBRs): one being upstream of the transcription start site, -17kbGBR; and two in introns, +45kbGBR and +71kbGBR. Together, these three GBRs contain four 15-bp glucocorticoid response elements (GREs). Micrococcal nuclease (MNase) assay revealed that Dex treatment increased the sensitivity to MNase in the GRE of +45kbGBR and +71kbGBR upon 30- and 60-min Dex treatment, respectively. Conversely, Dex treatment did not affect the chromatin structure near the -17kbGBR, in which the GRE is located in the linker region. Dex treatment also increased histone H3 and/or H4 acetylation in genomic regions near all three GBRs. Moreover, using chromatin conformation capture (3C) assay, we showed that Dex treatment increased the interaction between the -17kbGBR and two genomic regions: one located around +500 bp and the other around +73 kb. Finally, the transcriptional coregulator p300 was recruited to all three GBRs upon Dex treatment. The reduction of p300 expression decreased FoxO3 gene expression and Dex-stimulated interaction between distinct genomic regions of FoxO3 gene identified by 3C. Overall, our results demonstrate that glucocorticoids activated FoxO3 gene transcription through multiple GREs by chromatin structural change and DNA looping. PMID- 26758687 TI - The impact of global health initiatives on the health system in Angola. AB - We assessed the impact of global health initiatives (GHIs) on the health care system of Angola, as a contribution to documenting how GHIs, such as the Global Fund, GAVI and PEPFAR, influence the planning and delivery of health services in low-income countries and how national systems respond. We collected the views of national and sub-national key informants through 42 semi-structured interviews between April 2009 and May 2011 (12 at the national level and 30 at the sub national level). We used a snowball technique to identify respondents from government, donors and non-governmental organisations. GHIs stimulated the formulation of a health policy and of plans and strategies, but the country has yet to decide on its priorities for health. At the regional level, managers lack knowledge of how GHIs' function, but they assess the effects of external funds as positive as they increased training opportunities, and augment the number of workers engaged in HIV or other specific disease programmes. However, GHIs did not address the challenge of attraction and retention of qualified personnel in provinces. Since Angola is not entirely dependent on external funding, national strategic programmes and the interventions of GHIs co-habit well, in contrast to countries such as Mozambique, which heavily depend on external aid. PMID- 26758685 TI - AMPKgamma3 is dispensable for skeletal muscle hypertrophy induced by functional overload. AB - Mechanisms regulating skeletal muscle growth involve a balance between the activity of serine/threonine protein kinases, including the mammalian target of rapamycin (mTOR) and 5'-AMP-activated protein kinase (AMPK). The contribution of different AMPK subunits to the regulation of cell growth size remains inadequately characterized. Using AMPKgamma3 mutant-overexpressing transgenic Tg Prkag3(225Q) and AMPKgamma3-knockout (Prkag3(-/-)) mice, we investigated the requirement for the AMPKgamma3 isoform in functional overload-induced muscle hypertrophy. Although the genetic disruption of the gamma3 isoform did not impair muscle growth, control sham-operated AMPKgamma3-transgenic mice displayed heavier plantaris muscles in response to overload hypertrophy and underwent smaller mass gain and lower Igf1 expression compared with wild-type littermates. The mTOR signaling pathway was upregulated with functional overload but unchanged between genetically modified animals and wild-type littermates. Differences in AMPK related signaling pathways between transgenic, knockout, and wild-type mice did not impact muscle hypertrophy. Glycogen content was increased following overload in wild-type mice. In conclusion, our functional, transcriptional, and signaling data provide evidence against the involvement of the AMPKgamma3 isoform in the regulation of skeletal muscle hypertrophy. Thus, the AMPKgamma3 isoform is dispensable for functional overload-induced muscle growth. Mechanical loading can override signaling pathways that act as negative effectors of mTOR signaling and consequently promote skeletal muscle hypertrophy. PMID- 26758686 TI - Identification and antimicrobial resistance prevalence of pathogenic Escherichia coli strains from treated wastewater effluents in Eastern Cape, South Africa. AB - Antimicrobial resistance (AMR) is a global problem impeding the effective prevention/treatment of an ever-growing array of infections caused by pathogens; a huge challenge threatening the achievements of modern medicine. In this paper, we report the occurrence of multidrug resistance (MDR) in Escherichia coli strains isolated from discharged final effluents of two wastewater treatment facilities in the Eastern Cape Province of South Africa. Standard disk diffusion method was employed to determine the antibiotic susceptibility profile of 223 polymerase chain reaction (PCR)-confirmed E. coli isolates against 17 common antibiotics in human therapy and veterinary medicine. Seven virulence associated and fourteen antibiotic resistance genes were also evaluated by molecular methods. Molecular characterization revealed five pathotypes of E. coli in the following proportions: enterotoxigenic ETEC (1.4%), enteropathogenic EPEC (7.6%), enteroaggregative EAEC (7.6%), neonatal meningitis (NMEC) (14.8%), uropathogenic (41.7%), and others (26.9%). Isolates showed varying (1.7-70.6%) degrees of resistance to 15 of the test antibiotics. Multidrug resistance was exhibited by 32.7% of the isolates, with the commonest multiple antibiotic-resistant phenotype (MARP) being AP-T-CFX (12 isolates), while multiple antibiotic-resistant indices (MARI) estimated are 0.23 (Site 1) and 0.24 (Site 2). Associated antibiotic resistance genes detected in the isolates include: strA (88.2%), aadA (52.9%), cat I (15%), cmlA1 (4.6%), blaTEM (56.4%), tetA (30.4%), tetB (28.4%), tetC (42.2%), tetD (50%), tetK (11.8%), and tetM (68.6%). We conclude that municipal wastewater effluents are important reservoirs for the dissemination of potentially pathogenic E. coli (and possibly other pathogens) and antibiotic resistance genes in the aquatic milieu of the Eastern Cape and a risk to public health. PMID- 26758688 TI - Population structure of colonizing and invasive Staphylococcus aureus strains in northern Vietnam. AB - Staphylococcus aureus is an important global health problem worldwide. There is still scarce information on the population structure of S. aureus strains in Asia, where the majority of the world population lives. This study characterized the diversity of S. aureus strains in northern Vietnam through multilocus sequence typing (MLST). Eighty-five carriage isolates from the community and 77 invasive isolates from the clinical setting were selected and tested for meticillin resistance and the presence of Panton-Valentine leukocidin (PVL). MLST was performed on these isolates, of which CC59 (25.4 %), CC188 (17.3 %) and CC45 (16.7 %) were the predominant clonal complexes (CCs). CC59 carriage isolates had significantly lower rates of meticillin-resistant S. aureus (MRSA) than their corresponding clinical group isolates (32 vs 83 %). There were no significant differences in rates of MRSA between carriage isolates and clinical isolates of CC45 and CC188. CC59 carriage isolates were significantly lower in rates of PVL+ than CC59 clinical isolates (32 vs 83 %), but the converse was shown in CC45 isolates (14 vs 0 %, respectively). This study revealed vast differences in the molecular epidemiology and population structure of S. aureus in community and clinical settings in Vietnam. Nevertheless, the data underline the spread of virulent and/or resistant strains (MRSA and/or PVL+) in the community, suggesting the necessity for further surveillance to determine the mechanism of transmission of these strains (i.e. MRSA/PVL+) outside clinical settings. PMID- 26758689 TI - PCNA appears in two populations of slow and fast diffusion with a constant ratio throughout S-phase in replicating mammalian cells. AB - DNA replication is a fundamental cellular process that precedes cell division. Proliferating cell nuclear antigen (PCNA) is a central scaffold protein that orchestrates DNA replication by recruiting many factors essential for the replication machinery. We studied the mobility of PCNA in live mammalian cells using single-particle tracking in combination with photoactivated-localization microscopy (sptPALM) and found two populations. The first population which is only present in cells with active DNA replication, showed slow diffusion and was found to be located in replication foci. The second population showed fast diffusion, and represents the nucleoplasmic pool of unbound PCNA not involved in DNA replication. The ratio of these two populations remained constant throughout different stages of S-phase. A fraction of molecules in both populations showed spatially constrained mobility. We determined an exploration radius of ~100 nm for 13% of the slow-diffusing PCNA molecules, and of ~600 nm for 46% of the fast diffusing PCNA molecules. PMID- 26758690 TI - LRRK2 phosphorylates pre-synaptic N-ethylmaleimide sensitive fusion (NSF) protein enhancing its ATPase activity and SNARE complex disassembling rate. AB - BACKGROUND: Lrrk2, a gene linked to Parkinson's disease, encodes a large scaffolding protein with kinase and GTPase activities implicated in vesicle and cytoskeletal-related processes. At the presynaptic site, LRRK2 associates with synaptic vesicles through interaction with a panel of presynaptic proteins. RESULTS: Here, we show that LRRK2 kinase activity influences the dynamics of synaptic vesicle fusion. We therefore investigated whether LRRK2 phosphorylates component(s) of the exo/endocytosis machinery. We have previously observed that LRRK2 interacts with NSF, a hexameric AAA+ ATPase that couples ATP hydrolysis to the disassembling of SNARE proteins allowing them to enter another fusion cycle during synaptic exocytosis. Here, we demonstrate that NSF is a substrate of LRRK2 kinase activity. LRRK2 phosphorylates full-length NSF at threonine 645 in the ATP binding pocket of D2 domain. Functionally, NSF phosphorylated by LRRK2 displays enhanced ATPase activity and increased rate of SNARE complex disassembling. Substitution of threonine 645 with alanine abrogates LRRK2-mediated increased ATPase activity. CONCLUSIONS: Given that the most common Parkinson's disease LRRK2 G2019S mutation displays increased kinase activity, our results suggest that mutant LRRK2 may impair synaptic vesicle dynamics via aberrant phosphorylation of NSF. PMID- 26758691 TI - Inhibition of Glycolate Oxidase With Dicer-substrate siRNA Reduces Calcium Oxalate Deposition in a Mouse Model of Primary Hyperoxaluria Type 1. AB - Primary hyperoxaluria type 1 (PH1) is an autosomal recessive, metabolic disorder caused by mutations of alanine-glyoxylate aminotransferase (AGT), a key hepatic enzyme in the detoxification of glyoxylate arising from multiple normal metabolic pathways to glycine. Accumulation of glyoxylate, a precursor of oxalate, leads to the overproduction of oxalate in the liver, which accumulates to high levels in kidneys and urine. Crystalization of calcium oxalate (CaOx) in the kidney ultimately results in renal failure. Currently, the only treatment effective in reduction of oxalate production in patients who do not respond to high-dose vitamin B6 therapy is a combined liver/kidney transplant. We explored an alternative approach to prevent glyoxylate production using Dicer-substrate small interfering RNAs (DsiRNAs) targeting hydroxyacid oxidase 1 (HAO1) mRNA which encodes glycolate oxidase (GO), to reduce the hepatic conversion of glycolate to glyoxylate. This approach efficiently reduces GO mRNA and protein in the livers of mice and nonhuman primates. Reduction of hepatic GO leads to normalization of urine oxalate levels and reduces CaOx deposition in a preclinical mouse model of PH1. Our results support the use of DsiRNA to reduce liver GO levels as a potential therapeutic approach to treat PH1. PMID- 26758692 TI - Leveraging Optogenetic-Based Neurovascular Circuit Characterization for Repair. AB - Optogenetic techniques are a powerful tool for determining the role of individual functional components within complex neural circuits. By genetically targeting specific cell types, neural mechanisms can be actively manipulated to gain a better understanding of their origin and function, both in health and disease. The potential of optogenetics is not limited to answering biological questions, as it is also a promising therapeutic approach for neurological diseases. An important prerequisite for this approach is to have an identified target with a uniquely defined role within a given neural circuit. Here, we examine the retinal neurovascular unit, a circuit that incorporates neurons and vascular cells to control blood flow in the retina. We highlight the role of a specific cell type, the cholinergic amacrine cell, in modulating vascular cells, and demonstrate how this can be targeted and controlled with optogenetics. A better understanding of these mechanisms will not only extend our understanding of neurovascular interactions in the brain, but ultimately may also provide new targets to treat vision loss in a variety of retinal diseases. PMID- 26758693 TI - Imaging colon cancer development in mice: IL-6 deficiency prevents adenoma in azoxymethane-treated Smad3 knockouts. AB - The development of colorectal cancer in the azoxymethane-induced mouse model can be observed by using a miniaturized optical coherence tomography (OCT) imaging system. This system is uniquely capable of tracking disease development over time, allowing for the monitoring of morphological changes in the distal colon due to tumor development and the presence of lymphoid aggregates. By using genetically engineered mouse models deficient in Interleukin 6 (IL-6) and Smad family member 3 (Smad3), the role of inflammation on tumor development and the immune system can be elucidated. Smad3 knockout mice develop inflammatory response, wasting, and colitis associated cancer while deficiency of proinflammatory cytokine IL-6 confers resistance to tumorigenesis. We present pilot data showing that the Smad3 knockout group had the highest tumor burden, highest spleen weight, and lowest thymus weight. The IL-6 deficiency in Smad3 knockout mice prevented tumor development, splenomegaly, and thymic atrophy. This finding suggests that agents that inhibit IL-6 (e.g. anti-IL-6 antibody, non steroidal anti-inflammatory drugs [NSAIDs], etc.) could be used as novel therapeutic agents to prevent disease progression and increase the efficacy of anti-cancer agents. OCT can also be useful for initiating early therapy and assessing the benefit of combination therapy targeting inflammation. PMID- 26758696 TI - An experimental model of COD abatement in MBBR based on biofilm growth dynamic and on substrates' removal kinetics. AB - In this study, the performance of a lab-scale Moving Bed Biofilm Reactor (MBBR) under different operating conditions was analysed. Moreover, the dependence of the reaction rates both from the concentration and biodegradability of substrates and from the biofilm surface density, by means of several batch kinetic tests, was investigated. The reactor controls exhibited an increasing COD (Chemical Oxygen Demand) removal, reaching maximum yields (close to 90%) for influent loadings of up to12.5 gCOD/m(2)d. From this value, the pilot plant performance decreased to yields of only about 55% for influent loadings greater than 16 gCOD/m(2)d. In response to the influent loading increase, the biofilm surface density exhibited a logistic growing trend until reaching a maximum amount of total attached solids of about 9.5 g/m(2). The kinetic test results indicated that the COD removal rates for rapidly biodegradable, rapidly hydrolysable and slowly biodegradable substrates were not affected by the organic matter concentrations. Instead, first-order kinetics were detected with respect to biofilm surface density. The experimental results permitted the formulation of a mathematical model to predict the MBBR organic matter removal efficiency. The validity of the model was successfully tested in the lab-scale plant. PMID- 26758695 TI - A Novel c.554+5C>T Mutation in the DUOXA2 Gene Combined with p.R885Q Mutation in the DUOX2 Gene Causing Congenital Hypothyroidism. AB - The coexistence of mutations in the dual oxidase maturation factor 2 (DUOXA2) and dual oxidase 2 (DUOX2) genes is rarely identified in congenital hypothyroidism (CH). This study reports a boy with CH due to a novel splice-site mutation in the DUOXA2 gene and a missense mutation in the DUOX2 gene. A four-year-old boy was diagnosed with CH at neonatal screening and was enrolled in this study. The DUOXA2, DUOX2, thyroid peroxidase (TPO), and thyrotropin receptor (TSHR) genes were considered for genetic defects screening. Genomic DNA was extracted from peripheral blood leukocytes, and Sanger sequencing was used to screen the mutations in the exon fragments. Family members of the patient and the controls were also enrolled and evaluated. The boy harbored compound heterozygous mutations including a novel splice-site mutation c.554+5C>T in the maternal DUOXA2 allele and c.2654G>A (p.R885Q) in the paternal DUOX2 allele. The germline mutations from his parents were consistent with an autosomal recessive inheritance pattern. No mutations in the TPO and TSHR genes were detected. A novel splice-site mutation c.554+5C>T in the DUOXA2 gene and a mutation p.R885Q in the DUOX2 gene were identified in a 4-year-old patient with goitrous CH. PMID- 26758697 TI - Durable and self-healing superamphiphobic coatings repellent even to hot liquids. AB - Durable and self-healing superamphiphobic coatings with high repellency to both cool and hot liquids are successfully prepared on various substrates by the combination of rodlike palygorskite and organosilanes via spray-coating. The coatings feature high mechanical, environmental and chemical durability, and are self-healing. PMID- 26758694 TI - NO FLOWERING IN SHORT DAY (NFL) is a bHLH transcription factor that promotes flowering specifically under short-day conditions in Arabidopsis. AB - Flowering in plants is a dynamic and synchronized process where various cues including age, day length, temperature and endogenous hormones fine-tune the timing of flowering for reproductive success. Arabidopsis thaliana is a facultative long day (LD) plant where LD photoperiod promotes flowering. Arabidopsis still flowers under short-day (SD) conditions, albeit much later than in LD conditions. Although factors regulating the inductive LD pathway have been extensively investigated, the non-inductive SD pathway is much less understood. Here, we identified a key basic helix-loop-helix transcription factor called NFL (NO FLOWERING IN SHORT DAY) that is essential to induce flowering specifically under SD conditions in Arabidopsis. nfl mutants do not flower under SD conditions, but flower similar to the wild type under LD conditions. The no flowering phenotype in SD is rescued either by exogenous application of gibberellin (GA) or by introducing della quadruple mutants in the nfl background, suggesting that NFL acts upstream of GA to promote flowering. NFL is expressed at the meristematic regions and NFL is localized to the nucleus. Quantitative RT-PCR assays using apical tissues showed that GA biosynthetic genes are downregulated and the GA catabolic and receptor genes are upregulated in the nfl mutant compared with the wild type, consistent with the perturbation of the endogenous GA biosynthetic and catabolic intermediates in the mutant. Taken together, these data suggest that NFL is a key transcription factor necessary for promotion of flowering under non-inductive SD conditions through the GA signaling pathway. PMID- 26758698 TI - Budesonide-loaded solid lipid nanoparticles for pulmonary delivery: preparation, optimization, and aerodynamic behavior. AB - Advantages of lipid nanoparticles for pulmonary applications are possibility of deep lung deposition with prolonged release and low toxicity. This study aimed to evaluate the effects of formulation and processing parameters on particle size of prepared SLNs. Budesonide-loaded solid lipid nanoparticles (BUD-SLNs) were prepared with different values of drug content, ultrasonication amplitude, and homogenization time and the data were modeled using artificial neural networks (ANNs). Optimal conditions for fabrication of small-sized particles of 170-200 nm were found to be low drug content with high-amplitude and high-homogenization time. In vitro aerosolization performance of BUD-SLNs was then compared to that of commercial budesonide which indicated enhancement in fine particle fraction value. PMID- 26758699 TI - Structural organization of sterol molecules in DPPC bilayers: a coarse-grained molecular dynamics investigation. AB - We investigate the structural organization of cholesterol (CHOL) analogues in 1,2 dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayers using coarse-grained molecular dynamics simulations and the MARTINI forcefield. Different sterol molecules are modelled by increasing (CHOLL) or decreasing (CHOLS) the diameter of the sterol beads employed in the MARTINI model of CHOL. At high sterol concentrations, (xsterol = 0.5), typical of liquid ordered phases, we find that the sterol arrangement and sterol-DPPC interactions strongly depend on the sterol size. Smaller sterols (CHOLS and CHOL) form linear clusters, while the larger sterols (CHOLL) arrange themselves into disc shaped clusters. By combining structural and dynamical properties we also investigate the So-> Ld transition for the CHOLL and CHOLS sterols. We show that small changes in the sterol size significantly affect the stability of the gel phase with the gel phase stabilized by the small sterols, but destabilized by large sterols. The general dependence of the phase behaviour of the membrane with sterol content is reminiscent of the one observed in naturally occurring membranes. The relevance of our results to understand current cholesterol-bilayer structural models is discussed. PMID- 26758700 TI - Alpha-Melanocyte-Stimulating Hormone and Agouti-Related Protein: Do They Play a Role in Appetite Regulation in Childhood Obesity? AB - OBJECTIVE: The hypothalamus plays a crucial role in the regulation of feeding behavior. The anorexigenic neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) and the orexigenic neuropeptide agouti-related protein (AgRP) are among the major peptides produced in the hypothalamus. This study investigated the plasma concentrations of alpha-MSH and AgRP in underweight and obese children and their healthy peers. The associations between alpha-MSH and AgRP levels and anthropometric and nutritional markers of malnutrition and obesity were also assessed. METHODS: Healthy sex-matched subjects aged 2 to 12 years were divided into 3 groups, as underweight (n=57), obese (n=61), and of normal weight (n=57). Plasma fasting concentrations of alpha-MSH and AgRP were measured by enzyme linked immunosorbent assay. The differences between the three groups as to the relationships between plasma concentrations of alpha-MSH and AgRP and anthropometric data, serum biochemical parameters and homeostatic model assessment of insulin resistance were evaluated. RESULTS: Obese children had significantly lower alpha-MSH levels than underweight (1194+/-865 vs. 1904+/-1312 ng/mL, p=0.006) and normal weight (1194+/-865 vs. 1762+/-1463 ng/mL, p=0.036) children; there were no significant differences in the alpha-MSH levels between the underweight and normal weight children (p=0.811). Also, no significant differences were observed between the underweight and obese children regarding the AgRP levels (742+/-352 vs. 828+/-417 ng/mL, p=0.125). We found a significant positive correlation between plasma alpha-MSH and AgRP levels across the entire sample. CONCLUSION: This study is the first to demonstrate body weight-related differences in alpha-MSH and AgRP levels in children. Circulating plasma alpha MSH levels in obese children were markedly lower than those of underweight and normal-weight children. This suggests that alpha-MSH could play a role in appetite regulation. PMID- 26758702 TI - Cervical anterior hybrid technique with bi-level Bryan artificial disc replacement and adjacent segment fusion for cervical myelopathy over three consecutive segments. AB - This study aimed to assess the preliminary clinical efficacy and feasibility of the hybrid technique for multilevel cervical myelopathy. Considering the many shortcomings of traditional treatment methods for multilevel cervical degenerative myelopathy, hybrid surgery (bi-level Bryan artificial disc [Medtronic Sofamor Danek, Memphis, TN, USA] replacement and anterior cervical discectomy and fusion) should be considered. Between March 2006 and November 2012, 108 patients (68 men and 40 women, average age 45years) underwent hybrid surgery. Based on the Japanese Orthopaedic Association (JOA) score, Neck Disability Index (NDI), and Odom's criteria, the clinical symptoms and neurological function before and after surgery were evaluated. Mean surgery duration was 90minutes, with average blood loss of 30mL. Mean follow-up duration was 36months. At the final follow-up, the mean JOA (+/- standard deviation) scores were significantly higher compared with preoperative values (15.08+/-1.47 versus 9.18+/-1.22; P<0.01); meanwhile, NDI values were markedly decreased (12.32+/-1.03 versus 42.68+/-1.83; P<0.01). Using Odom's criteria, the clinical outcomes were rated as excellent (76 patients), good (22 patients), fair (six patients), and poor (four patients). These findings indicate that the hybrid method provides an effective treatment for cervical myelopathy over three consecutive segments, ensuring a good clinical outcome. PMID- 26758703 TI - Supraciliary keyhole craniotomy for anterior frontal lesions in children. AB - Treatment for anterior frontal space occupying lesions such as epidural hematoma, vascular malformations or brain tumors, have typically involved invasive craniotomies. This method often requires large incisions with wide exposure and may be associated with high morbidity rates. The basis for the "keyhole" method is that a minimally invasive craniotomy is often sufficient for exposing large areas deep in tissue, and may limit exposure and decrease surgically related morbidity while enabling adequate removal and decompression. The supraciliary method includes a cut above the eyebrow and a small craniotomy to uncover the base of the frontal lobe and the orbital roof. We demonstrate our experience with this method. We identified children who were operated via the supraciliary approach between January 2009 and December 2013, and gathered their pre- and post operative clinical and radiological statistics. Fourteen patients were identified. Pathologies included tumors, abscesses and epidural hematomas. Nine were operated due to epidural hematoma, two due to tumors, two due to brain abscesses, and one for anterior encephalocele. No significant peri-operative or post-operative complications were observed. Long-term follow-up shows that the surgical scars were nearly invisible. The supraciliary approach is a safe, effective and elegant technique for treating lesions in the anterior skull base. The method should be weighed alongside traditional methods on a case-by-case basis. PMID- 26758701 TI - Gender-related differential effect of tachykinin NK2 receptor-mediated visceral hyperalgesia in guinea pig colon. AB - BACKGROUND AND PURPOSE: The tachykinin NK2 receptor antagonist ibodutant is under Phase III clinical investigation to treat female patients with irritable bowel syndrome. The aim of this study was to investigate the NK2 receptor-related gender specificity in a model of colitis. EXPERIMENTAL APPROACH: Colitis was induced by rectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS, 0.5 mL, 30 mg.mL(-1) in 30% ethanol) in female and male guinea pigs. Electromyographic recording of the responses to colorectal distension (CRD) was made 3 days later. Ibodutant (0.33 , 0.65, 1.9 and 6.5 mg.kg(-1) ) was given s.c., 30 min before CRD. Release of neurokinin A and substance P from isolated mucosal and smooth muscle tissues following treatment with KCl (80 mM) or capsaicin (10 MUM) was measured by EIA. Plasma pharmacokinetics of ibodutant following a single s.c. administration (0.73 or 2.1 mg.kg(-1) ) were measured over 24 h. KEY RESULTS: Ibodutant did not affect abdominal contractions in control animals. After TNBS-induced colitis, ibodutant prevented the increased visceral hypersensitivity to CRD in females, at lower doses than in males. Ibodutant pharmacokinetics did not differ between females and males. Tachykinins release was greater in smooth muscle than in mucosal samples. Capsaicin stimulated release of tachykinins from inflamed mucosal samples from females was significantly lower than in males. CONCLUSIONS AND IMPLICATIONS: Ibodutant prevented abdominal nociception in a model of visceral hypersensitivity in guinea pigs with a greater efficacy in females than in males. Our results highlight a gender-related difference in colonic visceral hypersensitivity and mucosal nerve activation. PMID- 26758704 TI - Choice of valve type and poor ventricular catheter placement: Modifiable factors associated with ventriculoperitoneal shunt failure. AB - Ventriculoperitoneal (VP) shunt insertion is a common neurosurgical procedure, essentially unchanged in recent years, with high revision rates. We aimed to identify potentially modifiable associations with shunt failure. One hundred and forty patients who underwent insertion of a VP shunt from 2005-2009 were followed for 5-9years. Age at shunt insertion ranged from 0 to 91years (median 44, 26% <18years). The main causes of hydrocephalus were congenital (26%), tumour-related (25%), post-haemorrhagic (24%) or normal pressure hydrocephalus (19%). Fifty eight (42%) patients required ?1 shunt revision. Of these, 50 (88%) were for proximal catheter blockage. The median time to first revision was 108days. Early post-operative CT scans were available in 105 patients. Using a formal grading system, catheter placement was considered excellent in 49 (47%) but poor (extraventricular) in 13 (12%). On univariate analysis, younger age, poor ventricular catheter placement and use of a non-programmable valve were associated with shunt failure. On logistic regression modelling, the independent associations with VP shunt failure were poor catheter placement (odds ratio [OR] 4.9, 95% confidence interval [CI] 1.3-18.9, p=0.02) and use of a non-programmable valve (OR 0.4, 95% CI 0.2-1.0, p=0.04). In conclusion, poor catheter placement (revision rate 77%) was found to be the strongest predictor of shunt failure, with no difference in revisions between excellent (43%) and moderate (43%) catheter placement. Avoiding poor placement in those with mild or moderate ventriculomegaly may best reduce VP shunt failures. There may also be an influence of valve choice on VP shunt survival. PMID- 26758705 TI - Removal of dental implant displaced into maxillary sinus by combination of endoscopically assisted and bone repositioning techniques: a case report. AB - BACKGROUND: Accidental displacement of a dental implant into the maxillary sinus is an infrequent although not uncommon complication encountered in dental clinical practice, with the main cause thought to be inadequate bone height in the posterior maxilla. We report a case of migration of a dental implant into the maxillary sinus, and discuss the benefits of its removal by a combination of endoscopically assisted and bone repositioning techniques. CASE PRESENTATION: A 35-year-old Japanese man with a partially edentulous maxilla underwent implant placement at a private clinic. Three months later, at the time of abutment connection, the implant at the site of his maxillary right first molar was accidentally pushed into the sinus. The hole on the alveolar ridge made for placement of the implant was small and far from the dislocated implant, thus access was achieved in a transoral manner via the frontal wall of his maxillary sinus with an endoscopic approach. Piezoelectric instruments were used to perform an osteotomy. The bone lid was removed, and the implant was identified using a rigid endoscope and removed with a surgical aspirator, followed by repositioning of the bony segment; the area was secured with an absorbable suture. Removal of migrated implants should be considered in order to prevent possible sinusal disease complications. CONCLUSIONS: In the present case, removal of a dental implant displaced into the maxillary sinus by use of a combination of endoscopically assisted and bone repositioning techniques proved to be a safe and reliable procedure. PMID- 26758706 TI - Ethnic Variation in Lipid Profile and Its Associations with Body Composition and Diet: Differences Between Iranians, Indians and Caucasians Living in Australia. AB - Dyslipidaemia is a known risk factor for developing cardiovascular disease. The impact of ethnicity on variations in lipid patterns has been studied in certain racial and ethnic groups with limited data on other ethnicities, particularly Asian subgroups. This cross-sectional study evaluated the ethnic variation in lipid profile and its association with body composition and diet in ninety-one overweight and obese Australians of European (n = 32), Indian (n = 28) and Iranian (n = 31) ancestries. Different measures of total and truncal adiposity were assessed using the method of whole body dual energy X-ray absorptiometry. The results showed that serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-chol) levels in Iranians were significantly lower than in Europeans and Indians. Both Iranian and Indian groups exhibited lower mean high density lipoprotein cholesterol (HDL-chol) relative to Europeans. Triglycerides (TG) and HDL-chol, but not TC and LDL-chol, were significantly associated with different truncal adiposity measurements; however the degree of associations varied in ethnic groups. Regression analysis showed ethnicity as a significant predictor of TC (p = 0.01), TG (p = 0.03) and HDL-chol (p = 0.04), after controlling for potential confounders. However, LDL-chol was significantly associated with the intake of total (p = 0.005), and saturated fats (p = 0.004), which were also other significant determinants of serum TC (p = 0.04 and p = 0.02, respectively). In conclusion, ethnicity was a strong predictor of serum lipids, except LDL-chol which was significantly determined by dietary fat intake. Prevention and management of obesity, particularly abdominal adiposity may effectively reduce the risk of low HDL-chol reported in Iranians and Indians. PMID- 26758707 TI - Herpes Simplex Virus (HSV) Modulation of Staphylococcus aureus and Candida albicans Initiation of HeLa 299 Cell-Associated Biofilm. AB - Although herpes simplex virus type-1 (HSV-1), and type-2 (HSV-2), Staphylococcus aureus and Candida albicans co-habit the oral and genital mucosa, their interaction is poorly understood. We determined the effect HSV has on bacterial and/or fungal adherence, the initial step in biofilm formation. HeLa229 cells were infected with HSV-1 (KOS) gL86 or HSV-2 (KOS) 333gJ (-) at a multiplicity of infection (MOI) of 50 and 10. S. aureus (ATCC 25923) and/or C. albicans (yeast forms or germ tube forms) were co-incubated for 30 min (37 degrees C; 5 % CO2; 5:1 organism: HeLa cell ratio; n = 16) with virus-infected HeLa cells or uninfected HeLa cell controls. Post-incubation, the monolayers were washed (3x; PBS), lysed (RIPA), and the lysate plated onto Fungisel and/or mannitol salts agar for standard colony count. The level of HeLa-associated S. aureus was significantly decreased (P < 0.05) for both HSV-1- and HSV-2-infected cells, as compared to virus-free HeLa cell controls (38 and 59 % of control, respectively). In contrast, HSV-1 and HSV-2 significantly (P < 0.05) enhanced HeLa cell association of C. albicans yeast forms and germ tube approximately two-fold, respectively. The effect of S. aureus on germ tube and yeast form adherence to HSV-1- and HSV-2-infected cells was specific for the Candida phenotype tested. Our study suggests that HSV, while antagonist towards S. aureus adherence enhances Candida adherence. Furthermore, the combination of the three pathogens results in S. aureus adherence that is either unaffected, or partially restored depending on both the herpes viral species and the fungal phenotype present. PMID- 26758708 TI - Childhood Exposure to Religions With High Prevalence of Members Who Discourage Homosexuality Is Associated With Adult HIV Risk Behaviors and HIV Infection in Black Men Who Have Sex With Men. AB - Exposure to childhood religious affiliations where the majority of members discourage homosexuality may have negative psychological impacts for Black men who have sex with men. This study tested the hypothesis that exposures to these environments during childhood were associated with adulthood human immunodeficiency virus (HIV)/sexually transmitted infection (STI) behavioral risk and HIV infection, because these exposures influenced HIV/STI risk by undermining race/sexual identity congruence and increasing internalized homophobia and interpersonal anxiety. Structural equation modeling as well as logistic and Poisson regressions were performed using baseline data from HIV Prevention Trials Network 061 ( N = 1,553). Childhood religion affiliations that were more discouraging of homosexuality were associated with increased likelihood of HIV infection; however, the association was no longer significant after adjusting for age, income, and education. Having a childhood religion affiliation with high prevalence of beliefs discouraging homosexuality was associated with increased numbers of sexual partners (adjusted odds ratio = 4.31; 95% confidence interval [3.76, 4.94], p < .01). The hypothesized path model was largely supported and accounted for 37% of the variance in HIV infection; however, interpersonal anxiety was not associated with HIV/STI risk behaviors. Structural interventions are needed that focus on developing affirming theologies in religious institutions with Black men who have sex with men congregants. PMID- 26758710 TI - Association of increased monetary cost of dietary intake, diet quality and weight management in Spanish adults. AB - Higher monetary diet cost is associated with healthier food choices and better weight management. How changes in diet cost affect changes in diet quality and weight remains unknown. The aim of this study was to assess the impact of changes in individual monetary diet cost on changes in diet quality, measured by the modified Mediterranean diet score recommendations (MDS-rec) and by energy density (ED), as well as changes in weight and BMI. We conducted a prospective, population-based study of 2181 male and female Spaniards aged between 25 and 74 years, who were followed up to the 2009-2010 academic year. We measured weight and height and recorded dietary data using a validated FFQ. Average food cost was calculated from official Spanish government data. We fitted multivariate linear and logistic regression models. The average daily diet cost increased from 3.68(SD0.0.89)?/8.36 MJ to 4.97(SD1.16)?/8.36 MJ during the study period. This increase was significantly associated with improvement in diet quality (Delta ED and Delta MDS-rec; P<0.0001). Each 1? increase in monetary diet cost per 8.36 MJ was associated with a decrease of 0.3 kg in body weight (P=0.02) and 0.1 kg/m(2) in BMI (P=0.04). These associations were attenuated after adjusting for changes in diet quality indicators. An improvement in diet quality and better weight management were both associated with an increase in diet cost; this could be considered in food policy decisions. PMID- 26758709 TI - Quantitative research into the deconditioning of hemodynamic to disorder of consciousness carried out using transcranial Doppler ultrasonography and photoplethysmography obtained via finger-transmissive absorption. AB - In this study, transcranial Doppler ultrasonography (TCD) and photoplethysmography (PPG) have been utilized, through the observation of peripheral and cerebrovascular hemodynamic changes of the disorder of consciousness (DOC) patients, measured on clinical behavior scale of Coma Recovery Score-Revised (CRS-R) to obesrve their diagnostic value in evaluation of DOC patients. TCD ultrasound was used to evaluate the flow velocity and waveform patterns of middle cerebral artery (MCA), while PPG infrared signals were utilized to assess the peripheral circulation as a mean of measuring cardiovascular activities. The research was carried out on a sample of 36 individuals, of which 16 met the DOC criteria and 20 were healthy individuals. Each person in the patients groups was assessed by the CRS-R. The velocity of middle cerebral artery in tested patients in a whole cardiac cycle, detected by TCD, decreased comparing with normal values. The values of pulsatility index (PI) of the MCA increased in patients groups comparing with normal. Through binary variables correlation analysis, we found that the PI of the left MCA of TCD of the patients significantly inversely correlated with their motor subscore, included in their CRS-R in the level of alpha = 0.05 (Pearson's product-moment correlation coefficient = -0.556, p = 0.025). The values of photoplethysmographic augmentation index (PAI) that were detected by PPG increased comparing with normal. Finally, using binary variables correlation analysis we found the significant inverse correlation between the PAI of PPG and the mean velocity of the left MCA of the TCD in the level of alpha = 0.05 (Pearson's product-moment correlation coefficient = -0.377, p = 0.022) in all the groups. The results of this study revealed a specific relationship between PI and PAI in the DOC patients. That relationship can potentially be exploited to enhance the capabilities in early assessment of the deconditioning of the DOC patients' cardiovascular system and its influence on their cerebral vascular system. Ultimately, the dependency discovered can assist in predicting the tendency of the prognosis of the DOC patients in clinic. PMID- 26758711 TI - Differential Effects of Thidiazuron on Production of Anticancer Phenolic Compounds in Callus Cultures of Fagonia indica. AB - Fagonia indica, a very important anticancer plant, has been less explored for its in vitro potential. This is the first report on thidiazuron (TDZ)-mediated callogenesis and elicitation of commercially important phenolic compounds. Among the five different plant growth regulators tested, TDZ induced comparatively higher fresh biomass, 51.0 g/100 mL and 40.50 g/100 mL for stem and leaf explants, respectively, after 6 weeks of culture time. Maximum total phenolic content (202.8 MUg gallic acid equivalent [GAE]/mL for stem-derived callus and 161.3 MUg GAE/mL for leaf-derived callus) and total flavonoid content (191.03 MUg quercetin equivalent [QE]/mL for stem-derived callus and 164.83 MUg QE/mL for leaf-derived callus) were observed in the optimized callus cultures. The high performance liquid chromatography (HPLC) data indicated higher amounts of commercially important anticancer secondary metabolites such as gallic acid (125.10 +/- 5.01 MUg/mL), myricetin (32.5 +/- 2.05 MUg/mL), caffeic acid (12.5 +/ 0.52 MUg/mL), catechin (9.4 +/- 1.2 MUg/mL), and apigenin (3.8 +/- 0.45 MUg/mL). Owing to the greater phenolic content, a better 2-2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity (69.45 % for stem explant and 63.68 % for leaf explant) was observed in optimized calluses. The unusually higher biomass and the enhanced amount of phenolic compounds as a result of lower amounts of TDZ highlight the importance of this multipotent hormone as elicitor in callus cultures of F. indica. PMID- 26758712 TI - Synthesis and Characterisation of Biocompatible Polymer-Conjugated Magnetic Beads for Enhancement Stability of Urease. AB - We reported natural polymer-conjugated magnetic featured urease systems for removal of urea effectively. The optimum temperature (20-60 degrees C), optimum pH (3.0-10.0), kinetic parameters, thermal stability (4-70 degrees C), pH stability (4.0-9.0), operational stability (0-250 min), reusability (18 times) and storage stability (24 weeks) were studied for characterisation of the urease encapsulated biocompatible polymer-conjugated magnetic beads. Also, the surface groups and chemical structure of the magnetic beads were determined by using attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). The all urease-encapsulated magnetic beads protected their stability of 30-45 % relative activity at 70 degrees C. A significant increase was observed at their pH stability compared with the free urease for both acidic and alkaline medium. Besides this, their repeatability activity were approximately 100 % during 4(th) run. They showed residual activity of 50 % after 16 weeks. The importance of this work is enhancement stability of immobilised urease by biocompatible polymer conjugated magnetic beads for the industrial application based on removal of urea. PMID- 26758713 TI - Experimental studies and two-dimensional modelling of a packed bed bioreactor used for production of galacto-oligosaccharides (GOS) from milk whey. AB - In the present study, extensive experimental investigations and detailed theoretical analysis of a two-dimensional packed bed bioreactor, employed for the production of galacto-oligosaccharides (GOS) from milk whey were performed. Model equations, in one- and two-dimensions, capable of predicting the substrate concentration distribution in the bioreactor were developed by coupling mass balance equation with appropriate velocity distribution equation and solved numerically. Validation of the proposed model equations was done by a set of experimental data obtained from the bioreactor. The effects of reactor to catalyst particle diameter ratio (d t/d p), feed flowrate (10(-6)-10(-9) m(3) s( 1)), and initial lactose concentration (50-200 kg m(-3)) on substrate concentration distribution were investigated in detail. While, the distribution of substrate concentration in axial direction was independent of d t/d p, it was observed that for d t/d p <40, significant radial concentration distribution existed. It was further observed that the substrate conversion and product yield obtained experimentally showed an excellent agreement (97 +/- 2 %) with the results predicted by the two-dimensional model equation, whereas, the results predicted by the one-dimensional model equation did not lie within the desired confidence level (<90 %). The results were confirmed by both curve fitting and statistical analysis. The prediction of substrate concentration distribution in axial and radial directions using the developed two-dimensional model equation is necessary for computing the bioreactor volume to achieve the desired GOS yield. PMID- 26758714 TI - Enhanced truncated-t-PA (CT-b) expression in high-cell-density fed-batch cultures of Pichia pastoris through optimization of a mixed feeding strategy by response surface methodology. AB - Recently, Pichia pastoris has been the focal point of interest as an expression system for production of many recombinant proteins. The study and optimization of feeding strategy are of major importance to achieve maximum volumetric productivity in fed-batch cultivations. Among different feeding strategies used in P. pastoris fed-batch cultures, those trying to maintain a constant specific growth rate have usually resulted in superior productivities. The objective of the present study was to investigate and optimize the co-feeding of glycerol and methanol to attain maximum expression of t-PA in P. pastoris fed-batch cultures with constant specific growth rate. The experiments were designed by response surface methodology, considering the specific feeding rates of methanol and glycerol as independent variables. In each experiment, glycerol and methanol were fed according to a predetermined equation to maintain a constant specific growth rate. It was found that with glycerol feeding for higher specific growth rates, the inhibitory properties of glycerol are more pronounced, while the best expression level was achieved when the ratio of u set glycerol to that of methanol was around 1.67. In all specific growth rates tested, almost a similar ratio of the specific glycerol feeding rate to that of methanol led to the maximum protein production and activity. The statistical model predicted the optimal operating conditions for u set glycerol and that of methanol to be 0.05 and 0.03 h(-1), respectively. Applying the optimum strategy, maximum of 52 g/L biomass, 300 mg/L t-PA and 340,000 IU/mL enzyme activity were obtained. PMID- 26758715 TI - Unravelling Small-Polaron Transport in Metal Oxide Photoelectrodes. AB - Transition-metal oxides are a promising class of semiconductors for the oxidation of water, a process that underpins both photoelectrochemical water splitting and carbon dioxide reduction. However, these materials are limited by very slow charge transport. This is because, unlike conventional semiconductors, material aspects of metal oxides favor the formation of slow-moving, self-trapped charge carriers: small polarons. In this Perspective, we seek to highlight the salient features of small-polaron transport in metal oxides, offer guidelines for their experimental characterization, and examine recent transport studies of two prototypical oxide photoanodes: tungsten-doped monoclinic bismuth vanadate (W:BiVO4) and titanium-doped hematite (Ti:alpha-Fe2O3). Analysis shows that conduction in both materials is well-described by the adiabatic small-polaron model, with electron drift mobility (distinct from the Hall mobility) values on the order of 10(-4) and 10(-2) cm(2) V(-1) s(-1), respectively. Future directions to build a full picture of charge transport in this family of materials are discussed. PMID- 26758717 TI - Purification and characterization of dihydropyrimidine dehydrogenase enzyme from sheep liver and determination of the effects of some anaesthetic and antidepressant drugs on the enzyme activity. AB - Dihydropyrimidine dehydrogenase (DPD, E.C. 1.3.1.2) was purified from sheep liver with a yield of 16.7%, purification fold of 407.5 and specific activity of 0.705 EU/mg proteins. The purification procedure consisted of ammonium sulphate fractionation, DEAE ion exchange chromatography and 2',5'-ADP Sepharose-4B affinity chromatography. The molecular weight determined by SDS-PAGE and was found 111 kDa. Optimum pH, ionic strength temperature and stable pH were determined as 8.0, 0.9 mM, 50 degrees C and 6.0, respectively. The kinetic parameters (Km and Vmax) of the enzyme were determined with NADPH as 22.97 MUM and 0.17 EU/mL, respectively. The same parameters were determined with uracil as 17.46 MUM and 0.14 EU/mL, respectively. Additionally, in vitro inhibitory effects of some antidepressant drugs including escitalopram, fluoxetine, mirtazapine, haloperidol and some anaesthetic drugs including propofol and lidocaine were investigated against DPD. In addition, IC50 values for each active drug obtained for escitalopram, fluoxetine, mirtazapine, haloperidol, propofol and lidocaine were determined as 1736.11, 13.24, 86.65, 99.03, 0.21 and 15.07 MUM, respectively. PMID- 26758716 TI - Qatar pharmacists' understanding, attitudes, practice and perceived barriers related to providing pharmaceutical care. AB - BACKGROUND: Pharmaceutical care (PC) is the philosophy of practice that includes identifying and resolving medication therapy problems to improve patient outcomes. OBJECTIVES: The study objectives were to examine the extent of pharmaceutical care practice and the barriers to pharmaceutical care provision as perceived by Qatar pharmacists and to assess their level of understanding of pharmaceutical care and their attitudes about pharmaceutical care provision. Setting Qatar pharmacies. METHODS: A cross sectional survey of all pharmacists in Qatar was made. Consenting pharmacists were given the option to complete the survey either online using an online software or as paper by fax or by hand. MAIN OUTCOME MEASURES: 1. Extent of pharmaceutical care practice in Qatar. 2. Barriers to pharmaceutical care provision in Qatar. 3. Qatar pharmacists' level of understanding of pharmaceutical care. 4. Qatar pharmacists' attitudes toward pharmaceutical care provision. RESULTS: Over 8 weeks, 274 surveys were collected (34 % response rate). More than 80 % of respondents had correct understanding of the aim of PC and of the pharmacist role in PC. However, only 47 % recognized the patient role in PC and only 35 % were aware of the differences between clinical pharmacy and PC. Yet, more than 80 % believed that they could be advocates when it comes to patients' medications and health matters. Concerning their practice, respondents reported spending little time on PC activities. Offering feedback to the physician about the patient progress was always or most of the time performed by 21 % of respondents. The top perceived barriers for PC provision included inconvenient access to patient medical information (78 %) and lack of staff and time (77 and 74 % respectively). CONCLUSIONS: Although PC is not incorporated into pharmacy practice, Qatar pharmacists showed positive attitudes toward PC provision. Further work should focus on improving their PC understanding and on overcoming all barriers. PMID- 26758718 TI - Influence of different treatment techniques and clinical factors over the intrafraction variation on lung stereotactic body radiotherapy. AB - PURPOSE: In the present study we compared three different Stereotactic body radiation therapy (SBRT) treatment delivery techniques in terms of treatment time (TT) and their relation with intrafraction variation (IFV). Besides that, we analyzed if different clinical factors could have an influence on IFV. Finally, we appreciated the soundness of our margins. MATERIALS AND METHODS: Forty-five patients undergoing SBRT for stage I lung cancer or lung metastases up to 5 cm were included in the study. All underwent 4DCT scan to create an internal target volume (ITV) and a 5 mm margin was added to establish the planning target volume (PTV). Cone-beam CTs (CBCTs) were acquired before and after each treatment to quantify the IFV. Three different treatment delivery techniques were employed: fixed fields (FF), dynamically collimated arcs (AA) or a combination of both (FA). We studied if TT was different among these modalities of SBRT and whether TT and IFV were correlated. Clinical data related to patients and tumors were recorded as potential influential factors over the IFV. RESULTS: A total of 52 lesions and 147 fractions were analyzed. Mean IFV for x-, y- and z-axis were 1 +/ 1.16 mm, 1.29 +/- 1.38 mm and 1.17 +/- 1.08 mm, respectively. Displacements were encompassed by the 5 mm margin in 96.1 % of fractions. TT was significantly longer in FF therapy (24.76 +/- 5.4 min), when compared with AA (15.30 +/- 3.68 min) or FA (17.79 +/- 3.52 min) (p < 0.001). Unexpectedly, IFV did not change significantly between them (p = 0.471). Age (p = 0.003) and left vs. right location (p = 0.005) were related to 3D shift >=2 mm. In the multivariate analysis only age showed a significant impact on the IFV (OR = 1.07, p = 0.007). CONCLUSIONS: The choice of AA, FF or FA does not impact on IFV although FF treatment takes significantly longer treatment time. Our immobilization device offers enough accuracy and the 5 mm margin may be considered acceptable as it accounts for more than 95 % of tumor shifts. Age is the only clinical factor that influenced IFV significantly in our analysis. PMID- 26758719 TI - EEG frequency analysis of cortical brain activities induced by effect of light touch. AB - In human postural control, touching a fingertip to a stable object with a slight force (<1 N) reduces postural sway independent of mechanical support, which is referred to as the effect of light touch (LT effect). The LT effect is achieved by the spatial orientation according to haptic feedback acquired from an external spatial reference. However, the neural mechanism of the LT effect is incompletely understood. Therefore, the purpose of this study was to employ EEG frequency analysis to investigate the cortical brain activity associated with the LT effect when attentional focus was strictly controlled with the eyes closed during standing (i.e., control, fixed-point touch, sway-referenced touch, and only fingertip attention). We used EEG to measure low-alpha (about 8-10 Hz) and high alpha rhythm (about 10-12 Hz) task-related power decrease/increase (TRPD/TRPI). The LT effect was apparent only when the subject acquired the stable external spatial reference (i.e., fixed-point touch). Furthermore, the LT-specific effect increased the high-alpha TRPD of two electrodes (C3, P3), which were mainly projected from cortical brain activities of the left primary sensorimotor cortex area and left posterior parietal cortex area. Furthermore, there was a negative correlation between the LT effect and increased TRPD of C3. In contrast, the LT effect correlated positively with increased TRPD of P3. These results suggest that central and parietal high-alpha TRPD of the contralateral hemisphere reflects the sensorimotor information processing and sensory integration for the LT effect. These novel findings reveal a partial contribution of a cortical neural mechanism for the LT effect. PMID- 26758720 TI - In Parkinson's disease on a probabilistic Go/NoGo task deep brain stimulation of the subthalamic nucleus only interferes with withholding of the most prepotent responses. AB - The evidence on the impact of subthalamic nucleus deep brain stimulation (STN DBS) on action restraint on Go/NoGO reaction time (RT) tasks in Parkinson's disease (PD) is inconsistent; with some studies reporting no effect and others finding that STN stimulation interferes with withholding of responses and results in more commission errors relative to STN-DBS off. We used a task in which the probability of Go stimuli varied from 100% (simple RT task) to 80, 50 and 20% (probabilistic Go/NoGo RT task), thus altering the prepotency of the response and the difficulty in withholding it on NoGo trials. Twenty PD patients with STN-DBS, ten unoperated PD patients and ten healthy controls participated in the study. All participants were tested twice; the order of on versus off stimulation for STN-DBS PD patients was counterbalanced. Both STN-DBS and unoperated PD patients were tested on medication. The results indicated that STN-DBS selectively decreased discriminability when the response was most prepotent (high--80%, as compared to low Go probability trials--50 and 20%). Movement times were faster with STN stimulation than with DBS off across different Go probability levels. There was neither an overall nor a selective effect of STN-DBS on RTs depending on the level of Go probability. Furthermore, compared to healthy controls, both STN-DBS and unoperated PD patients were more prone to making anticipatory errors; which was not influenced by STN stimulation. The results provide evidence for 'load-dependent' effects of STN stimulation on action restraint as a function of the prepotency of the Go response. PMID- 26758721 TI - Rewarding imperfect motor performance reduces adaptive changes. AB - Could a pat on the back affect motor adaptation? Recent studies indeed suggest that rewards can boost motor adaptation. However, the rewards used were typically reward gradients that carried quite detailed information about performance. We investigated whether simple binary rewards affected how participants learned to correct for a visual rotation of performance feedback in a 3D pointing task. To do so, we asked participants to align their unseen hand with virtual target cubes in alternating blocks with and without spatial performance feedback. Forty participants were assigned to one of two groups: a 'spatial only' group, in which the feedback consisted of showing the (perturbed) endpoint of the hand, or to a 'spatial & reward' group, in which a reward could be received in addition to the spatial feedback. In addition, six participants were tested in a 'reward only' group. Binary reward was given when the participants' hand landed in a virtual 'hit area' that was adapted to individual performance to reward about half the trials. The results show a typical pattern of adaptation in both the 'spatial only' and the 'spatial & reward' groups, whereas the 'reward only' group was unable to adapt. The rewards did not affect the overall pattern of adaptation in the 'spatial & reward' group. However, on a trial-by-trial basis, the rewards reduced adaptive changes to spatial errors. PMID- 26758722 TI - In vivo phosphorylation of a peptide tag for protein purification. AB - OBJECTIVES: To design a new system for the in vivo phosphorylation of proteins in Escherichia coli using the co-expression of the alpha-subunit of casein kinase II (CKIIalpha) and a target protein, (Nanofitin) fused with a phosphorylatable tag. RESULTS: The level of the co-expressed CKIIalpha was controlled by the arabinose promoter and optimal phosphorylation was obtained with 2 % (w/v) arabinose as inductor. The effectiveness of the phosphorylation system was demonstrated by electrophoretic mobility shift assay (NUT-PAGE) and staining with a specific phosphoprotein-staining gel. The resulting phosphorylated tag was also used to purify the phosphoprotein by immobilized metal affinity chromatography, which relies on the specific interaction of phosphate moieties with Fe(III). CONCLUSION: The use of a single tag for both the purification and protein array anchoring provides a simple and straightforward system for protein analysis. PMID- 26758723 TI - Production of delta-decalactone from linoleic acid via 13-hydroxy-9(Z) octadecenoic acid intermediate by one-pot reaction using linoleate 13-hydratase and whole Yarrowia lipolytica cells. AB - OBJECTIVE: To produce delta-decalactone from linoleic acid by one-pot reaction using linoleate 13-hydratase with supplementation with whole Yarrowia lipolytica cells. RESULTS: Whole Y. lipolytica cells at 25 g l(-1) produced1.9 g l(-1) delta decalactone from 7.5 g 13-hydroxy-9(Z)-octadecenoic acid l(-1) at pH 7.5 and 30 degrees C for 21 h. Linoleate 13-hydratase from Lactobacillus acidophilus at 3.5 g l(-1) with supplementation with 25 g Y. lipolytica cells l(-1) in one pot at 3 h produced 1.9 g l(-1) delta-decalactone from 10 g linoleic acid l(-1) via 13 hydroxy-9(Z)-octadecenoic acid intermediate at pH 7.5 and 30 degrees C after 18 h, with a molar conversion yield of 31 % and productivity of 106 mg l(-1) h(-1). CONCLUSION: To the best of our knowledge, this is the first production of delta decalactone using unsaturated fatty acid. PMID- 26758724 TI - A dual near-infrared and dielectric spectroscopies strategy to monitor populations of Chinese hamster ovary cells in bioreactor. AB - OBJECTIVE: to develop a new strategy combining near-infrared (NIR) and dielectric spectroscopies for real-time monitoring and in-depth characterizing populations of Chinese hamster ovary cells throughout cultures performed in bioreactors. RESULTS: Spectral data processing was based on off-line analyses of the cells, including trypan blue exclusion method, and lactate dehydrogenase activity (LDH). Viable cell density showed a linear correlation with permittivity up to 6 * 10(6) cells ml(-1), while a logarithmic correlation was found between non-lysed dead cell density and conductivity up to 10(7) cells ml(-1). Additionally, partial least square technique was used to develop a calibration model of the supernatant LDH activity based on online NIR spectra with a RMSEC of 55 U l(-1). Considering the LDH content of viable cells measured to be 110 U per 10(9) cells, the lysed dead cell density could be then estimated. These calibration models provided real time prediction accuracy (R(2) >= 0.95) for the three types of cell populations. CONCLUSION: The high potential of a dual spectroscopy strategy to enhance the online bioprocesses characterization is demonstrated since it allows the simultaneous determination of viable, dead and lysed cell populations in real time. PMID- 26758725 TI - SfiNX: a method for assembly of protein coding sequences with high success rates. AB - OBJECTIVE: Concatenation of two NdeI-XhoI gene fragments via an oligonucleotide linker on a plasmid vector with an SfiI site was performed to evaluate success rates in construction of polycistronic genes expressible in Escherichia coli. RESULTS: A series of plasmids with an SfiI site between the selection marker and the replication origin were constructed. The three wheat eEF1B subunit genes inserted between the NdeI and XhoI sites of pET-22b were transferred to the SfiI containing plasmid with a spectinomycin-resistance gene. Then, the marker gene in the resultant plasmids was substituted with the ampicillin-resistance gene. These plasmids were used for concatenation of two different genes via a linker oligonucleotide containing a ribosome-binding site. During these operations, 42 clones were picked up out of which 41 had the intended product plasmid. CONCLUSION: This method, named as the SfiNX method, is useful for trial-and-error based testing of different combinations of fusion and co-expression partners for optimization of recombinant protein production. PMID- 26758727 TI - Long-distance continuous-variable quantum key distribution by controlling excess noise. AB - Quantum cryptography founded on the laws of physics could revolutionize the way in which communication information is protected. Significant progresses in long distance quantum key distribution based on discrete variables have led to the secure quantum communication in real-world conditions being available. However, the alternative approach implemented with continuous variables has not yet reached the secure distance beyond 100 km. Here, we overcome the previous range limitation by controlling system excess noise and report such a long distance continuous-variable quantum key distribution experiment. Our result paves the road to the large-scale secure quantum communication with continuous variables and serves as a stepping stone in the quest for quantum network. PMID- 26758726 TI - 18F-FDG PET/CT in the early prediction of pathological response in aggressive subtypes of breast cancer: review of the literature and recommendations for use in clinical trials. AB - Early assessment of response to neoadjuvant chemotherapy (NAC) might be helpful in avoiding the toxicity of ineffective chemotherapy and allowing refinement of treatment. We conducted a review of the literature regarding the applicability of (18)F-FDG PET/CT to the prediction of an early pathological response in different subgroups of breast cancer. Clinical research in this field has intensified in the last few years. Early studies by various groups have shown the potential of (18)F-FDG PET/CT in the early assessment of response to NAC. However, interim PET/CT in breast cancer has not yet gained wide acceptance compared to its use in other settings such as lymphomas. This is in part due to a lack of consensus that early evaluation of response can be used to direct change in therapy in the neoadjuvant breast cancer setting, and only limited data showing that response adaptive therapy leads to improved outcomes. However, one major element that has hampered the use of (18)F-FDG PET/CT in directing neoadjuvant therapy is its evaluation in populations with mixed subtypes of breast cancer. However, major improvements have occurred in recent years. Pilot studies have highlighted the need for considering breast cancer subtype and the type of treatment, and have offered criteria for the use of PET/CT for the early prediction of response in specific settings. (18)F-FDG PET/CT has considerable potential for the early prediction of pathological complete response to NAC in aggressive subtypes such as triple-negative or HER2-positive breast cancers. The results of a multicentre trial that used early metabolic response on (18)F-FDG PET/CT as a means to select poor responders to adapt neoadjuvant treatment have recently been published. Other trials are ongoing or being planned. PMID- 26758729 TI - Genetic diversity and molecular evolution of arabis mosaic virus based on the CP gene sequence. AB - Arabis mosaic virus (ArMV) is a virus with a wide host range. In this study, the genetic diversity of ArMV and the molecular mechanisms underlying its evolution were investigated using the coat protein (CP) sequence. Of the 33 ArMV isolates studied, three were found to be recombinants. The other 30 recombination-free ArMV isolates could be separated into two major lineages with a significant F ST value (0.384) and tended to cluster according to their geographical origin. Different evolutionary constraints were detected for the two linages, pointing to a role of natural selection in the differentiation of ArMV. PMID- 26758728 TI - Treatment of irreducible atlantoaxial dislocation using the transoral atlantoaxial pedicle screw technique. A report of 10 cases. AB - OBJECTIVE: The purpose of this work is to evaluate the outcome of the transoral atlantoaxial pedicle screw technique for the treatment of irreducible atlantoaxial dislocation (IAAD). PATIENTS AND METHODS: A total of 10 patients with IAAD were treated using the transoral atlantoaxial pedicle screw technique. We compared preoperative and postoperative JOA (Japanese Orthopedic Association) scores and observed bone graft fusion rate of the atlantoaxial joint, and examined whether our technique was suitable for the treatment of IAAD. RESULTS: The mean preoperative and postoperative JOA scores (9.2 +/- 0.63 and 12.9 +/- 0.73, respectively) were significantly different (P < 0.05). The atlantoaxial rigid bony fusion rate was 100 % in 10 cases. All cases were followed up for an average of 5.1 years (range 3.5-6 years). CONCLUSION: The transoral atlantoaxial screw reconstruction plate technique is a novel surgical technique for the treatment of IAAD in upper cervical diseases. PMID- 26758730 TI - Genomic characterization and evolution analysis of a mutant reovirus isolated from grass carp in Anhui. PMID- 26758731 TI - Identification of (-)-epigallocatechin-3-gallate as a potential agent for blocking infection by grass carp reovirus. AB - Grass carp reovirus (GCRV), the representative strain of the species Aquareovirus C, serves as a model for studying the pathogenesis of aquareoviruses. Previously, epigallocatechin gallate (EGCG) was shown to inhibit orthoreovirus infection. The aim of this study was to test its potential in blocking infection by GCRV. We show that adhesion to the CIK (Ctenopharyngodon idellus kidney) cell surface by GCRV particles is inhibited in a dose-dependent manner by EGCG, as well as by a crude extract of green tea. We also evaluated the safety of EGCG and green tea extract using CIK cells, and the results suggest that EGCG is a promising compound that may be developed as a plant-derived small molecular therapeutic agent against grass carp hemorrhagic disease caused by GCRV infection. As the ligand for the 37/67-kDa laminin receptor (LamR), EGCG's blocking effect on GCRV attachment was associated with the binding potential of GCRV particles to LamR, which was inferred from a VOPBA assay. PMID- 26758732 TI - Genetic heterogeneity of the VP6 gene and predominance of G6P[5] genotypes of Brazilian porcine rotavirus C field strains. AB - The aim of this study was to investigate the genetic diversity of the VP6, VP7, and VP4 genes of 15 Brazilian wild-type porcine RVC strains identified in diarrheic fecal samples. The VP6 gene analysis demonstrated heterogeneity between the 15 RVC strains, which clustered in three distinct genotypes (I1, I5, and I6). In the VP7 and VP4 gene analysis, the genotype combination G6P[4] was detected in only one strain (UEL-77), while G6P[5] was the most commonly (n = 14) detected in RVC strains identified in the Brazilian pig herds evaluated, indicating its probable predominance in this country, mainly in 2014. PMID- 26758736 TI - Efficacy of Positive Airway Pressure on Serum Brain Natriuretic Peptide Levels in Patients with Heart Failure and Sleep-Disordered Breathing. PMID- 26758733 TI - Current characteristics and management of ST elevation and non-ST elevation myocardial infarction in the Tokyo metropolitan area: from the Tokyo CCU network registered cohort. AB - Limited data exists on ST-segment elevation myocardial infarction (STEMI) and non STEMI (NSTEMI) managed by a well-organized cardiac care network in a metropolitan area. We analyzed the Tokyo CCU network database in 2009-2010. Of 4329 acute myocardial infarction (AMI) patients including STEMI (n = 3202) and NSTEMI (n = 1127), percutaneous coronary intervention (PCI) was performed in 88.8 % of STEMI and 70.4 % of NSTEMI patients. Mean onset-to-door and door-to-balloon times in STEMI patients were shorter than those in NSTEMI patients (167 vs 233 and 60 vs 145 min, respectively, p < 0.001). Coronary artery bypass graft surgery was performed in 4.2 % of STEMI and 11.4 % of NSTEMI patients. In-hospital mortality was significantly higher in STEMI patients than NSTEMI patients (7.7 vs 5.1 %, p < 0.007). Independent correlates of in-hospital mortality were advanced age, low blood pressure, and high Killip classification, statin-treated dyslipidemia and PCI within 24 h were favorable predictors for STEMI. High Killip classification, high heart rate, and hemodialysis were significant predictors of in-hospital mortality, whereas statin-treated dyslipidemia was the only favorable predictor for NSTEMI. In conclusion, patients with MI received PCI frequently (83.5 %) and promptly (door-to-balloon time; 66 min), and had favorable in-hospital prognosis (in-hospital mortality; 7.0 %). In addition to traditional predictors of in hospital death, statin-treated dyslipidemia was a favorable predictor of in hospital mortality for STEMI and NSTEMI patients, whereas hemodialysis was the strongest predictor for NSTEMI patients. PMID- 26758734 TI - Sutureless aortic bioprosthesis valve implantation and bicuspid valve anatomy: an unsolved dilemma? AB - Interest is growing in the clinical use of sutureless (SU) valves. However, indications in some anatomical sub-settings, like bicuspid aortic valves (BAV), have been so far limited. We discuss herein our initial experience with the implantation of the 3f Enable SU bioprosthesis in patients with a BAV. Patients with a BAV were selected in our unit between March 2011 and September 2014 for a SU 3f Enable valve implantation. Twenty of the 198 patients who underwent a 3f Enable valve implantation in our unit had a BAV. Procedural success was 100 %, but reclamping was necessary in one (5 %) case. Median size of implanted bioprosthesis was 23 mm. After a mean follow-up of 13.8 +/- 10.7 months, survival was 100 %. Two patients (10 %) showed an immediate grade 1 paravalvular leak (PVL) that progressed to grade 2 and 3+ (moderate/severe), respectively, during follow-up. Type of bicuspidy (Sievers classification) in these two patients was 0 and intraoperatively aortic annuli admitted the 25 mm calibrator. Among the 18 patients without PVL, no one had a type 0 large BAV. At 1 year, implantation of the 3f Enable SU bioprosthesis appears to be safe in patients with BAV type I and II, while in type 0 use of the SU valve seems to be safe only if the annular diameter is <25 mm. Larger studies are necessary to confirm our findings in order to clarify the indications for SU technology in the subset of bicuspid patients. PMID- 26758737 TI - Psychiatry Departments Under Constrained Funding Mechanisms or What Is a Chairperson to Do? AB - OBJECTIVE: The authors surveyed academic departments of psychiatry to examine what effect decreases in funding levels may be having. METHODS: An internet survey of all departments of psychiatry was conducted at US medical schools. The response rate was 43 of 120 programs. Both large more research intensive and smaller more clinical departments responded. RESULTS: Majorities of departments reported that funding decreases negatively impacted faculty recruitment, research, faculty retention, and teaching programs. Approximately, one-third reported laying-off non-tenured faculty members and almost half, staff members. Graduate Medical Education (GME) funding was also a challenge. Departments reported responding by attempting to develop alternative funding sources. Few departments in the sample were doing significant fund raising. CONCLUSIONS: Academic departments find themselves stressed financially and are constricting some functions that are thought important. They are, in general, not able to replace lost funding. The research enterprise appears to be disproportionately affected and results in problems recruiting faculty. GME programs thus far seem less affected. Overall, funding issues appear to be causing serious issues that will have long-term consequences. PMID- 26758738 TI - Medical Student Stress, Burnout and Depression in Trinidad and Tobago. AB - OBJECTIVE: Health-care workers in developed nations are well known to experience high levels of burnout and psychiatric morbidity, but little information is available from the Caribbean and other less well-developed regions. This study sought to explore the prevalence of stress, burnout, and depressive symptoms and associated risk factors among medical students in Trinidad and Tobago, the southernmost Caribbean island. METHODS: A cross-sectional survey design was used to sample students. Data was collected utilizing standardized questionnaires that assess stress, burnout, and depressive symptoms. Demographic data and information pertaining to potential risk factors was also gathered. Overall, 450 questionnaires were distributed and analysis was performed upon 381 completed surveys (response rate 85%). RESULTS: Students demonstrated high levels of stress and a significant prevalence of burnout (52%) and depressive symptoms (40%). Final year students demonstrated higher levels of burnout and depressive symptoms. Students who (i) felt they lacked emotional support, (ii) had little opportunity for relaxation and exercise, and (iii) did not feel they had control of their daily schedule all demonstrated higher levels of burnout and depressive symptoms. However, students who practiced from a faith base and considered their religion important demonstrated lower levels of both. CONCLUSIONS: Medical students in Trinidad and Tobago are experiencing high levels of stress with a large proportion suffering from burnout and depressive symptoms. These data suggest that immediate interventions are necessary to help students cope with the challenges faced during medical school. Additionally, more research is needed to explore the potential causal links between burnout and depression during medical school and the effectiveness of tailored interventions especially within the context of developing nations. PMID- 26758739 TI - Using a Retreat to Develop a 4-Year Sexual Orientation and Gender Identity Curriculum. AB - OBJECTIVE: Lesbian, gay, bisexual, and transgender (LGBT) populations experience significant health disparities, yet medical schools report devoting little educational time to the care of this population. In light of this, one School of Medicine utilized a daylong retreat to design a 4-year sexual orientation and gender identity (SOGI) curriculum. METHODS: The participants completed pre-and post-surveys on their perspectives and knowledge towards SOGI learning, and the school's curriculum database was reviewed 2 years later to ascertain the degree of implementation of the proposed curriculum. RESULTS: Significant improvements were observed in participants' confidence in creating an SOGI curriculum, knowledge of SOGI teaching resources, and where in the curriculum SOGI competencies are and should be taught. A 6-month follow-up survey yielded a lower response rate, but suggested strong ongoing support for the new curriculum and some continuing challenges to implementing the proposed curriculum. A review of the school's curriculum database 2 years later showed an implementation rate of 76 %. CONCLUSION: A focused and systematic retreat can be an effective tool for curriculum design and implementation. PMID- 26758740 TI - Noise reduction of diffusion tensor images by sparse representation and dictionary learning. AB - BACKGROUND: The low quality of diffusion tensor image (DTI) could affect the accuracy of oncology diagnosis. METHODS: We present a novel sparse representation based denoising method for three dimensional DTI by learning adaptive dictionary with the context redundancy between neighbor slices. In this study, the context redundancy among the adjacent slices of the diffusion weighted imaging volumes is utilized to train sparsifying dictionaries. Therefore, higher redundancy could be achieved for better description of image with lower computation complexity. The optimization problem is solved efficiently using an iterative block-coordinate relaxation method. RESULTS: The effectiveness of our proposed method has been assessed on both simulated and real experimental DTI datasets. Qualitative and quantitative evaluations demonstrate the performance of the proposed method on the simulated data. The experiments on real datasets with different b-values also show the effectiveness of the proposed method for noise reduction of DTI. CONCLUSIONS: The proposed approach well removes the noise in the DTI, which has high potential to be applied for clinical oncology applications. PMID- 26758741 TI - Active and legacy mining in an arid urban environment: challenges and perspectives for Copiapo, Northern Chile. AB - Urban expansion in areas of active and legacy mining imposes a sustainability challenge, especially in arid environments where cities compete for resources with agriculture and industry. The city of Copiapo, with 150,000 inhabitants in the Atacama Desert, reflects this challenge. More than 30 abandoned tailings from legacy mining are scattered throughout its urban and peri-urban area, which include an active copper smelter. Despite the public concern generated by the mining-related pollution, no geochemical information is currently available for Copiapo, particularly for metal concentration in environmental solid phases. A geochemical screening of soils (n = 42), street dusts (n = 71) and tailings (n = 68) was conducted in November 2014 and April 2015. Organic matter, pH and elemental composition measurements were taken. Notably, copper in soils (60-2120 mg/kg) and street dusts (110-10,200 mg/kg) consistently exceeded international guidelines for residential and industrial use, while a lower proportion of samples exceeded international guidelines for arsenic, zinc and lead. Metal enrichment occurred in residential, industrial and agricultural areas near tailings and the copper smelter. This first screening of metal contamination sets the basis for future risk assessments toward defining knowledge-based policies and urban planning. Challenges include developing: (1) adequate intervention guideline values; (2) appropriate geochemical background levels for key metals; (3) urban planning that considers contaminated areas; (4) cost-effective control strategies for abandoned tailings in water-scarce areas; and (5) scenarios and technologies for tailings reprocessing. Assessing urban geochemical risks is a critical endeavor for areas where extreme events triggered by climate change are likely, as the mud flooding that impacted Copiapo in late March 2015. PMID- 26758742 TI - The trade-off between heat tolerance and metabolic cost drives the bimodal life strategy at the air-water interface. AB - The principle of oxygen and capacity limitation of thermal tolerance in ectotherms suggests that the long-term upper limits of an organism's thermal niche are equivalent to the upper limits of the organism's functional capacity for oxygen provision to tissues. Air-breathing ectotherms show wider thermal tolerances, since they can take advantage of the higher availability of oxygen in air than in water. Bimodal species move from aquatic to aerial media and switch between habitats in response to environmental variations such as cyclical or anomalous temperature fluctuations. Here we tested the prediction that bimodal species cope better with thermal stress than truly aquatic species using the crab Pachygrapsus marmoratus as a model species. When in water, oxygen consumption rates of P. marmoratus acutely rise during warming. Beyond a temperature threshold of 23 degrees C the crab's aerobic metabolism in air remains lower than in water. In parallel, the haemolymph oxygen partial pressure of submerged animals progressive decreases during warming, while it remains low but constant during emersion. Our results demonstrate the ability of a bimodal breathing ectotherm to extend its thermal tolerance during air-breathing, suggesting that there are temperature-related physiological benefits during the evolution of the bimodal life style. PMID- 26758743 TI - DNA barcoding reveals commercial fraud related to yak jerky sold in China. PMID- 26758744 TI - Combining long-lasting insecticidal nets and indoor residual spraying for malaria prevention in Ethiopia: study protocol for a cluster randomized controlled trial. AB - BACKGROUND: Long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) are the main malaria prevention interventions in Ethiopia. There is conflicting evidence that the combined application of both interventions is better than either LLINs or IRS used alone. This trial aims to investigate whether the combination of LLINs (PermaNet 2.0, Vestergaard Frandsen, Lausanne, Switzerland) with IRS using propoxur will enhance the protective benefits and cost-effectiveness of the interventions against malaria and its effect on mosquito behavior, as compared to each intervention alone. METHODS/DESIGN: This 2 x 2 factorial cluster randomized controlled trial is being carried out in the Adami Tullu district in south-central Ethiopia for about 116 weeks from September 2014 to December 2016. The trial is based on four arms: LLINs + IRS, LLINs alone, IRS alone and control. Villages (or clusters) will be the unit of randomization. The sample size includes 44 clusters per arm, with each cluster comprised of approximately 35 households (about 175 people). Prior to intervention, all households in the LLINs + IRS and LLINs alone arms will be provided with LLINs free of charge. Households in the LLINs + IRS and IRS alone arms will be sprayed with carbamate propoxur once a year just before the main malaria transmission season throughout the investigation. The primary outcome of this trial will be a malaria incidence based on the results of the rapid diagnostic tests in patients with a fever or history of fever attending health posts by passive case detection. Community-based surveys will be conducted each year to assess anemia among children 5-59 months old. In addition, community-based malaria prevalence surveys will be conducted each year on a representative sample of households during the main transmission season. The cost-effectiveness of the interventions and entomological studies will be simultaneously conducted. Analysis will be based on an intention-to-treat principle. DISCUSSION: This trial aims to provide evidence on the combined use of LLINs and IRS for malaria prevention by answering the following research questions: Can the combined use of LLINs and IRS significantly reduce the incidence of malaria compared with the use of either LLINs or IRS alone? And is the reduced incidence justifiable compared to the added costs? Will the combined use of LLINs and IRS reduce vector density, infection, longevity and the entomological inoculation rate? These data are crucial in order to maximize the impact of vector control interventions on the morbidity and mortality of malaria. TRIAL REGISTRATION: PACTR201411000882128 (8 September 2014). PMID- 26758745 TI - Prognostic value of high FoxC2 expression in resectable non-small cell lung cancer, alone or in combination with E-cadherin expression. AB - BACKGROUND: FoxC2 is an epithelial-mesenchymal transition (EMT) regulator which induces metastasis. The purpose of this study is to assess the prognostic value of FoxC2 expression in non-small cell lung cancer (NSCLC), alone or in combination with E-cadherin expression. METHODS: A retrospective study was conducted using immunohistochemistry to investigate FoxC2 and E-cadherin expression in a cohort of 309 patients with surgically resected NSCLCs. The prognostic value of FoxC2 and E-cadherin on overall survival (OS) and recurrence free survival (RFS) was determined by Kaplan-Meier analysis and Cox proportional hazard models. RESULTS: High FoxC2 expression was detected in 26.5% of tumors, and significantly correlated with tobacco use (p = 0.047), adenocarcinoma (p = 0.008) and nodal involvement (p < 0.001). Univariate analysis revealed its association with OS (p = 0.036) and RFS (p = 0.011). By multivariate analysis, high FoxC2 expression lost its significance as an independent predictor of recurrence (p = 0.077), while TNM stage, nodal status and the presence of high FoxC2 and impaired E-cadherin expression retained independent prognostic significance in relation to both OS and RFS. Subset analyses indicated that high FoxC2 expression was significantly associated with disease outcome in node positive, but not in node-negative patients. CONCLUSION: Evaluation of FoxC2 expression, alone or in combination with E-cadherin expression, may help to stratify NSCLC patients for risk of disease progression, pointing to this EMT regulator as a potential prognostic marker. PMID- 26758746 TI - Analysis of trabecular bone microstructure in osteoporotic femoral heads in human patients: in vivo study using multidetector row computed tomography. AB - BACKGROUND: Lag screw position is very important in the treatment of intertrochanteric femoral fracture to prevent complications such as screw cut out. Current studies recommend central or inferior placement of the lag screw on the anteroposterior radiograph, and central placement on the lateral radiographs. These reports are based on radiographic evaluation, but few studies have investigated the importance of bone quality at the site of lag screw placement. In this study, we used multidetector row computed tomography (MDCT) to perform in vivo evaluation of the bone microstructure of the femoral head in patients with intertrochanteric femoral fractures. METHODS: This study was approved by the Ethics Committee of Okanami General Hospital. MDCT images were obtained in our hospital from ten patients who had sustained intertrochanteric femoral fracture. Patients who needed computed tomography to confirm fracture morphology were included. We defined six areas as regions of interest (ROI): ROI 1-3 were defined as the femoral head apex area, and ROI 4-6 were defined as the femoral neck area. Trabecular microstructure parameters, including mean bone volume to total volume (BV/TV), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), and structure model index (SMI), were evaluated with bone analysis software (TRI/3D BON). Statistical analyses were performed using EZR software; each parameter among the ROIs was statistically evaluated by analysis of variance (ANOVA) and Tukey's test. Statistical significance was established at p < 0.05. RESULTS: In the apical area, all parameters indicated that ROI 1 (superior) had the highest bone quality and ROI 2 (central) was higher in bone quality than ROI 3 (inferior). In the femoral neck, all parameters indicated that bone quality was significantly greater in ROI 6 (inferior) than ROI 5 (central). DISCUSSION AND CONCLUSIONS: We could evaluate bone quality with clinical MDCT in vivo. Bone quality in the central area of the femoral head apical was greater than in the inferior area, and bone quality in the inferior area of the femoral neck was greater than in the central area. Recognizing which area of femoral head has greater bone quality may lead to a better clinical result in treating intertrochanteric femoral fracture. PMID- 26758748 TI - Climate change and non-communicable diseases. PMID- 26758747 TI - A double blind community-based randomized trial of amoxicillin versus placebo for fast breathing pneumonia in children aged 2-59 months in Karachi, Pakistan (RETAPP). AB - BACKGROUND: Fast breathing pneumonia is characterized by tachypnoea in the absence of danger signs and is mostly viral in etiology. Current guidelines recommend antibiotic therapy for all children with fast breathing pneumonia in resource limited settings, presuming that most pneumonia is bacterial. High quality clinical trial evidence to challenge or support the continued use of antibiotics, as recommended by the World Health Organization is lacking. METHODS/DESIGN: This is a randomized double blinded placebo-controlled non inferiority trial using parallel assignment with 1:1 allocation ratio, to be conducted in low income squatter settlements of urban Karachi, Pakistan. Children 2-59 months old with fast breathing, without any WHO-defined danger signs and seeking care at the primary health care center are randomized to receive either three days of placebo or amoxicillin. From prior studies, a sample size of 2430 children is required over a period of 28 months. Primary outcome is the difference in cumulative treatment failure between the two groups, defined as a new clinical sign based on preset definitions indicating illness progression or mortality and confirmed by two independent primary health care physicians on day 0, 1, 2 or 3 of therapy. Secondary outcomes include relapse measured between days 5-14. Modified per protocol analysis comparing hazards of treatment failure with 95% confidence intervals in the placebo arm with hazards in the amoxicillin arm will be done. DISCUSSION: This study will provide evidence to support or refute the use of antibiotics for fast breathing pneumonia paving a way for guideline change. TRIAL REGISTRATION: Clinical Trials (NIH) Register NCT02372461. PMID- 26758749 TI - Price, value, and the cost of cancer drugs. PMID- 26758750 TI - Importance of including patients with comorbidities in clinical trials. PMID- 26758752 TI - Consume, digest, and expire: the risks of domesticated carcinogens. PMID- 26758751 TI - Melatonin: resetting the clock of cancer progression? PMID- 26758753 TI - Allo-HCT regimens with low toxicity needed in older patients with acute myeloid leukaemia--Authors' reply. PMID- 26758754 TI - Allo-HCT regimens with low toxicity needed in older patients with acute myeloid leukaemia. PMID- 26758755 TI - Barriers to access to opioid medicines: a review of national legislation and regulations of 11 central and eastern European countries. AB - Control measures designed to prevent the misuse of opioid medicines can often unintentionally restrict legitimate medical use, leaving patients with cancer in pain. This study aimed to develop and validate an assessment instrument based on WHO policy guidelines to systematically identify legal and regulatory barriers to opioid access in 11 European countries (Bulgaria, Cyprus, Estonia, Greece, Hungary, Latvia, Lithuania, Serbia, Slovakia, Slovenia, and Turkey) as part of the Access to Opioid Medication in Europe project. Relevant legislation and regulations were independently assessed by three reviewers and potential barriers were identified within nine categories including prescribing, penalties, and others. Potential barriers were identified in all countries, ranging from 22 potential barriers (Cyprus) to 128 potential barriers (Lithuania). The total number of barriers in a single category varied from one (Slovenia, usage category) to 49 (Greece, prescribing category). Differences, such as prescription validity, varied within one category, ranging from 5 days (Hungary) to 13 weeks (Cyprus). The results of this Review should give rise to a national review and revision of provisions that impede access to opioids, disproportionate to their (intended) benefit in preventing misuse, in these 11 European countries. PMID- 26758756 TI - The role of a meal on gastrointestinal toxicity and maximum tolerated dose. PMID- 26758757 TI - A new classification for mandibular defects after oncological resection. AB - No universally accepted classification system exists for mandibular defects after oncological resection. Here, we discuss the scientific literature on classifications for mandibular defects that are sufficiently presented either pictorially or descriptively, and propose a new classification system based on these findings. Of 167 studies included in the data analysis, 49 of these reports sufficiently described the defect for analysis. These reports were analysed for classification, reconstruction, size of defect, number of osteotomies needed, and complications. On the basis of these findings, a new classification is proposed based on the four corners of the mandible (two angles and two canines): class I (lateral), class II (hemimandibulectomy), class III (anterior), and class IV (extensive). Further classes (Ic, IIc, and IVc) include condylectomy. The increasing defect class relates to the size of the defect, osteotomy rate, and functional and aesthetic outcome, and could guide the method of reconstruction. PMID- 26758758 TI - Radiation dose and checkpoint blockade immunotherapy: unanswered questions. PMID- 26758759 TI - Postmarket policy considerations for biosimilar oncology drugs. AB - Oncology biological products are some of the most expensive drugs on the market and are a growing financial burden on patients and health-care systems. By 2020, numerous major biological cancer drugs will lose their patent protection allowing follow-on competitors, known as biosimilars, to enter the market. Clinical and regulatory considerations for biosimilars have begun to harmonise in Europe and the USA to help to define and streamline the pathway for biosimilar market authorisation. Yet, substantial international variation still exists in the pricing and market uptake of approved biosimilar oncology drugs. Differences in national postmarket policies for biosimilars might explain these disparities in pricing and uptake. In this Policy Review, policy approaches to competition between biosimilars and originators used by seven European countries--Belgium, France, Germany, Italy, the Netherlands, Norway, and the UK--and the USA are discussed, chosen because these countries represent a variety of postmarket policies and build on conclusions from previous work. We discuss these policies within the context of interchangeability, physician prescribing, substitutability, pharmacist dispensing, hospital financing and tendering, and pricing. PMID- 26758760 TI - Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. PMID- 26758762 TI - Increased expression of LncRNA BANCR and its prognostic significance in human hepatocellular carcinoma. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) have been proved to play important roles in the tumorigenesis and development of human hepatocellular carcinoma (HCC). The aim of our study is to investigate the expression and function of BRAF activated noncoding RNA (BANCR) in HCC. METHODS: BANCR expression was detected in HCC tissues and cell lines by using quantitative real-time PCR (qRT-PCR). Association between BANCR levels and clinicopathological factors and patient prognosis was also analyzed. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), flow cytometry, and transwell invasion and migration assays were used to investigate the role of BANCR in the regulation of biological behaviors of HCC cells. RESULTS: BANCR expression was remarkably increased in HCC tissues compared with adjacent noncancerous tissues (P<0.001). BANCR expression in four HCC cell lines was also significantly upregulated (P<0.05). Clinicopathologic analysis revealed that high BANCR expression correlated with high tumor grade, large tumor size, venous infiltration, advanced tumor, node, and metastasis (TNM) stage, and shorter overall survival. Multivariate regression analysis identified BANCR overexpression as an independent unfavorable prognostic factor (relative risk [RR] 4.245; P=0.015) in HCC patients. Moreover, BANCR downregulation in Hep3B cells impaired cell proliferation, promoted cell apoptosis, reduced cell invasion and migration, led to downregulated vimentin, and upregulated E-cadherin protein levels. CONCLUSIONS: These findings suggested that BANCR may contribute to HCC initiation and progression and would be used as not only a novel prognostic marker but also a potential therapeutic target for this disease. PMID- 26758764 TI - Influence of Controlled Postflowering Temperature and Daylength on Individual Phenolic Compounds in Four Black Currant Cultivars. AB - The effects of postflowering temperature and daylength on the concentration of individual phenolic compounds were studied in black currant (Ribes nigrum L.) berries under controlled phytotron conditions. The four cultivars studied varied greatly in their concentrations of individual phenolic compounds and temperature stability for accumulation. The concentrations of a wide range of identified phenolic compounds were strongly influenced by temperature over the 12-24 degrees C range, often with opposite temperature gradient patterns for compounds within the same subclass. Accumulation of anthocyanins and flavonols increased under natural long day conditions, which provided an increased daily light integral, while under identical light energy conditions, photoperiod had little or no effect on the concentration of phenolic compounds. Furthermore, with the exception of members of the hydroxycinnamic acid subclass, the concentration of most phenolic compounds was higher in berries ripened outdoors than in the phytotron, apparently due to screening of UV-B radiation by the glass cover. PMID- 26758763 TI - Medical students are afraid to include abortion in their future practices: in depth interviews in Maharastra, India. AB - BACKGROUND: Unsafe abortions are estimated to cause eight per-cent of maternal mortality in India. Lack of providers, especially in rural areas, is one reason unsafe abortions take place despite decades of legal abortion. Education and training in reproductive health services has been shown to influence attitudes and increase chances that medical students will provide abortion care services in their future practice. To further explore previous findings about poor attitudes toward abortion among medical students in Maharastra, India, we conducted in depth interviews with medical students in their final year of education. METHOD: We used a qualitative design conducting in-depth interviews with twenty-three medical students in Maharastra applying a topic guide. Data was organized using thematic analysis with an inductive approach. RESULTS: The participants described a fear to provide abortion in their future practice. They lacked understanding of the law and confused the legal regulation of abortion with the law governing gender biased sex selection, and concluded that abortion is illegal in Maharastra. The interviewed medical students' attitudes were supported by their experiences and perceptions from the clinical setting as well as traditions and norms in society. Medical abortion using mifepristone and misoprostol was believed to be unsafe and prohibited in Maharastra. The students perceived that nurse-midwives were knowledgeable in Sexual and Reproductive Health and many found that they could be trained to perform abortions in the future. CONCLUSIONS: To increase chances that medical students in Maharastra will perform abortion care services in their future practice, it is important to strengthen their confidence and knowledge through improved medical education including value clarification and clinical training. PMID- 26758765 TI - Granulocyte colony-stimulating factor in secondary prophylaxis for advanced-stage Hodgkin lymphoma treated with ABVD chemotherapy: a cost-effectiveness analysis. AB - Granulocyte colony-stimulating factor (G-CSF) is commonly administered to patients with Hodgkin lymphoma (HL) with neutropenia. We constructed a decision analytic model to compare the cost-effectiveness of secondary prophylaxis with G CSF to a strategy of 'no G-CSF' in response to severe neutropenia for adults with advanced-stage HL treated with ABVD. A Canadian public health payer's perspective was considered and costs were presented in 2013 Canadian dollars. The quality adjusted life years (QALYs) attained with the G-CSF and 'no G-CSF' strategies were 1.403 and 1.416, respectively. Costs for the strategies with and without G CSF were $38,971 and $33,982, respectively. In the base case analysis, the 'no G CSF' strategy was associated with cost savings and improved QALYs; therefore, 'no G-CSF' was the dominant approach. For patients with severe neutropenia during ABVD chemotherapy for advanced-stage HL, a strategy without G-CSF support is associated with improved quality-adjusted outcomes, cost savings, and is the preferred approach. PMID- 26758761 TI - Slowed aging during reproductive dormancy is reflected in genome-wide transcriptome changes in Drosophila melanogaster. AB - BACKGROUND: In models extensively used in studies of aging and extended lifespan, such as C. elegans and Drosophila, adult senescence is regulated by gene networks that are likely to be similar to ones that underlie lifespan extension during dormancy. These include the evolutionarily conserved insulin/IGF, TOR and germ line-signaling pathways. Dormancy, also known as dauer stage in the larval worm or adult diapause in the fly, is triggered by adverse environmental conditions, and results in drastically extended lifespan with negligible senescence. It is furthermore characterized by increased stress resistance and somatic maintenance, developmental arrest and reallocated energy resources. In the fly Drosophila melanogaster adult reproductive diapause is additionally manifested in arrested ovary development, improved immune defense and altered metabolism. However, the molecular mechanisms behind this adaptive lifespan extension are not well understood. RESULTS: A genome wide analysis of transcript changes in diapausing D. melanogaster revealed a differential regulation of more than 4600 genes. Gene ontology (GO) and KEGG pathway analysis reveal that many of these genes are part of signaling pathways that regulate metabolism, stress responses, detoxification, immunity, protein synthesis and processes during aging. More specifically, gene readouts and detailed mapping of the pathways indicate downregulation of insulin IGF (IIS), target of rapamycin (TOR) and MAP kinase signaling, whereas Toll dependent immune signaling, Jun-N-terminal kinase (JNK) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways are upregulated during diapause. Furthermore, we detected transcriptional regulation of a large number of genes specifically associated with aging and longevity. CONCLUSIONS: We find that many affected genes and signal pathways are shared between dormancy, aging and lifespan extension, including IIS, TOR, JAK/STAT and JNK. A substantial fraction of the genes affected by diapause have also been found to alter their expression in response to starvation and cold exposure in D. melanogaster, and the pathways overlap those reported in GO analysis of other invertebrates in dormancy or even hibernating mammals. Our study, thus, shows that D. melanogaster is a genetically tractable model for dormancy in other organisms and effects of dormancy on aging and lifespan. PMID- 26758776 TI - Fractal and Lacunarity Analyses: Quantitative Characterization of Hierarchical Surface Topographies. AB - Biomimetic hierarchical surface structures that exhibit features having multiple length scales have been used in many technological and engineering applications. Their surface topographies are most commonly analyzed using scanning electron microscopy (SEM), which only allows for qualitative visual assessments. Here we introduce fractal and lacunarity analyses as a method of characterizing the SEM images of hierarchical surface structures in a quantitative manner. Taking femtosecond laser-irradiated metals as an example, our results illustrate that, while the fractal dimension is a poor descriptor of surface complexity, lacunarity analysis can successfully quantify the spatial texture of an SEM image; this, in turn, provides a convenient means of reporting changes in surface topography with respect to changes in processing parameters. Furthermore, lacunarity plots are shown to be sensitive to the different length scales present within a hierarchical structure due to the reversal of lacunarity trends at specific magnifications where new features become resolvable. Finally, we have established a consistent method of detecting pattern sizes in an image from the oscillation of lacunarity plots. Therefore, we promote the adoption of lacunarity analysis as a powerful tool for quantitative characterization of, but not limited to, multi-scale hierarchical surface topographies. PMID- 26758766 TI - Analysis of a four generation family reveals the widespread sequence-dependent maintenance of allelic DNA methylation in somatic and germ cells. AB - Differential methylation of the homologous chromosomes, a well-known mechanism leading to genomic imprinting and X-chromosome inactivation, is widely reported at the non-imprinted regions on autosomes. To evaluate the transgenerational DNA methylation patterns in human, we analyzed the DNA methylomes of somatic and germ cells in a four-generation family. We found that allelic asymmetry of DNA methylation was pervasive at the non-imprinted loci and was likely regulated by cis-acting genetic variants. We also observed that the allelic methylation patterns for the vast majority of the cis-regulated loci were shared between the somatic and germ cells from the same individual. These results demonstrated the interaction between genetic and epigenetic variations and suggested the possibility of widespread sequence-dependent transmission of DNA methylation during spermatogenesis. PMID- 26758767 TI - Parental solicitation, parental control, child disclosure, and substance use: native and immigrant Dutch adolescents. AB - OBJECTIVES: The present study examined whether the relation of parental solicitation, parental control, and child disclosure with adolescent alcohol and cannabis use is similar for native and non-Western immigrant Dutch adolescents. DESIGN: Questionnaire data from two study-samples were used with a combined sample of 705 adolescents (mean age 16.2 years; 47.2% female; 25.2% non-Western immigrant background). RESULTS: Native Dutch adolescents reported more weekly alcohol use than immigrant adolescents, while rates of cannabis use by native and immigrant adolescents were similar. Immigrant females reported lower levels of parental solicitation and child disclosure, but higher levels of parental control than native females. There were no differences in the sources of parental knowledge between native and immigrant males. Regression analyses showed no significant interaction effects of parental solicitation, parental control, or child disclosure with ethnic background for both alcohol and cannabis use (all p values > .05). CONCLUSION: Despite mean level differences in various factors, we did not find evidence of an interaction effect of the sources of parental knowledge with ethnic background on alcohol and cannabis use. This suggests that theories and prevention strategies focusing on these sources of parental knowledge in relation to substance use can be applicable to both native and immigrant Dutch adolescents. PMID- 26758777 TI - Editorial for Chemical Reviews. PMID- 26758778 TI - Pull-out strength comparison of a novel expanding fastener against an orthopaedic screw in an ovine vertebral body: an ex-vivo study. AB - The purpose of this study was to mechanically test a novel Unthreaded Expandable Fastener (UEF), manufactured using Selective Laser Melting, which was designed for fixation in the cervical lateral mass. The pull-out strength and stiffness of the prototype UEFs was evaluated in a non-osteoporotic ovine bone model against equivalent screws. The prototype UEF demonstrated a 41% increase in failure force and a 60% reduction in failure force standard deviation compared to the screws. All bone samples were micro CT-scanned and no significant differences in bone microstructural properties was found between the screw and UEF sample sets, indicating that the UEFs may be less sensitive to bone quality variation. This increased performance can potentially translate into improved surgical outcome and reduced surgical risk for lateral mass fixation. With further design optimisation, additional improvement in performance over screws may be possible in future studies. PMID- 26758779 TI - Attentional biases to faces expressing disgust in children with autism spectrum disorders: an exploratory study. AB - Previous studies on attentional bias towards emotional faces in individuals with autism spectrum disorders (ASD) provided mixed results. This might be due to differences in the examined attentional bias components and emotional expressions. This study assessed three bias components, hypervigilance, disengagement, and avoidance, using faces with a disgust, happy, or neutral expression in a dot-probe and external cuing task in 18 children with ASD and 21 typically developing (TD) children. The children with ASD initially displayed hypervigilance towards the disgust faces, followed by a general tendency to avoid looking back at the spatial location at which any face, irrespective of its emotional expression, had been presented. These results highlight the importance of differentiating between attentional bias components in research on ASD. PMID- 26758781 TI - Single cells in confined volumes: microchambers and microdroplets. AB - Microfluidic devices capable of manipulating and guiding small fluid volumes open new methodical approaches in the fields of biology, pharmacy, and medicine. They have already proven their extraordinary value for cell analysis. The emergence of microfluidic platforms has paved the way to novel analytical strategies for the positioning, treatment and observation of living cells, for the creation of chemically defined liquid environments, and for tailoring biomechanical or physical conditions in small volumes. In this article, we particularly focus on two complementary approaches: (i) the isolation of cells in small chambers defined by microchannels and integrated valves and (ii) the encapsulation of cells in microdroplets. We review the advantages and limitations of both approaches and discuss their potential for single-cell analysis and related fields. Our intention is also to give a recommendation on which platform is most appropriate for a new question, i.e., a guideline to choose the most suitable platform. PMID- 26758782 TI - Mixed multilayered vertical heterostructures utilizing strained monolayer WS2. AB - Creating alternating layers of 2D materials forms vertical heterostructures with diverse electronic and opto-electronic properties. Monolayer WS2 grown by chemical vapour deposition can have inherent strain due to interactions with the substrate. The strain modifies the band structure and properties of monolayer WS2 and can be exploited in a wide range of applications. We demonstrate a non aqueous transfer method for creating vertical stacks of mixed 2D layers containing a strained monolayer of WS2, with Boron Nitride and Graphene. The 2D materials are all grown by CVD, enabling large area vertical heterostructures to be formed. WS2 monolayers grown by CVD directly on Si substrates with SiO2 surface are easily washed off by water and this makes aqueous based transfer methods challenging for creating vertical stacks on the growth substrate. 2D hexagonal Boron Nitride films are used to provide an insulating layer that limits interactions with a top graphene layer and preserve the strong photoluminescence from the WS2. This transfer method is suitable for layer by layer control of 2D material vertical stacks and is shown to be possible for all CVD grown samples, which opens up pathways for the rapid large scale fabrication of vertical heterostructure systems with atomic thickness depth control and large area coverage. PMID- 26758780 TI - A synergistic approach to the design, fabrication and evaluation of 3D printed micro and nano featured scaffolds for vascularized bone tissue repair. AB - 3D bioprinting has begun to show great promise in advancing the development of functional tissue/organ replacements. However, to realize the true potential of 3D bioprinted tissues for clinical use requires the fabrication of an interconnected and effective vascular network. Solving this challenge is critical, as human tissue relies on an adequate network of blood vessels to transport oxygen, nutrients, other chemicals, biological factors and waste, in and out of the tissue. Here, we have successfully designed and printed a series of novel 3D bone scaffolds with both bone formation supporting structures and highly interconnected 3D microvascular mimicking channels, for efficient and enhanced osteogenic bone regeneration as well as vascular cell growth. Using a chemical functionalization process, we have conjugated our samples with nano hydroxyapatite (nHA), for the creation of novel micro and nano featured devices for vascularized bone growth. We evaluated our scaffolds with mechanical testing, hydrodynamic measurements and in vitro human mesenchymal stem cell (hMSC) adhesion (4 h), proliferation (1, 3 and 5 d) and osteogenic differentiation (1, 2 and 3 weeks). These tests confirmed bone-like physical properties and vascular like flow profiles, as well as demonstrated enhanced hMSC adhesion, proliferation and osteogenic differentiation. Additional in vitro experiments with human umbilical vein endothelial cells also demonstrated improved vascular cell growth, migration and organization on micro-nano featured scaffolds. PMID- 26758783 TI - Paediatrics: T cells in necrotizing enterocolitis. PMID- 26758784 TI - Regenerative medicine in 2015: Generating and regenerating the digestive system. AB - Advances into understanding stem and progenitor cells and organoids of the gastrointestinal tract have continued apace. New research published in 2015 identified new cell populations involved in liver regeneration and highlighted the development of pancreatic and gastric organoids. PMID- 26758785 TI - IBD: Probiotics for IBD: a need for histamine? PMID- 26758786 TI - Immunology in the liver--from homeostasis to disease. AB - The liver is a central immunological organ with a high exposure to circulating antigens and endotoxins from the gut microbiota, particularly enriched for innate immune cells (macrophages, innate lymphoid cells, mucosal-associated invariant T (MAIT) cells). In homeostasis, many mechanisms ensure suppression of immune responses, resulting in tolerance. Tolerance is also relevant for chronic persistence of hepatotropic viruses or allograft acceptance after liver transplantation. The liver can rapidly activate immunity in response to infections or tissue damage. Depending on the underlying liver disease, such as viral hepatitis, cholestasis or NASH, different triggers mediate immune-cell activation. Conserved mechanisms such as molecular danger patterns (alarmins), Toll-like receptor signalling or inflammasome activation initiate inflammatory responses in the liver. The inflammatory activation of hepatic stellate and Kupffer cells results in the chemokine-mediated infiltration of neutrophils, monocytes, natural killer (NK) and natural killer T (NKT) cells. The ultimate outcome of the intrahepatic immune response (for example, fibrosis or resolution) depends on the functional diversity of macrophages and dendritic cells, but also on the balance between pro-inflammatory and anti-inflammatory T-cell populations. As reviewed here, tremendous progress has helped to understand the fine-tuning of immune responses in the liver from homeostasis to disease, indicating promising targets for future therapies in acute and chronic liver diseases. PMID- 26758787 TI - Liver fibrosis in 2015: Crucial steps towards an effective treatment. PMID- 26758788 TI - Pancreatic cancer in 2015: Precision medicine in pancreatic cancer--fact or fiction? AB - Late diagnosis and an inability to personalize treatment are major problems preventing reductions in pancreatic cancer mortality. In 2015, the identification of a highly discriminatory exosomal biomarker, culture systems that recapitulate human disease and new methods of analysing large data sets to identify prognostic markers have improved the future outlook for patients with this cancer. PMID- 26758789 TI - [Descending necrotizing mediastinitis : Treatment concept with focus on thoracic surgery]. AB - BACKGROUND: Descending necrotizing mediastinitis (DNM) originates from odontogenic or oropharyngeal infections which spread along preformed cervicothoracic spaces into the mediastinum and requires emergency multidisciplinary treatment. MATERIAL AND METHODS: A total of seven patients were diagnosed with DNM based on typical radiological features in a cervicothoracic computed tomography (CT) scan and subsequently underwent standardized transcervical and open transthoracic radical debridement. RESULTS: The initially detected polymicrobial spectrum of pathogens was dominated by streptococci followed by enterobacteriae. After calculated antibiotic treatment a shift in the spectrum of pathogens was noted and in particular a mycotic superinfection occurred in 43 % of the cases. Anterolateral thoracotomy was performed for radical removal of tissue necrosis and mediastinothoracic drainage extending to the posterior mediastinum was placed. In selected cases, cervico-mediastino thoracic tubes were transmediastinally placed by the rendevouz technique either in the previsceral or retrovisceral mediastinal space. Despite predominantly advanced mediastinitis (Endo classification type II B) in this patient cohort, the mortality only reached 14 %. CONCLUSION: Rapid diagnosis, anatomical knowledge, understanding of the progression of infections as well as critical care, antimicrobial treatment and multidisciplinary radical surgical therapy are paramount for successful treatment of DNM. We favor anterolateral thoracotomy as the standard open transthoracic approach to the mediastinum. Placement of cervico mediastino-thoracic irrigation drains can help to limit DNM. PMID- 26758790 TI - Simultaneous pancreas/kidney transplant recipients present with late-onset BK polyomavirus-associated nephropathy. AB - BACKGROUND: Infections have increased in simultaneous pancreas/kidney transplant recipients (SPKTRs) with BK polyomavirus (BKV)-associated nephropathy (BKVN) being the most important infectious cause of allograft loss. Comparisons of BKVN with kidney transplant recipients (KTRs), however, are lacking. METHODS: We studied all SPKTRs and KTRs at our transplant centre between 2003 and 2012. Eleven of 106 SPKTs (10.4%) and 21 of 1062 KTRs (2.0%) were diagnosed with BKVN with allograft loss in 1 SPKTR (9.1%) and 2 KTRs (9.5%). A control of 95 SPKTRs without BKVN was used for comparison. RESULTS: SPKTRs showed an increased incidence of BKVN compared with KTRs (P < 0.001). Onset of BKVN in SPKTRs was significantly later compared with KTRs (P = 0.033). While 67% of KTRs showed early-onset BKVN, 64% of SPKTRs developed late-onset BKVN. Older recipient age and male gender increased the risk of BKVN in SPKTRs (P < 0.05). No differences were observed for patient and allograft survival (P > 0.05). However, SPKTRs with BKVN showed inferior estimated glomerular filtration rate and a higher incidence of de novo donor-specific antibodies compared with SPKTRs without BKVN in long term follow-up (P < 0.05). SPKTRs showed higher peak BKV loads, a need for more intense therapeutic intervention and were more likely not to recover to baseline creatinine after BKVN (P < 0.05). CONCLUSIONS: Our results suggest a higher incidence, more severe course and inferior outcome of BKVN in SPKTRs. An increased vulnerability of the allograft kidney due to inferior organ quality may predispose KTRs to early-onset BKVN. In contrast, SPKTRs present with late-onset BKVN in the presence of high-dose immunosuppression. PMID- 26758792 TI - Charge- and thickness-dependent inplane deformation of multilayer graphene thin films. AB - The charge- and thickness-dependent inplane deformation of multilayer graphene thin films in an electrolyte was studied by joint first-principles/continuum calculations (JFPCC) and the surface eigenstress model. At thermodynamic equilibrium, a multilayer graphene film exhibits initial deformation, which is asymmetric with respect to negative and positive charges, and the thickness dependent minimal inplane C-C bond length occurs at the same positive charge of about 0.0381 * 10(20) |e| m(-2) for all studied films. The surface eigenstress model was further developed to take the charge-induced deformation into account, which yields analytical formulas. The analytical formulas describe the JFPCC results well for multilayer graphene thin films with a layer number larger than two, and are powerful and user friendly for understanding the charge and thickness dependent deformation in atomistic calculations and sophisticated experiments with multilayer graphene thin films. PMID- 26758791 TI - Incidence of intensive care unit admission, outcome and post intensive care survival in patients with diffuse large B-cell lymphoma. AB - Some patients with diffuse large B-cell lymphoma (DLBCL) require intensive care unit (ICU) admission prior to or during chemotherapy. We analyzed all unscheduled ICU admissions in 331 consecutive patients (18-93 years) with newly diagnosed DLBCL. Thirty-seven patients (11.2%) required ICU treatment primarily due to hemodynamic (37.8%) or respiratory failure (24.3%). Bulky disease and high IPI score were predictive of ICU admission in the early course. ICU and hospital survival was 75.7% and 70.3%, respectively. Overall survival in ICU patients with newly diagnosed DLBCL was worse compared to non-ICU-patients (40.7% vs. 72.7% at two years). However, survival of high-risk patients (IPI 3-5), continuous complete remission, and disease-free survival did not differ. Post-ICU survival was poor in patients with relapsed/refractory DLBCL (0.1-10 months). Our observations favor unrestricted ICU support in DLBCL patients undergoing first line therapy. ICU referral of patients with refractory/relapsed disease must be evaluated in the context of the hematologic prognosis. PMID- 26758793 TI - Cystatin C, a novel cardiometabolic risk marker in women with polycystic ovary syndrome. AB - OBJECTIVE: To investigate the impact of urinary albumin excretion (UAE) and cystatin C on the metabolic components of polycystic ovary syndrome (PCOS). METHODS: Seventy-five women with PCOS were divided into two groups according to metabolic syndrome as MetS + and MetS-. Clinical, metabolic and renal parameters were compared between the groups. Correlation analyses were performed between cystatin C, microalbuminuria and clinical and metabolic parameters in women with PCOS. RESULTS: Waist/hip ratio (WHR), body mass index, LDL cholesterol, triglyceride, total cholesterol, cystatin C, UAE were significantly higher in the MetS + group compared with the MetS - one. HDL cholesterol was significantly higher in the MetS - group than the MetS + one. The UAE positively correlates with LDL cholesterol, triglyceride and total cholesterol levels. Cystatin C positively correlates with UAE, WHR, LDL cholesterol, triglyceride, total cholesterol levels. CONCLUSIONS: Evaluating UAE and cystatin C may be important for the detection of target subjects at high risk for future metabolic syndrome and cardiovascular disease. PMID- 26758794 TI - Reversible switching of structural and plasmonic properties of liquid-crystalline gold nanoparticle assemblies. AB - Hybrid materials built of spherical gold nanoparticles with three different sizes covered with (pro)mesogenic molecules have been prepared. Small-angle X-ray diffraction studies showed that after thermal annealing most of the obtained materials formed long-range ordered assemblies. Variation of the (pro)mesogenic ligand architecture enabled us to achieve a switchable material, which could be reversibly reconfigured between 3D long-range ordered structures with tetragonal and face centred cubic symmetries. This structural reconfiguration induces changes to the plasmonic response of the material. This work demonstrates that it is possible to use LC-based self-assembling phenomena to prepare dynamic materials with structural properties important for the development of active plasmonic metamaterials. PMID- 26758795 TI - Molecular Dissection of Renal Ischemia-Reperfusion: Oxidative Stress and Cellular Events. AB - Ischemic reperfusion kidney injury (IRKI) is a complex pathophysiological event, which is the most common cause of the acute kidney injury. The key characteristic of IRKI is a reduction in glomerular filtration rate, which implies an underlying impairment in hemodynamic regulation. In recent decades, convincing evidence illuminated the molecular and pathological events in the acute kidney injury, revealing the role of ischemia/reperfusion, oxidative stress, apoptosis, inflammation, fibrosis and changes in gene expression which activate different signaling pathways. The cascade of inflammation events is a key mediator of IRKI, which includes the inflammation process, complement activation and mobilization of innate immunity. Oxidative stress represents the increased presence of various free radicals that cannot be buffered by the antioxidant capacity which comprises of enzymatic and non-enzymatic components. Renal tissue injury during ischemia/reperfusion comes as a result of membrane lipids peroxidation, oxidative damage of proteins and DNA and results in apoptosis and necrosis. It is evident from many studies that augmentation of the antioxidant defense mechanisms has a protective role on kidney tissue. In recent years, the importance of heat-shock proteins and MicroRNAs in the pathogenesis of IRKI has been revealed and there are promising indications that in future they could serve as diagnostic biomarkers or therapeutic targets. Striking changes in global gene expression were shown, providing a great potential for fundamental understanding and clinical management of IRKI. The clinical outcome among patients with kidney transplantation will have the furthermost advance from the better understanding of the underlying molecular pathology of IRKI. PMID- 26758797 TI - Targeting "Undruggable" Proteins: Design of Synthetic Cyclopeptides. AB - The development of synthetic macrocycles represents a powerful approach toward the identification of new protein binders or inhibitors of Protein-Protein Interactions (PPI) which are known to play key biological roles in cancer signaling as well as in the regulation of cell division cycle. Structural investigations led to identify "hot loops" sharing common motifs that are mainly involved in PPIs. Most PPIs occur through large and flat surfaces; currently these protein complexes are defined as "undruggable" by conventional drug discovery approaches, since the identification of small molecules to inhibit these targets is often unreachable. Typically macrocycles are 500-2000 Da in size, having 12-membered, or more, ring architecture: they do not obey the Lipinski's rule but, for them nature offers many examples as therapeutic agents such as erythromycin (antibiotic), cyclosporin (immunosuppressant) and somatostatin (hormone). Peptide-based macrocycles offer the advantages of directly mimicking secondary structures involved in PPIs and their pharmacological application is related to the potential improvement of lead peptides in terms of potency, selectivity, stability and cell permeation. The promising relevance of cyclopeptides prompted to develop new synthetic methods for cyclization: often biotechnological approaches as well as regioselective reactions have been employed to cyclize peptides rapidly and nearly quantitatively. Moreover, different synthetic strategies in peptidomimetics' macrocyclization are actually available based on surrogate peptide bonds or NCL (Native Chemical Ligation) methods. In this review we focus on the most common methods for the preparation of cyclopeptides and interesting applications of the last decade. PMID- 26758798 TI - Glycyrrhetinic Acid and Its Derivatives: Anti-Cancer and Cancer Chemopreventive Properties, Mechanisms of Action and Structure- Cytotoxic Activity Relationship. AB - The anti-cancer properties of liquorice have been attributed, at least in part, to glycyrrhizin (GL). However, GL is not directly absorbed through the gastrointestinal tract. It is hydrolyzed to 18-beta-glycyrrhetinic acid (GA), the pharmacologically active metabolite, by human intestinal microflora. GA exhibits remarkable cytotoxic and anti-tumor properties. The pro-apoptotic targets and mechanisms of action of GA have been extensively studied over the past decade. In addition, GA is an inexpensive and available triterpene with functional groups (COOH and OH) in its structure, which make it an attractive lead compound for medicinal chemists to prepare a large number of analogues. To date, more than 400 cytotoxic derivatives have been prepared on the basis of GA scaffold, including 128 cytotoxic derivatives with IC50 values less than 30 uM. Researchers have also succeeded in synthesizing very potent cytotoxic derivatives with IC50s <= 1 uM. Studies have shown that the introduction of a double bound at the C1-C2 position combined with an electronegative functional group, such as CN, CF3 or iodine at C2 position, and the oxidation of the hydroxyl group of C3 to the carbonyl group, significantly increased cytotoxicity. This review describes the cytotoxic and anti-tumor properties of GA and its derivatives, targets and mechanisms of action and provides insight into the structure-activity relationship of GA derivatives. PMID- 26758799 TI - Synthesis, optical properties, and helical self-assembly of a bivaline-containing tetraphenylethene. AB - A chiral tetraphenylethene derivative with two valine-containing attachments (TPE DVAL), was synthesized by Cu(I)-catalyzed azide-alkyne "click" reaction. The optical properties and self-assembling behaviours of TPE-DVAL were investigated. The molecule is non-emissive and circular dichroism (CD)-silent in solution, but shows strong fluorescence and Cotton effects in the aggregation state, demonstrating aggregation-induced emission (AIE) and CD (AICD) characteristics. TPE-DVAL exhibits good circularly polarized luminescence (CPL) when depositing on the surface of quartz to allow the evaporation of its 1,2-dichloroethane solution. SEM and TEM images of the molecule show that the molecule readily self assembles into right-handed helical nanofibers upon the evaporation of its solvent of DCE. The molecular alignments and interactions in assembling process are further explored through XRD analysis and computational simulation. The driving forces for the formation of the helical fibers were from the cooperative effects of intermolecular hydrogen bonding, pi-pi interactions and steric effect. PMID- 26758796 TI - Effective Delivery of Male Contraceptives Behind the Blood-Testis Barrier (BTB) - Lesson from Adjudin. AB - The blood-testis barrier (BTB) is one of the tightest blood-tissue barriers in the mammalian body. It divides the seminiferous epithelium of the seminiferous tubule, the functional unit of the testis, where spermatogenesis takes place, into the basal and the adluminal (apical) compartments. Functionally, the BTB provides a unique microenvironment for meiosis I/II and post-meiotic spermatid development which take place exclusively in the apical compartment, away from the host immune system, and it contributes to the immune privilege status of testis. However, the BTB also poses major obstacles in developing male contraceptives (e.g., adjudin) that exert their effects on germ cells in the apical compartment, such as by disrupting spermatid adhesion to the Sertoli cell, causing germ cell exfoliation from the testis. Besides the tight junction (TJ) between adjacent Sertoli cells at the BTB that restricts the entry of contraceptives from the microvessels in the interstitium to the adluminal compartment, drug transporters, such as P-glycoprotein and multidrug resistance-associated protein 1 (MRP1), are also present that actively pump drugs out of the testis, limiting drug bioavailability. Recent advances in drug formulations, such as drug particle micronization (<50 MUm) and co-grinding of drug particles with beta-cyclodextrin have improved bioavailability of contraceptives via considerable increase in solubility. Herein, we discuss development in drug formulations using adjudin as an example. We also put emphasis on the possible use of nanotechnology to deliver adjudin to the apical compartment with multidrug magnetic mesoporous silica nanoparticles. These advances in technology will significantly enhance our ability to develop effective non-hormonal male contraceptives for men. PMID- 26758801 TI - The Use of Ultrasound in Palliative Care and Hospice. AB - Palliative care aims to reduce symptom burden and enhance quality of life for those with terminal disease. Ultrasound has become an increasingly popular diagnostic and therapeutic modality due to its low cost, ease of portability, safety, and good patient acceptance. A review of the literature to date shows that as a diagnostic tool, as a therapeutic modality, and as a tool to accurately guide palliative procedures, ultrasound can have many roles in palliative care and hospice. Based on our clinical experience, musculoskeletal ultrasound can be of benefit to patients with terminal disease. Examples include adhesive capsulitis in advanced neurologic disease and chronic osteomyelitis in a patient with metastatic colon cancer. Ideally, further studies investigating the use of ultrasound in the palliative care population will be conducted in the future to enhance the availability of diagnostic and therapeutic capabilities of this particular modality. PMID- 26758800 TI - Host-associated coral reef microbes respond to the cumulative pressures of ocean warming and ocean acidification. AB - Key calcifying reef taxa are currently threatened by thermal stress associated with elevated sea surface temperatures (SST) and reduced calcification linked to ocean acidification (OA). Here we undertook an 8 week experimental exposure to near-future climate change conditions and explored the microbiome response of the corals Acropora millepora and Seriatopora hystrix, the crustose coralline algae Hydrolithon onkodes, the foraminifera Marginopora vertebralis and Heterostegina depressa and the sea urchin Echinometra sp. Microbial communities of all taxa were tolerant of elevated pCO2/reduced pH, exhibiting stable microbial communities between pH 8.1 (pCO2 479-499 MUatm) and pH 7.9 (pCO2 738-835 MUatm). In contrast, microbial communities of the CCA and foraminifera were sensitive to elevated seawater temperature, with a significant microbial shift involving loss of specific taxa and appearance of novel microbial groups occurring between 28 and 31 degrees C. An interactive effect between stressors was also identified, with distinct communities developing under different pCO2 conditions only evident at 31 degrees C. Microbiome analysis of key calcifying coral reef species under near-future climate conditions highlights the importance of assessing impacts from both increased SST and OA, as combinations of these global stressors can amplify microbial shifts which may have concomitant impacts for coral reef structure and function. PMID- 26758802 TI - Permanently porous hydrogen-bonded frameworks of rod-like thiophenes, selenophenes, and tellurophenes capped with MIDA boronates. AB - Permanently porous hydrogen-bonded organic frameworks comprising rod-like molecules with two MIDA boronate termini have been prepared. We show that MIDA boronates self-assemble through multiple hydrogen-bonding interactions. Thiophene containing frameworks are fluorescent and have a 6.6% absolute quantum yield. The approach appears to be general and introduces new design rules for constructing hydrogen-bonded organic frameworks. PMID- 26758803 TI - An integrated molecular modeling approach for in silico design of new tetracyclic derivatives as ALK inhibitors. AB - Anaplastic lymphoma kinase (ALK), a promising therapeutic target for treatment of human cancers, is a receptor tyrosine kinase that instigates the activation of several signal transduction pathways. In the present study, in silico methods have been employed in order to explore the structural features and functionalities of a series of tetracyclic derivatives displaying potent inhibitory activity toward ALK. Initially docking was performed using GLIDE 5.6 to probe the bioactive conformation of all the compounds and to understand the binding modes of inhibitors. The docking results revealed that ligand interaction with Met 1199 plays a crucial role in binding of inhibitors to ALK. Further to establish a robust 3D-QSAR model using CoMFA and CoMSIA methods, the whole dataset was divided into three splits. Model obtained from Split 3 showed high accuracy ([Formula: see text] of 0.700 and 0.682, [Formula: see text] of 0.971 and 0.974, [Formula: see text] of 0.673 and 0.811, respectively for CoMFA and CoMSIA). The key structural requirements for enhancing the inhibitory activity were derived from CoMFA and CoMSIA contours in combination with site map analysis. Substituting small electronegative groups at Position 8 by replacing either morpholine or piperidine rings and maintaining hydrophobic character at Position 9 in tetracyclic derivatives can enhance the inhibitory potential. Finally, we performed molecular dynamics simulations in order to investigate the stability of protein ligand interactions and MM/GBSA calculations to compare binding free energies of co-crystal ligand and newly designed molecule N1. Based on the coherence of outcome of various molecular modeling studies, a set of 11 new molecules having potential predicted inhibitory activity were designed. PMID- 26758804 TI - Strapping rowers to their sliding seat improves performance during the start of single-scull rowing. AB - In this study, the effect of strapping rowers to their sliding seat on performance during 75 m on-water starting trials was investigated. Well-trained rowers performed 75 m maximum-effort starts using an instrumented single scull equipped with a redesigned sliding seat system, both under normal conditions and while strapped to the sliding seat. Strapping rowers to their sliding seat resulted in a 0.45 s lead after 75 m, corresponding to an increase in average boat velocity of about 2.5%. Corresponding effect sizes were large. No significant changes were observed in general stroke cycle characteristics. No indications of additional boat heaving and pitching under strapped conditions were found. The increase in boat velocity is estimated to correspond to an increase in average mechanical power output during the start of on-water rowing between 5% and 10%, which is substantial but smaller than the 12% increase found in a previous study on ergometer starting. We conclude that, after a very short period of adaptation to the strapped condition, single-scull starting performance is substantially improved when the rower is strapped to the sliding seat. PMID- 26758805 TI - CRISPR/Cas9-induced disruption of gene expression in mouse embryonic brain and single neural stem cells in vivo. AB - We have applied the CRISPR/Cas9 system in vivo to disrupt gene expression in neural stem cells in the developing mammalian brain. Two days after in utero electroporation of a single plasmid encoding Cas9 and an appropriate guide RNA (gRNA) into the embryonic neocortex of Tis21::GFP knock-in mice, expression of GFP, which occurs specifically in neural stem cells committed to neurogenesis, was found to be nearly completely (~ 90%) abolished in the progeny of the targeted cells. Importantly, upon in utero electroporation directly of recombinant Cas9/gRNA complex, near-maximal efficiency of disruption of GFP expression was achieved already after 24 h. Furthermore, by using microinjection of the Cas9 protein/gRNA complex into neural stem cells in organotypic slice culture, we obtained disruption of GFP expression within a single cell cycle. Finally, we used either Cas9 plasmid in utero electroporation or Cas9 protein complex microinjection to disrupt the expression of Eomes/Tbr2, a gene fundamental for neocortical neurogenesis. This resulted in a reduction in basal progenitors and an increase in neuronal differentiation. Thus, the present in vivo application of the CRISPR/Cas9 system in neural stem cells provides a rapid, efficient and enduring disruption of expression of specific genes to dissect their role in mammalian brain development. PMID- 26758809 TI - Molecular characterization and drug susceptibility profile of a Mycobacterium avium subspecies avium isolate from a dog with disseminated infection. AB - Mycobacterium avium-intracellulare complex (MAC) infections have been described in many mammalian species, including humans and pets. We isolated and molecularly typed the causative agent of a rare case of disseminated mycobacteriosis in a dog. We identified the pathogen as M. avium subspecies avium by sequencing the partial genes gyrB and rpsA. Considering the zoonotic potential of this infection, and in an attempt to ensure the most effective treatment for the animal, we also determined the drug susceptibility profile of the isolate to the most common drugs used to treat MAC disease in humans. The pathogen was tested in vitro against the macrolide clarithromycin, as well as against amikacin, ciprofloxacin, rifampicin, ethambutol and linezolid, by the resazurin microdilution assay. It was found to be sensitive to all tested drugs apart from ethambutol. Despite the fact that the pathogen was sensitive to the therapies administered, the dog's overall clinical status worsened and the animal died shortly after antimicrobial susceptibility results became available. Nucleotide sequencing of the embB gene, the target gene most commonly associated with ethambutol resistance, showed new missense mutations when compared to sequences available in public databases. In conclusion, we molecularly identified the MAC pathogen and determined its drug susceptibility profile in a relatively short period of time (7 days). We also characterized new genetic mutations likely to have been involved in the observed ethambutol resistance. Our results confirmed the usefulness of both the gyrB and the rpsA genes as biomarkers for an accurate identification and differentiation of MAC pathogens. PMID- 26758808 TI - A pervasive role for biomass burning in tropical high ozone/low water structures. AB - Air parcels with mixing ratios of high O3 and low H2O (HOLW) are common features in the tropical western Pacific (TWP) mid-troposphere (300-700 hPa). Here, using data collected during aircraft sampling of the TWP in winter 2014, we find strong, positive correlations of O3 with multiple biomass burning tracers in these HOLW structures. Ozone levels in these structures are about a factor of three larger than background. Models, satellite data and aircraft observations are used to show fires in tropical Africa and Southeast Asia are the dominant source of high O3 and that low H2O results from large-scale descent within the tropical troposphere. Previous explanations that attribute HOLW structures to transport from the stratosphere or mid-latitude troposphere are inconsistent with our observations. This study suggest a larger role for biomass burning in the radiative forcing of climate in the remote TWP than is commonly appreciated. PMID- 26758810 TI - Perturbation correction for alanine dosimeters in different phantom materials in high-energy photon beams. AB - In modern radiotherapy the verification of complex treatments plans is often performed in inhomogeneous or even anthropomorphic phantoms. For dose verification small detectors are necessary and therefore alanine detectors are most suitable. Though the response of alanine for a wide range of clinical photon energies in water is well know, the knowledge about the influence of the surrounding phantom material on the response of alanine is sparse. Therefore we investigated the influence of twenty different surrounding/phantom materials for alanine dosimeters in clinical photon fields via Monte Carlo simulations. The relative electron density of the used materials was in the range [Formula: see text] up to 1.69, covering almost all materials appearing in inhomogeneous or anthropomorphic phantoms used in radiotherapy. The investigations were performed for three different clinical photon spectra ranging from 6 to 25 MV-X and Co-60 and as a result a perturbation correction [Formula: see text] depending on the environmental material was established. The Monte Carlo simulation show, that there is only a small dependence of [Formula: see text] on the phantom material and the photon energy, which is below +/-0.6%. The results confirm the good suitability of alanine detectors for in-vivo dosimetry. PMID- 26758806 TI - Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy. AB - Natural T-cell responses generally lack the potency to eradicate cancer. Enhanced affinity T-cell receptors (TCRs) provide an ideal approach to target cancer cells, with emerging clinical data showing significant promise. Nevertheless, the risk of off target reactivity remains a key concern, as exemplified in a recent clinical report describing fatal cardiac toxicity, following administration of MAGE-A3 specific TCR-engineered T-cells, mediated through cross-reactivity with an unrelated epitope from the Titin protein presented on cardiac tissue. Here, we investigated the structural mechanism enabling TCR cross-recognition of MAGE-A3 and Titin, and applied the resulting data to rationally design mutants with improved antigen discrimination, providing a proof-of-concept strategy for altering the fine specificity of a TCR towards an intended target antigen. This study represents the first example of direct molecular mimicry leading to clinically relevant fatal toxicity, mediated by a modified enhanced affinity TCR designed for cancer immunotherapy. Furthermore, these data demonstrate that self antigens that are expressed at high levels on healthy tissue should be treated with extreme caution when designing immuno-therapeutics. PMID- 26758811 TI - Evaluation of Iodine Deficiency in Children with Attention Deficit/Hyperactivity Disorder. AB - OBJECTIVE: To investigate the incidence of iodine deficiency (ID) and its effects on mental function in children referred to the Dr. Sami Ulus Maternity and Children's Training and Research Hospital with a prospective diagnosis of attention deficit/hyperactivity disorder (ADHD). METHODS: The study was conducted on 89 children referred in the period from September 2009 to June 2010 with a diagnosis of ADHD. A questionnaire was given to all parents. Conners' rating scales were applied to the parents (CPRS) and teachers (CTRS), and revised Wechsler intelligence scale for children (WISC-R) to the children. Serum thyroid stimulating hormone, free triiodothyronine and free thyroxine, thyroglobulin, anti-thyroid peroxidase, anti-thyroglobulin, and urinary iodine levels were measured in all children. RESULTS: Median age was 9.41+/-1.95 years, and 83.1% of subjects were male. The mean urinary iodine level of the children was 92.56+/ 22.25 MUg/L. ID was detected in 71.9% of subjects and all were mild ID. There was no significant relationship between urinary iodine levels with WISC-R subtest scores and CPRS. However, a significant association was found between urinary iodine levels and hyperactivity section of CTRS (p<0.05). Likewise, a significant relationship was found between learning disorder/mental retardation diagnosis and freedom subtest of WISC-R (p<0.05). CONCLUSION: This study highlights the effects of ID on comprehension, perception, attention, and learning. However, the results need to be supported by new randomized controlled trials. PMID- 26758812 TI - Pulsed corona discharge oxidation of aqueous carbamazepine micropollutant. AB - The anti-epileptic drug carbamazepine (CBZ) receives growing attention due to slow biodegradation and inherent accumulation in the aquatic environment. The application of a gas-phase pulsed corona discharge (PCD) was investigated to remove CBZ from synthetic solutions and spiked wastewater effluent from a municipal wastewater treatment facility. The treated water was showered between high voltage (HV) wires and grounded plate electrodes, to which ultra-short HV pulses were applied. CBZ was readily oxidized and 1-(2-benzaldehyde)-4 hydroquinazoline-2-one (BQM) and 1-(2-benzaldehyde)-4-hydro-quinazoline-2,4-dione (BQD) were identified as the most abundant primary transformation products, which, contrary to CBZ ozonation data available in the literature, were further easily oxidized with PCD: BQM and BQD attributed to only a minor portion of the target compound oxidized. In concentrations commonly found in wastewater treatment plant effluents (around 5 ug L(-1)), up to 97% reduction in CBZ concentration was achieved at mere 0.3 kW h m(-3) energy consumption, and over 99.9% was removed at 1 kW h m(-3). The PCD application proved to be efficient in the removal of both the parent substance and its known transformation products, even with the competing reactions in the complex composition of wastewater. PMID- 26758814 TI - NiO nanowall-assisted growth of thick carbon nanofiber layers on metal wires for fiber supercapacitors. AB - Thick carbon nanofiber (CNF) films were uniformly grown on metal wires with the assistance of pre-deposited NiO nanowalls. The as-prepared wire-shaped composites that integrate the capacitance of CNFs and Ni particles were directly used as electrodes to construct high capacitive fiber supercapacitors for micro-power supplies. PMID- 26758815 TI - Emergence of liposome as targeted magic bullet for inflammatory disorders: current state of the art. AB - Inflammatory diseases are considered to be highly dreadful ones responsible for higher mortality in the developed countries. This includes cancer, psoriasis, rheumatoid arthritis, and inflammatory bowel disease. The tremendous strides in the area of drug development to find newer molecules like non-steroidal and steroidal agents and immunosuppressant agents delivered by conventional formulation. These therapy have enhances the life expectancy of patient, but it provide the therapeutic benefits only to a limited extent. Recent advancement in liposomes based nanomedicines has led to the possibility of improves the efficacy and safety of the pharmacotherapy of inflammatory disorders. Of late, liposomes have been highly explored as one of the promising systems for delivering numerous anti-inflammatory drugs for attaining enhanced therapeutic outcomes. Over the conventional carriers, liposomal systems have numerous drug delivery merits including advantages in both passive and active targeting of drug molecules to the inflammatory lesions. The current review article, therefore, endeavors to provide a bird's eye view account on the success of liposome-based therapeutic systems in the management of dreadful inflammatory disorders along with updated knowledge to pharmaceutical scientists in the field. PMID- 26758813 TI - Novel (Hetero)arylalkenyl propargylamine compounds are protective in toxin induced models of Parkinson's disease. AB - BACKGROUND: Mitochondrial dysfunction, oxidative stress and their interplay are core pathological features of Parkinson's disease. In dopaminergic neurons, monoamines and their metabolites provide an additional source of reactive free radicals during their breakdown by monoamine oxidase or auto-oxidation. Moreover, mitochondrial dysfunction and oxidative stress have a supraadditive impact on the pathological, cytoplasmic accumulation of dopamine and its subsequent release. Here we report the effects of a novel series of potent and selective MAO-B inhibitory (hetero)arylalkenylpropargylamine compounds having protective properties against the supraadditive effect of mitochondrial dysfunction and oxidative stress. RESULTS: The (hetero)arylalkenylpropargylamines were tested in vitro, on acute rat striatal slices, pretreated with the complex I inhibitor rotenone and in vivo, using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced acute, subchronic, and chronic experimental models of Parkinson's disease in mice. The compounds exhibited consistent protective effects against i) in vitro oxidative stress induced pathological dopamine release and the formation of toxic dopamine quinone in the rat striatum and rescued tyrosine hydroxylase positive neurons in the substantia nigra after rotenone treatment; ii) in vivo MPTP-induced striatal dopamine depletion and motor dysfunction in mice using acute and subchronic, delayed application protocols. One compound (SZV558) was also examined and proved to be protective in a chronic mouse model of MPTP plus probenecid (MPTPp) administration, which induces a progressive loss of nigrostriatal dopaminergic neurons. CONCLUSIONS: Simultaneous inhibition of MAO-B and oxidative stress induced pathological dopamine release by the novel propargylamines is protective in animal models and seems a plausible strategy to combat Parkinson's disease. PMID- 26758816 TI - Highlights from Faraday Discussion 182: Solid Oxide Electrolysis: Fuels and Feedstocks from Water and Air, York, UK, July 2015. AB - The rising importance of converting high peak electricity from renewables to fuels has urged field specialists to organize this Faraday Discussion on Solid Oxide Electrolysis. The topic is of essential interest in order to achieve a greater utilization of renewable energy and storage at higher densities. PMID- 26758817 TI - Pediatric Reference Intervals for Free Thyroxine and Free Triiodothyronine by Equilibrium Dialysis-Liquid Chromatography-Tandem Mass Spectrometry. AB - OBJECTIVE: Thyroid hormone concentrations fluctuate during growth and development. To accurately diagnose thyroid disease in pediatric patients, reference intervals (RIs) should be established with appropriate age groups from an adequate number of healthy subjects using the most exact methods possible. Obtaining statistically useful numbers of healthy patients is particularly challenging for pediatric populations. The objective of this study was to determine non-parametric RIs for free thyroxine (fT4) and free triiodothyronine (fT3) using equilibrium dialysis-high performance liquid chromatography-tandem mass spectrometry with over 2200 healthy children 6 months-17 years of age. METHODS: Subjects were negative for both thyroglobulin and thyroid peroxidase autoantibodies and had normal thyrotropin concentrations. The study included 2213 children (1129 boys and 1084 girls), with at least 120 subjects (average of 125) from each year of life, except for the 6 month to 1 year age group (n=96). RESULTS: Non-parametric RIs (95th percentile) for fT4 were: 18.0-34.7 pmol/L (boys and girls, 6 months-6 years) and 14.2-25.7 pmol/L (boys and girls, 7-17 years). RIs for fT3 were: 5.8-13.1 pmol/L (girls, 6 months-6 years); 5.7-11.8 pmol/L (boys, 6 months-6 years); 5.7-10.0 pmol/L (boys and girls, 7-12 years); 4.5-8.6 pmol/L (girls, 13-17 years); and 5.2-9.4 pmol/L (boys, 13-17 years). CONCLUSION: Numerous significant differences were observed between pediatric age groups and previously established adult ranges. This emphasizes the need for well characterized RIs for thyroid hormones in the pediatric population. PMID- 26758819 TI - Emotional Appraisal of Moral Dilemmas: What Neuroimaging Can Tell about the Disgust-Morality Link. PMID- 26758818 TI - Performing monkeys of Bangladesh: characterizing their source and genetic variation. AB - The acquisition and training of monkeys to perform is a centuries-old tradition in South Asia, resulting in a large number of rhesus macaques kept in captivity for this purpose. The performing monkeys are reportedly collected from free ranging populations, and may escape from their owners or may be released into other populations. In order to determine whether this tradition involving the acquisition and movement of animals has influenced the population structure of free-ranging rhesus macaques in Bangladesh, we first characterized the source of these monkeys. Biological samples from 65 performing macaques collected between January 2010 and August 2013 were analyzed for genetic variation using 716 base pairs of mitochondrial DNA. Performing monkey sequences were compared with those of free-ranging rhesus macaque populations in Bangladesh, India and Myanmar. Forty-five haplotypes with 116 (16 %) polymorphic nucleotide sites were detected among the performing monkeys. As for the free-ranging rhesus population, most of the substitutions (89 %) were transitions, and no indels (insertion/deletion) were observed. The estimate of the mean number of pair-wise differences for the performing monkey population was 10.1264 +/- 4.686, compared to 14.076 +/- 6.363 for the free-ranging population. Fifteen free-ranging rhesus macaque populations were identified as the source of performing monkeys in Bangladesh; several of these populations were from areas where active provisioning has resulted in a large number of macaques. The collection of performing monkeys from India was also evident. PMID- 26758820 TI - Semantic Organization of Body Part Representations in the Occipitotemporal Cortex. PMID- 26758821 TI - Embodying Others in Immersive Virtual Reality: Electro-Cortical Signatures of Monitoring the Errors in the Actions of an Avatar Seen from a First-Person Perspective. AB - Brain monitoring of errors in one's own and other's actions is crucial for a variety of processes, ranging from the fine-tuning of motor skill learning to important social functions, such as reading out and anticipating the intentions of others. Here, we combined immersive virtual reality and EEG recording to explore whether embodying the errors of an avatar by seeing it from a first person perspective may activate the error monitoring system in the brain of an onlooker. We asked healthy participants to observe, from a first- or third-person perspective, an avatar performing a correct or an incorrect reach-to-grasp movement toward one of two virtual mugs placed on a table. At the end of each trial, participants reported verbally how much they embodied the avatar's arm. Ratings were maximal in first-person perspective, indicating that immersive virtual reality can be a powerful tool to induce embodiment of an artificial agent, even through mere visual perception and in the absence of any cross-modal boosting. Observation of erroneous grasping from a first-person perspective enhanced error-related negativity and medial-frontal theta power in the trials where human onlookers embodied the virtual character, hinting at the tight link between early, automatic coding of error detection and sense of embodiment. Error positivity was similar in 1PP and 3PP, suggesting that conscious coding of errors is similar for self and other. Thus, embodiment plays an important role in activating specific components of the action monitoring system when others' errors are coded as if they are one's own errors. SIGNIFICANCE STATEMENT: Detecting errors in other's actions is crucial for social functions, such as reading out and anticipating the intentions of others. Using immersive virtual reality and EEG recording, we explored how the brain of an onlooker reacted to the errors of an avatar seen from a first-person perspective. We found that mere observation of erroneous actions enhances electrocortical markers of error detection in the trials where human onlookers embodied the virtual character. Thus, the cerebral system for action monitoring is maximally activated when others' errors are coded as if they are one's own errors. The results have important implications for understanding how the brain can control the external world and thus creating new brain-computer interfaces. PMID- 26758823 TI - Bilingual Language Control in Perception versus Action: MEG Reveals Comprehension Control Mechanisms in Anterior Cingulate Cortex and Domain-General Control of Production in Dorsolateral Prefrontal Cortex. AB - For multilingual individuals, adaptive goal-directed behavior as enabled by cognitive control includes the management of two or more languages. This work used magnetoencephalography (MEG) to investigate the degree of neural overlap between language control and domain-general cognitive control both in action and perception. Highly proficient Arabic-English bilingual individuals participated in maximally parallel language-switching tasks in production and comprehension as well as in analogous tasks in which, instead of the used language, the semantic category of the comprehended/produced word changed. Our results indicated a clear dissociation of language control mechanisms in production versus comprehension. Language-switching in production recruited dorsolateral prefrontal regions bilaterally and, importantly, these regions were similarly recruited by category switching. Conversely, effects of language-switching in comprehension were observed in the anterior cingulate cortex and were not shared by category switching. These results suggest that bilingual individuals rely on adaptive language control strategies and that the neural involvement during language switching could be extensively influenced by whether the switch is active (e.g., in production) or passive (e.g., in comprehension). In addition, these results support that humans require high-level cognitive control to switch languages in production, but the comprehension of language switches recruits a distinct neural circuitry. The use of MEG enabled us to obtain the first characterization of the spatiotemporal profile of these effects, establishing that switching processes begin ~ 400 ms after stimulus presentation. SIGNIFICANCE STATEMENT: This research addresses the neural mechanisms underlying multilingual individuals' ability to successfully manage two or more languages, critically targeting whether language control is uniform across linguistic domains (production and comprehension) and whether it is a subdomain of general cognitive control. The results showed that language production and comprehension rely on different networks: whereas language control in production recruited domain-general networks, the brain bases of switching during comprehension seemed language specific. Therefore, the crucial assumption of the bilingual advantage hypothesis, that there is a close relationship between language control and general cognitive control, seems to only hold during production. PMID- 26758822 TI - Incorporating Midbrain Adaptation to Mean Sound Level Improves Models of Auditory Cortical Processing. AB - Adaptation to stimulus statistics, such as the mean level and contrast of recently heard sounds, has been demonstrated at various levels of the auditory pathway. It allows the nervous system to operate over the wide range of intensities and contrasts found in the natural world. Yet current standard models of the response properties of auditory neurons do not incorporate such adaptation. Here we present a model of neural responses in the ferret auditory cortex (the IC Adaptation model), which takes into account adaptation to mean sound level at a lower level of processing: the inferior colliculus (IC). The model performs high-pass filtering with frequency-dependent time constants on the sound spectrogram, followed by half-wave rectification, and passes the output to a standard linear-nonlinear (LN) model. We find that the IC Adaptation model consistently predicts cortical responses better than the standard LN model for a range of synthetic and natural stimuli. The IC Adaptation model introduces no extra free parameters, so it improves predictions without sacrificing parsimony. Furthermore, the time constants of adaptation in the IC appear to be matched to the statistics of natural sounds, suggesting that neurons in the auditory midbrain predict the mean level of future sounds and adapt their responses appropriately. SIGNIFICANCE STATEMENT: An ability to accurately predict how sensory neurons respond to novel stimuli is critical if we are to fully characterize their response properties. Attempts to model these responses have had a distinguished history, but it has proven difficult to improve their predictive power significantly beyond that of simple, mostly linear receptive field models. Here we show that auditory cortex receptive field models benefit from a nonlinear preprocessing stage that replicates known adaptation properties of the auditory midbrain. This improves their predictive power across a wide range of stimuli but keeps model complexity low as it introduces no new free parameters. Incorporating the adaptive coding properties of neurons will likely improve receptive field models in other sensory modalities too. PMID- 26758824 TI - Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Regulate Feeding and Reward. AB - The overconsumption of calorically dense, highly palatable foods is thought to be a major contributor to the worldwide obesity epidemic; however, the precise neural circuits that directly regulate hedonic feeding remain elusive. Here, we show that lateral hypothalamic area (LHA) glutamatergic neurons, and their projections to the lateral habenula (LHb), negatively regulate the consumption of palatable food. Genetic ablation of LHA glutamatergic neurons increased daily caloric intake and produced weight gain in mice that had access to a high-fat diet, while not altering general locomotor activity. Anterior LHA glutamatergic neurons send a functional glutamatergic projection to the LHb, a brain region involved in processing aversive stimuli and negative reward prediction outcomes. Pathway-specific, optogenetic stimulation of glutamatergic LHA-LHb circuit resulted in detectable glutamate-mediated EPSCs as well as GABA-mediated IPSCs, although the net effect of neurotransmitter release was to increase the firing of most LHb neurons. In vivo optogenetic inhibition of LHA-LHb glutamatergic fibers produced a real-time place preference, whereas optogenetic stimulation of LHA-LHb glutamatergic fibers had the opposite effect. Furthermore, optogenetic inhibition of LHA-LHb glutamatergic fibers acutely increased the consumption of a palatable liquid caloric reward. Collectively, these results demonstrate that LHA glutamatergic neurons are well situated to bidirectionally regulate feeding and potentially other behavioral states via their functional circuit connectivity with the LHb and potentially other brain regions. SIGNIFICANCE STATEMENT: In this study, we show that the genetic ablation of LHA glutamatergic neurons enhances caloric intake. Some of these LHA glutamatergic neurons project to the lateral habenula, a brain area important for generating behavioral avoidance. Optogenetic stimulation of this circuit has net excitatory effects on postsynaptic LHb neurons. This is the first study to characterize the functional connectivity and behavioral relevance of this circuit within the context of feeding and reward related behavior. PMID- 26758826 TI - Somatosensory Temporal Discrimination Threshold Involves Inhibitory Mechanisms in the Primary Somatosensory Area. AB - Somatosensory temporal discrimination threshold (STDT) is defined as the shortest time interval necessary for a pair of tactile stimuli to be perceived as separate. Although STDT is altered in several neurological disorders, its neural bases are not entirely clear. We used continuous theta burst stimulation (cTBS) to condition the excitability of the primary somatosensory cortex in healthy humans to examine its possible contribution to STDT. Excitability was assessed using the recovery cycle of the N20 component of somatosensory evoked potentials (SEP) and the area of high-frequency oscillations (HFO). cTBS increased STDT and reduced inhibition in the N20 recovery cycle at an interstimulus interval of 5 ms. It also reduced the amplitude of late HFO. All three effects were correlated. There was no effect of cTBS over the secondary somatosensory cortex on STDT, although it reduced the N120 component of the SEP. STDT is assessed conventionally with a simple ascending method. To increase insight into the effect of cTBS, we measured temporal discrimination with a psychophysical method. cTBS reduced the slope of the discrimination curve, consistent with a reduction of the quality of sensory information caused by an increase in noise. We hypothesize that cTBS reduces the effectiveness of inhibitory interactions normally used to sharpen temporal processing of sensory inputs. This reduction in discriminability of sensory input is equivalent to adding neural noise to the signal. SIGNIFICANCE STATEMENT: Precise timing of sensory information is crucial for nearly every aspect of human perception and behavior. One way to assess the ability to analyze temporal information in the somatosensory domain is to measure the somatosensory temporal discrimination threshold (STDT), defined as the shortest time interval necessary for a pair of tactile stimuli to be perceived as separate. In this study, we found that STDT depends on inhibitory mechanisms within the primary somatosensory area (S1). This finding helps interpret the sensory processing deficits in neurological diseases, such as focal dystonia and Parkinson's disease, and possibly prompts future studies using neurostimulation techniques over S1 for therapeutic purposes in dystonic patients. PMID- 26758825 TI - Electrical and Network Neuronal Properties Are Preferentially Disrupted in Dorsal, But Not Ventral, Medial Entorhinal Cortex in a Mouse Model of Tauopathy. AB - The entorhinal cortex (EC) is one of the first areas to be disrupted in neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia. The responsiveness of individual neurons to electrical and environmental stimuli varies along the dorsal-ventral axis of the medial EC (mEC) in a manner that suggests this topographical organization plays a key role in neural encoding of geometric space. We examined the cellular properties of layer II mEC stellate neurons (mEC-SCs) in rTg4510 mice, a rodent model of neurodegeneration. Dorsoventral gradients in certain intrinsic membrane properties, such as membrane capacitance and afterhyperpolarizations, were flattened in rTg4510 mEC-SCs, while other cellular gradients [e.g., input resistance (Ri), action potential properties] remained intact. Specifically, the intrinsic properties of rTg4510 mEC-SCs in dorsal aspects of the mEC were preferentially affected, such that action potential firing patterns in dorsal mEC SCs were altered, while those in ventral mEC-SCs were unaffected. We also found that neuronal oscillations in the gamma frequency band (30-80 Hz) were preferentially disrupted in the dorsal mEC of rTg4510 slices, while those in ventral regions were comparatively preserved. These alterations corresponded to a flattened dorsoventral gradient in theta-gamma cross-frequency coupling of local field potentials recorded from the mEC of freely moving rTg4510 mice. These differences were not paralleled by changes to the dorsoventral gradient in parvalbumin staining or neurodegeneration. We propose that the selective disruption to dorsal mECs, and the resultant flattening of certain dorsoventral gradients, may contribute to disturbances in spatial information processing observed in this model of dementia. SIGNIFICANCE STATEMENT: The medial entorhinal cortex (mEC) plays a key role in spatial memory and is one of the first areas to express the pathological features of dementia. Neurons of the mEC are anatomically arranged to express functional dorsoventral gradients in a variety of neuronal properties, including grid cell firing field spacing, which is thought to encode geometric scale. We have investigated the effects of tau pathology on functional dorsoventral gradients in the mEC. Using electrophysiological approaches, we have shown that, in a transgenic mouse model of dementia, the functional properties of the dorsal mEC are preferentially disrupted, resulting in a flattening of some dorsoventral gradients. Our data suggest that neural signals arising in the mEC will have a reduced spatial content in dementia. PMID- 26758827 TI - Tmc1 Point Mutation Affects Ca2+ Sensitivity and Block by Dihydrostreptomycin of the Mechanoelectrical Transducer Current of Mouse Outer Hair Cells. AB - The transduction of sound into electrical signals depends on mechanically sensitive ion channels in the stereociliary bundle. The molecular composition of this mechanoelectrical transducer (MET) channel is not yet known. Transmembrane channel-like protein isoforms 1 (TMC1) and 2 (TMC2) have been proposed to form part of the MET channel, although their exact roles are still unclear. Using Beethoven (Tmc1(Bth/Bth)) mice, which have an M412K point mutation in TMC1 that adds a positive charge, we found that Ca(2+) permeability and conductance of the MET channel of outer hair cells (OHCs) were reduced. Tmc1(Bth/Bth) OHCs were also less sensitive to block by the permeant MET channel blocker dihydrostreptomycin, whether applied extracellularly or intracellularly. These findings suggest that the amino acid that is mutated in Bth is situated at or near the negatively charged binding site for dihydrostreptomycin within the permeation pore of the channel. We also found that the Ca(2+) dependence of the operating range of the MET channel was altered by the M412K mutation. Depolarization did not increase the resting open probability of the MET current of Tmc1(Bth/Bth) OHCs, whereas raising the intracellular concentration of the Ca(2+) chelator BAPTA caused smaller increases in resting open probability in Bth mutant OHCs than in wild type control cells. We propose that these observations can be explained by the reduced Ca(2+) permeability of the mutated MET channel indirectly causing the Ca(2+) sensor for adaptation, at or near the intracellular face of the MET channel, to become more sensitive to Ca(2+) influx as a compensatory mechanism. SIGNIFICANCE STATEMENT: In the auditory system, the hair cells convert sound induced mechanical movement of the hair bundles atop these cells into electrical signals through the opening of mechanically gated ion channels at the tips of the bundles. Although the nature of these mechanoelectrical transducer (MET) channels is still unclear, recent studies implicate transmembrane channel-like protein isoform 1 (TMC1) channels in the mammalian cochlea. Using a mutant mouse model (Beethoven) for progressive hearing loss in humans (DFNA36), which harbors a point mutation in the Tmc1 gene, we show that this mutation affects the MET channel pore, reducing its Ca(2+) permeability and its affinity for the permeant blocker dihydrostreptomycin. A number of phenomena that we ascribe to Ca(2+) dependent adaptation appear stronger, in compensation for the reduced Ca(2+) entry. PMID- 26758829 TI - In Vivo MRI Mapping of Brain Iron Deposition across the Adult Lifespan. AB - Disruption of iron homeostasis as a consequence of aging is thought to cause iron levels to increase, potentially promoting oxidative cellular damage. Therefore, understanding how this process evolves through the lifespan could offer insights into both the aging process and the development of aging-related neurodegenerative brain diseases. This work aimed to map, in vivo for the first time with an unbiased whole-brain approach, age-related iron changes using quantitative susceptibility mapping (QSM)--a new postprocessed MRI contrast mechanism. To this end, a full QSM standardization routine was devised and a cohort of N = 116 healthy adults (20-79 years of age) was studied. The whole brain and ROI analyses confirmed that the propensity of brain cells to accumulate excessive iron as a function of aging largely depends on their exact anatomical location. Whereas only patchy signs of iron scavenging were observed in white matter, strong, bilateral, and confluent QSM-age associations were identified in several deep-brain nuclei--chiefly the striatum and midbrain-and across motor, premotor, posterior insular, superior prefrontal, and cerebellar cortices. The validity of QSM as a suitable in vivo imaging technique with which to monitor iron dysregulation in the human brain was demonstrated by confirming age-related increases in several subcortical nuclei that are known to accumulate iron with age. The study indicated that, in addition to these structures, there is a predilection for iron accumulation in the frontal lobes, which when combined with the subcortical findings, suggests that iron accumulation with age predominantly affects brain regions concerned with motor/output functions. SIGNIFICANCE STATEMENT: This study used a whole--brain imaging approach known as quantitative susceptibility mapping (QSM) to provide a novel insight into iron accumulation in the brain across the adult lifespan. Validity of the method was demonstrated by showing concordance with ROI analysis and prior knowledge of iron accumulation in subcortical nuclei. We discovered that, beyond these regions, there is extensive involvement of the frontal lobes that has been missed by past ROI analyses. Broadly speaking, therefore, the motor system selectively accumulates iron with age. The results offer insights into the aging process, but also offer a new approach to studying the role of iron dysregulation in the evolution of age related neurodegenerative diseases. PMID- 26758831 TI - Disrupted Prediction Error Links Excessive Amygdala Activation to Excessive Fear. AB - Basolateral amygdala (BLA) is critical for fear learning, and its heightened activation is widely thought to underpin a variety of anxiety disorders. Here we used chemogenetic techniques in rats to study the consequences of heightened BLA activation for fear learning and memory, and to specifically identify a mechanism linking increased activity of BLA glutamatergic neurons to aberrant fear. We expressed the excitatory hM3Dq DREADD in rat BLA glutamatergic neurons and showed that CNO acted selectively to increase their activity, depolarizing these neurons and increasing their firing rates. This chemogenetic excitation of BLA glutamatergic neurons had no effect on the acquisition of simple fear learning, regardless of whether this learning led to a weak or strong fear memory. However, in an associative blocking task, chemogenetic excitation of BLA glutamatergic neurons yielded significant learning to a blocked conditioned stimulus, which otherwise should not have been learned about. Moreover, in an overexpectation task, chemogenetic manipulation of BLA glutamatergic neurons prevented use of negative prediction error to reduce fear learning, leading to significant impairments in fear inhibition. These effects were not attributable to the chemogenetic manipulation enhancing arousal, increasing asymptotic levels of fear learning or fear memory consolidation. Instead, chemogenetic excitation of BLA glutamatergic neurons disrupted use of prediction error to regulate fear learning. SIGNIFICANCE STATEMENT: Several neuropsychiatric disorders are characterized by heightened activation of the amygdala. This heightened activation has been hypothesized to underlie increased emotional reactivity, fear over generalization, and deficits in fear inhibition. Yet the mechanisms linking heightened amygdala activation to heightened emotional learning are elusive. Here we combined chemogenetic excitation of rat basolateral amygdala glutamatergic neurons with a variety of behavioral approaches to show that, although simple fear learning is unaffected, the use of prediction error to regulate this learning is profoundly disrupted, leading to formation of inappropriate fear associations and impaired fear inhibition. PMID- 26758828 TI - Altered Intrinsic Pyramidal Neuron Properties and Pathway-Specific Synaptic Dysfunction Underlie Aberrant Hippocampal Network Function in a Mouse Model of Tauopathy. AB - The formation and deposition of tau protein aggregates is proposed to contribute to cognitive impairments in dementia by disrupting neuronal function in brain regions, including the hippocampus. We used a battery of in vivo and in vitro electrophysiological recordings in the rTg4510 transgenic mouse model, which overexpresses a mutant form of human tau protein, to investigate the effects of tau pathology on hippocampal neuronal function in area CA1 of 7- to 8-month-old mice, an age point at which rTg4510 animals exhibit advanced tau pathology and progressive neurodegeneration. In vitro recordings revealed shifted theta frequency resonance properties of CA1 pyramidal neurons, deficits in synaptic transmission at Schaffer collateral synapses, and blunted plasticity and imbalanced inhibition at temporoammonic synapses. These changes were associated with aberrant CA1 network oscillations, pyramidal neuron bursting, and spatial information coding in vivo. Our findings relate tauopathy-associated changes in cellular neurophysiology to altered behavior-dependent network function. SIGNIFICANCE STATEMENT: Dementia is characterized by the loss of learning and memory ability. The deposition of tau protein aggregates in the brain is a pathological hallmark of dementia; and the hippocampus, a brain structure known to be critical in processing learning and memory, is one of the first and most heavily affected regions. Our results show that, in area CA1 of hippocampus, a region involved in spatial learning and memory, tau pathology is associated with specific disturbances in synaptic, cellular, and network-level function, culminating in the aberrant encoding of spatial information and spatial memory impairment. These studies identify several novel ways in which hippocampal information processing may be disrupted in dementia, which may provide targets for future therapeutic intervention. PMID- 26758830 TI - Dynamic Changes in Striatal mGluR1 But Not mGluR5 during Pathological Progression of Parkinson's Disease in Human Alpha-Synuclein A53T Transgenic Rats: A Multi-PET Imaging Study. AB - Parkinson's disease (PD) is a prevalent degenerative disorder affecting the CNS that is primarily characterized by resting tremor and movement deficits. Group I metabotropic glutamate receptor subtypes 1 and 5 (mGluR1 and mGluR5, respectively) are important targets for investigation in several CNS disorders. In the present study, we investigated the in vivo roles of mGluR1 and mGluR5 in chronic PD pathology by performing longitudinal positron emission tomography (PET) imaging in A53T transgenic (A53T-Tg) rats expressing an abnormal human alpha-synuclein (ASN) gene. A53T-Tg rats showed a dramatic decline in general motor activities with age, along with abnormal ASN aggregation and striatal neuron degeneration. In longitudinal PET imaging, striatal nondisplaceable binding potential (BPND) values for [(11)C]ITDM (N-[4-[6-(isopropylamino) pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[(11)C]methylbenzamide), a selective PET ligand for mGluR1, temporarily increased before PD symptom onset and dramatically decreased afterward with age. However, striatal BPND values for (E) [(11)C]ABP688 [3-(6-methylpyridin-2-ylethynyl)-cyclohex-2-enone-(E)-O [(11)C]methyloxime], a specific PET ligand for mGluR5, remained constant during experimental terms. The dynamic changes in striatal mGluR1 BPND values also showed a high correlation in pathological decreases in general motor activities. Furthermore, declines in mGluR1 BPND values were correlated with decreases in BPND values for [(18)F]FE-PE2I [(E)-N-(3-iodoprop-2E-enyl)-2beta-carbo [(18)F]fluoroethoxy-3beta-(4-methylphenyl) nortropane], a specific PET ligand for the dopamine transporter, a biomarker for dopaminergic neurons. In conclusion, our results have demonstrated for the first time that dynamic changes occur in mGluR1, but not mGluR5, that accompany pathological progression in a PD animal model. SIGNIFICANCE STATEMENT: Synaptic signaling by glutamate, the principal excitatory neurotransmitter in the brain, is modulated by group I metabotropic glutamate receptors, including the mGluR1 and mGluR5 subtypes. In the brain, mGluR1 and mGluR5 have distinct functional roles and regional distributions. Their roles in brain pathology, however, are not well characterized. Using longitudinal PET imaging in a chronic rat model of PD, we demonstrated that expression of mGluR1, but not mGluR5, dynamically changed in the striatum accompanying pathological PD progression. These findings imply that monitoring mGluR1 in vivo may provide beneficial information to further understand central nervous system disorders. PMID- 26758832 TI - Cortical Plasticity Induction by Pairing Subthalamic Nucleus Deep-Brain Stimulation and Primary Motor Cortical Transcranial Magnetic Stimulation in Parkinson's Disease. AB - Noninvasive brain stimulation studies have shown abnormal motor cortical plasticity in Parkinson's disease (PD). These studies used peripheral nerve stimulation paired with transcranial magnetic stimulation (TMS) to primary motor cortex (M1) at specific intervals to induce plasticity. Induction of cortical plasticity through stimulation of the basal ganglia (BG)-M1 connections has not been studied. In the present study, we used a novel technique of plasticity induction by repeated pairing of deep-brain stimulation (DBS) of the BG with M1 stimulation using TMS. We hypothesize that repeated pairing of subthalamic nucleus (STN)-DBS and M1-TMS at specific time intervals will lead to plasticity in the M1. Ten PD human patients with STN-DBS were studied in the on-medication state with DBS set to 3 Hz. The interstimulus intervals (ISIs) between STN-DBS and TMS that produced cortical facilitation were determined individually for each patient. Three plasticity induction conditions with repeated pairings (180 times) at specific ISIs (~ 3 and ~ 23 ms) that produced cortical facilitation and a control ISI of 167 ms were tested in random order. Repeated pairing of STN-DBS and M1-TMS at short (~ 3 ms) and medium (~ 23 ms) latencies increased M1 excitability that lasted for at least 45 min, whereas the control condition (fixed ISI of 167 ms) had no effect. There were no specific changes in motor thresholds, intracortical circuits, or recruitment curves. Our results indicate that paired-associative cortical plasticity can be induced by repeated STN and M1 stimulation at specific intervals. These results show that STN-DBS can modulate cortical plasticity. SIGNIFICANCE STATEMENT: We introduced a new experimental paradigm to test the hypothesis that pairing subthalamic nucleus deep-brain stimulation (STN-DBS) with motor cortical transcranial magnetic stimulation (M1 TMS) at specific times can induce cortical plasticity in patients with Parkinson's disease (PD). We found that repeated pairing of STN-DBS with TMS at short (~ 3 ms) and medium (~ 23 ms) intervals increased cortical excitability that lasted for up to 45 min, whereas the control condition (fixed latency of 167 ms) had no effects on cortical excitability. This is the first demonstration of associative plasticity in the STN-M1 circuits in PD patients using this novel technique. The potential therapeutic effects of combining DBS and noninvasive cortical stimulation should be investigated further. PMID- 26758834 TI - Post-Traumatic Stress Constrains the Dynamic Repertoire of Neural Activity. AB - Post-traumatic stress disorder (PTSD) is an anxiety disorder arising from exposure to a traumatic event. Although primarily defined in terms of behavioral symptoms, the global neurophysiological effects of traumatic stress are increasingly recognized as a critical facet of the human PTSD phenotype. Here we use magnetoencephalographic recordings to investigate two aspects of information processing: inter-regional communication (measured by functional connectivity) and the dynamic range of neural activity (measured in terms of local signal variability). We find that both measures differentiate soldiers diagnosed with PTSD from soldiers without PTSD, from healthy civilians, and from civilians with mild traumatic brain injury, which is commonly comorbid with PTSD. Specifically, soldiers with PTSD display inter-regional hypersynchrony at high frequencies (80 150 Hz), as well as a concomitant decrease in signal variability. The two patterns are spatially correlated and most pronounced in a left temporal subnetwork, including the hippocampus and amygdala. We hypothesize that the observed hypersynchrony may effectively constrain the expression of local dynamics, resulting in less variable activity and a reduced dynamic repertoire. Thus, the re-experiencing phenomena and affective sequelae in combat-related PTSD may result from functional networks becoming "stuck" in configurations reflecting memories, emotions, and thoughts originating from the traumatizing experience. SIGNIFICANCE STATEMENT: The present study investigates the effects of post traumatic stress disorder (PTSD) in combat-exposed soldiers. We find that soldiers with PTSD exhibit hypersynchrony in a circuit of temporal lobe areas associated with learning and memory function. This rigid functional architecture is associated with a decrease in signal variability in the same areas, suggesting that the observed hypersynchrony may constrain the expression of local dynamics, resulting in a reduced dynamic range. Our findings suggest that the re experiencing of traumatic events in PTSD may result from functional networks becoming locked in configurations that reflect memories, emotions, and thoughts associated with the traumatic experience. PMID- 26758835 TI - Dissociations and Associations between Shape and Category Representations in the Two Visual Pathways. AB - The dorsal and ventral visual pathways represent both visual and conceptual object properties. Yet the relative contribution of these two factors in the representational content of visual areas is unclear. Indeed, research investigating brain category representations rarely dissociate visual and semantic properties of objects. We present a human event-related fMRI study with a two-factorial stimulus set with 54 images that explicitly dissociates shape from category to investigate their independent contribution as well as their interactions through representational similarity analyses. Results reveal a contribution from each dimension in both streams, with a transition from shape to category along the posterior-to-anterior anatomical axis. The nature of category representations differs in the two pathways: ventral areas represent object animacy and dorsal areas represent object action properties. Furthermore, information about shape evolved from low-level pixel-based to high-level perceived shape following a posterior-to-anterior gradient similar to the shape to-category emergence. To conclude, results show that representations of shape and category independently coexist, but at the same time they are closely related throughout the visual hierarchy. SIGNIFICANCE STATEMENT: Research investigating visual cortex conceptual category representations rarely takes into account visual properties of objects. In this report, we explicitly dissociate shape from category and investigate independent contributions and interactions of these two highly correlated dimensions. PMID- 26758833 TI - Isolated P/Q Calcium Channel Deletion in Layer VI Corticothalamic Neurons Generates Absence Epilepsy. AB - Generalized spike-wave seizures involving abnormal synchronization of cortical and underlying thalamic circuitry represent a major category of childhood epilepsy. Inborn errors of Cacna1a, the P/Q-type voltage-gated calcium channel alpha subunit gene, expressed throughout the brain destabilize corticothalamic rhythmicity and produce this phenotype. To determine the minimal cellular lesion required for this network disturbance, we used neurotensin receptor 1 (Ntsr1) cre driver mice to ablate floxed Cacna1a in layer VI pyramidal neurons, which supply the sole descending cortical synaptic input to thalamocortical relay cells and reticular interneurons and activate intrathalamic circuits. Targeted Cacna1a ablation in layer VI cells resulted in mice that display a robust spontaneous spike-wave absence seizure phenotype accompanied by behavioral arrest and inhibited by ethosuximide. To verify the selectivity of the molecular lesion, we determined that P/Q subunit proteins were reduced in corticothalamic relay neuron terminal zones, and confirmed that P/Q-mediated glutamate release was reduced at these synapses. Spike-triggered exocytosis was preserved by N-type calcium channel rescue, demonstrating that evoked release at layer VI terminals relies on both P/Q and N-type channels. Whereas intrinsic excitability of the P/Q channel depleted layer VI neurons was unaltered, T-type calcium currents in the postsynaptic thalamic relay and reticular cells were dramatically elevated, favoring rebound bursting and seizure generation. We find that an early P/Q-type release defect, limited to synapses of a single cell-type within the thalamocortical circuit, is sufficient to remodel synchronized firing behavior and produce a stable generalized epilepsy phenotype. SIGNIFICANCE STATEMENT: This study dissects a critical component of the corticothalamic circuit in spike-wave epilepsy and identifies the developmental importance of P/Q-type calcium channel mediated presynaptic glutamate release at layer VI pyramidal neuron terminals. Genetic ablation of Cacna1a in layer VI neurons produced synchronous spike-wave discharges in the cortex and thalamus that were inhibited by ethosuximide. These mice also displayed N-type calcium channel compensation at descending thalamic synapses, and consistent with other spike-wave models increased low-threshold T type calcium currents within postsynaptic thalamic relay and reticular neurons. These results demonstrate, for the first time, that preventing the developmental homeostatic switch from loose to tightly coupled synaptic release at a single class of deep layer cortical excitatory output neurons results in generalized spike-wave epilepsy. PMID- 26758836 TI - Spontaneous Fluctuations in the Flexible Control of Covert Attention. AB - Spontaneous fluctuations in cognitive flexibility are characterized by moment-to moment changes in the efficacy of control over attentional shifts. We used fMRI to investigate the neural correlates in humans of spontaneous fluctuations in readiness to covertly shift attention between two peripheral rapid serial visual presentation streams. Target detection response time (RT) after a shift or hold of covert spatial attention served as a behavioral index of fluctuations in attentional flexibility. In particular, the cost associated with shifting attention compared with holding attention varied as a function of pretrial brain activity in key regions of the default mode network (DMN), but not the dorsal attention network. High pretrial activity within the DMN was associated with a greater increase in shift trial RT relative to hold trial RT, revealing that these areas are associated with a state of attentional stability. Conversely, high pretrial activity within bilateral anterior insula and the presupplementary motor area/supplementary motor area was associated with a greater decrease in shift trial RT relative to hold trial RT, reflecting increased flexibility. Our results importantly clarify the roles of the precuneus, medial prefrontal cortex, and lateral parietal cortex, indicating that reduced activity may not simply indicate greater task engagement, but also, specifically, a readiness to update the focus of attention. Investigation of the neural correlates of spontaneous changes in attentional flexibility may contribute to our understanding of disorders of cognitive control as well as healthy variability in the control of spatial attention. SIGNIFICANCE STATEMENT: Individuals regularly experience fluctuations in preparatory cognitive control that affect performance in everyday life. For example, individuals are able to more quickly initiate a spatial shift of attention at some moments than at others. The current study revealed that pretrial brain activity in specific cortical regions predicted trial-by-trial changes in participants' abilities to flexibly shift the focus of attention. Intrinsically generated fluctuations in brain activity within several key default mode network regions, as well as within the anterior insula and presupplementary/supplementary motor areas, carried behavioral consequences for preparatory attentional control beyond lapses of attentional engagement. Our results are the first to link intrinsic variation in pretrial brain activity to moment-by-moment changes in preparatory attentional control over spatial selection. PMID- 26758837 TI - Causal Link between the Cortico-Rubral Pathway and Functional Recovery through Forced Impaired Limb Use in Rats with Stroke. AB - Intensive rehabilitation is believed to induce use-dependent plasticity in the injured nervous system; however, its causal relationship to functional recovery is unclear. Here, we performed systematic analysis of the effects of forced use of an impaired forelimb on the recovery of rats after lesioning the internal capsule with intracerebral hemorrhage (ICH). Forced limb use (FLU) group rats exhibited better recovery of skilled forelimb functions and their cortical motor area with forelimb representation was restored and enlarged on the ipsilesional side. In addition, abundant axonal sprouting from the reemerged forelimb area was found in the ipsilateral red nucleus after FLU. To test the causal relationship between the plasticity in the cortico-rubral pathway and recovery, loss-of function experiments were conducted using a double-viral vector technique, which induces selective blockade of the target pathway. Blockade of the cortico-rubral tract resulted in deficits of the recovered forelimb function in FLU group rats. These findings suggest that the cortico-rubral pathway is a substrate for recovery induced by intensive rehabilitation after ICH. SIGNIFICANCE STATEMENT: The research aimed at determining the causal linkage between reorganization of the motor pathway induced by intensive rehabilitative training and recovery after stroke. We clarified the expansion of the forelimb representation area of the ipsilesional motor cortex by forced impaired forelimb use (FLU) after lesioning the internal capsule with intracerebral hemorrhaging (ICH) in rats. Anterograde tracing showed robust axonal sprouting from the forelimb area to the red nucleus in response to FLU. Selective blockade of the cortico-rubral pathway by the novel double-viral vector technique clearly revealed that the increased cortico-rubral axonal projections had causal linkage to the recovery of reaching movements induced by FLU. Our data demonstrate that the cortico-rubral pathway is responsible for the effect of intensive limb use. PMID- 26758838 TI - De Novo Emergence of Odor Category Representations in the Human Brain. AB - Categorization allows organisms to efficiently extract relevant information from a diverse environment. Because of the multidimensional nature of odor space, this ability is particularly important for the olfactory system. However, categorization relies on experience, and the processes by which the human brain forms categorical representations about new odor percepts are currently unclear. Here we used olfactory psychophysics and multivariate fMRI techniques, in the context of a paired-associates learning task, to examine the emergence of novel odor category representations in the human brain. We found that learning between novel odors and visual category information induces a perceptual reorganization of those odors, in parallel with the emergence of odor category-specific ensemble patterns in perirhinal, orbitofrontal, piriform, and insular cortices. Critically, the learning-induced pattern effects in orbitofrontal and perirhinal cortex predicted the magnitude of categorical learning and perceptual plasticity. The formation of de novo category-specific representations in olfactory and limbic brain regions suggests that such ensemble patterns subserve the development of perceptual classes of information, and imply that these patterns are instrumental to the brain's capacity for odor categorization. SIGNIFICANCE STATEMENT: How the human brain assigns novel odors to perceptual classes and categories is poorly understood. We combined an olfactory-visual paired associates task with multivariate pattern-based fMRI approaches to investigate the de novo formation of odor category representations within the human brain. The identification of emergent odor category codes within the perirhinal, piriform, orbitofrontal, and insular cortices suggests that these regions can integrate multimodal sensory input to shape category-specific olfactory representations for novel odors, and may ultimately play an important role in assembling each individual's semantic knowledge base of the olfactory world. PMID- 26758839 TI - Myocardial Infarction Causes Transient Cholinergic Transdifferentiation of Cardiac Sympathetic Nerves via gp130. AB - Sympathetic and parasympathetic control of the heart is a classic example of norepinephrine (NE) and acetylcholine (ACh) triggering opposing actions. Sympathetic NE increases heart rate and contractility through activation of beta receptors, whereas parasympathetic ACh slows the heart through muscarinic receptors. Sympathetic neurons can undergo a developmental transition from production of NE to ACh and we provide evidence that mouse cardiac sympathetic nerves transiently produce ACh after myocardial infarction (MI). ACh levels increased in viable heart tissue 10-14 d after MI, returning to control levels at 21 d, whereas NE levels were stable. At the same time, the genes required for ACh synthesis increased in stellate ganglia, which contain most of the sympathetic neurons projecting to the heart. Immunohistochemistry 14 d after MI revealed choline acetyltransferase (ChAT) in stellate sympathetic neurons and vesicular ACh transporter immunoreactivity in tyrosine hydroxylase-positive cardiac sympathetic fibers. Finally, selective deletion of the ChAT gene from adult sympathetic neurons prevented the infarction-induced increase in cardiac ACh. Deletion of the gp130 cytokine receptor from sympathetic neurons prevented the induction of cholinergic genes after MI, suggesting that inflammatory cytokines induce the transient acquisition of a cholinergic phenotype in cardiac sympathetic neurons. Ex vivo experiments examining the effect of NE and ACh on rabbit cardiac action potential duration revealed that ACh blunted both the NE stimulated decrease in cardiac action potential duration and increase in myocyte calcium transients. This raises the possibility that sympathetic co-release of ACh and NE may impair adaptation to high heart rates and increase arrhythmia susceptibility. SIGNIFICANCE STATEMENT: Sympathetic neurons normally make norepinephrine (NE), which increases heart rate and the contractility of cardiac myocytes. We found that, after myocardial infarction, the sympathetic neurons innervating the heart begin to make acetylcholine (ACh), which slows heart rate and decreases contractility. Several lines of evidence confirmed that the source of ACh was sympathetic nerves rather than parasympathetic nerves that are the normal source of ACh in the heart. Global application of NE with or without ACh to ex vivo hearts showed that ACh partially reversed the NE-stimulated decrease in cardiac action potential duration and increase in myocyte calcium transients. That suggests that sympathetic co-release of ACh and NE may impair adaptation to high heart rates and increase arrhythmia susceptibility. PMID- 26758840 TI - Transitions between Multiband Oscillatory Patterns Characterize Memory-Guided Perceptual Decisions in Prefrontal Circuits. AB - Neuronal activity in the lateral prefrontal cortex (LPFC) reflects the structure and cognitive demands of memory-guided sensory discrimination tasks. However, we still do not know how neuronal activity articulates in network states involved in perceiving, remembering, and comparing sensory information during such tasks. Oscillations in local field potentials (LFPs) provide fingerprints of such network dynamics. Here, we examined LFPs recorded from LPFC of macaques while they compared the directions or the speeds of two moving random-dot patterns, S1 and S2, separated by a delay. LFP activity in the theta, beta, and gamma bands tracked consecutive components of the task. In response to motion stimuli, LFP theta and gamma power increased, and beta power decreased, but showed only weak motion selectivity. In the delay, LFP beta power modulation anticipated the onset of S2 and encoded the task-relevant S1 feature, suggesting network dynamics associated with memory maintenance. After S2 onset the difference between the current stimulus S2 and the remembered S1 was strongly reflected in broadband LFP activity, with an early sensory-related component proportional to stimulus difference and a later choice-related component reflecting the behavioral decision buildup. Our results demonstrate that individual LFP bands reflect both sensory and cognitive processes engaged independently during different stages of the task. This activation pattern suggests that during elementary cognitive tasks, the prefrontal network transitions dynamically between states and that these transitions are characterized by the conjunction of LFP rhythms rather than by single LFP bands. SIGNIFICANCE STATEMENT: Neurons in the brain communicate through electrical impulses and coordinate this activity in ensembles that pulsate rhythmically, very much like musical instruments in an orchestra. These rhythms change with "brain state," from sleep to waking, but also signal with different oscillation frequencies rapid changes between sensory and cognitive processing. Here, we studied rhythmic electrical activity in the monkey prefrontal cortex, an area implicated in working memory, decision making, and executive control. Monkeys had to identify and remember a visual motion pattern and compare it to a second pattern. We found orderly transitions between rhythmic activity where the same frequency channels were active in all ongoing prefrontal computations. This supports prefrontal circuit dynamics that transitions rapidly between complex rhythmic patterns during structured cognitive tasks. PMID- 26758841 TI - Seizure-Induced Sympathoexcitation Is Caused by Activation of Glutamatergic Receptors in RVLM That Also Causes Proarrhythmogenic Changes Mediated by PACAP and Microglia in Rats. AB - Cardiovascular autonomic dysfunction in seizure is a major cause of sudden unexpected death in epilepsy. The catecholaminergic neurons in the rostral ventrolateral medulla (RVLM) maintain sympathetic vasomotor tone and blood pressure through their direct excitatory projections to the intermediolateral (IML) cell column. Glutamate, the principal excitatory neurotransmitter in brain, is increased in seizures. Pituitary adenylate cyclase activating polypeptide (PACAP) is an excitatory neuropeptide with neuroprotective properties, whereas microglia are key players in inflammatory responses in CNS. We investigated the roles of glutamate, PACAP, and microglia on RVLM catecholaminergic neurons during the cardiovascular responses to 2 mg/kg kainic acid (KA)-induced seizures in urethane anesthetized, male Sprague Dawley rats. Microinjection of the glutamate antagonist, kynurenic acid (50 nl; 100 mM) into RVLM, blocked the seizure-induced 43.2 +/- 12.6% sympathoexcitation (p <= 0.05), and abolished the pressor responses, tachycardia, and QT interval prolongation. PACAP or microglia antagonists (50 nl) (PACAP(6-38), 15 pmol; minocycline 10 mg/ml) microinjected bilaterally into RVLM had no effect on seizure-induced sympathoexcitation, pressor responses, or tachycardia but abolished the prolongation of QT interval. The actions of PACAP or microglia on RVLM neurons do not cause sympathoexcitation, but they do elicit proarrhythmogenic changes. An immunohistochemical analysis in 2 and 10 mg/kg KA-induced seizure rats revealed that microglia surrounding catecholaminergic neurons are in a "surveillance" state with no change in the number of M2 microglia (anti-inflammatory). In conclusion, seizure-induced sympathoexcitation is caused by activation of glutamatergic receptors in RVLM that also cause proarrhythmogenic changes mediated by PACAP and microglia. SIGNIFICANCE STATEMENT: Sudden unexpected death in epilepsy is a major cause of death in epilepsy. Generally, seizures are accompanied by changes in brain function leading to uncontrolled nerve activity causing high blood pressure, rapid heart rate, and abnormal heart rhythm. Nevertheless, the brain chemicals causing these cardiovascular changes are unknown. Chemicals, such as glutamate and pituitary adenylate cyclase activating polypeptide, whose expression is increased after seizures, act on specific cardiovascular nuclei in the brain and influence the activity of the heart, and blood vessels. Microglia, which manage excitation in the brain, are commonly activated after seizure and produce pro- and/or anti-inflammatory factors. Hence, we aimed to determine the effects of blocking glutamate, pituitary adenylate cyclase activating polypeptide, and microglia in the RVLM and their contribution to cardiovascular autonomic dysfunction in seizure. PMID- 26758842 TI - Anxiety- and Depression-Like States Lead to Pronounced Olfactory Deficits and Impaired Adult Neurogenesis in Mice. AB - Numerous clinical reports underscore the frequency of olfactory impairments in patients suffering from major depressive disorders (MDDs), yet the underlying physiopathological mechanisms remain poorly understood. We hypothesized that one key link between olfactory deficits and MDD lies in hypercortisolemia, a cardinal symptom of MDD. Corticosterone (CORT) is known to negatively correlate with hippocampal neurogenesis, yet its effects on olfactory neurogenesis and olfaction remain unknown. Here we used a rodent model of anxiety/depression-like states, which is based on chronic CORT administration and studied the effects of the antidepressant fluoxetine (FLX) on behavior, olfaction, and adult neurogenesis in the dentate gyrus (DG), olfactory bulb (OB), and the olfactory epithelium (OE). Chronic CORT had no effect on cell proliferation in the OE or on olfactory sensory neurons projecting to the OB, but induced pronounced deficits in olfactory acuity, fine discrimination of odorants and olfactory memory. These alterations were accompanied by a significant decrease in the number of adult born neurons in both the DG and OB. Remarkably, FLX not only reversed depression like states as expected, but also improved olfactory acuity, memory, and restored impaired adult neurogenesis. However, fine olfactory discrimination was not restored. Morphological analysis of adult-born neurons in both the DG and the OB showed that dendritic complexity was not significantly affected by CORT, but was increased by FLX. These findings demonstrate an essential role for glucocorticoids in triggering olfactory impairments in MDD and highlight a novel therapeutic effect of FLX. SIGNIFICANCE STATEMENT: Increasing clinical reports show that major depression is characterized by pronounced olfactory deficits, yet the underlying mechanisms remain unknown. In this work, we used an endocrine model of depression to study whether hypothalamic-pituitary-adrenal axis perturbation could be sufficient to provoke olfactory impairments. We found that chronic corticosterone not only induces marked deficits in olfactory acuity, fine discrimination and olfactory memory, but also significantly decreases bulbar and hippocampal neurogenesis. Importantly, the antidepressant fluoxetine restores both adult neurogenesis and depressive states, and improves most olfactory functions. Our data reveal that impairment of hypothalamic-pituitary-adrenal axis during depression can lead to olfactory deficits and that the neurogenic effects of selective serotonin reuptake inhibitor antidepressants can successfully restore certain olfactory functions. PMID- 26758843 TI - Decentralized Multisensory Information Integration in Neural Systems. AB - How multiple sensory cues are integrated in neural circuitry remains a challenge. The common hypothesis is that information integration might be accomplished in a dedicated multisensory integration area receiving feedforward inputs from the modalities. However, recent experimental evidence suggests that it is not a single multisensory brain area, but rather many multisensory brain areas that are simultaneously involved in the integration of information. Why many mutually connected areas should be needed for information integration is puzzling. Here, we investigated theoretically how information integration could be achieved in a distributed fashion within a network of interconnected multisensory areas. Using biologically realistic neural network models, we developed a decentralized information integration system that comprises multiple interconnected integration areas. Studying an example of combining visual and vestibular cues to infer heading direction, we show that such a decentralized system is in good agreement with anatomical evidence and experimental observations. In particular, we show that this decentralized system can integrate information optimally. The decentralized system predicts that optimally integrated information should emerge locally from the dynamics of the communication between brain areas and sheds new light on the interpretation of the connectivity between multisensory brain areas. SIGNIFICANCE STATEMENT: To extract information reliably from ambiguous environments, the brain integrates multiple sensory cues, which provide different aspects of information about the same entity of interest. Here, we propose a decentralized architecture for multisensory integration. In such a system, no processor is in the center of the network topology and information integration is achieved in a distributed manner through reciprocally connected local processors. Through studying the inference of heading direction with visual and vestibular cues, we show that the decentralized system can integrate information optimally, with the reciprocal connections between processers determining the extent of cue integration. Our model reproduces known multisensory integration behaviors observed in experiments and sheds new light on our understanding of how information is integrated in the brain. PMID- 26758844 TI - The Neural Representation of Goal-Directed Actions and Outcomes in the Ventral Striatum's Olfactory Tubercle. AB - The ventral striatum is critical for evaluating reward information and the initiation of goal-directed behaviors. The many cellular, afferent, and efferent similarities between the ventral striatum's nucleus accumbens and olfactory tubercle (OT) suggests the distributed involvement of neurons within the ventral striatopallidal complex in motivated behaviors. Although the nucleus accumbens has an established role in representing goal-directed actions and their outcomes, it is not known whether this function is localized within the nucleus accumbens or distributed also within the OT. Answering such a fundamental question will expand our understanding of the neural mechanisms underlying motivated behaviors. Here we address whether the OT encodes natural reinforcers and serves as a substrate for motivational information processing. In recordings from mice engaged in a novel water-motivated instrumental task, we report that OT neurons modulate their firing rate during initiation and progression of the instrumental licking behavior, with some activity being internally generated and preceding the first lick. We further found that as motivational drive decreases throughout a session, the activity of OT neurons is enhanced earlier relative to the behavioral action. Additionally, OT neurons discriminate the types and magnitudes of fluid reinforcers. Together, these data suggest that the processing of reward information and the orchestration of goal-directed behaviors is a global principle of the ventral striatum and have important implications for understanding the neural systems subserving addiction and mood disorders. SIGNIFICANCE STATEMENT: Goal-directed behaviors are widespread among animals and underlie complex behaviors ranging from food intake, social behavior, and even pathological conditions, such as gambling and drug addiction. The ventral striatum is a neural system critical for evaluating reward information and the initiation of goal-directed behaviors. Here we show that neurons in the olfactory tubercle subregion of the ventral striatum robustly encode the onset and progression of motivated behaviors, and discriminate the type and magnitude of a reward. Our findings are novel in showing that olfactory tubercle neurons participate in such coding schemes and are in accordance with the principle that ventral striatum substructures may cooperate to guide motivated behaviors. PMID- 26758847 TI - The Matrix Proteins Hasp and Hig Exhibit Segregated Distribution within Synaptic Clefts and Play Distinct Roles in Synaptogenesis. AB - The synaptic cleft is the space through which neurotransmitters convey neural information between two synaptic terminals. This space is presumably filled with extracellular matrix molecules involved in synaptic function or differentiation. However, little is known about the identities of the matrix components, and it remains unclear how these molecules organize the matrix in synaptic clefts. In this study, we identified Hasp, a Drosophila secretory protein containing CCP and WAP domains. Molecular genetic analysis revealed that Hasp diffuses extracellularly and is predominantly captured at synaptic clefts of cholinergic synapses. Furthermore, Hasp regulates levels of DLG and the nAChR subunits Dalpha6 and Dalpha7 at postsynaptic terminals. Hasp is required for trapping of another matrix protein, Hig, which is also secreted and diffused in the brain, at synaptic clefts of cholinergic synapses; however, Hig is dispensable for localization of Hasp at synaptic clefts. In addition, in the brains of triple mutants for the nAChR subunits Dalpha5, Dalpha6, and Dalpha7, the level of Hig, but not Hasp, was markedly reduced in synaptic regions, indicating that these nAChR subunits are required to anchor Hig to synaptic clefts. High-resolution microscopy revealed that Hasp and Hig exhibit segregated distribution within individual synaptic clefts, reflecting their differing roles in synaptogenesis. These data provide insight into how Hasp and Hig construct the synaptic cleft matrix and regulate the differentiation of cholinergic synapses, and also illuminate a previously unidentified architecture within synaptic clefts. SIGNIFICANCE STATEMENT: The synapse has been extensively studied because it is essential for neurotransmission. By contrast, the space between the synaptic terminals, the synaptic cleft, is still an undeveloped research area despite its ubiquity in synapses. In fruit fly brains, we obtained evidence that the matrix protein Hasp and the previously identified Hig, both of which are secreted extracellularly, localize predominantly to synaptic clefts of cholinergic synapses, and modulate the levels of nAChR subunits on postsynaptic membranes. However, Hasp and Hig play differential roles in matrix formation and exhibit segregated distribution within synaptic clefts. These results reveal the molecular mechanisms of synaptic matrix construction and illuminate a molecular architecture within synaptic clefts previously unrevealed in any animal species. PMID- 26758845 TI - Normal Molecular Specification and Neurodegenerative Disease-Like Death of Spinal Neurons Lacking the SNARE-Associated Synaptic Protein Munc18-1. AB - The role of synaptic activity during early formation of neural circuits is a topic of some debate; genetic ablation of neurotransmitter release by deletion of the Munc18-1 gene provides an excellent model to answer the question of whether such activity is required for early circuit formation. Previous analysis of Munc18-1(-/-) mouse mutants documented their grossly normal nervous system, but its molecular differentiation has not been assessed. Munc18-1 deletion in mice also results in widespread neurodegeneration that remains poorly characterized. In this study, we demonstrate that the early stages of spinal motor circuit formation, including motor neuron specification, axon growth and pathfinding, and mRNA expression, are unaffected in Munc18-1(-/-) mice, demonstrating that synaptic activity is dispensable for early nervous system development. Furthermore, we show that the neurodegeneration caused by Munc18-1 loss is cell autonomous, consistent with apparently normal expression of several neurotrophic factors and normal GDNF signaling. Consistent with cell-autonomous degeneration, we demonstrate defects in the trafficking of the synaptic proteins Syntaxin1a and PSD-95 and the TrkB and DCC receptors in Munc18-1(-/-) neurons; these defects do not appear to cause ER stress, suggesting other mechanisms for degeneration. Finally, we demonstrate pathological similarities to Alzheimer's disease, such as altered Tau phosphorylation, neurofibrillary tangles, and accumulation of insoluble protein plaques. Together, our results shed new light upon the neurodegeneration observed in Munc18-1(-/-) mice and argue that this phenomenon shares parallels with neurodegenerative diseases. SIGNIFICANCE STATEMENT: In this work, we demonstrate the absence of a requirement for regulated neurotransmitter release in the assembly of early neuronal circuits by assaying transcriptional identity, axon growth and guidance, and mRNA expression in Munc18-1-null mice. Furthermore, we characterize the neurodegeneration observed in Munc18-1 mutants and demonstrate that this cell-autonomous process does not appear to be a result of defects in growth factor signaling or ER stress caused by protein trafficking defects. However, we find the presence of various pathological hallmarks of Alzheimer's disease that suggest parallels between the degeneration in these mutants and neurodegenerative conditions. PMID- 26758846 TI - Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease. AB - Increasing evidence supports a role of neuroinflammation in the pathogenesis of Alzheimer's disease (AD). Previously, we identified a neuron-glia signaling pathway whereby Abeta acts as an upstream activator of astroglial nuclear factor kappa B (NF-kappaB), leading to the release of complement C3, which acts on the neuronal C3a receptor (C3aR) to influence dendritic morphology and cognitive function. Here we report that astrocytic complement activation also regulates Abeta dynamics in vitro and amyloid pathology in AD mouse models through microglial C3aR. We show that in primary microglial cultures, acute C3 or C3a activation promotes, whereas chronic C3/C3a treatment attenuates, microglial phagocytosis and that the effect of chronic C3 exposure can be blocked by cotreatment with a C3aR antagonist and by genetic deletion of C3aR. We further demonstrate that Abeta pathology and neuroinflammation in amyloid precursor protein (APP) transgenic mice are worsened by astroglial NF-kappaB hyperactivation and resulting C3 elevation, whereas treatment with the C3aR antagonist (C3aRA) ameliorates plaque load and microgliosis. Our studies define a complement-dependent intercellular cross talk in which neuronal overproduction of Abeta activates astroglial NF-kappaB to elicit extracellular release of C3. This promotes a pathogenic cycle by which C3 in turn interacts with neuronal and microglial C3aR to alter cognitive function and impair Abeta phagocytosis. This feedforward loop can be effectively blocked by C3aR inhibition, supporting the therapeutic potential of C3aR antagonists under chronic neuroinflammation conditions. SIGNIFICANCE STATEMENT: The complement pathway is activated in Alzheimer's disease. Here we show that the central complement factor C3 secreted from astrocytes interacts with microglial C3a receptor (C3aR) to mediate beta amyloid pathology and neuroinflammation in AD mouse models. Our study provides support for targeting C3aR as a potential therapy for Alzheimer's disease. PMID- 26758849 TI - Calcium-Permeable AMPA Receptors Mediate the Induction of the Protein Kinase A Dependent Component of Long-Term Potentiation in the Hippocampus. AB - Two forms of NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) at hippocampal CA1 synapses can be distinguished based on their sensitivity to inhibitors of protein kinase A (PKA). The PKA-dependent form requires multiple episodes of high-frequency stimulation (HFS) or theta burst stimuli (TBS) with a spacing between episodes in the order of minutes. To investigate the mechanism by which spaced episodes induce the PKA-dependent form of LTP, we have compared, in interleaved experiments, spaced (s) and compressed (c) TBS protocols in the rat CA1 synapses. We find that LTP induced by sTBS, but not that induced by cTBS, involves the insertion of calcium-permeable (CP) AMPARs, as assessed using pharmacological and electrophysiological criteria. Furthermore, a single TBS when paired with rolipram [4-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrrolidin-2-one], to activate PKA, generates an LTP that also involves the insertion of CP-AMPARs. These data demonstrate that the involvement of CP-AMPARs in LTP is critically determined by the timing of the induction trigger and is associated specifically with the PKA-dependent form of LTP. SIGNIFICANCE STATEMENT: Long-term potentiation is a family of synaptic mechanisms that are believed to be important for learning and memory. Two of the most extensively studied forms are triggered by the synaptic activation of NMDA receptors and expressed by changes in AMPA receptor function. They can be distinguished on the basis of their requirement for activation of a protein kinase, PKA. We show that the PKA-dependent form also involves the transient insertion of calcium-permeable AMPA receptors. These results have implications for relating synaptic plasticity to learning and memory and suggest a specific linkage between PKA activation and the rapid synaptic insertion of calcium-permeable AMPA receptors during long-term potentiation. PMID- 26758848 TI - Context-Dependent Modulation of GABAAR-Mediated Tonic Currents. AB - Tonic GABA currents mediated by high-affinity extrasynaptic GABAA receptors, are increasingly recognized as important regulators of cell and neuronal network excitability. Dysfunctional GABAA receptor signaling that results in modified tonic GABA currents is associated with a number of neurological disorders. Consequently, developing compounds to selectively modulate the activity of extrasynaptic GABAA receptors underlying tonic inhibition is likely to prove therapeutically useful. Here, we examine the GABAA receptor subtype selectivity of the weak partial agonist, 5-(4-piperidyl)isoxazol-3-ol (4-PIOL), as a potential mechanism for modulating extrasynaptic GABAA receptor-mediated tonic currents. By using recombinant GABAA receptors expressed in HEK293 cells, and native GABAA receptors of cerebellar granule cells, hippocampal neurons, and thalamic relay neurons, 4-PIOL evidently displayed differential agonist and antagonist-type profiles, depending on the extrasynaptic GABAA receptor isoforms targeted. For neurons, this resulted in differential modulation of GABA tonic currents, depending on the cell type studied, their respective GABAA receptor subunit compositions, and critically, on the ambient GABA levels. Unexpectedly, 4 PIOL revealed a significant population of relatively low-affinity gamma2 subunit containing GABAA receptors in the thalamus, which can contribute to tonic inhibition under specific conditions when GABA levels are raised. Together, these data indicate that partial agonists, such as 4-PIOL, may be useful for modulating GABAA receptor-mediated tonic currents, but the direction and extent of this modulation is strongly dependent on relative expression levels of different extrasynaptic GABAA receptor subtypes, and on the ambient GABA levels. SIGNIFICANCE STATEMENT: A background level of inhibition (tonic) is important in the brain for controlling neuronal excitability. Increased levels of tonic inhibition are associated with some neurological disorders but there are no specific ligands capable of selectively reducing tonic inhibition. Here we explore the use of a GABA partial agonist as a selective chemical tool in three different brain regions. We discover that the activity of a partial agonist is heavily dependent upon the GABAA receptor subunit composition underpinning tonic inhibition, and on the ambient levels of GABA in the brain. PMID- 26758850 TI - Attenuation of beta-Amyloid Deposition and Neurotoxicity by Chemogenetic Modulation of Neural Activity. AB - Aberrant neural hyperactivity has been observed in early stages of Alzheimer's disease (AD) and may be a driving force in the progression of amyloid pathology. Evidence for this includes the findings that neural activity may modulate beta amyloid (Abeta) peptide secretion and experimental stimulation of neural activity can increase amyloid deposition. However, whether long-term attenuation of neural activity prevents the buildup of amyloid plaques and associated neural pathologies remains unknown. Using viral-mediated delivery of designer receptors exclusively activated by designer drugs (DREADDs), we show in two AD-like mouse models that chronic intermittent increases or reductions of activity have opposite effects on Abeta deposition. Neural activity reduction markedly decreases Abeta aggregation in regions containing axons or dendrites of DREADD expressing neurons, suggesting the involvement of synaptic and nonsynaptic Abeta release mechanisms. Importantly, activity attenuation is associated with a reduction in axonal dystrophy and synaptic loss around amyloid plaques. Thus, modulation of neural activity could constitute a potential therapeutic strategy for ameliorating amyloid-induced pathology in AD. SIGNIFICANCE STATEMENT: A novel chemogenetic approach to upregulate and downregulate neuronal activity in Alzheimer's disease (AD) mice was implemented. This led to the first demonstration that chronic intermittent attenuation of neuronal activity in vivo significantly reduces amyloid deposition. The study also demonstrates that modulation of beta-amyloid (Abeta) release can occur at both axonal and dendritic fields, suggesting the involvement of synaptic and nonsynaptic Abeta release mechanisms. Activity reductions also led to attenuation of the synaptic pathology associated with amyloid plaques. Therefore, chronic attenuation of neuronal activity could constitute a novel therapeutic approach for AD. PMID- 26758853 TI - Identification of Human Sulfotransferases Involved in Lorcaserin N-Sulfamate Formation. AB - Lorcaserin [(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine] hydrochloride hemihydrate, a selective serotonin 5-hydroxytryptamine (5-HT) 5 HT(2C) receptor agonist, is approved by the U.S. Food and Drug Administration for chronic weight management. Lorcaserin is primarily cleared by metabolism, which involves multiple enzyme systems with various metabolic pathways in humans. The major circulating metabolite is lorcaserin N-sulfamate. Both human liver and renal cytosols catalyze the formation of lorcaserin N-sulfamate, where the liver cytosol showed a higher catalytic efficiency than renal cytosol. Human sulfotransferases (SULTs) SULT1A1, SULT1A2, SULT1E1, and SULT2A1 are involved in the formation of lorcaserin N-sulfamate. The catalytic efficiency of these SULTs for lorcaserin N-sulfamate formation is widely variable, and among the SULT isoforms SULT1A1 was the most efficient. The order of intrinsic clearance for lorcaserin N-sulfamate is SULT1A1 > SULT2A1 > SULT1A2 > SULT1E1. Inhibitory effects of lorcaserin N-sulfamate on major human cytochrome P450 (P450) enzymes were not observed or minimal. Lorcaserin N-sulfamate binds to human plasma protein with high affinity (i.e., >99%). Thus, despite being the major circulating metabolite, the level of free lorcaserin N-sulfamate would be minimal at a lorcaserin therapeutic dose and unlikely be sufficient to cause drug-drug interactions. Considering its formation kinetic parameters, high plasma protein binding affinity, minimal P450 inhibition or induction potential, and stability, the potential for metabolic drug-drug interaction or toxicological effects of lorcaserin N-sulfamate is remote in a normal patient population. PMID- 26758852 TI - Does activity affect the outcome of the Oxford unicompartmental knee replacement? AB - BACKGROUND: High levels of activity are considered to be a contraindication to unicompartmental knee replacement (UKR) and are not recommended after UKR. To determine if these recommendations should apply to the mobile-bearing Oxford UKR, this study assessed the effect of post-operative activity level on the outcome of this device. METHODS: The outcome of the first 1000 Phase 3 cemented Oxford UKRs implanted between 1998 and 2010 was assessed using survival analysis, the Oxford Knee Score (OKS) and the American Knee Society Objective (KSS-O) and Functional (KSS-F) Scores. Patients were grouped according to the maximum post-operative Tegner Activity Score. RESULTS: The mean follow-up was 6.1 years (range 1 to 14). Overall, increasing activity was associated with superior survival (p=0.025). In the high activity group, with Tegner>=5 (n=115) 2.6% were revised and the 12-year survival was 97.3% (confidence interval (CI): 92.0% to 99.1%). In the low activity group, with Tegner<=4, (n=885) 4.3% were revised and the 12-year survival was 94.0% (CI: 91.4 to 95.8). The difference between the two groups was not significant (p=0.44). Although the final OKS and KSS-F were significantly better in the high activity group compared to the low activity group (OKS 45v40, KSS-F 95v78), there was no difference in the change in OKS or KSS-O. CONCLUSIONS: High activity does not compromise the outcome of the Oxford UKR and may improve it. Activity should not be restricted nor considered to be a contraindication. PMID- 26758854 TI - Efflux Transport Characterization of Resveratrol Glucuronides in UDP Glucuronosyltransferase 1A1 Transfected HeLa Cells: Application of a Cellular Pharmacokinetic Model to Decipher the Contribution of Multidrug Resistance Associated Protein 4. AB - Resveratrol undergoes extensive metabolism to form biologically active glucuronides in humans. However, the transport mechanisms for resveratrol glucuronides are not fully established. Here, we aimed to characterize the efflux transport of resveratrol glucuronides using UGT1A1-overexpressing HeLa cells (HeLa1A1 cells), and to determine the contribution of multidrug resistance associated protein (MRP) 4 to cellular excretion of the glucuronides. Two glucuronide isomers [i.e., resveratrol 3-O-glucuronide (R3G) and resveratrol 4'-O glucuronide (R4'G)] were excreted into the extracellular compartment after incubation of resveratrol (1-100 MUM) with HeLa1A1 cells. The excretion rate was linearly related to the level of intracellular glucuronide, indicating that glucuronide efflux was a nonsaturable process. MK-571 (a dual inhibitor of UGT1A1 and MRPs) significantly decreased the excretion rates of R3G and R4'G while increasing their intracellular levels. Likewise, short-hairpin RNA (shRNA) mediated silencing of MRP4 caused a significant reduction in glucuronide excretion but an elevation in glucuronide accumulation. Furthermore, beta glucuronidase expressed in the cells catalyzed the hydrolysis of the glucuronides back to the parent compound. A cellular pharmacokinetic model integrating resveratrol transport/metabolism with glucuronide hydrolysis/excretion was well fitted to the experimental data, allowing derivation of the efflux rate constant values in the absence or presence of shRNA targeting MRP4. It was found that a large percentage of glucuronide excretion (43%-46%) was attributed to MRP4. In conclusion, MRP4 participated in cellular excretion of R3G and R4'G. Integration of mechanistic pharmacokinetic modeling with transporter knockdown was a useful method to derive the contribution percentage of an exporter to overall glucuronide excretion. PMID- 26758856 TI - Sicario, directed by Denis Villeneuve, 2015. PMID- 26758855 TI - Spontaneous rupture of the long head of the biceps tendon in a woman with hypothyroidism: a case report. AB - BACKGROUND: Tendinitis can be a presenting complaint in hypothyroidism, with symptomatic relief being obtained by appropriate management of the primary thyroid deficiency. To the best of our knowledge no other cases of spontaneous rupture of the long head of the biceps tendon during uncontrolled hypothyroidism have yet been reported. CASE PRESENTATION: This case report describes an unusual case of spontaneous rupture of the long head of the biceps tendon in a 48-year old white woman with severe hypothyroidism. She described experiencing a sudden sharp pain and an audible pop in her right shoulder while using her personal computer. On physical examination she was positive for Yergason's sign and a subsequent magnetic resonance imaging scan showed complete rupture of the long head of her biceps tendon. Laboratory tests revealed significantly elevated thyrotropin levels (>100 MUIU/ml) and very low levels of both triiodothyronine (0.17 ng/ml) and free thyroxine (0.18 ng/dl). She was switched to a different thyroxin regimen with a progressive dosage increment. She declined surgical re anchorage of the tendon but despite the discreet Popeye sign, her overall strength and shoulder function were satisfactory. After 2 months, she was found to be clinically euthyroid, having normal thyroid function tests (thyrotropin 2.95 MUIU/mL, free thyroxine 1.07 ng/dl). At her last follow-up visit, 1 year post-injury, she reported nearly normal shoulder function in her daily activities and had a constant shoulder score of 93 points. CONCLUSIONS: The role of thyroid hormones in the synthesis and degeneration of collagen and in the proliferation and apoptosis of human tenocytes is discussed, providing a possible mechanism whereby hypothyroidism may lead to tendon tears. This report may have a greater impact among different subspecialties as it presupposes a high degree of awareness from internists, endocrinologists and orthopedic surgeons. PMID- 26758857 TI - Rituximab for recurrent IgA nephropathy in kidney transplantation: A report of three cases and proposed mechanisms. AB - AIM: Recurrent IgA nephropathy (IgAN) is a common recurrent glomerular disease after kidney transplantation. Recurrent IgAN, in particular, with crescent formation or endocapillary proliferation might result in kidney allograft loss. However, the current treatment options of recurrent IgAN are conflicting. METHODS: We have reported three kidney-transplanted recipients with biopsy-proven recurrent IgAN treated with four consecutive months of rituximab at the dose of 375 mg/1.73m2 without corticosteroids. RESULTS: At median follow-up 20 months following rituximab administration, all three recipients demonstrated decrease in proteinuria severity, slow disease progression with a well-tolerated condition. This therapeutic effect is most probably mediated by the B cell depletion. CONCLUSION: Our three case reports suggest that the disease severity of recurrent IgAN with endocapillary proliferation regardless of crescent formation can be minimized by the four doses of monthly rituximab regimen. PMID- 26758851 TI - ROS in gastrointestinal inflammation: Rescue Or Sabotage? AB - : The intestine is composed of many distinct cell types that respond to commensal microbiota or pathogens with immune tolerance and proinflammatory signals respectively. ROS produced by mucosa-resident cells or by newly recruited innate immune cells are essential for antimicrobial responses and regulation of signalling pathways including processes involved in wound healing. Impaired ROS production due to inactivating patient variants in genes encoding NADPH oxidases as ROS source has been associated with Crohn's disease and pancolitis, whereas overproduction of ROS due to up-regulation of oxidases or altered mitochondrial function was linked to ileitis and ulcerative colitis. Here, we discuss recent advances in our understanding of how maintaining a redox balance is crucial to preserve gut homeostasis. LINKED ARTICLES: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc. PMID- 26758858 TI - Association between depression and survival in Chinese amyotrophic lateral sclerosis patients. AB - To determine the prevalence of depression, to identify correlated factors for depression, and to explore the impact on the progression or survival of amyotrophic lateral sclerosis (ALS) by depression in a Chinese population. A total of 166 ALS patients were recruited. Diagnosis of depression disorders and the severity of depression were established by using the fourth diagnostic and statistical manual of mental disorders, Hamilton Depression Rating Scale-24 items (HDRS-24) and Beck Depression Inventory (BDI). Major depression was found in 15 patients (9.6 %). The multiple regression analysis showed that a lower ALS Functional Rating Scale-Revised (ALSFRS-R) score was correlated with increasing HDRS scores and BDI scores (P = 0.018 and P = 0.012). No significant difference in the median survival time between ALS patients with and without depression was revealed by Kaplan-Meier analysis (log-rank P = 0.282). Cox hazard model showed that the presence of depression in ALS was unrelated to the survival, while the severity of depression in ALS was correlated with the survival. The presence and severity of depression in ALS did not correlate with the progression of ALS. Major depression in ALS is uncommon. Depression evaluation should be given to ALS patients, especially those with lower ALSFRS-R score. The severity of depression may be associated with the survival; however, depression does not worse the progression of ALS. PMID- 26758860 TI - Optoelectronic Properties of CuInS2 Nanocrystals and Their Origin. AB - The capacity of fluorescent colloidal semiconductor nanocrystals for commercial application has led to the development of nanocrystals with nontoxic constituent elements as replacements for the currently available Cd- and Pb-containing systems. CuInS2 is a good candidate material because of its direct band gap in the near-infrared spectral region and large optical absorption coefficient. The ternary nature, flexible stoichiometry, and different crystal structures of CuInS2 lead to a range of optoelectronic properties, which have been challenging to elucidate. In this Perspective, the optoelectronic properties of CuInS2 nanocrystals are described and what is known of their origin is discussed. We begin with an overview of their synthesis, structure, and mechanism of formation. A complete discussion of the tunable luminescence properties and the radiative decay mechanism of this system is then presented. Finally, progress toward application of these "green" nanocrystals is summarized. PMID- 26758859 TI - The independent prospective associations of activity intensity and dietary energy density with adiposity in young adolescents. AB - There is limited evidence on the prospective association of time spent in activity intensity (sedentary (SED), moderate (MPA) or vigorous (VPA) physical activity) and dietary intake with adiposity indicators in young people. This study aimed to assess associations between (1) baseline objectively measured activity intensity, dietary energy density (DED) and 4-year change in adiposity and (2) 4-year change in activity intensity/DED and adiposity at follow-up. We conducted cohort analyses including 367 participants (10 years at baseline, 14 years at follow-up) with valid data for objectively measured activity (Actigraph), DED (4-d food diary), anthropometry (waist circumference (WC), %body fat (%BF), fat mass index (FMI), weight status) and covariates. Linear and logistic regression models were fit, including adjustment for DED and moderate-to vigorous physical activity. Results showed that baseline DED was associated with change in WC (beta for 1kJ/g difference: 0.71; 95% CI 0.26, 1.17), particularly in boys (1.26; 95% CI 0.41, 2.16 v. girls: 0.26; 95% CI -0.34, 0.87), but not with %BF, FMI or weight status. In contrast, baseline SED, MPA or VPA were not associated with any of the outcomes. Change in DED was negatively associated with FMI (beta for 1kJ/g increase: -0.86; 95% CI -1.59, -0.12) and %BF (-0.86; 95% CI 1.25, -0.11) but not WC (-0.27; 95% CI -1.02, 0.48). Change in SED, MPA and VPA did not predict adiposity at follow-up. In conclusion, activity intensity was not prospectively associated with adiposity, whereas the directions of associations with DED were inconsistent. To inform public health efforts, future studies should continue to analyse longitudinal data to further understand the independent role of different energy-balance behaviours in changes in adiposity in early adolescence. PMID- 26758861 TI - Recent developments in the diagnosis and treatment of covert/minimal hepatic encephalopathy. AB - The terms minimal hepatic encephalopathy and covert hepatic encephalopathy are defined. Clinical assessment is unreliable and both require the use of diagnostic tools. Of these, psychometric tests are the most widely used. They require proper standardization and may be biased by patient cooperation or lack thereof. The measure of the critical flicker frequency and of the electroencephalogram, possibly quantified, are also useful. The alteration of any of them is not strictly parallel in size and may vary from patient to patient. When possible, the use of multiple measures might increase diagnostic reliability. These functional measures should be interpreted within the clinical/biochemical profile of the patient to exclude other disorders. A flow chart for treatment is proposed on the basis of current knowledge. PMID- 26758863 TI - Understanding Biofilms in Chronic Sinusitis. AB - Chronic sinusitis is a burdensome disease that has substantial individual and societal impact. Although great advances in medical and surgical therapies have been made, some patients continue to have recalcitrant infections. Microbial biofilms have been implicated as a cause of recalcitrant chronic sinusitis, and recent studies have tried to better understand the pathogenesis of chronic sinusitis as it relates to microbial biofilms. Here, we provide an overview of biofilms in chronic sinusitis with emphasis on pathogenesis, treatment, and future directions. In addition, recent evidence is presented, elucidating the role of bitter taste receptors as a possible key factor leading to biofilm formation. PMID- 26758864 TI - Rapid Aspirin Challenge in Patients with Aspirin Allergy and Acute Coronary Syndromes. AB - Aspirin allergy in a patient with acute coronary syndrome represents one of the more urgent challenges an allergist may face. Adverse reactions to aspirin are reported in 1.5% of patients with coronary artery disease. A history of adverse reaction to aspirin often leads to unnecessary withholding of this medication or use of alternative antiplatelet therapy which may be inferior or more costly. Aspirin therapy has been shown to reduce morbidity and mortality in patients with coronary artery disease. Rapid aspirin challenge/desensitization in the aspirin allergic patient has been consistently shown to be both safe and successful in patients with acute coronary syndromes. PMID- 26758865 TI - Adherence to Sublingual Immunotherapy. AB - Adherence is a major issue in any medical treatment. Allergen immunotherapy (AIT) is particularly affected by a poor adherence because a flawed application prevents the immunological effects that underlie the clinical outcome of the treatment. Sublingual immunotherapy (SLIT) was introduced in the 1990s, and the early studies suggested that adherence and compliance to such a route of administration was better than the traditional subcutaneous route. However, the recent data from manufacturers revealed that only 13% of patients treated with SLIT reach the recommended 3-year duration. Therefore, improved adherence to SLIT is an unmet need that may be achieved by various approaches. The utility of patient education and accurate monitoring during the treatment was demonstrated by specific studies, while the success of technology-based tools, including online platforms, social media, e-mail, and a short message service by phone, is currently considered to improve the adherence. This goal is of pivotal importance to fulfill the object of SLIT that is to modify the natural history of allergy, ensuring a long-lasting clinical benefit, and a consequent pharmaco-economic advantage, when patients complete at least a 3-year course of treatment. PMID- 26758866 TI - Antioxidant Potential and In Situ Analysis of Major and Trace Element Determination of Ood-saleeb, a Known Unani Herbal Medicine by ICP-MS. AB - The intention of the present research work was to investigate the antioxidant activity and trace element analysis of Ood-saleeb, a known herbal medicine. Preliminary screening of phytochemicals showed that the extract of Ood-saleeb had flavonoids and phenolics. The significant activities in all antioxidant assays were observed in the extract of Ood-saleeb in comparison with the standard antioxidant with respect to dose of Ood-saleeb. Incredible activities to scavenge reactive oxygen species were also observed by the extract of Ood-saleeb. The IC50 values of all factors were determined using ascorbic acid as a standard. The inductive coupled plasma-mass spectroscopy (ICP-MS) was employed for the estimation of trace elements in Ood-saleeb extract. The concentrations of up to 18 elements were detected successfully. Silicon was found in high concentration (85.3 MUg/g) while lithium was in low concentration (3 ng/g). The trace elements in the sample were found at different percentage levels which play a key role in the treatment of diseases. PMID- 26758862 TI - The Immunologic Mechanisms of Eosinophilic Esophagitis. AB - Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease that is triggered by food and/or environmental allergens and is characterized by a clinical and pathologic phenotype of progressive esophageal dysfunction due to tissue inflammation and fibrosis. EoE is suspected in patients with painful swallowing, among other symptoms, and is diagnosed by the presence of 15 or more eosinophils per high-power field in one or more of at least four esophageal biopsy specimens. The prevalence of EoE is increasing and has now reached rates similar to those of other chronic gastrointestinal disorders such as Crohn's disease. In recent years, our understanding of the immunologic mechanisms underlying this condition has grown considerably. Thanks to new genetic, molecular, cellular, animal, and translational studies, we can now postulate a detailed pathway by which exposure to allergens results in a complex and coordinated type 2 inflammatory cascade that, if not intervened upon, can result in pain on swallowing, esophageal strictures, and food impaction. Here, we review the most recent research in this field to synthesize and summarize our current understanding of this complex and important disease. PMID- 26758867 TI - Effect of Stress from Cadmium Combined with Different Levels of Molybdenum on Serum Free Radical and Expression of Related Apoptosis Genes in Goat Livers. AB - Molybdenum (Mo) is an essential element for human beings and animals; however, high dietary intake of Mo can lead to adverse reactions. Cadmium (Cd) is one of the major transitional metals which have toxic effects in animals. The toxicity of simple Cd or Mo has been researched frequently. However, the toxicity of Mo combined with Cd was rarely studied. To investigate the toxicity of Mo combined with Cd in liver of goats, 36 Boer goats were randomly divided into four groups and assigned with one of the three oral treatments of CdCl2 (0.5 mg kg(-1) Cd) and [(NH4)6Mo7O24.4H2O] (15 mg kg(-1) Mo, group I; 30 mg kg(-1) Mo, group II; 45 mg kg(-1) Mo, group III), while the control group received deionized water. Blood samples were collected on days 0, 10, 20, 30, 40, and 50 to determine antioxidant indices in serum. In addition, liver tissues were collected on days 0, 25, and 50 for detecting the messenger RNA (mRNA) expression levels of Bcl-2 and Bax. Moreover, liver tissues at 50 days were subjected to histopathological analysis with the optical microscope. The results revealed a significant increase (P < 0.05 or P < 0.01) in the levels of nitric oxide (NO), malonaldehyde (MDA), and the activity of nitrix oxide synthase (NOS) and a significant decline (P < 0.05) in the activities of total superoxide dismutase (T-SOD) and total antioxidative capacity (T-AOC). The mRNA expression level of Bcl-2 was suppressed (P < 0.05), while the expression of Bax was increased (P < 0.05) in liver. The histopathological changes were observed in the liver of goats including a small amount of erythrocyte, the unclear structure of hepatic cord and hepatic sinusoid, granular degeneration, vacuolar degeneration, and steatosis. In conclusion, combined chronic toxicity of Cd with different levels of Mo might induce goat liver cell apoptosis and cause oxidative stress in serum, and it showed a possible synergistic relationship between the two elements. PMID- 26758868 TI - Analysis of Ionomic Profiles of Canine Hairs Exposed to Lipopolysaccharide (LPS) Induced Stress. AB - The purpose of this study was to provide a new insight on the response of canines to stress exposure; the ionomic profiles of canine hair (2.8 +/- 0.3 years, 15.17 +/- 2.1 kg) (n = 10) was determined before and after lipopolysaccharide (LPS) injections. LPS was intramuscularly injected to induce inflammatory stress responses which were confirmed by observing increases in the level of serum cortisol, aldosterone, and inflammatory cytokines such as IL-6, IL-1beta, and TNF alpha. The hair contents of 17 elements were obtained by applying analytical procedures using the inductively coupled plasma mass spectrometry (ICP-MS). The following elements: sodium(Na) and potassium(K) among macro-elements, iron(Fe) and manganese(Mn) among micro-elements, and aluminum(Al), nickel(Ni), and lead(Pb) for toxic elements, showed significant increased levels with the immunological stress. The degree of increase in toxic elements was remarkable with the stress exposure. A forty-five-fold increase seen in Al accumulation with the stress exposure was noteworthy. Although mercury(Hg) and cadmium(Cd) showed decreased levels with the stress exposure, the degree was negligible compared to the level of increase. Correlation pattern between the elements was changed with the immunological stress. Toxic elements became more correlated with macro- or micro-elements than with toxic elements themselves after the stress exposure. Principal component analysis (PCA) showed that LPS challenge shifted the overall hair mineral profiles to a consistent direction changing Al and K up, even in animals with different hair mineral profiles before LPS treatment. In conclusion, the multivariate data processing and study of element distribution patterns provided new information about the ionomic response of the canine hairs to immunological stress, i.e., the ionomic profiles of canine hairs is strongly affected by the stress induced by LPS injections. PMID- 26758869 TI - Prenatal Exposure to Soy Isoflavones Altered the Immunological Parameters in Female Rats. AB - Information on the effects of phytoestrogens on animals has increased recently; however, there were only few studies on prenatal exposure on cellular immune response. Pregnant rats were assigned to 3 groups (12 rats per group), the first was fed control diet, the second was fed low-dose (6.5 g/100 g of diet) soy isoflavones, while the third was fed high-dose (26 g/100 g of diet) soy isoflavones. The female offspring cell-mediated immune response was determined using phytohemagglutinin (PHA) injection, and intumesce index was calculated on postnatal day 50. After 24 hours of PHA injection, blood samples were collected for tumor necrosis factor alpha, interferon gamma (IFN-gamma), and interleukin (IL)-12 determination. Spleen, thymus, and PHA-injected footpads were fixed for histopathology. Intumesce index was significantly (P < 0.05) reduced in rats' offspring born from dams fed low- and high-dietary soy isoflavones than that in control groups. Thymic relative weights in offspring of rats fed high-dietary soy isoflavones showed a significant (P < 0.05) decrease compared to that in the control group. Female offspring where low and high-dietary soy isoflavones were fed to their dams showed a significant (P < 0.05) decrease in IFN-gamma and IL-12 than that in control ones. Spleen of rats born from dams fed high dose of dietary soy isoflavones showed lymphocytic depletion in white pulp. Taking together, it is clear that dietary soy isoflavones at prenatal period had immunosuppressive effect on female offspring after PHA stimulation. This effect was mediated through reduced IFN-gamma that interplayed in IL-12 production pathway thus reducing its level. PMID- 26758870 TI - Genetic Instability in Lymphocytes is Associated With Blood Plasma Antioxidant Levels in Health Care Workers Occupationally Exposed to Ionizing Radiation. AB - Earlier reports have suggested that exposure to radiation at workplace may induce cytogenetic abnormalities. However, the association between plasma antioxidants and the cytogenetic abnormalities in these patients has not been elucidated till now. Hence, the present study was undertaken to determine the relationship between the cytogenetic abnormalities, plasma antioxidant system, and the radiation exposure levels in men who were occupationally exposed to ionizing radiation. The study included 134 male volunteers, among whom 83 were occupationally exposed to ionizing radiation. Incidence of micronuclei and chromosomal aberration was assessed in lymphocytes. Total and reduced glutathione (GSH), total antioxidant capacity (TAC), superoxide dismutase (SOD), and lipid peroxidation were assessed in the plasma. The micronuclei frequency and chromosomal aberrations were significantly higher in the exposed group in comparison to the nonexposed group (P < 0.01-0.0001). Similarly, GSH, TAC, and SOD in the blood plasma were significantly higher in the exposed group than the nonexposed group (P < 0.01-0.0001). However, the level of malondialdehyde, which is an indicator of lipid peroxidation, did not differ significantly between both the groups. Importantly, radiation absorbed dose exhibited a positive correlation with the incidence of micronuclei in blood lymphocytes but not with chromosomal aberrations. This study shows that the susceptibility of peripheral blood lymphocytes to chromosomal damage is associated with plasma antioxidant levels. Furthermore, increased levels of blood plasma GSH, TAC, and SOD in occupationally exposed individuals could be an adaptive measure in response to oxidative stress to protect somatic cell genetic integrity. PMID- 26758871 TI - Actin capping protein CAPZB regulates cell morphology, differentiation, and neural crest migration in craniofacial morphogenesis?. AB - CAPZB is an actin-capping protein that caps the growing end of F-actin and modulates the cytoskeleton and tethers actin filaments to the Z-line of the sarcomere in muscles. Whole-genome sequencing was performed on a subject with micrognathia, cleft palate and hypotonia that harbored a de novo, balanced chromosomal translocation that disrupts the CAPZB gene. The function of capzb was analyzed in the zebrafish model. capzb(-/-) mutants exhibit both craniofacial and muscle defects that recapitulate the phenotypes observed in the human subject. Loss of capzb affects cell morphology, differentiation and neural crest migration. Differentiation of both myogenic stem cells and neural crest cells requires capzb. During palate morphogenesis, defective cranial neural crest cell migration in capzb(-/-) mutants results in loss of the median cell population, creating a cleft phenotype. capzb is also required for trunk neural crest migration, as evident from melanophores disorganization in capzb(-/-) mutants. In addition, capzb over-expression results in embryonic lethality. Therefore, proper capzb dosage is important during embryogenesis, and regulates both cell behavior and tissue morphogenesis. PMID- 26758873 TI - Pharmacologically induced mouse model of adult spinal muscular atrophy to evaluate effectiveness of therapeutics after disease onset. AB - Spinal muscular atrophy (SMA) is a genetic disease characterized by atrophy of muscle and loss of spinal motor neurons. SMA is caused by deletion or mutation of the survival motor neuron 1 (SMN1) gene, and the nearly identical SMN2 gene fails to generate adequate levels of functional SMN protein due to a splicing defect. Currently, several therapeutics targeted to increase SMN protein are in clinical trials. An outstanding issue in the field is whether initiating treatment in symptomatic older patients would confer a therapeutic benefit, an important consideration as the majority of patients with milder forms of SMA are diagnosed at an older age. An SMA mouse model that recapitulates the disease phenotype observed in adolescent and adult SMA patients is needed to address this important question. We demonstrate here that Delta7 mice, a model of severe SMA, treated with a suboptimal dose of an SMN2 splicing modifier show increased SMN protein, survive into adulthood and display SMA disease-relevant pathologies. Increasing the dose of the splicing modifier after the disease symptoms are apparent further mitigates SMA histopathological features in suboptimally dosed adult Delta7 mice. In addition, inhibiting myostatin using intramuscular injection of AAV1 follistatin ameliorates muscle atrophy in suboptimally dosed Delta7 mice. Taken together, we have developed a new murine model of symptomatic SMA in adolescents and adult mice that is induced pharmacologically from a more severe model and demonstrated efficacy of both SMN2 splicing modifiers and a myostatin inhibitor in mice at later disease stages. PMID- 26758874 TI - Hypokalemic Periodic Paralysis Associated with Glue-Sniffing. PMID- 26758872 TI - Keratin 12 missense mutation induces the unfolded protein response and apoptosis in Meesmann epithelial corneal dystrophy. AB - Meesmann epithelial corneal dystrophy (MECD) is a rare autosomal dominant disorder caused by dominant-negative mutations within the KRT3 or KRT12 genes, which encode the cytoskeletal protein keratins K3 and K12, respectively. To investigate the pathomechanism of this disease, we generated and phenotypically characterized a novel knock-in humanized mouse model carrying the severe, MECD associated, K12-Leu132Pro mutation. Although no overt changes in corneal opacity were detected by slit-lamp examination, the corneas of homozygous mutant mice exhibited histological and ultrastructural epithelial cell fragility phenotypes. An altered keratin expression profile was observed in the cornea of mutant mice, confirmed by western blot, RNA-seq and quantitative real-time polymerase chain reaction. Mass spectrometry (MS) and immunohistochemistry demonstrated a similarly altered keratin profile in corneal tissue from a K12-Leu132Pro MECD patient. The K12-Leu132Pro mutation results in cytoplasmic keratin aggregates. RNA-seq analysis revealed increased chaperone gene expression, and apoptotic unfolded protein response (UPR) markers, CHOP and Caspase 12, were also increased in the MECD mice. Corneal epithelial cell apoptosis was increased 17-fold in the mutant cornea, compared with the wild-type (P < 0.001). This elevation of UPR marker expression was also observed in the human MECD cornea. This is the first reporting of a mouse model for MECD that recapitulates the human disease and is a valuable resource in understanding the pathomechanism of the disease. Although the most severe phenotype is observed in the homozygous mice, this model will still provide a test-bed for therapies not only for corneal dystrophies but also for other keratinopathies caused by similar mutations. PMID- 26758875 TI - Palmitic Acid Reduces Circulating Bone Formation Markers in Obese Animals and Impairs Osteoblast Activity via C16-Ceramide Accumulation. AB - Obesity and impaired lipid metabolism increase circulating and local fatty acid (FA) levels. Our previous studies showed that a high high-saturated -fat diet induced greater bone loss in mice than a high high-unsaturated-fat diet due to increased osteoclast numbers and activity. The impact of elevated FA levels on osteoblasts is not yet clear. We induced obesity in 4 week old male mice using a palmitic acid (PA)- or oleic acid (OA)-enriched high fat high-fat diet (HFD) (20 % of calories from FA), and compared them to mice on a normal (R) caloric diet (10 % of calories from FA). We collected serum to determine FA and bone metabolism marker levels. Primary osteoblasts were isolated; cultured in PA, OA, or control (C) medium; and assessed for mineralization activity, gene expression, and ceramide levels. Obese animals in the PA and OA groups had significantly lower serum levels of bone formation markers P1NP and OC compared to normal weight animals (*p < 0.001), with the lowest marker levels in animals on an PA enriched HFD (*p < 0.001). Accordingly, elevated levels of PA significantly reduced osteoblast mineralization activity in vitro (*p < 0.05). Elevated PA intake significantly increased C16 ceramide accumulation. This accumulation was preventable through inhibition of SPT2 (serine palmitoyl transferase 2) using myriocin. Elevated levels of PA reduce osteoblast function in vitro and bone formation markers in vivo. Our findings suggest that saturated PA can compromise bone health by affecting osteoblasts, and identify a potential mechanism through which obesity promotes bone loss. PMID- 26758876 TI - Oral vaccine of Lactococcus lactis harbouring pandemic H1N1 2009 haemagglutinin1 and nisP anchor fusion protein elevates anti-HA1 sIgA levels in mice. AB - OBJECTIVE: An oral lactococcal-based vaccine which haboured the haemagglutinin1 (HA1) antigen fused to nisP anchor protein for the purpose of surface displaying the HA1 antigen was developed against H1N1 virus. RESULTS: Recombinant L. lactis strains expressed HA1-nisP fusion proteins when induced with nisin, as confirmed through western blotting. However, immunofluorescense did not detect any surface displayed proteins, suggesting that the protein was either unsuccessfully translocated or improperly displayed. Despite this, oral administration of recombinant L. lactis strains to BALB/c mice revealed that significant levels of anti-HA1 sIgA antibodies were detected in mice fecal suspension samples of mice group NZ9000 (pNZ:HN) when compared to the negative control NZ9000 (pNZ8048) group. CONCLUSION: Specific anti-HA1 sIgA antibodies were locally produced and live recombinant lactococcal vaccine was able to elicit humoral response of BALB/c mice despite unsuccessful surface display of the HA1 epitope. PMID- 26758877 TI - Recombinant production of a shell matrix protein in Escherichia coli and its application to the biomimetic synthesis of spherulitic calcite crystals. AB - OBJECTIVES: To overcome the limited production capability of shell matrix proteins and efficiently conduct in vitro CaCO3 biomineralization studies, a putative recombinant shell matrix protein was prepared and characterized. RESULTS: A glycine-rich protein (GRP_BA) was found in Pinctada fucata as a putative shell matrix protein (NCBI reference sequence; BAA20465). It was genetically redesigned for the production in Escherichia coli. The recombinant protein was obtained in a 400 ml shake-flask culture at approx. 30 mg l(-1) with a purity of >95 %. It efficiently formed a complex with Ca(2+). Ca(2+)-induced agglomeration was like other calcification-related proteins. Spherulitic calcite micro-particles, 20-30 um diam. with rosette- and sphere-like structures were synthesized in the presence of the recombinant shell protein, which could be formed by stacking and/or aggregation of calcite nanograins and the bound protein. CONCLUSIONS: Recombinant production of a shell matrix protein could overcome potential difficulties associated with the limited amount of protein available for biomineralization studies and provide opportunities to fabricate biominerals in practical aspects. PMID- 26758878 TI - [Supramacroparticulate polyethylene in inflammation of synovial-like interface membranes: Characterization and suggested nomenclature]. AB - BACKGROUND: The identification of particles of prosthesis material components in the histopathological diagnosis of synovialitis is of great importance in the evaluation of implant failure. MATERIALS AND METHODS: In histopathological particle algorithms, polyethylene (PE) particles with a maximum length of less than 100 um are designated with the term macroparticles; however, a systematic investigation and characterization are lacking. RESULTS: In SLIM knee specimens (n = 24) a minimum value of 210 um and a maximum value of 2100 um were measured; the mathematical mean length varied between 235 um and 1416 um. In SLIM hip specimens (n = 11) the minimum value was 290 um and the maximum value was 1806 um; the mean length varied between 353 and 1726 um. Because of this conspicuous size, and to distinguish from PE macroparticles, the designation PE supra macroparticulate is suggested. This new terminology acknowledges the fact that these PE particles are visible under magnification (e.g., * 12.5) and also macroscopically. The particles were also indirectly proven as there were completely separate and optically clear, column-shaped cavities corresponding to the shape of the PE particles (PE vacuoles). The life of the prosthesis is highly variable at between 12 and 300 months. In all cases loosening of the prosthesis, misalignment of the PE components, and/or damage to the PE inlay occurred. CONCLUSION: The cause and existence of these supra-macroparticulate PE particles (more than 100 um) is still unclear. A mechanical malfunction seems probable and should be discussed. In prostheses with short lives the proof of supra macroparticulate PE in SLIM could be a sign of an early mechanical problem. In the wider histopathological particle algorithm supra-macroparticulate PE was considered to fall in the category of macroparticles and should be considered in the histopathological diagnosis of implant failure. PMID- 26758880 TI - Decondensation of chromosomal 45S rDNA sites in Lolium and Festuca genotypes does not result in karyotype instability. AB - Fragile sites (FSs) in plants have been described for species like Lolium and other grasses. Whereas in humans FSs were shown to be involved in genome instabilities; the consequences of FSs expression in plants are not known yet. To evaluate whether FSs cause karyotype instabilities, we assessed the frequency of micronuclei and lagging chromosomes in meristematic cells, the stability of the DNA content, and the occurrence of neocentromeres in the presumed chromosomal fragments of Lolium perenne, Lolium multiflorum, Festuca arrundinacea, and two Festulolium hybrids. The cell cycle analysis along with flow cytometric genome size measurements showed high stability in all genomes evaluated. Neocentromeric activity was neither observed in the presumed fragments nor in any other chromosomal region, then this is not the mechanism responsible by the stability. However, Fluorescence in situ hybridization (FISH) with a 45S ribosomal DNA (rDNA) probe in combination with YOYO staining of metaphasic chromosomes showed that many extended nucleolus organizing region (NOR) form very thin YOYO-positive chromatin fibers connecting the acentric 'fragment' with the centromere containing chromosome region. The obtained data indicate that the expression of FSs does not result in genome instabilities or neocentromere formation. The FS containing 45S rDNA carrying chromatin fibers undergo a cell cycle and gene activity-dependent dynamic decondensation process. PMID- 26758881 TI - Influence of previous treatments on repeat surgery for recurrent craniopharyngiomas in children. AB - PURPOSE: Craniopharyngioma is a common pediatric brain tumor, with a high rate of recurrence after primary treatment. This retrospective study investigated the effect of various primary treatments on surgical strategies and outcomes for recurrent craniopharyngiomas. METHODS: The study population comprised 35 children (mean age 8.77 years, range 1-16 years) with recurrent craniopharyngioma re operated from January 1990 to January 2009. The recurrent craniopharyngiomas were excised whenever possible. For analysis, the patients were divided into four groups according to the primary treatment: radical tumor resection (A), incomplete tumor resection (B), radiotherapy + incomplete tumor resection (C), and Ommaya reservoir placement + incomplete tumor resection (D). RESULTS: Group B had a significantly shorter recurrence-free interval than groups A, C, or D. Outcomes were significantly different among the four groups. The hypothalamic status scores of groups A (2.38 +/- 0.27) and C (2.28 +/- 0.42) were significantly higher than that of group B (1.64 +/- 0.20). There were no statistical differences between any two other groups. CONCLUSIONS: In children, the primary treatments for craniopharyngioma should be considered when choosing the surgical strategy for recurrence. Radiotherapy before repeated surgery can result in a worse functional outcome and hypothalamic-pituitary function. PMID- 26758879 TI - Exemestane Use in Postmenopausal Women at High Risk for Invasive Breast Cancer: Evaluating Biomarkers of Efficacy and Safety. AB - This phase II trial evaluated clinical markers of efficacy and safety of exemestane in postmenopausal women at increased risk for breast cancer. Postmenopausal women (n = 42) at risk for invasive breast cancer received 25 mg exemestane daily for 2 years along with calcium and vitamin D. The primary outcome was change in mammographic density (MD) after one year. Secondary outcomes included change in serum steroid hormones as well as change in trefoil protein 1 (TFF1) and proliferating cell nuclear antigen (PCNA) in breast tissue. Safety and tolerability were also assessed. MD decreased at 1 year and was significant at 2 years [mean change = -4.1%; 95% confidence intervals (CI), -7.2 to -1.1; P = 0.009]. Serum estradiol and testosterone levels significantly decreased at 3 months and remained suppressed at 12 months. After 1 year of treatment, TFF1 intensity decreased (mean change -1.32; 95% CI, -1.87 to -0.76; P < 0.001). Exemestane was safe and well tolerated. Exemestane decreased MD and expression of breast tissue TFF1. It was well tolerated with few clinically relevant side effects. MD and breast tissue TFF1 are potential biomarkers of breast cancer-preventive effects of exemestane in high-risk postmenopausal women. PMID- 26758882 TI - Isolated thoracic syrinx in children with Chiari I malformation. AB - INTRODUCTION: Syrinx has been reported in 25-85 % of children with Chiari malformation type I (CMI), and it is most commonly cervical in location. As a result, cervical MRI is routinely included in an evaluation for CMI. Isolated thoracic syrinx without involvement of the cervical cord in this population is uncommon but clinically important because its presence may influence the decision to operate, surgical techniques employed, or interpretation of follow-up imaging. The purpose of this study was to determine the incidence of isolated thoracic syrinx in a large group of children evaluated for CMI. METHODS: We retrospectively reviewed all patients under 21 years of age who were evaluated for CMI at Columbia University/Morgan Stanley Children's Hospital of New York from 1998 to 2013. All patients underwent MRI of the entire spine as part of the CMI evaluation, regardless of whether surgery was planned. The proportion of patients exhibiting isolated thoracic syrinx was determined. Presenting signs, symptoms, and imaging findings were then studied in an attempt to identify any clinical features associated with isolated thoracic syrinx. RESULTS: We identified 266 patients evaluated over the study period. One-hundred thirty-two patients (50 %) presented with a syrinx, and 12 patients (4.5 % of all patients evaluated and 9.1 % of all patients with a syrinx) had an isolated thoracic syrinx. Demographic variables, clinical presentation, and extent of tonsillar ectopia showed great heterogeneity in this group, and no factor was consistently associated with isolated thoracic syrinx. CONCLUSIONS: Isolated thoracic syrinx is an uncommon but clinically significant finding in children with CMI. Our data demonstrate that the presence of a CMI-related thoracic syrinx cannot be reliably predicted clinically and is therefore likely to be missed in patients who do not undergo complete spinal cord imaging. MRI of the entire spinal cord should be considered for all children undergoing initial evaluation for CMI. PMID- 26758883 TI - Do the cerebellar tonsils move during flexion and extension of the neck in patients with Chiari I malformation? A radiological study with clinical implications. AB - BACKGROUND: In the past, diagnosis of the Chiari I malformation has primarily been made on midsagittal MRI. We hypothesized that based on the frequent presentation of opisthotonos in patients with hindbrain hernia (primarily Chiari II malformation but sometimes Chiari I malformation) that the hyperextension might be a compensatory technique used by such patients to bring the cerebellar tonsils up out of the cervical spine. PATIENTS AND METHODS: This prospective study reviewed imaging of patients with Chiari I malformation who underwent flexion/extension MRI for evaluation of their hindbrain herniation. Age-matched controls were used for comparison. RESULTS: In general, there was elevation of the cerebellar tonsils with extension and increased descent with flexion of the cervical spine. In 72 % of patients, flexion of the neck resulted in descent of the cerebellar tonsils. In 64 % of patients, extension of the neck resulted in ascent of the cerebellar tonsils. In the 14 patients with an associated syrinx, 71 % were found to have caudal movement of the cerebellar tonsils with neck flexion, and only 43 % were observed to have any movement of the cerebellar tonsils in neck extension compared to patients without a syrinx where ascent of the tonsils was seen in only nine during neck extension. Two patients were observed to have the reverse finding of ascent of the cerebellar tonsils with neck flexion and descent of the cerebellar tonsils with neck extension. Five patients had no movement of the cerebellar tonsils in either flexion or extension of the neck, and one of these had a small syrinx. CONCLUSIONS: Although minimal and not in all patients, we observed elevation of the herniated cerebellar tonsils with extension of the cervical spine in patients with Chiari I malformation. This finding provides evidence as to why some patients with hindbrain herniation present with opisthotonos and supports earlier findings that CSF flow is reduced at the craniocervical junction in flexion in patients with Chiari I malformation. PMID- 26758884 TI - Effects of Adding Tiotropium or Aclidinium as Triple Therapy Using Impulse Oscillometry in COPD. AB - INTRODUCTION: Long-acting muscarinic antagonists confer improvements in spirometry when used in addition to inhaled corticosteroids and long-acting beta agonists (ICS/LABA) in COPD. The dual objectives of this proof of concept study were to evaluate trough effects of tiotropium (TIO) or aclidinium (ACL) when used as triple therapy and to assess if impulse oscillometry (IOS) might be more sensitive than spirometry in detecting subtle differences in bronchodilator response. METHODS: Patients with moderate to severe COPD already taking ICS/LABA were randomized to receive add-on therapy in cross-over fashion with either TIO 18 ug od or ACL 322 ug bid for 2-3 weeks each. Measurements of IOS, spirometry, 6 min walk test, St George's Respiratory Questionnaire (SGRQ) and Baseline/Transition Dyspnoea Index (TDI) were made at baseline and after chronic dosing at trough (12 h for ACL and 24 h for TIO), in addition to domiciliary diurnal spirometry. RESULTS: 13 patients were completed: mean age 69 years, FEV1 52 % predicted, FEV1/FVC 0.48, and R5 202 % predicted. There were no differences in any visit-based trough IOS or spirometry outcomes comparing TIO versus ACL. Resonant frequency but not total airway resistance at 5 Hz (R5) significantly improved from baseline with both treatments while peripheral airway resistance (R5-R20) significantly improved with ACL. Visit-based FEV1, and forced and relaxed vital capacity were also significantly improved from baseline with both treatments. There were no significant differences in diurnal FEV1 and FEV6 profiles between treatments. 6-min walk distance and post-walk fatigue significantly improved from baseline with ACL, while post-walk dyspnea improved with TIO. SGRQ symptom score significantly improved to a similar degree with both treatments. TDI significantly improved with ACL versus TIO by 1.54 units. CONCLUSION: We observed comparable bronchodilator efficacy at trough with TIO and ACL when used as triple therapy in COPD, while IOS was no more sensitive than spirometry. PMID- 26758885 TI - Fusion of detected multi-channel maternal electrocardiogram (ECG) R-wave peak locations. AB - BACKGROUND: Almost all promising non-invasive foetal ECG extraction methods involve accurately determining maternal ECG R-wave peaks. However, it is not easy to robustly detect accurate R-wave peaks of the maternal ECG component in an acquired abdominal ECG since it often has a low signal-to-noise ratio (SNR), sometimes containing a large foetal ECG component or other noises and interferences. This paper discusses, under the condition of acquiring multi channel abdominal ECG signals, how to improve the robustness of maternal ECG R wave peak detection. METHODS: On the basis of summarising the current single channel ECG R-wave peak detection methods, the paper proposed a specific fusion algorithm of detected multi-channel maternal ECG R-wave peak locations. The proposed entire algorithm was then tested using two databases; one database, created by us, was composed of 343 groups of 8-channel data collected from 78 pregnant women, and the other one, called the challenge database, was from the Physionet/Computing in Cardiology Challenge 2013, including 175 groups of 4 channel data. When using these databases, each group of data was classified into two parts, called the training part and the validation test part respectively; the training part was the first 8.192 s of each group of data and the validation test part was the next 8.192 s. RESULTS: To show the results, three evaluation parameters-sensitivity (Se), positive predictive value (PPV) and F1-are used. The validation test results for the database we collected are Se = 99.93 %, PPV = 99.98 %, and F1 = 99.95 %, while the results for the challenge database are Se = 99.91 %, PPV = 99.86 %, and F1 = 99.88 %. CONCLUSION: The results of the test show that the robustness of our proposed whole fusion algorithm was superior to that of other outstanding algorithms for maternal R-wave detection, and is much better than that of single channel maternal R-wave detection algorithms. PMID- 26758886 TI - Association of genetic and phenotypic variability with geography and climate in three southern California oaks. AB - PREMISE OF THE STUDY: Geography and climate shape the distribution of organisms, their genotypes, and their phenotypes. To understand historical and future evolutionary and ecological responses to climate, we compared the association of geography and climate of three oak species (Quercus engelmannii, Quercus berberidifolia, and Quercus cornelius-mulleri) in an environmentally heterogeneous region of southern California at three organizational levels: regional species distributions, genetic variation, and phenotypic variation. METHODS: We identified climatic variables influencing regional distribution patterns using species distribution models (SDMs), and then tested whether those individual variables are important in shaping genetic (microsatellite) and phenotypic (leaf morphology) variation. We estimated the relative contributions of geography and climate using multivariate redundancy analyses (RDA) with variance partitioning. KEY RESULTS: The modeled distribution of each species was influenced by climate differently. Our analysis of genetic variation using RDA identified small but significant associations between genetic variation with climate and geography in Q. engelmannii and Q. cornelius-mulleri, but not in Q. berberidifolia, and climate explained more of the variation. Our analysis of phenotypic variation in Q. engelmannii indicated that climate had more impact than geography, but not in Q. berberidifolia. Throughout our analyses, we did not find a consistent pattern in effects of individual climatic variables. CONCLUSIONS: Our comparative analysis illustrates that climate influences tree response at all organizational levels, but the important climate factors vary depending on the level and on the species. Because of these species-specific and level-specific responses, today's sympatric species are unlikely to have similar distributions in the future. PMID- 26758887 TI - Population differentiation and countergradient variation throughout the geographic range in the fern gametophyte Vittaria appalachiana. AB - PREMISE OF THE STUDY: Theory predicts that limited gene flow between populations will promote population differentiation, and experimental studies have found that differentiation is often explained by local adaptation in sexually reproducing angiosperms. However, few experiments have examined the drivers of differentiation among populations in asexual land plants with limited dispersal potential. Here, we evaluated the role of temperature in driving population differentiation in an asexual, obligate gametophyte fern species. METHODS: We reciprocally transplanted Vittaria appalachiana gametophytes among six populations that spanned the species' geographic range in the Appalachian Mountains and Plateau. Temperature, survival, and senescence rates were measured for 1 year. KEY RESULTS: Populations had significantly different fitness responses to different sites, consistent with the hypothesis that populations have differentiated across the species' range. There was some evidence for local adaptation in marginal populations and for countergradient selection favoring particularly robust genotypes at the northern range edge. Most populations had relatively high fitness at the site with the most stable temperature conditions and were negatively affected by decreasing minimum temperatures. CONCLUSIONS: Populations of Vittaria appalachiana exhibit highly variable responses to transplantation across the species' range, and only a small subset of these responses are due to local adaptation. Differences in daily minimum temperature explain some variation in fitness, but other site-specific factors also have significant impacts on transplant fitness. These results indicate that asexual, patchily distributed species with limited dispersal may exhibit population specific responses to global climate change that have not been elucidated by empirical work focused on sexually reproducing angiosperms. PMID- 26758888 TI - Geographic patterns of seed mass are associated with climate factors, but relationships vary between species. AB - PREMISE OF THE STUDY: Seed size is a critical life history attribute with fitness effects that cascade throughout the lifespan of plants. Interspecific studies repeatedly report a negative correlation between seed mass and latitude. Yet, despite its importance, little is known about geographic variation in seed size within species' ranges. METHODS: To improve our understanding of intraspecific geographic variation in seed size, we collected and weighed seeds by maternal line from 8 to 17 populations of seven herbaceous plant species spanning large geographic areas, and measured a dispersal trait, awn length, for two grass species. We examined the overall relationship between seed mass and latitude, then divided the data into species-specific subsets to compare the fit of three models to explain seed mass and awn length: (1) latitude and longitude, (2) long term climate, and (3) collection-year weather. KEY RESULTS: Like previous work, we found a negative relationship between interspecific seed mass and latitude. However, the best-fit models explaining seed size and awn length differed between individual species and often included significant interaction terms. For all species, the best model was either long-term or collection-year climate data instead of latitude and longitude. CONCLUSIONS: Intraspecific geographic patterns for seed traits were remarkably inconsistent, covarying both negatively and positively with temperature and precipitation. The only apparent generalization is that annual species' seed mass corresponded more with collection-year weather while perennial species covaried more with long-term climate. Overall, this study suggests that the scale of climate variation that molds seed traits is highly species-specific. PMID- 26758889 TI - A novel method for texture-mapping conoscopic surfaces for minimally invasive image-guided kidney surgery. AB - PURPOSE: Organ-level registration is critical to image-guided therapy in soft tissue. This is especially important in organs such as the kidney which can freely move. We have developed a method for registration that combines three dimensional locations from a holographic conoscope with an endoscopically obtained textured surface. By combining these data sources clear decisions as to the tissue from which the points arise can be made. METHODS: By localizing the conoscope's laser dot in the endoscopic space, we register the textured surface to the cloud of conoscopic points. This allows the cloud of points to be filtered for only those arising from the kidney surface. Once a valid cloud is obtained we can use standard surface registration techniques to perform the image-space to physical-space registration. Since our methods use two distinct data sources we test for spatial accuracy and characterize temporal effects in phantoms, ex vivo porcine and human kidneys. In addition we use an industrial robot to provide controlled motion and positioning for characterizing temporal effects. RESULTS: Our initial surface acquisitions are hand-held. This means that we take approximately 55 s to acquire a surface. At that rate we see no temporal effects due to acquisition synchronization or probe speed. Our surface registrations were able to find applied targets with submillimeter target registration errors. CONCLUSION: The results showed that the textured surfaces could be reconstructed with submillimetric mean registration errors. While this paper focuses on kidney applications, this method could be applied to any anatomical structures where a line of sight can be created via open or minimally invasive surgical techniques. PMID- 26758890 TI - The effects of combined human parathyroid hormone (1-34) and simvastatin treatment on the interface of hydroxyapatite-coated titanium rods implanted into osteopenic rats femurs. AB - The effect of human parathyroid hormone 1-34 (PTH) and simvastatin (SIM) alone could promote bone healing in osteoporotic implant fixation, but there are no reports about the combined use of PTH and SIM for promotion of bone healing around implant in osteoporotic settings. This study aims to investigate effects of PTH + SIM on implant stabilization in osteopenic rats. Fourteen weeks after chronically fed a low protein diet, osteopenic rats randomly received implants. Subsequently, the animals were randomly divided into four groups: Control, SIM, PTH and PTH + SIM. Then all rats from groups PTH, SIM and PTH + SIM received PTH (40 MUg/kg, three times a week), SIM (25 mg/kg, daily), or both for 12 weeks. The results of our study indicated that all treatments promoted bone healing around implant compared to Control, but PTH + SIM treatment showed significantly stronger effects than PTH or SIM alone in histological, micro-CT, and biomechanical tests. The results indicated additive effects of PTH and SIM on implant fixation in osteoporotic rats. PMID- 26758891 TI - Levofloxacin-loaded star poly(epsilon-caprolactone) scaffolds by additive manufacturing. AB - The employment of a tissue engineering scaffold able to release an antimicrobial agent with a controlled kinetics represents an effective tool for the treatment of infected tissue defects as well as for the prevention of scaffolds implantation-related infectious complications. This research activity was aimed at the development of additively manufactured star poly(epsilon-caprolactone) (*PCL) scaffolds loaded with levofloxacin, investigated as antimicrobial fluoroquinolone model. For this purpose a computer-aided wet-spinning technique allowing functionalizing the scaffold during the fabrication process was explored. Scaffolds with customized composition, microstructure and anatomical external shape were developed by optimizing the processing parameters. Morphological, thermal and mechanical characterization showed that drug loading did not compromise the fabrication process and the final performance of the scaffolds. The developed *PCL scaffolds showed a sustained in vitro release of the loaded antibiotic for 5 weeks. The proposed computer-aided wet-spinning technique appears well suited for the fabrication of anatomical scaffolds endowed with levofloxacin-releasing properties to be tested in vivo for the regeneration of long bone critical size defects in a rabbit model. PMID- 26758894 TI - Electrochemical etching of micro-pores in medical grade cobalt-chromium alloy as reservoirs for drug eluting stents. AB - Drug eluting stents (DES) have shown efficacy in reducing restenosis after angioplasty followed by application of a coronary stent. However, polymer matrices typically used for immobilizing drugs on the stent surface may cause irritation and have limited drug loading capacity. In contrast, drug loading into micro- or nanopores created within the stent material could avoid these problems. We present a technology based on electrochemically induced pitting corrosion to form pores in medical grade steel, followed by loading with rapamycin. This process is applied to pore formation and drug loading in coronary stents consisting of L605 medical steel. Sustained release of the drug over 28 days at rates comparable to established DES was demonstrated. This technology is capable of creating pores with well-defined pore size and filling of these pores by a drug employing a crystallization process thus completely avoiding polymer matrices to immobilize drugs. Electrochemically induced pitting corrosion provides a generic means to introduce micro-pores suitable as drug reservoirs into medical grade steel without the need for any further matrix material. Further research will expand these findings to other materials and types of implants that could benefit from the additional function of drug release and/or improved implant/tissue integration. PMID- 26758893 TI - Determination of trace elements in rat organs implanted with endodontic repair materials by ICP-MS. AB - To investigate the levels of seven elements using an inductively coupled plasma mass spectrometry (ICP-MS) method in rat organs after the implantation of Micro Mega Mineral Trioxide Aggregate (MM-MTA), Bioaggregate (BA) and Biodentine (BD) materials. MM-MTA, BA and BD were implanted into the subcutaneous tissue of 15 Wistar albino rats; three control animals had no operation. After 45 days, the rats were sacrificed and their brains, kidneys and livers were removed. The ICP MS analysis was used to determine trace elements. Data were analysed using the Kruskal-Wallis and Connover post hoc tests. There was no significant difference between the control groups and the MM-MTA, BA and BD groups according to the concentration of aluminum, calcium, arsenic and lead in the rats' organs. Beryllium was not detected in all tissue samples. Chromium levels of these materials were higher than the control group in brain and kidney samples (P = 0.038 and P = 0.037); magnesium levels were higher than the control group in kidney and liver samples (P = 0.030 and P = 0.008). MM-MTA, BA and BD were nontoxic according to trace element levels in brain, kidney and liver samples of rats. Further investigation is required to understand the systemic effects of these materials. PMID- 26758892 TI - Surface modification of PVDF using non-mammalian sources of collagen for enhancement of endothelial cell functionality. AB - Although polyvinylidene fluoride (PVDF) is non-toxic and stable in vivo, its hydrophobic surface has limited its bio-applications due to poor cell-material interaction and thrombus formation when used in blood contacting devices. In this study, surface modification of PVDF using naturally derived non-mammalian collagen was accomplished via direct surface-initiated atom transfer radical polymerisation (SI-ATRP) to enhance its cytocompatibility and hemocompatibility. Results showed that Type I collagen was successfully extracted from fish scales and bullfrog skin. The covalent immobilisation of fish scale-derived collagen (FSCOL) and bullfrog skin-derived collagen (BFCOL) onto the PVDF surface improves the attachment and proliferation of human umbilical vein endothelial cells (HUVECs). Furthermore, both FSCOL and BFCOL had comparable anti-thrombogenic profiles to that of commercially available bovine collagen (BVCOL). Also, cell surface expression of the leukocyte adhesion molecule was lower on HUVECs cultured on non-mammalian collagen surfaces than on BVCOL, which is an indication of lower pro-inflammatory response. Overall, results from this study demonstrated that non-mammalian sources of collagen could be used to confer bioactivity to PVDF, with comparable cell-material interactions and hemocompatibility to BVCOL. Additionally, higher expression levels of Type IV collagen in HUVECs cultured on FSCOL and BFCOL were observed as compared to BVCOL, which is an indication that the non-mammalian sources of collagen led to a better pro-angiogenic properties, thus making them suitable for blood contacting applications. PMID- 26758895 TI - Electrophoretic deposition of graphene oxide reinforced chitosan-hydroxyapatite nanocomposite coatings on Ti substrate. AB - Electrophoretic deposition (EPD) is a facile and feasible technique to prepare functional nanocomposite coatings for application in orthopedic-related implants. In this work, a ternary graphene oxide-chitosan-hydroxyapatite (GO-CS-HA) composite coating on Ti substrate was successfully fabricated by EPD. Coating microstructure and morphologies were investigated by scanning electron microscopy, contact angle test, Raman spectroscopy, Fourier transform infrared spectroscopy and thermogravimetric analysis. It was found GO-CS surface were uniformly decorated by HA nanoparticles. The potentiodynamic polarization test in simulated body fluid indicated that the GO-CS-HA coatings could provide effective protection of Ti substrate from corrosion. This ternary composite coating also exhibited good biocompatibility during incubation with MG63 cells. In addition, the nanocomposite coatings could decrease the attachment of Staphylococcus aureus. PMID- 26758896 TI - In vitro antibacterial properties and UV induced response from Staphylococcus epidermidis on Ag/Ti oxide thin films. AB - Implanted materials are susceptible to bacterial colonization and biofilm formation, which can result in severe infection and lost implant function. UV induced photocatalytic disinfection on TiO2 and release of Ag(+) ions are two promising strategies to combat such events, and can be combined for improved efficiency. In the current study, a combinatorial physical vapor deposition technique was utilized to construct a gradient coating between Ag and Ti oxide, and the coating was evaluated for antibacterial properties in darkness and under UV light against Staphylococcus epidermidis. The findings revealed a potent antibacterial effect in darkness due to Ag(+) release, with near full elimination (97%) of viable bacteria and visible cell lysis on Ag dominated surfaces. The photocatalytic activity, however, was demonstrated poor due to low TiO2 crystallinity, and UV light irradiation of the coating did not contribute to the antibacterial effect. On the contrary, bacterial viability was in several instances higher after UV illumination, proposing a UV induced SOS response from the bacteria that limited the reduction rate during Ag(+) exposure. Such secondary effects should thus be considered in the development of multifunctional coatings that rely on UV activation. PMID- 26758897 TI - Debris of carbon-fibers originated from a CFRP (pEEK) wrist-plate triggered a destruent synovitis in human. AB - Application of carbon-fiber-reinforced-polymer (CFRP) artifacts in humans has been promoted in Orthopedic and Trauma Surgery. Literature documents the biocompatibility of materials used, namely carbon fibers (CF) and poly-ether thermoplastics, like poly-ether-ether-ketone (PEEK). A properly designed and accurately implanted composite artifact should not expose its fibers during or after surgery: however this may happen. A white Caucasian woman came to our attention 11 months after surgery for a wrist fracture. She had a severe impairment, being unable to flex the thumb; index finger and distal phalanx of third finger. We retrieved a correctly positioned plate and documented an aggressive erosive flexor tendons synovitis with eroded stumps of flexor tendons. The plate and soft tissues were analyzed by Visible Light and Scanning Electron Microscopy. Histopathology showed granulomatous fibrogenic process with CF engulfed inside multinucleated giant cells. Fibers were unmasked and disrupted inside the holes where screws were tightened and corrugation of the polymer coating led to further unmasking. The mechanism of foreign-body reaction to CF has not been studied in depth yet, particularly at the ultrastructural level and in Humans. This case documents a damage occurred in a clinical application and which was theoretically possible. Our opinion is that a proper way to promote the use of CRFP in the Clinic in the short term is to direct Research towards finding a better way to prevent CF debris to be exposed and released. In the longer term, the biological response to CF deserves a deeper understanding. PMID- 26758898 TI - Magnetic forces and magnetized biomaterials provide dynamic flux information during bone regeneration. AB - The fascinating prospect to direct tissue regeneration by magnetic activation has been recently explored. In this study we investigate the possibility to boost bone regeneration in an experimental defect in rabbit femoral condyle by combining static magnetic fields and magnetic biomaterials. NdFeB permanent magnets are implanted close to biomimetic collagen/hydroxyapatite resorbable scaffolds magnetized according to two different protocols . Permanent magnet only or non-magnetic scaffolds are used as controls. Bone tissue regeneration is evaluated at 12 weeks from surgery from a histological, histomorphometric and biomechanical point of view. The reorganization of the magnetized collagen fibers under the effect of the static magnetic field generated by the permanent magnet produces a highly-peculiar bone pattern, with highly-interconnected trabeculae orthogonally oriented with respect to the magnetic field lines. In contrast, only partial defect healing is achieved within the control groups. We ascribe the peculiar bone regeneration to the transfer of micro-environmental information, mediated by collagen fibrils magnetized by magnetic nanoparticles, under the effect of the static magnetic field. These results open new perspectives on the possibility to improve implant fixation and control the morphology and maturity of regenerated bone providing "in site" forces by synergically combining static magnetic fields and biomaterials. PMID- 26758899 TI - Exercise echocardiography for structural heart disease. AB - Since the introduction of transcatheter structural heart intervention, the term "structural heart disease" has been widely used in the field of cardiology. Structural heart disease refers to congenital heart disease, valvular heart disease, and cardiomyopathy. In structural heart disease, valvular heart disease is frequently identified in the elderly. Of note, the number of patients who suffer from aortic stenosis (AS) and mitral regurgitation (MR) is increasing in developed countries because of the aging of the populations. Transcatheter aortic valve replacement and percutaneous mitral valve repair has been widely used for AS and MR, individually. Echocardiography is the gold standard modality for initial diagnosis and subsequent evaluation of AS and MR, although the difficulties in assessing patients with these diseases still remain. Here, we review the clinical usefulness and prognostic impact of exercise echocardiography on structural heart disease, particularly on AS and MR. PMID- 26758900 TI - The influence of hormone therapies on colon and rectal cancer. AB - Exogenous sex hormones seem to play a role in colorectal carcinogenesis. Little is known about the influence of different types or durations of postmenopausal hormone therapy (HT) on colorectal cancer risk. A nationwide cohort of women 50 79 years old without previous cancer (n = 1,006,219) were followed 1995-2009. Information on HT exposures was from the National Prescription Register and updated daily, while information on colon (n = 8377) and rectal cancers (n = 4742) were from the National Cancer Registry. Potential confounders were obtained from other national registers. Poisson regression analyses with 5-year age bands included hormone exposures as time-dependent covariates. Use of estrogen-only therapy and combined therapy were associated with decreased risks of colon cancer (adjusted incidence rate ratio 0.77, 95 % confidence interval 0.68-0.86 and 0.88, 0.80-0.96) and rectal cancer (0.83, 0.72-0.96 and 0.89, 0.80-1.00), compared to never users. Transdermal estrogen-only therapy implied more protection than oral administration, while no significant influence was found of regimen, progestin type, nor of tibolone. The benefit of HT was stronger for long-term hormone users; and hormone users were at lower risk of advanced stage of colorectal cancer, which seems supportive for a causal association between hormone therapy and colorectal cancer. PMID- 26758901 TI - The TGFB1 gene is associated with curve severity but not with the development of adolescent idiopathic scoliosis: a replication study in the Chinese population. AB - BACKGROUND: The transforming growth factor beta-1 (TGFB1) gene was recently reported to be a new susceptible gene of adolescent idiopathic scoliosis (AIS) in Russian population. This study aimed to replicate the relationship between the TGFB1 gene and the susceptibility of AIS in a Chinese population, and to further describe its association with the curve severity. METHODS: A total of 1251 female AIS patients and 994 age-matched healthy controls were included in this study. The rs1800469 of TGFB1 gene was genotyped for all participants using the PCR based Invader assay. The differences of genotype and allele distributions between AIS patients and healthy controls were assessed using the Chi-square test. One way ANOVA test was used to compare the mean Cobb angles among patients with different genotypes. RESULTS: There was no significant difference in terms of the genotype and the allele frequency between the patients and the controls. The mean Cobb angle was 34.7 +/- 11.9 degrees (range 25-61 degrees ). Case-only analysis showed that rs1800469 was significantly associated with the curve severity. Patients with genotype TT had remarkably higher curve magnitude (39.1 +/- 12.8 degrees ) than those with genotype CT (34.8 +/- 11.1 degrees ) or CC (32.1 +/- 10.6 degrees ). CONCLUSIONS: The TGFB1 gene may not be a predisposition gene of AIS in the Chinese population. However, it can play a role in the curve progression of AIS. Replication studies in other ethnic groups are warranted to understand the implication of TGFB1 gene in AIS. PMID- 26758902 TI - Evaluating and excluding swap errors in analogue tests of working memory. AB - When observers retrieve simple visual features from working memory, two kinds of error are typically confounded in their recall. First, responses reflect noise or variability within the feature dimension they were asked to report. Second, responses are corrupted by "swap errors", in which a different item from the memory set is reported in place of the one that was probed. Independent evaluation of these error sources is vital for understanding the structure of internal representations and their binding. However, previous methods for disentangling these errors have been critically dependent on assumptions about the noise distribution, which is a priori unknown. Here I address this question with novel non-parametric (NP) methods, which estimate swap frequency and feature variability with fewer prior assumptions, and without a fitting procedure. The results suggest that swap errors are considerably more prevalent than previously appreciated (accounting for more than a third of responses at set size 8). These methods also identify which items are swapped in for targets: when the target item is cued by location, the items in closest spatial proximity are most likely to be incorrectly reported, thus implicating noise in the probe feature dimension as a source of swap errors. PMID- 26758903 TI - Ligation of lymph vessels for the treatment of recurrent inguinal lymphoceles following lymphadenectomy. AB - BACKGROUND: Recurrent lymphocele following groin dissection is generally a self limiting condition, but in a few cases, the lymphocele persists and for this, there are not many options. Few reports have proposed the efficacy of lymph vessel ligation with patent blue as a vessel locator. We have used this technique since 2007 in our very severe cases and herein present our results. METHODS: The study was a retrospective case series in a university hospital setting. All patients who had this procedure performed were included from the first procedure performed in 2007 until August 2015, and their data was retrieved from electronic patient records. RESULTS: In total, eight patients had this procedure performed for a total of ten inguinal regions. In all regions, leaking lymph vessels were easily found by the blue color and a median of 3 (range 1-5 vessels) vessels per region were ligated using titanium clips. For two patients, there was still a need for puncture which lasted 13-37 days postoperatively. For the remaining patients, there was an immediate stop in lymphocele formation but one patient developed a lymphatic malformation which after removal resulted in the recurrence of lymphocele and had the procedure performed again with immediate effect. CONCLUSIONS: Ligation of lymph vessels for the treatment of recurrent inguinal lymphoceles appears to be an appropriate treatment modality that is both quick and easy to perform with minimum risk, and in most cases, it results in immediate complete stop in the lymphocele formation. PMID- 26758904 TI - A retrospective analysis of eleven cases of invasive rhino-orbito-cerebral mucormycosis presented with orbital apex syndrome initially. AB - BACKGROUND: Rhino-orbito-cerebral mucormycosis(ROCM) is an invasive fungal infection that usually occurs in immunocompromised patients and sometimes presents as orbital apex syndrome(OAS) initially. It is rapidly fatal without an early diagnosis and treatment. We report the cases of invasive ROCM presenting with OAS initially in order to raise the attention of clinicians. METHODS: We retrospectively investigated eleven cases of invasive ROCM presenting initially with OAS admitted between January 2006 and December 2013. We analyzed clinical features, results of laboratory and radiological examinations, nasal endoscopy, aggressive surgical excision and debridement, and medical management outcomes of each case. RESULTS: A total of eleven cases of invasive ROCM with OAS as an initial sign were presented. Mucormycosis was accompanied by type II diabetes mellitus in nine cases, renal transplant in one case, and injury caused by traffic accident in one case. Anterior rhinoscopy revealed palatine or nasal necrotic lesions in all patients, and transethmoidal optic nerve decompression was carried out in three patients at the same time. CT scan revealed rhino orbital-cerebral involvement in every patient. All patients were given intravenous amphotericin B. Nine patients underwent surgical debridement of necrotic tissue. Three patients survived. CONCLUSIONS: ROCM is a severe, emergent and fatal infection requiring multidisciplinary management. It may often present with OAS initially. For ophthalmologist, mucormycosis must be considered in immunocompromised patients presenting with OAS initially, and anterior rhinoscopy is imperative before hormonotherapy, even in the cases absent of ketoacidosis induced by diabetes mellitus. PMID- 26758905 TI - Epidemiological investigation of an outbreak of cutaneous sporotrichosis, Northern Territory, Australia. AB - BACKGROUND: An outbreak of cutaneous sporotrichosis occurred in the Darwin region of the Northern Territory (NT) in 2014. We aimed to determine the source and risk factors associated with the outbreak and describe the clinical spectrum of cases seen. METHODS: Epidemiological investigation of cases of cutaneous sporotrichosis identified through the Royal Darwin Hospital was undertaken to investigate risk factors and potential sources of infection. Data were collected through chart review and individual patient interviews. Environmental investigation followed identification of a common risk factor. RESULTS: Nine confirmed cases of cutaneous sporotrichosis caused by Sporothrix schenckii were identified with onset of symptoms between April and July 2014. Patients were aged 29 to 70 years and seven were male (78%). Two strains of S. schenckii were identified, neither of which have been previously documented. One common risk factor was identified: all patients were occupational or recreational gardeners, with each reporting exposure to mulching hay, originating from a single NT farm. Local environmental health officers visited the farm and the owners confirmed that the implicated hay had been stored over the monsoon season and had been affected by rain. Storage of hay over the wet season was a new practice. CONCLUSIONS: This constitutes the third reported outbreak of S. schenckii sporotrichosis attributable to contaminated hay in Australia and the first outbreak of sporotrichosis in the NT. This outbreak prompted public health interventions, including distribution of information to general practitioners, farmers and suppliers in the Top End. Media reporting led to the identification and treatment of an additional case. Local practitioners should remain alert to the possibility of further occurrences of sporotrichosis. PMID- 26758907 TI - The process of coping with stress by Taiwanese medical interns: a qualitative study. AB - BACKGROUND: Internship, the transition period from medical student to junior doctor, is highly stressful for interns in the West; however, little is known about the experience of interns in coping with stress in Taiwan. This study aimed to develop a model for coping with stress among Taiwanese interns and to examine the relationship between stress and learning outcomes. METHODS: For this qualitative study, we used grounded theory methodology with theoretical sampling. We collected data through in-depth interviews and participant observations. We employed the constant comparative method to analyse the data until data saturation was achieved. RESULTS: The study population was 124 medical interns in a teaching hospital in northern Taiwan; 21 interns (12 males) participated. Data analysis revealed that the interns encountered stressors (such as sense of responsibility, coping with uncertainty, and interpersonal relationships) resulting from their role transition from observer to practitioner. The participants used self-directed learning and avoidance as strategies to deal with their stress. CONCLUSIONS: A self-directed learning strategy can be beneficial for an intern's motivation to learn as well as for patient welfare. However, avoiding stressors can result in less motivation to learn and hinder the quality of care. Understanding how interns experience and cope with stress and its related outcomes can help medical educators and policy makers improve the quality of medical education by encouraging interns' self-directed learning strategy and discouraging the avoidance of stressors. PMID- 26758906 TI - Colonization potential to reconstitute a microbe community in patients detected early after fecal microbe transplant for recurrent C. difficile. AB - BACKGROUND: Fecal microbiota transplants (FMT) are an effective treatment for patients with gut microbe dysbiosis suffering from recurrent C. difficile infections. To further understand how FMT reconstitutes the patient's gut commensal microbiota, we have analyzed the colonization potential of the donor, recipient and recipient post transplant fecal samples using transplantation in gnotobiotic mice. RESULTS: A total of nine samples from three human donors, recipient's pre and post FMT were transplanted into gnotobiotic mice. Microbiome analysis of three donor fecal samples revealed the presence of a high relative abundance of commensal microbes from the family Bacteriodaceae and Lachnospiraceae that were almost absent in the three recipient pre FMT fecal samples (<0.01%). The microbe composition in gnotobiotic mice transplanted with the donor fecal samples was similar to the human samples. The recipient samples contained Enterobacteriaceae, Lactobacillaceae, Enterococcaceae in relative abundance of 43, 11, 8%, respectively. However, gnotobiotic mice transplanted with the recipient fecal samples had an average relative abundance of unclassified Clostridiales of 55%, approximately 7000 times the abundance in the recipient fecal samples prior to transplant. Microbiome analysis of fecal samples from the three patients early (2-4 weeks) after FMT revealed a microbe composition with the relative abundance of both Bacteriodaceae and Lachnospiraceae that was approximately 7% of that of the donor. In contrast, gnotobioitc mice transplanted with the fecal samples obtained from the three at early times post FMT revealed increases in the relative abundance of Bacteriodaceae and Lachnospiraceae microbe compositions to levels similar to the donor fecal samples. Furthermore, the unclassified Clostridiales in the recipient samples post FMT was reduced to an average of 10%. CONCLUSION: We have used transplantation into gnotobiotic mice to evaluate the colonization potential of microbiota in FMT patients early after transplant. The commensal microbes present at early times post FMT out competed non-commensal microbes (e.g. such as unclassified Clostridiales) for niche space. The selective advantage of these commensal microbes to occupy niches in the gastrointestinal tract helps to explain the success of FMT to reconstitute the gut microbe community of patients with recurrent C. difficile infections. PMID- 26758909 TI - [Officinal bases and their characteristics]. PMID- 26758908 TI - Synthesis of Large-Area WS2 monolayers with Exceptional Photoluminescence. AB - Monolayer WS2 offers great promise for use in optical devices due to its direct bandgap and high photoluminescence intensity. While fundamental investigations can be performed on exfoliated material, large-area and high quality materials are essential for implementation of technological applications. In this work, we synthesize monolayer WS2 under various controlled conditions and characterize the films using photoluminescence, Raman and x-ray photoelectron spectroscopies. We demonstrate that the introduction of hydrogen to the argon carrier gas dramatically improves the optical quality and increases the growth area of WS2, resulting in films exhibiting mm(2) coverage. The addition of hydrogen more effectively reduces the WO3 precursor and protects against oxidative etching of the synthesized monolayers. The stoichiometric WS2 monolayers synthesized using Ar + H2 carrier gas exhibit superior optical characteristics, with photoluminescence emission full width half maximum (FWHM) values below 40 meV and emission intensities nearly an order of magnitude higher than films synthesized in a pure Ar environment. PMID- 26758910 TI - [Onychocola canadensis Sigler in onychomycosis : A new dermatophyte-like mould in Germany]. AB - Moulds or non-dermatophyte moulds (NDM) are being increasingly isolated as causative agent of onychomycoses. Known causes of a NDM-OM are Scopulariopsis brevicaulis, Fusarium, Aspergillus, Acremonium, Neoscytalidium dimidiatum, Arthrographis kalrae, and Chaetomium. In this article, 5 patients with suspected nail infection due to Onychocola canadensis are reported for the first time in Germany. Systemic antifungal agents are not considered to be effective in NDM onychomycosis. In individual cases, however, terbinafine seems to be effective in Onychocola canadensis infection of the nails. Treatment of choice represents, however, nontraumatic nail avulsion using 40 % urea ointment followed by antifungal nail lacquer with ciclopirox olamine or amorolfine. PMID- 26758911 TI - Does the use of IV tPA in the current era of rapid and predictable recanalization by mechanical embolectomy represent good value? AB - As healthcare delivery in the USA transforms into a model that at its core requires value-based considerations, ischemic stroke is confronted by intersecting forces. Modern techniques allow rapid revascularization in the majority of patients with large vessel occlusions. Dramatic advances in the evidentiary basis for mechanical embolectomy are increasing the number of patients treated with this therapy. A key part of the therapeutic arsenal in many patients treated with interventional techniques has been concurrent intravenous thrombolysis. We consider whether this paradigm warrants change. PMID- 26758913 TI - Quisinostat, bortezomib, and dexamethasone combination therapy for relapsed multiple myeloma. AB - The maximum tolerated dose (MTD) of quisinostat + bortezomib + dexamethasone in patients with relapsed multiple myeloma was evaluated in a phase-1b, open-label, multicenter, '3 + 3' dose-escalation study. Patients received escalating doses of oral quisinostat (6 mg [n = 3], 8 mg [n = 3], 10 mg [n = 6], and 12 mg [n = 6] on days 1, 3, and 5/week) plus subcutaneous bortezomib (1.3 mg/m(2)) and oral dexamethasone (20 mg) in cycles of 21 (cycles 1-8) or 35 d (cycles 9-11) until MTD was determined. No dose-limiting toxicities were reported in 6/8 mg groups except ventricular fibrillation (Grade 4 cardiac arrest, n = 1 [10 mg] cycle 6) and clinically significant cardiac toxicities (Grade 3 QTc prolongation, Grade 3 atrial fibrillation, n = 2 [12 mg]). Thrombocytopenia (n = 11), asthenia (n = 10), and diarrhea (n = 12) were most common adverse events. Overall, 88.2% patients achieved treatment response, median duration of response, and median progression-free survival were 9.4 and 8.2 months, respectively. The MTD of quisinostat was established as 10 mg thrice weekly oral dose with bortezomib + dexamethasone. PMID- 26758914 TI - Eculizumab salvage therapy for delayed hemolysis transfusion reaction in sickle cell disease patients. PMID- 26758912 TI - Genomic investigation reveals evolution and lifestyle adaptation of endophytic Staphylococcus epidermidis. AB - Staphylococcus epidermidis is a major human associated bacterium and also an emerging nosocomial pathogen. There are reports of its association to rodents, sheep and plants. However, comparative and evolutionary studies of ecologically diverse strains of S. epidermidis are lacking. Here, we report the whole genome sequences of four S. epidermidis strains isolated from surface sterilized rice seeds along with genome sequence of type strain. Phylogenomic analysis of rice endophytic S. epidermidis (RESE) with "type strain" unequivocally established their species identity. Whole genome based tree of 93 strains of S. epidermidis revealed RESE as distinct sub-lineage which is more related to rodent sub-lineage than to majority of human lineage strains. Furthermore, comparative genomics revealed 20% variable gene-pool in S. epidermidis, suggesting that genomes of ecologically diverse strains are under flux. Interestingly, we were also able to map several genomic regions that are under flux and gave rise to RESE strains. The largest of these genomic regions encodes a cluster of genes unique to RESE that are known to be required for survival and stress tolerance, apart from those required for adaptation to plant habitat. The genomes and genes of RESE represent distinct ecological resource/sequences and provided first evolutionary insights into adaptation of S. epidermidis to plants. PMID- 26758917 TI - Central nervous system complications and management in sickle cell disease. AB - With advances in brain imaging and completion of randomized clinical trials (RCTs) for primary and secondary stroke prevention, the natural history of central nervous system (CNS) complications in sickle cell disease (SCD) is evolving. In order of current prevalence, the primary CNS complications include silent cerebral infarcts (39% by 18 years), headache (both acute and chronic: 36% in children with sickle cell anemia [SCA]), ischemic stroke (as low as 1% in children with SCA with effective screening and prophylaxis, but ~11% in children with SCA without screening), and hemorrhagic stroke in children and adults with SCA (3% and 10%, respectively). In high-income countries, RCTs (Stroke Prevention in Sickle Cell Anemia [STOP], STOP II) have demonstrated that regular blood transfusion therapy (typically monthly) achieves primary stroke prevention in children with SCA and high transcranial Doppler (TCD) velocities; after at least a year, hydroxycarbamide may be substituted (TCD With Transfusions Changing to Hydroxyurea [TWiTCH]). Also in high-income countries, RCTs have demonstrated that regular blood transfusion is the optimal current therapy for secondary prevention of infarcts for children with SCA and strokes (Stroke With Transfusions Changing to Hydroxyurea [SWiTCH]) or silent cerebral infarcts (Silent Infarct Transfusion [SIT] Trial). For adults with SCD, CNS complications continue to be a major cause of morbidity and mortality, with no evidence-based strategy for prevention. PMID- 26758915 TI - Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. AB - Sickle cell disease (SCD) is a severe genetic blood disorder characterized by hemolytic anemia, episodic vaso-occlusion, and progressive organ damage. Current management of the disease remains symptomatic or preventative. Specific treatment targeting major complications such as vaso-occlusion is still lacking. Recent studies have identified various cellular and molecular factors that contribute to the pathophysiology of SCD. Here, we review the role of these elements and discuss the opportunities for therapeutic intervention. PMID- 26758920 TI - Sickle cell disease: challenges and progress. PMID- 26758918 TI - Pathophysiology and treatment of pulmonary hypertension in sickle cell disease. AB - Pulmonary hypertension affects ~10% of adult patients with sickle cell disease (SCD), particularly those with the homozygous genotype. An increase in pulmonary artery systolic pressure, estimated noninvasively by echocardiography, helps identify SCD patients at risk for pulmonary hypertension, but definitive diagnosis requires right-heart catheterization. About half of SCD-related pulmonary hypertension patients have precapillary pulmonary hypertension with potential etiologies of (1) a nitric oxide deficiency state and vasculopathy consequent to intravascular hemolysis, (2) chronic pulmonary thromboembolism, or (3) upregulated hypoxic responses secondary to anemia, low O2 saturation, and microvascular obstruction. The remainder have postcapillary pulmonary hypertension secondary to left ventricular dysfunction. Although the pulmonary artery pressure in SCD patients with pulmonary hypertension is only moderately elevated, they have a markedly higher risk of death than patients without pulmonary hypertension. Guidelines for diagnosis and management of SCD-related pulmonary hypertension were published recently by the American Thoracic Society. Management of adults with sickle-related pulmonary hypertension is based on anticoagulation for those with thromboembolism; oxygen therapy for those with low oxygen saturation; treatment of left ventricular failure in those with postcapillary pulmonary hypertension; and hydroxyurea or transfusions to raise the hemoglobin concentration, reduce hemolysis, and prevent vaso-occlusive events that cause additional increases in pulmonary pressure. Randomized trials have not identified drugs to lower pulmonary pressure in SCD patients with precapillary pulmonary hypertension. Patients with hemodynamics of pulmonary arterial hypertension should be referred to specialized centers and considered for treatments known to be effective in other forms of pulmonary arterial hypertension. There have been reports that some of these treatments improve SCD related pulmonary hypertension. PMID- 26758919 TI - Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease. AB - Despite Food and Drug Administration (FDA) approval of hydroxyurea to reduce the frequency of vaso-occlusive episodes, sickle cell disease (SCD) has continued to be treated primarily with analgesics for pain relief. However, elucidation of the multiple pathophysiologic mechanisms leading to vaso-occlusion and tissue injury in SCD has now resulted in a burgeoning effort to identify new treatment modalities to prevent or ameliorate the consequences of the disease. Development of new drugs as well as investigation of drugs previously used in other settings have targeted cell adhesion, inflammatory pathways, upregulation of hemoglobin F, hemoglobin polymerization and sickling, coagulation, and platelet activation. Although these efforts have not yet yielded drugs ready for FDA approval, several early studies have been extremely encouraging. Moreover, the marked increase in clinical pharmaceutical research addressing SCD and the new and old drugs in the pipeline make it reasonable to expect that we will soon have new treatments for SCD. PMID- 26758916 TI - Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease. AB - Effective medical management for sickle cell disease (SCD) remains elusive. As a prevalent and severe monogenic disorder, SCD has been long considered a logical candidate for gene therapy. Significant progress has been made in moving toward this goal. These efforts have provided substantial insight into the natural regulation of the globin genes and illuminated challenges for genetic manipulation of the hematopoietic system. The initial gamma-retroviral vectors, next-generation lentiviral vectors, and novel genome engineering and gene regulation approaches each share the goal of preventing erythrocyte sickling. After years of preclinical studies, several clinical trials for SCD gene therapies are now open. This review focuses on progress made toward achieving gene therapy, the current state of the field, consideration of factors that may determine clinical success, and prospects for future development. PMID- 26758922 TI - Beating heart on a chip: a novel microfluidic platform to generate functional 3D cardiac microtissues. AB - In the past few years, microfluidic-based technology has developed microscale models recapitulating key physical and biological cues typical of the native myocardium. However, the application of controlled physiological uniaxial cyclic strains on a defined three-dimension cellular environment is not yet possible. Two-dimension mechanical stimulation was particularly investigated, neglecting the complex three-dimensional cell-cell and cell-matrix interactions. For this purpose, we developed a heart-on-a-chip platform, which recapitulates the physiologic mechanical environment experienced by cells in the native myocardium. The device includes an array of hanging posts to confine cell-laden gels, and a pneumatic actuation system to induce homogeneous uniaxial cyclic strains to the 3D cell constructs during culture. The device was used to generate mature and highly functional micro-engineered cardiac tissues (MUECTs), from both neonatal rat and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), strongly suggesting the robustness of our engineered cardiac micro-niche. Our results demonstrated that the cyclic strain was effectively highly uniaxial and uniformly transferred to cells in culture. As compared to control, stimulated MUECTs showed superior cardiac differentiation, as well as electrical and mechanical coupling, owing to a remarkable increase in junction complexes. Mechanical stimulation also promoted early spontaneous synchronous beating and better contractile capability in response to electric pacing. Pacing analyses of hiPSC-CM constructs upon controlled administration of isoprenaline showed further promising applications of our platform in drug discovery, delivery and toxicology fields. The proposed heart-on-a-chip device represents a relevant step forward in the field, providing a standard functional three-dimensional cardiac model to possibly predict signs of hypertrophic changes in cardiac phenotype by mechanical and biochemical co-stimulation. PMID- 26758935 TI - Microbiota formed on attached stainless steel coupons correlates with the natural biofilm of the sink surface in domestic kitchens. AB - Stainless steel coupons are frequently used in biofilm studies in the laboratory, as this material is commonly used in the food industry. The coupons are attached to different surfaces to create a "natural" biofilm to be studied further in laboratory trials. However, little has been done to investigate how well the microbiota on such coupons represents the surrounding environment. The microbiota on sink wall surfaces and on new stainless steel coupons attached to the sink wall for 3 months in 8 domestic kitchen sinks was investigated by next-generation sequencing (MiSeq) of the 16S rRNA gene derived from DNA and RNA (cDNA), and by plating and identification of colonies. The mean number of colony-forming units was about 10-fold higher for coupons than sink surfaces, and more variation in bacterial counts between kitchens was seen on sink surfaces than coupons. The microbiota in the majority of biofilms was dominated by Moraxellaceae (genus Moraxella/Enhydrobacter) and Micrococcaceae (genus Kocuria). The results demonstrated that the variation in the microbiota was mainly due to differences between kitchens (38.2%), followed by the different nucleic acid template (DNA vs RNA) (10.8%), and that only 5.1% of the variation was a result of differences between coupons and sink surfaces. The microbiota variation between sink surfaces and coupons was smaller for samples based on their RNA than on their DNA. Overall, our results suggest that new stainless steel coupons are suited to model the dominating part of the natural microbiota of the surrounding environment and, furthermore, are suitable for different downstream studies. PMID- 26758921 TI - Characterization of vitamin K-dependent carboxylase mutations that cause bleeding and nonbleeding disorders. AB - Vitamin K-dependent coagulation factors deficiency is a bleeding disorder mainly associated with mutations in gamma-glutamyl carboxylase (GGCX) that often has fatal outcomes. Some patients with nonbleeding syndromes linked to GGCX mutations, however, show no coagulation abnormalities. The correlation between GGCX genotypes and their clinical phenotypes has been previously unknown. Here we report the identification and characterization of novel GGCX mutations in a patient with both severe cerebral bleeding disorder and comorbid Keutel syndrome, a nonbleeding malady caused by functional defects of matrix gamma carboxyglutamate protein (MGP). To characterize GGCX mutants in a cellular milieu, we established a cell-based assay by stably expressing 2 reporter proteins (a chimeric coagulation factor and MGP) in HEK293 cells. The endogenous GGCX gene in these cells was knocked out by CRISPR-Cas9-mediated genome editing. Our results show that, compared with wild-type GGCX, the patient's GGCX D153G mutant significantly decreased coagulation factor carboxylation and abolished MGP carboxylation at the physiological concentration of vitamin K. Higher vitamin K concentrations can restore up to 60% of coagulation factor carboxylation but do not ameliorate MGP carboxylation. These results are consistent with the clinical results obtained from the patient treated with vitamin K, suggesting that the D153G alteration in GGCX is the causative mutation for both the bleeding and nonbleeding disorders in our patient. These findings provide the first evidence of a GGCX mutation resulting in 2 distinct clinical phenotypes; the established cell-based assay provides a powerful tool for studying the clinical consequences of naturally occurring GGCX mutations in vivo. PMID- 26758936 TI - IGF-1 is associated with fetal growth and preterm delivery in type 1 diabetic pregnancy. AB - AIM: No data on IGF-1 and either preterm or preeclampsia have been reported so far in diabetic pregnancies. We evaluated consecutive measurements of IGF-1 for preeclampsia, preterm delivery and birth weight in type 1 diabetic pregnancy. SETTING: In an outpatient university clinic, 97 pregnant women were consecutively recruited for evaluation of indicators for deterioration of diabetes status and adverse perinatal outcome. At every visit, a blood sample for measurement of IGF 1 was drawn. RESULTS: IGF-1 levels from week 14 to 32 was consistently lower in women who delivered preterm compared with women whose delivered after gestational week 36; the increase in 2nd and 3rd trimester was steeper in those delivering at term than in women delivering preterm (p = 0.032). IGF-1 in preeclampsia did not show the same relation in diabetic women (p = 0.74). The lowest tertile of birth weight ratio (0.8-1.2) was associated with lower IGF-1 from week 14 to 32 (p = 0.047, adjusted for preterm delivery and preeclampsia). CONCLUSION: We found low IGF-1 levels associated with preterm delivery and low birth weight. PMID- 26758937 TI - Folic acid supplementation reduces plasma homocysteine in postmenopausal women. AB - Plasma homocysteine, which is increased after menopause, can be a risk factor for cardiovascular disease and osteoporosis. The purpose of the present study was to determine the effect of folic acid supplementation on plasma homocysteine in postmenopausal women. The study was performed as a randomized placebo controlled trial on 48 healthy postmenopausal women (aged 50-70 years) and plasma homocysteine of all women was measured. In the case group, folic acid, and in the control group, placebo was prescribed. The second plasma homocysteine was measured 16-17 weeks later and was compared in the two groups. There was no significant difference between the two groups according to age, BMI, parity, duration of menopause and the first plasma homocysteine level. Plasma homocysteine level was significantly lower in the case group than control group 16 weeks after folic acid administration (10.33 +/- 3.51 MUmol/l vs 13.21 +/- 3.11 MUmol/l, p=0.004). There was no significant correlation between plasma homocysteine level and BMI and parity. However, there was a weak-moderate positive correlation between plasma homocysteine and age (p<0.05, r=0.33), and there was a significant but weak correlation between plasma homocysteine and duration of menopause (p=0.05, r=0.28). PMID- 26758939 TI - Flexible transparent conductive films combining flexographic printed silver grids with CNT coating. AB - A high-performance ITO-free transparent conductive film (TCF) has been made by combining high resolution Ag grids with a carbon nanotube (CNT) coating. Ag grids printed with flexography have a 20 MUm line width at a grid interval of 400 MUm. The Ag grid/CNT hybrid film exhibits excellent overall performance, with a typical sheet resistance of 14.8 Omega/? and 82.6% light transmittance at room temperature. This means a 23.98% reduction in sheet resistance and only 2.52% loss in transmittance compared to a pure Ag grid film. Analysis indicates that filling areas between the Ag grids and interconnecting the silver nanoparticles with the CNT coating are the primary reasons for the significantly improved conductivity of the hybrid film that also exhibits excellent flexibility and mechanical strength compared to an ITO film. The hybrid film may fully satisfy the requirements of different applications, e.g. use as the anode of polymer solar cells (PSCs). The J-V curve shows that the power conversion efficiency (PCE) of the PSCs using the Ag grid/CNT hybrid anode is 0.61%, which is 24.5% higher than that of the pure Ag grids with a PCE of 0.49%. Further investigations to improve the performance of the solar cells based on the printed hybrid TCFs are ongoing. PMID- 26758938 TI - Understanding transport by the major facilitator superfamily (MFS): structures pave the way. AB - Members of the major facilitator superfamily (MFS) of transport proteins are essential for the movement of a wide range of substrates across biomembranes. As this transport requires a series of conformational changes, structures of MFS transporters captured in different conformational states are needed to decipher the transport mechanism. Recently, a large number of MFS transporter structures have been determined, which has provided us with an unprecedented opportunity to understand general aspects of the transport mechanism. We propose an updated model for the conformational cycle of MFS transporters, the 'clamp-and-switch model', and discuss the role of so-called 'gating residues' and the substrate in modulating these conformational changes. PMID- 26758940 TI - An innovative platform for quick and flexible joining of assorted DNA fragments. AB - Successful synthetic biology efforts rely on conceptual and experimental designs in combination with testing of multi-gene constructs. Despite recent progresses, several limitations still hinder the ability to flexibly assemble and collectively share different types of DNA segments. Here, we describe an advanced system for joining DNA fragments from a universal library that automatically maintains open reading frames (ORFs) and does not require linkers, adaptors, sequence homology, amplification or mutation (domestication) of fragments in order to work properly. This system, which is enhanced by a unique buffer formulation, provides unforeseen capabilities for testing, and sharing, complex multi-gene circuitry assembled from different DNA fragments. PMID- 26758941 TI - High Efficiency Dye-sensitized Solar Cells Constructed with Composites of TiO2 and the Hot-bubbling Synthesized Ultra-Small SnO2 Nanocrystals. AB - An efficient photo-anode for the dye-sensitized solar cells (DSSCs) should have features of high loading of dye molecules, favorable band alignments and good efficiency in electron transport. Herein, the 3.4 nm-sized SnO2 nanocrystals (NCs) of high crystallinity, synthesized via the hot-bubbling method, were incorporated with the commercial TiO2 (P25) particles to fabricate the photo anodes. The optimal percentage of the doped SnO2 NCs was found at ~7.5% (SnO2/TiO2, w/w), and the fabricated DSSC delivers a power conversion efficiency up to 6.7%, which is 1.52 times of the P25 based DSSCs. The ultra-small SnO2 NCs offer three benefits, (1) the incorporation of SnO2 NCs enlarges surface areas of the photo-anode films, and higher dye-loading amounts were achieved; (2) the high charge mobility provided by SnO2 was confirmed to accelerate the electron transport, and the photo-electron recombination was suppressed by the highly crystallized NCs; (3) the conduction band minimum (CBM) of the SnO2 NCs was uplifted due to the quantum size effects, and this was found to alleviate the decrement in the open-circuit voltage. This work highlights great contributions of the SnO2 NCs to the improvement of the photovoltaic performances in the DSSCs. PMID- 26758942 TI - A novel graphene-based label-free fluorescence 'turn-on' nanosensor for selective and sensitive detection of phosphorylated species in biological samples and living cells. AB - A novel label-free fluorescence 'turn-on' nanosensor has been developed for highly selective and sensitive detection of phosphorylated species (Ps) in biological samples and living cells. The design strategy relies on the use of Ti(4+)-immobilized polydopamine (PDA) coated reduced graphene oxide (rGO@PDA Ti(4+)) that serves as an attractive platform to bind riboflavin 5'-monophosphate molecules (FMNs) through ion-pair interactions between phosphate groups and Ti(4+). The as-prepared rGO@PDA-Ti(4+)-FMNs (nanosensor), fluoresce only weakly due to the ineffective Forster resonance energy transfer between the FMNs and rGO@PDA-Ti(4+). The experimental findings revealed that the microwave-assisted interaction of the nanosensor with alpha-, beta-casein, ovalbumin, human serum, non-fat milk, egg white, and living cells (all containing Ps) releases FMNs (due to the high formation constant between phosphate groups and Ti(4+)), leading to an excellent fluorescence 'turn-on' response. The fluorescence spectroscopy, confocal microscopy, and MALDI-TOF MS spectrometry were used to detect Ps both qualitatively and quantitatively. Under the optimized conditions, the nanosensor showed a detection limit of ca. 118.5, 28.9, and 54.8 nM for the tryptic digests of alpha-, beta-casein and ovalbumin, respectively. Furthermore, the standard addition method was used as a bench-mark proof for phosphopeptide quantification in egg white samples. We postulate that the present quantitative assay for Ps holds tremendous potential and may pave the way to disease diagnostics in the near future. PMID- 26758943 TI - Nanoelectrode array formation by electrolytic nanoparticle impacts. AB - We report the fabrication of functional nanoelectrode arrays by the electrolysis of AgBr nanoparticles (NPs) impacting on a glassy carbon electrode from suspension in aqueous solution. The impacted NPs result in Ag NP deposits of similar size to the originating NP, with the coverage of these arrays easily controlled by the time of the deposition step. The NPs constituting the array are deposited randomly across the surface with little aggregation or agglomeration. The fabricated arrays are themselves electrochemically active, mediating the reduction of hydrogen peroxide, H2O2. PMID- 26758944 TI - The Mevalonate Pathway and Innate Immune Hyper-Responsiveness in the Pathogenesis of COPD and Lung Cancer: Potential for Chemoprevention. AB - Current evidence suggests that persisting and/or exaggerated inflammation in the lungs initiated by smoking, and up-regulated through genetic susceptibility, may result in lung remodelling and impaired repair. The mevalonate pathway, through its modifying effects on innate immune responsiveness, may be involved in these processes providing a plausible pathogenic link between the development of chronic obstructive pulmonary disease (COPD) and lung cancer. The mevalonate pathway, mediates these effects through important intra-cellular signalling molecules called guanine phosphate transferases (GTPases) such as Rho-A. Smoke exposure activates cell surface proteins which, through the mediating influence of GTPases, then modify the activation of NFkB and its downstream effects on genes underlying innate immunity, neutrophilic inflammation and carcinogenesis. The mevalonate pathway is readily and substantially modified by inhibition of the enzyme 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMGCo-A) reductase. This enzyme controls the rate limiting step of the mevalonate pathway and is subject to inhibition by statin drugs and small chain fatty acids derived from high dietary fibre intake. Thus inhibiting the mevelonate pathway, and dampening the innate immune response to smoking, may play a critical role in modifying pulmonary inflammation and lung remodelling. Such an action might slow the progression of COPD and reduce the tendency to the development of lung cancer. This review examines the pre-clinical and clinical data suggesting that HMGCoA-reductase inhibition and it's modification of the mevalonate pathway, may have a chemo preventive effect on lung cancer, particularly in patients with COPD where pulmonary inflammation is increased and the risk of lung cancer is greatest. PMID- 26758945 TI - Clinical Studies of Statins in Asthma and COPD. AB - Immunomodulatory effects of statins in vitro and in experimental models of asthma and COPD could potentially be relevant to the treatment of chronic airway diseases. This article provides an overview of the evidence from the key clinical studies on the effects of statins on clinical outcomes and inflammatory biomarkers in asthma and COPD. Future directions for clinical studies of statins in asthma and COPD are discussed. A small number of randomized controlled trials (RCTs) in adults with mild to moderate asthma suggest that short-term statin treatment does not improve lung function or symptom control, except for a possible improvement in quality of life and symptoms in smokers with asthma. Several observation studies report that statin use in asthma is associated with a reduced risk of asthma-related emergency department visits, oral corticosteroid dispensing or hospital admissions. Statins treatment in asthma may have modest local anti-inflammatory effects in the airways. There is a need for a large RCT examining the effects of statins on reducing exacerbations, particularly in severe asthma. In COPD, observational studies suggest that statin use is associated with reduced morbidity and/or mortality, whereas a large RCT concluded that simvastatin did not reduce exacerbations in patients with COPD that had no cardiovascular indication for statin treatment. It is possible that a subgroup of COPD patients with cardiovascular indications for statins and/or systemic inflammation may obtain clinical benefit from statin treatment. Understanding the immunomodulatory effects of statins in asthma and COPD may lead to the development of novel targeted interventions. PMID- 26758946 TI - Basic and Clinical Observations of Mevalonate Depletion on the Mevalonate Signaling Pathway. AB - Inhibition of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase by pharmaceuticals, commonly referred to as statins, has proven to be an effective and efficient way in reducing cholesterol levels in patients. As a result of this intervention, mevalonate production, formed during cholesterol synthesis, is inhibited. Mevalonate is the precursor to a variety of crucial downstream products, including those involved with the mitochondrial electron transport chain, and localized activation of small GTPases. Statins have also been observed to induce changes of the immune system, favouring a reduced proinflammatory phenotype. However, near complete cessation of mevalonate and its downstream products have severe pro-inflammatory consequences as evident by patients suffering from mevalonate kinase deficiency who have increased inflammasome activity. It is evident that mevalonate production is a pivotal component of normal homeostatic cell processing, especially in maintaining a muted inflammatory response. PMID- 26758947 TI - Interconnection of Estrogen/Testosterone Metabolism and Mevalonate Pathway in Breast and Prostate Cancers. AB - The metabolic steroid hormones, 17beta stradiol (E2) and testosterone play key roles in several functions including carbohydrate, lipid and protein metabolism, cellular signaling, cell proliferation, and cancer promotion. Steroid hormones have long been characterized as cell proliferation and differentiation regulators and are closely related to the development of breast and prostate cancers. Moreover, cholesterol metabolism, mainly in adipose tissue, leads to the production of steroids and cytokines, thus increasing the risk of metabolic syndrome, obesity, and ER+ breast cancer in postmenopausal women. Recent studies also shown that testosterone and E2 increase the levels of key enzymes of the mevalonate pathway, leading to post-translational prenylation and farnesylation of numerous proteins in RAS signaling in several cancers, including breast and prostate cancers. There is accumulating evidence both clinically and experimentally suggesting that changes in the metabolism of cholesterol may also have an important role in carcinogenesis. In this regard, the cells treated with mevalonate in culture showed elevated proliferation. Therefore, investigation on cholesterol as a precursor of steroid hormones has confirmed the effects cholesterol metabolite on breast and prostate cancers. Indeed, recent evidence strongly suggests that the MVA pathway and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCOA) have a crucial regulatory role in cellular proliferation and transformation. Therefore, the use of mevalonate inhibitors decreases the production of several biologically active downstream products of the mevalonate pathway, including cholesterol. Although for approximately 20 years statins have been identified as anticancer agents, recent studies have sparked some controversy. Therefore, further investigation to evaluate mevalonate- dependent therapeutic agents per se and in combination with other agents is merited. The current review is an attempt to elucidate the role of cholesterol and E2/testosterone, as well as the mevalonate pathway and its inhibitors in breast and prostate tissues in normal and pathological states. PMID- 26758948 TI - Mevalonate Cascade and Neurodevelopmental and Neurodegenerative Diseases: Future Targets for Therapeutic Application. AB - The mevalonate cascade is a key metabolic pathway that regulates a variety of cellular functions and is thereby implicated in the pathophysiology of most brain diseases, including neurodevelopmental and neurodegenerative disorders. Emerging lines of evidence suggest that statins and Rho GTPase inhibitors are efficacious and have advantageous properties in treatment of different pathologic conditions that are relevant to the central nervous system. Beyond the original role of statins in lowering cholesterol synthesis, they have anti-inflammatory, antioxidant and modulatory effects on signaling pathways. Additionally, Rho GTPase inhibitors and statins share the mevalonate pathway as a common target of their therapeutic actions. In this review, we discuss potential mechanisms through which these drugs, via their role in the mevalonate pathway, exert their neuroprotective effects in neurodegenerative and neurodevelopmental disorders. PMID- 26758949 TI - Mevalonate Cascade and its Regulation in Cholesterol Metabolism in Different Tissues in Health and Disease. AB - The cholesterol biosynthesis pathway, also referred to as the mevalonate (MVA) pathway, is responsible for the biosynthesis of two key isoprenoids: farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Post-translational modification of small GTPases by FPP and GGPP has captured much attention due to their potential contribution to cancer, cardiovascular and neurodegenerative diseases. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) catalyzes the conversion of HMG-CoA to MVA, and is the rate-limiting step in the biosynthesis of cholesterol. Statins are HMGCR inhibitors that are used extensively in the treatment of hypercholesterolemia. Inhibitors of the MVA pathway exhibit anti-tumor effects and may reduce cancer incidence and cancer related mortality in humans. In this review, we will focus on the mevalonate cascade and its regulation in cholesterol metabolism as well as polymorphisms of the MVA cascade in cancer development, infectious and cardiovascular disease (CVD). PMID- 26758951 TI - Statins, Mevalonate Pathway and its Intermediate Products in Placental Development and Preeclampsia. AB - The mevalonate pathway synthesizes intermediates and products such as cholesterol and nonsterol isoprenoids that are crucial for cell survival and function. In the human placenta, the prenylation of proteins, rather than cholesterol synthesis, represents the main "metabolic target" of mevalonate metabolism. Major cellular functions depend on isoprenylation including proliferation, migration, metabolism and protein glycosylation that are all crucial for proper development of the embryo and the placenta. Statins are inhibitors of HMG-CoA reductase, the enzyme that catalyzes the reduction of HMG-CoA to mevalonic acid by NADPH. In vitro experiments using human placental explants suggest that statins elicit a detrimental effect on placental growth. However, animal and epidemiologic studies show no increase of fetal malformations after exposure to statins during pregnancy. Moreover, emerging evidence from mouse studies suggest that statins may be useful in preventing serious pregnancy complications like preeclampsia. PMID- 26758952 TI - Mevalonate Cascade and Small Rho GTPase in Spinal Cord Injury. AB - The mevalonate pathway has been extensively studied for its involvement in cholesterol synthesis. Inhibition of this pathway using statins (3-Hydroxy-3 methylglutaryl-coenzyme A reductase inhibitors; HMGR inhibitors) is the primarily selected method due to its cholesterol-lowering effect, making statins the most commonly used (86-94%) cholesterol-lowering drugs in adults. This pathway has several other by-products that are affected by statins including GTPase molecules (guanine triphosphate-binding kinases), such as Rho/Rho-associated coiled kinase (ROCK) kinases, that are implicated in other diseases, including those of the central nervous system (CNS). These molecules control several aspects of neural cell life including axonal growth, cellular migration, and cell death, and therefore, are of increasing interest in the field of spinal cord injury (SCI). Limited regeneration capacity of nerve fibers in adult CNS has been considered the main obstacle for finding a SCI cure. Over the past two decades, the identity of inhibitory factors for regeneration has been widely investigated. It is well established that the Rho/ROCK kinase system is specifically activated by the components of damaged spinal cord tissue, including oligodendrocytes and myelin, as well as extracellular matrix. This has led many groups to hypothesize that statin therapy may in fact enhance the current neurorestorative approaches. In this mini-review, a summary of SCI pathophysiology is discussed and the current literature targeting the regeneration obstacles in SCI are reviewed, with special attention to recent publications of the past decade. In addition, we focus on the current literature involving the use of pharmacological and molecular inhibitors of small GTPase molecules for treatment of neurotrauma. Inhibiting these molecules has been shown to increase neuroprotection, enhance axonal regeneration, and facilitate the implementation of cell replacement therapies. Based upon available literature, the need for clinical trials involving targeted inhibition of GTPase molecules remains strong. Some of these drugs are widely used for other diseases, and therefore re-purposing their application for neurotrauma can be fasttracked. These approaches can potentially modify the inhibitory environment of nervous tissue to allow the spontaneous repair capacity of injured tissue. PMID- 26758953 TI - Mevalonate Pathway and Human Cancers. AB - Mevalonate (MVA) is synthesized from 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) by HMG-CoA reductase (HMG-CoAR). MVA is further metabolized to farnesyl pyrophosphate (FPP), a precursor of cholesterol and sterols. FPP is also converted to geranylgeranyl pyrophosphate, and these lipids are used for post translational modification of proteins that are involved in various aspects of tumor development and progression. Many studies showed that the MVA pathway is up regulated in several cancers such as leukemia, lymphoma, multiple myeloma; as well as breast, hepatic, pancreatic, esophageal and prostate cancers. Several mechanisms may be involved in dysregulation of this pathway. They include p53 mutation, a mutation in HMG-CoAR and sterol-regulatory element binding protein (SREBP) cleavage-activating protein SCAP as its regulator, PKB/Akt activation, decreased AMPK activation, and activation of transcription factors such as: SREBP and HIF-1. Statins as inhibitors of MVA pathway might be useful for cancer prevention and/or treatment through their interactions with essential cellular functions, such as cell proliferation and differentiation. Other inhibitors are also designed for inhibition of this key pathway and their mechanism of action was investigated. In the present review, we will first describe about some inhibitors of MVA, including statins that have been suggested for cancer treatment. We will then discuss about the mechanisms involved in MVA dysregulation, especially in cancer. PMID- 26758954 TI - Role of Hexokinase and VDAC in Neurological Disorders. AB - Several neurological diseases such as bipolar disorders and schizophrenia are linked to impaired brain energy metabolism. A key feature of brain bioenergetics is hexokinase (HK) binding to the outer mitochondrial membrane through the voltage dependent anion channel (VDAC). This has metabolic consequences, with phosphorylation of glucose by mitochondrially bound hexokinase being closely coupled to production of substrate ATP by intramitochondrial oxidative phosphorylation. Additionally, binding of HK to mitochondria inhibits Bax-induced cytochrome c release and apoptosis. Moreover VDAC1 expression level is elevated in cerebellum of patients with Down 's syndrome, while in Alzheimer 's disease, VDAC1 levels are decreased in frontal cortex and VDAC2 elevated in temporal cortex. Thus, understanding the roles of VDAC and HK, either separate or interacting in brain, provides new opportunities and challenges to elucidate pathophysiological mechanisms for future therapeutic strategies. PMID- 26758950 TI - Roles of the Mevalonate Pathway and Cholesterol Trafficking in Pulmonary Host Defense. AB - The mevalonic acid synthesis pathway, cholesterol, and lipoproteins play fundamental roles in lung physiology and the innate immune response. Recent literature investigating roles for cholesterol synthesis and trafficking in host defense against respiratory infection was critically reviewed. The innate immune response and the cholesterol biosynthesis/trafficking network regulate one another, with important implications for pathogen invasion and host defense in the lung. The activation of pathogen recognition receptors and downstream cellular host defense functions are critically sensitive to cellular cholesterol. Conversely, microorganisms can co-opt the sterol/lipoprotein network in order to facilitate replication and evade immunity. Emerging literature suggests the potential for harnessing these insights towards therapeutic development. Given that >50% of adults in the U.S. have serum cholesterol abnormalities and pneumonia remains a leading cause of death, the potential impact of cholesterol on pulmonary host defense is of tremendous public health significance and warrants further mechanistic and translational investigation. PMID- 26758956 TI - Autofocus by Bayes Spectral Entropy Applied to Optical Microscopy. AB - This study introduces a passive autofocus method based on image analysis calculating the Bayes spectral entropy (BSE). The method is applied to optical microscopy and together with the specific construction of the opto-mechanical unit, it allows the analysis of large samples with complicated surfaces without subsampling. This paper will provide a short overview of the relevant theory of calculating the normalized discrete cosine transform when analyzing obtained images, in order to find the BSE measure. Furthermore, it will be shown that the BSE measure is a strong indicator, helping to determine the focal position of the optical microscope. To demonstrate the strength and robustness of the microscope system, tests have been performed using a 1951 USAF test pattern resolution chart determining the in focus position of the microscope. Finally, this method and the optical microscope system is applied to analyze an optical grating (100 lines/mm) demonstrating the detection of the focal position. The paper concludes with an outlook of potential applications of the presented system within quality control and surface analysis. PMID- 26758958 TI - Timescales for exploratory tactical behaviour in football small-sided games. AB - The aim of this study was to identify the dynamics of tactical behaviour emerging on different timescales in football small-sided games and to quantify short- and long-term exploratory behaviour according to the number of opponents. Two teams of four professional male footballers played small-sided games against two different teams with a variable number of opponents (3, 5 and 7). Data were collected using a combination of systematic observation and a non-differential global positioning system (15 Hz). The temporal diversity and structural flexibility of the players were determined by calculating the dynamic overlap order parameter q, entropy and trapping strength. Analysis of the exploratory dynamics revealed two different timescales, forming a different metastable landscape of action for each constraint. Fast dynamics lasted on average a few seconds and consisted of changes in tactical patterns. The long timescale corresponded to the shared tasks of offence and defence lasting tens of seconds. The players' tactical diversity decreased with an increasing number of opponents, especially in defence. Manipulating numerical imbalance is likely to promote changes in the diversity, unpredictability and flexibility of tactical solutions. The fact that the temporally nested structure of constraints shaped the emergence of tactical behaviour provides a new rationale for practice task design. The manipulation of numerical imbalance on the timescale of a few tens of seconds, on which the exploratory behaviour of players saturates, may help coaches to optimise the exploratory efficiency of the small-sided games. PMID- 26758957 TI - Poloxamer 407-based intranasal thermoreversible gel of zolmitriptan-loaded nanoethosomes: formulation, optimization, evaluation and permeation studies. AB - Zolmitriptan is the drug of choice for migraine, but low oral bioavailability (<50%) and recurrence of migraine lead to frequent dosing and increase in associated side effects. Increase in the residence time of drug at the site of drug absorption along with direct nose to brain targeting of zolmitriptan can be a solution to the existing problems. Hence, in the present investigation, thermoreversible intranasal gel of zolmitriptan-loaded nanoethosomes was formulated by using mucoadhesive polymers to increase the residence of the drug into the nasal cavity. The preparation of ethosomes was optimized by using 3(2) factorial design for percent drug entrapment efficiency, vesicle size, zeta potential, and polydispersity index. Optimized formulation E6 showed the vesicle size (171.67 nm) and entrapment efficiency (66%) when compared with the other formulations. Thermoreversible gels prepared by using poloxamer 407 showed the phase transition temperature at 32-33 degrees C which was in line with the nasal physiological temperature. The optimized ethosomes were loaded into the thermoreversible mucoadhesive gel optimized by varying concentrations of poloxamer 407, carbopol 934, HPMC K100, and evaluated for gel strength, gelation temperature, mucoadhesive strength, in vitro drug release, and ex vivo drug permeation, where G3 and G6 were found to be optimized formulations. In vitro drug release was studied by different kinetic models suggested that G3 (n = 0.582) and G6 (n = 0.648) showed Korsemeyer-Peppas (KKP) model indicating non Fickian release profiles. A permeation coefficient of 5.92 and 5.9 ug/cm(2) for G3 and G6, respectively, revealed very little difference in release rate after 24 h between both the formulations. Non-toxic nature of the gels on columnar epithelial cells was confirmed by histopathological evaluation. PMID- 26758959 TI - Hyperuniform disordered terahertz quantum cascade laser. AB - Laser cavities have been realized in various different photonic systems. One of the forefront research fields regards the investigation of the physics of amplifying random optical media. The random laser is a fascinating concept because, further to the fundamental research investigating light transport into complex media, it allows us to obtain non-conventional spectral distribution and angular beam emission patterns not achievable with conventional approaches. Even more intriguing is the possibility to engineer a priori the optical properties of a disordered distribution in an amplifying medium. We demonstrate here the realization of a terahertz quantum cascade laser in an isotropic hyperuniform disordered distribution exhibiting unique features, such as the presence of a photonic band gap, low threshold current density, unconventional angular emission and optical bistability. PMID- 26758960 TI - Erectile dysfunction is a marker for obstructive sleep apnea. AB - PURPOSE: To investigate the prevalence of erectile dysfunction (ED) in patients with obstructive sleep apnea (OSA) with and without any other comorbidities. METHODS: The patient group was newly diagnosed as having OSA (apnea-hypopnea index [AHI] > 5/h) using a polysomnographic examination. A group of subjects with simple snoring were included into the control group. Clinically relevant comorbidities were systematically assessed in face-to-face interviews. All patients were asked to complete the 15-item International Index of Erectile Function (IIEF-15) questionnaire for the evaluation of ED. The patients with OSA and ED were evaluated according to these comorbidities. RESULTS: Of the 94 patients, 39 patients were excluded because of severe diseases. OSA was observed in 38 (69.1%) of the 55 patients. ED was seen in 24 (63.2%) patients with OSA, and in 8 (47.1%) patients without OSA (p > 0.05). There were no statistical differences between the groups' ages, IIEF scores, and body mass index (BMI) scores. There were statistically significant differences between the groups' AHI scores (p < 0.05). There was a significant correlation between the groups' AHI scores, BMI, and age (p < 0.05). There was no statistically significant difference in patients with OSA, with and without comorbidity in terms of ED. CONCLUSION: The rate of ED was higher in patients with OSA who had no other comorbidities. Therefore, ED can be a sensitive marker of OSA. PMID- 26758955 TI - Functional nucleic acid-based hydrogels for bioanalytical and biomedical applications. AB - Hydrogels are crosslinked hydrophilic polymers that can absorb a large amount of water. By their hydrophilic, biocompatible and highly tunable nature, hydrogels can be tailored for applications in bioanalysis and biomedicine. Of particular interest are DNA-based hydrogels owing to the unique features of nucleic acids. Since the discovery of the DNA double helical structure, interest in DNA has expanded beyond its genetic role to applications in nanotechnology and materials science. In particular, DNA-based hydrogels present such remarkable features as stability, flexibility, precise programmability, stimuli-responsive DNA conformations, facile synthesis and modification. Moreover, functional nucleic acids (FNAs) have allowed the construction of hydrogels based on aptamers, DNAzymes, i-motif nanostructures, siRNAs and CpG oligodeoxynucleotides to provide additional molecular recognition, catalytic activities and therapeutic potential, making them key players in biological analysis and biomedical applications. To date, a variety of applications have been demonstrated with FNA-based hydrogels, including biosensing, environmental analysis, controlled drug release, cell adhesion and targeted cancer therapy. In this review, we focus on advances in the development of FNA-based hydrogels, which have fully incorporated both the unique features of FNAs and DNA-based hydrogels. We first introduce different strategies for constructing DNA-based hydrogels. Subsequently, various types of FNAs and the most recent developments of FNA-based hydrogels for bioanalytical and biomedical applications are described with some selected examples. Finally, the review provides an insight into the remaining challenges and future perspectives of FNA based hydrogels. PMID- 26758961 TI - Role of snow and cold environment in the fate and effects of nanoparticles and select organic pollutants from gasoline engine exhaust. AB - Exposure to vehicle exhaust can drive up to 70 % of excess lifetime cancer incidences due to air pollution in urban environments. Little is known about how exhaust-derived particles and organic pollutants, implicated in adverse health effects, are affected by freezing ambient temperatures and the presence of snow. Airborne particles and (semi)volatile organic constituents in dilute exhaust were studied in a novel low-temperature environmental chamber system containing natural urban snow under controlled cold environmental conditions. The presence of snow altered the aerosol size distributions of dilute exhaust in the 10 nm to 10 MUm range and decreased the number density of the nanoparticulate (<100 nm) fraction of exhaust aerosols, yet increased the 100-150 nm fraction. Upon 1 hour exhaust exposure, the total organic carbon increased in the natural snow from 0.218 +/- 0.014 to 0.539 +/- 0.009 mg L(-1), and over 40 additional (semi)volatile organic compounds and a large number of exhaust-derived carbonaceous and likely organic particles were identified. The concentrations of benzene, toluene, ethylbenzene, and xylenes (BTEX) increased from near the detection limit to 52.48, 379.5, 242.7, and 238.1 MUg kg(-1) (+/- 10 %), respectively, indicating the absorption of exhaust-derived toxic organic compounds by snow. The alteration of exhaust aerosol size distributions at freezing temperatures and in the presence of snow, accompanied by changes of the organic pollutant content in snow, has potential to alter health effects of human exposure to vehicle exhaust. PMID- 26758962 TI - Prevalence and care index of early childhood caries in mainland China: evidence from epidemiological surveys during 1987-2013. AB - Early childhood caries (ECC) is the most common chronic disease in young children. Its reported prevalence varies greatly across China. This systematic review aimed to explore the epidemiological characteristics of ECC in mainland China from 1987 to 2013. In total, 102 articles were included. The pooled national prevalence and care index (ft/dmft%) for ECC were 65.5% and 3.6%, respectively. The overall ECC prevalence declined from 77.9% during 1987-1994 to 56.4% during 2010-2013. The pooled ECC prevalence for children aged 1-6 years was 0.3%, 17.3%, 40.2%, 54.4%, 66.1%, and 70.7%, respectively. There was no significant difference in prevalence between boys (59.1%) and girls (58.9%); and the care index was also similar (8.1% versus 7.7%). Slightly higher ECC prevalence was observed in rural areas (63.5%) compared with urban areas (59.5%) (RR = 1.08, 95% CI: 1.02-1.14); but a much higher care index was reported in urban children (6.0%) than their rural counterparts (1.6%) (RR = 3.68, 95% CI: 2.54-5.35). The 2006-2013 map of ECC prevalence among 5-year-olds showed wide geographic variations across China. Four adjacent provinces, including Sichuan, Chongqing, Hubei, and Shaanxi, constituted the areas with the lowest ECC prevalence in mainland China. PMID- 26758967 TI - Cobalt PNC(NHC) 'pincers': ligand dearomatisation, formation of dinuclear and N2 complexes and promotion of C-H activation. AB - Studies of ligand dearomatisation in cobalt phosphino-picoline N-heterocyclic carbene (PNC(NHC))-type pincers have revealed the formation of dinuclear cobalt complexes by either side-arm metalation or C-H activation at the NHC backbone; in the latter case, the product complex, featuring an 'anionic dicarbene', originated from a dearomatised Co(I)-N2 complex. PMID- 26758963 TI - Coordinated activation of distinct Ca(2+) sources and metabotropic glutamate receptors encodes Hebbian synaptic plasticity. AB - At glutamatergic synapses, induction of associative synaptic plasticity requires time-correlated presynaptic and postsynaptic spikes to activate postsynaptic NMDA receptors (NMDARs). The magnitudes of the ensuing Ca2+ transients within dendritic spines are thought to determine the amplitude and direction of synaptic change. In contrast, we show that at mature hippocampal Schaffer collateral synapses the magnitudes of Ca2+ transients during plasticity induction do not match this rule. Indeed, LTP induced by time-correlated pre- and postsynaptic spikes instead requires the sequential activation of NMDARs followed by voltage sensitive Ca2+ channels within dendritic spines. Furthermore, LTP requires inhibition of SK channels by mGluR1, which removes a negative feedback loop that constitutively regulates NMDARs. Therefore, rather than being controlled simply by the magnitude of the postsynaptic calcium rise, LTP induction requires the coordinated activation of distinct sources of Ca2+ and mGluR1-dependent facilitation of NMDAR function. PMID- 26758964 TI - Clinical and Genetic Characteristics, Management and Long-Term Follow-Up of Turkish Patients with Congenital Hyperinsulinism. AB - OBJECTIVE: Mutations in the KATP channel genes is the most common cause of congenital hyperinsulinism (CHI) of infancy. Our aim was to report the clinical and genetic characteristics, treatment modalities, and long-term prognosis of patients with CHI. METHODS: Clinical and biochemical findings, operation procedures, and results of genetic analysis were retrospectively evaluated in 22 CHI patients from two pediatric endocrine centers in Turkey. RESULTS: Seven of the patients were born large for gestational age. Hypoglycemia was diagnosed within the first 24 hours of life in 9 patients and treatment with diazoxide (n=21) and/or somatostatin (n=8) had been attempted. Seven patients (31.8%) were unresponsive to medical treatment and underwent pancreatectomy. Histological examination of the pancreas confirmed diffuse disease in 6 patients. Diabetes developed in 3 patients following pancreatectomy (10 years, 2.5 years, and immediately after operation). The remaining four patients had neither recurrence of CHI nor of diabetes during the 3.67+/-0.7 years of follow-up. Sequence analysis identified mutations in 12 out of 19 patients (63%). Mutations in the ABCC8 gene were the most common finding and were found in 6 out of 7 patients who underwent pancreatectomy. Other mutations included a paternally inherited KCNJ11 mutation, a homozygous HADH mutation, and a heterozygous GLUD1 mutation. CONCLUSION: Mutations in the ABCC8 gene were the most common cause of CHI in our cohort. These mutations were identified in 85% of patients who underwent pancreatectomy. The development of diabetes mellitus after pancreatectomy may occur at any age and these patients should be screened regularly. PMID- 26758968 TI - How do patients feel about taking part in clinical trials in emergency care? AB - BACKGROUND: There is little in-depth research into how patients feel about emergency medical trials, and what influences these feelings. OBJECTIVES: To investigate patients' feelings on taking part in emergency medical research, particularly trials conducted without prospective consent. METHODS: Seventeen inpatients, all recently admitted with a medical emergency, were interviewed. Questions focused on feelings on taking part in hypothetical trials, particularly trials conducted with deferred consent. RESULTS: Five main themes were identified. Level of trust in the medical profession-high levels of trust tended to correlate with willingness to participate in trials. Previous bad healthcare experiences tended to diminish trust. Concerns for personal well-being-patients identified a conflict between aversion to unknown side effects and desire for access to newer and potentially better treatments. Some would be less inclined to participate in research if they were severely unwell, some more so. Altruism-many cited the importance of helping to advance medical knowledge and of 'giving back to the health service'. Concerns over autonomy-some felt that deferred consent was a violation of personal autonomy. Uncertainty-many patients seemed to struggle to understand the more complex concepts discussed. CONCLUSIONS: Patients are broadly trusting, and open to participating in emergency medical trials, but want to be kept as informed as possible throughout the process. Willingness may be improved by providing more complete explanations, although this may be limited by the complexity of relevant concepts. Good communication and improved public understanding of clinical trials would likely increase acceptance of emergency care research. PMID- 26758965 TI - Viewing 3D TV over two months produces no discernible effects on balance, coordination or eyesight. AB - With the rise in stereoscopic 3D media, there has been concern that viewing stereoscopic 3D (S3D) content could have long-term adverse effects, but little data are available. In the first study to address this, 28 households who did not currently own a 3D TV were given a new TV set, either S3D or 2D. The 116 members of these households all underwent tests of balance, coordination and eyesight, both before they received their new TV set, and after they had owned it for 2 months. We did not detect any changes which appeared to be associated with viewing 3D TV. We conclude that viewing 3D TV does not produce detectable effects on balance, coordination or eyesight over the timescale studied. Practitioner Summary: Concern has been expressed over possible long-term effects of stereoscopic 3D (S3D). We looked for any changes in vision, balance and coordination associated with normal home S3D TV viewing in the 2 months after first acquiring a 3D TV. We find no evidence of any changes over this timescale. PMID- 26758969 TI - Improving "lab-on-a-chip" techniques using biomedical nanotechnology: a review. AB - Nanotechnology and its applications in biomedical sciences principally in molecular nanodiagnostics are known as nanomolecular diagnostics, which provides new options for clinical nanodiagnostic techniques. Molecular nanodiagnostics are a critical role in the development of personalized medicine, which features point of care performance of diagnostic procedure. This can to check patients at point of-care facilities or in remote or resource-poor locations, therefore reducing checking time from days to minutes. In this review, applications of nanotechnology suited to biomedicine are discussed in two main class: biomedical applications for use inside (such as drugs, diagnostic techniques, prostheses, and implants) and outside the body (such as "lab-on-a-chip" techniques). A lab-on a-chip (LOC) is a tool that incorporates numerous laboratory tasks onto a small device, usually only millimeters or centimeters in size. Finally, are discussed the applications of biomedical nanotechnology in improving "lab-on-a-chip" techniques. PMID- 26758970 TI - [Reference ranges of insulin, insulin like growth factor-1 and adrenocorticotropic hormone in ponies]. AB - OBJECTIVES: The aim of this study was to validate a chemiluminescence immunometric assay using the IMMULITE 2000(r) for the determination of adrenocorticotropic hormone (ACTH), insulin and insulin-like growth factor-1 (IGF 1) from which reference ranges were calculated for ponies. MATERIAL AND METHODS: Blood samples of 130 ponies aged 3-32 years were collected in the afternoon. The reference ranges were calculated according to the Guideline EP28-A3C of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) from 2010. RESULTS: The determined intraday precision for insulin was 3.28%, for ACTH 3.35% and for IGF-1 1.84%. The interday precision (insulin: 3.45%; IGF-1: 2.89%; ACTH: 9.77%) was determined on three consecutive days, where the samples were stored at 4 degrees C. There was no significant loss of insulin activity nor of ACTH or IGF-1 concentration during this time. The reference ranges of insulin and IGF-1 (2.0-21.2 mU/l and 50.2-357.2 mU/l, respectively) were age independent, whereas for ACTH, an age-dependent reference range was established. Ponies aged 3-12 years had a significantly lower reference range (4.2-19.8 pg/ml) than ponies aged 13-32 years (5.0-22.6 pg/ml). CONCLUSION: The method used is suitable for the determination of ACTH, IGF-1 and insulin in serum of ponies, but the lowest detection limit for insulin is 2.0 mU/l. CLINICAL RELEVANCE: The calculated reference ranges of insulin and ACTH are helpful for the diagnosis and clinical monitoring of equine metabolic syndrome and pituitary pars intermedia dysfunction (PPID). PMID- 26758971 TI - Escherichia coli strain Nissle 1917 ameliorates experimental colitis by modulating intestinal permeability, the inflammatory response and clinical signs in a faecal transplantation model. AB - Inflammatory bowel diseases (IBDs) are a group of inflammatory conditions of the gut that include ulcerative colitis and Crohn's disease. Probiotics are live micro-organisms that may be used as adjuvant therapy for patients with IBD. The aim of this study was to evaluate the effect of prophylactic ingestion of Escherichia coli strain Nissle 1917 (EcN) in a murine model of colitis. For induction of colitis, mice were given a 3.5% dextran sodium sulfate (DSS) solution for 7 days in drinking water. EcN administration to mice subjected to DSS-induced colitis resulted in significant reduction in clinical and histopathological signs of disease and preservation of intestinal permeability. We observed reduced inflammation, as assessed by reduced levels of neutrophils, eosinophils, chemokines and cytokines. We observed an increase in the number of regulatory T-cells in Peyer's patches. Germ-free mice received faecal content from control or EcN-treated mice and were then subjected to DSS-induced colitis. We observed protection from colitis in animals that were colonized with faecal content from EcN-treated mice. These results suggest that preventative oral administration of EcN or faecal microbiota transplantation with EcN-containing microbiota ameliorates DSS-induced colitis by modifying inflammatory responsiveness to DSS. PMID- 26758972 TI - ENETS Consensus Guidelines Update for Neuroendocrine Neoplasms of the Jejunum and Ileum. PMID- 26758974 TI - Inattentional blindness in older adults: Effects of attentional set and to-be ignored distractors. AB - Inattentional blindness (IB) involves failing to detect an unexpected visual stimulus while undertaking another task. Previous research has predominantly investigated IB using young adult samples, with few studies exploring whether or how an observer's age affects their detection of unexpected events. To help address this gap, we compared younger adults (18-25 years of age) and older adults (60-80 years of age) on two IB tasks: one dynamic, one static. In the static task, older age was associated with substantially increased IB rates: 89 % for older adults versus 5 % for younger adults. In the dynamic task, we systematically manipulated the presence of to-be-ignored distractors and whether the unexpected stimulus color matched the observers' attentional set. We found a main effect of age on IB: As in the static task, older age was associated with increased IB rates (38 % for older adults vs. 8 % for younger adults). The presence of to-be-ignored distractors and attentional set mismatch interacted to substantially increase IB rates, but age did not interact with either factor. Overall, the results indicate that older age is associated with large increases in IB rates across a range of tasks. The pattern of results is consistent with attentional capacity models of cognitive aging, suggesting that older adults' reduced cognitive resources result in failure to consciously process stimuli that are inconsistent with their attentional set. PMID- 26758975 TI - Action-specific perception of speed is independent of attention. AB - According to the action-specific account of perception, a perceiver's ability to act influences how the environment is perceived. For example, in a computer-based task, participants perceive fish as moving faster when they use a smaller net, and are thus less effective at catching the fish (Witt & Sugovic, 2013a). Here, we examined the degree to which attention may influence perceptual judgments by requiring participants to engage in a secondary task that directed their attention either toward (Exp. 1) or away from (Exp. 2) the to-be-caught fish. Though perceived fish speed was influenced by participants' catching performance replicating previous results-attentional allocation did not impact this relationship between catching performance and perceived fish speed. The present results suggest that action directly influences spatial perception, rather than exerting indirect effects via attentional processes. PMID- 26758973 TI - Distribution of RET Mutations and Evaluation of Treatment Approaches in Hereditary Medullary Thyroid Carcinoma in Turkey. AB - OBJECTIVE: This retrospective multicenter study, centrally conducted and supported by the Society of Endocrinology and Metabolism of Turkey, aimed to evaluate the impact of free RET proto-oncogene testing in medullary thyroid carcinoma (MTC) patients. Surgical timing, adequacy of the treatment, and frequency of prophylactic thyroidectomy (PTx) in mutation carriers were also assessed. METHODS: Genetic testing for MTC and pheochromocytoma was conducted between July 2008 and January 2012 in 512 patients. Application forms and RET mutation analyses of these patients whose blood samples were sent from various centers around Turkey were assessed retrospectively. An evaluation form was sent to the physicians of the eligible 319 patients who had confirmed sporadic MTC, familial MTC (FMTC), multiple endocrine neoplasia type 2 (MEN2), or who were mutation carriers. Physicians were asked to give information about the surgical history, latest calcitonin levels, morbidity, mortality, genetic screening, and PTx among family members. Twenty-five centers responded by filling in the forms of 192 patients. RESULTS: Among the 319 patients, RET mutation was detected in 71 (22.3%). Cys634Arg mutation was the most prevalent mutation (43.7%), followed by Val804Met in 18 patients (25.4%), and Cys634Tyr in 6 patients (8.5%). Among 192 MTC patients, the diagnosis was sporadic MTC in 146 (76.4%), FMTC in 14 (7.3%), MEN2A in 15 patients (7.9%), and MEN2B in one patient. The number of mutation carriers among 154 apparently sporadic MTC patients was 8 (5.2%). Ten patients were submitted to PTx out of twenty-four mutation carriers at a mean age of 35+/ 19 years. CONCLUSION: Turkish people have a similar RET proto-oncogene mutation distribution when compared to other Mediterranean countries. Despite free RET gene testing, the number of the PTx in Turkey is limited and relatively late in the life span of the carriers. This is mainly due to patient and family incompliance and incomplete family counselling. PMID- 26758976 TI - Effect of different directions of attentional shift on inhibition of return in three-dimensional space. AB - When attention is oriented to a peripheral cue, the processing of nearby stimuli is facilitated. This brief period of facilitation is followed by a long-lasting inhibitory effect, during which there is a delayed response to stimuli presented at a previously cued location. Although the mechanisms underlying the facilitatory effect of attentional orienting/reorienting in three-dimensional (3 D) space have been documented, there is not yet consensus as to how attention orients/reorients in depth during the later inhibitory phase (i.e., inhibition of return [IOR]). In the present study, by incorporating the Posner exogenous cueing paradigm into a virtual 3-D environment, we aimed to investigate whether an IOR effect occurs when attention orients and reorients at the uncued depth in the same hemispace, and whether the IOR effects are the same or different when attention orients/reorients along different trajectories in 3-D space. Our results showed asymmetrical spatial IOR effects when attention was oriented/reoriented at the uncued depth in the same hemispace. Spatial IOR was depth-specific when targets appeared in the near depth plane, whereas it was not depth-specific when targets appeared in the far depth plane. Apart from these results, we also found that attention oriented/reoriented at the same depth but in a different hemispace experienced a reduction in IOR size, thus indicating that the direction-specific spatial IOR mechanisms when attention orients/reorients along different trajectories are different. Taken together, our results suggest that spatial IOR is not entirely "depth-blind," and that the ecological importance of the 3-D world influences the direction of attentional shifts of spatial IOR in 3-D space. PMID- 26758978 TI - Invited commentary: Evidence-based practise and physical therapy. PMID- 26758977 TI - The novel RAGE interactor PRAK is associated with autophagy signaling in Alzheimer's disease pathogenesis. AB - BACKGROUND: The receptor for advanced glycation end products (RAGE) has been found to interact with amyloid beta (Abeta). Although RAGE does not have any kinase motifs in its cytosolic domain, the interaction between RAGE and Abeta triggers multiple cellular signaling involved in Alzheimer's disease (AD). However, the mechanism of signal transduction by RAGE remains still unknown. Therefore, identifying binding proteins of RAGE may provide novel therapeutic targets for AD. RESULTS: In this study, we identified p38-regulated/activated protein kinase (PRAK) as a novel RAGE interacting molecule. To investigate the effect of Abeta on PRAK mediated RAGE signaling pathway, we treated SH-SY5Y cells with monomeric form of Abeta. We demonstrated that Abeta significantly increased the phosphorylation of PRAK as well as the interaction between PRAK and RAGE. We showed that knockdown of PRAK rescued mTORC1 inactivation induced by Abeta treatment and decreased the formation of Abeta-induced autophagosome. CONCLUSIONS: We provide evidence that PRAK plays a critical role in AD pathology as a key interactor of RAGE. Thus, our data suggest that PRAK might be a potential therapeutic target of AD involved in RAGE-mediated cell signaling induced by Abeta. PMID- 26758980 TI - Cancer rehabilitation in Austria--aspects of Physical Medicine and Rehabilitation. AB - In Austria, cancer rehabilitation is an important issue in the management of cancer patients. Survival rates and survival time of cancer patients are increasing, and cancer rehabilitation is an important part in the treatment and care of cancer patients with the goal to improve functional status, quality of life, and (social) participation. Today, in Austria there are approximately 600 beds for inpatient rehabilitation. The field of outpatient rehabilitation will maybe be expanded after evaluating the existing pilot projects. Beside other specialities, the field of Physical Medicine and Rehabilitation (PM&R) plays an important role in cancer rehabilitation. In cancer rehabilitation, especially activating modalities from PM&R such as exercise are very important and well accepted parts to improve functional status, quality of life, and participation of patients. PMID- 26758981 TI - Aspects of physical medicine and rehabilitation in geriatrics. AB - Specialists in physical medicine and rehabilitation are important partners during the ageing process: health promotion and prevention for fit elderly people, training and rehabilitation for prefrail people and support for frail people focusing on usage of what is left and dignity in the latest period of life. The main focus is the relationship between IC diagnoses and functioning in everyday life based on the International Classification of Functioning (ICF). The diseases lead to possible treatments; functioning shows the importance of rehabilitative strategies in a team approach. Physiatrists are experts on this complex issue.The main goal of rehabilitative strategies during life course is to maintain function, improve quality of life and delay dependency and need of care.Three settings are chosen to show the different aspects of physical medicine and rehabilitation: health promotion and prevention, rehabilitation and palliative rehabilitative procedures in long-term care. The non-pharmaceutical treatment of pain, the geriatric assessment, knowledge in discharge management and team communications are important skills. PMID- 26758979 TI - Pharmacological therapies for Angelman syndrome. AB - Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by a loss of the maternally inherited UBE3A; the paternal UBE3A is silenced in neurons by a mechanism involving an antisense transcript (UBE3A-AS). We reviewed the published information on clinical trials that have been completed as well as the publicly available information on ongoing trials of therapies for AS. Attempts at hypermethylating the maternal locus through dietary compounds were ineffective. The results of a clinical trial using minocycline as a matrix metalloproteinase-9 inhibitor were inconclusive; another clinical trial is underway. Findings from a clinical trial using L-dopa to alter phosphorylation of calcium/calmodulin dependent kinase II are awaited. Topoisomerase inhibitors and antisense oligonucleotides are being developed to directly inhibit UBE3A-AS. Other strategies targeting specific pathways are briefly discussed. We also reviewed the medications that are currently used to treat seizures and sleep disturbances, which are two of the more debilitating manifestations of AS. PMID- 26758982 TI - Aspects of physical medicine and rehabilitation in the treatment of deconditioned patients in the acute care setting: the role of skeletal muscle. AB - Skeletal muscles are essential for movement as well as for survival. Knowledge about the organ skeletal muscle is underrepresented. Ageing and multiple chronic diseases are accompanied by loss of muscle mass, termed "muscle wasting". Nevertheless, muscles are one of the target organs within the rehabilitation process. This review highlights the role of skeletal muscles from various aspects, diagnostic procedures to quantify muscle mass and strength and, most importantly, lists countermeasures to muscle wasting. Although structured and progressive strength training is the cornerstone in the treatment of muscle wasting, several other methods exist to slow down or reverse the process of muscle wasting. Among them are neuromuscular electrical stimulation and alternative exercise modes, positioning, stretching and, as an emerging field, drug therapy. PMID- 26758984 TI - Early onset epileptic encephalopathy or genetically determined encephalopathy with early onset epilepsy? Lessons learned from TSC. AB - BACKGROUND: In tuberous sclerosis complex (TSC) a relationship has been shown between early and refractory seizures and intellectual disability. However, it is uncertain whether epilepsy in TSC is simply a marker in infants who are destined to develop an encephalopathic process or if seizures play a causal role in developing an encephalopathy. METHODS: This paper summarizes the key points discussed during a European TSC workshop held in Rome, and reviews the experimental and clinical evidence in support of the two theories. RESULTS/CONCLUSION: There are many factors that influence the appearance of both early seizure onset and the encephalopathy resulting in neurodevelopmental deficits. Experimental studies show that as a consequence of the TSC genes mutation, mammalian target of Rapamycin (mTOR) overactivation determines an alteration in cellular morphology with cytomegalic neurons, altered synaptogenesis and an imbalance between excitation/inhibition, thus providing a likely neuroanatomical substrate for the early appearance of refractory seizures and for the encephalopathic process. At the clinical level, early signs of altered developmental trajectories are often unrecognized before 12 months of age. Evidence from experimental research shows that encephalopathy in TSC might have a genetic cause, and mTOR activation caused by TSC gene mutation can be directly responsible for the early appearance of seizures and encephalopathy. PMID- 26758985 TI - Molecular detection of Crimean-Congo haemorrhagic fever virus in ticks collected from infested livestock populations in a New Endemic Area, South of Iran. AB - OBJECTIVE: Crimean-Congo haemorrhagic fever (CCHF) is a viral zoonotic disease with potentially fatal systemic effects on man. We aimed to determine the presence of CCHF virus among collected ticks from domestic livestock from October 2012 to September 2013. METHODS: A total of 1245 hard and soft ticks were collected from naturally infested ruminants in Marvdasht County, Fars Province, south of Iran. Nine tick species and one unidentified species in four disparate genera were detected. A total of 200 ticks were randomly selected and analysed by reverse transcription-polymerase chain reaction (RT-PCR) for the presence of CCHF virus genome. RESULTS: The viral genome was detected in 4.5% (9 samples) of the studied tick population. The infected ticks belonged to the species of Hyalomma marginatum' Hyalomma anatolicum and Rhipicephalus sanguineus. The viruses detected in these three tick species were clustered in the same lineage as Matin and SR3 strains in Pakistan and some other Iranian strains. These results indicate that the ticks were wildly infected with a genetically closely related CCHF virus in the region. CONCLUSION: Regular controls and monitoring of livestock to reduce the dispersion of ticks and providing information to those involved in high-risk occupations are urgently required. PMID- 26758988 TI - Critical Red Components for Next-Generation White LEDs. AB - Warm white LEDs with a high color rendering index and a low correlated color temperature have undergone rapid development. In this regard, red-emitting materials-such as fluoride phosphors, namely, A2MF6:Mn(4+) (A = K, Na, and Cs; M = Si, Ge, Zr, Sn, and Ti) and XSiF6:Mn(4+) (X = Ba or Zn), nitridoaluminate phosphor (Sr[LiAl3N4]:Eu(2+)), and nanocrystals of cesium lead iodide perovskite (CsPbI3)-have been extensively investigated recently. These compounds generate narrow emissions in the visible red spectral region that are highly perceived by the human eye and lead to excellent chromatic saturation of the red spectra. This paper describes the structure, luminescence properties, morphologies, thermal features, and moisture resistance of critical red components, as well as their limitations for practical applications. This Perspective also provides a basis for future development and scientific challenges in optical research. PMID- 26758987 TI - Effects of chromium-enriched Bacillus subtilis KT260179 supplementation on growth performance, caecal microbiology, tissue chromium level, insulin receptor expression and plasma biochemical profile of mice under heat stress. AB - The aim of this study was to investigate the effect of providing supplementary Cr enriched Bacillus subtilis (CEBS) to mice with regard to their growth performance, caecal microbiology, tissue Cr concentration, insulin receptor (IR) expression and plasma biochemical profile. A total of ninety-six Kunming strain mice were allocated to four different groups: control, CEBS, inorganic Cr and B. subtilis. After 15 d of treatment, mice that received CEBS or normal B. subtilis had higher body weights than control mice, and after 30 d mice given either CEBS or B. subtilis had greater body weights than control mice or those given inorganic Cr. The concentration of Cr in tissues (heart, liver, spleen, kidney and skeletal muscle) increased after CEBS supplementation. B. subtilis and CEBS supplementation caused a significant increase in the numbers of Lactobacillus and Bifidobacterium in the caecum, whereas the numbers of Escherichia coli and Staphylococcus decreased significantly compared with the control. The levels of IR RNA and protein in skeletal muscles increased significantly. Plasma glucose, total cholesterol, TAG and LDL-cholesterol levels declined significantly in the CEBS group compared with the control group, whereas plasma insulin and HDL cholesterol levels increased significantly. In conclusion, CEBS supplementation enhanced the regulation of body growth, increased tissue organic Cr concentrations, altered caecal microbiota and enhanced IR expression to produce significant changes in plasma biochemistry. PMID- 26758986 TI - Biological impact of xeno-free chemically defined cryopreservation medium on amniotic epithelial cells. AB - BACKGROUND: Amnion-derived stem cells have been proposed for cell replacement therapy and tissue regeneration. An easily accessible cell source, the placenta, allows us to potentially establish a bio-bank of cells for immunotype matched clinical applications. Several xeno-free (XF) cryopreservation media are currently available for pluripotent stem cells, however, these media have not yet been evaluated for the cryopreservation of amnion-derived stem cells. METHODS: Human amniotic epithelial cells were collected using standard protocols, and stored at -160 degrees C in one of five commercially available media. Cells frozen in standard media containing fetal bovine serum served as controls. Cells were then thawed, and evaluated for viability, mitochondrial membrane stability, and senescence status. Quantitative real time PCR was utilized to assess for expression of stem cell genes, and flow cytometry was used to identify the stem cell surface markers. RESULTS: Cell recovery and repopulation assays indicated no significant difference between XF media versus standard cryopreservation medium. In addition, no impact was observed on the senescence status, the cytostructural or mitochondrial morphology between the tested cryopreservation media. Differences were observed on the expression of stem cell marker genes (OCT4, SOX2, and NANOG) and a cell surface marker (TRA1-60) following cryopreservation in different chemically defined XF media, however, these were not statistically significant. CONCLUSIONS: Xeno-free cryopreservation of human amnion-derived stem cells is feasible and can be standardized to establish a bio-bank with human amnion-derived stem cells for future clinical application. Optimization of this media may allow for improved preservation of stem cell-like characteristics. PMID- 26758983 TI - Effects of P2Y12 receptor antagonists beyond platelet inhibition--comparison of ticagrelor with thienopyridines. AB - The effect and clinical benefit of P2Y12 receptor antagonists may not be limited to platelet inhibition and the prevention of arterial thrombus formation. Potential additional effects include reduction of the pro-inflammatory role of activated platelets and effects related to P2Y12 receptor inhibition on other cells apart from platelets. P2Y12 receptor antagonists, thienopyridines and ticagrelor, differ in their mode of action being prodrugs instead of direct acting and irreversibly instead of reversibly binding to P2Y12 . These key differences may provide different potential when it comes to additional effects. In addition to P2Y12 receptor blockade, ticagrelor is unique in having the only well-documented additional target of inhibition, the equilibrative nucleoside transporter 1. The current review will address the effects of P2Y12 receptor antagonists beyond platelets and the protection against arterial thrombosis. The discussion will include the potential for thienopyridines and ticagrelor to mediate anti-inflammatory effects, to conserve vascular function, to affect atherosclerosis, to provide cardioprotection and to induce dyspnea. PMID- 26758990 TI - In memory of Marcos Vidal (1974-2016). AB - With the untimely death of Marcos Vidal, we have lost a good friend and a creative, brilliant colleague who made important contributions to the field of cancer biology through fruit fly research. Marcos began his research into Drosophila at Ross Cagan's laboratory in 2003, first at Washington University in St Louis and later at Mount Sinai Hospital in New York. In 2009 Marcos was appointed as Research Group Leader at the Beatson Institute for Cancer Research in Glasgow. PMID- 26758989 TI - Safety and diagnostic value of brain biopsy in HIV patients: a case series and meta-analysis of 1209 patients. AB - Early brain biopsy may be indicated in HIV patients with focal brain lesion. This study aimed to evaluate and compare the safety and diagnostic value of brain biopsy in HIV patients in the pre-highly active antiretroviral therapy (HAART) versus post-HAART era via meta-analysis. Appropriate studies were identified per search criteria. The local database was retrospectively reviewed to select a similar patient cohort. Patient demographics, brain biopsy technique, histopathology and patient outcomes were extracted from each study. Study specific outcomes were combined per random-effects model. Outcomes were compared between the pre-HAART and post-HAART era. Correlations between outcomes and baseline characteristics were assessed via meta-regression analysis. The proportions of histopathological diagnosis were tabulated and compared between the pre- and post-HAART era. Survival analysis was performed for patients in the post-HAART era. A total of 26 studies (including the local database) with 1209 patients were included in this meta-analysis. The most common indications for brain biopsy were diagnosis unlikely to be toxoplasmosis (n=8, 42.1%), focal brain lesion (n=5, 26.3%) or both (n=3, 15.8%). The weighted proportions for diagnostic success were 92% (95% CI 90.0% to 93.8%), change in management 57.7% (45.9% to 69.1%) and clinical improvement 36.6% (26.3% to 47.5%). Morbidity and mortality were 5.7% (3.6% to 8.3%) and 0.9% (0.3% to 1.9%), respectively. Diagnostic success rate was significantly higher in the post-HAART than the pre HAART era (97.5% vs 91.9%, p=0.047). The odds ratio (OR) for diagnostic success in patients with contrast-enhanced lesions was 2.54 ((1.25 to 5.15), p<0.01). The median survival for HIV patients who underwent biopsy in the post-HAART era was 225 days (90-2446). Brain biopsy in HIV patients is safe with high diagnostic yield. Early brain biopsy should be considered in patients without classic presentation of toxoplasmosis encephalitis. PMID- 26758991 TI - Buprenorphine--the unique opioid adjuvant in regional anesthesia. AB - Regional anesthesia techniques are commonly used for many surgical procedures alone or as an addition to general anesthesia, because they offer many advantages over general anesthesia. Unfortunately these techniques are partially limited by the time of action of local anesthetics. One of the methods of overcoming this limitation is adding to the local anesthetic solution additional drug--so called adjuvant. Among many adjuvants to local anesthetic drugs tested so far one seems to be particularly interesting--buprenorphine. The aim of this paper is to present pharmacological background for using buprenorphine for regional anesthesia and to review clinical trials of using buprenorphine for all regional anesthesia techniques: spinal and epidural anesthesia, peripheral nerves blocks, local anesthesia and intravenous regional anesthesia. PMID- 26758992 TI - Aneuploidy as a mechanism of adaptation to telomerase insufficiency. AB - Cells' survival is determined by their ability to adapt to constantly changing environment. Adaptation responses involve global changes in transcription, translation, and posttranslational modifications of proteins. In recent years, karyotype changes in adapting populations of single cell organisms have been reported in a number of studies. More recently, we have described aneuploidy as an adaptation mechanism used by populations of budding yeast Saccharomyces cerevisiae to survive telomerase insufficiency induced by elevated growth temperature. Genetic evidence suggests that telomerase insufficiency is caused by decreased levels of the telomerase catalytic subunit Est2. Here, we present experiments arguing that the underlying cause of this phenomenon may be within the telomerase RNA TLC1: changes in the expression of TLC1 as well as mutations in the TLC1 template region affect telomere length equilibrium and the temperature threshold for the induction of telomerase insufficiency. We discuss what lies at the root of telomerase insufficiency, how cell populations overcome it through aneuploidy and whether reversible aneuploidy could be an adaptation mechanism for a variety of environmental stresses. PMID- 26758994 TI - Pseudo-dominant inheritance in Wilson's disease. PMID- 26758993 TI - How do yeast cells become tolerant to high ethanol concentrations? AB - The brewer's yeast Saccharomyces cerevisiae displays a much higher ethanol tolerance compared to most other organisms, and it is therefore commonly used for the industrial production of bioethanol and alcoholic beverages. However, the genetic determinants underlying this yeast's exceptional ethanol tolerance have proven difficult to elucidate. In this perspective, we discuss how different types of experiments have contributed to our understanding of the toxic effects of ethanol and the mechanisms and complex genetics underlying ethanol tolerance. In a second part, we summarize the different routes and challenges involved in obtaining superior industrial yeasts with improved ethanol tolerance. PMID- 26758995 TI - Hypovitaminosis D is associated with erectile dysfunction in type 2 diabetes. AB - Diabetes is an established risk factor for erectile dysfunction (ED). The pathophysiology of ED in diabetic men is multifactorial, but it mainly involves a vascular disorder related to a reduction of endothelial function. Recently, several studies have correlated ED risk factors with vitamin D deficiency. In this study, we evaluate the relationship between 25-hydroxyvitamin D [25(OH)D] levels, erectile dysfunction, and vascular disease, in type 2 diabetes mellitus men (T2DM). In this observational study, 92 T2DM males (58.83 +/- 9.73 years) underwent medical history collection, International Index of Erectile Function (IIEF-5) questionnaire, that allows the identification and grading of DE, physical examination, biochemical/hormonal blood tests, and penile echo-color Doppler ultrasonography. T2DM patients with lower 25(OH)D levels (<25 nmol/l) showed higher penile IMT (p < 0.05), waist circonference (p < 0.05), glucose concentrations (p < 0.05), and lower IIEF-5 score (p < 0.005), testosterone concentrations (p < 0.05), and cavernous peak systolic velocity (PSV) (p < 0.05), compared to patients with 25(OH)D >50 nmol/l. 25(OH)D levels were directly correlated with IIEF-5 (R = 0.39; p = 0.0001), testosterone (R = 0.24; p = 0.02), and PSV (R = 0.24; p = 0.04) and inversely with waist (R = -0.33; p = 0.002), HbA1c (R = -0.22; p = 0.03), triglyceride (R = -0.21; p = 0.06), and penile IMT (R = -0.30; p = 0.009). At multivariate analysis, 25(OH)D deficiency remained an independent predictor of DE. We demonstrate a significant association between 25(OH)D deficiency and erectile dysfunction in T2DM men. This association may be due to the influence of 25(OH)D deficiency on cardiovascular risk factor (glycaemia, HDL cholesterol, and triglycerides), testosterone plasma levels and endothelial dysfunction. PMID- 26758996 TI - The 5-tiered categorization system for reporting cytology is sufficient for management of patients with thyroid nodules compared to the 6-tiered Bethesda system. AB - To analyze whether the 5-tiered categorization system without the atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) category is sufficient compared to the 6-tiered Bethesda system. This IRB-approved retrospective study was waived informed consent. The pre-Bethesda period was from March 2008 to December 2008 and the Bethesda period was from January 2012 to January 2013. Of 4677 nodules >=10 mm with initial ultrasonography-guided fine-needle aspiration, 2553 nodules were from the pre Bethesda period and 1754 nodules were from the Bethesda period. The utilization and malignancy rates of each category were compared between the two periods. The utilization rate of the benign category decreased from 67.7 % in the pre-Bethesda period to 60.0 % in the Bethesda period (p = 0.001). In the pre-Bethesda period, the malignancy rates of the non-diagnostic, benign, suspicious follicular neoplasm/Hurthle cell neoplasm, suspicious for malignancy, and malignancy categories were 3.8, 1.9, 25, 78.8, and 99.7 %, respectively. The malignancy rate of the benign category decreased from 1.9 to 0.3 % after the Bethesda system (p < 0.001). The utilization and malignancy rates of the AUS/FLUS category were 7 and 22.8 %. When the AUS/FLUS category was included in the benign category, the malignancy rate became 2.6 % which was not significantly different from 1.9 % in the pre-Bethesda period (p = 0.189). The malignancy rates of other categories were not significantly different. The 5-tiered categorization system without the AUS/FLUS category for reporting cytology was sufficient for management of patients with thyroid nodules compared to the 6-tiered categorization of the Bethesda system. PMID- 26758997 TI - Association between insulin resistance and impairment of FGF21 signal transduction in skeletal muscles. AB - Fibroblast growth factor (FGF) 21, was identified as a potent metabolic regulator of glucose and lipid metabolism. We investigated whether the levels and signalings of FGF21 changed in the skeletal muscle of type 2 diabetes mellitus (T2DM) patients, participants with impaired glucose tolerance (IGT), human skeletal muscle myotubes (HSMMs) under insulin-resistant conditions, and mice with diet-induced obesity (DIO). A percutaneous biopsy sample of the vastus lateralis muscle of T2DM patients, IGT subjects, and participants with normal glucose tolerance was obtained and the levels and signalings of FGF21 were assessed. We determined whether the expression and signalings of FGF21 in HSMMs altered according to palmitate concentrations and exposure time. Also, we confirmed whether changes of FGF21 signal transduction resulted in the alteration of FGF21 functions. DIO mice were treated intravenously with recombinant FGF21, and the levels and signalings of FGF21 were assessed in their soleus muscles. We checked whether or not FGF21 played a role in the gene transcription related to lipid oxidation. Levels of FGF21 increased, whereas levels of phosphorylated FGF receptor (p-FGFR), phosphorylated FGFR substrates 2alpha (p-FRS2alpha), and phosphorylated extracellular signal-regulated kinases (p-ERK) decreased in the skeletal muscle of both T2DM patients and IGT subjects. In vitro, palmitate increased the levels of FGF21 and significantly reduced the levels of beta klotho, p-FGFR, p-FRS2alpha, and p-ERK1/2 in HSMMs exposed to palmitate. Palmitate also decreased glucose uptake and glycogen contents of FGF21. Consistently, the levels of FGF21 were significantly higher and the levels of beta-klotho and p-FGFR were lower in the DIO mice than in normal lean mice. The levels of FGF21 increased but its signal transduction and actions were impaired in skeletal muscles of T2DM patients, IGT subjects, in insulin-resistant HSMMs, and DIO mice. PMID- 26758999 TI - Novel Trial Designs: Lessons Learned from Thrombus Aspiration During ST-Segment Elevation Myocardial Infarction in Scandinavia (TASTE) Trial. AB - In ST-elevation myocardial infarction (STEMI), thrombus material is often present in partial or total coronary occlusion of the coronary vessel. However, prior to the thrombus aspiration during ST-Segment Elevation Myocardial Infarction in Scandinavia (TASTE) trial, it remained unclear whether routine thrombus aspiration during percutaneous coronary intervention (PCI) treatment of STEMI would result in patients overall survival benefit. The TASTE trial was a multicenter, prospective, open-label, randomized, controlled clinical trial. In order to randomize patients to treatment and collect data, the infrastructure of a clinical population-based registry was used. Online data collection used the national comprehensive Swedish Coronary Angiography and Angioplasty Registry, a part of the SWEDEHEART registry. Monitoring and adjudication was done as part of the regular registry validation. There was no separate, dedicated monitoring or adjudication of endpoints. Included were 7244 patients with STEMI with chest pain and time of symptoms to hospital admission <24 h, in addition to new electrocardiographic ST-segment elevation or left bundle-branch block. Exclusion criteria were the need for emergency coronary artery bypass grafting. All-cause mortality at 30 days occurred in 2.8 % of the patients in the thrombus-aspiration group, as compared with 3.0 % in the PCI-only group (hazard ratio [HR] 0.94, 95 % confidence interval [CI] 0.72-1.22; p = 0.63). All-cause mortality at 1 year occurred in 5.3 % of the patients in the thrombus-aspiration group, as compared with 5.6 % in the PCI-only group (HR 0.94, 95 % CI 0.78-1.15; p = 0.57). No patients were lost to follow-up at 1 year. The incremental cost for trial execution was approximately US$ 300,000 or $50 per patient. Routine thrombus aspiration during PCI in patients with STEMI did not reduce the rate of all-cause mortality at 1 year. It is possible to design and conduct mega-trial at only small cost compared to a similar-sized conventional randomized clinical trial. PMID- 26758998 TI - Effects of glucagon-like peptide-1 on advanced glycation endproduct-induced aortic endothelial dysfunction in streptozotocin-induced diabetic rats: possible roles of Rho kinase- and AMP kinase-mediated nuclear factor kappaB signaling pathways. AB - Interaction between advanced glycation endproducts (AGEs) and receptor for AGEs (RAGE) as well as downstream pathways leads to vascular endothelial dysfunction in diabetes. Glucagon-like peptide-1 (GLP-1) has been reported to attenuate endothelial dysfunction in the models of atherosclerosis. However, whether GLP-1 exerts protective effects on aortic endothelium in diabetic animal model and the underlying mechanisms are still not well defined. Experimental diabetes was induced through administration with combination of high-fat diet and intraperitoneal injection of streptozotocin. Rats were randomly divided into four groups, including controls, diabetes, diabetes + sitagliptin (30 mg/kg/day), diabetes + exenatide (3 MUg/kg/12 h). Eventually, endothelial damage, markers of inflammation and oxidative stress, were measured. After 12 weeks administration, diabetic rats received sitagliptin and exenatide showed significant elevation of serum NO level and reduction of ET-1 as well as inflammatory cytokines levels. Moreover, sitagliptin and exenatide significantly inhibited aortic oxidative stress level and improved aortic endothelial function in diabetic rats. Importantly, these drugs inhibited the protein expression level in AGE/RAGE induced RhoA/ROCK/NF-kappaB/IkappaBalpha signaling pathways and activated AMPK in diabetic aorta. Finally, the target proteins of p-eNOS, iNOS, and ET-1, which reflect endothelial function, were also changed by these drugs. Our present study indicates that sitagliptin and exenatide administrations can improve endothelial function in diabetic aorta. Of note, RAGE/RhoA/ROCK and AMPK mediated NF-kappaB signaling pathways may be the intervention targets of these drugs to protect aortic endothelium. PMID- 26759001 TI - Identifying Moderators of Response to the Penn Resiliency Program: A Synthesis Study. AB - To identify moderators of a cognitive-behavioral depression prevention program's effect on depressive symptoms among youth in early adolescence, data from three randomized controlled trials of the Penn Resiliency Program (PRP) were aggregated to maximize statistical power and sample diversity (N = 1145). Depressive symptoms, measured with the Children's Depression Inventory (CDI; Kovacs 1992), were assessed at six common time points over two-years of follow-up. Latent growth curve models evaluated whether PRP and control conditions differed in the rate of change in CDI and whether youth- and family-level characteristics moderated intervention effects. Model-based recursive partitioning was used as a supplementary analysis for identifying moderators. There was a three-way interaction of PRP, initial symptom severity, and intervention site on growth in depressive symptoms. There was considerable variability in PRP's effects, with the nature of the interaction between PRP and initial symptom levels differing considerably across sites. PRP reduced depressive symptoms among youth with unmarried parents, but not among those with married parents. Finally, PRP's effects differed across school grade levels. Although initial symptom severity moderated PRP's effect on depressive symptoms, it was not a reliable indicator of how well the intervention performed, limiting its utility as a prescriptive variable. Our primary analyses suggest that PRP's effects are limited to youth whose parents are unmarried. The small number of fifth grade students (n = 25; 2 %) showed a delayed and sustained intervention response. Our findings underscore the importance of evaluating site, family, and contextual characteristics as moderators in future studies. PMID- 26759000 TI - Body weight-based prednisolone versus body surface area-based prednisolone regimen for induction of remission in children with nephrotic syndrome: a randomized, open-label, equivalence clinical trial. AB - BACKGROUND: Body surface area (BSA)-based prednisolone dosing for childhood nephrotic syndrome (NS) leads to higher cumulative prednisolone doses than body weight (BW)-based dosing. The clinical effects of this higher dosage have not been evaluated in prospective studies. METHODS: This parallel-group open-label randomized clinical trial enrolled 100 children with idiopathic NS, to receive BW based (n = 50) or BSA-based (n = 50) prednisolone dosing by block randomization in a 1:1 ratio. The time taken for remission, relapse rate per 6 months, and adverse effects of steroids were analyzed in both groups. RESULTS: There was no significant difference in the time taken for remission in the BW group versus the BSA group (median (IQR) 7 (4.5-9) versus 5.5 (4-8) days; p = 0.082); similar results were observed on subgroup analysis in new-onset and infrequently relapsing NS (IFRNS). The cumulative prednisolone dosage during the enrolment episode was higher in the BSA group. The incidence of hypertension was higher (p = 0.048) in the BSA group on per-protocol analysis. The relapse rates in the two groups per 6 months on follow-up were comparable. CONCLUSIONS: Clinical outcomes with BW-based dosing are equivalent to BSA dosing-related outcomes, although cumulative prednisolone doses are lower in the former. The practice of BW-based calculations for prescribing prednisolone in NS is a reasonable approach. PMID- 26759003 TI - Inhibition of ABCA1 Protein Expression and Cholesterol Efflux by TNF alpha in MLO Y4 Osteocytes. AB - Hip fracture and myocardial infarction cause significant morbidity and mortality. In vivo studies raising serum cholesterol levels as well as pro-inflammatory cytokines such as TNF alpha manifest bone loss and atherosclerotic vascular disease, suggesting that abnormalities of cholesterol transport may contribute to osteoporosis. We used the mouse osteocyte cell line (MLO-Y4) to investigate the effects of TNF alpha on the expression of cholesterol acceptor proteins such as apolipoprotein A-I (apo A-I) and apolipoprotein E (apo E), as well as on the cholesterol transporters ATP-binding cassette-1 (ABCA1), scavenger receptor class B type 1 (SRB1), and cluster of differentiation 36 (CD36). MLO-Y4 cells do not express apo A-I or apo E; however, they do express all three cholesterol transporters (ABCA1, SRB1, and CD36). Treatment of MLO-Y4 cells with TNF alpha had no effect on SRB1, CD36, and osteocalcin levels; however, TNF alpha reduced ABCA1 protein levels in a dose-dependent manner and cholesterol efflux to apo A I. Interestingly, TNF alpha treatment increased ABCA1 promoter activity and ABCA1 mRNA levels, and increased liver X receptor alpha protein expression, but had no effect on retinoid X receptor alpha and retinoic acid receptor alpha levels. Pharmacological inhibition of p38 mitogen-activated protein (MAP) kinase, but not c-jun-N-terminal kinase 1 or mitogen-activated protein kinase (MEK), restored ABCA1 protein levels in TNF alpha-treated cells. These results suggest that pro inflammatory cytokines regulate cholesterol metabolism in osteocytes in part by suppressing ABCA1 levels post-translationally in a p38 MAP kinase-dependent manner. PMID- 26759002 TI - When to Suspect and How to Diagnose Mitochondrial Disorders? AB - Disorders of the mitochondrial respiratory chain are an exceedingly diverse group. The clinical features can affect any tissue or organ and occur at any age, with any mode of inheritance. The diagnosis of mitochondrial disorders requires knowledge of the clinical phenotypes and access to a wide range of laboratory techniques. A few syndromes are associated with a specific genetic defect and in these cases it is appropriate to proceed directly to an appropriate test of blood or urine. In most cases, however, the best strategy starts with biochemical and histochemical studies on a muscle biopsy. Appropriate molecular genetic studies can then be chosen, based on these results and the clinical picture. Unfortunately, there is currently limited availability of respiratory chain studies in India. Exome sequencing is undertaken increasingly often; without preceding mitochondrial studies, this can lead to misleading results. PMID- 26759004 TI - A parallelized microfluidic DNA bisulfite conversion module for streamlined methylation analysis. AB - Aberrant methylation of DNA has been identified as an epigenetic biomarker for numerous cancer types. The vast majority of techniques aimed at detecting methylation require bisulfite conversion of the DNA sample prior to analysis, which until now has been a benchtop process. Although microfluidics has potential benefits of simplified operation, sample and reagent economy, and scalability, bisulfite conversion has yet to be implemented in this format. Here, we present a novel droplet microfluidic design that facilitates rapid bisulfite conversion by reducing the necessary processing steps while retaining comparable performance to existing methods. This new format has a reduced overall processing time and is readily scalable for use in high throughput DNA methylation analysis. PMID- 26759005 TI - 8th Annual Canadian Cancer Immunotherapy Consortium (CCIC) Symposium 2015--May 20 22, Vancouver, Canada. PMID- 26759006 TI - IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4(+) T cells. AB - Immunosuppression in tumor microenvironments critically affects the success of cancer immunotherapy. Here, we focused on the role of interleukin (IL)-6/signal transducer and activator of transcription (STAT3) signaling cascade in immune regulation by human dendritic cells (DCs). IL-6-conditioned monocyte-derived DCs (MoDCs) impaired the presenting ability of cancer-related antigens. Interferon (IFN)-gamma production attenuated by CD4(+) T cells co-cultured with IL-6 conditioned MoDCs corresponded with decreased DC IL-12p70 production. Human leukocyte antigen (HLA)-DR and CD86 expression was significantly reduced in CD11b(+)CD11c(+) cells obtained from peripheral blood mononuclear cells (PBMCs) of healthy donors by IL-6 treatment and was STAT3 dependent. Arginase-1 (ARG1), lysosomal protease, cathepsin L (CTSL), and cyclooxygenase-2 (COX2) were involved in the reduction of surface HLA-DR expression. Gene expressions of ARG1, CTSL, COX2, and IL6 were higher in tumor-infiltrating CD11b(+)CD11c(+) cells compared with PBMCs isolated from colorectal cancer patients. Expression of surface HLA-DR and CD86 on CD11b(+)CD11c(+) cells was down-regulated, and T cell-stimulating ability was attenuated compared with PBMCs, suggesting that an immunosuppressive phenotype might be induced by IL-6, ARG1, CTSL, and COX2 in tumor sites of colorectal cancer patients. There was a relationship between HLA-DR expression levels in tumor tissues and the size of CD4(+) T and CD8(+) T cell compartments. Our findings indicate that IL-6 causes a dysfunction in human DCs that activates cancer antigen-specific Th cells, suggesting that blocking the IL-6/STAT3 signaling pathway might be a promising strategy to improve cancer immunotherapy. PMID- 26759011 TI - Special Issue of Sexual Abuse: A Journal of Research and Treatment--Connecting Theory With Research: Testing Hypotheses About the Causes of Sexual Offending. PMID- 26759009 TI - Poly(I:C) potentiates Bacillus Calmette-Guerin immunotherapy for bladder cancer. AB - Non-specific immunotherapy consisting of intravesical instillation of Bacillus Calmette-Guerin (BCG) is currently the best available treatment to prevent non muscle-invasive bladder tumor recurrence and progression. This treatment however is suboptimal, and more effective immunotherapeutic approaches are needed. Toll like receptors (TLRs) play a major role in the activation of the immune system in response to pathogens and danger signals but also in anti-tumor responses. We previously showed that human urothelial cells express functional TLRs and respond to TLR2 and TLR3 agonists. In this study, we analyzed the potential of polyinosinic:polycytidylic acid [poly(I:C)], a TLR3 agonist, to replace or complement BCG in the treatment of non-muscle-invasive bladder cancer. We observed that poly(I:C) had an anti-proliferative, cytotoxic, and apoptotic effect in vitro on two low-grade human bladder cancer cell lines, MGH-U3 and RT4. In MGH-U3 cells, poly(I:C) induced growth arrest at the G1-S transition. Poly(I:C) also increased the immunogenicity of MGH-U3 and RT4 cells, inducing the secretion of MHC class I molecules and of pro-inflammatory cytokines. By comparison, poly(I:C) had less in vitro impact on two high-grade human bladder cancer cell lines, 5637 and T24, and on MBT-2 murine high-grade bladder cancer cells. The latter can be used as an immunocompetent model of bladder cancer. The combination poly(I:C)/BCG was much more effective in reducing MBT-2 tumor growth in mice than either treatment alone. It completely cured 29% of mice and also induced an immunological memory response. In conclusion, our study suggests that adding poly(I:C) to BCG may enhance the therapeutic effect of BCG. PMID- 26759008 TI - Galectin-1 is associated with poor prognosis in patients with cutaneous head and neck cancer with perineural spread. AB - Spread of head and neck cancer along the cranial nerves is often a lethal complication of this tumour. Current treatment options include surgical resection and/or radiotherapy, but recurrence is a frequent event suggesting that our understanding of this tumour and its microenvironment is incomplete. In this study, we have analysed the nature of the perineural tumour microenvironment by immunohistochemistry with particular focus on immune cells and molecules, which might impair anti-tumour immunity. Moderate to marked lymphocyte infiltrates were present in 58.8% of the patient cohort including T cells, B cells and FoxP3 expressing T cells. While human leukocyte antigen (HLA) class I and more variably HLA class II were expressed on the tumour cells, this did not associate with patient survival or recurrence. In contrast, galectin-1 staining within lymphocyte areas of the tumour was significantly associated with a poorer patient outcome. Given the known role of galectin-1 in immune suppression, the data suggest that galectin inhibitors might improve the prognosis of patients with perineural spread of cancer. PMID- 26759007 TI - Serum elevation of B lymphocyte stimulator does not increase regulatory B cells in glioblastoma patients undergoing immunotherapy. AB - Regulatory B cells that secrete IL-10 (IL-10(+) Bregs) represent a suppressive subset of the B cell compartment with prominent anti-inflammatory capacity, capable of suppressing cellular and humoral responses to cancer and vaccines. B lymphocyte stimulator (BLyS) is a key regulatory molecule in IL-10(+) Breg biology with tightly controlled serum levels. However, BLyS levels can be drastically altered upon chemotherapeutic intervention. We have previously shown that serum BLyS levels are elevated, and directly associated, with increased antigen-specific antibody titers in patients with glioblastoma (GBM) undergoing lymphodepletive temozolomide chemotherapy and vaccination. In this study, we examined corresponding IL-10(+) Breg responses within this patient population and demonstrate that the IL-10(+) Breg compartment remains constant before and after administration of the vaccine, despite elevated BLyS levels in circulation. IL 10(+) Breg frequencies were not associated with serum BLyS levels, and ex vivo stimulation with a physiologically relevant concentration of BLyS did not increase IL-10(+) Breg frequency. However, BLyS stimulation did increase the frequency of the overall B cell compartment and promoted B cell proliferation upon B cell receptor engagement. Therefore, using BLyS as an adjuvant with therapeutic peptide vaccination could promote humoral immunity with no increase in immunosuppressive IL-10(+) Bregs. These results have implications for modulating humoral responses in human peptide vaccine trials in patients with GBM. PMID- 26759013 TI - Acute cor pulmonale and the acute respiratory distress syndrome. PMID- 26759014 TI - Medical simulation for ICU staff: does it influence safety of care? PMID- 26759012 TI - Positive and negative effects of mechanical ventilation on sleep in the ICU: a review with clinical recommendations. AB - PURPOSE: Sleep is an essential physiologic process that helps to restore normal body homeostasis. Sleep disturbances have been shown to be associated with poor clinical outcomes, such as a greater risk of cardiovascular disease and increasing mortality. Critically ill patients, particularly those receiving mechanical ventilation, may be more susceptible to sleep disruption. METHODS AND RESULTS: Mechanical ventilation is an important factor influencing sleep in critically ill patients as it may have positive or negative effects, depending on patient population, mode, and specific settings. Other causes of sleep disruption include the acute illness itself, the daily routine care, and the effects of medications. Improving sleep in patients admitted to an intensive care unit has the potential to improve both short- and long-term clinical outcomes. In this article we review the specific aspects of sleep in critically ill mechanically ventilated patients, including abnormal sleep patterns and loss of circadian rhythm, as well as the effects of mechanical ventilation and intravenous sedatives on sleep quality and quantity. CONCLUSIONS: We provide recommendations for clinicians regarding optimal ventilatory settings and discuss fields for future research. PMID- 26759015 TI - Designing peptidic inhibitors of serum amyloid A aggregation process. AB - Amyloid A amyloidosis is a life-threatening complication of a wide range of chronic inflammatory, infectious and neoplastic diseases, and the most common form of systemic amyloidosis worldwide. It is characterized by extracellular tissue deposition of fibrils that are composed of fragments of serum amyloid A protein (SAA), a major acute-phase reactant protein, produced predominantly by hepatocytes. Currently, there are no approved therapeutic agents directed against the formation of fibrillar SAA assemblies. We attempted to develop peptidic inhibitors based on their similarity and complementarity to the regions critical for SAA self-association, which they should interact with and block their assembly into amyloid fibrils. Inh1 and inh4 which are comprised of the residues from the amyloidogenic region of SAA1.1 protein and Abeta peptide, respectively, were found by us as capable to significantly suppress aggregation of the SAA1-12 peptide. It was chosen as an aggregation model that mimicks the amyloidogenic nucleus of SAA protein. We suppose that aromatic interactions may be responsible for inhibitory activity of both compounds. We also recognized that aromatic residues are involved in self-association of SAA1-12. PMID- 26759017 TI - Letter to the Editor re: ICP monitoring in children with TBI. PMID- 26759016 TI - Application of peptide displaying phage as a novel diagnostic probe for human lung adenocarcinoma. AB - Despite the increasing lung cancer-associated death rate, its therapy has been constrained by impasse of early diagnosis. To apply non-invasive imaging for potential cancer diagnosis system, we screened human lung adenocarcinoma-specific peptides using the phage display technique. For in vivo phage-displayed peptide screening, M13 phage library displaying 2.9 * 10(9) random peptides was injected through tail vein to lung adenocarcinoma cell-derived xenograft mouse model. Through four rounds of biopanning, a specific peptide sequence (CAKATCPAC) was screened out with the highest frequency and was named as Pep-1, and it was analyzed for its targeting ability as an imaging probe by in vitro competitive assay to test its cell-binding ability, immunohistochemical detection in the tumor tissue, and in vivo NIR fluorescent optical imaging. The specificity of Pep 1 toward lung cancer was ensured by in vivo imaging using xenograft animals of various cancer types. The results suggest that Pep-1 is a promising diagnostic lead molecule for rapid and accurate detection of human lung adenocarcinoma. In addition, it was found that the targeting ability was much enhanced by ionizing radiation in both cell-derived and patient-derived lung adenocarcinoma xenografts, suggesting the possibility of applying Pep-1 for prognostic diagnosis after radiotherapy. Taken together, this study suggests that Pep-1 possesses a specific-targeting ability for human lung adenocarcinoma and that this peptide could be directly used as a clinically applicable imaging probe. PMID- 26759018 TI - Oberlin's procedure in children with obstetric brachial plexus palsy. AB - PURPOSE: Most cases of obstetric brachial plexus palsy (OBPP) involve C5 and C6 nerve roots (Erb's palsy). In those cases, re-establishing the elbow flexion is the primary goal of surgery. The partial transfer of the ulnar nerve to the musculocutaneous nerve (Oberlin's procedure) is widely used in adults, but incipient in children. The purpose of this study is to describe the results obtained with such procedure as regards the improvement of the elbow flexion and donor nerve morbidity. METHOD: Thirteen children aged 9 to 15 months underwent Oberlin's procedure. They were assessed preoperatively and 1 year postoperatively using the active movement scale and also according to the functionality of the affected limb. All of them were evaluated because of the possibility of movement loss resulting from the donor nerve. We used the non-parametric, statistic Wilcoxon signed rank test (alpha = 0,05) method. RESULTS: There was a significant improvement in the active elbow flexion between pre- and postoperative periods. Eleven children presented functional improvement. All of them maintained negative cookie test 1 year after the surgery. We did not observe any loss related to the donor nerve in terms of wrist flexion. CONCLUSION: The results suggest that Oberlin's procedure can be an effective and safe alternative to treat elbow flexion in Erb's palsy. PMID- 26759019 TI - Monosegmental laminoplasty for selective dorsal rhizotomy--operative technique and influence on the development of scoliosis in ambulatory children with cerebral palsy. AB - PURPOSE: Selective dorsal rhizotomy (SDR) reduces spasticity in children with cerebral palsy (CP) and is performed either through a lumbosacral multilevel laminectomy or a single-level laminectomy at the medullary conus. Spinal interventions generally involve the risk of subsequent instability depending on the extent of structural weakening. Destabilizing spasticity in CP might further increase this risk for both options. Laminoplasty is frequently applied to reduce instability through anatomical restoration, although the unavoidable interruption of interspinous ligaments might be a reason for inconsistent results. We report on a novel technique of laminoplasty, achieving complete restoration of the dorsal column. METHODS: One hundred sixteen ambulatory children with gross motor function classification scale (GMFCS) level I to III were submitted to SDR through a single-level approach. The lamina was reinserted with a previously unreported technique of laminoplasty. Osseous reintegration of the excised lamina was supposed, if its spinous process was located in place on late follow-up radiographs. Scoliosis was described via Cobb's angle. RESULTS: At a mean follow up of 33 months, radiographs were available from 72 children with a mean age at surgery of 7.2 years. Sixty-two out of the 72 reinserted laminae were supposed to be vital and reintegrated. Seven children developed a predominantly mild scoliosis. No association was found between development of scoliosis and GMFCS level or age. CONCLUSIONS: This novel laminoplasty technique provides the least invasive approach for SDR. The incidence of scoliosis after this single-level approach is comparable to the natural history of ambulatory CP children. PMID- 26759020 TI - High resolution transbulbar sonography in children with suspicion of increased intracranial pressure. AB - PURPOSE: To evaluate the accuracy of high resolution transbulbar sonography for the estimation of intracranial pressure (ICP) in children. METHODS: In children and adolescents with acute neurologic symptoms of various origin, transbulbar sonography was performed. Besides measurement of the optic nerve sheath diameter (ONSD), the ultrastructure of the subarachnoid space of the optic nerve sheath was evaluated. The results of transbulbar sonography were correlated with clinical data based on cross-sectional imaging, ICP measurement, and ophthalmologic examination. RESULTS: Eighty-one patients (age 3-17.8 years, mean 11.7 years) were included. In 25 children, cross-sectional imaging and ICP measurement revealed increased intracranial pressure. The mean ONSD was 6.85 +/- 0.81 mm. Twenty patients (20/25, 80 %) had a microcystic appearance of the subarachnoid space of the optic nerve. In 56 children without evidence of increased intracranial pressure, the mean ONSD was 5.77 +/- 0.48 mm. Forty-nine patients (49/56, 87.5 %) had a normal homogenous appearance of the subarachnoid space. The ONSD in children with increased intracranial pressure was significantly higher than in patients without (p < 0.001). CONCLUSION: High resolution transbulbar sonography of the optic nerve is a useful technique for the rapid and non-invasive estimation of intracranial pressure in children. Besides measurement of the optic nerve sheath diameter, evaluation of the ultrastructure of the subarachnoid space of the optic nerve is a helpful parameter. PMID- 26759021 TI - Interferon or late effect of radiotherapy? PMID- 26759022 TI - Transition in HCB Editor-in-Chief. PMID- 26759024 TI - Effects of icing or heat stress on the induction of fibrosis and/or regeneration of injured rat soleus muscle. AB - The effects of icing or heat stress on the regeneration of injured soleus muscle were investigated in male Wistar rats. Bupivacaine was injected into soleus muscles bilaterally to induce muscle injury. Icing (0 degrees C, 20 min) was carried out immediately after the injury. Heat stress (42 degrees C, 30 min) was applied every other day during 2-14 days after the bupivacaine injection. Injury related increase in collagen deposition was promoted by icing. However, the level of collagen deposition in heat-stressed animals was maintained at control levels throughout the experimental period and was significantly lower than that in icing treated animals at 15 and 28 days after bupivacaine injection. Furthermore, the recovery of muscle mass, protein content, and muscle fiber size of injured soleus toward control levels was partially facilitated by heat stress. These results suggest that, compared with icing, heat stress may be a beneficial treatment for successful muscle regeneration at least by reducing fibrosis. PMID- 26759025 TI - Immobilization induces nuclear accumulation of HDAC4 in rat skeletal muscle. AB - The study described herein aimed to examine changes in HDAC4 and its downstream targets in immobilization-induced rat skeletal muscle atrophy. Eleven male Wistar rats were used, and one hindlimb was immobilized in the plantar flexion position using a plaster cast. The contralateral, non-immobilized leg served as an internal control. After 10 days, the gastrocnemius muscles were removed from both hindlimbs. Ten days of immobilization resulted in a significant reduction (-27.3 %) in gastrocnemius muscle weight. A significant decrease in AMPK phosphorylation was also observed in nuclear fractions from immobilized legs relative to the controls. HDAC4 expression was significantly increased in immobilized legs in both the cytoplasmic and nuclear fractions. Moreover, Myogenin and MyoD mRNA levels were upregulated in immobilized legs, resulting in increased Atrogin-1 mRNA expression. Our data suggest that nuclear HDAC4 accumulation is partly related to immobilization-induced muscle atrophy. PMID- 26759026 TI - 18F-Fluorodeoxyglucose PET/CT in Langerhans cell histiocytosis: spectrum of manifestations. AB - The objective of this article is to provide an illustrative tutorial highlighting the utility of 18F-FDG PET/CT imaging to detect the spectrum of manifestations in patients with Langerhans cell histiocytosis. FDG PET/CT is a powerful tool for making an early diagnosis; it allows higher diagnostic confidence with regard to lesions, measuring the extent of disease (staging) and assessing disease activity, and is consequently useful for evaluating the response to therapy in patients with Langerhans cell histiocytosis. PMID- 26759027 TI - Effect of LYRM1 knockdown on proliferation, apoptosis, differentiation and mitochondrial function in the P19 cell model of cardiac differentiation in vitro. AB - To explore the effects of LYRM1 knockdown on proliferation, apoptosis, differentiation and mitochondrial function in the embryonic carcinoma (P19) cell model of cardiac differentiation. Knockdown of LYRM1 using small interfering RNA (siRNA) was confirmed by quantitative real-time PCR. Cell Counting Kit-8(CCK-8) proliferation assays and cell cycle analysis demonstrated that LYRM1 gene silencing significantly inhibited P19 cell proliferation. Flow cytometry and measurement of their caspase-3 activities revealed that knockdown of LYRM1 increased P19 cell apoptosis. Observation of morphological changes using an inverted microscope and expression analysis of specific differentiation marker genes using quantitative real-time PCR and Western blotting revealed that knockdown of LYRM1 significantly inhibited the differentiation of P19 cells into cardiomyocytes. Furthermore, real-time quantitative PCR applied to detect mitochondrial DNA (mtDNA) copy number implied that there was no significant difference in the LYRM1 knockdown group compared with the control group. Cellular ATP production investigated by luciferase-based luminescence assay was dramatically decreased in differentiated cells transfected with LYRM1 RNAi. Fluorescence microscopy and flow cytometery were used to detect the reactive oxygen species (ROS) and the mitochondrial membrane potential (MMP) showed that the level of ROS was dramatically increased and MMP was obviously decreased in differentiated cells transfected with LYRM1 RNAi. Collectively, knockdown of LYRM1 promoted apoptosis and suppressed proliferation and differentiation in P19 cells. In addition, knockdown of LYRM1 induced mitochondrial impairment in P19 cells during differentiation, which was reflected by decreased ATP synthesis, lower MMP and increased ROS levels. PMID- 26759028 TI - Molecular changes in mitochondrial respiratory activity and metabolic enzyme activity in muscle of four pig breeds with distinct metabolic types. AB - Skeletal muscles are metabolically active and have market value in meat-producing farm animals. A better understanding of biological pathways affecting energy metabolism in skeletal muscle could advance the science of skeletal muscle. In this study, comparative pathway-focused gene expression profiling in conjunction with muscle fiber typing were analyzed in skeletal muscles from Duroc, Pietrain, and Duroc-Pietrain crossbred pigs. Each breed type displayed a distinct muscle fiber-type composition. Mitochondrial respiratory activity and glycolytic and oxidative enzyme activities were comparable among genotypes, except for significantly lower complex I activity in Pietrain pigs homozygous-positive for malignant hyperthermia syndrome. At the transcriptional level, lactate dehydrogenase B showed breed specificity, with significantly lower expression in Pietrain pigs homozygous-positive for malignant hyperthermia syndrome. A similar mRNA expression pattern was shown for several subunits of oxidative phosphorylation complexes, including complex I, complex II, complex IV, and ATP synthase. Significant correlations were observed between mRNA expression of genes in focused pathways and enzyme activities in a breed-dependent manner. Moreover, expression patterns of pathway-focused genes were well correlated with muscle fiber-type composition. These results stress the importance of regulation of transcriptional rate of genes related to oxidative and glycolytic pathways in the metabolic capacity of muscle fibers. Overall, the results further the breed specific understanding of the molecular basis of metabolic enzyme activities, which directly impact meat quality. PMID- 26759030 TI - Fifteen-Year Survival of Endoscopic Anterior Cruciate Ligament Reconstruction in Patients Aged 18 Years and Younger. AB - BACKGROUND: The current body of literature surrounding anterior cruciate ligament (ACL) survival and the variables contributing to further ACL injuries after primary ACL reconstruction in children and adolescents is limited, with no long term evidence examining the incidence and contributing factors of further ACL injuries in this younger patient population. PURPOSE: To determine the long-term survival of the ACL graft and the contralateral ACL (CACL) after primary reconstruction in patients aged <=18 years and to identify the factors that increase the odds of subsequent ACL injuries. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Patients having undergone primary ACL reconstruction at age <=18 years between 1993 and 1998 who were included in a prospective database by a single surgeon were considered for this study. Single-incision endoscopic ACL reconstruction was performed with either an autologous bone-patellar tendon-bone graft or a hamstring tendon graft. At a minimum of 15 years after ACL reconstruction, patients completed a subjective survey involving the International Knee Documentation Committee (IKDC) questionnaire in addition to questions regarding current symptoms, further ACL injuries, family history of ACL injury, and current level of activity. RESULTS: A total of 288 adolescents (age range, 13-18 years) met the inclusion criteria, of whom 242 (84%) were reviewed at a mean of 16 years and 6 months after ACL reconstruction. Of these patients, 75 (31%) sustained a further ACL injury: 27 (11.2%) suffered an ACL graft rupture, 33 suffered a CACL injury (13.6%), and 15 sustained both an ACL graft rupture and a CACL injury (6.2%) over 15 years. Survival of the ACL graft was 95%, 92%, 88%, 85%, and 83% at 1, 2, 5, 10, and 15 years, respectively, and survival of the CACL was 99%, 98%, 90%, 83%, and 81%, respectively. Survival of the ACL graft was less favorable in those with a family history of ACL injury than in those without a family history (69% vs 90%, respectively; hazard ratio [HR], 3.6; P = .001). Survival of the CACL was less favorable in male patients than in female patients (75% vs 88%, respectively; HR, 2.1; P = .03) and in those who returned to competitive team ball sports than in those who did not (78% vs 89%, respectively; HR, 2.3; P = .05). CONCLUSION: After ACL reconstruction in patients aged <=18 years, a further ACL injury occurred in 1 in 3 patients over 15 years. The 15-year survival rate of the ACL graft was 83%, and the 15-year survival rate of the CACL was 81%. The ACL graft and CACL were most vulnerable within the first 5 years after index surgery. A family history of ACL rupture significantly increased the risk for ACL graft ruptures, and a CACL injury was more common in male patients and those who returned to team ball sports. High IKDC scores and continued participation in sports were maintained over the long term after ACL reconstruction in the adolescent population. PMID- 26759029 TI - Polysaccharide-based Noncovalent Assembly for Targeted Delivery of Taxol. AB - The construction of synthetic straightforward, biocompatible and biodegradable targeted drug delivery system with fluorescent tracking abilities, high anticancer activities and low side effects is still a challenge in the field of biochemistry and material chemistry. In this work, we constructed targeted paclitaxel (Taxol) delivery nanoparticles composed of permethyl-beta-cyclodextrin modified hyaluronic acid (HApCD) and porphyrin modified paclitaxel prodrug (PorTaxol), through host-guest and amphiphilic interactions. The obtained nanoparticles (HATXP) were biocompatible and enzymatic biodegradable due to their hydrophilic hyaluronic acid (HA) shell and hydrophobic Taxol core, and exhibited specific targeting internalization into cancer cells via HA receptor mediated endocytosis effects. The cytotoxicity experiments showed that the HATXP exhibited similar anticancer activities to, but much lower side effects than commercial anticancer drug Taxol. The present work would provide a platform for targeted paclitaxel drug delivery and a general protocol for the design of advanced multifunctional nanoscale biomaterials for targeted drug/gene delivery. PMID- 26759034 TI - Good news and best wishes for 2016 to the global nephrology community from Kidney International. PMID- 26759031 TI - Whole-genome sequencing reveals transmission of vancomycin-resistant Enterococcus faecium in a healthcare network. AB - BACKGROUND: Bacterial whole-genome sequencing (WGS) has the potential to identify reservoirs of multidrug-resistant organisms and transmission of these pathogens across healthcare networks. We used WGS to define transmission of vancomycin resistant enterococci (VRE) within a long-term care facility (LTCF), and between this and an acute hospital in the United Kingdom (UK). METHODS: A longitudinal prospective observational study of faecal VRE carriage was conducted in a LTCF in Cambridge, UK. Stool samples were collected at recruitment, and then repeatedly until the end of the study period, discharge or death. Selective culture media were used to isolate VRE, which were subsequently sequenced and analysed. We also analysed the genomes of 45 Enterococcus faecium bloodstream isolates collected at Cambridge University Hospitals NHS Foundation Trust (CUH). RESULTS: Forty-five residents were recruited during a 6-month period in 2014, and 693 stools were collected at a frequency of at least 1 week apart. Fifty-one stool samples from 3/45 participants (7 %) were positive for vancomycin-resistant E. faecium. Two residents carried multiple VRE lineages, and one carried a single VRE lineage. Genome analyses based on single nucleotide polymorphisms (SNPs) in the core genome indicated that VRE carried by each of the three residents were unrelated. Participants had extensive contact with the local healthcare network. We found that VRE genomes from LTCF residents and hospital-associated bloodstream infection were interspersed throughout the phylogenetic tree, with several instances of closely related VRE strains from the two settings. CONCLUSIONS: A proportion of LTCF residents are long-term carriers of VRE. Evidence for genetic relatedness between these and VRE associated with bloodstream infection in a nearby acute NHS Trust indicate a shared bacterial population. PMID- 26759032 TI - Heavy metal content in various types of candies and their daily dietary intake by children. AB - Children are vulnerable to heavy metal contamination through consumption of candies and chocolates. Considering this representative samples (69) of candies and chocolates based on cocoa, milk and sugar were analyzed for selected heavy metals by means of flame atomic absorption spectrometry. The average concentration of Zn, Pb, Ni, and Cd was found to be 2.52 +/- 2.49, 2.0 +/- 1.20, 0.84 +/- 1.35, and 0.17 +/- 0.22 MUg/g respectively. Results indicate that cocoa based candies have higher metal content than milk- or sugar-based candies. The daily dietary intake of metals for children eating candies and chocolates was also calculated, and results indicated highest intake of Pb and Zn followed by Ni, Cd, and Cu. Comparison of the current study results with other studies around the globe shows that the heavy metal content in candies and chocolates is lower in India than reported elsewhere. However, to reduce the further dietary exposure of heavy metals through candies and chocolates, their content should be monitored regularly and particularly for Pb as children are highly susceptible to its toxicity. PMID- 26759035 TI - Will a new tenofovir prodrug for the treatment of HIV reduce the risk of nephrotoxicity? AB - The widely used antiretroviral agent tenofovir disoproxil fumarate has been associated with proximal tubular injury and decreased glomerular filtration rate in HIV-infected individuals. Phase 3 trials of a new prodrug, tenofovir alafenamide, suggest a lower potential for kidney injury. PMID- 26759036 TI - Fibroblast growth factor receptor 4: the missing link between chronic kidney disease and FGF23-induced left ventricular hypertrophy? AB - Serum phosphorus and the regulatory hormone fibroblast growth factor 23 have been strongly linked to cardiovascular morbidity and mortality in patients with chronic kidney disease. A recent study identified fibroblast growth factor receptor 4 as the primary receptor mediating the effect of fibroblast growth factor 23 on left ventricular hypertrophy, providing new mechanistic insights and a potential therapeutic target to reduce cardiovascular morbidity in chronic kidney disease. PMID- 26759037 TI - Immunosuppression in IgA nephropathy: how certain are we? AB - The optimal role of immunosuppressive therapy in the treatment of IgA nephropathy is controversial. Results of a recently completed randomized controlled trial provide strong support for comprehensive supportive care rather than immunosuppressive therapy in patients at high risk for progression. PMID- 26759038 TI - Therapy for kidney fibrosis: is the Src kinase a potential target? AB - Chronic kidney disease (CKD) is a public health challenge worldwide. As CKD is associated with high rates of morbidity and mortality, identification of novel targets for effective therapy is urgently needed. Yan et al. provide evidence that the Src kinase plays a critical role in the pathogenesis of CKD by integrating multiple fibrogenic signal inputs. Therefore, targeted inhibition of Src kinase may hold promise as a new strategy in the fight against CKD. PMID- 26759039 TI - A grain of salt on kidney dendritic cell function in allograft rejection. AB - Acute kidney graft allorejection affects primarily the renal cortex. The present study by Chessa et al. offers an explanation for this phenomenon. The authors employ microarray-based gene expression analysis to provide evidence that the hyperosmolarity of the renal medulla induces a transcriptional fingerprint associated with anti-inflammatory functionality in medullary dendritic cells, which may attenuate local alloreactivity. This novel immunoregulatory mechanism hints at a new opportunity to prevent allorejection. PMID- 26759040 TI - Bone strength: more than just bone density. AB - The following bone density measurements have limited utility in determining bone strength because they do not include bone quality: microarchitecture, mineralization, ability to repair damage, collagen structure, crystal size, or marrow composition. Patients with kidney disease have poor bone quality. Newman et al. now describe beneficial effects with raloxifene in an animal model of progressive kidney disease. These biomechanical measurements will be important in the development of medications to decrease fractures in patients. PMID- 26759041 TI - Prognostic assessment of IgA nephropathy: how much does histology add? AB - IgA nephropathy exhibits a widely varying clinical course from asymptomatic urinary abnormalities to rapidly progressive renal failure. Determining the prognosis based on parameters obtained very early in the course of disease is of central importance in clinical decision making. Barbour et al. assessed whether adding biopsy findings to clinical parameters obtained at first presentation improves the predictive power. PMID- 26759042 TI - Dietary phosphorus restriction in predialysis chronic kidney disease: time for a cease-fire? AB - The increased awareness that disorders of phosphorus metabolism occur early in the course of chronic kidney disease fuels interest in early intervention strategies. A post hoc analysis of data from the Modification of Diet in Renal Disease (MDRD) Study questions the clinical relevance of early dietary phosphate restriction, so far considered a mainstay in the prevention and treatment of mineral metabolism disorders. Still, on the basis of available evidence, a cease fire in the war on dietary phosphate would be premature. PMID- 26759043 TI - Surgical intervention for urolithiasis: does it result in long-term medical complications? AB - The association of shock wave lithotripsy (SWL) and hypertension is a controversial subject. This Commentary discusses the article by Denberg et al., which found an association between new-onset hypertension and SWL, but not ureteroscopy. Ureteroscopy has improved significantly since its introduction and now plays a role as a primary initial treatment for stone disease. PMID- 26759044 TI - Moving East: the Euro-Lupus Nephritis regimen in Asia. AB - Treatment of lupus nephritis is more evidenced-based than ever. Yet many areas of uncertainty persist. The article by Rathi et al. brings a piece to the puzzle by comparing, in a group of Indian patients, the Euro-Lupus low-dose i.v. cyclophosphamide regimen with mycophenolate mofetil. Although some caveats must be raised, the results suggest that, after crossing the Atlantic, the Euro-Lupus regimen may well be moving East. PMID- 26759046 TI - Targeting serum calcium in chronic kidney disease and end-stage renal disease: is normal too high? AB - Hypocalcemia is common in advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD), and it is standard practice to correct this back to the normal range, presumably to prevent symptomatic hypocalcemia and help control hyperparathyroidism. However, there are few studies to support this approach, and recent data suggest that this promotes vascular calcification and adynamic bone disease. Whether setting a lower target will improve outcomes has not been tested, but existing data suggest that this may have minimal risks and substantial potential benefits and should be explored. PMID- 26759047 TI - Nonapoptotic cell death in acute kidney injury and transplantation. AB - Acute tubular necrosis causes a loss of renal function, which clinically presents as acute kidney failure (AKI). The biochemical signaling pathways that trigger necrosis have been investigated in detail over the past 5 years. It is now clear that necrosis (regulated necrosis, RN) represents a genetically driven process that contributes to the pathophysiology of AKI. RN pathways such as necroptosis, ferroptosis, parthanatos, and mitochondrial permeability transition-induced regulated necrosis (MPT-RN) may be mechanistically distinct, and the relative contributions to overall organ damage during AKI in living organisms largely remain elusive. In a synchronized manner, some necrotic programs induce the breakdown of tubular segments and multicellular functional units, whereas others are limited to killing single cells in the tubular compartment. Importantly, the means by which a renal cell dies may have implications for the subsequent inflammatory response. In this review, the recent advances in the field of renal cell death in AKI and key enzymes that might serve as novel therapeutic targets will be discussed. As a consequence of the interference with RN, the immunogenicity of dying cells in AKI in renal transplants will be diminished, rendering inhibitors of RN indirect immunosuppressive agents. PMID- 26759045 TI - Iron management in chronic kidney disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. AB - Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects. PMID- 26759048 TI - Megalin and cubilin in proximal tubule protein reabsorption: from experimental models to human disease. AB - Proximal tubule protein uptake is mediated by 2 receptors, megalin and cubilin. These receptors rescue a variety of filtered ligands, including biomarkers, essential vitamins, and hormones. Receptor gene knockout animal models have identified important functions of the receptors and have established their essential role in modulating urinary protein excretion. Rare genetic syndromes associated with dysfunction of these receptors have been identified and characterized, providing additional information on the importance of these receptors in humans. Using various disease models in combination with receptor gene knockout, the implications of receptor dysfunction in acute and chronic kidney injury have been explored and have pointed to potential new roles of these receptors. Based on data from animal models, this paper will review current knowledge on proximal tubule endocytic receptor function and regulation, and their role in renal development, protein reabsorption, albumin uptake, and normal renal physiology. These findings have implications for the pathophysiology and diagnosis of proteinuric renal diseases. We will examine the limitations of the different models and compare the findings to phenotypic observations in inherited human disorders associated with receptor dysfunction. Furthermore, evidence from receptor knockout mouse models as well as human observations suggesting a role of protein receptors for renal disease will be discussed in light of conditions such as chronic kidney disease, diabetes, and hypertension. PMID- 26759050 TI - A child with chronic asymptomatic intestinal peritoneal dialysis catheter migration. PMID- 26759051 TI - Calcium oxalate crystalluria points to primary hyperoxaluria type 1. PMID- 26759052 TI - Nephrology Crossword: Innovative renal pathology for precision diagnosis. PMID- 26759054 TI - GPR91: expanding the frontiers of Krebs cycle intermediates. AB - Since it was discovered, the citric acid cycle has been known to be central to cell metabolism and energy homeostasis. Mainly found in the mitochondrial matrix, some of the intermediates of the Krebs cycle are also present in the blood stream. Currently, there are several reports that indicate functional roles for Krebs intermediates out of its cycle. Succinate, for instance, acts as an extracellular ligand by binding to a G-protein coupled receptor, known as GPR91, expressed in kidney, liver, heart, retinal cells and possibly many other tissues, leading to a wide array of physiological and pathological effects. Through GPR91, succinate is involved in functions such as regulation of blood pressure, inhibition of lipolysis in white adipose tissue, development of retinal vascularization, cardiac hypertrophy and activation of stellate hepatic cells by ischemic hepatocytes. Along the current review, these new effects of succinate through GPR91 will be explored and discussed. PMID- 26759055 TI - Social and behavioural factors in Non-suspicious unexpected death in infancy; experience from metropolitan police project indigo investigation. AB - BACKGROUND: Risk factors for Sudden Unexpected Death in Infancy (SUDI) are well described, and such cases are now investigated according to standard protocols. In London, Project Indigo of the Metropolitan Police provides a unique, detailed framework for such data collection. We investigate such data to provide a contemporary account of SUDI in a large city and further link data to publically available datasets to investigate interactions with social factors. METHODS: Retrospective analysis of data routinely collected by the Metropolitan Police Service in all cases of non-suspicious SUDI deaths in London during a six year period. RESULTS: SUDI deaths are associated with markers of social deprivation in London. A significant proportion of such deaths are associated with potentially modifiable risk factors such as cigarette smoking and co-sleeping, such behaviour also being associated with social factors, including accommodation issues. CONCLUSIONS: Routinely collected data provide valuable insight into patterns and associations of mortality, with SUDI remaining a significant issue in London. Risk factors include social disadvantage, which may manifest in part by affecting behavioural patterns such as co-sleeping and public health interventions to reduce rates require significant social modification. PMID- 26759056 TI - HPV Vaccine utilization, Alberta 2008/09-2013/14 School year. AB - BACKGROUND: In Canada both bivalent (bHPV) vaccine and quadrivalent HPV vaccine (qHPV) are authorized for use. In Alberta, while both vaccines are available for private purchase, only qHPV is publicly funded for school girls in grades 5 and 9 as of 2013. We describe HPV vaccine uptake in Alberta, by school year, from the start of the publicly funded program in the Fall of 2008 through to August 31(st) 2014 and estimate the cumulative proportion of the female population who were vaccinated by the end of the 2013/14 school year. METHODS: We used data from the Alberta Ministry of Health Immunization and Adverse Reaction to Immunization repository (publicly funded vaccine), the population-based Pharmaceutical Information Network information systems (privately purchased vaccine) for the period September 1, 2008 to August 31, 2014 and demographic data from the Alberta Health Care Insurance Plan Registry. We estimate vaccine uptake rates and explore them by attributes of person, time, place, vaccine funding, and number of doses received. We estimated the cumulative proportions of the female population (by age group and number of doses received) who had received HPV vaccine by the end of the 2013/14 school year. RESULTS: Of the 169,259 unique individuals who received one or more doses of HPV vaccine over the period, 98.3% were females, and 83.8% received publicly funded vaccines. Vaccine uptake increased over the period. The cumulative proportion of females aged 9-26 years as of 2013/14 who had received two or more doses of vaccine was 34.3%; for those aged 10-11 years 59.6% and for those aged 14-15 years, 76.0%. For those aged 9-26 years, 31.3% had received three doses of vaccine. CONCLUSION: HPV vaccine uptake rates have increased in Alberta over the study period, most prominently among the age groups targeted by the publicly funded school-girl vaccine program. PMID- 26759053 TI - Incidence and prevalence of total joint replacements due to osteoarthritis in the elderly: risk factors and factors associated with late life prevalence in the AGES-Reykjavik Study. AB - BACKGROUND: Total joint replacements (TJRs) should be considered as one of few definite endpoints in osteoarthritis research. We analyzed factors associated with late-life prevalence and risk factors for incidence of TJRs due to osteoarthritis in a population based cohort. METHODS: After exclusion of inflammatory arthritis and fractures as causes of TJR, 5170 participants in the AGES-Reykjavik Study (mean age (SD) 76.4(6), 58% females) were included for osteoarthritis studies. Three thousand one hundred thirty-three of them had a follow-up visit 5 years later. RESULTS: The prevalence of having at least one joint replacement operation due to OA was 13.6% and the yearly incidence was 1.4%/year during the five-year follow-up. Factors positively associated with late life prevalence of TJR included BMI, hand OA severity, female gender, finger length ratio and spine BMD. Risk factors for TJRs in the incidence group were symptoms at initial visit, prior TJR in the contralateral joint and BMI. Much stronger associations were seen for TKR than for THR with discriminatory analysis showing an AUC 0.71 for late life prevalence and 0.84 for the incidence. CONCLUSIONS: This study illustrates the importance of the different information expressed by late life prevalence vs. incidence on the factors associated with severe osteoarthritis of the knee and hip. The observation that prior TJR is a risk factor for subsequent TJR in the contralateral joint has not been described previously. The high power predictions for TKR suggest that a predictive model may be feasible, particularly if it can be extended by the addition of further predictive variables, perhaps through genetic, biomarker or imaging data. PMID- 26759049 TI - The MEST score provides earlier risk prediction in lgA nephropathy. AB - The Oxford Classification of IgA nephropathy (IgAN) includes the following four histologic components: mesangial (M) and endocapillary (E) hypercellularity, segmental sclerosis (S) and interstitial fibrosis/tubular atrophy (T). These combine to form the MEST score and are independently associated with renal outcome. Current prediction and risk stratification in IgAN requires clinical data over 2 years of follow-up. Using modern prediction tools, we examined whether combining MEST with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than current best methods that use 2 years of follow-up data. We used a cohort of 901 adults with IgAN from the Oxford derivation and North American validation studies and the VALIGA study followed for a median of 5.6 years to analyze the primary outcome (50% decrease in eGFR or ESRD) using Cox regression models. Covariates of clinical data at biopsy (eGFR, proteinuria, MAP) with or without MEST, and then 2-year clinical data alone (2 year average of proteinuria/MAP, eGFR at biopsy) were considered. There was significant improvement in prediction by adding MEST to clinical data at biopsy. The combination predicted the outcome as well as the 2-year clinical data alone, with comparable calibration curves. This effect did not change in subgroups treated or not with RAS blockade or immunosuppression. Thus, combining the MEST score with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than our current best methods. PMID- 26759057 TI - Gamma oscillation in functional brain networks is involved in the spontaneous remission of depressive behavior induced by chronic restraint stress in mice. AB - BACKGROUND: Depression is one of the most prevalent mood disorders, and is known to be associated with abnormal functional connectivity in neural networks of the brain. Interestingly, a significant proportion of patients with depression experience spontaneous remission without any treatment. However, the relationship between electroencephalographic (EEG) functional connectivity and the spontaneous remission in depression remains poorly understood. Here, we investigated regional and network brain activity using EEG signals from a chronic restraint stress (CRS)-induced mouse model of depression. After 1 (CRS1W) or 3 weeks (CRS3W) following the cessation of a 4-week-long CRS, mice were subjected to depression associated behavioral tasks. EEG signals were obtained from eight cortical regions (frontal, somatosensory, parietal, and visual cortices in each hemisphere). RESULTS: The CRS1W group exhibited behavioral dysfunctions in the open field and forced swim tasks, whereas the CRS3W group displayed normal levels of behaviors in those tasks. In a linear correlation analysis, the CRS1W group exhibited increased correlation coefficient values at all frequency bands (delta, 1.5-4; theta, 4-8; alpha, 8-12; beta, 12-30; gamma, 30-80 Hz) compared with the control group. However, the differences in delta- and gamma-frequency bands between the control and CRS1W groups were no longer observed in the CRS3W group. Persistent brain network homology revealed significantly different functional connectivity between the control and CRS1W groups, and it demonstrated a huge restoration of the decreased distances in the gamma-frequency band for the CRS3W group. Moreover, the CRS3W group displayed a similar strength of connectivity among somatosensory and frontal cortices as the control group. CONCLUSION: A mouse model of CRS-induced depression showed spontaneous behavioral remission of depressive behavior. Using persistent brain network homology analysis of EEG signals from eight cortical regions, we found that restoration of gamma activity at the network level is associated with behavioral remission. PMID- 26759058 TI - Fair access to medicine? Retrospective analysis of UK medical schools application data 2009-2012 using three measures of socioeconomic status. AB - BACKGROUND: Medical students have historically largely come from more affluent parts of society, leading many countries to seek to broaden access to medical careers on the grounds of social justice and the perceived benefits of greater workforce diversity. The aim of this study was to examine variation in socioeconomic status (SES) of applicants to study medicine and applicants with an accepted offer from a medical school, comparing the four UK countries and individual medical schools. METHODS: Retrospective analysis of application data for 22 UK medical schools 2009/10-2011/12. Data were analysed for all 32,964 UK domiciled applicants aged <20 years to 22 non-graduate medical schools requiring applicants to sit the United Kingdom Clinical Aptitude Test (UKCAT). Rates of applicants and accepted offers were compared using three measures of SES: (1) Postcode-assigned Index of Multiple Deprivation score (IMD); (2) School type; (3) Parental occupation measured by the National Statistics Socio Economic Classification (NS-SEC). RESULTS: There is a marked social gradient of applicants and applicants with accepted offers with, depending on UK country of residence, 19.7-34.5% of applicants living in the most affluent tenth of postcodes vs 1.8 5.7% in the least affluent tenth. However, the majority of applicants in all postcodes had parents in the highest SES occupational group (NS-SEC1). Applicants resident in the most deprived postcodes, with parents from lower SES occupational groups (NS-SEC4/5) and attending non-selective state schools were less likely to obtain an accepted offer of a place at medical school further steepening the observed social gradient. Medical schools varied significantly in the percentage of individuals from NS-SEC 4/5 applying (2.3%-8.4%) and gaining an accepted offer (1.2%-7.7%). CONCLUSION: Regardless of the measure, those from less affluent backgrounds are less likely to apply and less likely to gain an accepted offer to study medicine. Postcode-based measures such as IMD may be misleading, but individual measures like NS-SEC can be gamed by applicants. The previously unreported variation between UK countries and between medical schools warrants further investigation as it implies solutions are available but inconsistently applied. PMID- 26759059 TI - [Digital health: A paradigm shift in clinical medicine?]. PMID- 26759060 TI - Whole-exome sequencing reveals potential molecular predictors of relapse after discontinuation of the targeted therapy in chronic myeloid leukemia patients. AB - Chronic myeloid leukemia (CML) is a myeloproliferative disease well treated by tyrosine kinase inhibitors (TKIs). The aim was to identify genes with a predictive value for relapse-free survival after TKI cessation in CML patients. We performed whole-exome sequencing of DNA from six CML patients in long-lasting deep molecular remission. Patients were divided into two groups with relapse (n = 3) and without relapse (n = 3) after TKI discontinuation. We found variants in genes CYP1B1, ALPK2, and IRF1 in group of patients with relapse and one variant in gene PARP9 in group of patients without relapse. We verified prognostic value of the found markers in a small group of patients with TKI discontinuation and demonstrated their high sensitivity (77%), specificity (86%), positive (85%), and negative (79%) predictive values. Thus we revealed genetic variants, which are potential markers of outcome prediction in CML patients after TKI discontinuation. PMID- 26759061 TI - Psmir: a database of potential associations between small molecules and miRNAs. AB - miRNAs are key post-transcriptional regulators of many essential biological processes, and their dysregulation has been validated in almost all human cancers. Restoring aberrantly expressed miRNAs might be a novel therapeutics. Recently, many studies have demonstrated that small molecular compounds can affect miRNA expression. Thus, prediction of associations between small molecules and miRNAs is important for investigation of miRNA-targeted drugs. Here, we analyzed 39 miRNA-perturbed gene expression profiles, and then calculated the similarity of transcription responses between miRNA perturbation and drug treatment to predict drug-miRNA associations. At the significance level of 0.05, we obtained 6501 candidate associations between 1295 small molecules and 25 miRNAs, which included 624 FDA approved drugs. Finally, we constructed the Psmir database to store all potential associations and the related materials. In a word, Psmir served as a valuable resource for dissecting the biological significance in small molecules' effects on miRNA expression, which will facilitate developing novel potential therapeutic targets or treatments for human cancers. Psmir is supported by all major browsers, and is freely available at http://www.bio-bigdata.com/Psmir/. PMID- 26759062 TI - An integrated paper-based sample-to-answer biosensor for nucleic acid testing at the point of care. AB - With advances in point-of-care testing (POCT), lateral flow assays (LFAs) have been explored for nucleic acid detection. However, biological samples generally contain complex compositions and low amounts of target nucleic acids, and currently require laborious off-chip nucleic acid extraction and amplification processes (e.g., tube-based extraction and polymerase chain reaction (PCR)) prior to detection. To the best of our knowledge, even though the integration of DNA extraction and amplification into a paper-based biosensor has been reported, a combination of LFA with the aforementioned steps for simple colorimetric readout has not yet been demonstrated. Here, we demonstrate for the first time an integrated paper-based biosensor incorporating nucleic acid extraction, amplification and visual detection or quantification using a smartphone. A handheld battery-powered heating device was specially developed for nucleic acid amplification in POC settings, which is coupled with this simple assay for rapid target detection. The biosensor can successfully detect Escherichia coli (as a model analyte) in spiked drinking water, milk, blood, and spinach with a detection limit of as low as 10-1000 CFU mL(-1), and Streptococcus pneumonia in clinical blood samples, highlighting its potential use in medical diagnostics, food safety analysis and environmental monitoring. As compared to the lengthy conventional assay, which requires more than 5 hours for the entire sample-to answer process, it takes about 1 hour for our integrated biosensor. The integrated biosensor holds great potential for detection of various target analytes for wide applications in the near future. PMID- 26759064 TI - [177Lu-DOTA0,Tyr3]-octreotate in the treatment of midgut neuroendocrine tumors. AB - Midgut neuroendocrine tumors (NETs) are relatively rare and remarkably heterogeneous. Although recent developments for pancreatic NETs have brought multiple new therapies to patients who need them, there has been little observed efficacy against midgut NETs. Peptide receptor radionuclide therapy utilizes somatostatin analogs conjugated to radioactive isotopes in order to deliver high doses of radiation directly to tumor cells, which express somatostatin receptors. Peptide receptor radionuclide therapy with [(177)Lu-DOTA(0),Tyr(3)]-octreotate (DOTATATE) has been reported and investigated for more than a decade, and the randomized controlled NETTER-1 study of this agent has recently been reported to show promising results. In this article, we will summarize and evaluate the rationale and existing clinical data for the activity of DOTATATE in midgut NETs, to give context for the interpretation of NETTER-1 results when they are fully available. PMID- 26759063 TI - DNA methylation is critical for tooth agenesis: implications for sporadic non syndromic anodontia and hypodontia. AB - Hypodontia is caused by interactions among genetic, epigenetic, and environmental factors during tooth development, but the actual mechanism is unknown. DNA methylation now appears to play a significant role in abnormal developments, flawed phenotypes, and acquired diseases. Methylated DNA immunoprecipitation (MeDIP) has been developed as a new method of scanning large-scale DNA methylation profiles within particular regions or in the entire genome. Here, we performed a genome-wide scan of paired DNA samples obtained from 4 patients lacking two mandibular incisors and 4 healthy controls with normal dentition. We scanned another female with non-syndromic anodontia and her younger brother with the same gene mutations of the PAX9,MSX1,AXIN2 and EDA, but without developmental abnormalities in the dentition. Results showed significant differences in the methylation level of the whole genome between the hypodontia and the normal groups. Nine genes were spotted, some of which have not been associated with dental development; these genes were related mainly to the development of cartilage, bone, teeth, and neural transduction, which implied a potential gene cascade network in hypodontia at the methylation level. This pilot study reveals the critical role of DNA methylation in hypodontia and might provide insights into developmental biology and the pathobiology of acquired diseases. PMID- 26759065 TI - Increased expression of Talin1 in the eutopic and ectopic endometria of women with adenomyosis. AB - Adenomyosis is a prevalent gynecologic benign disease in women. Despite its significance, there is only a limited understanding of its pathological mechanisms. Talin1, a cytoskeletal protein, plays an important role in cell survival, proliferation, invasion and migration. The objective of this study was to investigate the mRNA and protein expression of talin1 in both the eutopic and ectopic endometria of women with adenomyosis. Higher talin1 mRNA levels were observed in both ectopic and eutopic endometria from the adenomyosis subjects compared with the eutopic endometria from women without adenomyosis. Immunohistochemistry revealed increased epithelial expression of talin1 in the ectopic and eutopic endometria from patients with adenomyosis compared with those without adenomyosis. When tests were performed on matched samples of eutopic and ectopic endometria of adenomyosis subjects, the mRNA and protein expression of talin1 was much higher in the ectopic endometria than in the eutopic endometria. The results reveal that the expression pattern of talin1 in the eutopic and ectopic endometria is enhanced in women with adenomyosis. Increased talin1 expression may play a role in the pathogenesis and development of adenomyosis. PMID- 26759066 TI - Wharton's jelly: The significance of absence. PMID- 26759067 TI - SIENA: Efficient Compilation of Selective Protein Binding Site Ensembles. AB - Structural flexibility of proteins has an important influence on molecular recognition and enzymatic function. In modeling, structure ensembles are therefore often applied as a valuable source of alternative protein conformations. However, their usage is often complicated by structural artifacts and inconsistent data annotation. Here, we present SIENA, a new computational approach for the automated assembly and preprocessing of protein binding site ensembles. Starting with an arbitrarily defined binding site in a single protein structure, SIENA searches for alternative conformations of the same or sequentially closely related binding sites. The method is based on an indexed database for identifying perfect k-mer matches and a recently published algorithm for the alignment of protein binding site conformations. Furthermore, SIENA provides a new algorithm for the interaction-based selection of binding site conformations which aims at covering all known ligand-binding geometries. Various experiments highlight that SIENA is able to generate comprehensive and well selected binding site ensembles improving the compatibility to both known and unconsidered ligand molecules. Starting with the whole PDB as data source, the computation time of the whole ensemble generation takes only a few seconds. SIENA is available via a Web service at www.zbh.uni-hamburg.de/siena . PMID- 26759069 TI - Exciton pumping across type-I gallium chalcogenide heterojunctions. AB - Quasi-two-dimensional gallium chalcogenide heterostructures are created by transferring exfoliated few-layer GaSe onto bulk GaTe sheets. Luminescence spectroscopy measurements reveal that the light emission from underlying GaTe layers drastically increases on heterojunction regions where GaSe layers make contact with the GaTe. Density functional theory (DFT) and band offset calculations show that conduction band minimum (CBM) (valance band maximum (VBM)) values of GaSe are higher (lower) in energy compared to GaTe, forming type-I band alignment at the interface. Consequently, GaSe layers provide photo-excited electrons and holes to GaTe sheets through relatively large built-in potential at the interface, increasing overall exciton population and light emission from GaTe. Observed results are not specific to the GaSe/GaTe system but observed on GaS/GaSe heterolayers with type-I band alignment. Observed experimental findings and theoretical studies provide unique insights into interface effects across dissimilar gallium chalcogenides and offer new ways to boost optical performance by simple epitaxial coating. PMID- 26759068 TI - Assessing the toxicity of Pb- and Sn-based perovskite solar cells in model organism Danio rerio. AB - Intensive development of organometal halide perovskite solar cells has lead to a dramatic surge in power conversion efficiency up to 20%. Unfortunately, the most efficient perovskite solar cells all contain lead (Pb), which is an unsettling flaw that leads to severe environmental concerns and is therefore a stumbling block envisioning their large-scale application. Aiming for the retention of favorable electro-optical properties, tin (Sn) has been considered the most likely substitute. Preliminary studies have however shown that Sn-based perovskites are highly unstable and, moreover, Sn is also enlisted as a harmful chemical, with similar concerns regarding environment and health. To bring more clarity into the appropriateness of both metals in perovskite solar cells, we provide a case study with systematic comparison regarding the environmental impact of Pb- and Sn-based perovskites, using zebrafish (Danio Rerio) as model organism. Uncovering an unexpected route of intoxication in the form of acidification, it is shown that Sn based perovskite may not be the ideal Pb surrogate. PMID- 26759070 TI - Women aged 50 to 74 should have mammogram every two years, say US guidelines. PMID- 26759071 TI - Accurate quantification of creatinine in serum by coupling a measurement standard to extractive electrospray ionization mass spectrometry. AB - Ambient ionization (AI) techniques have been widely used in chemistry, medicine, material science, environmental science, forensic science. AI takes advantage of direct desorption/ionization of chemicals in raw samples under ambient environmental conditions with minimal or no sample preparation. However, its quantitative accuracy is restricted by matrix effects during the ionization process. To improve the quantitative accuracy of AI, a matrix reference material, which is a particular form of measurement standard, was coupled to an AI technique in this study. Consequently the analyte concentration in a complex matrix can be easily quantified with high accuracy. As a demonstration, this novel method was applied for the accurate quantification of creatinine in serum by using extractive electrospray ionization (EESI) mass spectrometry. Over the concentration range investigated (0.166 ~ 1.617 MUg/mL), a calibration curve was obtained with a satisfactory linearity (R(2) = 0.994), and acceptable relative standard deviations (RSD) of 4.6 ~ 8.0% (n = 6). Finally, the creatinine concentration value of a serum sample was determined to be 36.18 +/- 1.08 MUg/mL, which is in excellent agreement with the certified value of 35.16 +/- 0.39 MUg/mL. PMID- 26759073 TI - In situ processed gold nanoparticle-embedded TiO2 nanofibers enabling plasmonic perovskite solar cells to exceed 14% conversion efficiency. AB - We have demonstrated organometallic perovskite solar cells (PSCs) based on Au decorated TiO2 nanofibers and methylammonium lead iodide (MAPbI3). A power conversion efficiency of 14.92% was achieved, which is significantly higher than that of conventional mesoporous (mp) TiO2, as well as TiO2 nanofiber-based devices. The present synthetic process provides new opportunities for the development of efficient plasmonic PSCs based on metal oxide nanofibers. Solar cells based on these architectures exhibit a short-circuit current density J(SC) of 21.63 +/- 0.36 mA cm(-2), V(OC) of 0.986 +/- 0.01 V and fill factor of 70% +/- 3%, which provide a power conversion efficiency of 14.92% +/- 0.33% under standard AM 1.5 conditions. The results of time-resolved photoluminescence (TRPL) spectroscopy and solid-state impedance spectroscopy (ssIS) revealed that PSCs based on Au-decorated TiO2 nanofibers exhibit a low recombination rate. The present results are much higher than those for reported PSCs based on a Au@TiO2 electron-transporting layer (ETL). PMID- 26759072 TI - Establishment of a novel in vitro model of stratified epithelial wound healing with barrier function. AB - The repair of wounds through collective movement of epithelial cells is a fundamental process in multicellular organisms. In stratified epithelia such as the cornea and skin, healing occurs in three steps that include a latent, migratory, and reconstruction phases. Several simple and inexpensive assays have been developed to study the biology of cell migration in vitro. However, these assays are mostly based on monolayer systems that fail to reproduce the differentiation processes associated to multilayered systems. Here, we describe a straightforward in vitro wound assay to evaluate the healing and restoration of barrier function in stratified human corneal epithelial cells. In this assay, circular punch injuries lead to the collective migration of the epithelium as coherent sheets. The closure of the wound was associated with the restoration of the transcellular barrier and the re-establishment of apical intercellular junctions. Altogether, this new model of wound healing provides an important research tool to study the mechanisms leading to barrier function in stratified epithelia and may facilitate the development of future therapeutic applications. PMID- 26759074 TI - Precision feeding can significantly reduce lysine intake and nitrogen excretion without compromising the performance of growing pigs. AB - This study was developed to assess the impact on performance, nutrient balance, serum parameters and feeding costs resulting from the switching of conventional to precision-feeding programs for growing-finishing pigs. A total of 70 pigs (30.4+/-2.2 kg BW) were used in a performance trial (84 days). The five treatments used in this experiment were a three-phase group-feeding program (control) obtained with fixed blending proportions of feeds A (high nutrient density) and B (low nutrient density); against four individual daily-phase feeding programs in which the blending proportions of feeds A and B were updated daily to meet 110%, 100%, 90% or 80% of the lysine requirements estimated using a mathematical model. Feed intake was recorded automatically by a computerized device in the feeders, and the pigs were weighed weekly during the project. Body composition traits were estimated by scanning with an ultrasound device and densitometer every 28 days. Nitrogen and phosphorus excretions were calculated by the difference between retention (obtained from densitometer measurements) and intake. Feeding costs were assessed using 2013 ingredient cost data. Feed intake, feed efficiency, back fat thickness, body fat mass and serum contents of total protein and phosphorus were similar among treatments. Feeding pigs in a daily basis program providing 110%, 100% or 90% of the estimated individual lysine requirements also did not influence BW, body protein mass, weight gain and nitrogen retention in comparison with the animals in the group-feeding program. However, feeding pigs individually with diets tailored to match 100% of nutrient requirements made it possible to reduce (P<0.05) digestible lysine intake by 26%, estimated nitrogen excretion by 30% and feeding costs by US$7.60/pig (-10%) relative to group feeding. Precision feeding is an effective approach to make pig production more sustainable without compromising growth performance. PMID- 26759075 TI - Motor recovery of stroke patients after rehabilitation: one-year follow-up study. AB - Purpose To investigate motor recovery of stroke patients 1 year after rehabilitation. Materials and Methods A cross-sectional study of 192 stroke patients discharged from rehabilitation wards in nine tertiary hospitals was conducted. Motor recovery was assessed using the Brunnstrom motor recovery stages (BMRS), at 6 and 12 months after discharge. Factors related to the BMRS of the hand, arm and leg were analyzed. Results The mean age of patients was 62.2 years (57.3% male). Significantly more patients presented improvement of at least one BMRS of the hand, arm and leg compared with those with decreasing BMRS (p < 0.001). The percentage of patients with BMRS III- VI at 6 months was greater than that at discharge, but the recovery at 12 months was slightly higher than that at 6 months. It seems that motor recovery from stroke was near maximal at six months. Regarding the factors related to motor recovery, only lengths of stay (LOS) <30 d during the first admission and Barthel index at discharge >=10 were related to the improvement of BMRS of the hand, arm and leg on multivariate analysis. Additionally, no complication at discharge was associated with the improvement of BMRS of the leg. Conclusions Approximately half of our stroke patients had motor improvement of at least one stage of BMRS at one year. Motor recovery after stroke at the end of the first year was associated with shorter LOS during the first admission, higher discharge Barthel index score and absence of complications at discharge. PMID- 26759076 TI - Transport properties of hierarchical micro-mesoporous materials. AB - Adding mesopore networks in microporous materials using the principles of hierarchical structure design is recognized as a promising route for eliminating their transport limitations and, therefore, for improving their value in technological applications. Depending on the routes of physico-chemical procedures or post-synthesis treatments used, very different geometries of the intentionally-added transport mesopores can be obtained. Understanding the structure-dynamics relationships in these complex materials with multiple porosities under different thermodynamical conditions remains a challenging task. In this review, we summarize the results obtained so far on experimental and theoretical studies of diffusion in micro-mesoporous materials. By considering four common classes of bi-porous materials, which are differing by the inter connectivities of their sup-spaces as one of the most important parameter determining the transport rates, we discuss their generic transport properties and correlate the results delivered by the equilibrium and non-equilibrium techniques of diffusion measurements. PMID- 26759077 TI - Use of a novel smart heating sleeping bag to improve wearers' local thermal comfort in the feet. AB - Previous studies have revealed that wearers had low skin temperatures and cold and pain sensations in the feet, when using sleeping bags under defined comfort and limit temperatures. To improve wearers' local thermal comfort in the feet, a novel heating sleeping bag (i.e., MARHT) was developed by embedding two heating pads into the traditional sleeping bag (i.e., MARCON) in this region. Seven female and seven male volunteers underwent two tests on different days. Each test lasted for three hours and was performed in a climate chamber with a setting temperature deduced from EN 13537 (2012) (for females: comfort temperature of 0.4 degrees C, and for males: the limit temperature of -6.4 degrees C). MARHT was found to be effective in maintaining the toe and feet temperatures within the thermoneutral range for both sex groups compared to the linearly decreased temperatures in MARCON during the 3-hour exposure. In addition, wearing MARHT elevated the toe blood flow significantly for most females and all males. Thermal and comfort sensations showed a large improvement in feet and a small to moderate improvement in the whole body for both sex groups in MARHT. It was concluded that MARHT is effective in improving local thermal comfort in the feet. PMID- 26759078 TI - Titanium Mesh Technique in Rehabilitation of Totally Edentulous Atrophic Maxillae: A Retrospective Case Series. AB - BACKGROUND: This study evaluates implant-borne prosthetic rehabilitation of 10 totally edentulous atrophic maxillae after bone reconstruction with a titanium mesh technique and particulate bone graft. METHODS: Ten atrophic maxillae were reconstructed with 19 titanium meshes and particulate autologous-heterologous bone. Maxillae were rehabilitated at least 5 months, with placement of 67 implants connected to the prostheses after an additional 4 months of rehabilitation. Cases were evaluated retrospectively in terms of complication rates, particularly on the amount of mesh exposure, implant survival, and success rates at the end of follow-up. RESULTS: In seven cases, two meshes were prematurely exposed (within 4 to 6 weeks), and five were exposed later (after 4 to 6 weeks). Only two of the later exposures extended >1 cm(2). Nevertheless, reconstructions allowed implant placement and prosthetic rehabilitation in all cases. Two implants were lost before loading. After mean follow-up at 39.3 (20 to 56) months since prosthetic loading, all 65 implants were functional (100% implant survival), but 15 implants demonstrated a peri-implant mean bone resorption of 2.96 mm increased bone loss, yielding a cumulative implant success rate of 76.9%. No prosthetic problem was observed. CONCLUSIONS: Use of titanium mesh with particulate bone can be considered a valid option in reconstructing atrophic maxillae to allow for implant-borne prosthetic rehabilitation. A high level of dehiscence did not compromise final outcome. PMID- 26759082 TI - Mycobacterium tuberculosis-Secreted Tyrosine Phosphatases as Targets Against Tuberculosis: Exploring Natural Sources in Searching for New Drugs. AB - Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which primarily affects the respiratory tract. Combinations of drugs are used for therapeutic synergism and to prevent the emergence of drug resistant strains, but even first- or secondchoice drugs present some disadvantages, such as significant side effects and the need for long duration of treatments. Thus, new strategies for TB control and treatment are highly demanded. In this context, protein tyrosine phosphatases (PtpA and PtpB) are secreted by Mtb within the host macrophage and they have been shown to contribute to Mtb pathogenicity. The understanding of the role of these PTPs has led to interesting anti-TB drugs discovery. Here, we review the current knowledge on these two proteins as targets for novel anti-TB therapies, with particular emphasis on their mechanism of action and current advancements in developing small molecule inhibitors from natural sources. PMID- 26759081 TI - Chromatin topology is coupled to Polycomb group protein subnuclear organization. AB - The genomes of metazoa are organized at multiple scales. Many proteins that regulate genome architecture, including Polycomb group (PcG) proteins, form subnuclear structures. Deciphering mechanistic links between protein organization and chromatin architecture requires precise description and mechanistic perturbations of both. Using super-resolution microscopy, here we show that PcG proteins are organized into hundreds of nanoscale protein clusters. We manipulated PcG clusters by disrupting the polymerization activity of the sterile alpha motif (SAM) of the PcG protein Polyhomeotic (Ph) or by increasing Ph levels. Ph with mutant SAM disrupts clustering of endogenous PcG complexes and chromatin interactions while elevating Ph level increases cluster number and chromatin interactions. These effects can be captured by molecular simulations based on a previously described chromatin polymer model. Both perturbations also alter gene expression. Organization of PcG proteins into small, abundant clusters on chromatin through Ph SAM polymerization activity may shape genome architecture through chromatin interactions. PMID- 26759080 TI - Promotion of a cancer-like phenotype, through chronic exposure to inflammatory cytokines and hypoxia in a bronchial epithelial cell line model. AB - Globally, lung cancer accounts for approximately 20% of all cancer related deaths. Five-year survival is poor and rates have remained unchanged for the past four decades. There is an urgent need to identify markers of lung carcinogenesis and new targets for therapy. Given the recent successes of immune modulators in cancer therapy and the improved understanding of immune evasion by tumours, we sought to determine the carcinogenic impact of chronic TNF-alpha and IL-1beta exposure in a normal bronchial epithelial cell line model. Following three months of culture in a chronic inflammatory environment under conditions of normoxia and hypoxia (0.5% oxygen), normal cells developed a number of key genotypic and phenotypic alterations. Important cellular features such as the proliferative, adhesive and invasive capacity of the normal cells were significantly amplified. In addition, gene expression profiles were altered in pathways associated with apoptosis, angiogenesis and invasion. The data generated in this study provides support that TNF-alpha, IL-1beta and hypoxia promotes a neoplastic phenotype in normal bronchial epithelial cells. In turn these mediators may be of benefit for biomarker and/or immune-therapy target studies. This project provides an important inflammatory in vitro model for further immuno-oncology studies in the lung cancer setting. PMID- 26759083 TI - One Hundred Faces of Cyclopamine. AB - The natural steroidal alkaloid cyclopamine has been identified as the first inhibitor of the Hedgehog (Hh) signaling pathway, which is implicated in embryonic development and tumorigenesis, as well as is hyperactivated in cancer stem cells (CSCs). The list of Hh-dependent tumors is steadily growing, and it has been estimated that about 25% of all cancer deaths show signs of aberrant Hh pathway activation. Notably, cyclopamine has been found to exert anticancer activity against several types of human cancer and to inhibit CSCs proliferation, thus highlighting the druggability of the Hh pathway and paving new opportunities in anticancer drug discovery. The aim of the present work is to review the main synthetic strategies to cyclopamine and its derivatives, with particular emphasis on the challenging chemical modifications aimed at improving the biological activity of the molecule. PMID- 26759085 TI - Dehydrogenative coupling of silanes with alcohols catalyzed by Cu3(BTC)2. AB - Cu3(BTC)2 is an efficient and reusable heterogeneous catalyst for the dehydrogenative coupling of silanes with alcohols. Activity data and CO adsorption suggest that Cu(II) and in situ generated Cu(I) are the active species. Other MOFs such as Fe(BTC), MIL-101(Cr) and UiO-66(Zr) are unable to promote this cross-coupling. PMID- 26759084 TI - Early Presentation of Hyperinsulinism/Hyperammonemia Syndrome in Three Serbian Patients. AB - Hyperinsulinism/hyperammonemia (HI/HA) syndrome is considered as the second most common type of hereditary HI. Correlation of genotype and phenotype in HI/HA syndrome has been described in several studies. We present three Serbian patients with HI/HA syndrome with emphasis on a possible correlation between genotype and clinical manifestations. Patient 1 was heterozygous for a de novo mutation p.S445L in the GLUD1 gene, while patients 2 and 3 (son and mother) both carry the p.R221C mutation. Early onset of hypoglycaemia with generalized seizures was recorded in infancy in all three patients. The two male patients had mild developmental delay, while the female patient presented with epilepsy. Analysis of Serbian patients with HI/HA syndrome confirms the association of p.S445L and p.R221C mutations with hypoglycaemic seizures noted within the first three months of life and with subsequent risk for cognitive impairment and/or epilepsy. PMID- 26759095 TI - Gene therapy with IL-12 induced enhanced anti-tumor activity in fibrosarcoma mouse model. AB - Context Immunotherapy is among the most promising modalities for treatment of cancer. Recently, interleukin 12 (IL-12) has been used as an immunotherapeutic agent in cancer gene therapy. IL-12 can activate dendritic cells (DCs) and boost anti-tumor immune responses. Objective In the current study, we have investigated if IL-12 gene therapy can lead to the regression of tumor mass in a mouse model of fibrosarcoma. Material and methods To investigate the therapeutic efficacy of IL-12, WEHI-164 tumor cells were transfected with murine-IL12 plasmids using Lipofectamine. Enzyme linked immunosorbent assay (ELISA) was used to confirm IL 12 expression in transfected cells. The fibrosarcoma mouse model was established by subcutaneous injection of transfected cells to Balb/C mice. Mice were sacrificed and the tumors were extracted. Tumor sizes were measured by caliper. The expression of IL-12 and IFN-gamma was studied with real-time PCR and western blotting. The expression of Ki-67(a tumor proliferation marker) in tumor mass was studied by immunohistochemistry staining. Results and discussion The group treated with IL-12 showed a significant decrease in tumor mass volume (P: 0.000). The results of real-time PCR and western blotting showed that IL-12 and IFN-gamma expression increased in the group treated with IL-12 (relative expression of IL 12: 1.9 and relative expression of IFN-gamma: 1.766). Immunohistochemistry staining showed that Ki-67 expression was reduced in the group treated with IL 12. Conclusion IL-12 gene therapy successfully led to regress of tumor mass in the fibrosarcoma mouse model. This may serve as a candidate therapeutic approach for treatment of cancer. PMID- 26759097 TI - [Current status and challenges of diagnosis and monitoring of hematologic malignancies]. PMID- 26759096 TI - Early detection and treatment of lame cows. Effect on duration and prevalence of lesion-specific lameness. AB - OBJECTIVE: The aim of this study was to investigate the impact of specific hoof lesions on the locomotion score (LS) as well as the effect of early detection and treatment on duration and prevalence of lesion-specific lameness. MATERIAL AND METHODS: In a dairy herd in Lower Saxony, Germany, with 144 lactating cows, claw trimming was performed by a professional claw trimmer at the beginning and the end of a 41-week trial period. Weekly a veterinarian assessed the LS according to Sprecher et al. (1997) in 99 cows. The front and hind claws of cows with an LS > 1 were examined and treated within 5 days. For individual diagnoses, the duration of lameness was calculated as the number of weeks from first treatment until recovery (LS = 1). RESULTS: In total, 580 examinations and treatments were performed on 94 cows. There were 189 new lameness cases with a total of 290 diagnoses. At the first treatment, 81.0% of the cows displayed an LS of 2. Cows with digital dermatitis (DD), heel horn erosion and white line disease (WLD) more often had an LS > 2 compared to cows with Rusterholz' sole ulcer, interdigital hyperplasia or inadequate claw length/posture (p < 0.05). Cows with only one affected leg, more often had an LS > 2 than cows with several affected legs (p < 0.1). Lameness caused by WLD and arthritis/periarthritis remained for the longest time period. The prevalence of sole haemorrhages and/or double soles, WLD, interdigital dermatitis and interdigital hyperplasia decreased significantly during the test period. Prevalence of sole ulcer (sole ulcer and Rusterholz' sole ulcer) and DD remained unaffected. CONCLUSION AND CLINICAL RELEVANCE: Locomotion score was affected by the type of claw/limb disorder and the number of diseased limbs. Regular locomotion scoring and continuous treatment of cows with an LS > 1 is associated with a decrease in the prevalence of several claw lesions. Therefore, prevalence of severe claw lesions like WLD, which was associated with a long duration of lameness, can be reduced. In contrast, for decreasing prevalence of digital dermatitis more than weekly treatment of every cow with LS > 1 is required. Preventive measures like footbaths or improved hygiene should accompany the individual animal treatment. PMID- 26759098 TI - [Clinical significance of monitoring E2A- PBX1 fusion gene expression in patients with allogeneic hematopoietic stem cell transplantation]. AB - OBJECTIVE: To investigate the clinical characteristics of E2A-PBX1(immunoglobulin enhancer binding factor-pre-B leukemia)fusion gene in patients with acute lymphoblastic leukemia(ALL) after allogeneic stem cell transplantation(allo HSCT). METHODS: Clinical data of 10 patients received allo- HSCT in Peking University Institute of Hematology from December 2010 to January 2015 were retrospectively collected. The E2A-PBX1 gene was examined by real-time quantitative polymerase chain reaction(RQ- PCR). The correlation between its expression level and the disease status was analyzed. RESULTS: Among 10 cases of enrolled ALL, the E2A-PBX1 expression of six patients converted to positive after transplant at a median time of 90 days(range, 75-180 days). The expression level of the first positive sample was 25.200%(range, 0.022%-353.600%). The duration from E2A-PBX1 positive to hematological relapse was 30 days(range, 0-74 days). Finally, 4 patients underwent relapse at a median time of 164 days (range, 75- 240 days) after allo- HSCT. The expression of E2A- PBX1 and minimal residual disease (MRD)level examined by flow cytometry were positive correlated(Spearman r=0.743, P=0.002). Once E2A-PBX1 expression converted to positive after transplant, MRD would increase rapidly. Patients with this type of ALL would have little response to the current intervention towards relapse. CONCLUSION: Monitoring E2A-PBX1 by RQ-PCR could be used to evaluate MRD status after allo HSCT. Patients with positive E2A-PBX1 at early stage of transplant will have a poor prognosis. PMID- 26759099 TI - [Analysis of KIR3DL1 expression levels on 92 cases of normal donors for hematopoietic stem cells transplant]. AB - OBJECTIVE: To study KIR3DL1 expression level on NK cell surface of normal donors for hematopoietic stem cell transplantation(HSCT). METHODS: Ninety- two donors were performed by using of KIR genotyping, HLA high resolution genotyping and KIR3DL1 expression level using sequencebased testing(SBT), PCR- sequence specific primer(SSP)and flow cytometry methods. RESULTS: In 92 donors, the frequencies of KIR-A/A, Bx1, Bx2 for common genotypes were 46.74%(43/92), 18.48% (17/92)and 9.78%(9/92)respectively(P<0.001); KIR-A, B1, B2, B3 for common KIR haplo-type were 70.33%(128/182), 10.99%(20/182), 7.14%(13/182) and 4.39%(8/182) respectively(P<0.001); the frequencies of HLA-BW4/BW4, HLA-BW4/BW6, BW6/BW6 ligands were 13.79%, 67.81% and 18.39% respectively(P<0.001). KIR3DL1 middle expression level among haplo- type KIR- A/A and KIR- Bx, KIR-B/B were 18.77%(3.11%-49.24%), 13.14%(1.70%-63.32%)and 0.37%(0.20%-2.60%)respectively (P<0.05). KIR3DL1 expression level[18.77%(3.11%-49.24%)]in haplo-type KIR-A/A was higher than haplo-type KIR-Bx at the same time did not express 2DL2 group[11.20%(3.50%-36.08%)](P=0.019). KIR3DL1 expression level in recognition group(HLA-BW4 positive group)[17.61%(1.40%-49.24%)] was higher than KIR3DL1 unrecognized group(HLA-BW4 negative group)[10.60%(3.50%-18.56%)] (P=0.006). CONCLUSION: The expression levels of KIR3DL1 in different KIR genotypes, haplotypes and HLA ligands were statistically significance. PMID- 26759100 TI - [Impacts of ABO incompatibility on early outcome after single unit unrelated cord blood transplantation: a retrospective single center experience]. AB - OBJECTIVE: To retrospectively study the impacts of ABO incompatibility on early outcome after single unit unrelated cord blood transplantation(UCBT), such as cumulative incidence of engraftment, incidence of acute graft- versus- host disease (aGVHD) and 180- day transplant- related mortality(TRM). METHODS: 208 patients underwent single unit UCBT from April 2008 to October 2014 were analyzed, included 99 ABO- identical, 60 minor, 38 major and 11 bidirectional ABO incompatible recipients. All the patients received intensified myeloablative conditioning, and a combination of cyclosporine A and mycophenolate mofetil was given for GVHD prophylaxis. RESULTS: Cumulative incidences of neutrophil engraftment, platelet recovery, erythroid lineage reconstitution, II-IV aGVHD, III-IV aGVHD and 180- day TRM showed no significant difference among the patients receiving ABOidentical, minor, major, and bidirectional UCBT(all P>0.05, respectively). What's more, none of the patients developed pure red- cell aplasia(PRCA)after UCBT. Group A donor and a group O recipient patients didn't appeared to influence the clinical results when compared with others(all P>0.05, respectively). CONCLUSION: Patients receive ABO- incompatible UCBT may not develop PRCA. The presence of ABO- incompatibility did not influence the hematopoietic reconstitution, the incidence of aGVHD and 180-day TRM in this cohort. There is not support for the need to regard ABO-compatibility as an UCB graft selection criterion. PMID- 26759101 TI - [Outcomes of allogeneic hematopoietic stem cell transplantation for 18 patients with paroxysmal nocturnal haemoglobinuria]. AB - OBJECTIVE: To evaluate the outcomes of allogeneic hematopoietic stem cell transplantation(allo-HSCT)for paroxysmal nocturnal haemoglobinuria(PNH)and aplastic anemia(AA)- PNH syndrome. METHODS: The clinical data of 18 PNH or AA-PNH patients, including 4 classic PNH and 14 AA-PNH, received allo-HSCT from Dec 2007 to Feb 2015 were analyzed retrospectively. Nine patients received HLA haploidentical donor HSCT(1 patient received salvage HLA-haploidentical donor HSCT after the graft failure of double cord blood transplantation), 7 patients received HLA-identical sibling donor HSCT, and 2 HLA-identical unrelated donor HSCT. The conditioning regimens were as follow: 13 patients received modified BU/CY- based regimens, 5 non- myeloablative regimens [fludarabine (Flu) + antithymocyte globulin(ATG)+ cyclophosphamide(CY)or busulfan(BU)]. Prophylaxis for graft- versushost disease(GVHD): the patients with HLA-identical sibling donor received cyclosporine(CsA)plus short-term methotrexate(MTX), the patients with HLA -haploidentical donor or HLA-identical unrelated donor received CsA or tacrolimus(FK506)+ mycophenolate mofetil(MMF)+ short- term methotrexate (MTX). RESULTS: All patients were engrafted successfully(1 patient engrafted by haploidentical donor after the graft failure of double cord blood transplantation). The median days of neutrophils(ANC)above 0.5 * 109/L and platelets (PLT) more than 20 * 109/L were 11(10- 26)days and 15(11- 120)days, respectively. Three patients(17.6%)developed acute GVHD(aGVHD), 2 for grade II aGVHD, 1 for grade IV aGVHD. Of 16 patients, 2 occurred limited chronic GVHD(cGVHD). After a median follow-up of 14.6(2.0-86.7)months, 3 patients(17.6%)died, out of which one died of severe aGVHD, one died of severe pulmonary infection, one pulmonary infection with transplant- associated thrombotic microangiopathy. The 5- year estimated disease free survival was(80.5 +/- 10.2)%. No patient relapsed. CONCLUSION: Allo-HSCT is an effective and curable therapy for PNH or AA-PNH with improved prognosis, and offers a valid therapeutic option for these patients before humanized monoclonal antibody against C5 are widely used clinically. PMID- 26759102 TI - [Blastic plasmacytoid dendritic cell neoplasm without skin lesion: a case report]. PMID- 26759103 TI - [Short-term effects of hemogram in healthy donors after peripheral blood stem cell collection]. AB - OBJECTIVE: To observe the short- term effects of hemogram in donors after peripheral blood stem cell(PBSC)collection and donors' tolerance. METHODS: A total of 166 related allogeneic donors were selected from The First Affiliated Hospital of Medical School of Zhejiang University between January 2013 and December 2014, including 86 male and 80 female. All donors accepted granulocytecolony- stimulating factor(G-CSF)5-10 MUg.kg-1.d-1 until collection finished and were measured by blood cells count before and after PBSC collection. RESULTS: After PBSC collection, the hemoglobin level decreased from 145(94 181)g/L to 138(93-167)g/L, and the platelet counts decreased in all donors from 231(105- 490)* 109/L to 95(39- 210)* 109/L. The amount of hemoglobin contamination in collection products was weak correlated with the decreased hemoglobin in peripheral blood(r=0.297, P=0.017), and the platelet contamination was high correlated with that decreased in peripheral blood(r=0.719, P<0.001). The decline of hemoglobin level after twice PBSC collection was of no significant difference between four groups in different ages(P>=0.05). The decline of platelet counts was out of a significant difference(P> 0.05). In addition, the decline of hemoglobin level after once and twice PBSC collection was of a significant difference between four groups in different body mass index(BMI)(P=0.003 and P<0.001), especially in thinner group with obvious decrease. But the decline of platelet counts was out of a significant difference (P>0.05). CONCLUSION: The hemoglobin level decreased mildly in healthy allogeneic hematopoietic stem cell donors after PBSC collection and it is better to adjust parameters every time to ensure their safety for thinner donors. However, it will increase the risk of platelet decline, which is unrelated with ages and BMI and can be tolerated. PMID- 26759104 TI - [Autophagy level of bone marrow mononuclear cells in patients with myelodysplastic syndromes]. AB - OBJECTIVE: To investigate the change of autophagy level of bone marrow mononuclear cells(BMMNCs)in patients with myelodysplastic syndromes(MDS). METHODS: Thirty- eight patients with MDS and 26 megaloblastic anemia patients were enrolled in this study. The autophagic vacuoles were observed by transmission electron microscopy (TEM) and the quantity of autophagic vacuoles was detected by monodansylcadaverine (MDC) staining. The LC3 protein positive cells were counted by immunofluorescence assays. The expression of Beclin 1, LC3A, mTOR mRNA were measured by real time PCR. The expression of Beclin 1 proteins were detected by Western blotting. RESULTS: The autophgic vacuoles of double membrane that surrounds lysosomes appeared in MDS patients. The percentage of MDC positive cells was significantly higher in MDS patients[(9.75+/ 2.63)%]than that of controls[(2.90+/- 0.89)%, P<0.05). The percentage of LC3 protein cells was also increased in MDS patients(6.13+/-1.03)% vs(1.5+/-0.58)%, P<0.05). The expression of Beclin 1 and LC3A mRNA in low-risk and intermediate-1 MDS were higher compared with controls (3.61 +/- 3.02 vs 1.55 +/- 1.03 and 6.56 +/- 3.97 vs 1.21 +/- 0.95 respectively, both P<0.05). The expression of mTOR mRNA was down- regulated in low- risk and intermediate-1 MDS compared with controls(0.39+/-0.37 vs 1.50+/-1.03, P<0.05). There were no significant difference in expression of Beclin 1, LC3 and mTOR mRNA among intermediate-2 and high-risk MDS and controls. Beclin 1 protein expression was higher in low- risk and intermediate- 1 MDS patients(1.257 +/- 0.197)than that of controls(0.528+/ 0.086)and inermediate-2 and high-risk MDS patients(0.622+/-0.118). CONCLUSION: The autophagy levels were increased in low- risk and intermediate- 1 MDS, while not enhanced in intermediate-2 MDS. Autophagy might be considered as a cell protective mechanism in MDS. The relatively defective autophagy in intermediate- 2 and high- risk MDS might contribute to disease's progression. PMID- 26759105 TI - [Clinical features and risk factors for infections in adult acute leukemia after chemotherapy]. AB - OBJECTIVE: To observe the clinical characteristics of infections in adult acute leukemia (AL)patients during chemotherapy in hospital, and identify the risk factors for infections. METHODS: A retrospective study of patients with AL who underwent chemotherapy between July 2010 and Dec 2014 in the First Affiliated Hospital of Xiamen University was conducted. Clinical features and risk factors for infections were analyzed. RESULTS: 191 patients with AL received a total of 728 courses of chemotherapies. During these admissions, 385(52.9%) infections episodes occurred. The common infections sites were lower respiratory tract infection(36.3%,153/374), bloodstream infection(17.1%, 64/374), oral infection(13.6%,51/374), and perianal infection(13.4%, 50/374). 164 strains of pathogenic bacteria were detected. Gram- negative bacteria were recorded in 59.1% of documented pathogens, and Gram- positive bacteria were responsible for 32.9% of infections. Multivariate unconditioned logistic analysis of factors identified consistent independent risk factors for no completely remission(OR=0.142, P< 0.001), duration of neutropenia longer than 7 days(OR=12.764, P<0.001), general wards(OR=1.821, P< 0.001), and hospitalization interval longer than 10 days(OR=0.720, P=0.039). CONCLUSION: Infections after chemotherapy for AL continues to be common. AL patients with induction chemotherapy or severe neutropenia faced an increased risk of infections by multivariate analysis. And patients with short-term stay or laminar flow wards seem to be less susceptible to infections. PMID- 26759106 TI - [Outcomes of refractory or relapsed DNMT3A + cytogenetically normal acute myeloid leukemia patients followed the therapy including decitabine combined with CAG or CAG-like regimen]. AB - OBJECTIVE: To study clinical characteristics of refractory or relapsed DNMT3A+ cytogenetically normal acute myeloid leukemia(CN-AML)patients, and to explore the overall response rate(ORR)and side effects of these patients followed the therapy including decitabine with CAG or CAGlike regimen. METHODS: In this study we retrospectively analyzed 53 refractory or relapsed CN- AML patients receiving the therapy including decitabine combined with CAG and CAG- like regimen in our center from April 2011 to October 2014. The clinical characteristics and ORR were further analyzed. Based on gene mutations, these patients could be divided into 2 groups: DNMT3A+ AML patients(n=24)and DNMT3A- AML patients(n=29). RESULTS: The median age of DNMT3A+AML patients was 46 years old, higher white blood cells and bone marrow blasts were observed in DNMT3A+ AML group. The ORR and complete response(CR)rate of DNMT3A+ group were 62.50% and 54.17%, respectively. No differences were observed in ORR and CR rates(P>0.05)between these two groups. DNMT3A+/FLT3-ITD+ CN-AML patients(n=14)had higher ORR and CR rates than DNMT3A /FLT3-ITD+CN- AML patients(n=15)(P= 0.040 and 0.042, respectively). The one- year overall survival (OS) of DNMT3A+ AML group and DNMT3A- AML group were 59.58% , 54.09% , no differences were observed (P=0.438). 25 patients received further therapy of allo-HSCT, the one-year OS of DNMT3A+ CN-AML was 87.50% and one-year disease free survival(DFS)was 72.73%, while the one- year OS was 61.54% and one- year DFS was 58.02% in DNMT3A- group. No differences were observed between 2 groups (P=0.456, 0.217). CONCLUSION: Decitabine combined with CAG or CAG-like regimen was an effective and safe treatment for refractory or relapsed CN- AML patients. Compared to DNMT3A-/FLT3- ITD+ CN- AML patients, DNMT3A+/ FLT3-ITD+ CN AML patients had higher ORR and CR rates. Decitabine bridged hematopoietic stem cells transplant could likely improve the survival of refractory or relapsed CN AML patients. PMID- 26759107 TI - [Classification therapy in 405 children with immune thrombocytopenia]. AB - OBJECTIVE: To explore the efficiency and safety of immune thrombocytopenia(ITP)in children through classification treatment. METHODS: 405 newly diagnosed ITP patients were enrolled in this study from January 1st 2013 to August 31st 2014. The cases were divided into observation group and therapy group according to the initial platelet count of less than 20*109/L or the cases of active bleeding. There were 104 male cases and 76 female cases in observation group with the media platelet count of 46 (20-89)*109/L. They were followed up with a median of 20 months. The therapy group,including 131 males and 94 females with a median platelet count of 11(1-19)*109/L, were followed up by 22 months. RESULTS: The total curative rate at acute period was 80.44%(181/225)in therapy group with the first line treatment. In observation group, 148 cases(82.22%)reached complete response(CR)or response(R) criteria. 44 patients came into persistent period with an effective rate of 34.09%(15/44)in therapy group. The overall effectiveness over one year was 87.11%(196/255). In observation group, 32 cases came into persistent period and 13 cases(40.63%)got the CR or R line. After one year of observation, 161 cases (89.44%)reached the CR or R standard. In therapy group, 5 out of 29 patients(17.24%)in chronic period got CR or R. While in observation group, 6 out of 19 cases(31.58%)reached the CR or R standard. The elder children over 10 years had risk factors in response in two groups. There was no severe bleeding or adverse effect or dead cases in this study. CONCLUSION: It is reasonable to take platelet count <20*109/L and(or)active bleeding as the dividing line for classification therapy indications. Nearly half of the cases could avoid over therapy and decreased the risk of drugs side effect to improve life quality. PMID- 26759108 TI - [Abnormal expression of IL- 23/IL- 17 axis in peripheral blood of 45 patients with primary immune thrombocytopenia]. AB - OBJECTIVE: To investigate the expression of IL- 23/IL- 17 axis in peripheral blood of patients with primary immune thrombocytopenia (ITP) and its clinical significance. METHODS: The real-time quantitative reverse transcription polymerase chain reaction(RT-PCR)was used to determine the expression of IL 23p19, p40, p35, IL-23R, IL-12Rbeta1, IL-12Rbeta2, IL-17A, IL-17F mRNA in the peripheral blood of 45 ITP patients and 30 healthy controls. The correlations between the expression of IL-23 and IL- 17, platelet counts, serum cytokine concentrations of ITP patients were analyzed. Furthermore, nine newly diagnosed ITP patients were followed up during treatment. RESULTS: The gene expressions of IL-23p19, p40, IL-23R, IL-12Rbeta1, IL-17A, IL-17F in ITP patients were significantly higher than those in healthy controls, the relative expression levels of ITP were 5.58, 2.13, 4.20, 2.45, 4.29, 2.50 times as much as that of healthy controls. And elevated serum IL-23[(198.70+/-94.56)ng/L vs(50.72+/ 22.97)ng/L, t= 10.06, P<0.001], IL-17[(85.25+/-21.97)ng/L vs(11.39+/-4.27)ng/L, t=21.94,P<0.001]levels were also observed in these ITP patients. In addition, the serum IL-23 level in ITP patients was positively correlated with IL-17(r=0.496, P<0.01), but negatively correlated with the platelet counts(r=-0.408, P<0.01), and IL-17 level was negatively correlated with platelet counts(r=-0.464, P<0.01). CONCLUSION: The IL-23/IL- 17 expression in ITP patients was significantly elevated, indicating IL-23/IL-17 play an important role in the pathogenesis of ITP. PMID- 26759109 TI - [MRI for assessment of iron overload in patients with hematologic disease]. AB - OBJECTIVE: Compare the characteristics of magnetic resonance imaging(MRI)liver T2*, cardiac T2* and serum ferritin on the assessment of iron overload. METHODS: A total of sixty-nine patients from November 2011 to June 2014 were enrolled in this study. Their cardiac and liver iron concentration levels were measured through MRI examination, with other clinical data were collected to perform statistical analysis. RESULTS: The correlation between liver T2* and adjusted serum ferritin(ASF) was statistically significant(P=0.003). However, no significant correlation was found between cardiac T2* and liver T2*, ASF, respectively. According to the statistical analysis of the 69 cases, it is found that the number of iron overload cases diagnosed by liver T2* was 62 and 20 cases were severe iron overload (32.26%); the number of iron overload cases diagnosed by ASF was 47 and 14 cases were severe iron overload(29.79%), while the number of iron overload cases diagnosed by cardiac T2* was only 25 and no severe iron overload cases. CONCLUSION: Since SF was affected by other factors, it cannot reflect the level of iron overload in human body objectively. Now, liver T2* has become the gold standard for assessment of iron overload because of its good reliability and repeatability. However, cardiac T2* cannot correctly be used as assessment for iron overload, and it is only a method of evaluating the level of cardiac iron deposition. PMID- 26759110 TI - [Crosstalk between hematopoietic stem cells and immune system]. PMID- 26759111 TI - [Advances of aberrant signaling pathways and related targeting drugs in B cell non- Hodgkin lymphoma]. PMID- 26759112 TI - [Outline of bleeding scores in idopathic immune thrombocytopenia]. PMID- 26759113 TI - [Research advances in primary breast lymphoma]. PMID- 26759114 TI - Prediabetes and Cardiovascular Parameters in Obese Children and Adolescents. AB - OBJECTIVE: In this study, our aim was to determine cardiovascular risk and cardiac function in prediabetic obese children and adolescents. METHODS: The study was conducted on 198 obese children and adolescents 6-18 years of age. Anthropometric measurements, blood pressure measurements, oral glucose tolerance test, lipid profile, and HbA1c levels of patients were assessed. Prediabetes was defined according to American Diabetes Association criteria. Left ventricular mass index (LVMi), carotid intima-media thickness (c-IMT), and tissue Doppler measurements records were used. RESULTS: LVMi was found to be significantly higher in the prediabetes group (p=0.03). There were no statistically significant differences in right ventricular tissue Doppler measurements between the prediabetic and non-prediabetic groups. Left ventricular tissue Doppler measurements were significantly higher in the prediabetes group: LVEEM (left ventricular E/e ratio) (p=0.04); LVEM (left ventricular myocardial velocity cm/s) (p=0.035). LVMi was found to positively correlate with triglyceride level, diastolic blood pressure, waist circumference, body weight standard deviation score and to negatively correlate with high-density lipoprotein cholesterol (p=0.043, r=0.15; p=0.039, r=0.15; p=0.025, r=0.17; p=0.009, r=0.19; p=0.038, r= 0.15, respectively). LVEM was correlated with glucose (p=0.046, r=0.15) and LVEEM was correlated with systolic blood pressure (p=0.035, r=0.15). In linear regression analysis for clinical cardiovascular risk factors, fasting glucose level was the best predictor of LVEM. CONCLUSION: In this study, deterioration of cardiac function in prediabetic obese children and adolescents was shown. We recommend determining cardiovascular risk and cardiac dysfunction at early stages in prediabetic obese children and adolescents. PMID- 26759115 TI - Effects of 2,4-dichlorophenoxyacetic acid on the ventral prostate of rats during the peri-pubertal, pubertal and adult stage. AB - The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) is used on a wide variety of terrestrial and aquatic broadleaf weeds. 2,4-D has been shown to produce a wide range of adverse effects on animal and human health. The aim of the current study was to evaluate the effects of pre- and postnatal exposure to 2,4-D on rat ventral prostate (VP). Pregnant rats were exposed daily to oral doses of 70 mg/kg/day of 2,4-D from 16 days of gestation up to 23 days after delivery. Then, the treated groups (n = 8) were fed with a 2,4-D added diet until sacrificed by decapitation on postnatal day (PND) 45, 60, or 90. Morphometric studies were performed and androgen receptor (AR) protein levels in the VP were determined. AR, insulin-like growth factor-I (IGF-1) and insulin-like growth factor-I receptor (IGF-1R) mRNA expression in the VP along with testosterone (T), dihydroxytestosterone (DHT), growth hormone (GH) and IGF-1 serum levels were also determined to ascertain whether these parameters were differentially affected. Results of this study showed that 2,4-D exposure during gestation and until adulthood altered development of the prostate gland in male rats, delaying it at early ages while increasing its size in adults, indicate that 2,4-D could behave as endocrine disruptors (EDs). PMID- 26759116 TI - Dynamic nuclear polarization by frequency modulation of a tunable gyrotron of 260GHz. AB - An increase in Dynamic Nuclear Polarization (DNP) signal intensity is obtained with a tunable gyrotron producing frequency modulation around 260GHz at power levels less than 1W. The sweep rate of frequency modulation can reach 14kHz, and its amplitude is fixed at 50MHz. In water/glycerol glassy ice doped with 40mM TEMPOL, the relative increase in the DNP enhancement was obtained as a function of frequency-sweep rate for several temperatures. A 68 % increase was obtained at 15K, thus giving a DNP enhancement of about 80. By employing lambda/4 and lambda/8 polarizer mirrors, we transformed the polarization of the microwave beam from linear to circular, and achieved an increase in the enhancement by a factor of about 66% for a given power. PMID- 26759117 TI - Inactivation of Dengue and Yellow Fever viruses by heme, cobalt-protoporphyrin IX and tin-protoporphyrin IX. AB - AIMS: To investigate the effect of heme, cobalt-protoporphyrin IX and tin protoporphyrin IX (CoPPIX and SnPPIX), macrocyclic structures composed by a tetrapyrrole ring with a central metallic ion, on Dengue Virus (DENV) and Yellow Fever Virus (YFV) infection. METHODS AND RESULTS: Treatment of HepG2 cells with heme, CoPPIX and SnPPIX after DENV infection reduced infectious particles without affecting viral RNA contents in infected cells. The reduction of viral load occurs only with the direct contact of DENV with porphyrins, suggesting a direct effect on viral particles. Previously incubation of DENV and YFV with heme, CoPPIX and SnPPIX resulted in viral particles inactivation in a dose-dependent manner. Biliverdin, a noncyclical porphyrin, was unable to inactivate the viruses tested. Infection of HepG2 cells with porphyrin-pretreated DENV2 results in a reduced or abolished viral protein synthesis, RNA replication and cell death. Treatment of HepG2 or THP-1 cell lineage with heme or CoPPIX after DENV infection with a very low MOI resulted in a decreased DENV replication and protection from death. CONCLUSIONS: Heme, CoPPIX and SnPPIX possess a marked ability to inactivate DENV and YFV, impairing its ability to infect and induce cytopathic effects on target cells. SIGNIFICANCE AND IMPACT OF THE STUDY: These results open the possibility of therapeutic application of porphyrins or their use as models to design new antiviral drugs against DENV and YFV. PMID- 26759119 TI - Weight loss-induced stress in subcutaneous adipose tissue is related to weight regain. AB - Initial successful weight loss is often followed by weight regain after the dietary intervention. Compared with lean people, cellular stress in adipose tissue is increased in obese subjects. However, the relation between cellular stress and the risk for weight regain after weight loss is unclear. Therefore, we determined the expression levels of stress proteins during weight loss and weight maintenance in relation to weight regain. In vivo findings were compared with results from in vitro cultured human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes. In total, eighteen healthy subjects underwent an 8-week diet programme with a 10-month follow-up. Participants were categorised as weight maintainers or weight regainers (WR) depending on their weight changes during the intervention. Abdominal subcutaneous adipose tissue biopsies were obtained before and after the diet and after the follow-up. In vitro differentiated SGBS adipocytes were starved for 96 h with low (0.55 mm) glucose. Levels of stress proteins were determined by Western blotting. WR showed increased expressions of beta-actin, calnexin, heat shock protein (HSP) 27, HSP60 and HSP70. Changes of beta-actin, HSP27 and HSP70 are linked to HSP60, a proposed key factor in weight regain after weight loss. SGBS adipocytes showed increased levels of beta-actin and HSP60 after 96 h of glucose restriction. The increased level of cellular stress proteins in the adipose tissue of WR probably resides in the adipocytes as shown by in vitro experiments. Cellular stress accumulated in adipose tissue during weight loss may be a risk factor for weight regain. PMID- 26759120 TI - Accessing inoculation methods of maize and wheat with Azospirillum brasilense. AB - The utilization of inoculants containing Azospirillum is becoming more popular due to increasing reports of expressive gains in grain yields. However, incompatibility with pesticides used in seed treatments represents a main limitation for a successful inoculation. Therefore, in this study we searched for alternatives methods for seed inoculation of maize and wheat, aiming to avoid the direct contact of bacteria with pesticides. Different doses of inoculants containing Azospirillum brasilense were employed to perform inoculation in furrow, via soil spray at sowing and via leaf spray after seedlings had emerged, in comparison to seed inoculation. Experiments were conducted first under greenhouse controlled conditions and then confirmed in the field at different locations in Brazil. In the greenhouse, most parameters measured responded positively to the largest inoculant dose used in foliar sprays, but benefits could also be observed from both in-furrow and soil spray inoculation. However, our results present evidence that field inoculation with plant-growth promoting bacteria must consider inoculant doses, and point to the need of fine adjustments to avoid crossing the threshold of growth stimulation and inhibition. All inoculation techniques increased the abundance of diazotrophic bacteria in plant tissues, and foliar spray improved colonization of leaves, while soil inoculations favored root and rhizosphere colonization. In field experiments, inoculation with A. brasilense allowed for a 25 % reduction in the need for N fertilizers. Our results have identified alternative methods of inoculation that were as effective as the standard seed inoculation that may represent an important strategy to avoid the incompatibility between inoculant bacteria and pesticides employed for seed treatment. PMID- 26759118 TI - Alzheimer's disease-like APP processing in wild-type mice identifies synaptic defects as initial steps of disease progression. AB - BACKGROUND: Alzheimer's disease (AD) is the most frequent form of dementia in the elderly and no effective treatment is currently available. The mechanisms triggering AD onset and progression are still imperfectly dissected. We aimed at deciphering the modifications occurring in vivo during the very early stages of AD, before the development of amyloid deposits, neurofibrillary tangles, neuronal death and inflammation. Most current AD models based on Amyloid Precursor Protein (APP) overproduction beginning from in utero, to rapidly reproduce the histological and behavioral features of the disease within a few months, are not appropriate to study the early steps of AD development. As a means to mimic in vivo amyloid APP processing closer to the human situation in AD, we used an adeno associated virus (AAV)-based transfer of human mutant APP and Presenilin 1 (PS1) genes to the hippocampi of two-month-old C57Bl/6 J mice to express human APP, without significant overexpression and to specifically induce its amyloid processing. RESULTS: The human APP, betaCTF and Abeta42/40 ratio were similar to those in hippocampal tissues from AD patients. Three months after injection the murine Tau protein was hyperphosphorylated and rapid synaptic failure occurred characterized by decreased levels of both PSD-95 and metabolites related to neuromodulation, on proton magnetic resonance spectroscopy ((1)H-MRS). Astrocytic GLT-1 transporter levels were lower and the tonic glutamatergic current was stronger on electrophysiological recordings of CA1 hippocampal region, revealing the overstimulation of extrasynaptic N-methyl D-aspartate receptor (NMDAR) which precedes the loss of long-term potentiation (LTP). These modifications were associated with early behavioral impairments in the Open-field, Y-maze and Morris Mater Maze tasks. CONCLUSIONS: Altogether, this demonstrates that an AD-like APP processing, yielding to levels of APP, betaCTF and Abeta42/Abeta40 ratio similar to those observed in AD patients, are sufficient to rapidly trigger early steps of the amyloidogenic and Tau pathways in vivo. With this strategy, we identified a sequence of early events likely to account for disease onset and described a model that may facilitate efforts to decipher the factors triggering AD and to evaluate early neuroprotective strategies. PMID- 26759121 TI - Dorzolamide-induced relaxation of isolated rabbit ciliary arteries mediated by inhibition of extracellular calcium influx. AB - PURPOSE: The carbonic anhydrase inhibitor dorzolamide can increase optic nerve blood flow. The aim of the study reported here was to investigate the effect of dorzolamide on isolated rabbit ciliary arteries that supply the optic nerve. METHODS: Changes in ciliary artery isometric tension and intracellular Ca(2+) concentration ([Ca(2+)]i) were recorded to elucidate the underlying pharmacologic mechanisms by which dorzolamide regulates blood flow to the optic nerve. RESULTS: Dorzolamide induced concentration-dependent relaxation of rabbit ciliary arteries that had been precontracted by exposure to a high potassium (high-K) solution. Neither pretreatment with 10 uM KB-R 7943, an Na(+)/Ca(2+) exchanger inhibitor, nor alkalinization of the high-K solution had an effect on the dorzolamide induced relaxation. Pretreatment with 100 uM N(G)-nitro-L-arginine methylester, a nitric oxide synthase inhibitor (n = 10), 10 uM indomethacin, a prostacyclin inhibitor (n = 9), or 0.1 uM iberiotoxin, an inhibitor of endothelium-derived hyperpolarizing factor (n = 7), did not change the concentration-dependent relaxation induced by dorzolamide. Incubation with 3 mM dorzolamide in a Ca(2+) free solution did not change the transient contractions of the rabbit ciliary arteries induced by 1 uM histamine (n = 9). However, 3 mM dorzolamide significantly suppressed the increase in [Ca(2+)]i induced by the reintroduction of Ca(2+) to a calcium-free extracellular medium (P < 0.05). Furthermore, 3 mM dorzolamide significantly suppressed the [Ca(2+)]i increase induced by the high-K solution (P < 0.05). CONCLUSIONS: Taken together, our results reveal a novel role for dorzolamide in relaxing the ciliary arteries. Our data support the hypothesis that the vasodilatory action of dorzolamide is mediated by inhibition of Ca(2+) entry through voltage-dependent Ca(2+) channels. PMID- 26759122 TI - A Urinary Metabolic Signature for Multiple Sclerosis and Neuromyelitis Optica. AB - Urine is a metabolite-rich biofluid that reflects the body's effort to maintain chemical and osmotic homeostasis. Clinical diagnosis routinely relies on urine samples because the collection process is easy and noninvasive. Despite these advantages, urine is an under-investigated source of biomarkers for multiple sclerosis (MS). Nuclear magnetic resonance spectroscopy (NMR) has become a common approach for analyzing urinary metabolites for disease diagnosis and biomarker discovery. For illustration of the potential of urinary metabolites for diagnosing and treating MS patients, and for differentiating between MS and other illnesses, 38 urine samples were collected from healthy controls, MS patients, and neuromyelitis optica-spectrum disorder (NMO-SD) patients and analyzed with NMR, multivariate statistics, one-way ANOVA, and univariate statistics. Urine from MS patients exhibited a statistically distinct metabolic signature from healthy and NMO-SD controls. A total of 27 metabolites were differentially altered in the urine from MS and NMO-SD patients and were associated with synthesis and degradation of ketone bodies, amino acids, propionate and pyruvate metabolism, tricarboxylic acid cycle, and glycolysis. Metabolites altered in urine from MS patients were shown to be related to known pathogenic processes relevant to MS, including alterations in energy and fatty acid metabolism, mitochondrial activity, and the gut microbiota. PMID- 26759125 TI - One-year clinical outcome after ablation with a novel multipolar irrigated ablation catheter for treatment of atrial fibrillation: potential implications for clinical use. AB - AIMS: Pulmonary vein isolation (PVI) is an established therapy for atrial fibrillation (AF). However, PVI remains a time-consuming procedure. A novel multipolar irrigated radiofrequency (RF) ablation catheter (nMARQTM) is aiming to improve PVI. We investigated the influence on procedural parameters and assessed clinical outcomes after PVI using this novel catheter. METHODS AND RESULTS: Fifty eight consecutive patients with paroxysmal AF were equally allocated (n = 29/group) to PVI treatment with (i) the novel multipolar ablation catheter (nMARQTM) and (ii) a standard single-tip ablation catheter (SAC). Study endpoints included procedure time, fluoroscopy time, radiation dose, RF time, number of energy applications, and clinical outcome defined as freedom from AF after a single procedure. Successful PVI was confirmed by a separate circular, multipolar mapping catheter in all patients treated with the nMARQTM. Pulmonary vein isolation was achieved in 100% in the SAC group. In the nMARQTM group, PVI was suggested in all patients. However, confirmatory mapping revealed persistent pulmonary vein (PV) conduction in 19 out of 29 nMARQTM patients. These patients underwent further ablation, which still failed to achieve PVI in 5 of the 29 nMARQTM patients, mainly due to significant temperature rise in the oesophagus and device-related limitations reaching the right inferior PV. Mean fluoroscopy time (31 +/- 12 vs. 23 +/- 10 min, P < 0.05) and (132 +/- 37 vs. 109 +/- 30 min, P < 0.05) were longer in nMARQTM vs. SAC patients. Radiofrequency time was shorter in nMARQTM vs. SAC group (21 +/- 9 vs. 35 +/- 12 min, P < 0.001). Radiation dose and the number of energy applications did not differ between both groups. Clinical outcome analysis revealed no significant differences (nMARQTM: 72 vs. SAC: 72%) after a mean follow-up of 373 +/- 278 days. CONCLUSION: The use of the nMARQTM catheter is associated with important device-related limitations to achieve successful PVI. However, clinical outcomes were equivalent in nMARQTM- and SAC-treated patients. PMID- 26759124 TI - Early repolarization pattern is the strongest predictor of arrhythmia recurrence in patients with idiopathic ventricular fibrillation: results from a single centre long-term follow-up over 20 years. AB - AIMS: Idiopathic ventricular fibrillation (iVF) accounts for up to 14% of VF incidence. Data regarding long-term outcome and clinical risk markers of arrhythmia recurrence are scarce. The objective of our study was to describe a long-term follow-up (FU) of a cohort of iVF survivors in our centre during the past 20 years, and to investigate the influence of clinical parameters, e.g. presence of an early repolarization pattern (ERP), on recurrence rate of arrhythmias. METHODS AND RESULTS: Thirty-five iVF survivors were identified and retrospectively analysed regarding recurrent implantable cardioverter defibrillator (ICD) interventions and covariates potentially influencing arrhythmia recurrence. Appropriate ICD interventions occurred in 15 patients (43%) after a median of 6.6 years during a median FU period of 8.8 years. Two patients (13%) received the first appropriate therapy after an assumed average ICD battery longevity of 7 years, while in all other patients, the first therapy occurred within the first ICD period. Appropriate interventions were observed more often and earlier in patients with ERP (HR 3.9; 1.4-11.0; P = 0.01), whereas all other covariates failed to predict subsequent events. A high incidence of inappropriate ICD therapies (67 interventions in 14 patients) could be attributed to the occurrence of atrial fibrillation (66% of all inappropriate therapies). CONCLUSION: The recurrence rate of ventricular arrhythmias in iVF survivors is high and recurrence might occur delayed (>7 years after the initial event). ERP seems to be highly predictive with respect to early arrhythmia recurrence. Our results highlight that better pathophysiologic understanding of ERP might facilitate a better risk stratification before and an optimal treatment after an iVF event. The high rate of AF and ERP in iVF survivors might indicate an underlying heart disease or myocardial electrical disorder not apparent at the index event. PMID- 26759123 TI - The cell cycle as a brake for beta-cell regeneration from embryonic stem cells. AB - The generation of insulin-producing beta cells from stem cells in vitro provides a promising source of cells for cell transplantation therapy in diabetes. However, insulin-producing cells generated from human stem cells show deficiency in many functional characteristics compared with pancreatic beta cells. Recent reports have shown molecular ties between the cell cycle and the differentiation mechanism of embryonic stem (ES) cells, assuming that cell fate decisions are controlled by the cell cycle machinery. Both beta cells and ES cells possess unique cell cycle machinery yet with significant contrasts. In this review, we compare the cell cycle control mechanisms in both ES cells and beta cells, and highlight the fundamental differences between pluripotent cells of embryonic origin and differentiated beta cells. Through critical analysis of the differences of the cell cycle between these two cell types, we propose that the cell cycle of ES cells may act as a brake for beta-cell regeneration. Based on these differences, we discuss the potential of modulating the cell cycle of ES cells for the large-scale generation of functionally mature beta cells in vitro. Further understanding of the factors that modulate the ES cell cycle will lead to new approaches to enhance the production of functional mature insulin-producing cells, and yield a reliable system to generate bona fide beta cells in vitro. PMID- 26759127 TI - Birth control policies in Iran: a public health and ethics perspective. AB - In less than one generation, a unique demographic transition has taken place in Iran. A population growth rate of 4.06% in 1984 fell to 1.15% in 1993 and a total fertility rate of 6.4 births per woman in 1984 declined to 1.9 in 2010. In 2012, Iranian policymakers shifted away from a birth control policy towards a pro natalist policy. At first glance, this may seem reasonable since its goal is to avoid the consequences of an aging population. However, we argue that the policy package raises serious public health, socioeconomic, environmental and ethical concerns and is likely to fail on its own terms. PMID- 26759128 TI - Innovations in telemedicine for cardiovascular care. AB - Cardiovascular disease is one of the main fields of application for telemedicine, with benefits in almost all areas in the continuum of cardiovascular disease. The greatest impact has been shown in the early diagnosis of cardiovascular disease, in second consultation, between non-cardiologist and cardiologist and between cardiologists, and in follow-up and secondary prevention of cardiovascular disease. At present, the main area of implementation for telemedicine in cardiovascular disease is represented by pre-hospital triage, with telemedicine electrocardiogram in acute myocardial infarction. Significant results have also been achieved in the second opinion consultation of pediatric subjects with congenital cardiovascular disease, home-monitoring and the management of patients affected by chronic heart failure or with an implanted device. However, there is significant room for further improvement in delivering telemedicine assistance even in 'very-remote' populations, such as detainees, patients in developing countries or in underdeveloped areas of developed countries. PMID- 26759126 TI - Trajectories of maternal gestational weight gain and child cognition assessed at 5 years of age in a prospective cohort study. AB - BACKGROUND: There has been concern that low gestational weight gain may cause poor fetal neurodevelopment. METHODS: The association between maternal weight gain and child IQ was examined using serial antenatal weight measurements (median 12) from a prospective cohort of non-obese Scandinavian women (1986-1988). Linear mixed models with piecewise regression were used to estimate participants' (n=552) trimester-specific average rate of weight gain. Linear regression was used to assess the association between weight gain and children's (n=344) full scale, performance and verbal IQ measured at age 5 using the Wechsler Preschool and Primary Scales of Intelligence-Revised. RESULTS: Children born to mothers who gained below versus within the 2nd trimester 2009 recommendations tended to have lower IQ scores (Full-scale: 106.6 (SD 15.1) vs 110.2 (15.2), p=0.04; verbal: 102.5 (14.3) vs 105.0 (14.9), p=0.10; performance: 109.5 (15.4) vs 113.4 (14.5), p=0.03). After adjustment there were no differences in child IQ by weight gain adequacy (full-scale: betabelow=-1.1 (95% CI -5.1 to 2.9), betaabove=1.5 (-3.8 to 6.8); verbal: betabelow=-0.2 (-3.1 to 2.6), betaabove=1.8 (-3.6 to 7.3); performance betabelow=-1.2 (-4.6 to 2.2), betaabove=1.0 (-4.6 to 6.7)). No differences were observed based on 3rd trimester adequacy. No differences were observed in IQ scores by quintile of weight gain for any trimester, particularly after adjustment for maternal IQ. CONCLUSIONS: Our findings are reassuring that among normal weight women, pregnancy weight gain is not associated with child cognitive development. Further investigation should be conducted in contemporary cohorts that also include obese mothers, who are at the greatest risk for low weight gain. PMID- 26759129 TI - The non-silent epidemic: low back pain as a primary cause of hospitalisation. AB - Low back pain (LBP) is the most common cause of pain in adults and the second health condition that prompts patients to seek ambulatory medical care visits. To analyse the impact of LBP on hospitalisations in healthcare facilities within the official subsector in Argentina between 2006 and 2010. Discharges in which the original diagnosis had been either adult LBP or lumbosciatica were assessed. The data comprised age, gender, province of residence, average length of stay (LOS) in the hospital, intra-hospital death, and the Provincial Human Development Index (PHDI). 17,859 discharges had an original diagnosis of LBP and 10,948 of lumbosciatica, which jointly accounted for 18.7 % of all the discharges documented for Diseases of Osteomuscular System and Connective Tissue (DOMS). Hospital discharges of female patients represented 53.7 %. The average age upon admission was 47.7 years in men versus 47.9 in women. The average LOS was slightly higher in men (4.2 vs. 3.8 days, p 0.01). In provinces with a PHDI below the national average, a surgical procedure was performed in 3.1 % of the discharges versus 4.1 % in the provinces with a PHDI above the national average (p < 0.001). LBP was the most frequent cause of hospitalisation due to DOMS. It occurred with a slightly higher frequency in women and prompted short hospitalisations. A surgical procedure was carried out during hospitalisation in very few cases, but the percentage of surgeries during hospitalisation was higher in provinces with a PHDI above the national average. PMID- 26759130 TI - Does weather affect daily pain intensity levels in patients with acute low back pain? A prospective cohort study. AB - The aim of this study was to investigate the influence of various weather parameters on pain intensity levels in patients with acute low back pain (LBP). We performed a secondary analysis using data from the PACE trial that evaluated paracetamol (acetaminophen) in the treatment of acute LBP. Data on 1604 patients with LBP were included in the analysis. Weather parameters (precipitation, temperature, relative humidity, and air pressure) were obtained from the Australian Bureau of Meteorology. Pain intensity was assessed daily on a 0-10 numerical pain rating scale over a 2-week period. A generalised estimating equation analysis was used to examine the relationship between daily pain intensity levels and weather in three different time epochs (current day, previous day, and change between previous and current days). A second model was adjusted for important back pain prognostic factors. The analysis did not show any association between weather and pain intensity levels in patients with acute LBP in each of the time epochs. There was no change in strength of association after the model was adjusted for prognostic factors. Contrary to common belief, the results demonstrated that the weather parameters of precipitation, temperature, relative humidity, and air pressure did not influence the intensity of pain reported by patients during an episode of acute LBP. PMID- 26759131 TI - Wanting to See People Like Me? Racial and Gender Diversity in Popular Adolescent Television. AB - Media are one source for adolescent identity development and social identity gratifications. Nielsen viewing data across the 2014-2015 television season for adolescents ages 14-17 was used to examine racial and gender diversity in adolescent television exposure. Compared to US Census data, mainstream shows under represent women, but the proportion of Black characters is roughly representative. Black adolescents watch more television than non-Black adolescents and, after taking this into account, shows popular with Black adolescents are more likely than shows popular with non-Black adolescents to exhibit racial diversity. In addition, shows popular with female adolescents are more likely than shows popular with males to exhibit gender diversity. These results support the idea that adolescents seek out media messages with characters that are members of their identity groups, possibly because the characters serve as tools for identity development and social identity gratifications. PMID- 26759132 TI - Behavioral Engagement, Peer Status, and Teacher-Student Relationships in Adolescence: A Longitudinal Study on Reciprocal Influences. AB - Although teachers and peers play an important role in shaping students' engagement, no previous study has directly investigated transactional associations of these classroom-based relationships in adolescence. This study investigated the transactional associations between adolescents' behavioral engagement, peer status (likeability and popularity), and (positive and negative) teacher-student relationships during secondary education. A large sample of adolescents was followed from Grade 7 to 11 (N = 1116; 49 % female; M age = 13.79 years). Multivariate autoregressive cross-lagged modeling revealed only unidirectional effects from teacher-student relationships and peer status on students' behavioral engagement. Positive teacher-student relationships were associated with more behavioral engagement over time, whereas negative teacher student relationships, higher likeability and higher popularity were related to less behavioral engagement over time. We conclude that teachers and peers constitute different sources of influence, and play independent roles in adolescents' behavioral engagement. PMID- 26759133 TI - Neither plague nor malaria, but dysentery as a cause of death for St. Louis. PMID- 26759134 TI - Deaths from bee stings: a report of three cases from Pretoria, South Africa. AB - In South Africa bee stings are most commonly caused by either Apis mellifera capensis or A. mellifera scutellata, indigenous species which are notoriously aggressive when compared to European honey bees. According to Statistics South Africa, 109 deaths were documented for the period 2001-2011 as having been caused by hornets, wasps, and bees (ICD10-X26). This appears to be a small number but, as was reported in Australia, these statistics might be inaccurate due to either over- or underreporting of cases. We report 3 cases of fatalities due to bee stings, including one with postmortem features of diffuse intravascular coagulopathy. A brief overview of the venom of the honey bee, reactions following a bee sting and possible mechanisms of death are presented. Confirming the diagnosis in these cases may be very problematic for the forensic pathologist, as in many cases minimal history is available and both external and internal examination could fail to reveal any specific signs of bee sting or other obvious morphologic abnormalities. Thus, there is a need for reliable confirmatory or supportive diagnostic tests. PMID- 26759135 TI - On the strength of evidence in forensic pathology. PMID- 26759136 TI - Characteristics and time-dependence of cut marks and blunt force fractures on costal cartilages: an experimental study. AB - PURPOSE: The distinction between cut marks and blunt force injuries on costal cartilages is a crucial issue in the forensic field. Moreover, a correct distinction may further be complicated by decomposition, so the need arises to investigate the distinctive features of lesions on cartilage and their changes over time. METHODS: This study aimed to assess the stereomicroscopic features of cut marks (performed with six different knives) and blunt fractures (performed with a hammer and by means of manual bending) on 48 fragments of human costal cartilages. Moreover, in order to simulate decomposition, the cut and fractured surfaces were checked with stereomicroscopy and through casts after 1 and 2 days, 1 week, and 1, 2 and 4 months of drying in ambient air. RESULTS: In fresh samples, for single and unique cuts, striations were observed in between 44 and 88% of cases when non-serrated blades were used, and between 77 and 88% for serrated blades; in the case of "repeated" (back and forth movement) cuts, striations were detected in between 56 and 89% of cases for non-serrated blades, and between 66 and 100% for serrated blades. After only 1 week of decomposition the detection rates fell to percentages of between 28 and 39% for serrated blades and between 17 and 33% for non-serrated blades. Blunt force injuries showed non specific characteristics, which, if properly assessed, may lead to a reliable distinction between different cut marks in fresh samples. The most evident alterations of the structure of the cartilage occurred in the first week of decomposition in ambient air. After one week of drying, the characteristics of cut marks were almost undetectable, thereby making it extremely challenging to distinguish between cut marks, blunt force fractures and taphonomic effects. CONCLUSION: The study represents a contribution to the correct assessment and distinction of cut marks and blunt force injuries on cartilages, providing a glimpse on the modifications such lesions may undergo with decomposition. PMID- 26759137 TI - Is thyroid hormones evaluation of clinical value in the work-up of males of infertile couples? AB - STUDY QUESTION: Is thyroid hormones (TH) evaluation of clinical value in the work up of males of infertile couples? STUDY ANSWER: Our results suggest that TH evaluation is not mandatory in the work-up of male infertility. WHAT IS KNOWN ALREADY: A few previous studies performed on a limited series of subjects reported a negative impact of hyper- and hypo-thyroidism on semen volume, sperm concentration, progressive motility and normal morphology. No previous study has systematically evaluated associations between TH variation, semen parameters and ultrasound characteristics of the male genital tract. STUDY DESIGN, SIZE AND DURATION: Cross-sectional analysis of a consecutive series of 172 subjects seeking medical care for couple infertility from September 2010 to November 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the entire cohort, 163 men (age 38.9 +/- 8.0 years) free of genetic abnormalities were studied. All subjects underwent a complete andrological and physical examination, biochemical and hormonal assessment, scrotal and transrectal colour-Doppler ultrasound (CDUS) and semen analysis (including seminal interleukin 8 levels, sIL-8) evaluation within the same day. MAIN RESULTS AND THE ROLE OF CHANCE: Among the patients studied, 145 (88.9%) showed euthyroidism, 6 (3.7%) subclinical hyper- and 12 (7.4%) subclinical hypo-thyroidism. No subjects showed overt hyper- or hypo-thyroidism. At univariate analysis, no associations among thyroid-stimulating hormone (TSH) or TH levels and sperm parameters were observed. Conversely, we observed positive associations among free triiodothyronine (fT3) and free thyroxine (fT4) levels, ejaculate volume and seminal fructose levels. In a multivariate model, after adjusting for confounders such as age, body mass index, smoking habit, sexual abstinence, calculated free testosterone, prolactin and sIL-8 levels, only the associations found for fT3 levels were confirmed. When CDUS features were investigated, using the same multivariate model, we found positive associations between fT3 levels and seminal vesicles (SV) volume, both before and after ejaculation (adj. r = 0.354 and adj. r = 0.318, both P < 0.0001), as well as with SV emptying (DeltaSV volume; adj. r = 0.346, P < 0.0001) and echo-texture inhomogeneity. In addition, after adjusting for confounders, negative associations between fT4 levels and epididymal body and tail diameters were found. No significant associations between TSH or TH levels and CDUS features of other organs of the male genital tract, including testis and prostate, were found. Finally, when the features of subjects with euthyroidism, subclinical hypo and hyper-thyroidism were compared, no significant differences in seminal or hormonal parameters were found. Conversely, evaluating CDUS parameters, subjects with subclinical hyperthyroidism showed a higher difference between the SV longitudinal diameters measured before and after ejaculation when compared with that of subclinical hypothyroid men, even after adjusting for confounders (P < 0.007). All the other male genital tract CDUS characteristics did not differ among groups. LIMITATIONS, REASONS FOR CAUTION: First, the number of patients investigated is relatively small and those with (subclinical) thyroid dysfunctions are an even smaller number; hence, it is therefore difficult to draw firm conclusions. Moreover, the present results are derived from patients consulting an Italian Andrology Clinic for couple infertility, and could have different characteristics from the male general population or from those males consulting general practitioners for reasons other than couple infertility. Finally, due to the cross-sectional nature of the study, neither a causality hypothesis nor mechanistic models can be inferred. WIDER IMPLICATIONS OF THE FINDINGS: Although no associations between TH and sperm parameters were observed, present data support a positive effect of TH on SV size and a permissive role on the ejaculatory machinery, likely through an action on SV and epididymal contractility. This is the first study reporting such evidence. However, in contrast with the view that TH assessment is important for female fertility, our results do not support a systematic evaluation of thyroid function in males of infertile couples. How TH abnormalities impact male fertility needs to be addressed by further studies. STUDY FUNDING/COMPETING INTERESTS: No funding was received for the study. None of the authors have any conflict of interest to declare. PMID- 26759140 TI - Endometriosis and fertility: women's accounts of healthcare. AB - STUDY QUESTION: What do women with endometriosis recall being told about their fertility by their healthcare providers? SUMMARY ANSWER: Women recalled being given varied information and advice, and gave examples of empathic and individualized care from doctors but also reported opportunities for enhancing clinical practice. WHAT IS KNOWN ALREADY: There is evidence of an association between endometriosis and infertility. However, the strength of this association and the mechanisms that underlie it are not yet known nor are the implications for optimum healthcare. STUDY DESIGN, SIZE, DURATION: This study used in-depth cross-sectional qualitative research methods. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged at least 18 years who lived in Victoria, Australia, and who had been surgically diagnosed with endometriosis were invited to participate in in-depth interviews about their experience of endometriosis. Twenty-six women of diverse backgrounds and experiences of endometriosis were interviewed from January to September 2014. Interviews were transcribed and analysed thematically using a data-driven approach. MAIN RESULTS AND THE ROLE OF CHANCE: All women encountered medical professionals who were aware of the association between endometriosis and infertility, and who were proactive in ensuring fertility was addressed within endometriosis care. Women recalled being given varied, often conflicting, information about the consequences for their fertility of an endometriosis diagnosis. While some recounted positive experiences with the way their doctor communicated with them about endometriosis and fertility, all women reported adverse experiences such as receiving insufficient or inappropriate information or having their doctor prioritize their fertility over other aspects of their care, including quality of life and symptom relief, without first consulting them. LIMITATIONS, REASONS FOR CAUTION: The perspectives of the women's doctors were not sought. The findings may not translate to settings that differ from a predominantly Anglo-Saxon country with both universal public and private healthcare systems. WIDER IMPLICATIONS OF THE FINDINGS: Women's fertility needs and priorities differ for many reasons; there can be no 'one size fits all' approach to care. Women may benefit most from endometriosis care in which they are first asked about their fertility needs and preferences and in which medical uncertainty is acknowledged. STUDY FUNDING/COMPETING INTERESTS: K.Y. receives a scholarship from the National Health and Medical Research Council and Australian Rotary Health. J.F. is supported by a Monash Professional Fellowship and the Jean Hailes Professional Fellowship which is funded by Perpetual Trustees Pty Ltd. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 26759139 TI - Similar in vitro maturation rates of oocytes retrieved during the follicular or luteal phase offer flexible options for urgent fertility preservation in breast cancer patients. AB - STUDY QUESTION: Are in vitro maturation (IVM) rates of cumulus-oocyte complexes (COCs), retrieved from breast cancer patients seeking urgent fertility preservation (FP) before neoadjuvant chemotherapy, different between those recovered in the follicular or in the luteal phase of the cycle? SUMMARY ANSWER: The present investigation reveals no major difference in the number of COCs recovered or their IVM rates whatever the phase of the cycle at which egg retrieval is performed, suggesting that IVM is a promising tool for breast cancer patients seeking urgent oocyte cryopreservation. WHAT IS KNOWN ALREADY: FP now represents a standard of care for young cancer patients having to undergo gonadotoxic treatment. Mature oocyte cryopreservation after IVM of COCs has been proposed for urgent FP, especially in women, who have no time to undergo ovarian stimulation, or when it is contraindicated. STUDY DESIGN, SIZE, DURATION: From January 2011 to December 2014, we prospectively studied 248 breast cancer patients awaiting neoadjuvant chemotherapy, aged 18-40 years, candidates for oocyte vitrification following IVM, either at the follicular or the luteal phase of the cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum anti-Mullerian hormone and progesterone levels and antral follicle count (AFC) were measured prior to oocyte retrieval. Patients were sorted into two groups according to the phase of the cycle during which eggs were harvested (Follicular phase group, n = 127 and Luteal phase group, n = 121). Number of COCs recovered, maturation rates after 48 h of culture and total number of oocytes cryopreserved were assessed. Moreover, the oocyte retrieval rate (ORR) was calculated by the number of COCs recovered *100/AFC. MAIN RESULTS AND THE ROLE OF CHANCE: In the Follicular and the Luteal phase groups, women were comparable in terms of age, BMI and markers of follicular ovarian status. There was no significant difference in the number of COCs recovered (mean +/- SEM), 9.3 +/- 0.7 versus 11.1 +/- 0.8, and ORR (median (range)) 43.1 (1-100) versus 47.8 (7.7-100)%. Moreover, maturation rates after 48 h of culture (median (range)) were comparable in the follicular and luteal phase groups, 66.7 (20-100) versus 64.5 (0-100)%. Finally, the total number of oocytes cryopreserved (mean +/- SEM) was similar in both groups (6.2 +/ 0.4 versus 6.8 +/- 0.5). LIMITATIONS, REASONS FOR CAUTION: Despite the intact meiotic competence of immature oocytes recovered during the follicular or the luteal phase, there is a dramatic lack of data regarding the outcome of IVM oocytes cryopreserved in cancer patients. WIDER IMPLICATIONS OF THE FINDINGS: IVM of oocytes may be an interesting method of FP in urgent situations. Improving the culture conditions will be needed to increase the maturation rates and the overall potential of in vitro matured oocytes. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: N/A. PMID- 26759138 TI - Expanded findings from a randomized controlled trial of preconception low-dose aspirin and pregnancy loss. AB - STUDY QUESTION: What is the association between daily preconception-initiated low dose aspirin (LDA) treatment and very early pregnancy losses or euploid (chromosomally normal) losses among women with one to two prior losses? SUMMARY ANSWER: Daily LDA initiated preconception was not associated with the rate or type of pregnancy loss among women with a history of one to two prior pregnancy losses. WHAT IS KNOWN ALREADY: LDA is often used to treat recurrent pregnancy loss with reductions in pregnancy loss generally only observed among women with antiphospholipid antibodies, and null associations observed among women without antiphospholipid antibodies. We previously evaluated the association between LDA and pregnancy loss overall among women with one to two prior losses in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial and found no association, though did not distinguish between potential effects at different stages of pregnancy loss, including implantation failure, or between euploid and aneuploid losses. STUDY DESIGN, SIZE, DURATION: The EAGeR trial was a multi-site prospective block-randomized double-blind placebo-controlled trial. In total, 1228 women were randomized to daily LDA (81 mg/day) plus folic acid (400 mcg/day), or placebo plus folic acid. Participants were assigned study drug for less than or equal to six menstrual cycles or if they conceived, throughout pregnancy with study drug discontinued at 36 weeks gestation. This analysis includes additional outcome information obtained from chart abstractions after the completion of the trial, as well as testing of stored urine for measurement of hCG and detection of very early pregnancy losses, and karyotyping of the products of conception for assessment of aneuploidy of the losses. PARTICIPANTS, SETTING, METHODS: Women aged 18-40 with a history of one to two prior losses and actively trying to conceive were randomized (n = 615 LDA and n = 613 placebo) at four clinical centers in the USA (2007-2011). Log-binomial regression was used to estimate risk ratios under the intent-to-treat approach. MAIN RESULTS AND THE ROLE OF CHANCE: Daily LDA initiated preconception was not associated with clinically recognized pregnancy losses or implantation failures among women with proved fecundity and a history of one to two prior losses. Specifically, 1088 (88.6%) women completed the trial with 797 having an hCG detected pregnancy (64.9%). Overall there were 133 clinical losses (12.7% LDA versus 11.8% placebo, P = 0.71) and 55 implantation failures (5.2% LDA versus 4.9% placebo, P = 0.89). No differences were found in rate of euploid losses (RR 1.11, 95% confidence interval: 0.99, 1.26). LIMITATIONS, REASONS FOR CAUTION: Generalizability of these findings is limited to women with a history of one to two prior losses, and may further be limited to women of white race with higher socioeconomic status as given the rigors of the study protocol participants tended to be white and have higher incomes and more education. We were also missing karyotype information on approximately one-third of the clinically recognized pregnancy losses, which may limit our power to detect effects on euploid losses, though detailed sensitivity analysis showed similar results. WIDER IMPLICATIONS OF THE FINDINGS: Our data do not support the general use of LDA to decrease pregnancy loss and further demonstrate no increased risk of loss for women on LDA treatment. STUDY FUNDING/COMPETING INTERESTS: This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract Nos. HHSN267200603423, HHSN267200603424, HHSN267200603426). The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: The trial was registered at ClinicalTrials.gov #NCT00467363. TRIAL REGISTRATION DATE: 27 April 2007. DATE OF FIRST PATIENT'S ENROLLMENT: 15 June 2007. PMID- 26759141 TI - Assessment of the embryo flash position and migration with 3D ultrasound within 60 min of embryo transfer. AB - STUDY QUESTION: Does the air bubble (embryo flash) position and migration as visualized with 3D ultrasound (US) within 60 min of embryo transfer correlate with clinical outcome following fresh ART transfer cycles? SUMMARY ANSWER: The location of the embryo flash and the direction of its movement at 60 min, but not at 1 or 5 min after transfer, are associated with clinical pregnancy. WHAT IS KNOWN ALREADY: Studies assessing the relation between the pregnancy rate and the position of the catheter tip and/or the position of the air bubbles following embryo transfer show conflicting results to date. STUDY DESIGN, SIZE AND DURATION: This was a prospective cohort study including 277 infertile women undergoing ART between July 2011 and August 2013. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Good prognosis patients undergoing fresh ART cycles within a single tertiary University unit were assessed by 3D US at 1, 5 and 60 min after embryo transfer. The distance of the embryo flash from the fundus was measured at these time points, along with the direction of the embryo flash movement within 60 min of transfer. MAIN RESULTS AND THE ROLE OF CHANCE: Within 60 min of embryo transfer, 76.4% (198/259) of the embryo flashes migrated towards the fundus, 12.4% (32/259) migrated towards the cervix and 11.2% (29/259) remained static. There was no significant association between the embryo position or movement and the pregnancy rate at 1 and 5 min. At 60 min, however, the pregnancy and implantation rates among subjects with embryo flashes located <15 mm from the fundus was significantly higher than those with embryo flashes located >15 mm from the fundus (46.5 and 32.8% versus 25.8 and 18.2%, respectively; P < 0.05). The pregnancy and implantation rates when the embryo flash was seen moving towards the cervix (25.0 and 15.0%) was significantly lower (P < 0.05 and P < 0.01, respectively) compared with those remaining static (55.2 and 37.7%) or moving towards the fundus (45.5 and 32.8%). LIMITATIONS AND REASONS FOR CAUTION: Although the air bubbles seen at the time of embryo transfer are thought to represent the position of the embryo, they are in fact a surrogate marker of the embryo itself, as this cannot be directly visualized by US. WIDER IMPLICATIONS OF THE FINDINGS: Following embryo transfer the majority, but not all, embryo flashes undergo significant migration towards the fundus. The location of the embryo flash and the direction of its movement at 60 min, but not at 1 or 5 min after transfer, is associated with clinical outcome. These findings may challenge the traditional notion that the exact position of the embryo flash immediately following embryo transfer is related to clinical outcome. STUDY FUNDING/COMPETING INTERESTS: The authors have no relevant funding or conflicts of interest to disclose. PMID- 26759142 TI - Qualitative research methods: when to use them and how to judge them. PMID- 26759143 TI - Association of high fetuin-B concentrations in serum with fertilization rate in IVF: a cross-sectional pilot study. AB - STUDY QUESTION: Is serum fetuin-B associated with the fertilization rate in in vitro fertilization (IVF)? SUMMARY ANSWER: Serum fetuin-B increased during IVF cycles when oocytes could be fertilized while remained unchanged in fertilization failure. WHAT IS KNOWN ALREADY: Fetuin-B deficiency in mice causes premature zona pellucida hardening mediated by the zona protease ovastacin. Thus fetuin-B deficiency renders females infertile. STUDY DESIGN, SIZE, DURATION: We determined the human serum fetuin-B reference range, studying longitudinally, over the course of one month, five male and seven female volunteers without hormone treatment and four female volunteers on varying hormonal contraception. We sampled blood and determined serum fetuin-B, luteinizing hormone (LH), estradiol (E2) and progesterone (P4). In addition, we determined serum fetuin-B and estradiol in eight women undergoing intracytoplasmatic sperm injection (ICSI, nine ICSI cycles) and 19 women undergoing IVF (21 IVF cycles) after ovarian stimulation with recombinant human follicular stimulating hormone (rFSH) and/or a combined medication of FSH and LH. At least three blood samples were analyzed in each cycle. We compared serum fetuin-B and follicular fluid fetuin-B in nine patients by measuring follicular fetuin-B in pooled follicular fluid, and in fluid obtained from individual follicles. Samples were drawn from January 2012 to March 2014. PARTICIPANTS/MATERIALS, SETTING, METHOD: All volunteers and patients gave informed consent. Fetuin-B was measured employing a commercial sandwich enzyme-linked immunosorbent assay. Serum fetuin-B was determined as duplicates in 5 male (34 +/- 14.6 years) and 11 female volunteers (29.4 +/- 4.1 years) as well as in female volunteers on hormonal contraception (30.0 +/- 6.5 years). The duplicate standard deviation was 4.0 +/- 2.3%. The contraceptive drugs were mono or combined preparations containing 0-0.03 mg ethinyl estradiol, and 0.15-3.0 mg of various progestins. In addition, serum fetuin-B was determined as triplicates in 27 female patients undergoing conventional IVF (19) or ICSI (8). The triplicate standard deviation was 3.3 +/- 1.8%. IVF was declared as 'successful', if at least one oocyte was fertilized, and 'unsuccessful', if no oocyte could be fertilized. Patient age was 34.4 +/- 4.4 years in successful IVF, and 35.4 +/- 3.3 years in unsuccessful IVF. Serum and follicular fluid of patients undergoing controlled ovarian hyperstimulation were analyzed. Serum was drawn at the day of follicle aspiration. MAIN RESULTS AND THE ROLE OF CHANCE: Serum fetuin-B and follicular fluid fetuin-B were not significantly different in six out of nine patients suggesting, in principle, free exchange of fetuin-B between serum and follicular fluid. Thus serum fetuin-B may be used as a proxy of follicular fluid fetuin-B. Serum fetuin-B increased during successful IVF cycles (n = 15, P < 0.0001), but did not change in unsuccessful IVF cycles (n = 6, P = 0.118) despite increased estradiol levels (P = 0.0019 and P = 0.0254, respectively). LIMITATIONS, REASONS FOR CAUTION: The female volunteers self-reported their respective hormone medication. Medication was verified by serum estradiol, LH and progesterone measurements. For oocyte harvesting, the vaginal wall was punctured once only to minimize co-morbidity. Low grade cross-contamination of individual follicular fluid aspirates and contamination of the follicular fluid with small amounts of blood were inevitable. Samples were routinely checked for the presence of hemoglobin that would suggest blood contamination. Only samples containing <250 erythrocyte equivalents/ul were used for analysis. WIDER IMPLICATIONS OF THE FINDING: Serum fetuin-B may be used as a marker to predict the fertilization success in IVF. Fetuin-B levels attained during IVF stimulation may help to make an informed decision whether oocytes should be fertilized by IVF or by ICSI to overcome the zona pellucida as a barrier. STUDY FUNDING/COMPETING INTERESTS: The research was supported by a grant from Deutsche Forschungsgemeinschaft and by the START program of the Medical Faculty of RWTH Aachen University. J.F., E.D., J.N., B.R. and W.J.-D. declare that they are named inventors on the RWTH Aachen University patent application EP 13157317.2, 'Use of fetuin-B for culture of oocytes', applied for by RWTH Aachen University. PMID- 26759144 TI - Discontinuation of dialysis with eculizumab therapy in a pediatric patient with dense deposit disease. AB - BACKGROUND: Dense deposit disease (DDD) is a rare glomerular disease caused by an uncontrolled activation of the alternative complement pathway leading to end stage renal disease in 50 % of patients. As such, DDD has been classified within the spectrum of complement component 3 (C3) glomerulopathies due to its pathogenesis from alternative pathway dysregulation. Conventional immunosuppressive therapies have no proven effectiveness. Eculizumab, a terminal complement inhibitor, has been reported to mitigate disease in some cases. CASE DIAGNOSIS/TREATMENT: We report on the efficacy of eculizumab in a pediatric patient who failed to respond to cyclophosphamide, corticosteroids, and plasma exchange. Complement biomarker profiling was remarkable for low serum C3, low properdin, and elevated soluble C5b-9. Consistent with these findings, the alternative pathway functional assay was abnormally low, indicative of alternative pathway activity, although neither C3-nephritic factors nor Factor H autoantibodies were detected. Eculizumab therapy was associated with significant improvement in proteinuria and renal function allowing discontinuation of hemodialysis (HD). Repeat C3 and soluble C5b-9 levels normalized, showing that terminal complement pathway activity was successfully blocked while the patient was receiving eculizumab therapy. Repeat testing for alternative pathway activation allowed for a successful decrease in eculizumab dosing. CONCLUSIONS: The case reported here demonstrates the successful recovery of renal function in a pediatric patient on HD following the use of eculizumab. PMID- 26759145 TI - A Test of Outreach and Drop-in Linkage Versus Shelter Linkage for Connecting Homeless Youth to Services. AB - Outreach and service linkage are key for engaging marginalized populations, such as homeless youth, in services. Research to date has focused primarily on engaging individuals already receiving some services through emergency shelters, clinics, or other programs. Less is known about those who are not connected to services and, thus, likely the most vulnerable and in need of assistance. The current study sought to engage non-service-connected homeless youth (N = 79) into a strengths-based outreach and advocacy intervention. Youth were randomly assigned to receive 6 months of advocacy that focused on linking youth to a drop in center (n = 40) or to a crisis shelter (n = 39). All youth were assessed at baseline and 3, 6, and 9 months post-baseline. Findings indicated that youth prefer drop-in center services to the shelter. Also, the drop-in center linkage condition was associated with more service linkage overall (B = 0.34, SE = 0.04, p < 0.01) and better alcohol-l [B = -0.39, SE = 0.09, t(75) = -4.48, p < 0.001] and HIV-related outcomes [B = 0.62, SE = 0.10, t(78) = 6.34, p < 0.001] compared to the shelter linkage condition. Findings highlight the importance of outreach and service linkage for reconnecting service-marginalized youth, and drop-in centers as a primary service option for homeless youth. PMID- 26759146 TI - Liddle-Mutation of the beta-Subunit, but not the gamma-Subunit, Attenuates Protein Kinase C-Mediated Inhibition of Human Epithelial Sodium Channels (hENaC). AB - Mammalian distal nephron and distal colon, prime sites for Na(+) homeostasis, contain amiloride-sensitive epithelial sodium channels (ENaC). Protein kinase C (PKC) inhibits ENaC by phosphorylating serine and threonine residues within COOH termini of the beta- and/or gamma-subunits. Although some of these phosphorylation sites are close to the PY motifs, it is unclear whether they remain susceptible to PKC in Liddle-mutated ENaC beta- and/or gamma-subunits, where PY motifs are truncated, resulting in increased apical ENaC expression. We therefore studied the effects of PKC in wild-type and Liddle-mutated human epithelial Na(+) channels (hENaC) expressed in Xenopus oocytes, using the dual electrode voltage clamp technique. PKC activation using 500 nmol/l phorbol 12 myristate 13-acetate (PMA) decreased amiloride-sensitive Na(+) currents by 80 % in oocytes expressing wild-type hENaC, an effect largely prevented by co-exposure to 50 umol/l calphostin C (a specific inhibitor of PKC), whereas 500 nmol/l phorbol didecanoate (PDD), an inactive phorbol ester which does not stimulate PKC, had no effect. In oocytes expressing hENaC containing the Liddle-mutated beta-subunit, PMA elicited a 54 % decrease in amiloride-sensitive Na(+) currents, significantly (P < 0.0025) less than that in oocytes expressing wild-type hENaC. By contrast, in oocytes expressing hENaC containing the Liddle-mutated gamma subunit, PMA elicited a 68 % decrease in amiloride-sensitive Na(+) current, similar (P = 0.10) to that in oocytes expressing wild-type hENaC. We conclude that hENaC incorporating the Liddle-mutated beta-subunit lacks one or more PKC phosphorylation sites, thereby significantly reducing the inhibitory effect of PKC on Na(+) channel activity, whereas hENaC incorporating Liddle-mutated gamma subunits remains as susceptible to PKC as wild-type hENaC. PMID- 26759147 TI - Understanding Endoscopic Disease Activity in IBD: How to Incorporate It into Practice. AB - Endoscopic assessment of disease activity is an essential part of clinical practice in inflammatory bowel disease (IBD) and is used for diagnosis, prognosis, monitoring for dysplasia and increasingly for the evaluation of mucosal or endoscopic response to therapy. Recently, mucosal or endoscopic healing has emerged as a key goal of therapy as it has been found that patients who achieve endoscopic remission have improved outcomes compared to those who do not, and this may be independent of their clinical disease activity. However, there is currently no validated definition of mucosal healing and there are numerous endoscopic scoring systems proposed to define endoscopic activity and response to therapy in both ulcerative colitis and Crohn's disease. This article will discuss the most common endoscopic scores used to measure endoscopic disease activity in IBD, the pros and cons of each of these scoring systems and proposed definitions for endoscopic response or remission that exist for each. In addition, the role of endoscopy in prognosticating the disease course is discussed and how endoscopy can be utilized as part of a "treat-to-target" treatment strategy where endoscopy results direct decisions regarding medical strategies in clinical practice is highlighted. PMID- 26759149 TI - Maternal postpartum high-dose vitamin D3 supplementation (6400 IU/day) or conventional infant vitamin D3 supplementation (400 IU/day) lead to similar vitamin D status of healthy exclusively/fully breastfeeding infants by 7 months of age. PMID- 26759148 TI - Phosphaturic Mesenchymal Tumor Involving the Head and Neck: A Report of Five Cases with FGFR1 Fluorescence In Situ Hybridization Analysis. AB - Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm; however, it is the most common cause of tumor-induced osteomalacia (TIO), a paraneoplastic syndrome characterized by renal phosphate wasting and hypophosphatemia. A subset of PMTs harbours an FGFR1 translocation although this alteration has not been demonstrated in PMT involving a head and neck site. We present a series of five PMTs involving the head and neck and demonstrate the diagnostic utility of fluorescence in situ hybridization (FISH) for detecting FGFR1 translocations. Patients' age and sex, tumor location, original diagnosis, the duration of symptoms, the presence of TIO, biochemical results, and medical management were reviewed. The median age at presentation was 45 (range, 24-58 years) and TIO was present in three cases. Four tumors involved soft tissue and one involved bone. Four out of the five tumors in our series were initially misdiagnosed. Three tumors were ultimately categorized as malignant PMT (two patients developed metastatic disease). FGFR1 translocation was present in two out of four cases and remained unknown in one case. In summary, we report on five cases of PMTs arising in the head and neck and confirm utility of FGFR1 FISH in the diagnosis of a subset of PMT. PMID- 26759150 TI - Artemisinin-based combination therapy (ACT) versus atovaquone-proguanil: do not choose between but, rather, combine them. PMID- 26759152 TI - The reason why orthopaedic surgeons perform total knee replacement: results of a randomised study using case vignettes. AB - PURPOSE: End-stage knee osteoarthritis (OA) results in total knee arthroplasty (TKA) surgery. The decision to perform TKA is not well defined, resulting in variation of indications among orthopaedic surgeons. Non-operative treatment measures are often not extensively used. Aim of this study was to investigate factors influencing the decision to perform TKA by Dutch orthopaedic surgeons. METHODS: Three case vignettes, each case divided into two versions, being identical except for information on age (younger and older age), pain (mild and severe pain) or radiological OA (low and high grade) were developed. A questionnaire including these three case vignettes was sent to 599 Dutch orthopaedic surgeons, who were randomised to either one of the two versions. The orthopaedic surgeons were asked whether TKA would be the next step in treatment. Furthermore, from a list of patient factors they were asked how strong these factors would influence the decision to perform TKA. RESULTS: 54 % of the orthopaedic surgeons completed the questionnaire (n = 326). Orthopaedic surgeons indicated to perform TKA significantly more often at higher age (73.3 vs. 45.5 %, p < 0.001). In the presence of mild pain, orthopaedic surgeons were slightly more reluctant to perform a TKA compared to severe pain (57.0 vs. 64.0 %, n.s.). Mild radiological OA made surgeons more reluctant to perform TKA compared to severe OA (9.7 vs. 96.9 %, p < 0.001). CONCLUSION: Old age and severe radiological OA are variables which are considered to be important in the decision to perform a TKA. Pain symptoms of moderate or severe pain are unequivocal when considering a TKA. LEVEL OF EVIDENCE: Economic/decision analysis, Level III. PMID- 26759151 TI - Identification of the murine H-2D(b) and human HLA-A*0201 MHC class I-restricted HPV6 E7-specific cytotoxic T lymphocyte epitopes. AB - Recurrent respiratory papillomatosis is caused by human papillomavirus (HPV) infection, most commonly types 6 (HPV-6) and 11 (HPV-11). Due to failed host immune responses, HPV is unable to be cleared from the host, resulting in recurrent growth of HPV-related lesions that can obstruct the lumen of the airway within the upper aerodigestive tract. In our murine model, the HPV-6b and HPV-11 E7 antigens are not innately immunogenic. In order to enhance the host immune responses against the HPV E7 antigen, we linked calreticulin (CRT) to HPV-6b E7 and found that vaccinating C57BL/6 mice with the HPV-6b CRT/E7 DNA vaccine is able to induce a CD8+ T cell response that recognizes an H-2D(b)-restricted E7aa21-29 epitope. Additionally, vaccination of HLA-A*0201 transgenic mice with HPV-6b CRT/E7 DNA generated a CD8+ T cell response against the E7aa82-90 epitope that was not observed in the wild-type C57BL/6 mice, indicating this T cell response is restricted to HLA-A*0201. In vivo cytotoxic T cell killing assays demonstrated that the vaccine-induced CD8+ T cells are able to efficiently kill target cells. Interestingly, the H-2D(b)-restricted E7aa21-29 sequence and the HLA-A*0201-restricted E7aa82-90 sequence are conserved between HPV-6b and HPV-11 and may represent shared immunogenic epitopes. The identification of the HPV 6b/HPV-11 CD8+ T cell epitopes facilitates the evaluation of various immunomodulatory strategies in preclinical models. More importantly, the identified HLA-A*0201-restricted T cell epitope may serve as a peptide vaccination strategy, as well as facilitate the monitoring of vaccine-induced HPV specific immunologic responses in future human clinical trials. PMID- 26759154 TI - Noteworthy Articles in 2015 for Cardiothoracic Critical Care. AB - In 2015, the demand for the presence of cardiothoracic anesthesiologists outside of the cardiac operating rooms continues to expand. Most notably, cardiothoracic anesthesiologists now find themselves called on to care for patients postoperatively in the cardiothoracic surgical intensive care unit. This article is the first in this annual series to review relevant contributions in postoperative cardiac critical care that may influence the cardiac anesthesiologist. We explore the use of extracorporeal membrane oxygenation, management of postoperative atrial fibrillation and coagulopathy, metabolic support of the critically ill cardiothoracic surgical patient, and new insights into delirium and acute kidney injury. PMID- 26759153 TI - Midterm results of posterior arthroscopic ankle fusion. AB - PURPOSE: The presented study was performed to evaluate the midterm clinical and radiological results and complication rates of the first 40 patients with an ankle fusion through a posterior arthroscopic approach. METHODS: Forty consecutive patients with end-stage post-traumatic ankle osteoarthritis were treated with posterior arthroscopic ankle fusion. All patients were assessed clinically as well as radiologically with a minimum follow-up of 2 years. The Foot and Ankle Ability Measure (FAAM) and Foot Function Index (FFI) were used to assess clinical improvement. RESULTS: Clinical fusion was achieved in 40 patients within 3 months (100%), and radiological fusion was achieved in 40 patients at 12 months. Two screw mal-placements occurred. Both complications were solved following revision surgery. A significant improvement was noted for both the FAAM [median 38 (range 17-56) to 63 (range 9-84)] and FFI scores [median 66 (range 31 89) to 32 (range 11-98)] for all 40 patients. CONCLUSION: The posterior arthroscopic ankle fusion is an effective and safe treatment option for end-stage post-traumatic ankle osteoarthritis at midterm follow-up. LEVEL OF EVIDENCE: Prospective cohort study, Level IV. PMID- 26759155 TI - Aerobic training enhances muscle deoxygenation in early post-myocardial infarction. AB - PURPOSE: Exercise-induced skeletal muscle deoxygenation is startling by its absence in early post-myocardial infarction (MI) patients. Exercise training early post-MI is associated with reduced cardiovascular risk and increased aerobic capacity. We therefore investigated whether aerobic training could enhance the muscle deoxygenation in early post-MI patients. METHODS: 21 +/- 8 days after the first MI patients (n = 16) were divided into 12-week aerobic training (TR, n = 10) or non-training (CON, n = 6) groups. Before and after intervention, patients performed ramp bicycle exercise until exhaustion. Muscle deoxygenation was measured at vastus lateralis by near-infrared spectroscopy during exercise. RESULTS: Aerobic training significantly increased peak oxygen uptake (VO2) (18.1 +/- 3.0 vs. 22.9 +/- 2.8 mL/kg/min), decreased the change in muscle oxygen saturation from rest to submaximal and peak exercise (?SmO2; 2.4 +/ 5.7 vs. -7.0 +/- 3.4 %), and increased the relative change in deoxygenated hemoglobin/myoglobin concentration from rest to submaximal (-1.5 +/- 2.3 vs. 3.0 +/- 3.6 MUmol/L) and peak exercise (1.1 +/- 4.5 vs. 8.2 +/- 3.5 MUmol/L). Change in total hemoglobin/myoglobin concentration in muscle was not significantly affected by training. In CON, no significant alterations were found after 12 weeks in either muscle deoxygenation or peak VO2 (18.6 +/- 3.8 vs. 18.9 +/- 4.6 mL/kg/min). An increase in peak VO2 was significantly negatively correlated with change in ?SmO2 (r = -0.65) and positively associated with change in ?deoxy-Hb/Mb at peak exercise (r = 0.64) in TR. CONCLUSIONS: In early post-MI patients, aerobic training enhanced skeletal muscle deoxygenation, and the enhancement was related to increased aerobic capacity. PMID- 26759156 TI - The presence of anti-thyroglobulin (TgAb) and/or anti-thyroperoxidase antibodies (TPOAb) does not exclude the diagnosis of type 2 amiodarone-induced thyrotoxicosis. AB - PURPOSE: It is widely accepted that type 2 amiodarone-induced thyrotoxicosis (AIT) generally occurs in patients with a normal thyroid gland without signs of thyroid autoimmunity. However, it is currently unknown if the presence of anti thyroglobulin (TgAb) and/or anti-thyroperoxidase antibodies (TPOAb) in AIT patients without other signs of an underlying thyroid disease may impair the response to glucocorticoid therapy. METHODS: We performed a pilot retrospective cohort study with matched-subject design and an equivalence hypothesis, comparing the response to glucocorticoid therapy between 20 AIT patients with a normal thyroid gland, low radioiodine uptake, undetectable TSH receptor antibodies and positive TgAb and/or TPOAb (Ab+ group), and 40 patients with the same features and absent thyroid antibodies (Ab- group). RESULTS: The mean cure time was 54 +/- 68 days in the Ab+ group and 55 +/- 49 days in the Ab- group (p = 0.63). The equivalence test revealed an equivalent cure rate after 60, 90 and 180 days (p = 0.67, 0.88 and 0.278, respectively). The occurrence of permanent hypothyroidism was higher in the Ab+ group than in the Ab- group (26.3 vs 5.13 %, p = 0.032). CONCLUSIONS: The presence of TgAb and/or TPOAb does not affect the response to glucocorticoid therapy, suggesting that the patients with features of destructive form of AIT should be considered as having a type 2 AIT irrespective of the presence of TGAb or TPOAb. These patients have a higher risk of developing hypothyroidism after the resolution of thyrotoxicosis and should be monitored accordingly. PMID- 26759157 TI - Determinants and burden of chronic kidney disease in a high-risk population in Korea: results from a cross-sectional study. AB - BACKGROUND/AIMS: This study aimed to investigate the prevalence of chronic kidney disease (CKD) and associated risk factors in a high-risk population in Korea. METHODS: A total of 6,045 participants aged >= 65 years (mean age, 73.0 +/- 5.5) with diabetes or hypertension were enrolled. Participants were screened for CKD, which was defined as the presence of albuminuria (urine albumin-to-creatinine ratio >= 30 mg/g) or an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2). RESULTS: The prevalence of CKD was 39.6% (women, 40.3%; men, 38.4%). Albuminuria was detected in 22.6% of participants, whereas eGFR < 60 mL/min/1.73 m(2) was found in 24.6% of participants. The prevalence of CKD by stage was 4.4% for stage 1, 10.4% for stage 2, 23.4% for stage 3, 0.9% for stage 4, and 0.3% for stage 5. Older age, concomitant diabetes and hypertension, higher body mass index, higher systolic and diastolic blood pressure, and higher hemoglobin A1c levels were independently associated with the presence of CKD in multivariate-adjusted analyses that included with age, sex, body mass index, hypertension, diabetes, and smoking. CONCLUSIONS: The prevalence of CKD was very high in the present high-risk Korean population. Our results suggest that a screening method for early detection of CKD in high-risk populations is needed in Korea. PMID- 26759159 TI - Computer-aided detection (CADe) and diagnosis (CADx) system for lung cancer with likelihood of malignancy. AB - BACKGROUND: CADe and CADx systems for the detection and diagnosis of lung cancer have been important areas of research in recent decades. However, these areas are being worked on separately. CADe systems do not present the radiological characteristics of tumors, and CADx systems do not detect nodules and do not have good levels of automation. As a result, these systems are not yet widely used in clinical settings. METHODS: The purpose of this article is to develop a new system for detection and diagnosis of pulmonary nodules on CT images, grouping them into a single system for the identification and characterization of the nodules to improve the level of automation. The article also presents as contributions: the use of Watershed and Histogram of oriented Gradients (HOG) techniques for distinguishing the possible nodules from other structures and feature extraction for pulmonary nodules, respectively. For the diagnosis, it is based on the likelihood of malignancy allowing more aid in the decision making by the radiologists. A rule-based classifier and Support Vector Machine (SVM) have been used to eliminate false positives. RESULTS: The database used in this research consisted of 420 cases obtained randomly from LIDC-IDRI. The segmentation method achieved an accuracy of 97 % and the detection system showed a sensitivity of 94.4 % with 7.04 false positives per case. Different types of nodules (isolated, juxtapleural, juxtavascular and ground-glass) with diameters between 3 mm and 30 mm have been detected. For the diagnosis of malignancy our system presented ROC curves with areas of: 0.91 for nodules highly unlikely of being malignant, 0.80 for nodules moderately unlikely of being malignant, 0.72 for nodules with indeterminate malignancy, 0.67 for nodules moderately suspicious of being malignant and 0.83 for nodules highly suspicious of being malignant. CONCLUSIONS: From our preliminary results, we believe that our system is promising for clinical applications assisting radiologists in the detection and diagnosis of lung cancer. PMID- 26759160 TI - Failed caudal block due to physiologic changes associated with a cerebrospinal fluid leak: a case report. AB - PURPOSE: The sum of the volumes of brain tissue, cerebrospinal fluid (CSF), and intracranial blood remain constant. This tenet of the Monroe-Kellie hypothesis is most often considered in the setting of intracranial hypertension, but it can also be applied in the setting of CSF volume depletion. We used this hypothesis to explain a case of failed caudal block in a patient with an iatrogenic CSF leak. CLINICAL FEATURES: A one-month-old baby (3 kg) born at 35 weeks' gestation presented for right inguinal hernia repair. His past medical history was significant for arthrogryposis (congenital joint contractures in two or more areas of the body) as well as ongoing apneic episodes that required continuous positive airway pressure therapy and neonatal intensive care. An ultrasound confirmed caudal block was completed and within five minutes of the procedure, the patient's heart rate increased, with an accompanying slight increase in T wave amplitude. Pinch tests revealed anesthesia to the feet bilaterally but insufficient anesthesia to the abdomen. The surgery was delayed but successfully completed under general anesthesia the following week. Magnetic resonance imaging of the brain and spine following the surgery showed a significant CSF leak with engorgement of the epidural venous plexus along the entire spine. These findings were consistent with a CSF leak likely secondary to a prior lumbar puncture (at age 13 days) that was part of the investigation of his respiratory issues. CONCLUSIONS: The possible mechanism of this failed caudal block was high systemic absorption of anesthetic given the epidural venous plexus engorgement thus leaving less anesthetic acting within the CSF and on the exiting spinal nerves. Decreased CSF flow in the thecal sac might also have contributed, as might dilution of the remaining local anesthetic caused by large amounts of leaking CSF within the epidural space. PMID- 26759158 TI - Validation of the Korean coefficient for the modification of diet in renal disease study equation. AB - BACKGROUND/AIMS: Race and ethnicity are important determinants when estimatingglomerular filtration rate (GFR). The Korean coefficients for the isotope dilution mass spectrometry (IDMS) Modification of Diet in Renal Disease (MDRD) Study equations were developed in 2010. However, the coefficients have not been validated. The aim of this study was to validate the performance of the Korean coefficients for the IDMS MDRD Study equations. METHODS: Equation development and validation were performed in separate groups (development group, n = 147 from 2008 to 2009; validation group, n = 125 from 2010 to 2012). We compared the performance of the original IDMS MDRD equations and modified equations with Korean coefficients. Performance was assessed by comparing correlation coefficients, bias, and accuracy between estimated GFR and measured GFR, with systemic inulin clearance using a single injection method. RESULTS: The Korean coefficients for the IDMS MDRD equations developed previously showed good performance in the validation group. The new Korean coefficients for the four- and six-variable IDMS MDRD equations using both the development and validation cohorts were 1.02046 and 0.97300, respectively. No significant difference was detected for the new Korean coefficients, in terms of estimating GFR, between the original and modified IDMS MDRD Study equations. CONCLUSIONS: The modified equations with Korean coefficients for the IDMS MDRD Study equations were not superior to the original equations for estimating GFR. Therefore, we recommend using the original IDMS MDRD Study equation without ethnic adjustment in the Korean population. PMID- 26759161 TI - Tympanic membrane rupture during robotic-assisted laparoscopic prostatectomy. PMID- 26759162 TI - Effects of Senegenin against hypoxia/reoxygenation-induced injury in PC12 cells. AB - OBJECTIVE: To investigate the effect and the potential mechanism of Senegenin (Sen) against injury induced by hypoxia/reoxygenation (H/R) in highly differentiated PC12 cells. METHODS: The cultured PC12 cells were treated with H/R in the presence or absence of Sen (60 MUmol/L). Four groups were included in the experiment: control group, H/R group, H/R+Sen group and Sen group. Cell viability of each group and the level of lactate dehydrogenase (LDH) in culture medium were detected for the pharmacological effect of Sen. Hoechst 33258 staining and annexin V/propidium iodide double staining were used to analyze the apoptosis rate. Moreover, mitochondrial membrane potential (?Psim), reactive oxygen species (ROS) and intracellular free calcium ([Ca(2+)]i) were measured by fluorescent staining and flow cytometry. Cleaved caspase-3 and activity of NADPH oxidase (NOX) were determined by colorimetric protease assay and enzyme linked immunosorbent assay, respectively. RESULTS: Sen significantly elevated cell viability (P<0.05), decreased the leakage of LDH (P<0.05) and apoptosis rate (P<0.05) in H/R-injured PC12 cells. Sen maintained the value of ?Psim (P<0.05) and suppressed the activity of caspase-3 (P<0.05). Moreover, Sen reduced ROS accumulation P<0.05) and [Ca(2+)]i increment (P<0.05) by inhibiting the activity of NOX (P<0.05). CONCLUSION: Sen may exert cytoprotection against H/R injury by decreasing the levels of intracellular ROS and [Ca(2+)]i, thereby suppressing the mitochondrial pathway of cellular apoptosis. PMID- 26759163 TI - Effects of phosphorylation on the intrinsic propensity of backbone conformations of serine/threonine. AB - Each amino acid has its intrinsic propensity for certain local backbone conformations, which can be further modulated by the physicochemical environment and post-translational modifications. In this work, we study the effects of phosphorylation on the intrinsic propensity for different local backbone conformations of serine/threonine by molecular dynamics simulations. We showed that phosphorylation has very different effects on the intrinsic propensity for certain local backbone conformations for the serine and threonine. The phosphorylation of serine increases the propensity of forming polyproline II, whereas that of threonine has the opposite effect. Detailed analysis showed that such different responses to phosphorylation mainly arise from their different perturbations to the backbone hydration and the geometrical constraints by forming side-chain-backbone hydrogen bonds due to phosphorylation. Such an effect of phosphorylation on backbone conformations can be crucial for understanding the molecular mechanism of phosphorylation-regulated protein structures/dynamics and functions. PMID- 26759164 TI - Overexpression of TLR2 and TLR9 on monocyte subsets of active rheumatoid arthritis patients contributes to enhance responsiveness to TLR agonists. AB - BACKGROUND: Synovial infiltration of monocytes is commonly associated with inflammation in rheumatoid arthritis (RA). Toll-like receptors (TLRs) are innate sensors that recognize cell debris and microbial components in host, a process contributing to maintain chronic inflammation in RA. We assessed the expression levels of TLR2 and TLR9 in monocyte subsets of active RA patients and characterized their cytokine profiles in response to synthetic and viral TLR2 and TLR9 agonists, including Epstein-Barr virus (EBV) which is suspected to contribute to RA symptoms. METHODS: Prevalence of monocyte subsets CD14(++) CD16( ), CD14(+) CD16(+) and CD14(low) CD16(++) was evaluated in blood and synovial fluids of active RA patients and levels of TLR2 and TLR9 in monocyte subsets were measured by flow cytometry. Enriched monocytes derived from RA patients and healthy donors were stimulated in vitro with synthetic TLR2 and TLR9 agonists and with EBV particles or viral DNA. Intracellular cytokine profiles were determined in respective monocyte subsets. Finally, the presence of EBV genome was evaluated by real-time PCR in blood and synovial monocytes of RA patients. RESULTS: Numbers of CD14(+) CD16(+) and CD14(low) CD16(++) were found to increase in blood of RA patients compared to healthy controls, while all three subsets were detected in synovial fluids. TLR2 is abundantly expressed on blood and synovial CD14(++) CD16(-) and CD14(+) CD16(+) monocytes from RA patients. Levels of TLR9 were increased on all three subsets of blood monocytes but markedly enhanced in monocytes isolated from synovial fluids. Compared to healthy controls, CD14(++) CD16(-) monocytes of RA patients displayed an enlarged capacity to produce proinflammatory cytokines after stimulation with synthetic TLR2 and TLR9 agonists while both CD14(++) CD16(-) and CD14(+) CD16(+) monocytes showed increased response to EBV stimulation. The presence of EBV genome was also detected in monocytes and neutrophils of a significant proportion of patients. CONCLUSION: Patients with active RA show an increased expression of TLR2 and TLR9 on monocyte subsets and display higher production of inflammatory cytokines in response to TLR agonists. The presence of EBV genome in monocytes and neutrophils reinforces the suspected role of the virus in the exacerbation of RA symptoms. PMID- 26759165 TI - Cervical arthroplasty with ROTAIO(r) cervical disc prosthesis: first clinical and radiographic outcome analysis in a multicenter prospective trial. AB - BACKGROUND: Cervical Disc Arthroplasty (CDA) seems to be an alternative to Anterior Cervical Decompression and Fusion (ACDF) and was developed to minimize the risk of Adjacent Segment Disease (ASD). The ROTAIO Cervical Disc Prosthesis represents a new unconstrained implant with a variable centre of rotation which should enable physiological facet-guided movement. The aim of this current study was to evaluate the clinical outcomes after arthroplasty using ROTAIO Cervical Disc Prosthesis. METHOD: Twenty-seven female and 18 male patients (n = 45) with a mean age of 43.7 +/- 7.8 years were prospectively followed up for a maximum of 24 month. Clinical outcomes were assessed by Neck Disability Index (NDI), visual analogue scale (VAS) scores for neck and arm pain, patients' overall satisfaction and the usage of analgesics. Additionally, radiographic information including ROM of the functional spinal unit (FSU) and signs of adjacent segment disease were recorded. RESULTS: NDI and VAS scores showed significant improvement 6 months after surgery and at last follow-up (p < 0.001). Concerning overall satisfaction 95.7% of the patients showed good to excellent results at the last visit and a significant reduction of analgesic usage was observed (p < 0.001). Radiographic measurements showed a mean increase of ROM up to 8.40 degrees in the treated FSU at last follow-up (p < 0.001). No signs of anterior migration or dislocation of the prosthesis and no subsidence was recorded radiographically. There were no major complications and a low rate of secondary procedures (2.2%). CONCLUSION: In the 24-months follow-up the ROTAIO Cervical Disc Prosthesis provided excellent clinical and radiographical results and seems to be safe and effective for the treatment of symptomatic single-level degenerative disc disease. PMID- 26759166 TI - CDH1 germline mutations and hereditary lobular breast cancer. AB - Hereditary diffuse gastric cancer is an autosomal dominant inherited disease associated of CDH1 germline mutations (that encodes for the E-cadherin protein), and lobular breast cancer is the second most frequent type of neoplasia. Recently, novel E-cadherin constitutional alterations have been identified in pedigree clustering only for lobular breast carcinoma without evidence of diffuse gastric tumors and in absence of BRCA1/2 mutations. This first evidence opens novel questions about the inherited correlation between diffuse gastric and lobular breast cancers. In this brief review we revise the literature data about the CDH1 mutation frequency affecting exclusively lobular breast cancer, providing clinical recommendation for asymptomatic mutation carriers. PMID- 26759168 TI - Hygiene Without Numbers. PMID- 26759167 TI - Study protocol: a randomised controlled trial of cognitive remediation for a national cohort of forensic mental health patients with schizophrenia or schizoaffective disorder. AB - BACKGROUND: Evidence is accumulating that cognitive remediation therapy (CRT) is an effective intervention for patients with schizophrenia or schizoaffective disorder. To date there has been no randomised controlled trial (RCT) cohort study of cognitive remediation within a forensic hospital. The goal of this study is to examine the effectiveness of a trial of cognitive remediation for forensic mental health patients with schizophrenia or schizoaffective disorder. METHODS: An estimated sixty patients will be enrolled in the study. Participants will be randomised to one of two conditions: CRT with treatment as usual (TAU), or TAU. CRT will consist of 42 individual sessions and 14 group sessions. The primary outcome measure for this study is change in cognitive functioning using the MATRICS Consensus Cognitive Battery (MCCB). Secondary outcomes include change in social and occupational functioning, disorganised symptoms, negative symptoms, violence, participation in psychosocial treatment and recovery. In addition to these effectiveness measures, we will examine patient satisfaction. DISCUSSION: Cognitive difficulties experienced by schizophrenia spectrum patients are associated with general functioning, ability to benefit from psychosocial interventions and quality of life. Research into the treatment of cognitive difficulties within a forensic setting is therefore an important priority. The results of the proposed study will help answer the question whether cognitive remediation improves functional outcomes in forensic mental health patients with schizophrenia or schizoaffective disorder. Forensic mental health patients are detained for the dual purpose of receiving treatment and for public protection. There can be conflict between these two roles perhaps causing forensic services to have an increased length of stay compared to general psychiatric admissions. Ultimately a focus on emphasising cognition and general functioning over symptoms may decrease tension between the core responsibilities of forensic mental health services. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02360813. Trial registered Feb 4th 2015 and last updated May 1(st) 2015. PMID- 26759169 TI - Cisplatin-induced mesenchymal stromal cells-mediated mechanism contributing to decreased antitumor effect in breast cancer cells. AB - BACKGROUND: Cells of the tumor microenvironment are recognized as important determinants of the tumor biology. The adjacent non-malignant cells can regulate drug responses of the cancer cells by secreted paracrine factors and direct interactions with tumor cells. RESULTS: Human mesenchymal stromal cells (MSC) actively contribute to tumor microenvironment. Here we focused on their response to chemotherapy as during the treatment these cells become affected. We have shown that the secretory phenotype and behavior of mesenchymal stromal cells influenced by cisplatin differs from the naive MSC. MSC were more resistant to the concentrations of cisplatin, which was cytotoxic for tumor cells. They did not undergo apoptosis, but a part of MSC population underwent senescence. However, MSC pretreatment with cisplatin led to changes in phosphorylation profiles of many kinases and also increased secretion of IL-6 and IL-8 cytokines. These changes in cytokine and phosphorylation profile of MSC led to increased chemoresistance and stemness of breast cancer cells. CONCLUSION: Taken together here we suggest that the exposure of the chemoresistant cells in the tumor microenvironment leads to substantial alterations and might lead to promotion of acquired microenvironment-mediated chemoresistance and stemness. PMID- 26759170 TI - Mapping QTLs and association of differentially expressed gene transcripts for multiple agronomic traits under different nitrogen levels in sorghum. AB - BACKGROUND: Sorghum is an important C4 crop which relies on applied Nitrogen fertilizers (N) for optimal yields, of which substantial amounts are lost into the atmosphere. Understanding the genetic variation of sorghum in response to limited nitrogen supply is important for elucidating the underlying genetic mechanisms of nitrogen utilization. RESULTS: A bi-parental mapping population consisting of 131 recombinant inbred lines (RILs) was used to map quantitative trait loci (QTLs) influencing different agronomic traits evaluated under normal N (100 kg.ha(-1) fertilizer) and low N (0 kg.ha(-1) fertilizer) conditions. A linkage map spanning 1614 cM was developed using 642 polymorphic single nucleotide polymorphisms (SNPs) detected in the population using Genotyping-By Sequencing (GBS) technology. Composite interval mapping detected a total of 38 QTLs for 11 agronomic traits tested under different nitrogen levels. The phenotypic variation explained by individual QTL ranged from 6.2 to 50.8%. Illumina RNA sequencing data generated on seedling root tissues revealed 726 differentially expressed gene (DEG) transcripts between parents, of which 108 were mapped close to the QTL regions. CONCLUSIONS: Co-localized regions affecting multiple traits were detected on chromosomes 1, 5, 6, 7 and 9. These potentially pleiotropic regions were coincident with the genomic regions of cloned QTLs, including genes associated with flowering time, Ma3 on chromosome 1 and Ma1 on chromosome 6, gene associated with plant height, Dw2 on chromosome 6. In these regions, RNA sequencing data showed differential expression of transcripts related to nitrogen metabolism (Ferredoxin-nitrate reductase), glycolysis (Phosphofructo-2-kinase), seed storage proteins, plant hormone metabolism and membrane transport. The differentially expressed transcripts underlying the pleiotropic QTL regions could be potential targets for improving sorghum performance under limited N fertilizer through marker assisted selection. PMID- 26759171 TI - Decision-making capacity for research participation among addicted people: a cross-sectional study. AB - BACKGROUND: Informed consent is a key element of ethical clinical research. Addicted population may be at risk for impaired consent capacity. However, very little research has focused on their comprehension of consent forms. The aim of this study is to assess the capacity of addicted individuals to provide consent to research. METHODS: 53 subjects with DSM-5 diagnoses of a Substance Use Disorder (SUD) and 50 non psychiatric comparison subjects (NPCs) participated in the survey from December 2014 to March 2015. This cross-sectional study was carried out at a community-based Outpatient Treatment Center and at an urban located Health Centre in Spain. A binary judgment of capacity/incapacity was made guided by the MacArthur Competence Assessment Tool for Clinical Research (MacCAT CR) and a clinical interview. Demographics and clinical characteristics were assessed by cases notes and the Mini-Mental State Examination, the Global Assessment Functional Scale and the Clinical Global Impression Scale. RESULTS: NPCs performed the best on the MacCAT-CR, and patients with SUD had the worst performance, particularly on the Understanding and Appreciation subscales. 32.7% SUD people lacked research-related decisional capacity. There were no statistically significant differences between the groups in terms of capacity to consent to research. CONCLUSIONS: The findings of our study provide evidence that a large proportion of individuals with SUD had decisional capacity for consent to research. It is therefore inappropriate to draw conclusions about capacity to make research decisions on the basis of a SUD diagnosis. In the absence of advanced cognitive impairment, acute withdrawal or intoxication, we should assume that addicted persons possess decision-making capacity. Thus, the view that people with SUD would ipso facto lose decision-making power for research consent is flawed and stigmatizing. PMID- 26759172 TI - Proportion and factors associated with Hepatitis B viremia in antiretroviral treatment naive and experienced HIV co-infected Ghanaian patients. AB - BACKGROUND: The global burden of Hepatitis B virus (HBV) and HIV co-infection is enormous. The risk of developing cirrhosis and hepatocellular cancer is associated with HBV DNA levels. The main objective of the study was to determine proportion of Hepatitis B viremia in ART-naive and ART-experienced co-infected Ghanaian patients and factors associated with HBV viremia after at least 36 weeks of lamivudine with or without tenofovir containing ART. METHODS: Hepatitis B and HIV co-infected patients who were ART-naive or had received at least 9 months of lamivudine-containing ART were enrolled in a cross-sectional study at Korle-Bu Teaching Hospital. Demographic and clinical data were collected and samples obtained for Hepatitis B serology, liver function tests and HBV DNA. Factors associated with viremia were determined using univariate and multivariate logistic regression analysis. RESULTS: Of 3108 HIV-infected patients screened, 257 (8.3%) were HBsAg-positive, of which 235 enrolled. Overall, 152 (64.7%) were ART-experienced and 83 (35.3%) were ART-naive. Eighty-nine-percent of ART-naive and 42.1% of ART-experienced patients had HBV DNA > 20 IU/mL. In multivariate analysis of all patients, being ART-naive (OR 10.1, 95% CI 4.6-21.9) and elevated ALT (OR 3.7, 95% CI 1.8-7.9) were associated with Hepatitis B viremia. In treatment experienced patients, elevated ALT (OR 4.8 CI 2.0-12.1) and male sex (OR 2.1, 95% CI 1.0-4.2) were associated with Hepatitis B viremia. CONCLUSIONS: Majority of ART-naive (89%) and 42% of ART-experienced patients had detectable hepatitis B viremia > 20 IU/mL. An abnormal serum ALT was significantly associated with hepatitis B viremia in HBV and HIV co-infected patients irrespective of treatment status. Baseline and on-treatment ALT may be a useful non-invasive predictor of Hepatitis B viremia in resource-constrained countries in sub-Saharan Africa where infection is endemic and viral load tests are not widely available. PMID- 26759175 TI - Inhibition of KDM6 activity during murine ESC differentiation induces DNA damage. AB - Pluripotent embryonic stem cells (ESCs) are characterised by their capacity to self-renew indefinitely while maintaining the potential to differentiate into all cell types of an adult organism. Both the undifferentiated and differentiated states are defined by specific gene expression programs that are regulated at the chromatin level. Here, we have analysed the contribution of the H3K27me2- and H3K27me23-specific demethylases KDM6A and KDM6B to murine ESC differentiation by employing the GSK-J4 inhibitor, which is specific for KDM6 proteins, and by targeted gene knockout (KO) and knockdown. We observe that inhibition of the H3K27 demethylase activity induces DNA damage along with activation of the DNA damage response (DDR) and cell death in differentiating but not in undifferentiated ESCs. Laser microirradiation experiments revealed that the H3K27me3 mark, but not the KDM6B protein, colocalise with gammaH2AX-positive sites of DNA damage in differentiating ESCs. Lack of H3K27me3 attenuates the GSK J4-induced DDR in differentiating Eed-KO ESCs. Collectively, our findings indicate that differentiating ESCs depend on KDM6 and that the H3K27me3 demethylase activity is crucially involved in DDR and survival of differentiating ESCs. PMID- 26759173 TI - Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation. AB - How mechanical cues from the extracellular environment are translated biochemically to modulate the effects of TGF-beta on myofibroblast differentiation remains a crucial area of investigation. We report here that the focal adhesion protein, Hic-5 (also known as TGFB1I1), is required for the mechanically dependent generation of stress fibers in response to TGF-beta. Successful generation of stress fibers promotes the nuclear localization of the transcriptional co-factor MRTF-A (also known as MKL1), and this correlates with the mechanically dependent induction of alpha smooth muscle actin (alpha-SMA) and Hic-5 in response to TGF-beta. As a consequence of regulating stress fiber assembly, Hic-5 is required for the nuclear accumulation of MRTF-A and the induction of alpha-SMA as well as cellular contractility, suggesting a crucial role for Hic-5 in myofibroblast differentiation. Indeed, the expression of Hic-5 was transient in acute wounds and persistent in pathogenic scars, and Hic-5 colocalized with alpha-SMA expression in vivo. Taken together, these data suggest that a mechanically dependent feed-forward loop, elaborated by the reciprocal regulation of MRTF-A localization by Hic-5 and Hic-5 expression by MRTF-A, plays a crucial role in myofibroblast differentiation in response to TGF-beta. PMID- 26759174 TI - KIF17 regulates RhoA-dependent actin remodeling at epithelial cell-cell adhesions. AB - The kinesin KIF17 localizes at microtubule plus-ends where it contributes to regulation of microtubule stabilization and epithelial polarization. We now show that KIF17 localizes at cell-cell adhesions and that KIF17 depletion inhibits accumulation of actin at the apical pole of cells grown in 3D organotypic cultures and alters the distribution of actin and E-cadherin in cells cultured in 2D on solid supports. Overexpression of full-length KIF17 constructs or truncation mutants containing the N-terminal motor domain resulted in accumulation of newly incorporated GFP-actin into junctional actin foci, cleared E-cadherin from cytoplasmic vesicles and stabilized cell-cell adhesions to challenge with calcium depletion. Expression of these KIF17 constructs also increased cellular levels of active RhoA, whereas active RhoA was diminished in KIF17-depleted cells. Inhibition of RhoA or its effector ROCK, or expression of LIMK1 kinase-dead or activated cofilin(S3A) inhibited KIF17-induced junctional actin accumulation. Interestingly, KIF17 activity toward actin depends on the motor domain but is independent of microtubule binding. Together, these data show that KIF17 can modify RhoA-GTPase signaling to influence junctional actin and the stability of the apical junctional complex of epithelial cells. PMID- 26759176 TI - Pannexin 3 and connexin 43 modulate skeletal development through their distinct functions and expression patterns. AB - Pannexin 3 (Panx3) and connexin 43 (Cx43; also known as GJA1) are two major gap junction proteins expressed in osteoblasts. Here, we studied their functional relationships in skeletal formation by generating Panx3(-/-) and Panx3(-/-);Cx43( /-) mice and comparing their skeletal phenotypes with Cx43(-/-) mice. Panx3(-/-) mice displayed defects in endochondral and intramembranous ossification, resulting in severe dwarfism and reduced bone density. The skeletal abnormalities of Panx3(-/-);Cx43(-/-) mice were similar to those in Panx3(-/-) mice. The gross appearance of newborn Cx43(-/-) skeletons showed no obvious abnormalities, except for less mineralization of the skull. In Panx3(-/-) mice, proliferation of chondrocytes and osteoblasts increased and differentiation of these cells was inhibited. Panx3 promoted expression of osteogenic proteins such as ALP and Ocn (also known as ALPL and BGLAP, respectively), as well as Cx43, by regulating Osx (also known as SP7) expression. Panx3 was induced in the early differentiation stage and reduced during the maturation stage of osteoblasts, when Cx43 expression increased in order to promote mineralization. Furthermore, only Panx3 functioned as an endoplasmic reticulum (ER) Ca(2+) channel to promote differentiation, and it could rescue mineralization defects in Cx43(-/-) calvarial cells. Our findings reveal that Panx3 and Cx43 have distinct functions in skeletal formation. PMID- 26759177 TI - A True Metasurface Antenna. AB - We present a true metasurface antenna based on electrically-small resonators. The resonators are placed on a flat surface and connected to one feed point using corporate feed. Unlike conventional array antennas where the distance between adjacent antennas is half wavelength to reduce mutual coupling between adjacent antennas, here the distance between the radiating elements is electrically very small to affect good impedance matching of each resonator to its feed. A metasurface antenna measuring 1.2lambda * 1.2lambda and designed to operate at 3 GHz achieved a gain of 12 dBi. A prototype was fabricated and tested showing good agreement between numerical simulations and experimental results. Through numerical simulation, we show that the metasurface antenna has the ability to provide beam steering by phasing all the resonators appropriately. PMID- 26759179 TI - Ibrutinib for mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. Ibrutinib is a first-in-class, oral inhibitor of Bruton's tyrosine kinase which acts by downstream inhibition of the B-cell receptor. Early clinical trials have demonstrated excellent tolerability and a modest side-effect profile in relapsed/refractory MCL. Although the majority of disease responses are partial, efficacy data are impressive with more than two-thirds of patients demonstrating a durable response. This article focuses on all aspects of ibrutinib in the context of MCL, including a summary of the basic pharmacology and pharmacokinetics; a review of the safety and efficacy data published to date and a discussion of the future implications in MCL. PMID- 26759178 TI - Transcriptome analyses reveal genotype- and developmental stage-specific molecular responses to drought and salinity stresses in chickpea. AB - Drought and salinity are the major factors that limit chickpea production worldwide. We performed whole transcriptome analyses of chickpea genotypes to investigate the molecular basis of drought and salinity stress response/adaptation. Phenotypic analyses confirmed the contrasting responses of the chickpea genotypes to drought or salinity stress. RNA-seq of the roots of drought and salinity related genotypes was carried out under control and stress conditions at vegetative and/or reproductive stages. Comparative analysis of the transcriptomes revealed divergent gene expression in the chickpea genotypes at different developmental stages. We identified a total of 4954 and 5545 genes exclusively regulated in drought-tolerant and salinity-tolerant genotypes, respectively. A significant fraction (~47%) of the transcription factor encoding genes showed differential expression under stress. The key enzymes involved in metabolic pathways, such as carbohydrate metabolism, photosynthesis, lipid metabolism, generation of precursor metabolites/energy, protein modification, redox homeostasis and cell wall component biogenesis, were affected by drought and/or salinity stresses. Interestingly, transcript isoforms showed expression specificity across the chickpea genotypes and/or developmental stages as illustrated by the AP2-EREBP family members. Our findings provide insights into the transcriptome dynamics and components of regulatory network associated with drought and salinity stress responses in chickpea. PMID- 26759180 TI - A quinazoline-based HDAC inhibitor affects gene expression pathways involved in cholesterol biosynthesis and mevalonate in prostate cancer cells. AB - Chronic inflammation can lead to the development of cancers and resolution of inflammation is an ongoing challenge. Inflammation can result from dysregulation of the epigenome and a number of compounds that modify the epigenome are in clinical use. In this study the anti-inflammatory and anti-cancer effects of a quinazoline epigenetic-modulator compound were determined in prostate cancer cell lines using a non-hypothesis driven transcriptomics strategy utilising the Affymetrix PrimeView(r) Human Gene Expression microarray. GATHER and IPA software were used to analyse the data and to provide information on significantly modified biological processes, pathways and networks. A number of genes were differentially expressed in both PC3 and DU145 prostate cancer cell lines. The top canonical pathways that frequently arose across both cell lines at a number of time points included cholesterol biosynthesis and metabolism, and the mevalonate pathway. Targeting of sterol and mevalonate pathways may be a powerful anticancer approach. PMID- 26759181 TI - Variations in the buccal-lingual alveolar bone thickness of impacted mandibular third molar: our classification and treatment perspectives. AB - Selecting either buccal or lingual approach for the mandibular third molar surgical extraction has been an intense debate for years. The aim of this observational retrospective study was to classify the molar based on the proximity to the external cortical bone, and analyze the position of inferior alveolar canal (IAC) of each type. Cone-beam CT (CBCT) data of 110 deeply impacted mandibular third molars from 91 consecutive patients were analyzed. A new classification based on the mean deduction value (MD) of buccal-lingual alveolar bone thickness was proposed: MD>=1 mm was classified as buccal position, 1 mm>MD>-1 mm was classified as central position, MD<=-1 mm was classified as lingual position. The study samples were distributed as: buccal position (1.8%) in 2 subjects, central position (10.9%) in 12 and lingual position (87.3%) in 96. Ninety-six molars (87.3%) contacted the IAC. The buccal and inferior IAC course were the most common types in impacted third molar, especially in lingually positioned ones. Our study suggested that amongst deeply impacted mandibular third molars, lingual position occupies the largest proportion, followed by the central, and then the buccal type. PMID- 26759183 TI - Functional nickel-based deposits synthesized by focused beam induced processing. AB - Functional nanostructures fabricated by focused electron/ion beam induced processing (FEBIP/FIBIP) open a promising route for applications in nanoelectronics. Such developments rely on the exploration of new advanced materials. We report here the successful fabrication of nickel-based deposits by FEBIP/FIBIP using bis(methyl cyclopentadienyl)nickel as a precursor. In particular, binary compounds such as nickel oxide (NiO) are synthesized by using an in situ two-step process at room temperature. By this method, as-grown Ni deposits transform into homogeneous NiO deposits using focused electron beam irradiation under O2 flux. This procedure is effective in producing highly pure NiO deposits with resistivity of 2000 Omegacm and a polycrystalline structure with face-centred cubic lattice and grains of 5 nm. We demonstrate that systems based on NiO deposits displaying resistance switching and an exchange-bias effect could be grown by FEBIP using optimized parameters. Our results provide a breakthrough towards using these techniques for the fabrication of functional nanodevices. PMID- 26759182 TI - The role of radiotherapy for patients over age 60 with diffuse large B-cell lymphoma in the rituximab era. AB - The role of consolidative radiotherapy (RT) in patients >=60 years old with DLBCL in the rituximab era is controversial. We examined the impact on disease control and overall survival by the addition of consolidative RT after completion of chemotherapy, while adjusting for known adverse risk factors. Retrospective chart review from 2004 to 2012 of 83 consecutive patients >=60 years old with DLBCL treated in the rituximab era, 68 of which had a complete response to chemotherapy, was performed. Amongst patients with a complete response, consolidative RT use was associated with 100% 5-year local control, improved progression-free survival (p = 0.047), and a trend for overall survival (p = .098) on multivariate analysis. Amongst all patients, the use of consolidative RT was associated with improved overall survival (p = 0.03). The use of consolidative RT should be considered for patients >=60 years old independent of stage and response to chemotherapy. PMID- 26759185 TI - Proton pump inhibitors are associated with risk of chronic kidney disease, study finds. PMID- 26759184 TI - Genetic affinities of the Jewish populations of India. AB - Due to the lack of written records or inscription, the origin and affiliation of Indian Jewish populations with other world populations remain contentious. Previous genetic studies have found evidence for a minor shared ancestry of Indian Jewish with Middle Eastern (Jewish) populations. However, these studies (relied on limited individuals), haven't explored the detailed temporal and spatial admixture process of Indian Jewish populations with the local Indian populations. Here, using large sample size with combination of high resolution biparental (autosomal) and uniparental markers (Y chromosome and mitochondrial DNA), we reconstructed genetic history of Indian Jewish by investigating the patterns of genetic diversity. Consistent with the previous observations, we detected minor Middle Eastern specific ancestry component among Indian Jewish communities, but virtually negligible in their local neighbouring Indian populations. The temporal test of admixture suggested that the first admixture of migrant Jewish populations from Middle East to South India (Cochin) occurred during fifth century. Overall, we concluded that the Jewish migration and admixture in India left a record in their genomes, which can link them to the 'Jewish Diaspora'. PMID- 26759186 TI - Contamination and distribution of heavy metals, polybrominated diphenyl ethers and alternative halogenated flame retardants in a pristine mangrove. AB - Owing to the expanding metal and electronics industries, pollution in the Pearl River Estuary needs special concern. Given the hydrodynamic effect, the pristine mangrove in Qi'ao Island would be contaminated by tidal flushing. Thus, we examined (1) the contamination of pollutants in this mangrove, including heavy metals, polybrominated diphenyl ethers (PBDEs) and alternative halogenated flame retardants (AHFRs), and (2) how habitat characteristics and sediment properties affect their distribution. Results showed that the sediment in Qi'ao mangrove had higher concentrations of heavy metals, PBDEs and AHFRs than that in other pristine mangroves, and similar concentrations to those mangroves impacted by point sources. Heavy metal concentrations were lower in the vegetated areas than mudflat, while the opposite was found for PBDEs and AHFRs. The findings imply that tidal flushing was an important pollution source, while mangrove plants have the capacity to minimize the impact of heavy metals, but not PBDEs and AHFRs. PMID- 26759187 TI - The effects of prolonged fasting on the levels of adiponectin, leptin, apelin, and omentin in pregnant women. AB - The aim of the present study was to evaluate serum adiponectin, leptin, apelin and omentin levels to explore metabolic changes occurring during fasting in the month of Ramadan. The study was designed as a prospective study. The patients were divided into two groups, each comprising 20 patients: Group I, fasting pregnant women, and Group II, non-fasting pregnant women. The patients' age, parity, gestational week and body mass index were recorded. Adiponectin and omentin levels were significantly lower in fasting pregnant women (p < 0.001). When the two groups were compared in terms of serum leptin and apelin levels, both were found to be significantly higher in Group I than in Group II. The findings of the present study suggest that pregnant women who are willing to fast during 24-38 weeks' gestation should be informed about insulin resistance. PMID- 26759188 TI - Direct comparison of shot-to-shot noise performance of all normal dispersion and anomalous dispersion supercontinuum pumped with sub-picosecond pulse fiber-based laser. AB - Coherence of supercontinuum sources is critical for applications involving characterization of ultrafast or rarely occurring phenomena. With the demonstrated spectral coverage of supercontinuum extending from near-infrared to over 10 MUm in a single nonlinear fiber, there has been a clear push for the bandwidth rather than for attempting to optimize the dynamic properties of the generated spectrum. In this work we provide an experimental assessment of the shot-to-shot noise performance of supercontinuum generation in two types of soft glass photonic crystal fibers. Phase coherence and intensity fluctuations are compared for the cases of an anomalous dispersion-pumped fiber and an all-normal dispersion fiber. With the use of the dispersive Fourier transformation method, we demonstrate that a factor of 100 improvement in signal-to-noise ratio is achieved in the normal-dispersion over anomalous dispersion-pumped fiber for 390 fs long pump pulses. A double-clad design of the photonic lattice of the fiber is further postulated to enable a pump-related seeding mechanism of normal dispersion supercontinuum broadening under sub-picosecond pumping, which is otherwise known for similar noise characteristics as modulation instability driven, soliton-based spectra. PMID- 26759189 TI - DL-3-n-butylphthalide delays the onset and progression of diabetic cataract by inhibiting oxidative stress in rat diabetic model. AB - DL-3-n-butylphthalide (NBP) is a therapeutic drug used for ischemic stroke treatment. Here, we investigated the impact of NBP on the development of rat diabetic cataract induced by intraperitoneal injection of streptozotocin (STZ). NBP was then administrated by oral gavage for nine weeks. Cataract development was monitored through ophthalmoscope inspections. The levels of blood glucose and serum reactive oxygen species (ROS), malondialdehyde (MDA) and 8 Hydroxydeovexyguanosine (8-OHdG) were measured. Total and soluble protein and oxidative stress parameters, such as 2, 4- dinitrophenylhydrazone (DNP), 4 hydroxynonenal (4-HNE) and MDA in the lenses were determined by Western blot and thiobarbituric acid analyses. The expressions of NF-E2-related factor 2 (Nrf2) and its downstream antioxidant enzymes, thioredoxin (TRX), Catalase and nuclear accumulation of Nrf2 were determined by Western blot and immunohistochemistry analyses. We showed that NBP treatment significantly improved the cataract scores, the levels of DNP, 4-HNE, and MDA in the lens compared to the non-treated groups. NBP also enhanced the expressions of Nrf2, TRX and catalase in the lens of diabetic rats. In addition, NBP treatment also decreased levels of blood glucose, serum MDA and 8-OHdG. These results suggested that NBP treatment significantly delayed the onset and progression of diabetic cataract by inhibiting the oxidative stresses. PMID- 26759191 TI - Albert Moser. Concept and procedure in American photography. PMID- 26759190 TI - The changing epidemiology of group B streptococcus bloodstream infection: a multi national population-based assessment. AB - BACKGROUND: Population-based studies conducted in single regions or countries have identified significant changes in the epidemiology of invasive group B streptococcus (GBS) infection. However, no studies have concurrently compared the epidemiology of GBS infections among multiple different regions and countries over time. The study objectives were to define the contemporary incidence and determinants of GBS bloodstream infection (BSI) and assess temporal changes in a multi-national population. METHODS: Population-based surveillance for GBS BSI was conducted in nine regions in Australia, Canada, Denmark, Sweden, Finland and the UK during 2000-2010. Incidence rates were age- and gender-standardised to the EU population. RESULTS: During 114 million patient-years of observation, 3464 cases of GBS BSI were identified for an overall annual incidence of 3.4 patients per 100,000 persons. There were marked differences in the overall (range = 1.8-4.1 per 100,000 person-year) and neonatal (range = 0.19-0.83 per 1000 live births) incidences of GBS BSI observed among the study regions. The overall incidence significantly (p = 0.05) increased. Rates of neonatal disease were stable, while the incidence in individuals older than 60 years doubled (p = 0.003). In patients with detailed data (n = 1018), the most common co-morbidity was diabetes (25%). During the study period, the proportion of cases associated with diabetes increased. CONCLUSIONS: While marked variability in the incidence of GBS BSI was observed among these regions, it was consistently found that rates increased among older adults, especially in association with diabetes. The burden of this infection may be expected to continue to increase in ageing populations worldwide. PMID- 26759207 TI - [Ankylosing spondylitis: a neglected systemic disease]. PMID- 26759192 TI - Critical carbon input to maintain current soil organic carbon stocks in global wheat systems. AB - Soil organic carbon (SOC) dynamics in croplands is a crucial component of global carbon (C) cycle. Depending on local environmental conditions and management practices, typical C input is generally required to reduce or reverse C loss in agricultural soils. No studies have quantified the critical C input for maintaining SOC at global scale with high resolution. Such information will provide a baseline map for assessing soil C dynamics under potential changes in management practices and climate, and thus enable development of management strategies to reduce C footprint from farm to regional scales. We used the soil C model RothC to simulate the critical C input rates needed to maintain existing soil C level at 0.1 degrees * 0.1 degrees resolution in global wheat systems. On average, the critical C input was estimated to be 2.0 Mg C ha(-1) yr(-1), with large spatial variability depending on local soil and climatic conditions. Higher C inputs are required in wheat system of central United States and western Europe, mainly due to the higher current soil C stocks present in these regions. The critical C input could be effectively estimated using a summary model driven by current SOC level, mean annual temperature, precipitation, and soil clay content. PMID- 26759208 TI - [The pathogenesis of Sjogren's syndrome]. PMID- 26759209 TI - [How to develop the evidence-based clinical practice guideline]. PMID- 26759193 TI - Selective Audiovisual Semantic Integration Enabled by Feature-Selective Attention. AB - An audiovisual object may contain multiple semantic features, such as the gender and emotional features of the speaker. Feature-selective attention and audiovisual semantic integration are two brain functions involved in the recognition of audiovisual objects. Humans often selectively attend to one or several features while ignoring the other features of an audiovisual object. Meanwhile, the human brain integrates semantic information from the visual and auditory modalities. However, how these two brain functions correlate with each other remains to be elucidated. In this functional magnetic resonance imaging (fMRI) study, we explored the neural mechanism by which feature-selective attention modulates audiovisual semantic integration. During the fMRI experiment, the subjects were presented with visual-only, auditory-only, or audiovisual dynamical facial stimuli and performed several feature-selective attention tasks. Our results revealed that a distribution of areas, including heteromodal areas and brain areas encoding attended features, may be involved in audiovisual semantic integration. Through feature-selective attention, the human brain may selectively integrate audiovisual semantic information from attended features by enhancing functional connectivity and thus regulating information flows from heteromodal areas to brain areas encoding the attended features. PMID- 26759210 TI - [The relationship between mRNA level of glucocorticoid receptor alpha, heat shock protein 90, protein level of macrophage migration inhibitory factor and glucocorticoid resistance in systemic lupus erythematosus]. AB - OBJECTIVE: To investigate the mRNA level of glucocorticoid receptor alpha (GRalpha) and heat shock protein 90 (HSP90) in peripheral blood mononuclear cells (PBMCs) and the plasma protein level of macrophage migration inhibitory factor (MIF) in patients with systemic lupus erythematosus (SLE) and to analyze their association with glucocorticoid (GC) resistance. METHODS: One hundred and six patients with SLE and thirty-eight healthy controls were enrolled in this study. Transcription levels of GRalpha and HSP90 were determined by real-time polymerase chain reaction. Enzyme-linked immunosorbent assay was used to detect the protein level of plasma MIF. The association between these parameters and GC resistance was analyzed by Spearman correlation analysis. The multivariate logistic regression model was used to analyze the risk factors for GC resistance. RESULTS: The mRNA level of GRalpha and HSP90 in GC resistance group was significantly lower than that in GC sensitive group [10.18 (3.12, 17.20) vs 16.83 (12.01, 24.18), P=0.001; 18.46 (14.77, 26.45) vs 25.84 (17.97, 35.90), P= 0.005]. MIF protein level in GC resistance group was significantly higher than that in GC sensitive group [(23.21+/-7.98) ug/L vs (18.34+/-6.29) ug/L; P=0.013]. The mRNA level of HSP90 in the high MIF group was significantly lower than that in the low MIF group [23.67 (13.84, 28.32) vs 26.64 (23.61, 47.16); P=0.001], as well as HSP90/GRalpha ratio (P=0.008). Additionally, the plasma protein level of MIF was negatively correlated with HSP90 (r=-0.275, P=0.004) and HSP90/GRalpha ratio (r= 0.341, P<0.001). SLE activity index score in GC resistance group was significantly higher than that in GC sensitive group [(12.23+/-2.86) ug/L vs (9.63+/-3.48) ug/L; P=0.003]. Logistic regression model indicated that disease activity was an independent risk factor for GC resistance (OR=17.481, 95% CI 1.747-174.903, P=0.015). CONCLUSIONS: Our preliminary findings suggest that low mRNA level of GRalpha and HSP90 and high protein level of MIF are associated with GC resistance. Elevated MIF level in SLE patients may play an important role in the development of GC resistance through down-regulating HSP90 and destabilizing the balance of HSP90/Gralpha. Disease activity is the risk factor for GC resistance, which might be the viable evidence of therapy response. PMID- 26759211 TI - [An investigation of sleep disturbance and related factors in rheumatoid arthritis patients]. AB - OBJECTIVE: To explore the characteristics of sleep disturbance and its related factors in patients with rheumatoid arthritis (RA). METHODS: A total of 71 patients with RA in Department of Rheumatology Huaxi Hospital have completed the following questionnaires, including Pittsburgh sleeping quality index (PSQI), visual analogue scale (VAS), disease activity score in 28 joints (DAS28), health assessment questionnaire(HAQ), hospital anxiety and depression scale (HADS), fatigue severity scale (FSS) and a self-designed general status questionnaire. RESULTS: The prevalence of sleep disturbance was 42.3% (30/71) in rheumatoid arthritis patients (68.4%). The scores of DAS28, VAS, PSQI, HAQ, FSS and HADS in patients with sleep disturbance were significantly higher than those in patients with good sleep, which were respectively 3.90+/-1.12 vs 2.92+/-1.92, (5.03+/ 2.63) scores vs (2.41+/-1.84) scores, (10.87+/-2.42) scores vs (4.29+/-1.85) scores, 3.0(0.0,7.0) scores vs 2.0 (0.5, 4.0) scores, (39.17+/-14.02) scores vs (29.63+/-16.12) scores, (14.50+/-7.77) scores vs (9.49+/-6.57) scores (P<0.05 in all scales). According to the results of Pearson correlation analysis, PSQI had significantly positive correlation with DAS28 (r=0.462, P<0.01), VAS (r=0.556, P<0.01), HAQ (r=0.360, P<0.01), FSS (r=0.420, P<0.01) and HADS (r=0.447, P<0.01) respectively. The logistic regression analysis indicated that VAS was a predictor for poor sleep quality (P<0.01). The patients receiving biological agents had significantly (P<0.05) lower scores of DAS28 (2.86+/-1.39 vs 3.52+/-1.10), PSQI [(5.90+/-4.24) scores vs (8.53+/-3.78) scores], VAS (2.15+/-2.30 vs 4.05+/-2.46), HAQ [0.0 (0.0, 2.0) scores vs 3.0 (0.0, 6.0) scores] compared to those taking oral drugs. CONCLUSION: High prevalence of sleep disturbance in patients with RA is noted, which indirectly influences the activity of disease, quality of life, depression, fatigue and other physical and mental health. Biological agents can partly improve the sleep disturbance and functional status. PMID- 26759212 TI - [Cytomegalovirus reactivation and steroid refractory are the independent risk factors for colonic surgery in ulcerative colitis]. AB - OBJECTIVE: To explore the risk factors of surgery in patients with ulcerative colitis (UC). METHODS: Patients with UC, hospitalized from January 2005 to October 2012 were retrospectively enrolled in this study. Univariate and multivariate analyses were used to reveal the risk factors of colon surgery, including demographic features, clinical manifestations, laboratory examinations and medication. RESULTS: A total of 273 UC patients were enrolled in this study with 39 (14.3%) patients receiving colon surgery. Compared with the flare group, patients in surgery group 71.8% (28/39) had more proportion with severe disease (P=0.008), higher prevalence of active cytomegalovirus (CMV) infection [47.6% (10/21) vs 10.9% (11/101), P<0.001], higher ratio of steroid resistance [60.0% (15/25) vs 10.7% (18/168), P<0.001], more receiving cyclosporine A [28.2% (11/39) vs 7.3% (17/234), P<0.001], and lesser with 5-aminosalicylic acid [82.1% (32/39) vs 95.3% (223/234), P=0.007]. Based on multivariate logistic regression analyses, active CMV infection and steroid resistance were two independent risk factors of colon surgery in UC patients (P=0.006 and 0.030, OR=6.040 and 17.928). CONCLUSION: Active CMV infection and steroid resistance are independent risk factors of colon surgery in UC. PMID- 26759213 TI - [The relationship between season/latitude and multiple sclerosis]. AB - OBJECTIVE: To explore the impact of season and latitude on multiple sclerosis by study the onset/relapse season and latitude distribution in multiple sclerosis (MS) patients. METHODS: A total of 264 MS patients, with 88 males and 176 females, who were hospitalized in Beijing Tiantan Hospital from January 2002 to December 2012, were enrolled in the study and all the clinical data were retrospectively analyzed. The mean age was (33.9+/-12.3) years old, with the disease duration of (6.3+/-4.5) years and 453 cases of relapse. The recurrence of MS was collected by four seasons, with March to May defined as spring, June to August as summer, September to November as autumn and December to February as winter. MS patients lived in Beijing (39.39 degrees N-41.07 degrees N) were chosen to test the correlation between the incidence/recurrence and monthly mean temperature, sunlight exposure intensity and duration. All the patients were divided into the high latitude group and the low latitude group, taken the latitude median (40.22 degrees N) of Beijing area as the boundary. Gender composition, age of onset, disease duration and recurrence rate were compared between the two groups. RESULTS: Most of the onset/ relapse of MS were observed in winter (134 cases), while summer (97 cases) took the least. In the same latitude region (Beijing area), the onset/ relapse of MS was negatively correlated to the mean temperature and sunlight exposure intensity (r=-0.699, P=0.006; r=-0.623, P=0.015). Recurrence was higher in the high latitude group than in the low latitude group [68.7%(123/179) vs 63.0%(51/81), P=0.000], while no significant difference was found in gender composition, age of onset and disease duration between the two groups. CONCLUSION: The onset/recurrence of MS has obvious seasonal characteristics. The onset/recurrence of MS is correlated with latitude, temperature and sunlight exposure intensity of the habitation of MS patients. Environmental factors are important cause of the onset/recurrence of MS, with sunshine exposure as the most key factor. PMID- 26759214 TI - [Efficacy and safety of alogliptin in treatment of type 2 diabetes mellitus: a multicenter, randomized, double-blind, placebo-controlled phase III clinical trial in mainland China]. AB - OBJECTIVE: To evaluate the efficacy and safety of alogliptin in Chinese patients with type 2 diabetes (T2DM). METHODS: This was a multicenter, randomized, double blind, placebo-controlled phase III trial. A total of 491 subjects with T2DM were randomized in a 1:1 ratio to receive alogliptin (25 mg once daily) or placebo for 16 weeks. Among them, 181 were in the monotherapy group (group A), 186 were in the add-on to metformin group (group B), and 124 were in the add-on to pioglitazone group (group C). RESULTS: After 16 weeks of therapy, glycosylated hemoglobin A1c (HbA1c) levels decreased in both alogliptin and placebo groups. The mean changes in HbA1c for alogliptin and placebo were 1.00% and 0.43% (P<0.001), 0.91% and 0.23% (P<0.001), and 0.76% and 0.25% (P<0.001) in group A, B and C, respectively. Compared with placebo, alogliptin treatment led to a greater decrease in fasting plasma glucose (FPG) and a higher percentage of subjects who achieved HbA1c targets of <= 6.5% and <= 7.0%. The percentage of subjects who experienced all adverse events including hypoglycemia with alogliptin were comparable to those with placebo. CONCLUSIONS: Alogliptin 25 mg once daily reduced HbA1c and FPG, and increased a greater proportion of subjects achieving HbA1c goals of <=6.5% and <=7.0% compared with placebo when used as a monotherapy, add-on to metformin, or add-on to pioglitazone. The hypoglycemia rates and safety profiles with alogliptin were similar to those with placebo. PMID- 26759216 TI - [The prognostic value of serum albumin for in-hospital mortality in patients with heart failure basing on propensity score matching]. AB - OBJECTIVE: To analyze the prognostic value of serum albumin for in-hospital mortality in patients with heart failure. METHODS: A total of 2 430 consecutive heart failure patients aged at (68+/-14) years were enrolled in the study. Patients were divided into 2 groups according to serum albumin concentration on admission: the normoalbuminemia group (>=35 g/L) and the hypoalbuminemia group (<35 g/L). Propensity score matching was conducted to reduce confounding bias between the groups. Cox proportional-hazards regression models were used to evaluate the prognostic value of serum albumin for in-hospital mortality in patients with heart failure before and after matching. RESULTS: Compared with those in the normoalbuminemia group, subjects in the hypoalbuminemia group were older, and had higher NYHA functional status and higher in-hospital mortality. More patients were diagnosed with dilated cardiomyopathy and valvular heart disease, and fewer were with hypertension in the hypoalbuminemia group than those patients in the normoalbuminemia group. Moreover, patients in this group presented with faster heart rate and lower systolic blood pressure than those in the normoalbuminemia group. They had higher levels of direct bilirubin, alkaline phosphatase, glutamyltranspetidase, creatinine, uric acid, urea, and B-type natriuretic peptide (BNP) and lower levels of hemoglobin, total cholesterol (TC), and serum sodium compared with subjects in the normoalbuminemia group. Left ventricular ejection fractions (LVEF) of patients were lower in the hypoalbuminemia group than those of patients in the normoalbuminemia group. More patients were of long-duration and treated with spirolactone. With protensity score matching, 631 pairs of patients were successfully matched. Before matching, the in-hospital mortality in normoalbuminemia group was 1.2% and that in hypoalbuminemia group was 5.7%. The multivariate Cox regression analysis indicated that the risk for in-hospital death in patients with heart failure was 12.0% greater for each 1 g/L decrement in albumin level after adjusted for all clinical factors (HR 1.120, 95% CI 1.057-1.186; P<0.001). The same held after matching. The in-hospital mortality in normoalbuminemia group was 2.9%, and that in hypoalbuminemia group was 5.7%. The multivariate Cox regression analysis showed that the risk for in-hospital death in patients with heart failure was 11.0% greater for each 1 g/L decrement in albumin level after adjusted for all clinical factors (HR 1.110, 95% CI 1.043-1.181; P=0.001). CONCLUSIONS: Serum albuminis is an independent risk factor for in-hospital mortality in patients with heart failure. Treatment of hypoalbuminemia may lower the in-hospital mortality in patients with heart failure. PMID- 26759215 TI - [The diagnosis, treatment and following up of 7 patients with 45, X/46, XY mixed gonadal dysgenesis]. AB - OBJECTIVE: To investigate the clinical features, therapeutic regimens and follow up information of patients with 45, X/46, XY mixed gonadal dysgenesis in order to improve the diagnosis and treatment of the disease. METHODS: We performed a retrospective review of patients with 45, X/46, XY mosaicism hospitalized in Chinese PLA General Hospital between 2000 and 2014. The clinical features,sex hormones,treatment and follow-up information were summarized. RESULTS: (1) Seven patients ranging 12-17 years old were diagnosed as having 45, X/46, XY mixed gonadal dysgenesis. Six of them had female sex of rearing and one had male. (2) All of them presented with short stature and growth retardation, and had similar specific somatic signs to Turner syndrome. (3) The external genitalia presented with a wide variety of phenotypes. One patient presented with male phenotype with hypospadia, one presented with clitoridauxe, and five presented with female phenotype. The masculinization scores for the external genitalia showed that five patients presented with female phenotype, one patient with mild undervirilization and one patient with ambiguous genitalia. (4) By surgical exploration and ultrasound, two patients were found with testes and one was with ovary-like gonads. No gonad could be detected in the other four patients. (5) Five patients were treated with recombinant human growth hormone (rhGH). Two patients received sex hormone replacement therapy with one patient taking testosterone, whose penis became enlarged and erect after treatment, and one taking artificial cycle. CONCLUSIONS: The patients with 45, X/46, XY mosaicism share similar specific somatic signs to Turner syndrome. The 45, X/46, XY mosaicism presents with a wide spectrum of phenotypes with the highest proportion of being genital ambiguity. RhGH, testosterone and artificial cycle can be used accordingly. PMID- 26759217 TI - A Novel Homozygous Mutation in the Transient Receptor Potential Melastatin 6 Gene: A Case Report. AB - Hereditary hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disease caused by mutations in the transient receptor potential melastatin 6 (TRPM6) gene. Affected individuals present in early infancy with seizures caused by the severe hypocalcemia and hypomagnesemia. By presenting this case report, we also aimed to highlight the need for molecular genetic analysis in inbred or familial cases with hypomagnesemia. A Turkish inbred girl, now aged six years, had presented to another hospital at age two months with seizures diagnosed to be due to hypomagnesemia. She was on magnesium replacement therapy when she was admitted to our clinic with complaints of chronic diarrhea at age 3.6 years. During her follow-up in our clinic, she showed an age-appropriate physical and neurological development. In molecular genetic analysis, a novel homozygous frame-shift mutation (c.3447delT>p.F1149fs) was identified in the TRPM6 gene. This mutation leads to a truncation of the TRPM6 protein, thereby complete loss of function. We present the clinical follow-up findings of a pediatric HSH case due to a novel mutation in the TRPM6 gene and highlight the need for molecular genetic analysis in inbred or familial cases with hypomagnesemia. PMID- 26759218 TI - Evaluation of Endothelial (dys)Function, Left Ventricular Structure and Function in Patients with Chronic Kidney Disease. AB - BACKGROUND: Endothelial dysfunction is involved in the pathogenesis of atherosclerosis and cardiovascular complications in chronic kidney disease (CKD). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered as a marker of endothelial dysfunction. The aim of this study was to evaluate serum ADMA, eNOS concentration and left ventricular structure and function in CKD patients and to assess the impact of the type of dialyzer on serum ADMA and eNOS concentrations after a haemodialysis (HD) session. MATERIAL AND METHODS: Peripheral blood was collected from 35 predialysis CKD patients, 40 CKD patients on HD and 15 healthy subjects. Patients on HD were divided into two groups according to the dialyzer used based on polynephron or cellulose membranes. Plasma ADMA and eNOS concentrations were assessed. All subjects underwent echocardiography and were evaluated for selected biochemical parameters. RESULTS: We found significantly higher serum ADMA (p<0.05) and significantly lower eNOS (p<0.05) concentration in CKD patients compared with healthy subjects. Both dialyzers significantly reduced serum ADMA concentration (p<0.05) but none of the analysed dialyzers showed superiority when comparing the results. We showed that stage V CKD patients, who had the highest serum ADMA concentration had the lowest left ventricle ejection fraction (LVEF) and the highest left ventricle mass (LVM) and left ventricular end diastolic diameter (LVEDd). CONCLUSIONS: Our results supports the presence of endothelial dysfunction in CKD patients. Correlation between elevated serum AMDA concentration and disadvantageous changes in left ventricular structure and function may indicate an important role of endothelial dysfunction in cardiovascular complications in CKD patients. PMID- 26759219 TI - Drought and flooding have distinct effects on herbivore-induced responses and resistance in Solanum dulcamara. AB - In the field, biotic and abiotic stresses frequently co-occur. As a consequence, common molecular signalling pathways governing adaptive responses to individual stresses can interact, resulting in compromised phenotypes. How plant signalling pathways interact under combined stresses is poorly understood. To assess this, we studied the consequence of drought and soil flooding on resistance of Solanum dulcamara to Spodoptera exigua and their effects on hormonal and transcriptomic profiles. The results showed that S. exigua larvae performed less well on drought stressed plants than on well-watered and flooded plants. Both drought and insect feeding increased abscisic acid and jasmonic acid (JA) levels, whereas flooding did not induce JA accumulation. RNA sequencing analyses corroborated this pattern: drought and herbivory induced many biological processes that were repressed by flooding. When applied in combination, drought and herbivory had an additive effect on specific processes involved in secondary metabolism and defence responses, including protease inhibitor activity. In conclusion, drought and flooding have distinct effects on herbivore-induced responses and resistance. Especially, the interaction between abscisic acid and JA signalling may be important to optimize plant responses to combined drought and insect herbivory, making drought-stressed plants more resistant to insects than well-watered and flooded plants. PMID- 26759220 TI - Unusual scapular winging - A case report. AB - Scapular mobility has a central role in maintaining normal upper limb function. Scapular winging is characterized by a failure in the dynamic stabilization of the scapula against the thoracic wall resulting in a condition in which the medial border of the scapula is prominent. The following case describes a patient who was referred to physiotherapy due to abnormal scapular protrusion. The main findings of the physical examination showed weakness of the scapular stabilizers more prominent on the right side than of the left. Additionally, the physical examination demonstrated weakness of the abdominal muscles, hip adductors, and ankle dorsi-flexors, as well as some facial muscles. The electromyography results were inconclusive. Further examination led to clinical suspicion of Facioscapulohumeral Dystrophy (FSHD) as a diagnosis, which was confirmed by genetic testing. Facioscapulohumeral Dystrophy is characterized by symptoms related to motor function and in most cases becomes evident in patients in their 20s and 30s. The disease signs and symptoms are often identified in a clinical setting. Currently, there are no reports describing an effective treatment for the disease. However, physiotherapy, moderate physical exercise, counselling, and use of suitable aids and orthoses may help improve functionality and mobility. This case report aims to increase the awareness of musculoskeletal physiotherapists to this unique dystrophy, when encountering complex presentations with scapular winging. PMID- 26759221 TI - Relationship of sodium intake with obesity among Korean children and adolescents: Korea National Health and Nutrition Examination Survey. AB - We investigated whether dietary and urinary Na is associated with adiposity in Korean children and adolescents (10-18 years), a population with a high salt intake. Study subjects were Korean children and adolescents who participated in the cross-sectional nationally representative Korea National Health and Nutrition Examination Survey (2010-2011). This study used measures of dietary (24-h dietary recall) and urinary Na (Na:creatinine ratio) and three methods to determine obesity (BMI, waist circumference (WC) and total body per cent fat (TBPF)). Higher Na intake was significantly associated with obesity, adjusting for the covariates. Subjects in the highest tertile of urinary Na excretion had a significantly higher OR for higher adiposity compared with those in the lowest tertile (multivariate-adjusted OR 3.13 (95% CI 1.81, 5.50) for BMI, 2.15 (95% CI 1.27, 3.66) for WC and 1.92 (95% CI 1.29, 2.86) for TBPF, respectively). Na intake estimated by the 24-h recall method also showed significant association with adiposity (multivariate-adjusted OR 2.79 (95% CI 1.66, 4.68) for BMI and 2.14 (95% CI 1.25, 3.67) for WC, respectively). The significant associations between Na and adiposity remained significant after additionally adjusting for sugar-sweetened beverage (SSB) consumption. Our results revealed a significant positive association between urinary and dietary Na and adiposity in Korean children and adolescents, independent of SSB consumption. PMID- 26759222 TI - Hypoacetylation, hypomethylation, and dephosphorylation of H2B histones and excessive histone deacetylase activity in DU-145 prostate cancer cells. AB - BACKGROUND: Hypoacetylation on histone H3 of human prostate cancer cells has been described. Little is known about the modifications of other histones from prostate cancer cells. METHODS: Histones were isolated from the prostate cancer cell line DU-145 and the non-malignant prostatic cell line RC170N/h. Post translational modifications of histone H2B were determined by liquid chromatography-mass spectrometry (LC-MS)/MS. RESULTS: The histone H2B of the prostate cancer cell line DU-145 was found to have hypoacetylation, hypomethylation, and dephosphorylation as compared to the non-malignant prostatic cell line RC170N/h. H2B regained acetylation on multiple lysine residues, phosphorylation on Thr19, and methylation on Lys23 and Lys43 in the DU-145 cells after sodium butyrate treatment. CONCLUSIONS: The histone H2B of DU-145 prostate cancer cells are hypoacetylated, hypomethylated, and dephosphorylated. Histone deacetylase inhibitor reversed this phenotype. Epigenetic agent may therefore be useful for prostate cancer therapy and worth further investigation. PMID- 26759223 TI - Elevated C-reactive protein levels at ICU discharge as a predictor of ICU outcome: a retrospective cohort study. AB - BACKGROUND: Before discharging a patient from the ICU, an adequate patient evaluation is needed to detect individuals as high risk for unfavorable outcome. A pro- or anti-inflammatory status is a potential risk factor for an adverse outcome, and elevated CRP concentrations have shown to correlate with organ failure. Several studies have been performed to evaluate the use of CRP as a marker of post-ICU prognosis. Results are seemingly conflicting, and it is worthwhile to investigate these markers further as CRP is an adequate marker of pro- and anti-inflammatory status of the patient. We aimed to test the hypothesis that elevated CRP levels at ICU discharge are associated with an increased risk of ICU readmission and in-hospital mortality in patients with a prolonged ICU stay. METHODS: A retrospective cohort study was performed in a single-center hospital with an 18-bed mixed medical/surgical ICU. Patients discharged alive from the ICU with at least 48-h ICU length of stay were evaluated. Patients were distributed into two groups: 'high CRP' (>=75 mg/L) and 'low CRP' (<75 mg/L) at ICU discharge. We assessed the difference in adverse outcome (ICU readmission and/or in-hospital mortality) between these groups. RESULTS: A total of 998 patients were included. Compared to the 'low CRP' group, patients in the 'high CRP' group had a higher readmission rate (13.1 vs. 7.4 %; p = 0.003). The post ICU mortality rate in the 'high CRP' group and 'low CRP' group was 6.9 % and 4.7 %, respectively; p = 0.127. Combined readmission and mortality rates were significantly higher in the 'high CRP' group in comparison with the 'low CRP' group (17.9 vs. 10.1 %; p = 0.001). Hospital mortality in patients readmitted to the ICU was significantly higher than in non-readmitted patients (20 vs. 4.3 %; p < 0.001). Strikingly, the 'high CRP' group had significantly lower APACHE II and SOFA scores at ICU admission compared to the 'low CRP' group. This highlights the potential for ICU-acquired risk factors, including CRP. CONCLUSIONS: A high CRP concentration (>=75 mg/L) within 24 h before ICU discharge is associated with an increased risk of adverse outcome post-ICU discharge. However, CRP at discharge represents only a very moderate risk factor and may not be used for individual clinical decision-making. PMID- 26759224 TI - Systemic sclerosis and silica exposure: a rare association in a large Brazilian cohort. AB - The objective of this study is to describe the characteristics of patients with Erasmus syndrome (ES) in a large SSc Brazilian cohort. Nine hundred and forty seven SSc patients attended at the Scleroderma Outpatient Clinic at two academic medical centers in Brazil and classified as SSc according to the ACR/EULAR criteria were retrospectively studied. Information on demographics, clinical, and laboratory features was obtained by chart review. ES patients had their HLA class II characterized by PCR-SSO method as available. Among the 947 SSc patients studied, nine (0.9 %) had ES. These ES patients were predominantly male (78 %) and smokers (68 %) and presented diffuse SSc (67 %). Mean time of occupational exposure to silica was 13.7 years, with mean age at onset of 47 years. Previous history of tuberculosis was referred by 33 % of the ES patients. All the ES patients presented Raynaud's phenomenon, esophageal involvement, and interstitial lung disease (ILD). Antinuclear antibodies were present in all the ES patients, while anti-topoisomerase I was positive in 44 % and no patient had anticentromere antibody. Three different HLA-DQB alleles (0506, 0305, and 0303) were observed. Compared to non-ES cases, patients with ES were associated with male gender (p < 0.001), diffuse SSc (p < 0.05), ILD (p < 0.05), positive anti-topoisomerase I antibodies (p < 0.05), and death (p < 0.05). Multivariate analysis did not confirm that silicosis is an independent risk factor for SSc. To conclude, ES was rare in this large SSc cohort, although associated with a bad prognosis. PMID- 26759225 TI - Filling Gaps in the Acculturation Gap-Distress Model: Heritage Cultural Maintenance and Adjustment in Mexican-American Families. AB - The acculturation gap-distress model purports that immigrant children acculturate faster than do their parents, resulting in an acculturation gap that leads to family and youth maladjustment. However, empirical support for the acculturation gap-distress model has been inconclusive. In the current study, 428 Mexican American adolescents (50.2 % female) and their primary caregivers independently completed questionnaires assessing their levels of American and Mexican cultural orientation, family functioning, and youth adjustment. Contrary to the acculturation gap-distress model, acculturation gaps were not associated with poorer family or youth functioning. Rather, adolescents with higher levels of Mexican cultural orientations showed positive outcomes, regardless of their parents' orientations to either American or Mexican cultures. Findings suggest that youths' heritage cultural maintenance may be most important for their adjustment. PMID- 26759226 TI - CT Angiography Spot Sign, Hematoma Expansion, and Outcome in Primary Pontine Intracerebral Hemorrhage. AB - BACKGROUND AND PURPOSE: The computed tomography angiography (CTA) spot sign is a validated predictor of hematoma expansion and poor outcome in supratentorial intracerebral hemorrhage (ICH), but patients with brainstem ICH have typically been excluded from the analyses. We investigated the frequency of spot sign and its relationship with hematoma expansion and outcome in patients with primary pontine hemorrhage (PPH). METHODS: We performed a retrospective analysis of PPH cases obtained from a prospectively collected cohort of consecutive ICH patients who underwent CTA. CTA first-pass readings for spot sign presence were analyzed by two trained readers. Baseline and follow-up hematoma volumes on non-contrast CT scans were assessed by semi-automated computer-assisted volumetric analysis. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive and negative likelihood ratio, and accuracy of spot sign for prediction of in-hospital mortality were calculated. RESULTS: 49 subjects met the inclusion criteria of whom 11 (22.4 %) showed a spot sign. In-hospital mortality was higher in spot sign-positive versus spot sign-negative subjects (90.9 vs 47.4 %, p = 0.020). Spot sign showed excellent specificity (95 %) and PPV (91 %) in predicting in-hospital mortality. Absolute hematoma growth, defined as parenchymal and intraventricular hematoma expansion of any amount, was significantly higher in spot sign-positive versus spot sign-negative subjects (13.72 +/- 20.93 vs 3.76 +/- 8.55 mL, p = 0.045). CONCLUSIONS: As with supratentorial ICH, the CTA spot sign is a common finding and is associated with higher risk of hematoma expansion and mortality in PPH. This marker may assist clinicians in prognostic stratification. PMID- 26759227 TI - Application of Tauroursodeoxycholic Acid for Treatment of Neurological and Non neurological Diseases: Is There a Potential for Treating Traumatic Brain Injury? AB - The objective of this review was to evaluate the potential of tauroursodeoxycholic acid (TUDCA) for neuroprotection in traumatic brain injury (TBI) patients in the neurocritical care setting. Specifically, we surveyed preclinical studies describing the neuroprotective and systemic effects of TUDCA, and the potential therapeutic application of TUDCA. Preclinical studies have provided promising data supporting its use in neurological disease characterized by apoptosis-induced neuronal loss. TUDCA inhibits multiple proteins involved in apoptosis and upregulates cell survival pathways. In addition, TUDCA exhibits anti-inflammatory effects in models of neuroinflammation and attenuates neuronal loss in chronic neurodegenerative diseases. This may be applicable to TBI, which also triggers inflammatory and apoptotic processes. Additionally, preliminary data support the use of pharmacological therapies that reduce apoptosis and inflammation associated with TBI. The anti-apoptotic and anti-inflammatory mechanisms of TUDCA could prove promising in the treatment of TBI. Currently, there are no published data supporting improvement in clinical outcomes of TBI by treatment with TUDCA, but future studies should be considered. PMID- 26759230 TI - February-May temperature reconstruction based on tree-ring widths of Abies fargesii from the Shennongjia area in central China. AB - February-May temperature strongly affects ecological processes and socio economics in central China, yet its long-term variability has not been thoroughly assessed due to the shortness of instrumental records. In order to improve the understanding of the regularities of temperature variability in central China, in this study, we present a new tree-ring chronology from the Shengnongjia Mountains in central China which provides a valuable 245-year record of temperature variability. The reconstructed temperature correlated strongly with February-May mean temperature records of the Fangxian meteorological station from AD 1958 to AD 2011, and the derived reconstruction explained 44.5 % of the instrumental temperature variation during this period. The study shows that this region experienced three warm periods and two cool periods, i.e., the major warm periods occurred in AD 1783-1806, AD 1879-1909, and AD 1975 to the present, whereas the cool intervals occurred in AD 1807-1878 and AD 1910-1974. This reconstruction could aid in the evaluation of regional climate variability in subtropical China. PMID- 26759228 TI - Prospero homeobox 1 mediates the progression of gastric cancer by inducing tumor cell proliferation and lymphangiogenesis. AB - BACKGROUND: Prospero homeobox 1 (PROX1) functions as a tumor suppressor gene or an oncogene in various cancer types. However, the distinct function of PROX1 in gastric cancer is unclear. We determined whether PROX1 affected the oncogenic behavior of gastric cancer cells and investigated its prognostic value in patients with gastric cancer. METHODS: A small interfering RNA against PROX1 was used to silence PROX1 expression in gastric cancer cell lines AGS and SNU638. Expression of PROX1 in gastric cancer tissues was investigated by performing immunohistochemistry. Apoptosis, proliferation, angiogenesis, and lymphangiogenesis were determined by performing the TUNEL assay and immunohistochemical staining for Ki-67, CD34, and D2-40. RESULTS: PROX1 knockdown induced apoptosis by activating cleaved caspase-3, caspase-7, caspase-9, and poly(ADP-ribose) polymerase, and by decreasing the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL. PROX1 knockdown also suppressed tumor cell proliferation. In addition, PROX1 knockdown decreased lymphatic endothelial cell invasion and tube formation and the expression of vascular endothelial growth factor (VEGF)-C and -D and cyclooxygenase (COX)-2. However, PROX1 knockdown only decreased umbilical vein endothelial cell invasion, not tube formation. The mean Ki-67 labeling index and lymphatic vessel density value of PROX1-positive tumors were significantly higher than those of PROX1-negative tumors. However, no significant difference was observed between PROX1 expression and apoptotic index or microvessel density. PROX1 expression was significantly associated with age, cell differentiation, lymph node metastasis, cancer stage, and poor survival. CONCLUSIONS: These results indicate that PROX1 mediates the progression of gastric cancer by inducing tumor cell proliferation and lymphangiogenesis. PMID- 26759229 TI - Tetra- and Penta-Cyclic Triterpenes Interaction with Lipid Bilayer Membrane: A Structural Comparative Study. AB - The effect of tetracyclic (cortisol, prednisolone, and 9-fluorocortisol acetate) and pentacyclic (uvaol and erythrodiol) triterpenes (TTPs) on the fluidity of dipalmitoyl phosphatidyl choline (DPPC) liposome membrane was investigated by differential scanning calorimetry, Raman spectroscopy, and fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH). Liposomes were prepared in the absence and presence of TTPs at molar ratios DPPC:TTP 100:1, 100:2.5, and 100:10. All the studied TTPs abolished the pre-transition and modified the intensity of the Raman peak at 715 cm(-1) proving the interaction of TTP molecules with the choline head group of phospholipids. An increase in the Raman height intensity ratios of the peaks I 2935/2880, I 2844/2880, and I 1090/1130, giving information about the ratio disorder/order of the alkyl chains, and a decrease of the main transition temperature demonstrated the interaction of TTPs with the alkyl chains. The tetracyclic TTPs produced broadening of the phase transition profile. Besides, a scarcely splitting of the main transition peak was obtained with prednisolone and 9-fluorocortisol acetate. The results of fluorescence depolarization of DPH showed that the studied molecules fluidized the liposomal membrane at 25, 41, and 50 degrees C. Pentacyclic TTPs, being more hydrophobic than tetracyclic ones, demonstrated higher fluidizing effect than tetracyclic TTPs in the liquid crystalline phase suggesting a deeper incorporation in the lipid bilayer. The presence of a free polar head group at the ring D seems to control the TTP incorporation in the bilayer and consequently its effect on the membrane fluidity. PMID- 26759231 TI - Assisted reproductive techniques after fertility-sparing treatments in gynaecological cancers. AB - BACKGROUND: The trend toward late childbearing has made fertility preservation a major issue for women who face gynecological cancer. New techniques in assisted reproductive medicine enable conception after primary treatment of these cancers. Here, we aimed to review the efficacy and safety of assisted reproductive techniques (ART) after fertility-preserving treatment of gynaecological cancers. METHODS: We conducted a systematic literature review of both prospective and retrospective studies in the PubMed, EMBASE, CENTRAL and SciSearch databases. In the retrieved studies, we evaluated live births, clinical pregnancies, overall survival and disease-free survival. RESULTS: We identified many prospective and retrospective studies on this topic, but no relevant randomized clinical trials. Fertility-sparing treatments with safe oncological outcomes are feasible in endometrial, cervical and ovarian cancer cases. After cancer treatment, ART seem safe and show variable obstetrical outcomes. CONCLUSIONS: After fertility preserving treatment for gynaecological cancers, ART can enable pregnancy to be achieved with apparent oncological safety. The success of such procedures should directly impact clinical practice and management of those patients who require fertility-sparing treatment. PMID- 26759233 TI - Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation. AB - Head and neck cancer patients treated by radiation commonly suffer from a devastating side effect known as dry-mouth syndrome, which results from the irreversible loss of salivary gland function via mechanisms that are not completely understood. In this study, we used a mouse model of radiation-induced salivary hypofunction to investigate the outcomes of DNA damage in the head and neck region. We demonstrate that the loss of salivary function was closely accompanied by cellular senescence, as evidenced by a persistent DNA damage response (gammaH2AX and 53BP1) and the expression of senescence-associated markers (SA-betagal, p19ARF, and DcR2) and secretory phenotype (SASP) factors (PAI-1 and IL6). Notably, profound apoptosis or necrosis was not observed in irradiated regions. Signs of cellular senescence were also apparent in irradiated salivary glands surgically resected from human patients who underwent radiotherapy. Importantly, using IL6 knockout mice, we found that sustained expression of IL6 in the salivary gland long after initiation of radiation induced DNA damage was required for both senescence and hypofunction. Additionally, we demonstrate that IL6 pretreatment prevented both senescence and salivary gland hypofunction via a mechanism involving enhanced DNA damage repair. Collectively, these results indicate that cellular senescence is a fundamental mechanism driving radiation-induced damage in the salivary gland and suggest that IL6 pretreatment may represent a promising therapeutic strategy to preserve salivary gland function in head and neck cancer patients undergoing radiotherapy. PMID- 26759234 TI - Formation of Renal Cysts and Tumors in Vhl/Trp53-Deficient Mice Requires HIF1alpha and HIF2alpha. AB - The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in the majority of clear cell renal cell carcinomas (ccRCC), but genetic ablation of Vhl alone in mouse models is insufficient to recapitulate human tumorigenesis. One function of pVHL is to regulate the stability of the hypoxia-inducible factors (HIF), which become constitutively activated in the absence of pVHL. In established ccRCC, HIF1alpha has been implicated as a renal tumor suppressor, whereas HIF2alpha is considered an oncoprotein. In this study, we investigated the contributions of HIF1alpha and HIF2alpha to ccRCC initiation in the context of Vhl deficiency. We found that deleting Vhl plus Hif1a or Hif2a specifically in the renal epithelium did not induce tumor formation. However, HIF1alpha and HIF2alpha differentially regulated cell proliferation, mitochondrial abundance and oxidative capacity, glycogen accumulation, and acquisition of a clear cell phenotype in Vhl-deficient renal epithelial cells. HIF1alpha, but not HIF2alpha, induced Warburg-like metabolism characterized by increased glycolysis, decreased oxygen consumption, and decreased ATP production in mouse embryonic fibroblasts, providing insights into the cellular changes potentially occurring in Vhl mutant renal cells before ccRCC formation. Importantly, deletion of either Hif1a or Hif2a completely prevented the formation of renal cysts and tumors in Vhl/Trp53 mutant mice. These findings argue that both HIF1alpha and HIF2alpha exert protumorigenic functions during the earliest stages of cyst and tumor formation in the kidney. Cancer Res; 76(7); 2025-36. (c)2016 AACR. PMID- 26759235 TI - Arginine Methylation of SREBP1a via PRMT5 Promotes De Novo Lipogenesis and Tumor Growth. AB - Dysregulation of the sterol regulatory element-binding transcription factors sterol regulatory element-binding protein (SREBP) and SREBF activates de novo lipogenesis to high levels in cancer cells, a critical event in driving malignant growth. In this study, we identified an important posttranslational mechanism by which SREBP1a is regulated during metabolic reprogramming in cancer cells. Mass spectrometry revealed protein arginine methyltransferase 5 (PRMT5) as a binding partner of SREBP1a that symmetrically dimethylated it on R321, thereby promoting transcriptional activity. Furthermore, PRMT5-induced methylation prevented phosphorylation of SREBP1a on S430 by GSK3beta, leading to its disassociation from Fbw7 (FBXW7) and its evasion from degradation through the ubiquitin proteasome pathway. Consequently, methylation-stabilized SREBP1a increased de novo lipogenesis and accelerated the growth of cancer cells in vivo and in vitro. Clinically, R321 symmetric dimethylation status was associated with malignant progression of human hepatocellular carcinoma, where it served as an independent risk factor of poor prognosis. By showing how PRMT5-induced methylation of SREBP1a triggers hyperactivation of lipid biosynthesis, a key event in tumorigenesis, our findings suggest a new generalized strategy to selectively attack tumor metabolism. PMID- 26759232 TI - Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases after Surgical Stress. AB - Risks of tumor recurrence after surgical resection have been known for decades, but the mechanisms underlying treatment failures remain poorly understood. Neutrophils, first-line responders after surgical stress, may play an important role in linking inflammation to cancer progression. In response to stress, neutrophils can expel their protein-studded chromatin to form local snares known as neutrophil extracellular traps (NET). In this study, we asked whether, as a result of its ability to ensnare moving cells, NET formation might promote metastasis after surgical stress. Consistent with this hypothesis, in a cohort of patients undergoing attempted curative liver resection for metastatic colorectal cancer, we observed that increased postoperative NET formation was associated with a >4-fold reduction in disease-free survival. In like manner, in a murine model of surgical stress employing liver ischemia-reperfusion, we observed an increase in NET formation that correlated with an accelerated development and progression of metastatic disease. These effects were abrogated by inhibiting NET formation in mice through either local treatment with DNAse or inhibition of the enzyme peptidylarginine deaminase, which is essential for NET formation. In growing metastatic tumors, we found that intratumoral hypoxia accentuated NET formation. Mechanistic investigations in vitro indicated that mouse neutrophil derived NET triggered HMGB1 release and activated TLR9-dependent pathways in cancer cells to promote their adhesion, proliferation, migration, and invasion. Taken together, our findings implicate NET in the development of liver metastases after surgical stress, suggesting that their elimination may reduce risks of tumor relapse. PMID- 26759236 TI - Forced Activation of Notch in Macrophages Represses Tumor Growth by Upregulating miR-125a and Disabling Tumor-Associated Macrophages. AB - Tumor-associated macrophages (TAM) contribute greatly to hallmarks of cancer. Notch blockade was shown to arrest TAM differentiation, but the precise role and underlying mechanisms require elucidation. In this study, we employed a transgenic mouse model in which the Notch1 intracellular domain (NIC) is activated conditionally to define the effects of active Notch1 signaling in macrophages. NIC overexpression had no effect on TAM differentiation, but it abrogated TAM function, leading to repressed growth of transplanted tumors. Macrophage miRNA profiling identified a novel downstream mediator of Notch signaling, miR-125a, which was upregulated through an RBP-J-binding site at the first intronic enhancer of the host gene Spaca6A. miR-125a functioned downstream of Notch signaling to reciprocally influence polarization of M1 and M2 macrophages by regulating factor inhibiting hypoxia inducible factor-1alpha and IRF4, respectively. Notably, macrophages transfected with miR-125a mimetics increased phagocytic activity and repressed tumor growth by remodeling the immune microenvironment. We also identified a positive feedback loop for miR-125a expression mediated by RYBP and YY1. Taken together, our results showed that Notch signaling not only supported the differentiation of TAM but also antagonized their protumorigenic function through miR-125a. Targeting this miRNA may reprogram macrophages in the tumor microenvironment and restore their antitumor potential. PMID- 26759238 TI - Dual HER2 Targeting with Trastuzumab and Liposomal-Encapsulated Doxorubicin (MM 302) Demonstrates Synergistic Antitumor Activity in Breast and Gastric Cancer. AB - Trastuzumab is the standard of care for HER2-positive breast cancer patients, markedly improving disease-free and overall survival. Combined with chemotherapy, it enhances patient outcomes, but cardiotoxicity due to the trastuzumab treatment poses a serious adverse effect. MM-302 is a HER2-targeted PEGylated liposome that encapsulates doxorubicin to facilitate its delivery to HER2-overexpressing tumor cells while limiting exposure to nontarget tissues, including the heart. In this study, we evaluated the feasibility and preclinical activity of combining MM-302 with trastuzumab. MM-302 and trastuzumab target different domains of the HER2 receptor and thus could simultaneously bind HER2-overexpressing tumor cells in vitro and in vivo. Furthermore, trastuzumab did not disrupt the mechanism of action of MM-302 in delivering doxorubicin to the n0ucleus and inducing DNA damage. Reciprocally, MM-302 did not interfere with the ability of trastuzumab to block prosurvival p-Akt signaling. Interestingly, coadministration of the two agents acutely increased the deposition of MM-302 in human xenograft tumors and subsequently increased the expression of the DNA damage marker p-p53. Finally, the combination of MM-302 and trastuzumab induced synergistic antitumor activity in HER2-overexpressing xenograft models of breast and gastric cancer. Collectively, our findings highlight a novel combination therapy that efficiently targets HER2-overexpressing cells through multiple mechanisms and support the ongoing investigation of combined MM-302/trastuzumab therapy for HER2-positive metastatic breast cancer in a randomized phase II clinical trial. PMID- 26759237 TI - RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non-Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway. AB - Inactivation of the tumor suppressor gene RASSF1A by promoter hypermethylation represents a key event underlying the initiation and progression of lung cancer. RASSF1A inactivation is also associated with poor prognosis and may promote metastatic spread. In this study, we investigated how RASSF1A inactivation conferred invasive phenotypes to human bronchial cells. RNAi-mediated silencing of RASSF1A induced epithelial-to-mesenchymal transition (EMT), fomenting a motile and invasive cellular phenotype in vitro and increased metastatic prowess in vivo. Mechanistic investigations revealed that RASSF1A blocked tumor growth by stimulating cofilin/PP2A-mediated dephosphorylation of the guanine nucleotide exchange factor GEF-H1, thereby stimulating its ability to activate the antimetastatic small GTPase RhoB. Furthermore, RASSF1A reduced nuclear accumulation of the Hippo pathway transcriptional cofactor Yes-associated protein (YAP), which was reinforced by RhoB activation. Collectively, our results indicated that RASSF1 acts to restrict EMT and invasion by indirectly controlling YAP nuclear shuttling and activation through a RhoB-regulated cytoskeletal remodeling process, with potential implications to delay the progression of RASSF1-hypermethylated lung tumors. PMID- 26759239 TI - Small-Molecule Prodigiosin Restores p53 Tumor Suppressor Activity in Chemoresistant Colorectal Cancer Stem Cells via c-Jun-Mediated DeltaNp73 Inhibition and p73 Activation. AB - Tumor suppressor p53 is frequently mutated or inactivated in colorectal cancer. In contrast, p53 family member p73 is rarely mutated in colorectal cancer and p73 activation elicits p53-like tumor suppression. Colorectal cancer stem cells (CRCSC) comprise a rare self-renewing subpopulation that contributes to tumor maintenance and chemoresistance. p53 restoration is known to target CRCSCs, but p73 restoration in CRCSCs has not been examined. In this study, we investigated the effects of the small-molecule prodigiosin, which restores the p53 pathway in tumor cells via p73 activation, on CRCSCs in vitro and in vivo Prodigiosin prevented colonosphere formation independent of p53 status and reduced the viability of self-renewing, 5-fluorouracil-resistant Aldefluor positive [Aldefluor(+)] CRCSCs in vitro Furthermore, prodigiosin inhibited the growth of xenograft tumors initiated with Aldefluor+ cells without toxic effects and limited the tumorigenic potential of these cells. Consistently, prodigiosin induced activation of a p53-responsive luciferase reporter in colonospheres, Aldefluor(+) cells, and tumor xenografts. Mechanistic studies revealed that prodigiosin increased the levels of p73 and reduced levels of the oncogenic N terminally truncated isoform DeltaNp73 in Aldefluor(+) cells. Accordingly, p73 knockdown or DeltaNp73 overexpression suppressed prodigiosin-mediated inhibition of colonosphere formation. Moreover, prodigiosin increased levels of the transcription factor c-Jun, a regulator of p73 and DeltaNp73, in both the cytoplasm and nucleus. c-Jun knockdown attenuated prodigiosin-mediated p53 reporter activation, DeltaNp73 downregulation, p73 activation, and cell death. Collectively, our findings highlight the previously uncharacterized use of p73 activating therapeutics to target CRCSCs. Cancer Res; 76(7); 1989-99. (c)2016 AACR. PMID- 26759240 TI - Activating Mutations in PIK3CB Confer Resistance to PI3K Inhibition and Define a Novel Oncogenic Role for p110beta. AB - Activation of the PI3K pathway occurs commonly in a wide variety of cancers. Experience with other successful targeted agents suggests that clinical resistance is likely to arise and may reduce the durability of clinical benefit. Here, we sought to understand mechanisms underlying resistance to PI3K inhibition in PTEN-deficient cancers. We generated cell lines resistant to the pan-PI3K inhibitor GDC-0941 from parental PTEN-null breast cancer cell lines and identified a novel PIK3CB D1067Y mutation in both cell lines that was recurrent in cancer patients. Stable expression of mutant PIK3CB variants conferred resistance to PI3K inhibition that could be overcome by downstream AKT or mTORC1/2 inhibitors. Furthermore, we show that the p110beta D1067Y mutant was highly activated and induced PIP3 levels at the cell membrane, subsequently promoting the localization and activation of AKT and PDK1 at the membrane and driving PI3K signaling to a level that could withstand treatment with proximal inhibitors. Finally, we demonstrate that the PIK3CB D1067Y mutant behaved as an oncogene and transformed normal cells, an activity that was enhanced by PTEN depletion. Collectively, these novel preclinical and clinical findings implicate the acquisition of activating PIK3CB D1067 mutations as an important event underlying the resistance of cancer cells to selective PI3K inhibitors. PMID- 26759243 TI - Preclinical Anticancer Efficacy of BET Bromodomain Inhibitors Is Determined by the Apoptotic Response. AB - Small-molecule inhibitors of the bromodomain and extraterminal (BET) family of proteins are being tested in clinical trials for a variety of cancers, but patient selection strategies remain limited. This challenge is partly attributed to the heterogeneous responses elicited by BET inhibition (BETi), including cellular differentiation, senescence, and death. In this study, we performed phenotypic and gene-expression analyses of treatment-naive and engineered tolerant cell lines representing human melanoma and leukemia to elucidate the dominant features defining response to BETi. We found that de novo and acquired tolerance to BETi is driven by the robustness of the apoptotic response, and that genetic or pharmacologic manipulation of the apoptotic signaling network can modify the phenotypic response to BETi. We further reveal that the expression signatures of the apoptotic genes BCL2, BCL2L1, and BAD significantly predict response to BETi. Taken together, our findings highlight the apoptotic program as a determinant of response to BETi, and provide a molecular basis for patient stratification and combination therapy development. PMID- 26759241 TI - AKT1 Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer through Phosphorylation-Dependent Twist1 Degradation. AB - Epithelial-to-mesenchymal transition (EMT) is an essential physiologic process that promotes cancer cell migration, invasion, and metastasis. Several lines of evidence from both cellular and genetic studies suggest that AKT1/PKBalpha, but not AKT2 or AKT3, serves as a negative regulator of EMT and breast cancer metastasis. However, the underlying mechanism by which AKT1 suppresses EMT remains poorly defined. Here, we demonstrate that phosphorylation of Twist1 by AKT1 is required for beta-TrCP-mediated Twist1 ubiquitination and degradation. The clinically used AKT inhibitor MK-2206, which possesses higher specificity toward AKT1, stabilized Twist1 and enhanced EMT in breast cancer cells. However, we discovered that resveratrol, a naturally occurring compound, induced beta-TrCP mediated Twist1 degradation to attenuate MK-2206-induced EMT in breast cancer cells. Taken together, our findings demonstrate that resveratrol counteracts the unexpected metastatic potential induced by anti-AKT therapy and therefore suggest that the addition of resveratrol to an anti-AKT therapeutic regimen may provide extra support for limiting EMT. PMID- 26759242 TI - EGFR Signaling Enhances Aerobic Glycolysis in Triple-Negative Breast Cancer Cells to Promote Tumor Growth and Immune Escape. AB - Oncogenic signaling reprograms cancer cell metabolism to augment the production of glycolytic metabolites in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T-cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. EGF signaling, frequently dysregulated in triple-negative breast cancer (TNBC), is also associated with increased glycolysis. Here, we demonstrated in TNBC cells that EGF signaling activates the first step in glycolysis, but impedes the last step, leading to an accumulation of metabolic intermediates in this pathway. Furthermore, we showed that one of these intermediates, fructose 1,6 bisphosphate (F1,6BP), directly binds to and enhances the activity of the EGFR, thereby increasing lactate excretion, which leads to inhibition of local cytotoxic T-cell activity. Notably, combining the glycolysis inhibitor 2-deoxy-d-glucose with the EGFR inhibitor gefitinib effectively suppressed TNBC cell proliferation and tumor growth. Our results illustrate how jointly targeting the EGFR/F1,6BP signaling axis may offer an immediately applicable therapeutic strategy to treat TNBC. PMID- 26759244 TI - Cdx2 Expression and Intestinal Metaplasia Induced by H. pylori Infection of Gastric Cells Is Regulated by NOD1-Mediated Innate Immune Responses. AB - Chronic infection with the bacterial Helicobacter pylori is a major cause of gastric and duodenal ulcer disease, gastric mucosal atrophy, and cancer. H. pylori-induced expression of the intestinal epithelial-specific transcription factor caudal-related homeobox 2 (Cdx2) contributes to intestinal metaplasia, a precursor event to gastric cancer. Given a role for the bacterial pattern recognition molecule nucleotide-binding oligomerization domain 1 (NOD1) in the innate immune response to bacterial infection, we investigated mechanisms used by NOD1 to regulate H. pylori infection and its propensity towards the development of intestinal metaplasia. We found that Cdx2 was induced by H. pylori infection in both normal and neoplastic gastric epithelial cells in a manner that was inversely related to NOD1 signaling. Mechanistic investigations revealed that Cdx2 induction relied upon activation of NF-kappaB but was suppressed by NOD1 mediated activation of TRAF3, a negative regulator of NF-kappaB. In vivo, prolonged infection of NOD1-deficient mice with H. pylori led to increased Cdx2 expression and intestinal metaplasia. Furthermore, gastric epithelial cells from these mice exhibited increased nuclear expression of the NF-kappaB p65 subunit and decreased expression of TRAF3. Overall, our findings illuminated a role for NOD1 signaling in attenuating H. pylori-induced Cdx2 expression in gastric epithelial cells, suggesting a rationale to augment NOD1 signaling in H. pylori infected patients to limit their risks of accumulating precancerous gastric lesions. PMID- 26759245 TI - Identification of DNA Methylation-Independent Epigenetic Events Underlying Clear Cell Renal Cell Carcinoma. AB - Alterations in chromatin accessibility independent of DNA methylation can affect cancer-related gene expression, but are often overlooked in conventional epigenomic profiling approaches. In this study, we describe a cost-effective and computationally simple assay called AcceSssIble to simultaneously interrogate DNA methylation and chromatin accessibility alterations in primary human clear cell renal cell carcinomas (ccRCC). Our study revealed significant perturbations to the ccRCC epigenome and identified gene expression changes that were specifically attributed to the chromatin accessibility status whether or not DNA methylation was involved. Compared with commonly mutated genes in ccRCC, such as the von Hippel-Lindau (VHL) tumor suppressor, the genes identified by AcceSssIble comprised distinct pathways and more frequently underwent epigenetic changes, suggesting that genetic and epigenetic alterations could be independent events in ccRCC. Specifically, we found unique DNA methylation-independent promoter accessibility alterations in pathways mimicking VHL deficiency. Overall, this study provides a novel approach for identifying new epigenetic-based therapeutic targets, previously undetectable by DNA methylation studies alone, that may complement current genetic-based treatment strategies. Cancer Res; 76(7); 1954 64. (c)2016 AACR. PMID- 26759247 TI - Elevated levels of faecal calprotectin in primary Sjogren's syndrome is common and associated with concomitant organic gastrointestinal disease. AB - BACKGROUND: Primary Sjogren's syndrome (pSS) is a systemic rheumatic disease in which gastrointestinal (GI) symptoms are common. Faecal calprotectin (FC) is a non-invasive biomarker that has been suggested to discriminate organic intestinal disease from functional disorders. The purpose of this study was to explore the usefulness of FC testing in patients with pSS. METHODS: In total, 56 consecutive patients with pSS and 29 healthy control subjects were included in this cross sectional study. FC was measured with a commercially available enzyme-linked immunosorbent assay kit. GI symptoms were evaluated with the Rome III questionnaire and the Visual Analogue Scale for Irritable Bowel Syndrome. In patients with pSS, disease activity was estimated using the European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI), and patient-reported outcomes were evaluated with the EULAR Sjogren's Syndrome Patient-Reported Index. RESULTS: Patients with pSS had higher levels of FC than healthy control subjects (median 54 MUg/g, interquartile range [IQR 20-128]; vs. 20 MUg/g [20-43]; p = 0.002). Concomitant organic GI disease was found in 14 patients with pSS and included inflammatory bowel disease (n = 3), colonic adenoma (n = 2) and GI lymphoma (n = 1). Patients with organic GI disease had higher FC levels than the other patients with pSS (median 274 MUg/g [IQR 61-363] vs. median 34 MUg/g [IQR 20-76]; p < 0.001). Although patients with pSS reported abdominal discomfort more frequently than healthy control subjects did, such symptoms were not associated with organic GI disease or elevated FC levels. FC correlated moderately with ESSDAI. Excluding patients with organic GI disease, we did not identify any significant association between ESSDAI and FC levels. CONCLUSIONS: GI symptoms are frequent in pSS. Contrary to patient-reported outcomes, elevated FC levels in pSS indicate possible organic GI disease that warrants further investigation. PMID- 26759246 TI - The TRAIL receptor agonist drozitumab targets basal B triple-negative breast cancer cells that express vimentin and Axl. AB - Previously, we found that GST-tagged tumor necrosis factor-related apoptosis inducing ligand preferentially killed triple-negative breast cancer (TNBC) cells with a mesenchymal phenotype by activating death receptor 5 (DR5). The purpose of this study was to explore the sensitivity of breast cancer cell lines to drozitumab, a clinically tested DR5-specific agonist; identify potential biomarkers of drozitumab-sensitive breast cancer cells; and determine if those biomarkers were present in tumors from patients with TNBC. We evaluated viability, caspase activity, and sub-G1 DNA content in drozitumab-treated breast cancer cell lines and we characterized expression of potential biomarkers by immunoblot. Expression levels of vimentin and Axl were then explored in 177 TNBC samples from a publically available cDNA microarray dataset and by immunohistochemistry (IHC) in tumor tissue samples obtained from 53 African American women with TNBC. Drozitumab-induced apoptosis in mesenchymal TNBC cell lines but not in cell lines from other breast cancer subtypes. The drozitumab sensitive TNBC cell lines expressed the mesenchymal markers vimentin and Axl. Vimentin and Axl mRNA and protein were expressed in a subset of human TNBC tumors. By IHC, ~15 % of TNBC tumors had vimentin and Axl expression in the top quartile for both. These findings indicate that drozitumab-sensitive mesenchymal TNBC cells express vimentin and Axl, which can be identified in a subset of human TNBC tumors. Thus, vimentin and Axl may be useful to identify TNBC patients who would be most likely to benefit from a DR5 agonist. PMID- 26759248 TI - Towards elimination of mother-to-child transmission of HIV in Ghana: an analysis of national programme data. AB - BACKGROUND: Despite global scale up of interventions for Preventing Mother to child HIV Transmissions (PMTCT), there still remain high pediatric HIV infections, which result from unequal access in resource-constrained settings. Sub-Saharan Africa alone contributes more than 90 % of global Mother-to-Child Transmission (MTCT) burden. As part of efforts to address this, African countries (including Ghana) disproportionately contributing to MTCT burden were earmarked in 2009 for rapid PMTCT interventions scale-up within their primary care system for maternal and child health. In this study, we reviewed records in Ghana, on ANC registrants eligible for PMTCT services to describe regional disparities and national trends in key PMTCT indicators. We also assessed distribution of missed opportunities for testing pregnant women and treating those who are HIV positive across the country. Implications for scaling up HIV-related maternal and child health services to ensure equitable access and eliminate mother-to-child transmissions by 2015 are also discussed. METHODS: Data for this review is National AIDS/STI Control Programme (NACP) regional disaggregated records on registered antenatal clinic (ANC) attendees across the country, who are also eligible to receive PMTCT services. These records cover a period of 3 years (2011 2013). Number of ANC registrants, utilization of HIV Testing and Counseling among ANC registrants, number of HIV positive pregnant women, and number of HIV positive pregnant women initiated on ARVs were extracted. Trends were examined by comparing these indicators over time (2011-2013) and across the ten administrative regions. Descriptive statistics were conducted on the dataset and presented in simple frequencies, proportions and percentages. These are used to determine gaps in utilization of PMTCT services. All analyses were conducted using Microsoft Excel 2010 version. RESULTS: Although there was a decline in HIV prevalence among pregnant women, untested ANC registrants increased from 17 % in 2011 to 25 % in 2013. There were varying levels of missed opportunities for testing across the ten regions, which led to a total of 487,725 untested ANC clients during the period under review. In 2013, Greater Accra (31 %), Northern (27 %) and Volta (48 %) regions recorded high percentages of untested ANC clients. Overall, HIV positive pregnant women initiated onto ARVs remarkably increased from 57% (2011) to 82 % (2013), yet about a third (33 %) of them in the Volta and Northern regions did not receive ARVs in 2013. CONCLUSIONS: Missed opportunities to test pregnant women for HIV and also initiate those who are positive on ARVs across all the regions pose challenges to the quest to eliminate mother-to-child transmission of HIV in Ghana. For some regions these missed opportunities mimic previously observed gaps in continuous use of primary care for maternal and child health in those areas. Increased national and regional efforts aimed at improving maternal and child healthcare delivery, as well as HIV related care, is paramount for ensuring equitable access across the country. PMID- 26759249 TI - Secondary prevention of fractures after hip fracture: a qualitative study of effective service delivery. AB - There is variation in how services to prevent secondary fractures after hip fracture are delivered and no consensus on best models of care. This study identifies healthcare professionals' views on effective care for the prevention of these fractures. It is hoped this will provide information on how to develop services. INTRODUCTION: Hip fracture patients are at high risk of subsequent osteoporotic fractures. Whilst fracture prevention services are recommended, there is variation in delivery and no consensus on best models of care. This study aims to identify healthcare professionals' views on effective care for prevention of secondary fracture after hip fracture. METHODS: Forty-three semi structured interviews were undertaken with healthcare professionals involved in delivering fracture prevention across 11 hospitals in one English region. Interviews explored views on four components of care: (1) case finding, (2) osteoporosis assessment, (3) treatment initiation, and (4) monitoring and coordination. Interviews were audio-recorded, transcribed, anonymised and coded using NVivo software. RESULTS: Case finding: a number of approaches were discussed. Multiple methods ensured there was a 'backstop' if patients were overlooked. Osteoporosis assessment: there was no consensus on who should conduct this. The location of the dual energy X-ray absorptiometry (DXA) scanner influenced the likelihood of patients receiving a scan. Treatment initiation: it was felt this was best done in inpatients rather request initiation in the post discharge/outpatients period. Monitoring (adherence): adherence was a major concern, and participants felt more monitoring could be conducted by secondary care. Coordination of care: participants advocated using dedicated coordinators and formal and informal methods of communication. A gap between primary and secondary care was identified and strategies suggested for addressing this. CONCLUSIONS: A number of ways of organising effective fracture prevention services after hip fracture were identified. It is hoped that this will help professionals identify gaps in care and provide information on how to develop services. PMID- 26759250 TI - Isolation of a wide range of minerals from a thermally treated plant: Equisetum arvense, a Mare's tale. AB - Silica is the second most abundant biomineral being exceeded in nature only by biogenic CaCO3. Many land plants (such as rice, cereals, cucumber, etc.) deposit silica in significant amounts to reinforce their tissues and as a systematic response to pathogen attack. One of the most ancient species of living vascular plants, Equisetum arvense is also able to take up and accumulate silica in all parts of the plant. Numerous methods have been developed for elimination of the organic material and/or metal ions present in plant material to isolate biogenic silica. However, depending on the chemical and/or physical treatment applied to branch or stem from Equisetum arvense; other mineral forms such glass-type materials (i.e. CaSiO3), salts (i.e. KCl) or luminescent materials can also be isolated from the plant material. In the current contribution, we show the chemical and/or thermal routes that lead to the formation of a number of different mineral types in addition to biogenic silica. PMID- 26759251 TI - Iron overload of human colon adenocarcinoma cells studied by synchrotron-based X ray techniques. AB - Fast- and slow-proliferating human adenocarcinoma colorectal cells, HT-29 and HCA 7, respectively, overloaded with transferrin (Tf), Fe(III) citrate, Fe(III) chloride and Fe(II) sulfate were studied by synchrotron radiation total reflection X-ray spectrometry (TXRF), TXRF-X-ray absorption near edge structure (TXRF-XANES), and micro-X-ray fluorescence imaging to obtain information on the intracellular storage of overloaded iron (Fe). The determined TfR1 mRNA expression for the investigated cells correlated with their proliferation rate. In all cases, the Fe XANES of cells overloaded with inorganic Fe was found to be similar to that of deliquescent Fe(III) sulfate characterized by a distorted octahedral geometry. A fitting model using a linear combination of the XANES of Tf and deliquescent Fe(III) sulfate allowed to explain the near edge structure recorded for HT-29 cells indicating that cellular overload with inorganic Fe results in a non-ferritin-like fast Fe storage. Hierarchical cluster analysis of XANES spectra recorded for Fe overloaded HT-29 and HCA-7 cells was able to distinguish between Fe treatments performed with different Fe species with a 95% hit rate, indicating clear differences in the Fe storage system. Micro-X-ray fluorescence imaging of Fe overloaded HT-29 cells revealed that Fe is primarily located in the cytosol of the cells. By characterizing the cellular Fe uptake, Fe/S content ratios were calculated based on the X-ray fluorescence signals of the analytes. These Fe/S ratios were dramatically lower for HCA-7 treated with organic Fe(III) treatments suggesting dissimilarities from the Tf-like Fe uptake. PMID- 26759252 TI - The science of RJP Williams. PMID- 26759253 TI - Is Pulmonary non-Tuberculous Mycobacterial Disease Linked with a High Burden of Latent Cytomegalovirus? AB - Cytomegalovirus (CMV) establishes lifelong infections with episodes of active replication. We hypothesized that recurrent CMV replication in older individuals may suppress protective immune responses to non-tuberculous mycobacteria (NTM) and so potentiate pulmonary disease. Accordingly, levels of antibodies to three CMV antigen preparations were higher in NTM patients than in age-matched controls. This did not reflect broad-spectrum B cell activation as total immunoglobulin levels were not equivalently increased. PMID- 26759254 TI - Incidence and prevalence of lower extremity tendinopathy in a Dutch general practice population: a cross sectional study. AB - BACKGROUND: Lower extremity tendinopathy is a common sports injury, but it can also affect non-athletes. Because tendinopathy is difficult to treat and has negative effects on the ability to work and quality of life, development of preventive interventions is important. The first step in the Van Mechelen prevention model is to determine the extent of the problem. The primary aim of this study was to determine the incidence and prevalence of lower extremity tendinopathy in a Dutch general practice population. The secondary aim was to investigate possible associated factors. METHODS: A cross-sectional study was performed in a Dutch general practice. Using International Classification of Primary Care codes, the electronic patient files were searched to identify cases of adductor tendinopathy, greater trochanteric pain syndrome, jumper's knee, Achilles tendinopathy, and plantar fasciopathy in 2012. The tendinopathy patients were compared to the general practice population regarding age, gender, use of medication, and comorbidity using 95% confidence intervals. RESULTS: The prevalence and incidence rates of lower extremity tendinopathy found in this study were 11.83 and 10.52 per 1000 person-years. Lower extremity tendinopathy was more prevalent among older patients. No differences between tendinopathy patients and the general practice population were found regarding gender, use of medication, or comorbidity. CONCLUSIONS: In this cross-sectional study in a Dutch general practice, the prevalence and incidence rates of lower extremity tendinopathy were 11.83 and 10.52 per 1000 person-years. Lower extremity tendinopathy deserves a higher place in locomotor system research to develop preventive interventions. PMID- 26759255 TI - The Vienna and German heritage of orthopaedics from the first half of the twentieth century: Adolf Lorenz, Lorenz Bohler, Friedrich Pauwels, Gerhard Kuntscher. AB - In the last part of the nineteenth century and beginning of the twentieth century surgeons at the University of Vienna helped transform the practice of surgery. They developed new more effective procedures, analyzed the results of their operations, promoted the emergence and growth of surgical specialties and sought understanding of tissue structure, physiology and pathophysiology. Their efforts made Vienna one of the world's most respected centres for operative treatment, basic and clinical research and surgical education. Two individuals, Adolf Lorenz (1854-1946) and Lorenz Bohler (1885-1973) focused their research and clinical practice on orthopaedics. During the same period in Germany Friedrich Pauwels (1885-1980) founded an orthopaedic institute and an engineering workshop in Aachen in 1913 and rapidly developed a lifelong interest in biomechanical influences: Using these theories, he achieved in 1927 healing of a non-union of the femoral neck by a re-orientation osteotomy, a condition considered to be incurable until this osteotomy and created his famous classification of fracture angles at the hip into Pauwels types I, II and III. The German orthopaedist Gerhard Kuntscher (1900-1972) remained the most popular surgeon after the second war with his famous nail. PMID- 26759257 TI - High union rates of locking compression plating with cortical strut allograft for type B1 periprosthetic femoral fractures. AB - PURPOSE: Unified classification system (UCS) type B1 periprosthetic femoral fractures are associated with many complications, and management decisions continue to be controversial. The purpose of this study was to evaluate outcomes of UCS type B1 periprosthetic femoral fractures treated by locking compression plating with strut allograft augmentation. MATERIALS AND METHODS: We retrospectively reviewed 17 consecutive UCS type B1 periprosthetic femoral fractures treated by open reduction and internal fixation using a lateral locking compression plate supplemented with an anterior cortical strut allograft. There was one man and 16 women with an average age of 74 years (range, 57-92 years). All had a cementless hip arthroplasty, and eight of the arthroplasties were revisions. RESULTS: The mean duration of follow-up was 28 months (range, 12-74 months). All 17 fractures healed successfully at a mean of 20 weeks (range, 12-30 weeks). The mean post-operative Harris hip score was 86 points (range, 77-95 points). No mechanical complications such as failure of plate or screws and malalignment were noted. According to the graft-remodeling classification of Emerson et al., a partial bridging was observed in nine and a complete bridging in eight. Two patients required a removal of the plate due to irritation of the iliotibial band. No femoral stem loosening or deep infection was observed. CONCLUSION: Our findings indicate that open reduction and internal fixation of UCS type B1 periprosthetic femoral fractures using a lateral locking compression plate supplemented with anterior cortical strut allograft provides adequate mechanical stability of fracture fixation and enhances the fracture healing. PMID- 26759258 TI - FHL2 mediates tooth development and human dental pulp cell differentiation into odontoblasts, partially by interacting with Runx2. AB - The differentiation of mesenchymal cells in tooth germ and dental pulp cells into odontoblasts is crucial for dentin formation, and the transcription factor runt related transcription factor (Runx2) is necessary for odontoblast differentiation. Our previous study demonstrated that four and a half LIM domains 2 (FHL2) may play an important role in tooth development and human dental pulp cell differentiation. This study aimed to determine whether FHL2 mediated the mesenchymal cells in tooth development and human dental pulp cell differentiation into odontoblasts by interacting with Runx2. The expression patterns of FHL2 and Runx2 were examined at the early stages of mouse molar development using double immunofluorescence staining. Western blot analysis and co-immunoprecipitation (Co IP) were conducted for the preliminary study of the relationship between FHL2 and Runx2 in human dental pulp cell differentiation into odontoblasts. Results of double immunofluorescence staining showed that FHL2 and Runx2 exhibited similar expression patterns at the early stages of tooth development. Western blot analysis indicated that the expression patterns of FHL2 and Runx2 were synchronized on day 7 of induction, whereas those on day 14 differed. Co-IP analysis revealed positive bands of protein complexes, revealing the interaction of FHL2 and Runx2 on days 0, 7 and 14 of induction. Our data suggested that FHL2 might interact with Runx2 to mediate mesenchymal cell differentiation at the early stages of tooth development and human dental pulp cell differentiation. PMID- 26759259 TI - IGF1 3'UTR functions as a ceRNA in promoting angiogenesis by sponging miR-29 family in osteosarcoma. AB - Osteosarcoma is one of the most common malignant bone tumors in human worldwide. Angiogenesis is a pivotal process during osteosarcoma development. Insulin-like growth factor 1 (IGF1) has been reported to promote angiogenesis. However, the role of 3' untranslational region (3'UTR) of IGF1 mRNA in angiogenic activity in osteosarcomas is still unknown. In the present study, we performed gain-of function assays to investigate the role of IGF1-3'UTR in angiogenesis. For the first time, we demonstrated that IGF1 3'UTR increased VEGF expression and promotes angiogenesis in osteosarcoma cells. In addition, RNA-immunoprecipitation and luciferase reporter assays showed that IGF1 3'UTR was a direct target of miR 29s. Our data also demonstrated that there existed a competition of miR-29s between IGF1-3'UTR and VEGF mRNA, and IGF1-3'UTR promoted angiogenesis at least in part via sponging miR-29s. Taken together, our study suggests that IGF1-3'UTR functions as a ceRNA in promoting angiogenesis by sponging miR-29s in osteosarcoma. PMID- 26759260 TI - Four and a half LIM domains 2 contributes to the development of human tongue squamous cell carcinoma. AB - Four and a half LIM domains 2 (FHL2) is a protein of 279 amino acids in length containing four full LIM-domains and a half LIM-domain at the amino terminus. FHL2 is one transcriptional cofactor that can interact with many different proteins, such as AP-1, BRCA1, IGFBP, and integrin, and involved in organ differentiation, development, cell apoptosis, and carcinogenesis. Recent studies showed that FHL2 could play different roles acting as co-activator or corepressor in different cancer types, depending on the cell types involved. However, no report about FHL2 function in tongue squamous cell carcinoma (TSCC) is available to date. This study aims to determine the FHL2 expression and its biological functions in TSCC via in vitro and in vivo studies. Results show that FHL2 expression was associated with the pathological differentiation of TSCC samples through immunohistochemistry. FHL2 overexpression could stimulate cell proliferation, invasiveness, and metastases investigated by MTT, flow cytometry, Transwell and cell scratch methods. FHL2 could also elevate tumor-related molecule nuclear transcription factor-B (NF-kB) and beta-catenin expression levels both at transcriptional and translational levels through real-time PCR and Western blot analyses. The in vivo nude mice experiment showed that the tumorigenicity of FHL2 overexpression group was significantly increased compared with control groups. These results suggest that FHL2 overexpression could contribute to the growth, proliferation, invasiveness, and metastasis of human tongue squamous cell carcinoma; furthermore, its function in TSCC might be related with the upregulation of NF-kB and beta-catenin expressions. PMID- 26759261 TI - Effect of meal composition on postprandial glucagon-like peptide-1, insulin, glucagon, C-peptide, and glucose responses in overweight/obese subjects. AB - BACKGROUND: Glucagon-like peptide-1 (GLP-1), an incretin hormone, is released in response to food intake. It is unclear how meals high in protein (HP) and monounsaturated fat (HMF) affect GLP-1 response. PURPOSE: To examine the effect of a HP versus a HMF meal on GLP-1 response. METHODS: Twenty-four overweight/obese participants consumed two meals (HP: 31.9 % energy from protein; HMF: 35.2 % fat and 20.7 % monounsaturated fat) in a random order. Both meals contained the same energy and carbohydrate content. GLP-1, insulin, glucagon, C peptide, and glucose were assessed from blood drawn in the fasting and postprandial states. The effect of meal condition on hormone and glucose responses and appetite ratings were assessed by repeated measures analysis. RESULTS: Statistically significant (p < 0.01) time by meal condition effect was observed on active GLP-1, total GLP-1, insulin, C-peptide, and glucagon, but not glucose (p = 0.83). Area under the curve was significantly higher during the HP versus the HMF meal conditions for active GLP-1 (23.7 %; p = 0.0007), total GLP-1 (12.2 %; p < 0.0001), insulin (54.4 %; p < 0.0001), C-peptide (14.8 %; p < 0.0001), and glucagon (40.7 %; p < 0.0001). Blood glucose was not different between the HP versus HMF conditions (-4.8 %; p = 0.11). Insulin sensitivity was higher during the HMF versus HP conditions (Matsuda index mean difference: 16.3 %; p = 0.007). Appetite ratings were not different by meal condition. CONCLUSIONS: GLP-1 and insulin responses were higher during the HP condition. However, no difference was found in blood glucose between conditions, and insulin sensitivity was higher during the HMF condition, indicating that a HMF meal may be optimal at regulating blood glucose in overweight/obese individuals without type 2 diabetes. PMID- 26759262 TI - Responses of peripheral endocannabinoids and endocannabinoid-related compounds to hedonic eating in obesity. AB - PURPOSE: Hedonic eating occurs independently from homeostatic needs prompting the ingestion of pleasurable foods that are typically rich in fat, sugar and/or salt content. In normal weight healthy subjects, we found that before hedonic eating, plasma levels of 2-arachidonoylglycerol (2-AG) were higher than before nonhedonic eating, and although they progressively decreased after food ingestion in both eating conditions, they were significantly higher in hedonic eating. Plasma levels of anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), instead, progressively decreased in both eating conditions without significant differences. In this study, we investigated the responses of AEA, 2 AG, OEA and PEA to hedonic eating in obese individuals. METHODS: Peripheral levels of AEA, 2-AG, OEA and PEA were measured in 14 obese patients after eating favourite (hedonic eating) and non-favourite (nonhedonic eating) foods in conditions of no homeostatic needs. RESULTS: Plasma levels of 2-AG increased after eating the favourite food, whereas they decreased after eating the non favourite food, with the production of the endocannabinoid being significantly enhanced in hedonic eating. Plasma levels of AEA decreased progressively in nonhedonic eating, whereas they showed a decrease after the exposure to the favourite food followed by a return to baseline values after eating it. No significant differences emerged in plasma OEA and PEA responses to favourite and non-favourite food. CONCLUSION: Present findings compared with those obtained in our previously studied normal weight healthy subjects suggest deranged responses of endocannabinoids to food-related reward in obesity. PMID- 26759263 TI - New Zealand's new alcohol laws: protocol for a mixed-methods evaluation. AB - BACKGROUND: Alcohol consumption is a major cause of mortality and morbidity globally. In response to strong calls from the public for alcohol law reform, the New Zealand Government recently reduced the blood alcohol limit for driving and introduced the Sale and Supply of Alcohol Act which aim to (1) improve community input into local decision-making on alcohol; (2) reduce the availability of alcohol; and (3) reduce hazardous drinking and alcohol-related harm. In this project we seek to evaluate the new laws in terms of these objectives. DESIGN AND METHODS: A policy evaluation framework is proposed to investigate the implementation and outcomes of the reforms. We will use quantitative and qualitative methods, employing a pre-post design. Participants include members of the public, local government staff, iwi (Maori tribal groups that function collectively to support their members) and community group representatives. Data will be collected via postal surveys, interviews and analysis of local government documents. Liquor licensing, police and hospital injury data will also be used. Community input into local government decision-making will be operationalised as: the number of objections per license application and the number of local governments adopting a local alcohol policy (LAP). Outcome measures will be the 'restrictiveness' of LAPs compared to previous policies, the number (per 1000 residents) and density (per square kilometre) of alcohol outlets throughout NZ, and the number of weekend late-night (i.e., post 10 pm) trading hours. For consumption and harm, outcomes will be the prevalence of hazardous drinking, harm from own and others' drinking, community amenity effects, rates of assault, and rates of alcohol-involved traffic crashes. Multiple regression will be used to model how the outcomes vary by local government area from before to after the law changes take effect. These measures will be complemented by qualitative analysis of LAP development and public participation in local decision-making on alcohol. DISCUSSION: The project will evaluate how well the reforms meet their explicit public health objectives. PMID- 26759265 TI - The coordination dynamics of mobile conjugate reinforcement. AB - What we know about infant learning and memory is founded largely on systematic studies by the late Carolyn Rovee-Collier (1942-2014) and her associates of a phenomenon called mobile conjugate reinforcement. Experiments show that when a ribbon is attached from a 3-month-old infant's foot to a mobile suspended overhead the baby quickly realizes it can make the mobile move. The mobile, which offers interesting sights and sounds, responds conjugately to the baby's vigorous kicks which increase in rate by a factor of 3-4. In this paper, using the concepts, methods and tools of coordination dynamics, we present a theoretical model which reproduces the experimental observations of Rovee-Collier and others and predicts a number of additional features that can be experimentally tested. The model is a dynamical system consisting of three equations, one for the baby's leg movements, one for the jiggling motion of the mobile and one for the functional coupling between the two. A key mechanism in the model is positive feedback which is shown to depend sensitively on bifurcation parameters related to the infant's level of attention and inertial properties of the mobile. The implications of our model for the dynamical (and developmental) origins of agency are discussed. PMID- 26759264 TI - Malrotation of midgut in adults, an unsuspected and neglected condition--An analysis of 64 consensus confirmed cases. AB - INTRODUCTION: Malrotation of midgut is considered to be a condition of childhood. This study evaluated malrotation in adults with recurrent abdominal pain (RAP). METHODS: Sixty-four consensus-confirmed cases of intestinal malrotation were reviewed. The diagnosis was based on radiological criteria, and the consensus was arrived at by at least three of the five authors in any individual case. RESULTS: Abnormal duodenojejunal junction (DJJ) was a consensus finding in 64 cases referred for RAP. Most were in their fourth decade of life, and 12 were beyond 60 years. Besides RAP, intolerance to food was the next common symptom. Acute intestinal obstruction was seen in 16. Forty-two of 64 patients consented for surgery. Ladd's procedure was the commonest. All patients who underwent surgery were symptom free except for two, of which, one had liver cyst and the other had hernia. Of those who refused surgery (22), all had continued symptoms and 10 patients took alternative therapies. On follow up of initially unwilling patients (for surgery) with abnormal DJJ, only eight consented for surgery; three underwent open Ladd's procedure, and one had laparoscopic Ladd's done. CONCLUSION: Malrotation is not uncommon as a cause of RAP in adults. PMID- 26759266 TI - Quality assessment of osteoporosis clinical practice guidelines for physical activity and safe movement: an AGREE II appraisal. AB - Many osteoporosis clinical practice guidelines are published, and the extent to which physical activity and safe movement is addressed varies. To better inform clinical decision-making, a quality assessment and structured analysis of recommendations was undertaken. Guideline quality varied substantially, and improvement is necessary in physical activity and safe movement recommendations. PURPOSE: The purpose of the present study is to survey available osteoporosis clinical practice guidelines (CPGs) containing physical activity and safe movement recommendations in order to assess the methodological quality with which they were developed. An analysis of the various physical activity and safe movement recommendations was conducted to determine variability between CPGs. METHODS: An online literature search revealed 19 CPGs meeting our inclusion criteria. Three independent scorers evaluated CPG quality using the Appraisal of Guidelines for Research and Evaluation version II (AGREE II) instrument. Two separate individuals used a standard table to extract relevant recommendations. RESULTS: Intra-reviewer AGREE II score agreement ranged from fair to good (intra class correlation coefficient (ICC) = 0.34 to 0.65). The quality of the 19 included CPGs was variable (AGREE sub-scores: 14 to 100%). CPGs scored higher in the "scope and purpose" and "clarity of presentation" domains. They scored the lowest in "applicability" and "editorial independence." Four CPGs were classified as high quality, ten average quality, and five low quality. Most CPGs recommended weight-bearing, muscle-strengthening, and resistance exercises. Information on exercise dosage, progression, and contraindications was often absent. Immobility and movements involving spinal flexion and/or torsion were discouraged. CONCLUSIONS: There were several high-quality CPGs; however, variability in quality and lack of specific parameters for implementation necessitates caution and critical examination by readers. CPG development groups should pay special attention to the clinical applicability of their CPGs as well as fully disclosing conflicts of interest. CPGs were in general an agreement regarding safe physical activity and safe movement recommendations. However, recommendations were often vague and the more specific recommendations were inconsistent between CPGs. PMID- 26759268 TI - Molecular basis of influenza hemagglutinin inhibition with an entry-blocker peptide by computational docking and mass spectrometry. AB - BACKGROUND: The increased resistance of circulating strains to current antiviral inhibitors of the influenza virus necessitates that new antivirals and their mode of action are identified. Influenza hemagglutinin is an ideal target given inhibitors of its function can block the entry of the virus into host cells during the early stages of replication. This article describes the molecular basis for the inhibition of H1 and H5 hemagglutinin by an entry-blocker peptide using companion molecular docking and mass spectrometry-based experiments. METHODS: A combination of hemagglutination inhibition assays, computational molecular docking and a novel mass spectrometry-based approach are employed to explore the mode of action of the entry-blocker peptide at a molecular level. RESULTS: The entry-blocker peptide is shown to be able to maximally inhibit blood cell hemagglutination at a concentration of between 6.4 and 9.2 uM. The molecular basis for this inhibition is derived from the binding of the peptide to hemagglutinin in the vicinity of the reported sialic acid binding site surrounded by an alpha-helix (190-helix) and two loop (130-loop and 220-loop) regions in the case of a H1 hemagglutinin and the second loop region in the case of a H5 hemagglutinin. CONCLUSIONS: The results support the recognized potential of the entry-blocker peptide as an effective antiviral agent that can inhibit the early stages of viral replication and further illustrate the power of a combination of docking and a mass spectrometry approach to screen the molecular basis of new antiviral inhibitors to the influenza virus. PMID- 26759267 TI - Relationship between clinical findings and genetic mutations in patients with familial Mediterranean fever. AB - BACKGROUND: Familial Mediterranean fever (FMF) is one of the most frequent genetic diseases encountered in the Mediterranean region. We aimed to investigate the correlation between genetic mutations and the clinical findings in 562 patients with FMF. METHODS: In this retrospective cross-sectional study conducted with patients' files between 2006, and 2013, reverse hybridization assay for MEFV gene mutations was used and the 12 most frequent mutations were screened. Mutation types and clinical findings were compared with variance analysis. RESULTS: The mean age was 6.9 +/- 3.4 years (range, 1.8-11.6 years). The most common symptom was fever (97.3%). Thirty-four of the patients (6.04%) were admitted with periodic fever only. Of these patients, M694V was the most common mutation type (73.5%). The percentage of the patients predominantly presenting with recurrent abdominal pain was 77.78% and the most frequent mutations were M694V and E148Q. The rate of arthritis and arthralgia was significantly higher in patients with M694V and E148Q mutations. Chest pain was reported more often in patients homozygous for M694V (61.4%). Pericardial effusion was documented in the echocardiography of 10.9% of the 229 children with chest pain. Some patients had both FMF and Henoch Schonlein purpura (HSP), and were more likely to harbor either homozygote M694V or E148Q mutations. The frequency of episodes was higher in patients with homozygous M694V mutations (number of attacks = 4.4 +/- 1.6/month). Proteinuria was detected in 106 patients of cases (29.2%), at an average of 854 +/- 145 mg/L. Most of the patients with proteinuria and elevated serum amyloid-A had homozygous M694V mutation. CONCLUSION: The most common mutation in children in Turkey with FMF is the M694V mutation. Recurrent abdominal pain, arthritis or arthralgia, chest pain, and pericarditis were commonly seen in patients with M694V and E148Q mutations. PMID- 26759269 TI - Treatment of maternal perinatal depression in a low-income setting does not lead to improved outcomes for children. PMID- 26759271 TI - Utilization patterns of insulin therapy and healthcare services among Japanese insulin initiators during their first year: a descriptive analysis of administrative hospital data. AB - BACKGROUND: Type 2 diabetes poses an increasing healthcare burden in Japan. Although insulin treatment has diversified in recent years, the literature on the utilization of healthcare services among patients with type 2 diabetes undergoing different insulin therapy regimens is scarce. The current study aimed to characterize the real-world insulin treatment patterns and associated utilization of healthcare services among patients with type 2 diabetes who initiated insulin therapy during the study period. METHODS: We examined data from a hospital-based database consisting of administrative and laboratory data from 121 acute-phase hospitals throughout Japan from April 2008 to August 2012. Patients diagnosed with type 2 diabetes and receiving continuous insulin therapy, defined by three insulin claims or more, were included in the analysis. RESULTS: Of the 2,145 insulin initiators, at initiation 46.5% received rapid-acting insulin alone, 36.6% received an intensive regimen, 11.4% received long-acting insulin alone, and 5.5% received pre-mixed insulin alone. Patients treated with rapid-acting insulin alone were older, experienced more comorbid conditions, had lower HbA1c, and more often had initiated their insulin treatment at inpatient admission, compared to patients treated with other types of insulin. Inpatient admission was more common and longer for patients taking rapid-acting insulin and an intensive regimen than those taking long-acting or pre-mixed insulin, and most were readmitted within 1 year. Utilization of outpatient clinics was approximately once per month, and emergency department visits were observed to be rare. CONCLUSIONS: This retrospective observational descriptive study found varied treatment and healthcare service utilization patterns, as well as disparities in patient characteristics across insulin regimens. Future research should assess the basis for these various utilization patterns associated with insulin to conduct robust analyses of clinical and economic outcomes. PMID- 26759272 TI - Enhanced luminescence from GaN nanopillar arrays fabricated using a top-down process. AB - We report the fabrication of GaN nanopillar arrays with good structural uniformity using the top-down approach. The photoluminescence intensity from the nanopillar arrays is enhanced compared to the epilayer. We use finite difference time domain simulations to show that the enhancement in photoluminescence intensity from the nanopillar arrays is a result of anti-reflection properties of the arrays that result in enhanced light absorption and increase light extraction efficiency compared to the epilayer. The measured quantum efficiency of the nanopillars is comparable to that of an epitaxially grown GaN epilayer. PMID- 26759270 TI - FAS rs2234767 and rs1800682 polymorphisms jointly contributed to risk of colorectal cancer by affecting SP1/STAT1 complex recruitment to chromatin. AB - FAS rs2234767 (-1377 G>A), rs1800682 (-670 A>G) and FASLG rs763110 (-844 C>T) promoter polymorphisms can influence transcriptional activities of the genes and thus multiple tumors susceptibility. To investigate their association with risk of colorectal cancer (CRC), the three SNPs were genotyped in 878 cases and 884 controls and the results showed that the FAS rs2234767 and rs1800682 were in a high linkage disequilibrium (LD) with each other (D' = 0.994) and jointly contributed to an increased risk of CRC (without vs. with rs2234767 GG/rs1800682 AA genotypes, adjusted OR = 1.30, 95% CI = 1.05 - 1.61). In vivo ChIP assays evaluated the effect of rs2234767 and rs1800682 on recruitment of SP1 and STAT1, respectively, to chromatin. The results showed SP1 interacting specifically with STAT1 recruited to their respective motifs for transcriptional activation. The mutant alleles rs2234767 A and rs1800682 G jointly affected coupled SP1 and STAT1 recruitment to chromatin. The interplay between SP1 and STAT1 was critical for the functional outcome of rs2234767 and rs1800682 in view of their high LD. In conclusion, the FAS rs2234767 and rs1800682 polymorphisms were in high LD with each other, and they jointly contributed to an increased risk of CRC by altering recruitment of SP1/STAT1 complex to the FAS promoter for transcriptional activation. PMID- 26759273 TI - Radiographic occult cerebellar germinoma presenting with progressive ataxia and cranial nerve palsy. AB - BACKGROUND: Although the usefulness of susceptibility-weighted imaging (SWI) for detecting basal ganglia germinoma has been reported, the technique is not widely used. We recently encountered an unusual case of primary cerebellar germinoma, presenting with progressive ataxia and cranial nerve palsy, characterized by gradually enlarging low-intensity lesions visible with both T2*-weighted imaging (T2*WI), which were the key to the diagnosis. CASE PRESENTATION: A 30-year-old man was referred to our hospital because of slowly progressive dizziness and mild ataxia. Magnetic resonance imaging (MRI) revealed a small, low-intensity spot in the left cerebellar peduncle on the T2*WI and SWI without enhancement. Cerebral angiography revealed no vascular abnormality. The serum alpha-fetoprotein value was normal. A steroid-pulse was administered as a therapeutic and diagnostic trial, but the symptoms improved little. The patient was discharged from the hospital but soon developed brainstem dysfunction, characterized by dyspnea or hiccups, and he was readmitted. T2*WI imaging revealed expanded and extended spotty lesions in the cerebellum and brainstem, which had not enhanced with contrast agent previously. Targeted stereotactic biopsy of the newly enhanced cerebellar lesion was performed; histopathological examination of the tissue revealed pure germinoma. Serum and cerebral spinal fluid values of beta-human chorionic gonadotropin were not significantly elevated. Chemotherapy with carboplatin and etoposide was initiated. The enhanced lesion disappeared promptly, but the patient continued to require assisted automatic ventilation because of paralysis of respiratory muscles. CONCLUSIONS: We conclude that enlarging low-intensity lesions on T2*WI and SWI may be a reliable clue to the diagnosis of germinomas, irrespective of their location, even without enhancement. Biopsy of the tumor at an early stage is the only way to make the diagnosis conclusively and enable prompt start of treatment. PMID- 26759274 TI - Simultaneous exposure to estrogen and androgen resulted in feminization and endocrine disruption. AB - Estrogen, which is synthesized earlier in females than androgen in males, is critical for sex determination in non-mammalian vertebrates. However, it remains unknown that what would happen to the gonadal phenotype if estrogen and androgen were administrated simultaneously. In this study, XY and XX tilapia fry were treated with the same dose of 17alpha-methyltestosterone (MT) and 17beta estradiol (E2) alone and in combination from 0 to 30 days after hatching. Treatment of XY fish with E2 resulted in male to female sex reversal, while treatment of XX fish with MT resulted in female to male sex reversal. In contrast, simultaneous treatment of XX and XY fish with MT and E2 resulted in female, but with cyp11b2 and cyp19a1a co-expressed in the ovary. Serum 11 ketotestosteron level of the MT and E2 simultaneously treated XX and XY female was similar to that of the XY control, while serum E2 level of these two groups was similar to that of the XX control. Transcriptomic cluster analysis revealed that the MT and E2 treated XX and XY gonads clustered into the same branch with the XX control. However a small fraction of genes, which showed disordered expression, may be associated with stress response. These results demonstrated that estrogen could maintain the female phenotype of XX fish and feminize XY fish even in the presence of androgen. Simultaneous treatment with estrogen and androgen up-regulated the endogenous estrogen and androgen synthesis, and resulted in disordered gene expression and endocrine disruption in tilapia. PMID- 26759275 TI - Pre-pregnancy potato consumption and risk of gestational diabetes mellitus: prospective cohort study. AB - STUDY QUESTION: What is the association between potato consumption before pregnancy and the risk of gestational diabetes mellitus (GDM)? METHODS: This prospective cohort study included 15,632 women from the Nurses' Health Study II (1991-2001). They had no previous GDM or chronic diseases before pregnancy. Consumption of potatoes and other foods was assessed every four years. Incident first time GDM was ascertained from self reports of a physician diagnosis of GDM, which was previously validated by medical records. STUDY ANSWER AND LIMITATIONS: Over the 10 year follow-up there were 854 incident cases of GDM among 21,693 singleton pregnancies. After adjustment for age, parity, and dietary and non dietary factors, women who consumed more potatoes before pregnancy had higher rates of developing GDM. Substitution of two servings a week of total potatoes with other vegetables, legumes, and whole grain foods was significantly associated with a 9-12% lower risk of GDM. Consumption and diabetes were self reported, and severity of diabetes was unknown. More than 90% of women were white. A causal association cannot be assumed. WHAT THIS PAPER ADDS: Higher levels of potato consumption before pregnancy are associated with greater risk of GDM, and substitution of potatoes with other vegetables, legumes, or whole grain foods might lower the risk. FUNDING, COMPETING INTERESTS, DATA SHARING: Funding was received from the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, and the American Diabetes Association (No 7-12-MN-34). The authors have no competing interests or additional data to share. PMID- 26759277 TI - A rare cause of lymphadenopathy - Rosai-Dorfman disease in a HIV-positive Ugandan woman. AB - This case illustrates a rare cause of lymphadenopathy as a presenting feature of HIV and highlights the importance HIV testing in all patients who present with lymphadenopathy. PMID- 26759289 TI - [Advocating innovation, advocating technology]. PMID- 26759290 TI - [Maxillary sinus augmentation and implant placement following removal of a maxillary antral cyst: a preliminary clinical study]. AB - OBJECTIVE: To evaluate the clinical outcome of maxillary sinus augmentation and implant placement following removal of a maxillary antral cyst. METHODS: In this study 32 patients with 33 maxillary antral cysts were enrolled. The partial wall of cyst was removed through a small lateral sinus approach and cyst spontaneous shrink was expected when wall of cyst was destroyed for open drainage. Three to six months later the secondary sinus approach 1.5 mm circling the first approach for augmentation was undertaken. Dental implants were placed simultaneously or later. All patients finished prosthetic rehabilitation in the study and were followed up for (30.9 +/- 11.5) months. The intraoperative and postoperative complications were recorded. The survival rate of the implants was calculated. RESULTS: In this study, 33 maxillary antral cysts of 32 patients were removed. Maxillary sinus augmentation was performed after a mean of (4.5 +/- 1.5) months (range, 2-8 months). Sixty-two implants were inserted and all patients finished prosthetic rehabilitation after a mean of (10.8 +/- 2.7) months (range, 5-17 months). The survival rate of implants was 95% (59/62). Three implants failed before their prosthesis delivered due to failure of osseointegration and were reinserted later. No recurrence of cyst was observed until the last recall. In this study, 24 specimens were mucosal cysts. Five specimens were mucoceles and 4 specimens were not certain in pathology. CONCLUSIONS: Maxillary sinus cysts have a negative effect on maxillary sinus augumentation if not removed. The present preliminary data of the study suggests that the clinical result of maxillary sinus augmentation and implant placement following removal of a maxillary antral cyst is predictable. PMID- 26759276 TI - Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy. AB - BACKGROUND: Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, is used to treat solid tumors and tuberous sclerosis complex (TSC). Stomatitis, an inflammation of the mucous membranes of the mouth, is a common adverse event associated with mTOR inhibitors, including everolimus. We conducted a meta analysis of data from seven randomized, double-blind phase 3 clinical trials of everolimus to determine the clinical impact of stomatitis on efficacy and safety. PATIENTS AND METHODS: Data were pooled from the safety sets of solid tumor [breast cancer (BOLERO-2 and BOLERO-3), renal cell carcinoma (RECORD-1), carcinoid tumors (RADIANT-2), and pancreatic neuroendocrine tumors (RADIANT-3)] and TSC studies (EXIST-1 and EXIST-2). Data from solid tumor trials and TSC trials were analyzed separately. RESULTS: The rate of stomatitis was 67% in the solid tumor trials (973/1455 patients) and 70% in the TSC trials (110/157 patients). Most stomatitis events were grade 1/2, with grade 3/4 events reported in only 9% (solid tumor trials) and 8% (TSC trials) of patients. Low TSC patient numbers prevented an in-depth evaluation of stomatitis and response. In the solid tumor trials, most first stomatitis episodes (89%; n = 870) were observed within 8 weeks of starting everolimus. Patients with stomatitis occurring within 8 weeks of everolimus initiation had longer progression-free survival (PFS) than everolimus-treated patients without stomatitis in BOLERO-2 {8.5 versus 6.9 months, respectively; hazard ratio (HR), 0.78 [95% confidence interval (CI), 0.62 1.00]} and RADIANT-3 [13.9 versus 8.3 months, respectively; HR, 0.70 (95% CI, 0.48-1.04)]. A similar trend was observed in RECORD-1 [HR, 0.90 (95% CI, 0.66 1.22)] and RADIANT-2 [HR, 0.87 (95% CI, 0.61-1.22)] but not in BOLERO-3 [HR, 1.01 (95% CI, 0.75-1.36)]. CONCLUSIONS: Stomatitis did not adversely affect PFS, supporting the administration of everolimus in accordance with standard management guidelines. PMID- 26759291 TI - [Application of xenograft for alveolar ridge preservation in posterior sites: a randomized controlled clinical trial]. AB - OBJECTIVE: To investigate the effect of ridge preservation with Bio-Oss Collagen and Bio-Gide in posterior sites. METHODS: From May 2010 to July 2013, 16 patients with bilateral posterior teeth planned to be extracted and replaced by implants were enrolled. One of the sockets was randomly selected and presserved with Bio Oss Collagen and Bio-Gide (intervention group). The contralateral socket was left to heal spontaneously (control group). Cone-beam (CBCT) scans were performed immediately after the extraction and 6 month later. The bone cores were collected during the implant placement surgery and analyzed by micro-computed tomography. RESULTS: After 6 month healing, the vertical and horizontal dimensional alteration of the treatment group were (0.55 +/- 1.05) mm and (-0.99 +/- 0.94) mm respectively, while the vertical and horizontal change of control group were ( 0.71 +/- 1.41) mm and (-2.26 +/- 1.29) mm respectively. The micro-computed tomography results showed that there was no significant difference in new bone volume between control and intervention groups. CONCLUSIONS: Applying Bio-Oss Collagen and Bio-Gide for ridge preservation in posterior sites resulted in less vertical and horizontal bone resorption of sockets following extraction. PMID- 26759292 TI - [A retrospective study of six fractured platform-switching abutments]. AB - OBJECTIVE: To explore the reasons for platform-switching abutment fracture, the treatment and prevention methods. METHODS: Between March 2009 and December 2014, all of the fractured platform-switching abutments were evaluated. The fracture rate of platform-switching abutments was calculated and the gender, age, implant site, implant size, abutment size, prosthetic type, loading time and crown materials were analyzed. RESULTS: A total of 2 487 platform-switching implants were placed during this period and 6 abutments were fractured. The fracture rate was 0.24% (6/2 487). All of the 6 fractured abutments were placed in molar region. All occlusal planes were made of metal material. Five patients were male. All the fracture abutments could not be removed and the implants had to be removed and reimplanted. CONCLUSIONS: Without special abutment removing instruments, it is difficult to remove the fractured platform-switching abutment. In molar region, platform-switching implant system should be carefully used. Increasing implants number and splinting crowns with porcelain occlusal planes might reduce the abutment fracture risk. PMID- 26759293 TI - [Cone-beam CT assited to localize outside root canal instruments separation in a case]. PMID- 26759294 TI - [The changes of maxillary sinus membrane thickeness after maxillary sinus floor elevation surgery]. AB - OBJECTIVE: To evaluate the success rate of dental implants and the changes of sinus membrane thickness after sinus lift in cases of thickened sinus membrane. METHODS: Sixteen patients without maxillary sinusitis and with 5-8 mm residual alveolar bone heights were included in this study. The sinus membrane thickeness of these patients were more than 2 mm. All patients received sinus lift surgery and dental implants insertion. The changes of sinus membrane was evaluated by cone-beam CT (CBCT) pre-surgery and 6 months after sinus lift surgery, and the short term success rate of dental implants was also evaluated. RESULTS: A total of 18 implants from 16 subjects were inserted. The thickness of membrane was decreased in 14 cases after sinus lift and increased in 2 cases. All the orifice of maxillary sinus was unobstructed before surgery, one case was obstructed after surgery without inflammation. All the dental implants succeeded. CONCLUSIONS: Sinus augmentation with thickened sinus membrane is not contraindication of sinus lift. PMID- 26759295 TI - [Occlusal force and its distribution in the position of maximum intercuspation in individual normal occlusion: a cross-sectional study]. AB - OBJECTIVE: To investigate the occlusal force in the position of maximum intercuspation in the population with individual normal occlusion using a new occlusal analyzing equipment (TeeTester). METHODS: Twenty-nine volunteers aged from 21 to 32 years were recruited. Occlusal analysis was performed using TeeTester. An arch model of each subject was retrieved in order to measure the tooth width and to calculate the force applied on each tooth. RESULTS: The occlusal force in the position of maximum intercuspation was (900 +/- 361) N (range: 335-1 727 N). The maximum occlusal force was correlated with the contacting area. The mean value of occlusal force on the molars ranged from 107 to 156 N, with the mean value on the first molar greater than that on the second molar within the same quadrant. The mean value of occlusal force ranged from 39 to 66 N on the premolars, and from 11 to 33 N on the front teeth. CONCLUSIONS: There is a great variation of occlusal force in maximum intercuspation in individual normal occlusion. TeeTester occlusal analyzing system provides absolute occlusal force in kilogram and can be cowerted to N, which may assist clinical examination in patients. PMID- 26759296 TI - [Correlation of bone mineral density of the mandibular angle, hand and total body in 839 healthy individuals aged from 5 to 18 years]. AB - OBJECTIVES: To investigate the correlation of bone mineral density (BMD) of mandibular angle, hand and total body in healthy individuals aged from 5 to 18 years. METHODS: Eight hundred and thirty-nine healthy individuals from 5 to 18 years old (422 males, 417 females) in 5 primary and secondary schools in Guangzhou were divided into 14 age groups. Dual energy X-ray absorptiometry (DXA) was used to measure the BMD of mandibular angle, hand and total body. The data were statistically analyzed using Pearson correlation analysis. RESULTS: The BMD of mandibular angle increased with age. In females, the BMD of mandibular angle increased quickly from 12 to 16 years old, and its increasing rate gradually slowed down after 16 years old. In males, the BMD of mandibular angle increased quickly after 14 years old, and its increase had not been stopped until 18 years old. Females in 12, 13, 14, 15, 16, 17-year-old group had significantly higher mandibular angle BMD [(0.95 +/- 0.19), (1.01 +/- 0.17), (1.11 +/- 0.17), (1.25 +/ 0.13), (1.28 +/- 0.14), (1.30 +/- 0.13) g/cm(2)] than males in the age-matched group (P < 0.05). There was no significant difference between mandibular angle BMD in males and in females at the age of 18, and from 5 to 11 years old (P > 0.05). For males, the mandibular angle BMD was highly correlated with age (r = 0.696, P < 0.001), hand BMD (r = 0.779, P < 0.001) and total body BMD (r = 0.831, P < 0.001). For females, the mandibular angle BMD was highly correlated with age (r = 0.795, P < 0.001), hand BMD (r = 0.839, P < 0.001) and total body BMD (r = 0.872, P < 0.001). CONCLUSIONS: The mandibular angle BMD in healthy individuals from 5 to 18 years old increased with age. The mandibular angle BMD was closely related to hand BMD and total body BMD. PMID- 26759297 TI - [Clinical observation of glycine powder air-polishing during periodontal maintenance phase]. AB - OBJECTIVE: To evaluate the clinical effect of the 65 um glycine powder air polishing (GPAP) and ultrasonic scaling during periodontal maintenance phase. METHODS: Twenty-three patients at the age of 28-72 (8 males and 15 females) who were systematically healthy were involved in this study. According to splitting mouth design, one side of a mouth was randomly assigned to the experiment group with 65 um GPAP therapy, while the other side was the control group with ultrasonic scaling therapy. The clinical parameters including probing depth (PD), bleeding index (BI), gingival recession (Rec), plaque index (PLI), staining index (SI) were recorded. The patients' perception of treatment was assessed by visual analogue scale (VAS). The treatment time was recorded and compared between the two groups. RESULTS: Both of the two methods had good clinical effects. PD, BI and PLI of the two groups 12 weeks after treatment were better than those at baseline (P < 0.01). There was no significant deference between the two methods at baseline and at the 12 weeks after treatment. The VAS value of experiment group was better than that of control group (1.7 +/- 1.3 vs. 3.3 +/- 1.8, P < 0.01). The treatment time of experiment group was also shorter than that of control group [(192.7 +/- 82.7) s vs. (345.4 +/- 116.9) s, P < 0.01]. CONCLUSIONS: The results indicate that 65 um GPAP may be as effective as the ultrasonic scaling during periodontal maintenance phase. 65 um GPAP had the advantage of more comfort and less time consuming. PMID- 26759298 TI - [Effect of endoplasmic reticulum stress on the expression and osteogenic differentiation of periodontal ligament stem cells]. AB - OBJECTIVE: To determine the activity of endoplasmic reticulum stress (ERS) and its effect on osteogenic differentiation of periodontal ligament stem cells (PDLSC) in inflammatory microenvironment. METHODS: PDLSC were obtained from the primary culture of the human tooth and cloned with limited diluted method. Real time reverse transcription (RT)-PCR was used to examine the different expression of thapsigargin (TG) treated PDLSC and lipopolysaccharide (LPS) treated PDLSC. Real-time RT-PCR, alizarin red staining and cetyl pyridine chloride quantitative analyze were used to examine the osteogenic differentiation of PDLSC, TG + PDLSC, LPS + PDLSC and LPS + PDLSC + 4-PBA. RESULTS: Protein kinase receptor like endoplasmic reticulum kinase (PERK), glucose regulated protein 78 (GRP78), transcription activation factor 4(ATF4), CCAAT/enhancer-binding protein homologous protein (CHOP) mRNA expression in group PDLSC + TG in 6 h were respectively 1.49 +/- 0.24, 2.77 +/- 0.60, 1.75 +/- 0.16, 2.16 +/- 0.32, which were all greater than that in group PDLSC (P < 0.05). PERK, CHOP mRNA expression reached the peak at 6 h (1.76 +/- 0.08, 2.31 +/- 0.17) and were greater than group PDLSC (P < 0.05). ERS could suppress osteogenic differentiation of TG + PDLSC and LPS + PDLSC. The runt-related transcription factor-2 (RUNX2), alkaline phosphatase (ALP), osteocalcin (OCN) mRNA expression of group TG + PDLSC was respectively 0.73 +/- 0.06, 0.01 +/- 0.00, 0.20 +/- 0.06 (P < 0.05). The RUNX2, ALP, OCN mRNA expression of group LPS + PDLSC was respectively 0.80 +/- 0.06, 0.48 +/- 0.05, 0.29 +/- 0.04 (P < 0.05). The RUNX2, ALP, OCN mRNA expression of group PDLSC + TG + 4-PBA was respectively 1.10 +/- 0.09, 0.74 +/- 0.05, 0.67 +/- 0.13, which were greater higher than that of group LPS + PDLSC (P < 0.05). CONCLUSIONS: ERS was activated in PDLSC and suppressed osteogenic differentiation of PDLSC, which can simulate inflammatory microenvironment in vitro. This effect can be recovered by using ERS inhibitor 4-PBA. PMID- 26759299 TI - [Effect of luxS overexpression on biofilm formation by Streptococcus mutans]. AB - OBJECTIVE: To evaluate the effect of quorum sensing luxS gene on biofilm formation through construction of a luxS overexpression strain by Streptococcus mutans (Sm). METHODS: In order to construct pIB-luxS plasmid, the luxS gene fragment amplified by PCR was inserted into the shuttle plasmid pIB169 by corresponding double digests. The pIB-luxS plasmid was linearized electro transformed into Sm cell and the overexpression strain was selected on chloramphenicol plate and testified by electrophoresis and western blot. The growth rate of both Sm wild type strain and its luxS overexpression strain were observed. Methyl thiazolyl tetrazolium (MTT) assay method was used to compare the biofilm formation quantification by both strains at different time points and containing different sucrose. The structures of the biofilms were observed by using confocal laser scanning microscopy, and biofilm-related gene expressions were investigated by real-time PCR. All experiments were performed in triplicate. RESULTS: The luxS overexpression strain was successfully constructed and confirmed by electrophoresis and Western blotting. The planktonic growth mode of the wild-type and luxS overexpression strain showed no difference, but biofilm formed by Sm overexpression strain was 0.400 +/- 0.009 and 0.609 +/- 0.041 at 14 and 24 h, higher than the wild type strain biofilm at the same time point (0.352 +/- 0.028 and 0.533 +/- 0.014, respectively, P < 0.05). After adding 0.125% sucrose, biofilm formed by Sm overexpression strain raised to 1.041 +/- 0.038, higher than that by the wild type strain (0.831 +/- 0.020, P < 0.05). The biofilm formed by both strains were also increased with the sucrose concentration increase, but there was no difference between them. The overexpression strain aggregated into distinct clusters on structure, genes expression including gtfB, ftf, gbpB, relA, brpA, smu630, comDE, vicR were increased (6.10 +/- 0.12, 3.34 +/ 0.07, 8.75 +/- 0.13, 2.96 +/- 0.04, 5.20 +/- 0.19, 2.20 +/- 0.06, 2.32 +/- 0.07 and 10.67 +/- 0.57 fold) compared to the wild-type strain (P < 0.05). CONCLUSIONS: Quorum sensing luxS gene can promote the biofilm formation of Sm. PMID- 26759300 TI - [Three-dimensional finite element analysis on half of the structure defect with post core and all-ceramic crown restoration of mandibular first molar]. AB - OBJECTIVE: To make a mechanical analysis on three-dimensional finite element models of the mandibular first molar defect restored with post core and all ceramic crown, and to provide a guideline for planning restoration for such kind of tooth structure defect. METHODS: Cone-beam CT based three dimensional finite element models of post and core restored first mandibular molars were established, with 6 different ferrule designs (the ferrule with only 180 axial wall on different locations). The von Misses criterion was applied for comparing the maximum von Misses stress value of dentin and stress concentration areas in six models which restored with fiber post or cast NiGr alloy post core or Au alloy post core under the maximum, vertical, inclined and horizontal direct loads. RESULTS: The restoration effects in six models were compared, and the maximum von Misses stress concentration areas were not obviously different. The maximum von Misses stress value of NiCr alloy post core and crown was 62.81 MPa. Under horizontal load, the maximum von Misses stress value of dentin increased remarkably. CONCLUSIONS: The location of residual dentin has little influence on the stress distribution, when restored by post core and crown. Au alloy post core and crown or fiber post core and crown are superior to NiCr alloy post core and crown. PMID- 26759301 TI - [Comparison of platelet adhesion behavior on pure titanium surfaces modified by different techniques]. AB - OBJECTIVE: To evaluate the platelet adhesion ability on pure titanium surfaces modified with different techniques. METHODS: Pure titanium specimens were treated with 5 different surface modification techniques, including machine polish (MP), dual acid-etch (DAE), sand blast-large grit and acid-etch (SLA), micro-arc oxidation (MAO) and anodized titania nanotube (TNT). The surface topographies of specimens were observed by scanning electron microscopy (SEM). Chemical compositions, surface roughness and static water contact angle of specimens were detected by energy dispersive spectrometer (EDS), laser scanning confocal microscope (LSCM) and contact angle analyzer respectively. Platelets were cultured on specimen surfaces for 30 min. The amount and viability of adhered platelets adhered were evaluated. Platelet distribution and morphology were observed by LSCM and SEM. RESULTS: Surface topographies of the five groups of specimens differed significantly. MP, DAE, SLA and MAO surfaces showed micro scale topographies, while TNT surfaces showed nano-scale topography with nanotubes at the diameter of (80.46 +/- 0.35) nm. The surface roughness of MAO was the highest among the 5 groups. TNT surfaces demonstrated the lowest roughness as well as the lowest static water contact angle as 13.55 degrees +/- 0.96 degrees . The amount of platelets adhered on TNT surface was the greatest as (300 729 +/- 8 325) platelet/ul and the viability was the highest (A450 value 2.14 +/- 0.05). Platelet adhered intensively on TNT surfaces, forming pseudopodia, extending and connecting with each other. CONCLUSIONS: Surface properties of pure titanium affect platelet adhesion ability. Nano-scale topography can greatly improve platelet adhesion. Increased surface roughness and hydrophilicity can improve platelet adhesion ability. PMID- 26759302 TI - [Oral polygenic disorders and their research strategies]. PMID- 26759303 TI - [Characteristics of maxillofacial developmental deformities in patients with cleft lip and palate and related orthodontic treatment]. PMID- 26759304 TI - Aspergillus fumigatus promotes T helper type 2 responses through thymic stromal lymphopoietin production by human corneal epithelial cells. AB - BACKGROUND: Fungal keratitis is a major cause of blindness. To understand the mechanism of both innate and adaptive immunity in corneal infection is of great significance in the treatment and prevention of fungal keratitis. Our previous study concerned innate immunity. Here, we explored the potential role of thymic stromal lymphopoietin (TSLP) in adaptive immunity of fungal keratitis. METHODS: Human corneal epithelial cells (HCECs) were stimulated with Aspergillus fumigatus hyphae (10(6) pieces per millilitre) with or without TSLP siRNA, and peripheral blood mononuclear cells (PBMCs) were cultured with or without TSLP. HCECs and PBMCs were co-cultured in a transwell system for various periods. Then we collected PBMCs and detected the proliferation and activation as well as T helper type 2 (Th2) differentiation by flow cytometry and quantitative real-time reverse transcription polymerase chain reaction. IgG and IgA levels in supernatants of PBMCs were measured by means of ELISA. RESULTS: Thymic stromal lymphopoietin could induce a Th2 response in vitro, and the expression of TSLP was highly increased in HCECs stimulated with A. fumigatus hyphae. A. fumigatus-infected HCECs were capable of promoting human lymphocyte proliferation and activating human CD4(+) T cells, CD8(+) T cells and B cells by up-regulating the expression of activation marker CD69. Importantly, Th2 differentiation of CD4(+) T cells was induced during co-culture with A. fumigatus-infected HCECs in a transwell system. Interestingly, blockade of TSLP using siRNA prevented the proliferation and activation of lymphocytes as well as Th2 differentiation. We also detected an increased IgG level that was associated with TSLP. CONCLUSION: These findings suggested that HCEC-derived TSLP has a key role in adaptive immune responses of fungal keratitis via skewing Th2 differentiation and promoting humoral immunity. PMID- 26759305 TI - The human RNA surveillance factor UPF1 regulates tumorigenesis by targeting Smad7 in hepatocellular carcinoma. AB - BACKGROUND: In spite of progress in diagnostics and treatment of Hepatocellular Carcinoma (HCC), its prognosis remains poor, and improved treatment strategies for HCC require detailed understanding of the underlying mechanism. In this investigation we studied the role of Up-frameshift 1 (UPF1) in the tumorigenesis of HCC. METHODS: We determined the expression level of UPF1 in HCC tissues with quantitative real-time PCR and western blotting and then studied its clinical significance. Sodium bisulfite sequencing was used to investigate the regulation of UPF1. We explored the biological significance of UPF1 with gain-and-loss-of function analyses both in vitro and in vivo. The relationship between UPF1 and SMAD7 was also investigated by western blotting and immunofluorescence. RESULTS: A great downregulation of UPF1 due to promoter hypermethylation was observed in tumor tissues compared to their adjacent normal tissues. Meanwhile, patients with low UPF1 expression have significantly poorer prognosis than those with high expression. Functionally, UPF1 regulated HCC tumorigenesis both in vitro and in vivo. Moreover, the decreased UPF1 level in HCC reduces NMD efficiency and leads to up-regulation of Smad7, then affects the TGF-beta pathway. CONCLUSION: Our findings revealed that UPF1 is a potential tumor suppressive gene and may be a potential therapeutic target for HCC. PMID- 26759306 TI - Measuring cognitive load: mixed results from a handover simulation for medical students. AB - INTRODUCTION: The application of cognitive load theory to workplace-based activities such as patient handovers is hindered by the absence of a measure of the different load types. This exploratory study tests a method for measuring cognitive load during handovers. METHODS: The authors developed the Cognitive Load Inventory for Handoffs (CLI4H) with items for intrinsic, extraneous, and germane load. Medical students completed the measure after participating in a simulated handover. Exploratory factor and correlation analyses were performed to collect evidence for validity. RESULTS: Results yielded a two-factor solution for intrinsic and germane load that explained 50 % of the variance. The extraneous load items performed poorly and were removed from the model. The score for intrinsic load correlated with the Paas Cognitive Load scale (r = 0.31, p = 0.004) and was lower for students with more prior handover training (p = 0.036). Intrinsic load did not, however, correlate with performance. Germane load did not correlate with the Paas Cognitive Load scale but did correlate as expected with performance (r = 0.30, p = 0.005) and was lower for those students with more prior handover training (p = 0.03). CONCLUSIONS: The CLI4H yielded mixed results with some evidence for validity of the score from the intrinsic load items. The extraneous load items performed poorly and the use of only a single item for germane load limits conclusions. The instrument requires further development and testing. Study results and limitations provide guidance to future efforts to measure cognitive load during workplace-based activities, such as handovers. PMID- 26759308 TI - Evaluating the Prognostic Role of Elevated Preoperative Carcinoembryonic Antigen Levels in Colon Cancer Patients: Results from the National Cancer Database. AB - OBJECTIVES: Carcinoembryonic antigen (CEA) is a reliable tumor marker for the management and surveillance of colon cancer. However, limitations in previous studies have made it difficult to elucidate whether CEA should be established as a prognostic indicator. This study examines the association between elevated preoperative CEA levels and overall survival in colon cancer patients using a national population-based registry. METHODS: Stage I-III colon cancer patients were identified from the 2004-2006 National Cancer Database. A multivariable Cox proportional hazards model was used to estimate the association between elevated CEA levels and overall survival after controlling for important patient, hospital, and tumor characteristics. A Monte Carlo Markov Chain was used to impute the large degree of missing CEA data. All models controlled for the propensity score in order to account for selection bias. RESULTS: A total of 137,381 patients met the inclusion criteria. Overall, 34 % of patients had an elevated CEA level and 66 % had a normal CEA level, with a median survival of 70 and 100 months, respectively. Patients with an elevated CEA level had a 62 % increase in the hazard of death (HR 1.62, 95 % CI 1.53-1.74) compared with patients with a normal CEA level. CONCLUSIONS: Preoperative CEA was an independent predictor of overall survival across all stages. The results support recommendations to include CEA levels as another high-risk feature that clinicians can use to counsel patients on adjuvant chemotherapy, especially for stage II patients. PMID- 26759307 TI - Optimal Percent Myxoid Component to Predict Outcome in High-Grade Myxofibrosarcoma and Undifferentiated Pleomorphic Sarcoma. AB - BACKGROUND: Myxofibrosarcoma and undifferentiated pleomorphic sarcoma (UPS) are aggressive, genetically complex sarcomas. The minimum myxoid component used as a criterion for myxofibrosarcoma varies widely, so we determined the optimal myxoid component cutpoints for stratifying outcomes of UPS and myxofibrosarcoma. We also analyzed clinicopathologic factors associated with outcome. METHODS: Review of a prospective, single-institution database identified 197 patients with primary, high-grade extremity/truncal myxofibrosarcoma or UPS resected during 1992-2013. Histology was reviewed and percent myxoid component determined for each tumor. Disease-specific survival (DSS) and distant recurrence-free survival (DRFS) were analyzed using the Kaplan-Meier method, log-rank test, and Cox regression. RESULTS: Median follow-up for survivors was 6.4 years. In minimum p value analysis of myxoid component, the best cutpoint for both DSS and DRFS was 5% (adjusted p <= 0.001), followed by 70%. Therefore, sarcomas with <5% myxoid component (n = 69) were classified as UPS and those with >=5% myxoid component (n = 128) as myxofibrosarcoma. Five-year DRFS was 24% for UPS, 51% for 5-69% myxoid component myxofibrosarcoma, and 65% for >=70% myxoid component myxofibrosarcoma. Myxoid component, tumor size, and age were independently associated with DSS; myxoid component and tumor size were associated with DRFS. Only tumor site was associated with local recurrence. CONCLUSIONS: Percent myxoid component and tumor size are the two most important predictors of DSS and DRFS in high-grade myxofibrosarcoma and UPS. A 5% myxoid component cutpoint is an improved criterion for classifying myxofibrosarcoma. Myxoid component-based classification improves stratification of patient outcome and will aid in selection of patients for systemic therapy and clinical trials. PMID- 26759312 TI - Presidential Address: Do the Right Thing... Support Expansion of the Role of Pharmacy Technicians. PMID- 26759309 TI - Quantification of the increase in the frequency of early calving associated with late exposure to bluetongue virus serotype 8 in dairy cows: implications for syndromic surveillance. AB - A recent study evaluating whether reproductive data could be used for syndromic surveillance found an increased frequency of early calving (calving occurring a few days earlier than expected) in areas exposed to the Bluetongue virus serotype 8 (BTV-8) in northern Europe. A high proportion of herds infected during the 2006 2009 European outbreak were not reported through the surveillance system. The objectives of this study were (1) to quantify the increase in the frequency of early calving associated with the exposure to BTV-8 in late gestation and (2) to determine whether this association could be found in populations exposed to BTV-8 but without reported clinical signs. Increases in frequency of early calving were quantified for cows in herds located in the 2007 outbreak area in France, reported or not as cases. Increases were detected for cows in both categories of herds with a larger effect in herds reported after clinical signs. Moreover, the largest effect was found for exposures occurring during the latest stage of pregnancy, suggesting that BTV infection could trigger calving in cows in late gestation, a few days earlier than expected. This is the first study quantifying the association between a viral infection and a shortened pregnancy length (still within a normal range). The high magnitude of the increase in frequency of early calving, their occurrence in herds from infected areas but not reported, and the short time interval between exposure and the occurrence of the event confirm the interest of using early calving as an indicator for syndromic surveillance. PMID- 26759310 TI - Functional divergence of GhCFE5 homoeologs revealed in cotton fiber and Arabidopsis root cell development. AB - KEY MESSAGE: In GhCFE5 homoeologs, GhCFE5D interacted with more actin homologs and stronger interaction activity than GhCFE5A. GhCFE5D - but not GhCFE5A overexpression severely disrupted actin cytoskeleton organization and significantly suppressed cell elongation. Homoeologous genes are common in polyploid plants; however, their functional divergence is poorly elucidated. Allotetraploid Upland cotton (Gossypium hirsutum, AADD) is the most widely cultivated cotton; accounting for more than 90 % of the world's cotton production. Here, we characterized GhCFE5A and GhCFE5D homoeologs from G. hirsutum acc TM-1. GhCFE5 homoeologs are expressed preferentially in fiber cells; and a significantly greater accumulation of GhCFE5A mRNA than GhCFE5D mRNA was found in all tested tissues. Overexpression of GhCFE5D but not GhCFE5A seriously inhibits the Arabidopsis hypocotyl and root cell elongation. Yeast two-hybrid assay and bimolecular fluorescence complementation (BiFC) analysis showed that compared with GhCFE5A, GhCFE5D interacts with more actin homologs and has a stronger interaction activity both from Arabidopsis and Upland cotton. Interestingly, subcellular localization showed that GhCFE5 resides on the cortical endoplasmic reticulum (ER) network and is colocalized with actin cables. The interaction activities between GhCFE5 homoeologs and actin differ in their effects on F-actin structure in transgenic Arabidopsis root cells. The F-actin changed direction from vertical to lateral, and the actin cytoskeleton organization was severely disrupted in GhCFE5D-overexpressing root cells. These data support the functional divergence of GhCFE5 homoeologs in the actin cytoskeleton structure and cell elongation, implying an important role for GhCFE5 in the evolution and selection of cotton fiber. PMID- 26759311 TI - Emerging Therapies for Acute and Chronic Heart Failure: Hope or Hype? AB - Although the period from 1953 to 2001 resulted in the approval of more than 30 medications currently used to treat heart failure (HF), few novel drugs have been approved in the last decade. However, the investigational pipeline for HF medications once again appears promising. In patients with chronic heart failure with reduced ejection fraction (HFrEF), ivabradine and valsartan/sucubitril (LCZ696) were recently approved by the US Food and Drug Administration. Both agents have been shown to reduce the risk of cardiovascular death and HF hospitalization. In the treatment of acute HF, serelaxin and ularitide are the farthest along in development. Both agents have demonstrated favorable effects on surrogate end points and preliminary data suggest a possible mortality benefit with serelaxin. Consequently, phase 3 trials are ongoing to evaluate the effect of serelaxin and ularitide on clinical outcomes. Given the poor history of recent investigational acute HF drugs that have advanced to phase 3/4 studies, enthusiasm for both serelaxin and ularitide must be tempered until these trials are completed. PMID- 26759313 TI - Recent progresses in outcome-dependent sampling with failure time data. AB - An outcome-dependent sampling (ODS) design is a retrospective sampling scheme where one observes the primary exposure variables with a probability that depends on the observed value of the outcome variable. When the outcome of interest is failure time, the observed data are often censored. By allowing the selection of the supplemental samples depends on whether the event of interest happens or not and oversampling subjects from the most informative regions, ODS design for the time-to-event data can reduce the cost of the study and improve the efficiency. We review recent progresses and advances in research on ODS designs with failure time data. This includes researches on ODS related designs like case-cohort design, generalized case-cohort design, stratified case-cohort design, general failure-time ODS design, length-biased sampling design and interval sampling design. PMID- 26759314 TI - Spontaneous Peritoneal Rupture of Gastric Stromal Tumor. PMID- 26759315 TI - Frequency of level II and III axillary nodes metastases in patients with positive sentinel lymph nodes in melanoma: a multi-institutional study in Japan. AB - BACKGROUND: Axillary lymph node dissection (ALND) has been recommended to include levels I-III for melanoma patients who have evidence of metastasis in the axillary sentinel lymph node (SLN). The extent of the subsequent axillary dissection is in debate. The objective of this study was to determine the frequency of metastasis of level III nodes in addition to that of level II nodes in this setting. METHODS: A multi-institutional retrospective study was undertaken in 14 melanoma treatment centers in Japan. RESULTS: Between 2007 and 2012, 69 patients with involved axillary SLNs underwent a subsequent ALND and 55 underwent level I and II dissections. Level III metastatic nodes, which is our primary endpoint, were seen in only 1 patient (1.5 %). The level II metastatic rate was 4.4 %. CONCLUSIONS: Our study sample size was small, but melanoma patients with positive SLN rarely had level III disease, suggesting that level III dissection may be unnecessary. We also found that level II metastasis was not so frequent. More evidence is needed to standardize the extent of ALND and to identify the patients who would have the most benefit with undergoing level II dissection for positive axillary SLNs. PMID- 26759317 TI - Use of nonsteroidal anti-inflammatory drugs and renal failure in nursing home residents-results of the study "Inappropriate Medication in Patients with Renal Insufficiency in Nursing Homes". AB - BACKGROUND: Use of potentially inappropriate medications may result in increased morbidity, mortality and resource utilisation. Due to polypharmacy and age related decline in renal function the elderly population is at particular risk. Therefore, the Beers Criteria include use of nonsteroidal anti-inflammatory drugs in chronic renal failure stage 4 and 5 as these drugs may worsen renal function. According to the summary of product characteristics, the nonsteroidal anti inflammatory drugs ibuprofen and diclofenac are contraindicated in these patients. Objective was to assess the extent of nonsteroidal anti-inflammatory drug use in nursing homes with a focus on residents with severe renal failure. METHODS: Multi-centre cross-sectional study in 21 German nursing homes. The study population comprised residents for whom at least one serum creatinine value and information about sex were available, so that creatinine clearance rate could be estimated. RESULTS: In all, 685 of 852 residents were included as they fulfilled the abovementioned criteria. Renal failure was severe (estimated creatinine clearance rate < 30 ml/min) in 106 residents (15.5 %). Approximately one-fifth was treated with at least one nonsteroidal anti-inflammatory drug in both the total study population (20.3 %) and that with severe renal failure (20.8 %). With one exception, all residents prescribed nonsteroidal anti-inflammatory drugs with severe renal failure were treated with at least one nonsteroidal anti inflammatory drug that was contraindicated due to the underlying renal function. CONCLUSIONS: Notwithstanding their classification as potentially inappropriate medications and underlying contraindications, use of nonsteroidal anti inflammatory drugs is common among nursing home residents with severe renal failure. PMID- 26759316 TI - Fractional anisotropy in children with dystonia or spasticity correlates with the selection for DBS or ITB movement disorder surgery. AB - INTRODUCTION: There is increasing interest in neurosurgical interventions for hypertonicity in children and young people (CAYP), which often presents with a mixture of dystonia and spasticity. Significant spasticity would usually be considered a contraindication for deep brain stimulation (DBS) and more suitably treated with intrathecal baclofen (ITB). We aimed to explore whether white matter microstructure, as measured by Fractional Anisotropy (FA), differed between CAYP selected for DBS compared to ITB surgery. METHODS: We retrospectively analysed Diffusion Tensor Imaging for 31 CAYP selected for DBS surgery (14 primary dystonia, 17 secondary dystonia) and 10 CAYP selected for ITB surgery. A voxel wise comparison of FA values was performed using tract-based spatial statistics, comparing primary and secondary dystonia groups to the ITB group, and the two dystonia groups. RESULTS: Widespread areas of reduced FA were demonstrated in ITB compared to either DBS group and in CAYP with secondary compared to primary dystonia. These changes were not restricted to motor pathways. Region of interest (ROI) analysis from the corticospinal tract (CST) demonstrated groupwise differences but overlapping values at the individual level. CONCLUSIONS: DTI measures may contribute to decision making for CAYP selection for movement disorder surgery. Significant differences in CAYP with secondary dystonia selected for DBS surgery compared to CAYP selected for ITB pump implants, suggesting that more extensive white matter injury may be a feature of the spastic motor phenotype. Altered white matter microstructure could potentially explain the reduced responsiveness to interventions such as DBS in secondary compared to primary dystonia. PMID- 26759318 TI - Emerging Approaches for Targeting Metabolic Vulnerabilities in Malignant Glioma. AB - Malignant gliomas are intractable and among the most lethal human malignancies. Like other cancers, metabolic reprogramming is a key feature of glioma and is thought to accommodate the heightened nutrient requirements for tumor cell proliferation, growth, and survival. This metabolic rewiring, driven by oncogenic signaling and molded by the unique environment of the brain, may impose vulnerabilities that could be exploited therapeutically for increased tumor control. In this review, we discuss the prominent metabolic features of malignant glioma, the key pathways regulating glioma metabolism, and the potential therapeutic opportunities for targeting metabolic processes. PMID- 26759319 TI - Intraoperative Targeted Temperature Management in Acute Brain and Spinal Cord Injury. AB - Acute brain and spinal cord injuries affect hundreds of thousands of people worldwide. Though advances in pre-hospital and emergency and neurocritical care have improved the survival of some to these devastating diseases, very few clinical trials of potential neuro-protective strategies have produced promising results. Medical therapies such as targeted temperature management (TTM) have been trialed in traumatic brain injury (TBI), spinal cord injury (SCI), acute ischemic stroke (AIS), subarachnoid hemorrhage (SAH), and intracranial hemorrhage (ICH), but in no study has a meaningful effect on outcome been demonstrated. To this end, patient selection for potential neuro-protective therapies such as TTM may be the most important factor to effectively demonstrate efficacy in clinical trials. The use of TTM as a strategy to treat and prevent secondary neuronal damage in the intraoperative setting is an area of ongoing investigation. In this review we will discuss recent and ongoing studies that address the role of TTM in combination with surgical approaches for different types of brain injury. PMID- 26759321 TI - Stepwise discriminant function analysis for rapid identification of acute promyelocytic leukemia from acute myeloid leukemia with multiparameter flow cytometry. AB - Diagnosis of acute promyelocytic leukemia (APL) has been accelerated by multiparameter flow cytometry (MFC). However, diagnostic interpretation of MFC readouts for APL depends on individual experience and knowledge, which inevitably increases the risk of arbitrariness. We appraised the feasibility of using stepwise discriminant function analysis (SDFA) based on MFC to optimize the minimal variables needed to distinguish APL from other acute myeloid leukemia (AML) without complicated data interpretation. Samples from 327 patients with APL (n = 51) and non-APL AML (n = 276) were randomly allocated into training (243 AML) and test sets (84 AML) for SDFA. The discriminant functions from SDFA were examined by correct classification, and the final variables were validated by differential expression. Finally, additional 20 samples from patients with atypical APL and AML confusable with APL were also identified by SDFA method and morphological analysis. The weighed discriminant function reveals seven differentially expressed variables (CD2/CD9/CD11b/CD13/CD34/HLA-DR/CD117), which predict a molecular result for APL characterization with an accuracy that approaches 99% (99.6 and 98.8% for AML samples in training and test sets, respectively). Furthermore, the SDFA outperformed either single variable analysis or the more limited 3-component analysis (CD34/CD117/HLA-DR) via separate SDFA, and was also superior to morphological analysis in terms of diagnostic efficacy. The established SDFA based on MFC with seven variables can precisely and rapidly differentiate APL and non-APL AML, which may contribute to the urgent initiation of all-trans-retinoic acid-based APL therapy. PMID- 26759320 TI - Neurocutaneous Disorders for the Practicing Neurologist: a Focused Review. AB - The neurocutaneous disorders (NCDs) embrace an extensive group of developmental disorders associated with involvement of the skin, central nervous system (CNS), and/or the peripheral nervous system (PNS). The neurocutaneous manifestations relate to the common ectodermal origin of these organs. This review intended for the practicing clinical neurologist focuses on selected aspects of the NCDs primarily those associated with cerebrovascular disease. Our emphasis is primarily on those NCDs with genetic heterogeneity and their neurological manifestations. PMID- 26759323 TI - Prognostic value of Ki67 and p63 expressions in bladder cancer patients who underwent radical cystectomy. AB - INTRODUCTION: Radical cystectomy (RC) is the gold standard treatment for patients with high-risk non-muscle-invasive bladder cancer and muscle-invasive bladder cancer (MIBC) . However, despite aggressive treatment, mortality rates of patients are still high. Therefore, it is crucial to indentify some practical prognostic factors for cancer-specific survival in those patients to guide our therapeutic strategies. MATERIALS AND METHODS: We included 103 patients treated with RC for urothelial bladder cancer (UBC) between July 2007 and June 2014 in our institution and analyzed their clinicopathological parameters. The mean follow-up was 22 months (range 2-89 months). RESULTS: Advanced tumor T stage, N stage, ABO blood type, a history of DM and positive p63 expression were independent factors for worse survival in all patients who underwent RC. Moreover, in female gender, high Ki67 expression was significant risk factor for cancer-specific survival (CSS) in MIBC patients. CONCLUSION: Our study demonstrated that immunohistochemical expressions of Ki67 and p63 are potential prognostic factors for UBC patients who underwent RC. PMID- 26759322 TI - Insurance approval of mesenchymal stem cell for acute GVHD in Japan: need of follow up for some remaining concerns. AB - Acute graft-versus-host disease (aGVHD) is a major obstacle following allogeneic hematopoietic stem cell transplantation. Steroid is the standard treatment for aGVHD grade II-IV; however, nearly half of patients do not respond to the therapy. Many drugs have been proposed, but no standard therapy has been determined. This is because of the resistance to these drugs and of infections due to prolonged immunosuppressive states. Over the past decade a new approach using mesenchymal stem cells (MSCs) has been emerging in Japan and western countries. MSCs have unique characteristics such as specific immunosuppressive properties, no immunogenicity on their own and supportive activity for hematopoiesis. Most of the published trials have reported a favorable effect in acute GVHD, but a phase III trial failed to reach the primary endpoint, although, subgroup analyses found significant effects on gut and liver GVHD in the patients with MSCs infusion. In Japan several institutes are trying to develop MSC for clinical use in post HSCT patients. However, several limitations make it difficult to use MSC in clinical practice. Recently we conducted a phase II/III study using MSC (JR-031) for patients with steroid-refractory grade III or IV aGVHD. From the feasible clinical results, JR-031 was approved by PMDA as the first product which meets the Act to Revise the Pharmaceutical Affairs Act and the Act to Ensure the Safety of Regenerative Medicine. The cost of one series of the treatment is more than ten million yen. Now we encounter new issues such as cost, indication, safety and efficacy. The mechanism of MSC is still unclear and potential concerns about ectopic tissue formation and MSC related malignancy in vivo remain. In conclusion, MSC infusions are well tolerated and show benefit in some patients without adverse safety effects; however, long-term follow-up is needed to be more certain of this. PMID- 26759324 TI - Treatment strategy for bladder cancer in patients on hemodialysis: a clinical review of 28 cases. AB - PURPOSE: To clarify the background, clinical symptoms, pathological characteristics, and duration of survival in patients with bladder cancer on hemodialysis and to examine the appropriate treatment strategies. METHODS: Between April 1988 and May 2012, 28 patients in whom bladder cancer was diagnosed and treated after dialysis was initiated were included in this retrospective study. We examined the clinicopathological characteristics and survival. RESULTS: Twenty men and 8 women were included (mean age 64.1 +/- 11.9 years). The mean duration of dialysis was 80.2 +/- 79.1 months. The duration of follow-up after treatment was 43.9 +/- 41.2 months. Fourteen patients underwent immediate total cystectomy after the diagnosis of muscle-invasive bladder cancer or high-grade pT1 tumors. Of these, four died of cancer and two had surgery-related deaths. Fourteen patients underwent transurethral resection, and the initial diagnosis was non-muscle-invasive bladder cancer. Of these, three underwent delayed total cystectomy because the time to recurrence was short or there were multiple intravesical recurrences; none died of cancer. The duration of hemodialysis tended to be longer in patients who underwent immediate total cystectomy than in those who underwent only transurethral resection or delayed total cystectomy (107.1 +/- 92.0 vs. 53.3 +/- 63.9 months, p = 0.10). CONCLUSIONS: Bladder cancer in hemodialysis patients can be treated using the same strategy as for the general population. Bladder cancer in longer-term hemodialysis patients tends to be pathologically more advanced; thus, total cystectomy, although highly invasive, is often needed. Establishing bladder cancer screening for patients on dialysis is desirable. PMID- 26759325 TI - Fibroblast growth factor-23 but not sKlotho levels are related to diastolic dysfunction in type 1 diabetic patients with early diabetic nephropathy. AB - PURPOSE: To investigate the soluble Klotho (sKlotho) and fibroblast growth factor 23 (FGF-23) levels and echocardiographic findings in type 1 diabetic patients with no or early diabetic nephropathy. METHODS: A total of 147 subjects (mean age 34.1 +/- 9.2 years, 55.8 % were females) including type 1 diabetic patients with glomerular filtration rate (GFR) >60 ml/min (n = 71, mean age 34.3 +/- 9.5 years, 54.9 % were females) and healthy controls (n = 76, mean age 33.9 +/- 9.1 years, 56.6 % were females) were included in this study. Data on demographic characteristics, blood biochemistry, urinalysis, diabetes-related complications and echocardiography were recorded. Serum levels for sKlotho and FGF-23 were determined by ELISA method. RESULTS: Patient and control groups were similar in terms of mean sKlotho (509.2 +/- 183.5 and 547.6 +/- 424.0 pg/ml, respectively) and FGF-23 (76.2 +/- 15.6 and 77.2 +/- 15.1 pg/ml, respectively) levels as well as echocardiographic findings. No significant correlation of sKlotho (pg/ml) and FGF-23 (pg/ml) levels with cardiac parameters was noted among diabetic patients. In subgroup analysis, the correlations between FGF-23 levels and isovolumic relaxation time (ms) and early diastolic velocity at medial/septal annulus (E'med) (m/s) were significant only in patients with early diabetic nephropathy (DN) but not in non-DN patients. No significant association of sKlotho levels with echocardiographic findings was noted. CONCLUSIONS: Our findings in young adult type 1 diabetic patients with GFR >60 ml/min versus healthy controls revealed no difference between groups in terms of sKlotho and FGF-23 levels and echocardiographic findings, while a significant correlation of FGF-23 (pg/ml) levels and diastolic dysfunction was noted only in patients with DN. PMID- 26759326 TI - Ultrasound findings in EHEC-associated hemolytic-uremic syndrome and their clinical relevance. AB - PURPOSE: Hemolytic-uremic syndrome (HUS) and acute kidney injury (AKI) after infection with Shiga toxin-producing E. coli (EHEC) are clinically important complications. We present a retrospective analysis of abdominal ultrasound findings in patients with HUS caused by EHEC O104:H4 (n = 41). METHODS: We assessed intrarenal resistance indices and quantitated kidney parenchymal density by the kidney/liver intensity ratio using computer-based image analysis. Findings in EHEC-HUS were compared to those in AKI due to other reasons (n = 60) and 19 healthy volunteers. RESULTS: Kidneys in EHEC-HUS patients showed severe morphologic changes with striking parenchymal echogenicity. Renal resistance index was increased in HUS (0.80 +/- 0.08) compared to patients with AKI due to glomerulopathy (0.69 +/- 0.08, p < 0.001) or patients with other causes of AKI (0.74 +/- 0.10, p < 0.01). Parenchymal density was increased in EHEC-HUS (1.39 +/ 0.35) compared to AKI due to glomerulopathy (1.18 +/- 0.20, p < 0.05), other causes of AKI (1.12 +/- 0.21, p < 0.001) and healthy controls (0.86 +/- 0.16, p < 0.001). Patients with atypical HUS showed increased parenchymal density (1.43 +/- 0.37), similar to those with EHEC-HUS. EHEC-HUS patients who required dialysis treatment had higher parenchymal density (1.58 +/- 0.08) compared to those without dialysis (1.14 +/- 0.05, p = 0.0004). Extrarenal findings in EHEC-HUS included hepatomegaly (45%), splenomegaly (39%), ascites (84%) and pleural effusions (84%). CONCLUSIONS: Patients with EHEC-HUS had a characteristic constellation of morphologic abnormalities on ultrasound examination, indicating that the effects of HUS are not limited to the kidney but include multiple organs, possibly mediated through systemic capillary leakage. Assessment of parenchymal echogenicity contributes to the differential diagnosis of AKI. Parameters reflecting renal perfusion correlated with severity of disease and thus may have prognostic value in future patient evaluation. PMID- 26759328 TI - Pattern of biopsy-proven kidney disease in the elderly in a tertiary care hospital in India: a clinicopathological study. AB - BACKGROUND: An aging population is an important demographic issue in India. The knowledge base about kidney diseases among the elderly Indians is inadequate. We aim to delineate the clinical profile and spectrum of biopsy-proven kidney disease in elderly patients. METHODS: Records of all elderly patients (>=60 years) who had undergone kidney biopsy in the nephrology department from January 2010 to December 2014 were reviewed. Their clinical details and laboratory investigations at the time of biopsy were noted. Details of kidney biopsy were recorded from their biopsy reports. RESULTS: In total, 1728 patients underwent kidney biopsy during this period and 124 were elderly (7.2%). Their mean age was 64.9 +/- 4.9 years, and they were predominantly males (63.7%). Mean serum creatinine was 3.0 +/- 2.8 mg/dl, proteinuria was 4.0 +/- 2.7 g/day, and 39.5% had microscopic hematuria. The most common indications for biopsy were nephrotic syndrome (NS)--39.5% and acute kidney injury/rapidly progressive glomerulonephritis (AKI/RPGN)--24.2%. Another 8.1% patients had NS with AKI. MN (39.0%) was the chief cause of NS, and pauci-immune crescentic glomerulonephritis (GN) (28.2%) was the leading cause of AKI/RPGN. MN, pauci-immune crescentic GN and acute on chronic tubulointerstitial nephritis (A/CTIN) and acute tubular injury (ATI) were more common in the elderly, while MCD, FSGS, IgA nephropathy and lupus nephritis were more frequent in the younger patients. 68.5% of the elderly patients biopsied were diagnosed with a renal disease which was potentially amenable to specific treatment. CONCLUSION: The spectrum of biopsy proven kidney disease in the elderly Indians seen in our tertiary care hospital varies from the younger population. Kidney biopsy provides useful information with therapeutic and prognostic implications in these patients. The percentage of elderly patients among the total biopsied population is low in India, and these patients present late with renal dysfunction. Prospective studies are needed to assess the outcome of the commonly seen kidney diseases in elderly patients. PMID- 26759329 TI - Long-term functional results of aspiration and sclerotherapy with ethanol in patients with autosomal dominant polycystic kidney disease: a non-randomized pilot clinical study. AB - PURPOSE: To evaluate the long-term effect of aspiration and sclerotherapy treatment on the pain control, blood pressure regulation, and quality of life (QoL) in patients with autosomal dominant polycystic disease (ADPKD). METHODS: Twenty-five ADPKD patients with a total of 32 dominant cysts were treated with ultrasound guidance percutaneous aspiration and 96% ethanol injection, between 2002 and 2014. Twenty-one dominant cysts of 16 patients who had a minimum of 10 year follow-up were included in this study. The level of pain [visual analog score (VAS)], narcotic usage, blood pressure and serum creatinine level, QoL questionnaire, and radiological dominant cyst size was evaluated before and after procedure, retrospectively. RESULTS: The mean dominant cyst size was even smaller after follow-up of 10 years. Mean dominant cyst size was 7.2 +/- 2.3 cm before the procedure and 0.9 +/- 0.9 and 3.3 +/- 1.2 cm after the one- and 10-year follow-ups, respectively (p < 0.05). VAS and QoL scores were improved after 10 years of follow-up. There was no relation between cyst size and VAS score as well as QoL questionnaire score. End-stage renal disease occurred in 50%, and there was no significant improvement in blood pressure of these patients. CONCLUSIONS: Aspiration and sclerotherapy with ethanol is a minimal-invasive, safe, and inexpensive outpatient treatment method with acceptable short- and long-term results in ADPKD patients. Aspiration and sclerotherapy with ethanol can be an option for patients with ADPKD. PMID- 26759331 TI - Pigmented spherical body floating within the globe. AB - Vitreous cysts are rare ocular malformations. We report an unusual case of a pigmented free-floating vitreous cyst incidentally detected in a highly myopic 28 year-old woman who was referred by her optometrist. PMID- 26759330 TI - Validating multiparametric MRI for diagnosis and monitoring of prostate cancer in patients for active surveillance. AB - PURPOSE: To compare multiparametric magnetic resonance imaging (mpMRI) with transrectal ultrasound-guided prostate biopsy (TRUS-bx) for the diagnosis and monitoring of small-volume prostate cancer (PCa) in patients on active surveillance (AS). METHODS: In a retrospective cross-sectional validation study, 100 patients on AS for PCa underwent a systematic 12-core TRUS-bx (the gold standard) as well as mpMRI, on either a 1.5 or 3 Tesla scanner (32 and 68 patients, respectively). Three pathologists reported biopsy histology separately. A single, experienced radiologist scored mpMRI scans using the PI-RADS system. We compared left- and right-sided PI-RADS scores of the peripheral zone with TRUS-bx results of the relevant prostate lobe. We then estimated the specificity and sensitivity of mpMRI in diagnosing low-grade low-risk PCa in our AS cohort. RESULTS: The sensitivity of mpMRI was 37% (95% CI 28-47%) and specificity was 85% (CI 76-92%) for cancer. The negative predictive value was 51% (CI 44-60%), and the positive predictive value was 76% (CI 62-87%). The positive and negative likelihood ratios were 2.5 and 0.7, respectively. CONCLUSION: Because of its low specificity and low negative predictive value, mpMRI is not suitable for diagnosing low-grade small-volume PCa. However, because of a specificity of 85% and a negative likelihood ratio of 0.7, mpMRI may be useful for follow-up of previously TRUS-bx diagnosed patients who are on AS. PMID- 26759332 TI - Lifestyle factors and risk of leukemia and non-Hodgkin's lymphoma: a case-control study. AB - PURPOSE: Risk factors for leukemia and lymphomas in adults are largely unknown. This study was aimed at evaluating the association between lifestyle factors and the risk of hematological malignancies in an adult population. METHODS: Data were drawn from a population-based case-control study carried out in Italy and included 294 cases (199 lymphoid and 95 myeloid) and 279 controls. Analyses were performed using standard multivariable logistic regression. RESULTS: Hair dye use for at least 15 years was associated with a higher risk of lymphoid malignancies among females (OR 2.3, 95 % CI 1.0-4.9, p = 0.036, test for trend). Furthermore, a protective effect of a moderate to heavy tea consumption on the risk of myeloid malignancies was observed (OR 0.4, 95 % CI 0.2-0.9, p = 0.017). No association was found for the use of alcoholic beverages and tobacco smoking. CONCLUSIONS: Our results confirm the potential carcinogenic effect of prolonged hair dye use observed in previous investigations. The excess risk could be explained by exposure to a higher concentration of toxic compounds in hair products used in the past. The protective effect of regular tea consumption observed in an area with a very high prevalence of black tea consumers deserves further investigation. PMID- 26759333 TI - Comparison of anthropometric measurements of adiposity in relation to cancer risk: a systematic review of prospective studies. AB - PURPOSE: In epidemiology, the relationship between increased adiposity and cancer risk has long been recognized. However, whether the association is the same for measures of abdominal or whole body adiposity is unclear. The aim of this systematic review is to compare cancer risk, associated with body mass index (BMI), an indicator of whole body adiposity, with indicators of abdominal adiposity in studies in which these indicators have been directly measured. METHODS: We conducted a systematic search from 1974 (EMBASE) and 1988 (PubMed) to September 2015 with keywords related to adiposity and cancer. Included studies were limited to cohort studies reporting directly measured anthropometry and performing mutually adjusted analyses. RESULTS: Thirteen articles were identified, with two reporting on breast cancer, three on colorectal cancer, three on endometrial cancer, two on gastro-oesophageal cancer, two on renal cancer, one on ovarian cancer, one on bladder cancer, one on liver and biliary tract cancer and one on leukaemia. Evidence suggests that abdominal adiposity is a stronger predictor than whole body adiposity for gastro-oesophageal, leukaemia and liver and biliary tract cancer in men and women and for renal cancer in women. Abdominal adiposity was a stronger predictor for bladder and colorectal cancer in women, while only BMI was a predictor in men. In contrast, BMI appears to be a stronger predictor for ovarian cancer. For breast and endometrial cancer, both measures were predictors for cancer risk in postmenopausal women. CONCLUSIONS: Only few studies used mutually adjusted and measured anthropometric indicators when studying adiposity-cancer associations. Further research investigating cancer risk and adiposity should include more accurate non-invasive indicators of body fat deposition and focus on the understudied cancer types, namely leukaemia, ovarian, bladder and liver and biliary tract cancer. PMID- 26759327 TI - New molecular insights in diabetic nephropathy. AB - Diabetes mellitus represents one of the major causes of functional kidney impairment. The review highlights the most significant steps made over the last decades in understanding the molecular basis of diabetic nephropathy (DN), which may provide reliable biomarkers for early diagnosis and prognosis, along with new molecular targets for personalized medicine. There is an increased interest in developing new therapeutic strategies to slow DN progression for improving patients' quality of life and reducing all-cause morbidity and disease-associated mortality. It is highly important to have a science-based medical attitude when facing diabetic patients with associated comorbidities and risk of rapid evolution toward end-stage renal disease. The data discussed herein were mainly from MEDLINE and PubMed articles published in English from 1990 to 2015 and from up-to-date. The search term was "diabetic nephropathy and oxidative stress". PMID- 26759334 TI - Usefulness of daily teriparatide treatment in elderly patients over 80 years of age. AB - The percent and absolute lumbar spine and femoral neck bone mineral densities and procollagen type I N-terminal propeptide (PINP) and urinary N-telopeptide level increases noted after teriparatide 20 MUg/day treatment for 24 months were similar in the older (age >= 80 years) and younger (age < 80 years) subgroups. INTRODUCTION: Many individuals are living into their eighth and ninth decades, but little is known about the efficacy of osteoporosis medication for this population. We retrospectively compared usefulness of daily teriparatide therapy in osteoporosis patients >=80 and <80 years to detect possible age-related differences. METHODS: We analyzed 628 osteoporosis patients treated with teriparatide 20 MUg/day for 24 months. The primary efficacy measures were changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD) over 24 months. Changes in serum procollagen type I N-terminal propeptide levels and urinary N-telopeptide (uNTX) excretion were also measured. Patients were divided into age subgroups (older, >=80 years; younger, <80 years) for BMD and bone turnover marker comparison. RESULTS: In the older subgroup, the percent LS BMD significantly increased by 14.6 +/- 10.4 % (mean +/- SD) and FN BMD significantly increased by 4.5 +/- 10.7 % at 24 months. In the younger subgroup, the percent LS BMD significantly increased by 12.2 +/- 8.5 % and FN BMD significantly increased by 2.9 +/- 8.3 % at 24 months. In the older subgroup, the mean absolute LS BMD change was 0.111 +/- 0.071 g/cm(2) and FN BMD change was 0.019 +/- 0.043 g/cm(2). In the younger subgroup, the mean absolute LS BMD change was 0.098 +/- 0.065 g/cm(2) and FN BMD change was 0.016 +/- 0.045 g/cm(2). The percent and absolute BMD increases in LS and FN and changes in PINP and uNTX were similar between the subgroups. CONCLUSIONS: The usefulness of daily teriparatide treatment is not age dependent. PMID- 26759335 TI - Acoustic method respiratory rate monitoring is useful in patients under intravenous anesthesia. AB - Respiratory depression can occur during intravenous general anesthesia without tracheal intubation. A new acoustic method for respiratory rate monitoring, RRa(r) (Masimo Corp., Tokyo, Japan), has been reported to show good reliability in post-anesthesia care and emergency units. The purpose of this study was to investigate the reliability of the acoustic method for measurement of respiratory rate during intravenous general anesthesia, as compared with capnography. Patients with dental anxiety undergoing dental treatment under intravenous anesthesia without tracheal intubation were enrolled in this study. Respiratory rate was recorded every 30 s using the acoustic method and capnography, and detectability of respiratory rate was investigated for both methods. This study used a cohort study design. In 1953 recorded respiratory rate data points, the number of detected points by the acoustic method (1884, 96.5 %) was significantly higher than that by capnography (1682, 86.1 %) (P < 0.0001). In the intraoperative period, there was a significant difference in the LOA (95 % limits of agreement of correlation between difference and average of the two methods)/ULLOA (under the lower limit of agreement) in terms of use or non-use of a dental air turbine (P < 0.0001). In comparison between capnography, the acoustic method is useful for continuous monitoring of respiratory rate in spontaneously breathing subjects undergoing dental procedures under intravenous general anesthesia. However, the acoustic method might not accurately detect in cases in with dental air turbine. PMID- 26759336 TI - Effect of wearing an N95 filtering facepiece respirator on superomedial orbital infrared indirect brain temperature measurements. AB - To determine any effect of wearing a filtering facepiece respirator on brain temperature. Subjects (n = 18) wore a filtering facepiece respirator (FFR) for 1 h at rest while undergoing infrared thermography measurements of the superomedial periobital region of the eye, a non-invasive indirect method of brain temperature measurements we termed the superomedial orbital infrared indirect brain temperature (SOIIBT) measurement. Temperature of the facial skin covered by the FFR, infrared temperature measurements of the tympanic membrane and superficial temporal artery region were concurrently measured, and subjective impressions of thermal comfort obtained simultaneously. The temperature of the skin under the FFR and subjective impressions of thermal discomfort both increased significantly. The mean tympanic membrane temperature did not increase, and the superficial temporal artery region temperature decreased significantly. The SOIIBT values did not change significantly, but subjects who switched from nasal to oronasal breathing during the study (n = 5) experienced a slight increase in the SOIIBT measurements. Wearing a FFR for 1 h at rest does not have a significant effect on brain temperatures, as evaluated by the SOIIBT measurements, but a change in the route of breathing may impact these measurements. These findings suggest that subjective impressions of thermal discomfort from wearing a FFR under the study conditions are more likely the result of local dermal sensations rather than brain warming. PMID- 26759337 TI - Apical debris extrusion associated with oval shaped canals: a comparative study of WaveOne vs Self-Adjusting File. AB - OBJECTIVES: The aim was to evaluate ex vivo apical debris extrusion associated with WaveOne and Self-Adjusting File instruments when used in oval canals. METHODS: Twenty-four extracted human mandibular premolars with oval-shaped canals were assigned in two equal groups. Following coronal cavity preparation, a glide path was created. Group A was subjected to canal preparation using a WaveOne primary file, which was used along with syringe and needle irrigation and 10 mL of 2.4 % NaOCl solution, followed by flushing with 10 mL of 17 % EDTA solution, activation with EndoActivator for 1 min and final flushing with 10 mL of 2.4 % NaOCl solution, and activation for 30 s. Group B, the SAF system was used with continuous simultaneous irrigation, provided by the system's pump. The irrigant was supplied at 5 mL/min, alternating every minute between 2.4 % NaOCl solution and 17 % EDTA solution, over a total of 4 min followed by final flushing with 10 mL of 2.4 % NaOCl solution. Extruded apical debris from each root canal was collected into a preweighed glass vial and dried. The mean weight of the debris from each group was assessed and analyzed statistically. Both systems resulted in apical debris extrusion. RESULTS: The WaveOne system was associated with a statistically significant greater mean mass of apically extruded debris (2.18 +/- 0.44 mg) than the SAF system (0.49 +/- 0.33 mg, permutation-based Wilcoxon test, p < 0.001). CONCLUSION: Both WaveOne and the SAF systems were associated with apical debris extrusion. The amount of debris extruded by the WaveOne system was 4.4 times greater than that extruded by the SAF system. CLINICAL RELEVANCE: The results of the present ex vivo comparative study cannot be directly applied to the clinical situation. Difference between both groups remains completely unclear; maybe the amount of extrusion is harmless in both groups or similarly deleterious for the periradicular tissues in both groups or may be dose-related to the amount of the extruded material. PMID- 26759338 TI - Effect of ozone to remineralize initial enamel caries: in situ study. AB - OBJECTIVES: Effect of ozonated water in remineralizing artificially created initial enamel caries was investigated using laser fluorescence and polarized light microscopy in an in situ study. MATERIALS AND METHODS: Teeth specimens (buccal sections) were immersed in 5-ml solution of 2 mM CaCl2, 2 mM NaH2P04, and 50 mM CH3COOH at pH of 4.55 for 5 h in an incubator at 37 degrees to create subsurface demineralization. After which, they were randomly allocated into one of the following remineralization regimens: ozone (ozonated water 0.1 mg/l and 10 % nano-hydroxyapatite paste, Aclaim(TM)), without ozone (only 10 % nano hydroxyapatite paste, Aclaim(TM)), and control (subjects' saliva alone). Specimens were embedded in acrylic retainers worn by orthodontic patients throughout the 21-day study duration and constantly exposed to their saliva. Laser fluorescence was recorded for all the specimens at baseline, after demineralization, and remineralization using DIAGNOdent, and the results were validated using polarized microscopic examination. The results were analyzed using repeated measures, one-way ANOVA with post hoc multiple comparisons. RESULTS: Reduced DIAGNOdent scores and greater depth of remineralization following application of ozonated water and nano-hydroxyapatite were found compared to those of the without ozone and control groups (P < 0.001), and the ozone-treated group exhibited maximum remineralization under the polarized light microscopy. CONCLUSION: Ozonated water can be considered an effective agent in reversing the initial enamel caries alongside with nano-hydroxyapatite compared to nano-hydroxyapatite alone and saliva. CLINICAL RELEVANCE: Ozone water can be used to remineralize incipient carious lesions, and it enhances the remineralizing potential of nano-hydroxyapatite thereby preventing the tooth from entering into the repetitive restorative cycle. PMID- 26759339 TI - In-vitro activity of sodium-hypochlorite gel on bacteria associated with periodontitis. AB - OBJECTIVES: The aim of the present study was to assess the antimicrobial activity of a sodium hypochlorite formulation including its components against bacteria associated with periodontal disease. MATERIALS AND METHODS: Sodium hypochlorite formulation (NaOCl gel), its components sodium hypochlorite (NaOCl), and the activating vehicle were compared with 0.1 % chlorhexidine digluconate (CHX) solution. The antimicrobial activity was proven by determination of minimal inhibitory concentrations (MIC), minimal bactericidal concentrations, and killing assays. Furthermore, the influence on formation as well as on a 4-day-old 6 species biofilm was tested. RESULTS: Except for one strain (Parvimonas micra ATCC 33270 in case of NaOCl gel), the MICs both of the CHX solution and NaOCl gel did not exceed 10 % of the formulations' concentration. In general, MICs of the NaOCl gel were equal as of the CHX solution against Gram-negatives but higher against Gram-positive bacteria. CHX but not NaOCl gel clearly inhibited biofilm formation; however, the activity of NaOCl gel was more remarkable on a 4-day-old biofilm. NaOCl killed bacteria in the biofilm and interfered with the matrix. CONCLUSIONS: The NaOCl gel acts antimicrobial in particular against Gram-negative species associated with periodontitis. Moreover, its component NaOCl hypochlorite is able to alter biofilm matrices. CLINICAL RELEVANCE: The NaOCl gel may represent a potential alternative for adjunctive topical antimicrobial treatment in periodontitis. PMID- 26759341 TI - A New Blueprint for Addressing Tobacco Use Disparities to Reduce Health Disparities: The Sociopharmacology Theory of Tobacco Addiction. PMID- 26759340 TI - Fluoride toothpaste supplemented with sodium hexametaphosphate reduces enamel demineralization in vitro. AB - OBJECTIVE: The aim of this study was to evaluate the effect of fluoride dentifrices combined with sodium hexametaphosphate (HMP) on enamel demineralization in vitro. MATERIAL AND METHODS: Enamel bovine blocks were selected by initial surface hardness (SHi) and then divided into five experimental groups (n = 12): placebo (without fluoride and without HMP); 1100 ppm F (1100F); and 1100F associated with HMP at 0.5 % (1100HMP0.5%), 1 % (1100HMP1%), and 2 % of HMP (1100HMP2%). Blocks were submitted to five pH cycles (demineralizing/remineralizing solutions) at 37 degrees C. After pH cycling, final surface hardness (SHf), percentage of surface hardness loss (%SH), integrated differential hardness (DeltaIH), integrated loss of subsurface hardness (DeltaKHN), and enamel firmly bound fluoride (F) were determined. Data were submitted to one-way ANOVA, followed by Student-Newman-Keuls test (p < 0.05). RESULTS: Significant differences were observed among all groups regarding %SH and DeltaKHN. 1100HMP1% promoted the lowest mineral loss among all groups (p < 0.001), and led to significantly lower demineralization in the deeper regions of the subsurface lesion when compared with the other HMP-containing toothpastes (p < 0.001). Significantly higher mineral loss was observed for 1100HMP2% when compared to the other fluoridated dentifrices, mainly in the outer part of the lesion (p < 0.001). Enamel F uptake was similar for 1100F and 1100HMP1% but significantly reduced for other HMP concentrations. CONCLUSION: The supplementation of a 1100-ppm F dentifrice with 1 % HMP promoted a higher inhibitory effect against enamel demineralization when compared to a dentifrice containing the same amount of fluoride in vitro. CLINICAL RELEVANCE: This dentifrice could potentially be indicated to patients at high risk of caries. PMID- 26759346 TI - Are cattle dangerous to walkers? A scoping review. AB - Anecdotal evidence suggests that people coming into contact with cattle while participating in outdoor pursuits can sustain severe, even fatal injuries. This has negative implications for farmers, cattle and the public. This study outlines findings from a review of published literature, UK media reports and internet guidelines currently available to the UK public for walking near cattle. A total of 54 cattle attacks were reported in the UK media from 1 January 1993 to 31 May 2013; approximately one-quarter resulted in fatality and two-thirds involved dogs. Walking with dogs among cows, particularly with calves present, was a problematic context. Twenty pieces of commonly occurring advice were found within various guidelines. However, there are no definitive approved guidelines, no published studies describing the prevalence of cattle attacks on members of the public and no system in place to document them. Attacks by cattle are underinvestigated and further work should assess their public health impact. PMID- 26759348 TI - Nivolumab-induced organizing pneumonia in a melanoma patient. AB - We report the case of a 70-year-old woman with vaginal melanoma and multiple metastases in the lung. After the third dose of nivolumab, decreased room-air resting arterial oxygen saturation with bilateral basal fine crackles on auscultation developed despite the absence of respiratory symptoms. Computed tomography showed ground-glass opacities with airspace consolidations scattered with a peculiar distribution, and most were observed around the existing metastatic tumors in the lung. From the 42nd day to the 56th day after the last administration of nivolumab, she received dexamethasone 1-2 mg/body for the prevention of adverse events after stereotactic radiation for brain metastasis. At 3 months after the last administration of nivolumab, a computed tomography scan revealed improvement of the pneumonia and a decreased size and number of metastatic lesions in the lung, although some lesions showed enlargement. Further examination is needed to clarify the relationship between the pattern of pneumonia after Nivo therapy and clinical effects. PMID- 26759347 TI - Can you really swim? Validation of self and parental reports of swim skill with an inwater swim test among children attending community pools in Washington State. AB - BACKGROUND: Drowning is the second leading cause of unintentional injury death among US children. Multiple studies describe decreased drowning risk among children possessing some swim skills. Current surveillance for this protective factor is self/proxy-reported swim skill rather than observed inwater performance; however, children's self-report or parents' proxy report of swim skill has not been validated. This is the first US study to evaluate whether children or parents can validly report a child's swim skill. It also explores which swim skill survey measure(s) correlate with children's inwater swim performance. METHODS: For this cross-sectional convenience-based sample, pilot study, child/parent dyads (N=482) were recruited at three outdoor public pools in Washington State. Agreement between measures of self-reports and parental-reports of children's swim skill was assessed via paired analyses, and validated by inwater swim test results. RESULTS: Participants were representative of pool's patrons (ie, non-Hispanic White, highly educated, high income). There was agreement in child/parent dyads' reports of the following child swim skill measures: 'ever taken swim lessons', perceived 'good swim skills' and 'comfort in water over head'. Correlation analyses suggest that reported 'good swim skills' was the best survey measure to assess a child's swim skill-best if the parent was the informant (r=0.25-0.47). History of swim lessons was not significantly correlated with passing the swim test. CONCLUSIONS: Reported 'good swim skills' was most correlated with observed swim skill. Reporting 'yes' to 'ever taken swim lessons' did not correlate with swim skill. While non-generalisable, findings can help inform future studies. PMID- 26759349 TI - A short interval between bevacizumab and anti-epithelial growth factor receptor therapy interferes with efficacy of subsequent anti-EGFR therapy for refractory colorectal cancer. AB - BACKGROUND: Both bevacizumab and anti-epithelial growth factor receptor (EGFR) agents (e.g. cetuximab and panitumumab) are sequentially used for metastatic colorectal cancer (mCRC). Their co-administration as a first-line treatment does not improve outcome, indicating that there are negative interactions between these agents. A long-term pharmacokinetics study demonstrated serum persistence of bevacizumab following termination of bevacizumab 6 months after the last administration. This prompted us to investigate the impact of short intervals between bevacizumab and anti-EGFR antibody on the efficacy of subsequent anti EGFR therapy. METHODS: We retrospectively reviewed consecutive patients with KRAS exon 2 wild-type mCRC who underwent anti-EGFR therapy after the failure of fluoropyrimidines, oxaliplatin and irinotecan. We divided patients into two groups (Group A: the interval between bevacizumab and anti-EGFR agent< 6 months; Group B: the interval >6 months). RESULTS: Of the 114 included patients (median age, 63 years), 78 (68%) were male. Most patients (88%) were treated with cetuximab plus irinotecan. Groups A and B consisted of 74 and 40 patients, respectively. There were no significant differences in patient characteristics. Group B patients had significantly longer progression-free survival (4.2 vs. 6.6 months; HR, 0.65; 95% CI, 0.43-0.98; P = 0.038) and longer overall survival (11.6 vs. 14.3 months; HR, 0.63; 95% CI, 0.41-0.98, P = 0.039). The response rate was 24.3% in Group A and 47.5% in Group B (P = 0.012). CONCLUSION: A short interval between bevacizumab and anti-EGFR antibody treatment may interfere with the efficacy of subsequent anti-EGFR therapy. PMID- 26759351 TI - Science and Culture: Kirigami and technology cut a fine figure, together. PMID- 26759353 TI - Concentration- and Temperature-Induced Phase Transitions in PrAlO3-SrTiO3 System. AB - Single-phase mixed aluminates-titanates Pr1-x Sr x Al1-x Ti x O3 (x = 0.1, 0.2, 0.3, 0.5, 0.7) with rhombohedral perovskite structure were prepared by solid state reaction technique at 1823-1873 K. Morphotropic rhombohedral-to-cubic phase transition in Pr1-x Sr x Al1-x Ti x O3 series is predicted to occur at x = 0.88. The temperature-induced structural phase transition R [Formula: see text] s - Pm [Formula: see text] m in Pr0.5Sr0.5Al0.5Ti0.5O3, detected at 930 K by in situ high-temperature X-ray synchrotron powder diffraction, occurs at considerably lower temperature as the corresponding transformation in the parent compound PrAlO3 (1770 K). Such remarkable drop of the transition temperature is explained by gradual decrease of the perovskite structure deformation in the Pr1-x Sr x Al1 x Ti x O3 series with increasing Sr and Ti contents as a consequence of the increasing Goldschmidt tolerance factor. For Pr0.3Sr0.7Al0.3Ti0.7O3 phase, a sequence of the low-temperature phase transformation R [Formula: see text] s - Immb(C2/m) - I4/mcm was detected. PMID- 26759354 TI - Electrochemical Properties of Nanoporous Carbon Material in Aqueous Electrolytes. AB - The paper is devoted to the study of the behavior of capacitor type electrochemical system in the K(+)-containing aqueous electrolytes. Nanoporous carbon material (NCM) was used as the electrode material, obtained by carbonization of plant raw materials with the following chemical activation. Optimization of pore size distribution was carried out by chemical-thermal method using potassium hydroxide as activator. It is shown that obtained materials have high values of capacitance which is realized by charge storage on the electrical double layer and by pseudocapacitive ion storage on the surface of the material. It is established that based on NCM, electrochemical capacitors are stable in all range of current density and material capacity essentially depends on appropriate choice of electrolyte. PMID- 26759355 TI - SPR Detection and Discrimination of the Oligonucleotides Related to the Normal and the Hybrid bcr-abl Genes by Two Stringency Control Strategies. AB - In this study, we applied two stringency control strategies for surface plasmon resonance (SPR) detection of DNA hybridization and discrimination of completely and partially complementary 24-mer sequences. These sequences are specific to the human normal bcr and the hybrid bcr-abl genes, protein products of which are responsible for some leukemia. SPR sensors based on resonance phenomena in nanoscale gold films are well suited for label-free, real-time investigations of the macromolecule interactions. Thermodynamic parameters obtained using the web server DINAMelt allowed supposing the possibility for realization (a) stringency control based on the ionic strength of the hybridization buffer and (b) stringency control based on the temperature elevation. The first one resulted in that the discrimination index of completely complementary and partially complementary oligonucleotides depending on the target concentration varied from 1.3 to 1.8 in 2 * SSC and from 2.0 to 2.9 in 0.5 * SSC. For implementation of the second stringency control strategy, SPR spectrometer measuring flow cell with built-in high-precision temperature control and regulation as well as corresponding software was created. It is shown that the duplexes formed by the immobilized probes mod-Ph and completely complementary oligonucleotides P1 remained without significant changes until ~50 degrees C, while the duplexes formed with partially complementary oligonucleotide Bcrex14 almost entirely disrupted at 40 degrees C. Thus, the absolutely effective thermodiscrimination of this pair of oligonucleotides was achieved in this temperature range (40-50 degrees C). PMID- 26759350 TI - The extrinsic proteins of photosystem II: update. AB - MAIN CONCLUSION: Recent investigations have provided important new insights into the structures and functions of the extrinsic proteins of Photosystem II. This review is an update of the last major review on the extrinsic proteins of Photosystem II (Bricker et al., Biochemistry 31:4623-4628 2012). In this report, we will examine advances in our understanding of the structure and function of these components. These proteins include PsbO, which is uniformly present in all oxygenic organisms, the PsbU, PsbV, CyanoQ, and CyanoP proteins, found in the cyanobacteria, and the PsbP, PsbQ and PsbR proteins, found in the green plant lineage. These proteins serve to stabilize the Mn4CaO5 cluster and optimize oxygen evolution at physiological calcium and chloride concentrations. The mechanisms used to perform these functions, however, remain poorly understood. Recently, important new findings have significantly advanced our understanding of the structures, locations and functions of these important subunits. We will discuss the biochemical, structural and genetic studies that have been used to elucidate the roles played by these proteins within the photosystem and their locations within the photosynthetic complex. Additionally, we will examine open questions needing to be addressed to provide a coherent picture of the role of these components within the photosystem. PMID- 26759356 TI - Free-Volume Nanostructurization in Ga-Modified As2Se3 Glass. AB - Different stages of intrinsic nanostructurization related to evolution of free volume voids, including phase separation, crystalline nuclei precipitation, and growth, were studied in glassy As2Se3 doped with Ga up to 5 at. %, using complementary techniques of positron annihilation lifetime spectroscopy, X-ray powder diffraction, and scanning electron microscopy with energy-dispersive X-ray analysis. Positron lifetime spectra reconstructed in terms of a two-state trapping model testified in favor of a native void structure of g-As2Se3 modified by Ga additions. Under small Ga content (below 3 at. %), the positron trapping in glassy alloys was dominated by voids associated with bond-free solid angles of bridging As2Se4/2 units. This void agglomeration trend was changed on fragmentation with further Ga doping due to crystalline Ga2Se3 nuclei precipitation and growth, these changes being activated by employing free volume from just attached As-rich glassy matrix with higher content of As2Se4/2 clusters. Respectively, the positron trapping on free-volume voids related to pyramidal AsSe3/2 units (like in parent As2Se3 glass) was in obvious preference in such glassy crystalline alloys. PMID- 26759357 TI - Leakage Current Mechanism of InN-Based Metal-Insulator-Semiconductor Structures with Al2O3 as Dielectric Layers. AB - InN-based metal-insulator-semiconductor (MIS) structures were prepared with Al2O3 as the gate oxides. Surface morphologies of InN films are improved with increasing Mg doping concentrations. At high frequencies, the measured capacitance densities deviate from the real ones with turning frequencies inversely proportional to series resistances. An ultralow leakage current density of 1.35 * 10(-9) A/cm(2) at 1 V is obtained. Fowler-Nordheim tunneling is the main mechanism of the leakage current at high fields, while Schottky emission dominates at low fields. Capacitance densities shift with different biases, indicating that the InN-based MIS structures can serve as potential candidates for MIS field-effect transistors. PMID- 26759358 TI - Titanium induced polarity inversion in ordered (In,Ga)N/GaN nanocolumns. AB - We report on the formation of polarity inversion in ordered (In,Ga)N/GaN nanocolumns grown on a Ti-masked GaN-buffered sapphire substrate by plasma assisted molecular beam epitaxy. High-resolution transmission electron microscopy and electron energy-loss spectroscopy reveal a stacking fault-like planar defect at the homoepitaxial GaN interface due to Ti incorporation, triggering the generation of N-polar domains in Ga-polar nanocolumns. Density functional theory calculations are applied to clarify the atomic configurations of a Ti monolayer occupation on the GaN (0002) plane and to prove the inversion effect. The polarity inversion leads to an enhanced indium incorporation in the subsequent (In,Ga)N segment of the nanocolumn. This study provides a deeper understanding of the effects of Ti mask in the well-controlled selective area growth of (In,Ga)N/GaN nanocolumns. PMID- 26759359 TI - Opioids in pregnancy. PMID- 26759361 TI - Shackleton's heart. PMID- 26759360 TI - Optic Neuritis Associated or Not with TNF Antagonists in Patients with Inflammatory Bowel Disease. AB - BACKGROUND AND AIMS: Acute optic neuritis [ON] is an inflammatory condition affecting the optic nerve. Clinicians should suspect optic neuritis in cases of painful and rapidly progressive loss of central visual field. This condition may be associated with a multitude of diseases, and mostly with multiple sclerosis [MS] where it may present as an initial symptom. The literature reports that optic neuritis and MS occur in patients with inflammatory bowel disease [IBD] before and after the era of anti-tumour necrosis factor-alpha [TNFalpha] drugs. At the present moment, there is little consensus for managing this complication, currently treated with corticosteroids and discontinuation of the causative agents. METHODS: We collected cases through a retrospective multicentre European Crohn's and Colitis Organisation CONFER [COllaborative Network For Exceptionally Rare case reports] project. We also performed a comprehensive retrospective search of the available literature on this topic. RESULTS: We report herein 12 new cases of ON, including 10 under anti-TNF therapy, collected through the CONFER project. We also compare characteristics of ON associated or not with anti TNFalpha agents. CONCLUSIONS: The exceptional and current observation of distant family history of MS in 17% of our patients who developed ON, despite the small number and the lack of a control arm, might be an important signal that should be taken into account in our therapeutic strategies in the future. PMID- 26759362 TI - Linear Plasmids and the Rate of Sequence Evolution in Plant Mitochondrial Genomes. AB - The mitochondrial genomes of flowering plants experience frequent insertions of foreign sequences, including linear plasmids that also exist in standalone forms within mitochondria, but the history and phylogenetic distribution of plasmid insertions is not well known. Taking advantage of the increased availability of plant mitochondrial genome sequences, we performed phylogenetic analyses to reconstruct the evolutionary history of these plasmids and plasmid-derived insertions. Mitochondrial genomes from multiple land plant lineages (including liverworts, lycophytes, ferns, and gymnosperms) include fragmented remnants from ancient plasmid insertions. Such insertions are much more recent and widespread in angiosperms, in which approximately 75% of sequenced mitochondrial genomes contain identifiable plasmid insertions. Although conflicts between plasmid and angiosperm phylogenies provide clear evidence of repeated horizontal transfers, we were still able to detect significant phylogenetic concordance, indicating that mitochondrial plasmids have also experienced sustained periods of (effectively) vertical transmission in angiosperms. The observed levels of sequence divergence in plasmid-derived genes suggest that nucleotide substitution rates in these plasmids, which often encode their own viral-like DNA polymerases, are orders of magnitude higher than in mitochondrial chromosomes. Based on these results, we hypothesize that the periodic incorporation of mitochondrial genes into plasmids contributes to the remarkable heterogeneity in substitution rates among genes that has recently been discovered in some angiosperm mitochondrial genomes. In support of this hypothesis, we show that the recently acquired psitrnP-trnW gene region in a maize linear plasmid is evolving significantly faster than homologous sequences that have been retained in the mitochondrial chromosome in closely related grasses. PMID- 26759365 TI - The effectiveness of the use of consumer health information technology in patients with heart failure: A meta-analysis and narrative review of randomized controlled trials. AB - Purpose The purpose of this study was to examine whether the use of consumer health information technologies (CHITs) has an impact on outcomes of patients in the self-management of heart failure (HF). Methods A literature search of six electronic databases was conducted to identify relevant reports of randomized controlled trials (RCTs) for the analysis. Mortality, hospitalization and length of hospital stay were meta-analyzed and other patient outcomes were synthesized using a narrative approach. Results The literature search identified 50 studies, representing 43 RCTs, comparing the use of CHITs with usual care for HF patients. The meta-analysis showed that the use of CHITs reduced the risk of HF-caused mortality (relative risk (RR) = 0.70, 95% confidence interval (CI): 0.54-0.91), p = 0.007), lowered the risk of HF-caused hospitalization (RR = 0.80, 95% CI: 0.66 0.96), p = 0.020), and shortened HF-caused length of hospital stay (mean difference = -0.52, 95% CI: -0.77 to -0.27, p < 0.00), but not all-cause mortality, all-cause hospitalization or all-cause length of hospital stay, compared with usual care. The narrative synthesis indicated that only a small proportion of the trials reported positive effects of CHITs over usual care. Conclusions Evidence from RCTs presents mixed results on the impacts of CHITs for HF management. Further studies are required to assess whether and how CHITs would play a role in enhancing health care and patient outcomes and what specific CHIT features and functions are relevant to different HF treatment goals and self-care objectives. PMID- 26759366 TI - GP who orchestrated cigarette scam is struck off. PMID- 26759363 TI - Potential of lactoferrin to prevent antibiotic-induced Clostridium difficile infection. AB - OBJECTIVES: Clostridium difficile infection (CDI) is a global healthcare problem. Recent evidence suggests that the availability of iron may be important for C. difficile growth. This study evaluated the comparative effects of iron-depleted (1% Fe(3+) saturated) bovine apo-lactoferrin (apo-bLf) and iron-saturated (85% Fe(3+) saturated) bovine holo-lactoferrin (holo-bLf) in a human in vitro gut model that simulates CDI. METHODS: Two parallel triple-stage chemostat gut models were inoculated with pooled human faeces and spiked with C. difficile spores (strain 027 210, PCR ribotype 027). Holo- or apo-bLf was instilled (5 mg/mL, once daily) for 35 days. After 7 days, clindamycin was instilled (33.9 mg/L, four times daily) to induce simulated CDI. Indigenous microflora populations, C. difficile total counts and spores, cytotoxin titres, short chain fatty acid concentrations, biometal concentrations, lactoferrin concentration and iron content of lactoferrin were monitored daily. RESULTS: In the apo-bLf model, germination of C. difficile spores occurred 6 days post instillation of clindamycin, followed by rapid vegetative cell proliferation and detectable toxin production. By contrast, in the holo-bLf model, only a modest vegetative cell population was observed until 16 days post antibiotic administration. Notably, no toxin was detected in this model. In separate batch culture experiments, holo-bLf prevented C. difficile vegetative cell growth and toxin production, whereas apo bLf and iron alone did not. CONCLUSIONS: Holo-bLf, but not apo-bLf, delayed C. difficile growth and prevented toxin production in a human gut model of CDI. This inhibitory effect may be iron independent. These observations suggest that bLf in its iron-saturated state could be used as a novel preventative or treatment strategy for CDI. PMID- 26759364 TI - Dietary rescue of altered metabolism gene reveals unexpected Drosophila mating cues. AB - To develop and reproduce, animals need long-chain MUFAs and PUFAs. Although some unsaturated FAs (UFAs) can be synthesized by the organism, others must be provided by the diet. The gene, desat1, involved in Drosophila melanogaster UFA metabolism, is necessary for both larval development and for adult sex pheromone communication. We first characterized desat1 expression in larval tissues. Then, we found that larvae in which desat1 expression was knocked down throughout development died during the larval stages when raised on standard food. By contrast pure MUFAs or PUFAs, but not saturated FAs, added to the larval diet rescued animals to adulthood with the best effect being obtained with oleic acid (C18:1). Male and female mating behavior and fertility were affected very differently by preimaginal UFA-rich diet. Adult diet also strongly influenced several aspects of reproduction: flies raised on a C18:1-rich diet showed increased mating performance compared with flies raised on standard adult diet. Therefore, both larval and adult desat1 expression control sex-specific mating signals. A similar nutrigenetics approach may be useful in other metabolic mutants to uncover cryptic effects otherwise masked by severe developmental defects. PMID- 26759367 TI - Impact of the Egg Parasitoid, Gryon pennsylvanicum (Hymenoptera: Scelionidae), on Sentinel and Wild Egg Masses of the Squash Bug (Hemiptera: Coreidae) in Maryland. AB - Seasonal changes in egg parasitism and predation rates on sentinel (laboratory reared) and wild (naturally occurring) egg masses of the squash bug, Anasa tristis (De Geer), were evaluated in squash fields in Maryland from June through September in 2013 and 2014. Rates of egg parasitism were significantly higher on wild egg masses than on sentinel egg masses. Squash bug nymphal emergence was significantly higher on sentinel egg masses than on wild egg masses. Between the first week of July and the first week of September of both survey years, squash bug nymphs emerged from 24.2% of wild eggs compared with 46.2% of sentinel eggs and parasitoids emerged from 55.7% of wild eggs compared with only 21.8% of sentinel eggs. Sentinel egg masses significantly underestimated the rate of natural egg parasitism. The egg parasitoid, Gryon pennsylvanicum (Ashmead), was responsible for over 99% of parasitism of squash bug eggs. There was a significant negative correlation between parasitoid emergence and nymphal emergence, suggesting that parasitoids were able to suppress squash bug populations. The average rate of parasitoid emergence peaked on wild egg masses on the fifth week of July at 72.8%, whereas the average rate of nymphal emergence from wild egg masses was <20% from the fifth week of July until the first week of September. These results demonstrate that G. pennsylvanicum was able to efficiently track wild squash bug eggs throughout the season and that it has the potential to be an effective biological control agent of the squash bug in Maryland. PMID- 26759370 TI - Plasma Thrombin Generation and Sensitivity to Activated Protein C Among Patients With Myeloma and Monoclonal Gammopathy of Undetermined Significance. AB - The etiology of the prothrombotic state in myeloma has yet to be definitively characterized. Similarly, while recent evidence suggests that patients with monoclonal gammopathy of undetermined significance (MGUS) may also be at increased risk of thrombosis, the magnitude and the etiology of this risk have also yet to be defined. The present study aims to characterize patterns of plasma thrombin generation and sensitivity to the anticoagulant activity of activated protein C (APC) at the time of initial diagnosis of myeloma and in response to therapy in comparison to that observed among patients with MGUS and matched, healthy volunteers. Patients presenting with newly diagnosed/newly relapsed myeloma (n = 8), MGUS (n = 8), and matched healthy volunteers (n = 8) were recruited. Plasma thrombin generation was determined by calibrated automated thrombography. Peak thrombin generation was significantly higher in patients with myeloma (383.4 +/- 33.4 nmol/L) and MGUS (353.4 +/- 16.5 nmol/L) compared to healthy volunteers (276.7 +/- 20.8 nmol/L; P < .05). In the presence of APC, endogenous thrombin potential was significantly lower in control plasma (228.6 +/ 44.5 nmol/L * min) than in either myeloma (866.2 +/- 241.3 nmol/L * min, P = .01) or MGUS plasma (627 +/- 91.5 nmol/L * min, P = .003). Within the myeloma cohort, peak thrombin generation was significantly higher at diagnosis (353.2 +/- 15.9 nmol/L) than following completion of the third cycle of therapy (282.1 +/- 15.2 nmol/L; P < .005). Moreover, sensitivity to APC increased progressively with each cycle of chemotherapy. Further study of the etiology and evolving patterns of hypercoagulability among patients with these conditions is warranted and may have future implications for thromboprophylaxis strategies. PMID- 26759368 TI - Versatile strategy for controlling the specificity and activity of engineered T cells. AB - The adoptive transfer of autologous T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a promising cancer therapy. Despite impressive clinical efficacy, the general application of current CAR-T--cell therapy is limited by serious treatment-related toxicities. One approach to improve the safety of CAR-T cells involves making their activation and proliferation dependent upon adaptor molecules that mediate formation of the immunological synapse between the target cancer cell and T-cell. Here, we describe the design and synthesis of structurally defined semisynthetic adaptors we refer to as "switch" molecules, in which anti-CD19 and anti-CD22 antibody fragments are site-specifically modified with FITC using genetically encoded noncanonical amino acids. This approach allows the precise control over the geometry and stoichiometry of complex formation between CD19- or CD22-expressing cancer cells and a "universal" anti-FITC-directed CAR-T cell. Optimization of this CAR-switch combination results in potent, dose-dependent in vivo antitumor activity in xenograft models. The advantage of being able to titrate CAR-T-cell in vivo activity was further evidenced by reduced in vivo toxicity and the elimination of persistent B-cell aplasia in immune-competent mice. The ability to control CAR-T cell and cancer cell interactions using intermediate switch molecules may expand the scope of engineered T-cell therapy to solid tumors, as well as indications beyond cancer therapy. PMID- 26759371 TI - Plasma ADAMTS13, von Willebrand Factor (VWF), and VWF Propeptide Profiles in Patients With Connective Tissue Diseases and Antiphospholipid Syndrome. AB - Thrombotic thrombocytopenic purpura (TTP) frequently develops in patients with connective tissue diseases (CTDs). ADAMTS13 and von Willebrand factor (VWF) are closely related to the onset of TTP. We investigated the roles of ADAMTS13 and VWF in thrombotic events of patients with CTD. ADAMTS13 activity and VWF and VWF propeptide (VWFpp) levels in CTD, primary antiphospholipid antibody syndrome (pAPS), and controls were measured to examine their relationship with thrombosis. ADAMTS13 activity levels were significantly low in the patients with CTD but not in the patients with pAPS. No significant difference in the ADAMTS13 activity levels among the various CTD subgroups was found. The levels of VWF and VWFpp were significantly elevated in the patients with pAPS and CTD compared with that of control groups. Eleven patients with CTD developed TTP, and their ADAMTS13 activity levels were significantly lower than patients having CTD without TTP. However, the ADAMTS13 activity levels showed no difference between the patients having CTD with and without thrombotic events. The VWF antigen levels were significantly high in the patients having CTD with TTP. There were no significant differences in the VWF levels of the patients having CTD with TTP and thrombosis. The VWFpp levels were significantly high in the patients having CTD with TTP and thrombosis. The VWF and VWFpp levels were significantly high in the patients with pAPS. Decreased ADAMTS13 activity and elevated VWF and VWFpp levels were observed in patients with CTD. These abnormalities in patients with CTD may represent the increased risk of thrombosis in CTD. PMID- 26759372 TI - Prognostic Value of Treatment Setting in Patients With Cancer Having Pulmonary Embolism: Comparison With the Pulmonary Embolism Severity Index. AB - BACKGROUND: Active cancer is a poor prognostic factor for survival after pulmonary embolism (PE). This retrospective cohort study was performed to investigate how accurately the pulmonary embolism severity index (PESI) predicts 30-day mortality in patients with active cancer. Whether the treatment setting (palliative vs curative) could predict mortality in these patients was also investigated. METHODS: All consecutive patients with active cancer and PE who visited the emergency department of Asan Medical Center in January 2007 to June 2014 were identified. The covariates for predicting 30-day mortality were PESI classification, treatment setting (curative vs palliative), brain natriuretic peptide >= 150 ng/L, troponin I >= 0.10 ng/mL, right ventricular dysfunction, deep vein thrombosis, and anticoagulants used. Cox proportional hazards regression analysis was used to assess the association between treatment setting and 30-day mortality. RESULTS: The PESI classification and 30-day mortality did not associate significantly. Area under the receiver-operating curve of the PESI was 0.565 (95% confidence interval [CI]: 0.453-0.677). Palliative treatment setting associated with an increased risk of 30-day mortality, regardless of the PESI classification (adjusted hazard ratio: 3.72, 95% CI: 1.49-9.26). Treatment setting predicted mortality 30 days, 3 months, and 6 months after PE presentation better than PESI. CONCLUSION: The PESI did not accurately predict mortality in patients with active cancer. Treatment setting was the most important determinant of clinical outcome in these patients. When stratifying patients with active cancer and PE, palliative treatment setting should be considered as it is predictive of high mortality. PMID- 26759373 TI - The Relationship Between Lymphocyte-to-Monocyte Ratio and Bare-Metal Stent In Stent Restenosis in Patients With Stable Coronary Artery Disease. AB - In-stent restenosis (ISR) is a common clinical problem in patients with coronary artery disease treated with percutaneous coronary intervention. Inflammatory process plays a pivotal role in the development of ISR. Both lymphocytes and monocytes are associated with inflammatory status. Recently, it has been shown that the lymphocyte-to-monocyte ratio (LMR) is a novel inflammatory marker. We aimed to investigate the association of serum LMR levels and ISR in patients undergoing bare-metal stent (BMS) implantation. The study included 273 patients (aged 61 +/- 11 years, 66.5% men) with a history of BMS implantation and a further control coronary angiography due to stable angina pectoris. Patients were divided into 2 groups: patients with and without ISR. The LMR levels were significantly lower in patients with ISR than in those without ISR (2.50 +/- 0.95 vs 3.87 +/- 1.51, respectively, P < .001). On multivariate logistic regression analysis, the LMR was independently associated with ISR (odds ratio [OR]: 0.310, 95% confidence interval: 0.166-0.579, P < .001) together with high-sensitivity C reactive protein (OR: 1.244, P = .008), reason for stent implantation (OR: 6.566, P = .003), stent diameter (OR: 0.015, P < .001), and stent length (OR: 1.137, P = .007). In conclusion, LMR levels are inversely related to ISR in patients treated with BMS implantation. PMID- 26759375 TI - Computerised cognitive behaviour therapy (cCBT) as treatment for depression in primary care (REEACT trial): large scale pragmatic randomised controlled trial. PMID- 26759374 TI - Higher CHA2DS2-VASc Score Is Associated With Increased Mortality in Acute Pulmonary Embolism. AB - BACKGROUND: CHA2DS2-VASc score has been validated in risk prediction for stroke and thromboembolism in patients with atrial fibrillation (AF). Association of CHA2DS2-VASc score with higher risk of venous thromboembolism and pulmonary embolism (PE) has also been shown. In this study, we investigated the long-term prognostic value of CHA2DS2-VASc score in patients with acute pulmonary embolism (APE). METHODS: Consecutive patients with APE presenting to our emergency department were retrospectively recruited. Patients with AF and who died secondary to causes other than PE were excluded from the study. The CHA2DS2-VASc score and pulmonary embolism severity index (PESI) were calculated. RESULTS: Two hundred seventy seven participants were included in the study. The mortality rate was 18.7%. Twenty-two cases died within 30 days, and 30 cases died during the follow-up period (median: 13 months). The mean CHA2DS2-VASc score was significantly higher in dead patients compared to survivors (3.61 +/- 1.35 vs 1.95 +/- 1.52, P < .01). In multivariate regression analysis, systolic pulmonary artery pressure (hazard ratio [HR]: 1.03, 95% confidence interval [CI]: 1.01 1.06, P = .02), PESI score (HR: 1.010, 95% CI: 1.004-1.017, P < .01), and CHA2DS2 VASc score (HR: 1.67, 95% CI: 1.19-2.16, P < .01) were found to be independently correlated with mortality. The patients whose CHA2DS2-VASc score was between 1 and 3 had 5.67 times and patients whose CHA2DS2-VASc score was >=4 had 16.8 times higher risk of mortality compared to patients with CHA2DS2-VASc score = 0. CONCLUSION: Patients with higher CHA2DS2-VASc scores had higher rates of mortality after APE. PMID- 26759376 TI - An essential role for functional lysosomes in ferroptosis of cancer cells. AB - Pharmacological challenges to oncogenic Ras-expressing cancer cells have shown a novel type of cell death, ferroptosis, which requires intracellular iron. In the present study, we assessed ferroptosis following treatment of human fibrosarcoma HT1080 cells with several inhibitors of lysosomal activity and found that they prevented cell death induced by the ferroptosis-inducing compounds erastin and RSL3. Fluorescent analyses with a reactive oxygen species (ROS) sensor revealed constitutive generation of ROS in lysosomes, and treatment with lysosome inhibitors decreased both lysosomal ROS and a ferroptotic cell-death-associated ROS burst. These inhibitors partially prevented intracellular iron provision by attenuating intracellular transport of transferrin or autophagic degradation of ferritin. Furthermore, analyses with a fluorescent sensor that detects oxidative changes in cell membranes revealed that formation of lipid ROS in perinuclear compartments probably represented an early event in ferroptosis. These results suggest that lysosomal activity is involved in lipid ROS-mediated ferroptotic cell death through regulation of cellular iron equilibria and ROS generation. PMID- 26759369 TI - Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies. AB - Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive results in clinical trials for B-cell malignancies. However, safety concerns related to the inability to control CAR-T cells once infused into the patient remain a significant challenge. Here we report the engineering of recombinant antibody based bifunctional switches that consist of a tumor antigen-specific Fab molecule engrafted with a peptide neo-epitope, which is bound exclusively by a peptide specific switchable CAR-T cell (sCAR-T). The switch redirects the activity of the bio-orthogonal sCAR-T cells through the selective formation of immunological synapses, in which the sCAR-T cell, switch, and target cell interact in a structurally defined and temporally controlled manner. Optimized switches specific for CD19 controlled the activity, tissue-homing, cytokine release, and phenotype of sCAR-T cells in a dose-titratable manner in a Nalm-6 xenograft rodent model of B-cell leukemia. The sCAR-T-cell dosing regimen could be tuned to provide efficacy comparable to the corresponding conventional CART-19, but with lower cytokine levels, thereby offering a method of mitigating cytokine release syndrome in clinical translation. Furthermore, we demonstrate that this methodology is readily adaptable to targeting CD20 on cancer cells using the same sCAR-T cell, suggesting that this approach may be broadly applicable to heterogeneous and resistant tumor populations, as well as other liquid and solid tumor antigens. PMID- 26759377 TI - HSF-1 is involved in regulation of ascaroside pheromone biosynthesis by heat stress in Caenorhabditis elegans. AB - The nematode worm Caenorhabditis elegans survives by adapting to environmental stresses such as temperature extremes by increasing the concentrations of ascaroside pheromones, termed ascarosides or daumones, which signal early C. elegans larvae to enter a non-aging dauer state for long-term survival. It is well known that production of ascarosides is stimulated by heat stress, resulting in enhanced dauer formation by which worms can adapt to environmental insults. However, the molecular mechanism by which ascaroside pheromone biosynthesis is stimulated by heat stress remains largely unknown. In the present study, we show that the heat-shock transcription factor HSF-1 can mediate enhanced ascaroside pheromone biosynthesis in response to heat stress by activating the peroxisomal fatty acid beta-oxidation genes in C. elegans. To explore the potential molecular mechanisms, we examined the four major genes involved in the ascaroside biosynthesis pathway and then quantified the changes in both the expression of these genes and ascaroside production under heat-stress conditions. The transcriptional activation of ascaroside pheromone biosynthesis genes by HSF-1 was quite notable, which is not only supported by chromatin immunoprecipitation assays, but also accompanied by the enhanced production of chemically detectable major ascarosides (e.g. daumones 1 and 3). Consequently, the dauer formation rate was significantly increased by the ascaroside pheromone extracts from N2 wild type but not from hsf-1(sy441) mutant animals grown under heat-stress conditions. Hence heat-stress-enhanced ascaroside production appears to be mediated at least in part by HSF-1, which seems to be important in adaptation strategies for coping with heat stress in this nematode. PMID- 26759378 TI - The mammalian homologue of yeast Afg1 ATPase (lactation elevated 1) mediates degradation of nuclear-encoded complex IV subunits. AB - Mitochondrial protein homeostasis is crucial for cellular function and integrity and is therefore maintained by several classes of proteins possessing chaperone and/or proteolytic activities. In the present study, we focused on characterization of LACE1 (lactation elevated 1) function in mitochondrial protein homeostasis. LACE1 is the human homologue of yeast mitochondrial Afg1 (ATPase family gene 1) ATPase, a member of the SEC18-NSF, PAS1, CDC48-VCP, TBP family. Yeast Afg1 was shown to mediate degradation of mitochondrially encoded complex IV subunits, and, on the basis of its similarity to CDC48 (p97/VCP), it was suggested to facilitate extraction of polytopic membrane proteins. We show that LACE1, which is a mitochondrial integral membrane protein, exists as part of three complexes of approximately 140, 400 and 500 kDa and is essential for maintenance of fused mitochondrial reticulum and lamellar cristae morphology. We demonstrate that LACE1 mediates degradation of nuclear-encoded complex IV subunits COX4 (cytochrome c oxidase 4), COX5A and COX6A, and is required for normal activity of complexes III and IV of the respiratory chain. Using affinity purification of LACE1-FLAG expressed in a LACE1-knockdown background, we show that the protein interacts physically with COX4 and COX5A subunits of complex IV and with mitochondrial inner-membrane protease YME1L. Finally, we demonstrate by ectopic expression of both K142A Walker A and E214Q Walker B mutants, that an intact ATPase domain is essential for LACE1-mediated degradation of nuclear encoded complex IV subunits. Thus the present study establishes LACE1 as a novel factor with a crucial role in mitochondrial protein homeostasis. PMID- 26759385 TI - Web of causation and its implications for epidemiological research. PMID- 26759379 TI - Epithelial-mesenchymal transition, IP3 receptors and ER-PM junctions: translocation of Ca2+ signalling complexes and regulation of migration. AB - Disconnection of a cell from its epithelial neighbours and the formation of a mesenchymal phenotype are associated with profound changes in the distribution of cellular components and the formation of new cellular polarity. We observed a dramatic redistribution of inositol trisphosphate receptors (IP3Rs) and stromal interaction molecule 1 (STIM1)-competent endoplasmic reticulum-plasma membrane junctions (ER-PM junctions) when pancreatic ductal adenocarcinoma (PDAC) cells disconnect from their neighbours and undergo individual migration. In cellular monolayers IP3Rs are juxtaposed with tight junctions. When individual cells migrate away from their neighbours IP3Rs preferentially accumulate at the leading edge where they surround focal adhesions. Uncaging of inositol trisphosphate (IP3) resulted in prominent accumulation of paxillin in focal adhesions, highlighting important functional implications of the observed novel structural relationships. ER-PM junctions and STIM1 proteins also migrate to the leading edge and position closely behind the IP3Rs, creating a stratified distribution of Ca(2+) signalling complexes in this region. Importantly, migration of PDAC cells was strongly suppressed by selective inhibition of IP3Rs and store-operated Ca(2+) entry (SOCE), indicating that these mechanisms are functionally required for migration. PMID- 26759383 TI - miRNA-148b regulates radioresistance in non-small lung cancer cells via regulation of MutL homologue 1. AB - Radioresistance represents a major obstacle in cancer treatment, the underlying mechanism of which is complex and not well understood. miR-148b has been reported to be implicated regulating radioresistance in lymphoma cells. However, this function has not been investigated in lung cancer cells. Microarray analysis was performed in A549 cells 48 h after exposure to 8 Gy of gamma-irradiation or sham irradiation to identify differentially expressed miRNAs. miR-148b mimic and inhibitor were transfected, followed by clonogenic survival assay to examine response to irradiation in A549 cells. Western Blot and luciferase assay were performed to investigate the direct target of miR-148b Xenograft mouse models were used to examine in vivo function of miR-148b Our data showed that expression of miR-148b was significantly down-regulated in both serum and cancerous tissues of radioresistant lung cancer patients compared with radiosensitive patients. Overexpression of miR-148b reversed radioresistance in A549 cells. MutL homologue 1 (MLH1) is the direct target of miR-148b which is required for the regulatory role of miR-148b in radioresistance. miR-148b mimic sensitized A549 xenografts to irradiation in vivo Our study demonstrated that miR-148b regulates radioresistance of lung cancer cells by modulating MLH1 expression level. miR 148b may represent a new therapeutic target for the intervention of lung cancer. PMID- 26759386 TI - New stories on protein modification. PMID- 26759384 TI - Human fallopian tube proteome shows high coverage of mesenchymal stem cells associated proteins. AB - The object of this research was to report a draft proteome of human fallopian tube (hFT) comprises 5416 identified proteins, which could be considered as a physiological reference to complement Human Proteome Draft. The proteomic raw data and metadata were stored in an integrated proteome resources centre iProX (IPX00034300). This hFT proteome contains many hFT markers newly identified by mass spectrum. This hFT proteome comprises 660 high-, 3605 medium- and 1181 low abundant proteins. Ribosome, cytoskeleton, vesicle and protein folding associated proteins showed obvious tendency to be higher abundance in hFT. The extraordinary high coverage of mesenchymal stem cells (MSCs)-associated proteins were identified in this hFT proteome, which highly supported that hFT should contain a plenty of MSCs. PMID- 26759387 TI - Feasibility of 24-Hr Urine Collection for Measurement of Biomarkers in Community Dwelling Older Adults. AB - Biologic markers are becoming a key part of gerontological research, including their measurement at multiple intervals to detect changes over time. This report examined the feasibility and quality of 24-hr urine collection to measure neuroendocrine biomarkers in a community-based sample of older caregivers and non caregivers. At each interview, participants were instructed on the correct method to collect and store the sample. As incentives, participants selected a day for urine collection within 5 days of the interview, received a reimbursement, and study staff travelled to their home to retrieve the specimen. Between 2008 and 2013, 256 participants were enrolled; all but two participants (99%) provided a baseline urine specimen, of which 93% were considered adequate. Urine collection and quality remained high over three annual follow-up interviews and did not vary by caregiver status or perceived stress level. Our results indicate that 24-hr urine collection is feasible in active, community-dwelling older adults. PMID- 26759388 TI - Interface Pressure Behavior During Painful Cuff Algometry. AB - OBJECTIVE: Cuff algometry is used for the psychophysical assessment of deep tissue pain sensitivity. The cuff pressure homogeneity may affect the pain sensitivity assessment and potentially be improved by alternative cuff designs optimizing the pressure distribution. The aim of this study was to investigate the relationship between pain sensitivity, inflation pressure, and distribution of interface pressure between the skin and cuff during stimulation with a conventional air tourniquet and a novel tourniquet including a water tube interfacing the air cuff with the skin. METHODS: Air and water cuff stimulations were applied separately on the right lower leg of 12 subjects until the tolerance pain threshold. The inflation pressure was controlled and recorded by a computer control program, while the interface pressure distribution was measured by a flexible pressure sensor mat located between the cuff and skin. RESULTS: The mean interface pressure across the entire stimulation surface was not significantly different from inflating pressure during air-cuff algometry. For the water cuff there was a significant reduction in the mean interface pressure compared with the inflating pressure at both the detection and tolerance pain levels (P < 0.002). The interface pressure distribution of the water cuff around the limb was significantly more homogeneous compared with the air cuff (P < 0.03). This homogeneity showed a significant correlation with pain sensitivity (P < 0.008). CONCLUSION: Cuff systems with a liquid medium optimize the homogeneity of the interface pressure distribution. However, the deviation of the interface pressure from the inflating pressure is crucial as it counteracts the effects of pressure homogeneity on pain sensitivity in water-cuff algometry. PMID- 26759390 TI - Functionalized graphene oxide-based thermosensitive hydrogel for near-infrared chemo-photothermal therapy on tumor. AB - PURPOSE: A functionalized graphene oxide-based thermosensitive hydrogel loaded with docetaxel for intratumoral delivery was designed to enhance therapeutic efficacy and alleviate system toxicity. METHODS: First, graphene oxide was functionalized with chitosan to acquire high stability in physiological solutions. And then docetaxel-graphene oxide/chitosan gel was formed by mixed docetaxel-graphene oxide/chitosan suspension with hydrogel which was made from Poloxamer 407 and Poloxamer 188. Cellular uptake, antitumor effect in vitro and in vivo, cell apoptosis, and biodistribution of docetaxel-graphene oxide/chitosan gel were investigated, compared with the docetaxel solution. RESULTS: Graphene oxide/chitosan was stable in physiological solution, and docetaxel released much slower from docetaxel-graphene oxide/chitosan gel with a pH-responsive feature. Compared with free docetaxel, docetaxel-graphene oxide/chitosan could afford higher antitumor efficacy in Michigan Cancer Foundation-7 (MCF-7) cells in vitro. Furthermore, docetaxel-grapheme oxide/chitosan gel which was injected within tumor could afford higher concentration and longer resident time in tumor tissues of mice in vivo, without obvious toxic effects to normal organs. Meanwhile, the combination of near-infrared laser irradiation at 808 nm significantly enhanced tumor inhibition in vitro and in vivo. CONCLUSIONS: Docetaxel-graphene oxide/chitosan gel in combination with 808 nm near-infrared laser irradiation had great potential for cancer chemo-photothermal therapy. PMID- 26759389 TI - You Present like a Drug Addict: Patient and Clinician Perspectives on Trust and Trustworthiness in Chronic Pain Management. AB - OBJECTIVE: Past research has demonstrated that trust is central to an effective therapeutic relationship, but the role of trust in chronic pain management is not well understood. The objective of this study was to provide an in-depth examination of how adults living with chronic pain negotiate trust and demonstrate trustworthiness with clinicians in therapeutic encounters. METHODS: This qualitative study focused on adults living in an urban setting in British Columbia, Canada. Semi-structured interviews (N = 27) were conducted with participants with chronic low back pain. The results were triangulated by two feedback groups comprising re-contacted interview participants (n = 4) and physicians with expertise in pain and addiction management (n = 6). RESULTS: Grounded theory analysis of the adult patient interviews and feedback groups yielded four major themes: 1) threats to trustworthiness and iatrogenic suffering; 2) communicating the invisible and subjective condition of chronic pain; 3) motive, honesty, and testimony; and 4) stigmatized identities. The following two themes emerged from the analysis of the physician feedback group: 1) challenges of the practice context, and 2) complicated clinical relationships. CONCLUSIONS: We found that perceived trustworthiness is important in therapeutic encounters as it helps to negotiate tensions with respect to subjective pain symptoms, addiction, and prescription opioid use. An attitude of epistemic humility may help both clinicians and patients cultivate a trustworthy clinical environment, manage the challenges associated with uncertain testimony, place trust wisely, and promote optimal pain care. PMID- 26759391 TI - Novel mitochondrial complex I inhibitors restore glucose-handling abilities of high-fat fed mice. AB - Metformin is the main drug of choice for treating type 2 diabetes, yet the therapeutic regimens and side effects of the compound are all undesirable and can lead to reduced compliance. The aim of this study was to elucidate the mechanism of action of two novel compounds which improved glucose handling and weight gain in mice on a high-fat diet. Wildtype C57Bl/6 male mice were fed on a high-fat diet and treated with novel, anti-diabetic compounds. Both compounds restored the glucose handling ability of these mice. At a cellular level, these compounds achieve this by inhibiting complex I activity in mitochondria, leading to AMP activated protein kinase activation and subsequent increased glucose uptake by the cells, as measured in the mouse C2C12 muscle cell line. Based on the inhibition of NADH dehydrogenase (IC50 27umolL(-1)), one of these compounds is close to a thousand fold more potent than metformin. There are no indications of off target effects. The compounds have the potential to have a greater anti diabetic effect at a lower dose than metformin and may represent a new anti diabetic compound class. The mechanism of action appears not to be as an insulin sensitizer but rather as an insulin substitute. PMID- 26759392 TI - 60 YEARS OF POMC: N-terminal POMC peptides and adrenal growth. AB - The peptide hormones contained within the sequence of proopiomelanocortin (POMC) have diverse roles ranging from pigmentation to regulation of adrenal function to control of our appetite. It is generally acknowledged to be the archetypal hormone precursor, and as its biology has been unravelled, so too have many of the basic principles of hormone biosynthesis and processing. This short review focuses on one group of its peptide products, namely, those derived from the N terminal of POMC and their role in the regulation of adrenal growth. From a historical and a personal perspective, it describes how their role in regulating proliferation of the adrenal cortex was identified and also highlights the key questions that remain to be answered. PMID- 26759393 TI - Kaposi's sarcoma presenting as violaceous macules on the chest of a kidney transplanted patient. AB - Organ transplant recipients have a high incidence of cancer associated with persistent viral infections, such as human herpes virus 8. This virus is associated with Kaposi's sarcoma, and a change in the dose or type of immunosuppression regimen should be the first step in its treatment. A multidisciplinary approach with nephrologists, dermatologists and oncologists is necessary for the management of this disease. We report a clinical case with atypical presentation and discuss the treatment options. PMID- 26759394 TI - Unusual case of HIV with Kaposi sarcoma and neuroendocrine tumour. PMID- 26759395 TI - An avulsion fracture of the calcaneal tuberosity: delay of treatment causes the 'Achilles heel' of optimal recovery. AB - A 72-year-old woman was diagnosed with an avulsion fracture of the tuberosity of the calcaneus. The fracture was planned for elective fixation 12 days after the accident. The planned open reduction and internal fixation was not possible due to a decubital wound on the Achilles heel as a result of pressure on the skin of the fractured tuberosity. Closed reduction and internal fixation was performed, leading to an acceptable outcome. Avulsion fractures of the tuberosity of the calcaneus are rare injuries, and delay in treatment should be avoided as it may lead to preventable complications. PMID- 26759396 TI - Benign cylindroma: a rare differential diagnosis of external ear canal tumour. AB - Cylindromas are rare adnexal skin tumours that usually occur in the head and neck area. This article reports a case of benign cylindroma arising in the external auditory canal. A 75-year-old man presented with a 3-month history of right aural fullness; no other symptoms were reported. Ear microscopy examination revealed a skin mass on the floor of the external ear canal. Alpha CT scan of the skull showed a well-circumscribed soft tissue mass, with no signs of underlying cortical bone erosion. Tumour resection through an endaural approach was performed. Histological examination revealed a benign cylindroma with margins free of tumour, so that no further treatment was necessary. 8 months after surgery the patient is asymptomatic with normal findings in the ear microscopy examination. Benign cylindroma has a high recurrence rate and can undergo malignant transformation. Therefore, complete surgical removal and close follow up are of great importance. PMID- 26759397 TI - Rare case of Mirizzi syndrome associated with cholecystogastric fistula. AB - A woman in her mid-30s presented with upper right quadrant abdominal pain. On examination, there was mild upper right quadrant tenderness and negative Murphy's sign. Basic laboratory investigations revealed normal results except for elevated alkaline phosphatase. Subsequent imaging revealed chronic calculous cholecystitis and the dilated common bile duct harbouring stones, with pneumobilia. The patient underwent open cholecystectomy with common bile duct exploration. Intraoperatively, the gallbladder was found contracted, and densely adherent to and fistulising with the common bile duct and stomach. PMID- 26759398 TI - Scaphoid non-union in osteogenesis imperfecta. AB - We report a case of scaphoid non-union in a child with osteogenesis imperfecta (OI) presenting 7 months after a fall. Following diagnosis, conservative treatment was initiated, but despite 4 months in a plaster cast, the fracture had failed to unite. Open reduction and internal fixation was performed (Acutrak screw) with bone graft harvested from the distal radius. Postoperative immobilisation continued for 10 weeks, and at 4 months the child was pain free and had resumed normal activities. The fracture had fully united radiologically at 9 months. Non-union is reported to occur in 23% of paediatric scaphoid fractures when treatment is delayed, and conservative and surgical treatment have both been described. Since OI increases the risk of non-union in long bone fractures, the scaphoid may also be at risk. We recommend a high level of suspicion for non-union in this patient group and a low threshold for consideration of surgical treatment. PMID- 26759399 TI - Macular infarction in a patient with Toxoplasma retinochoroditis. AB - Toxoplasma retinochoroditis is one of the commonest causes of infectious posterior uveitis and may lead to occlusive retinitis. We present a case of a patient with Toxoplasma retinochoroditis who developed macular infarction after initial improvement on pharmacotherapy. The potential aetiology and outcome are described. PMID- 26759400 TI - A rare presentation of bilateral spontaneous superficial femoral arteriovenous fistulas. AB - Spontaneous arteriovenous fistulas are a rare clinical entity with very few cases reported in the literature. Prompt diagnosis and treatment is crucial and can prevent further complications in such patients. We report a case of a patient who presented with progressive bilateral claudication, discolouration of feet, hypaesthesia and non-healing ulcers. The patient had no history of trauma, aneurysm or surgery. After abnormal non-invasive studies, a peripheral angiogram revealed significant disease and obstruction of bilateral superficial femoral arteries. Spontaneous bilateral femoral arteriovenous fistulas were also found incidentally. After discussing the risks and benefits of multiple treatment options with the patient, percutaneous intervention with orbital atherectomy, balloon angioplasty and covered stent placements were performed. This treatment improved the patient's symptoms significantly. PMID- 26759401 TI - Myxoedema coma in the setting of hyperglycaemic hyperosmolar state. AB - Decompensated hypothyroidism is a rare endocrine emergency but a differential that should be considered in patients presenting critically unwell with systemic illness. We report a case of myxoedema coma in a woman presenting with respiratory failure, hypotension, hypothermia and a reduced level of consciousness, all of which are poor prognostic features in decompensated hypothyroidism. The patient was admitted to critical care for mechanical ventilation and cardiovascular support and treated with a combination of insulin, liothyronine and levothyroxine, making a good recovery. We wanted to highlight this case of myxoedema coma occurring in the context of a hyperglycaemic hyperosmolar state (HHS), as the former condition is normally associated with hypoglycaemia, hyponatraemia and hypo-osmolality. Decompensated hypothyroidism should be considered in presentations of HHS as well as with other metabolic derangements, as delays in thyroid hormone replacement are associated with poorer outcomes. It has multisystem effects challenging its recognition and we discuss potential complications and their management. PMID- 26759402 TI - Acute necrotising encephalopathy in a child with H1N1 influenza infection: a clinicoradiological diagnosis and follow-up. AB - Acute necrotising encephalopathy of childhood (ANEC) is a fulminant disorder with rapid progressive encephalopathy, seizures and poor outcome. It has been reported in association with various viral infections. We describe the clinicoradiological findings and short-term follow-up in a child with H1N1 influenza-associated ANEC. Laminar, target or tricolour pattern of involvement of the thalami was seen on apparent diffusion coefficient images. Our patient had significant morbidity at discharge despite early diagnosis and management with oseltamivir and immunoglobulin. Repeat imaging after 3 months had shown significant resolution of thalamic swelling, but there was persistence of cytotoxic oedema involving bilateral thalami. She was pulsed with intravenous steroids and maintained on a tapering schedule of oral steroids. This report emphasises the need for a high index of suspicion to establish early diagnosis, promotion of widespread immunisation strategies to prevent influenza outbreak, and more research to establish standard treatment protocols for this under-recognised entity. PMID- 26759403 TI - To stop or not? Tamoxifen therapy for secondary prevention of breast cancer in a patient with ocular toxicity. AB - We report a case of a patient with treated breast cancer whose dilated fundus examination showed crystalline deposits in the central region of the macula. She was taking tamoxifen for secondary prevention. Optical coherence tomography revealed individual refractile deposits associated with intraretinal cysts in both eyes. Tamoxifen-related retinopathy was suspected. A decision to discontinue treatment with tamoxifen was considered but had to be taken in conjunction with the oncologist. PMID- 26759404 TI - Etanercept-induced myositis: do we have to stop it? A surprising outcome. AB - We discuss a case of a 47-year-old man who presented with progressive proximal muscle weakness of the upper and lower extremities and unstable gait. He had been on etanercept for 6 months for severe psoriasis and psoriatic arthritis with good control of his disease. Serum creatine kinase (CK) level was found to be 5666 U/L and muscle biopsy showed a marked inflammatory myopathic process likely secondary to etanercept. He was started on high-dose steroids and advised to discontinue etanercept. Despite our recommendation, he never stopped using etanercept due to fear of a psoriasis flare. Three months later, he had significant improvement of clinical symptoms, normalised serum CK levels and discontinued prednisone. PMID- 26759405 TI - Lymphoedema-distichiasis syndrome. PMID- 26759406 TI - Dermoscopic signs of lichen planus. PMID- 26759407 TI - Bronchial anthracofibrosis with interstitial lung disease: an association yet to be highlighted. AB - Bronchial anthracofibrosis (BAF), an emerging pulmonary disease due to long standing exposure to biomass fuel smoke, is predominantly seen in females from developing nations. BAF is known to be associated with tuberculosis, pneumonia, chronic obstructive pulmonary disease and lung cancer, but the association of BAF with interstitial lung disease (ILD) is rare and yet to be highlighted. A 72-year old woman with a 30-year history of exposure to biomass fuel smoke presented with dry cough and exertional dyspnoea. Imaging demonstrated interlobular, intralobular and peribronchovascular interstitial thickening and honeycombing adjoining the subpleural regions, suggestive of the usual interstitial pneumonia pattern. A restrictive pattern with diffusion defect was noted. Fibrebronchoscopy revealed a bluish-black anthracotic pigmentation with a narrowed and distorted left upper lobe, and apical segment of left lower lobe bronchus, confirming BAF. A diagnosis of BAF with ILD was made. To the best of our knowledge, this is the first detailed description of this association. PMID- 26759409 TI - Confronting the Need for Evidence Regarding Prevention. PMID- 26759408 TI - Arabidopsis Mg-Protoporphyrin IX Methyltransferase Activity and Redox Regulation Depend on Conserved Cysteines. AB - Redox regulation is an essential post-translational regulatory mechanism in prokaryotes and eukaryotes. The reversible oxidation and reduction of cysteine residues of proteins is also important in photosynthetic organisms to control enzymatic activities, protein stability and the interaction with other proteins of chloroplast-localized proteins. Several enzymes of the plant tetrapyrrole biosynthesis pathway have been identified to be redox regulated by thioredoxins (TRXs) and NADPH-dependent thioredoxin reductase C (NTRC). Among these proteins, Mg protoporphyrin IX methyltransferase (encoded by CHLM) was identified to be activated and stabilized by interaction with NTRC. CHLM catalyzes a methyl group transfer by using S-adenosylmethionine (SAM). Here we demonstrate that three conserved cysteine residues of Arabidopsis CHLM are essential for catalytic function and redox-dependent activation of the enzyme. In vitro and in planta biochemical assays of recombinant CHLM and the Arabidopsis chlm knockout mutant overexpressing wild-type and cysteine substitution mutants of CHLM revealed modified methyltransferase activity, when the conserved cysteine residues of CHLM are replaced by serine. While C177 is responsible for redox-dependent enzyme activation, exchange of the two cysteine residues, C111 and C115, has a strong impact on enzyme activity. The modified CHLM activity of single and double mutants with cysteine substitution is presented, and the role of each cysteine residue is discussed based on a modeled structure of CHLM. These studies contribute to enhanced understanding of the physiological and enzymatic significance of redox-regulated CHLM. PMID- 26759410 TI - Erythema Marginatum as an Early Symptom of Hereditary Angioedema: Case Report of 2 Newborns. AB - Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare genetic disease that causes recurrent swelling attacks that may affect various body tissues. Angioedematous attacks can be fatal in the case of upper airway edema and are often preceded by prodromal symptoms like erythema marginatum. Initial symptoms usually occur in the first decade of life. We report on manifestation of profound and recurrent erythema marginatum in 2 newborns. In both cases, prodromal symptoms could help determine the diagnosis of C1-INH-HAE such that, at a later time, angioedematous attacks could be treated promptly and effectively. Awareness of C1-INH-HAE is low among physicians and even lower among the general public. This report aims at raising the level of awareness and shows that initial symptoms of the potentially life-threatening condition can manifest in newborns and that erythema marginatum can even be present at birth. Recognition of early symptoms and timely diagnosis of the disease along with adequate education of the pediatrician and parents are a prerequisite for prompt and effective treatment of attacks and the successful management of the disease. PMID- 26759412 TI - Editorial. PMID- 26759411 TI - Neurodevelopmental Outcomes After Neonatal Surgery for Major Noncardiac Anomalies. AB - CONTEXT: Increasing concerns have been raised about the incidence of neurodevelopmental delay in children with noncardiac congenital anomalies (NCCA) requiring neonatal surgery. OBJECTIVE: This study aimed to determine the incidence and potential risk factors for developmental delay after neonatal surgery for major NCCA. DATA SOURCES: A systematic search in PubMed, Embase and the Cochrane Library was performed through March 2015. STUDY SELECTION: Original research articles on standardized cognitive or motor skills tests. DATA EXTRACTION: Data on neurodevelopmental outcome, the Bayley Scales of Infant Development, and risk factors for delay were extracted. RESULTS: In total, 23 eligible studies were included, reporting on 895 children. Meta-analysis was performed with data of 511 children, assessed by the Bayley Scales of Infant Development at 12 and 24 months of age. Delay in cognitive development was reported in a median of 23% (3%-56%). Meta-analysis showed a cognitive score of 0.5 SD below the population average (Mental Development Index 92 +/- 13, mean +/- SD; P < .001). Motor development was delayed in 25% (0%-77%). Meta-analysis showed a motor score of 0.6 SD below average (Psychomotor Development Index 91 +/ 14; P < .001). Several of these studies report risk factors for psychomotor delay, including low birth weight, a higher number of congenital anomalies, duration of hospital admission, and repeated surgery. LIMITATIONS: All data were retrieved from studies with small sample sizes and various congenital anomalies using different neurodevelopmental assessment tools. CONCLUSIONS: Cognitive and motor developmental delay was found in 23% of patients with NCCA. Meta-analysis showed that the mean neurodevelopmental outcome scores were 0.5 SD below the normative score of the healthy population. PMID- 26759413 TI - Response to letter to the editor. PMID- 26759414 TI - Female genital mutilation. PMID- 26759415 TI - Female sexual dysfunction in female genital mutilation. AB - Female genital mutilation (FGM), otherwise known as female genital cutting (FGC), is currently very topical and has become a significant global political issue. The impact of FGM on the lives of women and girls is enormous, as it often affects both their psychology and physical being. Among the complications that are often under-reported and not always acknowledged is female sexual dysfunction (FSD). FSD presents with a complex of symptoms including lack of libido, arousability and orgasm. This often occurs in tandem with chronic urogenital pain and anatomical disruption due to perineal scarring.To treat FSD in FGM each woman needs specifically directed holistic care, geared to her individual case. This may include psychological support, physiotherapy and, on occasion, reconstructive surgery. In many cases the situation is complicated by symptoms of chronic pelvic pain, which can make treatment increasingly difficult as this issue needs a defined multidisciplinary approach for its effective management in its own right. The problems suffered by women with FGM are wholly preventable, as the practice need not happen. The current global momentum to address the social, cultural, economic and medical issues of FGM is being supported by communities, governments, non-governmental agencies (NGOs) and healthcare providers. It is only by working together that the practice can be abolished and women and girls may be free from this practice and its associated consequences. PMID- 26759416 TI - Research on help-seeking for mental illness in Africa: Dominant approaches and possible alternatives. AB - There is growing concern within the global mental health arena that interventions currently being executed to scale up mental health services in Africa will be ineffective unless simultaneous steps are taken to address people's help-seeking behaviour. Drawing upon two conceptual tools arising from science and technology studies (STS), those of a "classification system" and "the black box," this paper looks critically at discursive constructions of help-seeking in Africa within mental health research over the last decade. Research in this area can be divided into two dominant traditions: the knowledge-belief-practice survey and indigenous knowledge-system approaches. Although the content and value-codes between these approaches differ, structurally they are very similar. Both are mediated by the same kind of system of classification, which demarcates the world into homogenous entities and binary oppositions. This system of ordering is one of the most stubborn and powerful forms of classification buried in the "black box" of the modernist/colonial knowledge archive and is fraught with many questionable Eurocentric epistemological assumptions. I consider whether there might be other ways of understanding help-seeking for mental illness in Africa and discuss two studies that illustrate such alternative approaches. In conclusion, I discuss some of the challenges this alternative kind of research faces in gaining more influence within contemporary global mental health discourse and practice. PMID- 26759417 TI - Bullying Perpetration, Victimization, and Demographic Differences in College Students: A Review of the Literature. AB - Although bullying has been widely recognized as a serious issue in elementary and secondary school and in the workplace, little is known about the prevalence of bullying in postsecondary education. We conducted a comprehensive search of the peer-reviewed literature and found 14 studies that reported the prevalence of bullying perpetration, victimization, or both in college or university students. Prevalence estimates varied widely been studies, but on average about 20-25% of students reported noncyberbullying victimization during college and 10-15% reported cyberbullying victimization. Similarly, approximately 20% of students on average reported perpetrating noncyberbullying during college, with about 5% reporting cyber perpetration. Men were more likely to report perpetration, but no consistent gender differences in victimization were found. Few studies reported prevalence by sexual orientation or race/ethnicity, and none reported prevalence by disability status. Overall, these results indicate that bullying continues to be prevalent in postsecondary education, but more research needs to be conducted, particularly that which uses multiuniversity samples and examines demographic differences in prevalence rates. PMID- 26759418 TI - Relationship of Circulating C5a and Complement Factor H Levels With Disease Control in Pregnant Women With Asthma. AB - BACKGROUND: Asthma often complicates pregnancy and represents a risk of serious pregnancy complications. The complement system contributes to asthma pathogenesis and is up-regulated in healthy gestation as well. The anaphylatoxin C5a has a major pro-inflammatory role, and the complement factor H is a main soluble regulator protein both in asthma and during pregnancy; however, peripheral levels of these complement factors and their relationship to disease control have not yet been evaluated in pregnant subjects with asthma. METHODS: The present study aimed to investigate circulating C5a and complement factor H levels in asthma (non-pregnant subjects with asthma; n = 19) and in pregnancy with asthma (pregnant subjects with asthma; n = 22), compared with healthy non-pregnant (n = 21) and healthy pregnant women (n = 13) and to test their relationship to clinical parameters of asthma (lung function, airway inflammation, and symptoms). RESULTS: Circulating C5a levels were higher in the pregnant asthma subject group compared with the healthy non-pregnant, healthy pregnant, and non-pregnant asthma groups: median 2.629 (interquartile range [IQR] 2.257-3.052) ng/mL versus 1.84 (IQR 1.576-2.563), 1.783 (IQR 0.6064-2.786), and 2.024 (IQR 1.232-2.615) ng/mL, respectively (P = .02 in all cases). C5a correlated negatively with FEV1 (r = 0.44, P = .039) and FVC values (r = -0.64, P = .001) in the pregnant asthma group and positively with fraction of exhaled nitric oxide levels in the non-pregnant asthma group (n = 12, r = 0.78, P = .004). Complement factor H levels were elevated in both the healthy pregnant and pregnant asthma subject groups compared with the healthy non-pregnant group (median 1,082 [IQR 734.9-1,224] and 910.7 [IQR 614.5-1076] MUg/mL vs. 559.7 [IQR 388.7-783.1] MUg/mL, P = .002 and P = .004, respectively) but not in the pregnant asthma group compared with the non pregnant asthma group (median 687.4 [IQR 441.6-947.6] MUg/mL, P = .10). CONCLUSIONS: Asthma during pregnancy increases the circulating level of pro inflammatory C5a, which is accompanied by impaired lung function and partly counteracted by the gestation-specific elevation of regulatory complement factor H level (detected in pregnancy both in healthy and subjects with asthma). PMID- 26759419 TI - The Objective Use of Pulse Oximetry to Predict Respiratory Support Transition in Preterm Infants: An Observational Pilot Study. AB - BACKGROUND: Preterm infants often require some form of respiratory support with supplemental oxygen and are monitored by continuous pulse oximetry (SpO2 ). The study objective was to determine whether the histogram distribution of SpO2 over a 24-h period will predict readiness for weaning respiratory support in preterm infants. We hypothesize that infants with >=15% of time spent with SpO2 <86% before transitioning from CPAP or high-flow nasal cannula (HFNC) to low-flow nasal cannula, oxyhood, or room air are more likely to fail transitioning. METHODS: The SpO2 histograms were downloaded daily for 31 infants, 24-32 weeks gestational age, before transition from CPAP or HFNC to low-flow nasal cannula, oxyhood, or room air. The SpO2 histogram downloads were continued for each infant for 1 week after transition or when the infant reached 36 weeks postmenstrual age or when SpO2 monitoring was discontinued. Failure was defined as an increase in respiratory support within 72 h of transitioning. We compared the percentage of time for each SpO2 quintile for the 24-h periods before and immediately following CPAP/HFNC transitioning between groups. RESULTS: Twenty-four subjects transitioned successfully, but 7 subjects failed. Two of 7 subjects (28.6%) who failed transition experienced SpO2 <86% >=15% of the time pretransition compared with none in the success group (P = .045). The failure group experienced SpO2 <86% 10.7 +/- 11.9% of time pre-wean compared with 3.3 +/- 4.7% of time in the success group (P = .02). In contrast, infants who were successfully weaned tended to experience a greater percentage of time with SpO2 >95% compared with the failure group, both pre-wean (54.3 +/- 36.1% vs. 33 +/- 27.7%, P = .16) and post wean (52 +/- 35.4% vs. 27.4 +/- 27.7%, P = .10). CONCLUSIONS: These data suggest that pulse oximetry histograms may be useful in assessing CPAP/HFNC support transition readiness. PMID- 26759420 TI - Successful Use of Early Percutaneous Dilatational Tracheotomy and the No Sedation Concept in Respiratory Failure in Critically Ill Obese Subjects. AB - BACKGROUND: The prevalence of obesity in developed countries is rising. Currently, Europe has a prevalence of 9-30% with significant impact on public health systems. Obese patients in ICUs require special management and treatment. Altered anatomy in obese patients complicates procedures such as mechanical ventilation. Obesity affects cardiopulmonary physiology and requires elevated ventilation pressures. In our retrospective study, we determined the effect of early percutaneous dilatational tracheotomy (PDT) and cessation of sedation on respiratory parameters in severely obese subjects. METHODS: From June 2010 to July 2014, we included all subjects with a body weight of >130 kg (body mass index >35 kg/m(2)) and respiratory failure who were admitted to the medical ICU of the University Hospital of Munster. All subjects were treated with early PDT and immediate cessation of sedative drugs. We compared ventilator parameters and blood gas analysis before and after PDT. Parameters were recorded on days 0, 1, 3, and 5. Day 0 represents values during ventilation via an endotracheal tube, and days 1, 3, 5 represent values during ventilation via a tracheotomy tube. PDT was performed on day 0 after recording values during ventilation via an endotracheal tube. RESULTS: We included 23 subjects with a mean body mass index of 53.1 kg/m(2) and respiratory failure. After PDT and cessation of sedation, the required ventilation pressures and FIO2 could be rapidly reduced (P < .001), whereas blood gas parameters significantly improved. We observed no severe PDT associated complications in our cohort. CONCLUSIONS: In severe obesity, respiratory failure might be increased by problems in mechanical ventilation due to required high pressures and obesity-induced pulmonary restriction. Rapid tracheotomy with reduction of dead-space ventilation and airway resistance as well as cessation of sedation to enable spontaneous breathing might be a key factor in the therapy of respiratory failure. PMID- 26759421 TI - Impact of Clinical and Quality of Life Outcomes of Long-Stay ICU Survivors Recovering From Rehabilitation on Caregivers' Burden. AB - BACKGROUND: The objective of this work was to evaluate the time course of clinical and health-related quality of life outcomes of long-stay ICU survivors' and caregivers' burden. METHODS: The study included 23 subjects of mixed diagnosis (66 +/- 11 y, body mass index 26.5 +/- 5.6 kg/m(2)) with a recent episode of acute respiratory failure needing in-hospital rehabilitation. Subjects and caregivers were evaluated at hospital discharge (T0, n = 23) and 6 months later (T6, n = 16). At T0 and T6, subjects' clinical status (Dependence Nursing Scale), FVC (percent-of-predicted FVC and percent-of-predicted FEV), maximum inspiratory/expiratory pressures, effort tolerance (sit-to-stand, Takahashi test, 6-min walking distance), and disability (Barthel index) were evaluated. EuroQol 5D (EQ-5D), McGill Quality of Life, General Perceived Self-Efficacy Scale, and Hospital Anxiety and Depression Scale (HADS-A/HADS-D) were assessed. Caregivers' burden was measured by the Family Strain Questionnaire short form and Caregiver Needs Assessment. Correlation between subjects' clinical status and caregiver assessments was performed at T0. RESULTS: At T0, subjects showed compromised EQ 5Dindex (0.42 +/- 0.28); 69% of caregivers had high Family Strain Questionnaire and moderate Caregiver Needs Assessment scores (30 +/- 13). EQ-5Dindex was significantly related to Dependence Nursing Scale score (P < .001), percent-of predicted FVC (P < .02), effort tolerance (all P < .01), disability (P < .001), and caregiver Family Strain Questionnaire score (P < .02). At T6, subjects significantly improved percent-of-predicted FVC (P < .05), maximum expiratory pressure (P < .01), effort tolerance (all P < .05), disability (P < .02), and EQ 5Dindex (P < .05), whereas caregivers' burden scores were unchanged. However, the percentage of caregivers with strain increased. CONCLUSIONS: In prolonged-ICU stay survivors, EQ-5Dindex at hospital discharge is related to clinical status and caregivers' strain. Subjects' clinical status and EQ-5Dindex improves over time, but caregivers' burden remains high, suggesting the need to monitor/support caregivers. PMID- 26759423 TI - Erratum. PMID- 26759422 TI - Serum Telomerase Levels and COPD Exacerbations. AB - BACKGROUND: To our knowledge, there is no study on the level of telomerase in subjects with COPD during an exacerbation period. The objective of this work was to compare lipid peroxidation, telomerase, zinc (Zn), copper (Cu), and malondialdehyde levels in asymptomatic smokers and subjects with COPD exacerbation. METHODS: The study included 45 subjects with COPD exacerbation and 42 healthy subjects with tobacco use as a control group. Samples were taken from blood and after the serum levels of telomerase malondialdehyde, Cu, and Zn were measured, the values were compared between the 2 groups. Tests for respiratory function were performed, and sedimentation and C-reactive protein levels were measured. RESULTS: The COPD exacerbation group had a significantly (P < .001) lower Cu/Zn ratio compared with the control group; however, the COPD exacerbation group had significantly (P < .001) higher levels of telomerase malondialdehyde, Cu, and Zn compared with the control group. Malondialdehyde, Cu, Zn, and FEV1 were found negatively correlated in the COPD exacerbation and control groups (P < .001). The COPD exacerbation group had lower FEV1 and FVC compared with the control group. The COPD exacerbation group had significantly (P < .001) higher levels of C-reactive protein and a higher blood cell sedimentation rate compared with the control group. CONCLUSIONS: The reason why the subjects had a reduced Cu/Zn ratio and increased levels of telomerase, Cu, and Zn is likely to be oxidative stress, which can be defined as an increased exposure to oxidants and/or decreased antioxidant capacities It is obvious from this study that lung oxidant-antioxidant balance is abnormal in subjects with COPD exacerbation and also that the increased level of telomerase is associated with this imbalance. PMID- 26759424 TI - Bacterial Biofilm in Salivary Gland Stones: Cause or Consequence? AB - OBJECTIVE: The pathogenesis of salivary calculi is not yet clear; however, 2 theories have been formulated: (1) "the classic theory," based on calcium microdeposits in serous and ductal acinous cells, successively discharged into the ducts; (2) "the retrograde theory," based on a retrograde migration of food, bacteria, and so on from the oral cavity to the salivary duct. The aim of the present study is to highlight the role of bacteria and biofilm in stone formation. STUDY DESIGN: Case series without comparison. SETTING: Laboratory of the Department of Anatomical Pathology. SUBJECTS AND METHODS: Traditional optic microscopy and scanning electron microscopy were carried out on 15 salivary gland calculi that were collected from 12 patients. A qPCR (quantitative real-time polymerase chain reaction) assay was performed to highlight the presence of bacterial DNA on each stone. RESULTS: Optic microscopy showed formations that-due to their size, shape, and Gram and Giemsa staining-seemed to be Gram-positive bacterial cells. PAS- (periodic acid-Schiff) and alcian-PAS-positive staining matrix was present around them. The ultrastructural observation of the material processed for scanning electron microscopy showed the presence of structures resembling bacterial cells in the middle of the stones, surrounded by soft, amorphous material. Results of qPCR showed the presence of bacterial DNA in the internal part of the tissue sample. CONCLUSIONS: The presence of bacteria and/or bacterial products resembling biofilm in salivary gland stones supports the "retrograde theory." This evidence may support the hypothesis that biofilm could be the causative effect of lithiasic formations. PMID- 26759425 TI - Predicting Surgical Response Using Tensiometry in OSA Patients after Genioglossus Advancement with Uvulopalatopharyngoplasty. AB - OBJECTIVE: To evaluate the role of tension on the genioglossus muscle in the performance of genioglossus advancement on sleep-disordered breathing in patients undergoing multilevel obstructive sleep apnea (OSA) surgery. STUDY DESIGN: Prospective study. SETTING: Academic practice. SUBJECTS AND METHODS: Twenty-three subjects underwent genioglossus advancement with uvulopalatopharyngoplasty for OSA. Subjects underwent pre- and postoperative polysomnography, cephalometry, and subjective assessment questionnaires. Eighteen subjects completed the study. The tension force of the mandible and the bicortical width of the genial tubercle were measured and surgical response determined. RESULTS: Improvement in apnea hypopnea index (AHI) was seen in 15 of 18 subjects (83.3%). Eleven subjects were classified as responders and 7 as nonresponders (61.1% success), with responders exhibiting a statistically significant reduction in mean delta AHI as compared with nonresponders: 28.3 +/- 26.2 versus 2.0 +/- 22.0 events per hour (95% confidence interval, 1.8-50.8; P = .037). The Epworth Sleepiness Scale improved from 13.2 +/- 4.5 to 7.6 +/- 3.4 (P = .002). There was no significant difference in body mass index, neck circumference, overall tension, or mandibular width between responders and nonresponders. However, there was a significant difference in the tension:width ratio between responders (53.9 +/- 6.38 g/mm) and nonresponders (65.4 +/- 11.2 g/mm; 95% confidence interval, 0.92-22.1; P = .036). CONCLUSION: This article describes a novel approach to determine the force applied to the genioglossus during advancement and its correlation to postoperative outcomes. The tension:width ratio may be an indicator for postoperative success and delta AHI improvement in OSA patients. PMID- 26759427 TI - Thirty Years. PMID- 26759426 TI - Variability of Ratings in the Otolaryngology Standardized Letter of Recommendation. AB - OBJECTIVE: To determine the variability of ratings given to students on the otolaryngology standardized letter of recommendation (SLOR). STUDY DESIGN: Retrospective review. SETTING: Academic otolaryngology training program. SUBJECTS AND METHODS: 496 SLORs to the Cleveland Clinic Otolaryngology Training Program were reviewed. The SLORs were extracted from the applications and analyzed. The distributions of ratings across the 10 categories were statistically analyzed including distribution and standard deviation. Rankings were grouped into deciles for this analysis. RESULTS: Ratings across the 10 domains revealed clustering of results across the top 2 deciles. The distribution of the bell-shaped curve was shifted significantly to the left, representing the upper deciles. No evidence of gender or geographic bias was found. Longer length of time of association between the applicant and the letter writer correlated to a higher ranking. CONCLUSION: The explosion of applications being sent out by candidates for otolaryngology residency programs has prompted the implementation of the SLOR. The lack of variation in the ratings across the 10 domains does not allow for differentiation among student applicants. Reliance on the narrative letter of recommendation attached to the SLOR still remains the most significant way to differentiate among applicants. Refinements will need to be made in either the structure or use of the SLOR for it to be a more useful tool. PMID- 26759429 TI - Timothy J. Bartness. PMID- 26759430 TI - Risk of work loss due to illness or disability in patients with osteoarthritis: a population-based cohort study. AB - OBJECTIVES: To estimate the risk of work loss due to illness or disability in a cohort of employed persons with OA compared with matched non-OA individuals. METHODS: We performed a population-based cohort analysis using the last six cycles of the Canadian longitudinal National Population Health Survey from 2000 to 2010. OA cases and up to four age- and sex-matched non-OA individuals were selected. Discrete time hazard regression models were used to estimate the hazard of work loss due to illness or disability. To analyse the effect of a self reported OA measure on the outcome, we performed a sensitivity analyses for case selection. RESULTS: From 7273 employed individuals between the ages of 20 and 70 years in the National Population Health Survey, 659 OA cases were selected and matched to 2144 non-OA individuals. The proportion of OA cases who experienced work loss due to illness or disability during the follow-up period was 12.6%, compared with 9.3% for non-OA individuals (P < 0.001). OA cases had a 90% [hazard ratio (HR) 1.90 (95% CI 1.36, 3.23)] higher hazard of work loss due to illness or disability compared with their matched non-OA individuals after adjusting for sociodemographic, health and work-related status. The adjusted HRs were 1.61 (95% CI 1.13, 2.30) and 2.04 (95% CI 1.74, 4.75) for females and males, respectively. CONCLUSION: OA is independently associated with an increased risk of work loss due to illness or disability. Given the high prevalence of OA in the population of working age, future research may wish to investigate ways to improve occupational participation among OA patients. PMID- 26759431 TI - Ischemic penumbra as a trigger for intracranial pressure rise - A potential cause for collateral failure and infarct progression? AB - We have recently shown that intracranial pressure (ICP) increases dramatically 24 h after minor intraluminal thread occlusion with reperfusion, independent of edema. Some of the largest ICP rises were observed in rats with the smallest final infarcts. A possible alternate mechanism for this ICP rise is an increase of cerebrospinal fluid (CSF) volume secondary to choroid plexus damage (a known complication of the intraluminal stroke model used). Alternatively, submaximal injury may be needed to induce ICP elevation. Therefore, we aimed to determine (a) if choroid plexus damage contributes to the ICP elevation, (b) if varying the patency of an important internal collateral supply to the middle cerebral artery (MCA), the anterior choroidal artery (AChA), produces different volumes of ischemic penumbra and (c) if presence of ischemic penumbra (submaximal injury) is associated with ICP elevation. We found (a) no association between choroid plexus damage and ICP elevation, (b) animals with a good internal collateral supply through the AChA during MCAo had significantly larger penumbra volumes and (c) ICP elevation at ~24 h post-stroke only occurred in rats with submaximal injury, shown in two different stroke models. We conclude that active cellular processes within the ischemic penumbra may be required for edema-independent ICP elevation. PMID- 26759433 TI - Solid recovered fuels in the cement industry--semi-automated sample preparation unit as a means for facilitated practical application. AB - One of the challenges for the cement industry is the quality assurance of alternative fuel (e.g., solid recovered fuel, SRF) in co-incineration plants- especially for inhomogeneous alternative fuels with large particle sizes (d95?100 mm), which will gain even more importance in the substitution of conventional fuels due to low production costs. Existing standards for sampling and sample preparation do not cover the challenges resulting from these kinds of materials. A possible approach to ensure quality monitoring is shown in the present contribution. For this, a specially manufactured, automated comminution and sample divider device was installed at a cement plant in Rohoznik. In order to prove its practical suitability with methods according to current standards, the sampling and sample preparation process were validated for alternative fuel with a grain size >30 mm (i.e., d95=approximately 100 mm), so-called 'Hotdisc SRF'. Therefore, series of samples were taken and analysed. A comparison of the analysis results with the yearly average values obtained through a reference investigation route showed good accordance. Further investigations during the validation process also showed that segregation or enrichment of material throughout the comminution plant does not occur. The results also demonstrate that compliance with legal standards regarding the minimum sample amount is not sufficient for inhomogeneous and coarse particle size alternative fuels. Instead, higher sample amounts after the first particle size reduction step are strongly recommended in order to gain a representative laboratory sample. PMID- 26759432 TI - Impact of age on cerebrovascular dilation versus reactivity to hypercapnia. AB - This study quantified the effect of age on cerebrovascular reactivity and cerebrovascular conductance while accounting for differences in grey matter volume in younger (YA: n = 12; 24 +/- 4 years, six females) and older adults (OA: n = 10; 66 +/- 7 years; five females). Cerebral blood flow velocity (CBFV; transcranial Doppler) in the middle cerebral artery (MCA), MCA cross-sectional area (CSA), intracranial volumes (magnetic resonance imaging), and mean arterial pressure (MAP; Finometer), were measured under normocapnic and hypercapnic (6% carbon dioxide) conditions. Cerebral blood flow (CBF) was quantified from CBFV and MCA CSA and normalized to grey matter volume. Grey matter volume was 719 +/- 98 mL in YA and 622 +/- 50 mL in OA (P = 0.009). Cerebrovascular reactivity (%DeltaCBF/DeltaPETCO2) was not different between YA and OA. In contrast, cerebrovascular conductance (CBF/MAP) in response to hypercapnia was reduced in OA (P = 0.02). Of note, MAP increased more with hypercapnia in OA compared with YA. Therefore, the central hemodynamic response to hypercapnia compensated for a diminished dilatory response downstream from the MCA so that the CBF response to hypercapnia per unit of brain mass was not affected by age. This impairment was not detected by traditional measures of cerebrovascular reactivity. PMID- 26759434 TI - Seismic characterization and dynamic site response of a municipal solid waste landfill in Bangalore, India. AB - Seismic design of landfills requires an understanding of the dynamic properties of municipal solid waste (MSW) and the dynamic site response of landfill waste during seismic events. The dynamic response of the Mavallipura landfill situated in Bangalore, India, is investigated using field measurements, laboratory studies and recorded ground motions from the intraplate region. The dynamic shear modulus values for the MSW were established on the basis of field measurements of shear wave velocities. Cyclic triaxial testing was performed on reconstituted MSW samples and the shear modulus reduction and damping characteristics of MSW were studied. Ten ground motions were selected based on regional seismicity and site response parameters have been obtained considering one-dimensional non-linear analysis in the DEEPSOIL program. The surface spectral response varied from 0.6 to 2 g and persisted only for a period of 1 s for most of the ground motions. The maximum peak ground acceleration (PGA) obtained was 0.5 g and the minimum and maximum amplifications are 1.35 and 4.05. Amplification of the base acceleration was observed at the top surface of the landfill underlined by a composite soil layer and bedrock for all ground motions. Dynamic seismic properties with amplification and site response parameters for MSW landfill in Bangalore, India, are presented in this paper. This study shows that MSW has less shear stiffness and more amplification due to loose filling and damping, which need to be accounted for seismic design of MSW landfills in India. PMID- 26759435 TI - Implementation of a multi-variable regression analysis in the assessment of the generation rate and composition of hospital solid waste for the design of a sustainable management system in developing countries. AB - Forecasting of hospital solid waste generation is a critical challenge for future planning. The composition and generation rate of hospital solid waste in hospital units was the field where the proposed methodology of the present article was applied in order to validate the results and secure the outcomes of the management plan in national hospitals. A set of three multiple-variable regression models has been derived for estimating the daily total hospital waste, general hospital waste, and total hazardous waste as a function of number of inpatients, number of total patients, and number of beds. The application of several key indicators and validation procedures indicates the high significance and reliability of the developed models in predicting the hospital solid waste of any hospital. Methodology data were drawn from existent scientific literature. Also, useful raw data were retrieved from international organisations and the investigated hospitals' personnel. The primal generation outcomes are compared with other local hospitals and also with hospitals from other countries. The main outcome, which is the developed model results, are presented and analysed thoroughly. The goal is this model to act as leverage in the discussions among governmental authorities on the implementation of a national plan for safe hospital waste management in Palestine. PMID- 26759436 TI - Unusual neurological presentation of Fusobacterium necrophorum disease. AB - A 2-year-old girl presented to hospital, with reduced consciousness and fever. She had a 4-week history of fever treated with two courses of amoxicillin for tonsillitis diagnosed in primary care. Neuroimaging revealed multiple cerebral abscesses and subdural empyema. Pus aspirated from the intracranial collections grew Fusobacterium necrophorum and meropenem was started. Following neurosurgery, the patient continued to be agitated with fluctuating fever. She underwent close monitoring with regular neuroimaging. To control the progression of intracranial infection, she underwent three separate neurosurgical procedures following which she made a good recovery. This case demonstrates how an organism rarely associated with childhood illnesses presented atypically and progressed into a complex potentially fatal intracranial infection requiring a high degree of neurosurgical intervention. Awareness of this organism is important. The combination of source control together with appropriate antibiotic use was crucial in controlling the infection. PMID- 26759437 TI - Uncommon inflammatory swelling of the lips: orofacial granulomatosis. AB - Orofacial granulomatosis (OFG) is an unusual condition associated with permanent or recurrent swelling of orofacial tissues together with oral mucosal ulceration and a variety of orofacial characteristics. The chronic inflammation inherent to OFG often displays granulomas in the subepithelial stroma. We present a case of OFG and its management. The patient responded to intralesional injections of corticosteroids. PMID- 26759438 TI - Somatic symptom disorder, a new DSM-5 diagnosis of an old clinical challenge. AB - Somatic symptom disorder (SSD) is characterised by a dysfunctional preoccupation with one or more physical symptoms. Patients with SSD often pursue excessive and unnecessary investigations, hospitalisations and treatments that significantly affect quality of life and drain healthcare resources. Thus, appropriate diagnosis and careful management are required to mitigate the patient's distress and to reduce the burden to the healthcare system. SSD is a new disorder defined in the Diagnostic and Statistical Manual Fifth Edition (DSM-5), replacing somatoform and related disorders in the DSM-4-Text Revision with diagnostic criteria that are inclusive of a broad array of presentations. This report presents a detailed clinical case of an elderly man with a history of frequent hospital visits presenting with SSD. We discuss diagnostic challenges and evidence-based management in acute inpatient as well as in outpatient settings. We also review data on healthcare utilisation associated with SSD. PMID- 26759439 TI - Aggressive eosinophilic granulomatosis with polyangiitis and transverse sinus thrombosis. AB - We report a case of a patient with eosinophilic granulomatosis with polyangiitis (EGPA, previously known as Churg-Strauss syndrome) who succumbed to respiratory failure complicated by sepsis, pneumonitis and transverse sinus thrombosis. In the absence of antineutrophilic cytoplasmic antibodies positivity, a clinical diagnosis was made based on The American College of Rheumatology-1990 criteria. Glucocorticoids, cyclophosphamide, rituximab and intravenous immunoglobulin were administered at different stages. The patient recovered momentarily after each cycle of treatment, but his vasculitis progressed and he eventually died. Cardiac or renal involvement, which is more commonly associated with an adverse outcome, was not present. PMID- 26759440 TI - Nystagmus in a newborn: a manifestation of Joubert syndrome in the neonatal period. AB - Joubert syndrome is a rare disorder, usually autosomal recessive, with a prevalence of 1:80,000 to 1:100,000. This disease presents most commonly as breathing irregularities, although the two major clinical criteria are hypotonia and developmental delay, sometimes associated with ocular movement abnormalities. The severity of the presentation varies, ranging from mild cases with normal intelligence to severe developmental delays associated with early death. We report a case of a newborn who presented to the emergency department for absent ocular fixation and torsional nystagmus without other neurological abnormalities. Her cranial MR showed cerebellar vermis agenesis and a molar tooth sign. Her laboratory evaluation, and renal and abdominal ultrasound were normal. An electroretinogram showed mixed retinal dystrophy and an AHI1 homozygous missense c.1981T>C mutation was identified (parents are carriers). Throughout infancy, she has shown mild developmental delay and hypotonia, but no respiratory abnormalities. Owing to variable expressivity, a high level of suspicion is required. PMID- 26759441 TI - Pneumatocele or something more? PMID- 26759442 TI - Oral mucosal manifestations of chronic eosinophilic leukaemia with FIP1L1 PDGFRalpha. PMID- 26759443 TI - Colonic vasculopathy and perforation in the initial presentation of adult dermatomyositis in a patient with improving muscle weakness. AB - A 63-year-old woman with diabetes presented with 8 weeks of proximal muscle weakness and change in bowel habits. Muscle biopsy confirmed myositis, and serological studies were consistent with dermatomyositis (DM), without evidence of overlapping connective tissue disease or malignancy. On day 12 of prednisone therapy and after receiving one dose of IVIG with improvement in muscle strength, the patient developed abdominal pain and was diagnosed with a gastrointestinal (GI) perforation and peritonitis requiring emergent colectomy. The pathology revealed diffuse mucosal ulceration, prominent lymphoplasmacytic infiltration, venous occlusion and arterial hyperplasia. Although GI manifestations due to GI vasculopathy are rare in adult DM and are often a delayed complication, in this patient, it was one of the initial manifestations of this condition. In addition to being a fatal complication, clinicians should be aware of these complications, as immunosuppression used to control the muscular and cutaneous inflammation may not control the GI vasculopathy. PMID- 26759444 TI - Xanthelasma palpebrarum: a new side effect of nilotinib. AB - Chronic myeloid leucaemia (CML) is a chronic myeloproliferative disorder characterised by a reciprocal translocation between the chromosomes 9 and 22 resulting in constitutionally active tyrosine kinase signalling. BCR-ABL tyrosine kinase inhibitors (TKIs) are highly effective molecules in the treatment of CML. Unfortunately, these novel therapeutic agents are accompanied by various side effects, and haematological, cutaneous and metabolic abnormalities are among the most prevalent. Nilotinib, a second-generation TKI, has been shown to cause both- cutaneous lesions and lipid profile abnormalities. We present two CML cases developing xanthelasma palpebrarum while receiving nilotinib. Case 1 also acquired a lipid abnormality following the start of nilotinib therapy, while case 2 meanwhile stayed normolipidemic. In addition to a low cholesterol diet, atorvastatin was prescribed to case 1. Currently, both cases are normolipidemic and continuing their nilotinib therapy. Xanthelasma palpebrarum secondary to nilotinib therapy is new to the literature. PMID- 26759445 TI - Excision of a distended chronic non-functional large ileoanal pouch. PMID- 26759446 TI - Group B streptococcal meningitis in a previously healthy man. AB - Group B Streptococcus (GBS) is an infrequent cause of meningitis in adults, usually affecting elderly patients and those with serious underlying disease. It is more commonly recognised as one of the leading aetiological agents of neonatal sepsis following maternally derived infection during pregnancy. We report a case of a previously healthy 26-year-old man who presented with fevers, confusion and headache. Lumbar puncture results were consistent with bacterial meningitis, and blood cultures grew GBS. To the best of our knowledge, our patient represents one of the few reported cases of GBS meningitis in a previously healthy young man. Interestingly, our patient had a significant family history of central nervous system infection including a son with herpes simplex virus encephalitis, a sister with meningococcal meningitis and a great-uncle with meningitis of unknown cause. We discuss genetic factors that may predispose certain people to develop meningitis with normally harmless microorganisms such as GBS. PMID- 26759447 TI - General practitioners' perceptions of the stigma of dementia and the role of reciprocity. AB - A qualitative exploration of the stigma of dementia reported that general practitioners described lack of reciprocity as one way in which people with dementia are perceived within society. This was closely linked to their perception of dementia as a stigma. In this article, we explore whether general practitioners perceive people with dementia as lacking reciprocity and, if so, if this is linked with societal opinions about dementia as a stigma. The implications of both perceptions of people with dementia failing to reciprocate and of stigma for timely diagnosis are explored. Our approach is to follow the thread of reciprocity in the data from our initial study. In this follow-up study, general practitioners' perceptions of societal views of people with dementia included a perception of a lack of reciprocity specifically linked with; failing to respond to human contact, the absence of an appropriate return on social investment and failing to contribute to, or being a burden on, society. General practitioners reported a link between societal perceptions of lack of reciprocity and stereotypes about advanced dementia, difficulties communicating with people with dementia, and lack of opportunities for people with dementia to reciprocate. General practitioners occupy a key position, they can challenge stereotypes and, with support and targeted training about communicating with people living with dementia, can emphasize the ways in which people with dementia can communicate, thereby enhancing their potential to reciprocate. Such changes have implications for improved care and quality of life through the continued maintenance of social inclusion and perceptions of personhood. PMID- 26759448 TI - Assessment of Psychopathology and Quality of Life in Children and Adolescents With Migraine. AB - AIM: The aims of this study were to investigate comorbid psychiatric disorders and to identify anxiety and depression levels and quality of life in children and adolescents with migraine; and to assess their relationship with migraine. METHOD: 35 patients aged 9-16 years were followed in our neurology clinic and their parents were included into the study. 35 age- and sex-matched patients were employed as the control group. In the subjects included, psychiatric disorders were assessed by using the Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime Version. All children and adolescents were assessed by using the Children's Depression Inventory, the State-Trait Anxiety Inventory and the Pediatric Quality of Life Inventory. In addition, the Pediatric Migraine Disability Assessment Tool and visual analog scale were used to identify the degree of disability and pain severity in patients with migraine. FINDINGS: In the psychiatric assessment of children and adolescents with migraine, it was found that a psychiatric diagnosis was made in 40% of patients; and depression scale scores were significantly higher than those of controls. Quality of life was found to be poorer in patients with migraine compared to controls. It was found that quality of life was negatively correlated with pain severity and degree of disability; while it was positively correlated with depression scores. DISCUSSION: In children and adolescents with migraine, treatment of psychiatric disorders in addition to migraine therapy can facilitate migraine management and may decrease the need for prophylactic therapy. PMID- 26759449 TI - Autism in Phenylketonuria Patients: From Clinical Presentation to Molecular Defects. AB - Autism has been reported in untreated patients with phenylketonuria. The authors aimed to explore autism in 15 Tunisian and 4 Algerian phenylketonuria patients, and report their clinical, biochemical and molecular peculiarities. The Childhood Autism Rating Scale and the Autism Diagnostic Interview-Revised were used for the diagnosis of autism. Five exons of phenylalanine hydroxylase gene (7, 6, 10, 11, and 5) were amplified by polymerase chain reaction and directly sequenced. Among these patients, 15 were suffering from autism at the time of evaluation. Six mutations were identified: p.E280K, p.G352Vfs, IVS10nt11, p.I224T, p.R261Q, and p.R252W. There was no correlation between autism and mutations affecting the phenylalanine hydroxylase gene, but the age of diet onset was the determining factor in autistic symptoms' evolution. PMID- 26759450 TI - Cross-backbone templating; ribodinucleotides made on poly(C). AB - G(5')pp(5')G synthesis from pG and chemically activated 2MeImpG is accelerated by the addition of complementary poly(C), but affected only slightly by poly(G) and not at all by poly(U) and poly(A). This suggests that 3'-5' poly(C) is a template for uncatalyzed synthesis of 5'-5' GppG, as was poly(U) for AppA synthesis, previously. The reaction occurs at 50 mM mono- and divalent ion concentrations, at moderate temperatures, and near pH 7. The reactive complex at the site of enhanced synthesis of 5'-5' GppG seems to contain a single pG, a single phosphate activated nucleotide 2 MeImpG, and a single strand of poly(C). Most likely this structure is base-paired, as the poly(C)-enhanced reaction is completely disrupted between 30 and 37 degrees C, whereas slower, untemplated synthesis of GppG accelerates. More specifically, the reactive center acts as would be expected for short, isolated G nucleotide stacks expanded and ordered by added poly(C). For example, poly(C)-mediated GppG production is very nonlinear in overall nucleotide concentration. Uncatalyzed NppN synthesis is now known for two polymers and their complementary free nucleotides. These data suggest that varied, simple, primordial 3'-5' RNA sequences could express a specific chemical phenotype by encoding synthesis of complementary, reactive, coenzyme-like 5'-5' ribodinucleotides. PMID- 26759452 TI - The ribonuclease polynucleotide phosphorylase can interact with small regulatory RNAs in both protective and degradative modes. AB - In all bacterial species examined thus far, small regulatory RNAs (sRNAs) contribute to intricate patterns of dynamic genetic regulation. Many of the actions of these nucleic acids are mediated by well-characterized chaperones such as the Hfq protein, but genetic screens have also recently identified the 3'-to 5' exoribonuclease polynucleotide phosphorylase (PNPase) as an unexpected stabilizer and facilitator of sRNAs in vivo. To understand how a ribonuclease might mediate these effects, we tested the interactions of PNPase with sRNAs and found that the enzyme can readily degrade these nucleic acids in vitro but, nonetheless, copurifies from cell extracts with the same sRNAs without discernible degradation or modification to their 3' ends, suggesting that the associated RNA is protected against the destructive activity of the ribonuclease. In vitro, PNPase, Hfq, and sRNA can form a ternary complex in which the ribonuclease plays a nondestructive, structural role. Such ternary complexes might be formed transiently in vivo, but could help to stabilize particular sRNAs and remodel their population on Hfq. Taken together, our results indicate that PNPase can be programmed to act on RNA in either destructive or stabilizing modes in vivo and may form complex, protective ribonucleoprotein assemblies that shape the landscape of sRNAs available for action. PMID- 26759451 TI - A DEAD-box RNA helicase promotes thermodynamic equilibration of kinetically trapped RNA structures in vivo. AB - RNAs must assemble into specific structures in order to carry out their biological functions, but in vitro RNA folding reactions produce multiple misfolded structures that fail to exchange with functional structures on biological time scales. We used carefully designed self-cleaving mRNAs that assemble through well-defined folding pathways to identify factors that differentiate intracellular and in vitro folding reactions. Our previous work showed that simple base-paired RNA helices form and dissociate with the same rate and equilibrium constants in vivo and in vitro. However, exchange between adjacent secondary structures occurs much faster in vivo, enabling RNAs to quickly adopt structures with the lowest free energy. We have now used this approach to probe the effects of an extensively characterized DEAD-box RNA helicase, Mss116p, on a series of well-defined RNA folding steps in yeast. Mss116p overexpression had no detectable effect on helix formation or dissociation kinetics or on the stability of interdomain tertiary interactions, consistent with previous evidence that intracellular factors do not affect these folding parameters. However, Mss116p overexpression did accelerate exchange between adjacent helices. The nonprocessive nature of RNA duplex unwinding by DEAD-box RNA helicases is consistent with a branch migration mechanism in which Mss116p lowers barriers to exchange between otherwise stable helices by the melting and annealing of one or two base pairs at interhelical junctions. These results suggest that the helicase activity of DEAD-box proteins like Mss116p distinguish intracellular RNA folding pathways from nonproductive RNA folding reactions in vitro and allow RNA structures to overcome kinetic barriers to thermodynamic equilibration in vivo. PMID- 26759453 TI - circTAIL-seq, a targeted method for deep analysis of RNA 3' tails, reveals transcript-specific differences by multiple metrics. AB - Post-transcriptionally added RNA 3' nucleotide extensions, or tails, impose numerous regulatory effects on RNAs, including effects on RNA turnover and translation. However, efficient methods for in-depth tail profiling of a transcript of interest are still lacking, hindering available knowledge particularly of tail populations that are highly heterogeneous. Here, we developed a targeted approach, termed circTAIL-seq, to quantify both major and subtle differences of heterogeneous tail populations. As proof-of-principle, we show that circTAIL-seq quantifies the differences in tail qualities between two selected Trypanosoma brucei mitochondrial transcripts. The results demonstrate the power of the developed method in identification, discrimination, and quantification of different tail states that the population of one transcript can possess. We further show that circTAIL-seq can detect the tail characteristics for variants of transcripts that are not easily detectable by conventional approaches, such as degradation intermediates. Our findings are not only well supported by previous knowledge, but they also expand this knowledge and provide experimental evidence for previous hypotheses. In the future, this approach can be used to determine changes in tail qualities in response to environmental or internal stimuli, or upon silencing of genes of interest in mRNA-processing pathways. In summary, circTAIL-seq is an effective tool for comparing nonencoded RNA tails, especially when the tails are extremely variable or transcript of interest is low abundance. PMID- 26759457 TI - A Snapshot of the State of Cancer Care in America. PMID- 26759454 TI - Fingerprinting the junctions of RNA structure by an open-paddlewheel diruthenium compound. AB - RNA function is determined by its structural organization. The RNA structure consists of the combination of distinct secondary structure motifs connected by junctions that play an essential role in RNA folding. Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) probing is an established methodology to analyze the secondary structure of long RNA molecules in solution, which provides accurate data about unpaired nucleotides. However, the residues located at the junctions of RNA structures usually remain undetected. Here we report an RNA probing method based on the use of a novel open-paddlewheel diruthenium (OPW-Ru) compound [Ru2Cl2(u-DPhF)3(DMSO)] (DPhF = N,N' diphenylformamidinate). This compound has four potential coordination sites in a singular disposition to establish covalent bonds with substrates. As a proof of concept, we have analyzed the reactivity of OPW-Ru toward RNA using two viral internal ribosome entry site (IRES) elements whose function depends on the structural organization of the molecule. Our study suggests that the compound OPW Ru preferentially attacks at positions located one or two nucleotides away from junctions or bulges of the RNA structure. The OPW-Ru fingerprinting data differ from that obtained by other chemical reagents and provides new information about RNA structure features. PMID- 26759455 TI - Rules of UGA-N decoding by near-cognate tRNAs and analysis of readthrough on short uORFs in yeast. AB - The molecular mechanism of stop codon recognition by the release factor eRF1 in complex with eRF3 has been described in great detail; however, our understanding of what determines the difference in termination efficiencies among various stop codon tetranucleotides and how near-cognate (nc) tRNAs recode stop codons during programmed readthrough in Saccharomyces cerevisiae is still poor. Here, we show that UGA-C as the only tetranucleotide of all four possible combinations dramatically exacerbated the readthrough phenotype of the stop codon recognition deficient mutants in eRF1. Since the same is true also for UAA-C and UAG-C, we propose that the exceptionally high readthrough levels that all three stop codons display when followed by cytosine are partially caused by the compromised sampling ability of eRF1, which specifically senses cytosine at the +4 position. The difference in termination efficiencies among the remaining three UGA-N tetranucleotides is then given by their varying preferences for nc-tRNAs. In particular, UGA-A allows increased incorporation of Trp-tRNA whereas UGA-G and UGA-C favor Cys-tRNA. Our findings thus expand the repertoire of general decoding rules by showing that the +4 base determines the preferred selection of nc-tRNAs and, in the case of cytosine, it also genetically interacts with eRF1. Finally, using an example of the GCN4 translational control governed by four short uORFs, we also show how the evolution of this mechanism dealt with undesirable readthrough on those uORFs that serve as the key translation reinitiation promoting features of the GCN4 regulation, as both of these otherwise counteracting activities, readthrough versus reinitiation, are mediated by eIF3. PMID- 26759458 TI - Curing Metastatic Breast Cancer. AB - Metastatic breast cancer is generally considered incurable, and this colors doctor-patient interactions for patients with metastatic disease. Although true for most patients, there appear to be important exceptions, instances where long term disease-free survival occurs. Although these instances are few in number, they suggest the possibility of cure. How will we move toward cure for a much larger population of patients with metastatic disease? This article outlines a potential research agenda that might move us toward that distant goal. PMID- 26759460 TI - Is Breast Cancer a Curable Disease? PMID- 26759459 TI - Conquering Metastatic Breast Cancer. PMID- 26759461 TI - Clinical Insights Into the Biology and Treatment of Pancreatic Cancer. AB - Pancreatic cancer is a devastating disease with a universally poor prognosis. In 2015, it is estimated that there will be 48,960 new cases of pancreatic cancer and that 40,560 people will die of the disease. The 5-year survival rate is 7.2% for all patients with pancreatic cancer; however, survival depends greatly on the stage at diagnosis. Unfortunately, 53% of patients already have metastatic disease at diagnosis, which corresponds to a 5-year survival rate of 2.4%. Even for the 9% of patients with localized disease confined to the pancreas, the 5 year survival is still modest at only 27.1%. These grim statistics highlight the need for ways to identify cohorts of individuals at highest risk, methods to screen those at highest risk to identify preinvasive pathologic precursors, and development of effective systemic therapies. Recent clinical and translational progress has emphasized the relationship with diabetes, the role of the stroma, and the interplay of each of these with inflammation in the pathobiology of pancreatic cancer. In this article, we will discuss these relationships and how they might translate into novel management strategies for the treatment of this disease. PMID- 26759462 TI - Pancreatic Adenocarcinoma: The Emperor of All Cancer Maladies. PMID- 26759463 TI - Early Detection and Treatment Opportunities in Pancreatic Adenocarcinoma. PMID- 26759464 TI - Surgical Management of Liver Metastases From Colorectal Cancer. AB - Surgical resection remains one of the major curative treatment options available to patients with colorectal liver metastases. Surgery and chemotherapy form the backbone of the treatment in patients with colorectal liver metastases. With more effective chemotherapy regimens being available, the optimal timing and sequencing of treatments are important. A multidisciplinary approach with the involvement of medical oncologists and surgical oncologists from the beginning is crucial. Identification of the clinical and molecular prognostic factors may help personalize the treatment approaches for these patients. This article provides an overview of the surgical management of colorectal liver metastases. PMID- 26759465 TI - Colorectal Liver Metastases: A Changing Treatment Landscape. PMID- 26759466 TI - Treatment of Colorectal Liver Metastases: None of Us Is As Smart As All of Us. PMID- 26759467 TI - Improving Price Transparency in Cancer Care. PMID- 26759469 TI - Assessing Cultural Competence Among Oncology Surgeons. AB - PURPOSE: Racial and ethnic minority groups in the United States have the highest mortality rates for the most common cancers. Various factors, including a perceived lack of culturally congruent care and culturally competent providers, might lead minority patients to decline or delay care. As part of a large multimethod study to understand barriers to care among American Indian and Alaskan native patients with cancer, we examined surgical provider attributes associated with culturally congruent care. PATIENTS AND METHODS: Surgical providers from six hospitals in the Puget Sound region of Washington State were invited to participate. Participants completed a 50-item survey that assessed demographic data and incorporated the Cultural Competence Assessment (CCA) and the Marlowe-Crowne Social Desirability Scale. RESULTS: Survey response rate was 51.1% (N = 253). Participants reported treating diverse patient populations; 71% encountered patients from six or more racial and ethnic groups. More than one half of participants (58%) reported completing cultural diversity training, with employer-sponsored training being the most common type reported (48%; 71 of 147). CCA scores ranged from 5.99 to 13.75 of a possible 14 (mean, 10.3; standard deviation, +/-1.3), and receipt of diversity training was associated with higher scores than nonreceipt of diversity training (10.56 v 9.82, respectively; P<.001). After controlling for Marlowe-Crowne Social Desirability Scale score and hospital system,participation in diversity training was the variable most significantly associated with CCA score (P<.001). CONCLUSION: Culturally competent care is an essential but often overlooked component of high-quality health care. Future work should compare training offered by various hospital systems. PMID- 26759470 TI - The ASCO Oncology Composite Provider Utilization File: New Data, New Insights. AB - As we seek to understand the changing practice environment in oncology, the need for accurate information about demand for services, distribution of the delivery system in this sector of the health economy, and other practice trends is apparent. In this article, we present analysis of the sector using one of the public use files from the Centers for Medicare & Medicaid Services in combination with other publicly available data. Medicare data are particularly useful for this analysis because cancer is associated with aging and Medicare is the primary payer in the United States for patients older than age 65. As a result, nearly all oncologists who serve adult populations are represented in these data. By combining publicly available datasets into what we call the ASCO Provider Utilization File,we can investigate a wide range of supply, demand, and practice issues. We calculate the average work performed per physician, observe regional differences in work production,and quantify the downside risk and upside potential associated with the provision of chemotherapy drugs. Comparing the supply of oncologists by state with physician work relative value units and with estimates of cancer incidence by state reveals intriguing differences in the distribution of physicians and the demand for oncology services. In addition, our analysis demonstrates significant downside practice risk associated with the provision of drug therapy to Medicare beneficiaries. The economic risk associated with the purchase and delivery of chemotherapy is of particular concern as pressure for value increases. This article provides a description of a new dataset and interesting observations from these data. PMID- 26759468 TI - Economic Evaluation Alongside a Clinical Trial of Telephone Versus In-Person Genetic Counseling for BRCA1/2 Mutations in Geographically Underserved Areas. AB - PURPOSE: BRCA1/2 counseling and mutation testing is recommended for high-risk women, but geographic barriers exist, and no data on the costs and yields of diverse delivery approaches are available. METHODS: We performed an economic evaluation with a randomized clinical trial comparing telephone versus in-person counseling at 14 locations (nine geographically remote). Costs included fixed overhead, variable staff, and patient time costs; research costs were excluded. Outcomes included average per-person costs for pretest counseling; mutations detected; and overall counseling, testing, and disclosure. Sensitivity analyses were performed to assess the impact of uncertainty. RESULTS: In-person counseling was more costly per person counseled than was telephone counseling ($270 [range, $180 to $400] v $120 [range, $80 to $200], respectively). Counselors averaged 285 miles round-trip to deliver in-person counseling to the participants (three participants per session). There were no differences by arm in mutation detection rates (approximately 10%); therefore, telephone counseling was less costly per positive mutation detected than was in-person counseling ($37,160 [range, $36,080 to$38,920] v $40,330 [range, $38,010 to $43,870]). In-person counseling would only be less costly than telephone counseling if the most favorable assumptions were applied to in personc ounseling and the least favorable assumptions were applied to telephone counseling. CONCLUSION: In geographically underserved areas, telephone counseling is less costly than in-person counseling. PMID- 26759472 TI - Kikuchi's Disease Masquerading As Refractory Lymphoma. PMID- 26759471 TI - Improving the Quality of Radiation Treatment for Patients in Ontario: Increasing Peer Review Activities on a Jurisdictional Level Using a Change Management Approach. AB - PURPOSE: Peer review of radiation treatment (RT) plans is a key component of quality assurance programs in radiation medicine. A 2011 current state assessment identified considerable variation in the percentage of RT plans peer reviewed across Ontario's 14 cancer centers.In response, Cancer Care Ontario launched an initiative to increase peer review of plans for patients receiving radical intent RT. METHODS: The initiative was designed consistent with the Kotter eight-step process for organizational transformation. A multidisciplinary team conducted site visits to promote and guide peer review and to develop education and implementation processes in collaboration with the centers. A centralized reporting infrastructure enabled the monitoring of the percentage of RT courses peer reviewed and the timing of peer review (before completion of 25%of treatment visits, after completion of >25%treatment visits). RESULTS: The initiative is ongoing, but early results indicate that the proportion of radical intent RT courses peer reviewed province wide increased from 43.5% (April 2013) to 68.0%(March 2015). This proportion is now a quality metric in Ontario and is publicly reported through the Cancer System Quality Index. The performance target for this metric was initially set at 50%(cases treated with radical intent) and revised to 60% in 2014. Provincial performance exceeded targets in both years (58.2% and 68.2%, respectively). Considerable variation was observed, however, in rates and timing of peer review among Cancer Care Ontario centers. CONCLUSION: This initiative demonstrates that a change management framework can be useful for planning and achieving substantial increases in jurisdictional peer review activities. PMID- 26759473 TI - Erratum. PMID- 26759474 TI - Reduction of Inappropriate Prophylactic Pegylated Granulocyte Colony-Stimulating Factor Use for Patients With Non-Small-Cell Lung Cancer Who Receive Chemotherapy: An ASCO Quality Training Program Project of the Cleveland Clinic Taussig Cancer Institute. AB - PURPOSE: Routine prophylactic pegylated granulocyte colony-stimulating factor (pGCSF) administration for patients receiving chemotherapy regimens associated with low risk (< 10%) for neutropenic fever (LRNF) is not recommended. Inappropriate use of pGCSF increases patient morbidity and health care costs. METHODS: A multidisciplinary team reviewed the charts of patients with non-small cell lung cancer (NSCLC) at the Taussig Cancer Institute in whom a new chemotherapy regimen was initiated from April through November 2013. pGCSF use was identified and deemed appropriate if prescribed for chemotherapy associated with high risk of neutropenic fever (> 20%) or intermediate risk (10% to 20%) if other risk factors for neutropenic fever were present. Use with LRNF chemotherapy was recorded as inappropriate. RESULTS: One hundred eighty patients with NSCLC received a new chemotherapy regimen during the specified time period. Thirty-four of 119 patients (28%) treated with LRNF chemotherapy received pGCSF. Each patient received an average of 2.6 doses of pGCSF (total, 89 doses). We implemented three plan-do-study-act cycles: education of providers, development of Taussig Cancer Institute consensus guidelines for pGCSF in NSCLC, and removal of standing pGCSF orders from LRNF chemotherapy in the electronic medical record. Analysis during the change period revealed 4% of patients with NSCLC treated with LRNF chemotherapy received pGCSF. Cost analysis showed an 84% decrease in billed charges per month. No increase in neutropenic fever admissions was found. CONCLUSION: pGCSF was excessively prescribed for patients with NSCLC. Factors contributing to inappropriate use included provider lack of familiarity with guidelines and knowledge with regard to the risk of neutropenic fever for individual chemotherapy regimens, and electronic medical record chemotherapy templates that contain standing GCSF orders. Interventions to address these gaps quickly produced improved compliance with guidelines and led to significant cost savings. PMID- 26759475 TI - EURADOS INTERCOMPARISONS IN EXTERNAL RADIATION DOSIMETRY: SIMILARITIES AND DIFFERENCES AMONG EXERCISES FOR WHOLE-BODY PHOTON, WHOLE-BODY NEUTRON, EXTREMITY, EYE-LENS AND PASSIVE AREA DOSEMETERS. AB - The European Radiation Dosimetry Group (EURADOS) has been organising dosimetry intercomparisons for many years in response to an identified requirement from individual monitoring services (IMS) for independent performance tests for dosimetry systems. The participation in intercomparisons gives IMS the opportunity to show compliance with their own quality management system, compare results with other participants and develop plans for improving their dosimetry systems. In response to growing demand, EURADOS has increased the number of intercomparisons for external radiation dosimetry. Most of these fit into the programme of self-financing intercomparisons for dosemeters routinely used by IMS. This programme is being coordinated by EURADOS working group 2 (WG2). Up to now, this programme has included four intercomparisons for whole-body dosemeters in photon fields, one for extremity dosemeters in photon and beta fields, and one for whole-body dosemeters in neutron fields. Other EURADOS working groups have organised additional intercomparisons including events in 2014 for eye-lens dosemeters and passive area dosemeters for environmental monitoring. In this paper, the organisation and achievements of these intercomparisons are compared in detail focusing on the similarities and differences in their execution. PMID- 26759476 TI - THE PHE FORTUITOUS DOSIMETRY CAPABILITY BASED ON OPTICALLY STIMULATED LUMINESCENCE OF MOBILE PHONES. AB - The Public Health England fortuitous dosimetry capability is reviewed, with particular attention focussed on the derivation of its energy and fading corrections, the Monte Carlo techniques used to generate the calibration factors between phone and body doses, and the procedures set in place to facilitate a reliable and effective service. PMID- 26759477 TI - Asymmetry and Structure of the Fronto-Parietal Networks Underlie Visuomotor Processing in Humans. AB - Research in both humans and monkeys has shown that even simple hand movements require cortical control beyond primary sensorimotor areas. An extensive functional neuroimaging literature demonstrates the key role that cortical fronto parietal regions play for movements such as reaching and reach-to-grasp. However, no study so far has examined the specific white matter connections linking the fronto-parietal regions, namely the 3 parallel pathways of the superior longitudinal fasciculus (SLF). The aim of the current study was to explore how selective fronto-parietal connections are for different kinds of hand movement in 30 right-handed subjects by correlating diffusion imaging tractography and kinematic data. We showed that a common network, consisting of bilateral SLF II and SLF III, was involved in both reaching and reach-to-grasp movements. Larger SLF II and SLF III in the right hemisphere were associated with faster speed of visuomotor processing, while the left SLF II and SLF III played a role in the initial movement trajectory control. Furthermore, the right SLF II was involved in the closing grip phase necessary for efficient grasping of the object. We demonstrated for the first time that individual differences in asymmetry and structure of the fronto-parietal networks were associated with visuomotor processing in humans. PMID- 26759478 TI - Intracortical Microstimulation Maps of Motor, Somatosensory, and Posterior Parietal Cortex in Tree Shrews (Tupaia belangeri) Reveal Complex Movement Representations. AB - Long-train intracortical microstimulation (LT-ICMS) is a popular method for studying the organization of motor and posterior parietal cortex (PPC) in mammals. In primates, LT-ICMS evokes both multijoint and multiple-body-part movements in primary motor, premotor, and PPC. In rodents, LT-ICMS evokes complex movements of a single limb in motor cortex. Unfortunately, very little is known about motor/PPC organization in other mammals. Tree shrews are closely related to both primates and rodents and could provide insights into the evolution of complex movement domains in primates. The present study investigated the extent of cortex in which movements could be evoked with ICMS and the characteristics of movements elicited using both short train (ST) and LT-ICMS in tree shrews. We demonstrate that LT-ICMS and ST-ICMS maps are similar, with the movements elicited with ST-ICMS being truncated versions of those elicited with LT-ICMS. In addition, LT-ICMS-evoked complex movements within motor cortex similar to those in rodents. More complex movements involving multiple body parts such as the hand and mouth were also elicited in motor cortex and PPC, as in primates. Our results suggest that complex movement networks present in PPC and motor cortex were present in mammals prior to the emergence of primates. PMID- 26759479 TI - Facial Expressions Evoke Differential Neural Coupling in Macaques. AB - In humans and monkeys, face perception activates a distributed cortical network that includes extrastriate, limbic, and prefrontal regions. Within face responsive regions, emotional faces evoke stronger responses than neutral faces ("valence effect"). We used fMRI and Dynamic Causal Modeling (DCM) to test the hypothesis that emotional faces differentially alter the functional coupling among face-responsive regions. Three monkeys viewed conspecific faces with neutral, threatening, fearful, and appeasing expressions. Using Bayesian model selection, various models of neural interactions between the posterior (TEO) and anterior (TE) portions of inferior temporal (IT) cortex, the amygdala, the orbitofrontal (OFC), and ventrolateral prefrontal cortex (VLPFC) were tested. The valence effect was mediated by feedback connections from the amygdala to TE and TEO, and feedback connections from VLPFC to the amygdala and TE. Emotional faces were associated with differential effective connectivity: Fearful faces evoked stronger modulations in the connections from the amygdala to TE and TEO; threatening faces evoked weaker modulations in the connections from the amygdala and VLPFC to TE; and appeasing faces evoked weaker modulations in the connection from VLPFC to the amygdala. Our results suggest dynamic alterations in neural coupling during the perception of behaviorally relevant facial expressions that are vital for social communication. PMID- 26759480 TI - Ordering Information in Working Memory and Modulation of Gamma by Theta Oscillations in Humans. AB - Ordering information is a critical process underlying several cognitive functions, especially working memory. Theta phase-gamma amplitude coupling is regarded as a neurophysiological representation of ordering information during working memory performance. However, direct evidence has been lacking in humans. Seventy healthy subjects performed the N-back task, a working memory task that tests ordering information at 3 different levels of difficulties and with 3 different types of trials. Using electroencephalography (EEG) during N-back performance, theta-gamma coupling was assessed during response trials. Multivariate general linear model (GLM) and discriminant analysis were used to assess coupling and theta and gamma power across the N-back conditions and the trial types. During the N-back trials that required ordering of information, N back condition had independent effects on coupling and on theta and gamma power, with equal contributions among these 3 variables. Theta-gamma coupling contribution declined significantly on the trials that did not require ordering and was intermediate on trials that favored but not necessarily required ordering. Our findings demonstrate for the first time the role of theta-gamma coupling as a mechanism that supports ordering information. They also highlight the potential of using theta-gamma coupling as a neurophysiological marker of brain function in health or disease states. PMID- 26759481 TI - Intraneuronal Amyloid Beta Accumulation Disrupts Hippocampal CRTC1-Dependent Gene Expression and Cognitive Function in a Rat Model of Alzheimer Disease. AB - In Alzheimer disease (AD), the accumulation of amyloid beta (Abeta) begins decades before cognitive symptoms and progresses from intraneuronal material to extracellular plaques. To date, however, the precise mechanism by which the early buildup of Abeta peptides leads to cognitive dysfunction remains unknown. Here, we investigate the impact of the early Abeta accumulation on temporal and frontal lobe dysfunction. We compared the performance of McGill-R-Thy1-APP transgenic AD rats with wild-type littermate controls on a visual discrimination task using a touchscreen operant platform. Subsequently, we conducted studies to establish the biochemical and molecular basis for the behavioral alterations. It was found that the presence of intraneuronal Abeta caused a severe associative learning deficit in the AD rats. This coincided with reduced nuclear translocation and genomic occupancy of the CREB co-activator, CRTC1, and decreased production of synaptic plasticity-associated transcripts Arc, c-fos, Egr1, and Bdnf. Thus, blockade of CRTC1-dependent gene expression in the early, preplaque phase of AD-like pathology provides a molecular basis for the cognitive deficits that figure so prominently in early AD. PMID- 26759484 TI - Spatio-Temporal Patterning in Primary Motor Cortex at Movement Onset. AB - Voluntary movement initiation involves the engagement of large populations of motor cortical neurons around movement onset. Despite knowledge of the temporal dynamics that lead to movement, the spatial structure of these dynamics across the cortical surface remains unknown. In data from 4 rhesus macaques, we show that the timing of attenuation of beta frequency local field potential oscillations, a correlate of locally activated cortex, forms a spatial gradient across primary motor cortex (MI). We show that these spatio-temporal dynamics are recapitulated in the engagement order of ensembles of MI neurons. We demonstrate that these patterns are unique to movement onset and suggest that movement initiation requires a precise spatio-temporal sequential activation of neurons in MI. PMID- 26759483 TI - Perceptual Learning Induces Persistent Attentional Capture by Nonsalient Shapes. AB - Visual attention can be attracted automatically by salient simple features, but whether and how nonsalient complex stimuli such as shapes may capture attention in humans remains unclear. Here, we present strong electrophysiological evidence that a nonsalient shape presented among similar shapes can provoke a robust and persistent capture of attention as a consequence of extensive training in visual search (VS) for that shape. Strikingly, this attentional capture that followed perceptual learning (PL) was evident even when the trained shape was task irrelevant, was presented outside the focus of top-down spatial attention, and was undetected by the observer. Moreover, this attentional capture persisted for at least 3-5 months after training had been terminated. This involuntary capture of attention was indexed by electrophysiological recordings of the N2pc component of the event-related brain potential, which was localized to ventral extrastriate visual cortex, and was highly predictive of stimulus-specific improvement in VS ability following PL. These findings provide the first evidence that nonsalient shapes can capture visual attention automatically following PL and challenge the prominent view that detection of feature conjunctions requires top-down focal attention. PMID- 26759482 TI - Common Neural Representations for Visually Guided Reorientation and Spatial Imagery. AB - Spatial knowledge about an environment can be cued from memory by perception of a visual scene during active navigation or by imagination of the relationships between nonvisible landmarks, such as when providing directions. It is not known whether these different ways of accessing spatial knowledge elicit the same representations in the brain. To address this issue, we scanned participants with fMRI, while they performed a judgment of relative direction (JRD) task that required them to retrieve real-world spatial relationships in response to either pictorial or verbal cues. Multivoxel pattern analyses revealed several brain regions that exhibited representations that were independent of the cues to access spatial memory. Specifically, entorhinal cortex in the medial temporal lobe and the retrosplenial complex (RSC) in the medial parietal lobe coded for the heading assumed on a particular trial, whereas the parahippocampal place area (PPA) contained information about the starting location of the JRD. These results demonstrate the existence of spatial representations in RSC, ERC, and PPA that are common to visually guided navigation and spatial imagery. PMID- 26759485 TI - Biomechanical design considerations for transradial prosthetic interface: A review. AB - Traditional function and comfort assessment of transradial prostheses pay scant attention to prosthetic interface. With better understanding of the biomechanics of prosthetic interface comes better efficiency and safety for interface design; in this way, amputees are more likely to accept prosthetic usage. This review attempts to provide design and selection criteria of transradial interface for prosthetists and clinicians. Various transradial socket types in the literature were chronologically reviewed. Biomechanical discussion of transradial prosthetic interface design from an engineering point of view was also done. Suspension control, range of motion, stability, as well as comfort and safety of socket designs have been considered in varying degrees in the literature. The human machine interface design should change from traditional "socket design" to new "interface design." From anatomy and physiology to biomechanics of the transradial residual limb, the force and motion transfer, together with comfort and safety, are the two main aspects in prosthetic interface design. Load distribution and transmission should mainly rely on achieving additional skeletal control through targeted soft tissue relief. Biomechanics of the residual limb soft tissues should be studied to find the relationship between mechanical properties and the comfort and safety of soft tissues. PMID- 26759486 TI - Microwave-Assisted Extraction Followed by Solid-Phase Extraction for the Chromatographic Analysis of Alkaloids in Stephania cepharantha. AB - A procedure involving microwave-assisted extraction (MAE) followed by solid-phase extraction (SPE) was established for the extraction and purification of three bisbenzylisoquinoline alkaloids from Stephania cepharantha, and a reversed-phase high-performance liquid chromatography (HPLC) method was developed for the quantification of the target alkaloids. Chromatographic separation was achieved on a Phenomenex Luna Phenyl-Hexyl column. Prior to the HPLC analysis, the alkaloids were rapidly extracted by an optimized MAE process using 0.01 mol/L hydrochloric acid as the solvent. The MAE extract was subsequently purified by SPE using a cation-exchange polymeric cartridge. The MAE-SPE procedure extracted the three alkaloids with satisfactory recoveries ranging from 100.44 to 102.12%. In comparison with the MAE, Soxhlet and ultrasonic-assisted extractions, the proposed MAE-SPE method showed satisfactory cleanup efficiency. Thus, the validated MAE-SPE-HPLC method is specific, accurate and applicable to the determination of alkaloids in S. cepharantha. PMID- 26759487 TI - Stability-Indicating HPTLC Method for Studying Stress Degradation Behavior of Sulbutiamine HCl. AB - Sulbutiamine (SUL) is an ester of thiazides with neurotropic action. A new stability indicating HPTLC method has been developed and validated for the determination of SUL in the presence of different degradation products. The drug was subjected to different stress conditions following ICH strategy such as hydrolytic degradation (neutral, alkaline and acidic hydrolysis), oxidation, photodegradation and dry heat degradation. The drug demonstrated degradation under all decomposition conditions except neutral hydrolysis and dry heat, where the drug was completely degraded with 0.1 N NaOH, 1 N HCl and 30% H2O2 while it was partially degradaed by 0.1 N HCl, 3% H2O2 and UV light. Structure elucidation of the resulting degradation products was performed using ESI-Q-MS-MS. A well defined peak for SUL was obtained at Rf = 0.46 and was completely separated from all obtained degradation products. Chromatographic separation was carried out on HPTLC aluminum plates precoated with silica gel 60 F254 using acetone-methylene chloride-ammonia buffer (pH 8.5 +/- 0.2) (7:3:0.5, v/v) as a developing system. Densitometric scanning of the separated peaks was performed at 254 nm. System suitability testing parameters were calculated to ascertain the quality performance of the developed method. The method was validated with respect to USP guidelines regarding accuracy, precision, specificity, robustness and ruggedness. Good correlation coefficients were achieved in the range of 0.4-5.0 ug/band, and the limit of detection and limit of quantitation were found to be 0.11 and 0.33 ug/band, respectively. The utility of the suggested method was verified by application to Arcalion forte(r) tablets where no interference from additives was found. PMID- 26759488 TI - Determination of Aromatic Amines Using Solid-Phase Microextraction Based on an Ionic Liquid-Mediated Sol-Gel Technique. AB - A headspace solid-phase microextraction (HS-SPME) method was developed for isolation of monocyclic aromatic amines from water samples followed by gas chromatography-flame ionization detector (GC-FID). In this work, the effect of the presence of ionic liquid (namely, 1-hexyl-3-methyl-imidazolium hexafluorophosphate [C6MIM][PF6]) was investigated in the sol-gel coating solutions on the morphology and extraction behavior of the resulting hybrid organic-inorganic sol-gel sorbents utilized in SPME. Hydroxy-terminated poly(dimethylsiloxane) (PDMS) was used as the sol-gel active organic component for sol-gel hybrid coatings. Two different coated fibers that were prepared are PDMS and PDMS-IL ([C6MIM][PF6]) fibers. Under the optimal conditions, the method detection limits (S/N = 3) with PDMS-IL were in the range of 0.001-0.1 ng/mL and the limits of quantification (S/N = 10) between 0.005 and 0.5 ng/mL. The relative standard deviations for one fiber (n = 5) were obtained from 3.1 up to 8.5% and between fibers or batch to batch (n = 3) in the range of 5.3-10.1%. The developed method was successfully applied to real water and juice fruits samples while the relative recovery percentages obtained for the spiked water samples at 0.1 ng/mL were from 83.3 to 95.0%. PMID- 26759489 TI - Circular economy: European policy on shaky ground. PMID- 26759490 TI - Refining the Standard of Care: How Oncology Treatment Pathways Can Make a Difference. PMID- 26759491 TI - American Society of Clinical Oncology Policy Statement on Clinical Pathways in Oncology. AB - The use of clinical pathways in oncology care is increasingly important to patients and oncology providers as a tool for enhancing both quality and value. However, with increasing adoption of pathways into oncology practice, concerns have been raised by ASCO members and other stakeholders. These include the process being used for pathway development, the administrative burdens on oncology practices of reporting on pathway adherence, and understanding the true impact of pathway use on patient health outcomes. To address these concerns, ASCO's Board of Directors established a Task Force on Clinical Pathways, charged with articulating a set of recommendations to improve the development of oncology pathways and processes, allowing the demonstration of pathway concordance in a manner that promotes evidence-based, high-value care respecting input from patients, payers, and providers. These recommendations have been approved and adopted by ASCO's Board of Directors on August 12, 2015, and are presented herein. PMID- 26759492 TI - Development of a Cancer Care Summary Through the Electronic Health Record. AB - INTRODUCTION: Our objective was to improve communication concerning lung cancer patients by developing and distributing a Cancer Care Summary that would provide clinically useful information about the patient's diagnosis and care to providers in diverse settings. METHODS: We designed structured, electronic forms for the electronic health record (EHR), detailing tumor staging, classification, and treatment. To ensure completeness and accuracy of the information, we implemented a data quality cycle, composed of reports that are reviewed by oncology clinicians. The data from the EHR forms are extracted into a structured query language database system on a daily basis, from which the Summaries are derived. We conducted focus groups regarding the utility, format, and content of the Summary. Cancer Care Summaries are automatically generated 4 months after a patient's date of diagnosis, then every 6 months for those receiving treatment, and on an as-needed basis for urgent care or hospital admission. RESULTS: The product of our improvement project is the Cancer Care Summary. To date, 102 individual patient Summaries have been generated. These documents are automatically entered into the National Jewish Health (NJH) EHR, attached to correspondence to primary care providers, available to patients as electronic documents on the NJH patient portal, and faxed to emergency departments and admitting physicians on patient evaluation. CONCLUSION: We developed a sustainable tool to improve cancer care communication. The Cancer Care Summary integrates information from the EHR in a timely manner and distributes the information through multiple avenues. PMID- 26759493 TI - Using Quality Improvement Methods and Time-Driven Activity-Based Costing to Improve Value-Based Cancer Care Delivery at a Cancer Genetics Clinic. AB - PURPOSE: To meet increasing demand for cancer genetic testing and improve value based cancer care delivery, National Cancer Centre Singapore restructured the Cancer Genetics Service in 2014. Care delivery processes were redesigned. We sought to improve access by increasing the clinic capacity of the Cancer Genetics Service by 100% within 1 year without increasing direct personnel costs. METHODS: Process mapping and plan-do-study-act (PDSA) cycles were used in a quality improvement project for the Cancer Genetics Service clinic. The impact of interventions was evaluated by tracking the weekly number of patient consultations and access times for appointments between April 2014 and May 2015. The cost impact of implemented process changes was calculated using the time driven activity-based costing method. RESULTS: Our study completed two PDSA cycles. An important outcome was achieved after the first cycle: The inclusion of a genetic counselor increased clinic capacity by 350%. The number of patients seen per week increased from two in April 2014 (range, zero to four patients) to seven in November 2014 (range, four to 10 patients). Our second PDSA cycle showed that manual preappointment reminder calls reduced the variation in the nonattendance rate and contributed to a further increase in patients seen per week to 10 in May 2015 (range, seven to 13 patients). There was a concomitant decrease in costs of the patient care cycle by 18% after both PDSA cycles. CONCLUSION: This study shows how quality improvement methods can be combined with time-driven activity-based costing to increase value. In this paper, we demonstrate how we improved access while reducing costs of care delivery. PMID- 26759494 TI - Data Sharing to Support the Cancer Journey in the Digital Era. PMID- 26759495 TI - Journal of Antimicrobial Chemotherapy: in the beginning.... PMID- 26759496 TI - Alternative Radioligands for Investigating the Molecular Pharmacology of Melatonin Receptors. AB - Melatonin exerts a variety of physiologic activities that are mainly relayed through the melatonin receptors MT1 and MT2 Low expressions of these receptors in tissues have led to widespread experimental use of the agonist 2-[(125)I] iodomelatonin as a substitute for melatonin. We describe three iodinated ligands: 2-(2-[(2-iodo-4,5-dimethoxyphenyl)methyl]-4,5-dimethoxy phenyl) (DIV880) and (2 iodo-N-2-[5-methoxy-2-(naphthalen-1-yl)-1H-pyrrolo[3,2-b]pyridine-3-yl])acetamide (S70254), which are specific ligands at MT2 receptors, and N-[2-(5-methoxy-1H indol-3-yl)ethyl]iodoacetamide (SD6), an analog of 2-[(125)I]-iodomelatonin with slightly different characteristics. Here, we further characterized these new ligands with regards to their molecular pharmacology. We performed binding experiments, saturation assays, association/dissociation rate measurements, and autoradiography using sheep and rat tissues and recombinant cell lines. Our results showed that [(125)I]-S70254 is receptor, and can be used with both cells and tissue. This radioligand can be used in autoradiography. Similarly, DIV880, a partial agonist [43% of melatonin on guanosine 5'-3-O-(thio)triphosphate binding assay], selective for MT2, can be used as a tool to selectively describe the pharmacology of this receptor in tissue samples. The molecular pharmacology of both human melatonin receptors MT1 and MT2, using a series of 24 ligands at these receptors and the new radioligands, did not lead to noticeable variations in the profiles. For the first time, we described radiolabeled tools that are specific for one of the melatonin receptors (MT2). These tools are amenable to binding experiments and to autoradiography using sheep or rat tissues. These specific tools will permit better understanding of the role and implication in physiopathologic processes of the melatonin receptors. PMID- 26759498 TI - Cognitive Dysfunction After Cranial Radiation for a Brain Tumor. PMID- 26759500 TI - Update From the Advisory Committee on Immunization Practices. PMID- 26759497 TI - Shedding of Oral Poliovirus Vaccine (OPV) by HIV-Infected and -Uninfected Mothers of OPV-Vaccinated Zimbabwean Infants. AB - Community circulation of oral poliovirus vaccine (OPV) likely begins with household transmission. We analyzed stool collected from Zimbabwean mothers who were infected with human immunodeficiency virus (HIV) and those who were uninfected with HIV 1 to 24 weeks after infant oral poliovirus vaccination. Overall, only 5% of the mothers had detectable OPV (16 of 304) despite high infant shedding rates. OPV shedding was similar between HIV-infected mothers and those who were uninfected (11 [6.4%] of 171 vs 5 [3.8%] of 133, respectively) and between mothers of HIV-infected infants and those of uninfected infants (2 [3.5%] of 57 vs 9 [6.3%] of 144, respectively). Mothers of vaccinated infants are unlikely to shed OPV, even when they are infected with HIV. PMID- 26759502 TI - Audit of annual medical appraisal and revalidation activity across the UK Defence Medical Services 2013-2014. AB - AIM: To provide the first annual audit of Defence Medical Services (DMS) medical appraisal and revalidation activity. CONTENT: A questionnaire-based survey of appraisal and revalidation activity within the 2013-2014 appraisal year (1 April 2013 - 1 March 2014) across the Royal Navy (RN), Army, Royal Air Force (RAF) and Ministry of Defence (MOD) and Defence Postgraduate Medical Deanery (DPMD) Designated Bodies (DBs). RELEVANCE: Mandatory annual medical appraisal of all DMS doctors was introduced in 2002. The General Medical Council (GMC) introduced licences to practise in November 2011. Revalidation went live in December 2012. In the 2013-2014 appraisal year, there were 1379 DMS doctors. The Responsible Officers (ROs) of the RN, Army, RAF, MOD and Defence Postgraduate Medical Deanery (DPMD) provide appraisal and revalidation services for doctors within their DBs. OUTCOMES: In the 2013-2014 appraisal year, 82% of DMS doctors completed an annual appraisal. ROs provided positive revalidation recommendations for 90% of DMS doctors without the need for additional supporting information. Additional supporting evidence was required for 10% of DMS trained doctors, but ultimately 100% of DMS doctors due revalidation in the 2013-2014 appraisal year received a positive recommendation. DISCUSSION: To assist DMS compliance with GMC quality assurance requirements, HQ Surgeon General now maintains a central database of appraisal and revalidation data across the five DMS DBs. Appropriately targeted appraiser training and 'revalidation ready top-up' training should be provided to ensure the demand for military appraisers is met, and that DMS appraisers appropriately maintain their skills. MOD now maintains a central live database for ongoing appraisal and revalidation monitoring. PMID- 26759501 TI - Are Belgian military students in medical sciences better educated in disaster medicine than their civilian colleagues? AB - INTRODUCTION: Historically, medical students have been deployed to care for disaster victims but may not have been properly educated to do so. A previous evaluation of senior civilian medical students in Belgium revealed that they are woefully unprepared. Based on the nature of their military training, we hypothesised that military medical students were better educated and prepared than their civilian counterparts for disasters. We evaluated the impact of military training on disaster education in medical science students. METHODS: Students completed an online survey on disaster medicine, training, and knowledge, tested using a mixed set of 10 theoretical and practical questions. The results were compared with those of a similar evaluation of senior civilian medical students. RESULTS: The response rate was 77.5%, mean age 23 years and 59% were males. Overall, 95% of military medical students received some chemical, biological, radiological and nuclear training and 22% took part in other disaster management training; 44% perceived it is absolutely necessary that disaster management should be incorporated into the regular curriculum. Self-estimated knowledge ranged from 3.75 on biological incidents to 4.55 on influenza pandemics, based on a 10-point scale. Intention to respond in case of an incident ranged from 7 in biological incidents to 7.25 in chemical incidents. The mean test score was 5.52; scores improved with educational level attained. A comparison of survey data from civilian senior medical master students revealed that, except for influenza pandemic, military students scored higher on knowledge and capability, even though only 27% of them were senior master students. Data on willingness to work are comparable between the two groups. Results of the question/case set were significantly better for the military students. CONCLUSIONS: The military background and training of these students makes them better prepared for disaster situations than their civilian counterparts. PMID- 26759503 TI - Substance Use Disorders, Comorbidity, and Arrest among Indigenous Adolescents. AB - Indigenous adolescents are overrepresented at multiple stages of the justice system, but we know very little about the role that mental health, particularly substance use disorder, plays in Indigenous pathways to arrest. This study examined the association between substance use disorder, its comorbidity with other disorders, and arrest using a longitudinal sample of Indigenous youth from the Northern Midwest and Canada. Of the 16% of youth who reported at least one arrest at Wave 5, half met criteria for substance abuse/dependence, and slightly more for conduct disorder. Substance abuse/dependence and conduct disorder were each associated with an increased risk of arrest, although co-occurring disorders were not. The reciprocal effects of arrest and mental disorder are discussed. PMID- 26759504 TI - Reasons why West Africa continues to be a hotbed for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) exhibits a huge disease burden on West Africa, with a large proportion of all HCC cases worldwide occurring in the sub-region. The high HCC prevalence is due to the endemicity of a number of risk factors, most notably hepatitis B, C and HIV. West African HCC also displays a poor prognosis. Generally speaking, this is owing to more aggressive tumours, late patient presentation and inadequate management. Exposure to chronic viral hepatitis, more carcinogenic West African strains of hepatitis B virus and carcinogens such as aflatoxin B1 all encourage tumour growth. Lack of patient confidence in the healthcare system contributes to poor health-seeking behaviors and management of the disease can be lacking, due in part to poor health infrastructure, resources available and lack of access to expensive treatment. There is also much we do not know about West African HCC, especially the effect rising obesity and alcohol use may have on this disease in the future. Suggestions for improvement are discussed, including surveillance of high-risk groups. Although there is much to be done before West African HCC is thought to be a curable disease, many steps have been taken to move in the right direction. PMID- 26759505 TI - Maternal overweight/obesity characteristics and child anthropometric status in Jos, Nigeria. AB - OBJECTIVE: This study is to determine the pattern of overweight and obesity and its relationship with childhood anthropometric status in Nigeria. MATERIALS AND METHODS: This cross-sectional study was conducted in Jos, Nigeria. Interviewer administered questionnaire was used in data collection. Maternal and child anthropometric measurements were obtained using standard WHO methods. Child anthropometric Z scores were obtained from WHO Anthroplus while BMI of mothers were also determined. Totally, 262 mother-child pairs were recruited. RESULTS: Mean maternal age and mean child age were 30.8 +/- 6.3 yrs (15-47 yrs) and 22.3 +/- 18.7 months (3-72 months). Prevalence of maternal underweight, overweight and obesity was 4.2% (11/262), 29.4% (77/262) and 25.9% (68/262), respectively. Child overweight/obesity was 5.4% (14/262), severe under-nutrition 5.7% (15/262). Mean maternal BMI was higher in the older, more educated and higher socioeconomic status (SES). Child mean birth-weight, weight-for-age Z-score and BMI-for-age Z score (BAZ) were higher among mothers with BMI >= 25 kg/m(2). All large-for-age babies were in mothers with maternal BMI >= 25 kg/m(2). Childhood over-nutrition was more common in maternal BMI of >=25 kg/m(2). Overall, BAZ was directly related with maternal BMI, maternal age and birth-weight, although it was inversely related with maternal BM I >= 25 kg/m(2). CONCLUSION: Higher BMI is seen in educated and higher SES mothers and this impact on childhood anthropometry. PMID- 26759506 TI - Analysis of 46 cases of malignant jaw tumours in Calabar, Nigeria. AB - BACKGROUND: The occurrence and distribution of malignant jaw tumours differs across the globe because of differences in geographical, cultural, racial, and socioeconomic factors. The aim of this study was to determine the types and pattern of malignant jaw tumours in Calabar, located in South-South Nigeria. MATERIALS AND METHODS: The histopathologic results, as well as demographic and clinical information of all consecutive patients diagnosed of having a malignant jaw tumour at the Oral and Maxillofacial Unit of University of Calabar Teaching Hospital, Calabar, Nigeria from January 2000 to December 2013 was retrospectively collected and analyzed. RESULTS: A total of 46 (25.1%) out of the 180 cases of jaw neoplasms seen over the 14 year period were malignant. There was a slight male predominance with a ratio of 1.7:1 and the age ranged from 4 to 70 years, mean (standard deviation) 34.6 (4.56) years. The most common malignant lesion was squamous cell carcinoma (SCC) (n = 20; 43.5%), followed by Burkitt lymphoma (n = 8; 17.4%). The gender distributions of the lesions were significant, with more SCC seen in females in a ratio of 1.5:1 in relation to males. Osteosarcoma (n = 6; 13%) and rhabdomyosarcoma (n = 4; 8.7%) were observed only in males and females, respectively. About half of the lesions occurred in the mandible (47.8%). The age distribution of lesions was significant (P < 0.001), with SCC frequently seen in the sixth and seventh decades while Burkitt's lymphoma and rhabdomyosarcoma were seen around the first decade. Clinical presentations ranged from swelling (n = 31), pain (n = 26), loosed teeth (n = 15), toothache (n = 11) to missing teeth (n = 9) among others and occurring either singly or in two or more combinations. The duration of symptoms on presentation ranged from 1 to 46 months, mean 21.7 (13.12) months and this was not different for male or female (P > 0.05). CONCLUSION: Oral cancer awareness campaign and advocacy is necessary to steer the awareness of the population on the need for regular dental visits, early recognition, and the dangers associated with late presentation of orofacial malignancy. PMID- 26759507 TI - Stigmatisation of mental illness among employees of a Northern Nigerian University. AB - BACKGROUND: Prejudices against people with mental illness are widespread in many societies leading to a number of detrimental consequences. In order to adequately develop programmes and services that will help protect the rights and privileges of people with mental illness, it is imperative to study the nature of stigma and factors associated with it. Our objective in this study was to observe the level of stigmatisation of the mentally ill among employees of a Nigerian University and the factors associated with it. MATERIALS AND METHODS: The study was carried out at the Ahmadu Bello University Teaching Hospital and the Ahmadu Bello University main campus. Employing a two-staged random sampling technique, 15 departments were chosen from both institutions, after which 10 participants were further sampled from each department to obtain a total of 150 participants. All the participants were administered the socio-demographic questionnaire and Mental Illness Clinicians' Attitude 4(th) version (MICA 4). RESULTS: The findings indicate that 53.4% of respondents' classified as high stigmatisation while 46.6% was classified as low stigmatisation. Low scores on stigmatisation were observed among departments of psychiatry, nursing and ophthalmology, while high scores were observed among respondents from administration and engineering. Relationship between variables and predictors of stigmatisation were also established. CONCLUSION: There is a high tendency to stigmatise persons with mental illness except where there has been some contact with mental health practice or among the clinical departments in the hospital. We recommend community psychiatry care for the mentally ill and psycho-education for staff periodically to reduce this level of stigmatisation. PMID- 26759508 TI - Comparative study of intralesional steroid injection and cryotherapy in alopecia areata. AB - BACKGROUND AND OBJECTIVES: Alopecia areata (AA) is a common, non-scarring type of hair loss, affecting approximately 2.1% of the population, many modality of treatment recommended like steroid injection, topical Immunotherapy and several systemic therapies. The aim of this study was to compare intralesional steroid injection and cryotherapyoutcomes in AA. MATERIALS AND METHODS: In an analytical descriptive study, 120 AA patients treated with intralesionalsteroid injection and 120 AA patients treated with cryotherapy were randomly selected. These two groups matched for location, duration and size of lesion and also matched for age and gender. From March 2011 to September 2013, the effect and complications of the therapies after 3, 6, 9 and 12 weeks were assessed and results were compared between the two groups. RESULTS: Mean age of patients in steroid injection group was 30.2 +/- 6.8 and in cryotherapy group was 31.8 +/- 7.1. Sexual distribution in both groups was 56.7% and 43.3 % for male and female, respectively. Location of disease in 80% was in scalp and 20% was in face in both groups. The time of beginning response in steroid group was 4.13 +/- 2.13 weeks and in cryotherapy group was 6.14 +/- 0.29 weeks, difference between two groups was significant (P = 0.001). In term of clinical response at the end of study, in steroid group,20 patients (16.7%) no response, 32 patients (26.7%), moderate response and68 patients (56.7%) had a complete response, and also in cryotherapy group was, 52 patients (43.3%) no response, 40 patients (33.3%) moderate response and 28 patients (23.3%) had a complete response. There was significant different in complete response rate and steroid injection was more effective than cryotherapy(P < 0.05). CONCLUSION: As the cryotherapy isa considerable treatment of AA, alsothis study proposes intralesional injection of corticosteroid, as a replacement of AA therapy; particularly the short-term complications are not significantly different. PMID- 26759509 TI - Echocardiographic pattern of acquired heart diseases in Nigeria. AB - BACKGROUND: Acquired heart diseases (AHDs) are present from childhood to old age, and the frequency of pathology differs according to age and the geographical region of the patients. The aim of this study was to document the echocardiographic patterns of AHDs in our setting. MATERIALS AND METHODS: Retrospective analysis of echocardiographic diagnosis of AHD was done for age, sex, and echocardiographic pattern. RESULTS: There were 190 diagnoses in the 163 patients with 27 patients having a double diagnosis, consisting of 88 (54%) males and 75 (46%) females. The mean age was 50.4 years (age range 9-85 years). Ten types of acquired heart pathologies were identified and they included hypertensive heart disease in 49.47%, rheumatic heart disease in 26.32%, cardiomyopathy in 11.05%, endomyocardial fibrosis in 4.74%, and pericarditis in 3.68%. Others were cor pulmonale, pulmonary hypertension, intracardiac thrombi, left atrial myxoma and degenerative heart disease which accounted for the remaining 4.74%. CONCLUSION: This study identifies 10 types of AHDs among the study population. The huge impact of hypertensive heart disease and rheumatic heart disease is a big indicator pointing to the existence of a sub-optimal level of healthcare in the country. PMID- 26759510 TI - Pulmonary and extra-pulmonary manifestations of sarcoidosis. AB - BACKGROUND: Sarcoidosis is a systemic multi-organ granulomatous disease of unknown etiology that is characterized by the presence of granuloma in various organs. The clinical features of sarcoidosis are heterogeneous but pulmonary involvement is cardinal manifestations. The aim of this study was to determine radiologic, clinical and laboratory findings of patients with sarcoidosis. PATIENTS AND METHODS: In a cross-sectional study, all patients visiting sarcoidosis clinic were enrolled in the study. Computed tomography (CT) scan was obtained and lab exams were obtained from patient and reports were recorded in data sheet. RESULTS: Total of 55 patients with sarcoidosis were enrolled in the study. The average of age was 44.6 (range 25-62) years. Thirty-seven patients were male and 18 were female. The most common extra-pulmonary manifestation was arthritis (in 18% of cases) and then lupus pernio (12.8%) and uveitis (10.9%). Bilateral hilar adenopathy and para tracheal lymphadenopathy was observed in 39(70%) and 22 (40%) of patients. Parenchymal nodules (30%), bronchiectasia (25%), ground-glass opacification (18%) were the most common findings. Percentages of patients with dyspnea were 29% and percentages of patients with cough were 21%. Among abnormal lab tests, high urine calcium (Ca) were positive in 21% and high angiotensin-converting enzyme (ACE) in 16% of patients. CONCLUSION: Pulmonary involvements are both fibrosis and granulomatosis and the most common manifestations are parenchymal nodules, bronchiectasia and high-grade fibrosis. The most common extra-pulmonary involvement is arthritis. Lab tests are non-specific and have no correlation with duration or severity of disease. PMID- 26759511 TI - Routine prenatal ultrasound anomaly screening program in a Nigerian university hospital: Redefining obstetrics practice in a developing African country. AB - BACKGROUND: Congenital anomalies are among the leading causes of fetal and infant morbidity and mortality worldwide. Prenatal ultrasound (US) screening has become an essential part of antenatal care in the developed world. Such practice is just evolving in the developing countries such as Nigeria. The aim of this article is to present our initial experience and demonstrate the effectiveness of a prenatal US screening program in detecting congenital malformation in a developing country. MATERIALS AND METHODS: This was a prospective evaluation of the prenatal US screenings conducted at a major referral hospital in Southwestern Nigeria. All pregnant women referred to the antenatal clinic for mid-trimester screening during the period of study were assessed. RESULTS: Two hundred and eighty-seven pregnant women (5 with twin gestations) were presented for fetal anomaly scan during the study period. Twenty-nine anomalies (9.9%) were detected among the scanned population. Sixteen of the anomalies were followed to delivery/termination with a specificity of 93.5%. The commonest malformations were demonstrated in the genitourinary tract (34.5%) followed by malformations within the central nervous system (27.6%). Six (20.6%) of the anomalies were lethal. Five of the anomalies were surgically correctable. CONCLUSION: Institutions and hospitals across Nigeria and other low- and middle-income countries need to develop policies and programs that would incorporate a standardized routine screening prenatal US in order to improve feto-maternal well being and reduce the high perinatal mortality and morbidity in developing nations. PMID- 26759512 TI - An assessment of the clinical utility of echocardiography criteria in a Tertiary Health Center. AB - BACKGROUND: The rising prevalence of cardiovascular diseases in the population has increased the demand for cardiovascular imaging procedures (specifically echocardiography) in our center. AIM: To determine the percentage of appropriate indications for echocardiography. MATERIALS AND METHODS: This was a prospective study conducted over a period of 1 year in the Department of Medicine of a Tertiary Health Care Center. The clinical diagnoses by the referring clinician and the indications (specific reasons for the study) for the echocardiography were consecutively recorded. The age and gender of the patients were also recorded. The indications were given a score of one to nine according to the revised appropriate use criteria of the American College of Cardiology Foundation and the American Society of Echocardiography (ASE). These indications were then classified into appropriate, inappropriate or uncertain based on the score. (1-3) inappropriate use, (4-6) were derived. RESULTS: There were 25 indications, 16 (64%) were appropriate, 6 (24%) were inappropriate and three (12%) were rated as uncertain. CONCLUSION: Sixty-four percent of the indications for echocardiography are appropriate for the procedure. This implies that the criteria for echocardiography are yet to be fully implemented resulting in overutilization of the procedure. PMID- 26759513 TI - Antioxidative and antidiabetic activities of watermelon (Citrullus lanatus) juice on oxidative stress in alloxan-induced diabetic male Wistar albino rats. AB - BACKGROUND: The nutritional and medicinal importance of watermelon has been emphasized and its diseases preventive and curative power must be evaluated. Hence, this study was designed to evaluate the antioxidative and antidiabetic potentials of watermelon. MATERIALS AND METHODS: The in vivo assay was carried out on 15 male albino rats which were divided into groups of three stages. In stage I, all animals received normal feeds and water for 1-week after, which five animals were selected and sacrificed for biochemical analyses which form the nondiabetic control, group. The remaining animals were fasted for 24 h before injected intra-peritoneally with a freshly prepared solution of alloxan at a dosage of 35 mg/kg body weight. Five out of the 10 rats were sacrificed as diabetic group while last five animals were fed with water melon juice for a week after, which they were sacrificed to form the treated group animals. In all the groups, body weights, fasting blood sugar, total protein level in the blood, and other biochemical parameters such as reduced glutathione (GSH), glutathione peroxidase (GPx), malondialdehyde (MDA) concentration; catalase, and superoxide dismutase (SOD) % inhibition activities were determined. RESULTS: The results of the biochemical analyses showed a significant increase in the concentration of blood glucose level after treatment with alloxan, which indicates that diabetic was induced. Hence, watermelon juice caused increased in weight, hypoglycemia; and increases in GSH, GPx, catalase, and SOD % inhibition activities with reduced MDA concentration after treatments. CONCLUSION: The watermelon juice resulted in the restoration of impaired conditions of the rats. PMID- 26759514 TI - Malaria rapid diagnostic test in children: The Zamfara, Nigeria experience. AB - BACKGROUND: Malaria remains a major cause of under-five morbidity and mortality in Nigeria, and prompt diagnosis occupies a strategic position in its management. Malaria rapid diagnostic test (RDT), a nontechnical, easy to perform test promises to meet this need. It is important to locally document the usefulness of the use of RDT in making prompt malaria diagnosis in children. OBJECTIVE: To determine the prevalence of malaria and evaluate the diagnostic performance of malaria RDT kit in febrile under-five children presenting to a Tertiary Health Facility in Gusau, North-Western Nigeria. MATERIALS AND METHODS: A cross sectional study of children aged 6-59 months, evaluated for malaria in a tertiary health facility from August 2012 to January 2013. Information was obtained from care providers of all subjects with fever and a presumptive diagnosis of malaria. All subjects were investigated using Giemsa stain microscopy and CarestartTM malaria RDT. RESULTS: The prevalence of malaria in 250 febrile under-five children was 54%. Three-quarter (79%) of the children received inappropriate nonrecommended antimalaria prior to their presentation, including 20% who received chloroquine. The overall sensitivity of RDT was 40.3%. The specificity, positive and negative predictive values were 89.6%, 81.8%, and 56.5%, respectively. CONCLUSION: Use of RDT should be encouraged for screening and diagnosis using a protocol such that febrile children with positive RDT results are confirmed as having malaria while those with negative results are further evaluated using microscopy. PMID- 26759515 TI - Poor semen parameters among infertile couples presenting at a gynaecological clinic of Federal Medical Centre Birnin Kudu North-west Nigeria. AB - BACKGROUND: Male partners contribute significantly to infertile couple problem. The present study was undertaken to review the seminal fluid analysis (SFA) of couples presenting with inability to conceive at the gynecological clinic of Federal Medical Centre, Birnin Kudu, Jigawa State using World Health Organization 2010 criteria, identify the correlation between poor semen quality and age and to identify culture and sensitivity patterns of isolates. MATERIALS AND METHODS: This was a retrospective study. The sample size was 63 Ethical clearance was obtained. Patients' case records and laboratory registers were retrieved. The volume, viscosity, pH, sperm count, motility, and the morphology of the seminal fluid were determined. Semen m/c/s was done. Data were analyzed by using SPSS version 16 (SPSS Inc., Chicago, Il, USA). Descriptive statistics was used. Association between age and semen parameters were determined using Pearson's coefficient of correlations and Chi-square test and P < 0.05 was considered statistically significant. MAIN OUTCOME MEASURES: The proportion of infertile male with abnormal semen parameters. RESULTS: Of the 308 couple presenting for infertility evaluation, only 63 male partners presented for SFA. This is 20.5% of the couples. After analysis, 52.38% were normospermic while 26.98% and 20.64% were azoospermic and oligospermic, respectively. Asthenospermia was the commonest motility/morphology abnormality occurring in 60.3%. The mean volume, sperm count, motility, morphology, and pH were 2.8 +/- 1.8, 40.1 +/- 52.3, 28.2 +/- 27.7, 46.1 +/- 35.6, and 8.3 +/- 0.67, respectively. The volume, motility, morphology, and pH showed weak correlations with age. CONCLUSION: Male partners are significant contributors to the infertile couple problems in this study; therefore awareness is needed in order to engage more males in evaluation and treatment of infertility. PMID- 26759516 TI - Predictors of mortality in children due to severe and very severe pneumonia. AB - BACKGROUND: Mortality due to pneumonia in children is more than any other illness. Limited data is available to predict mortality in children with pneumonia from central India. AIM: To study predictors of mortality in children aged 1-59 months hospitalised with severe and very severe pneumonia. MATERIALS AND METHODS: Present study was observational longitudinal study that was done in a tertiary care hospital of central India. Two hundred and ninety children, aged 1-59 months, presented with severe and very severe pneumonia were enrolled in this study. Outcome and predictors of mortality were studied. Data was analysed with Chi-square test, univariate and multivariate regression analysis. RESULTS: Out of 270 enrolled study subjects, maximum (108, 37.24%) were belonged to 1-6 months age group. Proportion of mortality was maximum (16, 64.00%) in that age group. Overall case fatality rate was 8.62%. Among significant variables, delayed hospital referral [adjusted odds ratio (OR)-52.09, 95% confidence interval (CI)- 6.74-402.39], incomplete immunisation (OR-12.28, 95% CI-2.15-69.93), severe malnutrition (Z score < -3) (OR-15.51, 95% CI- 2.04-117.83), refusal to feed (OR- 30.57, 95% CI- 2.47-378.26), and hypoglycaemia (OR- 6.98, 95% CI- 1.05-46.30) were found significant independently on multivariate regression analysis. CONCLUSION: Delayed hospital referral, incomplete immunisation, severe malnutrition, refusal to feed, and hypoglycaemia were independent predictors of mortality in children with severe and very severe pneumonia. PMID- 26759517 TI - Dipstick urinalysis findings in children with Plasmodium falciparum in the South Tongu District: A case-control study. AB - BACKGROUND: Malaria ranks among the major health and developmental challenges facing some of the poorest countries in tropical and sub-tropical regions across the globe. We determined urinary abnormalities and its relationship with parasite density in children <=12 years with Plasmodium falciparum infection. MATERIALS AND METHODS: From December 2013 to March 2014, we randomly recruited 116 participants comprising 58 malaria patients (cases) and 58 healthy controls from the Comboni Mission and the Sogakope District Hospitals both in the South Tongu district. Blood was collected for the estimation of hemoglobin and total white blood cells; thick and thin blood films were used for the determination of malaria parasite density. Urine was collected for the measurement of the various biochemical components using the automated urine analyzer. A pretested questionnaire was used to obtain demographic and clinical data. RESULTS: Urine protein (P < 0.001), blood (P < 0.001), bilirubin (P < 0.001), urobilinogen (P < 0.001), and ketones (P = 0.001) were significantly higher in individuals with P. falciparum infection than in healthy controls. Proteinuria (P = 0.247; r = 0.155), hematuria (P = 0.142; r = 0.195), bilirubinuria (P = 0.001; r = 0.438), urobilinogenuria (P = 0.876; r = 0.021), and ketonuria (P = 0.136; r = 0.198) were positively correlated with malaria parasite density; however, only bilirubinuria was significantly higher at higher parasitemia. CONCLUSION: Malaria has a significant effect on the chemical composition of urine with bilirubin positively correlated with parasite density. Dipstick urinalysis can be used together with light microscopy in resource-limited malaria-endemic areas to accurately diagnose falciparum malaria infection. PMID- 26759518 TI - Profiles of acute bacterial meningitis isolates in children in National Hospital, Abuja. AB - BACKGROUND: Acute bacterial meningitis (ABM) is an important cause of morbidity and mortality throughout the world. It is an acute medical emergency that requires urgent rational antibiotic therapy, especially in neonates and young infants. Determining the pattern and susceptibility of isolates of ABM among children for prompt treatment of this important cause of mortality and morbidity is very important. This study determined the types and the antimicrobial susceptibility pattern of ABM isolates among children at the National Hospital, Abuja. MATERIALS AND METHODS: This is a retrospective study carried out at the National Hospital Abuja (NHA), Nigeria. Laboratory data for a period of 3 years, January 2010-December 2013 were reviewed, and all bacterial isolates and their antibiotics sensitivity testing results for children aged 0-15 years, and other relevant information extracted and analyzed. Study center was the NHA. RESULTS: Twenty-eight bacterial pathogens were isolated from a total of 542 cerebrospinal specimens over the study period, giving a yield of 5.2%. The four most common pathogens isolated were Staphylococcus aureus (32.2%), Klebsiella pneumoniae (21.5%), Streptococcus pneumoniae (17.6%), and Escherichia coli (14.3%). Whereas, 28.6% of all the infections occurred in neonates alone, children 2 years and below had 85.7% of all the infections, with male preponderance. Isolates of S. aureus and S. pneumonia tested were both 100% susceptible to amoxicillin clavulanic acid and Cefuroxime; S. pneumoniae was equally sensitive to Ceftriaxone. K. pneumoniae was 100% sensitive to Imipenem, but 83% to ceftriaxone. 75% of the isolated E. coli strains were sensitive to ceftriaxone, amoxicillin-clavulanic acid, and amikacin, 100% sensitive to imipenem. CONCLUSION: Meningitis in children as seen in the National hospital is almost equally caused by both Gram-positive and Gram-negative organisms, predominantly by S. aureus, S. pneumoniae, K. pneumoniae, and E. coli. Available drugs remain active against these organisms. PMID- 26759519 TI - Barriers to uptake of human papilloma virus vaccine in Nigeria: A population in need. PMID- 26759520 TI - Knowledge regarding Ebola Hemorrhagic Fever among private dental practitioners. PMID- 26759522 TI - Learning interactions via hierarchical group-lasso regularization. AB - We introduce a method for learning pairwise interactions in a linear regression or logistic regression model in a manner that satisfies strong hierarchy: whenever an interaction is estimated to be nonzero, both its associated main effects are also included in the model. We motivate our approach by modeling pairwise interactions for categorical variables with arbitrary numbers of levels, and then show how we can accommodate continuous variables as well. Our approach allows us to dispense with explicitly applying constraints on the main effects and interactions for identifiability, which results in interpretable interaction models. We compare our method with existing approaches on both simulated and real data, including a genome-wide association study, all using our R package glinternet. PMID- 26759521 TI - Retraction: What makes a Journal Great. AB - [This retracts the article on p. 1 in vol. 52, PMID: 21968564.]. PMID- 26759524 TI - Foreword. PMID- 26759523 TI - The Influence of Paternal and Maternal Major Depressive Disorder on Offspring Psychiatric Disorders. PMID- 26759526 TI - Optimising the treatment of the partially platinum-sensitive relapsed ovarian cancer patient. AB - The choice of second-line chemotherapy in patients with recurrent ovarian cancer (ROC) is complex, with several factors to be considered, the most important of which is the length of the platinum-free treatment interval (PFI). Recently ROC patients have been further stratified into platinum sensitive (PS), partially platinum sensitive (PPS) and platinum resistant (PR) subgroups depending on the length of the PFI. Response to second-line therapy, progression-free survival (PFS) and overall survival (OS) are linked to the PFI, all of them improving as the PFI increases. Consequently, there is increasing interest in PFI extension strategies with platinum-free therapeutic options. Such strategies are currently being studied in patients with partially platinum-sensitive disease (PFI 6-12 months), as the treatment of these patients remains clinically challenging. A non platinum option, trabectedin + pegylated liposomal doxorubicin (PLD) combination, has been evaluated in ROC patients in the pivotal phase III OVA-301 study. The OVA-301 study differed from previous trials in the same setting as it included only patients who were not expected to benefit from or who were ineligible for or who were unwilling to receive re-treatment with platinum-based chemotherapy, including those with PPS and PR disease. Subset analysis of patients with PPS disease in OVA-301 showed that the trabectedin + PLD combination significantly improved PFS compared with PLD alone; median PFS 7.4 versus 5.5 months, p=0.0152. Final survival data from the same subset of patients, showed that trabectedin + PLD also achieved a significant 36% decrease in the risk of death compared with PLD alone (HR=0.64; 95% CI, 0.47-0.88; p=0.0027). Median overall survival (OS) was 22.4 months in the trabectedin + PLD arm versus 16.4 months in the PLD arm. This represents a statistically significant 6-month improvement in median OS in patients treated with trabectedin + PLD compared to those treated with PLD alone. PMID- 26759525 TI - Introduction to managing patients with recurrent ovarian cancer. AB - Ovarian cancer is the 5th most common cancer found in women in the UK. It is the leading cause of death from gynaecological cancer, and is the 4th most common cause of cancer death among UK women. Similar to the majority of other cancers, relative survival rates for ovarian cancer are improving, although 5-year mortality rates remain stubbornly low. The stage of the disease at diagnosis is the single most important determinant of ovarian cancer survival, as many patients first present with advanced disease. Treatment of ovarian cancer involves a combination of 'upfront' primary surgery followed by chemotherapy. Platinum/taxane-based chemotherapy is the recommended standard-of-care first-line chemotherapy, but the majority of patients will relapse with drug-resistant disease within 3-5 years. However, not all patients can continue with platinum combination therapies due to loss of activity or toxicity-related issues, including hypersensitivity, neurotoxicity, alopecia and ototoxicity. Therefore the choice of second-line chemotherapy must take into account factors such as platinum-free treatment interval (PFI); patient's performance status; current symptoms; history of and likely future toxicities while on chemotherapy; dosing schedule requirement; and cost of treatment. A consensus in 2010 established 4 distinct subgroups within the ROC patient population based on the PFI: (platinum sensitive <12 months, partially platinum sensitive 6-12 months, platinum resistant <6 months, and refractory disease <=4 weeks). Within patients with platinum sensitive disease, those with partially platinum sensitive disease remain the most clinically challenging to manage effectively. Non-platinum based combination therapies, in particular trabectedin with pegylated liposomal doxorubicin (PLD), offers new options together with a significant survival advantage relative to PLD alone for these patients. PMID- 26759527 TI - Limitations to the use of carboplatin-based therapy in advanced ovarian cancer. AB - Most patients with recurrent ovarian cancer (ROC) undergo a series of remissions and recurrences, therefore the additive or cumulative toxicity of chemotherapy must be factored into their treatment plan. There are challenges in defining tailored therapeutic approaches, including optimal timing and drug sequencing management strategies to treat patients with ROC. This is particularly relevant as new cytotoxic drugs and biological agents become available. Many of these drugs are associated with increased toxicity and with no observable survival advantage. Therefore current treatment options for the heavily-pretreated relapsing OC patient population are frequently guided by safety considerations and convenience. Rechallenge with platinum-based combination regimes is commonly limited by the risk of cumulative long-term toxicities. Not all patients can continue with platinum at second-line or, indeed, further relapses due to loss of activity or toxicity-related issues including hypersensitivity, neurotoxicity, alopecia and ototoxicity. In particular, hypersensitivity reactions are a concern and have been reported in approximately 15-20% of women receiving the drug. Trabectedin + PLD is a non-platinum combination that is well tolerated, with a manageable safety profile, which is independent of age. PMID- 26759528 TI - Real-life experience using trabectedin plus pegylated liposomal doxorubicin combination to treat patients with relapsed ovarian cancer. AB - The goal of recurrent ovarian cancer (ROC) treatment is no longer just palliation, but prolonging survival. This is usually through administering a new line of chemotherapy at each relapse. A novel treatment sequencing strategy to achieve this is through the intercalation of an effective non-platinum alternative, in between platinum-based therapies. Trabectedin in combination with pegylated liposomal doxorubicin (PLD) has been fully available privately in the UK since 2009 for treating patients with ROC. A single institution's experience with the trabectedin + PLD combination, as a non-platinum/non-taxane alternative, to intercalate between platinum-based therapies is reported here. To date 6 patients have been successfully treated with trabectedin + PLD at Broomfield Hospital, Chelmsford, Essex. Here we describe a new, practice-changing treatment approach in a real-life case study of a heavily-treated patient with advanced ROC treated with trabectedin + PLD at fourth-line and then subsequently rechallenged at seventh-line; with treatment continuing until disease progression. PMID- 26759529 TI - How can students contribute? A qualitative study of active student involvement in development of technological learning material for clinical skills training. AB - BACKGROUND: Policy initiatives and an increasing amount of the literature within higher education both call for students to become more involved in creating their own learning. However, there is a lack of studies in undergraduate nursing education that actively involve students in developing such learning material with descriptions of the students' roles in these interactive processes. METHOD: Explorative qualitative study, using data from focus group interviews, field notes and student notes. The data has been subjected to qualitative content analysis. RESULTS: Active student involvement through an iterative process identified five different learning needs that are especially important to the students: clarification of learning expectations, help to recognize the bigger picture, stimulation of interaction, creation of structure, and receiving context specific content. CONCLUSION: The iterative process involvement of students during the development of new technological learning material will enhance the identification of important learning needs for students. The use of student and teacher knowledge through an adapted co-design process is the most optimal level of that involvement. PMID- 26759532 TI - Investigation of Risk Factors, Stage and Outcome in Patients with Gestational Trophoblastic Disease since 2001 to 2011 in Iran-Yazd. AB - BACKGROUND AND AIM: Gestational trophoblastic disease (GTN) is one of the high risk forms of pregnancy that requires a lot of attention in terms of research studies, considering its incidence and the importance of the disease in advanced form. The aim of this study was to investigate the risk factors and clinical procedure of patients with gestational trophoblastic disease from 2001 to 2002. METHOD OF STUDY: This is a retrospective descriptive study, which was carried out on 150 patients with trophoblastic disease. These patients' files were obtained from Shohadaye Kargar and Shahid Sadoughi hospitals and women's oncology offices of Yazd city. The patients were contacted one by one and their disease situation was determined. The data obtained were recorded in a questionnaire and analyzed by SPSS software. RESULT: The results indicated that the average age of the patients was 27.65 +/- 8.22 with variations in age ranging from 15 to 35 year. In addition, majorities were in the age group of 20 to 40 years. 43.2 percent of the women were affected during their first gestation. 4% had molar gestation record, and 9.4% had positive family record. Mean time of survival was 93.38 +/- 0.62 months (MIN +/- SE), and only one died owing to chemotherapy complication. Vaginal bleeding (90%) was the most common symptom. 54.6 percent of the disease had complete mole, 30% had incomplete mole, 8.6% had invasive mole, 4.6% had choriocarcinoma and 2% had placenta site trophoblastic tumor (PSTT). Among the patients studied, 28.7% were benign in GTN group while 71.3 % were malignant in the GTN group. The malignant patients were divided into three groups per risk, and 41.2% were in the high-risk group. There was theca-lutein cyst in 54% of the patients, which had a significant relationship with the disease risk of persistent GTN. CONCLUSION: Choriocarcinoma and invasive mole is the most malignant pathology. There was significant relationship between disease interval and the beginning of chemotherapy, and theca lutein cyst and persistent GTN. PMID- 26759530 TI - Salt intakes in sub-Saharan Africa: a systematic review and meta-regression. AB - BACKGROUND: High sodium intake increases the risk of hypertension and cardiovascular diseases. For this reason the World Health Organization recommends a maximum intake of 2 g per day and a 30 % reduction in population sodium intake by 2025. However, in global reviews, data on sodium intake in sub-Saharan Africa have been limited. METHODS: A systematic review was conducted to identify studies reporting sodium intake in sub-Saharan African populations. Meta-regression analyses were used to test the effect of year of data collection and method of data collection (urinary/dietary), as well as any association between sex, urban/rural status or a country's economic development, and population sodium intake. RESULTS: We identified 42 papers reporting 67 estimates of adult population sodium intakes and 12 estimates of child population sodium intakes since 1967. Of the 67 adult populations, 54 (81 %) consumed more than 2 g sodium/day, as did four of the 12 (33 %) child populations. Sixty-five adult estimates were included in the meta-regression, which found that urban populations consumed higher amounts of salt than rural populations and that urine collection gave lower estimates of sodium intake than dietary data. CONCLUSIONS: Sodium intake in much of sub-Saharan Africa is above the World Health Organization's recommended maximum intake and may be set to increase as the continent undergoes considerable urbanization. Few identified studies used stringent measurement criteria or representative population samples. High quality studies will be required to identify where and with whom to intervene, in order to meet the World Health Organization's target of a 30 % reduction in population sodium intake and to demonstrate progress towards this target. PMID- 26759531 TI - Adding Genetic Testing to Evidence-Based Guidelines to Determine the Safest and Most Effective Chronic Pain Treatment for Injured Workers. AB - Published guidelines for treating injured workers include the need for personalized treatment to manage chronic pain symptoms and increase functional status. However, they often fail to clarify how to objectively personalize these treatments. Further, certain patients need analgesic relief beyond the short term. In these cases, it is not sufficient or reasonable to utilize the typical broad protocol-based justifications for reduction of opioids and other medications in a haphazard manner based purely on poor response, without attempting to elucidate possible pharmacogenetic reasons for this. These guidelines acknowledge the problem of substance abuse and set forth methods for treatment and prevention. Although it has been established in the scientific community that an individual's experience of pain and likelihood for addiction both have genetic components, genetic testing is not routinely included as part of the overall treatment plan for injured workers with chronic pain. Because decisions in cases of workplace injury should be based on scientific evidence, genetic testing results can add some objective information to the existing subjective and objective clinical data; help ascertain the efficacy and potential for toxicity of treatment; and therefore provide more information for accurate clinical decisions. We propose the addition of genetic testing to consensus guidelines for treating injured workers in order to improve patients' functional status, increase productivity, improve safety of prescribing, decrease the likelihood of substance abuse, and save on overall healthcare costs. PMID- 26759533 TI - The Most Common Type of HPV in Women with Atypical Squamous Cell of Undetermined Significance (ASCUS) in Pap Smear in Iran-Yazd. AB - INTRODUCTION: Cervical cancer is the third most gynecological cancer and one of the common causes of cancer death in women in Iran and the other developing countries. Human Papilloma Virus (HPV) is a known Risk factor in cervical cancer, but according to HPV deference types, the high risk and low risks differ. MATERIAL AND METHOD: We evaluate the most common high risk and low risk HPV type in 180 females with an atypical squamous cells of undetermined significance (ASCUS) results in pap smear in Gynecological Oncology Clinic in Shahid Sadoughi Hospital in Yazd, Iran within 2012 to 2014.HPV typing was done with polymerase chain reaction (PCR) method. The data obtained were recorded in a questionnaire and analyzed by SPSS software. RESULT: More common low risk HPV type in ASCUS patients was type 6 (63.6%) and then type 11 (36.4%). Type 16 was the most common high risk HPV type. DISCUSSION: HPV DNA typing for better management of women With ASCUS is important and this study showed HPV type 16 is the most prevalent type in ASCUS patients. It seems the living region is important in HPV type distribution and Quadri-valant Vaccine can prevent cervical cancer in Iran because the most common low risk HPV is type6 and 11, and HPV 16 is the most common high risk HPV. PMID- 26759534 TI - Neutralization by Acetyl Salicylic Acid of the Testosterone induced Impaired Maspin Synthesis Stimulated by Estriol in Neutrophils through Nitric Oxide Synthesis. AB - PURPOSE: Maspin, an anti breast cancer protein in the mammary cell and normal neutrophil has been reported to be synthesised by the stimulation of NO production induced by estriol. The role of testosterone was investigated in the synthesis of maspin in relation to that of estriol. METHODS: Fifty normal female between the ages of 25-65 years old participated in the study. Maspin synthesis was demonstrated by in vitro translation of maspin mRNA, followed by the quantification of maspin by enzyme linked immune absorbent assay. NO was determined by methomoglobin method. RESULTS: Incubation of the neutrophils in HBSS both with 30 nM estriol resulted in the synthesis of 1.8 ngm maspin with simultaneous increase of NO synthesis. In contrast incubating neutrophils with 20 nM testosterone in the presence of estriol inhibited maspin synthesis to 0.33 nM with simultaneous inhibition of NO synthesis from 1.89 nM to 0 nM at the same time. Addition of 0.2uM flutamide, a testosterone receptor blocker to the incubation mixture restored the synthesis of maspin by 60.64 %. Incubation of 25uM aspirin that stimulated NO synthesis restored the inhibition of maspin synthesis by testosterone by 79.1%. I-NAME, an inhibitor of nitric oxide synthase, abolished both maspin and NO synthesis. Scatchard plot of estriol binding in the presence of testosterone demonstrated that the male sex hormone inhibited the female sex hormone binding to its receptor by "cross talk" between the receptors. It was found that while 1.02 * 10(3) molecules of estriol bind each neutrophil at equilibrium, in the presence of testosterone (20nM) in the binding mixture decreases the binding of estriol to 0.5 * 10(3) with little change in the dissociation constant compared to controls. CONCLUTION: Estriol was found to stimulate maspin synthesis through the stimulation of NO, testosterone inhibited maspin synthesis through the inhibition of NO synthesis. PMID- 26759535 TI - Enhanced Chromatographic Determination of Nicotine in Human Plasma: Applied to Human Volunteers. AB - Development of enhanced UPLC-UV method for determination of nicotine in human plasma was achieved on a Symmetry((r)) C18 column (100 mm * 2.1 mm, 2.2 MUm) applying isocratic elution based on Methanol: Acetonitrile: Phosphate Buffer (pH: 2.7) with the ratio (20:30:50, v/v/v) as a mobile phase. The ultraviolet detector was operated at 260 nm. The mobile phase was pumped through the column at a flow rate of 0.2 mL min(-1). The column temperature was adjusted to 50oC and the injection volume was 2 MUL. Quinine was selected as an internal standard (IS) due to its structure similarity to nicotine having basic pyridine ring to optimize the liquid liquid extraction procedure using diethyl ether coupled with vacuum evaporation at 40 degrees C. Validation parameters for nicotine were found to be acceptable over the concentration range of 2.5-50 ng ml(-1). The application of the proposed method on four healthy human volunteers was approved by the ethical committee. The study was carried out under fasting conditions and the concerned subjects were informed about the objectives and possible risks involved in the study. The proposed method proved to be simple and fast which is a major advantage to analyze large number of samples per day using the accelerated vacuum evaporation technique. The method showed satisfactory data for all the parameters tested within the limits for bioanalytical assays. The lower limit of quantification (LLOQ) permits the application of the method for further pharmacological and clinical studies. PMID- 26759536 TI - Improved Chromatographic Separation of Sitagliptin Phosphate and Metformin Hydrochloride. AB - New UPLC method was developed for determination of sitagliptin and metformin using Symmetry C18 column (100 mm * 2.1 mm, 2.2 MUm) and isocratic elution (methanol 20%), pH (3.5) as a mobile phase. The ultraviolet detector was operated at 220 nm and the column temperature was 50 degrees C. Linearity parameters were acceptable over the concentration ranges of 2-12 MUgml(-1) and 5-35 MUgml(-1) for sitagliptin and metformin, respectively. The variables were premeditated to adjust the chromatographic conditions using design of experiment. The proposed method was proved to be accurate for the quality control of the mentioned drugs in their pharmaceutical dosage form. PMID- 26759537 TI - Synthesis and Biological Evaluation of New Hydrazone Derivatives of Quinoline and Their Cu(II) and Zn(II) Complexes against Mycobacterium tuberculosis. AB - A new series of quinoline hydrazone derivatives and their metal complexes have been synthesized and their biological properties have been evaluated against Mycobacterium tuberculosis (H37 RV strain). Most of the newly synthesized compounds displayed 100% inhibitory activity at a concentration of 6.25-25 MUg/mL, against Mycobacterium tuberculosis. Fluorescence properties of all the synthesized compounds have been studied. PMID- 26759538 TI - Polymorphisms in the cytochrome P-450 (CYP) 1A1 and 17 genes are not associated with acne vulgaris in the Polish population. AB - INTRODUCTION: The pathogenesis of acne is complex, multifactorial and not well understood. The genetic background of this dermatosis is well documented. AIM: To assess the frequency of -34 T > C single nucleotide polymorphism in the promoter of the CYP17 gene as well as m1 (+6,235 T > C) and m2 (+4,889 A > G) mutation in the coding region CYP1A1 gene acne patients from the Northern Polish population. MATERIAL AND METHODS: The study included 115 acne patients and 94 healthy controls (aged over 20) without acne in anamnesis. The CYP1A1 polymorphism was analyzed by polymerase chain reaction (PCR). The restriction fragment length polymorphism (RFLP) was used to analyze m1 mutation and allele-specific PCR in the case of m2 mutation. The CYP17 polymorphism was analyzed by RFLP. The results were evaluated by the Pearson's chi(2) test. RESULTS: There were no statistically significant associations between allele and genotype frequencies between the acne and the control group. CONCLUSIONS: We did not confirm the role of the CYP1A1 and CYP17 gene as predictor factors for acne development in the Polish population. PMID- 26759539 TI - Etiopathogenetic factors, thyroid functions and thyroid autoimmunity in melasma patients. AB - INTRODUCTION: Melasma is a common chronic, acquired pigmentation disorder with a significant impact on the quality of life of patients. AIM: To investigate the etiopathogenetic factors, thyroid functions and thyroid autoimmunity in patients with melasma. MATERIAL AND METHODS: Forty-five women with melasma and 45 age matched healthy women were included in the study group. A detailed history was taken from the patients including triggering factors of melasma. Serum free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), anti-thyroglobulin (AbTG) and anti-thyroid peroxidase (Ab-TPO) were measured and thyroid ultrasonography was performed for each subject. RESULTS: In 26.7% of patients, pregnancy, in 17.8%, oral contraceptive use and in 13.3%, intense sunlight exposure were the triggering factors. 17.8% of patients had a family history of melasma. FT4, TSH and AbTG levels were significantly higher in the patient group. CONCLUSIONS: The results suggest that a combination of factors including pregnancy, oral contraceptive use, sunlight and genetic factors often trigger melasma. Thyroid hormones and thyroid autoimmunity may also play a role in the pathogenesis which needs to be proven by further studies. PMID- 26759541 TI - Selected applications of Er:YAG and CO2 lasers for treatment of benign neoplasms and tumorous lesions in the mouth. AB - INTRODUCTION: Benign neoplasms and hyperplastic tumorous lesions are common oral pathologies. These lesions require to be surgically removed by conventional surgery, laser, or electrosurgery. Surgical treatment aims at complete removal of pathological lesions and ensuring proper healing of the tissues to minimize the risk of lesion recurrence. AIM: To present possible applications of Er:YAG and CO2 lasers in removal of benign neoplasms and tumorous lesions developing on oral mucosa as well as to specify indications and limitations of these two methods. MATERIAL AND METHODS: Temperature-induced injuries due to laser light application, possibility of post-operative histopathological evaluation of the removed tissue, efficacy of the cut and coagulation, healing process and completeness of laser surgeries give rise to our special concern. RESULTS: The main asset of the CO2 laser comparing to Er:YAG laser is an effective coagulation while thermal injury to the tissues is its limitation, especially with multiple passage of the beam and too high power applied. Er:YAG laser application does not exclude histopathological examination of the removed lesion tissue which is its advantage over CO2 laser. CONCLUSIONS: Still, insufficient coagulation is a limitation ofits use in the case of richly vascularized lesions. PMID- 26759540 TI - The association between smoking and the prevalence of metabolic syndrome and its components in patients with psoriasis aged 30 to 49 years. AB - INTRODUCTION: Cigarette smoking may exacerbate and cause psoriasis. Moreover, smokers are more likely to develop insulin resistance and metabolic syndrome (MS). AIM: To assess the prevalence of MS and its components in patients with psoriasis, who smoke, compared with the general Polish population of smokers. MATERIAL AND METHODS: We studied 29 patients with psoriasis (female = 9, male = 20), smokers, aged 30 to 49 years. Metabolic syndrome and its components were assessed using the IDF definition and compared to the results obtained in a representative sample of adult Poles in the NATPOL 2011 study in the same age group, including smokers. RESULTS: The results have shown that patients with psoriasis are more likely to be smokers (p < 0.0034) and the frequency of smoking in men is approximately 25% higher than in males of the control group (p < 0.0017). The prevalence of MS in patients with psoriasis who smoke was 27.58% and in the control group 25.2% (p > 0.05). Mean body mass index was 26.07 kg/m(2) in psoriasis patients and 25.59 kg/m(2) in the control group (p > 0.05), and abdominal obesity was 88.82 cm and 90.02 cm (p > 0.05), respectively. There were no differences in hypertension (34.48% vs. 31.6%, p < 0.05) and mean HOMA-IR (1.80 vs. 1.77, p > 0.05). In lipid parameters, the differences were observed only in women with psoriasis - higher levels of HDL, triglycerides and ApoB/ApoA1 index compared with addicted women in the control group. CONCLUSIONS: Men with psoriasis are more often addicted to smoking. Women with psoriasis who smoke have often disturbances of the lipid profile. PMID- 26759542 TI - Assessment of psychiatric morbidity and quality of life in children and adolescents with cutaneous leishmaniasis and their parents. AB - INTRODUCTION: Cutaneous leishmaniasis (CL) is a common parasitic infectious disease caused by different species of the leishmania genus. The skin lesions are usually found on exposed areas, especially the face, arms and legs. Although the disease does not cause significant morbidity, the lesions can be troublesome and unsightly. The disease have negative impacts in areas such as patients' psychological well-being, social life and daily activities in adults. AIM: To determine the frequency of psychiatric morbidity in children and adolescents who have cutaneous leishmaniasis (CL) and to determine the effect of CL on their levels of depression and anxiety and on their quality of life (QoL). MATERIAL AND METHODS: Fifty-four patients with CL (29 males and 25 females), who were 7 to 18 years of age, were assessed with the Child Depression Inventory (CDI) and the State-Trait Anxiety Inventories for Children (STAIC). The patients and their mothers were assessed with the Pediatric Quality of Life Inventory Parent and Child Versions (PedQL-P and C, respectively). This questionnaires were filled in by the control group consisting of 40 healthy children and adolescents (20 males and 20 females) and their parents from the local community matched for age, gender, and education level of the parents. RESULTS: Both the patient group and the control group had high scores on the depression measurement scale (t = 5.36, p < 0.05). These measurements also show significant differences between children and adolescents, who were defined as 12 years of age and under as well as older than 12 years, respectively (12 years of age and under (t = 3.14, p = 0.04); over 12 years (t = 5.37, p < 0.001)). However, there was no significant difference between the anxiety scores of the general patient group and the control group when classified according to age. The anxiety sensitivity index scores did not differ in either group from those of the control group. The patients' and the mothers' QoL scores for all of the scales, including all subscale scores, were significantly different from those of the control group (both 12 years of age and under as well as older than 12 years). CONCLUSIONS: The results have shown that the frequency of depressive symptoms is much higher in patients who have CL than in healthy controls. In addition, the QoL of children and adolescents with CL and of their mothers was found to be much lower than that of the control group. Therefore, the follow-up for patients with CL who are referred to dermatology clinics should include a psychiatric evaluation. If necessary, they should be referred for psychiatric support. PMID- 26759543 TI - Application of direct oral microscopy in evaluating mucosal margins around invasive oral squamous cell carcinoma. AB - INTRODUCTION: Direct oral microscopy constitutes a novel, non-invasive diagnostic technique, which aids clinical examination of the oral cavity. The oral mucosa is examined at multiple magnifications and features such as sub-epithelial mucosal vessels, surface patterns, colour tone, transparency and the exact demarcation of mucosal lesions are estimated. The incidence of oral squamous cell carcinoma (OSCC) oscillates between 1.9% and 3.5%, which makes it the eighth most common carcinoma occurring around the world and in Poland. The 5-year survival rates oscillate between 20% and 30%. AIM: The aim of the study was to evaluate clinically unchanged mucosal margins around OSCC by direct oral microscopy. The authors approached the question whether the borders of mucosal margins around OSCC established via direct oral microscopy differ from those established based on clinical examination. MATERIAL AND METHODS: Fifteen patients diagnosed with OSCC were enrolled. Patients were first clinically examined to evaluate the extent of the tumour and to plan resection margins. Eventually, direct oral microscopy was performed to establish the width of the subclinically unchanged mucosal margins based on a standard picture of healthy oral mucosae, followed by comparison with those established by clinical evaluation. RESULTS: Histopathologic results of biopsies from areas indicated by direct oral microscopy revealed dysplasia in 86.7% of patients, whereas biopsies from areas indicated by clinical examination revealed dysplasia only in 40% of individuals, resulting in the need for widening of mucosal margins. CONCLUSIONS: Direct oral microscopy enables detection of dysplasia within clinically unaltered mucosal margins around OSCC, which results in more precise establishing of resection boundaries, contributing to improvement of resection totality. PMID- 26759544 TI - Serum IL-17A in Behcet's disease. AB - INTRODUCTION: Behcet's disease is a chronic multisystem disease with spontaneous remissions and relapses. Several studies show that autoimmune mechanisms play an important role in the development of Behcet's disease. Activation of T cells and neutrophils is important in the pathogenesis of the disease. Interleukin 17 (IL 17) is a new cytokine that induces several types of cells to secrete proinflammatory cytokines in many inflammatory and autoimmune diseases. AIM: This study evaluated the serum levels of IL-17A in active and stable Behcet's disease patients. MATERIAL AND METHODS: Seventy-six patients who had active clinic findings of Behcet's disease were enrolled in our study. Seventy age- and sex matched controls were also enrolled. Serum IL-17 levels were studied in peripheral venous blood samples. RESULTS: No significant differences were found between active Behcet's disease patients and controls in terms of serum IL-17A (p > 0.05). CONCLUSIONS: These results suggest that IL-17A serum levels do not play an important role in active Behcet's disease. PMID- 26759545 TI - Brachytherapy in the treatment of skin cancer: an overview. AB - The incidence of skin cancer worldwide is constantly growing and it is the most frequently diagnosed tumor. Brachytherapy (BT) in particular localizations is a valuable tool of the exact radiation depot inside the tumor mass. In localizations such as the face, skull skin and inoperable tumors, relapses after surgery, radiotherapy are usually not suitable for primary or secondary invasive treatment. Brachytherapy is a safe procedure for organs at risk according to rapid fall of a dose outside the axis of the applicator with satisfactory dose localization inside the target. The complications rate is acceptable and treatment costs are low. In some tumors (great skin lesions in the scalp, near eyes or on the nose) BT allows for a great dose reduction in surrounding healthy tissues. Brachytherapy provides minimal dose delivery to surrounding healthy tissue, thus enabling good functional and cosmetic results. Treatment is possible almost in all cases on an outpatient basis. PMID- 26759547 TI - Biosimilars in dermatology. AB - Over the last decade the availability of biological drugs for the treatment of psoriasis vulgaris, psoriatic arthritis and many other inflammatory diseases has revolutionized the treatment of these diseases around the world. Due to the high cost of therapy, the search has started for biosimilars. In dermatology the greatest interest in biosimilar medicines concerns inhibitors of tumor necrosis factor a (TNF-alpha), for use in the treatment of psoriasis vulgaris and psoriatic arthritis (infliximab, etanercept, adalimumab). The most important element of the safety of biologicals is their immunogenicity. Therefore, when discussing biosimilars, attention needs to be paid to the dangers of their immune activity. In view of the fact that the drugs contain and aggregates, produced by living organisms or cultures of living cells, they cannot be compared in any way to low molecular weight synthetic generics (called generics). Biosimilars are authorized for use in patients and treated as equivalent to the reference medicine only after passing a number of studies and assessments. As it is well known, the development of medicine and pharmacology is extremely intense, and the market in biological medicine is developing much faster than that of all other drugs, which underlines their important role in modern medicine. Currently, the subject of biosimilars is one of the most important challenges and topics of discussion around the world, including pharmacovigilance and legal and economic regulatory standards. It seems inevitable that biosimilar products will be introduced for the treatment of diseases with indications corresponding to the original product on which they are based. PMID- 26759549 TI - The clinical spectrum of reactions developed based on paraphenylenediamine hypersensitivity two pediatric cases. PMID- 26759548 TI - Drugs as important factors causing allergies. AB - Medications can cause many adverse reactions, both non-immunologic and immunologic ones. Allergies can take many forms, allergic reactions include all types of reactions according to Gell and Coombs. Typically, allergic reactions to drugs are manifested by skin lesions such as maculopapular rash or urticaria and life-threatening systemic reactions such as anaphylaxis. Allergy to drugs is diagnosed based on medical history and a number of specific tests: skin tests, blood tests. In diagnosing the causes of anaphylaxis, the basophil activation test is used to exclude false negative and false positive results of skin tests and specific IgE levels. Allergic reactions to medications usually resolve themselves after discontinuation of the drug. Sometimes in the treatment anti allergic drugs are used to inhibit the development of skin lesions. After observing any signs of drug allergy it is important to accurately diagnose the cause, since the subsequent exposure to the drug may lead to a strong anaphylactic reaction and consequently death. PMID- 26759546 TI - Primary cutaneous lymphomas: diagnosis and treatment. AB - Primary cutaneous lymphomas (CLs) are a heterogeneous group of lymphoproliferative neoplasms, with lymphatic proliferation limited to the skin with no involvement of lymph nodes, bone marrow or viscera at the diagnosis. Cutaneous lymphomas originate from mature T-lymphocytes (65% of all cases), mature B-lymphocytes (25%) or NK cells. Histopathological evaluation including immunophenotyping of the skin biopsy specimen is the basis of the diagnosis, which must be complemented with a precise staging of the disease and identification of prognostic factors, to allow for the choice of the best treatment method as well as for the evaluation of the treatment results. PMID- 26759550 TI - Blindness resulting from orbital complications of ophthalmic zoster. AB - Herpes zoster ophthalmicus occurs when the latent varicella zoster virus (VZV) reactivates in the trigeminal ganglion and ophthalmic branch of the trigeminal nerve. In the elderly, there is a sharp increase in the tendency of secondary skin bacterial infections occurrence due to the deterioration of capabilities of self-care and changed sanitation. We present a case of patient who developed phlegmon of the orbit, which resulted with complete unilateral blindness. Varicella zoster virus infection in the elderly may have a severe course due to the progressive weakening of the immune system related to the age. Moreover, skin lesions around the eye socket require special care in prevention of bacterial superinfections due to the extremely high risk of life-threatening complications or disability. Neuralgia resistant to pharmacological treatment present in the course of ophthalmic zoster and difficulty in caring about skin lesions predispose to the occurrence of complications. PMID- 26759551 TI - Madelung disease. PMID- 26759552 TI - Mycosis fungoides: therapeutic difficulties. PMID- 26759554 TI - Assessment of Disease Activity in Small Bowel Crohn's Disease: Comparison between Endoscopy and Magnetic Resonance Enterography Using MRIA and Modified MRIA Score. AB - Objectives. To retrospectively compare the results of the MRIA (magnetic resonance index of activity) with a modified MRIA (mMRIA), which was calculated excluding from MRIA formula the data of relative contrast enhancement (RCE). Materials and Methods. MR-E and corresponding endoscopic records of 100 patients were reviewed. MRIA, mMRIA, and SES endoscopic index were calculated for all the patients. Namely, MRIA was calculated as follows: (1.5 * wall thickening + 0.02 * RCE + 5 * intramural edema + 10 * ulcers), while mMRIA was calculated with the modified formula (1.5 * wall thickening + 5 * intramural edema + 10 * ulcers). Results. Mean MRIA and mMRIA values were 19.3 and 17.68, respectively (p < 0.0001). A significant correlation (p < 0.0001) was observed between MRIA and mMRIA scores and between both MR indexes and SES (p < 0.0001). Conclusions. mMRIA was comparable to MRIA in the evaluation of disease activity in Crohn's disease. PMID- 26759556 TI - Delivering on our potential: Pharmacists and diabetes care / Deployer notre potentiel : Les pharmaciens et le traitement du diabete. PMID- 26759553 TI - MRBrainS Challenge: Online Evaluation Framework for Brain Image Segmentation in 3T MRI Scans. AB - Many methods have been proposed for tissue segmentation in brain MRI scans. The multitude of methods proposed complicates the choice of one method above others. We have therefore established the MRBrainS online evaluation framework for evaluating (semi)automatic algorithms that segment gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) on 3T brain MRI scans of elderly subjects (65 80 y). Participants apply their algorithms to the provided data, after which their results are evaluated and ranked. Full manual segmentations of GM, WM, and CSF are available for all scans and used as the reference standard. Five datasets are provided for training and fifteen for testing. The evaluated methods are ranked based on their overall performance to segment GM, WM, and CSF and evaluated using three evaluation metrics (Dice, H95, and AVD) and the results are published on the MRBrainS13 website. We present the results of eleven segmentation algorithms that participated in the MRBrainS13 challenge workshop at MICCAI, where the framework was launched, and three commonly used freeware packages: FreeSurfer, FSL, and SPM. The MRBrainS evaluation framework provides an objective and direct comparison of all evaluated algorithms and can aid in selecting the best performing method for the segmentation goal at hand. PMID- 26759555 TI - Management of the polyallergic patient with allergy immunotherapy: a practice based approach. AB - BACKGROUND: The great majority (60-80 %) of patients consulting specialist physicians for allergic respiratory disease are polysensitized and thus may be potentially clinically polyallergic. However, management approaches to allergen immunotherapy (AIT) in polysensitized and polyallergic patients are not standardized. METHODS: An international group of clinicians with in-depth expertise in AIT product development, clinical trials and clinical practice met to generate up-to-date, unambiguous, pragmatic guidance on AIT in polysensitized and polyallergic patients. The guidance was developed after reviewing (1) the current stance of regulatory bodies and learned societies, (2) the literature data on single- and multi-AIT and (3) the members' confirmed clinical experience with polysensitized patients. RESULTS: AIT is safe and effective in polysensitized and polyallergic patients, and should always be based on the identification of one or more clinically relevant allergens (based on the type and severity of symptoms, the duration of induced symptoms, the impact on quality of life and how difficult an allergen is to avoid). Single-AIT is recommended in polyallergic patients in whom one of the relevant allergens is nevertheless clearly responsible for the most intense and/or bothersome symptoms. Parallel 2 allergen immunotherapy or mixed 2-allergen immunotherapy is indicated in polyallergic patients in whom two causal relevant allergens have a marked clinical and QoL impact. In parallel 2-allergen immunotherapy (whether subcutaneous or sublingual), high-quality, standardized, single-allergen formulations must be administered with an interval of 30 min. Mixing of allergen extracts may be considered, as long as (1) the mixture is technically feasible, (2) the mixture is allowed from a regulatory standpoint, (3) the allergen doses are reduced in proportion to the number of components but are still at concentrations with demonstrated efficacy. CONCLUSIONS: Physicians can prescribe AIT (preferably with high-quality, standardized, single-allergen formulations) with confidence in polysensitized and polyallergic patients by focusing on clinical/QoL relevance and safety. PMID- 26759558 TI - Self-denigrating actions. PMID- 26759557 TI - Self-denigration in pharmacy. PMID- 26759559 TI - Self-denigrating actions. PMID- 26759560 TI - Evidence for pharmacist care in the management of hypertension. PMID- 26759561 TI - Usefulness of the NC-stat DPNCheck nerve conduction test in a community pharmacy as an educational tool for patients with diabetes. PMID- 26759563 TI - Initial uptake of the Ontario Pharmacy Smoking Cessation Program: Descriptive analysis over 2 years. AB - BACKGROUND: Smoking is a significant public health concern. The Ontario Pharmacy Smoking Cessation Program was launched in September 2011 to leverage community pharmacists and expand access to smoking cessation services for public drug plan beneficiaries. METHODS: We examined health care utilization data in Ontario to describe public drug plan beneficiaries receiving, and pharmacies providing, smoking cessation services between September 2011 and September 2013. Patient characteristics were summarized, stratified by drug plan group: seniors (age >=65 years) or social assistance. Trends over time were examined by plotting the number of services, unique patients and unique pharmacies by month. We then examined use of follow-up services and prescription smoking cessation medications. RESULTS: We identified 7767 residents receiving pharmacy smoking cessation services: 28% seniors (mean age = 69.9, SD = 4.8; 53% male) and 72% social assistance (mean age = 44.4 years, SD = 11.8; 48% male). Cumulative patient enrollment increased over time with an average of 311 (SD = 61) new patients per month, and one-third (n = 1253) of pharmacies participated by the end of September 2013. Regions with the highest number of patients were Erie St. Clair (n = 1328) and Hamilton Niagara Haldimand Brant (n = 1312). Sixteen percent of all patients received another pharmacy service (e.g., MedsCheck) on the same day as smoking cessation program enrollment. Among patients with follow-up data, 56% received follow-up smoking cessation services (60% seniors, 55% social assistance) and 74% received a prescription smoking cessation medication. One year quit status was reported for 12%, with a 29% success rate. CONCLUSIONS: Program enrollment has increased steadily since its launch, yet only a third of pharmacies participated and 56% of patients received follow-up services. PMID- 26759564 TI - Recent trials in neurology that should influence your practice. PMID- 26759562 TI - Updated guidelines for the management of dyslipidemia and prevention of cardiovascular disease by pharmacists. PMID- 26759565 TI - CPhA Advocacy: Year in review. PMID- 26759566 TI - The Health Action Lobby releases its pre-election health platform. PMID- 26759567 TI - Primary cutaneous lymphomas: A clinical and histological study of 99 cases in Isfahan, Iran. AB - BACKGROUND: Primary cutaneous lymphomas (PCLs) represent a heterogeneous group of T- and B-cell lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. The aim of this study was to assess and report the epidemiological characteristics of PCLs in Isfahan, Isfahan Province, Iran - as a main province of Iran. MATERIALS AND METHODS: A total of 99 patients were recruited over a recent 10-year period (2003-2013) with diagnosis of PCLs; the patients were classified according to the The World Health Organization/European Organization for Research and Treatment of Cancer (WHO EORTC) criteria. Mean and standard deviations (SDs) were used to describe continuous data, numbers, and percentages for categorical data. Statistical significance was defined as P < 0.05. RESULTS: The patients comprised 45 men and 54 women aged 5-80 years (median 36) at diagnosis. The male-to-female ratio was 1:1.2. Histological examination showed features of primary cutaneous B-cell lymphomas (PCBCLs) in four cases. The mean +/- SD age in primary cutaneous T-cell lymphomas (PCTCLs) and PCBCLs was 37.9 +/- 16.5 years and 39.7 +/- 9.1 years, respectively (P = 0.72). The mean +/- SD latent period between the time of diagnosis and initiation of skin lesions in men and women was 2.3 +/- 4.1 years and 5.9 +/- 10.1 years, respectively (P = 0.02). The most frequent subtypes were mycosis fungoides (MFs) (86.9%) followed by Siotazary syndrome (SS) (4%). Five patients died from PCL-related deaths. CONCLUSION: The distinguishing epidemiologic characteristics of PCL in Iran are the absence of a male predominance and a lower age of diagnosis. The study highlights the ethnic or regional variations in the clinicoepidemiological characteristics of PCLs. PMID- 26759568 TI - Dietary approaches to stop hypertension influence on insulin receptor substrate 1gene expression: A randomized controlled clinical trial. AB - BACKGROUND: Insulin receptor substrate (IRS) Type 1 is a main substrate for the insulin receptor, controls insulin signaling in skeletal muscle, adipose tissue, and the vascular, so it is an important candidate gene for insulin resistance (IR). We aimed to compare the effects of the Dietary Approaches to Stop Hypertension (DASH) and Usual Dietary Advices (UDA) on IRS1 gene expression in women at risk for cardiovascular disease. MATERIALS AND METHODS: A randomized controlled clinical trial was performed in 44 women at risk for cardiovascular disease. Participants were randomly assigned to a UDA diet or the DASH diet. The DASH diet was rich in fruits, vegetables, whole grains, and low-fat dairy products and low in saturated fat, total fat, cholesterol, refined grains, and sweets, with a total of 2400 mg/day sodium. The UDA diet was a regular diet with healthy dietary advice. Gene expression was assessed by the real-time polymerase chain reaction at the first of study and after 12 weeks. Independent sample t test and paired-samples t-test were used to compare means of all variables within and between two groups respectively. RESULTS: IRS1 gene expression was increased in DASH group compared with UDA diet (P = 0.00). Weight and waist circumference decreased in DASH group significantly compared to the UDA group (P < 0.05) but the results between the two groups showed no significant difference. CONCLUSION: DASH diet increased IRS1 gene expression and probably has beneficial effects on IR risks. PMID- 26759569 TI - Aggressive hydration with Lactated Ringer's solution as the prophylactic intervention for postendoscopic retrograde cholangiopancreatography pancreatitis: A randomized controlled double-blind clinical trial. AB - BACKGROUND: Pancreatitis is a serious complication of endoscopic retrograde cholangiopancreatography (ERCP) and may cause significant morbidity and even death. There is no effective prophylactic intervention for patients with average risk yet. This study aims to investigate preventive effect of aggressive hydration for post-ERCP pancreatitis. MATERIALS AND METHODS: In a double-blind controlled setting, 150 patient were randomly assigned to receive either aggressive hydration with lactated Ringer's solution (3 mL/kg/h during ERCP, followed by a 20 mL/kg bolus and 3 mL/kg/h for 8 h after the procedure, n = 75) or standard amount of hydration (1.5 mL/kg/h during and for 8 h after ERCP, n = 75). Patients were observed for volume overload as well as pancreatic pain and serum levels of amylase at baseline and 2, 8, and 24 h after ERCP. Post-ERCP pancreatitis was defined as hyperamylasemia (level of amylase >300) and pancreatic pain during the 24 h follow-up. Hyperamylasemia and pancreatic pain were the secondary end points. RESULTS: Mean age of the patients was 50.8 +/- 13.5 years. Most of the patients were female (66%). Pancreatitis developed in 21 patients, including 22.7% of patients receiving standard hydration and 5.3% patients receiving aggressive hydration (P = 0.002). Hyperamylasemia was detected in 44.0% of patients receiving standard hydration and 22.7% of patients aggressive hydration (P = 0.006). The pancreatic pain was reported by 5.3% of patients receiving aggressive hydration and 37.3% of patients receiving standard hydration (P <= 0.005). CONCLUSION: Aggressive hydration with lactated Ringer's solution may effectively prevent post-ERCP pancreatitis as well as hyperamylasemia and pancreatic pain in patients with average risk. PMID- 26759570 TI - Comparison of haloperidol and midazolam in restless management of patients referred to the Emergency Department: A double-blinded, randomized clinical trial. AB - BACKGROUND: Restless and violent behaviors are common in Emergency Departments (EDs), which need therapeutic interventions in most of the times. The first generation anti-psychotic drugs are one of the most applicable therapeutic agents in the management of such patients, but their use has some limitations. Some studies suggest midazolam as an alternative medicine. Therefore, this study was performed with the aim of comparison of the efficacy and safety of haloperidol and midazolam in the restless management of referring patients to EDs. MATERIALS AND METHODS: The present double-blinded trial was done on patients needed sedation and referred to the ED of Alzahra Hospital, Isfahan, Iran, in 2014. The patients were categorized into two random groups of haloperidol (5 mg) and midazolam receivers (2.5 mg for those weighing <50 kg and 5 mg in >50 kg), as intramuscular administration. The time to achieve sedation, need for rescue dose, need to resedation within the first 60 min, and adverse effects of drugs were compared among the groups. RESULTS: Forty-eight patients were entered to the study. The mean age in the haloperidol and midazolam groups was 44.8 +/- 4.1 years and 45.5 +/- 4.7 years, respectively (P = 0.91). The mean time of sedation in the haloperidol and midazolam groups was 5.6 +/- 0.3 min and 5.2 +/- 0.1 min, respectively (P = 0.31). The mean time of full consciousness after sedation was 36.2 +/- 4.5 min and 38.2 +/- 3.4 min in the haloperidol and midazolam groups, respectively (P = 0.72). On average, time to arousal in the midazolam group was 10.33 min more than the haloperidol group, but it was not statistically significant. CONCLUSION: The results of the present study show that administration of midazolam and haloperidol have similar efficacy in the treatment of restless symptoms with the same recovery time from drug effects for referring patients to the ED. In addition, none of the adverse effects were observed in this study. PMID- 26759571 TI - The effect of prophylactic peripapillary administration of methylprednisolone in reducing the risk and severity of postendoscopic retrograde cholangiopancreatography pancreatitis: A double blind clinical trial. AB - BACKGROUND: The most common complication of diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP) is acute pancreatitis. A number of therapeutic trials have been studied due to reduce the occurrence of postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) but many of them were unsuccessful. Periampullary corticosteroid injection was proposed to use as prophylactic agents for PEP because of its anti-inflammatory property with relative low systemic side effects. MATERIALS AND METHODS: By conducting a double blinded clinical trial study in a single center university hospital, all patients undergoing therapeutic or diagnostic ERCP in our gastrointestinal endoscopy ward, enrolled the study. During ERCP, we randomly assigned the patients in blocks of 40 to undergo a locally injection of methylprednisolone acetate (corticosteroid group) or saline (control group) on the major papilla and prospectively evaluated the occurrence of PEP pancreatitis in each groups. Clinical and laboratory findings of acute pancreatitis were collected by means of a validated questionnaire during the procedure and before discharge. At baseline and end of the study, were compared pancreatitis prevalence and also its severity by using Chi-square and t-test statistics. RESULTS: The frequency of moderate to severe PEP pain was not significantly between the placebo and corticosteroid receiving group (13.7% +/- 3.2% vs. 9.3% +/- 2.1%, respectively; P = 0.8). There is no significant difference in the mean concentration of lipase and amylase between corticosteroid receiving group and placebo receiving group at the first, second, and third time. In the corticosteroid receiving group, 3 patients (10.3%) while in the control group, 11 patients (11.3%) developed pancreatitis. CONCLUSION: We found no significant difference in PEP rates and also severity between the corticosteroid and placebo groups. The mean increase in serum amylase and amylase level in pancreatitis patients and the frequency of abdominal pain were not significantly higher in the placebo group. Besides, there were no cases of severe PEP pancreatitis in either group. PMID- 26759572 TI - Food allergy among Iranian children with inflammatory bowel disease: A preliminary report. AB - BACKGROUND: Evidence has shown a link between allergic disease and inflammatory bowel diseases (IBDs). We investigated food allergy in Iranian pediatric IBD patients. MATERIALS AND METHODS: A cross-sectional study was conducted on a consecutive sample of children with newly diagnosed IBD referring to Mofid Children's University Hospital in Tehran (Iran) between November 2013 and March 2015. Data on age, gender, history of cow's milk allergy (CMA), IBD type, routine laboratory tests, and colonoscopic and histopathological findings were gathered. Food allergy was assessed with the skin prick test (SPT). RESULTS: A total of 28 patients including 19 ulcerative colitis (UC), 7 Cronh's disease (CD), and two with unclassified colitis with a mean age of 8.3 +/- 4.4 years. (57.1% females, 42.9% were studied. History of CMA was present in eight patients (28.6%). Seventeen patients (60.7%) had at least one food allergy (68.4% of UC vs. 42.9% of CD, P = 0.230). Ten patients (35.7%) had multiple food allergies (36.8% of UC vs. 42.9% of CD, P > 0.999). Common allergic foods were cow's milk (28.6%), beef, seafood, albumen, wheat, and walnuts (each 10.7%), and peanuts and chestnuts (each 7.1%). The SPT showed CMA in 68.4% (8/17) of UC but none of the CD patients (P = 0.077). CONCLUSION: Food allergy is frequent in Iranian pediatric IBD patients with CMA being the most common observed allergy. The CMA seems to be more frequent in UC than in CD patients. PMID- 26759573 TI - Ketamine administration makes patients and physicians satisfied during gastro enteric endoscopies. AB - BACKGROUND: A suitable sedative status during gastro-enteric endoscopies results in better physicians' approach and more stable view of internal organs. Therefore, we evaluated the effect of ketamine for sedation in endoscopic procedures of adult patients. MATERIALS AND METHODS: Patients who were candidates for gastro-enteric endoscopy during the years 2014-2015 were included into the study and divided into two groups of case (administered 5 mg/kg of oral ketamine half an hour before initiation of the procedure) and control (administered placebo in a same pattern). After endoscopy, patients and physicians' satisfaction of sedation was assessed. SPSS-22 was used for data analysis. RESULTS: Eighty-six patients participated into the study of which divided into each groups. The pain and discomfort scores were 2.4 +/- 1.8 and 5.81 +/- 1.48 in case and control groups, respectively, (P < 0.001). Mann-Whitney test revealed statistical difference among groups about physician's satisfaction of sedation during endoscopy (P < 0.001). Patients who received ketamine had better sedative status (P < 0.001). None of the patients in the case group was completely awake but all of the patients in the control group were awake. The number of retching during endoscopy showed that individuals in the control group had more frequent retching episodes (P = 0.04). CONCLUSION: Low-dose oral administration of ketamine could make a satisfied sedation for gastro-enteric endoscopy. PMID- 26759575 TI - A management plan for hospitals and medical centers facing radiation incidents. AB - BACKGROUND: Nowadays, application of nuclear technology in different industries has largely expanded worldwide. Proportionately, the risk of nuclear incidents and the resulting injuries have, therefore, increased in recent years. Preparedness is an important part of the crisis management cycle; therefore efficient preplanning seems crucial to any crisis management plan. Equipped with facilities and experienced personnel, hospitals naturally engage with the response to disasters. The main purpose of our study was to present a practical management pattern for hospitals and medical centers in case they encounter a nuclear emergency. MATERIALS AND METHODS: In this descriptive qualitative study, data were collected through experimental observations, sources like Safety manuals released by the International Atomic Energy Agency and interviews with experts to gather their ideas along with Delphi method for polling, and brainstorming. In addition, the 45 experts were interviewed on three targeted using brainstorming and Delphi method. RESULTS: We finally proposed a management plan along with a set of practicality standards for hospitals and medical centers to optimally respond to nuclear medical emergencies when a radiation incident happens nearby. CONCLUSION: With respect to the great importance of preparedness against nuclear incidents adoption and regular practice of nuclear crisis management codes for hospitals and medical centers seems quite necessary. PMID- 26759574 TI - Mean platelet volume is an important predictor of hepatitis C but not hepatitis B liver damage. AB - BACKGROUND: The mean platelet volume (MPV) is the most commonly used measure of platelet size and is a potential marker of platelet reactivity. In this study, we aimed to explore the relationship between hepatic histopathology in viral hepatitis and MPV levels, which are associated with platelet count and activity. MATERIALS AND METHODS: We performed a retrospective case-control study of baseline histological and clinical parameters in chronic hepatitis B and C patients in our tertiary reference center between January 2005 and January 2011. Two hundred and five chronic hepatitis B patients and 133 chronic hepatitis C patients who underwent liver biopsy were included in the study. The patients were divided into two groups: Chronic hepatitis B and chronic hepatitis C and were additionally divided into groups of two according to histological activity index (HAI) and fibrosis scores obtained by liver biopsy results (according to the Ishak scoring system). The clinical characteristics of chronic viral hepatitis patients, including demographics, laboratory (especially MPV), and liver biopsy findings, were reviewed. RESULTS: One hundred and forty-three patients were male (69.1%), and the mean age was 41.9 +/- 12.75 with an age range of 18-71 years in hepatitis B patients. In the classification made according to HAI, 181 patients were in the low activity group (88.3%) and 24 in the high activity group (11.7%). In the evaluation made according to fibrosis score, 169 patients were found to have early fibrosis (82.4%) and 36 were found to have advanced fibrosis (17.6%). In patients with hepatitis B, there was no statistically significant difference in terms of their MPV values between the two groups, separated according to their degree of activity and fibrosis. Sixty-three patients were male (47.3%), and the mean age was 50.03 +/- 12.75 with an age range of 19-75 years. In the classification made according to HAI, 109 patients were in low activity group (81.9%) and 24 in high activity group (18.1%). In the evaluation made according to fibrosis score, 101 patients were found to have early fibrosis (75.9%) and 32 have advanced fibrosis (24.1%). There was a statistically significant difference between the activity and fibrosis groups of the hepatitis C patients (P = 0.04 and P = 0.02, respectively). CONCLUSION: MPV values are more reliable in hepatitis C patients than hepatitis B for predicting the advanced damage in liver histology. This finding might be useful for the detection of early fibrosis and also starting early treatment, which is important in hepatitis C. PMID- 26759576 TI - Uterine and arcuate arteries blood flow for predicting of ongoing pregnancy in in vitro fertilization. AB - BACKGROUND: In this study, we aimed to investigate the ability of transvaginal Doppler ultrasonography in predicting in vitro fertilization (IVF) outcome in women undergoing this procedure. MATERIALS AND METHODS: In this prospective observational study, 65 infertile women underwent IVF procedure in Isfahan, during 2013-2014, were studied. The pulsatility index (PI), resistive index (RI) and peak systolic velocity (PSV) of the uterine arteries and arcuate arteries were measured in all selected women using transvaginal color and pulsed Doppler measurements on the day of human chorionic gonadotrophin injection. The women followed up for the primary endpoint which was a successful pregnancy. The mean of PI, RI, and PSV were compared in groups of women who had successful IVF and not. The receiver operating characteristic (ROC) curve was used to determine the predictive value of studied indices. RESULTS: In this study, from 65 women, 32 (49.2%) and 33 (50.8%) have successful and unsuccessful IVF outcome, respectively. The mean of PI and RI of both uterine and arcuate arteries were significantly lower in pregnant women than non-pregnant ones (P < 0.001). The area under the ROC curve of PI (84.7%) and RI (84.4%) for uterine arteries was higher than other indices. The most accurate indices for predicting the outcome of IVF was RI of uterine arteries with an accuracy of 81.5%. CONCLUSION: The findings of this study indicated that PI and RI assessments of uterine arteries could be used as a routine non-invasive factor, before hCG stimulation, for predicting the outcome of IVF. PMID- 26759577 TI - Diagnosis and treatment of patients with nonacid gastroesophageal reflux-induced chronic cough. AB - Gastroesophageal reflux (GER) is one of the most common causes of chronic cough, and chronic cough due to GER represents a subtype of GER-related diseases. Gastroesophageal reflux-induced chronic cough (GERC) can be divided into two subgroups based on the pH of the GER. Nonacid GERC is less common than acid GERC, and its diagnosis and treatment strategy have not been standardized. However, nonacid GERC usually presents with its unique set of characteristics and features upon diagnosis and treatment in the clinic. Although the underlying molecular mechanism of nonacid GERC is not fully understood, it is considered to be associated with reflux theory, reflex theory and airway hypersensitivity. Multi channel intraluminal impedance combined with pH monitoring is a promising new technique that can detect both acid and nonacid reflux, and our findings as well as those of others have shown its usefulness in diagnosing nonacid GERC. Development of new diagnostic techniques has led to an increased rate of nonacid GERC diagnosis. We summarize our experience in the diagnosis and treatment of nonacid GERC and provide a guide for future therapeutic approaches. PMID- 26759578 TI - Dietary isoflavones and gastric cancer: A brief review of current studies. AB - BACKGROUND: Although several in vitro and animal studies have suggested that isoflavones might exert inhibitory effects on gastric carcinogenesis, epidemiologic studies have reported inconclusive results in this field. The aim of this brief review was to investigate whether such an association exists among dietary isoflavones and gastric cancer incidence, prevention, and mortality in epidemiologic studies. MATERIALS AND METHODS: We conducted a search of PubMed, Google Scholar, Cochrane, Science direct, and Iranian Scientific Databases including Scientific Information Database and IranMedex Database (up to November 2014) using common keywords for studies that focused on dietary isoflavones and gastric cancer risk. RESULTS: A total of nine epidemiologic studies consisting of five case-controls, three prospective cohorts, and one ecologic study were included in this review. An inverse association between dietary isoflavones and gastric cancer was shown in only one case-control and one ecologic study. CONCLUSION: In summary, whether anticarcinogenic properties of isoflavones are established, research found no substantial correlation in this field. There are insufficient studies to draw any firm conclusions about the relationship between isoflavones intake and the risk of gastric cancer. Hence, further evidence from cohort and trial studies are needed. PMID- 26759579 TI - A systematic review and meta-analysis on controlled treatment trials of metacognitive therapy for anxiety disorders. AB - BACKGROUND: To conduct a systematic review and meta-analysis on controlled treatment trials of meta-cognitive therapy for anxiety disorders. MATERIALS AND METHODS: Studies were included if they employed controlled methodology and treated people above 18 years with anxiety disorders. Case studies (with less than 4 cases) and single case designed studies were excluded. A comprehensive literature search identified 15 trials for systematic review. RESULTS: All included studies showed better treatment results in the MCT arms compared to the control groups. We also statistically pooled the results across studies (when possible). The meta-analyses also showed that MCT had statistically significant better results compared to the control groups in GAD (both immediately post treatment and 12 months post-therapy results), OCD, and PTSD (p-values ranged <0.0001-0.025). CONCLUSION: Based on the results of our systematic review, MCT seems to be an effective treatment for anxiety disorders and can effectively control their psychological problems. PMID- 26759581 TI - How World Health Organization has fared in tackling the 2014-2015 outbreak of Ebola virus disease? PMID- 26759582 TI - Epidemiology and trend in skin cancer mortality in Iran. PMID- 26759583 TI - Cylindroma of the scalp. PMID- 26759580 TI - The effect of glutamine intake on complications of colorectal and colon cancer treatment: A systematic review. AB - BACKGROUND: Improvement in complications of antitumor agents and surgery is important to enhance life quality and survival among patients with colon and colorectal cancer. It has been reported that some dietary components such as glutamine (Gln) have beneficial effects on these complications of cancer therapies. However, the results of studies are inconsistent in this area. We performed a review on randomized controlled trials (RCTs) evaluating the effects of Gln intake on complications related to therapeutic strategies of the colon and colorectal cancer. MATERIALS AND METHODS: A systematic search was conducted in PubMed, Google Scholar, Cochrane Library, and SID databases to find the relevant literature, published before July 2015. RESULTS: Nine RCTs of 217 screened articles were included in this systematic review. The results of the present review suggested that Gln intake among colon and colorectal cancer patients could reduce some complications induced by chemotherapy such as gut mucositis and diarrhea and improve nitrogen balance, immune system and wound healing after surgery, whereas benefits role of Gln on radiochemotherapy side effects were not provided. CONCLUSION: The role of Gln intake on some improvement of complications induced by cancer therapeutic methods and shorten the length of hospital stay may be promising and one that is worthy of further exploration. PMID- 26759584 TI - Cyclosporine A: Novel concepts in its role in drug-induced gingival overgrowth. AB - Cyclosporine is a selective immunosuppressant that has a variety of applications in medical practice. Like phenytoin and the calcium channel blockers, the drug is associated with gingival overgrowth. This review considers the pharmacokinetics, pharmacodynamics, and unwanted effects of cyclosporine, in particular the action of the drug on the gingival tissues. In addition, elucidates the current concepts in mechanisms of cyclosporine-induced gingival overgrowth. Clinical and cell culture studies suggest that the mechanism of gingival overgrowth is a result of the interaction between the drug and its metabolites with susceptible gingival fibroblasts. Plaque-induced gingival inflammation appears to enhance this interaction. However, understanding of the pathogenesis of gingival overgrowth is incomplete at best. Hence, it would be pertinent to identify and explore possible risk factors relating to both prevalence and severity of drug-induced gingival overgrowth. Newer molecular approaches are needed to clearly establish the pathogenesis of gingival overgrowth and to provide novel information for the design of future preventive and therapeutic modalities. PMID- 26759585 TI - Comparison of prevalence of periodontal disease in women with polycystic ovary syndrome and healthy controls. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age, affecting 4-18% of them. Previous studies also showed that periodontal diseases are associated with different components of the metabolic syndrome. The aim of this study is to determine the association between PCOS and periodontal diseases. MATERIALS AND METHODS: A total of 196 women (98 with PCOS and 98 healthy controls) were enrolled. PCOS diagnosis was confirmed by history, clinical signs, physical examination, laboratory parameters, and ultrasound studies. Both cases and controls were examined by the same periodontist. Periodontal parameters including bleeding on probing (BOP), probing depth, clinical attachment loss (CAL), plaque index, and tooth loss were investigated in all participants. Pregnant women, smokers, individuals with a history of malignancy or osteoporosis, and those taking prophylactic antibiotics for dental procedures or receiving periodontal treatment during the 6-month period before examination were excluded. Data were analyzed using t-test, Chi square test, and linear regression. Statistical significance was set at P < 0.05. RESULTS: CAL and sites with BOP were significantly higher in women with PCOS (P < 0.05). However, no significant difference was observed in the tooth loss rate between PCOS and non-PCOS participants (P = 0.384). CONCLUSION: The prevalence of periodontal disease seems to be higher in women with PCOS. This may be related to the role of chronic systemic inflammation in the pathophysiology of both PCOS and periodontal diseases. PMID- 26759586 TI - Mechanical or cold lateral compaction: The incidence of dentinal defects. AB - BACKGROUND: The incidence of dentinal defects may influence the outcome of root canal treatment. The aims of this study were to evaluate and compare the incidence of dentinal defects following root canal obturation with two different techniques. MATERIALS AND METHODS: A total of 110 mesial roots of human mandibular first molars were selected. Twenty-seven roots were left unprepared as negative controls (NCs). The mesiobuccal canals of 83 roots were prepared using rotary instruments. Twenty-seven roots were left unobturated as positive controls (PCs). Twenty-eight roots were obturated with cold lateral compaction (CLC) technique and the others were obturated with mechanical lateral compaction (MLC) technique. In the CLC and MLC groups, spreader penetration depth was measured by an electromechanical testing machine in canals containing master Gutta-percha cones. After root canal obturation, all the roots were sectioned horizontally at four levels from the apex and evaluated under a stereomicroscope at a magnification of *40. The presence of dentinal defects was noted. Data were analyzed using the Chi-square and t-tests. RESULTS: The number of defects was not significantly different between the CLC, MLC, and PC groups. The CLC, MLC, and PC groups had significantly more defects compared to the NC group. CONCLUSION: According to the results of this study, the MLC and CLC techniques were the same in producing dentinal defects. PMID- 26759587 TI - Volume fraction and location of voids and gaps in ultraconservative restorations by X-ray computed micro-tomography. AB - BACKGROUND: Volume fraction (Vf) and location of internal voids and gaps in relation to material type and cavity dimensions in ultraconservative restorations were investigated in this study. MATERIALS AND METHODS: Forty-eight round cavities of 1.3 mm mean diameter and 2.6 mm mean depth were made on buccal and lingual surfaces of recently extracted human teeth. These were filled and thermocycled with two low viscosity composites (AeliteFlo LV [AF], PermaFlo [PF]), one high viscosity composite (Aelite aesthetic enamel [AA]) and one glass ionomer (GCFuji IX GP). X-ray microtomography, following a specific procedure, was applied to all cavities before and after their restoration, using SkyScan 1072 microtomographer. Vf percent (Vf%) and location of voids and gaps were recorded and analysed statistically at a = 0.05. Kruskal-Wallis nonparametric analysis of variance, post-hoc analysis, Mann-Whitney test, Spearman's correlation analysis were used to analyze data. RESULTS: Cavities filled with AF and PF showed significantly lower Vf % of voids and gaps than all other restorations (P < 0.05). Only for the cavities filled with AA, cavity width and depth was significantly correlated with Vf % (P < 0.05). 50-75% of the filled cavities contained internal voids regardless of the restorative material (P > 0.05). The proportion of cavities with gaps at the bottom and side walls was lower in those filled with AF and PF (P < 0.05). CONCLUSION: Cavities filled with low viscosity composites presented the lowest amount of internal voids and gaps. Glass-ionomer and high viscosity composite restorative materials showed the highest amount of interfacial gaps. Only in the high viscosity composite restorations the amount of voids and gaps correlated with the cavity depth, width and volume. PMID- 26759588 TI - Efficacy and safety of premedication with single dose of oral pregabalin in children with dental anxiety: A randomized double-blind placebo-controlled crossover clinical trial. AB - BACKGROUND: Dental anxiety is a relatively frequent problem that can lead to more serious problems such as a child entering a vicious cycle as he/she becomes reluctant to accept the required dental treatments. The aim of this randomized double-blind clinical trial study was to evaluate the anxiolytic and sedative effect of pregabalin in children. MATERIALS AND METHODS: Twenty-five children were randomized to a double-blind placebo-controlled crossover clinical trial. Two visits were scheduled for each patient. At the first visit, 75 mg pregabalin or placebo was given randomly, and the alternative was administered at the next visit. Anxiolytic and sedative effects were measured using the visual analogue scale. The child's behavior was rated with the Frankl behavioral rating scale and the sedation level during the dental procedure was scored using the Ramsay sedation scale. The unpaired, two-tailed Student's t-test was used to compare the mean changes of visual analog scale (VAS) for anxiety in the pregabalin group with that of the placebo group. A repeated measures MANOVA model was used to detect differences in sedation level in the pregabalin and placebo groups regarding the interaction of 3-time measurements; sub-group analysis was performed using Student's t-test. The Mann-Whitney U-test was used to analyze the nonparametric data of the Frankl and Ramsay scales. A P < 0.05 was considered significant. RESULTS: The reduction of the VAS-anxiety score from 2 h post-dose was statistically significant in the pregabalin group. From 2 h to 4 h post-dose, the VAS-sedation score increased significantly in the pregabalin group. The child's behavior rating was not significantly different between the groups. The number of "successful" treatment visits was higher in the pregabalin group compared to the placebo group. CONCLUSION: Significant anxiolytic and sedative effects can be anticipated 2 h after oral administration of pregabalin without serious side effects. PMID- 26759589 TI - Influence of the glide path on various parameters of root canal prepared with WaveOne reciprocating file using cone beam computed tomography. AB - BACKGROUND: Nickel-titanium (NiTi) rotary instrumentation carries a risk of fracture, mainly as a result of flexural (fatigue fracture) and torsional (shear failure) stresses. This risk might be reduced by creating a glide path before NiTi rotary instrumentation. The aim of this study was to compare various root canal parameters with the new WaveOne single-file reciprocating system in mesial canals of mandibular molars with and without glide path using cone beam computed tomography (CBCT). MATERIALS AND METHODS: One hundred mandibular molar teeth with canal curvature between 20 degrees and 30 degrees were divided into two groups of 50 teeth each. In Group 1, no glide path was created, whereas in Group 2, a glide path was created with PathFiles at working length (WL). In both groups, canals were shaped with WaveOne primary reciprocating files to the WL. Canals were scanned in a CBCT unit before and after instrumentation. Postinstrumentation changes in canal curvature, cross-sectional area, centric ability, residual dentin thickness, and the extent of canal transportation were calculated using image analysis software and subjected to statistical analysis. Data were analyzed using Student's t-test and Mann-Whitney U-test (P < 0.05). RESULTS: The mean difference of root canal curvature, cross-sectional area, centric ability, and residual dentin thickness increased, whereas it reduced significantly for canal transportation in Group 2. CONCLUSION: WaveOne NiTi files appeared to maintain the original canal anatomy and the presence of a glide path further improves their performance and was found to be beneficial for all the parameters tested in this study. PMID- 26759590 TI - Characteristics and relationship of periodontal disease with juvenile idiopathic and rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is the most prevalent chronic inflammatory disease of the joints. It is correlated with periodontal disease due to similar factors that exist in both diseases. The present study assessed the relationship of periodontal disease with RA and juvenile idiopathic arthritis (JIA). MATERIALS AND METHODS: In this case-control study, 30 RA and 30 JIA patients along with similar number of matched controls were selected among patients referred to Imam Khomeini Hospital, Tehran, Iran. Periodontal parameters including pocket depth (PD), clinical attachment level (CAL), O'Leary and Bay plaque index (PI) and bleeding on probing (BOP) were determined in cases and controls. Erythrocyte sedimentation rate, number of painful and inflamed joints and severity of disease were evaluated in RA and JIA patients. Mann-Whitney U-test nonparametric, Spearman and Pearson's correlation coefficients, and Chi-square tests were used as statistical analysis (alpha = 0.05). RESULTS: PD (4.17 vs. 3.6 mm; P < 0.0001), CAL (4.89 vs. 4.18 mm; P < 0.002), percentage of sites with PD >4 mm (58.83% vs. 44.33%; P < 0.002), percentage of sites with CAL >3 mm (74.13% vs. 64.4%; P < 0.001), percentage of sites with BOP (9.67% vs. 6.87%; P < 0.0001) and PI index (85.73% vs. 80.63%; P < 0.0001) were significantly higher in RA patients than controls. In this group, direct and significant correlations were found between serologic findings, disease severity and number of painful and inflamed joints with periodontal factors. In JIA patients, no significant relationships were found between JIA findings and periodontal parameters. CONCLUSION: Considering the limitations of this study, there was a relationship between RA and periodontal disease. Severity of periodontal disease increases in patients with RA, while no increased risk of periodontal disease or its severity was observed among JIA patients. PMID- 26759591 TI - Alveolar ridge augmentation by connective tissue grafting using a pouch method and modified connective tissue technique: A prospective study. AB - BACKGROUND: Localized alveolar ridge defect may create physiological and pathological problems. Developments in surgical techniques have made it simpler to change the configuration of a ridge to create a more aesthetic and more easily cleansable shape. The purpose of this study was to compare the efficacy of alveolar ridge augmentation using a subepithelial connective tissue graft in pouch and modified connective tissue graft technique. MATERIALS AND METHODS: In this randomized, double blind, parallel and prospective study, 40 non-smoker individuals with 40 class III alveolar ridge defects in maxillary anterior were randomly divided in two groups. Group I received modified connective tissue graft, while group II were treated with subepithelial connective tissue graft in pouch technique. The defect size was measured in its horizontal and vertical dimension by utilizing a periodontal probe in a stone cast at base line, after 3 months, and 6 months post surgically. Analysis of variance and Bonferroni post hoc test were used for statistical analysis. A two-tailed P < 0.05 was considered to be statistically significant. RESULTS: Mean values in horizontal width after 6 months were 4.70 +/- 0.87 mm, and 4.05 +/- 0.89 mm for group I and II, respectively. Regarding vertical heights, obtained mean values were 4.75 +/- 0.97 mm and 3.70 +/- 0.92 mm for group I and group II, respectively. CONCLUSION: Within the limitations of this study, connective tissue graft proposed significantly more improvement as compare to connective tissue graft in pouch. PMID- 26759592 TI - Effects of three surface conditioning techniques on repair bond strength of nanohybrid and nanofilled composites. AB - BACKGROUND: Repair bond strength of different composite resins has been assessed in few studies. In addition, reports on the efficacy of surface treatments are debated. Therefore, this in vitro study was conducted to evaluate the effect of three surface treatments on two nanocomposites versus a microhybrid composite. MATERIALS AND METHODS: In this experimental study, 135 composite blocks (45 specimens per composite) of microhybrid (Filtek Supreme Z250, 3M ESPE, USA), nanohybrid (Filtek Supreme XT, 3M ESPE), and nanofilled (Filtek Supreme Z350, 3M ESPE) were thermocycled (5000 rounds) and then surface roughened (except in a control group of 9 specimens of three composite types). Each composite type was divided into three subgroups of surface treatments: (1) Bur abrading and phosphoric acid (PA) etching, (2) sandblasting and PA etching, and (3) hydrofluoric etching and silane application (n = 15 * 9, complying with ISO TR11405). Composite blocks were repaired with the same composite type but of a different color. Microtensile bond strength and modes of failure were analyzed statistically using two-way analyses of variance, Tukey and Chi-square tests (alpha = 0.05). RESULTS: There were significant differences between three composite resins (P < 0.0001) and treatment techniques (P < 0.0001). Their interaction was nonsignificant (P = 0.228). The difference between nanofilled and nanohybrid was not significant. However, the microhybrid composite showed a significantly higher bond strength (Tukey P < 0.05). Sandblasting was significantly superior to the other two methods, which were not different from each other. CONCLUSION: Within the limitations of this in vitro study, it seems that microhybrid composite might have higher repair strengths than two evaluated nanocomposites. Among the assessed preparation techniques, sandblasting followed by PA etching might produce the highest bond strength. PMID- 26759593 TI - The minimum thickness of a multilayer porcelain restoration required for masking severe tooth discoloration. AB - BACKGROUND: Although studies have shown that porcelain veneers are very efficient for treating discolored teeth, they did not address in particular the minimum thickness of a multilayer IPS e.max Press (IvoclarVivadent, Schaan, Liechtenstein) restoration required to mask discolored tooth. The aim of this study was to determine the minimum thickness of a multilayer porcelain restoration required for masking severe tooth discoloration. MATERIALS AND METHODS: A total of 24 disk-shaped multilayer specimens were prepared from IPS e.max Press with the diameter of 13 mm and four different thicknesses (core/veneer: 0.4/0.4 mm, 0.5/0.5 mm, 0.6/0.6 mm and 0.8/0.7 mm). Two backgrounds, C4-shade body porcelain and an opaque background from the selected IPS e.max ceramic itself were fabricated to mimic a discolored or stained natural tooth structure and to determine the masking ability. After applying the resin cement layer (Panavia F2.0) with 0.01 mm thickness on each background, all specimens were measured on both background using a spectrophotometer and values of L*, a* and b* were calculated to determine the color differences (DeltaE*ab). One-way ANOVA and post-hoc tests of specimen average one-to-one comparison (Tukey HSD) were conducted and P <= 0.05 was set as the level of significance. RESULTS: DeltaE*ab of all groups were within the range of the clinically acceptable color difference (DeltaE<=3.3), thus all the groups could mask the C4 background even group 1 with only 0.8 mm thickness. A trend was shown in the results as by increasing the thickness, DeltaE*ab is was decreased. The mean DeltaE*1*a*b between different thicknesses were statistically significant (P < 0.05) only between group 4 with groups 1 and 2, respectively. CONCLUSION: Within the limitations of this study, all studied thicknesses could mask the C4 background. However, the minimum thickness of a multilayer porcelain restoration (IPS e.max Press) required for masking severe tooth discoloration was 0.8 mm. PMID- 26759594 TI - Effect of milk and yogurt on streptococcus sobrinus counts and caries score in rats. AB - BACKGROUND: An anti-cariogenic diet containing probiotics can be effective in caries prevention. This animal study compared the effects of milk and yogurt on Streptococcus sobrinus counts and caries score. MATERIALS AND METHODS: A total of 36 male rats were infected with S. sobrinus (27,607) and divided into three groups. Group A and B received 200 mL of milk and 100 g of yogurt per day, respectively, and a control group received 2.5 mL of NCP number 2 diet twice daily for 21 days. After killing the animals, their lower left jaws were removed and sonicated to quantify the colonies of S. sobrinus. Dental caries was scored using Keyes technique. Data were analyzed using ANOVA and Kruskal-Wallis, Mann Whitney and Wilcoxon-Signed Rank tests. Statistical significance was set at P < 0.05. RESULTS: The mean (+/-standard error of the mean) of S. sobrinus colonies in the milk, yogurt and control groups were determined at 119666.67 (+/-20733), 46416.666 (+/-12846) and 163,250 (+/-33493), respectively. Microbial counts decreased in the yogurt group compared with the milk and control groups (P = 0.004 and P = 0.000; respectively). There were significant differences between caries scores of smooth surfaces in the milk and yogurt groups compared with the control group (P = 0.000 and P = 0.000, respectively). Both milk and yogurt significantly reduced caries score of fissured surfaces compared with controls (P = 0.004 and P = 0.000, respectively). CONCLUSION: Considering the limitations of this study, yogurt administration reduces S. sobrinus counts. In addition, yogurt and milk regimens reduce the caries scores of smooth and fissured surfaces. PMID- 26759595 TI - Clinical comparison of various esthetic restorative options for coronal build-up of primary anterior teeth. AB - BACKGROUND: This study was designed to compare the clinical performance of composite, strip crowns, biological restoration, and composite with stainless steel band when used for the coronal build-up of anterior teeth. MATERIALS AND METHODS: A total of 20 patients aged 3-6 years presenting with mutilated primary anterior teeth due to caries or trauma were selected for the study using randomized simple sampling. A total of 52 primary anterior teeth were randomly divided into four equal groups having 13 teeth in each group. Teeth in Group I were restored with composite, in Group II with strip crowns, in Group III with biologic restoration and with stainless steel band reinforced composite in group IV. The restorations were evaluated for color match, retention, surface texture, and anatomic form according to Ryge's Direct (US Public Health Service) evaluation criteria at baseline (immediate postoperative), after 48 h, 3, 6, and 9 months. The data obtained were statistically analyzed using Chi-square test, and level of significance, that is, P value was determined. RESULTS: At baseline, none of the groups showed any color changes. Other than Group III all other groups showed highly significant changes (P < 0.05) in color after 3 months. Loss of retention was seen in both Groups I and IV after 3 months. After 6 months, retention loss was seen in all the groups except Group II, in which loss was seen after 9 months (P > 0.05). Deterioration in surface texture was exhibited maximum by restorations in Group IV followed by Group I at 3 months. Whereas, no surface changes were seen in Group II and III. Only Group I and IV showed discontinuity in anatomic form after 3 months. After 6 months, except in Group II, discontinuity in anatomic form was observed in all the groups. Discontinuity in anatomic form was seen in all the 4 groups after 9 months although the difference was not significant (P > 0.05). CONCLUSION: Biological restoration was found to be most satisfying esthetically owing to color compatibility with the patient's tooth. Thus, it has a great potential to be used as esthetic restorative option in primary anteriors. PMID- 26759597 TI - Evaluation of the effect of different stretching patterns on force decay and tensile properties of elastomeric ligatures. AB - BACKGROUND: There have been numerous researches on elastomeric ligatures, but clinical conditions in different stages of treatment are not exactly similar to laboratory conditions. The aim of this in vitro study was to simulate clinical conditions and evaluate the effect of three stretching patterns on the amount of force, tensile strength (TS) and extension to TS of the elastomers during 8 weeks. MATERIALS AND METHODS: Forces, TS and extension to TS of two different brands of elastomers were measured at initial, 24 h and 2, 4, and 8-week intervals using a testing machine. During the study period, the elastomers were stored in three different types of jig (uniform stretching, 1 and 3 mm point stretching) designed by the computer-aided design and computer-aided manufacturing technique in order to simulate the different stages of orthodontic treatment. RESULTS: The elastomeric ligatures under study exhibited a similar force decay pattern. The maximum force decay occurred during the first 24 h (49.9% +/- 15%) and the amount of force decay was 75.7% +/- 8% after 8 weeks. In general, the TS decreased during the study period, and the amount of extension to TS increased. CONCLUSION: Although the elastic behavior of all ligatures under study was similar, the amount of residual force, TS and extension to TS increased in elastomers under point stretching pattern. PMID- 26759598 TI - Oral manifestations in liver transplant recipients. PMID- 26759596 TI - Coronal microleakage of three different dental biomaterials as intra-orifice barrier during nonvital bleaching. AB - BACKGROUND: This study was designed to assess the microleakage of glass-ionomer (GI), mineral trioxide aggregate (MTA), and calcium-enriched mixture (CEM) cement as coronal orifice barrier during walking bleaching. MATERIALS AND METHODS: In this experimental study, endodontic treatment was done for 70 extracted human incisors without canal calcification, caries, restoration, resorption, or cracks. The teeth were then divided into three experimental using "Simple randomization allocation" (n = 20) and two control groups (n = 5). The three cements were applied as 3-mm intra-orifice barrier in test groups, and bleaching process was then conducted using a mixture of sodium perborate powder and distilled water, for 9 days. For leakage evaluation, bovine serum albumin marker was traced in a dual-chamber technique with Bradford indicator. The Kruskal-Wallis and Mann Whitney tests were used for statistical analysis. RESULTS: The mean +/- standard deviation leakage of samples from negative control, positive control, GI, MTA, and CEM cement groups were 0.0, 8.9 +/- 0.03, 0.47 +/- 0.02, 0.48 +/- 0.02, and 0.49 +/- 0.02 mg/mL, respectively. Statistical analysis showed no significant difference between three experimental groups (P > 0.05). CONCLUSION: It is concluded that GI, MTA, and CEM cements are considered as suitable intra-orifice barrier to provide coronal seal during walking bleaching. PMID- 26759599 TI - Pneumococcal colonization in older adults. AB - BACKGROUND: Little is known about pneumococcal carrier states in older adults. The main aim of this study was to evaluate pneumococcal colonization patterns among older adults in two centres in Milan, Italy, before the widespread use of the 13-valent pneumococcal vaccine (PCV13) in this age group, to investigate demographic and clinical features that are associated with pneumococcal colonization and to estimate the potential coverage offered by PCV13. RESULTS: Among 417 adults >=65 years old (171, 41.1 %, >=75 years), 41 (9.8 %) were pneumococcal carriers. Univariate and multivariate analyses revealed that pneumococcal colonization was significantly less common among individuals with underlying co-morbidities than among those without (odds ratio [OR] 0.453, 95 % confidence interval [CI] 0.235-0.875, p = 0.018; adjusted OR 0.503, 95 % CI 0.255 0.992, p = 0.047). Moreover, among these patients, those with cardiac disease had a significantly lower risk of colonization (OR 0.308, 95 % CI 0.119-0.795, p = 0.015; adjusted OR 0.341, 95 % CI 0.13-0.894, p = 0.029). Only one vaccinated subject who received 23-valent polysaccharide pneumococcal vaccine (PPV23) was colonized. Twenty-five (89.3 %) of the subjects who were <75 years old and 9 (75.0 %) of those who were >=75 years old were colonized by at least one of the serotypes that is included in PCV13, with serotype 19 F being the most common. Respiratory allergies as well as overall co-morbidities were more common in subjects who were positive for only non-PCV13 serotypes compared with negative subjects and those who were carriers of only PCV13 serotypes. CONCLUSIONS: Although this study included a relatively small number of subjects and has been performed in a limited geographic setting, results showed that pneumococcal colonization in older people is common, and the monitoring of carriers can offer useful information about the circulation of this pathogen among older people and the potential protective effect of pneumococcal vaccines. Because the colonization in most cases involves the strains that are included in PCV13, this vaccine could be useful in the prevention of pneumococcal infections in the overall population of older people. In subjects with respiratory allergies and in those with co-morbidities, the addition of the PPV23 to PCV13 should be recommended. Due to the low vaccination coverage, urgent educational programmes are required to inform older adults and their medical doctors of the risks of pneumococcal infection and the efficacy and safety of the available pneumococcal vaccines. PMID- 26759601 TI - The relationship of telomere length to baseline corticosterone levels in nestlings of an altricial passerine bird in natural populations. AB - BACKGROUND: Environmental stressors increase the secretion of glucocorticoids that in turn can shorten telomeres via oxidative damage. Modification of telomere length, as a result of adversity faced early in life, can modify an individual's phenotype. Studies in captivity have suggested a relationship between glucocorticoids and telomere length in developing individuals, however less is known about that relationship in natural populations. METHODS: In order to evaluate the effect of early environmental stressors on telomere length in natural populations, we compared baseline corticosterone (CORT) levels and telomere length in nestlings of the same age. We collected blood samples for hormone assay and telomere determination from two geographically distinct populations of the Thorn-tailed Rayadito (Aphrastura spinicauda) that differed in brood size; nestlings body mass and primary productivity. Within each population we used path analysis to evaluate the relationship between brood size, body mass, baseline CORT and telomere length. RESULTS: Within each distinct population, path coefficients showed a positive relationship between brood size and baseline CORT and a strong and negative correlation between baseline CORT and telomere length. In general, nestlings that presented higher baseline CORT levels tended to present shorter telomeres. When comparing populations it was the low latitude population that presented higher levels of baseline CORT and shorter telomere length. CONCLUSIONS: Taken together our results reveal the importance of the condition experienced early in life in affecting telomere length, and the relevance of integrative studies carried out in natural conditions. PMID- 26759602 TI - Involvement of lysosomal dysfunction in silver nanoparticle-induced cellular damage in A549 human lung alveolar epithelial cells. AB - BACKGROUND: While silver nanoparticles (AgNPs) are widely used in consumer and medical products, the mechanism by which AgNPs cause pulmonary cytotoxicity is not clear. AgNP agglomerates are found in endo-lysosomal structures within the cytoplasm of treated cells. In this study, the functional role of lysosomes in AgNP-induced cellular damage was examined in A549 human lung alveolar epithelial cells. We evaluated the intracellular distribution of AgNPs, lysosomal pH, cellular viability, Ag dissolution, and metallothionein (MT) mRNA levels in AgNP exposed A549 cells that were treated with bafilomycin A1, the lysosomal acidification inhibitor. FINDINGS: Exposure of A549 cells to citrate-coated AgNPs (20 nm diameter) for 24 h induced cellular damage and cell death at 100 and 200 MUg Ag/ml, respectively. Confocal laser microscopic examination of LysoTracker stained cells showed that AgNPs colocalized with lysosomes and their agglomeration increased in a dose-dependent manner (50-200 MUg Ag/ml). In addition, the fluorescence signals of LysoTracker were reduced following exposure to AgNPs, suggesting the elevation of lysosomal pH. Treatment of A549 cells with 200 nM bafilomycin A1 and AgNPs (50 MUg Ag/ml) further reduced the fluorescence signals of LysoTracker. AgNP-induced cell death was also increased by bafilomycin A1 treatment. Finally, treatment with bafilomycin A1 suppressed the dissolution of Ag and decreased the mRNA expression levels of MT-I and MT-II following exposure to AgNPs. CONCLUSIONS: The perturbation of lysosomal pH by AgNP exposure may play a role in AgNP agglomeration and subsequent cellular damage in A549 cells. PMID- 26759603 TI - Novel cycloartane triterpenoid from Cimicifuga foetida (Sheng ma) induces mitochondrial apoptosis via inhibiting Raf/MEK/ERK pathway and Akt phosphorylation in human breast carcinoma MCF-7 cells. AB - BACKGROUND: Cycloartane triterpenoids exhibited anticancer effects. This study aims to identify any potential novel anticancer cycloartane triterpenoids from Cimicifuga foetida L. rhizome (Sheng ma) and the mode of actions. METHODS: Cycloartane triterpenoids were isolated from the C. foetida rhizome by a series of column chromatography and identified by IR, MS and NMR. Their anticancer effects on several human cancer cell lines, MCF-7, HepG2, HepG2/ADM, HeLa, and PC3, and normal human mammary epithelial cells MCF10A were investigated by colony formation and MTT assays. Morphological analysis of apoptosis induction was performed by acridine orange/ethidium bromide dual-staining and Hoechst 33258 nuclear staining. The cell-cycle profile and annexin V staining were evaluated by flow cytometry. Apoptosis were investigated by measuring changes in mitochondrial membrane potential and analyzing expression of cell cycle- and apoptosis-related proteins in MCF-7 cells by Western blotting. RESULTS: A novel cycloartane triterpenoid, 25-O-acetyl-7,8-didehydrocimigenol-3-O-beta-d-(2 acetyl)xylopyranoside (ADHC-AXpn), together with the known 7,8-didehydrocimigenol 3-O-beta-d-xylopyranoside (DHC-Xpn) were isolated. MCF-7 growth was significantly inhibited by ADHC-AXpn in a dose- and time-dependent manner (IC50: 27.81 uM at 48 h; P = 0.004 vs. control at 25 MUM for 48 h treatment), and ADHC-AXpn was selectively cytotoxic for cancerous cells (MCF-7, HepG2/ADM, HepG2 and HELA cells) based on its higher IC50 values for normal cells MCF10A (IC50: 78.63 uM at 48 h) than for tumor cells. In MCF-7 cells, ADHC-AXpn induced G2/M cell cycle arrest by mediating cyclin-B1, and CDK1 and its phosphorylation; and induced apoptosis through the mitochondrial-mediated apoptotic pathway, with inhibition of Akt activation. As ADHC-AXpn suppressed phosphorylation of ERK1/2, Raf and Akt proteins in MCF-7 cells, its apoptotic effect might be associated with Raf/MEK/ERK signaling and Akt activation. CONCLUSIONS: ADHC-AXpn significantly suppressed the growth of MCF-7 cells, induced mitochondrial apoptosis and cell cycle arrest, and inhibited Raf/MEK/ERK signaling pathway and Akt phosphorylation. PMID- 26759600 TI - The obese gut microbiome across the epidemiologic transition. AB - The obesity epidemic has emerged over the past few decades and is thought to be a result of both genetic and environmental factors. A newly identified factor, the gut microbiota, which is a bacterial ecosystem residing within the gastrointestinal tract of humans, has now been implicated in the obesity epidemic. Importantly, this bacterial community is impacted by external environmental factors through a variety of undefined mechanisms. We focus this review on how the external environment may impact the gut microbiota by considering, the host's geographic location 'human geography', and behavioral factors (diet and physical activity). Moreover, we explore the relationship between the gut microbiota and obesity with these external factors. And finally, we highlight here how an epidemiologic model can be utilized to elucidate causal relationships between the gut microbiota and external environment independently and collectively, and how this will help further define this important new factor in the obesity epidemic. PMID- 26759604 TI - Biological lignocellulose solubilization: comparative evaluation of biocatalysts and enhancement via cotreatment. AB - BACKGROUND: Feedstock recalcitrance is the most important barrier impeding cost effective production of cellulosic biofuels. Pioneer commercial cellulosic ethanol facilities employ thermochemical pretreatment and addition of fungal cellulase, reflecting the main research emphasis in the field. However, it has been suggested that it may be possible to process cellulosic biomass without thermochemical pretreatment using thermophilic, cellulolytic bacteria. To further explore this idea, we examine the ability of various biocatalysts to solubilize autoclaved but otherwise unpretreated cellulosic biomass under controlled but not industrial conditions. RESULTS: Carbohydrate solubilization of mid-season harvested switchgrass after 5 days ranged from 24 % for Caldicellulosiruptor bescii to 65 % for Clostridium thermocellum, with intermediate values for a thermophilic horse manure enrichment, Clostridium clariflavum, Clostridium cellulolyticum, and simultaneous saccharification and fermentation (SSF) featuring a fungal cellulase cocktail and yeast. Under a variety of conditions, solubilization yields were about twice as high for C. thermocellum compared to fungal cellulase. Solubilization of mid-season harvested switchgrass was about twice that of senescent switchgrass. Lower yields and greater dependence on particle size were observed for Populus as compared to switchgrass. Trends observed from data drawn from six conversion systems and three substrates, including both time course and end-point data, were (1) equal fractional solubilization of glucan and xylan, (2) no biological solubilization of the non carbohydrate fraction of biomass, and (3) higher solubilization for three of the four bacterial cultures tested as compared to the fungal cellulase system. Brief (5 min) ball milling of solids remaining after fermentation of senescent switchgrass by C. thermocellum nearly doubled carbohydrate solubilization upon reinnoculation as compared to a control without milling. Greater particle size reduction and solubilization were observed for milling of partially fermented solids than for unfermented solids. Physical disruption of cellulosic feedstocks after initiation of fermentation, termed cotreatment, warrants further study. CONCLUSIONS: While the ability to achieve significant solubilization of minimally pretreated switchgrass is widespread, a fivefold difference between the most and least effective biocatalyst-feedstock combinations was observed. Starting with nature's best biomass-solubilizing systems may enable a reduction in the amount of non-biological processing required, and in particular substitution of cotreatment for pretreatment. PMID- 26759605 TI - A rare de novo interstitial duplication of 15q15.3q21.2 in a boy with severe short stature, hypogonadism, global developmental delay and intellectual disability. AB - BACKGROUND: Interstitial duplications distal to 15q13 are very rare. CASE PRESENTATION: Here, we reported a 14-year-old boy with severe short stature, delayed bone age, hypogonadism, global developmental delay and intellectual disability. His had distinctive facial features including macrocephaly, broad forehead, deep-set and widely spaced eyes, broad nose bridge, shallow philtrum and thick lips. A de novo 6.4 Mb interstitial duplication of 15q15.3q21.2 was detected by chromosomal microarray analysis. We compared our patient's clinical phenotypes with those of several individuals with overlapping duplications and several candidate genes responsible for the phenotypes were identified as well. CONCLUSION: The results suggest a novel contiguous gene duplication syndrome characterized with shared features including short stature, hypogonadism, global developmental delay and other congenital anomalies. PMID- 26759606 TI - Detection of complex deletions in chromosomes 13 and 21 in a fetus by noninvasive prenatal testing. AB - BACKGROUND: To detect complex fetal subchromosomal abnormalities by noninvasive prenatal testing (NIPT). CASE PRESENTATION: After routine prenatal serum screening, the plasma of high-risk pregnant women were tested via NIPT, and the NIPT results were further validated by fetal karyotype analysis and array-based comparative genomic hybridization (aCGH) through amniocentesis. In addition, the chromosome karyotypes of the parents were also analyzed. NIPT results indicated subchromosomal abnormalities in chromosomes 13 and 21; aCGH results showed 22 Mb and 16 Mb deletions in 13 q31.3 - q34 and 21q11.1 - q21.3, respectively; and the fetal karyotype was 45,XX, der(13),-21. The maternal karyotype 46,XX,inv(9)(p12q13),t(13;21)(q31.3;q21.3) was abnormal, while the paternal karyotype showed no obvious abnormality. CONCLUSION: In this study, we successfully detected complex deletions in chromosomes 13 and 21 in a fetus using NIPT, and NIPT can provide effective genetic information for the detection of fetal subchromosomal abnormalities. PMID- 26759607 TI - Helicobacter pylori strains harboring babA2 from Indian sub population are associated with increased virulence in ex vivo study. AB - BACKGROUND: The babA2 gene along with the cagA and vacA of Helicobacter pylori has been considered as a risk factor for the disease outcome in certain populations. This study was aimed to understand the role of babA2 of H. pylori with the background of cagA and vacA in disease manifestations in Indian sub population. METHODS: A total of 114 H. pylori strains isolated from duodenal ulcer (DU) (n = 53) and non-ulcer dyspepsia (NUD) patients (n = 61) were screened for the prevalence of these virulence markers by PCR. The comparative study of IL 8 production and apoptosis were done by co-culturing the AGS cell line with H. pylori strains with different genotypes. Adherence assay was performed with babA2 positive and negative strains. Two isogenic mutants of babA2 were constructed and the aforesaid comparative studies were carried out. RESULTS: PCR results indicated that 90.6 % (48/53), 82 % (50/61) and 73.6 % (39/53) strains from DU patients were positive for cagA, vacA, and babA2, respectively. Whereas the prevalence of these genes in NUD subjects were 70.5 % (43/61); 69.8 % (37/53), and 65.6 % (39/61), respectively. Although adherence to AGS cells was comparable among strains with babA2 positive and negative genotypes, but the triple positive strains could induce highest degree of IL-8 production and apoptosis, followed by the cagA (-)/vacA (-)/babA2 (+) strains and triple negative strains, respectively. The wild type strains showed significantly higher IL-8 induction as well as apoptosis in ex vivo than its isogenic mutant of babA2. CONCLUSION: PCR study demonstrated that there was no significant association between the distribution of babA2 genotype or of triple positive strains and disease outcome in this sub population. The adherence assay showed that there was no significant difference in the extent of adherence to AGS cells among babA2 positive and negative strains. But the ex vivo study indicated that the triple positive or even the babA2 only positive strains are involved in increased virulence. The wild type strains also exhibited increased virulence compared to the babA2 mutant strains. This inconsistency demonstrated that bacterial genotype along with host genetic polymorphisms or other factors play important role in determining the clinical manifestation of H. pylori infections. PMID- 26759608 TI - Elevated glycated hemoglobin levels impair blood pressure in children and adolescents with type 1 diabetes mellitus. AB - BACKGROUND: Deregulation of glycemic and glycated hemoglobin (HbA1) levels accelerate the progression of cardiovascular complications in type 1 diabetes mellitus (T1DM). The aim of this study was to investigate the association between HbA1 and changes in blood pressure of children and adolescents with T1DM. METHODS: A total of 60 children and adolescents were recruited and allocated into two groups (prehypertension and control group). Blood pressure and HbA1 were measured by the oscillometric method and high-performance liquid chromatography, respectively. RESULTS: The prehypertensive group had (P < 0.05) higher disease duration, body weight, Z score for body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP) and a higher HbA1 when compared with the control children and adolescents. Multiple regression to predict alterations in DBP from HbA1 adjusted for age, disease duration, and body mass index demonstrated a positive relationship with DBP (P < 0.05). A 1 % increase in HbA1 was associated with 1.73 mmHg increase in DBP. CONCLUSIONS: High levels of HbA1 may be associated with increased blood pressure in T1DM. A tight control of HbA1 levels may provide long-term cardiovascular protection in children and adolescents with T1DM. PMID- 26759610 TI - Dancing eyes and dancing feet in scrub typhus. AB - A 26-year-old male, presented to us with complaints of fever for five days and breathlessness for one day. During the hospital stay, he developed myoclonic jerks in all four limbs, head titubation, and saccadomania. Magnetic resonance imaging (MRI) of the brain ruled out structural lesions and cerebro spinal fluid (CSF) analysis ruled out meningo-encephalitis. Weil Felix was strongly positive, OX K titres were one in 640, and IgM for scrub typhus was positive. He was treated with doxycycline for one week. On follow-up he was found to be doing well with resolution of opsoclonus myoclonus. PMID- 26759609 TI - Exenatide infusion decreases atrial natriuretic peptide levels by reducing cardiac filling pressures in type 2 diabetes patients with decompensated congestive heart failure. AB - BACKGROUND: The vascular effects exerted by GLP-1 are mediated by several synergistic mechanisms such as involvement of nitric oxide and natriuresis. Recently, it was demonstrated that atrial natriuretic peptide (ANP) is essential for the glucagon-like peptide-1 (GLP-1)-stimulated vascular smooth muscle relaxation that mediates anti-hypertensive action in rodents. Therefore a GLP-1 ANP axis has been suggested. The aim of this study was to investigate whether this effect can be demonstrated in patients with type 2 diabetes and congestive heart failure. METHODS: The study was a post hoc analysis of a randomized double blinded, placebo-controlled trial. Twenty male patients with type 2 diabetes and congestive heart failure were randomized to receive a 6-h infusion of exenatide or placebo. Cardiac filling pressures were measured by right heart catheterization, and plasma levels of ANP, N-terminal pro-brain natriuretic peptide, and exenatide were measured at baseline and at the end of the exenatide infusion. RESULTS: Exenatide infusion resulted in a significant decrease of circulating ANP levels compared with placebo, concomitant with a decrease in pulmonary capillary wedge pressure (PCWP), pulmonary artery pressure (PAP) and right arterial pressure (RAP), and increased cardiac output. There was no correlation between plasma ANP levels and exenatide levels. A negative correlation between ANP levels and PCWP, PAP, and RAP, which remained significant after adjustment for plasma exenatide levels, was demonstrated during exenatide infusion. CONCLUSIONS: Exenatide infusion decreases cardiac filling pressure and ANP levels. The reduction of ANP levels was primarily because of the reduction in cardiac filling pressure, independent of exenatide levels. It seems unlikely that this was mediated via ANP. TRIAL REGISTRATION: http://www.isrctn.org/ISRCTN47533126. PMID- 26759611 TI - Anatomy and its impact on medicine: Will it continue? PMID- 26759612 TI - A defining moment for medical research beyond 2015. PMID- 26759614 TI - The practice of OTC counseling by community pharmacists in Parana, Brazil. AB - BACKGROUND: In order to provide appropriate advice to the patient at the time of dispensing and over-the-counter (OTC) medication counseling, community pharmacists need access to current and reliable information about medicines. Brazilian pharmacists have assumed new functions such as prescribing medication, in a dependent model, based in protocols. OBJECTIVE: To examine the practice of community pharmacists in a Brazilian State, focusing on OTC recommendation. METHOD: A cross-sectional survey of community pharmacists in a state of Brazil was conducted from October 2013 to January 2014, with data collection through a pre-piloted self-administered anonymous survey via Survey Monkey((r)) platform. Following ethical approval, the online instrument was sent to 8,885 pharmacists registered in Parana State, Brazil, focusing on professionals working in community pharmacies. The questionnaire assessed the community pharmacy setting, the search for information, the knowledge of the evidence-based practice, the important factors to consider when recommending an OTC medicine, and the pharmacist prescribing. Responses were imported into SPSS((r)) (version 22.0) for analysis. Nonparametric tests were used to assess the association between responses and demographic information with a significance level less than 5% (p<0.05). RESULTS: Of the pharmacists, 97.4% dispensed medications and counseled patients for a median of six hours per day. Product's efficacy (97%) and adverse effects (62.3%) were the most important factors taken into account when counseling a nonprescription medicine. Few pharmacists knew the meaning of terms related to evidence-based health. Most respondents agreed that pharmacists have the necessary training to prescribe. CONCLUSION: Over-the-counter medication counseling is a daily practice among Brazilian pharmacists. Learning needs exist for community pharmacists in relation to evidence-based practice. Thus, sources of information with good evidence could be used daily by community pharmacists, especially as regards nonprescription medication counseling. PMID- 26759615 TI - The prevalence of major potential drug-drug interactions at a University health centre pharmacy in Jamaica. AB - OBJECTIVE: To identify major potential drug-drug interactions (DDIs) on prescriptions filled at the University Health Centre Pharmacy, Mona Campus, Jamaica. METHODS: This investigation utilised a cross-sectional analysis on all prescriptions with more than one drug that were filled at the Health Centre Pharmacy between November 2012 and February 2013. Potential DDIs were identified using the online Drug Interactions Checker database of Drugs.com. RESULTS: During the period of the study, a total of 2814 prescriptions were analysed for potential DDIs. The prevalence of potential DDIs found during the study period was 49.82%. Major potential DDIs accounted for 4.7 % of the total number of interactions detected, while moderate potential DDIs and minor potential DDIs were 80.8 % and 14.5 % respectively. The three most frequently occurring major potential DDIs were amlodipine and simvastatin (n=46), amiloride and losartan (n=27) and amiloride and lisinopril (n=16). CONCLUSION: This study has highlighted the need for educational initiatives to ensure that physicians and pharmacists collaborate in an effort to minimise the risks to the patients. These interactions are avoidable for the most part, as the use of online tools can facilitate the selection of therapeutic alternatives or guide decisions for closer patient monitoring and thus reduce the risks of adverse events. PMID- 26759613 TI - The influence of menstrual cycle and endometriosis on endometrial methylome. AB - BACKGROUND: Alterations in endometrial DNA methylation profile have been proposed as one potential mechanism initiating the development of endometriosis. However, the normal endometrial methylome is influenced by the cyclic hormonal changes, and the menstrual cycle phase-dependent epigenetic signature should be considered when studying endometrial disorders. So far, no studies have been performed to evaluate the menstrual cycle influences and endometriosis-specific endometrial methylation pattern at the same time. RESULTS: Infinium HumanMethylation 450K BeadChip arrays were used to explore DNA methylation profiles of endometrial tissues from various menstrual cycle phases from 31 patients with endometriosis and 24 healthy women. The DNA methylation profile of patients and controls was highly similar and only 28 differentially methylated regions (DMRs) between patients and controls were found. However, the overall magnitude of the methylation differences between patients and controls was rather small (Deltabeta ranging from -0.01 to -0.16 and from 0.01 to 0.08, respectively, for hypo- and hypermethylated CpGs). Unsupervised hierarchical clustering of the methylation data divided endometrial samples based on the menstrual cycle phase rather than diseased/non-diseased status. Further analysis revealed a number of menstrual cycle phase-specific epigenetic changes with largest changes occurring during the late-secretory and menstrual phases when substantial rearrangements of endometrial tissue take place. Comparison of cycle phase- and endometriosis specific methylation profile changes revealed that 13 out of 28 endometriosis specific DMRs were present in both datasets. CONCLUSIONS: The results of our study accentuate the importance of considering normal cyclic epigenetic changes in studies investigating endometrium-related disease-specific methylation patterns. PMID- 26759616 TI - Objective structured clinical examination (OSCE) in pharmacy education - a trend. AB - Pharmacy education has undergone a radical change as it evolves towards becoming a more patient oriented profession. With a greater emphasis on problem based teaching and competency, the Objective Structured Clinical Examination (OSCE), supported by its reliability and validity became the gold standard for the evaluation of clinical skills of undergraduate students of medicine and pharmacy worldwide. Core competency evaluation has become a mandatory and critical norm for accountability of educational objectives as the traditional testing tools cannot evaluate clinical competence. Interpersonal and communication skills, professional judgment, skills of resolution etc., may be best assessed through a well- structured OSCE in comparison to oral examinations, multiple choice tests and other methods of assessment. Though OSCEs as an objective method of evaluation offer several advantages to both students and teachers, it also has disadvantages and pitfalls in implementation. This article reviews the OSCE as a trend in pharmacy education. PMID- 26759617 TI - Impact of pharmacy-led medication reconciliation on medication errors during transition in the hospital setting. AB - OBJECTIVE: To assess if the pharmacy department should be more involved in the medication reconciliation process to assist in the reduction of medication errors that occur during transition of care points in the hospital setting. METHODS: This was an observational prospective cohort study at a 531-bed hospital in Pensacola, FL from June 1, 2014 to August 31, 2014. Patients were included in the study if they had health insurance and were taking five or more medications. Patients with congestive heart failure were excluded from the study. Student pharmacists collected and evaluated medication histories obtained from patients' community pharmacies, and directed patient interviews. Primary care providers were only contacted on an as needed basis. The information collected was presented to the clinical pharmacist, where interventions were made utilizing clinical judgment. RESULTS: During the three month study, 1045 home medications were reviewed by student pharmacist. Of these, 290 discrepancies were discovered (27.8%; p=0.02). The most common medication discrepancy found was dose optimization (45.5%). The remaining discrepancies included: added therapy (27.6%), other (15.2%), and discontinued therapy (11.7%). Pharmacists made 143 interventions based on clinical judgment (49.3%; p=0.04). CONCLUSION: Involvement of pharmacy personnel during the medication reconciliation process can be an essential component in reducing medical errors. With the addition of the pharmacy department during the admission process, accuracy, cost savings, and patient safety across all phases and transition points of care were achieved. PMID- 26759618 TI - Personality traits of pharmacy and medical students throughout their course of studies. AB - BACKGROUND: Pharmacists and medical doctors are two professional groups that very often receive their education and practice in the same environment. However, their approach to patient care and collaboration tends to be different and this may lead to both frustration and conflict which may adversely affect patient care. Personality has been identified as a psychological issue that could contribute to conflict in a work situation. OBJECTIVE: To study the personality traits of a cohort of students studying pharmacy and medicine at the University of Malta in their first and final year. METHODS: The Gordon Personal Profile - Inventory was administered to a cohort of pharmacy and medical students in their first year and once again administered to the same cohort who completed their course of study in their final year. Basic demographic data was also collected. RESULTS: In first year the most pronounced traits for both student groups were those of Emotional Stability and Personal Relations. Over a period of five years, there were shifts in personality traits. In their final year pharmacy students were characterized by high scores for Cautiousness and Personal Relations while medical students exhibited medium scores in Cautiousness and Emotional Stability. CONCLUSION: The changes in personality traits over the duration of the course were not radical changes but rather that of traits becoming more pronounced. PMID- 26759619 TI - The attitudes of pharmacists, students and the general public on mHealth applications for medication adherence. AB - BACKGROUND: During recent years mobile technology has developed tremendously and has infiltrated the healthcare field. Mobile healthcare (mHealth) applications, or apps, may be used to support patient adherence to medication thus promoting optimal treatment outcomes and reducing medication wastage. OBJECTIVE: This study shall consider the opinions of United Kingdom (UK) based pharmacists, pharmacy undergraduates and members of the general public towards the use of mHealth apps to promote adherence to prescribed medication regimens. METHODS: On Liverpool John Moores University (LJMU) ethical approval, the 25 item questionnaire was distributed to UK registered pharmacists within inner city Liverpool and Manchester (n=500), pharmacy undergraduates studying at LJMU (n=420) and members of the general public within Liverpool City Centre (n=400). The questions were formatted as multiple choice, Likert scales or the open answer type. The data were analysed using simple frequencies, cross tabulations and non-parametric techniques in the SPSS v22 program. RESULTS: The number of completed questionnaires from the pharmacist, student and general public cohorts were 245, 333 and 400; respectively. The data indicated that the general public rely heavily upon daily routine to take medication as prescribed (54.1%) with mHealth app use being extremely low (1.5%); a similar trend was noted for the pharmacist / student cohorts. The age of the individual is an important consideration, with the younger generation likely to engage with mHealth apps and the older generation less so. Here, education and training are important. Pharmacists (82.3%) would be happy to deliver training packages to the public who would in turn happily receive such training (84%). Key barriers precluding mHealth app use include data reliability, security and technical difficulties. CONCLUSION: Adherence apps hold great promise to support the patient and their healthcare needs. In order to increase acceptance and uptake simple, user-friendly designs must be considered and constructed. In addition, such technology requires effective promotion and end user training in order to reach its full potential. Furthermore, the regulation of mobile adherence apps will be essential in order to overcome underlying patient concerns. PMID- 26759620 TI - Evaluating the impact of pharmacist health education on the perceptions of the pharmacist's role among women living in a homeless shelter. AB - OBJECTIVES: To determine the impact of pharmacist-provided educational seminars on the participant's perception of the pharmacist's role in providing women's health education. Secondary objectives include the participant's level of perceived benefit from the information provided during each presentation, as well as determining characteristics of participants who are interested in attending seminars. METHODS: This is a prospective study conducted within a homeless women's shelter in Phoenix, Arizona. Pharmacists and pharmacy students provided 10 monthly educational seminars on topics related to women's health. Participants completed a pre- and post-seminar survey regarding their perceptions of the presentations and pharmacists. RESULTS: Fifty-six participants attended at least one of 10 seminars from January to November 2014. The average age was 46 years old, taking approximately 3 medications, and 66% completed a high school degree or lower. Prior to the presentations, 30% of participants agreed or strongly agreed that they would seek advice from a pharmacist on the topic presented, which increased significantly to 82% of participants after the presentation (p<0.001). Similarly, 55% of participants rated themselves as agreeing or strongly agreeing with being knowledgeable on the topic presented prior to the presentation, and this increased significantly to 77% after the presentation (p=0.001). After attending the educational session, 70% of participants agreed or strongly agreed that they would make changes to their health, and that they would attend an additional session. The participants noted their increased learning about the topic, the clarity of visual aids and presentation, and knowledge of the presenters as the best parts of the presentation. CONCLUSION: Pharmacist's participation in providing educational seminars in the homeless women's population increases the participant's knowledge and perception of the pharmacist's role within the population. Future studies can further investigate an evolving role of pharmacists in optimizing healthcare in the homeless population. PMID- 26759621 TI - Medication regimen complexity in adults and the elderly in a primary healthcare setting: determination of high and low complexities. AB - BACKGROUND: The complexity of a medication regimen is related to the multiple characteristics of the prescribed regimen and can negatively influence the health outcomes of patients. OBJECTIVE: To propose cut-off points in the complexity of pharmacotherapy to distinguish between patients with low and high complexities seen in a primary health care (PHC) setting to enable prioritization of patient management. METHODS: This is a cross-sectional study, which included 517 adult and elderly patients, analyzing different cut-off points to define the strata of low and high pharmacotherapy complexities based on percentiles of the population evaluated. Data collection began with the solicitation of prescriptions, followed by a questionnaire that was administered by an interviewer. The complexity of a medication regimen was estimated from the Medication Regimen Complexity Index (MRCI). High complexity pharmacotherapy scores were analyzed from patient profiles, the use of health services, and pharmacotherapy. The criteria for subject inclusion in the sample population were as follows: inhabitant of the area covered by the municipality, 18 years or older, and being prescribed at least one drug during the collection period. Exclusion criteria at the time of collection were the use of any medication whose prescription was not available. All medications were accessed through the Primary Healthcare Service (PHS). RESULTS: The median total pharmacotherapy complexity score was 8.5. High MRCI scores were correlated with age, medications taken with in the Brazilian PHS, having at least one potential drug-related problem, receiving up to eight years of schooling, number of medications and polypharmacy (five or more medicines), number of medical conditions, number of medical appointments, and number of cardiovascular diseases and endocrine metabolic diseases. We suggest different complexity tracks according to age (e.g., adult or elderly) that consider the pharmacotherapy and population coverage characteristics as high complexity limits. For the elderly patients, the tracks were as follows: MRCI>=25.4, MRCI>=20.9, MRCI>=17.5, MRCI>=15.7, MRCI>=14.0, and MRCI>=13.0. For adult patients, the limits of high complexity were MRCI>=25.1; MRCI >= 23.8; MRCI>=21.0; MRCI>=17.0; MRCI>=16.5; and MRCI>=15.5. CONCLUSION: The medication regimen complexity is associated with the patient's illness profile and problems with the use of drugs; therefore, the proposed scores can be useful in prioritizing patients for clinical care by pharmacists and other health professionals. PMID- 26759622 TI - Evaluation of urban-rural differences in pharmacy practice needs in Maine with the MaPPNA. AB - BACKGROUND: Maine is a rural state with an aging population located in the northeastern United States. Pharmacists play an important role in serving the public's health as they are often the most available point-of-contact within a community. OBJECTIVE: To assess the current pharmacy practice needs as viewed by licensed pharmacists across our rural state, and to distinguish issues that are unique to rural pharmacy practice. METHODS: An online survey was sent to all licensed pharmacists in the state in the fall of 2014 (n=1,262) to assess their pharmacy practice needs, and specify an rural-specific needs, within the categories of (1) opioid misuse, abuse, and diversion, (2) challenges associated with access to healthcare, (3) poly-pharmacy use, (4) meeting the needs of special populations, (5) lack of antibiotic stewardship, and (6) resources, such as staffing. RESULTS: The response rate was 22.1 % (n=279). We found the most agreed upon issue facing pharmacists' in Maine is opioid use, misuse and diversion, followed closely by shortages in staffing. We also learned that pharmacists' view pharmaceutical care for older adults, those with low health literacy, and those with mental disabilities more time-consuming. Some urban rural differences were discovered in with regard to the pharmacists' views; such as the magnitude of the distance barrier, and limited transportation options available to rural residents. Issues related to polypharmacy were viewed as more problematic by pharmacists practicing in urban versus rural sites. CONCLUSIONS: Pharmaceutical care in Maine must focus on meeting the needs of the elderly, those with disabilities, and those with limited health literacy. As with the rest of the nation, opioids challenge pharmacy practice in a variety of ways. These findings clarify areas that present opportunities for pharmacists to focus more specifically on Maine's largely rural population. PMID- 26759623 TI - Quality of drug information for healthcare professionals: The ARCA acronym. PMID- 26759624 TI - Dexlansoprazole - a new-generation proton pump inhibitor. AB - Dexlansoprazole modified release (MR) is an R-enantiomer of lansoprazole and a new-generation proton pump inhibitor exhibiting high efficacy in the treatment of symptoms and lesions associated with erosive oesophagitis caused by gastroesophageal reflux disease (GERD). The dual release of the active ingredient - in the duodenum and the small intestine - makes it possible to achieve two peak concentrations at various times, within two and five hours of administration. Dexlansoprazole MR ensures the longest maintenance of drug concentration in the plasma of all known proton pump inhibitors, and the longest proton pump inhibitory effect. The basic indications for the drug include all forms of gastroesophageal reflux disease, especially with night-time heartburn and sleep disorders resulting from GERD. Dexlansoprazole can be taken regardless of meal times. It has a good safety profile and carries a low risk of adverse interactions with other drugs. PMID- 26759625 TI - Economic implications of biological therapy for Crohn's disease. AB - In the early 90s American authors estimated that if a theoretical new drug was introduced that was capable of changing the natural course of the disease and reducing direct non-drug medical costs (including hospitalisation and surgery) by 20%, despite doubling the overall drugs bill, there would still be a reduction in total direct medical costs of Crohn's disease by 13%. Infliximab proved to be efficacious in reducing and maintaining remission in moderate to severe active Crohn's disease and/or fistulising Crohn's disease. A higher acquisition cost still remains its major limitation. Currently only the use of infliximab in case of treatment for flares seems to be cost-effective. However, this statement may be modified in the near future. PMID- 26759626 TI - Interleukin 18 as an early marker or prognostic factor in acute pancreatitis. AB - INTRODUCTION: Acute pancreatits (AP) still reqiures better diagnostic and therapeutic options to be introduced in order to decrease its morbidity and mortality. It appears that the assessment of serum levels of interleukin 18 (IL 18) and its correlation with C-reactive protein (CRP) may provide adequate prognostic value. AIM: To measure serum concentrations of IL-18 and inflammation markers such as CRP in patients with AP during subsequent hospital stay days and to assess the role of IL-18 as an early AP marker and prognostic factor. MATERIAL AND METHODS: Thirty-two patients aged 47 +/-16.7 years were included into the study (17 males and 15 females), in whom AP was diagnosed based on ultrasound and computer aided tomography imaging and amylase. Serum amylase, CRP, and IL-18 levels were measured on the 1(st), 2(nd), 3(rd), and 5(th) days of hospital stay. All patients were scored "B" according to Balthazar and mild AP based on Ranson criteria. The control group consisted of 30 healthy volunteers aged 50.7 +/-12.4 years (15 males and 15 females). RESULTS: The average IL-18 serum level in the control group was 86.91 +/-4.94 pg/ml. Mean IL-18 study group levels were 128.4 +/-7.6 pg/ml on the 1(st), 112.0 +/-4.4 pg/ml on the 3(rd), and 122.8 +/-6.8 pg/ml on the 5(th) day of AP, and were significantly higher than those in the control group, accordingly: p < 0.001, p < 0.005, p < 0.001. A positive correlation between IL-18 and CRP serum concentrations was observed. A slight increase in correlation was observed as the days went by. CONCLUSIONS: We concluded that the serum IL-18 level increases in the initial phase of AP, and it may be used as an inflammatory reaction marker in patients with AP, and it is correlated with CRP, which may indicate its prognostic role in AP. PMID- 26759627 TI - The state of nutrition and the self-assessment of symptoms of depression in the group of seniors living in the countryside of Lublin province - preliminary report. AB - INTRODUCTION: The incidence of malnutrition increases together with the number of chronic diseases and medications taken daily. There are also other factors causing changes in the nutrition of the elderly, raising the risk of undernourishment. Such factors include difficulties with daily shopping, meal preparation and other everyday activities, hindering access to food with proper quantitative and qualitative properties. The nutritional state of the elderly is influenced not only by somatic disorders, but also by mental disorders such as depression. AIM: To define the relationship between the nutritional state of the elderly living in their home environment and the incidence of depression. MATERIAL AND METHODS: The described sample consisted of 116 (100%) elderly persons living in the Lubelskie Voivodeship, using the services carried out within primary healthcare. The nutritional state of the elderly was assessed with the use of the full version of the Mini Nutritional Assessment (MNA) questionnaire. In order to determine the intensity of depression symptoms, the Geriatric Depression Scale (GDS) (the 15-item version by Yesavage) was applied. RESULTS: During analysis of the impact of depression on malnutrition risk, a correlation with a high statistical significance level was found. Malnutrition was significantly more often identified in people in whom the GDS scale revealed severe depression (p = 0.00002). The risk of depression has a substantial impact on nutritional state. The nutritional state of the elderly deteriorates together with the increase of the risk of depression. CONCLUSIONS: In over 48% of respondents, including those living with their families, an intensification of depression symptoms was found. PMID- 26759628 TI - The impact of osteoporosis on health-related quality of life in patients after liver transplantation - a pilot study. AB - INTRODUCTION: Liver transplantation (LT) is now a well-established procedure with 5-year survival rates over 70%, and one of its ultimate goals is the improvement of patient health-related quality of life (HRQOL). Osteoporosis remains a serious potential complication of LT, leading to fragility fractures, pain, and functional impairment. AIM: To assess the degree of osteoporosis and the impact of fragility fractures on HRQOL in patients with chronic liver diseases treated with LT. MATERIAL AND METHODS: Twenty-seven patients (14 female, 13 male) at a median period of 3.5 years post LT participated in the study. HRQOL was assessed by Short Form-36 and PBC-40 instruments. Bone mineral density (BMD) in the lumbar spine and hip neck were measured by dual-energy X-ray absorptiometry. Physical activity was assessed by questionnaire. Data on the duration of the liver disease, time from LT, and fragility fractures were also collected. RESULTS: As many as 74.1% of the patients had reduced BMD (t-score < -1.0 SD) in the hip. Mean values of the spine and hip BMD z-scores were -1.1 and -0.9 SD, respectively. Time after LT, percentage of lean tissue, and physical activity were positively associated with BMD. The prevalence of fractures was 48%. We did not find significant differences in age, gender, body composition parameters, physical activity, BMD, and HRQOL scores between the subjects with and without fractures. CONCLUSIONS: We found a high prevalence of fragility fractures and a decreased BMD in LT recipients. Patients with a history of fractures had similar HRQOL scores to those without fractures. PMID- 26759630 TI - Assessment of nutritional knowledge of patients with pancreatitis. AB - INTRODUCTION: Proper nourishment is one of the basic elements in the treatment of patients with both acute and chronic pancreatitis. Following acute pancreatitis, the essential element of nutritional treatment is dietary education. The dietary approach is used not only for treatment, but also for prevention of reoccurrence of the condition. AIM: To evaluate nutritional knowledge of patients with acute and chronic pancreatitis. MATERIAL AND METHODS: The selected group consisted of 36 patients, 19 females and 17 males, suffering from acute or chronic pancreatitis. Participation in our survey was anonymous and voluntary. The study population was divided into two groups: 12 patients with acute pancreatitis (5 males and 7 females) and 24 patients with chronic pancreatitis (12 males and 12 females). The median age of patients was 42.4 +/-14 years (range: 20-76 years). The duration of illness among the study population was varied. The biggest group of 16 (44.4%) patients suffered from pancreatitis for more than 5 years, 8 (22.2%) patients had pancreatitis diagnosed 1-2 years previously, only 3 (8.3%) subjects suffered from pancreatitis for shorter than half a year. To analyse patients' nutritional knowledge an authorial questionnaire was used that contained 17 closed questions and open-type questions were used three times. RESULTS: Most (97%) subjects with acute and chronic pancreatitis adhered to the diet to various degrees, but almost 50% of people up to 35 years of age declared that they didn't respect the diet, or that they followed only a few recommendations. Despite each interviewer admitted to follow dietary recommendations for pancreatitis, 11.1% of patients could not indicate any of them. Most patients knew that their diet should contain a low amount of fat (61% of patients). Awareness of alcohol abstinence was confirmed in 44.4% of subjects. One third (33.3%) of patients knew that fried food should be avoided. Only a few patients were aware that smoking, spicy food, and strong coffee should be excluded from their diet. About 80% of the surveyed patients evaluated their level of nutritional knowledge as good or very good. Only 20% of the study population admitted their dietary knowledge was unsatisfactory, and most of these were woman (86%). CONCLUSIONS: The results of the present study demonstrate that dietary knowledge among patients suffering from acute and chronic pancreatitis is insufficient. Although patients have theoretical knowledge about nutritional management, they have problems implementing the diet on a daily basis. It is necessary to pay more attention to nutritional education for patients suffering from pancreatitis. PMID- 26759629 TI - The crossroads of gastroenterology and psychiatry - what benefits can psychiatry provide for the treatment of patients suffering from gastrointestinal symptoms. AB - INTRODUCTION: Gastrointestinal symptoms are very common in the general population. Many of them coincide with mental disorders (especially with neuroses, stress-related disorders, somatisation disorders, autonomic dysfunction, and anxiety) that are associated with psychological trauma, conflicts, and difficulties with interpersonal relationships. AIM: Assessment of the association between gastrointestinal complaints and stressful situations in relationships, among patients admitted to day hospital for neurotic and behavioural disorders. MATERIAL AND METHODS: Analysis of the likelihood of co occurrence of abdominal symptoms and stressful situations, reported by patients before admission, in a large group of subjects treated with psychotherapy. RESULTS: Gastrointestinal symptoms were highly prevalent in the studied group (they were reported by 40-50% of patients). The most common complaints in women were: loss of appetite (52%), nausea (49%), and constipation and flatulence (45%). In men the most prevalent symptoms were: loss of appetite (47%), heartburn (44%), and flatulence (43%). Functional gastrointestinal symptoms (especially vomiting in cases of nervousness in females or heartburn in males) were significantly associated with greater likelihood of current difficulties in interpersonal relationships, such as conflicts with partner/spouse or parent. CONCLUSIONS: The results suggest that in many cases symptoms of anxiety disorders or somatisation disorders coexisted with irritable bowel syndrome and functional dyspepsia. PMID- 26759631 TI - Enema versus polyethylene glycol for the management of rectal faecal impaction in children with constipation - a systematic review of randomised controlled trials. AB - INTRODUCTION: Rectal faecal impaction (RFI) from functional constipation is a common problem in children. Maintenance therapy should start after successful disimpaction. However, there is uncertainty with regard to the optimal disimpaction regimen. AIM: We systematically evaluated the effect of polyethylene glycol (PEG) compared to enema for treating RFI. MATERIAL AND METHODS: The MEDLINE, EMBASE, and the Cochrane Library, with no language restrictions, were searched up to July 2014 for randomised controlled trials (RCTs) evaluating the effect of PEG compared with enema for disimpaction in children with functional constipation. The risk of bias was assessed using the Cochrane risk of bias tool. RESULTS: Two RCTs, involving 170 children aged 1 to 17 years, met the inclusion criteria. The studies were generally low in methodological quality. Compared with the enema group, the PEG 3350 group had significantly reduced chance for treatment success, but the difference was of a borderline statistical significance (RR = 0.83, 95% CI: 0.7-0.99). The use of PEG was also more likely to increase defecation frequency, but increased the risk of watery stools and increased faecal incontinence. Other outcomes, in general, were similar in both groups. CONCLUSIONS: Current evidence does not allow us to conclude which intervention is more effective for treating RFI in children with functional constipation. These results should be interpreted with caution due to the limited number of trials and the low quality of reporting in these trials, high or unknown risk of bias, and sparse data. Further high-quality, adequately powered RCTs are needed to determine the optimal management. PMID- 26759632 TI - Endoscopic treatment of gastric varices bleeding with the use of n-butyl-2 cyanoacrylate. AB - INTRODUCTION: Oesophageal varices and gastric varices are naturally-formed, pathological portosystemic shunts that occur in patients with portal hypertension. Gastric varices are responsible for about 10% of variceal bleeding; however, they are also the cause of massive haemorrhage, often with dramatic progress. AIM: To assess the results of endoscopic treatment of gastrointestinal bleeding from oesophageal and gastric varices using tissue glue Histoacryl. MATERIAL AND METHODS: From January 2013 to May 2015 170 patients underwent a total of 244 obliterations with the administration of tissue glue due to gastroesophageal varices. We analysed 35 patients who received urgent endoscopic intervention due to life-threatening gastric variceal bleeding. RESULTS: Thirty five patients underwent 47 endoscopic procedures of haemorrhage management. Immediate haemostasis was achieved in 32 (91.4%) patients. In 3 (8.6%) cases endoscopy failed. In 2 patients a Linton tube was applied before secondary endoscopy. A single trans jugular portosystemic shunt (TIPS) was performed. Permanent haemostasis during the first endoscopy was achieved in 26 (74%) patients. Six (17%) patients presented recurrent bleeding 1-4 days following the initial treatment. Three patients had a splenic artery embolisation performed. One of the embolised patients required surgery, and a splenectomy was carried out. CONCLUSIONS: If this kind of therapy is unavailable at the time, it is advised that one of the conventional methods of controlling bleeding is used, introducing basic life support and transporting the patient to a specialist centre with adequate endoscopic facilities, radiological possibilities of endovascular intervention, and surgical treatment of liver transplantation. PMID- 26759633 TI - Anaemia due to gastric haemorrhage by a metastatic Merkel cell carcinoma. PMID- 26759634 TI - Mucous membrane pemphigoid as a cause of acute dysphagia - an endoscopic study. PMID- 26759635 TI - The importance of anti-transglutaminase IgA antibody detection in the diagnosis of celiac disease - case report of an inappropriate diagnostic approach. PMID- 26759636 TI - Measurements of DNA barcode label separations in nanochannels from time-series data. AB - We analyzed time-series data for fluctuations of intramolecular segments of barcoded E. coli genomic DNA molecules confined in nanochannels with sizes near the persistence length of DNA. These dynamic data allowed us to measure the probability distribution governing the distance between labels on the DNA backbone, which is a key input into the alignment methods used for genome mapping in nanochannels. Importantly, this dynamic method does not require alignment of the barcode to the reference genome, thereby removing a source of potential systematic error in a previous study of this type. The results thus obtained support previous evidence for a left-skewed probability density for the distance between labels, albeit at a lower magnitude of skewness. We further show that the majority of large fluctuations between labels are short-lived events, which sheds further light upon the success of the linearized DNA genome mapping technique. This time-resolved data analysis will improve existing genome map alignment algorithms, and the overall idea of using dynamic data could potentially improve the accuracy of genome mapping, especially for complex heterogeneous samples such as cancer cells. PMID- 26759637 TI - Microfluidic platform for separation and extraction of plasma from whole blood using dielectrophoresis. AB - Microfluidic based blood plasma extraction is a fundamental necessity that will facilitate many future lab-on-a-chip based point-of-care diagnostic systems. However, current approaches for providing this analyte are hampered by the requirement to provide external pumping or dilution of blood, which result in low effective yield, lower concentration of target constituents, and complicated functionality. This paper presents a capillary-driven, dielectrophoresis-enabled microfluidic system capable of separating and extracting cell-free plasma from small amounts of whole human blood. This process takes place directly on-chip, and without the requirement of dilution, thus eliminating the prerequisite of pre processed blood samples and external liquid handling systems. The microfluidic chip takes advantage of a capillary pump for driving whole blood through the main channel and a cross flow filtration system for extracting plasma from whole blood. This filter is actively unblocked through negative dielectrophoresis forces, dramatically enhancing the volume of extracted plasma. Experiments using whole human blood yield volumes of around 180 nl of cell-free, undiluted plasma. We believe that implementation of various integrated biosensing techniques into this plasma extraction system could enable multiplexed detection of various biomarkers. PMID- 26759638 TI - A microfluidic platform for size-dependent generation of droplet interface bilayer networks on rails. AB - Droplet interface bilayer (DIB) networks are emerging as a cornerstone technology for the bottom up construction of cell-like and tissue-like structures and bio devices. They are an exciting and versatile model-membrane platform, seeing increasing use in the disciplines of synthetic biology, chemical biology, and membrane biophysics. DIBs are formed when lipid-coated water-in-oil droplets are brought together-oil is excluded from the interface, resulting in a bilayer. Perhaps the greatest feature of the DIB platform is the ability to generate bilayer networks by connecting multiple droplets together, which can in turn be used in applications ranging from tissue mimics, multicellular models, and bio devices. For such applications, the construction and release of DIB networks of defined size and composition on-demand is crucial. We have developed a droplet based microfluidic method for the generation of different sized DIB networks (300 1500 pl droplets) on-chip. We do this by employing a droplet-on-rails strategy where droplets are guided down designated paths of a chip with the aid of microfabricated grooves or "rails," and droplets of set sizes are selectively directed to specific rails using auxiliary flows. In this way we can uniquely produce parallel bilayer networks of defined sizes. By trapping several droplets in a rail, extended DIB networks containing up to 20 sequential bilayers could be constructed. The trapped DIB arrays can be composed of different lipid types and can be released on-demand and regenerated within seconds. We show that chemical signals can be propagated across the bio-network by transplanting enzymatic reaction cascades for inter-droplet communication. PMID- 26759639 TI - Intubating Ebola Patients: Technical Limitations of Extensive Personal Protective Equipment. PMID- 26759640 TI - Epidemiology of Advance Directives in Extended Care Facility Patients Presenting to the Emergency Department. AB - INTRODUCTION: We conducted an epidemiologic evaluation of advance directives and do-not-resuscitate (DNR) prevalence among residents of extended care facilities (ECF) presenting to the emergency department (ED). METHODS: We performed a retrospective medical record review on ED patients originating from an ECF. Data were collected on age, sex, race, triage acuity, ED disposition, DNR status, power-of attorney (POA) status, and living will (LW) status. We generated descriptive statistics, and used logistic regression to evaluate predictors of DNR status. RESULTS: A total of 754 patients over 20 months met inclusion criteria; 533 (70.7%) were white, 351 (46.6%) were male, and the median age was 66 years (IQR 54-78). DNR orders were found in 124 (16.4%, 95% CI [13.9-19.1%]) patients. In univariate analysis, there was a significant difference in DNR by gender (10.5% female vs. 6.0% male with DNR, p=0.013), race (13.4% white vs. 3.1% non-white with DNR, p=0.005), and age (4.0% <65 years; 2.9% 65-74 years, p=0.101; 3.3% 75-84 years, p=0.001; 6.2% >84 years, p<0.001). Using multivariate logistic regression, we found that factors associated with DNR status were gender (OR 1.477, p=0.358, note interaction term), POA status (OR 6.612, p<0.001), LW (18.032, p<0.001), age (65-74 years OR 1.261, p=0.478; 75-84 years OR 1.737, p=0.091, >84 years OR 5.258, P<0.001), with interactions between POA and gender (OR 0.294, P=0.016) and between POA and LW (OR 0.227, p<0.005). Secondary analysis demonstrated that DNR orders were not significantly associated with death during admission (p=0.084). CONCLUSION: Age, gender, POA, and LW use are predictors of ECF patient DNR use. Further, DNR presence is not a predictor of death in the hospital. PMID- 26759641 TI - Abdominal CT Does Not Improve Outcome for Children with Suspected Acute Appendicitis. AB - INTRODUCTION: Acute appendicitis in children is a clinical diagnosis, which often requires preoperative confirmation with either ultrasound (US) or computed tomography (CT) studies. CTs expose children to radiation, which may increase the lifetime risk of developing malignancy. US in the pediatric population with appropriate clinical follow up and serial exam may be an effective diagnostic modality for many children without incurring the risk of radiation. The objective of the study was to compare the rate of appendiceal rupture and negative appendectomies between children with and without abdominal CTs; and to evaluate the same outcomes for children with and without USs to determine if there were any associations between imaging modalities and outcomes. METHODS: We conducted a retrospective chart review including emergency department (ED) and inpatient records from 1/1/2009-2/31/2010 and included patients with suspected acute appendicitis. RESULTS: 1,493 children, aged less than one year to 20 years, were identified in the ED with suspected appendicitis. These patients presented with abdominal pain who had either a surgical consult or an abdominal imaging study to evaluate for appendicitis, or were transferred from an outside hospital or primary care physician office with the stated suspicion of acute appendicitis. Of these patients, 739 were sent home following evaluation in the ED and did not return within the subsequent two weeks and were therefore presumed not to have appendicitis. A total of 754 were admitted and form the study population, of which 20% received a CT, 53% US, and 8% received both. Of these 57%, 95% CI [53.5,60.5] had pathology-proven appendicitis. Appendicitis rates were similar for children with a CT (57%, 95% CI [49.6,64.4]) compared to those without (57%, 95% CI [52.9,61.0]). Children with perforation were similar between those with a CT (18%, 95% CI [12.3,23.7]) and those without (13%, 95% CI [10.3,15.7]). The proportion of children with a negative appendectomy was similar in both groups: CT (7%, 95% CI [2.1,11.9]), US (8%, 95% CI [4.7,11.3]) and neither (12%, 95% CI [5.9,18.1]). CONCLUSION: In this uncontrolled study, the accuracy of preoperative diagnosis of appendicitis and the incidence of pathology-proven perforation appendix were similar for children with suspected acute appendicitis whether they had CT, US or neither imaging, in conjunction with surgical consult. The imaging modality of CT was not associated with better outcomes for children presenting to the ED with suspected appendicitis. PMID- 26759642 TI - Chest Pain of Suspected Cardiac Origin: Current Evidence-based Recommendations for Prehospital Care. AB - INTRODUCTION: In the United States, emergency medical services (EMS) protocols vary widely across jurisdictions. We sought to develop evidence-based recommendations for the prehospital evaluation and treatment of chest pain of suspected cardiac origin and to compare these recommendations against the current protocols used by the 33 EMS agencies in the state of California. METHODS: We performed a literature review of the current evidence in the prehospital treatment of chest pain and augmented this review with guidelines from various national and international societies to create our evidence-based recommendations. We then compared the chest pain protocols of each of the 33 EMS agencies for consistency with these recommendations. The specific protocol components that we analyzed were use of supplemental oxygen, aspirin, nitrates, opiates, 12-lead electrocardiogram (ECG), ST segment elevation myocardial infarction (STEMI) regionalization systems, prehospital fibrinolysis and beta blockers. RESULTS: The protocols varied widely in terms of medication and dosing choices, as well as listed contraindications to treatments. Every agency uses oxygen with 54% recommending titrated dosing. All agencies use aspirin (64% recommending 325 mg, 24% recommending 162 mg and 15% recommending either), as well as nitroglycerin and opiates (58% choosing morphine). Prehospital 12-Lead ECGs are used in 97% of agencies, and all but one agency has some form of regionalized care for their STEMI patients. No agency is currently employing prehospital fibrinolysis or beta-blocker use. CONCLUSION: Protocols for chest pain of suspected cardiac origin vary widely across California. The evidence based recommendations that we present for the prehospital diagnosis and treatment of this condition may be useful for EMS medical directors tasked with creating and revising these protocols. PMID- 26759643 TI - Impact of Burnout on Self-Reported Patient Care Among Emergency Physicians. AB - INTRODUCTION: Burnout is a syndrome of depersonalization, emotional exhaustion and sense of low personal accomplishment. Emergency physicians (EPs) experience the highest levels of burnout among all physicians. Burnout is associated with greater rates of self-reported suboptimal care among surgeons and internists. The association between burnout and suboptimal care among EPs is unknown. The objective of the study was to evaluate burnout rates among attending and resident EPs and examine their relationship with self-reported patient care practices. METHODS: In this cross-sectional study burnout was measured at two university based emergency medicine residency programs with the Maslach Burnout Inventory. We also measured depression, quality of life (QOL) and career satisfaction using validated questionnaires. Six items assessed suboptimal care and the frequency with which they were performed. RESULTS: We included 77 out of 155 (49.7%) responses. The EP burnout rate was 57.1%, with no difference between attending and resident physicians. Residents were more likely to screen positive for depression (47.8% vs 18.5%, p=0.012) and report lower QOL scores (6.7 vs 7.4 out of 10, p=0.036) than attendings. Attendings and residents reported similar rates of career satisfaction (85.2% vs 87.0%, p=0.744). Burnout was associated with a positive screen for depression (38.6% vs 12.1%, p=0.011) and lower career satisfaction (77.3% vs 97.0%, p=0.02). EPs with high burnout were significantly more likely to report performing all six acts of suboptimal care. CONCLUSION: A majority of EPs demonstrated high burnout. EP burnout was significantly associated with higher frequencies of self-reported suboptimal care. Future efforts to determine if provider burnout is associated with negative changes in actual patient care are necessary. PMID- 26759644 TI - Outcomes of Patients Requiring Blood Pressure Control Before Thrombolysis with tPA for Acute Ischemic Stroke. AB - INTRODUCTION: The purpose of this study was to assess safety and efficacy of thrombolysis in the setting of aggressive blood pressure (BP) control as it compares to standard BP control or no BP control prior to thrombolysis. METHODS: We performed a retrospective review of patients treated with tissue plasminogen activator (tPA) for acute ischemic stroke (AIS) between 2004-2011. We compared the outcomes of patients treated with tPA for AIS who required aggressive BP control prior to thrombolysis to those requiring standard or no BP control prior to thrombolysis. The primary outcome of interest was safety, defined by all grades of hemorrhagic transformation and neurologic deterioration. The secondary outcome was efficacy, determined by functional status at discharge, and in hospital deaths. RESULTS: Of 427 patients included in the analysis, 89 received aggressive BP control prior to thrombolysis, 65 received standard BP control, and 273 required no BP control prior to thrombolysis. Patients requiring BP control had more severe strokes, with median arrival National Institutes of Health Stroke Scale of 10 (IQR [6-17]) in patients not requiring BP control versus 11 (IQR [5 16]) and 13 (IQR [7-20]) in patients requiring standard and aggressive BP lowering therapies, respectively (p=0.048). In a multiple logistic regression model adjusting for baseline differences, there were no statistically significant differences in adverse events between the three groups (P>0.10). CONCLUSION: We observed no association between BP control and adverse outcomes in ischemic stroke patients undergoing thrombolysis. However, additional study is necessary to confirm or refute the safety of aggressive BP control prior to thrombolysis. PMID- 26759645 TI - Troponin Marker for Acute Coronary Occlusion and Patient Outcome Following Cardiac Arrest. AB - INTRODUCTION: The utility of troponin as a marker for acute coronary occlusion and patient outcome after out-of-hospital cardiac arrest (OHCA) is unclear. We sought to determine whether initial or peak troponin was associated with percutaneous coronary intervention (PCI), OHCA survival or neurological outcome. METHODS: Single-center retrospective-cohort study of OHCA patients treated in a comprehensive clinical pathway from November 2007 to October 2012. Troponin I levels were acquired at presentation, four and eight hours after arrest, and then per physician discretion. Cardiac catheterization was at the cardiologist's discretion. Survival and outcome were determined at hospital discharge, with cerebral performance category score 1-2 defined as a good neurological outcome. RESULTS: We enrolled 277 patients; 58% had a shockable rhythm, 44% survived, 41% good neurological outcome. Of the 107 (38%) patients who underwent cardiac catheterization, 30 (28%) had PCI. Initial ED troponin (median, ng/mL) was not different in patients requiring PCI vs no PCI (0.32 vs 0.09, p=0.06), although peak troponin was higher (4.19 versus 1.57, p=0.02). Of the 85 patients who underwent cardiac catheterization without STEMI (n=85), there was no difference in those who received PCI vs no PCI in initial troponin (0.22 vs 0.06, p=0.40) or peak troponin (2.58 vs 1.43, p=0.27). Regarding outcomes, there was no difference in initial troponin in survivors versus non-survivors (0.09 vs 0.22, p=0.11), or those with a good versus poor neurological outcome (0.09 vs 0.20, p=0.11). Likewise, there was no difference in peak troponin in survivors versus non survivors (1.64 vs 1.23, p=0.07), or in those with a good versus poor neurological outcome (1.57 vs 1.26, p=0.14). CONCLUSION: In our single-center patient cohort, peak troponin, but not initial troponin, was associated with higher likelihood of PCI, while neither initial nor peak troponin were associated with survival or neurological outcome in OHCA patients. PMID- 26759646 TI - Written Informed Consent for Computed Tomography of the Abdomen/Pelvis is Associated with Decreased CT Utilization in Low-Risk Emergency Department Patients. AB - INTRODUCTION: The increasing rate of patient exposure to radiation from computerized tomography (CT) raises questions about appropriateness of utilization. There is no current standard to employ informed consent for CT (ICCT). Our study assessed the relationship between informed consent and CT utilization in emergency department (ED) patients. METHODS: An observational multiphase before-after cohort study was completed from 4/2010-5/2011. We assessed CT utilization before and after (Time I/Time II) the implementation of an informed consent protocol. Adult patients were included if they presented with symptoms of abdominal/pelvic pathology or completed ED CT. We excluded patients with pregnancy, trauma, or altered mental status. Data on history, exam, diagnostics, and disposition were collected via standard abstraction tool. We generated a multivariate logistic model via stepwise regression, to assess CT utilization across risk groups. Logistic models, stratified by risk, were generated to include study phase and a propensity score that controlled for potential confounders of CT utilization. RESULTS: 7,684 patients met inclusion criteria. In PHASE 2, there was a 24% (95% CI [10-36%]) reduction in CT utilization in the low-risk patient group (p<0.002). ICCT did not affect CT utilization in the high-risk group (p=0.16). In low-risk patients, the propensity score was significant (p<0.001). There were no adverse events reported during the study period. CONCLUSION: The implementation of ICCT was associated with reduced CT utilization in low-risk ED patients. ICCT has the potential to increase informed, shared decision making with patients, as well as to reduce the risks and cost associated with CT. PMID- 26759648 TI - Achieving the Triple Aim Through Informed Consent for Computed Tomography. PMID- 26759647 TI - Inpatient Readmissions and Emergency Department Visits within 30 Days of a Hospital Admission. AB - INTRODUCTION: Inpatient hospital readmissions have become a focus for healthcare reform and cost-containment efforts. Initiatives targeting unanticipated readmissions have included care coordination for specific high readmission diseases and patients and health coaching during the post-discharge transition period. However, little research has focused on emergency department (ED) visits following an inpatient admission. The objective of this study was to assess 30 day ED utilization and all-cause readmissions following a hospital admission. METHODS: This was a retrospective study using inpatient and ED utilization data from two hospitals with a shared patient population in 2011. We assessed the 30 day ED visit rate and 30-day readmission rate and compared patient characteristics among individuals with 30-day inpatient readmissions, 30-day ED discharges, and no 30-day visits. RESULTS: There were 13,449 patients who met the criteria of an index visit. Overall, 2,453 (18.2%) patients had an ED visit within 30 days of an inpatient stay. However, only 55.6% (n=1,363) of these patients were admitted at one of these 30-day visits, resulting in a 30-day all cause readmission rate of 10.1%. CONCLUSION: Approximately one in five patients presented to the ED within 30 days of an inpatient hospitalization and over half of these patients were readmitted. Readmission measures that incorporate ED visits following an inpatient stay might better inform interventions to reduce avoidable readmissions. PMID- 26759649 TI - Distracted Driving, A Major Preventable Cause of Motor Vehicle Collisions: "Just Hang Up and Drive". AB - For years, public health experts have been concerned about the effect of cell phone use on motor vehicle collisions, part of a phenomenon known as "distracted driving." The Morbidity and Mortality Weekly Report (MMWR) article "Mobile Device Use While Driving - United States and Seven European Countries 2011" highlights the international nature of these concerns. Recent (2011) estimates from the National Highway Traffic Safety Administration are that 10% of fatal crashes and 17% of injury crashes were reported as distraction-affected. Of 3,331 people killed in 2011 on roadways in the U.S. as a result of driver distraction, 385 died in a crash where at least one driver was using a cell phone. For drivers 15 19 years old involved in a fatal crash, 21% of the distracted drivers were distracted by the use of cell phones. Efforts to reduce cell phone use while driving could reduce the prevalence of automobile crashes related to distracted driving. The MMWR report shows that there is much ground to cover with distracted driving. Emergency physicians frequently see the devastating effects of distracted driving on a daily basis and should take a more active role on sharing the information with patients, administrators, legislators, friends and family. PMID- 26759651 TI - Screening for Fall Risks in the Emergency Department: A Novel Nursing-Driven Program. AB - INTRODUCTION: Seniors represent the fasting growing population in the U.S., accounting for 20.3 million visits to emergency departments (EDs) annually. The ED visit can provide an opportunity for identifying seniors at high risk of falls. We sought to incorporate the Timed Up & Go Test (TUGT), a commonly used falls screening tool, into the ED encounter to identify seniors at high fall risk and prompt interventions through a geriatric nurse liaison (GNL) model. METHODS: Patients aged 65 and older presenting to an urban ED were evaluated by a team of ED nurses trained in care coordination and geriatric assessment skills. They performed fall risk screening with the TUGT. Patients with abnormal TUGT results could then be referred to physical therapy (PT), social work or home health as determined by the GNL. RESULTS: Gait assessment with the TUGT was performed on 443 elderly patients between 4/1/13 and 5/31/14. A prior fall was reported in 37% of patients in the previous six months. Of those screened with the TUGT, 368 patients experienced a positive result. Interventions for positive results included ED-based PT (n=63, 17.1%), outpatient PT referrals (n=56, 12.2%) and social work consultation (n=162, 44%). CONCLUSION: The ED visit may provide an opportunity for older adults to be screened for fall risk. Our results show ED nurses can conduct the TUGT, a validated and time efficient screen, and place appropriate referrals based on assessment results. Identifying and intervening on high fall risk patients who visit the ED has the potential to improve the trajectory of functional decline in our elderly population. PMID- 26759650 TI - Systematic Review of ED-based Intimate Partner Violence Intervention Research. AB - INTRODUCTION: Assessment reactivity may be a factor in the modest results of brief interventions for substance use in the emergency department (ED). The presence of assessment reactivity in studies of interventions for intimate partner violence (IPV) has not been studied. Our objectives were to identify ED IPV intervention studies and evaluate the presence of a consistently positive effect on the control groups. METHODS: We performed a systematic search of electronic databases for English=language intervention studies addressing IPV in the ED published since 1990. Study selection and assessment of methodologic quality were performed by two independent reviewers. Data extraction was performed by one reviewer and then independently checked for completeness and accuracy by a second reviewer. RESULTS: Of 3,620 unique manuscripts identified by database search, 667 underwent abstract review and 12 underwent full-text review. Only three met full eligibility criteria; data on the control arm were available for two studies. In these two studies, IPV-related outcomes improved for both the experimental and control condition. CONCLUSION: The paucity of controlled trials of IPV precluded a robust evaluation for assessment reactivity. This study highlighted a critical gap in ED research on IPV. PMID- 26759652 TI - Impact of Health Information Exchange on Emergency Medicine Clinical Decision Making. AB - INTRODUCTION: The objective of the study was to understand the immediate utility of health information exchange (HIE) on emergency department (ED) providers by interviewing them shortly after the information was retrieved. Prior studies of physician perceptions regarding HIE have only been performed outside of the care environment. METHODS: Trained research assistants interviewed resident physicians, physician assistants and attending physicians using a semi-structured questionnaire within two hours of making a HIE request. The responses were recorded, then transcribed for qualitative analysis. The transcribed interviews were analyzed for emerging qualitative themes. RESULTS: We analyzed 40 interviews obtained from 29 providers. Primary qualitative themes discovered included the following: drivers for requests for outside information; the importance of unexpected information; historical lab values as reference points; providing context when determining whether to admit or discharge a patient; the importance of information in refining disposition; improved confidence of provider; and changes in decisions for diagnostic imaging. CONCLUSION: ED providers are driven to use HIE when they're missing a known piece of information. This study finds two additional impacts not previously reported. First, providers sometimes find additional unanticipated useful information, supporting a workflow that lowers the threshold to request external information. Second, providers sometimes report utility when no changes to their existing plan are made as their confidence is increased based on external records. Our findings are concordant with previous studies in finding exchanged information is useful to provide context for interpreting lab results, making admission decisions, and prevents repeat diagnostic imaging. PMID- 26759653 TI - Direct Versus Video Laryngoscopy for Intubating Adult Patients with Gastrointestinal Bleeding. AB - INTRODUCTION: Video laryngoscopy (VL) has been advocated for several aspects of emergency airway management; however, there are still concerns over its use in select patient populations such as those with large volume hematemesis secondary to gastrointestinal (GI) bleeds. Given the relatively infrequent nature of this disease process, we sought to compare intubation outcomes between VL and traditional direct laryngoscopy (DL) in patients intubated with GI bleeding, using the third iteration of the National Emergency Airway Registry (NEARIII). METHODS: We performed a retrospective analysis of a prospectively collected national database (NEARIII) of intubations performed in United States emergency departments (EDs) from July 1, 2002, through December 31, 2012. All cases where the indication for intubation was "GI bleed" were analyzed. We included patient, provider and intubation characteristics. We compared data between intubation attempts initiated as DL and VL using parametric and non-parametric tests when appropriate. RESULTS: We identified 325 intubations, 295 DL and 30 VL. DL and VL cases were similar in terms of age, sex, weight, difficult airway predictors, operator specialty (emergency medicine, anesthesia or other) and level of operator training (post-graduate year 1, 2, etc). Proportion of successful first attempts (DL 261/295 (88.5%) vs. VL 28/30 (93.3%) p=0.58) and Cormack-Lehane grade views (p=0.89) were similar between devices. The need for device change was similar between DL [2/295 (0.7%) and VL 1/30 (3.3%); p=0.15]. CONCLUSION: In this national registry of intubations performed in the ED for patients with GI bleeds, both DL and VL had similar rates of success, glottic views and need to change devices. PMID- 26759654 TI - Ultrasound of Sternal Fracture. PMID- 26759656 TI - Association of Emergency Department Length of Stay and Crowding for Patients with ST-Elevation Myocardial Infarction. AB - INTRODUCTION: With the majority of U.S. hospitals not having primary percutaneous coronary intervention (pPCI) capabilities, the time spent at transferring emergency departments (EDs) is predictive of clinical outcomes for patients with ST-elevation myocardial infarction (STEMI). Compounding the challenges of delivering timely emergency care are the known delays caused by ED crowding. However, the association of ED crowding with timeliness for patients with STEMI is unknown. We sought to examine the relationship between ED crowding and time spent at transferring EDs for patients with STEMI. METHODS: We analyzed the Centers for Medicare and Medicaid Services (CMS) quality data. The outcome was time spent at a transferring ED (i.e., door-in-door-out [DIDO]), was CMS measure OP-3b for hospitals with >=10 acute myocardial infarction (AMI) cases requiring transfer (i.e., STEMI) annually: Time to Transfer an AMI Patient for Acute Coronary Intervention. We used four CMS ED timeliness measures as surrogate measures of ED crowding: admitted length of stay (LOS), discharged LOS, boarding time, and waiting time. We analyzed bivariate associations between DIDO and ED timeliness measures. We used a linear multivariable regression to evaluate the contribution of hospital characteristics (academic, trauma, rural, ED volume) to DIDO. RESULTS: Data were available for 405 out of 4,129 hospitals for the CMS DIDO measure. These facilities were primarily non-academic (99.0%), non-trauma centers (65.4%), and in urban locations (68.5%). Median DIDO was 54.0 minutes (IQR 42.0,68.0). Increased DIDO time was associated with longer admitted LOS and boarding times. After adjusting for hospital characteristics, a one-minute increase in ED LOS at transferring facilities was associated with DIDO (coefficient, 0.084 [95% CI [0.049,0.119]]; p<0.001). This translates into a five minute increase in DIDO for every one-hour increase in ED LOS for admitted patients. CONCLUSION: Among patients with STEMI presenting to U.S. EDs, we found that ED crowding has a small but operationally insignificant effect on time spent at the transferring ED. PMID- 26759655 TI - Derivation and Validation of Predictive Factors for Clinical Deterioration after Admission in Emergency Department Patients Presenting with Abnormal Vital Signs Without Shock. AB - INTRODUCTION: Strategies to identify high-risk emergency department (ED) patients often use markedly abnormal vital signs and serum lactate levels. Risk stratifying such patients without using the presence of shock is challenging. The objective of the study is to identify independent predictors of in-hospital adverse outcomes in ED patients with abnormal vital signs or lactate levels, but who are not in shock. METHODS: We performed a prospective observational study of patients with abnormal vital signs or lactate level defined as heart rate >=130 beats/min, respiratory rate >=24 breaths/min, shock index >=1, systolic blood pressure <90 mm/Hg, or lactate >=4 mmole/L. We excluded patients with isolated atrial tachycardia, seizure, intoxication, psychiatric agitation, or tachycardia due to pain (ie: extremity fracture). The primary outcome was deterioration, defined as development of acute renal failure (creatinine 2* baseline), non elective intubation, vasopressor requirement, or mortality. Independent predictors of deterioration after hospitalization were determined using logistic regression. RESULTS: Of 1,152 consecutive patients identified with abnormal vital signs or lactate level, 620 were excluded, leaving 532 for analysis. Of these, 53/532 (9.9+/-2.5%) deteriorated after hospital admission. Independent predictors of in-hospital deterioration were: lactate >4.0 mmol/L (OR 5.1, 95% CI [2.1 12.2]), age >=80 yrs (OR 1.9, CI [1.0-3.7]), bicarbonate <21 mEq/L (OR 2.5, CI [1.3-4.9]), and initial HR>=130 (OR 3.1, CI [1.5-6.1]). CONCLUSION: Patients exhibiting abnormal vital signs or elevated lactate levels without shock had significant rates of deterioration after hospitalization. ED clinical data predicted patients who suffered adverse outcomes with reasonable reliability. PMID- 26759657 TI - Voluntary Medical Incident Reporting Tool to Improve Physician Reporting of Medical Errors in an Emergency Department. AB - INTRODUCTION: Medical errors are frequently under-reported, yet their appropriate analysis, coupled with remediation, is essential for continuous quality improvement. The emergency department (ED) is recognized as a complex and chaotic environment prone to errors. In this paper, we describe the design and implementation of a web-based ED-specific incident reporting system using an iterative process. METHODS: A web-based, password-protected tool was developed by members of a quality assurance committee for ED providers to report incidents that they believe could impact patient safety. RESULTS: The utilization of this system in one residency program with two academic sites resulted in an increase from 81 reported incidents in 2009, the first year of use, to 561 reported incidents in 2012. This is an increase in rate of reported events from 0.07% of all ED visits to 0.44% of all ED visits. In 2012, faculty reported 60% of all incidents, while residents and midlevel providers reported 24% and 16% respectively. The most commonly reported incidents were delays in care and management concerns. CONCLUSION: Error reporting frequency can be dramatically improved by using a web-based, user-friendly, voluntary, and non-punitive reporting system. PMID- 26759658 TI - The Changing Use of Intravenous Opioids in an Emergency Department. AB - INTRODUCTION: Government agencies are increasingly emphasizing opioid safety in hospitals. In 2012, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) started a sentinel event program, the "Safe Use of Opioids in Hospitals." We sought to determine if opioid use patterns in our emergency department (ED) changed from 2011, before the program began, to 2013, after start of the program. METHODS: This was a retrospective study of all adult ED patients who received an intravenous opioid and had a serum creatinine measured. We recorded opioids used, dose prescribed, and serum creatinine. As an index of the safety of opioids, uses of naloxone after administration of an opioid was recorded. RESULTS: Morphine is still the most commonly used opioid by doses given, but its percentage of opioids used decreased from 68.9% in 2011 to 52.8% in 2013. During the same period, use of hydromorphone increased from 27.5% to 42.9%, while the use of fentanyl changed little (3.6% to 4.3%). Naloxone administration was rare after an opioid had been given. Opioids were not dosed in an equipotent manner. CONCLUSION: The use of hydromorphone in our ED increased by 56% (absolute increase of 15.4%), while the use of morphine decreased by 30.5% (absolute decrease 16.1%) of total opioid use from 2011 to 2013. The JCAHO program likely was at least indirectly responsible for this change in relative dosing of the opioids. Based on frequency of naloxone administered after administration of an opioid, the use of opioids was safe. PMID- 26759659 TI - Opioid Considerations for Emergency Practice. PMID- 26759660 TI - Transformative Leadership: Emergency Physicians Lead AOA and AMA. PMID- 26759661 TI - Inability of Physicians and Nurses to Predict Patient Satisfaction in the Emergency Department. AB - INTRODUCTION: Patient satisfaction is a commonly assessed dimension of emergency department (ED) care quality. The ability of ED clinicians to estimate patient satisfaction is unknown. We sought to evaluate the ability of emergency medicine resident physicians and nurses to predict patient-reported satisfaction with physician and nursing care, pain levels, and understanding of discharge instructions. METHODS: We studied a convenience sample of 100 patients treated at an urban academic ED. Patients rated satisfaction with nursing care, physician care, pain level at time of disposition and understanding of discharge instructions. Resident physicians and nurses estimated responses for each patient. We compared patient, physician and nursing responses using Cohen's kappa, weighting the estimates to account for the ordinal responses. RESULTS: Overall, patients had a high degree of satisfaction with care provided by the nurses and physicians, although this was underestimated by providers. There was poor agreement between physician estimation of patient satisfaction (weighted kappa=0.23, standard error: 0.078) and nursing estimates of patient satisfaction (weighted kappa=0.11, standard error: 0.043); physician estimation of patient pain (weighted kappa=0.43, standard error: 0.082) and nursing estimates (weighted kappa=0.39, standard error: 0.081); physician estimates of patient comprehension of discharge instruction (weighted kappa=0.19, standard error: 0.082) and nursing estimates (weighted kappa=0.13, standard error: 0.078). Providers underestimated pain and patient comprehension of discharge instructions. CONCLUSION: ED providers were not able to predict patient satisfaction with nurse or physician care, pain level, or understanding of discharge instructions. PMID- 26759662 TI - The Need for More Prehospital Research on Language Barriers: A Narrative Review. AB - INTRODUCTION: Despite evidence from other healthcare settings that language barriers negatively impact patient outcomes, the literature on language barriers in emergency medical services (EMS) has not been previously summarized. The objective of this study is to systematically review existing studies of the impact of language barriers on prehospital emergency care and identify opportunities for future research. METHODS: A systematic review with narrative synthesis of publications with populations specific to the prehospital setting and outcome measures specific to language barriers was conducted. A four-prong search strategy of academic databases (PubMed, Academic Search Complete, and Clinical Key) through March 2015, web-based search for gray literature, search of citation lists, and review of key conference proceedings using pre-defined eligibility criteria was used. Language-related outcomes were categorized and reported as community-specific outcomes, EMS provider-specific outcomes, patient specific outcomes, or health system-specific outcomes. RESULTS: Twenty-two studies met eligibility criteria for review. Ten publications (45%) focused on community-specific outcomes. Language barriers are perceived as a barrier by minority language speaking communities to activating EMS. Eleven publications (50%) reported outcomes specific to EMS providers, with six of these studies focused on EMS dispatch. EMS dispatchers describe less accurate and delayed dispatch of resources when confronted with language discordant callers, as well as limitations in the ability to provide medical direction to callers. There is a paucity of research on EMS treatment and transport decisions, and no studies provided patient-specific or health system-specific outcomes. Key research gaps include identifying the mechanisms by which language barriers impact care, the effect of language barriers on EMS utilization and clinically significant outcomes, and the cost implications of addressing language barriers. CONCLUSION: The existing research on prehospital language barriers is largely exploratory, and substantial gaps in understanding the interaction between language barriers and prehospital care have yet to be addressed. Future research should be focused on clarifying the clinical and cost implications of prehospital language barriers. PMID- 26759663 TI - A Delphi Method Analysis to Create an Emergency Medicine Educational Patient Satisfaction Survey. AB - INTRODUCTION: Feedback on patient satisfaction (PS) as a means to monitor and improve performance in patient communication is lacking in residency training. A physician's promotion, compensation and job satisfaction may be impacted by his individual PS scores, once he is in practice. Many communication and satisfaction surveys exist but none focus on the emergency department setting for educational purposes. The goal of this project was to create an emergency medicine-based educational PS survey with strong evidence for content validity. METHODS: We used the Delphi Method (DM) to obtain expert opinion via an iterative process of surveying. Questions were mined from four PS surveys as well as from group suggestion. The DM analysis determined the structure, content and appropriate use of the tool. The group used four-point Likert-type scales and Lynn's criteria for content validity to determine relevant questions from the stated goals. RESULTS: Twelve recruited experts participated in a series of seven surveys to achieve consensus. A 10-question, single-page survey with an additional page of qualitative questions and demographic questions was selected. Thirty one questions were judged to be relevant from an original 48-question list. Of these, the final 10 questions were chosen. Response rates for individual survey items was 99.5%. CONCLUSION: The DM produced a consensus survey with content validity evidence. Future work will be needed to obtain evidence for response process, internal structure and construct validity. PMID- 26759664 TI - The Physiologically Difficult Airway. AB - Airway management in critically ill patients involves the identification and management of the potentially difficult airway in order to avoid untoward complications. This focus on difficult airway management has traditionally referred to identifying anatomic characteristics of the patient that make either visualizing the glottic opening or placement of the tracheal tube through the vocal cords difficult. This paper will describe the physiologically difficult airway, in which physiologic derangements of the patient increase the risk of cardiovascular collapse from airway management. The four physiologically difficult airways described include hypoxemia, hypotension, severe metabolic acidosis, and right ventricular failure. The emergency physician should account for these physiologic derangements with airway management in critically ill patients regardless of the predicted anatomic difficulty of the intubation. PMID- 26759665 TI - Lactate Clearance Predicts Survival Among Patients in the Emergency Department with Severe Sepsis. AB - INTRODUCTION: Lactate clearance has been implicated as a predictor of mortality among emergency department (ED) patients with severe sepsis or septic shock. We aimed to validate prior studies showing that lactate clearance during the ED stay is associated with decreased mortality. METHODS: Retrospective dual-centered cross-sectional study using patients identified in the Yale-New Haven Hospital Emergency Medicine sepsis registry with severe sepsis or septic shock who had initial lactate levels measured in the ED and upon arrival (<24 hours) to the hospital floor. Lactate clearance was calculated as percent of serum lactate change from ED to floor measurement. We compared mortality and hospital interventions between patients who cleared lactate and those who did not. RESULTS: 207 patients (110 male; 63.17+/-17.9 years) were included. Two reviewers extracted data with 95% agreement. One hundred thirty-six patients (65.7%) had severe sepsis and 71 patients (34.3%) had septic shock. There were 171 patients in the clearance group and 36 patients in the non-clearance group. The 28-day mortality rates were 15.2% in the lactate clearance group and 36.1% in the non clearance group (p<0.01). Vasopressor support was initiated more often in the non clearance group (61.1%) than in the clearance group (36.8%, p<0.01) and mechanical ventilation was used in 66.7% of the non-clearance group and 36.3% of the clearance group (p=0.001). CONCLUSION: Patients who do not clear their lactate in the ED have significantly higher mortality than those with decreasing lactate levels. Our results are confirmatory of other literature supporting that lactate clearance may be used to stratify mortality-risk among patients with severe sepsis or septic shock. PMID- 26759668 TI - Staying in the Room. PMID- 26759666 TI - Evidence-based Comprehensive Approach to Forearm Arterial Laceration. AB - INTRODUCTION: Penetrating injury to the forearm may cause an isolated radial or ulnar artery injury, or a complex injury involving other structures including veins, tendons and nerves. The management of forearm laceration with arterial injury involves both operative and nonoperative strategies. An evolution in management has emerged especially at urban trauma centers, where the multidisciplinary resource of trauma and hand subspecialties may invoke controversy pertaining to the optimal management of such injuries. The objective of this review was to provide an evidence-based, systematic, operative and nonoperative approach to the management of isolated and complex forearm lacerations. A comprehensive search of MedLine, Cochrane Library, Embase and the National Guideline Clearinghouse did not yield evidence-based management guidelines for forearm arterial laceration injury. No professional or societal consensus guidelines or best practice guidelines exist to our knowledge. DISCUSSION: The optimal methods for achieving hemostasis are by a combination approach utilizing direct digital pressure, temporary tourniquet pressure, compressive dressings followed by wound closure. While surgical hemostasis may provide an expedited route for control of hemorrhage, this aggressive approach is often not needed (with a few exceptions) to achieve hemostasis for most forearm lacerations. Conservative methods mentioned above will attain the same result. Further, routine emergent or urgent operative exploration of forearm laceration injuries are not warranted and not cost-beneficial. It has been widely accepted with ample evidence in the literature that neither injury to forearm artery, nerve or tendon requires immediate surgical repair. Attention should be directed instead to control of bleeding, and perform a complete physical examination of the hand to document the presence or absence of other associated injuries. Critical ischemia will require expeditious surgical restoration of arterial perfusion. In a well-perfused hand, however, the presence of one intact artery is adequate to sustain viability without long-term functional disability, provided the palmar arch circulation is intact. Early consultation with a hand specialist should be pursued, and follow-up arrangement made for delayed primary repair in cases of complex injury. CONCLUSION: Management in accordance with well established clinical principles will maximize treatment efficacy and functional outcome while minimizing the cost of medical care. PMID- 26759667 TI - A Simulation-based Randomized Controlled Study of Factors Influencing Chest Compression Depth. AB - INTRODUCTION: Current resuscitation guidelines emphasize a systems approach with a strong emphasis on quality cardiopulmonary resuscitation (CPR). Despite the American Heart Association (AHA) emphasis on quality CPR for over 10 years, resuscitation teams do not consistently meet recommended CPR standards. The objective is to assess the impact on chest compression depth of factors including bed height, step stool utilization, position of the rescuer's arms and shoulders relative to the point of chest compression, and rescuer characteristics including height, weight, and gender. METHODS: Fifty-six eligible subjects, including physician assistant students and first-year emergency medicine residents, were enrolled and randomized to intervention (bed lowered and step stool readily available) and control (bed raised and step stool accessible, but concealed) groups. We instructed all subjects to complete all interventions on a high fidelity mannequin per AHA guidelines. Secondary end points included subject arm angle, height, weight group, and gender. RESULTS: Using an intention to treat analysis, the mean compression depths for the intervention and control groups were not significantly different. Subjects positioning their arms at a 90-degree angle relative to the sagittal plane of the mannequin's chest achieved a mean compression depth significantly greater than those compressing at an angle less than 90 degrees. There was a significant correlation between using a step stool and achieving the correct shoulder position. Subject height, weight group, and gender were all independently associated with compression depth. CONCLUSION: Rescuer arm position relative to the patient's chest and step stool utilization during CPR are modifiable factors facilitating improved chest compression depth. PMID- 26759669 TI - Emergency Department Visits by Older Adults with Mental Illness in North Carolina. AB - INTRODUCTION: We analyzed emergency department (ED) visits by patients with mental health disorders (MHDs) in North Carolina from 2008-2010 to determine frequencies and characteristics of ED visits by older adults with MHDs. METHODS: We extracted ED visit data from the North Carolina Disease Event Tracking and Epidemiologic Collection Tool (NC DETECT). We defined mental health visits as visits with a mental health ICD-9-CM diagnostic code, and organized MHDs into clinically similar groups for analysis. RESULTS: Those >=65 with MHDs accounted for 27.3% of all MHD ED visits, and 51.2% were admitted. The most common MHD diagnoses for this age group were psychosis, and stress/anxiety/depression. CONCLUSION: Older adults with MHDs account for over one-quarter of ED patients with MHDs, and their numbers will continue to increase as the "boomer" population ages. We must anticipate and prepare for the MHD-related needs of the elderly. PMID- 26759671 TI - Correlation of the National Emergency Medicine M4 Clerkship Examination with USMLE Examination Performance. AB - INTRODUCTION: Assessment of medical students' knowledge in clinical settings is complex yet essential to the learning process. Clinical clerkships use various types of written examinations to objectively test medical knowledge within a given discipline. Within emergency medicine (EM), a new national standardized exam was developed to test medical knowledge in this specialty. Evaluation of the psychometric properties of a new examination is an important issue to address during test development and use. Studies have shown that student performance on selected standardized exams will reveal students' strengths and/or weaknesses, so that effective remedial efforts can be implemented. Our study sought to address these issues by examining the association of scores on the new EM national exam with other standardized exam scores. METHODS: From August 2011 to April 2013, average National EM M4 examination scores of fourth-year medical students taken at the end of a required EM clerkship were compiled. We examined the correlation of the National EM M4 examination with the scores of initial attempts of the United States Medical Licensing Exam (USMLE) Step 1 and Step 2 Clinical Knowledge (CK) examinations. Correlation coefficients and 95% confidence intervals of correlation coefficients are reported. We also examined the association between the national EM M4 examination score, final grades for the EM rotation, and USMLE Step 1 and Step 2 CK scores. RESULTS: 133 students were included in the study and achieved a mean score of 79.5 SD 8.0 on the National EM M4 exam compared to a national mean of 79.7 SD 3.89. The mean USMLE Step 1 score was 226.8 SD 19.3. The mean USMLE Step 2 CK score was 238.5 SD 18.9. National EM M4 examination scores showed moderate correlation with both USMLE Step 1 (mean score=226.8; correlation coefficient=0.50; 95% CI [0.28-0.67]) and USMLE Step 2 CK (mean score=238.5; correlation coefficient=0.47; 95% CI [0.25-0.65]). Students scoring below the median on the national EM M4 exam also scored well below their colleagues on USMLE exams. CONCLUSION: The moderate correlation of the national EM M4 examination and USMLE Step 1 and Step 2 CK scores provides support for the utilization of the CDEM National EM M4 examination as an effective means of assessing medical knowledge for fourth-year medical students. Identification of students scoring lower on standardized exams allows for effective remedial efforts to be undertaken throughout the medical education process. PMID- 26759670 TI - Alcohol Use as Risk Factors for Older Adults' Emergency Department Visits: A Latent Class Analysis. AB - INTRODUCTION: Late middle-aged and older adults' share of emergency department (ED) visits is increasing more than other age groups. ED visits by individuals with substance-related problems are also increasing. This paper was intended to identify subgroups of individuals aged 50+ by their risk for ED visits by examining their health/mental health status and alcohol use patterns. METHODS: Data came from the 2013 National Health Interview Survey's Sample Adult file (n=15,713). Following descriptive analysis of sample characteristics by alcohol use patterns, latent class analysis (LCA) modeling was fit using alcohol use pattern (lifetime abstainers, ex-drinkers, current infrequent/light/moderate drinkers, and current heavy drinkers), chronic health and mental health status, and past-year ED visits as indicators. RESULTS: LCA identified a four-class model. All members of Class 1 (35% of the sample; lowest-risk group) were infrequent/light/moderate drinkers and exhibited the lowest probabilities of chronic health/mental health problems; Class 2 (21%; low-risk group) consisted entirely of lifetime abstainers and, despite being the oldest group, exhibited low probabilities of health/mental health problems; Class 3 (37%; moderate-risk group) was evenly divided between ex-drinkers and heavy drinkers; and Class 4 (7%; high-risk group) included all four groups of drinkers but more ex-drinkers. In addition, Class 4 had the highest probabilities of chronic health/mental problems, unhealthy behaviors, and repeat ED visits, with the highest proportion of Blacks and the lowest proportions of college graduates and employed persons, indicating significant roles of these risk factors. CONCLUSION: Alcohol nonuse/use (and quantity of use) and chronic health conditions are significant contributors to varying levels of ED visit risk. Clinicians need to help heavy drinking older adults reduce unhealthy alcohol consumption and help both heavy drinkers and ex-drinkers improve chronic illnesses self-management. PMID- 26759673 TI - Posterior Reversible Encephalopathy Syndrome (PRES) After Acute Pancreatitis. AB - Posterior reversible encephalopathy syndrome (PRES) is an unusual condition typified by acute visual impairment caused by sudden, marked parieto-occipital vasogenic edema. Thought to be inflammatory in origin, it has been described in patients undergoing chemotherapy, with autoimmune disease, and in some infections. We report a case of PRES that occurred one week after an episode of acute pancreatitis in an otherwise healthy 40-year-old female. There was progressive visual impairment over a 24-hour period with almost complete visual loss, with characteristic findings on magnetic resonance imaging. After treatment with steroids, the visual loss recovered. Clinicians should retain an index of suspicion of this rare condition in patients with visual impairment after acute pancreatitis. PMID- 26759672 TI - Simulation in Pre-departure Training for Residents Planning Clinical Work in a Low-Income Country. AB - INTRODUCTION: Increasingly, pediatric and emergency medicine (EM) residents are pursuing clinical rotations in low-income countries. Optimal pre-departure preparation for such rotations has not yet been established. High-fidelity simulation represents a potentially effective modality for such preparation. This study was designed to assess whether a pre-departure high-fidelity medical simulation curriculum is effective in helping to prepare residents for clinical rotations in a low-income country. METHODS: 43 pediatric and EM residents planning clinical rotations in Liberia, West Africa, participated in a simulation based curriculum focused on severe pediatric malaria and malnutrition and were then assessed by survey at three time points: pre-simulation, post-simulation, and after returning from work abroad. RESULTS: Prior to simulation, 1/43 (2%) participants reported they were comfortable with the diagnosis and management of severe malnutrition; this increased to 30/42 (71%) after simulation and 24/31 (77%) after working abroad. Prior to simulation, 1/43 (2%) of residents reported comfort with the diagnosis and management of severe malaria; this increased to 26/42 (62%) after simulation and 28/31 (90%) after working abroad; 36/42 (86%) of residents agreed that a simulation-based global health curriculum is more useful than a didactic curriculum alone, and 41/42 (98%) felt a simulator-based curriculum should be offered to all residents planning a clinical trip to a low income country. CONCLUSION: High-fidelity simulation is effective in increasing residents' self-rated comfort in management of pediatric malaria and malnutrition and a majority of participating residents feel it should be included as a component of pre-departure training for all residents rotating clinically to low income countries. PMID- 26759674 TI - Posterior Scleritis with Inflammatory Retinal Detachment. AB - A 14-year-old African American male presented to the emergency department with worsening left eye redness, swelling, and vision loss over the preceding three days. History was notable for similar eye redness and swelling without vision loss four months earlier, which improved following a brief course of prednisone. He endorsed mild eye irritation and tearing with bright lights. There was no history of fever, respiratory symptoms or trauma. Mother was medicating patient with leftover antibiotic eye drops x3 days without improvement. Physical examination on presentation notable for proptosis of left eye, lid, and periorbital swelling, mild scleral injection, and central vision loss in affected eye (20/200 OS, 20/25 OD). Extraocular movements and pupillary exam were normal. No corneal fluorescein uptake, abnormal cell, flare, or siedel sign were seen during slit lamp exam. Eye pressures were 24 mmHg in both eyes. Bedside ultrasonography was performed (Figure 1 showing retinal detachment, Ultrasound Video 2 showing detachment in orbital scan). PMID- 26759676 TI - More Than Just an Abscess: Ultrasound-Assisted Diagnosis of Ventriculoperitoneal Shunt Infection. PMID- 26759675 TI - A Massive Overdose of Dalfampridine. AB - Multiple sclerosis (MS) is an immune mediated inflammatory disease that attacks myelinated axons in the central nervous system. Dalfampridine (4-aminopyridine) was approved by the Food and Drug Administration in January 2010 for treatment of MS. Our patient was a 34-year-old male with a history of MS, who was brought to the emergency department after being found unresponsive. His current medications were valacyclovir, temazepam, dalfampridine (4-AP) and a tysabri intravenous (IV) infusion. Fifteen minutes after arrival the patient seized. The seizures were refractory to benzodiazepines, barbiturates and phenytoin. The 4-AP level was 530 ng/mL (25 ng/mL and 49 ng/mL). The patient stopped seizing on hospital day 3 and was discharged 14 days later with normal mental status and neurologic exam. 4-AP is a potassium channel blocker that blocks the potassium ion current of repolarization following an action potential. The blockade of the potassium channel at the level of the membrane widens the action potential and enhances the release of acetylcholine, thus increasing post-synaptic action potentials. The treatment of patients with 4-AP overdose is supportive. Animal data suggest that patients with toxic levels of 4-AP may respond to phenytoin. Our case illustrates the highest recorded level of 4-AP in an overdose. Our patient appeared to be refractory to a combination of high doses of anticonvulsants and only improved with time. PMID- 26759677 TI - Computed Tomography Following Body Stuffing Heroin. PMID- 26759678 TI - Primary Epiploic Appendagitis. PMID- 26759679 TI - An Unusual Case of Angiotensin-Converting-Enzyme Inhibitor-Related Penile Angioedema with Evolution to the Oropharynx. AB - A 52-year-old African American male with a long history of poorly controlled hypertension presented to the emergency department (ED) with two days of genital edema and pain. During ED work-up, the patient developed sudden onset of non pitting, non-pruritic, and non-urticarial upper lip edema. Review of his antihypertensive medication list revealed that he normally took benazepril, highly suggestive of a diagnosis of angiotensin-converting-enzyme inhibitor related angioedema (ACEI-RA). We present the first reported case of penile ACEI RA that progressed to involve the oropharynx. The ED management of the condition and some of the newer treatment options available for ACEI-RA is also briefly discussed. PMID- 26759680 TI - Single Fascia Iliaca Compartment Block is Safe and Effective for Emergency Pain Relief in Hip-fracture Patients. AB - INTRODUCTION: Currently, it is common practice in the emergency department (ED) for pain relief in hip-fracture patients to administer pain medication, commonly systemic opioids. However, with these pain medications come a high risk of side effects, especially in elderly patients. This study investigated the safety profile and success rate of fascia iliaca compartment block (FICB) in a busy ED. This ED was staffed with emergency physicians (EPs) and residents of varying levels of experience. This study followed patients' pain levels at various hourly intervals up to eight hours post procedure. METHODS: Between September 2012 and July 2013, we performed a prospective pilot study on hip-fracture patients who were admitted to the ED of a teaching hospital in the Netherlands. These patients were followed and evaluated post FICB for pain relief. Secondary outcome was the use of opioids as rescue medication. RESULTS: Of the 43 patients in this study, patients overall experienced less pain after the FICB (p=0.04). This reduction in pain was studied in conjunction with the use and non-use of opioids. A clinically meaningful decrease in pain was achieved after 30 minutes in 62% of patients (54% with the use of opioids, 8% without opioids); after 240 minutes in 82% of patients (18% with opioids, 64% without opioids); after 480 minutes in 88% of patients (16% with opioids, 72% without opioids). No adverse events were reported. CONCLUSION: In a busy Dutch ED with rotating residents of varying levels of experience, FICB seems to be an efficient, safe and practical method for pain reduction in patients with a hip fracture. Even without the use of opioids, pain reduction was achieved in 64% of patients after four hours and in 72% of patients after eight hours. PMID- 26759681 TI - Iliac Pseudoaneurysm from Endoleak. PMID- 26759682 TI - Oral Ulcerations. PMID- 26759683 TI - Adult Female with Abdominal Pain. PMID- 26759684 TI - Mal-positioned Gastrojejunostomy Tube. PMID- 26759685 TI - Vallecular Varix: A Perplexing Cause of Oral Cavity Bleeding. AB - Often discovered only after an extensive work up for hemoptysis and hematemesis, vallecular varices are a rare cause of oral bleeding that increase patient morbidity due to delay of diagnosis. We describe an 89-year-old male who presented with a week of intermittent oral blood production. A vallecular varix was identified on fiberoptic laryngoscopy after studies for hematemesis and hemoptysis had been performed, including negative esophagogastroduodenoscopy and bronchoscopy. Awareness of this pathology and key points in the patient history can direct the clinician toward the correct diagnosis, expediting treatment and limiting invasive diagnostic procedures for pulmonary or gastric etiologies of bleeding. PMID- 26759686 TI - Mistaken ST-Elevation Myocardial Infarction. PMID- 26759687 TI - When the Secondary Survey is Primary: Knife Blade in the Spine. PMID- 26759688 TI - Chilaiditi Sign: Rare Incidental Finding on Chest Radiograph. PMID- 26759689 TI - Undifferentiated Thyroid Carcinoma Caused Sudden Airway Obstruction. PMID- 26759690 TI - Erratum: This article corrects: "Hydrocele of the Canal of Nuck". PMID- 26759691 TI - Thumb Hypoplasia. PMID- 26759693 TI - [Should we continue to infiltrate the scalp with a local anesthetic for a craniotomy?]. PMID- 26759694 TI - [Adnexal torsion after abdominal hysterectomy: a first observation]. PMID- 26759697 TI - Long Noncoding RNA MHRT Protects Cardiomyocytes against H2O2-Induced Apoptosis. AB - Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. The exploration of new biomarkers with high sensitivity and specificity for early diagnosis of AMI therefore becomes one of the primary task. In the current study, we aim to detect whether there is any heart specific long noncoding RNA (lncRNA) releasing into the circulation during AMI, and explore its function in the neonatal rat cardiac myocytes injury induced by H2O2. Our results revealed that the cardiac-specific lncRNA MHRT (Myosin Heavy Chain Associated RNA Transcripts) was significantly elevated in the blood from AMI patients compared with the healthy control ((*) p<0.05). Using an in vitro neonatal rat cardiac myocytes injury model, we demonstrated that lncRNA MHRT was upregulated in the cardiac myocytes after treatment with hydrogen peroxide (H2O2) via real-time RT PCR (qRT-PCR). Furthermore, we knockdowned the MHRT gene by siRNA to confirm its roles in the H2O2-induced cardiac cell apoptosis, and found that knockdown of MHRT led to significant more apoptotic cells than the non-target control ((**) p<0.01), indicating that the lncRNA MHRT is a protective factor for cardiomyocyte and the plasma concentration of MHRT may serve as a biomarker for myocardial infarction diagnosis in humans AMI. PMID- 26759696 TI - NDRG2 Expression Decreases Tumor-Induced Osteoclast Differentiation by Down regulating ICAM1 in Breast Cancer Cells. AB - Bone matrix is properly maintained by osteoclasts and osteoblasts. In the tumor microenvironment, osteoclasts are increasingly differentiated by the various ligands and cytokines secreted from the metastasized cancer cells at the bone metastasis niche. The activated osteoclasts generate osteolytic lesions. For this reason, studies focusing on the differentiation of osteoclasts are important to reduce bone destruction by tumor metastasis. The N-myc downstream-regulated gene 2 (NDRG2) has been known to contribute to the suppression of tumor growth and metastasis, but the precise role of NDRG2 in osteoclast differentiation induced by cancer cells has not been elucidated. In this study, we demonstrate that NDRG2 expression in breast cancer cells has an inhibitory effect on osteoclast differentiation. RAW 264.7 cells, which are monocytic preosteoclast cells, treated with the conditioned media (CM) of murine breast cancer cells (4T1) expressing NDRG2 are less differentiated into the multinucleated osteoclast-like cells than those treated with the CM of 4T1-WT or 4T1-mock cells. Interestingly, 4T1 cells stably expressing NDRG2 showed a decreased mRNA and protein level of intercellular adhesion molecule 1 (ICAM1), which is known to enhance osteoclast maturation. Osteoclast differentiation was also reduced by ICAM1 knockdown in 4T1 cells. In addition, blocking the interaction between soluble ICAM1 and ICAM1 receptors significantly decreased osteoclastogenesis of RAW 264.7 cells in the tumor environment. Collectively, these results suggest that the reduction of ICAM1 expression by NDRG2 in breast cancer cells decreases osteoclast differentiation, and demonstrate that excessive bone resorption could be inhibited via ICAM1 down-regulation by NDRG2 expression. PMID- 26759695 TI - Alpha-Ketoglutarate: Physiological Functions and Applications. AB - Alpha-ketoglutarate (AKG) is a key molecule in the Krebs cycle determining the overall rate of the citric acid cycle of the organism. It is a nitrogen scavenger and a source of glutamate and glutamine that stimulates protein synthesis and inhibits protein degradation in muscles. AKG as a precursor of glutamate and glutamine is a central metabolic fuel for cells of the gastrointestinal tract as well. AKG can decrease protein catabolism and increase protein synthesis to enhance bone tissue formation in the skeletal muscles and can be used in clinical applications. In addition to these health benefits, a recent study has shown that AKG can extend the lifespan of adult Caenorhabditis elegans by inhibiting ATP synthase and TOR. AKG not only extends lifespan, but also delays age-related disease. In this review, we will summarize the advances in AKG research field, in the content of its physiological functions and applications. PMID- 26759698 TI - Lobaric Acid Inhibits VCAM-1 Expression in TNF-alpha-Stimulated Vascular Smooth Muscle Cells via Modulation of NF-kappaB and MAPK Signaling Pathways. AB - Lichens have been known to possess multiple biological activities, including anti proliferative and anti-inflammatory activities. Vascular cell adhesion molecule-1 (VCAM-1) may play a role in the development of atherosclerosis. Hence, VCAM-1 is a possible therapeutic target in the treatment of the inflammatory disease. However, the effect of lobaric acid on VCAM-1 has not yet been investigated and characterized. For this study, we examined the effect of lobaric acid on the inhibition of VCAM-1 in tumor necrosis factor-alpha (TNF-alpha)-stimulated mouse vascular smooth muscle cells. Western blot and ELISA showed that the increased expression of VCAM-1 by TNF-alpha was significantly suppressed by the pre treatment of lobaric acid (0.1-10 MUg/ml) for 2 h. Lobaric acid abrogated TNF alpha-induced NF-kappaB activity through preventing the degradation of IkappaB and phosphorylation of extracellular signal-regulated kinases (ERK), c-Jun N terminal kinases (JNK), and p38 mitogen activated protein (MAP) kinase. Lobaric acid also inhibited the expression of TNF-alpha receptor 1 (TNF-R1). Overall, our results suggest that lobaric acid inhibited VCAM-1 expression through the inhibition of p38, ERK, JNK and NF-kappaB signaling pathways, and downregulation of TNF-R1 expression. Therefore, it is implicated that lobaric acid may suppress inflammation by altering the physiology of the atherosclerotic lesion. PMID- 26759699 TI - Protopanaxatriol Ginsenoside Rh1 Upregulates Phase II Antioxidant Enzyme Gene Expression in Rat Primary Astrocytes: Involvement of MAP Kinases and Nrf2/ARE Signaling. AB - Oxidative stress activates several intracellular signaling cascades that may have deleterious effects on neuronal cell survival. Thus, controlling oxidative stress has been suggested as an important strategy for prevention and/or treatment of neurodegenerative diseases. In this study, we found that ginsenoside Rh1 inhibited hydrogen peroxide-induced reactive oxygen species generation and subsequent cell death in rat primary astrocytes. Rh1 increased the expression of phase II antioxidant enzymes, such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1, superoxide dismutase-2, and catalase, that are under the control of Nrf2/ARE signaling pathways. Further mechanistic studies showed that Rh1 increased the nuclear translocation and DNA binding of Nrf2 and c-Jun to the antioxidant response element (ARE), and increased the ARE-mediated transcription activities in rat primary astrocytes. Analysis of signaling pathways revealed that MAP kinases are important in HO-1 expression, and act by modulating ARE mediated transcriptional activity. Therefore, the upregulation of antioxidant enzymes by Rh1 may provide preventive therapeutic potential for various neurodegenerative diseases that are associated with oxidative stress. PMID- 26759700 TI - PXR Mediated Protection against Liver Inflammation by Ginkgolide A in Tetrachloromethane Treated Mice. AB - The pregnane X receptor (PXR), a liver and intestine specific receptor,, has been reported to be related with the repression of inflammation as well as activation of cytochromosome P450 3A (CYP3A) expression. We examined the effect of PXR on tetrachloromethane (CCl4)-induced mouse liver inflammation in this work. Ginkgolide A, one main component of Ginkgo biloba extracts (GBE), activated PXR and enhanced PXR expression level, displayed both significant therapeutic effect and preventive effect against CCl4-induced mouse hepatitis. siRNA-mediated decrease of PXR expression significantly reduced the efficacy of Ginkgolide A in treating CCl4-induced inflammation in mice. Flavonoids, another important components of GBE, were shown anti-inflammatory effect in a different way from Ginkgolide A which might be independent on PXR because flavonoids significantly inhibited CYP3A11 activities in mice. The results indicated that anti inflammatory effect of PXR might be mediated by enhancing transcription level of IkappaBalpha through binding of IkappaBalpha. Inhibition of NF-kappaB activity by NF-kappaB-specific suppressor IkappaBalpha is one of the potential mechanisms of Ginkgolide A against CCl4-induced liver inflammation. PMID- 26759701 TI - Aloe-Emodin Protects RIN-5F (Pancreatic beta-cell) Cell from Glucotoxicity via Regulation of Pro-Inflammatory Cytokine and Downregulation of Bax and Caspase 3. AB - To determine the protective effect of aloe-emodin (AE) from high glucose induced toxicity in RIN-5F (pancreatic beta-cell) cell and restoration of its function was analyzed. RIN-5F cells have been cultured in high glucose (25 mM glucose) condition, with and without AE treatment. RIN-5F cells cultured in high glucose decreased cell viability and increased ROS levels after 48 hr compared with standard medium (5.5 mM glucose). Glucotoxicity was confirmed by significantly increased ROS production, increased pro-inflammatory (IFN-gamma, IL-1beta,) & decreased anti-inflammatory (IL-6&IL-10) cytokine levels, increased DNA fragmentation. In addition, we found increased Bax, caspase 3, Fadd, and Fas and significantly reduced Bcl-2 expression after 48 hr. RIN-5F treated with both high glucose and AE (20 MUM) decreased ROS generation and prevent RIN-5F cell from glucotoxicity. In addition, AE treated cells cultured in high glucose were transferred to standard medium, normal responsiveness to glucose was restored within 8hr and normal basal insulin release within 24 hr was achieved when compared to high glucose. PMID- 26759702 TI - Endothelium-Independent Effect of Fisetin on the Agonist-Induced Regulation of Vascular Contractility. AB - Fisetin, a natural flavonoid found in a variety of vegetables and fruits, has been shown to possess many biological functions. The present study was undertaken to investigate the influence of fisetin on vascular smooth muscle contractility and to determine the mechanism involved. Denuded aortic rings from male rats were used and isometric contractions were recorded and combined with molecular experiments. Fisetin significantly relaxed fluoride-, thromboxane A2- or phorbol ester-induced vascular contraction suggesting as a possible anti-hypertensive on the agonist-induced vascular contraction regardless of endothelial nitric oxide synthesis. Furthermore, fisetin significantly inhibited fluoride-induced increases in pMYPT1 levels and phorbol ester-induced increases in pERK1/2 levels suggesting the mechanism involving the inhibition of Rho-kinase activity and the subsequent phosphorylation of MYPT1 and MEK activity and the subsequent phosphorylation of ERK1/2. This study provides evidence regarding the mechanism underlying the relaxation effect of fisetin on agonist-induced vascular contraction regardless of endothelial function. PMID- 26759703 TI - Amygdalin Regulates Apoptosis and Adhesion in Hs578T Triple-Negative Breast Cancer Cells. AB - Amygdalin, D-mandelonitrile-beta-D-glucoside-6-beta-glucoside, belongs to aromatic cyanogenic glycoside group derived from rosaceous plant seed. Mounting evidence has supported the anti-cancer effects of amygdalin. However, whether amygdalin indeed acts as an anti-tumor agent against breast cancer cells is not clear. The present study aimed to investigate the effect of amygdalin on the proliferation of human breast cancer cells. Here, we show that amygdalin exerted cytotoxic activities on estrogen receptors (ER)-positive MCF7 cells, and MDA-MB 231 and Hs578T triple-negative breast cancer (TNBC) cells. Amygdalin induced apoptosis of Hs578T TNBC cells. Amygdalin downregulated B-cell lymphoma 2 (Bcl 2), upregulated Bcl-2-associated X protein (Bax), activated of caspase-3 and cleaved poly ADP-ribose polymerase (PARP). Amygdalin activated a pro-apoptotic signaling molecule p38 mitogen-activated protein kinases (p38 MAPK) in Hs578T cells. Treatment of amygdalin significantly inhibited the adhesion of Hs578T cells, in which integrin alpha5 may be involved. Taken together, this study demonstrates that amygdalin induces apoptosis and inhibits adhesion of breast cancer cells. The results suggest a potential application of amygdalin as a chemopreventive agent to prevent or alleviate progression of breast cancer, especially TNBC. PMID- 26759704 TI - Inhibition of Lung Inflammation by Acanthopanax divaricatus var. Albeofructus and Its Constituents. AB - In order to find potential therapeutic agents on lung inflammatory conditions, the extracts of Acanthopanax divaricatus var. albeofructus were prepared and its constituents were isolated. They include lignans such as (+)-syringaresinol (1), acanthoside B (2), salvadoraside (3) and acanthoside D (4), lariciresinol-9-O beta-D-glucopyranoside (5) and phenylpropanoids such as 4-[(1E)-3-methoxy-1 propenyl]phenol (6), coniferin (7), and methyl caffeate (8). The extracts and several constituents such as compound 1, 6 and 8 inhibited the production of inflammatory markers, IL-6 and nitric oxide, from IL-1beta-treated lung epithelial cells and lipopolysaccharide (LPS)-treated alveolar macrophages. Furthermore, the extracts and compound 4 significantly inhibited lung inflammation in lipolysaccharide-treated acute lung injury in mice by oral administration. Thus it is suggested that A. divaricatus var. albeofructus and its several constituents may be effective against lung inflammation. PMID- 26759706 TI - Anti-Melanogenic Potentials of Nanoparticles from Calli of Resveratrol-Enriched Rice against UVB-Induced Hyperpigmentation in Guinea Pig Skin. AB - We already reported that genetically engineered resveratrol-enriched rice (RR) showed to down-regulate skin melanogenesis. To be developed to increase the bioactivity of RR using calli from plants, RR was adopted for mass production using plant tissue culture technologies. In addition, high-pressure homogenization (HPH) was used to increase the biocompatibility and penetration of the calli from RR into the skin. We aimed to develop anti-melanogenic agents incorporating calli of RR (cRR) and nanoparticles by high-pressure homogenization, examining the synergistic effects on the inhibition of UVB induced hyperpigmentation. Depigmentation was observed following topical application of micro-cRR, nano-calli of normal rice (cNR), and nano-cRR to ultraviolet B (UVB)-stimulated hyperpigmented guinea pig dorsal skin. Colorimetric analysis, tyrosinase immunostaining, and Fontana-Masson staining for UVB-promoted melanin were performed. Nano-cRR inhibited changes in the melanin color index caused by UVB-promoted hyperpigmentation, and demonstrated stronger anti-melanogenic potential than micro-cRR. In epidermal skin, nano-cRR repressed UVB-promoted melanin granules, thereby suppressing hyperpigmentation. The UVB enhanced, highly expressed tyrosinase in the basal layer of the epidermis was inhibited by nano-cRR more prominently than by micro-cRR and nano-cNR. The anti melanogenic potency of nano-cRR also depended on pH and particle size. Nano-cRR shows promising potential to regulate skin pigmentation following UVB exposure. PMID- 26759705 TI - Rosmarinic Acid Attenuates Cell Damage against UVB Radiation-Induced Oxidative Stress via Enhancing Antioxidant Effects in Human HaCaT Cells. AB - This study was designed to investigate the cytoprotective effect of rosmarinic acid (RA) on ultraviolet B (UVB)-induced oxidative stress in HaCaT keratinocytes. RA exerted a significant cytoprotective effect by scavenging intracellular ROS induced by UVB. RA also attenuated UVB-induced oxidative macromolecular damage, including protein carbonyl content, DNA strand breaks, and the level of 8 isoprostane. Furthermore, RA increased the expression and activity of superoxide dismutase, catalase, heme oxygenase-1, and their transcription factor Nrf2, which are decreased by UVB radiation. Collectively, these data indicate that RA can provide substantial cytoprotection against the adverse effects of UVB radiation by modulating cellular antioxidant systems, and has potential to be developed as a medical agent for ROS-induced skin diseases. PMID- 26759707 TI - Effects of Bisphosphonates on Glucose Transport in a Conditionally Immortalized Rat Retinal Capillary Endothelial Cell Line (TR-iBRB Cells). AB - The objective of the present study was to elucidate the effect of bisphosphonates, anti-osteoporosis agents, on glucose uptake in retinal capillary endothelial cells under normal and high glucose conditions. The change of glucose uptake by pre-treatment of bisphosphonates at the inner blood-retinal barrier (iBRB) was determined by measuring cellular uptake of [(3)H]3-O-methyl glucose (3 OMG) using a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB cells) under normal and high glucose conditions. [(3)H]3-OMG uptake was inhibited by simultaneous treatment of unlabeled D-glucose and 3-OMG as well as glucose transport inhibitor, cytochalasin B. On the other hand, simultaneous treatment of alendronate or pamidronate had no significant inhibitory effect on [(3)H]3-OMG uptake by TR-iBRB cells. Under high glucose condition of TR-iBRB cells, [(3)H]3-OMG uptake was increased at 48 h. However, [(3)H]3-OMG uptake was decreased significantly by pre-treatment of alendronate or pamidronate compared with the values for normal and high glucose conditions. Moreover, geranylgeraniol (GGOH), a mevalonate pathway intermediate, increased the uptake of [(3)H]3-OMG reduced by bisphosphonates pre-treatment. But, pre-treatment of histamine did not show significant inhibition of [(3)H]3-OMG uptake. The glucose uptake may be down regulated by inhibiting the mevalonate pathway with pre-treatment of bisphosphonates in TR-iBRB cells at high glucose condition. PMID- 26759708 TI - Effects of Triclosan on Neural Stem Cell Viability and Survival. AB - Triclosan is an antimicrobial or sanitizing agent used in personal care and household products such as toothpaste, soaps, mouthwashes and kitchen utensils. There are increasing evidence of the potentially harmful effects of triclosan in many systemic and cellular processes of the body. In this study, we investigated the effects of triclosan in the survivability of cultured rat neural stem cells (NSCs). Cortical cells from embryonic day 14 rat embryos were isolated and cultured in vitro. After stabilizing the culture, triclosan was introduced to the cells with concentrations ranging from 1 MUM to 50 MUM and in varied time periods. Thereafter, cell viability parameters were measured using MTT assay and PI staining. TCS decreased the cell viability of treated NSC in a concentration dependent manner along with increased expressions of apoptotic markers, cleaved caspase-3 and Bax, while reduced expression of Bcl2. To explore the mechanisms underlying the effects of TCS in NSC, we measured the activation of MAPKs and intracellular ROS. TCS at 50 MUM induced the activations of both p38 and JNK, which may adversely affect cell survival. In contrast, the activities of ERK, Akt and PI3K, which are positively correlated with cell survival, were inhibited. Moreover, TCS at this concentration augmented the ROS generation in treated NSC and depleted the glutathione activity. Taken together, these results suggest that TCS can induce neurodegenerative effects in developing rat brains through mechanisms involving ROS activation and apoptosis initiation. PMID- 26759709 TI - An ontology for major histocompatibility restriction. AB - BACKGROUND: MHC molecules are a highly diverse family of proteins that play a key role in cellular immune recognition. Over time, different techniques and terminologies have been developed to identify the specific type(s) of MHC molecule involved in a specific immune recognition context. No consistent nomenclature exists across different vertebrate species. PURPOSE: To correctly represent MHC related data in The Immune Epitope Database (IEDB), we built upon a previously established MHC ontology and created an ontology to represent MHC molecules as they relate to immunological experiments. DESCRIPTION: This ontology models MHC protein chains from 16 species, deals with different approaches used to identify MHC, such as direct sequencing verses serotyping, relates engineered MHC molecules to naturally occurring ones, connects genetic loci, alleles, protein chains and multi-chain proteins, and establishes evidence codes for MHC restriction. Where available, this work is based on existing ontologies from the OBO foundry. CONCLUSIONS: Overall, representing MHC molecules provides a challenging and practically important test case for ontology building, and could serve as an example of how to integrate other ontology building efforts into web resources. PMID- 26759710 TI - Ontogenetic differences in localization of glutamine transporter ApGLNT1 in the pea aphid demonstrate that mechanisms of host/symbiont integration are not similar in the maternal versus embryonic bacteriome. AB - BACKGROUND: Obligate intracellular symbionts of insects are metabolically and developmentally integrated with their hosts. Typically, reproduction fails in many insect nutritional endosymbioses when host insects are cured of their bacterial symbionts, and yet remarkably little is known about the processes that developmentally integrate host and symbiont. Here in the best studied insect obligate intracellular symbiosis, that of the pea aphid, Acyrthosiphon pisum, with the gammaproteobacterium Buchnera aphidicola, we tracked the expression and localization of amino acid transporter ApGLNT1 gene products during asexual embryogenesis. Recently being characterized as a glutamine transporter, ApGLNT1 has been proposed to be a key regulator of amino acid biosynthesis in A. pisum bacteriocytes. To determine when this important mediator of the symbiosis becomes expressed in aphid embryonic bacteriocytes, we applied whole-mount in situ hybridization and fluorescent immunostaining with a specific anti-ApGLNT1 antibody to detect the temporal and spatial expression of ApGLNT1 gene products during asexual embryogenesis. RESULTS: During embryogenesis, ApGLNT1 mRNA and protein localize to the follicular epithelium that surrounds parthenogenetic viviparous embryos, where we speculate that it functions to supply developing embryos with glutamine from maternal hemolymph. Unexpectedly, in the embryonic bacteriome ApGLNT1 protein does not localize to the membrane of bacteriocytes, a pattern that leads us to conclude that the regulation of amino acid metabolism in the embryonic bacteriome mechanistically differs from that in the maternal bacteriome. Paralleling our earlier report of punctate cytoplasmic localization of ApGLNT1 in maternal bacteriocytes, we find ApGLNT1 protein localizing as cytoplasmic puncta throughout development in association with Buchnera. CONCLUSIONS: Our work that documents ontogenetic shifts in the localization of ApGLNT1 protein in the host bacteriome demonstrates that maternal and embryonic bacteriomes are not equivalent. Significantly, the persistent punctate cytoplasmic localization of ApGLNT1 in association with Buchnera in embryos prior to bacteriocyte formation and later in both embryonic and maternal bacteriomes suggests that ApGLNT1 plays multiple roles in this symbiosis, roles that include amino acid transport and possibly nutrient sensing. PMID- 26759711 TI - Large-scale gene expression study in the ophiuroid Amphiura filiformis provides insights into evolution of gene regulatory networks. AB - BACKGROUND: The evolutionary mechanisms involved in shaping complex gene regulatory networks (GRN) that encode for morphologically similar structures in distantly related animals remain elusive. In this context, echinoderm larval skeletons found in brittle stars and sea urchins provide an ideal system. Here, we characterize for the first time the development of the larval skeleton in the ophiuroid Amphiura filiformis and compare it systematically with its counterpart in sea urchin. RESULTS: We show that ophiuroids and euechinoids, that split at least 480 Million years ago (Mya), have remarkable similarities in tempo and mode of skeletal development. Despite morphological and ontological similarities, our high-resolution study of the dynamics of genetic regulatory states in A. filiformis highlights numerous differences in the architecture of their underlying GRNs. Importantly, the A.filiformis pplx, the closest gene to the sea urchin double negative gate (DNG) repressor pmar1, fails to drive the skeletogenic program in sea urchin, showing important evolutionary differences in protein function. hesC, the second repressor of the DNG, is co-expressed with most of the genes that are repressed in sea urchin, indicating the absence of direct repression of tbr, ets1/2, and delta in A. filiformis. Furthermore, the absence of expression in later stages of brittle star skeleton development of key regulatory genes, such as foxb and dri, shows significantly different regulatory states. CONCLUSION: Our data fill up an important gap in the picture of larval mesoderm in echinoderms and allows us to explore the evolutionary implications relative to the recently established phylogeny of echinoderm classes. In light of recent studies on other echinoderms, our data highlight a high evolutionary plasticity of the same nodes throughout evolution of echinoderm skeletogenesis. Finally, gene duplication, protein function diversification, and cis-regulatory element evolution all contributed to shape the regulatory program for larval skeletogenesis in different branches of echinoderms. PMID- 26759713 TI - Low expression of estrogen receptor beta in T lymphocytes and high serum levels of anti-estrogen receptor alpha antibodies impact disease activity in female patients with systemic lupus erythematosus. AB - BACKGROUND: Current evidence indicates that estrogens, in particular 17beta estradiol (E2), play a crucial role in the gender bias of autoimmune diseases although the underlying molecular mechanisms have not yet been fully elucidated. Immune cells have estrogen receptors (ERs), i.e., ERalpha and ERbeta, that play pro- and anti-inflammatory functions, respectively, and the presence of one estrogen receptor (ER) subtype over the other might change estrogen effects, promoting or dampening inflammation. In this study, we contributed to define the influences of E2 on T cells from female patients with systemic lupus erythematosus (SLE), a representative autoimmune disease characterized by a higher prevalence in women than in men (female/male ratio 9:1). Particularly, our aim was to evaluate whether alterations of ERalpha and ERbeta expression in T cells from female SLE patients may impact lymphocyte sensitivity to E2 and anti ERalpha antibody (anti-ERalpha Ab) stimulation interfering with cell signaling and display a direct clinical effect. METHODS: Sixty-one premenopausal female patients with SLE and 40 age-matched healthy donors were recruited. Patients were divided into two groups based on the SLE Disease Activity Index 2000 (SLEDAI-2K) (i.e., <6 and >=6). ER expression was evaluated in T lymphocytes by flow cytometry, immunofluorescence, and Western blot analyses. Serum anti-ERalpha Ab levels were analyzed by enzyme-linked immunosorbent assay (ELISA). ER-dependent signaling pathways were measured by a phosphoprotein detection kit. RESULTS: Intracellular ERbeta expression was significantly lower in T cells from patients with SLEDAI-2K >=6 as compared with healthy donors and patients with SLEDAI-2K <6 and negatively correlated with disease activity. The expression of intracellular and membrane-associated-ERalpha was similar in SLE and control T cells. ER dependent signaling pathways were activated in T cells from SLE patients with SLEDAI-2K >=6, but not with SLEDAI-2K <6, when both membrane and intracellular ERs were stimulated by co-treatment with E2 and anti-ERalpha Abs. CONCLUSIONS: Our results demonstrate an altered ER profile in SLE patients, possibly contributing to SLE pathogenesis and interfering with clinical activity, and highlight the potential exploitation of T cell-associated ERbeta as a biomarker of disease activity. PMID- 26759712 TI - Interaction between neonatal maternal deprivation and serum leptin levels on metabolism, pubertal development, and sexual behavior in male and female rats. AB - BACKGROUND: Maternal deprivation (MD) during neonatal life can have long-term effects on metabolism and behavior, with males and females responding differently. We previously reported that MD during 24 h at postnatal day (PND) 9 blocks the physiological neonatal leptin surge in both sexes. It is known that modifications in neonatal leptin levels can affect metabolism in adulthood. Thus, we hypothesized that at least some of the long-term metabolic changes that occur in response to MD are due to the decline in serum leptin during this critical period of development. Hence, we predicted that treatment with leptin during MD would normalize these metabolic changes, with this response also differing between the sexes. METHODS: MD was carried-out in Wistar rats for 24 h on PND9. Control and MD rats of both sexes were treated from PND 9 to 13 with leptin (3 mg/kg/day sc) or vehicle. Weight gain, food intake, glucose tolerance, and pubertal onset were monitored. Sexual behavior was analyzed in males. Rats were killed at PND90, and serum hormones and hypothalamic neuropeptides involved in metabolic control and reproduction were measured. Results were analyzed by three way analysis of covariance using sex, MD, and leptin treatment as factors and litter as the covariate and employing repeated measures where appropriate. RESULTS: In males, MD advanced the external signs of puberty and increased serum insulin and triglyceride levels and hypothalamic proopiomelanocortin mRNA levels at PND90. Neonatal leptin treatment normalized these effects. In contrast, MD decreased circulating triglycerides, as well as estradiol levels, in females at PND90 and these changes were also normalized by neonatal leptin treatment. Neonatal leptin treatment also had long-term effects in control rats as it advanced the external signs of puberty in control males, but delayed them in females. Neonatal leptin treatment increased serum insulin and hypothalamic mRNA levels of the leptin receptor and cocaine- and amphetamine-regulated transcript in control males and increased orexin mRNA levels in controls of both sexes. Although pubertal onset in males was advanced by either MD or neonatal leptin treatment in males and delayed by leptin treatment in females, the mRNA levels of hypothalamic neuropeptides and receptors related to reproduction were not affected by MD or neonatal leptin treatment in either sex at PND90. CONCLUSIONS: These findings indicate that some of the long-term changes in metabolic and reproductive parameters induced by MD, such as advanced pubertal onset and increased hypothalamic proopiomelanocortin (POMC) expression, hyperinsulinemia, and hypertriglyceridemia in adult males and decreased serum triglyceride and estradiol levels in females, are most likely due to the decrease in leptin levels during the period of MD. PMID- 26759714 TI - Perinatal testosterone exposure is critical for the development of the male specific sexually dimorphic gastrin-releasing peptide system in the lumbosacral spinal cord that mediates erection and ejaculation. AB - BACKGROUND: In rats, a sexually dimorphic spinal gastrin-releasing peptide (GRP) system in the lumbosacral spinal cord projects to spinal centers that control erection and ejaculation. This system controls the sexual function of adult males in an androgen-dependent manner. In the present study, we assessed the influence of androgen exposure on the spinal GRP system during a critical period of the development of sexual dimorphism. METHODS: Immunohistochemistry was used to determine if the development of the spinal GRP system is regulated by the perinatal androgen surge. We first analyzed the responses of neonates administered with anti-androgen flutamide. To remove endogenous androgens, rats were castrated at birth. Further, neonatal females were administered androgens during a critical period to evaluate the development of the male-specific spinal GRP system. RESULTS: Treatment of neonates with flutamide on postnatal days 0 and 1 attenuated the spinal GRP system during adulthood. Castrating male rats at birth resulted in a decrease in the number of GRP neurons and the intensity of neuronal GRP in the spinal cord during adulthood despite testosterone supplementation during puberty. This effect was prevented if the rats were treated with testosterone propionate immediately after castration. Moreover, treating female rats with androgens on the day of birth and the next day, masculinized the spinal GRP system during adulthood, which resembled the masculinized phenotype of adult males and induced a hypermasculine appearance. CONCLUSIONS: The perinatal androgen surge plays a key role in masculinization of the spinal GRP system that controls male sexual behavior. Further, the present study provides potentially new approaches to treat sexual disorders of males. PMID- 26759715 TI - Spatial sexual dimorphism of X and Y homolog gene expression in the human central nervous system during early male development. AB - BACKGROUND: Renewed attention has been directed to the functions of the Y chromosome in the central nervous system during early human male development, due to the recent proposed involvement in neurodevelopmental diseases. PCDH11Y and NLGN4Y are of special interest because they belong to gene families involved in cell fate determination and formation of dendrites and axon. METHODS: We used RNA sequencing, immunocytochemistry and a padlock probing and rolling circle amplification strategy, to distinguish the expression of X and Y homologs in situ in the human brain for the first time. To minimize influence of androgens on the sex differences in the brain, we focused our investigation to human embryos at 8 11 weeks post-gestation. RESULTS: We found that the X- and Y-encoded genes are expressed in specific and heterogeneous cellular sub-populations of both glial and neuronal origins. More importantly, we found differential distribution patterns of X and Y homologs in the male developing central nervous system. CONCLUSIONS: This study has visualized the spatial distribution of PCDH11X/Y and NLGN4X/Y in human developing nervous tissue. The observed spatial distribution patterns suggest the existence of an additional layer of complexity in the development of the male CNS. PMID- 26759716 TI - How fast can glucose be infused in the perioperative setting? AB - BACKGROUND: How the initial infusion rate of glucose solution should be set to avoid hyperglycemia in the perioperative setting is unclear. METHODS: Computer simulations were performed based on data from seven studies where the kinetics of glucose was calculated using a one-compartment model. Glucose had been infused intravenously on 44 occasions to volunteers and on 256 occasions to surgical patients at various stages of the perioperative process. The rates that yield plasma glucose concentrations of 7, 9, and 12 mmol/l were calculated and standardized to a 5 % glucose solution infused in a subject weighing 70 kg. RESULTS: The lowest infusion rates were found during surgery and the first hours after surgery. No more than 0.5 ml/min of glucose 5 % could be infused if plasma glucose above 7 mmol/l was not allowed, while 2 ml/min maintained a steady state concentration of 9 mmol/l. Intermediate infusion rates could be used in the preoperative period and 1-2 days after moderate-sized surgery (e.g., hysterectomy or hip replacement). Here, the half-lives averaged 30 min, which means that plasma glucose would rise by another 25 % if a control sample is taken 1 h after a continuous infusion is initiated. The highest infusion rates were found in non surgical volunteers, where 8 ml/min could be infused before 9 mmol/l was reached. CONCLUSIONS: Computer simulations suggested that rates of infusion of glucose should be reduced by 50 % in the perioperative period and a further 50 % on the day of surgery in order to avoid hyperglycemia. PMID- 26759718 TI - Effects of mindfulness training on different components of impulsivity in borderline personality disorder: results from a pilot randomized study. AB - BACKGROUND: Impulsivity is considered a core characteristic of borderline personality disorder (BPD). Previous research on the effects of mindfulness training (MT) has shown that it might modify impulsivity-related aspects of BPD. Therefore, the aim of this study was to investigate the impact of MT on various facets of impulsivity in BPD patients. METHODS: Subjects with BPD diagnosis (n = 64) were randomly assigned to 10 weeks of MT (n = 32) or interpersonal effectiveness skills training (IE; n = 32). All participants were assessed pre- and post-intervention with a self-reported measure of impulsivity and five behavioral neuropsychological tasks to evaluate response inhibition, tolerance for delay rewards, and time perception. RESULTS: An interaction effect of time * group was only observed for some of the behavioral paradigms used. Participants in the MT group improved their ability to delay gratification and showed changes in time perception, consistent with a decrease in impulsivity. No differences were observed between treatments in terms of trait impulsivity and response inhibition. CONCLUSIONS: Mindfulness training might improve some aspects of impulsivity but not others. Further study is warranted to better determine the effects of mindfulness training on the components of impulsivity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02397031. PMID- 26759719 TI - Performance comparison of a new automated cuff pressure controller with currently available devices in both basic research and clinical settings. AB - BACKGROUND: The management of tracheal tube cuff pressure in patients receiving mechanical ventilation is important for the prevention of ventilator-associated pneumonia. Currently, cuff pressure is intermittently monitored with a pressure gauge and adjusted when necessary in a routine practice. However, this method results in wide variations in pressure, and adequate management is difficult due to the spontaneous release of air from the cuff, which reduces cuff pressure. In order to continuously maintain a uniform cuff pressure, we developed a new automated cuff pressure controller and compared its properties with existing devices. METHODS: The effectiveness of the new device was assessed with a model trachea/lung and tracheal tube by measuring cuff pressure while on mechanical ventilation. An electrically powered automatic cuff controller or manual cuff pressure control was used for comparison purposes. The effectiveness of the new device was also examined in patients receiving mechanical ventilation by continuously measuring cuff pressure for a 24-h period. RESULTS: Cuff pressure was uniformly maintained with the new device. Moreover, in the clinical setting, variation in pressure from the set pressure was minimal with both the new device and existing device, relative to the intermittent monitoring method. This suggests that, as with the existing device, uniform cuff pressure management is possible with the new device. CONCLUSIONS: Our results demonstrate the ability of the new cuff pressure controller to manage cuff pressure without the need of a power source, highlighting its potential utility in clinical settings. PMID- 26759720 TI - Sodium bicarbonate prophylactic therapy in the prevention of contrast-induced nephropathy in patients admitted to the intensive care unit of a teaching hospital: a retrospective cohort study. AB - BACKGROUND: Intravenously administered iodine-containing contrast medium (CM) is associated with the development of contrast-induced nephropathy (CIN). Data on the effectiveness of sodium bicarbonate therapy in the prevention of CIN are controversial. Furthermore, the incidence of and risk factors for CIN in intensive care unit (ICU) patients are poorly defined. We investigated the effectiveness of sodium bicarbonate prophylaxis and the incidence of and risk factors for CIN in a heterogeneous ICU population. METHODS: This retrospective cohort study included patients admitted to the ICU in 2009-2011 who received CM for computed tomography (CT). RESULTS: Two hundred eleven CT scans with CM, performed in 170 patients, were included in the study. Contrast prophylaxis with sodium bicarbonate was administered in 48 of the 211 cases. CIN developed in 19 of the 48 cases receiving prophylaxis and in 39 of 163 cases not receiving prophylaxis (p = 0.03). In 115 CTs performed in patients with a glomerular filtration rate (GFR) >60 mL/min, prophylaxis was administered 15 times (13 %) and no prophylaxis was administered 100 times (87 %). CIN developed in 12 and 13 % of these cases, respectively (NS). In 96 CTs in patients with a GFR <60 mL/min, 17 of 33 (51.5 %) cases receiving prophylaxis developed CIN and 27 of 63 (42.9 %) cases not receiving prophylaxis developed CIN (NS). Prophylactic sodium bicarbonate therapy did not prevent CIN in our patients, irrespective of pre existing renal failure. Pre-existing renal impairment (odds ratio 4.41), an elevated Acute Physiology and Chronic Health Evaluation (APACHE) IV score (odds ratio 1.02), and higher haemoglobin levels (odds ratio 0.64) were significant and independent risk factors associated with the development of CIN. CONCLUSIONS: Prophylactic isotonic sodium bicarbonate was not associated with a decreased incidence of CIN in ICU patients. Current sodium bicarbonate prophylaxis guidelines cannot be generalized to a heterogeneous ICU population. Pre-existing renal impairment was associated with the highest CIN risk. PMID- 26759721 TI - Sepsis induces incomplete M2 phenotype polarization in peritoneal exudate cells in mice. AB - BACKGROUND: Macrophages can differentiate into pro-inflammatory (M1) or anti inflammatory (M2) phenotypes upon exposure to a pathogen or a cytokine microenvironment. However, M1/M2 macrophage polarization in polymicrobial sepsis has not been fully characterized. METHODS: The polarity of peritoneal exudate (PE) cells from mice that had undergone cecal ligation and puncture (CLP) and the response of those cells to lipopolysaccharide (LPS) in terms of cytokine and chemokine expression were examined. RESULTS: PE cells from CLP mice demonstrated a shift toward the M2 phenotype in terms of marker enzyme expression. In addition, the CLP-derived PE cells showed apparent unresponsiveness to LPS stimulation with regard to expression of pro-inflammatory cytokines such as TNF alpha, while the expression of anti-inflammatory cytokines such as IL-10 was induced. Nevertheless, the CLP-PE cells failed to express M2 chemokines including chemokine (C-C motif) ligand 17 (CCL17), CCL22, and CCL24, all of which are important for T cell recruitment. CONCLUSIONS: The results suggested that a shift of naive monocytes/macrophages to the M2 phenotype, along with the lack of M2 chemokine expression in septic monocytes/macrophages, might be responsible for immunosuppression after sepsis. PMID- 26759717 TI - Genomic analyses reveal FAM84B and the NOTCH pathway are associated with the progression of esophageal squamous cell carcinoma. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the sixth most lethal cancer worldwide and the fourth most lethal cancer in China. Genomic characterization of tumors, particularly those of different stages, is likely to reveal additional oncogenic mechanisms. Although copy number alterations and somatic point mutations associated with the development of ESCC have been identified by array-based technologies and genome-wide studies, the genomic characterization of ESCCs from different stages of the disease has not been explored. Here, we have performed either whole-genome sequencing or whole-exome sequencing on 51 stage I and 53 stage III ESCC patients to characterize the genomic alterations that occur during the various clinical stages of ESCC, and further validated these changes in 36 atypical hyperplasia samples. RESULTS: Recurrent somatic amplifications at 8q were found to be enriched in stage I tumors and the deletions of 4p-q and 5q were particularly identified in stage III tumors. In particular, the FAM84B gene was amplified and overexpressed in preclinical and ESCC tumors. Knockdown of FAM84B in ESCC cell lines significantly reduced in vitro cell growth, migration and invasion. Although the cancer associated genes TP53, PIK3CA, CDKN2A and their pathways showed no significant difference between stage I and stage III tumors, we identified and validated a prevalence of mutations in NOTCH1 and in the NOTCH pathway that indicate that they are involved in the preclinical and early stages of ESCC. CONCLUSIONS: Our results suggest that FAM84B and the NOTCH pathway are involved in the progression of ESCC and may be potential diagnostic targets for ESCC susceptibility. PMID- 26759723 TI - Comment to: Mansson C, Nilsson A, Karlson B-M. Severe complications with irreversible electroporation of the pancreas in the presence of a metallic stent: a warning of a procedure that never should be performed. Acta Radiologica Short Reports 2014;3(11):1-3. PMID- 26759722 TI - Indirect traumatic optic neuropathy. AB - Indirect traumatic optic neuropathy (ITON) refers to optic nerve injury resulting from impact remote to the optic nerve. The mechanism of injury is not understood, and there are no confirmed protocols for prevention, mitigation or treatment. Most data concerning this condition comes from case series of civilian patients suffering blunt injury, such as from sports- or motor vehicle-related concussion, rather than military-related ballistic or blast damage. Research in this field will likely require the development of robust databases to identify patients with ITON and follow related outcomes, in addition to both in-vivo animal and virtual human models to study the mechanisms of damage and potential therapies. PMID- 26759724 TI - Risk Factors for Sensorineural Hearing Loss Among High-Risk Infants in Golestan Province, Iran in 2010 - 2011. AB - BACKGROUND: Hearing impairment, as one of the most common birth defects, is a hidden disability with negative impacts on speech and cognitive development. OBJECTIVES: The aim of this study was to assess the prevalence of sensorineural hearing loss (SNHL) and determine the associated risk factors among infants admitted to neonatal intensive care units (NICUs) and neonatal wards of teaching hospitals, affiliated to Golestan University of Medical Sciences, Gorgan, Iran. PATIENTS AND METHODS: In this cross-sectional study, 791 infants were recruited via non-random sampling. Demographic and clinical characteristics of the subjects were gathered, and the Automated Auditory Brainstem Response (AABR) test was performed upon admission. Afterwards, the subjects were followed-up and re assessed, using the AABR test. For infants with abnormal AABR results, the Auditory Brainstem Response (ABR) test was performed on the day of discharge. RESULTS: The mean age of the infants was 3.75 +/- 4.86 days upon admission, and 56.4% of the subjects were female. The mean length of hospital stay was 9.63 +/- 1.1 days; the subjects were hospitalized for 3.50 +/- 10.21 days in the NICUs and 6.1 +/- 5.27 days in the neonatal wards. In total, 3.4% of the infants presented with SNHL. No significant difference was found between SNHL and neonates' age (P = 0.52), sex (P = 0.5), or sepsis (P = 0.94). However, SNHL was significantly associated with gestational age (P = 0.045), birth weight (P < 0.001), length of hospital stay (P < 0.001), pathological jaundice (P=0.033), antibiotic treatments (P = 0.007), and total serum bilirubin level (P = 0.01). Additionally, binary logistic regression analysis demonstrated the association between SNHL and these factors. CONCLUSIONS: In this study, the prevalence of SNHL among hospitalized neonates was similar to previous reports in Iran and other countries. Based on the findings, administration of ototoxic drugs during the neonatal period can lead to SNHL. Therefore, it seems essential to regularly screen newborns under treatment and limit the indiscriminate use of ototoxic drugs. PMID- 26759726 TI - The Prevalence and Distribution of Vitreoretinal Interface Abnormalities among Urban Community Population in China. AB - The aim of this research was to identify the prevalence and distribution of vitreoretinal interface abnormalities (VIAs) among urban community population in Shenyang, China. According to the WHO criteria, a cross-sectional study was carried out among 304 Type 2 diabetes (T2D) patients and 304 people without diabetes as control over 45 years old. The presence of VIAs was determined by standardized grading of macular optical coherence tomography (Optovue OCT; Optovue, Inc., Fremont, CA) scans and two-field fundus photographs in at least one eye. For both men and women, high prevalence of VIAs (70.79%) was observed among over 65-years-old T2D patients. Prevalence of VIAs was observed to be high among T2D patients in all age groups compared to normal subjects. Prevalence of VIAs increased with age in all subjects. Prevalence of components of VIAs was epiretinal membrane (ERM) 11.43%, posterior vitreous detachment (PVD) 17.76%, vitreomacular traction syndrome (VMT) 5.67%, macular cysts/macular edema (MC/ME) 4.61%, full-thickness macular hole (FTMH) 0.82%, and partial thickness macular hole (PTMH) 0.74% in any eye, respectively. ERM and MC/ME were more prevalent in T2D in both males and females. The results highlight the need for early detection using OCT and approaches for the prevention of VIAs of diabetes in urban community. PMID- 26759725 TI - Effect of Pulsed Wave Low-Level Laser Therapy on Tibial Complete Osteotomy Model of Fracture Healing With an Intramedullary Fixation. AB - BACKGROUND: Fractures pose a major worldwide challenge to public health, causing tremendous disability for the society and families. According to recent studies, many in vivo and in vitro experiments have shown the positive effects of PW LLLT on osseous tissue. OBJECTIVES: The aim of this study was to evaluate the outcome of infrared pulsed wave low-level laser therapy (PW LLLT) on the fracture healing process in a complete tibial osteotomy in a rat model, which was stabilized by an intramedullary pin. MATERIALS AND METHODS: This experimental study was conducted at Shahid Beheshti University of Medical Sciences in Tehran, Iran. We performed complete tibial osteotomies in the right tibias for the population of 15 female rats. The rats were divided randomly into three different groups: I) Control rats with untreated bone defects; II) Rats irradiated by a 0.972 J/cm(2) PW LLLT; and III) Rats irradiated by a 1.5 J/cm(2) PW LLLT. The right tibias were collected six weeks following the surgery and a three-point bending test was performed to gather results. Immediately after biomechanical examination, the fractured bones were prepared for histological examinations. Slides were examined using stereological method. RESULTS: PW LLLT significantly caused an increase in maximum force (N) of biomechanical repair properties for osteotomized tibias in the first and second laser groups (30.0 +/- 15.9 and 32.4 +/- 13.8 respectively) compared to the control group (8.6 +/- 4.5) LSD test, P = 0.019, P = 0.011 respectively). There was a significant increase in the osteoblast count of the first and second laser groups (0.53 +/- 0.06, 0.41 +/- 0.06 respectively) compared to control group (0.31 +/- 0.04) (LSD test, P = 0001, P = 0.007 respectively). CONCLUSIONS: This study confirmed the efficacy of PW LLLT on biomechanical strength, trabecular bone volume, callus volume, and osteoblast number of repairing callus in a complete tibial osteotomy animal model at a relatively late stage of the bone healing process. PMID- 26759728 TI - Colorectal Adenocarcinoma Metastasis to the Tongue. AB - This case presentation examines a rare clinical entity: colorectal adenocarcinoma (CRC) metastasis to the tongue. CRC is among the least common tumors to metastasize to the oral cavity. Objectives for this case report are to (1) maintain a high index of suspicion for oral cavity tumors representing metastatic disease, (2) consider appropriate surgical and adjunctive interventions, and (3) recognize the significance of identifying the primary tumor via immunohistochemical staining. We present a case of a 57-year-old male with a history of stage IV rectal adenocarcinoma metastatic to the lung who presented to our clinic with a painful mass of the right lateral tongue that he noticed one month before. MRI of the neck revealed a mass involving the anterior two-thirds of the right tongue with irregular margins and an ipsilateral enlarged right jugulodigastric lymph node. The patient underwent right partial glossectomy with primary reconstruction and right modified radical neck dissection. Pathology confirmed poorly differentiated adenocarcinoma consistent with a colorectal primary with lymphovascular and perineural invasion. The tumor was staged as T2N1, and the patient was referred for chemoradiation. In this report, we discuss the presentation, diagnosis, and treatment of this uncommon disease, with a thorough review of the world literature. PMID- 26759727 TI - Early Detection of Fetal Malformation, a Long Distance Yet to Cover! Present Status and Potential of First Trimester Ultrasonography in Detection of Fetal Congenital Malformation in a Developing Country: Experience at a Tertiary Care Centre in India. AB - BACKGROUND: Early detection of malformation is tremendously improved with improvement in imaging technology. Yet in a developing country like India majority of pregnant women are not privileged to get timely diagnosis. AIMS AND OBJECTIVES: To assess the present status and potential of first trimester ultrasonography in detection of fetal congenital structural malformations. METHODOLOGY: This was a retrospective observational study conducted at Sanjay Gandhi Postgraduate Institute of Medical Sciences. All pregnant women had anomaly scan and women with fetal structural malformations were included. RESULTS: Out of 4080 pregnant women undergoing ultrasound, 312 (7.6%) had fetal structural malformation. Out of 139 patients who were diagnosed after 20 weeks, 47 (33.8%) had fetal structural anomalies which could have been diagnosed before 12 weeks and 92 (66.1%) had fetal malformations which could have been diagnosed between 12 and 20 weeks. CONCLUSION: The first trimester ultrasonography could have identified 50% of major structural defects compared to 1.6% in the present scenario. This focuses on the immense need of the hour to gear up for early diagnosis and timely intervention in the field of prenatal detection of congenital malformation. PMID- 26759729 TI - Determinants and Regression Equations for the Calculation of z Scores of Left Ventricular Tissue Doppler Longitudinal Indexes in a Healthy Italian Pediatric Population. AB - Aim. We investigated the predictors of tissue Doppler left ventricular (LV) longitudinal indexes in a healthy Italian pediatric population and established normative data and regression equations for the calculation of z scores. Methods and Results. A total of 369 healthy subjects aged 1-17 years (age of 6.4 +/- 1.1 years, 49.1% female) underwent echocardiography. LV peak longitudinal velocity at systole (s (')), early diastole (e (')), and late diastole (a (')) was determined by tissue Doppler. The ratio of peak early diastolic LV filling velocity to e (') was calculated. Age was the only independent determinant of s (') (beta = 0.491, p < 0.0001) and the strongest determinant of e (') (beta = 0.334, p < 0.0001) and E/e (') (beta = -0.369, p < 0.0001). Heart rate was the main determinant of a (') (beta = 0.265, p < 0.0001). Male gender showed no effects except for a weak association with lateral s ('), suggesting no need of gender-specific reference ranges. Age-specific reference ranges, regression equations, and scatterplots for the calculation of z scores were determined for each index. Conclusion. In a pediatric Italian population, age was the strongest determinant of LV longitudinal dynamics. The availability of age-specific normality data for the calculation of z scores may allow for correctly detecting LV dysfunction in pediatric pathological populations. PMID- 26759730 TI - Evaluation of Gingival Microleakage in Class II Composite Restorations with Different Lining Techniques: An In Vitro Study. AB - Aim. To compare the microleakage in class II composite restorations without a liner/with resin modified glass ionomer and flowable composite liner. Method. Forty standardized MO cavities were prepared on human permanent mandibular molars extracted for periodontal reasons and then divided into 4 groups of ten specimens. The cavity preparations were etched, rinsed, blot dried, and light cured and Adper Single Bond 2 is applied. Group 1 is restored with Filtek P60 packable composite in 2 mm oblique increments. Group 2 is precure group where 1 mm Filtek Z350 flowable liner is applied and light cured for 20 sec. Group 3 is the same as Group 2, but the liner was cocured with packable composite. In Group 4, 1 mm RMGIC, Fuji Lining LC is applied and cured for 20 sec. All the teeth were restored as in Group 1. The specimens were coated with nail varnish leaving 1 mm around the restoration, subjected to thermocycling, basic fuchsin dye penetration, sectioned mesiodistally, and observed under a stereomicroscope. Results. The mean leakage scores of the individual study groups were Group 1 (33.40), Group 2 (7.85), Group 3 (16.40), and Group 4 (24.35). Group 1 without a liner showed maximum leakage. Flowable composite liner precured was the best. PMID- 26759731 TI - Occipital neuralgia secondary to unilateral atlantoaxial osteoarthritis: Case report and review of the literature. AB - BACKGROUND: Atlantoaxial osteoarthritis (AAOA), either in isolation or in the context of generalized peripheral or spinal arthritis, presents most commonly with neck pain and limitation of cervical rotational range of motion. Occipital neuralgia (ON) is only rarely attributed to AAOA, as fewer than 30 cases are described in the literature. CASE DESCRIPTION: A 64-year-old female presented with progressive incapacitating cervicalgia and occipital headaches, refractory to medications, and local anesthetic blocks. Computed tomography and magnetic resonance imaging studies documented advanced unilateral atlantoaxial arthrosis with osteophytic compression that dorsally displaced the associated C2 nerve root. Surgical decompression and atlantoaxial fusion achieved rapid and complete relief of neuralgia. Ultimately, postoperative spinal imaging revealed osseous union. CONCLUSIONS: Atlantoaxial arthrosis must be considered in the differential diagnosis of ON. Surgical treatment is effective for managing refractory cases. Intraoperative neuronavigation is also a useful adjunct to guide instrumentation and the intraoperative extent of bony decompression. PMID- 26759732 TI - Delayed intracranial hypertension after surgery for nonsyndromic craniosynostosis. PMID- 26759733 TI - Role of external ventricular drainage in the management of intraventricular hemorrhage; its complications and management. AB - BACKGROUND: External ventricular drainage (EVD) is the procedure of choice for the treatment of acute hydrocephalus and increased intracranial pressure in patients of subarachnoid hemorrhage (SAH) and intracerebral hemorrhage with hydrocephalus and its sequelae. We evaluated the use of EVD in patients of SAHs (spontaneous/posttraumatic with/without hydrocephalus), hypertensive intracerebral bleeds with interventricular extensions, along with evaluation of the frequency of occurrence of complications of the procedure, infectious and noninfectious, and their management. METHODS: During the period of 21/2 years, between September 2012 and February 2015, 130 patients were subjected to external drainage procedure and were prospectively enrolled in this study. Information was collected on each patient regarding age, sex, diagnosis, underlying illness, secondary complications, other coexisting infections, use of systemic steroids, antibiotic treatment (systemic and intraventricular), and whether any other neurosurgical procedures were performed within 2 weeks of EVD insertion or any time the duration of ventriculostomy. RESULTS: The study population of 130 patients underwent a total of 193 ventriculostomies. Thirty-six patients had ventriculostomy infection (27.6%). Evaluation of the use of EVD was done by comparing preoperative and postoperative grading scores. Forty-nine patients survived and improved their score from Grade 3-5 to Grade 2-4. Twenty-nine patients were moderately disable, 16 were severely disable, and 5 were left in the vegetative state. Evaluation of outcome of patients revealed that there was an overall mortality of 61 (46.9%) patients both in the acute phase and later. 33 of the 39 patients having Glasgow Coma Score (GCS) 3-5 at the time of EVD insertion expired, as against 20 of the 51 patients in GCS 6-8. Patients in GCS 9 12 had an even better outcome, with 8 of the 35 patients in this group expiring. CONCLUSIONS: The use of EVD should be undertaken only in situation where it is absolutely necessary and ventriculostomy should be kept only for the duration required, and this should be monitored on a daily basis, given the exponential increase in infection after 5 days. PMID- 26759734 TI - Classification of neurovascular compression in glossopharyngeal neuralgia: Three dimensional visualization of the glossopharyngeal nerve. AB - BACKGROUND: We introduce a method of noninvasive topographical analysis of the neurovascular relationships of the glossopharyngeal nerve (CN IX) by three dimensional (3D) visualization. Patients with glossopharyngeal neuralgia (GN) resulting from neurovascular compression (NVC) were studied. METHODS: 15 patients with GN were prospectively examined with 3D visualization using high-resolution magnetic resonance imaging with constructive interference in steady state (MR CISS). The datasets were segmented and visualized with the real, individual neurovascular relationships by direct volume rendering. Segmentation and 3D visualization of the CN IX and corresponding blood vessels were performed. The 3D visualizations were interactively compared with the intraoperative setup during microvascular decompression (MVD) in order to verify the results by the observed surgical-anatomical findings. RESULTS: 15 patients (female/male: 5/10) were examined. All of them underwent MVD (100%). Microvascular details were documented. The posterior inferior cerebellar artery (PICA) was the most common causative vessel in 12 of 15 patients (80%), the vertebral artery (VA) alone in one case (6.7%), and the combination of compression by the VA and PICA in 3 patients (13.3%). We identified three distinct types of NVC within the root entry zone of CN IX. CONCLUSION: 3D visualization by direct volume rendering of MR-CISS data offers the opportunity of noninvasive exploration and anatomical categorization of the CN IX. It proves to be advantageous in supporting to establish the diagnosis and microneurosurgical interventions by representing original, individual patient data in a 3D fashion. It provides an excellent global individual view over the entire neurovascular relationships of the brainstem and corresponding nerves in each case. PMID- 26759735 TI - Fenestration of bone flap during interval autologous cranioplasty. AB - BACKGROUND: Symptomatic extra-axial fluid may complicate cranioplasty and require urgent evacuation. Fenestration (F) of the bone flap may encourage extra-axial fluid absorption; however, literature has not explored this technique. METHODS: Thirty-two consecutive patients who underwent interval autologous cranioplasty were divided into two groups: Fenestration, n = 24, and no fenestration (NF), n = 8. Fenestration involves placement of twist-drill holes 1-2 cm apart throughout the bone flap. Clinical data (age, sex, underlying pathology for cranioplasty, history of antiplatelet/anticoagulation [A/A], presence of drains, and length of Intensive Care Unit [ICU] stay) were collected. Postoperative volume and midline shift (MLS) were measured. Univariate analysis was performed for continuous variables; Fisher's exact test was performed for categorical variables. RESULTS: For postoperative volume, NF group exhibited 33.745 +/- 48.701 cm(3); F group exhibited 20.832 +/- 26.103 cm(3) (P = 0.351). For MLS, NF group exhibited 3.055 +/- 0.472 mm; F group exhibited 0.75 +/- 0.677 mm (P = 0.009). MLS for the NF group subset with drains was 1.235 +/- 0.566 mm, (P = 0.587 when compared to F group). For ICU length of stay, NF group exhibited 1.958 +/- 1.732 days; F group exhibited 2.290 +/- 0.835 days (P = 0.720). In NF group, for patients with no A/A, no drain exhibited MLS 4.00 +/- 0.677 mm while a drain exhibited 1.845 +/- 0.605 mm (P = 0.025); with A/A, no drain exhibited 5.75 +/- 1.353 mm while a drain exhibited 0.625 +/- 0.957 (P = 0.005). Four NF patients required reoperation compared to zero F patients (P = 0.550). CONCLUSION: Presumably, fenestrations augment surface area for extra-axial fluid absorption through the bone flap. Our results, regarding MLS and postoperative volume, provide support for this concept. Accordingly, bone flap fenestration has the potential to reduce extra-axial fluid accumulation. PMID- 26759736 TI - Emergent surgical embolectomy in conjunction with cervical internal carotid ligation and superficial temporal artery-middle cerebral artery bypass to treat acute tandem internal carotid and middle cerebral artery occlusion due to cervical internal carotid artery dissection. AB - BACKGROUND: Acute tandem cervical dissecting internal carotid artery (ICA) occlusion and intracranial embolic middle cerebral artery (MCA) occlusion can be devastating, and the optimal treatment strategy for this condition has not been established yet. CASE DESCRIPTION: A 45-year-old male presented with aphasia and right hemiparesis preceded by neck pain. Computed tomography showed a high density signal along the left MCA, suggesting extensive emboli. Magnetic resonance angiography demonstrated tandem occlusion of the left cervical ICA and intracranial MCA with minimal diffusion-weighted imaging lesion. Emergent surgical embolectomy was performed, and long intracranial MCA emboli were retrieved with collateral cross-flow restoration. The cervical ICA was exposed, and dissection was confirmed. The cervical ICA was ligated, and superficial temporal artery (STA)-MCA anastomosis was added. Postoperatively, the patient demonstrated recovery from right hemiparesis and aphasia. At the 6(th) postoperative month, follow-up studies demonstrated a robustly patent STA-MCA bypass and no additional ischemic lesion on T2-weighted imaging. CONCLUSIONS: Surgical embolectomy in conjunction with ligation of the cervical ICA followed by STA-MCA bypass might be a safe alternative method to endovascular recanalization, when the cervical dissection is extensive and when huge secondary emboli are present along the MCA. PMID- 26759737 TI - C1 anterior arch preservation in transnasal odontoidectomy using three dimensional endoscope: A case report. AB - BACKGROUND: The transoral ventral corridor is the most common approach used to reach the craniovertebral junction (CVJ). Over the last decade, many case reports have demonstrated the transnasal corridor to the odontoid peg represents a practicable route to remove the tip of the odontoid process. The biomechanical consequences of the traditional odontoidectomy led to the necessity of a cervical spine stabilization. Preserving the inferior portion of the C1 anterior arch should prevent instability. CASE DESCRIPTION: This is the first report in which the technique to remove the tip of the odontoid while preserving the C1 anterior arch is described by means of a three-dimensional (3D) endoscope. A 53-year-old man underwent a transnasal 3D endoscopic approach because of a complex CVJ malformation. The upper-medial portion of the C1 anterior arch was removed preserving its continuity, and the odontoidectomy was performed. After surgery, a dynamic X-ray scan showed no difference in CVJ motility in comparison with the preoperative one. CONCLUSIONS: The stereoscopic perception augmented the precision of the surgical gesture in the deep field. The importance of a 3D view relates to the depth of field, which a two-dimensional endoscopy cannot provide. This affects the preservation of the C1 anterior arch because of the presence of critical structures that are exposed to potential damage if not displayed. PMID- 26759738 TI - True mycotic aneurysm in a patient with gonadotropinoma after trans-sphenoidal surgery. AB - BACKGROUND: Immunosuppressive therapy, prolonged antibiotic use, and intrathecal injections are known risk factors for the development of invasive aspergillosis. Central nervous system (CNS) aspergillosis can manifest in many forms, including mycotic aneurysm formation. The majority of the mycotic aneurysms presents with subarachnoid hemorrhage after rupture and are associated with high mortality. Only 3 cases of true mycotic aneurysms have been reported following trans sphenoidal surgery. CASE DESCRIPTION: A 38-year-old man was admitted with nonfunctioning pituitary adenoma for which he underwent trans-sphenoidal surgery. Three weeks later, he presented with cerebrospinal fluid (CSF) rhinorrhea and meningitis. He was treated with intrathecal and intravenous antibiotics, stress dose of glucocorticoids, and lumbar drain. The defect in the sphenoid bone was closed endoscopically. After 3 weeks of therapy, he suddenly became unresponsive, and computed tomography of the head showed subarachnoid hemorrhage. He succumbed to illness on the next day, and a limited autopsy of the brain was performed. The autopsy revealed extensive subarachnoid hemorrhage and aneurysmal dilatation, thrombosis of the basilar artery (BA), multiple hemorrhagic infarcts in the midbrain, and pons. Histopathology of the BA revealed the loss of internal elastic lamina and septate hyphae with an acute angle branching on Grocott's methenamine silver stain, conforming to the morphology of Aspergillus. CONCLUSION: The possibility of intracranial fungal infection should be strongly considered in any patient receiving intrathecal antibiotics who fails to improve in 1-2 weeks, and frequent CSF culture for fungi should be performed to confirm the diagnosis. Since CSF culture has poor sensitivity in the diagnosis of fungal infections of CNS; empirical institution of antifungal therapy may be considered in this scenario. PMID- 26759739 TI - Alcohol-responsive Action Myoclonus of the Leg in Prostate Cancer: A Novel Paraneoplastic Syndrome? AB - BACKGROUND: Paraneoplastic movement disorders in prostate cancer are rare, and to our knowledge paraneoplastic myoclonus has not previously been reported. CASE REPORT: We report two men with adenocarcinoma of the prostate who developed isolated alcohol-responsive action myoclonus of one leg. Myoclonus was absent at rest but triggered by movement, standing, or walking. Evaluations excluded malignant invasion of the nervous system, and testing for commercial paraneoplastic antibodies in serum and cerebrospinal fluid were unrevealing. Both patients experienced significant improvement with alcohol, and sodium oxybate was used in one patient with good initial benefit. DISCUSSION: Alcohol-responsive leg myoclonus might be a novel paraneoplastic syndrome associated with prostate cancer. The nature of the syndrome and the source of the myoclonus are currently unknown. PMID- 26759740 TI - An empirical analysis of land property lawsuits and rainfalls. AB - This article using the database of Taiwanese land property lawsuits studies the economic effects of rainfalls on land property lawsuits during the period of Japanese colonial rule (1920-1941). The results obtained from basic ordinary least squares indicate that it shows no significant influences. However, an interesting result is that, when we adopt the approach of two stage least squares and use the variables of temperature and evaporation as the instrument variables of rainfalls, we find that there are highly significant influences on the lawsuits of land property. If 1 year comes with low average rainfalls, it means that the costs of productive inputs increase, because the available natural resource will decrease, and brings the distorted using of land property. PMID- 26759742 TI - Talc seromadesis in patients with chronic seroma formation after breast surgery. AB - BACKGROUND: Seroma formation, after breast surgery is a commonly seen complication with an incidence ranging from 10 to 85 %. In general, though seroma usually disappears within several weeks, some patients are troubled with chronic seroma. Seroma predisposes to infection leading to wound related complications and may also delay adjuvant chemoradiation, leading to less effective breast cancer treatment. CASE DESCRIPTION: A 52-years-old Dutch woman presenting with a pT3N1M0 infiltrating lobular breast carcinoma received neo-adjuvant chemotherapy, following modified radical mastectomy with sentinel node procedure. She suffered from chronic seroma formation, delaying adjuvant radiation therapy. We successfully performed talc seromadesis to eliminate seroma formation. During six month follow-up, no seroma was detected. DISCUSSION AND EVALUATION: Talc seromadesis after breast surgery is a rarely described in literature. In order to develop this technique further research aimed to evaluate its effectiveness on safety and possible later breast reconstruction must be carried out. CONCLUSION: Talc seromadesis may be a safe, cost effective and minimally invasive solution to treat chronic seroma after breast surgery. PMID- 26759741 TI - Hypoxia-induced inflammation and purinergic signaling in cross clamping the human aorta. AB - Open aortic surgery evokes a systemic inflammatory response and is associated with high morbidity and mortality. Purinergic signaling has been shown to be crucial for maintaining vascular integrity and attenuating inflammation related to hypoxia. The involvement of purinergic signaling in cross clamping of major human arteries is unknown. Our aim was to compare systemic inflammatory responses and hypoxia-induced purinergic signaling in patients undergoing either open infra renal abdominal aortic repair or infra-inguinal revascularization. Pre- and 24 h post-operative blood samples were gathered from 6 patients undergoing aortic clamping and 6 similar patients undergoing common femoral artery cross-clamping. Using Biorad MultipexTM 21- and 27-panels 48 different cytokines, chemokines and growth factors were analyzed, in addition to circulating levels of ATP, ADP, CD39, CD73 and HIF-1alpha, and compared between the groups. Several inflammatory cytokines were elevated from baseline levels after aortic clamping, but not after femoral cross clamping. Most pronoun rises were seen in IL-6 (667 %, P = 0.016) and HGF (760 %, P = 0.016). HIF-1alpha values showed a steady increase after clamping of either artery unless the subject underwent blood transfusion. Despite an adequate increase in HIF-1alpha CD39 and CD73 activity decreased significantly after aortic clamping (P = 0.047 and P = 0.016, respectively). Aortic clamping is associated with a clear and strong systemic inflammatory response and impaired repair mechanisms in terms of purinergic signaling. Patients undergoing open aorta repair could benefit from pre-operative medical therapy, which enhances CD73 expression. PMID- 26759743 TI - Vascular architecture of the monocot Cyperus involucratus Rottb. (Cyperaceae). AB - The arrangement of vascular bundles in the stems of monocots has been described repeatedly as "scattered." But to the trained eye it is clearly ordered as verified by the use of the R index of Clark and Evans. The arrangement of bundles in leaves and sclerenchyma bundles in stems are also ordered. An equation was developed for the probability distribution frequencies (pdf) for leaf intervein distances which curiously also fits for cell size in proliferating tissues. Another equation was developed for the pdf for intervein distances in stems which can also be applied to epidermal deriviatives such as stomata and trichomes. PMID- 26759744 TI - Supplemental effects of mixed ingredients and rice bran on the growth performance, survival and yield of Nile tilapia, Oreochromis niloticus reared in fertilized earthen ponds. AB - Unaffordability of commercial feeds to semi-intensive Nile tilapia, Oreochromis niloticus farmers has led to reliance on supplemental feeding and fertilization for nutrition of their fish without a scientific basis. This study compared the growth, survival, condition factor and yield performance of O. niloticus fed on mixed ingredients (MI) and rice bran alone (RB) diets reared in fertilized earthen ponds in small scale farmers' ponds. The study also determined phytoplankton composition, biomass and abundance in the experimental ponds. Quadruplicate ponds were stocked with O. niloticus and African sharptooth catfish, Clarias gariepinus at a stocking ratio of 1:3. The initial mean weights of O. niloticus and C. gariepinus were 14.62 +/- 0.61 and 20.34 +/- 1.44 g respectively. The fish were fed on MI and RB diets with protein content of 184.74 and 126.06 g kg(-1) respectively for 270 days. The results showed that growth performance, survival rate and condition factor of O. niloticus were not affected by either feeding with MI or RB diet (p > 0.05). Moreover, there were no significant differences obtained in phytoplankton biomass and abundance in O. niloticus ponds fed on the two diets (p > 0.05). Furthermore, feeding O. niloticus either on MI or RB diet did not affect the net and gross fish yields (p > 0.05). The study revealed that the use of either MI or RB diet does not significantly affect the performance of O. niloticus cultured in semi-intensive earthen ponds where natural food organisms are an integral part of the culture system. Rice bran could be used for semi-intensive culture of O. niloticus in fertilized ponds to boost the production based on its availability and low cost. PMID- 26759745 TI - The association between perception of health during pregnancy and the risk of cardiovascular disease: a prospective study. AB - There is some evidence that self-rated perceptions of health are predictive of objective health outcomes, including cardiovascular disease, and mortality. The objective of this study was to examine the prospective association between perceptions of health during pregnancy and cardiovascular risk factors of mothers 21 years after the pregnancy. Data used were from the Mater University Study of Pregnancy (MUSP), a community-based prospective birth cohort study begun in Brisbane, Australia, in 1981. Logistic regression analyses were conducted. Data were available for 3692 women. Women who perceived themselves as not having a straight forward pregnancy had twice the odds (adjusted OR 2.0, 95 % CI 1.1-3.8) of being diagnosed with heart disease 21 years after the pregnancy when compared with women with a straight forward pregnancy (event rate of 5.2 versus 2.6 %). Women who experienced complications (other than serious pregnancy complications) during their pregnancy were also at 30 % increased odds (adjusted OR 1.3, 95 % CI 1.0-1.6) of having hypertension 21 years later (event rate of 25.7 versus 20 %). As a whole, our study suggests that pregnant women who perceived that they had complications and did not have a straight forward pregnancy were likely to experience poorer cardiovascular outcomes 21 years after that pregnancy. PMID- 26759746 TI - Clinical impact of bacterial contamination of perfusion fluid in kidney transplantation. AB - Contamination of perfusion fluid (PF) could lead to serious infections in kidney transplant recipients. Preemptive therapy (PE-T) in case of yeast contamination of PF is mandatory. The usefulness of PE-T in presence of bacteria remains unclear. In this study we evaluated the incidence of PF bacterial contamination and the impact of PE-T on clinical outcome. Microbiological data of 290 PF and clinical data of the corresponding recipients collected in our hospital from January 2010 and December 2012 were analyzed. Recipients with bacterial contaminated PF (101) were divided in 3 groups: group 1 (n = 52) PE-T treated bacteria resistant to perioperative antibiotic prophylaxis (PAP), group 2 (n = 28) bacteria sensitive to PAP, group 3 (n = 21) PE-T-untreated bacteria resistant to PAP. Incidence of positive PF was 34.8 %, 50.4 % staphylococci, 9.9 % C. albicans. No significant differences in the rate of PF-related infections between the three groups were found. In conclusion, although PF contamination is frequent, the incidence of PF-related infections is very low. In addition, in this study PE-T did not help to reduce the rate of PF-related infection suggesting that a resonable reduction in the use of antibiotic terapy could be made. However, waiting for largest and prospective clinical trials to confirm our findings, a closely clinical and microbiologic monitoring of the recipient is highly recommended in case of PF contamination. PMID- 26759747 TI - Rifampin-warfarin interaction in a mitral valve replacement patient receiving rifampin for infective endocarditis: a case report. AB - INTRODUCTION: Warfarin therapy is associated with many drug interactions that may cause a significant alteration in its anticoagulant effect. Rifampin is a widely used antimicrobial that has major interactions with several medications including warfarin due to its strong P-glycoprotein and liver enzyme inducer activity especially on CYP2C9, CYP3A4, CYP1A2 and CYP2C19. PRESENTATION: We report a case of a 34-year-old Srilankan female chronically treated with warfarin for her mitral valve replacement. The patient developed infective endocarditis and was started on a 6-week treatment with rifampin along with other antibiotics. Warfarin dose was increased from 52.5 to 210 mg/week over the course of the rifampin therapy, however, the INR remained subtherapeutic throughout the whole period and reached 2.4 by the end of rifampin therapy. DISCUSSION AND EVALUATION: Anticoagulation management was challenging in the period following the end of rifampin therapy as well, and multiple dose adjustments starting with an increase and followed by reduction were required till she was stable on an 80 mg/week warfarin dose 5 weeks post-rifampin therapy. CONCLUSION: Our findings suggest the importance of close monitoring of warfarin therapy during and after the use of rifampin to minimize the risks of under and over-anticoagulation and improve the safety and efficacy of warfarin therapy. PMID- 26759748 TI - Intravoxel incoherent motion diffusion-weighted imaging in differentiating uterine fibroid from focal adenomyosis: initial results. AB - To evaluate the performance of intravoxel incoherent motion (IVIM)-diffusion weighted imaging (DWI) in differentiating uterine fibroids from focal adenomyosises. Twenty-five uterine fibroids and 21 focal adenomyosises prospectively underwent IVIM-DWI examination prior to surgery. Four parameters including apparent diffusion coefficient total values (ADCtot), true diffusion coefficient (D), pseudodiffusion coefficient (D*) and perfusion fraction (f) derived from IVIM-DWI images were separately calculated and compared across four groups. There was a statistically significant difference in IVIM-derived f parameter between fibroid and focal adenomyosis (p = 0.01) and control group (p = 0.02). Uterine fibroids gave higher coefficient of variation (CV) of all IVIM derived parameters than focal adenomyosises. IVIM-DWI could improve the sensitivity and specificity of detecting focal adenomyosis to 100 and 92.6 %, respectively. IVIM-f parameter could be potentially used to better distinguish uterine fibroid from focal adenomyosis. The higher CV of IVIM-derived parameters with acceptable range is often observed in the diseased group. PMID- 26759749 TI - Electrocardiographic changes caused by lithium intoxication in an elderly patient. AB - Lithium intoxication can cause serious cardiac toxicity and is associated with electrocardiogram (ECG) changes. This paper described a case of a 76-year-old man who was lithium intoxicated and showed a variety of ECG abnormalities including sinus bradycardia, rapid atrial fibrillation, second-degree atrioventricular block and T wave changes. We monitored his ECGs during the after 3 days consecutively. After hemodialysis, his ECG abnormalities partially eased along with his serum lithium concentration decreased. PMID- 26759750 TI - MAP3K1-targeting therapeutic artificial miRNA suppresses the growth and invasion of breast cancer in vivo and in vitro. AB - Recent investigations have highlighted that therapeutic artificial microRNAs could be promising candidates for cancer therapy through the modulation of tumor promoter or suppressor. MEK kinase 1 (MEKK1) is expressed by mitogen-activated kinase kinase kinase 1 (MAP3K1), an important kinase that links Ras activation to MAPK signaling. In the present study, we showed that synthetic MAP3K1-targeting artificial miRNA may provide considerable beneficial effects in the prevention of breast cancer growth and metastasis. We showed that MEKK1 was highly expressed in human breast cancer specimens, compared with adjacent normal tissues. Using a miRNA-expressing lentivirus system, we delivered a artificial miRNA (Map3k1 amiRNA) that targets MAP3K1 into 4T1 breast cancer cells and investigated the impact of MAP3K1-targeting miRNA on the growth and invasive behavior of breast cancer in vitro and in vivo. We found that overexpression of Map3k1 amiRNA led to impaired activities of p-ERK and p-p38. In addition, Map3k1 amiRNA induced marked proliferative impairment and invasive attenuation in breast cancer cells. However, Map3k1 amiRNA did not have evident influence on the apoptotic response of 4T1 cells. Moreover, using in vivo nude mice model, we identified that Map3k1 amiRNA attenuated tumor growth and lung metastasis of breast cancer cells. Taken together, our findings explicitly indicated that MEKK1 exerted important oncogenic property in breast cancer development, and MAP3K1-targeting artificial miRNA may provide promising therapeutic effects in the treatment of breast cancer. PMID- 26759751 TI - Usefulness of diffusion tensor imaging for the differentiation between low-fat angiomyolipoma and clear cell carcinoma of the kidney. AB - To investigate the value of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in differentiating clear-cell renal cell carcinoma (CCRCC) from low-fat renal angiomyolipomas (RAML), and to obtain the optimal b value. Fifty patients, including 30 cases of CCRCC and 20 cases of low-fat RAML, were retrospectively recruited to participate in this study. Before renal nephrectomy, all subjects underwent functional magnetic resonance imaging. For diffusion tensor imaging (DTI), a respiratory-triggered coronal echo planar imaging sequence was performed with three groups of different b values (0 and 400, 600, and 800). The ADC and FA of kidneys were analyzed and compared between different b values using analysis of variance. Receiver operation characteristic analysis was computed to assess the diagnostic performance of ADC and FA in differentiating low-fat RAML from CCRCC and to determine the optimal b values. With either CCRCC or low-fat RAML, the ADC values decreased with increased b values and significant differences were observed (F = 11.34, 23.15, P < 0.05), while the FA values were not significantly different (F = 0.28, 2.80, P > 0.05). The statistical differences in ADC, and the FA values for CCRCC and low-fat RAML were significantly different (P < 0.05). When the b value was 0.800 s/mm(2), the cutoff FA value for differentiating CCRCC from low-fat RAML was 0.254 * 10.3 mm(2)/s, and had a sensitivity of 100 %, and a specificity of 73.3 %. MR-DTI can be used to differentiate CCRCC from low-fat RAML. PMID- 26759752 TI - Dynamic contrast-enhanced breast MRI at 7T and 3T: an intra-individual comparison study. AB - The aim of this study is to compare the current state of lesion identification, the BI-RADS classification and the contrast-enhancement behavior at 7T and 3T breast MRI in the same patient group. Twenty-seven patients with thirty suspicious lesions were selected for this prospective study and underwent both 7T and 3T MRI. All examinations were rated by two radiologists (R1 and R2) independently on image quality, lesion identification and BI-RADS classification. We assessed sensitivity, specificity, NPV and PPV, observer agreement, lesion sizes, and contrast-enhancement-to-noise ratios (CENRs) of mass lesions. Fifteen of seventeen histopathological proven malignant lesions were detected at both field strengths. Image quality of the dynamic series was good at 7T, and excellent at 3T (P = 0.001 for R1 and P = 0.88 for R2). R1 found higher rates of specificity, NPV and PPV at 7T when compared to 3T, while R2 found the same results for sensitivity, specificity, NPV and PPV for both field strengths. The observers showed excellent agreement for BI-RADS categories at 7T (kappa = 0.86) and 3T (kappa = 0.93). CENRs were higher at 7T (P = 0.015). Lesion sizes were bigger at 7T according to R2 (P = 0.039). Our comparison study shows that 7T MRI allows BI-RADS conform analysis. Technical improvements, such as acquisition of T2w sequences and adjustment of B1+ field inhomogeneity, are still necessary to allow clinical use of 7T breast MRI. PMID- 26759753 TI - Impact of race and tumor subtype on second malignancy risk in women with breast cancer. AB - PURPOSE: Women with breast cancer are at increased risk of second malignancy (SM). However, the impact of race and the hormone receptor (HR) status of the primary breast tumor on risk of SM are not known. The purpose of this study is to analyze the incidence of SM in women with a history of breast cancer according to race and HR status. METHODS: In the surveillance, epidemiology, and end results database, multiple primary standardized incidence ratio sessions were used to compare the incidence of SM in women with a history breast cancer to the cancer incidence in the general population. Analyses of SM by age, race, and hormone receptor status were performed using the absolute excess risk (AER) and observed/expected (O/E) ratio. RESULTS: Younger black women (under the age of 50) were at greater risk of SM with an AER = 76.03 (O/E = 2.3, 95 % CI = 12.19-2.4) compared to younger white women who had an AER = 38.59 (O/E = 1.55, 95 % CI = 1.53-1.58). Older black women (50 years and older) had at an increased risk of SM with an AER = 42.26 (O/E = 1.3, 95 % CI = 1.26-1.34) compared to older white women who had an AER = 11.56 (O/E = 1.07, 95 % CI = 1.06-1.08). Second breast malignancy is the predominant SM in both black and white women. Women with hormone-receptor (HR)-negative breast cancer had higher risk of SMs with an AER = 43.53 (O/E = 1.41, 95 % CI = 1.38- 0.145-3.31) compared to women with HR-positive disease with an AER = 21.43 (O/E = 1.17, 95 % CI = 1.16-0.1.18). In HR-negative women, younger black women had an AER = 96.46 (O/E = 2.99, 95 % CI = 2.70-3.31), younger white women had an AER = 66 (O/E = 2.25, 95 % CI = 2.13-2.36), older black women had an AER = 58.58 (O/E = 1.45, 95 % CI = 1.34-1.57), and older white women had an AER = 20.88 (O/E = 1.14, 95 % CI = 1.11-1.18). CONCLUSIONS: Black breast cancer survivors and women with HR-negative breast cancer are at increased risk of SM, which deserves further evaluation to understand the biological and clinical basis for this increased risk. PMID- 26759754 TI - The effect of different methods of intravenous injection on glass particle contamination from ampules. AB - There have been many studies on glass particle contamination from glass ampules during the injection of glass ampules, but only the contamination from direct IV bolus injection has been measured. This research aimed to study the difference in glass particle contamination from ampules with different intravenous administration methods commonly used in clinical practice. Four methods were studied: IV bolus injection directly after immediate aspiration, IV bolus injection directly after 2 min' delayed aspiration, IV bolus injection directly after aspiration with a filter needle, and side shooting to an infusion set with an in-line filter. 45 ampules per method for a total of 180 ampules were used. The number and length of glass particles were measured using a slide scanner. Aspiration was performed without specifically using a slow aspiration method. The longest glass particle was observed in the immediate aspiration group. The side shooting group showed the lowest maximum number of glass particles per ampule. The side shooting group also showed the smallest number of glass particles, but it was statistically insignificant. Using a filter needle syringe and 2 min' delayed aspiration, which are frequently recommended to minimize contamination, may not be as effective as commonly believed, unless combined with a slow and low pressure aspiration method. Using a side shooting to an infusion set with an in line filter may minimize glass particle contamination from ampules even without a slow and low pressure aspiration method, but more evidence from a larger study is needed. PMID- 26759756 TI - Color reproduction and processing algorithm based on real-time mapping for endoscopic images. AB - In this paper, we present a real-time preprocessing algorithm for image enhancement for endoscopic images. A novel dictionary based color mapping algorithm is used for reproducing the color information from a theme image. The theme image is selected from a nearby anatomical location. A database of color endoscopy image for different location is prepared for this purpose. The color map is dynamic as its contents change with the change of the theme image. This method is used on low contrast grayscale white light images and raw narrow band images to highlight the vascular and mucosa structures and to colorize the images. It can also be applied to enhance the tone of color images. The statistic visual representation and universal image quality measures show that the proposed method can highlight the mucosa structure compared to other methods. The color similarity has been verified using Delta E color difference, structure similarity index, mean structure similarity index and structure and hue similarity. The color enhancement was measured using color enhancement factor that shows considerable improvements. The proposed algorithm has low and linear time complexity, which results in higher execution speed than other related works. PMID- 26759755 TI - Emergency laparoscopic ileo-colic resection and primary intracorporeal anastomosis for Crohn's acute ileitis with free perforation and faecal peritonitis: first ever reported laparoscopic treatment. AB - INTRODUCTION: Laparoscopy for abdominal surgical emergencies is gaining increasing acceptance given the spreading of advanced laparoscopic skills among modern surgeons, as it may allow at the same time an accurate diagnosis and appropriate treatment of acute abdomen. The use of the laparoscopic approach also in case of diffuse peritonitis is now becoming accepted provided hemodynamic stability, despite the common belief in the past decades that such severe condition represented an indication for conversion to open surgery or an immediate contraindication to continue laparoscopy. Crohn's Disease (CD) is a rare cause of acute abdomen and peritonitis, only a few cases of CD acute perforations are reported in the published literature; these cases have always been approached and treated by open laparotomy. CASE DESCRIPTION: We report on a case of a faecal peritonitis due to an acute perforation caused by a terminal ileitis in an undiagnosed CD. The patient underwent diagnostic laparoscopy followed by a laparoscopic ileo-colic resection and primary intracorporeal anastomosis, with a successful postoperative outcome. CONCLUSIONS: Complicated CD has to be considered within the possible causes of small bowel non-traumatic perforation. Emergency laparoscopy with resection and primary intra-corporeal anastomosis can be feasible and may be a safe and effective minimally invasive alternative to open surgery even in case of faecal peritonitis, in selected stable patients and in presence of appropriate laparoscopic colorectal surgical skills and experience. To the best of our knowledge the present experience is the first ever reported case managed with a totally laparoscopic extended ileocecal resection with intracorporeal anastomosis in case of acutely perforated CD and diffuse peritonitis. PMID- 26759757 TI - Ondansetron-related hemorrhagic posterior reversible encephalopathy syndrome (PRES) following gastric bypass. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a clinical radiographic syndrome formally recognized in 1996, which describes specific changes noted on neuroimaging thought to be related to impaired cerebral blood flow autoregulation and endothelial dysfunction. We report a case of PRES in the setting of increased ingestion of ondansetron; complicated by hemorrhagic transformation and refractory intracranial hypertension. We hypothesize an association of 5-HT3 antagonism and PRES. FINDINGS: This is a case study report; with review of previously published literature through PubMed search. We describe the case of a 25 year old man following bariatric surgery who increased his ingestion of ondansetron, taking up to 40 tablets/day due to excessive nausea and vomiting. The patient was hospitalized for progressively more severe headache of 1 week's duration. Computed tomography (CT) revealed bilateral cerebral edema in the parietal and occipital lobes in the setting of elevated blood pressure (BP). Three days into his admission, following improvement in his BP with oral anti hypertensive but continued use of the ondansetron, the patient developed near complete blindness. CT head imaging revealed progression of the posterior cerebral edema and intraparenchymal hemorrhage. He was admitted to our ICU and despite supportive treatment, his neurological examination worsened while CT head imaging findings remained stable. Invasive multimodality monitoring revealed elevated intracranial pressure. The patient was aggressively treated and after a prolonged hospitalization and rehabilitation course, made a significant recovery. CONCLUSION: This case highlights a very rare potential neurological complication of ondansetron, a commonly used medication. We hypothesize an underlying association between PRES and 5-HT3 antagonism, via the latter's potential role in endothelial dysfunction. Prompt recognition and treatment of PRES is essential, in order to prevent secondary cerebral injury and the associated potentially grave consequences. PMID- 26759758 TI - Stabilization of zwitterionic versus canonical proline by water molecules. AB - At physiological conditions, a majority of biomolecules (e.g., amino acids, peptides and proteins) exist predominantly in the zwitterionic form that usually decides the biological functions. However, zwitterionic amino acids are not geometrically stable in gas phase and this seriously hampers the understanding of their structures, properties and biological functions. To this end, one of the recent research focuses is to demonstrate the stabilization effects of zwitterionic amino acids. Relative stabilities of canonical conformers are dependent on water contents, while zwitterionic stability improves monotonously and pronouncedly with increase of water contents. We find that one water molecule can render zwitterionic proline geometrically stable, and stabilities of different zwitterionic amino acids increase as glycine = 0.05) in migratory levels of each individual compound within the same brand for both BTEX and phthalates. When compared among different brands, BTEX levels indicated significant differences (p <= 0.05), while phthalate levels were observed to not be significantly different (p >= 0.05). A significant difference was also observed (p <= 0.05) among the migratory levels of compounds under each test condition evaluated as factors affecting the migratory level. Furthermore, the solvent based colorants added to color the latex were found to be the source of BTEX and phthalates in the NRL balloons. PMID- 26759761 TI - Perspective of trust towards e-government initiatives in Sri Lanka. AB - In this article, the author focuses on understanding the antecedent conditions of trustworthiness of the users towards the use of e-government services and attempt to propose a model to assess the influences of the trustworthiness for the use of e-government services in Sri Lanka. Trustworthiness was considered as an additional construct along with the technology acceptance model (TAM) constructs. Structural equation modeling (SEM) approach was used to test the proposed model by utilizing the responses of 898 citizens. SEM results reveal that the proposed model is acceptable showing goodness of fit. The proposed model tested by SEM is appropriate to assess what extend trustworthiness of the users influence for the use of e-government services and this would be worth to pay more attention on trust when develop and implement e-government initiatives. PMID- 26759760 TI - The prevalence of lymphoedema in women who attended an information and exercise class to reduce the risk of breast cancer-related upper limb lymphoedema. AB - Breast cancer-related upper limb lymphoedema (BCRL) affects approximately 20 % of women undergoing axillary intervention. Women who attended a "reducing your risk of lymphoedema" class, including exercise instruction, anecdotally reported positive BCRL outcomes. The aim of this study was to examine BCRL outcomes and perceived benefit for attendees at a "reducing your risk of lymphoedema" class between 2000 and 2005. A cross-sectional study was conducted in two parts: (1) self-report questionnaire regarding lymphoedema status and benefit received from class and exercise programme; (2) clinical evaluation and objective measurement to confirm BCRL. 46 women completed questionnaires; 40 continued to clinical evaluation and objective measurement. BCRL prevalence defined as >=10 % excess limb volume was only 5 %, although clinician judgement identified 23 % with arm lymphoedema and 8 % with lymphoedema limited to the hand. Clinician judgement correlated highly with patient self-report (Kappa = 0.833, p = 0.000). All women found the class beneficial, reporting increased confidence to return to normal life and a wide range of activities/exercise. We conclude that prevalence of BCRL should be determined by both clinical judgement and objective measurement to avoid underestimation. The benefit of group education with a lymphoedema expert and of exercise instruction should be further explored, and the potential for exercise to reduce BCRL prevalence should be examined. PMID- 26759762 TI - Fibrin glue as a protective tool for microanastomoses in limb reconstructive surgery. AB - AIM: Fibrin glue becomes a more and more routinely used tool for stabilization of microanastomoses and nerve repair. This paper summarizes the technical properties and advantages of its use in a wide variety of microsurgical contexts, and includes an exemplary limb reconstructive case. PATIENTS AND METHODS: A total of 131 patients who had undergone elective and emergency microsurgery mainly of the limbs were retrospectively analyzed, as was the use of free flaps. RESULTS: The use of fibrin glue allows for proper positioning of anastomoses and repaired nerves. No torsion of the pedicle could be seen. The flap survival rated >94%. The fibrin glue could stay in place in >99%. In the rare case of revision, the fibrin glue could easily be removed without damaging the region of the microanastomosis. CONCLUSION: Fibrin glue should not be used to repair insufficient, i.e., leaking anastomoses, but it does protect the site of anastomosis from tissue and fluid pressure. It prevents the pedickle from torsion and its use facilitates relocation of the microanastomoses in cases of revision surgery. PMID- 26759764 TI - Technique of Arthroscopically Assisted Transtrochanteric Drilling for Femoral Head Chondral Defects. AB - Microfracture is a marrow-stimulation technique in which damaged cartilage is drilled or punched, perforating the subchondral bone and generating a blood clot within the defect that matures into fibrocartilage. Microfracture for the treatment of small cartilage defects of the hip has shown good results. Arthroscopic procedures are less invasive than open procedures and have a reduced incidence of complications such as infection or avascular necrosis of the femoral head. Furthermore, arthroscopic procedures allow for a shorter recovery time, resulting in not only lower overall treatment costs but also higher patient satisfaction. Medial and parafoveal cartilage defects of the femoral head can be challenging to effectively microfracture using standard arthroscopy portals because of the acute angles required for instrument manipulation. This report describes a technique for microfracturing these challenging areas of the femoral head using a 2.7-mm K-wire and drilling in a transtrochanteric direction using arthroscopic and imaging guidance to target the area of chondral damage. PMID- 26759765 TI - Arthroscopic-Assisted Acromioclavicular Joint Reconstruction Using the TightRope Device With Allograft Augmentation: Surgical Technique. AB - Surgical management of acromioclavicular (AC) joint separations remains challenging, especially in the revision setting. Most commonly, Rockwood type I and II injuries are managed nonoperatively whereas type IV, V, and VI injuries are managed with surgery. Type III separations are more controversial, with evidence supporting both nonoperative and operative treatment options. Multiple different arthroscopic techniques have been described; however, there is no current gold standard. AC joint reconstruction with the TightRope device (Arthrex, Naples, FL) with the patient in the lateral decubitus position is a method of restoring joint stability that allows for a minimally invasive, low profile fixation construct using a single drill hole through the clavicle. Allograft augmentation of this fixation construct helps to eliminate the stress risers potentially created by this device while increasing overall repair construct stability. The purpose of this article is to describe the surgical technique for arthroscopic AC joint reconstruction using a TightRope device with allograft augmentation. PMID- 26759766 TI - Arthroscopic Management of a Posterior Femoral Condyle (Hoffa) Fracture: Surgical Technique. AB - Unicondylar fractures of the lower end of the femur are uncommon injuries that usually occur in the sagittal plane. A coronal (tangential) plane fracture, first described by Hoffa in 1904, is unusual. It is an intrinsically unstable type of intra-articular fracture that warrants operative fixation, usually by an open technique. A simple method for the treatment of lateral femoral condyle coronal fractures with arthroscopic-assisted reduction and internal fixation by cannulated screws is reported. Managing fractures of the posterior femoral condyle with arthroscopic reduction and fixation with cannulated screws is simple and effective and could be reproducible with good results and a good prognosis. PMID- 26759767 TI - Arthroscopic Transtendinous Double-Pulley Remplissage Technique in the Beach Chair Position for Large Hill-Sachs Lesions. AB - Hill-Sachs lesions are a common finding in patients with glenohumeral instability. There have been numerous methods described for addressing Hill-Sachs deformity. One popular method includes transferring a portion of the infraspinatus muscle into the posterior-superior defect (remplissage) to prevent the lesion from engaging and the resultant instability. We present a method of arthroscopic remplissage whereby the lesion is addressed through transtendinous insertion of arthroscopic anchors. Once 2 anchors have been inserted, 1 limb of each suture is tied to the other anchor, the so-called pulley repair technique. This can be performed either under direct visualization in the subacromial space or blindly while the surgeon is viewing from the articular side. Once both limbs have been tied, the infraspinatus tendon nicely spans the defect, and there has been minimal morbidity to the tendon itself. We have found this method to be useful for addressing a large Hill-Sachs deformity. PMID- 26759768 TI - Use of 3-Dimensional Printing for Preoperative Planning in the Treatment of Recurrent Anterior Shoulder Instability. AB - Recurrent anterior shoulder instability often results from large bony Bankart or Hill-Sachs lesions. Preoperative imaging is essential in guiding our surgical management of patients with these conditions. However, we are often limited to making an attempt to interpret a 3-dimensional (3D) structure using conventional 2-dimensional imaging. In cases in which complex anatomy or bony defects are encountered, this type of imaging is often inadequate. We used 3D printing to produce a solid 3D model of a glenohumeral joint from a young patient with recurrent anterior shoulder instability and complex Bankart and Hill-Sachs lesions. The 3D model from our patient was used in the preoperative planning stages of an arthroscopic Bankart repair and remplissage to determine the depth of the Hill-Sachs lesion and the degree of abduction and external rotation at which the Hill-Sachs lesion engaged. PMID- 26759769 TI - Capsular Suspension Technique for Hip Arthroscopy. AB - Hip arthroscopy has recently become a common procedure to treat central and peripheral hip pathology. Capsulotomies are necessary in these procedures, and negotiating adequate visualization, as well as capsular preservation, is a challenge. We describe a capsular suspension technique that allows for adequate visualization of the central and peripheral compartments while facilitating preservation of the native hip capsule. This technique eliminates the need for additional personnel for retraction, potentially decreases iatrogenic hip injury, eliminates the need for excessive capsular debridement, and allows for capsular closure under minimal tension. PMID- 26759770 TI - Arthroscopic Labral Reconstruction of the Hip Using Semitendinosus Allograft. AB - The labrum of the hip is recognized as being important to the stability of the hip and a major cause of hip pain. Damage to the labrum may result in increased joint stress and articular damage. Labral damage is often treated through various methods, among them simple stitch repair, base refixation, and debridement. Labral reconstruction becomes necessary when the labrum is too damaged to salvage, which renders labral repair improbable and labral debridement ineffective. In contrast to other methods that have been described for this treatment, our technique uses a semitendinosus allograft as a graft source, allowing for arthroscopic hip labral reconstruction. This technique has many advantages and is easily reproducible. It has shown promising results in patients with labral damage. The purpose of this article is to detail the step-by-step surgical technique of labral reconstruction using a semitendinosus allograft, in addition to the indications, pearls, and pitfalls of the technique. PMID- 26759771 TI - Anatomic Single-Bundle Anterior Cruciate Ligament Reconstruction With Remnant Preservation Using Outside-In Technique. AB - This report describes a modified anatomic single-bundle anterior cruciate ligament (ACL) reconstruction technique using the FlipCutter guide pin (Arthrex, Naples, FL) as a retrograde drill and a cortical suspensory fixation device (TightRope; Arthrex) with an adjustable graft loop length. Preservation of the ACL remnant as a biological sleeve for the graft is an important issue from the viewpoints of acceleration of revascularization and ligamentization, preservation of the proprioceptive nerve fibers, enhancement of the biological environment for healing, and maintenance of the anchor point at the native tibial attachment, in addition to yielding a lower incidence of tibial bone tunnel enlargement. The goal of our technique is to obtain some advantages of the remnant-preserving technique through an anatomic single-bundle ACL reconstruction, which is performed to minimize damage to the ACL tibial remnant. PMID- 26759772 TI - Dry Arthroscopy of the Elbow. AB - Dry arthroscopy is attractive because it affords an unsurpassed clarity of view and minimizes swelling. The elbow is a challenging joint to assess arthroscopically; however, dry arthroscopy has some particular benefits in the elbow. The primary benefit is the quality of the tissue definition, but dry arthroscopy also increases the working time for surgery by reducing swelling and results in less postoperative discomfort for the patient. With dry arthroscopy, all joint surfaces are covered in synovial fluid, which reflects light, to provide a clearer image of the joint surfaces and depth of field. The air-fluid interface provides an uninterrupted appreciation of the synovial recesses and tissue perfusion. This article describes the technique and indications for dry elbow arthroscopy, which will allow other surgeons to reap the benefits of dry arthroscopy without the need for special equipment or changes in their basic technique. PMID- 26759773 TI - A Simple Traction Assembly for Shoulder Arthroscopy in Lateral Decubitus Position: A Cost-Effective Alternative. AB - The lateral decubitus position shoulder arthroscopy requires traction for positioning, as well as distraction. We describe a cost-effective lateral decubitus traction assembly for shoulder arthroscopy. PMID- 26759774 TI - Bridging Suture Repair for Acetabular Chondral Carpet Delamination. AB - Acetabular chondral carpet delamination is a frequent finding at hip arthroscopy. The cartilage is macroscopically normal but deboned from the subchondral bone, without a disruption at the chondrolabral junction. Arthroscopic anatomic repair of delaminated cartilage is challenging. We propose that a combination of microfracture and use of stitches to press the delaminated cartilage against the subchondral bone using a suture limb offers an effective method to provide an environment for cartilage repair. This article describes the technique of bridging suture repair for carpet delamination in detail; the technique enables the surgeon to stabilize the delaminated acetabular cartilage. Intra-articular soft anchors and an acetabular rim knotless anchor footprint provide a stable repair for delaminated cartilage. This technique is especially helpful in cases with acetabular cartilage carpet delamination. PMID- 26759775 TI - Modified Technique of Tibial Tuberosity Transfer. AB - Tibial tuberosity transfer is a well-established procedure in the treatment of patellar instability and in selected cases of anterior knee pain. Several techniques have been advocated in the literature. Some of the common complications associated with this procedure have been pain and discomfort due to prominent screw heads, necessitating their removal; nonunion and delayed union of the osteotomy; and failure of fixation. Tibial fractures have also been reported in some case reports. We present our technique of tibial tuberosity transfer using two 4-mm cannulated screws for stabilization of the tuberosity fragment. We have used this technique either for isolated tibial tuberosity transfer or as part of a combined procedure along with medial patellofemoral ligament reconstruction in treating patellar instability. Using this technique, we have encountered no patients with wound problems, nonunion, delayed union, or loss of fixation and only 1 patient with a metal work problem needing a second procedure for its removal. We attribute our good outcomes to the preservation of the soft tissue attachments to the tuberosity fragment; minimal soft-tissue dissection, which allows rapid bony consolidation of the osteotomy, which in turn allows accelerated rehabilitation; and the use of 4-mm cannulated screws for fixation of the osteotomy, minimizing the potential for metal work problems. PMID- 26759776 TI - Endoscopic Sciatic Neurolysis. AB - Despite remaining a controversial diagnosis, piriformis syndrome continues to affect patients' quality of life with pain, sitting discomfort, and exercise intolerance. Open sciatic neurolysis has been noted by the senior author to often only bring temporary relief of the symptoms, with the recurrence presumably due to postoperative scar tissue. Minimally invasive techniques used to decompress the nerve have met with mixed results. This article describes a step-by-step surgical technique designed to maximize patient safety, as well as surgeon orientation, and achieve a thorough neurolysis. Preoperative findings suggestive of piriformis syndrome are described and include retro-trochanteric pain, sciatica-like leg pain, and paresthesias, as well as a positive response to computed tomography-guided injection of dilute ropivacaine hydrochloride and 40 mg of triamcinolone. The operation is performed with the patient in the lateral decubitus position through 2 portals 6 to 8 cm apart, allowing for good triangulation. Dissection is undertaken with a combination of radiofrequency and a laparoscopic peanut, with the assistance of a vascular sling to control the sciatic nerve. Encouraging results have been achieved, and with increasing interest in this procedure, a step-by-step technical description with an accompanying video may prove useful for other experienced hip arthroscopists. Pearls and pitfalls are discussed. PMID- 26759777 TI - Arthroscopically Assisted Latissimus Dorsi Tendon Transfer in Beach-Chair Position. AB - Irreparable rotator cuff tears remain a surgical problem. The open technique of latissimus dorsi (LD) tendon transfer to "replace" the irreparable rotator cuff is already well known. The aim of this article is to present a modified arthroscopically assisted LD tendon transfer technique. This technique was adopted to operate on patients in the beach-chair position with several improvements in tendon harvesting and fixation. It can be divided into 6 steps, and only 1 step-LD muscle and tendon release-is performed open. The advantages of the arthroscopic procedure are sparing of the deltoid muscle, the possibility of repairing the subscapularis tendon, and the ability to visualize structures at risk while performing tendon harvesting (radial nerve) and passing into the subacromial space (axillary nerve). It is performed in a similar manner to standard rotator cuff surgery-the beach-chair position does not need any modification, and no sophisticated equipment for either the open or arthroscopic part of the procedure is necessary. Nevertheless, this is a challenging procedure and should only be attempted after training, as well as extensive practice. PMID- 26759778 TI - Endoscopic Surgical Removal of Calcific Tendinitis of the Rectus Femoris: Surgical Technique. AB - Calcific tendinitis of the rectus femoris (CTRF) is an under-recognized condition and, because of its self-limiting nature, is usually managed conservatively. Nevertheless, when nonsurgical therapy fails, further invasive alternatives are required. At this point, arthroscopic resection provides a minimally invasive and interesting alternative to open surgery. The aim of this work is to report the surgical technique of endoscopic surgical removal in patients with CTRF at the periarticular region of the hip joint. Endoscopic surgical removal of CTRF was performed without traction following anatomic landmarks for hip arthroscopy portal placement. We used the anterolateral portal and the proximal accessory portal to obtain access to the lesion. A shaver and radiofrequency device are useful tools to depict the calcific lesion while the whole resection is performed with a 5-mm round burr. Intraoperative fluoroscopy control during the entire procedure is essential. Endoscopic treatment of calcific tendinitis of the hip is a valuable technique in the treatment of patients who do not respond to conservative treatment. PMID- 26759779 TI - Arthroscopic Marginal Resection of a Lipoma of the Supraspinatus Muscle in the Subacromial Space. AB - Subacromial impingement syndrome is a common cause of shoulder pain in young adults and seniors at present. The etiology of this syndrome is associated with several shoulder disorders, most related to aging, overhead activities, and overuse. The subacromial space is well circumscribed and limited in size, and soft-tissue growing lesions, such as tumors, can endanger the normal function of the shoulder girdle. We present a case of shoulder impingement syndrome caused by an intramuscular lipoma of the supraspinatus muscle in the subacromial space in a 50-year-old male bank manager. Radiographs, magnetic resonance imaging, and a computed tomography scan showed a well-circumscribed soft-tissue tumor at the supraspinatus-musculotendinous junction. It was arthroscopically inspected and dissected and complete marginal excision was performed through a conventional augmented anterolateral portal, avoiding the need to open the trapezius fascia or perform an acromial osteotomy. Microscopic study showed a benign lipoma, and the shoulder function of the patient was fully recovered after a rehabilitation period of 4 months. This less invasive technique shows similar results to conventional open surgery. PMID- 26759780 TI - An Arthroscopic Technique for Long Head of Biceps Tenodesis With Double Knotless Screw. AB - Tenodesis of the long head of the biceps (LHB) is a frequently performed procedure during shoulder arthroscopy for the treatment of degenerative, traumatic, or inflammatory lesions of the LHB tendon. Arthroscopic techniques for LHB tenodesis using knotless screw techniques offer the advantage of circumventing the need for arthroscopic knot tying. In 2012 Song and Williams described a novel tenodesis technique that does not require any knot-tying procedures by using a knotless anchor. However, a single-anchor configuration may not offer adequate stabilization of the LHB tendon. Therefore we propose a modified method that uses a double knotless anchor that offers advantages over the single knotless anchor, such as an increase in the contact area between the tendon and bone to facilitate tendon-to-bone healing and strengthening of the tenodesis construct. PMID- 26759781 TI - Endoscopic Resection of Gouty Tophus of the Patellar Tendon. AB - Tophaceous deposition of tendon can result in spontaneous patellar tendon rupture. Surgical therapy may be needed to control symptoms and prevent tendon rupture. Open debridement of the lesion requires a lengthy incision over the lesion; this may result in symptomatic scar adhesion of the patellar tendon or an unhealed wound with persistent tophaceous discharge. Moreover, the other part of the patellar tendon cannot be examined through the incision. We describe a technique for endoscopic resection of a gouty tophus of the patellar tendon. It has the advantage of small incisions away from the lesion and tendon and minimizes wound problems. The whole patellar tendon can be examined endoscopically. PMID- 26759782 TI - Arthroscopic Biceps Tenodesis From a Superior Viewing Portal in the Shoulder. AB - The purpose of this report is to describe our modification of the Verma-Trenhaile biceps tenodesis technique using a superior viewing portal that allows placement of the tenodesis site at the top of the pectoralis major tendon with interference screw fixation. The advantages of this technique include the following: (1) There is no need to exteriorize the tendon through the skin. (2) Viewing from superiorly allows a panoramic view of the groove all the way to the pectoralis major tendon insertion. (3) This panoramic view allows a more complete view of the biceps down to the muscle-tendon junction beneath the pectoralis major tendon. (4) The improved visualization permits the drill hole to be contained within the constraints of the groove. Short-term follow-up shows favorable results clinically, and no major complications have been associated with this technique. PMID- 26759783 TI - Basic Hip Arthroscopy: Supine Patient Positioning and Dynamic Fluoroscopic Evaluation. AB - Hip arthroscopy serves as both a diagnostic and therapeutic tool for the management of various conditions that afflict the hip. This article reviews the basics of hip arthroscopy by demonstrating supine patient positioning, fluoroscopic evaluation of the hip under anesthesia, and sterile preparation and draping. Careful attention to detail during the operating theater setup ensures adequate access to the various compartments of the hip to facilitate the diagnosis of disease and treatment with minimally invasive arthroscopy. Furthermore, having a routine method for patient positioning and operative setup improves patient safety, as well as operative efficiency, as the operative team becomes familiar with the surgeon's standard approach to hip arthroscopy cases. PMID- 26759784 TI - Cortical thinning in the anterior cingulate cortex predicts multiple sclerosis patients' fluency performance in a lateralised manner. AB - Cognitive impairment is as an important feature of Multiple Sclerosis (MS), and might be even more relevant to patients than mobility restrictions. Compared to the multitude of studies investigating memory deficits or basic cognitive slowing, executive dysfunction is a rarely studied cognitive domain in MS, and its neural correlates remain largely unexplored. Even rarer are topological studies on specific cognitive functions in MS. Here we used several structural MRI parameters - including cortical thinning and T2 lesion load - to investigate neural correlates of executive dysfunction, both on a global and a regional level by means of voxel- and vertex-wise analyses. Forty-eight patients with relapsing remitting MS and 48 healthy controls participated in the study. Five executive functions were assessed, i.e. verbal and figural fluency, working memory, interference control and set shifting. Patients scored lower than controls in verbal and figural fluency only, and displayed widespread cortical thinning. On a global level, cortical thickness independently predicted verbal fluency performance, when controlling for lesion volume and central brain atrophy estimates. On a regional level, cortical thinning in the anterior cingulate region correlated with deficits in verbal and figural fluency and did so in a lateralised manner: Left-sided thinning was related to reduced verbal - but not figural - fluency, whereas the opposite pattern was observed for right-sided thinning. We conclude that executive dysfunction in MS patients can specifically affect verbal and figural fluency. The observed lateralised clinico-anatomical correlation has previously been described in brain-damaged patients with large focal lesions only, for example after stroke. Based on focal grey matter atrophy, we here show for the first time comparable lateralised findings in a white matter disease with widespread pathology. PMID- 26759786 TI - Studying depression using imaging and machine learning methods. AB - Depression is a complex clinical entity that can pose challenges for clinicians regarding both accurate diagnosis and effective timely treatment. These challenges have prompted the development of multiple machine learning methods to help improve the management of this disease. These methods utilize anatomical and physiological data acquired from neuroimaging to create models that can identify depressed patients vs. non-depressed patients and predict treatment outcomes. This article (1) presents a background on depression, imaging, and machine learning methodologies; (2) reviews methodologies of past studies that have used imaging and machine learning to study depression; and (3) suggests directions for future depression-related studies. PMID- 26759787 TI - Topography of acute stroke in a sample of 439 right brain damaged patients. AB - Knowledge of the typical lesion topography and volumetry is important for clinical stroke diagnosis as well as for anatomo-behavioral lesion mapping analyses. Here we used modern lesion analysis techniques to examine the naturally occurring lesion patterns caused by ischemic and by hemorrhagic infarcts in a large, representative acute stroke patient sample. Acute MR and CT imaging of 439 consecutively admitted right-hemispheric stroke patients from a well-defined catchment area suffering from ischemia (n = 367) or hemorrhage (n = 72) were normalized and mapped in reference to stereotaxic anatomical atlases. For ischemic infarcts, highest frequencies of stroke were observed in the insula, putamen, operculum and superior temporal cortex, as well as the inferior and superior occipito-frontal fascicles, superior longitudinal fascicle, uncinate fascicle, and the acoustic radiation. The maximum overlay of hemorrhages was located more posteriorly and more medially, involving posterior areas of the insula, Heschl's gyrus, and putamen. Lesion size was largest in frontal and anterior areas and lowest in subcortical and posterior areas. The large and unbiased sample of stroke patients used in the present study accumulated the different sub-patterns to identify the global topographic and volumetric pattern of right hemisphere stroke in humans. PMID- 26759785 TI - Placebo analgesia: Self-report measures and preliminary evidence of cortical dopamine release associated with placebo response. AB - Placebo analgesia is measured by self-report, yet current, expected, and recalled efficacy may be differentially related to brain function. Here we used a human thermal pain model to compare self-reports of expected, concurrent, and recalled efficacy of a topical placebo analgesic, and tested associations of the three measures of efficacy with changes in dopamine D2/D3 receptor availability in brain using [(18)F]fallypride with positron emission tomography (PET). Participants (15 healthy women) were assessed on three test days. The first test day included a laboratory visit, during which the temperature needed to evoke consistent pain was determined, placebo analgesia was induced via verbal and experience-based expectation, and the placebo response was measured. On two subsequent test days, PET scans were performed in Control and Placebo conditions, respectively, in counterbalanced order. During Visit 1, concurrent and recalled placebo efficacy were unrelated; during the Placebo PET visit, expected and recalled efficacy were highly correlated (rho = 0.68, p = 0.005), but concurrent efficacy was unrelated to expected or recalled efficacy. Region of interest analysis revealed dopamine D2/D3 receptor availability was lower in left ventrolateral prefrontal cortex in the Placebo condition (p < 0.001, uncorrected), and greater change in this measure was associated with higher levels of recalled analgesic efficacy (rho = 0.58, p = 0.02). These preliminary findings underscore the need to consider how self-reported symptom improvement is assessed in clinical trials of analgesics and suggest that dopaminergic activity in the ventrolateral prefrontal cortex may promote recalled efficacy of placebo. PMID- 26759789 TI - Separate neural systems support representations for actions and objects during narrative speech in post-stroke aphasia. AB - BACKGROUND: Representations of objects and actions in everyday speech are usually materialized as nouns and verbs, two grammatical classes that constitute the core elements of language. Given their very distinct roles in singling out objects (nouns) or referring to transformative actions (verbs), they likely rely on distinct brain circuits. METHOD: We tested this hypothesis by conducting network based lesion-symptom mapping in 38 patients with chronic stroke to the left hemisphere. We reconstructed the individual brain connectomes from probabilistic tractography applied to magnetic resonance imaging and obtained measures of production of words referring to objects and actions from narrative discourse elicited by picture naming tasks. RESULTS: Words for actions were associated with a frontal network strongly engaging structures involved in motor control and programming. Words for objects, instead, were related to a posterior network spreading across the occipital, posterior inferior temporal, and parietal regions, likely related with visual processing and imagery, object recognition, and spatial attention/scanning. Thus, each of these networks engaged brain areas typically involved in cognitive and sensorimotor experiences equivalent to the function served by each grammatical class (e.g. motor areas for verbs, perception areas for nouns). CONCLUSIONS: The finding that the two major grammatical classes in human speech rely on two dissociable networks has both important theoretical implications for the neurobiology of language and clinical implications for the assessment and potential rehabilitation and treatment of patients with chronic aphasia due to stroke. PMID- 26759788 TI - Frontoparietal white matter integrity predicts haptic performance in chronic stroke. AB - Frontoparietal white matter supports information transfer between brain areas involved in complex haptic tasks such as somatosensory discrimination. The purpose of this study was to gain an understanding of the relationship between microstructural integrity of frontoparietal network white matter and haptic performance in persons with chronic stroke and to compare frontoparietal network integrity in participants with stroke and age matched control participants. Nineteen individuals with stroke and 16 controls participated. Haptic performance was quantified using the Hand Active Sensation Test (HASTe), an 18-item match-to sample test of weight and texture discrimination. Three tesla MRI was used to obtain diffusion-weighted and high-resolution anatomical images of the whole brain. Probabilistic tractography was used to define 10 frontoparietal tracts total; Four intrahemispheric tracts measured bilaterally 1) thalamus to primary somatosensory cortex (T-S1), 2) thalamus to primary motor cortex (T-M1), 3) primary to secondary somatosensory cortex (S1 to SII) and 4) primary somatosensory cortex to middle frontal gyrus (S1 to MFG) and, 2 interhemispheric tracts; S1-S1 and precuneus interhemispheric. A control tract outside the network, the cuneus interhemispheric tract, was also examined. The diffusion metrics fractional anisotropy (FA), mean diffusivity (MD), axial (AD) and radial diffusivity (RD) were quantified for each tract. Diminished FA and elevated MD values are associated with poorer white matter integrity in chronic stroke. Nine of 10 tracts quantified in the frontoparietal network had diminished structural integrity poststroke compared to the controls. The precuneus interhemispheric tract was not significantly different between groups. Principle component analysis across all frontoparietal white matter tract MD values indicated a single factor explained 47% and 57% of the variance in tract mean diffusivity in stroke and control groups respectively. Age strongly correlated with the shared variance across tracts in the control, but not in the poststroke participants. A moderate to good relationship was found between ipsilesional T-M1 MD and affected hand HASTe score (r = - 0.62, p = 0.006) and less affected hand HASTe score (r = 0.53, p = 0.022). Regression analysis revealed approximately 90% of the variance in affected hand HASTe score was predicted by the white matter integrity in the frontoparietal network (as indexed by MD) in poststroke participants while 87% of the variance in HASTe score was predicted in control participants. This study demonstrates the importance of frontoparietal white matter in mediating haptic performance and specifically identifies that T-M1 and precuneus interhemispheric tracts may be appropriate targets for piloting rehabilitation interventions, such as noninvasive brain stimulation, when the goal is to improve poststroke haptic performance. PMID- 26759790 TI - Task-independent effects are potential confounders in longitudinal imaging studies of learning in schizophrenia. AB - Learning impairment is a core deficit in schizophrenia that impacts on real-world functioning and yet, elucidating its underlying neural basis remains a challenge. A key issue when interpreting learning-task experiments is that task-independent changes may confound interpretation of task-related signal changes in neuroimaging studies. The nature of these task-independent changes in schizophrenia is unknown. Therefore, we examined task-independent "time effects" in a group of participants with schizophrenia contrasted with healthy participants in a longitudinal fMRI learning-experiment designed to allow for examination of non-specific effects of time. Flanking the learning portions of the experiment with a task-of-no-interest allowed us to extract task-independent BOLD changes. Task-independent effects occurred in both groups, but were more robust in the schizophrenia group. There was a significant interaction effect between group and time in a distributed activity pattern that included inferior and superior temporal regions, frontal areas (left anterior insula and superior medial gyri), and parietal areas (posterior cingulate cortices and precuneus). This pattern showed task-independent linear decrease in BOLD amplitude over the two scanning sessions for the schizophrenia group, but showed either opposite effect or no activity changes for the control group. There was a trend towards a correlation between task-independent effects and the presence of more negative symptoms in the schizophrenia group. The strong interaction between group and time suggests that both the scanning experience as a whole and the transition between task-types evokes a different response in persons with schizophrenia and may confound interpretation of learning-related longitudinal imaging experiments if not explicitly considered. PMID- 26759792 TI - Acquired and introduced macroparasites of the invasive Cuban treefrog, Osteopilus septentrionalis. AB - Because shifts in host-parasite relationships can alter host populations, attention should be given to the parasites that introduced species take with them or acquire in their introduced range. The Cuban treefrog, Osteopilus septentrionalis, is a successful invasive species in Florida with its parasites in the native range being well-documented, but there is a void in the literature regarding what parasites were lost or introduced in its expansion. We necropsied 330 O. septentrionalis from Tampa, FL and compared their macroparasites to those of O. septentrionalis in their native range and to the parasites of anurans native to the Tampa, FL area to determine the species O. septentrionalis likely introduced or acquired in Florida. At least nine parasite species (Aplectana sp., Oswaldocruzia lenteixeirai, Cylindrotaenia americana, Physaloptera sp., Rhabdias sp., Centrorhynchus sp., unidentified trematode metacercariae, unidentified larval acuariids, and unidentified pentastomids) were isolated. We found no differences in parasite communities of adult male and female frogs, which averaged 19.36 parasite individuals and 1.39 parasite species per adult frog, and had an overall prevalence of 77.52%. Acuariid larvae were likely acquired by O. septentrionalis in FL because they are not found in their native range. O. lenteixeirai was likely introduced because it is commonly reported in O. septentrionalis' native range but has never been reported in FL-native anurans. Aplectana sp. is also likely introduced because it has been reported in several anurans in Cuba but only reported once in Florida. O. septentrionalis tended to harbor fewer of its native parasites in the introduced range, which is consistent with the enemy release hypothesis and potentially creates an immunological advantage for this invasive host. Because native populations can be threatened by introduced parasites, there is a need to further explore the frequency and rate at which non-native hosts introduce parasites. PMID- 26759793 TI - Mitochondrial DNA diversity in the acanthocephalan Prosthenorchis elegans in Colombia based on cytochrome c oxidase I (COI) gene sequence. AB - Prosthenorchis elegans is a member of the Phylum Acanthocephala and is an important parasite affecting New World Primates in the wild in South America and in captivity around the world. It is of significant management concern due to its pathogenicity and mode of transmission through intermediate hosts. Current diagnosis of P. elegans is based on the detection of eggs by coprological examination. However, this technique lacks both specificity and sensitivity, since eggs of most members of the genus are morphologically indistinguishable and shed intermittently, making differential diagnosis difficult, and coprological examinations are often negative in animals severely infected at death. We examined sequence variation in 633 bp of mitochondrial DNA (mtDNA) cytochrome c oxidase I (COI) sequence in 37 isolates of P. elegans from New World monkeys (Saguinus leucopus and Cebus albifrons) in Colombia held in rescue centers and from the wild. Intraspecific divergence ranged from 0.0 to 1.6% and was comparable with corresponding values within other species of acanthocephalans. Furthermore, comparisons of patterns of sequence divergence within the Acanthocephala suggest that Prosthenorchis represents a separate genus within the Oligacanthorhynchida. Six distinct haplotypes were identified within P. elegans which grouped into one of two well-supported mtDNA haplogroups. No association between haplogroup/haplotype, holding facility and species was found. This information will help pave the way to the development of molecular-based diagnostic tools for the detection of P. elegans as well as furthering research into the life cycle, intermediate hosts and epidemiological aspects of the species. PMID- 26759791 TI - Neurostructural abnormalities associated with axes of emotion dysregulation in generalized anxiety. AB - BACKGROUND: Despite the high prevalence of generalized anxiety disorder (GAD) and its negative impact on society, its neurobiology remains obscure. This study characterizes the neurostructural abnormalities associated with key symptoms of GAD, focusing on indicators of impaired emotion regulation (excessive worry, poor concentration, low mindfulness, and physiological arousal). METHODS: These domains were assessed in 19 (16 women) GAD patients and 19 healthy controls matched for age and gender, using questionnaires and a low demand behavioral task performed before and after an induction of perseverative cognition (i.e. worry and rumination). Continuous pulse oximetry was used to measure autonomic physiology (heart rate variability; HRV). Observed cognitive and physiological changes in response to the induction provided quantifiable data on emotional regulatory capacity. Participants underwent structural magnetic resonance imaging; voxel-based morphometry was used to quantify the relationship between gray matter volume and psychological and physiological measures. RESULTS: Overall, GAD patients had lower gray matter volume than controls within supramarginal, precentral, and postcentral gyrus bilaterally. Across the GAD group, increased right amygdala volume was associated with prolonged reaction times on the tracking task (indicating increased attentional impairment following the induction) and lower scores on the 'Act with awareness' subscale of the Five Facets Mindfulness Questionnaire. Moreover in GAD, medial frontal cortical gray matter volume correlated positively with the 'Non-react mindfulness' facet. Lastly, smaller volumes of bilateral insula, bilateral opercular cortex, right supramarginal and precentral gyri, anterior cingulate and paracingulate cortex predicted the magnitude of autonomic change following the induction (i.e. a greater decrease in HRV). CONCLUSIONS: Results distinguish neural structures associated with impaired capacity for cognitive, attentional and physiological disengagement from worry, suggesting that aberrant competition between these levels of emotional regulation is intrinsic to symptom expression in GAD. PMID- 26759794 TI - Critical evaluation of incidence and prevalence of white spot lesions during fixed orthodontic appliance treatment: A meta-analysis. AB - OBJECTIVE: Development of dental caries, specifically, white spot lesions (WSLs), continues to be a well-recognized and troubling side effect of orthodontic fixed appliance therapy, despite vast improvement in preventive dental techniques and procedures. The aim of this meta-analysis is to evaluate, determine, and summarize the incidence and prevalence rates of WSLs during orthodontic treatment that have been published in the literature. MATERIALS AND METHODS: According to predetermined criteria, databases were searched for appropriate studies. References of the selected articles and relevant reviews were searched for any missed publications. RESULTS: In the 14 studies evaluated for WSLs, the incidence of new carious lesions formed during orthodontic treatment in patients was 45.8% and the prevalence of lesions in patients undergoing orthodontic treatment was 68.4%. CONCLUSION: The incidence and prevalence rates of WSLs in patients undergoing orthodontic treatment are quite high and significant. This widespread problem of WSL development is an alarming challenge and warrants significant attention from both patients and providers, which should result in greatly increased emphasis on effective caries prevention. PMID- 26759795 TI - Artifacts: The downturn of CBCT image. AB - Cone-beam computed tomography (CBCT) has been accepted as a useful tool for diagnosis and treatment planning in dentistry. Despite a growing trend of CBCT in dentistry, it has some disadvantages like artifacts. Artifacts are discrepancies between the reconstructed visual image and the actual content of the subject which degrade the quality of CBCT images, making them diagnostically unusable. Additionally, structures that do not exist in the subject may appear within images. Such structures can occur because of patient motion, the image capture and reconstruction process. To optimize image quality, it is necessary to understand the types of artifacts. This article aims to throw light on the various types of artifacts associated with CBCT images. PMID- 26759796 TI - Evaluation of serum sialic acid, fucose levels and their ratio in oral squamous cell carcinoma. AB - BACKGROUND: Detection of cancer at the early stage is of utmost importance to decrease the morbidity and mortality of the disease. Apart from the conventional biopsy, minimally invasive methods like serum evaluation are used for screening large populations. Thus, this study aimed to estimate serum levels of sialic acid and fucose and their ratio in oral cancer patients and in healthy control group to evaluate their role in diagnosis. MATERIALS AND METHODS: Serum samples were collected from 52 healthy controls (group I) and 52 squamous cell carcinoma patients (group II). Estimation of serum levels of sialic acid and fucose and their ratio was performed. This was correlated histopathologically with the grades of carcinoma. Statistical analysis was done by using analysis of variance (ANOVA) test and unpaired "t" test. RESULTS: Results showed that serum levels of sialic acid and fucose were significantly higher in oral cancer patients compared to normal healthy controls (P < 0.001). The sialic acid to fucose ratio was significantly lower in cancer patients than in normal controls (P < 0.01). However, comparison with histological grading, habits, gender, and age group did not show any significant result. CONCLUSION: The mean serum sialic acid and fucose levels showed an increasing trend from controls to malignant group and their corresponding ratio showed decreasing trend from controls to malignant group. The ratio of sialic acid to fucose can be a useful diagnostic aid for oral cancer patients. PMID- 26759797 TI - Parental views on fluoride tooth brushing and its impact on oral health: A cross sectional study. AB - OBJECTIVE: This study aimed to describe the current use and knowledge about fluoride toothpaste and children's oral hygiene habits among parents of Saudi children. MATERIALS AND METHODS: In this cross-sectional study, the parents of children aged 7-12 years who visited the undergraduate pediatric dental clinics at the College of Dentistry in Riyadh, Saudi Arabia were interviewed. The interview included questions to assess the parents' level of fluoride knowledge, the dental appearance of their children, and any general dental health concerns and practices. RESULTS: A total of 463 parents (women 55.5%, men 44.5%) were included. Over half (60.3%) of the participants reported that they were unhappy with the appearance of their child's teeth. Only 11.5% received high fluoride knowledge scores. The additive index for the level of fluoride knowledge was significantly lower among mothers than among fathers. The majority of the parents were not able to correctly report whether the toothpaste their children used contained fluoride. Furthermore, the majority of the respondents were unaware of the benefits of fluoride in preventing dental caries. CONCLUSIONS: There is a need to enhance parental knowledge regarding high fluoride intake and its harmful consequences on children's health. Both mothers and fathers should have higher levels of awareness regarding oral health promotion to maintain optimal oral health in their children. PMID- 26759798 TI - A comparative evaluation of plaque-removing efficacy of air polishing and rubber cup, bristle brush with paste polishing on oral hygiene status: A clinical study. AB - OBJECTIVES: Over the years, professional dental prophylaxis has involved the use of rubber-cup, bristle brush, and abrasive paste for coronal polishing. Although air polishing is an excellent alternative for removal of tooth stain and dental plaque, very few studies have compared their efficacy in vivo. The present study attempts to evaluate and compare the efficacy of air polishing (test) alone versus rubber-cup polishing (control). MATERIALS AND METHODS: A total of 35 individuals having generalized mild to moderate gingivitis were enrolled as the study population after obtaining their informed consent. Before commencement of the study, all subjects underwent scaling to remove calculus deposits (if any), following which the ipsilateral quadrant of the patient's mouth was randomly assigned as the test side and the contralateral quadrant of the same arch was assigned as the control side for polishing procedures. Time employed for both methods of polishing was held constant at 5 min for each technique. Subjects were assessed before and immediately after polishing and again after 15 days following treatment, for plaque and gingival status along with gingival bleeding. RESULTS: Overall, the results of the intra-group comparison of both the polishing procedure sites indicated similar but significant plaque and gingival status changes, whereas the inter-group comparison showed no significant difference between the efficacies of both the groups. CONCLUSIONS: Air polishing and the rubber-cup, bristle brush with paste polishing demonstrated equivalent efficacy regarding removal of supragingival plaque and in reducing gingival inflammation. PMID- 26759799 TI - A comparative evaluation of 4% articaine and 2% lidocaine in mandibular buccal infiltration anesthesia: A clinical study. AB - BACKGROUND: To compare 4% articaine and 2% lidocaine local anesthetics in achieving pulpal anesthesia of the lower first permanent molar teeth objectively, and to assess and compare lip and lingual mucosa numbness subjectively. MATERIALS AND METHODS: All subjects received 1.7 ml of any one anesthetic in the mucobuccal fold adjacent to mandibular first molar teeth; the same individuals received the second infiltration at least 1 week after the first. Later, comparisons for pulpal anesthesia, lip and lingual mucosa numbness between these two anesthetics solutions were made. RESULTS: Articaine showed significant results with P = 0.006 in achieving pulpal anesthesia objectively, when compared with lidocaine. Articaine also showed very high significant results subjectively with P = 0.0006 in achieving lip numbness, when compared with lidocaine. But the results in achieving lingual mucosa numbness with articaine subjectively was not significant with P = 0.01, when compared with lidocaine. CONCLUSION: Endodontic and operative treatments are one of the most common oral non-surgical procedures done under local anesthesia. The diversity of anesthetic substances currently available on the market requires dental professionals to assess the drug both by its pharmacokinetic and also by its clinical characteristics during dental treatments. Our study used 4% articaine, which is available in the market, for comparison with 2% lidocaine. Further studies are required to use an equal concentration of solutions to achieve more accurate results. PMID- 26759800 TI - Evaluation of cuspal deflection in premolar teeth restored with low shrinkable resin composite (in vitro study). AB - OBJECTIVES: This study evaluated cuspal deflection in premolar teeth restored with low shrinkable resin composite. MATERIALS AND METHODS: A total of 40 human premolars were used for cuspal deflection evaluation in this study. Each group was divided into four equal groups according to the type of resin composite and the adhesive used as follows: group A: Using low shrinkable resin composite (silorane) with its adhesive system; group B: Using low shrinkable composite (silorane) with G-bond; group C: Using Filtek Z350 composite with G-bond; and group D: Using Filtek Z350 composite with AdheSE. Cusp deflection was detected using Universal measuring microscope and laser horizontal metroscope. RESULTS: This study was done to investigate the effect of polymerization shrinkage stresses of two resin composite materials (Filtek Z350 and Filtek P90) on cuspal deflection of mesio-occluso-distal restoration. For this study, the extracted non carious maxillary second premolars were selected. Forty teeth that showed no more than 5% variation in their dimensions were used. A significant increase in cuspal deflection of cavities restored with the methacrylate-based (Filtek Z350) compared with the silorane (P90) resin-based composites was obtained. CONCLUSION: The change in the organic matrix or materials formulation of the resin composite using silorane has a positive effect on controlling the cusp deflection. PMID- 26759801 TI - Qualitative assessment of red blood cell parameters for signs of anemia in patients with chronic periodontitis. AB - AIM: Anemia of chronic disease is defined as anemia occurring in chronic infections and inflammatory conditions that is not caused by marrow deficiencies or other diseases and in the presence of adequate iron stores and vitamins. The present case control study was aimed to assess the red blood cell parameters for signs of anemia in patients with mild, moderate, and severe chronic periodontitis. MATERIALS AND METHODS: A simple random sampling method was used to select 80 healthy male patients, who were divided into four groups based on full mouth periodontal examination as follows: group I patients comprised the control group (n = 20), which included patients with a clinically healthy periodontium, group II patients (n = 20) were diagnosed with mild chronic periodontitis, group III (n = 20) included moderate chronic periodontitis patients, and patients with severe chronic periodontitis formed group IV (n = 20). Laboratory blood investigations included total number of erythrocytes, hemoglobin concentration, packed cell volume, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration. RESULTS: Data analysis showed a statistically significant decrease in red blood cell parameters with increase in different grades of periodontitis. CONCLUSION: Results of the present study show a substantial decrease in red blood cell parameters with increase in the severity of periodontal destruction. PMID- 26759802 TI - Oral health related quality of life in cleft lip and palate patients rehabilitated with conventional prostheses or dental implants. AB - OBJECTIVES: Cleft lip and/or palate (CLP) is the most common congenital craniofacial abnormality, with a prevalence of 9.92 per 10,000 live births. In treating patients with CLP, oral rehabilitation is definitely a very important phase of the treatment in order to improve the patient's oral health related quality of life (OH-QoL). The aim of this retrospective study is to assess the OH QoL in patients rehabilitated with different prosthetic options, thus comparing the conventional treatments, which include removable partial dentures and fixed partial dentures, with the implant-supported prostheses. MATERIALS AND METHODS: Sixty-three patients were enrolled in this retrospective survey [44 females (69.84%) and 19 males (30.16%)] with a mean age of 34.93 +/- 7.04 years (age range 21-53 years). They were all treated for CLP and rehabilitated with a conventional prosthesis or an implant-supported denture. Two different questionnaires were used in the present study to evaluate patients' OH-QoL: The Italian version of the 49-item Oral Health Impact Profile (OHIP-49) and the Italian version of the Cleft Evaluation Profile (CEP). Statistical analysis was performed using analysis of variance (ANOVA) test, with a significant P < 0,05. RESULTS: Data analysis revealed that patients rehabilitated with implant supported dentures and fixed partial dentures showed a good level of satisfaction with their prostheses, scoring low values in the OHIP-49 and high values in the CEP, while subjects with removable partial dentures scored the highest values in the OHIP-49 and the lowest values in the CEP, which means an unsatisfactory feeling (P < 0.05). CONCLUSIONS: OH-QoL is a challenging demand for all prosthodontists. Our results show, clearly, that patients rehabilitated with implant-supported dentures are more satisfied compared to subjects with fixed partial dentures and removable partial dentures. PMID- 26759803 TI - Comparative evaluation of sealing ability of glass ionomer-resin continuum as root-end filling materials: An in vitro study. AB - BACKGROUND AND OBJECTIVES: Root-end filling is a prudent procedure aimed at sealing the root canal to prevent penetration of tissue fluids into the root canals. An ideal root-end filling material should produce a complete apical seal. Therefore, the aim of this study is to compare the leakage behavior of four different root-end filling materials. MATERIALS AND METHODS: Sixty-eight maxillary central incisors were obturated with laterally condensed gutta-percha and AH plus sealer. The roots were resected at the level of 3 mm perpendicular to the long axis of the tooth. Root-end cavities were prepared with straight fissure stainless steel bur. The teeth were then divided into four experimental and two control groups, and cavities restored as per the groupings. The teeth were immersed in methylene blue for 48 h, split longitudinally, and dye penetration was measured. RESULTS: A highly significant difference existed in the mean dye penetration of Group I (conventional glass ionomer) and the other groups (resin modified glass ionomer, polyacid-modified composite, and composite resin). There was no statistically significant difference among the three groups. CONCLUSIONS: (1) Significant difference was found in the dye penetration values of conventional glass ionomer cement and other groups. (2) No statistically significant difference was found in the dye penetration values of groups II, III, and IV. PMID- 26759804 TI - The prevalence and pattern of cavitated carious lesions in primary dentition among children under 5 years age in Sirsa, Haryana (India). AB - BACKGROUND: To determine the prevalence and pattern of cavitated carious lesions in primary dentition in children below 5 years of age in Sirsa, Haryana. AIMS: The aim of this study was to evaluate the status of dental caries in primary dentition and compute data for planning anticipatory programs in children aged less than 5 years. SETTINGS AND DESIGN: The study was conducted among children attending the outpatient department of pedodontics, JCD Dental College, Sirsa, Haryana (India) from April to December 2014. MATERIALS AND METHODS: This study consisted of 576 children of both sexes (311 males and 265 females) up to 5 years of age. Dentition status and treatment proforma (WHO, 1997) was used to assess the prevalence of cavitated carious lesions. Selection of children for the study was done by simple random sampling method. STATISTICAL ANALYSIS: Chi-square test and t-test were used to compute data for statistical analysis. RESULTS: 33.85% of children in the study population showed presence of cavitated carious lesions. Males showed slightly higher prevalence of cavitated carious lesions than females (P = 0.35). Incidence of caries was higher in mandibular arch in both the sexes (males P = 0.9, females P = 0.7) and in posterior teeth (both sex wise and arch wise). Higher caries prevalence was noticed in maxillary anterior teeth (P = 0.04) and mandibular posterior teeth (P = 0.7). Primary second molars showed highest caries prevalence (P = 0.39) in both the arches and sexes. CONCLUSION: The mean prevalence of cavitated carious lesions in primary dentition was found to be 33.85%. Males were more affected than females. Mandibular molars and maxillary anterior teeth were the predominantly affected teeth. Mandibular anterior teeth were least affected. The increase in incidence of cavitated carious lesions shows that there is necessity of implementing dental health awareness programs and modifications in types of food consumed are needed to eliminate the cause of decay. PMID- 26759805 TI - Effect of 3D animation videos over 2D video projections in periodontal health education among dental students. AB - BACKGROUND: There is limited evidence about the distinguished effect of 3D oral health education videos over conventional 2 dimensional projections in improving oral health knowledge. This randomized controlled trial was done to test the effect of 3 dimensional oral health educational videos among first year dental students. MATERIALS AND METHODS: 80 first year dental students were enrolled and divided into two groups (test and control). In the test group, 3D animation and in the control group, regular 2D video projections pertaining to periodontal anatomy, etiology, presenting conditions, preventive measures and treatment of periodontal problems were shown. Effect of 3D animation was evaluated by using a questionnaire consisting of 10 multiple choice questions given to all participants at baseline, immediately after and 1month after the intervention. Clinical parameters like Plaque Index (PI), Gingival Bleeding Index (GBI), and Oral Hygiene Index Simplified (OHI-S) were measured at baseline and 1 month follow up. RESULTS: A significant difference in the post intervention knowledge scores was found between the groups as assessed by unpaired t-test (p<0.001) at baseline, immediate and after 1 month. At baseline, all the clinical parameters in the both the groups were similar and showed a significant reduction (p<0.001)p after 1 month, whereas no significant difference was noticed post intervention between the groups. CONCLUSION: 3D animation videos are more effective over 2D videos in periodontal disease education and knowledge recall. The application of 3D animation results also demonstrate a better visual comprehension for students and greater health care outcomes. PMID- 26759806 TI - Prevalence of denture-related oral lesions among patients attending College of Dentistry, University of Dammam: A clinico-pathological study. AB - BACKGROUND: Heterogeneous groups of oral lesions are likely to develop among denture wearers. The objectives of this study were to determine the exact prevalence of oral lesions among denture wearers attending the clinics of the College of Dentistry, University of Dammam. MATERIALS AND METHODS: All denture wearers attending the dental clinics in the period between January 2012 and April 2013 were included in this study. Of the total 210 patients, 166 (79%) were males and 44 (21%) were females. Comprehensive oral examination was performed for all patients. Any denture-induced lesion was biopsied. Data collected were analyzed using SPSS program. RESULTS: Oral lesions were found in 20.5% of the cases under study (43 out of the total 210 denture wearers). Denture-induced fibrous hyperplasia was the most common type of lesion detected (41.9%). A significant correlation (P = 0.004) was found between the type of denture and oral lesions in this study. CONCLUSION: The prevalence of denture-induced oral lesions was found to differ significantly from that reported in other studies. The diversity of these lesions among different studies depends on the quality and materials of dentures delivered, the techniques used, and the methods of patients' instructions adopted. PMID- 26759807 TI - Diagnostic features of Angle's Class II div 2 malocclusion. AB - STATEMENT OF PROBLEM: A thorough knowledge of the salient features of malocclusion makes the practitioner to come to a proper diagnosis and to formulate proper mechanotherapy. It also helps to predict the prognosis, prior to the onset of treatment process. Among the various malocclusions, Class II div 2 occurs the least often. The literature review does not clearly describe the classical skeletal and dental features of Angle's Class II div 2 malocclusion. PURPOSE OF STUDY: The aim of this study is to describe the unique features of Angle's Class II division 2 malocclusion. MATERIALS AND METHODS: A total of 612 pre-treatment records (study models and cephalograms), with age ranging from 14 to 25 years, were obtained from the hospital records of Drs Sudha and Nageswar Rao Siddhartha Institute of Dental Sciences. Among these samples, 317 were Class II div 1 and 295 were Class II div 2. The lateral cephalograms were analyzed by using Kodak software and the arch width analysis was calculated by using digital vernier calipers. RESULTS: Student's t test was used for the study. On the cephalograms, the vertical skeletal measurements and few of the dental variables showed a significant difference. On the plaster models, the maxillary transverse measurements revealed a notable discrimination between the groups. CONCLUSION: Angle's Class II div 2 malocclusion has a marked horizontal growth pattern with decreased lower facial thirds, palatally inclined upper anteriors, and remarkably increased transverse maxillary arch dimensions. PMID- 26759808 TI - Experimental study of iron and multivitamin drops on enamel microhardness of primary tooth. AB - OBJECTIVES: Iron and multivitamin drops are being frequently prescribed in children less than 2 years of age. Due to their low pH levels, these drops may lead to the softening of enamel and accelerate the destructive process. The aim of the present study was to investigate the enamel microhardness of primary teeth after exposing them to iron and multivitamin drops. MATERIALS AND METHODS: Forty healthy anterior teeth were randomly divided into four groups of 10 samples each. Samples were exposed to two iron drops of Kharazmi (Iran) and Ironorm (UK) and two multivitamin drops of Shahdarou (Iran) and Eurovit (Germany) for 5 min. The surface microhardness was measured before and after exposure and data processing was done using statistical paired t-test and analysis of variance (ANOVA) test. The surface structure of the teeth was examined by scanning electron microscope (SEM). RESULTS: In all groups, microhardness was decreased, but it was not significant in Eurovit multivitamin group (P = 0.088). The reduction rate in Kharazmi iron group was significant compared to that in other groups (P < 0.005). Hardness reduction percent for Kharazmi iron drop was 28/12 +/- 47/43. In SEM analysis, irregular granular appearance was observed in the enamel exposed to Kharazmi iron drop. CONCLUSION: The results showed that all the studied drugs have the potential to cause erosion; this potential is the most in Kharazmi iron drop and the least in Eurovit multivitamin drops. Therefore, after using these kinds of drops, preventive measures should be used in children. PMID- 26759810 TI - Improvement of D-Ribose Production from Corn Starch Hydrolysate by a Transketolase-Deficient Strain Bacillus subtilis UJS0717. AB - D-Ribose is a five-carbon sugar and generally used as an energy source to improve athletic performance and the ability. The culture conditions for maximum D-ribose production performance from cheap raw material corn starch hydrolysate were improved by using one-factor-at-a-time experiments and a three-level Box-Behnken factorial design. The optimal fermentation parameters were obtained as 36 degrees C culture temperature, 10% inoculum volume, and 7.0 initial pH. The mathematical model was then developed to show the effect of each medium composition and their interactions on the production of D-ribose and estimated that the optimized D ribose production performance with the concentration of 62.13 g/L, yield of 0.40 g/g, and volumetric productivity of 0.86 g/L.h could be obtained when the medium compositions were set as 157 g/L glucose, 21 g/L corn steep liquor, 3.2 g/L (NH4)2SO4, 1 g/L yeast extract, 0.05 g/L MnSO4.H2O, and 20 g/L CaCO3. These findings indicated the D-ribose production performance was significantly improved compared to that under original conditions. PMID- 26759811 TI - Riboflavin Arrests Cisplatin-Induced Neurotoxicity by Ameliorating Cellular Damage in Dorsal Root Ganglion Cells. AB - Cis-Diamminedichloroplatinum II- (CP-) induced neurotoxicity is one of the least explored aspects of this drug. Dorsal root ganglia (DRG) cells are considered as the primary target, and their damage plays a vital role in pathogenesis and etiology of CP-induced neurotoxicity. The present study is aimed at confirming if riboflavin (RF) has any protective role in shielding the DRG from CP-induced toxicity. After conducting the established treatment strategy on mice under photoillumination, it was observed that, despite the fact that RF alone is partially toxic, its combination with CP significantly ameliorated the drug induced damage in DRG cells as evidenced by histological analysis. In addition, it was interesting to observe that the combination group (RF + CP) was able to induce apoptosis in the target cells up to a significant extent which is considered as the most preferred way of countering cancer cells. Therefore, RF can act as an effective adjuvant compound in CP-based chemoradiotherapy to improve clinical outcomes in the contemporary anticancer treatment regimes. PMID- 26759809 TI - Controversies in Pediatric Perioperative Airways. AB - Pediatric airway management is a challenge in routine anesthesia practice. Any airway-related complication due to improper procedure can have catastrophic consequences in pediatric patients. The authors reviewed the current relevant literature using the following data bases: Google Scholar, PubMed, Medline (OVID SP), and Dynamed, and the following keywords: Airway/s, Children, Pediatric, Difficult Airways, and Controversies. From a summary of the data, we identified several controversies: difficult airway prediction, difficult airway management, cuffed versus uncuffed endotracheal tubes for securing pediatric airways, rapid sequence induction (RSI), laryngeal mask versus endotracheal tube, and extubation timing. The data show that pediatric anesthesia practice in perioperative airway management is currently lacking the strong evidence-based medicine (EBM) data that is available for adult subpopulations. A number of procedural steps in airway management are derived only from adult populations. However, the objective is the same irrespective of patient age: proper securing of the airway and oxygenation of the patient. PMID- 26759812 TI - Comment on "Simulating Radiotherapy Effect in High-Grade Glioma by Using Diffusive Modeling and Brain Atlases". PMID- 26759816 TI - Descriptive data on cardiovascular and metabolic risk factors in ambulatory and non-ambulatory adults with cerebral palsy. AB - Forty-two participants with cerebral palsy were recruited for a study examining traditional and novel indicators of cardiovascular risk (McPhee et al., 2015 [1]). Data pertaining to the prevalence of obesity, smoking, hypertension, and metabolic risk are provided. These data are presented along with the scoring methods used in evaluation of the study participants. Percentages are included for comparative purposes with the existing literature. PMID- 26759817 TI - Supporting evidences for potential biomarkers of endometriosis detected in peripheral blood. AB - Incidence of endometriosis is very high in women in the reproductive age (around 10%). To date, a reliable non-invasive diagnostic test for early diagnosis of endometriosis is not available. In this article we describe the potential value as diagnostic markers for endometriosis of two proteins (serum albumin and complement C3 precursor), previously identified as differentially expressed in women with endometriosis respect to healthy control by 2D gel analysis. A detailed description of the results obtained with this proteomic approach can be found in Signorile and Baldi [1]. ELISAs were performed on a large cohort of endometriosis (n=100) and healthy patients (n=10) to establish the differential expression of the identified proteins. ROC analyses confirmed the statistical significance of the differential expression of these proteins: serum albumin (p=0.028) ad complement C3 precursor (p=0.082). Evaluation of these two proteins, together with the already described Zn-alpha2-glycoprotein [1], could help in the early identification of endometriosis patients. PMID- 26759814 TI - Superficial vessel reconstruction with a multiview camera system. AB - We aim at reconstructing superficial vessels of the brain. Ultimately, they will serve to guide the deformation methods to compensate for the brain shift. A pipeline for three-dimensional (3-D) vessel reconstruction using three mono complementary metal-oxide semiconductor cameras has been developed. Vessel centerlines are manually selected in the images. Using the properties of the Hessian matrix, the centerline points are assigned direction information. For correspondence matching, a combination of methods was used. The process starts with epipolar and spatial coherence constraints (geometrical constraints), followed by relaxation labeling and an iterative filtering where the 3-D points are compared to surfaces obtained using the thin-plate spline with decreasing relaxation parameter. Finally, the points are shifted to their local centroid position. Evaluation in virtual, phantom, and experimental images, including intraoperative data from patient experiments, shows that, with appropriate camera positions, the error estimates (root-mean square error and mean error) are [Formula: see text]. PMID- 26759813 TI - Exenatide Activates the APPL1-AMPK-PPARalpha Axis to Prevent Diabetic Cardiomyocyte Apoptosis. AB - OBJECTIVE: To investigate the effect and mechanism of the exenatide on diabetic cardiomyopathy. METHODS: Rats were divided into control group, diabetes group (D), diabetes treated with insulin (DI) group, and diabetes treat with exenatide (DE) group. We detected apoptosis rate by TUNEL, the adiponectin and high molecular weight adiponectin (HMW-adiponectin) by ELISA, and the expression of APPL1, p-AMPK/T-AMPK, PPARalpha, and NF-kappaB by immunohistochemistry and western blotting. RESULTS: Compared with the D group, the apoptosis in the Control and DE groups was decreased (P < 0.05); the adiponectin and HMW adiponectin were increased (P < 0.05); the APPL1, p-AMPK/T-AMPK, PPARalpha, and LV -dP/dt were increased (P < 0.05); and the NF-kappaB, GRP78, and LVEDP were decreased (P < 0.05). Compared with DE group, the glucose levels in the DI group were similar (P < 0.05); the apoptosis and LVEDP were increased; the APPL1, p AMPK/T-AMPK, PPARalpha, and LV -dP/dt were decreased (P < 0.05); the NF-kappaB and GRP78 were increased (P < 0.05); the adiponectin and HMW-adiponectin were significantly decreased (P < 0.05). CONCLUSION: Our model of diabetic cardiomyopathy was constructed successfully. After being treated with exenatide, the adiponectin and HMW-adiponectin and the APPL1-AMPK-PPARalpha axis were increased, the NF-kappaB and the apoptosis were decreased, the cardiac function of the diabetic rats was improved, and these effects were independent of glucose control. PMID- 26759815 TI - Computational assessment of visual search strategies in volumetric medical images. AB - When searching through volumetric images [e.g., computed tomography (CT)], radiologists appear to use two different search strategies: "drilling" (restrict eye movements to a small region of the image while quickly scrolling through slices), or "scanning" (search over large areas at a given depth before moving on to the next slice). To computationally identify the type of image information that is used in these two strategies, 23 naive observers were instructed with either "drilling" or "scanning" when searching for target T's in 20 volumes of faux lung CTs. We computed saliency maps using both classical two-dimensional (2 D) saliency, and a three-dimensional (3-D) dynamic saliency that captures the characteristics of scrolling through slices. Comparing observers' gaze distributions with the saliency maps showed that search strategy alters the type of saliency that attracts fixations. Drillers' fixations aligned better with dynamic saliency and scanners with 2-D saliency. The computed saliency was greater for detected targets than for missed targets. Similar results were observed in data from 19 radiologists who searched five stacks of clinical chest CTs for lung nodules. Dynamic saliency may be superior to the 2-D saliency for detecting targets embedded in volumetric images, and thus "drilling" may be more efficient than "scanning." PMID- 26759818 TI - Effects of intraperitoneal injection of microencapsulated Sertoli cells on chronic and presymptomatic dystrophic mice. AB - We report data about the effects of intraperitoneal (i.p.) injection of specific pathogen-free (SPF) porcine Sertoli cells (SeC) encapsulated into clinical grade alginate-based microcapsules (SeC-MC) on muscles of chronic and presymptomatic dystrophic, mdx mice. Mdx mouse is the best characterized animal model of Duchenne muscular dystrophy (DMD), an X-linked lethal myopathy due to mutation in the gene of dystrophin, which is crucial for myofiber integrity during muscle contraction. Our data show that three weeks after i.p. injection of SeC-MC significantly reduced adipose and fibrous tissue deposition, reduced macrophage infiltrate, and reduced numbers of damaged myofibers are found in muscles of 12 month-old mdx mice, which reproduce chronic DMD conditions. Compared with muscles of mock-treated mdx mice muscles of SeC-MC-treated mice show upregulation of the dystrophin paralogue, utrophin which is localized to the periphery of myofibers. Moreover, our data show that i.p. injection of SeC-MC into presymptomatic, 2-week old mdx mice, although not fully preventing myofiber degeneration, results in protection against myofiber necrosis and muscle inflammation. Extensive discussion of these data can be found in Ref. [1]. PMID- 26759819 TI - Data in support of the discovery of alternative splicing variants of quail LEPR and the evolutionary conservation of qLEPRl by nucleotide and amino acid sequences alignment. AB - Leptin receptor (LEPR) belongs to the class I cytokine receptor superfamily which share common structural features and signal transduction pathways. Although multiple LEPR isoforms, which are derived from one gene, were identified in mammals, they were rarely found in avian except the long LEPR. Four alternative splicing variants of quail LEPR (qLEPR) had been cloned and sequenced for the first time (Wang et al., 2015 [1]). To define patterns of the four splicing variants (qLEPRl, qLEPR-a, qLEPR-b and qLEPR-c) and locate the conserved regions of qLEPRl, this data article provides nucleotide sequence alignment of qLEPR and amino acid sequence alignment of representative vertebrate LEPR. The detailed analysis was shown in [1]. PMID- 26759820 TI - Expression of hepatic miRNAs targeting porcine glucocorticoid receptor (GR) 3'UTR in the neonatal piglets under a maternal gestational betaine supplementation. AB - Glucocorticoid receptor (GR) has been previously demonstrated an important transcriptional factor of hepatic metabolic genes in the neonates under a maternal gestational betaine supplementation ("Gestational dietary betaine supplementation suppresses hepatic expression of lipogenic genes in neonatal piglets through epigenetic and glucocorticoid receptor-dependent mechanisms" Cai et al., 2015 [1]). Here we provide accompanying data about the expression of hepatic miRNAs targeting porcine GR 3'UTR in the neonatal piglets. Liver samples were obtained and RNA was isolated. RNA was polyadenylated by poly (A) polymerase and then dissolved and reverse transcribed using poly (T) adapter. The diluted cDNA were used in each real-time PCR assay. The sequences of all the porcine miRNAs were acquired from miRBase (http://www.mirbase.org/). miRNAs targeting GR were predicted using the PITA algorithm. Among all the predicted miRNAs, 4 miRNAs targeting GR were quantitated by real-time PCR and miRNA-124a, which has been identified to target GR 3'UTR [2], [3], was more highly expressed in betaine exposed neonatal livers. PMID- 26759821 TI - Phylogeny of the plant 4/1 proteins. AB - The Nt-4/1 protein of unknown function has been shown to be alpha-helical and predominantly expressed in conductive tissues of tobacco plants. So far, obvious Nt-4/1 orthologs were found only in flowering plants. We report the analysis of 4/1 genes and the encoded proteins of lower land plants (Morozov et al., 2015) [1]. In this data article, we present two phylogenetic trees of angiosperm 4/1 proteins together with orthologs from liverworts, lycophytes, ferns and gymnosperms. PMID- 26759822 TI - Data set for transcriptome analysis of the Chinese giant salamander (Andrias davidianus ). AB - The Chinese giant salamander (Andrias davidianus) occupies a seat at the phylogenetic and species evolution process, which makes it an invaluable model for genetics; however, the genetic information and gene sequences about the Chinese giant salamander in public databases are scanty. Hence, we aimed to perform transcriptome analysis with the help of high-throughput sequencing. In this data, 61,317,940 raw reads were acquired from Chinese giant salamander mRNA using Illumina paired-end sequencing platform. After de novo assembly, a total of 72,072 unigenes were gained, in which 33,834 (46.95%) and 29,479 (40.91%) transcripts exhibited homology to sequences in the Nr database and Swiss-Prot database, (E-value <10(-5)), respectively. In the obtained unigenes, 18,019 (25%) transcripts were assigned with at least one Gene Ontology term, of which 1218 (6.8%) transcripts were assigned to immune system processes. In addition, a total of 17,572 assembled sequences were assigned into 241 predicted KEGG metabolic pathways. Among these, 2552 (14.5%) transcripts were assigned to the immune system relevant pathway and 5 transcripts were identified as potential antimicrobial peptides (AMPs). PMID- 26759823 TI - Optimization of solid lipid nanoparticles prepared by a single emulsification solvent evaporation method. AB - This data article contains the data related to the research article "Characterization, biorecognitive activity and stability of WGA grafted lipid nanostructures for the controlled delivery of rifampicin" (Pooja et al. 2015) [1]. In the present study, SLN were prepared by a single emulsification-solvent evaporation method and the various steps of SLN preparation are shown in a flow chart. The preparation of SLN was optimized for various formulation variables including type and quantity of lipid, surfactant, amount of co-surfactant and volume of organic phase. Similarly, effect of variables related to homogezation, sonication and stirring processes, on the size and surface potential of SLN was determined and optimized. PMID- 26759824 TI - Time lapse imaging analysis of the effect of ER stress modulators on apoptotic cell assessed by caspase3/7 activation in NG108-15 cells. AB - This paper reports the data from the long term time lapse imaging of neuronal cell line NG108-15 that were treated with apoptosis inducer or various ER stress inducers. Use of the fluorescent reporter for activated caspase3/7 in combination with the conventional light microscope allowed us to investigate the time course of apoptosis induction at the single cell level. Quantitative as well as qualitative data are presented here to show the effect of two different ER stress modulating chemical compounds on caspase3/7-dependent apoptosis in neuronal cell line NG108-15 cells. Additional results and interpretation of our data concerning ER stress and apoptosis in NG108-15 cells can be found in Suga et al. (2015) [1] and in Suga et al. (2015) [2]. PMID- 26759825 TI - Data on acylglycerophosphate acyltransferase 4 (AGPAT4) during murine embryogenesis and in embryo-derived cultured primary neurons and glia. AB - Whole mouse embryos at three developmental timepoints, embryonic (E) day E10.5, E14.5, and E18.5, were analyzed for Agpat4 mRNA expression. Primary cortical mouse cultures prepared from E18.5 mouse brains were used for immunohistochemistry. Our data show that Agpat4 is differentially expressed at three timepoints in murine embryogenesis and is immunodetectable in both neurons and glial cells derived from the developing mouse brain. This paper contains data related to research concurrently published in Bradley et al. (2015) [1]. PMID- 26759826 TI - Data on carotid intima-media thickness and lipoprotein subclasses in type 1 diabetes from the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC). AB - Type 1 diabetes (T1DM) is associated with increased risk of macrovascular complications. We examined longitudinal associations of serum conventional lipids and nuclear magnetic resonance (NMR)-determined lipoprotein subclasses with carotid intima-media thickness (IMT) in adults with T1DM (n=455) enrolled in the Diabetes Control and Complications Trial (DCCT). Data on serum lipids and lipoproteins were collected at DCCT baseline (1983-89) and were correlated with common and internal carotid IMT determined by ultrasonography during the observational follow-up of the DCCT, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, at EDIC 'Year 1' (199-1996) and EDIC 'Year 6' (1998-2000). This article contains data on the associations of DCCT baseline lipoprotein profiles (NMR-based VLDL & chylomicrons, IDL/LDL and HDL subclasses and 'conventional' total, LDL-, HDL-, non-HDL-cholesterol and triglycerides) with carotid IMT at EDIC Years 1 and 6, stratified by gender. The data are supplemental to our original research article describing detailed associations of DCCT baseline lipids and lipoprotein profiles with EDIC Year 12 carotid IMT (Basu et al. in press) [1]. PMID- 26759827 TI - Quantification of gene-specific methylation of DNMT3B and MTHFR using sequenom EpiTYPER(r). AB - Among 272 patients undergoing a screening colonoscopy, DNA methylation of DNMT3B and MTHFR, genes encoding enzymes critical to one-carbon metabolism, was quantified in blood leukocytes using Sequenom EpiTYPER(r). DNA methylation was quantified in 66 and 28 CpG sites of DNMT3B and MTHFR respectively, and conceptualized using two approaches. First, measures representing average methylation across all CpG sites were created. Second, unsupervised principal component (PC) analysis was used as a pattern derivation and data-reduction approach, to develop two summary variables (PC1 and PC2). These two summary variables represented methylation around the transcription start site (PC1) and in the gene-coding area (PC2) for both DNMT3B and MTHFR. The data contained in this article presents the variation of methylation levels for individual CpG sites within the DNMT3B and MTHFR genes and possible correlations uncovered using PC analysis. The data are related to the research article "Gene-specific DNA methylation of DNMT3B and MTHFR and colorectal adenoma risk" in Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. PMID- 26759828 TI - The Performance of Four Different Mineral Liners on the Transportation of Chlorinated Phenolic Compounds to Groundwater in Landfills. AB - The aim of this study was to investigate the efficiency of four different mineral liners (clay, bentonite, kaoline, and zeolite) which could be utilized to prevent the transport of phenolic compounds to groundwater through alternative liner systems. Four laboratory-scale HDPE reactors with 80 cm height and 40 cm inner diameter were operated for a period of 180 days. Results indicated that the transport of mono- or dichlorophenols is significantly prevented by the liner systems used, while the transport of highly chlorinated phenolic compounds cannot be prevented by the landfill liner system effectively. Highly chlorinated phenolic compounds in groundwater can be found in higher concentrations than the leachate, as a result of the degradation and transformation of these compounds. Thus, the analysis of highly chlorinated phenolic compounds such as 2,4,6-TCP, 2,3,6-TCP, 3,4,5-TCP, and PCP is of great significance for the studies to be conducted on the contamination of groundwater around landfills. PMID- 26759829 TI - Game Theory Based Security in Wireless Body Area Network with Stackelberg Security Equilibrium. AB - Wireless Body Area Network (WBAN) is effectively used in healthcare to increase the value of the patient's life and also the value of healthcare services. The biosensor based approach in medical care system makes it difficult to respond to the patients with minimal response time. The medical care unit does not deploy the accessing of ubiquitous broadband connections full time and hence the level of security will not be high always. The security issue also arises in monitoring the user body function records. Most of the systems on the Wireless Body Area Network are not effective in facing the security deployment issues. To access the patient's information with higher security on WBAN, Game Theory with Stackelberg Security Equilibrium (GTSSE) is proposed in this paper. GTSSE mechanism takes all the players into account. The patients are monitored by placing the power position authority initially. The position authority in GTSSE is the organizer and all the other players react to the organizer decision. Based on our proposed approach, experiment has been conducted on factors such as security ratio based on patient's health information, system flexibility level, energy consumption rate, and information loss rate. Stackelberg Security considerably improves the strength of solution with higher security. PMID- 26759830 TI - Comparison of Groundwater Level Models Based on Artificial Neural Networks and ANFIS. AB - Water table forecasting plays an important role in the management of groundwater resources in agricultural regions where there are drainage systems in river valleys. The results presented in this paper pertain to an area along the left bank of the Danube River, in the Province of Vojvodina, which is the northern part of Serbia. Two soft computing techniques were used in this research: an adaptive neurofuzzy inference system (ANFIS) and an artificial neural network (ANN) model for one-month water table forecasts at several wells located at different distances from the river. The results suggest that both these techniques represent useful tools for modeling hydrological processes in agriculture, with similar computing and memory capabilities, such that they constitute an exceptionally good numerical framework for generating high-quality models. PMID- 26759832 TI - UV-assisted Fenton digestion of rice for the determination of trace cadmium by hydride generation atomic fluorescence spectrometry. AB - A new digestion method using UV-assisted Fe(0) Fenton reaction was developed for the determination of trace Cd in rice by hydride generation atomic fluorescence spectrometry. The proposed method integrated the advantages of simplicity, small dose of reagents, low cost and moderate reaction conditions, and was successfully utilized to analyze a Certified Reference Material (CRM) and real rice samples. A 1 mL mixture of the sample and reagents (0.0500 g rice powder, 0.2% (m/v) Fe(0), 0.75% (v/v) HNO3 and 18% (v/v) H2O2) was irradiated by UV-light for 50 min and then a clear solution was obtained by separating excess Fe(0) with a magnet prior to spectral analysis. The limit of detection (LOD) for Cd was found to be 0.02 mg kg(-1) and the relative standard deviation was better than 5.0% at a concentration level of 0.40 mg kg(-1). The recovery obtained by analyzing the CRM was 103% and spiked recoveries with 0.40 mg kg(-1) Cd in rice samples were 93% and 101%. The t-test proved that there is no significant difference between the certified value and the determined value of the CRM, and between the proposed method and microwave-assisted digestion coupled with inductively coupled plasma mass spectrometry (MWD-ICP-MS) at 95% confidence level. PMID- 26759831 TI - Plasmonic nanostructures for surface enhanced spectroscopic methods. AB - A comprehensive review of theoretical approaches to simulate plasmonic-active metallic nano-arrangements is given. Further, various fabrication methods based on bottom-up, self-organization and top-down techniques are introduced. Here, analytical approaches are discussed to investigate the optical properties of isotropic and non-magnetic spherical or spheroidal particles. Furthermore, numerical methods are introduced to research complex shaped structures. A huge variety of fabrication methods are reviewed, e.g. bottom-up preparation strategies for plasmonic nanostructures to generate metal colloids and core-shell particles as well as complex-shaped structures, self-organization as well as template-based methods and finally, top-down processes, e.g. electron beam lithography and its variants as well as nanoimprinting. The review article is aimed at beginners in the field of surface enhanced spectroscopy (SES) techniques and readers who have a general interest in theoretical modelling of plasmonic substrates for SES applications as well as in the fabrication of the desired structures based on methods of the current state of the art. PMID- 26759834 TI - A universal strategy for visual chiral recognition of alpha-amino acids with L tartaric acid-capped gold nanoparticles as colorimetric probes. AB - The ability to recognize and quantify the chirality of alpha-amino acids constitutes the basis of many critical areas for specific targeting in drug development and metabolite probing. It is still challenging to conveniently distinguish the enantiomer of amino acids largely due to the lack of a universal and simple strategy. In this work, we report a strategy for the visual recognition of alpha-amino acids. It is based on the chirality of L-tartaric acid capped gold nanoparticles (L-TA-capped AuNPs, ca. 13 nm in diameter). All of 19 right-handed alpha-amino acids can induce a red-to-blue color change of L-TA capped AuNP solution, whereas all of the left-handed amino acids (except cysteine) cannot. The chiral recognition can be achieved by the naked eye and a simple spectrophotometer. This method does not require complicated chiral modification, and excels through its low-cost, good availability of materials and its simplicity. Another notable feature of this method is its high generality, and this method can discriminate almost all native alpha-amino acid enantiomers. This versatile method could be potentially used for high-throughput chiral recognition of amino acids. PMID- 26759835 TI - Multifunctional organic nanoparticles with aggregation-induced emission (AIE) characteristics for targeted photodynamic therapy and RNA interference therapy. AB - We report the design of AIE fluorogen (AIEgen)-based multifunctional organic nanoparticles with surface siRNA decoration for targeted photodynamic therapy and RNA interference therapy. PMID- 26759833 TI - Therapeutic drug monitoring in dried blood spots using liquid microjunction surface sampling and high resolution mass spectrometry. AB - Dried blood spots (DBS) are a versatile and stable tool for direct clinical blood analysis. Ambient high-resolution mass spectrometry is emerging as a method of choice for their quantitative analysis, for instance in therapeutic drug monitoring. Here, we coupled liquid microjunction surface sampling technology, a so-called Flowprobe, with an Orbitrap mass spectrometer and demonstrated the utility of this set-up for direct quantification of multiple drugs in DBS on filter paper. A three-layer set-up that we had introduced earlier enabled introduction of internal standards into DBS. We furthermore took an established point-of-care test system a step further and analyzed disposable test fields for blood glucose monitoring also for Flowprobe-based acetaminophen screening without additional sample preparation. Using as little as 2 MUL blood, the method had an LOD of 1 MUg mL(-1) (coefficient of variation of <=15%) and acetaminophen recoveries of 82 to 119% for blinded samples, as assessed by LC-MS/MS. Half an hour after ingestions of a single 1000 mg acetaminophen dose, indistinguishable drug levels were measured in three healthy volunteers by LC-MS/MS and Flowprobe Orbitrap MS analysis of DBS. Flowprobe analysis of DBS was 6- to 100-times more sensitive than corresponding desorption electrospray ionization MS analysis for four drugs. For instance, the LOD for salicylic acid analysis was 0.07 ng mL(-1) with Flowprobe measurement. Furthermore, we showed that multi-component analysis of five different substances, which may mimic polypharmacy in diabetes patients, in one blood sample for screening purposes was feasible. Taken together, our study suggests that microjunction surface sampling of DBS on filter paper and disposable point-of-care test fields may be developed into routine methods for near-patient multi-compound therapeutic drug monitoring that may advance blood screening analysis for patients with polypharmacy. PMID- 26759836 TI - Rational design and synthesis of substrate-product analogue inhibitors of alpha methylacyl-coenzyme A racemase from Mycobacterium tuberculosis. AB - 2,2-Bis(4-isobutylphenyl)propanoyl-CoA and 2,2-bis(4-t-butylphenyl)propanoyl-CoA are rationally designed, gem-disubstituted substrate-product analogues that competitively inhibit alpha-methylacyl-coenzyme A racemase from Mycobacterium tuberculosis with Ki values of 16.9 +/- 0.6 and 21 +/- 4 MUM, respectively, exceeding the enzyme's affinity for the substrate by approximately 5-fold. PMID- 26759837 TI - Water-soluble sulfonated hyperbranched poly(arylene oxindole) catalysts as functional biomimics of cellulases. AB - A new polymer acid catalyst, sulfonated hyperbranched poly(arylene oxindole), 5 OH-SHPAO, was prepared for selective cellulose hydrolysis. Its superior catalysis, showing high glucose selectivity at almost full cellulose conversion, is attributed to the presence of an hydroxyl group next to the sulfonic acid, therefore mimicking the separate acid-base pair in the cellulase active site. PMID- 26759838 TI - Interfacial nano-biosensing in microfluidic droplets for high-sensitivity detection of low-solubility molecules. AB - Taking advantage of the properties of the high surface-area-to-volume ratio of microfluidic droplets, we developed an innovative interfacial nanosensing strategy based on aptamer-functionalized graphene oxide nanosensors in microfluidic droplets for the high-sensitivity one-step detection of 17beta estradiol and other low-solubility molecules, with the detection sensitivity improved by about 3 orders of magnitude compared to conventional systems. PMID- 26759839 TI - Development and sensing applications of fluorescent motifs within the mitochondrial environment. AB - The potential use of fluorescent molecular probes to measure ions and biomolecules has contributed incessantly to the understanding of chemical and biological systems. The approach has many advantages such as high sensitivity, simplicity and non-destructive cellular imaging that offer visible information about the targeted species. In this article, our objective is to discuss fluorescent probes that have sensing applications within the mitochondrial environment. Mitochondria are cellular organelles which are well known for their unique physiological functions and have been found to be associated with various diseases and disorders. It is therefore, important to develop new tools and tactics that can provide useful information concerning the mitochondrial environment which in turn is essential to understand its biophysical functioning and related diseases. PMID- 26759842 TI - Acute rheumatic fever in First Nations communities in northwestern Ontario: Social determinants of health "bite the heart". AB - OBJECTIVE: To document a case series of 8 young First Nations patients diagnosed with acute rheumatic fever (ARF), a preventable disease that resulted in the death of 2 patients, in northwestern Ontario in the context of late diagnosis, overcrowded housing, and inadequate public health response. DESIGN: Retrospective case series over an 18-month period. SETTING: Remote First Nations communities in northwestern Ontario. PARTICIPANTS: Eight patients with ARF. MAIN OUTCOME MEASURES: Incidence, mortality, residual rheumatic heart disease, time to diagnosis, barriers to diagnosis and treatment, housing situation of patients, patient demographic characteristics (age, sex), and investigation results. RESULTS: The incidence of ARF in this population was 21.3 per 100,000, which is 75 times greater than the overall Canadian estimated incidence. The average patient age was 9.4 years. Most cases developed joint findings, and 5 of the surviving patients had rheumatic heart disease when they received echocardiography. The average time to diagnosis was 88 days. Two 4-year-old children died from ARF. Most patients lived in inadequate and crowded housing. CONCLUSION: This rare disease still exists in remote First Nations communities. These communities demonstrate an incidence equal to that in aboriginal communities in Australia and New Zealand, which have among the highest international incidence of ARF. Primordial prevention, including improved on reserve housing, is urgently needed. Case detection and ongoing surveillance for primary and secondary prophylaxis requires a well resourced regional strategy. PMID- 26759844 TI - Fluconazole use during breastfeeding. AB - QUESTION: I have a patient with persistent breast and nipple thrush. Other therapies have failed, so I have decided to treat her with a loading dose of 400 mg of oral fluconazole followed by 100 mg twice daily for at least 2 weeks. Is there any need for her to interrupt breastfeeding during this treatment? ANSWER: Available data regarding fluconazole use during breastfeeding are reassuring. Fluconazole is also used in the treatment of fungal diseases in infants and has a good safety profile. Therefore, there is no need to interrupt breastfeeding when a mother is treated with fluconazole. PMID- 26759845 TI - Missed connections: Unintended consequences of updated cervical cancer screening guidelines on screening rates for sexually transmitted infections. AB - OBJECTIVE: To examine the effects of the updated 2012 cervical cancer screening guidelines on the rates of sexually transmitted infection (STI) screening in primary care. DESIGN: Retrospective chart review. SETTING: Five academic family practice units at St Michael's Hospital in Toronto, Ont. PARTICIPANTS: Female patients, aged 19 to 25, who had at least 1 visit with a physician at 1 of the 5 academic family practice units during a 12-month period before (May 1, 2011, to April 30, 2012) or after (November 1, 2012, to October 31, 2013) the release of the updated guidelines. MAIN OUTCOME MEASURES: Number of women who received Papanicolaou tests or underwent STI screening; rates of STI screening performed during a Pap test or a periodic health examination; screening rates for HIV, syphilis, and hepatitis C; and the methods used for STI screening before and after the release of the updated guidelines. Results Before the release of the 2012 guidelines, 42 of 100 women had Pap tests and 40 of 100 women underwent STI screening. After the release of the guidelines, 17 of 100 women had Pap tests and 20 of 100 women received STI screening. Female patients were less likely to undergo STI screening under the 2012 guidelines compared with the 2005 guidelines (odds ratio 0.38, 95% CI 0.19 to 0.74; P = .003). CONCLUSION: Implementation of the 2012 cervical cancer screening guidelines was associated with lower rates of STI screening in the primary care setting. Primary care physicians should screen at-risk women for STIs at any clinically appropriate encounter and consider using noninvasive self-sampling methods. PMID- 26759846 TI - Access to and use of sexual health care services among young Canadians with and without a history of sexual coercion. AB - OBJECTIVE: To determine access to and use of sexual health care services among adolescents and young adults with and without a history of sexual coercion, and to examine whether a history of sexual coercion was a barrier to using sexual health care services. DESIGN: Online survey. SETTING: Canada. PARTICIPANTS: A total of 405 adolescents and young adults aged 16 to 21. MAIN OUTCOME MEASURES: Participants' sexual histories, sexual coercion histories, current psychological functioning, and perceptions and use of health care services. RESULTS: A history of sexual coercion was reported by 29.6% of participants; more female participants reported a history of sexual coercion than male participants did, and female participants reported more related distress than male participants did. Those with a history of sexual coercion reported more sexual health-related visits than those without a history of sexual coercion did. Among participants with and without sexual coercion histories, there were no differences in difficulty accessing care, perceived quality of care, or rates of unmet health needs. Among those who reported a history of sexual coercion, the odds of having a sexual health-related visit increased for those who had had a routine checkup in the previous year (odds ratio = 8.29) and those who believed it was not difficult to access care (odds ratio = 1.74). CONCLUSION: Having a history of sexual coercion was not a barrier to the use of health care services among adolescents and young adults. In fact, rates of health care service use were higher among those with a history of sexual coercion than those without such a history. PMID- 26759848 TI - High-Temperature Electromechanical Characterization of AlN Single Crystals. AB - Hexagonal AlN is a non-ferroelectric material and does not have any phase transition up to its melting point (>2000 degrees C), which indicates the potential use of AlN for high-temperature sensing. In this work, the elastic, dielectric, and piezoelectric constants of AlN single crystals were investigated at elevated temperatures up to 1000 degrees C by the resonance method. We used resonators of five different modes to obtain a complete set of material constants of AlN single crystals. The electrical resistivity of AlN at elevated temperature (1000 degrees C) was found to be greater than 5 * 10(10) Omega . cm. The resonance frequency of the resonators, which was mainly determined by the elastic compliances, decreased linearly with increasing temperature, and was characterized by a relatively low temperature coefficient of frequency, in the range of -20 to -36 ppm/ degrees C. For all the investigated resonator modes, the elastic constants and the electromechanical coupling factors exhibited excellent temperature stability, with small variations over the full temperature range, <11.2% and <17%, respectively. Of particular significance is that due to the pyroelectricity of AlN, both the dielectric and the piezoelectric constants had high thermal resistivity even at extreme high temperature (1000 degrees C). Therefore, high electrical resistivity, temperature independence of electromechanical properties, as well as high thermal resistivity of the elastic, dielectric, and piezoelectric properties, suggest that AlN single crystals are a promising candidate for high-temperature piezoelectric sensing applications. PMID- 26759847 TI - Identifying patients with asthma in primary care electronic medical record systems Chart analysis-based electronic algorithm validation study. AB - OBJECTIVE: To develop and test a variety of electronic medical record (EMR) search algorithms to allow clinicians to accurately identify their patients with asthma in order to enable improved care. DESIGN: A retrospective chart analysis identified 5 relevant unique EMR information fields (electronic disease registry, cumulative patient profile, billing diagnostic code, medications, and chart notes); asthma-related search terms were designated for each field. The accuracy of each term was tested for its ability to identify the asthma patients among all patients whose charts were reviewed. Increasingly sophisticated search algorithms were then designed and evaluated by serially combining individual searches with Boolean operators. SETTING: Two large academic primary care clinics in Hamilton, Ont. PARTICIPANTS: Charts for 600 randomly selected patients aged 16 years and older identified in an initial EMR search as likely having asthma (n = 150), chronic obstructive pulmonary disease (n = 150), other respiratory conditions (n = 150), or nonrespiratory conditions (n = 150) were reviewed until 100 patients per category were identified (or until all available names were exhausted). A total of 398 charts were reviewed in full and included. MAIN OUTCOME MEASURES: Sensitivity and specificity of each search for asthma diagnosis (against the reference standard of a physician chart review-based diagnosis). RESULTS: Two physicians reviewed the charts identified in the initial EMR search using a standardized data collection form and ascribed the following diagnoses in 398 patients: 112 (28.1%) had asthma, 81 (20.4%) had chronic obstructive pulmonary disease, 104 (26.1%) had other respiratory conditions, and 101 (25.4%) had nonrespiratory conditions. Concordance between reviewers in chart abstraction diagnosis was high (kappa = 0.89, 95% CI 0.80 to 0.97). Overall, the algorithm searching for patients who had asthma in their cumulative patient profiles or for whom an asthma billing code had been used was the most accurate (sensitivity of 90.2%, 95% CI 87.3% to 93.1%; specificity of 83.9%, 95% CI 80.3% to 87.5%). CONCLUSION: Usable, practical search algorithms that accurately identify patients with asthma in existing EMRs are presented. Clinicians can apply 1 of these algorithms to generate asthma registries for targeted quality improvement initiatives and outcome measurements. This methodology can be emulated for other diseases. PMID- 26759850 TI - Mole's Wow! So now you have your own lab! Part VI - FCTWAWKI. By Caveman. PMID- 26759849 TI - Increased Fetal Nuchal Translucency - Also a Risk for a Rare Submicroscopic Chromosomal Abnormalities. PMID- 26759851 TI - [The beginnings of real-time ultrasound cross sectional image diagnosis 50 years ago]. PMID- 26759853 TI - In reply. PMID- 26759852 TI - In reply. PMID- 26759854 TI - Deaths: Leading Causes for 2012. AB - OBJECTIVES: This report presents final 2012 data on the 10 leading causes of death in the United States by age, sex, race, and Hispanic origin. Leading causes of infant, neonatal, and postneonatal death are also presented. This report supplements "Deaths: Final Data for 2012," the National Center for Health Statistics' annual report of final mortality statistics. METHODS: Data in this report are based on information from all death certificates filed in the 50 states and the District of Columbia in 2012. Causes of death classified by the International Classification of Diseases, Tenth Revision (ICD-10) are ranked according to the number of deaths assigned to rankable causes. Cause-of-death statistics are based on the underlying cause of death. RESULTS: In 2012, the 10 leading causes of death were, in rank order: Diseases of heart; Malignant neoplasms; Chronic lower respiratory diseases; Cerebrovascular diseases; Accidents (unintentional injuries); Alzheimer's disease; Diabetes mellitus; Influenza and pneumonia; Nephritis, nephrotic syndrome and nephrosis; and Intentional self-harm (suicide). These causes accounted for 74% of all deaths occurring in the United States. Differences in the rankings are evident by age, sex, race, and Hispanic origin. Leading causes of infant death for 2012 were, in rank order: Congenital malformations, deformations and chromosomal abnormalities; Disorders related to short gestation and low birth weight, not elsewhere classified; Sudden infant death syndrome; Newborn affected by maternal complications of pregnancy; Accidents (unintentional injuries); Newborn affected by complications of placenta, cord and membranes; Bacterial sepsis of newborn; Respiratory distress of newborn; Diseases of the circulatory system; and Neonatal hemorrhage. Important variations in the leading causes of infant death are noted for the neonatal and postneonatal periods. PMID- 26759855 TI - Deaths: Final Data for 2012. AB - OBJECTIVES: This report presents final 2012 data on U.S. deaths, death rates, life expectancy, infant mortality, and trends by selected characteristics such as age, sex, Hispanic origin, race, state of residence, and cause of death. METHODS: Information reported on death certificates, which is completed by funeral directors, attending physicians, medical examiners, and coroners, is presented in descriptive tabulations. The original records are filed in state registration offices. Statistical information is compiled in a national database through the Vital Statistics Cooperative Program of the Centers for Disease Control and Prevention's National Center for Health Statistics. Causes of death are processed in accordance with the International Classification of Diseases, Tenth Revision. RESULTS: In 2012, a total of 2,543,279 deaths were reported in the United States. The age-adjusted death rate was 732.8 deaths per 100,000 U.S. standard population, a decrease of 1.1% from the 2011 rate and a record low figure. Life expectancy at birth rose 0.1 year, from 78.7 years in 2011 to a record high of 78.8 in 2012. Age-specific death rates decreased in 2012 from 2011 for age groups 5-14, 15-24, 45-54, 65-74, 75-84, and 85 and over. Age-specific death rates increased only for age group 55-64. The leading causes of death in 2012 remained the same as in 2011. The infant mortality rate of 5.98 deaths per 1,000 live births in 2012 was a historically low value, but it was not significantly different from the 2011 rate. CONCLUSIONS: The decline of the age-adjusted death rate to a record low value for the United States, and the increase in life expectancy to a record high value of 78.8 years, are consistent with long-term trends in mortality. PMID- 26759857 TI - [US approval of flibanserin. Germany should make no hype over the "lust pill" ]. PMID- 26759856 TI - [A rare differential diagnosis of acute lower gastrointestinal bleeding: Small bowel diverticulosis]. PMID- 26759858 TI - [Return from the tropics with a fever. Nine questions to determine the cause]. PMID- 26759859 TI - [Diabetes mellitus. SGLT2 inhibitor reduces cardiovascular mortality]. PMID- 26759860 TI - [Autonomic neuropathy of the gastrointestinal tract. Diabetes can be hard on the stomach]. PMID- 26759861 TI - [Cardiovascular comorbidity in chronic obstructive bronchitis. COPD patients frequently also have heart manifestations]. PMID- 26759862 TI - [Herbal drugs and teas for the common cold]. PMID- 26759863 TI - [Evidence under scrutiny. Neuraminidase inhibitors in severe influenza: yes or no?]. PMID- 26759864 TI - [Fibromyalgia syndrome. Patients request osteopathy]. PMID- 26759865 TI - [Reply from Prof. Fuessl]. PMID- 26759866 TI - [Your patient needs an antithrombotic drug. Venous thrombosis of the leg: how and how long anticoagulation?]. PMID- 26759867 TI - [Suspected severe pneumonia. Antibiotics are ineffective - what now?]. PMID- 26759868 TI - [Rheumatic ailments. Can arthritis drugs be tapered?]. PMID- 26759869 TI - [In telephone consultation Nr. 3 GOA is also possible]. PMID- 26759871 TI - [GOA exclusion? Calculate expenses anyway!]. PMID- 26759872 TI - [Patients an incorrigible sweet tooth I do not want in my practice]. PMID- 26759870 TI - [Using the troponin test economically]. PMID- 26759873 TI - [Physician shortage in Saxony-Anhalt. The former youngster returns as country doctor]. PMID- 26759874 TI - [Patient service. Is our practice stuck with the copying costs?]. PMID- 26759875 TI - [Physician practice organization. The fine art of time management]. PMID- 26759877 TI - [CT angiography in suspected coronary heart disease has no advantage]. PMID- 26759876 TI - [Patient triage already via telephone]. PMID- 26759878 TI - [Why experts consider themselves omniscient]. PMID- 26759879 TI - [Even bicycling is not just healthy]. PMID- 26759880 TI - [Vaccinations do not cause multiple sclerosis]. PMID- 26759881 TI - [Improved air quality allows children to breathe]. PMID- 26759882 TI - [From this dungeon the lung cannot escape alone]. PMID- 26759884 TI - [To walk to work instead of of "eat only half"]. PMID- 26759883 TI - [Chest pain symptoms not predictive of acute coronary syndrome]. PMID- 26759886 TI - [Malignant melanoma of the conjunctiva]. PMID- 26759887 TI - ["Sweet home"--endangered by domestic accidents?]. PMID- 26759885 TI - [An active life protects against dementia]. PMID- 26759888 TI - [Accidental caustic injuries]. PMID- 26759889 TI - [Emergency treatment of electrical injuries]. PMID- 26759890 TI - [Burn injury in children--recent trends in treatment]. PMID- 26759891 TI - [3D-navigated iliosacral screw for pelvic fractures]. PMID- 26759892 TI - [Management of solitary pulmonary nodules]. PMID- 26759893 TI - [Man with severe abdominal pain]. PMID- 26759894 TI - [Adverse reactions due to antihypertensives--single and multiple drug intolerance]. PMID- 26759895 TI - Improving the system: One action at a time. PMID- 26759896 TI - Multicolor Quantum Dot-Based Chemical Nose for Rapid and Array-Free Differentiation of Multiple Proteins. AB - Nanomaterial-based differential sensors (e.g., chemical nose) have shown great potential for identification of multiple proteins because of their modulatable recognition and transduction capability but with the limitation of array separation, single-channel read-out, and long incubation time. Here, we develop a multicolor quantum dot (QD)-based multichannel sensing platform for rapid identification of multiple proteins in an array-free format within 1 min. A protein-binding dye of bromophenol blue (BPB) is explored as an efficient reversible quencher of QDs, and the mixture of BPB with multicolor QDs may generate the quenched QD-BPB complexes. The addition of proteins will disrupt the QD-BPB complexes as a result of the competitive protein-BPB binding, inducing the separation of BPB from the QDs and the generation of distinct fluorescence patterns. The multicolor patterns may be collected at a single-wavelength excitation and differentiated by a linear discriminant analysis (LDA). This multichannel sensing platform allows for the discrimination of ten proteins and seven cell lines with the fastest response rate reported to date, holding great promise for rapid and high-throughput medical diagnostics. PMID- 26759897 TI - Tunable Excited-State Properties and Dynamics as a Function of Pt-Pt Distance in Pyrazolate-Bridged Pt(II) Dimers. AB - The influence of molecular structure on excited-state properties and dynamics of a series of cyclometalated platinum dimers was investigated through a combined experimental and theoretical approach using femtosecond transient absorption (fs TA) spectroscopy and density functional theory (DFT) calculations. The molecules have the general formula [Pt(ppy)(MU-R2pz)]2, where ppy = 2-phenylpyridine, pz = pyrazolate, and R = H, Me, Ph, or (t)Bu, and are strongly photoluminescent at room temperature. The distance between the platinum centers in this A-frame geometry can be varied depending on the steric bulk of the bridging pyrazolate ligands that exert structural constraints and compress the Pt-Pt distance. At large Pt-Pt distances there is little interaction between the subunits, and the chromophore behaves similar to a monomer with excited states described as mixtures of ligand-centered and metal-to-ligand charge transfer (LC/MLCT) transitions. When the Pt(II) centers are brought closer together with bulky bridging ligands, they interact through their dz(2) orbitals and the S1 and T1 states are best characterized as metal-metal-to-ligand charge transfer (MMLCT) in character. The results of the femtoseconds TA experiments reveal that intersystem crossing (ISC) occurs on ultrafast time scales (tauS1 < 200 fs), while there are two relaxation processes occurring within the triplet manifold, tau1 = 0.5-3.2 ps and tau2 = 20-70 ps; the longer time constants correspond to the presence of bulkier bridging ligands. DFT calculations illustrate that the Pt-Pt distances further contract in the T1 (3)MMLCT states; therefore, slower relaxation may be related to a larger structural reorganization. Subsequent investigations using faster time resolution are planned to measure the ISC process as well as to identify any potential coherent interaction(s) between the platinum centers that may occur. PMID- 26759914 TI - Synthesis of Nucleoside Triphosphates from 2'-3'-Protected Nucleosides Using Trimetaphosphate. AB - Chemists have been attempting to triphosphorylate nucleosides and other alcohols using trimetaphosphate (TriMP) since the 1960s. However, this route appears to have been abandoned due to poor yields. The first practical syntheses of nucleoside triphosphates (NTPs) are reported using TriMP as the key reagent. This was achieved by reacting the tetrabutylammonium salt of TriMP with mesitylenesulfonyl chloride in the presence of DABCO in pyridine followed by the addition of an appropriately protected nucleoside and phthalimide. Quenching the reaction with aqueous buffer followed by hydrolysis of the OH protecting groups gave the NTPs in good yield. PMID- 26759915 TI - Molecular Recognition of Lys and Arg Methylation. AB - A network of reader proteins and enzymes precisely controls gene transcription through the dynamic addition, removal, and recognition of post-translational modifications (PTMs) of histone tails. Histone PTMs work in concert with this network to regulate gene transcription through the histone code, and the dysregulation of PTM maintenance is linked to a large number of diseases, including many types of cancer. A wealth of research aims to elucidate the functions of this code, but our understanding of the effects of PTMs, specifically the methylation of lysine (Lys) and arginine (Arg), is lacking. The development of new tools to study PTMs relies on a sophisticated understanding of the mechanisms that drive protein and small molecule recognition in water. In this review, we outline the physical organic concepts that drive the molecular recognition of Lys and Arg methylation by reader proteins and draw comparisons to the binding mechanisms of small molecule receptors for methylated Lys and Arg that have been developed recently. PMID- 26759917 TI - Unabsorbed dura patch removed eight years after pituitary surgery. AB - The Codman ETHISORB Dura Patch is a synthetic, absorbable material whose absorption is complete within approximately 90 days. We report the first case of an unabsorbed Codman Dura patch, in which a patient was presented with nasal obstruction and epistaxis 8 years after pituitary surgery for Cushing's disease. PMID- 26759916 TI - Completing the Link between Exposure Science and Toxicology for Improved Environmental Health Decision Making: The Aggregate Exposure Pathway Framework. AB - Driven by major scientific advances in analytical methods, biomonitoring, computation, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition from a field of observation to a field of prediction. Deployment of an organizational and predictive framework for exposure science analogous to the "systems approaches" used in the biological sciences is a necessary step in this evolution. Here we propose the aggregate exposure pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the adverse outcome pathway (AOP) concept in the toxicological sciences. Aggregate exposure pathways offer an intuitive framework to organize exposure data within individual units of prediction common to the field, setting the stage for exposure forecasting. Looking farther ahead, we envision direct linkages between aggregate exposure pathways and adverse outcome pathways, completing the source to outcome continuum for more meaningful integration of exposure assessment and hazard identification. Together, the two frameworks form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making. PMID- 26759918 TI - Development of a semidefined growth medium for Pedobacter cryoconitis BG5 using statistical experimental design. AB - Pedobacter cryoconitis BG5 are psychrophiles isolated from the cold environment and capable of proliferating and growing well at low temperature regime. Their cellular products have found a broad spectrum of applications, including in food, medicine, and bioremediation. Therefore, it is imperative to develop a high-cell density cultivation strategy coupled with optimized growth medium for P. cryoconitis BG5. To date, there has been no published report on the design and optimization of growth medium for P. cryoconitis, hence the objective of this research project. A preliminary screening of four commercially available media, namely tryptic soy broth, R2A, Luria Bertani broth, and nutrient broth, was conducted to formulate the basal medium. Based on the preliminary screening, tryptone, glucose, NaCl, and K2HPO4 along with three additional nutrients (yeast extract, MgSO4, and NH4Cl) were identified to form the basal medium which was further analyzed by Plackett-Burman experimental design. Central composite experimental design using response surface methodology was adopted to optimize tryptone, yeast extract, and NH4Cl concentrations in the formulated growth medium. Statistical data analysis showed a high regression factor of 0.84 with a predicted optimum optical (600 nm) cell density of 7.5 using 23.7 g/L of tryptone, 8.8 g/L of yeast extract, and 0.7 g/L of NH4Cl. The optimized medium for P. cryoconitis BG5 was tested, and the observed optical density was 7.8. The cost-effectiveness of the optimized medium was determined as 6.25 unit prices per gram of cell produced in a 250-ml Erlenmeyer flask. PMID- 26759919 TI - Photoexcited Surface Frustrated Lewis Pairs for Heterogeneous Photocatalytic CO2 Reduction. AB - In this study we investigated, theoretically and experimentally, the unique photoactive behavior of pristine and defected indium oxide surfaces providing fundamental insights into their excited state properties as well as an explanation for the experimentally observed enhanced activity of defected indium oxide surfaces for the gas-phase reverse water gas shift reaction, CO2 + H2 + hnu > CO + H2O in the light compared to the dark. To this end, a detailed excited state study of pristine and defected forms of indium oxide (In2O3, In2O3-x, In2O3(OH)y and In2O3-x(OH)y) surfaces was performed using time dependent density functional theory (TDDFT) calculations, the results of which were supported experimentally by transient absorption spectroscopy and photoconductivity measurements. It was found that the surface frustrated Lewis pairs (FLPs) created by a Lewis acidic coordinately unsaturated surface indium site proximal to an oxygen vacancy and a Lewis basic surface hydroxide site in In2O3-x(OH)y become more acidic and basic and hence more active in the ES compared to the GS. This provides a theoretical mechanism responsible for the enhanced activity and reduced activation energy of the photochemical reverse water gas shift reaction observed experimentally for In2O3-x(OH)y compared to the thermochemical reaction. This fundamental insight into the role of photoexcited surface FLPs for catalytic CO2 reduction could lead to improved photocatalysts for solar fuel production. PMID- 26759921 TI - One-Pot Synthesis of Multisubstituted Benzimidazoles via Sequential Ugi and Catalytic Aza-Wittig Reaction Starting from 2-Aminobenzoyl Azides. AB - A simple and one-pot synthesis of multisubstituted benzimidazoles by a Ugi 4CC/catalytic aza-Wittig sequence was developed. The reaction of 2-aminobenzoyl azide 2, aldehyde 3, acid 4, and isocyanide 5 produced the benzimidazoles 8 in moderate to good yields via a sequential Ugi condensation and catalytic aza Wittig in the presence of a catalytic amount of phospholene oxide. PMID- 26759922 TI - Cost and Utilization of Retail Clinics vs. Other Providers for Treatment of Pediatric Acute Otitis Media. AB - A common acute condition seen by providers in retails clinics is the evaluation and treatment of acute otitis media (AOM) in children younger than age 20. Annual direct treatment costs for AOM were US $5.3 billion in 1998 dollars. Based on the experience of a large retail pharmacy employer, the authors compared AOM episodes in covered dependents younger than age 20 in retail clinic states to those in states without retail clinic access. Relative costs as well as frequency of visits and antibiotic prescriptions were analyzed for both retail clinic-based, and non-retail clinic-based episodes. Rates of AOM episodes were lower in retail clinic than in non-retail clinic states (62.5 vs. 76.9 per 1000 members per year; P < .0001). The average number of visits per episode was similar between retail clinic and non-retail clinic states (1.417 vs. 1.430, respectively; P = 0.657), suggesting that retail clinics do not result in an increase in overall utilization. On a risk-adjusted basis, retail clinic episodes cost approximately $30-$130 less than community episodes, depending on year. In retail clinic states, the antibiotic prescription fill rate was 95.4% for retail clinic episodes and 82.8% for community episodes, consistent with rates in the literature. This study confirms results of earlier studies that retail clinics are a less costly setting than the community for the treatment of episodes of otitis media There also is little evidence that retail clinics lead to duplication of services (patients receiving follow-up care in other settings). PMID- 26759923 TI - Enantioselective Total Synthesis of Mandelalide A and Isomandelalide A: Discovery of a Cytotoxic Ring-Expanded Isomer. AB - The total synthesis of mandelalide A and its ring-expanded macrolide isomer isomandelalide A has been achieved. Unexpected high levels of cytotoxicity were observed with the ring-expanded isomandelalide A with a rank order of potency: mandelalide A > isomandelalide A > mandelalide B. Key aspects of the synthesis include Ag-catalyzed cyclizations (AgCC's) to construct both the THF and THP rings present in the macrocycle, diastereoselective Sharpless dihydroylation of a cis-enyne, and lithium acetylide coupling with a chiral epoxide. PMID- 26759920 TI - Gold Nanorods Based Air Scanning Electron Microscopy and Diffusion Reflection Imaging for Mapping Tumor Margins in Squamous Cell Carcinoma. AB - A critical challenge arising during a surgical procedure for tumor removal is the determination of tumor margins. Gold nanorods (GNRs) conjugated to epidermal growth factor receptors (EGFR) (GNRs-EGFR) have long been used in the detection of cancerous cells as the expression of EGFR dramatically increases once the tissue becomes cancerous. Optical techniques for the identification of these GNRs EGFR in tumor are intensively developed based on the unique scattering and absorption properties of the GNRs. In this study, we investigate the distribution of the GNRs in tissue sections presenting squamous cell carcinoma (SCC) to evaluate the SCC margins. Air scanning electron microscopy (airSEM), a novel, high resolution microscopy is used, enabling to localize and actually visualize nanoparticles on the tissue. The airSEM pictures presented a gradient of GNRs from the tumor to normal epithelium, spread in an area of 1 mm, suggesting tumor margins of 1 mm. Diffusion reflection (DR) measurements, performed in a resolution of 1 mm, of human oral SCC have shown a clear difference between the DR profiles of the healthy epithelium and the tumor itself. PMID- 26759924 TI - Norovirus gastroenteritis outbreak transmitted by food and vomit in a high school. AB - We investigated an outbreak of norovirus that affected students and teachers of a high school in Lleida, Spain through various transmission mechanisms. A case control epidemiological study of the risk of disease and the relative importance of each mode of transmission was carried out. Cases and controls were selected from a systematic sample of students and teachers present at the school on 28 January. Faecal samples were taken from three food handlers and 16 cases. The influence of each factor was studied using the adjusted odds ratio (aOR) and the estimated population attributable risk (ePAR) with 95% confidence intervals (CI). We interviewed 210 people (42 cases, 168 controls). The proportion of symptoms in these individuals was nausea 78.6%, vomiting 59.5%, diarrhoea 45.2%, and fever 19.0%. The epidemic curve showed transmission for at least 4 days. The risk of disease was associated with exposure to food (aOR 5.8) in 66.1% of cases and vomit (aOR 4.7) in 24.8% of cases. Faecal samples from 11 patients and two food handlers were positive for norovirus GII.12 g. Vomit may co-exist with other modes of transmission in norovirus outbreaks and could explain a large number of cases. PMID- 26759925 TI - Traffic accident reconstruction and an approach for prediction of fault rates using artificial neural networks: A case study in Turkey. AB - OBJECTIVE: Currently, in Turkey, fault rates in traffic accidents are determined according to the initiative of accident experts (no speed analyses of vehicles just considering accident type) and there are no specific quantitative instructions on fault rates related to procession of accidents which just represents the type of collision (side impact, head to head, rear end, etc.) in No. 2918 Turkish Highway Traffic Act (THTA 1983). The aim of this study is to introduce a scientific and systematic approach for determination of fault rates in most frequent property damage-only (PDO) traffic accidents in Turkey. METHODS: In this study, data (police reports, skid marks, deformation, crush depth, etc.) collected from the most frequent and controversial accident types (4 sample vehicle-vehicle scenarios) that consist of PDO were inserted into a reconstruction software called vCrash. Sample real-world scenarios were simulated on the software to generate different vehicle deformations that also correspond to energy-equivalent speed data just before the crash. These values were used to train a multilayer feedforward artificial neural network (MFANN), function fitting neural network (FITNET, a specialized version of MFANN), and generalized regression neural network (GRNN) models within 10-fold cross-validation to predict fault rates without using software. The performance of the artificial neural network (ANN) prediction models was evaluated using mean square error (MSE) and multiple correlation coefficient (R). RESULTS: It was shown that the MFANN model performed better for predicting fault rates (i.e., lower MSE and higher R) than FITNET and GRNN models for accident scenarios 1, 2, and 3, whereas FITNET performed the best for scenario 4. The FITNET model showed the second best results for prediction for the first 3 scenarios. Because there is no training phase in GRNN, the GRNN model produced results much faster than MFANN and FITNET models. However, the GRNN model had the worst prediction results. The R values for prediction of fault rates were close to 1 for all folds and scenarios. CONCLUSIONS: This study focuses on exhibiting new aspects and scientific approaches for determining fault rates of involvement in most frequent PDO accidents occurring in Turkey by discussing some deficiencies in THTA and without regard to initiative and/or experience of experts. This study yields judicious decisions to be made especially on forensic investigations and events involving insurance companies. Referring to this approach, injury/fatal and/or pedestrian related accidents may be analyzed as future work by developing new scientific models. PMID- 26759926 TI - An MMP-2 Responsive Liposome Integrating Antifibrosis and Chemotherapeutic Drugs for Enhanced Drug Perfusion and Efficacy in Pancreatic Cancer. AB - Fibrotic stroma, a critical character of pancreatic tumor microenvironment, provides a critical barrier against the penetration and efficacy of various antitumor drugs. Therefore, new strategies are urgently needed to alleviate the fibrotic mass and increase the drug perfusion within pancreatic cancer tissue. In our current work, we developed a beta-cyclodextrin (beta-CD) modified matrix metalloproteinase-2 (MMP-2) responsive liposome, integrating antifibrosis and chemotherapeutic drugs for regulation of pancreatic stellate cells (PSCs), a key source of the fibrosis, and targeted delivery of cytotoxic drugs for pancreatic cancer therapy. These liposomes disassembed into two functional parts upon MMP-2 cleavage at the tumor site. One part was constituted by the beta-CDs and the antifibrosis drug pirfenidone, which was kept in the stroma and inhibited the expression of collagen I and TGF-beta in PSCs, down-regulating the fibrosis and decreasing the stromal barrier. The other segment, the RGD peptide-modified liposome loading the chemotherapeutic drug gemcitabine, targeted and killed pancreatic tumor cells. This integrated nanomedicine, showing an increased drug perfusion without any overt side effects, may provide a potential strategy for improvement of the pancreatic cancer therapy. PMID- 26759927 TI - Dangerous student car drop-off behaviors and child pedestrian-motor vehicle collisions: An observational study. AB - OBJECTIVES: The objective of this study was to examine the association between dangerous student car drop-off behaviors and historical child pedestrian-motor vehicle collisions (PMVCs) near elementary schools in Toronto, Canada. METHODS: Police-reported child PMVCs during school travel times from 2000 to 2011 were mapped within 200 m of 118 elementary schools. Observers measured dangerous student morning car drop-off behaviors and number of children walking to school during one day in 2011. A composite score of school social disadvantage was obtained from the Toronto District School Board. Built environment and traffic features were mapped and included as covariates. A multivariate Poisson regression was used to model the rates of PMVC/number of children walking and dangerous student car drop-off behaviors, adjusting for the built environment and social disadvantage. RESULTS: There were 45 child PMVCs, with 29 (64%) sustaining minor injuries resulting in emergency department visits. The mean collision rate was 2.9/10,000 children walking/year (SD = 6.7). Dangerous drop-off behaviors were observed in 104 schools (88%). In the multivariate analysis, each additional dangerous drop-off behavior was associated with a 45% increase in collision rates (incident rate ratio [IRR] = 1.45, 95% confidence interval [CI], 1.02, 2.07). Higher speed roads (IRR = 1.27, 95% CI, 1.13, 1.44) and social disadvantage (IRR = 2.99, 95% CI, 1.03, 8.68) were associated with higher collision rates. CONCLUSIONS: Dangerous student car drop-off behaviors were associated with historical nonfatal child PMVC rates during school travel times near schools. Some caution must be taken in interpreting these results due small number of events and limitations in the data collection, because collision data were collected historically over a 12-year period, whereas driving behavior was only observed on a single day in 2011. Targeted multifaceted intervention approaches related to the built environment, enforcement, and education could address dangerous drop-off behaviors near schools to reduce child PMVCs and promote safe walking to school. PMID- 26759929 TI - Outcomes from a departmental performance audit and qualitative survey of midwives at Great Western Hospital, Swindon. PMID- 26759928 TI - Spinal intramedullary mature cystic teratoma in an adult. AB - Spinal intramedullary teratoma is a rare tumour characterised with slow progression course. Although symptoms are generally mild, long-term complaints can be observed due to the slow progression. In this report, we discuss a 29-year old female diagnosed as mature cystic teratoma in thoracolumbar junction. PMID- 26759930 TI - Practical Applications in Immunohistochemistry: Evaluation of Rejection and Infection in Organ Transplantation. AB - CONTEXT: -Immunohistochemical analysis of tissue biopsy specimens is a crucial tool in diagnosis of both rejection and infection in patients with solid organ transplants. In the past 15 years, the concept of antibody-mediated rejection has been refined, and diagnostic criteria have been codified in renal, heart, pancreas, and lung allografts (with studies ongoing in liver, small intestine, and composite grafts), all of which include immunoanalysis for the complement split product C4d. OBJECTIVES: -To review the general concepts of C4d biology and immunoanalysis, followed by organ-allograft-specific data, and interpretative nuances for kidney, pancreas, and heart, with discussion of early literature for lung and liver biopsies. Additionally, practical applications and limitations of immunostains for infectious organisms (Polyomavirus, Adenoviridae [adenovirus], and the herpes virus family, including Herpes simplex virus, Cytomegalovirus, Human herpes virus 8, and Epstein-Barr virus) are reviewed in the context of transplant recipients. DATA SOURCES: -Our experience and published primary and review literature. CONCLUSIONS: -Immunohistochemistry continues to have an important role in transplant pathology, most notably C4d staining in assessment of antibody-mediated rejection and assessment of viral pathogens in tissue. In all facets of transplant pathology, correlation of morphology with special studies and clinical data is critical, as is close communication with the transplant team. PMID- 26759931 TI - Falling Together--Empathetic Care for the Dying. PMID- 26759932 TI - Functional Alignment of Metabolic Networks. AB - Network alignment has become a standard tool in comparative biology, allowing the inference of protein function, interaction, and orthology. However, current alignment techniques are based on topological properties of networks and do not take into account their functional implications. Here we propose, for the first time, an algorithm to align two metabolic networks by taking advantage of their coupled metabolic models. These models allow us to assess the functional implications of genes or reactions, captured by the metabolic fluxes that are altered following their deletion from the network. Such implications may spread far beyond the region of the network where the gene or reaction lies. We apply our algorithm to align metabolic networks from various organisms, ranging from bacteria to humans, showing that our alignment can reveal functional orthology relations that are missed by conventional topological alignments. PMID- 26759933 TI - Testing Hypotheses About the Person-Response Function in Person-Fit Analysis. AB - The person-response function (PRF) relates the probability of an individual's correct answer to the difficulty of items measuring the same latent trait. Local deviations of the observed PRF from the expected PRF indicate person misfit. We discuss two new approaches to investigate person fit. The first approach uses kernel smoothing to estimate continuous PRF estimates. Graphical displays of PRFs were used to localize and diagnose misfit. The second approach approximates the PRF by a logistic regression model. Hypothesis tests on the regression parameters were used to detect certain types of misfit. A simulation study was conducted to investigate the Type I error rates and the detection rates of the regression approach. PMID- 26759934 TI - Comparison of Approaches in Estimating Interaction and Quadratic Effects of Latent Variables. AB - Various approaches using the maximum likelihood (ML) option of the LISREL program and products of indicators have been proposed to analyze structural equation models with non-linear latent effects on the basis of Kenny and Judd's formulation. Recently, some methods based on the Bayesian approach and the exact ML approaches have been developed. This article reviews, elaborates and compares several approaches for analyzing nonlinear models with interaction and/or quadratic effects. A total of four approaches are examined, including the product indicator ML approaches proposed by Jaccard and Wan (1995) and Joreskog and Yang (1996), a Bayesian approach and an exact ML approach. The empirical performances of these approaches are assessed using simulation studies in terms of their capabilities in producing reliable parameter and standard error estimates. It is found that whilst the Bayesian and the exact ML approaches produce satisfactory results in all the settings under consideration, and are in general very reliable; the product indicator ML approaches can only produce reasonable results in simple models with large sample sizes. PMID- 26759935 TI - Constrained and Unconstrained Multivariate Normal Finite Mixture Modeling of Piagetian Data. AB - We present the results of multivariate normal mixture modeling of Piagetian data. The sample consists of 101 children, who carried out a (pseudo-)conservation computer task on four occasions. We fitted both cross-sectional mixture models, and longitudinal models based on a Markovian transition model. Piagetian theory of cognitive development provides a strong basis for the number and interpretation of the components in the mixtures. Most studies of Piagetian development have been based on mixture modeling of discrete responses. The present results show that normal mixture modeling is a useful approach, when responses are continuous and approximately normal within the components. Multivariate normal mixture modeling has the advantage that the covariance structure within the components may be modeled. Generally the results are consistent with the presence of distinct modes of responding. This provides support for the hypothesis of stage-wise development. PMID- 26759937 TI - Recognition of MBR Reviewers. PMID- 26759936 TI - The Consequence of Ignoring a Level of Nesting in Multilevel Analysis. AB - Multilevel analysis is an appropriate tool for the analysis of hierarchically structured data. There may, however, be reasons to ignore one of the levels of nesting in the data analysis. In this article a three level model with one predictor variable is used as a reference model and the top or intermediate level is ignored in the data analysis. Analytical results show that this has an effect on the estimated variance components and that standard errors of regression coefficients estimators may be overestimated, leading to a lower power of the test of the effect of the predictor variable. The magnitude of these results depends on the ignored level and the level at which the predictor variable varies, and on the values of the variance components and the sample sizes. PMID- 26759938 TI - A Pseudomonas strain isolated from date-palm rhizospheres improves root growth and promotes root formation in maize exposed to salt and aluminum stress. AB - The aim of this study was to evaluate the effectiveness of Pseudomonas fluorescens 002 (P.f.002.), isolated from the rhizosphere of date palms from the Ghardaia region in the Algerian Sahara, to promote root growth of two varieties of maize under conditions of salt and aluminum stress. Primary roots of 5-day-old seedlings were inoculated with P.f.002., and seedlings were then grown under both control and stressed conditions. Primary, lateral, and seminal root lengths and numbers, as well as root dry mass, were evaluated. P.f.002 increased all parameters measured under both salt and aluminum stress. Hence, the use of P.f.002 may represent an important biotechnological approach to decrease the impact of salinity and acidity in crops. PMID- 26759939 TI - Rating of perceived exertion in maximal incremental tests during head-out water based aerobic exercises. AB - The present study aimed to assess the relationship between rating of perceived exertion (RPE) and percentage of peak oxygen uptake ([Formula: see text]) during three head-out water-based aerobic exercises. In addition, the RPE at the second ventilatory threshold (VT2) was also compared among them. Twenty young women performed head-out water-based maximal tests for the exercises stationary running (SR), frontal kick (FK) and cross-country skiing (CCS). RPE was monitored during the tests and the values corresponding to VT2 and training zones corresponding to 50-59%, 60-69%, 70-79%, 80-89% and [Formula: see text] were determined. Regression analysis, descriptive statistics and ANOVA with repeated measures were used. Significant relationships were observed between the RPE and [Formula: see text] (r = 0.858-0.893; P < 0.001) for all head-out water-based aerobic exercises. Average RPE ranged from 12.1-12.7 in the training zone corresponding to 50-59%, from 13.7-14.8 to 60-69%, from 15.8-16.4 to 70-79%, from 17.3-18.1 to 80-89% and from 18.5-18.9 to [Formula: see text]. No significant differences were found among the three head-out water-based aerobic exercises at VT2 (P > 0.05; SR: 16.1 +/- 0.9, FK: 16.7 +/- 1.5, CCS: 15.9 +/- 1.3). The results support the use of RPE to control the relative intensity of training during head-out water based aerobic exercises and indicate values near to 16-17 when targeting VT2 intensity for young women. PMID- 26759940 TI - The Speedy A, Cdk2, p27 triangle. PMID- 26759941 TI - [Pulmonary Arterioplasty with Autologous Pericardial Patch for Lung Cancer]. AB - Three patients underwent left upper lobectomy with arterioplasty of left pulmonary artery trunk for lung cancer. For pulmonary arterioplasty, wide wedge resection and patch plasty with autologous pericardium was performed. No in hospital death or no postoperative complications due to arterioplasty was encountered. The mean follow-up period was 3.6 years and long-term patency of the reconstructed pulmonary artery was confirmed by computed tomography in all patients. PMID- 26759942 TI - [Left Ventricular Torsion in Papillary Muscle Relocation for Severe Functional Mitral Regurgitation]. AB - A 42-year-old woman with a history of old myocardial infarction was admitted to our hospital with complaints of worsening orthopnea. Doppler echocardiography exhibited severe functional mitral valve regurgitation. Because of the tethered mitral valve, we performed mitral valve annuloplasty concomitantly with papillary muscle relocation procedure. The patient recovered well. Postoperative echocardiography had not exhibited recurrent mitral valve insufficiency. Moreover, postoperative left ventricular torsion using 2-dimentional speckle tracking imaging, improved at rest and at peak exercise, and this findings suggest that the reversal of left ventricular remodeling in relocation patients following preserved and connected mitral subvalvular apparatus may result from restoration of the global sequence of left ventricular twist mechanics. The analysis of left ventricular torsion may provide a more comprehensive evaluation of left ventricular mechanics and may help understand the effects of papillary muscle relocation with preserving mitral subvalvular apparatus. PMID- 26759943 TI - [Familial Annulo-aortic Ectasia without Marfan Syndrome]. AB - Marfan syndrome is a hereditary disease that presents ocular, skeletal, and cardiovascular abnormalities. In recent years, there have been several reports of patients with familial cardiovascular disease but no physical features of Marfan syndrome. We encountered 3 cases of familial annulo-aortic ectasia (AAE). Their father had also had aortic regurgitation, and died during surgery 10 years before. No case demonstrated any physical characteristics of Marfan syndrome or any other connective tissue disease. All cases were operated successfully. One case showed cystic medial necrosis, and 2 cases showed degenerative change. The present report suggests that familial AAE may be caused by weakness of the aortic wall related to heredity. If AAE is left untreated, it can lead to aortic dissection. Thus, we recommend that patients with familial AAE should undergo screening and follow-up similar to patients with Marfan syndrome. PMID- 26759944 TI - [Aortoesophageal Fistula Long after Single Staged Hybrid Procedure for Extended Thoracic Aortic Aneurysm]. AB - 70-year-old male who had a history of Y-shaped graft replacement of abdominal aortic aneurysm was referred to our hospital for surgical intervention of extended thoracic aortic aneurysm. Although 1 debranching thoracic endovascular aortic repair (TEVAR) was initially scheduled, deployment of the main endograft was eventually cancelled due to severely tortuous bilateral rims of Y-shaped graft, and left carotid artery-left subclavian artery bypass followed by the coil embolization to the orifice of left subclavian artery to prepare for the next operation was performed. Single hybrid operation, including total aortic arch replacement along with elephant trunk insertion and TEVAR was performed at 3 months after the initial operation. On the 191th postoperative day, he was readmitted to our hospital due to marked elevation of C-reactive protein and unknown fever, and enhanced computed tomography showed the pneumomediastinum. Also, fistula formation was identified at the middle portion of the esophagus on the esophagogastroduodenoscopy, and the contrast agent leakage to the outside of the esophagus was demonstrated on the esophagography. He was transferred to another hospital at 7th day after readmission under the definitive diagnosis of mediastinitis due to aortoesophageal fistula for surgical of esophagectomy and mediastinum drainage. Currently, he is discharged from the hospital, and returning for follow-up visit for taking a course of antibiotics. PMID- 26759945 TI - [Tricuspid Valve Regurgitation and Right Heart Failure due to Perioperative Right Ventricular Myocardial Infarction]. AB - We herein experienced 2 cases of severe tricuspid valve regurgitation (TR) and right heart failure after mitral valve surgery. In these cases, echocardiography showed a marked right ventricular dilatation and severe TR, which ware suspected to result from a right ventricular myocardial infarction at the time of the 1st operation. We considered the cause of right ventricular infarction to be an air embolism of the right coronary artery or inadequate cardioplegic perfusion to the right ventricle. Since these incidences, we have paid more careful attention to the de-airing of the left ventricle and aortic root and provided more frequent and strict delivery of antegrade and retrograde cardioplegic perfusion. Consequently, we have not since experienced any similar complications at our institute. PMID- 26759946 TI - [Temporary Middle Lobe Congestion after Wedge Resection]. AB - A 55-year-old woman, who had undergone laparoscopic resection for colorectal cancer, detected a solitary pulmonary nodule on her surveillance chest computed tomography. The lesion located in the right middle lobe, and she received thoracoscopic resection for metastasis from the colorectal cancer. The lesion was removed by wedge resection. During the operation we noticed the middle pulmonary vein was partially stapled because the nodule located close to the vein. There was no macroscopic and hemodynamic problem after the wedge resection, therefore, we decided to complete the operation without resection of the residual middle lobe. After the operation, pulmonary congestion localized to the residual middle lobe progressed within a few days. Because she had no severe symptom nor hemodynamic instability, we continued observation without additional intervention. The congestion gradually improved, and then she discharged from our hospital on 20 days after operation. PMID- 26759947 TI - [Neuroendovascular Treatment for Cerebral Embolism in a Patient just after Aortic Valve Replacement;Report of a Case]. AB - A 67-year-old woman suffered from severe aortic stenosis and atrial fibrillation, and underwent aortic valve replacement with a St. Jude Medical Regent 23-mm valve and pulmonary vein isolation using an AtriCure Isolator Synergy.At 6 days after the operation, she experienced sudden onset of atrial fibrillation, left side paralysis, and dysarthria. Right internal carotid artery embolism was diagnosed via magnetic resonance imaging, and we promptly performed neuroendovascular therapy with a Solitaire FR. Neuroendovascular treatment succeeded, and her neurological function was restored to near-normal. Her post-treatment course was uneventful, and she is currently well without neurological dysfunction. PMID- 26759948 TI - [Successful Emergency Pulmonary Embolectomy in a Patient with Shock;Report of a Case]. AB - The patient was a 48-year-old man, who had hemodynamic shock after orthopedic surgery. He was then diagnosed with right pulmonary artery embolism. Circulatory collapse remained, despite cardiac resuscitation. Therefore, he was treated with percutaneous cardiopulmonary support (PCPS) and intra-aortic balloon pumping (IABP). He was then transferred to our hospital and emergency pulmonary embolectomy was performed under cardiopulmonary bypass. The postoperative course was uneventful, and he was discharged without complications. Early diagnosis and early placement of PCPS and IABP allows safe transfer of patients and successful performance of emergency pulmonary embolectomy. PMID- 26759949 TI - [Tricuspid Valve Replacement in a Case of an Adult Patient with Corrected Transposition of the Great Arteries;Report of a Case]. AB - The patient was a 69-year-old man with corrected transposition of the great arteries. Chest X-ray abnormality had been pointed out since his childhood. Recently he was admitted with congestive heart failure. Examination revealed severe regurgitation of the tricuspid valve (systemic atrioventricular valve) with mild systemic ventricular dysfunction. After a median sternotomy, the operation was conducted with the surgeon standing on the patient's left side. Tricuspid valve was approached through left superior atriotomy. Tricuspid valve was facing almost dorsal to the patient, and there was a big cleft between anterior and posterior leaflets. Tricuspid valve replacement with a mechanical valve was performed with leaflets preserved. The patients had a favorable postoperative course. PMID- 26759950 TI - [Mitral Valve Replacement under Ventricular Fibrillation through Right Thoracotomy for Severe Mitral Regurgitation with Low Left Ventricular Function after Coronary Artery Bypass Grafting;Report of a Case]. AB - A 64-year-old woman had undergone coronary artery bypass grafting (CABG:left internal thoracic artery-left anterior descending artery, right internal thoracic artery-1st diagonal branch, saphenous vein graft-posterior descending artery) 5 years before. However, she was referred to us due to worsening of dyspnea. Severe mitral regurgitation with tethering and tricuspid regurgitation were observed by echocardiography, and low left ventricular function with ejection fraction of 32.6% was noted. Coronary artery computed tomography revealed patency of all grafts, and the right internal thoracic artery ran across the front of the ascending aorta. To avoid injuring the patent grafts, mitral valve replacement under ventricular fibrillation and tricuspid annuloplasty were performed with a right thoracotomy approach. The postoperative course was uneventful, and she was discharged in an improved state on hospital day 28. This method appears safe and useful for avoiding secondary injuries in patients with severe mitral regurgitation with low left ventricular function after CABG. PMID- 26759951 TI - [Hemorrhagic Shock due to an Aortoesophageal Fistula in an Infant with a Double Aortic Arch;Report of a Case]. AB - We experienced a case of a female infant with a double aortic arch (DAA) which formed an aortoesophageal fistula, leading to hemorrhagic shock. The patient had severe dyspnea at birth, and was intubated and tube-feeding was started through a nasogastric tube immediately after birth. A DAA was diagnosed by contrast enhanced computed tomography. Due to abdominal organ malformation, we proceeded with abdominal surgery. Forty-nine days after birth, she suddenly developed massive hematemesis and went into hemorrhagic shock. The bleeding was stopped using an endoscope and was shown to have originated from the esophagus membrane. Compression of the esophageal wall by both the inserted nasogastric tube and vascular ring led to the development of ulceration, resulting in a fistula associated with massive hematemesis. An operation for a DAA was performed on the 53rd day after birth. The inferior side of the DAA was cut, to decompress the bronchus and esophagus and close the fistula. The patient's postoperative course was good and there was no further bleeding. In severe cases of a DAA who require respiratory intubation and tube feeding from a nasogastric tube it is important to carry out surgery as soon as possible. PMID- 26759952 TI - [Surgery for Ventricular Tachycardia Arising from Left Ventricular Aneurysm in a Patient with Dilated Cardiomyopathy;Report of a Case]. AB - A left ventricular aneurysm (LVA) generally results from myocardial infarction, but rarely LVA can be associated with dilated cardiomyopathy (DCM). We herein report a surgical case of malignant ventricular tachycardia (VT) in a patient with LVA associated with DCM. A 57-year-old woman was diagnosed with DCM and LVA when she 1st presented with sustained VT. She had anti-arrhythmic medical therapy and implantable cardiac defibrillator. Subsequently, she presented with recurrent monomorophic VT arising from the LVA. Because anti-arrhythmic medical therapy and endocardial ablation were not effective, the patient was performed left ventricular aneurysmectomy and encircling endocardial cryoablation and could achive good arrhythmic control and clinical outcome. PMID- 26759953 TI - [Resection of Recurrent Leiomyosarcoma of the Inferior Vena Cava with Extention into the Right Atrium and Z stent implantation;Report of a Case]. AB - 79-year-old woman, who had undergone resection of a leiomyosarcoma of the inferior vena cava(IVC)[at 68 years old], was admitted to our hospital due to local recurrence of the leiomyosarcoma with extention into the right atrium (RA). She had progressive dyspnea and bilateral edema of the lower extremities. A computed tomography (CT) scan revealed a tumor that obstructed the IVC. A transthoracic echocardiography showed a large mobile right atrial mass. To prevent sudden death, a reoperation was performed. The tumor in the IVC and the RA was resected under deep hypothermic circulatory arrest. A postoperative CT scan showed stenosis of the IVC by residual tumor, and a Z-stent was therefore implanted in the IVC. Postoperative recovery was uneventful and the patient no longer showed any symptoms. PMID- 26759954 TI - [Bilateral Pneumothorax due to Pulmonary Metastasis from Angiosarcoma of the Forehead;Report of a Case]. AB - Angiosarcoma is rare but highly malignant tumor arising from vascular endothelial cells. A 85-year-old man with difficulty in breathing for 3 days was referred to our hospital. He had a history of angiosarcoma of forehead 4 months before. A chest computed tomography (CT) scan showed left pneumothorax with multiple cystic changes and ground grass attenuations of bilateral lungs, which had obviously increased in recent 2 months. Pulmonary metastases with secondary pneumothorax was highly suspected by the serial CT findings. He was treated with tube thoracostomy and the instillation of a sclerosing agent (minocycline hydrochloride 200 mg). Seven weeks after his initial presentation, he died from obstructive pneumonia and an autopsy was held. Histologic examinations revealed that the tumor foci were peripheral, multiple and generally formed nodules. These cells were cluster differentiation (CD)31 and CD34 positive and negative for calretinin, cytokeratin, carcinoembryonic antigen (CEA), thyroid transcription factor (TTF-1) and epithelial membrane antigen (EMA). These findings were compatible with pulmonary metastases of angiosarcoma of forehead. PMID- 26759956 TI - [Vagal Nerve Schwannoma Complicated with Bloody Pleural Effusion;Report of a Case]. AB - A 51-year-old male who had received hemodialysis twice a week was referred to our hospital for a further examination of bloody pleural effusion in the right chest. He has been suffering from a fever and cough for 2 months. Chest computed tomography and magnetic resonance imaging revealed a pleural effusion in the right pleural cavity and posterior mediastinal tumor in paravertebral lesion. Chest drainage was performed, and cytological diagnosis did not show malignant findings. To make a definite diagnosis and treatment, surgical resection was carried out. During surgery, posterior mediastinal tumor originated from vagal nerve, and a schwannoma was diagnosed by frozen section. After resection, postoperative course was uneventful, and bloody pleural effusion disappeared. PMID- 26759955 TI - [Metastasizing Leiomyoma of the Lung Detected on Chest X-ray after Surgery for Breast Cancer;Report of a Case]. AB - A 60-year-old postmenopausal woman presented with a lung nodule, which was detected on a chest X-ray 2 years after surgery for breast cancer. Pulmonary metastasis from the breast cancer was suspected and surgical resection was performed. On histopathological examination, the lung nodule showed a smooth muscle cell tumor, and immunohistochemical staining was positive for estrogen and progesterone receptors. As a mass in the uterine was detected by computed tomography images before surgical resection, benign metastasizing leiomyoma of the lung was suspected. Subsequently, the patient underwent hysterectomy and bilateral salpingo-oophorectomy. The pathological findings revealed that the mass in the uterine was atypical leiomyoma, which was consistent with the primary lesion of the lung metastasis. Atypical leiomyoma is classified as a benign tumor, but in this case, careful follow-up is required because of its clinical course and histological features. PMID- 26759957 TI - [Hemorrhagic Cerebral Infarction after Right Segmental Lung Resection;Report of a Case]. AB - Postoperative hemorrhagic cerebral infarction is rare but fatal complication. We report a case of hemorrhagic cerebral infarction after lung cancer surgery without a history of atrial fibrillation and cerebrovascular disease. A 58-year old man who have a history of diabetes mellitus, hypertension and dyslipidemia underwent right segmental lung resection. During surgery, he had no atrial fibrillation episode. On postoperative day 1, he presented a slight consciousness disturbance. On the day 2, he suffered from a headache and nausea. Brain computed tomography demonstrated a hemorrhagic infarction at the right posterior cerebral artery territory. Transesophageal echocardiography and magnetic resonance angiography did not show the thrombus. The symptoms were gradually improved with intensive medical therapy, and he was discharged with a left homonymous hemianopsia. Although a diagnosis of the consciousness disturbance in the early phase postoperative period is difficult, perioperative cerebral infarction should be recognized as a postoperative complication. PMID- 26759958 TI - [Castleman's Disease of the Chest Wall Successfully Resected by Thoracoscopic Surgery;Report of a Case]. AB - A 61-year-old woman without a significant past medical history was pointed out the abnormal shadow on the annual medical checkup. Chest computed tomography (CT) revealed a well-defined paravertebral chest wall tumor of 20 mm in maxmum size. Furthermore, diffusion weighted image on magnetic resonance imaging (MRI) showed high intensity, and standardized uptake value (SUV) max on positron emission tomography/computed tomography (PET/CT) was 13.4. Schwanoma, solitary fibrous tumor (SFT) or malignant lymphoma was suggested. Complete resection was performed with thoracoscopic surgery. The histological diagnosis was Castleman's disease with hyalineized type. PMID- 26759959 TI - Temperature dependence of spin pumping and Gilbert damping in thin Co/Pt bilayers. AB - We report on the temperature dependence of the spin-pumping effect and the Gilbert damping in Co/Pt bilayers grown on Silicon oxide by measuring the change of the linewidth in a ferromagnetic resonance (FMR) experiment. By varying the Co thickness d(Co) between 1.5 nm and 50 nm we find that the damping increases inversely proportional to d(Co) at all temperatures between 300 K and 5 K, showing that the spin pumping effect does not depend on temperature. We also find that the linewidth increases with decreasing temperature for all thicknesses down to about 30 K, before leveling off to a constant, or even decreasing again. This behavior is similar to what is found in bulk ferromagnets, leading to the conclusion that in thin films a conductivity-like damping mechanism is present similar to what is known in crystals. PMID- 26759960 TI - Adult Attachment and Dyadic Adjustment: The Mediating Role of Shame. AB - Although it is widely recognized that adult attachment is associated with romantic relationship quality, the mechanisms involved remain poorly understood. This study aimed to investigate the mediating role of external and internal shame on the association between attachment and dyadic adjustment. A battery of self report measures was completed by 228 Portuguese participants and a serial multiple mediation model was tested. Data showed that, in the population under study, attachment dimensions were associated with worse dyadic adjustment through high external and internal shame. Internal shame alone also mediated the association between attachment avoidance and dyadic adjustment. This study identifies a new putative mechanism linking adult attachment and intimate relationship functioning that may be targeted in couples therapy to promote a better dyadic adjustment and relationship functioning. PMID- 26759961 TI - Increased complement C4d deposition at the maternal-fetal interface in unexplained recurrent miscarriage. AB - C4d is a footprint of antibody-mediated classical complement activation, and has evolved as a useful diagnostic marker of antibody-mediated rejection. It is unknown if complement activation, as reflected by C4d deposition plays a role in unexplained recurrent miscarriage. In a case-control study products of conception of 35 women with three or more unexplained consecutive miscarriages within 20 weeks of gestation with the same partner (case group), 22 women with one spontaneous sporadic miscarriage and no history of complicated pregnancy(ies) (control group 1), and 40 women who underwent an elective abortion for psychosocial reasons (control group 2) were included. Immunohistochemical staining for C4d was performed on products of conception. Positivity for C4d was scored semi-quantitatively. C4d deposition was present in products of conception of 14 out of 35 women with unexplained recurrent miscarriage (40.0%), compared to 6 out of 22 women with a sporadic miscarriage (27.3%), and 4 out of 40 women with an elective abortion (10.0%) (p=0.020). C4d is increased at the maternal-fetal interface in women with unexplained recurrent miscarriage, which may reflect an aberrant anti-fetal immunity in these women. Further knowledge of the specific pathogenic mechanism may lead to the development of new treatment strategies for this group of women. PMID- 26759962 TI - Multi-parameter flow cytometric analysis of uterine immune cell fluctuations over the murine estrous cycle. AB - Investigating immune cell populations within various reproductive tissues commonly utilises flow cytometric methods. With advances in fluorophore technology and equipment capabilities, multiple cell types from a single tissue sample can be identified by using different combinations of cell surface markers to distinguish specific cell populations. Here a protocol optimized for mouse uterine tissue was used to show the proportional changes in dendritic cells, monocyte/macrophages, T and B cells, NK and NK T cells, and the granulocytes, neutrophils and eosinophils at each of the four stages of the estrous cycle. Importantly, we demonstrate that use of anti-SiglecF or assessment of FSC/SSC plots could be used to differentiate monocyte/macrophage and eosinophil populations that otherwise cannot be distinguished by use of the common combination of antibodies against F4/80 and CD11b. Our results clearly indicate that within the uterus a dynamic population of immune cells resides, with many cell types reaching peak abundance at estrus and metestrus phases of the cycle, consistent with their importance in the response to paternal antigens and/or pathogens encountered after insemination. PMID- 26759965 TI - Functional disability of adults in Brazil: prevalence and associated factors. AB - OBJECTIVE: To estimate the prevalence and factors associated with functional disability in adults in Brazil. METHODS: We used information from the health supplement of the National Household Sample Survey in 2008. The dependent variable was the functional disability among adults of 18 to 65 years, measured by the difficulty of walking about 100 meters; independent variables were: health plan membership, region of residence, state of domicile, education level, household income, economic activity, self-perception of health, hospitalization, chronic diseases, age group, sex, and color. We calculated the gross odds ratios (OR), and their respective confidence intervals (95%), and adjusted them for variables of study by ordinal logistic regression, following hierarchical model. Sample weights were considered in all calculations. RESULTS: We included 18,745 subjects, 74.0% of whom were women. More than a third of adults reported having functional disability. The disability was significantly higher among men (OR = 1.17; 95%CI 1.09;1.27), people from 35 to 49 years (OR = 1.30; 95%CI 1.17;1.45) and 50 to 65 years (OR = 1.38; 95%CI 1.24;1.54); economically inactive individuals (OR = 2.21; 95%CI 1.65;2.96); adults who reported heart disease (OR = 1.13; 95%CI 1.03;1.24), diabetes mellitus (OR = 1.16; 95%CI 1.05;1.29), arterial systemic hypertension (OR = 1.10; 95%CI 1.02;1.18), and arthritis/rheumatism (OR = 1.24; 95%CI 1.15;1.34); and participants who were admitted in the last 12 months (OR = 2.35; 95%CI 1.73;3.2). CONCLUSIONS: Functional disability is common among Brazilian adults. Hospitalization is the most strongly associated factor, followed by economic activity, and chronic diseases. Sex, age, education, and income are also associated. Results indicate specific targets for actions that address the main factors associated with functional disabilities and contribute to the projection of interventions for the improvement of the well-being and promotion of adults' quality of life. PMID- 26759966 TI - Influence of the support offered to breastfeeding by maternity hospitals. AB - OBJECTIVE: To evaluate whether the support offered by maternity hospitals is associated with higher prevalences of exclusive and predominant breastfeeding. METHODS: This is a cross-sectional study including a representative sample of 916 infants less than six months who were born in maternity hospitals, in Ribeirao Preto, Sao Paulo, Southeastern Brazil, 2011. The maternity hospitals were evaluated in relation to their fulfillment of the Ten Steps to Successful Breastfeeding. Data were collected regarding breastfeeding patterns, the birth hospital and other characteristics. The individualized effect of the study factor on exclusive and predominant breastfeeding was analyzed using Poisson multiple regression with robust variance. RESULTS: Predominant breastfeeding tended to be more prevalent when the number of fulfilled steps was higher (p of linear trend = 0.057). The step related to not offering artificial teats or pacifiers to breastfed infants and that related to encouraging the establishment of breastfeeding support groups were associated, respectively, to a higher prevalence of exclusive (PR = 1.26; 95%CI 1.04;1.54) and predominant breastfeeding (PR = 1.55; 95%CI 1.01;2.39), after an adjustment was performed for confounding variables. CONCLUSIONS: We observed a positive association between support offered by maternity hospitals and prevalences of exclusive and predominant breastfeeding. These results can be useful to other locations with similar characteristics (cities with hospitals that fulfill the Ten Steps to Successful Breastfeeding) to provide incentive to breastfeeding, by means of promoting, protecting and supporting breastfeeding in maternity hospitals. PMID- 26759964 TI - Methods and challenges for the health impact assessment of vaccination programs in Latin America. AB - OBJECTIVE: To describe methods and challenges faced in the health impact assessment of vaccination programs, focusing on the pneumococcal conjugate and rotavirus vaccines in Latin America and the Caribbean. METHODS: For this narrative review, we searched for the terms "rotavirus", "pneumococcal", "conjugate vaccine", "vaccination", "program", and "impact" in the databases Medline and LILACS. The search was extended to the grey literature in Google Scholar. No limits were defined for publication year. Original articles on the health impact assessment of pneumococcal and rotavirus vaccination programs in Latin America and the Caribbean in English, Spanish or Portuguese were included. RESULTS: We identified 207 articles. After removing duplicates and assessing eligibility, we reviewed 33 studies, 25 focusing on rotavirus and eight on pneumococcal vaccination programs. The most frequent studies were ecological, with time series analysis or comparing pre- and post-vaccination periods. The main data sources were: health information systems; population-, sentinel- or laboratory-based surveillance systems; statistics reports; and medical records from one or few health care services. Few studies used primary data. Hospitalization and death were the main outcomes assessed. CONCLUSIONS: Over the last years, a significant number of health impact assessments of pneumococcal and rotavirus vaccination programs have been conducted in Latin America and the Caribbean. These studies were carried out few years after the programs were implemented, meet the basic methodological requirements and suggest positive health impact. Future assessments should consider methodological issues and challenges arisen in these first studies conducted in the region. PMID- 26759963 TI - Autophagy and modular restructuring of metabolism control germline tumor differentiation and proliferation in C. elegans. AB - Autophagy can act either as a tumor suppressor or as a survival mechanism for established tumors. To understand how autophagy plays this dual role in cancer, in vivo models are required. By using a highly heterogeneous C. elegans germline tumor, we show that autophagy-related proteins are expressed in a specific subset of tumor cells, neurons. Inhibition of autophagy impairs neuronal differentiation and increases tumor cell number, resulting in a shorter life span of animals with tumors, while induction of autophagy extends their life span by impairing tumor proliferation. Fasting of animals with fully developed tumors leads to a doubling of their life span, which depends on modular changes in transcription including switches in transcription factor networks and mitochondrial metabolism. Hence, our results suggest that metabolic restructuring, cell-type specific regulation of autophagy and neuronal differentiation constitute central pathways preventing growth of heterogeneous tumors. PMID- 26759968 TI - Use of medicines recommended for secondary prevention of acute coronary syndrome. AB - OBJECTIVE: To analyze if the demographic and socioeconomic variables, as well as percutaneous coronary intervention are associated with the use of medicines for secondary prevention of acute coronary syndrome. METHODS: In this cohort study, we included 138 patients with acute coronary syndrome, aged 30 years or more and of both sexes. The data were collected at the time of hospital discharge, and after six and twelve months. The outcome of the study was the simultaneous use of medicines recommended for secondary prevention of acute coronary syndrome: platelet antiaggregant, beta-blockers, statins and angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker. The independent variables were: sex, age, education in years of attending, monthly income in tertiles and percutaneous coronary intervention. We described the prevalence of use of each group of medicines with their 95% confidence intervals, as well as the simultaneous use of the four medicines, in all analyzed periods. In the crude analysis, we verified the outcome with the independent variables for each period through the Chi-square test. The adjusted analysis was carried out using Poisson Regression. RESULTS: More than a third of patients (36.2%; 95%CI 28.2;44.3) had the four medicines prescribed at the same time, at the moment of discharge. We did not observe any differences in the prevalence of use in comparison with the two follow-up periods. The most prescribed class of medicines during discharge was platelet antiaggregant (91.3%). In the crude analysis, the demographic and socioeconomic variables were not associated to the outcome in any of the three periods. CONCLUSIONS: The prevalence of simultaneous use of medicines at discharge and in the follow-ups pointed to the under-utilization of this therapy in clinical practice. Intervention strategies are needed to improve the quality of care given to patients that extend beyond the hospital discharge, a critical point of transition in care. PMID- 26759967 TI - Validity and reliability of the Questionnaire for Compliance with Standard Precaution. AB - OBJECTIVE: To evaluate the validity and reliability of the Questionnaire for Compliance with Standard Precaution for nurses. METHODS: This methodological study was conducted with 121 nurses from health care facilities in Sao Paulo's countryside, who were represented by two high-complexity and by three average complexity health care facilities. Internal consistency was calculated using Cronbach's alpha and stability was calculated by the intraclass correlation coefficient, through test-retest. Convergent, discriminant, and known-groups construct validity techniques were conducted. RESULTS: The questionnaire was found to be reliable (Cronbach's alpha: 0.80; intraclass correlation coefficient: (0.97) In regards to the convergent and discriminant construct validity, strong correlation was found between compliance to standard precautions, the perception of a safe environment, and the smaller perception of obstacles to follow such precautions (r = 0.614 and r = 0.537, respectively). The nurses who were trained on the standard precautions and worked on the health care facilities of higher complexity were shown to comply more (p = 0.028 and p = 0.006, respectively). CONCLUSIONS: The Brazilian version of the Questionnaire for Compliance with Standard Precaution was shown to be valid and reliable. Further investigation must be conducted with nurse samples that are more representative of the Brazilian reality. The use of the questionnaire may support the creation of educational measures considering the possible gaps that can be identified, focusing on the workers' health and on the patients' safety. PMID- 26759969 TI - Strategies for price reduction of HIV medicines under a monopoly situation in Brazil. AB - OBJECTIVE: To analyze Government strategies for reducing prices of antiretroviral medicines for HIV in Brazil. METHODS: Analysis of Ministry of Health purchases of antiretroviral medicines, from 2005 to 2013. Expenditures and costs of the treatment per year were analyzed and compared to international prices of atazanavir. Price reductions were estimated based on the terms of a voluntary license of patent rights and technology transfer in the Partnership for Productive Development Agreement for atazanavir. RESULTS: Atazanavir, a patented medicine, represented a significant share of the expenditures on antiretrovirals purchased from the private sector. Prices in Brazil were higher than international references, and no evidence was found of a relationship between purchase volume and price paid by the Ministry of Health. Concerning the latest strategy to reduce prices, involving local production of the 200 mg capsule, the price reduction was greater than the estimated reduction. As for the 300 mg capsule, the amounts paid in the first two years after the Partnership for Productive Development Agreement were close to the estimated values. Prices in nominal values for both dosage forms remained virtually constant between 2011 (the signature of the Partnership for Productive Development Agreement), 2012 and 2013 (after the establishment of the Partnership). CONCLUSIONS: Price reduction of medicines is complex in limited-competition environments. The use of a Partnership for Productive Development Agreement as a strategy to increase the capacity of local production and to reduce prices raises issues regarding its effectiveness in reducing prices and to overcome patent barriers. Investments in research and development that can stimulate technological accumulation should be considered by the Government to strengthen its bargaining power to negotiate medicines prices under a monopoly situation. PMID- 26759971 TI - Investigation of PDMS based bi-layer elasticity via interpretation of apparent Young's modulus. AB - As the need of new methods for the investigation of thin films on various kinds of substrates becomes greater, a novel approach based on AFM nanoindentation is explored. Substrates of polydimethylsiloxane (PDMS) coated by a layer of hard material are probed with an AFM tip in order to obtain the force profile as a function of the indentation. The equivalent elasticity of those composite systems is interpreted using a new numerical approach, the Coated Half-Space Indentation Model of Elastic Response (CHIMER), in order to extract the thicknesses of the upper layer. Two kinds of coating are investigated. First, chitosan films of known thicknesses between 30 and 200 nm were probed in order to test the model. A second type of samples is produced by oxygen plasma oxidation of the PDMS substrate, which results in the growth of a relatively homogeneous oxide layer. The local nature of this protocol enables measurements at long oxidation time, where the apparition of cracks prevents other kinds of measurements. PMID- 26759970 TI - Factors associated with exclusive breastfeeding in the first six months of life in Brazil: a systematic review. AB - OBJECTIVE: To identify factors associated with exclusive breastfeeding in the first six months of life in Brazil. METHODS: Systematic review of epidemiological studies conducted in Brazil with exclusive breastfeeding as outcome. Medline and LILACS databases were used. After the selection of articles, a hierarchical theoretical model was proposed according to the proximity of the variable to the outcome. RESULTS: Of the 67 articles identified, we selected 20 cross-sectional studies and seven cohort studies, conducted between 1998 and 2010, comprising 77,866 children. We identified 36 factors associated with exclusive breastfeeding, being more often associated the distal factors: place of residence, maternal age and education, and the proximal factors: maternal labor, age of the child, use of a pacifier, and financing of primary health care. CONCLUSIONS: The theoretical model developed may contribute to future research, and factors associated with exclusive breastfeeding may subsidize public policies on health and nutrition. PMID- 26759972 TI - Advances in stem cell research for the treatment of male sexual dysfunctions. AB - PURPOSE OF REVIEW: To summarize recent literature on basic stem cell research in erectile dysfunction in cavernous nerve injury, aging, diabetes, and Peyronie's disease and to provide a perspective on clinical translation of these cellular therapies. RECENT FINDINGS: Stem cell research has been concentrated on mesenchymal stem (stromal) cells from bone marrow and adipose tissue. Application of both cell types has produced positive effects on erectile function in various animal models of erectile dysfunction. In acute animal models, such as cavernous nerve injury-induced erectile dysfunction and chemically induced Peyronie's disease, engraftment and differentiation have not been observed, and stem cells are believed to interact with the host tissue in a paracrine fashion, whereas in chronic disease models some evidence suggests both engraftment and paracrine factors may support improved function. Clinical trials are now investigating therapeutic efficacy of cellular therapy, whereas the first safety studies in humans have recently been published. SUMMARY: Evidence from preclinical studies has established stem cells as a potential curative treatment for erectile dysfunction and early phase clinical trials are currently performed. PMID- 26759973 TI - Effects of fatigue on the chemical and mechanical degradation of model stent sub units. AB - Understanding the fatigue and durability performance of implantable cardiovascular stents is critical for assessing their performance. When the stent is manufactured from an absorbable material, however, this durability assessment is complicated by the transient nature of the device. Methodologies for evaluating the fatigue performance of absorbable stents while accurately simulating the degradation are limited and little is known about the interaction between fatigue and degradation. In this study, we investigated the fatigue behavior and effect of fatigue on the degradation rate for a model absorbable cardiovascular stent. Custom v-shaped stent sub-units manufactured from poly(L lactide), i.e., PLLA, were subjected to a simultaneous fatigue and degradation study with cycle counts representative of one year of expected in vivo use. Fatigue loading was carried out such that the polymer degraded at a rate that was aligned with a modest degree of fatigue acceleration. Control, un-loaded specimens were also degraded under static immersion conditions representative of simulated degradation without fatigue. The study identified that fatigue loading during degradation significantly increased specimen stiffness and lowered the force at break. Fatigue loading also significantly increased the degree of molecular weight decline highlighting an interaction between mechanical loading and chemical degradation. This study demonstrates that fatigue loading during degradation can affect both the mechanical properties and the chemical degradation rate. The results are important for defining appropriate in vitro degradation conditions for absorbable stent preclinical evaluation. PMID- 26759974 TI - Preventive Care Quality of Medicare Accountable Care Organizations: Associations of Organizational Characteristics With Performance. AB - BACKGROUND: Accountable Care Organizations (ACOs) are a delivery and payment model aiming to coordinate care, control costs, and improve quality. Medicare ACOs are responsible for 8 measures of preventive care quality. OBJECTIVES: To create composite measures of preventive care quality and examine associations of ACO characteristics with performance. DESIGN: This is a cross-sectional study of Medicare Shared Savings Program and Pioneer participants. We linked quality performance to descriptive data from the National Survey of ACOs. We created composite measures using exploratory factor analysis, and used regression to assess associations with organizational characteristics. RESULTS: Of 252 eligible ACOs, 246 reported on preventive care quality, 177 of which completed the survey (response rate=72%). In their first year, ACOs lagged behind PPO performance on the majority of comparable measures. We identified 2 underlying factors among 8 measures and created composites for each: disease prevention, driven by vaccines and cancer screenings, and wellness screening, driven by annual health screenings. Participation in the Advanced Payment Model, having fewer specialists, and having more Medicare ACO beneficiaries per primary care provider were associated with significantly better performance on both composites. Better performance on disease prevention was also associated with inclusion of a hospital, greater electronic health record capabilities, a larger primary care workforce, and fewer minority beneficiaries. CONCLUSIONS: ACO preventive care quality performance is related to provider composition and benefitted by upfront investment. Vaccine and cancer screening quality performance is more dependent on organizational structure and characteristics than performance on annual wellness screenings, likely due to greater complexity in eligibility determination and service administration. PMID- 26759975 TI - Cost Analysis of the STONE Randomized Trial: Can Health Care Costs be Reduced One Test at a Time? AB - BACKGROUND: Decreasing the use of high-cost tests may reduce health care costs. OBJECTIVE: To compare costs of care for patients presenting to the emergency department (ED) with suspected kidney stones randomized to 1 of 3 initial imaging tests. RESEARCH DESIGN: Patients were randomized to point-of-care ultrasound (POC US, least costly), radiology ultrasound (RAD US), or computed tomography (CT, most costly). Subsequent testing and treatment were the choice of the treating physician. SUBJECTS: A total of 2759 patients at 15 EDs were randomized to POC US (n=908), RAD US, (n=893), or CT (n=958). Mean age was 40.4 years; 51.8% were male. MEASURES: All medical care documented in the trial database in the 7 days following enrollment was abstracted and coded to estimate costs using national average 2012 Medicare reimbursements. Costs for initial ED care and total 7-day costs were compared using nonparametric bootstrap to account for clustering of patients within medical centers. RESULTS: Initial ED visit costs were modestly lower for patients assigned to RAD US: $423 ($411, $434) compared with patients assigned to CT: $448 ($438, $459) (P<0.0001). Total costs were not significantly different between groups: $1014 ($912, $1129) for POC US, $970 ($878, $1078) for RAD US, and $959 ($870, $1044) for CT. Hospital admissions contributed over 50% of total costs, though only 11% of patients were admitted. Mean total costs (and admission rates) varied substantially by site from $749 to $1239. CONCLUSIONS: Assignment to a less costly test had no impact on overall health care costs for ED patients. System-level interventions addressing variation in admission rates from the ED might have greater impact on costs. PMID- 26759976 TI - Hospital Revisits Within 30 Days After Conventional and Robotically Assisted Hysterectomy. AB - OBJECTIVES: To compare the rates of hospital readmissions, emergency department, and outpatient clinic visits after discharge for robotically assisted (RA) versus nonrobotic hysterectomy in women age 30 or more with nonmalignant conditions. DATA SOURCES: Discharges for 2011 for 8 states (CA, FL, GA, IA, MO, NE, NY, TN) (>86,000 inpatient hysterectomies) were drawn from the statewide databases of the Healthcare Cost and Utilization Project. Data from 4 of these states were used to study revisits after 29,000 outpatient hysterectomies. METHODS: Matched pairs of patients were constructed with propensity scores derived from each patient's age group, severity of illness, insurance coverage, and type of procedure. Both the full set of revisits and a set limited to diagnoses for revisits judged in other research to be related to the initial surgery (about 70% of all revisits) were analyzed. The analyses were repeated with an instrumental variables regression design. KEY RESULTS: Using the propensity score matched pairs, revisits, and specifically readmissions, after inpatient hysterectomy were greater for RA versus non-RA patients (relative risk of readmission=124%, P<0.01). Similar results were found for readmissions after outpatient hysterectomy, and readmissions after inpatient hysterectomy for the restricted set of related revisits. In the method with instrumental variables, RA was associated with an increase of 32% in the likelihood of any revisit (P<0.01). CONCLUSIONS: Using 2 different methods to control for selection, this study found higher rates of revisits among women undergoing RA versus non-RA hysterectomy for benign conditions. While selection bias cannot be ruled out completely in an observational study, the study supports broader use of revisits for analyses of outcomes of hysterectomy. PMID- 26759977 TI - Estimating the Population Benefits and Costs of Rituximab Therapy in the United States from 1998 to 2013 Using Real-World Data. AB - BACKGROUND: Rituximab was approved in 1997 and is regularly one of the largest drug expenditures for Medicare; however, its benefits and costs have not been estimated from a population perspective. OBJECTIVES: To estimate both the clinical and the economic outcomes of rituximab for its approved hematological uses at the population level. RESEARCH DESIGN: Analyses using cancer registry incidence data from the Surveillance, Epidemiology, and End Results (SEER) program, and outcomes data from SEER data linked with Medicare administrative claims (SEER-Medicare data). These results were incorporated into an epidemiological simulation model of the population over time. SUBJECTS: We modeled all United States patients from 1998 to 2013 diagnosed with diffuse large B-cell lymphoma, follicular lymphoma, or chronic lymphocytic leukemia. MEASURES: Using this model, we estimated the life-years saved, as well as their economic benefit, in the United States population. We also estimated the incremental cost of adding rituximab to chemotherapy. All economic inputs were based on Medicare reimbursed amounts inflated to 2013 dollars. RESULTS: There were 279,704 cumulative life-years saved which were valued at $25.44 billion. The incremental direct medical cost of rituximab was estimated to be $8.92 billion, resulting in an incremental economic gain of $16.52 billion. CONCLUSIONS: These analyses, based on real-world evidence, show that the introduction of rituximab into clinical practice has produced a substantial number of incremental life-years. Importantly, the economic benefit of the life-years gained greatly exceeds the added costs of treatment. PMID- 26759978 TI - Patient-initiated Electronic Messages and Quality of Care for Patients With Diabetes and Hypertension in a Large Fee-for-Service Medical Group: Results From a Natural Experiment. AB - BACKGROUND: Few studies have examined the association between patient-initiated electronic messaging (e-messaging) and clinical outcomes in fee-for-service settings. OBJECTIVE: To estimate the association between patient-initiated e messages and quality of care among patients with diabetes and hypertension. DESIGN: Longitudinal observational study from 2009 to 2013. In March 2011, the medical group eliminated a $60/year patient user fee for e-messaging and established a provider payment of $3-5 per patient-initiated e-message. Quality of care for patients initiating e-messages was compared before and after March 2011, relative to nonmessaging patients. Propensity score weighting accounted for differences between e-messaging and nonmessaging patients in generalized estimating equations. SETTING: Large multispecialty practice in California compensating providers' fee-for-service. SUBJECTS: Patients with diabetes (N=4232) or hypertension (N=15,463) who had activated their online portal but not e-messaged before e-messaging became free. MEASURES: Quality of care included HEDIS-based process measures for hemoglobin (Hb) A1c, blood pressure, low-density lipoprotein (LDL), nephropathy, and retinopathy tests, and outcome measures for HbA1c, blood pressure, and LDL. E-messaging was measured as counts of patient initiated e-message threads sent to providers. Patients were categorized into quartiles by e-messaging frequency. RESULTS: The probability of annually completing indicated tests increased by 1%-7% for e-messaging patients, depending on the outcome and e-messaging frequency. E-messaging was associated with small improvements in HbA1c and LDL for some patients with diabetes. CONCLUSION: Patient-initiated e-messaging may increase the likelihood of completing recommended tests, but may not be sufficient to improve clinical outcomes for most patients with diabetes or hypertension without additional interventions. PMID- 26759979 TI - Access is Not Enough: Characteristics of Physicians Who Treat Medicaid Patients. AB - BACKGROUND: Access to physicians is a major concern for Medicaid programs. However, little is known about relationships between physician participation in Medicaid and the individual-level and practice-level characteristics of physicians. METHODS: We used the 2011 Massachusetts All Payer Claims Database, containing all commercial and Medicaid claims; we linked with data on physician characteristics. We measured Medicaid participation intensity (fraction of the physician's patient panel with Medicaid) for primary care physicians (PCPs) and medical specialists. We measured influence of physicians within a patient referral network using eigenvector centrality. We used regression models to associate Medicaid intensity with physician individual-level and practice-level characteristics. FINDINGS: About 92.6% of physicians treated at least 1 Medicaid patient, but the median physician's panel contained only 5.7% Medicaid patients. Medicaid intensity was associated with physician training and influence for PCPs and specialists. For medical specialists, a 1 percentage point increase in Medicaid intensity was associated with a lower probability of being board certified (-0.22 percentage points; 95% CI, -0.30, -0.14), lower probability of attending a domestic medical school (-0.14 percentage points; 95% CI, -0.22, 0.05), having attended a less well-ranked domestic medical school (0.23 ranks; 95% CI, 0.15, 0.30), and having slightly less influence in the referral network. PCPs displayed similar results but high Medicaid intensity physicians had substantially less influence in the referral network. CONCLUSIONS: Medicaid participation intensity shows substantial variation across physicians, indicating limits of binary participation measures. Physicians with more Medicaid patients had characteristics often perceived by patients to be of lower quality. PMID- 26759980 TI - Outcomes and Resource Use of Sepsis-associated Stays by Presence on Admission, Severity, and Hospital Type. AB - OBJECTIVE: To establish a baseline for the incidence of sepsis by severity and presence on admission in acute care hospital settings before implementation of a broad sepsis screening and response initiative. METHODS: A retrospective cohort study using hospital discharge abstracts of 5672 patients, aged 18 years and above, with sepsis-associated stays between February 2012 and January 2013 at an academic medical center and 5 community hospitals in Texas. RESULTS: Sepsis was present on admission in almost 85% of cases and acquired in-hospital in the remainder. The overall inpatient death rate was 17.2%, but was higher in hospital acquired sepsis (38.6%, medical; 29.2%, surgical) and Stages 2 (17.6%) and 3 (36.4%) compared with Stage 1 (5.9%). Patients treated at the academic medical center had a higher death rate (22.5% vs. 15.1%, P<0.001) and were more costly ($68,050+/-184,541 vs. $19,498+/-31,506, P<0.001) versus community hospitals. CONCLUSIONS: Greater emphasis is needed on public awareness of sepsis and the detection of sepsis in the prehospitalization and early hospitalization period. Hospital characteristics and case mix should be accounted for in cross-hospital comparisons of sepsis outcomes and costs. PMID- 26759981 TI - Performance Measures in Neurosurgical Patient Care: Differing Applications of Patient Safety Indicators. AB - BACKGROUND: Patient Safety Indicators (PSIs) are administratively coded identifiers of potentially preventable adverse events. These indicators are used for multiple purposes, including benchmarking and quality improvement efforts. Baseline PSI evaluation in high-risk surgeries is fundamental to both purposes. OBJECTIVE: Determine PSI rates and their impact on other outcomes in patients undergoing cranial neurosurgery compared with other surgeries. RESEARCH DESIGN: The Agency for Healthcare Research and Quality (AHRQ) PSI software was used to flag adverse events and determine risk-adjusted rates (RAR). Regression models were built to assess the association between PSIs and important patient outcomes. SUBJECTS: We identified cranial neurosurgeries based on International Classification of Diseases, Ninth Revision, Clinical Modification codes in California, Florida, New York, Arkansas, and Mississippi State Inpatient Databases, AHRQ, 2010-2011. MEASURES: PSI development, 30-day all-cause readmission, length of stay, hospital costs, and inpatient mortality. RESULTS: A total of 48,424 neurosurgical patients were identified. Procedure indication was strongly associated with PSI development. The neurosurgical population had significantly higher RAR of most PSIs evaluated compared with other surgical patients. Development of a PSI was strongly associated with increased length of stay and hospital cost and, in certain PSIs, increased inpatient mortality and 30 day readmission. CONCLUSIONS: In this population-based study, certain accountability measures proposed for use as value-based payment modifiers show higher RAR in neurosurgery patients compared with other surgical patients and were subsequently associated with poor outcomes. Our results indicate that for quality improvement efforts, the current AHRQ risk-adjustment models should be viewed in clinically meaningful stratified subgroups: for profiling and pay-for performance applications, additional factors should be included in the risk adjustment models. Further evaluation of PSIs in additional high-risk surgeries is needed to better inform the use of these metrics. PMID- 26759982 TI - Health Care Expenditures After Initiating Long-term Services and Supports in the Community Versus in a Nursing Facility. AB - BACKGROUND: Individuals who receive long-term services and supports (LTSS) are among the most costly participants in the Medicare and Medicaid programs. OBJECTIVES: To compare health care expenditures among users of Medicaid home and community-based services (HCBS) versus those using extended nursing facility care. RESEARCH DESIGN: Retrospective cohort analysis of California dually eligible adult Medicaid and Medicare beneficiaries who initiated Medicaid LTSS, identified as HCBS or extended nursing facility care, in 2006 or 2007. SUBJECTS: Propensity score matching for demographic, health, and functional characteristics resulted in a subsample of 34,660 users who initiated Medicaid HCBS versus extended nursing facility use. Those with developmental disabilities or in managed care plans were excluded. MEASURES: Average monthly adjusted acute, postacute, long-term, and total Medicare and Medicaid expenditures for the 12 months following initiation of either HCBS or extended nursing facility care. RESULTS: Those initiating extended nursing facility care had, on average, $2919 higher adjusted total health care expenditures per month compared with those who initiated HCBS. The difference was primarily attributable to spending on LTSS $2855. On average, the monthly LTSS expenditures were higher for Medicare $1501 and for Medicaid $1344 when LTSS was provided in a nursing facility rather than in the community. CONCLUSIONS: The higher cost of delivering LTSS in a nursing facility rather than in the community was not offset by lower acute and postacute spending. Medicare and Medicaid contribute similar amounts to the LTSS cost difference and both could benefit financially by redirecting care from institutions to the community. PMID- 26759983 TI - Mammography Use Among Medicare Beneficiaries After Elimination of Cost Sharing. AB - BACKGROUND: We examined mammography use before and after Medicare eliminated cost sharing for screening mammography in January 2011. METHODS: Using National Health Interview Survey data, we examined changes in mammography use between 2010 and 2013 among Medicare beneficiaries aged 65-74 years. Logistic regression and predictive margins were used to examine changes in use after adjusting for covariates. RESULTS: In 2013, 74.7% of women reported a mammogram within 2 years, a 3.5 percentage point increase (95% confidence interval, -0.3, 7.2) compared with 2010. Increases occurred among women aged 65-69 years, unmarried women, and women with usual sources of care and 2-5 physician visits in the prior year. After adjustment, mammography use increased in 2013 versus 2010 (74.8% vs. 71.3%, P=0.039). Interactions between year and income, insurance, race, or ethnicity were not significant. CONCLUSIONS: There was a modest increase in mammography use from 2010 to 2013 among Medicare beneficiaries aged 65-74 years, possibly consistent with an effect of eliminating Medicare cost sharing during this time. Findings suggest that eliminating cost sharing might increase use of recommended screening services. PMID- 26759987 TI - Current advances of murine models for food allergy. AB - Food allergy affects an increasing population in Western world but also developing countries. Researchers have been taking great efforts in identifying and characterising food allergens using molecular tools. However, there are still many mechanistic hypotheses that need to be tested using an appropriate in vivo experimental platform. To date, a number of mouse models for food allergy have been established and provided valuable insights into food allergenicity, development of therapies and allergic inflammation mechanisms. Nevertheless, a large diversity of protocols have been developed for the establishment of relevant mouse models. As a result, comparisons of outcomes between different models are very difficult to be conducted. The phenotypes of mouse models are greatly influenced by genetic background, gender, route of allergen exposure, the nature and concentration of food allergens, as well as the usage of adjuvants. This review focuses on IgE-mediated food allergy, compares the differential approaches in developing appropriate murine models for food allergy and details specific findings for three major food allergens, peanut, milk and shellfish. PMID- 26759984 TI - Linking Costs and Survival in the Treatment of Older Adults With Chronic Myeloid Leukemia: An Analysis of SEER-Medicare Data From 1995 to 2007. AB - BACKGROUND: The high prices of chronic myeloid leukemia (CML) therapy are well recognized, but less discussion has focused on the value of health care spending on the disease. This study examined whether the added costs have been "worth" the benefits among older adults with CML. MATERIALS AND METHODS: We analyzed trends in health care costs and survival over time of 2164 CML patients over age 65 using the Surveillance, Epidemiology and End Results-Medicare-linked database. We estimated life expectancy over a 15-year duration after diagnosis using a Weibull survival model and projected the corresponding costs using a 2-part model, adjusting for patient characteristics. We estimated population-level survival, total health care costs, and incremental cost-effectiveness ratios (expressed as cost per life year gained) over the period of 1995-2007. RESULTS: We found that therapeutic improvements in the treatment of CML have been associated with survival gains among older adults. Mean life expectancy was 2.2 years in 1995 and increased to 4.2 years in 2007. During the same timeframe, CML care costs have increased, from $127,000 in 1995 to $278,000 in 2007 (2010 dollars), mostly due to increasing tyrosine kinase inhibitor costs. The aggregated incremental cost effectiveness ratio was $74,000/life year gained. CONCLUSIONS: Our findings showed that, despite high costs, CML care may provide reasonable value for money among older patients between 1995-2007. Our study sheds light on the value of health care spending on CML by considering both the costs and the benefits. Future research should investigate strategies to improve treatment adherence to maximize the value of CML care. PMID- 26759988 TI - Development of new therapeutical/adjuvant molecules by pepscan mapping of autophagy and IFN inducing determinants of rhabdoviral G proteins. AB - Surface glycoproteins of enveloped virus are potent elicitors of both innate and adaptive host immune responses. Therefore, the identification of viral glycoprotein determinants directly implicated in the induction of these responses might be of special interest for designing new therapeutical/adjuvant molecules. In this work we review the contribution of the "pepscan" approach to the screening of viral functions in the sequence of glycoprotein G (gpG) of the fish rhabdovirus of viral hemorrhagic septicemia (VHSV). Among others, by scanning gpG peptides, it has been possible to identify and validate minimal determinants for gpG directly implicated in initiating the fish type I Interferon-associated immune responses as well as in the antiviral autophagy program. Further fine tunning of the identified peptides in the gpG of VHSV has allowed designing novel adjuvants that decrease DNA vaccine requirements and identify possible innovative antiviral molecules. In addition, these results have also contributed to improve our knowledge on how to stimulate the fish immune system. PMID- 26759989 TI - Early functional and morphological brain disturbances in late-onset intrauterine growth restriction. AB - AIMS: To determine whether the brain disturbances develop in late-onset intrauterine growth restriction (IUGR) before blood flow redistribution towards the fetal brain (detected by Doppler measurements in the middle cerebral artery and umbilical artery). Further, to evaluate predictive values of Doppler arterial indices and umbilical cord blood gases and pH for early functional and/or morphological brain disturbances in late-onset IUGR. STUDY DESIGN: This cohort study included 60 singleton term pregnancies with placental insufficiency caused late-onset IUGR (IUGR occurring after 34 gestational weeks). Umbilical artery resistance index (URI), middle cerebral artery resistance index (CRI), and cerebroumbilical (C/U) ratio (CRI/URI) were monitored once weekly. Umbilical blood cord samples (arterial and venous) were collected for the analysis of pO2, pCO2 and pH. Morphological neurological outcome was evaluated by cranial ultrasound (cUS), whereas functional neurological outcome by Amiel-Tison Neurological Assessment at Term (ATNAT). RESULTS: 50 fetuses had C/U ratio>1, and 10 had C/U ratio<=1; among these 10 fetuses, 9 had abnormal neonatal cUS findings and all 10 had non-optimal ATNAT. However, the total number of abnormal neurological findings was much higher. 32 neonates had abnormal cUS (53.37%), and 42 (70.00%) had non-optimal ATNAT. Furthermore, Doppler indices had higher predictive validity for early brain disturbances than umbilical cord blood gases and pH. C/U ratio had the highest predictive validity with threshold for adverse neurological outcome at value 1.13 (ROC analysis), i.e., 1.18 (party machine learning algorithm). CONCLUSION: Adverse neurological outcome at average values of C/U ratios>1 confirmed that early functional and/or structural brain disturbances in late-onset IUGR develop even before activation of fetal cardiovascular compensatory mechanisms, i.e., before Doppler signs of blood flow redistribution between the fetal brain and the placenta. PMID- 26759991 TI - Integrated Free Energy Model (IFEM) for microemulsions. AB - The Integrated Free Energy Model (IFEM) is a platform used to predict the solubilization of nonpolar oils in nonionic alkyl-polyethylene oxide (C(X)EO(Y)) micelles starting from a free energy balance of costs and gains when surfactants from empty micelles and oil from a continuous oil phase assemble to form an oil swollen micelle. IFEM considers lipophilic interactions between surfactant tails and oil solubilized in the core of micelles, and the interaction between surfactant tails and the oil solubilized in the surfactant tail domain, as well as oil-oil and surfactant-surfactant tail interactions. Expressions to calculate these lipophilic interactions from van der Waals (VDW) interaction potential were introduced in a previous publication. In this article, two new surfactant-water interactions are considered, surfactant headgroup dehydration during solubilization, and surfactant tail group dehydration. These six interaction terms, in addition to two entropy of mixing contributions (in the lipophilic and in the hydrophilic domains) make up the eight terms of the IFEM platform. Of these terms, only the headgroup dehydration requires a calibrated parameter. After calibrating this parameter, the model is capable of predicting experimental solubilization data, and the experimental trends reflected by a semi-empirical model, the Hydrophilic-Lipophilic-Difference+Net-Average-Curvature (HLD-NAC). Although there are numerous approaches to predict the surfactant-oil-water (SOW) phase behavior, the IFEM platform is the only one, to the knowledge of the authors that produces an explicit connection between molecular interactions and experimental data for real SOW systems. The IFEM platform can be programmed in a personal computer using relatively inexpensive software and its explicit nature opens the possibility to introduce additional interaction terms for more complex SOW systems. PMID- 26759993 TI - Hetero-cellular prototyping by synchronized multi-material bioprinting for rotary cell culture system. AB - Bottom-up tissue engineering requires methodological progress of biofabrication to capture key design facets of anatomical arrangements across micro, meso and macro-scales. The diffusive mass transfer properties necessary to elicit stability and functionality require hetero-typic contact, cell-to-cell signaling and uniform nutrient diffusion. Bioprinting techniques successfully build mathematically defined porous architecture to diminish resistance to mass transfer. Current limitations of bioprinted cell assemblies include poor micro scale formability of cell-laden soft gels and asymmetrical macro-scale diffusion through 3D volumes. The objective of this work is to engineer a synchronized multi-material bioprinter (SMMB) system which improves the resolution and expands the capability of existing bioprinting systems by packaging multiple cell types in heterotypic arrays prior to deposition. This unit cell approach to arranging multiple cell-laden solutions is integrated with a motion system to print heterogeneous filaments as tissue engineered scaffolds and nanoliter droplets. The set of SMMB process parameters control the geometric arrangement of the combined flow's internal features and constituent material's volume fractions. SMMB printed hepatocyte-endothelial laden 200 nl droplets are cultured in a rotary cell culture system (RCCS) to study the effect of microgravity on an in vitro model of the human hepatic lobule. RCCS conditioning for 48 h increased hepatocyte cytoplasm diameter 2 MUm, increased metabolic rate, and decreased drug half-life. SMMB hetero-cellular models present a 10-fold increase in metabolic rate, compared to SMMB mono-culture models. Improved bioprinting resolution due to process control of cell-laden matrix packaging as well as nanoliter droplet printing capability identify SMMB as a viable technique to improve in vitro model efficacy. PMID- 26759994 TI - Incidence of skin conditions in neonates born at a public hospital associated with some variables in pregnant women at risk. AB - OBJECTIVES: To verify the incidence of skin diseases in newborns of pregnant women at risk of a public hospital in the city of Santos, Brazil (Hospital Guilherme Alvaro), determining the potential relation between these dermatoses and diseases presented by the mothers. METHODS: A total of 1,000 neonates were examined in the first 36 hours of life. The examination was repeated daily in each child up to hospital discharge. The paternal and newborn variables were submitted to analysis to detect statistically significant associations. RESULTS: The most frequent skin disorders were: Mongolian spot (69.8%), erythema toxicum neonatorum (19.7%), Port-wine stain (angiomatous naevi) (13.9%), and hypertrichosis lanuginose (10.3%). CONCLUSIONS: Minipuberty had a low incidence in neonates of diabetic mothers. The incidence of Mongolian spot was very low among newborns classified as caucasian. PMID- 26759996 TI - Financial incentives for generic drugs: case study on a reimbursement program. AB - OBJECTIVE: To discuss the use of financial incentives in choice of medication and to assess the economic results concerning the use of financial incentives to promote the use of genetic medication in lieu of reference drugs in a company with a reimbursement program. METHODS: A case study was carried out in a large supermarket. The data was obtained in the company responsible for managing medication. The study reached 83,625 users between August 2005 and July 2007. The data was submitted to regressions in order to analyze trends and hypothesis tests to assess differences in medication consumption. The results were compared with general data regarding medication consumption of five other organizations and also with data about the national consumption of generic medication in Brazil. RESULTS: The use of financial incentives to replace brand medications for generics, in the company studied, increased the consumption of generic drugs without reducing the company expenses with the reimbursement programs. CONCLUSIONS: This study show the occurrence of unplanned results (increase in the consumption of medications) and the positive consequences of the reimbursement program concerning access to medication. PMID- 26759992 TI - Clinical outcome after antipsychotic treatment discontinuation in functionally recovered first-episode nonaffective psychosis individuals: a 3-year naturalistic follow-up study. AB - OBJECTIVE: The timing of antipsychotic discontinuation in patients who have fully recovered from their initial episode of psychosis is still open to discussion. We aimed to evaluate the risk of symptom recurrence during the 3 years after antipsychotic discontinuation in a sample of functionally recovered first-episode nonaffective psychosis (FEP) patients (DSM-IV criteria) with schizophrenia spectrum disorder. METHOD: Participants in this open-label, nonrandomized, prospective study were drawn from an ongoing longitudinal intervention program of FEP from a university hospital setting in Spain. From July 2004 to February 2011, functionally recovered FEP individuals were eligible if they met the inclusion criteria of (1) a minimum of 18 months on antipsychotic treatment, (2) clinical remission for at least 12 months, (3) functional recovery for at least 6 months, and (4) stabilization at the lowest effective doses for at least 3 months. Forty six individuals who were willing to discontinue medication were included in the discontinuation group (target group). Twenty-two individuals opted to stay on the prescribed antipsychotic medication and therefore were included in the maintenance group (control group). Primary outcome measures were relapse rate at 18 and 36 months and time to relapse. RESULTS: The rates of relapse over the 3 year period were 67.4% (31 of 46) in the discontinuation group and 31.8% (7 of 22) in the maintenance group. The mean time to relapse was 209 (median = 122) days and 608 (median = 607) days, respectively (log rank = 10.106, P = .001). The resumption of antipsychotic medication after the relapse occurred was associated with clinical stability and lack of further relapses. When the overall group of relapsed individuals from the 2 conditions (N = 38) was compared to those who remained asymptomatic after 3 years (N = 30), there were significant differences (P < .05) in total scores on the Scale for the Assessment of Negative Symptoms, the Clinical Global Impressions scale, and the Disability Assessment Schedule. CONCLUSIONS: Antipsychotic treatment discontinuation in individuals who had accomplished a functional recovery after a single psychotic episode was associated with a high risk of symptom recurrence. Relapsed individuals had a greater severity of symptoms and lower functional status after 3 years. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02220504. PMID- 26759997 TI - Assessing knowledge of Medical undergraduate students on palliative care in end stage disease patients. AB - OBJECTIVE: To assess the knowledge on palliative care of undergraduate medical students of the 9th and 10th semesters at Universidade Nove de Julho. METHODS: A self-applied and self-explanatory questionnaire was prepared with 9 objective questions and given to 50 undergraduate medical students of these semesters. The content was related to palliative care, addressing some topics, such as orthothanasia, dysthanasia, euthanasia and clinical cases. The questionnaire was applied from November 2007 to February 2008. RESULTS: As to correct answers, the rates were 84%, 42%, 38% and 40% to questions 1, 2, 3 and 4, respectively. Question 7 was correctly answered by 84% and Question 8 by 30%. Question 9 achieved 100% correct answers. Regarding Question 5, there was no right or wrong answer, and 24% of the students chose alternative A, 32%, alternative B and 44%, alternative C. In Question 6, the students could tick more than one alternative, if necessary: 22% chose alternative A, 6%, alternative B, 2%, alternative C, 20% chose D and 6% responded alternative E; 36% opted for both alternatives B and D, and 6% of students answered alternatives B, C and D. CONCLUSIONS: Medical students that will conclude the undergraduate course are aware of the nature and the importance of palliative care, even when they have no previous experience during training at university. PMID- 26759995 TI - Denver II: evaluation of the development of children treated in the outpatient clinic of Project Einstein in the Community of Paraisopolis. AB - OBJECTIVES: To evaluate the neuropsychomotor development of children treated in an outpatient clinic, using the Denver Developmental Screening Test II (DDST-R). METHODS: This was an exploratory descriptive research using a quantitative approach, conducted in the outpatient clinic of the Project Einstein in the Community of Paraisopolis (PECP), Sao Paulo, Brazil. The sample consisted of 35 children, from birth to 6 years of age, most of them from 1 to 3 years old (19; 54.3%). They underwent the Denver II Test, which assesses four neuropsychomotor development areas: gross motor, fine motor adaptive, language and personal social. RESULTS: Most of the children (24, 68.6%) had test results compatible with normal development, while 10 (28.6%) had a "risk" test and 1 (2.9%) was "untestable" due to refusal to carry out the proposed activities. As to the items evaluated in each area, 7 children (20%) showed a developmental "delay" (when the child does not perform the activity passed by more than 90% of the children of his/her age) and 18 (51%) required "attention" (when the child does not perform the activity passed by 75 to 90% of the children of his/her age), predominantly in the language area. CONCLUSIONS: Although most of the children (68.6%) presented normal development in the test, we point out that in the remaining children (31.4%), the number of items classified as "delay" or "attention", and tests classified as "risk" or "untestable" suggest impairment in neuropsychomotor development. We underscore the importance of the routine administration of the DDST-R for an early detection of developmental disabilities and thus establish primary prevention programs. PMID- 26759990 TI - Outer membrane Protein A plays a role in pathogenesis of Acinetobacter nosocomialis. AB - Acinetobacter nosocomialis is an important nosocomial pathogen that causes a variety of human infections. However, the specific virulence factors of this microorganism have not yet been determined. We investigated the role of outer membrane protein A (OmpA) in the pathogenesis of A. nosocomialis. A DeltaompA mutant of the A. nosocomialis ATCC 17903(T) strain was constructed using markerless gene deletion. The DeltaompA mutant displayed reduced biofilm formation in polystyrene tubes and reduced adherence to A549 cells in comparison to the wild-type strain. These virulence traits of the DeltaompA mutant strain were restored when the ompA gene was complemented. Cytotoxicity was not significantly different between the wild-type strain and the DeltaompA mutant when A549 cells were infected with bacteria or treated with outer membrane vesicles (OMVs). However, OMVs from the wild-type strain induced cytotoxicity in HEp-2 cells, whereas OMVs from the DeltaompA mutant did not induce cytotoxicity. Proteomic analysis of OMVs revealed that OmpA influenced the distribution of envelope and periplasmic proteins. Overall, this study is the first report that links OmpA to A. nosocomialis pathogenesis, and highlights OmpA as a putative target to develop anti-virulence agents or vaccines against A. nosocomialis infection. PMID- 26759998 TI - Bone mineral density and body composition in adolescents with failure to thrive. AB - ObjectiveTo evaluate bone mineral mass in adolescents with failure to thrive in relation to body composition.MethodsA case control study involving 126 adolescents (15 to 19 years), in final puberty maturation being 76 eutrophic and 50 with failure to thrive (genetic or constitutional delay of growth), of matching ages, gender and pubertal maturation. The weight, height and calculated Z score for height/age and body mass index; bone mineral content, bone mineral density and adjusted bone mineral density were established for total body, lower back and femur; total fat-free mass and height-adjusted fat-free mass index, total fat mass and height-adjusted. The statistical analyses were performed using the Student's t-test (weight, height and body composition); Mann-Whitney test (bone mass) and multiple linear regression (bone mass determinants).Resultsweight, height and height/age Z-score were significantly higher among eutrophic subjects. Both groups did not show statistically significant differences for fat mass, percentage of fat mass, total fat mass height adjusted and fat-free mass index height sadjusted. However, total free fat maass was smaller for the failure to thrive group.ConclusionsThere was no statistically significant difference for bone mass measurements among adolescents with failure to thrive; however, the factors that determine bone mass formation should be better studied due to the positive correlation with free fat mass detected in these individuals. PMID- 26760000 TI - Follow-up of premature children with high risk for growth and development delay: a multiprofessional assessment. AB - OBJECTIVE: To describe the activities of a multiprofessional outpatient clinic performed by neonatologist, physiatrist, physical therapist, occupational therapist, speech therapist, audiologist and psychologist, who evaluated the development of premature newborns. METHODS: Twenty children born at a tertiary care hospital (Sao Paulo, Brazil), between April 2006 and April 2007, with birth weight below 1250 g or less than 32 weeks of gestation, were evaluated. The multiprofessional evaluation included assessment of development using the Bayley III scale, at the corrected age of 3, 6, 9, 12, 18 and 24 months. RESULTS: The mean gestation age at birth was 28.8 weeks; mean birth weight was 1055 g. The mean maternal age was 35 years and the mean length of stay of neonates was 46.3 days. Fifteen percent of children presented impaired sensory motor skills, 20% had hearing abnormalities and 10% motor alterations. Bayley III showed alterations in the communication area in 10% of subjects and in the motor area in 10% of individuals. The parents were oriented to stimulate the child or a specific intervention was suggested. The major development delay was observed between 6 and 18 months of age and the development was improved at 24 months of age. CONCLUSIONS: Most children evaluated had improved growth and development at 24 corrected-age months. Further studies with a larger sample are recommended, as well as the possibility to follow this population group up till the primary school. PMID- 26759999 TI - Adverse drug events leading to emergency department visits in elderly: the role of inappropriate prescription. AB - OBJECTIVE: Adverse drug reactions are more incident among the elderly and are frequently associated to inappropriate prescription for this group. The objective of the current study was to investigate the incidence and the characteristics of emergency department visits, related to inappropriate prescription, at the Hospital Israelita Albert Einstein. METHODS: Patients aged 60 years or older, admitted to the emergency department at Unidade Avancada Ibirapuera of Hospital Israelita Albert Einstein, were included in the study. Potentially inappropriate medication for the elderly was evaluated using updated 2003 Beers criteria. RESULTS: Over a period of 6 months, 214 individuals were included in the study, being 53.7% male. The mean age was 70.8 years (60-107). A total of 48 registries of inappropriate prescription were recorded in 42 patients (19.6% of sample). An emergency visit related to adverse drug event was verified in 27 individuals (12.5% of the sample). From these patients, 34.5% were admitted to the emergency department because of an adverse event caused by an inappropriate medication. CONCLUSION: Inappropriate prescription is frequent among elderly patients admitted to emergency department. A surveillance system and a program to educate physicians on the most recent criteria of appropriate prescription may help reducing emergency visits and adverse drug events in the elderly population. PMID- 26760001 TI - Evaluation of chemiluminescence method for the analysis of plasma homocysteine and comparison with HPLC method in children samples. AB - OBJECTIVE: To compare the results for homocysteine concentration using chemiluminescence and HPLC methods in samples from school-age children. In addition, to determine the reference values for patients of this age group and assess the real prognostic value of homocysteine in healthy children. METHODS: A prospective observational study was undertaken to determine plasma levels of homocysteine using two different assays, HPLC and chemiluminescence, in 185 samples from school-age children living in Santo Andre, with no chronic or inflammatory diseases, and absence of pubertal development. RESULTS: The results were presented in percentiles and reference values were determined within this age group (7-9 years old). Homocysteine concentration ranged from 2.0 to 9.9 umol/l (r = 0.821 and p < 0.001). CONCLUSIONS: It was verified that chemiluminescence is comparable to HPLC when both techniques are used to detect homocysteine in school-age children. There is an important correlation between both methods, which allows investigation of this amino acid as a risk factor for heart diseases. PMID- 26760003 TI - Prevalence of upper respiratory tract infections at a tertiary care hospital in the city of Sao Paulo. AB - OBJECTIVE: To evaluate the prevalence of pathogens in the upper respiratory tract according to age at a tertiary care hospital in the city of Sao Paulo. METHODS: A total of 6,144 biological material tests from upper respiratory airways were analyzed: 740 bacterial cultures, 726 virus screenings and 4,678 rapid tests for S. pyogenes. RESULTS: The most frequently found etiological agent was respiratory syncytial virus (29.6%; 215/726). The main agents detected per age groups were: respiratory syncytial virus (25.34%; 184/726) in patients aged 28 days-3 years; S. pyogenes (9.5%; 70/740) in 3-12 year-old children; influenza virus (8.8%; 64/726) in adults (18-59 years). CONCLUSIONS: The etiologic agents of upper respiratory infections vary according to age and imply diverse clinical and therapeutic management. PMID- 26760002 TI - Urinary incontinence after vaginal delivery or cesarean section. AB - OBJECTIVE: To assess the prevalence of stress urinary incontinence, urge incontinence and mixed urinary incontinence among women residing in the city of Jundiai (Sao Paulo, Brazil), and the relation between the type of incontinence and the obstetric history of these women. METHODS: A cross-sectional community based study was conducted. A total of 332 women were interviewed; they were seen for whatever reason at the public primary healthcare units of the city of Jundiai, from March 2005 to April 2006. A pre-tested questionnaire was administered and consisted of questions used in the EPINCONT Study (Epidemiology of Incontinence in the County of Nord-Trondelag). Statistical analysis was carried out using the chi2 test and odds ratio (95%CI). RESULTS: Urinary incontinence was a complaint for 23.5% of the women interviewed. Stress urinary incontinence prevailed (50%), followed by mixed urinary incontinence (35%) and urge incontinence (15%). Being in the age group of 35-64 years, having a body mass index of 30 or greater and having had only vaginal delivery or cesarean section, with uterine contraction, regardless of the number of pregnancies, were factors associated with stress urinary incontinence. However, being in the age group of 55 or older, having a body mass index of 30 or greater and having had three or more pregnancies, only with vaginal deliveries, were factors associated with mixed urinary incontinence. CONCLUSIONS: One third of the interviewees complained of some type of urinary incontinence, and half of them presented stress urinary incontinence. Cesarean section, only when not preceded by contractions, was not associated with stress urinary incontinence. The body mass index is only relevant when the stress factor is present. PMID- 26760004 TI - Comparative analysis of radical prostatectomy techniques using perineal or suprapubic approach in the treatment of localized prostate cancer. AB - OBJECTIVE: To compare the results of radical prostatectomy by perineal and suprapubic approaches as to operative time, procedure costs, and surgical site complications. METHODS: The medical records of localized prostate cancer patients (PSA <= 10 ng/ml and Gleason score <= 6) were analyzed. Fifty-five patients were submitted to radical prostatectomy by perineal approach and 54 via suprapubic approach. RESULTS: There were statistical differences between groups as to operative time (p < 0.05); for perineal approach it was in average 114 minutes (SD +/- 0.03) and for suprapubic approach, an average of 167 minutes (SD +/- 0.041). Prostatectomy via perineal approach resulted in 11 cases of surgical complications, and suprapubic approach, 3 cases. CONCLUSIONS: Radical prostatectomy via perineal approach took less time at a lower cost as compared to the suprapubic approach. However, there were more complications in patients submitted to perineal approach, mainly rectal lesions. PMID- 26760005 TI - Comparison of methods of measurement of the finger flexor muscles' strength through dynamometry and modified manual sphygmomanometer. AB - OBJECTIVE: To evaluate the reproducibility of the modified sphygmomanometer compared to hand dynamometer to measure muscle strength of the flexor muscles of fingers. METHODS: We assessed 40 healthy volunteers of both genders, aged between 20 and 55 years, who underwent the muscle strength test in the finger flexor muscles on both hands using two instruments for which the comparison was made between them. RESULTS: After statistical analysis by the paired Student's ttest, there was no significant difference between the values obtained in modified sphygmomanometer and hand dynamometer tests in relation to right and left sides (p > 0.05). Pearson's coefficient of correlation observed good correlations between them. CONCLUSIONS: The modified sphygmomanometer proved to be a reproducible technique for measuring muscle strength of the finger flexor muscles. PMID- 26760006 TI - Patient care and administrative activities of nurses in clinical/surgical units. AB - OBJECTIVES: To identify the administrative and nursing care activities most performed by nurses in clinical/surgical units and to determine which are most and least pleasant to them. METHODS: A descriptive-exploratory field study, with a quantitative approach and with a sample made up of 40 nurses working in clinical/surgical units who answered a three-part questionnaire composed of identification data and characterization of the professional; a list of nursing and administrative activities for the nurse to grade according to the numbers: "0 = I do not perform it", "1 = I perform it occasionally", "2 = I perform it often", "3 = I perform it daily"; two open-ended questions, in which the nurse listed the activities he/she enjoyed the most and the least. RESULTS: The administrative activities most performed by the nurses were: changing work shifts, preparing employee daily task charts and managing tests; the most performed nursing care activities were related to the stages of the Nursing Care Systematization and the interaction with the multi-professional team; the most enjoyable activities were direct patient care, patient evaluation and implementation of the systematization; the least enjoyable activities were administrative and bureaucratic routines, justification of complaints/problem solving and preparation of employee task charts. CONCLUSION: Compared to administrative activities, nursing activities were performed most during the daily routine of the nurse, and the most enjoyable activities were those related to patient care, according to the opinions of the professionals. PMID- 26760007 TI - Pharmacy contribution to the prescription and rational use of human albumin at a large hospital. AB - OBJECTIVE: The purpose of this survey was to reduce the use of human albumin 20% in non-supported indications at Hospital Israelita Albert Einstein. METHODS: During a 30-day period, in December 2006, a preliminary prospective analysis of medical prescriptions of human albumin 20% and therapeutic indications according to ANVISA RDC 115 guidelines was performed. Based on this analysis, a project was developed. In January 2007, a daily routine to follow up albumin prescriptions by the Hospital pharmacists was established. RESULTS: From January to October 2007, 14,799 vials of albumin 20% were used, out of which 4,191 had non-supported indications, resulting in a R$ 1.36 million loss. In 2008 (from January to October), 13,519 vials of albumin 20% were prescribed, and 1,648 of them had non supported indications, causing a R$ 535 thousand loss. The ratio between loss risk and consumed amount was 91.99 between January and October 2007. During the same period in 2008, this ratio was 39.60. Between January and October 2007, the average percentage of albumin prescribed for non-supported indications was 28%, whereas this percentage dropped to 13%, i.e., a decrease by 54%, during the same period of 2008. CONCLUSIONS: The inclusion of a pharmacist in the process of verifying medicine indications and justification of use was translated into safer processes to patients, ensuring that they received the correct medication for the correct indication, therefore reducing the chance of adverse events and contributing to reduce red-tape procedures and unnecessary expenditures by the institution. PMID- 26760008 TI - Humanization according to cancer patients with extended hospitalization periods. AB - OBJECTIVE: To identify the concept of humanization and raise aspects that contribute towards and that hinder humanization of hospital care, according to the opinion of oncology patients. METHODS: This is a descriptive-exploratory survey, with a qualitative-quantitative approach. The sample was made up of 10 patients hospitalized for more than 30 days at the Oncology Unit of Hospital Israelita Albert Einstein, who, after satisfying ethical and legal procedures, were interviewed and answered three questions in reference to humanization in oncology. RESULTS: The factors that contributed more towards humanization were warmth in giving care, friendliness, and smiles, and the factors that hindered it were bad moods, noise, and not being promptly attended. CONCLUSIONS: Hospital humanization should be experienced and felt by all those who work at hospital and needs to be reflected in the care offered to the client and his/her family members. These aspects become vital in oncology in order to understand the difficult period the patient is going through during the hospital stay, showing an interest in his/her problems and struggles with an attitude of empathy and cordiality, always acting ethically and with professional responsibility. PMID- 26760009 TI - Pleuropericardial cyst torsion: case report. AB - Pericardial cysts account for 12-18% of all mediastinal masses. They are usually asymptomatic and incidentally detected. However, when large, they can cause symptoms. Most pericardial cysts are located in the right cardiophrenic angle, but they can be anywhere in the mediastinum. We reported a pleuropericardial cyst torsion after physical stress, a very rare complication of this condition. The diagnosis was made by computed tomography and confirmed by video-assisted thoracoscopy. PMID- 26760010 TI - Developed foot drop as a complication of bariatric surgery: case reports. AB - Two cases of patients with morbid obesity submitted to bariatric surgery and with considerable weight loss are presented. During follow-up, they complained of weakness in the legs and the physical examination showed reduction of ankle dorsiflexion muscle strength (foot drop). In these cases, the symptoms subsided spontaneously. A literature review is presented. PMID- 26760011 TI - Indications of Sentinel Node Biopsy in Thin Melanoma. AB - OBJECTIVE: To assess data on survival, recurrence and histological factors in positive and negative sentinel lymph nodes in thin melanoma cases. METHODS: A systematic review was conducted on observational studies in four databases (Cochrane Library, Medline, Embase and Lilacs). Positive and negative micrometastases in sentinel lymph node biopsy were compared regarding the clinical outcomes - death and recurrence - and six histological factors - vertical growth phase, Breslow thickness, Clark level, ulceration, regression and mitosis rate. RESULTS: Positive sentinel lymph node is statistically associated with greater risk of death in six studies (OR: 7.2; 95%CI [2.37-21.83]; I2 0%) and also to recurrence in three studies (OR: 30.7; 95%CI [12.58-74.92]; I2 36%). Comparing positive and negative groups, the histological factors predicting positive sentinel nodes and poor prognosis were: mitosis rate >= 5/mm2 (OR: 16.29; 95%CI [3.64-72.84]; I2 40%); VGP (OR: 2.93; 95%CI [1.08-7.93]; I2 59%); Breslow thickness >= 0.75mm (OR: 2.23; 95%CI [1.29-3.86]; I2 0%); and Clark level IV-V (OR: 1.61; 95%CI [1.06-2.44]; I234%). CONCLUSIONS: The statistically significant results associated with the presence of micrometastases in thin melanomas were Breslow thickness >= 0.75 mm, Clark level IV-V and mitoses >= 5/mm2, absence of regression. This histological factor of ulceration was associated, but not statistically significant. PMID- 26760012 TI - The need to include obstetric nurses in prenatal care visits in the public health system. AB - OBJECTIVE: To investigate, with a qualitative approach, the role of Obstetric Nurses at the primary level of care given to women's health as a vital component of the multidisciplinary team, which today is fundamental for providing care, prevention as well as health education and promotion, especially in programs whose activities are geared towards primary care of pregnant, parturient, and puerpera women. METHODS: Brazilian laws and the determinations of Nursing Councils in reference to the activities of the obstetric nurse were researched, including the nurse's responsibilities and limits. The bibliographic search was conducted in health-related journals, lay publications, and the Internet. RESULTS: The conflicts between professional physicians and nurses were discussed. CONCLUSIONS: It was concluded that the activities of the nurse, conducting low risk prenatal clinical visits in the basic healthcare network, has legal and ethical support and provides true benefit to the clients. PMID- 26760013 TI - Pathogenesis of pulmonary emphysema - cellular and molecular events. AB - Pulmonary emphysema is a chronic obstructive disease, resulting from important alterations in the whole distal structure of terminal bronchioles, either by enlargement of air spaces or by destruction of the alveolar wall, leading to loss of respiratory surface, decreased elastic recoil and lung hyperinflation. For many years, the hypothesis of protease-antiprotease unbalance prevailed as the central theme in the pathogenesis of pulmonary emphysema. According to this hypothesis, the release of active proteolytic enzymes, produced mainly by neutrophils and macrophages, degrades the extracellular matrix, affecting the integrity of its components, especially collagen and elastic fibers. However, new concepts involving cellular and molecular events were proposed, including oxidative stress, cell apoptosis, cellular senescence and failed lung tissue repair. The aim of this review paper was to evaluate the cellular and molecular mechanisms seen in the pathogenesis of pulmonary emphysema. PMID- 26760014 TI - Tractography. PMID- 26760016 TI - Erratum. PMID- 26760015 TI - Effects of dietary fiber intake on inflammation in chronic diseases. AB - Chronic diseases such as obesity, type-2 diabetes, metabolic syndrome and cardiovascular diseases are associated with inflammation due the increase of TNF alpha, IL-6 and C-reactive protein concentrations. Occidental life style, specially related to the changes in food habits as observed in the past years, have an important role in the development of these diseases. Among the life style changes identified as having an impact in the development of diseases, is the decrease in dietary fiber consumption. Some studies have shown the negative relationship between fiber ingestion and inflammatory markers in chronic diseases. Dietary fibers have an important and a well-known role in different physiologic functions such as intestinal peristalsis, weight reduction by acting on satiety mechanisms, preventing colon cancer, reducing cholesterol and post prandial glycaemia. PMID- 26760033 TI - Anthropogenic Radio-Frequency Electromagnetic Fields Elicit Neuropathic Pain in an Amputation Model. AB - Anecdotal and clinical reports have suggested that radio-frequency electromagnetic fields (RF EMFs) may serve as a trigger for neuropathic pain. However, these reports have been widely disregarded, as the epidemiological effects of electromagnetic fields have not been systematically proven, and are highly controversial. Here, we demonstrate that anthropogenic RF EMFs elicit post neurotomy pain in a tibial neuroma transposition model. Behavioral assays indicate a persistent and significant pain response to RF EMFs when compared to SHAM surgery groups. Laser thermometry revealed a transient skin temperature increase during stimulation. Furthermore, immunofluorescence revealed an increased expression of temperature sensitive cation channels (TRPV4) in the neuroma bulb, suggesting that RF EMF-induced pain may be due to cytokine-mediated channel dysregulation and hypersensitization, leading to thermal allodynia. Additional behavioral assays were performed using an infrared heating lamp in place of the RF stimulus. While thermally-induced pain responses were observed, the response frequency and progression did not recapitulate the RF EMF effects. In vitro calcium imaging experiments demonstrated that our RF EMF stimulus is sufficient to directly contribute to the depolarization of dissociated sensory neurons. Furthermore, the perfusion of inflammatory cytokine TNF-alpha resulted in a significantly higher percentage of active sensory neurons during RF EMF stimulation. These results substantiate patient reports of RF EMF-pain, in the case of peripheral nerve injury, while confirming the public and scientific consensus that anthropogenic RF EMFs engender no adverse sensory effects in the general population. PMID- 26760035 TI - Toward Human-Carnivore Coexistence: Understanding Tolerance for Tigers in Bangladesh. AB - Fostering local community tolerance for endangered carnivores, such as tigers (Panthera tigris), is a core component of many conservation strategies. Identification of antecedents of tolerance will facilitate the development of effective tolerance-building conservation action and secure local community support for, and involvement in, conservation initiatives. We use a stated preference approach for measuring tolerance, based on the 'Wildlife Stakeholder Acceptance Capacity' concept, to explore villagers' tolerance levels for tigers in the Bangladesh Sundarbans, an area where, at the time of the research, human tiger conflict was severe. We apply structural equation modeling to test an a priori defined theoretical model of tolerance and identify the experiential and psychological basis of tolerance in this community. Our results indicate that beliefs about tigers and about the perceived current tiger population trend are predictors of tolerance for tigers. Positive beliefs about tigers and a belief that the tiger population is not currently increasing are both associated with greater stated tolerance for the species. Contrary to commonly-held notions, negative experiences with tigers do not directly affect tolerance levels; instead, their effect is mediated by villagers' beliefs about tigers and risk perceptions concerning human-tiger conflict incidents. These findings highlight a need to explore and understand the socio-psychological factors that encourage tolerance towards endangered species. Our research also demonstrates the applicability of this approach to tolerance research to a wide range of socio economic and cultural contexts and reveals its capacity to enhance carnivore conservation efforts worldwide. PMID- 26760034 TI - Controlled Delivery of Vancomycin via Charged Hydrogels. AB - Surgical site infection (SSI) remains a significant risk for any clean orthopedic surgical procedure. Complications resulting from an SSI often require a second surgery and lengthen patient recovery time. The efficacy of antimicrobial agents delivered to combat SSI is diminished by systemic toxicity, bacterial resistance, and patient compliance to dosing schedules. We submit that development of localized, controlled release formulations for antimicrobial compounds would improve the effectiveness of prophylactic surgical wound antibiotic treatment while decreasing systemic side effects. Our research group developed and characterized oligo(poly(ethylene glycol)fumarate)/sodium methacrylate (OPF/SMA) charged copolymers as biocompatible hydrogel matrices. Here, we report the engineering of this copolymer for use as an antibiotic delivery vehicle in surgical applications. We demonstrate that these hydrogels can be efficiently loaded with vancomycin (over 500 MUg drug per mg hydrogel) and this loading mechanism is both time- and charge-dependent. Vancomycin release kinetics are shown to be dependent on copolymer negative charge. In the first 6 hours, we achieved as low as 33.7% release. In the first 24 hours, under 80% of total loaded drug was released. Further, vancomycin release from this system can be extended past four days. Finally, we show that the antimicrobial activity of released vancomycin is equivalent to stock vancomycin in inhibiting the growth of colonies of a clinically derived strain of methicillin-resistant Staphylococcus aureus. In summary, our work demonstrates that OPF/SMA hydrogels are appropriate candidates to deliver local antibiotic therapy for prophylaxis of surgical site infection. PMID- 26760039 TI - Converting Predation Cues into Conservation Tools: The Effect of Light on Mouse Foraging Behaviour. AB - Prey face a conflict between acquiring energy and avoiding predators and use both direct and indirect cues to assess predation risk. Illumination, an indirect cue, influences nocturnal rodent foraging behaviour. New Zealand holds no native rodent species but has introduced mice (Mus musculus) that severely impair native biodiversity. We used Giving-Up Densities (GUDs) and observations of foraging frequency and duration to assess if artificial light induces risk avoidance behaviour in mice and could limit their activity. We found both captive (wild strain) mice in outdoor pens and wild mice within a pest fenced sanctuary (Maungatautari, New Zealand) displayed avoidance behaviour in response to illumination. In captivity, total foraging effort was similar across lit and unlit pens but mice displayed a strong preference for removing seeds from dark control areas (mean: 15.33 SD: +/-11.64 per 3.5 hours) over illuminated areas (2.00 +/-3.44). Wild mice also removed fewer seeds from illuminated areas (0.42 +/-1.00 per 12 hours) compared to controls (6.67 +/-9.20). Captive mice spent less than 1.0% of available time at illuminated areas, versus 11.3% at controls; visited the lit areas less than control areas (12.00 +/- 9.77 versus 29.00 +/ 21.58 visits respectively); and spent less time per visit at illuminated versus control areas (8.17 +/-7.83 versus 44.83 +/-87.52 seconds per visit respectively). Illumination could provide protection at ecologically sensitive sites, damaged exclusion fences awaiting repair, fence terminus zones of peninsula sanctuaries and shipping docks that service offshore islands. We promote the hypothesis that the tendency of mice to avoid illumination could be a useful conservation tool, and advance knowledge of risk assessment and foraging under perceived danger. PMID- 26760037 TI - Epithelial-to-Mesenchymal Transition of RPE Cells In Vitro Confers Increased beta1,6-N-Glycosylation and Increased Susceptibility to Galectin-3 Binding. AB - Epithelial-to-mesenchymal transition (EMT) of retinal pigment epithelial cells is a crucial event in the onset of proliferative vitreoretinopathy (PVR), the most common reason for treatment failure in retinal detachment surgery. We studied alterations in the cell surface glycan expression profile upon EMT of RPE cells and focused on its relevance for the interaction with galectin-3 (Gal-3), a carbohydrate binding protein, which can inhibit attachment and spreading of human RPE cells in a dose- and carbohydrate-dependent manner, and thus bares the potential to counteract PVR-associated cellular events. Lectin blot analysis revealed that EMT of RPE cells in vitro confers a glycomic shift towards an abundance of Thomsen-Friedenreich antigen, poly-N-acetyllactosamine chains, and complex-type branched N-glycans. Using inhibitors of glycosylation we found that both, binding of Gal-3 to the RPE cell surface and Gal-3-mediated inhibition of RPE attachment and spreading, strongly depend on the interaction of Gal-3 with tri- or tetra-antennary complex type N-glycans and sialylation of glycans but not on complex-type O-glycans. Importantly, we found that beta1,6 N acetylglucosaminyltransferase V (Mgat5), the key enzyme catalyzing the synthesis of tetra- or tri-antennary complex type N-glycans, is increased upon EMT of RPE cells. Silencing of Mgat5 by siRNA and CRISPR-Cas9 genome editing resulted in reduced Gal-3 binding. We conclude from these data that binding of recombinant Gal-3 to the RPE cell surface and inhibitory effects on RPE attachment and spreading largely dependent on interaction with Mgat5 modified N-glycans, which are more abundant on dedifferentiated than on the healthy, native RPE cells. Based on these findings we hypothesize that EMT of RPE cells in vitro confers glycomic changes, which account for high affinity binding of recombinant Gal-3, particularly to the cell surface of myofibroblastic RPE. From a future perspective recombinant Gal-3 may disclose a therapeutic option allowing for selectively targeting RPE cells with pathogenic relevance for development of PVR. PMID- 26760036 TI - Arabidopsis Flower and Embryo Developmental Genes are Repressed in Seedlings by Different Combinations of Polycomb Group Proteins in Association with Distinct Sets of Cis-regulatory Elements. AB - Polycomb repressive complexes (PRCs) play crucial roles in transcriptional repression and developmental regulation in both plants and animals. In plants, depletion of different members of PRCs causes both overlapping and unique phenotypic defects. However, the underlying molecular mechanism determining the target specificity and functional diversity is not sufficiently characterized. Here, we quantitatively compared changes of tri-methylation at H3K27 in Arabidopsis mutants deprived of various key PRC components. We show that CURLY LEAF (CLF), a major catalytic subunit of PRC2, coordinates with different members of PRC1 in suppression of distinct plant developmental programs. We found that expression of flower development genes is repressed in seedlings preferentially via non-redundant role of CLF, which specifically associated with LIKE HETEROCHROMATIN PROTEIN1 (LHP1). In contrast, expression of embryo development genes is repressed by PRC1-catalytic core subunits AtBMI1 and AtRING1 in common with PRC2-catalytic enzymes CLF or SWINGER (SWN). This context-dependent role of CLF corresponds well with the change in H3K27me3 profiles, and is remarkably associated with differential co-occupancy of binding motifs of transcription factors (TFs), including MADS box and ABA-related factors. We propose that different combinations of PRC members distinctively regulate different developmental programs, and their target specificity is modulated by specific TFs. PMID- 26760038 TI - Effect of Voluntary Ethanol Consumption Combined with Testosterone Treatment on Cardiovascular Function in Rats: Influence of Exercise Training. AB - This study evaluated the effects of voluntary ethanol consumption combined with testosterone treatment on cardiovascular function in rats. Moreover, we investigated the influence of exercise training on these effects. To this end, male rats were submitted to low-intensity training on a treadmill or kept sedentary while concurrently being treated with ethanol for 6 weeks. For voluntary ethanol intake, rats were given access to two bottles, one containing ethanol and other containing water, three 24-hour sessions per week. In the last two weeks (weeks 5 and 6), animals underwent testosterone treatment concurrently with exercise training and exposure to ethanol. Ethanol consumption was not affected by either testosterone treatment or exercise training. Also, drug treatments did not influence the treadmill performance improvement evoked by training. However, testosterone alone, but not in combination with ethanol, reduced resting heart rate. Moreover, combined treatment with testosterone and ethanol reduced the pressor response to the selective alpha1-adrenoceptor agonist phenylephrine. Treatment with either testosterone or ethanol alone also affected baroreflex activity and enhanced depressor response to acetylcholine, but these effects were inhibited when drugs were coadministrated. Exercise training restored most cardiovascular effects evoked by drug treatments. Furthermore, both drugs administrated alone increased pressor response to phenylephrine in trained animals. Also, drug treatments inhibited the beneficial effects of training on baroreflex function. In conclusion, the present results suggest a potential interaction between toxic effects of testosterone and ethanol on cardiovascular function. Data also indicate that exercise training is an important factor influencing the effects of these substances. PMID- 26760040 TI - Regional Inequalities in Lung Cancer Mortality in Belgium at the Beginning of the 21st Century: The Contribution of Individual and Area-Level Socioeconomic Status and Industrial Exposure. AB - Being a highly industrialized country with one of the highest male lung cancer mortality rates in Europe, Belgium is an interesting study area for lung cancer research. This study investigates geographical patterns in lung cancer mortality in Belgium. More specifically it probes into the contribution of individual as well as area-level characteristics to (sub-district patterns in) lung cancer mortality. Data from the 2001 census linked to register data from 2001-2011 are used, selecting all Belgian inhabitants aged 65+ at time of the census. Individual characteristics include education, housing status and home ownership. Urbanicity, unemployment rate, the percentage employed in mining and the percentage employed in other high-risk industries are included as sub-district characteristics. Regional variation in lung cancer mortality at sub-district level is estimated using directly age-standardized mortality rates. The association between lung cancer mortality and individual and area characteristics, and their impact on the variation of sub-district level is estimated using multilevel Poisson models. Significant sub-district variations in lung cancer mortality are observed. Individual characteristics explain a small share of this variation, while a large share is explained by sub-district characteristics. Individuals with a low socioeconomic status experience a higher lung cancer mortality risk. Among women, an association with lung cancer mortality is found for the sub-district characteristics urbanicity and unemployment rate, while for men lung cancer mortality was associated with the percentage employed in mining. Not just individual characteristics, but also area characteristics are thus important determinants of (regional differences in) lung cancer mortality. PMID- 26760041 TI - Expression of VSTM1-v2 Is Increased in Peripheral Blood Mononuclear Cells from Patients with Rheumatoid Arthritis and Is Correlated with Disease Activity. AB - Rheumatoid arthritis (RA) is a chronic, systematic autoimmune disease that mainly affects joints and bones. Although the precise etiology is still unknown, Th17 cell is being recognized as an important mediator in pathogenesis of RA. VSTM1-v2 is a novel cytokine which has recently been reported to promote the differentiation of Th17 cells. This study is performed to study whether VSTM1-v2 can be recognized as a biomarker of RA, and is correlated to IL-17 expression. We obtained peripheral blood mononuclear cells (PBMCs) from 40 patients with RA and 40 age- and sex-matched healthy controls by standard Ficoll-Paque Plus density centrifugation. The mRNA expression levels of VSTM1-v2 and IL-17A in PBMCs were detected by real time-PCR. Disease activity parameters of RA were measured by routine methods. Our results showed that VSTM1-v2 mRNA expression in PBMCs from RA patients was significantly increased in comparison of that in healthy individuals. The VSTM1-v2 mRNA expression level was positively correlated with IL 17A mRNA expression level, DAS28, CRP and ESR, but was not correlated to RF, Anti CCP or ANA. VSTM1-v2 might be a biomarker of RA and a novel factor in the pathogenesis of RA. PMID- 26760043 TI - Incidences of Feto-Fetal Transfusion Syndrome and Perinatal Outcomes in Triplet Gestations with Monochorionic Placentation. AB - INTRODUCTION: This study aimed to determine the incidences of feto-fetal transfusion syndrome (FFTS) and perinatal outcomes in triplet gestations with monochorionic placentation. MATERIALS AND METHODS: In this retrospective cohort study, we evaluated the incidences of FFTS and perinatal outcomes at 28 days of age in cases of triplet gestations with monochorionic placentation who visited our centers before 16 weeks of gestation and delivered over a period of 11 years. RESULTS: In 41 triplet gestations (17 monochorionic triamniotic, 22 dichorionic triamniotic, 1 dichorionic diamniotic, and 1 monochorionic monoamniotic), the incidence of FFTS was 17.1%, and the median gestational age at FFTS diagnosis was 19 weeks. In 123 triplets, the incidences of fetal death and neonatal death at 28 days of age were 8.1 and 0.9%, respectively. None of the surviving infants had grade 3 or 4 intraventricular hemorrhage, while cystic periventricular leukomalacia occurred in 6 of 113 infants (5.3%). The incidence of poor outcomes (death or any major neurological complication at 28 days of age) was 13.8%. DISCUSSION: Seventeen percent of triplet pregnancies with monochorionic placentation developed FFTS, and 14% had a poor outcome. Therefore, triplet gestations with monochorionic placentation should be followed carefully. PMID- 26760042 TI - The Conoid Associated Motor MyoH Is Indispensable for Toxoplasma gondii Entry and Exit from Host Cells. AB - Many members of the phylum of Apicomplexa have adopted an obligate intracellular life style and critically depend on active invasion and egress from the infected cells to complete their lytic cycle. Toxoplasma gondii belongs to the coccidian subgroup of the Apicomplexa, and as such, the invasive tachyzoite contains an organelle termed the conoid at its extreme apex. This motile organelle consists of a unique polymer of tubulin fibres and protrudes in both gliding and invading parasites. The class XIV myosin A, which is conserved across the Apicomplexa phylum, is known to critically contribute to motility, invasion and egress from infected cells. The MyoA-glideosome is anchored to the inner membrane complex (IMC) and is assumed to translocate the components of the circular junction secreted by the micronemes and rhoptries, to the rear of the parasite. Here we comprehensively characterise the class XIV myosin H (MyoH) and its associated light chains. We show that the 3 alpha-tubulin suppressor domains, located in MyoH tail, are necessary to anchor this motor to the conoid. Despite the presence of an intact MyoA-glideosome, conditional disruption of TgMyoH severely compromises parasite motility, invasion and egress from infected cells. We demonstrate that MyoH is necessary for the translocation of the circular junction from the tip of the parasite, where secretory organelles exocytosis occurs, to the apical position where the IMC starts. This study attributes for the first time a direct function of the conoid in motility and invasion, and establishes the indispensable role of MyoH in initiating the first step of motility along this unique organelle, which is subsequently relayed by MyoA to enact effective gliding and invasion. PMID- 26760046 TI - Step aerobic combined with resistance training and plasma adiponectic. PMID- 26760047 TI - Interventions for promoting reintegration and reducing harmful behaviour and lifestyles in street-connected children and young people. AB - BACKGROUND: Millions of street-connected children and young people worldwide live or work in street environments. They are vulnerable to many risks, whether or not they remain connected to families of origin, and despite many strengths and resiliencies, they are excluded from mainstream social structures and opportunities. OBJECTIVES: Primary research objectivesTo evaluate and summarise the effectiveness of interventions for street-connected children and young people that aim to:* promote inclusion and reintegration;* increase literacy and numeracy;* facilitate access to education and employment;* promote mental health, including self esteem;* reduce harms associated with early sexual activity and substance misuse. Secondary research objectives* To explore whether effects of interventions differ within and between populations, and whether an equity gradient influences these effects, by extrapolating from all findings relevance for low- and middle-income countries (LMICs) (Peters 2004).* To describe other health, educational, psychosocial and behavioural effects, when appropriate outcomes are reported.* To explore the influence of context in design, delivery and outcomes of interventions.* To explore the relationship between numbers of components and duration and effects of interventions.* To highlight implications of these findings for further research and research methods to improve evidence in relation to the primary research objective.* To consider adverse or unintended outcomes. SEARCH METHODS: We searched the following bibliographic databases, searched for the original review, from inception to 2012, and various relevant non-governmental and organisational websites: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE and Pre-MEDLINE; EMBASE and EMBASE Classic; Cumulative Index to Nursing and Allied Health Literature (CINAHL); PsycINFO; Education Resource Information Center (ERIC); Sociological Abstracts; Social Services Abstracts; Social Work Abstracts; Healthstar; Latin American Caribbean Health Sciences Literature (LILACS); System for Grey literature in Europe (OpenGrey); ProQuest Dissertations and Theses; EconLit; IDEAS Economics and Finance Research; JOLIS Library Catalog of the holdings of the World Bank Group and International Monetary Fund (IMF) Libraries; British Library for Development Studies (BLDS); Google and Google Scholar. We updated the search in April 2015 for the review update, using the same methods. SELECTION CRITERIA: This review includes data from harm reduction or reintegration intervention studies that used a comparison group study design; all were randomised or quasi-randomised studies. Studies were included if they evaluated interventions provided for street connected children and young people, from birth to 24 years, in all contexts. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias and other factors presented in the Discussion and Summary quality assessment (Grades of Recommendation, Assessment, Development and Evaluation (GRADE)). We extracted data on intervention delivery, context, process factors, equity and outcomes, and grouped outcomes into psychosocial outcomes, risky sexual behaviours or substance use. We conducted meta-analyses for outcomes where the outcome measures were sufficiently similar. We evaluated other outcomes narratively. MAIN RESULTS: We included 13 studies evaluating 19 interventions from high-income countries (HICs). We found no sufficiently robust evaluations conducted in low- and middle-income countries (LMICs). Study quality overall was low and measurements used by studies variable. Participants were classified as drop-in and shelter-based. No studies measured the primary outcome of reintegration and none reported on adverse effects.We found no consistent results on a range of relevant outcomes within domains of psychosocial health, substance misuse and sexually risky behaviours . Interventions evaluated consisted of time limited therapeutically based programmes that proved no more effective than standard shelter or drop-in services and other control interventions used for most outcomes in most studies. Favourable changes from baseline were reported for outcomes for most participants following therapy interventions and standard services. We noted considerable heterogeneity between studies and inconsistent reporting of equity data. No studies measured the primary outcome of reintegration or reported on adverse effects. AUTHORS' CONCLUSIONS: Analysis revealed no consistently significant benefit for focused therapeutic interventions compared with standard services such as drop-in centres, case management and other comparable interventions for street-connected children and young people. Commonly available services, however, were not rigorously evaluated. Robust evaluation of interventions, including comparison with no intervention, would establish a more reliable evidence base to inform service implementation. More robust research is needed in LMICs to examine interventions for street-connected children and young people with different backgrounds and service needs. PMID- 26760048 TI - LC-MS-Based Metabolomics Discovers Purine Endogenous Associations with Low-Dose Salbutamol in Urine Collected for Antidoping Tests. AB - Current antidoping analytical methods are tailored mainly to the targeting of known drugs and endogenous molecules. This causes difficulties in rapidly reacting to emerging threats, such as designer drugs, biological therapeutic agents, and technologies. Biomarkers are considered as a promising approach for the fight against these threats to sport. The main purpose of this study was to find surrogate biomarkers induced by the intake of small amounts of the model compound salbutamol and explore a sensitive approach to help screen for possible drug misuse. Urine samples (91) from athletes with detectable salbutamol (30) and negative samples (61) were analyzed using a UHPLC-MS. A third group (30) was created by spiking salbutamol into negative samples to eliminate confounding effects. Data were then analyzed in XCMS to extract metabolic features. Orthogonal partial least squares-discriminant analysis was performed to select features correlated with detectable salbutamol (p(corr) > 0.5) and ROC analysis was performed to measure the predictive potential of the markers. Univariate analysis including Mann-Whitney U test and Spearman's correlation was conducted on selected markers. A total of 7000 metabolic features were parsed, one feature identified as hypoxanthine increased with salbutamol (p < 0.001). The ROC curve of hypoxanthine returned an AUC of 0.79 (p < 0.001). Correlation with salbutamol (r = 0.415, p < 0.01, Spearman's correlation) showed hypoxanthine and purine metabolism have association with salbutamol administration. This surrogate discovery approach needs further PK studies but in the meantime can be used as an intelligence-based complementary approach for targeting of athletes to be further tested. PMID- 26760049 TI - Photoassisted Diversity-Oriented Synthesis: Intramolecular Cycloadditions of Photogenerated Azaxylylenes with Oxazole Pendants, and Subsequent Postphotochemical Multicomponent Modifications. AB - Photogenerated aza-o-xylylenes undergo intramolecular cycloaddition reactions to tethered oxazoles, with primary photoproducts featuring a reactive cyclic imine moiety suitable for multicomponent postphotochemical transformations. For example, the reaction of these imine photoproducts with bromoacetyl bromide leads to a key 1,4-dielectrophilic synthon, offering access to diverse polyheterocyclic molecular architectures. This reaction sequence is accompanied by rapid growth complexity in a very few simple synthetic steps, and is in keeping with the philosophy of diversity-oriented synthesis (DOS). PMID- 26760050 TI - Probing Scattering Resonances in (Ultra)Cold Inelastic NO-He Collisions. AB - We theoretically study inelastic collisions between NO radicals and He atoms at low collision energies, focusing on the occurrence of scattering resonances. We specifically investigate de-excitation of rotationally excited NO radicals (X (2)Pi1/2, v = 0, j = 3/2, f) at collision energies ranging from 10(-3) to 20 cm( 1) and compute integral and differential cross sections using quantum mechanical close-coupling calculations. Although unconventional, we show that the measurement of rotational de-excitation cross sections brings several advantages to experiments that aim to study rotational energy transfer at temperatures approaching zero kelvin. We analyze the nature and partial wave composition of the quasi-bound states associated with each individual resonance and compute the scattering wave functions. The differential cross sections contain the partial wave fingerprints of the scattering process and are found to change drastically as the collision energy is varied over the resonances. The prospects for measuring these differential cross sections in inelastic de-excitation collisions at low energies are discussed. PMID- 26760045 TI - Preclinical studies of a Pro-antibody-drug conjugate designed to selectively target EGFR-overexpressing tumors with improved therapeutic efficacy. AB - Antibody-drug conjugates (ADCs) have exhibited potent clinical benefits in cancer therapy. However, development of ADCs against epidermal growth factor receptor (EGFR) has limitations because of wide expression of EGFR in both normal and tumor tissues. Previously, we developed an anti-EGFR protease-activated antibody (pro-antibody), termed as PanP, which remains inert against EGFR until activated by tumor-specific protease. Herein, we for the first time report a new class of pro-antibody-drug conjugate (PDC) against EGFR, denoted as PanP-DM1. It has been designed to selectively target the EGFR-overexpressing tumor cells and exert greater anti-tumor activity compared with PanP. Our data showed that PanP-DM1 also could be selectively activated by tumor-specific protease 'uPA'. Furthermore, activated PanP-DM1 was potently cytotoxic against EGFR overexpressing tumor cell lines in vitro. Crucially, our data indicated that PanP DM1 was significantly more effective in eradicating EGFR-overexpressing tumors in vivo. Additionally, toxicity was preliminarily evaluated in mice as measured by body weight loss. In summary, our study suggests that PanP-DM1, a novel pro antibody-drug conjugate, has cancer-selectivity, efficacy and safety profile that supports its potential use for EGFR-overexpressing tumors. PMID- 26760051 TI - Mechanics of an Asymmetric Hard-Soft Lamellar Nanomaterial. AB - Nanolayered lamellae are common structures in nanoscience and nanotechnology, but most are nearly symmetric in layer thickness. Here, we report on the structure and mechanics of highly asymmetric and thermodynamically stable soft-hard lamellar structures self-assembled from optimally designed PS1-(PI-b-PS2)3 miktoarm star block copolymers. The remarkable mechanical properties of these strong and ductile PS (polystyrene)-based nanomaterials can be tuned over a broad range by varying the hard layer thickness while maintaining the soft layer thickness constant at 13 nm. Upon deformation, thin PS lamellae (<100 nm) exhibited kinks and predamaged/damaged grains, as well as cavitation in the soft layers. In contrast, deformation of thick lamellae (>100 nm) manifests cavitation in both soft and hard nanolayers. In situ tensile-SAXS experiments revealed the evolution of cavities during deformation and confirmed that the damage in such systems reflects both plastic deformation by shear and residual cavities. The aspects of the mechanics should point to universal deformation behavior in broader classes of asymmetric hard-soft lamellar materials, whose properties are just being revealed for versatile applications. PMID- 26760044 TI - Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. AB - OBJECTIVE: This clinical practice guideline addresses the diagnosis and treatment of primary adrenal insufficiency. PARTICIPANTS: The Task Force included a chair, selected by The Clinical Guidelines Subcommittee of the Endocrine Society, eight additional clinicians experienced with the disease, a methodologist, and a medical writer. The co-sponsoring associations (European Society of Endocrinology and the American Association for Clinical Chemistry) had participating members. The Task Force received no corporate funding or remuneration in connection with this review. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to determine the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: The evidence used to formulate recommendations was derived from two commissioned systematic reviews as well as other published systematic reviews and studies identified by the Task Force. The guideline was reviewed and approved sequentially by the Endocrine Society's Clinical Guidelines Subcommittee and Clinical Affairs Core Committee, members responding to a web posting, and the Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. CONCLUSIONS: We recommend diagnostic tests for the exclusion of primary adrenal insufficiency in all patients with indicative clinical symptoms or signs. In particular, we suggest a low diagnostic (and therapeutic) threshold in acutely ill patients, as well as in patients with predisposing factors. This is also recommended for pregnant women with unexplained persistent nausea, fatigue, and hypotension. We recommend a short corticotropin test (250 MUg) as the "gold standard" diagnostic tool to establish the diagnosis. If a short corticotropin test is not possible in the first instance, we recommend an initial screening procedure comprising the measurement of morning plasma ACTH and cortisol levels. Diagnosis of the underlying cause should include a validated assay of autoantibodies against 21-hydroxylase. In autoantibody-negative individuals, other causes should be sought. We recommend once-daily fludrocortisone (median, 0.1 mg) and hydrocortisone (15-25 mg/d) or cortisone acetate replacement (20-35 mg/d) applied in two to three daily doses in adults. In children, hydrocortisone (~8 mg/m(2)/d) is recommended. Patients should be educated about stress dosing and equipped with a steroid card and glucocorticoid preparation for parenteral emergency administration. Follow-up should aim at monitoring appropriate dosing of corticosteroids and associated autoimmune diseases, particularly autoimmune thyroid disease. PMID- 26760052 TI - Chemical Aspects of Astrophysically Observed Extraterrestrial Methanol, Hydrocarbon Derivatives, and Ions. AB - Astrophysically observed extraterrestrial molecular matter contains, besides hydrogen and water, methane and methanol as the most abundant species. Feasible pathways and chemical aspects of their formation as well as of derived hydrocarbon homologues and their ions (carbocations and carbanions) are discussed on the basis of observed similarities with our studied terrestrial chemistry. The preferred pathway for converting extraterrestrial methane according to Ali et al. is based on CH5(+) and Olah's related nonclassical carbonium ion chemistry. On the basis of the observed higher reactivity of methanol compared with methane in various chemical reactions, a feasible new pathway is proposed for the conversion of extraterrestrial methanol to hydrocarbons, their derivatives, and carbocations together with a possible connection with methonium ion-based chemistry. PMID- 26760053 TI - Silver-Catalyzed Decarboxylative Addition/Cyclization of Activated Alkenes with Aliphatic Carboxylic Acids. AB - A silver-catalyzed decarboxylative addition/aryl migration/desulfonylation of N phenyl-N-(phenylsulfonyl)methacrylamide with primary, secondary, and tertiary carboxylic acids was described. The protocol provides an efficient approach for the synthesis of alpha-all-carbon quaternary stereocenters amides and isoquinolinediones. It was proposed that the radical generated from the silver catalyzed decarboxylation was involved in the sequence reaction. PMID- 26760054 TI - Hierarchical Porous Zeolite Structures for Pressure Swing Adsorption Applications. AB - Porous adsorbents with hierarchical structured macropores ranging from 1 to 100 MUm are prepared using a combination of freeze casting and additional sacrificial templating of polyurethane foams, with a zeolite 13X powder serving as adsorbent. The pore system of the prepared monoliths features micropores assigned to the zeolite 13X particle framework, interparticular pores of ~1-2 MUm, lamellar pores derived from freeze casting of ~10 MUm, and an interconnected pore network obtained from the sacrificial templates ranging from around 100 to 200 MUm with a total porosity of 71%. Gas permeation measurements show an increase in intrinsic permeability by a factor of 14 for monoliths prepared with an additional sacrificial templated foam compared to monoliths solely providing freeze casting pores. Cyclic CO2 adsorption and desorption tests where pressure swings between 8 and 140 kPa reveal constant working capacities over multiple cycles. Furthermore, the monoliths feature a high volumetric working capacity of ~1.34 mmol/cm(3) which is competitive to packed beds made of commercially available zeolite 13X beads (~1.28 mmol/cm(3)). Combined with the faster CO2 uptake showing an adsorption of 50% within 5-8 s (beads ~10 s), the monoliths show great potential for pressure swing adsorption applications, where high volumetric working capacities, fast uptakes, and low pressure drops are needed for a high system performance. PMID- 26760055 TI - Investigating the Energy-Water Usage Efficiency of the Reuse of Treated Municipal Wastewater for Artificial Groundwater Recharge. AB - This project investigates the energy-water usage efficiency of large scale civil infrastructure projects involving the artificial recharge of subsurface groundwater aquifers via the reuse of treated municipal wastewater. A modeling framework is introduced which explores the various ways in which spatially heterogeneous variables such as topography, landuse, and subsurface infiltration capacity combine to determine the physical layout of proposed reuse system components and their associated process energy-water demands. This framework is applied to the planning and evaluation of the energy-water usage efficiency of hypothetical reuse systems in five case study regions within the State of California. Findings from these case study analyses suggest that, in certain geographic contexts, the water requirements attributable to the process energy consumption of a reuse system can exceed the volume of water that it is able to recover by as much as an order of magnitude. PMID- 26760056 TI - Structure-Based Consensus Scoring Scheme for Selecting Class A Aminergic GPCR Fragments. AB - Aminergic G-protein coupled receptors (GPRCs) represent well-known targets of central nervous-system related diseases. In this study a structure-based consensus virtual screening scheme was developed for designing targeted fragment libraries against class A aminergic GPCRs. Nine representative aminergic GPCR structures were selected by first clustering available X-ray structures and then choosing the one in each cluster that performs best in self-docking calculations. A consensus scoring protocol was developed using known promiscuous aminergic ligands and decoys as a training set. The consensus score (FrACS-fragment aminergic consensus score) calculated for the optimized protein ensemble showed improved enrichments in most cases as compared to stand-alone structures. Retrospective validation was carried out on public screening data for aminergic targets (5-HT1 serotonin receptor, TA1 trace-amine receptor) showing 8-17-fold enrichments using an ensemble of aminergic receptor structures. The performance of the structure based FrACS in combination with our ligand-based prefilter (FrAGS) was investigated both in a retrospective validation on the ChEMBL database and in a prospective validation on an in-house fragment library. In prospective validation virtual fragment hits were tested on 5-HT6 serotonin receptors not involved in the development of FrACS. Six out of the 36 experimentally tested fragments exhibited remarkable antagonist efficacies, and 4 showed IC50 values in the low micromolar or submicromolar range in a cell-based assay. Both retrospective and prospective validations revealed that the methodology is suitable for designing focused class A GPCR fragment libraries from large screening decks, commercial compound collections, or virtual databases. PMID- 26760057 TI - The Boston Children's Hospital Academy: Development and Initial Assessment of a Hospital-Based Teaching Academy. AB - PROBLEM: Medical education academies play an important role in the recognition and career advancement of educators. However, hospital-based clinical faculty have unique professional development needs that may not be met by medical-school based academies. APPROACH: The Boston Children's Hospital Academy was founded in 2008 to serve the needs of its clinician-educators. It was open to junior faculty scholars and to senior faculty scholars and mentors, including interprofessional educators. To maintain membership, individuals must propose and work toward an education project or serve as a project mentor. In 2012, a survey was sent to all members, and annual project reports were reviewed to assess the academy's impact. OUTCOMES: Sixty-five members completed the survey. The majority agreed that the academy created a community of educators, provided opportunities for networking and scholarship, contributed to their personal identity as an educator, and led to recognition by their chief. Projects addressed curriculum development, faculty development, learner assessment, program assessment, and resource development. They largely focused on graduate medical education and on patient safety and quality. During their tenure in the academy (mean length of membership = 2.4 years), members produced an average of 4.4 education presentations and 1.9 education publications, and 11 members were promoted. NEXT STEPS: A hospital based academy provides opportunities for interprofessional faculty development. Next steps include increasing interprofessional membership, wider dissemination of members' successes, better integration with the hospital's mission, specifically regarding graduate medical education and patient safety, and additional evaluation of the academy's impact on project completion and members' accomplishments. PMID- 26760058 TI - Exemplary Care and Learning Sites: A Model for Achieving Continual Improvement in Care and Learning in the Clinical Setting. AB - PROBLEM: Current models of health care quality improvement do not explicitly describe the role of health professions education. The authors propose the Exemplary Care and Learning Site (ECLS) model as an approach to achieving continual improvement in care and learning in the clinical setting. APPROACH: From 2008-2012, an iterative, interactive process was used to develop the ECLS model and its core elements--patients and families informing process changes; trainees engaging both in care and the improvement of care; leaders knowing, valuing, and practicing improvement; data transforming into useful information; and health professionals competently engaging both in care improvement and teaching about care improvement. In 2012-2013, a three-part feasibility test of the model, including a site self-assessment, an independent review of each site's ratings, and implementation case stories, was conducted at six clinical teaching sites (in the United States and Sweden). OUTCOMES: Site leaders reported the ECLS model provided a systematic approach toward improving patient (and population) outcomes, system performance, and professional development. Most sites found it challenging to incorporate the patients and families element. The trainee element was strong at four sites. The leadership and data elements were self-assessed as the most fully developed. The health professionals element exhibited the greatest variability across sites. NEXT STEPS: The next test of the model should be prospective, linked to clinical and educational outcomes, to evaluate whether it helps care delivery teams, educators, and patients and families take action to achieve better patient (and population) outcomes, system performance, and professional development. PMID- 26760059 TI - Is Reflective Ability Associated With Professionalism Lapses During Medical School? AB - PURPOSE: Recently, many have argued that learning to reflect on one's experiences is a critical component of professional identity formation and of professionalism. However, little empirical evidence exists to support this claim. This study explored the association between reflective ability and professionalism lapses among medical students. METHOD: The authors conducted a retrospective case-control study of all students who matriculated at Indiana University School of Medicine from 2001 to 2009. The case group (n = 70) included those students who had been cited for a professionalism lapse during medical school; the students in the control group (n = 230) were randomly selected from the students who had not been cited for a professionalism lapse. Students' professionalism journal entries were scored using a validated rubric to assess reflective ability. Mean reflection scores were compared across groups using t tests, and logistic regression analysis was used to assess the relationship between reflective ability and professionalism lapses. RESULTS: Reflection scores for students in the case group (2.46 +/- 1.05) were significantly lower than those for students in the control group (2.82 +/- 0.83) (P = .01). A lower reflection score was associated with an increased likelihood that the student had been cited for a professionalism lapse (odds ratio = 1.56; P < .01). CONCLUSIONS: This study revealed a significant relationship between reflective ability and professionalism, although further study is needed to draw any conclusions regarding causation. These findings provide quantitative evidence to support current anecdotal claims about the relationship between reflection and professionalism. PMID- 26760060 TI - Race-Conscious Professionalism and African American Representation in Academic Medicine. AB - African Americans remain substantially less likely than other physicians to hold academic appointments. The roots of these disparities stem from different extrinsic and intrinsic forces that guide career development. Efforts to ameliorate African American underrepresentation in academic medicine have traditionally focused on modifying structural and extrinsic barriers through undergraduate and graduate outreach, diversity and inclusion initiatives at medical schools, and faculty development programs. Although essential, these initiatives fail to confront the unique intrinsic forces that shape career development. America's ignoble history of violence, racism, and exclusion exposes African American physicians to distinct personal pressures and motivations that shape professional development and career goals. This article explores these intrinsic pressures with a focus on their historical roots; reviews evidence of their effect on physician development; and considers the implications of these trends for improving African American representation in academic medicine. The paradigm of "race-conscious professionalism" is used to understand the dual obligation encountered by many minority physicians not only to pursue excellence in their field but also to leverage their professional stature to improve the well-being of their communities. Intrinsic motivations introduced by race conscious professionalism complicate efforts to increase the representation of minorities in academic medicine. For many African American physicians, a desire to have their work focused on the community will be at odds with traditional paths to professional advancement. Specific policy options are discussed that would leverage race-conscious professionalism as a draw to a career in academic medicine, rather than a force that diverts commitment elsewhere. PMID- 26760061 TI - Cipacinoids A-D, Four Limonoids with Spirocyclic Skeletons from Cipadessa cinerascens. AB - Four limonoids, cipacinoids A-D (1-4), with spirocyclic skeletons were isolated from Cipadessa cinerascens. It is particularly notable that compounds 1-3 had a 17S-configuration for the first time in the limonoid family. Their structures with absolute configurations were assigned by spectroscopic data, X-ray crystallography, and CD analysis. Compound 1 showed moderate protein tyrosine phosphatase 1B (PTP1B) inhibition. PMID- 26760077 TI - How do children learn to cross the street? The process of pedestrian safety training. AB - OBJECTIVE: Pedestrian injuries are a leading cause of child death and may be reduced by training children to cross streets more safely. Such training is most effective when children receive repeated practice at the complex cognitive perceptual task of judging moving traffic and selecting safe crossing gaps, but there is limited data on how much practice is required for children to reach adult levels of functioning. Using existing data, we examined how children's pedestrian skills changed over the course of 6 pedestrian safety training sessions, each composed of 45 crossings within a virtual pedestrian environment. METHODS: As part of a randomized controlled trial on pedestrian safety training, 59 children ages 7-8 crossed the street within a semi-immersive virtual pedestrian environment 270 times over a 3-week period (6 sessions of 45 crossings each). Feedback was provided after each crossing, and traffic speed and density were advanced as children's skill improved. Postintervention pedestrian behavior was assessed a week later in the virtual environment and compared to adult behavior with identical traffic patterns. RESULTS: Over the course of training, children entered traffic gaps more quickly and chose tighter gaps to cross within; their crossing efficiency appeared to increase. By the end of training, some aspects of children's pedestrian behavior was comparable to adult behavior but other aspects were not, indicating that the training was worthwhile but insufficient for most children to achieve adult levels of functioning. CONCLUSIONS: Repeated practice in a simulated pedestrian environment helps children learn aspects of safe and efficient pedestrian behavior. Six twice weekly training sessions of 45 crossings each were insufficient for children to reach adult pedestrian functioning, however, and future research should continue to study the trajectory and quantity of child pedestrian safety training needed for children to become competent pedestrians. PMID- 26760079 TI - Frequency of Participation in an Employee Fitness Program and Health Care Expenditures. AB - Regular physical activity is strongly linked to prevention of costly chronic health conditions. However, there has been limited examination of the impact that level of participation in physical activity promotion programs has on health care costs. This study examined a fitness reimbursement program (FRP) offered to small employers. FRP participants received $20 reimbursement every month they visited their fitness center >=12 days. Visits were recorded electronically. Participants were assigned to 4 mutually exclusive cohorts by mean monthly fitness center visits: low (<4 visits); low-moderate (>=4 and <8 visits), high-moderate (>=8 and <12 visits), and high (>=12 visits, which qualified for reimbursement). Cohorts were matched by inverse propensity score weighting on demographic, health status, health care supply, and socioeconomic characteristics. Between-cohort differences in propensity score-weighted health care costs, starting from FRP program sign up, were examined with a generalized linear model. Analyses were conducted with and without high-cost outliers during the pre- and post-FRP period. A total of 8723 participants (mean follow-up: 11.1 months) were identified during October 2010-June 2013. With high-cost outliers removed (n = 226), a pattern of lower per member-per-month health care costs was observed with increasing participation: compared with the low cohort, monthly savings were: $6.14 (2.6%) for low-moderate (P = 0.60), $16.40 (6.9%) for moderate-high (P = 0.16), and $20.01 (8.4%) for high (P = 0.08). With high-cost outliers included, significant monthly cost savings were observed for the moderate-high ($43.52, P < 0.01) and high ($52.66, P < 0.001) cohorts. These results indicate directionally positive cost outcomes associated with increasing level of fitness center participation. PMID- 26760078 TI - The prevalence and severity of injuries in field hockey drag flickers: a retrospective cross-sectional study. AB - The drag flick is the preferred method of scoring during a penalty corner in field hockey. Performing the drag flick requires a combination of strength, coordination and timing, which may increase susceptibility to injuries. However, injury prevalence in drag flickers has not previously been investigated. Therefore, this study compared the injury prevalence and severity of lower limb and lower back injuries between drag flickers and non-drag flickers in field hockey. A total of 432 local, national and international adult field hockey players (242 males, 188 females) completed an online questionnaire to retrospectively determine the 3-month prevalence and severity of ankle, knee, hip and lower back injuries. Of this group, 140 self-identified as drag flickers and 292 as non-drag flickers. The results showed that drag flickers had significantly higher prevalence of hip (OR: 1.541; 95% CI: 1.014, 2.343) and lower back injury (OR: 1.564; 95% CI: 1.034, 2.365) compared to non-drag flickers. No significant differences were observed between drag flickers and non-drag flickers in injury prevalence at the ankle and knee. There were no significant between-group differences in injury severity scores. Overall, the prevalence of hip and lower back injuries was significantly higher in drag flickers compared to non-drag flickers. PMID- 26760062 TI - Progress and prospects for blood-stage malaria vaccines. AB - There have been significant decreases in malaria mortality and morbidity in the last 10-15 years, and the most advanced pre-erythrocytic malaria vaccine, RTS,S, received a positive opinion from European regulators in July 2015. However, no blood-stage vaccine has reached a phase III trial. The first part of this review summarizes the pros and cons of various assays and models that have been and will be used to predict the efficacy of blood-stage vaccines. In the second part, blood-stage vaccine candidates that showed some efficacy in human clinical trials or controlled human malaria infection models are discussed. Then, candidates under clinical investigation are described in the third part, and other novel candidates and strategies are reviewed in the last part. PMID- 26760081 TI - Shared Decision Making--Finding the Sweet Spot. PMID- 26760080 TI - Cloning, expression, and characterization of catechol 1,2-dioxygenase from a phenol-degrading Candida tropicalis JH8 strain. AB - The sequence cato encoding catechol 1,2-dioxygenase from Candida tropicalis JH8 was cloned, sequenced, and expressed in Escherichia coli. The sequence cato contained an ORF of 858 bp encoding a polypeptide of 285 amino acid residues. The recombinant catechol 1,2-dioxygenase exists as a homodimer structure with a subunit molecular mass of 32 KD. Recombinant catechol 1,2-dioxygenase was unstable below pH 5.0 and stable from pH 7.0 to 9.0; its optimum pH was at 7.5. The optimum temperature for the enzyme was 30 degrees C, and it possessed a thermophilic activity within a broad temperature range. Under the optimal conditions with catechol as substrate, the Km and Vmax of recombinant catechol 1,2-dioxygenase were 9.2 uM and 0.987 uM/min, respectively. This is the first article presenting cloning and expressing in E. coli of catechol 1,2-dioxygenase from C. tropicalis and characterization of the recombinant catechol 1,2 dioxygenase. PMID- 26760082 TI - Medical Taylorism. PMID- 26760083 TI - Mr. Gilbreth's Motion Pictures--The Evolution of Medical Efficiency. PMID- 26760085 TI - A Randomized Trial of Low-Cost Mesh in Groin Hernia Repair. AB - BACKGROUND: The most effective method for repair of a groin hernia involves the use of a synthetic mesh, but this type of mesh is unaffordable for many patients in low- and middle-income countries. Sterilized mosquito meshes have been used as a lower-cost alternative but have not been rigorously studied. METHODS: We performed a double-blind, randomized, controlled trial comparing low-cost mesh with commercial mesh (both lightweight) for the repair of a groin hernia in adult men in eastern Uganda who had primary, unilateral, reducible groin hernias. Surgery was performed by four qualified surgeons. The primary outcomes were hernia recurrence at 1 year and postoperative complications. RESULTS: A total of 302 patients were included in the study. The follow-up rate was 97.3% after 2 weeks and 95.6% after 1 year. Hernia recurred in 1 patient (0.7%) assigned to the low-cost mesh and in no patients assigned to the commercial mesh (absolute risk difference, 0.7 percentage points; 95% confidence interval [CI], -1.2 to 2.6; P=1.0). Postoperative complications occurred in 44 patients (30.8%) assigned to the low-cost mesh and in 44 patients (29.7%) assigned to the commercial mesh (absolute risk difference, 1.0 percentage point; 95% CI, -9.5 to 11.6; P=1.0). CONCLUSIONS: Rates of hernia recurrence and postoperative complications did not differ significantly between men undergoing hernia repair with low-cost mesh and those undergoing hernia repair with commercial mesh. (Funded by the Swedish Research Council and others; Current Controlled Trials number, ISRCTN20596933.). PMID- 26760084 TI - Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis. AB - BACKGROUND: Tuberculous meningitis is often lethal. Early antituberculosis treatment and adjunctive treatment with glucocorticoids improve survival, but nearly one third of patients with the condition still die. We hypothesized that intensified antituberculosis treatment would enhance the killing of intracerebral Mycobacterium tuberculosis organisms and decrease the rate of death among patients. METHODS: We performed a randomized, double-blind, placebo-controlled trial involving human immunodeficiency virus (HIV)-infected adults and HIV uninfected adults with a clinical diagnosis of tuberculous meningitis who were admitted to one of two Vietnamese hospitals. We compared a standard, 9-month antituberculosis regimen (which included 10 mg of rifampin per kilogram of body weight per day) with an intensified regimen that included higher-dose rifampin (15 mg per kilogram per day) and levofloxacin (20 mg per kilogram per day) for the first 8 weeks of treatment. The primary outcome was death by 9 months after randomization. RESULTS: A total of 817 patients (349 of whom were HIV-infected) were enrolled; 409 were randomly assigned to receive the standard regimen, and 408 were assigned to receive intensified treatment. During the 9 months of follow up, 113 patients in the intensified-treatment group and 114 patients in the standard-treatment group died (hazard ratio, 0.94; 95% confidence interval, 0.73 to 1.22; P=0.66). There was no evidence of a significant differential effect of intensified treatment in the overall population or in any of the subgroups, with the possible exception of patients infected with isoniazid-resistant M. tuberculosis. There were also no significant differences in secondary outcomes between the treatment groups. The overall number of adverse events leading to treatment interruption did not differ significantly between the treatment groups (64 events in the standard-treatment group and 95 events in the intensified treatment group, P=0.08). CONCLUSIONS: Intensified antituberculosis treatment was not associated with a higher rate of survival among patients with tuberculous meningitis than standard treatment. (Funded by the Wellcome Trust and the Li Ka Shing Foundation; Current Controlled Trials number, ISRCTN61649292.). PMID- 26760086 TI - Relationship between Nonmedical Prescription-Opioid Use and Heroin Use. PMID- 26760087 TI - IMAGES IN CLINICAL MEDICINE. Squamous-Cell Carcinoma of the Penis with Human Papillomavirus. PMID- 26760088 TI - CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 1-2016. An 18-Year-Old Man with Fever, Abdominal Pain, and Thrombocytopenia. PMID- 26760089 TI - The Obesity Epidemic--Understanding the Disease and the Treatment. PMID- 26760090 TI - Chemotherapy for Tuberculous Meningitis. PMID- 26760091 TI - Future of Long-Term Care and the Expanding Role of Medicaid Managed Care. PMID- 26760092 TI - Benznidazole for Chronic Chagas' Cardiomyopathy. PMID- 26760093 TI - Benznidazole for Chronic Chagas' Cardiomyopathy. PMID- 26760094 TI - Benznidazole for Chronic Chagas' Cardiomyopathy. PMID- 26760096 TI - FTO Obesity Variant and Adipocyte Browning in Humans. PMID- 26760095 TI - Benznidazole for Chronic Chagas' Cardiomyopathy. PMID- 26760097 TI - FTO Obesity Variant and Adipocyte Browning in Humans. PMID- 26760098 TI - FTO Obesity Variant and Adipocyte Browning in Humans. PMID- 26760099 TI - FTO Obesity Variant and Adipocyte Browning in Humans. PMID- 26760100 TI - Chimeric Antigen Receptor T Cells in Myeloma. PMID- 26760101 TI - Chimeric Antigen Receptor T Cells in Myeloma. PMID- 26760102 TI - Dependent Coverage under the ACA and Medicaid Coverage for Childbirth. PMID- 26760103 TI - State Medicaid Expansion and Changes in Hospital Volume According to Payer. PMID- 26760104 TI - IMAGES IN CLINICAL MEDICINE. Lancisi's Sign. PMID- 26760105 TI - Maximum Likelihood Analysis of Nonlinear Structural Equation Models With Dichotomous Variables. AB - In this article, a maximum likelihood approach is developed to analyze structural equation models with dichotomous variables that are common in behavioral, psychological and social research. To assess nonlinear causal effects among the latent variables, the structural equation in the model is defined by a nonlinear function. The basic idea of the development is to augment the observed dichotomous data with the hypothetical missing data that involve the latent underlying continuous measurements and the latent variables in the model. An EM algorithm is implemented. The conditional expectation in the E-step is approximated via observations simulated from the appropriate conditional distributions by a Metropolis-Hastings algorithm within the Gibbs sampler, whilst the M-step is completed by conditional maximization. Convergence is monitored by bridge sampling. Standard errors are also obtained. Results from a simulation study and a real example are presented to illustrate the methodology. PMID- 26760106 TI - Comparison of Two Procedures for Analyzing Small Sets of Repeated Measures Data. AB - This article compares two methods for analyzing small sets of repeated measures data under normal and non-normal heteroscedastic conditions: a mixed model approach with the Kenward-Roger correction and a multivariate extension of the modified Brown-Forsythe (BF) test. These procedures differ in their assumptions about the covariance structure of the data and in the method of estimation of the parameters defining the mean structure. Simulation results show that the BF test outperformed its competitor, in terms of Type I errors, particularly when the total sample size was small, and the data were normally distributed. Under non normal distributions the BF test tended to err on the side of conservatism. Results also indicate that neither method was uniformly more powerful. With very few exceptions, the power differences between these two methods depended on the population covariance structure, the nature of the pairing of covariance matrices and group sizes, and the relationship between mean vectors and dispersion matrices. PMID- 26760107 TI - Statistical Modeling of the Individual: Rationale and Application of Multivariate Stationary Time Series Analysis. AB - Results obtained with interindividual techniques in a representative sample of a population are not necessarily generalizable to the individual members of this population. In this article the specific condition is presented that must be satisfied to generalize from the interindividual level to the intraindividual level. A way to investigate whether this condition is satisfied is by means of multivariate time series analysis. More generally, time series analysis can be used to investigate psychological processes situated within individuals. In this article we consider a well established class of multivariate stationary time series models that may be used to study the intraindividual covariance structure. We demonstrate the application of some of these models with an empirical example consisting of state measurements of behavior associated with the Five Factor Model of Personality. We illustrate how one can investigate whether individuals are similar with respect to their intraindividual structure of variation, and whether this structure is similar to the structure of interindividual variation. PMID- 26760108 TI - Using Parcels to Convert Path Analysis Models Into Latent Variable Models. AB - The biasing effects of measurement error in path analysis models can be overcome by the use of latent variable models. In cases where path analysis is used in practice, it is often possible to use parcels as indicators of a latent variable. The purpose of the current study was to compare latent variable models in which parcels were used as indicators of the latent variables, path analysis models of the aggregated variables, and models in which reliability estimates were used to correct for measurement error in path analysis models. Results showed that point estimates of path coefficients were smallest for the path analysis models and largest for the latent variable models. It is concluded that, whenever possible, it is better to use a latent variable model in which parcels are used as indicators than a path analysis model using total scale scores. PMID- 26760109 TI - Further Empirical Results on Parametric Versus Non-Parametric IRT Modeling of Likert-Type Personality Data. AB - Chernyshenko, Stark, Chan, Drasgow, and Williams (2001) investigated the fit of Samejima's logistic graded model and Levine's non-parametric MFS model to the scales of two personality questionnaires and found that the graded model did not fit well. We attribute the poor fit of the graded model to small amounts of multidimensionality present in their data. To verify this conjecture, we compare the fit of these models to the Social Problem Solving Inventory-Revised, whose scales were designed to be unidimensional. A calibration and a cross-validation sample of new observations were used. We also included the following parametric models in the comparison: Bock's nominal model, Masters' partial credit model, and Thissen and Steinberg's extension of the latter. All models were estimated using full information maximum likelihood. We also included in the comparison a normal ogive model version of Samejima's model estimated using limited information estimation. We found that for all scales Samejima's model outperformed all other parametric IRT models in both samples, regardless of the estimation method employed. The non-parametric model outperformed all parametric models in the calibration sample. However, the graded model outperformed MFS in the cross-validation sample in some of the scales. We advocate employing the graded model estimated using limited information methods in modeling Likert-type data, as these methods are more versatile than full information methods to capture the multidimensionality that is generally present in personality data. PMID- 26760110 TI - Stereotactic mesencephalotomy for palliative care pain control: A case report, literature review and plea to rediscover this operation. AB - Introduction Stereotactic mesencephalotomy is an ablative procedure which lesions the pain pathways (spinothalamic and trigeminothalamic tracts) at the midbrain level to treat medically refractory, nociceptive, contralateral pain. Sparsely reported in contemporary English language literature, this operation is at risk of being lost from the modern-day neurosurgical practice. Methods We present a case report and brief review of the literature on stereotactic mesencephalotomy. A 17-year-old girl with cervical cord glioblastoma and medically refractory unilateral head and neck pain was treated with contralateral stereotactic mesencephalotomy. The lesion was placed at the level of the inferior colliculus, half way between the lateral edge of the aqueduct and lateral border of the midbrain. Results The patient had no head and neck pain immediately after the procedure and remained pain-free for the remainder of her life (five months). She was weaned off her pre-operative narcotics and was able to leave hospital, meeting her palliative care goals. Conclusions Cancer-related unilateral head and neck nociceptive pain in the palliative care setting can be successfully treated with stereotactic mesencephalotomy. We believe that stereotactic mesencephalotomy is the treatment of choice for a small number of patients typified by our case. The authors make a plea to the palliative care and neurosurgical communities to rediscover this operation. PMID- 26760112 TI - Are neurosurgeons prepared to electively resample glioblastoma in patients without symptomatic relapse? A qualitative study. AB - Background This is a qualitative study designed to examine neurosurgeons' and neuro-oncologists' perceptions of resampling surgery for glioblastoma multiforme electively, post-therapy or at asymptomatic relapse. Methods Twenty-six neurosurgeons, three radiation oncologists and one neuro-oncologist were selected using convenience sampling and interviewed. Participants were presented with hypothetical scenarios in which resampling surgery was offered within a clinical trial and another in which the surgery was offered on a routine basis. Results Over half of the participants were interested in doing this within a clinical trial. About a quarter of the participants would be willing to consider routine resampling surgery if: (1) a resection were done rather than a simple biopsy; (2) they could wait until the patient becomes symptomatic and (3) there was a preliminary in vitro study with existing tumour samples to be able to offer patients some trial drugs. The remaining quarter of participants was entirely against the trial. Participants also expressed concerns about resource allocation, financial barriers, possibilities of patient coercion and the fear of patients' inability to offer true informed consent. Conclusion Overall, if surgeons are convinced of the benefits of the trial from their information from scientists, and they feel that patients are providing truly informed consent, then the majority would be willing to consider performing the surgery. Many surgeons would still feel uncomfortable with the procedure unless they are able to offer the patient some benefit from the procedure such that the risk to benefit ratio is balanced. PMID- 26760111 TI - Timothy grass pollen therapeutic vaccine: optimal dose for subcutaneous immunotherapy. AB - AIMS: To establish the optimal dose of Phleum pratense subcutaneous immunotherapy (SCIT) in patients with allergic rhinoconjunctivitis with/without asthma. MATERIALS & METHODS: One hundred and fifty-one patients were randomized to receive SCIT 0.25, 0.5, 1.0, 2.0 or 4.0 skin-prick test units (SPT) or placebo. The primary end point was the variation in the concentration of Phleum pratense extract needed to produce a positive nasal provocation test from baseline (V0) to final visit (FV). RESULTS: After 17 weeks, a dose-dependent trend was apparent in the concentration of P. pratense extract needed to produce a positive nasal provocation response. Systemic adverse reactions occurred with 3.2% of administered doses. Grade III (n = 2) and IV (n = 2) events were observed only at the two highest doses. CONCLUSION: P. pratense depot SCIT showed signs of clinical and immunological efficacy by dose-dependently decreasing the allergen sensitization rate. Risk-benefit favored doses below 1.0 SPT units for confirmatory trials. PMID- 26760114 TI - Journal of Agromedicine "Leader in the Field" 2016: Kevin Keaney. PMID- 26760113 TI - Personal injury recovery cost of pedestrian-vehicle collisions in New South Wales, Australia. AB - BACKGROUND: There is a need for routine estimates of injury recovery costs from pedestrian collisions using hospital separation records for economic evaluations. OBJECTIVE: To estimate the cost of injury recovery following pedestrian-vehicle collisions using the personal injury recover cost (PIRC) equation using key demographic and injury characteristics. METHOD: An estimation of the costs of on road pedestrian-vehicle collisions involving individuals who were injured and hospitalized in New South Wales (NSW), Australia, from 2002 to 2011 using the PIRC equation. The PIRC estimates individual injury recovery costs and does not include costs associated with property damage, vehicle repair, or rescue services. Individual recovery costs associated with severe traumatic brain injury (TBI) were estimated. The injured individual's mean, median, and total injury recovery costs are described for key demographic, injury, and crash characteristics. RESULTS: There were 9,781 pedestrians who were injured, costing an estimated total of $2.4 billion in personal injury recovery costs, an annual cost of $243 million. Males had a total injury recovery cost 1.7 times higher than females. The median injury recovery cost decreased with increasing age. TBI ($248,491) and spinal cord and vertebral column injuries ($264,103) had the highest median injury recovery costs for the body region of the most severe injury. TBI accounted for 22.6% of the total injury recovery costs for the most severe injury sustained. Just over one third of pedestrians sustained 4 or more injuries, with a median cost of $243,992, which was 1.6 times higher than the cost for a pedestrian who sustained a single injury ($153,682). CONCLUSIONS: Personal injury recovery costs following pedestrian-vehicle collisions where a pedestrian is injured are substantial in NSW. The PIRC equation enables the economic cost burden of road traffic injury to be calculated using hospital separation data. The PIRC enables comprehensive personal injury recovery costs to be estimated and would aid in economic evaluations of preventive strategies in road safety. PMID- 26760115 TI - Journal of Agromedicine "Peer Reviewer of the Year" 2016: Lorann Stallones, PhD, MPH. PMID- 26760116 TI - Low Oxygen Tension Modulates the Insulin-Like Growth Factor-1 or -2 Signaling via Both Insulin-Like Growth Factor-1 Receptor and Insulin Receptor to Maintain Stem Cell Identity in Placental Mesenchymal Stem Cells. AB - Placental mesenchymal stem cells (PMSCs) are readily available multipotent stem cells for potential use in regenerative therapies. For this purpose, PMSCs must be maintained in culture conditions that mimic the in vivo microenvironment. IGFs (IGF-1 and IGF-2) and oxygen tension are low in the placenta in early gestation and increase as pregnancy progresses. IGFs bind to two receptor tyrosine kinases, the IGF-1 receptor (IGF-1R) and the insulin receptor (IR), and their hybrid receptors. We hypothesized that IGF-1 and IGF-2 signal via distinct signaling pathways under low-oxygen tension to maintain PMSC multipotency. In preterm PMSCs, low-oxygen tension increased the expression of IGF-2 and reduced IGF-1. IGF-1 stimulated higher phosphorylation of IGF-1Rbeta, ERK1/2, and AKT, which was maintained at steady lower levels by low oxygen tension. PMSC proliferation was increased by IGF-1 more than IGF-2,and was potentiated by low-oxygen tension. This IGF/low oxygen tension-mediated proliferation was receptor dependent because neutralization of the IGF-1R inhibited PMSC proliferation in the presence of IGF 1 and the IR in presence of IGF-2. These findings suggest that both IGF-1R and the IR can participate in mediating IGF signaling in maintaining PMSCs multipotency. We conclude that low-oxygen tension can modify the IGF-1 or IGF-2 signaling via the IGF-1R and IR in PMSCs. PMID- 26760118 TI - Pressure dependent structural changes and predicted electrical polarization in perovskite RMnO3. AB - High pressure x-ray diffraction measurements on perovskite RMnO3 (R = Dy, Ho and Lu) reveal that varying structural changes occur for different R ions. Large lattice changes (orthorhombic strain) occur in DyMnO3 and HoMnO3 while the Jahn Teller (JT) distortion remains stable. Conversely, in the small R-ion system LuMnO3, Mn-O bond distortions are observed between 4 and 8 GPa with a broad minimum in the JT distortion. High pressure infrared measurements indicate that a phonon near 390 cm(-1) corresponding to the complex motion of the Mn and O ions changes anomalously for LuMnO3. It softens in the 4-8 GPa region, which is consistent with the structural change in Mn-O bonds and then hardens at higher pressures. By contrast, the phonons continuously harden with increasing pressure for DyMnO3 and HoMnO3. Density functional theory methods show that E-phase LuMnO3 is the most stable phase up to the 10 GPa pressure examined. Simulations indicate that the distinct structural change under pressure in LuMnO3 can possibly be used to optimize the electric polarization by pressure/strain. PMID- 26760117 TI - PROX1 Promotes Secretory Granule Formation in Medullary Thyroid Cancer Cells. AB - Mechanisms of endocrine secretory granule (SG) formation in thyroid C cells and medullary thyroid cancer (MTC) cells have not been fully elucidated. Here we directly demonstrated that PROX1, a developmental homeobox gene, is transcriptionally involved in SG formation in MTC, which is derived from C cells. Analyses using gene expression databases on web sites revealed that, among thyroid cancer cells, MTC cells specifically and highly express PROX1 as well as several SG-forming molecule genes. Immunohistochemical analyses showed that in vivo MTC and C cells expressed PROX1, although follicular thyroid cancer and papillary thyroid cancer cells, normal follicular cells did not. Knockdown of PROX1 in an MTC cells reduced SGs detected by electron microscopy, and decreased expression of SG-related genes (chromogranin A, chromogranin B, secretogranin II, secretogranin III, synaptophysin, and carboxypeptidase E). Conversely, the introduction of a PROX1 transgene into a papillary thyroid cancer and anaplastic thyroid cancer cells induced the expression of SG-related genes. Reporter assays using the promoter sequence of chromogranin A showed that PROX1 activates the chromogranin A gene in addition to the known regulatory mechanisms, which are mediated via the cAMP response element binding protein and the repressor element 1-silencing transcription factor. Furthermore, chromatin immunoprecipitation-PCR assays demonstrated that PROX1 binds to the transcriptional regulatory element of the chromogranin A gene. In conclusion, PROX1 is an important regulator of endocrine SG formation in MTC cells. PMID- 26760119 TI - Nanog dynamics in single embryonic stem cells. PMID- 26760122 TI - Stroke is still a neglected disease in Brazil. PMID- 26760121 TI - Circulating extracellular miR-22, miR-155, and miR-365 as candidate biomarkers to assess transport-related stress in turkeys. AB - MicroRNA (miRNA) have been identified in circulating blood and might have the potential to be used as biomarkers for several pathophysiological conditions. To identify miRNA that are altered following stress events, turkeys (Meleagris gallopavo) were subjected to 2 h of road transportation. The expression levels of five circulating miRNA, namely miR-22, miR-155-5p, miR-181a-3p, miR-204 and miR 365-3p, were detected and assessed by quantitative polymerase chain reaction using TaqMan(r) probes, as potential biomarkers of stress. The areas under the receiver operating characteristic curves were then used to evaluate the diagnostic performance of miRNA. A panel of three stress-responsive miRNA, miR 22, miR-155 and miR-365 were identified; their expression levels were significantly higher after road transportation and the area under the curve (AUC) were 0.763, 0.71 and 0.704, respectively. Combining the three miRNA a specificity similar to the one found for the three miRNA separately was found. The AUC of the weighted average of the three miRNA was 0.763. This preliminary study suggests that the expression levels of circulating miR-22, miR-155 and miR-365 are increased during transport-related stress and that they may have diagnostic value to discriminate between stressed- and unstressed animals. PMID- 26760123 TI - Cohort study on the factors associated with survival post-cardiac arrest. AB - CONTEXT AND OBJECTIVE: Cardiac arrest is a common occurrence, and even with efficient emergency treatment, it is associated with a poor prognosis. Identification of predictors of survival after cardiopulmonary resuscitation may provide important information for the healthcare team and family. The aim of this study was to identify factors associated with the survival of patients treated for cardiac arrest, after a one-year follow-up period. DESIGN AND SETTING: Prospective cohort study conducted in the emergency department of a Brazilian university hospital. METHODS: The inclusion criterion was that the patients presented cardiac arrest that was treated in the emergency department (n = 285). Data were collected using the In-hospital Utstein Style template. Cox regression was used to determine which variables were associated with the survival rate (with 95% significance level). RESULTS: After one year, the survival rate was low. Among the patients treated, 39.6% experienced a return of spontaneous circulation; 18.6% survived for 24 hours and of these, 5.6% were discharged and 4.5% were alive after one year of follow-up. Patients with pulseless electrical activity were half as likely to survive as patients with ventricular fibrillation. For patients with asystole, the survival rate was 3.5 times lower than that of patients with pulseless electrical activity. CONCLUSIONS: The initial cardiac rhythm was the best predictor of patient survival. Compared with ventricular fibrillation, pulseless electrical activity was associated with shorter survival times. In turn, compared with pulseless electrical activity, asystole was associated with an even lower survival rate. PMID- 26760124 TI - Attributable causes of chronic kidney disease in adults: a five-year retrospective study in a tertiary-care hospital in the northeast of the Malaysian Peninsula. AB - CONTEXT AND OBJECTIVE: Chronic kidney disease (CKD) is an escalating medical and socioeconomic problem worldwide. Information concerning the causes of CKD, which is a prerequisite for reducing the disease burden, is sparse in Malaysia. Therefore, this study aimed to evaluate the attributable causes of CKD in an adult population at a tertiary referral hospital. DESIGN AND SETTING: Retrospective study at Hospital Universiti Sains Malaysia (HUSM). METHODS: This was an analysis based on medical records of adult patients at HUSM. Data regarding demographics, laboratory investigations, attributable causes and CKD stage were gathered. RESULTS: A total of 851 eligible cases were included. The patients' mean age was 61.18 +/- 13.37 years. CKD stage V was found in 333 cases (39.1%) whereas stages IV, IIIb, IIIa, and II were seen in 240 (28.2%), 186 (21.9%), 74 (8.7%) and 18 (2.1%), respectively. The percentage of CKD stage V patients receiving renal replacement therapy was 15.6%. The foremost attributable causes of CKD were diabetic nephropathy (DN) (44.9%), hypertension (HPT) (24.2%) and obstructive uropathy (9.2%). The difference in the prevalence of CKD due to DN, HPT and glomerulonephritis between patients <= 50 and > 50 years old was statistically significant. CONCLUSION: Our results suggest that DN and HPT are the major attributable causes of CKD among patients at a Malaysian tertiary-care hospital. Furthermore, the results draw attention to the possibility that greater emphasis on primary prevention of diabetes and hypertension will have a great impact on reduction of hospital admissions due to CKD in Malaysia. PMID- 26760126 TI - Acupuncture for migraine prophylaxis. PMID- 26760125 TI - Sodium and potassium intake estimated using two methods in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - CONTEXT AND OBJECTIVE: Sodium and potassium intake from different food sources is an important issue regarding cardiovascular physiology. Epidemiological assessment of the intake of these electrolytes intake is done through food frequency questionnaires or urinary excretion measurements. Our aim was to compare these methods using a sample of Brazilian civil servants. DESIGN AND SETTING: Cross-sectional baseline evaluation from the Brazilian Longitudinal Study of Adult Health. METHODS: Sodium and potassium intake was obtained using two methods: a semi-quantitative questionnaire including 114 food items; and overnight 12-hour urinary excretion measurement. Sodium and potassium estimates obtained through the questionnaire were adjusted for energy intake using the residual method. Urinary excretion measurements were considered valid if they met three adequacy criteria: collection time, volume and total creatinine excretion. Mean nutrients were estimated, and Spearman correlations were calculated. Sodium and potassium intake was categorized into quintiles, and weighted kappa coefficients and percentage agreement were calculated. The significance level for all tests was 0.05. RESULTS: Data from 15,105 participants were analyzed, and significant differences between mean intakes of sodium (questionnaire: 4.5 +/- 1.7 g; urine: 4.2 +/- 2.1 g) and potassium (questionnaire: 4.7 +/- 1.8 g; urine: 2.4 +/- 1 g) were found. Weak agreement was found for sodium (K = 0.18) and potassium (K = 0.16). The percentage disagreement between methods ranged from 41.8 to 44.5%, while exact concordance ranged from 22.1% to 23.9%. CONCLUSIONS: The agreement between the food frequency questionnaire and urinary excretion measurements for assessment of sodium and potassium intakes was modest. PMID- 26760127 TI - HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. PMID- 26760128 TI - RUFY4: Immunity piggybacking on autophagy? AB - Although autophagy is a highly conserved mechanism among species and cell types, few are the molecules involved with the autophagic process that display cell- or tissue- specific expression. We have unraveled the positive regulatory role on autophagy of RUFY4 (RUN and FYVE domain containing 4), which is expressed in subsets of immune cells, including dendritic cells (DCs). DCs orchestrate the eradication of pathogens by coordinating the action of the different cell types involved in microbe recognition and destruction during the immune response. To fulfill this function, DC display particular regulation of their endocytic and autophagy pathways in response to the immune environment. Autophagy flux is downmodulated in DCs upon microbe sensing, but is remarkably augmented, when cells are differentiated in the presence of the pleiotropic cytokine IL4 (interleukin 4). From gene expression studies aimed at comparing the impact of IL4 on DC differentiation, we identified RUFY4, as a novel regulator that augments autophagy flux and, when overexpressed, induces drastic membrane redistribution and strongly tethers lysosomes. RUFY4 is therefore one of the few known positive regulators of autophagy that is expressed in a cell-specific manner or under specific immunological conditions associated with IL4 expression such as allergic asthma. PMID- 26760130 TI - Looking Back to What's Ahead. PMID- 26760133 TI - Trifluoperazine: A Sprightly Old Drug. AB - Trifluoperazine, developed in the mid-1950s and introduced in 1959 as an anxiolytic and antipsychotic agent, has been an extensively studied drug molecule that has been used as a calmodulin inhibitor. Regulation of calmodulin has important roles in cellular proliferation, inflammation, neurodegeneration, and other pathological processes. Trifluoperazine also inhibits P-glycoprotein, a protein that transports organic compounds across cell membranes and the blood brain barrier. Trifluoperazine is currently approved for the treatment of schizophrenia as well as for the treatment of non-psychotic anxiety, but has other potential clinical uses based on calmodulin and P-glycoprotein inhibition. PMID- 26760134 TI - What's New in Treating Inpatients With Personality Disorders?: Dialectical Behavior Therapy and Old-Fashioned, Good Communication. AB - Psychiatric unit inpatients often have serious mental illnesses with comorbid personality disorders. Mental illnesses usually respond favorably to medication and psychotherapy, but personality disorders do not. Two personality disorders are commonly seen on inpatient units: borderline and antisocial. These personality disorders may destabilize the milieu with disruptive behaviors and present a challenge to nurses. Difficult patient behaviors and therapeutic responses by nurses are examined. Dialectical behavior therapy techniques and good communication skills may be used by nurses to (a) interact therapeutically with patients with personality disorders and (b) protect other patients and the milieu. PMID- 26760136 TI - Diffusion of eccentric microswimmers. AB - We model the two-dimensional diffusive dynamics of an eccentric artificial microswimmer in a highly viscous medium. We assume that the swimmer's propulsion results from an effective force applied to a center distinct from its center of mass, both centers resting on a body's axis parallel to its average self propulsion velocity. Moreover, we allow for angular fluctuations of the velocity about the body's axis. We prove, both analytically and numerically, that the ensuing active diffusion of the swimmer is suppressed to an extent that strongly depends on the model parameters. In particular, the active diffusion constant undergoes a transition from a quadratic to a linear dependence on the self propulsion speed, with practical consequences on the interpretation of the experimental data. Finally, we extend our model to describe the diffusion of chiral eccentric swimmers. PMID- 26760129 TI - The inhibition of the apoptosis pathway by the Coxiella burnetii effector protein CaeA requires the EK repetition motif, but is independent of survivin. AB - ABSRTACT Coxiella burnetii is an obligate intracellular bacterium that causes Query (Q) fever, a zoonotic disease. It requires a functional type IV secretion system (T4SS) which translocate bacterial effector proteins into the host cell cytoplasm and thereby facilitates bacterial replication. To date, more than 130 effector proteins have been identified, but their functions remain largely unknown. Recently, we demonstrated that one of these proteins, CaeA (CBU1524) localized to the host cell nucleus and inhibited intrinsic apoptosis of HEK293 or CHO cells. In the present study we addressed the question whether CaeA also affects the extrinsic apoptosis pathway. Ectopic expression of CaeA reduced extrinsic apoptosis and prevented the cleavage of the executioner caspase 7, but did not impair the activation of initiator caspase 9. CaeA expression resulted in an up-regulation of survivin (an inhibitor of activated caspases), which, however, was not causal for the anti-apoptotic effect of CaeA. Comparing the sequence of CaeA from 25 different C. burnetii isolates we identified an EK (glutamic acid/ lysine) repetition motif as a site of high genetic variability. The EK motif of CaeA was essential for the anti-apoptotic activity of CaeA. From these data, we conclude that the C. burnetii effector protein CaeA interferes with the intrinsic and extrinsic apoptosis pathway. The process requires the EK repetition motif of CaeA, but is independent of the upregulated expression of survivin. PMID- 26760137 TI - Major depressive disorder, antidepressant use, and subsequent 2-year weight change patterns in the Netherlands Study of Depression and Anxiety. AB - BACKGROUND: Although depression and obesity are bidirectionally associated, little is known about weight changes following major depressive disorder (MDD). This study compared 2-year weight changes between patients with current MDD (cMDD), patients with remitted MDD (rMDD), and healthy controls. Additionally, we examined the relationship between antidepressant medication use and 2-year weight change. METHOD: Data from 2,542 adults aged 18-65 y were sourced from the Netherlands Study of Depression and Anxiety. Data were collected at baseline and after 2, 4, and 6 years (September 2004-April 2013). Depression status (DSM-IV criteria for MDD) was established with the Composite International Diagnostic Interview. Subsequent 2-year weight changes were categorized as weight loss (> 5% loss), weight stable (within 5% weight loss or gain), and weight gain (> 5% gain). The association of depression status with subsequent weight change, with weight stable as reference category, was studied by combining all repeated measurements in a mixed multinomial logistical regression model. RESULTS: cMDD, but not rMDD, was significantly associated with both weight gain and weight loss over a 2-year period after adjustment for covariates (odds ratio [OR] = 1.67; 95% confidence interval [CI], 1.37-2.03; P < .001; and OR = 1.27; 95% CI 1.01-1.61; P = .045, respectively). Antidepressant use was associated with weight gain (SSRIs: OR = 1.26; 95% CI, 1.05-1.52; other antidepressants: OR = 1.36; 95% CI, 1.00 1.84; P < .05 for both), but not after considering depression status. Compared to cMDD patients who lost weight, those who gained weight had lower initial weight, were younger, had more comorbid anxiety disorders, and reported poorer quality of mood and reduced appetite as depressive symptoms. CONCLUSIONS: Compared to controls, cMDD participants have greater odds of either gaining or losing weight over a 2-year period, regardless of antidepressant use. PMID- 26760139 TI - Research knowledge in undergraduate school in Brazil: a comparison between medical and law students. AB - OBJECTIVE: Exposure to science education during college may affect a student's profile, and research experience may be associated with better professional performance. We hypothesized that the impact of research experience obtained during graduate study differs among professional curricula and among graduate courses. METHODS: A validated multiple-choice questionnaire concerning scientific concepts was given to students in the first and fourth years of medical and law school at a public Brazilian educational institution. RESULTS: Medical students participated more frequently in introductory scientific programs than law students, and this trend increased from the first to the fourth years of study. In both curricula, fourth-year students displayed a higher percentage of correct answers than first-year students. A higher proportion of fourth-year students correctly defined the concepts of scientific hypothesis and scientific theory. In the areas of interpretation and writing of scientific papers, fourth-year students, in both curricula, felt more confident than first-year students. Although medical students felt less confident in planning and conducting research projects than law students, they were more involved in research activities. CONCLUSION: Medical graduation seems to favor the development of critical scientific maturity than law graduation. Specific policy in medical schools is a reasonable explanation for medical students' participation in more scientific activities. PMID- 26760140 TI - Correlation between two physical activity programs in the gait of sedentary elderly subjects. AB - OBJECTIVES: To assess the effect of exercise on gait using two different programs: a group of aerobic exercises (Group A, n = 18) and a group of flexibility and balance exercises (Group B, n = 19). METHODS: A casualized controlled study, in which each sample controlled itself, was undertaken. The sample comprised 37 male and female subjects, aged from 60 to 90 years, from the outpatient clinic of the Geriatrics Unit of Hospital das Clinicas of Faculdade de Medicina of Universidade de Sao Paulo; the patients were sedentary and had not exercised regularly during the past six months. RESULTS: Improvement of gait was seen mainly in the group that did specific exercises. CONCLUSION: The results of this study underline the importance of physical exercises in sedentary elderly subjects, but show the need for programming the exercises towards specific goals, which can optimize the results of this tool of health promotion for the elderly. PMID- 26760138 TI - Advanced biomaterial strategies to transplant preformed micro-tissue engineered neural networks into the brain. AB - OBJECTIVE: Connectome disruption is a hallmark of many neurological diseases and trauma with no current strategies to restore lost long-distance axonal pathways in the brain. We are creating transplantable micro-tissue engineered neural networks (micro-TENNs), which are preformed constructs consisting of embedded neurons and long axonal tracts to integrate with the nervous system to physically reconstitute lost axonal pathways. APPROACH: We advanced micro-tissue engineering techniques to generate micro-TENNs consisting of discrete populations of mature primary cerebral cortical neurons spanned by long axonal fascicles encased in miniature hydrogel micro-columns. Further, we improved the biomaterial encasement scheme by adding a thin layer of low viscosity carboxymethylcellulose (CMC) to enable needle-less insertion and rapid softening for mechanical similarity with brain tissue. MAIN RESULTS: The engineered architecture of cortical micro-TENNs facilitated robust neuronal viability and axonal cytoarchitecture to at least 22 days in vitro. Micro-TENNs displayed discrete neuronal populations spanned by long axonal fasciculation throughout the core, thus mimicking the general systems level anatomy of gray matter-white matter in the brain. Additionally, micro columns with thin CMC-coating upon mild dehydration were able to withstand a force of 893 +/- 457 mN before buckling, whereas a solid agarose cylinder of similar dimensions was predicted to withstand less than 150 MUN of force. This thin CMC coating increased the stiffness by three orders of magnitude, enabling needle-less insertion into brain while significantly reducing the footprint of previous needle-based delivery methods to minimize insertion trauma. SIGNIFICANCE: Our novel micro-TENNs are the first strategy designed for minimally invasive implantation to facilitate nervous system repair by simultaneously providing neuronal replacement and physical reconstruction of long-distance axon pathways in the brain. The micro-TENN approach may offer the ability to treat several disorders that disrupt the connectome, including Parkinson's disease, traumatic brain injury, stroke, and brain tumor excision. PMID- 26760141 TI - Impact of educational lectures on female adolescents' knowledge about sexually transmitted diseases and cervical cancer in the city of Jundiai, SP. AB - OBJECTIVE: To evaluate the knowledge of adolescents living in Vila Ana and Morada das Vinhas region, in the city of Jundiai, State of Sao Paulo, Brazil, on prevention and diagnosis of the main sexually transmitted diseases (STDs) and on cervical cancer, as well as the immediate impact of educational lectures. METHODS: A prospective cross-sectional study was performed to assess the knowledge of a particular group of female adolescents about STDs and cervical cancer, by means of a questionnaire applied before and after educational lectures. RESULTS: After the lecture, there was an increased number of correct answers about sexual education, knowledge about HPV (44%), and prevention of cervical cancer (22%). CONCLUSION: The adolescents in our study had little knowledge about STDs and cervical cancer, but educative lectures could change this reality at a low cost to Public Health services. PMID- 26760143 TI - Analysis of possible food/nutrient and drug interactions in hospitalized patients. AB - OBJECTIVE: To evaluate the prescription in relation to the possible interactions between drugs and foods/nutrients in the diets of patients in the Hospital Regional Justino Luz in the municipality of Picos, Piaui, Brazil. METHODS: The sample consisted of 60 medical records of patients admitted at the hospital. The records were analyzed according to the presence or absence of interactions between drugs and foods/nutrients of the prescribed diets. RESULTS: Of the 82 drugs prescribed in all periods, there were 16 drugs (19.5%) with possible interaction with food, a total of 60 interactions between nutrient/food and medicine. Thus, 18 (30%), 10 (17%) and 8 (13%) possible interactions were identified with captopril (cardiovascular drug) with acetylsalicylic acid (anti inflammatory) and spironolactone (diuretic), respectively representing the highest numbers of interactions among the classes of investigated drugs. It was also found that the total interactions between food/nutrients and drugs, 32 (53%) accounted for interactions with cardiovascular drugs, 13 (22%) with anti inflammatory drugs, 11 (18%) with diuretic agents e 4 (7%) with drugs that act on the digestive tract. CONCLUSION: There was a high number of interactions between food/nutrients and medicines emphasizing the need for prior knowledge of these interactions as a way to avoid impairment in the treatment, longer hospital stays and/or damage to the nutritional status of the patients. PMID- 26760142 TI - Biomarkers in Parkinson Disease: global gene expression analysis in peripheral blood from patients with and without mutations in PARK2 and PARK8. AB - OBJECTIVE: To evaluate the performance of gene expression analysis in the peripheral blood of Parkinson disease patients with different genetic profiles using microarray as a tool to identify possible diseases related biomarkers which could contribute to the elucidation of the pathological process, as well as be useful in diagnosis. METHODS: Global gene expression analysis by means of DNA microarrays was performed in peripheral blood of Parkinson disease patients with previously identified mutations in PARK2 or PARK8 genes, Parkinson disease patients without known mutations in these genes and normal controls. Each group consisted of five individuals. RESULTS: Global gene expression profiles were heterogeneous among patients and controls, and it was not possible to detect a consistent pattern between groups. However, analyzing genes with differential expression of p < 0.005 and fold change >= 1.2, we were able to identify a small group of well-annotated genes. CONCLUSIONS: Despite the small sample size, the identification of differentially expressed genes suggests that the microarray technique may be useful in identifying potential biomarkers in the peripheral blood of Parkinson disease patients or in people at risk of developing the disease. This will be important once neuroprotective therapies become available, and may contribute to the identification of new pathways involved in the disease physiopathology. Results presented here should be further validated in larger groups of patients. PMID- 26760144 TI - Communication and access to information in assessing the quality of multiprofessional care of patients. AB - OBJECTIVE: To assess the quality of a multiprofessional healthcare model for in hospital patients by means of two performance indicators (communication and knowledge about the case). METHODS: A cross-sectional study assessed the knowledge that professionals had about the clinical information of patients and the use of communication strategies by the team. Healthcare professionals were interviewed during their work period. Seven occupational categories were interviewed. A total of 199 medical charts were randomly selected for interviews, and 312 professionals of different categories were interviewed. The sample comprised mostly nurses and physical therapists in the charts that were interviewed. RESULTS: There were no statistically significant differences between the expected performing model group and the under-performing model group for sex, location and job. In the under-performing model group, a larger number of professionals correlated with less knowledge. Communication was improved when nurses had the relevant information about interdisciplinary care (97.4%), appropriate use of the Plan of Care form (97.0%), and formalized discussions with physicians (88.2%). In the expected performing model group, it was observed that the higher the number of healthcare professionals involved, the higher the communication levels. CONCLUSIONS: This model of care based on case knowledge and multiprofessional team communication performance indices allowed to assess quality of care. This assessment is measurable and there is the possibility of establishing the quality of care delivered. PMID- 26760145 TI - Morbidity in neonates according to the mode of delivery: a comparative study. AB - OBJECTIVE: The objective of this study was to compare the effects of the modes of delivery on the health of newborns in a private maternity hospital in the city of Sao Paulo. METHODS: Between January 1995 and December 1998, all patients consecutively admitted for deliveries were included in this cross-sectional retrospective study. A total of 8,457 medical records were analyzed, being excluded of the sample 460 multiple pregnancies and 517 pregnant women with obstetric and/or clinical disorders. The incidence of neonatal birth injury, respiratory distress and anoxia was analyzed, as well as birth weight, type of delivery and gestational age (according to Naegele and Capurro). RESULTS: The final sample consisted of 7,480 neonates, and 69.6% were born by cesarean section, 24% vaginally and 6.4% through the vagina with the aid of forceps. A significant association was found between anoxia and the three types of delivery (p < 0.001). Respiratory distress was more frequent in cesarean delivery in newborns with gestational age superior to 37 weeks and in newborns weighing more than or equal to 2,500 g. Respiratory distress was significantly associated with cesarean delivery and/or forceps delivery, as compared with vaginal delivery, in the entire sample. Neonatal birth injury was associated with the use of forceps. In neonates born by cesarean section, anoxia was associated with lower gestational age estimated by the Capurro method and with lower weight. CONCLUSIONS: The abdominal approach is associated with greater morbidity of fetuses due to respiratory distress. Vaginal delivery is safer in newborns with more than 37 weeks of gestation and in those weighing more than 2,500 g. PMID- 26760147 TI - Timing of initial surfactant treatment in very low birth weight newborns. AB - OBJECTIVE: To correlate the timing of treatment using exogenous surfactant with the main variables related to respiratory distress syndrome or prematurity. METHODS: A historic cohort study between January 1, 2004 and June 30, 2007, including very low birth weight newborns (birth weight <1,500 g) admitted to the hospital and who required surfactant therapy. Newborns were divided into three study groups: early (treatment during the first two hours); intermediate (treatment between two and six hours) and late (treatment after six hours). Variables analyzed were: air leak syndrome, mortality, bronchopulmonary dysplasia, intracranial hemorrhage, patent ductus arteriosus, retinopathy of prematurity, duration of oxygen therapy, duration of mechanical ventilation, length of hospital stay and number of surfactant doses. RESULTS: A total of 63 newborns were included (Early Group, n = 21; Intermediate Group, n = 26 and Late Group, n = 16), there was a statistical significance between birth weight and gestational age. Multivariate logistic regression analysis was used to compensate the effects of gestational age, birth weight and other possible interferences over the variables. This analysis revealed a greater incidence of air leak syndrome among newborns of the Early Group compared to the Intermediate Group (OR = 6.98; 95%CI = 1.24-39.37; p = 0.028), with no difference compared to the Late Group (OR = 3.72; 95% CI = 0.28-49.76; p = 0.321). There were no differences regarding the other variables analyzed. CONCLUSIONS: In this retrospective, non randomized study, surfactant administration during the first two hours of life enhanced the risk of air leak syndrome, compared to the treatment between two and six hours after birth, with no reduction of early or late neonatal mortality or bronchopulmonary dysplasia, compared to later treatment after birth. PMID- 26760146 TI - Frequency of peri-intraventricular hemorrhage and its associated factors in premature newborns. AB - OBJECTIVE: To identify the frequency of intracranial hemorrhage and its associated factors in premature newborns. METHODS: A cross-sectional study based on a survey of medical records of premature neonates submitted to transfontanellar ultrasound at a hospital located in a southern neighborhood of the city of Sao Paulo, in 2007. RESULTS: A 50% rate of intracranial hemorrhage was found among premature newborns submitted to transfontanellar ultrasound, and 15.35% among all premature babies born in this hospital in 2007. The statistically significant factors associated to intracranial hemorrhage were gestational age less than 32 weeks, absence of prenatal care, invasive mechanical ventilation, infection, blood transfusion, hyaline membrane disease, hyponatremia and hyperglycemia. CONCLUSIONS: The frequency of peri-intraventricular hemorrhage was 50% in patients at risk and 15.35% among all premature babies; the associated factors were gestational age less than 32 weeks, absence of prenatal care, need of invasive mechanical ventilation, infection, blood transfusion, hyaline membrane disease, hyponatremia and hyperglycemia. PMID- 26760148 TI - Impact of treadmill gait training with neuromuscular electrical stimulation on the urodynamic profile of patients with high cervical spinal cord injury. AB - OBJECTIVE: To evaluate the impact of gait training with neuromuscular electrical stimulation on urodynamic parameters of patients with neurogenic bladder. METHODS: Eight male quadriplegic patients with complete cervical injury level ranging from C4 to C7 comprised the study population. They underwent treadmill gait training with neuromuscular electrical stimulation for six months, only after having their quadriceps and tibialis anterior muscles stimulated for five months in order to support at least 50% of their body weight (pre-gait training). Urodynamic testing was performed before the treadmill gait training and six months after. RESULTS: The mean time after cervical lesion was 74.63 months. The urodynamic parameters before and after neuromuscular training by electrical stimulation did not show significant difference. CONCLUSION: This study demonstrated that neuromuscular training with electrical stimulation can benefit the urinary tract. This promising minimally invasive field requires further and more complete studies to confirm a possible benefit to the low urinary tract. PMID- 26760149 TI - A new experimental model for inducing interstitial cystitis by oxidative stress using intravesical instillation of a nitric oxide donor gel. AB - OBJECTIVE: The aim of this study was to develop an experimental model of inducing interstitial cystitis through intravesical instillation of a polymeric solution containing the NO donor S-nitrousglutathione (GSNO) and to compare it to the experimental interstitial cystitis induced by vesical instillation of protamine and potassium chloride. METHODS: A total of 40 female Wistar rats were used and divided into four groups: 1 - ten rats treated with saline solution + GSNO; 2 - ten rats treated with saline solution + polymeric solution (without GNSO); 3 - ten rats treated with protamine sulphate + KCl; 4 - ten rats treated with protamine sulphate + GSNO. The rats received one application (five animals in each group) or three applications (five animals in each group) of the corresponding substance through intravesical instillation, and after six days (five animals in each group) or nine days (five animals in each group) they were euthanized and their bladders were removed for macroscopic evaluation and histological study. RESULTS: In the macroscopic evaluation edema and hyperemia of the mucosa were observed in 2 (22%) animals in Group 1, in no (0%) animal in Group 2, in 10 (100%) animals in Group 3, and in 5 (50%) animals in Group 4. In the protamine + KCl group and in saline + GSNO, similar effects were observed in the bladder wall. The animals in Group 2 (saline + polymeric solution) showed significantly less vascular congestion compared to the other groups after 9 days of the instillation (p = 0.0035). Significant fibrosis was observed in Groups 3 and 4, 6 days (p = 0.3781) and 9 days (p = 0.0459) after instillations, when compared to controls (Group 2). All groups presented neutrophilic infiltrate of variable intensity, 6 days after instillations (p = 0.7277). After 9 days, there was a regression of the infiltrate, with no evidence of accentuated neutrophilic reaction in all the groups (p = 0.2301). CONCLUSIONS: The inflammatory response to bladder instillation with an aqueous solution of S-nitrousglutathione was very similar to that induced by bladder instillation of protamine and KCl. Instillation of an aqueous solution of S-nitrousglutathione can be considered a new model for experimental induction of interstitial cystitis. PMID- 26760150 TI - Efficacy and toxicity of mitoxantrone and oral etoposide in the treatment of hormone-refractory prostate cancer: pilot study. AB - OBJECTIVE: To evaluate the efficacy and toxicity of the association of mitoxantrone and oral etoposide. METHODS: Twelve consecutive patients with metastatic hormone-refractory prostate cancer were treated with mitoxantrone and oral etoposide. Toxicity, response rate and response duration were assessed. RESULTS: Partial response was observed in two patients (response duration of seven and four months) and one patient had stable disease (during four months). Mitoxantrone and oral Etoposide were well tolerated and did not affect tolerability to subsequent chemotherapy. CONCLUSION: Mitoxantrone and oral etoposide association is an active and well-tolerated regimen in hormone refractory prostate cancer. PMID- 26760151 TI - Thoracic trauma: analysis of 100 consecutive cases. AB - OBJECTIVE: To analyze thoracic trauma assisted by the Emergency Service of Hospital da Irmandade da Santa Casa de Misericordia de Sao Paulo. METHODS: One hundred patients with thoracic trauma were assisted throughout six months in 2006. Data from their records were collected and a protocol of thoracic trauma was fulfilled. The Revised Trauma Score was used to evaluate gravity of injury and to calculate the survival index. RESULTS: Prevalence of trauma injury in male from 20 to 29 years old was observed. Out of all patients, 44 had blunt trauma and 56 penetrating trauma (78.6% presented stab wounds and 21.4% gun shots). Up to the settings of injuries, 23% were in the thoracoabdominal transition, 7% in the precordium and 70% in the remainder thoracic area. In those with the thoracoabdominal transition injury, 22.7% were hemodynamically unstable and 77.3% stable. Thoracoabdominal injury patients presented 40.9% of diaphragm wound and all were stable. Of those with precordium wound, 37.5% presented cardiac injury. In cardiac onset, 66.7% presented stable and 33.3% unstable. Thoracic drainage was the most accomplished surgical procedure (71%). CONCLUSIONS: The thoracic trauma patient is most prevalently young male with stab wound penetrating injury, without associated injuries, hemodynamically stable, presenting hemothorax, with high probability of survival. PMID- 26760152 TI - Two-dimensional analysis of gait asymmetry in spastic hemiplegia. AB - OBJECTIVE: Simple measures of gait for routine clinical use could be useful when the complex gait analysis systems are not available. The aim of this study was to quantify asymmetry in children with spastic hemiplegia using a two-dimensional gait analysis by videography and to relate the asymmetry to motor function. METHODS: Twenty-four children with spastic hemiplegia (19 males, 5 females; mean age 49 months [SD 5 months], range from 39 to 60 months) were assessed with a two dimensional gait analysis by videography and the analyzed parameters were compared with normal values and with clinical and functional data. RESULTS: There were significant differences in swing time (p = 0.002), stance time (p = 0.01) and stance/swing time ratio (p < 0.001). The comparison with the normal values described by Sutherland also demonstrated gait asymmetry. There was no direct relationship between the motor function and asymmetry but a score analysis for specific Gross Motor Function Measure items could quantify it in terms of age of gait acquisition. Children with more adequate muscle tone presented longer stance time in the involved limb than those with more spasticity (p = 0.03). CONCLUSIONS: These results suggest that the best performance is associated with the smallest asymmetry in this sample. Although two-dimensional gait analysis does not provide as much data as three dimensional gait analyses, we believe it can contribute significantly to the gait assessment of children with cerebral palsy. PMID- 26760153 TI - Total hip and knee joint replacement: perioperative clinical aspects. AB - OBJECTIVE: To understand the profile of patients undergoing hip and knee replacement during two years, and to compare the data obtained with the literature. METHODS: A total of 323 medical records were reviewed to analyze the perioperative data of patients submitted to hip and knee replacement. RESULTS: Osteoarthritis was the main indication for both procedures and male patients were heavier than females (p < 0.05). Hypertension was the prevalent disease among patients. Blood loss was more frequent in knee surgery than in the hip. CONCLUSIONS: The profile of patients undergoing total arthroplasty improved substantially over the past decade due to shorter hospital stay, lower risk of thromboembolic events and no infection as compared to previous reports. PMID- 26760154 TI - Benign bone tumors subperiosteal on the talar neck resected anthroscopically: case reports. AB - Two cases of benign chondral tumors of the talar neck region (an osteoid osteoma and a chondroblastoma) were described. Because of their specific, unusual site they could be resected by arthroscopy. The imaging aspects, incidence in foot bones and possibilities of treatment were discussed, and a literature review is presented. PMID- 26760155 TI - Cefepime-induced encephalopathy in patient without renal failure. AB - This case report describes neurotoxicity in an older patient on cefepime 2 g twice a day. The 81-year-old male patient developed non-convulsive status epilepticus during cefepime treatment with 1 g twice a day. There was recovery 30 days after discontinuation of cefepime. PMID- 26760156 TI - Magnetohyperthermia for treatment of gliomas: experimental and clinical studies. AB - Gliomas comprise a group of heterogeneous primary tumors of the central nervous system that originate from glial cells. Malignant gliomas account for the majority of primary malignant CNS tumors and are associated with high morbidity and mortality. Glioblastoma is the most frequent malignant glioma, and despite recent advances in diagnosis and new treatment options, its prognosis remains dismal. New opportunities for the development of effective therapies for malignant gliomas are urgently needed. Magnetohyperthermia consists of heat generation in the region of the tumor through the application of magnetic nanoparticles subjected to an alternating magnetic field and has shown positive results in both preclinical and clinical assays. The aim of this review was to assess the relevance of hyperthermia induced by magnetic nanoparticles in treating gliomas and to describe possible variations of the technique and its implication in the effectiveness of treatment. An electronic search in the literature of articles published from January 1990 to November 2009 was performed, in databases ISI Web of Science and PubMed, and after screening according to the inclusion criteria, 11 articles were selected. Animal models showed that magnetohyperthermia was effective in promoting tumor cell death and reducing tumor mass or increasing survival of the animals. One clinical study demonstrated that magnetohyperthermia could be applied safely and with few adverse effects. Some studies suggested that mechanisms of cell death, such as apoptosis, necrosis, and antitumor immune response were triggered by magnetohyperthermia. Based on these data, it was concluded that the technique proved to be effective in most experiments, and improvement of the nanocomposites, as well as of the alternating magnetic field equipment, can contribute towards establishing magnetohyperthermia as a promising tool to treat malignant gliomas. PMID- 26760157 TI - The effects of alcohol in newborns. AB - The purpose of this article was to present a review of the effects of alcohol consumption by pregnant mothers on their newborn. Definitions, prevalence, pathophysiology, clinical features, diagnostic criteria, follow-up, treatment and prevention were discussed. A search was performed in Medline, LILACS, and SciELO databases using the following terms: "fetus", "newborn", "pregnant woman", "alcohol", "alcoholism", "fetal alcohol syndrome", and "alcohol-related disorders". Portuguese and English articles published from 2000 to 2009 were reviewed. The effects of alcohol consumed by pregnant women on newborns are extremely serious and occur frequently; it is a major issue in Public Health worldwide. Fetal alcohol spectrum disorders cause harm to individuals, their families, and the entire society. Nevertheless, diagnostic difficulties and inexperience of healthcare professionals result in such damage, being remembered rarely or even remaining uncovered. Alcohol-related injury to the fetus is fully avoidable; all it takes is for women not to drink alcoholic beverages during pregnancy. Therefore, detecting women who consume alcohol during pregnancy is paramount, as are specific programs to educate people about the consequences of alcohol use during pregnancy and breastfeeding. PMID- 26760158 TI - Markov Models in health care. AB - Markov Chains provide support for problems involving decision on uncertainties through a continuous period of time. The greater availability and access to processing power through computers allow that these models can be used more often to represent clinical structures. Markov models consider the patients in a discrete state of health, and the events represent the transition from one state to another. The possibility of modeling repetitive events and time dependence of probabilities and utilities associated permits a more accurate representation of the evaluated clinical structure. These templates can be used for economic evaluation in health care taking into account the evaluation of costs and clinical outcomes, especially for evaluation of chronic diseases. This article provides a review of the use of modeling within the clinical context and the advantages of the possibility of including time for this type of study. PMID- 26760159 TI - Centennial, but still current. PMID- 26760160 TI - Robotic assisted radical prostatectomy: a different treatment for prostate cancer? AB - Considering the Health Care System in Brazil, a developing country, and public healthcare policies, robotic surgery is a reality to very few citizens. Therefore, robotic assisted radical prostatectomy is far removed from the daily practice of the vast majority of Brazilian urologists. Scientific evidence of the superiority of robotic assisted radical prostatectomy does not presently justify public investments for widespread development of robotic centers. Maybe over time and with reductions in costs, robotic technology will become a more established practice, as observed in other countries, and more feasible for the Brazilian urological community. PMID- 26760174 TI - Weight Loss Is Associated With Increased NAD(+)/SIRT1 Expression But Reduced PARP Activity in White Adipose Tissue. AB - CONTEXT: Sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs) are 2 important nicotinamide adenine dinucleotide (NAD)(+)-dependent enzyme families with opposing metabolic effects. Energy shortage increases NAD(+) biosynthesis and SIRT activity but reduces PARP activity in animals. Effects of energy balance on these pathways in humans are unknown. OBJECTIVE: We compared NAD(+)/SIRT pathway expressions and PARP activities in sc adipose tissue (SAT) between lean and obese subjects and investigated their change in the obese subjects during a 12-month weight loss. DESIGN, SETTING AND PARTICIPANTS: SAT biopsies were obtained from 19 clinically healthy obese subjects (mean +/- SE body mass index, 34.6 +/- 2.7 kg/m(2)) during a weight-loss intervention (0, 5, and 12 mo) and from 19 lean reference subjects (body mass index, 22.7 +/- 1.1 kg/m(2)) at baseline. MAIN OUTCOME MEASURES: SAT mRNA expressions of SIRTs 1-7 and the rate limiting gene in NAD(+) biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT) were measured by Affymetrix, and total PARP activity by ELISA kit. RESULTS: SIRT1, SIRT3, SIRT7, and NAMPT expressions were significantly lower, whereas total PARP activity was increased in obese compared with lean subjects. SIRT1 and NAMPT expressions increased in obese subjects between 0 and 5 months, after a mean weight loss of 11.7%. In subjects who continued to lose weight between 5 and 12 months, SIRT1 expression increased progressively, whereas in subjects with weight regain, SIRT1 reverted to baseline levels. PARP activity significantly decreased in all subjects upon weight loss. CONCLUSIONS: Calorie restriction is an attractive strategy to improve the NAD(+)/SIRT pathway and decrease PARPs in SAT in human obesity. PMID- 26760175 TI - JAG1 Loss-Of-Function Variations as a Novel Predisposing Event in the Pathogenesis of Congenital Thyroid Defects. AB - CONTEXT: The pathogenesis of congenital hypothyroidism (CH) is still largely unexplained. We previously reported that perturbations of the Notch pathway and knockdown of the ligand jagged1 cause a hypothyroid phenotype in the zebrafish. Heterozygous JAG1 variants are known to account for Alagille syndrome type 1 (ALGS1), a rare multisystemic developmental disorder characterized by variable expressivity and penetrance. OBJECTIVE: Verify the involvement of JAG1 variants in the pathogenesis of congenital thyroid defects and the frequency of unexplained hypothyroidism in a series of ALGS1 patients. DESIGN, SETTINGS, AND PATIENTS: A total of 21 young ALGS1 and 100 CH unrelated patients were recruited in academic and public hospitals. The JAG1 variants were studied in vitro and in the zebrafish. RESULTS: We report a previously unknown nonautoimmune hypothyroidism in 6/21 ALGS1 patients, 2 of them with thyroid hypoplasia. We found 2 JAG1 variants in the heterozygous state in 4/100 CH cases (3 with thyroid dysgenesis, 2 with cardiac malformations). Five out 7 JAG1 variants are new. Different bioassays demonstrate that the identified variants exhibit a variable loss of function. In zebrafish, the knock-down of jag1a/b expression causes a primary thyroid defect, and rescue experiments of the hypothyroid phenotype with wild-type or variant JAG1 transcripts support a role for JAG1 variations in the pathogenesis of the hypothyroid phenotype seen in CH and ALGS1 patients. CONCLUSIONS: clinical and experimental data indicate that ALGS1 patients have an increased risk of nonautoimmune hypothyroidism, and that variations in JAG1 gene can contribute to the pathogenesis of variable congenital thyroid defects, including CH. PMID- 26760176 TI - HMGB1 Is Increased by CFTR Loss of Function, Is Lowered by Insulin, and Increases In Vivo at Onset of CFRD. AB - CONTEXT: Cystic fibrosis-related diabetes (CFRD) is associated with worsening of inflammation and infections, and the beginning of insulin treatment is debated. OBJECTIVES: To verify high-mobility group box 1 protein (HMGB1) levels in CF patients according to glucose tolerance state, and analyze relationships with insulin secretion and resistance. To verify, in an in vitro model, whether HMGB1 gene expression and protein content were affected by insulin administration and whether these changes were dependent on CF transmembrane conductance regulator (CFTR) loss of function. PATIENTS AND METHODS: Forty-three patients in stable clinical conditions and 35 age- and sex-matched controls were enrolled. Glucose tolerance was established in patients based on a 5 point oral glucose tolerance test (OGTT). Fasting glucose to insulin ratio (FGIR), HOMA-IR index, whole-body insulin sensitivity index (WIBISI), and the areas under the curve for glucose (AUCG) and insulin (AUCI) were calculated. HMGB1 was assayed in serum, in cell lysates and conditioned media using a specific ELISA kit. For the in vitro study we used CFBE41o- cells, homozygous for the F508del mutation, and 16HBE14o- as non CF control. HMGB1 gene expression was studied by real-time RT-PCR. Cells were stimulated with insulin at 2.5 and 5 ng/mL. The CFTR inhibitor 172 and CFTR gene silencing were used to induce CFTR loss of function in 16HBE14o- cells. RESULTS: HMGB1 levels were increased at onset of CFRD (5.04 +/- 1.2 vs 2.7 +/- 0.3 ng/mL in controls; P < .05) and correlated with FGIR (R = +0.43; P = .038), and AUCI (R = +0.43; P = .013). CFTR loss of function in the 16HBE14o- cells increased HMGB1 and was lowered by insulin. CONCLUSION: HMGB1 was increased in CF patients with deranging glucose metabolism and showed relationships with indexes of glucose metabolism. The increase in HMGB1 was related to CFTR loss of function, and insulin lowered HMGB1. Further research is required to verify whether HMGB1 could potentially be a candidate marker of onset of CFRD and to establish when to start insulin treatment. PMID- 26760177 TI - Diabetes, Diabetes Treatment, and Risk of Thyroid Cancer. AB - OBJECTIVE: The objective of this study was to assess the relationships among diabetes, diabetes treatment and thyroid cancer risk using a large prospective cohort, the Women's Health Initiative. METHODS: A total of 147 934 women who were free of known cancer at baseline were followed prospectively. Diabetes status and diabetes treatment at baseline and during follow-up were ascertained. Incident cases of thyroid cancers were confirmed by physician review of central medical records and pathology reports. Time-dependent Cox proportional hazards regressions were used to estimate hazard ratios and 95% confidence intervals for thyroid cancer risk associated with diabetes status, diabetes treatment, and duration of diabetes. RESULTS: With a median follow-up time of 15.9 years, 391 incident thyroid cancers were identified. We found no significant associations between thyroid cancer and diabetes (hazard ratio = 1.09; 95% confidence interval, 0.79-1.52), diabetes treatment, or duration of diabetes. CONCLUSION: Our findings do not support the hypothesis that diabetes, or treatment of diabetes is associated with risk of thyroid cancer among postmenopausal women. Studies to investigate the specific effects of hyperinsulinemia and insulin resistance on thyroid cancer risk may provide additional information. PMID- 26760178 TI - HIV/Sexually Transmitted Infection Prevention Messaging: Targeting Root Causes of Sexual Risk Behavior. AB - INTRODUCTION: Sexual risk behaviors (SRBs) often lead to sexually transmitted infections (STI), yet little is known about what drives SRB and whether this differs by sex. METHOD: Participants (n = 920; 75% white) were drawn from the Raising Healthy Children study, enrolled in 1993 and 1994 in grades 1 to 2, and followed up through age 24/25 years. Lifetime STI diagnosis was defined by self report or seropositivity for Chlamydia trachomatis or herpes simplex virus 2. Multivariable models assessed individual (social skills, behavioral disinhibition) and environmental factors (family involvement, school bonding, antisocial friends) predictive of STI diagnosis as mediated by 3 proximal SRB (sex under the influence of drugs or alcohol, condom use, lifetime number of sex partners). RESULTS: Twenty-five percent of participants had ever had an STI. All SRBs differed by sex (P < 0.001), and female participants were more likely to have had an STI (P < 0.001). Behavioral disinhibition and antisocial friends in adolescence were associated with more SRB for both sexes, whereas social skills were associated with less SRB in female but more in male participants. Considering SRB and individual and environmental factors together, lifetime number of sex partners (adjusted relative risk [ARR], 1.04per partner; 95% confidence interval [CI], 1.03-1.05) and inconsistent condom use (ARR, 1.10per year; 95% CI, 1.04-1.16) were associated with increased risk of STI, whereas social skills were associated with decreased risk of STI (ARR, 0.84; 95% CI, 0.75 0.93). Behavioral disinhibition seemed to drive SRB, but family involvement mitigated this in several cases. CONCLUSIONS: Adolescent environmental influences and individual characteristics drive some SRB and may be more effective targets for STI/HIV prevention interventions than proximal risk behaviors. PMID- 26760180 TI - A Retrospective Review of Treatment Failures Using Azithromycin and Doxycycline in the Treatment of Rectal Chlamydia Infections in Women and Men Who Have Sex With Men. AB - We examined the prevalence of rectal chlamydia treatment failures in men who have sex with men and women attending Alberta sexually transmitted infection clinics. Among those completing a test of cure, there was no significant difference among patients treated initially with azithromycin (treatment failure, 39/460 [8.5%]; 95% confidence interval, 5.9%-11.0%) compared with patients treated with doxycycline (0/16; 95% confidence interval, 0%-0.2%; P = 0.63). PMID- 26760179 TI - Condom Breakage Among Young Black Men Who Have Sex With Men: An In-Depth Investigation Including Men Living With HIV/AIDS. AB - Correlates of condom breakage (reported by 19% of 398 young black who have sex with men) for anal insertive sex included the following: condoms drying out (P = 0.018), erection loss during application (P = 0.03), and using erection-enhancing drugs (P = 0.003). Breakage was 2.7 times greater for HIV-positive men (P = 0.001). Breakage was associated with testing positive for urethral infections (P = 0.012). PMID- 26760181 TI - Risk Factors for Incident and Redetected Chlamydia trachomatis Infection in Women: Results of a Population-Based Cohort Study. AB - OBJECTIVES: To investigate risk factors for incident and redetected Chlamydia trachomatis (CT) infection in women, including the role of high-risk human papillomavirus (HPV). METHODS: In this population-based, prospective cohort study conducted in Copenhagen, Denmark, 10,729 women aged 20 to 29 years were tested for CT and HPV DNA and provided information on sexual and health behavior at baseline. Of these, 7998 (74.5%) participated in a follow-up visit 2 years later with identical data collection. We used logistic regression to investigate risk factors for incident and redetected CT infection at follow-up. RESULTS: Among CT DNA negative women at baseline (n = 7529), 106 (1.4%) were CT DNA positive at follow-up (incident infection). Increasing number of sexual partners during follow-up (odds ratio [OR], 1.07 per partner; 95% confidence interval (CI), 1.02 1.11), low educational level (OR, 1.69; 95% CI, 1.11-2.56; for basic education vs. high school or higher), and high-risk HPV positivity at baseline (OR, 1.66; 95% CI, 1.06-2.58) were risk factors for incident infection, whereas older age (OR, 0.86 per year increase; 95% CI, 0.80-0.93) and condom use (OR, 0.60; 95% CI, 0.38-0.94) were associated with reduced risk. Among CT DNA positive women at baseline (n = 469), 108 (23.0%) tested positive at follow-up (redetected infection). We found no statistically significant associations between age, educational level, sexual behavior, smoking, or high-risk HPV status and the risk for redetected CT. CONCLUSION: Young age, low educational level, high number of sexual partners, failure to use condoms, and high-risk HPV positivity are associated with increased risk for incident CT infection. These findings may guide the development of targeted CT prevention strategies, including screening and information campaigns. PMID- 26760182 TI - Gonococcal Conjunctivitis Despite Successful Treatment of Male Urethritis Syndrome. AB - We report a case of progressive, cephalosporin-susceptible, Neisseria gonorrhoeae conjunctivitis despite successful treatment of male urethritis syndrome. We hypothesize that conjunctival infection progressed due to insufficient penetration of cefixime and azithromycin and point out that extragenital infection and male urethritis may not be cured simultaneously in settings where the syndromic approach is used. PMID- 26760183 TI - Ease, Comfort, and Performance of the HerSwab Vaginal Self-Sampling Device for the Detection of Chlamydia trachomatis and Neisseria gonorrhoeae. AB - BACKGROUND: Many sexually transmitted diseases are asymptomatic in the lower genital tract and can cause upper tract complications if left untreated. Self collected vaginal (SCV) swabs enable the accurate detection of many sexually transmitted infections and give women the option of collecting their own samples while providing them with privacy and convenience. METHODS: We compared SCV samples collected and transported dry using the HerSwab device to physician collected vaginal (PCV) Aptima swabs for the detection of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG), and measured patients' ease and comfort with self-collection. A total of 189 women aged 16 to 41 years were consented into the study and answered a standardized anonymized questionnaire regarding self collection with the HerSwab device. RESULTS: Women reported self-collection with HerSwab to be easy (97.1%) and comfortable (88.3%). They preferred self collection over physician collection (80.9%) and would consider using HerSwab for self-collection at home (79.7%). Samples of SCV and PCV showed an overall agreement of 94.7% (kappa = 0.64) for CT and of 98.4% (kappa = 0.56) for NG, and HerSwab collection detected 7 more positive patients than PCV collection. The overall prevalence of infection was 10.6% for CT and 2.6% for NG. CONCLUSION: HerSwab SCV samples are suitable for the diagnosis of CT and NG. PMID- 26760184 TI - Verifying Treatment of Reported Cases of Gonorrhea. AB - BACKGROUND: Verifying correct treatment of reported cases of gonorrhea may slow antibiotic resistance, but verification remains challenging for many sexually transmitted disease (STD) programs due to increased laboratory case reporting and decreased provider reporting. The objectives of this study were to document current reported levels of correct treatment of gonorrhea and to identify approaches and barriers to verifying treatment. METHODS: We reviewed funding opportunity reports for the Centers for Disease Control and Prevention's directly funded STD programs and conducted key-informant interviews to elicit further treatment verification details. RESULTS: Among STD programs containing at least one high-morbidity area, a median of 63.0% of gonorrhea cases were reported as treated correctly with a Centers for Disease Control and Prevention-recommended regimen, although the range reported was wide (11.2%-95.2%). Among cases with some type of documented treatment information, the proportion treated correctly was higher (median, 82.2%) but the use of correct treatment was quite variable among STD programs (range, 56.4%-98.5%). Approaches to verifying gonorrhea treatment included modifying outdated surveillance systems and educating providers about case reporting to enhance the passive capture of treatment information as well as active approaches that supported routine and immediate communication with providers regarding cases missing treatment information. Barriers to treatment verification included low levels of provider reporting, outdated surveillance systems, and human and financial resource constraints. CONCLUSIONS: Baseline assessments revealed that levels of correct gonorrhea treatment vary widely, even after accounting for those cases missing treatment information. Baseline data can help determine whether the active verification of treatment of all cases is warranted. PMID- 26760185 TI - Differentiating Transition Zone Cancers From Benign Prostatic Hyperplasia by Quantitative Multiparametric Magnetic Resonance Imaging. AB - OBJECTIVE: The aim of this study was to evaluate the value of quantitative diffusion and perfusion parameters to aid in discriminating between transition zone carcinomas and benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Twenty-four transition zone cancers and BPH nodules were contoured on T2-weighted magnetic resonance imaging (MRI), apparent diffusion coefficient (ADC) maps, and raw dynamic contrast-enhanced (DCE) MRI. Benign prostatic hyperplasia nodules were then stratified into 2 groups based on the presence or absence of a capsule. Apparent diffusion coefficient values, per-voxel Ktrans, kep, vp, and ve were all compared across all groups. RESULTS: Average ADCs (*10 mm/s) were 1019.22, 1338.11, and 1272.46 for cancer, encapsulated BPH, and nonencapsulated BPH, respectively. Both subgroups of BPH were found to be significantly different than that of cancer (P < 0.05). No individual DCE-MRI parameter was significantly different between cancer and either BPH group. The area under the curve for ADC alone was 0.83, and no individual DCE imaging parameter improved the area under the curve of ADC. CONCLUSIONS: Apparent diffusion coefficient may play a role in distinguishing TZ cancers from non-encapsulated BPH nodules that closely resemble cancer. PMID- 26760186 TI - Maximizing Information From Routine Staging Computed Tomography in Functional Neuroendocrine Neoplasms: Are There Findings Indicating the Presence of Carcinoid Heart Disease? AB - PURPOSE: The aim of this study was to evaluate signs of right-sided heart dysfunction on staging computed tomography (CT) as indirect indicators of carcinoid heart disease. PATIENTS AND METHODS: Patients with functionally active neuroendocrine neoplasm and different grades of tricuspid valve regurgitation (TR) were identified. Two readers independently reviewed contrast-enhanced staging CT performed within 90 days before or after echocardiography. Logistic regression and receiver operating analyses were used to asses the predictive value of right ventricle-left ventricle ratio (RV-LV ratio), ventricular septal bowing, retrograde contrast filling of the hepatic veins during contrast injection, and time to aortal enhancement greater than 100 Hounsfield units during bolus tracking for TR. RESULTS: Forty-four examinations were evaluated (11 with TR = 0, 16 with TR = 1, 9 with TR = 2, and 8 with TR = 3). Right ventricle LV ratio was found to predict TR less than or equal to 1 versus TR greater than 1 (P = 0.0188) and TR less than or equal to 1 versus TR equals 2 (P = 0.0082). A prolonged time to aortal enhancement greater than 100 Hounsfield units during bolus tracking predicted TR less than or equal to 1 versus TR greater than 1 (P = 0.0077). Area under the curve for RV-LV ratio was 0.86 when differentiating TR less than or equal to 1 versus TR equals 2. With a cutoff of 1.07, sensitivity was 0.89, and specificity was 0.72. CONCLUSIONS: In patients with functionally active neuroendocrine neoplasm, an RV-LV ratio of more than 1.07 predicted TR with a relatively high sensitivity and moderate specificity and thus could serve as an indicator of subclinical carcinoid heart disease on routine staging CT. PMID- 26760187 TI - Dual-Energy Computed Tomography Gemstone Spectral Imaging: A Novel Technique to Determine Human Cardiac Calculus Composition. AB - OBJECTIVE: Understanding the chemical composition of any calculus in different human organs is essential for choosing the best treatment strategy for patients. The purpose of this study was to assess the capability of determining the chemical composition of a human cardiac calculus using gemstone spectral imaging (GSI) mode on a single-source dual-energy computed tomography (DECT) in vitro. METHODS: The cardiac calculus was directly scanned on the Discovery CT750 HD FREEdom Edition using GSI mode, in vitro. A portable fiber-optic Raman spectroscopy was also applied to verify the quantitative accuracy of the DECT measurements. RESULTS: The results of spectral DECT measurements indicate that effective Z values in 3 designated positions located in this calculus were 15.02 to 15.47, which are close to values of 15.74 to 15.86, corresponding to the effective Z values of calcium apatite and hydroxyapatite. The Raman spectral data were also reflected by the predominant Raman peak at 960 cm for hydroxyapatite and the minor peak at 875 cm for calcium apatite. CONCLUSIONS: A potential single source DECT with GSI mode was first used to examine the morphological characteristics and chemical compositions of a giant human cardiac calculus, in vitro. The CT results were consistent with the Raman spectral data, suggesting that spectral CT imaging techniques could be accurately used to diagnose and characterize the compositional materials in the cardiac calculus. PMID- 26760188 TI - Pure Iterative Reconstruction Improves Image Quality in Computed Tomography of the Abdomen and Pelvis Acquired at Substantially Reduced Radiation Doses in Patients With Active Crohn Disease. AB - We assessed diagnostic accuracy and image quality of modified protocol (MP) computed tomography (CT) of the abdomen and pelvis reconstructed using pure iterative reconstruction (IR) in patients with Crohn disease (CD). METHODS: Thirty-four consecutive patients with CD were referred with suspected extramural complications. Two contemporaneous CT datasets were acquired in all patients: standard protocol (SP) and MP. The MP and SP protocols were designed to impart radiation exposures of 10% to 20% and 80% to 90% of routine abdominopelvic CT, respectively. The MP images were reconstructed with model-based IR (MBIR) and adaptive statistical IR (ASIR). RESULTS: The MP-CT and SP-CT dose length product were 88 (58) mGy.cm (1.27 [0.87] mSv) and 303 [204] mGy.cm (4.8 [2.99] mSv), respectively (P < 0.001). Median diagnostic acceptability, spatial resolution, and contrast resolution were significantly higher and subjective noise scores were significantly lower on SP-ASIR 40 compared with all MP datasets. There was perfect clinical agreement between MP-MBIR and SP-ASIR 40 images for detection of extramural complications. CONCLUSIONS: Modified protocol CT using pure IR is feasible for assessment of active CD. PMID- 26760189 TI - Improving Image Quality for Lung Cancer Imaging With Optimal Monochromatic Energy Level in Dual Energy Spectral Computed Tomography. AB - OBJECTIVE: The aim of this study was to find optimal monochromatic spectral computed tomography (CT) level to improve image quality of lung cancer. METHODS: Fifty patients with lung cancers were scanned by spectral CT; monochromatic images at 50, 60, 70 and 80 keV energy levels were generated; and objective analysis including image noise, lesion-to-lung contrast-to-noise ratio, and CT number difference between central and peripheral regions of tumor (dCT value) were measured and compared. Subjective assessment about the overall image quality and inhomogeneity enhancement was compared. RESULTS: The highest contrast-to noise ratio value and subjective score of image quality were obtained at 70 keV, which were superior to those of 50- and 80-keV series (all P < 0.05). The subjective score of the inhomogeneity evaluation was peaked at 60-keV series and significantly higher than other energy levels (all P < 0.05). CONCLUSIONS: Both objective and subjective image analysis of lung cancers may be improved with the combined observation of 60 keV and 70 keV monochromatic images in spectral CT. PMID- 26760190 TI - Improved Image Quality and Decreased Radiation Dose of Lower Extremity Computed Tomography Angiography Using Low-Tube-Voltage and Adaptive Iterative Reconstruction. AB - OBJECTIVE: The aim of the study was to investigate the feasibility of low-tube voltage computed tomography (CT) in combination with 3-dimensional adaptive iterative dose reduction (AIDR-3D) algorithm in lower extremity CT angiography. METHODS: The CT data of the 120-kV group (n = 30) were reconstructed with filtered back projection (FBP) algorithm. The CT data of the 100-kV group (n = 30) were reconstructed with FBP as well as AIDR-3D algorithms. RESULTS: The 100 kV group showed significantly lower dose-length product than the 120-kV group (P < 0.05). In comparison with the 120-kV and FBP protocol, the 100-kV and FBP protocol showed significantly increased vascular density and noise (P < 0.05). However, in the 100-kV group, images reconstructed with AIDR-3D showed significantly lower noise and significantly higher signal-to-noise ratio and contrast-to-noise ratio than FBP (P < 0.05). CONCLUSIONS: Low-tube-voltage (100 kV) 320-row CT in combination with AIDR-3D reconstruction can significantly improve the image quality and reduce radiation dose of lower extremity CT angiography. PMID- 26760191 TI - Assessment of Blood Oxygen Level-Dependent Magnetic Resonance Imaging for Differentiating Renal Dysfunction From Control Group: Comparing T2* Histogram With Conventional Method. AB - OBJECTIVE: The aim of the study was to investigate the potential of T2* histogram (HIST) in the analysis of blood oxygen level-dependent magnetic resonance imaging for differentiating a renal dysfunction group from a control group. METHODS: This study consisted of 13 control subjects and 20 patients with renal dysfunction. T2* maps were analyzed using both HIST and the conventional method. For the HIST, each region of interest covering renal parenchyma was applied to T2* map to generate a T2* HIST. The T2* HISTs were classified into type 1, 2, 3, and 4 on the basis of their morphologies. In each T2* HIST, the parameters were acquired from the peak with the smallest mean T2* values, which acted as the medullary T2* values, and from the peak with largest mean T2* values, which acted as the cortical T2* values. For the conventional method, small regions of interest were placed in the cortex and medulla for the quantitative analysis of the cortical and medullary T2* values, respectively. RESULTS: The type distribution of the T2* HISTs was significantly different between the 2 groups (control group: type 1, 0; 2, 4; 3, 5; and 4, 17 vs renal dysfunction group: type 1, 4; 2, 1; 3, 33; and 4, 2; P < 0.05). The medullary T2* values measured using both methods were significantly higher in the renal dysfunction group than that in the control group (29.38 [6.44] vs 22.79 [4.22] milliseconds for HIST, 30.61 [8.65] vs 21.37 [4.88] milliseconds for conventional method; P < 0.05). The area under the receiver operating characteristic curve for the medullary T2* measured using HIST was not greater than that using the conventional method (0.89 vs 0.82, P > 0.05). CONCLUSIONS: Histogram can automatically characterize the T2* map of renal parenchyma, thereby reducing the tediousness of placing ROIs and making it comparable with the conventional method in its ability to distinguish the renal dysfunction group from the control group. PMID- 26760192 TI - Is There a Relationship Between Paratracheal Air Cysts and Upper Lobe Fibrosis? AB - OBJECTIVE: The purpose of this study was to determine the characteristics of paratracheal air cysts (PACs) and their relationship with upper lobe pulmonary fibrosis. MATERIALS AND METHODS: The routine thoracic computed tomography scans of 3549 patients carried out between January 2014 and April 2015 were retrospectively evaluated. The presence, location, structural characteristics (uniloculated or multiloculated), number of cysts, and anterior-posterior and transverse dimensions of the PAC and its communication with the tracheal lumen were evaluated. The presence of upper lobe fibrosis, emphysema, and bronchiectasis was also evaluated. The relationship between upper lobe fibrosis, emphysema, bronchiectasis, and the presence of paratracheal cysts was evaluated in all patients. An equal number of randomized patients with no paratracheal cysts were selected as a control group. RESULTS: A total of 190 PAC cases were diagnosed, with a prevalence rate of 5.35%: 146 (76.8%) of the cases were men, 44 (23.2%) were female, and the mean (SD) age was 53.79 (16.64) years (range, 12-89 years). The control group included 105 men (57.4%) and 78 women (42.6%), and the mean (SD) age was 53.87 (16.65) years (range, 13-87 years). The groups were similar in terms of age (P = 0.876), whereas the proportion of men in the PAC group was significantly higher (P < 0.001). Most of the PACs were located on the right side (n = 188, 98.9%). The incidence of fibrosis in the paratracheal cyst group was 45.8% (n = 87) compared with 19.5% (n = 37) in the control group; this difference was statistically significant (P < 0.001). The prevalence rates of emphysema in the cyst group and the control group were 29.5% (n = 56) and 11.6% (n = 22), respectively, and the difference was statistically significant (P < 0.001). When the groups were compared regarding bronchiectasis (scar and non-scar related), the rate of bronchiectasis in the paratracheal cyst group was 17.9% (n = 34), compared with 3.7% (n = 7) in the control group; this difference was statistically significant (P < 0.001). CONCLUSIONS: Paratracheal air cysts are relatively common, but the etiology is still unclear. We detected increased rates of cyst formation that may result from the traction effect on the tracheal wall in the presence of upper lobe fibrosis. PMID- 26760193 TI - Correlation Between Computed Tomography Density and Functional Status of the Thyroid Gland. AB - OBJECTIVE: This study aimed to determine the correlation between thyroid computed tomography (CT) density and thyroid functional status. METHODS: Thyroid CT densities were determined in patients who had a noncontrast CT of the cervical spine and a recent thyroid-stimulating hormone (TSH) measurement in a cohort of 157 patients. Thyroid CT densities of patients with abnormally low TSH and high TSH were compared to those with normal TSH. A correlation analysis was performed to determine the correlation between TSH levels and CT densities. RESULTS: Both low and high TSH groups demonstrated significantly decreased thyroid CT densities (P < 0.0001). There was significant positive correlation between thyroid CT densities and TSH levels (r = 0.40; P < 0.0001) for subjects with a TSH level of less than 3.0 MUIU/mL and a significant negative correlation (r = -0.66; P < 0.0001) for those with a TSH level of greater than or equal to 3.0 MUIU/mL. CONCLUSIONS: There is a significant correlation between thyroid CT density and serum TSH levels. A low thyroid CT density indicates abnormal thyroid function. PMID- 26760194 TI - Histogram-Based Discrimination of Intravenous Contrast in Abdominopelvic Computed Tomography. AB - OBJECTIVE: The aim of this study was to evaluate the accuracy of fully automated machine learning methods for detecting intravenous contrast in computed tomography (CT) studies of the abdomen and pelvis. METHODS: A set of 591 labeled CT image volumes of the abdomen and pelvis was obtained from 5 different CT scanners, of which 434 (73%) were performed with intravenous contrast. A stratified split of this set was performed into training and test sets of 443 and 148 studies, respectively. Subsequently, support vector machine and logistic regression classifiers were trained using 5-fold cross-validation for parameter optimization. RESULTS: The best in-sample performance was seen with a support vector machine classifier with a chi kernel (98.9% accuracy); however, test set performance was similar across the trained classifiers, with 95% to 97% accuracy. CONCLUSIONS: Histogram-based automated classifiers for the presence of intravenous contrast are accurate and may be useful for verifying the accurate labeling of the presence of intravenous contrast in CT body studies. PMID- 26760195 TI - Investigation of Multisequence Magnetic Resonance Imaging for Detection of Recurrent Tumor After Transurethral Resection for Bladder Cancer. AB - PURPOSE: The aim of this study was to evaluate multisequence magnetic resonance imaging (MRI) in detecting local recurrence after transurethral resection for bladder cancer. METHODS: Thirty-six patients with bladder cancer with previous transurethral resection underwent bladder MRI incorporating T2-weighted imaging, diffusion-weighted imaging, and delayed contrast-enhanced T1-weighted imaging, followed by cystoscopy. Two radiologists (R1 and R2) evaluated examinations for suspicious findings. RESULTS: Forty-seven percent of patients had recurrent tumor at cystoscopy and biopsy. Using multisequence MRI, sensitivity and specificity were 67% and 81% for R1 and 73% and 62% for R2. Both readers missed 1 high-grade pathologic stage T1 recurrent tumor; otherwise, all missed tumors were low-grade pathologic stage Ta lesions. All false positives for R1 and 7 of 9 false positives for R2 were in patients receiving previous bacillus Calmette-Guerin therapy. Furthermore, 40% to 50% of solitary abnormalities and 83% to 100% of multifocal abnormalities were tumor recurrences; 12% to 20% of smooth wall thickening, 50% to 75% of irregular wall thickening, and 88% to 100% of papillary masses were tumor recurrences. CONCLUSIONS: Although multisequence MRI exhibited moderate performance for detecting recurrent tumor, nearly all missed tumors were low grade and noninvasive. PMID- 26760196 TI - Hydrogen sulfide prevents OGD/R-induced apoptosis by suppressing the phosphorylation of p38 and secretion of IL-6 in PC12 cells. AB - Hydrogen sulfide (H2S), a well-known endogenous mediator, has been shown to exert protective effects against neuronal damage caused by brain ischemia, but the mechanism of its action remains unclear. We have reported the neuroprotective properties of H2S against oxygen-glucose deprivation/reoxygenation (OGD/R) induced injury by inhibiting the phosphorylation of p38. The present study evaluates the effect of H2S on OGD/R-induced cell injury or apoptosis and the mechanisms for its action in PC12 cells. Pretreatment of PC12 cells with exogenous sodium hydrosulfide (NaHS) (a H2S donor, 100 or 300 uM) for 12 h before exposure to OGD/R markedly attenuated p38 phosphorylation. Activation of p38 MAPK by transfection of activated p38alpha, but not p38beta, reversed the protective effect of NaHS, as measured by enzyme-linked immunosorbent assay analysis. Importantly, SB203580 (a p38 MAPK inhibitor) also reversed the protective effects of p38alpha-activated p38 MAPK. Interleukin-6 secretion after OGD/R decreased significantly with NaHS compared with without NaHS. Taken together, we show that the p38 pathway contributes toward OGD/R-induced cell death and p38alpha plays a key role in OGD/R-induced interleukin-6 secretion. PMID- 26760198 TI - Bias in High-Throughput Analysis of miRNAs and Implications for Biomarker Studies. AB - A certain degree of bias in high-throughput molecular technologies including microarrays and next-generation sequencing (NGS) is known. To quantify the actual impact of the biomarker discovery platform on miRNA profiles, we first performed a meta-analysis: raw data of 1 539 microarrays and 705 NGS blood-borne miRNomes were statistically evaluated, suggesting a substantial influence of the technology on biomarker profiles. We observed highly significant dependency of the miRNA nucleotide composition on the expression level. Higher expression in NGS was discovered for uracil-rich miRNAs (p = 7 * 10(-37)), while high expression in microarrays was found predominantly for guanine-rich miRNAs (p = 3 * 10(-33)). To verify the findings, 10 identical replicates of one individual were measured using NGS and microarrays (2 525 miRNAs from miRBase version 21). Overall, we calculated a correlation coefficient of 0.414 for both technologies. Detailed analysis however revealed that the correlation was observed only for miRNAs in the early miRBase versions (<8). The majority of miRNAs (2 013 from miRBase version 8 onward) was not correlated between microarray and NGS. Specifically, we observed 67 miRNAs with a median read count above 10 in NGS, while they were not detected in any of the 10 replicated array experiments. In contrast, 234 miRNAs were discovered in all 10 replicated array measurements but were not found in any of the NGS experiments of the same individual. While the first group had average guanine content of 22%, the latter group consisted of 41% of this nucleotide. Selected concordant and discordant miRNAs were tested in quantitative real-time-polymerase chain reaction (RT-qPCR) experiments again of the same individual, providing further evidence for the substantial bias depending on the base composition. As a consequence, biomarkers that have been discovered by specific high-throughout technologies have to be carefully considered. Especially for validation of the platform, the selection of reasonable candidates is essential. PMID- 26760197 TI - Full validation of therapeutic antibody sequences by middle-up mass measurements and middle-down protein sequencing. AB - The regulatory bodies request full sequence data assessment both for innovator and biosimilar monoclonal antibodies (mAbs). Full sequence coverage is typically used to verify the integrity of the analytical data obtained following the combination of multiple LC-MS/MS datasets from orthogonal protease digests (so called "bottom-up" approaches). Top-down or middle-down mass spectrometric approaches have the potential to minimize artifacts, reduce overall analysis time and provide orthogonality to this traditional approach. In this work we report a new combined approach involving middle-up LC-QTOF and middle-down LC-MALDI in source decay (ISD) mass spectrometry. This was applied to cetuximab, panitumumab and natalizumab, selected as representative US Food and Drug Administration- and European Medicines Agency-approved mAbs. The goal was to unambiguously confirm their reference sequences and examine the general applicability of this approach. Furthermore, a new measure for assessing the integrity and validity of results from middle-down approaches is introduced - the "Sequence Validation Percentage." Full sequence data assessment of the 3 antibodies was achieved enabling all 3 sequences to be fully validated by a combination of middle-up molecular weight determination and middle-down protein sequencing. Three errors in the reference amino acid sequence of natalizumab, causing a cumulative mass shift of only -2 Da in the natalizumab Fd domain, were corrected as a result of this work. PMID- 26760199 TI - Development of Insertion Models Predicting Cochlear Implant Electrode Position. AB - OBJECTIVES: To assess the possibility to define a preferable range for electrode array insertion depth and surgical insertion distance for which frequency mismatch is minimalized. To develop a surgical insertion guidance tool by which a preferred target angle can be attained using preoperative available anatomical data and surgically controllable insertion distance. DESIGN: Multiplanar reconstructions of pre- and post-operative CT scans were evaluated in a population of 336 patients implanted with the CII HiFocus1 or HiFocus1J implant (26 bilaterally implantees included). Cochlear radial distances were measured on four measurement axes on the preoperative CT scan. Electrode contact positions were obtained in angular depth, distance from the round window and to the modiolus center. Frequency mismatch was calculated based on the yielded frequency as a function of the angular position per contact. Cochlear diameters were clustered into three cochlear size groups with K-sample clustering. Using spiral fitting and general linear regression modeling, the feasibility of different insertion models with cochlear size measures and surgical insertion as input parameters was analyzed. The final developed model was internally validated with bootstrapping to calculate the optimism-corrected R. RESULTS: Frequency mismatch was minimalized for surgical insertion of 6.7 mm and insertion depth of 484 degrees . Cochlear size clusters were derived consisting of a "small" (N = 117), "medium" (N = 171), and "large" (N = 74) cluster with mean insertion depths of 506 degrees , 480 degrees , and 441 degrees , respectively. The relation between surgical insertion (LE16) and insertion depth (thetaE1) differed significantly between the three clusters (p < 0.01). The insertion models based on spiral fitting showed an R of 62% with mean of the residuals of -0.5 mm (SD = 1.2 mm) between the measured and predicted LE16 and a mean of 15 degrees (SD = 83 degrees ) for thetaE1. Using general linear regression modeling resulted in a residual mean of -0.2 MUm (SD = 0.9 mm) for measured and predicted LE16 and 0.01 degrees (SD = 33 degrees ) for thetaE1. The model derived from general linear regression modeling resulted in an R of 78.7% and was validated with bootstrapping. An optimism of 0.6% was calculated using this analysis. The optimism-corrected R of 78.1% defined the estimated performance of the final insertion model in future populations. CONCLUSIONS: A minimal frequency mismatch for an electrode array design can be calculated to define preferable electrode array position within the cochlea. In general, to achieve a minimal frequency mismatch, the surgeon should attempt to insert the HiFocus 1 or 1J array around 6, 7, or 8 mm in case of a "small," "medium," or "large" cochlea, respectively. Development of different insertion models showed the feasibility of obtaining a surgical guidance tool to lead the surgeon during cochlear implantation depending on individual cochlear size and controllable surgical distance. The developed final insertion model predicted 78.1% of the variation in final HiFocus1 or HiFocus1J implant position. PMID- 26760200 TI - The Cost of Meniere's Disease: A Novel Multisource Approach. AB - OBJECTIVES: To estimate the annual cost of Meniere's disease and the cost per person in the UK population and to investigate the direct and indirect costs of the condition. DESIGN: The authors utilized a multidata approach to provide the first estimate of the cost of Meniere's. Data from the UK Biobank (a study of 500,000 individuals collected between 2007 and 2012), the Hospital Episode Statistics (data on all hospital admissions in England from 2008 to 2012) and the UK Meniere's Society (2014) were used to estimate the cost of Meniere's. Cases were self-reported in the UK Biobank and UK Meniere's Society, within the Hospital Episode Statistics cases were clinician diagnosed. The authors estimated the direct and indirect costs of the condition, using count data to represent numbers of individuals reporting specific treatments, operations etc. and basic statistical analyses (chi tests, linear and logistic regression) to compare cases and controls in the UK Biobank. RESULTS: Meniere's was estimated to cost between L541.30 million and L608.70 million annually (equivalent to US $829.9 to $934.2 million), equating to L3,341 to L3,757 ($5112 to $5748) per person per annum. The indirect costs were substantial, with loss of earnings contributing to over L400 million per annum. CONCLUSIONS: For the first time, the authors were able to estimate the economic burden of Meniere's disease. In the UK, the annual cost of this condition is substantial. Further research is required to develop cost effective treatments and management strategies for Meniere's to reduce the economic burden of the disease. These findings should be interpreted with caution due to the uncertainties inherent in the analysis. PMID- 26760201 TI - A phosphoinositide conversion mechanism for exit from endosomes. AB - Phosphoinositides are a minor class of short-lived membrane phospholipids that serve crucial functions in cell physiology ranging from cell signalling and motility to their role as signposts of compartmental membrane identity. Phosphoinositide 4-phosphates such as phosphatidylinositol 4-phosphate (PI(4)P) and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) are concentrated at the plasma membrane, on secretory organelles, and on lysosomes, whereas phosphoinositide 3-phosphates, most notably phosphatidylinositol 3-phosphate (PI(3)P), are a hallmark of the endosomal system. Directional membrane traffic between endosomal and secretory compartments, although inherently complex, therefore requires regulated phosphoinositide conversion. The molecular mechanism underlying this conversion of phosphoinositide identity during cargo exit from endosomes by exocytosis is unknown. Here we report that surface delivery of endosomal cargo requires hydrolysis of PI(3)P by the phosphatidylinositol 3 phosphatase MTM1, an enzyme whose loss of function leads to X-linked centronuclear myopathy (also called myotubular myopathy) in humans. Removal of endosomal PI(3)P by MTM1 is accompanied by phosphatidylinositol 4-kinase-2alpha (PI4K2alpha)-dependent generation of PI(4)P and recruitment of the exocyst tethering complex to enable membrane fusion. Our data establish a mechanism for phosphoinositide conversion from PI(3)P to PI(4)P at endosomes en route to the plasma membrane and suggest that defective phosphoinositide conversion at endosomes underlies X-linked centronuclear myopathy caused by mutation of MTM1 in humans. PMID- 26760202 TI - Super-resolution imaging reveals distinct chromatin folding for different epigenetic states. AB - Metazoan genomes are spatially organized at multiple scales, from packaging of DNA around individual nucleosomes to segregation of whole chromosomes into distinct territories. At the intermediate scale of kilobases to megabases, which encompasses the sizes of genes, gene clusters and regulatory domains, the three dimensional (3D) organization of DNA is implicated in multiple gene regulatory mechanisms, but understanding this organization remains a challenge. At this scale, the genome is partitioned into domains of different epigenetic states that are essential for regulating gene expression. Here we investigate the 3D organization of chromatin in different epigenetic states using super-resolution imaging. We classified genomic domains in Drosophila cells into transcriptionally active, inactive or Polycomb-repressed states, and observed distinct chromatin organizations for each state. All three types of chromatin domains exhibit power law scaling between their physical sizes in 3D and their domain lengths, but each type has a distinct scaling exponent. Polycomb-repressed domains show the densest packing and most intriguing chromatin folding behaviour, in which chromatin packing density increases with domain length. Distinct from the self-similar organization displayed by transcriptionally active and inactive chromatin, the Polycomb-repressed domains are characterized by a high degree of chromatin intermixing within the domain. Moreover, compared to inactive domains, Polycomb repressed domains spatially exclude neighbouring active chromatin to a much stronger degree. Computational modelling and knockdown experiments suggest that reversible chromatin interactions mediated by Polycomb-group proteins play an important role in these unique packaging properties of the repressed chromatin. Taken together, our super-resolution images reveal distinct chromatin packaging for different epigenetic states at the kilobase-to-megabase scale, a length scale that is directly relevant to genome regulation. PMID- 26760203 TI - Integrative modelling reveals mechanisms linking productivity and plant species richness. AB - How ecosystem productivity and species richness are interrelated is one of the most debated subjects in the history of ecology. Decades of intensive study have yet to discern the actual mechanisms behind observed global patterns. Here, by integrating the predictions from multiple theories into a single model and using data from 1,126 grassland plots spanning five continents, we detect the clear signals of numerous underlying mechanisms linking productivity and richness. We find that an integrative model has substantially higher explanatory power than traditional bivariate analyses. In addition, the specific results unveil several surprising findings that conflict with classical models. These include the isolation of a strong and consistent enhancement of productivity by richness, an effect in striking contrast with superficial data patterns. Also revealed is a consistent importance of competition across the full range of productivity values, in direct conflict with some (but not all) proposed models. The promotion of local richness by macroecological gradients in climatic favourability, generally seen as a competing hypothesis, is also found to be important in our analysis. The results demonstrate that an integrative modelling approach leads to a major advance in our ability to discern the underlying processes operating in ecological systems. PMID- 26760204 TI - Ecology: Biodiversity and productivity entwined. PMID- 26760205 TI - Neuroscience: A mechanism for myelin injury. PMID- 26760207 TI - Corrigendum: D14-SCF(D3)-dependent degradation of D53 regulates strigolactone signalling. PMID- 26760206 TI - Codon influence on protein expression in E. coli correlates with mRNA levels. AB - Degeneracy in the genetic code, which enables a single protein to be encoded by a multitude of synonymous gene sequences, has an important role in regulating protein expression, but substantial uncertainty exists concerning the details of this phenomenon. Here we analyse the sequence features influencing protein expression levels in 6,348 experiments using bacteriophage T7 polymerase to synthesize messenger RNA in Escherichia coli. Logistic regression yields a new codon-influence metric that correlates only weakly with genomic codon-usage frequency, but strongly with global physiological protein concentrations and also mRNA concentrations and lifetimes in vivo. Overall, the codon content influences protein expression more strongly than mRNA-folding parameters, although the latter dominate in the initial ~16 codons. Genes redesigned based on our analyses are transcribed with unaltered efficiency but translated with higher efficiency in vitro. The less efficiently translated native sequences show greatly reduced mRNA levels in vivo. Our results suggest that codon content modulates a kinetic competition between protein elongation and mRNA degradation that is a central feature of the physiology and also possibly the regulation of translation in E. coli. PMID- 26760208 TI - Motor neurons control locomotor circuit function retrogradely via gap junctions. AB - Motor neurons are the final stage of neural processing for the execution of motor behaviours. Traditionally, motor neurons have been viewed as the 'final common pathway', serving as passive recipients merely conveying to the muscles the final motor program generated by upstream interneuron circuits. Here we reveal an unforeseen role of motor neurons in controlling the locomotor circuit function via gap junctions in zebrafish. These gap junctions mediate a retrograde analogue propagation of voltage fluctuations from motor neurons to control the synaptic release and recruitment of the upstream V2a interneurons that drive locomotion. Selective inhibition of motor neurons during ongoing locomotion de-recruits V2a interneurons and strongly influences locomotor circuit function. Rather than acting as separate units, gap junctions unite motor neurons and V2a interneurons into functional ensembles endowed with a retrograde analogue computation essential for locomotor rhythm generation. These results show that motor neurons are not a passive recipient of motor commands but an integral component of the neural circuits responsible for motor behaviour. PMID- 26760210 TI - Erratum: Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation. PMID- 26760211 TI - Cell biology: Lipid code for membrane recycling. PMID- 26760209 TI - Exposed water ice on the nucleus of comet 67P/Churyumov-Gerasimenko. AB - Although water vapour is the main species observed in the coma of comet 67P/Churyumov-Gerasimenko and water is the major constituent of cometary nuclei, limited evidence for exposed water-ice regions on the surface of the nucleus has been found so far. The absence of large regions of exposed water ice seems a common finding on the surfaces of many of the comets observed so far. The nucleus of 67P/Churyumov-Gerasimenko appears to be fairly uniformly coated with dark, dehydrated, refractory and organic-rich material. Here we report the identification at infrared wavelengths of water ice on two debris falls in the Imhotep region of the nucleus. The ice has been exposed on the walls of elevated structures and at the base of the walls. A quantitative derivation of the abundance of ice in these regions indicates the presence of millimetre-sized pure water-ice grains, considerably larger than in all previous observations. Although micrometre-sized water-ice grains are the usual result of vapour recondensation in ice-free layers, the occurrence of millimetre-sized grains of pure ice as observed in the Imhotep debris falls is best explained by grain growth by vapour diffusion in ice-rich layers, or by sintering. As a consequence of these processes, the nucleus can develop an extended and complex coating in which the outer dehydrated crust is superimposed on layers enriched in water ice. The stratigraphy observed on 67P/Churyumov-Gerasimenko is therefore the result of evolutionary processes affecting the uppermost metres of the nucleus and does not necessarily require a global layering to have occurred at the time of the comet's formation. PMID- 26760214 TI - Organocatalyzed Asymmetric 1,6-Conjugate Addition of para-Quinone Methides with Dicyanoolefins. AB - A chiral thiourea catalyzed asymmetric 1,6-conjugate addition of para-quinone methides with dicyanoolefins has been developed. The reaction provided an efficient approach to the synthesis of chiral diarylmethine skeletons in good yields (up to 99% yield) with high diastereo- and enantioselectivity (>20:1 dr and up to 99.5:0.5 er), also on a gram scale. The preliminary mechanistic study showed that the remote stereocontrol was achieved through intermolecular hydrogen bond interaction between the chiral thiourea catalyst and the para-quinone methides directly for the first time. PMID- 26760215 TI - Mechanical Chameleon through Dynamic Real-Time Plasmonic Tuning. AB - The development of camouflage methods, often through a general resemblance to the background, has recently become a subject of intense research. However, an artificial, active camouflage that provides fast response to color change in the full-visible range for rapid background matching remains a daunting challenge. To this end, we report a method, based on the combination of bimetallic nanodot arrays and electrochemical bias, to allow for plasmonic modulation. Importantly, our approach permits real-time light manipulation readily matchable to the color setting in a given environment. We utilize this capability to fabricate a biomimetic mechanical chameleon and an active matrix display with dynamic color rendering covering almost the entire visible region. PMID- 26760212 TI - Proton-gated Ca(2+)-permeable TRP channels damage myelin in conditions mimicking ischaemia. AB - The myelin sheaths wrapped around axons by oligodendrocytes are crucial for brain function. In ischaemia myelin is damaged in a Ca(2+)-dependent manner, abolishing action potential propagation. This has been attributed to glutamate release activating Ca(2+)-permeable N-methyl-D-aspartate (NMDA) receptors. Surprisingly, we now show that NMDA does not raise the intracellular Ca(2+) concentration ([Ca(2+)]i) in mature oligodendrocytes and that, although ischaemia evokes a glutamate-triggered membrane current, this is generated by a rise of extracellular [K(+)] and decrease of membrane K(+) conductance. Nevertheless, ischaemia raises oligodendrocyte [Ca(2+)]i, [Mg(2+)]i and [H(+)]i, and buffering intracellular pH reduces the [Ca(2+)]i and [Mg(2+)]i increases, showing that these are evoked by the rise of [H(+)]i. The H(+)-gated [Ca(2+)]i elevation is mediated by channels with characteristics of TRPA1, being inhibited by ruthenium red, isopentenyl pyrophosphate, HC-030031, A967079 or TRPA1 knockout. TRPA1 block reduces myelin damage in ischaemia. These data suggest that TRPA1-containing ion channels could be a therapeutic target in white matter ischaemia. PMID- 26760216 TI - A Stable Pyrophosphoserine Analog for Incorporation into Peptides and Proteins. AB - Protein pyrophosphorylation is a covalent modification of proteins, mediated by the inositol pyrophosphate messengers. Although the inositol pyrophosphates have been linked to a range of cellular processes, the role of protein pyrophosphorylation remains minimally characterized in vivo. The inherent instability of the phosphoanhydride bond has hampered the development of useful bioanalytical techniques to interrogate this novel signaling mechanism. Here, we describe the preparation of a pyrophosphoserine analog containing a stable methylene-bisphosphonate group that is compatible with solid-phase peptide synthesis. The resulting peptides demonstrate enhanced stability in Eukaryotic cell lysates and mammalian plasma and display resistance toward chemical degradation, when compared to the corresponding pyrophosphopeptides. In addition, the peptides containing the stable pyrophosphoserine analog are highly compatible with common ligation methods, such as native chemical ligation, maleimide conjugation, and glutaraldehyde ligation. The bisphosphonate-containing peptides will, therefore, be well-suited for future pyrophosphoserine antibody generation and affinity capture of pyrophosphoprotein binding partners and provide a key entry point to study the regulatory role of protein pyrophosphorylation. PMID- 26760218 TI - Evaluation of the CO2 Poisoning Effect on a Highly Active Cathode SrSc(0.175)Nb(0.025)Co(0.8)O(3-delta) in the Oxygen Reduction Reaction. AB - A solid oxide fuel cell (SOFC) is a highly efficient device for converting chemical energy to electrical energy. In addition to the efforts to reduce the operating temperature of SOFCs to below 600 degrees C, research studies of the basic mechanism of CO2 poisoning on cathode materials are envisioned to improve the operation of dual-chamber SOFCs using ambient air. In this work, we comparatively studied the CO2 poisoning effect on two highly active perovskites SrSc(0.175)Nb(0.025)Co(0.8)O(3-delta) (SSNC) and Ba(0.5)Sr(0.5)Co(0.8)Fe(0.2)O(3 delta) (BSCF), using complementary characterization techniques, e.g., powder X ray diffraction (XRD), Fourier transform-infrared (FT-IR) spectroscopy, atomic force microscopy (AFM), scanning electron microscopy (SEM), CO2-temperature programmed desorption (CO2-TPD), and electrochemical impedance spectroscopy (EIS). The SSNC cathode shows better tolerance to CO2 as compared with BSCF, which is attributed to the absence of Ba, higher average metal-oxygen bond energy (ABE) of SSNC, and the higher acidity of Nb(5+) cations, whereas the oxygen vacancy concentration plays a less important role. PMID- 26760217 TI - Intramolecular C-H and C-F Bond Oxygenation Mediated by a Putative Terminal Oxo Species in Tetranuclear Iron Complexes. AB - Herein we report the intramolecular arene C-H and C-F bond oxygenation by tetranuclear iron complexes. Treatment of [LFe3(PhPz)3OFe][OTf]2 (1) or its fluorinated analog [LFe3(F2ArPz)3OFe][OTf]2 (5) with iodosobenzene results in the regioselective hydroxylation of a bridging pyrazolate ligand, converting a C-H or C-F bond into a C-O bond. The observed reactivity suggests the formation of terminal and reactive Fe-oxo intermediates. With the possibility of intramolecular electron transfer within clusters in 1 and 5, different reaction pathways (Fe(IV)-oxo vs Fe(III)-oxo) might be responsible for the observed arene hydroxylation. PMID- 26760219 TI - Photolysis of a Benzyne Precursor Studied by Time-Resolved FTIR Spectroscopy. AB - The 266 nm laser flash photolysis of phtaloyl peroxide (2) in liquid acetonitrile solution at room temperature has been investigated. Upon 266 nm laser irradiation, 2 is effectively photodecarboxylated leading to the formation of o benzyne (1) and two equivalents of CO2, yet a small fraction of photolyzed 2 follows a different pathway leading to 6-oxocyclohexa-2,4-dienylideneketene (3) and one equivalent of CO2. Compound 3 is kinetically reactive and reacts in the microsecond time scale following a first-order kinetic law. The presence of 1 in the photolysis experiment is confirmed by trapping experiments with methyl 1 methylpyrrole-2-carboxylate (6). The Diels-Alder reaction between 1 and 6 occurs under the selected experimental conditions on a time scale shorter than 100 ms. PMID- 26760220 TI - Crystal Structure of the PdAu24(SR)18(0) Superatom. AB - The single-crystal X-ray structure of Pd-doped Au25(SR)18 was solved. The crystal structure reveals that in PdAu24(SR)18, the Pd atom is localized only to the centroid of the Au25(SR)18 cluster. This single-crystal X-ray structure shows that PdAu24(SR)18(0) is well conceptualized with the superatom theory. The PdAu24(SR)18(0) charge state is isoelectronic with Au25(SR)18(+1) as determined by a first order Jahn-Teller effect of similar magnitude and by electrochemical comparison. The previously reported increased stability of PdAu24(SR)18 can be rationalized in terms of Pd-Au bonds that are shorter than the Au-Au bonds in Au25(SR)18. PMID- 26760221 TI - Root endophytic bacteria of a (137)Cs and Mn accumulator plant, Eleutherococcus sciadophylloides, increase (137)Cs and Mn desorption in the soil. AB - We found that root endophytes of (137)Cs accumulator plant produce siderophores, resulting in the desorption of (137)Cs from the contaminated soil collected at Fukushima, Japan. We selected an endemic Japanese deciduous tree, Eleutherococcus sciadophylloides (Franch. et Sav), that accumulates high concentrations of (137)Cs and Mn. Root endophytic bacteria were isolated from E. sciadophylloides and microbial siderophore production was evaluated via chrome azurol S (CAS) Fe and CAS Al assays. Of the 463 strains that we isolated, 107 (23.1%) produced the siderophores. Using eight strains that showed high siderophore production in our assays, we examined desorption of (137)Cs, Mn, Fe and Al by the bacterial culture filtrates from (137)Cs-contaminated soil after decomposing the soil organic matter using hydrogen peroxide. We found (137)Cs and Mn desorption concomitant with Al and Fe desorption, as well as a decrease of pH. We also detected succinic acid, a well-known siderophore, in the bacterial culture filtrates of our two root endophytic bacteria. Our results strongly suggest that the root endophytic bacteria of E. sciadophylloides produce the siderophores that enhance (137)Cs and Mn desorption in the rhizosphere, making the resulting (137)Cs and Mn ions easier for E. sciadophylloides to absorb from the rhizosphere. PMID- 26760222 TI - Hofmeister Ion-Induced Changes in Water Structure Correlate with Changes in Solvation of an Aggregated Protein Complex. AB - RecA is a naturally aggregating Escherichia coli protein that catalyzes the strand exchange reaction utilized in DNA repair. Previous studies have shown that the presence of salts influence RecA activity, aggregation, and stability and that salts stabilize RecA in an inverse-anionic Hofmeister series. Here we utilized attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy and circular dichroism (CD) to investigate how various Hofmeister salts alter the water structure and RecA solvation and aggregation. Spectroscopic studies performed in water and deuterium oxide suggest that salts alter water O (1)H and O-(2)H stretch and bend vibrations as well as protein amide I (or I') and amide II (or II') vibrations. Anions have a much larger influence on water vibrations than cations. Water studies also show increased water-water and/or water-ion interactions in the presence of strongly hydrated SO4(2-) salts and evidence for decreased interactions with weakly hydrated Cl(-) and ClO4(-) salts. Salt-water difference infrared spectra show that kosmotropic salts are more hydrated than chaotropic salts. Interestingly, this is the opposite trend to the changes in protein solvation. Infrared spectra of RecA show that vibrations associated with protein desolvation were observed in the presence of SO4(2-) salts. Conversely, vibrations associated with protein solvation were observed in the presence of Cl(-) and ClO4(-) salts. Difference infrared studies on the dehydration of model proteins aided in identifying changes in RecA-solvent interactions. This study provides evidence that salt-induced changes in water vibrations correlate to changes in protein solvent interactions and thermal stability. PMID- 26760223 TI - Enantioselective analysis of 4-hydroxycyclophosphamide in human plasma with application to a clinical pharmacokinetic study. AB - Cyclophosphamide (CY) is one of the most common immunosuppressive agents used in autologous hematopoietic stem cell transplantation. CY is a prodrug and is metabolized to active 4-hydroxycyclophosphamide (HCY). Many authors have suggested an association between enantioselectivity in CY metabolism and treatment efficacy and/or complications. This study describes the development and validation of an analytical method of HCY enantiomers in human plasma by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) that can be applied to pharmacokinetic studies, filling this gap in the literature. HCY enantiomers previously derivatized with phenylhydrazine were extracted from 200 MUL plasma aliquots spiked with antipyrine as internal standard and a mixture of hexane and dichloromethane (80:20, v/v) was used as the extraction solvent. The derivatized HCY enantiomers were resolved on a Chiracel((r)) OD-R column using water:acetonitrile:formic acid (55:45:0.2, v/v) as the mobile phase. No matrix effect was observed and the analysis of HCY enantiomers was linear for plasma concentrations of 5-5000ng of each enantiomer/mL plasma. The coefficients of variation and inaccuracy calculated in precision and accuracy assessments were less than 15%. HCY was stable in human plasma after three successive freeze/thaw cycles, during 3h at room temperature, and in the autosampler at 4 degrees C for 24h after processing, with deviation values less than 15%. The method was applied to evaluate the kinetic disposition of HCY in a patient with multiple sclerosis who was pretreated with intravenous racemic CY for stem cell transplantation. The clinical study showed enantioselectivity in the pharmacokinetics of HCY. PMID- 26760224 TI - A sensitive LC-MS/MS method to quantify methylergonovine in human plasma and its application to a pharmacokinetic study. AB - Methylergonovine (ME) is a semisynthetic ergot alkaloid that is used for the treatment and prophylaxis of postpartum hemorrhage. In recent years, methylergonovine has been effective in the control of refractory headaches and is likely to be employed as chemosensitizers for cancer. However, this alkaloid sometimes causes elevated blood pressure. Therefore, a sensitive and accurate method for the quantification of this drug in biological matrices is necessary. In this study, ME was extracted from 500MUL plasma samples by a liquid-liquid extraction under alkaline conditions and detected using positive multi-reaction monitoring mode (+MRM) mass spectrometry. The method was validated according to US FDA guidelines and covered a working range from 0.025 to 10ng/mL with a lower limit of quantification (LLOQ) of 0.025ng/mL. In conclusion, a rapid, sensitive, selective and accurate quantification by an LC-MS/MS method was developed and successfully applied to a clinical pharmacokinetics study in female volunteers after a single intramuscular injection or oral administration of a 0.2mg dose of ME maleate. It is suitable for both preclinical and clinical studies on ME. PMID- 26760225 TI - Water repellent/wetting characteristics of various bio-inspired morphologies and fluid drag reduction testing research. AB - It is well-known that the bio-inspired sharkskin covering the original pattern has the apparent drag reduction function in the turbulent flowing stations, which can be regarded as "sharkskin effect", and it has progressively been put application into the fluid engineering with obtaining great profits. In this paper, the anisotropic wetting phenomena on sharkskin are discovered, the contact angles and rolling angles on different orientations are not the same. In addition, the hydrodynamic experiments on different sharkskin surfaces are conducted, and the experimental results illustrate that the super-hydrophobic and drag-reducing properties on deformed biological surfaces are improved to some extent compared to the original morphology, which has important significance to expand its practical applications. PMID- 26760226 TI - Quantitative characterization and comparative study of feather melanosome internal morphology using surface analysis. AB - A successful feather development implies in a precise orchestration of cells in the follicle, which culminates in one of the most complex epidermal structures in nature. Melanocytes contribute to the final structure by delivering melanosomes to the barb and barbule cells. Disturbance to the tissue during the feather growth can damage the final structure. Here, melanosomes seen in an unusual outgrowth on the barb cortex of a flight feather are reported and compared to commonly observed melanosomes embedded in the cortex. Transmission Electron Microscopy in scanning-transmission mode (STEM) generated images coupled with secondary electron detection. The two classes of melanosomes were registered on images combining transmitted and secondary electron signals. Image processing allowed surface analyses of roughness and texture of the internal morphology of these organelles. Results showed that the two classes of melanosomes are significantly distinct internally, indicating that different physiological processes up to feather maturation could have occurred. Surface analysis methods are not regularly used in cell biology studies, but here it is shown that it has great potential for microscopic image analysis, which could add robust information to studies of cell biology events. PMID- 26760227 TI - Csp(3)-P versus Csp(2)-P Bond Formation: Catalyst-Controlled Highly Regioselective Tandem Reaction of Ene-Yne-Ketones with H-Phosphonates. AB - Under copper-catalyzed or base-promoted conditions, a wide range of ene-yne ketones react with H-phosphonates to afford various phosphorylated furans in good yields. A copper carbene generation or a Michael addition is proposed as the key step in the selective construction of the Csp(3)-P or Csp(2)-P bond, which is supported by carbene capture reactions and interval (31)P NMR experiments. Furthermore, this method features inexpensive metal catalysts, no usage of oxidant, and high atom economy, which make it attractive and practical. PMID- 26760213 TI - Divergent clonal selection dominates medulloblastoma at recurrence. AB - The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy. PMID- 26760229 TI - Assessing the treatment of acetaminophen-contaminated brewery wastewater by an anaerobic packed-bed reactor. AB - The treatment of high-strength organic brewery wastewater with added acetaminophen (AAP) by an anaerobic digester was investigated. An anaerobic packed-bed reactor (APBR) was operated as a continuous process with an organic loading rate of 1.5-g COD per litre per day and a hydraulic retention time of three days. The results of steady-state analysis showed that the greatest APBR performances for removing COD and TOC were as high as 98 and 93%, respectively, even though the anaerobic digestibility after adding the different AAP concentrations of 5, 10 and 15 mg L(-1) into brewery wastewater can affect the efficiency of organic matter removal. The average CH4 production decreased from 81 to 72% is counterbalanced by the increased CO2 production from 11 to 20% before and after the injection of AAP, respectively. The empirical kinetic models for substrate utilisation and CH4 production were used to predict that, under unfavourable conditions, the performance of the APBR treatment process is able to remove COD with an efficiency of only 6.8%. PMID- 26760228 TI - Lipid Exchange Envelope Penetration (LEEP) of Nanoparticles for Plant Engineering: A Universal Localization Mechanism. AB - Nanoparticles offer clear advantages for both passive and active penetration into biologically important membranes. However, the uptake and localization mechanism of nanoparticles within living plants, plant cells, and organelles has yet to be elucidated.1 Here, we examine the subcellular uptake and kinetic trapping of a wide range of nanoparticles for the first time, using the plant chloroplast as a model system, but validated in vivo in living plants. Confocal visible and near infrared fluorescent microscopy and single particle tracking of gold-cysteine AF405 (GNP-Cys-AF405), streptavidin-quantum dot (SA-QD), dextran and poly(acrylic acid) nanoceria, and various polymer-wrapped single-walled carbon nanotubes (SWCNTs), including lipid-PEG-SWCNT, chitosan-SWCNT and 30-base (dAdT) sequence of ssDNA (AT)15 wrapped SWCNTs (hereafter referred to as ss(AT)15-SWCNT), are used to demonstrate that particle size and the magnitude, but not the sign, of the zeta potential are key in determining whether a particle is spontaneously and kinetically trapped within the organelle, despite the negative zeta potential of the envelope. We develop a mathematical model of this lipid exchange envelope and penetration (LEEP) mechanism, which agrees well with observations of this size and zeta potential dependence. The theory predicts a critical particle size below which the mechanism fails at all zeta potentials, explaining why nanoparticles are critical for this process. LEEP constitutes a powerful particulate transport and localization mechanism for nanoparticles within the plant system. PMID- 26760231 TI - Isolation of an HIV-1 neutralizing peptide mimicking the CXCR4 and CCR5 surface from the heavy-chain complementary determining region 3 repertoire of a viremic controller. AB - OBJECTIVES: The recent identification of neutralizing antibodies able to prevent viral rebound reemphasized the interest in humoral immune responses to control HIV-1 infection. In this study, we characterized HIV-1-inhibiting sequences from heavy-chain complementary determining region 3 (HCDR3) repertoires of a viremic controller. DESIGN AND METHODS: IgM and IgG-derived HCDR3 repertoires of a viremic controller presenting plasma-neutralizing activity and characterized by over 20 years of infection with a stable CD4 T-cell count were displayed on filamentous phage to identify HCDR3 repertoire-derived peptides inhibiting HIV-1 entry. RESULTS: Screening of phage libraries against recombinant gp120 led to the identification of an HCDR3-derived peptide sequence (LRTV-1) displaying antiviral properties against both X4 and R5 viruses. The interaction of LRTV-1 with gp120 was enhanced upon CD4 binding and sequence comparison revealed homology between LRTV-1 and the second extracellular loop of C-X-C chemokine receptor type 4 (CXCR4) (11/23) and the N-terminus of C-C chemokine receptor type 5 (CCR5) (7/23). Alanine scanning experiments identified different clusters of residues critical for interaction with the viral envelope protein. CONCLUSIONS: LRTV-1 peptide is to date the smallest human HCDR3 repertoire-derived peptide identified by phage display inhibiting HIV entry of R5 and X4 viruses. This peptide recognizes a CD4-dependent gp120 epitope critical for coreceptor binding and mimics the surface of CXCR4 and CCR5. Our data emphasize the potential of human HCDR3 immune repertoires as sources of small biologically active peptides for HIV cure. PMID- 26760230 TI - Dimerization and DNA recognition rules of mithramycin and its analogues. AB - The antineoplastic and antibiotic natural product mithramycin (MTM) is used against cancer-related hypercalcemia and, experimentally, against Ewing sarcoma and lung cancers. MTM exerts its cytotoxic effect by binding DNA as a divalent metal ion (Me(2+))-coordinated dimer and disrupting the function of transcription factors. A precise molecular mechanism of action of MTM, needed to develop MTM analogues selective against desired transcription factors, is lacking. Although it is known that MTM binds G/C-rich DNA, the exact DNA recognition rules that would allow one to map MTM binding sites remain incompletely understood. Towards this goal, we quantitatively investigated dimerization of MTM and several of its analogues, MTM SDK (for Short side chain, DiKeto), MTM SA-Trp (for Short side chain and Acid), MTM SA-Ala, and a biosynthetic precursor premithramycin B (PreMTM B), and measured the binding affinities of these molecules to DNA oligomers of different sequences and structural forms at physiological salt concentrations. We show that MTM and its analogues form stable dimers even in the absence of DNA. All molecules, except for PreMTM B, can bind DNA with the following rank order of affinities (strong to weak): MTM=MTM SDK>MTM SA-Trp>MTM SA-Ala. An X(G/C)(G/C)X motif, where X is any base, is necessary and sufficient for MTM binding to DNA, without a strong dependence on DNA conformation. These recognition rules will aid in mapping MTM sites across different promoters towards development of MTM analogues as useful anticancer agents. PMID- 26760232 TI - Antiretroviral therapy induces a rapid increase in bone resorption that is positively associated with the magnitude of immune reconstitution in HIV infection. AB - OBJECTIVE: Antiretroviral therapy (ART) paradoxically intensifies bone loss in the setting of HIV infection. Although the extent of bone loss varies, it occurs with virtually all ART types, suggesting a common pathway that may be aligned with HIV disease reversal. Using an animal model of immunodeficiency we recently demonstrated that immune activation associated with CD4 T-cell reconstitution induces increased production of the osteoclastogenic cytokines RANKL and TNFalpha by immune cells, driving enhanced bone resorption and loss in bone mineral density. DESIGN: To confirm these findings in humans, we investigated the early kinetics of CD4 T-cell recovery in relation to biomarkers of bone turnover and osteoclastogenic regulators in a prospective 24-week cohort study. METHODS: Clinical data and blood sampling for HIV-RNA PCR, CD4 T-cell counts, bone turnover biomarkers, and osteoclastogenic regulators were obtained from ART-naive HIV-infected study participants initiating standard doses of lopinavir/ritonavir plus tenofovir disoproxil fumarate/emtricitabine at baseline and at weeks 2, 8, 12, and 24 post ART. RESULTS: C-terminal telopeptide of collagen (CTx) a sensitive biomarker of bone resorption rose by 200% above baseline at week 12, remaining elevated through week 24 (alpha<0.01), and was associated with significant increases in plasma levels of osteoclastogenic regulators [receptor activator of NF-kB ligand (RANKL), tumor necrosis factor alpha, (TNFalpha)]. Importantly, the magnitude of CD4 T-cell recovery correlated significantly with CTx (rs = 0.387, alpha=0.01). CONCLUSION: Our data suggest that ART-induced bone loss occurs early, is aligned with early events of immune reconstitution, and these immune changes provide a unifying mechanism to explain in part the skeletal decline common to all ART. PMID- 26760234 TI - Impact of patatin-like phospholipase domain-containing 3 gene polymorphism (rs738409) on severity of liver disease in HIV/hepatitis C virus-coinfected patients. AB - OBJECTIVE: To analyze the association between patatin-like phospholipase domain containing 3 gene (PNPLA3) rs738409 polymorphism and severity of liver disease in HIV/hepatitis C virus-coinfected patients. METHODS: We performed a cross sectional study of 215 patients who underwent a liver biopsy. PNPLA3 rs738409 polymorphism was genotyped using GoldenGate assay. The outcome variables were as follows: advanced fibrosis (F >=3 and FIB-4 >=3.25), rapid fibrosis progression (FPR >=0.10 fibrosis units/year), severe activity grade (A>=3), and steatosis (fatty hepatocytes >=10%). The genetic association analysis was carried out according to an additive genetic model through logistic regressions adjusted by the most significant covariables. RESULTS: Overall, 21.4% had F at least 3, 8.9% had FIB-4 at least 3.25, 11.4% had A at least 3, 60.6% had steatosis, and 32.5% had FPR at least 0.10. For each rs738409 G allele, we found an increased frequency of patients with advanced fibrosis (F at least 3) (0% CC, 18.5% CG, and 25.2% GG; P = 0.049) and FIB-4 at least 3.25 (0% CC, 3.8% CG, and 13.2% GG; P = 0.016). Furthermore, for each rs738409 G allele, the odds of having F at least 3 increased 2.15 times (95% confidence interval=1.07; 4.35; P = 0.029) and having FIB-4 at least 3.25 increased 8.77 times (95% of confidence interval = 1.11; 69.0; P = 0.039). Note that rs738409 G allele carriers tended to higher likelihood of having FPR at least 0.10, but statistical significance was not reached (P = 0.054). Finally, we did not find any association for A at least 3 and liver steatosis. CONCLUSION: PNPLA3 rs738409 polymorphism was associated with the severity of liver fibrosis in patients coinfected with HIV and hepatitis C virus, suggesting that this polymorphism might also play a significant role in the progression of hepatic fibrosis in this group of patients. PMID- 26760233 TI - Long-term impact of HIV wasting on physical function. AB - BACKGROUND: The long-term consequences of wasting among HIV-infected persons are not known. DESIGN: HIV-infected men surviving >=2 years based on Kaplan-Meier analysis after a clinical diagnosis or weight trajectory consistent with wasting and with available physical function assessment data [grip strength, gait speed, and quality of life (QoL)] were matched to HIV-infected and uninfected men without wasting. METHODS: Matching criteria at the functional assessment included age, calendar year, and CD4 T-cell count and plasma HIV-1 RNA (HIV-infected only). Multivariable linear regression analyses adjusted for age, cohort, race, hepatitis C status, and number of comorbid illnesses were used to assess the impact of wasting on subsequent physical function. RESULTS: Among 85 HIV-infected men surviving >=2 years after wasting, we evaluated physical function outcomes compared with 249 HIV-infected and 338 HIV-uninfected men with no historical wasting. In multivariable regression models, HIV-infected men with prior wasting had lower grip strength and poorer physical QoL than HIV-infected men with no wasting (P <= 0.03), and poorer physical QoL, but higher mental QoL than HIV uninfected men (P <= 0.05). When controlling for measures of immune suppression (nadir CD4 T-cell count/AIDS, the association between wasting and physical QoL was markedly attenuated, whereas there was minimal impact on the association between wasting and grip strength. CONCLUSIONS: HIV-infected wasting survivors had weaker grip strength compared with HIV-infected persons without wasting; immune suppression was associated only with physical QoL. HIV-infected survivors of wasting may represent a population of adults at increased risk for physical function decline. PMID- 26760235 TI - Placental transfer of anti-group B Streptococcus immunoglobulin G antibody subclasses from HIV-infected and uninfected women to their uninfected infants. AB - OBJECTIVES: Placental antibody transfer is impaired in the context of HIV infection, which may render HIV-exposed, uninfected infants vulnerable to group B Streptococcus (GBS) disease. The GBS antibody response predominately consists of immunoglobulin G2 (IgG2) antibody. Thus we determined whether concentration and placental transfer of anti-GBS antibody subclasses was altered in HIV-infected compared with HIV-uninfected mothers. DESIGN: A retrospective analysis of anti GBS antibody subclasses in 38 HIV-infected and 33 HIV-uninfected mothers and their uninfected infants. METHODS: Sera were analysed using a novel flow cytometric assay that quantified binding of IgG1, IgG2, IgG3 and IgG4 to serotype (ST)Ia, STIII and STV GBS bacteria. RESULTS: IgG2 binding to GBS STIa and V was lower in HIV-infected women compared with HIV-uninfected women. Moreover, IgG2 binding to GBS STIa was also lower in HIV-exposed, uninfected infants compared with unexposed infants. However, there were no statistically significant differences in the transplacental transfer ratio of IgG2 for any GBS serotype. The transplacental transfer of total IgG was reduced for GBS STIII and V and IgG1 subclass for STIII; placental transfer of all other subclasses was comparable in HIV-affected and HIV-unaffected pregnancies. CONCLUSION: Anti-GBS IgG2 placental transfer is not affected by HIV infection. This is important for functional antibody against the capsular polysaccharide of GBS and provides confidence that maternal GBS vaccination may result in functional activity in HIV-infected and uninfected women. PMID- 26760236 TI - Uncontrolled hepatitis delta virus infection after initial suppression on tenofovir in a HIV/HBV-coinfected patient. PMID- 26760237 TI - Favorable outcome of severe human herpes virus-6 encephalitis in an HIV-infected patient. PMID- 26760238 TI - Quantification of piroxicam and 5'-hydroxypiroxicam in human plasma and saliva using liquid chromatography-tandem mass spectrometry following oral administration. AB - Saliva sampling used to quantify piroxicam and 5'-hydroxypiroxicam is a noninvasive and painless method when compared to sequential blood sampling. For that, a rapid, selective and sensitive liquid chromatography-tandem mass spectrometric method for simultaneous determination of piroxicam and 5' hydroxypiroxicam in saliva and human plasma was developed and validated. Piroxicam and its major metabolite were separated using a LiChroCART 125-4 RP Select-B Sorbent C18 column using a mixture of methanol and 2% phosphoric acid (pH 2.7) (70:30, v/v) for the mobile phase with a flow injection of 1mL/min. The run time was 4min. Volunteers had saliva and blood sampled before, 1, 2, 3, 4, 5, 6, 8, 11, 24, 48 and 72h after taking a 20mg oral dose of piroxicam. The pharmacokinetic parameters of piroxicam in plasma samples were as follows: AUC0 72 (64819hng/mL), predicted clearance (0.2L/h), distribution volume (14.8L), elimination half-life (50.7h) and saliva/plasma concentration ratio (0.003). The estimation of all pharmacokinetic parameters for 5'-hydroxypiroxicam would require collections beyond 72h; however, it was possible to quantify the mean maximum concentration (133ng/mL), time to peak concentration (53.6h), mean AUC0 72 (6213hng/mL), predicted clearance (110.3L/h) and saliva/plasma concentration ratio (0.04). The developed methods proved effective and sensitive for determining the lower quantification limit of piroxicam in plasma (6.1ng/mL) and saliva (0.15ng/mL) and of 5'-hydroxypiroxicam in plasma (1.2ng/mL) and saliva (0.15ng/mL). PMID- 26760239 TI - Simultaneous enantioseparation and purity determination of chiral switches of amlodipine and atenolol by liquid chromatography. AB - A novel, selective and robust enantiospecific HPLC method was developed for simultaneous determination of amlodipine and atenolol enantiomers. Box-Behnken design was employed to identify the effect of factors (% ethanol, % diethylamine and flow rate) and their interactions on enantioresolution and analysis time. Chromatography was performed using mobile phase comprising acetonitrile, ethanol and DEA (92:8:0.2% v/v/v) delivered at a flow rate of 1.2mLmin(-1) on a Lux Cellulose-4 column. The enantiomers were monitored at a wavelength of 240nm and separation was achieved within 8min. The method was validated in terms of specificity, linearity, accuracy, precision, limit of detection and quantification. The method was found to be linear (R(2)>=0.991), accurate (99.8 101.4%) and precise (%RSD<=3%). Additionally, fractional factorial design was used to evaluate the robustness of the method and non-significant intervals for mixture related factors were established using contour profiling. Furthermore, the pertinence of this validated method was established by analyzing three different commercially available formulations. The obtained results confirmed that the proposed method can be extended for routine enantiopurity assay of amlodipine and atenolol in pharmaceutical formulations. PMID- 26760240 TI - HPLC-MS/MS method for the simultaneous determination of MB07133 and its metabolites, cytarabine and arabinofuranosyluracil, in rat plasma. AB - MB07133 is an intravenously administered cytarabine mononucleotide (araCMP) prodrug, for the treatment of hepatocellular carcinoma (HCC). A simple, selective and sensitive HPLC-MS/MS method using high pressure liquid chromatography (HPLC) coupled to triple-quadrupole mass spectrometer, was developed and validated for the detection of prodrug MB07133 and its metabolites, cytarabine (araC) and arabinofuranosyluracil (araU) in rat plasma. Protein precipitation using 3% trichloroacetic acid (TCA) was employed to extract analytes from 100MUL rat plasma. Adequate separation of araC and araU from their endogenous compounds was achieved on the Synergi((r)) fusion-RP column (150mm*4.6mm, 4MUm) by a gradient elution with a mobile phase consisting of ammonium formate (1mM) and methanol at a flow rate of 1mL/min. Multiple reaction monitoring mode (MRM) was applied in the detection of MB07133, araC, araU and Ganciclovir (internal standard) with ion pairs 441.2/330.2, 244.2/112.2, 245.2/113.2 and 256.1/152.2, respectively. The assays were validated with respect to specificity, linearity (100-50000ng/mL for MB07133, 2-1000ng/mL for araC and araU), accuracy and precision, extraction recovery, matrix effect and stability. The validated method has been successfully applied to an intravenous bolus pharmacokinetic study of MB07133 in male Sprague Dawley rats (18mg/kg i.v.). PMID- 26760241 TI - An in vitro AChE inhibition assay combined with UF-HPLC-ESI-Q-TOF/MS approach for screening and characterizing of AChE inhibitors from roots of Coptis chinensis Franch. AB - In this study, an in vitro acetylcholinesterase (AChE) inhibition assay based on microplate reader combined with ultrafiltration high performance liquid chromatography-electrospray quadrupole time of flight mass (UF-HPLC-ESI-Q-TOF/MS) was developed for the rapid screening and identification of acetylcholinesterase inhibitors (AChEI) from roots of Coptis chinensis Franch. Incubation conditions such as enzyme concentration, incubation time, incubation temperature and co solvent was optimized so as to get better screening results. Five alkaloids including columbamine, jatrorrhizine, coptisine, palmatine and berberine were found with AChE inhibition activity in the 80% ethanol extract of C. chinensis Franch. The screened compounds were identified by HPLC-DAD-ESI-Q-TOF/MS compared with the reference stands and literatures. The screened results were verified by in vitro AChE inhibition assays, palmatine showed the best AChE inhibitory activities with IC50 values of 36.6MUM among the five compounds. Results of the present study indicated that the combinative method using in vitro AChE inhibition assay and UF-HPLC-ESI-Q-TOF/MS could be widely applied for rapid screening and identification of AChEI from complex TCM extract. PMID- 26760242 TI - An improved HPLC-DAD method for clavulanic acid quantification in fermentation broths of Streptomyces clavuligerus. AB - Clavulanic acid (CA) is an important secondary metabolite commercially produced by cultivation of Streptomyces clavuligerus (Sc). It is a potent inhibitor of bacterial beta-lactamases. In this work, a specific and improved high performance liquid chromatography (HPLC) method, using a C-18 reversed phase column, diode array detector and gradient elution for CA quantification in fermentation broths of Sc, was developed and successfully validated. Samples were imidazole derivatized for the purpose of creating a stable chromophore (clavulanate imidazole). The calibration curve was linear over a typical range of CA concentration between 0.2 and 400mg/L. The detection and quantification limits were 0.01 and 0.02mg/L, respectively. The precision of the method was evaluated for CA spiked into production media and a recovery of 103.8%, on average, was obtained. The clavulanate-imidazole complex was not stable when the samples were not cooled during the analysis. The recovery rate was 39.3% on average. This assay was successfully tested for CA quantification in samples from Sc fermentation, using both, a chemically defined and a complex medium. PMID- 26760244 TI - Human liver cytosolic sulfotransferase 2A1-dependent dehydroepiandrosterone sulfation assay by ultra-high performance liquid chromatography-tandem mass spectrometry. AB - Sulfotransferase 2A1 (SULT2A1) is a major catalyst of the sulfation of dehydroepiandrosterone (DHEA) to dehydroepiandrosterone sulfate (DHEA-S) in human liver cytosol. However, there is a lack of a sensitive and fast analytical method for the human liver cytosolic SULT2A1-dependent DHEA sulfation assay. Therefore, we developed and validated an ultra-high performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to quantify DHEA-S and used it to optimize the human liver cytosolic SULT2A1-dependent DHEA sulfation assay. DHEA-S and cortisol (internal standard) eluted at 2.95 and 2.75min, respectively. Negative multiple reaction monitoring was used to quantify DHEA-S (m/z 367.3->97.0) and cortisol (m/z 407.2->331.3). No interfering peaks were observed in blank samples. The lower limit of quantification was 0.2pmol DHEA-S and the calibration curve was linear from 0.2 to 200pmol. The intra-day and inter-day accuracy and precision was <11.7%. DHEA-S in the quality control samples was stable at room temperature, 4 degrees C, and -20 degrees C. The cytosolic matrix (20-100MUg cytosolic protein) did not affect DHEA-S quantification. Our UPLC-MS/MS method was applied to optimize the human liver cytosolic SULT2A1-dependent DHEA sulfation assay. The optimal levels of MgCl2 and 3'-phosphoadenosine 5' phosphosulfate (PAPS) cofactor were 2.5mM and 20MUM, respectively. Reducing agents, including 2-mercaptoethanol and DL-dithiothreitol, did not affect the enzyme activity. A linear relationship existed between DHEA sulfation and amount of human liver cytosol (20-200MUg cytosolic protein) or incubation time (5 30min). This UPLC-MS/MS approach is safer, easier, and faster than existing radiometric-based sulfotransferase enzyme assays, and it is the first UPLC-MS/MS method for determining SULT2A1-dependent DHEA sulfation in human liver cytosol. PMID- 26760243 TI - Four process-related potential new impurities in ticagrelor: Identification, isolation, characterization using HPLC, LC/ESI-MS(n), NMR and their synthesis. AB - Five process-related impurities were detected in the range of 0.08-0.22% in ticagrelor laboratory batches by HPLC and LC-MS methods. These impurities were named as TIC Imp-I, -II, -III, -IV and -V. Four of these impurities, TIC Imp-I to -IV were unknown and have not been reported previously. Based on LC-ESI/MS(n) study, the chemical structures of new impurities were presumed as (1S,2S,3S,5S)-3 (2-hydroxyethoxy)-5-(7-amino-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d] pyrimidin-3 yl)cyclopentane-1,2-diol (TIC Imp-I), (1S,2S,3S,5S)-3-(7-((1R,2S)-2-(3,4 difluorophenyl)cyclopropylamino)-5-(propylsulfinyl)-3H-[1,2,3]triazolo [4,5 d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (TIC Imp-II), (1S,2R,3S,4S)-4-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5 (propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)cyclopentane-1,2,3-triol (TIC Imp-III) and (3S,5S)-3-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5 (propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2 hydroxyethoxy)cyclopentane-1,2-diol (TIC Imp-IV). The unknown impurities were isolated from enriched crude sample by column chromatography and preparative HPLC. The complete spectral analysis, MS, 1D NMR ((1)H, (13)C and DEPT), 2D NMR (HSQC and HMBC) and IR confirmed the proposed chemical structures of impurities. Identification, isolation, structural characterization, prospects for the formation of impurities and their synthesis were first reported in this paper. PMID- 26760245 TI - MALDI-TOF mass spectrometry and reversed-phase HPLC-ELSD chromatography for structural and quantitative studies of major steroid saponins in commercial extracts of Yucca schidigera Roezl. AB - This paper describes a new, improved systematic qualitative analysis of yucca saponins in commercial products by combined use of high-pressure liquid chromatography (HPLC) coupled to an evaporative light scattering detector (ELSD) and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS). Three groups with four saponins in each were completely resolved by HPLC-ELSD under C18 reversed-phase conditions using a linear gradient composed of methanol and water. The selectivity of the described HPLC-ELSD method is given by the sapogenin differences at C12 (carbonyl group) and at C2 (hydroxyl group), followed by the presence or absence of an exomethylene group at C25, and the composition and length of the oligosaccharidic chain at C3 in the sapogenins. The saponins were identified by chemical and spectroscopic methods including MALDI-TOF MS(1) and MS(2), high resolution MS, and one and bi-dimensional nuclear magnetic resonance (NMR) experiments. Among the twelve saponins identified, eleven were previously reported, and one is reported for the first time in Yucca schidigera. An identification flowchart procedure based on the analysis of the sodium adducts of intact saponins [M+Na](+) and the oligosaccharidic chain ions obtained in the MALDI-TOF MS(1) and the MS(2) spectrums, was developed for the analysis of Y. schidigera saponins. Two intact isomeric saponins were differentiated by this method, which could also be applied to the structural assignment of other steroid and triterpenic saponins. Using the four-major saponins as reference standards, a C18 reversed-phase HPLC-ELSD method was validated for their specific analysis in commercial extracts of Y. schidigera. Finally, the applicability of the HPLC-ELSD method for the relative quantification of yucca saponins is discussed. PMID- 26760246 TI - Simple alternative to sialic acid determination in meningococcal polysaccharides W or Y. AB - Physicochemical methods are the primary tests used to ensure that batches of meningococcal polysaccharide (PS) antigens are manufactured consistently to those shown to be safe and effective in clinical trials. Although modern physicochemical methods of analysis providing structural information about the antigens have been developed and used, simpler assays, which can be readily validated, are still in use for polysaccharide batch release. The simple and cheap method for Neisseria meningitidis serogroup W or Y polysaccharide (MenW or MenY PS) content quantification has been developed. This colorimetric method is based on the galactose or glucose quantification in MenW or MenY PS hydrolysate, respectively. Intra- and inter-assay precision and accuracy of the novel method have been demonstrated, in comparison to the same properties of the current regulatory approved method for the same purpose - sialic acid quantification. We provided the calculation of the possible future regulatory requirement for the galactose or glucose content in MenW or MenY PS, respectively, and revealed in detail the stoichiometric calculation behind it. PMID- 26760247 TI - Weight-based rejection sensitivity: Scale development and implications for well being. AB - We integrated theories of social stigma and rejection sensitivity to develop a new construct for understanding the effects of day-to-day experiences of interpersonal weight stigma: weight-based rejection sensitivity (W-RS), or a tendency to anxiously expect weight-based rejection. We created a new scale to measure W-RS. Studies 1 and 2 together established the scale as valid and reliable in a college student population. Study 3 examined the outcomes and predictive validity of W-RS by testing the effects of W-RS longitudinally across college students' first semester. Those who were high in W-RS were found to be at additional risk for compromised psychological and physical well-being over time. W-RS also predicted poorer adjustment to college. Overall, W-RS could help to explain individual reactions to stigma and to predict when weight stigmatization may have a greater likelihood of impacting a target. PMID- 26760264 TI - Foot-and-mouth disease vaccines: progress and problems. AB - Foot-and-mouth disease (FMD) has been a major threat to livestock across the world. The predominant method of controlling this disease in endemic regions is through regular vaccination with inactivated vaccine. However, there are many limitations. For instance, cultivation of virulent FMD virus (FMDV) in the manufacturing units poses a risk of escape from production sites. Vaccines may sometimes contain traces of FMD viral non-structural proteins (NSPs), therefore, interfering with the NSP-based serological differentiation infected from vaccinated animals (DIVA). Moreover, vaccines are unable to eliminate virus from carrier animals. To address the shortcomings of inactivated vaccines, many efforts are currently devoted to develop novel vaccines including attenuated and/or marker inactivated vaccines, recombinant protein vaccines, synthetic peptide vaccines, and empty capsid vaccines. Here, we review the research progress of novel vaccines, problems that remain to be solved, and also raise some suggestions that would help in the development of FMD vaccines. PMID- 26760265 TI - Does the improved stability offered by motorcycle antilock brakes (ABS) make sliding crashes less common? In-depth analysis of fatal crashes involving motorcycles fitted with ABS. AB - OBJECTIVE: This research investigated the following issue. Though several tests indicate that motorcycle ABS may increase motorcycle stability, thus reducing the risk of a sliding crash involving braking (i.e., the rider is separated from the motorcycle and slides along the road surface prior to collision), there is limited research showing to what extent sliding crashes are reduced by ABS in real-life conditions. METHODS: The Swedish Transport Administration (STA) and the Norwegian Public Roads Administration (NPRA) carry out in-depth studies for all road fatalities. A total of 38 in-depth studies with ABS motorcycles were included: 22 in Sweden and 16 in Norway (2005-2014). These were compared with 98 cases in Sweden and 32 in Norway involving motorcycles of the same types but without ABS. The data sets were analyzed separately and also merged together. The difference between the proportions of sliding crashes regardless braking was analyzed; selective recruitment was handled with a sensitivity analysis. Induced exposure was used to calculate the reduction of all crashes and those involving braking. RESULTS: Four ABS cases (11%) involved falling off the motorcycle prior to collision, and 35% of the non-ABS crashes were sliding (P =.004). The sensitivity analysis showed that the results were stable, with a relative difference of sliding crashes ranging between 65 and 78%. None of the 4 sliding crashes with ABS occurred during braking; that is, all ABS riders who braked prior to collision crashed in an upright position. In the 4 sliding cases with ABS, the riders lost control of their motorcycles: 2 while accelerating on asphalt with very poor friction, 1 while negotiating a curve with an excessive lean angle, and 1 by abruptly releasing the throttle in the middle of a curve. Although based on a limited number of cases, the distributions of sliding and upright collisions among crashes without braking were similar, thus suggesting that the crash posture would not be affected by ABS if no braking occurred. The calculations with induced exposure showed that upright crashes with braking were also reduced by ABS; all fatal crashes, regardless of braking, were reduced by 52%. CONCLUSIONS: Though this research was based on a limited material, it confirmed that sliding fatal crashes are significantly decreased by ABS. Considering that ABS will soon be mandatory in the European Union on all new motorcycles with engine displacement over 125cc, these findings should be taken into account in the future design and testing of motorcycle-friendly road barriers and integrated protection systems. PMID- 26760266 TI - Two-stage anaerobic and post-aerobic mesophilic digestion of sewage sludge: Analysis of process performance and hygienization potential. AB - Sequential anaerobic-aerobic digestion has been demonstrated to be effective for enhanced sludge stabilization, in terms of increased solid reduction and improvement of sludge dewaterability. In this study, we propose a modified version of the sequential anaerobic-aerobic digestion process by operating the aerobic step under mesophilic conditions (T=37 degrees C), in order to improve the aerobic degradation kinetics of soluble and particulate chemical oxygen demand (COD). Process performance has been assessed in terms of "classical parameters" such as volatile solids (VS) removal, biogas production, COD removal, nitrogen species, and polysaccharide and protein fate. The aerobic step was operated under intermittent aeration to achieve nitrogen removal. Aerobic mesophilic conditions consistently increased VS removal, providing 32% additional removal vs. 20% at 20 degrees C. Similar results were obtained for nitrogen removal, increasing from 64% up to 99% at the higher temperature. Improved sludge dewaterability was also observed with a capillary suction time decrease of ~50% during the mesophilic aerobic step. This finding may be attributable to the decreased protein content in the aerobic digested sludge. The post-aerobic digestion exerted a positive effect on the reduction of microbial indicators while no consistent improvement of hygienization related to the increased temperature was observed. The techno-economic analysis of the proposed digestion layout showed a net cost saving for sludge disposal estimated in the range of 28 35% in comparison to the single-phase anaerobic digestion. PMID- 26760267 TI - Stomatal uptake of O3 in a Schima superba plantation in subtropical China derived from sap flow measurements. AB - Canopy stomatal ozone (O3) flux (Fst,O3) in a plantation of Schima superba, an ecologically and economically important evergreen pioneer tree species in subtropical China, was quantified based on sap flow measurements during a 2-year period. Mean Fst,O3 and accumulated Fst,O3 (AFst0) were significantly higher in wet seasons from April to September (4.62 nmol m(-2) s(-1) and 35.37 mmol m(-2), respectively) than in dry seasons from October to March (3.90 nmol m(-2) s(-1) and 24.15 mmol m(-1), respectively), yet comparable between the 2 years of the experiment, being 4.23 nmol m(-2) s(-1) and 58.23 mmol m(-2) in April 2013-March 2014 and 4.29 nmol m(-2) s(-1) and 60.80 mmol m(-2) in April 2014-March 2015, respectively. At the diurnal scale, Fst,O3 generally peaked in the early to middle afternoon hours (13:00-15:00), while the maximum stomatal conductance (Gst,O3) typically occurred in the middle to late morning hours (09:00-11:00). Monthly integrated AFst0 reached the maximum in July, although accumulated O3 exposure (SUM0) was highest in October. Seasonally or yearly, the accumulated O3 doses, either exposure-based or flux-based, notably exceeded the currently adopted critical thresholds for the protection of forest trees. These results, on the one hand, demonstrated the decoupling between the stomatal uptake of O3 and its environmental exposure level; on the other hand, indicated the potential O3 risk for S. superba in the experimental site. Therefore, the present study endorses the use of sap flow measurements as a feasible tool for estimating Fst,O3, and the transition from the exposure-based toward flux-based metrics for assessing O3 risk for forest trees. Further studies are urgently needed to relate stomatal O3 uptake doses with tree growth reductions for an improved understanding of O3 effects on trees under natural conditions. PMID- 26760268 TI - Photocatalytic degradation kinetics, mechanism and ecotoxicity assessment of tramadol metabolites in aqueous TiO2 suspensions. AB - This study investigated for the first time the photocatalytic degradation of three well-known transformation products (TPs) of pharmaceutical Tramadol, N desmethyl-(N-DES), N,N-bidesmethyl (N,N-Bi-DES) and N-oxide-tramadol (N-OX-TRA) in two different aquatic matrices, ultrapure water and secondary treated wastewater, with high (10 mg L(-1)) and low (50 MUg L(-1)) initial concentrations, respectively. Total disappearance of the parent compounds was attained in all experiments. For initial concentration of 10 mg L(-1), the target compounds were degraded within 30-40 min and a mineralization degree of more than 80% was achieved after 240 min of irradiation, while the contained organic nitrogen was released mainly as NH4(+) for N-DES, N,N-Bi-DES and NO3(-) for N-OX TRA. The degradation rates of all the studied compounds were considerably decreased in the wastewater due to the presence of inorganic and organic constituents typically found in effluents and environmental matrices which may act as scavengers of the HO(*). The effect of pH (4, 6.7, 10) in the degradation rates was studied and for N-DES-TRA and N,N-Bi-DES-TRA, the optimum pH value was 6.7. In contrast, N-OX-TRA showed an increasing trend in the photocatalytic degradation kinetic in alkaline solutions (pH 10). The major transformation products were identified by high resolution accurate mass spectrometry coupled with liquid chromatography (HR-LC-MS). Scavenging experiments indicated for all studied compounds the important role of HO(*) in the photocatalytic degradation pathways that included mainly hydroxylation and further oxidation of the parent compounds. In addition, Microtox bioassay (Vibrio fischeri) was employed for evaluating the ecotoxicity of photocatalytically treated solutions. Results clearly demonstrate the progressive decrease of the toxicity and the efficiency of the photocatalytic process in the detoxification of the irradiated solutions. PMID- 26760269 TI - Identification of the microbes mediating Fe reduction in a deep saline aquifer and their influence during managed aquifer recharge. AB - In this study, indigenous microbes enabling Fe reduction under saline groundwater conditions were identified, and their potential contribution to Fe release from aquifer sediments during managed aquifer recharge (MAR) was evaluated. Sediment and groundwater samples were collected from a MAR feasibility test site in Korea, where adjacent river water will be injected into the confined aquifer. The residual groundwater had a high salinity over 26.0 psu, as well as strong reducing conditions (dissolved oxygen, DO<2.0mg/L; oxidation-reduction potential, ORP<-100 mV) with high Fe(2+) concentrations. The indigenous microbes that mediate the reduction of Fe-minerals in this deep saline aquifer were found to be Citrobacter sp. However, column experiments to simulate field operation scenarios indicated that additional Fe release would be limited during MAR, as the dominant microbial community in the sediment would shift from Citrobacter sp. to Pseudomonas sp. and Limnohabitans sp. as river water injection alters the pore water chemistry. PMID- 26760270 TI - Enrichment and mechanisms of heavy metal mobility in a coastal quaternary groundwater system of the Pearl River Delta, China. AB - The risks posed by heavy metal mobilization strongly depend on the pathways that the metals follow, with the sediment-water pathway representing a direct risk to groundwater contamination. Monitoring and sequential extraction experiments in the laboratory generally have limitations with respect to understanding the mechanisms of heavy metal mobilization in the field. The Quaternary coastal groundwater system of the Pearl River Delta, China was chosen as the study area to understand heavy metal enrichment and mobility. Heavy metals including V, Cr, Co, Ni, Cu, Zn, Ba, Pb, Mo, Cd, Sr, Ga, Ge, Rb, and Cs in both sediments and groundwater were analyzed. Geochemical parameters including Fe2O3, MnO, sedimentary organic matter, and carbonate content as well as hydrochemical parameters including K(+), Na(+), Ca(2+), Mg(2+), NH4(+), SO4(2-), Cl(-), HCO3( ), pH, TDS, and dissolved organic carbon were also measured. The enrichment of heavy metals in the solid sediment phase as well as the mobilization mechanisms of heavy metals in groundwater are discussed as informed by Pearson's correlation analysis. Hydrochemical analyses demonstrated that the mobility of V, Ba, Cr, Rb, and Cs is closely related to the decomposition of buried sedimentary organic matter; the mobility of Co, Ni, Cu, Zn, Pb, and Cd is closely linked with the reductive dissolution of Fe-Mn oxides; and the mobility of Co, Ni, Cu, Ba, Zn, Pb, Cd, Mn, Sr and Ga is probably controlled by ion exchange processes. This study demonstrates that heavy metal mobility in the field is not entirely consistent with the potential mobility as indicated by sediment analysis, due to the complicated hydrogeochemical conditions in the groundwater system, and suggests that comprehensive geochemical and hydrochemical studies are useful ways to understand the mobility mechanisms of heavy metals in the field. PMID- 26760271 TI - Mercury and cadmium in ringed seals in the Canadian Arctic: Influence of location and diet. AB - Concentrations of total mercury (THg) and total cadmium (TCd) were determined in muscle and liver of ringed seals (Pusa hispida) from up to 14 locations across the Canadian Arctic. Location, trophic position (TP) and relative carbon source best predicted the THg and TCd concentrations in ringed seals. THg concentrations in ringed seals were highest in the western Canadian Arctic (Beaufort Sea), whereas TCd was highest in the eastern Canadian Arctic (Hudson Bay and Labrador). A positive relationship between THg and TP and a negative relationship between THg and relative carbon source contributed to the geographical patterns observed and elevated THg levels at certain sites. In contrast, a negative relationship between TCd and TP was found, indicating that high TCd concentrations are related to seals feeding more on invertebrates than fish. Feeding ecology appears to play an important role in THg and TCd levels in ringed seals, with biomagnification driving elevated THg levels and a dependence on low-trophic position prey resulting in high TCd concentrations. The present study shows that both natural geological differences and diet variability among regions explain the spatial patterns for THg and TCd concentrations in ringed seals. PMID- 26760272 TI - Assessing the global warming potential of human settlement expansion in a mesic temperate landscape from 2005 to 2050. AB - Expansion of human settlements is an important driver of global environmental change that causes land use and land cover change (LULCC) and alters the biophysical nature of the landscape and climate. We use the state of Massachusetts, United States (U.S.) to present a novel approach to quantifying the effects of projected expansion of human settlements on the biophysical nature of the landscape. We integrate nationally available datasets with the U.S. Environmental Protection Agency's Integrated Climate and Land Use Scenarios model to model albedo and C storage and uptake by forests and vegetation within human settlements. Our results indicate a 4.4 to 14% decline in forest cover and a 35 to 40% increase in developed land between 2005 and 2050, with large spatial variability. LULCC is projected to reduce rates of forest C sequestration, but our results suggest that vegetation within human settlements has the potential to offset a substantial proportion of the decline in the forest C sink and may comprise up to 35% of the terrestrial C sink by 2050. Changes in albedo and terrestrial C fluxes are expected to result in a global warming potential (GWP) of +0.13 Mg CO2-C-equivalence ha(-1)year(-1) under the baseline trajectory, which is equivalent to 17% of the projected increase in fossil fuel emissions. Changes in terrestrial C fluxes are generally the most important driver of the increase in GWP, but albedo change becomes an increasingly important component where housing densities are higher. Expansion of human settlements is the new face of LULCC and our results indicate that when quantifying the biophysical response it is essential to consider C uptake by vegetation within human settlements and the spatial variability in the influence of C fluxes and albedo on changes in GWP. PMID- 26760273 TI - Storage and release of road-salt contamination from a calcareous lake-basin fen, western Massachusetts, USA. AB - Road salt (NaCl) applications to highways have increased stream sodium and chloride concentrations due to retention within watersheds. The mechanisms for retention and export of Na(+) and Cl(-) from different environments are not fully understood. This field study examines the hydrologic and cation exchange processes that store and release Na(+) and Cl(-) from a calcareous fen adjacent to a highway. Despite high concentrations of Ca(2+) and Mg(2+), elevated salt concentrations enable Na(+) to occupy up to 15% of the cation exchange capacity of shallow peat. Calculations of selectivity coefficients show that Na(+) preferentially exchanges with Mg(2+), and Na(+) can be desorbed under more dilute conditions caused by precipitation and snowmelt. Detailed sampling of surface and ground waters during three snowmelt events illustrate early releases of Na(+) and Cl(-) at the onset of melting, with maximum fluxes coinciding with peak discharge. From 7 March through 4 April 2005, the flux of dissolved salt exiting the wetland amounts to 13% (Na) and 17% (Cl) of annual rock salt applied to the highway. For all of 2005, the total salt mass leaving the wetland via Kampoosa Brook is similar to the amount of road salt applied; 50% of the annual salt efflux occurred during the snowmelt season of March through May. In general, exported Na(+) and Cl(-) correlate with the number of lane miles of highway crossing the watershed. Large rain events outside of winter months are more effective than snowmelt with reducing dissolved salts because snowmelt also introduces contamination. For this and other wetlands having alkaline geochemistry and high flushing rates, management strategies that reduce rock salt amounts to roadways will assist with reducing salt contamination to levels less toxic to vegetation and aquatic organisms. PMID- 26760274 TI - Inter-annual variability of wintertime PM2.5 chemical composition in Xi'an, China: Evidences of changing source emissions. AB - Chemical characteristics of PM2.5 in Xi'an in wintertime of 2006, 2008, and 2010 were investigated. Markers of OC2, EC1, and NO3(-)/SO4(2-) ratio were calculated to investigate the changes in PM2.5 emission sources over the 5-year period. Positive matrix factorization (PMF) model was used to identify and quantify the main sources of PM2.5 and their contributions. The results showed that coal combustion, motor vehicular emissions, fugitive dust, and secondary inorganic aerosol accounted for more than 80% of PM2.5 mass. The importance of these major sources to the PM2.5 mass varied yearly: coal combustion was the largest contributor (31.2% +/- 5.2%), followed by secondary inorganic aerosol (20.9% +/- 5.2%) and motor vehicular emissions (19.3% +/- 4.8%) in 2006; the order was still coal combustion emissions (27.6% +/- 3.4%), secondary inorganic aerosol (23.2% +/ 6.9%), and motor vehicular emissions (20.9% +/- 4.6%) in 2008; while coal combustion emission further decreased (24.1% +/- 3.1%) with fugitive dust (19.4% +/- 5.5%) increasing in 2010. The changes in PM2.5 chemical compositions and source contributions can be attributed to the social and economic developments in Xi'an, China, including energy structure adjustment, energy consumption, the expansion of civil vehicles, and the increase of urban construction activities. PMID- 26760275 TI - Critical evaluation of essential oils as rumen modifiers in ruminant nutrition: A review. AB - Ruminant livestock systems contribute significantly to emission of methane, a potent greenhouse gas as they waste a portion of the ingested energy (2-15%) as methane and a large proportion (75-95%) of the ingested nitrogen as ammonia. Recently, numerous researches have been conducted to evaluate plant secondary metabolites, including essential oils (EO), as natural feed additives in ruminant nutrition and to exploit their potential to improve rumen fermentation efficiency. Essential oils appeared to be very promising compounds as they selectively reduced methane production and protein breakdown in both in vitro and in vivo studies. However, in some studies, the use of EO as feed additives was accompanied with decreased feed degradability and lowered volatile fatty acid. These adverse effects could be attributed to their broad and often non-specific antimicrobial activities within the rumen. Future research should be directed to identification of the active and useful EO compounds, optimization of EO doses, and use of a whole-farm approach with a focus on animal welfare, performance and economic benefits. PMID- 26760276 TI - The effects of arsenic and seawater acidification on antioxidant and biomineralization responses in two closely related Crassostrea species. AB - Ocean acidification processes are major threats to marine calcifying organisms, mostly affecting biomineralization related processes. Abiotic stressors acting on marine systems do not act alone, rather in a combination of multiple stressors, especially in coastal habitats such as estuaries, where anthropogenic and environmental pressures are high. Arsenic (As) is a widely distributed contaminant worldwide and its toxicity has been studied on a variety of organisms. However, the effect of low pH on the toxicity of As on marine organisms is unknown. Here, we studied the combined effects of ocean acidification and As exposure on two closely related oyster species (Crassostrea angulata and Crassostrea gigas), by use of a biochemical approach. Oxidative stress related parameters were studied along with the assessment of biomineralization enzymes activity after 28days of exposure. Results showed that both species were sensitive to all tested conditions (low pH, As and pH+As), showing enhancement of antioxidant and biotransformation defenses and impairment of biomineralization processes. Glutathione S-transferases (GSTs) activity were significantly higher in oysters exposed to As, showing activation of detoxification mechanisms, and a lower GSTs activity was observed in low pH+As condition, indicating an impact on the oysters capacity to detoxify As in a low pH scenario. Carbonic anhydrase (CA) activity was significantly lower in all tested conditions, showing to be affected by both As and low pH, whereas the combined effect of low pH+As was not different from the effect of low pH alone. Multivariate analysis of biochemical data allowed for the comparison of both species performance, showing a clear distinction of response in both species. C. gigas presented overall higher enzymatic activity (GSTs; superoxide dismutase; catalase; CA and acid phosphatase) and higher cytosolic GSH content in As exposed oysters than C. angulata. Results obtained indicate a higher tolerance capacity of the Pacific oyster C. gigas towards the tested conditions. PMID- 26760277 TI - Fate of glyphosate and degradates in cover crop residues and underlying soil: A laboratory study. AB - The increasing use of cover crops (CC) may lead to an increase in glyphosate application for their destruction. Sorption and degradation of (14)C-glyphosate on and within 4 decaying CC-amended soils were compared to its fate in a bare soil. (14)C-Glyphosate and its metabolites distribution between mineralized, water-soluble, NH4OH-soluble and non-extractable fractions was determined at 5 dates during a 20 degrees C/84-d period. The presence of CC extends (14)C glyphosate degradation half-life from 7 to 28 days depending on the CC. (14)C Glyphosate dissipation occurred mainly through mineralization in soils and through mineralization and bound residue formation in decaying CC. Differences in sorption and degradation levels were attributed to differences in composition and availability to microorganisms. CC- and soil-specific dissipation patterns were established with the help of explicit relationships between extractability and microbial activity. PMID- 26760279 TI - Incorporating water consumption into crop water footprint: A case study of China's South-North Water Diversion Project. AB - The crop water footprint (WF) indicates the consumption of water for a crop during the planting period, mainly through evapotranspiration. However, as irrigated agriculture accounts for nearly 25% of the global agriculture water usage, evaluation of WF during transportation becomes essential to improve the efficiency of irrigated agriculture. This study aims at building an improved WF model to understand how much WF is produced due to water diversion and how much crop WF increases during the transfer. The proposed model is then used to calculate the WF of four major crops in five provinces along China's South-North Water Transfer Project in two steps. First, the WF of the water transfer project (WFeng) is assessed in a supply chain analysis method. Second, a WF allocation model is built to distribute the project WF for each crop/province. The results show that the evaporation and seepage are the main sources of WFeng. Out of five provinces, two namely Tianjin and Hebei present higher WFblue and WF increase. A positive correlation between water diversion distance and crop WF increase is noted. Among the four crops, cotton presents higher WFblue and WF increase. The crops with higher WFblue tend to be more strongly influenced by the water diversion project, due to high irrigation water dependency. This analysis may expand the WF concept from an evaporation-related term to a term reflecting crop biological processes and water consumption by artificial irrigation projects. Thus, it may serve as an indicator for optimizing future objectives and strategies associated to water resource planning in China and elsewhere. PMID- 26760278 TI - Acute and chronic effects of erythromycin exposure on oxidative stress and genotoxicity parameters of Oncorhynchus mykiss. AB - Erythromycin (ERY) is a macrolide antibiotic used in human and veterinary medicine, and has been detected in various aquatic compartments. Recent studies have indicated that this compound can exert biological activity on non-target organisms environmentally exposed. The present study aimed to assess the toxic effects of ERY in Oncorhynchus mykiss after acute and chronic exposures. The here adopted strategy involved exposure to three levels of ERY, the first being similar to concentrations reported to occur in the wild, thus ecologically relevant. Catalase (CAT), total glutathione peroxidase (GPx), glutathione reductase (GRed) activities and lipid peroxidation (TBARS levels) were quantified as oxidative stress biomarkers in gills and liver. Genotoxic endpoints, reflecting different types of genetic damage in blood cells, were also determined, by performing analysis of genetic damage (determination of the genetic damage index, GDI, measured by comet assay) and of erythrocytic nuclear abnormalities (ENAs). The results suggest the occurrence of a mild, but significant, oxidative stress scenario in gills. For acutely exposed organisms, significant alterations were observed in CAT and GRed activities, and also in TBARS levels, which however are modifications with uncertain biological interpretation, despite indicating involvement of an oxidative effect and response. After chronic exposure, a significant decrease of CAT activity, increase of GPx activity and TBARS levels in gills was noticed. In liver, significant decrease in TBARS levels were observed in both exposures. Comet and ENAs assays indicated significant increases on genotoxic damage of O. mykiss, after erythromycin exposures. This set of data (acute and chronic) suggests that erythromycin has the potential to induce DNA strand breaks in blood cells, and demonstrate the induction of chromosome breakage and/or segregational abnormalities. Overall results indicate that both DNA damaging effects induced by erythromycin may be related to the oxidative damage observed, shown to occur at environmentally relevant concentrations of erythromycin. PMID- 26760280 TI - Exploring spatiotemporal changes in ecosystem-service values and hotspots in China. AB - Although ecosystems are valuable, they have been allowed to deteriorate globally in recent decades. However, the spatiotemporal changes in ecosystem-service values (ESVs) and their hotspots in China are not well understood. Here, long term land-cover data, the spatial analysis method and an econometric analysis model were used to examine these changes. The results indicate that the total terrestrial ESV decreased from US$2398.31 billion in 1990 to US$2347.56 billion in 2010 (converted to 2009 dollar values), which provides strong evidence for the tendency of ecosystems in China to deteriorate over time, albeit slightly. We also found that the changes in ESVs had significant spatial heterogeneity. Our analysis showed that the relationship between ESV and gross domestic product (GDP) is generally negative, but this relationship is not always fixed. The Loess Plateau, Guizhou, Hubei, Henan and Xinjiang continually presented concentrated hotspot areas of ESV changes, whereas coastal regions continually presented concentrated cold-spot areas. Overlap analyses and logistic regressions demonstrate that national ecological programs have clear effects on the improvement of ecosystems but that the effectiveness of different policies varies on spatial and temporal scales. The results of this study will support more effective decision-making around the implementation of ecological conservation policies. PMID- 26760281 TI - The Effectiveness of a Worksite Lifestyle Intervention Program on High-Risk Individuals as Potential Candidates for Bariatric Surgery: My Unlimited Potential (MyUP). AB - This is a single-arm, pre and post effectiveness study that evaluated the impact of a comprehensive workplace lifestyle program on severe obesity among high cardiovascular disease risk individuals in a large, diverse employee population. Employees of Baptist Health South Florida were considered eligible to participate if they had 2 or more of the following cardiometabolic risk factors: total cholesterol >=200 mg/dL, systolic blood pressure >=140 mmHg or diastolic blood pressure >=90 mmHg, hemoglobin A1c >=6.5%, body mass index >=30kg/m(2). Participants received a personalized diet plan and physical activity intervention, and were followed for 1 year. Data on anthropometric measurements, blood pressure, blood glucose, and other biochemical measures were collected. Participants' body mass index was calculated and their eligibility for bariatric surgery (BS) also assessed. A total of 297 persons participated in the program; 160 participants completed all procedures through 12 months of follow-up. At baseline, 34% (n = 100) of all participants were eligible for BS. In an intention to-treat analysis, 27% (n = 27) of BS eligible participants at baseline became ineligible after 12 months. Considering program completers only, 46% of BS eligible participants at baseline became ineligible. Irrespective of BS eligibility at 12 months, mean values of cardiometabolic risk factors among program completers improved after the follow-up period. Workplace wellness programs provide an important option for weight loss that can obviate the need for BS, reduce cardiovascular disease risk, and potentially reduce costs. However, in designing future worksite lifestyle interventions, measures should be taken to improve participation and retention rates in such programs. PMID- 26760282 TI - Development of a low-serum medium for the production of monoclonal antibody against congenital adrenal hyperplasia by hybridoma culture. AB - Statistically designed experiments were used in developing a low-serum medium for the production of a diagnostic monoclonal antibody against congenital adrenal hyperplasia using hybridoma 192. A two-level half-fractional factorial design was used for screening six components (Minimum Essential Medium Eagle amino acids, 2 mercaptoethanol, ethanolamine, ferric citrate, zinc sulfate, and sodium selenite). The experimental design was then augmented to central composite design. The basal Dulbecco's modified Eagle's medium (DMEM; containing 4 mM L glutamine, 1% antibiotic-antimycotic agent) supplemented with 0.4% by volume fetal bovine serum (FBS), 311.8 mM ferric citrate, 17.3 nM sodium selenite, and 4.5 mM zinc sulfate (LSD) was found to support the growth of the hybridoma. Specific cell growth rate in the LSD (0.033 +/- 0.001/h) was slightly lower than in the control medium (i.e., basal DMEM supplemented with 2% FBS; 0.0045 +/- 0.003/h). Nevertheless, the specific MAb production rate for LSD was higher (0.057 +/- 0.015 pg/cell . h versus 0.004 +/- 0.002 pg/cell . h in LSD and control, respectively). The antibody produced in the LSD showed high specificity and no cross-reactivity with the other structural resemblance's steroid hormones, revealing no structural changes owing to the new medium formulation developed. The new medium formulation effectively reduced the medium cost by up to 64.6%. PMID- 26760284 TI - The Degree of Dependence Between Multiple-Treatment Effect Sizes. AB - We examined the degree of dependence between standardized-mean-difference effect sizes in multiple-treatment studies in meta-analysis in terms of the correlation formula provided by Gleser and Olkin (1994) . To explore the impact of group size and the values of the true multiple-treatment effect sizes, we simplified the formula for the correlation in terms of the ratio of group sizes and under conditions of equality of sample and effect sizes. The results showed that the group-size ratio affects the correlation between effects much more than do the values of the effect sizes. A relatively smaller control-group size and large effect sizes of the same sign were associated with stronger dependence. We also showed that ignoring the dependence between individual standardized-mean difference effect sizes always decreases the precision of differences in mean effects across studies in a meta-analysis. The difference in precision was largest when treatment groups were much larger than the control group, regardless of the size of the effects or the number of studies in the meta-analysis. PMID- 26760285 TI - A Meta-Meta-Analysis: Empirical Review of Statistical Power, Type I Error Rates, Effect Sizes, and Model Selection of Meta-Analyses Published in Psychology. AB - This article uses meta-analyses published in Psychological Bulletin from 1995 to 2005 to describe meta-analyses in psychology, including examination of statistical power, Type I errors resulting from multiple comparisons, and model choice. Retrospective power estimates indicated that univariate categorical and continuous moderators, individual moderators in multivariate analyses, and tests of residual variability within individual levels of categorical moderators had the lowest and most concerning levels of power. Using methods of calculating power prospectively for significance tests in meta-analysis, we illustrate how power varies as a function of the number of effect sizes, the average sample size per effect size, effect size magnitude, and level of heterogeneity of effect sizes. In most meta-analyses many significance tests were conducted, resulting in a sizable estimated probability of a Type I error, particularly for tests of means within levels of a moderator, univariate categorical moderators, and residual variability within individual levels of a moderator. Across all surveyed studies, the median effect size and the median difference between two levels of study level moderators were smaller than Cohen's (1988) conventions for a medium effect size for a correlation or difference between two correlations. The median Birge's (1932) ratio was larger than the convention of medium heterogeneity proposed by Hedges and Pigott (2001) and indicates that the typical meta-analysis shows variability in underlying effects well beyond that expected by sampling error alone. Fixed-effects models were used with greater frequency than random effects models; however, random-effects models were used with increased frequency over time. Results related to model selection of this study are carefully compared with those from Schmidt, Oh, and Hayes (2009), who independently designed and produced a study similar to the one reported here. Recommendations for conducting future meta-analyses in light of the findings are provided. PMID- 26760286 TI - Detecting Social Desirability Bias Using Factor Mixture Models. AB - Based on the conceptualization that social desirable bias (SDB) is a discrete event resulting from an interaction between a scale's items, the testing situation, and the respondent's latent trait on a social desirability factor, we present a method that makes use of factor mixture models to identify which examinees are most likely to provide biased responses, which items elicit the most socially desirable responses, and which external variables predict SDB. Problems associated with the common use of correlation coefficients based on scales' total scores to diagnose SDB and partial correlations to correct for SDB are discussed. The method is demonstrated with an analysis of SDB in the Attitude toward Interprofessional Service-Learning scale with a sample of students from health-related fields. PMID- 26760283 TI - A Qualitative Study Exploring Factors Associated with Provider Adherence to Severe Pediatric Traumatic Brain Injury Guidelines. AB - Despite demonstrated improvement in patient outcomes with use of the Pediatric Traumatic Brain Injury (TBI) Guidelines (Guidelines), there are differential rates of adherence. Provider perspectives on barriers and facilitators to adherence have not been elucidated. This study aimed to identify and explore in depth the provider perspective on factors associated with adherence to the Guidelines using 19 focus groups with nurses and physicians who provided acute management for pediatric patients with TBI at five university-affiliated Level 1 trauma centers. Data were examined using deductive and inductive content analysis. Results indicated that three inter-related domains were associated with clinical adherence: 1) perceived guideline credibility and applicability to individual patients, 2) implementation, dissemination, and enforcement strategies, and 3) provider culture, communication styles, and attitudes towards protocols. Specifically, Guideline usefulness was determined by the perceived relevance to the individual patient given age, injury etiology, and severity and the strength of the evidence. Institutional methods to formally endorse, codify, and implement the Guidelines into the local culture were important. Providers wanted local protocols developed using interdisciplinary consensus. Finally, a culture of collaboration, including consistent, respectful communication and interdisciplinary cooperation, facilitated adherence. Provider training and experience, as well as attitudes towards other standardized care protocols, mirror the use and attitudes towards the Guidelines. Adherence was determined by the interaction of each of these guideline, institutional, and provider factors acting in concert. Incorporating provider perspectives on barriers and facilitators to adherence into hospital and team protocols is an important step toward improving adherence and ultimately patient outcomes. PMID- 26760287 TI - The Other Side of Method Bias: The Perils of Distinct Source Research Designs. AB - Common source bias has been the focus of much attention. To minimize the problem, researchers have sometimes been advised to take measurements of predictors from one observer and measurements of outcomes from another observer or to use separate occasions of measurement. We propose that these efforts to eliminate biases due to common source variance create serious problems. To demonstrate the problems of using what we term the "distinct sources" measurement design, we provide an integrative review of the literature regarding both contamination and deficiency of measures. Building on this theme, the article uses simulated data to demonstrate how using data from distinct observers or occasions of measurement can distort estimates of predictor importance at least as much as common source variance. Alternative multisource designs are advocated and examined for tractability by simulating various numbers of observations and sources in the research design. PMID- 26760288 TI - Variability in Parameter Estimates and Model Fit Across Repeated Allocations of Items to Parcels. AB - Different random or purposive allocations of items to parcels within a single sample are thought not to alter structural parameter estimates as long as items are unidimensional and congeneric. If, additionally, numbers of items per parcel and parcels per factor are held fixed across allocations, different allocations of items to parcels within a single sample are thought not to meaningfully alter model fit-at least when items are normally distributed. We show analytically that, although these statements hold in the population, they do not necessarily hold in the sample. We show via a simulation that, even under these conservative conditions, the magnitude of within-sample item-to-parcel-allocation variability in structural parameter estimates and model fit can alter substantive conclusions when sampling error is high (e.g., low N, low item communalities, few items per few parcels). We supply a software tool that facilitates reporting and ameliorating the consequences of item-to-parcel-allocation variability. The tool's utility is demonstrated on an empirical example involving the Neuroticism Extroversion-Openness (NEO) Personality Inventory and the Computer Assisted Panel Study data set. PMID- 26760289 TI - The Multigroup Multilevel Categorical Latent Growth Curve Models. AB - Longitudinal data describe developmental patterns and enable predictions of individual changes beyond sampled time points. Major methodological issues in longitudinal data include modeling random effects, subject effects, growth curve parameters, and autoregressive residuals. This study embedded the longitudinal model within a multigroup multilevel framework and allowed for autoregressive residuals. The parameter in the new model can be estimated using the computer program WinBUGS, which adopts Markov Chain Monte Carlo algorithms. Two simulation studies were conducted. An empirical example was raised and established based on models generated by the results of empirical data, which have been fitted and compared. PMID- 26760290 TI - Iatrogenic intracranial placement of nasopharyngeal airway after trauma. AB - CT images of an 18-year-old woman who had sustained head trauma after a motor vehicle accident are presented demonstrating the iatrogenic intracranial placement of a nasopharyngeal airway. Treatment required a decompressive craniectomy, removal of the nasopharyngeal airway under direct vision, and duraplasty. The patient made a good neurological recovery, but did require ongoing medical treatment for diabetes insipidus. The case illustrates the importance of avoiding intranasal placement of any object in a patient with head trauma and suspected skull base fractures prior to diagnostic imaging. PMID- 26760291 TI - Trends in cancer of the head and neck in the elderly in Denmark, 1980-2012. AB - BACKGROUND: Squamous cell carcinoma of the head and neck (HNSCC) comprises a variety of malignant tumors. Due to the rarity of each individual malignant entity, knowledge of epidemiological changes and trends over time may be derived from data compiled in regional and national registries. This study analyzed the development in incidence rates and mortality in elderly HNSCC patients in Denmark between 1980 and 2012 with specific attention to compliance to radiotherapy, the main treatment modality of HNSCC in Denmark. MATERIAL AND METHODS: HNSCC consisting of more than 25 patients per year over the age of 70 years were analyzed. This included cancer of the oral cavity defined as ICD-codes C00.3-4, C02-04, C05.0, C06; oropharynx as C01, C05.1-9, C09-10; and larynx as C32 recorded in the NORDCAN database. Additional data from the DAHANCA database was added to assess differences in compliance to treatment between younger and older patient groups. RESULTS: HNSCC was predominant in younger patients. Only 17% were older than 70 years. The median age was 60 years. Generally, incidence rates rose for cancer of the oral cavity and oropharynx between 1980 and 2012 and stabilized for laryngeal cancer. Mortality rates had a shallower increase, especially in younger age groups, which translated into improved age-specific survival rates. Compliance to radiotherapy was high for all age groups. Failure to receive at least 60 Gy during radical radiation treatment was 2.3% despite a significant increase in patients with poor WHO performance status over time. CONCLUSION: HNSCC is a rare disease in patients above 70 years accounting for only 17% of all HNSCC patients. Incidence rates increased over time, but age-specific survival rates improved, especially in younger patients. Failure rates to comply with radiation treatment, however, were low in both young and elderly patients. PMID- 26760292 TI - Perceptions, misconceptions and review of a neurosurgery on-call service in a university teaching hospital. AB - BACKGROUND: No published guidelines exist for how receiving unit doctors should manage referrals. Feedback regarding the quality of neurosurgical referral handling in our hospital has, in the past, been poor. We designed a novel means to appraise specialist referral handling, such that service delivery could be improved. We also aimed to identify differences, if any, between doctor perceptions versus actual satisfaction with the on-call neurosurgery service in our centre. METHODS: We first distributed questionnaires to gauge doctors' perceptions of our neurosurgery on-call service ('Perceptions of Neurosurgery Service' or 'PONS' questionnaire). Next we distributed a novel quality-of-service questionnaire ('Neurosurgery Service Assessment Questionnaire' or 'NSAQ') to all referring doctors over the three-month period between 01 March 2014 and 01 June 2014. RESULTS: Of the 57 respondents to the PONS questionnaire, 47.3% perceived the neurosurgical referral service to be 'poor' (36.8%, n = 21) or 'very poor' (10.5%, n = 6). Next the NSAQ was sent via email to the referring doctor of each of the 502 referrals received in the study period. A total of 52 responses were received by referring doctors (response rate = 10.36%). Actual referral handling ratings were overwhelmingly positive; 82.7% rated the handling of their referral as 'good' (21.2%, n = 11), 'very good' (32.7%, n = 17) or 'excellent' (28.9%, n = 15). CONCLUSIONS: We describe a novel method for receiving units to appraise their referral services and demonstrate its usefulness in our tertiary neurosurgical unit. We also demonstrate that most referring doctors are satisfied with the handling of their neurosurgical referrals, despite perceptions to the contrary. PMID- 26760293 TI - Analysis of naturalistic driving videos of fleet services drivers to estimate driver error and potentially distracting behaviors as risk factors for rear-end versus angle crashes. AB - OBJECTIVE: The objective of this study was to estimate the prevalence and odds of fleet driver errors and potentially distracting behaviors just prior to rear-end versus angle crashes. METHODS: Analysis of naturalistic driving videos among fleet services drivers for errors and potentially distracting behaviors occurring in the 6 s before crash impact. Categorical variables were examined using the Pearson's chi-square test, and continuous variables, such as eyes-off-road time, were compared using the Student's t-test. Multivariable logistic regression was used to estimate the odds of a driver error or potentially distracting behavior being present in the seconds before rear-end versus angle crashes. RESULTS: Of the 229 crashes analyzed, 101 (44%) were rear-end and 128 (56%) were angle crashes. Driver age, gender, and presence of passengers did not differ significantly by crash type. Over 95% of rear-end crashes involved inadequate surveillance compared to only 52% of angle crashes (P < .0001). Almost 65% of rear-end crashes involved a potentially distracting driver behavior, whereas less than 40% of angle crashes involved these behaviors (P < .01). On average, drivers spent 4.4 s with their eyes off the road while operating or manipulating their cell phone. Drivers in rear-end crashes were at 3.06 (95% confidence interval [CI], 1.73-5.44) times adjusted higher odds of being potentially distracted than those in angle crashes. CONCLUSIONS: Fleet driver driving errors and potentially distracting behaviors are frequent. This analysis provides data to inform safe driving interventions for fleet services drivers. Further research is needed in effective interventions to reduce the likelihood of drivers' distracting behaviors and errors that may potentially reducing crashes. PMID- 26760294 TI - Correlates and Predictors of Psychological Distress Among Older Asian Immigrants in California. AB - Psychological distress occurs frequently in older minority immigrants because many have limited social resources and undergo a difficult process related to immigration and acculturation. Despite a rapid increase in the number of Asian immigrants, relatively little research has focused on subgroup mental health comparisons. This study examines the prevalence of psychological distress, and relationship with socio-demographic factors, and health care utilization among older Asian immigrants. Weighted data from Asian immigrants 65 and older from 5 countries (n = 1,028) who participated in the California Health Interview Survey (CHIS) were analyzed descriptively and in multiple linear regressions. The prevalence of psychological distress varied significantly across the 5 ethnic groups, from Filipinos (4.83%) to Chinese (1.64%). General health status, cognitive and physical impairment, and health care utilization are all associated (p < .05) with psychological distress in multiple linear regressions. These findings are similar to those from previous studies. The findings reinforce the need to develop more culturally effective mental health services and outreach programs. PMID- 26760295 TI - X-ray scatter correction method for dedicated breast computed tomography: improvements and initial patient testing. AB - A previously proposed x-ray scatter correction method for dedicated breast computed tomography was further developed and implemented so as to allow for initial patient testing. The method involves the acquisition of a complete second set of breast CT projections covering 360 degrees with a perforated tungsten plate in the path of the x-ray beam. To make patient testing feasible, a wirelessly controlled electronic positioner for the tungsten plate was designed and added to a breast CT system. Other improvements to the algorithm were implemented, including automated exclusion of non-valid primary estimate points and the use of a different approximation method to estimate the full scatter signal. To evaluate the effectiveness of the algorithm, evaluation of the resulting image quality was performed with a breast phantom and with nine patient images. The improvements in the algorithm resulted in the avoidance of introduction of artifacts, especially at the object borders, which was an issue in the previous implementation in some cases. Both contrast, in terms of signal difference and signal difference-to-noise ratio were improved with the proposed method, as opposed to with the correction algorithm incorporated in the system, which does not recover contrast. Patient image evaluation also showed enhanced contrast, better cupping correction, and more consistent voxel values for the different tissues. The algorithm also reduces artifacts present in reconstructions of non-regularly shaped breasts. With the implemented hardware and software improvements, the proposed method can be reliably used during patient breast CT imaging, resulting in improvement of image quality, no introduction of artifacts, and in some cases reduction of artifacts already present. The impact of the algorithm on actual clinical performance for detection, diagnosis and other clinical tasks in breast imaging remains to be evaluated. PMID- 26760296 TI - A Standardized Reference Data Set for Vertebrate Taxon Name Resolution. AB - Taxonomic names associated with digitized biocollections labels have flooded into repositories such as GBIF, iDigBio and VertNet. The names on these labels are often misspelled, out of date, or present other problems, as they were often captured only once during accessioning of specimens, or have a history of label changes without clear provenance. Before records are reliably usable in research, it is critical that these issues be addressed. However, still missing is an assessment of the scope of the problem, the effort needed to solve it, and a way to improve effectiveness of tools developed to aid the process. We present a carefully human-vetted analysis of 1000 verbatim scientific names taken at random from those published via the data aggregator VertNet, providing the first rigorously reviewed, reference validation data set. In addition to characterizing formatting problems, human vetting focused on detecting misspelling, synonymy, and the incorrect use of Darwin Core. Our results reveal a sobering view of the challenge ahead, as less than 47% of name strings were found to be currently valid. More optimistically, nearly 97% of name combinations could be resolved to a currently valid name, suggesting that computer-aided approaches may provide feasible means to improve digitized content. Finally, we associated names back to biocollections records and fit logistic models to test potential drivers of issues. A set of candidate variables (geographic region, year collected, higher level clade, and the institutional digitally accessible data volume) and their 2 way interactions all predict the probability of records having taxon name issues, based on model selection approaches. We strongly encourage further experiments to use this reference data set as a means to compare automated or computer-aided taxon name tools for their ability to resolve and improve the existing wealth of legacy data. PMID- 26760299 TI - Dating of Pregnancy in First versus Second Trimester in Relation to Post-Term Birth Rate: A Cohort Study. AB - OBJECTIVES: To evaluate in a national standardised setting whether the performance of ultrasound dating during the first rather than the second trimester of pregnancy had consequences regarding the definition of pre- and post term birth rates. METHODS: A cohort study of 8,551 singleton pregnancies with spontaneous delivery was performed from 2006 to 2012 at Copenhagen University Hospital, Holbaek, Denmark. We determined the duration of pregnancy calculated by last menstrual period, crown rump length (CRL), biparietal diameter (1st trimester), BPD (2nd trimester), and head circumference and compared mean and median durations, the mean differences, the systematic discrepancies, and the percentages of pre-term and post-term pregnancies in relation to each method. The primary outcomes were post-term and pre-term birth rates defined by different dating methods. RESULTS: The change from use of second to first trimester measurements for dating was associated with a significant increase in the rate of post-term deliveries from 2.1-2.9% and a significant decrease in the rate of pre term deliveries from 5.4-4.6% caused by systematic discrepancies. Thereby 25.1% would pass 41 weeks when GA is defined by CRL and 17.3% when BPD (2nd trimester) is used. Calibration for these discrepancies resulted in a lower post-term birth rate, from 3.1-1.4%, when first compared to second trimester dating was used. CONCLUSIONS: Systematic discrepancies were identified when biometric formulas were used to determine duration of pregnancy. This should be corrected in clinical practice to avoid an overestimation of post-term birth and unnecessary inductions when first trimester formulas are used. PMID- 26760297 TI - MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria. AB - MPV17 is a mitochondrial inner membrane protein whose dysfunction causes mitochondrial DNA abnormalities and disease by an unknown mechanism. Perturbations of deoxynucleoside triphosphate (dNTP) pools are a recognized cause of mitochondrial genomic instability; therefore, we determined DNA copy number and dNTP levels in mitochondria of two models of MPV17 deficiency. In Mpv17 ablated mice, liver mitochondria showed substantial decreases in the levels of dGTP and dTTP and severe mitochondrial DNA depletion, whereas the dNTP pool was not significantly altered in kidney and brain mitochondria that had near normal levels of DNA. The shortage of mitochondrial dNTPs in Mpv17-/- liver slows the DNA replication in the organelle, as evidenced by the elevated level of replication intermediates. Quiescent fibroblasts of MPV17-mutant patients recapitulate key features of the primary affected tissue of the Mpv17-/- mice, displaying virtual absence of the protein, decreased dNTP levels and mitochondrial DNA depletion. Notably, the mitochondrial DNA loss in the patients' quiescent fibroblasts was prevented and rescued by deoxynucleoside supplementation. Thus, our study establishes dNTP insufficiency in the mitochondria as the cause of mitochondrial DNA depletion in MPV17 deficiency, and identifies deoxynucleoside supplementation as a potential therapeutic strategy for MPV17-related disease. Moreover, changes in the expression of factors involved in mitochondrial deoxynucleotide homeostasis indicate a remodeling of nucleotide metabolism in MPV17 disease models, which suggests mitochondria lacking functional MPV17 have a restricted purine mitochondrial salvage pathway. PMID- 26760298 TI - Epigenetic Pattern on the Human Y Chromosome Is Evolutionarily Conserved. AB - DNA methylation plays an important role for mammalian development. However, it is unclear whether the DNA methylation pattern is evolutionarily conserved. The Y chromosome serves as a powerful tool for the study of human evolution because it is transferred between males. In this study, based on deep-rooted pedigrees and the latest Y chromosome phylogenetic tree, we performed epigenetic pattern analysis of the Y chromosome from 72 donors. By comparing their respective DNA methylation level, we found that the DNA methylation pattern on the Y chromosome was stable among family members and haplogroups. Interestingly, two haplogroup specific methylation sites were found, which were both genotype-dependent. Moreover, the African and Asian samples also had similar DNA methylation pattern with a remote divergence time. Our findings indicated that the DNA methylation pattern on the Y chromosome was conservative during human male history. PMID- 26760300 TI - AMS Radiocarbon Dating of Large Za Baobabs (Adansonia za) of Madagascar. AB - The article reports the radiocarbon investigation of Anzapalivoro, the largest za baobab (Adansonia za) specimen of Madagascar and of another za, namely the Big cistern baobab. Several wood samples collected from the large inner cavity and from the outer part/exterior of the tree were investigated by AMS (accelerator mass spectrometry) radiocarbon dating. For samples collected from the cavity walls, the age values increase with the distance into the wood up to a point of maximum age, after which the values decrease toward the outer part. This anomaly of age sequences indicates that the inner cavity of Anzapalivoro is a false cavity, practically an empty space between several fused stems disposed in a ring shaped structure. The radiocarbon date of the oldest sample was 780 +/- 30 bp, which corresponds to a calibrated age of around 735 yr. Dating results indicate that Anzapalivoro has a closed ring-shaped structure, which consists of 5 fused stems that close a false cavity. The oldest part of the biggest za baobab has a calculated age of 900 years. We also disclose results of the investigation of a second za baobab, the Big cistern baobab, which was hollowed out for water storage. This specimen, which consists of 4 fused stems, was found to be around 260 years old. PMID- 26760301 TI - Birds of Two Oceans? Trans-Andean and Divergent Migration of Black Skimmers (Rynchops niger cinerascens) from the Peruvian Amazon. AB - Seasonal flooding compels some birds that breed in aquatic habitats in Amazonia to undertake annual migrations, yet we know little about how the complex landscape of the Amazon region is used seasonally by these species. The possibility of trans-Andes migration for Amazonian breeding birds has largely been discounted given the high geographic barrier posed by the Andean Cordillera and the desert habitat along much of the Pacific Coast. Here we demonstrate a trans-Andes route for Black Skimmers (Rynchops niger cinerascens) breeding on the Manu River (in the lowlands of Manu National Park, Peru), as well as divergent movement patterns both regionally and across the continent. Of eight skimmers tracked with satellite telemetry, three provided data on their outbound migrations, with two crossing the high Peruvian Andes to the Pacific. A third traveled over 1800 km to the southeast before transmissions ended in eastern Paraguay. One of the two trans-Andean migrants demonstrated a full round-trip migration back to its tagging location after traveling down the Pacific Coast from latitude 9 degrees South to latitude 37 degrees S, spending the austral summer in the Gulf of Arauco, Chile. This is the first documentation of a trans Andes migration observed for any bird breeding in lowland Amazonia. To our knowledge, this research also documents the first example of a tropical-breeding waterbird migrating out of the tropics to spend the non-breeding season in the temperate summer, this being the reverse pattern with respect to seasonality for austral migrants in general. PMID- 26760303 TI - Correction: Early Loss of Splenic Tfh Cells in SIV-Infected Rhesus Macaques. AB - [This corrects the article DOI: 10.1371/journal.ppat.1005287.]. PMID- 26760304 TI - Sophisticated Communication in the Brazilian Torrent Frog Hylodes japi. AB - Intraspecific communication in frogs plays an important role in the recognition of conspecifics in general and of potential rivals or mates in particular and therefore with relevant consequences for pre-zygotic reproductive isolation. We investigate intraspecific communication in Hylodes japi, an endemic Brazilian torrent frog with territorial males and an elaborate courtship behavior. We describe its repertoire of acoustic signals as well as one of the most complex repertoires of visual displays known in anurans, including five new visual displays. Previously unknown in frogs, we also describe a bimodal inter-sexual communication system where the female stimulates the male to emit a courtship call. As another novelty for frogs, we show that in addition to choosing which limb to signal with, males choose which of their two vocal sacs will be used for visual signaling. We explain how and why this is accomplished. Control of inflation also provides additional evidence that vocal sac movement and color must be important for visual communication, even while producing sound. Through the current knowledge on visual signaling in Neotropical torrent frogs (i.e. hylodids), we discuss and highlight the behavioral diversity in the family Hylodidae. Our findings indicate that communication in species of Hylodes is undoubtedly more sophisticated than we expected and that visual communication in anurans is more widespread than previously thought. This is especially true in tropical regions, most likely due to the higher number of species and phylogenetic groups and/or to ecological factors, such as higher microhabitat diversity. PMID- 26760302 TI - Academic Cross-Pollination: The Role of Disciplinary Affiliation in Research Collaboration. AB - Academic collaboration is critical to knowledge production, especially as teams dominate scientific endeavors. Typical predictors of collaboration include individual characteristics such as academic rank or institution, and network characteristics such as a central position in a publication network. The role of disciplinary affiliation in the initiation of an academic collaboration between two investigators deserves more attention. Here, we examine the influence of disciplinary patterns on collaboration formation with control of known predictors using an inferential network model. The study group included all researchers in the Institute of Clinical and Translational Sciences (ICTS) at Washington University in St. Louis. Longitudinal data were collected on co-authorships in grants and publications before and after ICTS establishment. Exponential-family random graph models were used to build the network models. The results show that disciplinary affiliation independently predicted collaboration in grant and publication networks, particularly in the later years. Overall collaboration increased in the post-ICTS networks, with cross-discipline ties occurring more often than within-discipline ties in grants, but not publications. This research may inform better evaluation models of university-based collaboration, and offer a roadmap to improve cross-disciplinary collaboration with discipline-informed network interventions. PMID- 26760305 TI - The COX-2-Selective Antagonist (NS-398) Inhibits Choroidal Neovascularization and Subretinal Fibrosis. AB - Choroidal neovascularization (CNV) is an important pathologic component of neovascular age-related macular degeneration (AMD), and CNV lesions later develop into fibrous scars, which contribute to the loss of central vision. Nowadays, the precise molecular and cellular mechanisms underlying CNV and subretinal fibrosis have yet to be fully elucidated. Cyclooxygenase-2 (COX-2) has previously been implicated in angiogenesis and fibrosis. However, the role of COX-2 in the pathogenesis of CNV and subretinal fibrosis is poorly understood. The present study reveals several important findings concerning the relationship of COX-2 signaling with CNV and subretinal fibrosis. Experimental CNV lesions were attenuated by the administration of NS-398, a COX-2-selective antagonist. NS-398 induced CNV suppression was found to be mediated by the attenuation of macrophage infiltration and down-regulation of VEGF in the retinal pigment epithelium choroid complex. Additionally, NS-398 attenuated subretinal fibrosis, in an experimental model of subretinal scarring observed in neovascular AMD, by down regulation of TGF-beta2 in the retinal pigment epithelium-choroid complex. Moreover, we cultured mouse RPE cells and found that NS-398 decreased the secretion of VEGF and TGF-beta2 in mouse RPE cells. The results of the present study provide new findings regarding the molecular basis of CNV and subretinal fibrosis, and provide a proof-of-concept approach for the efficacy of COX-2 inhibition in treating subretinal fibrosis. PMID- 26760306 TI - Biomechanical and biochemical regulation of cathepsin K expression in endothelial cells converge at AP-1 and NF-kappaB. AB - Cathepsins K and V are powerful elastases elevated in endothelial cells by tumor necrosis factor-alpha (TNFalpha) stimulation and disturbed blood flow both of which contribute to inflammation-mediated arterial remodeling. However, mechanisms behind endothelial cell integration of biochemical and biomechanical cues to regulate cathepsin production are not known. To distinguish these mechanisms, human aortic endothelial cells (HAECs) were stimulated with TNFalpha and exposed to pro-remodeling or vasoprotective shear stress profiles. TNFalpha upregulated cathepsin K via JNK/c-jun activation, but vasoprotective shear stress inhibited TNFalpha-stimulated cathepsin K expression. JNK/c-jun were still phosphorylated, but cathepsin K mRNA levels were significantly reduced to almost null indicating separate biomechanical regulation of cathepsin K by shear stress separate from biochemical stimulation. Treatment with Bay 11-7082, an inhibitor of IkappaBalpha phosphorylation, was sufficient to block induction of cathepsin K by both pro-remodeling shear stress and TNFalpha, implicating NF-kappaB as the biomechanical regulator, and its protein levels were reduced in HAECs by vasoprotective shear stress. In conclusion, NF-kappaB and AP-1 activation were necessary to activate cathepsin K expression in endothelial cells, highlighting integration of biochemical and biomechanical stimuli to control cathepsins K and V, powerful elastases implicated for arterial remodeling due to chronic inflammation and disturbed blood flow. PMID- 26760307 TI - New insights into the substrate specificity of macrophage elastase MMP-12. AB - Macrophage elastase, or MMP-12, is mainly produced by alveolar macrophages and is believed to play a major role in the development of chronic obstructive pulmonary disease (COPD). The catalytic domain of MMP-12 is unique among MMPs in that it is very highly active on numerous substrates including elastin. However, measuring MMP-12 activity in biological fluids has been hampered by the lack of highly selective substrates. We therefore synthesized four series of fluorogenic peptide substrates based on the sequences of MMP-12 cleavage sites in its known substrates. Human MMP-12 efficiently cleaved peptide substrates containing a Pro at P3 in the sequence Pro-X-X?Leu but lacked selectivity towards these substrates compared to other MMPs, including MMP-2, MMP-7, MMP-9 and MMP-13. On the contrary, the substrate Abz-RNALAVERTAS-EDDnp derived from the CXCR5 chemokine was the most selective substrate for MMP-12 ever reported. All substrates were cleaved more efficiently by full-length MMP-12 than by its catalytic domain alone, indicating that the C-terminal hemopexin domain influences substrate binding and/or catalysis. Docking experiments revealed unexpected interactions between the peptide substrate Abz-RNALAVERTAS-EDDn and MMP-12 residues. Most of our substrates were poorly cleaved by murine MMP-12 suggesting that human and murine MMP-12 have different substrate specificities despite their structural similarity. PMID- 26760309 TI - Multiple qualitative and quantitative methods for free light chain analysis are necessary as first line tests for AL amyloidosis. AB - The objective of this study was to demonstrate the necessity of using different methods for amyloidogenic light chain detection. Serum and urine agarose gel electrophoresis and immunofixation, as well as serum free light chain (FLC) immunoassay measurements, were evaluated in a patient with verified multiple myeloma and consequent AL amyloidosis confirmed by Congo red staining and immunofluorescence techniques. Conventional chemistry tests [serum and urine electrophoresis (SPE and UPE); serum and urine immunofixation (SIFE and UIFE)] were inconclusive. Only quantitative FLC immunoassay (serum free light chain immunoanalysis, SFLC) provided correct diagnostic information. A combination of gel-based SIFE and UIFE with more novel quantitative FLC immunoassays appears necessary when searching for monoclonal immunoglobulin light chain-related diseases. PMID- 26760310 TI - Sigma metric or defects per million opportunities (DPMO): the performance of clinical laboratories should be evaluated by the Sigma metrics at decimal level with DPMOs. PMID- 26760311 TI - Brivaracetam for the treatment of epilepsy. AB - INTRODUCTION: Approximately one third of patients with epilepsy fail to respond to existing medications. Levetiracetam is an effective antiepileptic drug (AED) postulated to act by binding to synaptic vesicle protein 2A. Brivaracetam is a novel high affinity SV2A ligand with approximately 20-fold higher affinity for SV2A protein than levetiracetam. It is at an advanced stage of clinical development for treatment of epilepsy. AREAS COVERED: This article reviews animal data, pharmacokinetics, and phase 1-3 data of Brivaracetam treatment of epilepsy. Brivaracetam has broad-spectrum anticonvulsant activity in animal models. EXPERT OPINION: Phase 1 studies indicated that single oral doses of 5-800 mg and repeated oral doses of up to 600 mg were well tolerated and showed favorable pharmacokinetic profile. Phase 2 studies indicated good safety and tolerability of brivaracetam in the dose range of 5-150 mg/day and provided proof of concept for efficacy in treating refractory partial onset seizures. Efficacy and safety have been evaluated in 4 phase 3 studies with dose range of 5-200 mg which have demonstrated efficacy in the range of 100-200 mg/day dose and, in most studies, also with 50 mg/day dose, and good safety and tolerability profile across 5-200 mg doses in adjunctive treatment of refractory partial onset seizures. PMID- 26760308 TI - RAS and downstream RAF-MEK and PI3K-AKT signaling in neuronal development, function and dysfunction. AB - In postmitotic neurons, the activation of RAS family small GTPases regulates survival, growth and differentiation. Dysregulation of RAS or its major effector pathway, the cascade of RAF-, mitogen-activated and extracellular-signal regulated kinase kinases (MEK), and extracellular-signal regulated kinases (ERK) causes the RASopathies, a group of neurodevelopmental disorders whose pathogenic mechanisms are the subject of intense research. I here summarize the functions of RAS-RAF-MEK-ERK signaling in neurons in vivo, and discuss perspectives for harnessing this pathway to enable novel treatments for nervous system injury, the RASopathies, and possibly other neurological conditions. PMID- 26760314 TI - Phenotypic switching of Candida tropicalis is associated with cell damage in epithelial cells and virulence in Galleria mellonella model. PMID- 26760312 TI - Mechanoprotection by skeletal muscle caveolae. AB - Caveolae, small bulb-like pits, are the most abundant surface feature of many vertebrate cell types. The relationship of the structure of caveolae to their function has been a subject of considerable scientific interest in view of the association of caveolar dysfunction with human disease. In a recent study Lo et al. (1) investigated the organization and function of caveolae in skeletal muscle. Using quantitative 3D electron microscopy caveolae were shown to be predominantly organized into multilobed structures which provide a large reservoir of surface-connected membrane underlying the sarcolemma. These structures were preferentially disassembled in response to changes in membrane tension. Perturbation or loss of caveolae in mouse and zebrafish models suggested that caveolae can protect the muscle sarcolemma against damage in response to excessive membrane activity. Flattening of caveolae to release membrane into the bulk plasma membrane in response to increased membrane tension can allow cell shape changes and prevent membrane rupture. In addition, disassembly of caveolae can have widespread effects on lipid-based plasma membrane organization. These findings suggest that the ability of the caveolar membrane system to respond to mechanical forces is a crucial evolutionarily-conserved process which is compromised in disease conditions associated with mutations in key caveolar components. PMID- 26760313 TI - Profile of the Pleximmune blood test for transplant rejection risk prediction. AB - The PleximmuneTM test (Plexision Inc., Pittsburgh, PA, USA) is the first cell based test approved by the US FDA, which predicts acute cellular rejection in children with liver- or intestine transplantation. The test addresses an unmet need to improve management of immunosuppression, which incurs greater risks of opportunistic infections and Epstein-Barr virus-induced malignancy during childhood. High-dose immunosuppression and recurrent rejection after intestine transplantation also result in a 5-year graft loss rate of up to 50%. Such outcomes seem increasingly unacceptable because children can experience rejection free survival with reduced immunosuppression. Pleximmune test sensitivity and specificity for predicting acute cellular rejection is 84% and 80% respectively in training set-validation set testing of 214 children. Among existing gold standards, the biopsy detects but cannot predict rejection. Anti-donor antibodies, which presage antibody-mediated injury, reflect late-stage allosensitization as a downstream effect of engagement between recipient and donor cells. Therefore, durable graft and patient outcomes also require accurate management of cellular immune responses in clinical practice. PMID- 26760316 TI - The HIV-Infected Adult Patient In The Emergency Department, The Changing Landscape Of Disease. AB - The care of the HIV-infected patient in the emergency department has changed since the development of highly active antiretroviral therapy. This therapy has resulted in longer life expectancies and increased quality of life for HIV infected patients, and in cases of treatment compliance and success, virtual elimination of AIDS-associated opportunistic infections. As a result, the emergency clinician is now more often confronted with adverse events related to medication and the diseases associated with aging and chronic disease. This issue focuses on the differences in evaluation of HIV patients on long-term therapy and patients with medication noncompliance and low CD4 counts, as well as recognition of life-threatening and rare opportunistic infections. Disease processes related to the effect of longstanding HIV infection, even with good control, on many organ systems are addressed. PMID- 26760317 TI - Nearly perfect valley filter in silicene. AB - We demonstrate theoretically how a perfect valley filter can be obtained in silicene under the effects of a ferromagnetic stripe and an electric field perpendicular to silicene. A ferromagnetic stripe or an electric field alone can not generate any valley polarization in silicene, but a combination of them can make a perfect valley filter. Two configurations, one with magnetization of the ferromagnetic stripe being perpendicular to the silicene plane and one being parallel to the current direction, are considered. Our proposed device is useful for the realization of a valley beam filter in the development of valleytronic devices. PMID- 26760315 TI - Response of biopolymer networks governed by the physical properties of cross linking molecules. AB - In this study, we examine how the physical properties of cross-linking molecules affect the bulk response of bio-filament networks, an outstanding question in the study of biological gels and the cytoskeleton. We show that the stress-strain relationship of such networks typically undergoes linear increase - strain hardening - stress serration - total fracture transitions due to the interplay between the bending and stretching of individual filaments and the deformation and breakage of cross-linkers. Interestingly, the apparent network modulus is found to scale with the linear and rotational stiffness of the crosslinks to a power exponent of 0.78 and 0.13, respectively. In addition, the network fracture energy will reach its minimum at intermediate rotational compliance values, reflecting the fact that most of the strain energy will be stored in the distorted filaments with rigid cross-linkers while the imposed deformation will be "evenly" distributed among significantly more crosslinking molecules with high rotational compliance. PMID- 26760319 TI - Administration of BAY 41-2272 prevents bladder dysfunction in nitric-oxide deficient rats. AB - OBJECTIVE: to evaluate the protective effects of BAY 41-2272, a soluble guanylate cyclase activator, on changes in cystometric parameters in rats deficient in nitric oxide (NO). METHODS: Rats were divided into the following groups: (a) control; (b) DMSO; (c) L-NAME; (d) BAY 41-2272 alone; (e) L-NAME + BAY 41-2272. The NO synthase blocker L-NAME (20 mg/rat/day) was given in drinking water concomitantly or not with BAY 41-2272 (10 mg/kg/day, given by gavage). RESULTS: Chronic L-NAME treatment markedly increased the mean arterial blood pressure, and co-treatment with BAY 41-2272 nearly reversed L-NAME-induced rise on mean arterial blood pressure. Non-void contractions were significantly increased in L NAME group (0.90 +/- 0.1 number/minute) compared with either DMSO or control group (0.49 +/- 0.1 number/minute), which were prevented by co-treatment with BAY 41-2272 (0.56 +/- 025 number/minute; p < 0.05). The threshold and peak pressure increased by 70 and 44%, respectively, after chronic L-NAME treatment, while co treatment with BAY 41-2272 largely attenuated both effects (27 and 22% increase, respectively). The frequency of micturition cycles decreased by about of 50% in L NAME-treated rats compared with control animals, and co-treatment with BAY 41 2272 normalized this parameter. CONCLUSIONS: Our data show that long-term oral administration of BAY 41-2272 counteracts the bladder dysfunction seen in NO deficient rats, indicating that restoration of the NO-cGMP pathway by this compound may be of beneficial value to treat bladder symptoms. PMID- 26760318 TI - Sexuality in women with polycystic ovary syndrome: a pilot study. AB - OBJECTIVE: The objective of this study was to evaluate the sexual behavior of women with polycystic ovary syndrome and the relationship between sexual behavior and the clinical parameters related to this syndrome (obesity, hirsutism and menstrual irregularities). METHODS: A cross-sectional study was carried out involving 48 women with polycystic ovary syndrome. The evaluation was based on the complaints reported by the women with particular emphasis on sexual satisfaction, the presence of a sexual partner, phases of the sexual response cycle (desire, arousal, orgasm and resolution phases), sexual frequency, practice of masturbation, evaluation of less usual sexual habits, degree of intimacy and the quality of communication in the women's involvement with their sexual partner. The variables of sexual behavior (sexual satisfaction, masturbation, sexual fantasies, frequency of desire, arousal and orgasm) were compared with three clinical parameters: menstrual cycle, hirsutism and body mass index (BMI). RESULTS: The sexual initiation, ways of expressing sexuality, communication and intimacy with partner and sexual satisfaction were not influenced by the clinical aspects of the syndrome. With respect to association of polycystic ovary syndrome clinical parameters with sexual behavior, a statistically significant correlation was found with the menstrual cycle. CONCLUSION: The absence of menstruation affected sexual interest in activities not involving the partner, thus increasing the frequency of masturbation. PMID- 26760320 TI - An outbreak of norovirus infection in a long-term care facility in Brazil. AB - OBJECTIVE: To describe a norovirus outbreak in a Brazilian long-term care facility from July 8 to 29, 2005. METHODS: In the first 48 to 72 hours after onset of symptoms in inpatients and employees, the main infection control strategies were staff education, emphasis on hand washing, implementing contact precautions up to 48-72 hours after resolution of symptoms, complete cleaning of the rooms and exclusion of symptomatic employees from work until 48-72 hours after resolution of their symptoms. Epidemiological and clinical characteristics of the norovirus infections were described based on chart review. RESULTS: The incidence among inpatients and employees was 41.3% and 16.25%, respectively. The main symptom was diarrhea, affecting 100% of inpatients and employees. Forty-four percent of specimens were positive by RIDASCREEN(r) Norovirus analyses, and identified as norovirus genogroup GII. Seventy percent of inpatients were women and their age range was 51-98 years. Inpatients had in average two comorbid conditions - 87.3% with cardiovascular or chronic pulmonary condition and 47.6% with dementia. There was not relapse or death. CONCLUSIONS: The early infection control measures associated to surveillance are required to keep long-term care facilities free of noroviruses and to protect those who are most vulnerable. PMID- 26760321 TI - Evaluation of the concentration of malondialdehyde and nitrite in patients with sickle cell anemia treated or not with hydroxyurea. AB - OBJECTIVE: To determine the serum levels of malondialdehyde and nitrite in patients with sickle cell anemia treated or not with hydroxyurea in outpatient's setting. METHODS: Of the 65 patients with sickle cell anemia selected for the study, 51 were not treated with hydroxyurea (Group 1), 14 made chronic use of hydroxyurea (Group 2) and 20 individuals had no hemoglobinopathies (Control Group). RESULTS: The Control Group had a lower and more homogeneous concentration of malondialdehyde levels as compared to the other groups. The results of Groups 1 and 2 showed increased values of malondialdehyde levels when compared to the Control Group. Considering the values of Groups 1 and 2, there were no significant changes in the malondialdehyde levels. There was no significant difference in the serum levels of nitrite between the groups. Group 2 presented a statistically significant correlation between serum malondialdehyde levels and the clinical variables investigated. In turn, Group 1 showed correlation only with occurrence of three or more vaso-occlusive crises. There was no correlation between nitrite levels and the clinical variables. CONCLUSION: The results revealed that during the pathogenesis of sickle cell anemia, an increase in lipid peroxidation was observed. On the other hand, no changes in oxidative parameters were detected during treatment with hydroxyurea, probably due to the short period of treatment of the patients studied. PMID- 26760322 TI - Physical activity and stress coping in the elderly. AB - OBJECTIVE: To analyze the value of a physical activity program on stress coping of the elderly. METHODS: Intervention study with a group of 18 elderly people referred by the Geriatric Service of the Hospital das Clinicas of the Universidade de Sao Paulo, who attended a supervised exercise program, evaluated by the human activity profile and the coping questionnaire. RESULTS: In the coping and functional performance scales, increased stress coping capacity and improvement of daily activities were found after exposure to a physical activity program. CONCLUSIONS: The practice of supervised and regular physical activity, combining aerobic, resistance, stretching, and respiratory exercises, yields positive effects in the coping capacity and in the accomplishment of the daily activities. PMID- 26760323 TI - Evaluation of semen parameters in semen donors in a ten-year period in the city of Sao Paulo. AB - OBJECTIVE: To evaluate sperm concentration, morphology and motility of Brazilian semen donors from 1992 to 2003, in the city of Sao Paulo. METHODS: Retrospective study analyzing 182 donor semen samples from 1992 to 2003. The first and the second donated sample were analyzed for each donor. Donor average age was 30.8 years. Means with standard errors, medians with minimum and maximum values, and interquartile ranges were calculated for age, sperm concentration, semen volume, oval morphology and motility. The relation between each characteristic of the semen samples and the year of donation, as well as donor age and season of the year were studied by linear and multiple regression analysis. RESULTS: Linear regression analysis showed that the sperm concentration (R2 = 19.1%, R2 = 20.2%, p < 0.0001 respectively) and the oval morphology (R2 = 13%; R2 = 13.5%; p < 0.0001, respectively) decreased significantly, even when the first or the second sperm collection is considered. The ejaculated volume showed slight increase during the period for both samples (R2 = 2.2%, p = 0.048; R-sq = 2.4%. p = 0.038, respectively). All characteristics did not depend on the donors' age or season of the year when the samples were obtained. CONCLUSIONS: There was a decrease in spermatic concentration and percentage of oval sperm of semen donors samples from 1992 to 2003, in the city of Sao Paulo. PMID- 26760324 TI - Diagnosis of growing pains in a Brazilian pediatric population: a prospective investigation. AB - OBJECTIVE: To establish the clinical aspects of growing pains and to determine, through differential diagnosis, how many patients who referred themselves to a specialized clinic were found to have growing pains. METHODS: This study prospectively examined the presence of growing pains in a self-reported population of children and adolescents with signs and symptoms (lower limb pains) of unexplained etiology. RESULTS: A total of 345 children and adolescents were evaluated; 174 (50.4%) were males and 171 (49.6%) were females. Three hundred cases were classified as growing pains (87%). CONCLUSION: A high frequency of growing pains was found in our study population and it shows that in a prospective evaluation of patients with signs and symptoms of unknown etiology we can find a frequency higher than that reported in literature. PMID- 26760325 TI - A descriptive study of prostate cancer mortality in the state of Sao Paulo, from 1980 to 2007. AB - OBJECTIVE: Prostate cancer is the second most common neoplasm among men worldwide. This study aimed to examine the trend in mortality rates of prostate cancer among the population in the state of Sao Paulo, Brazil, from 1980 to 2007. METHODS: a descriptive study of temporal series was conducted using mortality data due to prostate cancer between1980 and 2007 in the state of Sao Paulo. Mortality rates were obtained from the SUS Information System on Mortality (SIM/SUS - DATASUS). The age-specific mortality rates were calculated as well as linear regression and temporal trend analysis. RESULTS: It could be observed that mortality increased according to age, being very similar only between the age group 70-79 years and >= 80 years (p = 0.047). The mortality peak in the age group 50-79 years occurred at the same time; however, the drop in mortality rates since then has been much more pronounced in the group of 50-59 years. There was a linear increase and direct association between the number of biopsies and the incidence of prostate cancer (r = 0.714, p = 0.024). CONCLUSIONS: Prostate cancer is a major cause of mortality in Sao Paulo and effective screening and treatment measures should be adopted to improve this scenario. PMID- 26760326 TI - Correlation between urodynamic tests, history and clinical findings in treatment of women with urinary incontinence. AB - OBJECTIVE: The aim of this study was to evaluate the role of urodynamic test in diagnosis of urinary incontinence, comparing detailed data of history and physical examination, and some easy- to-apply clinical tests. METHODS: A cross sectional retrospective study was carried out by reviewing the medical charts of 55 patients with complaint of loss of urine, seen at the Urogynecology Service of Women's Health Outpatient Clinic of Hospital Universitario de Jundiai, between October 2006 and March 2007. The patients answered a specific questionnaire involving the epidemiological and physical examination variables considered in this study. They were submitted to physical examination and urodynamic tests. RESULTS: The complaint of loss of urine upon exertion, either isolated or associated with urge incontinence, was confirmed by urodynamic tests in most women, and only 4 of 49 symptomatic women had negative results. The clinical sign was present in 35 patients (63.6%), and 46 patients (83.6%) had the exertion component in the urodynamic test. The exertion component was observed in 10 (18%) out of 15 patients without symptoms (30%). The positive and negative predictive values of the clinical sign for diagnosis of any type of urinary incontinence in this studied group were 97.1 and 26.7%, respectively. As for the clinical complaint of urinary loss upon exertion, the positive and negative predictive values for any type of urinary incontinence were 92 and 40%, respectively. For the clinical complaint of urge incontinence, the positive and negative predictive values of 92.5 and 23.1%, respectively. CONCLUSIONS: It was concluded that the urodynamic evaluation is an important instrument to evaluate the severity of incontinence, although it was not necessary to diagnose loss of urine. The finding of urinary loss during physical examination had low sensitivity and specificity in diagnosis of the type of loss of urine. Urodynamic tests had better performance in demonstrating urinary incontinence in patients with complaint of incontinence upon exertion and without loss of urine seen upon physical examination than in confirming urge incontinence in patients with those symptoms. PMID- 26760327 TI - Expression of p53, p16 and Ki67 proteins in ductal adenocarcinoma of the pancreatic head and their relation with survival and cell differentiation. AB - OBJECTIVE: To determine the expression of p53, p16 and Ki-67 and its relevance in survival and cell differentiation. METHODS: Fifteen duodenopancreatectomized patients were included. Immunohistochemical expression of p53, p16 and Ki-67 was determined in paraffin embedded tumor blocks. The relation of these expressions with different variables was studied. RESULTS: Ninety-three per cent of tumors showed expression of p53 and p16. Ki-67 was expressed in 86.66% of tumors (labeling index - LI 11.91 +/- 9.47). The presence of combined alterations was not related to significant differences in tumor type, stage or survival; similar results were obtained analyzing isolated expressions. When groups of p16 and Ki 67 expressions where created, the median survival was not significant. However, there was a slightly better survival in patients with focal expression of p16 (median survival 20.75 versus 14.34), when compared to patients with diffuse expression. CONCLUSION: The overexpression of p53, p16 and Ki-67 was not related to survival or tumor grade, when comparing isolated or combined expressions. PMID- 26760328 TI - Adjustment of oxygen use by means of pulse oximetry: an important tool for patient safety. AB - OBJECTIVE: To assess patient's level of oxygenation by means of pulse oximetry, avoiding hypoxia (that causes rapid and severe damage), hyperoxia, and waste. METHODS: Calculations were made with a 7% margin of error and a 95% confidence interval. Physical therapists were instructed to check pulse oximetry of all patients with prescriptions for physical therapy, observing the scheduled number of procedures. RESULTS: A total of 129 patients were evaluated. Hyperoxia predominated in the sectors in which the patient was constantly monitored and hypoxia in the sectors in which monitoring was not continuous. CONCLUSIONS: Professionals involved in patient care must be made aware of the importance of adjusting oxygen use and the risk that non-adjustment represents in terms of quality of care and patient safety. PMID- 26760329 TI - Comparison between laparoscopic and subcostal mini-incision for live donor nephrectomy. AB - OBJECTIVES: The aim of this study was to compare the results of laparoscopic donor nephrectomy with open donor nephrectomy. METHODS: A non-randomized prospective analysis was conducted of living donor kidney transplantations (118 open donor nephrectomies; 57 laparoscopic donor nephrectomies) between January 2005 and December 2007 in the Kidney Transplantation Unit of Hospital das Clinicas of Faculdade de Medicina of the Universidade de Sao Paulo. RESULTS: Mean donor operative time, mean donor hospital stay, mean postoperative creatinine values, and rates of complications and graft survival were similar for both groups. A significant statistical difference in warm ischemia time was observed between the open donor nephrectomy and laparoscopic donor nephrectomy groups (p < 0.001). There was only one conversion in the laparoscopic donor nephrectomy group. CONCLUSIONS: Laparoscopic donor nephrectomy is a safe procedure for a donor nephrectomy, comparable to an open procedure with similar results despite a longer warm ischemia time. PMID- 26760330 TI - Congenital malformations in newborns of alcoholic mothers. AB - OBJECTIVE: To identify the presence of fetal alcohol syndrome, other alcohol related congenital defects, and/or neurodevelopment disorders in newborns of mothers who consumed alcohol during gestation. METHODS: In a public maternity in the city of Sao Paulo, 1,964 puerperal women were interviewed and 654 had consumed alcohol at some point during gestation. The newborns were clinically and laboratorially examined in order to identify the occurrence of fetal alcohol syndrome, congenital defects or neurodevelopment disorders related to alcohol. RESULTS: Three children were found with fetal alcohol syndrome (1.5/1,000 live births), 6 with congenital defects related to alcohol (3.0/1,000 live births), and 67 with developmental disorders related to alcohol (34.1/1,000 live births). The congenital malformations found in these children were thin or absent corpus callosum, brain cyst, asymmetry of the cerebral ventricles, meningomyelocele, cleft lip, anteverted nose, low-set ears, megaureter, hydronephrosis, polydactyly, congenital clubfoot, aphalangia of the toes, cryptorchidism, and hypospadia. CONCLUSION: Newborns of mothers who consumed alcohol may have congenital malformations of various organs and systems, and early diagnosis is fundamental for a probable and occasional more effective resolution and progress. PMID- 26760331 TI - [Adductor pollicis muscle and hand grip strength: potential methods of nutritional assessment in outpatients with stroke]. AB - OBJECTIVE: To evaluate and compare the effectiveness of different methods used for nutritional assessment of outpatients who had hemiplegic stroke. METHODS: A cross-section study with adult and elderly patients of both genders enrolled in a rehabilitation center. The analyzed variables were anthropometric measurements, bioelectrical impedance, hand grip strength and thickness of the adductor pollicis muscle. The Pearson chi2 test was used to check the association between variables with a significance level of alpha = 5%. RESULTS: When evaluating the association between indicators of muscle mass, it was observed that the hand grip strength in both genders was positively correlated with arm muscle circumference (p = 0.0196) and lean mass (p = 0.0002). Fat mass measured by the bioelectrical impedance method already showed a significant inverse relationship with the grip (r = -0.3879). The thickness of the adductor pollicis muscle showed significant association with lean mass (p = 0.0052) and hand grip (p = 0.0024). CONCLUSION: In this study, the hand grip strength and thickness of the adductor pollicis muscle were well correlated with measurements determined by anthropometry and bioimpedance. The results show the applicability of grip strength and thickness of the adductor pollicis muscle in clinical practice as nutritional assessment methods for this population, especially elderly patients, since they detect functional changes not captured by other parameters in the short term and are important for early identification of risk nutrition. PMID- 26760332 TI - Amount of tobacco consumption is associated with superficial bladder cancer progression. AB - OBJECTIVE: To evaluate the association between smoking habits and outcome of patients with superficial bladder cancer. METHODS: A retrospective study was performed evaluating 99 patients (67.0 +/- 13.2 years, ranging from 31.4-93.4 years, 72.7% males and 27.3% females) treated at our institution with non muscle invasive bladder cancer, between 1994 and 2000, with a mean follow-up of 49.3 months (range 4.0-177.9 months). Patients were divided according to smoking status, and the main measured outcome was progression to invasive disease. Additional cohort analysis was performed dividing patients according to previous tobacco exposure: smokers and non-smokers. Smokers were stratified into former smokers, early-quitters, late quitters and continued smokers. RESULTS: Smoking habit was significantly more common in males (p = 0.03). Cancer also occurred at an earlier age among smokers (70.8 versus 64.8 years, p = 0.030). Tobacco consumption was present in 62.7% of the patients with bladder cancer. There was a significant higher progression rate to muscle-invasive disease in patients that had more than 60 pack-years of exposure (52.9 versus 26.2%, p = 0.037). These patients had a mean progression time of 59.3 months, whereas patients who had smoked less than 60 pack-years progressed after a mean time of 131.8 months. CONCLUSIONS: A direct association between the amount of tobacco consumed and disease progression is observed in patients with bladder cancer, as suggested by the present study. Tobacco consumption has a direct association with progression of superficial bladder cancer to invasive disease and also shortens the period of time for muscle invasion. Larger and prospective studies are still necessary to bring further definitive conclusions about reproducibility of our data and to better understand how smoking cessation affects progression of superficial bladder cancer. PMID- 26760333 TI - Delayed traumatic spinal epidural hematoma with neurological deficits. AB - To describe the mechanism that causes spinal epidural hematoma with neurologic deficit and review the literature. We report a case of a 62-year-old man with post-traumatic epidural hematoma in the cervicothoracic spine, who developed progressive neurological deficit which eventually resulted in complete paralysis below T1. During surgical evacuation significant spine compression due to an organizing hematoma was observed. After surgery, the patient's motor function improved and there was a complete recovery of the neurologic deficit after a rehabilitation program. CONCLUSION: Epidural hematoma can happen after delayed traumatic event leading to a variable degree of neurologic damage. PMID- 26760335 TI - Patients' anxiety before cardiac catheterization. AB - OBJECTIVE: To identify researches related to anxiety and strategies to reduce it in patients who are in the pre-cardiac catheterization period. METHODS: A bibliographic research was carried out in the on line databases of PubMed, MedLine, CINAHL, LILACS and SciELO, from 1997 to 2009 in MedLine and from 1999 to 2009 in the others databases. The boolean expressions "and" and "or" has been used with the descriptors in Portuguese and in English. The inclusion of discerning was related about the presence, level and workable of the anxiety from the period of pre-cardiac catheterization. RESULTS: Coping most of 17 researches selected were in American scientific publications, with experimental-descriptive studies. The possibilities of intercurrence and/or complications during and post procedure, diagnostic, possibility of bad prognostic, being alone during the waiting, the first time submission the procedure, lost information and/or orientation and long time waiting could cause anxiety in pre-cardiac catheterization. Maintenance of escort and family alongside the patient, information adapted to the patient understanding level, overcoming traumas and difficulties with a multiprofessional approach, pharmacologic and non pharmacologic therapies were strategies to reduce the anxiety. CONCLUSIONS: The nurses are responsible to provide a humanized assistance to offer a fast recuperation, minimize traumas of the hospitalization and the procedure. The knowledge of the causes and the strategies are fundamental to reduce the level of anxiety in pre-catheterization cardiac. PMID- 26760334 TI - Severe osteogenesis imperfecta: case report. AB - The authors present a case of Osteogenesis Imperfecta, emphasizing the clinical and epidemiological characteristics, forms of classification and treatment of the disease. This is an important case not only to the knowledge of pediatricians and orthopedists, but also for other professionals involved with the problem. This article has been jointly described by the Departments of Pediatrics and Neonatology of the Girassol Clinic in Luanda Capital of the Republic of Angola, Africa. PMID- 26760336 TI - Endovascular surgery in gynecology. AB - Endovascular surgery has presented a high evolution since 1960 with Charles Dotter, who changed the concept of catheter utilization as a mean to diagnose and introduce therapeutic in interventionist vascular environment. The first reports of bleeding control of gastrointestinal and transluminal angioplasty input the development of new techniques for endovascular access, and new materials use, such as microcatheters and embolic agents, become this procedure effective and viable for treatment of several pathologies. The embolization of several organs of human body is a procedure carried out for more than 30 years all over the world showing safety, efficacy and of simple execution. In obstetrics and gynecology, particularly, the first reports refer to pelvic hemorrhage control of varied etiology, including pelvic trauma, bladder and gynecology neoplasia, anteriovenous fistulas and puerperal hemorrhages. The embolization of uterine myoma appears in the 1990's as an alternative for treat of uterine leiomyoma, and a number of studies try to clarify the risks and benefits of this procedure. It is a multidisciplinary technique, with diagnostic and indication performed by gynecologist and the procedure done by interventional vascular radiologist. This review is a critical analysis of interventionist vascular radiologic methods and its main therapeutic indications in gynecology. PMID- 26760337 TI - Apoptosis and in vivo models to study the molecules related to this phenomenon. AB - Apoptosis or programmed cell death is a physiological process, essential for eliminating cells in excess or that are no longer necessary to the organism, acting on tissue homeostasis, although the phenomenon is also involved in pathological conditions. Apoptosis promotes activation of biochemical pathways inside cells called caspase pathway, of the proteins responsible for the cleavage of several cell substrates, leading to cell death. Antiapoptotic members of the Bcl-2 family (B cell CLL/lymphoma 2), that belong to the intrinsic route of the activation of caspases, such as Bcl-xL (extra-large B-cell lymphoma) and Bcl-w (Bcl-2-like 2), act predominantly to prevent that pro-apoptotic members, such as Bax (Bcl-2-associated X protein) and Bak (Bcl-2 relative bak) lead to cell death. Antiapoptotic molecules are considered potentially oncogenic. Murine models are known to be valuable systems for the experimental analysis of oncogenes in vivo, and for the identification of pharmacological targets for cancer and to assess antitumor therapies. Given the importance of tumorigenesis studies on the immune responses to cancer and the possibility of investigating the participation of antiapoptotic molecules in tumor progression in vivo, the development of new models may be platforms for studies on tumorigenesis, immune antitumor responses, investigation of the ectopic expression of antiapoptotic molecules and immunotherapies for tumors. PMID- 26760338 TI - PET-CT findings in arteritis. PMID- 26760339 TI - Pancreas transplantation: an overview. AB - Pancreas transplantation is the only treatment able to reestablish normal glucose and glycated hemoglobin levels in insulin-dependent diabetic patients without the use of exogenous insulin. The evolution of pancreas transplantation in treatment of diabetes was determined by advances in the fields of surgical technique, organ preservation and immunosuppressants. The main complication leading to graft loss is technical failure followed by acute or chronic rejection. Technical failure means graft loss within the first three months following transplantation due to vascular thrombosis (50%), pancreatitis (20%), infection (18%), fistula (6.5%) and bleeding (2.4%). Immunological complications still affect 30% of patients, and rejection is the cause of graft loss in 10% of cases. Chronic rejection is the most common late complication. Cardiovascular diseases are the most common causes of late mortality in pancreas transplantation, so it remains the most effective treatment for type 1 diabetes patients. There is a significant improvement in quality of life and in patient's survival rates. The development of islet transplantation could eliminate or minimize surgical complications and immunosuppression. PMID- 26760375 TI - The Acceptability of Caning Children in Singapore: The Fine Line Between Discipline and Physical Maltreatment. AB - Child maltreatment is a worldwide phenomenon with far-reaching negative consequences, and physical abuse is its most visible and widely reported form of maltreatment. There is a fine line between nonabusive physical punishment and physical child abuse, and where this line is drawn is often influenced by prevailing cultural practices and child-rearing beliefs. This article focus on Singapore-a modern Asian society that remains rooted in traditional attitudes and practices-as a case study in exploring the boundaries. In particular, the local practice of caning (hitting with a rattan cane) as a disciplinary measure for children, the ambiguity of the law on the issue of physical abuse, and the influence of judicial caning on the acceptability of this common practice are examined. Finally, the possible means of safeguarding children and discouraging the use of physical punishment in the home are discussed. PMID- 26760374 TI - Cycloartane Triterpenes from the Aerial Parts of Actaea racemosa. AB - Investigating the phytochemical equivalence of the aerial parts of Actaea racemosa (syn. Cimicifuga racemosa) relative to the widely used roots/rhizomes, this study provides a perspective for the potential use of renewable ("green") plant parts as a source of black cohosh botanical preparations. In addition to the characterization of Nomega-methylserotonin as one representative marker of the Actaea alkaloids, nine cycloartane triterpenes were isolated and characterized, including the two new triterpene glycosides (1S,15R)-1,15,25 trihydroxy-3-O-beta-d-xylopyranosyl-acta-(16S,23R,24R)-16,23;16,24-binoxoside (1) and 3-O-alpha-l-arabinopyranosyl-(1S,24R)-1,24,25-trihydroxy-15-oxo-acta (16R,23R)-16,23-monoxoside (2). Their structures were elucidated by spectroscopic data interpretation. The relative configuration of 1 was deduced by (1)H iterative full-spin analysis (HiFSA), making it the first example of the complete analysis of the complex (1)H NMR spectrum of a triterpene glycoside. In addition to the new compounds 1 and 2, the aerial plant parts were shown to contain the previously known binoxosides 3, 4, 6, and 7, the monoxoside 8, and the binoxols 5 and 9. Overall, the metabolome of the aerial plant parts consists of a variety of Actaea triterpenes, similar to those found in roots/rhizomes, a tendency toward C 1 and C-7 hydroxylation of the cycloartanol skeleton, a greater abundance of aglycones, and the presence of comparable amounts of Nomega-methylserotonin. PMID- 26760376 TI - A 9-Year-Old Girl Discovers That Her Mother Was Murdered. AB - CASE: Susan was a 9-year-old girl living with her mother; she had never met her father. Her mother returned one evening from her job as a cocktail waitress and Susan met her at the apartment door to let her know they had run out of cat food. Her mother said she would go and buy some the next morning because it was late and she was tired, but Susan insisted she go out that evening because the cat had not eaten all day. Her mother was fatally shot in the parking lot of the convenience store shortly thereafter; since there was no robbery involved, the police suspected it was someone that she knew. Susan's extended family had her move out of the apartment that evening and relocate to live with her aunt and uncle out-of-state. The transition happened quickly. Susan was unable to return to her apartment to pick up any additional belongings and never returned to say goodbye to her friends. The family decided she was too young to attend the funeral. Susan had trouble fitting in with her aunt and uncle's family; they had 2 children who were 8 and 6 years old, and Susan felt she was being treated like a baby. She resented having a bedtime (her mother allowed her to stay up as late as she wished), and she complained that the work at school was boring and her classmates were childish. When the family went to a festival in town, she left abruptly without telling them, which frightened Susan's aunt and uncle. They wanted to be supportive but felt that she needed more structure than her mother had provided her. Susan's aunt and uncle sought bereavement support for Susan from her pediatrician and parenting advice for themselves. PMID- 26760378 TI - Unnecessary numbering invites medication errors. PMID- 26760382 TI - Nurse residency program attracts and retains novice nurses. PMID- 26760377 TI - Degradation-mediated protein quality control at the inner nuclear membrane. AB - An intricate machinery protects cells from the accumulation of misfolded, non functional proteins and protein aggregates. Protein quality control pathways have been best described in the cytoplasm and the endoplasmic reticulum, however, recent findings indicate that the nucleus is also an important compartment for protein quality control. Several nuclear ubiquitinylation pathways target soluble and membrane proteins in the nucleus and mediate their degradation through nuclear proteasomes. In addition, emerging data suggest that nuclear envelope components are also degraded by autophagy, although the mechanisms by which cytoplasmic autophagy machineries get access to nuclear targets remain unclear. In this minireview we summarize the nuclear ubiquitin-proteasome pathways in yeast, focusing on pathways involved in the protein degradation at the inner nuclear membrane. In addition, we discuss potential mechanisms how nuclear targets at the nuclear envelope may be delivered to the cytoplasmic autophagy pathways in yeast and mammals. PMID- 26760381 TI - Reporting a physician colleague for unsafe practice: What's the law? PMID- 26760383 TI - Reiki's effect on patients with total knee arthroplasty: A pilot study. AB - BACKGROUND: In the immediate postoperative period, managing postsurgical pain with pain medication can contribute to complications. A more effective approach might include a combination of pharmacologic and nonpharmacologic measures, such as Reiki therapy. PURPOSE: The purpose of this pilot study was to determine the impact of Reiki therapy on the pain perception of patients undergoing total knee arthroplasty (TKA) following Reiki sessions, satisfaction with Reiki therapy, satisfaction with the hospital experience overall, and pain medication use following surgery. WHAT IS REIKI?: Reiki is a technique for relaxation and stress reduction that also promotes healing. LITERATURE REVIEW: Reiki has been studied in women undergoing abdominal hysterectomies and in patients with cancer who were receiving chemotherapy. A review of 66 biofield therapy studies, including Reiki, suggested, "strong evidence for the effects of biofield therapy in the reduction of pain intensity in pain populations and moderate evidence for decreased pain in hospitalized patients." THEORETICAL FRAMEWORK: Martha Rogers's Theory of Unitary Human Beings formed the framework for this study. METHODS: The sample included 43 patients undergoing TKA, who were randomized into Reiki (N = 23) and non-Reiki (N = 20) groups. All subjects in this pilot study had unilateral TKA at the same hospital. Pain was assessed before and after Reiki therapy using the numeric rating scale in the preoperative area, postanesthesia care unit (PACU), and on each of 3 postoperative days. A questionnaire was distributed the day of discharge to measure satisfaction with Reiki and the hospital experience. RESULTS: All Reiki therapy sessions resulted in statistically significant reductions in pain, except those sessions in the PACU. Subjects receiving Reiki responded positively to questionnaires completed on the day of discharge. No statistically significant differences were found in pain medication use. DISCUSSION: Reiki may be an effective component in the management of surgical patients' postoperative pain. LIMITATIONS AND IMPLICATIONS: Subject numbers were limited due to the difficulty of meeting with the patients and obtaining informed consent. Due to the nature of Reiki therapy, the study was not blinded. Music played during Reiki therapy could have contributed to the effect experienced by the patients. Not all questionnaires were collected before patient discharge. RECOMMENDATIONS FOR FURTHER STUDIES: Future studies should include more subjects, control for music use during the Reiki session, and measure the length of time pain is decreased following Reiki treatments. UNANTICIPATED OUTCOMES: As a result of positive feedback and decreased pain ratings following Reiki sessions, a Reiki program has been established at the hospital. Ten nurses became trained and certified in Reiki. PMID- 26760384 TI - Teaching a great online class: Six tips for nurse educators. PMID- 26760385 TI - Flying high. PMID- 26760389 TI - One of our own. PMID- 26760390 TI - The ABCDEs of nursing: Essentials for new nurses to know. PMID- 26760391 TI - Herbal supplements: Widely used, poorly understood. PMID- 26760392 TI - Tranexamic acid in the trauma patient. PMID- 26760393 TI - "Teach-back" from a patient's perspective. PMID- 26760394 TI - Assessing pain in verbal older adults. PMID- 26760397 TI - Nutritional consequences of long-term acid suppression; are they clinically important? AB - PURPOSE OF REVIEW: As acid suppression therapies with proton pump inhibitors are an extremely common practice for common acid-related diseases, there has been increased scrutiny on the safety of this class of therapy. RECENT FINDINGS: There have been increasing reports of allegation of harm with the sustained use of proton pump inhibitors, in particular with potential adverse effects on vitamin and mineral absorption. This has prompted a number of product label changes directed by the US Food and Drug Administration, raising concerns for ongoing continued use among clinicians and patients. SUMMARY: This review highlights the most recent information around these controversies and provides evidence summaries to help guide care providers in their care plans as well as discussions with patients. PMID- 26760398 TI - A gut (microbiome) feeling about the brain. AB - PURPOSE OF REVIEW: There is an increasing realization that the microorganisms which reside within our gut form part of a complex multidirectional communication network with the brain known as the microbiome-gut-brain axis. In this review, we focus on recent findings which support a role for this axis in modulating neurodevelopment and behavior. RECENT FINDINGS: A growing body of research is uncovering that under homeostatic conditions and in response to internal and external stressors, the bacterial commensals of our gut can signal to the brain through a variety of mechanisms to influence processes such neurotransmission, neurogenesis, microglia activation, and modulate behavior. Moreover, the mechanisms underlying the ability of stress to modulate the microbiota and also for microbiota to change the set point for stress sensitivity are being unraveled. Dysregulation of the gut microbiota composition has been identified in a number of psychiatric disorders, including depression. This has led to the concept of bacteria that have a beneficial effect upon behavior and mood (psychobiotics) being proposed for potential therapeutic interventions. SUMMARY: Understanding the mechanisms by which the bacterial commensals of our gut are involved in brain function may lead to the development of novel microbiome-based therapies for these mood and behavioral disorders. PMID- 26760399 TI - Leaky gut - concept or clinical entity? AB - PURPOSE OF REVIEW: This article evaluates the current status of the gut barrier in gastrointestinal disorders. RECENT FINDINGS: The gut barrier is a complex, multicomponent, interactive, and bidirectional entity that includes, but is not restricted to, the epithelial cell layer. Intestinal permeability, the phenomenon most readily and commonly studied, reflects just one (albeit an important one) function of the barrier that is intimately related to and interacts with luminal contents, including the microbiota. The mucosal immune response also influences barrier integrity; effects of inflammation per se must be accounted for in the interpretation of permeability studies in disease states. SUMMARY: Although several aspects of barrier function can be assessed in man, one must be aware of exactly what a given test measures, as well as of its limitations. The temptation to employ results from a test of paracellular flux to imply a role for barrier dysfunction in disorders thought to be based on bacterial or macromolecular translocation must be resisted. Although changes in barrier function have been described in several gastrointestinal disorders, their primacy remains to be defined. At present, few studies support efficacy for an intervention that improves barrier function in altering the natural history of a disease process. PMID- 26760400 TI - Implementing situation-background-assessment-recommendation in an anaesthetic clinic and subsequent information retention among receivers: A prospective interventional study of postoperative handovers. AB - BACKGROUND: Communication errors cause clinical incidents and adverse events in relation to surgery. To ensure proper postoperative patient care, it is essential that personnel remember and recall information given during the handover from the operating theatre to the postanaesthesia care unit. Formalizing the handover may improve communication and aid memory, but research in this area is lacking. OBJECTIVE: The objective of this study was to evaluate whether implementing the communication tool Situation-Background-Assessment-Recommendation (SBAR) affects receivers' information retention after postoperative handover. DESIGN: A prospective intervention study with an intervention group and comparison nonintervention group, with assessments before and after the intervention. SETTING: The postanaesthesia care units of two hospitals in Sweden during 2011 and 2012. PARTICIPANTS: Staff involved in the handover between the operating theatre and the postanaesthesia care units within each hospital. INTERVENTION: Implementation of the communication tool SBAR in one hospital. MAIN OUTCOME MEASURES: The main outcome was the percentage of recalled information sequences among receivers after the handover. Data were collected using both audio recordings and observations recorded on a study-specific protocol form. RESULTS: Preintervention, 73 handovers were observed (intervention group, n = 40; comparison group, n = 33) involving 72 personnel (intervention group, n = 40; comparison group, n = 32). Postintervention, 91 handovers were observed (intervention group, n = 44; comparison group, n = 47) involving 57 personnel (intervention group, n = 31; comparison group, n = 26). In the intervention group, the percentage of recalled information sequences by the receivers increased from 43.4% preintervention to 52.6% postintervention (P = 0.004) and the SBAR structure improved significantly (P = 0.028). In the comparison group, the corresponding figures were 51.3 and 52.6% (P = 0.725) with no difference in SBAR structure. When a linear regression generalised estimating equation model was used to account for confounding influences, we were unable to show a significant difference in the information recalled between the intervention group and the nonintervention group over time. CONCLUSION: Compared with the comparison group with no intervention, when SBAR was implemented in an anaesthetic clinic, we were unable to show any improvement in recalled information among receivers following postoperative handover. TRIAL REGISTRATION: Current controlled trials http://www.controlled-trials.com Identifier: ISRCTN37251313. PMID- 26760401 TI - The effect of a modified GlideScope intubation technique on procedure times, airway morbidity and haemodynamic response. PMID- 26760402 TI - Preoperative celecoxib in noncardiac surgery: A systematic review and meta analysis of randomised controlled trials. AB - BACKGROUND: Postoperative pain continues to be undertreated after noncardiac surgery. Preoperative analgesic administration may enhance postoperative analgesia. OBJECTIVE: To determine the effects of preoperative administration of celecoxib in noncardiac surgery on pain and postoperative outcomes. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: MEDLINE, EMBASE, CENTRAL, CINHAL Web of Sciences and ProQuest databases were searched from inception to 2014. Reference lists of retrieved articles and grey literature were searched for additional trials. ELIGIBILITY CRITERIA: Articles were included if they enrolled patients of at least 18 years of age and randomised patients to receive celecoxib within 4 h of noncardiac surgery. Studies were excluded if they were animal studies, reviews/meta-analyses, did not report pain as an outcome or used epidural analgesia. RESULTS: Twenty trials met the eligibility criteria. Preoperative celecoxib in 14 studies (994 patients) amenable to meta-analysis demonstrated a significant decrease in 24-h parenteral morphine-equivalent consumption (mean difference -4.13 mg, 95% confidence interval -5.58 to -2.67, I = 94%). Eleven studies (755 patients) assessed postoperative pain scores at 24 h and found a significant decrease with celecoxib use [mean difference (on a 0-10 pain scale) -1.02, 95% confidence interval -1.54 to -0.50, I = 99%]. The risks of postoperative nausea and vomiting were also decreased by 44% (P = 0.01) and 38% (P = 0.03), respectively. Preoperative celecoxib did not improve patient satisfaction or length of recovery room stay, or increase intraoperative bleeding. Subgroup analyses indicated no difference between celecoxib 200 and 400 mg or between a single preoperative dose and continued postoperative dosing. CONCLUSION: Results of this study are limited by significant heterogeneity and inclusion of mainly small trials. However, there appears to be a slight to modest benefit of preoperative celecoxib on reducing postoperative morphine consumption, pain, nausea and vomiting. PMID- 26760404 TI - On patient safety, teams and psychologically disturbed pilots. PMID- 26760403 TI - Simulation unmasks deficit in the knowledge of the WHO checklist among junior anaesthetists: Simulation scenario and survey. PMID- 26760405 TI - Correct positioning of central venous catheters with ECG guidance in paediatric patients. PMID- 26760406 TI - Bilateral hypoglossal nerve palsy and unilateral recurrent laryngeal nerve palsy following lumbar discectomy: A case report. PMID- 26760407 TI - Blind intubation through Air-Q SP laryngeal mask in morbidly obese patients. PMID- 26760409 TI - The Potential Impact of Over-the-Counter Access to Oral Contraceptives to Reduce Unintended Pregnancy. PMID- 26760412 TI - Family History, Social Media, and a Diagnostic Surprise. PMID- 26760413 TI - Treatment of Allergic Rhinitis. AB - Allergic rhinitis is a common and chronic immunoglobulin E-mediated respiratory illness that can affect quality of life and productivity, as well as exacerbate other conditions such as asthma. Treatment should be based on the patient's age and severity of symptoms. Patients should be educated about their condition and advised to avoid known allergens. Intranasal corticosteroids are the most effective treatment and should be first-line therapy for persistent symptoms affecting quality of life. More severe disease that does not respond to intranasal corticosteroids should be treated with second-line therapies, including antihistamines, decongestants, cromolyn, leukotriene receptor antagonists, and nonpharmacologic therapies such as nasal irrigation. Subcutaneous or sublingual immunotherapy should be considered if usual treatments do not adequately control symptoms and in patients with allergic asthma. Evidence does not support the use of mite-proof impermeable mattresses and pillow covers, breastfeeding, air filtration systems, or delayed exposure to solid foods in infancy or to pets in childhood. PMID- 26760414 TI - Newborn Respiratory Distress. AB - Newborn respiratory distress presents a diagnostic and management challenge. Newborns with respiratory distress commonly exhibit tachypnea with a respiratory rate of more than 60 respirations per minute. They may present with grunting, retractions, nasal flaring, and cyanosis. Common causes include transient tachypnea of the newborn, respiratory distress syndrome, meconium aspiration syndrome, pneumonia, sepsis, pneumothorax, persistent pulmonary hypertension of the newborn, and delayed transition. Congenital heart defects, airway malformations, and inborn errors of metabolism are less common etiologies. Clinicians should be familiar with updated neonatal resuscitation guidelines. Initial evaluation includes a detailed history and physical examination. The clinician should monitor vital signs and measure oxygen saturation with pulse oximetry, and blood gas measurement may be considered. Chest radiography is helpful in the diagnosis. Blood cultures, serial complete blood counts, and C reactive protein measurement are useful for the evaluation of sepsis. Most neonates with respiratory distress can be treated with respiratory support and noninvasive methods. Oxygen can be provided via bag/mask, nasal cannula, oxygen hood, and nasal continuous positive airway pressure. Ventilator support may be used in more severe cases. Surfactant is increasingly used for respiratory distress syndrome. Using the INSURE technique, the newborn is intubated, given surfactant, and quickly extubated to nasal continuous positive airway pressure. Newborns should be screened for critical congenital heart defects via pulse oximetry after 24 hours but before hospital discharge. Neonatology consultation is recommended if the illness exceeds the clinician's expertise and comfort level or when the diagnosis is unclear in a critically ill newborn. PMID- 26760415 TI - Evaluation of Patients with Leukocytosis. AB - An elevated white blood cell count has many potential etiologies, including malignant and nonmalignant causes. It is important to use age- and pregnancy specific normal ranges for the white blood cell count. A repeat complete blood count with peripheral smear may provide helpful information, such as types and maturity of white blood cells, uniformity of white blood cells, and toxic granulations. The leukocyte differential may show eosinophilia in parasitic or allergic conditions, or it may reveal lymphocytosis in childhood viral illnesses. Leukocytosis is a common sign of infection, particularly bacterial, and should prompt physicians to identify other signs and symptoms of infection. The peripheral white blood cell count can double within hours after certain stimuli because of the large bone marrow storage and intravascularly marginated pools of neutrophils. Stressors capable of causing an acute leukocytosis include surgery, exercise, trauma, and emotional stress. Other nonmalignant etiologies of leukocytosis include certain medications, asplenia, smoking, obesity, and chronic inflammatory conditions. Symptoms suggestive of a hematologic malignancy include fever, weight loss, bruising, or fatigue. If malignancy cannot be excluded or another more likely cause is not suspected, referral to a hematologist/oncologist is indicated. PMID- 26760416 TI - Chlorthalidone vs. Hydrochlorothiazide for Treatment of Hypertension. PMID- 26760417 TI - Petechiae in a Newborn. PMID- 26760423 TI - Gabapentin for Chronic Neuropathic Pain. PMID- 26760424 TI - Chemotherapy for resistant or recurrent gestational trophoblastic neoplasia. AB - BACKGROUND: Gestational trophoblastic neoplasia (GTN) is a highly curable group of pregnancy-related tumours; however, approximately 25% of GTN tumours will be resistant to, or will relapse after, initial chemotherapy. These resistant and relapsed lesions will require salvage chemotherapy with or without surgery. Various salvage regimens are used worldwide. It is unclear which regimens are the most effective and the least toxic. OBJECTIVES: To determine which chemotherapy regimen/s for the treatment of resistant or relapsed GTN is/are the most effective and the least toxic. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4), MEDLINE and EMBASE up to October 2011. In addition, we handsearched the relevant society conference proceedings and study reference lists. For the updated review, we searched Cochrane Group Specialised Register, CENTRAL, MEDLINE and EMBASE to 16 Novemeber 2015. In addition, we searched online clinical trial registries for ongoing trials. SELECTION CRITERIA: Only randomised controlled trials (RCTs) were included. DATA COLLECTION AND ANALYSIS: We designed a data extraction form and planned to use random-effects methods in Review Manager 5.1 for meta-analyses. MAIN RESULTS: The search identified no RCTs; therefore we were unable to perform any meta-analyses. AUTHORS' CONCLUSIONS: RCTs in GTN are scarce owing to the low prevalence of this disease and its highly chemosensitive nature. As chemotherapeutic agents may be associated with substantial side effects, the ideal treatment should achieve maximum efficacy with minimal side effects. For methotrexate-resistant or recurrent low-risk GTN, a common practice is to use sequential five-day dactinomycin, followed by MAC (methotrexate, dactinomycin, cyclophosphamide) or EMA/CO (etoposide, methotrexate, dactinomycin, cyclophosphamide, vinblastine) if further salvage therapy is required. However, five-day dactinomycin is associated with more side effects than pulsed dactinomycin, therefore an RCT comparing the relative efficacy and safety of these two regimens in the context of failed primary methotrexate treatment is desirable.For high-risk GTN, EMA/CO is the most commonly used first-line therapy, with platinum-etoposide combinations, particularly EMA/EP (etoposide, methotrexate, dactinomycin/etoposide, cisplatin), being favoured as salvage therapy. Alternatives, including TP/TE (paclitaxel, cisplatin/ paclitaxel, etoposide), BEP (bleomycin, etoposide, cisplatin), FAEV (floxuridine, dactinomycin, etoposide, vincristine) and FA (5-fluorouracil (5 FU), dactinomycin), may be as effective as EMA/EP and associated with fewer side effects; however, this is not clear from the available evidence and needs testing in well-designed RCTs. In the UK, an RCT comparing interventions for resistant/recurrent GTN will be very challenging owing to the small numbers of patients with this scenario. International multicentre collaboration is therefore needed to provide the high-quality evidence required to determine which salvage regimen/s have the best effectiveness-to-toxicity ratio in low- and high-risk disease. Future research should include economic evaluations and long-term surveillance for secondary neoplasms. PMID- 26760425 TI - Patient-initiated e-mails to providers: associations with out-of-pocket visit costs, and impact on care-seeking and health. AB - OBJECTIVES: To understand when patients use secure e-mail messaging with healthcare providers across several types of questions or concerns, associations between out-of-pocket costs for in-person visits and use of secure messaging, and to examine patient-reported impacts on care-seeking behavior and overall health. STUDY DESIGN: Cross-sectional survey of patients in an integrated healthcare delivery system, with access to a patient portal to send secure e-mail messages to providers at no out-of-pocket cost. METHODS: The study included patients with a chronic condition (N = 1041). We described patient-reported preferences for contacting providers and patient-reported impact of e-mail use on phone calls, in person visits, and overall health. We used multivariate analyses to examine patient characteristics associated with using e-mail as a first contact method, and effects on care-seeking and health. RESULTS: Overall, 56% of patients sent their provider an e-mail within 1 year, and 46% reported e-mail as their first method of contact for 1 or more types of medical concerns. After adjustment, higher out-of-pocket costs for in-person visits were significantly associated with choosing e-mail as a first method of contact (P < .05). Among patients who had e-mailed their provider, 42% reported that it reduced their phone contacts, 36% reduced in-person office visits and 32% reported e-mailing improved their overall health. CONCLUSIONS: Patients reported using e-mail broadly to initiate conversations with their providers, and patients with higher out-of-pocket costs for in-person visits were more likely to choose e-mail as a first contact method. Use of secure e-mails reduced patients' use of other types of healthcare and resulted in improved overall health. PMID- 26760426 TI - E-consult implementation: lessons learned using consolidated framework for implementation research. AB - OBJECTIVES: In 2011, the Veterans Health Administration (VHA) implemented electronic consults (e-consults) as an alternative to in-person specialty visits to improve access and reduce travel for veterans. We conducted an evaluation to understand variation in the use of the new e-consult mechanism and the causes of variable implementation, guided by the Consolidated Framework for Implementation Research (CFIR). STUDY DESIGN: Qualitative case studies of 3 high- and 5 low implementation e-consult pilot sites. Participants included e-consult site leaders, primary care providers, specialists, and support staff identified using a modified snowball sample. METHODS: We used a 3-step approach, with a structured survey of e-consult site leaders to identify key constructs, based on the CFIR. We then conducted open-ended interviews, focused on key constructs, with all participants. Finally, we produced structured, site-level ratings of CFIR constructs and compared them between high- and low-implementation sites. RESULTS: Site leaders identified 14 initial constructs. We conducted 37 interviews, from which 4 CFIR constructs distinguished high implementation e-consult sites: compatibility, networks and communications, training, and access to knowledge and information. For example, illustrating compatibility, a specialist at a high implementation site reported that the site changed the order of consult options so that all specialties listed e-consults first to maintain consistency. High implementation sites also exhibited greater agreement on constructs. CONCLUSIONS: By using the CFIR to analyze results, we facilitate future synthesis with other findings, and we better identify common patterns of implementation determinants common across settings. PMID- 26760427 TI - Impact of a national specialty e-consultation implementation project on access. AB - OBJECTIVES: To assess the early impact of implementation of the electronic consults (e-consults) initiative by the Veterans Health Administration (VHA), designed to improve specialty care access. STUDY DESIGN: Observational cohort study exploiting a natural experiment begun in May 2011 at 12 VHA medical centers and expanded to 122 medical centers by December 2013. METHODS: The following were assessed: 1) growth of e-consults by VHA regional networks, medical centers, and specialty; 2) location of patient's primary care provider (medical center vs community-based outpatient clinic [CBOC]); 3) potential patient miles needed to travel for a specialty care face-to-face consult in place of the observed e consults using estimated geodesic distance; 4) use of specialty care subsequent to the e-consult. RESULTS: Of 11,270,638 consults completed in 13 clinics of interest, 217,014 were e-consults (adjusted rate, 1.93 e-consults per 100 consults). The e-consult rate was highest in endocrinology (5.0 per 100), hematology (3.0 per 100), and gastroenterology (3.0 per 100). The percentage of e consult patients with CBOC-based primary care grew from 28.5% to 44.4% in the first year of implementation and to 45.6% at year 3. Of those e-consult patients from community clinics, the average potential miles needed to travel was 72.1 miles per patient (SD = 72.6; median = 54.6; interquartile range = 17.1-108), translating to a potential savings of 6,875,631 total miles and travel reimbursement costs of $2,853,387. CONCLUSIONS: E-consult volume increased significantly since inception within many medical and surgical specialties. For patients receiving primary care at one of more than 800 CBOCs, e-consults may decrease travel burden and direct travel costs for patients. PMID- 26760428 TI - Using aggregated pharmacy claims to identify primary nonadherence. AB - OBJECTIVES: Aggregate pharmacy claims available within an electronic health record (EHR) provide an opportunity to understand primary nonadherence in real time. The objective of this study was to use pharmacy claims data available within the EHR to identify the prevalence and predictors of primary nonadherence to antihypertensive drug therapy in a multi-payer primary care network. STUDY DESIGN: We conducted a retrospective cohort study of patients prescribed a new antihypertensive medication in a large primary care practice network between January 2011 and September 2012. METHODS: We matched prescriptions for the new antihypertensive to pharmacy claims listed in the EHR. The primary outcome was the presence of a fill for the new medication within 30 days of the prescription. RESULTS: Of 791 patients in our study cohort, two-thirds (522; 66%) filled their prescription within 30 days. The majority (409; 78.4%) of that group filled the prescription on the day it was issued. Lower diastolic blood pressure and Medicare coverage increased the probability of nonadherence. CONCLUSIONS: Medication fill data within the provider EHR can identify primary nonadherence in clinical practice. As adoption of this technology increases, it provides an opportunity to identify nonadherence, allowing for the effective design of interventions to improve adherence to therapy. PMID- 26760429 TI - Innovations in chronic care delivery using data-driven clinical pathways. AB - OBJECTIVES: Chronic diseases are common, complex, and expensive health conditions that can benefit from innovations in healthcare service delivery enabled by information technology and advanced analytic methods. This paper proposes a data driven approach, illustrated in the context of chronic kidney disease (CKD), to develop clinical pathways of care delivery from electronic health record (EHR) data. STUDY DESIGN: We analyzed structured and de-identified EHR data from 2009 to 2013 of 664 CKD patients with multiple chronic conditions. METHODS: Machine learning algorithms were used to learn data-driven and practice-based clinical pathways that cluster patients into subgroups and model the co-progression of their encounter types, diagnoses, medications, and biochemical measurements. Given a pattern of biochemical measurements, our algorithm identifies the most probable clinical pathways, and makes predictions regarding future states, with and without temporal information. CKD stages, their complications, and common medications are included in the clinical pathways. RESULTS: Using the EHR data of 664 patients who were initially in CKD stage 3 and hypertensive, we identified 7 patient subgroups-each distinguished primarily by the type of complications suffered by the patients. Our algorithm demonstrates fair accuracy (up to 44% and 75%, respectively) in learning the most probable clinical pathways and predicting future states associated with temporal patterns of biochemical measurements and patient subgroups. CONCLUSIONS: Data-driven clinical pathway learning summarizes multidimensional and longitudinal information from EHRs into clusters of common sequences of patient visits that may assist in the efficient review of current practices and identifying potential innovations in the care delivery process. PMID- 26760430 TI - Characteristics of residential care communities that use electronic health records. AB - OBJECTIVES: Residential care communities' (RCCs) use of electronic health records (EHRs) has the potential to improve communication and facilitate care coordination. This study describes the use of, and examines characteristics associated with, any type of EHR system among RCCs in the United States, nationally and by Census division. STUDY DESIGN: This study examined organizational and geographic characteristics, as well as resident case-mix in association with the use of EHRs among RCCs. METHODS: Data from the 2012 National Study of Long-Term Care Providers were used for the analyses. Of 4694 sampled RCCs that completed the questionnaire, 3987 cases with complete data were included in the study. RESULTS: About 20.2% of RCCs used any type of EHR system and 3.1% used EHRs that had 6 selected computerized capabilities to meet this study's definition for a basic EHR system. Compared with the national rate of 20.2%, a higher percentage of RCCs in the following Census divisions used some type of an EHR system: New England (23.2%), East North Central (26.3%), and West North Central (32.9%). Larger size, being chain affiliated, owned by other organizations or part of a continuing care retirement community, and geographic location were independently associated with the use of any EHRs among RCCs. CONCLUSIONS: As RCCs serve increasingly less healthy and more disabled residents, improved communication and effective care coordination among RCC staff and across different care settings are critical. The estimates presented in this study can be used to establish a baseline for monitoring trends in EHR use among RCCs. PMID- 26760431 TI - Health information technology adoption in California community health centers. AB - OBJECTIVES: National and state initiatives to spur adoption of electronic health records (EHRs) and health information exchange (HIE) among providers in rural and underserved communities have been in place for 15 years. Our goal was to systematically assess the impact of these initiatives by quantifying the level of adoption and key factors associated with adoption among community health centers in California. STUDY DESIGN: Cross-sectional statewide survey. METHODS: We conducted a telephone survey of all California primary care community health centers (CHCs) from August to September 2013. Multiple logistic regressions were fit to test for associations between various practice characteristics and adoption of EHRs, meaningful use-certified EHRs, and HIE. For the multivariable model, we included those variables which were significant at the P = .10 level in the univariate tests. RESULTS: We received responses from 194 CHCs (73.5% response rate). Adoption of any EHRs (80.3%) and meaningful use-certified EHRs (94.6% of those with an EHR) was very high. Adoption of HIE is substantial (48.7%) and took place within a few years (mean = 2.61 years; SD = 2.01). More than half (54.7%) of CHCs are able to receive data into the EHR indicating some level of interoperability. Patient engagement capacity is moderate, with 21.6% offering a PHR, and 55.2% electronic visit summaries. Rural location and belonging to a multi-site clinic organization both increase the odds of adoption of EHRs, HIE, and electronic visit summary, with the odds ratio ranging from 0.63 to 3.28 (all P values < .05). CONCLUSIONS: Greater adoption of health information technology (IT) in rural areas may be the result of both federal and state investments. As CHCs lack access to capital for investments, continued support of technology infrastructure may be needed for them to further leverage health IT to improve healthcare. PMID- 26760432 TI - Physician attitudes on ease of use of EHR functionalities related to Meaningful Use. AB - OBJECTIVES: To assess physician attitudes on ease of use of electronic health record (EHR) functionalities related to "Meaningful Use" (MU) and whether perceived ease of use was associated with EHR characteristics, including meeting MU criteria, technical assistance from EHR vendors or regional extension centers, and the amount of clinical staff training. STUDY DESIGN: A cross sectional analysis of the 2011 Physician Workflow study, nationally representative of US office-based physicians. METHODS: Cross-sectional data were used to examine physician attitudes on ease of use of 14 EHR functionalities related to MU, among physicians with any EHR system. RESULTS: For 11 of the 14 EHR functions examined, physicians with EHRs that met MU criteria were significantly more likely than physicians that also utilized EHR systems to report that EHR functions were easy to use. For 8 of the functions examined, physicians receiving technical assistance from a vendor or regional extension center were significantly more likely to report that the EHR function was easy to use. CONCLUSIONS: Our study of a nationally representative survey of office-based physicians found that physicians' adoption and perceived ease of use of EHR functionalities related to MU was generally high. PMID- 26760433 TI - Flakelike LiCoO2 with Exposed {010} Facets As a Stable Cathode Material for Highly Reversible Lithium Storage. AB - A thick and dense flakelike LiCoO2 with exposed {010} active facets is synthesized using Co(OH)2 nanoflake as a self-sacrificial template obtained from a simple coprecipitation method, and served as a cathode material for lithium ion batteries. When operated at a high cutoff voltage up to 4.5 V, the resultant LiCoO2 exhibits an outstanding rate capability, delivering a reversible discharge capacity as high as 179, 176, 168, 116, and 96 mA h g(-1) at 25 degrees C under the current rate of 0.1, 0.5, 1, 5, and 10 C, respectively. When charge/discharge cycling at 55 degrees C, a high specific capacity of 148 mA h g(-1) (~88% retention) can be retained after 100 cycles under 1 C, demonstrating excellent cycling and thermal stability. Besides, the flakelike LiCoO2 also shows an impressive low-temperature electrochemical activity with specific capacities of 175 (0.1 C) and 154 mA h g(-1) (1 C) at -10 degrees C, being the highest ever reported for a subzero-temperature lithium storage capability, as well as 52% capacity retention even after 80 cycles under 1 C. Such superior high-voltage electrochemical performances of the flakelike LiCoO2 operated at a wide temperature range are mainly attributed to its unique hierarchical structure with specifically exposed facets. The exposed {010} active facets provide a preferential crystallographic orientation for Li-ion migration, while the micrometer-sized secondary particles agglomerated by submicron primary LiCoO2 flakes endow the electrode with better structural integrity, both of which ensure the LiCoO2 cathode to manifest remarkably enhanced reversible lithium storage properties. PMID- 26760435 TI - Native Cellulose Microfiber-Based Hybrid Piezoelectric Generator for Mechanical Energy Harvesting Utility. AB - A flexible hybrid piezoelectric generator (HPG) based on native cellulose microfiber (NCMF) and polydimethylsiloxane (PDMS) with multi wall carbon nanotubes (MWCNTs) as conducting filler is presented where the further chemical treatment of the cellulose and traditional electrical poling steps for piezoelectric voltage generation is avoided. It delivers a high electrical throughput that is an open circuit voltage of ~30 V and power density ~9.0 MUW/cm(3) under repeated hand punching. We demonstrate to power up various portable electronic units by HPG. Because cellulose is a biocompatible material, suggesting that HPG may have greater potential in biomedical applications such as implantable power source in human body. PMID- 26760434 TI - MaJAZ1 Attenuates the MaLBD5-Mediated Transcriptional Activation of Jasmonate Biosynthesis Gene MaAOC2 in Regulating Cold Tolerance of Banana Fruit. AB - Previous studies indicated that methyl jasmonate (MeJA) treatment could effectively reduce the chilling injury of many fruits, including banana, but the underlying mechanism is poorly understood. In this study, one lateral organ boundaries (LOB) domain (LBD) gene, designated as MaLBD5, was isolated and characterized from banana fruit. Expression analysis revealed that accumulation of MaLBD5 was induced by cold temperature and MeJA treatment. Subcellular localization and transactivation assays showed that MaLBD5 was localized to the nucleus and possessed transcriptional activation activity. Protein-protein interaction analysis demonstrated that MaLBD5 physically interacted with MaJAZ1, a potential repressor of jasmonate signaling. Furthermore, transient expression assays indicated that MaLBD5 transactivated a jasmonate biosynthesis gene, termed MaAOC2, which was also induced by cold and MeJA. More interestingly, MaJAZ1 attenuated the MaLBD5-mediated transactivation of MaAOC2. These results suggest that MaLBD5 and MaJAZ1 might act antagonistically in relation to MeJA-induced cold tolerance of banana fruit, at least partially via affecting jasmonate biosynthesis. Collectively, our findings expand the knowledge of the transcriptional regulatory network of MeJA-mediated cold tolerance of banana fruit. PMID- 26760436 TI - Probing Bioluminescence Resonance Energy Transfer in Quantum Rod-Luciferase Nanoconjugates. AB - We describe the necessary design criteria to create highly efficient energy transfer conjugates containing luciferase enzymes derived from Photinus pyralis (Ppy) and semiconductor quantum rods (QRs) with rod-in-rod (r/r) microstructure. By fine-tuning the synthetic conditions, CdSe/CdS r/r-QRs were prepared with two different emission colors and three different aspect ratios (l/w) each. These were hybridized with blue, green, and red emitting Ppy, leading to a number of new BRET nanoconjugates. Measurements of the emission BRET ratio (BR) indicate that the resulting energy transfer is highly dependent on QR energy accepting properties, which include absorption, quantum yield, and optical anisotropy, as well as its morphological and topological properties, such as aspect ratio and defect concentration. The highest BR was found using r/r-QRs with lower l/w that were conjugated with red Ppy, which may be activating one of the anisotropic CdSe core energy levels. The role QR surface defects play on Ppy binding, and energy transfer was studied by growth of gold nanoparticles at the defects, which indicated that each QR set has different sites. The Ppy binding at those sites is suggested by the observed BRET red-shift as a function of Ppy-to-QR loading (L), where the lowest L results in highest efficiency and furthest shift. PMID- 26760437 TI - Vibrational Inelasticity of Highly Vibrationally Excited NO on Ag(111). AB - Multiquantum relaxation of highly vibrationally excited nitric oxide on noble metals has become one of the best studied examples of the Born-Oppenheimer approximation's failure to describe molecular interactions at metal surfaces. When first reported, relaxation of highly vibrationally excited NO occurring in collisions with Au(111) surfaces exhibited the largest vibrational inelasticity seen in molecule-surface collisions, and no system has been found to date exhibiting a greater vibrational inelasticity. In this work, we compare the relaxation of NO(v = 11) in scattering events on Ag(111) to that on Au(111). The relaxation probability and the average vibrational energy loss are much higher when scattering from Ag(111). We discuss possible reasons for this remarkable phenomenon, which may be related to the dissociation of NO, possible on Ag(111) at lower energy compared with Au(111). PMID- 26760439 TI - Assessing the Effectiveness of a Cadaveric Teaching Model for Performing Arthrocentesis with Veterinary Students. AB - The purpose of this study was to determine if a recently developed cadaveric canine model was an effective tool for teaching arthrocentesis to fourth-year veterinary students. Arthrocentesis is an important diagnostic tool and technical skill that can be difficult to teach in the clinical setting. Eighteen fourth year veterinary students participated in a within-subjects experiment that evaluated their ability to successfully perform arthrocentesis in the canine model and in an unmodified control cadaver. Students completed an online survey about the experience. Ability to perform the procedure was assessed by monitoring the number of attempts and redirects required to enter the joint and by recording any volume recovered from the arthrocentesis. In both phases of the study, the participants were able to aspirate a measurable volume of fluid from the joints of the model. Participants recorded an increase in confidence with arthrocentesis after using the model in the first phase of the study and unanimously supported inclusion of the exercise in future teaching situations. PMID- 26760438 TI - Fighting Cholera One-on-One: The Development and Efficacy of Multivalent Cholera Toxin-Binding Molecules. AB - A series of diseases, ranging from cholera via travelers' diarrhea to hamburger disease, are caused by bacterially produced toxic proteins. In particular, a toxic protein unit is brought into the host cell upon binding to specific membrane-bound oligosaccharides on the host cell membrane. For example, the protein that causes cholera, cholera toxin (CT), has five identical, symmetrically placed binding pockets (B proteins), on top of which the toxic A protein resides. A promising strategy to counteract the devastating biological effects of this AB5 protein involves the development of inhibitors that can act as mimics of membrane-bound GM1 molecules, i.e., that can bind CT strongly and selectively. To reach this goal, two features are essential: First of all, the inhibitor should display oligosaccharides that resemble as much as possible the naturally occurring cell-surface pentasaccharide onto which CT normally binds, the so-called GM1 sugar (the oligosaccharide part of which is then labeled GM1os). Second, the inhibitor should be able to bind CT via multivalent interactions so as to bind CT as strongly as possible to allow for a real competition with the cell-membrane-bound GM1 molecules. In this Account, we present elements of the path that leads to strong CT inhibition by outlining the roles of multivalency and the development and use of GM1 mimics. First, multivalency effects were investigated using "sugar-coated" platforms, ranging from dendritic structures with up to eight oligosaccharides to platforms that mimicked the fivefold symmetry of CT itself. The latter goal was reached either via synthetic scaffolds like corannulene or calix[5]arene or via the development of a neolectin CT mimic that itself carries five GM1os groups. Second, the effect of the nature of the oligosaccharide appended to this platform was investigated via the use of oligosaccharides of increasing complexity, from galactose and lactose to the tetrasaccharide GM2os and eventually to GM1os itself. The combination of these threads gives rise to a series of inhibitors that can strongly bind CT, with IC50 values below 100 pM, and in some cases can even bind one-on-one. PMID- 26760440 TI - Quantitation of Alpha-Glucosidase Activity Using Fluorinated Carbohydrate Array and MALDI-TOF-MS. AB - Quantitation of alpha-glucosidase (alpha-GD) activity is of significance to diagnosis of many diseases including Pompe disease and type II diabetes. We report here a new method to determine alpha-GD activity using matrix-assisted laser desorption/ionization (MALDI)-time-of-flight (TOF) mass spectrometry (MS) in combination with carbohydrate microarray and affinity surface chemistry. Carbohydrate probes are synthesized for capture of the enzymatic reaction products and the adducts are loaded onto a fluorinated gold surface to generate an array, which is followed by characterization by MALDI-TOF-MS. The ratio of intensities is used to determine the level of activity of several enzymes. In addition, half maximal inhibitory concentration (IC50) of acarbose and epigallocatechin gallate are also determined using this approach, and the results agree well with the reported values. This method is advantageous as compared to conventional colorimetric techniques that typically suffer matrix interference problems from samples. The use of the polyfluorinated surface has effectively suppressed the interference. PMID- 26760441 TI - Implementation of Ultraviolet Photodissociation on a Benchtop Q Exactive Mass Spectrometer and Its Application to Phosphoproteomics. AB - Proteomics applications performed on the popular benchtop Q Exactive Orbitrap mass spectrometer have so far relied exclusively on higher collision-energy dissociation (HCD) fragmentation for peptide sequencing. While this fragmentation technique is applicable to a wide range of biological questions, it also has limitations, and all questions cannot be addressed equally well. Here, we demonstrate that the fragmentation capabilities of the Q Exactive mass spectrometer can be extended with ultraviolet photodissociation (UVPD) fragmentation, complete with synchronization triggering to make it compatible with liquid chromatography (LC)/tandem mass spectrometry (MS/MS) workflows. We show that UVPD not only is directly compatible with LC/MS workflows but also, when combined with these workflows, can result in higher database scores and increased identification rates for complex samples as compared to HCD methods. UVPD as a fragmentation technique offers prompt, high-energy fragmentation, which can potentially lead to improved analyses of labile post-translational modifications. Techniques like HCD result in substantial amounts of modification losses, competing with fragmentation pathways that provide information-rich ion fragments. We investigate here the utility of UVPD for identification of phosphorylated peptides and find that UVPD fragmentation reduces the extent of labile modification loss by up to ~60%. Collectively, when integrated into a complete workflow on the Q Exactive Orbitrap, UVPD provides distinct advantages to the analysis of post-translational modifications and is a powerful and complementary addition to the proteomic toolbox. PMID- 26760444 TI - Raman Optical Activity Spectra for Large Molecules through Molecules-in-Molecules Fragment-Based Approach. AB - We present an efficient method for the calculation of the Raman optical activity (ROA) spectra for large molecules through the molecules-in-molecules (MIM) fragment-based method. The relevant higher energy derivatives from smaller fragments are used to build the property tensors of the parent molecule to enable the extension of the MIM method for evaluating ROA spectra (MIM-ROA). Two factors were found to be particularly important in yielding accurate results. First, the link-atom tensor components are projected back onto the corresponding host and supporting atoms through the Jacobian projection method, yielding a mathematically rigorous method. Second, the long-range interactions between fragments are taken into account by using a less computationally expensive lower level of theory. The performance of the MIM-ROA model is calibrated on the enantiomeric pairs of 10 carbohydrate benchmark molecules, with strong intramolecular interactions. The vibrational frequencies and ROA intensities are accurately reproduced relative to the full, unfragmented, results for these systems. In addition, the MIM-ROA method is employed to predict the ROA spectra of d-maltose, alpha-D-cyclodextrin, and cryptophane-A, yielding spectra in excellent agreement with experiment. The accuracy and performance of the benchmark systems validate the MIM-ROA model for exploring ROA spectra of large molecules. PMID- 26760442 TI - Crystal Structures and Coordination Behavior of Aqua- and Cyano-Co(III) Tetradehydrocorrins in the Heme Pocket of Myoglobin. AB - Myoglobins reconstituted with aqua- and cyano-Co(III) tetradehydrocorrins, rMb(Co(III)(OH2)(TDHC)) and rMb(Co(III)(CN)(TDHC)), respectively, were prepared and investigated as models of a cobalamin-dependent enzyme. The former protein was obtained by oxidation of rMb(Co(II)(TDHC)) with K3[Fe(CN)6]. The cyanide coordinated Co(III) species in the latter protein was prepared by ligand exchange of rMb(Co(III)(OH2)(TDHC)) with exogenous cyanide upon addition of KCN. The X-ray crystallographic study reveals the hexacoordinated structures of rMb(Co(III)(OH)(TDHC)) and rMb(Co(III)(CN)(TDHC)) at 1.20 and 1.40 A resolution, respectively. The (13)C NMR chemical shifts of the cyanide in rMb(Co(III)(CN)(TDHC)) were determined to be 108.6 and 110.6 ppm. IR measurements show that the cyanide of rMb(Co(III)(CN)(TDHC)) has a stretching frequency peak at 2151 cm(-1) which is higher than that of cyanocobalamin. The (13)C NMR and IR measurements indicate weaker coordination of the cyanide to Co(III)(TDHC) relative to cobalamin, a vitamin B12 derivative. Thus, the extent of pi-back donation from the cobalt ion to the cyanide ion is lower in rMb(Co(III)(CN)(TDHC)). Furthermore, the pK(1/2) values of rMb(Co(III)(OH2)(TDHC)) and rMb(Co(III)(CN)(TDHC)) were determined by a pH titration experiment to be 3.2 and 5.5, respectively, indicating that the cyanide ligation weakens the Co-N(His93) bond. Theoretical calculations also demonstrate that the axial ligand exchange from water to cyanide elongates the Co-N(axial) bond with a decrease in the bond dissociation energy. Taken together, the cyano Co(III) tetradehydrocorrin in myoglobin is appropriate for investigation as a structural analogue of methylcobalamin, a key intermediate in methionine synthase reaction. PMID- 26760445 TI - Self-Assembly of Nanoparticle-Surfactant Complexes with Rodlike Micelles: A Molecular Dynamics Study. AB - The self-assembly of nanoparticles (NPs) with cationic micelles of cetyltrimethylammonium chloride (CTAC) is known to produce stable nanogels with rich rheological and optical properties. Coarse-grained molecular dynamics (MD) simulations are performed to explore the molecular mechanisms underlying this self-assembly process. In an aqueous solution of CTAC surfactants, a negatively charged NP with a zeta potential of less than -45 mV is observed to form a stable vesicular structure in which the particle surface is almost entirely covered with a double layer of surfactants. In comparison, surfactants form a monolayer, or a corona, around an uncharged hydrophobic NP with the tailgroups physically adsorbed onto the particle. In the presence of sodium salicylate salt, such NP surfactant complexes (NPSCs) interact with rodlike CTAC micelles, resulting in the formation of stable junctions through the opening up of the micelle end-cap followed by surfactant exchange, which is diffusion-limited. The diffusive regime spans several hundred nanoseconds, thereby necessitating MD simulations over microsecond time scales. The energetics of NPSC-micelle complexation is analyzed from the variation in the total pair-potential energy of the structures. PMID- 26760443 TI - Extensive management of field margins enhances their potential for off-site soil erosion mitigation. AB - Soil erosion is a widespread problem in agricultural landscapes, particularly in regions with strong rainfall events. Vegetated field margins can mitigate negative impacts of soil erosion off-site by trapping eroded material. Here we analyse how local management affects the trapping capacity of field margins in a monsoon region of South Korea, contrasting intensively and extensively managed field margins on both steep and shallow slopes. Prior to the beginning of monsoon season, we equipped a total of 12 sites representing three replicates for each of four different types of field margins ("intensive managed flat", "intensive managed steep", "extensive managed flat" and "extensive managed steep") with Astroturf mats. The mats (n = 15/site) were placed before, within and after the field margin. Sediment was collected after each rain event until the end of the monsoon season. The effect of management and slope on sediment trapping was analysed using linear mixed effects models, using as response variable either the sediment collected within the field margin or the difference in sediment collected after and before the field margin. There was no difference in the amount of sediment reaching the different field margin types. In contrast, extensively managed field margins showed a large reduction in collected sediment before and after the field margins. This effect was pronounced in steep field margins, and increased with the size of rainfall events. We conclude that a field margin management promoting a dense vegetation cover is a key to mitigating negative off-site effects of soil erosion in monsoon regions, particularly in field margins with steep slopes. PMID- 26760446 TI - Development of epilepsy after posterior reversible encephalopathy syndrome. AB - PURPOSE: This study was intended to describe the risk of epilepsy subsequent to posterior reversible encephalopathy syndrome (PRES) and the clinical features of post-PRES epilepsy. METHOD: We retrospectively identified all patients with PRES who were admitted to Severance Hospital and consulted with the Department of Neurology between 2001 and 2013 and the subgroup of these patients who subsequently developed epilepsy. We also describe clinical features of patients who were not treated with PRES as inpatients at our center but who presented later with post-PRES epilepsy during the study period. We studied clinical characteristics during the acute symptomatic phase of PRES and after the development of epilepsy. RESULTS: During the study period 102 patients were treated at our center during the acute phase of PRES. Four of these patients (3.9%) subsequently developed epilepsy. Two additional patients with a history of PRES presented to our hospital after the acute phase of their illness with post PRES epilepsy. During the acute phase, five of six patients had acute symptomatic seizures and four had convulsive or nonconvulsive status epilepticus (SE). Acute phase MRI showed cytotoxic edema in five patients, and follow-up MRI showed focal atrophic changes including hippocampal sclerosis in four. Presumptive epileptogenic foci were located in the left-side temporal, parietal and occipital lobes, corresponding to the regions that showed cytotoxic edema or severe vasogenic edema as well as with the location or lateralization of EEG abnormalities during the acute phase. CONCLUSION: Our findings indicate a small but not insignificant risk for the development of epilepsy after PRES. The presence of cytotoxic edema and severe, acute symptomatic seizures, such as SE suggests irreversible brain damage and may predict the development of epilepsy. PMID- 26760447 TI - Direct Measurement of the Tunable Electronic Structure of Bilayer MoS2 by Interlayer Twist. AB - Using angle-resolved photoemission on micrometer-scale sample areas, we directly measure the interlayer twist angle-dependent electronic band structure of bilayer molybdenum-disulfide (MoS2). Our measurements, performed on arbitrarily stacked bilayer MoS2 flakes prepared by chemical vapor deposition, provide direct evidence for a downshift of the quasiparticle energy of the valence band at the Brillouin zone center (Gamma point) with the interlayer twist angle, up to a maximum of 120 meV at a twist angle of ~40 degrees . Our direct measurements of the valence band structure enable the extraction of the hole effective mass as a function of the interlayer twist angle. While our results at Gamma agree with recently published photoluminescence data, our measurements of the quasiparticle spectrum over the full 2D Brillouin zone reveal a richer and more complicated change in the electronic structure than previously theoretically predicted. The electronic structure measurements reported here, including the evolution of the effective mass with twist-angle, provide new insight into the physics of twisted transition-metal dichalcogenide bilayers and serve as a guide for the practical design of MoS2 optoelectronic and spin-/valley-tronic devices. PMID- 26760448 TI - A new framework for modeling decisions about changing information: The Piecewise Linear Ballistic Accumulator model. AB - In the real world, decision making processes must be able to integrate non stationary information that changes systematically while the decision is in progress. Although theories of decision making have traditionally been applied to paradigms with stationary information, non-stationary stimuli are now of increasing theoretical interest. We use a random-dot motion paradigm along with cognitive modeling to investigate how the decision process is updated when a stimulus changes. Participants viewed a cloud of moving dots, where the motion switched directions midway through some trials, and were asked to determine the direction of motion. Behavioral results revealed a strong delay effect: after presentation of the initial motion direction there is a substantial time delay before the changed motion information is integrated into the decision process. To further investigate the underlying changes in the decision process, we developed a Piecewise Linear Ballistic Accumulator model (PLBA). The PLBA is efficient to simulate, enabling it to be fit to participant choice and response-time distribution data in a hierarchal modeling framework using a non-parametric approximate Bayesian algorithm. Consistent with behavioral results, PLBA fits confirmed the presence of a long delay between presentation and integration of new stimulus information, but did not support increased response caution in reaction to the change. We also found the decision process was not veridical, as symmetric stimulus change had an asymmetric effect on the rate of evidence accumulation. Thus, the perceptual decision process was slow to react to, and underestimated, new contrary motion information. PMID- 26760449 TI - Age differences in the Attention Network Test: Evidence from behavior and event related potentials. AB - The Attention Network Test (ANT) is widely used to capture group and individual differences in selective attention. Prior behavioral studies with younger and older adults have yielded mixed findings with respect to age differences in three putative attention networks (alerting, orienting, and executive control). To overcome the limitations of behavioral data, the current study combined behavioral and electrophysiological measures. Twenty-four healthy younger adults (aged 18-29years) and 24 healthy older adults (aged 60-76years) completed the ANT while EEG data were recorded. Behaviorally, older adults showed reduced alerting, but did not differ from younger adults in orienting or executive control. Electrophysiological components related to alerting and orienting (P1, N1, and CNV) were similar in both age groups, whereas components related to executive control (N2 and P3) showed age-related differences. Together these results suggest that comparisons of network effects between age groups using behavioral data alone may not offer a complete picture of age differences in selective attention, especially for alerting and executive control networks. PMID- 26760451 TI - Stereoselective Synthesis of Fused Aziridines via One-Pot Sequential Decarboxylative Mannich Reaction and Oxidative C-H Amination of Cyclic Imines with beta-Ketoacids. AB - A novel one-pot sequential transformation via decarboxylative Mannich reaction (DMR) and oxidative C-H amination of cyclic imines with beta-ketoacids is described. This methodology has been utilized to provide access to fused aziridines with excellent diastereoselectivity. Several examples of catalytic enantioselective sequential transformation are presented. PMID- 26760450 TI - HPA axis function predicts development of working memory in boys with FXS. AB - The present study examines verbal working memory over time in boys with fragile X syndrome (FXS) compared to nonverbal mental-age (NVMA) matched, typically developing (TD) boys. Concomitantly, the relationship between cortisol-a physiological marker for stress-and verbal working memory performance over time is examined to understand the role of physiological mechanisms in cognitive development in FXS. Participants were assessed between one and three times over a 2-year time frame using two verbal working memory tests that differ in complexity: memory for words and auditory working memory with salivary cortisol collected at the beginning and end of each assessment. Multilevel modeling results indicate specific deficits over time on the memory for words task in boys with FXS compared to TD controls that is exacerbated by elevated baseline cortisol. Similar increasing rates of growth over time were observed for boys with FXS and TD controls on the more complex auditory working memory task, but only boys with FXS displayed an association of increased baseline cortisol and lower performance. This study highlights the benefit of investigations of how dynamic biological and cognitive factors interact and influence cognitive development over time. PMID- 26760453 TI - Interferon-free treatment with sofosbuvir/daclatasvir achieves sustained virologic response in 100% of HIV/hepatitis C virus-coinfected patients with advanced liver disease. AB - AIM: We aimed to investigate the safety and efficacy of interferon (IFN) and ribavirin (RBV)-free therapy with sofosbuvir along with daclatasvir (SOF/DCV) in HIV/hepatitis C virus (HCV)-coinfected patients (HIV/HCV), who have an urgent need for effective antiviral therapy. We also assessed its impact on liver stiffness and liver enzymes. DESIGN: Thirty-one patients thoroughly documented HIV/HCV with advanced liver disease (advanced liver fibrosis and/or portal hypertension) who were treated with SOF/DCV were retrospectively studied. METHODS: The following treatment durations were applied: HCV-genotype (HCV-GT)1/4 without cirrhosis: 12 weeks; HCV-GT1/4 with cirrhosis: 24 weeks; HCV-GT3: 24 weeks; if HCV-RNA was detectable 4 weeks before the end of treatment, treatment was extended by 4 weeks at a time. RESULTS: Fifty-two percent of patients were treatment-experienced. The majority of patients had HCV-GT1 (68%), whereas HCV GT3 and HCV-GT4 were observed in 23 and 10% of patients, respectively. Ninety four percent had liver stiffness greater than 9.5 kPa or METAVIR fibrosis stage higher than F2 and 45% had liver stiffness above 12.5 kPa or METAVIR F4. Portal hypertension (HVPG >=6 mmHg) and clinically significant portal hypertension (HVPG >=10 mmHg) were observed in 67% (18/27) and 26% (7/27) of patients, respectively. Sustained virologic response 12 weeks after the end of treatment (SVR12) was achieved in 100% (31/31). Treatment with SOF/DCV was generally well tolerated and there were no treatment discontinuations. HCV eradication improved liver stiffness from 11.8 [interquartile range (IQR): 11.5 kPa] to 6.9 (IQR: 8.2) kPa [median change: -3.6 (IQR:5.2) kPa; P < 0.001] and decreased liver enzymes. The mean time period between treatment initiation and follow-up liver stiffness measurement was 32.7 +/- 1.2 weeks. CONCLUSION: IFN- and RBV-free treatment with SOF/DCV was well tolerated and achieved SVR12 in all HIV/HCV with advanced liver disease. It also significantly improved liver stiffness, suggesting anti-fibrotic and anti-portal hypertensive effects. PMID- 26760452 TI - Short message service (SMS) reminders and real-time adherence monitoring improve antiretroviral therapy adherence in rural Uganda. AB - OBJECTIVE: To explore the effects of four types of short message service (SMS) plus real-time adherence monitoring on antiretroviral therapy (ART) adherence: daily reminders, weekly reminders, reminders triggered after a late or missed dose (delivered to patients), and notifications triggered by sustained adherence lapses (delivered to patient-nominated social supporters). DESIGN: Pilot randomized controlled trial. METHODS: Sixty-three individuals initiating ART received a real-time adherence monitor and were randomized (1 : 1 : 1): (1) Scheduled SMS reminders (daily for 1 month, weekly for 2 months), then SMS reminders triggered by a late or missed dose (no monitoring signal within 2 h of expected dosing); SMS notifications to social supporters for sustained adherence lapses (no monitoring signal for >48 h) added after 3 months. (2) Triggered SMS reminders starting at enrolment; SMS notifications to social supporters added after 3 months. (3) CONTROL: No SMS. HIV RNA was determined at 9 months. Percentage adherence and adherence lapses were compared by linear generalized estimating equations and Poisson regression, respectively. RESULTS: Median age was 31 years, 65% were women, and median enrolment CD4 cell count was 322 cells/MUl 97% took once daily tenofovir/emtricitabine/efavirenz. Compared to control, adherence was 11.1% higher (P = 0.04) and more than 48-h lapses were less frequent (IRR 0.6, P = 0.02) in the scheduled SMS arm. Adherence and more than 48-h lapses were similar in the triggered SMS arm and control. No differences in HIV RNA were seen. CONCLUSION: Scheduled SMS reminders improved ART in the context of real-time monitoring. Larger studies are needed to determine the impact of triggered reminders and role of social supporters in improving adherence. PMID- 26760454 TI - Assessing efficacy of a retention-in-care intervention among HIV patients with depression, anxiety, heavy alcohol consumption and illicit drug use. AB - OBJECTIVE: We evaluated whether heavy alcohol use, illicit drug use or high levels of anxiety, and depression symptoms were modifiers of the retention through enhanced personal contact intervention. The intervention had previously demonstrated overall efficacy in the parent study. DESIGN: Randomized trial. METHODS: A total of 1838 patients from six US HIV clinics were enrolled into a randomized trial in which intervention patients received an 'enhanced contact' protocol for 12 months. All participants completed an audio computer-assisted self-interview that measured depression and anxiety symptoms from the Brief Symptom Inventory, alcohol use from the Alcohol Use Disorders Identification Test Consumption instrument, and drug use from the WHO (Alcohol, Smoking and Substance Involvement Screening Test) questions. The 12-month binary outcome was completing an HIV primary care visit in three consecutive 4-month intervals. The outcome was compared between intervention and standard of care patients within subgroups on the effect modifier variables using log-binomial regression models. RESULTS: Persons with high levels of anxiety or depression symptoms and those reporting illicit drug use, or heavy alcohol consumption had no response to the intervention. Patients without these 'higher risk' characteristics responded significantly to the intervention. Further analysis revealed higher risk patients were less likely to have successfully received the telephone contact component of the intervention. Among higher risk patients who did successfully receive this component, the intervention effect was significant. CONCLUSION: Our findings suggest that clinic-based retention-in-care interventions are able to have significant effects on HIV patients with common behavioral health issues, but the design of those interventions should assure successful delivery of intervention components to increase effectiveness. PMID- 26760455 TI - Tenofovir exposure alters associations of serum bicarbonate with chronic kidney disease risk in HIV-infected veterans. AB - OBJECTIVE: Among HIV-infected persons, tenofovir disoproxil fumarate (TDF) use is associated with higher risk of developing chronic kidney disease (CKD). Because lower serum bicarbonate concentrations may precede CKD onset, this study investigated the associations between TDF use and bicarbonate concentrations, and between bicarbonate with CKD risk among TDF users and nonusers. METHODS: Retrospective cohort study of 16,070 HIV-infected US veterans who initiated antiretroviral therapy between 1997-2011. The association between TDF use with longitudinal bicarbonate concentrations and associations between bicarbonate with incident CKD stratified by TDF use (never, initial, and later user) were evaluated. RESULTS: Compared with TDF users, never users had faster declines in bicarbonate concentrations: change in bicarbonate -0.11 mmol/l per year (95% confidence interval -0.16, -0.05), compared with -0.04 mmol/l per year (-0.06, 0.05) in initial users and -0.02 mmol/l per year (-0.05, 0.01) in later users. Low baseline bicarbonate (<22 mmol/l) was significantly associated with CKD risk among TDF never users (1.80; 1.21, 2.68), but not among TDF users (0.98; 0.69, 1.38). Similarly, declining bicarbonate concentrations were associated with higher CKD risk among never users (hazard ratio 1.67 per mmol/l; 1.34, 2.08), but not among TDF users (1.09; 0.98, 1.22). Interactions were highly significant for both analyses (P value = 0.001). CONCLUSION: Despite associations with nephrotoxicity, TDF use was associated with higher serum bicarbonate concentrations longitudinally. Additionally, TDF use obscured the strong associations of bicarbonate with CKD risk in HIV-infected persons. Therefore, the role of bicarbonate concentrations as a tool to monitor kidney health in HIV infected persons may be limited in the setting of TDF use. PMID- 26760456 TI - Anxiety trajectories in response to a speech task in social anxiety disorder: Evidence from a randomized controlled trial of CBT. AB - The subjective experience of anxiety plays a central role in cognitive behavioral models of social anxiety disorder (SAD). However, much remains to be learned about the temporal dynamics of anxiety elicited by feared social situations. The aims of the current study were: (1) to compare anxiety trajectories during a speech task in individuals with SAD (n=135) versus healthy controls (HCs; n=47), and (2) to compare the effects of CBT on anxiety trajectories with a waitlist control condition. SAD was associated with higher levels of anxiety and greater increases in anticipatory anxiety compared to HCs, but not differential change in anxiety from pre- to post-speech. CBT was associated with decreases in anxiety from pre- to post-speech but not with changes in absolute levels of anticipatory anxiety or rates of change in anxiety during anticipation. The findings suggest that anticipatory experiences should be further incorporated into exposures. PMID- 26760458 TI - Destabilization of mayonnaise induced by lipid crystallization upon freezing. AB - The thermal and rheological history of mayonnaise during freezing and its dispersion stability after the freeze-thaw process were investigated. Mayonnaise was cooled to freeze and stored at -20 to -40 degrees C while monitoring the temperature; penetration tests were conducted on the mayonnaise, which was sampled at selected times during isothermal storage at -20 degrees C. Significant increases in the temperature and stress values due to water-phase crystallization and subsequent oil-phase crystallization were observed. The water phase crystallized during the cooling step in all the tested mayonnaise samples. The oil phases of the prepared mayonnaise (with rapeseed oil) and commercial mayonnaise crystallized during isothermal storage after 6 and 4 h, respectively, at -20 degrees C. The dispersion stability was evaluated from the separation ratio, which was defined as the weight ratio of separated oil after centrifuging to the total amount of oil in the commercial mayonnaise. The separation ratio rapidly increased after 4 h of freezing. This result suggests that crystallization of the oil phase is strongly related to the dispersion stability of mayonnaise. PMID- 26760479 TI - Common and unique associations of adolescents' affective and cognitive empathy development with conflict behavior towards parents. AB - Adolescents' development of two empathy dimensions, affective empathic concern and cognitive perspective taking, may be associated with shifts towards more constructive behaviors in conflict with parents. This six-year longitudinal study (ages 13-18) used multivariate latent growth curve modeling to investigate correlations between the developmental trajectories of adolescents' (N = 497) empathic dispositions and trajectories of their conflict behaviors towards both parents. There were some similarities between the associations of both empathy dimensions with conflict behaviors. Both empathy dimensions were associated with reduced conflict escalation with mothers, and increased problem solving with both parents. However, these associations were consistently stronger for perspective taking than for empathic concern. Furthermore, higher levels of compliance with mothers in early adolescence were uniquely associated with over-time increasing empathic concern. Perspective taking was uniquely associated with decreased withdrawal from conflicts. Perspective taking thus appears to be more strongly associated with a pattern of constructive conflict behaviors. PMID- 26760480 TI - Caveat Emptor: Employer Evaluation of Private Exchange Performance. PMID- 26760457 TI - Intertrial auditory neural stability supports beat synchronization in preschoolers. AB - The ability to synchronize motor movements along with an auditory beat places stringent demands on the temporal processing and sensorimotor integration capabilities of the nervous system. Links between millisecond-level precision of auditory processing and the consistency of sensorimotor beat synchronization implicate fine auditory neural timing as a mechanism for forming stable internal representations of, and behavioral reactions to, sound. Here, for the first time, we demonstrate a systematic relationship between consistency of beat synchronization and trial-by-trial stability of subcortical speech processing in preschoolers (ages 3 and 4 years old). We conclude that beat synchronization might provide a useful window into millisecond-level neural precision for encoding sound in early childhood, when speech processing is especially important for language acquisition and development. PMID- 26760481 TI - Bioprocess optimization for production of thermoalkali-stable protease from Bacillus subtilis K-1 under solid-state fermentation. AB - Cost-effective production of proteases, which are robust enough to function under harsh process conditions, is always sought after due to their wide industrial application spectra. Solid-state production of enzymes using agro-industrial wastes as substrates is an environment-friendly approach, and it has several advantages such as high productivity, cost-effectiveness, being less labor intensive, and less effluent production, among others. In the current study, different agro-wastes were employed for thermoalkali-stable protease production from Bacillus subtilis K-1 under solid-state fermentation. Agricultural residues such as cotton seed cake supported maximum protease production (728 U ml(-1)), which was followed by gram husk (714 U ml(-1)), mustard cake (680 U ml(-1)), and soybean meal (653 U ml(-1)). Plackett-Burman design of experiment showed that peptone, moisture content, temperature, phosphates, and inoculum size were the significant variables that influenced the protease production. Furthermore, statistical optimization of three variables, namely peptone, moisture content, and incubation temperature, by response surface methodology resulted in 40% enhanced protease production as compared to that under unoptimized conditions (from initial 728 to 1020 U ml(-1)). Thus, solid-state fermentation coupled with design of experiment tools represents a cost-effective strategy for production of industrial enzymes. PMID- 26760482 TI - Resection extent of the supplementary motor area and post-operative neurological deficits in glioma surgery. AB - Objective The supplementary motor area (SMA) is important for the prediction of post-operative symptoms after surgical resection of gliomas. We investigated the relationships between clinical factors and the resection range of SMA gliomas, and the post-operative neurological symptoms. Methods We retrospectively studied 18 consecutive surgeries for gliomas involving the SMA proper performed in 13 patients. Seven cases were recurrence of the tumour. Clinical factors and details of specific resection of the SMA proper (resection of posterior part, medial wall) and cingulate motor area (CMA) were examined. Results Eight cases suffered new post-operative neurological deficits. Six of these eight cases had transient deficits. Permanent deficits persisted in two cases with partial weakness or paresis, after rapid improvement of post-operative global weakness or hemiplegia, respectively. The risk of post-operative neurological deficits was not associated with the resection of the posterior part of the SMA proper or the CMA, but was associated with resection of the medial wall of the SMA proper. Surgery for recurrent tumour was associated with post-operative neurological deficits. The medial wall was frequently resected in recurrent cases. Discussion The frequency of post-operative neurological symptoms, including SMA syndrome, may be higher after resection of the medial wall of the SMA proper compared with the resection of only the lateral surface of the SMA proper. PMID- 26760483 TI - Nitrite production in a partial denitrifying upflow sludge bed (USB) reactor equipped with gas automatic circulation (GAC). AB - Nitrite production in a partial denitrifying (NO3(-)-N->NO2(-)-N) upflow sludge bed (USB) reactor equipped with gas automatic circulation (GAC) was investigated at ambient temperature (28.8-14.1 degrees C). The nitrite production rate (NPR) increased with the nitrate loading rate (NLR). Average NPR of 6.63 kgN m(-3) d( 1) was obtained at 28.0 degrees C with the organic loading rate (OLR) and NLR of 25.38 KgCOD?m(-3)?d(-1) and 10.82 kgN m(-3) d(-1), respectively. However, serious sludge floatation was observed when the NLR increased to 13.18 kgN m(-3) d(-1), which might be attributed to sludge bulking at high NLR. The USB reactor recovered rapidly when seeded with the sludge discharged before the deteriorated period, and a stable NPR of ~4.35 kgN m(-3) d(-1) was achieved at 14.1-15.7 degrees C in the following 100-day operation, during which the maximum nitrate-to nitrite transformation ratio (NTR) of 81.4% was achieved at the GAC rate of 1.08 L h(-1). The application of GAC in the partial denitrifying USB reactor enhanced mass transfer, which effectively avoided the channel and dead space, and improved the nitrate transform to nitrite. Moreover, it was found that the GAC system played an important role in promoting the stability of the USB reactor by preventing the sludge floatation. The Illumina high-throughput sequencing analysis revealed that the genus of Thauera was dominate in the USB reactor (67.2 50.2%), which may be responsible for the high nitrite accumulation. Results in this study have an important application in treating nitrate wastewater with an economic and efficient way by combining with ANAMMOX process. PMID- 26760484 TI - Linking biofilm growth to fouling and aeration performance of fine-pore diffuser in activated sludge. AB - Aeration is commonly identified as the largest contributor to process energy needs in the treatment of wastewater and therefore garners significant focus in reducing energy use. Fine-pore diffusers are the most common aeration system in municipal wastewater treatment. These diffusers are subject to fouling and scaling, resulting in loss in transfer efficiency as biofilms form and change material properties producing larger bubbles, hindering mass transfer and contributing to increased plant energy costs. This research establishes a direct correlation and apparent mechanistic link between biofilm DNA concentration and reduced aeration efficiency caused by biofilm fouling. Although the connection between biofilm growth and fouling has been implicit in discussions of diffuser fouling for many years, this research provides measured quantitative connection between the extent of biofouling and reduced diffuser efficiency. This was clearly established by studying systematically the deterioration of aeration diffusers efficiency during a 1.5 year period, concurrently with the microbiological study of the biofilm fouling in order to understand the major factors contributing to diffuser fouling. The six different diffuser technologies analyzed in this paper included four different materials which were ethylene propylene-diene monomer (EPDM), polyurethane, silicone and ceramic. While all diffusers foul eventually, some novel materials exhibited fouling resistance. The material type played a major role in determining the biofilm characteristics (i.e., growth rate, composition, and microbial density) which directly affected the rate and intensity at what the diffusers were fouled, whereas diffuser geometry exerted little influence. Overall, a high correlation between the increase in biofilm DNA and the decrease in alphaF was evident (CV < 14.0 +/- 2.0%). By linking bacterial growth with aeration efficiency, the research was able to show quantitatively the causal connection between bacterial fouling and energy wastage during aeration. PMID- 26760485 TI - Fouling characteristics of reverse osmosis membranes at different positions of a full-scale plant for municipal wastewater reclamation. AB - Membrane fouling is an important shortcoming limiting the efficiency and wide application of reverse osmosis (RO) technology. In this paper, RO membranes in a full-scale municipal wastewater reclamation plant were autopsied. From the lead to tail position RO membranes in RO system, both of organic and inorganic matters on membranes reduced gradually. The higher ion products in RO concentrate didn't result in more serious inorganic scaling on the last position RO membranes, which was contrast with some other researches. Fe, Ca and Mg were major inorganic elements. Fe had a relatively low concentration in RO influent but the highest content on membranes. However, there was no specific pretreatment in terms of Fe removal. Ca and Mg scaling was controlled by the antiscalants injected. Organic fouling (75.0-84.5% of dry weights) was major problem on RO membranes due to the large amount of dissolved organic matters in secondary effluent as raw water. Hydrophilic acid (HIA, 48.0% of total DOC), hydrophobic acid (HOA, 23.6%) and hydrophobic neutral (HON, 19.0%) fraction was largest among the six fractions in RO influent, while HON (38.2-51.1%) and HOA (22.1-26.1%) tended to accumulate on membranes in higher quantities. Monitoring HON and HOA might help to forecast organic fouling. PMID- 26760487 TI - Incorporating Student Mobility in Achievement Growth Modeling: A Cross-Classified Multiple Membership Growth Curve Model. AB - Multiple membership random effects models (MMREMs) have been developed for use in situations where individuals are members of multiple higher level organizational units. Despite their availability and the frequency with which multiple membership structures are encountered, no studies have extended the MMREM approach to hierarchical growth curve modeling (GCM). This study introduces a cross-classified multiple membership growth curve model (CCMM-GCM) for modeling, for example, academic achievement trajectories in the presence of student mobility. Real data are used to demonstrate and compare growth curve model estimates using the CCMM-GCM and a conventional GCM that ignores student mobility. Results indicate that the CCMM-GCM represents a promising option for modeling growth for multiple membership data structures. PMID- 26760486 TI - Hepatotoxic microcystin removal using pumice embedded monolithic composite cryogel as an alternative water treatment method. AB - Microcystins are the most commonly encountered water-borne cyanotoxins which present short- and long-term risks to human health. Guidelines at international and national level, and legislation in some countries, have been introduced for the effective health risk management of these potent hepatotoxic, tumour promoters. The stable cyclic structure of microcystins and their common production by cyanobacteria in waterbodies at times of high total dissolved organic carbon content presents challenges to drinking water treatment facilities, with conventional, advanced and novel strategies under evaluation. Here, we have studied the removal of microcystins using three different forms of pumice particles (PPs), which are embedded into macroporous cryogel columns. Macroporous composite cryogel columns (MCCs) are a new generation of separation media designed to face this challenging task. Three different MCCs were prepared by adding plain PPs, Cu(2+)-attached PPs and Fe(3+)-attached PPs to reaction media before the cryogelation step. Column studies showed that MCCs could be successfully used as an alternative water treatment method for successful microcystin removal. PMID- 26760488 TI - Sensitivity of Fit Indices to Misspecification in Growth Curve Models. AB - This study investigated the sensitivity of fit indices to model misspecification in within-individual covariance structure, between-individual covariance structure, and marginal mean structure in growth curve models. Five commonly used fit indices were examined, including the likelihood ratio test statistic, root mean square error of approximation, standardized root mean square residual, comparative fit index, and Tucker-Lewis Index. The fit indices were found to have differential sensitivity to different types of misspecification in either the mean or covariance structures with severity of misspecification controlled. No fit index was always more (or less) sensitive to misspecification in the marginal mean structure relative to those in the covariance structure. Specifying the covariance structure to be saturated can substantially improve the sensitivity of fit indices to misspecification in the marginal mean structure; this result might help identify the sources of specification error in a growth curve model. An empirical example of children's growth in math achievement ( Wu, West, & Hughes, 2008 ) was used to illustrate the results. PMID- 26760489 TI - Bootstrap Standard Error Estimates in Dynamic Factor Analysis. AB - Dynamic factor analysis summarizes changes in scores on a battery of manifest variables over repeated measurements in terms of a time series in a substantially smaller number of latent factors. Algebraic formulae for standard errors of parameter estimates are more difficult to obtain than in the usual intersubject factor analysis because of the interdependence of successive observations. Bootstrap methods can fill this need, however. The standard bootstrap of individual timepoints is not appropriate because it destroys their order in time and consequently gives incorrect standard error estimates. Two bootstrap procedures that are appropriate for dynamic factor analysis are described. The moving block bootstrap breaks down the original time series into blocks and draws samples of blocks instead of individual timepoints. A parametric bootstrap is essentially a Monte Carlo study in which the population parameters are taken to be estimates obtained from the available sample. These bootstrap procedures are demonstrated using 103 days of affective mood self-ratings from a pregnant woman, 90 days of personality self-ratings from a psychology freshman, and a simulation study. PMID- 26760490 TI - On the Misconception of Multicollinearity in Detection of Moderating Effects: Multicollinearity Is Not Always Detrimental. AB - Due to its extensive applicability and computational ease, moderated multiple regression (MMR) has been widely employed to analyze interaction effects between 2 continuous predictor variables. Accordingly, considerable attention has been drawn toward the supposed multicollinearity problem between predictor variables and their cross-product term. This article attempts to clarify the misconception of multicollinearity in MMR studies. The counterintuitive yet beneficial effects of multicollinearity on the ability to detect moderator relationships are explored. Comprehensive treatments and numerical investigations are presented for the simplest interaction model and more complex three-predictor setting. The results provide critical insight that both helps avoid misleading interpretations and yields better understanding for the impact of intercorrelation among predictor variables in MMR analyses. PMID- 26760491 TI - Using a Multivariate Multilevel Polytomous Item Response Theory Model to Study Parallel Processes of Change: The Dynamic Association Between Adolescents' Social Isolation and Engagement With Delinquent Peers in the National Youth Survey. AB - The application of multidimensional item response theory models to repeated observations has demonstrated great promise in developmental research. It allows researchers to take into consideration both the characteristics of item response and measurement error in longitudinal trajectory analysis, which improves the reliability and validity of the latent growth curve (LGC) model. The purpose of this study is to demonstrate the potential of Bayesian methods and the utility of a comprehensive modeling framework, the one combining a measurement model (e.g., a multidimensional graded response model, MGRM) with a structural model (e.g., an associative latent growth curve analysis, ALGC). All analyses are implemented in WinBUGS 1.4.3 ( Spiegelhalter, Thomas, Best, & Lunn, 2003 ), which allows researchers to use Markov chain Monte Carlo simulation methods to fit complex statistical models and circumvent intractable analytic or numerical integrations. The utility of this MGRM-ALGC modeling framework was investigated with both simulated and empirical data, and promising results were obtained. As the results indicate, being a flexible multivariate multilevel model, this MGRM-ALGC model not only produces item parameter estimates that are readily estimable and interpretable but also estimates the corresponding covariation in the developmental dimensions. In terms of substantive interpretation, as adolescents perceived themselves more socially isolated, the chance that they are engaged with delinquent peers becomes profoundly larger. Generally, boys have a higher initial exposure extent than girls. However, there is no gender difference associated with other latent growth parameters. PMID- 26760492 TI - Reporting Diagnostic Scores in Educational Testing: Temptations, Pitfalls, and Some Solutions. AB - Diagnostic scores are of increasing interest in educational testing due to their potential remedial and instructional benefit. Naturally, the number of educational tests that report diagnostic scores is on the rise, as are the number of research publications on such scores. This article provides a critical evaluation of diagnostic score reporting in educational testing. The existing methods for diagnostic score reporting are discussed. A recent method ( Haberman, 2008a ) that examines if diagnostic scores are worth reporting is reviewed. It is demonstrated, using results from operational and simulated data, that diagnostic scores have to be based on a sufficient number of items and have to be sufficiently distinct from each other to be worth reporting and that several operationally reported subscores are actually not worth reporting. Several recommendations are made for those interested to report diagnostic scores for educational tests. PMID- 26760493 TI - Investigation of Multiple Imputation in Low-Quality Questionnaire Data. AB - The performance of multiple imputation in questionnaire data has been studied in various simulation studies. However, in practice, questionnaire data are usually more complex than simulated data. For example, items may be counterindicative or may have unacceptably low factor loadings on every subscale, or completely missing subscales may complicate computations. In this article, it was studied how well multiple imputation recovered the results of several psychometrically important statistics in a data set with such properties. Analysis of this data set revealed that multiple imputation was able to recover the results of these analyses well. Also, a simulation study showed that multiple imputation produced small bias in these statistics for simulated data sets with the same properties. PMID- 26760494 TI - Chemoreduction of Progressive Intraocular Retinoblastoma by Systemic Topotecan. AB - PURPOSE: To evaluate our experience with systemic Toptecan (TPT) chemotherapy as a second-line systemic chemotherapeutic regimen for treatment of refractory or recurrent intraocular retinoblastoma (RB). METHODS AND MATERIALS: A retrospective case series of 14 eyes from patients with intraocular RB who received systemic TPT as second-line chemotherapy from April 2008 until June 2010. The following data were collected: patient demographics, laterality, international intraocular retinoblastoma stage (ICRB) at diagnosis, treatment received before and after TPT, side effects related to TPT, eye salvage, and survival. RESULTS: The median age at diagnosis was 5 months (range, 1-16 months), and the median age at starting TPT was 10 months (range, 8-24 months). There were 6 (60%) females and 9 (90%) patients; all with bilateral retinoblastoma. The median number of TPT cycles was three per patient (range, 1-6), and the total number of administered cycles was 29. After TPT therapy; 4 (29%) eyes showed favorable response, 3 (21%) eyes showed minimal regression, 5 (36%) eyes had stable disease, and 2 (14%) eyes showed tumor progression. At a median follow-up of 48 months; 9 (64%) eyes were salvaged, 3 (21%) eyes received radiation therapy, and 3 (21%) eyes were enucleated (one was post radiation). Grade 3/4 neutropenia were noticed in a total of 59% of given cycles and admission for febrile neutropenia was required after seven cycles. CONCLUSIONS: Our report suggests that systemic TPT chemotherapy could be used as a salvage second-line regimen with low toxicity for patients with progressive intraocular retinoblastoma if systemic therapy is needed. PMID- 26760495 TI - Injury prevention programs against distracted driving: Are they effective? AB - INTRODUCTION: Distracted driving (talking and/or texting) is a growing public safety problem, with increasing incidence among adult drivers. The aim of this study was to identify the incidence of distracted driving (DD) among health care providers and to create awareness against DD. We hypothesized that distracted driving is prevalent among health care providers and a preventive campaign against distracted driving would effectively decrease distracted driving among health care providers. METHODS: We performed a 4-phase prospective interventional study of all health care providers at our level 1 trauma center. Phase 1: one week of pre-intervention observation; phase 2: one week of intervention; phase 3: one week of postintervention observation; and phase 4: one week of 6 months of postintervention observation. Observations were performed outside employee parking garage at the following time intervals: 6:30-8:30 a.m., 4:40-5:30 p.m., and 6:30-7:30 p.m. Intervention included an e-mail survey, pamphlets and banners in the hospital cafeteria, and a postintervention survey. Hospital employees were identified with badges and scrubs, employees exiting through employee gate, and parking pass on the car. Outcome measure was incidence of DD pre, post, and 6 months postintervention. RESULTS: A total of 15,416 observations (pre: 6,639, post: 4,220, 6 months post: 4,557) and 520 survey responses were collected. The incident of DD was 11.8% among health care providers. There was a significant reduction in DD in each time interval of observation between pre- and postintervention. On subanalysis, there was a significant decrease in talking (P = .0001) and texting (P = .01) while driving postintervention compared to pre intervention. In the survey, 35.5% of respondents admitted to DD and 4.5% respondents were involved in an accident due to DD. We found that 77% respondents felt more informed after the survey and 91% respondents supported a state legislation against DD. The reduction in the incidence of DD postintervention was sustained even at 6-month follow-up. CONCLUSION: There was a 32% reduction in the incidence of distracted driving postintervention, which remained low even at 6 month follow-up. Implementation of an effective injury prevention campaign could reduce the incidence of distracted driving nationally. PMID- 26760496 TI - Fusion set selection with surrogate metric in multi-atlas based image segmentation. AB - Multi-atlas based image segmentation sees unprecedented opportunities but also demanding challenges in the big data era. Relevant atlas selection before label fusion plays a crucial role in reducing potential performance loss from heterogeneous data quality and high computation cost from extensive data. This paper starts with investigating the image similarity metric (termed 'surrogate'), an alternative to the inaccessible geometric agreement metric (termed 'oracle') in atlas relevance assessment, and probes into the problem of how to select the 'most-relevant' atlases and how many such atlases to incorporate. We propose an inference model to relate the surrogates and the oracle geometric agreement metrics. Based on this model, we quantify the behavior of the surrogates in mimicking oracle metrics for atlas relevance ordering. Finally, analytical insights on the choice of fusion set size are presented from a probabilistic perspective, with the integrated goal of including the most relevant atlases and excluding the irrelevant ones. Empirical evidence and performance assessment are provided based on prostate and corpus callosum segmentation. PMID- 26760497 TI - A Population-Based Study of the Prevalence and Correlates of Self-Harm in Juvenile Detention. AB - BACKGROUND: Suicide is the number one cause of death among incarcerated youth. We examined the demographic and forensic risk factors for self-harm in youth in juvenile detention using a Canadian provincial correctional database. METHOD: We analyzed data from de-identified youth aged 12 to 18 at the time of their offense who were in custody in a Manitoba youth correctional facility between January 1, 2005 and December 30, 2010 (N = 5,102). Univariate and multivariate logistic regression analyses determined the association between staff-identified self-harm events in custody and demographic and custodial variables. Time to the event was examined based on the admission date and date of event. RESULTS: Demographic variables associated with self-harm included female sex, lower educational achievement, older age, and child welfare involvement. Custodial variables associated with self-harm included higher criminal severity profiles, younger age at first incarceration, longer sentence length, disruptive institutional behavior, and a history of attempting escape. Youth identified at entry as being at risk for suicide were more likely to self-harm. Events tended to occur earlier in the custodial admission. INTERPRETATION: Self-harm events tended to occur within the first 3 months of an admission stay. Youth with more serious offenses and disruptive behaviors were more likely to self-harm. Individuals with problematic custodial profiles were more likely to self-harm. Suicide screening identified youth at risk for self-harm. Strategies to identify and help youth at risk are needed. PMID- 26760498 TI - Structural Changes and Lack of HCN1 Channels in the Binaural Auditory Brainstem of the Naked Mole-Rat (Heterocephalus glaber). AB - Naked mole-rats (Heterocephalus glaber) live in large eu-social, underground colonies in narrow burrows and are exposed to a large repertoire of communication signals but negligible binaural sound localization cues, such as interaural time and intensity differences. We therefore asked whether monaural and binaural auditory brainstem nuclei in the naked mole-rat are differentially adjusted to this acoustic environment. Using antibody stainings against excitatory and inhibitory presynaptic structures, namely the vesicular glutamate transporter VGluT1 and the glycine transporter GlyT2 we identified all major auditory brainstem nuclei except the superior paraolivary nucleus in these animals. Naked mole-rats possess a well structured medial superior olive, with a similar synaptic arrangement to interaural-time-difference encoding animals. The neighboring lateral superior olive, which analyzes interaural intensity differences, is large and elongated, whereas the medial nucleus of the trapezoid body, which provides the contralateral inhibitory input to these binaural nuclei, is reduced in size. In contrast, the cochlear nucleus, the nuclei of the lateral lemniscus and the inferior colliculus are not considerably different when compared to other rodent species. Most interestingly, binaural auditory brainstem nuclei lack the membrane-bound hyperpolarization-activated channel HCN1, a voltage-gated ion channel that greatly contributes to the fast integration times in binaural nuclei of the superior olivary complex in other species. This suggests substantially lengthened membrane time constants and thus prolonged temporal integration of inputs in binaural auditory brainstem neurons and might be linked to the severely degenerated sound localization abilities in these animals. PMID- 26760499 TI - Buruli Ulcer in Cameroon: The Development and Impact of the National Control Programme. AB - BACKGROUND: Cameroon is endemic for Buruli ulcer (BU) and organised institutional BU control began in 2002. The objective was to describe the evolution, achievements and challenges of the national BU control programme (NBUCP) and to make suggestions for scaling up the programme. METHODS: We analysed collated data on BU from 2001 to 2014 and reviewed activity reports NBUCP in Cameroon. Case detection rates and key BU control indicators were calculated and plotted on a time scale to determine trends in performance. A linear regression analysis of BU detection rate from 2005-2014 was done. The regression coefficient was tested statistically for the significance in variation of BU detection rate. PRINCIPAL FINDINGS: In 14 years of BU control, 3700 cases were notified. The BU detection rate dropped significantly from 3.89 to 1.45 per 100 000 inhabitants. The number of BU endemic health districts rose from two to 64. Five BU diagnostic and treatment centres are functional and two more are planned for 2015. The health system has been strengthened and BU research and education has gained more interest in Cameroon. CONCLUSION/SIGNIFICANCE: Although institutional BU control Cameroon only began 30 years after the first cases were reported in 1969, a number of milestones have been attained. These would serve as stepping stones for charting the way forward and improving upon control activities in the country if the major challenge of resource allocation is dealt with. PMID- 26760501 TI - TRPV4-AQP4 interactions 'turbocharge' astroglial sensitivity to small osmotic gradients. PMID- 26760500 TI - Metformin Treatment Does Not Inhibit Growth of Pancreatic Cancer Patient-Derived Xenografts. AB - There is currently tremendous interest in developing anti-cancer therapeutics targeting cell signaling pathways important for both cancer cell metabolism and growth. Several epidemiological studies have shown that diabetic patients taking metformin have a decreased incidence of pancreatic cancer. This has prompted efforts to evaluate metformin, a drug with negligible toxicity, as a therapeutic modality in pancreatic cancer. Preclinical studies in cell line xenografts and one study in patient-derived xenograft (PDX) models were promising, while recently published clinical trials showed no benefit to adding metformin to combination therapy regimens for locally advanced and metastatic pancreatic cancer. PDX models in which patient tumors are directly engrafted into immunocompromised mice have been shown to be excellent preclinical models for biomarker discovery and therapeutic development. We evaluated the response of four PDX tumor lines to metformin treatment and found that all four of our PDX lines were resistant to metformin. We found that the mechanisms of resistance may occur through lack of sustained activation of adenosine monophosphate-activated protein kinase (AMPK) or downstream reactivation of the mammalian target of rapamycin (mTOR). Moreover, combined treatment with metformin and mTOR inhibitors failed to improve responses in cell lines, which further indicates that metformin alone or in combination with mTOR inhibitors will be ineffective in patients, and that resistance to metformin may occur through multiple pathways. Further studies are required to better understand these mechanisms of resistance and inform potential combination therapies with metformin and existing or novel therapeutics. PMID- 26760502 TI - Hydrogen Sulfide Inhibits Transforming Growth Factor-beta1-Induced EMT via Wnt/Catenin Pathway. AB - Hydrogen sulfide (H2S) has anti-fibrotic potential in lung, kidney and other organs. The exogenous H2S is released from sodium hydrosulfide (NaHS) and can influence the renal fibrosis by blocking the differentiation of quiescent renal fibroblasts to myofibroblasts. But whether H2S affects renal epithelial-to mesenchymal transition (EMT) and the underlying mechanisms remain unknown. Our study is aimed at investigating the in vitro effects of H2S on transforming growth factor-beta1 (TGF-beta1)-induced EMT in renal tubular epithelial cells (HK 2 cells) and the associated mechanisms. The induced EMT is assessed by Western blotting analysis on the expressions of alpha-SMA, E-cadherin and fibronectin. HK 2 cells were treated with NaHS before incubating with TGF-beta1 to investigate its effect on EMT and the related molecular mechanism. Results demonstrated that NaHS decreased the expression of alpha-SMA and fibronectin, and increased the expression of E-cadherin. NaHS reduced the expression of TGF-beta receptor type I (TbetaR I) and TGF-beta receptor type II (TbetaR II). In addition, NaHS attenuated TGF-beta1-induced increase of beta-catenin expression and ERK phosphorylation. Moreover, it inhibited the TGF-beta1-induced nuclear translocation of betabeta-catenin. These effects of NaHS on fibronectin, E cadherin and TbetaR I were abolished by the ERK inhibitor U0126 or beta-catenin inhibitor XAV939, or beta-catenin siRNA interference. We get the conclusion that NaHS attenuated TGF-beta1-induced EMT in HK-2 cells through both ERK-dependent and beta-catenin-dependent pathways. PMID- 26760503 TI - Is angiotensin-converting enzyme inhibitors/angiotensin receptor blockers therapy protective against prostate cancer? AB - Emerging evidence suggests that renin-angiotensin system (RAS) may act as a molecular and therapeutic target for treating site-specific cancers, including prostate cancer. However, previous observational studies regarding the association between RAS inhibitors and prostate cancer risk have reported inconsistent results. We examined this association by performing a systematic review and meta-analysis. A total of 20,267 patients from nine cohort studies were enrolled. Compared with non-users of RAS inhibitors, individuals using RAS inhibitors had a reduced risk of prostate cancer (RR 0.92, 95 % CI 0.87-0.98), without statistically significant heterogeneity among studies (P = 0.118 for heterogeneity, I2 = 37.6 %). In addition, when subgroup analyses by study quality and number of cases, more statistically significant associations were observed in studies of high quality (RR 0.93, 95 % CI 0.88-0.97) and large sample size (RR 0.94, 95 % CI 0.91-0.98). There was no evidence of significant publication bias with Begg's test (P = 0.602) or with Egger's test (P = 0.350). Overall, this study indicates that use of RAS inhibitors may be associated with a decreased risk of prostate cancer. Large-scale well designed studies are needed to further explore this association. PMID- 26760505 TI - Gene amplification during myogenic differentiation. AB - Gene amplifications are mostly an attribute of tumor cells and drug resistant cells. Recently, we provided evidence for gene amplifications during differentiation of human and mouse neural progenitor cells. Here, we report gene amplifications in differentiating mouse myoblasts (C2C12 cells) covering a period of 7 days including pre-fusion, fusion and post-fusion stages. After differentiation induction we found an increase in copy numbers of CDK4 gene at day 3, of NUP133 at days 4 and 7, and of MYO18B at day 4. The amplification process was accompanied by gamma-H2AX foci that are indicative of double stand breaks. Amplifications during the differentiating process were also found in primary human myoblasts with the gene CDK4 and NUP133 amplified both in human and mouse myoblasts. Amplifications of NUP133 and CDK4 were also identified in vivo on mouse transversal cryosections at stage E11.5. In the course of myoblast differentiation, we found amplifications in cytoplasm indicative of removal of amplified sequences from the nucleus. The data provide further evidence that amplification is a fundamental mechanism contributing to the differentiation process in mammalians. PMID- 26760507 TI - One-Particle Representation of Heat Conduction Described within the Scope of the Second Law. AB - The Carnot cycle and its deduction of maximum conversion efficiency of heat inputted and outputted isothermally at different temperatures necessitated the construction of isothermal and adiabatic pathways within the cycle that were mechanically "reversible", leading eventually to the Kelvin-Clausius development of the entropy function S with differential dS = dq/T such that [symbol: see text]C dS = 0 where the heat absorption occurs at the isothermal paths of the elementary Carnot cycle. Another required condition is that the heat transfer processes take place infinitely slowly and "reversibly", implying that rates of transfer are not explicitly featured in the theory. The definition of 'heat' as that form of energy that is transferred as a result of a temperature difference suggests that the local mode of transfer of "heat" in the isothermal segments of the pathway implies a Fourier-like heat conduction mechanism which is apparently irreversible, leading to an increase in entropy of the combined reservoirs at either end of the conducting material, and which is deemed reversible mechanically. These paradoxes are circumvented here by first clarifying the terms used before modeling heat transfer as a thermodynamically reversible but mechanically irreversible process and applied to a one dimensional atomic lattice chain of interacting particles subjected to a temperature difference exemplifying Fourier heat conduction. The basis of a "recoverable trajectory" i.e. that which follows a zero entropy trajectory is identified. The Second Law is strictly maintained in this development. A corollary to this zero entropy trajectory is the generalization of the Zeroth law for steady state non-equilibrium systems with varying temperature, and thus to a statement about "equilibrium" in steady state non-thermostatic conditions. An energy transfer rate term is explicitly identified for each particle and agrees quantitatively (and independently) with the rate of heat absorbed at the reservoirs held at different temperatures and located at the two ends of the lattice chain in MD simulations, where all energy terms in the simulation refer to a single particle interacting with its neighbors. These results validate the theoretical model and provides the necessary boundary conditions (for instance with regard to temperature differentials and force fields) that thermodynamical variables must comply with to satisfy the conditions for a recoverable trajectory, and thus determines the solution of the differential and integral equations that are used to model these processes. These developments and results, if fully pursued would imply that not only can the Carnot cycle be viewed as describing a local process of energy-work conversion by a single interacting particle which feature rates of energy transfer and conversion not possible in the classical Carnot development, but that even irreversible local processes might be brought within the scope of this cycle, implying a unified treatment of thermodynamically (i) irreversible (ii) reversible (iii) isothermal and (iv) adiabatic processes by conflating the classically distinct concept of work and heat energy into a single particle interactional process. A resolution to the fundamental and long-standing conjecture of Benofy and Quay concerning the Fourier principle is one consequence of the analysis. PMID- 26760506 TI - R152C DNA Pol beta mutation impairs base excision repair and induces cellular transformation. AB - DNA polymerase beta (Pol beta) is a key enzyme in DNA base excision repair (BER), a pathway that maintains genome integrity and stability. Pol beta mutations have been detected in various types of cancers, suggesting a possible linkage between Pol beta mutations and cancer. However, it is not clear whether and how Pol beta mutations cause cancer onset and progression. In the current work, we show that a substitution mutation, R152C, impairs Pol beta polymerase activity and BER efficiency. Cells harboring Pol beta R152C are sensitive to the DNA damaging agents methyl methanesulfonate (MMS) and H2O2. Moreover, the mutant cells display a high frequency of chromatid breakages and aneuploidy and also form foci. Taken together, our data indicate that Pol beta R152C can drive cellular transformation. PMID- 26760504 TI - The cytoskeletal arrangements necessary to neurogenesis. AB - During the process of neurogenesis, the stem cell committed to the neuronal cell fate starts a series of molecular and morphological changes. The understanding of the physio-pathology of mechanisms controlling the molecular and morphological changes occurring during neuronal differentiation is fundamental to the development of effective therapies for many neurologic diseases. Unfortunately, our knowledge of the biological events occurring in the cell during neuronal differentiation is still poor. In this study, we focus preliminarily on the relevance of the cytoskeletal rearrangements, which earlier drive the morphology of the neuronal precursors, and later the migrating/mature neurons. In fact, neuritogenesis, neurite branching, outgrowth and retraction are seminal to the development of a fully functional nervous system. With this in mind, we highlight the importance of iPSC technology to study the processes of cytoskeletal-driven morphological changes during neuronal differentiation. PMID- 26760508 TI - Lung stereotactic ablative radiotherapy (SABR): dosimetric considerations for chest wall toxicity. AB - OBJECTIVE: To investigate chest wall pain in patients with peripheral early stage lung cancer treated with stereotactic ablative radiotherapy (SABR), and to identify factors predictive of Common Terminology Criteria of Adverse Events Grade 2 + chest wall pain. METHODS: Patients who received 55 Gy in five fractions were included. A chest wall structure was retrospectively defined on planning scans, and chest wall dosimetry and tumour-related factors recorded. Logistic regression was performed to identify factors predictive of >=Grade 2 chest wall pain. RESULTS: 182 patients and 187 tumours were included. There were 20 (10.9%) episodes of >=Grade 2 chest wall pain. Multivariate logistic regression demonstrated that the maximum dose received by 1 cm(3) of chest wall (Dmax1 cm(3)) and tumour size were significant predictors of >=Grade 2 chest wall pain [Dmax1 cm(3) odds ratio : 1.104, 95% confidence interval : 1.012-1.204, p = 0.025; tumour size (mm) odds ratio : 1.080, 95% confidence interval : 1.026 1.136, p = 0.003]. This model was an adequate fit to the data (Hosmer and Lemeshow test non-significant) and a fair discriminator for chest wall pain (area under receiver-operating characteristic curve: 0.74). Using the multivariate logistic regression model, parameters for Dmax1 cm(3) are provided, which predict <10% and <20% risks of >=Grade 2 chest wall pain for different tumour sizes. CONCLUSION: Grade 2+ chest wall pain is an uncommon side effect of lung SABR. Larger tumour size and increasing Dmax1 cm(3) are significant predictors of >=Grade 2 chest wall pain. When planning lung SABR, it is prudent to try to avoid hot volumes in the chest wall, particularly for larger tumours. ADVANCES IN KNOWLEDGE: This article demonstrates that Grade 2 or greater chest wall pain following lung SABR is more common when the tumour is larger in size and the Dmax1 cm(3) of the chest wall is higher. When planning lung SABR, the risk of chest wall pain may be reduced if maximum doses are minimized, particularly for larger tumours. PMID- 26760509 TI - The Effect of Elevated Ozone Concentrations with Varying Shading on Dry Matter Loss in a Winter Wheat-Producing Region in China. AB - Surface-level ozone pollution causes crop production loss by directly reducing healthy green leaf area available for carbon fixation. Ozone and its precursors also affect crop photosynthesis indirectly by decreasing solar irradiance. Pollutants are reported to have become even more severe in Eastern China over the last ten years. In this study, we investigated the effect of a combination of elevated ozone concentrations and reduced solar irradiance on a popular winter wheat Yangmai13 (Triticum aestivum L.) at field and regional levels in China. Winter wheat was grown in artificial shading and open-top-chamber environments. Treatment 1 (T1, i.e., 60% shading with an enhanced ozone of 100+/-9 ppb), Treatment 2 (T2, i.e., 20% shading with an enhanced ozone of 100+/-9 ppb), and Control Check Treatment (CK, i.e., no shading with an enhanced ozone of 100+/-9 ppb), with two plots under each, were established to investigate the response of winter wheat under elevated ozone concentrations and varying solar irradiance. At the field level, linear temporal relationships between dry matter loss and cumulative stomatal ozone uptake were first established through a parameterized stomatal-flux model. At the regional level, ozone concentrations and meteorological variables, including solar irradiance, were simulated using the WRF-CMAQ model (i.e., a meteorology and air quality modeling system). These variables were then used to estimate cumulative stomatal ozone uptake for the four major winter wheat-growing provinces. The regional-level cumulative ozone uptake was then used as the independent variable in field data-based regression models to predict dry matter loss over space and time. Field-level results showed that over 85% (T1: R(2) = 0.85 & T2: R(2) = 0.89) of variation in dry matter loss was explained by cumulative ozone uptake. Dry matter was reduced by 3.8% in T1 and 2.2% in T2 for each mmol O3.m(-2) of cumulative ozone uptake. At the regional level, dry matter loss in winter wheat would reach 50% under elevated ozone concentrations and reduced solar irradiance as determined in T1, and 30% under conditions as determined in T2. Results from this study suggest that a combination of elevated ozone concentrations and reduced solar irradiance could result in substantial dry matter loss in the Chinese wheat-growing regions. PMID- 26760510 TI - Regional-Scale Declines in Productivity of Pink and Chum Salmon Stocks in Western North America. AB - Sockeye salmon (Oncorhynchus nerka) stocks throughout the southern part of their North American range have experienced declines in productivity over the past two decades. In this study, we tested the hypothesis that pink (O. gorbuscha) and chum (O. keta) salmon stocks have also experienced recent declines in productivity by investigating temporal and spatial trends in productivity of 99 wild North American pink and chum salmon stocks. We used a combination of population dynamics and time series models to quantify individual stock trends as well as common temporal trends in pink and chum salmon productivity across local, regional, and continental spatial scales. Our results indicated widespread declines in productivity of wild chum salmon stocks throughout Washington (WA) and British Columbia (BC) with 81% of stocks showing recent declines in productivity, although the exact form of the trends varied among regions. For pink salmon, the majority of stocks in WA and BC (65%) did not have strong temporal trends in productivity; however, all stocks that did have trends in productivity showed declining productivity since at least brood year 1996. We found weaker evidence of widespread declines in productivity for Alaska pink and chum salmon, with some regions and stocks showing declines in productivity (e.g., Kodiak chum salmon stocks) and others showing increases (e.g., Alaska Peninsula pink salmon stocks). We also found strong positive covariation between stock productivity series at the regional spatial scale for both pink and chum salmon, along with evidence that this regional-scale positive covariation has become stronger since the early 1990s in WA and BC. In general, our results suggest that common processes operating at the regional or multi-regional spatial scales drive productivity of pink and chum salmon stocks in western North America and that the effects of these process on productivity may change over time. PMID- 26760513 TI - To the Editor: Vitamin B12 deficiency. PMID- 26760512 TI - The simple lab test is sometimes more complex than we think, if we think about it at all. PMID- 26760514 TI - In Reply: Vitamin B12 deficiency. PMID- 26760511 TI - Anticipatory Posturing of the Vocal Tract Reveals Dissociation of Speech Movement Plans from Linguistic Units. AB - Models of speech production typically assume that control over the timing of speech movements is governed by the selection of higher-level linguistic units, such as segments or syllables. This study used real-time magnetic resonance imaging of the vocal tract to investigate the anticipatory movements speakers make prior to producing a vocal response. Two factors were varied: preparation (whether or not speakers had foreknowledge of the target response) and pre response constraint (whether or not speakers were required to maintain a specific vocal tract posture prior to the response). In prepared responses, many speakers were observed to produce pre-response anticipatory movements with a variety of articulators, showing that that speech movements can be readily dissociated from higher-level linguistic units. Substantial variation was observed across speakers with regard to the articulators used for anticipatory posturing and the contexts in which anticipatory movements occurred. The findings of this study have important consequences for models of speech production and for our understanding of the normal range of variation in anticipatory speech behaviors. PMID- 26760515 TI - To the Editor: Preoperative testing. PMID- 26760516 TI - Bony bumps in the mouth. PMID- 26760517 TI - Eventration of the diaphragm presenting as spontaneous pneumothorax. PMID- 26760518 TI - Serum allergen-specific IgE testing: How much is too much? PMID- 26760519 TI - Obstructive sleep apnea: Who should be tested, and how? PMID- 26760520 TI - Not all abdominal pain is gastrointestinal. PMID- 26760522 TI - Autoantibody-mediated encephalitis: Not just paraneoplastic, not just limbic, and not untreatable. AB - Autoantibody-mediated encephalitis is a heterogeneous group of recently identified disorders, all caused by autoimmunity directed against components of the central nervous system. Despite severe and even prolonged neurologic deficits, dramatic improvements may occur with aggressive treatment. PMID- 26760521 TI - Approach to asymptomatic creatine kinase elevation. AB - How to manage a patient who has an elevated serum creatine kinase (CK) level but no or insignificant muscle-related signs and symptoms is a clinical conundrum. The authors provide a systematic approach, including repeat testing after a period of rest, defining higher thresholds over which pursuing a diagnosis is worthwhile, and evaluating for a variety of nonneuromuscular causes. They also outline a workup for neuromuscular causes. PMID- 26760523 TI - Managing interstitial lung disease detected on CT during lung cancer screening. AB - As long-term smokers undergo computed tomography (CT) to screen for lung cancer, cases of interstitial lung disease are being discovered incidentally. This article explains how to distinguish among the most common forms of interstitial lung disease in this situation and the role of primary care physicians in managing them. PMID- 26760524 TI - Alcohol withdrawal syndrome in medical patients. AB - The authors provide a critical review focusing on pharmacotherapy of alcohol withdrawal syndrome in hospitalized patients who are not critically ill. They outline recommendations for patient assessment and monitoring. PMID- 26760526 TI - The choice of amniotic fluid in metabolomics for the monitoring of fetus health. AB - Amniotic fluid (AF) is a biological fluid in which metabolite transport is regulated by the placenta, the permeable skin, fetal lung egress and gastric fluid. During pregnancy, the composition of AF changes from similar to the interstitial fluid of the mother, to a more complex system, influenced by the fetus's urine. Since AF reflects the mother's and the fetus's health status at the same time, it may be an important diagnostic tool for a wider spectrum of clinical conditions. Indeed, the metabolic characterization of AF in relation to pathological occurrences may lead to the discovery of new biomarkers for a better clinical practice. For this reason, metabolomics may be the most suitable strategy for this task. In this review, research works on metabolomic AF analysis are discussed according to the morbidity of interest, being preterm birth/labor, gestational age and diabetes and fetal malformations, along with a number of other important studies. PMID- 26760528 TI - Locked plate stabilization of problem fractures. PMID- 26760525 TI - SNAREs in the maturation and function of LROs. AB - The early/recycling endosomes of an eukaryotic cell perform diverse cellular functions. In addition, the endosomal system generates multiple organelles, including certain cell type-specific organelles called lysosome-related organelles (LROs). The biosynthesis of these organelles possibly occurs through a sequential maturation process in which the cargo-containing endosomal vesicular/tubular structures are fused with the maturing organelle. The molecular machinery that regulates the cargo delivery or the membrane fusion during LRO biogenesis is poorly understood. Here, we describe the known key molecules, such as SNAREs, that regulate both the biogenesis and secretion of multiple LROs. Moreover, we also describe other regulatory molecules, such as Rab GTPases and their effectors that modulate the SNARE activity for cargo delivery to one such LRO, the melanosome. Overall, this review will increase our current understanding of LRO biogenesis and function. PMID- 26760530 TI - Strain and electric field co-modulation of electronic properties of bilayer boronitrene. AB - The electronic properties of bilayer strained boronitrenes are investigated under an external electric field using density functional methods. Our result is just the same as the previous conclusion: ie, that the electric field will reduce their band gaps. Except for the decrease of their band gaps, the degeneracy of pi valence bands at K points will be lifted and the degenerate gap will increase with the electric field increasing. Moreover, the widths of pi valence bands are nearly robust and increase a little. In addition, a simple tight-binding model, where different electrostatic potentials are applied to boronitrene layers, can be sufficient to describe the variations of their band gaps. It is found that the interlayer hopping interaction increases while the intralayer hopping parameter changes little with increasing the electric field. Furthermore, a band gap phase diagram is determined within the in-plane strain [-0.2, 0.2] and the interlayer bias [0, 10] V nm(-1). The strain could make the bottom of conduction bands shift from K to M, then to Gamma in the Brillouin zone, while the top of valence bands shifts from K to Gamma. Thus, a direct-gap semiconductor at K points is changed into an indirect-gap semiconductor, and then a semiconductor with the direct band gap at Gamma points. When bilayer boronitrene is a semiconductor with a direct gap at K points, the electric field and strain are inverse proportional relationships. Particularly, when the compressive strain exceeds -0.194, there is an insulator-metal transition and the system becomes metallic with sizable pocket Fermi surfaces. PMID- 26760531 TI - Probing the interactions of phenol with oxygenated functional groups on curved fullerene-like sheets in activated carbon. AB - The mechanism(s) of interactions of phenol with oxygenated functional groups (OH, COO and COOH) in nanopores of activated carbon (AC) is a contentious issue among researchers. This mechanism is of particular interest because a better understanding of the role of such groups in nanopores would essentially translate to advances in AC production and use, especially in regard to the treatment of organic-based wastewaters. We therefore attempt to shed more light on the subject by employing density functional theory (DFT) calculations in which fullerene-like models integrating convex or concave structure, which simulate the eclectic porous structures on AC surface, are adopted. TEM analysis, EDS mapping and Boehm titration are also conducted on actual phenol-adsorbed AC. Our results suggest the widely-reported phenomenon of decreased phenol uptake on AC due to increased concentration of oxygenated functional groups is possibly attributed to the increased presence of the latter on the convex side of the curved carbon sheets. Such a system effectively inhibits phenol from getting direct contact with the carbon sheet, thus constraining any available pi-pi interaction, while the effect of groups acting on the concave part of the curved sheet does not impart the same detriment. PMID- 26760532 TI - Enhanced Nitric Oxide Synthase Activation via Protease-Activated Receptor 2 Is Involved in the Preserved Vasodilation in Aortas from Metabolic Syndrome Rats. AB - Endothelium-dependent vasodilation via protease-activated receptor 2 (PAR2) is preserved in mesenteric arteries from SHRSP.Z-Leprfa/IzmDmcr rats (SHRSP.ZF) with metabolic syndrome even though nitric oxide (NO)-mediated vasodilation is attenuated. Therefore, we examined the PAR2 mechanisms underlying metabolic syndrome-resistant vasodilation in SHRSP.ZF aortas with ageing. In isolated aortas, the PAR2 agonist 2-furoyl-LIGRLO-amide (2fly) caused vasodilation that was sustained in male SHRSP.ZF until 18 weeks of age, but was attenuated afterwards compared with age-matched Wistar-Kyoto rats (controls) at 23 weeks. In contrast, acetylcholine-induced vasodilation was impaired in SHRSP.ZF already at 18 weeks of age. Treatments of aortas with inhibitors of NO synthase and soluble guanylate cyclase abolished the sustained 2fly- and residual acetylcholine induced vasodilation in SHRSP.ZF at 18 weeks of age. In the aortas of SHRSP.ZF, 8 bromo-cGMP-induced vasodilation, NO production and cGMP accumulation elicited by 2fly were not different from in the controls. PAR2 agonist increased phospho Ser1177-eNOS protein content only in SHRSP.ZF aortas. These results indicate that vasodilation mediated by PAR2 is sustained even though NO-dependent relaxation is attenuated with ageing/exposure to metabolic disorders in large-caliber arteries from SHRSP.ZF. PAR2 stimulation of NO production via an additional pathway that targets phosphorylation of Ser1177-eNOS suggests a regulatory mechanism for sustaining agonist-mediated vasodilation in metabolic syndrome. PMID- 26760527 TI - Bloodstream infections in the Intensive Care Unit. AB - Bloodstream infections (BSIs) represent a common complication among critically ill patients and a leading cause of morbidity and mortality. The prompt initiation of an effective antibiotic therapy is necessary in order to reduce mortality and to improve clinical outcomes. However, the choice of the empiric antibiotic regimen is often challenging, due to the worldwide spread of multi drug resistant (MDR) organisms with reduced susceptibility to the available broad spectrum antimicrobials. New therapeutic strategies are 5 to improve the effectiveness of antibiotic treatment while minimizing the risk of resistance selection. PMID- 26760529 TI - Mapping translation 'hot-spots' in live cells by tracking single molecules of mRNA and ribosomes. AB - Messenger RNA localization is important for cell motility by local protein translation. However, while single mRNAs can be imaged and their movements tracked in single cells, it has not yet been possible to determine whether these mRNAs are actively translating. Therefore, we imaged single beta-actin mRNAs tagged with MS2 stem loops colocalizing with labeled ribosomes to determine when polysomes formed. A dataset of tracking information consisting of thousands of trajectories per cell demonstrated that mRNAs co-moving with ribosomes have significantly different diffusion properties from non-translating mRNAs that were exposed to translation inhibitors. These data indicate that ribosome load changes mRNA movement and therefore highly translating mRNAs move slower. Importantly, beta-actin mRNA near focal adhesions exhibited sub-diffusive corralled movement characteristic of increased translation. This method can identify where ribosomes become engaged for local protein production and how spatial regulation of mRNA protein interactions mediates cell directionality. PMID- 26760546 TI - Impact of a program to promote health and quality of life of elderly. AB - OBJECTIVE: To evaluate the effect on quality of life of elderly people enrolled in GAMIA - Multidisciplinary Care Group to Outpatient Elderly Subjects (Grupo de Assistencia Multidisciplinar ao Idoso Ambulatorial) of the Geriatric Department, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo. METHODS: Between 2000 and 2002, 83 elderly participants of GAMIA were assessed by the World Health Organization Quality of Life scale (WHOQOL-bref) at the beginning and the end of the program. Functionality was assessed by Katz and Lawton scales and sociodemographic data were obtained from medical charts. RESULTS: Females predominated (79.5%) and overall mean age was 69.30 years. Data analysis showed a reduction in the physical domain of WHOQOL-bref (p = 0.014) and increased psychological health and environment domains (p = 0.029 and p = 0.007, respectively), detecting a trend of increase in social relationships and in general domains (p = 0.062 and p = 0.052, respectively). CONCLUSIONS: The clinical evaluation of the elderly detected previously unknown diseases and determination of the use of new drugs, which might have been the predominant factor for the deterioration of their perception in the physical domain. Improvement in psychological health and the environment can be related to psychological and social support that the elderly received from peers and professionals and the benefits of group activities, as well as the upward trend observed in social relationships and general domains. Participation in a program to promote healthy aging was effective in improving the quality of life of the elderly. PMID- 26760545 TI - Haiti's earthquake: a multiprofessional experience. PMID- 26760547 TI - Impact of screening and monitoring of capillary blood glucose in the detection of hyperglycemia and hypoglycemia in non-critical inpatients. AB - OBJECTIVE: To evaluate the impact of screening hyper and hypoglycemia measured by capillary glycemia and standard monitorization of hyperglycemic patients hospitalized in regular care units of Hospital Israelita Albert Einstein. METHODS: The capillary glycemia was measured by the Precision PCx (Abbott) glucosimeter, using the PrecisionWeb (Abbott) software. The detection of hyper and hypoglycemia during the months of May/June were compared to those of March/April in 2009 and to the frequency of the diagnosis of diabetes in 2007. RESULTS: There was an increase in the glycemia screening from 27.7 to 77.5% of hospitalized patients (p < 0.001), of hyperglycemia detection (from 9.3 to 12.2%; p < 0.001) and of hypoglycemia (from 1.5 to 3.3%; p < 0.001) during the months of May/June 2009. According to this action 14 patients for each additional case of hyperglycemia and 26 cases for each case of hypoglycemia were identified. The detection of hyperglycemia was significantly higher (p < 0.001) than the frequency of registered diagnosis related do diabetes in the year of 2007. CONCLUSIONS: the adoption of an institutional program of glycemia monitorization improves the detection of hyper and hypoglycemia and glycemia control in hospitalized patients in regular care units. PMID- 26760548 TI - Potentially inappropriate medication prescribed to elderly outpatients at a general medicine unit. AB - OBJECTIVE: To establish the prevalence of potentially inappropriate medications prescribed for elderly patients, to identify the most commonly involved drugs, and to investigate whether age, sex and number of medications were related with the prescription of these drugs. METHODS: Prescriptions for 1,800 elderly patients (>= 60 years) were gathered from a database. These prescriptions were written by general physicians at a tertiary level university hospital in the city of Sao Paulo, Brazil, from February to May 2008. Only one prescription per patient was considered. The prescriptions were classified according to sex and age (60-69, 70-79 and >= 80). The Beers criteria (2003 version) were used to evaluate potentially inappropriate medications. RESULTS: Most of the sample comprised women (66.6%) with a mean age of 71.3 years. The mean prevalence of potentially inappropriate medication prescriptions was 37.6%. The 60-69 age group presented the highest prevalence (49.9%). The most frequently prescribed potentially inappropriate medications to women were carisoprodol, amitriptyline, and fluoxetine; amitriptyline, carisoprodol, fluoxetine and clonidine were prescribed more often to men. The female sex (p<0.001; OR=2.0) and number of medications prescribed (p<0.001) were associated with prescription of potentially inappropriate medications. The chance of having a prescription of these drugs was lower among patients aged over 80 years (OR=0.7). The mean number of prescribed medications for both sexes and all age groups was 7.1. The mean number of medications per patient was higher among females (p<0.001); this result was not age-dependent (p=0.285). CONCLUSION: The prevalence of potentially inappropriate medications was similar to previously reported values in the literature and was correlated with the female sex. The chance of having a potentially inappropriate medication prescription was lower among patients aged over 80 years. The chance of having a potentially inappropriate medications prescription increased proportionally with the number of medications prescribed (>= 5). PMID- 26760549 TI - Mother/child bond in mothers of overweight and eutrophic children: depression and socioeconomic factors. AB - OBJECTIVE: To verify the presence of depression, age, level of schooling, occupation, marital status, number of children and nutritional status (maternal and of the child) in mothers of overweight and eutrophic children and relate the data to mother/child bonding. METHODS: A total of 120 mothers of children aged up to 10 years participated; 30 of them were overweight and 30 were eutrophic (low income bracket); 30 were overweight and 30 eutrophic (high-income bracket). The control group was composed of eutrophic children paired according to sex, age, level of schooling, and social condition. Data collection was made through interviews. The assessment instruments were: Mother/Child Bonding Assessment Protocol and Beck Depression Inventory. The nutritional classification was defined by calculation of the body mass index, as per the curves of the World Health Organization. For statistics, McNemar, chi2, and Fisher's exact tests were used. A 5% level of rejection of the null hypothesis was set. RESULTS: There was no significant result between mother/child bonding and the variables studied, or between the presence of depression and level of schooling, marital status, occupation, and maternal nutritional status. Nevertheless, mothers of eutrophic children (high-income bracket) showed less depression than mothers of eutrophic children (low-income bracket). Mothers with three or more children displayed more depression than mothers with less than three children. Mothers under 30 years of age showed more depression than mothers aged 30 years or older. CONCLUSION: There was no significant result between mother/child bonding and the variables studied, but the bond was compromised in all mothers of the sample. There was a significant result regarding the presence of depression. PMID- 26760550 TI - Habituation of the blink reflex in the neonatal period and development of auditory processing. AB - OBJECTIVE: To check the existence of an association between the presence/absence of the blink reflex habituation in the neonatal period and auditory processing development. METHODS: The occurrence of blink reflex habituation was studied in 33 neurologically normal neonates, aged between 9 and 25 months, who had their behavioral responses analyzed and classified according to Azevedo (1993). Habituation of the blink reflex was verified using 90-dB sound stimulus. The stage of auditory processing development was evaluated through 41-dB sound stimulus. Statistical data were analyzed with Fischer and chi2 tests. RESULTS: Out of the 33 studied children, 22 presented blink reflex habituation in the first stage of the study. In 7 of them, the auditory processing stage matched their chronological age, while in 15 of them the auditory processing stage was not in accordance with their chronological age. Eleven children failed to present habituation of the blink reflex in the first stage of the study. From this group, eight children presented auditory responses that were appropriate to their chronological age, whereas three had inappropriate responses. A statistically significant association between the presence of blink reflex habituation and auditory processing delay was verified, in addition to an association between the absence of the blink reflex habituation and chronologically suitable responses. CONCLUSIONS: The presence of blink reflex habituation in the neonatal period does not seem to be a predictive factor of suitable auditory processing. PMID- 26760552 TI - Contrasting roles of donor and recipient TGFB1 and IFNG gene polymorphic variants in chronic kidney transplant rejection. AB - OBJECTIVE: To assess the long-term impact (minimum of 3 years follow-up) of polymorphisms in cytokine genes in donor:recipient pairs on the results of the transplant. METHODS: We compared genetic cytokine polymorphisms and the primary factors of risk for the development of chronic rejection in paired groups of renal transplant patients with and without chronic allograft nephropathy [CAN]. RESULTS: Multivariate analysis indicated that the presence of the high-production TT genotype (codon 10) of the transforming growth factor beta-1 (TGFB1) was protective in receptors (p=0.017), contrasting with the increased risk when present in donor samples (p=0.049). On the other hand, in the case of the gamma interferon studied, the greater frequency of the high production allele was protective in the analysis of the donor group (p=0.013), increasing the risk of chronic nephropathy of the allograft when present in the recipients (p=0.036). CONCLUSION: Our results highlight the importance of TGFB1 genotyping in donors, and indicate that polymorphisms in the gene of this cytokine in donor cells might contribute to the development of chronic allograft nephropathy. PMID- 26760551 TI - Role of adipose tissue-derived stem cells in the progression of renal disease. AB - OBJECTIVE: To analyze the role of adipose tissue-derived stem cells in reducing the progression of renal fibrosis. METHODS: adipose tissue-derived stem cells were isolated from C57Bl/6 mice and characterized by cytometry and differentiation. Renal fibrosis was established after unilateral clamping of the renal pedicle for 1 hour. Four hours after reperfusion, 2.105 adipose tissue derived stem cells were administered intraperitoneally and the animals were followed for 24 hours during 6 weeks. In another experimental group, 2.105adipose tissue-derived stem cells were administered only after 6 weeks of reperfusion, and they were euthanized and studied 4 weeks later. Twenty-four hours after reperfusion, the animals treated with adipose tissue-derived stem cells displayed reduced renal and tubular dysfunction and an increase of the regenerative process. Renal expression of IL-6 and TNF mRNA were decreased in the animals treated with adipose tissue-derived stem cells, while the levels of IL-4, IL-10, and HO-1 were increased, despite the fact that adipose tissue-derived stem cells were not observed in the kidneys via SRY analysis. RESULTS: In 6 weeks, the kidneys of non-treated animals decreased in size, and the kidneys of the animals treated with adipose tissue-derived stem cells remained at normal size and display less deposition of type 1 collagen and FSP-1. The renal protection observed in animals treated with adipose tissue-derived stem cells was followed by a drop in serum levels of TNF-alpha, KC, RANTES, and IL-1a. Treatment with adipose tissue-derived stem cells after 6 weeks, when the animals already displayed established fibrosis, demonstrated an improvement in functional parameters and less fibrosis analyzed by Picrosirius stain, as well as a reduction of the expression of type 1 collagen and vimentin mRNA. CONCLUSION: Treatment with adipose tissue-derived stem cells may deter the progression of renal fibrosis by modulation of the early inflammatory response, likely via reduction of the epithelial-mesenchymal transition. PMID- 26760553 TI - Procalcitonin in patients with influenza A (H1N1) infection and acute respiratory failure. AB - OBJECTIVE: To verify serum procalcitonin levels of patients with acute respiratory failure secondary to influenza A (H1N1) upon their admission to the Intensive Care Unit and to compare these results to values found in patients with sepsis and trauma admitted to the same unit. METHODS: Analysis of records of patients infected with influenza A (H1N1) and respiratory failure admitted to the General Intensive Care Unit during in a period of 60 days. The values of serum procalcitonin and clinical and laboratory data were compared to those of all patients admitted with sepsis or trauma in the previous year. RESULTS: Among patients with influenza A (H1N1) (n = 16), the median serum procalcitonin level upon admission was 0.11 ng/mL, lower than in the sepsis group (p < 0.001) and slightly lower than in trauma patients. Although the mean values were low, serum procalcitonin was a strong predictor of hospital mortality in patients with influenza A (H1N1). CONCLUSION: Patients with influenza A (H1N1) with severe acute respiratory failure presented with low serum procalcitonin values upon admission, although their serum levels are predictors of hospital mortality. The kinetics study of this biomarker may be a useful tool in the management of this group of patients. PMID- 26760554 TI - Immunological induction with thymoglobulin: reduction in the number of doses in renal transplant from deceased donor. AB - OBJECTIVE: To compare three different regimens of thymoglobulin induction. METHODS: One hundred seventy two patients submitted to renal transplantation from a dead donor were divided into three groups according to the total number of thymoglobulin doses used in the post-transplantation surgery: Group 1, until 14 doses - May 2002 to June 2004 (n = 48); Group 2, until 7 doses - July 2004 to December 2006 (n = 57); Group 3, until 4 doses - January 2007 to July 2009 (n = 67). The three groups were compared according to the main outcomes. RESULTS: The main demographic differences among the groups were: greater dialysis time in Group 3 (p < 0.001 for Group 1; and p = 0.04 for Group 2); donor age, greater in Groups 2 and 3 (p = 0.02; p = 0.01, respectively); and cold ischemia time progressively greater from Group 1 to 3: 19.5 +/- 5.1 to 24.6 +/- 5.7 hours (p < 0.001). In relation to the inhibitor of calcineurin, the relation Tac/Csa was 14.6/66.7% in Group 1, 78.9/12.3% in Group 2 and 100/0% in Group 3. Reflecting the increase in cold ischemia time, the incidence of delayed graft function was 64.6%, 68.4% e 82.1% in Groups 1, 2 and 3, respectively (p = ns). The incidence of acute rejection was similar in the three groups: 16.7% (1); 16.3% (2) and 16.4 (3) - p = ns. The prevalence of viremia for cytomegalovirus was 61.7% in Group 1, 66.1% in Group 2 and 83.3% in Group 3 (p = ns). There were no difference related to the number of infected cells with cytomegalovirus in antigenemia, according to the groups, however, patients in Group 3 had an earlier diagnosis: from 64.3 +/- 28.5 days in Grup 2, to 47.1 +/- 22.5 days, in Group 3, p < 0.001. Survival of the graft in one year was 89.6%, 92.9% and 91.0%, in Groups 1, 2 and 3, respectively (p = ns). The graft function was much better with the lower doses of thymoglobulin: Group 1: 57.0 +/- 20.0 mL/min; Group 2: 67.0 +/- 18.4 mL/min (p = 0.008); Group 3: 71.2 +/- 18.4 mL/min (p < 0.001, Group 1 versus Group 3; p = 0.06, Group 1 versus Group 2). There was a significant reduction in the costs of induction protocol from U$ 7,567.02 to U$ 3,485.56 (p < 0.001). CONCLUSIONS: The total number of thymoglobulin doses for immunologic induction could be reduced in a safe and effective way, without a negative impact in graft rejection or survival, preserving renal function and being significantly cheaper. PMID- 26760555 TI - Sterilization of single-use helical stone baskets: an experimental study. AB - OBJECTIVES: To experimentally evaluate the efficacy of a standard sterilization protocol employed during reuse of disposable helical stone baskets. METHODS: Study performed on 20 helical stone baskets: 10 were used in the initial validation process, contaminated with Escherichia coli ATCC 25922 and imprinted on Mueller-Hinton media; 10 catheters were contaminated with Geobacillus stearothermophilus ATCC 7953, processed, inoculated in TSB and incubated in a water bath at a temperature of 55 degrees C. Bacterial growth was evaluated after 1, 3, 5 and 7 days. After sterilization, stone baskets were also opened and closed 40 times to check for functional problems. All plastic and basket parts were carefully checked for damages. RESULTS: After the 72-hour incubation period, there was growth of E. coli ATCC 25922 in 100% of imprints. After the sterilization process and up to 7 days incubation period on a blood agar plate, there was no growth of G. stearothermophilus ATCC 7953 or any other bacteria. There were no functional problems or damage to baskets after the sterilization process. CONCLUSION: The ethylene oxide system is efficacious and safe for sterilization of disposable helical stone baskets. However, further clinical studies are required and should provide more safety information. PMID- 26760556 TI - A new spectrophotometric method to detect residual amounts of peroxide after reprocessing hemodialysis filters. AB - OBJECTIVE: Reuse of hemodialysis filters is a standard practice and the sterilizing chemical most often employed is peracetic acid. Before starting the dialysis session, filters and lines are checked for residual levels of peracetic acid by means of a non-quantitative colorimetric test that is visually interpreted. The objective of this study was to investigate a new quantitative spectrophotometric test for detection of peracetic acid residues. METHODS: Peracetic acid solutions were prepared in concentrations ranging from 0.01 to 10 ppm. A reagent (potassium-titanium oxide + sulfuric acid) was added to each sample in proportions varying from 0.08 to 2.00 drops/mL of solution. Optical densities were determined in a spectrophotometer using a 405-nm filter and subjected to visual qualitative test by different observers. RESULTS: A relation between peroxide concentrations and respective optical densities was observed and it was linear with R2 > 0.90 for all reagent/substrate proportions. The peak optical densities were obtained with the reagent/substrate ratio of 0.33 drops/mL, which was later standardized for all further experiments. Both qualitative and quantitative tests yielded a specificity of 100%. The quantitative test was more sensitive than the qualitative test and resulted in higher positive and negative predictive values. There was a difference between observers in the qualitative test and some samples with significant amounts of peroxide were not detected. CONCLUSION: A quantitative spectrophotometric test may improve detection of residues of peracetic acid when compared to the standard visual qualitative test. This innovation may contribute to the development of safer standards for reuse of hemodialysis filters. PMID- 26760558 TI - A newborn with neck mass. AB - Congenital goiter is a rare cause of neonatal neck mass and may result from a fetal defectin synthesis of thyroxine, or administration of antithyroid drugs or iodides during pregnancy. The thyroid dysfunction often accompanies it. This report describes a case of a male term newborn with congenital goiter and primary hypothyroidism. Hormonal replacement treatment was started leading to normal levels of free thyroxine and triiodothyronine. In face of a maternal negative investigation, dyshormonogenesis was considered to be the most probable cause of hypothyroidism. PMID- 26760557 TI - Perforated diverticulitis of the appendix: ultrasonographic diagnosis. AB - Appendiceal diverticulitis is an uncommon condition, mimicking appendicitis, but with greater risk of perforation and complications. Preoperative diagnosis is rare, but can be achieved by ultrasonography as identification of the diverticulum and classical signs of appendicitis. We report a case of ultrasonographic diagnosis of a perforated appendiceal diverticulitis in an adult male and discuss this condition. PMID- 26760559 TI - A rare case of hematuria. AB - The infestation by Schistosoma haematobium is common in African countries and West Asia. Its chronic phase is characterized by the deposition of eggs of the parasite in various tissues of the body causing inflammatory response, formation of granulomas and fibrosis. The disease often affects the urinary tract, presenting with hematuria and, in the terminal stage, renal failure by urinary obstruction and bladder squamous neoplasia. Since chronic infection can lead to significant morbidity, it is imperative that the physicians who serve this immigrant population become familiar with this disease. A case of an immigrant boy from Guinea-Bissau seen in a Nephrology appointment for monosymptomatic terminal hematuria is presented. The diagnosis of urinary schistosomiasis was confirmed by parasitological examination of urine and the pathological examination of bladder biopsies. After therapy with praziquantel, the patient became asymptomatic. PMID- 26760560 TI - Aquatic physical therapy as a treatment modality in healthcare for non institutionalized elderly persons: a systematic review. AB - OBJECTIVE: To review scientific literature pertaining to aquatic physical therapy in the elderly and institutionalized population. METHODS: A qualitative systematic review of electronic databases MEDLINE and LILACS, with the topic index terms: "hydrotherapy," "homes for the aged or residential facilities," and "aged. In light of the lack of studies carried out on the institutionalized population, we opted for reviewing literature on the effectiveness of this modality of physical therapy treatment on the non-institutionalized elderly population in order to produce knowledge that can be critically analyzed according to its potential applicability for the institutionalized population. The methodological quality of the studies was assessed using the Delphi listing. RESULTS: Of the 27 studies analyzed by their abstracts, 10 studies were excluded since they did not correspond to the eligibility criteria. We analyzed the subject characteristics of each study, as well as the quality of the methods (good methodological quality in 47% of the studies), the result measurements considered, the intervention strategies, the sites where they took place, and the professionals involved (76% by physical therapists). CONCLUSION: Although a large part of the studies demonstrated good results with aquatic physical therapy practice, none of them had been applied on long-stay institution for the elderly. Therefore, more studies are needed in this area for a model of assistance to long stay institution for the elderly to be proposed. PMID- 26760561 TI - Noninvasive ventilation for acute respiratory failure in children - a systematic review. AB - OBJECTIVE: To assess the role of noninvasive ventilation in the treatment of children with acute respiratory failure. METHODS: A systematic review of literature on noninvasive ventilation in MEDLINE, LILACS, EMBASE, and Cochrane databases, besides references in articles. The outcomes evaluated were responses in blood oxygenation and ventilation, and patient survival. RESULTS: A total of 120 studies on noninvasive ventilation were found as of May, 2010. Of these, only 19 were about noninvasive ventilation in children. On the other hand, there are prospective and cohort clinical trials leading to a level II quality of evidence concerning the use of noninvasive ventilation in children. CONCLUSION: There is scientific evidence for proposing the use of noninvasive ventilation, with a B-II degree of recommendation. PMID- 26760562 TI - Molecular aspects of bladder cancer. AB - One of the most important objectives of genetic markers of cancer will be the possible identification of individuals at greatest risk in order to allow better management and prognosis. Many urological tumors were associated to various types of gene alterations with a great number of genes involved in the process, hindering gene therapy. This treatment uses specific techniques and one or several genes are manipulated in the laboratory in order to induce molecular alterations that may block the oncogenic process. The article addresses these issues emphasizing the importance of the new molecular biology techniques. PMID- 26760563 TI - Low-energy femoral shaft fracture in elderly patient with prolonged use of alendronate. PMID- 26760564 TI - Hearing rehabilitation through telemedicine to enhance public policies in Brazil. AB - Since 2004, the Brazilian government has run one of the most all-inclusive hearing rehabilitation program based on hearing aids worldwide. In 2007 this investment in hearing aids topped U$ 68 million, apart from covering the cost of physicians and audiologists. Nearly 140 centers are certified by the government to dispense fitted hearing aids, figures which are still low when one considers the size of the country. Telemedicine can represent a field of knowledge which broadens hearing rehabilitations services in Brazil, for it may help increase the number of hearing rehabilitation centers, enable remote training and provide for an "online second opinion". As far as public administration is concerned, it may enable process standardization and the very control over this hugely complex operation. The present article aimed to consider Telemedicine a powerful ally to improve hearing health care policies in Brazil. PMID- 26760565 TI - Kidney Donor Profile Index Does Not Accurately Predict the Graft Survival of Pediatric Deceased Donor Kidneys. AB - BACKGROUND: The new deceased donor kidney allocation algorithm uses a Kidney Donor Profile Index (KDPI) based on donor characteristics to predict graft survival and divides kidneys into 4 quality groups (ie, KDPI-A, -B, -C, and -D). Pediatric kidneys constitute 10% to 12% of deceased donor kidneys. We hypothesized that KDPI would not accurately predict pediatric donor graft survival and superior predictive models could be created. METHODS: Scientific Registry of Transplant Recipients data for years 2000 to 2010 for transplants from child (<10 years) and adolescent (10-17 years inclusive) donors into first time adult recipients were analyzed with graft failure as the principle outcome. Two novel indices, Child Donor Index (CDI) and Adolescent Donor Index (ADI), were developed using stepwise variable deletion to identify significant model covariates in a Cox Regression. Pediatric donor kidneys were then classified into the 4 quality groups based on both KDPI and CDI/ADI scores. The performance of the KDPI, CDI, and ADI models were compared with respect to the 4 quality groups defined by the new allocation system. RESULTS: The KDPI did not effectively discriminate between quality groups (P > 0.05 for all but 1 comparison) in Kaplan Meier survival analyses. The CDI and ADI included novel variables (eg, body mass index percentiles) and successfully discriminated between quality groups (P < 0.05 by log rank test). The Net Reclassification Index showed improvement when switching from KDPI to CDI and ADI, with values of 0.09 (P < 0.001) and 0.073 (P < 0.001), respectively. CONCLUSIONS: The KDPI does not accurately predict pediatric kidney graft survival. Alternative indices can improve allocation efficiency. PMID- 26760566 TI - A National Registry Analysis of Kidney Allografts Preserved With Marshall's Solution in the United Kingdom. AB - BACKGROUND: The preservation fluids most commonly used for renal allograft preservation in the UK are University of Wisconsin Solution (UW, L120 per liter) and Marshall's Solution (hyperosmolar citrate, L10 per liter). The aim of this study was to compare the outcomes of deceased donor renal allografts preserved with these fluids using data from the UK national transplant registry. METHODS: Data regarding transplants performed between January 1, 2005, and December 31, 2008, was analyzed (n = 5027 kidneys). Kidneys from Donation after Brain Death (DBD) and Donation after Circulatory Death (DCD) were included. After univariate analysis, multivariate logistic and linear regression models were fitted for adult recipients of first grafts (n = 3703 kidneys). RESULTS: Marshall's solution was associated with longer cold ischemic time, older donors, kidney-only donors, donors with hypertension, and DBD (all P < 0.01). After adjusting for confounding, the choice of preservation fluid was not associated with the risk of PNF (OR, 0.82; 95% CI, 0.46-1.46; P = 0.50), DGF (OR, 1.22; 95% CI, 0.96-1.56; P = 0.11), acute rejection (OR, 0.95; 95% CI, 0.76-1.19; P = 0.63), renal function at 1 year (coefficient, 0.97; 95% CI, 0.91-1.04; P = 0.41), or graft survival (DBD HR, 0.71; 95% CI, 0.46-1.10; P = 12; DCD HR, 0.99; 95% CI, 0.58-1.73; P = 1.00). CONCLUSIONS: Marshall's solution has been used for the preservation of large numbers of kidneys in the UK. It is associated with transplant outcomes that are equivalent to those with UW solution. Thus, on the basis of this analysis and cost, a strong case can be made for the continued use of Marshall's solution as a preferred fluid for renal allograft preservation. PMID- 26760567 TI - Simultaneous Living Donor Kidney and Parathyroid Allotransplantation: First Case Report and Review of Literature. AB - BACKGROUND: Congenital hypoparathyroidism can be severely debilitating for patients, leading to renal failure at young age. Parathyroid transplantation may represent a permanent parathyroid replacement therapy. In patients already on immunosuppression for other organ transplant, there is little additional risk involved with parathyroid allotransplantation. METHODS: Robotic assisted transaxillary single parathyroidectomy is performed on a living donor also donating a kidney to her sibling. RESULTS: Recipient total serum PTH levels became detectable after 3 days from the procedure and maintained for 9 months after transplant with minimal calcium supplementation after the procedure. Literature review and previous results are summarized. CONCLUSIONS: Obtaining a parathyroid gland and a kidney from the same donor reduces the exposure to different HLA antigens. The combined procedure using minimally invasive surgery is safe, with the additional cosmetic advantage and convenience for the willing donor. In the setting of need for immunosuppression, additional transplantation to treat the cause is safe and justified in the recipients. PMID- 26760568 TI - Surgical Strategy for Lung Transplantation in Adults With Small Chests: Lobar Transplant Versus a Pediatric Donor. AB - BACKGROUND: Adult lung transplant recipients with small chests have traditionally received lungs from pediatric donors, placing an additional strain on the already restricted pediatric donor pool. Performing lobar lung transplantation (LLT) can circumvent issues with donor-recipient size mismatch; however, LLT imparts additional risks. Here, we review our experience using LLT and standard lung transplantation using a pediatric donor (PDLT) for adults with small chests. METHODS: We retrospectively reviewed consecutive patients with end-stage lung disease and a height of 65 inches or less who underwent LLT (n = 15) or PDLT (n = 15) between 2006 and 2012 at our institution, a high-volume lung transplant center. RESULTS: Lobar lung transplantation recipients were older (54 +/- 10 vs 48 +/- 8 years) and had higher pulmonary pressure (57 +/- 11 vs 52 +/- 27 mmHg) and higher lung allocation scores (70 +/- 9 vs 51 +/- 8) than PDLT recipients (all P < 0.05). Mean waiting time was 62 days for PDLT and 9 days for LLT. Postoperatively, the incidence of severe primary graft dysfunction and the incidence of acute renal insufficiency were higher, and the mean intensive care unit stay was longer in the LLT group, but the incidence of bronchial anastomotic complications was higher in the PDLT group because of significant size discrepancy in the main bronchus (P < 0.05). Interestingly, long-term functional outcomes and survival rates were similar between the groups. CONCLUSIONS: Both LLT and PDLT are viable surgical options for adult patients with small chests. Because of the potential impact on posttransplant outcomes, the technical complexity of transplantation, decisions regarding the best surgical approach should be made by experienced surgeons. PMID- 26760569 TI - Safety of Live Liver Donation by Individuals With G6PD Deficiency: Initial Results and Comparative Study. AB - BACKGROUND: G6PD deficiency (G6PDd) is the commonest genetic enzyme defect in the world. However, baring a single case report, there is no published literature regarding the safety of donor hepatectomy in G6PDd individuals. METHODS: Potential donors with World Health Organization class III or class IV G6PDd without evidence of hemolysis were evaluated for donation, if there was no other suitable donor. Postoperatively, donors were closely monitored for hemolysis and medications, which can induce hemolysis, were avoided. Outcomes of our first 14 G6PDd donors are presented. Postoperative course of these donors was also compared with a matched cohort of 30 non-G6PDd donors. RESULTS: There were 9 left lateral segment, 2 left lobe, and 3 right lobe donors. Two G6PDd donors had biochemical evidence of postoperative hemolysis not needing any specific treatment. Postoperative liver function tests, intensive care unit stay, hospital stay, and morbidity (greater than Clavien II) were similar in the G6PDd and non G6PDd donor cohorts. Donors in the G6PDd group had lower trough hemoglobin in postoperative period (P = 0.006), greater drop in postoperative hemoglobin (P = 0.007), and a higher need for postoperative blood transfusion (4/14 vs 2/30, P = 0.071). CONCLUSIONS: This is the first case series reporting the safety of liver resection in G6PDd individuals. Hepatectomy in G6PD-deficient donors is associated with a greater drop in postoperative hemoglobin and a marginally increased need for postoperative transfusion. Use of these donors can be considered with caution, and it should not be an absolute contraindication for live liver donation. PMID- 26760570 TI - The Safety of Neuromuscular Blockade Reversal in Patients With Cardiac Transplantation. AB - BACKGROUND: Neuromuscular blockade (NMB) reversal with neostigmine and glycopyrrolate has been reported to cause cardiac arrest in patients with a history of cardiac transplantation. The purpose of this study was to examine the safety of NMB reversal with acetylcholinesterase inhibitors and muscarinic anticholinergics in these patients. METHODS: We queried the medical records of a large tertiary referral center for patients with a history of prior heart transplantation who underwent anesthesia including receipt of NMB reversal. Patient records were reviewed to investigate maximal decrease in heart rate (HR) after NMB reversal and incidence of death and cardiac arrest. RESULTS: Seventy seven heart transplant patients underwent 118 subsequent anesthetics during which they received neostigmine and glycopyrrolate for NMB reversal. No patients had active pacemakers at the time of their anesthetics. Mean time from heart transplantation to NMB reversal was 2.9 +/- 3.2 (median, 1.9; range, 0.01- 12.5) years. After NMB reversal, no patients received atropine or epinephrine, suffered cardiac arrest, or died within 30 days. Mean HR decrease, defined as the difference between the HR immediately before NMB reversal and the lowest HR within 5 minutes thereafter, after NMB reversal was 0.5 +/- 3.2 with median 0 (range, -8 to 17) beats per minute. Mean HR decrease was not associated with transplantation type (biatrial versus bicaval, P = 0.2029) or with increasing duration of time from cardiac transplantation (P = 0.0874). CONCLUSIONS: Although rare cases of cardiac arrest after NMB reversal have been reported, our experience would support the safety of neostigmine and glycopyrrolate in cardiac transplantation patients. PMID- 26760571 TI - In Kidney Transplant Recipients With a Positive Virtual Crossmatch, High PRA was Associated With Lower Incidence of Viral Infections. AB - BACKGROUND: There is little information on the incidence, risk factors, and outcomes associated with CMV and BK infections in sensitized patients. METHODS: We examined 254 consecutive kidney transplant recipients with positive virtual crossmatch and negative flow crossmatch. RESULTS: A total of 111 patients (43%) developed CMV disease or BK infection or nephropathy (BKVN). Specifically, 78 patients (30.7%) developed BK infection, 19 (7.5%) had BKVN, and 33 (12.9%) presented with CMV disease. Four patients (1.5%) developed both infections. Mean time from transplant to diagnosis for BK and CMV was 4.07 +/- 3.10 and 8.35 +/- 5.20 months, respectively. African American (HR, 2.64; 95% CI, 1.37-5.07; P = 0.003), thymoglobulin induction (HR, 2.18; 95% CI, 1.38-3.43; P = 0.0008), DSA greater than 500 MFI at transplant (HR, 1.64; 95% CI, 1.05-2.57; P = 0.03), history of diabetes (HR, 1.62; 95% CI, 1.01-2.60; P = 0.04), CMV D+/R- (HR, 2.30; 95% CI, 1.06-5.01; P = 0.03), and acute rejection (HR, 1.49; 95% CI, 0.99-2.24; P = 0.05) were associated with increase incident of BK/CMV, whereas rituximab (HR, 0.47; 95% CI, 0.24-0.91; P = 0.02), peak PRA greater than 80% (HR, 0.48; 95% CI, 0.27-0.84; P = 0.01), and living donor transplant (HR, 0.57; 95% CI, 0.36-0.87; P = 0.01) were associated with a lower likelihood of infection. Thymoglobulin induction (HR, 2.50; 95% CI, 1.02-6.13; P = 0.04), and peak PRA greater than 80% (HR, 0.45; 95% CI, 0.23-0.86; P = 0.02) remained significant predictors of infection after multivariate adjustment. CONCLUSIONS: Although more than 40% of patients with a positive virtual crossmatch presented with BK infection/CMV disease, high PRA greater than 80% seemed to be protective. PMID- 26760573 TI - BK Virus Infection After Kidney Transplantation: The Data Are Mounting for a Personalized Approach. PMID- 26760574 TI - Dry Needling on the Infraspinatus Latent and Active Myofascial Trigger Points in Older Adults With Nonspecific Shoulder Pain: A Randomized Clinical Trial. AB - BACKGROUND AND PURPOSE: Shoulder pain is a prevalent condition in older adults. Some authors associate nonspecific shoulder pain with myofascial trigger points (MTrPs) in the infraspinatus muscle. Dry needling is recommended to relieve the MTrP pain of shoulders in the short term (<9 days). Active MTrPs dry needling improves shoulder pain and the irritability of the satellite MTrPs in the referred pain area. Nociceptive activity at a latent MTrP may influence motor activity and the sensitivity of MTrPs in distant muscles at a similar segmental level. Therefore, this study aimed to evaluate dry needling on 1 latent MTrP, in conjunction with 1 active MTrP, in the infraspinatus muscle of older adults with nonspecific shoulder pain. METHODS: A single-center, randomized, single-blinded, controlled study (NCT02032602) was carried out. Sixty-six patients aged 65 years and older with trigger points in the ipsilateral infraspinatus of the painful shoulder were randomly assigned to (1) of (2) treatment groups. A session of dry needling on the infraspinatus was performed in (1) the most hyperalgesic active and latent MTrP or (2) only the most hyperalgesic active MTrP. The Numeric Rating Scale, the pressure pain threshold (primary outcome) on the anterior deltoid and extensor carpi radialis brevis latent MTrPs, and grip strength were assessed before, after, and 1 week after the intervention. RESULTS: Statistically significant differences in the reduction of pain intensity (P <= .001; eta = 0.159-0.269; d = 1.017-1.219) and the increase of pressure pain threshold (P < .001; eta = 0.206-0.481; d = 0.870-1.924) were found for the (1) treatment group immediately and 1 week postintervention. Nevertheless, no statistical significant differences were found in grip strength (P >. 05; eta = 0.006-0.033; d = 0.158 0.368). CONCLUSIONS: One dry needling intervention of the latent MTrP associated with the key active MTrP of the infraspinatus reduces pain intensity and the irritability of the satellite MTrPs located in the referred pain area in the short term in older adults with nonspecific shoulder pain. PMID- 26760577 TI - Prevalence of Refractive Errors in the INK Area, Durban, South Africa. AB - PURPOSE: To determine the prevalence and types of refractive errors in persons aged 35 years and older in the Inanda, Ntuzuma, and KwaMashu (INK) area of Durban, KwaZulu-Natal Province, South Africa. METHODS: Refractive error data were obtained by autorefraction (Retinomax K-Plus; Nikon, Tokyo, Japan), retinoscopy, and subjective refraction. Refractive error was defined using spherical equivalents as myopia (<-0.5D) and hyperopia (>+0.5D). Astigmatism was defined as cylinder equal to or greater than -0.5D in either eye. RESULTS: Participants' ages ranged from 35 to 90 years, with a mean of 53.05 +/- 11.4 years. Women comprised 75% of the subjects. The prevalence of refractive error was 57.3%, with myopia 11.4%, hyperopia 37.7%, and astigmatism 25.7%. Myopia and astigmatism were significantly more prevalent in men (p < 0.01), whereas hyperopia was more prevalent in women (p < 0.01). Hyperopia was significantly associated with education (p < 0.01), whereas myopia and astigmatism were not (p = 0.09 and p = 0.15, respectively). CONCLUSIONS: Approximately 57.3% of the population 35 years and older in the INK area of Durban were affected by refractive errors, with myopia, hyperopia, and astigmatism being significantly associated with sex. This study suggests that there is a need for interventions to alleviate refractive error in the INK area as well as in other communities affected by the lack of access to affordable services. PMID- 26760576 TI - Variability in Presentation of Bilateral Vitreomacular Traction. AB - PURPOSE: Vitreomacular traction (VMT) is a condition characterized by an incomplete posterior vitreous detachment resulting in traction on the macula and possible subsequent decrease in visual acuity and/or other symptomatology. Vitreomacular traction often presents as a unilateral condition, with some cases developing bilaterality with disease progression. The natural course and presentation of VMT vary widely among individuals. There is no extensive literature regarding the prevalence of VMT in the general population; therefore, little is known on the laterality. CASE REPORTS: We present eight cases of bilateral VMT encountered in a primary care setting. These cases highlight the variability in presentation, symptomatology, and clinical outcome between and within eyes of patients with bilateral VMT. CONCLUSIONS: Spectral-domain optical coherence tomography has provided new insight into VMT by allowing better visualization of the vitreoretinal interface. Using spectral-domain optical coherence tomography, eight unique cases of bilateral VMT were confirmed and classified. However, despite the bilaterality noted in each case, the clinical presentation and course of disease varied among patients. Because of the paucity of epidemiological data regarding VMT, the laterality of the condition, risk factors for involvement, and overall prognosis remain unclear. PMID- 26760572 TI - A New Window into the Human Alloresponse. AB - Alloreactive T lymphocytes are the primary mediators of allograft rejection. The size and diversity of the HLA-alloreactive T cell repertoire has thus far precluded the ability to follow these T cells and thereby to understand their fate in human transplant recipients. This review summarizes the history, challenges, and recent advances in the study of alloreactive T cells. We highlight the historical development of assays to measure alloreactivity and discuss how high-throughput T cell receptor (TCR) sequencing-based assays can provide a new window into the fate of alloreactive T cells in human transplant recipients. A specific approach combining a classical in vitro assay, the mixed lymphocyte reaction, with deep T cell receptor sequencing is described as a tool to track the donor-reactive T cell repertoire for any specific HLA-mismatched donor-recipient pair. This assay can provide mechanistic insights and has potential as a noninvasive, highly specific biomarker for rejection and tolerance. PMID- 26760578 TI - Retest Variability in the Medmont M700 Automated Perimeter. AB - PURPOSE: To investigate the level of test-retest variability in the Medmont M700 automated perimeter. We compare the retest variability of the outer 20 degrees test points of one test method to test points in the inner 10 degrees of two test methods to determine whether test points from different tests and regions exhibit different retest variability. We also generate some clinically applicable coefficient of repeatability (CoR) values for M700 Overall Defect (OD) and Pattern Defect (PD) indices. METHODS: Twenty-four glaucoma patients with varying degrees of field loss were enrolled, and 21 patients (40 eyes) had usable results. The Central (30 degrees ) test and the Macula (10 degrees ) test were performed on each eye on the same day. To determine retest variability, the tests were repeated 1 week later at the same time of day. RESULTS: Test points from 5 to 20 dB in the outer 20 degrees of the 30 degrees test showed lower retest variance than points of equal decibel value in the central 10 degrees of the same test. For the 30 degrees test, the OD CoR was 2.4 dB. The PD retest CoR varied with glaucoma severity, ranging from 1.24 dB for PD less than or equal to 2.8 to 3.1 dB for PD more than 5.7. The 10 degrees test CoR for OD was 2.1 dB, and PD retest CoR ranged from 1.58 for PD less than or equal to 2.8 to 2.4 for PD more than 5.7. CONCLUSIONS: In glaucoma patients, retest variance for some decibel values does not seem to increase with increasing eccentricity in the M700. The OD values as graded by the M700 do not appear to correspond well with the amount of visual field loss and are not directly comparable to mean deviation results reported by other perimeters. Pattern defect values in the M700 seem to correlate well with the degree of field loss. PMID- 26760575 TI - High-throughput analyses of hnRNP H1 dissects its multi-functional aspect. AB - hnRNPs are polyvalent RNA binding proteins that have been implicated in a range of regulatory roles including splicing, mRNA decay, translation, and miRNA metabolism. A variety of genome wide studies have taken advantage of methods like CLIP and RIP to identify the targets and binding sites of RNA binding proteins. However, due to the complex nature of RNA-binding proteins, these studies are incomplete without assays that characterize the impact of RBP binding on mRNA target expression. Here we used a suite of high-throughput approaches (RIP-Seq, iCLIP, RNA-Seq and shotgun proteomics) to provide a comprehensive view of hnRNP H1s ensemble of targets and its role in splicing, mRNA decay, and translation. The combination of RIP-Seq and iCLIP allowed us to identify a set of 1,086 high confidence target transcripts. Binding site motif analysis of these targets suggests the TGGG tetramer as a prevalent component of hnRNP H1 binding motif, with particular enrichment around intronic hnRNP H1 sites. Our analysis of the target transcripts and binding sites indicates that hnRNP H1s involvement in splicing is 2-fold: it directly affects a substantial number of splicing events, but also regulates the expression of major components of the splicing machinery and other RBPs with known roles in splicing regulation. The identified mRNA targets displayed function enrichment in MAPK signaling and ubiquitin mediated proteolysis, which might be main routes by which hnRNP H1 promotes tumorigenesis. PMID- 26760579 TI - Comparison of Two Optical Biometers. AB - PURPOSE: To compare a new optical biometer device, Galilei G6 (Ziemer, Port, Switzerland), with the present optical biometer, Lenstar LS 900 (Haag-Streit, Koeniz, Switzerland), for intraocular lens (IOL) power calculation. METHODS: One hundred forty eyes of 140 cataract patients were evaluated with two optical biometers: the Galilei G6 and the Lenstar. The mean keratometry (K), axial length (AL), anterior chamber depth (ACD), crystalline lens thickness (LT), white-to white (WTW), and IOL powers using the SRK/T, Holladay 1, Hoffer Q, and Haigis formulas were compared. The intrasession repeatability of the Galilei G6 measurements was assessed in 25 eyes. RESULTS: All ocular parameters measured by the Galilei G6 were highly repeatable (all intraclass correlation coefficients > 0.980). Although K and ACD did not show statistical differences between the two devices (all p > 0.05), the measurements for AL, LT, and WTW were statistically different for the two devices. The K, AL, ACD, LT, and WTW showed good correlations (r = 0.975, 0.998, 0.973, 0.946, and 0.710, respectively; all p < 0.001); however, the agreements of LT and WTW were not good between the two devices. The IOL powers using four formulas did not show statistical differences (all p > 0.05); however, agreements between the IOL powers were not strong. The ranges of 95% limit of agreements were between 1.54 and 1.90D according to the formulas. CONCLUSIONS: The ocular parameters and IOL powers using the Galilei G6 cannot be used interchangeably with those of the Lenstar in clinical practice. PMID- 26760580 TI - Intraocular Pressure Response to Moderate Exercise during 30-Min Recovery. AB - PURPOSE: The aim of the study was to evaluate intraocular pressure (IOP) before and after moderate exercise in normal healthy individuals with defined physical exertion. The second aim of this investigation was to determine the correlation between resting IOP (IOPr) and its change induced by exercise as well as the relationship between resting heart rate (HRr) and changes in IOP after exercise. METHODS: Forty-one healthy volunteers between the ages of 19 and 25 years were recruited for the study. First, the resting (reference) values IOPr and HRr were measured after 30 min of resting time. Volunteers consequently performed 30 min of exercise on a bicycle ergometer. Intraocular pressure was remeasured immediately after the end of exercise (the relevant IOP change was denoted as DeltaIOP0) and subsequently repeated 5, 10, 20, and 30 min after exercise. RESULTS: A significant decrease in IOP compared with the resting value (post hoc Tukey honest significant difference test) was found immediately after exercise (p = 2 * 10) and 5 and 10 min after exercise (p = 2 * 10 and p = 3 * 10). Significant relationships were found between the change in IOP (DeltaIOP0) and baseline IOP (IOPr) and between the baseline resting heart rate (HRr) and the change in IOP (DeltaIOP0). CONCLUSIONS: There was a significant IOP-lowering effect, which was persistent for 10 min after 30 min of exercise. The IOP change was dependent on the initial IOP reading and initial HR. PMID- 26760581 TI - How Do Patients Choose Their Spectacles in the Public Sector of South Africa? AB - PURPOSE: This study was designed to understand the profiles of the patients who attended and chose to purchase spectacles from the public sector eye clinics in KwaZulu Natal, South Africa. Furthermore, we wished to explore patients' perceptions of the spectacle frames on offer and to understand the motivation of the patients in selecting their spectacle frames. METHODS: This descriptive study consented 674 patients from seven eye clinics in KwaZulu Natal. Each was interviewed using a questionnaire containing open-ended, close-ended questions and questions with a Likert-scale response. RESULTS: Females comprised 68.4% of the study population. The majority of participants had not completed secondary school or had no schooling (78.9%), were unemployed (70.9%), and earned less than R2000 per month or did not have any form of income (89.2%). Of the 670 who chose to buy spectacles from the eye clinics, 79.4% indicated that this was convenient (79.4%) and 23.0% said that they were motivated in their decision because they liked the available frames. More than 95% of participants rated the design, quality, and price as good to excellent. Factors influencing their decisions included design, recommendations from staff, and quality. Those who bought the spectacles from the budget range were prepared to pay more for the next pair of spectacles, whereas almost all reported that they would return to the same eye clinic for their next pair of spectacles and that they would recommend relatives and friends to the clinic. CONCLUSIONS: The results from the study indicate that there is high acceptance by patients of the range of spectacles offered in public sector eye clinics with specific suggestions to improve it. Increased understanding of the perceptions and motivations in spectacle choice will help inform planning and procurement decisions in supplying the needs of the patients and broadening the patient base. PMID- 26760582 TI - Neophyte Skill Judging Corneoscleral Lens Clearance. AB - PURPOSE: This study examines the accuracy of neophyte clinicians' assessments of central corneal clearance (CCC) of a corneoscleral lens using lens center thickness (CT) as a biometric scale. METHODS: A normal participant was fit with a corneoscleral lens on both eyes. Observers (n = 34) from the final semester of their fourth year in optometric clinical training were instructed to estimate the amount of CCC through the approximate geometrical center of the lens using a standardized script which included a photograph identifying various zones. Observer estimates were then compared against anterior segment-OCT (AS-OCT) values obtained during calibration. RESULTS: Mean observer estimates of central corneal clearances were OD 220.5 +/- 121.microns (range 50 to 480 microns) and OS 398.0 +/- 159.1 microns (range 140 to 800 microns). The mean AS-OCT values were OD 105.5 +/- 11.microns (range 84 to 121 microns) and OS 340.8 +/- 15.2 microns (range 315 to 362 microns). Mann-Whitney test was statistically significant for comparison of median values OD (177.0; p = 0.001) and OS (260.0; p = 0.012). CONCLUSIONS: Neophyte clinicians in the final semester of their fourth year of optometric clinical training tend to significantly overestimate the amount of CCC in a normal subject with declining accuracy as the amount of clearance diminishes. PMID- 26760583 TI - Intraoperative Complications of Cataract Surgery in Tehran Province, Iran. AB - PURPOSE: To determine the prevalence and types of intraoperative complications of cataract surgery and examine potential risk factors. METHODS: Data were obtained from the 2011 Iranian Cataract Surgery Survey in which information about cataract surgeries throughout the nation was collected. In the Province of Tehran, 55 centers and 1 week per season per center were randomly selected for sampling. In each center, the charts of all patients who underwent cataract surgery during the selected weeks (total of 20 weeks per center) were reviewed for data extraction. The prevalence of different types of intraoperative cataract surgery complications were determined, and their relationships with age, sex, surgical method, surgeon, and hospitalization time were examined. RESULTS: The prevalence of intraoperative complications of cataract surgery was 4.15% (95% confidence interval, 0.94 to 7.36). The prevalence of posterior capsular rupture with vitreous loss, posterior capsular rupture without vitreous loss, retrobulbar hemorrhage, suprachoroidal effusion/hemorrhage, intraocular lens drop, and nucleus drop was 2.86, 0.69, 0.06, 0.39, 0.03, and 0.11%, respectively. The prevalence of cataract surgery complications decreased from 6.95% in 2006 to 3.07% in 2010. The results of multiple logistic regression showed that surgery by residents, nonphacoemulsification methods of surgery, and patient age less than 10 years and more than 70 years were the risk factors for complications. CONCLUSIONS: This study evaluated the prevalence of intraoperative complications of cataract surgery for the first time in Tehran Province. The prevalence of complications was high in this study. To achieve the goals of the Vision 2020 Initiative and improve surgical quality, it is necessary to minimize complication rates. Factors to note for decreasing complication rates include type of surgery, surgeon experience, and patient age. PMID- 26760584 TI - Hypoxic Corneal Changes following Eight Hours of Scleral Contact Lens Wear. AB - PURPOSE: To examine the change in corneal thickness and posterior curvature following 8 hours of miniscleral contact lens wear. METHODS: Scheimpflug imaging (Pentacam HR; Oculus) was captured before, and immediately following, 8 hours of miniscleral contact lens wear for 15 young (mean age 22 +/- 3 years), healthy participants with normal corneae. Natural diurnal variations were considered by measuring baseline corneal changes obtained on a separate control day without contact lens wear. RESULTS: Over the central 6 mm of the cornea, a small but highly statistically significant amount of edema was observed following 8 hours of miniscleral lens wear, after accounting for normal diurnal fluctuations (mean +/- standard deviation percentage swelling 1.70 +/- 0.98%, p < 0.0001). Posterior corneal topography remained stable following lens wear (-0.01 +/- 0.07 mm steepening over the central 6 mm, p = 0.60). The magnitude of posterior corneal topographical changes following lens wear did not correlate with the extent of lens-related corneal edema (r = -0.16, p = 0.57). Similarly, the initial central corneal vault (maximum post-lens tear layer depth) was not associated with corneal swelling following lens removal (r = 0.27, p = 0.33). CONCLUSIONS: Although a small amount of corneal swelling was induced following 8 hours of miniscleral lens wear (on average <2%), modern high Dk miniscleral contact lenses that vault the cornea do not induce clinically significant corneal edema or hypoxic-related posterior corneal curvature changes during short-term wear. Longer-term studies of compromised eyes (e.g. corneal ectasia) are still required to inform the optimum lens and fitting characteristics for safe scleral lens wear to minimize corneal hypoxia. PMID- 26760585 TI - Rigid Gas Permeable Contact Lens Fitting Using New Software in Keratoconic Eyes. AB - PURPOSE: To determine the repeatability of the back optic zone radius (BOZR) of rigid gas permeable (GP) contact lens (CL) proposed by new software for fitting in healthy and keratoconus eyes and to compare with the diagnostic CL fitting method. METHODS: Three consecutive corneal topographies (Oculus-Keratograph) were performed and analyzed with APEX new software CL fitting (Hecht-Contactlinsen, Germany) in 40 healthy and 40 keratoconus eyes fitted with GP using conventional diagnostic method. The coefficient of variation (CV) of the BOZR suggested by APEX was calculated. The BOZR of both fitting methods (software versus diagnostic) were compared maintaining the same lens diameter. RESULTS: BOZR proposed by APEX showed good repeatability in healthy (CV = 0.32%) and keratoconus eyes (CV = 0.51%). APEX proposed flatter BOZR than the diagnostic method in healthy (7.91 +/- 0.24 and 7.84 +/- 0.26 mm, p < 0.01) and keratoconus eyes (7.34 +/- 0.38 and 7.23 +/- 0.37 mm, p < 0.01). A strong linear correlation in healthy (BOZR_Diagnostic_Method = (BOZR_APEX * 1.06) - 0.53; p < 0.01, R = 0.969) and keratoconus eyes (BOZR_Diagnostic_Method = (BOZR_APEX * 0.88) + 0.77; p < 0.01, R = 0.825) was found. A detailed analysis showed a similar trend in different keratoconus stages (Amsler-Krumeich classification); stage 1: 7.42 +/- 0.30 and 7.40 +/- 0.25 mm, BOZR_Diagnostic_Method = (BOZR_APEX * 0.81) + 1.38, R = 0.973; stage 2: 7.30 +/- 0.44 and 7.23 +/- 0.38 mm, BOZR_Diagnostic_Method = (BOZR_APEX * 0.84) + 1.07, R = 0.929; and stage 3: 7.33 +/- 0.39 and 7.11 +/- 0.40 mm, BOZR_Diagnostic_Method = (BOZR_APEX * 0.93) + 0.28, R = 0.831. Applying these regression formulas, the BOZR difference could be reduced in healthy (-0.01 +/- 0.05 mm) and keratoconus eyes (-0.01 +/- 0.14 mm) for each keratoconus stage (0.01 +/- 0.04, 0.03 +/- 0.10, and 0.02 +/- 0.16 mm in stages 1, 2, and 3, respectively). CONCLUSIONS: APEX software provides repeatable BOZR in healthy and keratoconus eyes, but it tends to propose flatter BOZR than the diagnostic method. APEX BOZR should be improved with new equations and helping with the GP fitting procedure. PMID- 26760586 TI - What's new in the pathogenesis of the coagulopathy in acute promyelocytic leukemia? AB - PURPOSE OF REVIEW: Acute promyelocytic leukemia (APL) is associated with a complex coagulopathy. In spite of substantial recent improvements in treatment regimens, hemorrhagic death remains the main cause of induction failure. In this review, we delineate recent understanding of the pathophysiology and management of the hemorrhagic diathesis of APL. RECENT FINDINGS: Laboratory and clinical data suggest that the malignant leukocytes mediate the hemorrhagic diathesis associated with APL through multiple mechanisms which lead to a combination of consumptive coagulopathy and primary hyperfibrinolysis. Exposure of tissue factor and Annexin II by the leukemic blasts is the main determinants of these processes. Promyelocyte-derived microparticles have recently been implicated in the coagulopathy as well. Total white cell count and platelet count have emerged as good general predictors of hemorrhagic death, along with the different routine hemostatic parameters. Prompt treatment with all-trans retinoic acid, with or without arsenic trioxide, is the most important step in preventing bleeding complications. Repletion of coagulation factors and platelets with blood products remains the mainstay of supportive treatment, whereas the role of recombinant soluble thrombomodulin is currently being investigated. SUMMARY: The coagulopathy of APL is multifactorial, with both disseminated intravascular coagulation and primary hyperfibrinolysis mediated largely by the malignant leukocytes. PMID- 26760590 TI - Influenza 2015-2016: Challenges and Recommendations. PMID- 26760588 TI - Identifying predictors of low adherence in patients with inflammatory bowel disease. AB - BACKGROUND AND AIM: Inflammatory bowel diseases (IBDs) are chronic gastrointestinal conditions requiring medical therapy to maintain clinical remission. Low adherence to therapy leads to poorer disease outcome. Therefore, we aimed to identify predictors of low adherence in the Belgian IBD population. PATIENTS AND METHODS: Between November 2013 and March 2014, 570 ambulatory patients (471 patients with IBD and 99 non-IBD controls) visiting a tertiary IBD referral centre were requested to complete the Morisky 8-Item Medication Adherence Scale (MMAS-8) questionnaire as well as a survey of sociodemographic data (smoking, educational level, marital status and occupation). On the basis of the self-reported MMAS questionnaire, adherence was categorized as low (MMAS-8 score: >2), medium (MMAS-8 score: 1-2) or high (MMAS-8 score: 0). RESULTS: The response rate in the IBD population was as high as 99%. Low adherence was reported less frequently in the IBD population than in the non-IBD controls (36 vs. 49%, P=0.021). In multivariate analysis, factors associated independently with low adherence in the IBD population were age younger than 40 [odds ratio: 1.589 (95% confidence interval: 1.057-2.389), P=0.026], higher educational level [1.961 (1.305-2.946), P=0.001], being single [1.641 (1.020-2.639), P=0.041] and the use of mesalamine [1.591 (1.018-2.487), P=0.041]. Self-employment was identified as a protective factor for low adherence [0.397 (0.167-0.946), P=0.041]. CONCLUSION: Approximately one-third of the IBD patients were low adherers. Predictors of low adherence were aged younger than 40 years, higher educational level, being single and mesalamine use, whereas being self-employed was a protective factor. On the basis of these data, personalized algorithms may be developed to improve patient education, empowerment and follow-up. PMID- 26760587 TI - Review of imaging techniques in the diagnosis of hepatocellular carcinoma in patients who require a liver transplant. AB - OBJECTIVES: The aim of the study was to retrospectively compare the diagnostic performance of ultrasound (US), contrast-enhanced multidetector computed tomography (MDCT) and contrast-enhanced MRI in cirrhotic patients who were candidates for liver transplantation. MATERIALS AND METHODS: A total of 273 consecutive patients with 218 hepatocellular carcinoma (HCC) nodules, who underwent imaging and subsequent transplantation, were examined. Diagnosis of HCC was based on explant correlation of the whole liver. Three different imaging data sets were evaluated: US, MDCT and MRI unenhanced and dynamic phases. Diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive value, with corresponding 95% confidence intervals, were determined. Statistical analysis was performed for all lesions and for two lesion subgroups (<=2 and >2 cm). Preoperative tumour staging was analysed. RESULTS: Patient sensitivity to US, MDCT and MRI was 80.4, 81.1 and 90.5%, respectively. Specificity was 96.3, 96.2 and 82.1%. Combined US and MDCT improved sensitivity (88%) without significant loss in specificity (95.7%). Imaging tests resulted in accurate tumour staging in 83.4% of the patients. In per-nodule analysis, technique sensitivity was 55.6, 52.4 and 65.9%, respectively. Sensitivity figures improved when the nodule was larger than 2 cm. CONCLUSION: Combining imaging techniques is a good strategy for pretransplant HCC diagnosis and provides more accurate cancer staging in patients, which is necessary to decide the correct therapeutic approach. PMID- 26760591 TI - Fewer Americans Report a Personal Physician as Their Usual Source of Health Care. PMID- 26760592 TI - Nonpharmacologic Management of Chronic Insomnia. AB - Insomnia affects 10% to 30% of the population with a total cost of $92.5 to $107.5 billion annually. Short-term, chronic, and other types of insomnia are the three major categories according to the International Classification of Sleep Disorders, 3rd ed. The criteria for diagnosis are difficulty falling asleep, difficulty staying asleep, or early awakening despite the opportunity for sleep; symptoms must be associated with impaired daytime functioning and occur at least three times per week for at least one month. Factors associated with the onset of insomnia include a personal or family history of insomnia, easy arousability, poor self-reported health, and chronic pain. Insomnia is more common in women, especially following menopause and during late pregnancy, and in older adults. A comprehensive sleep history can confirm the diagnosis. Psychiatric and medical problems, medication use, and substance abuse should be ruled out as contributing factors. Treatment of comorbid conditions alone may not resolve insomnia. Patients with movement disorders (e.g., restless legs syndrome, periodic limb movement disorder), circadian rhythm disorders, or breathing disorders (e.g., obstructive sleep apnea) must be identified and treated appropriately. Chronic insomnia is associated with cognitive difficulties, anxiety and depression, poor work performance, decreased quality of life, and increased risk of cardiovascular disease and all-cause mortality. Insomnia can be treated with nonpharmacologic and pharmacologic therapies. Nonpharmacologic therapies include sleep hygiene, cognitive behavior therapy, relaxation therapy, multicomponent therapy, and paradoxical intention. Referral to a sleep specialist may be considered for refractory cases. PMID- 26760593 TI - Management of Sickle Cell Disease: Recommendations from the 2014 Expert Panel Report. AB - Family physicians are the primary and sometimes only health care resource for families affected by sickle cell disease. Recently published guidelines provide important recommendations for health maintenance, acute care, and monitoring of disease-modifying therapy in persons with this condition. This overview highlights some of the most important clinical activities that can and should be carried out in the community care setting. Children with sickle cell anemia should receive prophylactic penicillin from birth through at least five years of age, and all persons with sickle cell disease require vaccination to prevent invasive pneumococcal disease. Annual screening with transcranial Doppler ultrasonography is recommended for all children with sickle cell disease beginning at two years of age and continuing through adolescence to evaluate the risk of stroke and to initiate transfusion therapy in those at high risk. Vasoocclusive crises require immediate and adequate analgesia appropriate to the level of patient-reported pain. Antibiotics, hospitalization, and incentive spirometry are indicated for those with acute chest syndrome. There is strong evidence to support the promotion and use of hydroxyurea therapy in patients nine months and older who have sickle cell anemia because its use can decrease the frequency of vasoocclusive crises and acute chest syndrome with limited adverse effects. PMID- 26760594 TI - Evaluation of the Solitary Pulmonary Nodule. AB - A solitary pulmonary nodule is a common radiologic finding that is often discovered incidentally and may require significant workup to establish a definitive diagnosis. A solitary pulmonary nodule is a well-circumscribed round lesion measuring up to 3 cm in diameter and surrounded by aerated lung. Once a nodule is discovered, clinical and radiologic features and quantitative models can be used to determine the likelihood of malignancy. Evaluation is guided by nodule size and assessment of probability of malignancy. Surgical resection or nonsurgical biopsy should be performed in patients with solid or subsolid solitary pulmonary nodules that show clear growth on serial imaging. Solid solitary pulmonary nodules that have been stable for at least two years typically do not need further evaluation. The workup for patients with solid solitary pulmonary nodules measuring 8 mm or greater in diameter, nodules measuring less than 8 mm in diameter, and subsolid nodules should be guided by the probability of malignancy, imaging results, and the risks and benefits of different management strategies. Management should be individualized according to patient values and preferences. Medicare now covers lung cancer screening with low-dose computed tomography for high-risk patients 55 to 77 years of age at institutions that can provide a comprehensive approach to the management of solitary pulmonary nodules. PMID- 26760595 TI - Addressing Suspected Labor Trafficking in the Office. PMID- 26760596 TI - Timothy Grass Pollen Allergen Extract (Grastek) for Allergic Rhinitis. PMID- 26760597 TI - Screening for Iron Deficiency Anemia in Young Children. PMID- 26760598 TI - Diffuse, Erythematous, Scaly Eruption. PMID- 26760600 TI - Screening for Iron Deficiency Anemia in Young Children: Recommendation Statement. PMID- 26760601 TI - Chronic Insomnia: What You Can Do to Sleep Better. PMID- 26760602 TI - Lung Nodules. PMID- 26760603 TI - ERCP practitioners in China: results from national surveys in 2007 and 2013. PMID- 26760605 TI - Comparison between different colon cleansing products for screening colonoscopy. A noninferiority trial in population-based screening programs in Italy. AB - BACKGROUND AND STUDY AIMS: The high volume and poor palatability of 4 L of polyethylene glycol (PEG)-based bowel cleansing preparation required before a colonoscopy represent a major obstacle for patients. The aim of this study was to compare two low volume PEG-based preparations with standard 4 L PEG in individuals with a positive fecal immunochemical test (FIT) within organized screening programs in Italy. PATIENTS AND METHODS: A total of 3660 patients with a positive FIT result were randomized to receive, in a split-dose regimen, 4 L PEG or 2 L PEG plus ascorbate (PEG-A) or 2 L PEG with citrate and simethicone plus bisacodyl (PEG-CS). The noninferiority of the low volume preparations vs. 4 L PEG was tested through the difference in proportions of adequate cleansing. RESULTS: A total of 2802 patients were included in the study. Adequate bowel cleansing was achieved in 868 of 926 cases (93.7 %) in the 4 L PEG group, in 872 out of 911 cases in the PEG-A group (95.7 %, difference in proportions + 1.9 %, 95 % confidence interval [CI] - 0.1 to 3.9), and in 862 out of 921 cases in the PEG-CS group (93.6 %, difference in proportions - 0.2 %, 95 %CI - 2.4 to 2.0). Bowel cleansing was adequate in 95.5 % of cases when the preparation-to colonoscopy interval was between 120 and 239 minutes, whereas it dropped to 83.3 % with longer intervals. Better cleansing was observed in patients with regular bowel movements (95.6 %) compared with those with diarrhea (92.4 %) or constipation (90.8 %). CONCLUSION: Low volume PEG-based preparations administered in a split-dose regimen guarantee noninferior bowel cleansing compared with 4 L PEG. Constipated patients require a personalized preparation. TRIAL REGISTRATION: EudraCT 2012 - 003958 - 82. PMID- 26760673 TI - Differences between the Bud End and Stem End of Potatoes in Dry Matter Content, Starch Granule Size, and Carbohydrate Metabolic Gene Expression at the Growing and Sprouting Stages. AB - Potatoes usually have the tuber bud end dominance in growth during tuber bulking and in tuber sprouting, likely using carbohydrates from the tuber stem end. We hypothesized that the tuber bud end and tuber stem end coordination in carbohydrate metabolism gene expression is different between the bulking dominance and sprouting dominance of the tuber bud end. After comparing the growing tubers at harvest from a green vine and the stage that sprouts just started to emerge after storage of tubers at room temperature, we found the following: (1) Dry matter content was higher in the tuber stem end than the tuber bud end at both stages. (2) The starch granule size was larger in the tuber bud end than in the tuber stem end. (3) The tuber bud end had higher gene expression for starch synthesis but a lower gene expression of sucrose transporters than the tuber stem end during tuber growing. (4) The tuber stem end at the sprouting stage showed more active gene expression in both starch degradation and resynthesis, suggesting more active export of carbohydrates, than the tuber bud end. The results indicate that the starch accumulation mechanism in the tuber bud end was different between field growing and post-harvest sprouting tubers and that tubers already increased dry matter and average starch granule sizes in the tuber bud end prior to the rapid growth of sprouts. PMID- 26760672 TI - Effect of Polyethylene Glycol on Properties and Drug Encapsulation-Release Performance of Biodegradable/Cytocompatible Agarose-Polyethylene Glycol Polycaprolactone Amphiphilic Co-Network Gels. AB - We synthesized agarose-polycaprolactone (Agr-PCL) bicomponent and Agr polyethylene glycol-PCL (Agr-PEG-PCL) tricomponent amphiphilic co-network (APCN) gels by the sequential nucleophilic substitution reaction between amine functionalized Agr and activated halide terminated PCL or PCL-b-PEG-b-PCL copolymer for the sustained and localized delivery of hydrophilic and hydrophobic drugs. The biodegradability of the APCNs was confirmed using lipase and by hydrolytic degradation. These APCN gels displayed good cytocompatibility and blood compatibility. Importantly, these APCN gels exhibited remarkably high drug loading capacity coupled with sustained and triggered release of both hydrophilic and hydrophobic drugs. PEG in the APCNs lowered the degree of phase separation and enhanced the mechanical property of the APCN gels. The drug loading capacity and the release kinetics were also strongly influenced by the presence of PEG, the nature of release medium, and the nature of the drug. Particularly, PEG in the APCN gels significantly enhanced the 5-fluorouracil loading capacity and lowered its release rate and burst release. Release kinetics of highly water soluble gemcitabine hydrochloride and hydrophobic prednisolone acetate depended on the extent of water swelling of the APCN gels. Cytocompatibility/blood compatibility and pH and enzyme-triggered degradation together with sustained release of drugs show great promise for the use of these APCN gels in localized drug delivery and tissue engineering applications. PMID- 26760604 TI - Balloon catheter versus basket catheter for endoscopic bile duct stone extraction: a multicenter randomized trial. AB - BACKGROUND AND STUDY AIMS: Endoscopic bile duct stone (BDS) removal is a well established treatment; however, the preference for basket or balloon catheters for extraction is operator-dependent. We therefore conducted a multicenter prospective randomized trial to compare catheter performance. PATIENTS AND METHODS: We enrolled patients with a BDS diameter <= 10 mm and common bile duct diameter <= 15 mm. Participants were randomly assigned to groups that were treated with basket or balloon catheters between October 2013 and September 2014. The primary endpoint was the rate of complete clearance of the duct; the secondary endpoints were the rate and time to complete clearance in one endoscopic session. RESULTS: We initially enrolled 172 consecutive patients; 14 were excluded after randomization. The complete clearance rates were 92.3 % (72/78) in the balloon group and 80.0 % (64 /80) in the basket group. The difference in the rates between the two groups was 12.3 percentage points, indicating non-inferiority of the balloon method (non-inferiority limit -10 %; P < 0.001 for non-inferiority). Moreover, the balloon was superior to the basket (P = 0.037). The rate of complete clearance in one endoscopic session was 97.4 % using the balloon and 97.5 % using the basket (P = 1.00). The median times to complete clearance in one endoscopic session were 6.0 minutes (1 - 30) and 7.8 minutes (1 - 37) in the balloon and basket groups, respectively (P = 0.15). CONCLUSIONS: For extraction of BDSs <= 10 mm, complete endoscopic treatment with a single catheter is more likely when choosing a balloon catheter over a basket catheter.University Hospital Medical Information Network Trials Registry: UMIN000011887. PMID- 26760676 TI - Photomediated Controlled Radical Polymerization and Block Copolymerization of Vinylidene Fluoride. AB - This review summarizes recent research on novel photochemical methods for the initiation and control of the polymerization of main chain fluorinated monomers as exemplified by vinylidene fluoride (VDF) and for the synthesis of their block copolymers. Such reactions can be carried out at ambient temperature in glass tubes using visible light. Novel, original protocols include the use of hypervalent iodide carboxylates alone or in conjunction with molecular iodine, as well as the use of photoactive transition metal carbonyls in the presence of alkyl, fluoroalkyl, and perfluoroalkyl halides. An in-depth study of the reaction parameters highlights the use of dimethyl carbonate as a preferred polymerization solvent and outlines the structure-property relationship for hypervalent iodide carboxylates and halide initiators in both the free radical and iodine degenerative transfer controlled radical polymerization (IDT-CRP) of VDF. Finally, the rational selection of metal carbonyls that are successful not only as IDT mediators but, more importantly, in the quantitative activation of both PVDF-CH2-CF2-I and PVDF-CF2-CH2-I chain ends toward the synthesis of well-defined PVDF block copolymers is presented. PMID- 26760675 TI - Correction to "Evaluating the Extent of Intramolecular Charge Transfer in the Excited States of Rhenium(I) Donor-Acceptor Complexes with Time-Resolved Vibrational Spectroscopy". PMID- 26760674 TI - Mini-Mental State Examination (MMSE) for the detection of dementia in clinically unevaluated people aged 65 and over in community and primary care populations. AB - BACKGROUND: The Mini Mental State Examination (MMSE) is a cognitive test that is commonly used as part of the evaluation for possible dementia. OBJECTIVES: To determine the diagnostic accuracy of the Mini-Mental State Examination (MMSE) at various cut points for dementia in people aged 65 years and over in community and primary care settings who had not undergone prior testing for dementia. SEARCH METHODS: We searched the specialised register of the Cochrane Dementia and Cognitive Improvement Group, MEDLINE (OvidSP), EMBASE (OvidSP), PsycINFO (OvidSP), LILACS (BIREME), ALOIS, BIOSIS previews (Thomson Reuters Web of Science), and Web of Science Core Collection, including the Science Citation Index and the Conference Proceedings Citation Index (Thomson Reuters Web of Science). We also searched specialised sources of diagnostic test accuracy studies and reviews: MEDION (Universities of Maastricht and Leuven, www.mediondatabase.nl), DARE (Database of Abstracts of Reviews of Effects, via the Cochrane Library), HTA Database (Health Technology Assessment Database, via the Cochrane Library), and ARIF (University of Birmingham, UK, www.arif.bham.ac.uk). We attempted to locate possibly relevant but unpublished data by contacting researchers in this field. We first performed the searches in November 2012 and then fully updated them in May 2014. We did not apply any language or date restrictions to the electronic searches, and we did not use any methodological filters as a method to restrict the search overall. SELECTION CRITERIA: We included studies that compared the 11-item (maximum score 30) MMSE test (at any cut point) in people who had not undergone prior testing versus a commonly accepted clinical reference standard for all-cause dementia and subtypes (Alzheimer disease dementia, Lewy body dementia, vascular dementia, frontotemporal dementia). Clinical diagnosis included all-cause (unspecified) dementia, as defined by any version of the Diagnostic and Statistical Manual of Mental Disorders (DSM); International Classification of Diseases (ICD) and the Clinical Dementia Rating. DATA COLLECTION AND ANALYSIS: At least three authors screened all citations.Two authors handled data extraction and quality assessment. We performed meta-analysis using the hierarchical summary receiver operator curves (HSROC) method and the bivariate method. MAIN RESULTS: We retrieved 24,310 citations after removal of duplicates. We reviewed the full text of 317 full-text articles and finally included 70 records, referring to 48 studies, in our synthesis. We were able to perform meta-analysis on 28 studies in the community setting (44 articles) and on 6 studies in primary care (8 articles), but we could not extract usable 2 x 2 data for the remaining 14 community studies, which we did not include in the meta-analysis. All of the studies in the community were in asymptomatic people, whereas two of the six studies in primary care were conducted in people who had symptoms of possible dementia. We judged two studies to be at high risk of bias in the patient selection domain, three studies to be at high risk of bias in the index test domain and nine studies to be at high risk of bias regarding flow and timing. We assessed most studies as being applicable to the review question though we had concerns about selection of participants in six studies and target condition in one study.The accuracy of the MMSE for diagnosing dementia was reported at 18 cut points in the community (MMSE score 10, 14-30 inclusive) and 10 cut points in primary care (MMSE score 17-26 inclusive). The total number of participants in studies included in the meta-analyses ranged from 37 to 2727, median 314 (interquartile range (IQR) 160 to 647). In the community, the pooled accuracy at a cut point of 24 (15 studies) was sensitivity 0.85 (95% confidence interval (CI) 0.74 to 0.92), specificity 0.90 (95% CI 0.82 to 0.95); at a cut point of 25 (10 studies), sensitivity 0.87 (95% CI 0.78 to 0.93), specificity 0.82 (95% CI 0.65 to 0.92); and in seven studies that adjusted accuracy estimates for level of education, sensitivity 0.97 (95% CI 0.83 to 1.00), specificity 0.70 (95% CI 0.50 to 0.85). There was insufficient data to evaluate the accuracy of the MMSE for diagnosing dementia subtypes.We could not estimate summary diagnostic accuracy in primary care due to insufficient data. AUTHORS' CONCLUSIONS: The MMSE contributes to a diagnosis of dementia in low prevalence settings, but should not be used in isolation to confirm or exclude disease. We recommend that future work evaluates the diagnostic accuracy of tests in the context of the diagnostic pathway experienced by the patient and that investigators report how undergoing the MMSE changes patient-relevant outcomes. PMID- 26760677 TI - Real-Time Capture and Visualization of Individual Viruses in Complex Media. AB - Label-free imaging of individual viruses and nanoparticles directly in complex solutions is important for virology research and biosensing applications. A successful visualization technique should be rapid, sensitive, and inexpensive, while needing minimal sample preparation or user expertise. Current approaches typically require fluorescent labeling or the use of an electron microscope, which are expensive and time-consuming to use. We have developed an imaging technique for real-time, sensitive, and label-free visualization of viruses and nanoparticles directly in complex solutions such as serum. By combining the advantages of a single-particle reflectance imaging sensor, with microfluidics, we perform real-time digital detection of individual 100 nm vesicular stomatitis viruses as they bind to an antibody microarray. Using this approach, we have shown capture and visualization of a recombinant vesicular stomatitis virus Ebola model (rVSV-ZEBOV) at 100 PFU/mL in undiluted fetal bovine serum in less than 30 min. PMID- 26760679 TI - Dynamic Micropatterning of Cells on Nanostructured Surfaces Using a Cell-friendly Photoresist. AB - Cellular dynamics under complex topographical microenvironments are important for many biological processes in development and diseases, but systematic investigation has been limited due to the lack of technology. Herein, we developed a new dynamic cell patterning method based on a cell-friendly photoresist polymer that allows in situ control of cell dynamics on nanostructured surfaces. Using this method, we quantitatively compared the spreading dynamics of cells on nanostructured surfaces to those on flat surfaces. Furthermore, we investigated how cells behaved when they simultaneously encountered two topographically distinct surfaces during spreading. This method will allow many exciting opportunities in the fundamental study of cellular dynamics. PMID- 26760678 TI - MAPK1/3 regulate hepatic lipid metabolism via ATG7-dependent autophagy. AB - Although many biological functions of MAPK1/ERK2-MAPK3/ERK1 (mitogen-activated protein kinase 1/3) have been reported, a direct effect of MAPK1/3 on hepatic lipid metabolism remains largely unknown. We recently showed that activation of MAPK1/3 ameliorates liver steatosis in LEPR (leptin receptor)-deficient (db/db) mice, a classic animal model for liver steatosis. Consistent with these results, knockdown of MAPK1/3 promotes liver steatosis in C57/B6J wild-type (WT) mice. Autophagic flux and ATG7 (autophagy related 7) levels are increased by MAPK1/3 activation or decreased by MAPK1/3 knockdown in livers and primary hepatocytes. Blockade of autophagic flux by chloroquine (CQ) or ATG7 knockdown reverses the ameliorated liver steatosis in MAPK1/3-activated db/db mice. Together, these findings identify a beneficial role for MAPK1/3 in liver steatosis that is mediated by ATG7-dependent autophagy, which provides novel insights into the mechanisms underlying liver steatosis and create a rationale for targeting MAPK1/3 in the treatment of liver steatosis. PMID- 26760680 TI - Alpha 3 ganglionic acetylcholine receptor antibody associated refractory status epilepticus. PMID- 26760681 TI - Pt-Based Icosahedral Nanocages: Using a Combination of {111} Facets, Twin Defects, and Ultrathin Walls to Greatly Enhance Their Activity toward Oxygen Reduction. AB - Engineering the surface structure of noble-metal nanocrystals offers an effective route to the development of catalysts or electrocatalysts with greatly enhanced activity. Here, we report the synthesis of Pt-based icosahedral nanocages whose surface is enclosed by both {111} facets and twin boundaries while the wall thickness can be made as thin as six atomic layers. The nanocages are derived from Pd@Pt4.5L icosahedra by selectively etching away the Pd in the core. During etching, the multiply twinned structure can be fully retained whereas the Pt atoms in the wall reconstruct to eliminate the corrugated structure built in the original Pt shell. The Pt-based icosahedral nanocages show a specific activity of 3.50 mA cm(-2) toward the oxygen reduction reaction, much greater than those of the Pt-based octahedral nanocages (1.98 mA cm(-2)) and a state-of-the-art commercial Pt/C catalyst (0.35 mA cm(-2)). After 5000 cycles of accelerated durability test, the mass activity of the Pt-based icosahedral nanocages drops from 1.28 to 0.76 A mg(-1)Pt, which is still about four times greater than that of the original Pt/C catalyst (0.19 A mg(-1)Pt). PMID- 26760682 TI - Shifting patterns of variance in adolescent alcohol use: Testing consumption as a developing trait-state. AB - While average rates of change in adolescent alcohol consumption are frequently studied, variability arising from situational and dispositional influences on alcohol use has been comparatively neglected. We used variance decomposition to test differences in variability resulting from year-to-year fluctuations in use (i.e., state-like) and from stable individual differences (i.e., trait-like) using data from the Project on Adolescent Trajectories and Health (PATH), a cohort-sequential study spanning grades 7 to 11 using three cohorts starting in grades seven, eight, and nine, respectively. We tested variance components for alcohol volume, frequency, and quantity in the overall sample, and changes in components over time within each cohort. Sex differences were tested. Most variability in alcohol use reflected state-like variation (47-76%), with a relatively smaller proportion of trait-like variation (19-36%). These proportions shifted across cohorts as youth got older, with increases in trait-like variance from early adolescence (14-30%) to later adolescence (30-50%). Trends were similar for males and females, although females showed higher trait-like variance in alcohol frequency than males throughout development (26-43% vs. 11-25%). For alcohol volume and frequency, males showed the greatest increase in trait-like variance earlier in development (i.e., grades 8-10) compared to females (i.e., grades 9-11). The relative strength of situational and dispositional influences on adolescent alcohol use has important implications for preventative interventions. Interventions should ideally target problematic alcohol use before it becomes more ingrained and trait-like. PMID- 26760684 TI - Eccrine Angiomatous Hamartoma: A Clinicopathologic Review of 18 Cases. AB - BACKGROUND: Eccrine angiomatous hamartoma (EAH) is a benign cutaneous lesion defined by the proliferation of hamartomatous eccrine and capillary-like vascular elements in the dermis. However, the epidemiologic, morphologic, and histopathologic aspects of this uncommon disorder have yet to be fully delineated. METHODS: The authors retrospectively reviewed 18 EAH cases (including 14 accompanying skin biopsy specimens) diagnosed at 4 American university hospitals from 1996 to 2014. RESULTS: Patients ranged from 3 days to 84 years at time of diagnosis with a median age of 15 years. A male:female ratio of 11:7 was observed. Sixty-seven percent of cases presented in the extremities, but lesions in the trunk and head/neck regions also occurred. Four patients had multiple lesions, and 2 displayed a segmental pattern. Histologically, dermal vascular dilatation and acanthosis often accompanied EAH's typical eccrine and vascular comingling. One individual developed EAH at the site of a recurrent squamous cell carcinoma after previous excision. CONCLUSIONS: Although previously thought to occur primarily as a solitary angiomatous-appearing malformation on the extremities of children, EAH may develop with some frequency in adults and may manifest in a multifocal linear distribution. The authors also raise additional histopathologic consideration in support of the vascular theory of histogenesis for this condition. PMID- 26760683 TI - A Pot-Economical Approach to the Total Synthesis of Sch-725674. AB - A pot-economical total synthesis of antifungal Sch-725674, 1, is reported. The approach takes advantage of a number of one-pot, sequential transformations, including a phosphate tether-mediated one-pot, sequential RCM/CM/chemoselective hydrogenation protocol, a one-pot tosylation/acrylation sequence, and a one-pot, sequential Finkelstein reaction/Boord olefination/acetonide deprotection procedure to streamline the synthesis route by reducing isolation and purification procedures, thus saving time. Overall, an asymmetric route has been developed that is efficiently accomplished in seven pots from phosphate (S,S) triene and with minimal purification. PMID- 26760685 TI - Malignant Glomus Tumor Arising in a Long Standing Precursor Lesion. AB - Malignant glomus tumor is an exceedingly rare vascular malignancy of unclear etiology, which is believed to arise de novo or from malignant transformation of a benign glomus tumor. The authors present a case of an elderly woman evaluated for a painful 2.5-cm purple-brown tumor on the right forearm that grew rapidly within a long-standing, seemingly benign lesion. An excisional biopsy revealed a multilobular dermal tumor composed of areas of benign-appearing glomus tumor cells interspersed with areas of dense, pleomorphic cells arranged in sheets and fascicles with an elevated mitotic rate. The diagnosis of malignant glomus tumor was made on the basis of the lesion's nuclear atypia and elevated mitotic rate. This case demonstrates malignant transformation of a presumably benign glomus tumor precursor lesion highlighting this rarely reported phenomenon. The authors present this case to raise awareness of this vascular malignancy that carries a significant risk of metastasis. PMID- 26760686 TI - Infundibulocystic Structures and Prominent Squamous Metaplasia in Sebaceoma-A Rare Feature. A Clinicopathologic Study of 10 Cases. AB - The authors describe 10 cases of sebaceoma that manifested prominent infundibulocystic structures in all cases and, additionally, conspicuous squamous metaplasia in 6 neoplasms. All tumors occurred on the scalp or the face (2 cases lacked clinical information) and presented as a solitary lesion, measuring from 5 to 20 mm. The patients' age ranged from 22 to 89 years. The main component of all tumors was small, uniform basaloid cells (immature sebocytes) intermixed with mature sebocytes clearly arranged in nodules, classifying the lesions as a sebaceoma. In all neoplasms, the tumor cells showed organoid growth patterns of sebaceoma, including rippled, sinusoidal/labyrinthine, and carcinoid-like, occurring alone or in combination. Additionally, numerous infundibulocystic structures were readily noticed and were either distributed multifocally or unilocular within the tumors. In some cases, they were segregated from the main tumor bulk. The authors posit that these structures, which are different from both sebaceous ductal differentiation and squamous metaplasia, represent an authentic follicular differentiation. The infundibulocystic features (combined with squamous metaplasia), when prominent and in a limited biopsy specimen, may cause a confusion with trichoadenoma or even microcystic adnexal carcinoma. PMID- 26760687 TI - Cellular Angiofibroma With Sarcomatous Transformation Showing Pleomorphic Liposarcoma-Like and Atypical Lipomatous Tumor-Like Features. PMID- 26760688 TI - A Bayesian ridge regression analysis of congestion's impact on urban expressway safety. AB - With the rapid growth of traffic in urban areas, concerns about congestion and traffic safety have been heightened. This study leveraged both Automatic Vehicle Identification (AVI) system and Microwave Vehicle Detection System (MVDS) installed on an expressway in Central Florida to explore how congestion impacts the crash occurrence in urban areas. Multiple congestion measures from the two systems were developed. To ensure more precise estimates of the congestion's effects, the traffic data were aggregated into peak and non-peak hours. Multicollinearity among traffic parameters was examined. The results showed the presence of multicollinearity especially during peak hours. As a response, ridge regression was introduced to cope with this issue. Poisson models with uncorrelated random effects, correlated random effects, and both correlated random effects and random parameters were constructed within the Bayesian framework. It was proven that correlated random effects could significantly enhance model performance. The random parameters model has similar goodness-of fit compared with the model with only correlated random effects. However, by accounting for the unobserved heterogeneity, more variables were found to be significantly related to crash frequency. The models indicated that congestion increased crash frequency during peak hours while during non-peak hours it was not a major crash contributing factor. Using the random parameter model, the three congestion measures were compared. It was found that all congestion indicators had similar effects while Congestion Index (CI) derived from MVDS data was a better congestion indicator for safety analysis. Also, analyses showed that the segments with higher congestion intensity could not only increase property damage only (PDO) crashes, but also more severe crashes. In addition, the issues regarding the necessity to incorporate specific congestion indicator for congestion's effects on safety and to take care of the multicollinearity between explanatory variables were also discussed. By including a specific congestion indicator, the model performance significantly improved. When comparing models with and without ridge regression, the magnitude of the coefficients was altered in the existence of multicollinearity. These conclusions suggest that the use of appropriate congestion measure and consideration of multicolilnearity among the variables would improve the models and our understanding about the effects of congestion on traffic safety. PMID- 26760689 TI - Using mental mapping to unpack perceived cycling risk. AB - Cycling is the most energy-efficient mode of transport and can bring extensive environmental, social and economic benefits. Research has highlighted negative perceptions of safety as a major barrier to the growth of cycling. Understanding these perceptions through the application of novel place-sensitive methodological tools such as mental mapping could inform measures to increase cyclist numbers and consequently improve cyclist safety. Key steps to achieving this include: (a) the design of infrastructure to reduce actual risks and (b) targeted work on improving safety perceptions among current and future cyclists. This study combines mental mapping, a stated-preference survey and a transport infrastructure inventory to unpack perceptions of cycling risk and to reveal both overlaps and discrepancies between perceived and actual characteristics of the physical environment. Participants translate mentally mapped cycle routes onto hard-copy base-maps, colour-coding road sections according to risk, while a transport infrastructure inventory captures the objective cycling environment. These qualitative and quantitative data are matched using Geographic Information Systems and exported to statistical analysis software to model the individual and (infra)structural determinants of perceived cycling risk. This method was applied to cycling conditions in Galway City (Ireland). Participants' (n=104) mental maps delivered data-rich perceived safety observations (n=484) and initial comparison with locations of cycling collisions suggests some alignment between perception and reality, particularly relating to danger at roundabouts. Attributing individual and (infra)structural characteristics to each observation, a Generalised Linear Mixed Model statistical analysis identified segregated infrastructure, road width, the number of vehicles as well as gender and cycling experience as significant, and interactions were found between individual and infrastructural variables. The paper concludes that mental mapping is a highly useful tool for assessing perceptions of cycling risk with a strong visual aspect and significant potential for public participation. This distinguishes it from more traditional cycling safety assessment tools that focus solely on the technical assessment of cycling infrastructure. Further development of online mapping tools is recommended as part of bicycle suitability measures to engage cyclists and the general public and to inform 'soft' and 'hard' cycling policy responses. PMID- 26760690 TI - 'Total girlfriend experience': examining marketplace mythologies on sex tourism websites. AB - The purpose of this study was to conduct a systematic content analysis of sex tour websites to understand how sex tours are marketed to potential clients. A total of 380 web pages from 21 sex tour websites were reviewed. The sex tour websites sought to promote privacy and hassle-free travel with a local 'escort' and the opportunity for 'hooks-ups' with no strings attached. Three themes emerged around the description of sex workers: (1) enjoyment and complete acceptance, (2) a 'total girlfriend experience' and (3) exoticisation of the 'Third World' woman. The majority of the sex tourism websites used marketplace mythologies concerning racism, sexism and imperialism to appeal to sex tourists' desires for fantasy experiences, power and domination, and a renewed sense of identity. Legal and STI-related information was largely missing from the websites, and when it was included it was aimed at protecting sex tourists, not sex workers. It is of importance for researchers, social workers and others engaging with sex workers and sexscapes to recognise the power of language, cultural myths and framings and their ability to generate real-world social and health implications. PMID- 26760708 TI - Early detection of prostate cancer: can we have our cake and eat it too? PMID- 26760709 TI - Association of Apolipoprotein A5 Gene Polymorphisms with Metabolic Syndrome in the Korean Population. AB - AIMS: Functional defects of the ApoA5 protein have been identified as risk factors for hypertriglyceridemia, vascular diseases and susceptibility to metabolic syndrome (MetS). These associations are neither strong nor consistent in all populations studied. In this study, we investigated the association between the ApoA5 -1131T>C and -12,238T>C polymorphic loci in Korean patients with MetS. METHODS: A total of 1074 subjects, including 415 patients with MetS and 659 healthy control subjects, were enrolled to investigate the affect of ApoA5 polymorphisms on risk of MetS. Genotyping of the ApoA5 polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism techniques. RESULTS: The CC genotype and the dominant (TT vs. TC+CC) and recessive (TT+TC vs. CC) models of the -1131T>C polymorphism were associated with increased MetS susceptibility (p < 0.001, p = 0.018, and p = 0.002, respectively). The association was male-specific when stratified by gender. With regard to the -12,238T>C polymorphism, the TC and CC genotypes and the dominant (TT vs. TC+CC) and recessive (TT+TC vs. CC) models were frequently found in the patient group, compared with the control group (p = 0.001, p < 0.001, p < 0.001, and p = 0.031, respectively). The T-C, C-T, and C-C haplotypes of the ApoA5 1131T>C and -12,238T>C polymorphisms were associated with an increased risk for MetS (p < 0.001, p = 0.001, and p < 0.001, respectively). The variant of the ApoA5 -1131T>C polymorphism was also associated with increased triglyceride (TG) levels. Dominant models of ApoA5 -1131T>C and -12,238T>C polymorphisms were associated with the risk components of MetS by the stratification analysis. CONCLUSION: The -1131C and -12,238C variants and the C-containing haplotypes of ApoA5 -1131T>C and -12,238T>C polymorphisms were associated with higher risk for MetS in the Korean population. The -1131C variant was also associated with the increased level of TG. PMID- 26760710 TI - Variability in exposure to ambient ultrafine particles in urban schools: Comparative assessment between Australia and Spain. AB - Ambient ultrafine particle number concentrations (PNC) have inhomogeneous spatio temporal distributions and depend on a number of different urban factors, including background conditions and distant sources. This paper quantitatively compares exposure to ambient ultrafine particles at urban schools in two cities in developed countries, with high insolation climatic conditions, namely Brisbane (Australia) and Barcelona (Spain). The analysis used comprehensive indoor and outdoor air quality measurements at 25 schools in Brisbane and 39 schools in Barcelona. PNC modes were analysed with respect to ambient temperature, land use and urban characteristics, combined with the measured elemental carbon concentrations, NOx (Brisbane) and NO2 (Barcelona). The trends and modes of the quantified weekday average daily cycles of ambient PNC exhibited significant differences between the two cities. PNC increases were observed during traffic rush hours in both cases. However, the mid-day peak was dominant in Brisbane schools and had the highest contribution to total PNC for both indoors and outdoors. In Barcelona, the contribution from traffic was highest for ambient PNC, while the mid-day peak had a slightly higher contribution for indoor concentrations. Analysis of the relationships between PNC and land use characteristics in Barcelona schools showed a moderate correlation with the percentage of road network area and an anti-correlation with the percentage of green area. No statistically significant correlations were found for Brisbane. Overall, despite many similarities between the two cities, school-based exposure patterns were different. The main source of ambient PNC at schools was shown to be traffic in Barcelona and mid-day new particle formation in Brisbane. The mid day PNC peak in Brisbane could have been driven by the combined effect of background and meteorological conditions, as well as other local/distant sources. The results have implications for urban development, especially in terms of air quality mitigation and management at schools. PMID- 26760711 TI - Transport And Health: A Marriage Of Convenience Or An Absolute Necessity. AB - BACKGROUND: The recent diesel scandal has again highlighted the impact that the transport sector can have on public health. AIM: To describe the current impact of transport planning on public health. RESULT: Transport is fundamental to our cities' economic and social development, but causes large health effects and impact through accidents, air pollution, noise, green space and lack of physical activity. CONCLUSION: There is an urgent need to rebalance and provide better and safer infrastructures and policy support for transport, and particularly, active transport modes, building a new culture for it. A parallel transition in transport and urban planning is needed to improve, in a global and structural way, the relations between urban mobility and health. PMID- 26760712 TI - Heat and air pollution exposure as triggers of delivery: A survival analysis of population-based pregnancy cohorts in Rome and Barcelona. AB - INTRODUCTION: Environmental exposures have been linked to length of gestation but the question as to during which weeks of gestation pregnancies are most susceptible still remains little explored. We estimated the effect of maximum apparent temperature and air pollution levels on risk of birth by week of gestation. METHODS: We analyzed two cohorts of singleton live births in Rome (2001-2010) and Barcelona (2007-2012). Maximum apparent temperature (MAT), PM10, O3 and NO2 were analyzed in the warm period (1st April-31st October). Gestational week-specific hazard ratios of giving birth associated to a 1-unit increase in exposure were estimated fitting Cox regression models adjusted for seasonality, and demographic and clinical characteristics of the mother. RESULTS: We observed 78,633 births (5.5% preterm) in Rome and 27,255 (4.5% preterm) in Barcelona. The highest hazard ratios for 1 degrees C increase in MAT were in the 22nd-26th weeks of gestation, 1.071, (95% CI 1.052-1.091) in Rome and 1.071 (95% CI 1.036-1.106) in Barcelona, and decreased to 1.032 (95% CI 1.026-1.038) and 1.033 (95% CI 1.020 1.045) at the 36th week of gestation, respectively. Similar associations and trends were observed for PM10 and NO2 after adjusting for MAT. O3 showed similar trends but weaker associations. CONCLUSIONS: We found, consistently in Rome and Barcelona, an increased risk of delivery for a unit increase in MAT, PM10, NO2 and O3, especially in the second half of the second trimester, thus effectively increasing the risk of preterm and particularly early preterm birth. Results may help to increase awareness of these risks among public-health regulators and clinicians, leading to better preventive strategies. PMID- 26760713 TI - A new conceptual model for quantifying transboundary contribution of atmospheric pollutants in the East Asian Pacific rim region. AB - Transboundary transport of air pollution is a serious environmental concern as pollutant affects both human health and the environment. Many numerical approaches have been utilized to quantify the amounts of pollutants transported to receptor regions, based on emission inventories from possible source regions. However, sparse temporal-spatial observational data and uncertainty in emission inventories might make the transboundary transport contribution difficult to estimate. This study presents a conceptual quantitative approach that uses transport pathway classification in combination with curve fitting models to simulate an air pollutant concentration baseline for pollution background concentrations. This approach is used to investigate the transboundary transport contribution of atmospheric pollutants to a metropolitan area in the East Asian Pacific rim region. Trajectory analysis categorized pollution sources for the study area into three regions: East Asia, Southeast Asia, and Taiwan cities. The occurrence frequency and transboundary contribution results suggest the predominant source region is the East Asian continent. This study also presents an application to evaluate heavy pollution cases for health concerns. This new baseline construction model provides a useful tool for the study of the contribution of transboundary pollution delivered to receptors, especially for areas deficient in emission inventories and regulatory monitoring data for harmful air pollutants. PMID- 26760714 TI - Widespread contamination of wildflower and bee-collected pollen with complex mixtures of neonicotinoids and fungicides commonly applied to crops. AB - There is considerable and ongoing debate as to the harm inflicted on bees by exposure to agricultural pesticides. In part, the lack of consensus reflects a shortage of information on field-realistic levels of exposure. Here, we quantify concentrations of neonicotinoid insecticides and fungicides in the pollen of oilseed rape, and in pollen of wildflowers growing near arable fields. We then compare this to concentrations of these pesticides found in pollen collected by honey bees and in pollen and adult bees sampled from bumble bee colonies placed on arable farms. We also compared this with levels found in bumble bee colonies placed in urban areas. Pollen of oilseed rape was heavily contaminated with a broad range of pesticides, as was the pollen of wildflowers growing nearby. Consequently, pollen collected by both bee species also contained a wide range of pesticides, notably including the fungicides carbendazim, boscalid, flusilazole, metconazole, tebuconazole and trifloxystrobin and the neonicotinoids thiamethoxam, thiacloprid and imidacloprid. In bumble bees, the fungicides carbendazim, boscalid, tebuconazole, flusilazole and metconazole were present at concentrations up to 73nanogram/gram (ng/g). It is notable that pollen collected by bumble bees in rural areas contained high levels of the neonicotinoids thiamethoxam (mean 18ng/g) and thiacloprid (mean 2.9ng/g), along with a range of fungicides, some of which are known to act synergistically with neonicotinoids. Pesticide exposure of bumble bee colonies in urban areas was much lower than in rural areas. Understanding the effects of simultaneous exposure of bees to complex mixtures of pesticides remains a major challenge. PMID- 26760715 TI - Concentrations of phthalates and DINCH metabolites in pooled urine from Queensland, Australia. AB - Dialkyl phthalate esters (phthalates) are ubiquitous chemicals used extensively as plasticizers, solvents and adhesives in a range of industrial and consumer products. 1,2-Cyclohexane dicarboxylic acid, diisononyl ester (DINCH) is a phthalate alternative introduced due to a more favourable toxicological profile, but exposure is largely uncharacterised. The aim of this study was to provide the first assessment of exposure to phthalates and DINCH in the general Australian population. De-identified urine specimens stratified by age and sex were obtained from a community-based pathology laboratory and pooled (n=24 pools of 100). Concentrations of free and total species were measured using online solid phase extraction isotope dilution high performance liquid chromatography tandem mass spectrometry. Concentrations ranged from 2.4 to 71.9ng/mL for metabolites of di(2 ethylhexyl)phthalate, and from <0.5 to 775ng/mL for all other metabolites. Our data suggest that phthalate metabolites concentrations in Australia were at least two times higher than in the United States and Germany; and may be related to legislative differences among countries. DINCH metabolite concentrations were comparatively low and consistent with the limited data available. Ongoing biomonitoring among the general Australian population may help assess temporal trends in exposure and assess the effectiveness of actions aimed at reducing exposures. PMID- 26760717 TI - Investigating the mechanisms of bioconcentration through QSAR classification trees. AB - This paper proposes a scheme to predict whether a compound (1) is mainly stored within lipid tissues, (2) has additional storage sites (e.g., proteins), or (3) is metabolized/eliminated with a reduced bioconcentration. The approach is based on two validated QSAR (Quantitative Structure-Activity Relationship) trees, whose salient features are: (a) descriptor interpretability and (b) simplicity. Trees were developed for 779 organic compounds, the TGD approach was used to quantify the lipid-driven bioconcentration, and a refined machine-learning optimization procedure was applied. We focused on molecular descriptor interpretation, which allowed us to gather new mechanistic insights into the bioconcentration mechanisms. PMID- 26760716 TI - Contribution of post-harvest agricultural paddy residue fires in the N.W. Indo Gangetic Plain to ambient carcinogenic benzenoids, toxic isocyanic acid and carbon monoxide. AB - In the north west Indo-Gangetic Plain (N.W.IGP), large scale post-harvest paddy residue fires occur every year during the months of October-November. This anthropogenic perturbation causes contamination of the atmospheric environment with adverse impacts on regional air quality posing health risks for the population exposed to high concentrations of carcinogens such as benzene and toxic VOCs such as isocyanic acid. These gases and carbon monoxide are known to be emitted from biomass fires along with acetonitrile. Yet no long-term in-situ measurements quantifying the impact of this activity have been carried out in the N.W. IGP. Using high quality continuous online in-situ measurements of these gases at a strategic downwind site over a three year period from 2012 to 2014, we demonstrate the strong impact of this anthropogenic emission activity on ambient concentrations of these gases. In contrast to the pre-paddy harvest period, excellent correlation of benzenoids, isocyanic acid and CO with acetonitrile (a biomass burning chemical tracer); (r>=0.82) and distinct VOC/acetonitrile emission ratios were observed for the post-paddy harvest period which was also characterized by high ambient concentrations of these species. The average concentrations of acetonitrile (1.62+/-0.18ppb), benzene (2.51+/-0.28ppb), toluene (3.72+/-0.41ppb), C8-aromatics (2.88+/-0.30ppb), C9-aromatics (1.55+/ 0.19ppb) and CO (552+/-113ppb) in the post-paddy harvest periods were about 1.5 times higher than the annual average concentrations. For isocyanic acid, a compound with both primary and secondary sources, the concentration in the post paddy harvest period was 0.97+/-0.17ppb. The annual average concentrations of benzene, a class A carcinogen, exceeded the annual exposure limit of 1.6ppb at NTP mandated by the National Ambient Air Quality Standard of India (NAAQS). We show that mitigating the post-harvest paddy residue fires can lower the annual average concentration of benzene and ensure compliance with the NAAQS. Calculations of excessive lifetime cancer risk due to benzene amount to 25 and 10 per million inhabitants for children and adults, respectively, exceeding the USEPA threshold of 1 per million inhabitants. Annual exposure to isocyanic acid was close to 1ppb, the concentration considered to be sufficient to enhance risks for cardiovascular diseases and cataracts. This study makes a case for urgent mitigation of post-harvest paddy residue fires as the unknown synergistic effect of multi-pollutant exposure due to emissions from this anthropogenic source may be posing grave health risks to the population of the N.W. IGP. PMID- 26760718 TI - Sources and environmental behaviors of Dechlorane Plus and related compounds - A review. AB - Although Dechlorane Plus (DP) has been used as a polychlorinated flame retardant for almost half a century, its detection in the environment was not reported until 2006. The subsequent intensive research has confirmed its global ubiquity. A few reviews have presented the properties, analytical methods and environmental occurrence of DP and related compounds in the past several years. The present review emphasizes on the environmental behavior of DP isomers which is assessed by the variation of the isomer ratio of DP in various matrices. Other aspects including the analytical methods, emission sources, general environmental occurrence and bioaccumulation of DP are also summarized. In this review, three typical emission sources in the environment are categorized after introducing the measurement method of DP. The temporal-spatial distribution is then evaluated at the global scale, which provides an integrated representation of the environmental occurrence of DP and potential impact on the human health and ecosystems. The variations of DP isomer ratio in various matrices reinforce its source related distribution and their stereoselective bioaccumulation. Thereafter, DP related compounds and dechlorinated analogs are briefly summarized in regards to their occurrence in various matrices, suggesting their ubiquity in the environment and bioavailability. Further studies are required to better assess the exposures and toxicological effects of DP and its analogs. A special concern is the serious contamination in e-waste recycling areas in developing countries, where long-term monitoring data on the association of DP exposure and adverse effects to human health and ecosystems is urgently needed. PMID- 26760719 TI - Self-reported load carriage injuries of military soldiers. AB - The aim of this study was to investigate whether occupational load carriage constitutes a significant source of injury to military soldiers. An online survey was sent to soldiers serving in specific Australian Army Corps known to experience the greatest occupational exposure to load carriage. Of the 338 respondents, 34% sustained at least one load carriage injury. Fifty-two per cent of those injured during initial training reported sustaining an additional load carriage injury. The majority of injuries (61%) were to the lower limbs with bones and joints the most frequently injured body structures (39%). Endurance marching (continuous marching as part of a physical training session) was the activity accounting for most (38%) injuries. Occupational load carriage is associated with military soldier injuries and, once injured, soldiers are at a high risk of future load carriage injury. The bodily sites and nature of self reported injuries in this study are akin to those of formally reported injuries and those of other militaries. PMID- 26760720 TI - An Elephant in the Emergency Department: Symptom of Disparities in Cancer Care. AB - Reliance on emergency departments (EDs) by economically disadvantaged people for initial cancer diagnosis in place of primary care and early diagnosis and treatment is 1 obvious plausible explanation for cancer disparities. Claims data from a safety net hospital for the years 2009-2010 were merged with hospital tumor registry data to compare hospitalizations for ED-associated initial cancer diagnoses to non-ED associated initial diagnoses. The proportion of initial cancer diagnoses associated with hospital admissions through the ED was relatively high (32%) for all safety net hospital patients, but disproportionately higher for African Americans and residents of the impoverished urban core. Use of the ED for initial diagnosis was associated with a 75% higher risk of stage 4 versus stage 1 cancer diagnosis, and a 176% higher risk of dying during the 2-year study period. Findings from this study of ED use within a safety net hospital documented profound disparities in cancer care and outcomes with major implications for monitoring disparities, Affordable Care Act impact, and safety net hospital utilization. (Population Health Management 2016;19:95 101). PMID- 26760721 TI - Metastatic malignant peripheral nerve sheath tumour presenting as a spontaneous extradural haematoma - A case report. AB - Malignant peripheral nerve sheath tumours may arise from any cranial or somatic nerve. The median survival with best therapy is 49 months. The present case reports a patient with an MPNST that exhibited an unusually indolent behaviour. Besides this, the patient developed a dural metastasis from the lesion and presented with a spontaneous extra-dural haematoma. This has not been reported hitherto in literature. PMID- 26760722 TI - Impact of microbial growth inhibition and proteolytic activity on the stability of a new formulation containing a phytate-degrading enzyme obtained from mushroom. AB - The development of stable enzymes is a key issue in both the food and feed industries. Consequently, the aim of the current study is to evaluate the impact of various additives (sodium chloride, sodium citrate, mannitol, methylparaben, polyethylene glycol 3350, ethylenediaminetetraacetic acid disodium salt, and a serine protease inhibitor) on the stability of a mushroom phytase produced by solid-state cultivation and recovery. Also observed was the effect of the additives on microbial growth inhibition by monitoring both the change in optical density over 30 days of storage and proteolytic activity. Initially, eight experimental formulations were prepared along with a control. After screening, a 3(2) factorial design was applied to define suitable concentrations of the selected additives. Among the eight formulations tested, the formulation containing NaCl, PEG 3350, and methylparaben retained all of the initial phytase activity after 50 days of storage, with no detected interference from protease activity. Sodium citrate, a metal chelation agent, presented the unusual effect of reducing protease activity in the formulations. Although all formulations presented better phytase stability when compared to the control, NaCl and PEG were both able to prolong the stability of the enzyme activity and also to inhibit microbial growth during storage, making them favorable for application as food and feed additives. PMID- 26760723 TI - Selection Between Linear Factor Models and Latent Profile Models Using Conditional Covariances. AB - A method for selecting between K-dimensional linear factor models and (K + 1) class latent profile models is proposed. In particular, it is shown that the conditional covariances of observed variables are constant under factor models but nonlinear functions of the conditioning variable under latent profile models. The performance of a convenient inferential method suggested by the main result is examined via data simulation and is shown to have acceptable error rate control when deciding between the 2 types of models. The proposed test is illustrated using examples from vocational assessment and developmental psychology. PMID- 26760724 TI - Item Response Modeling of Paired Comparison and Ranking Data. AB - The comparative format used in ranking and paired comparisons tasks can significantly reduce the impact of uniform response biases typically associated with rating scales. Thurstone's (1927, 1931) model provides a powerful framework for modeling comparative data such as paired comparisons and rankings. Although Thurstonian models are generally presented as scaling models, that is, stimuli centered models, they can also be used as person-centered models. In this article, we discuss how Thurstone's model for comparative data can be formulated as item response theory models so that respondents' scores on underlying dimensions can be estimated. Item parameters and latent trait scores can be readily estimated using a widely used statistical modeling program. Simulation studies show that item characteristic curves can be accurately estimated with as few as 200 observations and that latent trait scores can be recovered to a high precision. Empirical examples are given to illustrate how the model may be applied in practice and to recommend guidelines for designing ranking and paired comparisons tasks in the future. PMID- 26760725 TI - Improvement in Detection of Differential Item Functioning Using a Mixture Item Response Theory Model. AB - Usually, methods for detection of differential item functioning (DIF) compare the functioning of items across manifest groups. However, the manifest groups with respect to which the items function differentially may not necessarily coincide with the true source of the bias. It is expected that DIF detection under a model that includes a latent DIF variable is more sensitive to this source of bias. In a simulation study, it is shown that a mixture item response theory model, which includes a latent grouping variable, performs better in identifying DIF items than DIF detection methods using manifest variables only. The difference between manifest and latent DIF detection increases as the correlation between the manifest variable and the true source of the DIF becomes smaller. Different sample sizes, relative group sizes, and significance levels are studied. Finally, an empirical example demonstrates the detection of heterogeneity in a minority sample using a latent grouping variable. Manifest and latent DIF detection methods are applied to a Vocabulary test of the General Aptitude Test Battery (GATB). PMID- 26760726 TI - DataToText: A Consumer-Oriented Approach to Data Analysis. AB - DataToText is a project developed where the user communicates the relevant information for an analysis and DataToText computer routine produces text output that describes in words, tables, and figures the results from the analyses. Two extended examples are given, one an example of a moderator analysis and the other an example of a dyadic data analysis. The advantages and disadvantages of DataToText are discussed in terms of the statement of the problem, the steps in the analysis, and understanding the meaning of the results. Also discussed is the potential role of DataToText in pedagogy. Although there are some clear deficiencies in a DataToText analysis, it is argued that, more often than not, DataToText will lead to better analyses. Finally, a call is made for methodologists to become more consumer oriented by providing researchers with tools to facilitate the use of methodological developments. PMID- 26760727 TI - Special MBR Section: SMEP Student Paper Competition Abstracts. PMID- 26760728 TI - Abstract: A Comparison of Classification Techniques for Diagnosis in an Alzheimer's Study. PMID- 26760729 TI - Abstract: Mediation Analysis of Poisson Distributed Count Outcomes. PMID- 26760730 TI - Abstract: Measurement and Structural Model Class Separation in Mixture-CFA. PMID- 26760732 TI - Abstract: Evaluating Shared Parameter Mixture Models for Longitudinal Analysis With Missing Data. PMID- 26760731 TI - Abstract: Evaluating the Efficacy of Item Enhancements. PMID- 26760733 TI - Abstract: Assessing the Reliability of Within-Person Change Over Time: A Dynamic Factor Analysis Approach. PMID- 26760734 TI - Abstract: Bayesian Inference for Growth Mixture Models With Nonignorable Missing Data. PMID- 26760735 TI - Abstract: Case Diagnostics in Structural Equation Models: Illustrations and Issues. PMID- 26760736 TI - 3D Orbital Reconstruction in a Patient with Microphthalmos and a Large Orbital Cyst-A Case Report. AB - BACKGROUND: Orbital cysts are rare developmental anomalies that can occur in microphthalmic and anophthalmic patients. Such cysts can promote orbital growth and subsequently markedly increase the size of the orbit, which is commonly underdeveloped in these patients. Cyst removal is therefore generally dissuaded (at least) in the first 5 years. CLINICAL CASE: A 6-year-old boy with a microphthalmos and a cyst developed protrusion of his prosthetic eye and a swelling of the lower eyelid. MRI showed a large cyst causing distortion of the right orbit. Due to the expansive orbital growth and subsequent misfitting of the prosthesis, cystectomy and orbital floor reconstruction was performed using 3D technology. CONCLUSION: 3D imaging and printing enables exact delineation of orbital cysts and the adjacent bony structures. Furthermore it offers the possibility to plan an individual surgical approach and to design and fabricate a custom fit orbital floor implant. PMID- 26760737 TI - The influence of lower extremity postures on kinematics and injuries of cyclists in vehicle side collisions. AB - OBJECTIVE: A cyclist assumes various cyclic postures of the lower extremities while pushing the pedals in a rotary motion while pedaling. In order to protect cyclists in collisions, it is necessary to understand what influence these postures have on the global kinematics and injuries of the cyclist. METHOD: Finite element (FE) analyses using models of a cyclist, bicycle, and car were conducted. In the simulations, the Total Human Model of Safety (THUMS) occupant model was employed as a cyclist, and the simulation was set up such that the cyclist was hit from its side by a car. Three representative postures of the lower extremities of the cyclist were examined, and the kinematics and injury risk of the cyclist were compared to those obtained by a pedestrian FE model. The risk of a lower extremity injury was assessed based on the knee shear displacement and the tibia bending moment. RESULTS: When the knee position of the cyclist was higher than the hood leading edge, the hood leading edge contacted the leg of the cyclist, and the pelvis slid over the hood top and the wrap-around distance (WAD) of the cyclist's head was large. The knee was shear loaded by the hood leading edge, and the anterior cruciate ligament (ACL) ruptured. The tibia bending moment was less than the injury threshold. When the cyclist's knee position was lower than the hood leading edge, the hood leading edge contacted the thigh of the cyclist, and the cyclist rotated with the femur as the pivot point about the hood leading edge. In this case, the head impact location of the cyclist against the car was comparable to that of the pedestrian collision. The knee shear displacement and the tibia bending moment were less than the injury thresholds. CONCLUSION: The knee height of the cyclist relative to the hood leading edge affected the global kinematics and the head impact location against the car. The loading mode of the lower extremities was also dependent on the initial positions of the lower extremities relative to the car structures. In the foot up and front posture, the knee was loaded in a lateral shear direction by the hood leading edge and as a result the ACL ruptured. The bicycle frame and the struck-side lower extremity interacted and could influence the loadings on lower extremities. PMID- 26760738 TI - Comparative Study on the Nutritional Value of Pidan and Salted Duck Egg. AB - Pidan and salted duck eggs are of nutritional rich alternative duck egg products which are predominantly consumed in China, Thailand, South Korea and other Chinese migrated countries. Both eggs are rich in proteins, lipids, unsaturated fatty acids and minerals. A Pidan whole egg contains 13.1% of protein, 10.7% of fat, 2.25% of carbohydrate and 2.3% of ash, whereas the salted duck egg contains 14% of protein, 16.6% of fat, 4.1% of carbohydrate and 7.5% of ash. The fresh duck egg contains a range of 9.30-11.80% of protein, 11.40-13.52% of fat, 1.50 1.74% of sugar and 1.10-1.17% of ash. Proteins, lipids, and ash contents are found to be greatly enhanced during the pickling and salting process of pidan and salted duck eggs. However, the alkaline induced aggregation of pidan leads to degradation and subsequent generation of free peptides and amino acids. Very few amino acids are found to be lost during the pickling and storage. However, no such losses of amino acids are reported in salted duck eggs during the salting process of 14 d. Phospholipids and cholesterol contents are lower in pidan oil and salted duck egg yolk oil. Thus, the pidan and salted duck eggs are nutritionally rich alternatives of duck egg products which will benefit the human health during consumption. PMID- 26760739 TI - Meat Consumption Culture in Ethiopia. AB - The consumption of animal flesh food in Ethiopia has associated with cultural practices. Meat plays pivotal and vital parts in special occasions and its cultural symbolic weight is markedly greater than that accorded to most other food. Processing and cooking of poultry is a gender based duty and has socio cultural roles. Ethiopians are dependent on limited types of animals for meats due to the taboo associated culturally. Moreover, the consumption of meat and meat products has a very tidy association with religious beliefs, and are influenced by religions. The main religions of Ethiopia have their own peculiar doctrines of setting the feeding habits and customs of their followers. They influence meat products consumption through dictating the source animals that should be used or not be used for food, and scheduling the days of the years in periodical permeation and restriction of consumptions which in turn influences the pattern of meat consumption in the country. In Ethiopia, a cow or an ox is commonly butchered for the sole purpose of selling within the community. In special occasions, people have a cultural ceremony of slaughtering cow or ox and sharing among the group, called Kircha, which is a very common option of the people in rural area where access of meat is challenging frequently. PMID- 26760740 TI - Effect of High Pressure on the Porcine Placenral Hydrolyzing Activity of Pepsin, Trypsin and Chymotrypsin. AB - This study investigated the effects of protease treatments (trypsin, chymotrypsin, and pepsin) under various pressure levels (0.1-300 MPa) for the characteristics of porcine placenta hydrolysates. According to gel electrophoretic patterns, the trypsin showed the best placental hydrolyzing activity followed by chymotrypsin, regardless of the pressure levels. In particular, the peptide bands of tryptic-digested hydrolysate were not shown regardless of applied pressure levels. The peptide bands of hydrolysate treated chymotrypsin showed gradual decreases in molecular weights (M w) with increasing pressure levels. However, the pepsin did not show any evidences of placental hydrolysis even though the pressure levels were increased to 300 MPa. The gel permeation chromatography (GPC) profiles showed that the trypsin and pepsin had better placental hydrolyzing activities under high pressure (particularly at 200 MPa), with lower M w distributions of the hydrolysates. Pepsin also tend to lower the M w of peptides, while the major bands of hydrolysates being treated at 300 MPa were observed at more than 7,000 Da. There were some differences in amino acid compositions of the hydrolysates, nevertheless, the peptides were mainly composed of glycine (Gly), alanine (Ala), hydroxyproline (Hyp) and proline (Pro). Consequently, the results indicate that high pressure could enhance the placental hydrolyzing activities of the selected proteases and the optimum pressure levels at which the maximum protease activity is around 200 MPa. PMID- 26760741 TI - Gastric Fluid and Heat Stress Response of Listeria monocytogenes Inoculated on Frankfurters Formulated with 10%, 20%, and 30% Fat Content. AB - This study evaluated the effects of frankfurter fat content on Listeria monocytogenes resistance to heat stress and gastric fluid, and the Caco-2 cell invasion efficiency of the pathogen. A 10-strain mixture of L. monocytogenes was inoculated on frankfurters formulated with 10%, 20%, and 30% fat content (10%: F10, 20%: F20, 30%: F30) and stored at 10C for 30 d. The samples were analyzed for L. monocytogenes resistance to heat stress and a simulated gastric fluid challenge. The total bacteria and L. monocytogenes survival rates were measured on tryptic soy agar plus 0.6% yeast extract and Palcam agar, respectively. L. monocytogenes colonies inoculated on F10, F20, and F30 samples were used for a Caco-2 cell invasion assay. In general, no obvious differences were observed between the survival rates of total bacteria and L. monocytogenes grown on different fat contents under heat stress and gastric fluid challenge. However, L. monocytogenes obtained from the F30 samples had a significantly higher Caco-2 cell invasion efficiency than those in the F10 and F20 samples (p<0.05). These results indicate that although high fat content in food may not be related to L. monocytogenes resistance to heat stress and gastric fluid, it may increase the Caco-2 cell invasion efficiency of the pathogen. PMID- 26760742 TI - Effects of Egg Shell Membrane Hydrolysates on Anti-Inflammatory, Anti-Wrinkle, Anti-Microbial Activity and Moisture-Protection. AB - This study was conducted to examine the effects of eggshell membrane hydrolysates (ESMH) on the anti-inflammatory, anti-wrinkle, anti-microbial activity, and moisture-protection for cosmetic use. Whole ESMH (before fractionation), and fraction I (>10 kDa), fraction II (3-10 kDa), and fraction III (<3 kDa) of the hydrolysates were assessed in this experiment. As lipopolysaccharide (LPS) and IFN-gamma caused the inflammation on Raw264.7 cell, whole ESMH and fraction I showed to be effective in inhibiting the induction of cell inflammation depending on the concentration, and also showed outstanding effect to suppress the skin inflammation. Fraction I inhibited collagenase and elastase activities to a greater extent than the other fractions, while all fractions had antibiotic effects at concentrations of 10 mg/disc and 20 mg/disc. In addition, it showed the moisture protection effects of skin on the holding amount and losing amount of moisture in upper-inner arm of the human body with a relatively low loss rate in skin, which confirmed that the hydrolyzed fractions of ESM helps to form the superior protective layer of moisture. It was concluded that ESMH fractions with different molecular weights, especially the 10 kDa fraction, have anti lipopolysaccharide, anti-IFN-gamma-induced inflammation, anti- collagenase and elastase activities, and thus can be used as a cosmetic agent to protect skin. PMID- 26760743 TI - Effects of Pressure-shift Freezing on the Structural and Physical Properties of Gelatin Hydrogel Matrices. AB - This study investigates the effects of the gelatin concentration (10-40%, w/v), freezing temperatures (from -20C to -50C) and freezing methods on the structural and physical properties of gelatin matrices. To freeze gelatin, the pressure shift freezing (PSF) is being applied at 0.1 (under atmospheric control), 50 and 100 MPa, respectively. The freezing point of gelatin solutions decrease with increasing gelatin concentrations, from -0.2C (10% gelatin) to -6.7C (40% gelatin), while the extent of supercooling did not show any specific trends. The rheological properties of the gelatin indicate that both the storage (G') and loss (G") moduli were steady in the strain amplitude range of 0.1-10%. To characterize gelatin matrices formed by the various freezing methods, the ice crystal sizes which were being determined by the scanning electron microscopy (SEM) are affected by the gelatin concentrations. The ice crystal sizes are affected by gelatin concentrations and freezing temperature, while the size distributions of ice crystals depend on the freezing methods. Smaller ice crystals are being formed with PSF rather than under the atmospheric control where the freezing temperature is above -40C. Thus, the results of this study indicate that the PSF processing at a very low freezing temperature (-50C) offers a potential advantage over commercial atmospheric freezing points for the formation of small ice crystals. PMID- 26760744 TI - Lipolytic Changes in Fermented Sausages Produced with Turkey Meat: Effects of Starter Culture and Heat Treatment. AB - In this study, the effects of two different commercial starter culture mixes and processing methodologies (traditional and heat process) on the lipolytic changes of fermented sausages manufactured with turkey meat were evaluated during processing stages and storage. Free fatty acid (FFA) value increased with fermentation and during storage over 120 d in all fermented sausage groups produced with both processing methodologies (p<0.05). After drying stage, free fatty acid values of traditional style and heat processed fermented sausages were between 10.54-13.01% and 6.56-8.49%, respectively. Thiobarbituric acid (TBA) values of traditionally processed fermented sausages were between 0.220-0.450 mg.kg(-1), and TBA values of heat processed fermented sausages were in a range of 0.405-0.795 mg.kg(-1). Oleic and linoleic acids were predominant fatty acids in all fermented sausages. It was seen that fermented sausage groups produced with starter culture had lower TBA and FFA values in comparison with the control groups, and heat application inhibited the lipase enzyme activity and had an improving effect on lipid oxidation. As a result of these effects, heat processed fermented sausages had lower FFA and higher TBA values than the traditionally processed groups. PMID- 26760745 TI - The Preventive Effects of Nanopowdered Peanut Sprout-added Caciocavallo Cheese on Collagen-induced Arthritic Mice. AB - The present study was carried out to investigate the effects of nanopowdered peanut sprout-added Caciocavallo cheese (NPCC) on the prevention and treatment of rheumatoid arthritis in DBA/IJ mice immunized with type II collagen. After the induction of arthritis, the mice were being divided into five groups: (1) normal, no immunization; (2) CIA, collagen-induced arthritis; (3) MTX, collagen-induced arthritis treated with methotrexate (0.3 mg/kg body weight); (4) CC, collagen induced arthritis treated with Caciocavallo cheese (0.6 g/d); (5) NPCC, collagen induced arthritis treated with nanopowdered peanut sprout-added Caciocavallo cheese (0.6 g/d). Nanopowdered peanut sprout was ranged from 300 to 350 nm, while regular powdered peanut sprouts were ranged from 50 to 150 MUm. The NPCC group had considerable reductions of clinical scores and paw thicknesses at the end of experiment as compared to the CIA group. In the serum analysis, the TNF-alpha, IL 1beta, IL- 6 and IgG1 levels in the NPCC group have decreased by 69.4, 75.9, 66.6, and 61.9%, respectively, when compared to the CIA group. The histological score and spleen index of the NPCC group were significantly lower than the CIA group. In conclusion, the feeding NPCC method could delay and/or prevent the rheumatoid arthritis in the collagen-induced arthritis mouse model. Based on this study, nanopowdered peanut sprouts could be applied to various functional cheeses. PMID- 26760746 TI - Physicochemical and Sensory Properties of Nanopowdered Chitosan-Added Maribo Cheese during Ripening. AB - Nanopowdered chitosan (NPC) has high biological activities, such as blood cholesterol lowering effect and antidiabetic activity. This study is carried out to determine the effects of nano-powdered chitosan-added Maribo cheese (NCMC) for the physicochemical properties and sensory analysis during its ripening at 14C for 6 mon. From the results, the moisture and fat levels are not significantly influenced from the addition of chitosan (p>0.05), but ash contents increased with increasing chitosan concentrations and the protein contents decreased with increasing chitosan concentrations. In the short-chain fatty acids analysis during the ripening, the total production is initially 13.79 ppm in 0.2% NCMC and 13.81 ppm in control, and their levels have steadily increased to 59.94 and 53.11 ppm, respectively. For the color levels, the L* values decreased, while the a* and b* values significantly increased during ripening for all samples (p<0.05). In texture analysis, the hardness and gumminess of NCMC significantly decreased as compared to the control during ripening (p<0.05), while the cohesiveness, springiness and chewiness were not significantly different among the treatments (p>0.05). In sensory analysis, the butyric off-flavor and bitterness increased slightly with increasing concentrations of NCMC during ripening. The overall acceptability of 0.2% NCMC held the highest score amongst the samples during the ripening. From the results obtained, the 0.2% NCMC was preferred during the ripening and observed the possibility of functional cheese. PMID- 26760747 TI - Selection and Characteristics of Fermented Salted Seafood (jeotgal)-Originated Strains with Excellent S-adenosyl-L-methionine (SAM) Production and Probiotics Efficacy. AB - This study is executed to develop probiotics which produce S-adenosyl-L methionine (SAM), a methyl group donor of the 5-methyltetrahydrofolate methylation reaction within the animal cell. SAM is an essential substance for the synthesis, activation, and metabolism of hormones, neurotransmitters, nucleic acids, phospholipids, and cell membranes of animals. The SAM is also known as a nutritional supplement to improve brain functions of the human. In this study, the SAM-producing strains are identified in 18 types of salted fish, and then, the strains with excellent SAM productions are being identified, with 1 strain in the Enterococcus genus and 9 strains in the Bacillus genus. Strains with a large amount of SAM production include the lactic acid bacteria such as En. faecium and En. durans, En. sanguinicola, as well as various strains in the Bacil-lus genus. The SAM-overproducing strains show antibacterial activities with certain harmful microbes in addition to the weak acid resistances and strong bile resistances, indicating characteristics of probiotics. It is possible that the jeotgal originated beneficial strains with overproducing SAM can be commercially utilized in order to manufacture SAM enriched foods. PMID- 26760748 TI - Differentiation of Deboned Fresh Chicken Thigh Meat from the Frozen-Thawed One Processed with Different Deboning Conditions. AB - This study was performed to evaluate the quality characteristics of three deboned categories of chicken thigh meat: one which was slaughtered and deboned in the same plant (fresh); one which was slaughtered, deboned, frozen, and thawed in the same plant (frozen-thawed); and the last which was slaughtered in a plant, deboned in a different plant, but then transferred to the original plant (fresh outside). Surface color, drip loss, 2-thiobarbituric acid reactive substances (TBARS) value, sensory evaluation, and total aerobic bacterial counts of the chicken samples were determined. Moreover, the torrymeter was used to measure the differences in freshness of the chicken meat. The surface color and the TBARS values did not show significant differences among the three categories. However, the total aerobic bacterial counts of fresh-outside and frozen-thawed chicken meat were significantly higher than the fresh chicken meat on the first storage day, and the drip loss of frozen-thawed chicken meat was significantly higher than the fresh-outside and fresh chicken meat. In addition, the sensory evaluation of frozen-thawed chicken meat was significantly lower than the fresh outside and fresh chicken meat. Torrymeter values were higher in fresh chicken meat than fresh-outside and frozen-thawed chicken meat during the storage period. These results indicate that the quality of frozen-thawed chicken meat is comparatively lower than the fresh chicken meat, and the torrymeter values can accurately differentiate the fresh-outside and frozen-thawed chicken meat from the fresh ones. PMID- 26760749 TI - Effects of Temperature and Packaging on the Growth Kinetics of Clostridium perfringens in Ready-to-eat Jokbal (Pig's Trotters). AB - Ready-to-eat (RTE) Jokbal (Pig's trotter), which consists of pig's feet cooked in soy sauce and various spices, is a very popular and widely sold in Korean retail markets. Commercially, the anaerobically packed Jokbal have also become a popular RTE food in several convenience stores. This study evaluates the effects of storage temperature and packaging methods for the growth of C. perfringens in Jokbal. Growth kinetic parameters of C. perfringens in aerobically and anaerobically packed Jokbals are determined at each temperature by the modified Gompertz equation. The lag time, specific growth rate, and maximum population density of C. perfringens are being analyzed as a function of temperature and packaging method. The minimum growth temperature of C. perfringens in aerobically and anaerobically packed Jokbal is 24C and 18C, respectively. The C. perfringens in Jokbal did not grow under conditions of over 50C regardless of the packaging methods, indicating that the holding temperature of Jokbal in markets must be maintained at above 50C or below 18C. Growth of C. perfringens in anaerobically packed Jokbal is faster than in aerobically packed Jokbal when stored under the same conditions. This indicates that there are a higher risks associated with C. perfringens for anaerobically packed meat products. PMID- 26760751 TI - Physicochemical Characteristics of Beef Jerky Cured with Salted-fermented Anchovy and Shrimp. AB - The aim of this study is to evaluate the availability of salted and fermented fish (SFF) including salted and fermented anchovy (SFA) and shrimp (SFS) as a marinade of beef jerky. In curing solutions, half (SFA 1 and SFS 1) or whole (SFA 2 and SFS 2) salt-water was replaced with SFF juices. Higher water activity (aw) was found in the beef jerky cured with SFFs than the control (C) (p< 0.05). The SFFs had the effect of causing a decrease in hardness and an increase in cohesiveness (p<0.05). Among the treatment samples, springiness was the highest in SFA2 and SFS2 (p<0.05) and the lowest values of Warner-Bratzler shear force were found in SFA1 and SFA2 (p<0.05). The SFFs also had the effect of increasing the flavor of the sensory properties; however, color measurements from both the instrumental surface color (L*, a*, b*, chroma, and hue angle) and color of sensory evaluation were decreased by addition of SFFs (p<0.05). Therefore, we conclude the SFFs can improve the texture and sensory properties of the beef jerky. In particular, the SFS is a good ingredient for the curing solution. However, studies are still needed on improving the aw, pH, and surface color of the beef jerky to apply the SFFs for making beef jerky. PMID- 26760750 TI - Goat Milk Yoghurt by Using Lacto-B Culture Modulates the Production of Tumor Necrosis Factor-Alpha and Interleukin-10 in Malnourished Rats. AB - Total spleen lymphocytes, lymphocyte proliferation, tumor necrosis factor-alpha (TNF-alpha), and interleukin-10 (IL-10) in spleen lymphocyte culture were studied in malnourished Wistar rats fed with goat milk yoghurt. Malnourished rats were created by using standard feed restriction as much as 50% of normal rats for 21 d. Goat milk yoghurt containing three types of microorganism e.g., Lactobacillus acidophilus, Sterptococcus thermophilus and Bifidobacterium longum derived from Lacto-B culture in powder form. After 21 d, the rats continued to receive restricted feeding and supplemented with goat milk yoghurt for 7 d. Total splenocytes were counted by hemocytometer. Splenocytes proliferation was expressed as stimulation index, whereas the TNF-alpha and IL-10 of spleen lymphocyte culture were measured by ELISA technique. The total number of splenocytes and stimulation index of splenocytes in moderate malnourished and normal rats supplemented with goat milk yoghurt was not significantly different. The level of TNF-alpha in the rat supplemented with goat milk yoghurt was lower (p<0.05) than the control group, whereas the level of IL-10 in the rat supplemented with goat milk yoghurt was higher (p<0.05) than the control group. In conclusion, goat milk yoghurt supplementation in malnourished rats could decrease TNF-alpha as a representation of the proinflammatory cytokine, while it increases IL-10 as a representation of the anti-inflammatory cytokine. PMID- 26760753 TI - Effects of Water or Brine Immersion Thawing Combined with Ultrasound on Quality Attributes of Frozen Pork Loin. AB - This study explored the effects of water or brine (2% NaCl, w/v) immersion thawing combined with ultrasound treatment (40 kHz, 150 W) on the quality characteristics of pork. Ultrasound treatment of pork was conducted in two cold media (at 4C), water and 2% (w/v) brine, respectively. Because the ultrasound treatment caused temperature increase in the media from 4C to 16C, the qualities of pork thawed by ultrasound were compared with those thawed by immersion either in water or brine where the temperature was being maintained at either 4C (low temperature control) or 17C (high temperature control). The ultrasound treatment resulted in rapid thawing of pork where the thawing rate was similar to those thawed in the 17C media. For quality characteristics, ultrasound-treated pork in brine had an advantage of less cooking losses when comparing to the control. In particular, ultrasound treatment in brine exhibited the lowest shear force (or highest tenderness) among the freezing/thawing treatments. Although the ultrasound processing in brine caused discoloration of the pork, this thawing technique had potential to be applied as a commercial thawing technology for frozen foods. PMID- 26760752 TI - Physiological Characteristics and Production of Folic Acid of Lactobacillus plantarum JA71 Isolated from Jeotgal, a Traditional Korean Fermented Seafood. AB - Folic acid, one of the B group of vitamins, is an essential substance for maintaining the functions of the nervous system, and is also known to decrease the level of homocysteine in plasma. Homocysteine influences the lowering of the cognitive function in humans, and especially in elderly people. In order to determine the strains with a strong capacity to produce folic acid, 190 bacteria were isolated from various kinds of jeotgal and chungkuk-jang. In our test experiment, JA71 was found to contain 9.03MUg/mL of folic acid after 24 h of incubation in an MRS broth. This showed that JA71 has the highest folic acid production ability compared to the other lactic acid bacteria that were isolated. JA71 was identified as Lactobacillus plantarum by the result of API carbohydrate fermentation pattern and 16s rDNA sequence. JA71 was investigated for its physiological characteristics. The optimum growth temperature of JA71 was 37C, and the cultures took 12 h to reach pH 4.4. JA71 proved more sensitive to bacitracin when compared with fifteen different antibiotics, and showed most resistance to neomycin and vancomycin. Moreover, it was comparatively tolerant of bile juice and acid, and displayed resistance to Escherichia coli, Salmonella Typhimurium, and Staphylococcus aureus with restraint rates of 60.4%, 96.7%, and 76.2%, respectively. These results demonstrate that JA71 could be an excellent strain for application to functional products. PMID- 26760754 TI - Effects of Chicken Breast Meat on Quality Properties of Mackerel (Scomber japonicus) Sausage. AB - This study was performed to evaluate the effects of chicken breast meat on the quality of mackerel sausages. The mackerel sausages were manufactured by additions of 5%, 7%, and 10% of chicken breast meat. The lightness of mackerel sausages showed no significant differences between the control and addition groups. The redness increased in a dose-dependent manner, but the yellowness decreased significantly with the addition of 7% chicken breast meat (p<0.05). The whiteness value of mackerel sausage added with 7% chicken breast meat was significantly higher than those of the other groups (p<0.05). In texture analysis, the hardness and adhesiveness of the mackerel sausage added with 5% of chicken breast meat showed no significant differences as compared to the control. However, the mackerel sausages added with 7% and 10% of chicken breast meat showed a dose-dependent decrease. The gel strength of the mackerel sausage added with 5% chicken breast meat was not significantly different from the control, but the addition of 7% and 10% chicken breast meat reduced the gel strength of the mackerel sausage. In sensory evaluation, the mackerel sausages prepared with chicken breast meat have higher scores in smell, taste, texture, hardness, chewiness, and overall preference as compared to the no addition group. Therefore, these results suggest that the optimal condition for improving the properties within mackerel sausages was 5% addition of chicken breast meat. PMID- 26760755 TI - Optimizing Carnosine Containing Extract Preparation from Chicken Breast for Anti glycating agents. AB - Optimization of carnosine and anserine extraction from chicken breast was performed using response surface methodology (RSM) to obtain the maximized physiological activities for anti-glycation and anti-oxidation. The optimum extraction conditions were water extraction for 1.6 h in the case of the 20-wk laying hen muscle and water extraction for 2.12 h in the case of 90-wk laying hen muscle. Higher carnosine and anserine contents were measured in the 20-wk laying hen muscle, along with higher physiological activities, which increased in direct proportion with the dipeptide contents. The extracts prepared from the 20-wk laying hen under optimum conditions showed 57% inhibition of advanced glycated end-product formation, 64% inhibition of lipid peroxidation, and 61% of DPPH radical scavenging effects. On the other hand, 52% inhibition of AGE formation, 62% inhibition of lipid peroxidation, and 53% of DPPH radical scavenging effect were demonstrated within the 90-wk laying hen. In addition, the ratio of carnosine was a key indicator for the physiological activities of the extracts. PMID- 26760756 TI - Characteristic of nitrous oxide production in partial denitrification process with high nitrite accumulation. AB - Nitrous oxide (N2O) production during the partial denitrification process with nitrate (NO3(-)-N) to nitrite (NO2(-)-N) transformation ratio of 80% was investigated in this study. Results showed that N2O was seldom observed before complete depletion of NO3(-)-N, but it was closely related to the reduction of NO2(-)-N rather than NO3(-)-N. High COD/NO3(-)-N was in favor of N2O production in partial denitrification with high NO2(-)-N accumulation. It was seriously enhanced at constant acidic pH due to the free nitrous acid (FNA) inhibition. However, the N2O production was much lower at initial pH of 5.5 and 6.5 due to the pH increase during denitrification process. Significantly, the pH turning point could be chosen as a controlled parameter to denote the end of NO3(-)-N reduction, which could not only achieve high NO2(-)-N accumulation but also decrease the N2O production significantly for practical application. PMID- 26760757 TI - High-dose-rate prostate brachytherapy inverse planning on dose-volume criteria by simulated annealing. AB - High-dose-rate brachytherapy is a tumor treatment method where a highly radioactive source is brought in close proximity to the tumor. In this paper we develop a simulated annealing algorithm to optimize the dwell times at preselected dwell positions to maximize tumor coverage under dose-volume constraints on the organs at risk. Compared to existing algorithms, our algorithm has advantages in terms of speed and objective value and does not require an expensive general purpose solver. Its success mainly depends on exploiting the efficiency of matrix multiplication and a careful selection of the neighboring states. In this paper we outline its details and make an in-depth comparison with existing methods using real patient data. PMID- 26760758 TI - Erratum. PMID- 26760759 TI - Mitigating health risks associated with alcoholic beverages through metabolic engineering. AB - Epidemiological studies have established a positive relationship between the occurrence of cancer and consumption of alcoholic beverages. Metabolic engineering of brewing yeast to reduce potential carcinogenic compounds in alcoholic beverage is technically feasible as well as economically promising. This review presents the mechanisms of formation of potentially carcinogenic components in alcoholic beverages, such as formaldehyde, acetaldehyde, ethyl carbamate, acrylamide, and heavy metals, and introduces effective genetic perturbations to minimize the concentrations of these harmful components. As precise and effective genome editing tools for polyploid yeast are now available, we envision that yeast metabolic engineering might open up new research directions for improving brewing yeast in order to ensure product safety as well as to increase overall quality of alcoholic beverages. PMID- 26760760 TI - Expanding the Iroquois genes repertoire: a non-transcriptional function in cell cycle progression. AB - Drosophila Iroquois (Iro) proteins are components of the TALE homeodomain family of transcriptional regulators. They play key roles in territorial specification and pattern formation. A recent study has disclosed a novel developmental function of the Iro proteins. In the eye and wing imaginal discs, they can regulate the size of the territories that they specify. They do so by cell autonomously controlling cell cycle progression. Indeed, Iro proteins down regulate the activity of the CyclinE/Cdk2 complex by a transcription-independent mechanism. This novel function is executed mainly through 2 evolutionarily conserved domains of the Iro proteins: the Cyclin Binding Domain and the IRO-box, which mediate their binding to CyclinE-containing protein complexes. Here we discuss the functional implications of the control of the cell cycle by Iro proteins for development and oncogenesis. PMID- 26760762 TI - Temporal Patterns of Larval Fish Occurrence in a Large Subtropical River. AB - Knowledge of temporal patterns of larval fish occurrence is limited in south China, despite its ecological importance. This research examines the annual and seasonal patterns of fish larval presence in the large subtropical Pearl River. Data is based on samples collected every two days, from 2006 to 2013. In total, 45 taxa representing 13 families and eight orders were sampled. The dominant larval family was Cyprinidae, accounting for 27 taxa. Squaliobarbus curriculus was the most abundant species, followed by Megalobrama terminalis, Xenocypris davidi, Cirrhinus molitorella, Hemiculter leuscisculus and Squalidus argentatus. Fish larvae abundances varied significantly throughout the seasons (multivariate analyses: Cluster, SIMPROF and ANOSIM). The greatest numbers occurred between May and September, peaking from June through August, which corresponds to the reproductive season. In this study, redundancy analysis was used to describe the relationship between fish larval abundance and associated environmental factors. Mean water temperature, river discharge, atmospheric pressure, maximum temperature and precipitation play important roles in larval occurrence patterns. According to seasonal variations, fish larvae occurrence is mainly affected by water temperature. It was also noted that the occurrence of Salanx reevesii and Cyprinus carpio larvae is associated with higher dissolved oxygen (DO) concentrations, higher atmospheric pressure and lower water temperatures which occur in the spring. On the other hand, M. terminalis, X. davidi, and C. molitorella are associated with high precipitation, high river discharge, low atmospheric pressure and low DO concentrations which featured during the summer months. S. curriculus also peaks in the summer and is associated with peak water temperatures and minimum NH3-N concentrations. Rhinogobius giurinus occur when higher atmospheric pressure, lower precipitation and lower river discharges occur in the autumn. Dominant fish species stagger their spawning period to avoid intraspecific competition for food resources during early life stages; a coexistence strategy to some extent. This research outlines the environmental requirements for successful spawning for different fish species. Understanding processes such as those outlined in this research paper is the basis of conservation of fish community diversity which is a critical resource to a successful sustainable fishery in the Pearl River. PMID- 26760761 TI - Production of Biologically Active Cecropin A Peptide in Rice Seed Oil Bodies. AB - Cecropin A is a natural antimicrobial peptide that exhibits fast and potent activity against a broad spectrum of pathogens and neoplastic cells, and that has important biotechnological applications. However, cecropin A exploitation, as for other antimicrobial peptides, is limited by their production and purification costs. Here, we report the efficient production of this bioactive peptide in rice bran using the rice oleosin 18 as a carrier protein. High cecropin A levels were reached in rice seeds driving the expression of the chimeric gene by the strong embryo-specific oleosin 18 own promoter, and targeting the peptide to the oil body organelle as an oleosin 18-cecropin A fusion protein. The accumulation of cecropin A in oil bodies had no deleterious effects on seed viability and seedling growth, as well as on seed yield. We also show that biologically active cecropin A can be easily purified from the transgenic rice seeds by homogenization and simple flotation centrifugation methods. Our results demonstrate that the oleosin fusion technology is suitable for the production of cecropin A in rice seeds, which can potentially be extended to other antimicrobial peptides to assist their exploitation. PMID- 26760763 TI - MiRNAs and piRNAs from bone marrow mesenchymal stem cell extracellular vesicles induce cell survival and inhibit cell differentiation of cord blood hematopoietic stem cells: a new insight in transplantation. AB - Hematopoietic stem cells (HSC), including umbilical cord blood CD34+ stem cells (UCB-CD34+), are used for the treatment of several diseases. Although different studies suggest that bone marrow mesenchymal stem cells (BM-MSC) support hematopoiesis, the exact mechanism remains unclear. Recently, extracellular vesicles (EVs) have been described as a novel avenue of cell communication, which may mediate BM-MSC effect on HSC. In this work, we studied the interaction between UCB-CD34+ cells and BM-MSC derived EVs. First, by sequencing EV derived miRNAs and piRNAs we found that EVs contain RNAs able to influence UCB-CD34+ cell fate. Accordingly, a gene expression profile of UCB-CD34+ cells treated with EVs, identified about 100 down-regulated genes among those targeted by EV-derived miRNAs and piRNAs (e.g. miR-27b/MPL, miR-21/ANXA1, miR-181/EGR2), indicating that EV content was able to modify gene expression profile of receiving cells. Moreover, we demonstrated that UCB-CD34+ cells, exposed to EVs, significantly changed different biological functions, becoming more viable and less differentiated. UCB-CD34+ gene expression profile also identified 103 up regulated genes, most of them codifying for chemokines, cytokines and their receptors, involved in chemotaxis of different BM cells, an essential function of hematopoietic reconstitution. Finally, the exposure of UCB-CD34+ cells to EVs caused an increased expression CXCR4, paralleled by an in vivo augmented migration from peripheral blood to BM niche in NSG mice. This study demonstrates the existence of a powerful cross talk between BM-MSC and UCB-CD34+ cells, mediated by EVs, providing new insight in the biology of cord blood transplantation. PMID- 26760766 TI - Association of nucleotide excision repair pathway gene polymorphisms with gastric cancer and atrophic gastritis risks. AB - Polymorphisms of NER genes could change NER ability, thereby altering individual susceptibility to GC. We systematically analyzed 39 SNPs of 8 key genes of NER pathway in 2686 subjects including 898 gastric cancer (GC), 851 atrophic gastritis (AG) and 937 controls (CON) in northern Chinese. SNP genotyping were performed using Sequenom MassARRAY platform. The results demonstrated that DDB2 rs830083 GG genotype was significantly associated with increased GC risk compared with wild-type CC (OR=2.32, P= 6.62 * 10-9); XPC rs2607775 CG genotype conferred a 1.73 increased odds of GC risk than non-cancer subjects compared with wild-type CC (OR=1.73, P= 3.04 * 10-4). The combined detection of these two polymorphisms demonstrated even higher GC risk (OR=3.05). Haplotype analysis suggested that DDB2 rs2029298-rs326222-rs3781619-rs830083 GTAG haplotype was significantly associated with disease risk in each step of CON->AG->GC development (AG vs. CON: OR=2.88, P= 7.51 * 10-7; GC vs. AG: OR=2.90, P=5.68 * 10-15; GC vs. CON: OR=8.42, P=2.22 * 10-15); DDB2 GTAC haplotype was associated with reduced risk of GC compared with CON (OR=0.63, P= 8.31 * 10-12). XPC rs1870134-rs2228000-rs2228001 rs2470352-rs2607775 GCAAG haplotype conferred increased risk of GC compared with AG (OR=1.88, P= 6.98 * 10-4). XPA rs2808668 and drinking, DDB2 rs326222, rs3781619, rs830083 and smoking demonstrated significant interactions in AG; XPC rs2607775 had significant interaction with smoking in GC. In conclusion, NER pathway polymorphisms especially in "damage incision" step were significantly associated with GC risk and had interactions with environment factors. The detection of NER pathway polymorphisms such as DDB2 and XPC might be applied in the prediction of GC risk and personalized prevention in the future. NER pathway polymorphisms especially in "damage incision" step were significantly associated with GC risk and had interactions with environment factors, which might be applied in the prediction of GC risk and personalized prevention in the future. PMID- 26760764 TI - Annexin A1 sustains tumor metabolism and cellular proliferation upon stable loss of HIF1A. AB - Despite the approval of numerous molecular targeted drugs, long-term antiproliferative efficacy is rarely achieved and therapy resistance remains a central obstacle of cancer care. Combined inhibition of multiple cancer-driving pathways promises to improve antiproliferative efficacy. HIF-1 is a driver of gastric cancer and considered to be an attractive target for therapy. We noted that gastric cancer cells are able to functionally compensate the stable loss of HIF-1alpha. Via transcriptomics we identified a group of upregulated genes in HIF 1alpha-deficient cells and hypothesized that these genes confer survival upon HIF 1alpha loss. Strikingly, simultaneous knock-down of HIF-1alpha and Annexin A1 (ANXA1), one of the identified genes, resulted in complete cessation of proliferation. Using stable isotope-resolved metabolomics, oxidative and reductive glutamine metabolism was found to be significantly impaired in HIF 1alpha/ANXA1-deficient cells, potentially explaining the proliferation defect. In summary, we present a conceptually novel application of stable gene inactivation enabling in-depth deconstruction of resistance mechanisms. In theory, this experimental approach is applicable to any cancer-driving gene or pathway and promises to identify various new targets for combination therapies. PMID- 26760765 TI - VDAC3 as a sensor of oxidative state of the intermembrane space of mitochondria: the putative role of cysteine residue modifications. AB - Voltage-Dependent Anion selective Channels (VDAC) are pore-forming mitochondrial outer membrane proteins. In mammals VDAC3, the least characterized isoform, presents a set of cysteines predicted to be exposed toward the intermembrane space. We find that cysteines in VDAC3 can stay in different oxidation states. This was preliminary observed when, in our experimental conditions, completely lacking any reducing agent, VDAC3 presented a pattern of slightly different electrophoretic mobilities. This observation holds true both for rat liver mitochondrial VDAC3 and for recombinant and refolded human VDAC3. Mass spectroscopy revealed that cysteines 2 and 8 can form a disulfide bridge in native VDAC3. Single or combined site-directed mutagenesis of cysteines 2, 8 and 122 showed that the protein mobility in SDS-PAGE is influenced by the presence of cysteine and by the redox status. In addition, cysteines 2, 8 and 122 are involved in the stability control of the pore as shown by electrophysiology, complementation assays and chemico-physical characterization. Furthermore, a positive correlation between the pore conductance of the mutants and their ability to complement the growth of porin-less yeast mutant cells was found. Our work provides evidence for a complex oxidation pattern of a mitochondrial protein not directly involved in electron transport. The most likely biological meaning of this behavior is to buffer the ROS load and keep track of the redox level in the inter-membrane space, eventually signaling it through conformational changes. PMID- 26760768 TI - Identifying and functionally characterizing tissue-specific and ubiquitously expressed human lncRNAs. AB - Recent advances in transcriptome sequencing have made it possible to distinguish ubiquitously expressed long non-coding RNAs (UE lncRNAs) from tissue-specific lncRNAs (TS lncRNAs), thereby providing clues to their cellular functions. Here, we assembled and functionally characterized a consensus lncRNA transcriptome by curating hundreds of RNA-seq datasets across normal human tissues from 16 independent studies. In total, 1,184 UE and 2,583 TS lncRNAs were identified. These different lncRNA populations had several distinct features. Specifically, UE lncRNAs were associated with genomic compaction and highly conserved exons and promoter regions. We found that UE lncRNAs are regulated at the transcriptional level (with especially strong regulation of enhancers) and are associated with epigenetic modifications and post-transcriptional regulation. Based on these observations we propose a novel way to predict the functions of UE and TS lncRNAs through analysis of their genomic location and similarities in epigenetic modifications. Our characterization of UE and TS lncRNAs may provide a foundation for lncRNA genomics and the delineation of complex disease mechanisms. PMID- 26760767 TI - Disruption of KIF3A in patient-derived glioblastoma cells: effects on ciliogenesis, hedgehog sensitivity, and tumorigenesis. AB - KIF3A, a component of the kinesin-2 motor, is necessary for the progression of diverse tumor types. This is partly due to its role in regulating ciliogenesis and cell responsiveness to sonic hedgehog (SHH). Notably, primary cilia have been detected in human glioblastoma multiforme (GBM) tumor biopsies and derived cell lines. Here, we asked whether disrupting KIF3A in GBM cells affected ciliogenesis, in vitro growth and responsiveness to SHH, or tumorigenic behavior in vivo. We used a lentiviral vector to create three patient-derived GBM cell lines expressing a dominant negative, motorless form of Kif3a (dnKif3a). In all unmodified lines, we found that most GBM cells were capable of producing ciliated progeny and that dnKif3a expression in these cells ablated ciliogenesis. Interestingly, unmodified and dnKif3a-expressing cell lines displayed differential sensitivities and pathway activation to SHH and variable tumor associated survival following mouse xenografts. In one cell line, SHH-induced cell proliferation was prevented in vitro by either expressing dnKif3a or inhibiting SMO signaling using cyclopamine, and the survival times of mice implanted with dnKif3a-expressing cells were increased. In a second line, expression of dnKif3a increased the cells' baseline proliferation while, surprisingly, sensitizing them to SHH-induced cell death. The survival times of mice implanted with these dnKif3a-expressing cells were decreased. Finally, expression of dnKif3a in a third cell line had no effect on cell proliferation, SHH sensitivity, or mouse survival times. These findings indicate that KIF3A is essential for GBM cell ciliogenesis, but its role in modulating GBM cell behavior is highly variable. PMID- 26760769 TI - Epigallocatechin-3-gallate induces oxidative phosphorylation by activating cytochrome c oxidase in human cultured neurons and astrocytes. AB - Mitochondrial dysfunction and resulting energy impairment have been identified as features of many neurodegenerative diseases. Whether this energy impairment is the cause of the disease or the consequence of preceding impairment(s) is still under discussion, however a recovery of cellular bioenergetics would plausibly prevent or improve the pathology. In this study, we screened different natural molecules for their ability to increase intracellular adenine triphosphate purine (ATP). Among them, epigallocatechin-3-gallate (EGCG), a polyphenol from green tea, presented the most striking results. We found that it increases ATP production in both human cultured astrocytes and neurons with different kinetic parameters and without toxicity. Specifically, we showed that oxidative phosphorylation in human cultured astrocytes and neurons increased at the level of the routine respiration on the cells pre-treated with the natural molecule. Furthermore, EGCG-induced ATP production was only blocked by sodium azide (NaN3) and oligomycin, inhibitors of cytochrome c oxidase (CcO; complex IV) and ATP synthase (complex V) respectively. These findings suggest that the EGCG modulates CcO activity, as confirmed by its enzymatic activity. CcO is known to be regulated differently in neurons and astrocytes. Accordingly, EGCG treatment is acting differently on the kinetic parameters of the two cell types. To our knowledge, this is the first study showing that EGCG promotes CcO activity in human cultured neurons and astrocytes. Considering that CcO dysfunction has been reported in patients having neurodegenerative diseases such as Alzheimer's disease (AD), we therefore suggest that EGCG could restore mitochondrial function and prevent subsequent loss of synaptic function. PMID- 26760770 TI - BAY 1024767 blocks androgen receptor mutants found in castration-resistant prostate cancer patients. AB - Androgen receptor (AR) mutations arise in patients developing resistance to hormone deprivation therapies. Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wild-type AR. Antagonism was maintained, though reduced, at increased androgen levels. Anti tumor efficacy was evidenced in vivo in the KuCaP-1 prostate cancer model which bears the W741C bicalutamide resistance mutation and in the syngeneic prostate cancer rat model Dunning R3327-G. The prevalence of six selected AR mutations was determined in plasma DNA originating from 100 resistant patients and found to be at least 12%. Altogether the results show BAY 1024767 to be a strong antagonist for several AR mutants linked to therapy resistance, which opens the door for next-generation compounds that can benefit patients based on their mutation profile. PMID- 26760771 TI - Gene 33/Mig6 inhibits hexavalent chromium-induced DNA damage and cell transformation in human lung epithelial cells. AB - Hexavalent Chromium [Cr(VI)] compounds are human lung carcinogens and environmental/occupational hazards. The molecular mechanisms of Cr(VI) carcinogenesis appear to be complex and are poorly defined. In this study, we investigated the potential role of Gene 33 (ERRFI1, Mig6), a multifunctional adaptor protein, in Cr(VI)-mediated lung carcinogenesis. We show that the level of Gene 33 protein is suppressed by both acute and chronic Cr(VI) treatments in a dose- and time-dependent fashion in BEAS-2B lung epithelial cells. The inhibition also occurs in A549 lung bronchial carcinoma cells. Cr(VI) suppresses Gene 33 expression mainly through post-transcriptional mechanisms, although the mRNA level of gene 33 also tends to be lower upon Cr(VI) treatments. Cr(VI)-induced DNA damage appears primarily in the S phases of the cell cycle despite the high basal DNA damage signals at the G2M phase. Knockdown of Gene 33 with siRNA significantly elevates Cr(VI)-induced DNA damage in both BEAS-2B and A549 cells. Depletion of Gene 33 also promotes Cr(VI)-induced micronucleus (MN) formation and cell transformation in BEAS-2B cells. Our results reveal a novel function of Gene 33 in Cr(VI)-induced DNA damage and lung epithelial cell transformation. We propose that in addition to its role in the canonical EGFR signaling pathway and other signaling pathways, Gene 33 may also inhibit Cr(VI)-induced lung carcinogenesis by reducing DNA damage triggered by Cr(VI). PMID- 26760772 TI - Epigenetic silencing of JMJD5 promotes the proliferation of hepatocellular carcinoma cells by down-regulating the transcription of CDKN1A 686. AB - Proteins that contain jumonji C (JmjC) domains have recently been identified as major contributors to various malignant human cancers through epigenetic remodeling. However, the roles of these family members in the pathogenesis of hepatocellular carcinoma (HCC) are obscure. By mining public databases, we found that the HCC patients with lower JmjC domain-containing protein 5 (JMJD5) expression exhibited shorter survival time. We then confirmed that JMJD5 expression was indeed decreased in HCC specimens, which was caused by the altered epigenetic histone modifications, the decreased H3K9ac, H3K27ac and H3K4me2/3 together with the increased trimethylation of H3K27 and H3K9 on the JMJD5 promoter. Functional experiments revealed that JMJD5 knockdown promoted HCC cell proliferation and in vivo tumorigenicity by accelerating the G1/S transition of the cell cycle; in contrast, ectopic JMJD5 expression had the opposite effects. At molecular mechanism, we found that, in HCC cell lines including TP53-null Hep3B, JMJD5 knockdown led to the down-regulation of CDKN1A and ectopic expression of JMJD5 not only increased but also rescued CDKN1A transcription. Moreover, CDKN1A knockdown could abrogate the effect of JMJD5 knockdown or overexpression on cell proliferation, suggesting that JMJD5 inhibits HCC cell proliferation mainly by activating CDKN1A expression. We further revealed that JMJD5 directly enhances CDKN1A transcription by binding to CDKN1A's promoter independent of H3K36me2 demethylase activity. In short, we first prove that JMJD5 is a tumor suppressor gene in HCC pathogenesis, and the epigenetic silencing of JMJD5 promotes HCC cell proliferation by directly down-regulating CDKN1A transcription. PMID- 26760773 TI - Development of a Simple Dipstick Assay for Operational Monitoring of DDT. AB - BACKGROUND: Indoor residual spraying (IRS) of DDT is used to control visceral leishmaniasis (VL) in India. However, the quality of spraying is severely compromised by a lack of affordable field assays to monitor target doses of insecticide. Our aim was to develop a simple DDT insecticide quantification kit (IQK) for monitoring DDT levels in an operational setting. METHODOLOGY/ PRINCIPLE FINDINGS: DDT quantification was based on the stoichiometric release of chloride from DDT by alkaline hydrolysis and detection of the released ion using Quantab chloride detection strips. The assay was specific for insecticidal p,p'-DDT (LoQ = 0.082 g/m2). Bostik discs were effective in post spray wall sampling, extracting 25-70% of active ingredient depending on surface. Residual DDT was sampled from walls in Bihar state in India using Bostik adhesive discs and DDT concentrations (g p,p'-DDT/m2) were determined using IQK and HPLC (n = 1964 field samples). Analysis of 161 Bostik samples (pooled sample pairs) by IQK and HPLC produced excellent correlation (R2 = 0.96; Bland-Altman bias = -0.0038). IQK analysis of the remaining field samples matched HPLC data in identifying households that had been under sprayed, in range or over sprayed. INTERPRETATION: A simple dipstick assay has been developed for monitoring DDT spraying that gives comparable results to HPLC. By making laboratory-based analysis of DDT dosing accessible to field operatives, routine monitoring of DDT levels can be promoted in low- and middle- income countries to maximise the effectiveness of IRS. PMID- 26760774 TI - The Protective Effect of Human Umbilical Cord Blood CD34+ Cells and Estradiol against Focal Cerebral Ischemia in Female Ovariectomized Rat: Cerebral MR Imaging and Immunohistochemical Study. AB - Human umbilical cord blood derived CD34+ stem cells are reported to mediate therapeutic effects in stroke animal models. Estrogen was known to protect against ischemic injury. The present study wished to investigate whether the protective effect of CD34+ cells against ischemic injury can be reinforced with complemental estradiol treatment in female ovariectomized rat and its possible mechanism. Experiment 1 was to determine the best optimal timing of CD34+ cell treatment for the neuroprotective effect after 60-min middle cerebral artery occlusion (MCAO). Experiment 2 was to evaluate the adjuvant effect of 17beta estradiol on CD34+ cell neuroprotection after MCAO. Experiment 1 showed intravenous infusion with CD34+ cells before MCAO (pre-treatment) caused less infarction size than those infused after MCAO (post-treatment) on 7T magnetic resonance T2-weighted images. Experiment 2 revealed infarction size was most significantly reduced after CD34+ + estradiol pre-treatment. When compared with no treatment group, CD34+ + estradiol pre-treatment showed significantly less ADC reduction at 2 h and 2 d, less CBF reduction at 2 h and less hyperperfusion at 2 d. The immunoreactivity of c-Fos, c-Jun and GFAP was attenuated, and BDNF showed significant recovery from 2 h to 2 d after MCAO, especially after CD34+ + estradiol pre-treatment. The present study suggests pre-treatment with CD34+ cells with complemental estradiol can be most protective against ischemic injury, which may act through stabilization of cerebral hemodynamics and normalization of the expressions of immediate early genes and BDNF. PMID- 26760775 TI - Host-Specific and Segment-Specific Evolutionary Dynamics of Avian and Human Influenza A Viruses: A Systematic Review. AB - Understanding the evolutionary dynamics of influenza viruses is essential to control both avian and human influenza. Here, we analyze host-specific and segment-specific Tajima's D trends of influenza A virus through a systematic review using viral sequences registered in the National Center for Biotechnology Information. To avoid bias from viral population subdivision, viral sequences were stratified according to their sampling locations and sampling years. As a result, we obtained a total of 580 datasets each of which consists of nucleotide sequences of influenza A viruses isolated from a single population of hosts at a single sampling site within a single year. By analyzing nucleotide sequences in the datasets, we found that Tajima's D values of viral sequences were different depending on hosts and gene segments. Tajima's D values of viruses isolated from chicken and human samples showed negative, suggesting purifying selection or a rapid population growth of the viruses. The negative Tajima's D values in rapidly growing viral population were also observed in computer simulations. Tajima's D values of PB2, PB1, PA, NP, and M genes of the viruses circulating in wild mallards were close to zero, suggesting that these genes have undergone neutral selection in constant-sized population. On the other hand, Tajima's D values of HA and NA genes of these viruses were positive, indicating HA and NA have undergone balancing selection in wild mallards. Taken together, these results indicated the existence of unknown factors that maintain viral subtypes in wild mallards. PMID- 26760776 TI - Gender and the Publication Output of Graduate Students: A Case Study. AB - We examine gender differences among the six PhD student cohorts 2004-2009 at the California Institute of Technology using a new dataset that includes information on trainees and their advisors and enables us to construct detailed measures of teams at the advisor level. We focus on the relationship between graduate student publications and: (1) their gender; (2) the gender of the advisor, (3) the gender pairing between the advisor and the student and (4) the gender composition of the team. We find that female graduate students co-author on average 8.5% fewer papers than men; that students writing with female advisors publish 7.7% more. Of particular note is that gender pairing matters: male students working with female advisors publish 10.0% more than male students working with male advisors; women students working with male advisors publish 8.5% less. There is no difference between the publishing patterns of male students working with male advisors and female students working with female advisors. The results persist and are magnified when we focus on the quality of the published articles, as measured by average Impact Factor, instead of number of articles. We find no evidence that the number of publications relates to the gender composition of the team. Although the gender effects are reasonably modest, past research on processes of positive feedback and cumulative advantage suggest that the difference will grow, not shrink, over the careers of these recent cohorts. PMID- 26760777 TI - Using both strands: The fundamental nature of antisense transcription. AB - Non-coding transcription across the antisense strands of genes is an abundant, pervasive process in eukaryotes from yeast to humans, however its biological function remains elusive. Here, we provide commentary on a recent study of ours, which demonstrates a genome-wide role for antisense transcription: establishing a unique, dynamic chromatin architecture over genes. Antisense transcription increases the level of nucleosome occupancy and histone acetylation at the promoter and body of genes, without necessarily modulating the level of protein coding sense transcription. It is also associated with high levels of histone turnover. By allowing genes to sample a wider range of chromatin configurations, antisense transcription could serve to make genes more sensitive to changing signals, priming them for responses to developmental programs or stressful cellular environments. Given the abundance of antisense transcription and the breadth of these chromatin changes, we propose that antisense transcription represents a fundamental, canonical feature of eukaryotic genes. PMID- 26760778 TI - Molecular Characterization of Invasive Streptococcus dysgalactiae subsp. equisimilis, Japan. AB - We collected beta-hemolytic streptococci (1,611 isolates) from patients with invasive streptococcal infections in Japan during April 2010-March 2013. Streptococcus dysgalactiae subsp. equisimilis (SDSE) was most common (n = 693); 99% of patients with SDSE infections were elderly (mean age 75 years, SD +/-15 years). We aimed to clarify molecular and epidemiologic characteristics of SDSE isolates and features of patient infections. Bacteremia with no identified focus of origin and cellulitis were the most prevalent manifestations; otherwise, clinical manifestations resembled those of S. pyogenes infections. Clinical manifestations also differed by patient's age. SDSE isolates were classified into 34 emm types; stG6792 was most prevalent (27.1%), followed by stG485 and stG245. Mortality rates did not differ according to emm types. Multilocus sequence typing identified 46 sequence types and 12 novel types. Types possessing macrolide- and quinolone-resistance genes were 18.4% and 2.6%, respectively; none showed beta lactam resistance. Among aging populations, invasive SDSE infections are an increasing risk. PMID- 26760779 TI - Epidemiological Trends of Traumatic Brain Injury Identified in the Emergency Department in a Publicly-Insured Population, 2002-2010. AB - OBJECTIVES: To examine epidemiological trends of Traumatic Brain Injury (TBI) treated in the Emergency Department (ED), identify demographic groups at risk of TBI, and determine the factors associated with hospitalization following an ED visit for TBI. METHODS: A province-wide database was used to identify all ED visits for TBI in Ontario, Canada between April 2002 and March 2010. Trends were analyzed using linear regression, and predictors of hospital admission were evaluated using logistic regression. RESULTS: There were 986,194 ED visits for TBI over the eight-year study period, resulting in 49,290 hospitalizations and 1,072 deaths. The age- and sex-adjusted rate of TBI decreased by 3%, from 1,013.9 per 100,000 (95% CI 1,008.3-1,010.6) to 979.1 per 100,000 (95% CI 973.7-984.4; p = 0.11). We found trends towards increasing age, comorbidity level, length of stay, and ambulatory transport use. Children and young adults (ages 5-24) sustained peak rates of motor vehicle crash (MVC) and bicyclist-related TBI, but also experienced the greatest decline in these rates (p = 0.003 and p = 0.005). In contrast, peak rates of fall-related TBI occurred among the youngest (ages 0 4) and oldest (ages 85+) segments of the population, but rates remained stable over time (p = 0.52 and 0.54). The 5-24 age group also sustained the highest rates of sports-related TBI but rates remained stable (p = 0.80). On multivariate analysis, the odds of hospital admission decreased by 1% for each year over the study period (OR = 0.991, 95% CI = 0.987-0.995). Increasing age and comorbidity, male sex, and ambulatory transport were significant predictors of hospital admission. CONCLUSIONS: ED visits for TBI are involving older populations with increasingly complex comorbidities. While TBI rates are either stable or declining among vulnerable groups such as young drivers, youth athletes, and the elderly, these populations remain key targets for focused injury prevention and surveillance. Clinicians in the ED setting should be cognizant of factors associated with hospitalization following TBI. LEVEL OF EVIDENCE: III. STUDY DESIGN: Cross-sectional. PMID- 26760781 TI - Remote Ischemic Postconditioning Ameliorates the Mesenchymal Stem Cells Engraftment in Reperfused Myocardium. AB - OBJECTIVES: Remote Ischemic postconditioning (RIPoC) is a cardioprotective strategy for alleviating the reperfusion injury. We hypothesized that RIPoC or ischemic postconditioning (IPoC) could protect the engrafted mesenchymal stem cells (MSCs) in reperfusion myocardium. METHODS: Female Sprague-Dawley rats were subject to 30 minutes of occlusion of left anterior descending (LAD). Ischemia reperfusion (IR) received reperfusion without interruption after ischemia. RIPoC received 3 cycles of 30 seconds reperfusion and re-occlusion on the limb at the onset of reperfusion. IPoC received 3 cycles of 30 seconds reperfusion and re occlusion on the LAD at the same time. Male MSCs were intramyocardially administered after ischemia. RESULTS: Compared with that in IR group, ischemic myocardium in RIPoC+IPoC group, RIPoC group and IPoC group were found to have higher anti-oxidative stress and mitochondrial function level, lower lipid peroxidation and inflammational injury level, higher level of stromal cell derived factor-1 alpha and vascular endothelium growth factor gene expression at 3 days later. By immunohistochemical examination and quantitative polymerase chain reaction, more engrafted MSCs, better cardiac function and less cardiac fibrosis in RIPoC+IPoC group, RIPoC group and IPoC group were detected at 3 weeks after delivery. There were no significant differences between RIPoC and RIPoC+IPoC group. CONCLUSIONS: Combination therapy using intramyocardial MSCs transplantation with RIPoC enhanced transplantation efficiency and cardiac function, and reduced cardiac fibrosis. These beneficial effects were mainly attributed to hospitable milieu for engrafted cells. IPoC could not render additional effect on MSCs engraftment elicited by RIPoC. PMID- 26760780 TI - Bloodstream infections in internal medicine. AB - Bloodstream infections (BSI) carry a heavy burden of morbidity and mortality in modern internal medicine wards (IMW). These wards are often filled with elderly subjects with several risk factors for BSI, such as multiple comorbidities, polypharmacy, immunosuppression, and indwelling devices. Diagnosing BSI in such a setting might require a high degree of suspicion, since the clinical presentation could be affected by underlying conditions and concomitant medications, which might delay the administration of an appropriate antimicrobial therapy, an event strongly and unfavorably influencing survival. Furthermore, selecting the appropriate antimicrobial therapy to treat these patients is becoming an increasingly complex task in which all possible benefits and costs should be carefully analyzed from patient and public health perspectives. Only a specialized, continuous, and interdisciplinary approach could really improve the management of IMW patients in an era of increasing antimicrobial resistance and complexity of care. PMID- 26760785 TI - Defect charge states in Si doped hexagonal boron-nitride monolayer. AB - We perform ab initio density functional theory calculations to investigate the energetics, electronic and magnetic properties of isolated stoichiometric and non stoichiometric substitutional Si complexes in a hexagonal boron-nitride monolayer. The Si impurity atoms substituting the boron atom sites SiB giving non stoichiometric complexes are found to be the most energetically favourable, and are half-metallic and order ferromagnetically in the neutral charge state. We find that the magnetic moments and magnetization energies increase monotonically when Si defects form a cluster. Partial density of states and standard Mulliken population analysis indicate that the half-metallic character and magnetic moments mainly arise from the Si 3p impurity states. The stoichiometric Si complexes are energetically unfavorable and non-magnetic. When charging the energetically favourable non-stoichiometric Si complexes, we find that the formation energies strongly depend on the impurity charge states and Fermi level position. We also find that the magnetic moments and orderings are tunable by charge state modulation q = -2, -1, 0, +1, +2. The induced half-metallic character is lost (retained) when charging isolated (clustered) Si defect(s). This underlines the potential of a Si doped hexagonal boron-nitride monolayer for novel spin-based applications. PMID- 26760784 TI - Galectin-3: A Link between Myocardial and Arterial Stiffening in Patients with Acute Decompensated Heart Failure? AB - BACKGROUND: Heart failure is accompanied by abnormalities in ventricular-vascular interaction due to increased myocardial and arterial stiffness. Galectin-3 is a recently discovered biomarker that plays an important role in myocardial and vascular fibrosis and heart failure progression. OBJECTIVES: The aim of this study was to determine whether galectin-3 is correlated with arterial stiffening markers and impaired ventricular-arterial coupling in decompensated heart failure patients. METHODS: A total of 79 inpatients with acute decompensated heart failure were evaluated. Serum galectin-3 was determined at baseline, and during admission, transthoracic echocardiography and measurements of vascular indices by Doppler ultrasonography were performed. RESULTS: Elevated pulse wave velocity and low arterial carotid distensibility are associated with heart failure in patients with preserved ejection fraction (p = 0.04, p = 0.009). Pulse wave velocity, carotid distensibility and Young's modulus did not correlate with serum galectin 3 levels. Conversely, raised galectin-3 levels correlated with an increased ventricular-arterial coupling ratio (Ea/Elv) p = 0.047, OR = 1.9, 95% CI (1.0 3.6). Increased galectin-3 levels were associated with lower rates of left ventricular pressure rise in early systole (dp/dt) (p=0.018) and raised pulmonary artery pressure (p = 0.046). High galectin-3 levels (p = 0.038, HR = 3.07) and arterial pulmonary pressure (p = 0.007, HR = 1.06) were found to be independent risk factors for all-cause mortality and readmissions. CONCLUSIONS: This study showed no significant correlation between serum galectin-3 levels and arterial stiffening markers. Instead, high galectin-3 levels predicted impaired ventricular-arterial coupling. Galectin-3 may be predictive of raised pulmonary artery pressures. Elevated galectin-3 levels correlate with severe systolic dysfunction and together with pulmonary hypertension are independent markers of outcome. PMID- 26760786 TI - Self-generated concentration and modulus gradient coating design to protect Si nano-wire electrodes during lithiation. AB - Surface coatings as artificial solid electrolyte interphases have been actively pursued as an effective way to improve the cycle efficiency of nanostructured Si electrodes for high energy density lithium ion batteries, where the mechanical stability of the surface coatings on Si is as critical as Si itself. However, the chemical composition and mechanical property change of coating materials during the lithiation and delithiation process imposed a grand challenge to design coating/Si nanostructure as an integrated electrode system. In our work, we first developed reactive force field (ReaxFF) parameters for Li-Si-Al-O materials to simulate the lithiation process of Si-core/Al2O3-shell and Si-core/SiO2-shell nanostructures. With reactive dynamics simulations, we were able to simultaneously track and correlate the lithiation rate, compositional change, mechanical property evolution, stress distributions, and fracture. A new mechanics model based on these varying properties was developed to determine how to stabilize the coating with a critical size ratio. Furthermore, we discovered that the self-accelerating Li diffusion in Al2O3 coating forms a well-defined Li concentration gradient, leading to an elastic modulus gradient, which effectively avoids local stress concentration and mitigates crack propagation. Based on these results, we propose a modulus gradient coating, softer outside, harder inside, as the most efficient coating to protect the Si electrode surface and improve its current efficiency. PMID- 26760783 TI - Reduction in Post-Marathon Peak Oxygen Consumption: Sign of Cardiac Fatigue in Amateur Runners? AB - BACKGROUND: Prolonged aerobic exercise, such as running a marathon, produces supraphysiological stress that can affect the athlete's homeostasis. Some degree of transient myocardial dysfunction ("cardiac fatigue") can be observed for several days after the race. OBJECTIVE: To verify if there are changes in the cardiopulmonary capacity, and cardiac inotropy and lusitropy in amateur marathoners after running a marathon. METHODS: The sample comprised 6 male amateur runners. All of them underwent cardiopulmonary exercise testing (CPET) one week before the Sao Paulo Marathon, and 3 to 4 days after that race. They underwent echocardiography 24 hours prior to and immediately after the marathon. All subjects were instructed not to exercise, to maintain their regular diet, ingest the same usual amount of liquids, and rest at least 8 hours a day in the period preceding the CPET. RESULTS: The athletes completed the marathon in 221.5 (207; 250) minutes. In the post-marathon CPET, there was a significant reduction in peak oxygen consumption and peak oxygen pulse compared to the results obtained before the race (50.75 and 46.35 mL.kg-1 .min-1; 19.4 and 18.1 mL.btm, respectively). The echocardiography showed a significant reduction in the s' wave (inotropic marker), but no significant change in the E/e' ratio (lusitropic marker). CONCLUSIONS: In amateur runners, the marathon seems to promote changes in the cardiopulmonary capacity identified within 4 days after the race, with a reduction in the cardiac contractility. Such changes suggest that some degree of "cardiac fatigue" can occur. PMID- 26760782 TI - Strong Expression of Hypoxia-Inducible Factor-1alpha (HIF-1alpha) Is Associated with Axl Expression and Features of Aggressive Tumors in African Breast Cancer. AB - PURPOSE: Inhibition of hypoxia-inducible factor (HIF) and Axl receptor tyrosine kinase is being evaluated for targeted therapy in solid tumors. Both HIF-1alpha and Axl influence tumor growth and metastatic potential, and they have been linked to treatment failure in many cancers. However, there is a lack of reports on HIF-1alpha expression in African breast cancer, which has a poor prognosis, and novel treatment targets must therefore be established. Here, we aimed to evaluate HIF-1alpha in relation to Axl expression, angiogenesis markers, and other tumor characteristics in a series of African breast cancer. METHODS: Using immunohistochemistry, we examined 261 invasive breast cancers on tissue microarrays for HIF-1alpha and Axl as well as several other markers, and a subset of 185 cases had information on VEGF (vascular endothelial growth factor) expression, microvessel density (MVD), proliferating microvessel density (pMVD) and vascular proliferation index (VPI) for important comparisons. RESULTS: Strong HIF-1alpha expression was associated with increased Axl (p = 0.007), VEGF (p<0.0005), and p53 (p = 0.032) expression, as well as high tumor cell proliferation by Ki-67 (p = 0.006), and high tumor grade (p = 0.003). Tumors with strong HIF-1alpha expression had significantly higher MVD (p = 0.019) and higher pMVD (p = 0.027) than tumors with weak expression. CONCLUSIONS: High HIF-1alpha expression is significantly associated with Axl and VEGF expression, and with markers of poor prognosis in this series of breast cancer, suggesting HIF-1alpha and Axl as potential therapeutic targets in African breast cancer. PMID- 26760802 TI - Autologous stem-cell transplantation for multiple myeloma: a Brazilian institution experience in 15 years of follow-up. AB - OBJECTIVE: To determine the 5-year post-transplant survival of patients with multiple myeloma. METHODS: A retrospective study in patients diagnosed with multiple myeloma submitted to autologous bone marrow transplantation at a Brazilian institution, during the period of 1993 to 2007. RESULTS: Seventy-three patients were evaluated with a median age of 55 years. Survival in 5 years was 75% (2.4 to 60 months). Statistical analysis demonstrated statistical significance for the applied grade of response prior to treatment with autologous bone marrow transplantation (p = 0.01). There was no statistical significance for clinical staging or time of diagnosis (before or after the year 2000). CONCLUSION: Experience in autologous bone marrow transplantation for multiple myeloma at a Brazilian institution demonstrated an evolution consistent with that of medical literature and highlighted the importance of a response to treatment prior to transplantation in the survival of these patients. PMID- 26760803 TI - Autologous stem-cell transplantation in Hodgkin's lymphoma: analysis of a therapeutic option. AB - OBJECTIVE: To report the clinical progress of patients with Hodgkin's lymphoma treated with autologous transplantation after failure or relapse of first-line treatment with chemotherapy and/or radiation therapy. METHODS: The results of a retrospective analysis of 31 patients submitted to autologous transplantation as second-line treatment, between April 2000 and December 2008, were analyzed. Fourteen men and seventeen women, with a median age of 27 years, were submitted to autologous transplantation for relapsed (n = 21) or refractory (n = 10) Hodgkin's lymphoma. RESULTS: Mortality related to treatment in the first 100 days after transplant was 3.2%. With a mean follow-up period of 18 months (range: 1 to 88 months), the probability of global survival and progression-free survival in 18 months was 84 and 80%, respectively. The probability of global survival and progression-free survival at 18 months for patients with chemosensitive relapses (n = 21) was 95 and 90%, respectively, versus 60 and 45% for patients with relapses resistant to chemotherapy (n = 10) (p = 0.001 for global survival; p = 0.003 for progression-free survival). In the multivariate analysis, absence of disease or pretransplant disease < 5 cm were favorable factors for global survival (p= 0.02; RR: 0.072; 95%CI: 0.01-0.85) and progression-free survival (p= 0.01; RR: 0.040; 95%CI: 0.007-0.78). CONCLUSION: Autologous transplantation of stem-cells is a therapeutic option for Hodgkin's lymphoma patients after the first relapse. Promising results were observed in patients with a low tumor burden at transplant. PMID- 26760804 TI - Thrombocytopenia: diagnosis with flow cytometry and antiplatelet antibodies. AB - OBJECTIVE: To identify antiplatelet antibodies by flow cytometry (direct method) in patients with thrombocytopenia. METHODS: Between January 1997 and March 2004 a total of 15100 patients were referred to the Centro de Hematologia de Sao Paulo for hematological investigation of several diagnoses (anemia, leukopenia, thrombocytopenia, coagulation abnormalities, adenomegaly, leukemia and others). Of those, 1057 were referred because of thrombocytopenia and were divided into two groups: Group Idiopathic thrombocytopenic purpura, with no identifiable cause; and Group Other thrombocytopenia, which included low normal platelet counts cause to be established, hepatitis C and HIV infection, hypersplenism, EDTA-induced artifacts, laboratory error, and other causes. Flow cytometry immunophenotyping was done in 115 cases to identify platelet autoantibodies (direct method). RESULTS: Of the total number of patients, 1057 (7%) presented low platelet counts, 670 were females (63.4%) and age range of one to 75 years. Of the 115 cases (9.7%) submitted to immunophenotyping, the results were positive in 40% and the test was inconclusive in 5%. Idiopathic thrombocytopenic purpura was found in 52% of patients, more often in women. Hepatitis C virus infection was found in 7% and HIV infection in 1%. Low normal platelet counts were found in 17%, laboratory errors in 6%, and laboratory artifacts in 1% of cases. Platelet autoantibodies were found in 76.9% of all idiopathic thrombocytopenic purpura cases. It was negative in 83.3% of the low normal counts. CONCLUSION: antiplatelet autoantibodies when present help to diagnose idiopathic thrombocytopenic purpura. When absent, suggest other causes of thrombocytopenia. PMID- 26760805 TI - Red blood cell transfusion practice in a Pediatric Intensive Care Unit. AB - OBJECTIVES: To describe a population of children that received red blood cell transfusions. METHODS: A retrospective observational study carried out at the Pediatric Intensive Care Unit of the Instituto da Crianca of Hospital das Clinicas of Faculdade de Medicina of Universidade de Sao Paulo in 2004, with children that received red blood cell transfusions. RESULTS: Transfusion of red blood cells was performed in 50% of the patients hospitalized. Median age was 18 months, and the primary motive for admission was respiratory insufficiency (35%). Underlying disease was present in 84% of the cases and multiple organ and system dysfunction in 46.2%. The median value of pretransfusion hemoglobin concentration was 7.8 g/dL. Transfused patients were undergoing some form of therapeutic procedure in 82% of the cases. CONCLUSIONS: Red blood cell transfusions are performed at all ages. Hemoglobin concentration and hematocrit rate are the primary data used to indicate these transfusions. The values of arterial serum lactate and SvO2were seldom used. Most patients transfused were submitted to some form of therapeutic procedure, and in many cases, transfusions were carried out in patients with multiple organ and system dysfunctions. PMID- 26760806 TI - Allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies: Hospital Israelita Albert Einstein experience. AB - OBJECTIVE: To report the experience of a tertiary care hospital with allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies. METHODS: Seven pediatric patients with primary immunodeficiencies (severe combined immunodeficiency: n = 2; combined immunodeficiency: n = 1; chronic granulomatous disease: n = 1; hyper-IgM syndrome: n = 2; and IPEX syndrome: n = 1) who underwent eight hematopoietic stem cell transplants in a single center, from 2007 to 2010, were studied. RESULTS: Two patients received transplants from HLA-identical siblings; the other six transplants were done with unrelated donors (bone marrow: n = 1; cord blood: n = 5). All patients had pre-existing infections before hematopoietic stem cell transplants. One patient received only anti-thymocyte globulin prior to transplant, three transplants were done with reduced intensity conditioning regimens and four transplants were done after myeloablative therapy. Two patients were not evaluated for engraftment due to early death. Three patients engrafted, two had primary graft failure and one received a second transplant with posterior engraftment. Two patients died of regimen related toxicity (hepatic sinusoidal obstruction syndrome); one patient died of progressive respiratory failure due to Parainfluenza infection present prior to transplant. Four patients are alive and well from 60 days to 14 months after transplant. CONCLUSION: Patients' status prior to transplant is the most important risk factor on the outcome of hematopoietic stem cell transplants in the treatment of these diseases. Early diagnosis and the possibility of a faster referral of these patients for treatment in reference centers may substantially improve their survival and quality of life. PMID- 26760807 TI - Multiple myeloma: five-year experience at a University Hospital. AB - OBJECTIVE: To present a descriptive analysis of patients diagnosed with multiple myeloma, correlating it with mortality. METHODS: A retrospective study that analyzed consecutive patients diagnosed with multiple myeloma under follow-up at the Faculdade de Medicina do ABC from 2006 to 2010. RESULTS: The median age was 58.5 years. Anemia was observed upon diagnosis in 87% of patients, hypercalcemia in 38%, and creatinine levels higher than 2 mg/dL in 19%. M protein was detected in 85.7%. The five-year survival rate was 74.6%. Multivariate analysis showed statistical significance for Durie-Salmon staging (p = 0.037). The International Staging System and immunoglobulin type did not correlate significantly with survival of the group. CONCLUSION: This set of cases from a tertiary public healthcare service reflect the approach of multiple myeloma in a predominantly young population with advanced clinical staging, with results comparable to those of the literature. PMID- 26760808 TI - Correlation between flow cytometry and histologic findings: ten year experience in the investigation of lymphoproliferative diseases. AB - OBJECTIVE: To demonstrate the advantages of correlating flow cytometry immunophenotyping with the pathology/ immunohistochemistry of lymph nodes or nodules in the diagnosis of lymphoproliferative diseases. METHODS: A retrospective study was carried out of 157 biopsy or fine-needle aspiration lymph nodes/ nodule specimens taken from 142 patients, from 1999 and 2009. The specimens were simultaneously studied with fow cytometry and pathology at Hospital Israelita Albert Einstein. The specimens were prepared in hematoxylin/eosin, Giemsa, or monoclonal antibody stained slides for detecting specific antibodies for the purposes of pathology/immunohistochemical analysis. The samples were hemolyzed and marked with different monoclonal antibody panels for different antigens in fow cytometry immunophenotyping. RESULTS: The diagnostic results of pathology/immunohistochemical studies and flow cytometry immunophenotyping agreed in 115 patients (81%), corresponding to 127 specimens, as follows according to the pathologic diagnosis: 63 patients with non-Hodgkin's B-cell lymphoma; 26 patients with reactive lymphoid hyperplasia; 5 patients with non-Hodgkin's T-cell lymphoma; 4 patients with atypical lymphoid proliferation; 5 patients with a chronic granulomatous inflammatory process; 5 patients with a non hematologic diagnosis; 2 patients with granulocytic sarcoma; 2 patients with thymoma; 1 patient with byphenotypic leukemia; 1 patient with kappa plasmocytoma; 1 patient with Hodgkin's lymphoma. Subtypes of lymphomas could be classified by associating the two techniques: 19 patients with follicular lymphoma; 15 patients with diffuse large B-cell lymphoma; 7 patients with small lymphocytic B-cell lymphoma/chronic lymphocytic leukemia; 3 patients with mantle cell lymphoma; 1 patient with Burkitt's lymphoma; 1 patient with MALT type lymphoma; 1 patient with post-transplant lymphoproliferative disease; 2 patients with high grade non Hodgkin's B-cell lymphoma; 1 patient with low grade non-Hodgkin's B-cell lymphoma not otherwise specified; 1 patient with Hodgkin's lymphoma; and 12 patients with B-cell non-Hodgkin's lymphoma not otherwise specified. CONCLUSION: Flow cytometry adds to the results of morphologic and immunohistochemical studies, facilitating a rapid and accurate diagnosis of lymphoproliferative diseases. PMID- 26760809 TI - Incidence of alloimunization in sickle cell disease: experience of a center in Sao Paulo. AB - OBJECTIVE: To identify the incidence of alloimmunization in sickle cell disease patients, as well as autoantibodies and the phenotypic profile of these patients for the following erythrocyte antigen groups: Rh, Kell, Kidd, Duffy and MNS. METHODS: fifty-seven patients were evaluated during follow-up at the Anemia Outpatient Clinic of Irmandade da Santa Casa de Sao Paulo, where a search for irregular antibodies and phenotyping was carried out. RESULTS: Patients' median alloimmunization age in sickle cell disease was 25 years, and irregular antibodies were found in 22.6% of them. Anti-Kell antibody was the most frequent (7.5%) followed by anti-C (5.7%). CONCLUSION: The prevalence of alloimmunization and of patients with autoantibodies among individuals with sickle cell disease followed at the Anemia Outpatient Clinic of Irmandade da Santa Casa de Misericordia de Sao de Paulo was determined. The risk of alloimmunization was higher in patients who received more than 3 red blood cell units in the past 2 years. The most prevalent alloantibodies were anti-Kell and anti-C. PMID- 26760810 TI - Iron overload in Brazilian thalassemic patients. AB - ABSTRACTObjectives:To evaluate the use of magnetic resonance imaging in patients with beta-thalassemia and to compare T2* magnetic resonance imaging results with serum ferritin levels and the redox active fraction of labile plasma iron. METHODS: We have retrospectively evaluated 115 chronically transfused patients (65 women). We tested serum ferritin with chemiluminescence, fraction of labile plasma iron by cellular fluorescence and used T2* MRI to assess iron content in the heart, liver, and pancreas. Hepatic iron concentration was determined in liver biopsies of 11 patients and the results were compared with liver T2* magnetic resonance imaging. RESULTS: The mean serum ferritin was 2,676.5 +/- 2,051.7 ng/mL. A fraction of labile plasma iron was abnormal (> 0,6 Units/mL) in 48/83 patients (57%). The mean liver T2* value was 3.91 +/- 3.95 ms, suggesting liver siderosis in most patients (92.1%). The mean myocardial T2* value was 24.96 +/- 14.17 ms and the incidence of cardiac siderosis (T2* < 20 ms) was 36%, of which 19% (22/115) were severe cases (T2* < 10 ms). The mean pancreas T2* value was 11.12 +/- 11.20 ms, and 83.5% of patients had pancreatic iron deposition (T2* < 21 ms). There was significant curvilinear and inverse correlation between liver T2* magnetic resonance imaging and hepatic iron concentration (r= -0.878; p < 0.001) and moderate correlation between pancreas and myocardial T2* MRI (r = 0.546; p < 0.0001). CONCLUSION: A high rate of hepatic, pancreatic and cardiac impairment by iron overload was demonstrated. Ferritin levels could not predict liver, heart or pancreas iron overload as measured by T2* magnetic resonance imaging. There was no correlation between liver, pancreas, liver and myocardial iron overload, neither between ferritin and fraction of labile plasma iron with liver, heart and pancreas T2* values. PMID- 26760811 TI - Prevalence of erythrocyte alloimmunization in polytransfused patients. AB - OBJECTIVE: To determine the incidence and the rate of red blood cell alloimmunization in polytransfused patients. METHODS: A polytransfused patient was defined as having received at least 6 units of red cell concentrates during a 3-month period. The records of all patients (n = 12,904) who had received red blood cell units were examined retrospectively by searching the computer database at Hospital Israelita Albert Einstein in Sao Paulo, Brazil, over a 6-year period, between 2003 and 2009. RESULTS: During this time, 77,049 red cell concentrate transfusions were performed in 12,904 patients. There were 3,044 polytransfused patients, 227 of whom (7.5%) presented with irregular erythrocyte antibodies. The prevalence of alloantibody specificity was: Anti-E>anti-D>anti-K>anti-C>anti Dia>anti-c>anti-Jka>anti-S in 227 polytransfused patients. We found combinations of alloantibodies in 79 patients (34.8%), and the most common specificities were against the Rh and/or Kell systems. These antibodies show clinical significance, as they can cause delayed hemolytic transfusion reactions and perinatal hemolytic disease. About 20% of the patients showed an IgG autoantibody isolated or combined with alloantibodies. Interestingly, a high incidence of antibodies against low frequency antigens was detected in this study, mainly anti-Dia. CONCLUSION: Polytransfused patients have a high probability of developing alloantibodies whether alone or combined with autoantibodies and antibodies against low frequency antigens. Transfusion of red blood cells with a phenotype compatible with RH (C, E, c), K, Fya, and Jka antigens is recommended for polytransfused patients in order to prevent alloimmunization and hemolytic transfusion reactions. PMID- 26760813 TI - Molecular and cytogenetic abnormalities in acute myeloid leukemia: review and case studies. AB - OBJECTIVE: To study the frequency of mutations that may lead to a good or bad prognosis, as well as their relation with the karyotype and immunophenotype in patients with acute myeloid leukemia. METHODS: Thirty samples of patients with acute myeloid leukemia were studied, in which FLT3-ITD, FLT3-TKD and NPM1 mutations were investigated. All samples were submitted to immunophenotyping and 25 to karyotyping. RESULTS: An occurrence of 33.3% NPM1 mutation and an equal number of FLT3-ITD mutation were observed. When only the cases with normal karyotype were studied, this figures increased to 50 and 40%, respectively. Eight percent of cases with normal karyotype and genotype NPM1+/FLT3- were included in the group of acute myeloid leukemia with good prognosis. The typical phenotype of acute myeloid leukemia with normal karyotype and mutated NPM1 (HLA-DR and CD34 negative) was not observed in this small series. CONCLUSION: Good prognosis cases were identified in this series, emphasizing the need to include new genetic markers in the diagnostic routine for the correct classification of acute myeloid leukemia, to more properly estimate prognosis and determine treatment. PMID- 26760814 TI - Use of gemtuzumab ozogamycin combined with conventional chemotherapy in patients with acute myeloid leukemia. AB - OBJECTIVE: To analyze the outcome of patients treated with gemtuzumab ozogamycin combined with conventional therapy treated at Hospital Israelita Albert Einstein. METHODS: 14 patients who had high risk features (secondary leukemia, unfavorable cytogenetics, and refractory disease) were treated with gemtuzumab ozogamycin combined with conventional therapy and their outcome was analysed by reviewing their medical records. RESULTS: Overall response rate was 58%, with 43% achieving complete response, with a median follow-up of 11 months, event-free survival was 3 months. Eleven patients died, 6 of them due to refractory acute myeloid leukemia. Only four patients presented with grade 3 to 4 toxicities and only one patient had sinusoidal obstruction syndrome after bone marrow transplant. CONCLUSION: gemtuzumab ozogamycin combined with chemotherapy is a feasible treatment regimen in acute myeloid leukemia patients. However, further studies are necessary to clarify which subgroup of patients may beneft from this treatment. PMID- 26760812 TI - Acute myeloid leukemia: update in diagnosis and treatment in Brazil. AB - OBJECTIVE: To identify how the Brazilian hematology centers treated and diagnosed cases of acute myeloid leukemia in 2009. METHODS: An epidemiological observational multicenter study of 11 listed Brazilian centers that treat acute myeloid leukemia and perform bone marrow transplantation. Data were collected from clinical charts of patients with acute myeloid leukemia treated at the said centers between 2005 and 2009. The availability for immunophenotyping and cytogenetic tests was assessed. RESULTS: During 2009, a total of 345 new cases of acute myeloid leukemia were diagnosed. Differences were noted in the tests performed between patients who initiated treatment at the center and those referred for treatment. Of the participating centers, 72% conducted some type of molecular study in acute myeloid leukemia upon diagnosis. CONCLUSION: Treatment for acute myeloid leukemia in Brazil shows significantly inferior results when compared to other centers worldwide. PMID- 26760815 TI - Factors affecting autologous peripheral blood hematopoietic stem cell collections by large-volume leukapheresis: a single center experience. AB - OBJECTIVE: To evaluate factors affecting peripheral blood hematopoietic stem cell yield in patients undergoing large-volume leukapheresis for autologous peripheral blood stem cell collection. METHODS: Data from 304 consecutive autologous peripheral blood stem cell donors mobilized with hematopoietic growth factor (usually G-CSF), associated or not with chemotherapy, at Hospital Israelita Albert Einstein between February 1999 and June 2010 were retrospectively analyzed. The objective was to obtain at least 2 * 106 CD34+ cells/kg of body weight. Pre-mobilization factors analyzed included patient's age, gender and diagnosis. Post mobilization parameters evaluated were pre-apheresis peripheral white blood cell count, immature circulating cell count, mononuclear cell count, peripheral blood CD34+ cell count, platelet count, and hemoglobin level. The effect of pre and post-mobilization factors on hematopoietic stem cell collection yield was investigated using logistic regression analysis (univariate and multivariate approaches). RESULTS: Pre-mobilization factors correlating to poor CD34 + cell yield in univariate analysis were acute myeloid leukemia (p = 0.017) and other hematological diseases (p = 0.023). Significant post-mobilization factors included peripheral blood immature circulating cells (p = 0.001), granulocytes (p = 0.002), hemoglobin level (p = 0.016), and CD34+ cell concentration (p < 0.001) in the first harvesting day. However, according to multivariate analysis, peripheral blood CD34+ cell content (p < 0.001) was the only independent factor that significantly correlated to poor hematopoietic stem cell yield. CONCLUSION: In this study, peripheral blood CD34+ cell concentration was the only factor significantly correlated to yield in patients submitted to for autologous collection. PMID- 26760816 TI - The influence of dental care associated with laser therapy on oral mucositis during allogeneic hematopoietic cell transplant: retrospective study. AB - OBJECTIVE: To verify decrease in frequency and severity of oral mucositis in patients submitted to dental care and laser therapy during allogeneic hematopoietic cell transplant. METHODS: Medical records of patients submitted or not to dental care associated with laser therapy during allogeneic transplant were reviewed. The following data were collected: sex, age, underlying disease, myeloablative conditioning regimens, prophylaxis for graft versus host disease, extension and severity of oral mucositis, pain in the oral cavity and when swallowing, diarrhea, need of peripheral parenteral nutrition and presence of acute graft versus host disease. RESULTS: Significant reduction in extension and severity of oral mucositis, as well as in frequency of oral cavity pain, was observed in patients with dental care/laser therapy (p < 0.01). There were no statistically significant differences regarding frequency of diarrhea, pain when swallowing, and need of parenteral nutrition among the groups. Significant association was found between acute graft versus host disease and pain when swallowing (p < 0.01). Acute graft versus host disease was not associated with oral mucositis severity, oral cavity pain, and diarrhea. CONCLUSION: Dental care associated with laser therapy reduces the extension and severity of oral mucositis in patients with allogeneic hematopoietic transplant. Further studies are necessary to clarify the isolate efficacy of laser therapy in these conditions, mainly regarding the influence of reduced oral mucositis on the graft versus host disease. PMID- 26760817 TI - Does the time between collecting and processing umbilical cord blood samples affect the quality of the sample? AB - OBJECTIVE: To assess the association between the time from umbilical cord blood collection until processing and the quality of the sample. METHODS: Umbilical cord blood samples collected during the third stage of labor were placed in temperature-controlled boxes for the transport of biological material and sent to an umbilical cord blood bank, where the number of nucleated cells, viable cells and CD34+ cells were counted, and samples were additionally tested for contamination at the following time intervals: up to 24 hours, up to 48 hours and up to 72 hours following sampling. Data were analyzed using the multivariate analysis of variance (MANOVA) and compared using McNemar's chi2 test. Significance was defined at p < 0.05. RESULTS: Means and medians of the number of nucleated cells, viable cells and CD34+ cells decreased significantly (p < 0.0001) as a function of the increased time between sampling and analysis, the difference between 24 and 48 hours being less than the difference between 24 and 72 hours. A linear correlation was found between the mean number of viable cells and CD34+ cells at the three moments of analysis. Contamination testing was negative in all samples. CONCLUSION: The increase in time interval from sampling until analysis negatively affected the number of nucleated cells, viable cells and CD34+ cells but was not associated with specimen contamination. A linear correlation was found between decrease in the number of viable cells and CD34+ cells. PMID- 26760818 TI - Livedoid vasculopathy: fast involution after anticoagulant and hyperbaric oxygen therapy. AB - The livedoid vasculopathy is a rare condition characterized by the presence of recurrent painful ulcers in distal extremities of lower limbs. Histologically there is thickness of dermal vessels, occlusion of its light by fibrin thrombi associated with minimal inflammatory infiltrate. It might occur as an isolated condition or be associated with an underlying systemic disease, including coagulation and collagen disorders, or neoplasms. Because it is a rare disease there is no consensus for its treatment. We report a case of a 41-year-old man with painful ulcers in the lower extremities. We did not find any associated diseases. The lesions improved dramatically after treatment with anticoagulant and hyperbaric therapy. We concluded that anticoagulation associated with hyperbaric oxygenation may be benefit for the treatment of patients with livedoid vasculopathy. However, further studies should be done with a larger population to confirm our results. PMID- 26760819 TI - Hodgkin's disease and pregnancy: case series and proposal for treatment protocol. AB - The peak frequency of Hodgkin's disease convergesmatches with women of reproductive fertility age. Currently, this disease is the fourth more diagnosed neoplasia during pregnancy. In addition, there is no consensus in the literature on how to treat pregnant women because of the risks of chemotherapy for mothers and for fetuses. We report three cases of pregnant women with Hodgkin's disease. A review of the literature was made aiming to suggest a protocol to treat these patients. PMID- 26760820 TI - Bilirubin encephalopathy due to Rh incompatibility. AB - The authors present the case of a newborn of an Rh-factorsensitized mother, who received early hospital discharge while icteric only to be readmitted at an Emergency Service at five days of age with signs of kernicterus. Despite treatment given, the neonate progressed with a clinical picture of bilirubin encephalopathy. The lack of interaction between the obstetric and neonatal teams, premature hospital discharge, and lack of concern of neonatologists with jaundice in a full-term infant are highlighted as causes of a condition that should have disappeared if there had been adequate prevention. PMID- 26760821 TI - Immunomodulatory effect of mesenchymal stem cells. AB - Mesenchymal stem cells represent an adult population of nonhematopoietic cells, which can differentiate into a variety of cell types such as osteocytes, chondrocytes, adipocytes, and myocytes. They display immunomodulatory properties that have led to the consideration of their use for the inhibition of immune responses. In this context, mesenchymal stem cells efficiently inhibit maturation, cytokine production, and the T cell stimulatory capacity of dendritic cells. They also can impair proliferation, cytokine secretion, and cytotoxic potential of T lymphocytes. Moreover, mesenchymal stem cells are able to inhibit the differentiation of B cells to plasma cells by inhibiting their capacity to produce antibodies. A variety of animal models confirm the immunomodulatory properties of mesenchymal stem cells. Clinical studies including patients with severe acute graft-versus-host disease have revealed that the administration of mesenchymal stem cells results in significant clinical responses. Therefore, mesenchymal stem cells improve acute graft-versus-host disease and represent a promising candidate for the prevention and treatment of immune-mediated diseases, due to their immunomodulatory capability and their low immunogenicity. PMID- 26760822 TI - Current management of severe acquired aplastic anemia. AB - Overall survival in severe aplastic anemia has markedly improved in the past four decades due to advances in stem cell transplantation, immunosuppressive therapies and supportive care. Horse anti-thymocyte globulin plus cyclosporine is the standard immunosuppressive regimen in severe aplastic anemia, and often employed as initial therapy as most are not candidates for a matched related stem cell transplantation. With this regimen, hematologic response can be achieved in 60 to 70% of cases, but relapse is observed in 30 to 40% of responders and clonal evolution in 10 to 15% of patients. Efforts to improve outcomes beyond horse anti thymocyte globulin plus cyclosporine have been disappointing, with no significant improvement in the critical parameter of hematologic response, which strongly correlates with long-term survival in severe aplastic anemia. Furthermore, rates of relapse and clonal evolution have also not improved with the development of three drug regimens or with more lymphocytotoxic therapies. Therefore, horse anti thymocyte globulin plus cyclosporine remains the standard immunosuppression of choice as first therapy in severe aplastic anemia. Interestingly, survival has markedly improved over the years in large part due to better anti-infective therapy and more successful salvage therapies with immunosuppression and stem cell transplantation. In this review general aspects of diagnosis and management are discussed. PMID- 26760823 TI - Chronic myeloid leukemia: past, present, future. AB - The discovery of the Philadelphia chromosome in 1960, and of the BCR-ABL oncogene in 1984, enabled the development in subsequent years of a targeted therapy that revolutionized the treatment of chronic myeloid leukemia, thus changing its natural history. The use of imatinib resulted in a significant improvement of the prognosis and outcome of patients with chronic myeloid leukemia. However, the occurrence of mechanisms of resistance or intolerance precludes the eradication of the disease in some of the patients. Second-generation tyrosine-kinase inhibitors are efficient in most of these patients, except for those with T315I mutation. We present an overall review of chronic myeloid leukemia, with emphasis on the progress in its treatment. PMID- 26760824 TI - From bone marrow transplantation to complex biological therapy. AB - The major complications after bone marrow transplant are related to opportunistic infections or to graft-versus-host disease. Today, there is a wealth of information associated with bone marrow transplantation and new treatment approaches have been proposed to overcome these complications. Behind these new therapies, such as adoptive transfer of T cells or mesenchymal stem cell infusions, there is significant basic research to support these clinical advances. Most of this knowledge has derived from the development of animal models and intense laboratory work to test and confirm hypotheses. There is no doubt that basic research is still necessary to better understand the basis for clinical outcome improvements. PMID- 26760825 TI - Megakaryocyte. PMID- 26760826 TI - Nomenclature for factors of the HLA system. AB - The Nomenclature Committee for Factors of the HLA System of the World Health Organization standardizes the nomenclature of the HLA system and meets regularly during the International Histocompatibility Workshops. During the 15th International Histocompatibility Workshop in Buzios (RJ), Brazil, in September 2008, there was a meeting of the nomenclature committee when new rules were established, which were implemented in April 2010. PMID- 26760829 TI - Do Adolescents With Higher Knowledge of HIV Have Lower Sexual Risk Behaviors? AB - OBJECTIVES: Human immunodeficiency virus (HIV) remains a leading cause of morbidity and mortality in the United States, and adolescents account for a disproportionate number of new cases. We aimed to assess knowledge of HIV in relation to sexual risk behaviors among adolescents seeking care in our pediatric emergency department and to assess sources of HIV knowledge among this population. METHODS: Adolescents aged 14 to 21 years who presented to the pediatric emergency department participated in a questionnaire assessing HIV knowledge, sexual risk behaviors, and sources of HIV knowledge. For purposes of statistical analysis, patients were divided into a high-score (greater than or equal to the median score) or low-score (less than the median score) group based on the HIV-Knowledge Questionnaire 18 portion of the survey. RESULTS: A total of 240 adolescents were enrolled. Of those, 112 patients scored higher than or equal to the median HIV-Knowledge Questionnaire 18 score of 11. High-scoring knowledge was independently associated with patients 18 years or older (P = 0.001), any lifetime sexual activity (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.30-3.67; P = 0.003), previous testing for HIV (OR, 2.40; 95% CI, 1.40-4.11; P = 0.002), and an "expert" source (school-based or medical professionals) as their primary source of knowledge (OR, 1.88; 95% CI, 1.05-3.41; P = 0.034). Age of first sexual encounter, number of partners, and condom use were not significantly associated with knowledge score. CONCLUSIONS: Education from "expert" sources is important in providing adolescents with accurate information. However, education alone is unlikely to change sexual practices. A more comprehensive approach to HIV prevention is needed to decrease HIV transmission among this patient population. PMID- 26760828 TI - Characteristics of Rib Fractures in Child Abuse-The Role of Low-Dose Chest Computed Tomography. AB - OBJECTIVES: Our aim is to describe the radiologic characteristics of rib fractures in clinically diagnosed cases of child abuse and suggest a complementary imaging for radiographically occult injuries in highly suspicious cases of child abuse. METHODS: Retrospective analysis of initial and follow-up skeletal surveys and computed tomography (CT) scans of 16 patients younger than 12 months were reviewed after obtaining approval from our institutional review board. The number, location, displacement, and age of the rib fractures were recorded. RESULTS: Out of a total 105 rib fractures, 84% (87/105) were detected on the initial skeletal survey. Seventeen percent (18/105) were seen only after follow-up imaging, more than half of which (11/18) were detected on a subsequent CT. Majority of the fractures were posterior (43%) and anterior (30%) in location. An overwhelming majority (96%) of the fractures are nondisplaced. CONCLUSIONS: Seventeen percent of rib fractures analyzed in the study were not documented on the initial skeletal survey. Majority of fractures are nondisplaced and located posteriorly or anteriorly, areas that are often difficult to assess especially in the acute stage. The CT scan is more sensitive in evaluating these types of fractures. Low-dose chest CT can be an important imaging modality for suspicious cases of child abuse when initial radiographic findings are inconclusive. PMID- 26760827 TI - Immune activation in the central nervous system throughout the course of HIV infection. AB - PURPOSE OF REVIEW: Robust and dynamic innate and adaptive responses characterize the acute central nervous system (CNS) response to HIV and other viral infections. In a state of chronic infection or viral latency, persistent immune activation associates with abnormality in the CNS. Understanding this process is critical, as immune-mediated abnormality in nonrenewable CNS cells may result in long-term neurologic sequelae for HIV-infected individuals. RECENT FINDINGS: In humans, immune activation is reduced by suppressive combination antiretroviral therapy, but persists at abnormally elevated levels on treatment. CNS immune activation is initiated in acute infection and progressively increases until combination antiretroviral therapy is started. Newly identified characteristics of the CNS immune surveillance network include features of homeostasis and function of brain microglial cells, lymphatic drainage from CNS to cervical lymph nodes, and cells in cerebrospinal fluid associated with neurocognitive impairment. SUMMARY: More research is required to determine whether early intervention to reduce infection limits the immunopathology established by sustained immune responses that ultimately fail to resolve infection, and to unravel mechanisms of persistent immune activation during treated HIV so that strategies can be developed to therapeutically protect the brain. PMID- 26760830 TI - Alcaligenes faecalis Cellulitis After a Dog Bite: Case Report and Literature Review. AB - Alcaligenes faecalis is a gram-negative organism that is commonly found in the environment and may also be a part of normal fecal flora in humans. Although various infections with this bacteria have been described in the pediatric population, it has not been previously identified in infections as the pathogen after a dog bite. A case of a 19-month-old boy is presented with a cellulitis secondary to a dog bite, which failed oral antibiotic therapy, and progressed to worsening fever and swelling. The patient ultimately required hospitalization, intravenous antibiotics, and incision and drainage. The wound culture grew A. faecalis, whose identity was confirmed through recombinant DNA sequence analysis. Although it has been identified in cat bite wounds, A. faecalis has not been cited in the literature before in an infection after a dog bite. PMID- 26760831 TI - Out-of-Hospital Cardiac Arrest in the Pediatric Population in Hong Kong: A 10 Year Review at a University Hospital. AB - AIM: To describe the epidemiology and outcomes of out-of-hospital cardiac arrest (OHCA) in a Hong Kong (HK) pediatric population and to identify factors associated with favorable outcomes. METHODS: Retrospective case note review of patients younger than 18 years who presented to the emergency department of Prince of Wales Hospital, HK with cardiac arrest from 2003 to 2013. Patients were classified as infants (<1 year), children (1-11 years) and adolescents (12-18 years). Patient characteristics, OHCA details, interventions, and outcomes were reported following the Utstein format. RESULTS: There were 53 patients in the study (77.4% men) and 34.6% of patients had chronic illnesses. In the infant group, 35.7% had complicated pregnancies. The incidence of OHCA in HK was 5.37 per 100,000 person-years. Out-of-hospital cardiac arrest was identified by bystanders in 62.3%, but bystander cardiopulmonary resuscitation was provided in only 28.3%. Shockable rhythms were uncommon (9.4%). Most OHCA in infants had unknown causes. In children, commonest causes were respiratory illness and environmental hazards, and in adolescents, trauma and cardiogenic events. Overall survival to hospital discharge rate was 20.8%; 13.2% had good neurological outcomes. Bystander cardiopulmonary resuscitation (odds ratio [OR], 7.44; 95% confidence interval [95% CI], 1.75-31.7; P = 0.007), prehospital return of spontaneous circulation (OR, 11.4; 95% CI, 1.75-74.7; P = 0.013), and return of spontaneous circulation within 30 minutes (OR, 90.0; 95% CI, 11.1-727; P < 0.0005) were associated with survival to discharge. CONCLUSIONS: The incidence of OHCA in HK is comparable to global data. The outcome of OHCA in the pediatric population has improved over the decades. Better prehospital care could improve outcome. PMID- 26760832 TI - A 10-year journey in sustaining fall reduction in an academic medical center in Singapore. AB - BACKGROUND: The incidence rate of falls at 1.3 falls/1000 patient-days at a tertiary hospital in 2004 was found to be high when benchmarked against other hospitals' fall rates in Singapore. This marked the starting point of a journey of reducing fall incidence by successfully combining evidence-based healthcare measures with quality-improvement strategies. AIM: The aim of this project was to implement fall-reduction strategies in the inpatient care areas in an acute care tertiary hospital. METHODS: Two action research studies commissioned for ascertaining an appropriate fall-risk assessment and effectiveness of targeted individualized interventions formed the foundation of fall-reduction strategies. Evidence-based healthcare measures were combined with quality-improvement strategies that addressed fall risks to prevent falls and mitigate injuries. The process of managing fall-related incidents was standardized as the fall rate continues to be a key nursing performance indicator. RESULTS: The overall fall trend decreased from 1.09/1000 patient-days in 2008 to 0.82/1000 patient-days in 2012. The decreasing trends were sustained in 2013 and 2014 at 0.91/100 and 0.85/1000, respectively. The fall injury rate reduced from 0.31/1000 patient-days in 2008 and was maintained at a rate of 0.20-0.24 during 2009-2012. CONCLUSION: The implementation of fall-reduction strategies reduced the fall incidence rate in this acute care setting. However, more work is required to ensure the changes made to the fall assessment, interventions, and processes are sustained and incorporated in patient care. PMID- 26760834 TI - Should Family Physicians Routinely Screen Patients for Hepatitis C? Yes: Screening Makes Sense for High-Risk Adults. PMID- 26760835 TI - Should Family Physicians Routinely Screen Patients for Hepatitis C? No: One-time Screening Still Has Too Many Unanswered Questions. PMID- 26760836 TI - Therapist-Supported Online Cognitive Behavior Therapy for Adult Anxiety. PMID- 26760837 TI - Home Visits for Pregnant Adolescents. PMID- 26760838 TI - Treatment of Adult Obesity with Bariatric Surgery. AB - In 2013, approximately 179,000 bariatric surgery procedures were performed in the United States, including the laparoscopic sleeve gastrectomy (42.1%), Roux-en-Y gastric bypass (34.2%), and laparoscopic adjustable gastric banding (14.0%). Choice of procedure depends on the medical conditions of the patient, patient preference, and expertise of the surgeon. On average, weight loss of 60% to 70% of excess body weight is achieved in the short term, and up to 50% at 10 years. Remission of type 2 diabetes mellitus occurs in 60% to 80% of patients two years after surgery and persists in about 30% of patients 15 years after Roux-en-Y gastric bypass. Other obesity-related comorbidities are greatly reduced, and health-related quality of life improves. The Roux-en-Y procedure carries an increased risk of malabsorption sequelae, which can be minimized with nutritional supplementation and surveillance. Overall, these procedures have a mortality risk of less than 0.5%. Cohort studies show that bariatric surgery reduces all-cause mortality by 30% to 50% at seven to 15 years postsurgery compared with patients with obesity who did not have surgery. Dietary changes, such as consuming protein first at every meal, and regular physical activity are critical for patient success after bariatric surgery. The family physician is well positioned to counsel patients about bariatric surgical options, the risks and benefits of surgery, and to provide long-term support and medical management postsurgery. PMID- 26760839 TI - Common Questions About the Evaluation of Acute Pelvic Pain. AB - Acute pelvic pain is defined as lower abdominal or pelvic pain of less than three months' duration. It is a common presentation in primary care. Evaluation can be challenging because of a broad differential diagnosis and because many associated signs and symptoms are nonspecific. The most common diagnoses in reproductive aged women with acute pelvic pain are idiopathic pelvic pain, pelvic inflammatory disease, acute appendicitis, ovarian cysts, ectopic pregnancy, and endometriosis. Among postmenopausal women, cancer must be considered. Findings from the history and physical examination can point to likely diagnoses, and laboratory testing and imaging can help confirm. Women of reproductive age should take a pregnancy test. In early pregnancy, transvaginal ultrasonography and beta human chorionic gonadotropin levels can help identify ectopic pregnancy and spontaneous abortion. For nonpregnant women, ultrasonography or computed tomography is indicated, depending on the possible diagnosis (e.g., ultrasonography is preferred when ovarian pathology is suspected). If ultrasonography results are nondiagnostic, magnetic resonance imaging can be helpful in pregnant women when acute appendicitis is suspected. If magnetic resonance imaging is unavailable, computed tomography may be indicated. PMID- 26760840 TI - Somatic Symptom Disorder. AB - With the release of the Diagnostic and Statistical Manual of Mental Disorders, 5th ed., the diagnostic category previously known as somatoform disorders is now called somatic symptom and related disorders. The revisions were intended to increase their relevance in the primary care setting. The main feature of this disorder is a patient's concern with physical symptoms that he or she attributes to a nonpsychiatric disease. Primary care physicians often treat patients who manifest symptoms for which there are no biologic cause, and patients with somatic symptom disorder may be subjected to unnecessary testing and procedures. As a result, appropriate diagnosis is essential. Screening instruments are useful in determining the presence of somatic symptom disorder. It is important for the primary care physician to schedule regular appointments, establish a strong therapeutic alliance, acknowledge and legitimize the patient's symptoms, and limit diagnostic testing or referrals to subspecialists. Proven treatments include cognitive behavior therapy, mindfulness-based therapy, and pharmacotherapy. The use of selective serotonin reuptake inhibitors or tricyclic antidepressants has been effective in alleviating symptoms. Referral to a mental health professional may be necessary when treatment by the primary care physician is ineffective. PMID- 26760841 TI - Making Lifestyle Changes After Gastric Bypass. PMID- 26760843 TI - More Nuanced Guidelines for Lipid Lowering to Prevent CVD. PMID- 26760842 TI - Skin Ulcers of Unknown Etiology. PMID- 26760844 TI - Routine CT Scans for Occult Malignancy Not Useful in Patients with Unprovoked VTE. PMID- 26760845 TI - CBT Effective for Chronic Insomnia. PMID- 26760846 TI - Early Peanut Introduction and Prevention of Peanut Allergy in High-Risk Infants: Consensus Communication. PMID- 26760847 TI - Weight Loss Surgery. PMID- 26760848 TI - Thyroid nodules with minimal cystic changes have a low risk of malignancy. AB - PURPOSE: The goal of this study was to determine the risk of malignancy of thyroid nodules with minimal cystic changes. METHODS: A total of consecutive 1,000 thyroid nodules (>=1 cm) with final diagnoses from twoinstitutions were included in this study. The risk of malignancy of thyroid nodules was analyzed according to the internal content, which was categorized as purely solid, minimally cystic (cystic changes <=10%), and partially cystic (cystic changes >10%). We also assessed the risk of malignancy of nodules with minimal cystic changes depending on echogenicity and presence of any suspicious ultrasonografic (US) features. RESULTS: The overall frequency of purely solid, minimally cystic, and partially cystic noduleswas 730/1,000 (73%), 61/1,000 (6.1%), and 209/1,000 (20.9%), respectively, with risks ofmalignancy of 14.8% (108/730), 3.3% (2/61), and 3.3% (7/209), respectively. The risk ofmalignancy of nodules with minimal cystic changes was significantly lower than that of purelysolid nodules (P=0.013). The risk of malignancy of nodules with minimal cystic changes was also lower than that of purely solid nodules in the group of hypoechoic nodules (P=0.063) and in the group of nodules with suspicious US features (P=0.028), but was not significantly different from that of partially cystic nodules regardless of echogenicity or the presence of suspicious US features (P>=0.652). CONCLUSION: Thyroid nodules with minimal cystic changes have a low risk of malignancy, similar to that of partially cystic nodules regardless of echogenicity or the presence of suspicious US features. The US lexicon could define solid nodules as nodules with purely solid internal content in order to enhance the accuracy of estimated risks of malignancy. PMID- 26760849 TI - A Novel Variant in the HINT1 Gene in a Girl with Autosomal Recessive Axonal Neuropathy with Neuromyotonia: Thorough Neurological Examination Gives the Clue. AB - We report a girl with autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM) who presented with asymmetric gait impairment, foot drop, and action myotonia on fast handgrip. Electrophysiological studies showed symmetrical axonal motor greater than sensory neuropathy, and neuromyotonic discharges on needle electromyography. ARAN-NM was confirmed by molecular genetic testing, which revealed a novel homozygous missense variant c.100G > A [p.(Glu34Lys)] in HINT1. This case shows that the diagnosis of ARAN-NM, as a new entity, has to be considered in the differential diagnosis of polyneuropathy in combination with neuromyotonia/action myotonia in children, even with asymmetric clinical presentation. PMID- 26760896 TI - Reversibly Stretchable, Optically Transparent Radio-Frequency Antennas Based on Wavy Ag Nanowire Networks. AB - We report a facile approach for producing reversibly stretchable, optically transparent radio-frequency antennas based on wavy Ag nanowire (NW) networks. The wavy configuration of Ag NWs is obtained by floating the NW networks on the surface of water, followed by compression. Stretchable antennas are prepared by transferring the compressed NW networks onto elastomeric substrates. The resulting antennas show excellent performance under mechanical deformation due to the wavy configuration, which allows the release of stress applied to the NWs and an increase in the contact area between NWs. The antennas formed from the wavy NW networks exhibit a smaller return loss and a higher radiation efficiency when strained than the antennas formed from the straight NW networks, as well as an improved stability in cyclic deformation tests. Moreover, the wavy NW antennas require a relatively small quantity of NWs, which leads to low production costs and provides an optical transparency. These results demonstrate the potential of these wavy Ag NW antennas in applications of wireless communications for wearable systems. PMID- 26760898 TI - Fully Atomistic Simulations of Protein Unfolding in Low Speed Atomic Force Microscope and Force Clamp Experiments with the Help of Boxed Molecular Dynamics. AB - The results of boxed dynamics (BXD) fully atomistic simulations of protein unfolding by atomic force microscopy (AFM) in both force clamp (FC) and velocity clamp (VC) modes are reported. In AFM experiments the unfolding occurs on a time scale which is too long for standard atomistic molecular dynamics (MD) simulations, which are usually performed with the addition of forces which exceed those of experiment by many orders of magnitude. BXD can reach the time scale of slow unfolding and sample the very high free energy unfolding pathway, reproducing the experimental dependence of pulling force against extension and extension against time. Calculations show the presence of the pulling force "humps" previously observed in the VC AFM experiments and allow the identification of intermediate protein conformations responsible for them. Fully atomistic BXD simulations can estimate the rate of unfolding in the FC experiments up to the time scale of seconds. PMID- 26760897 TI - Assessing the Fatty Acid, Carotenoid, and Tocopherol Compositions of Amaranth and Quinoa Seeds Grown in Ontario and Their Overall Contribution to Nutritional Quality. AB - Various fatty acids, tocopherols, carotenoids, and their respective antioxidant contributions in 7 amaranth seed and 11 quinoa seed samples along with a new evaluation method are reported. The lipid yield was 6.98-7.22% in amaranth seeds and 6.03-6.74% in quinoa seeds, with unsaturated fatty acids (UFAs) being the predominant fatty acids, 71.58-72.44% in amaranth seeds and 81.44-84.49% in quinoa seeds, respectively. Carotenoids, mainly lutein and zeaxanthin, are confirmed for the first time in amaranth seeds, while beta-carotene is reported first in quinoa seeds. The predominant tocopherols in amaranth seeds are delta- and alpha-tocopherol, whereas gamma- and alpha-tocopherol are the primary tocopherols in quinoa seeds. UFAs, carotenoids, and tocopherols showed good correlation with antioxidant activity. All of the amaranth seeds demonstrated lower overall lipophilic quality than quinoa seeds, with the AS1 and QS10 cultivars providing the highest scores for amaranth and quinoa seeds, respectively. Results from this study will contribute to developing quinoa seeds and related functional foods with increased benefits. PMID- 26760899 TI - Chemistry of Ketene N,S-Acetals: An Overview. AB - Push-pull alkenes, which bear electron-donating and -accepting group(s) at both termini of a C?C double bond, respectively, are of interest not only for their unique electronic properties but also for their importance as versatile building blocks in organic synthesis. In the world of ketene acetals having the push-pull alkene skeleton, ketene N,S-acetal is most likely the biggest family according to the number and types of these compounds. The first ketene N,S-acetal compound was reported in 1956. As a cyclic ketene N,S-acetal compound, nithiazine, the first lead structure of neonicotinoid insecticides, was reported in 1978. The characteristics of ketene N,S-acetals, which have the structural feature of ketene S,S-acetals and enaminones, make them versatile and easy to use, especially in cyclization and multicomponent reactions for the synthesis of various heterocyclic systems and related natural products. There has been an increasing wealth of information about the synthesis and synthetic applications of ketene N,S-acetals, especially, in recent years. This review provides comprehensive knowledge on the chemistry of ketene N,S-acetals. PMID- 26760901 TI - Correction to Full Electron Ligand-to-Ligand Charge Transfer in a Compact Rhenium(I) Complex. PMID- 26760900 TI - The COP9 signalosome coerces autophagy and the ubiquitin-proteasome system to police the heart. AB - We demonstrated for the first time that the COP9 signalosome (COPS) controls the degradation of a surrogate and a bona fide misfolded protein in the cytosol of cardiomyocytes likely via supporting ubiquitination by CUL/cullin-RING ligases, and that Cops8 hypomorphism exacerbates cardiac proteinopathy in mice, in which autophagic impairment appears to be in play. It will be extremely imprtant to investigate cardiac ablation of another Cops gene to decipher whether COPS8 deficiency phenotypes are attributable to the COPS or unique to COPS8. PMID- 26760907 TI - Development of an analytical method for simultaneous detection of psychotropic phenylalkylamines in hair by LC-MS/MS with a multi-mode reversed-phase column using pH gradient elution. AB - Phenylalkylamine derivatives, such as methamphetamine (MA), 3,4 methylenedioxymethamphetamine (MDMA), phentermine, fenfluramine, phendimetrazine, amfepramone, and ketamine, are widely abused recreational or anorectic drugs in Korea, and their abuse has become a serious social problem. Hair is a useful specimen to prove chronic use and liquid chromatography-tandem mass spectrometry (LC-MS/MS) has recently become a more popular tool for hair analysis due to sensitivity and simplicity in sample preparation. In order to overcome limitations of standard reversed-phase column to separate low molecular weight amines, we adopted a multi-mode reversed-phase column, Scherzo SS-C18, which was composed of strong ionic ligands and C18 ligands, and used pH gradient elution to separate seven psychotropic phenylalkylamines and their metabolites. The essential validation parameters including selectivity, LOD, LLOQ, linearity, intra- and inter-assay precision and accuracy, recovery, and the matrix effect were satisfactory. The LODs ranged from 0.1ng/5mg hair (diethylnorephedrine, fenfluramine, ketamine, and MA) to 0.5ng/5mg hair (amfepramone, MDA, phendimetrazine, and phentermine). The LLOQs were 1ng/5mg hair for all analytes. The developed method was successfully applied to determination of phenylalkylamines in authentic hair samples analyzed previously by a routine gas chromatography/mass spectrometry (GC-MS) method. A good correlation was observed between the two methods, with a slope near one. PMID- 26760908 TI - Molecular identification and phylogenetic analysis of the forensically important family Piophilidae (Diptera) from different European locations. AB - Species identification plays an important role in forensic entomology and is mandatory for an accurate calculation of the minimum post-mortem interval. Many important Diptera and Coleoptera taxa of the cadaver community can already be identified by common barcoding approaches, i.e., by sequencing a 658bp region in the mitochondrial cytochrome c oxidase subunit I (coI) gene. Nevertheless, there is still a lack of reference barcodes for species, in particular, that can be found on cadavers at later decomposition stages. Flies of the family Piophilidae illustrate this gap of knowledge perfectly. Due to the fact that a reliable morphological identification key for the immature stages of this flies is still missing and the immature stages of many piophilids cannot be assigned to a certain species, there is need for additional tools to identify forensically relevant taxa. We collected adult piophilid specimens at 10 locations in five European countries: Spain (n=3 locations), Germany (n=3), Portugal (n=2), Poland (n=1) and Switzerland (n=1). Apart from the coI barcoding region, we additionally analyzed a 398bp long region of the nuclear elongation factor 1 alpha (ef1a) and subsequently established the molecular identifier for nine piophilid species. In addition, we present the molecular phylogeny of the examined taxa. PMID- 26760909 TI - Multifunctional Fe3O4@SiO2-Au Satellite Structured SERS Probe for Charge Selective Detection of Food Dyes. AB - Nanofabrication of multifunctional surface-enhanced Raman scattering (SERS) substrates is strongly desirable but currently remains a challenge. The motivation of this study was to design such a substrate, a versatile core satellite Fe3O4@SiO2-Au (FA) hetero-nanostructure, and demonstrate its use for charge-selective detection of food dye molecules as an exemplary application. Our experimental results and three-dimensional finite difference time domain (FDTD) simulation suggest that tuning the Au nanoparticle (NP) gap to sub-10 nm, which could be readily accomplished, substantially enhanced the Raman signals. Further layer-by-layer deposition of a charged polyelectrolyte on this magnetic SERS substrate induced active adsorption and selective detection of food dye molecules of opposite charge on the substrates. Molecular dynamics (MD) simulations suggest that the selective SERS enhancement could be attributed to the high affinity and close contact (within a 20 A range) between the substrate and molecules. Density function theory (DFT) calculations confirm the charge transfer from food dye molecules to Au NPs via the polyelectrolytes. This multifunctional SERS platform provides easy separation and selective detection of charged molecules from complex chemical mixtures. PMID- 26760910 TI - Continuous Tempering Molecular Dynamics: A Deterministic Approach to Simulated Tempering. AB - Continuous tempering molecular dynamics (CTMD) generalizes simulated tempering (ST) to a continuous temperature space. Opposed to ST the CTMD equations of motion are fully deterministic and feature a conserved quantity that can be used to validate the simulation. Three variants of CTMD are discussed and compared by means of a simple test system. The implementation features of the most stable and simplest variant CTMD-U in the program package Iphigenie are described. Two applications--alanine dipeptide (Ac-Ala-NHMe) in explicit water and octa-alanine (Ac-(Ala)8-NHMe) simulated in a dielectric continuum--demonstrate the functionality of CTMD-U. Furthermore, they serve to evaluate its sampling efficiency. Here, CTMD-U outperforms ST by 35% and replica exchange even by 75%. PMID- 26760913 TI - Adiponectin Single Nucleotide Polymorphisms and Serum Levels Are Relevant to Prognosis of Patients With Aneurysmal Subarachnoid Hemorrhages. AB - To investigate the association of adiponectin gene polymorphisms and its levels with aneurysmal subarachnoid hemorrhages (aSAHs) prognosis. This case-control study enrolled 138 patients with aSAH and 102 healthy controls as case group and control group, respectively. Prognosis of case group was evaluated using Glasgow Outcome Scale. Polymerase chain reaction-restriction fragment length polymorphism was used to examine the genotypes of 45T>G and -11377C>G. Enzyme-linked immunosorbent assay was used to detect adiponectin levels. Logistic regression analysis was applied to assess the association of adiponectin gene polymorphism with aSAH prognosis. Case group had increased GG genotype and G allele genotype frequencies of 45T>G and -11377C>G compared with control group (all P < 0.01). In case group, TT genotype had the highest adiponectin level compared with both TG and GC genotypes (both P < 0.05). As for -11377C>G, GG genotype had the lowest adiponectin levels, followed by CG genotype and CC genotype in both groups (P < 0.05). In general, case group had decreased adiponectin levels compared with control group (P < 0.05). Univariate analysis showed that hypertension, Hunt-Hess grade, aneurysm size, aneurysms multiplicity and -11377C>G were associated with aSAH prognosis, while multivariate logistic regression analysis confirmed that hypertension, Hunt-Hess grade, residual flow in aneurysms and aneurysm size were independent risk factors for aSAH prognosis. Decreased adiponectin levels may be a pathological index for aSAH, which may be explain by the G allele of -11377C>G in adiponectin. Moreover, hypertension, Hunt-Hess grade, residual flow in aneurysms and aneurysm size may be independent risk factors for aSAH prognosis. PMID- 26760911 TI - Cellular and subcellular oxidative stress parameters following severe spinal cord injury. AB - The present study undertook a comprehensive assessment of the acute biochemical oxidative stress parameters in both cellular and, notably, mitochondrial isolates following severe upper lumbar contusion spinal cord injury (SCI) in adult female Sprague Dawley rats. At 24h post-injury, spinal cord tissue homogenate and mitochondrial fractions were isolated concurrently and assessed for glutathione (GSH) content and production of nitric oxide (NO(*)), in addition to the presence of oxidative stress markers 3-nitrotyrosine (3-NT), protein carbonyl (PC), 4 hydroxynonenal (4-HNE) and lipid peroxidation (LPO). Moreover, we assessed production of superoxide (O2(*-)) and hydrogen peroxide (H2O2) in mitochondrial fractions. Quantitative biochemical analyses showed that compared to sham, SCI significantly lowered GSH content accompanied by increased NO(*) production in both cellular and mitochondrial fractions. SCI also resulted in increased O2(*-) and H2O2 levels in mitochondrial fractions. Western blot analysis further showed that reactive oxygen/nitrogen species (ROS/RNS) mediated PC and 3-NT production were significantly higher in both fractions after SCI. Conversely, neither 4-HNE levels nor LPO formation were increased at 24h after injury in either tissue homogenate or mitochondrial fractions. These results indicate that by 24h post injury ROS-induced protein oxidation is more prominent compared to lipid oxidation, indicating a critical temporal distinction in secondary pathophysiology that is critical in designing therapeutic approaches to mitigate consequences of oxidative stress. PMID- 26760915 TI - Non-Precious-Metal Catalytic Systems Involving Iron or Cobalt Carboxylates and Alkyl Isocyanides for Hydrosilylation of Alkenes with Hydrosiloxanes. AB - A mixture of an iron or a cobalt carboxylate and an isocyanide ligand catalyzed the hydrosilylation of alkenes with hydrosiloxanes with high efficiency (TON >10(3)) and high selectivity. The Fe catalyst showed excellent activity for hydrosilylation of styrene derivatives, whereas the Co catalyst was widely effective in reaction of alkenes. Both of them catalyzed the reaction with allylic ethers. Chemical modification and cross-linking of silicones were achieved by choosing the right catalyst and reaction conditions. PMID- 26760914 TI - An evaluation of extraction techniques for arsenic in staple diets (fish and rice) utilising both classical and enzymatic extraction methods. AB - Enzymatic extraction methods were evaluated with classical extraction approaches for the determination of arsenic in food. The extraction efficiency for total arsenic was determined by analysing CRM materials DORM-3 fish protein, NIES 106 rice flour and GBW10015 spinach. These were compared with total arsenic concentration determined using microwave-assisted acid digestion and ICP-MS. The total arsenic concentrations in the CRM materials were in good agreement with the certified values. Enzymatic hydrolysis using trypsin has been successfully employed to extract arsenic species in DORM-3 and fish samples. Whilst this method of hydrolysing the proteins worked well for the fish samples, an alternative approach was required to facilitate the digestion of cellulose in plant materials. However, enzymatic extraction using cellulase was found to give unsatisfactory results for both the NIES and GBW10015 CRM materials. Dilute nitric acid (1% HNO3) was found to give a more efficient extraction for arsenic species in the same CRM materials and rice samples. The study was extended to evaluate a range of real samples. Total arsenic concentrations in 13 different types of fish tissue were determined following microwave-assisted acid digestion using nitric acid/hydrogen peroxide, followed by measurement using HPLC-ICP-MS for speciation analysis. The results obtained for fish were in the range of 3.53 98.80 ug g(-1) As (dry weight). Similarly, the results of 17 rice samples were in the range of 0.054-0.823 ug g(-1). This study demonstrates the importance of selecting an appropriate extraction technique for the quantitative measurement of arsenic species in food. PMID- 26760917 TI - Construct Validity and Construct Similarity: Methods for Use in Test Development and Test Validation. AB - A procedure is suggested for test development and construct validation based on a theory about the criterion performance. The procedure involves building a criterion test and testing its fit to the theory by experimental or correlational methods, and assessing the construct validity of the desired operational test in terms of its similarity to the criterion test. The method is illustrated by describing a study concerned with the selection of medical school students, where the criterion is a measure of clinical problem-solving ability. PMID- 26760916 TI - Pd-Catalyzed Hydroborylation of Alkynes: A Ligand Controlled Regioselectivity Switch for the Synthesis of alpha- or beta-Vinylboronates. AB - A ligand controlled selective hydroborylation of alkynes to alpha- or beta vinylboronates has been developed using a Pd catalyst. The high alpha-selectivity displayed by this reaction can be switched to furnish beta-vinylboronates by altering the ligand from a trialkylphosphine to N-heterocyclic carbene. A variety of terminal alkynes are shown to furnish the corresponding alpha- or beta vinylboronates in good to excellent selectivity and yield. The mechanistic studies suggest that the solvent is the proton source and bromobenzene functions as an important additive in driving this reaction forward. PMID- 26760912 TI - The thioredoxin system in breast cancer cell invasion and migration. AB - Metastasis is the most life threatening aspect of breast cancer. It is a multi step process involving invasion and migration of primary tumor cells with a subsequent colonization of these cells at a secondary location. The aim of the present study was to investigate the role of thioredoxin (Trx1) in the invasion and migration of breast cancer cells and to assess the strength of the association between high levels of Trx1 and thioredoxin reductase (TrxR1) expression with breast cancer patient survival. Our results indicate that the expression of both Trx1 and TrxR1 are statistically significantly increased in breast cancer patient cells compared with paired normal breast tissue from the same patient. Over-expression of Trx1 in MDA-MB-231 breast cancer cell lines enhanced cell invasion in in vitro assays while expression of a redox inactive mutant form of Trx1 (designated 1SS) or the antisense mRNA inhibited cell invasion. Addition of exogenous Trx1 also enhanced cell invasion, while addition of a specific monoclonal antibody that inhibits Trx1 redox function decreased cell invasion. Over-expression of intracellular Trx1 did not increase cell migration but expression of intracellular 1SS inhibited migration. Addition of exogenous Trx1 enhanced cell migration while 1SS had no effect. Treatment with auranofin inhibited TrxR activity, cell migration and clonogenic activity of MDA MB-231 cells, while increasing reactive oxygen species (ROS) levels. Analysis of 25 independent cohorts with 5910 patients showed that Trx1 and TrxR1 were both associated with a poor patient prognosis in terms of overall survival, distant metastasis free survival and disease free survival. Therefore, targeting the Trx system with auranofin or other specific inhibitors may provide improved breast cancer patient outcomes through inhibition of cancer invasion and migration. PMID- 26760918 TI - Some Relationships Between Descriptive Comparisons of Components from Different Studies. AB - This paper considers descriptive methods of comparing components from different studies, based on correlations between columns of component scores matrices, on congruence coefficients between columns of pattern, structure or component scores coefficient matrices, or on coefficients of invariance. Contrary to common belief, it is shown that coefficients of invariance are unrelated to correlations between component scores. On the other hand, having a perfect coefficient of invariance is shown to be equivalent to having a perfect congruence between corresponding columns of the component scores coefficient matrices. A similar but weaker relationship between the latter congruence and congruence between columns of pattern matrices is demonstrated. PMID- 26760919 TI - Rotation to Perfect Congruence and the Cross Validation of Component Weights Across Populations. AB - This paper deals with strategies of congruence studies, aimed at evaluating recoverableness of a given set of components from a first population in a second population where the same variables have been used. Five decisions inherent to congruence studies are analysed in detail. Confirmatory evidence with respect to recoverableness can be obtained from an independent component analysis for the second population, parallel to that of the first population. Disconfirmatory evidence requires oblique rotation to perfect congruence, which can always be attained. Rotation to perfect congruence is advocated as a new strategy, in which amounts of variance explained are of major concern. The perfect congruence strategy can be applied to variable-component correlations and to weights. The latter approach is to be preferred for two reasons. First, rotating weights to perfect congruence can be easily understood as a cross-validation method, closely related to the well-known multiple group method. Second, this approach appears to give more satisfactory results in practical applications than are obtained from rotating variable-component correlations to perfect congruence. PMID- 26760920 TI - Age-Related Changes in Auditory Abilities and in a Competing Task. AB - This study explores the relationship between age and performance on auditory tasks. The primary auditory factors which define broad auditory functions (Ga) show a clear decline with age. This finding supports a claim that Ga is an independent function, separate from crystallized intelligence (Gc). This study also explores the assumption, derived from several theories about the causes of intellectual decline, that competing (dual) tasks would show greater decline in performance than single tests. Present data do not provide evidence to support this assumption. PMID- 26760921 TI - Contrasting Alternatives to Least Squares in Regression Using Diagnostics for Identifying Influential Data. AB - The implicit assumptions associated with several alternative methods for estimating regression coefficients are identified using the regression diagnostic measures of leverage and influence. A formulation of these measures for use with the Ridge, Stein, principal component and equal weight estimators is presented and then used to contrast competing assumptions. Based on the implicit priors, situations are denoted where each of the alternatives can be expected to perform best. PMID- 26760922 TI - The Structure of the Clinical Analysis Questionnaire and Depression Symptomatology. AB - The purpose of this study was to assess the conceptual distinctions among seven depression factors contained in the Clinical Analysis Questionnaire. This assessment was done by factor analyzing a representative pool of 62 items from existing depression measures and 56 CAQ subscale marker variables. The results showed that the majority of the 28 CAQ factors as defined by the marker variables can be sustained following procedures used previously by Cattell. However, the results pertaining to the depression factors indicate that revisions of the CAQ at the item level appear necessary for distinguishing the CAQ depression scales. PMID- 26760923 TI - Neutral Responses to Structured Questionnaires within Organizational Settings: Roles of Rater Affective Feelings and Demographic Characteristics. AB - This study is a follow-up to a prior publication by the authors dealing with influences behind neutral responses to structured questionnaires. The earlier study found rater affective feelings, nationality, and age to be significant influences, while sex was not. The questionnaire used in the first study dealt primarily with supervision and relied on a three-point scale. The present instrument covers a broader range of topics and uses a five-point Likert-type scale. The results on the influence of rater affective feelings are consistent with previous studies, but there is some variation in the demographic influences. Implications of the findings are discussed and suggestions are offered for additional research. PMID- 26760924 TI - Drug-related pneumonitis during mammalian target of rapamycin inhibitor therapy in patients with neuroendocrine tumors: a radiographic pattern-based approach. AB - PURPOSE: The purpose of this study was to investigate the incidence of drug related pneumonitis during mammalian target of rapamycin (mTOR) inhibitor therapy in patients with neuroendocrine tumours (NET) and characterise radiographic patterns of pneumonitis. METHODS: Sixty-six patients (39 males, 27 females, age: 22-79 years) with advanced NET treated with mTOR inhibitor, everolimus, were retrospectively studied. Chest computed tomography scans during therapy were reviewed for abnormalities suspicious for drug-related pneumonitis by an independent review of two radiologists. Extent, distributions, and specific findings were evaluated in cases positive for pneumonitis. Radiographic patterns of pneumonitis were classified using the American Thoracic Society/European Respiratory Society classification of interstitial pneumonia. RESULTS: Drug related pneumonitis was radiographically detected in 14 patients (21%). Time from the initiation of therapy to pneumonitis was within 6 months of therapy in 10 patients (71%), while it ranged from 1.0 to 27.7 months. Pneumonitis was more common in patients who had never smoked (p=0.03). Lower lungs were more extensively involved than upper and middle lungs. Peripheral and lower distributions were most common (n=8), followed by peripheral and multifocal distributions (n=3). Ground glass and reticular opacities were present in all cases, with consolidation in eight cases. The radiographic pattern of pneumonitis was classified as cryptogenic organising pneumonia (COP) pattern in eight patients, non-specific interstitial pneumonia (NSIP) pattern in five, and hypersensitivity pneumonitis pattern in one patient. CONCLUSION: Drug-related pneumonitis was noted in 21% of the advanced NET patients treated with everolimus. Radiographic pattern of pneumonitis was most commonly COP pattern, followed by NSIP pattern. PMID- 26760926 TI - Bilateral fracture of the superior articular process of S1 - An unusual fracture seen in a speed skater. AB - Background Fractures of the superior articular process are rarely seen in clinical practice. Repetitive spinal movements may lead to fractures of the pars interarticularis, resulting in spondylolysis. Traumatic spinal fractures often involve the vertebral body, transvers and/or the spinous processes. The superior articular processes, however, are seldom involved in both traumatic and stress induced fractures. Purpose The purpose of this report is to present an unusual case of symptomatic bilateral fracture of the superior articular process of the sacrum in a 21-year-old speed skater. Study design This is a case report. Methods The patient was admitted for close observation after complaining of excruciating lower back pain and bilateral dysesthesia along the L5 nerve root. Post myelography computed tomography (CT) revealed a bilateral facet joint deformity at L5/S1 and a bilateral fracture of the superior articular process of the sacrum. A facet joint block at the L5/S1 joint alleviated the pain, and a nerve root block at the L5 nerve root improved the dysesthesia. The patient underwent an L5/S1 decompression, whereby the nonunion bone fragments were removed, followed by a posterior lumbar inter-body fusion (PLIF) at L5/S1. Results The patient showed immediate improvement and returned to training six months post operatively. Conclusion We have presented a case of bilateral fractures of the superior articular process of the sacrum in a speed skater. His presenting symptoms were similar to those found in patients with spondylolysis and the etiology appears to be similar. Surgical treatment was opted given his symptomatic relief from nerve root and facet joint blocks. PMID- 26760925 TI - Delayed Microvascular Shear Adaptation in Pulmonary Arterial Hypertension. Role of Platelet Endothelial Cell Adhesion Molecule-1 Cleavage. AB - RATIONALE: Altered pulmonary hemodynamics and fluid flow-induced high shear stress (HSS) are characteristic hallmarks in the pathogenesis of pulmonary arterial hypertension (PAH). However, the contribution of HSS to cellular and vascular alterations in PAH is unclear. OBJECTIVES: We hypothesize that failing shear adaptation is an essential part of the endothelial dysfunction in all forms of PAH and tested whether microvascular endothelial cells (MVECs) or pulmonary arterial endothelial cells (PAECs) from lungs of patients with PAH adapt to HSS and if the shear defect partakes in vascular remodeling in vivo. METHODS: PAH MVEC (n = 7) and PAH PAEC (n = 3) morphology, function, protein, and gene expressions were compared with control MVEC (n = 8) under static culture conditions and after 24, 72, and 120 hours of HSS. MEASUREMENTS AND MAIN RESULTS: PAH MVEC showed a significantly delayed morphological shear adaptation (P = 0.03) and evidence of cell injury at sites of nonuniform shear profiles that are critical loci for vascular remodeling in PAH. In clear contrast, PAEC isolated from the same PAH lungs showed no impairments. PAH MVEC gene expression and transcriptional shear activation were not altered but showed significant decreased protein levels (P = 0.02) and disturbed interendothelial localization of the shear sensor platelet endothelial cell adhesion molecule-1 (PECAM-1). The decreased PECAM-1 levels were caused by caspase-mediated cytoplasmic cleavage but not increased cell apoptosis. Caspase blockade stabilized PECAM-1 levels, restored endothelial shear responsiveness in vitro, and attenuated occlusive vascular remodeling in chronically hypoxic Sugen5416-treated rats modeling severe PAH. CONCLUSIONS: Delayed shear adaptation, which promotes shear-induced endothelial injury, is a newly identified dysfunction specific to the microvascular endothelium in PAH. The shear response is normalized on stabilization of PECAM-1, which reverses intimal remodeling in vivo. PMID- 26760928 TI - Optimization of tetanus toxoid ammonium sulfate precipitation process using response surface methodology. AB - Tetanus toxoid (TTd) is a highly immunogenic, detoxified form of tetanus toxin, a causative agent of tetanus disease, produced by Clostridium tetani. Since tetanus disease cannot be eradicated but is easily prevented by vaccination, the need for the tetanus vaccine is permanent. The aim of this work was to investigate the possibility of optimizing TTd purification, i.e., ammonium sulfate precipitation process. The influence of the percentage of ammonium sulfate, starting amount of TTd, buffer type, pH, temperature, and starting purity of TTd on the purification process were investigated using optimal design for response surface models. Responses measured for evaluation of the ammonium sulfate precipitation process were TTd amount (Lf/mL) and total protein content. These two parameters were used to calculate purity (Lf/mgPN) and the yield of the process. Results indicate that citrate buffer, lower temperature, and lower starting amount of TTd result in higher purities of precipitates. Gel electrophoresis combined with matrix assisted laser desorption ionization-mass spectrometric analysis of precipitates revealed that there are no inter-protein cross-links and that all contaminating proteins have pIs similar to TTd, so this is most probably the reason for the limited success of purification by precipitation. PMID- 26760927 TI - Novel insights into human respiratory syncytial virus-host factor interactions through integrated proteomics and transcriptomics analysis. AB - The lack of vaccine and limited antiviral options against respiratory syncytial virus (RSV) highlights the need for novel therapeutic strategies. One alternative is to develop drugs that target host factors required for viral replication. Several microarray and proteomics studies had been published to identify possible host factors that are affected during RSV replication. In order to obtain a comprehensive understanding of RSV-host interaction, we integrated available proteome and transcriptome datasets and used it to construct a virus-host interaction network. Then, we interrogated the network to identify host factors that are targeted by the virus and we searched for drugs from the DrugBank database that interact with these host factors, which may have potential applications in repositioning for future treatment options of RSV infection. PMID- 26760930 TI - Effect of Mixing Ratio between Pork Loin and Chicken Breast on Textural and Sensory Properties of Emulsion Sausages. AB - This study is conducted to evaluate the effects of the mixing ratio between pork loin and chicken breast for textural and sensory properties of emulsion sausages. Meat homogenates are prepared by using five mixing ratios between pork loin and chicken breast (100:0, 70:30, 50:50, 30:70, and 0:100), and the emulsion sausages are also formulated with five mixing ratios. The additions of chicken breast increase the salt soluble protein solubility due to high pH levels of chicken breast, thereby resulting in the reduction of cooking losses. In addition, the apparent viscosity of meat homogenates increase with increasing amounts of chicken breast. In terms of emulsion sausages formulated with pork loin and chicken breast, the addition of chicken breast above 50% may contribute to a softer and more flexible texture of emulsion sausages. For sensory evaluations, an increase in the added amount of chicken breast contributes to a rich umami taste and deeper flavor within the emulsion sausages, resulting in the high overall acceptance score for the formulation of 0-30% pork loin and 70-100% chicken breast. Therefore, the optimal mixing ratios between pork loin and chicken breast are 0-30% and 70-100% for enhancing the textural and sensory properties of emulsion sausages. PMID- 26760929 TI - Antiosteoporotic activity of Du-Zhong-Wan water extract in ovariectomized rats. AB - Context Eucommiae Cortex and Radix Dipsaci, occurring in a ratio of 1:1 in Du Zhong-Wan (DZW), a Chinese herbal medicine, is available as a water extract followed by ethanol precipitation for the treatment of osteoporosis, fractures and menopausal syndrome. Objective This study investigates the protective effects of DZW in ovariectomy (OVX)-induced bone loss in a rat osteopenia model. Materials and methods Sixty Sprague-Dawley rats were randomly divided into the sham-operated group (SHAM) and five OVX subgroups: OVX with vehicle (OVX), 17beta estradiol (E2) and with three graded doses of DZW. Daily oral administration of the different samples started on the fifth week and lasted for 12 weeks, respectively. The body weight, uterus wet weight, serum biochemical parameters, bone mineral density (BMD), bone biomechanical properties, bone microarchitecture and immunohistochemistry were examined. Results Compared with the SHAM group, the DZW treatment significantly reversed the osteoporotic changes in OVX rats. The DZW-H group showed that serum tartrate-resistant acid phosphatase 5b (TRACP-5b) levels reduced by 152.25% (p < 0.01) and osteocalein (OCN) levels dose dependently increased by 118.43% (p < 0.01) as compared with the OVX group. Compared with the OVX group, the DZW at different three dosages of DZW evidently increased the right femur BMD by 112.43, 114.56 and 116.45%, and dramatically promoted bone quality and bone strength (p < 0.05). Further, immunohistochemical evaluation also showed that DZW administration increased ER expression in uteri (p < 0.01). Conclusions DZW exhibits an anti-osteoporotic effect, probably mediated via phyto-estrogenic effects. It might be a potential herbal alternative for the management of postmenopausal osteoporosis. PMID- 26760931 TI - Effect of Hempseed (Cannabis sativa sp.) Inclusion to the Diet on Performance, Carcass and Antioxidative Activity in Japanese Quail (Coturnix coturnix japonica). AB - This study was conducted to determine the effects of hempseed (H) on performance, carcass traits, and antioxidant activity in Japanese quail (Coturnix coturnix japonica). A total of 192 quail with seven-days old were divided into four experimental groups with four replicates. The treatments were; i) Control diet (C, no hempseed); ii) 5% hempseed in diet (H5); iii) 10% hempseed in diet (H10); and iv) 20% hempseed in diet (H20). The body weight (BW) and feed intake (FI) of quail was determined at 7, 21 and 42 d of age. At 42 d of age four quail were slaughtered and the carcass and internal organ traits were determined. Malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), nitric oxide (NO) and total protein were determined in the blood serum end of the experiment. The BW of the groups were not significant at 7 and 21 d, however in the 20% hempseed group BW decreased at 42 d (p<0.05). The FI and feed conversion ratio were not significant among the treatment groups. The carcass, liver, intestine and heart weight and their percentage to carcass were significantly differ in treatment groups (p<0.05). The serum MDA and NO decreased in hempseed addition (p <0.001). The serum SOD, CAT and GSH-Px were increased by hempseed supplementation (p<0.001). In conclusion, hempseed supplementation to quail diets may not improve quail performance traits but increase antioxidant activity in blood. PMID- 26760932 TI - Effects of Concentration and Reaction Time of Trypsin, Pepsin, and Chymotrypsin on the Hydrolysis Efficiency of Porcine Placenta. AB - This study investigated the effects of three proteases (trypsin, pepsin and chymotrypsin) on the hydrolysis efficiency of porcine placenta and the molecular weight (Mw) distributions of the placental hydrolysates. Because placenta was made up of insoluble collagen, the placenta was gelatinized by applying thermal treatment at 90 C for 1 h and used as the sample. The placental hydrolyzing activities of the enzymes at varying concentrations and incubation times were determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) and gel permeation chromatography (GPC). Based on the SDS-PAGE, the best placental hydrolysis efficiency was observed in trypsin treatments where all peptide bands disappeared after 1 h of incubation as compared to 6 h of chymotrypsin. Pepsin hardly hydrolyzed the placenta as compared to the other two enzymes. The Mw distribution revealed that the trypsin produced placental peptides with Mw of 106 and 500 Da. Peptides produced by chymotrypsin exhibited broad ranges of Mw distribution (1-20 kDa), while the pepsin treatment showed Mw greater than 7 kDa. For comparisons of pre-treatments, the subcritical water processing (37.5 MPa and 200 C of raw placenta improved the efficiency of tryptic digestions to a greater level than that of a preheating treatment (90 C for 1 h). Consequently, subcritical water processing followed by enzymatic digestions has the potential of an advanced collagen hydrolysis technique. PMID- 26760933 TI - Effects of Replacing Pork Back Fat with Brewer's Spent Grain Dietary Fiber on Quality Characteristics of Reduced-fat Chicken Sausages. AB - The effects of replacing pork back fat with brewer's spent grain (BSG) pre emulsion for physicochemical, textural properties, and sensory evaluations of reduced-fat chicken sausages are evaluated. Control was prepared with 15% pork back fat, and three reduced-fat chicken sausages were formulated with the replacement of 20, 25, and 30% pork back fat with BSG pre-emulsion. The pH level of reduced-fat sausages formulated with BSG pre-emulsion is lower than that of the control (p<0.05). The redness, yellowness, and apparent viscosity of reduced fat chicken sausages increase proportionally with increasing BSG pre-emulsion (p<0.05). With increasing BSG pre-emulsion concentration, the fat contents and energy values are decreased in reduced-fat chicken sausages (p<0.05). The BSG pre emulsion improves the hardness, gumminess, and chewiness of reduced-fat chicken sausages (p<0.05), and the reduction in fat and the addition of BSG pre-emulsion had no influence on the cohesiveness of the chicken sausage. And there is no significant difference in the overall acceptability among control, T1 (chicken sausage with 20% of BSG pre-emulsion, 10% of fat addition), and T2 (chicken sausage with 25% of BSG pre-emulsion, 5% of fat addition) (p>0.05). Therefore, our results indicate that BSG is effective dietary fiber source for manufacturing of reduced-fat meat product and suggest that 20-25% of BSG pre-emulsion is suitable for pork back fat in chicken sausages. PMID- 26760934 TI - The Influence of Spices on the Volatile Compounds of Cooked Beef Patty. AB - The aim of this study is to examine the influences of spices on the amounts and compositions of volatile compounds released from cooked beef patty. Beef patty with 0.5% of spice (nutmeg, onion, garlic, or ginger powder, w/w) was cooked by electronic pan until they reached an internal temperature of 75C. A total of 46 volatile compounds (6 alcohols, 6 aldehydes, 5 hydrocarbons, 6 ketones, 9 sulfur compounds, and 14 terpenes) from cooked beef patties were detected by using purgeand- trap GC/MS. The addition of nutmeg, onion, or ginger powder significantly reduced the production of the volatile compounds via lipid oxidation in cooked beef patty when compared to those from the control. Also, the addition of nutmeg and garlic powder to beef patty generated a lot of trepans or sulfur volatile compounds, respectively. From these results, the major proportion by chemical classes such as alcohols, aldehydes, hydrocarbons, ketones, sulfur compounds, and terpenes was different depending on the spice variations. The results indicate that addition of spices to the beef patty meaningfully changes the volatile compounds released from within. Therefore, it can be concluded that spices can interact with meat aroma significantly, and thus, the character of each spice should be considered before adding to the beef patty. PMID- 26760935 TI - The Tissue Distribution of Lutein in Laying Hens Fed Lutein Fortified Chlorella and Production of Chicken Eggs Enriched with Lutein. AB - Two experiments were conducted to investigate the dietary effects of conventional or lutein fortified chlorella on lutein absorptions, the tissue distributions and the changes in lutein content of eggs in laying hens. In Exp 1, a total of one hundred and fifty, 70 wk-old Hy-Line brown layers were divided into three groups with five replicates and fed with each experiment diet (control diet, diet with 1% conventional chlorella or lutein fortified chlorella) for 2 wk, respectively. The egg production in groups fed diets containing both chlorella powders were higher than that of the control group (p<0.01). With chlorella supplementations, the yolk color significantly increased, although there were no significant differences in the eggshell qualities. The lutein contents of serum, liver and growing oocytes were greatly increased by feeding conventional or lutein fortified chlorella (p<0.01). In Exp. 2, a total of ninety 60 wk-old Hy-Line brown layers were assigned into three groups with three replicates per group (10 birds per replicate). The birds were fed with one of three experimental diets (0, 0.1 or 0.2% lutein fortified chlorella) for 2 wk, respectively. The egg production was not affected by dietary treatments. The egg weight in the group fed with diet containing 0.2% of lutein fortified chlorella was higher than that of the control (p<0.05). As the dietary chlorella levels increased, the daily egg mass linearly increased, although not significantly. The yolk colors in groups fed diets containing lutein fortified chlorella were dramatically increased as compared to the control (p<0.001). The lutein in chicken eggs significantly increased when fed with 0.2% of lutein fortified chlorella (p<0.01). These results suggested that the dietary lutein derived from chlorella was readily absorbed into the serum and absorbed by the liver with growing oocyte for commercial laying hens. Particularly, the lutein fortified chlorella was a valuable natural source for the production of lutein enriched chicken eggs. PMID- 26760936 TI - Application of Ganghwa Mugwort in Combination with Ascorbic Acid for the Reduction of Residual Nitrite in Pork Sausage during Refrigerated Storage. AB - The application of ganghwa mugwort (GM), ascorbic acid (AC), and their combinations for reduction of residual nitrite contents was analyzed in pork sausages during storage of 28 d. Six treatments of pork sausages contained the following: Control (no antioxidant added), AC (0.05% AC), GM 0.1 (0.1% GM), GM 0.2 (0.2% GM), AC+GM 0.1 (0.05% AC + 0.1% GM) and AC+GM 0.2 (0.05% AC + 0.2% GM). Results showed that the mixture of 0.05% AC and 0.2% GM was most effective for reducing thiobarbituric acid reactive substances (TBARS) and residual nitrite contents than the control and GM added sausages alone (p<0.05). The color values of all treatments were significantly affected by adding GM (either alone or with AC). Additionally, the total color difference (DeltaE) and hue angle (H degrees ) values of treatments added with GM were higher than those of the control as the amount of GM increased (p<0.05). However, there were no significant differences in the pH values between the control and all treatments during the storage period (p>0.05). Our results showed possible applications of antioxidant combination, for preventing the lipid oxidation and decreasing the residual nitrite levels of meat products. PMID- 26760937 TI - Quality Comparison of Pork Loin and Belly from Three-way Crossbred Pigs during Postmortem Storage. AB - This study was performed to determine the meat quality characteristics of pork loin and belly from 3 different three-way crossbred pigs: Yorkshire * Landrace * Duroc (YLD), Yorkshire * Chester White * Yorkshire (YCY), and Yorkshire * Berkshire * Duroc (YBD). Each of the twenty crossed pigs were randomly selected with their live weights at the range of 110-120 kg. After being slaughtered and cooled at 0C for 24 h in a chilling room, the parts of loin and belly on the left side of the cooled carcasses were cut and prepared for analysis. The intramuscular fat contents of the loins from YLD were higher than those of the other crossbreds (p<0.05), and the YCY bellies had the highest moisture contents (p<0.05). Water holding capacity (WHC) of the loins from YCY were higher than the other crossbreds (p<0.05). Shear force values of the YBD loins were higher than the others (p<0.05). The TBARS values of YCY loins were significantly lower than the others at 0 d, but the difference disappeared after 14 d of storage. Sensory scores of YLD were ranked higher than the YCY or YBD in both the loins and bellies (p<0.05). The relatively high sensory values of YLD crossbred pork could be explained by the better WHC, the low shear forces, and the higher fat contents. The results indicated that the meat qualities could be altered by three way crossbreeding. PMID- 26760938 TI - The Effects of Mechanically Deboned Chicken Hydrolysates on the Characteristics of Imitation Crab Stick. AB - The effects of adding mechanically deboned chicken (MDC) hydrolysates on the quality characteristics of imitation crab stick (ICS) during storage were investigated. ICS was prepared from Alaska Pollack, chicken breast surimi, and protein hydrolysates enzymatically extracted from MDC. ICS samples were divided into 4 groups: without protein hydrolysate (control), added with 0.5% protein hydrolysate (T1), added with 1.0% protein hydrolysate (T2), and added with 1.5% protein hydrolysate (T3). Results showed that crude protein content did not differ significantly among the ICS samples (p>0.05). ICS sample added with MDC hydrolysates had higher crude fat and ash content but lower moisture content than the control (p<0.05). Lightness was significantly lower in T2 and T3 than in the other groups at 0 and 4 wk of storage. Also, whiteness decreased in the groups contained MDC hydrolysates. Breaking force and jelly strength were higher in samples containing MDC hydrolysates compared to control samples (p<0.05). Additionally, saturated fatty acid contents were lower in the groups containing MDC hydrolysates than in control sample groups (p<0.05). Polyunsaturated fatty acid (PUFA) and essential fatty acids (EFA) were significantly higher in T2 and T3 than the control samples. In particular, all samples containing MDC hydrolysates had reduced thiobarbituric acid-reactive substances (TBARS) values at 4 wk. Free radical scavenging activity also was increased with addition of MDC hydrolysates. PMID- 26760939 TI - Effect of Grape Pomace Powder Addition on TBARS and Color of Cooked Pork Sausages during Storage. AB - To determine the effects of grape skin and seed pomace (GSP) additions on the lipid oxidation susceptibility and the color change of cooked pork sausages, the chemical characteristics of GSP itself and the addition for two different levels of GSP (0.5 and 1.0% GSP, respectively) to sausages were examined. Both the redness and blueness of the GSP were significantly reduced as the pH level was increased from 5 to 7, but a reverse result was determined in the color tint and yellowness (p<0.05). The GSP polyphenol and flavonoid contents were influenced by the percentages of methanol solvents, and more flavonoids were established when 100% of methanol was applied as a solvent to the GSP. But, similar results were not observed in the polyphenol of GSP. In cooked pork sausages, significant decreases in the lightness and redness were found in both the 0.5% and 1.0% of GSP sausages during the storage period (p<0.05). However, an incompatible effect was observed in terms of yellowness, which increased as compared to the control sausage after 6 days of storage. The 0.5% addition of GSP decreased the levels of TBARS (p<0.05), but the ability of GSP to minimize lipid oxidation was not dose dependent. Therefore, the results indicated that the GSP is an efficient suppressor of lipid oxidation and has latent effects as a natural antioxidant when 0.5% of GSP is added to the cooked pork sausages. PMID- 26760940 TI - Effects of pH-Shift Processing and Microbial Transglutaminase on the Gel and Emulsion Characteristics of Porcine Myofibrillar System. AB - This study investigated the effects of microbial transglutaminase (MTGase) and pH shift processing on the functional properties of porcine myofibrillar proteins (MP). The pH-shift processing was carried out by decreasing the pH of MP suspension to 3.0, followed by re-adjustment to pH 6.2. The native (CM) and pH shifted MP (PM) was reacted with and without MTGase, and the gelling and emulsion characteristics were compared. To compare the pH-shifted MTGase-treated MP (PT), deamidation (DM) was conducted by reacting MTGase with MP at pH 3.0. Rigid thermal gel was produced by MTGase-treated native MP (CT) and PT. PM and DM showed the lowest storage modulus (G') at the end of thermal scanning. Both MTGase and pH-shifting produced harder MP gel, and the highest gel strength was obtained in PT. All treatments yielded lower than CM, and CT showed significantly higher yield than PM and DM treatments. For emulsion characteristics, pH-shifting improved the emulsifying ability of MP-stabilized emulsion, while the treatments had lower emulsion stability. PM-stabilized emulsion exhibited the lowest creaming stability among all treatments. The emulsion stability could be improved by the usage of MTGase. The results indicated that pH-shifting combined with MTGase had a potential application to modify or improve functional properties of MP in manufacturing of meat products. PMID- 26760941 TI - Nutritional Characteristics and Active Components in Liver from Wagyu*Qinchuan Cattle. AB - We investigated nutritional characteristics and active components in the liver of Wagyu*Qinchuan cattle and Qinchuan cattle produced in Shaanxi (China). We observed significant differences (p<0.05) in the proximate composition of protein, fat, carbohydrate, total energy, and glycogen. Wagyu*Qinchuan cattle liver showed higher (p<0.05) sodium, iron, zinc, and selenium concentrations than Qinchuan cattle liver. The amino acid composition of Wagyu*Qinchuan cattle liver was richer (p<0.05) in 13 types of amino acids, with the exception of Asp (10.06%), Val (5.86%), and Met (1.72%). Total essential amino acids accounted for almost half the composition (39.69%) in Wagyu*Qinchuan cattle liver. Wagyu*Qinchuan cattle liver had lower (p<0.05) levels of monounsaturated fatty acids (18.2%), but higher (p<0.05) levels of polyunsaturated fatty acids (35.11%), compared with Qinchuan cattle liver (23.29% and 28.11%, respectively). The thrombogenic index was higher in Qinchuan cattle liver (0.86) than in Wagyu*Qinchuan cattle liver (0.70), and the glutathione (38.0 mg/100g) and L carnitine (2.12 MUM/g) content was higher (p<0.05) in Wagyu*Qinchuan cattle liver than in Qinchuan cattle liver (29.8 mg/100g and 1.41 MUM/g, respectively). According to the results obtained, the liver of Wagyu*Qinchuan cattle, which is insufficiently used, should be increasingly utilized to improve its commercial value. PMID- 26760942 TI - Antimicrobial Effect of Calcium Chloride Alone and Combined with Lactic Acid Injected into Chicken Breast Meat. AB - Chicken breast meat was injected with calcium chloride alone and in combination with lactic acid (0.01% and 0.002%, respectively). The inhibitory effects of the treatments on microbial growth were determined in the injected chicken breast meat stored at 4 degrees C under aerobic packaging condition for 0, 3, and 7 d. Calcium chloride combined with 0.002% and 0.01% lactic acid reduced microbial counts by 0.14 and 1.08 Log CFU/g, respectively, however, calcium chloride alone was unable to inhibit microbial growth. Calcium chloride combined with 0.01% lactic acid was the most effective antimicrobial treatment and resulted in the highest initial redness value. Calcium chloride alone and combined with lactic acid suppressed changes in pH and the Hunter color values during storage. However, injection of calcium chloride and lactic acid had adverse effects on lipid oxidation and sensory characteristics. The higher TBARS values were observed in samples treated with calcium chloride and lactic acid when compared to control over the storage period. Addition of calcium chloride and lactic acid resulted in lower sensory scores for parameters tested, except odor and color, compared to control samples. Therefore, the formulation should be improved in order to overcome such defects prior to industrial application. PMID- 26760943 TI - Effect of Coating Method on the Survival Rate of L. plantarum for Chicken Feed. AB - This study was designed to find the most suitable method and wall material for microencapsulation of the Lactobacillus plantarum to maintain cell viability in different environmental conditions. To improve the stability of L. plantarum, we developed an encapsulation system of L. plantarum, using water-in-oil emulsion system. For the encapsulation of L. plantarum, corn starch and glyceryl monostearate were selected to form gel beads. Then 10% (w/v) of starch was gelatinized by autoclaving to transit gel state, and cooled down at 60oC and mixed with L. plantarum to encapsulate it. The encapsulated L. plantarum was tested for the tolerance of acidic conditions at different temperatures to investigate the encapsulation ability. The study indicated that the survival rate of the microencapsulated cells in starch matrix was significantly higher than that of free cells in low pH conditions with relatively higher temperature. The results showed that corn starch as a wall material and glycerol monostearate as a gelling agent in encapsulation could play a role in the viability of lactic acid bacteria in extreme conditions. Using the current study, it would be possible to formulate a new water-in-oil system as applied in the protection of L. plantarum from the gastric conditions for the encapsulation system used in chicken feed industry. PMID- 26760944 TI - Comparison of Carcass Characteristics and Meat Quality between Duroc and Crossbred Pigs. AB - This study was conducted to compare the carcass characteristics and meat quality characteristics of Duroc breed and crossbred pigs (Landrace * Yorkshire * Duroc, LYD). Duroc and crossbred pigs did not show differences in carcass characteristics. Crossbred pigs had higher moisture and protein content than Duroc breeds. However, Duroc breeds had a higher fat content than the crossbred pigs. In meat quality characteristics, crossbred pigs showed higher values of drip loss and cooking loss over Duroc breeds, while Duroc breeds showed higher ultimate pH value compared to that of crossbred pigs. However, there were no differences in water holding capacity and shear force value. In myoglobin content, crossbred pigs had higher content compared to that in the Duroc population. In subjective evaluation and sensory characteristics, Duroc breeds showed significantly higher scores in all categories except for tenderness over the crossbred pigs. However, in storage characteristics, Duroc breeds showed reduced tendency relative to crossbred pigs. Crossbred pigs had higher unsaturated fatty acid content than Duroc breeds did. In these results, Duroc breeds showed excellent meat quality characteristics with its higher intramuscular fat content and pH value, lower drip loss and cooking loss and higher juiciness and flavor, compared to the crossbred pigs. PMID- 26760945 TI - Determination of Shelf Life for Butter and Cheese Products in Actual and Accelerated Conditions. AB - The aim of this study was to estimate the shelf life of butter and cheese products, with shelf life being a guide used to determine the storage period of food before deterioration. Butter and cheese samples stored at 10C and 15C had a shelf life of 221 d, while those stored at 25C and 35C had a shelf life of 109 d. Quality changes, including total cell count, coliform counts, Listeria monocytogenes counts, acid value, moisture content, pH, acidity and overall sensory evaluation, were monitored. In order to pass the overall sensory evaluation, a quality score of 5 points on a 9-point scale was required. For other quality criteria, legal quality limits were established based on the "Process Criteria and Ingredient Standard of Livestock Products" by the Animal, Plant and Fisheries Quarantine and Inspection Agency (Republic of Korea). The nonlegal quality limit was estimated by regression analysis between non-quality criteria (y) and overall sensory evaluation (x). The shelf life was estimated based on the number of days that the product passed the quality limit of the quality criteria. The shelf life of samples stored at 10C, 15C, 25C and 35C was 21.94, 17.18, 6.10 and 0.58 mon, respectively, for butter and 10.81, 9.47, 4.64 and 0.20 mon, respectively, for cheese. PMID- 26760946 TI - Effect of Dietary Supplementation of Blood Meal and Additional Magnesium on Carnosine and Anserine Concentrations of Pig Muscles. AB - The objective of this study was to investigate the effect of dietary supplementation of blood meal as a source of L-histidine, and the addition of magnesium (Mg) as a catalyst of carnosine synthetase for the carnosine and anserine concentrations of pig muscles (longissimus dorsi, LD and vastus intermedius, VI). A total of twenty-four pigs with an average body weight of 60.2+/-4.2 kg were randomly allotted to one of three dietary treatments (eight replicates), during 56 d of the feeding trial. Dietary treatments included: (1) Basal: basal diet; (2) BM: 95% basal diet + 5% blood meal; and (3) BM+Mg: 94.8% basal diet + 5% blood meal + 0.2% MgO (60% Mg). Results indicated that drip loss in the LD was less (p<0.05) for meat with BM+Mg treatment than that with Basal treatment, but the values for BM treatment did not differ from those of the other two treatment groups. The concentrations of carnosine in the LD were increased by 10.0% in both BM and BM+Mg treatment groups over the Basal treatment group (significance not verified). The concentrations of carnosine and anserine in the VI were not affected by the dietary treatments. Inclusion of additional Mg in diets had no effect on carnosine and anserine concentrations in the LD and VI. In conclusion, dietary supplementation of blood meal could be a potential method of fortifying the pork with carnosine. Inclusion of additional Mg in the diets containing blood meal had no benefit on carnosine and anserine depositions in pig muscles. PMID- 26760947 TI - Effect of NaCl on Biofilm Formation of the Isolate from Staphylococcus aureus Outbreak Linked to Ham. AB - The objective of this study was to evaluate the effects of NaCl on the biofilm formations of the isolate from Staphylococcus aureus outbreaks linked to ham. The S. aureus ATCC13565 isolated from ham was exposed to NaCl concentrations of 0%, 2%, 4%, and 6% supplemented in tryptic soy broth (TSB) for 24 h at 35C, followed by plating 0.1 mL of the culture on tryptic soy agar containing 0%, 2%, 4%, and 6% NaCl, respectively. After incubating at 35C for 24 h, the colonies on the plates were collected and diluted to OD600 = 0.1. The diluents of S. aureus were incubated on a 96-well flat bottom plate containing TSB plus the appropriate NaCl concentrations, and the biofilm formation was quantified by crystal violet staining after being incubated at 35C for 9 h. Confocal laser scanning microscope (CLSM) was also used for visualizing the biofilm formation of S. aureus at NaCl concentrations of 0%, 2%, 4%, and 6%. The transcriptional analysis of biofilm related genes, such as icaA, atl, clfA, fnbA, sarA, and rbf, was conducted by quantitative real-time PCR. Crystal violet staining and CLSM showed that the biofilm formations of S. aureus increased (p<0.05) along with the NaCl concentrations. Moreover, the expression of the icaA genes was higher at the NaCl concentrations of 4% and 6% as compared with 0% of NaCl by approximately 9-folds and 20-folds, respectively. These results indicated that the NaCl formulated in processed food may increase the biofilm formations of S. aureus by increasing the icaA gene expressions. PMID- 26760948 TI - Ankle fracture patterns in drivers are associated with femoral fracture, higher BMI, and advanced age. AB - OBJECTIVE: Despite advances in vehicle safety systems, motor vehicle crashes continue to cause ankle fractures. This study attempts to provide insight into the mechanisms of injury and to identify the at-risk population groups. METHODS: A study was made of ankle fractures patients treated at an urban level 1 trauma center following motor vehicle crashes, with a concurrent analysis of a nationally representative crash data set. The national data set focused on ankle fractures in drivers involved in frontal crashes. Statistical analysis was applied to the national data set to identify factors associated with fracture risk. RESULTS: Malleolar fractures occurred most frequently in the driver's right foot due to pedal interaction. The majority of complex/open fractures occurred in the left foot due to interaction with the vehicle floor. These fractures occurred in association with a femoral fracture, but their broad injury pattern suggests a range of fracture causation mechanisms. The statistical analysis indicated that the risk of fracture increased with increasing driver body mass index (BMI) and age. CONCLUSIONS: Efforts to reduce the risk of driver ankle injury should focus on right foot and pedal interaction. The range of injury patterns identified here suggest that efforts to minimize driver ankle fracture risk will likely need to consider injury tolerances for flexion, pronation/supination, and axial loading in order to capture the full range of injury mechanisms. In the clinical environment, physicians examining drivers after a frontal crash should consider those who are older or obese or who have severe femoral injury without concurrent head injury as highly suspicious for an ankle injury. PMID- 26760949 TI - Dopant-Free All-Back-Contact Si Nanohole Solar Cells Using MoOx and LiF Films. AB - We demonstrate novel all-back-contact Si nanohole solar cells via the simple direct deposition of molybdenum oxide (MoOx) and lithium fluoride (LiF) thin films as dopant-free and selective carrier contacts (SCCs). This approach is in contrast to conventionally used high-temperature thermal doping processes, which require multistep patterning processes to produce diffusion masks. Both MoOx and LiF thin films are inserted between the Si absorber and Al electrodes interdigitatedly at the rear cell surfaces, facilitating effective carrier collection at the MoOx/Si interface and suppressed recombination at the Si and LiF/Al electrode interface. With optimized MoOx and LiF film thickness as well as the all-back-contact design, our 1 cm(2) Si nanohole solar cells exhibit a power conversion efficiency of up to 15.4%, with an open-circuit voltage of 561 mV and a fill factor of 74.6%. In particular, because of the significant reduction in Auger/surface recombination as well as the excellent Si-nanohole light absorption, our solar cells exhibit an external quantum efficiency of 83.4% for short-wavelength light (~400 nm), resulting in a dramatic improvement (54.6%) in the short-circuit current density (36.8 mA/cm(2)) compared to that of a planar cell (23.8 mA/cm(2)). Hence, our all-back-contact design using MoOx and LiF films formed by a simple deposition process presents a unique opportunity to develop highly efficient and low-cost nanostructured Si solar cells. PMID- 26760950 TI - NMR shift and relaxation measurements in pulsed high-field magnets up to 58T. AB - Nuclear magnetic resonance (NMR) experiments at fields up to 58T in pulsed magnets at the Dresden High Magnetic Field Laboratory are reported. The challenge to resolve NMR shifts in these time-dependent fields is addressed for the first time, and it is shown that this can indeed be accomplished with high precision with an internal reference. As a result, signal averaging is possible during a single magnetic field pulse, but also for multiple pulses. Thus, even very weak signals can in principle be recorded and their shifts can be determined. In a second set of experiments, the measurement of nuclear relaxation is investigated. Using adiabatic inversion with the inherent time dependence of the magnetic field and small-angle inspection, it is shown that relaxation measurements are possible, as well. The shift experiments were performed with (27)Al NMR on a mixture of aluminum metal and a Linde type A zeolite. For the relaxation studies, (27)Al NMR and (69)Ga NMR on the metals aluminum and gallium were preformed, respectively. PMID- 26760951 TI - Automated radiosynthesis of [(11)C]L-deprenyl-D2 and [(11)C]D-deprenyl using a commercial platform. AB - Two (11)C-labelled PET tracers, (R)-N-[(11)C]methyl-N-(3,3-dideuteropropargyl)-1 phenylpropan-2-amine ([(11)C]L-deprenyl-D2, [(11)C]DED) and (S)-N-[(11)C]methyl-N propargyl-1-phenylpropan-2-amine ([(11)C]D-deprenyl, [(11)C]DDE) were synthesised. One step N-alkylation with [(11)C]MeI or [(11)C]MeOTf was performed using the automated platform TRACERlab(r) FX-C Pro. The labelled products were obtained with (37+/-15)% (n=10) (end of synthesis, decay corrected from [(11)C]MeI) radiochemical yields from [(11)C]MeI after 38+/-3min synthesis time. In all cases, radiochemical purity was over 99% when [(11)C]MeOTf was used. This synthesis using a commercial platform makes these tracers more accessible for clinical research purposes. PMID- 26760952 TI - Sporadic aggressive fibromatosis of the colon and abdominal wall in an emergency setting. AB - AIM: Our aim is to present an utterly unique case of sporadic aggressive fibromatosis (AF), infiltrating both the abdominal wall and the colon; and especially, to discuss the usefulness of porcine dermal meshes for the reconstruction of a large parietal gap in contaminated surgery and in an emergency setting. CASE EXPERIENCE: We report the case of a 40 years old woman affected by sporadic AF, involving both the anterior abdominal wall and the colon, with an effective intestinal stricture. The surgery consisted in removing "en bloc" the portions of the colon and abdominal wall affected by fibromatosis, with no residual tumor (R0), that left an important parietal gap. A biological prosthesis of cross-linked acellular porcine dermal collagen (APDC) has been used for the contextual reconstruction of the abdominal wall, sutured inlay by a double line of non absorbable stitches. No complications have been observed. After one year follow up, there is no tumour recurrence and the abdominal wall has fully consolidated. DISCUSSION: The peculiar problems arising about differential diagnosis, therapeutic indications and reconstructive surgical procedures are discussed, especially with regard to prosthetic implants in contaminated surgery and to cross-linked APDC prosthesis. CONCLUSIONS: Complete surgical removal is the first line treatment in sporadic AF, whenever feasible. In the reported case, an R0 resection was obtained at the cost of a wide parietal gap. According to our experience, cross-linked APDC is effective for the prosthetic reconstruction of abdominal wall in contaminated surgery and in an emergency setting. KEY WORDS: Abdominal wall, Aggressive fibromatosis, Desmoid tumor, Prosthetic devices, Reconstructive surgical procedures, desmoid tumor. PMID- 26760953 TI - Comparative proteomic analysis of beta-aminobutyric acid-mediated alleviation of salt stress in barley. AB - The non-protein amino acid beta-aminobutyric acid (BABA) is known to induce plant resistance to a broad spectrum of biotic and abiotic stresses. This is the first study describing the effect of BABA seed priming on physiological and proteomic changes under salt stress conditions in barley (Hordeum vulgare). The aim of our study was to investigate the changes of fresh weight, dry weight and relative water content (RWC) as well as root proteome changes of two barley lines contrasting in salt tolerance (DH14, DH 187) in response to salt stress after seed priming in water or in 800 MUM BABA. Seed priming with BABA significantly increased (p <= 0.05) RWC in both barley lines, which indicates considerably lower water loss in BABA-primed plants than in the non-primed control plants. Dry and fresh matter increased significantly in line DH 187, whereas no changes were detected in line DH14. BABA-primed plants of both lines showed different proteomic patterns than the non-primed control plants. The root proteins exhibiting significant abundance changes (1.75-fold change, p <= 0.05) were separated by two-dimensional polyacrylamide gel electrophoresis (2D- PAGE). Thirty-one spots, representing 24 proteins, were successfully identified by MALDI TOF/TOF mass spectrometry. The most prominent differences include the up regulation of antioxidant enzymes (catalase, peroxidase and superoxide dismutase), PR proteins (chitinase, endo-1,3-beta-glucosidase), and chaperones (cyclophilin, HSC 70). Our results indicate that BABA induces defence and detoxification processes which may enable faster and more effective responses to salt stress, increasing the chances of survival under adverse environmental conditions. PMID- 26760954 TI - Responses of growth, antioxidants and gene expression in smooth cordgrass (Spartina alterniflora) to various levels of salinity. AB - Salinity is a major environmental factor limiting the productivity and quality of crop plants. While most cereal crops are salt-sensitive, several halophytic grasses are able to maintain their growth under saline conditions. Elucidating the mechanisms for salinity responses in halophytic grasses would contribute to the breeding of salt-tolerant cereal and turf species belonging to the Poaceae family. Smooth cordgrass (Spartina alterniflora) is a dominant native halophytic grass in the Hackensack Meadowlands, the coastal salt marshes located in northeastern New Jersey. The goals of this study were to examine the growth pattern of S. alterniflora in a salinity gradient and identify an optimal range of salinity for its maximal growth. The regulation of its antioxidant system and gene expression under supraoptimal salinity conditions was also investigated. Our results showed that a salinity of 4 parts per thousand (ppt) (68 mM) was most favorable for the growth of S. alterniflora, followed by a non-salt environment. S. alterniflora responded to salts in the environment by regulating antioxidant enzyme activities and the expression of stress-induced proteins such as ALDH, HVA22 and PEPC. The plant may tolerate salinity up to the concentration of sea water, but any salinity above 12 ppt retarded its growth and altered the expression of genes encoding critical proteins. PMID- 26760955 TI - Mesenchymal to epithelial transition during tissue homeostasis and regeneration: Patching up the Drosophila midgut epithelium. AB - Stem cells are responsible for preserving morphology and function of adult tissues. Stem cells divide to self-renew and to generate progenitor cells to sustain cell demand from the tissue throughout the organism's life. Unlike stem cells, the progenitor cells have limited proliferation potential but have the capacity to terminally differentiate and thereby to substitute older or damaged mature cells. Recent findings indicate that adult stem cells can adapt their division kinetics dynamically to match changes in tissue demand during homeostasis and regeneration. However, cell turnover not only requires stem cell division but also needs timed differentiation of the progenitor cells, which has been much less explored. In this Extra View article, we discuss the ability of progenitor cells to actively postpone terminal differentiation in the absence of a local demand and how tissue demand activates terminal differentiation via a conserved mesenchymal-epithelial transition program revealed in our recent EMBO J paper and other published and unpublished data. The extent of the significance of these results is discussed for models of tissue dynamics during both homeostasis and regeneration. PMID- 26760958 TI - Early Stage Health Technology Assessment for Precision Biomarkers in Oral Health and Systems Medicine. AB - Health technology assessment (HTA) is a crucial science that influences the responsible and evidence-based transition of new discoveries from laboratory to applications in the clinic and society. HTA has recently moved "upstream" so as to assess technologies from their onset at their discovery, design, or planning phase. Biomarker research is relatively recent in oral health, but growing rapidly with investments made to advance dentistry and oral health and importantly, to build effective bridges between oral health and systems medicine since what happens in oral health affects systems pathophysiology, and vice versa. This article offers a synthesis of the latest trends and approaches in early phase HTA, with a view to near future applications in oral health, systems medicine, and biomarker-guided precision medicine. In brief, this review underscores that demonstrating health outcomes of biomarkers and next-generation diagnostics is particularly challenging because they do not always influence long term outcomes directly, but rather impact subsequent care processes. Biomarker testing costs are typically less of a barrier to uptake in practice than the biomarker's impact on longer term health outcomes. As a single biomarker or next generation diagnostic in oral health can inform decisions about numerous downstream diagnosis-treatment combinations, early stage "upstream" HTA is crucial in prioritizing the most valuable diagnostic applications to pursue first. For the vast array of oral health biomarkers currently developed, early HTA is necessary to timely and iteratively assess their comparative effectiveness and anticipate the inevitable questions about value for money from regulators and payers. PMID- 26760956 TI - Extracellular Protease Inhibition Alters the Phenotype of Chondrogenically Differentiating Human Mesenchymal Stem Cells (MSCs) in 3D Collagen Microspheres. AB - Matrix remodeling of cells is highly regulated by proteases and their inhibitors. Nevertheless, how would the chondrogenesis of mesenchymal stem cells (MSCs) be affected, when the balance of the matrix remodeling is disturbed by inhibiting matrix proteases, is incompletely known. Using a previously developed collagen microencapsulation platform, we investigated whether exposing chondrogenically differentiating MSCs to intracellular and extracellular protease inhibitors will affect the extracellular matrix remodeling and hence the outcomes of chondrogenesis. Results showed that inhibition of matrix proteases particularly the extracellular ones favors the phenotype of fibrocartilage rather than hyaline cartilage in chondrogenically differentiating hMSCs by upregulating type I collagen protein deposition and type II collagen gene expression without significantly altering the hypertrophic markers at gene level. This study suggests the potential of manipulating extracellular proteases to alter the outcomes of hMSC chondrogenesis, contributing to future development of differentiation protocols for fibrocartilage tissues for intervertebral disc and meniscus tissue engineering. PMID- 26760957 TI - Materiomics for Oral Disease Diagnostics and Personal Health Monitoring: Designer Biomaterials for the Next Generation Biomarkers. AB - We live in exciting times for a new generation of biomarkers being enabled by advances in the design and use of biomaterials for medical and clinical applications, from nano- to macro-materials, and protein to tissue. Key challenges arise, however, due to both scientific complexity and compatibility of the interface of biology and engineered materials. The linking of mechanisms across scales by using a materials science approach to provide structure-process property relations characterizes the emerging field of 'materiomics,' which offers enormous promise to provide the hitherto missing tools for biomaterial development for clinical diagnostics and the next generation biomarker applications towards personal health monitoring. Put in other words, the emerging field of materiomics represents an essentially systematic approach to the investigation of biological material systems, integrating natural functions and processes with traditional materials science perspectives. Here we outline how materiomics provides a game-changing technology platform for disruptive innovation in biomaterial science to enable the design of tailored and functional biomaterials--particularly, the design and screening of DNA aptamers for targeting biomarkers related to oral diseases and oral health monitoring. Rigorous and complementary computational modeling and experimental techniques will provide an efficient means to develop new clinical technologies in silico, greatly accelerating the translation of materiomics-driven oral health diagnostics from concept to practice in the clinic. PMID- 26760960 TI - Adenomatous polyposis coli genotype-dependent toll-like receptor 4 activity in colon cancer. AB - Toll-like receptors (TLRs)/NF-kappaB activation stimulated by lipopolysaccharide (LPS) was associated with diverse biological response in colon cancer, but the underlying mechanism was largely unknown. In the current study, we reported cell proliferation was elevated in adenomatous polyposis coli (APC) mutated- and APC knockdown cell lines, while the proliferation was inhibited in APC wild-type cell lines. Besides, in vivo experiments showed that LPS promoted APC knockdown tumor growth while inhibited proliferation of APC wild type. Further study confirmed that activation of TLRs/NF-kappaB signaling pathway by LPS cross regulated with APC/GSK-3beta/beta-catenin pathway, which were depend on APC status of cell lines. Taken together, APC genotypes play a key role in LPS induced different colon cancer biological response by cross-regulating beta-catenin and NF-kappaB, which may provide a novel strategy for carcinogenesis prevention. PMID- 26760961 TI - Hepatitis B virus X protein binding to hepsin promotes C3 production by inducing IL-6 secretion from hepatocytes. AB - Hepatitis B virus (HBV) X protein (HBx) is an important effector for HBV associated pathogenesis. In this study, we identified hepsin as an HBx interacting protein and investigated the effects of hepsin on HBx-mediated complement component 3 (C3) secretion in hepatocytes. In vivo and in vitro binding between HBx and hepsin was confirmed by co-immunoprecipitation and Glutathione S-transferase pull-down assays. HBx synergized with hepsin to promote C3 production by potentiating interleukin-6 (IL-6) secretion. Knockdown of endogenous hepsin attenuated C3 and IL-6 secretion induced by HBx in hepatic cells. In addition, levels of hepsin protein correlated positively with C3 expression in human non-tumor liver tissues. Further exploration revealed that HBx and hepsin increased C3 promoter activity by up-regulating the expression and phosphorylation of the transcription factor CAAT/enhancer binding protein beta (C/EBP-beta), which binds to the IL-6/IL-1 response element in the C3 promoter. HBx and hepsin synergistically enhanced IL-6 mRNA levels and promoter activity by increasing the nuclear translocation of nuclear factor kappaB (NF-kappaB). Our findings show for the first time that binding between HBx and hepsin promotes C3 production by inducing IL-6 secretion in hepatocytes. PMID- 26760959 TI - Repurposing L-Menthol for Systems Medicine and Cancer Therapeutics? L-Menthol Induces Apoptosis through Caspase 10 and by Suppressing HSP90. AB - The objective of the present study was to repurpose L-menthol, which is frequently used in oral health and topical formulations, for cancer therapeutics. In this article, we argue that monoterpenes such as L-menthol might offer veritable potentials in systems medicine, for example, as cheaper anti-cancer compounds. Other monoterpenes such as limonene, perillyl alcohol, and geraniol have been shown to induce apoptosis in various cancer cell lines, but their mechanisms of action are yet to be completely elucidated. Earlier, we showed that L-menthol modulates tubulin polymerization and apoptosis to inhibit cancer cell proliferation. In the present report, we used an apoptosis-related gene microarray in conjunction with proteomics analyses, as well as in silico interpretations, to study gene expression modulation in human adenocarcinoma Caco 2 cell line in response to L-menthol treatment. The microarray analysis identified caspase 10 as the important initiator caspase, instead of caspase 8. The proteomics analyses showed downregulation of HSP90 protein (also corroborated by its low transcript abundance), which in turn indicated inhibition of AKT mediated survival pathway, release of pro-apoptotic factor BAD from BAD and BCLxL complex, besides regulation of other factors related to apoptosis. Based on the combined microarray, proteomics, and in silico data, a signaling pathway for L menthol-induced apoptosis is being presented for the first time here. These data and literature analysis have significant implications for "repurposing" L-menthol beyond oral medicine, and in understanding the mode of action of plant-derived monoterpenes towards development of cheaper anticancer drugs in future. PMID- 26760963 TI - GPR171 expression enhances proliferation and metastasis of lung cancer cells. AB - G protein-coupled receptors (GPCRs) are among the most significant therapeutic targets and some of them promote the growth and metastasis of cancer. Here, we show that an increase in the levels of GPR171 is crucial for lung cancer tumor progression in vitro and in vivo. Immunostaining of clinical samples indicated that GPR171 was overexpressed in 46.8% of lung carcinoma tissues. Depletion of GPR171 with an anti-GPR171 antibody decreased proliferation of lung carcinoma cells and attenuated tumor progression in a mouse xenograft model. Knockdown of GPR171 also inhibited migration and invasion of the lung cancer cell lines. Notably, inhibition of GPR171 synergistically enhanced the tumoricidal activity of an epidermal growth factor receptor (EGFR) inhibitor in lung cancer cells. These results indicate that GPR171 blockade is a promising antineoplastic strategy and provide a preclinical rationale for combined inhibition of GPR171 and EGFR. PMID- 26760962 TI - PHLPP negatively regulates cell motility through inhibition of Akt activity and integrin expression in pancreatic cancer cells. AB - Pancreatic adenocarcinoma is currently the fourth leading cause for cancer related mortality. Malignant progression of pancreatic cancer depends not only on rapid proliferation of tumor cells but also on increased cell motility. In this study, we showed that increased PHLPP expression significantly reduced the rate of migration in pancreatic ductal adenocarcinoma (PDAC) cells whereas knockdown of PHLPP had the opposite effect. In addition, cell motility at the individual cell level was negatively regulated by PHLPP as determined using time-lapse imaging. Interestingly, the expression of beta1 and beta4 integrin proteins were decreased in PHLPP overexpressing cells and increased in PHLPP knockdown cells whereas the mRNA levels of integrin were not altered by changes in PHLPP expression. In determining the molecular mechanism underlying PHLPP-mediated regulation of integrin expression, we found that inhibition of lysosome activity rescued integrin expression in PHLPP overexpressing cells, thus suggesting that PHLPP negatively controls cell motility by inhibiting Akt activity to promote lysosome-dependent degradation of integrins. Functionally, the increased cell migration observed in PHLPP knockdown cells was effectively blocked by the neutralizing antibodies against beta1 or beta4 integrin. Taken together, our study identified a tumor suppressor role of PHLPP in suppressing cell motility by negatively regulating integrin expression in pancreatic cancer cells. PMID- 26760964 TI - Inhibition of NADPH oxidase 1 activity and blocking the binding of cytosolic and membrane-bound proteins by honokiol inhibit migratory potential of melanoma cells. AB - Overexpression of NADPH oxidase 1 (Nox1) in melanoma cells is often associated with increased migration/metastasis rate. To develop effective treatment options, we have examined the effect of honokiol, a phytochemical from Magnolia plant, on the migratory potential of human melanoma cell lines (A375, Hs294t, SK-Mel119 and SK-Mel28) and assessed whether Nox1 is the target. Using an in vitro cell migration assay, we observed that treatment of different melanoma cell lines with honokiol for 24 h resulted in a dose-dependent inhibition of cell migration that was associated with reduction in Nox1 expression and reduced levels of oxidative stress. Treatment of cells with N-acetyl-L-cysteine, an anti-oxidant, also inhibited the migration of melanoma cells. Treatment of cells with diphenyleneiodonium chloride, an inhibitor of Nox1, significantly decreased the migration ability of Hs294t and SK-Mel28 cells. Further, we examined the effect of honokiol on the levels of core proteins (p22(phox) and p47(phox)) of the NADPH oxidase complex. Treatment of Hs294t and SK-Mel28 cells with honokiol resulted in accumulation of the cytosolic p47(phox) protein and decreased levels of the membrane-bound p22(phox) protein, thus blocking their interaction and inhibiting Nox1 activation. Our in vivo bioluminescence imaging data indicate that oral administration of honokiol inhibited the migration/extravasation and growth of intravenously injected melanoma cells in internal body organs, such as liver, lung and kidney in nude mice, and that this was associated with an inhibitory effect on Nox1 activity in these internal organs/tissues. PMID- 26760965 TI - Large-Scale Spatio-Temporal Patterns of Mediterranean Cephalopod Diversity. AB - Species diversity is widely recognized as an important trait of ecosystems' functioning and resilience. Understanding the causes of diversity patterns and their interaction with the environmental conditions is essential in order to effectively assess and preserve existing diversity. While diversity patterns of most recurrent groups such as fish are commonly studied, other important taxa such as cephalopods have received less attention. In this work we present spatio temporal trends of cephalopod diversity across the entire Mediterranean Sea during the last 19 years, analysing data from the annual bottom trawl survey MEDITS conducted by 5 different Mediterranean countries using standardized gears and sampling protocols. The influence of local and regional environmental variability in different Mediterranean regions is analysed applying generalized additive models, using species richness and the Shannon Wiener index as diversity descriptors. While the western basin showed a high diversity, our analyses do not support a steady eastward decrease of diversity as proposed in some previous studies. Instead, high Shannon diversity was also found in the Adriatic and Aegean Seas, and high species richness in the eastern Ionian Sea. Overall diversity did not show any consistent trend over the last two decades. Except in the Adriatic Sea, diversity showed a hump-shaped trend with depth in all regions, being highest between 200-400 m depth. Our results indicate that high Chlorophyll a concentrations and warmer temperatures seem to enhance species diversity, and the influence of these parameters is stronger for richness than for Shannon diversity. PMID- 26760966 TI - Hsp90 inhibitor celastrol reinstates growth plate angiogenesis in thiram-induced tibial dyschondroplasia. AB - Tibial dyschondroplasia (TD) is an important long bone defect of broiler chickens that disturbs the proximal growth plate and is characterized by non-vascularized cartilage, a distended growth plate and lameness. Celastrol, a medicinal root extract from the plant Tripterygium wilfordii, is reported widely as a well-known heat-shock protein 90 (Hsp90) inhibitor. Recently, Hsp90 inhibition in chondrocyte differentiation and growth-plate vascularization were effective in restoring the morphology of the growth plate. The present study was aimed at investigating Hsp90 inhibition in TD using celastrol. The broiler chicks were divided into three groups; Control; TD induced (40 mg/kg thiram) and celastrol treatment. Hsp90, vascular endothelial growth factor and Flk-1 expressions were evaluated by quantitative real-time polymerase chain reaction and the protein levels of Hsp90 were measured by Western blot analysis. Antioxidant enzymes were determined to assess the liver damage caused by thiram and the protective effects of the medicine were evaluated by levels of serum biomarkers. The expression levels of Hsp90 and vascular endothelial growth factor mRNA transcripts were increased while Flk-1 receptor was decreased in TD-affected chicks. Celastrol therapy inhibited Hsp90 mRNA and protein levels and up-regulated the expressions of receptor Flk-1 in TD-affected tibial growth plates significantly (P < 0.05) in addition to rectifying the damaging effects of thiram on the liver by decreasing the levels of aspartate aminotransferase, alanine aminotransferase and malondialdehyde and correcting the oxidative imbalance. In conclusion, administering celastrol to dyschondroplastic chicks prevented un-vascularized growth plate, lameness and reinstated angiogenesis. Celastrol may be efficacious for the treatment of TD through the inhibition of Hsp90 expression and limiting the liver damage caused by thiram in broiler chickens. PMID- 26760968 TI - Discrimination and Characterization of Parkinsonian Rest Tremors by Analyzing Long-Term Correlations and Multifractal Signatures. AB - GOAL: We analyze 48 signals of rest tremor velocity related to 12 distinct subjects affected by the Parkinson's disease. The subjects belong to two different groups, high- and low-amplitude rest tremors, with four and eight subjects, respectively. Each subject has been tested in four settings given by combining the use of deep brain stimulation and L-DOPA medication. METHODS: We develop two main feature-based representations of the signals, which are obtained by considering 1) the long-term correlations and multifractal properties, and 2) the power spectra. RESULTS: Our results show that, when medication is used, a qualitative change is observed in the related signals from anticorrelated to long term positively correlated. In addition, the medication effect yields statistically significant differences in both high- and low-amplitude tremor groups. We successively consider three different classification problems, involving the recognition of 1) the use of medication, 2) the use of deep brain stimulation, and 3) the membership to the high- and low-amplitude tremor groups. Classification results show that the best results are obtained with a parsimonious, two-dimensional (2-D) representation encoding the long-term correlations and multifractal properties of the signals. CONCLUSIONS: Long-term correlations and multifractal signatures of time series provided an effective tool to analyze Parkinsonian rest tremor signals. SIGNIFICANCE: The developed 2-D representation is a parsimonious and effective representation for rest tremor signals that could be adopted in clinical settings, even by considering resource constrained scenarios. PMID- 26760967 TI - Detection of Coupling in Short Physiological Series by a Joint Distribution Entropy Method. AB - OBJECTIVE: In this study, we developed a joint distribution entropy (JDistEn) method to robustly estimate the coupling in short physiological series. METHODS: The JDistEn method is derived from a joint distance matrix which is constructed from a combination of the distance matrix corresponding to each individual data channel using a geometric mean calculation. A coupled Rossler system and a coupled dual-kinetics neural mass model were used to examine how well JDistEn performed, specifically, its sensitivity for detecting weak coupling, its consistency in gauging coupling strength, and its reliability in processing input of decreased data length. Performance of JDistEn in estimating physiological coupling was further examined with bivariate electroencephalography data from rats and RR interval and diastolic time interval series from human beings. Cross sample entropy (XSampEn), cross-conditional entropy (XCE), and Shannon entropy of diagonal lines in the joint recurrence plots (JENT) were applied for purposes of comparison. RESULTS: Simulation results suggest that JDistEn showed markedly higher sensitivity than XSampEn, XCE, and JENT for dynamics in weak coupling, although as the simulation models were more intensively coupled, JDistEn performance was comparable to the three others. In addition, this improved sensitivity was much more pronounced for short datasets. Experimental results further confirmed that JDistEn outperformed XSampEn, XCE, and JENT for detecting weak coupling, especially for short physiological data. CONCLUSION: This study suggested that our proposed JDistEn could be useful for continuous and even real time coupling analysis for physiological signals in clinical practice. PMID- 26760969 TI - Spatial patterns of benthic foraminifera as a support to the oceanographic characterisation of Arvoredo biological marine reserve (South Atlantic, Brazil). AB - This paper analyses the distribution of benthic foraminifera in a sector of the inner continental shelf of Santa Catarina State (Brazil), which comprises a Marine Protected Area (MPA). Species indicators of continental input suggest that waters under the influence of continental drainage can eventually reach the southwestern part of the reserve, which might jeopardise the ecosystems of this MPA due to the transport of contaminants related to human activities. Species known to be indicators of high marine benthic productivity were more abundant below 30 m, and were associated with areas under the stronger influence of nutrient-enriched water mass. The high density of foraminifera and the low dominance of species found in most samples inside the reserve might be evidence for the positive effects of the prohibition of bottom trawling, ensuring a higher ecological equilibrium of benthic communities. These results can contribute to the current debate about the reclassification and change in the extent of this MPA. PMID- 26760970 TI - Correction: The Influence of Socio-economic, Behavioural and Environmental Factors on Taenia spp. Transmission in Western Kenya: Evidence from a Cross Sectional Survey in Humans and Pigs. AB - [This corrects the article DOI: 10.1371/journal.pntd.0004223.]. PMID- 26760972 TI - How Do People Become W.E.I.R.D.? Migration Reveals the Cultural Transmission Mechanisms Underlying Variation in Psychological Processes. AB - Cultural psychologists have shown that people from Western, Educated, Industrialised, Rich, Democratic (WEIRD) countries often exhibit different psychological processing to people from less-WEIRD countries. The former exhibit more individualistic and less collectivistic social orientation, and more analytic and less holistic cognition, than non-Westerners. Yet the mechanisms responsible for maintaining this cultural variation are unclear. Immigration is an ideal 'natural experiment' for uncovering such mechanisms. We used a battery of psychological measures previously shown to vary cross-culturally to compare the social orientation and cognitive style of 286 residents of East London from three cultural backgrounds: (i) 1st-generation British Bangladeshi immigrants; (ii) 2nd-generation British Bangladeshis raised in the UK to Bangladeshi-raised parents; and (iii) non-migrants whose parents were born and raised in the UK. Model comparison revealed that individualism and dispositional attribution, typical of Western societies, are driven primarily by horizontal cultural transmission (e.g. via mass media), with parents and other family members having little or no effect, while collectivism, social closeness and situational attribution were driven by a mix of vertical/oblique cultural transmission (e.g. via family contact) and horizontal cultural transmission. These individual-level transmission dynamics can explain hitherto puzzling population-level phenomena, such as the partial acculturation of 2nd-generation immigrants on measures such as collectivism (due to the mix of vertical and horizontal cultural transmission), or the observation in several countries of increasing individualism (which is transmitted horizontally and therefore rapidly) despite little corresponding change in collectivism (which is transmitted partly vertically and therefore more slowly). Further consideration of cultural transmission mechanisms, in conjunction with the study of migrant communities and model comparison statistics, can shed light on the persistence of, and changes in, culturally-variable psychological processes. PMID- 26760973 TI - Genotyping Yersinia pestis in Historical Plague: Evidence for Long-Term Persistence of Y. pestis in Europe from the 14th to the 17th Century. AB - Ancient DNA (aDNA) recovered from plague victims of the second plague pandemic (14th to 17th century), excavated from two different burial sites in Germany, and spanning a time period of more than 300 years, was characterized using single nucleotide polymorphism (SNP) analysis. Of 30 tested skeletons 8 were positive for Yersinia pestis-specific nucleic acid, as determined by qPCR targeting the pla gene. In one individual (MP-19-II), the pla copy number in DNA extracted from tooth pulp was as high as 700 gene copies/MUl, indicating severe generalized infection. All positive individuals were identical in all 16 SNP positions, separating phylogenetic branches within nodes N07_N10 (14 SNPs), N07_N08 (SNP s19) and N06_N07 (s545), and were highly similar to previously investigated plague victims from other European countries. Thus, beside the assumed continuous reintroduction of Y. pestis from central Asia in multiple waves during the second pandemic, long-term persistence of Y. pestis in Europe in a yet unknown reservoir host has also to be considered. PMID- 26760971 TI - Changes in Cognitive Functions in the Elderly Living in Temporary Housing after the Great East Japan Earthquake. AB - On March 11, 2011, Japan experienced an earthquake of magnitude 9.0 and subsequent enormous tsunamis. This disaster destroyed many coastal cities and caused nearly 20,000 casualties. In the aftermath of the disaster, many tsunami survivors who lost their homes were forced to live in small temporary apartments. Although all tsunami survivors were at risk of deteriorating health, the elderly people were particularly at a great risk with regard to not only their physical health but also their mental health. In the present study, we performed a longitudinal cohort study to investigate and analyze health conditions and cognitive functions at 28, 32, and 42 months after the disaster in the elderly people who were forced to reside in temporary apartments in Kesennuma, a city severely damaged by the tsunamis. The ratio of people considered to be cognitively impaired significantly increased during the research period. On the other hand, the mean scores of the Kessler Psychological Distress Scale-6 and Athens Insomnia Scale improved based on the comparison between the data at 24 and 42 months. The multiple logistic regression analysis revealed that frequency of "out-of-home activities" and "walking duration" were independently associated with an increase in the ratio of people with cognitive impairment. We concluded that the elderly people living in temporary apartments were at a high risk of cognitive impairment and "out-of-home activities" and "walking" could possibly maintain the stability of cognitive functions. PMID- 26760974 TI - Novel Endothelial Cell-Specific AQP1 Knockout Mice Confirm the Crucial Role of Endothelial AQP1 in Ultrafiltration during Peritoneal Dialysis. AB - The water channel aquaporin-1 (AQP1) mediates about 50% ultrafiltration during a 2-hour hypertonic dwell in global AQP1 knockout (AQP1-/-) mice. Although AQP1 is widely expressed in various cell types including mesothelial cells, the ultrafiltration has been assumed to be mediated via endothelial AQP1 of the peritoneum. The partial embryonic lethality and reduced body weight in AQP1-/- mice may reflect potential confounding phenotypic effects evoked by ubiquitous AQP1 deletion, which may interfere with functional analysis of endothelial AQP1. Using a Cre/loxP approach, we generated and characterised endothelial cell- and time-specific AQP1 knockout (AQP1fl/fl; Cdh5-Cre+) mice. Compared to controls, AQP1fl/fl; Cdh5-Cre+ mice showed no difference in an initial clinical and biological analysis at baseline, including body weight and survival. During a 1 hour 3.86% mini-peritoneal equilibration test (mini-PET), AQP1fl/fl; Cdh5-Cre+ mice exhibited strongly decreased indices for AQP1-related transcellular water transport (43.0% in net ultrafiltration, 93.0% in sodium sieving and 57.9% in free water transport) compared to controls. The transport rates for small solutes of urea and glucose were not significantly altered. Our data provide the first direct experimental evidence for the functional relevance of endothelial AQP1 to the fluid transport in peritoneal dialysis and thereby further validate essential predictions of the three-pore model of peritoneal transport. PMID- 26760975 TI - Caste-Specific and Sex-Specific Expression of Chemoreceptor Genes in a Termite. AB - The sophisticated colony organization of eusocial insects is primarily maintained through the utilization of pheromones. The regulation of these complex social interactions requires intricate chemoreception systems. The recent publication of the genome of Zootermopsis nevadensis opened a new avenue to study molecular basis of termite caste systems. Although there has been a growing interest in the termite chemoreception system that regulates their sophisticated caste system, the relationship between division of labor and expression of chemoreceptor genes remains to be explored. Using high-throughput mRNA sequencing (RNA-seq), we found several chemoreceptors that are differentially expressed among castes and between sexes in a subterranean termite Reticulitermes speratus. In total, 53 chemoreception-related genes were annotated, including 22 odorant receptors, 7 gustatory receptors, 12 ionotropic receptors, 9 odorant-binding proteins, and 3 chemosensory proteins. Most of the chemoreception-related genes had caste-related and sex-related expression patterns; in particular, some chemoreception genes showed king-biased or queen-biased expression patterns. Moreover, more than half of the genes showed significant age-dependent differences in their expression in female and/or male reproductives. These results reveal a strong relationship between the evolution of the division of labor and the regulation of chemoreceptor gene expression, thereby demonstrating the chemical communication and underlining chemoreception mechanism in social insects. PMID- 26760978 TI - Clinical Characteristics of Pediatric Patients with Ocular Toxocariasis in China. AB - OBJECTIVE: The aim of the study was to analyze the clinical characteristics of pediatric patients with ocular toxocariasis. METHODS: Ocular toxocariasis was diagnosed and treated in 46 children from Shanghai and surrounding provinces. The diagnosis of ocular toxocariasis was confirmed immunologically by performing an enzyme-linked immunosorbent assay on serum and/or intraocular fluid. All pediatric patients and their guardians completed a questionnaire concerning their cases and living habits. RESULTS: The mean age of onset was 6 +/- 3 years. Most children (85%) resided in rural areas, and 91% of the children had contact with adult dogs or puppies. At the first visit, visual acuity (VA) was <20/200 in 36 cases, and we detected peripheral granuloma in 36 patients. In our study, the most common signs were vitritis, vitreous strands, and tractional retinal detachment. The Optomap 200Tx device detected granuloma with an 85% sensitivity, which is much higher than that of other techniques. We treated 40 cases (87%) with topical corticosteroids, while 28 patients (61%) were treated with systemic corticosteroids. Only 18 children (39%) required surgical intervention. All patients were examined and treated by the same ophthalmologists. CONCLUSIONS: Preschool children in China are more often affected by toxocariasis compared with other age groups. The most common signs included unilateral granuloma and ocular inflammation. In our study, clinical manifestations were severe and complicated. At the first visit, VA was <20/200 in most patients. Ocular toxocariasis was diagnosed on the basis of clinical signs and symptoms; the diagnosis was confirmed by immunological testing. Techniques using the Optomap 200Tx device can facilitate the early detection and lead to better visual prognosis. PMID- 26760976 TI - Imbalances in Mobilization and Activation of Pro-Inflammatory and Vascular Reparative Bone Marrow-Derived Cells in Diabetic Retinopathy. AB - Diabetic retinopathy is a sight-threatening complication of diabetes, affecting 65% of patients after 10 years of the disease. Diabetic metabolic insult leads to chronic low-grade inflammation, retinal endothelial cell loss and inadequate vascular repair. This is partly due to bone marrow (BM) pathology leading to increased activity of BM-derived pro-inflammatory monocytes and impaired function of BM-derived reparative circulating angiogenic cells (CACs). We propose that diabetes has a significant long-term effect on the nature and proportion of BM derived cells that circulate in the blood, localize to the retina and home back to their BM niche. Using a streptozotocin mouse model of diabetic retinopathy with GFP BM-transplantation, we have demonstrated that BM-derived circulating pro inflammatory monocytes are increased in diabetes while reparative CACs are trapped in the BM and spleen, with impaired release into circulation. Diabetes also alters activation of splenocytes and BM-derived dendritic cells in response to LPS stimulation. A majority of the BM-derived GFP cells that migrate to the retina express microglial markers, while others express endothelial, pericyte and Muller cell markers. Diabetes significantly increases infiltration of BM-derived microglia in an activated state, while reducing infiltration of BM-derived endothelial progenitor cells in the retina. Further, control CACs injected into the vitreous are very efficient at migrating back to their BM niche, whereas diabetic CACs have lost this ability, indicating that the in vivo homing efficiency of diabetic CACs is dramatically decreased. Moreover, diabetes causes a significant reduction in expression of specific integrins regulating CAC migration. Collectively, these findings indicate that BM pathology in diabetes could play a role in both increased pro-inflammatory state and inadequate vascular repair contributing to diabetic retinopathy. PMID- 26760977 TI - Human S100A10 plays a crucial role in the acquisition of the endometrial receptivity phenotype. AB - In assisted reproduction, about 30% of embryo implantation failures are related to inadequate endometrial receptivity. To identify molecules involved in endometrial receptivity acquisition, we investigated, using a SELDI-TOF approach, the protein expression profile of early-secretory and mid-secretory endometrium samples. Among the proteins upregulated in mid-secretory endometrium, we investigated the function of S100A10 in endometrial receptivity and implantation process. S100A10 was expressed in epithelial and stromal cells of the endometrium of fertile patients during the implantation windows. Conversely, it was downregulated in the mid-secretory endometrium of infertile patients diagnosed as non-receptive. Transcriptome analysis of human endometrial epithelial and stromal cells where S100A10 was silenced by shRNA revealed the deregulation of 37 and 256 genes, respectively, related to components of the extracellular matrix and intercellular connections. Functional annotations of these deregulated genes highlighted alterations of the leukocyte extravasation signaling and angiogenesis pathways that play a crucial role during implantation. S100A10 silencing also affected the migration of primary endometrial epithelial and stromal cells, decidualization and secretory transformation of primary endometrial stromal cells and epithelial cells respectively, and promoted apoptosis in serum-starved endometrial epithelial cells. Our findings identify S100A10 as a player in endometrial receptivity acquisition. PMID- 26760979 TI - Overexpression of APOBEC3F in tumor tissues is potentially predictive for poor recurrence-free survival from HBV-related hepatocellular carcinoma. AB - The relationship between members of APOBEC3 in tumor tissues and hepatocellular carcinoma prognosis was not well studied. We compared APOBEC3 expression between tumor and non-tumor tissues based on the expression profile GSE14520 from Gene Expression Omnibus (GEO), and correlated APOBEC3 in tumor tissues with outcomes of HCC patients. APOBEC3B, which was significantly up-regulated in HCC tumor tissues (P < 0.001), was negatively associated with HCC overall survival by Cox regression (HR = 1.005, 95% CI = 1.0-1.009, P = 0.033). However, no significant difference was found of APOBEC3B and HCC overall survival by Kaplan-Meier method. HCC patients with high APOBEC3F expression in tumor tissues more likely coexist with multinodular tumors than those with low APOBEC3F level (26.4% and 13.6%, respectively, P = 0.018). Cox univariate and multivariate regression analyses revealed that APOBEC3F overexpression in tumor tissues was negatively associated with HCC recurrence (HR = 1.132, 95% CI = 1.013-1.265, P = 0.028). Additionally, the higher the APOBEC3F expressed, the greater risk of poor recurrence-free survival for HCC patients (mean survival time high = 32.25 and low = 42.68 months, respectively; log rank P = 0.012) when grouped by lower quartile cut-off of 10.98. CONCLUSIONS: Overexpression of APOBEC3F in tumor tissues is potentially predictive for poor recurrence-free survival from HBV-HCC patients. The role of other APOBEC3 members in HCC development needed further research. PMID- 26760980 TI - Decreased expression of Rab27A and Rab27B correlates with metastasis and poor prognosis in colorectal cancer. AB - The Rab27 subfamily of secretory small GTPase plays a vital role in vesicle trafficking and regulates tumor growth and metastasis in several cancer types. Thus, this research was designed to explore the clinical and prognostic significance of Rab27A and Rab27B in colorectal cancer (CRC) patients. Reverse transcription-polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry (IHC) analysis were used to examine Rab27A and Rab27B expression in human CRC cell lines and primary tumors. The correlation of gene expression with clinicopathological features and prognosis was also evaluated. Our results indicated that Rab27A expression was down-regulated in primary tumors compared with matched adjacent tissues (100%, 8/8), as detected by western blot. IHC analysis revealed that the positive expression rate of Rab27A in primary CRC tissues was lower than in adjacent normal tissues (P = 0.005). Negative expression of Rab27A and Rab27B significantly correlated with poor tumor differentiation (both P < 0.001) and positive vascular invasion (P = 0.005, P = 0.021, respectively). Moreover, absence of Rab27A was associated with advanced tumor node metastasis (TNM) stage (P = 0.006), distant metastasis (P = 0.002), and local recurrence (P = 0.038). Survival analysis also showed a significant correlation between unfavorable survival and negative expression of Rab27A (P = 0.002). In addition, positive expression of both Rab27A and Rab27B was a protective factor in CRC. In conclusion, decreased expression of Rab27A and Rab27B, especially Rab27A, closely correlated with tumor progression and are valuable prognostic indicators in CRC patients. PMID- 26760982 TI - A new paradigm about HERV-K102 particle production and blocked release to explain cortisol mediated immunosenescence and age-associated risk of chronic disease. AB - The majority of chronic diseases in the aging adult are thought to relate to immune aging characterized by dominant immunosuppression and paradoxically, concomitant inflammation. This is known collectively as immunosenescence. The main change thought to be controlling immune aging is the age-related decline in dehydroepiandrosterone (DHEA) and corresponding increase in cortisol; the net effect which decreases the DHEA/cortisol ratio. Exactly how this translates to immunosuppression and concomitant inflammation remains unclear. Recently a new component of the human innate immune system has been discovered. Human endogenous retrovirus K102 (HERV-K102) is a replication-competent foamy retrovirus unique to humans which has been implicated in chronic diseases. Accumulating evidence suggests that HERV-K102 may defend the host against viral infections, as well as against breast and other cancers. Particles are produced in activated monocytes and released into vacuoles but do not bud through the cell surface. This renders macrophages foamy, while the release of particles is only through cell lysis. New evidence presented here suggests DHEA but not DHEA-S may specifically bind and inactivate alpha-fetoprotein (AFP). AFP is a well-established immunosuppressive factor which importantly, also blocks cell lysis induction in macrophages through the 67 kilodalton (kD) AFP receptor (AFPr). Here, it is proposed that a decreased DHEA/cortisol ratio may favor the accumulation of foamy macrophages reflecting the cortisol induction of HERV-K102 particle production concomitant with the blocked release of particles by secreted AFP. This is a new paradigm to explain how cortisol-mediated immunosenescence can result in the persistence of foamy macrophages, and how this relates to risk of chronic disease. PMID- 26760983 TI - Advances in the integration of optical and mass spectrometry molecular imaging technologies: from omics data to molecular signature discovery. AB - Many molecular mechanisms in complex biological processes of diseases cannot be fully understood without direct visualization. In the last decades, advances in imaging principles and technologies have expanded our ability to capture and analyze the morphology of tissues and cells' components on conventional widefield optical and fluorescence microscopies and their derivatives confocal and multiphoton fluorescence laser-scanning microscopes, as well as transmission electron microscopes. Innovative imaging technologies are now emerging for constructing fine structural features, precise localization and the dynamic interplay of single and macromolecular assemblies that drive cell growth, differentiation and cell death as well as stromal and chromatin remodeling within many cellular context. The newer super-resolution microscopies capture images with unprecedented sensitivity and clarity allowing the exploration of interactions between individual molecules with a distance resolution as low as 20 nm. But these techniques are not robust enough to quantitate molecules on a genome-wide scale. Mass spectrometry imaging is a high-throughput chemical imaging technique for the identification, quantitation and distribution of proteins, lipids and chemical metabolites at picomol level within a single-cell and complex multicellular tissue. Here we provide an overview on imaging instrumentations and computational platforms to store, data mining, analyze and retrieving genomic, proteomic and immunohistochemistry digital image information which are available for multilevel academic-private collaborations. The expansion of these data sets will lead to a merge picture from it we will retrieve knowledge for more rational-design systems to basic and clinical research in near future. PMID- 26760981 TI - Guanylate-binding protein 1 (GBP1) promotes lymph node metastasis in human esophageal squamous cell carcinoma. AB - Lymphatic metastasis is an important determinant of aggressive malignant tumors. Identification of key genes that regulate carcinoma cell metastasis will aid in understanding progression of esophageal squamous cell carcinoma (ESCC). Guanylate binding protein 1 (GBP1) is a GTP-binding protein family member with high GTPase activity. While the role of GBP1 has been demonstrated in colorectal cancer (CRC) and ovarian cancer, such a role has not been identified in ESCC. Herein, we assessed GBP1 expression in ESCC via immunohistochemistry (IHC) analysis of 215 clinical ESCC specimens and found that the expression of GBP1 was significantly upregulated in lymph node metastatic ESCCs compared with non-metastatic cases. We further demonstrated that GBP1 expression was increased with epidermal growth factor (EGF) stimulus in ESCC cell lines and had a positive correlation with EGFR expression in ESCC tissue samples. Finally, we found that overexpression of GBP1 in ESCC cells induced more lymph node metastasis in an animal model. In summary, our results demonstrate that GBP1 promotes lymph node metastasis and has a positive correlation with EGFR expression in ESCC. PMID- 26760984 TI - Deep brain stimulation: current applications and future prospects. AB - Deep Brain Stimulation (DBS) has proven to be an effective and minimally invasive surgical treatment for a variety of neurological and psychiatric diseases such as Parkinson's Disease, essential tremor, dystonia, Tourette's Syndrome and depression. In contrast to early surgical lesioning procedures, DBS has a considerably lower side-effect rate and is usually reversible. Common targets include nuclei involved in the basal ganglia circuitry as well as its efferent and afferent pathways such as the subthalamic nucleus (STN), the globus pallidus internus (GPi) or the ventral striatal region. Despite the increasing application of DBS, the exact mechanism of action is still matter of debates. Current trials focus on establishing alternative targets, exploring new indications as well as on capturing cortical responses during DBS in order to improve individual stimulation parameters. PMID- 26760985 TI - Statins as anti-cancer therapy; Can we translate preclinical and epidemiologic data into clinical benefit? AB - Statins, the most commonly prescribed class of drug, have demonstrated effects beyond cholesterol reduction including anti-tumor and immunomodulatory properties. Several epidemiological studies have suggested an anti-neoplastic effect of statins evidenced by reductions in cancer incidence and cancer-related mortality. Clinical trials on statins as part of therapy for cancer have generated interest in the oncology community. Statins have been investigated for a variety of cancers, early and late stage, and in combination with chemotherapy and radiation. So far promising results have been reported with statin use in pediatric brainstem tumors, early stage breast cancer, hepatocellular carcinoma (HCC), colorectal cancer (CRC), refractory or relapsed multiple myeloma (MM), and refractory acute myeloid leukemia (AML). There is still much investigation to be completed to determine which subtypes of patients benefit from statin therapy, how statins may potentiate other anticancer approaches, and the appropriate dosing schedule to use. PMID- 26760986 TI - Chinese herbal medicines for unexplained recurrent miscarriage. AB - BACKGROUND: Recurrent miscarriage affects 1% to 3% of women of reproductive age and mostly occurs before the 10th week of gestation (and around the same gestational week in subsequent miscarriages). Although most pregnant women may not recognise a miscarriage until uterine bleeding and cramping occur, a repeat miscarriage after one or more pregnancy loss and the chance of having a successful pregnancy varies. To date, there is no universally accepted treatment for unexplained recurrent miscarriage. Chinese herbal medicines have been widely used in Asian societies for millennia and have become a popular alternative to Western medicines in recent years. Many clinical studies have reported that Chinese herbal medicines can improve pregnancy outcomes for pregnant women who had previously suffered recurrent miscarriage. This systematic review evaluated the efficacy of Chinese herbal medicines for recurrent miscarriage. OBJECTIVES: To assess the effectiveness and safety of Chinese herbal medicines for the treatment of unexplained recurrent miscarriage. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (01 June 2015), Embase (1980 to 01 June 2015); Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 01 June 2015); Chinese Biomedical Database (CBM) (1978 to 01 June 2015); China Journal Net (CJN) (1915 to 01 June 2015); China Journals Full text Database (1915 to 01 June 2015); and WanFang Database (Chinese Ministry of Science & Technology) (1980 to 01 June 2015). We also searched reference lists of relevant trials and reviews. We identified and contacted organisations, individual experts working in the field, and medicinal herb manufacturers. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials, including cluster-randomised trials, with or without full text, comparing Chinese herbal medicines (alone or combined with other intervention or other pharmaceuticals) with placebo, no treatment, other intervention (including bed rest and psychological support), or other pharmaceuticals as treatments for unexplained recurrent miscarriage. Cross-over studies were not eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed all the studies for inclusion in the review, assessed risk of bias and extracted the data. Data were checked for accuracy. MAIN RESULTS: We included nine randomised clinical trials (involving 861 women). The trials compared Chinese herbal medicines (various formulations) either alone (one trial), or in combination with other pharmaceuticals (seven trials) versus other pharmaceuticals alone. One study compared Chinese herbal medicines and other pharmaceuticals versus psychotherapy. We did not identify any trials comparing Chinese herbal medicines with placebo or no treatment, including bed rest.Various Chinese herbal medicines were used in the different trials (and some of the classical the formulations were modified in the trials). The Western pharmaceutical medicines included tocolytic drugs such as salbutamol and magnesium sulphate; hormonal supplementation with human chorionic gonadotrophin (HCG), progesterone or dydrogesterone; and supportive supplements such as vitamin E, vitamin K and folic acid.Overall, the methodological quality of the included studies was poor with unclear risk of bias for nearly all the 'Risk of bias' domains assessed.Chinese herbal medicines alone versus other pharmaceuticals alone - the live birth rate was no different between the two groups (risk ratio (RR) 1.05; 95% confidence interval (CI) 0.67 to 1.65; one trial, 80 women). No data were available for the outcome of pregnancy rate (continuation of pregnancy after 20 weeks of gestation).In contrast, the continuing pregnancy rate (RR 1.27 95% CI 1.10 to 1.48, two trials, 189 women) and live birth rate (average RR 1.55; 95% CI 1.14 to 2.10; six trials, 601 women, Tau2 = 0.10; I2 = 73%) were higher among the group of women who received a combination of Chinese herbal medicines and other pharmaceuticals when compared with women who received other pharmaceuticals alone.For Chinese herbal medicines and psychotherapy versus psychotherapy alone (one study) - there was a higher live birth rate (RR 1.32; 95% CI 1.07 to 1.64; one trial, 90 women) in the group of women who received a combination of Chinese herbal medicines and psychotherapy compared to those women who received psychotherapy alone. No data were available on the continuing pregnancy rate for this comparison.Other primary outcomes (maternal adverse effect and toxicity rate and the perinatal adverse effect and toxicity rate) were not reported in most of the included studies. Two trials (341 women) reported that no maternal adverse effects were found (one trial compared (combined) medicines with other pharmaceuticals, and one trial compared combined Chinese herbal medicine alone versus other pharmaceuticals). One trial (Chinese herbal medicine alone versus other pharmaceuticals alone) reported that there were no abnormal fetuses (ultrasound) or after delivery.There were no data reported for any of this review's secondary outcomes. AUTHORS' CONCLUSIONS: We found limited evidence (from nine studies with small sample sizes and unclear risk of bias) to assess the effectiveness of Chinese herbal medicines for treating unexplained recurrent miscarriage; no data were available to assess the safety of the intervention for the mother or her baby. There were no data relating to any of this review's secondary outcomes. From the limited data we found, a combination of Chinese herbal medicines and other pharmaceuticals (mainly Western medicines) may be more effective than Western medicines alone in terms of the rate of continuing pregnancy and the rate of live births. However, the methodological quality of the included studies was generally poor.A comparison of Chinese herbal medicines alone versus placebo or no treatment (including bed rest) was not possible as no relevant trials were identified.More high-quality studies are needed to further evaluate the effectiveness and safety of Chinese herbal medicines for unexplained recurrent miscarriage. In addition to assessing the effect of Chinese herbal medicines on pregnancy rate and the rate of live births, future studies should also consider safety issues (adverse effects and toxicity for the mother and her baby) as well as the secondary outcomes listed in this review. This review would provide more valuable information if the included studies could overcome the problems in their designs, such as lacking of qualified placebo-controlled trials, applying adequate randomisation methods and avoiding potential bias. PMID- 26760987 TI - Nutrition Composition and Single, 14-Day and 13-Week Repeated Oral Dose Toxicity Studies of the Leaves and Stems of Rubus coreanus Miquel. AB - The leaves and stems of the plant Rubus coreanus Miquel (RCMLS) are rich in vitamins, minerals and phytochemicals which have antioxidant, anti-hemolytic, anti-inflammatory, anti-fatigue and anti-cancer effects. However, RCMLS is not included in the Korean Food Standards Codex due to the lack of safety assurance concerning RCMLS. We evaluated single and repeated oral dose toxicity of RCMLS in Sprague-Dawley rats. RCMLS did not induce any significant toxicological changes in both male and female rats at a single doses of 2500 mg/kg/day. Repeated oral dose toxicity studies showed no adverse effects in clinical signs, body weight, food consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology at doses of 625, 1250, and 2500 mg/kg/day. The LD50 and LOAEL of RCMLS might be over 2500 mg/kg body weight/day and no target organs were identified. Therefore, this study revealed that single and repeated oral doses of RCMLS are safe. PMID- 26760988 TI - Genetic Diversity and Association of EST-SSR and SCoT Markers with Rust Traits in Orchardgrass (Dactylis glomerata L.). AB - Orchardgrass (Dactylis glomerata L.), is a well-known perennial forage species; however, rust diseases have caused a noticeable reduction in the quality and production of orchardgrass. In this study, genetic diversity was assessed and the marker-trait associations for rust were examined using 18 EST-SSR and 21 SCoT markers in 75 orchardgrass accessions. A high level of genetic diversity was detected in orchardgrass with an average genetic diversity index of 0.369. For the EST-SSR and SCoT markers, 164 and 289 total bands were obtained, of which 148 (90.24%) and 272 (94.12%) were polymorphic, respectively. Results from an AMOVA analysis showed that more genetic variance existed within populations (87.57%) than among populations (12.43%). Using a parameter marker index, the efficiencies of the EST-SSR and SCoT markers were compared to show that SCoTs have higher marker efficiency (8.07) than EST-SSRs (4.82). The results of a UPGMA cluster analysis and a STRUCTURE analysis were both correlated with the geographic distribution of the orchardgrass accessions. Linkage disequilibrium analysis revealed an average r2 of 0.1627 across all band pairs, indicating a high extent of linkage disequilibrium in the material. An association analysis between the rust trait and 410 bands from the EST-SSR and SCoT markers using TASSEL software revealed 20 band panels were associated with the rust trait in both 2011 and 2012. The 20 bands obtained from association analysis could be used in breeding programs for lineage selection to prevent great losses of orchardgrass caused by rust, and provide valuable information for further association mapping using this collection of orchardgrass. PMID- 26760989 TI - Garlic Supplementation Ameliorates UV-Induced Photoaging in Hairless Mice by Regulating Antioxidative Activity and MMPs Expression. AB - UV exposure is associated with oxidative stress and is the primary factor in skin photoaging. UV-induced reactive oxygen species (ROS) cause the up-regulation of metalloproteinase (MMPs) and the degradation of dermal collagen and elastic fibers. Garlic and its components have been reported to exert antioxidative effects. The present study investigated the protective effect of garlic on UV induced photoaging and MMPs regulation in hairless mice. Garlic was supplemented in the diet, and Skh-1 hairless mice were exposed to UV irradiation five days/week for eight weeks. Mice were divided into four groups; Non-UV, UV irradiated control, UV+1% garlic powder diet group, and UV+2% garlic powder diet group. Chronic UV irradiation induced rough wrinkling of the skin with hyperkeratosis, and administration of garlic diminished the coarse wrinkle formation. UV-induced dorsal skin and epidermal thickness were also ameliorated by garlic supplementation. ROS generation, skin and serum malondialdehyde levels were significantly increased by UV exposure and were ameliorated by garlic administration although the effects were not dose-dependent. Antioxidant enzymes such as superoxide dismutase and catalase activities in skin tissues were markedly reduced by UV irradiation and garlic treatment increased these enzyme activities. UV-induced MMP-1 and MMP-2 protein levels were suppressed by garlic administration. Furthermore, garlic supplementation prevented the UV-induced increase of MMP-1 mRNA expression and the UV-induced decrease of procollagen mRNA expression. These results suggest that garlic may be effective for preventing skin photoaging accelerated by UV irradiation through the antioxidative system and MMP regulation. PMID- 26760990 TI - Design, Synthesis, DFT Study and Antifungal Activity of Pyrazolecarboxamide Derivatives. AB - A series of novel pyrazole amide derivatives were designed and synthesized by multi-step reactions from phenylhydrazine and ethyl 3-oxobutanoate as starting materials, and their structures were characterized by NMR, MS and elemental analysis. The antifungal activity of the title compounds was determined. The results indicated that some of title compounds exhibited moderate antifungal activity. Furthermore, DFT calculations were used to study the structure-activity relationships (SAR). PMID- 26760991 TI - Biochanin A Ameliorates Arsenic-Induced Hepato- and Hematotoxicity in Rats. AB - Biochanin A (BCA) is a natural organic compound of the phytoestrogenic isoflavone class that has antioxidant and metal chelator properties in the presence of transition metal ions, however, its efficacy in animal models is still obscure. Therefore, the objective of this study was to investigate the protective effects of BCA against arsenic-induced hepatic injury and hematotoxicity in rats. The results suggest that arsenic intoxicated rats showed significantly higher levels of plasma hepatic markers than normal control rats. Furthermore, an increase in lipid peroxidation with depletion of reduced glutathione (GSH) and activities of superoxide dismutase (SOD) and catalase (CAT) occurred in the livers of rats exposed to arsenic. Administration of BCA (20 mg/kg.bw/day) and selenium (3 mg/kg.bw/day) resulted in a significant reversal of hepatic and oxidative stress markers in arsenic-intoxicated rats. A low dose of BCA (10 mg/kg.bw/day) did not show any preventive effect, while a high dose of BCA (40 mg/kg.bw/day) partially prevented all hepatotoxicity events. These biochemical perturbations were supported by histopathological observations of the liver. Our results suggest that administration of BCA (20 mg/kg.bw/day) attenuated the arsenic hepatotoxicity, a property that could contribute to the therapeutic approaches for chronic liver diseases. PMID- 26760992 TI - The Protective Effects of Alisol A 24-Acetate from Alisma canaliculatum on Ovariectomy Induced Bone Loss in Vivo. AB - Alisma canaliculatum is a herb commonly used in traditional Korean medicine, and has been shown in scientific studies to have antitumor, diuretic hepatoprotective, and antibacterial effects. Recently, the anti osteoclastogenesis of alisol A 24-acetate from Alisma canaliculatum was investigated in vitro. However, the influence of alisol A 24-acetate on osteoporosis in animals has not been investigated. The present study was undertaken to investigate the anti-osteoporotic effect of alisol A 24-acetate on bone mass in ovariectomized (OVX) mice and to identify the mechanism responsible for its effects. OVX mice were treated daily with 0.5 or 2 MUg/g of alisol A 24 acetate for a period of six weeks. It was found that these administrations significantly suppressed osteoporosis in OVX mice and improved bone morphometric parameters. The serum estradiol, bone alkaline phosphatase levels, regulatory T/Th17 cell numbers were significantly increased by alisol A 24-acetate as compared with untreated OVX mice. In addition, TRAP activity was inhibited by alisol A 24-acetate in OVX mice. These results suggest alisol A 24-acetate effectively prevents bone loss in OVX mice, and that it can be considered a potential therapeutic for the treatment of postmenopausal osteoporosis. PMID- 26760993 TI - Effect of Donepezil, Tacrine, Galantamine and Rivastigmine on Acetylcholinesterase Inhibition in Dugesia tigrina. AB - Dugesia tigrina is a non-parasitic platyhelminth, which has been recently utilized in pharmacological models, regarding the nervous system, as it presents a wide sensitivity to drugs. Our trials aimed to propose a model for an in vivo screening of substances with inhibitory activity of the enzyme acetylcholinesterase. Trials were performed with four drugs commercialized in Brazil: donepezil, tacrine, galantamine and rivastigmine, utilized in the control of Alzheimer's disease, to inhibit the activity of acetylcholinesterase. We tested five concentrations of the drugs, with an exposure of 24 h, and the mortality and the inhibition of acetylcholinesterase planarian seizure-like activity (pSLA) and planarian locomotor velocity (pLMV) were measured. Galantamine showed high anticholinesterasic activity when compared to the other drugs, with a reduction of 0.05 MUmol.min(-1) and 63% of convulsant activity, presenting screw-like movement and hypokinesia, with pLMV of 65 crossed lines during 5 min. Our results showed for the first time the anticholinesterasic and convulsant effect, in addition to the decrease in locomotion induced by those drugs in a model of invertebrates. The experimental model proposed is simple and low cost and could be utilized in the screening of substances with anticholinesterasic action. PMID- 26760994 TI - Antibacterial Activity of Alkaloid Fractions from Berberis microphylla G. Forst and Study of Synergism with Ampicillin and Cephalothin. AB - Berberis microphylla is a native plant that grows in Patagonia and is commonly used by aboriginal ethnic groups in traditional medicine as an antiseptic for different diseases. The present study evaluated the antibacterial and synergistic activity of alkaloid extracts of B. microphylla leaves, stems and roots used either individually or in combination with antibiotics against Gram-positive and Gram-negative bacteria. The in vitro antibacterial activities of leaf, stem and root alkaloid extracts had significant activity only against Gram-positive bacteria. Disc diffusion tests demonstrated that the root extract showed similar activity against B. cereus and S. epidermidis compared to commercial antibiotics, namely ampicillin and cephalothin, and pure berberine, the principal component of the alkaloid extracts, was found to be active only against S. aureus and S. epidermidis with similar activity to that of the root extract. The minimum inhibitory concentrations (MICs) of the alkaloid extracts ranged from 333 to 83 MUg/mL, whereas minimum bactericidal concentrations (MBCs) varied from 717 to 167 MUg/mL. In addition, synergistic or indifferent effects between the alkaloid extracts and antibiotics against bacterial strains were confirmed. PMID- 26760995 TI - The Protective Effects of HJB-1, a Derivative of 17-Hydroxy-Jolkinolide B, on LPS Induced Acute Distress Respiratory Syndrome Mice. AB - Acute respiratory distress syndrome (ARDS),which is inflammatory disorder of the lung, which is caused by pneumonia, aspiration of gastric contents, trauma and sepsis, results in widespread lung inflammation and increased pulmonary vascular permeability. Its pathogenesis is complicated and the mortality is high. Thus, there is a tremendous need for new therapies. We have reported that HJB-1, a 17 hydroxy-jolkinolide B derivative, exhibited strong anti-inflammatory effects in vitro. In this study, we investigated its impacts on LPS-induced ARDS mice. We found that HJB-1 significantly alleviated LPS-induced pulmonary histological alterations, inflammatory cells infiltration, lung edema, as well as the generation of inflammatory cytokines TNF-alpha, IL-1beta and IL-6 in BALF. In addition, HJB-1 markedly suppressed LPS-induced IkappaB-alpha degradation, nuclear accumulation of NF-kappaB p65 subunit and MAPK phosphorylation. These results suggested that HJB-1 improved LPS-induced ARDS by suppressing LPS-induced NF-kappaB and MAPK activation. PMID- 26760996 TI - Anti-Oncogenic gem-Dihydroperoxides Induce Apoptosis in Cancer Cells by Trapping Reactive Oxygen Species. AB - Organic gem-dihydroperoxides (DHPs) and their derived peroxides have attracted a great deal of attention as potential anti-cancer agents. However, the precise mechanism of their inhibitory effect on tumors is unknown. To determine the mechanism of the inhibitory effects of DHPs, we examined the effects of DHPs on leukemia K562 cells. As a result, certain DHPs used in this study exhibited growth-inhibitory activity according to a clear structure-activity relationship. The most potent DHP, 12AC3O, induced apoptosis in K562 cells, but not in peripheral blood monocytes (PBMCs) or fibroblast cells. 12AC3O induced apoptosis through the intrinsic mitochondrial pathway and thereafter through the extrinsic pathway. The activity of the former pathway was partly attenuated by a JNK inhibitor. Interestingly, 12AC3O induced apoptosis by trapping a large amount of ROS, leading to an extremely lower intracellular ROS level compared with that in the cells in the steady-state condition. These results suggest that an appropriate level of intracellular ROS was necessary for the maintenance of cancer cell growth. DHPs may have a potential to be a novel anti-cancer agent with minimum adverse effects on normal cells. PMID- 26760997 TI - NLRP3 Upregulation in Retinal Pigment Epithelium in Age-Related Macular Degeneration. AB - Inflammation and oxidative stress are involved in age-related macular degeneration (AMD) and possibly associated with an activation of neuronal apoptosis inhibitor protein/class II transcription activator of the Major Histocompatibility Complex (MHC)/heterokaryon incompatibility/telomerase associated protein 1, leucine-rich repeat or nucleotide-binding domain, leucine rich repeat-containing family, and pyrin domain-containing 3 (NLRP3) inflammasome. In the present study, we used a translational approach to address this hypothesis. In patients with AMD, we observed increased mRNA levels of NLRP3, pro-interleukin-1 beta (IL-1beta) and pro-IL-18 in AMD lesions of the retinal pigment epithelium (RPE) and photoreceptor. In vitro, a similar increase was evoked by oxidative stress or lipopolysaccharide (LPS) stimulation in the adult retinal pigment epithelium (ARPE-19) cell line, and the increase was reduced in siRNA transfected cells to knockdown NLRP3. Ultrastructural studies of ARPE-19 cells showed a swelling of the cytoplasm, mitochondrial damage, and occurrence of autophagosome-like structures. NLRP3 positive dots were detected within autophagosome-like structures or in the extracellular space. Next, we used a mouse model of AMD, Ccl2/Cx3cr1 double knockout on rd8 background (DKO rd8) to ascertain the in vivo relevance. Ultrastructural studies of the RPE of these mice showed damaged mitochondria, autophagosome-like structures, and cytoplasmic vacuoles, which are reminiscent of the pathology seen in stressed ARPE-19 cells. The data suggest that the NLRP3 inflammasome may contribute in AMD pathogenesis. PMID- 26760999 TI - Antiproliferative Activity of Double Point Modified Analogs of 1,25 Dihydroxyvitamin D2 Against Human Malignant Melanoma Cell Lines. AB - Vitamin D is a lipid soluble steroid hormone with pleiotropic biological properties, including regulation of cell proliferation, differentiation and apoptosis. As to these desirable anticancer actions, 1,25-dihydroxyvitamins D and analogs have been reported to inhibit the proliferation and to induce differentiation of a wide variety of cancer cell types, including human malignant melanoma. However, there is a need for novel and more efficacious vitamin D analogs, and how best to design such is still an open issue. A series of double point modified (DPM) analogs of 1,25-dihydroxyvitamin D2 (1,25(OH)2D2) induced differentiation of the vitamin D receptor (VDR) positive A375 and VDR negative SK MEL 188b human malignant melanoma cell lines. Surprisingly, the dose of 1,25(OH)2D2 required to inhibit the proliferation of the A375 melanoma cell line by was several fold lower than that required in the case of 1,25(OH)2D3. To evaluate the impact of the modification in the side chain (additional 22 hydroxyl) and in the A-ring (5,6-trans modification), the regular side-chain of vitamin D2 or D3 was retained in the structure of our analogs. As expected, 5,6 trans modification was advantageous to enhancing the anti-proliferative activity of analogs, but not as a single point modification (SPM). Very unexpectedly, the additional 22-hydroxyl in the side-chain reduced significantly the anti proliferative activity of both the natural and 5,6-trans series analogs. Finally, an induction of pigmentation in melanoma SK-MEL 188b cells was observed to sensitized cells to the effect of vitamin D analogs. PMID- 26761000 TI - MiRNA-Target Interaction Reveals Cell-Specific Post-Transcriptional Regulation in Mammalian Cell Lines. AB - MicroRNAs are 18-22 nucleotides long, non-coding RNAs that bind transcripts with complementary sequences leading to either mRNA degradation or translational suppression. However, the inherent differences in preferred mode of miRNA regulation among cells of different origin have not been examined. In our previous transcriptome profiling studies, we observed that post-transcriptional regulation can differ substantially depending on the cell in context. Here we examined mechanistic differences in the regulation of a let-7a targeted (wild type) or resistant (mutant) engineered renilla transcript across various mammalian cell lines of diverse origin. Dual luciferase assays show that compared to mutant (mut), the reporter gene containing wild type (wt) let-7a binding sites was efficiently suppressed upon transfection in various cell lines. Importantly, the strength of miRNA regulation varied across the cell lines. Total RNA analysis demonstrates that wt renilla mRNA was expressed to similar or higher levels compared to mut suggesting that translation repression is a predominant mode of miRNA regulation. Nonetheless, transcript degradation was observed in some cell lines. Ago-2 immunoprecipitation show that miRNA repressed renilla mRNA are associated with functional mi-RISC (miRNA-RNA induced silencing complex). Given the immense potential of miRNA as a therapeutic option, these findings highlight the necessity to thoroughly examine the mode of mRNA regulation in order to achieve the beneficial effects in targeting cells. PMID- 26760998 TI - The Roles of RNase-L in Antimicrobial Immunity and the Cytoskeleton-Associated Innate Response. AB - The interferon (IFN)-regulated endoribonuclease RNase-L is involved in multiple aspects of the antimicrobial innate immune response. It is the terminal component of an RNA cleavage pathway in which dsRNA induces the production of RNase-L activating 2-5A by the 2'-5'-oligoadenylate synthetase. The active nuclease then cleaves ssRNAs, both cellular and viral, leading to downregulation of their expression and the generation of small RNAs capable of activating retinoic acid inducible gene-I (RIG-I)-like receptors or the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome. This leads to IFNbeta expression and IL-1beta activation respectively, in addition to broader effects on immune cell function. RNase-L is also one of a growing number of innate immune components that interact with the cell cytoskeleton. It can bind to several cytoskeletal proteins, including filamin A, an actin-binding protein that collaborates with RNase-L to maintain the cellular barrier to viral entry. This antiviral activity is independent of catalytic function, a unique mechanism for RNase-L. We also describe here the interaction of RNase-L with the E3 ubiquitin ligase and scaffolding protein, ligand of nump protein X (LNX), a regulator of tight junction proteins. In order to better understand the significance and context of these novel binding partners in the antimicrobial response, other innate immune protein interactions with the cytoskeleton are also discussed. PMID- 26761001 TI - Revealing the Effects of Missense Mutations Causing Snyder-Robinson Syndrome on the Stability and Dimerization of Spermine Synthase. AB - Missense mutations in spermine synthase (SpmSyn) protein have been shown to cause the Snyder-Robinson syndrome (SRS). Depending on the location within the structure of SpmSyn and type of amino acid substitution, different mechanisms resulting in SRS were proposed. Here we focus on naturally occurring amino acid substitutions causing SRS, which are situated away from the active center of SpmSyn and thus are not directly involved in the catalysis. Two of the mutations, M35R and P112L, are reported for the first time in this study. It is demonstrated, both experimentally and computationally, that for such mutations the major effect resulting in dysfunctional SpmSyn is the destabilization of the protein. In vitro experiments indicated either no presence or very little amount of the mutant SpmSyn in patient cells. In silico modeling predicted that all studied mutations in this work destabilize SpmSyn and some of them abolish homo dimer formation. Since dimerization and structural stability are equally important for the wild type function of SpmSyn, it is proposed that the SRS caused by mutations occurring in the N-domain of SpmSyn is a result of dysfunctional mutant proteins being partially unfolded and degraded by the proteomic machinery of the cell or being unable to form a homo-dimer. PMID- 26761002 TI - Regulatory System for Stem/Progenitor Cell Niches in the Adult Rodent Pituitary. AB - The anterior lobe of the pituitary gland is a master endocrine tissue composed of five types of endocrine cells. Although the turnover rate of pituitary endocrine cells is as low as about 1.6% per day, recent studies have demonstrated that Sex determining region Y-box 2 (SOX2)+-cells exist as pituitary stem/progenitor cells in the adult anterior lobe and contribute to cell regeneration. Notably, SOX2+ pituitary stem/progenitor cells form two types of niches in this tissue: the marginal cell layer (MCL-niche) and the dense cell clusters scattering in the parenchyma (parenchymal-niche). However, little is known about the mechanisms and factors for regulating the pituitary stem/progenitor cell niches, as well as the functional differences between the two types of niches. Elucidation of the regulatory mechanisms in the niches might enable us to understand the cell regeneration system that acts in accordance with physiological demands in the adult pituitary. In this review, so as to reveal the regulatory mechanisms of the two types of niche, we summarize the regulatory factors and their roles in the adult rodent pituitary niches by focusing on three components: soluble factors, cell surface proteins and extracellular matrixes. PMID- 26761004 TI - New 9-Hydroxybriarane Diterpenoids from a Gorgonian Coral Briareum sp. (Briareidae). AB - Six new 9-hydroxybriarane diterpenoids, briarenolides ZI-ZVI (1-6), were isolated from a gorgonian coral Briareum sp. The structures of briaranes 1-6 were elucidated by spectroscopic methods and by comparison of their spectroscopic data with those of related analogues. Briarenolides ZII (2) and ZVI (6) were found to significantly inhibit the expression of the pro-inflammatory inducible nitric oxide synthase (iNOS) protein of lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. PMID- 26761006 TI - Intelligent Condition Diagnosis Method Based on Adaptive Statistic Test Filter and Diagnostic Bayesian Network. AB - A new fault diagnosis method for rotating machinery based on adaptive statistic test filter (ASTF) and Diagnostic Bayesian Network (DBN) is presented in this paper. ASTF is proposed to obtain weak fault features under background noise, ASTF is based on statistic hypothesis testing in the frequency domain to evaluate similarity between reference signal (noise signal) and original signal, and remove the component of high similarity. The optimal level of significance alpha is obtained using particle swarm optimization (PSO). To evaluate the performance of the ASTF, evaluation factor Ipq is also defined. In addition, a simulation experiment is designed to verify the effectiveness and robustness of ASTF. A sensitive evaluation method using principal component analysis (PCA) is proposed to evaluate the sensitiveness of symptom parameters (SPs) for condition diagnosis. By this way, the good SPs that have high sensitiveness for condition diagnosis can be selected. A three-layer DBN is developed to identify condition of rotation machinery based on the Bayesian Belief Network (BBN) theory. Condition diagnosis experiment for rolling element bearings demonstrates the effectiveness of the proposed method. PMID- 26761007 TI - Global Calibration of Multiple Cameras Based on Sphere Targets. AB - Global calibration methods for multi-camera system are critical to the accuracy of vision measurement. Proposed in this paper is such a method based on several groups of sphere targets and a precision auxiliary camera. Each camera to be calibrated observes a group of spheres (at least three), while the auxiliary camera observes all the spheres. The global calibration can be achieved after each camera reconstructs the sphere centers in its field of view. In the process of reconstructing a sphere center, a parameter equation is used to describe the sphere projection model. Theoretical analysis and computer simulation are carried out to analyze the factors that affect the calibration accuracy. Simulation results show that the parameter equation can largely improve the reconstruction accuracy. In the experiments, a two-camera system calibrated by our method is used to measure a distance about 578 mm, and the root mean squared error is within 0.14 mm. Furthermore, the experiments indicate that the method has simple operation and good flexibility, especially for the onsite multiple cameras without common field of view. PMID- 26761008 TI - RAQ-A Random Forest Approach for Predicting Air Quality in Urban Sensing Systems. AB - Air quality information such as the concentration of PM2.5 is of great significance for human health and city management. It affects the way of traveling, urban planning, government policies and so on. However, in major cities there is typically only a limited number of air quality monitoring stations. In the meantime, air quality varies in the urban areas and there can be large differences, even between closely neighboring regions. In this paper, a random forest approach for predicting air quality (RAQ) is proposed for urban sensing systems. The data generated by urban sensing includes meteorology data, road information, real-time traffic status and point of interest (POI) distribution. The random forest algorithm is exploited for data training and prediction. The performance of RAQ is evaluated with real city data. Compared with three other algorithms, this approach achieves better prediction precision. Exciting results are observed from the experiments that the air quality can be inferred with amazingly high accuracy from the data which are obtained from urban sensing. PMID- 26761009 TI - A New Node Deployment and Location Dispatch Algorithm for Underwater Sensor Networks. AB - Considering that deployment strategies for underwater sensor networks should contribute to fully connecting the networks, a Guaranteed Full Connectivity Node Deployment (GFCND) algorithm is proposed in this study. The GFCND algorithm attempts to deploy the coverage nodes according to the greedy iterative strategy, after which the connectivity nodes are used to improve network connectivity and fully connect the whole network. Furthermore, a Location Dispatch Based on Command Nodes (LDBCN) algorithm is proposed, which accomplishes the location adjustment of the common nodes with the help of the SINK node and the command nodes. The command nodes then dispatch the common nodes. Simulation results show that the GFCND algorithm achieves a comparatively large coverage percentage and a fully connected network; furthermore, the LDBCN algorithm helps the common nodes preserve more total energy when they reach their destination locations. PMID- 26761003 TI - Circulating MicroRNAs as Biomarkers for Sepsis. AB - Sepsis represents a major cause of lethality during intensive care unit (ICU) treatment. Pharmacological treatment strategies for sepsis are still limited and mainly based on the early initiation of antibiotic and supportive treatment. In this context, numerous clinical and serum based markers have been evaluated for the diagnosis, the severity, and the etiology of sepsis. However until now, few of these factors could be translated into clinical use. MicroRNAs (miRNAs) do not encode for proteins but regulate gene expression by inhibiting the translation or transcription of their target mRNAs. Recently it was demonstrated that miRNAs are released into the circulation and that the spectrum of circulating miRNAs might be altered during various pathologic conditions, such as inflammation, infection, and sepsis. By using array- and single PCR-based methods, a variety of deregulated miRNAs, including miR-25, miR-133a, miR-146, miR-150, and miR-223, were described in the context of sepsis. Some of the miRNAs correlated with the disease stage, as well as patients' short and long term prognosis. Here, we summarize the current findings on the role of circulating miRNAs in the diagnosis and staging of sepsis in critically ill patients. We compare data from patients with findings from animal models and, finally, highlight the challenges and drawbacks that currently prevent the use of circulating miRNAs as biomarkers in clinical routine. PMID- 26761011 TI - Silica Bottle Resonator Sensor for Refractive Index and Temperature Measurements. AB - We propose and theoretically demonstrate a bottle resonator sensor with a nanoscale altitude and with alength several of hundreds of microns made on the top of the fiber with a radius of tens microns for refractive index and temperature sensor applications. The whispering gallery modes (WGMs) in the resonators can be excited with a taper fiber placed on the top of the resonator. These sensors can be considered as an alternative to fiber Bragg grating (FBG) sensors.The sensitivity of TM-polarized modes is higher than the sensitivity of the TE-polarized modes, but these values are comparable and both polarizations are suitable for sensor applications. The sensitivity ~150 (nm/RIU) can be reached with abottle resonator on the fiber with the radius 10 MUm. It can be improved with theuse of a fiber with a smaller radius. The temperature sensitivity is found to be ~10 pm/K. The temperature sensitivity can decrease ~10% for a fiber with a radius r(co) = 10 MUm instead of a fiber with a radius r(co) = 100 MUm. These sensors have sensitivities comparable to FBG sensors. A bottle resonator sensor with a nanoscale altitude made on the top of the fiber can be easily integrated in any fiber scheme. PMID- 26761010 TI - An Energy-Efficient Skyline Query for Massively Multidimensional Sensing Data. AB - Cyber physical systems (CPS) sense the environment based on wireless sensor networks. The sensing data of such systems present the characteristics of massiveness and multi-dimensionality. As one of the major monitoring methods used in in safe production monitoring and disaster early-warning applications, skyline query algorithms are extensively adopted for multiple-objective decision analysis of these sensing data. With the expansion of network sizes, the amount of sensing data increases sharply. Then, how to improve the query efficiency of skyline query algorithms and reduce the transmission energy consumption become pressing and difficult to accomplish issues. Therefore, this paper proposes a new energy efficient skyline query method for massively multidimensional sensing data. First, the method uses a node cut strategy to dynamically generate filtering tuples with little computational overhead when collecting query results instead of issuing queries with filters. It can judge the domination relationship among different nodes, remove the detected data sets of dominated nodes that are irrelevant to the query, modify the query path dynamically, and reduce the data comparison and computational overhead. The efficient dynamic filter generated by this strategy uses little non-skyline data transmission in the network, and the transmission distance is very short. Second, our method also employs the tuple cutting strategy inside the node and generates the local cutting tuples by the sub-tree with the node itself as the root node, which will be used to cut the detected data within the nodes of the sub-tree. Therefore, it can further control the non-skyline data uploading. A large number of experimental results show that our method can quickly return an overview of the monitored area and reduce the communication overhead. Additionally, it can shorten the response time and improve the efficiency of the query. PMID- 26761005 TI - The Importance of Thrombin in Cerebral Injury and Disease. AB - There is increasing evidence that prothrombin and its active derivative thrombin are expressed locally in the central nervous system. So far, little is known about the physiological and pathophysiological functions exerted by thrombin in the human brain. Extra-hepatic prothrombin expression has been identified in neuronal cells and astrocytes via mRNA measurement. The actual amount of brain derived prothrombin is expected to be 1% or less compared to that in the liver. The role in brain injury depends upon its concentration, as higher amounts cause neuroinflammation and apoptosis, while lower concentrations might even be cytoprotective. Its involvement in numerous diseases like Alzheimer's, multiple sclerosis, cerebral ischemia and haemorrhage is becoming increasingly clear. This review focuses on elucidation of the cerebral thrombin expression, local generation and its role in injury and disease of the central nervous system. PMID- 26761013 TI - Mobile Crowd Sensing for Traffic Prediction in Internet of Vehicles. AB - The advances in wireless communication techniques, mobile cloud computing, automotive and intelligent terminal technology are driving the evolution of vehicle ad hoc networks into the Internet of Vehicles (IoV) paradigm. This leads to a change in the vehicle routing problem from a calculation based on static data towards real-time traffic prediction. In this paper, we first address the taxonomy of cloud-assisted IoV from the viewpoint of the service relationship between cloud computing and IoV. Then, we review the traditional traffic prediction approached used by both Vehicle to Infrastructure (V2I) and Vehicle to Vehicle (V2V) communications. On this basis, we propose a mobile crowd sensing technology to support the creation of dynamic route choices for drivers wishing to avoid congestion. Experiments were carried out to verify the proposed approaches. Finally, we discuss the outlook of reliable traffic prediction. PMID- 26761014 TI - Design Optimization for the Measurement Accuracy Improvement of a Large Range Nanopositioning Stage. AB - Both an accurate machine design and an adequate metrology loop definition are critical factors when precision positioning represents a key issue for the final system performance. This article discusses the error budget methodology as an advantageous technique to improve the measurement accuracy of a 2D-long range stage during its design phase. The nanopositioning platform NanoPla is here presented. Its specifications, e.g., XY-travel range of 50 mm * 50 mm and sub micrometric accuracy; and some novel designed solutions, e.g., a three-layer and two-stage architecture are described. Once defined the prototype, an error analysis is performed to propose improvement design features. Then, the metrology loop of the system is mathematically modelled to define the propagation of the different sources. Several simplifications and design hypothesis are justified and validated, including the assumption of rigid body behavior, which is demonstrated after a finite element analysis verification. The different error sources and their estimated contributions are enumerated in order to conclude with the final error values obtained from the error budget. The measurement deviations obtained demonstrate the important influence of the working environmental conditions, the flatness error of the plane mirror reflectors and the accurate manufacture and assembly of the components forming the metrological loop. Thus, a temperature control of +/-0.1 degrees C results in an acceptable maximum positioning error for the developed NanoPla stage, i.e., 41 nm, 36 nm and 48 nm in X-, Y- and Z-axis, respectively. PMID- 26761012 TI - Synthesis and Application of an Aldazine-Based Fluorescence Chemosensor for the Sequential Detection of Cu2+ and Biological Thiols in Aqueous Solution and Living Cells. AB - A fluorescence chemosensor, 2-hydroxy-1-naphthaldehyde azine (HNA) was designed and synthesized for sequential detection of Cu(2+) and biothiols. It was found that HNA can specifically bind to Cu(2+) with 1:1 stoichiometry, accompanied with a dramatic fluorescence quenching and a remarkable bathochromic-shift of the absorbance peak in HEPES buffer. The generated HNA-Cu(2+) ensemble displayed a "turn-on" fluorescent response specific for biothiols (Hcy, Cys and GSH) based on the displacement approach, giving a remarkable recovery of fluorescence and UV Vis spectra. The detection limits of HNA-Cu(2+) to Hcy, Cys and GSH were estimated to be 1.5 MUM, 1.0 MUM and 0.8 MUM, respectively, suggesting that HNA Cu(2+) is sensitive enough for the determination of thiols in biological systems. The biocompatibility of HNA towards A549 human lung carcinoma cell, was evaluated by an MTT assay. The capability of HNA-Cu(2+) to detect biothiols in live A549 cells was then demonstrated by a microscopy fluorescence imaging assay. PMID- 26761015 TI - An Ensemble Successive Project Algorithm for Liquor Detection Using Near Infrared Sensor. AB - Spectral analysis technique based on near infrared (NIR) sensor is a powerful tool for complex information processing and high precision recognition, and it has been widely applied to quality analysis and online inspection of agricultural products. This paper proposes a new method to address the instability of small sample sizes in the successive projections algorithm (SPA) as well as the lack of association between selected variables and the analyte. The proposed method is an evaluated bootstrap ensemble SPA method (EBSPA) based on a variable evaluation index (EI) for variable selection, and is applied to the quantitative prediction of alcohol concentrations in liquor using NIR sensor. In the experiment, the proposed EBSPA with three kinds of modeling methods are established to test their performance. In addition, the proposed EBSPA combined with partial least square is compared with other state-of-the-art variable selection methods. The results show that the proposed method can solve the defects of SPA and it has the best generalization performance and stability. Furthermore, the physical meaning of the selected variables from the near infrared sensor data is clear, which can effectively reduce the variables and improve their prediction accuracy. PMID- 26761016 TI - Anti-Inflammatory Activity of Tanzawaic Acid Derivatives from a Marine-Derived Fungus Penicillium steckii 108YD142. AB - Chemical investigation of a marine-derived fungus, Penicillium steckii 108YD142, resulted in the discovery of a new tanzawaic acid derivative, tanzawaic acid Q (1), together with four known analogues, tanzawaic acids A (2), C (3), D (4), and K (5). The structures of tanzawaic acid derivatives 1-5 were determined by the detailed analysis of 1D, 2D NMR and LC-MS data, along with chemical methods and literature data analysis. These compounds significantly inhibited nitric oxide (NO) production and the new tanzawaic acid Q (1) inhibited the lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins and mRNA expressions in RAW 264.7 macrophages. Additionally, compound 1 reduced the mRNA levels of inflammatory cytokines. Taken together, the results of this study demonstrated that the new tanzawaic acid derivative inhibits LPS induced inflammation. This is the first report on the anti-inflammatory activity of tanzawaic acid Q (1). PMID- 26761017 TI - The Oligo Fucoidan Inhibits Platelet-Derived Growth Factor-Stimulated Proliferation of Airway Smooth Muscle Cells. AB - In the pathogenesis of asthma, the proliferation of airway smooth muscle cells (ASMCs) is a key factor in airway remodeling and causes airway narrowing. In addition, ASMCs are also the effector cells of airway inflammation. Fucoidan extracted from marine brown algae polysaccharides has antiviral, antioxidant, antimicrobial, anticlotting, and anticancer properties; however, its effectiveness for asthma has not been elucidated thus far. Platelet-derived growth factor (PDGF)-treated primary ASMCs were cultured with or without oligo fucoidan (100, 500, or 1000 ug/mL) to evaluate its effects on cell proliferation, cell cycle, apoptosis, and Akt, ERK1/2 signaling pathway. We found that PDGF (40 ng/mL) increased the proliferation of ASMCs by 2.5-fold after 48 h (p < 0.05). Oligo-fucoidan reduced the proliferation of PDGF-stimulated ASMCs by 75%-99% after 48 h (p < 0.05) and induced G1/G0 cell cycle arrest, but did not induce apoptosis. Further, oligo-fucoidan supplementation reduced PDGF-stimulated extracellular signal-regulated kinase (ERK1/2), Akt, and nuclear factor (NF) kappaB phosphorylation. Taken together, oligo-fucoidan supplementation might reduce proliferation of PDGF-treated ASMCs through the suppression of ERK1/2 and Akt phosphorylation and NF-kappaB activation. The results provide basis for future animal experiments and human trials. PMID- 26761018 TI - Descriptive Characteristics of Surface Water Quality in Hong Kong by a Self Organising Map. AB - In this study, principal component analysis (PCA) and a self-organising map (SOM) were used to analyse a complex dataset obtained from the river water monitoring stations in the Tolo Harbor and Channel Water Control Zone (Hong Kong), covering the period of 2009-2011. PCA was initially applied to identify the principal components (PCs) among the nonlinear and complex surface water quality parameters. SOM followed PCA, and was implemented to analyze the complex relationships and behaviors of the parameters. The results reveal that PCA reduced the multidimensional parameters to four significant PCs which are combinations of the original ones. The positive and inverse relationships of the parameters were shown explicitly by pattern analysis in the component planes. It was found that PCA and SOM are efficient tools to capture and analyze the behavior of multivariable, complex, and nonlinear related surface water quality data. PMID- 26761019 TI - Unemployment Rate, Smoking in China: Are They Related? AB - BACKGROUND: Studies on the relationship between unemployment rate and smoking have yielded mixed results. The issue in China has not been studied. This study aims to examine the influence of unemployment rate on smoking in China. METHODS: Logit model and two-stage least squares (2SLS) estimation were used to estimate the effects. Estimations were done for 4585 individual over 45 using data from China Health and Retirement Longitudinal Study conducted in Zhejiang and Gansu provinces in 2008 and 2012. RESULTS: A percent increase in the unemployment rate resulted in the increase in the likelihood of smoking by a combined 9.1 percent for those who smoked including a 2.9% increase for those who smoked 1-10 cigarettes per day; a 2.8% increase for those who smoked 11-20 cigarettes per day; and a 3.4% increase for those who smoked 20 cigarettes or more per day. The effects were stronger for those who were employed. Non-drinkers were more likely to engage in smoking with increased unemployment rate. 2SLS estimation revealed the same association. CONCLUSIONS: The unemployment rate was positively associated with smoking behavior. Smoking control and intervention strategies should focus on both the individual's characteristics and the physical environment in which unemployment rate tend to rise. PMID- 26761020 TI - Regional Differences in Correlates of Daily Walking among Middle Age and Older Australian Rural Adults: Implications for Health Promotion. AB - Rural Australians are less physically active than their metropolitan counterparts, and yet very little is known of the candidate intervention targets for promoting physical activity in rural populations. As rural regions are economically, socially and environmentally diverse, drivers of regular physical activity are likely to vary between regions. This study explored the region specific correlates of daily walking among middle age and older adults in rural regions with contrasting dominant primary industries. Participants were recruited through print and electronic media, primary care settings and community organisations. Pedometers were worn by 153 adults for at least four days, including a weekend day. A questionnaire identified potential intra-personal, social and environmental correlates of physical activity, according to a social ecological framework. Regression modelling identified independent correlates of daily walking separately in the two study regions. In one region, there were independent correlates of walking from all levels of the social ecological framework. In the other region, significant correlates of daily walking were almost all demographic (age, education and marital status). Participants living alone were less likely to be physically active regardless of region. This study highlights the importance of considering region-specific factors when designing strategies for promoting regular walking among rural adults. PMID- 26761021 TI - Heat and Humidity in the City: Neighborhood Heat Index Variability in a Mid-Sized City in the Southeastern United States. AB - Daily weather conditions for an entire city are usually represented by a single weather station, often located at a nearby airport. This resolution of atmospheric data fails to recognize the microscale climatic variability associated with land use decisions across and within urban neighborhoods. This study uses heat index, a measure of the combined effects of temperature and humidity, to assess the variability of heat exposure from ten weather stations across four urban neighborhoods and two control locations (downtown and in a nearby nature center) in Knoxville, Tennessee, USA. Results suggest that trees may negate a portion of excess urban heat, but are also associated with greater humidity. As a result, the heat index of locations with more trees is significantly higher than downtown and areas with fewer trees. Trees may also reduce heat stress by shading individuals from incoming radiation, though this is not considered in this study. Greater amounts of impervious surfaces correspond with reduced evapotranspiration and greater runoff, in terms of overall mass balance, leading to a higher temperature, but lower relative humidity. Heat index and relative humidity were found to significantly vary between locations with different tree cover and neighborhood characteristics for the full study time period as well as for the top 10% of heat index days. This work demonstrates the need for high-resolution climate data and the use of additional measures beyond temperature to understand urban neighborhood exposure to extreme heat, and expresses the importance of considering vulnerability differences among residents when analyzing neighborhood-scale impacts. PMID- 26761022 TI - Self-Exempting Beliefs and Intention to Quit Smoking within a Socially Disadvantaged Australian Sample of Smokers. AB - An investigation of beliefs used to rationalise smoking will have important implications for the content of anti-smoking programs targeted at socioeconomically disadvantaged groups, who show the lowest rates of cessation in the population. This study aimed to assess the types of self-exempting beliefs reported by a sample of socioeconomically disadvantaged smokers, and identify associations between these beliefs and other smoking-related factors with quit intentions. A cross-sectional survey was conducted from March-December 2012 with smokers seeking welfare assistance in New South Wales (NSW), Australia (n = 354; response rate 79%). Responses to a 16-item self-exempting beliefs scale and intention to quit, smoker identity, and enjoyment of smoking were assessed. Most participants earned =70) and significantly correlated with website rank (Spearman rho = -0.3164; P = 0.009). CONCLUSIONS: Rhinoplasty internet health information is generally of low quality, unreliable and less readable than recommended. Improvements are needed to increase the quality of internet rhinoplasty resources for patients. PMID- 26761155 TI - Cross-Coupling of Meyer-Schuster Intermediates under Dual Gold-Photoredox Catalysis. AB - Under dual gold/photoredox catalytic conditions, intermediates from the Meyer Schuster rearrangement underwent an efficient cross-coupling with arene diazonium salts, leading to alpha-arylated enones. Diazonium salts assisted the dissociation of the propargyl hydroxyl group by forming alkoxydiazenes in the Meyer-Schuster rearrangement, and the coupling was proposed to proceed through an allenyl methyl ether. PMID- 26761156 TI - You Can't Classify All of the People All of the Time. AB - When performing a classification study, it is sometimes a sound strategy not to classify all subjects but to leave a residue of unclassified entities to be analyzed separately. Starting from an interactional paradigm, theoretical reasons for this approach were given. A procedure, RESIDAN, for carrying out a classification analysis using a residue was presented and empirical results for two data sets were given, both of which indicated that belonging to a residue is a property of individuals that has a significant stability over time. Although RESIDAN can be applied to data from a single measurement period, test-retest data are useful for separating subjects with true deviant patterns from subjects with deviant patterns caused by errors of measurement. It was argued that the concept of antitype (= rare pattern) has theoretical significance and could be studied within the presented framework. PMID- 26761157 TI - Uniform Indices-of-Fit for Factor Analysis Models. PMID- 26761154 TI - Improved Accuracy from Joint X-ray and NMR Refinement of a Protein-RNA Complex Structure. AB - Integrated experimental approaches play an increasingly important role in structural biology, taking advantage of the complementary information provided by different techniques. In particular, the combination of NMR data with X-ray diffraction patterns may provide accurate and precise information about local conformations not available from average-resolution X-ray structures alone. Here, we refined the structure of a ternary protein-protein-RNA complex comprising three domains, Sxl and Unr, bound to a single-stranded region derived in the msl2 mRNA. The joint X-ray and NMR refinement reveals that-despite the poor quality of the fit found for the original structural model-the NMR data can be largely accommodated within the uncertainty in the atom positioning (structural noise) from the primary X-ray data and that the overall domain arrangements and binding interfaces are preserved on passing from the crystalline state to the solution. The refinement highlights local conformational differences, which provide additional information on specific features of the structure. For example, conformational dynamics and heterogeneity observed at the interface between the CSD1 and the Sxl protein components in the ternary complex are revealed by the combination of NMR and crystallographic data. The joint refinement protocol offers unique opportunities to detect structural differences arising from various experimental conditions and reveals static or dynamic differences in the conformation of the biomolecule between the solution and the crystals. PMID- 26761158 TI - Cognitive Differentiation Analysis: A Regression Extension of the Reynolds Sutrick Model. AB - Cognitive Differentiation Analysis (CDA) represents a method to directly measure the correspondence of an individual vector or a composite vector of descriptor ratings to a matrix of pairwise dissimilarity judgments where both sets of judgments are assumed to be ordinal. The zero intercept regression extension of CDA detailed in this paper yields a weight for each descriptor in the set, as opposed to the standard equal weighting case from which a composite vector would be constructed. An artifical example and an applied example are presented utilizing both ordinal and interval assumptions for the descriptor variables. PMID- 26761159 TI - Multiple Group Factor Analysis of Multitrait-Multimethod Matrices. AB - Jackson (1975) suggested a two step procedure for analysis of multitrait multimethod matrices: (1) The trait measures within each method are transformed into principal components, which are then rotated to maximize the correlations with the original trait measures; (2) A principal components analysis is applied to the intercorrelation matrix of these variables. A third step, suggested here, transforms the solution to a classical multiple group factor analysis. A reanalysis of two numerical illustrations shows that the classical procedure yields similar results. PMID- 26761161 TI - The Development of a Leader Power Inventory. AB - The objective of this study was the development of an instrument containing factorially independent subscales for measuring five bases of leader power: coercive, reward, legitimate, expert, and referent. The items for the instrument were selected on the basis of feedback from the Ss and faculty and an iterative process of factor analyses of data from six successive convenience samples and a random sample (N = 1,256). Data on the final instrument from a national random sample of executives (n = 476) and a collegiate sample of employed business students (n = 297) showed that the instrument had adequate reliability and validity and was free from social desirability response set. PMID- 26761160 TI - Factor Analysis of the WAIS-R Using the Factor Replication Procedure, FACTOREP. AB - The factor structure of the WAIS-R has been the subject of much debate and recently researchers have examined multiple independent samples and compared the resulting factor structures using the coefficient of congruence. On the basis of this, one recent study concluded that the WAIS-R had three clear factors. In the present study this conclusion was questioned and it was claimed that the previous result was an artifact caused by the large general factor found in the WAIS-R. The present study aimed to clarify the situation by using identical data but the alternative factor comparison technique, FACTOREP, which was able to reduce the influence of both error variance and the general factor. On the basis of this comparison it was demonstrated that the WAIS-R has two strong factors but that there is little evidence for the existence of a third factor. PMID- 26761162 TI - Imagery Measures of Ego, Id, Superego, and Identity: Validity Studies. AB - Five validity studies of scales in the Study of Imagery are reported. Multistage Bonferroni procedures are used to evaluate significance of results. Scales of superego strength and id derivatives both correlate positively with neuroticism as measured by the Eysenck Personality Inventory. The scale of ego strength correlates positively with a measure indicating aspects of behavioral self control. The scale measuring sense of identity correlates positively with measures of adaptive ego strength and of behavioral self-control, and negatively with a measure of behavioral conflict and one measure of toughmindedness. PMID- 26761163 TI - Psychometric and Geometric Characteristics of the Revised Interpersonal Adjective Scales (IAS-R). AB - Previous research has suggested that the Interpersonal Adjective Scales (IAS) have properties that are compatible with the substantive, structural, and external characteristics required by the circumplex-based interpersonal theory which guided scale construction procedures. In the present study, we describe an item-analytic procedure that identifies and selects items in terms of their estimated geometric location within a circumplex model and we apply the procedure to the task of reducing the 128-item IAS to a 64-item short form version (IAS-R). Scales constructed to conform to a circumplex model are evaluated by somewhat different structural criteria than are those developed to conform to other multivariate models and these differences are illustrated. The resultant IAS-R was found to have improved substantive and structural characteristics and acceptable reliability. We discuss possible applications of this highly efficient measure of interpersonal behavior. PMID- 26761164 TI - A Monte Carlo Investigation of the Likelihood Ratio Test for Number of Classes in Latent Class Analysis. AB - When using latent class analysis to explore multivariate categorical data an important question is -- how many classes are appropriate for this data? An obvious candidate to answer the question is the likelihood ratio test of c[SUB0] against c[SUB1] classes. In this paper this test is investigated by Monte Carlo methods; results confirm that the usually assumed null distribution is inappropriate. PMID- 26761165 TI - Primary Ciliary Dyskinesia: Ciliary Beat Pattern/Frequency, Role of Molecular Analysis in the Diagnosis, and Neonatal Distress. PMID- 26761166 TI - Effect of Addition of Allium hookeri on the Quality of Fermented Sausage with Meat from Sulfur Fed Pigs during Ripening. AB - The effect of the addition of Allium hookeri on the quality of fermented sausage made with meat from sulfur fed pigs was examined, throughout a 60 d ripening period. There were two treatments in animal management: normal feed fed pigs, and sulfur fed pigs given 0.3% sulfur mixed normal feed. Fermented sausage manufactured with meat from normal feed fed pigs, and with meat from sulfur fed pigs, and 1% A. hookeri-containing fermented sausage processed with meat from sulfur fed pigs, were determined at 1 d, 15 d, 30 d, and 60 d. The meat qualities in fermented sausage were measured by DPPH radical scavenging activity (DPPH), ABTS(+) radical scavenging activity (ABTS(+)), total phenolic acids, and total flavonoid contents. Fermented sausage made from pigs that had been fed with 0.3% sulfur was protected from oxidation by reduced free radical, as shown by the significant increase in DPPH and ABTS(+) values, compared with fermented sausage made from normal feed fed pigs (p<0.05). A. hookeri-added fermented sausage with sulfur fed pork was shown to increase the values in DPPH, ABTS(+), total phenolic acid, and total flavonoid contents, by comparison with both the control sausage, and sausage with sulfur fed pork, at 60 d. These results suggest that A. hookeri in meat from sulfur fed pigs could be a source of natural addition, to increase quality in the food industry. PMID- 26761167 TI - Effect of Packaging Method on the Lipid Oxidation, Protein Oxidation, and Color in Aged Top Round from Hanwoo (Korean Native Cattle) during Refrigerated Storage. AB - The objective of this study was to investigate the effects of the packaging method on the lipid and protein oxidation, and color in aged top round from Hanwoo (Korean native cattle) for 14 d at 4C. Catalase activity was the highest (p<0.05) in vacuum packaging (VP) treatment during storage, and was higher (p<0.05) in 50% Ox-MAP and 50% Ox-MAP+vacuum skin packaging (VSP) treatments than in other treatments at d 14. Superoxide dismutase activity was higher (p<0.05) in VP, 50% Ox-MAP, and 50% Ox-MAP+VSP treatments than in other treatments at d 14. During storage, total antioxidant activity was the highest (p<0.05) in VP treatment and was higher (p<0.05) in 50% Ox-MAP+VSP treatment than in 80% Ox-MAP treatment. TBARS value was the lowest (p<0.05) in VP treatment during storage and was lower (p<0.05) in 50% Ox-MAP and Ox-MAP+VSP treatments than in 80% Ox-MAP and Ox-MAP treatments, respectively. Carbonyl content was the lowest (p<0.05) in VP treatment from 10 d. From 7 d, the a* value was the highest (p<0.05) in VP treatment and was higher (p<0.05) in 50% Ox-MAP and 50% Ox-MAP+VSP treatments than in other treatments. The b* value was the highest (p<0.05) in VP treatment from 3 d, and was higher (p<0.05) in 80% Ox-MAP+VSP, 50% Ox-MAP, and 50% Ox-MAP+ VSP treatments than in 80% Ox-MAP treatment at d 14. Therefore, VP improved the oxidation and red color stabilities in stored-aged top round compared with Ox MAP. In addition, 50% Ox-MAP improved the lipid oxidation and red color stabilities compared with 80% Ox-MAP, and its inhibitory effect on lipid oxidation was enhanced by combination with VSP. PMID- 26761168 TI - In Vitro Effects of Cooking Methods on Digestibility of Lipids and Formation of Cholesterol Oxidation Products in Pork. AB - This study investigated the effects of cooking methods on the digestibility of lipids and formation of cholesterol oxidation products (COPs) in pork, during in vitro human digestion. Pork patties were cooked using four different methods (oven cooking, pan frying, boiling, and microwaving), to an internal temperature of approximately 85C. The digestibility of pork patties were then evaluated, using the in vitro human digestion model that simulated the composition (pH, minerals, surfaceactive components, and enzymes) of digestive juices in the human mouth, stomach, and small intestine. The total lipid digestibility was higher after microwave cooking, whereas pan-frying resulted in lower in vitro digestibility, compared to the other cooking methods. The microwaving method followed by in vitro digestion also showed significantly higher content of free fatty acids and thiobarbituric acid reactive substances (TBARS), compared to the other cooking methods; whereas, the pan frying and boiling methods showed the lowest. Cholesterol content was not significantly different among the cooked samples before, and after in vitro human digestion. The formation of COPs was significantly higher in the microwave-treated pork samples, compared to those cooked by the other methods, which was consistent with the trend for lipid peroxidation (TBARS). We propose that from the point of view of COPs formation and lipid oxidation, the pan-frying or boiling methods would be useful. PMID- 26761169 TI - Comparison of Physicochemical and Functional Traits of Hanwoo Steer Beef by the Quality Grade. AB - The physicochemical and functional traits for loin muscles of Hanwoo steers were compared by quality grade (QG). A total of 500 Hanwoo steers were slaughtered, their carcasses were categorized into four groups (QG 1++, 1+, 1, and 2), and the longissimus dorsi muscles were analyzed. QG 1++ group had the highest fat and lowest moisture content (p<0.05). QG 1++ showed higher L* and b* color values, higher cooking loss, and lower shear force values, compared with the other groups (p<0.05). The flavor, tenderness, juiciness, and preference scores by sensory evaluation were highly ranked for premium QG groups (1++ and 1+). Regarding the micro compounds, QG 1 and QG 2 had greater amounts of inosine monophosphate, and QG 2 had greater amounts of anserine, carnosine, and creatine, than QG 1++ (p<0.05). QG 1++ and 1+ had higher percentages of oleic acid (C18:1) than QG 2 (p<0.05). Within premium QG 1++ and 1+, the results of the nucleotides, free amino acids, dipeptides, and fatty acids did not show any distinctive differences. Hanwoo beef as determined by the current grading system was not significantly different in terms of functional components; the only significant difference was in intramuscular fat content. PMID- 26761170 TI - Characterization of Edible Pork By-products by Means of Yield and Nutritional Composition. AB - Basic information regarding the yield and nutritional composition of edible pork by-products, namely heart, liver, lung, stomach, spleen, uterus, pancreas, and small and large intestines, was studied. Our results revealed that the yields varied widely among the pork by-products examined; in particular, liver had the highest yield (1.35%); whereas, spleen had the lowest yield (0.16%). The approximate composition range (minimum to maximum) of these by-products was found to be: moisture 71.59-82.48%; fat 0.28-19.54%; ash 0.155-1.34%, and protein 8.45 22.05%. The highest protein, vitamin A, B2, B6, and total essential amino acid (EAA) contents were found in liver. Large intestine had the highest fat content and lowest EAA content. Heart had the highest vitamin B1 content, whereas pancreas had the highest niacin and vitamin B3 contents. The concentrations of Fe and Zn were highest in liver and pancreas. Total saturated fatty acids (SFA) levels and polyunsaturated fatty acids (PUFA) levels between the by-products ranged from 43.15-50.48%, and 14.92-30.16%, respectively. Furthermore, with the exception of large intestine, all the by-products showed favorable PUFA/SFA ratios. The study indicated that almost all of the pork by-products examined were good sources of important nutrients, and that these data will be of great importance in the promotion of the consumption of edible pork by-products, as well as their utilization in meat processing. PMID- 26761171 TI - Effects of pH-treated Fish Sarcoplasmic Proteins on the Functional Properties of Chicken Myofibrillar Protein Gel Mediated by Microbial Transglutaminase. AB - pH adjustment would be of advantage in improving the water holding capacity of muscle proteins. The objective of this study was to evaluate the addition of fish sarcoplasmic protein (SP) solution, which was adjusted to pH 3.0 or 12.0, neutralized to pH 7.0, and lyophilized to obtain the acid- and alkaline-treated SP samples, on the functional properties of the chicken myofibrillar protein induced by microbial transglutaminase (MTG). The solubility of alkaline-treated SP was higher than that of the acid counterpart; however, those values of the two pH-treated samples were lower than that of normal SP (p<0.05). All SP solutions were mixed with myofibrillar proteins (MP) extracted from chicken breast, and incubated with MTG. The shear stresses of MP with acid- and alkaline-treated SP were higher than that of normal SP. The thermal stability of MP mixture reduced upon adding SP, regardless of the pH treatment. The breaking force of MP gels with acid-treated SP increased more than those of alkaline-treated SP, while normal SP showed the highest value. The MP gel lightness increased, but cooking loss reduced, with the addition of SP. Smooth microstructure of the gel surface was observed. These results indicated that adjusting the pH of SP improved the water holding capacity of chicken myofibrillar proteins induced by MTG. PMID- 26761172 TI - Determination of the Authenticity of Dairy Products on the Basis of Fatty Acids and Triacylglycerols Content using GC Analysis. AB - Milk fat is an important food component, and plays a significant role in the economics, functional nutrition, and chemical properties of dairy products. Dairy products also contain nutritional resources and essential fatty acids (FAs). Because of the increasing demand for dairy products, milk fat is a common target in economic fraud. Specifically, milk fat is often replaced with cheaper or readily available vegetable oils or animal fats. In this study, a method for the discrimination of milk fat was developed, using FAs profiles, and triacylglycerols (TGs) profiles. A total of 11 samples were evaluated: four milk fats (MK), four vegetable oils (VG), two pork lards (PL), and one beef tallow (BT). Gas chromathgraphy analysis were performed, to monitor the FAs content and TGs composition in MK, VG, PL, and BT. The result showed that qualitative determination of the MK of samples adulterated with different vegetable oils and animal fats was possible by a visual comparision of FAs, using C14:0, C16:0, C18:1n9c, C18:0, and C18:2n6c, and of TGs, using C36, C38, C40, C50, C52, and C54 profiles. Overall, the objective of this study was to evaluate the potential of the use of FAs and TGs in the detection of adulterated milk fat, and accordingly characterize the samples by the adulterant oil source, and level of adulteration. Also, based on this preliminary investigation, the usefulness of this approach could be tested for other oils in the future. PMID- 26761174 TI - Effects of Ripening Conditions on the 'Lomo embuchado' Sausage Quality. AB - The objective of this study was to investigate the effects of two different ripening durations, with, or without adding rosemary powder, on Lomo embuchado (LEO) sausage quality. All LEOs were ripened for two different durations, 45 or 60 d, with, or without the addition of rosemary powder, as follows: 1) LEO ripened for 45 d (LER45), 2) LEO ripened for 60 d (LER60), 3) rosemary LEO ripened for 45 d (RLE45), and 4) rosemary LEO ripened for 60 d (RLE60). Significant differences were observed in both moisture and ash content, with higher moisture and less ash content in LER45 (p<0.05). No trend was shown in the crude protein content of the four different treatments, but significantly low protein content was shown only in RLE45 (p<0.05). Ripening for 45 d improved the lightness, yellowness, and water activity of LEOs (p<0.05). However, ripening duration together with rosemary powder addition had no significant effects on redness (p>0.05). The LER45 generated significantly improved chewiness, gumminess, and hardness, as compared to both LER60 and RLE60 (p<0.05). In conclusion, the results suggest that ripening for 45 d seems to enhance LEO quality, but that rosemary powder addition may not be required to develop good LEO quality. PMID- 26761173 TI - Porcine Splenic Hydrolysate has Antioxidant Activity in vivo and in vitro. AB - The antioxidant capacity of porcine splenic hydrolysate (PSH) was studied in vitro and in vivo. Peptide hydrolysates were prepared, using the proteolytic enzyme Alcalase((r)). The molecular weights of PSH were 37,666, 10,673, 6,029, and 2,918 g/mol. Rats were fed a 5% (w/v) PSH diet, instead of a casein diet, for 4 wk. The food intake, body weight gain, and liver weight of rats in the PSH group were similar to those in the control (CONT) group. There were no differences in the serum total cholesterol, triglyceride, total protein, or albumin levels between PSH and CONT groups. However, the level of in vivo hepatic lipid peroxidation in PSH group was significantly lower than that in CONT. In vivo hepatic catalase and glutathione peroxidase activities in the PSH group were significantly higher than those in the control group. The in vitro protein digestibility of PSH was lower than that of casein. The in vitro trolox equivalent antioxidant capacity of PSH was significantly higher than that of the peptide hydrolysate from casein. The in vitro radical scavenging activities of PSH were significantly higher than those of the peptide hydrolysate from casein. The present findings suggest that porcine splenic peptides improve the antioxidant status in rats by enhancing hepatic catalase and GSH-Px activities, and indicate a potential mechanism of radical scavenging activity during gastrointestinal passage. PMID- 26761175 TI - Development of Rapid Diagnostic Kit for Identification of Hanwoo (Korean Native Cattle) Brand Meat by Detecting BIO-TAG. AB - This study was performed to develop a rapid immuno-assay kit, by using a specific antigen to detect Hanwoo brand meat. We selected a synthetic antigen specific to our target antibody, named BIO-TAG (Tyr-D-Ala-Phe), by utilizing a computer-based analysis and literature review. BIO-TAG tagged with adjuvant was subcutaneously injected in sheep and Hanwoo. The serum and meat juice of the immunized or non immunized animal were then analyzed, to measure the titer of antibody by ELISA and Western blot. The amount of antibodies against the BIO-TAG increased (p<0.05) in serum by vaccination. Furthermore, meat juice from the immunized Hanwoo showed greater (p<0.05) antibody titer, compared with those from non-immunized groups. To optimze the dilution factor, we performed dot-ELISA, with various combination levels of BIO-TAG. Results from dot-ELISA showed that 2 mg/mL BIO-TAG was sufficient to distinguish the immunized meat from non-immunized groups. These results support our hypothesis that simple immunization of Hanwoo generates a sufficient amount of antibodies to be detectable in the meat juice by means of the immune-assay. Therefore, specific Hanwoo brand meat can be more precisely identified by our rapid diagnostic kit. This technology can deter possible fraud of counterfeit meat brands in the Korean domestic market with ease and rapidity; and offers a new tool that guarantees consumers high quality Hanwoo brand beef. PMID- 26761176 TI - Evaluation of Fermented Sausages Manufactured with Reduced-fat and Functional Starter Cultures on Physicochemical, Functional and Flavor Characteristics. AB - Fermented foods with probiotics having functional properties may provide beneficial effects on health. These effects are varied, depending on the type of lactic acid bacteria (LAB). Different probiotic LAB might have different functional properties. Thus, this study was performed to evaluate the quality of fermented sausages manufactured with functional starter cultures (Lactobacillus plantarum 115 and 167, and Pediococcus damnosus L12) and different fat levels, and to determine the optimum condition for the manufacture of these products. Medium-fat (~15%) fermented sausages reduced the drying time and cholesterol contents, as compared to regular-fat counterparts. In proximate analysis, the contents of moisture and protein of regular-fat products were lower than medium fat with reduced fat content. The regular-fat products also had a lighter color and less redness, due to reduced fat content. Approximately 35 volatile compounds were identified in functional fermented sausages, and hexanal, trans caryophyllene, and tetradecanal were the major volatile compounds. Selected mixed starter culture showed the potential possibility of replacing the commercial starter culture (LK30 plus) in flavor profiles. However, medium-fat fermented sausage containing selected mixed starter culture tended to be less acceptable than their high-fat counterparts, due to excess dry ring developed in the surface. These results indicate that the use of combinations of L. plantarum 115 and 167, and P. damnosus L12 as a starter culture, will prove useful for manufacturing the fermented sausage. PMID- 26761177 TI - Alteration of Porcine Serum Albumin Levels in Pork Meat by Marination in Kiwi or Pineapple Juice and Subsequent Pan Broiling. AB - This study was conducted to evaluate the changes in porcine serum albumin (PSA), a major allergen, which occur when raw pork ham is marinated with kiwi or pineapple juice, and/or when the ham is pan broiled at 300C for 4 min after marination. In this study, raw pork ham was soaked for 4 h or 8 h in marinades containing commercial marinating sauce only, commercial marinating sauce and 7% kiwi juice, or commercial marinating sauce and 7% pineapple juice. When the meat was marinated and then pan-broiled, pork ham meat protein was significantly denatured and hydrolyzed, and the level of PSA in the meat was significantly reduced. The PSA contents of pork broiled without marination, pork that had been marinated in commercial marinating sauce alone, pork that had been marinated in commercial marinating sauce with kiwi juice, and pork that had been marinated in commercial marinating sauce with pineapple juice, were 95.4, 43.3, 14.3, and 5.4 ng/mL, respectively (p<0.05). Marinating with pineapple juice was more effective than marinating with kiwi juice; and marination for 8 h was more effective than marinating for 4 h. These results indicate that the level of PSA in pork ham is effectively reduced, when the meat is first marinated in sauces that contain kiwi or pineapple extracts for 8 h, rather than 4 h, and then cooked. Further study is needed to determine whether marinated pork meat reduces allergenicity in vivo, as well. PMID- 26761179 TI - Effect of Oyster Shell Calcium Powder on the Quality of Restructured Pork Ham. AB - This study was conducted to evaluate the effects of oyster shell calcium powder (OSCP) as a substitute for phosphates in curing agent, on the quality of restructured pork ham. Restructured pork ham was processed under six treatment conditions: T1 (no additives), T2 (0.3% sodium tripolyphosphate), T3 (1.5% NaCl+0.5% whey protein), T4 (1.5% NaCl+0.5% whey protein+0.15% OSCP), T5 (1.5% NaCl+0.5% whey protein+0.3% OSCP), and T6 (1.5% NaCl+0.5% whey protein+0.5% OSCP). Addition of OSCP significantly increased the ash content and pH of restructured pork ham (p<0.05), but did not affect the cooking loss and water holding capacity values of restructured pork ham. Addition of OSCP had no effect on Hunter a and b surface color values of restructured pork ham, but did decrease the Hunter L surface color value (p<0.05). The addition of 0.5% OSCP showed significantly higher chewiness and springiness values of restructured pork ham, compared with the addition of phosphates (p<0.05). In conclusion, the addition of OSCP combined with low NaCl and 0.5% whey protein can be considered a viable substitute for phosphates in the curing agent, when processing restructured pork ham. PMID- 26761178 TI - Antioxidant Effect and Functional Properties of Hydrolysates Derived from Egg White Protein. AB - This study utilized commercially available proteolytic enzymes to prepare egg white protein hydrolysates (EPHs) with different degrees of hydrolysis. The antioxidant effect and functionalities of the resultant products were then investigated. Treatment with Neutrase yielded the most alpha-amino groups (6.52 mg/mL). Alcalase, Flavourzyme, Protamex, and Ficin showed similar degrees of alpha-amino group liberation (3.19-3.62 mg/mL). Neutrase treatment also resulted in the highest degree of hydrolysis (23.4%). Alcalase and Ficin treatment resulted in similar degrees of hydrolysis. All hydrolysates, except for the Flavourzyme hydrolysate, had greater radical scavenging activity than the control. The Neutrase hydrolysate showed the highest 2,2-azino-bis-(3 ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity (IC50=3.6mg/mL). Therefore, Neutrase was identified as the optimal enzyme for hydrolyzing egg-white protein to yield antioxidant peptides. During Neutrase hydrolysis, the reaction rate was rapid over the first 4 h, and then subsequently declined. The IC50 value was lowest after the first hour (2.99 mg/mL). The emulsifying activity index (EAI) of EPH treated with Neutrase decreased, as the pH decreased. The EPH foaming capacity was maximal at pH 3.6, and decreased at an alkaline pH. Digestion resulted in significantly higher 1,1-diphenyl-2 picrylhydrazyl (DPPH) and ABTS radical scavenging activity. The active peptides released from egg-white protein showed antioxidative activities on ABTS and DHHP radical. Thus, this approach may be useful for the preparation of potent antioxidant products. PMID- 26761180 TI - Effects of Red and Green Glassworts (Salicornia herbacea L.) on Physicochemical and Textural Properties of Reduced-salt Cooked Sausages. AB - This study was conducted to determine the effects of red and green glasswort on the physicochemical and textural properties of reduced-salt cooked sausages. The control was formulated with 1.5% NaCl; then, three reduced-salt treatments were prepared, with 0.75% NaCl (RS), 0.75% NaCl+1.0% red glasswort (RSR) and 0.75% NaCl+1.0% green glasswort (RSG), respectively. The addition of glasswort within the added amount of 1% had no influence on the pH value of the reduced-salt cooked sausages, regardless of the glasswort type. In terms of color, RSG treatment conveyed a higher hue angle value than the RSR treatment (p<0.05). Increases in the protein solubility (total and myofibrillar proteins) and apparent viscosity of reduced-salt meat batter that were due to the addition of glasswort were observed; however, there were no differences according to the type of glasswort (p>0.05). Furthermore, the addition of glasswort, regardless of its type, resulted in decreased cooking loss, and increased emulsion stability. As a result, reduced-salt cooked sausages formulated with either red or green glasswort demonstrated similar textural properties to those of the control. In conclusion, the type of glasswort within an added amount of 1% had no influence on the physicochemical and textural properties of reduced-salt cooked sausages, except for the color characteristics. In terms of color alteration by the addition of glasswort, the red glasswort, which in comparison with the green glasswort could minimize the color changes of reduced-salt cooked sausages, might be an effective source for manufacturing meat products. PMID- 26761181 TI - Effect of Duck Feet Gelatin Concentration on Physicochemical, Textural, and Sensory Properties of Duck Meat Jellies. AB - This study was conducted to determine the effect of duck feet gelatin concentration on the physicochemical, textural and sensory properties of duck meat jellies. Duck feet gelatin was prepared with acidic swelling and hot water extraction. In this study, four duck meat jellies were formulated with 3, 4, 5, and 6% duck feet gelatin, respectively. In the preliminary experiment, the increase in duck feet gelatin ranged from 5 to 20%, resulting in a significant (p<0.001) increase in the color score, but a decline in the hardness and dispersibility satisfaction scores. An increase in the added amount of duck feet gelatin contributed to decreased lightness and increased protein content in duck meat jellies. Regarding the textural properties, increase in the added amount of duck feet gelatin highly correlated with the hardness in the center (p<0.01, R (2)=0.91), and edge (p<0.01, R (2)=0.89), of duck meat jellies. Meanwhile, the increase in duck feet gelatin decreased the score for textural satisfaction; duck meat jellies containing 6% duck feet gelatin had a significantly lower textural satisfaction score, than those containing 3% duck feet gelatin (p<0.05). Furthermore, a significant difference in the overall acceptance of duck meat jellies formulated with 5% duck feet gelatin was observed, as compared to those prepared with 3% duck feet gelatin. Therefore, this study suggested that duck feet gelatin is a useful ingredient for manufacturing cold-cut meat products. In consideration of the sensory acceptance, the optimal level of duck feet gelatin in duck meat jellies was determined to be 5%. PMID- 26761182 TI - Effects of Kaolinite (Macsumsuk) and Herb Mixtures on the Quality and Physicochemical Properties of Pork. AB - The current study was conducted to identify technology for the production of high quality pork, based on the meat consumption habits of consumers. Macsumsuk, a type of kaolinite (a clay mineral), and/or a mixture of herbs (Mori Folium, Sophorae Radix, Glycyrrhizae Radix, Citri Leiocarpae Exocarpium, and Pogostemi Herba) were added to the diets of fattening pigs. Sixty barrow pigs (4 kinds of treatment * 5 pigs/treatment * 3 replicates) were randomly assigned to either the Control (no additives), T1 (3% Macsumsuk), T2 (3% Herb mixtures), or T3 (3% Macsumsuk + 3% Herb mixtures) groups, and were fed the diets for 60 d. Dressed weights were in the order of T1 (93.40+/-4.68kg) > T2 (91.40+/-6.52kg) > Control (88.80+/-1.57kg) > T3 (86.80+/-2.01kg). Back-fat thickness of the Control animals (23.2+/-1.03) was significantly greater than that of the various treatment groups (p<0.01). Numeric values representing the carcass yield and quality grade were higher for all the treated groups than the Control group, thought the difference was not statistically significant. Crude fat content was significantly higher in the Control group (2.23+/-0.34%) than in the treated groups (p<0.05). The addition of both Macsumsuk and herb mixtures into the diets of the pigs significantly reduced cooking loss of the pork compared to the Control (p<0.05). No statistically significant changes were observed in the shear force (average 5.87+/-0.54 kg/cm(2)), water holding capacity (average 54.59+/-3.16%), or CIE values of the pork, whereas cholesterol levels significantly decreased (p<0.01) in those fed Macsumsuk and/or the herb mixtures. No significant changes in fatty acid composition, total saturated fatty acid (SFA), total unsaturated fatty acid (UFA), or UFA/SFA ratios were observed by any of the treatments. In conclusion, the results obtained from this study suggest that the addition of Macsumsuk and/or herb mixtures into the diets of growing and fattening pigs improves the pork quality by reducing cooking loss, decreasing cholesterol content, and enhancing sensory characteristics. PMID- 26761183 TI - Malignant transformation of residual posterior fossa epidermoid cyst to squamous cell carcinoma. AB - Malignant transformation of intracranial epidermoid cysts to squamous cell carcinoma is a rare occurrence and only a small number have been reported to date. MRI recurrence in combination with neurological decline should prompt surgery to exclude malignant transformation. Herein, we describe our experience of such a case and contribute to the evolving series within the literature. PMID- 26761184 TI - Targeting mitochondrial function to protect against vision loss. AB - INTRODUCTION: Mitochondria, essential to multicellular life, convert food into ATP to satisfy cellular energy demands. Since different tissues have different energy requirements, mitochondrial density is high in tissues with high metabolic needs, such as the visual system, which is therefore highly susceptible to limited energy supply as a result of mitochondrial dysfunction. AREAS COVERED: Vision impairment is a common feature of most mitochondrial diseases. At the same time, there is mounting evidence that mitochondrial impairment contributes to the pathogenesis of major eye diseases such as glaucoma and might also be involved in the reported vision impairment in neurodegenerative disorders such as Alzheimer's disease. EXPERT OPINION: Rather than relying on symptomatic treatment, acknowledging the mitochondrial origin of visual disorders in mitochondrial, neurodegenerative and ocular diseases could lead to novel therapeutics that aim to modulate mitochondrial function in order to protect against vision loss. This approach has already shown some promising clinical results in inherited retinal disorders, which supports the idea that targeting mitochondria could also be a treatment option for other optic neuropathies. PMID- 26761185 TI - Zika Virus in the Americas--Yet Another Arbovirus Threat. PMID- 26761186 TI - Relative electromyographic activity in trunk, hip, and knee muscles during unilateral weight bearing exercises: Implications for rehabilitation. AB - BACKGROUND: Clinicians routinely prescribe unilateral weight bearing exercises to strengthen the lower extremity. Researchers have primarily examined thigh muscle activation with minimal attention to the hip and trunk muscles. The purpose of this study was to quantify trunk, hip, and thigh muscle activation during these types of exercises. METHODS: Electromyographic (EMG) activity was collected for the abdominal obliques (AO), lumbar extensors (LE), gluteus maximus (GMX), gluteus medius (GM), and vastus medialis (VM) as subjects performed four unilateral weight bearing exercises. Data were expressed as 100% of a maximum voluntary isometric contraction (% MVIC). Separate analyses of variance with repeated measures were used to identify muscle activity differences across exercise. The sequentially-rejective Bonferroni test was used for all post-hoc analyses. RESULTS: EMG activity for the AO, LE, and GMX was low (5.7-18.9% MVIC) during all the exercises. The GM activity was moderate (21.4-26.5% MVIC) while VM activity was high (40.0-45.2% MVIC). CONCLUSION: Lower AO and LE activation most likely resulted from subjects maintaining a vertical trunk position over the stance limb during each exercise. The fact that the exercises required greater frontal plane control (from balancing on a single limb) most likely accounted for lower GMX activity. The exercises would provide little, if any, benefit for individuals with AO, LE, or GMX weakness. The unilateral weight bearing exercises would be beneficial for GM neuromuscular re-education and endurance and VM strengthening. PMID- 26761187 TI - Tumor necrosis factor (TNF)-alpha -308G/A (rs1800629) polymorphism distribution in North India and its association with pemphigus: Case-control study and meta analysis. AB - Pemphigus is an autoimmune blistering disorder of skin and/or mucosal surfaces characterized by intraepithelial lesions and immunoglobulin-G autoantibodies against desmogleins (proteins critical in cell-to-cell adhesion). Genetic, immunological, hormonal, and environmental factors are known to contribute to its etiology. Tumor necrosis factor-alpha (TNF-alpha) which plays a key role in pathogenesis of many infectious and inflammatory diseases has been found in high levels in lesional skin and sera of pemphigus patients. However, studies on association of single nucleotide polymorphism (SNP) in promoter region of TNF alpha at position -308 affecting G to A transition with pemphigus has been scarce. This study was conducted to evaluate the TNF-alpha -308G/A SNP distribution in North Indian cohort, and to define the association between the TNF-alpha -308G/A SNP distribution and pemphigus, globally, by means of meta analysis. TNF-alpha -308G/A SNP in pemphigus patients was investigated by cytokine genotyping using genomic DNA by PCR with sequence-specific primers. Meta analysis of the data, including four previously published studies from other populations, was performed to generate a meaningful relationship. The results of our case-control study indicate non-significant differences between patients and controls in TNF-alpha -308G/A SNP. The meta-analysis also revealed that TNF-alpha -308G/A SNP is not associated with pemphigus risk in population at large; however, it may be contributing towards autoimmune phenomenon in pemphigus by being a part of its multi-factorial etiology. This study provides evidence that the TNF-alpha -308G/A polymorphism is not associated with overall pemphigus susceptibility. Nevertheless, further studies on specific ethnicity and pemphigus variants are necessary to validate the findings. PMID- 26761188 TI - Crowdsourcing: an overview and applications to ophthalmology. AB - PURPOSE OF REVIEW: Crowdsourcing involves the use of the collective intelligence of online communities to produce solutions and outcomes for defined objectives. The use of crowdsourcing is growing in many scientific areas. Crowdsourcing in ophthalmology has been used in basic science and clinical research; however, it also shows promise as a method with wide-ranging applications. This review presents current findings on the use of crowdsourcing in ophthalmology and potential applications in the future. RECENT FINDINGS: Crowdsourcing has been used to distinguish normal retinal images from images with diabetic retinopathy; the collective intelligence of the crowd was able to correctly classify 81% of 230 images (19 unique) for US$1.10/eye in 20 min. Crowdsourcing has also been used to distinguish normal optic discs from abnormal ones with reasonable sensitivity (83-88%), but low specificity (35-43%). Another study used crowdsourcing for quick and reliable manual segmentation of optical coherence tomography images. Outside of ophthalmology, crowdsourcing has been used for text and image interpretation, language translation, and data analysis. SUMMARY: Crowdsourcing has the potential for rapid and economical data processing. Among other applications, it could be used in research settings to provide the 'ground truth' data, and in the clinical settings to relieve the burden of image processing on experts. PMID- 26761189 TI - Characteristics and predictors of recidivist drink-drivers. AB - OBJECTIVE: The current study compared characteristics of nonrecidivist versus recidivist drink-drivers and of recidivists in their first versus second appearance at Back on Track (BOT), the remedial measures program for impaired drivers in Ontario, Canada. METHODS: Information from 59,134 convicted drivers who participated in BOT between 2000 and 2010 was examined to identify drivers who completed the program a second time following reconviction. RESULTS: A total of 586 recidivists were identified. Compared to nonrecidivist drivers, recidivists at first attendance were more likely to be male and had higher scores on measures of alcohol dependence and adverse legal consequences of substance use. Compared to nonrecidivist drivers, recidivists at second attendance were significantly older, had a higher income, were more likely to be retired, and were less likely to be employed part-time. They had fewer legal problems. Recidivists reported fewer drinking days and fewer drinks per occasion but greater use of benzodiazepines than nonrecidivists and had higher scores on a measure of future risk of alcohol- and drug-related problems. Comparison of recidivists' characteristics at first versus second attendance confirmed many of these findings, with second-time recidivists reporting fewer drinks per drinking day and greater use of benzodiazepines and having higher scores on a measure of future substance use problems than first-time recidivists. CONCLUSIONS: Results suggest that identification of drivers at increased risk of recidivism may be possible at first program attendance by examining indicators of increased alcohol related problems. In addition, recidivists appear to show a greater readiness to change at second attendance. Implications for remedial program development and recommendations for future research are discussed. PMID- 26761190 TI - Ballistic Transport Exceeding 28 MUm in CVD Grown Graphene. AB - We report on ballistic transport over more than 28 MUm in graphene grown by chemical vapor deposition (CVD) that is fully encapsulated in hexagonal boron nitride. The structures are fabricated by an advanced dry van-der-Waals transfer method and exhibit carrier mobilities of up to three million cm(2)/(Vs). The ballistic nature of charge transport is probed by measuring the bend resistance in cross- and square-shaped devices. Temperature-dependent measurements furthermore prove that ballistic transport is maintained exceeding 1 MUm up to 200 K. PMID- 26761191 TI - The Symmetrical Quasi-Classical Model for Electronically Non-Adiabatic Processes Applied to Energy Transfer Dynamics in Site-Exciton Models of Light-Harvesting Complexes. AB - In a recent series of papers, it has been illustrated that a symmetrical quasi classical (SQC) windowing model applied to the Meyer-Miller (MM) classical vibronic Hamiltonian provides an excellent description of a variety of electronically non-adiabatic benchmark model systems for which exact quantum results are available for comparison. In this paper, the SQC/MM approach is used to treat energy transfer dynamics in site-exciton models of light-harvesting complexes, and in particular, the well-known 7-state Fenna-Mathews-Olson (FMO) complex. Again, numerically "exact" results are available for comparison, here via the hierarchical equation of motion (HEOM) approach of Ishizaki and Fleming, and it is seen that the simple SQC/MM approach provides very reasonable agreement with the previous HEOM results. It is noted, however, that unlike most (if not all) simple approaches for treating these systems, because the SQC/MM approach presents a fully atomistic simulation based on classical trajectory simulation, it places no restrictions on the characteristics of the thermal baths coupled to each two-level site, e.g., bath spectral densities (SD) of any analytic functional form may be employed as well as discrete SD determined experimentally or from MD simulation (nor is there any restriction that the baths be harmonic), opening up the possibility of simulating more realistic variations on the basic site-exciton framework for describing the non-adiabatic dynamics of photosynthetic pigment complexes. PMID- 26761192 TI - Bayesian Non-Parametric Clustering of Ranking Data. AB - This paper studies the estimation of Dirichlet process mixtures over discrete incomplete rankings. The generative model for each mixture component is the generalized Mallows (GM) model, an exponential family model for permutations which extends seamlessly to top- t rankings. While the GM is remarkably tractable in comparison with other permutation models, its conjugate prior is not. Our main contribution is to derive the theory and algorithms for sampling from the desired posterior distributions under this DPM. We introduce a family of partially collapsed Gibbs samplers, containing as one extreme point an exact algorithm based on slice-sampling, and at the other a fast approximate sampler with superior mixing that is still very accurate in all but the lowest ranks. We empirically demonstrate the effectiveness of the approximation in reducing mixing time, the benefits of the Dirichlet process approach over alternative clustering techniques, and the applicability of the approach to exploring large real-world ranking datasets. PMID- 26761193 TI - Survey on RGB, 3D, Thermal, and Multimodal Approaches for Facial Expression Recognition: History, Trends, and Affect-Related Applications. AB - Facial expressions are an important way through which humans interact socially. Building a system capable of automatically recognizing facial expressions from images and video has been an intense field of study in recent years. Interpreting such expressions remains challenging and much research is needed about the way they relate to human affect. This paper presents a general overview of automatic RGB, 3D, thermal and multimodal facial expression analysis. We define a new taxonomy for the field, encompassing all steps from face detection to facial expression recognition, and describe and classify the state of the art methods accordingly. We also present the important datasets and the bench-marking of most influential methods. We conclude with a general discussion about trends, important questions and future lines of research. PMID- 26761194 TI - Depth Estimation with Occlusion Modeling Using Light-Field Cameras. AB - Light-field cameras have become widely available in both consumer and industrial applications. However, most previous approaches do not model occlusions explicitly, and therefore fail to capture sharp object boundaries. A common assumption is that for a Lambertian scene, a pixel will exhibit photo consistency, which means all viewpoints converge to a single point when focused to its depth. However, in the presence of occlusions this assumption fails to hold, making most current approaches unreliable precisely where accurate depth information is most important - at depth discontinuities. In this paper, an occlusion-aware depth estimation algorithm is developed; the method also enables identification of occlusion edges, which may be useful in other applications. It can be shown that although photo-consistency is not preserved for pixels at occlusions, it still holds in approximately half the viewpoints. Moreover, the line separating the two view regions (occluded object versus occluder) has the same orientation as that of the occlusion edge in the spatial domain. By ensuring photo-consistency in only the occluded view region, depth estimation can be improved. Occlusion predictions can also be computed and used for regularization. Experimental results show that our method outperforms current state-of-the-art light-field depth estimation algorithms, especially near occlusion boundaries. PMID- 26761195 TI - Cardiac Rupture: New Features of the Old Disease. AB - OBJECTIVES: Myocardial rupture is a rare but a fatal complication of acute myocardial infarction. During recent years, treatment strategies of acute myocardial infarction have changed. Primary percutaneous coronary interventions have replaced fibrinolytic therapy, thus reducing one of the major risk factors for myocardial rupture. In this work, we describe a group of patients who suffered myocardial rupture, none of whom were treated with thrombolytic therapy. METHODS: The digital database of our hospital was searched for all patients who experienced myocardial rupture between 2008 and 2015. The demographic, clinical, angiographic and echocardiographic data of these patients were analyzed. RESULTS: Out of 2,380 patients admitted with acute myocardial infarction, 12 (0.5%) developed myocardial rupture. The mean age was 78 years, and there were 7 males and 5 females. Ten patients already had pericardial effusion on admission. Seven patients underwent coronary angiography, whilst primary percutaneous intervention was performed in 4 patients. Six patients entered the operating room and all survived the procedure. All patients who were treated conservatively died due to rupture. Factors related to the treatment strategy were advanced age (>= 90 years) and cognitive impairment. CONCLUSIONS: The risk of myocardial rupture may be diminished by primary coronary intervention during myocardial infarction, but mortality remains high. An early, comprehensive echocardiographic examination and rapid surgery may contribute to improved survival. PMID- 26761196 TI - Uncovering the Potential Pan Proteomes Encoded by Genomic Strand RNAs of Influenza A Viruses. AB - Influenza A virus genomes are composed of eight negative sense RNAs. In total, 16 proteins encoded by eight positive sense RNAs were identified. One putative protein coding sequence (PCS) encoded by genomic strand RNA of segment 8 has been previously proposed. In this study, 95,608, 123,965 and 35,699 genomic strand RNA sequences from influenza A viruses from avian, human and mammalian hosts, respectively, were used to identify PCSs encoded by the genomic strand RNAs. In total, 326,069 PCSs with lengths equal to or longer than 80 amino acids were identified and clustered into 270 PCS groups. Twenty of the 270 PCS groups which have greater than 10% proportion in influenza A viruses from avian, human or mammalian hosts were selected for detailed study. Maps of the 20 PCSGs in the influenza A virus genomes were constructed. The proportions of the 20 PCSGs in influenza A viruses from different hosts and serotypes were analyzed. One secretory and five membrane proteins predicted from the PCS groups encoded by genomic strand RNAs of segments 1, 2, 4, 6, 7 and 8 were identified. These results suggest the possibility of the ambisense nature of the influenza A virus genomic RNAs and a potential coding sequence reservoir encoding potential pan proteomes of influenza A viruses. PMID- 26761197 TI - Echinostomes in Felid Coprolites from Brazil. AB - The first record of Echinostoma (Trematoda: Echinostomatidae) in coprolites was from a mummified human body in Minas Gerais State, Brazil. The finding raised questions on this parasite's incidence in prehistoric populations and the natural hosts of each species in remote times. Echinostomes occur worldwide and, despite the wide range of hosts, there is no record of Echinostomatidae in felines in Brazil. This study reports the finding of Echinostomatidae eggs in felid coprolites in the Furna do Estrago Archaeological Site, located in Pernambuco State in the Brazilian semiarid. Despite the possibility of false parasitism, the finding expands the distribution of this Digenea in remote times and raises the hypothesis of other cases of echinostomiasis in pre-Colombian populations. PMID- 26761198 TI - A Pilot Study to Propose a "Harm Scale", a New Method to Predict Risk of Harm to the Corneal Endothelium Caused by Longitudinal Phacoemulsification, and the Subsequent Effect of Endothelial Damage on Post Operative Visual Acuity. AB - PURPOSE: To study the effect of longitudinal phacoemulsification energy on corneal endothelium and to evaluate the relationship between changes of endothelial cells and postoperative visual acuity. METHODS: This prospective clinical observational cohort study included 50 patients with cataract who underwent longitudinal phacoemulsification. Sequential quantitative and qualitative morphometric endothelial cell analyses of the cornea were performed 4 weeks preoperatively and 6 weeks postoperatively using noncontact specular microscopy. RESULTS: There was a relationship between ECL percentage (ECL%) and the 5-score harm scale, well-described by a linear model (one-way ANOVA, R2 = 73.3%). Analyzing the distribution of ECL% Mean with Tukey post-hoc pairwise comparison test (P < 0.001), the value of ECL = 20% has been regarded as cut-off to discriminate patients who obtained an excellent postoperative best-corrected visual acuity (BCVA > 85 letters) from those who just had a good visual outcome (BCVA <= 85 letters). There was a significant correlation among the 5-score harm scale, phaco energy intraoperatively delivered, and average cell area postoperatively. CONCLUSIONS: The 5-score harm scale, a new method that enables to pigeonhole cataracts taking into account nucleus hardness and phaco times, allows to predict the harm on corneal endothelium after longitudinal phacoemulsification. Assessment of ECL% permits to discriminate between patients with excellent BCVA and with just good BCVA, postoperatively. PMID- 26761199 TI - The aminoacyl-tRNA synthetases of Drosophila melanogaster. AB - Aminoacyl-tRNA synthetases (aaRSs) ligate amino acids to their cognate tRNAs, allowing them to decode the triplet code during translation. Through different mechanisms aaRSs also perform several non-canonical functions in transcription, translation, apoptosis, angiogenesis and inflammation. Drosophila has become a preferred system to model human diseases caused by mutations in aaRS genes, to dissect effects of reduced translation or non-canonical activities, and to study aminoacylation and translational fidelity. However, the lack of a systematic annotation of this gene family has hampered such studies. Here, we report the identification of the entire set of aaRS genes in the fly genome and we predict their roles based on experimental evidence and/or orthology. Further, we propose a new, systematic and logical nomenclature for aaRSs. We also review the research conducted on Drosophila aaRSs to date. Together, our work provides the foundation for further research in the fly aaRS field. PMID- 26761200 TI - Vectors and strategies for nonviral cancer gene therapy. AB - INTRODUCTION: This review presents recent developments in the use of nonviral vectors and transfer technologies in cancer gene therapy. Tremendous progress has been made in developing cancer gene therapy in ways that could be applicable to treatments. Numerous efforts are focused on methods of attacking known and novel targets more efficiently and specifically. In parallel to progress in nonviral vector design and delivery technologies, important achievements have been accomplished for suicide, gene replacement, gene suppression and immunostimulatory therapies. New nonviral cancer gene therapies have been developed based on emerging RNAi (si/shRNA-, miRNA) or ODN. AREAS COVERED: This review provides an overview of recent gene therapeutic strategies in which nonviral vectors have been used experimentally and in clinical trials. Furthermore, we present current developments in nonviral vector systems in association with important chemical and physical gene delivery technologies and their potential for the future. EXPERT OPINION: Nonviral gene therapy has maintained its position as an approach for treating cancer. This is reflected by the fact that more than 17% of all gene therapy trials employ nonviral approaches. Thus, nonviral vectors have emerged as a clinical alternative to viral vectors for the appropriate expression and delivery of therapeutic genes. PMID- 26761202 TI - Correction: Hydrologic Alterations from Climate Change Inform Assessment of Ecological Risk to Pacific Salmon in Bristol Bay, Alaska. PMID- 26761201 TI - Genetic Variation at Exon 2 of the MHC Class II DQB Locus in Blue Whale (Balaenoptera musculus) from the Gulf of California. AB - The genes of the Major Histocompatibility Complex (MHC) play an important role in the vertebrate immune response and are among the most polymorphic genes known in vertebrates. In some marine mammals, MHC genes have been shown to be characterized by low levels of polymorphism compared to terrestrial taxa; this reduction in variation is often explained as a result of lower pathogen pressures in marine habitats. To determine if this same reduction in variation applies to the migratory population of blue whales (Balaenoptera musculus) that occurs in the Gulf of California, we genotyped a 172 bp fragment of exon 2 of the MHC Class II DQB locus for 80 members of this population. Twenty-two putatively functional DQB allotypes were identified, all of which were homologous with DQB sequences from other cetacean species. Up to 5 putative alleles per individual were identified, suggesting that gene duplication has occurred at this locus. Rates of non-synonymous to synonymous substitutions (omega) and maximum likelihood analyses of models of nucleotide variation provided potential evidence of ongoing positive selection at this exon. Phylogenetic analyses of DQB alleles from B. musculus and 16 other species of cetaceans revealed trans-specific conservation of MHC variants, suggesting that selection has acted on this locus over prolonged periods of time. Collectively our findings reveal that immunogenic variation in blue whales is comparable to that in terrestrial mammals, thereby providing no evidence that marine taxa are subject to reduced pathogen-induced selective pressures. PMID- 26761203 TI - Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption. AB - Arterial stiffening accompanies both aging and atherosclerosis, and age-related stiffening of the arterial intima increases RhoA activity and cell contractility contributing to increased endothelium permeability. Notably, statins are 3 hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors whose pleiotropic effects include disrupting small GTPase activity; therefore, we hypothesized the statin simvastatin could be used to attenuate RhoA activity and inhibit the deleterious effects of increased age-related matrix stiffness on endothelial barrier function. Using polyacrylamide gels with stiffnesses of 2.5, 5, and 10 kPa to mimic the physiological stiffness of young and aged arteries, endothelial cells were grown to confluence and treated with simvastatin. Our data indicate that RhoA and phosphorylated myosin light chain activity increase with matrix stiffness but are attenuated when treated with the statin. Increases in cell contractility, cell-cell junction size, and indirect measurements of intercellular tension that increase with matrix stiffness, and are correlated with matrix stiffness-dependent increases in monolayer permeability, also decrease with statin treatment. Furthermore, we report that simvastatin increases activated Rac1 levels that contribute to endothelial barrier enhancing cytoskeletal reorganization. Simvastatin, which is prescribed clinically due to its ability to lower cholesterol, alters the endothelial cell response to increased matrix stiffness to restore endothelial monolayer barrier function, and therefore, presents a possible therapeutic intervention to prevent atherogenesis initiated by age-related arterial stiffening. PMID- 26761204 TI - Post-transcriptional down regulation of ICAM-1 in feto-placental endothelium in GDM. AB - Maternal gestational diabetes (GDM) is associated with hyperglycaemia and hyperinsulinemia in the fetal circulation which consequently may induce endothelial dysfunction in the feto-placental vasculature. In fact, feto placental vasculature reveals various morphological changes in response to GDM. The cell adhesion molecules (CAMs) ICAM-1, VCAM-1 and E-selectin promote attachment and trans-endothelial migration of leukocytes, and are up regulated in inflammation and endothelial dysfunction. Thus, we hypothesized that the GDM environment upregulates ICAM-1, VCAM-1 and E-selectin in the feto-placental endothelium. We isolated primary feto-placental endothelial cells (fpEC) after normal (n=18) and GDM pregnancy (n=11) and analyzed mRNA (RT-qPCR) and protein expression (Immunoblot) of ICAM-1, VCAM-1 and E-selectin. While other CAMs were unchanged on mRNA and protein levels, ICAM-1 protein was decreased by GDM. Further analysis revealed also a decrease in the release of soluble ICAM-1 (sICAM 1), whose levels correlated negatively with maternal BMI. We conclude that this reduction of ICAM-1 protein species is the result of post-translational regulation, since ICAM-1 mRNA expression was unchanged. In fact, miRNAs targeting ICAM-1 were upregulated in GDM fpEC. Immunohistochemistry showed weaker ICAM-1 staining in the placental endothelium after GDM pregnancies, and demonstrated ICAM-1 binding partners CD11a and CD18 expressed on leukocytes in fetal circulation and on placental tissue macrophages. This study identified reduction of ICAM-1 protein in fpEC in GDM pregnancy, which was regulated post transcriptionally. Low ICAM-1 protein production may represent a protective, placenta-specific mechanism to avoid leukocyte transmigration into the placenta in response to GDM. PMID- 26761205 TI - Loneliness, Social Networks, and Health: A Cross-Sectional Study in Three Countries. AB - OBJECTIVE: It is widely recognized that social networks and loneliness have effects on health. The present study assesses the differential association that the components of the social network and the subjective perception of loneliness have with health, and analyzes whether this association is different across different countries. METHODS: A total of 10 800 adults were interviewed in Finland, Poland and Spain. Loneliness was assessed by means of the 3-item UCLA Loneliness Scale. Individuals' social networks were measured by asking about the number of members in the network, how often they had contacts with these members, and whether they had a close relationship. The differential association of loneliness and the components of the social network with health was assessed by means of hierarchical linear regression models, controlling for relevant covariates. RESULTS: In all three countries, loneliness was the variable most strongly correlated with health after controlling for depression, age, and other covariates. Loneliness contributed more strongly to health than any component of the social network. The relationship between loneliness and health was stronger in Finland (|beta| = 0.25) than in Poland (|beta| = 0.16) and Spain (|beta| = 0.18). Frequency of contact was the only component of the social network that was moderately correlated with health. CONCLUSIONS: Loneliness has a stronger association with health than the components of the social network. This association is similar in three different European countries with different socio economic and health characteristics and welfare systems. The importance of evaluating and screening feelings of loneliness in individuals with health problems should be taken into account. Further studies are needed in order to be able to confirm the associations found in the present study and infer causality. PMID- 26761207 TI - Nuclear Data Evaluation for Mass Chain A=217:Odd-Proton Nuclei. AB - Thallium (81(217)Tl, Bismuth (83(217)Bi), Astatine (85(217)At), Francium (87(217)Fr), Actinium (89(217)Ac) and Protactinium (91(217)Pa) are of odd-proton numbers among the mass chain A = 217. In the present work, the half-lives and gamma transitions for the six nuclei have been studied and adopted based on the recently published interactions or unevaluated nuclear data sets XUNDL. The Q (alpha) has been updated based on the recent published work of the Atomic Mass Evaluation AME2012 as well. Moreover, the total conversion electrons as well as the K-Shell to L-Shell, L-Shell to M-Shell and L-Shell to N-Shell Conversion Electron Ratios have been calculated using BrIcc code v2.3. An updated skeleton decay scheme for each of the above nuclei has been presented here. The decay hindrance factors (HF) calculated using the ALPHAD program, which is available from Brookhaven National Laboratory's website, have been calculated for the alpha decay data sets for (221)Fr-, (221)Ac- and (221)Pa-alpha-decays. PMID- 26761206 TI - Evidence for the Cost of Reproduction in Humans: High Lifetime Reproductive Effort Is Associated with Greater Oxidative Stress in Post-Menopausal Women. AB - Life history theory predicts trade-offs between reproductive effort and maternal survivorship in energy-restricted environments. However, empirical evidence for the positive association between maternal mortality and reproductive effort from energetically challenged human populations are mixed and physiological mechanisms that may underlie this association are poorly understood. We hypothesized that increases in aerobic metabolism during repeated periods of pregnancy and lactation result in increased oxidative stress that may contribute to somatic deterioration, vulnerability to illness, and accelerated aging. We therefore predicted that lifetime gravidity and parity would be related to levels of biomarkers of oxidative stress, as well as antioxidative defence enzymes in post menopausal women. Our hypothesis was supported by positive linear associations between levels of 8-OHdG, a biomarker of DNA oxidative damage (beta = 0.21, p<0.05), levels of antioxidative defence enzyme Cu-Zn SOD (beta = 0.25, p<0.05), and number of lifetime pregnancies. Furthermore, independent of age and health status, post-menopausal women with higher gravidity and parity (> = 4 pregnancies per lifetime) had 20% higher levels of 8-OHdG and 60% higher levels of Cu-Zn SOD compared to women with lower gravidity and parity (<4 pregnancies per lifetime). Our results present the first evidence for oxidative stress as a possible cost of reproductive effort in humans. PMID- 26761209 TI - A Two-Stage Algorithm for Origin-Destination Matrices Estimation Considering Dynamic Dispersion Parameter for Route Choice. AB - This paper proposes a two-stage algorithm to simultaneously estimate origin destination (OD) matrix, link choice proportion, and dispersion parameter using partial traffic counts in a congested network. A non-linear optimization model is developed which incorporates a dynamic dispersion parameter, followed by a two stage algorithm in which Generalized Least Squares (GLS) estimation and a Stochastic User Equilibrium (SUE) assignment model are iteratively applied until the convergence is reached. To evaluate the performance of the algorithm, the proposed approach is implemented in a hypothetical network using input data with high error, and tested under a range of variation coefficients. The root mean squared error (RMSE) of the estimated OD demand and link flows are used to evaluate the model estimation results. The results indicate that the estimated dispersion parameter theta is insensitive to the choice of variation coefficients. The proposed approach is shown to outperform two established OD estimation methods and produce parameter estimates that are close to the ground truth. In addition, the proposed approach is applied to an empirical network in Seattle, WA to validate the robustness and practicality of this methodology. In summary, this study proposes and evaluates an innovative computational approach to accurately estimate OD matrices using link-level traffic flow data, and provides useful insight for optimal parameter selection in modeling travelers' route choice behavior. PMID- 26761210 TI - The role of PD-L1 in the radiation response and prognosis for esophageal squamous cell carcinoma related to IL-6 and T-cell immunosuppression. AB - The aim of this study was to assess the significance of programmed cell death 1 ligand 1 (PD-L1) in esophageal squamous cell carcinoma (ESCC) and its association with IL-6 and radiation response. Weretrospectively enrolled 162 patients with ESCC, and examined the correlation between PD-L1 levels and clinical outcomes in esophageal cancer patients. Furthermore, the human esophageal SCC cell line CE81T and TE2 were selected for cellular experiments to investigate the role of PD-L1 in T cell functions and radiation response. Here we demonstrated that PD-L1 expression was significantly higher in esophageal cancer specimens than in non malignant epithelium. In clinical outcome analysis, this staining of PD-L1 was positively linked to the clinical T4 stage (p=0.004), development of LN metastasis (p=0.012) and higher loco-regional failure rate (p=0.0001). In addition, the frequency of PD-L1 immunoreactivity was significantly higher in IL 6-positive esophageal cancer specimens. When IL-6 signaling was inhibited in vitro, the level of PD-L1 is significantly down-regulated. PD-L1 is a significant predictor for poor treatment response and shorter survival.As demonstrated through in vitro experiments, Irradiation increased PD-L1 expression in human esophageal cancer cells. The inhibition of T cell functions including proliferation and cytotoxicity against tumor cells might be the mechanisms responsible to the role of PD-L1 in radiation response. In conclusion, PD-L1 is important in determining the radiation response and could predict the prognosis of patients with esophageal SCC. Therefore, we suggest inhibition of PD-L1 as a potential strategy for the treatment of esophageal SCC. PMID- 26761211 TI - Hypoxia-inducible factor 1 upregulation of both VEGF and ANGPTL4 is required to promote the angiogenic phenotype in uveal melanoma. AB - PURPOSE: Expression of the hypoxia-inducible factor (HIF)-1-regulated gene product, vascular endothelial growth factor (VEGF), correlates with tumor vascularity in patients with uveal melanoma (UM). While the relationship between HIF-1 and VEGF in cancer is well-studied, their relative contribution to the angiogenic phenotype in UM has not previously been interrogated. Here we evaluate the contribution of HIF-1, VEGF, and a second HIF-1-regulated gene product, angiopoietin-like 4 (ANGPTL4), to angiogenesis in UM. EXPERIMENTAL DESIGN: UM cells were examined for expression of HIF-1alpha, VEGF, and ANGPTL4. Their contribution to the angiogenic potential of UM cells was assessed using the endothelial cell tubule formation and directed in vivo angiogenesis assays. These results were corroborated in tissue from UM animal models and in tissue from patients with UM. RESULTS: Inhibition of VEGF partially reduced tubule formation promoted by conditioned medium from UM cells. Inhibition of ANGPTL4, which was highly expressed in hypoxic UM cells, a UM orthotopic transplant model, a UM tumor array, and vitreous samples from UM patients, inhibited the angiogenic potential of UM cells in vitro and in vivo; this effect was additive to VEGF inhibition. CONCLUSIONS: Targeting both ANGPTL4 and VEGF may be required for the effective inhibition of angiogenesis in UM. PMID- 26761212 TI - Interplay between PCBP2 and miRNA modulates ARHGDIA expression and function in glioma migration and invasion. AB - RNA-RNA and protein-RNA interactions are essential for post-transcriptional regulation in normal development and may be deregulated in cancer initiation and progression. The RNA-binding protein PCBP2, an oncogenic protein in human malignant gliomas, is an essential regulator of mRNA and miRNA biogenesis, stability and activity. Here, we identified Rho GDP dissociation inhibitor alpha (ARHGDIA) as a target mRNA that binds to PCBP2, and we uncovered the role of ARHGDIA as a putative metastasis suppressor through analyses of in vitro and in vivo models of EMT and metastasis. Furthermore, we demonstrated that ARHGDIA is a potential target of miR-151-5p and miR-16 in gliomas. The interaction between PCBP2 and the 3'UTR of the ARHGDIA mRNA may induce a local change in RNA structure that favors subsequent binding of miR-151-5p and miR-16, thus leading to the suppression of ARHGDIA expression. PCBP2 may facilitate miR-151-5p and miR 16 promotion of glioma cell migration and invasion through mitigating the function of ARHGDIA. PMID- 26761213 TI - Phase III study of cisplatin with pemtrexed or vinorelbine plus concurrent late course accelerated hyperfractionated radiotherapy in patients with unresectable stage III non-small cell lung cancer. AB - Our aim was to evaluate the efficacy and safety of cisplatin with pemtrexed or vinorelbine and concurrent late course accelerated hyperfractionated radiotherapy (LCAHRT). Patients with unresectable stage III non-small-cell lung cancer (NSCLC) were randomly assigned to two regimens. The experimental (PP) arm included cisplatin, pemtrexed and concurrent LCAHRT based on bilateral lung V20 = 33%. The control (NP) arm used cisplatin, vinorelbine with the same radiotherapy protocol. The primary endpoint was overall survival. Median survival times were 26.0 months (95% CI 23.2 to 28.7 months) and 28.5 months (95% CI 17.1 to 39.9 months) for the NP and PP arms, respectively (P = 0.26). Median progression-free survival was 12.5 months and 17.5 months in the NP and PP arms (P = 0.07). In both arms of the study, there were no differences in overall survival between patients with squamous and nonsquamous NSCLC. The incidences of grade 3 or 4 toxicity were higher in NP than PP arm. With concurrent LCAHRT, pemetrexed/cisplatin was equally as efficacious as vinorelbine/cisplatin, but showed a more favorable toxicity profile. PMID- 26761215 TI - Immunohistochemical Analysis of PDGFR-alpha, PDGFR-beta and c-Abl in Retinoblastoma: Potential Therapeutic Targets. AB - BACKGROUND: Our laboratory previously reported that imatinib mesylate (IM) has an inhibitory effect on two retinoblastoma (Rb) cell lines in vitro. AIMS: The purpose of this project was to determine the immunoexpression of platelet-derived growth factor receptor (PDGFR)-alpha, PDGFR-beta and c-Abl in 61 human samples of Rb to determine if IM-sensitive receptors are present. Additionally, this paper seeks to establish a correlation between the expression of PDGFR, c-Abl and the histopathological prognosis. METHODS: Sixty-one paraffin-embedded Rbs were collected from the Henry C. Witelson Ocular Pathology Registry. PDGFR-alpha, PDGFR-beta and c-Abl immunostaining was performed according to the protocol provided by Ventana Medical System Inc. Immunoreactivity was correlated with the presence or absence of invasion into the choroid and optic nerve. RESULTS: Overall, c-Abl expression was identified in 50 out of 61 specimens (81.97%), PDGFR-alpha was identified in 20 out of 60 specimens (33.33%) and PDGFR-beta expression was identified in 57 out of 61 specimens (93.44%). Histopathological prognosis was not correlated with immunoreactivity except in the case of PDGFR beta. CONCLUSIONS: Rb is a cancer that expresses PDGFR-alpha, PDGFR-beta and c Abl, which are known targets of IM. These markers may be responsible for the documented therapeutic effect of IM on Rb cell lines. PMID- 26761216 TI - Synovium and cartilage biomarkers in hemophilic arthropathy. AB - Some promising cartilage and synovium biomarkers are at various stages of development and awaiting further validation in larger patient populations with osteoarthritis (OA). Various reports have shown increased levels of inflammatory biomarkers, both locally (synovial fluid) and systemically (serum and plasma) in such patients. The clinical value of these parameters in combination with imaging biomarkers in order to predict early onset and the burden of OA is being investigated. This review article aims to describe the potential usefulness of synovial and cartilage biomarkers for the diagnosis and prognosis of hemophilic arthropathy (HA) by using the existing literature on OA as an applicable model. A systematic review found that serum cartilage oligomeric matrix protein (sCOMP) is elevated in patients with knee OA and is sensitive to OA disease progression. PMID- 26761214 TI - Long lasting MDM2/Translocator protein modulator: a new strategy for irreversible apoptosis of human glioblastoma cells. AB - The development of multi-target drugs and irreversible modulators of deregulated signalling proteins is the major challenge for improving glioblastoma multiforme (GBM) treatment. Reversible single-target drugs are not sufficient to sustain a therapeutic effect over time and may favour the activation of alternative signalling pathways and the onset of resistance phenomena. Thus, a multi-target compound that has a long-lasting mechanism of action might have a greater and longer life span of anti-proliferative activity. Recently, a dual-target indol 3ylglyoxyldipeptide derivative, designed to bind to the Translocator Protein (TSPO) and reactivate p53 function via dissociation from its physiological inhibitor, murine double minute 2 (MDM2), has been developed as a potent GBM pro apoptotic agent. In this study, this derivative was chemically modified to irreversibly bind MDM2 and TSPO. The new compound elicited a TSPO-mediated mitochondrial membrane dissipation and restored p53 activity, triggering a long lasting apoptosis of GBM cells. These effects were sustained over time, involved a stable activation of extracellular signal regulated kinases and were specifically observed in cancer cells, in which these protein kinases are deregulated. Dual-targeting and irreversible binding properties combined in the same molecule may represent a useful strategy to overcome the time-limited effects elicited by classical chemotherapies. PMID- 26761217 TI - Dulaglutide (LY-2189265) for the treatment of type 2 diabetes. AB - Dulaglutide is a new once-weekly glucagon-like peptide-1 receptor agonist for the management of hyperglycemia in adult patients with type 2 diabetes. It stimulates dose-dependent insulin secretion and reduces glucagon secretion, both in a glucose-dependent manner. Efficacy on blood glucose control and safety were demonstrated in the large AWARD program in type 2 diabetic patients treated with diet, metformin, dual oral therapy or insulin lispro with or without metformin, confirming findings of pilot studies in Caucasian patients and data in Japanese patients. Dulaglutide 1.5 mg once weekly was superior to metformin, sitagliptin, insulin glargine and exenatide twice daily, and non-inferior to liraglutide 1.8 mg once daily regarding the reduction in glycated hemoglobin. A modest but significant weight loss was consistently observed. Most frequent adverse events were transient and generally mild gastrointestinal disturbances. Clinical outcomes of dulaglutide will not be known until the large prospective cardiovascular outcome trial REWIND is complete. PMID- 26761218 TI - First-in-man study of ACT-453859, a potent CRTH2 antagonist--Is the metabolite formation influenced by a polymorphic enzyme? PMID- 26761241 TI - Liver markers, prevalence of the metabolic syndrome abnormalities and effect of Roux-en-Y gastric bypass in morbidly obese subjects. AB - OBJECTIVES: To evaluate the relations between liver markers (GGT, ALT and AST) and the metabolic syndrome (and its components) in morbidly obese subjects, and to determine the response of these metabolic factors and hepatic enzymes after weight loss induced by Roux-en-Y gastric bypass. METHODS: This study was carried out at a university hospital, in Santo Andre (SP), Brazil. We evaluated 140 morbidly obese subjects aged from 18 to 60 years submitted to a Roux-en-Y gastric bypass, who were followed for a mean period of 8 months. Patients with a history of heavy drinking, type 1 diabetes, and/or liver disease were excluded. RESULTS: Liver markers, most notably GGT, were strongly associated with metabolic abnormalities, mainly hyperglycemia. The prevalence of type 2 diabetes significantly increased with increasing levels of GGT (highest versus lowest quartile GGT: odds ratio 3.89 [95%CI: 1.07-14.17]). Liver markers significantly decreased 8 months after the Roux-en-Y gastric bypass and the reduction of GGT levels were associated with the reduction of glucose levels (Pearson r = 0.286; p = 0.001). CONCLUSIONS: Elevated levels of liver markers, principally GGT, in morbidly obese subjects are associated with metabolic abnormalities. In addition to the well-known benefits of bariatric surgery, Roux-en-Y gastric bypass, reduced the levels of liver markers to the normal range. PMID- 26761240 TI - Interpreting the Dependence of Mutation Rates on Age and Time. AB - Mutations can originate from the chance misincorporation of nucleotides during DNA replication or from DNA lesions that arise between replication cycles and are not repaired correctly. We introduce a model that relates the source of mutations to their accumulation with cell divisions, providing a framework for understanding how mutation rates depend on sex, age, and cell division rate. We show that the accrual of mutations should track cell divisions not only when mutations are replicative in origin but also when they are non-replicative and repaired efficiently. One implication is that observations from diverse fields that to date have been interpreted as pointing to a replicative origin of most mutations could instead reflect the accumulation of mutations arising from endogenous reactions or exogenous mutagens. We further find that only mutations that arise from inefficiently repaired lesions will accrue according to absolute time; thus, unless life history traits co-vary, the phylogenetic "molecular clock" should not be expected to run steadily across species. PMID- 26761242 TI - Nanostructured SBA-15 silica as an adjuvant in immunizations with hepatitis B vaccine. AB - OBJECTIVE: To evaluate the applicability of SBA-15 silica as an adjuvant in immunizations with purified particles of the viral protein HBsAg, the main component of hepatitis B vaccine, Butang(r), produced by Instituto Butantan. METHODS: BALB/c mice orally or subcutaneously received 0.5 MUg of HBsAg adsorbed/encapsulated to SBA-15 or adsorbed to Al(OH)3. To assess the secondary immune response, a subcutaneous booster was administered 30 days after the first immunization. Individual serum and fecal samples of each group were periodically collected for specific antibody titration by ELISA. RESULTS: Analysis of secretory IgA showed that mice orally primed with HBsAg on SBA-15 had increased levels of specific antibodies in primary and secondary immune responses. Specific serum IgA and IgG titers in HBsAg:SBA-15-orally immunized mice reached higher levels after the booster, demonstrating the effectiveness of oral vaccination with the use of silica. All immunized groups showed higher IgG1 levels. CONCLUSION: Our results clearly indicate the promising use of SBA-15 as an adjuvant, especially in oral immunizations. PMID- 26761243 TI - Evaluation of microRNA expression in head and neck squamous cell carcinoma cell lines and in primary culture of oral keratinocytes. AB - OBJECTIVE: Functional in vitro studies are fundamental to understand the role of microRNAs, small non coding RNA molecules that function as post-transcriptional regulators, in cancer. The objective of this study was to determine the applicability of head and neck squamous cell carcinoma cell lines and human oral keratinocytes as models for functional studies on microRNAs previously identified as deregulated in head and neck squamous cell carcinomas. METHODS: The expression level of four microRNAs was assessed in cell lines and in primary cultures of oral keratinocytes using specific real-time polymerase chain reactions. The identity of oral squamous cell carcinoma cell lines was confirmed by means of STR (short tandem repeats) profiling. The possible impact of feeder-layer gene expression in global microRNA expression results from keratinocyte primary culture was also evaluated. RESULTS: Significant differences in microRNA gene expression were observed among squamous cell carcinoma cell lines, particularly among cells lines from distinct subsites, as well as between primary culture of human keratinocytes and immortalized keratinocyte cell lines. CONCLUSIONS: Primary cultures of human keratinocytes and diverse tumor cell lines are relatively easy to obtain. However, each cell model possesses a characteristic phenotype; whereas one may be useful for a specific study, it may be inappropriate for another. Therefore, it is imperative that suitable cell lines are cautiously selected for functional studies in cancer. PMID- 26761244 TI - Isolation of human umbilical cord blood-derived osteoprogenitor cells: a promising candidate for cell-based therapy for bone repair. AB - OBJECTIVE: The aim of this study was to evaluate the osteogenic potential of human umbilical cord blood-derived osteoprogenitor cells and to prove its applicability as a promising candidate for cell-based therapeutics for bone repair. METHODS: Primary cultures of human umbilical blood cord adherent cells were expanded in vitro until passage 2 and seeded for osteodifferentiation study. Morphological (light microscopy), cytochemical (Von Kossa's method), and functional analyses (calcium level, alkaline phosphatase activity, and total protein content in cell culture) were carried out 7, 14, 21, and 28 days after the osteoinduction protocol. RESULTS: The proliferative step showed colony forming units in 7 days. After osteoinduction, cuboidal cellular morphology similar to osteoblasts at 14 days and mineralization nodules and biochemical changes (increased alkaline phosphatase level and calcium deposits) at 21 days confirmed the osteodifferentiation process. CONCLUSION: Cell culture of human umbilical blood cord is a reliable technique, constituting itself as an alternative source of osteoprogenitor cells for experimental needs. More animal tests and clinical trials must be carried out to validate its use and to establish quality control of future autologous or allogeneic cell-based therapy aimed at bone repair. PMID- 26761245 TI - Implementation and progress of clinical pharmacy in the rational medication use in a large tertiary hospital. AB - OBJECTIVE: To show developments and contributions of a clinical pharmacy service in safety and rational use of medications in a large tertiary hospital. METHODS: Clinical pharmacists were responsible for all issues using medications at the hospital. In the beginning this professional was responsible for analyzing medical prescriptions, horizontal visits, and to set up protocols. Afterwards, other activities were designated such as monitoring for drug safety, participating in committees and managed routines. If problems were found, the pharmacist reported them for the physician and, after intervention, registered the management on the prescription or in medical records. The data collected were presented as reports to medical managers. RESULTS: There was an increase of clinical pharmacist employed in 2010, reaching 22 individuals. Interventions types also increased from 1,706 in 2003 to 30,727 in 2010. The adhesion observed in medical team in 2003 was 93.4%, reaching 99.5% of adhesion in 2010. CONCLUSION: Clinical pharmacy service shows a positive impact when it comes to performed interventions. It also promotes a rational use of medicines and increase patient safety. Pharmacists were included and their importance confirmed within the multidisciplinary team and in the process of patient safety. PMID- 26761246 TI - Incidence of sleep disorders in patients with Alzheimer disease. AB - OBJECTIVE: To determine the incidence of sleep disorder at a follow-up examination from 1 to 4 years, in demented patients diagnosed at first visit, besides analyzing associated demographic and comorbidities characteristics. METHODS: A total of 122 elderly patients aged 60 years or older and diagnosed with dementia (Alzheimer and other) were followed in a reference geriatric center for dementia. The clinical protocols included interviews with patient and caregiver, complete physical examination, laboratory and imaging tests. Criteria for the diagnosis of sleep disorder included complain of insomnia from the patient or caregiver using the Neuropsychiatric Inventory nighttime. RESULTS: The incidence density of sleep disorder among dements was 18.7/100 person/years. The risk of developing sleep disorder within the frst and fourth years of follow-up was 9.8% and 50.9%, respectively. Multivariate Coxregression analysis revealed that educational level less than 8 years and report of aggressiveness at baseline were an independent predictor of sleep disorder, increased risk in 3.1 (95%CI: 1.30-9.22) and 2.1 times (95%CI: 1.16-4.17), respectively. CONCLUSION: The incidence of sleep disorder in demented patients was elevated, and was particularly associated to low educational level and aggressiveness at admission. PMID- 26761247 TI - Vertigo and dizziness in elderly patients with neurological disorders. AB - OBJECTIVE: To evaluate the frequency of central vestibular disorders, vertigo and dizziness in patients aged 65 to 90 years. METHODS: We analyzed 735 patients in this age range seen consecutively from January 1990 to December 2009. RESULTS: A total of 32 patients had central vestibular disorders, and 11 had neurological disorders diagnosed by imaging. CONCLUSION: Vertigo and dizziness occur frequently in elderly people with neurological disorders, and affect their quality of life. Falling is common and may lead to disabling consequences. PMID- 26761249 TI - Quality assessment of inhospital patients unable to speak who use alternative and extended communication. AB - OBJECTIVE: To implement the use of alternative communication boards in patients hospitalized and unable to communicate by speech. METHODS: A descriptive study with a sample of 30 patients hospitalized and unable to communicate by speech. Boards were made with Boardmaker(r) Software that consists of a graphical database containing Pictorial Communication Symbols. To assess the quality of life of these patients, the Portuguese SF-36, a translated version of the Medical Outcomes Study, was applied before and after the study. RESULTS: We found that all domains of the SF-36 showed changes after the application of communication boards. We observed that the minimum score was assigned to the mental health domain, whereas the most affected and with greatest involvement and least compromise was the overall health status. CONCLUSION: The quality of life assessment of patients showed improvement with the use of communication boards, demonstrating the importance and necessity of communication between the patient and staff and the patient and family members. PMID- 26761248 TI - Postural control in blind subjects. AB - OBJECTIVE: To analyze postural control in acquired and congenitally blind adults. METHODS: A total of 40 visually impaired adults participated in the research, divided into 2 groups, 20 with acquired blindness and 20 with congenital blindness - 21 males and 19 females, mean age 35.8 +/- 10.8. The Brazilian version of Berg Balance Scale and the motor domain of functional independence measure were utilized. RESULTS: On Berg Balance Scale the mean for acquired blindness was 54.0 +/- 2.4 and 54.4 +/- 2.5 for congenitally blind subjects; on functional independence measure the mean for acquired blind group was 87.1 +/- 4.8 and 87.3 +/- 2.3 for congenitally blind group. CONCLUSION: Based upon the scale used the results suggest the ability to control posture can be developed by compensatory mechanisms and it is not affected by visual loss in congenitally and acquired blindness. PMID- 26761250 TI - Clinical and epidemiological aspects of prematurity in a Normal Delivery Center, Sao Paulo, Brazil. AB - OBJECTIVE: To present clinical and epidemiological aspects of prematurity in a Normal Delivery Center, and to describe outcomes. METHODS: A cross-sectional retrospective study, with 189 medical records of premature, single, and living fetuses, with gestational ages between 25 and 36.6 weeks. RESULTS: The prevalence of preterm births was 7.8%, and 23.2% in adolescent mothers. The most frequent obstetric complication was premature rupture of ovular membranes (35.4%), followed by hypertensive syndrome (18.5%). Cesarean section was performed in 33% of cases. The Apgar score in the 1st minute was < 7 in 36.0% of cases, and in the 5th minute of life, in 9.5% of cases. CONCLUSION: Among the aspects studied, results showed that the prevalence of preterm births was higher than expected for the adolescent mothers, however, with a satisfactory perinatal outcome. PMID- 26761252 TI - Aspiration and ethanol sclerotherapy to treat recurrent ovarian endometriomas prior to in vitro fertilization - a pilot study. AB - OBJECTIVE: To describe the evolution of controlled ovarian hyperstimulation in women with recurrent ovarian endometriomas treated with sclerotherapy. METHODS: Twenty-one patients with a laparoscopic diagnosis of stage III or IV endometriosis who had an endometrioma larger than 3 cm before ovarian hyperstimulation for in vitro fertilization were included in the study. After using a GnRH agonist analog for at least 20 days, the cysts were punctured using ultrasound guidance and subsequent ethanol sclerotherapy was performed. Then, the patients were stimulated with 100 or 200 U/day of recombinant follicle stimulating hormone, varying the dose according to the patient's age or history of a previous unilateral oophorectomy. RESULTS: The ovarian cysts had an average diameter of 4.7 +/- 1.4 cm and did not recur after aspiration during the ovulation induction. Oocyte extraction occurred after 11 days of hyperstimulation, with 3.95 +/- 3.30 oocytes obtained per cycle, on average. Embryo transfer occurred in 71.4% (15/21) of patients, and the pregnancy rate after transfer was 20% (3/15). CONCLUSION: Aspiration followed by ethanol sclerotherapy prior to in vitro fertilization can be an option for patients who desire a pregnancy and have recurrent endometriomas. PMID- 26761251 TI - Prevalence of lower back pain and physical inactivity: the impact of psychosocial factors in pregnant women served by the Family Health Strategy. AB - OBJECTIVE: This study analyzed the impact of psychosocial factors on pregnant women with lower back pain and an associated lack of physical activity prior to pregnancy. METHODS: The sample included 66 pregnant women who were randomly selected from a total of 84 patients in the waiting rooms of the Family Health Units in Cuitegi, Paraiba, from September to November 2009. An epidemiological questionnaire adapted from the Quebec Back Pain Disability Scale was used for data collection. The questions about back pain, physical activity, and psychosocial factors were emphasized. SPSS 16.0 was used for the data analysis. The prevalence of lower back pain and its relationship to gestational age, habitual physical activity, and psychosocial factors were studied using the descriptive statistics and relative percentages in the SPSS Crosstabs procedure. The odds ratio and 95% confidence interval for lower back pain were calculated. RESULTS: The prevalence of lower back pain was 75%, which suggests that psychosocial factors were related to the presence of pain. Anxiety was reported in 42.8% of the women with lower back pain, and 38.7% of the women with lower back pain experienced physical fatigue at the end of the day. A higher percentage of pain (53%) was noted in the women who did not exercise prior to pregnancy. CONCLUSION: Lower back pain prior to pregnancy is associated with lack of physical activity and with psychosocial factors in the Family Health Strategy patients of Cuitegi county. PMID- 26761253 TI - The value of diagnostic hysteroscopy with biopsy in the preoperative of endometrial ablation. AB - OBJECTIVE: To assess the value of diagnostic hysteroscopy with biopsy in the preoperative preparation for endometrial ablation. METHODS: It was a prospective non-randomized study conducted at the division of Gynecologic Endoscopy of Hospital do Servidor Publico Estadual "Francisco Morato de Oliveira" from March 2007 to May 2009. A total of 45 patients with abnormal uterine bleeding, and referred to endometrial ablation were included. All women underwent a diagnostic hysteroscopy, and were treated with a GnRH analogous - goserelin - 10.8 mg before surgery. The endometrial ablation was performed with a surgical resectoscope. Patients were submitted to one directed endometrial biopsy, one guided endometrial biopsy with Novak curette, and to endometrial ablation, which was considered as reference for pathological examination with samples from the biopsies. Data were analyze using the SPSS-v16 software, and considered significance at p = 0.05. RESULTS: The mean age of women was 44.20 years (33-56), parity of 2.67 (0-9), uterus size of 139.99 calculated in cc (42-278), and the mean duration of symptoms was 3.68 years (0.5-15). The guided endometrial biopsy showed sensitivity of 80% for endometrium without atypia, and the directed endometrial biopsy had sensitivity of 60%. For proliferative endometrium the directed endometrial biopsy showed sensitivity of 76 and 100% for secretory endometrium, which was higher than the guided endometrial biopsy with 53 and 50%, respectively. CONCLUSION: The directed biopsy before endometrial ablation had lower sensitivity than guided biopsy for endometrium without atypia, however it was higher for proliferative and secretory endometrium. PMID- 26761254 TI - Dental caries in children participating in a Dentistry for infants Program. AB - OBJECTIVE: To assess the impact of the "Dentistry for Infants" early dental care program run by Jacarei County (SP) by comparing the caries of individuals participating and not participating in this program. METHODS: In total, 300 children between 0 and 48 months old were assessed in the following two groups: infants not participating in the program (G1, n = 100) and infants participating in the program (G2, n = 200). Each group was further divided according to age in subgroups of 0 to 24 months and 25 to 48 months. All children were clinically assessed for carious lesions using the visual-tactile method. The data were statistically analyzed using a paired Student's t-test, Mann-Whitney test, and chi2 test at a 5% significance level. RESULTS: There was a significant difference in the prevalence (P) and mean index of deciduous teeth (deft) (C) that were decayed, indicated for extraction and filled, and the highest values were observed in G1 (p < 0.0001). The values were as follows: PG1, 73%; PG2, 22%; CG1, 3.45 +/- 3.84; and CG2, 0.66 +/- 1.57. CONCLUSION: Participating in the program positively impacted the infants' oral health. PMID- 26761255 TI - Malnutrition in school children in an urban-rural region of the extreme South of Sao Paulo city. AB - OBJECTIVE: To evaluate the persistence of nutritional deficit in a sample of schoolchildren. METHODS: A cross-sectional study of 1,761 schoolchildren between 6 and 10 years from 3 schools. They were assessed by Z scores of weight for height and height for age, according to the World Health Organization. The variables studied were gender, age, grade and school year. The chi2 test was used to relate the nutritional deficit with the variables. RESULTS: Of all children 8.5% were malnourished according to the weight for height Z score, 21.6%, according to height for age. The analysis of the weight for height Z score revealed that 59.7% were male and 40.3% female. The mean age was 8.9 years. As to the Z score of height for age, 53.9% were males and 46.1% females. The risk of malnutrition was higher among boys: 59.7% for the weight for height index and 53.9% for height for age. There was no statistical difference between schools, gender and school year. As to nutritional status, school period (p < 0.0001) and students' grade (p = 0.0105), we observed statistical significance. CONCLUSION: Malnutrition still persists among the low-income population and males had a higher percentage of malnutrition. Nutritional evaluation of students is an extremely important tool for understanding the dynamics of child nutrition and development. PMID- 26761256 TI - Evaluation of hospitalization of children aged 0 to 5 years admitted for respiratory infections at a large hospital. AB - OBJECTIVE: To evaluate the admission of children aged 0 to 5 years due to respiratory infections at a major hospital in the Southern region of the city of Sao Paulo. METHODS: A total of 4,240 clinical records of children hospitalized and diagnosed with pneumonia, bronchopneumonia, bronchiolitis and bronchitis were evaluated for the 2008-2009 period, based on age, gender and year season. RESULTS: Out of this total of children aged 0 to 60-months, 139 (3.2%) presented with pneumonia, with a slight predominance in female babies, and 73.4% occurred between 12 and 60 months (102 cases), particularly during the winter. No significant difference was found as to gender in bronchopneumonia. Age range and year seasons showed to be significant. As regards to bronchiolitis, there was a slight increase in male babies (253 cases) aged less than 12 months and in the autumn season. A total of 182 (4.3%) presented with bronchitis, mainly boys (101 cases) in children aged 12 to 60 months, predominantly during autumn/summer seasons. CONCLUSION: The assessment of admissions of children aged 0 to 5 years due to respiratory infections at a major hospital at the Southern region of the city of Sao Paulo, in the 2008-2009 period, showed that respiratory diseases affect age groups, and gender in a different way occurring in specific periods of the year. PMID- 26761257 TI - Costs for in hospital treatment of urinary lithiasis in the Brazilian public health system. AB - OBJECTIVE: To estimate costs associated to hospital treatment of urinary lithiasis in the Brazilian public health system as well as to evaluate demographic and epidemiological data referred to hospital admissions in the Brazilian public health system (or unified health care system). METHODS: Data from the Informatic Department of Brazilian public health system were obtained as referred to costs in hospital admissions for urinary lithiasis during 2010 and also epidemiological data from 1996 through 2010. RESULTS: There were 69,039 hospital admissions for urinary lithiasis, totaling 0.61% of all hospital admissions in the Brazilian public health system. The mean cost of each of these hospital admissions was US$ 240,23 or R$ 423.42 having as result an overall cost of US$ 16,240,378.00 or R$ 29.232.682,56. Hospital admissions for urinary lithiasis in the Brazilian public health system increased 69% from 1996 to 2010 (43,176 versus 69,309; p < 0.001; OR = 1.69). The number of hospital admissions was 5% greater between December and March as compared to the period between June and September (35,290 versus 33,749; p < 0.001; OR = 1.10). For Caucasian patients the hospital admission was 75% greater as compared to black patients (63.2% versus 35.8%; p = 0.02; OR = 1,75). CONCLUSION: Hospital admission for urinary liyhiasis has an elevated impact on the public health system with a cost of US$ 16,2 or R$ 29.2 million per year. The number of hospital admissions was greater in hotter months than in cold ones and also in the last decade, mainly in Caucasian population. These data may be helpful for the organization and optimization of health programs in the public health system as referred to prevention and treatment of urinary lithiasis in Brazil. PMID- 26761258 TI - High-grade primary pulmonary leiomyosarcoma. AB - Primary sarcomas of the lung are rare and account for 0.5% of all primary lung tumors. There were approximately 300 cases described in the literature as of 2006. All histologic types of sarcoma were described, and the most common intrathoracic types reported were angiosarcoma, leiomyosarcoma, fibrosarcoma, hemangiopericytoma, and rhabdomyosarcoma. The biological behavior of these tumors is not well-known due to their low frequency. Leiomyosarcomas represent one of the most common subtypes encountered in the lungs, and usually occur during the sixth decade, with male predominance. Although the frequency of metastatic disease is not related to tumor size, prognosis was reported to be poorer in high grade tumors. In comparison with other sarcomas, survival after complete resection of pulmonary leiomyosarcoma was reported as longer. We report on a patient with primary leiomyosarcoma originating from the bronchus with complete resection and long-term follow-up. PMID- 26761259 TI - Does negative retroperitoneal CT in adolescents with paratesticular rhabdomyosarcoma preclude the need of retroperitoneal lymph node dissection? AB - We report on a 16-year-old male with paratesticular rhabdomyosarcoma who underwent retroperitoneal lymph node dissection due to a stage I tumor (normal retroperitoneal computed tomoghaphy). The surgical finding was three enlarged nodes, positive for metastatic disease. Patient was referred to adjuvant chemotherapy. This case suggests that the Intergroup Rhabdomyosarcoma Study Group IV protocol is subject to questions regarding adolescents with paratesticular rhabdomyosarcoma, and that negative retroperitoneal CT does not preclude the need of lymph node dissection. PMID- 26761260 TI - Herniated lumbar disc surgery in triathlon athletes with intraoperative neurophysiologic monitoring. AB - Intraoperative neurophysiologic monitoring was performed in a patient by somatosensory evoked potential, motor evoked potential and free-running electromyography with intraoperative stimulation. It was verified that after decompression, there was an increase in the amplitude of motor evoked potential responses, showing an immediate improvement of the treated levels. Intraoperative neurophysiologic monitoring for surgical lumbar disc herniation in an athlete allowed a dynamic neurophysiological diagnosis, differentiation of the involvement of compression at the central or foraminal levels, and clinical awareness of the iatrogenic damage, thereby increasing safety. PMID- 26761261 TI - Panniculitis in the newborn: a case report. AB - The authors present a case of panniculitis in a newborn, a rare disease in the neonatal period discussing its causes and differential diagnosis, emphasizing a possible diagnosis of erythema nodosum. PMID- 26761262 TI - Chemotherapy-induced peripheral neuropathy: a literature review. AB - Peripheral neuropathy is a common side effect in patients undergoing cancer treatment with chemotherapy. This condition can affect patients in several different ways, interfering in their activities of daily living and autonomy. The present study aimed to review the literature on chemotherapy-induced peripheral neuropathy and its treatment or other possible interventions. The findings reveal that chemotherapy-induced peripheral neuropathy is a common condition that affects patients undergoing treatment with some specific drugs. Besides, several different substances have been used to treat or control this condition, although no significant evidence could be found in these studies. PMID- 26761263 TI - Premature ejaculation: is there an efficient therapy? AB - Premature ejaculation is the most frequent male sexual dysfunction, estimated to affect 20 to 30% of men at some time in their life. A Pubmed search from the year 2000 to the present was performed to retrieve publications related to management or treatment of premature ejaculation. Behavioral techniques have been the mainstay of premature ejaculation management for many years, although evidence of their short-term efficacy is limited. Topical therapies for premature ejaculation act by desensitizing the penis and do not alter the sensation of ejaculation. Selective serotonin reuptake inhibitors (SSRIs), commonly used in the treatment of depression, are often used to treat premature ejaculation, based on the observation that delayed ejaculation is a frequent side effect of this drug class. Dapoxetine is a short-acting SSRI formulated to treat premature ejaculation, and results seem very promising. PMID- 26761264 TI - Congenital cytomegalovirus infection. PMID- 26761265 TI - Interventional radiology to treat severe obstetric hemorrhages. AB - The author discusses the recent role of interventional radiology to prevent postpartum hemorrhagic complications that represent an important cause of maternal morbidity and mortality all over the world. Hence, hemorrhage control is mandatory. Traditional management and recent minimally invasive radiological procedures by means of inserting occluding balloons into appropriate vessels are analyzed. It is advisable that maternity hospitals have protocols for the management of obstetric hemorrhage by means of interventional radiology, either in their own departments or in association with other large healthcare units that may have proper equipment and trained staff. However, the evidence related to its efficacy is limited to series of cases analyzed in tertiary centers. This is a promising technique that may be applied to severe obstetric hemorrhages and may bring beneficial results in the majority of cases. PMID- 26761266 TI - Treatment dropout and missed appointments among adults with attention deficit/hyperactivity disorder: associations with patient- and disorder-related factors. AB - OBJECTIVE: Knowledge of factors associated with treatment dropout and missed appointments in adults with attention-deficit/hyperactivity disorder (ADHD) is very limited. On the basis of proposed hypotheses that past behavior patterns are more predictive of current behaviors of treatment dropout and missed appointments than are sociodemographic and clinical characteristics, we examined the associations of sociodemographic variables, clinical variables, risk-taking behavior, educational and occupational instability, and behaviors during mandatory schooling with the primary outcome measures of treatment dropout and missed appointments. METHOD: In a naturalistic cohort study of 151 adult outpatients with ADHD initiating assessment in a Danish ADHD unit from September 1, 2010, to September 1, 2011, the Adult ADHD Self-Report Scale v1.1 symptom checklist (ASRS) and a thorough clinical interview were used to assess ADHD according to DSM-IV-TR criteria. Stepwise logistic regression analysis was used to estimate reported associations. RESULTS: A total of 27% of patients dropped out of treatment and a total of 42% had >= 3 missed appointments during treatment. Mood and anxiety disorders significantly lowered the odds of treatment dropout (odds ratio [OR] = 0.18; 95% confidence interval [CI], 0.05-0.65), whereas having started but not completed 2 or more educational programs apart from mandatory schooling significantly increased the odds of dropout (OR = 3.01; 95% CI, 1.32-6.89). Variables significantly associated with most missed appointments were low educational level (OR = 2.19; 95% CI, 1.12-4.31), 3 or more employments of less than 3 months' duration (OR = 2.86; 95% CI, 1.30-6.28), and having skipped class often/very often during mandatory schooling (OR = 2.65; 95% CI, 1.29-5.43). Additionally, the predominantly inattentive ADHD (ADHD-I) subtype lowered the odds of missed appointments (OR = 0.17; 95% CI, 0.05-0.62). CONCLUSION: Our results suggest that past behavior in terms of highest dropout rates in the educational and occupational systems and highest rates of skipping class during mandatory schooling is equally associated with current behavior of treatment dropout and missed appointments as are sociodemographic and clinical factors. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02226445. PMID- 26761267 TI - Critical Review: Mechanisms of HIV Transmission in Depo-Provera Users: The Likely Role of Hypoestrogenism. AB - Almost half of new HIV infections worldwide occur in women, and vaginal intercourse is the most common mode of transmission. Accumulating evidence suggests that depot medroxyprogesterone acetate may increase HIV transmission, but little is known about the underlying mechanisms. We propose that hypoestrogenism in depot medroxyprogesterone acetate may contribute to increased HIV transmission. We present supportive evidence and propose potential interventions to prevent or treat vaginal hypoestrogenism using vaginal estrogens. PMID- 26761268 TI - HIV-Specific CD8+ T Cell-Mediated Viral Suppression Correlates With the Expression of CD57. AB - BACKGROUND: Virus-specific CD8(+) T-cell responses are believed to play an important role in the control of HIV-1 infection; however, what constitutes an effective HIV-1 CD8(+) T-cell response remains a topic of debate. The ex vivo viral suppressive capacity was measured of CD8(+) T cells from 44 HIV-1-positive individuals. The phenotypic and cytokine profiles, and also the specificity of the CD8(+) T cells, were correlated with the suppression of HIV-1 replication. We also aimed to determine whether antiretroviral therapy (ART) had any positive effect on the HIV-1 suppressive CD8(+) T cells. METHOD: Ex vivo suppression assay was used to evaluate the ability of CD8(+) T cells to suppress HIV-1 replication in autologous CD4(+) T cells. The CD107a, interferon-gamma, interleukin-2, tumor necrosis factor-alpha (TNF-alpha), and macrophage inflammatory protein-1beta (MIP 1beta) responses to HIV-1 were evaluated by intracellular staining. The phenotypic profile of CD8(+) T cells was determined by whole blood staining. RESULTS: The expression of CD57 on effector CD8(+) T cells correlated with the suppression of HIV-1 replication and to the duration of ART. CD107a and tumor necrosis factor-alpha expression levels were significantly higher in individuals with ex vivo suppressive activity compared with individuals without suppressive activity. CONCLUSIONS: Standard in vitro assays measuring one or several cytokines do not correlate with the functional viral suppressive capacity of CD8(+) T cells from HIV-1-positive individuals. The best correlation of viral suppression was found to be CD57 expression. CD57 expression correlated with the duration of ART, suggesting that ART restores the cytotoxic capacity of CD8(+) T lymphocytes. PMID- 26761269 TI - Brief Report: Seminal Plasma Anti-HIV Antibodies Trigger Antibody-dependent Cellular Cytotoxicity: Implications for HIV Transmission. AB - Recent evidence from HIV vaccine trials in humans and non-human primates suggests that nonneutralizing antibody functions, such as antibody-dependent cellular cytotoxicity (ADCC), are an important component of vaccine-mediated protection. Whether anti-HIV ADCC antibodies are present in seminal fluid, however, is not known. We assessed whether anti-HIV antibodies within seminal plasma mediate ADCC and activate natural killer (NK) cells. Using matched blood and seminal plasma samples, we detected anti-HIV IgG within samples from all 11 HIV-infected donors. Furthermore, anti-HIV antibodies within the seminal plasma triggered detectable ADCC in 9 of 11 donors and activated NK cells in 6 of 11 donors. The ability of seminal plasma-derived IgG to activate NK cells in an anti-HIV antibody-dependent manner was enhanced when IgG were enriched and other seminal plasma components were removed. These observations have relevance for understanding natural immunity to HIV infection and provide assistance with HIV vaccine design. PMID- 26761270 TI - Effective Treatment of Depressive Disorders in Medical Clinics for Adolescents and Young Adults Living With HIV: A Controlled Trial. AB - OBJECTIVE: Preliminary test of a manualized, measurement-guided treatment for depression for adolescents and young adults in care at 4 sites of the Adolescent Trials Network for HIV/AIDS Interventions. DESIGN: The US sites were randomly assigned to either a 24-week, combination cognitive behavioral therapy and medication management algorithm (COMB) tailored for youth living with HIV (YLWH) or to treatment as usual (TAU). METHODS: Youth at TAU sites had access to therapists and medication management as needed. COMB-site clinicians were trained in the manualized intervention and participated in supervision calls to monitor intervention fidelity. RESULTS: Over the course of the study with 44 participants, those in COMB, compared with those in TAU, reported fewer depressive symptoms, P < 0.01 (as measured by the Quick Inventory for Depression symptoms) and were more likely to be in remission, P < 0.001 (65% vs. 10% at week 24, end of treatment, and 71% vs. 7% at week 48, final follow-up). A greater proportion of COMB participants received psychotherapy (95% vs. 45%, P < 0.001) and attended more sessions (12.6 vs. 5, P < 0.001) than those in TAU. Viral load decreased in both groups and was associated (P < 0.05) with reduction in depressive symptoms. CONCLUSIONS: A 24-week manualized, measurement-guided psychotherapy and medication management algorithm tailored for YLWH was more effective in achieving and sustaining remission from depression than TAU at HIV care clinic sites. Given observed treatment efficacy, this structured combination treatment could be disseminated to medical clinics to successfully treat YLWH, who are at particular risk for depression. PMID- 26761272 TI - Feasibility of Identifying a Female Sex Worker Cohort at High Risk of HIV Infection in the Caribbean for HIV Vaccine Efficacy Trials: Longitudinal Results of HVTN 907. AB - BACKGROUND: Identifying cohorts of Caribbean women with HIV infection rates sufficient for inclusion in HIV vaccine efficacy trials has been challenging. HVTN 907 determined the feasibility of identifying and retaining a cohort of women at high risk for HIV acquisition by focusing recruitment on female sex workers (FSWs). METHODS: HIV uninfected FSWs, residing in Haiti, Dominican Republic, and Puerto Rico, who reported unprotected sex and met previously described more stringent site-specific eligibility criteria, were eligible. Behavioral risk assessment, HIV counseling and testing, and pregnancy testing were performed at baseline, 6, 12, and 18 months. RESULTS: Among 799 FSWs (264 from Dominican Republic, 334 from Haiti, and 201 from Puerto Rico), the median age was 26 years, with 54% having less than a high school education and 45% having a monthly household income of less than $US 100. Median number of male partners 6 months before screening was 200. Retention at 18 months was 93%. Twelve women became HIV infected, 9 from Haiti. The annualized HIV incidence was 1.07% (95% confidence interval: 0.55% to 1.87%). Pregnancy incidence was 22.5% (95% confidence interval: 21.9% to 29.5%). Statistically significant declines in risk behaviors occurred between screening and the 18-month visit assessment. DISCUSSION: The HVTN 907 study identified a high-risk cohort of women with excellent retention for all 3 sites, despite major challenges especially in Haiti. These results show that a bridging study of a vaccine shown to be efficacious in other clade settings would be possible among FSWs in the region, particularly in Haiti. PMID- 26761271 TI - Longitudinal Changes Over 10 Years in Free Testosterone Among HIV-Infected and HIV-Uninfected Men. AB - BACKGROUND: Aging in males is associated with lower testosterone levels and a decrease in diurnal variation of testosterone secretion. Cross-sectional studies have shown lower than expected testosterone levels among HIV-infected men, but whether age-related changes in serum testosterone differ by HIV serostatus are not known. METHODS: HIV-infected men from the Multicenter AIDS Cohort Study (MACS), age >= 45 years at highly active antiretroviral therapy initiation, who had >= 2 samples from the subsequent 10 years, were matched to HIV-uninfected men by age, race, MACS site, and calendar time of samples. Linear mixed-effects regression models were used to determine whether free testosterone (FT) and its rate of change differed by HIV serostatus. RESULTS: One hundred eighty-two HIV infected and 267 HIV-uninfected men were included, median age: 48.8 years (interquartile range: 45.8-53.4), median numbers of FT measurements per participant 4 (interquartile range: 3-5), 65% were drawn in the adjusted morning (AM). Mean-adjusted FT levels were lower among HIV-infected than HIV-uninfected men in AM samples {-6.1 ng/dL [95% confidence interval (CI): -9.8 to -2.4], P = 0.001}, but not in afternoon samples [-1.7 ng/dL (-6.0 to 2.6), P = 0.441]. The rate of FT decline with age did not differ by HIV serostatus: 9.2 ng/dL (95% CI: 13.4 to -5.0) per 10 years for HIV-infected vs. 7.9 ng/dL (95% CI: -10.2 to -5.5) for HIV-uninfected men, P = 0.578. CONCLUSIONS: FT decreased similarly with increasing age regardless of HIV serostatus. The lower AM, but not adjusted afternoon, FT levels among HIV-infected men compared with HIV-uninfected men suggest a loss of diurnal variation in FT levels among HIV-infected men. PMID- 26761273 TI - Clinical and Virologic Outcomes After Changes in First Antiretroviral Regimen at 7 Sites in the Caribbean, Central and South America Network. AB - BACKGROUND: HIV-infected persons in resource-limited settings may experience high rates of antiretroviral therapy (ART) change, particularly because of toxicity or other nonfailure reasons. Few reports address patient outcomes after these modifications. METHODS: HIV-infected adults from the 7 Caribbean, Central and South America network clinical cohorts who modified >1 drug from the first ART regimen (ART-1) for any reason thereby starting a second regimen (ART-2) were included. We assessed cumulative incidence of, and factors associated with, death, virologic failure (VF), and regimen change after starting ART-2. RESULTS: Five thousand five hundred sixty-five ART-naive highly active ART initiators started ART-2 after a median of 9.8 months on ART-1; 39% changed to ART-2 because of toxicity and 11% because of failure. Median follow-up after starting ART-2 was 2.9 years; 45% subsequently modified ART-2. Cumulative incidences of death at 1, 3, and 5 years after starting ART-2 were 5.1%, 8.4%, and 10.5%, respectively. In adjusted analyses, death was associated with older age, clinical AIDS, lower CD4 at ART-2 start, earlier calendar year, and starting ART-2 because of toxicity (adjusted hazard ratio = 1.5 vs. failure, 95% confidence interval: 1.0 to 2.1). Cumulative incidences of VF after 1, 3, and 5 years were 9%, 19%, and 25%. In adjusted analyses, VF was associated with younger age, earlier calendar year, lower CD4 at the start of ART-2, and starting ART-2 because of failure (adjusted hazard ratio = 2.1 vs. toxicity, 95% confidence interval: 1.5 to 2.8). CONCLUSIONS: Among patients modifying the first ART regimen, risks of subsequent modifications, mortality, and virologic failure were high. Access to improved antiretrovirals in the region is needed to improve initial treatment success. PMID- 26761275 TI - Implementation and Operational Research: Implementation of the WHO 2011 Recommendations for Isoniazid Preventive Therapy (IPT) in Children Living With HIV/AIDS: A Ugandan Experience. AB - BACKGROUND: Intensified tuberculosis (TB) case finding and isoniazid preventive therapy (IPT) are strongly recommended for children who are HIV infected. Data are needed to assess the feasibility of the WHO 2011 intensified tuberculosis case finding/IPT clinical algorithm. METHODS: Children who are HIV infected and attending Nsambya Home Care at Nsambya Hospital, Uganda, were screened for TB following WHO recommendations. IPT was given for 6 months after excluding TB. Factors associated with time to IPT initiation were investigated by multivariate Cox proportional hazard regression. Health care workers were interviewed on reasons for delay in IPT initiation. RESULTS: Among the 899 (49% male) children with HIV, 529 (58.8%) were screened for TB from January 2011 to February 2013. Children with active TB were 36/529 (6.8%), 24 (4.5%) were lost to follow-ups and 280 (52.9%) started IPT, 86/280 (30.7%) within 3 months of TB screening and 194/280 (69.3%) thereafter. Among the 529 children screened for TB, longer time to IPT initiation was independently associated with cough at TB screening (hazard ratio 0.62, P = 0.02, 95% confidence interval: 0.41 to 0.94). Four children (1% of those starting treatments) interrupted IPT because of a 5-fold increase in liver function measurements. In the survey, Health care workers reported poor adherence to antiretroviral therapy, poor attendance to periodic HIV follow-ups, and pill burden as the 3 main reasons to delay IPT. CONCLUSION: In resource constrained settings, considerable delays in IPT initiation may occur, particularly in children with HIV who are presenting with cough at TB screening. The good safety profile of isoniazid in antiretroviral-therapy-experienced children provides further support to IPT implementation in this population. PMID- 26761274 TI - Ten Years of Screening and Testing for Acute HIV Infection in North Carolina. AB - OBJECTIVE: To describe demographic and behavioral characteristics of persons with acute HIV infection (AHI) over time. METHODS: We conducted a retrospective assessment of AHI identified through the Screening and Tracing Active Transmission (STAT) program from 2003 to 2012 in North Carolina (NC). AHI was identified using pooled nucleic acid amplification for antibody negative samples and individual HIV-1 RNA for antibody indeterminate samples. The STAT program provides rapid notification and evaluation. We compared STAT-collected demographic and risk characteristics with all persons requesting tests and all non-AHI diagnoses from the NC State Laboratory of Public Health. RESULTS: The STAT Program identified 236 AHI cases representing 3.4% (95% confidence interval: 3.0% to 3.9%) of all HIV diagnoses. AHI cases were similar to those diagnosed during established HIV. On pretest risk-assessments, AHI cases were predominately black (69.1%), male (80.1%), young (46.8% < 25 years), and men who have sex with men (MSM) (51.7%). Per postdiagnosis interviews, the median age decreased from 35 (interquartile range 25-42) to 27 (interquartile range 22-37) years, and the proportion <25 years increased from 23.8% to 45.2% (trend P = 0.04) between 2003 and 2012. AHI men were more likely to report MSM risk post-diagnosis than on pretest risk-assessments (64%-82.9%; P < 0.0001). Post-diagnosis report of MSM risk in men with AHI increased from 71.4% to 96.2%. CONCLUSIONS: In NC, 3.4% of individuals diagnosed with HIV infection have AHI. AHI screening provides a real time source of incidence trends, improves the diagnostic yield of HIV testing, and offers an opportunity to limit onward transmission. PMID- 26761277 TI - Maillard Reaction of Pidan White as Inhibited by Chinese Black Tea Extract (Camellia sinensis) in the Pickling Solution. AB - Changes in Maillard reaction of pidan white were monitored with A294, fluorescence intensity, and browning intensity during pickling in the absence and presence of Chinese black tea extract (Camellia sinensis) at levels of 2% and 5% together with 0.2% ZnCl2 or 0.2% CaCl2 up to 3 wk, followed by ageing for another 3 wk. Browning intensity and A294 of pidan white increased with increasing pickling/ageing, while fluorescence intensity decreased during ageing (p<0.05), irrespective of treatments. At wk 6, pidan white treated with 0.2% ZnCl2 and 0.2% CaCl2 showed slightly higher browning intensity, fluorescence intensity and A294 than those treated with divalents together with Chinese black tea (p<0.05). Free amino group and sugar contents showed continuous decrease during pickling and ageing irrespective of tea and cations used. However, pidan treated without Chinese black tea extract showed significantly lower free amino group and sugar during the ageing of 6 wk (p<0.05). Thus, Chinese black tea extract had an inhibitory effect on the Maillard reaction during ageing of pidan white. PMID- 26761276 TI - Synthesis of zeolite NaA membrane from fused fly ash extract. AB - Zeolite-NaA membranes were synthesized from an extract of fused South African fly ash on a porous titanium support by a secondary growth method. The influence of the synthesis molar regime on the formation of zeolite NaA membrane layer was investigated. Two synthesis mixtures were generated by adding either aluminium hydroxide or sodium aluminate to the fused fly ash extract. The feedstock material and the synthesized membranes were characterized by X-diffraction (XRD), scanning electron microscopy (SEM) and X-ray fluorescence spectroscopy (XRF). It was found by XRD and SEM that the cubic crystals of a typical zeolite NaA with a dense intergrown layer was formed on the porous Ti support. The study shows that the source of Al used had an effect on the membrane integrity as sodium aluminate provided the appropriate amount of Na(+) to form a coherent membrane of zeolite NaA, whereas aluminium hydroxide did not. Morphological, the single hydrothermal stage seeded support formed an interlocked array of zeolite NaA particles with neighbouring crystals. Also, a robust, continuous and well-intergrown zeolite NaA membrane was formed with neighbouring crystals of zeolite fused to each other after the multiple stage synthesis. The synthesized membrane was permeable to He (6.0 * 10(6) L m(-2)h(-1) atm(-1)) and CO2 (5.6 * 10(6) L m(-2)h(-1) atm(-1)), which indicate that the layer of the membrane was firmly attached to the porous Ti support. Membrane selectivity was maintained showing membrane integrity with permselectivity of 1.1, showing that a waste feedstock, fly ash, could be utilized for preparing robust zeolite NaA membranes on Ti support. PMID- 26761278 TI - Quality Characteristics of Stirred Yoghurt Added with Fermented Red Pepper. AB - Pungency of hot pepper has limited its usage even though it shows various health beneficial effects. This study was conducted to develop the novel yoghurt containing hot pepper with diminishing pungency and aimed to examine the quality characteristics of yoghurt prepared with fermented red pepper. Hot pepper was first fermented with Bacillus licheniformis SK1230 to reduce the pungency of capsaicin. We then examined the quality, sensory characteristics, and antioxidant activity of yoghurt containing the fermented red pepper. The titratable acidity of this yoghurt increased whereas the viscosity decreased with increasing amounts of added red pepper. The total polyphenol content increased in proportion to the amount of added red pepper. The antioxidant activity significantly increased with the addition of red pepper (p<0.05). Color evaluation showed that the L value decreased whereas the a and b values increased significantly with the amount of red pepper added (p<0.05). In the sensory evaluation, yoghurt prepared with higher amounts of fermented red pepper received lower scores. However, yoghurt containing fermented red pepper at a concentration of 0.05% received higher scores for taste, flavor, and overall acceptability than yoghurt prepared with non-fermented pepper. Therefore, it can be concluded that the application of red pepper fermented by Bacillus licheniformis SK1230 gives beneficial feature to the preparation of yoghurt. PMID- 26761279 TI - Effect of Duck Feet Gelatin on Physicochemical, Textural, and Sensory Properties of Low-fat Frankfurters. AB - Duck feet gelatin (DFG) gel was added as a fat replacer to low-fat frankfurters and the effect of DFG on physicochemical, textural, and sensory characteristics of low-fat frankfurters was evaluated. DFG gel was prepared with a 20% duck feet gelatin concentration (w/w). Adding DFG decreased lightness and increased yellowness of the low-fat frankfurters (p<0.05). However, DFG did not affect redness of low-fat frankfurters (p>0.05). The statistical results indicated that adding DFG improved cooking yield of low-fat frankfurters (p<0.05). In addition, replacing pork back fat with DFG resulted in increased moisture content, protein content, and ash content of low-fat frankfurters, and the low-fat frankfurter formulated with 5% pork back fat and 15% DFG gel had the highest moisture content and lowest fat content (p<0.05). Adding of DFG increased all textural parameters including hardness, springiness, cohesiveness, chewiness, and gumminess of low fat frankfurters (p<0.05). In terms of sensory properties, the low-fat frankfurter formulated with 5% pork back fat and 15% DFG gel showed similar satisfaction scores for the flavor, tenderness, juiciness, and overall acceptance when compared to the regular frankfurters (20% back fat). Therefore, our results suggest that DFG could be an effective novel source, as a fat replacer, for manufacturing of low-fat frankfurters. PMID- 26761280 TI - Evaluation of the Nutritional and Storage Quality of Meatballs Formulated with Bee Pollen. AB - In this study, the nutritional and storage quality of meatballs formulated with different levels (0, 1.5, 3.0, 4.5 and 6.0%) of bee pollen were investigated during storage at 41C for 9 d. Protein content of meatballs increased, while moisture content decreased with increased pollen. The addition of pollen improved cooking loss but decreased the redness (Hunter a value) and sensory scores. Textural parameters (hardness, springsness, gumminess, and chewiness) were affected by pollen addition and the hardness and gumminess values of meatballs decreased as the pollen content increased. While C18:0 content of meatballs slightly decreased with pollen addition, C18:2n-6c, C18:3n-3, C20:5n-3, and PUFA contents increased. The PUFA/saturated fatty acids (P/S) ratio increased from 0.05 in the control to 0.09 in meatballs with 6.0% pollen. The n-6/n-3 ratio decreased from 11.84 in the control to 3.65 in the meatballs with 6.0% pollen. The addition of pollen retarded the lipid oxidation and inhibited the bacterial growth in meatballs. The pH, redness, TBA value and total aerobic mesophilic bacteria, coliform bacteria and S. aureus counts values changed significantly during storage. The results suggest that bee pollen could be added to enhance the nutritional and storage quality of meatballs with minimal changes in composition and/or sensory properties. PMID- 26761281 TI - Characterization of Hanwoo Bovine By-products by Means of Yield, Physicochemical and Nutritional Compositions. AB - Though the edible bovine by-products are widely used for human consumption in most countries worldwide but the scientific information regarding the nutritional quality of these by-products is scarce. In the present study, the basic information regarding the yields, physicochemical and nutritional compositions of edible Hanwoo bovine by-products was studied. Our results showed that the yields, physicochemical and nutritional composition widely varied between the by-products examined. The highest pH values were found in rumen, reticulum, omasum and reproductive organ. Heart, liver, kidney and spleen had the lowest CIE L* values and highest CIE a* values. Liver had the highest vitamin A, B2 and niacin contents whereas the highest B1 and B5 contents were found in kidney. The highest Ca content was found in rumen, reticulum, omasum, head and leg while the highest Mn and Fe contents were found in rumen, omasum and spleen, respectively. Liver had the highest Cu content. Total essential amino acids (EAA)/amino acids (AA) ratios ranged between the by-products from 38.37% to 47.41%. Total polyunsaturated fatty acids (PUFA) levels ranged between the by-products from 2.26% to 26.47%, and most by-products showed favorable PUFA/SFA ratios. It is concluded that most of by-products examined are good sources of essential nutrients and these data will be of great importance for promotion of consumption and utilization of beef by-products in future. PMID- 26761282 TI - Effect of Sex on Flavor-related and Functional Compounds in Freeze-dried Broth Made from Korean Native Chicken. AB - Studies on the flavour characteristics of meat-based broth, quantification of flavour-related and functional compounds, and factors affecting the availability of such compounds are minimal. The present study was designed to determine the effects of sex on flavor-related and functional compounds in freeze-dried broth (FDB) made from Korean native chickens (KNC). Male and female KNC from a commercial strain (Woorimatdag (TM)) were reared under similar commercial conditions. FDB was separately prepared using male and female birds aged 100 d (six birds of each sex) and analyzed for nucleotide, free amino acid, betaine, carnitine, carnosine, anserine, and creatine contents, and fatty acid composition. The levels of betaine, carnitine and creatine in FDB were not significantly different between the two sexes (p>0.05) in KNC. Carnosine and anserine were not detected in FDB samples. However, FDB from female chickens had significantly higher inosine-5-monophosphate and arachidonic acid contents than did FDB from male chickens. FDB prepared with male KNC contained higher levels of inosine, linoleic acid, glycine, alanine, lysine, and serine (p<0.05). However, glutamic acid, oleic acid, and DHA were present in comparable amounts (p>0.05) in FDB made from male and female KNC. Our findings suggest that the sex of KNC has significant effect on the contents of flavor-related compounds, but not functional compounds. PMID- 26761283 TI - Effects of Different Levels of Concentrate in the Diet on Physicochemical Traits of Korean Native Black Goat Meats. AB - The effects of feeding of diets based on roughage supplemented with concentrate on the carcass and meat quality attributes of Korean black goats were investigated. The 40 male goats at 5 mon age were divided into four treatment groups; T1 (1.5%), T2 (2.0%), T3 (2.5%) and T4 (ad libitum) feeding of concentrate with ad libitum rice straw. Forty bucks at the end of the feeding were fasted for 12 h before slaughter and were then slaughtered. For carcass measurement, cold buck carcasses were examined after 24 h of chilling at 5C. The carcasses were chilled in refrigerator at 2+/-2C for 24 h, then the longissimus dorsi muscle was removed from the carcasses. The samples were separately vacuum packaged, frozen and stored at -20C for up to 1 mon, prior to physicochemical evaluations. Carcass yields were greatly affected by rate of concentrate feeding. T4 showed the heaviest live and carcass weights and the highest dressing and fat percentages (p<0.05). The moisture contents were lower in T4 compared with other treatments, while the crude protein and fat contents were higher (p<0.05). monounsaturated fatty acid in T4 was significantly higher than others, which showed the highest percentages of oleic acid (C18:1). For the sensory test, T4 was tenderer and produced better flavor scores than others. Increasing the level of concentrate in the diet resulted in an improvement in growth performance, and carcass and physicochemical characteristics of goat meats. PMID- 26761284 TI - Comparison of Quality of Bologna Sausage Manufactured by Electron Beam or X-Ray Irradiated Ground Pork. AB - Ground lean pork was irradiated by an electron beam or X-rays to compare the effects of two types of radiation generated by a linear accelerator on the quality of Bologna sausage as a model meat product. Raw ground lean pork was vacuum packaged at a thickness of 1.5 cm and irradiated at doses of 2, 4, 6, 8, or 10 kGy by an electron beam (2.5 MeV) or X-rays (5 MeV). Solubility of myofibrillar proteins, bacterial counts, and thiobarbituric acid reactive substance (TBARS) values were determined for raw meat samples. Bologna sausage was manufactured using the irradiated lean pork, and total bacterial counts, TBARS values, and quality properties (color differences, cooking yield, texture, and palatability) were determined. Irradiation increased the solubility of myofibrillar proteins in a dose-dependent manner (p<0.05). Bacterial contamination of the raw meat was reduced as the absorbed dose increased, and the reduction was the same for both radiation types. Differences were observed only between irradiated and non-irradiated samples (p<0.05). X-ray irradiation may serve as an alternative to gamma irradiation and electron beam irradiation. PMID- 26761285 TI - The Assessment of Red Beet as a Natural Colorant, and Evaluation of Quality Properties of Emulsified Pork Sausage Containing Red Beet Powder during Cold Storage. AB - The purpose of this study was to assess red beet as a natural colorant in emulsified pork sausage and to investigate the effect of red beet on quality characteristics of emulsified pork sausage during 20 d of cold storage. Red beet was prepared as a powder and a substitute with sodium nitrite at 0.5% and 1.0% levels in emulsified pork sausage. Red beet significantly increased the moisture content and pH (p<0.0001) and affected color traits. Lightness of emulsified pork sausage decreased by the addition of red beet powder (p<0.01), whereas lightness with red beet treatments slightly increased during 20 d of cold storage at 4C (p<0.05). Redness dramatically increased with red beet powder (p<0.0001). Color by sensory evaluation also showed a significant effect from red beet addition (p<0.05), whereas the other sensory properties such as flavor, tenderness, juiciness, and overall acceptability were not affected by the addition of red beet powder (p>0.05). Texture and 2-thiobabituric acid reactive substance were also not affected by red beet addition (p>0.05). Therefore, red beet could be a good natural colorant in emulsified pork sausage but it needs additional processing, such as betalain concentration and extraction as a juice, to be used as an antioxidant in meat products. PMID- 26761286 TI - Effect of Repeated Freeze-Thaw Cycles on Beef Quality and Safety. AB - The objectives of this study were to know the effect of repeated freeze-thaw cycles of beef on the sensory, physicochemical quality and microbiological assessment. The effects of three successive freeze-thaw cycles on beef forelimb were investigated comparing with unfrozen fresh beef for 75 d by keeping at -20+/ 1C. The freeze-thaw cycles were subjected to three thawing methods and carried out to know the best one. As the number of freeze-thaw cycles increased color and odor declined significantly before cook within the cycles and tenderness, overall acceptability also declined among the cycles after cook by thawing methods. The thawing loss increased and dripping loss decreased significantly (p<0.05). Water holding capacity (WHC) increased (p<0.05) until two cycles and then decreased. Cooking loss increased in cycle 1 and 3, but decreased in cycle 2. pH decreased significantly (p<0.05) among the cycles. Moreover, drip loss, cooking loss and WHC were affected (p<0.05) by thawing methods within the cycles. 2-Thiobarbituric acid (TBARS) value increased (p<0.05) gradually within the cycles and among the cycles by thawing methods. Total viable bacteria, total coliform and total yeast mould count decreased significantly (p<0.05) within and among the cycles in comparison to the initial count in repeated freeze-thaw cycles. As a result, repeated freeze-thaw cycles affected the sensory, physicochemical and microbiological qua- lity of beef, causing the deterioration of beef quality, but improved the microbiological quality. Although repeated freeze-thaw cycles did not affect much on beef quality and safety but it may be concluded that repeated freeze and thaw should be minimized in terms of beef color for commercial value and WHC and tenderness/juiciness for eating quality. PMID- 26761287 TI - Effects of Partial Substitution of Lean Meat with Pork Backfat or Canola Oil on Sensory Properties of Korean Traditional Meat Patties (Tteokgalbi). AB - Korean traditional meat patties (Tteokgalbi) were prepared by replacing part of the lean meat content with either pork backfat or canola oil and the effect of substitution on sensory quality of the meat patties was investigated. Compared to the control patties, pork-loin Tteokgalbi with 10% pork backfat or 10% canola oil had significantly higher overall acceptability and higher perceived intensity of meat flavor, sweetness, umami, and oiliness. The pork-loin patties containing 10% fat also had lower perceived firmness, toughness, and chalkiness of than the control Tteokgalbi. The chicken breast Tteokgalbi with 10% canola oil had the lowest perceived firmness and chalkiness (control > pork backfat > canola oil). No significant difference was noted in the overall acceptability of chicken breast patties with 10% pork backfat and those with 10% canola oil. These results indicate that substituting 10% of lean meat of Tteokgalbi with fat improved the sensory acceptability of the product for Korean customers regardless of the lean meat and/or fat source used in the patties. Lean meat patties formulated with a limited amount of vegetable oil such as canola oil can be a healthy option for Korean consumers by providing desirable fatty acid profiles without sacrificing sensory quality of the product. PMID- 26761288 TI - Effects of Partial Substitutions of NaCl with KCl, CaSO4 and MgSO4 on the Quality and Sensorial Properties of Pork Patties. AB - This study investigated the effects of NaCl replacers (KCl, CaSO4, and MgSO4) on the quality and sensorial properties of pork patty. In the characteristics of spray-dried salt particles, KCl showed the largest particle size with low viscosity in solution. Meanwhile CaSO4 treatment resulted in the smallest particle size and the highest viscosity (p<0.05). In comparison of the qualities of pork patties manufactured by varying level of Na replacers, MgSO4 treatment exhibited low cooking loss comparing to control (p<0.05). Textural properties of KCl and MgSO4 treatments showed similar pattern, i.e., low level of the replacers caused harder and less adhesive texture than those of control (p<0.05), whereas the hardness of these products was not different with control when the replacers were added more than 1.0%. The addition of CaSO4 also manifested harder and less adhesive than control (p<0.05), but the textural properties of CaSO4 treatment was not affected by level of Ca-salt. Eventually, sensorial properties indicated that KCl and CaSO4 influenced negative effects on pork patties. In contrast, MgSO4 showed better sensorial properties in juiciness intensity, tenderness intensity as well as overall acceptability than control, reflecting that MgSO4 was an effective Na-replacer in meat product formulation. PMID- 26761289 TI - An Outline of Meat Consumption in the Indian Population - A Pilot Review. AB - The consumption of meat is increasing in India and agriculture is considered as the backbone of a majority of people. Livestock plays a significant role, and poultry and dairy are the major sectors contributing to economic development. The majority of meats consumed in India are fish, bovine, mutton, goat, pig, and poultry. In Indian context, culture, traditions, customs, and taboos influence meat consumption to a great extent. However, studies show that urbanization has been causing a rise in demand for meat products. India is the world's second largest exporter of beef. In India, 95% of goat meat produced is consumed locally. Meat consumption, in particular, is determined by the religions where pork is forbidden to Muslims and beef is prohibited to Hindus. The preference and consumption of chicken meat can be considered as a universal phenomenon and chicken meat is greatly accepted by consumers in India as compared to the other meat consumption. The increase of chicken meat consumption is due to the versatility of the meat, relatively low cost in comparison to other meat, and the acceptance of the chicken meat to all religions. There has been a great rise in the production of livestock products and this is expected to continue in the future. The pattern of meat consumption depends considerably on culture, tradition and urbanization. This review was formulated with the objective of identifying the meat consumption patterns in a typical Indian society. PMID- 26761290 TI - Effects of the Plane of Nutrition on Physicochemical Characteristics and Sensory Quality Traits of the Muscle in Finishing Pigs. AB - This study was performed to examine the feasibility of using the low plane of nutrition (LPN) as a means of improving the meat quality of crossbred finishing pigs with a medium weight gain potential. Twenty-four barrows and 24 gilts weighing approximately 48 kg were placed on LPN [a finisher (2.86 Mcal ME/kg and 0.67% lysine) for 91 d] or on a high plane of nutrition [HPN; a commercial grower for 38 d and a finisher (3.35 Mcal ME/kg and 0.9% lysine) for 46 d]. Five barrows and five gilts per treatment weighing approximately 125 kg were slaughtered after the indicated days on the respective diets, followed by physicochemical analysis and sensory evaluation on their muscles. Overall average daily gain was 12.6% less in the LPN group vs. the HPN group (p<0.05). The redness (a*) of fresh longissimus muscle (LM) from the loin as well as from Boston butt was greater in the LPN group vs. HPN whereas the shear force for fresh LM from these primals and semimembranosus muscle was lower in the former. In sensory evaluation for cooked LM, no treatment effect was detected in any of the quality traits examined, except for a lower color score in the LPN vs. HPN group. Results suggest that meat quality of the finishing pigs can be improved to some extent by using LPN. However, the present pigs, whose backfat thickness was 24 mm at 125 kg, are thought not to be lean enough to be fattened over 120 kg. PMID- 26761291 TI - Effect of Gaseous Ozone Exposure on the Bacteria Counts and Oxidative Properties of Ground Hanwoo Beef at Refrigeration Temperature. AB - This study was designed to elucidate the effect of ozone exposure on the bacteria counts and oxidative properties of ground Hanwoo beef contaminated with Escherichia coli O157:H7 at refrigeration temperature. Ground beef was inoculated with 7 Log CFU/g of E. coli O157:H7 isolated from domestic pigs and was then subjected to ozone exposure (10*10(-6) kg O3 h(-1)) at 4C for 3 d. E. coli O157:H7, total aerobic and anaerobic bacterial growth and oxidative properties including instrumental color changes, TBARS, catalase (CAT) and glutathione peroxidase (GPx) activity were evaluated. Ozone exposure significantly prohibited (p<0.05) the growths of E. coli O157:H7, total aerobic and anaerobic bacteria in ground beef samples during storage. Ozone exposure reduced (p<0.05) the CIE a* value of samples over storage time. The CIE L* and CIE b* values of the samples fluctuated over storage time, and ozone had no clear effect. Ozone exposure increased the TBARS values during 1 to 3 d of storage (p<0.05). The CAT and GPx enzyme activities were not affected by ozone exposure until 2 and 3 d of storage, respectively. This study provides information about the use of ozone exposure as an antimicrobial agent for meat under refrigerated storage. The results of this study provide a foundation for the further application of ozone exposure by integrating an ozone generator inside a refrigerator. Further studies regarding the ozone concentrations and exposure times are needed. PMID- 26761292 TI - Effects of Lemon Balm on the Oxidative Stability and the Quality Properties of Hamburger Patties during Refrigerated Storage. AB - This study was performed to investigate the effects of lemon balm (Melissa officinalis L.) on various quality and antioxidant activity of hamburger patties. Lemon balm extract (LBE) showed the highest amount of total polyphenol (801.00 mg TAE/g DW) and flavonoids (65.05 mg RA/g DW). The IC50 value of DPPH hydroxyl scavenging of LBE was 132 MUg/mL. The hamburger patties were prepared by 0% (N), 0.1% (L1), 0.5% (L2), and 1.0% (L3) of the lemon balm powder. The addition of lemon balm powder increased the chewiness value, but did not affect the hardness, cohesiveness, and springiness values. Lemon balm powder had positive effects on sensory evaluation of patties. The pH of all patties decreased with longer storage period. 2-Thiobarbituric acid value, volatile basic nitrogen content, and the total microbial counts of hamburger patties in the L3 group were lower, compared to those of the normal (N group). In conclusion, the L3 group had significantly delayed lipid peroxidation compared to other treatment groups. However, the addition of lemon balm powder into patties showed no significantly influence on proximate composition, calorie contents, water holding capacity and cooking loss of patties. Therefore, lemon balm might be a useful natural antioxidant additive in meat products. PMID- 26761293 TI - Effects of Psychrotrophic Bacteria, Serratia liquefaciens and Acinetobacter genomospecies 10 on Yogurt Quality. AB - The aim of this study was to evaluate the effect of proteolytic (Serratia liquefaciens, match %: 99.39) or lipolytic (Acinetobacter genomospecies 10, match %: 99.90) psychrotrophic bacteria (bacterial counts, analysis of free fatty acids (FFA) and analysis of free amino acids) on the microbial and chemical properties (yogurt composition), and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of yogurt during storage. Yogurts were prepared with raw milk preinoculated with each psychrotrophic bacteria. The total solid, fat, and protein content were not affected by preinoculation, but the pH of yogurt preinoculated with psychrotrophic bacteria was higher than in control. There was a dramatic increase in short chain free fatty acids among FFA in yogurt with Acinetobacter genomospecies 10. For 14 d of cold storage condition, SCFFA was 25.3 mg/kg to 34.4 mg/kg (1.36 times increased), MCFFA was 20.4 mg/kg to 25.7 mg/kg (1.26 times increased), and LCFFA was 240.2 mg/kg to 322.8 mg/kg (1.34 times increased). Serratia liquefaciens (match %: 99.39) in yogurt caused a greater accumulation of free amino acids (FAA), especially bitter peptides such as leucine, valine, arginine, and tyrosine, but SDS-PAGE showed that the inoculation of Serratia liquefaciens did not affect the degree of casein degradation during storage. Taken together, the excessive peptides and FFA in yogurt generated from psychrotrophic bacteria could develop off-flavors that degrade the quality of commercial yogurt products. PMID- 26761294 TI - Effects of NaCl Replacement with Gamma-Aminobutyric acid (GABA) on the Quality Characteristics and Sensorial Properties of Model Meat Products. AB - This study investigated the effects of gamma-aminobutylic acid (GABA) on the quality and sensorial properties of both the GABA/NaCl complex and model meat products. GABA/NaCl complex was prepared by spray-drying, and the surface dimensions, morphology, rheology, and saltiness were characterized. For model meat products, pork patties were prepared by replacing NaCl with GABA. For characteristics of the complex, increasing GABA concentration increased the surface dimensions of the complex. However, GABA did not affect the rheological properties of solutions containing the complex. The addition of 2% GABA exhibited significantly higher saltiness than the control (no GABA treatment). In the case of pork patties, sensory testing indicated that the addition of GABA decreased the saltiness intensity. Both the intensity of juiciness and tenderness of patties containing GABA also scored lower than the control, based on the NaCl reduction. These results were consistent with the quality characteristics (cooking loss and texture profile analysis). Nevertheless, overall acceptability of the pork patties showed that up to 1.5%, patties containing GABA did not significantly differ from the control. Consequently, the results indicated that GABA has a potential application in meat products, but also manifested a deterioration of quality by the NaCl reduction, which warrants further exploration. PMID- 26761295 TI - Introducing the New Family Practice Management Website. PMID- 26761297 TI - Be Present. PMID- 26761296 TI - An Overlooked Cause of Physician Burnout. PMID- 26761298 TI - Coding and Billing Rules in 2016: Out With the Old in With the New. PMID- 26761299 TI - The Evolution of Meaningful Use: Today, Stage 3, and Beyond. PMID- 26761300 TI - The Problem With Patient Satisfaction Scores. PMID- 26761301 TI - Four Tools for Reducing Burnout by Finding Work-Life Balance. PMID- 26761309 TI - Why Your Health Care Team Doesn't Get Along. PMID- 26761340 TI - Durlaza--a 24-hour extended-release aspirin. PMID- 26761342 TI - Talimogene laherparepvec (Imlygic) for unresectable melanoma. PMID- 26761341 TI - Fluad--an adjuvanted seasonal influenza vaccine for older adults. PMID- 26761343 TI - Elvitegravir (Vitekta) for HIV. PMID- 26761344 TI - Mepolizumab (Nucala) for severe eosinophilic asthma. PMID- 26761345 TI - Is the Collagen Primed for Mineralization in Specific Regions of the Turkey Tendon? An Investigation of the Protein-Mineral Interface Using Raman Spectroscopy. AB - The tendons in the turkey leg have specific well-defined areas which become mineralized as the animal ages and they are a thoroughly characterized model system for studying the mineralization process of bone. In this study, nondestructive Raman spectroscopic analysis was used to explore the hypothesis that regions of the turkey tendon that are associated with mineralization exhibit distinct and observable chemical modifications of the collagen prior to the onset of mineralization. The Raman spectroscopy features associated with mineralization were identified by probing (on the micrometer scale) the transition zone between mineralized and nonmineralized regions of turkey leg tendons. These features were then measured in whole tendons and identified in regions of tendon which are destined to become rapidly mineralized around 14 weeks of age. The data show there is a site-specific difference in collagen prior to the deposition of mineral, specifically the amide III band at 1270 cm(-1) increases as the collagen becomes more ordered (increased amide III:amide I ratio) in regions that become mineralized compared to collagen destined to remain nonmineralized. If this mechanism were present in materials of different mineral fraction (and thus material properties), it could provide a target for controlling mineralization in metabolic bone disease. PMID- 26761347 TI - Etiology of Diarrhea in Children Younger Than 5 Years Attending the Bengo General Hospital in Angola. AB - BACKGROUND: Diarrheal disease is among the leading causes of death in children younger than 5 years, especially in developing countries. The aim of this study was to investigate the most frequent etiological agents of diarrhea and its associated factors in children younger than 5 years attending the Bengo General Hospital in Angola. METHODS: From September 2012 through December 2013, stool samples were collected from 344 children presenting with diarrhea to investigate the presence of viral, bacterial and parasitic agents. Relevant sociodemographic and clinical data were obtained from parents and caregivers. RESULTS: An enteric pathogen was detected in 66.6% of stool samples: Cryptosporidium spp. (30.0%), rotavirus (25.1%), Giardia lamblia (21.6%), diarrheagenic Escherichia coli (6.3%), Ascaris lumbricoides (4.1%), adenovirus (3.8%), Strongyloides stercoralis (3.5%), astrovirus (2.6%), Hymenolepis nana (1.7%), Entamoeba histolytica/dispar (0.9%), Taenia spp. (0.6%), Trichuris trichiura (0.3%) and Entamoeba histolytica (0.3%). Children younger than 12 months were more frequently infected with Cryptosporidium spp. compared with older children (age: 12-59 months), independently of sex, season, lethargy and wasting [odds ratio (OR): 3.5, 95% confidence interval (95% CI): 2.0-6.2]. Age (OR: 5.0, 95% CI: 2.6-9.3), vomiting (OR: 2.7, 95% CI: 1.5-4.8) and type of admission (inpatients, OR: 0.5, 95% CI: 0.3-0.9) were significantly associated with rotavirus infection. CONCLUSIONS: This study demonstrates high rates of infection with an enteric pathogen, particularly in children younger than 12 months, emphasizing the need to address diarrheal disease in this age group. PMID- 26761364 TI - How do polydisperse repulsive colloids crystallize? AB - A modified version of the Gibbs-ensemble Monte-Carlo method reveals how polydisperse charged colloidal particles can build complex colloidal crystals. It provides general rules that are applicable to this fractionated crystallization that stems from size segregation. It explains the spontaneous formation of complex crystals with very large unit-cells in suspensions of nanoparticles with a broad size distribution. PMID- 26761365 TI - Resistive switching and electrical control of ferromagnetism in a Ag/HfO2/Nb:SrTiO3/Ag resistive random access memory (RRAM) device at room temperature. AB - Electrically induced resistive switching and modulated ferromagnetism are simultaneously found in a Ag/HfO2/Nb:SrTiO3/Ag resistive random access memory device at room temperature. The bipolar resistive switching (RS) can be controlled by the modification of a Schottky-like barrier with an electron injection-trapped/detrapped process at the interface of HfO2-Nb:SrTiO3. The multilevel RS transition can be observed in the reset process with larger negative voltage sweepings, which is connected to the different degree of electron detrapping in the interfacial depletion region of the HfO2 layer during the reset process. The origin of the electrical control of room-temperature ferromagnetism may be connected to the change of density of oxygen vacancies in the HfO2 film. The multilevel resistance states and the electric field controlled ferromagnetism have potential for applications in ultrahigh-density storage and magnetic logic device. PMID- 26761363 TI - Systemic antibiotics and the risk of superinfection in peri-implantitis. AB - Peri-implantitis has emerged in the last few years as a complication difficult to resolve. The etiopathogenesis consensus is mainly attributed to bacteria. Following the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines, a PubMed/Medline literature search was performed using the US National Library of Medicine database up to 2015 to analyze available scientific data on the rationale and risk of superinfection associated to systemic antimicrobials in human peri-implant disease. A hand search was also conducted on relevant medical and microbiology journals. The methodological index for non-randomized studies (MINORS) was independently assessed for quality on the selected papers. Proposed combined therapies use broad-spectrum antibiotics to halt the disease progression. A major associated risk, particularly when prescribed empirically without microbiological follow-up, is the undetected development of superinfections and overgrowth of opportunistic pathogens difficult to eradicate. Peri-implant superinfections with opportunistic bacteria, yeast and viruses, are plausible risks associated to the use of systemic antibiotics in immunocompetent individuals. Lack of microbiological follow-up and antibiotic susceptibility testing may lead to ongoing microbial challenges that exacerbate the disease progression. The increased proliferation of antimicrobial resistance, modern implant surface topography and indiscriminative empiric antibiotic regimens may promote the escalation of peri-implant disease in years to come. A personalized 3-month supportive therapy may help prevent risks by sustaining a normal ecological balance, decreasing specific pathogen proportions and maintaining ideal plaque control. PMID- 26761346 TI - Drosophila Mitf regulates the V-ATPase and the lysosomal-autophagic pathway. AB - An evolutionarily conserved gene network regulates the expression of genes involved in lysosome biogenesis, autophagy, and lipid metabolism. In mammals, TFEB and other members of the MiTF-TFE family of transcription factors control this network. Here we report that the lysosomal-autophagy pathway is controlled by Mitf gene in Drosophila melanogaster. Mitf is the single MiTF-TFE family member in Drosophila and prior to this work was known only for its function in eye development. We show that Mitf regulates the expression of genes encoding V ATPase subunits as well as many additional genes involved in the lysosomal autophagy pathway. Reduction of Mitf function leads to abnormal lysosomes and impairs autophagosome fusion and lipid breakdown during the response to starvation. In contrast, elevated Mitf levels increase the number of lysosomes, autophagosomes and autolysosomes, and decrease the size of lipid droplets. Inhibition of Drosophila MTORC1 induces Mitf translocation to the nucleus, underscoring conserved regulatory mechanisms between Drosophila and mammalian systems. Furthermore, we show Mitf-mediated clearance of cytosolic and nuclear expanded ATXN1 (ataxin 1) in a cellular model of spinocerebellar ataxia type 1 (SCA1). This remarkable observation illustrates the potential of the lysosomal autophagy system to prevent toxic protein aggregation in both the cytoplasmic and nuclear compartments. We anticipate that the genetics of the Drosophila model and the absence of redundant MIT transcription factors will be exploited to investigate the regulation and function of the lysosomal-autophagy gene network. PMID- 26761366 TI - Cardiac Rehabilitation: Far Beyond Coronary Artery Disease. PMID- 26761367 TI - Risk Factors for Cardiovascular Disease, Metabolic Syndrome and Sleepiness in Truck Drivers. AB - BACKGROUND: Truck driver sleepiness is a primary cause of vehicle accidents. Several causes are associated with sleepiness in truck drivers. Obesity and metabolic syndrome (MetS) are associated with sleep disorders and with primary risk factors for cardiovascular diseases (CVD). We analyzed the relationship between these conditions and prevalence of sleepiness in truck drivers. METHODS: We analyzed the major risk factors for CVD, anthropometric data and sleep disorders in 2228 male truck drivers from 148 road stops made by the Federal Highway Police from 2006 to 2011. Alcohol consumption, illicit drugs and overtime working hours were also analyzed. Sleepiness was assessed using the Epworth Sleepiness Scale. RESULTS: Mean age was 43.1 +/- 10.8 years. From 2006 to 2011, an increase in neck (p = 0.011) and abdominal circumference (p < 0.001), total cholesterol (p < 0.001), triglyceride plasma levels (p = 0.014), and sleepiness was observed (p < 0.001). In addition, a reduction in hypertension (39.6% to 25.9%, p < 0.001), alcohol consumption (32% to 23%, p = 0.033) and overtime hours (52.2% to 42.8%, p < 0.001) was found. Linear regression analysis showed that sleepiness correlated closely with body mass index (beta = 0.19, Raj2 = 0.659, p = 0.031), abdominal circumference (beta = 0.24, Raj2 = 0.826, p = 0.021), hypertension (beta = -0.62, Raj2 = 0.901, p = 0.002), and triglycerides (beta = 0.34, Raj2 = 0.936, p = 0.022). Linear multiple regression indicated that hypertension (p = 0.008) and abdominal circumference (p = 0.025) are independent variables for sleepiness. CONCLUSIONS: Increased prevalence of sleepiness was associated with major components of the MetS. PMID- 26761368 TI - Variations in the Prevalence of Risk Factors for Coronary Artery Disease in Rio Grande do Sul-Brazil: A Comparative Analysis between 2002 and 2014. AB - BACKGROUND: Due to the importance of coronary artery disease (CAD), continuous investigation of the risk factors (RFs) is needed. OBJECTIVE: To evaluate the prevalence of RFs for CAD in cities in Rio Grande do Sul State, and compare it with that reported in a similar study conducted in the same cities in 2002. METHODS: Cross-sectional study on 1,056 healthy adults, investigating the prevalence and absolute and relative frequencies of the following RFs for CAD: obesity, systemic arterial hypertension (SAH), dyslipidemias, smoking, sedentary lifestyle, diabetes mellitus, and family history, as well as age and sex. Data was collected in 19 cities, host of the Offices of the Regional Coordinators of Health, as in the 2002 study. RESULTS: Twenty-six percent of the sample consisted of older adults and 57% were women. The prevalence of sedentary lifestyle was 44%, history family 50%, smoking 23%, overweight/obesity 68%, dyslipidemia (high cholesterol levels) 43%, SAH 40%, and diabetes 11%. When compared to the 2002 study, the prevalence of active smoking and sedentary behavior decreased, whereas the prevalence of hypertension, dyslipidemia and obesity increased. Obesity is the most prevalent RF in women, and SAH the most prevalent in men. CONCLUSIONS: The prevalence of RFs for CAD in Rio Grande do Sul State remains high. Hypertension, obesity and dyslipidemia are still prevalent and require major prevention programs. Smoking and physical inactivity have decreased in the state, suggesting the efficacy of related campaigns. PMID- 26761369 TI - Obesity Resistance Promotes Mild Contractile Dysfunction Associated with Intracellular Ca2+ Handling. AB - BACKGROUND: Diet-induced obesity is frequently used to demonstrate cardiac dysfunction. However, some rats, like humans, are susceptible to developing an obesity phenotype, whereas others are resistant to that. OBJECTIVE: To evaluate the association between obesity resistance and cardiac function, and the impact of obesity resistance on calcium handling. METHODS: Thirty-day-old male Wistar rats were distributed into two groups, each with 54 animals: control (C; standard diet) and obese (four palatable high-fat diets) for 15 weeks. After the experimental protocol, rats consuming the high-fat diets were classified according to the adiposity index and subdivided into obesity-prone (OP) and obesity-resistant (OR). Nutritional profile, comorbidities, and cardiac remodeling were evaluated. Cardiac function was assessed by papillary muscle evaluation at baseline and after inotropic maneuvers. RESULTS: The high-fat diets promoted increase in body fat and adiposity index in OP rats compared with C and OR rats. Glucose, lipid, and blood pressure profiles remained unchanged in OR rats. In addition, the total heart weight and the weight of the left and right ventricles in OR rats were lower than those in OP rats, but similar to those in C rats. Baseline cardiac muscle data were similar in all rats, but myocardial responsiveness to a post-rest contraction stimulus was compromised in OP and OR rats compared with C rats. CONCLUSION: Obesity resistance promoted specific changes in the contraction phase without changes in the relaxation phase. This mild abnormality may be related to intracellular Ca2+ handling. PMID- 26761371 TI - Case 6/2015 - 40-Year-Old Female with Acute Chest Pain, Dyspnea and Shock. PMID- 26761370 TI - Methodological Gaps in Left Atrial Function Assessment by 2D Speckle Tracking Echocardiography. AB - The assessment of left atrial (LA) function is used in various cardiovascular diseases. LA plays a complementary role in cardiac performance by modulating left ventricular (LV) function. Transthoracic two-dimensional (2D) phasic volumes and Doppler echocardiography can measure LA function non-invasively. However, evaluation of LA deformation derived from 2D speckle tracking echocardiography (STE) is a new feasible and promising approach for assessment of LA mechanics. These parameters are able to detect subclinical LA dysfunction in different pathological condition. Normal ranges for LA deformation and cut-off values to diagnose LA dysfunction with different diseases have been reported, but data are still conflicting, probably because of some methodological and technical issues. This review highlights the importance of an unique standardized technique to assess the LA phasic functions by STE, and discusses recent studies on the most important clinical applications of this technique. PMID- 26761372 TI - Resolution of Extensive Coronary Thrombosis under Rivaroxaban Treatment. PMID- 26761373 TI - Massive Intraventricular Thrombosis in a Young Woman with Idiopathic Dilated Cardiomyopathy. PMID- 26761374 TI - [Magnetic Resonance Imaging, Arthroscopy and Near-Infrared Spectroscopy (NIRS) for Grading Osteoarthritis in the Knee]. AB - PURPOSE: This study was aimed to evaluate the meaningfulness of the MRI Score WORMS (Whole Organ Magnetic Resonance Imaging), the arthroscopic WOAKS (Whole Organ Arthroscopic Knee Score) and the result of NIRS (near-infrared spectroscopy) measurements. MATERIALS AND METHODS: A total of 49 patients with knee pain (> 3 months) underwent MRI with a standardised protocol. In the results the WORMS was calculated. The WOAKS was calculated from the results of an arthroscopic evaluation. In the same procedure, NIRS measurements were performed in the identical 14 regions of interest. From these measurements, the WOAKS_NIRS was calculated. RESULTS: The highest grade of degeneration in all evaluations was found in the patella. The medial compartment showed moderate lesions compared with the lateral compartment. The relative WORMS was only 3.7 % (95 % CI 2.8-4.6; 0-15.6 %). During arthroscopy, we calculated a mean WOAKS of 15.2 % (95 % CI 13.2 17.2; 5-39 %). The degree of joint degeneration was highest in NIRS measurements. The mean WOAKS_NIRS was 50.9 % (95 % CI 48.1-53.7 %). These differences are significant (p < 0.001). CONCLUSION: The methods to detect early cartilage degenerations in MRI are flawed. Thus in our patients, we detected a full grade of degeneration in only 3.7 % of the patients. Arthroscopy mostly gives higher damage within the knee joint. The initial stages of cartilage lesion are usually undetectable. Spectroscopy has the best sensitivity for the evaluation of early degeneration within the hyaline cartilage. The clinical relevance of our results is still unclear. Further outcome studies are needed. PMID- 26761376 TI - Socioeconomic inequality in health in the British household panel: Tests of the social causation, health selection and the indirect selection hypothesis using dynamic fixed effects panel models. AB - Despite social inequality in health being well documented, it is still debated which causal mechanism best explains the negative association between socioeconomic position (SEP) and health. This paper is concerned with testing the explanatory power of three widely proposed causal explanations for social inequality in health in adulthood: the social causation hypothesis (SEP determines health), the health selection hypothesis (health determines SEP) and the indirect selection hypothesis (no causal relationship). We employ dynamic data of respondents aged 30 to 60 from the last nine waves of the British Household Panel Survey. Household income and location on the Cambridge Scale is included as measures of different dimensions of SEP and health is measured as a latent factor score. The causal hypotheses are tested using a time-based Granger approach by estimating dynamic fixed effects panel regression models following the method suggested by Anderson and Hsiao. We propose using this method to estimate the associations over time since it allows one to control for all unobserved time-invariant factors and hence lower the chances of biased estimates due to unobserved heterogeneity. The results showed no proof of the social causation hypothesis over a one to five year period and limited support for the health selection hypothesis was seen only for men in relation to HH income. These findings were robust in multiple sensitivity analysis. We conclude that the indirect selection hypothesis may be the most important in explaining social inequality in health in adulthood, indicating that the well-known cross-sectional correlations between health and SEP in adulthood seem not to be driven by a causal relationship, but instead by dynamics and influences in place before the respondents turn 30 years old that affect both their health and SEP onwards. The conclusion is limited in that we do not consider the effect of specific diseases and causal relationships in adulthood may be present over a longer timespan than 5 years. PMID- 26761375 TI - Situated knowledge of pathogenic landscapes in Ghana: Understanding the emergence of Buruli ulcer through qualitative analysis. AB - Successfully addressing neglected tropical diseases requires nuanced understandings of pathogenic landscapes that incorporate situated, contexualized community knowledge. In the case of Buruli ulcer (BU), the role of social science is vital to investigate complex human-environment interactions and navigate different ways of knowing. We analyze a set of qualitative data from our interdisciplinary project on BU in Ghana, drawing from participatory mapping, focus group discussions, semi-structured interviews, and open-ended survey questions to explore how people in endemic and non-endemic areas see themselves embedded in changing environmental and social landscapes. We pay particular attention to landscape disturbance through logging and small-scale alluvial gold mining. The results from our participatory research underscore the holistic nature of BU emergence in landscapes, encapsulated in partial and incomplete local descriptions, the relevance of collective learning to distill complexity, and the potential of rich qualitative data to inform quantitative landscape disease models. PMID- 26761377 TI - Fluorine-Free Oil Absorbents Made from Cellulose Nanofibril Aerogels. AB - Aerogels based on cellulose nanofibrils (CNFs) have been of great interest as absorbents due to their high absorption capacity, low density, biodegradability, and large surface area. Hydrophobic aerogels have been designed to give excellent oil absorption tendency from water. Herein, we present an in situ method for CNF surface modification and hydrophobic aerogel preparation. Neither solvent exchange nor fluorine chemical is used in aerogel preparations. The as-prepared hydrophobic aerogels exhibit low density (23.2 mg/cm(-3)), high porosity (98.5%), good flexibility, and solvent-induced shape recovery property. Successful surface modification was confirmed through field emission scanning electron microscopy (FE-SEM), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and water contact angle measurements. The hydrophobic aerogels show high absorption capacities for various oils, depending on liquid density, up to 47* their original weight but with low water uptake (<0.5 g/g aerogel). PMID- 26761379 TI - Unilateral paravertebral block compared with subarachnoid anesthesia for the management of postoperative pain syndrome after inguinal herniorrhaphy: a randomized controlled clinical trial. AB - Inguinal herniorrhaphy is a common surgical procedure. The aim of this investigation was to determine whether unilateral paravertebral block could provide better control of postoperative pain syndrome compared with unilateral subarachnoid block (SAB). A randomized controlled study was conducted using 50 patients with unilateral inguinal hernias. The patients were randomized to receive either paravertebral block (S group) or SAB (C group). Paravertebral block was performed by injecting a total of 20 mL of 0.5% levobupivacaine from T9 to T12 under ultrasound guidance, whereas SAB was performed by injecting 13 mg of 0.5% levobupivacaine at the L3 to L4 level. Data regarding anesthesia, hemodynamic changes, side effects, time spent in the postanesthesia care unit, the Karnofsky Performance Status, acute pain and neuropathic disturbances were recorded. Paravertebral block provided good anesthesia of the inguinal region without patient or surgeon discomfort, with better hemodynamic stability and safety and with a reduced time to discharge from the postanesthesia care unit compared with SAB. During the postsurgical and posthospital discharge follow-ups, rest and incident pain and neuropathic positive phenomena were better controlled in the S group than in the C group. The consumption of painkillers was higher in the C group than in the S group throughout the follow-up period. Paravertebral block can be considered a viable alternative to common anesthetic procedures performed for inguinal hernia repair surgery. Paravertebral block provided good management of acute postoperative pain and limited neuropathic postoperative disturbances. PMID- 26761378 TI - Recombinant neural progenitor transplants in the spinal dorsal horn alleviate chronic central neuropathic pain. AB - Neuropathic pain induced by spinal cord injury (SCI) is clinically challenging with inadequate long-term treatment options. Partial pain relief offered by pharmacologic treatment is often counterbalanced by adverse effects after prolonged use in chronic pain patients. Cell-based therapy for neuropathic pain using GABAergic neuronal progenitor cells (NPCs) has the potential to overcome untoward effects of systemic pharmacotherapy while enhancing analgesic potency due to local activation of GABAergic signaling in the spinal cord. However, multifactorial anomalies underlying chronic pain will likely require simultaneous targeting of multiple mechanisms. Here, we explore the analgesic potential of genetically modified rat embryonic GABAergic NPCs releasing a peptidergic NMDA receptor antagonist, Serine-histogranin (SHG), thus targeting both spinal hyperexcitability and reduced inhibitory processes. Recombinant NPCs were designed using either lentiviral or adeno-associated viral vectors (AAV2/8) encoding single and multimeric (6 copies of SHG) cDNA. Intraspinal injection of recombinant cells elicited enhanced analgesic effects compared with nonrecombinant NPCs in SCI-induced pain in rats. Moreover, potent and sustained antinociception was achieved, even after a 5-week postinjury delay, using recombinant multimeric NPCs. Intrathecal injection of SHG antibody attenuated analgesic effects of the recombinant grafts suggesting active participation of SHG in these antinociceptive effects. Immunoblots and immunocytochemical assays indicated ongoing recombinant peptide production and secretion in the grafted host spinal cords. These results support the potential for engineered NPCs grafted into the spinal dorsal horn to alleviate chronic neuropathic pain. PMID- 26761380 TI - Pain and distress caused by endotracheal suctioning in neonates is better quantified by behavioural than physiological items: a comparison based on item response theory modelling. AB - Pain cannot be directly measured in neonates. Therefore, scores based on indirect behavioural signals such as crying, or physiological signs such as blood pressure, are used to quantify neonatal pain both in clinical practice and in clinical studies. The aim of this study was to determine which of the physiological and behavioural items of 2 validated pain assessment scales (COMFORT and premature infant pain profile) are best able to detect pain during endotracheal and nasal suctioning in ventilated newborns. We analysed a total of 516 PIPP and COMFORT scores from 118 newborns. A graded response model was built to describe the data and item information was calculated for each of the behavioural and physiological items. We found that the graded response model was able to well describe the data, as judged by agreement between the observed data and model simulations. Furthermore, a good agreement was found between the pain estimated by the graded response model and the investigator-assessed visual analogue scale scores (Spearman rho correlation coefficient = 0.80). The information scores for the behavioural items ranged from 1.4 to 27.2 and from 0.0282 to 0.131 for physiological items. In these data with mild to moderate pain levels, behavioural items were vastly more informative of pain and distress than were physiological items. The items that were the most informative of pain are COMFORT items "calmness/agitation," "alertness," and "facial tension." PMID- 26761382 TI - Headache under simulated microgravity is related to endocrine, fluid distribution, and tight junction changes. AB - Head-down-tilted bed rest (HDTBR) induces headaches similar to headaches during space flights. The objective of this investigation was to study hematological, endocrinological, fluid changes and tight junctions in HDTBR-induced headaches as a proxy for space headache. The randomized crossover HDTBR design by the European Space Agency included 12 healthy, nonheadache male subjects. Before, during, and after confined HDTBR periods, epinephrine (urine), cortisol (saliva), hematological, endothelium markers, and fluid distribution parameters were measured. Headaches were assessed with a validated headache questionnaire. Compared with baseline, HDTBR in all subjects was associated with higher hematocrit, hemoglobin, and epinephrine levels, higher erythrocyte counts, and lower relative plasma volumes (all P < 0.05). In total, 26 headache episodes occurred. In subjects with headaches during HDTBR, epinephrine levels were exaggerated (vs headache-free subjects; HDTBR day 3; 5.1 +/- 1.7 vs 3.4 +/- 2.4; P = 0.023), cortisol levels were decreased (vs headache-free subjects; HDTBR day 1; 0.37 +/- 0.16 vs 0.50 +/- 0.20; P < 0.001) and the tight junction marker zonulin was elevated (vs headache-free subjects in HDTBR days 1, 3, 5; P < 0.05). HDTBR induces hemoconcentration and fluid redistribution in all subjects. During headache episodes, endocrinological changes, fluid distribution, and tight junctions were more pronounced, suggesting an additional role in headache pathophysiology. PMID- 26761383 TI - Sex differences in subjective and objective measures of pain, functional impairment, and health-related quality of life in patients with lumbar degenerative disc disease. AB - Sex differences in pain perception are known to exist; however, the exact pathomechanism remains unclear. This work aims to elucidate sex differences in subjective and objective measures of pain, functional impairment, and health related quality of life (HRQoL) in patients with lumbar degenerative disc disease. In a prospective 2-center study, back and leg pain (visual analogue scale [VAS]), functional disability (Oswestry Disability Index and Roland-Morris Disability Index), and HRQoL (EuroQol-5D and Short Form [SF12]) were collected for consecutive patients undergoing lumbar spine surgery. Objective functional impairment (OFI) was estimated using age-adjusted and sex-adjusted cutoff values for the timed-up-and-go (TUG) test. A healthy cohort of n = 110 subjects served as the control group. Univariate and multivariate analyses were performed to test the association between sex and pain, subjective and OFIs, and HRQoL. The study comprised n = 305 patients (41.6% females). Female patients had more VAS back pain (P = 0.002) and leg pain (P = 0.014). They were more likely to report higher functional impairment in terms of Oswestry Disability Index (P = 0.005). Similarly, HRQoL measured with the EuroQol-5D index (P = 0.012) and SF12 physical composite score (P = 0.005) was lower in female patients. Female patients reported higher VAS back and leg pain, functional impairment, and reduced HRQoL than male patients. However, there were no sex differences with respect to the presence and degree of OFI measured by the TUG test using age-adjusted and sex adjusted cutoff values. As such, the TUG may be a good test to overcome sex bias for the clinical assessment of patients with degenerative disc disease. PMID- 26761381 TI - Differences in regional homogeneity between patients with Crohn's disease with and without abdominal pain revealed by resting-state functional magnetic resonance imaging. AB - Abnormal pain processing in the central nervous system may be related to abdominal pain in patients with Crohn's disease (CD). The purpose of this study was to investigate changes in resting-state brain activity in patients with CD in remission and its relationship with the presence of abdominal pain. Twenty-five patients with CD and with abdominal pain, 25 patients with CD and without abdominal pain, and 32 healthy subjects were scanned using a 3.0-T functional magnetic resonance imaging scanner. Regional homogeneity (ReHo) was used to assess resting-state brain activity. Daily pain scores were collected 1 week before functional magnetic resonance imaging. We found that patients with abdominal pain exhibited lower ReHo values in the insula, middle cingulate cortex (MCC), and supplementary motor area and higher ReHo values in the temporal pole. In contrast, patients without abdominal pain exhibited lower ReHo values in the hippocampal/parahippocampal cortex and higher ReHo values in the dorsomedial prefrontal cortex (all P < 0.05, corrected). The ReHo values of the insula and MCC were significantly negatively correlated with daily pain scores for patients with abdominal pain (r = -0.53, P = 0.008 and r = -0.61, P = 0.002, respectively). These findings suggest that resting-state brain activities are different between remissive patients with CD with and without abdominal pain and that abnormal activities in insula and MCC are closely related to the severity of abdominal pain. PMID- 26761384 TI - Primary somatosensory/motor cortical thickness distinguishes paresthesia-dominant from pain-dominant carpal tunnel syndrome. AB - Paresthesia-dominant and pain-dominant subgroups have been noted in carpal tunnel syndrome (CTS), a peripheral neuropathic disorder characterized by altered primary somatosensory/motor (S1/M1) physiology. We aimed to investigate whether brain morphometry dissociates these subgroups. Subjects with CTS were evaluated with nerve conduction studies, whereas symptom severity ratings were used to allocate subjects into paresthesia-dominant (CTS-paresthesia), pain-dominant (CTS pain), and pain/paresthesia nondominant (not included in further analysis) subgroups. Structural brain magnetic resonance imaging data were acquired at 3T using a multiecho MPRAGE T1-weighted pulse sequence, and gray matter cortical thickness was calculated across the entire brain using validated, automated methods. CTS-paresthesia subjects demonstrated reduced median sensory nerve conduction velocity (P = 0.05) compared with CTS-pain subjects. In addition, cortical thickness in precentral and postcentral gyri (S1/M1 hand area) contralateral to the more affected hand was significantly reduced in CTS paresthesia subgroup compared with CTS-pain subgroup. Moreover, in CTS paresthesia subjects, precentral cortical thickness was negatively correlated with paresthesia severity (r(34) = -0.40, P = 0.016) and positively correlated with median nerve sensory velocity (r(36) = 0.51, P = 0.001), but not with pain severity. Conversely, in CTS-pain subjects, contralesional S1 (r(9) = 0.62, P = 0.042) and M1 (r(9) = 0.61, P = 0.046) cortical thickness were correlated with pain severity, but not median nerve velocity or paresthesia severity. This double dissociation in somatotopically specific S1/M1 areas suggests a neuroanatomical substrate for symptom-based CTS subgroups. Such fine-grained subgrouping of CTS may lead to improved personalized therapeutic approaches, based on superior characterization of the linkage between peripheral and central neuroplasticity. PMID- 26761385 TI - High-resolution transcriptome analysis reveals neuropathic pain gene-expression signatures in spinal microglia after nerve injury. AB - Microglial cells, the resident immune cells of the spinal cord, become activated in response to peripheral nerve injury. Microglia activation contributes to the development of neuropathic pain. Here we employed microarray analysis of individually collected pools of 10 spinal microglia cells to identify changes of levels and cell-to-cell expression variance of microglial genes during their activation after peripheral nerve injury. The analysis of microglia on postoperative day 1 (POD1) identified miR-29c as a critical factor for microglial activation and the development of neuropathic pain. Early POD1 microglia exhibited a very distinct expression profile compared to late POD7 microglia, possibly leading to the transition from initiation to maintenance of neuropathic pain. We found sample variance patterns that were consistent with the hypothesis that microglia were highly heterogeneous at the level of individual cells, and variation analysis identified 56 microglial genes potentially linked to the maintenance of neuropathic pain which included Gria1. This study provides insights into spinal microglial biology and reveals novel microglial targets for the treatment of neuropathic pain. PMID- 26761386 TI - Opioid dose and risk of suicide. AB - Chronic pain is associated with increased risk of suicide, and opioids are commonly used to treat moderate to severe pain. However, the association between opioid dose and suicide mortality has not been examined closely. This retrospective data analysis described the risk of suicide associated with differing prescribed opioid doses. Data were from Veterans Affairs health care system treatment records and the National Death Index. Records analyzed were those of Veterans Affairs patients with chronic pain receiving opioids in fiscal years 2004 to 2005 (N = 123,946). Primary predictors were maximum prescribed morphine-equivalent daily opioid dose and opioid fill type. The main outcome measured was suicide death, by any mechanism, and intentional overdose death during 2004 to 2009. Controlling for demographic and clinical characteristics, higher prescribed opioid doses were associated with elevated suicide risk. Compared with those receiving <=20 milligrams/day (mg/d), hazard ratios were 1.48 (95% confidence intervals [CI], 1.25-1.75) for 20 to <50 mg/d, 1.69 (95% CI, 1.33 2.14) for 50 to <100 mg/d, and 2.15 (95% CI, 1.64-2.81) for 100+ mg/d. The magnitude of association between opioid dose and suicide by intentional overdose was not substantially different from that observed for the overall measure of suicide mortality. Risk of suicide mortality was greater among individuals receiving higher doses of opioids, and treatment providers may want to view high opioid dose as a marker of elevated risk for suicide. Additional research is needed on opioid use, pain treatment, and suicide. PMID- 26761388 TI - Acquisition and extinction of operant pain-related avoidance behavior using a 3 degrees-of-freedom robotic arm. AB - Ample empirical evidence endorses the role of associative learning in pain related fear acquisition. Nevertheless, research typically focused on self reported and psychophysiological measures of fear. Avoidance, which is overt behavior preventing the occurrence of an aversive (painful) stimulus, has been largely neglected so far. Therefore, we aimed to fill this gap and developed an operant conditioning procedure for pain-related avoidance behavior. Participants moved their arm to a target location using the HapticMaster (FCS Robotics; Moog Inc, East Aurora, New York), a 3 degrees-of-freedom, force-controlled robotic arm. Three movement trajectories led to the target location. If participants in the Experimental Group took the shortest/easiest trajectory, they always received a painful stimulus (T1 = 100% reinforcement; no resistance). If they deviated from this trajectory, the painful stimulus could be partly or totally prevented (T2 = 50% reinforcement; T3 = 0% reinforcement), but more effort was needed (T2 = moderate resistance and deviation; T3 = strongest resistance and largest deviation). The Yoked Group received the same reinforcement schedule irrespective of their own behavior. During the subsequent extinction phase, no painful stimuli were delivered. Self-reported pain-expectancy and pain-related fear were assessed, and avoidance behavior was operationalized as the maximal distance from the shortest trajectory. During acquisition, the Experimental Group reported more pain-related fear and pain-expectancy to T1 vs T2 vs T3 and deviated more from the shortest trajectory than the Yoked Group. During subsequent extinction, avoidance behavior, self-reported fear, and pain-expectancy decreased significantly, but conditioned differences persisted despite the absence of painful stimuli. To conclude, this operant learning task might provide a valid paradigm to study pain-related avoidance behavior in future studies. PMID- 26761387 TI - Does changing pain-related knowledge reduce pain and improve function through changes in catastrophizing? AB - Evidence from randomized controlled studies shows that reconceptualizing pain improves patients' knowledge of pain biology, reduces catastrophizing thoughts, and improves pain and function. However, causal relationships between these variables remain untested. It is hypothesized that reductions in catastrophizing could mediate the relationship between improvements in pain knowledge and improvements in pain and function. To test this causal mechanism, we conducted longitudinal mediation analyses on a cohort of 799 patients who were exposed to a pain education intervention. Patients provided responses to the neurophysiology of pain questionnaire, catastrophic thoughts about pain scale, visual analogue pain scale, and the patient specific functional scale, at baseline, 1-month, 6 month, and 12-month follow-up. With adjustment for potential confounding variables, an improvement in pain biology knowledge was significantly associated with a reduction in pain intensity (total effect = -2.20, 95% confidence interval [CI] = -2.96 to -1.44). However, this effect was not mediated by a reduction in catastrophizing (indirect effect = -0.16, 95% CI = -0.36 to 0.02). This might be due to a weak, nonsignificant relationship between changes in catastrophizing and pain intensity (path b = 0.19, 95% CI = -0.03 to 0.41). Similar trends were found in models with function as the outcome. Our findings indicate that change in catastrophizing did not mediate the effect of pain knowledge acquisition on change in pain or function. The strength of this conclusion is moderated, however, if patient-clinician relational factors are conceptualized as a consequence of catastrophizing, rather than a cause. PMID- 26761389 TI - Nonparalytic botulinum molecules for the control of pain. AB - Local injections of botulinum toxins have been reported to be useful not only for the treatment of peripheral neuropathic pain and migraine but also to cause long lasting muscle paralysis, a potentially serious side effect. Recently, a botulinum A-based molecule ("BiTox") has been synthesized that retains neuronal silencing capacity without triggering muscle paralysis. In this study, we examined whether BiTox delivered peripherally was able to reduce or prevent the increased nociceptive sensitivity found in animal models of inflammatory, surgical, and neuropathic pain. Plasma extravasation and edema were also measured as well as keratinocyte proliferation. No motor deficits were seen and acute thermal and mechanical nociceptive thresholds were unimpaired by BiTox injections. We found reduced plasma extravasation and inflammatory edema as well as lower levels of keratinocyte proliferation in cutaneous tissue after local BiTox injection. However, we found no evidence that BiTox was transported to the dorsal root ganglia or dorsal horn and no deficits in formalin-elicited behaviors or capsaicin or formalin-induced c-Fos expression within the dorsal horn. In contrast, Bitox treatment strongly reduced A-nociceptor-mediated secondary mechanical hyperalgesia associated with either complete Freund's adjuvant (CFA) induced joint inflammation or capsaicin injection and the hypersensitivity associated with spared nerve injury. These results imply that although local release of neuromodulators from C-fibers was inhibited by BiTox injection, C nociceptive signaling function was not impaired. Taken together with recent clinical data the results suggest that BiTox should be considered for treatment of pain conditions in which A-nociceptors are thought to play a significant role. PMID- 26761392 TI - Infrared Plasmonic Biosensor for Real-Time and Label-Free Monitoring of Lipid Membranes. AB - In this work, we present an infrared plasmonic biosensor for chemical-specific detection and monitoring of biomimetic lipid membranes in a label-free and real time fashion. Lipid membranes constitute the primary biological interface mediating cell signaling and interaction with drugs and pathogens. By exploiting the plasmonic field enhancement in the vicinity of engineered and surface modified nanoantennas, the proposed biosensor is able to capture the vibrational fingerprints of lipid molecules and monitor in real time the formation kinetics of planar biomimetic membranes in aqueous environments. Furthermore, we show that this plasmonic biosensor features high-field enhancement extending over tens of nanometers away from the surface, matching the size of typical bioassays while preserving high sensitivity. PMID- 26761393 TI - Engineering Functionalization in a Supramolecular Polymer: Hierarchical Self Organization of Triply Orthogonal Non-covalent Interactions on a Supramolecular Coordination Complex Platform. AB - Here we present a method for the construction of functionalizable supramolecular polymers by controlling three orthogonal interactions within a single system: (i) coordination-driven self-assembly; (ii) H-bonding; and (iii) host-guest interactions between crown ether and dialkylammonium substrates. Three unique molecules constitute the supramolecular construct, including a 2-ureido-4 pyrimidinone (UPy)-functionalized rigid dipyridyl donor and a complementary organoplatinum(II) acceptor decorated with a crown ether moiety that provide the basis for self-assembly and polymerization. The final host-guest interaction is demonstrated by using one of two dialkylammonium molecules containing fluorophores that bind to the benzo-21-crown-7 (B21C7) groups of the acceptors, providing a spectroscopic handle to evaluate the functionalization. An initial coordination-driven self-assembly yields hexagonal metallacycles with alternating UPy and B21C7 groups at their vertices. The assembly does not interfere with H bonding between the UPy groups, which link the discrete metallacycles into a supramolecular network, leaving the B21C7 groups free for functionalization via host-guest chemistry. The resultant network results in a cavity-cored metallogel at high concentrations or upon solvent swelling. The light-emitting properties of the dialkylammonium substrates were transferred to the network upon host-guest binding. This method is compatible with any dialkylammonium substrate that does not disrupt coordination nor H-bonding, and thus, the unification of these three orthogonal interactions represents a simple yet highly efficient strategy to obtain supramolecular polymeric materials with desirable functionality. PMID- 26761390 TI - Classification of neck/shoulder pain in epidemiological research: a comparison of personal and occupational characteristics, disability, and prognosis among 12,195 workers from 18 countries. AB - To inform case definition for neck/shoulder pain in epidemiological research, we compared levels of disability, patterns of association, and prognosis for pain that was limited to the neck or shoulders (LNSP) and more generalised musculoskeletal pain that involved the neck or shoulder(s) (GPNS). Baseline data on musculoskeletal pain, disability, and potential correlates were collected by questionnaire from 12,195 workers in 47 occupational groups (mostly office workers, nurses, and manual workers) in 18 countries (response rate = 70%). Continuing pain after a mean interval of 14 months was ascertained through a follow-up questionnaire in 9150 workers from 45 occupational groups. Associations with personal and occupational factors were assessed by Poisson regression and summarised by prevalence rate ratios (PRRs). The 1-month prevalence of GPNS at baseline was much greater than that of LNSP (35.1% vs 5.6%), and it tended to be more troublesome and disabling. Unlike LNSP, the prevalence of GPNS increased with age. Moreover, it showed significantly stronger associations with somatising tendency (PRR 1.6 vs 1.3) and poor mental health (PRR 1.3 vs 1.1); greater variation between the occupational groups studied (prevalence ranging from 0% to 67.6%) that correlated poorly with the variation in LNSP; and was more persistent at follow-up (72.1% vs 61.7%). Our findings highlight important epidemiological distinctions between subcategories of neck/shoulder pain. In future epidemiological research that bases case definitions on symptoms, it would be useful to distinguish pain that is localised to the neck or shoulder from more generalised pain that happens to involve the neck/shoulder region. PMID- 26761394 TI - Berry Shriveling Significantly Alters Shiraz (Vitis vinifera L.) Grape and Wine Chemical Composition. AB - Berry shriveling is an often reported occurrence in the Shiraz (Vitis vinifera L.) cultivar. This study investigated the effect of berry shriveling occurring in a high yielding (18.6 +/- 1.6 kg/vine) Shiraz vineyard in relation to a temporal investigation of grape and wine composition using three harvest dates. Berry shriveling resulted in delayed total soluble solids and amino acid accumulation into the berry, however differences between treatments diminished or became smaller by the third harvest date. Similarly, ethyl esters of fatty acids and higher alcohol acetates were lower in wines from shriveled berries from the first two harvests; anthocyanins were reduced in wines from shriveled berries at all harvest dates, whereas terpenes were unaltered. Wines made from shriveled berries had higher gamma-nonalactone and beta-damascenone concentrations. This study provides novel information on the chemical alterations of grapes and wines made from grapes affected by shriveling. PMID- 26761391 TI - Fluorescent MoS2 Quantum Dots: Ultrasonic Preparation, Up-Conversion and Down Conversion Bioimaging, and Photodynamic Therapy. AB - Small size molybdenum disulfide (MoS2) quantum dots (QDs) with desired optical properties were controllably synthesized by using tetrabutylammonium-assisted ultrasonication of multilayered MoS2 powder via OH-mediated chain-like Mo-S bond cleavage mode. The tunable up-bottom approach of precise fabrication of MoS2 QDs finally enables detailed experimental investigations of their optical properties. The synthesized MoS2 QDs present good down-conversion photoluminescence behaviors and exhibit remarkable up-conversion photoluminescence for bioimaging. The mechanism of the emerging photoluminescence was investigated. Furthermore, superior (1)O2 production ability of MoS2 QDs to commercial photosensitizer PpIX was demonstrated, which has great potential application for photodynamic therapy. These early affording results of tunable synthesis of MoS2 QDs with desired photo properties can lead to application in fields of biomedical and optoelectronics. PMID- 26761395 TI - Atrial fibrillation ablation by single ring isolation versus wide antral isolation: Effects on left atrial size and function. AB - BACKGROUND: Pulmonary vein isolation (PVI) by single ring isolation (SRI) has been demonstrated to reduce recurrence of atrial fibrillation (AF) compared to the standard technique of wide antral isolation (WAI). In this study, we examine the differential effect of these techniques on left atrial size and function. METHODS: We examined left atrial (LA) size (LA maximum and LA minimum volumes) and function (LA emptying fraction and LA expansion index) over a period of 6 months following PVI as measured by transthoracic echocardiography in 187 patients that were enrolled in a randomised controlled trial of SRI vs WAI. RESULTS: Compared to pre-ablation, at 6 months post-PVI, there was a small decrease in the LA maximum volume in the WAI group (67.3 vs 62.7 mL, p=0.02). The LA size did not change significantly over 6 months in the SRI group. Patients who underwent SRI had a small reduction in the LA expansion index at 6 months post PVI compared to baseline (80.6 vs 66.6%, p=0.02). LA function did not change significantly over 6 months in the WAI group. However, at 6 months, there was no difference in any measure of LA size or function between the SRI and WAI groups. CONCLUSIONS: SRI, whilst previously demonstrated to be more effective than WAI in preventing AF recurrence, is associated with minimal adverse effects on left atrial function at medium term follow-up despite the isolation of a larger region of LA myocardium. PMID- 26761397 TI - Human herpesvirus 6 U11 protein is critical for virus infection. AB - All herpesviruses contain a tegument layer comprising a protein matrix; these proteins play key roles during viral assembly and egress. Here, liquid chromatography and tandem mass spectrometry analysis (LC-MS/MS) of proteins from human herpesvirus 6 (HHV-6)-infected cells revealed a possible association between two major tegument proteins, U14 and U11. This association was verified by immunoprecipitation experiments. Moreover, U11 protein was expressed during the late phase of infection and incorporated into virions. Finally, in contrast to its revertant, a U11 deletion mutant could not be reconstituted. Taken together, these results suggest that HHV-6 U11 is an essential gene for virus growth and propagation. PMID- 26761396 TI - Effects of modification of the HIV-1 Env cytoplasmic tail on immunogenicity of VLP vaccines. AB - We investigated the effects on assembly and antigenic properties of specific modifications of the transmembrane spanning (TMS) and cytoplasmic tail (CT) domains of HIV-1 Env from a transmitted/founder (T/F) ZM53 Env glycoprotein. A construct containing a short version of the TMS domain derived from the mouse mammary tumor virus (MMTV) Env with or without a GCN4 trimerization sequence in the CT exhibited the highest levels of incorporation into VLPs and induced the highest titers of anti-Env IgG immune responses in a VLP context. Sera from guinea pigs immunized by VLPs with high Env content, and containing the CT trimerization sequence, had increased neutralization activity and antibody avidity. A cross-clade prime-boost regimen with clade B SF162 or clade C ZM53 Env DNA priming and boosting with VLPs containing modified ZM53 Env further enhanced these immune responses. The modified VLPs demonstrate improved potential as HIV-1 vaccine antigens. PMID- 26761399 TI - "Sizing" Heterogeneous Chemistry in the Conversion of Gaseous Dimethyl Sulfide to Atmospheric Particles. AB - The oxidation of biogenic dimethyl sulfide (DMS) emissions is a global source of cloud condensation nuclei. The amounts of the nucleating H2SO4(g) species produced in such process, however, remain uncertain. Hydrophobic DMS is mostly oxidized in the gas phase into H2SO4(g) + DMSO(g) (dimethyl sulfoxide), whereas water-soluble DMSO is oxidized into H2SO4(g) in the gas phase and into SO4(2-) + MeSO3(-) (methanesulfonate) on water surfaces. R = MeSO3(-)/(non-sea-salt SO4(2 )) ratios would therefore gauge both the strength of DMS sources and the extent of DMSO heterogeneous oxidation if Rhet = MeSO3(-)/SO4(2-) for DMSO(aq) + .OH(g) were known. Here, we report that Rhet = 2.7, a value obtained from online electrospray mass spectra of DMSO(aq) + .OH(g) reaction products that quantifies the MeSO3(-) produced in DMSO heterogeneous oxidation on aqueous aerosols for the first time. On this basis, the inverse R dependence on particle radius in size segregated aerosol collected over Syowa station and Southern oceans is shown to be consistent with the competition between DMSO gas-phase oxidation and its mass accommodation followed by oxidation on aqueous droplets. Geographical R variations are thus associated with variable contributions of the heterogeneous pathway to DMSO atmospheric oxidation, which increase with the specific surface area of local aerosols. PMID- 26761398 TI - A Mixed Methods Approach to Identify Cognitive Warning Signs for Suicide Attempts. AB - This study used a mixed methods approach to examine pathways to suicidal behavior by identifying cognitive warning signs that occurred within 1 day of a suicide attempt. Transcripts of cognitive therapy sessions from 35 patients who attempted suicide were analyzed using a modified grounded theory approach. Cognitive themes emerging from these transcripts included: state hopelessness, focus on escape, suicide as a solution, fixation on suicide, and aloneness. Differences in demographic and baseline diagnostic and symptom data were explored in relation to each cognitive theme. We propose a potential conceptual model of cognitive warning signs for suicide attempts that requires further testing. PMID- 26761401 TI - Ruthenium Catalyzed Intramolecular C-S Coupling Reactions: Synthetic Scope and Mechanistic Insight. AB - A ruthenium catalyzed intramolecular C-S coupling reaction of N-arylthioureas for the synthesis of 2-aminobenzothiazoles has been developed. Kinetic, isotope labeling, and computational studies reveal the involvement of an electrophilic ruthenation pathway instead of a direct C-H activation. Stereoelectronic effect of meta-substituents on the N-arylthiourea dictates the final regioselective outcome of the reaction. PMID- 26761400 TI - Origin of Water-Induced Fluorescence Turn-On from a Schiff Base Compound: AIE or H-Bonding Promoted ESIPT? AB - A nonfluorescent Schiff base compound (4) in an aprotic solvent (e.g., CH3CN) is found to give blue fluorescence turn-on (lambdaem ~ 475 nm) upon addition of H2O. By using a wide range of spectroscopic methods, including (1)H NMR and dynamic light scattering, the fluorescence response is shown to be not originating from the molecular aggregation-induced emission (AIE). Spectroscopic studies at low temperatures further reveal a dynamic response of 4 to temperature, showing that the excited state intramolecular proton transfer (ESIPT) can be ON or OFF through interaction with protic solvent. In the binary solvent (with composition CH3CN/H2O = 3:1), the Schiff base gives ESIPT emission (lambdaem ~ 524 nm) only at extremely low temperature (below -80 degrees C), which is turned off when being warmed to -60 degrees C, attributing to the increasing photoinduced electron transfer (PET) effect. When the temperature is further raised to -20 degrees C, ESIPT emission is reactivated to give blue emission (lambdaem ~ 475 nm) that is observed at room temperature. The observed dynamic fluorescence response reveals that ESIPT could be a predominant mechanism in the fluorescence turn-on of Schiff base compounds, although both AIE and ESIPT mechanisms could operate. The assumption is further verified by examining the response of Schiff base to Al(3+) cation. PMID- 26761403 TI - Longitudinal Patterns of Group Decisions: An Exploratory Analysis. AB - This article presents an exploratory investigation into longitudinal patterns of influence in group decision-making. In particular, we focus on how the outcomes of past decisions affect group members' relative influence in future joint decisions. Results suggest that past outcomes play an important role in the resolution of disagreements when group member preferences are equally intense. Losers in prior decisions are likely to win in the future (and vice versa) due to what appears to be promotion of equity in the group. PMID- 26761404 TI - A Set-Theoretical Model of Person Perception. AB - A set-theoretical structural model of person perception is presented in which self and other people that the individual knows are partitioned into person classes and the attributes that are perceived to describe self and others are partitioned into attribute classes. A novel feature of the model is that superset subset relationships among person classes and among attribute classes are explicitly represented. The model was tested empirically by fitting it to free response descriptions of self and others made by 14 college students, using HICLAS, a computer algorithm for the model. It was found that persons in superordinate classes and in classes with many elements were in general perceived by the subjects to be the most significant and important persons in their lives. These persons included self, nuclear and extended family, lovers and friends. Persons in subordinate classes that contained few elements were generally perceived as the least significant/important persons and included disliked and/or superficially known people. It was also found that the set theoretical analysis provided a significantly better account of the data than did hierarchical clustering. PMID- 26761405 TI - Rationale, Detection, and Implications of Interactions Between Independent Variables and Unmeasured Variables in Linear Models. AB - Conceptual rationales from five research contexts are presented which share the similarity that all posit unmeasured variables which interact with observed independent variables to produce a complete model of the dependent variable. For the class of linear underspecified models involving only observed effects, it is shown that estimated effects of the observed independent variables are overestimated, that squared error of the misspecified model overestimates true error, and that this misspecified squared error is a function of at least the square of the measured independent variable(s). A statistical test for this last relationship is presented (Cook & Weisberg, 1983). The effect of this phenomenon on statistical power is discussed. Possible analytic and design strategies to overcome the effect of such unmeasured interactions include use of the rank transform (Conover & Iman, 1981), use of several longitudinal assessments, and oversampling of levels of independent variables where variance heterogeneity is large relative to other levels. Limitations of these strategies are discussed. PMID- 26761406 TI - A Simple Rule for Generating Equivalent Models in Covariance Structure Modeling. AB - This study introduces the replacing rule as a simplification of Stelzl's (1986) four rules for the generation of recursive equivalent models. The replacing rule is applicable to nonrecursive as well as recursive models, and generates equivalent models through the replacement of direct paths with residual correlations, through the replacement of residual correlations with direct paths, or through the inversion of path directions. Examples of the use of the replacing rule are provided, and its advantages over Stelzl's four rules are discussed. PMID- 26761407 TI - Testing Multivariate Partial, Semipartial and Bipartial Correlation Coefficients. AB - Stressing the close resemblance between univariate and multivariate situations, it is shown that a proper test for a multivariate semipartial correlation being zero is given by the test for the corresponding partial correlation. No legitimate test seems to be available for bipartial correlations. The procedures proposed by Cohen (1982) and Timm and Carlson (1976) are not well-founded and, in the case of multivariate semipartial correlations, unnecessarily conservative. PMID- 26761409 TI - Residual Scaling: An Alternative to Correspondence Analysis for the Graphical Representation of Residuals from Log-Linear Models. AB - The method of correspondence analysis, applied to a contingency table, provides a graphical representation of departures from the independence model. Generalized correspondence analysis has been proposed as a way of graphically representing departures from models other than independence. However, generalized correspondence analysis does not necessarily decompose a chi-square statistic for departures from non-independence models. We propose a method, called residual scaling (RESCAL), that does decompose chi-square and can also be used for decomposing the difference between any two log-linear models. The decomposition is represented graphically for ease of interpretation. RESCAL analysis results differ in interpretation from correspondence analysis results, although the differences have some advantages over correspondence analysis. RESCAL is demonstrated empirically with data concerning earned doctorates conferred in the United States from 1960 through 1982. PMID- 26761408 TI - Robustness of Type I Error and Power in Set Correlation Analysis of Contingency Tables. AB - The analysis of contingency tables by means of set correlation makes possible the assessment of sub-hypotheses involving contrast functions of the categories of the nominal scales. This follow-up analysis of the overall association provides greater interpretive yield than do the standard methods, but has the problem that its significance tests violate the assumption of multivariate normality. The robustness of such tests both with regard to Type I error and statistical power was addressed by Monte Carlo experiments. From 31 contingency tables of varying size (2 X 3, 3 X 4, and 4 X 6) and marginal distributions, random samples of 1000 cases of sizes 30, 60, 120, and 240 were drawn. The sample multivariate R(2) y,x of each sample was tested for significance at the .01 and .05 levels using the Rao F-test. By comparing the Monte Carlo and theoretical rates, 232 determinations of bias for Type I error and 100 determinations of power bias were made. Bias was found to be negligible and it was concluded that the procedure is generally robust for both Type I error and power. PMID- 26761402 TI - Host genetics of severe influenza: from mouse Mx1 to human IRF7. AB - Influenza viruses cause mild to moderate respiratory illness in most people, and only rarely devastating or fatal infections. The virulence factors encoded by viral genes can explain seasonal or geographic differences at the population level but are unlikely to account for inter-individual clinical variability. Inherited or acquired immunodeficiencies may thus underlie severe cases of influenza. The crucial role of host genes was first demonstrated by forward genetics in inbred mice, with the identification of interferon (IFN)-alpha/beta inducible Mx1 as a canonical influenza susceptibility gene. Reverse genetics has subsequently characterized the in vivo role of other mouse genes involved in IFN alpha/beta and -lambda immunity. A series of in vitro studies with mouse and human cells have also refined the cell-intrinsic mechanisms of protection against influenza viruses. Population-based human genetic studies have not yet uncovered variants with a significant impact. Interestingly, human primary immunodeficiencies affecting T and B cells were also not found to predispose to severe influenza. Recently however, human IRF7 was shown to be essential for IFN alpha/beta- and IFN-lambda-dependent protective immunity against primary influenza in vivo, as inferred from a patient with life-threatening influenza revealed to be IRF7-deficient by whole exome sequencing. Next generation sequencing of human exomes and genomes will facilitate the analysis of the human genetic determinism of severe influenza. PMID- 26761410 TI - Discrimination Measures Using Contingency Tables. AB - Discrimination in organizations based on race or sex is a contentious issue. Sensible discussion of the issue will be enhanced by the availability of measures of discrimination enabling comparisons to be made between organizations and across time. Linear models are of limited validity. A contingency table approach is suggested. Given an observed distribution of categorical variables (such as rank, sex and qualifications) loglinear modelling of the odds ratios across ranks enables maximum likelihood measures distinguishing direct and total discrimination to be established. The analogy between item bias and direct discrimination is discussed, and the proposed maximum likelihood measure of direct discrimination is compared with the Mantel-Haenszel estimator and with a measure derived by collapsing fitted subtables. The proposed discrimination measure can be shown to have a chi-square distribution, and therefore can readily be tested for significance. The methods are illustrated by applying them to examine the extent of sex discrimination in the ranks of staff within an Australian university, but can readily be used to measure discrimination in respect of a sub-group in any employment or membership context. PMID- 26761411 TI - Towards a General Hierarchical Model of Meaning and Satisfaction in Life. PMID- 26761412 TI - Androgyny and Sex-Typing as Continuous Independent Factors, and a Glimpse of the Future. AB - Models for operationalizing the sex-role constructs androgyny and sex-typing are reviewed, and problems discussed. A new (principal components) model representing an exact solution is derived and shown to solve existing problems. In this model, androgyny is a function of the sum of standardized instrumentality and expressiveness scores, and sex-typing a function of the difference between these scores. Formal operationalization of these constructs reveals that they may have theoretical utility in only very contrived contingencies, and an alternative profile matching model is proposed. This latter theory, which is not yet fully specified, hypothesizes that an individual's performance is maximized when the critical operating characteristics of a contingency (i.e., instrumental and expressive behaviors required for maximal performance to result) exactly match the individual's specific instrumental and expressive predispositions, and that performance decreases as the discrepancy between the instrumental/expressive profiles of the individual and the contingency increases. PMID- 26761413 TI - On the roles of close shell interactions in the structure of acyl-substituted hydrazones: An experimental and theoretical approach. AB - The 2-(phenyl-hydrazono)-succinic acid dimethyl ester compound was synthesized by reacting phenylhydrazine with dimethylacetylene dicarboxylate at room temperature and characterized by elemental analysis, infrared, Raman, (1)H and (13)C NMR spectroscopies and mass spectrometry. Its solid state structure was determined by X-ray diffraction methods. The X-ray structure determination corroborates that the molecule is present in the crystal as the hydrazone tautomer, probably favored by a strong intramolecular N-H...O=C hydrogen bond occurring between the carbonyl (-C=O) and the hydrazone -C=N-NH- groups. A substantial fragment of the molecular skeleton is planar due to an extended pi-bonding delocalization. The topological analysis of the electron densities (Atom in Molecule, AIM) allows characterization of intramolecular N-H...O interaction, that can be classified as a resonant assisted hydrogen bond (RAHB). Moreover, the Natural Bond Orbital population analysis confirms that a strong hyperconjugative lpO1->sigma*(N2-H) remote interaction between the C2=O1 and N2-H groups takes place. Periodic system electron density and topological analysis have been applied to characterize the intermolecular interactions in the crystal. Weak intermolecular interactions determine the crystal packing, and the prevalence of non-directional dispersive contributions are inferred on topological grounds. The IR spectrum of the crystalline compound was investigated by means of density functional theory calculations carried out with periodic boundary conditions on the crystal, showing excellent agreement between theory and the experiments. The vibrational assignment is complemented with the analysis of the Raman spectrum. PMID- 26761414 TI - Evaluation of portable Raman spectroscopy and handheld X-ray fluorescence analysis (hXRF) for the direct analysis of glyptics. AB - In archaeometry, the advantages of a combined use of Raman spectroscopy and X-ray fluorescence spectroscopy are extensively discussed for applications such as the analysis of paintings, manuscripts, pottery, etc. Here, we demonstrate for the first time the advantage of using both techniques for analysing glyptics. These engraved gemstones or glass materials were originally used as stamps, to identify the owner, for instance on letters, but also on wine vessels. For this research, a set of 64 glyptics (42 Roman glass specimens and 22 modern ones), belonging to the collection of the museum 'Quinta das Cruzes' in Funchal (Madeira, Portugal), was analysed with portable Raman spectroscopy and handheld X-ray fluorescence (hXRF). These techniques were also used to confirm the gemological identification of these precious objects and can give extra information about the glass composition. Raman spectroscopy identifies the molecular composition as well as on the crystalline phases present. On the other hand, hXRF results show that the antique Roman glass samples are characterised with low Pb and Sn levels and that the modern specimens can be discriminated in two groups: lead-based and non-lead based ones. PMID- 26761415 TI - Nickel titanium T-loop wire dimensions for en masse retraction. AB - OBJECTIVE: To compare the force system produced by nickel-titanium T-loop springs made with wires of different dimensions. MATERIAL AND METHODS: Thirty compound T loop springs were divided into three groups according to the dimensions of the nickel-titanium wire used for its design: 0.016" * 0.022", 0.017" * 0.025", and 0.018" * 0.025". The loops were tested on the Orthodontic Force Tester machine at an interbracket distance of 23 mm and activated 9 mm. The force in the y-axis and the moment in the x-axis were registered while the calculated moment to force ratio was recorded at each .5 mm of deactivation. The data were analyzed by three analyses of variance of repeated measures to detect differences and interactions between deactivation and wire size on force, moment, and moment-force ratios (M/F). RESULTS: All groups had significantly different forces (P < .001). The 0.016" * 0.022" wire produced 1.78N of force while the 0.017" * 0.025" and the 0.018" * 0.025" produced 2.81 N and 3.25 N, respectively. The 0.016" * 0.022" wire produced lower moments (11.6 Nmm) than the 0.017" * 0.025" and 0.018" * 0.025" wires, which produced similar moments (13.9 Nmm and 14.4Nmm, respectively). The M/F produced was different for all groups; 0.016" * 0.022" T loops produced 6.7 mm while the 0.017" * 0.025" and 0.018" * 0.025" T-loops produced 5.0 mm and 4.5 mm, respectively. An interaction was detected for all variables between deactivation and groups. CONCLUSION: The larger wires tested produced higher forces with slight increase on the moments, but the M/F produced by the 0.016" * 0.022" wire was the highest found. PMID- 26761416 TI - Intracranial and intradural nasal polyposis after iatrogenic skull base defect: A case report. AB - We report the first case of an intracranial and intradural nasal polyposis occurring in a close topographical relation to a previous, iatrogenic anterior skull base defect. The tumour was resected and the skull base defect was closed transnasally by an interdisciplinary team. The histopathological report confirmed recurrent polyposis. PMID- 26761417 TI - MicroRNAs as Circulating Biomarkers of Left Ventricular Remodeling after Myocardial Infarction. PMID- 26761419 TI - The Neglected Dimension of Global Security--A Framework for Countering Infectious Disease Crises. PMID- 26761420 TI - The microbiome and its implications in intestinal transplantation. AB - PURPOSE OF REVIEW: This article summarizes the complex interplay between the microbiota and host immune responses, and its impact on intestinal transplantation and allograft rejection. RECENT FINDINGS: Recent findings highlight the importance of Paneth cells as crucial producers of antimicrobial peptides that control the intestinal host-microbial interface as well as the essential role of NOD2 as a master regulator of antimicrobial host defenses. Moreover, complex interactions between innate and adaptive immune responses have been shown to critically shape host antimicrobial Th17 responses, which may be key for the pathogenesis of inflammatory bowel diseases and intestinal allograft rejection. SUMMARY: A growing body of evidence indicates that crosstalk between the microbiome and innate and adaptive host immunity determines alloimmune responses and outcomes in intestinal transplantation. Elaboration of this emerging field might lead to novel mechanistic insight into these complex interactions and allow for new therapeutic approaches. PMID- 26761421 TI - Multiple-Resonance Local Wave Functions for Accurate Excited States in Quantum Monte Carlo. AB - We introduce a novel class of local multideterminant Jastrow-Slater wave functions for the efficient and accurate treatment of excited states in quantum Monte Carlo. The wave function is expanded as a linear combination of excitations built from multiple sets of localized orbitals that correspond to the bonding patterns of the different Lewis resonance structures of the molecule. We capitalize on the concept of orbital domains of local coupled-cluster methods, which is here applied to the active space to select the orbitals to correlate and construct the important transitions. The excitations are further grouped into classes, which are ordered in importance and can be systematically included in the Jastrow-Slater wave function to ensure a balanced description of all states of interest. We assess the performance of the proposed wave function in the calculation of vertical excitation energies and excited-state geometry optimization of retinal models whose pi -> pi* state has a strong intramolecular charge-transfer character. We find that our multiresonance wave functions recover the reference values of the total energies of the ground and excited states with only a small number of excitations and that the same expansion can be flexibly used at very different geometries. Furthermore, significant computational saving can also be gained in the orbital optimization step by selectively mixing occupied and virtual orbitals based on spatial considerations without loss of accuracy on the excitation energy. Our multiresonance wave functions are therefore compact, accurate, and very promising for the calculation of multiple excited states of different character in large molecules. PMID- 26761418 TI - A critical review of perfluorooctanoate and perfluorooctanesulfonate exposure and immunological health conditions in humans. AB - Whether perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS), two widely used and biopersistent synthetic chemicals, are immunotoxic in humans is unclear. Accordingly, this article systematically and critically reviews the epidemiologic evidence on the association between exposure to PFOA and PFOS and various immune related health conditions in humans. Twenty-four epidemiologic studies have reported associations of PFOA and/or PFOS with immune-related health conditions, including ten studies of immune biomarker levels or gene expression patterns, ten studies of atopic or allergic disorders, five studies of infectious diseases, four studies of vaccine responses, and five studies of chronic inflammatory or autoimmune conditions (with several studies evaluating multiple endpoints). Asthma, the most commonly studied condition, was evaluated in seven studies. With few, often methodologically limited studies of any particular health condition, generally inconsistent results, and an inability to exclude confounding, bias, or chance as an explanation for observed associations, the available epidemiologic evidence is insufficient to reach a conclusion about a causal relationship between exposure to PFOA and PFOS and any immune-related health condition in humans. When interpreting such studies, an immunodeficiency should not be presumed to exist when there is no evidence of a clinical abnormality. Large, prospective studies with repeated exposure assessment in independent populations are needed to confirm some suggestive associations with certain endpoints. PMID- 26761422 TI - Defects Engineered Monolayer MoS2 for Improved Hydrogen Evolution Reaction. AB - MoS2 is a promising and low-cost material for electrochemical hydrogen production due to its high activity and stability during the reaction. However, the efficiency of hydrogen production is limited by the amount of active sites, for example, edges, in MoS2. Here, we demonstrate that oxygen plasma exposure and hydrogen treatment on pristine monolayer MoS2 could introduce more active sites via the formation of defects within the monolayer, leading to a high density of exposed edges and a significant improvement of the hydrogen evolution activity. These as-fabricated defects are characterized at the scale from macroscopic continuum to discrete atoms. Our work represents a facile method to increase the hydrogen production in electrochemical reaction of MoS2 via defect engineering, and helps to understand the catalytic properties of MoS2. PMID- 26761423 TI - Blood alcohol concentration in fatally injured drivers and the efficacy of alcohol policies of the new law on road traffic safety: A retrospective 10-year study in autonomous province of Vojvodina, Republic of Serbia. AB - OBJECTIVE: The aim of this study was primarily to evaluate inebriated fatally injured drivers (FIDs) according to blood alcohol concentration (BAC) in a 10 year period (2004-2013) in Autonomous Province (AP) of Vojvodina, Republic of Serbia, to analyze the efficacy of alcohol polices in the new law on road traffic safety through changes in the number of inebriated FIDs before and after implementation of the law, as well as to identify factors that influence the occurrence of FIDs with BACs above the legal limit. METHODS: All data for this retrospective study were obtained from the Centre of Forensic Medicine, Toxicology and Molecular Genetics of Clinical Centre of Vojvodina, Novi Sad. Autopsy records for each case included age, gender, BAC, type of vehicle, and date of accident (year, month, and recalculated day of the week). BAC was determined by gas chromatography with flame ionization detection. Statistical analysis was carried out by chi-square tests and Student's t test, with P < .05 as a statistical significance, and multiple binary logistic regression. RESULTS: Of the 354 inebriated FIDs (60% of all FIDs), the majority had BACs between of 0.031 and 0.3 mg/ml (28%), followed by those with BAC > 2.01 mg/ml (23%). The average BAC of those driving under the influence of alcohol (DUIA) for the whole period was 1.235 +/- 1.00 mg/ml and the average number of DUIA/year was 35. Among the total number of FIDs there were significantly more males (93.7%; P < .001) than females (6.3%), though the distribution of intoxicated men and women was not different (P > .05). There was a statistically significant difference in the distribution of sober and inebriated FIDs according to age (P < .001) with the predominance of inebriated FIDs between 21 and 30 years. Although gender and age were found to be significant predictors of BAC above legal limit in FIDs, the area under the receiver operating characteristics (ROC) curve showed that the model had poor discrimination (ROC = 0.673). Of all observed FIDs, 65 cases per year were attributed to the first 5-year period (2004-2009) and 49 to the second 5-year (2010-2013) period, which indicates that there was no statistically significant decrease in the number of FIDs after implementation of the new law. CONCLUSION: The highest number of intoxicated FIDs during the period in AP Vojvodina were mildly and completely inebriated. In the 4-year post-policy period (2010-2013), the number of FIDs and average BAC levels of inebriated FIDs did not significantly change. The abolition of a permissible BAC should be considered. PMID- 26761425 TI - Rotational Mode Specificity in Cl + CH4(v3=1,|jNl?): Role of Reactant's Vibrational Angular Momentum. AB - The effect of initial rotational states in the reaction of antisymmetric-excited CH4(v3=1,|jNl?) with Cl atom was investigated in a crossed-beam, product-imaging experiment over the collisional energy (Ec) range of 2-5 kcal mol(-1). We found that while the initial rotational excitations exert a noticeable effect on total reactivity, they leave little imprint on the more detailed product-state and angular distributions. This finding echoes the previous conclusion in the analogous Cl + CHD3(v1=1,|NK?) reaction. However, the rotational enhancement factor is substantial at low Ec and then becomes insignificant at higher Ec, in contrast to the Cl + CHD3 case. A more intriguing finding is the role of the vibrational angular momentum (l) in promoting the reactivity. A heuristic picture is proposed to rationalize the observations. PMID- 26761424 TI - CHO cell production and sequence improvement in the 13C6FR1 anti-Ebola antibody. AB - From March 2014 through February 2015, the Ebola virus spread rapidly in West Africa, resulting in almost 30,000 infections and approximately 10,000 deaths. With no approved therapeutic options available, an experimental antibody cocktail known as ZMappTM was administered to patients on a limited compassionate-use basis. The supply of ZMappTM was highly constrained at the time because it was in preclinical development and a novel production system (tobacco plants) was being used for manufacturing. To increase the production of ZMappTM for an uncertain future demand, a consortium was formed in the fall of 2014 to quickly manufacture these anti-Ebola antibodies in Chinese hamster ovary (CHO) cells using bioreactors for production at a scale appropriate for thousands of doses. As a result of the efforts of this consortium, valuable lessons were learned about the processing of the antibodies in a CHO-based system. One of the ZMappTM cocktail antibodies, known as c13C6FR1, had been sequence-optimized in the framework region for production in tobacco and engineered as a chimeric antibody. When transfected into CHO cells with the unaltered sequence, 13C6FR1 was difficult to process. This report describes efforts to produce 13C6FR1 and the parental murine hybridoma sequence, 13C6mu, in CHO cells, and provides evidence for the insertion of a highly conserved framework amino acid that improved the physical properties necessary for high-level expression and purification. Furthermore, it describes the technical and logistical lessons learned that may be beneficial in the event of a future Ebola virus or other pandemic viral outbreaks where mAbs are considered potential therapeutics. PMID- 26761426 TI - Epigenetic alterations underlying autoimmune diseases. AB - Recent breakthroughs in genetic explorations have extended our understanding through discovery of genetic patterns subjected to autoimmune diseases (AID). Genetics, on the contrary, has not answered all the conundrums to describe a comprehensive explanation of causal mechanisms of disease etiopathology with regard to the function of environment, sex, or aging. The other side of the coin, epigenetics which is defined by gene manifestation modification without DNA sequence alteration, reportedly has come in to provide new insights towards disease apprehension through bridging the genetics and environmental factors. New investigations in genetic and environmental contributing factors for autoimmunity provide new explanation whereby the interactions between genetic elements and epigenetic modifications signed by environmental agents may be responsible for autoimmune disease initiation and perpetuation. It is aimed through this article to review recent progress attempting to reveal how epigenetics associates with the pathogenesis of autoimmune diseases. PMID- 26761428 TI - Pararhinebothroides-Neither the Sister-Taxon of Rhinebothroides Nor a Valid Genus. AB - The genus Pararhinebothroides was established for a species of cestode (Parahinebothroides hobergi) found parasitizing the Tumbes round stingray, Urobatis tumbesensis (McEachran & Chirichigno), in the inshore Pacific waters in the Gulf of Guayaquil, Ecuador. Its apparent affinities with the freshwater endemic genus Rhinebothroides were considered evidence to support the long standing, yet controversial, biogeographical hypothesis that freshwater stingrays of the family Potamotrygonidae derived from a Pacific marine ancestor during the Cretaceous Period before the uplifting of the Andes. Here, we re-evaluate the phylogenetic and taxonomic status of P. hobergi based on examination of the available type material and newly collected material from the type host near the type locality. The new material allowed the description of tegumental structures using scanning electron microscopy and the generation of a hypothesis for the phylogenetic position of the species based on molecular data for the first time. Morphological investigations revealed that P. hobergi shares all the diagnostic features of the most recent concept of Anthocephalum, including the previously overlooked presence of bothridial apical suckers. Phylogenetic analyses based on partial 28S rDNA (D1-D3) and complete 18S rDNA sequence data for 4 specimens of P. hobergi, 45 species of other rhinebothriideans, and 5 non-rhinebothriidean outgroup species provided unequivocal support for the transfer of P. hobergi to Anthocephalum. Since this is the type and only species of the genus, Pararhinebothroides is considered a junior synonym of Anthocephalum, and Anthocephalum hobergi n. comb. is redescribed. Furthermore, our results reveal Rhinebothroides and Anthocephalum to be only distantly related among the Rhinebothriidea. Not only do our results confirm reservations expressed earlier about the affinities of P. hobergi, but they also substantially challenge inferences drawn previously about the biogeographical history of potamotrygonid stingrays based on parasitological data. PMID- 26761427 TI - Recognition of Intensive Valence and Arousal Affective States via Facial Electromyographic Activity in Young and Senior Adults. AB - BACKGROUND: Research suggests that interaction between humans and digital environments characterizes a form of companionship in addition to technical convenience. To this effect, humans have attempted to design computer systems able to demonstrably empathize with the human affective experience. Facial electromyography (EMG) is one such technique enabling machines to access to human affective states. Numerous studies have investigated the effects of valence emotions on facial EMG activity captured over the corrugator supercilii (frowning muscle) and zygomaticus major (smiling muscle). The arousal emotion, specifically, has not received much research attention, however. In the present study, we sought to identify intensive valence and arousal affective states via facial EMG activity. METHODS: Ten blocks of affective pictures were separated into five categories: neutral valence/low arousal (0VLA), positive valence/high arousal (PVHA), negative valence/high arousal (NVHA), positive valence/low arousal (PVLA), and negative valence/low arousal (NVLA), and the ability of each to elicit corresponding valence and arousal affective states was investigated at length. One hundred and thirteen participants were subjected to these stimuli and provided facial EMG. A set of 16 features based on the amplitude, frequency, predictability, and variability of signals was defined and classified using a support vector machine (SVM). RESULTS: We observed highly accurate classification rates based on the combined corrugator and zygomaticus EMG, ranging from 75.69% to 100.00% for the baseline and five affective states (0VLA, PVHA, PVLA, NVHA, and NVLA) in all individuals. There were significant differences in classification rate accuracy between senior and young adults, but there was no significant difference between female and male participants. CONCLUSION: Our research provides robust evidences for recognition of intensive valence and arousal affective states in young and senior adults. These findings contribute to the successful future application of facial EMG for identifying user affective states in human machine interaction (HMI) or companion robotic systems (CRS). PMID- 26761429 TI - Olanzapine pamoate for the treatment of schizophrenia--a safety evaluation. AB - INTRODUCTION: Non-adherence to long-term treatment is a major issue for patients with schizophrenia and is associated with an increased risk of relapse. Long acting injectable (LAI) antipsychotics can offer a useful option to improve adherence. Due to the type of sustained-release mechanism, olanzapine pamoate (OLAI) can differ in safety as compared with oral olanzapine. Recent safety data concerning olanzapine pamoate required an update of previous systematic reviews. AREAS COVERED: Safety data were found in US and EU clinical trial registries, and a literature search was undertaken using the databases PubMed and EMBASE to find all relevant published studies. Where appropriate, the number needed to harm and 95% confidence interval for categorical safety outcomes were calculated. EXPERT OPINION: The safety profile of OLAI was similar to the well-known safety profile of oral olanzapine, except for the risk of occurrence of post-injection delirium/sedation syndrome (PDSS). Olanzapine pamoate can be a choice for schizophrenic patients with a history of response to and acceptable tolerance of oral olanzapine, who have easy access to mental healthcare settings with emergency services for the treatment of PDSS. Long-term, prospective studies assessing the efficacy and safety of OLAI and head-to-head comparisons with other LAI and oral antipsychotics are needed. PMID- 26761432 TI - Asthma in adults (acute): magnesium sulfate treatment. AB - INTRODUCTION: About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. Patients with severe disease have an increased risk of death, but patients with mild to moderate disease are also at risk of exacerbations. Most guidelines about the management of asthma follow stepwise protocols. This overview does not endorse or follow any particular protocol, but presents the evidence about a specific intervention, magnesium sulfate. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of magnesium sulfate for acute asthma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 50 studies. After deduplication and removal of conference abstracts, 24 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 10 studies and the further review of 14 full publications. Of the 14 full articles evaluated, one systematic review was updated and one systematic review was added at this update. We performed a GRADE evaluation for five PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for two comparisons based on information about the effectiveness and safety of magnesium sulfate (iv) versus placebo and magnesium sulfate (nebulised) plus short-acting beta2 agonists (inhaled) versus short-acting beta2 agonists (inhaled) alone. PMID- 26761430 TI - Is Western Diet-Induced Nonalcoholic Steatohepatitis in Ldlr-/- Mice Reversible? AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a major public health burden in western societies. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is characterized by hepatosteatosis, inflammation, oxidative stress, and hepatic damage that can progress to fibrosis and cirrhosis; risk factors for hepatocellular carcinoma. Given the scope of NASH, validating treatment protocols (i.e., low fat diets and weight loss) is imperative. METHODS: We evaluated the efficacy of two diets, a non-purified chow (NP) and purified (low-fat low-cholesterol, LFLC) diet to reverse western diet (WD)-induced NASH and fibrosis in Ldlr-/- mice. RESULTS: Mice fed WD for 22-24 weeks developed robust hepatosteatosis with mild fibrosis, while mice maintained on the WD an additional 7-8 weeks developed NASH with moderate fibrosis. Returning WD-fed mice to the NP or LFLC diets significantly reduced body weight and plasma markers of metabolic syndrome (dyslipidemia, hyperglycemia) and hepatic gene expression markers of inflammation (Mcp1), oxidative stress (Nox2), fibrosis (Col1A, LoxL2, Timp1) and collagen crosslinking (hydroxyproline). Time course analyses established that plasma triglycerides and hepatic Col1A1 mRNA were rapidly reduced following the switch from the WD to the LFLC diet. However, hepatic triglyceride content and fibrosis did not return to normal levels 8 weeks after the change to the LFLC diet. Time course studies further revealed a strong association (r2 >= 0.52) between plasma markers of inflammation (TLR2 activators) and hepatic fibrosis markers (Col1A, Timp1, LoxL2). Inflammation and fibrosis markers were inversely associated (r2 >= 0.32) with diet-induced changes in hepatic omega3 and omega6 polyunsaturated fatty acids (PUFA) content. CONCLUSION: These studies establish a temporal link between plasma markers of inflammation and hepatic PUFA and fibrosis. Low-fat low-cholesterol diets promote reversal of many, but not all, features associated with WD-induced NASH and fibrosis in Ldlr /- mice. PMID- 26761431 TI - Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-kappaB pathway dependent repression of PP2Ac. AB - Previous studies have indicated that inflammatory stimulation represses protein phosphatase 2A (PP2A), a well-known tumor suppressor. However, whether PP2A repression participates in pancreatic cancer progression has not been verified. We used lipopolysaccharide (LPS) and macrophage-conditioned medium (MCM) to establish in vitro inflammation models, and investigated whether inflammatory stimuli affect pancreatic cancer cell growth and invasion PP2A catalytic subunit (PP2Ac)-dependently. Via nude mouse models of orthotopic tumor xenografts and dibutyltin dichloride (DBTC)-induced chronic pancreatitis, we evaluated the effect of an inflammatory microenvironment on PP2Ac expression in vivo. We cloned the PP2Acalpha and PP2Acbeta isoform promoters to investigate the PP2Ac transcriptional regulation mechanisms. MCM accelerated pancreatic cancer cell growth; MCM and LPS promoted cell invasion. DBTC promoted xenograft growth and metastasis, induced tumor-associated macrophage infiltration, promoted angiogenesis, activated the nuclear factor-kappaB (NF-kappaB) pathway, and repressed PP2Ac expression. In vitro, LPS and MCM downregulated PP2Ac mRNA and protein. PP2Acalpha overexpression attenuated JNK, ERK, PKC, and IKK phosphorylation, and impaired LPS/MCM-stimulated cell invasion and MCM-promoted cell growth. LPS and MCM activated the NF-kappaB pathway in vitro. LPS and MCM induced IKK and IkappaB phosphorylation, leading to p65/RelA nuclear translocation and transcriptional activation. Overexpression of the dominant negative forms of IKKalpha attenuated LPS and MCM downregulation of PP2Ac, suggesting inflammatory stimuli repress PP2Ac expression NF-kappaB pathway dependently. Luciferase reporter gene assay verified that LPS and MCM downregulated PP2Ac transcription through an NF-kappaB-dependent pathway. Our study presents a new mechanism in inflammation-driven cancer progression through NF-kappaB pathway-dependent PP2Ac repression. PMID- 26761435 TI - Retraction: Metagenomic Human Repiratory Air in a Hospital Environment. PMID- 26761433 TI - Dogs Evaluate Threatening Facial Expressions by Their Biological Validity- Evidence from Gazing Patterns. AB - Appropriate response to companions' emotional signals is important for all social creatures. The emotional expressions of humans and non-human animals have analogies in their form and function, suggesting shared evolutionary roots, but very little is known about how animals other than primates view and process facial expressions. In primates, threat-related facial expressions evoke exceptional viewing patterns compared with neutral or positive stimuli. Here, we explore if domestic dogs (Canis familiaris) have such an attentional bias toward threatening social stimuli and whether observed emotional expressions affect dogs' gaze fixation distribution among the facial features (eyes, midface and mouth). We recorded the voluntary eye gaze of 31 domestic dogs during viewing of facial photographs of humans and dogs with three emotional expressions (threatening, pleasant and neutral). We found that dogs' gaze fixations spread systematically among facial features. The distribution of fixations was altered by the seen expression, but eyes were the most probable targets of the first fixations and gathered longer looking durations than mouth regardless of the viewed expression. The examination of the inner facial features as a whole revealed more pronounced scanning differences among expressions. This suggests that dogs do not base their perception of facial expressions on the viewing of single structures, but the interpretation of the composition formed by eyes, midface and mouth. Dogs evaluated social threat rapidly and this evaluation led to attentional bias, which was dependent on the depicted species: threatening conspecifics' faces evoked heightened attention but threatening human faces instead an avoidance response. We propose that threatening signals carrying differential biological validity are processed via distinctive neurocognitive pathways. Both of these mechanisms may have an adaptive significance for domestic dogs. The findings provide a novel perspective on understanding the processing of emotional expressions and sensitivity to social threat in non-primates. PMID- 26761434 TI - Cardiac phenylethanolamine N-methyltransferase: localization and regulation of gene expression in the spontaneously hypertensive rat. AB - Phenylethanolamine N-methyltransferase (PNMT) is the terminal enzyme in the catecholamine biosynthetic pathway responsible for adrenaline biosynthesis. Adrenaline is involved in the sympathetic control of blood pressure; it augments cardiac function by increasing stroke volume and cardiac output. Genetic mapping studies have linked the PNMT gene to hypertension. This study examined the expression of cardiac PNMT and changes in its transcriptional regulators in the spontaneously hypertensive (SHR) and wild type Wistar-Kyoto (WKY) rats. SHR exhibit elevated levels of corticosterone, and lower levels of the cytokine IL 1beta, revealing systemic differences between SHR and WKY. PNMT mRNA was significantly increased in all chambers of the heart in the SHR, with the greatest increase in the right atrium. Transcriptional regulators of the PNMT promoter show elevated expression of Egr-1, Sp1, AP-2, and GR mRNA in all chambers of the SHR heart, while protein levels of Sp1, Egr-1, and GR were elevated only in the right atrium. Interestingly, only AP-2 protein-DNA binding was increased, suggesting it may be a key regulator of cardiac PNMT in SHR. This study provides the first insights into the molecular mechanisms involved in the dysregulation of cardiac PNMT in a genetic model of hypertension. PMID- 26761438 TI - Identifying high-risk adult AML patients: epigenetic and genetic risk factors and their implications for therapy. AB - Acute myeloid leukemia (AML) is a heterogeneous disease at molecular level, in response to therapy and prognosis. The molecular landscape of AML is evolving with new technologies revealing complex panorama of genetic abnormalities where genomic instability and aberrations of epigenetic regulators play a key role in pathogenesis. The characterization of AML diversity has led to development of new personalized therapeutic strategies to improve outcome of the patients. PMID- 26761437 TI - Toward Bioremediation of Methylmercury Using Silica Encapsulated Escherichia coli Harboring the mer Operon. AB - Mercury is a highly toxic heavy metal and the ability of the neurotoxin methylmercury to biomagnify in the food chain is a serious concern for both public and environmental health globally. Because thousands of tons of mercury are released into the environment each year, remediation strategies are urgently needed and prompted this study. To facilitate remediation of both organic and inorganic forms of mercury, Escherichia coli was engineered to harbor a subset of genes (merRTPAB) from the mercury resistance operon. Protein products of the mer operon enable transport of mercury into the cell, cleavage of organic C-Hg bonds, and subsequent reduction of ionic mercury to the less toxic elemental form, Hg(0). E. coli containing merRTPAB was then encapsulated in silica beads resulting in a biological-based filtration material. Performing encapsulation in aerated mineral oil yielded silica beads that were smooth, spherical, and similar in diameter. Following encapsulation, E. coli containing merRTPAB retained the ability to degrade methylmercury and performed similarly to non-encapsulated cells. Due to the versatility of both the engineered mercury resistant strain and silica bead technology, this study provides a strong foundation for use of the resulting biological-based filtration material for methylmercury remediation. PMID- 26761436 TI - Sirt6 regulates dendritic cell differentiation, maturation, and function. AB - Dendritic cells (DCs) are antigen-presenting cells that critically influence decisions about immune activation or tolerance. Impaired DC function is at the core of common chronic disorders and contributes to reduce immunocompetence during aging. Knowledge on the mechanisms regulating DC generation and function is necessary to understand the immune system and to prevent disease and immunosenescence. Here we show that the sirtuin Sirt6, which was previously linked to healthspan promotion, stimulates the development of myeloid, conventional DCs (cDCs). Sirt6-knockout (Sirt6KO) mice exhibit low frequencies of bone marrow cDC precursors and low yields of bone marrow-derived cDCs compared to wild-type (WT) animals. Sirt6KO cDCs express lower levels of class II MHC, of costimulatory molecules, and of the chemokine receptor CCR7, and are less immunostimulatory compared to WT cDCs. Similar effects in terms of differentiation and immunostimulatory capacity were observed in human monocyte derived DCs in response to SIRT6 inhibition. Finally, while Sirt6KO cDCs show an overall reduction in their ability to produce IL-12, TNF-alpha and IL-6 secretion varies dependent on the stimulus, being reduced in response to CpG, but increased in response to other Toll-like receptor ligands. In conclusion, Sirt6 plays a crucial role in cDC differentiation and function and reduced Sirt6 activity may contribute to immunosenescence. PMID- 26761439 TI - Projected Scenarios for Coastal First Nations' Fisheries Catch Potential under Climate Change: Management Challenges and Opportunities. AB - Studies have demonstrated ways in which climate-related shifts in the distributions and relative abundances of marine species are expected to alter the dynamics and catch potential of global fisheries. While these studies assess impacts on large-scale commercial fisheries, few efforts have been made to quantitatively project impacts on small-scale subsistence and commercial fisheries that are economically, socially and culturally important to many coastal communities. This study uses a dynamic bioclimate envelope model to project scenarios of climate-related changes in the relative abundance, distribution and richness of 98 exploited marine fishes and invertebrates of commercial and cultural importance to First Nations in coastal British Columbia, Canada. Declines in abundance are projected for most of the sampled species under both the lower (Representative Concentration Pathway [RCP] 2.6) and higher (RCP 8.5) emission scenarios (-15.0% to -20.8%, respectively), with poleward range shifts occurring at a median rate of 10.3 to 18.0 km decade(-1) by 2050 relative to 2000. While a cumulative decline in catch potential is projected coastwide ( 4.5 to -10.7%), estimates suggest a strong positive correlation between the change in relative catch potential and latitude, with First Nations' territories along the northern and central coasts of British Columbia likely to experience less severe declines than those to the south. Furthermore, a strong negative correlation is projected between latitude and the number of species exhibiting declining abundance. These trends are shown to be robust to alternative species distribution models. This study concludes by discussing corresponding management challenges that are likely to be encountered under climate change, and by highlighting the value of joint-management frameworks and traditional fisheries management approaches that could aid in offsetting impacts and developing site specific mitigation and adaptation strategies derived from local fishers' knowledge. PMID- 26761440 TI - Endometrial LGR7 expression and implantation failure. AB - Implantation failure is considered as a major cause of infertility in women with recurrent pregnancy loss (RPL) and in otherwise healthy women with unexplained infertility. Preliminary data in primates suggested that relaxin (RLX) is involved in endometrial preparation for implantation. In a prospective observational study, the endometrial RLX receptor (LGR7) expression was assessed in three groups of patients with regular ovulatory cycle and normal uterine cavity: 23 with RPL (Group A), 23 with unexplained infertility undergone at least three cycles of failed in vitro fertilization (IVF) reporting good oocyte and embryo quality (Group B), 23 with proven fertility (Group C). Assessment of LGR7 expression was performed with both polymerase chain reaction (PCR) analysis and immunohistochemistry on endometrial samples obtained with hysteroscopic biopsy performed in the secretory phase of the menstrual cycle. Endometrial LGR7 was less expressed in group A and B versus C, both by PCR analysis (p = 0.024) and immunohistochemistry. The decreased expression of the endometrial RLX receptor in women with implantation failures, both in vitro fertilization failure and recurrent pregnancy loss, suggests that RLX may play a crucial role in the structural and functional changes of the endometrium during the window of implantation. PMID- 26761441 TI - Paleobiology of the Latest Tithonian (Late Jurassic) Ammonite Salinites grossicostatum Inferred from Internal and External Shell Parameters. AB - Based on material from the uppermost Tithonian La Caja Formation at Puerto Pinones, northeastern Mexico, the complete ontogenetic development (protoconch to adult) of the ammonite Salinites grossicostatum is outlined by a detailed morphometrical shell analysis. The embryonic stage, consisting of a small ellipsoid protoconch and ammonitella, ends at about 0.6 mm. Four major morphological changes are differentiated throughout ontogeny based on internal features such as reduced septal spacing and siphuncle position. Sexual dimorphism is reflected by shell size, siphuncular diameter, differences in the morphology of the apophysis, and by two distinct general trends in septal spacing. In addition, macroconchs are characterized by septal crowding at different stages, followed by the return to normal septum distances. Our analysis indicates a change in the mode of life after the neanic stage. A change in habitat preference is inferred for adult individuals. While microconchs persisted at Puerto Pinones, large mature macroconchs temporarily migrated to other areas, possibly for egg deposition. Salinites grossicostatum is endemic to the ancient Gulf of Mexico and is there restricted to outer continental shelf environments. PMID- 26761442 TI - An Evaluation of Rebuilding Policies for U.S. Fisheries. AB - Rebuilding depleted fish populations is a priority of modern fisheries management. In the U.S., strong statutory mandates extend to both the goals and process by which stocks are to be rebuilt. However, the National Standard Guidelines that govern the implementation of the Magnuson-Stevens Fishery Conservation and Management Act may change to increase flexibility in rebuilding requirements. In this study we evaluate performance of the status quo approach to fish stock rebuilding in the United States against 3 alternatives that have been proposed to improve rebuilding outcomes. These alternatives either simplify the analytical requirements of rebuilding analyses or apply 'best practices' in fisheries management, thereby avoiding the need for rebuilding analyses altogether. We use a Management Strategy Evaluation framework to evaluate rebuilding options across 6 fish life history types and 5 possible real-world fishery scenarios that include options for stock assessment quality, multiple fleets, and the degree to which the stocks are overfished at the start of the analysis. We show that the status quo rebuilding plan and a harvest control rule that reduces harvest rates at low stock size generally achieve the best rebuilding outcomes across all life-history types and fishery scenarios. Both approaches constrain fishing in the short term, but achieve high catches in the medium and long term as stocks rebuild to productive levels. These results support a growing body of literature that indicates that efforts to end overfishing early pay off in the medium- to long-term with higher cumulative catches than the alternative. PMID- 26761462 TI - Myelin Sheath Injury in Kaolin-Induced Hydrocephalus: A Light and Electron Microscopy Study. AB - BACKGROUND: In hydrocephalus, the impairment of cognitive and motor functions is thought to be partly due to injury to the myelin sheath of axons in the central nervous system. The exact nature of this injury is not completely understood. METHODS: We induced hydrocephalus in 3-week-old rats with an intracisternal injection of kaolin suspension (0.04 ml of 200 mg/ml) and examined paraffin and ultrathin sections of the subcortical white matter from coronal slices of the cerebrum obtained at the level of the optic chiasm after sacrifice at weekly intervals for 4 weeks. RESULTS: Over time, there was a progression of injury to the myelin sheath consisting of attenuation, lamella separation and accumulation of myelin debris, focal degeneration, and the appearance of casts and loops. CONCLUSION: The results suggest that myelin injury in kaolin-induced hydrocephalus progresses with the duration and severity of ventriculomegaly. PMID- 26761461 TI - Frequent Prescription of Antibiotics and High Burden of Antibiotic Resistance among Deceased Patients in General Medical Wards of Acute Care Hospitals in Korea. AB - BACKGROUND: Antibiotics are often administered to terminally ill patients until death, and antibiotic use contributes to the emergence of multidrug-resistant organisms (MDROs). We investigated antibiotic use and the isolation of MDROs among patients who died in general medical wards. METHODS: All adult patients who died in the general internal medicine wards at four acute care hospitals between January and June 2013 were enrolled. For comparison with these deceased patients, the same number of surviving, discharged patients was selected from the same divisions of internal medicine subspecialties during the same period. RESULTS: During the study period, 303 deceased patients were enrolled; among them, 265 (87.5%) had do-not-resuscitate (DNR) orders in their medical records. Antibiotic use was more common in patients who died than in those who survived (87.5% vs. 65.7%, P<0.001). Among deceased patients with DNR orders, antibiotic use was continued in 59.6% of patients after obtaining their DNR orders. Deceased patients received more antibiotic therapy courses (two [interquartile range (IQR) 1-3] vs. one [IQR 0-2], P<0.001). Antibiotics were used for longer durations in deceased patients than in surviving patients (13 [IQR 5-23] vs. seven days [IQR 0 18], P<0.001). MDROs were also more common in deceased patients than in surviving patients (25.7% vs. 10.6%, P<0.001). CONCLUSIONS: Patients who died in the general medical wards of acute care hospitals were exposed to more antibiotics than patients who survived. In particular, antibiotic prescription was common even after obtaining DNR orders in patients who died. The isolation of MDROs during the hospital stay was more common in these patients who died. Strategies for judicious antibiotic use and appropriate infection control should be applied to these patient populations. PMID- 26761463 TI - Intracranial pressure monitoring in the torture chambre. PMID- 26761464 TI - Neurological outcomes after cardiac arrest: cold and dark issues. PMID- 26761465 TI - A look at the diastolic function in severe sepsis and septic shock. PMID- 26761466 TI - Fluid resuscitation in the critically ill: what is the next challenge? PMID- 26761467 TI - Improving outcomes for the critically ill in developing countries: what is next? PMID- 26761468 TI - Measurement of intracranial pressure and short-term outcomes of patients with traumatic brain injury: a propensity-matched analysis. AB - OBJECTIVE: To assess the impact of intracranial pressure monitoring on the short term outcomes of traumatic brain injury patients. METHODS: Retrospective observational study including 299 consecutive patients admitted due to traumatic brain injury from January 2011 through July 2012 at a Level 1 trauma center in Sao Paulo, Brazil. Patients were categorized in two groups according to the measurement of intracranial pressure (measured intracranial pressure and non measured intracranial pressure groups). We applied a propensity-matched analysis to adjust for possible confounders (variables contained in the Crash Score prognostic algorithm). RESULTS: Global mortality at 14 days (16%) was equal to that observed in high-income countries in the CRASH Study and was better than expected based on the CRASH calculator score (20.6%), with a standardized mortality ratio of 0.77. A total of 28 patients received intracranial pressure monitoring (measured intracranial pressure group), of whom 26 were paired in a 1:1 fashion with patients from the non-measured intracranial pressure group. There was no improvement in the measured intracranial pressure group compared to the non-measured intracranial pressure group regarding hospital mortality, 14-day mortality, or combined hospital and chronic care facility mortality. Survival up to 14 days was also similar between groups. CONCLUSION: Patients receiving intracranial pressure monitoring tend to have more severe traumatic brain injuries. However, after adjusting for multiple confounders using propensity scoring, no benefits in terms of survival were observed among intracranial pressure-monitored patients and those managed with a systematic clinical protocol. PMID- 26761469 TI - Therapeutic hypothermia after cardiac arrest: outcome predictors. AB - OBJECTIVE: The determination of coma patient prognosis after cardiac arrest has clinical, ethical and social implications. Neurological examination, imaging and biochemical markers are helpful tools accepted as reliable in predicting recovery. With the advent of therapeutic hypothermia, these data need to be reconfirmed. In this study, we attempted to determine the validity of different markers, which can be used in the detection of patients with poor prognosis under hypothermia. METHODS: Data from adult patients admitted to our intensive care unit for a hypothermia protocol after cardiac arrest were recorded prospectively to generate a descriptive and analytical study analyzing the relationship between clinical, neurophysiological, imaging and biochemical parameters with 6-month outcomes defined according to the Cerebral Performance Categories scale (good 1 2, poor 3-5). Neuron-specific enolase was collected at 72 hours. Imaging and neurophysiologic exams were carried out in the 24 hours after the rewarming period. RESULTS: Sixty-seven patients were included in the study, of which 12 had good neurological outcomes. Ventricular fibrillation and electroencephalographic theta activity were associated with increased likelihood of survival and improved neurological outcomes. Patients who had more rapid cooling (mean time of 163 versus 312 minutes), hypoxic-ischemic brain injury on magnetic resonance imaging or neuron-specific enolase > 58ng/mL had poor neurological outcomes (p < 0.05). CONCLUSION: Hypoxic-ischemic brain injury on magnetic resonance imaging and neuron-specific enolase were strong predictors of poor neurological outcomes. Although there is the belief that early achievement of target temperature improves neurological prognoses, in our study, there were increased mortality and worse neurological outcomes with earlier target-temperature achievement. PMID- 26761470 TI - Prognostic value of ventricular diastolic dysfunction in patients with severe sepsis and septic shock. AB - OBJECTIVES: To evaluate the prevalence of myocardial dysfunction and its prognostic value in patients with severe sepsis and septic shock. METHODS: Adult septic patients admitted to an intensive care unit were prospectively studied using transthoracic echocardiography within the first 48 hours after admission and thereafter on the 7th-10th days. Echocardiographic variables of biventricular function, including the E/e' ratio, were compared between survivors and non survivors. RESULTS: A total of 99 echocardiograms (53 at admission and 46 between days 7 - 10) were performed on 53 patients with a mean age of 74 (SD 13) years. Systolic and diastolic dysfunction was present in 14 (26%) and 42 (83%) patients, respectively, and both types of dysfunction were present in 12 (23%) patients. The E/e' ratio, an index of diastolic dysfunction, was the best predictor of hospital mortality according to the area under the ROC curve (0.71) and was an independent predictor of outcome, as determined by multivariate analysis (OR = 1.36 [1.05 - 1.76], p = 0.02). CONCLUSION: In septic patients admitted to an intensive care unit, echocardiographic systolic dysfunction is not associated with increased mortality. In contrast, diastolic dysfunction is an independent predictor of outcome. PMID- 26761471 TI - Is venous blood drawn from femoral access adequate to estimate the central venous oxygen saturation and arterial lactate levels in critically ill patients? AB - OBJECTIVES: The purpose of this study was to test if venous blood drawn from femoral access can be used to estimate the central venous oxygen saturation and arterial lactate levels in critically ill patients. METHODS: Bland-Altman analysis and Spearman correlations were used to compare the femoral venous oxygen saturation and central venous oxygen saturation as well as arterial lactate levels and femoral lactate. A pre-specified subgroup analysis was conducted in patients with signs of hypoperfusion. In addition, the clinical agreement was also investigated. RESULTS: Blood samples were obtained in 26 patients. In 107 paired samples, there was a moderate correlation (r = 0.686, p < 0.0001) between the central venous oxygen saturation and femoral venous oxygen saturation with a bias of 8.24 +/- 10.44 (95% limits of agreement: -12.23 to 28.70). In 102 paired samples, there was a strong correlation between the arterial lactate levels and femoral lactate levels (r = 0.972, p < 0.001) with a bias of -2.71 +/- 9.86 (95% limits of agreement: -22.03 to 16.61). The presence of hypoperfusion did not significantly change these results. The clinical agreement for venous saturation was inadequate, with different therapeutic decisions in 22.4% of the situation; for lactate, this was the case only in 5.2% of the situations. CONCLUSION: Femoral venous oxygen saturation should not be used as a surrogate of central venous oxygen saturation. However, femoral lactate levels can be used in clinical practice, albeit with caution. PMID- 26761472 TI - Influence of different degrees of head elevation on respiratory mechanics in mechanically ventilated patients. AB - OBJECTIVE: The positioning of a patient in bed may directly affect their respiratory mechanics. The objective of this study was to evaluate the respiratory mechanics of mechanically ventilated patients positioned with different head angles hospitalized in an intensive care unit. METHODS: This was a prospective physiological study in which static and dynamic compliance, resistive airway pressure, and peripheral oxygen saturation were measured with the head at four different positions (0 degrees = P1, 30 degrees = P2, 45 degrees = P3, and 60 degrees = P4). Repeated-measures analysis of variance (ANOVA) with a Bonferroni post-test and Friedman analysis were used to compare the values obtained at the different positions. RESULTS: A comparison of the 35 evaluated patients revealed that the resistive airway pressure values in the 0 degrees position were higher than those obtained when patients were positioned at greater angles. The elastic pressure analysis revealed that the 60 degrees position produced the highest value relative to the other positions. Regarding static compliance, a reduction in values was observed from the 0 degrees position to the 60 degrees position. The dynamic compliance analysis revealed that the 30 degrees angle produced the greatest value compared to the other positions. The peripheral oxygen saturation showed little variation, with the highest value obtained at the 0 degrees position. CONCLUSION: The highest dynamic compliance value was observed at the 30 degrees position, and the highest oxygenation value was observed at the 0 degrees position. PMID- 26761473 TI - Adverse events caused by potential drug-drug interactions in an intensive care unit of a teaching hospital. AB - OBJECTIVE: To evaluate the incidence of potential drug-drug interactions in an intensive care unit of a hospital, focusing on antimicrobial drugs. METHODS: This cross-sectional study analyzed electronic prescriptions of patients admitted to the intensive care unit of a teaching hospital between January 1 and March 31, 2014 and assessed potential drug-drug interactions associated with antimicrobial drugs. Antimicrobial drug consumption levels were expressed in daily doses per 100 patient-days. The search and classification of the interactions were based on the Micromedex(r) system. RESULTS: The daily prescriptions of 82 patients were analyzed, totaling 656 prescriptions. Antimicrobial drugs represented 25% of all prescription drugs, with meropenem, vancomycin and ceftriaxone being the most prescribed medications. According to the approach of daily dose per 100 patient days, the most commonly used antimicrobial drugs were cefepime, meropenem, sulfamethoxazole + trimethoprim and ciprofloxacin. The mean number of interactions per patient was 2.6. Among the interactions, 51% were classified as contraindicated or significantly severe. Highly significant interactions (clinical value 1 and 2) were observed with a prevalence of 98%. CONCLUSION: The current study demonstrated that antimicrobial drugs are frequently prescribed in intensive care units and present a very high number of potential drug-drug interactions, with most of them being considered highly significant. PMID- 26761474 TI - Delirium in intensive care unit patients under noninvasive ventilation: a multinational survey. AB - OBJECTIVE: To conduct a multinational survey of intensive care unit professionals to determine the practices on delirium assessment and management, in addition to their perceptions and attitudes toward the evaluation and impact of delirium in patients requiring noninvasive ventilation. METHODS: An electronic questionnaire was created to evaluate the profiles of the respondents and their related intensive care units, the systematic delirium assessment and management and the respondents' perceptions and attitudes regarding delirium in patients requiring noninvasive ventilation. The questionnaire was distributed to the cooperative network for research of the Associacao de Medicina Intensiva Brasileira (AMIB Net) mailing list and to researchers in different centers in Latin America and Europe. RESULTS: Four hundred thirty-six questionnaires were available for analysis; the majority of the questionnaires were from Brazil (61.9%), followed by Turkey (8.7%) and Italy (4.8%). Approximately 61% of the respondents reported no delirium assessment in the intensive care unit, and 31% evaluated delirium in patients under noninvasive ventilation. The Confusion Assessment Method for the intensive care unit was the most reported validated diagnostic tool (66.9%). Concerning the indication of noninvasive ventilation in patients already presenting with delirium, 16.3% of respondents never allow the use of noninvasive ventilation in this clinical context. CONCLUSION: This survey provides data that strongly reemphasizes poor efforts toward delirium assessment and management in the intensive care unit setting, especially regarding patients requiring noninvasive ventilation. PMID- 26761475 TI - Relationship between adductor pollicis muscle thickness and subjective global assessment in a cardiac intensive care unit. AB - OBJECTIVE: To verify the relationship between the adductor pollicis muscle thickness test and the subjective global assessment and to correlate it with other anthropometric methods. METHODS: This observational cross-sectional study was conducted in the intensive care unit of a cardiology hospital in the state of Rio Grande do Sul, Brazil. The hospitalized patients underwent subjective global assessment and adductor pollicis muscle thickness tests on both hands, along with measurement of the right calf circumference. Laboratory parameters, length of stay, vital signs and electronic medical record data and tests were all collected. RESULTS: The study population included 83 patients, of whom 62% were men. The average age was 68.6 +/- 12.5 years. The most common reason for hospitalization was acute myocardial infarction (34.9%), and the most common pathology was systolic blood pressure (63.9%), followed by diabetes mellitus (28.9%). According to subjective global assessment classifications, 62.7% of patients presented no nutritional risk, 20.5% were moderately malnourished and 16.9% were severely malnourished. Women had a higher nutritional risk, according to both the subjective global assessment and the adductor pollicis muscle thickness test, the cutoff for which was < 6.5mm (54.8%; p = 0.001). The pathology presenting the greatest nutritional risk was congestive heart failure (p = 0.001). Evaluation of the receiver operating characteristic (ROC) curve between adductor pollicis muscle thickness and subjective global assessment showed the accuracy of the former, with an area of 0.822. CONCLUSION: Adductor pollicis muscle thickness proved to be a good method for evaluating nutritional risk. PMID- 26761476 TI - Serum concentrations of vitamin D and organ dysfunction in patients with severe sepsis and septic shock. AB - OBJECTIVES: To evaluate the serum concentrations of vitamin D and their variations in patients with severe sepsis or septic shock and in control subjects upon admission and after 7 days of hospitalization in the intensive care unit and to correlate these concentrations with the severity of organ dysfunction. METHODS: This case-control, prospective, observational study involved patients aged > 18 years with severe sepsis or septic shock paired with a control group. Serum vitamin D concentrations were measured at inclusion (D0) and on the seventh day after inclusion (D7). Severe deficiency was defined as vitamin D levels < 10ng/ml, deficiency as levels between 10 and 20ng/ml, insufficiency as levels between 20 and 30ng/ml, and sufficiency as levels >= 30ng/mL. We considered a change to a higher ranking, together with a 50% increase in the absolute concentration, to represent an improvement. RESULTS: We included 51 patients (26 with septic shock and 25 controls). The prevalence of vitamin D concentration <= 30ng/ml was 98%. There was no correlation between the serum concentration of vitamin D at D0 and the SOFA score at D0 or D7 either in the general population or in the group with septic shock. Patients with improvement in vitamin D deficiency had an improved SOFA score at D7 (p = 0.013). CONCLUSION: In the population studied, patients with septic shock showed improvement in the serum concentrations of vitamin D on the seventh day compared with the controls. We also found a correlation between higher vitamin D concentrations and a greater decrease in the severity of organ dysfunction. PMID- 26761477 TI - Evaluation of the role of the cannabidiol system in an animal model of ischemia/reperfusion kidney injury. AB - OBJECTIVE: This work aimed to investigate the effects of the administration of cannabidiol in a kidney ischemia/reperfusion animal model. METHODS: Kidney injury was induced by 45 minutes of renal ischemia followed by reperfusion. Cannabidiol (5mg/kg) was administered immediately after reperfusion. RESULTS: Ischemia/reperfusion increased the IL-1 and TNF levels, and these levels were attenuated by cannabidiol treatment. Additionally, cannabidiol was able to decrease lipid and protein oxidative damage, but not the nitrite/nitrate levels. Kidney injury after ischemia/reperfusion seemed to be independent of the cannabidiol receptor 1 and cannabidiol receptor 2 (CB1 and CB2) expression levels, as there was no significant increase in these receptors after reperfusion. CONCLUSION: The cannabidiol treatment had a protective effect against inflammation and oxidative damage in the kidney ischemia/reperfusion model. These effects seemed to be independent of CB1/CB2 receptor activation. PMID- 26761478 TI - Noninvasive ventilation in status asthmaticus in children: levels of evidence. AB - OBJECTIVE: To evaluate the quality of available evidence to establish guidelines for the use of noninvasive ventilation for the management of status asthmaticus in children unresponsive to standard treatment. METHODS: Search, selection and analysis of all original articles on asthma and noninvasive ventilation in children, published until September 1, 2014 in all languages in the electronic databases PubMed, Web of Science, Cochrane Library, Scopus and SciELO, located using the search terms: "asthma", "status asthmaticus", "noninvasive ventilation", "Bronchospasm", "continuous positive airway pressure", "child", "infant", "pediatrics", "hypercapnia", "respiratory failure" and the keywords "BIPAP", "CPAP", "Bilevel", "acute asthma" and "near fatal asthma". The articles were assessed based on the levels of evidence of the GRADE system. RESULTS: Only nine original articles were located; two (22%) articles had level of evidence A, one (11%) had level of evidence B and six (67%) had level of evidence C. CONCLUSION: The results suggest that noninvasive ventilation is applicable for the treatment of status asthmaticus in most pediatric patients unresponsive to standard treatment. However, the available evidence cannot be considered as conclusive, as further high-quality research is likely to have an impact on and change the estimate of the effect. PMID- 26761479 TI - Use of venoarterial extracorporeal membrane oxygenation in fulminant chagasic myocarditis as a bridge to heart transplant. AB - A 17-year-old Brazilian male presented with progressive dyspnea for 15 days, worsening in the last 24 hours, and was admitted in respiratory failure and cardiogenic shock, with multiple organ dysfunctions. Echocardiography showed a left ventricle ejection fraction of 11%, severe diffuse hypokinesia, and a systolic pulmonary artery pressure of 50mmHg, resulting in the need for hemodynamic support with dobutamine (20mcg/kg/min) and noradrenaline (1.7mcg/kg/min). After 48 hours with no clinical or hemodynamic improvement, an extracorporeal membrane oxygenation was implanted. The patient presented with hemodynamic, systemic perfusion and renal and liver function improvements; however, his cardiac function did not recover after 72 hours, and he was transfer to another hospital. Air transport was conducted from Salvador to Recife in Brazil. A heart transplant was performed with rapid recovery of both liver and kidney functions, as well as good graft function. Histopathology of the explanted heart showed chronic active myocarditis and amastigotes of Trypanosoma cruzi. The estimated global prevalence of T. cruzi infections declined from 18 million in 1991, when the first regional control initiative began, to 5.7 million in 2010. Myocarditis is an inflammatory disease due to infectious or non-infectious conditions. Clinical manifestation is variable, ranging from subclinical presentation to refractory heart failure and cardiogenic shock. Several reports suggest that the use of extracorporeal membrane oxygenation in patients presenting with severe refractory myocarditis is a potential bridging therapy to heart transplant when there is no spontaneous recovery of ventricular function. In a 6-month follow-up outpatient consult, the patient presented well and was asymptomatic. PMID- 26761482 TI - Spontaneous intracranial hemorrhage in children: report of a hemophilia patient who survived due to a brain cyst. AB - We report the case of a 2-year-old child who survived an acute episode of severe spontaneous intracranial hemorrhage with clinical and radiological signs of intracranial hypertension and transtentorial herniation. The patient underwent emergency surgery to drain the hematoma, and a catheter was inserted to monitor intracranial pressure. In the initial computed tomography analysis performed prior to hematoma drainage, a brain cyst was evident contralateral to the hematoma, which, based on the analysis by the care team, possibly helped to avoid a worse outcome because the cyst accommodated the brain after the massive hemorrhage. After the investigation, the patient was determined to have previously undiagnosed hemophilia A. The patient underwent treatment in intensive care, which included the control of intracranial pressure, factor VIII replacement and discharge without signs of neurological impairment. PMID- 26761480 TI - Severe hypercalcemia as a form of acute lymphoblastic leukemia presentation in children. AB - Hypercalcemia is a rare metabolic disorder in children and is potentially fatal. It has a wide differential diagnosis, including cancer. Here, we report the case of a previously healthy 3-year-old who was admitted to the emergency room with fatigue, hyporeactivity, fever and limping gait that had evolved over 5 days and that was progressively worsening. On examination the patient was unconscious (Glasgow coma score: 8). Laboratory tests indicated severe hypercalcemia (total calcium 21.39mg/dL, ionized calcium 2.93mmol/L) and microcytic anemia. Hyperhydration was initiated, and the child was transferred to the pediatric intensive care unit. Continuous venovenous hemodiafiltration with calcium-free solution was instituted, which brought progressive normalization of serum calcium and an improved state of consciousness. Zoledronate was administered, and metabolic and infectious causes and poisoning were excluded. The bone marrow smear revealed a diagnosis of acute lymphoblastic leukemia. Hypercalcemia associated with malignancy in children is rare and occurs as a form of cancer presentation or recurrence. Continuous venovenous hemodiafiltration should be considered in situations where there is imminent risk to life. PMID- 26761483 TI - To: The reality of patients requiring prolonged mechanical ventilation: a multicenter study. PMID- 26761481 TI - Use of thoracic electrical impedance tomography as an auxiliary tool for alveolar recruitment maneuvers in acute respiratory distress syndrome: case report and brief literature review. AB - Thoracic electrical impedance tomography is a real-time, noninvasive monitoring tool of the regional pulmonary ventilation distribution. Its bedside use in patients with acute respiratory distress syndrome has the potential to aid in alveolar recruitment maneuvers, which are often necessary in cases of refractory hypoxemia. In this case report, we describe the monitoring results and interpretation of thoracic electrical impedance tomography used during alveolar recruitment maneuvers in a patient with acute respiratory distress syndrome, with transient application of high alveolar pressures and optimal positive end expiratory pressure titration. Furthermore, we provide a brief literature review regarding the use of alveolar recruitment maneuvers and monitoring using thoracic electrical impedance tomography in patients with acute respiratory distress syndrome. PMID- 26761484 TI - To: Out-of-bed extubation: a feasible study. PMID- 26761485 TI - To: Changes in respiratory mechanics during respiratory physiotherapy in mechanically ventilated patients. PMID- 26761486 TI - Racial and ethnic disparities in parent-reported diagnosis of ADHD: National Survey of Children's Health (2003, 2007, and 2011). AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed mental disorder among children in the United States. While overall ADHD prevalence continues to rise, few have examined difference by race/ethnicity. OBJECTIVE: To examine trends in parent-reported ADHD prevalence between 2003 and 2011 across racial/ethnic groups and the role of sociodemographic factors in observed differences in ADHD. METHOD: Data were from 3 waves of the National Survey of Children's Health (2003, 2007, and 2011), including 190,408 children aged 5-17 years. Independent variables included race/ethnicity (white non Hispanic, black non-Hispanic, Hispanic, other non-Hispanic), gender, age, poverty level, primary language, insurance status, parental marital status, and neighborhood safety. Sociodemographic factors and year were compared among those diagnosed with ADHD and between racial/ethnic groups using chi(2) tests. Adjusted logistic regression models, stratified by race/ethnicity, were fit to examine the association between identified risk factors and ADHD across racial/ethnic groups. Parental report of an ADD or ADHD diagnosis for a child aged 5-17 years was the dependent variable. If the household included more than 1 child aged 5-17 years, 1 was selected at random. RESULTS: Increasing trends were observed over the past decade in the prevalence of parent-reported ADHD overall (43%, P < .001), among children aged 10-14 years (47%, P < .001), and adolescents aged 15-17 years (52%, P < .001). Although the ADHD prevalence was still highest among whites, increasing trends were observed for all racial/ethnic groups, most notably among Hispanics, increasing 83% from 2003 to 2011 (P < .001). A greater increase in ADHD was also observed among females (55%, P < .001) than among males (40%). CONCLUSIONS: Economics, family status, non-English language in the home, and neighborhood safety factors differentially impacted diagnosed ADHD across racial/ethnic groups. Although new insights into the role of economic, family, and neighborhood factors on parent-reported ADHD diagnoses were noted, more research is needed to understand causes of the observed racial/ethnic disparities. PMID- 26761487 TI - Asymmetrical Damage Partitioning in Bacteria: A Model for the Evolution of Stochasticity, Determinism, and Genetic Assimilation. AB - Non-genetic phenotypic variation is common in biological organisms. The variation is potentially beneficial if the environment is changing. If the benefit is large, selection can favor the evolution of genetic assimilation, the process by which the expression of a trait is transferred from environmental to genetic control. Genetic assimilation is an important evolutionary transition, but it is poorly understood because the fitness costs and benefits of variation are often unknown. Here we show that the partitioning of damage by a mother bacterium to its two daughters can evolve through genetic assimilation. Bacterial phenotypes are also highly variable. Because gene-regulating elements can have low copy numbers, the variation is attributed to stochastic sampling. Extant Escherichia coli partition asymmetrically and deterministically more damage to the old daughter, the one receiving the mother's old pole. By modeling in silico damage partitioning in a population, we show that deterministic asymmetry is advantageous because it increases fitness variance and hence the efficiency of natural selection. However, we find that symmetrical but stochastic partitioning can be similarly beneficial. To examine why bacteria evolved deterministic asymmetry, we modeled the effect of damage anchored to the mother's old pole. While anchored damage strengthens selection for asymmetry by creating additional fitness variance, it has the opposite effect on symmetry. The difference results because anchored damage reinforces the polarization of partitioning in asymmetric bacteria. In symmetric bacteria, it dilutes the polarization. Thus, stochasticity alone may have protected early bacteria from damage, but deterministic asymmetry has evolved to be equally important in extant bacteria. We estimate that 47% of damage partitioning is deterministic in E. coli. We suggest that the evolution of deterministic asymmetry from stochasticity offers an example of Waddington's genetic assimilation. Our model is able to quantify the evolution of the assimilation because it characterizes the fitness consequences of variation. PMID- 26761488 TI - The Effects of Potato Puree and Bread Crumbs on Some Quality Characteristics of Low Fat Meatballs. AB - The purpose of this study was to determine the effects of using different amounts of potato puree (PP) (10 or 20%) and 10% bread crumbs (BC) as an extender and also control samples (C) with no added extender on chemical composition, energy values, cooking analyses, colour measurements, water holding capacity (WHC), penetration values, thiobarbituric acid value (TBA) and sensory analyses of meatballs. Meatball samples were cooked in a pre-heated 180C electric oven. Uncooked meatballs formulated with 20% PP had the highest moisture content. No significant differences were recorded for protein contents of uncooked samples. The highest cooking yield was found in samples extended with 10% BC. Increasing PP from 10% to 20% increased cooking yield of meatballs. 20% PP increased moisture and fat retention values and water holding capacity of meatballs. Meatballs with 10% BC had the lowest (the hardness in the texture) and meatballs with the 20% PP had the highest (the softness in the texture) penetration values. Formulating meatballs at a level of 20% resulted lower L* values. TBA values of control samples were higher than in PP added samples at the end of the storage period. Flavour scores for meatballs formulated with PP were higher than control and meatballs formulated with BC. Meatballs formulated with 10% PP had similar overall acceptability with meatballs added with 10% BC. PMID- 26761489 TI - Comparison Study on Changes of Antigenicities of Egg Ovalbumin Irradiated by Electron Beam or X-Ray. AB - This study was conducted to compare the effects of two forms of radiation (electron and X-ray; generated by an electron beam accelerator) on the conformation and antigenic properties of hen's egg albumin, ovalbumin (OVA), which was used as a model protein. OVA solutions (2.0 mg/mL) were individually irradiated by electron beam or X-ray at the absorbed doses of 0 (control), 2, 4, 6, 8, and 10 kGy. No differences between the two forms of radiation on the structural properties of OVA were shown by spectrometric and electrophoretic analyses. The turbidity of OVA solution increased and the main OVA bands on polyacrylamide gels disappeared after irradiation, regardless of the radiation source. In competitive indirect enzyme-linked immunosorbent assay, OVA samples irradiated by electron beam or X-ray showed different immunological responses in reactions with monoclonal and polyclonal antibodies (immunoglobulin G) produced against non-irradiated OVA. The results indicate that electron beam irradiation and X-ray irradiation produced different patterns of structural changes to the OVA molecule. PMID- 26761490 TI - Effect of NaCl/Monosodium Glutamate (MSG) Mixture on the Sensorial Properties and Quality Characteristics of Model Meat Products. AB - Sodium chloride is an important ingredient added to most of foods which contributes to flavor enhancement and food preservation but excess intake of sodium chloride may also cause various diseases such as heart diseases, osteoporosis and so on. Therefore, this study was carried out to investigate the effect of monosodium glutamate (MSG) as a salty flavor enhancer on the quality and sensorial properties of the NaCl/MSG complex and actual food system. For characterizing the spray-dried NaCl/MSG complex, surface dimension, morphology, rheology, and saltiness intensity were estimated by increasing MSG (0-2.0%) levels at a fixed NaCl concentration (2.0%). MSG levels had no effect of the characteristics of the NaCl/MSG complex, although the addition of MSG increased the surface dimension of the NaCl/MSG complex significantly (p<0.05). Furthermore, the effect of MSG on enhancing the salty flavor was not observed in the solution of the NaCl/MSG complex. In the case of an actual food system, model meat products (pork patties) were prepared by replacing NaCl with MSG. MSG enhanced the salty flavor, thereby increasing overall acceptability of pork patties. Replacement of NaCl with MSG (<1.0%) did not result in negative sensorial properties of pork patties, although quality deterioration such as high cooking loss was found. Nevertheless, MSG had a potential application in meat product formulation as a salty flavor enhancer or a partial NaCl replacer when meat products were supplemented with binding agents. PMID- 26761491 TI - Enhanced Antioxidant Activity of Mugwort Herb and Vitamin C in Combination on Shelf-life of Chicken Nuggets. AB - The effect of mugwort extract (ME) and vitamin C (VC), added individually or in combination, on color, lipid oxidation, and sensory characteristics of chicken nuggets stored for 12 d was investigated. Eight treatments of chicken nuggets contained the following: Control (no antioxidant added), VC (0.05% VC), ME 0.05 (0.05% ME), ME 0.1 (0.1% ME), ME 0.2 (0.2% ME), VC+ME 0.05 (0.05% VC + 0.05% ME) and VC+ME 0.1 (0.05% VC + 0.1% ME), VC+ME 0.2 (0.05% VC + 0.2% ME). Results showed that the mixture of 0.05% VC and 0.2% ME was most effective for delaying lipid oxidation (thiobarbituric acid reactive substances, conjugated dienies, and peroxide formation) when compared to the control or ME alone added. The color values of all treatments were significantly affected by adding ME. Additionally, the total color difference (DeltaE), chroma (C*), and hue angle (H degrees ) values of all treatments, except for VC, were lower than those of the control as the amount of ME increased. The sensory characteristics (flavor, odor, and overall acceptability) did not differ significantly in any of the chicken nugget samples, whereas storage time had a significant effect. The results suggest that the possibility of utilizing chicken nuggets with a mixture of mugwort extract and vitamin C for the increase of shelf-life and quality. PMID- 26761493 TI - Quality Evaluation of Pork with Various Freezing and Thawing Methods. AB - In this study, the physicochemical and sensory quality characteristics due to the influence of various thawing methods on electro-magnetic and air blast frozen pork were examined. The packaged pork samples, which were frozen by air blast freezing at -45C or electro-magnetic freezing at -55C, were thawed using 4 different methods: refrigeration (4+/-1C), room temperature (RT, 25C), cold water (15C), and microwave (2450 MHz). Analyses were carried out to determine the drip and cooking loss, water holding capacity (WHC), moisture content and sensory evaluation. Frozen pork thawed in a microwave indicated relatively less thawing loss (0.63-1.24%) than the other thawing methods (0.68-1.38%). The cooking loss after electro-magnetic freezing indicated 37.4% by microwave thawing, compared with 32.9% by refrigeration, 36.5% by RT, and 37.2% by cold water in ham. The thawing of samples frozen by electro-magnetic freezing showed no significant differences between the methods used, while the moisture content was higher in belly thawed by microwave (62.0%) after electro-magnetic freezing than refrigeration (54.8%), RT (61.3%), and cold water (61.1%). The highest overall acceptability was shown for microwave thawing after electro-magnetic freezing but there were no significant differences compared to that of the other samples. PMID- 26761492 TI - Use of Antimicrobial Food Additives as Potential Dipping Solutions to Control Pseudomonas spp. Contamination in the Frankfurters and Ham. AB - This study evaluated the effect of sodium diacetate and sodium lactate solutions for reducing the cell count of Pseudomonas spp. in frankfurters and hams. A mixture of Pseudomonas aeruginosa (NCCP10338, NCCP10250, and NCCP11229), and Pseudomonas fluorescens (KACC10323 and KACC10326) was inoculated on cooked frankfurters and ham. The inoculated samples were immersed into control (sterile distilled water), sodium diacetate (5 and 10%), sodium lactate (5 and 10%), 5% sodium diacetate + 5% sodium lactate, and 10% sodium diacetate + 10% sodium lactate for 0-10 min. Inoculated frankfurters and ham were also immersed into acidified (pH 3.0) solutions such as acidified sodium diacetate (5 and 10%), and acidified sodium lactate (5 and 10%) in addition to control (acidified distilled water) for 0-10 min. Total aerobic plate counts for Pseudomonas spp. were enumerated on Cetrimide agar. Significant reductions (ca. 2 Log CFU/g) in Pseudomonas spp. cells on frankfurters and ham were observed only for a combination treatment of 10% sodium lactate + 10% sodium diacetate. When the solutions were acidified to pH 3.0, the total reductions of Pseudomonas spp. were 1.5-4.0 Log CFU/g. The order of reduction amounts of Pseudomonas spp. cell counts was 10% sodium lactate > 5% sodium lactate >= 10% sodium diacetate > 5% sodium diacetate > control for frankfurters, and 10% sodium lactate > 5% sodium lactate > 10% sodium diacetate > 5% sodium diacetate > control for ham. The results suggest that using acidified food additive antimicrobials, as dipping solutions, should be useful in reducing Pseudomonas spp. on frankfurters and ham. PMID- 26761494 TI - Effects of Various Kinds of Salt on the Quality and Storage Characteristics of Tteokgalbi. AB - This study was carried out to evaluate the effects of various kinds of salt on the quality and storage characteristics of tteokgalbi. The tteokgalbi was prepared using four types of salt: 1.5% purified salt (control, C), 1.5% five year-old solar salt (FS), 1.5% Topan solar salt (TS), and 1.5% French Guerande solar salt (GS). The moisture, crude lipid, crude ash, crude protein and calorie contents, water holding capacity, and cooking loss were not significantly different between control and all other treatments. As for the textural characteristics, the use of GS increased the hardness of the tteokgalbi. According to the sensory evaluation, the use of TS had the best score in springiness. Tteokgalbi made with TS and GS had the two highest scores in flavor and total acceptability. During 15 d of storage, the contents of 2-thiobarbituric acid (TBA) value, volatile basic nitrogen (VBN) and the total microbial counts increased, while the pH decreased. The TBA values of the tteokgalbi containing TS and GS were lower than that of C. Lightness (L) and yellowness (b) values decreased during storage, but redness (a) displayed no significant difference during storage. Overall, the best results, in terms of TBA value and sensory attributes, were obtained for the tteokgalbi containing TS and GS. PMID- 26761495 TI - Screening of Bacteriocin-producing Enterococcus faecalis Strains for Antagonistic Activities against Clostridium perfringens. AB - This study was conducted to isolate and characterize bacteriocin-producing bacteria against Clostridium perfringens (C. perfringens) from domestic animals to determine their usefulness as probiotics. Bacteriocin-producing bacteria were isolated from pig feces by the spot-on-lawn method. A total of 1,370 bacterial stains were isolated, and six were tentatively selected after identifying the inhibitory activity against the pathogenic indicator C. perfringens KCTC 3269 and KCTC 5100. The selected strains were identified as Enterococcus faecalis (E. faecalis) by 16s rRNA sequencing. Most of the isolated bacterial strains were resistant to 0.5% bile salts for 48 h and remained viable after 2 h at pH 3.0. Some E. faecalis also showed strong inhibitory activity against Listeria monocytogenes KCTC 3569, KCTC 3586 and KCTC 3710. In the present study, we finally selected E. faecalis AP 216 and AP 45 strain based on probiotic selection criteria such as antimicrobial activity against C. perfringens and tolerance to acid and bile salts. The bacteriocins of E. faecalis AP 216 and AP 45 strains were highly thermostable, showing anticlostridial activities even after incubation at 121C for 15 min. These bacteriocinproducing bacteria and/or bacteriocins could be used in feed manufacturing as probiotics as an alternative to antibiotics in the livestock industry. PMID- 26761496 TI - The Growth Performance, Carcass Characteristics, and Meat Quality of Egg-Type Male Growing Chicken and White-Mini Broiler in Comparison with Commercial Broiler (Ross 308). AB - The present study was conducted to compare the growth performance, carcass characteristics, and meat quality of the egg-type male growing chicken (EM), white-mini broiler (WB), and commercial broiler (Ross 308, CB). A total of 360 1 d-old chicks were reared together using a completely randomized design with 4 replicates for each group under the identical feeding and rearing conditions. The ADG and gain:feed were the highest in CB, intermediate in WB, and the lowest in EM (p<0.05), and the live and carcass weights of CB and EM were significantly higher than those of WB (p<0.05). The pH of breast meat from WB and CB was significantly higher (p<0.05) than that from EM with a similar body weight. The EM had the lowest moisture (p<0.05) and the highest protein content (p<0.05), whereas the fat and ash contents were not different among groups. The mystiric acid (C14:0), palmitoleic acid (C16:1 omega7), and oleic acid (C18:1 omega9) levels were significantly higher in breast meat from CB (p<0.05). The monounsaturated fatty acid (MUFA) content showed the highest (p<0.05) levels in CB. In contrast, the polyunsaturated fatty acid (PUFA) contents of breast meat, including linoleic acid (C18:2 omega6) and arachidonic acid (C20:4 omega6), were higher (p<0.05) in EM and WB than in CB. In conclusion, the EM and WB had less growth performances in comparison with CB, but they each had some unique features (taste, flavor, and physiological characteristics) when raised under the identical rearing and feeding conditions. PMID- 26761497 TI - Effects of Egg White Consumption on Allergy, Immune Modulation, and Blood Cholesterol Levels in BALB/c Mice. AB - We previously demonstrated that water-soluble egg yolk extract is not related to elevation of serum immunoglobulin E, which can initiate allergic reactions; however, it increases the level of high density lipoprotein (HDL)-cholesterol and the activity of B lymphocytes. In this study, egg white (EW) was fed to BALB/c mice to determine its influence on growth efficiency, immune modulation, and changes in serum lipid levels. A total of 50 five-wk-old BALB/c male mice were divided into 5 groups, 4 of which were fed 0, 10, 50, or 100 mg/d EW for 4 wk. Mice with an uptake of 10, 50 and 100 mg/d EW showed no significant changes in daily weight gain, feed efficiency rate, or populations of white blood cells. However, the activities of both B and T lymphocytes were significantly increased in all three EW groups at the final week of treatment. Interestingly, serum levels immunoglobulin E were not altered by EW consumption, but the IgG level was significantly increased in the 100 mg/d EW group. Serum lipid profile analyses showed no significant changes in total cholesterol, HDL, low density lipoprotein, or triglyceride levels by EW consumption. Taken together, these data demonstrate that consumption of EW promotes immune cell activities and the upregulation of serum IgG levels. However, we found no changes in serum lipid profiles and IgE levels. Therefore, our study suggests that consumption of EW might not be related to the risk of food allergy, but could be an excellent candidate for the maintenance of physiological homeostasis. PMID- 26761498 TI - Effect of Fresh Garlic on Lipid Oxidation and Microbiological Changes of Pork Patties during Refrigerated Storage. AB - The effects of two levels (1.4 vs 2.8%) of fresh garlic on lipid oxidation and microbial growth in pork patties were evaluated. Hunter color (L, a, b), pH, thiobarbituric acid reactive substances (TBARS), oxidative volatile compounds, total bacteria and Enterobacteriaceae in the pork patties with or without fresh garlic were measured during storage at 4C. Addition of fresh garlic decreased redness (a), while increased pH and yellowness (b) values of the fresh pork patties were observed, regardless of the levels added. The TBARS values of the pork patties were increased with the addition of fresh garlic (p<0.05). Similar results were observed in oxidative volatile compounds. A total of 13 volatile compounds were detected in the patties (5 sulfur-containing compounds, including allyl mercaptan, allyl methyl sulfide, diallyl sulfide, methyl-(E)-propenyl disulfide, and diallyl disulfide, and the 8 other oxidative compounds, including 1-pentanol, hexanal, 1-hexanol, heptanal, (E)-2-heptenal, 1-octen-3-ol, (E)-2 octenal and nonanal). Fresh garlic accelerated development of oxidative products in the pork patties, especially hexanal and the total oxidative volatile compounds. However, the addition of 1.4 and 2.8% of fresh garlic inhibited the growth of total bacteria and Enterobacteriaceae, indicating low total bacterial counts and Enterobacteriaceae than the controls. PMID- 26761499 TI - Physiological Characteristics and Anti-obesity Effect of Lactobacillus plantarum Q180 Isolated from Feces. AB - Obesity is strongly associated with several metabolic and chronic diseases and has become a major public health problem of worldwide concern. This study aimed to investigate the physiological characteristics and anti-obesity effects of Lactobacillus plantarum Q180. Lactobacillus plantarum Q180 was isolated from the faces of healthy adults and found to have a lipase inhibitory activity of 83.61+/ 2.32% and inhibited adipocyte differentiation of 3T3-L1 cells (14.63+/-1.37%) at a concentration of 100 MUg/mL. The strain was investigated for its physiological characteristics. The optimum growth temperature of L. plantarum Q180 was 37C. Lactobacillus plantarum Q180 showed higher sensitivity to novobiocin in a comparison of fifteen different antibiotics and showed the highest resistance to rifampicin, polymyxin B and vancomycin. The strain showed higher beta galactosidase and N-acetyl-beta-glucosaminidase activities. It also did not produce carcinogenic enzymes such as beta-glucuronidase. The survival rate of L. plantarum Q180 in MRS broth containing 0.3% bile was 97.8%. Moreover, the strain showed a 97.2% survival rate after incubation for 3 h in pH 2.0. Lactobacillus plantarum Q180 was displayed resistance to Escherichia coli, Salmonella Typhimurium and Staphylococcus aureus with rates of 55.6%, 38.0% and 47.6%, respectively. These results demonstrate that L. plantarum Q180 has potential as a probiotic with anti-obesity effects. PMID- 26761500 TI - Analysis of Myosin Heavy Chain Isoforms from Longissimus Thoracis Muscle of Hanwoo Steer by Electrophoresis and LC-MS/MS. AB - The purpose of this study was to analyze myosin heavy chain (MHC) isoforms in bovine longissimus thoracis (LT) muscle by liquid chromatography (LC) and mass spectrometry (MS). LT muscles taken from Hanwoo (Korean native cattle) steer (n=3) used to separate myosin bands by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The peptide queries were obtained from the myosin bands by LC MS/MS analysis following in-gel digestion with trypsin. A total of 33 and 43 queries were identified as common and unique peptides, respectively, of MHC isoforms (individual ions scores >43 indicate identity or extensive homology, p<0.05). MHC-1 (IIx), -2 (IIa), -4 (IIb), and -7 (slow/I) were identified based on the Mowse score (5118, 3951, 2526, and 2541 for MHC-1, -2, -4, and -7, respectively). However, more analysis is needed to confirm the expression of MHC 4 in bovine LT muscle because any query identified as a unique peptide of MHC-4 was not found. The queries that were identified as unique peptides could be used as peptide markers to confirm MHC-1 (14 queries), -2 (8 queries), and -7 (21 queries) in bovine LT muscle; no query identified as a unique peptide of MHC-4 was found. LC-MS/MS analysis is a useful approach to study MHC isoforms at the protein level. PMID- 26761501 TI - Comparison of Culture, Conventional and Real-time PCR Methods for Listeria monocytogenes in Foods. AB - We compared standard culture methods as well as conventional PCR and real-time PCR for the detection of Listeria monocytogenes (L. monocytogenes) in milk, cheese, fresh-cut vegetables, and raw beef that have different levels of background microflora. No statistical differences were observed in sensitivity between the two selective media in all foods. In total, real-time PCR assay exhibited statistically excellent detection sensitivity (p<0.05) and was less time consuming and laborious as compared with standard culture methods. Conventional culture methods showed poor performance in detecting L. monocytogenes in food with high levels of background microflora, generating numerous false negative results. While the detection of L. monocytogenes in fresh cut vegetable by culture methods was hindered only by L. innocua, various background microflora, such as L. innocua, L. welshimeri, L. grayi, and Enterococcus faecalis appeared on the two selective media as presumptive positive colonies in raw beef indicating the necessity of improvement of current selective media. It appears that real-time PCR is an effective and sensitive presumptive screening tool for L. monocytogenes in various types of foods, especially foods samples with high levels of background microflora, thus complementing standard culture methodologies. PMID- 26761502 TI - Physico-chemical Meat Qualities of Loin and Top Round Beef from Holstein Calves with Different Slaughtering Ages. AB - The objective of this study was to investigate the physico-chemical and sensory properties of loin (m. longissimus dorsi) and top round (m. semimembranosus) beef from 3-, 6-, 9-, and 12 mon-old Holstein calves. For both loin and top round muscles, the moisture contents were decreased, whereas the protein and fat contents were increased, as the slaughtering age increased. In terms of meat color, for both muscle types, CIE L* values were decreased, whereas CIE a* values and myoglobin content increased as the slaughtering age increased. pH values were significantly higher in the 3 mon-old group than in the other groups. The Warner Bratzler shear force (WBSF) values were lowest for loin muscles from the 12 mon old group; however, there was no significant difference for top round muscle among the 4 age groups. Cooking loss for both loin and top round muscles were significantly higher for the 3 mon-old group than for the other groups. The water holding capacity (WHC) of both muscles were highest for the 12 mon-old groups (p<0.05). In fatty acid composition of the 12 mon-old groups, loin muscles had significantly higher levels of C14:0, C16:1n7, C18:1n9, and mono-unsaturated fatty acids (MUFA), and top round muscles had significantly higher levels of C16:1n7, C18:1n7, C18:1n9, MUFA, MUFA/SFA. Loin muscle from the 3- and 12 mon-old groups had significantly higher scores for tenderness and overall likeness. Top round muscle from the 9- and 12 mon-old groups had significantly higher scores for overall likeness than those from the other age groups. PMID- 26761503 TI - Effects of Sucrose Stearate Addition on the Quality Improvement of Ready-To-Eat Samgyetang During Storage at 25C. AB - The effects of sucrose stearate at various concentrations (0.1%, 0.2%, and 0.3%, w/v) on the physico-chemical characteristics of ready-to-eat (RTE) Samgyetang were investigated during storage at 25C for 12 mon. Over the storage duration, the addition of sucrose stearate had no significant effects on the proximate composition of Samgyetang, including meat, broth, and porridge, or the hardness and spreadability of the porridge, although it resulted in significantly higher CIE L* values for the porridge. The CIE L* values of Samgyetang porridge with added sucrose stearate increased until 9 mon, while the control decreased until 6 mon, and the values for both changed insignificantly thereafter. The breast meat of Samgyetang treated with sucrose stearate showed higher percentages of polyunsaturated fatty acid after 3 mon and lower percentages of monounsaturated fatty acid after 6 mon compared to the control (p<0.05), while no significant differences were observed with the different sucrose stearate concentrations (p>0.05). The overall sensory acceptability scores were higher at sucrose stearate concentrations of 0.2% or 0.3% after 6 mon and at 0.1% after 9 mon compared to those of the control. PMID- 26761504 TI - Microencapsulation of Lactobacillus plantarum DKL 109 using External Ionic Gelation Method. AB - The aim of this study was to apply the external ionic gelation using an atomizing spray device comprised of a spray gun to improve the viability of Lactobacillus plantarum DKL 109 and for its commercial use. Three coating material formulas were used to microencapsulate L. plantarum DKL 109: 2% alginate (Al), 1% alginate/1% gellan gum (Al-GG), and 1.5% alginate/3% gum arabic (Al-GA). Particle size of microcapsules was ranged from 18.2 to 23.01 MUm depending on the coating materials. Al-GA microcapsules showed the highest microencapsulation yield (98.11%) and resulted in a significant increase in survivability of probiotic in a high acid and bile environment. Encapsulation also improved the storage stability of cells. The viability of encapsulated cells remained constant after 1 mon storage at ambient temperature. The external ionic gelation method using an atomizing spray device and the Al-GA seems to be an efficient encapsulation technology for protecting probiotics in terms of scale-up potential and small microcapsule size. PMID- 26761505 TI - The Global Volatile Signature of Veal via Solid-phase Microextraction and Gas Chromatography-mass Spectrometry. AB - The volatile composition of veal has yet to be reported and is one of the important factors determining meat character and quality. To identify the most important aroma compounds in veal from Holstein bull calves fed one of three diets, samples were subjected to solid-phase microextraction (SPME) combined with gas chromatography-quadrupole mass spectrometry (GC-MS). Most of the important odorants were aldehydes and alcohols. For group A (veal calves fed entirely on milk for 90 d before slaughter), the most abundant compound class was the aldehydes (52.231%), while that was alcohols (26.260%) in group C (veal calves fed starter diet for at least 60 d before slaughter). In both classes the absolute percentages of the volatile compounds in veal were different indicating that the veal diet significantly (p<0.05) affected headspace volatile composition in veal as determined by principal component analysis (PCA). Twenty three volatile compounds showed significance by using a partial least-squared discriminate analysis (PLS-DA) (VIP>1). The establishment of the global volatile signature of veal may be a useful tool to define the beef diet that improves the organoleptic characteristics of the meat and consequently impacts both its taste and economic value. PMID- 26761506 TI - Quality Assessment of the Breast Meat from Woorimatdag (TM) and Broilers. AB - The objective of this study was to compare the characteristics that define the quality of Woorimatdag (TM) (WM, a certified meat-type commercial Korea indigenous chicken breed) and a commercial broiler breed (Ross, CB). Two hundred WM and 200 CB chickens that were 1-d-old and mixed sex were obtained from a commercial hatchery and randomly assigned to floor pens (20 chickens per pen, 3.0*2.0 m) and raised under the same environmental conditions. WM breast meat contained significantly higher crude protein and ash as well as lower crude fat than CB breast meat (p<0.05). WM breast meat had slightly higher alanine, histidine, isoleucine, and glycine as well as lower phenylalanine content than CB breast meat (p<0.05), and the WM breast meat had a low ratio of unsaturated to saturated fatty acid composition (p<0.05). However, arachidonic acid composition was higher in the WM than the CB breast meat. In addition, the inosin-5' monophosphate content was also higher in the WM compared with the CB breast (p<0.05). The WM breast meat had higher total collagen content compared with CB breast meat. WM soup taste received higher scores with regard to sensory evaluation compared with CB soup (p<0.05). From these results, we conclude that higher amount of protein and flavor precursors and lower amount of fat in the breast meat of WM could be attractive by consumer when compared with CB. PMID- 26761507 TI - Simultaneous Detection of Listeria monocytogenes, Escherichia coli O157:H7, Bacillus cereus, Salmonella spp., and Staphylococcus aureus in Low-fatted Milk by Multiplex PCR. AB - A rapid and specific PCR assay for the simultaneous detection of Listeria monocytogenes, Escherichia coli O157:H7, Bacillus cereus, Salmonella spp., and Staphylococcus aureus in foods was developed to reduce the detection time and to increase sensitivity. Multiplex PCR developed in this study produced only actA, fliC, hbl, invA, ileS amplicons, but did not produce any non-specific amplicon. The primer sets successfully amplified the target genes in the multiplex PCR without any non-specific or additional bands on the other strains. The multiplex PCR assays also amplified some target genes from five pathogens, and multiplex amplification was obtained from as little as 1 pg of DNA. According to the results from the sensitivity evaluation, the multiplex PCR developed in this study detected 10 cells/mL of the pathogens inoculated in milk samples, respectively. The results suggested that multiplex PCR was an effective assay demonstrating high specificity for the simultaneous detection of five target pathogens in food system. PMID- 26761508 TI - Obituary Christian Sprung. PMID- 26761509 TI - Leonardo da Vinci's Vitruvian Man: The Ideal Human Proportions and Man as a Measure of All Things. PMID- 26761510 TI - Adipose Stem Cells Isolated from Excised Burned Tissue: Is There Potential for Clinical Use? PMID- 26761511 TI - Reply: Permissive Intraabdominal Hypertension following Complex Abdominal Wall Reconstruction. PMID- 26761513 TI - Lengthening Temporalis Myoplasty for Single-Stage Smile Reconstruction in Children with Facial Paralysis. AB - BACKGROUND: Free muscle transfer for dynamic smile reanimation in facial paralysis is not always predictable with regard to cosmesis. Hospital stays range from 5 to 7 days. Prolonged operative times, longer hospital stays, and excessive cheek bulk are associated with free flap options. Lengthening temporalis myoplasty offers single-stage smile reanimation with theoretical advantages over free tissue transfer. METHODS: From 2012 to 2014, 18 lengthening temporalis myoplasties were performed in 14 children for smile reconstruction. A retrospective chart review was completed for demographics, operative times, length of hospital stay, and perioperative complications. RESULTS: Fourteen consecutive patients with complete facial paralysis were included. Four patients underwent single-stage bilateral reconstruction, and 10 underwent unilateral procedures. Diagnoses included Mobius syndrome (n = 5), posterior cranial fossa tumors (n = 4), posttraumatic (n = 2), hemifacial microsomia (n = 1), and idiopathic (n = 2). Average patient age was 10.1 years. Average operative time was 410 minutes (499 minutes for bilateral lengthening temporalis myoplasty and 373 for unilateral lengthening temporalis myoplasty). Average length of stay was 3.3 days (4.75 days for bilateral lengthening temporalis myoplasty and 2.8 for unilateral lengthening temporalis myoplasty). Nine patients required minor revisions. CONCLUSIONS: Lengthening temporalis myoplasty is a safe alternative to free tissue transfer for dynamic smile reconstruction in children with facial paralysis. Limited donor-site morbidity, shorter operative times, and shorter hospital stays are some benefits over free flap options. However, revisions are required frequently secondary to tendon avulsions and adhesions. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26761514 TI - Surgical Treatment of Facial Infantile Hemangiomas: An Analysis Based on Tumor Characteristics and Outcomes. AB - BACKGROUND: Surgical treatment of infantile hemangiomas may interfere with patient appearance. The use of an algorithm is essential to select candidates. The objective of this study was to evaluate outcomes of surgical treatment based on tumor characteristics. METHODS: Seventy-four patients were treated surgically between 1997 and 2010. Demographics, tumor characteristics, surgical approach, and outcomes were evaluated. RESULTS: The female-to-male ratio was 5.7:1. Mean age and follow-up were 24 years and 33 months, respectively. Surgery was elective in 83.8 percent and emergent in 16.2 percent of patients. Most frequent locations were lips, nose, eyelids, and cheeks. Surgery was performed during the proliferative phase in 43 patients (58.1 percent), and growth-related deformity was the main indication. No significant association between sex and the presence of complications or treatment indication was observed. Patients who underwent emergency procedures were younger (p = 0.0031) and had a higher incidence of evolutional complications (p = 0.012). Also, they were more frequently operated on during the proliferative phase (p = 0.011). Favorable outcome of surgical treatment was observed in both simple and complex cases for facial contour, volume reduction, and need for reoperation. The best candidates for elective surgery were patients with localized eyelid, nasal, or lip hemangiomas, presenting growth-related deformities during the proliferative phase. For patients undergoing emergency procedures, the best candidates were nonresponders to pharmacologic therapy with segmental periorbital hemangiomas, treated by partial resection. CONCLUSIONS: A profile of patients and their specific surgical approach was established. Satisfactory results could be achieved following the proposed algorithm. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26761515 TI - Applying to Integrated Plastic Surgery Residency Programs: Trends in the Past 5 Years of the Match. AB - BACKGROUND: The average integrated plastic surgery applicant spends over $6000 for interviews. The average program director reviews over 200 applications per cycle. It is important to make the application process efficient and cost effective for both applicants and programs. The authors analyzed recent trends and the literature in an attempt to increase the likelihood that applicants match, suggest means of reducing applicants' costs, and improve the process. METHODS: A cross-sectional study of the National Residency Matching Program Charting Outcomes and results and data for the years 2009 to 2014 was performed. Applicant profile elements were examined for differences between matched/unmatched U.S. senior medical students. In addition, a literature review was performed. RESULTS: The number of integrated plastic surgery positions rose from 69 in 2010 to 130 in 2014. Both matched and unmatched U.S. senior medical students have higher Step 2 scores, research and volunteer experiences, than 5 years ago. The likelihood of matching into an integrated plastic surgery residency has increased (2009, 52 percent; 2011, 44 percent; and 2014, 71 percent). Successful match rates were associated with Alpha Omega Alpha status and graduating from a top-40 ranked medical school (p < 0.05). Applicants with a lower number of ranked programs had increased match rates in 2014 than in previous years. Literature review revealed that program directors also value strong recommendation letters, publications, persistent work ethic ("grit"), away rotations, and an accurate curriculum vitae. CONCLUSIONS: Within the setting of increased applicant competitiveness, the authors recommend maximizing subjective qualities in order to differentiate themselves from a highly eligible applicant pool. In addition, applicants should diversify the types of programs at which they interview to maximize their chances of matching. PMID- 26761516 TI - Comments on Effects of nitroglycerin ointment on mastectomy flap necrosis in immediate breast reconstruction: a randomized controlled trial: Nitroglycerin ointment on mastectomy flap necrosis. PMID- 26761517 TI - Reply to: Comments on Effects of Nitroglycerin Ointment on Mastectomy Flap Necrosis in Immediate Breast Reconstruction: A Randomized Controlled Trial. PMID- 26761520 TI - Partner Disclosure of PrEP Use and Undetectable Viral Load on Geosocial Networking Apps: Frequency of Disclosure and Decisions About Condomless Sex. AB - BACKGROUND: Recent advances in biomedical prevention strategies, including pre exposure prophylaxis (PrEP) and achieving an undetectable viral load (UVL) among HIV-infected persons, show promise in curbing the rising incidence of HIV among men who have sex with men (MSM) in the United States. This mixed-methods study aimed to investigate the frequency with which MSM encounter potential sex partners on geosocial networking apps who disclose biomedical prevention use, and how MSM make decisions about condom use after these disclosures. METHOD: Participants were recruited through advertisements placed on a large geosocial networking app for MSM. A total of 668 and 727 participants, respectively, responded to questionnaires assessing partner disclosure of PrEP use and UVL. Each questionnaire included an open-ended item assessing reasons for condomless anal sex (CAS) with partners using biomedical prevention. RESULTS: Across both surveys, most respondents encountered potential sex partners who disclosed PrEP use or UVL, and the majority of those who met up with these partners engaged in CAS at least once. Qualitative analyses found that most participants who reported CAS did so after making a calculated risk about HIV transmission. We also describe a novel risk reduction strategy, "biomed-matching," or having CAS only when both individuals use PrEP or have UVL. We report serostatus differences in both quantitative and qualitative findings. CONCLUSIONS: Disclosure of PrEP use and UVL is not uncommon among MSM. Many MSM make accurate appraisals of the risks of CAS with biomedical prevention, and mobile apps may aid with disclosing biomedical prevention use. PMID- 26761519 TI - Impact of Hepatitis C Virus on the Circulating Levels of IL-7 in HIV-1 Coinfected Women. AB - OBJECTIVES: Hepatitis C virus (HCV) infection causes an alteration in T-cell maturation and activation in patients coinfected with human immunodeficiency virus (HIV). Because interleukin 7 (IL-7) is a major cytokine controlling T-cell homeostasis, we analyzed the potential influence of HCV coinfection on circulating IL-7 levels in HIV-infected women before and after highly active antiretroviral therapy (HAART). DESIGN AND METHODS: This prospective study included 56 HIV monoinfected, 55 HIV/HCV coinfected without HCV viremia, 132 HIV/HCV coinfected with HCV viremia, and 61 HIV/HCV-uninfected women for whom plasma levels of IL-7 were determined by enzyme-linked immunosorbent assay at 1 or more follow-up visits before and after HAART. Cross-sectional analyses of the associations between plasma IL-7 levels and HCV infection, demographic, clinical, and immunologic characteristics were evaluated using univariate and multivariate linear regression models before and after HAART. RESULTS: In multivariate models, IL-7 levels were significantly higher in coinfected HCV viremic women than in HIV monoinfected women (multiplicative effect = 1.48; 95% confidence interval: 1.01 to 2.16; P = 0.04) before HAART, but were similar between these two groups among women after HAART. In addition to HCV viremia, higher IL-7 levels were associated with older age (P = 0.02), lower CD4(+) T-cell count (P = 0.0007), and higher natural killer T-cell count (P = 0.02) in women before HAART. Among HAART-treated women, only lower CD4(+) T-cell count was significantly associated with IL-7 level (P = 0.006). CONCLUSIONS: Our data demonstrate that in HIV-infected women, circulating levels of IL-7 are strongly associated with CD4 T-cell depletion both before and after HAART. Our data also demonstrate that HCV viremia increases circulating IL-7 levels before HAART but not after HAART in coinfected women. This suggests that the effect of HCV on lymphopenia is abrogated by HAART. PMID- 26761518 TI - The Safety and Immunogenicity of an Interleukin-12-Enhanced Multiantigen DNA Vaccine Delivered by Electroporation for the Treatment of HIV-1 Infection. AB - BACKGROUND: Therapeutic vaccination is being studied in eradication and "functional cure" strategies for HIV-1. The Profectus Biosciences multiantigen (MAG) HIV-1 DNA vaccine encodes HIV-1 Gag/Pol, Nef/Tat/Vif, and Envelope, and interleukin-12 (IL-12) and is delivered by electroporation combined with intramuscular injection (IM-EP). METHODS: Sixty-two HIV-1-infected patients on antiretroviral therapy (plasma HIV-1 RNA levels <= 200 copies/mL; CD4(+) T-cell counts >= 500 cells/mm(3)) were randomly allocated 5:1 to receive vaccine or placebo. At weeks 0, 4, and 12, 4 consecutive cohorts received 3000 MUg HIV MAG pDNA with 0, 50, 250, or 1000 MUg of IL-12 pDNA by IM-EP. A fifth cohort received HIV MAG pDNA and 1000 MUg of IL-12 pDNA by standard IM injection. RESULTS: CD4(+) T cells expressing IL-2 in response to Gag and Pol and interferon-gamma responses to Gag, Pol, and Env increased from baseline to week 14 in the low-dose (50-MUg) IL-12 arm vs. placebo (P < 0.05; intracellular cytokine staining). The total increase in the IL-2-expressing CD4 T-cell responses to any antigen was also higher in the low-dose IL-12 arm vs. placebo (P = 0.04). Cytokine responses by CD8 T cells to HIV antigens were not increased in any vaccine arm relative to placebo. CONCLUSIONS: HIV-1 MAG/low-dose IL-12 DNA vaccine delivered by IM-EP augmented CD4(+) but not CD8(+) T-cell responses to multiple HIV-1 antigens. PMID- 26761521 TI - Viral Load and Risk of Tuberculosis in HIV Infection. PMID- 26761522 TI - Effects of the soil microbial community on mobile proportions and speciation of mercury (Hg) in contaminated soil. AB - The precise characterization of the behavior of individual microorganisms in the presence of increased mercury contents in soil is necessary for better elucidation of the fate of mercury in the soil environment. In our investigation, resistant bacterial strains isolated from two mercury contaminated soils, represented by Paenibacillus alginolyticus, Burkholderia glathei, Burkholderia sp., and Pseudomonas sp., were used. Two differently contaminated soils (0.5 and 7 mg kg(-1) total mercury) were chosen. Preliminary soil analysis showed the presence of methylmercury and phenylmercury with the higher soil mercury level. Modified rhizobox experiments were performed to assess the ability of mercury accumulating strains to deplete the mobile and mobilizable mercury portions in the soil by modification; microbial agar cultures were used rather than the plant root zone. A sequential extraction procedure was performed to release the following mercury fractions: water soluble, extracted in acidic conditions, bound to humic substances, elemental, and bound to complexes, HgS and residual. Inductively coupled plasma mass spectrometry (ICP-MS) and a single-purpose atomic absorption spectrometer (AMA-254) were applied for mercury determination in the samples and extracts. Gas chromatography coupled to atomic fluorescence spectrometry (GC-AFS) was used for the determination of organomercury compounds. The analysis of the microbial community at the end of the experiment showed a 42% abundance of Paenibacillus sp. followed by Acetivibrio sp., Brevibacillus sp., Cohnella sp., Lysinibacillus sp., and Clostridium sp. not exceeding 2% abundance. The results suggest importance of Paenibacillus sp. in Hg transformation processes. This genus should be tested for potential bioremediation use in further research. PMID- 26761523 TI - 9-Glutathionyl-6,7-dihydro-1-hydroxymethyl-5H-pyrrolizine Is the Major Pyrrolic Glutathione Conjugate of Retronecine-Type Pyrrolizidine Alkaloids in Liver Microsomes and in Rats. AB - Retronecine-, otonecine-, and heliotridine-type pyrrolizidine alkaloids (PAs) are all reported to be hepatotoxic. These PAs are suggested to be metabolized to the corresponding electrophilic dehydropyrrolizidine alkaloids (dehydro-PAs) and subsequently conjugated with macromolecules, such as glutathione (GSH). In the present study, a total of five glutathione conjugates, named M1-M5, were detected in rat and human liver microsomal incubations with three retrornecine-type PAs (isoline, retrorsine, or monocrotaline) in the presence of glutathione, and were chemically synthesized. M1 and M3 were unambiguously identified as a pair of epimers of 7-glutathionyl-6,7-dihydro-1-hydroxymethyl-5H-pyrrolizine (7-GSH-DHP), and M4 and M5 were epimers of 7,9-diglutathionyl-6,7-dihydro-1-hydroxymethyl-5H pyrrolizine (7,9-diGSH-DHP). M2, an extremely unstable conjugate, was proposed to be 9-glutathionyl-6,7-dihydro-1-hydroxymethyl-5H-pyrrolizine (9-GSH-DHP). It was the most abundant among the five GSH conjugates, and the finding corrects the mistake that 7-GSH-DHP is the predominant GSH conjugate derived from dehydro-PAs. Similar patterns in glutathione conjugate profile were observed in the bile of rats treated with the PAs. This is the first study to describe 9-GSH-DHP as a major pyrrolic GSH conjugate of retronecine-type PAs, providing insight into the interactions of dehydro-PAs with biomolecules. PMID- 26761525 TI - Effects of protein flexibility and active site water molecules on the prediction of sites of metabolism for cytochrome P450 2C19 substrates. AB - Structure-based prediction of sites of metabolism (SOMs) mediated by cytochrome P450s (CYPs) is of great interest in drug discovery and development. However, protein flexibility and active site water molecules remain a challenge for accurate SOM prediction. CYP2C19 is one of the major drug-metabolizing enzymes and has attracted considerable attention because of its polymorphism and capability of metabolizing ~7% clinically used drugs. In this study, we systematically evaluated the effects of protein flexibility and active site water molecules on SOM prediction for CYP2C19 substrates. Multiple conformational sampling techniques including GOLD flexible residues sampling, molecular dynamics (MD) and tCONCOORD side-chain sampling were adopted for assessing the influence of protein flexibility on SOM prediction. The prediction accuracy could be significantly improved when protein flexibility was considered using the tCONCOORD sampling method, which indicated that the side-chain conformation was important for accurate prediction. However, the inclusion of the crystallographic or MD-derived water molecule(s) does not necessarily improve the prediction accuracy. Finally, a combination of docking results with SMARTCyp was found to be able to increase the SOM prediction accuracy. PMID- 26761526 TI - RadioGraphics Approaches 35: The Year of the Author: Editor's Page. PMID- 26761528 TI - The Breast Imager's Approach to Nonmammary Masses at Breast and Axillary US: Imaging Technique, Clues to Origin, and Management. AB - Ultrasonography (US) of the breast and axilla is primarily used to evaluate a symptomatic patient or to further investigate findings identified with other imaging modalities. Breast imagers are generally familiar with US evaluation of level I, II, and III axillary lymph nodes in the diagnosis and staging of breast cancer. However, the axilla contains nonlymphatic tissue as well, including muscle, fat, and vascular and neurologic structures, and anatomically the breast lies on the chest wall. Therefore, lesions of nonmammary and non-lymph node origin in the axilla or chest wall are not infrequently encountered during US evaluation of the breast or axilla. In fact, such lesions may be the reason that the patient presents to the breast imaging department for evaluation. Understanding the anatomy of the chest wall and axilla and using a systematic US approach will help radiologists expedite accurate diagnosis, suggest optimal additional imaging, and streamline appropriate clinical referral. Key imaging features of nonmammary non-lymph node masses are highlighted, and case examples are provided to illustrate these features. Appropriate patient management is critical in these cases because referral to a breast surgeon may not be the best next step. Depending on institutional referral patterns, other subspecialty surgeons will be involved. Online supplemental material is available for this article. PMID- 26761524 TI - Chaperone-mediated autophagy regulates proliferation by targeting RND3 in gastric cancer. AB - LAMP2A is the key protein of chaperone-mediated autophagy (CMA), downregulation of LAMP2A leads to CMA blockade. CMA activation has been implicated in cancer growth, but the exact mechanisms are unclear. Elevated expression of LAMP2A was found in 8 kinds of tumors (n=747), suggesting that LAMP2A may have an important role in cancer progression. Unsurprisingly, LAMP2A knockdown in gastric cancer (GC) cells hindered proliferation, accompanied with altered expression of cell cycle-related proteins and accumulation of RND3/RhoE. Interactomic and KEGG analysis revealed that RND3 was a putative CMA substrate. Further study demonstrated that RND3 silencing could partly rescue the proliferation arrest induced by LAMP2A knockdown; RND3 was increased upon lysosome inhibition via both chemicals and LAMP2A-shRNA; Furthermore, RND3 could interact with CMA components HSPA8 and LAMP2A, and be engulfed by isolated lysosomes. Thus, constant degradation of RND3 by CMA is required to sustain rapid proliferation of GC cells. At last, the clinical significance of LAMP2A was explored in 593 gastric noncancerous lesions and 173 GC tissues, the results revealed that LAMP2A is a promising biomarker for GC early warning and prognosis of female GC patients. PMID- 26761530 TI - Dual-Energy CT: Spectrum of Thoracic Abnormalities. AB - Recent studies have demonstrated that dual-energy computed tomography (CT) can provide useful information in several chest-related clinical indications. Compared with single-energy CT, dual-energy CT of the chest is feasible with the use of a radiation-dose-neutral scanning protocol. This article highlights the different types of images that can be generated by using dual-energy CT protocols such as virtual monochromatic, virtual unenhanced (ie, water), and pulmonary blood volume (ie, iodine) images. The physical basis of dual-energy CT and material decomposition are explained. The advantages of the use of virtual low monochromatic images include reduced volume of intravenous contrast material and improved contrast resolution of images. The use of virtual high-monochromatic images can reduce beam hardening and contrast streak artifacts. The pulmonary blood volume images can help differentiate various parenchymal abnormalities, such as infarcts, atelectasis, and pneumonias, as well as airway abnormalities. The pulmonary blood volume images allow quantitative and qualitative assessment of iodine distribution. The estimation of iodine concentration (quantitative assessment) provides objective analysis of enhancement. The advantages of virtual unenhanced images include differentiation of calcifications, talc, and enhanced thoracic structures. Dual-energy CT has applications in oncologic imaging, including diagnosis of thoracic masses, treatment planning, and assessment of response to treatment. Understanding the concept of dual-energy CT and its clinical application in the chest are the goals of this article. PMID- 26761529 TI - Pre- and Postoperative Imaging of the Aortic Root. AB - Three-dimensional datasets acquired using computed tomography and magnetic resonance imaging are ideally suited for characterization of the aortic root. These modalities offer different advantages and limitations, which must be weighed according to the clinical context. This article provides an overview of current aortic root imaging, highlighting normal anatomy, pathologic conditions, imaging techniques, measurement thresholds, relevant surgical procedures, postoperative complications and potential imaging pitfalls. Patients with a range of clinical conditions are predisposed to aortic root disease, including Marfan syndrome, bicuspid aortic valve, vascular Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. Various surgical techniques may be used to repair the aortic root, including placement of a composite valve graft, such as the Bentall and Cabrol procedures; placement of an aortic root graft with preservation of the native valve, such as the Yacoub and David techniques; and implantation of a biologic graft, such as a homograft, autograft, or xenograft. Potential imaging pitfalls in the postoperative period include mimickers of pathologic processes such as felt pledgets, graft folds, and nonabsorbable hemostatic agents. Postoperative complications that may be encountered include pseudoaneurysms, infection, and dehiscence. Radiologists should be familiar with normal aortic root anatomy, surgical procedures, and postoperative complications, to accurately interpret pre and postoperative imaging performed for evaluation of the aortic root. Online supplemental material is available for this article. PMID- 26761531 TI - Primary Pulmonary Lymphoid Lesions: Radiologic and Pathologic Findings. AB - The pulmonary lymphoid system is complex and is composed of two compartments: the pulmonary lymphatics and the bronchus-associated lymphoid tissue (BALT). Additional important cells that function in the pulmonary lymphoid system include dendritic cells, Langherhans cells, macrophages, and plasma cells. An appreciation of the normal lymphoid anatomy of the lung as well as its immunology is helpful in understanding the radiologic and pathologic findings of the primary pulmonary lymphoid lesions. Primary lymphoid lesions of the lung arise from the BALT and are uncommon. However, they are increasingly recognized within the growing number of posttransplant patients as well as other patients who are receiving immunosuppressive therapies. Primary lymphoid lesions encompass a wide range of benign and malignant lesions. Benign lymphoid lesions of the lung include reactive lymphoid hyperplasia, follicular bronchiolitis, lymphoid interstitial pneumonia, and nodular lymphoid hyperplasia. Malignant lymphoid lesions of the lung include low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), other non-Hodgkin lymphomas, and Hodgkin lymphoma. Last, a miscellaneous group of primary lymphoid lesions includes lymphomatoid granulomatosis, posttransplant lymphoproliferative disorders, acquired immunodeficiency syndrome (AIDS)-related lymphoma, and intravascular lymphoma/lymphomatosis. These lesions are best evaluated with multidetector chest computed tomography. The radiologic findings of the primary lymphoid lesions are often nonspecific and are best interpreted in correlation with clinical data and pathologic findings. The purpose of this article is to review pulmonary lymphoid anatomy as well as the most common primary pulmonary lymphoid disorders. PMID- 26761532 TI - Imaging of Drug-induced Complications in the Gastrointestinal System. AB - Drug-induced injury commonly affects the gastrointestinal and hepatobiliary systems because of the mechanisms of absorption and metabolism. In pill esophagitis, injury is frequently related to direct contact with the esophageal mucosa, resulting in small superficial ulcers in the mid esophagus. Nonsteroidal anti-inflammatory drugs can lead to gastrointestinal tract ulcers and small bowel mucosal diaphragms (thin weblike strictures). Injury to the pancreatic and hepatobiliary systems can manifest as pancreatitis, acute or chronic hepatitis, cholestasis, or steatosis and steatohepatitis (which may progress to cirrhosis). Various drugs may also insult the hepatic vasculature, resulting in Budd-Chiari and sinusoidal obstructive syndromes. Focal lesions such as hepatic adenomas may develop after use of oral contraceptives or anabolic steroids. Ultrasonography, computed tomography, and magnetic resonance imaging can aid in diagnosis of drug induced injuries and often are necessary to exclude other causes. PMID- 26761533 TI - Esophagectomy and Gastric Pull-through Procedures: Surgical Techniques, Imaging Features, and Potential Complications. AB - Esophagectomy takes the center stage in the curative treatment of local and local regional esophageal cancer. It is a complex procedure with a high postoperative complication rate. When interpreting imaging studies, radiologists must understand the surgical techniques used and their potential complications. The most common surgical techniques are transthoracic esophagectomies, such as the Ivor Lewis and McKeown techniques, and transhiatal esophagectomy. Variations of these techniques include different choices of conduit (ie, stomach, colon, or jejunum) to serve in lieu of the resected esophagus. Postoperative imaging and accurate interpretation is vital in the aftercare of these patients. Chest radiographs, esophagrams, and computed tomographic images play an essential role in early identification of complications. Pulmonary complications and anastomotic leaks are the leading causes of postoperative morbidity and mortality secondary to esophagectomy. Other complications include technical and functional problems and delayed complications such as anastomotic strictures and disease recurrence. An esophagographic technique is described that is performed by using hand injection of contrast material into an indwelling nasogastric tube. Familiarity with the various types of esophagectomy and an understanding of possible complications are of utmost importance for radiologists and allow them to be key participants in the treatment of patients undergoing these complicated procedures. PMID- 26761534 TI - Radiologic-Pathologic Features to Discern Nonepithelial versus Epithelial Pancreatic Tumors. PMID- 26761535 TI - Nonepithelial Neoplasms of the Pancreas: Radiologic-Pathologic Correlation, Part 1--Benign Tumors: From the Radiologic Pathology Archives. AB - Solid and cystic pancreatic neoplasms are being recognized more frequently with increasing utilization and spatial resolution of modern imaging techniques. In addition to the more common primary pancreatic solid (ductal adenocarcinoma) and cystic neoplasms of epithelial origin, nonepithelial neoplasms of the pancreas may appear as well-defined solid or cystic neoplasms. Most of these lesions have characteristic imaging features, such as a well-defined border, which allows differentiation from ductal adenocarcinoma. Solid masses include neurofibroma, ganglioneuroma, leiomyoma, lipoma, and perivascular epithelioid cell tumor (PEComa). Schwannomas and desmoid tumors can be solid or cystic. Cystic tumors include mature cystic teratoma and lymphangioma. Lipoma, PEComa, and mature cystic teratoma can contain fat, and ganglioneuroma and mature cystic teratoma may contain calcification. Although these unusual benign neoplasms are rare, the radiologist should at least consider them in the differential diagnosis of well defined lesions of the pancreas. The goal of this comprehensive review is to improve understanding of these rare primary pancreatic mesenchymal tumors. PMID- 26761537 TI - Shoulder Arthroplasty, from Indications to Complications: What the Radiologist Needs to Know. AB - The replaced shoulder is increasingly encountered by the radiologist, both on a dedicated and incidental basis, in this era of the growing population of aging patients wishing to preserve their mobility and function. Knowledge of the normal biomechanics of the glenohumeral joint-particularly the function of the rotator cuff and the unique relationship of the humeral head to the glenoid-is essential for understanding the need for shoulder replacement and its subsequent complications, because the intent of shoulder arthroplasty is to approximate the normal joint as closely as possible. The most common indications for shoulder arthroplasty are osteoarthritis, inflammatory arthritis, proximal humerus fractures, irreparable rotator cuff tears, rotator cuff arthropathy, and avascular necrosis of the humeral head. Knowledge of the key imaging features of these indications helps facilitate a correlative understanding between the initial diagnosis and the choice of which type of arthroplasty is used-total shoulder arthroplasty, reverse total shoulder arthroplasty, or partial joint replacement (humeral head resurfacing arthroplasty or hemiarthroplasty). The preoperative requirements and usual postoperative appearance of each arthroplasty type are summarized, as well as the complications of shoulder arthroplasty, including those unique to or closely associated with each type of arthroplasty and those that can be encountered with any type of shoulder arthroplasty. PMID- 26761536 TI - Natural Language Processing Technologies in Radiology Research and Clinical Applications. AB - The migration of imaging reports to electronic medical record systems holds great potential in terms of advancing radiology research and practice by leveraging the large volume of data continuously being updated, integrated, and shared. However, there are significant challenges as well, largely due to the heterogeneity of how these data are formatted. Indeed, although there is movement toward structured reporting in radiology (ie, hierarchically itemized reporting with use of standardized terminology), the majority of radiology reports remain unstructured and use free-form language. To effectively "mine" these large datasets for hypothesis testing, a robust strategy for extracting the necessary information is needed. Manual extraction of information is a time-consuming and often unmanageable task. "Intelligent" search engines that instead rely on natural language processing (NLP), a computer-based approach to analyzing free-form text or speech, can be used to automate this data mining task. The overall goal of NLP is to translate natural human language into a structured format (ie, a fixed collection of elements), each with a standardized set of choices for its value, that is easily manipulated by computer programs to (among other things) order into subcategories or query for the presence or absence of a finding. The authors review the fundamentals of NLP and describe various techniques that constitute NLP in radiology, along with some key applications. PMID- 26761538 TI - US-guided Biopsy of Neck Lesions: The Head and Neck Neuroradiologist's Perspective. AB - Ultrasonographically (US) guided percutaneous biopsy of a neck lesion is a cost effective, safe, and diagnostically effective procedure without radiation exposure. The benefit of real-time visualization of the needle location allows for instantaneous maneuvering of the needle trajectory for safe and accurate tissue sampling with short procedural time. Effective US-guided biopsy requires technical experience, strong clinical acumen, and skillful biopsy technique. A neuroradiologist's knowledge of head and neck anatomy and pathology allows correlation with cross-sectional imaging and enhances the understanding of US imaging evaluation. Familiarity with a spectrum of neck surgeries and reconstructions and expertise in imaging evaluation of the treated neck are invaluable in accurate identification of the target for biopsy in patients with treatment-related altered anatomy using US guidance. After thyroid nodules, the common adult neck masses are lymphadenopathy, head and neck cancer, salivary neoplasms, nerve sheath tumors, and inflammatory and infectious pseudomasses. Diagnostic expertise in the imaging characteristics of these individual pathologic conditions and their differential diagnoses also play an important role in choosing the biopsy technique and in procuring an adequate sample for diagnosis, including material for ancillary laboratory testing. Using an anatomic zone approach, this article illustrates the practical considerations in patient selection, the methodical analysis of preprocedure cross-sectional imaging and its correlation with real-time US evaluation, general principles for optimizing US instrumentation, and biopsy technique. In skillful hands, the versatility and portability of US make it the valuable modality for histologic sampling of superficial head and neck lesions. Online supplemental material is available for this article. PMID- 26761539 TI - Contrast-enhanced Reformatted MR Images for Preoperative Assessment of the Bridging Veins of the Skull Base. AB - Magnetic resonance (MR) venography and computed tomographic (CT) venography are suited for displaying the convexity veins that drain the medial and lateral surfaces of the brain hemispheres. However, such is not the case for the bridging veins of the skull base. Technical factors prevent contrast material-enhanced MR or CT images obtained in standard axial, coronal, and sagittal planes from fully displaying the curved pathways of these clinically important venous structures. This limitation can be overcome by using a reconstruction technique that depicts these venous structures and their interconnections. Curved and multiplanar reformatted images that distill the important venous features often require knowledgeable manipulation of source images by an operator who is familiar with numerous venous variants and their surgical implications. The normal anatomy of the draining veins is detailed-anatomy that radiologists must master before they can show the surgeon the important venous anatomy that is often missing at standard imaging; this information will foster better communication between radiologists and their surgical colleagues. As a practical matter, the skull base veins are arbitrarily subdivided into those that are at greatest risk with the pterional approach and the subtemporal approach, respectively. These approaches can be expanded to define connections between the superficial venous system and the other valveless venous networks that drain the deep portions of the cerebral hemisphere, the scalp, face, muscles of the neck, diploe of the skull, and meninges. As radiologists gain experience, their image interpretations should mature beyond simple analysis of the primary hemodynamic changes induced by intraoperative sacrifice or injury. PMID- 26761540 TI - MIBG in Neuroblastoma Diagnostic Imaging and Therapy. AB - Neuroblastoma is a common malignancy observed in infants and young children. It has a varied prognosis, ranging from spontaneous regression to aggressive metastatic tumors with fatal outcomes despite multimodality therapy. Patients are divided into risk groups on the basis of age, stage, and biologic tumor factors. Multiple clinical and imaging tests are needed for accurate patient assessment. Iodine 123 ((123)I) metaiodobenzylguanidine (MIBG) is the first-line functional imaging agent used in neuroblastoma imaging. MIBG uptake is seen in 90% of neuroblastomas, identifying both the primary tumor and sites of metastatic disease. The addition of single photon emission computed tomography (SPECT) and SPECT/computed tomography to (123)I-MIBG planar images can improve identification and characterization of sites of uptake. During scan interpretation, use of MIBG semiquantitative scoring systems improves description of disease extent and distribution and may be helpful in defining prognosis. Therapeutic use of MIBG labeled with iodine 131 ((131)I) is being investigated as part of research trials, both as a single agent and in conjunction with other therapies. (131)I MIBG therapy has been studied in patients with newly diagnosed neuroblastoma and those with relapsed disease. Development and implementation of an institutional (131)I-MIBG therapy research program requires extensive preparation with a focus on radiation protection. PMID- 26761541 TI - 11C-Choline PET/CT in Recurrent Prostate Cancer and Nonprostatic Neoplastic Processes. AB - Choline positron emission tomography (PET)/computed tomography (CT), with both carbon 11 ((11)C) choline and fluorine 18 ((18)F) choline, is an increasingly used tool in the evaluation of patients with biochemically recurrent prostate cancer. It has allowed detection and localization of locally recurrent and metastatic lesions that were difficult or impossible to identify using more conventional modalities. Many of the patients followed for their prostate cancer are elderly and have a higher rate of nonprostate cancer lesions or malignancies. As our experience with choline PET/CT has grown, it has become apparent that many of these nonprostate cancer processes, both benign and malignant, can be detected. Invasive thymoma, renal cell carcinoma, papillary thyroid carcinoma, and parathyroid adenoma are a few of the processes that have been incidentally detected with (11)C-choline PET/CT at our institution and have significantly altered subsequent clinical management of the patient. Although most of the secondary lesions are detected due to their increased (11)C-choline avidity, several have been detected due to their decreased or lack of avidity in the background of a highly avid organ. For instance, large liver masses that are relatively non-choline-avid create large activity defects in the otherwise highly active liver. Familiarity with normal (11)C-choline physiologic activity, the most common prostate metastatic patterns, and imaging characteristics of secondary lesions is essential for the detection and correct diagnosis of such lesions so that proper follow-up and management can be recommended. PMID- 26761542 TI - Malignancies with Low Fluorodeoxyglucose Uptake at PET/CT: Pitfalls and Prognostic Importance: Resident and Fellow Education Feature. PMID- 26761543 TI - Blast Injuries: From Improvised Explosive Device Blasts to the Boston Marathon Bombing. AB - Although most trauma centers have experience with the imaging and management of gunshot wounds, in most regions blast wounds such as the ones encountered in terrorist attacks with the use of improvised explosive devices (IEDs) are infrequently encountered outside the battlefield. As global terrorism becomes a greater concern, it is important that radiologists, particularly those working in urban trauma centers, be aware of the mechanisms of injury and the spectrum of primary, secondary, tertiary, and quaternary blast injury patterns. Primary blast injuries are caused by barotrauma from the initial increased pressure of the explosive detonation and the rarefaction of the atmosphere immediately afterward. Secondary blast injuries are caused by debris carried by the blast wind and most often result in penetrating trauma from small shrapnel. Tertiary blast injuries are caused by the physical displacement of the victim and the wide variety of blunt or penetrating trauma sustained as a result of the patient impacting immovable objects such as surrounding cars, walls, or fences. Quaternary blast injuries include all other injuries, such as burns, crush injuries, and inhalational injuries. Radiography is considered the initial imaging modality for assessment of shrapnel and fractures. Computed tomography is the optimal test to assess penetrating chest, abdominal, and head trauma. The mechanism of blast injuries and the imaging experience of the victims of the Boston Marathon bombing are detailed, as well as musculoskeletal, neurologic, gastrointestinal, and pulmonary injury patterns from blast injuries. PMID- 26761544 TI - Teaching Imaging Metrics to Radiology Trainees. PMID- 26761545 TI - Evaluation of Xpert HIV-1 Qual assay for resolution of HIV-1 infection in samples with negative or indeterminate Geenius HIV-1/2 results. AB - BACKGROUND: Diagnosis of HIV infection is a multistage algorithm. Following screening with 4(th) generation combination immunoassay, confirmation of HIV infection is performed with an antibody assay that differentiates HIV-1 from HIV 2 infection. In the newly updated algorithm, samples that are nonreactive or indeterminate in the differentiation assay are to be tested with an HIV-1 nucleic acid amplification (NAAT) test for resolution. Xpert HIV-1 Qual is a new NAAT assay approved for the identification of HIV infection in whole and dried blood. OBJECTIVES: To assess the performance of Xpert HIV-1 Qual supplementary assay in resolving the clinical status of serum samples reactive by 4(th) generation immunoassays and indeterminate or negative by Geenius HIV-1/2 confirmatory assay. STUDY DESIGN: In a retrospective study, samples from 97 individuals for whom the true HIV-1 status was already known (by follow-up samples) and which were negative or indeterminate by HIV-1/2 Geenius assay were tested with Xpert Qual HIV-1 assay. RESULTS: Xpert Qual assay correctly classified all 97 samples from HIV-1 positive (n=49) and negative (n=48) individuals. The sensitivity and specificity of Xpert Qual when using the true HIV status as a reference were 100% (92.7-100% at 95% confidence interval [CI] and 92.6-100% at 95% CI, respectively). CONCLUSIONS: Applying Xpert Qual HIV-1 assay in the new HIV multi stage diagnostic algorithm correctly classified 100% of HIV-1 infections including 49 from HIV-1 carriers who have not yet seroconverted. With this assay the total time required for acute HIV diagnosis could be significantly reduced. PMID- 26761546 TI - Prostate cancer: what is the right message? PMID- 26761547 TI - Suspected melanoma only when the lesion is greater than 6mm may harm patients. AB - OBJECTIVE: To analyze the distribution of larger diameter in the pathological report of cutaneous melanoma patients. METHODS: Data were obtained from patients seen from 1994 to 2015. Date, sex, age, maximum diameter, histological subtype, primary site, microscopic thickness, mitoses, ulceration, vertical growth phase, and regression were the variables studied. This study was approved by the National Ethics Committee - Brazil Platform. Patients were grouped into smaller diameter (<=6mm) and larger diameter (>6mm). The statistical analysis used the chi2test (p<0.05). RESULTS: Of the 292 patients analyzed, 123 were seen between 1994 and 2004, and 169 between 2005 and 2015; in that, 151 women and 141 men, mean age of 52 years. The diameters ranged from 2 to 76mm (mean of 14mm), 81 patients with smaller diameter (<=6mm) and 211 with larger diameter (>6mm). Out of 81 patients with smaller diameter, 29 had invasive melanoma, while 179 of the 211 with larger diameter were invasive. A difference was observed in frequency of vertical growth phase. CONCLUSION: Pigmented skin lesions with diameter smaller than 6mm should not be an excluding factor for biopsies, especially when patients present risk of developing skin cancer. PMID- 26761548 TI - Glycomics expression analysis of sulfated glycosaminoglycans of human colorectal cancer tissues and non-neoplastic mucosa by electrospray ionization mass spectrometry. AB - OBJECTIVE: To determine the presence of glycosaminoglycans in the extracellular matrix of connective tissue from neoplastic and non-neoplastic colorectal tissues, since it has a central role in tumor development and progression. METHODS: Tissue samples from neoplastic and non-neoplastic colorectal tissues were obtained from 64 operated patients who had colorectal carcinoma with no distant metastases. Expressions of heparan sulphate, chondroitin sulphate, dermatan sulphate and their fragments were analyzed by electrospray ionization mass spectrometry, with the technique for extraction and quantification of glycosaminoglycans after proteolysis and electrophoresis. The statistical analysis included mean, standard deviation, and Student'st test. RESULTS: The glycosaminoglycans extracted from colorectal tissue showed three electrophoretic bands in agarose gel. Electrospray ionization mass spectrometry showed characteristic disaccharide fragments from glycosaminoglycans, indicating their structural characterization in the tissues analyzed. Some peaks in the electrospray ionization mass spectrometry were not characterized as fragments of sugars, indicating the presence of fragments of the protein structure of proteoglycans generated during the glycosaminoglycan purification. The average amount of chondroitin and dermatan increased in the neoplastic tissue compared to normal tissue (p=0.01). On the other hand, the average amount of heparan decreased in the neoplastic tissue compared to normal tissue (p= 0.03). CONCLUSION: The method allowed the determination of the glycosaminoglycans structural profile in colorectal tissue from neoplastic and non-neoplastic colorectal tissue. Neoplastic tissues showed greater amounts of chondroitin sulphate and dermatan sulphate compared to non-neoplastic tissues, while heparan sulphate was decreased in neoplastic tissues. PMID- 26761549 TI - Reference breast temperature: proposal of an equation. AB - OBJECTIVE: To develop an equation to estimate the breast reference temperature according to the variation of room and core body temperatures. METHODS: Four asymptomatic women were evaluated for three consecutive menstrual cycles. Using thermography, the temperature of breasts and eyes was measured as indirect reference of core body and room temperatures. To analyze the thermal behavior of the breasts during the cycle, the core body and room temperatures were normalized by means of a mathematical equation. RESULTS: We performed 180 observations and the core temperature had the highest correlation with the breast temperature, followed by room temperature. The proposed prediction model could explain 45.3% of the breast temperature variation, with variable room temperature variable; it can be accepted as a way to estimate the reference breast temperature at different room temperatures. CONCLUSION: The average breast temperature in healthy women had a direct relation with the core and room temperature and can be estimated mathematically. It is suggested that an equation could be used in clinical practice to estimate the normal breast reference temperature in young women, regardless of the day of the cycle, therefore assisting in evaluation of anatomical studies. PMID- 26761550 TI - Retinal diseases in a reference center from a Western Amazon capital city. AB - OBJECTIVE: To describe retinal diseases found in patients who were waiting for treatment at a tertiary care hospital in Rio Branco, Acre, Brazil. METHODS: Patients underwent slit lamp biomicroscopy, dilated fundus exam and ocular ultrasound. Patients were classified according to phakic status and retinal disease of the most severely affected eye. RESULTS: A total of 138 patients were examined. The mean age was 51.3 years. Diabetes was present in 35.3% and hypertension in 45.4% of these patients. Cataract was found in 23.2% of patients, in at least one eye. Retinal examination was possible in 129 patients. The main retinal diseases identified were rhegmatogenous retinal detachment (n=23; 17.8%) and diabetic retinopathy (n=32; 24.8%). Out of 40 patients evaluated due to diabetes, 13 (32.5%) had absent or mild forms of diabetic retinopathy and did not need further treatment, only observation. CONCLUSION: Diabetic retinopathy was the main retinal disease in this population. It is an avoidable cause of blindness and can be remotely evaluated, in its initial stages, by telemedicine strategies. In remote Brazilian areas, telemedicine may be an important tool for retinal diseases diagnosis and follow-up. PMID- 26761551 TI - Analisys of pectoralis major tendon in weightlifting athletes using ultrasonography and elastography. AB - OBJECTIVE: To evaluate tendinopathy of the pectoralis major muscle in weightlifting athletes using ultrasound and elastography. METHODS: This study included 20 patients, 10 with rupture of the pectoralis major muscle and 10 control patients. We evaluated pectoralis major muscle contralateral tendon with ultrasonographic and elastography examinations. The ultrasonographic examinations were performed using a high-resolution B mode ultrasound device. The elastography evaluation was classified into three patterns: (A), if stiff (more than 50% area with blue staining); (B), if intermediate (more than 50% green); and (C), if softened (more than 50% red). RESULTS: Patients' mean age was 33+/-5.3 years. The presence of tendinous injury measured by ultrasound had a significant different (p=0.0055), because 80% of cases had tendinous injury versus 10% in the Control Group. No significant differences were seen between groups related with change in elastography (p=0.1409). CONCLUSION: Long-term bodybuilders had ultrasound image with more tendinous injury than those in Control Group. There was no statistical significance regarding change in tendon elasticity compared with Control Group. PMID- 26761552 TI - Differential diagnosis of dental fluorosis made by undergraduate dental students. AB - OBJECTIVE: To check knowledge of undergraduate dental students to make diagnosis of dental fluorosis with varying degrees of severity and choose its appropriate treatment. METHODS: Data were collected using a semi-structured questionnaire addressing knowledge of undergraduates based on ten images of mouths presenting enamel changes. RESULTS: Only three images were correctly diagnosed by most undergraduates; the major difficulty was in establishing dental fluorosis severity degree. CONCLUSION: Despite much information about fluorosis conveyed during the Dentistry training, as defined in the course syllabus, a significant part of the students was not able to differentiate it from other lesions; they did not demonstrate expertise as to defining severity of fluorosis and indications for treatment, and could not make the correct diagnosis of enamel surface changes. PMID- 26761553 TI - Bone health in cerebral palsy and introduction of a novel therapy. AB - OBJECTIVE: To assess the bone health status of children with cerebral palsy and the therapeutic effect of denosumab in a subgroup of children with cerebral palsy and decreased bone mass. METHODS: Children with cerebral palsy were evaluated according to their motor disability score (classification system gross motor functions III to V), bone density and bone turnover markers. Dual X-ray energy absorption was used to measure the lumbar spine, and total body, except the head. Thereafter a group of children with cerebral palsy and osteoporosis was treated with denosumab, a fully human monoclonal antibody. Bone turnover markers were measured before and three months after treatment. RESULTS: Reduction in bone mineral density was observed, particularly in children with greater impairment evaluated by the motor score. Decreased bone turnover markers were found in a selected group of children three months after exposure to denosumab. CONCLUSION: Bone loss was present in children with significant impairment of motor function, as well as decreased serum levels of bone resorption markers with new forms. PMID- 26761554 TI - Sensitization by subcutaneous route is superior to intraperitoneal route in induction of asthma by house dust mite in a murine mode. AB - OBJECTIVE: To develop a new experimental model of chronic allergic pulmonary disease induced by house dust mite, with marked production of specific immunoglobulin E (IgE), eosinophilic inflammatory infiltrate in the airways and remodeling, comparing two different routes of sensitization. METHODS: The protocol lasted 30 days. BALB/c mice were divided into six groups and were sensitized subcutaneously or intraperitoneally with saline (negative control), Dermatophagoides pteronyssinus (Der p) 50 or 500 mcg in three injections. Subsequently they underwent intranasal challenge with Der p or saline for 7 days and were sacrificed 24 hours after the last challenge. We evaluated the titration of specific IgE anti-Der p, eosinophilic density in peribronchovascular space and airway remodeling. RESULTS: Both animals sensitized intraperitoneally and subcutaneously produced specific IgE anti-Der p. Peribronchovascular eosinophilia increased only in mice receiving lower doses of Der p. However, only the group sensitized with Der p 50 mcg through subcutaneously route showed significant airway remodeling. CONCLUSION: In this murine model of asthma, both pathways of sensitization led to the production of specific IgE and eosinophilia in the airways. However, only the subcutaneously route was able to induce remodeling. Furthermore, lower doses of Der p used in sensitization were better than higher ones, suggesting immune tolerance. Further studies are required to evaluate the efficacy of this model in the development of bronchial hyperresponsiveness, but it can already be replicated in experiments to create new therapeutic drugs or immunotherapeutic strategies. PMID- 26761555 TI - Histological analysis of the repair of dural lesions with silicone mesh in rats subjected to experimental lesions. AB - OBJECTIVE: To evaluate inflammatory reaction, fibrosis and neovascularization in dural repairs in Wistar rats using four techniques: simple suture, bovine collagen membrane, silicon mesh and silicon mesh with suture. METHODS: Thirty Wistar rats were randomized in five groups: the first was the control group, submitted to dural tear only. The others underwent durotomy and simple suture, bovine collagen membrane, silicon mesh and silicon mesh with suture. Animals were euthanized and the spine was submitted to histological evaluation with a score system (ranging from zero to 3) for inflammation, neovascularization and fibrosis. RESULTS: Fibrosis was significantly different between simple suture and silicon mesh (p=0.005) and between simple suture and mesh with suture (p=0.015), showing that fibrosis is more intense when a foreign body is used in the repair. Bovine membrane was significantly different from mesh plus suture (p=0.011) regarding vascularization. Inflammation was significantly different between simple suture and bovine collagen membrane. CONCLUSION: Silicon mesh, compared to other commercial products available, is a possible alternative for dural repair. More studies are necessary to confirm these findings. PMID- 26761556 TI - Effects of physical exercise on the cartilage of ovariectomized rats submitted to immobilization. AB - OBJECTIVE: To analyze the effects of physical exercise on cartilage histomorphometry in osteoporosis-induced rats subjected to immobilization. METHODS: We used 36 Wistar rats that were separated into six groups: G1, G2 and G3 submitted to pseudo-oophorectomy, and G4, G5 and G6 submitted to oophorectomy. After 60 days at rest, G2, G3, G5 and G6 had the right hind limbs immobilized for 15 days, followed by the same period in remobilization, being free in the box to G2 and G5, and climb ladder to G3 and G6. At the end of the experiment, the rats were euthanized, their tibias bilaterally removed and submitted to histological routine. RESULTS: There was significant increase in thickness of the articular cartilage (F(5;29)=13.88; p<0.0001) and epiphyseal plate (F(5;29)=14.72; p<0.0001) as the number of chondrocytes (F(5;29)=5.11; p=0.0021) in ovariectomized rats, immobilized and submitted to exercise. In the morphological analysis, degeneration of articular cartilage with subchondral bone exposure, loss of cellular organization, discontinuity of tidemark, presence of cracks and flocculation in ovariectomized, immobilized and free remobilization rats were found. In ovariectomized and immobilized remobilization ladder rats, signs of repair of the cartilaginous structures in the presence of clones, pannus, subcortical blood vessel invasion in the calcified zone, increasing the amount of isogenous groups and thickness of the calcified zone were observed. CONCLUSION: Exercise climb ladder was effective in cartilaginous tissue recovery process damaged by immobilization, in model of osteoporosis by ovariectomy in rats. PMID- 26761557 TI - An assessment of the quality indicators of operative and non-operative times in a public university hospital. AB - OBJECTIVE: To assess the operative time indicators in a public university hospital. METHODS: A descriptive cross-sectional study was conducted using data from operating room database. The sample was obtained from January 2011 to January 2012. The operations performed in sequence in the same operating room, between 7:00 am and 5:00 pm, elective or emergency, were included. The procedures with incomplete data in the system were excluded, as well as the operations performed after 5:00 pm or on weekends or holidays. RESULTS: We measured the operative and non-operative time of 8,420 operations. The operative time (mean and standard deviation) of anesthesias and operations were 177.6 +/- 110 and 129.8 +/- 97.1 minutes, respectively. The total time of the patient in operative room (mean and standard deviation) was 196.8 +/- 113.2. The non-operative time, e.g., between the arrival of the patient and the onset of anesthesia was 14.3 +/- 17.3 minutes. The time to set the next patient in operating room was 119.8 +/- 79.6 minutes. Our total non-operative time was 155 minutes. CONCLUSION: Delays frequently occurred in our operating room and had a major effect on patient flow and resource utilization. The non-operative time was longer than the operative time. It is possible to increase the operating room capacity by management and training of the professionals involved. The indicators provided a tool to improve operating room efficiency. PMID- 26761558 TI - Application of preventive medicine resources in the health insurance system. AB - OBJECTIVE: To identify the financial resources and investments provided for preventive medicine programs by health insurance companies of all kinds. METHODS: Data were collected from 30 large health insurance companies, with over 100 thousand individuals recorded, and registered at the Agencia Nacional de Saude Suplementar. RESULTS: It was possible to identify the percentage of participants of the programs in relation to the total number of beneficiaries of the health insurance companies, the prevention and promotion actions held in preventive medicine programs, the inclusion criteria for the programs, as well as the evaluation of human resources and organizational structure of the preventive medicine programs. CONCLUSION: Most of the respondents (46.7%) invested more than US$ 50,000.00 in preventive medicine program, while 26.7% invested more than US$ 500,000.00. The remaining, about 20%, invested less than US$ 50,000.00, and 3.3% did not report the value applied. PMID- 26761559 TI - Spermatogonial stem cells as a therapeutic alternative for fertility preservation of prepubertal boys. AB - Spermatogonial stem cells, which exist in the testicles since birth, are progenitors cells of male gametes. These cells are critical for the process of spermatogenesis, and not able to produce mature sperm cells before puberty due to their dependency of hormonal stimuli. This characteristic of the reproductive system limits the preservation of fertility only to males who are able to produce an ejaculate. This fact puts some light on the increase in survival rates of childhood cancer over the past decades because of improvements in the diagnosis and effective treatment in pediatric cancer patients. Therefore, we highlight one of the most important challenges concerning male fertility preservation that is the toxic effect of cancer therapy on reproductive function, especially the spermatogenesis. Currently, the experimental alternative for fertility preservation of prepubertal boys is the testicular tissue cryopreservationfor, for future isolation and spermatogonial stem cells transplantation, in order to restore the spermatogenesis. We present a brief review on isolation, characterization and culture conditions for the in vitro proliferation of spermatogonial stem cells, as well as the future perspectives as an alternative for fertility preservation in prepubertal boys. The possibility of restoring male fertility constitutes a research tool with an huge potential in basic and applied science. The development of these techniques may be a hope for the future of fertility preservation in cases that no other options exist, e.g, pediatric cancer patients. PMID- 26761560 TI - Bedside echocardiography in critically ill patients. AB - The echocardiography has become a vital tool in the diagnosis of critically ill patients. The use of echocardiography by intensivists has been increasing since the 1990's. This tool has become a common procedure for the cardiovascular assessment of critically ill patients, especially because it is non-invasive and can be applied in fast and guided manner at the bedside. Physicians with basic training in echocardiography, both from intensive care unit or emergency department, can assess the left ventricle function properly with good accuracy compared with assessment made by cardiologists. The change of treatment approach based on echocardiographic findings is commonly seen after examination of unstable patient. This brief review focuses on growing importance of echocardiography as an useful tool for management of critically ill patients in the intensive care setting along with the cardiac output assessment using this resource. PMID- 26761561 TI - Physical exercise for functional capacity, blood immune function, fatigue, and quality of life in high-risk prostate cancer patients during radiotherapy: a prospective, randomized clinical study. AB - BACKGROUND: During radiotherapy (RT), prostate cancer (PCa) patients may report cancer related fatigue (CRF), which impairs functional capacity, psychological status, and quality of life (QoL). RT can induce cytokine responses that could play a role in mediating radiation toxicity by increasing inflammation. While it is known that physical exercise plays an important anti-inflammatory role in healthy adults, its specific anti-inflammatory effects in PCa patients with CRF have not yet been determined. AIM: Previous studies have shown that physical exercise in cancer patients undergoing RT improves cardiac fitness, muscle strength, and QoL, however it is still unknown how physical exercise affects inflammation and its specific consequences in PCa patients. Therefore, the purpose of this trial was to examine the effect of supervised physical exercise on inflammatory blood markers, as well as the relationship of these parameters with functional capacity, fatigue, and QoL in high-risk PCa patients undergoing RT. DESIGN: This was a prospective, two-arm randomized controlled clinical trial. SETTING: The study was performed in our outpatients center. POPULATION: Fifty four high-risk PCa men were randomly allocated to two groups prior to undergoing RT. METHODS: Twenty-seven patients performed supervised, moderate-intensity physical exercise (exercise group; EG) and the other 27 formed a control group that carried out normal daily physical activity (usual group; UG). The following parameters were assessed before and after RT: functional capacity, changes in blood count variables and production of pro-inflammatory cytokines (interleukin [IL]-1beta, IL-6, tumor necrosis factor [TNF]-alpha), fatigue, and QoL (using FACT-F score and EORTC questionnaires). RESULTS: No significant differences existed between the study groups at baseline assessment. After RT, there was a significant improvement in functional capacity (P<0.05) and a decrease in pro inflammatory cytokine levels (P>0.05) and fatigue (P<0.05) in the EG compared to the UG. Fatigue level was significantly higher in the UG (F[2.126]; P<0.05) after RT than before. Physical exercise had no effect on the correlation between inflammatory blood markers and functional capacity and fatigue scores provided by study participants. CONCLUSIONS: Regular, moderate-intensity physical exercise improves functional capacity, decreases the production of inflammatory markers and fatigue, and has a positive influence on QoL in high-risk PCa patients during RT. CLINICAL REHABILITATION IMPACT: This is one of the first studies to examine the effects of supervised exercise training on pro-inflammatory cytokine levels during RT in PCa patients by measuring functional capacity, fatigue, and QoL. PMID- 26761562 TI - Improving executive function deficits by playing interactive video-games: secondary analysis of a randomized controlled trial for individuals with chronic stroke. AB - BACKGROUND: Executive function deficits negatively impact independence and participation in everyday life of individuals with chronic stroke. Therefore, it is important to explore therapeutic interventions to improve executive functions. AIM: The aim of this study was to determine the effectiveness of a 3-month interactive video-game group intervention compared to a traditional motor group intervention for improving executive functions in individuals with chronic stroke. DESIGN: This study is a secondary analysis of a single-blind randomized controlled trial for improving factors related to physical activity of individuals with chronic stroke. Assessments were administered pre and post the intervention and at 3-month follow-up by assessors blind to treatment allocation. METHODS: Thirty-nine individuals with chronic stroke with executive function deficits participated in an interactive video-game group intervention (N.=20) or a traditional group intervention (N.=19). The intervention included two 1-hour group sessions per week for three months, either playing video-games or performing traditional exercises/activities. Executive function deficits were assessed using The Trail Making Test (Parts A and B) and by two performance-based assessments; the Bill Paying Task from the Executive Function Performance Test (EFPT) and the Executive Function Route-Finding Task (EFRT). RESULTS: Following intervention, scores for the Bill Paying Task (EFPT) decreased by 27.5% and 36.6% for the participants in the video-game and traditional intervention, respectively (F=17.3, P<0.000) and continued to decrease in the video-game group with small effect sizes. Effect size was small to medium for the TMT-B (F=0.003, P=0.954) and EFRT (F=1.2, P=0.28), without any statistical significance difference. CONCLUSIONS: Interactive video-games provide combined cognitive-motor stimulation and therefore have potential to improve executive functioning of individuals with chronic stroke. Further research is needed. CLINICAL REHABILITATION IMPACT: These findings highlight the potential of utilizing interactive video-games in a small group for keeping these individuals active, while maintaining and improving executive functioning especially for individuals with chronic stroke, who have completed their formal rehabilitation. PMID- 26761563 TI - Does hemiplegic shoulder pain share clinical and sensory characteristics with central neuropathic pain? A comparative study. AB - BACKGROUND: Hemiplegic shoulder pain (HSP) is a common poststroke complication and is considered to be a chronic pain syndrome. It is negatively correlated with the functional recovery of the affected arm and the quality of life of the individual. It also leads to a longer length of stay in rehabilitation. Today, there is no consensus as to the underlying mechanism causing HSP, making the syndrome difficult to treat. AIM: The aim of this study was to compare the clinical and sensory profile of individuals with HSP to that of individuals with established central neuropathic pain (CNP) in order to identify common features and the presence of neuropathic components in HSP. DESIGN: Cross sectional controlled study. SETTINGS: Outpatient rehabilitation clinics. POPULATION: Sixteen chronic HSP patients and 18 chronic CNP patients with spinal cord injury (SCI-CNP). METHODS: The chronic pain characteristics, thresholds of thermal and tactile sensations and presence of pathological sensations were compared between groups, and between painful and pain free body regions within groups. Correlations were calculated between HSP intensity and sensory and musculoskeletal characteristics. RESULTS: Patients with HSP and patients with SCI CNP had similar decrease of thermal sensibility in the painful compared to intact body regions and both groups presented similar rates of pathological sensations in painful regions. HSP and SCI-CNP differed however, in the quality of pain and aggravating factors. Significant correlations were found between HSP intensity and heat-pain threshold, presence of subluxation and spasticity. CONCLUSIONS: The similarities between HSP and SCI-CNP and the altered spinothalamic function and sensitization suggest that HSP has neuropathic components in its mechanism. Nevertheless, the unique features of HSP point towards additional possible mechanisms. CLINICAL REHABILITATION IMPACT: The use of specific therapy options for neuropathic pain should be considered when treating patients with HSP. PMID- 26761564 TI - Monolayer MoS2-Graphene Hybrid Aerogels with Controllable Porosity for Lithium Ion Batteries with High Reversible Capacity. AB - Monolayer MoS2 nanosheets (NSs) are promising anode materials for lithium-ion batteries because all redox reactions take place at the surface without lithium ion diffusion limit. However, the expanded band gap of monolayer MoS2 NSs (~1.8 eV) compared to their bulk counterparts (~1.2 eV) and restacking tendency due to the van der Waals forces result in poor electron transfer and loss of the structure advantage. Here, a facile approach is developed to fabricate the MoS2 graphene aerogels comprising controlled three-dimensional (3D) porous architectures constructed by interconnected monolayer MoS2-graphene hybrid NSs. The robust 3D architectures combining with the monolayer feature of the hybrid NSs not only prevent the MoS2 and graphene NSs from restacking, but also enable fast electrode kinetics due to the surface reaction mechanism and highly conductive graphene matrix. As a consequence, the 3D porous monolayer MoS2 graphene composite aerogels exhibit a large reversible capacity up to 1200 mAh g( 1) as well as outstanding cycling stability and rate performance, making them promising as advanced anode materials for lithium-ion batteries. PMID- 26761578 TI - Molecular design and downstream processing of turoctocog alfa (NovoEight), a B domain truncated factor VIII molecule. AB - Turoctocog alfa (NovoEight) is a third-generation recombinant factor VIII (rFVIII) with a truncated B-domain that is manufactured in Chinese hamster ovary cells. No human or animal-derived materials are used in the process. The aim of this study is to describe the molecular design and purification process for turoctocog alfa. A five-step purification process is applied to turoctocog alfa: protein capture on mixed-mode resin; immunoaffinity chromatography using a unique, recombinantly produced anti-FVIII mAb; anion exchange chromatography; nanofiltration and size exclusion chromatography. This process enabled reduction of impurities such as host cell proteins (HCPs) and high molecular weight proteins (HMWPs) to a very low level. The immunoaffinity step is very important for the removal of FVIII-related degradation products. Manufacturing scale data shown in this article confirmed the robustness of the purification process and a reliable and consistent reduction of the impurities. The contribution of each step to the final product purity is described and shown for three manufacturing batches. Turoctocog alfa, a third-generation B-domain truncated rFVIII product is manufactured in Chinese hamster ovary cells without the use of animal or human derived proteins. The five-step purification process results in a homogenous, highly purified rFVIII product. PMID- 26761579 TI - Hydatid cyst surgery complicated by hemorrhage resistant to activated recombinant factor VII, in a hemophiliac A patient with an inhibitor. AB - Factor VII is a new coagulation factor replacement therapy. It has permitted the practice of invasive procedures which were up until recently associated with a huge risk of bleeding in patients with hemophilia with inhibitors. Our case illustrates factor replacement therapy failure in a 13-year-old child operated on for hepatic cysts associated with a pelvic cyst. Major bleeding occurred postoperatively requiring several transfusions, an increase in dosage of factor VII, and administration of a heavy dose of factor VIII as a last resort. This case highlights the possibility of failure of factor replacement therapies constituting a life-threatening situation in which alternatives are few. PMID- 26761580 TI - Assessment of heat shock proteins and endothelial dysfunction in acute pulmonary embolism. AB - We determined the levels of some heat shock proteins (HSP27, HSP70, and HSP90), L arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) levels in patients with acute pulmonary embolism. The present case-control study comprised a healthy control group (n = 57) and patients with acute pulmonary embolism (n = 84). HSPs, L-arginine, ADMA, and SDMA levels were measured in all of the cases. The mean age of the control group was 56.72 +/- 8.44 years, and the mean age of the patients with acute pulmonary embolism was 60.20 +/- 16.56 years (P = 0.104). Compared with controls, patients with acute pulmonary embolism had significantly higher mean serum HSP27, HSP90, and ADMA levels, whereas the mean serum L-arginine and SDMA levels were lower (P < 0.001, for all parameters). In patients with acute pulmonary embolism serum HSP27, HSP70, and ADMA levels were negatively correlated with partial pressures of arterial oxygen levels (r = -0.281, P = 0.01; r = -0.263, P = 0.016; and r = 0.275, P = 0.011, respectively) and arterial oxygen saturation (r = -0.225, P = 0.039; r = -0.400, P < 0.001; r = -0.299, P = 0.006, respectively). The findings of the present study demonstrated that oxidative stress and endothelial damage increase in acute pulmonary embolism. PMID- 26761581 TI - Severe coagulation factor VII deficiency caused by a novel homozygous mutation (p. Trp284Gly) in loop 140s. AB - Congenital coagulation factor VII (FVII) deficiency is a rare disorder caused by mutation in F7 gene. Herein, we reported a patient who had unexplained hematuria and vertigo with consanguineous parents. He has been diagnosed as having FVII deficiency based on the results of reduced FVII activity (2.0%) and antigen (12.8%). The thrombin generation tests verified that the proband has obstacles in producing thrombin. Direct sequencing analysis revealed a novel homozygous missense mutation p.Trp284Gly. Also noteworthy is the fact that the mutational residue belongs to structurally conserved loop 140s, which majorly undergo rearrangement after FVII activation. Model analysis indicated that the substitution disrupts these native hydrophobic interactions, which are of great importance to the conformation in the activation domain of FVIIa. PMID- 26761582 TI - Association of TNF-alpha -308G>A and TNF-beta +252A>G genes polymorphisms with primary immune thrombocytopenia: a North Indian study. AB - Primary immune thrombocytopenia (ITP) is manifested by platelet autoantibodies that are not only responsible for platelet destruction by phagocytosis but also inhibit their production. Bleeding is the most common clinical manifestation of thrombocytopenia. ITP is a multifactorial disease in which both environmental and genetic factors have been implicated. It has been reported that several gene polymorphisms influence host susceptibility to ITP. This study was aimed to investigate the association of polymorphisms in tumor necrosis factor-alpha (TNF alpha) 308 G>A and TNF-beta +252 A>G genes with primary ITP in Indian patients. Genotyping for the TNF-alpha -308 G>A and TNF-beta +252 A>G was performed in 80 ITP patients and 100 controls by polymerase chain reaction and restriction fragment length polymorphism. We found no significant difference in distribution of TNF-alpha heterozygous variant genotype (GA) among patients and controls. Homozygous variant genotype (AA) was absent both in patients and controls. No statistical difference was observed in the distribution of heterozygous variant (AG) and homozygous variant (GG) genotypes of TNF-beta, between patients and controls. Heterozygous (AG) genotype of TNF-beta -308G>A was associated with persistent ITP. The study showed that heterozygous variant (AG) genotype of TNF beta was associated with persistent ITP, when compared with controls. We could not find any association of TNF-alpha with susceptibility in developing ITP. Furthermore, no association was observed with respect to different categories of ITP. In addition, additive model showed two-fold increased susceptibility to ITP. We conclude that single nucleotide polymorphism in TNF-beta +252 A>G gene may have impact on susceptibility to ITP. PMID- 26761583 TI - Use of recombinant activated factor VII for acute bleeding episodes in acquired hemophilia: final analysis from the Hemostasis and Thrombosis Research Society Registry acquired hemophilia study. AB - The Hemostasis and Thrombosis Research Society Registry was used to monitor the postapproval use and safety of recombinant activated factor VII (rFVIIa). The objective of this article is to evaluate the data from the Hemostasis and Thrombosis Research Society Registry related to rFVIIa-treated bleeding episodes in patients with acquired hemophilia. For each rFVIIa-treated bleeding episode, the initial dose, total dose, average infused dose, number of doses, and treatment duration were calculated. Efficacy was assessed on a three-point scale. Out of the 166 registered patients with acquired hemophilia, 110 patients were treated for 237 bleeding episodes (139 rFVIIa treated); the majority (70%) were in patients older than 60 years. The most frequently reported bleeding locations were subcutaneous (40%) and mucosal (32%). Subcutaneous bleeding episodes were more commonly reported in women (55% vs. 40% men) and white patients (44 vs. 27% black). Of the 139 rFVIIa-treated bleeding episodes, rFVIIa was used as first line treatment in 127 bleeding episodes. The median initial dose was 90 MUg/kg; the median total dose per episode was 333.5 MUg/kg. Physician-rated efficacy of rFVIIa for each bleeding episode was reported as 'bleeding stopped' in 85% of bleeding episodes, 'bleeding slowed' in 11% of bleeding episodes, 'no improvement' in 4% of bleeding episodes, and was not documented in 1 bleeding episode. One thromboembolic event was reported; transient neurologic symptoms were reported in a 31-year-old postpartum patient after 110 doses of rFVIIa. Adequate hemostasis was provided for most rFVIIa-treated bleeding episodes at doses largely conforming to the package insert. No major safety concerns were reported. PMID- 26761584 TI - Surgery in patients with von Willebrand disease. AB - Von Willebrand disease (vWD) is the most common inherited bleeding disorder. The biggest challenge in the management of vWD is the difficulty in performing surgical procedures because of bleeding. Treatment guidelines recommend the use of pure von Willebrand factor or von Willebrand factor/factor VIII (vWF/FVIII) concentrate in patients with type 2 or type 3 vWD undergoing surgery, in patients with type 1 vWD undergoing surgery who are unresponsive, and in patients for whom desmopressin acetate is contraindicated. However, there is no consensus on the dosage and optimum levels of these factors to date. The aim of this study was to evaluate the perioperative management of patients with vWD during surgical procedures. Data pertaining to surgical procedures performed at our center from 2003 to 2014 were analyzed retrospectively. All operations, except one appendectomy, were elective, and a plan for the management of hemostasis was prepared for each patient. During this period, 37 surgical procedures (major, minor, and dental) were performed in 23 patients with vWD. Complications occurred in four out of 37 procedures (10.8%). No deaths or life-threatening bleeding occurred during any of the operations and no thromboembolic events were observed. The results from this retrospective study indicate that surgery can be safely performed by providing adequate and timely hemostasis during and after the procedure in patients with vWD. Perioperative and postoperative bleeding complications are rare when patients are closely and carefully monitored. PMID- 26761585 TI - Impacts of laparoscopic hysterectomy on functions of coagulation and fibrinolysis system. AB - The main objective of the study is to compare the impacts of laparoscopic hysterectomy and total abdominal hysterectomy on the functions of coagulation and fibrinolysis system. Seventy-five patients who had undergone hysterectomy were randomly divided into laparoscopic hysterectomy group (n = 38) and total abdominal hysterectomy group (n = 37). The prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, D-dimer, von Willebrand factor, alpha-granule membrane protein-140, thrombin-activated fibrinolysis inhibitor (TAFI) and platelet count were detected at preoperative 24 h (N0), postoperative 24 h (N1) and postoperative 48 h (N2). Compared with N0, values of PT, APTT and TT were significantly decreased at N1 in both groups, whereas von Willebrand factor, platelet count and alpha-granule membrane protein 140 levels at N1 were significantly increased (P < 0.05). There was no significant difference between N0 and N2 (P > 0.05). Compared with N0, fibrinogen, D-dimer and TAFI levels in both groups were significantly higher at N1 (P < 0.05), and there was no significant difference between N0 and N2 (P > 0.05). The intergroup comparison showed no significant difference of above indexes between two groups (P > 0.05). The univariate analysis showed that TAFI was negatively correlated with TT (r = -0.365, P < 0.01), APTT (r = -0.183, P < 0.05) and PT (r = -0.121, P < 0.05), whereas not correlated with other indicators. Laparoscopic hysterectomy may increase the risk of postoperative venous thrombosis. PMID- 26761586 TI - Contribution of protein Z gene single-nucleotide polymorphism to systemic lupus erythematosus in Egyptian patients. AB - Protein Z has been reported to exert an important role in inhibiting coagulation. Polymorphisms in the protein Z gene (PROZ) may affect protein Z levels and thus play a role in thrombosis. This study aimed to investigate the prevalence and clinical significance of protein Z gene G79A polymorphism in Egyptian patients with systemic lupus erythematosus (SLE). We studied the distribution of the protein Z gene (rs17882561) (G79A) single-nucleotide polymorphism by PCR restriction fragment length polymorphism in 100 Egyptian patients with SLE and 100 age, sex, and ethnically matched controls. There was no statistically significant difference in the distribution of the genotypes between SLE patients and the control group in our study (P = 0.103). But a statistically significant difference in the frequency of the alleles between SLE patients and controls was observed (P = 0.024). Also a significant association was detected between protein Z genotypes (and also A allele) and thrombosis, which is one of the manifestations of SLE (P = 0.004 and P = 0.001, respectively). Moreover, we observed a significant association between the protein Z AA and GA genotypes (and also A allele) and the presence of anticardiolipin antibodies (P = 0.016 and P = 0.004, respectively). The minor A allele of the G79A polymorphism in the protein Z gene might contribute to the genetic susceptibility of SLE in Egyptian patients. Also, an influence for this polymorphism on some of the disease manifestations has been elucidated, so protein Z G79A AG/AA may be a risk factor for thrombosis. PMID- 26761587 TI - Tissue factor-positive monocytes expression in children with sickle cell disease: clinical implication and relation to inflammatory and coagulation markers. AB - Hemostatic abnormalities are well documented in sickle cell disease (SCD). Nevertheless, whether these perturbations could contribute to sickle vasculopathy is still not clear. We evaluated monocytes tissue factor (TF) expression in children with SCD correlating the results with the clinical state and some inflammatory and coagulation markers. The study included 24 children with SCD in steady state, 24 in painful crisis and 20 healthy age and sex-matched children as controls. Complete blood count, prothrombin time (%), activated partial thromboplastin time, fibrinogen, D-dimer, thrombin-antithrombin complex and quantitative C-reactive protein were assayed. TF expression on monocytes was analyzed by flow cytometry. TF-positive monocytes were significantly higher in both patient groups compared with the controls, being higher in painful crisis group (2.06 +/- 0.64, 8.01 +/- 1.53, 13.5 +/- 4.3 for the controls, steady state and painful crisis groups, respectively). Among painful crisis group, TF expression on monocytes was positively correlated with the pain rate, reticulocytes (%) and three out of six markers of inflammation and coagulation (C reactive protein, D-dimer and fibrinogen) with inverse correlation with hemoglobin and the red blood cells count. TF-positive monocytes were more expressed in SCD both in steady state and in painful crisis, being significantly higher in painful crisis. This expression was significantly related to the pain rate as well as to markers of hemolysis, inflammation and coagulation among patients in painful crisis. These results confirm the substantial role played by TF-positive monocytes in the pathogenesis of SCD painful crisis. PMID- 26761589 TI - Thermal conductivity of the diamond-chain compound Cu3(CO3)2(OH)2. AB - Thermal conductivity (kappa) of a distorted spin diamond-chain system, Cu3(CO3)2(OH)2, is studied at low temperatures down to 0.3 K and in magnetic fields up to 14 T. In zero field, the kappa(T) curve with heat current along the chain direction has very small magnitudes and shows a pronounced three-peak structure. The magnetic fields along and perpendicular to the chains change the kappa strongly in a way having good correspondence to the changes of magnetic specific heat in fields. The data analysis based on the Debye model for phononic thermal conductivity indicates that the heat transport is due to phonons and the three-peak structure is caused by two resonant scattering processes by the magnetic excitations. In particular, the spin excitations of the chain subsystem are strongly scattering phonons rather than transporting heat. PMID- 26761590 TI - Investigations on Substrate Temperature-Induced Growth Modes of Organic Semiconductors at Dielectric/semiconductor Interface and Their Correlation with Threshold Voltage Stability in Organic Field-Effect Transistors. AB - Influence of substrate temperature on growth modes of copper phthalocyanine (CuPc) thin films at the dielectric/semiconductor interface in organic field effect transistors (OFETs) is investigated. Atomic force microscopy (AFM) imaging at the interface reveals a change from 'layer+island' to "island" growth mode with increasing substrate temperatures, further confirmed by probing the buried interfaces using X-ray reflectivity (XRR) and positron annihilation spectroscopic (PAS) techniques. PAS depth profiling provides insight into the details of molecular ordering while positron lifetime measurements reveal the difference in packing modes of CuPc molecules at the interface. XRR measurements show systematic increase in interface width and electron density correlating well with the change from layer + island to coalesced huge 3D islands at higher substrate temperatures. Study demonstrates the usefulness of XRR and PAS techniques to study growth modes at buried interfaces and reveals the influence of growth modes of semiconductor at the interface on hole and electron trap concentrations individually, thereby affecting hysteresis and threshold voltage stability. Minimum hole trapping is correlated to near layer by layer formation close to the interface at 100 degrees C and maximum to the island formation with large voids between the grains at 225 degrees C. PMID- 26761588 TI - Photoactivation of Mutant Isocitrate Dehydrogenase 2 Reveals Rapid Cancer Associated Metabolic and Epigenetic Changes. AB - Isocitrate dehydrogenase is mutated at a key active site arginine residue (Arg172 in IDH2) in many cancers, leading to the synthesis of the oncometabolite (R)-2 hydroxyglutarate (2HG). To investigate the early events following acquisition of this mutation in mammalian cells we created a photoactivatable version of IDH2(R172K), in which K172 is replaced with a photocaged lysine (PCK), via genetic code expansion. Illumination of cells expressing this mutant protein led to a rapid increase in the levels of 2HG, with 2HG levels reaching those measured in patient tumor samples, within 8 h. 2HG accumulation is closely followed by a global decrease in 5-hydroxymethylcytosine (5-hmC) in DNA, demonstrating that perturbations in epigenetic DNA base modifications are an early consequence of mutant IDH2 in cells. Our results provide a paradigm for rapidly and synchronously uncloaking diverse oncogenic mutations in live cells to reveal the sequence of events through which they may ultimately cause transformation. PMID- 26761591 TI - Application of wavelet techniques for cancer diagnosis using ultrasound images: A Review. AB - Ultrasound is an important and low cost imaging modality used to study the internal organs of human body and blood flow through blood vessels. It uses high frequency sound waves to acquire images of internal organs. It is used to screen normal, benign and malignant tissues of various organs. Healthy and malignant tissues generate different echoes for ultrasound. Hence, it provides useful information about the potential tumor tissues that can be analyzed for diagnostic purposes before therapeutic procedures. Ultrasound images are affected with speckle noise due to an air gap between the transducer probe and the body. The challenge is to design and develop robust image preprocessing, segmentation and feature extraction algorithms to locate the tumor region and to extract subtle information from isolated tumor region for diagnosis. This information can be revealed using a scale space technique such as the Discrete Wavelet Transform (DWT). It decomposes an image into images at different scales using low pass and high pass filters. These filters help to identify the detail or sudden changes in intensity in the image. These changes are reflected in the wavelet coefficients. Various texture, statistical and image based features can be extracted from these coefficients. The extracted features are subjected to statistical analysis to identify the significant features to discriminate normal and malignant ultrasound images using supervised classifiers. This paper presents a review of wavelet techniques used for preprocessing, segmentation and feature extraction of breast, thyroid, ovarian and prostate cancer using ultrasound images. PMID- 26761592 TI - The relationship of exposure to air pollutants in pregnancy with surrogate markers of endothelial dysfunction in umbilical cord. AB - BACKGROUND: This study aims to investigate the association of exposure to ambient air pollution during pregnancy with cord blood concentrations of surrogate markers of endothelial dysfunction. METHODS: This population-based cohort was conducted from March 2014 to March 2015 among 250 mother-neonate pairs in urban areas of Isfahan, the second large and air-polluted city in Iran. We analyzed the association between the ambient carbon monoxide (CO), ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), particular matter 10 (PM10), and air quality index (AQI) with cord blood levels of endothelin-1, vascular adhesion molecule (VCAM), and intercellular adhesion molecule (ICAM). Multiple regression analysis was conducted after adjustment for potential confounding factors and covariates. The regression coefficient (beta), standard error of the estimate (SE), and 95% confidence intervals for each regression coefficient (95% CI) are reported. RESULTS: Data of 233 mother-neonate pairs were complete, and included in the analysis. Multiple regression analyses showed that AQI, CO and O3 had significant correlation with cord blood ICAM-1 [Beta (SE), 95%CI: 2.93 (0.72), 1.33,5.54; 2.28(1.44), 1.56,5.12; and 2.02(0.01), 1.03,2.04, respectively] as well as with VCAM-1 [2.78(0.91), 1.69,4.57; 2.47(1.47), 1.43,5.37; and 2.01(0.01),1.07,2.04, respectively]. AQI, PM10, and SO2 were significantly associated with Endothelin-1 concentrations [Beta (SE), 95%CI: 10.16(5.08),7.61,14.28; 9.70(3.46), 2.88,16.52; and 1.07(0.02), 1.03,2.11, respectively]. CONCLUSIONS: The significant associations of air pollutants with markers of endothelial dysfunction during fetal period may provide another evidence on the adverse health effects of air pollutants on early stages of atherosclerosis from fetal period. Our findings underscore the importance of considering environmental factors in primordial prevention of chronic diseases. PMID- 26761593 TI - Microbial-processing of fruit and vegetable wastes for production of vital enzymes and organic acids: Biotechnology and scopes. AB - Wastes generated from fruits and vegetables are organic in nature and contribute a major share in soil and water pollution. Also, green house gas emission caused by fruit and vegetable wastes (FVWs) is a matter of serious environmental concern. This review addresses the developments over the last one decade on microbial processing technologies for production of enzymes and organic acids from FVWs. The advances in genetic engineering for improvement of microbial strains in order to enhance the production of the value added bio-products as well as the concept of zero-waste economy have been briefly discussed. PMID- 26761594 TI - Tuning of Charge Transfer Assisted Phase Transition and Slow Magnetic Relaxation Functionalities in {Fe(9-x)Co(x)[W(CN)8]6} (x = 0-9) Molecular Solid Solution. AB - Precisely controlled stoichiometric mixtures of Co(2+) and Fe(2+) metal ions were combined with the [W(V)(CN)8](3-) metalloligand in a methanolic solution to produce a series of trimetallic cyanido-bridged {Fe(9 x)Co(x)[W(CN)8]6(MeOH)24}.12MeOH (x = 0, 1, ..., 8, 9; compounds 0, 1, ..., 8, 9) clusters. All the compounds, 0-9, are isostructural, and consist of pentadecanuclear clusters of a six-capped body-centered cube topology, capped by methanol molecules which are coordinated to 3d metal centers. Thus, they can be considered as a unique type of a cluster-based molecular solid solution in which different Co/Fe metal ratios can be introduced while preserving the coordination skeleton and the overall molecular architecture. Depending on the Co/Fe ratio, 0 9 exhibit an unprecedented tuning of magnetic functionalities which relate to charge transfer assisted phase transition effects and slow magnetic relaxation effects. The iron rich 0-5 phases exhibit thermally induced reversible structural phase transitions in the 180-220 K range with the critical temperatures being linearly dependent on the value of x. The phase transition in 0 is accompanied by (HS)Fe(II) W(V) <-> (HS)Fe(III) W(IV) charge transfer (CT) and the additional minor contribution of a Fe-based spin crossover (SCO) effect. The Co-containing 1 5 phases reveal two simultaneous electron transfer processes which explore (HS)Fe(II) W(V) <-> (HS)Fe(III) W(IV) CT and the more complex (HS)Co(II) W(V) <-> (LS)Co(III) W(IV) charge transfer induced spin transition (CTIST). Detailed structural, spectroscopic, and magnetic studies help explain the specific role of both types of CN(-)-bridged moieties: the Fe-NC-W linkages activate the molecular network toward a phase transition, while the subsequent Co-W CTIST enhances structural changes and enlarges thermal hysteresis of the magnetic susceptibility. On the second side of the 0-9 series, the vanishing phase transition in the cobalt rich 6-9 phases results in the high-spin ground state, and in the occurrence of a slow magnetic relaxation process at low temperatures. The energy barrier of the magnetic relaxation gradually increases with the increasing value of x, reaching up to DeltaE/kB = 22.3(3) K for compound 9. PMID- 26761595 TI - Sulfate and chromate increased each other's uptake and translocation in As hyperaccumulator Pteris vittata. AB - We investigated the effects of chromate (CrVI) and sulfate on their uptake and translocation in As-hyperaccumulator Pteris vittata. Plants were exposed to 1) 0.1 mM CrVI and 0, 0.25, 1.25 or 2.5 mM sulfate or 2) 0.25 mM sulfate and 0, 0.5, 2.5 or 5.0 mM CrVI for 1 d in hydroponics. P. vittata accumulated 26 and 1261 mg kg(-1) Cr in the fronds and roots at CrVI0.1, and 2197 and 1589 mg kg(-1) S in the fronds and roots at S0.25. Increasing sulfate concentrations increased Cr root concentrations by 16-66% and helped CrVI reduction to CrIII whereas increasing CrVI concentrations increased frond sulfate concentrations by 3-27%. Increasing sulfate concentrations enhanced TBARS concentrations in the biomass, indicating oxidative stress caused lipid peroxidation in plant cell membranes. However, addition of 0.25-2.5 mM sulfate alleviated CrVI's toxic effects and decreased TBARS from 23.5 to 9.46-12.3 MUmol g(-1) FW. Though CrVI was supplied, 78-96% of CrIII was in the biomass, indicating efficient CrVI reduction to CrIII by P. vittata. The data indicated the amazing ability of P. vittata in Cr uptake at 289 mg kg(-1) h(-1) with little translocation to the fronds. These results indicated that P. vittata had potential in Cr phytoremediation in contaminated sites but further studies are needed to evaluate this potential. The facts that CrVI and sulfate helped each other in uptake by P. vittata suggest that CrVI was not competing with sulfate uptake in P. vittata. However, the mechanisms of how sulfate and CrVI enhance each other's accumulation in P. vittata need further investigation. PMID- 26761596 TI - Effect of aqueous Fe(II) on Sb(V) sorption on soil and goethite. AB - The effects of Fe(II) on the sorption and precipitation of Sb(V) on soils and goethite were investigated using batch experiments and X-ray photoelectron spectroscopy (XPS) in this study. The sorption capacity of Sb(V) were much higher in anoxic soil than oxic soil. Typically, dissolved Fe(II) concentration in anoxic soils decreased significantly with increasing Sb(V), which may be suggestive of Fe-Sb precipitation. The elevated concentrations of Fe(II) (1 mM) enhanced the sorption capacity of Sb(V) on goethite significantly. However, synchrotron radiation X-ray diffraction showed no new characteristic peak, indicating that this Fe-Sb precipitate might be poor crystallinity or amorphous. Moreover, Sb(III) was detected in anoxic soil, and the reduction of Sb(V) to Sb (III) improved the sorption capacity of Sb in anoxic soil because of the low solubility and migration of Sb(III). Nevertheless, Fe-Sb co-precipitation and Sb(V) reduction to Sb(III) might contribute simultaneously to the increased sorption capacity of Sb(V) on anoxic soils. This research could improve our current understanding of soil Sb chemistry in paddy and wetland soils. PMID- 26761598 TI - Ultrafine particles derived from mineral processing: A case study of the Pb-Zn sulfide ore with emphasis on lead-bearing colloids. AB - Although mining and mineral processing industry is a vast source of heavy metal pollutants, the formation and behavior of micrometer- and nanometer-sized particles and their aqueous colloids entered the environment from the technological media has received insufficient attention to date. Here, the yield and characteristics of ultrafine mineral entities produced by routine grinding of the Pb-Zn sulfide ore (Gorevskoe ore deposit, Russia) were studied using laser diffraction analysis (LDA), dynamic light scattering (DLS) and zeta potential measurement, microscopy, X-ray photoelectron spectroscopy, with most attention given to toxic lead species. It was revealed, in particular, that the fraction of particles less that 1 MUm in the ground ore typical reaches 0.4 vol. %. The aquatic particles in supernatants were micrometer size aggregates with increased content of zinc, sulfur, calcium as compared with the bulk ore concentrations. The hydrodynamic diameter of the colloidal species decreased with time, with their zeta potentials remaining about -12 mV. The colloids produced from galena were composed of 20-50 nm PbS nanoparticles associated with lead sulfate and thiosulfate, while the surface oxidation products at precipitated galena were largely lead oxyhydroxides. The size and zeta potential of the lead-bearing colloids decreased with time down to about 100 nm and from -15 mV to -30 mV, respectively. And, conversely, lead sulfide nanoparticles were mobilized before the aggregates during redispersion of the precipitates in fresh portions of water. The potential environmental impact of the metal-bearing colloids, which is due to the large-scale production and relative stability, is discussed. PMID- 26761597 TI - Understanding acoustic cavitation for sonolytic degradation of p-cresol as a model contaminant. AB - Many modern techniques exist for the degradation of organic pollutants in water. Numerous treatment processes which utilize the formation of hydroxyl radicals for oxidation of pollutants have been studied thoroughly. In this study, a three pronged approach has been used to characterize and understand the effect of two distinct acoustic frequencies (37 kHz and 1 MHz) on cavitation behavior. Correlation of this behavior with sonolysis of a target phenol pollutant is described. Hydroxyl radical capture, hydrophone, and microelectrode studies in this work show that megasonic frequencies are more effective for generation of hydroxyl radicals and stable cavitation events than ultrasonic frequencies. UV absorption and fluorescence measurements confirm that the combination of ultrasonic sonolysis with a Fenton reagent achieved complete degradation of p cresol at 50 mg/L in about 30 min. Cost estimates have been made for different sonication processes and compared with traditional advanced oxidation processes. PMID- 26761600 TI - Cellular and aqueous microcystin-LR following laboratory exposures of Microcystis aeruginosa to copper algaecides. AB - Microcystin release from algal cells influences use of copper-algaecides in water resources. Accurate data regarding relationships between copper-algaecide exposures and responses of microcystin-producing algae are needed to make informed management decisions. Responses of Microcystis aeruginosa were measured in terms of cellular microcystin-LR (MC-LR), aqueous MC-LR, and chlorophyll-a following exposure to CuSO4 and copper-ethanolamine. Comparisons were made between treated and untreated samples, and copper formulations. EC50s and slopes for M. aeruginosa responses to copper exposures were calculated. Algal responses followed a sigmoidal exposure-response relationship, and cellular MC-LR and chlorophyll-a were negatively related to copper concentrations. Aqueous MC-LR increased with copper concentrations, although the increase in aqueous MC-LR was not proportional to decreases in cellular MC-LR and chlorophyll-a. Cellular MC-LR and chlorophyll a declined at a greater rate than aqueous MC-LR increased. Total MC-LR was less than untreated controls following copper exposure. Differences were measured between copper formulations in terms of aqueous and total MC-LR concentrations at concentrations of 0.5 and 1.0 mg Cu L-1. Aqueous and total MC LR were greater (10-20%) following exposure to CuSO4 compared to copper ethanolamine one day following exposure. The positive relationship between copper concentration and aqueous MC-LR at 0.07-1.0 mg Cu L-1 demonstrates that lower copper concentrations were as effective as higher concentrations in controlling M. aeruginosa while decreasing the total amount of MC-LR, and minimizing the proportion of MC-LR released to the aqueous-phase. Results serve to support more accurate risk evaluations of MC-LR concentrations when M. aeruginosa is exposed to copper-algaecides and when it is untreated. PMID- 26761599 TI - Metal absorption properties of Mentha spicata grown under tannery sludge amended soil-its effect on antioxidant system and oil quality. AB - Tannery sludge (TS) is hazardous to environment and its disposal in an ecofriendly manner is a major challenge. An experiment was conducted to investigate the metal absorption properties of Mentha spicata grown under different levels of TS amended soil (soil: sludge in 100:0, 75:25, 50:50, 25:75 and 0:100 ratio) and its effect on the antioxidant system and oil quality. At 75:25 ratio of sludge and soil, metal translocation factor was >=0.5 for Cr, Cd, and Co and for Ni and for Pb >= 1. Carvone, limonene, dihydrocarvone and other oil constituents along with biomass were maximum in 75:25 ratio of sludge and soil. Superoxide dismutase (SOD), CAT (Catalases), POD (Peroxidases), MDA (Malondialdehyde) and proline play a major role in detoxification of reactive oxygen species generated due to TS (heavy metal stress). Antioxidant (SOD, CAT and POD), MDA and proline showed an increasing trend as the concentration of TS increased with the treatments. To test the relationship between 23 character principal component analysis (PCA) was performed. PC-I contributed 56% of total variance while PC-II contributed 37% of total variance. The results concluded that M. spicata performed well in terms of oil yield and multiple metal translocations in 75:25 sludge and soil ratio. PMID- 26761601 TI - Aquatic acute toxicity assessments of molybdenum (+VI) to Daphnia magna. AB - Generally, molybdenum (Mo) metals in the environment are very rare, but wastewater discharges from industrial processes may contain high concentrations of Mo, which has the potential to contaminate water or soil if not handled properly. In this study, the impact of three common compounds of hexavalent Mo (sodium molybdate (Na2MoO4?2H2O), ammonium molybdate ((NH4)6Mo7O24?4H2O) and molybdenum trioxide (MoO3)) in an aquatic system were assessed based on 48-h exposure acute toxicity to Daphnia magna (D. magna). The LC50 toxicities for associated conjugate ions including Na(+), Cl(-), SO4(2-), and NH4(+) were determined. Furthermore, the LC50 values for the three forms of hexavalent Mo were determined, and the acute toxicities of the Mo forms were found to follow the order: (NH4)6Mo7O24?4H2O > MoO3 > Na2MoO4?2H2O in solution. (NH4)6Mo7O24?4H2O exhibited the lowest LC50 of 43.3 mg L(-1) (corresponding to 23.5 mg Mo L(-1)) among the three molybdenum salts. The research confirmed that the toxicity of molybdenum in the aquatic system is highly dependent on the form of molybdenum salts used, and is also associated with the influence of the background water quality. PMID- 26761602 TI - Arbuscular mycorrhizae alleviate negative effects of zinc oxide nanoparticle and zinc accumulation in maize plants--A soil microcosm experiment. AB - ZnO nanoparticles (NPs) are considered an emerging contaminant when in high concentration, and their effects on crops and soil microorganisms pose new concerns and challenges. Arbuscular mycorrhizal (AM) fungi (AMF) form mutualistic symbioses with most vascular plants, and putatively contribute to reducing nanotoxicity in plants. Here, we studied the interactions between ZnO NPs and maize plants inoculated with or without AMF in ZnO NPs-spiked soil. ZnO NPs had no significant adverse effects at 400 mg/kg, but inhibited both maize growth and AM colonization at concentrations at and above 800 mg/kg. Sufficient addition of ZnO NPs decreased plant mineral nutrient acquisition, photosynthetic pigment concentrations, and root activity. Furthermore, ZnO NPs caused Zn concentrations in plants to increase in a dose-dependent pattern. As the ZnO NPs dose increased, we also found a positive correlation with soil diethylenetriaminepentaacetic acid (DTPA)-extractable Zn. However, AM inoculation significantly alleviated the negative effects induced by ZnO NPs: inoculated-plants experienced increased growth, nutrient uptake, photosynthetic pigment content, and SOD activity in leaves. Mycorrhizal plants also exhibited decreased ROS accumulation, Zn concentrations and bioconcentration factor (BCF), and lower soil DTPA-extractable Zn concentrations at high ZnO NPs doses. Our results demonstrate that, at high contamination levels, ZnO NPs cause toxicity to AM symbiosis, but AMF help alleviate ZnO NPs-induced phytotoxicity by decreasing Zn bioavailability and accumulation, Zn partitioning to shoots, and ROS production, and by increasing mineral nutrients and antioxidant capacity. AMF may play beneficial roles in alleviating the negative effects and environmental risks posed by ZnO NPs in agroecosystems. PMID- 26761604 TI - Zn Isotope Fractionation during Sorption onto Kaolinite. AB - In this study, we quantify zinc isotope fractionation during its sorption onto kaolinite, by performing experiments under various pH, ionic strength, and total Zn concentrations. A systematic enrichment in heavy Zn isotopes on the surface of kaolinite was measured, with Delta(66)Znadsorbed-solution ranging from 0.110/00 at low pH and low ionic strength to 0.490/00 at high pH and high ionic strength. Both the measured Zn concentration and its isotopic ratio are correctly described using a thermodynamic sorption model that considers two binding sites: external basal surfaces and edge sites. Based on this modeling approach, two distinct Zn isotopic fractionation factors were calculated: Delta(66)Znadsorbed-solution = 0.18 +/- 0.060/00 for ion exchange onto basal sites, and Delta(66)Znadsorbed solution = 0.49 +/- 0.060/00 for specific complexation onto edge sites. These two distinct factors indicate that Zn isotope fractionation is dominantly controlled by the chemical composition of the solution (pH, ionic strength). PMID- 26761603 TI - The influence of cathode material on electrochemical degradation of trichloroethylene in aqueous solution. AB - In this study, different cathode materials were evaluated for electrochemical degradation of aqueous phase trichloroethylene (TCE). A cathode followed by an anode electrode sequence was used to support reduction of TCE at the cathode via hydrodechlorination (HDC). The performance of iron (Fe), copper (Cu), nickel (Ni), aluminum (Al) and carbon (C) foam cathodes was evaluated. We tested commercially available foam materials, which provide large electrode surface area and important properties for field application of the technology. Ni foam cathode produced the highest TCE removal (68.4%) due to its high electrocatalytic activity for hydrogen generation and promotion of HDC. Different performances of the cathode materials originate from differences in the bond strength between atomic hydrogen and the material. With a higher electrocatalytic activity than Ni, Pd catalyst (used as cathode coating) increased TCE removal from 43.5% to 99.8% for Fe, from 56.2% to 79.6% for Cu, from 68.4% to 78.4% for Ni, from 42.0% to 63.6% for Al and from 64.9% to 86.2% for C cathode. The performance of the palladized Fe foam cathode was tested for degradation of TCE in the presence of nitrates, as another commonly found groundwater species. TCE removal decreased from 99% to 41.2% in presence of 100 mg L(-1) of nitrates due to the competition with TCE for HDC at the cathode. The results indicate that the cathode material affects TCE removal rate while the Pd catalyst significantly enhances cathode activity to degrade TCE via HDC. PMID- 26761605 TI - Hope and General Self-efficacy: Two Measures of the Same Construct? AB - The aim of this study was to test the extent to which hope measure is equivalent to general self-efficacy measure. Questionnaire data on these two constructs and other external variables were collected from 199 Chinese college students. The factor analytic results suggested that hope and self-efficacy items measured the same construct. The unidimensional model combining hope items and GSE items fit the data as well as the bidimensional model, indicating that their corresponding items measured the same underlying construct. Further analyses showed that hope and GSE did not correlate with external variables differently in a systematic manner. Most of these correlational differences were non-significant and negligible. These findings suggested that the literatures studying GSE and hope could be considered to be integrated and that researchers need to recognize and acknowledge the conceptual and operational similarities among these constructs in the literature. PMID- 26761607 TI - Phase Analysis for Frequency Standards in the Microwave and Optical Domains. AB - Coherent manipulation of atomic states is a key concept in high-precision spectroscopy and used in atomic fountain clocks and a number of optical frequency standards. Operation of these standards can involve a number of cyclic switching processes, which may induce cycle-synchronous phase excursions of the interrogation signal and thus lead to shifts in the output of the frequency standard. We have built a field-programmable gate array (FPGA)-based phase analyzer to investigate these effects and conducted measurements on two kinds of frequency standards. For the caesium fountains PTB-CSF1 and PTB-CSF2, we were able to exclude phase variations of the microwave source at the level of a few microradians, corresponding to relative frequency shifts of less than [Formula: see text]. In the optical domain, we investigated phase variations in PTB's Yb (+) optical frequency standard and made detailed measurements of acousto-optic modulator (AOM) chirps and their scaling with duty cycle and driving power. We ascertained that cycle-synchronous as well as long-term phase excursion do not cause frequency shifts larger than [Formula: see text]. PMID- 26761608 TI - Surface Potential of DPPC Monolayers on Concentrated Aqueous Salt Solutions. AB - The presence and exchange of electrical charges on the surfaces of marine aerosols influence their ability to act as cloud condensation nuclei and play a role in thundercloud electrification. Although interactions exist between surface active inorganic ions and organic compounds, their role in surface charging of marine aerosols is not well understood. In this study, the surface potential of dipalmitoylphosphatidylcholine (DPPC) monolayers, a zwitterionic phospholipid found in the sea surface microlayer, is measured on concentrated (0.3-2.0 M) chloride salt solutions containing marine-relevant cations (Na(+), K(+), Mg(2+), Ca(2+)) to model and elucidate the electrical properties of organic-covered marine aerosols. Monovalent cations show only a weak effect on the surface potential of DPPC monolayers in the condensed phase compared to water. In contrast, Mg(2+) and Ca(2+) increase the surface potential, indicating different cation binding modes and affinities for the PC headgroup. Moreover, it is found that for divalent chloride salt solutions, the PC headgroup and interfacial water molecules make the largest dipolar contribution to the surface potential. This study shows that for equal charge concentrations, divalent cations impact surface potential of DPPC monolayers more strongly than monovalents likely through changes in the PC headgroup orientation induced by their complexation along with the lesser ordering of interfacial water molecules caused by phosphate group charge screening. PMID- 26761610 TI - Studying Multivariate Change Using Multilevel Models and Latent Curve Models. AB - In longitudinal research investigators often measure multiple variables at multiple points in time and are interested in investigating individual differences in patterns of change on those variables. In the vast majority of applications, researchers focus on studying change in one variable at a time. In this article we consider methods for studying relations1.1ips between patterns of change on different variables. We show how the multilevel modeling framework, which is often used to study univariate change, can be extended to the multivariate case to yield estimates of covariances of parameters representing aspects of change on different variables. We illustrate this approach using data from a study of physiological response to marital conflict in older married couples, showing a substantial correlation between rate of linear change on different stress-related hormones during conflict. We also consider how similar issues can be studied using extensions of latent curve models to the multivariate case, and we show how such models are related to multivariate multilevel models. PMID- 26761609 TI - Palladium-Catalyzed Dehydrative Cross-Coupling of Allylic Alcohols and N Heterocycles Promoted by a Bicyclic Bridgehead Phosphoramidite Ligand and an Acid Additive. AB - A mild and efficient dehydrative cross-coupling reaction between allylic alcohols and N-heterocycles using palladium catalysis is reported. A bicyclic bridgehead phosphoramidite (briphos) ligand together with Pd(dba)2 is a highly efficient catalyst, and an acid additive involved in the rate-determining step promotes the catalytic cycle. The coupling reaction of allylic alcohols with N-heterocycles including imidazoles, benzimidazoles, and triazole proceeds under mild reaction conditions with high yields using Pd/briphos and pentafluorophenol. PMID- 26761611 TI - Testing Repeated Measures Hypotheses when Covariance Matrices are Heterogeneous: Revisiting the Robustness of the Welch-James Test. AB - This article examines the recommendations given by Keselman, Carriere and Lix (1993) regarding choice of sample size for obtaining robust tests of the repeated measures main and interaction hypotheses in a one Between-Subjects by one Within Subjects design with a Welch-James type multivariate test when covariance matrices were heterogeneous and data were non-normal in unbalanced designs. We examined the generalizablility of their recommendations by varying the (a) size of the design, (b) degree of covariance heterogeneity, and (c) degree of nonsphericity. Our results indicate that the Keselman et al. recommendations for the test of the repeated measures main effect hold in some situations and can be relaxed in others. Consequently, with a relatively modest sample size, the Welch James test provides a robust test of the main effect. On the other hand, the required sample size for the interaction can be quite large; accordingly, the Keselman et al. recornmendations must be increased as the number of groups increases and when the data are skewed. We recommend the Welch-James test for testing the main effect hypothesis. The Welch-James test should also be used to test the interaction hypothesis when the sample sizes are sufficiently large to permit a robust test. In other conditions, the researcher should use an alternative such as Huynh's (1978) Improved General Approximation test. PMID- 26761613 TI - A Note on Schonemann's Refutation of Spearman's Hypothesis. AB - Spearman's hypothesis states that there is a positive relationship between the standardized black-white differences in means on cognitive tests and the loadings (of these tests on the general common factor identified as general cognitive ability. Schonemann (1992) claims to demonstrate that, within an analysis of principal components, this relationship is ascribable to a statistical artifact. In the present note, Schonemann's refutation is shown to be incorrect. PMID- 26761612 TI - Latent Variable Modeling of Longitudinal and Multilevel Substance Use Data. AB - This article demonstrates the use of a general model for latent variable growth analysis which takes into account cluster sampling. Multilevel Latent Growth Modeling (MLGR4) was used to analyze longitudinal and multilevel data for adolescent and parent substance use measured at four annual time points. An associative LGM model was tested for alcohol, marijuana, and cigarette use with a sample of 435 families. Hypotheses concerning the shape of the growth curve and the extent of individual differences in the common trajectory over time were tested. The effects of marital and family status and socio-economic status on family levels of substance use were also examined. Findings are discussed in terms of family-level substance use and similarities in developmental trajectories across substances, and the impact of contextual factors on family levels of substance use and development. PMID- 26761606 TI - Review of Quantitative Ultrasound: Envelope Statistics and Backscatter Coefficient Imaging and Contributions to Diagnostic Ultrasound. AB - Conventional medical imaging technologies, including ultrasound, have continued to improve over the years. For example, in oncology, medical imaging is characterized by high sensitivity, i.e., the ability to detect anomalous tissue features, but the ability to classify these tissue features from images often lacks specificity. As a result, a large number of biopsies of tissues with suspicious image findings are performed each year with a vast majority of these biopsies resulting in a negative finding. To improve specificity of cancer imaging, quantitative imaging techniques can play an important role. Conventional ultrasound B-mode imaging is mainly qualitative in nature. However, quantitative ultrasound (QUS) imaging can provide specific numbers related to tissue features that can increase the specificity of image findings leading to improvements in diagnostic ultrasound. QUS imaging can encompass a wide variety of techniques including spectral-based parameterization, elastography, shear wave imaging, flow estimation, and envelope statistics. Currently, spectral-based parameterization and envelope statistics are not available on most conventional clinical ultrasound machines. However, in recent years, QUS techniques involving spectral based parameterization and envelope statistics have demonstrated success in many applications, providing additional diagnostic capabilities. Spectral-based techniques include the estimation of the backscatter coefficient (BSC), estimation of attenuation, and estimation of scatterer properties such as the correlation length associated with an effective scatterer diameter (ESD) and the effective acoustic concentration (EAC) of scatterers. Envelope statistics include the estimation of the number density of scatterers and quantification of coherent to incoherent signals produced from the tissue. Challenges for clinical application include correctly accounting for attenuation effects and transmission losses and implementation of QUS on clinical devices. Successful clinical and preclinical applications demonstrating the ability of QUS to improve medical diagnostics include characterization of the myocardium during the cardiac cycle, cancer detection, classification of solid tumors and lymph nodes, detection and quantification of fatty liver disease, and monitoring and assessment of therapy. PMID- 26761614 TI - Nano-TiO2 modified carbon paste sensor for electrochemical nicotine detection using anionic surfactant. AB - A newly competitive electrochemical sensor for nicotine (NIC) detection was successfully achieved. Nano-TiO2 with a carbon paste electrode (CPE) were used for the sensor construction, where Nano-TiO2 was considered as one of the richest and highly variable class of materials. The sensor showed electrocatalytic activity in both aqueous and micellar media toward the oxidation of NIC at Britton-Robinson (B-R) buffer solution (4*10(-2)M) of pH range (2.0-8.0) containing (1.0mM) sodium dodecylsulfate (SDS) using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) techniques. Scanning electron microscope (SEM) and Energy Dispersive X-Ray Analysis (EDX) techniques were also used. The linear range of detection for NIC using the new Nano-TiO2 Modified Carbon Paste sensor (NTMCP) was detected using diffrential pulse voltammetry (DPV) technique and it was found between 2*10(-6)M and 5.4*10(-4)M with a detection limit of 1.34*10(-8)M. The obtained results clarified the simplicity, high sensitivity and selectivity of the new NTMCPE for nicotine determination in real cigarettes and urine samples. PMID- 26761615 TI - Direct RNA detection without nucleic acid purification and PCR: Combining sandwich hybridization with signal amplification based on branched hybridization chain reaction. AB - We have developed a convenient, robust and low-cost RNA detection system suitable for high-throughput applications. This system uses a highly specific sandwich hybridization to capture target RNA directly onto solid support, followed by on site signal amplification via 2-dimensional, branched hybridizing chain polymerization through toehold-mediated strand displacement reaction. The assay uses SYBR Green to detect targets at concentrations as low as 1 pM, without involving nucleic acid purification or any enzymatic reaction, using ordinary oligonucleotides without modification or labeling. The system was demonstrated in the detection of malaria RNA in blood and GAPDH gene expression in cell lysate. PMID- 26761616 TI - Novel optical sensing film based on a functional nonwoven nanofibre mat for an easy, fast and highly selective and sensitive detection of tryptamine in beer. AB - In this paper, the combination of Solid Surface-Room Temperature Phosphorescence (SS-RTP) and nanotechnology has led to a new approach in the detection of biogenic amines in complex matrices. This novel approach allows, for the first time, the direct determination of the concentration of tryptamine in beers. The novelty of the proposed optical sensor resides in its simplicity, rapidity, absence of complex chromatographic separation, sample clean-up, preconcentration, and derivatization protocols. Therefore, this novel methodology simplifies and reduces considerably the time and cost of the analysis, resolving the two major problems of the determination of tryptamine in beer up to now: low sensitivity and matrix effects. The proposed sensor is based on a novel white, uncharged, and non-luminescent functional nonwoven nanofibre mat (Tiss(r)-Link) formed by hydrophilic nanofibres of 300 nm of diameter functionalized with a high concentration of active vinyl groups (330 umol g(-1)). It is used to carry out a kinetically controlled covalent immobilisation of tryptamine via Michael type reaction. The transduction of the sensor is phosphorescence; the covalently immobilized tryptamine is quantified by SS-RTP, obtaining a detection limit of 6 ng mL(-1) with short response times (15 min). The applicability of the sensor was demonstrated by analysing tryptamine in 10 different varieties of beers, obtaining recovery percentages close to 100%. PMID- 26761617 TI - Bioelectronic tongues: New trends and applications in water and food analysis. AB - Over the last years, there has been an increasing demand for fast, highly sensitive and selective methods of analysis to meet new challenges in environmental monitoring, food safety and public health. In response to this demand, biosensors have arisen as a promising tool, which offers accurate chemical data in a timely and cost-effective manner. However, the difficulty to obtain sensors with appropriate selectivity and sensitivity for a given analyte, and to solve analytical problems which do not require the quantification of a certain analyte, but an overall effect on a biological system (e.g. toxicity, quality indices, provenance, freshness, etc.), led to the concept of electronic tongues as a new strategy to tackle these problems. In this direction, to improve the performance of electronic tongues, and thus to spawn new application fields, biosensors have recently been incorporated to electronic tongue arrays, leading to what is known as bioelectronic tongues. Bioelectronic tongues provide superior performance by combining the capabilities of electronic tongues to derive meaning from complex or imprecise data, and the high selectivity and specificity of biosensors. The result is postulated as a tool that exploits chemometrics to solve biosensors' interference problems, and biosensors to solve electronic tongues' selectivity problems. The review presented herein aims to illustrate the capabilities of bioelectronic tongues as analytical tools, especially suited for screening analysis, with particular emphasis in water analysis and the characterization of food and beverages. After briefly reviewing the key concepts related to the design and principles of electronic tongues, we provide an overview of significant contributions to the field of bioelectronic tongues and their future perspectives. PMID- 26761618 TI - Early diagnosis of fungal infections using piezomicrogravimetric and electric chemosensors based on polymers molecularly imprinted with d-arabitol. AB - An elevated concentration of d-arabitol in urine, especially compared to that of l-arabitol or creatinine, is indicative of a fungal infection. For that purpose, we devised, fabricated, and tested chemical sensors determining d-arabitol. These chemosensors comprised the quartz crystal resonator (QCR) or extended-gate field effect transistor (EG-FET) transducers integrated with molecularly imprinted polymer (MIP) film recognition units. To this end, we successfully applied a covalent approach to molecular imprinting, which involved formation of weak reversible covalent bonds between vicinal hydroxyl groups of arabitol and boronic acid substituents of the bithiophene functional monomer used. The MIP films were synthesized and simultaneously deposited on gold electrodes of quartz crystal resonators (Au-QCRs) or Au-glass slides by oxidative potentiodynamic electropolymerization. With the QCR and EG-FET chemosensors, the d-arabitol concentration was determined under flow-injection analysis and stagnant-solution binding conditions, respectively. Selectivity with respect to common interferences, and l-arabitol in particular, of the devised chemosensors was superior. Limits of detection and linear dynamic concentration ranges of the QCR and EG-FET chemosensors were 0.15 mM and 0.15 to 1.25 mM as well as 0.12 mM and 0.12 to 1.00 mM, respectively, being lower than the d-arabitol concentrations in urine of patients with invasive candidiasis (>220 MUM). Therefore, the devised chemosensors are suitable for early diagnosis of fungal infections caused by Candida sp. yeasts. PMID- 26761619 TI - An incremental double-layer capacitance of a planar nano gap and its application in cardiac-troponin T detection. AB - Surface potential is one of the most important properties at solid-liquid interfaces. It can be modulated by the voltage applied on the electrode or by the surface properties. Hence, surface potential is a good indicator for surface modifications, such as biomolecular bindings. In this work, we proposed a planar nano-gap structure for surface-potential difference monitoring. Based on the proposed architecture, the variance of surface-potential difference can be determined by electrical double layer capacitance (EDLC) between the nano-gap electrodes. Using cyclic voltammetry method, in this work, we demonstrated a relationship between surface potential and EDLC by chemically modifying surface properties. Finally, we also showed the proposed planar nano-gap device provides the capability for cardiac-troponin T (cTnT) measurements with co-existed 10 ug/ml BSA interference. The detection dynamic range is from 100 pg/ml to 1 ug/ml. Based on experimental results and extrapolation, the detection limit is less than 100 pg/ml in diluted PBS buffer (0.01X PBS). These results demonstrated the planar nano-gap architecture having potentials on biomolecular detection through monitoring of surface-potential variation. PMID- 26761621 TI - Increased arterial stiffness in South Dakota American Indian children. AB - Arterial stiffness has been observed in white American obese children, yet there are no data in American Indian youth, who are affected disproportionately by the cardiovascular consequences of childhood obesity and its accompanying risk factors. The purpose of this study was to determine the association of childhood overweight-obesity and cardiometabolic risk factors with arterial stiffness in South Dakota white American and American Indian children. Thirty-six (28 white American and 8 American Indian) children (age, 13 +/- 1 years; grades 6-8) from a rural South Dakota elementary and middle school were studied: 18 had a healthy weight (body mass index (BMI), 19.5 +/- 1.9 kg/m(2)) and 18 were overweight-obese (BMI, 26.8 +/- 3.5 kg/m(2)). Arterial stiffness was assessed using applanation tonometry via pulse wave analysis to determine carotid-radial pulse wave velocity (crPWV) and aortic augmentation index (AIx). There were no differences (P = 0.94) in crPWV between healthy weight (7.1 +/- 1.4 m/s) and overweight-obese (7.3 +/- 1.0 m/s) children, even after controlling for risk factors. However, crPWV was markedly elevated (P = 0.002) in overweight-obese American Indian children (7.7 +/- 1.1 m/s) compared with white American children (6.8 +/- 0.5 m/s), and these differences remained after controlling for blood pressure and more severe obesity in the American Indians. An obesity-matched subgroup analysis indicated that crPWV (7.7 +/- 1.1 vs 6.8 +/- 0.4 m/s) remained significantly greater in the American Indians (P = 0.03). There were no between-group differences in aortic AIx. These findings indicate an adverse influence of American Indian ethnicity on arterial stiffening in children with elevated adiposity. Arterial stiffness in American Indian children may accelerate early adulthood vascular disease. PMID- 26761620 TI - Human Induced Pluripotent Stem Cells for Tumor Targeted Delivery of Gold Nanorods and Enhanced Photothermal Therapy. AB - How to improve effective accumulation and intratumoral distribution of plasmonic gold nanoparticles has become a great challenge for photothermal therapy of tumors. Herein, we reported a nanoplatform with photothermal therapeutic effects by fabricating Au nanorods@SiO2@CXCR4 nanoparticles and loading the prepared nanoparticles into the human induced pluripotent stem cells(AuNRs-iPS). In virtue of the prominent optical properties of Au nanorods@SiO2@CXCR4 and remarkable tumor target migration ability of iPS cells, the Au nanorods delivery mediated by iPS cells via the nanoplatform AuNRs-iPS was found to have a prolonged retention time and spatially even distribution in MGC803 tumor-bearing nude mice observed by photoacoustic tomography and two-photon luminescence. On the basis of these improvements, the nanoplatform displayed a robust migration capacity to target the tumor site and to improve photothermal therapeutic efficacy on inhibiting the growth of tumors in xenograft mice under a low laser power density. The combination of gold nanorods with human iPS cells as a theranostic platform paves an alternative road for cancer theranostics and holds great promise for clinical translation in the near future. PMID- 26761623 TI - Design and Synthesis of Photodissociable Ligands Based on Azoimidazoles for Light Driven Coordination-Induced Spin State Switching in Homogeneous Solution. AB - Light-switchable azoimidazoles were rationally designed and synthesized, and their performance was investigated as photodissociable ligands (PDL) and for spin state switching of Ni porphyrins. The rationally designed ligands exhibit a high photochemical conversion rate (trans -> cis > 98%) and no measurable fatigue over a large number of switching cycles at room temperature under air. As compared to the known phenylazopyridines, the phenylazoimidazoles exhibit a much stronger affinity as axial ligands to Ni porphyrin in the binding trans configuration and a low affinity in their cis form. This affinity switching was used to control the coordination number of Ni(2+). Concomitant with the change in coordination number is the change of the spin state from triplet (high spin) to singlet state (low spin). We report on phenylazoimidazole-based PDLs that switch the paramagnetic ratio of the investigated nickel species by up to 70%. Consequently, azoimidazoles exhibit considerably higher switching efficiencies than previously described pyridine-based PDLs. PMID- 26761622 TI - Effects of exercise and dietary epigallocatechin gallate and beta-alanine on skeletal muscle in aged mice. AB - Aging leads to sarcopenia and loss of physical function. We examined whether voluntary wheel running, when combined with dietary supplementation with (-) epigallocatechin-3-gallate (EGCG) and beta-alanine (beta-ALA), could improve muscle function and alter gene expression in the gastrocnemius of aged mice. Seventeen-month-old BALB/cByJ mice were given access to a running wheel or remained sedentary for 41 days while receiving either AIN-93M (standard feed) or AIN-93M containing 1.5 mg.kg(-1) EGCG and 3.43 mg.kg(-1) beta-ALA. Mice underwent tests over 11 days from day 29 to day 39 of the study period, including muscle function testing (grip strength, treadmill exhaustive fatigue, rotarod). Following a rest day, mice were euthanized and gastrocnemii were collected for analysis of gene expression by quantitative PCR. Voluntary wheel running (VWR) improved rotarod and treadmill exhaustive fatigue performance and maintained grip strength in aged mice, while dietary intervention had no effect. VWR increased gastrocnemius expression of several genes, including those encoding interleukin-6 (Il6, p = 0.001), superoxide dismutase 1 (Sod1, p = 0.046), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a, p = 0.013), forkhead box protein O3 (Foxo3, p = 0.005), and brain-derived neurotrophic factor (Bdnf, p = 0.008), while reducing gastrocnemius levels of the lipid peroxidation marker 4-hydroxynonenal (p = 0.019). Dietary intervention alone increased gastrocnemius expression of Ppargc1a (p = 0.033) and genes encoding NAD-dependent protein deacetylase sirtuin-1 (Sirt1, p = 0.039), insulin-like growth factor I (Igf1, p = 0.003), and macrophage marker CD11b (Itgam, p = 0.016). Exercise and a diet containing beta-ALA and EGCG differentially regulated gene expression in the gastrocnemius of aged mice, while VWR but not dietary intervention improved muscle function. We found no synergistic effects between dietary intervention and VWR. PMID- 26761624 TI - Bone flap resorption following cranioplasty in a cost-constrained scenario. AB - Bone flap resorption is an infrequently reported yet significant late complication of autologous bone cranioplasty. It requires serial imaging both to pick up and to monitor progression. Custom-made implants avoid this complication, but are expensive. In a resource-limited situation, when bone flaps placed in the abdomen undergo demineralisation and sutures are used to fix the flap as opposed to plates, where artificial cranial flap substitutes are prohibitively expensive and frequent postoperative imaging may not be feasible, prevention and management of this complication will continue to remain a problem. PMID- 26761626 TI - 2-Amino-2-deoxy-glucose conjugated cobalt ferrite magnetic nanoparticle (2DG-MNP) as a targeting agent for breast cancer cells. AB - In this study, 2-amino-2-deoxy-glucose (2DG) was conjugated to COOH modified cobalt ferrite magnetic nanoparticles (COOH-MNPs), which were designed to target tumor cells as a potential targetable drug/gene delivery agent for cancer treatment. According to our results, it is apparent that, 2DG labeled MNPs were internalized more efficiently than COOH-MNPs under the same conditions in all cell types (MDA-MB-231 and MCF-7 cancer and MCF-10A normal breast cells) (p<0.001). Moreover, the highest amount of uptake was observed in MDA-MB-231, followed by MCF-7 and normal MCF-10A cells for both MNPs. The apoptotic effects of 2DG-MNPs were further evaluated, and it was found that apoptosis was not induced at low concentrations of 2DG-MNPs in all cell types, whereas dramatic cell death was observed at higher concentrations. In addition, the gene expression levels of four drug-metabolizing enzymes, two Phase I (CYP1A1, CYP1B1) and two Phase II (GSTM3, GSTZ1) were also increased with the high concentrations of 2DG-MNPs. PMID- 26761625 TI - Reduction in Late Mortality among 5-Year Survivors of Childhood Cancer. AB - BACKGROUND: Among patients in whom childhood cancer was diagnosed in the 1970s and 1980s, 18% of those who survived for 5 years died within the subsequent 25 years. In recent decades, cancer treatments have been modified with the goal of reducing life-threatening late effects. METHODS: We evaluated late mortality among 34,033 patients in the Childhood Cancer Survivor Study cohort who survived at least 5 years after childhood cancer (i.e., cancer diagnosed before the age of 21 years) for which treatment was initiated during the period from 1970 through 1999. The median follow-up was 21 years (range, 5 to 38). We evaluated demographic and disease factors that were associated with death from health related causes (i.e., conditions that exclude recurrence or progression of the original cancer and external causes but include the late effects of cancer therapy) using cumulative incidence and piecewise exponential models to estimate relative rates and 95% confidence intervals. RESULTS: Of the 3958 deaths that occurred during the study period, 1618 (41%) were attributable to health-related causes, including 746 deaths from subsequent neoplasms, 241 from cardiac causes, 137 from pulmonary causes, and 494 from other causes. A reduction in 15-year mortality was observed for death from any cause (from 12.4% in the early 1970s to 6.0% in the 1990s, P<0.001 for trend) and from health-related causes (from 3.5% to 2.1%, P<0.001 for trend). These reductions were attributable to decreases in the rates of death from subsequent neoplasm (P<0.001), cardiac causes (P<0.001), and pulmonary causes (P=0.04). Changes in therapy according to decade included reduced rates of cranial radiotherapy for acute lymphoblastic leukemia (85% in the 1970s, 51% in the 1980s, and 19% in the 1990s), of abdominal radiotherapy for Wilms' tumor (78%, 53%, and 43%, respectively), of chest radiotherapy for Hodgkin's lymphoma (87%, 79%, and 61%, respectively), and of anthracycline exposure. Reduction in treatment exposure was associated with reduced late mortality among survivors of acute lymphoblastic leukemia and Wilms' tumor. CONCLUSIONS: The strategy of lowering therapeutic exposure has contributed to an observed decline in late mortality among 5-year survivors of childhood cancer. (Funded by the National Cancer Institute and the American Lebanese-Syrian Associated Charities.). PMID- 26761627 TI - Pulmonary health effects of agriculture. AB - PURPOSE OF REVIEW: Occupational exposures in the agricultural industry are associated with numerous lung diseases, including chronic obstructive pulmonary disease, asthma, hypersensitivity pneumonitis, lung cancer, and interstitial lung diseases. Efforts are ongoing to ascertain contributing factors to these negative respiratory outcomes and improve monitoring of environmental factors leading to disease. In this review, recently published studies investigating the deleterious effects of occupational exposures in the agricultural industry are discussed. RECENT FINDINGS: Occupational exposures to numerous agricultural environment aerosols, including pesticides, fungi, and bacteria are associated with impaired respiratory function and disease. Increases in certain farming practices, including mushroom and greenhouse farming, present new occupational exposure concerns. Improved detection methods may provide opportunities to better monitor safe exposure levels to known lung irritants. SUMMARY: In the agricultural industry, occupational exposures to organic and inorganic aerosols lead to increased risk for lung disease among workers. Increased awareness of respiratory risks and improved monitoring of agricultural environments are necessary to limit pulmonary health risks to exposed populations. PMID- 26761629 TI - Update on flavoring-induced lung disease. AB - PURPOSE OF REVIEW: Since the initial report of bronchiolitis obliterans in microwave popcorn workers, exposures to flavoring substances have been identified in a variety of food and flavor manufacturing facilities and in the consumer market. Attempts to decrease the risk of lung disease have included the use of flavoring substitutes; however, these chemicals may cause similar injury. This article reviews recent flavoring exposures and data on the pathogenesis, clinical characteristics, and surveillance of flavoring-induced lung disease. RECENT FINDINGS: Diacetyl and 2,3-pentanedione exposures have occurred in food production facilities that make cookies, cereal, chocolate, and coffee. Airborne levels often exceed proposed occupational exposure limits. Cases of biopsy-proven bronchiolitis obliterans in heavy popcorn consumers have also been reported. New data demonstrate the presence of diacetyl and 2,3-pentanedione in flavored nicotine liquids used in electronic nicotine delivery systems. SUMMARY: Diacetyl substitutes cause similar peri-bronchiolar fibrotic lesions in animal studies. Their use may continue to place workers at risk for flavoring-induced lung disease, which may present in forms beyond that of fixed airflow obstruction, contributing to delays in identifying and treating patients with flavoring induced lung disease. Engineering controls, medical surveillance and personal protective equipment can limit flavorings exposure and risk for lung disease. PMID- 26761630 TI - Lung disease and coal mining: what pulmonologists need to know. AB - PURPOSE OF REVIEW: Coal mine workers are at risk for a range of chronic respiratory diseases including coal workers' pneumoconiosis, diffuse dust-related fibrosis, and chronic obstructive pulmonary disease. The purpose of this review is to describe coal mining processes and associated exposures to inform the diagnostic evaluation of miners with respiratory symptoms. RECENT FINDINGS: Although rates of coal workers' pneumoconiosis declined after regulations were enacted in the 1970s, more recent data shows a reversal in this downward trend. Rapidly progressive pneumoconiosis with progressive massive fibrosis (complicated coal workers' pneumoconiosis) is being observed with increased frequency in United States coal miners, with histologic findings of silicosis and mixed-dust pneumoconiosis. There is increasing evidence of decline in lung function in individuals with pneumoconiosis. Multiple recent cohort studies suggest increased risk of lung cancer in coal miners. SUMMARY: A detailed understanding of coal mining methods and processes allows clinicians to better evaluate and confirm chronic lung diseases caused by inhalational hazards in the mine atmosphere. PMID- 26761632 TI - Impacts of Ion Segregation on Local Optical Properties in Mixed Halide Perovskite Films. AB - Despite the recent astronomical success of organic-inorganic perovskite solar cells (PSCs), the impact of microscale film inhomogeneities on device performance remains poorly understood. In this work, we study CH3NH3PbI3 perovskite films using cathodoluminescence in scanning transmission electron microscopy and show that localized regions with increased cathodoluminescence intensity correspond to iodide-enriched regions. These observations constitute direct evidence that nanoscale stoichiometric variations produce corresponding inhomogeneities in film cathodoluminescence intensity. Moreover, we observe the emergence of high-energy transitions attributed to beam induced iodide segregation, which may mirror the effects of ion migration during PSC operation. Our results demonstrate that such ion segregation can fundamentally change the local optical and microstructural properties of organic-inorganic perovskite films in the course of normal device operation and therefore address the observed complex and unpredictable behavior in PSC devices. PMID- 26761628 TI - Pulmonary health effects of air pollution. AB - PURPOSE OF THE REVIEW: Air pollution continues to be a major public health concern affecting nine out of 10 individuals living in urban areas worldwide. Exposure to air pollution is the ninth leading risk factor for cardiopulmonary mortality. The aim of this review is to examine the current literature for the most recent updates on health effects of specific air pollutants and their impact on asthma, chronic obstructive pulmonary disease, lung cancer, and respiratory infection. RECENT FINDINGS: A total of 52 publications were reviewed to establish new insights as to how air pollution is associated with pulmonary morbidity and mortality. Considerable past evidence suggests that air pollution is an important factor that enhances pulmonary disease, while also causing greater harm in susceptible populations, such as children, the elderly, and those of low socio economic status worldwide. Asthma, chronic obstructive pulmonary disease, lung cancer, and respiratory infections all seem to be exacerbated because of exposure to a variety of environmental air pollutants with the greatest effects because of particulate matter, ozone, and nitrogen oxides. New publications reviewed reaffirm these findings. SUMMARY: Continued vigilance will be essential to lessen the effects of air pollution on human health and pulmonary disease. Cooperation at a multinational level will be required on the part of governments, industry, energy-based enterprises, and the public working together to solve our air quality issues at the local, national, and global level. PMID- 26761635 TI - DFTB/PCM Applied to Ground and Excited State Potential Energy Surfaces. AB - Accounting for solvent effects in quantum chemical calculations is vital for the accurate description of potential energy surfaces in solution. In this study, we derive a formulation of the analytical first-order geometrical derivative of ground- and excited-state energies within the time-dependent density-functional tight-binding (TD-DFTB) method with the polarizable continuum model (PCM), TD DFTB/PCM. The performance of this is then evaluated for a series of halogen exchange SN2 reactions. DFTB/PCM reproduces DFT results well for isolated monohalogenated methanes, but its agreement for transition structures significantly depends on the halogen element. The performance of TD-DFTB/PCM is evaluated for the excited-state intramolecular proton transfer (ESIPT) reaction of 3-hydroxyflavone (3HF) in ethanol. TD-DFTB/PCM reproduces the barrier height of the ESIPT reaction in terms of geometry and energy relatively well, but it fails to reproduce the experimental absorption and fluorescence energies as a consequence of the absence of long-range corrections. Computational timings with and without PCM show that the additional cost of PCM for C500H502 is only 10% greater than the corresponding calculation in vacuum. Furthermore, the potential applications of TD-DFTB/PCM are highlighted by applying it to a double-stranded DNA complexed with dye (PDB ID 108D ). We conclude that TD-DFTB/PCM single-point calculations and geometry optimizations for systems consisting of more than 1000 and 500 atoms, respectively, is now manageable and that properties predicted with TD-DFTB must be interpreted with care. PMID- 26761633 TI - Reducing the risk of rear-end collisions with infrastructure-to-vehicle (I2V) integration of variable speed limit control and adaptive cruise control system. AB - OBJECTIVE: Adaptive cruise control (ACC) has been investigated recently to explore ways to increase traffic capacity, stabilize traffic flow, and improve traffic safety. However, researchers seldom have studied the integration of ACC and roadside control methods such as the variable speed limit (VSL) to improve safety. The primary objective of this study was to develop an infrastructure-to vehicle (I2V) integrated system that incorporated both ACC and VSL to reduce rear end collision risks on freeways. METHODS: The intelligent driver model was firstly modified to simulate ACC behavior and then the VSL strategy used in this article was introduced. Next, the I2V system was proposed to integrate the 2 advanced techniques, ACC and VSL. Four scenarios of no control, VSL only, ACC only, and the I2V system were tested in simulation experiments. Time exposed time to collision (TET) and time integrated time to collision (TIT), 2 surrogate safety measures derived from time to collision (TTC), were used to evaluate safety issues associated with rear-end collisions. The total travel times of each scenario were also compared. RESULTS: The simulation results indicated that both the VSL-only and ACC-only methods had a positive impact on reducing the TET and TIT values (reduced by 53.0 and 58.6% and 59.0 and 65.3%, respectively). The I2V system combined the advantages of both ACC and VSL to achieve the most safety benefits (reduced by 71.5 and 77.3%, respectively). Sensitivity analysis of the TTC threshold also showed that the I2V system obtained the largest safety benefits with all of the TTC threshold values. The impact of different market penetration rates of ACC vehicles in I2V system indicated that safety benefits increase with an increase in ACC proportions. CONCLUSIONS: Compared to VSL-only and ACC-only scenarios, this integrated I2V system is more effective in reducing rear-end collision risks. The findings of this study provide useful information for traffic agencies to implement novel techniques to improve safety on freeways. PMID- 26761634 TI - Cross-arm binding efficiency of an EGFR x c-Met bispecific antibody. AB - Multispecific proteins, such as bispecific antibodies (BsAbs), that bind to two different ligands are becoming increasingly important therapeutic agents. Such BsAbs can exhibit markedly increased target binding and target residence time when both pharmacophores bind simultaneously to their targets. The cross-arm binding efficiency (chi) describes an increase in apparent affinity when a BsAb binds to the second target or receptor (R2) following its binding to the first target or receptor (R1) on the same cell. chi is an intrinsic characteristic of a BsAb mostly related to the binding epitopes on R1 and R2. chi can have significant impacts on the binding to R2 for BsAbs targeting two receptors on the same cell. JNJ-61186372, a BsAb that targets epidermal growth factor receptor (EGFR) and c-Met, was used as the model compound for establishing a method to characterize chi. The chi for JNJ-61186372 was successfully determined via fitting of in vitro cell binding data to a ligand binding model that incorporated chi. The model-derived chi value was used to predict the binding of JNJ-61186372 to individual EGFR and c-Met receptors on tumor cell lines, and the results agreed well with the observed IC50 for EGFR and c-Met phosphorylation inhibition by JNJ-61186372. Consistent with the model, JNJ-61186372 was shown to be more effective than the combination therapy of anti-EGFR and anti-c-Met monovalent antibodies at the same dose level in a mouse xenograft model. Our results showed that chi is an important characteristic of BsAbs, and should be considered for rationale design of BsAbs targeting two membrane bound targets on the same cell. PMID- 26761636 TI - IL-12 receptor 1beta deficiency with features of autoimmunity and photosensitivity. AB - Primary immunodeficiences are often accompanied by autoimmune phenomena. IL-12 receptor deficiency is a well characterized primary immunodeficiency that leads to propensity to intracellular infections mainly with mycobacteria and Salmonella. We report on two patients with IL-12 receptor beta1 deficiency that presented with autoimmune manifestations and photosensitivity dermatitis and describe possible pathogenetic mechanisms leading to development of clinically significant autoimmune phenomena. PMID- 26761637 TI - Diffusion Tensor Imaging in Patients with Glioblastoma Multiforme Using the Supertoroidal Model. AB - PURPOSE: Diffusion Tensor Imaging (DTI) is a powerful imaging technique that has led to improvements in the diagnosis and prognosis of cerebral lesions and neurosurgical guidance for tumor resection. Traditional tensor modeling, however, has difficulties in differentiating tumor-infiltrated regions and peritumoral edema. Here, we describe the supertoroidal model, which incorporates an increase in surface genus and a continuum of toroidal shapes to improve upon the characterization of Glioblastoma multiforme (GBM). MATERIALS AND METHODS: DTI brain datasets of 18 individuals with GBM and 18 normal subjects were acquired using a 3T scanner. A supertoroidal model of the diffusion tensor and two new diffusion tensor invariants, one to evaluate diffusivity, the toroidal volume (TV), and one to evaluate anisotropy, the toroidal curvature (TC), were applied and evaluated in the characterization of GBM brain tumors. TV and TC were compared with the mean diffusivity (MD) and fractional anisotropy (FA) indices inside the tumor, surrounding edema, as well as contralateral to the lesions, in the white matter (WM) and gray matter (GM). RESULTS: The supertoroidal model enhanced the borders between tumors and surrounding structures, refined the boundaries between WM and GM, and revealed the heterogeneity inherent to tumor infiltrated tissue. Both MD and TV demonstrated high intensities in the tumor, with lower values in the surrounding edema, which in turn were higher than those of unaffected brain parenchyma. Both TC and FA were effective in revealing the structural degradation of WM tracts. CONCLUSIONS: Our findings indicate that the supertoroidal model enables effective tensor visualization as well as quantitative scalar maps that improve the understanding of the underlying tissue structure properties. Hence, this approach has the potential to enhance diagnosis, preoperative planning, and intraoperative image guidance during surgical management of brain lesions. PMID- 26761638 TI - On the pharmacogenetics of non-small cell lung cancer treatment. AB - INTRODUCTION: Despite many clinical efforts, non-small-cell lung cancer (NSCLC) has a dismal 5-year survival rate of 16%, and high incidence of recurrence. The success of biologically targeted agents, as well as the activity of well established chemotherapeutic regimens, has been limited by inherited/acquired resistance, and biomarkers to adapt the prescription of anticancer drugs to patients' features are urgently warranted. Areas covered. In oncology, pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best match the individual and tumor genetic profile, thus allowing maximum activity and minimal toxicity. The present review summarizes the main findings on NSCLC pharmacogenetics, critically reappraising the most important studies on polymorphisms correlated with outcome of pemetrexed and EGFR inhibitors, and provides perspective on clinical application of genomic tests for treatment decision-making. Expert Opinion. A major challenge in NSCLC is the identification of subgroups of diseases/patients that will truly benefit from specific treatments. Ideally, convenient and minimally invasive tests to decipher biomarkers of chemosensitivity/resistance and toxicity should be developed alongside novel anticancer treatments. Integration with the latest generation of whole-genome analyses and liquid biopsies as well as prospective validation in large cohorts of patients will overcome the limitations of the traditional pharmacogenetic approaches. PMID- 26761640 TI - [Radiotherapy and breast conserving therapy: past, present and future]. AB - Clinical trials in the 1970s and 80s showed the survival rate of women with early breast cancer (stage I-II, 0-5 cm) who underwent treatment by means of breast conserving therapy (BCT) to be equal to that of those who underwent radical mastectomy. Since the 1980s the risk of both local recurrence and late toxicity after BCT has been significantly reduced. Studies are identifying subgroups of patients with low-risk breast cancer in whom it is possible to abstain from giving further radiation treatment. Over recent years the number of effective systemic therapy options has increased, leading to a reduction in the risk of recurrence in breast cancer. Developments in genetic profiling are expected to lead to further individualized loco-regional treatment. PMID- 26761639 TI - Spatial regulation of greatwall by Cdk1 and PP2A-Tws in the cell cycle. AB - Entry into mitosis requires the phosphorylation of multiple substrates by cyclin B-Cdk1, while exit from mitosis requires their dephosphorylation, which depends largely on the phosphatase PP2A in complex with its B55 regulatory subunit (Tws in Drosophila). At mitotic entry, cyclin B-Cdk1 activates the Greatwall kinase, which phosphorylates Endosulfine proteins, thereby activating their ability to inhibit PP2A-B55 competitively. The inhibition of PP2A-B55 at mitotic entry facilitates the accumulation of phosphorylated Cdk1 substrates. The coordination of these enzymes involves major changes in their localization. In interphase, Gwl is nuclear while PP2A-B55 is cytoplasmic. We recently showed that Gwl suddenly relocalizes from the nucleus to the cytoplasm in prophase, before nuclear envelope breakdown and that this controlled localization of Gwl is required for its function. We and others have shown that phosphorylation of Gwl by cyclin B Cdk1 at multiple sites is required for its nuclear exclusion, but the precise mechanisms remained unclear. In addition, how Gwl returns to its nuclear localization was not explored. Here we show that cyclin B-Cdk1 directly inactivates a Nuclear Localization Signal in the central region of Gwl. This phosphorylation facilitates the cytoplasmic retention of Gwl, which is exported to the cytoplasm in a Crm1-dependent manner. In addition, we show that PP2A-Tws promotes the return of Gwl to its nuclear localization during cytokinesis. Our results indicate that the cyclic changes in Gwl localization at mitotic entry and exit are directly regulated by the antagonistic cyclin B-Cdk1 and PP2A-Tws enzymes. PMID- 26761642 TI - Systematic review to determine the prevalence of transmitted drug resistance mutations to rilpivirine in HIV-infected treatment-naive persons. AB - BACKGROUND: Transmitted drug resistance to antiretrovirals in HIV-1-infected individuals is rising in some regions and could compromise the effectiveness of first-line treatment. It is important to understand the prevalence of resistance to rilpivirine to inform treatment provision. METHODS: A PUBMED/EMBASE search identified analyses of transmitted genotypic resistance to specific non nucleoside reverse transcriptase inhibitor mutations worldwide. Patients were to be HIV-1-infected and antiretroviral-naive. Rilpivirine mutations assessed were: L100I, K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188L, H221Y, F227C and M230I/L. Additionally, frequency of resistance mutations were extracted and pooled by HIV subtype from the Stanford HIV drug resistance database. RESULTS: 138 eligible articles from 65 countries were identified (n=64,466). Among these 64,466 samples, 7 of the 9 genotypic rilpivirine mutations had a prevalence <0.1%. Two mutations were more prevalent: E138A/G/K/Q/R (0.7%, 95% CI 0.2, 1.3) and Y181C/I/V (0.3%, 95% CI 0.2, 0.4). Prevalence of E138 rilpivirine-related mutations varied between regions: highest in Latin America/Caribbean (3.6%, 95% CI 1.0, 7.6) and in Europe (3.2%, 95% CI 0.7, 6.9). Pooled results from the Stanford database (n=52,680) correlated with these findings indicating a low prevalence of 8/9 rilpivirine mutations (<0.1%), except for E138A/G/K/Q/R (2.9%, 95% CI 1.8, 4.4). Prevalence of the mutations at E138 varied significantly by HIV subtype and was highest for subtype-C (6.1%), subtype-F (5.1%) and subtype-A (3.3%). CONCLUSIONS: The prevalence of most transmitted rilpivirine-related HIV mutations is generally low in treatment-naive HIV-1-infected individuals (<0.1%). The prevalence of E138A/G/K/Q/R mutations is higher (0.7%) and varies according to geographical region and HIV subtype. PMID- 26761643 TI - Quantification and Statistical Analysis Methods for Vessel Wall Components from Stained Images with Masson's Trichrome. AB - PURPOSE: To develop a digital image processing method to quantify structural components (smooth muscle fibers and extracellular matrix) in the vessel wall stained with Masson's trichrome, and a statistical method suitable for small sample sizes to analyze the results previously obtained. METHODS: The quantification method comprises two stages. The pre-processing stage improves tissue image appearance and the vessel wall area is delimited. In the feature extraction stage, the vessel wall components are segmented by grouping pixels with a similar color. The area of each component is calculated by normalizing the number of pixels of each group by the vessel wall area. Statistical analyses are implemented by permutation tests, based on resampling without replacement from the set of the observed data to obtain a sampling distribution of an estimator. The implementation can be parallelized on a multicore machine to reduce execution time. RESULTS: The methods have been tested on 48 vessel wall samples of the internal saphenous vein stained with Masson's trichrome. The results show that the segmented areas are consistent with the perception of a team of doctors and demonstrate good correlation between the expert judgments and the measured parameters for evaluating vessel wall changes. CONCLUSION: The proposed methodology offers a powerful tool to quantify some components of the vessel wall. It is more objective, sensitive and accurate than the biochemical and qualitative methods traditionally used. The permutation tests are suitable statistical techniques to analyze the numerical measurements obtained when the underlying assumptions of the other statistical techniques are not met. PMID- 26761641 TI - comets (Constrained Optimization of Multistate Energies by Tree Search): A Provable and Efficient Protein Design Algorithm to Optimize Binding Affinity and Specificity with Respect to Sequence. AB - Practical protein design problems require designing sequences with a combination of affinity, stability, and specificity requirements. Multistate protein design algorithms model multiple structural or binding "states" of a protein to address these requirements. comets provides a new level of versatile, efficient, and provable multistate design. It provably returns the minimum with respect to sequence of any desired linear combination of the energies of multiple protein states, subject to constraints on other linear combinations. Thus, it can target nearly any combination of affinity (to one or multiple ligands), specificity, and stability (for multiple states if needed). Empirical calculations on 52 protein design problems showed comets is far more efficient than the previous state of the art for provable multistate design (exhaustive search over sequences). comets can handle a very wide range of protein flexibility and can enumerate a gap-free list of the best constraint-satisfying sequences in order of objective function value. PMID- 26761644 TI - Clinical and economic benefits of extended treatment with apixaban for the treatment and prevention of recurrent venous thromboembolism in Canada. AB - Background and objective Venous thromboembolism (VTE) is associated with long term clinical and economic burden. Clinical guidelines generally recommend at least 3 months of anticoagulation, but, in clinical practice, concerns over bleeding risk often limit extended treatment. Apixaban was studied for extended VTE treatment in the AMPLIFY-EXT trial, demonstrating superiority to placebo in VTE reduction without increasing risk of major bleeding. This study assessed the long-term clinical and economic benefits of extending treatment with apixaban when clinical equipoise exists compared to standard of care with enoxaparin/warfarin and other novel oral anti-coagulants (NOACs) for the treatment and prevention of recurrent VTE in Canada. Methods A Markov model was developed to follow patients with VTE over their lifetimes. Efficacy and safety for apixaban and enoxaparin/warfarin were based on AMPLIFY and AMPLIFY-EXT, while relative efficacy to other NOACs was synthesized by network meta-analysis (NMA). Dosages for NOACs and enoxaparin/warfarin were based on their respective trials and were given up to 18 months and up to 6 months, followed by no treatment, respectively. Patient quality adjusted life years (QALYs) were based on published studies, and costs for resource utilization were from a Ministry of Health perspective, expressed as 2014 CAD ($). Results Extended treatment with apixaban compared to enoxaparin/warfarin resulted in fewer recurrent VTEs, VTE-related deaths, and bleeding events, but at slightly increased cost. The incremental cost effectiveness ratio was $4828 per QALY gained. Compared to other NOACs, apixaban had the fewest bleeding events, similar recurrent VTE events, and the lowest overall cost, which was driven by the strong bleeding profile. In scenario analyses of acute and lifetime treatments, apixaban was cost-effective against all strategies. Conclusions Extended treatment with apixaban can offer substantial clinical benefits and is a cost-effective alternative to enoxaparin/warfarin and other NOACs. PMID- 26761645 TI - The Curious Acoustic Behavior of Estuarine Snapping Shrimp: Temporal Patterns of Snapping Shrimp Sound in Sub-Tidal Oyster Reef Habitat. AB - Ocean soundscapes convey important sensory information to marine life. Like many mid-to-low latitude coastal areas worldwide, the high-frequency (>1.5 kHz) soundscape of oyster reef habitat within the West Bay Marine Reserve (36 degrees N, 76 degrees W) is dominated by the impulsive, short-duration signals generated by snapping shrimp. Between June 2011 and July 2012, a single hydrophone deployed within West Bay was programmed to record 60 or 30 seconds of acoustic data every 15 or 30 minutes. Envelope correlation and amplitude information were then used to count shrimp snaps within these recordings. The observed snap rates vary from 1500-2000 snaps per minute during summer to <100 snaps per minute during winter. Sound pressure levels are positively correlated with snap rate (r = 0.71-0.92) and vary seasonally by ~15 decibels in the 1.5-20 kHz range. Snap rates are positively correlated with water temperatures (r = 0.81-0.93), as well as potentially influenced by climate-driven changes in water quality. Light availability modulates snap rate on diurnal time scales, with most days exhibiting a significant preference for either nighttime or daytime snapping, and many showing additional crepuscular increases. During mid-summer, the number of snaps occurring at night is 5-10% more than predicted by a random model; however, this pattern is reversed between August and April, with an excess of up to 25% more snaps recorded during the day in the mid-winter. Diurnal variability in sound pressure levels is largest in the mid-winter, when the overall rate of snapping is at its lowest, and the percentage difference between daytime and nighttime activity is at its highest. This work highlights our lack of knowledge regarding the ecology and acoustic behavior of one of the most dominant soniforous invertebrate species in coastal systems. It also underscores the necessity of long-duration, high-temporal-resolution sampling in efforts to understand the bioacoustics of animal behaviors and associated changes within the marine soundscape. PMID- 26761646 TI - Correction: New Fungus-Insect Symbiosis: Culturing, Molecular, and Histological Methods Determine Saprophytic Polyporales Mutualists of Ambrosiodmus Ambrosia Beetles. PMID- 26761647 TI - Aetiology of Acute Respiratory Tract Infections in Hospitalised Children in Cyprus. AB - In order to improve clinical management and prevention of viral infections in hospitalised children improved etiological insight is needed. The aim of the present study was to assess the spectrum of respiratory viral pathogens in children admitted to hospital with acute respiratory tract infections in Cyprus. For this purpose nasopharyngeal swab samples from 424 children less than 12 years of age with acute respiratory tract infections were collected over three epidemic seasons and were analysed for the presence of the most common 15 respiratory viruses. A viral pathogen was identified in 86% of the samples, with multiple infections being observed in almost 20% of the samples. The most frequently detected viruses were RSV (30.4%) and Rhinovirus (27.4%). RSV exhibited a clear seasonality with marked peaks in January/February, while rhinovirus infections did not exhibit a pronounced seasonality being detected almost throughout the year. While RSV and PIV3 incidence decreased significantly with age, the opposite was observed for influenza A and B as well as adenovirus infections. The data presented expand our understanding of the epidemiology of viral respiratory tract infections in Cypriot children and will be helpful to the clinicians and researchers interested in the treatment and control of viral respiratory tract infections. PMID- 26761667 TI - Effects of Mechanically Deboned Chicken Meat (MDCM) and Collagen on the Quality Characteristics of Semi-dried Chicken Jerky. AB - This study was conducted to determine the effects of using mechanically deboned chicken meat (MDCM) and collagen on quality characteristics of semi-dried chicken jerky. In experiment I, semi-dried chicken jerky was prepared with the replacement of chicken breast with MDCM (0, 10, 20, and 30%). The pH value of the jerky formulated with only chicken breast was 5.94, while the replacement of chicken breast with MDCM significantly increased the pH (p<0.05). The protein content and shear force of the jerkies decreased with increasing amounts of MDCM, whereas the fat, ash content and processing yield showed the opposite tendency (p<0.05). Replacement with up to 10% MDCM had no adverse effects on the sensory characteristics of the semi-dried chicken jerky. In experiment II, four levels of pork collagen (0, 1, 2, and 3%) were added to the semi-dried chicken jerky formulated with 90% chicken breast and 10% MDCM. The addition of collagen increased the moisture content, but decreased the ash content of the jerkies produced (p<0.05). The processing yield of the jerkies increased with increasing added amounts of collagen (p<0.05). It was found that the jerkies formulated with 0-2% collagen had significantly higher overall acceptance score than those prepared with 3% collagen (p<0.05). In conclusion, MDCM and collagen could be useful ingredients to reduce the production cost and improve the processing yield of semi-dried chicken jerky. The optimal levels of MDCM and collagen which could be added without adverse effects on the sensory characteristics were up to 10% and 2%, respectively. PMID- 26761666 TI - Biogeochemical, Isotopic and Bacterial Distributions Trace Oceanic Abyssal Circulation. AB - We explore the possibility of tracing routes of dense waters toward and within the ocean abyss by the use of an extended set of observed physical and biochemical parameters. To this purpose, we employ mercury, isotopic oxygen, biopolymeric carbon and its constituents, together with indicators of microbial activity and bacterial diversity found in bottom waters of the Eastern Mediterranean. In this basin, which has been considered as a miniature global ocean, two competing sources of bottom water (one in the Adriatic and one in the Aegean seas) contribute to the ventilation of the local abyss. However, due to a recent substantial reduction of the differences in the physical characteristics of these two water masses it has become increasingly complex a water classification using the traditional approach with temperature, salinity and dissolved oxygen alone. Here, we show that an extended set of observed physical and biochemical parameters allows recognizing the existence of two different abyssal routes from the Adriatic source and one abyssal route from the Aegean source despite temperature and salinity of such two competing sources of abyssal water being virtually indistinguishable. Moreover, as the near-bottom development of exogenous bacterial communities transported by convectively-generated water masses in the abyss can provide a persistent trace of episodic events, intermittent flows like those generating abyssal waters in the Eastern Mediterranean basin may become detectable beyond the availability of concomitant measurements. PMID- 26761668 TI - Probabilistic Models to Predict the Growth Initiation Time for Pseudomonas spp. in Processed Meats Formulated with NaCl and NaNO2. AB - This study developed probabilistic models to determine the initiation time of growth of Pseudomonas spp. in combinations with NaNO2 and NaCl concentrations during storage at different temperatures. The combination of 8 NaCl concentrations (0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, and 1.75%) and 9 NaNO2 concentrations (0, 15, 30, 45, 60, 75, 90, 105, and 120 ppm) were prepared in a nutrient broth. The medium was placed in the wells of 96-well microtiter plates, followed by inoculation of a five-strain mixture of Pseudomonas in each well. All microtiter plates were incubated at 4, 7, 10, 12, and 15C for 528, 504, 504, 360 and 144 h, respectively. Growth (growth initiation; GI) or no growth was then determined by turbidity every 24 h. These growth response data were analyzed by a logistic regression to produce growth/no growth interface of Pseudomonas spp. and to calculate GI time. NaCl and NaNO2 were significantly effective (p<0.05) on inhibiting Pseudomonas spp. growth when stored at 4-12C. The developed model showed that at lower NaCl concentration, higher NaNO2 level was required to inhibit Pseudomonas growth at 4-12C. However, at 15C, there was no significant effect of NaCl and NaNO2. The model overestimated GI times by 58.2+/-17.5 to 79.4+/-11%. These results indicate that the probabilistic models developed in this study should be useful in calculating the GI times of Pseudomonas spp. in combination with NaCl and NaNO2 concentrations, considering the over-prediction percentage. PMID- 26761669 TI - Evaluation of the Activities of Antioxidant Enzyme and Lysosomal Enzymes of the Longissimus dorsi Muscle from Hanwoo (Korean Cattle) in Various Freezing Conditions. AB - This study was conducted to evaluate the activities of antioxidant enzyme (glutathione peroxidase (GSH-Px)) and lysosomal enzymes (alpha-glucopyranosidase (AGP) and beta-N-acetyl-glucosaminidase (BNAG)) of the longissimus dorsi (LD) muscle from Hanwoo (Korean cattle) in three freezing conditions. Following freezing at -20, -60, and -196C (liquid nitrogen), LD samples (48 h post slaughter) were treated as follows: 1) freezing for 14 d, 2) 1 to 4 freeze-thaw cycles (2 d of freezing in each cycle), and 3) refrigeration (4C) for 7 d after 7 d of freezing. The control was the fresh (non-frozen) LD. Freezing treatment at all temperatures significantly (p<0.05) increased the activities of GSH-Px, AGP, and BNAG. The -196 C freezing had similar effects to the -20C and -60C freezing. Higher (p<0.05) enzymes activities were sustained in frozen LD even after 4 freeze-thaw cycles and even for 7 d of refrigeration after freezing. These findings suggest that freezing has remarkable effects on the activities of antioxidant enzyme and lysosomal enzymes of Hanwoo beef in any condition. PMID- 26761670 TI - Rapid Determination of L-carnitine in Infant and Toddler Formulas by Liquid Chromatography Tandem Mass Spectrometry. AB - A rapid and simple analytical method for L-carnitine was developed for infant and toddler formulas by liquid chromatography tandem mass spectrometry (LC-MS/MS). A 0.3 g of infant formula and toddler formula sample was mixed in a 50 mL conical tube with 9 mL water and 1 mL 0.1 M hydrochloric acid (HCl) to chemical extraction. Then, chloroform was used for removing a lipid fraction. After centrifuged, L-carnitine was separated and quantified using LC-MS/MS with electrospray ionization (ESI) mode. The precursor ion for L-carnitine was m/z 162, and product ions were m/z 103 (quantitative) and m/z 85 (qualitative), respectively. The results for spiked recovery test were in the range of 93.18 95.64% and the result for certified reference material (SRM 1849a) was within the range of the certificated values. This method could be implemented in many laboratories that require time and labor saving. PMID- 26761671 TI - Studies on Physical and Sensory Properties of Premium Vanilla Ice Cream Distributed in Korean Market. AB - The object of this study was to investigate the difference in physical and sensory properties of various premium ice creams. The physical properties of the various ice creams were compared by manufacturing brand. The water contents of the samples differed, with BR having the highest value at 60.5%, followed by NT and CS at 57.8% and 56.9%, respectively. The higher the water content, the lower Brix and milk fat contents in all samples. The density of the samples showed almost similar values in all samples (p>0.05). The viscosity of each ice cream had no effect on the water content in any of the brands. Before melting of the ice cream, the total color difference was dependent on the lightness, especially in the vanilla ice cream, owing to the reflection of light on the surface of the ice crystals. The CS product melted the fastest. In the sensory test, CS obtained a significantly higher sweetness intensity score but a lower score for color intensity, probably due to the smaller difference in total color, by which consumers might consider the color of CS as less intense. From this study, the cold chain system for ice cream distribution might be important to decide the physical properties although the concentration of milk fat is key factor in premium ice cream. PMID- 26761672 TI - Comparison of the Microsatellite and Single Nucleotide Polymorphism Methods for Discriminating among Hanwoo (Korean Native Cattle), Imported, and Crossbred Beef in Korea. AB - The identity of 45 Hanwo and 47 imported beef (non-Hanwoo) samples from USA and Australia were verified using the microsatellite (MS) marker and single nucleotide polymorphism (SNP) methods. Samples were collected from 19 supermarkets located in the city of Seoul and Gyeonggi province, South Korea, from 2009 to 2011. As a result, we obtained a 100% concordance rate between the MS and SNP methods for identifying Hanwoo and non-Hanwoo beef. The MS method presented a 95% higher individual discriminating value for Hanwoo (97.8%) than for non-Hanwoo (61.7%) beef. For further comparison of the MS and SNP methods, blood samples were collected and tested from 54 Hanwoo * Holstein crossbred cattle (first, second, and third generations). By using the SNP and MS methods, we correctly identified all of the first-generation crossbred cattle as non Hanwoo; in addition, among the second and third generation crossbreds, the ratio identified as Hanwoo was 20% and 10%, respectively. The MS method used in our study provides more information, but requires sophisticated techniques during each experimental process. By contrast, the SNP method is simple and has a lower error rate. Our results suggest that the MS and SNP methods are useful for discriminating Hanwoo from non-Hanwoo breeds. PMID- 26761673 TI - Preparation and Characterization of Antioxidant Peptides from Fermented Goat Placenta. AB - The goat placenta was fermented by Bacillus subtilis and the optimal fermentation parameters of strongest antioxidant capacity of peptides were obtained using response surface methodology (RSM). The effects of fermentation time, initial pH value and glucose content on the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging capacity of the goat peptides were well fitted to a quadric equation with high determination coefficients. According to the data analysis of design expert, the strongest DPPH radical scavenging capacity value was obtained with the following conditions: content of glucose was 2.23%, initial pH value was 7.00 and fermentation time was 32.15 h. The DPPH radical scavenging capacity commonly referring antioxidant activity showed a concentration dependency and increased with increasing peptide concentration. The effects of temperature and pH were assessed to determine the stability of antioxidant peptides prepared from goat placenta. Antioxidant peptides showed good stabilities when temperature was lower than 70C. However, the antioxidant peptides lost antioxidant activities rapidly under alkaline and excessive acid condition. Ultrafiltration technique was performed to separate fermentation broth with different Mw (molecular weight). It was found that peptides in the range of < 3 KDa mainly accounted for the antioxidant activities. PMID- 26761675 TI - Effects of Ground, Concentrated, and Powdered Beef on the Quality of Noodle Products. AB - The aim of this study was to ascertain the effects of beef on the quality characteristics, such as color, texture profile, water absorption ratio, volume, turbidity, and sensory evaluation, of noodle products. Various types of beef were added to the flour at a mixture ratio of ground beef (BG) 10, 15, 20, 25%; concentrated beef (BC) 9, 11, 13, 15%; and powdered beef (BP) 1, 3, 5, 7%. Each treatment was analyzed and compared with a 100% flour noodle as a control. With increasing BG, BC, and BP ratios, the L and b values for color decreased, while the a value increased, from that in the control. The hardness of the noodles treated with BG increased with increasing mixture ratios, but hardness decreased in the BC and BP treatments with increasing mixture ratios (p<0.05). The noodles with the largest beef composition in the mixtures of each treatment exhibited the highest turbidity scores, which was believed to be because the solid contents would be transferred to the soup during heating. In the sensory evaluation of cooked noodles, the BG 10%, BC 9%, and BP 1% treatments exhibited the best color. In an overall preference test, 20% of BG and 3% of BP could be added to the noodles. The best palatability was exhibited by the BG 10%, BC 13%, and BP 3% treatments. PMID- 26761674 TI - Effect of Novel Quick Freezing Techniques Combined with Different Thawing Processes on Beef Quality. AB - This study investigated the effect of various freezing and thawing techniques on the quality of beef. Meat samples were frozen using natural convection freezing (NF), individual quick freezing (IQF), or cryogenic freezing (CF) techniques, followed by natural convection thawing (NCT) or running water thawing (RT). The meat was frozen until the core temperature reached -12C and then stored at -24C, followed by thawing until the temperature reached 5C. Quality parameters, such as the pH, water binding properties, CIE color, shear force, and microstructure of the beef were elucidated. Although the freezing and thawing combinations did not cause remarkable changes in the quality parameters, rapid freezing, in the order of CF, IQF, and NF, was found to minimize the quality deterioration. In the case of thawing methods, NCT was better than RT and the meat quality was influence on the thawing temperature rather than the thawing rate. Although the microstructure of the frozen beef exhibited an excessive loss of integrity after the freezing and thawing, it did not cause any remarkable change in the beef quality. Taken together, these results demonstrate that CF and NCT form the best combination for beef processing; however, IQF and NCT may have practical applications in the frozen food industry. PMID- 26761676 TI - Distribution Channel and Microbial Characteristics of Pig By-products in Korea. AB - The distribution channel of meat by-products from the pig farm to the final consumer can include a meat processor, wholesale market, wholesaler, retailer, and butcher shop. Bacterial contamination at any of these steps remains to be a serious public health concern. The aim of this study was to evaluate the distribution channel and microbial characteristics of pig by-products in Korea. Upon evaluation of pig by-products in cold storage, we found that the small and large intestine were significantly (p<0.05) higher in pH value compared to the heart and liver. The total plate counts were not significantly different among offals until cold storage for 7 d. The coliform count after 1 d of cold storage was significantly (p<0.05) higher in small and large intestine than in the other organs. The coliform count of heart, liver, and stomach showed a higher coliform count than small and large intestine until 7 d of cold storage. As determined by 16S rRNA sequencing, contamination of major pig by-products with Escherichia coli, Shigella spp., and other bacterial species occurred. Therefore, our results suggest that a more careful washing process is needed to maintain quality and hygiene and to ensure the safety of pig by-products, especially for small and large intestine. PMID- 26761677 TI - Meat Species Identification using Loop-mediated Isothermal Amplification Assay Targeting Species-specific Mitochondrial DNA. AB - Meat source fraud and adulteration scandals have led to consumer demands for accurate meat identification methods. Nucleotide amplification assays have been proposed as an alternative method to protein-based assays for meat identification. In this study, we designed Loop-mediated isothermal amplification (LAMP) assays targeting species-specific mitochondrial DNA to identify and discriminate eight meat species; cattle, pig, horse, goat, sheep, chicken, duck, and turkey. The LAMP primer sets were designed and the target genes were discriminated according to their unique annealing temperature generated by annealing curve analysis. Their unique annealing temperatures were found to be 85.56+/-0.07C for cattle, 84.96+/-0.08C for pig, and 85.99+/-0.05C for horse in the BSE-LAMP set (Bos taurus, Sus scrofa domesticus and Equus caballus); 84.91+/ 0.11C for goat and 83.90+/-0.11C for sheep in the CO-LAMP set (Capra hircus and Ovis aries); and 86.31+/-0.23C for chicken, 88.66+/-0.12C for duck, and 84.49+/ 0.08C for turkey in the GAM-LAMP set (Gallus gallus, Anas platyrhynchos and Meleagris gallopavo). No cross-reactivity was observed in each set. The limits of detection (LODs) of the LAMP assays in raw and cooked meat were determined from 10 pg/MUL to 100 fg/MUL levels, and LODs in raw and cooked meat admixtures were determined from 0.01% to 0.0001% levels. The assays were performed within 30 min and showed greater sensitivity than that of the PCR assays. These novel LAMP assays provide a simple, rapid, accurate, and sensitive technology for discrimination of eight meat species. PMID- 26761678 TI - Effect of NaCl, Gum Arabic and Microbial Transglutaminase on the Gel and Emulsion Characteristics of Porcine Myofibrillar Proteins. AB - This study investigated the effect of gum arabic (GA) combined with microbial transglutaminase (TG) on the functional properties of porcine myofibrillar protein (MP). As an indicator of functional property, heat-set gel and emulsion characteristics of MP treated with GA and/or TG were explored under varying NaCl concentrations (0.1-0.6 M). The GA improved thermal gelling ability of MP during thermal processing and after cooling, and concomitantly added TG assisted the formation of viscoelastic MP gel formation. Meanwhile, the addition of GA decreased cooking yield of MP gel at 0.6 M NaCl concentration, and the yield was further decreased by TG addition, mainly attributed by enhancement of protein protein interactions. Emulsion characteristics indicated that GA had emulsifying ability and the addition of GA increased the emulsification activity index (EAI) of MP-stabilized emulsion. However, GA showed a negative effect on emulsion stability, particularly great drop in the emulsion stability index (ESI) was found in GA treatment at 0.6 M NaCl. Consequently, the results indicated that GA had a potential advantage to form a viscoelastic MP gel. For the practical aspect, the application of GA in meat processing had to be limited to the purposes of texture enhancer such as restructured products, but not low-salt products and emulsion-type meat products. PMID- 26761679 TI - Changes in the Microbiological Characteristics of Korean Native Cattle (Hanwoo) Beef Exposed to Ultraviolet (UV) Irradiation Prior to Refrigeration. AB - The effects of ultraviolet (UV) radiation were investigated with regards to the microbial growth inhibitory effect on the shelf life of Korean native cattle (Hanwoo) beef prior to refrigerated storage. The Hanwoo samples were exposed to UV radiation (4.5 mW/cm(2)) for 0, 5, 10, 15, and 20 min. The UV-irradiated beef that was exposed for 20 min showed significantly reduced mesophilic and psychrotrophic bacterial populations to the extent of approximately 3 log cycles, as compared to that of non-irradiated beef. About 2.5 Log CFU/g of mesophilic bacteria were different compared with UV-irradiated and nonirradiated meat. UV irradiation showed the most significant growth inhibition effects on mesophilic and psychrotrophic bacteria. Coliform and Gram-negative bacteria were also reduced by 1 log cycle. The population of L. monocytogenes, S. Typhimurium, and E. coli O157:H7 decreased significantly to 53.33, 39.68, and 45.76% after 10 min of UV irradiation. They decreased significantly to 84.64, 80.76, and 84.12%, respectively, after 20 min of UV irradiation. The results show that UV irradiation time and the inhibitory effect were proportional. These results verified that UV radiation prior to refrigeration can effectively reduce the number of pathogenic bacteria on the surface of meat and improve the meat's microbial safety. PMID- 26761680 TI - Skeletal Muscle Troponin I (TnI) in Animal Fat Tissues to Be Used as Biomarker for the Identification of Fat Adulteration. AB - In this study, the existence of skeletal muscle troponin I (smTnI), well-known as a muscle protein in fat tissues, and the utilization of smTnI as a biomarker for the identification of fat adulteration were investigated. A commercial antibody (ab97427) specific to all of animals smTnI was used in this study. Fat and meat samples (cooked and non-cooked) of pork and beef, and chicken considered as representative meats were well minced and extracted by heating and non-heating methods, and the extracts from fat and meat tissues were probed by the antibody used in both enzyme-linked immunosorbent assay (ELISA) and immunoblot. The antibody exhibited a strong reaction to all meat and fat extracts in ELISA test. On the other hand, the results of immunoblot analsis revealed a 23 kDa high intensity band corresponding to the molecular weight of smTnI (23786 Da). These results demonstrate that the existence of smTnI in all animal fat tissues. Since there are monoclonal antibodies specific to each species smTnI, smTnI in fat tissues could be used as a biomarker to identify or determine animal species adulterated in meat products. Therefore, an analytical method to identify fraudulent fat adulteration can be developed with an antibody specific to each species smTnI. PMID- 26761682 TI - Application of Response Surface Methodology (RSM) for Optimization of Anti Obesity Effect in Fermented Milk by Lactobacillus plantarum Q180. AB - Obesity, a condition in which an abnormally large amount of fat is stored in adipose tissue, causing an increase in body weight, has become a major public health concern worldwide. The purpose of this study was to optimize the process for fermented milk for the production of a functional product with an anti obesity effect by using Lactobacillus plantarum Q180 isolated from human feces. We used a 3-factor, 3-level central composite design (CCD) combined with the response surface methodology (RSM). Concentration of skim milk powder (%, X1), incubation temperature (C, X2), and incubation time (h, X3) were used as the independent factors, whereas pH (pH, Y1), anti-lipase activity (%, Y2) and anti adipogenetic activity (%, Y3) were used as the dependent factors. The optimal conditions of fermented milk for the highest anti-lipase and antiadipogenetic activity with pH 4.4 were the 9.5% of skim milk powder, 37C of incubation temperature, 28 h of incubation time. In the fermentation condition, the predicted values of pH, anti-lipase activity and anti-adipogenetic activity were 4.47, 55.55, and 20.48%, respectively. However, the actual values of pH, anti lipase activity and anti-adipogenetic activity were 4.50, 52.86, and 19.25%, respectively. These results demonstrate that 9.5% of skim milk powder and incubation at 37C for 28 h were the optimum conditions for producing functional fermented milk with an anti-obesity effect. PMID- 26761683 TI - Anti-oxidation and Anti-wrinkling Effects of Jeju Horse Leg Bone Hydrolysates. AB - This study focused on the anti-oxidative and collagenase- and elastase inhibition effects of low molecular weight peptides (LMP) from commercial Jeju horse leg bone hydrolysates (JHLB) on pancreatin, via enzymatic hydrolysis. Cell viability of dermal fibroblasts exposed to UVB radiation upon treatment with LMP from JHLB was evaluated. Determination of the antioxidant activity of various concentrations of LMP from JHLB were carried out by assessing 1,1-diphenyl-2 picrylhydrazyl (DPPH) and 2,2-azino-bis-3-ethybenzothiazoline-6-sulphonic acid (ABTS) radical scavenging activity, ferric reducing antioxidant power (FRAP), and oxygen radical absorbance capacity (ORAC). The DPPH radical scavenging activity of LMP from JHLB (20 mg/mL) was 92.21% and ABTS radical scavenging activity (15 mg/mL) was 99.50%. FRAP activity (30 mg/mL) was 364.72 MUM/TE and ORAC activity (1 mg/mL) was 101.85 MUM/TE. The anti-wrinkle potential was assessed by evaluating the elastase- and collagenase inhibition potential of these LMP. We found that 200 mg/mL of LMP from JHLB inhibited elastase activity by 41.32%, and 100 mg/mL of LMP from JHLB inhibited collagenase activity by 91.32%. The cell viability of untreated HS68 human dermal fibroblasts was 45% when exposed to a UVB radiation dose of 100 mJ/cm(2). After 24 h of incubation with 500 MUg/mL LMP from JHLB, the cell viability increased to 60%. These results indicate that LMP from JHLB has potential utility as an anti-oxidant and anti-wrinkle agent in the food and cosmetic industry. Additional in vivo tests should be carried out to further characterize these potential benefits. PMID- 26761681 TI - Lysate of Probiotic Lactobacillus plantarum K8 Modulate the Mucosal Inflammatory System in Dextran Sulfate Sodium-induced Colitic Rats. AB - Inflammatory bowel disease (IBD) is caused by dysregulation of colon mucosal immunity and mucosal epithelial barrier function. Recent studies have reported that lipoteichoic acid (LTA) from Lactobacillus plantarum K8 reduces excessive production of pro-inflammatory cytokine. In this study, we investigated the preventive effects of lysate of Lb. plantarum K8 in dextran sulfate sodium (DSS) induced colitis. Male Sprague-Dawley rats were orally pretreated with lysate of Lb. plantarum K8 (low dose or high dose) or live Lb. plantarum K8 prior to the induction of colitis using 4% DSS. Disease progression was monitored by assessment of disease activity index (DAI). Histological changes of colonic tissues were evaluated by hematoxylin and eosin (HE) staining. Tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) levels were measured using enzyme linked immunosorbent assay (ELISA). The colon mRNA expressions of TNF-alpha, IL 6, and toll like receptor-2 (TLR-2) were examined by quantitative real-time transcription polymerase chain reaction (qPCR). Lysate of Lb. plantarum K8 suppressed colon shortening, edema, mucosal damage, and the loss of DSS-induced crypts. The groups that received lysate of Lb. plantarum K8 exhibited significantly decreased levels of the pro-inflammatory cytokines TNF-alpha and IL 6 in the colon. Interestingly, colonic expression of toll like receptor-2 mRNA in the high-dose lysate of Lb. plantarum K8 group increased significantly. Our study demonstrates the protective effects of oral lysate of Lb. plantarum K8 administration on DSS-induced colitis via the modulation of pro-inflammatory mediators of the mucosal immune system. PMID- 26761684 TI - Novel Convenient Method to Determine Wettability and Dispersibility of Dairy Powders. AB - This study was carried out to develop a simple, convenient, and reproducible testing device to determine wettability and dispersibility of dairy powders. The testing device consists of a sieve (150 MUm) attached to a sample chamber, sensors mounted on a supporting body and a main control unit containing a display panel. The sensors detect the difference in electrical resistance between air and water. A timer is automatically triggered by the sensor when the bottom of sample loaded chamber contacts water in the petri dish. Wettability and dispersibility of commercial skim milk powders (SMPs) produced at different heating strengths (low-, medium-, and high-heat SMP) are compared using the new testing device. Wettability of the SMPs were correlated with particle size and are found to increase in the order of medium-, low-, and high-heat SMP regardless of the amount of sample tested. Dispersibility of SMPs showed the same trend and high heat-SMP which has the smallest particle size resulted in the lowest dispersibility. Unlike existing methods, the new testing device can determine both wettability and dispersibility of powders and successfully detected differences among the samples. PMID- 26761685 TI - The University's two vocations: centralizing research and development; decentralizing useful information. PMID- 26761686 TI - Incidence of pressure ulcers in cardiopulmonary intensive care unit patients. AB - Objective Identify and analyze the incidence coefficients of pressure ulcers (PU) and the risk factors for PU development in critical patients with cardiopulmonary diseases. Method A prospective cohort study conducted in the cardiopulmonary intensive care unit (ICU) of a large hospital in the city of Sao Paulo, from November 2013 to February 2014. In total, 370 patients over 18 years old who did not present PU at admission and who had been in the ICU for less than 24 hours were studied. Data were analyzed by univariate and multivariate analyses (Classification And Regression Tree - CART). Results The incidence coefficients of PU were: 11.0% for total participants, 8.0% for male and 3.0% for female patients (p=0.018); 10.0% for white patients and 6.5% for patients 60 years or older. The main risk factors were length of stay in the ICU for 9.5 days or more, age 42.5 years or older, and being of the white race. Conclusion This study was related to the epidemiology of PU in critical patients with cardiopulmonary diseases, facilitating the planning of specific preventive care for these patients. PMID- 26761687 TI - Measuring professional satisfaction and nursing workload among nursing staff at a Greek Coronary Care Unit. AB - Objective To explore potential associations between nursing workload and professional satisfaction among nursing personnel (NP) in Greek Coronary Care Units (CCUs). Method A cross-sectional study was performed involving 66 members of the NP employed in 6 randomly selected Greek CCUs. Job satisfaction was assessed by the IWS and nursing workload by NAS, CNIS and TISS-28. Results The response rate was 77.6%. The reliability of the IWS was alpha=0.78 and the mean score 10.7 (+/-2.1, scale range: 0.5-39.7). The most highly valued component of satisfaction was "Pay", followed by "Task requirements", "Interaction", "Professional status", "Organizational policies" and "Autonomy". NAS, CNIS and TISS-28 were negatively correlated (p<=0.04) with the following work components: "Autonomy", "Professional status", "Interaction" and "Task requirements". Night shift work independently predicted the score of IWS. Conclusion The findings show low levels of job satisfaction, which are related with nursing workload and influenced by rotating shifts. PMID- 26761688 TI - Perception of the nursing team of a Surgical Center regarding Hospital Accreditation at a University Hospital. AB - Objective To analyze the perception of nursing teams at a surgical center regarding the process of hospital accreditation, in the evaluative aspects of structure, process, and result. Method The study takes a quantitative and exploratory-descriptive approach, carried out at a university hospital. Result The population consisted of 69 nursing professionals, and the data collection was performed in the months of January and February 2014 by way of a questionnaire, utilizing the Likert scale. The methodology used a Cronbach's Alpha equal to 0.812. In the comparison of the three aspects, the one with the highest favorability score was "result", with an average of 47.12 (dp+/-7.23), and the smallest was "structure," with an average of 40.70 (dp+/-5.19). Conclusion This situational diagnostic can assist in the restructuring of the vulnerable areas evaluated in these three aspects, mainly in the aspect of structure, with a goal of level 2 accreditation by the ONA (Brazilian's National Organization for Accreditation) defended by the Institution. PMID- 26761689 TI - Pattern of nursing interventions performed on trauma victims according to the Nursing Activities Score. AB - Objective To identify the pattern of nursing interventions performed on trauma victims in the Intensive Care Unit (ICU). Method Prospective study performed in the ICU of a hospital in Sao Paulo, Brazil. Nursing interventions were identified using the Nursing Activities Score (NAS). Results The sample consisted of 200 patients, most of them male, with a mean age of 40.7, victims of transport accidents. The NAS mean was 71.3%. The pattern of nursing interventions identified included monitoring and titration, laboratory investigations, medication (with the exception of vasoactive drugs), hygiene procedures, caring for drains, mobilization and positioning, support and care of relatives and patient, administrative and managerial tasks, respiratory support, care of artificial airways, treatment for improving lung function, and quantitative urine output measurement. The monitoring and mobilization interventions required care beyond what is normally required by ICU patients. Conclusion The results of this study provide important contributions to plan training activities and to size ICU nursing team. PMID- 26761690 TI - Nursing workload: is it a predictor of healthcare associated infection in intensive care unit? AB - Objective To analyze the influence of nursing workload on the occurrence of healthcare associated infection (HAI) in patients in the intensive care unit (ICU), according to type of treatment. Method Retrospective cohort study developed in nine ICUs in Sao Paulo, Brazil, from September to December 2012. Nursing workload was measured by the Nursing Activities Score (NAS). The Student's t and Fisher's exact tests and logistic regressions were used in the analyses. Results The sample was composed of 835 patients (54.3+/-17.3 years; 57.5% male), of which 12.5% acquired HAI in the ICU. The NAS of the patients admitted for clinical treatment was 71.3+/-10.9, and for surgery 71.6+/-9.2. Length of stay in ICU and severity were predictive factors for occurrence of HAI in patients admitted to the unit for clinical or surgical treatment, and male sex only for surgical patients. When considering the admissions independent of type of treatment, in addition to the variables mentioned above, index of comorbidities also remained in the regression model. The NAS was not a predictive factor of HAI. Conclusion Nursing workload did not influence occurrence of HAI in the patients included in this study. PMID- 26761691 TI - The medication process, workload and patient safety in inpatient units. AB - Objective To conduct a survey of critical points in the medication process, its repercussions on the demands made on the nursing team and risks related to patient safety. Method This was a qualitative descriptive study that adopted an ecological-restorative approach. The data were collected through focus groups and photographs. Participants consisted of nurses and nursing technicians. Results Three categories emerged from the thematic analysis: challenges related to the process of prescribing and dispensing medication; medication administration with relation to work shift organization; and the use of new technologies to reduce medication errors. The results indicated that the medication process plays a central role in organizing nursing care, being that these professionals represent the last barrier for detecting medication prescription and administration errors. Conclusion By identifying vulnerabilities in the medication administration phase, the use of technology can help ensure patient safety. PMID- 26761692 TI - Prevalence and characteristics of lesions in elderly people living in the community. AB - Objective To describe the profile and the characteristics of elderly people with mobility restrictions who are residents in the community and have skin lesions. Method This was an exploratory and descriptive study that was part of the Health, Welfare and Ageing (SABE) study which assessed the presence of skin lesions in a probabilistic sample of elderly people living in the city of Sao Paulo in relation to factors such as socio-demographic issues, blood biomarkers, health conditions and the use of services. The analysis used the chi-square test with the Rao-Scott correction for complex samples, with a level of significance of 5%. Results In 2010, 20.7% of elderly people with restricted mobility had skin lesions due to this problem. The most common sites of these lesions were the sacral region for both sexes, the scapular region for women and the trochanteric region for men. Older age, multimorbidity and functional impairment were more prevalent among the elderly people with lesions, as well as greater levels of care that were required. Family dysfunction was associated with higher burdens on caregivers, which may affect the quality of care provided. It was observed that elderly people who are priorities for home care do not receive such care adequately. Conclusion The prevalence of skin lesions in the elderly with mobility restrictions living in the community was low; however, these elderly people require special attention, which is not currently being adequately provided. The reorganization of policies and care services appears to be essential. PMID- 26761693 TI - Stress, coping and burnout among Intensive Care Unit nursing staff: associated factors. AB - Objective To investigate emotional stress, coping and burnout among nursing staff and their association with biosocial factors and characteristics of work in Intensive Care Units (ICU). Method This was a cross-sectional study, conducted in eight ICUs at a teaching hospital in the city of Sao Paulo, Brazil, in October 2012. Biosocial data and information about the professionals' work was gathered, and they were given the Scale of Occupational Stress, Scale of Occupational Coping, List of Signs and Symptoms of Stress and the Maslach Burnout Inventory. Results The study sample consisted of 287 subjects, predominately women, with partners and children. Most professionals presented moderate stress levels and control as a coping strategy (74.47% and 79.93%, respectively), and burnout was present among 12.54%. Factors associated with stress were related to working conditions. The most prevalent protective factors were having a partner, working in the clinical ICU and liking work, while adequate amount of sleep was a protective factor for burnout. Conclusion Control of the working environment and adequate sleep are decisive and protective factors in dealing with situations of occupational stress. PMID- 26761694 TI - Evaluation of Programs of Infection Control related to Healthcare Assistance in Hospitals. AB - Objective To evaluate the Infection Control Programs in the state of Parana's hospitals, considering a hypothesis of a minimum overall performance of 75%. Method This was a cross-sectional study of procedural evaluation, using a previously established instrument comprised of four indicators that evaluate the technical-operational structure (PCET), the operational guidelines (PCDO), the system of epidemiological surveillance (PCET), and activities of control and prevention (PCCP). The study was carried out between 2013 and 2014 in 50 hospitals for the initial sample. Results The overall compliance obtained was 71.0% (23.88pd), with the indicators of PCET being 79.4% (18.9pd); PCVE 76.0% (30.5pd); PCDO 65.5% (26.9pd); and PCCP 63.2%/(39.5pd). There was statistical significance to indicate the greater performance of PCIRAS in carrying out internal audits (p=0.0099), quality certification (p=0.01949), exclusive nurses (p<0.0001), contracted or permanent medical professionals (p=0.0005), longer work schedule of doctors exclusively dedicated for 4 hours (p=0.001), greater experience of doctors (p=0.0028) and nurses (p=0.0094). Conclusion The general compliance of these programs did not prove the hypothesis originally formulated, due to the PCDO and PCCP indicators. As such, it is possible to argue that the programs demonstrate the minimal suitability for their operations and to carry out the epidemiological surveillance of HAI, but they are impaired by the quantitative and qualitative insufficiency of the operational guidelines (PCDO) and the actions for control and prevention of these infections (PCCP). PMID- 26761696 TI - Assessment of workload in the postoperative period of cardiac surgery according to the Nursing Activities Score. AB - Objective Identify factors associated with the workload of nursing care for patients in the postoperative period of cardiac surgery. Method Prospective cohort study conducted with 187 patients in the surgical intensive care unit (ICU) of the Instituto do Coracao(Heart Institute) in Sao Paulo-Brazil. Data were collected at 24 and 72 hours of the patients' admittance in the ICU. The dependent variable was workload as calculated by the Nursing Activities Score (NAS). The independent variables were demographic and clinical, as well as mortality scores. For data analysis, the Wilcoxon-Mann-Whitney test and Spearman correlation were used, and linear regression with mixed effects model. Results The majority of patients were male (59.4%), with a mean age of 61 years (+/ 12.7), and 43.9% developed some kind of complication in the postoperative period. In the first 24 hours, the workload was 82.4% (+/-3.4), and 58.1% (+/-3.4) in 72 hours. Factors associated with increased NAS were: patient's length of stay in the ICU (p=0.036) and the presence of complications (p<0.001). Conclusion In contrast to numerous other studies, the severity of the patient's condition in the first 24 hours of the postoperative period did not increase workload, the increase was associated with length of stay in the ICU and complications. PMID- 26761695 TI - Prevention of amphotericin B nephrotoxicity through use of phytotherapeutic medication. AB - Objective To evaluate the effect of diosmin and hesperidin flavonoids in the prevention of amphotericin B nephrotoxicity, through an experimental model on rats. Method Adult, male Wistar rats were distributed into the following groups: saline; diosmin hesperidin (animals that received 50 mg/kg of diosmin hesperidin, drinking water, for ten days); amphotericin B (animals that received 15 mg/kg/day of amphotericin B through intraperitoneal treatment for five days); amphotericin B+diosmin hesperidin. Renal function, fractional excretion of sodium; potassium and magnesium and oxidative metabolites were evaluated. Results Treatment with amphotericin B reduced renal function, as shown by the clearance of creatinine, increased tubular function markers and fractional excretion of sodium, potassium, magnesium and oxidative metabolites. Pre-treatment with diosmin hesperidin ameliorated clearance of creatinine and reduced tubular and oxidative injury. Conclusion Administration of amphotericin B resulted in reduction of renal function with tubular injury, and diosmin hesperidin showing an antioxidant protective effect on the kidneys. PMID- 26761697 TI - The impact of the final rinse on the cytoxicity of critical products submitted for processing. AB - Objective To assess the cytotoxicity of products subsequent to a cleaning process based on a validated standard operating procedure (SOP), and a final rinse with different types of water: tap, deionized, distilled, treated by reverse osmosis and ultra-purified. Method This was an experimental and laboratory study. The sample consisted of 130 hydrodissection cannulas, 26 per experimental group, characterized according to type of water used in the final rinse. The samples were submitted to internal and external contamination challenge with a solution containing 20% defibrinated sheep blood and 80% of sodium chloride 0.9%. Next, the lumens were filled with a ophthalmic viscosurgical device, remaining exposed for 50 minutes, and then were processed according to the validated SOP. Cytotoxicity was assessed using neutral red uptake assay. Results No cytoxicity was detected in the sample extracts. Conclusion The samples did not display signs of cytotoxicity, regardless of final rinse quality. The results obtained were reached by using only a validated cleaning operating procedure, based on the scientific literature, and on official recommendations and related regulation. PMID- 26761698 TI - Nursing workload in hematopoietic stem cell transplantation: a cohort study. AB - Objective Measure nursing workload required by patients submitted to autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and analyze the Nursing Activities Score (NAS) of the nursing team during the hospitalization period for HSCT. Method A prospective cohort study conducted from January 2013 to April 2014 with 62 patients hospitalized in the HSCT unit of a university hospital in Campinas, Sao Paulo, Brazil. The workload was measured through NAS and data analysis was through chi-square test or Fisher's exact test, Mann Whitney test and Spearman's correlation coefficient; with 5% significance level. Results Mean nursing workload was 67.3% (SD of 8.2) in autologous HSCT patients and 72.4% (SD of 13.0) in allogeneic HSCT patients (p=0.1380).Monitoring and titration showed, in more than 50% of the time, patients demanded intensified care, requiring two hours or more in a nursing shift for reasons of safety, severity or therapy. Conclusion The nursing workload and the NAS items with the highest scores reflect the magnitude, complexity and specificity of care required by patients submitted to HSCT. PMID- 26761699 TI - Hypertensive patients with and without kidney disease: assessment of risk factors. AB - Objective To compare hypertensive patients with and without chronic kidney disease and identify factors associated with their clinical condition and antihypertensive treatment. Method This was a cross-sectional study conducted with patients hospitalized in a general medical ward at a university hospital in the city of Sao Paulo, Brazil. Data were collected from medical records. Significance was set at p<0.05. Results Of the 386 patients studied, 59.3% presented hypertension and, of these, 37.5% presented chronic kidney disease. The data showed an independent association between chronic kidney disease and prior history of diabetes (OR 1.86; CI 1.02-3.41), congestive heart failure (OR 3.42; CI 1.36-9.03) and living with a partner (OR 1.99; CI 1.09-3.69). Regarding antihypertensive treatment, there was a difference (p<0.05) between hypertensive patients with and without chronic kidney disease in terms of administering healthcare treatment (93.2% versus 77.7%); ongoing use of antihypertensive drugs, (79.1% versus 66.4%); higher number of antihypertensive drugs; the use of beta adrenergic blockers (34.9%versus 19.6%), calcium channel blockers (29.1%versus 11.2%), loop diuretics (30.2%versus 10.5%) and vasodilators (9.3%versus 2.1%). Conclusion The hypertensive patients with chronic kidney disease presented a more compromised clinical profile; however, the attitudes of these patients toward antihypertensive treatment were more positive than those without chronic kidney disease. PMID- 26761700 TI - Atypical secretion of cortisol in Nursing professionals. AB - Objective To describe the frequency with which nursing staff in hospitals presents an altered diurnal pattern of cortisol secretion. Method These findings were based on results obtained from 56 randomly selected professional nursing staff working in outpatient clinics, medical clinics, surgical clinics, operating theaters, pediatric and adult emergency units, adult and pediatric intensive care units of a university hospital. The analysis of the diurnal cortisol pattern was based on saliva samples collected over two consecutive working days. Results 42.5% of these nursing staff members presented an atypical pattern of cortisol secretion. Furthermore, the longer the period of exercising this profession, the higher the cortisol concentration (r=0.346; p=0.020). Conclusion Over one-third of nursing staff samples displayed atypical cortisol secretion patterns. This suggests that these professionals are exposed, not only to a mental, but also to a biological, overload and thus, to a risk of contracting stress-related illnesses. PMID- 26761701 TI - Interrater reliability of Nursing Activities Score among Intensive Care Unit health professionals. AB - Objective To analyze the interrater reliability of NAS among critical care nurses and managers in an ICU. Method This was a methodological study performed in an adult, general ICU in Norway. In a random selection of patients, the NAS was scored on 101 patients by three raters: a critical care nurse, an ICU physician and a nurse manager. Interrater reliability was analyzed by agreement between groups and kappa statistics. Results The mean NAS were 88.4 (SD=16.2) and 88.7 (SD=24.5) respectively for the critical care nurses and nurse managers. A lower mean of 83.7 (SD=21.1) was found for physicians. The 18 medical interventions showed higher agreement between critical care nurses and physicians (85.6%), than between critical care nurses and nurse managers (78.7). In the five nursing activities the Kappa-coefficients were low for all activities in all compared groups. Conclusion The study indicated a satisfactory agreement of nursing workload between critical care nurses and managers. PMID- 26761702 TI - Organizational culture and climate for patient safety in Intensive Care Units. AB - Objective To assess the perception of health professionals about patient safety climate and culture in different intensive care units (ICUs) and the relationship between scores obtained on the Hospital Survey on Patient Safety Culture (HSOPSC) and the Safety Attitudes Questionnaire (SAQ). Method A cross-sectional study conducted at a teaching hospital in the state of Sao Paulo, Brazil, in March and April 2014. As data gathering instruments, the HSOPSC, SAQ and a questionnaire with sociodemographic and professional information about the staff working in an adult, pediatric and neonatal ICU were used. Data analysis was conducted with descriptive statistics. Results The scales presented good reliability. Greater weaknesses in patient safety were observed in the Working conditions andPerceptions of management domains of the SAQ and in the Nonpunitive response to error domain of the HSOPSC. The strengths indicated by the SAQ wereTeamwork climate and Job satisfactionand by the HSOPC, Supervisor/manager expectations and actions promoting safety and Organizational learning-continuous improvement. Job satisfaction was higher among neonatal ICU workers when compared with the other ICUs. The adult ICU presented lower scores for most of the SAQ and HSOPSC domains. The scales presented moderate correlation between them (r=0.66). Conclusion There were differences in perception regarding patient safety among ICUs, which corroborates the existence of local microcultures. The study did not demonstrate equivalence between the SAQ and the HSOPSC. PMID- 26761703 TI - Nursing Activities Score: an updated guideline for its application in the Intensive Care Unit. AB - Objective To describe nursing workload in Intensive Care Units (ICU) in different countries according to the scores obtained with Nursing Activities Score (NAS) and to verify the agreement among countries on the NAS guideline interpretation. Method This cross-sectional study considered 1-day measure of NAS (November 2012) obtained from 758 patients in 19 ICUs of seven countries (Norway, the Netherlands, Spain, Poland, Egypt, Greece and Brazil). The Delphi technique was used in expertise meetings and consensus. Results The NAS score was 72.8% in average, ranging from 44.5% (Spain) to 101.8% (Norway). The mean NAS score from Poland, Greece and Egypt was 83.0%, 64.6% and 57.1%, respectively. The NAS score was similar in Brazil (54.0%) and in the Netherlands (51.0%). There were doubts in the understanding of five out 23 items of the NAS (21.7%) which were discussed until researchers' consensus. Conclusion NAS score were different in the seven countries. Future studies must verify if the fine standardization of the guideline can have a impact on differences in the NAS results. PMID- 26761704 TI - Performance of Trauma and Injury Severity Score(TRISS) adjustments: an integrative review. AB - Objective Identify studies that made adjustments to the equation of Trauma and Injury Severity Score (TRISS) and compared the discriminatory ability of both modified and original equations. Method An integrative review of studies published between 1990 and 2014 using the following databases: LILACS, MEDLINE, PubMed and SciELO, based on searches using the term "TRISS". Results 32 studies were included in this review. Of 67 adjustments to TRISS equations identified, 35 (52.2%) resulted in improved accuracy of this index in the prediction of survival probability for trauma patients. Adjustments of TRISS coefficients to study population were frequent, but did not always improve the predictive ability of the analyzed models. Replacement of physiological variables of the Revised Trauma Score (RTS) and changes in the Injury Severity Score (ISS) in the original equation presented varied performance. An alteration to the method of age inclusion in the equation, and the insertion of gender, comorbidities and trauma mechanism, presented a tendency towards improved performance of the TRISS. Conclusion Different proposals of adjustments to the TRISS were identified in this review and indicated, in particular, RTS fragilities in the original model and the need to change the method of age inclusion in the equation to improve the predictive ability of this index. PMID- 26761705 TI - The use of the Nursing Activities Score in clinical settings: an integrative review. AB - Objective analyze how studies have approached the results obtained from the application of the Nursing Activities Score (NAS) based on Donabedian's model of healthcare organization and delivery. Method CINAHL and PubMed databases were searched for papers published between 2003 and March 2015. Results 36 articles that met the inclusion criteria were reviewed and double-coded by three independent coders and analyzed based on the three elements of Donabedian's health care quality framework: structure, process and outcome. The most frequently addressed, but not always tested, variables were those that fell into the structure category. Conclusion variables that fell into the process category were used less frequently. Beside NAS, the most frequently used variables in the outcome category were mortality and length of stay. However, no study used a quality framework for healthcare or NAS to evaluate costs, and it is recommended that further research should explore this approach. PMID- 26761706 TI - Patient safety in Intensive Care Units: development of a research project. AB - OBJECTIVE: To describe our experience in the many processes involved in the development of a Project on Research into Intensive Care Unit Patient Safety. METHOD: Mixed design study: historic cohort study of the collection of data on patients and on adverse events/incidents and transversal design on the collection of data on a nursing team. The data were collected over a period of 90 days in 2012 at the Instituto Central do Hospital das Clinicas da Faculdade de Medicina of the Universidade de Sao Paulo (ICHC-FMUSP)and the University Hospital of the Universidade de Sao Paulo HU-USP).Procedures carried out: This study involved a number of stages: application of the Nursing Activities Score (NAS) at the ICHC FMUSP, creation of a database system, hospital record inputs, monitor training, patient data extraction and load, collection of data during duty shift changes, and records. Final considerations : Training, researcher commitment, and collaboration with IT (Information Technology) professionals were crucial to the quality of the results obtained and of scientific production achieved. We hope that our report will serve to guide and encourage researchers to carry out complex surveys contributing to improve nursing and health knowledge. PMID- 26761708 TI - Extensive white matter abnormalities and clinical symptoms in drug-naive patients with first-episode schizophrenia: a voxel-based diffusion tensor imaging study. AB - BACKGROUND: Increasing evidence shows that disruption of connectivity has been implicated as a central abnormality in schizophrenia, and the alterations in white matter may be the core basis for this disconnection. Diffusion tensor imaging (DTI) has shown white matter abnormalities in first-episode schizophrenia. However, few studies have examined the correlation between clinical symptoms and white matter abnormalities in drug-naive patients with first-episode schizophrenia. METHOD: The white matter fractional anisotropy (FA) values of the whole-brain were determined by using voxel-based DTI in 39 drug naive patients with first-episode schizophrenia (diagnosed according to DSM-IV) and 30 healthy controls matched for age and gender. The psychopathology of schizophrenia was assessed with the Positive and Negative Syndrome Scale (PANSS). The study was conducted from April 2009 to March 2010. RESULTS: The patients showed widespread FA reduction in several brain regions, including corpus callosum, brainstem, internal capsule, cingulate, and cerebellum in patients with first-episode schizophrenia when compared to healthy controls (all P values < .01 after adjusting for gender, age, and education). The correlation analysis showed a significant negative correlation between the FA value in the left cerebellum and positive symptoms (r38 = -0.32, P < .05) and a significant positive correlation between the FA values in the corpus callosum and both the PANSS general psychopathology subscore (r38 = 0.39, P < .01) and the PANSS total score (r38 = 0.33, P < .05). CONCLUSIONS: Our results indicate that widespread disruption of white matter integrity occurs in an early stage of schizophrenic onset, suggesting an important role in pathogenesis and symptomatology of schizophrenia. PMID- 26761707 TI - Accelerating Influenza Research: Vaccines, Antivirals, Immunomodulators and Monoclonal Antibodies. The Manufacture of a New Wild-Type H3N2 Virus for the Human Viral Challenge Model. AB - BACKGROUND: Influenza and its associated diseases are a major cause of morbidity and mortality. The United States Advisory Committee on Immunization Practices recommends influenza vaccination for everyone over 6 months of age. The failure of the flu vaccine in 2014-2015 demonstrates the need for a model that allows the rapid development of novel antivirals, universal/intra-seasonal vaccines, immunomodulators, monoclonal antibodies and other novel treatments. To this end we manufactured a new H3N2 influenza virus in compliance with Good Manufacturing Practice for use in the Human Viral Challenge Model. METHODS AND STRAIN SELECTION: We chose an H3N2 influenza subtype, rather than H1N1, given that this strain has the most substantial impact in terms of morbidity or mortality annually as described by the Centre for Disease Control. We first subjected the virus batch to rigorous adventitious agent testing, confirmed the virus to be wild-type by Sanger sequencing and determined the virus titres appropriate for human use via the established ferret model. We built on our previous experience with other H3N2 and H1N1 viruses to develop this unique model. HUMAN CHALLENGE AND CONCLUSIONS: We conducted an initial safety and characterisation study in healthy adult volunteers, utilising our unique clinical quarantine facility in London, UK. In this study we demonstrated this new influenza (H3N2) challenge virus to be both safe and pathogenic with an appropriate level of disease in volunteers. Furthermore, by inoculating volunteers with a range of different inoculum titres, we established the minimum infectious titre required to achieve reproducible disease whilst ensuring a sensitive model that can be translated to design of subsequent field based studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT02525055. PMID- 26761709 TI - Microbial Community Structure and Arsenic Biogeochemistry in an Acid Vapor-Formed Spring in Tengchong Geothermal Area, China. AB - Arsenic biogeochemistry has been studied extensively in acid sulfate-chloride hot springs, but not in acid sulfate hot springs with low chloride. In this study, Zhenzhuquan in Tengchong geothermal area, a representative acid sulfate hot spring with low chloride, was chosen to study arsenic geochemistry and microbial community structure using Illumina MiSeq sequencing. Over 0.3 million 16S rRNA sequence reads were obtained from 6-paired parallel water and sediment samples along its outflow channel. Arsenic oxidation occurred in the Zhenxhuquan pool, with distinctly high ratios of arsenate to total dissolved arsenic (0.73-0.86). Coupled with iron and sulfur oxidation along the outflow channel, arsenic accumulated in downstream sediments with concentrations up to 16.44 g/kg and appeared to significantly constrain their microbial community diversity. These oxidations might be correlated with the appearance of some putative functional microbial populations, such as Aquificae and Pseudomonas (arsenic oxidation), Sulfolobus (sulfur and iron oxidation), Metallosphaera and Acidicaldus (iron oxidation). Temperature, total organic carbon and dissolved oxygen significantly shaped the microbial community structure of upstream and downstream samples. In the upstream outflow channel region, most microbial populations were microaerophilic/anaerobic thermophiles and hyperthermophiles, such as Sulfolobus, Nocardia, Fervidicoccus, Delftia, and Ralstonia. In the downstream region, aerobic heterotrophic mesophiles and thermophiles were identified, including Ktedonobacteria, Acidicaldus, Chthonomonas and Sphingobacteria. A total of 72.41 95.91% unassigned-genus sequences were derived from the downstream high arsenic sediments 16S rRNA clone libraries. This study could enable us to achieve an integrated understanding on arsenic biogeochemistry in acid hot springs. PMID- 26761710 TI - Titanium Implant Impairment and Surrounding Muscle Cell Death Following High-Salt Diet: An In Vivo Study. AB - AIM OF THE STUDY: High-salt consumption has been widely described as a risk factor for cardiovascular, renal and bone functions. In the present study, the extent to which high-salt diet could influence Ti6Al4V implant surface characteristic, its adhesion to rat tibial crest, and could modify muscle cell viability of two surrounding muscles, was investigated in vivo. These parameters have also been assessed following a NMES (neuro-myoelectrostimulation) program similar to that currently used in human care following arthroplasty. RESULTS: After a three-week diet, a harmful effect on titanium implant surface and muscle cell viability was noted. This is probably due to salt corrosive effect on metal and then release of toxic substance around biologic tissue. Moreover, if the use of NMES with high-salt diet induced muscles damages, the latter were higher when implant was added. Unexpectedly, higher implant-to-bone adhesion was found for implanted animals receiving salt supplementation. CONCLUSION: Our in vivo study highlights the potential dangerous effect of high-salt diet in arthroplasty based on titanium prosthesis. This effect appears to be more important when high-salt diet is combined with NMES. PMID- 26761711 TI - Management of Intrapleural Sepsis with Once Daily Use of Tissue Plasminogen Activator and Deoxyribonuclease. AB - BACKGROUND: Pleural infection remains a significant cause of morbidity, mortality, prolonged hospital stay, and increased healthcare costs, despite advances in therapy. Twice daily intrapleural tissue plasminogen activator (tPA)/deoxyribonuclease (DNase) initiated at the time of diagnosis has been shown to significantly improve radiological outcomes and decrease the need for surgery. OBJECTIVES: To analyze our experience with once daily tPA/DNase for intrapleural sepsis. METHODS: Data derived from consecutive patients with empyema and complicated parapneumonic effusion who received once daily intrapleural tPA/DNase between January 2012 and August 2014 were reviewed. Measured outcomes included treatment success at 30 days, volume of pleural fluid drained, improvement in radiographic pleural opacity, length of hospital stay, need for surgery, and adverse events. RESULTS: 55 consecutive patients (33 male; mean age +/- SD, 54.6 +/- 16.1 years) were treated with once daily intrapleural tPA/DNase for 3 days. The majority of the patients (n = 51; 92.7%) were successfully managed without the need for surgical intervention. The mean change in pleural opacity measured on chest radiograph at day 7 was -28.8 +/-17.6%. The median amount of fluid drained was 2,195 ml. No serious adverse events requiring discontinuation of intrapleural medications were observed. The most common complication was pain requiring escalating doses of analgesics (n = 8; 15%). Compliance with the protocol was excellent. CONCLUSION: Early administration of once daily intrapleural tPA/DNase for 3 days is safe, effective, and represents a viable option for the management of empyema and complicated parapneumonic effusion. PMID- 26761713 TI - The Predictive Value of Depressive Symptoms for All-Cause Mortality: Findings From the PRIME Belfast Study Examining the Role of Inflammation and Cardiovascular Risk Markers. AB - OBJECTIVES: To improve understanding about the potential underlying biological mechanisms in the link between depression and all-cause mortality and to investigate the role that inflammatory and other cardiovascular risk factors may play in the relationship between depressive symptoms and mortality. METHODS: Depression and blood-based biological markers were assessed in the Belfast PRIME prospective cohort study (N = 2389 men, aged 50-59 years) in which participants were followed up for 18 years. Depression was measured using the 10-item Welsh Pure Depression Inventory. Inflammation markers (C-reactive protein [CRP], neopterin, interleukin [IL]-1 receptor antagonist [IL-1Ra], and IL-18) and cardiovascular-specific risk factors (N-terminal pro-b-type natriuretic peptide, midregion pro-atrial natriuretic peptide, midregion pro-adrenomedullin, C terminal pro-endothelin-1 [CT-proET]) were obtained at baseline. We used Cox proportional hazards modeling to examine the association between depression and biological measures in relation to all-cause mortality and explore the mediating effects. RESULTS: During follow-up, 418 participants died. Higher levels of depressive symptoms were associated with higher levels of CRP, IL-1Ra, and CT proET. After adjustment for socioeconomic and life-style risk factors, depressive symptoms were significantly associated with all-cause mortality (hazard ratio = 1.10 per scale unit, 95% confidence interval = 1.04-1.16). This association was partly explained by CRP (7.3%) suggesting a minimal mediation effect. IL-1Ra, N terminal pro-b-type natriuretic peptide, midregion pro-atrial natriuretic peptide, midregion pro-adrenomedullin, and CT-proET contributed marginally to the association between depression and subsequent mortality. CONCLUSIONS: Inflammatory and cardiovascular risk markers are associated with depression and with increased mortality. However, depression and biological measures show additive effects rather than a pattern of meditation of biological factors in the association between depression and mortality. PMID- 26761712 TI - Comparison of Phosphate Binding Capacities of PA21, A Novel Phosphate Binder, with those of other Phosphate Binders in vitro and in vivo. AB - PURPOSE: The phosphate binding capacity of PA21, a novel phosphate binder, was compared with those of other phosphate binders in vitro and in vivo. METHODS: 1) For in vitro studies, PA21, sevelamer hydrochloride, lanthanum carbonate hydrate, calcium carbonate, and ferric citrate hydrate were incubated with a phosphate solution at 37 degrees C for 2 h. Phosphate binding capacity was assessed at simulated gastrointestinal tract pH levels of 2, 5, and 8 for estimation of clinical effects, and the quantity of phosphate adsorbed by each phosphate binder was determined. 2) For in vivo studies, rats were orally administered various phosphate binders after the oral administration of phosphate solution (100 mg/kg) adjusted to pH 2, 5, or 8, and the effects of PA21 and other phosphate binders on the serum phosphorus level of the rats were investigated. RESULTS: 1) The in vitro studies revealed that PA21 and sevelamer hydrochloride adsorbed phosphate better at all tested pH levels than lanthanum carbonate hydrate, calcium carbonate, and ferric citrate hydrate, and PA21 showed the most potent phosphate binding capacity among the tested compounds. 2) The in vivo studies showed that PA21 dose-dependently inhibited the increase in the serum phosphorus level after the administration of phosphate solution and no difference in the extent of inhibition by PA21 was observed at the different pH levels (in contrast to other phosphate binders). CONCLUSION: These results indicated that PA21 has a phosphate binding capacity over the entire pH range of the GI tract. PMID- 26761714 TI - Associations of Psychological Well-Being With Carotid Intima Media Thickness in African American and White Middle-Aged Women. AB - OBJECTIVES: The present cross-sectional study aimed to a) examine associations between measures of psychological well-being, specifically life satisfaction and life engagement, and intima media thickness, a subclinical marker of atherosclerosis; b) investigate if the interaction of psychological well-being and life events correlated with intima media thickness; and c) explore these relationships across race. METHODS: A sample of 485 women (38% African American and 62% white; mean [standard deviation] age = 50.2 [2.9] years) underwent ultrasonography to assess carotid artery intima media thickness (IMT). The women completed self-report measures of life satisfaction, life engagement, and life events. RESULTS: Average (standard deviation) IMT was 0.666 (0.10) mm. Life satisfaction showed a significant, independent, inverse relationship with IMT, after controlling for demographic, behavioral, psychological, and cardiovascular covariates (beta = -0.105, p = .039), such that each 1-point higher life satisfaction score was correlated with a significant 0.008-mm lower level of mean IMT. No significant association was seen between life events and IMT (r = 0.05, p = .32), and life satisfaction did not interact with life events on IMT (beta = 0.036, p = .46). No significant interaction between life satisfaction and race on IMT was observed (beta = 0.068, p = .37). In contrast to life satisfaction, life engagement was not a significant correlate of IMT (r = -0.07, p = .12). CONCLUSIONS: Life satisfaction, a measure of psychological well-being, is an important independent correlate of subclinical atherosclerosis in middle-aged women. PMID- 26761715 TI - Exonic Splicing Mutations Are More Prevalent than Currently Estimated and Can Be Predicted by Using In Silico Tools. AB - The identification of a causal mutation is essential for molecular diagnosis and clinical management of many genetic disorders. However, even if next-generation exome sequencing has greatly improved the detection of nucleotide changes, the biological interpretation of most exonic variants remains challenging. Moreover, particular attention is typically given to protein-coding changes often neglecting the potential impact of exonic variants on RNA splicing. Here, we used the exon 10 of MLH1, a gene implicated in hereditary cancer, as a model system to assess the prevalence of RNA splicing mutations among all single-nucleotide variants identified in a given exon. We performed comprehensive minigene assays and analyzed patient's RNA when available. Our study revealed a staggering number of splicing mutations in MLH1 exon 10 (77% of the 22 analyzed variants), including mutations directly affecting splice sites and, particularly, mutations altering potential splicing regulatory elements (ESRs). We then used this thoroughly characterized dataset, together with experimental data derived from previous studies on BRCA1, BRCA2, CFTR and NF1, to evaluate the predictive power of 3 in silico approaches recently described as promising tools for pinpointing ESR-mutations. Our results indicate that DeltatESRseq and DeltaHZEI-based approaches not only discriminate which variants affect splicing, but also predict the direction and severity of the induced splicing defects. In contrast, the DeltaPsi-based approach did not show a compelling predictive power. Our data indicates that exonic splicing mutations are more prevalent than currently appreciated and that they can now be predicted by using bioinformatics methods. These findings have implications for all genetically-caused diseases. PMID- 26761716 TI - 7-cysteine-pyrrole conjugate: A new potential DNA reactive metabolite of pyrrolizidine alkaloids. AB - Pyrrolizidine alkaloids (PAs) require metabolic activation to exert cytotoxicity, genotoxicity, and tumorigenicity. We previously reported that (+/-)-6,7-dihydro-7 hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts are responsible for PA-induced liver tumor formation in rats. In this study, we determined that metabolism of riddelliine and monocrotaline by human or rat liver microsomes produced 7-cysteine-DHP and DHP. The metabolism of 7-glutathionyl-DHP by human and rat liver microsomes also generated 7-cysteine-DHP. Further, reaction of 7 cysteine-DHP with calf thymus DNA in aqueous solution yielded the described DHP derived DNA adducts. This study represents the first report that 7-cysteine-DHP is a new PA metabolite that can lead to DNA adduct formation. PMID- 26761718 TI - Multi-scale strain-stiffening of semiflexible bundle networks. AB - Bundles of polymer filaments are responsible for the rich and unique mechanical behaviors of many biomaterials, including cells and extracellular matrices. In fibrin biopolymers, whose nonlinear elastic properties are crucial for normal blood clotting, protofibrils self-assemble and bundle to form networks of semiflexible fibers. Here we show that the extraordinary strain-stiffening response of fibrin networks is a direct reflection of the hierarchical architecture of the fibrin fibers. We measure the rheology of networks of unbundled protofibrils and find excellent agreement with an affine model of extensible wormlike polymers. By direct comparison with these data, we show that physiological fibrin networks composed of thick fibers can be modeled as networks of tight protofibril bundles. We demonstrate that the tightness of coupling between protofibrils in the fibers can be tuned by the degree of enzymatic intermolecular crosslinking by the coagulation factor XIII. Furthermore, at high stress, the protofibrils contribute independently to the network elasticity, which may reflect a decoupling of the tight bundle structure. The hierarchical architecture of fibrin fibers can thus account for the nonlinearity and enormous elastic resilience characteristic of blood clots. PMID- 26761717 TI - Nanoparticles restore lysosomal acidification defects: Implications for Parkinson and other lysosomal-related diseases. AB - Lysosomal impairment causes lysosomal storage disorders (LSD) and is involved in pathogenesis of neurodegenerative diseases, notably Parkinson disease (PD). Strategies enhancing or restoring lysosomal-mediated degradation thus appear as tantalizing disease-modifying therapeutics. Here we demonstrate that poly(DL lactide-co-glycolide) (PLGA) acidic nanoparticles (aNP) restore impaired lysosomal function in a series of toxin and genetic cellular models of PD, i.e. ATP13A2-mutant or depleted cells or glucocerebrosidase (GBA)-mutant cells, as well as in a genetic model of lysosomal-related myopathy. We show that PLGA-aNP are transported to the lysosome within 24 h, lower lysosomal pH and rescue chloroquine (CQ)-induced toxicity. Re-acidification of defective lysosomes following PLGA-aNP treatment restores lysosomal function in different pathological contexts. Finally, our results show that PLGA-aNP may be detected after intracerebral injection in neurons and attenuate PD-related neurodegeneration in vivo by mechanisms involving a rescue of compromised lysosomes. PMID- 26761719 TI - Deleterious Effects of Intra-arterial Administration of Particulate Steroids on Microvascular Perfusion in a Mouse Model. AB - Purpose To determine the in vivo effects of several particulate steroids on microvascular perfusion by using intravital microscopy in a mice model and to investigate the in vitro interactions between these particulate steroids and red blood cells (RBCs). Materials and Methods The study was conducted in agreement with the guidelines of the National Committee of Ethic Reflection on Animal Experimentation. By using intravital microscopy of mouse cremaster muscle, the in vivo effects of several particulate steroids on microvascular perfusion were assessed. Four to five mice were allocated to each of the following treatment groups: saline solution, dexamethasone sodium phosphate, a nonparticulate steroid, and the particulate steroids cortivazol, methylprednisolone, triamcinolone, and prednisolone. By using in vitro blood microcinematography and electron microscopy, the interactions between these steroids and human RBCs were studied. All results were analyzed by using nonparametric tests. Results With prednisolone, methylprednisolone, or triamcinolone, blood flow was rapidly and completely stopped in all the arterioles and venules (median RBC velocity in first-order arterioles, 5 minutes after administration was zero for these three groups) compared with a limited effect in mice treated with saline, dexamethasone, and cortivazol (20.3, 21.3, and 27.5 mm/sec, respectively; P < .003). This effect was associated with a large decrease in the functional capillary density (4.21, 0, and 0 capillaries per millimeter for methylprednisolone, triamcinolone, or prednisolone, respectively, vs 21.0, 21.4, and 19.1 capillaries per millimeter in mice treated with saline, dexamethasone, and cortivazol, respectively; P < .003). This was because of the rapid formation of RBC aggregates. However, no change in microvascular perfusion was associated with administration of cortivazol or dexamethasone. In vitro experiments confirmed the formation of RBC aggregates associated with the transformation of RBCs into spiculated RBCs with the same steroids. Conclusion Several particulate steroids have an immediate and massive effect on microvascular perfusion because of formation of RBC aggregates associated with the transformation of RBCs into spiculated RBCs. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 26761720 TI - Detection of Prostate Cancer: Quantitative Multiparametric MR Imaging Models Developed Using Registered Correlative Histopathology. AB - Purpose To develop multiparametric magnetic resonance (MR) imaging models to generate a quantitative, user-independent, voxel-wise composite biomarker score (CBS) for detection of prostate cancer by using coregistered correlative histopathologic results, and to compare performance of CBS-based detection with that of single quantitative MR imaging parameters. Materials and Methods Institutional review board approval and informed consent were obtained. Patients with a diagnosis of prostate cancer underwent multiparametric MR imaging before surgery for treatment. All MR imaging voxels in the prostate were classified as cancer or noncancer on the basis of coregistered histopathologic data. Predictive models were developed by using more than one quantitative MR imaging parameter to generate CBS maps. Model development and evaluation of quantitative MR imaging parameters and CBS were performed separately for the peripheral zone and the whole gland. Model accuracy was evaluated by using the area under the receiver operating characteristic curve (AUC), and confidence intervals were calculated with the bootstrap procedure. The improvement in classification accuracy was evaluated by comparing the AUC for the multiparametric model and the single best performing quantitative MR imaging parameter at the individual level and in aggregate. Results Quantitative T2, apparent diffusion coefficient (ADC), volume transfer constant (K(trans)), reflux rate constant (kep), and area under the gadolinium concentration curve at 90 seconds (AUGC90) were significantly different between cancer and noncancer voxels (P < .001), with ADC showing the best accuracy (peripheral zone AUC, 0.82; whole gland AUC, 0.74). Four-parameter models demonstrated the best performance in both the peripheral zone (AUC, 0.85; P = .010 vs ADC alone) and whole gland (AUC, 0.77; P = .043 vs ADC alone). Individual-level analysis showed statistically significant improvement in AUC in 82% (23 of 28) and 71% (24 of 34) of patients with peripheral-zone and whole gland models, respectively, compared with ADC alone. Model-based CBS maps for cancer detection showed improved visualization of cancer location and extent. Conclusion Quantitative multiparametric MR imaging models developed by using coregistered correlative histopathologic data yielded a voxel-wise CBS that outperformed single quantitative MR imaging parameters for detection of prostate cancer, especially when the models were assessed at the individual level. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 26761722 TI - Intranasal curcumin ameliorates airway inflammation and obstruction by regulating MAPKinase activation (p38, Erk and JNK) and prostaglandin D2 release in murine model of asthma. AB - Asthma, a multifactorial, chronic inflammatory disease encompasses multiple complex pathways releasing number of mediators by activated mast cells, eosinophils and T lymphocytes, leading to its severity. Presently available medications are associated with certain limitations, and hence, it is imperative to search for anti-inflammatory drug preferably targeting signaling cascades involved in inflammation thereby suppressing inflammatory mediators without any side effect. Curcumin, an anti-inflammatory molecule with potent anti-asthmatic potential has been found to suppress asthmatic features by inhibiting airway inflammation and bronchoconstriction if administered through nasal route. The present study provides new insight towards anti-asthmatic potential of intranasal curcumin at lower doses (2.5 and 5.0 mg/kg) in Balb/c mice sensitized and challenged with ovalbumin (OVA) which is effective in inhibiting airway inflammation. These investigations suggest that intranasal curcumin (2.5 and 5.0 mg/kg) regulates airway inflammation and airway obstruction mainly by modulating cytokine levels (IL-4, 5, IFN-y and TNF-alpha) and sPLA2 activity thereby inhibiting PGD2 release and COX-2 expression. Further, the suppression of p38 MAPK, ERK 42/44 and JNK54/56 activation elucidate the mechanism behind the inhibitory role of intranasal curcumin in asthma progression. Thus, curcumin could be better alternative for the development of nasal formulations and inhalers in near future. PMID- 26761721 TI - Evolution of Volume and Signal Intensity on Fluid-attenuated Inversion Recovery MR Images after Endovascular Stroke Therapy. AB - Purpose To analyze both volume and signal evolution on magnetic resonance (MR) fluid-attenuated inversion recovery (FLAIR) images between the images after endovascular therapy and day 5 (which was the prespecified end point for infarct volume in the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution [DEFUSE 2] trial) in a subset of patients enrolled in the DEFUSE 2 study. Materials and Methods This study was approved by the local ethics committee at all participating sites. Informed written consent was obtained from all patients. In this post hoc analysis of the DEFUSE 2 study, 35 patients with FLAIR images acquired both after endovascular therapy (median time after symptom onset, 12 hours) and at day 5 were identified. Patients were separated into two groups based on the degree of reperfusion achieved on time to maximum greater than 6-second perfusion imaging (>=90% vs <90%). After coregistration and signal normalization, lesion volumes and signal intensity were assessed by using FLAIR imaging for the initial lesion (ie, visible after endovascular therapy) and the recruited lesion (the additional lesion visible on day 5, but not visible after endovascular therapy). Statistical significance was assessed by using Wilcoxon signed-rank, Mann-Whitney U, and Fisher exact tests. Results All 35 patients had FLAIR lesion growth between the after-revascularization examination and day 5. Median lesion growth was significantly larger in patients with <90% reperfusion (27.85 mL) compared with >=90% (8.12 mL; P = .003). In the initial lesion, normalized signal did not change between after endovascular therapy (median, 1.60) and day 5 (median, 1.58) in the >=90% reperfusion group (P = .97), but increased in the <90% reperfusion group (from 1.60 to 1.73; P = .01). In the recruited lesion, median normalized signal increased significantly in both groups between after endovascular therapy and day 5 (after endovascular therapy, from 1.19 to 1.56, P < .001; and day 5, from 1.18 to 1.63, P < .001). Conclusion Patients with >=90% reperfusion after endovascular therapy have significantly less lesion growth on FLAIR images between after therapy and day 5 compared with patients who have <90% reperfusion. Therefore, the effect of reperfusion therapies on lesion volumes are likely more apparent at day 5 than after therapy. ((c)) RSNA, 2016. PMID- 26761723 TI - Anti-inflammatory effect of corymbocoumarin from Seseli gummiferum subsp. corymbosum through suppression of NF-kappaB signaling pathway and induction of HO 1 expression in LPS-stimulated RAW 264.7 cells. AB - This study investigated the anti-inflammatory activity of corymbocoumarin, an angular-type pyranocoumarin isolated from Seseli gummiferum subsp. corymbosum in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Corymbocoumarin not only inhibited the production of nitric oxide (NO) and prostaglandin E2 (PGE2), but also inhibited the protein and mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Corymbocoumarin also attenuated pro inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Investigation of the effect on nuclear factor kappaB (NF-kappaB) signaling pathway showed that corymbocoumarin inhibited the phosphorylation of Akt and inhibitory kappaB (IkappaB)-alpha and decreased the subsequent translocation of the p65 and p50 NF kappaB subunits to the nucleus. A further study revealed that corymbocoumarin exerted anti-inflammatory activity through induction of heme oxygenase (HO)-1 expression. The in vivo study showed that corymbocoumarin (20mg/kg, i.p.) reduced paw swelling in carrageenan-induced acute inflammation model. Taken together, these results suggest that corymbocoumarin exerts its anti-inflammatory effect in LPS-stimulated RAW 264.7 cells by suppressing NF-kappaB activation and inducing HO-1 expression. Corymbocoumarin may provide a useful therapeutic approach for inflammation-associated diseases. PMID- 26761724 TI - alpha1-Antitrypsin-primed tolerogenic dendritic cells prolong allograft kidney transplants survival in rats. PMID- 26761725 TI - Blunt Policy Instruments Deliver Blunt Policy Outcomes: Why Cost Sharing is Not Effective at Controlling Utilization and Improving Health System Efficiency. PMID- 26761726 TI - Reductions in Diagnostic Imaging With High Deductible Health Plans. AB - BACKGROUND: Diagnostic imaging utilization grew rapidly over the past 2 decades. It remains unclear whether patient cost-sharing is an effective policy lever to reduce imaging utilization and spending. MATERIALS AND METHODS: Using 2010 commercial insurance claims data of >21 million individuals, we compared diagnostic imaging utilization and standardized payments between High Deductible Health Plan (HDHP) and non-HDHP enrollees. Negative binomial models were used to estimate associations between HDHP enrollment and utilization, and were repeated for standardized payments. A Hurdle model were used to estimate associations between HDHP enrollment and whether an enrollee had diagnostic imaging, and then the magnitude of associations for enrollees with imaging. Models with interaction terms were used to estimate associations between HDHP enrollment and imaging by risk score tercile. All models included controls for patient age, sex, geographic location, and health status. RESULTS: HDHP enrollment was associated with a 7.5% decrease in the number of imaging studies and a 10.2% decrease in standardized imaging payments. HDHP enrollees were 1.8% points less likely to use imaging; once an enrollee had at least 1 imaging study, differences in utilization and associated payments were small. Associations between HDHP and utilization were largest in the lowest (least sick) risk score tercile. CONCLUSIONS: Increased patient cost-sharing may contribute to reductions in diagnostic imaging utilization and spending. However, increased cost-sharing may not encourage patients to differentiate between high-value and low-value diagnostic imaging services; better patient awareness and education may be a crucial part of any reductions in diagnostic imaging utilization. PMID- 26761727 TI - Impact of Medical Home Implementation Through Evidence-based Quality Improvement on Utilization and Costs. AB - BACKGROUND: Evidence-based quality improvement (EBQI) methods may facilitate practice redesign for more effective implementation of the patient-centered medical home (PCMH). OBJECTIVE: We assessed changes in health care utilization and costs for patients receiving care from practices using an EBQI approach to implement PCMH and comparison practices over a 5-year period. RESEARCH DESIGN: We used longitudinal, electronic data from patients in 6 practices using EBQI and 28 comparison practices implementing standard PCMH for 1 year before and 4 years after PCMH implementation. We analyzed trends in utilization and costs using bivariate analyses and independent effects of EBQI status on outcomes using multivariate regressions adjusting for year, patient and clinic factors, and patient random effects for repeated measures. SUBJECTS: A total of 136,856 patients using Veterans Affairs primary care. MEASURES: Veterans Affairs ambulatory care encounters, emergency department visits, admissions, and total health care costs per patient. RESULTS: After PCMH implementation, overall utilization for primary care, specialty care, and mental health/substance abuse care decreased, whereas utilization for telephone care increased among all practices. Patients also had fewer hospitalizations and lower costs per patient. In adjusted analyses, EBQI practice was independently associated with fewer primary care (IRR=0.85), specialty care (IRR=0.83), and mental health care encounters (IRR=0.69); these effects attenuated over time (all P<0.01). There was no independent effect of EBQI on prescription drug use, acute care, health care costs, or mortality rate relative to comparison practices. CONCLUSION: EBQI methods enhanced the effects of PCMH implementation by reducing ambulatory care while increasing non-face-to-face care. PMID- 26761728 TI - The Impact of the Medicare Hospital Readmission Reduction Program in New York State. AB - BACKGROUND: Medicare's Hospital Readmission Reduction Program (HRRP) created clear financial incentives for hospitals to prevent readmissions. Although existing evidence suggests readmission rates have been declining, the direct contribution of this policy to these reductions is unclear. Furthermore, it is unknown whether HRRP has produced unintended effects, including the substitution of outpatient hospital care for readmissions. OBJECTIVES: To determine the effect of HRRP in New York State on both the likelihood of being readmitted and returning to hospital emergency department (ED) care within 30 days of discharge. RESEARCH DESIGN: Difference-in-difference estimation using prepolicy and postpolicy hospital claims data and the proportion of a hospital's inpatient revenue at risk for HRRP penalization to identify policy exposure. Policy effects are estimated using multivariate logistic regressions. RESULTS: We find significant global reductions in readmissions in the postpolicy years, but no evidence of a differential policy effect on patients discharged from hospitals at risk for proportionally larger HRRP penalties in either postpolicy year 1 [adjusted odd ratio (AOR) =1.00, P=0.733] or 2 (AOR=1.01, P=0.315). HRRP did increase the odds of patients from hospitals facing greater financial risk having a 30-day ED visit in both postpolicy years (AOR=1.04, P=0.009 and AOR=1.07, P<0.001). CONCLUSIONS: Our findings suggest that while readmissions have decreased in New York State, these declines may not be directly attributable to HRRP penalties. The policy did produce significant potentially unintended effects in the form of greater postdischarge ED utilization among facilities facing proportionally larger penalties. PMID- 26761729 TI - A Fast and Accurate Unconstrained Face Detector. AB - We propose a method to address challenges in unconstrained face detection, such as arbitrary pose variations and occlusions. First, a new image feature called Normalized Pixel Difference (NPD) is proposed. NPD feature is computed as the difference to sum ratio between two pixel values, inspired by the Weber Fraction in experimental psychology. The new feature is scale invariant, bounded, and is able to reconstruct the original image. Second, we propose a deep quadratic tree to learn the optimal subset of NPD features and their combinations, so that complex face manifolds can be partitioned by the learned rules. This way, only a single soft-cascade classifier is needed to handle unconstrained face detection. Furthermore, we show that the NPD features can be efficiently obtained from a look up table, and the detection template can be easily scaled, making the proposed face detector very fast. Experimental results on three public face datasets (FDDB, GENKI, and CMU-MIT) show that the proposed method achieves state of-the-art performance in detecting unconstrained faces with arbitrary pose variations and occlusions in cluttered scenes. PMID- 26761730 TI - A Generalized Probabilistic Framework for Compact Codebook Creation. AB - Compact and discriminative visual codebooks are preferred in many visual recognition tasks. In the literature, a number of works have taken the approach of hierarchically merging visual words of an initial large-sized codebook, but implemented this approach with different merging criteria. In this work, we propose a single probabilistic framework to unify these merging criteria, by identifying two key factors: the function used to model the class-conditional distribution and the method used to estimate the distribution parameters. More importantly, by adopting new distribution functions and/or parameter estimation methods, our framework can readily produce a spectrum of novel merging criteria. Three of them are specifically discussed in this paper. For the first criterion, we adopt the multinomial distribution with the Bayesian method; For the second criterion, we integrate the Gaussian distribution with maximum likelihood parameter estimation. For the third criterion, which shows the best merging performance, we propose a max-margin-based parameter estimation method and apply it with the multinomial distribution. Extensive experimental study is conducted to systematically analyze the performance of the above three criteria and compare them with existing ones. As demonstrated, the best criterion within our framework achieves the overall best merging performance among the compared merging criteria developed in the literature. PMID- 26761732 TI - Fast Direct Methods for Gaussian Processes. AB - A number of problems in probability and statistics can be addressed using the multivariate normal (Gaussian) distribution. In the one-dimensional case, computing the probability for a given mean and variance simply requires the evaluation of the corresponding Gaussian density. In the n-dimensional setting, however, it requires the inversion of an n *n covariance matrix, C, as well as the evaluation of its determinant, det(C). In many cases, such as regression using Gaussian processes, the covariance matrix is of the form C = sigma(2) I + K, where K is computed using a specified covariance kernel which depends on the data and additional parameters (hyperparameters). The matrix C is typically dense, causing standard direct methods for inversion and determinant evaluation to require O(n(3)) work. This cost is prohibitive for large-scale modeling. Here, we show that for the most commonly used covariance functions, the matrix C can be hierarchically factored into a product of block low-rank updates of the identity matrix, yielding an O (n log(2) n) algorithm for inversion. More importantly, we show that this factorization enables the evaluation of the determinant det(C), permitting the direct calculation of probabilities in high dimensions under fairly broad assumptions on the kernel defining K. Our fast algorithm brings many problems in marginalization and the adaptation of hyperparameters within practical reach using a single CPU core. The combination of nearly optimal scaling in terms of problem size with high-performance computing resources will permit the modeling of previously intractable problems. We illustrate the performance of the scheme on standard covariance kernels. PMID- 26761733 TI - Flexible Clustered Multi-Task Learning by Learning Representative Tasks. AB - Multi-task learning (MTL) methods have shown promising performance by learning multiple relevant tasks simultaneously, which exploits to share useful information across relevant tasks. Among various MTL methods, clustered multi task learning (CMTL) assumes that all tasks can be clustered into groups and attempts to learn the underlying cluster structure from the training data. In this paper, we present a new approach for CMTL, called flexible clustered multi task (FCMTL), in which the cluster structure is learned by identifying representative tasks. The new approach allows an arbitrary task to be described by multiple representative tasks, effectively soft-assigning a task to multiple clusters with different weights. Unlike existing counterpart, the proposed approach is more flexible in that (a) it does not require clusters to be disjoint, (b) tasks within one particular cluster do not have to share information to the same extent, and (c) the number of clusters is automatically inferred from data. Computationally, the proposed approach is formulated as a row sparsity pursuit problem. We validate the proposed FCMTL on both synthetic and real-world data sets, and empirical results demonstrate that it outperforms many existing MTL methods. PMID- 26761734 TI - Generalized Canonical Time Warping. AB - Temporal alignment of human motion has been of recent interest due to its applications in animation, tele-rehabilitation and activity recognition. This paper presents generalized canonical time warping (GCTW), an extension of dynamic time warping (DTW) and canonical correlation analysis (CCA) for temporally aligning multi-modal sequences from multiple subjects performing similar activities. GCTW extends previous work on DTW and CCA in several ways: (1) it combines CCA with DTW to align multi-modal data (e.g., video and motion capture data); (2) it extends DTW by using a linear combination of monotonic functions to represent the warping path, providing a more flexible temporal warp. Unlike exact DTW, which has quadratic complexity, we propose a linear time algorithm to minimize GCTW. (3) GCTW allows simultaneous alignment of multiple sequences. Experimental results on aligning multi-modal data, facial expressions, motion capture data and video illustrate the benefits of GCTW. The code is available at http://humansensing.cs.cmu.edu/ctw. PMID- 26761735 TI - Image Super-Resolution Using Deep Convolutional Networks. AB - We propose a deep learning method for single image super-resolution (SR). Our method directly learns an end-to-end mapping between the low/high-resolution images. The mapping is represented as a deep convolutional neural network (CNN) that takes the low-resolution image as the input and outputs the high-resolution one. We further show that traditional sparse-coding-based SR methods can also be viewed as a deep convolutional network. But unlike traditional methods that handle each component separately, our method jointly optimizes all layers. Our deep CNN has a lightweight structure, yet demonstrates state-of-the-art restoration quality, and achieves fast speed for practical on-line usage. We explore different network structures and parameter settings to achieve trade-offs between performance and speed. Moreover, we extend our network to cope with three color channels simultaneously, and show better overall reconstruction quality. PMID- 26761736 TI - Isotonic Modeling with Non-Differentiable Loss Functions with Application to Lasso Regularization. AB - In this paper we present an algorithmic approach for fitting isotonic models under convex, yet non-differentiable, loss functions. It is a generalization of the greedy non-regret approach proposed by Luss and Rosset (2014) for differentiable loss functions, taking into account the sub-gradiental extensions required. We prove that our suggested algorithm solves the isotonic modeling problem while maintaining favorable computational and statistical properties. As our suggested algorithm may be used for any non-differentiable loss function, we focus our interest on isotonic modeling for either regression or two-class classification with appropriate log-likelihood loss and lasso penalty on the fitted values. This combination allows us to maintain the non-parametric nature of isotonic modeling, while controlling model complexity through regularization. We demonstrate the efficiency and usefulness of this approach on both synthetic and real world data. An implementation of our suggested solution is publicly available from the first author's website (https://sites.google.com/site/amichaipainsky/software). PMID- 26761731 TI - A Stochastic Approach to Diffeomorphic Point Set Registration with Landmark Constraints. AB - This work presents a deformable point set registration algorithm that seeks an optimal set of radial basis functions to describe the registration. A novel, global optimization approach is introduced composed of simulated annealing with a particle filter based generator function to perform the registration. It is shown how constraints can be incorporated into this framework. A constraint on the deformation is enforced whose role is to ensure physically meaningful fields (i.e., invertible). Further, examples in which landmark constraints serve to guide the registration are shown. Results on 2D and 3D data demonstrate the algorithm's robustness to noise and missing information. PMID- 26761737 TI - Mixture of Switching Linear Dynamics to Discover Behavior Patterns in Object Tracks. AB - We present a novel non-parametric Bayesian model to jointly discover the dynamics of low-level actions and high-level behaviors of tracked objects. In our approach, actions capture both linear, low-level object dynamics, and an additional spatial distribution on where the dynamic occurs. Furthermore, behavior classes capture high-level temporal motion dependencies in Markov chains of actions, thus each learned behavior is a switching linear dynamical system. The number of actions and behaviors is discovered from the data itself using Dirichlet Processes. We are especially interested in cases where tracks can exhibit large kinematic and spatial variations, e.g. person tracks in open environments, as found in the visual surveillance and intelligent vehicle domains. The model handles real-valued features directly, so no information is lost by quantizing measurements into 'visual words', and variations in standing, walking and running can be discovered without discrete thresholds. We describe inference using Markov Chain Monte Carlo sampling and validate our approach on several artificial and real-world pedestrian track datasets from the surveillance and intelligent vehicle domain. We show that our model can distinguish between relevant behavior patterns that an existing state-of-the-art hierarchical model for clustering and simpler model variants cannot. The software and the artificial and surveillance datasets are made publicly available for benchmarking purposes. PMID- 26761738 TI - NUS-PRO: A New Visual Tracking Challenge. AB - Numerous approaches on object tracking have been proposed during the past decade with demonstrated success. However, most tracking algorithms are evaluated on limited video sequences and annotations. For thorough performance evaluation, we propose a large-scale database which contains 365 challenging image sequences of pedestrians and rigid objects. The database covers 12 kinds of objects, and most of the sequences are captured from moving cameras. Each sequence is annotated with target location and occlusion level for evaluation. A thorough experimental evaluation of 20 state-of-the-art tracking algorithms is presented with detailed analysis using different metrics. The database is publicly available and evaluation can be carried out online for fair assessments of visual tracking algorithms. PMID- 26761739 TI - Robust Model Fitting Using Higher Than Minimal Subset Sampling. AB - Identifying the underlying model in a set of data contaminated by noise and outliers is a fundamental task in computer vision. The cost function associated with such tasks is often highly complex, hence in most cases only an approximate solution is obtained by evaluating the cost function on discrete locations in the parameter (hypothesis) space. To be successful at least one hypothesis has to be in the vicinity of the solution. Due to noise hypotheses generated by minimal subsets can be far from the underlying model, even when the samples are from the said structure. In this paper we investigate the feasibility of using higher than minimal subset sampling for hypothesis generation. Our empirical studies showed that increasing the sample size beyond minimal size ( p ), in particular up to p+2, will significantly increase the probability of generating a hypothesis closer to the true model when subsets are selected from inliers. On the other hand, the probability of selecting an all inlier sample rapidly decreases with the sample size, making direct extension of existing methods unfeasible. Hence, we propose a new computationally tractable method for robust model fitting that uses higher than minimal subsets. Here, one starts from an arbitrary hypothesis (which does not need to be in the vicinity of the solution) and moves until either a structure in data is found or the process is re-initialized. The method also has the ability to identify when the algorithm has reached a hypothesis with adequate accuracy and stops appropriately, thereby saving computational time. The experimental analysis carried out using synthetic and real data shows that the proposed method is both accurate and efficient compared to the state-of-the-art robust model fitting techniques. PMID- 26761740 TI - Robust Regression. AB - Discriminative methods (e.g., kernel regression, SVM) have been extensively used to solve problems such as object recognition, image alignment and pose estimation from images. These methods typically map image features ( X) to continuous (e.g., pose) or discrete (e.g., object category) values. A major drawback of existing discriminative methods is that samples are directly projected onto a subspace and hence fail to account for outliers common in realistic training sets due to occlusion, specular reflections or noise. It is important to notice that existing discriminative approaches assume the input variables X to be noise free. Thus, discriminative methods experience significant performance degradation when gross outliers are present. Despite its obvious importance, the problem of robust discriminative learning has been relatively unexplored in computer vision. This paper develops the theory of robust regression (RR) and presents an effective convex approach that uses recent advances on rank minimization. The framework applies to a variety of problems in computer vision including robust linear discriminant analysis, regression with missing data, and multi-label classification. Several synthetic and real examples with applications to head pose estimation from images, image and video classification and facial attribute classification with missing data are used to illustrate the benefits of RR. PMID- 26761741 TI - Shape and Reflectance Estimation in the Wild. AB - Our world is full of objects with complex reflectances situated in rich illumination environments. Though stunning, the diversity of appearance that arises from this complexity is also daunting. For this reason, past work on geometry recovery has tried to frame the problem into simplistic models of reflectance (such as Lambertian, mirrored, or dichromatic) or illumination (one or more distant point light sources). In this work, we directly tackle the problem of joint reflectance and geometry estimation under known but uncontrolled natural illumination by fully exploiting the surface orientation cues that become embedded in the appearance of the object. Intuitively, salient scene features (such as the sun or stained glass windows) act analogously to the point light sources of traditional geometry estimation frameworks by strongly constraining the possible orientations of the surface patches reflecting them. By jointly estimating the reflectance of the object, which modulates the illumination, the appearance of a surface patch can be used to derive a nonparametric distribution of its possible orientations. If only a single image exists, these strongly constrained surface patches may then be used to anchor the geometry estimation and give context to the less-descriptive regions. When multiple images exist, the distribution of possible surface orientations becomes tighter as additional context is given, though integrating the separate views poses additional challenges. In this paper we introduce two methods, one for the single image case, and another for the case of multiple images. The effectiveness of our methods is evaluated extensively on synthetic and real-world data sets that span the wide range of real-world environments and reflectances that lies between the extremes that have been the focus of past work. PMID- 26761742 TI - Texture Illumination Separation for Single-Shot Structured Light Reconstruction. AB - Active illumination based methods have a trade-off between acquisition time and resolution of the estimated 3D shapes. Multi-shot approaches can generate dense reconstructions but require stationary scenes. Single-shot methods are applicable to dynamic objects but can only estimate sparse reconstructions and are sensitive to surface texture. We present a single-shot approach to produce dense shape reconstructions of highly textured objects illuminated by one or more projectors. The key to our approach is an image decomposition scheme that can recover the illumination image of different projectors and the texture images of the scene from their mixed appearances. We focus on three cases of mixed appearances: the illumination from one projector onto textured surface, illumination from multiple projectors onto a textureless surface, or their combined effect. Our method can accurately compute per-pixel warps from the illumination patterns and the texture template to the observed image. The texture template is obtained by interleaving the projection sequence with an all-white pattern. The estimated warps are reliable even with infrequent interleaved projection and strong object deformation. Thus, we obtain detailed shape reconstruction and dense motion tracking of the textured surfaces. The proposed method, implemented using a one camera and two projectors system, is validated on synthetic and real data containing subtle non-rigid surface deformations. PMID- 26761743 TI - Weakly Supervised Large Scale Object Localization with Multiple Instance Learning and Bag Splitting. AB - Localizing objects of interest in images when provided with only image-level labels is a challenging visual recognition task. Previous efforts have required carefully designed features and have difficulty in handling images with cluttered backgrounds. Up-scaling to large datasets also poses a challenge to applying these methods to real applications. In this paper, we propose an efficient and effective learning framework called MILinear, which is able to learn an object localization model from large-scale data without using bounding box annotations. We integrate rich general prior knowledge into a learning model using a large pre trained convolutional network. Moreover, to reduce ambiguity in positive images, we present a bag-splitting algorithm that iteratively generates new negative bags from positive ones. We evaluate the proposed approach on the challenging Pascal VOC 2007 dataset, and our method outperforms other state-of-the-art methods by a large margin; some results are even comparable to fully supervised models trained with bounding box annotations. To further demonstrate scalability, we also present detection results on the ILSVRC 2013 detection dataset, and our method outperforms supervised deformable part-based model without using box annotations. PMID- 26761744 TI - Birth weight distribution of Hospital Geral do Grajau population compared to Sao Paulo city population. AB - OBJECTIVE: To compare the growth curves from a population from a large city suburban hospital with those of the city of Sao Paulo, Sao Paulo State, Brazil. METHODS: At Hospital Geral do Grajau, that serves the high pregnancy risk population lacking health facilities, of low education level and smaller number of prenatal visits and great morbidity, a growth curve was built for the newborns, as the Hospital is provided with updated equipment and personnel. The curve was built from the database available containing information on live births during the 2003 to 2007 period and totaling 9,952 newborns, as their weight at birth and gestational age were taken as parameters. The distribution curves of 3%, 10%, 50% and 90% of the Grajau were compared to those of the city of Sao Paulo curve. RESULTS: The curves did not significantly differ from those of the Sao Paulo curve percentiles, as shown by the mean deviation (Z score) calculation, notwithstanding the higher rates for prematurity, low weight, teenager mothers and lack of prenatal visits among the Grajau population as compared to those of Sao Paulo. CONCLUSIONS: The Sao Paulo city curve showed to be appropriate for the suburban population despite the existing differences. PMID- 26761745 TI - Pilot study in neonates using low-level laser therapy in the immediate postoperative period of myelomeningocele. AB - OBJECTIVE: To analyze the tissue repair behavior after corrective surgical incision in neonates submitted to low-level laser therapy, in an attempt to diminish the incidence of postoperative dehiscence following the surgery for myelomeningocele performed immediately after birth. METHODS: It is a prospective pilot study with 13 myelomeningocele patients submitted to surgery at birth who received adjuvant treatment with low-level laser therapy (Group A). Diode laser C.W., lambda = 685t nm, p = 21 mW, E = 0.19 J was punctually applied along the surgical incision, summing up 4 to 10 J energy delivered per patient, according to the surgical wound area and, then, compared with the previous results, which were obtained from 23 patients undergoing surgery without laser therapy (Group B). RESULTS: This pilot study showed a significant decline in dehiscence of surgical wounds in neonates submitted to low-level laser therapy as compared to controls (7.69 versus 17.39%, respectively), demonstrating this is an effective, safe and noninvasive treatment method. CONCLUSION: This new adjuvant therapeutic proposal with low-level laser therapy aided healing of surgical wounds, preventing morbidities, as well as decreasing hospital stay, which implies cost of reduction for patients and for the institution. PMID- 26761746 TI - Evaluation of the behavior of the preschool one just admitted in the unit of pediatrics and the use of the therapeutic toy. AB - OBJECTIVE: To evaluate the behavior of children before and after a therapeutic play session. METHODS: A quantitative and descriptive study was carried out in a major hospital of the city of Santos, State of Sao Paulo, involving 30 preschool children recently admitted to a pediatric ward. A behavior scale was applied before and after a therapeutic play session. This scale comprises six categories: moving, gazing, expressing feelings, talking, playing, and not responding to stimuli or requests. Each category is scored from 1 to 3, the lowest score representing the least interaction. RESULTS: Before therapeutic play sessions, children showed no interest and were scored 1 and 2: moving parts of their bodies and expressing emotions, such as seriousness, and gazing rapidly to a place as if expecting something. After therapeutic play, the children progressed to level 3: changing position, moving with a purpose, observing attentively to what they saw, and expressing emotions such as joy. CONCLUSION: Children interact well with the toys, representing home and hospital situations, and expressing feelings of anger and love. We also observed that therapeutic play improved the interactions of children with this new situation, making it easier for them to accept treatment and perceiving hospitalization as less aggressive and painful. PMID- 26761747 TI - Modification of the gasless fetoscopy technique for the treatment of large myelomeningocele: a study in sheep. AB - OBJECTIVE: To change the gasless fetoscopy technique in order to reduce the diameter of entry orifices in the myometrium. METHODS: Seven pregnant ewes were submitted to fetoscopy for repairing a large skin defect measuring 4.0 * 3.0 cm, created in the fetal lumbar region at the gestational age of 100 days. The defect was repaired through continuous suture of the skin with approximation of borders. Gasless fetoscopy was used for performing the suture with three orifices to allow entry of the trocar into the myometrium. A 5.0-mm optical trocar, and 3.5-mm grasping, dissecting and suturing forceps were used. After surgery, pregnancy was maintained until the animals were euthanized on the 133rd day of gestation, and the fetuses were evaluated. RESULTS: Seven pregnant ewes underwent surgery; the first two cases were characterized as the Pilot Group, in which the endoscopic technique was modified and caliber reduction was possible in two out of three entry orifices in the myometrium. In the five remaining cases (Study Group), the repair was successfully carried out in all the fetuses, and the mean duration of fetoscopy was 98 minutes. There was a case of maternal death attributed to intrauterine infection. Mean intrauterine permanence after surgery was 12 days. CONCLUSIONS: The technique was successfully modified, allowing reduction of the uterine orifices necessary to perform the repair of a skin defect in the fetal lumbar region through a new fetoscopy technique. The impact of this modification in repair of myelomeningocele in human fetuses should be studied. PMID- 26761748 TI - Evaluation of pain in outpatient diagnostic hysteroscopy with gas. AB - OBJECTIVE: To evaluate the intensity of pain reported by patients undergoing outpatient diagnostic hysteroscopy. METHODS: Exam performed with a 5-mm lens hysteroscope, vaginal speculum, tenaculum and uterine distention with carbon dioxide gas. Before and after the examination, patients were interviewed to define, in a verbal scale from 0 to 10, pain values that they expected to feel and that they experienced after the end, and also if they would repeat it if indicated. Data were analyzed using Statistical Package for the Social Sciences 15.0, statistic significance was defined as p < 0.05 with a study power of 95%. RESULTS: Fifty-eight patients were included with mean age of 50.9 years, with 32.8% at postmenopause and 6.9% nulliparous. Among those with previous deliveries, mean parity was 2.21 and at least one vaginal delivery had occurred in 63.8%. Only 24.1% of patients knew how the exam would be done, 62.1% needed an endometrial sample and the result was considered satisfactory in 89.7%. The means of expected and experienced pain were similar (6.0 versus 6.1), and 91.4% of women would repeat the hysteroscopy if necessary. The only factor associated with less pain after the exam was previous vaginal delivery, with a decrease of pain score from 7.1 to 5.5 (p = 0.03). Mean pain was significantly lower in those who agreed to repeat the exam (5.8 versus 9.4; p = 0.003). CONCLUSIONS: Outpatient diagnostic hysteroscopy with gas can be associated with moderate but tolerable discomfort and satisfactory results. PMID- 26761749 TI - Endometrial hysteroscopic and histological evaluation in menopausal women in continuous use of raloxifene. AB - OBJECTIVE: To study the effect of raloxifene on endometrial histopathology of menopausal women. METHODS: Thirty-one patients under raloxifene treatment (60 mg/day) for a six-month period and submitted to diagnostic videohysteroscopy at the Climateric Outpatients Clinic, Department of Gynecology and Obstetrics, Hospital do Servidor Publico Estadual Francisco Morato de Oliveira, in the city of Sao Paulo, and at Hospital Guilherme Alvaro, in the city of Santos, from September 10th, 2003 to June 22nd, 2004, were analyzed. Guided endometrial biopsy was performed on all patients on the anterior wall, using a 3-mm or 5-mm biopsy forceps. A 3-mm or 5-mm hysteroscope was used with TV imaging by an endocamera. The results of the hysteroscopic tests were compared before and six months after the use of raloxifene. RESULTS: The comparison between both biopsies was performed by means of the McNemar's test (marginal homogeneity test), and showed a descriptive level of 0.001 that indicates difference between the estrogen effects assessed at different moments. The estrogen effect on the endometrial tissue did not increase in any of the 31 patients analyzed. Twenty-one patients (68%) showed smaller estrogen effect in the final evaluation. CONCLUSIONS: The study showed no evidence of endometrial stimulation of raloxifene and, in fact, many women presented less estrogen effect after its use. PMID- 26761751 TI - Effects of Tai Chi Chuan on cognition of elderly women with mild cognitive impairment. AB - OBJECTIVE: To detect the effects of Tai Chi Chuan practice on the cognition of elderly subjects with Mild Cognitive Impairment. METHODS: This is a pilot study with 26 elderly patients (mean age of 74 years) with Mild Cognitive Impairment. The evaluation instruments were Subjective Memory Complaint Scale (SMC), Rivermead Behavioral Memory Test (RBMT) and Digit Span Forward and Backward (DSF and DSB) from the Wechsler Adult Intelligence Scale (WAIS). One group of 13 patients received two weekly 60-minute classes of Tai Chi Chuan (Yang style) for 6 consecutive months, and the rest formed the Control Group. The Tai Chi Chuan Group was also evaluated as to learning of the Tai Chi Chuan practical exercises by means of a Specific Learning Test applied after three months of intervention. RESULTS: After six months of intervention, the TCC Group showed significant improvement on the RBMT and the SMC (p = 0.007 and p = 0.023, respectively). The Control Group showed no significant differences in the cognitive tests during the study. There was a significant correlation between the Tai Chi Chuan Learning Test and RBMT (p = 0.008), showing that patients with a better performance in exercising TCC also showed a better performance in memory. CONCLUSIONS: In this study, a six-month program of Tai Chi Chuan afforded a significant improvement of the performance of memory complaints in the elderly with Mild Cognitive Impairment. Additional randomized studies with larger samples and more prolonged follow-up are needed to confirm these benefits. PMID- 26761750 TI - Active search of women as an efficacy factor for a breast and cervical cancer screening program in the city of Jundiai, Sao Paulo, Brazil. AB - OBJECTIVE: To compare the profile of women looking for gynecological care to the profile of women invited to participate in the program, assessing breast and cervical cancer risk factors in each group and comparing Papanicolaou's test and mammography results. METHODS: Medical records of 46 women participating in a breast and cervical cancer prevention program and 42 medical reports of women that regularly visited the primary healthcare unit from August to December 2006 were examined. RESULTS: The mean interval between the last Papanicolaou's tests was of approximately 19.7 months when comparing women visiting their physician and 25.3 participants in the program. There was one case (1.1%) of high grade intraepithelial lesion in one woman included in the program. Regarding breast cancer, when comparing both groups, we verified that all women above the age of 40 years that participated in the program underwent mammography; this was not verified in the group seeing a physician. This shows the efficacy of this screening, actively looking for women in the age group at risk for breast cancer. CONCLUSIONS: Active search is important to recruit women; the screening program needs improvement to show its real impact on morbidity and mortality of these cancers. PMID- 26761752 TI - The impact of motivational interventions for increasing physical activity. AB - OBJECTIVE: To assess whether incentives for practicing regular physical activities in fact help raising the frequency of exercising. METHODS: Male and female subjects undergoing two to three assessments in the Check-Up Unit of Hospital Israelita Albert Einstein (HIAE) were evaluated by noting any increase in levels of physical activity, improvements in mean metabolic unit numbers, and the sensitization index. The International Physical Activity Questionnaire was applied to assess the sample. RESULTS: There were 1,879 subjects - 1,559 (83%) males and 320 (17%) females - aged 20 to 76 years (mean age = 45.8 years, standard deviation +/- 8.8) who underwent a Continued Health Review at the Center for Preventive Medicine of the HIAE, Check-Up Unit, Jardins. Initially, over half of the sample was insufficiently active (sedentary or poorly active); there were more women than men in this group. After the health review, most subjects increased their level of physical activity; this increase was higher among women. Males encouraged three times to exercising showed better results (increased level of physical activity) as compared to males encouraged twice for exercising. The best results in females were found in the group that went through two evaluations. This result is due to the fact that the sample of females comprising the group that received incentives on three occasions was small. This was also the only group that showed no increase in mean metabolic units. The sensitization index assessment in the overall sample was very satisfactory, as the expected results were achieved. CONCLUSIONS: These results show that motivational interventions are effective for raising the level of physical activity. We concluded that to encourage the practice of regular physical activity through information programs about its health benefits is very important. PMID- 26761754 TI - Exercise-induced ventricular arrhythmias: analysis of predictive factors in a population with sleep disorders. AB - OBJECTIVE: To assess the prevalence of ventricular arrhythmias induced by exercise in a population with sleep disorders and to analyze the triggering factors. METHODS: Patients were consecutively selected from the database of the Sleep Clinic of Universidade Federal de Sao Paulo. All subjects were submitted to basal polysomnography, blood sample collection, physical examination, 12-lead ECG, spirometry, cardiorespiratory exercise study on a treadmill, and echocardiogram. The Control Group was matched for age and gender. RESULTS: A total of 312 patients were analyzed. Exercise-induced ventricular arrhythmia was observed in 7%. The aortic diameter was larger (3.44 +/- 0.30, 3.16 +/- 0.36, p = 0.04) and the minimal saturation was lower (92.75 +/- 3.05, 95.50 +/- 1.73, p=0.01) in the ventricular arrhythmia group when compared to controls, respectively. After correction of the aortic root to body surface, there was only a trend to a larger diameter being associated with the emergence of arrhythmia. CONCLUSIONS: Exercise-induced ventricular arrhythmia was observed in 7% of sample and it was associated with lower oxygen saturation during exercise. PMID- 26761755 TI - Can the lymph node reactivity pattern in the pN0 neck analysis provide any additional prognostic information in patients with laryngeal squamous cell carcinoma? AB - OBJECTIVE: To evaluate the influence of lymph node reactivity on recurrence and survival rates in a population of pT3 or pT4 pN0 patients with laryngeal squamous cell carcinoma. METHODS: Between 2002 and 2005, 105 patients with LSSC underwent total laryngectomy with bilateral selective neck dissection including levels II, III and IV. Most (69) received PO radiotherapy. All pathological specimens were either pT3 or pT4, and all necks were pN0. All lymph nodes were analyzed and their reactivity status were classified as the following four patterns: follicular hyperplasia associated with humoral response, paracortical hyperplasia associated with cellular response, sinus histiocytosis with no association with specific immune response, or normal lymph node. Only the first two patterns were considered stimulated, whereas the last two were considered non-stimulated. The most prevalent pattern in a particular neck specimen was considered for the analysis of recurrence and survival. RESULTS: The total number of lymph nodes studied was 3,648, with an average of 34.7 lymph nodes/neck specimens. The most frequent lymph node reactivity patterns were sinusal histiocytosis (50 cases), paracortical hyperplasia (35 cases), and follicular hyperplasia (20 cases). There was no statistical association of these individual patterns with recurrence rate (p = 0.98) or mortality (p = 0.49). However, there was a statistically significant association between paracortical hyperplasia pattern (related to cellular lymph node immunity) and improved five-year survival (76 versus 60%; log rank = 0.05). CONCLUSIONS: There was a positive correlation between stimulated cellular lymph node pattern and improved 5-year survival rate in patients with pN0 laryngeal squamous cell carcinoma, suggesting the indication of adjuvant treatment for those individuals with decreased immune response, even in the absence of pathologic metastases detected by the usual methods. PMID- 26761753 TI - Relation between three-dimensional and two-dimensional echocardiography and biochemical analysis in patients with ST-segment elevation myocardial infarction percutaneously treated. AB - OBJECTIVE: The prognosis of patients with acute myocardial infarction depends on multiple features that can demonstrate myocardial injury degree (such as serum markers of cardiac necrosis), and also on adaptive mechanisms relative to the acute event. The aim of the study was to assess the relation between biochemical and echocardiographic findings from three-dimensional echocardiographic (3D Echo) analysis and echocardiographic two-dimensional (2D Echo) left ventricular ejection fraction in patients with ST-segment elevation acute myocardial infarction, submitted to primary percutaneous treatment. METHODS: A prospective study with 2D Echo and 3D Echo of 23 patients (17 males, mean age of 57 +/- 13 years) with ST-segment elevation acute myocardial infarction, primarily percutaneously treated (stent). Serum cardiac markers (creatine kinase MB, Troponin I and Myoglobin) and serum brain natriuretic peptide were compared to echocardiographic parameters (volumes, left ventricular ejection fraction and ventricular dyssynchrony index). The statistical analysis was performed using Pearson's correlation coefficient, 95% CI, p < 0.05, linear regression equation and Bland & Altman test. RESULTS: Pearson's correlation coefficient (r)relative to 3D left ventricular ejection fraction: 1- brain natriuretic peptide: r: - 0.7427, p < 0.0001; 2- creatine kinase MB: r: - 0.660, p = 0.001. Left ventricular ejection fraction 2D (r) : 1- brain natriuretic peptide: r: - 0.5478, p = 0.001; 2- creatine kinase MB: r: - 0.4800, p < 0.0277. Other associations were not significant. CONCLUSIONS: In this series, it was observed better correlation in regard to serum creatine kinase MB, brain natriuretic peptide and 3D Echo left ventricular ejection fraction, when compared to 2D Echo left ventricular ejection fraction. PMID- 26761756 TI - A mobile interventional radiology unit: innovation and social responsibility. AB - OBJECTIVE: To present the preliminary results of a feasibility study performed to determine the value of a mobile interventional radiology unit used to promote a uterine embolization program for low-income patients. METHODS: Forty patients with symptomatic fibroids were treated with uterine embolization. Procedures were performed in four public hospitals in the metropolitan area of Sao Paulo. This study was approved by the institutional research ethics committee and all patients signed an informed consent form. A mobile interventional radiology unit, named ANGIOMOVEL, was conceived and implemented utilizing a small truck to transport one mobile C arm, one radiological table, protection aprons and a small trolley containing specific supplies for the procedures. The ANGIOMOVEL team consisted of two interventional radiologists, one nurse, one driver and one assistant. The unit visited one hospital per week during a three-month period. Patient inclusion was contingent upon several factors, such as evaluation by a trained gynecologist, completion of a pelvic MRI, routine serological laboratory tests and completion of a quality of life questionnaire (QOL). Outcomes, MRI and QOL were evaluated. Data obtained after 12 weeks were collected and analyzed. RESULTS: Technical success was achieved in 100% of cases, with a mean procedure time of 43 minutes and a mean fluoroscopic time of 24 minutes. The mean hospital stay was 1.07 day and the mean time for recovery and return to normal activities was 10 days. After 12 weeks, 36 (90%) of patients noticed improvement of their symptoms and 4 (10%) did not notice any improvement. Thirty-eight patients (95%) were satisfied or very satisfied and 39 (97.5%) said they would recommend the procedure. Pre- and post-procedure magnetic resonance imaging analysis showed that complete fibroid ischemia was achieved in 92.5% of cases with a mean uterine volume reduction of 38% and a mean fibroid volume reduction of 52%. Health related quality of life scores showed improvement, increasing from 39.30 before the treatment to 79.62 points after therapy. CONCLUSIONS: The initial results indicate that using a Mobile Interventional Radiology Unit is feasible, efficient and safe to develop a successful uterine fibroid embolization program providing care to the underserved patient community. PMID- 26761757 TI - Communication difficulties and strategies used by the nurses and their team in caring for the hearing impaired. AB - OBJECTIVES: To identify communication difficulties faced by the nursing staff and to learn the strategies developed for non-oral communication. METHODS: This is a descriptive, exploratory, level I study with a quantitative approach. The sample group comprised 37 registered nurses and 63 licensed practical nurses of a private hospital who, after undergoing the ethical-legal procedures, answered a questionnaire to identify difficulties faced and strategies used in the care for hearing-impaired patients. RESULTS: Difficulty in explaining matters of interest to the patient was reported by 66% of professionals; and 32% reported difficulties in understanding patients in their way of communicate. The strategy adopted by 100% of respondents was mimicry, followed by lip reading, used by 94% of respondents; help from a person accompanying the patient was used by 65%, and written communication by 42% of respondents. Only 1% used communication via the Brazilian Sign Language (LIBRAS). CONCLUSIONS: The difficulties found and the strategies adopted by the nursing staff in communicating with hearing-impaired patients justify the need to train these professionals to deliver a more humanized care, developing a more inclusive society for those with special needs. PMID- 26761758 TI - Nursing and spirituality. AB - OBJECTIVES: To evaluate the spiritual well-being of nurses; to appraise their opinions as to the importance of offering patients spiritual assistance, and to verify whether nurses received any specific type of preparation during their professional training for giving spiritual assistance to patients. METHODS: This is an exploratory and descriptive study, carried out with a sample of 30 nurses who worked at the Stepdown Unit and Oncology Unit of Hospital Israelita Albert Einstein, using the application of the Spiritual Well-Being Scale (SWS) and a questionnaire prepared by the authors. RESULTS: On the Spiritual Well-Being Scale, 76.6% of nurses produced positive scores. On the Existential Well-Being subscale, 80% had positive scores, and on the Religious Well-Being subscale, 76.6% had positive scores. On the SWBS, the general average score was 107.26, and for the Existential and Religious ones, the average scores were 54.4 and 53.2, respectively. Most nurses responded affirmatively as to the importance of offering patients spiritual assistance, and 40% of nurses offered as rationale "to provide well-being and comfort to the patient". Most nurses reported not having received professional training for giving spiritual assistance to patients in any of the nursing courses they had done. CONCLUSIONS: The results indicate the need for professional training and/or continued education courses in nursing to extend the reflection and discussion on spirituality and spiritual assistance to patients. PMID- 26761759 TI - Magnetic resonance imaging findings in adnexial torsion. AB - Adnexial torsion is an unusual event, but a major cause of abdominal pain in women. It is often associated with ovarian tumor or cyst, but can occur in normal ovaries, especially in children. The twisting of adnexial structures may involve the ovary or tube, but frequently affects both. In most cases, it is unilateral, with slight predilection for the right side. In imaging findings, increased ovarian volume and adnexial masses are observed, with reduced or absent vascularization. In cases of undiagnosed or untreated complete twist, hemorrhagic necrosis may occur leading to complications; in that, peritonitis is the most frequent. Early diagnosis helps preventing irreversible damage with conservative treatment, thereby saving the ovary. Limitations in performing physical examination, possible inconclusive results in ultrasound and exposure to radiation in computed tomography makes magnetic resonance imaging a valuable tool in emergency assessment of gynecological diseases. The objective of this study was to report two confirmed cases of adnexial twist, emphasizing the contribution of magnetic resonance imaging in the diagnosis of this condition. PMID- 26761760 TI - En bloc pancreaticoduodenectomy and right hemicolectomy to treat locally advanced right colon cancer: report of three cases. AB - Although colorectal tumors are fairly common surgical conditions, 5 to 12% of these tumors are locally advanced (T4 tumors) upon diagnosis. In this particular situation, the efficacy of en bloc multivisceral resection has been proven. When right-colon cancer invades the proximal duodenum or even the pancreatic head, a challenging dilemma arises due to complexity of the curative surgical procedure. Therefore, en bloc pancreaticoduodenectomy with right hemicolectomy should be performed to obtain free margins. The present study reports three cases of locally advanced right-colon cancer invading the proximal duodenum. All of these cases underwent successful en bloc pancreaticoduodenectomy plus right hemicolectomy, with no death occurrence. Long-term survival was observed in two cases (30 and 50 months). In the third case, the patient did not present any recurrence twelve months after surgical treatment. Multivisceral resection with en bloc pancreaticoduodenectomy should be considered for patients who present acceptable risk for major surgery and no distant dissemination. This approach seems justified since the length of postoperative survival is longer in radically ressected groups (R0) than in palliativelly resected groups (R1-2). PMID- 26761761 TI - Integrative review: what is it? How to do it? AB - INTRODUCTION: The integrative review is the methodology that provides synthesis of knowledge and applicability of results of significant studies to practice. OBJECTIVE: To present the phases of an integrative review and the relevant aspects to be taken into account when using this methodological resource. METHODS: This study was based on bibliographic search and on the experience of the authors when performing an integrative review. RESULTS: Presentation of the six stages of the integrative review process: preparing the guiding question, searching or sampling the literature, data collection, critical analysis of the studies included, discussion of results and presentation of the integrative review. CONCLUSIONS: Considering the need to assure care based on scientific evidence, the integrative review has been identified as a unique tool in healthcare for it synthesizes investigations available on the given topic and guides practice based on scientific knowledge. PMID- 26761762 TI - Microcirculatory assessment in daily clinical practice - not yet ready but not too far! AB - Shock is characterized by an alteration in tissue perfusion that may lead to tissue hypoxia. Recent guidelines recommend aggressive and early resuscitation therapy, but mortality rate is still unacceptably high. Unfortunately, traditional clinical surrogates used to guide resuscitation therapy poorly correlate with microcirculatory blood flow, a key determinant of tissue perfusion. New techniques that directly assess microcirculatory perfusion at the bedside have emerged as a complement to traditional macrohemodynamic parameters. These techniques have been supported by several studies showing microcirculatory alterations in different clinical settings. In addition, these microcirculatory alterations are related with outcome and persist regardless of arterial pressure normalization, being a better predictor of organ dysfunction and mortality than global hemodynamic and laboratory parameters. These findings allowed the concept of "microcirculatory-goal directed therapy", which is now in its preliminary phase, as the impact of many interventions still needs to be assessed. Finally, microcirculation assessment has also been explored in other medical fields such as perioperative, systemic arterial hypertension, heart failure, and hyperviscosity syndromes. In this review, we shortly present the characteristics of microcirculation and the main determinants of capillary blood flow, and we discuss advantages and limitations of some recently available techniques to evaluate microcirculation at the bedside, and how they could be useful for the general clinician in daily practice. PMID- 26761763 TI - Autoimmune uveitis: study of treatment therapies. AB - Experimental autoimmune uveitis is an organ-specific T-cell mediated autoimmune disease characterized by inflammation and consequent destruction of the neural retina and adjacent tissues. Inflammation in experimental autoimmune uveitis may be induced in rodents by immunization with retinal antigens, such as interphotoreceptor retinoid-binding protein. We present a review of experimental studies that correlate primary immunobiological functions with this chronic disease and the possible use of molecules for the treatment of autoimmune uveitis. PMID- 26761764 TI - Perinatal varicella. PMID- 26761765 TI - Natural orifice surgery: new concept in minimally invasive surgery. AB - We present the concept of natural orifice surgery and of scarless operations, with their access routes, their multidisciplinary character, and challenges to their development. We point out the intra- and postoperative advantages. We emphasize the use of the vaginal route and posterior colpotomy in the application of natural orifice surgery in vaginal hysterectomies and surgical access to adnexa, which includes tubal ligation. We highlight the need for mastering these surgical modalities, which can bring great advantages to patients in Brazil. PMID- 26761767 TI - Methotrexate: practical use in dermatology. AB - Methotrexate (MTX) is an anti-inflammatory, anti-proliferative and immunosuppressant drug largely used worldwide with a well-known efficacy, and it is considered a safe and easy to use agent. MTX was first used in psoriasis, but it represents an effective and safe therapeutic option in a wide range of skin diseases. Despite its common employ, it is still the subject of numerous researches, with the purpose to develop new strategies to increase the manageability and evaluate the efficacy of the treatment, alone and in association with other therapies. Starting up from the official guidelines, we have reviewed the scientific literature, along with our clinical experience, in order to update the uses of MTX in dermatology. PMID- 26761766 TI - Treatment patterns with systemic antipsoriatic agents in childhood psoriasis: an Italian database analysis. AB - BACKGROUND: The majority of available systemic therapies have never been systematically investigated in moderate to severe childhood plaque psoriasis. For this reason, treatment preferences for moderate to severe psoriasis in childhood are still unknown. The aim of this study was to investigate the systemic treatment patterns of moderate to severe psoriasis in children and adolescents aged 18 or older in Italy. Additional secondary outcomes were duration of treatment and reasons for discontinuation. METHODS: In order to define differences in treatment patterns, we performed a chart review of all consecutive patients treated with systemic drugs during an index period of 5 years. Consecutive sampling of all patients with psoriasis aged <=18 years, who had been treated with at least one systemic drug over a 5-year period, was made. RESULTS: The records of 58 consecutive patients, 27 males, 31 females. with moderate to severe psoriasis treated with at least one systemic therapy were reviewed. The median age (standard deviation) at the start of the first systemic treatment was 11.7+/-3.7 years. The most preferred first-line systemic treatment was cyclosporine, which was administered as first systemic treatment in 53.4% of patients, followed by acitretin in 22.4% of patients, etanercept and PUVA respectively in 8.6%, methotrexate in 6.8%. 48.2% of patients received a second systemic treatment due to inefficacy or side effects of the first-line therapy during the index period. Because of the small sample, and voluntary contribution, selection bias may have occurred. CONCLUSIONS: A considerable variation in the management of the first-line systemic therapy in children with moderate to severe psoriasis was observed. Cyclosporine was most commonly preferred as a first-line treatment. The availability of new therapeutic agents could change the scenario of treatment patterns in childhood psoriasis. PMID- 26761768 TI - Efficacy and tolerability of a topical gel containing 3% hydrogen peroxide, 1.5% salicylic acid and 4% D-panthenol in the treatment of mild-moderate acne. AB - BACKGROUND: The aim of this paper was to evaluate efficacy and tolerability of a topical gel (ACNAID TM gel medical device) containing 3% hydrogen peroxide (HPO), 1.5% salicylic acid (SA) and 4% D-panthenol (D-p) in the treatment of mild moderate acne, comparing it with a previous formulation (ACNAID TM gel Cosmetic) containing 4% HPO, 0.5% SA, 4% D-p. METHODS: Twenty patients of both sex with mild-moderate acne have been selected. The topical gel was applied twice a day for 60 days. Evaluations included: Global Acne Grading System (GAGS); lesions count; photographic assessment; a questionnaire to assess the tolerability. The results have been compared with those obtained in a previous study conducted with the formulation containing 4% HPO, 0.5% SA, 4% D-p. RESULTS: The GAGS score showed a reduction of 43% from T0 to T1 and of 61% from T0 to T2. Count of lesions: comedones reduction of 62% from T0 to T1 and of 95% from T0 to T2; papules reduction of 49% from T0 to T1 and of 68% from T0 to T2; pustules reduction of 75% from T0 to T1 and of 100% from T0 to T2. Digital images showed a significant reduction of acne lesions. At T2 the tolerability of the topical product was excellent according to 83% of patients and good according to 17% of patients. CONCLUSIONS: The topical gel has demonstrated to be effective and safe for treatment of mild to moderate acne. No patients reported side effects. These results are superior to those obtained in the previous study. PMID- 26761769 TI - Plasma levels of apolipoprotein E and risk of ischemic heart disease in the general population. AB - BACKGROUND AND AIMS: Triglyceride-rich lipoproteins are causally associated with high risk of ischemic heart disease (IHD), and apolipoprotein E (apoE) has a central role in their plasma clearance. While both quantitative and qualitative changes of apoE are established causes of rare dyslipidemia syndromes, it remains unclear whether plasma levels of apoE are associated with risk of IHD in the general population. METHODS: We tested whether plasma levels of apoE at enrollment were associated with future risk of IHD and myocardial infarction (MI) in 91,695 individuals from the general population. RESULTS: Multifactorially adjusted hazard ratios (HRs) for highest versus lowest apoE tertile were 1.15 (1.04-1.27) for IHD and 1.16 (1.00-1.36) for MI in men, and 0.94 (0.84-1.05) and 1.04 (0.85-1.26) in women. These associations were attenuated by adjustments for triglyceride levels. Corresponding HRs for highest versus lowest apoE tertile in epsilon33 carriers were 1.18 (1.03-1.36) for IHD and 1.21 (0.98-1.49) for MI in men, and 0.91 (0.78-1.06) and 0.93 (0.71-1.21) in women. Thus, the present associations were independent of APOE genotype. CONCLUSION: These findings suggest that high plasma levels of apoE are associated with IHD in men but not in women. Triglyceride-rich lipoproteins may partly explain these associations. PMID- 26761770 TI - Brain microangiopathy and macroangiopathy share common risk factors and biomarkers. AB - AIMS: Besides carotid or cardiac embolism, stroke can occur via microangiopathy (small arterial disease [SAD]) and macroangiopathy (intracranial atherosclerotic stroke [ICAS]) of the intracranial vasculature. There have been efforts to identify risk factors specific to microangiopathy and macroangiopathy, including vascular risk factors, and protein and genetic biomarkers. We hypothesized that despite the anatomic and pathophysiological differences between microvessels and macrovessels, microangiopathy and macroangiopathy share common risk factors during disease progression. METHODS: Among 714 patients with acute infarctions within middle cerebral artery territory, 126 with SAD and 116 with ICAS were included in this study. Subclinical microangiopathy (degree of leukoaraiosis) and macroangiopathy (number of tandem stenosis) was graded in each patient. Inflammatory biomarkers (C-reactive protein, E-selectin, and LpPLA2), endothelial dysfunction (asymmetric dimethylarginine, urinary albumin-to-creatinine ratio, endostatin, and homocysteine), atherogenesis (lipoprotein(a), adiponectin, and resistin), and renal function (creatinine clearance and estimated glomerular filtration rate) were assessed. RESULTS: Compared with the patients with isolated SAD, those with isolated ICAS were younger, were current smokers, and showed higher apoB levels (p < 0.05 in all cases). However, with the progression of subclinical microangiopathy, asymptomatic macroangiopathy worsened and vice versa. No significant differences in risk factors were observed between advanced SAD and ICAS. Decreased renal function was independently associated with progression of microangiopathy and macroangiopathy. Markers of endothelial dysfunction, but not the other markers, were significantly related to creatinine clearance level. CONCLUSIONS: Mild to moderate loss of renal function is strongly associated with both intracranial microangiopathy and macroangiopathy. Endothelial dysfunction may be associated with this relationship. PMID- 26761771 TI - Characterization of the NPC1L1 gene and proteome from an exceptional responder to ezetimibe. AB - BACKGROUND: Strategies to reduce LDL-cholesterol involve reductions in cholesterol synthesis or absorption. We identified a familial hypercholesterolemia patient with an exceptional response to the cholesterol absorption inhibitor, ezetimibe. Niemann-Pick C 1-like 1 (NPC1L1) is the molecular target of ezetimibe. METHODS AND RESULTS: Sequencing identified nucleotide changes predicted to change amino acids 52 (L52P), 300 (I300T) and 489 (S489G) in exceptional NPC1L1. In silico analyses identified increased stability and cholesterol binding affinity in L52P-NPC1L1 versus WT-NPC1L1. HEK293 cells overexpressing WT-NPC1L1 or NPC1L1 harboring amino acid changes singly or in combination (Comb-NPC1L1) had reduced cholesterol uptake in Comb-NPC1L1 when ezetimibe was present. Cholesterol uptake was reduced by ezetimibe in L52P NPC1L1, I300T-NPC1L1, but increased in S489G-NPC1L1 overexpressing cells. Immunolocalization studies found preferential plasma membrane localization of mutant NPC1L1 independent of ezetimibe. Flotillin 1 and 2 expression was reduced and binding to Comb-NPC1L1 was reduced independent of ezetimibe exposure. Proteomic analyses identified increased association with proteins that modulate intermediate filament proteins in Comb-NPC1L1 versus WT-NPC1L1 treated with ezetimibe. CONCLUSION: This is the first detailed analysis of the role of NPC1L1 mutations in an exceptional responder to ezetimibe. The results point to a complex set of events in which the combined mutations were shown to affect cholesterol uptake in the presence of ezetimibe. Proteomic analysis suggests that the exceptional response may also lie in the nature of interactions with cytosolic proteins. PMID- 26761773 TI - Soluble LR11 is a novel biomarker for vascular lesions late after Kawasaki disease. AB - OBJECTIVE: Coronary artery lesions (CALs) and a risk for early onset of atherosclerosis are major concerns following Kawasaki disease (KD). Intimal smooth muscle cells (SMCs) have an important role in vascular lesions in KD. It is known that soluble LR11 (sLR11) is a novel biomarker for vascular lesions and LR11 is markedly expressed in intimal SMCs in atherosclerotic lesions. In this study, we hypothesized that sLR11 reflects the presence of vascular lesions late after KD. METHODS: Twenty-three age-matched controls (group 1) and 59 patients with a history of KD were enrolled; 36 with KD had normal coronary arteries or regressed aneurysms (group 2), and 23 had CALs (group 3). RESULTS: Serum sLR11 levels in group 3 (median, interquartile range (IQR): 11.1 ng/mL, 9.3-13.9 ng/mL) were significantly higher than those in groups 1 (8.4 ng/mL, 7.1-10.2 ng/mL, p < 0.001) and 2 (9.0 ng/mL, 7.7-10.1 ng/mL, p < 0.01). Levels of sLR11 were positively correlated with levels of high-sensitivity C-reactive protein (r = 0.480, p < 0.01) and lipoprotein (a) (r = 0.486, p < 0.01). CONCLUSION: These findings suggest that sLR11 reflects the development of vascular lesions in patients with serious CALs. PMID- 26761772 TI - Metabolic syndrome, adherence to the Mediterranean diet and 10-year cardiovascular disease incidence: The ATTICA study. AB - BACKGROUND AND AIMS: To better understand the metabolic syndrome (MS) spectrum through principal components analysis and further evaluate the role of the Mediterranean diet on MS presence. METHODS: During 2001-2002, 1514 men and 1528 women (>18 y) without any clinical evidence of CVD or any other chronic disease, at baseline, living in greater Athens area, Greece, were enrolled. In 2011-2012, the 10-year follow-up was performed in 2583 participants (15% of the participants were lost to follow-up). Incidence of fatal or non-fatal CVD was defined according to WHO-ICD-10 criteria. MS was defined by the National Cholesterol Education Program Adult Treatment panel III (revised NCEP ATP III) definition. Adherence to the Mediterranean diet was assessed using the MedDietScore (range 0 55). RESULTS: Five principal components were derived, explaining 73.8% of the total variation, characterized by the: a) body weight and lipid profile, b) blood pressure, c) lipid profile, d) glucose profile, e) inflammatory factors. All components were associated with higher likelihood of CVD incidence. After adjusting for various potential confounding factors, adherence to the Mediterranean dietary pattern for each 10% increase in the MedDietScore, was associated with 15% lower odds of CVD incidence (95%CI: 0.71-1.06). For the participants with low adherence to the Mediterranean diet all five components were significantly associated with increased likelihood of CVD incidence. However, for the ones following closely the Mediterranean pattern positive, yet not significant associations were observed. CONCLUSION: Results of the present work propose a wider MS definition, while highlighting the beneficial role of the Mediterranean dietary pattern. PMID- 26761774 TI - CONCOLOR: Constrained Non-Convex Low-Rank Model for Image Deblocking. AB - Due to independent and coarse quantization of transform coefficients in each block, block-based transform coding usually introduces visually annoying blocking artifacts at low bitrates, which greatly prevents further bit reduction. To alleviate the conflict between bit reduction and quality preservation, deblocking as a post-processing strategy is an attractive and promising solution without changing existing codec. In this paper, in order to reduce blocking artifacts and obtain high-quality image, image deblocking is formulated as an optimization problem within maximum a posteriori framework, and a novel algorithm for image deblocking using constrained non-convex low-rank model is proposed. The l(p) (0 < p < 1) penalty function is extended on singular values of a matrix to characterize low-rank prior model rather than the nuclear norm, while the quantization constraint is explicitly transformed into the feasible solution space to constrain the non-convex low-rank optimization. Moreover, a new quantization noise model is developed, and an alternatively minimizing strategy with adaptive parameter adjustment is developed to solve the proposed optimization problem. This parameter-free advantage enables the whole algorithm more attractive and practical. Experiments demonstrate that the proposed image deblocking algorithm outperforms the current state-of-the-art methods in both the objective quality and the perceptual quality. PMID- 26761775 TI - Robust Point Set Matching for Partial Face Recognition. AB - Over the past three decades, a number of face recognition methods have been proposed in computer vision, and most of them use holistic face images for person identification. In many real-world scenarios especially some unconstrained environments, human faces might be occluded by other objects, and it is difficult to obtain fully holistic face images for recognition. To address this, we propose a new partial face recognition approach to recognize persons of interest from their partial faces. Given a pair of gallery image and probe face patch, we first detect keypoints and extract their local textural features. Then, we propose a robust point set matching method to discriminatively match these two extracted local feature sets, where both the textural information and geometrical information of local features are explicitly used for matching simultaneously. Finally, the similarity of two faces is converted as the distance between these two aligned feature sets. Experimental results on four public face data sets show the effectiveness of the proposed approach. PMID- 26761776 TI - Discovery and SAR of N-(1-((substituted piperidin-4-yl)methyl)-3-methoxypiperidin 4-yl)-2-methoxybenzamide derivatives: 5-Hydroxytryptamine receptor 4 agonist as a potent prokinetic agent. AB - A series of novel benzamide derivatives, altering the 4-fluorophenylalkyl moiety in cisapride, were synthesized as 5-HT4 receptor agonists, and SAR of these analogs was examined on in vitro and in vivo prokinetic activities. These compounds were synthesized for high 5-HT4 receptor binding affinities and low hERG affinities. Several types of analogs were obtained and screened for 5-HT4 binding, hERG blocking, agonism, and gastric emptying assessment. Among the analogues, compound 23g showed promising results compared with the other analogs with respect to gastric emptying rates in rats. Therefore, we suggest that it may be a clinical candidate for the development of a potent prokinetic agent to treat GI disorders. PMID- 26761777 TI - The interplay between biological and physical scenarios of bacterial death induced by non-thermal plasma. AB - Direct interactions of plasma matter with living cells and tissues can dramatically affect their functionality, initiating many important effects from cancer elimination to bacteria deactivation. However, the physical mechanisms and biochemical pathways underlying the effects of non-thermal plasma on bacteria and cell fate have still not been fully explored. Here, we report on the molecular mechanisms of non-thermal plasma-induced bacteria inactivation in both Gram positive and Gram-negative strains. We demonstrate that depending on the exposure time plasma induces either direct physical destruction of bacteria or triggers programmed cell death (PCD) that exhibits characteristic features of apoptosis. The interplay between physical disruption and PCD is on the one hand driven by physical plasma parameters, and on the other hand by biological and physical properties of bacteria. The explored possibilities of the tuneable bacteria deactivation provide a basis for the development of advanced plasma-based therapies. To a great extent, our study opens new possibilities for controlled non-thermal plasma interactions with living systems. PMID- 26761778 TI - In depth study on thermosensitive liposomes: Optimizing formulations for tumor specific therapy and in vitro to in vivo relations. AB - In numerous studies, thermosensitive liposomes (TSLs) for local heat-triggered delivery of Doxorubicin (Dox) to tumors have been investigated, with TSLs having different lipid formulations, drug loading methodology and testing procedures. To gain more insight in these parameters, we investigated TSLs with four variable DSPC-DPPC lipid ratios (50, 60, 70 or 80% DPPC and 5 mol% of DSPE-PEG2000) using either ammonium sulfate or a citrate buffer for Dox loading. Ammonium sulfate loading of Dox yielded more stable TSLs than citrate loading. At 37 degrees C, leakage was unnoticeable for all ammonium sulfate TSLs. At 42 degrees C, complete release occurred within seconds, except for 50% DPPC TSLs, where slow and incomplete release was observed in vitro but also in vivo using a dorsal skinfold window chamber. In contrast to in vitro assays, blood kinetics studies indicated a burst release of Dox upon injection and higher leakage for all TSLs. In therapeutic studies, hyperthermia in combination with TSLs repressed BFS-1 sarcoma growth. Our study shows that prediction of therapeutic efficacy purely based on differences found in vitro is difficult, instead, parameters obtained from pharmacokinetic studies in vivo, and the exact timing of the delivery protocol need to be taken into account. PMID- 26761779 TI - Low-dose phase-based X-ray imaging techniques for in situ soft tissue engineering assessments. AB - In tissue engineering, non-invasive imaging of biomaterial scaffolds and tissues in living systems is essential to longitudinal animal studies for assessments without interrupting the repair process. Conventional X-ray imaging is inadequate for use in soft tissue engineering due to the limited absorption difference between the soft tissue and biomaterial scaffolds. X-ray phase-based imaging techniques that derive contrast from refraction or phase effects rather than absorption can provide the necessary contrast to see low-density biomaterial scaffolds and tissues in large living systems. This paper explores and compares three synchrotron phase-based X-ray imaging techniques-computed tomography (CT) diffraction enhanced imaging (DEI), -analyzer based imaging (ABI), and -phase contrast imaging (PCI)-for visualization and characterization of low-density biomaterial scaffolds and tissues in situ for non-invasive soft tissue engineering assessments. Intact pig joints implanted with polycaprolactone scaffolds were used as the model to assess and compare the imaging techniques in terms of different qualitative and quantitative criteria. For long-term in vivo live animal imaging, different strategies for reducing the imaging radiation dose and scan time-reduced number of CT projections, region of interest, and low resolution imaging-were examined with the presented phase-based imaging techniques. The results demonstrated promising capabilities of the phase-based techniques for visualization of biomaterial scaffolds and soft tissues in situ. The low-dose imaging strategies were illustrated effective for reducing the radiation dose to levels appropriate for live animal imaging. The comparison among the imaging techniques suggested that CT-DEI has the highest efficiency in retaining image contrast at considerably low radiation doses. PMID- 26761781 TI - Responses of antioxidant defense system to polyfluorinated dibenzo-p-dioxins (PFDDs) exposure in liver of freshwater fish Carassius auratus. AB - In this study, we evaluated the toxicity of ten polyfluorinated dibenzo-p-dioxins (PFDDs) congeners to freshwater fish Carassius auratus, by determining the antioxidative responses and lipid peroxidation in the liver after the fish were injected with two different concentrations (10 and 100 umol/kg) of individual PFDDs for 3 and 14 days. The results showed that oxidative stress was obviously induced in some PFDDs-treated groups, as implied by the significantly inhibited antioxidants levels (superoxide dismutase, catalase, reduced glutathione, and glutathione S-transferase) and elevated malondialdehyde content. In addition, the oxidative stress inducing ability was variable for different PFDDs congeners, which was related with the substitution number and position of fluorine atom. Based on the calculated integrated biomarker response (IBR) values, the toxicity was ranked as 2,3,7,8-FDD>Octa-FDD>1,2,3,4,7-FDD>1,3,6,8-FDD>1,2,3,4,6,7 FDD>1,2,6,7-FDD>1,2,7-FDD>DD>2,7-FDD>2-FDD. This study can enhance the general understanding of the PFDDs induced oxidative stress in aquatic organisms. PMID- 26761780 TI - Cell source determines the immunological impact of biomimetic nanoparticles. AB - Recently, engineering the surface of nanotherapeutics with biologics to provide them with superior biocompatibility and targeting towards pathological tissues has gained significant popularity. Although the functionalization of drug delivery vectors with cellular materials has been shown to provide synthetic particles with unique biological properties, these approaches may have undesirable immunological repercussions upon systemic administration. Herein, we comparatively analyzed unmodified multistage nanovectors and particles functionalized with murine and human leukocyte cellular membrane, dubbed Leukolike Vectors (LLV), and the immunological effects that may arise in vitro and in vivo. Previously, LLV demonstrated an avoidance of opsonization and phagocytosis, in addition to superior targeting of inflammation and prolonged circulation. In this work, we performed a comprehensive evaluation of the importance of the source of cellular membrane in increasing their systemic tolerance and minimizing an inflammatory response. Time-lapse microscopy revealed LLV developed using a cellular coating derived from a murine (i.e., syngeneic) source resulted in an active avoidance of uptake by macrophage cells. Additionally, LLV composed of a murine membrane were found to have decreased uptake in the liver with no significant effect on hepatic function. As biomimicry continues to develop, this work demonstrates the necessity to consider the source of biological material in the development of future drug delivery carriers. PMID- 26761782 TI - Significance of black carbon in the sediment-water partitioning of organochlorine pesticides (OCPs) in the Indus River, Pakistan. AB - This study was conducted with the aim of assessing the levels and black carbon mediated sediment-water partitioning of organochlorine pesticides (OCPs) from the Indus River. ?OCPs ranged between 52-285 ng L(-1) and 5.6-29.2 ng g(-1) in water and sediment samples respectively. However, the ranges of sedimentary fraction of total organic carbon (f(TOC)) and black carbon (f(BC)) were 0.82-2.26% and 0.04 0.5% respectively. Spatially, OCPs concentrations were higher at upstream sites as compared to downstream sites. Source diagnostic ratios indicated the technical usage of HCH (alpha-HCH/gamma-HCH>4) and significant presence of DDT metabolites with fresh inputs into the Indus River as indicated by the ratios of (DDE+DDD)/?DDTs (0.27-0.96). The partitioning of OCPs between the sediments and water can be explained by two carbon Freundlich adsorption model which included both organic carbon and black carbon pools as partitioning media. PMID- 26761783 TI - A new dispersive liquid-liquid microextraction using ionic liquid based microemulsion coupled with cloud point extraction for determination of copper in serum and water samples. AB - A simple and rapid dispersive liquid-liquid microextraction procedure based on ionic liquid assisted microemulsion (IL-uE-DLLME) combined with cloud point extraction has been developed for preconcentration copper (Cu(2+)) in drinking water and serum samples of adolescent female hepatitits C (HCV) patients. In this method a ternary system was developed to form microemulsion (uE) by phase inversion method (PIM), using ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate ([C4mim][PF6]) and nonionic surfactant, TX-100 (as a stabilizer in aqueous media). The Ionic liquid microemulsion (IL-uE) was evaluated through visual assessment, optical light microscope and spectrophotometrically. The Cu(2+) in real water and aqueous acid digested serum samples were complexed with 8-hydroxyquinoline (oxine) and extracted into IL-uE medium. The phase separation of stable IL-uE was carried out by the micellar cloud point extraction approach. The influence of of different parameters such as pH, oxine concentration, centrifugation time and rate were investigated. At optimized experimental conditions, the limit of detection and enhancement factor were found to be 0.132 ug/L and 70 respectively, with relative standard deviation <5%. In order to validate the developed method, certified reference materials (SLRS-4 Riverine water) and human serum (Sero-M10181) were analyzed. The resulting data indicated a non-significant difference in obtained and certified values of Cu(2+). The developed procedure was successfully applied for the preconcentration and determination of trace levels of Cu(2+) in environmental and biological samples. PMID- 26761784 TI - Renal function, body surface area, and age are associated with risk of early onset fluoropyrimidine-associated toxicity in patients treated with capecitabine based anticancer regimens in daily clinical care. AB - BACKGROUND: The objective of this analysis was to determine the factors associated with early onset treatment-related toxicity in patients treated with capecitabine-based anticancer regimens in daily clinical care. PATIENTS AND METHODS: A total of 1463 patients previously included in a prospective cohort study and treated with standard-of-care capecitabine-based anticancer regimens (monotherapy or combined with other chemotherapy or radiotherapy) were analysed. Logistic regression models were developed to investigate associations between patient- and treatment-related factors and occurrence of early--i.e. cycle one or two--severe (grade >= 3) treatment-related toxicity, toxicity-related hospitalisation, and toxicity-related treatment discontinuation. Performance of models was evaluated using receiver-operating characteristic (ROC) curves and internal validity was explored using bootstrap analysis. RESULTS: Among 1463 patients included, 231 patients (16%) experienced early severe toxicity, 132 patients (9%) were hospitalised for toxicity, and 146 patients (10%) discontinued treatment for toxicity; in total, 321 patients (22%) experienced any early toxicity-related adverse outcome. Predictors of early grade >= 3 toxicity, after adjustment for treatment regimen, were renal function (odds ratio [OR] 0.85 per 10 ml/min/1.73 m(2), p = 0.0007), body surface area (BSA) (OR 0.33 per m(2), p = 0.0053), age (OR 1.14 per decade, p = 0.0891), and elevated pre-treatment uracil concentrations (OR 2.41 per 10 ng/ml, p = 0.0046). Age was significantly associated with fatal treatment-related toxicity (OR 5.75, p = 0.0008). Area under the ROC curve (AUC) of a model to predict early grade >= 3 toxicity was 0.704 (95% confidence interval 0.666-0.743, optimism-corrected AUC 0.690). CONCLUSION: Renal function, BSA, and age, in addition to pre-treatment uracil, are associated with clinically relevant differences in risk of early severe toxicity in patients treated with capecitabine in routine clinical care. PMID- 26761786 TI - Enhancing spin injection efficiency through half-metallic miniband conduction in a spin-filter superlattice. AB - We theoretically and numerically studied the band structure and spin transport of electrons subject to a superlattice structure where magnetic semiconductor layers lie between normal semiconductor layers to form periodic spin-filter tunnel barriers. In this alternately deposited superlattice structure, due to the induced periodicity of the envelope wavefunctions, there are additional allowed and forbidden energy regions established, i.e. forming minibands that are far narrower than the conventional conduction bands. The number and thickness of the stacked potential profiles can finely tune these minibands. The spin dependent potential barriers also induce spin splitting at the bottom of each miniband, which generates strongly spin-dependent miniband conduction. Most strikingly, the lowest lying miniband is 100% spin-polarized mimicking a half-metallic behavior on this conduction channel. The total transmission electron current carries thus near-perfectly polarized spin currents when the superlattice falls into suitable miniband conduction regime. This half-metallic miniband enhanced spin-filtering capability paves the way to generate highly polarized spin current without incurring exponentially increased device impedance, as usually happens when only a single spin-filter barrier is applied. PMID- 26761788 TI - Maintaining intimacy for prostate cancer patients on androgen deprivation therapy. AB - PURPOSE OF REVIEW: Androgen deprivation therapy (ADT) causes erectile dysfunction and increases patients' emotionality while diminishing their sexual interest. ADT has been linked to erosion of spousal bonds; however, this is not an invariant outcome. Understanding the factors that lead to these various outcomes may help couples deal with ADT. RECENT FINDINGS: A subset of couples report that they became closer as a result of the patients going on ADT. Recent data suggest that what helps couples most is preemptive awareness of ADT's side-effects and congruence in how patients and their partners understand and accept the psychosexual impact of ADT. Sex therapy for prostate cancer patients divides along gendered lines, with distinctly 'male' (recovery of erections) and 'female' (promoting sexual practices that are not erection dependent) approaches. Unfortunately, neither is very effective for couples when the patient is on ADT. Options beyond the standard gendered framework, such as use of an external penile prosthesis, may be worth offering to ADT patients trying to find a 'new normal' that is sexually rewarding for them. SUMMARY: Intimacy is sharing something with someone that one shares with no one else. Exploring novel sexual practices can help couples stay intimate, even when the patient is on ADT. PMID- 26761785 TI - Gene expression test for the non-invasive diagnosis of bladder cancer: A prospective, blinded, international and multicenter validation study. AB - OBJECTIVE: This study aimed to validate, in a prospective, blinded, international and multicenter cohort, our previously reported four non-invasive tests for bladder cancer (BC) diagnosis based on the gene expression patterns of urine. METHODS: Consecutive voided urine samples from BC patients and controls were prospectively collected in five European centres (n=789). Finally, 525 samples were successfully analysed. Gene expression values were quantified using TaqMan Arrays and previously reported diagnostic algorithms were applied to gene expression data. Results from the most accurate gene signature for BC diagnosis were associated with clinical parameters using analysis of variance test. RESULTS: High diagnostic accuracy for the four gene signatures was found in the independent validation set (area under curve [AUC]=0.903-0.918), with the signature composed of two genes (GS_D2) having the best performance (sensitivity: 81.48%; specificity: 91.26%; AUC: 0.918). The diagnostic accuracy of GS_D2 was not affected by the number of tumours (p=0.58) but was statistically associated with tumour size (p=0.008). Also, GS_D2 diagnostic accuracy increases with increasing BC tumour risk. We found no differences in the performance of the GS_D2 test among the populations and centres in detecting tumours (p=0.7) and controls (p=0.2). CONCLUSIONS: Our GS_D2 test is non-invasive, non-observer dependent and non-labour-intensive, and has demonstrated diagnostic accuracy in an independent, international and multicenter study, equal or superior to the current gold standard (cystoscopy combined with cytology). Additionally, it has higher sensitivity than cytology while maintaining its specificity. Consequently, it meets the requirements for consideration as a molecular test applicable to clinical practice in the management of BC. PMID- 26761787 TI - A systematic review and meta-synthesis of the effects and experience of mentoring in eating disorders and disordered eating. AB - In this review, we aimed to explore the benefits, effects and experiences of mentoring on those with an eating disorder or disordered eating. After a systematic search of the literature, four papers were included in the review. A qualitative analysis of the papers identified three key themes. The themes were (1) diverse benefits (mentees), (2) finding comfort in belonging (mentees), and (3) affirmation of the transformation they have made (mentors). The experience of mentoring was shown to have value for both mentors and mentees. Mentorship should be further utilized in the areas of eating disorders and disordered eating, as it shows promising reciprocal benefits for both mentor and mentee. PMID- 26761789 TI - Has pain management improved over the last decade in the Rapid Response Radiotherapy Program? PMID- 26761791 TI - Effect of Climate Change on Mediterranean Winter Ranges of Two Migratory Passerines. AB - We studied the effect of climate change on the distribution of two insectivorous passerines (the meadow pipit Anthus pratensis and the chiffchaff Phylloscopus collybita) in wintering grounds of the Western Mediterranean basin. In this region, precipitation and temperature can affect the distribution of these birds through direct (thermoregulation costs) or indirect effects (primary productivity). Thus, it can be postulated that projected climate changes in the region will affect the extent and suitability of their wintering grounds. We studied pipit and chiffchaff abundance in several hundred localities along a belt crossing Spain and Morocco and assessed the effects of climate and other geographical and habitat predictors on bird distribution. Multivariate analyses reported a positive effect of temperature on the present distribution of the two species, with an additional effect of precipitation on the meadow pipit. These climate variables were used with Maxent to model the occurrence probabilities of species using ring recoveries as presence data. Abundance and occupancy of the two species in the study localities adjusted to the distribution models, with more birds in sectors of high climate suitability. After validation, these models were used to forecast the distribution of climate suitability according to climate projections for 2050-2070 (temperature increase and precipitation reduction). Results show an expansion of climatically suitable sectors into the highlands by the effect of warming on the two species, and a retreat of the meadow pipit from southern sectors related to rain reduction. The predicted patterns show a mean increase in climate suitability for the two species due to the warming of the large highland expanses typical of the western Mediterranean. PMID- 26761790 TI - Endothelial Dysfunction in Rheumatoid Arthritis: Mechanistic Insights and Correlation with Circulating Markers of Systemic Inflammation. AB - OBJECTIVES: To determine mechanisms involved in endothelial dysfunction (ED) during the course of arthritis and to investigate the link between cytokines, chemokines and osteoprotegerin. APPROACH AND RESULTS: Experiments were conducted on aortic rings at day 4 (preclinical), day 11 (onset of disease), day 33 (acute disease) and day 90 (chronic disease) after adjuvant-induced arthritis (AIA) in Lewis rats. At day 4, the unique vascular abnormality was a reduced norepinephrine-induced constriction. At day 11, endothelial function assessed by the relaxation to acetylcholine was normal despite increased cyclo-oxygenase-2 activity (COX-2) and overproduction of superoxide anions that was compensated by increased nitric oxide synthase (NOS) activity. At day 33, ED apparition coincides with the normalization of NOS activity. At day 90, ED was only observed in rats with a persisting imbalance between endothelial NOS and COX-2 pathways and higher plasma levels of IL-1beta and TNFalpha. Plasma levels of IL-1beta, TNFalpha and MIP-1alpha negatively correlated with Ach-induced relaxation throughout the course of AIA. CONCLUSIONS: Our data identified increased endothelial NOS activity as an important compensatory response that opposes the ED in the early arthritis. Thereafter, a cross-talk between endothelial COX-2/NOS pathways appears as an important element for the occurrence of ED. Our results encourage determining the clinical value of IL-1beta, TNFalpha and MIP-1alpha as biomarkers of ED in RA. PMID- 26761792 TI - Lack of Critical Slowing Down Suggests that Financial Meltdowns Are Not Critical Transitions, yet Rising Variability Could Signal Systemic Risk. AB - Complex systems inspired analysis suggests a hypothesis that financial meltdowns are abrupt critical transitions that occur when the system reaches a tipping point. Theoretical and empirical studies on climatic and ecological dynamical systems have shown that approach to tipping points is preceded by a generic phenomenon called critical slowing down, i.e. an increasingly slow response of the system to perturbations. Therefore, it has been suggested that critical slowing down may be used as an early warning signal of imminent critical transitions. Whether financial markets exhibit critical slowing down prior to meltdowns remains unclear. Here, our analysis reveals that three major US (Dow Jones Index, S&P 500 and NASDAQ) and two European markets (DAX and FTSE) did not exhibit critical slowing down prior to major financial crashes over the last century. However, all markets showed strong trends of rising variability, quantified by time series variance and spectral function at low frequencies, prior to crashes. These results suggest that financial crashes are not critical transitions that occur in the vicinity of a tipping point. Using a simple model, we argue that financial crashes are likely to be stochastic transitions which can occur even when the system is far away from the tipping point. Specifically, we show that a gradually increasing strength of stochastic perturbations may have caused to abrupt transitions in the financial markets. Broadly, our results highlight the importance of stochastically driven abrupt transitions in real world scenarios. Our study offers rising variability as a precursor of financial meltdowns albeit with a limitation that they may signal false alarms. PMID- 26761794 TI - Genome of Bifidobacteria and Carbohydrate Metabolism. AB - In recent years, the knowledge about bifidobacteria has considerably evolved thanks to recent progress in molecular biology. The analysis of the whole genome sequences of 48 taxa of bifidobacteria offers new perspectives for their classification, especially to set up limit between two species. Indeed, several species are presenting a high homology and should be reclassified. On the other hand, some subspecies are presenting a low homology and should therefore be reclassified into different species. In addition, a better knowledge of the genome of bifidobacteria allows a better understanding of the mechanisms involved in complex carbohydrate metabolism. The genome of some species of bifidobacteria from human but also from animal origin demonstrates high presence in genes involved in the metabolism of complex oligosaccharides. Those species should be further tested to confirm their potential to metabolize complex oligosaccharides in vitro and in vivo. PMID- 26761795 TI - Effect of Growth on Fatty Acid Composition of Total Intramuscular Lipid and Phospholipids in Ira Rabbits. AB - The changes in fatty acid composition of total intramuscular lipid and phospholipids were investigated in the longissimus dorsi, left-hind leg muscle, and abdominal muscle of male Ira rabbits. Changes were monitored at 35, 45, 60, 75, and 90 d. Analysis using gas chromatography identified 21 types of fatty acids. Results showed that the intramuscular lipid increased and the intramuscular phospholipids (total intramuscular lipid %) decreased in all muscles with increasing age (p<0.05). An abundant amount of unsaturated fatty acids, especially polyunsaturated fatty acids, was distributed in male Ira rabbits at different ages and muscles. Palmitic acid (C16:0), stearic acid (C18:0), oleic acid (C18:1), linoleic acid (C18:2), and arachidonic acid (C20:4) were the major fatty acids, which account to the dynamic changes of the n-6/n-3 value in Ira rabbit meat. PMID- 26761793 TI - Regulation of Rac1 and Reactive Oxygen Species Production in Response to Infection of Gastrointestinal Epithelia. AB - Generation of reactive oxygen species (ROS) during infection is an immediate host defense leading to microbial killing. APE1 is a multifunctional protein induced by ROS and after induction, protects against ROS-mediated DNA damage. Rac1 and NAPDH oxidase (Nox1) are important contributors of ROS generation following infection and associated with gastrointestinal epithelial injury. The purpose of this study was to determine if APE1 regulates the function of Rac1 and Nox1 during oxidative stress. Gastric or colonic epithelial cells (wild-type or with suppressed APE1) were infected with Helicobacter pylori or Salmonella enterica and assessed for Rac1 and NADPH oxidase-dependent superoxide production. Rac1 and APE1 interactions were measured by co-immunoprecipitation, confocal microscopy and proximity ligation assay (PLA) in cell lines or in biopsy specimens. Significantly greater levels of ROS were produced by APE1-deficient human gastric and colonic cell lines and primary gastric epithelial cells compared to control cells after infection with either gastric or enteric pathogens. H. pylori activated Rac1 and Nox1 in all cell types, but activation was higher in APE1 suppressed cells. APE1 overexpression decreased H. pylori-induced ROS generation, Rac1 activation, and Nox1 expression. We determined that the effects of APE1 were mediated through its N-terminal lysine residues interacting with Rac1, leading to inhibition of Nox1 expression and ROS generation. APE1 is a negative regulator of oxidative stress in the gastrointestinal epithelium during bacterial infection by modulating Rac1 and Nox1. Our results implicate APE1 in novel molecular interactions that regulate early stress responses elicited by microbial infections. PMID- 26761797 TI - Changes in Ultrastructure and Sensory Characteristics on Electro-magnetic and Air Blast Freezing of Beef during Frozen Storage. AB - The ultrastructure in the beef muscle of the electro-magnetic resonance and air blast freezing during the frozen storage, and the changes in the quality characteristics after thawing were evaluated. The size of ice crystal was small and evenly formed in the initial freezing period, and it showed that the size was increased as the storage period was elapsed (p<0.05). The beef stored by the electro-magnetic resonance freezing showed the size of ice crystal with a lower rate of increase than the air blast freezing during the frozen storage. The thawing loss of beef stored by the electro-magnetic resonance freezing was significantly lower than the air blast freezing during frozen storage (p<0.05), and it showed that the thawing loss of the round was higher than the loin. Water holding capacity decreased as the storage period became longer while the electro magnetic resonance freezing was higher than the air blast on 8 month (p<0.05). As a result of sensory evaluation, the beef stored by the electro-magnetic resonance freezing did not show the difference until 4 months, and it showed higher acceptability in comparison with the beef stored by the air blast freezing. Thus, it is considered that the freezing method has an effect on the change in the ultrastructure and quality characteristics of the beef. PMID- 26761796 TI - Quality Evaluation of Chicken Nugget Formulated with Various Contents of Chicken Skin and Wheat Fiber Mixture. AB - This study aimed to investigate the effects of various mixtures of the chicken skin and wheat fiber on the properties of chicken nuggets. Two skin and fiber mixtures (SFM) were prepared using the following formulations; SFM-1: chicken skin (50%), wheat fiber (20%), and ice (30%); and SFM-2: chicken skin (30%), wheat fiber (20%), and ice (50%). Chicken nugget samples were prepared by adding the following amounts of either SFM-1 or SFM-2: 0%, 2.5%, 5%, 7.5%, and 10%. The water content for samples formulated with SFM-1 or SFM-2 was higher than in the control (p<0.05), and increased with increasing the concentrations of SFM-1 and SFM-2. The addition of SFM-1 and SFM-2 had no significant effect on the pH of the samples. The lightness value of uncooked chicken nuggets was higher than that of cooked chicken nuggets for all the samples tested. Chicken nuggets formulated with SFM-1 and SFM-2 displayed higher cooking yields than the control sample. The hardness of the control sample was also lower than the samples containing SFM-1 and SFM-2. The sensory evaluation showed no significant differences between the control and the samples containing SFM. Therefore, the incorporation of a chicken skin and wheat fiber mixture improved the quality of chicken nuggets. PMID- 26761798 TI - Effect of Sub- and Super-critical Water Treatment on Physicochemical Properties of Porcine Skin. AB - Super- and sub-critical water treatments have been of interest as novel methods for protein hydrolysis. In the present study, we studied the effect of sub critical water (Sub-H2O, 300C, 80 bar) treatment as well as super-critical water (Super-H2O, 400C, 280 bar) treatment on the physicochemical properties of porcine skin (PS), which has abundant collagen. Porcine skin was subjected to pre-thermal treatment by immersion in water at 70C, and then treated with sub- or super critical water. Physicochemical properties of the hydrolysates, such as molecular weight distribution, free amino acid content, amino acid profile, pH, color, and water content were determined. For the molecular weight distribution analysis, 1 kDa hydrolyzed porcine skin (H-PS) was produced by Super-H2O or Sub-H2O treatment. The free amino acid content was 57.18 mM and 30.13 mM after Sub-H2O and Super-H2O treatment, respectively. Determination of amino acid profile revealed that the content of Glu (22.5%) and Pro (30%) was higher after Super-H2O treatment than after Sub-H2O treatment, whereas the content of Gly (28%) and Ala (13.1%) was higher after Sub-H2O treatment. Super-H2O or Sub-H2O treatment affected the pH of PS, which changed from 7.29 (Raw) to 9.22 (after Sub-H2O treatment) and 9.49 (after Super-H2O treatment). Taken together, these results showed that Sub-H2O treatment was slightly more effective for hydrolysis than Super-H2O was. However, both Sub-H2O and Super-H2O treatments were effective processing methods for hydrolysis of PS collagen in a short time and can be regarded as a green chemistry technology. PMID- 26761799 TI - Antioxidant Activity of Allium hookeri Root Extract and Its Effect on Lipid Stability of Sulfur-fed Pork Patties. AB - This study was performed to assess the antioxidant activity of Allium hookeri root extract (AHE) on lipid oxidation of raw sulfur-fed pork patties for 14 d of refrigerated storage. Different concentration of ethanol (0-100%) and time (1-12 h) were applied to determine the extraction condition. Water (0% ethanol) extraction for 1 h was selected as an optimal extraction condition of AHE for the following study showing the highest total phenolic content and total flavonoid content, as well as the strongest antioxidant activity. The 1% AHE (SP1), 3% AHE (SP2), and 0.05% ascorbic acid (SP3) were added into sulfur-fed pork patties against controls; SP0 (sulfur-fed pork patties with no AHE) and P0 (normal pork patties with no AHE). The pH values of P0 and SP0 significantly increased (p<0.05) than others on 14 d and redness of P0 showed the largest decrement during storage. P0 and SP0 showed higher production of conjugated dienes on d 7 than others (p<0.05). Thiobarbituric acid reactive substances (TBARS) values were decreased in proportion to the increased level of AHE on 14 d (p<0.05) resulting in higher TBARS values on P0 and SP0 (p<0.05) and the negative correlation between AHE level and TBARS were also demonstrated (r=-0.910, p=0.001). Therefore, the results suggest that AHE effectively retarded the lipid oxidation rate of sulfur-fed pork patties indicating the potential usage of AHE as a natural preservative. PMID- 26761800 TI - Evaluation of Acid-treated Fish Sarcoplasmic Proteins on Physicochemical and Rheological Characteristics of Pork Myofibrillar Protein Gel Mediated by Microbial Transglutaminase. AB - Fish sarcoplasmic protein (SP) is currently dumped as waste from surimi industry and its recovery by practical method for being the non-meat ingredient in meat industry would be a strategy to utilize effectively the fish resource. This study was aimed to apply pH treatment for fish SP recovery and evaluated its effect on pork myofibrillar protein (MP) gel. The pH values of fish SP were changed to 3 and 12, and neutralized to pH 7 before lyophilizing the precipitated protein after centrifugation. Acid-treated fish SP (AFSP) showed about 4-fold higher recovery yield than that of alkaline-treated SP and water absorption capacity was also about 1.2-fold greater. Because of the high recovery yield and water absorption capacity, AFSP was selected to incorporate into MP with/without microbial transglutaminase (MTG). The effects of AFSP and MTG on the physicochemical and rheological characteristics of MP and MP gel were evaluated. MTG induced an increase shear stress of the MP mixture and increase the breaking force of MP gels. MP gel lightness was decreased by adding AFSP. MP gel with MTG showed higher cooking loss than that without MTG. A reduction of cooking loss was observed when the AFSP was added along with MTG, where the insoluble particles were found. Therefore, AFSP could be contributed as a water holding agent in meat protein gel. PMID- 26761801 TI - Effects of Egg Shell Membrane Hydrolysates on UVB-radiation-induced Wrinkle Formation in SKH-1 Hairless Mice. AB - This study was conducted to examine the effect of egg shell membrane hydrolysates (ESMH) on wrinkle, UV, and moisture protection for cosmetic use. ESMH were fragmented as whole ESMH (before fractioning), Fraction I (> 10 kDa), Fraction II (3-10 kDa), and Fraction III (< 3 kDa). In order to test whether fractionated ESMH can be used for functional cosmetic materials, we examined not only the level of hyaluronic acid and collagen production, but also the MMP-1 activity using a HaCaT and CCD-986Sk cell line. Our study treated each sample of fractionated ESMH with different concentrations (0.01, 0.1, 1 mg/mL). In our in vivo research, we used hairless mice that had been exposed to UV-B to induce wrinkles for 7 wk, then applied Fraction I to the treatment group for 5 wk and then tested skin thickness, minimum erythema dose and moisture content. In addition, Fraction I was high in collagen and HA biosynthesis and it was better than TGF-beta in improving of the skin. When TNF-alpha caused MMP-1 activity in the CCD-986Sk cells, the whole ESMH and Fraction I proved to be effective in hindering the induction of collagenase depending on the concentration, and also showed outstanding effects in the suppression of skin aging. We found that the treatment group mice's UV-B radiation-induced skin damage was largely mitigated compared to that of the non-treatment group mice. Thus, we have concluded that EMSH helps to mitigate UV-B radiation-induced wrinkles, collagen, HA, MMP-1 activity and can be used for functional cosmetic materials. PMID- 26761802 TI - Changes in Quality Characteristics of Pork Patties Containing Multilayered Fish Oil Emulsion during Refrigerated Storage. AB - This study was performed to determine the effect of multilayered fish oil (FO) emulsion without or with trans-cinnamaldehyde on pork patties. Multilayered FO ( primary, -secondary, -tertiary) emulsions were prepared using a layer-by-layer deposition technique with Tween 20, chitosan, and low methoxyl pectin, and were added to pork patties at the same concentration. Pork patties were then stored for 20 d in a refrigerator (5C) to study changes in quality. The results showed that the pH value of all samples significantly decreased but cooking loss increased during storage (p<0.05). However, water-holding capacity and moisture content showed no remarkable difference between treatments and storage periods (p>0.05). All pork patties containing multilayered FO (treated samples) showed higher values for lightness and significantly lower values for yellowness compared to control pork patties (untreated sample). Lipid oxidation was higher in treated pork patties than in control pork patties during storage. In addition, lipid oxidation and total viable bacterial count in pork patties decreased as the number of coating layers increased. However, hardness, cohesiveness, and springiness of all samples showed no significant change during storage (p>0.05) as compared to fresh pork patties. Furthermore, these did not remarkable change with addition of trans-cinnamaldehyde in all pork patties. From our results, we suggest that FO emulsion did not affect the texture characteristics of fresh pork patties, indicating that it could be used to improve the quality of pork patties by contributing high-quality fat such as unsaturated fatty acids. PMID- 26761803 TI - Effects of Duroc Breeding Lines on Carcass Composition and Meat Quality. AB - This study was performed to investigate the carcass composition and pork quality of Duroc breeding lines in Korea. A total of 200 Duroc pigs were used, and those were originated from four different great-grandparent (GGP) breeding stock farms (L1: N farm, L2: W farm, L3: S farm, L4: R farm). The carcasses of pigs from these farms were collected, and meat quality traits were evaluated. L1 and L2 had smaller carcass weights and thin backfat, whereas L3 and L4 had heavy carcass weights and thick backfat. L3 and L4 had higher contents of fat and protein than L1 and L2. For the meat quality characteristics, L1, L2, and L4 had higher pH values than L3. In addition, L4 had higher water holding capacity than the other lines. L4 had the highest sensory evaluation scores with regard to both juiciness and flavor. Consequently, the study results indicate that pork quality information from domestic Duroc breeding stock lines could be used to effectively improve pork quality in Korea. PMID- 26761804 TI - Genome Analysis of Phage SMSAP5 as Candidate of Biocontrol for Staphylococcus aureus. AB - In this study, we reported the morphogenetic analysis and genome sequence by genomic analysis of the newly isolated staphylococcal phage SMSAP5 from soil of slaughterhouses for cattle. Based on transmission electron microscopy evident morphology, phage SMSAP5 belonged to the Siphoviridae family. Phage SMSAP5 had a double-stranded DNA genome with a length of 45,552 bp and 33 % G+C content. Bioinformatics analysis of the phage genome revealed 43 open reading frames. A blastn search revealed that its nucleotide sequence shared a high degree of similarity with that of the Staphylococcus phage tp310-2. In conclusion, this study is the first report to show the morphological features and the complete genome sequence of the phage SMSAP5 from soil of slaughterhouses for cattle. PMID- 26761805 TI - Screening and Characterization of Lactic Acid Bacteria Strains with Anti inflammatory Activities through in vitro and Caenorhabditis elegans Model Testing. AB - The present study was conducted to screen candidate probiotic strains for anti inflammatory activity. Initially, a nitric oxide (NO) assay was used to test selected candidate probiotic strains for anti-inflammatory activity in cultures of the murine macrophage cell line, RAW 264.7. Then, the in vitro probiotic properties of the strains, including bile tolerance, acid resistance, and growth in skim milk media, were investigated. We also performed an in vitro hydrophobicity test and an intestinal adhesion assay using Caenorhabditis elegans as a surrogate in vivo model. From our screening, we obtained 4 probiotic candidate lactic acid bacteria (LAB) strains based on their anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated RAW 264.7 cell cultures and the results of the in vitro and in vivo probiotic property assessments. Molecular characterization using 16S rDNA sequencing analysis identified the 4 LAB strains as Lactobacillus plantarum. The selected L. plantarum strains (CAU1054, CAU1055, CAU1064, and CAU1106) were found to possess desirable in vitro and in vivo probiotic properties, and these strains are good candidates for further investigations in animal models and human clinical studies to elucidate the mechanisms underlying their anti-inflammatory activities. PMID- 26761806 TI - Quality Characteristics of Marinated Chicken Breast as Influenced by the Methods of Mechanical Processing. AB - The aim of this study was to investigate the effects of various marination processes on the quality characteristics of chicken breast prepared with chicken feet gelatin and wheat fiber. The chicken feet gelatin was swollen with hydrochloric solution (0.1 N HCl, pH 1.31+/-0.02) and dehydrated by freeze drying. The composition (w/w) of the marinade was water (10%), soy sauce (12%), phosphate (0.3%), wheat fiber (1.5%), and chicken feet gelatin (1.5%). Three samples of chicken breast were manufactured with Tumbler (only tumbler), Tenderizer (tenderizer and tumbler), and Injector (injector and tumbler). The water content of the Injector sample was significantly higher than those of the Tumbler and Tenderizer samples (p<0.05). During heating, the lightness of all chicken breasts increased and the redness decreased. The tumbling and cooking yield of the Injector sample were significantly higher than those of the Tumbler and Tenderizer samples (p<0.05). The shear force of the Tenderizer sample was significantly lower than that of the Tumbler and Injector samples (p<0.05). No significant differences, except for color, were observed in the sensory analysis of the samples. Thus, the proper selection of mechanical processing is important to improve the quality characteristics of marinated chicken breast, considering the types of final products. PMID- 26761807 TI - Growth Modelling of Listeria monocytogenes in Korean Pork Bulgogi Stored at Isothermal Conditions. AB - The purpose of this study was to develop predictive models for the growth of Listeria monocytogenes in pork Bulgogi at various storage temperatures. A two strain mixture of L. monocytogenes (ATCC 15313 and isolated from pork Bulgogi) was inoculated on pork Bulgogi at 3 Log CFU/g. L. monocytogenes strains were enumerated using general plating method on Listeria selective medium. The inoculated samples were stored at 5, 15, and 25C for primary models. Primary models were developed using the Baranyi model equations, and the maximum specific growth rate was shown to be dependent on storage temperature. A secondary model of growth rate as a function of storage temperature was also developed. As the storage temperature increased, the lag time (LT) values decreased dramatically and the specific growth rate of L. monocytogenes increased. The mathematically predicted growth parameters were evaluated based on the modified bias factor (B f ), accuracy factor (A f ), root mean square error (RMSE), coefficient of determination (R (2)), and relative errors (RE). These values indicated that the developed models were reliably able to predict the growth of L. monocytogenes in pork Bulgogi. Hence, the predictive models may be used to assess microbiological hygiene in the meat supply chain as a function of storage temperature. PMID- 26761808 TI - Comparison of Bioactive Compounds and Quality Traits of Breast Meat from Korean Native Ducks and Commercial Ducks. AB - The aim of this research was to compare the bioactive compound content and quality traits of breast meat from male and female Korean native ducks (KND) and commercial ducks (CD, Cherry Valley). Meat from three 6-wk old birds of each sex from KND and CD were evaluated for carcass and breast weights, pH, color, cooking loss, shear force, and bioactive compound (creatine, carnosine, anserine, betaine, and L-carnitine) content. KND showed significantly higher carcass weights than CD whereas no such difference (p>0.05) was found between male and female ducks. The breed and sex had no significant effects on the breast weight, pH value, and shear force. However, KND had significantly lower cooking loss values than did CD. Creatine, anserine, and L-carnitine contents were significantly higher in KND than in CD and were predominant in female ducks compared to males. The results of this study provide rare information regarding the amounts and the determinants of several bioactive compounds in duck meat, which can be useful for selection and breeding programs, and for popularizing indigenous duck meat. PMID- 26761810 TI - Effect of Replacing Pork Fat with Vegetable Oils on Quality Properties of Emulsion-type Pork Sausages. AB - This study was conducted to evaluate the quality properties of emulsion-type pork sausages when pork fat is replaced with vegetable oil mixtures during processing. Pork sausages were processed under six treatment conditions: T1 (20% pork fat), T2 (10% pork fat + 2% grape seed oil + 4% olive oil + 4% canola oil), T3 (4% grape seed oil + 16% canola oil), T4 (4% grape seed oil + 4% olive oil + 12% canola oil), T5 (4% grape seed oil + 8% olive oil + 8% canola oil), and T6 (4% grape seed oil + 12% olive oil + 4% canola oil). Proximate analysis showed significant (p<0.05) differences in the moisture, protein, and fat content among the emulsion-type pork sausages. Furthermore, replacement with vegetable oil mixtures significantly decreased the ash content (p<0.05), increased water holding capacity in emulsion-type pork sausages. Also, cholesterol content in T6 was significantly lower than T2 (p<0.05). In the texture profile analysis, hardness and chewiness of emulsion-type pork sausages were significantly (p<0.05) decreased by vegetable oil mixtures replacement. On the contrary, cohesiveness and springiness in the T4 group were similar to those of group T1. The unsaturated fatty acid content in emulsion-type pork sausages was increased by vegetable oil mixtures replacement. Replacement of pork fat with mixed vegetable oils had no negative effects on the quality properties of emulsion-type pork sausages, and due to its reduced saturated fatty acid composition, the product had the quality characteristics of the healthy meat products desired by consumers. PMID- 26761809 TI - Development and Application of a Method for Rapid and Simultaneous Determination of Three beta-agonists (Clenbuterol, Ractopamine, and Zilpaterol) using Liquid Chromatography-tandem Mass Spectrometry. AB - beta-agonists are anabolic compounds that promote fat loss and muscle gain, and their administration to livestock may provide economic benefits by increasing growth rate and feed efficiency. For these reasons, beta-agonists are also commonly added to livestock feed as growth promoters. This can introduce a significant risk of secondary human poisoning through intake of contaminated meat. A new method for the simultaneous determination of three beta-agonists (clenbuterol, ractopamine, and zilpaterol) was developed in this study and applied to various meat samples. The limits of quantification, derived through a validation test following Codex guidelines, were 0.2 MUg/kg for clenbuterol and zilpaterol, and 0.4 MUg/kg for ractopamine. The average recoveries for clenbuterol, ractopamine, and zilpaterol ranged from 109.1% to 118.3%, 95.3% to 109.0%, and 94.1% to 120.0%, respectively. The recovery and coefficient of variation (CV) values fell within the acceptable range according to the Codex guidelines. This method reduced the analysis time without decreasing detection efficiency by modifying the pretreatment steps. This method could be utilized to manage the safety of imported meat products from countries where zilpaterol use is still permitted, thereby improving public health and preventing beta-agonist poisoning due to secondary contamination. PMID- 26761811 TI - Antilisterial Bacteriocin from Lactobacillus rhamnosus CJNU 0519 Presenting a Narrow Antimicrobial Spectrum. AB - A lactic acid bacterium presenting antimicrobial activity against a Lactobacillus acidophilus strain used for eradication of acid inhibition was isolated from a natural cheese. The 16S rRNA gene sequence of the isolate best matched with a strain of L. rhamnosus and was designated L. rhamnosus CJNU 0519. The antimicrobial activity of the partially purified bacteriocin of CJNU 0519 was abolished when treated with a protease, indicating the protein nature of the bacteriocin. The partially purified bacteriocin (rhamnocin 519) displayed a narrow antimicrobial activity against L. acidophilus, Listeria monocytogenes, and Staphylococcus aureus among several tested bacterial and yeast strains. Rhamnocin 519 in particular showed strong bactericidal action against L. monocytogenes. PMID- 26761812 TI - Survey of Yogurt Powder Storage in Ambient Export Countries A Safety Evaluation Standard Compliance and Comparative Analysis. AB - Yogurt powder is fermented milk processed in the form of dry yogurt, and has advantages such as stability, storability, convenience, and portability. China and Vietnam are important export target countries because of the increased demand for dairy products. Therefore, we surveyed dairy product standardization in order to establish an export strategy. Lactic acid bacteria counts are unregulated in Korea and Vietnam. In China, lactic acid bacteria counts are regulated at 1*10(6) colony-forming units (CFU)/mL and detected at 6.24+/-0.33 Log CFU/mL. All three countries have regulated standards for total bacterial counts. In China, total bacterial counts of milk powder are regulated to n=5, c=2, m=50,000, M=200,000 and detected at 6.02+/-0.12 Log CFU/mL, exceeding the acceptable level. Lactic acid bacterial counts appeared to exceed total bacterial counts. Coliform group counts, Staphylococcus aureus, Listeria monocytogenes, and Salmonella species were not detected. Acidity is not regulated in Korea and Vietnam. In China, acidity was regulated to over 70 degrees T and detected 352.38+/-10.24 degrees T. pH is unregulated in all three countries. pH was compared to that of general fermented milk, which is 4.2, and that of the sample was 4.28+/-0.01. Aflatoxin levels are not regulated in Korea and China. In Vietnam, aflatoxin level is regulated at 0.05 ppb. Therefore, all ingredients of the yogurt powder met the safety standards. This data obtained in this study can be used as the basic data in assessing the export quality of yogurt powder. PMID- 26761813 TI - Increased Engraftment of Human Short Term Repopulating Hematopoietic Cells in NOD/SCID/IL2rgammanull Mice by Lentiviral Expression of NUP98-HOXA10HD. AB - Techniques to expand human hematopoietic stem cells ex-vivo could be beneficial to the fields of clinical hematopoietic stem cell transplantation and gene therapy targeted at hematopoietic stem cells. NUP98-HOXA10HD is a relatively newly discovered fusion gene that in mouse transplant experiments has been shown to increase numbers of hematopoietic stem cells. We evaluated whether this fusion gene could be used to expand engrafting human primitive CD34+ cells in an immunodeficient mouse model. Gene transfer was achieved using a lentiviral based vector. The engraftment of mobilized peripheral blood human CD34+ cells grown in culture for one week after gene transfer was evaluated 3-4 months after transplant and found to be 2-3 fold higher in the NUP98-HOXA10HD groups as compared to controls. These data suggest an expansive effect at least at the short term human repopulating cell level. Further evaluation in long term repopulating models and investment in a NUP98-HOXA10HD protein seems worthy of consideration. Additionally, the results here provide strong impetus to utilize NUP98-HOXA10HD as a tool to search for underlying genes and pathways involved in hematopoietic stem cell expansion that can be enhanced and have an even more potent expansive effect. PMID- 26761814 TI - Offspring Hormones Reflect the Maternal Prenatal Social Environment: Potential for Foetal Programming? AB - Females of many species adaptively program their offspring to predictable environmental conditions, a process that is often mediated by hormones. Laboratory studies have shown, for instance, that social density affects levels of maternal cortisol and testosterone, leading to fitness-relevant changes in offspring physiology and behaviour. However, the effects of social density remain poorly understood in natural populations due to the difficulty of disentangling confounding influences such as climatic variation and food availability. Colonially breeding marine mammals offer a unique opportunity to study maternal effects in response to variable colony densities under similar ecological conditions. We therefore quantified maternal and offspring hormone levels in 84 Antarctic fur seals (Arctocephalus gazella) from two closely neighbouring colonies of contrasting density. Hair samples were used as they integrate hormone levels over several weeks or months and therefore represent in utero conditions during foetal development. We found significantly higher levels of cortisol and testosterone (both P < 0.001) in mothers from the high density colony, reflecting a more stressful and competitive environment. In addition, offspring testosterone showed a significant positive correlation with maternal cortisol (P < 0.05). Although further work is needed to elucidate the potential consequences for offspring fitness, these findings raise the intriguing possibility that adaptive foetal programming might occur in fur seals in response to the maternal social environment. They also lend support to the idea that hormonally mediated maternal effects may depend more strongly on the maternal regulation of androgen rather than cortisol levels. PMID- 26761815 TI - A New ELISA Using the ANANAS Technology Showing High Sensitivity to diagnose the Bovine Rhinotracheitis from Individual Sera to Pooled Milk. AB - Diagnostic tests for veterinary surveillance programs should be efficient, easy to use and, possibly, economical. In this context, classic Enzyme linked ImmunoSorbent Assay (ELISA) remains the most common analytical platform employed for serological analyses. The analysis of pooled samples instead of individual ones is a common procedure that permits to certify, with one single test, entire herds as "disease-free". However, diagnostic tests for pooled samples need to be particularly sensitive, especially when the levels of disease markers are low, as in the case of anti-BoHV1 antibodies in milk as markers of Infectious Bovine Rhinotracheitis (IBR) disease. The avidin-nucleic-acid-nanoassembly (ANANAS) is a novel kind of signal amplification platform for immunodiagnostics based on colloidal poly-avidin nanoparticles that, using model analytes, was shown to strongly increase ELISA test performance as compared to monomeric avidin. Here, for the first time, we applied the ANANAS reagent integration in a real diagnostic context. The monoclonal 1G10 anti-bovine IgG1 antibody was biotinylated and integrated with the ANANAS reagents for indirect IBR diagnosis from pooled milk mimicking tank samples from herds with IBR prevalence between 1 to 8%. The sensitivity and specificity of the ANANAS integrated method was compared to that of a classic test based on the same 1G10 antibody directly linked to horseradish peroxidase, and a commercial IDEXX kit recently introduced in the market. ANANAS integration increased by 5-fold the sensitivity of the 1G10 mAb-based conventional ELISA without loosing specificity. When compared to the commercial kit, the 1G10-ANANAS integrated method was capable to detect the presence of anti-BHV1 antibodies from bulk milk of gE antibody positive animals with 2-fold higher sensitivity and similar specificity. The results demonstrate the potentials of this new amplification technology, which permits improving current classic ELISA sensitivity limits without the need for new hardware investments. PMID- 26761816 TI - Efficacy of PPV23 in Preventing Pneumococcal Pneumonia in Adults at Increased Risk--A Systematic Review and Meta-Analysis. AB - BACKGROUND: Pneumococcal community-acquired pneumonia (pCAP) is the most frequent form of pneumonia. The elderly and adults with underlying diseases are at an increased risk of developing pCAP. The 23-valent pneumococcal polysaccharide vaccine (PPV23) was licensed over 30 years ago and is recommended as the standard intervention in many countries across the globe, although its efficacy continues to be debated. We performed a meta-analysis of randomized controlled trials (RCTs) to investigate the effect of PPV23 for preventing pCAP in adults >=60 years of age. METHODS: An existing Cochrane Review was updated to Oct 2014 using a systematic literature search to select appropriate RCTs. DerSimonian and Laird random-effects meta-analyses were performed and odd ratios (OR) with 95% confidence intervals (CI) and p-values were calculated for the descriptive analyses. Reasons for heterogeneity were explored by subgroup analyses. RESULTS: Meta-analysis of PPV23 efficacy included four studies. Three of them did not demonstrate efficacy for PPV23. The body of evidence indicated statistically significant heterogeneity (I2 = 78%, p = 0.004) that could be explained by subgroup analysis by "study setting". Further effect modifiers for pCAP were "continent of trial" (p<0.01), and "method of pneumococcal diagnostics" (p = 0.001). Subgroup analyses revealed that the only study showing efficacy for PPV23 was an outlier. Overall, the validity of the meta-analytic PPV23 efficacy assessment was confirmed by the meta-analysis of all-cause CAP including six studies. DISCUSSION: Inconsistencies in PPV23 treatment effects to prevent pCAP could solely be explained by one outlier study that was performed in nursing homes in Japan. The effect modifier "method of pneumococcal diagnostics" should be interpreted carefully, since methodological weaknesses are not restricted to one special method only, which would justify the exclusion of certain studies. Overall, we conclude from our meta-analysis that to date there is no proof that PPV23 can prevent pCAP in a general, community-dwelling elderly population. PMID- 26761818 TI - TopicPanorama: A Full Picture of Relevant Topics. AB - This paper presents a visual analytics approach to analyzing a full picture of relevant topics discussed in multiple sources, such as news, blogs, or micro blogs. The full picture consists of a number of common topics covered by multiple sources, as well as distinctive topics from each source. Our approach models each textual corpus as a topic graph. These graphs are then matched using a consistent graph matching method. Next, we develop a level-of-detail (LOD) visualization that balances both readability and stability. Accordingly, the resulting visualization enhances the ability of users to understand and analyze the matched graph from multiple perspectives. By incorporating metric learning and feature selection into the graph matching algorithm, we allow users to interactively modify the graph matching result based on their information needs. We have applied our approach to various types of data, including news articles, tweets, and blog data. Quantitative evaluation and real-world case studies demonstrate the promise of our approach, especially in support of examining a topic-graph based full picture at different levels of detail. PMID- 26761819 TI - CUBu: Universal Real-Time Bundling for Large Graphs. AB - Visualizing very large graphs by edge bundling is a promising method, yet subject to several challenges: speed, clutter, level-of-detail, and parameter control. We present CUBu, a framework that addresses the above problems in an integrated way. Fully GPU-based, CUBu bundles graphs of up to a million edges at interactive framerates, being over 50 times faster than comparable state-of-the-art methods, and has a simple and intuitive control of bundling parameters. CUBu extends and unifies existing bundling techniques, offering ways to control bundle shapes, separate bundles by edge direction, and shade bundles to create a level-of-detail visualization that shows both the graph core structure and its details. We demonstrate CUBu on several large graphs extracted from real-life application domains. PMID- 26761820 TI - 3D Beam Tracing Based on Visibility Lookup for Interactive Acoustic Modeling. AB - We present a method for accelerating the computation of specular reflections in complex 3D enclosures, based on acoustic beam tracing. Our method constructs the beam tree on the fly through an iterative lookup process of a precomputed data structure that collects the information on the exact mutual visibility among all reflectors in the environment (region-to-region visibility). This information is encoded in the form of visibility regions that are conveniently represented in the space of acoustic rays using the Plucker coordinates. During the beam tracing phase, the visibility of the environment from the source position (the beam tree) is evaluated by traversing the precomputed visibility data structure and testing the presence of beams inside the visibility regions. The Plucker parameterization simplifies this procedure and reduces its computational burden, as it turns out to be an iterative intersection of linear subspaces. Similarly, during the path determination phase, acoustic paths are found by testing their presence within the nodes of the beam tree data structure. The simulations show that, with an average computation time per beam in the order of a dozen of microseconds, the proposed method can compute a large number of beams at rates suitable for interactive applications with moving sources and receivers. PMID- 26761817 TI - L1 Cell Adhesion Molecule-Specific Chimeric Antigen Receptor-Redirected Human T Cells Exhibit Specific and Efficient Antitumor Activity against Human Ovarian Cancer in Mice. AB - New therapeutic modalities are needed for ovarian cancer, the most lethal gynecologic malignancy. Recent clinical trials have demonstrated the impressive therapeutic potential of adoptive therapy using chimeric antigen receptor (CAR) redirected T cells to target hematological cancers, and emerging studies suggest a similar impact may be achieved for solid cancers. We sought determine whether genetically-modified T cells targeting the CE7-epitope of L1-CAM, a cell adhesion molecule aberrantly expressed in several cancers, have promise as an immunotherapy for ovarian cancer, first demonstrating that L1-CAM was highly over expressed on a panel of ovarian cancer cell lines, primary ovarian tumor tissue specimens, and ascites-derived primary cancer cells. Human central memory derived T cells (TCM) were then genetically modified to express an anti-L1-CAM CAR (CE7R), which directed effector function upon tumor antigen stimulation as assessed by in vitro cytokine secretion and cytotoxicity assays. We also found that CE7R+ T cells were able to target primary ovarian cancer cells. Intraperitoneal (i.p.) administration of CE7R+ TCM induced a significant regression of i.p. established SK-OV-3 xenograft tumors in mice, inhibited ascites formation, and conferred a significant survival advantage compared with control-treated animals. Taken together, these studies indicate that adoptive transfer of L1-CAM-specific CE7R+ T cells may offer a novel and effective immunotherapy strategy for advanced ovarian cancer. PMID- 26761821 TI - Measuring and Predicting Visual Importance of Similar Objects. AB - Similar objects are ubiquitous and abundant in both natural and artificial scenes. Determining the visual importance of several similar objects in a complex photograph is a challenge for image understanding algorithms. This study aims to define the importance of similar objects in an image and to develop a method that can select the most important instances for an input image from multiple similar objects. This task is challenging because multiple objects must be compared without adequate semantic information. This challenge is addressed by building an image database and designing an interactive system to measure object importance from human observers. This ground truth is used to define a range of features related to the visual importance of similar objects. Then, these features are used in learning-to-rank and random forest to rank similar objects in an image. Importance predictions were validated on 5,922 objects. The most important objects can be identified automatically. The factors related to composition (e.g., size, location, and overlap) are particularly informative, although clarity and color contrast are also important. We demonstrate the usefulness of similar object importance on various applications, including image retargeting, image compression, image re-attentionizing, image admixture, and manipulation of blindness images. PMID- 26761822 TI - Optimizing the Combination of Smoking and Boiling on Quality of Korean Traditional Boiled Loin (M. longissimus dorsi). AB - The combined effects of smoking and boiling on the proximate composition, technological quality traits, shear force, and sensory characteristics of the Korean traditional boiled loin were studied. Cooking loss, processing loss, and shear force were lower in the smoked/boiled samples than those in the control (without smoking treatment) (p<0.05). The results showed that the boiled loin samples between the control and treatment did not differ significantly in protein, fat, or ash contents, or pH values (p>0.05). The treated samples had higher score for overall acceptability than the control (p<0.05). Thus, these results show that the Korean traditional boiled loin treated with smoking for 60 min before boiling had improved physicochemical properties and sensory characteristics. PMID- 26761823 TI - Effect of Porcine Collagen Peptides on the Rheological and Sensory Properties of Ice Cream. AB - The effects of low molecular-weight collagen peptides derived from porcine skin were investigated on the physicochemical and sensorial properties of chocolate ice cream. Collagen peptides less than 1 kDa in weight were obtained by sub critical water hydrolysis at a temperature of 300C and a pressure of 80 bar. Ice cream was then prepared with gelatin powder and porcine skin hydrolysate (PSH) stabilizers mixed at seven different ratios (for a total of 0.5 wt%). There was no significant difference in color between the resulting ice cream mixtures. The increase in apparent viscosity and shear thinning of the ice cream was more moderate with PSH added than with gelatin. Moreover, the samples containing more than 0.2 wt% PSH had enhanced melting resistance, while the mixture with 0.2 wt% PSH had the lowest storage modulus at -20C and the second highest loss modulus at 10C, indicating that this combination of hydrocolloids leads to relatively softer and creamier chocolate ice cream. Among the seven types of ice creams tested, the mixture with 0.2 wt% PSH and 0.3 wt% gelatin had the best physicochemical properties. However, in sensory evaluations, the samples containing PSH had lower chocolate flavor scores and higher off-flavor scores than the sample prepared with just 0.5 wt% gelatin due to the strong off-flavor of PSH. PMID- 26761824 TI - Effect of Porcine Placenta Extract from Subcritical Water Extraction on Photodamage in Human Keratinocytes. AB - The objective of this study was to evaluated the photoprotective effects of porcine placenta extract (PPE) on ultraviolet B (UVB)-induced oxidative stress in human keratinocytes (HaCaT) to evaluate its functional activities as a skin food ingredient. PPE prepared by subcritical water extraction was termed SPE, and subsequently digested by enzymes to prepare E-SPE. Increased intracellular reactive oxygen species (ROS) levels (192.0%) induced by UVB were decreased by SPE and E-SPE. SPE had more effective ROS scavenging activity than E-SPE treatment. UVB treatment increased expression of tissue inhibitor of metalloproteinase 1 (TIMP-1), and this elevated expression was decreased by E-SPE treatment. High-dose treatment with E-SPE (50 and 100 ug/mL) reduced TIMP-1 expression levels of UVB-C (control) to 33.5 and 34.6%, respectively. In contrast, at low SPE doses (1 and 10 ug/mL), the treatment slightly decreased TIMP-1 expression levels to 73.3% and 71.3% of UVB-C, respectively. In conclusion, the present study demonstrated the protective effect of SPE and E-SPE against UVB damage in keratinocytes via ROS scavenging, down-regulating MMP-2 expression and up-regulating TIMP-1 expression. This highlights the potential for SPE as an ingredient in the preparation of functional food against photoaging. PMID- 26761825 TI - Effect of Lactobacillus plantarum FH185 on the Reduction of Adipocyte Size and Gut Microbial Changes in Mice with Diet-induced Obesity. AB - This study aimed to investigate the effects of Lactobacillus plantarum FH185 on the reduction of adipocyte size and gut microbial changes in mice with diet induced obesity. The strain was found to have a lipase inhibitory activity of 70.09+/-2.04% and inhibited adipocyte differentiation of 3T3-L1 cells (18.63+/ 0.98%) at a concentration of 100 ug/mL. To examine the effect of the strain supplementation on gut microbial changes in mice with diet-induced obesity, male C57BL/6J mice were fed on four different diets (i.e., A, normal diet (ND); B, high-fat diet (HFD); C, HFD with ABT-3 (10(9) CFU/day); and D, HFD with L. plantarum FH185 (10(9) CFU/day)) for 6 wk. According to the results of fecal pyrosequencing, the ratio of Firmicutes to Bacteroidetes in groups C and D was lower than in the control groups at the phylum level. At the family level, Lactobacillaceae in groups C and D was observed to dominate, while Lachnospiraceae in groups A and B was observed to dominate. At the genus level, Lactobacillus in groups C and D was comparatively higher than in groups A and B. To examine the effects of strain supplementation on the reduction of adipocyte size, the left and right epididymal fat pads were quickly isolated after the animals were sacrificed, and the adipocyte sizes were measured. In groups A, C and D, the percentage of 2,000 m(2) of adipocyte was higher than in the other size of adipocyte, while the percentage of over 5,000 m(2) of adipocyte was highest in group B. The mean adipocyte size of group D was significantly larger than that of group A, but smaller than that of group B. PMID- 26761826 TI - Characterization of Chicken By-products by Mean of Proximate and Nutritional Compositions. AB - Though a great amount of chicken by-products are consumed everyday in many countries worldwide, however, no attention has been paid to the investigation of nutritional composition of these by-products. In the present work, the basic information regarding the aspects of nutritional composition of chicken by products such as; liver, gizzard, heart, lung, crop, small intestines, cecum and duodenum was studied. Our results revealed that the approximate composition range (minimum to maximum) of these by-products was found as such: moisture 76.68 83.23%; fat 0.81-4.53%, protein 10.96-17.70% and calories 983.20-1,426.0 cal/g tissue, in which liver and gizzard had the highest protein content. Liver had higher (p<0.05) vitamin A, B1, B2, B3, B5 and B6 contents in comparison to other remaining by-products. Total saturated fatty acids (SFA), unsaturated fatty acids (UFA), polyunsaturated fatty acids (PUFA) levels ranged between the by-products from 31.82% to 43.96%, 56.04% to 68.19%, and 18.27% to 32.05%, respectively. Remarkably, all of by-products showed desirable PUFA/SFA ratios. Furthermore, all of chicken by-products, especially liver, contained higher levels of trace elements (e.g., Fe, Mn and Zn) in comparison with those from muscle tissues published in literature. Overall, the study indicated that most of chicken by products examined are good sources of essential nutrients and these obtained results will be the useful information to consumers and meat processors. PMID- 26761827 TI - Production of Functional High-protein Beverage Fermented with Lactic Acid Bacteria Isolated from Korean Traditional Fermented Food. AB - The aim of this study was to manufacture functional high protein fermented beverage, using whey protein concentrate (WPC) and Lactobacillus plantarum DK211 isolated from kimchi, and to evaluate the physicochemical, functional, and sensory properties of the resulting product. The fermented whey beverage (FWB) was formulated with whey protein concentrate 80 (WPC 80), skim milk powder, and sucrose; and fermented with Lactobacillus plantarum DK211 as single, or mixed with Lactococcus lactis R704, a commercial starter culture. The pH, titratable acidity, and viable cell counts during fermentation and storage were evaluated. It was found that the mixed culture showed faster acid development than the single culture. The resulting FWB had high protein (9%) and low fat content (0.2%). Increased viscosity, and antioxidant and antimicrobial activity were observed after fermentation. A viable cell count of 10(9) CFU/mL in FWB was achieved within 10 h fermentation, and it remained throughout storage at 15C for 28 d. Sensory analysis was also conducted, and compared to that of a commercial protein drink. The sensory scores of FWB were similar to those of the commercial protein drink in most attributes, except sourness. The sourness was highly related with the high lactic acid content produced during fermentation. The results showed that WPC and vegetable origin lactic acid bacteria isolated from kimchi might be used for the development of a high protein fermented beverage, with improved functionality and organoleptic properties. PMID- 26761828 TI - Effect of Palm or Coconut Solid Lipid Nanoparticles (SLNs) on Growth of Lactobacillus plantarum in Milk. AB - This study was performed to investigate the effect of palm or coconut solid lipid nanoparticles (PO-SLNs or CO-SLNs) on growth of Lactobacillus plantarum (L. plantarum) in milk during storage period. The PO or CO (0.1% or 1.0%) was dispersed both in distilled water (DW) and ultra high temperature milk (UHTM), and subsequently emulsified with Tween((r)) 80 by ultrasonication (30% power, 2 min). Increase in particle size and encapsulation efficiency (EE%) in DW was observed with an increase in oil concentration, whereas a decrease in zeta potential of SLNs was noted with an increment in oil concentration. Moreover, the CO-SLNs exhibited relatively smaller particle size and higher EE% than PO-SLNs. The CO-SLNs were found to be more stable than PO-SLNs. Higher lipid oxidation of PO or CO-SLNs in UHTM was observed during the storage test, when compared to PO or CO-SLNs in DW. However, there was no remarkable difference in lipid oxidation during storage period (p>0.05). In the growth test, the viability of L. plantarum in control (without PO or CO-SLNs in DW) exhibited a dramatic decrease with increasing storage period. In addition, viability of L. plantarum of PO or CO SLNs in UHTM was higher than that of SLNs in DW. Based on the present study, production of SLNs containing PO or CO in UHTM is proposed, which can be used in lactobacilli fortified beverages in food industry. PMID- 26761829 TI - Physicochemical and Microbiological Properties of Yogurt-cheese Manufactured with Ultrafiltrated Cow's Milk and Soy Milk Blends. AB - The objective of this study was to develop yogurt-cheese using cow's milk, ultrafiltrated cow's milk, and soy milk. The addition of soy milk and ultrafiltrated milk increased the amount of protein in the yogurt-cheese. Yogurt cheeses were made using cheese base using 10% and 20% soy milk with raw and ultrafiltrated cow's milk, and stored at 4C during 2 wk. The yield of yogurt cheeses made with added soy milk was decreased and the cutting point was delayed compared to yogurt-cheese made without soy milk. Yogurt-cheese made using ultrafiltrated cow's milk showed the highest yield. However, yogurt-cheese made with added soy milk had higher protein content and titratable acidity than yogurt cheese made using raw and ultrafiltrated cow's milk. Fat and lactose contents in the yogurt-cheese made with added soy milk were lower. Yogurt-cheeses made with added soy milk contained several soy protein bands corresponding to the sizes of alpha2-, beta-, and kappa-casein band. Yogurt-cheese made with added soy milk had similar elasticity to yogurt-cheese made without soy milk but had lower cohesiveness. There was no significant difference in the number of lactic acid bacteria in the different cheeses, as all had over 8.0 Log CFU/g. Considering these data and the fact that proteins and fats of vegetable origin with high biological value were observed as well as unsaturated fats, yogurt-cheese made with added soy milk can be considered to be a functional food. PMID- 26761830 TI - Antilisterial Effect of Bacteriocin SH01, Obtained from Enterococcus faecium SH01, in Ground Beef. AB - From the previous study, Enterococcus faecium SH01 was isolated from mukeunji, an over-ripened kimchi, and it produced bacteriocin SH01. Bacteriocin SH01 showed an inhibitory effect against Listeria monocytogenes ATCC 19111, a bacterial strain causing human listeriosis. Crude bacteriocin SH01 was purified by ammonium sulfate precipitation and its inhibitory activity at two concentrations (500 and 1,000 AU/g) against Listeria monocytogenes ATCC 19111 was investigated in ground beef at increasing temperatures (5, 10, 15, and 20C) for 8 d. The number of Listeria monocytogenes ATCC 19111 significantly decreased (p<0.05) as the concentration of bacteriocin increased from 500 to 1,000 AU/g. Intrinsic crude protease activities in ground beef were examined and increased as the temperature increased. Experiments varying both the concentrations of added bacteriocin SH01 and temperature demonstrated a maximum inhibition (2.33 log reduction of bacteria) in samples containing 1,000 AU/g of bacteriocin SH01 incubated at 20C. When the crude bacteriocin SH01 solution (1,280 AU/mL) was incubated with crude protease solutions at different temperatures, its activity decreased by only half (640 AU/mL), as assessed in an agar well diffusion assay. The finding that the antilisterial activity of bacteriocin SH01 increased with temperature can be explained by the fact that higher temperatures increase bacterial membrane fluidity, thereby promoting the cellular penetration of bacteriocin SH01 into L. monocytogenes. Bacteriocin SH01 may be an excellent candidate as a biopreservative for controlling L. monocytogenes growth in ground beef. PMID- 26761831 TI - Chitosan/whey Protein (CWP) Edible Films Efficiency for Controlling Mould Growth and on Microbiological, Chemical and Sensory Properties During Storage of Gobek Kashar Cheese. AB - The objective of present study was to evaluate the effects of the application of chitosan and chitosan/whey protein on the chemical, microbial and organoleptic properties of Gobek Kashar cheese during ripening time (on 3(rd), 30(th), 60(th) and 90(th) d). Difference in microbiological and chemical changes between samples was found to be significant (p<0.05) during ripening period. Cheese samples with edible coating had statistically lower mould counts compared to the uncoated samples. Furthermore the highest and lowest mould counts were determined in control (4.20 Log CFU/g) and other samples (<1 Log CFU/g) at 60(th) and 90(th) d of storage. All samples exhibited higher levels of water soluble nitrogen and ripening index at the end of storage process. At the end of 90 day storage period, no signicant dierences in salt and fat values were observed among the cheeses studied. The edible coatings had a beneficial effect on the sensory quality of cheese samples. In the result of sensory analysis, while cheese C and the chitosan coated cheese samples were more preferred by the panellists, the chitosan/whey protein film-coated cheese samples received the lowest scores. This study shows coating suggests could be used to improve the quality of cheese during ripening time. PMID- 26761832 TI - Effect of Fish Sarcoplasmic Protein on Quality Attributes of No-fat Chicken Sausages Mediated by Microbial Transglutaminase. AB - Fish sarcoplasmic protein (SP) obtaining from lyophilization was evaluated its effect on the qualities of the no-fat chicken sausages in the presence of microbial transglutaminase (MTG) as compared to sodium tripolyphosphate (STPP). The cooking yields of all sausage samples were not different. Expressible moisture (EM) of sausage samples was reduced by adding fish SP, while the lowest EM values were observed in sausage samples containing STPP. The pH values of sausage samples were increased with the addition of fish SP and STPP. Proximate analysis revealed that the moisture, fat, and protein contents of all samples were not different (p>0.05). Textural properties (TP), measured by texture profile analysis, showed that hardness of no-fat sausages increased upon adding fish SP. However, the highest TP values were found in sausage samples with STPP. The redness values were reduced in sausage samples with STPP, while other color values were not affected by STPP. Sensory evaluation revealed that sausages with fish SP were accepted at the higher level than that of control. However, sausage samples with STPP showed highest TP and acceptability. Thus, partial substitution of STPP by SP would be possible to reduce phosphate level in the chicken sausages. PMID- 26761833 TI - Physicochemical and Sensory Properties of Appenzeller Cheese Supplemented with Shrimp Powder. AB - The effects of adding shrimp (Periclimenes imperator) powder to Appenzeller cheese on quality and characteristics during ripening were investigated. Cheese samples were prepared containing 1.0%, 2.0%, and 3.0% shrimp powder. Changes in the lactic acid bacterial populations, pH, water-soluble nitrogen concentrations, consumer acceptability, colour and texture were monitored during ripening. The addition of shrimp powder did not affect the appearance or consumer sensory characteristics of the cheeses. Likewise, cheese cohesiveness, fracturability, and springiness were not significantly altered. It was concluded that the quality of the Appenzeller cheese was not affected by adding shrimp powder. PMID- 26761834 TI - Effect of Replacing Beef Fat with Poppy Seed Oil on Quality of Turkish Sucuk. AB - Sucuk is the most popular dry-fermented meat product. Sucuk has a relatively high fat. Poppy seed oil as animal fat replacer was used in Turkish sucuk and effects of its use on sucuk quality were investigated. There was a significant (p<0.5) treatment * ripening time interaction for moisture, pH (p<0.05) and 2 thiobarbituric acid reactive substances (TBARS) values (p<0.01). Increasing poppy seed oil level decreased (p<0.05) TBARS values. Addition of poppy seed oil to the sucuks had a significant effect (p<0.01) on hardness, cohesiveness, gumminess, chewiness and springiness values. Cholesterol content of sucuks decreased (p<0.05) with poppy seed oil addition. Using pre-emulsified poppy seed oil as partial fat replacer in Turkish sucuk decreased cholesterol and saturated fatty acid content, but increased polyunsaturated fatty acids. Poppy seed oil as partial animal fat replacer in Turkish sucuk may have significant health benefits. PMID- 26761835 TI - Effect of Packaging and Antioxidant Combinations on Physicochemical Properties of Irradiated Restructured Chicken Rolls. AB - Effects of double packaging (combinational use of aerobic and vacuum conditions) and antioxidants on physicochemical properties in irradiated restructured chicken rolls were determined. Chicken breast treated with antioxidants (none, sesamol+a tocopherol) was used to process restructured chicken breast rolls. The sliced rolls were vacuum, aerobic, or double packaged (vacuum for 7 d then aerobic for 3 d) and electron beam irradiated at 2.5 kGy. Color, 2-thiobarbituric acid reactive substances (TBARS), oxidation reduction potentials (ORP), and volatile profiles of the samples were determined at 0 and 10 d. Irradiation made restructured chicken rolls redder (p<0.05), and the increased redness was more distinct in irradiated vacuum-packaged than irradiated aerobic or double packaged meats. TBARS values of antioxidant-treated double packaged rolls were lower than even nonirradiated vacuum-packaged meat, and those were distinct at 10 d (p<0.05). ORP and lipid oxidation values were lower in irradiated vacuum and double packaged samples than those in irradiated aerobic packaged ones at 0 d (p<0.05). Irradiation of restructured chicken rolls increased the amount of total volatiles. Considerable amounts of off-odor volatiles were reduced or not detected by double packaging and antioxidant treatment at 10 d. Therefore, the combined use of antioxidants and double packaging would be useful to reduce redness and control the oxidative quality changes of irradiated restructured chicken rolls. PMID- 26761836 TI - Emulsion Mapping in Pork Meat Emulsion Systems with Various Lipid Types and Brown Rice Fiber. AB - This study was conducted to evaluate emulsion mapping between emulsion stability and cooking yields, apparent viscosity, and hardness of reduced-fat pork emulsion systems. The reduced-fat emulsion systems were supplemented with different lipid types and brown rice bran fiber (BRF) concentrations. Compared to the control with 30% back fat, lower emulsion stability and higher cooking yield of meat emulsion systems were observed in T1 (30% back fat+1% BRF), T2 (30% back fat+2% BRF), T3 (30% back fat+3% BRF), T4 (30% back fat+6% BRF), and T15 (10% back fat+10% canola oil+2% BRF). Lower emulsion stability and higher apparent viscosity were observed in T1, T2, T3, T4, and T8 (20% back fat+3% BRF) compared to the control. Lower emulsion stability and higher hardness was detected in all treatments compared with the control, except T5 (20% back fat), T10 (10% back fat+10% canola oil+2% BRF), T11 (10% back fat+10% olive oil+2% BRF), T12 (10% back fat+10% grape seed oil+2% BRF), and T13 (10% back fat+10% soybean oil+2% BRF). This approach has been found particularly useful for highlighting differences among the emulsified properties in emulsion meat products. Thus, the results obtained with emulsion mapping are useful in making emulsified meat products of desired quality characteristics, partially replacing pork back fat with a mix of 10% back fat, 10% canola oil and 2% BRF was most similar to the control with 30% pork back fat. PMID- 26761837 TI - Effects of Ethanol Addition on the Efficiency of Subcritical Water Extraction of Proteins and Amino Acids from Porcine Placenta. AB - In a previous study, hydrolysates of porcine placenta were obtained and the extraction efficiency for proteins and amino acids was compared between sub- and super-critical water extraction systems; optimum efficiency was found to be achieved using subcritical water (170C, 10 bar). In this study, the effects of adding ethanol to the subcritical water system were investigated. The lowest molecular-weight extraction product detected weighed 434 Da, and the efficiency of extraction for low-molecular-weight products was increased when either the concentration of ethanol was decreased, or the extraction time was lengthened from 10 min to 30 min. The highest concentration of free amino acids (approximately 8 mM) was observed following 30 min extraction using pure distilled water. The concentration of free amino acids was significantly lower when ethanol was added or a shorter extraction time was used (p<0.05). Color change of the solution following extraction was measured. There were no significant differences in color between lysates produced with different extraction times when using distilled water (p>0.05); however, using different extraction times produced significant differences in color when using 20% or 50% ethanol solution for subcritical extraction (p<0.05). The range of pH for the hydrolysate solutions was 6.4-7.5. In conclusion, the investigated extraction system was successful in the extraction of <= 500 Da hydrolysates from porcine placenta, but addition of ethanol did not yield higher production of low molecular-weight hydrolysates than that achieved by DW alone. PMID- 26761838 TI - Antimicrobial Effect of Nisin against Bacillus cereus in Beef Jerky during Storage. AB - The microbial distribution of raw materials and beef jerky, and the effect of nisin on the growth of Bacillus cereus inoculated in beef jerky during storage, were studied. Five strains of pathogenic B. cereus were detected in beef jerky, and identified with 99.8% agreement using API CHB 50 kit. To evaluate the effect of nisin, beef jerky was inoculated with approximately 3 Log CFU/g of B. cereus mixed culture and nisin (100 IU/g and 500 IU/g). During the storage of beef jerky without nisin, the number of mesophilic bacteria and B. cereus increased unlikely for beef jerky with nisin. B. cereus started to grow after 3 d in 100 IU nisin/g treatment, and after 21 d in 500 IU nisin/g treatment. The results suggest that nisin could be an effective approach to extend the shelf-life, and improve the microbial safety of beef jerky, during storage. PMID- 26761839 TI - Force Modelling of Upper Limb Biomechanics Using Ensemble Fast Orthogonal Search on High-Density Electromyography. AB - An important quality of upper limb force estimation is the repeatability and worst-case performance of the estimator. The following paper proposes a methodology using an ensemble learning technique coupled with the fast orthogonal search (FOS) algorithm to reliably predict varying isometric contractions of the right arm. This method leverages the rapid and precise modelling offered by FOS combined with a univariate outlier detection algorithm to dynamically combine the output of numerous FOS models. This is performed using high-density surface electromyography (HD-SEMG) obtained from three upper-arm muscles, the biceps brachii, triceps brachii and brachioradialis. This method offers improved performance over other HD-SEMG and SEMG based force estimators, with a substantial reduction in the number of channels required. PMID- 26761840 TI - Combined Effect of Kimchi Powder and Onion Peel Extract on Quality Characteristics of Emulsion Sausages Prepared with Irradiated Pork. AB - This study was conducted to investigate the effects of kimchi powder and onion peel extract on the quality characteristics of emulsion sausage manufactured with irradiated pork. The emulsion sausages were formulated with 2% kimchi powder and/or 0.05% onion peel extract. The changes in pH value of all treatments were similar, depending on storage periods. The addition of kimchi powder increased the redness and yellowness of the emulsion sausage. The addition of onion peel extract decreased the thiobarbituric acid reactive substances value of the emulsion sausages prepared with irradiated pork. The volatile basic nitrogen value of the emulsion sausage prepared with kimchi powder was the highest, whereas that of the emulsion sausage prepared with onion peel extract was the lowest. The treatment without kimchi powder or onion peel extract and the treatments prepared with onion peel extract showed lower microbial populations than the other treatment. Sensory evaluations indicated that a higher acceptability was attained when kimchi powder was added to the emulsion sausages manufactured with irradiated pork. In conclusion, our results suggest that combined use of kimchi powder and onion peel extract could improve quality characteristics and shelf stability of the emulsion sausage formulated with irradiated pork during chilled storage. PMID- 26761841 TI - Comparison of longissimus dorsi Fatty Acids Profiles in Gansu Black Yak and Chinese Yellow Cattle Steers and Heifers. AB - Fatty acid (FA) composition of longissimus dorsi intramuscular fat in Black Yak and Chinese Yellow Cattle were evaluated in 44 Black Yak and 41 Chinese Yellow Cattle of both genders. Interactions of species with gender were observed for total saturated fatty acid (SFA), unsaturated fatty acid (UFA), monounsaturated fatty acid (MUFA), polyunsaturated fatty acid (PUFA), palmitic acid, stearic acid, oleic acid, linolenic acid, arachidonic acid, EPA, and DHA concentrations, as well as PUFA/SFA ratio in the longissimus dorsi (p<0.05). The SFA percentage was greater in yellow cattle than yak in both genders but the species difference in heifers was greater than in steers (p<0.05). Yak had greater UFA, MUFA and PUFA percentages than yellow cattle in both steers and heifers (p<0.05) but the difference between yak and yellow cattle heifers was greater than yak and yellow cattle steers. The percentages of inolenic acid, arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid; and PUFA/SFA were greater in yak than yellow cattle in both steers and heifers (p<0.05). In addition, the ratio of n-6/n-3 PUFA in yak was lesser than in yellow cattle (p<0.05). These results indicated that FA composition generally differed between yak and yellow cattle but the differences were not the same in heifers as compared to steers. Results also suggested that species differences in FA composition tended to favor Black Yak over Chinese Yellow Cattle, indicating that the longissimus dorsi of Black Yak may have a higher nutritive value than that of Chinese Yellow Cattle and potential for development as a desirable natural product. PMID- 26761842 TI - Enhanced Anti-inflammatory Effects of gamma-irradiated Pig Placenta Extracts. AB - Porcine placenta extract (PPE) is known to possess anti-inflammatory properties owing to its high concentration of bioactive substances. However, the need to eliminate blood-borne infectious agents while maintaining biological efficacy raises concerns about the optimal method for sterilizing PPE. Therefore, the objective of this study was to compare the effects of the standard pressurized heat (autoclaving) method of sterilization with gamma-irradiation on the anti inflammatory effects of PPE. The anti-inflammatory actions of these two preparations of PPE were evaluated by measuring their inhibitory effects on the production of NO, the expression of iNOS protein, and the expression of iNOS, COX2, TNF-alpha, IL-1beta, and IL-6 mRNA in lipopolysaccharide-stimulated RAW 264.7 cells. Compared with autoclaved PPE, gamma-irradiated PPE showed significantly greater inhibition of NO production and iNOS protein expression, and produced a greater reduction in the expression of iNOS, COX2, TNF-alpha, IL 1beta, and IL-6 mRNA. These results provide evidence that the sterilization process is crucial in determining the biological activity of PPE, especially its anti-inflammatory activity. Collectively, our data suggest that gamma-irradiated PPE acts at the transcriptional level to effectively and potently suppresses the production of NO and the expression of pro-inflammatory cytokines. PMID- 26761843 TI - Profile of Hanwoo Steer Carcass Characteristics, Meat Quality and Fatty Acid Composition after Feeding Italian Ryegrass Silage. AB - The objective of this work was to evaluate the growth performance, feed intake, slaughter characteristics, meat quantity and quality characteristics of Hanwoo steers fed with Italian ryegrass (IRG) silage (TRT). IRG silage consisted 11.70% protein, 2.84% ether extract, 53.50% dry matter digestibility and 63.34% total digestible nutrients. The daily weight gain and feed conversion ratio of TRT were significantly (p<0.01) higher than that of control diet (CON; fed rice straw) in the whole periods. However, the slaughter weight, dressing percentage, quantity grade and quantity traits (marbling score, meat color, fat color, and quality grade) of either TRT or CON were similar. Meat fed TRT diet showed higher crude fat and lightness (L*) value and lower moisture content and pH value compared with the CON diet (p<0.05). Overall the carcass yield was 12.5% higher than CON diet. PMID- 26761844 TI - Effect of Dietary Fiber Extracted from Algelica keiskei Koidz on the Quality Characteristics of Chicken Patties. AB - In this study, we evaluated the effects of dietary fiber extracted from Algelica keiskei Koidz on the chemical composition, cooking characteristics, and sensory properties of chicken patties. The chicken patties with Algelica keiskei Koidz dietary fiber had significantly higher moisture and ash content, and yellowness than the control sample (p<0.05). Energy value, cooking loss, reduction in diameter, reduction in thickness, lightness, redness, hardness, cohesiveness, gumminess, and chewiness of the control samples was significantly higher than chicken patties with Algelica keiskei Koidz dietary fiber (p<0.05). The sensory evaluation indicated that the greatest overall acceptability in chicken patties was achieved at Algelica keiskei Koidz dietary fiber levels of 1% and 2%. Chicken patties supplemented with 2% Algelica keiskei Koidz dietary fiber had improved quality characteristics. PMID- 26761845 TI - Effect of NaCl Concentration on the Emulsifying Properties of Myofibrilla Protein in the Soybean Oil and Fish Oil Emulsion. AB - The aim of the present work was to investigate the effect of NaCl concentration on the emulsifying and rheological properties of porcine myofibrillar protein (MF)-stabilized soybean oil and fish oil emulsion (SO-EMs and FO-EMs). Emulsions (EMs) were prepared from 1% MF with 10% SO or FO at various NaCl concentration (0 0.5 M). The emulsifying ability index (EAI) of the EMs increased with increasing NaCl concentration for both oil types. Conversely, increasing NaCl manifested decrease in the emulsion stability index (ESI). In addition, creaming index (CI) also increased with NaCl concentration. From the microscopic observation, droplets of the EMs were more aggregated at relatively higher NaCl concentrations, especially for FO-EMs. All EMs had a gel-like structure owing to G' > G" from the rheological analysis. Comparing the oil types, the emulsifying capacity of SO-EMs was more stable than that of FO-EMs at all NaCl concentrations as determined from the CI value and microscopic observation. Therefore, it can be concluded that SO-EMs and FO-EMs are more stable at relatively lower concentrations of NaCl. In addition, the dispersed stability of SO-EMs was better than that of FO-EMs at the same concentration of NaCl. PMID- 26761846 TI - Effect of GdL Addition on Physico-chemical Properties of Fermented Sausages during Ripening. AB - This study investigated the effects of glucono-delta-lactone (GdL) addition on physicochemical and microbiological characteristics of fermented sausages during ripening and drying. Five batches of sausages were produced under ripening conditions: without GdL and with 0, 0.1, 0.25, 0.5 and 0.75% of GdL addition. Samples from each treatment were taken for physicochemical and microbiological analyses on the 0, 1, 3, 5, 7, 10, 15, 20 and 25th day of ripening. Chemical analysis showed a significant decrease in moisture content of sausages with increasing amounts of GdL added (p<0.05). The moisture contents decreased, whereas the fat, protein and ash contents increased throughout ripening (p<0.05). Increasing levels of GdL caused a decrease in the pH values (p<0.05), which can have an inhibitory effect against microflora. Water holding capacity content of samples decreased with increasing GdL concentration (p<0.05). The shear force values of fermented sausages showed the highest in T4 (p<0.05). During ripening, the shear force values of sausages were increased on the 25th day compared to day 0 (p<0.05). The higher GdL level produced lighter and more yellow sausages. The addition of 0.75% GdL was effective in controlling bacteria counts. Addition of GdL in sausages resulted in the physicochemical and microbiological attributes equal to or better than no addition of GdL without any harmful effect. PMID- 26761848 TI - Assessment of Characteristics and Functional Properties of Lactobacillus Species Isolated from Kimchi for Dairy Use. AB - The objective of this study was to identify lactic acid bacteria (LAB) isolated from kimchi and to evaluate its characteristics and functional properties for application in fermented dairy products as a probiotic or commercial starter culture. Eight stains isolated from kimchi were selected through an investigation of phenotypic characteristics. Two strains (DK211 and DK303) were identified as Lactobacillus plantarum, another two (DK207 and DK215) as Lactobacillus paracasei, and one (DK301) as Lactobacillus sakei. The remaining three strains were identified as species of Weissella. All selected Lactobacillus strains had acid and bile tolerance, even though there was wide variation in the ability of each strain. DK303 showed a remarkably higher proteolytic activity. There were no significant differences in beta-galactosidase activity among the tested strains, except that DK301 showed no activity. Auto-aggregation varied between 82.1 and 90.0%, and hydrophobicity values ranged from 0.5 to 51.6%.The strongest auto aggregation and hydrophobicity were observed in DK211. All selected strains showed better 1,1-diphenyl-2-picrylhydrzyl (DPPH) scavenging activity than commercial strains. DK211, DK215, DK301, and DK303 had effective inhibitory activity against all pathogens tested except E. coli. When selected strains were used for yogurt preparation as a single starter culture, the time required to reach target titratable acidity (0.9) was 11-12 h. The yogurt fermented with DK211 had favorable panelists ratings for most sensory attributes, which were comparable with yogurt fermented with a commercial strain. The results suggest that strains isolated from kimchi could be potential probiotic and starter cultures for use in yogurt manufacturing. PMID- 26761847 TI - Effect of Dietary Supplementation with Processed Sulfur on Meat Quality and Oxidative Stability in Longissimus dorsi of Pigs. AB - The effects of dietary supplementation of processed sulfur in pigs according to the level provided during the fattening phase were examined. The pigs were divided into three groups: control (CON), non-sulfur fed pigs; T1, 0.1% processed sulfur fed pigs; T2, 0.3% processed sulfur fed pigs. Physicochemical and sensory properties, as well as meat quality and oxidative stability of the Longissimus dorsi muscle were investigated. The feeding of processed sulfur did not affect moisture and protein contents (p>0.05). However, the crude fat content of T2 was significantly decreased compared to CON (p<0.05), while the pH value of T2 was significantly higher than those of both CON and T1 (p<0.05). Cooking loss and expressible drip of T2 were also significantly lower than that of CON (p<0.05). The redness of meat from T1 was significantly higher than both CON and T2 (p<0.01). During storage, lipid oxidation of the meat from sulfur fed pigs (T1 and T2) was inhibited compared to CON. Examination of omega-3 polyunsaturated fatty acids revealed T2 to have significantly higher content than CON (p<0.05). In the sensory test, the juiciness and overall acceptability of T2 recorded higher scores than CON. This study demonstrated that meat from 0.3% processed sulfur fed pigs had improved nutrition and quality, with extended shelf-life. PMID- 26761850 TI - Comparison of Antioxidant Activities of Hydrolysates of Domestic and Imported Skim Milk Powders Treated with Papain. AB - Milk proteins have many potential sequences within their primary structure, each with a specific biological activity. In this study, we compared and investigated the bioactivities of hydrolysates of the domestic (A, B) and imported (C, D) skim milk powders generated using papain digestion. MALDI-TOF analysis revealed that all milk powder proteins were intact, indicating no autolysis. Electrophoretic analysis of hydrolysates showed papain treatment caused degradation of milk proteins into peptides of various size. The antioxidant activity of the hydrolysates, determined using 2,2-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and total phenolic contents (TPC) assays, increased with incubation times. In all skim milk powders, the antioxidant activities of hydrolysates were highest following 24 h papain treatment (TPC: A, 196.48 MUM GE/L; B, 194.52 MUM GE/L; C, 194.76 MUM GE/L; D, 163.75 MUM GE/L; ABTS: A, 75%; B, 72%; C, 72%; D, 57%). The number of peptide derived from skim milk powders, as determined by LC MS/MS, was 308 for A, 283 for B, 208 for C, and 135 for D. Hydrolysate A had the highest antioxidant activity and the most potential antioxidant peptides amongst the four skim milk powder hydrolysates. A total of 4 beta-lactoglobulin, 4 alphas1-casein, and 56 beta-casein peptide fragments were identified as potential antioxidant peptides in hydrolysate A by LC-MS/MS. These results suggest that domestic skim milk could have applications in various industries, i.e., in the development of functional foods. PMID- 26761849 TI - Improved Functional Characteristics of Whey Protein Hydrolysates in Food Industry. AB - This review focuses on the enhanced functional characteristics of enzymatic hydrolysates of whey proteins (WPHs) in food applications compared to intact whey proteins (WPs). WPs are applied in foods as whey protein concentrates (WPCs), whey protein isolates (WPIs), and WPHs. WPs are byproducts of cheese production, used in a wide range of food applications due to their nutritional validity, functional activities, and cost effectiveness. Enzymatic hydrolysis yields improved functional and nutritional benefits in contrast to heat denaturation or native applications. WPHs improve solubility over a wide range of pH, create viscosity through water binding, and promote cohesion, adhesion, and elasticity. WPHs form stronger but more flexible edible films than WPC or WPI. WPHs enhance emulsification, bind fat, and facilitate whipping, compared to intact WPs. Extensive hydrolyzed WPHs with proper heat applications are the best emulsifiers and addition of polysaccharides improves the emulsification ability of WPHs. Also, WPHs improve the sensorial properties like color, flavor, and texture but impart a bitter taste in case where extensive hydrolysis (degree of hydrolysis greater than 8%). It is important to consider the type of enzyme, hydrolysis conditions, and WPHs production method based on the nature of food application. PMID- 26761851 TI - The Comparative Effect of Carrot and Lemon Fiber as a Fat Replacer on Physico chemical, Textural, and Organoleptic Quality of Low-fat Beef Hamburger. AB - This study was designed to determine the usability of lemon fiber (LF-2%, 4%, 6%) and carrot fiber (CF-2%, 4%, 6%) to produce low-fat beef hamburgers. To that end, a certain amount of fat was replaced with each fiber. The proximate composition, pH value, cholesterol content, cooking characteristics, color, texture profile, and sensory properties of low-fat beef hamburgers were investigated. LF increased moisture content and cooking yield due to its better water binding properties, while CF caused higher fat and cholesterol contents owing to its higher fat absorption capacity (p<0.05). LF resulted in a lighter, redder, and more yellow color (p<0.05). Hardness, gumminess, springiness, and chewiness parameters decreased when the usage level of both fibers increased (p<0.05). However, more tender, gummy, springy, and smoother hamburgers were produced by the addition of CF in comparison with LF (p<0.05). Moreover, hamburgers including CF were rated with higher sensory scores (p<0.05). In conclusion, LF demonstrated better technological results in terms of cooking yield, shrinkage, moisture retention, and fat retention. However it is suggested that CF produces better low-fat hamburgers since up to 2% CF presented sensory and textural properties similar to those of regular hamburgers. PMID- 26761852 TI - A Simultaneous Analytical Method for Duplex Identification of Porcine and Horse in the Meat Products by EvaGreen based Real-time PCR. AB - A duplex real-time polymerase chain reaction (PCR) based assay for the detection of porcine and horse meat in sausages was designed by using EvaGreen fluorescent dye. Primers were selected from mitochondrial 12S rRNA and 16S rRNA genes which are powerful regions for identification of horse and porcine meat. DNA from reference samples and industrial products was successfully extracted using the GIDAGEN(r) Multi-Fast DNA Isolation Kit. Genomes were identified based on their specific melting peaks (Mp) which are 82.5C and 78C for horse and porcine, respectively. The assay used in this study allowed the detection of as little as 0.0001% level of horse meat and 0.001% level of porcine meat in the experimental admixtures. These findings indicate that EvaGreen based duplex real-time PCR is a potentially sensitive, reliable, rapid and accurate assay for the detection of meat species adulterated with porcine and horse meats. PMID- 26761853 TI - Influence of Perilla frutescens var. acuta Water Extract on the Shelf Life and Physicochemical Qualities of Cooked Beef Patties. AB - This study investigated the effects of Perilla frutescens var. acuta water extract (WEP) on the shelf life and physicochemical qualities of cooked beef patties. The WEP contained phenolic compounds (80.65 mg gallic acid equivalents/g) and had half-maximal effective concentrations of 0.437 and 4.509 mg/mL for scavenging of DPPH and ABTS(+) radicals, respectively. Treatment with 0.6% WEP inhibited the growth of Escherichia coli O157:H7 (p<0.05). Based on the result of the antioxidative potential and antimicrobial potential of WEP, beef patties were prepared with three treatment groups: (1) beef patties without added antioxidant (control); (2) beef patties with 0.02% L-ascorbic acid (BAA); and (3) beef patties with 0.6% WEP (BWEP). The pH and cooking loss of BWEP were lower and higher than those in the control, respectively (p<0.05). When cooked beef patties were stored for 21 d at 4C, the total number of aerobic bacteria in BWEP was lower than those in the control on all days except day 14 (p<0.05). The TBARS values in BWEP were lower than those of controls on days 7, 14, and 21 (p<0.05). Compared to control and BAA, BWEP had lower L* and b* values and higher a* values throughout the storage period (p<0.05). Except on day 0, acceptability was higher in BWEP than in control and BAA (p<0.05). According to results, WEP can be used as a natural ingredient that improves the shelf life and sensorial qualities of meat products. PMID- 26761854 TI - Effects of Egg White Consumption on Immune Modulation in a Mouse Model of Trimellitic Anhydride-induced Allergy. AB - Egg allergy has been shown to be the most common food allergy in children with atopic dermatitis. Allergic reactions to proteins derived from egg white (EW) are more common than those derived from egg yolk. Ovomucoid, ovalbumin, ovotransferrin, and lysozyme have been identified as major allergens in EW. This study was conducted to evaluate the effect of EW on immune modulation in an induced allergy mouse model. A total of 50 five-week-old BALB/c male mice were treated with trimellitic anhydride (TMA) for three weeks to induce allergy-like symptoms. The TMA-treated mice were rested for one week and then divided into five groups and fed 0, 10, 50, and 100 mg/d EW for four weeks. All EW consumption groups showed no significant increase or decrease in the populations of white blood cells; however, a significant increase in B-lymphocyte activity was observed in the fourth week. Furthermore, EW consumption did not influence serum immunoglobulin G and immunoglobulin E levels. Taken together, these data demonstrate that the consumption of EW by TMA-treated mice did not increase allergic parameters such as serum IgE level, but enhanced the lymphocyte activities against pathogens. Therefore, this study suggests that the consumption of EW promotes Th2 immune modulation, and EW could be an excellent candidate for maintaining health. PMID- 26761855 TI - Combined Effect of Irradiation and Ageing Condition on Physicochemical and Microbial Quality of Hanwoo Eye of Round. AB - The combined effects of electron-beam irradiation and ageing of beef were examined. The irradiated samples at dose of 0 or 2 kGy were kept and analyzed for the microbial growth, shear values, meat color, and nucleotide-related flavor compounds at different ageing temperatures (2, 10, or 25C) for 8 d. The irradiation effect on inactivation of foodborne pathogens was also investigated. The population of Listeria monocytogenes and E. coli O157:H7 inoculated in beef samples decreased in proportion to the irradiation dose, showing D10 values of 0.66 and 0.65 kGy respectively. The irradiated beef eye of round had lower number of total aerobic bacteria (TAB) than non-irradiated one during the storage, but the TAB increased with higher ageing temperature (p<0.05). Especially, TAB increased sharply in non-irradiated samples aged at 25C after 4 d (p<0.05). With increasing ageing temperature and ageing time, shear force values decreased (p<0.05). The color a* values of the irradiated beef were lower than those of the non-irradiated throughout the ageing period (p<0.05). As ageing time and temperature increased, the amounts of inosine monophosphate decreased and the hypoxanthine increased (p<0.05). Relatively high ageing temperature could be used at irradiated beef eye of round to shorten the ageing time. PMID- 26761856 TI - Effects of Porcine Placenta Extract Ingestion on Ultraviolet B-induced Skin Damage in Hairless Mice. AB - The aim of our study was to evaluate the potential benefits of an oral supplement containing porcine placenta extract (PPE) on skin parameters related to cutaneous physiology and aging. PPEs were administered orally to hairless mice for 12 wk. The effects of oral PPE administration on skin water-holding capacity and Transepidermal Water Loss (TEWL) were similar to those of oral collagen (HYCPU2) administered as a positive control. Magnified photographs and replica images showed a reduction in UVB-induced wrinkle formation after collagen and PPE treatments. PPE treatments ameliorated the thicker skin surface that results from UVB exposure, based on a histological examination of skin tissue. The groups that were orally administered PPE (0.05%, OL; 0.1%, OH group) showed significantly reduced Matrix Metaloproteinase-2 (MMP-2) mRNA expression levels compared with the UVB control (Con), by 33.5% and 35.2%, respectively. The mRNA expression of another collagen-degrading protein, MMP-9, was also significantly lower in the groups that received oral administration of PPE (especially in the OH group) than in the control group. Additionally, oral administration of PPE significantly upregulated tissue inhibitor of metalloproteinase-1 (TIMP-1) and -2 mRNA expression levels compared with expression levels in the control group (p<0.05). This indicates that orally administered PPE activated the expression of Timp-1 and -2, inhibitors of MMP, which is responsible for collagen degradation in skin. Taken together, we propose that long-term oral administration of PPE might have a beneficial effect with respect to skin photo-aging. PMID- 26761857 TI - A New Approach for Feature Selection from Microarray Data Based on Mutual Information. AB - Mutual information (MI) is a powerful concept for correlation-centric applications. It has been used for feature selection from microarray gene expression data in many works. One of the merits of MI is that, unlike many other heuristic methods, it is based on a mature theoretic foundation. When applied to microarray data, however, it faces some challenges. First, due to the large number of features (i.e., genes) present in microarray data, the true distributions for the expression values of some genes may be distorted by noise. Second, evaluating inter-group mutual information requires estimating multi variate distributions, which is quite difficult if not impossible. To address these problems, in this paper, we propose a new MI-based feature selection approach for microarray data. Our approach relies on two strategies: one is relevance boosting, which requires a desirable feature to show substantially additional relevance with class labeling beyond the already selected features, the other is feature interaction enhancing, which probabilistically compensates for feature interaction missing from simple aggregation-based evaluation. We justify our approach from both theoretical perspective and experimental results. We use a synthetic dataset to show the statistical significance of the proposed strategies, and real-life datasets to show the improved performance of our approach over the existing methods. PMID- 26761858 TI - Sorting Circular Permutations by Super Short Reversals. AB - We consider the problem of sorting a circular permutation by super short reversals (i.e., reversals of length at most 2), a problem that finds application in comparative genomics. Polynomial-time solutions to the unsigned version of this problem are known, but the signed version remained open. In this paper, we present the first polynomial-time solution to the signed version of this problem. Moreover, we perform experiments for inferring phylogenies of two different groups of bacterial species and compare our results with the phylogenies presented in previous works. Finally, to facilitate phylogenetic studies based on the methods studied in this paper, we present a web tool for rearrangement-based phylogenetic inference using short operations, such as super short reversals. PMID- 26761859 TI - On the Variable Ordering in Subgraph Isomorphism Algorithms. AB - Graphs are mathematical structures to model several biological data. Applications to analyze them require to apply solutions for the subgraph isomorphism problem, which is NP-complete. Here, we investigate the existing strategies to reduce the subgraph isomorphism algorithm running time with emphasis on the importance of the order with which the graph vertices are taken into account during the search, called variable ordering, and its incidence on the total running time of the algorithms. We focus on two recent solutions, which are based on an effective variable ordering strategy. We discuss their comparison both with the variable ordering strategies reviewed in the paper and the other algorithms present in the ICPR2014 contest on graph matching algorithms for pattern search in biological databases. PMID- 26761861 TI - Private Data Analytics on Biomedical Sensing Data via Distributed Computation. AB - Advances in biomedical sensors and mobile communication technologies have fostered the rapid growth of mobile health (mHealth) applications in the past years. Users generate a high volume of biomedical data during health monitoring, which can be used by the mHealth server for training predictive models for disease diagnosis and treatment. However, the biomedical sensing data raise serious privacy concerns because they reveal sensitive information such as health status and lifestyles of the sensed subjects. This paper proposes and experimentally studies a scheme that keeps the training samples private while enabling accurate construction of predictive models. We specifically consider logistic regression models which are widely used for predicting dichotomous outcomes in healthcare, and decompose the logistic regression problem into small subproblems over two types of distributed sensing data, i.e., horizontally partitioned data and vertically partitioned data. The subproblems are solved using individual private data, and thus mHealth users can keep their private data locally and only upload (encrypted) intermediate results to the mHealth server for model training. Experimental results based on real datasets show that our scheme is highly efficient and scalable to a large number of mHealth users. PMID- 26761860 TI - An Application of Invertibility of Boolean Control Networks to the Control of the Mammalian Cell Cycle. AB - In Faure et al. (2006), the dynamics of the core network regulating the mammalian cell cycle is formulated as a Boolean control network (BCN) model consisting of nine proteins as state nodes and a tenth protein (protein CycD) as the control input node. In this model, one of the state nodes, protein Cdc20, plays a central role in the separation of sister chromatids. Hence, if any Cdc20 sequence can be obtained, fully controlling the mammalian cell cycle is feasible. Motivated by this fact, we study whether any Cdc20 sequence can be obtained theoretically. We formulate the foregoing problem as the invertibility of BCNs, that is, whether one can obtain any Cdc20 sequence by designing input (i.e., protein CycD) sequences. We give an algorithm to verify the invertibility of any BCN, and find that the BCN model for the core network regulating the mammalian cell cycle is not invertible, that is, one cannot obtain any Cdc20 sequence. We further present another algorithm to test whether a finite Cdc20 sequence can be generated by the BCN model, which leads to a series of periodic infinite Cdc20 sequences with alternately active and inactive Cdc20 segments. States of these sequences are alternated between the two attractors in the proposed model, which reproduces correctly how a cell exits the cell cycle to enter the quiescent state, or the opposite. PMID- 26761862 TI - Combined Effects of Mugwort Herb and Vitamin C on Shelf-Life of Vacuum-Packed Seasoned Pork. AB - This study was performed to investigate the possibility of the addition of mugwort herb extract (MH) and vitamin C (VC) alone (0.05%) and in combination (0.05% each) on shelf-life of seasoned pork. The combination of VC+MH demonstrated a significant reduction in thiobarbituric acid reactive substances, and volatile basic nitrogen in seasoned pork. Also, the pH values, total lactic acid concentration, lactic acid bacteria count, and the sensory properties (discoloration, flavor, and overall acceptability) of seasoned pork were not significantly affected by adding MH and/or VC. All seasoned pork were rejected by sensory panel when LAB count reached levels of 5-6 Log CFU/g, TLA concentration has been above a level of 3.6-3.9 mg lactic acid/g, and pH values ranged from 5.31-5.51 (15 d). Therefore, the findings showed that spoilage of seasoned pork does not appear to be the result of lipid oxidation, but is caused by lactic acid producing bacteria which result in sour odor. PMID- 26761863 TI - Optimization of a Multi-Step Procedure for Isolation of Chicken Bone Collagen. AB - Chicken bone is not adequately utilized despite its high nutritional value and protein content. Although not a common raw material, chicken bone can be used in many different ways besides manufacturing of collagen products. In this study, a multi-step procedure was optimized to isolate chicken bone collagen for higher yield and quality for manufacture of collagen products. The chemical composition of chicken bone was 2.9% nitrogen corresponding to about 15.6% protein, 9.5% fat, 14.7% mineral and 57.5% moisture. The lowest amount of protein loss was aimed along with the separation of the highest amount of visible impurities, non collagen proteins, minerals and fats. Treatments under optimum conditions removed 57.1% of fats and 87.5% of minerals with respect to their initial concentrations. Meanwhile, 18.6% of protein and 14.9% of hydroxyproline were lost, suggesting that a selective separation of non-collagen components and isolation of collagen were achieved. A significant part of impurities were selectively removed and over 80% of the original collagen was preserved during the treatments. PMID- 26761864 TI - Quality Characteristics of Beef by Different Cooking Methods for Frozen Home Meal Replacements. AB - Blanching beef for use in home meal replacements (HMR) is an important process that determines the final quality of the beef after the cooking process. Thermal pretreatment also minimizes the change in quality during the main cooking process or storage. In this study, beef samples were washed and sliced, then treated by immersion in boiling water (1-10 min), steaming (1-10 min), or pan-frying in oil (30-240 s). The color after each thermal treatment showed higher L* and b* values and lower a* values compared with the raw beef, except for the pan-frying thermal treatment. The total color difference (?E) and pH value were significantly increased by panfrying (p<0.05). There was no significant difference in the shear force of the beef samples, except for the sample pan-fried for 210 s. The nutritional content of beef was measured as the moisture, protein, fat, and ash contents, which were 69.96, 16.64, 3.49, and 1.13%, respectively, in raw beef. After thermal treatment, the crude protein and fat contents were increased, whereas the moisture and ash contents decreased. The mineral content, including Na, Mg, Fe, and Ca was highest after pan-frying. The heat treatment decreased microorganisms in all the samples. The total bacteria count in raw beef was 4.5 4.7 Log CFU/g, whereas the bacteria count decreased to 2.2-2.8 Log CFU/g after blanching. Thermophilic bacteria, coliform, mold, and yeast not detected in any thermally treated sample. PMID- 26761865 TI - Effect of Quality Grade and Storage Time on the Palatability, Physicochemical and Microbial Quality of Hanwoo Striploin Beef. AB - The effects of quality grade and storage time on physicochemical, sensory properties and microbial population of Hanwoo striploin beef were investigated. After a total of 30 Hanwoo beef were slaughtered, the cold carcasses were graded by official meat grader at 24 h postmortem. The carcasses were categorized into five groups (quality grade 1++, 1+, 1, 2, and 3) and were vacuum-packaged and stored. The samples were kept for 1, 4, 6, 8, 11, 13, 15, 18, 20, 22 and 25 d for analyses. As the quality grade was increased, moisture, protein and ash contents decreased (p<0.05). Higher quality grade corresponded with higher fat contents. The shear force values decreased with increasing quality grade and showed decreases sharply during the first 4 d (p<0.05). pH, water holding capacity, cooking loss, and volatile basic nitrogen for grade 1++ groups were lower than for grade 3 (p<0.05). CIE L* and b* values increased as increased quality grade (p<0.05). Meat color decreased until 13 d and fluctuated after 15 d of storage (p<0.05). Regarding the sensory scores, higher quality grade corresponded with higher juiciness, tenderness, flavor, fatty and palatability scores (p<0.05). Generally, increased storage time for 15 d improved sensory scores attributes. Results indicate that a high quality grade could positively influence physicochemical and sensory properties. PMID- 26761866 TI - Comparison of Total RNA Isolation Methods for Analysis of Immune-Related microRNAs in Market Milks. AB - Bovine milk provides essential nutrients, including immunologically important molecules, as the primary source of nutrition to newborns. Recent studies showed that RNAs from bovine milk contain immune-related microRNAs (miRNA) that regulate various immune systems. To evaluate the biological and immunological activity of miRNAs from milk products, isolation methods need to be established. Six methods for extracting total RNAs from bovine colostrums were adopted to evaluate the isolating efficiency and expression of miRNAs. Total RNA from milk was presented in formulation of small RNAs, rather than ribosomal RNAs. Column-combined phenol isolating methods showed high recovery of total RNAs, especially the commercial columns for biofluid samples, which demonstrated outstanding efficiency for recovering miRNAs. We also evaluated the quantity of five immune-related miRNAs (miR-93, miR-106a, miR-155, miR-181a, miR-451) in milk processed by temperature treatments including low temperature for long time (LTLT, 63C for 30 min)-, high temperature for short time (HTST, 75C for 15 s)-, and ultra heat treatment (UHT, 120-130C for 0.5-4 s). All targeted miRNAs had significantly reduced levels in processed milks compared to colostrum and raw mature milk. Interestingly, the amount of immune-related miRNAs from HTST milk was more resistant than those of LTLT and UHT milks. Our present study examined defined methods of RNA isolation and quantification of immune-specific miRNAs from small volumes of milk for use in further analysis. PMID- 26761867 TI - Development Rapid Analytical Methods for Inositol as a Trace Component by HPLC and LC-MS/MS in Infant Formula. AB - A rapid and simple analytical method, using liquid chromatography tandem mass spectrometry (LC-MS/MS), was developed to detect myo-inositol (MI) in infant formulas. For protein removal: acid hydrolysis and lipid removal through organic solvent extraction. The operating conditions for instrumental analysis were determined based on previously reported analogous methods that used LC-MS/MS. Quantitative analysis was used for the detection limit test, infant formula recovery test, and standard reference material (SRM) 1849a to verify the validity of our LC-MS/MS analytical method, which was developed to quantify MI. For validation, the results of our method were compared with the results of quantitative analyses of certified values. The test results showed that the limit of detection was 0.05 mg/L, the limit of quantitation was 0.17 mg/L, and the method detection limit was 17 mg/kg. The recovery test exhibited a recovery between 98.07-98.43% and a relative standard deviation between 1.93-2.74%. Therefore, the result values were good. Additionally, SRM 1849a was measured to have an MI content of 401.84 mg/kg and recovery of 98.25%, which is comparable to the median certified value of 409 mg/kg. From the aforementioned results, we judged that the instrumental analysis conditions and preparation method used in this study were valid. The rapid analytical method developed herein could be implemented in many laboratories that seek to save time and labor. PMID- 26761868 TI - In vitro Characterization of Bacteriocin Produced by Lactic Acid Bacteria Isolated from Nem Chua, a Traditional Vietnamese Fermented Pork. AB - The aim of this study was to screen and In vitro characterize the properties of bacteriocin produced by lactic acid bacteria isolated from Vietnamese fermented pork (Nem chua). One hundred and fifty LAB were isolated from ten samples of Nem chua and screened for bacteriocin-producing lactic acid bacteria. Antimicrobial activity of bacteriocin was carried out by spot on lawn method against both gram positive and gram negative bacteria. One isolate, assigned as KL-1, produced bacteriocin and showed inhibitory activity against Lactobacillus sakei, Leuconostoc mesenteroides and Enterococcus faecalis. To characterize the bacteriocin-producing strain, optimum temperature, incubation period for maximum bacteriocin production and identification of bacteriocin-producing strain were determined. It was found that the optimum cultivation temperature of the strain to produce the maximum bacteriocin activity (12,800 AU/mL) was obtained at 30C. Meanwhile, bacteriocin production at 6,400 AU/mL was found when culturing the strain at 37C and 42C. The isolate KL-1 was identified as L. plantarum. Antimicrobial activity of cell-free supernatant was completely inhibited by proteolytic enzyme of trypsin, alpha-chymotrypsin and proteinase K. Bacteriocin activity was stable at high temperature up to 100C for 10 min and at 4C storage for 2 d. However, the longer heating at 100C and 4C storage, its activity was reduced. PMID- 26761870 TI - Texture Softening of Beef and Chicken by Enzyme Injection Process. AB - This research focuses on a new softening technology for use with chicken breast and eye of round beef in order to assist elderly individuals who have difficulty with eating due to changes in their ability to chew (masticatory function) or swallow. We investigated the hardness of chicken breast and eye of round beef through use of a texture analyzer after injection of a commercial enzyme. Among 7 commercial enzymes, bromelain and collupulin exhibited a marked softening effect on the tested chicken breast and eye of round beef given a 1.00% enzyme concentration. The hardness of bromelain-treated chicken breast reached 1.4*10(4) N/m(2), of collupulin-treated chicken breast reached 3.0*10(4) N/m(2), and of bromelain-treated eye of round beef reached 3.2*10(4) N/m(2), respectively, while their original shapes did not change. To find the level of tissue degradation with specific enzyme concentrations, enzyme injections at 0.1%, 0.25%, 0.50%, and 1.00% concentration of bromelain and papain were also evaluated. The results of this research could be useful for softening chicken breast and eye of round beef and will contribute to the development of foods that can be more easily eaten as part of a balanced diet for elderly adults. PMID- 26761869 TI - Effects of Yogurt Containing Fermented Pepper Juice on the Body Fat and Cholesterol Level in High Fat and High Cholesterol Diet Fed Rat. AB - This experiment investigated whether yogurt containing fermented pepper juice (FPJY) affects cholesterol level in high fat and high cholesterol diet (HFCD) fed rat. Twenty five Sprague-Dawley male rats of 7 wk were divided into 5 groups, and fed following diets for 9 wk; CON (control diet), HFCD (HFCD), PY (HFCD supplemented with 2% of plain yogurt), LFY (HFCD supplemented with 2% of FPJY), and HFY (HFCD supplemented with 5% of FPJY). In the LFY group, hepatic total lipid level decreased significantly compared to the HFCD group (p<0.05). Serum HDL cholesterol level tended to increase and hepatic total cholesterol level decreased and were comparable to the CON group (p>0.05). In HFY group, body weight and hepatic total lipid level significantly decreased over the HFCD group (p<0.05). Serum and hepatic total cholesterol level, kidney, and body fat weights decreased, and were compared to the CON group (p>0.05). Liver weight decreased as FPJY content was increased. Results suggested FPJY would inhibit organ hypertrophy and accumulation of body fat, hepatic lipid, and cholesterol in HFCD fed rat. PMID- 26761871 TI - Effect of Pre-cooking Conditions on the Quality Characteristics of Ready-To-Eat Samgyetang. AB - The aim of this study was to examine the effectiveness of pre-cooking conditions on the quality characteristics of ready-to-eat (RTE) Samgyetang. Raw chickens were steamed under the different conditions of 50C/30 min (T1), 65C/30 min (T2), 85C/30 min (T3), and 90C/10 min (T4) prior to retorting at 120C for 65 min. The results showed that pre-cooking conditions in all treated samples could reduce fat contents in breast and leg meats by 8.5-11.7% and 10.0-11.0% compared to the control, even though there were no significant differences among treatments (p>0.05). The L* and b* values of breast and leg meats treated with the higher temperature and longer time conditions were significantly higher than the control (p<0.05), while a* values tended to decrease despite of not to a significant extent (p>0.05). Moreover, apparent viscosity and water soluble protein showed insignificant differences (p>0.05) among the samples as a result of the retorting process, which might have more negative influences on the quality. T2 samples obtained significantly the highest average Quantitative Descriptive Analysis (QDA) score and transmittance value, representing the most clear broth among the samples, compared to the control. On the other hand, T3 showed the highest cooking loss among the treatments and the lowest QDA scores among the samples. In conclusion, pre-cooking treatment prior to retorting in manufacturing Samgyetang is a plausible way to reduce its fat content. A pre-cooking condition at either 65C for 30 min, or 90C for 10 min are recommended for producing Samgyetang with optimum quality. PMID- 26761872 TI - Virulence Factors of Staphylococcus aureus Isolated from Korean Pork bulgogi: Enterotoxin Production and Antimicrobial Resistance. AB - The aim of this study was to investigate the antimicrobial resistance profiles of and the enterotoxin gene distribution in 4 strains of Staphylococcus aureus (S10 2, S10-3, S12-2, and S13-2) isolated from 90 bulgogi samples. The S. aureus enterotoxin H gene (seh) was found in all the strains, while the S. aureus enterotoxin A gene (sea) was found only in 3 of the 4 strains. The S10-2 strain expressed a combination of enterotoxin genes - seg, seh, sei, sej, selm, and seln. The strains S10-2 and S13-2 were resistant to ampicillin and penicillin G, and all the isolated strains were resistant to tetracycline. The S10-2 strain was the only mecA-positive strain; it was also resistant to beta-lactam antibiotics. Thus, genes encoding enterotoxin as well as those conferring antibiotic resistance were identified in the S. aureus strains isolated from pork bulgogi. These results represents the potential occurrence of MRSA in pork bulgogi, and the need for a monitoring system for pork bulgogi in order to prevent an outbreak of staphylococcal food poisoning. PMID- 26761873 TI - First Evidence that Sika Deer (Cervus nippon) Velvet Antler Extract Suppresses Migration of Human Prostate Cancer Cells. AB - Deer velvet antler (DVA) is one of the most popular medicines in China. Numerous studies have demonstrated that velvet antler possess biological effects. However, data regarding its anti-migration activity on prostate cancer is scarce. In this study, we investigated the inhibitory effect of top DVA (T-DVA) on the expression of prostate-specific antigen (PSA) and migration-related genes in the human prostate cancer cell, LNCaP. The T-DVA down-regulated the expression of PSA. In addition, the Radius(TM) assay revealed that T-DVA inhibited the migration behavior of prostate cancer cells. Furthermore, the expression of matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF) was also decreased with T-DVA. On the contrary, T-DVA increased the tissue inhibition of metalloproteinase (TIMP)-1 and (TIMP)-2. Taken together, our findings indicate that the T-DVA possesses anti-migration activity on prostate cancer cells. This is the first study of DVA to report the anti-migration activity on prostate cancer. PMID- 26761874 TI - Optimization for Reduced-Fat / Low-NaCl Meat Emulsion Systems with Sea Mustard (Undaria pinnatifida) and Phosphate. AB - The effects of reducing fat levels from 30% to 20% and salt concentrations from 1.5% to 1.0% by partially substituting incorporated phosphate and sea mustard were investigated based on physicochemical properties of reduced-fat / low-NaCl meat emulsion systems. Cooking loss and emulsion stability, hardness, springiness, and cohesiveness for reduced-fat / low-NaCl meat emulsion systems with 20% pork back fat and 1.2% sodium chloride samples with incorporation of phosphate and sea mustard were similar to the control with 30% pork back fat and 1.5% sodium chloride. Results showed that reduced-fat / low-NaCl meat emulsion system samples containing phosphate and sea mustard had higher apparent viscosity. The results of this study show that the incorporation of phosphate and sea mustard in the formulation will successfully reduce fat and salt in the final meat products. PMID- 26761875 TI - Quality Characteristics of PSE-Like Turkey Pectoralis major Muscles Generated by High Post-Mortem Temperature in a Local Turkish Slaughterhouse. AB - The objective of this study was to investigate the effects of high post-mortem temperature application on development of pale, soft, exudative (PSE) turkey meat characteristics in terms of local slaughter conditions. Within this scope, it was targeted to obtain PSE-like muscles benefiting from different post-mortem temperature applications. Immediately after slaughter, turkey Pectoralis major (n=15) muscles were kept at various post-mortem temperatures (0, 10, 20, 30, and 40C) for 5 h. pH values of 40C treatment were lower than four other treatments (p<0.05). L* values, drip loss, cook loss, and thawing loss of 40C group were higher than the other groups (p< 0.05). Napole yield of 40C treatment indicated that high post-mortem temperature decreases brine uptake. Protein solubility of 40C group was lower than 0C group (p<0.05). Expressible moisture did not differ between 0 and 40C treatments. Hardness, gumminess and chewiness of 40C treatment were higher than 0C treatment. The results of this research showed that high post mortem temperature treatment induced development of PSE-like turkey meat, with lower pH, paler color, higher technological and storage losses, and reduced protein solubility and texture. PMID- 26761876 TI - Tenderization of Bovine Longissimus Dorsi Muscle using Aqueous Extract from Sarcodon aspratus. AB - The aim of this study was to investigate the effects of aqueous extract from Sarcodon aspratus on tenderization of the bovine longissimus dorsi muscles in comparison with commercial proteolytic enzymes. Furthermore, meat quality and muscle protein degradation were examined. We marinated meat with 2% Sarcodon aspratus extract, 2% kiwi extract, and 0.2% papain. Beef chunks (3*3*3 cm(3)) were marinated with distilled water (control), Sarcodon aspratus extract (T1), kiwi extract (T2) or papain (T3) for 48 h at 4C. There were no significant differences in muscle pH and lightness between control and treated samples. T1 had the lowest redness (p<0.01), and higher cooking loss and water holding capacity than control and T2 (p<0.05). T1 and T3 exhibited lower shear force values than control (p<0.05). Total protein solubility did not differ significantly between T1 and control, but T1 had less myofibrillar protein solubility than control and T2 (p<0.001). The degradation of myosin heavy chain in T1 and T3 was observed. This degradation of myofibrillar protein suggests that Sarcodon aspratus extract could influence tenderization. These results show that aqueous extract of Sarcodon aspratus extract actively affect the tenderness of the bovine longissimus dorsi muscle. PMID- 26761877 TI - Screening of Immune-Active Lactic Acid Bacteria. AB - The purpose of this study was to investigate the effect of lactic acid bacteria (LAB) cell wall extract on the proliferation and cytokine production of immune cells to select suitable probiotics for space food. Ten strains of LAB (Lactobacillus bulgaricus, L. paracasei, L. casei, L. acidophilus, L. plantarum, L. delbruekii, Lactococcus lactis, Streptococcus thermophilus, Bifidobacterium breve, and Pedicoccus pentosaceus) were sub-cultured and further cultured for 3 d to reach 7-10 Log colony-forming units (CFU)/mL prior to cell wall extractions. All LAB cell wall extracts failed to inhibit the proliferation of BALB/c mouse splenocytes or mesenteric lymphocytes. Most LAB cell wall extracts except those of L. plantarum and L. delbrueckii induced the proliferation of both immune cells at tested concentrations. In addition, the production of TH1 cytokine (IFN-gamma) rather than that of TH2 cytokine (IL-4) was enhanced by LAB cell wall extracts. Of ten LAB extracts, four (from L. acidophilus, L. bulgaricus, L. casei, and S. thermophiles) promoted both cell proliferating and TH1 cytokine production. These results suggested that these LAB could be used as probiotics to maintain immunity and homeostasis for astronauts in extreme space environment and for general people in normal life. PMID- 26761878 TI - Characterization of Selected Lactobacillus Strains for Use as Probiotics. AB - The aim of this study was to evaluate the functional properties of lactic acid bacteria from various sources and to identify strains for use as probiotics. Ten Lactobacillus strains were selected and their properties such as bile tolerance, acid resistance, cholesterol assimilation activity, and adherence to HT-29 cells were assessed to determine their potential as probiotics. Lactobacillus sp. JNU 8829, L. casei MB3, L. sakei MA9, L. sakei CH8, and L. acidophilus M23 were found to show full tolerance to the 0.3% bile acid. All strains without L. acidophilus M23 were the most acid-tolerant strains. After incubating the strains at pH 2.5 for 2 h, their viability decreased by 3 Log cells. Some strains survived at pH 2.5 in the presence of pepsin and 0.3% bile acid. Lactobacillus sp. JNU 8829, L. acidophilus KU41, L. acidophilus M23, L. fermentum NS2, L. plantarum M13, and L. plantarum NS3 were found to reduce cholesterol levels by >50% in vitro. In the adhesion assay, Lactobacillus sp. JNU 8829, L. casei MB3, L. sakei MA9, and L. sakei CH8 showed higher adhesion activities after 2 h of co-incubation with the intestinal cells. The results of this comprehensive analysis shows that this new probiotic strain named, Lactobacillus sp. JNU 8829 could be a promising candidate for dairy products. PMID- 26761879 TI - Effect of Soy Protein Hydrolysates Prepared by Subcritical Water Processing on the Physicochemical Properties of Pork Patty during Chilled Storage. AB - The present study was carried out to investigate the effects of soy protein hydrolysates (SPHs) addition on the quality characteristics of pork patties. The SPHs was prepared by subcritical water process (SWP) at 180C without holding time and mixed with the pork patty components at varying concentrations (0-3%), and the patties were stored at 4C for 14 d. As quality parameters, instrumental color, thiobarbituric acid-reactive substances (TBARS), pH, water holding capacity (WHC) and shear force were measured at the end of storage. Regardless of SPHs concentration, the addition of SPHs significantly manifested low L* and high a* values compared to those of untreated control (p<0.05). For b* value, addition of SPHs in the 0.5-1.5% was unaffected, while >2.0% of SPHs caused significantly lower b* than control (p<0.05). The color changes in pork patties with and without SPHs were also identified in visual appearance where the pork patties containing 0.5-2.0% showed bright red color which was comparable to brownish color of control and patties containing >2.5% SPHs. Lipid oxidation was delayed by the addition of 0.5-1.5% SPHs, while it was accelerated by the addition of 3% SPHs. The pH of patties increased with increasing concentration of SPHs, whereas there were no significant differences in WHC and shear force of patties. Consequently, the results indicated that the addition of 0.5-1.5% SPHs had a potential advantage in suppressing oxidative deterioration of fat-containing meat products during chilled storage. PMID- 26761880 TI - Effects of Procyanidin on Meat Quality and Shelf-Life for Preserving Pork Patties during Chilled Storage. AB - Grape seeds and pericarp are rich in procyanidins, a class of natural antioxidants and antimicrobials that can provide phytonutrients for healthy eating and extend food shelf life. The objective of this study was to assess the effect of procyanidins as preservatives in pork meat patties for 14 d. Pork patties were treated with 0, 0.1, or 0.3% procyanidin, and meat color, pH, volatile basic nitrogen (VBN), 2-thiobarbituric acid reactive substance (TBARS) values, and microbial populations were determined during storage at 4C for 14 d. The color of pork patties treated with procyanidin showed lower lightness and higher redness values than untreated controls, and procyanidin treatment reduced pH values significantly (p<0.05). VBN values decreased significantly (p<0.05) with the 0.3% procyanidin treatment and increased significantly (p<0.05) during storage. TBARS values were markedly lower in procyanidin-treated meat than in the untreated control. In addition, procyanidin suppressed total bacterial colony and Escherichia coli counts significantly (p<0.05) relative to the control samples. Our findings suggest that procyanidin could be used as a food preservative in pork patties due to its natural antioxidation and antimicrobial activities, and that it may contribute to an improved healthy diet. PMID- 26761881 TI - Galactooligosaccharide and Sialyllactose Content in Commercial Lactose Powders from Goat and Cow Milk. AB - The most commonly used infant formulas contain lactose originating from cow milk. Goat milk has recently been claimed to be nutritionally more effective for infants than other milks. In baby foods, much emphasis is placed on the concentrations of intestinal microflora-promoting oligosaccharides, which are generally transferred into lactose from milk during crystallization process. Here we show that higher level of free sialic acid is present in goat lactose powder compared to cow lactose powder. Without proteinase K treatment, the amount of 3 sialyllactose and 6-sialyllactose were similar in goat and cow lactose powders. However, after proteolysis, 6-sialyllactose was present at higher levels in goat than in cow lactose powder. Galactooligosaccharides, a group of prebiotics, are present in milk in the form of glycoproteins. Galactooligosaccharide content was also higher in goat lactose powder than in cow lactose powder. PMID- 26761882 TI - A CMOS Amperometric System for Multi-Neurotransmitter Detection. AB - In vivo multi-target and selective concentration monitoring of neurotransmitters can help to unravel the brain chemical complex signaling interplay. This paper presents a dedicated integrated potentiostat transducer circuit and its selective electrode interface. A custom 2-electrode time-based potentiostat circuit was fabricated with 0.13 MUm CMOS technology and provides a wide dynamic input current range of 20 pA to 600 nA with 56 MU W, for a minimum sampling frequency of 1.25 kHz. A multi-working electrode chip is functionalized with carbon nanotubes (CNT)-based chemical coatings that offer high sensitivity and selectivity towards electroactive dopamine and non-electroactive glutamate. The prototype was experimentally tested with different concentrations levels of both neurotransmitter types, and results were similar to measurements with a commercially available potentiostat. This paper validates the functionality of the proposed biosensor, and demonstrates its potential for the selective detection of a large number of neurochemicals. PMID- 26761883 TI - A 9 MHz-2.4 GHz Fully Integrated Transceiver IC for a Microfluidic-CMOS Platform Dedicated to Miniaturized Dielectric Spectroscopy. AB - This paper presents a fully integrated transceiver IC as part of a self sustained, microfluidic-CMOS platform for miniaturized dielectric spectroscopy (DS) from MHz to GHz. Fabricated in AMS 0.35 MUm 2P/4M RF CMOS, the transmitter (TX) part of the IC generates a single-tone sinusoidal signal with frequency tunability in the range of ~ 9 MHz-2.4 GHz to excite a three-dimensional (3D), parallel-plate, capacitive sensor with a floating electrode and 9 MUL microfluidic channel for sample delivery. With a material-under-test (MUT) loaded into the sensor, the receiver (RX) part of the IC employs broadband frequency response analysis (bFRA) methodology to measure the amplitude and phase of the RF excitation signal after transmission through the sensor. A one-time, 6-point sensor calibration algorithm then extracts both the real and imaginary parts of the MUT complex permittivity, epsilonr, from IC measurements of the sensor transmission characteristics in the voltage domain. The "sensor + IC" is fully capable of differentiating among de-ionized (DI) water, phosphate-buffered saline (PBS), and alcoholic beverages in tests conducted at four excitation frequencies of ~ 50 MHz , 500 MHz, 1.5 GHz, and 2.4 GHz generated by the TX. Moreover, permittivity readings of PBS by the sensor interfaced with the IC at six excitation frequencies in the range of ~ 50 MHz-2.4 GHz are in excellent agreement (rms error of 1.7% (real) and 7.2% (imaginary)) with those from bulk solution reference measurements by commercial benchtop equipment. The total power consumption of the IC is with 1.5 V (analog) and 3.3 V (digital) supplies. PMID- 26761884 TI - Effect of Pre-rigor Salting Levels on Physicochemical and Textural Properties of Chicken Breast Muscles. AB - This study was conducted to evaluate the effect of pre-rigor salting level (0-4% NaCl concentration) on physicochemical and textural properties of pre-rigor chicken breast muscles. The pre-rigor chicken breast muscles were de-boned 10 min post-mortem and salted within 25 min post-mortem. An increase in pre-rigor salting level led to the formation of high ultimate pH of chicken breast muscles at post-mortem 24 h. The addition of minimum of 2% NaCl significantly improved water holding capacity, cooking loss, protein solubility, and hardness when compared to the non-salting chicken breast muscle (p<0.05). On the other hand, the increase in pre-rigor salting level caused the inhibition of myofibrillar protein degradation and the acceleration of lipid oxidation. However, the difference in NaCl concentration between 3% and 4% had no great differences in the results of physicochemical and textural properties due to pre-rigor salting effects (p>0.05). Therefore, our study certified the pre-rigor salting effect of chicken breast muscle salted with 2% NaCl when compared to post-rigor muscle salted with equal NaCl concentration, and suggests that the 2% NaCl concentration is minimally required to ensure the definite pre-rigor salting effect on chicken breast muscle. PMID- 26761885 TI - Influence of Citric Acid on the Pink Color and Characteristics of Sous Vide Processed Chicken Breasts During Chill Storage. AB - Chicken breast dipped with citric acid (CA) was treated by sous vide processing and stored in a refrigerated state for 0, 3, 6, 9, and 14 d. A non-dipped control group (CON) and three groups dipped in different concentrations of citric acid concentration were analyzed (0.5%, 0.5CIT; 2.0%, 2CIT and 5.0%, 5CIT; w/v). Cooking yield and moisture content increased due to the citric acid. While the redness of the juice and meat in all groups showed significant increase during storage, the redness of the citric acid groups was reduced compared to the control group (p<0.05). The percentage of myoglobin denaturation (PMD) of the CA groups was also increased according to the level of CA during storage. Total aerobic counts, Enterobacteriaceae counts, volatile basic nitrogen and thiobarbituric acid reactive substances (TBARS) were generally lower in the citric acid-treated samples than in untreated ones, indicating extended shelf life of the cooked chicken breast dipped in citric acid solution. The shear force of the 2CIT and 5CIT groups was significantly lower (p<0.05). The findings indicated positive effects in the physicochemical properties and storage ability of sous vide chicken breast at 2% and 5% citric acid concentrations. PMID- 26761886 TI - Effects of Drying Condition and Binding Agent on the Quality Characteristics of Ground Dried-Pork Meat Products. AB - The purpose of this study was to investigate the influence of processing conditions (temperature and time) and binding agent types (glutinous rice flour, potato starch, bean flour, and acorn flour) on the physicochemical and sensory characteristics of ground dried-pork meat product. For this purpose, ground dried pork meat product was produced by adding several binding agents at different drying temperatures and times. The drying time affected moisture content and water activity in all drying temperature. However, under the similar drying conditions, the extent of drying varied depending on the type of binding agents. The results of sensory evaluation for texture degree and overall acceptability indicated the following: overall, higher drying temperatures and longer drying time heightened the degree of texture, and the overall acceptability varied depending on binding agent type. Physicochemical and sensory characteristics were analyzed to determine any possible correlation. The results revealed a high correlation between moisture content, water activity, shear forces, and sensory evaluation (p<0.01). However, there was no correlation with respect to overall acceptability. PMID- 26761887 TI - The Synergic Anti-inflammatory Impact of Gleditsia sinensis Lam. and Lactobacillus brevis KY21 on Intestinal Epithelial Cells in a DSS-induced Colitis Model. AB - We investigated the synergic anti-inflammatory activity of Gleditsia sinensis Lam. (GS) extract and Lactobacillus brevis KY21 both in vitro and in vivo. Western blot analysis and immunostaining showed that AKT phosphorylation that increased by the exposure of LPS were significantly decreased by the presence of either GS extract or L. brevis KY21. In addition, p65 intracellular transport was critically inhibited by GS extract and L. brevis KY21. We further studied these effects using an in vivo dextran sulfate sodium (DSS)-induced mouse model. Body weight, food intake, and clinical scores were dramatically decreased after treatment with DSS, whereas these effects were palliated by the addition of GS extract and L. brevis KY21. Importantly, transcription of genes encoding pro inflammatory cytokines including IL-1beta, TNF-alpha, and IFN-gamma in mesenteric lymph nodes (MLN) and the spleen were increased by DSS treatment, whereas they were inhibited by the presence of GS extract and L. brevis KY21. PMID- 26761888 TI - Application of an Antimicrobial Protein Film in Beef Patties Packaging. AB - This study was performed to apply a protein film containing a natural antimicrobial compound to meat packaging and determine quality change of meat during storage. Proteins obtained from the by-products of food processing have been utilized as biodegradable film sources. Porcine meat and bone meal (MBM) is obtained during meat processing, and proteins from the MBM can be extracted and used as a film base material. Previously, an antimicrobial MBM film containing coriander oil (CO) was prepared and its physical properties and antimicrobial activity were characterized. In this study, the antimicrobial MBM-CO film was applied to beef patties packaging, and the microbial population and the degree of lipid oxidation were determined during storage at 4C for 15 d. The population of inoculated E. coli O157:H7 in the samples wrapped with the MBM-CO film was 6.78 log colony forming unit (CFU)/g after 15 d of storage, whereas the control had 8.05 Log CFU/g, thus reducing the microbial population by 1.29 Log CFU/g. In addition, retardation of lipid oxidation in the patties was observed during storage for the samples packaged by the MBM-CO film, compared with the control samples. These results suggest that the MBM-CO film can be useful for enhancing the quality of beef patties during storage. PMID- 26761889 TI - Probiotic Characteristics of Lactobacillus plantarum FH185 Isolated from Human Feces. AB - Lactobacillus plantarum FH185 was isolated from the feces of healthy adults. In our previous study, L. plantarum FH185 was demonstrated that it has anti-obesity effect in the in vitro and in vivo test. In order to determine its potential for use as a probiotic, we investigated the physiological characteristics of L. plantarum FH185. The optimum growth temperature of L. plantarum FH185 was 40C. L. plantarum FH185 showed higher sensitivity to novobiocin in a comparison of fifteen different antibiotics and showed higher resistance to polymyxin B and vancomycin. It also showed higher beta-galactosidase and N-acetyl-beta glucosaminidase activities. Moreover, it was comparatively tolerant to bile juice and acid, and inhibited the growths of Salmonella Typhimurium and Staphylococcus aureus with rates of 44.76% and 53.88%, respectively. It also showed high adhesion activity to HT-29 cells compared to L. rhamnosus GG. PMID- 26761890 TI - Effects of Replacing Sucrose with Various Sugar Alcohols on Quality Properties of Semi-dried Jerky. AB - The objective of this study was to investigate the effects of replacing sucrose with sugar alcohols (sorbitol, glycerol and xylitol) on the quality properties of semi-dried jerky. Total 7 treatments of jerkies were prepared as follows: control with sucrose, and treatments with 2.5 and 5.0% of sucrose replaced by each sugar alcohol, respectively. Drying yield, pH, water activity, moisture content, shear force, myofibrillar fragmentation index (MFI), 2-thiobarbituric acid reactive substance (TBARS) value, sugar content, and sensory evaluation were evaluated. Xylitol slightly decreased the pH when compared to the other sugar alcohols (p>0.05). The water activity of the semi-dried jerky was significantly reduced by treatment with glycerol and xylitol (p<0.05). The moisture content of semi-dried jerky containing various sugar alcohols was significantly higher than that of the control (p<0.05), while replacing sucrose with glycerol yielded the highest moisture content. The shear force of semi-dried jerky containing sugar alcohols was not significantly different for the sorbitol and glycerol treatments, but that replacing sucrose with 5.0% xylitol demonstrated the lowest shear force (p<0.05). The TBARS values of semi-dried jerkies with sugar alcohols were lower than the control (p<0.05). The sugar content of the semi-dried jerkies containing sorbitol and glycerol were lower than the control and xylitol treatment (p<0.05). In comparison with the control, the 5.0% xylitol treatment was found to be significantly different in the sensory evaluation (p<0.05). In conclusion, semi dried jerky made by replacement with sugar alcohols improved the quality characteristics, while xylitol has applicability in manufacturing meat products. PMID- 26761891 TI - Effect of High Pressure Homogenization on the Physicochemical Properties of Natural Plant-based Model Emulsion Applicable for Dairy Products. AB - In the dairy industry, natural plant-based powders are widely used to develop flavor and functionality. However, most of these ingredients are water-insoluble; therefore, emulsification is essential. In this study, the efficacy of high pressure homogenization (HPH) on natural plant (chocolate or vanilla)-based model emulsions was investigated. The particle size, electrical conductivity, Brix, pH, and color were analyzed after HPH. HPH significantly decreased the particle size of chocolate-based emulsions as a function of elevated pressures (20-100 MPa). HPH decreased the mean particle size of chocolate-based emulsions from 29.01 MUm to 5.12 MUm, and that of vanilla-based emulsions from 4.18 MUm to 2.44 MUm. Electrical conductivity increased as a function of the elevated pressures after HPH, for both chocolate- and vanilla-based model emulsions. HPH at 100 MPa increased the electrical conductivity of chocolate-based model emulsions from 0.570 S/m to 0.680 S/m, and that of vanilla-based model emulsions from 0.573 S/m to 0.601 S/m. Increased electrical conductivity would be attributed to colloidal phase modification and dispersion of oil globules. Brix of both chocolate- and vanilla-based model emulsions gradually increased as a function of the HPH pressure. Thus, HPH increased the solubility of plant-based powders by decreasing the particle size. This study demonstrated the potential use of HPH for enhancing the emulsification process and stability of the natural plant powders for applications with dairy products. PMID- 26761892 TI - Quality Properties of Sausages Made with Replacement of Pork with Corn Starch, Chicken Breast and Surimi during Refrigerated Storage. AB - This effect of replacing pork with corn starch, chicken breast and surimi on the chemical composition, physical, texture and sensory properties of sausage were investigated during storage. Five treatments of sausage such as; T1 (10:0:0, %), T2 (10:5:0, %), T3 (10:10:5, %), T4 (10:15:10, %) and T5 (10:20:15, %) were prepared with replacement of pork with corn starch, chicken breast and surimi. The sausage made with pork meat served as control (C). The sausage in the control had higher moisture and fat contents, but lower protein content than the treatments (p<0.05). The sausages in the T2 and T5 had decreased pH values after 3 wk storage (p<0.05). The lightness value was lowest in the T3, while the yellowness values were lowest in the T5 during the storage. The TBARS (2 thiobarbituric acid reactive substance) values were lowest in the control in all storage times (p<0.05). However, the sausage in the control had higher VBN (volatile basic nitrogen) value than the treatments during the 1 wk storage (p<0.05). All treatments had significantly higher hardness, cohesiveness, springiness, gumminess and chewiness values (p<0.05) than the control. The results indicated that corn starch, chicken breast and surimi can used as a pork replacer, that it also improves the physicochemical and texture properties of pork sausages. PMID- 26761894 TI - Anti-obesity Effect of Fermented Whey Beverage using Lactic Acid Bacteria in Diet induced Obese Rats. AB - High-protein fermented whey beverage (FWB) was manufactured using whey protein concentrate (WPC) and Lactobacillus plantarum DK211 isolated from kimchi. This study was designed to evaluate the anti-obesity activity of FWB in male rats fed a high-fat diet. Male Sprague-Dawley rats were randomly assigned to three groups (n=8 per group). The three groups differed in their diet; one group received a normal diet (ND), another, a high-fat diet (HD), and the third, a HD plus fermented whey beverage (HDFWB), for 4 wk. Supplementation with FWB (the HDFWB group) prevented weight gain and body fat accumulation. The food intake in the HDWFB group was significantly lower (p<0.05) than that of the HD group. The HDWFB group also showed a significant decrease in organ weights (p<0.05), except for the weight of the testis. There was a significant decrease in total cholesterol, LDL-cholesterol, and triglycerides in the HDFWB group compared with the HD group (p<0.05), but there was no significant difference in serum HDL-cholesterol levels among the experimental groups. Rats ingesting FWB (the HDFWB group) also showed a significant decrease in blood glucose levels, and plasma levels of insulin, leptin, and ghrelin compared to HD group (p<0.05). These results indicate that FWB has beneficial effects on dietary control, weight control, and reduction in fat composition and serum lipid level; consequently, it may provide antiobesity and hypolipidemic activity against high fat diet-induced obesity in rats. PMID- 26761893 TI - Evaluation of Meat Color and Physiochemical Characteristics in Forequarter Muscles of Holstein Steers. AB - The beef forequarter muscle comprises approximately 52% of carcass weight. The objective of this study was to evaluate the physiochemical characteristics and meat color from forequarter muscle of Holstein steers. Fifteen forequarter muscles were trimmed of external connective tissue and fat. An experimental group of eight Holstein steers was assessed using meat color, water-holding capacity, drip loss, and Warner-Bratzler shear force value at the same quality grade. The M. omotransversarius (0.45 kg) had the highest (p<0.05) lightness (L*) value, whereas the M. teres major (0.4 kg) and M. triceps brachii (caput laterale) (0.52 kg) had the lowest (p<0.05) values. The M. semispanitus capitus (1.48 kg), which is a neck muscle, had the highest values for both redness (a*) and yellowness (b*), whereas the lowest (p<0.05) values were for the M. teres major. The M. omotransversarius, M. latissimus dorsi (1.68 kg), and M. rhomboideus (1.2 kg) were ranked high (p<0.05) in water-holding capacity. The drip loss value was the highest for the M. longissimus dorsi thoracis (p<0.05; 1.86 kg), while the M. infraspinatus (2.28 kg), M. supraspinatus (1.38 kg), M. brachiocephalicus (1.01 kg), and M. pectoralis superficialis (1.18 kg) had the lowest (p<0.05). The Warner-Bratzler shear force value indicated that the M. pectoralis profundus (3.39 kg), M. omotransversarius, and M. brachiocephalicus were the toughest (p<0.05), whereas the M. subscapularis (0.86 kg), M. longissimus dorsi thoracis, M. teres major, and M. infraspinatus were the most tender cuts (p<0.05). Here, muscle type explained most of the variability in the forequarter physiochemical characteristics. Thus, our findings suggest that these muscle profile data will allow for more informed decisions when selecting individual muscles to produce value-added products from Holstein steers. PMID- 26761895 TI - Effect of Dietary Processed Sulfur Supplementation on Texture Quality, Color and Mineral Status of Dry-cured Ham. AB - This study was performed to investigate the chemical composition, mineral status, oxidative stability, and texture attributes of dry-cured ham from pigs fed processed sulfur (S, 1 g/kg feed), and from those fed a basal diet (CON), during the period from weaning to slaughter (174 d). Total collagen content and soluble collagen of the S group was significantly higher than that of the control group (p<0.05). The pH of the S group was significantly higher than that of the control group, whereas the S group had a lower expressible drip compared to the control group. The S group also showed the lower lightness compared to the control group (p<0.05). In regard to the mineral status, the S group had significantly lower Fe(2+) and Ca(2+) content than the control group (p<0.05), whereas the proteolysis index of the S group was significantly increased compared to the control group (p<0.05). The feeding of processed sulfur to pigs led to increased oxidative stability, related to lipids and pigments, in the dry-cured ham (p<0.05). Compared to the dry-cured ham from the control group, that from the S group exhibited lower springiness and gumminess; these results suggest that feeding processed sulfur to pigs can improve the quality of the texture and enhance the oxidative stability of dry-cured ham. PMID- 26761897 TI - Quantitative Microbial Risk Assessment for Campylobacter spp. on Ham in Korea. AB - The objective of this study was to evaluate the risk of illness from Campylobacter spp. on ham. To identify the hazards of Campylobacter spp. on ham, the general characteristics and microbial criteria for Campylobacter spp., and campylobacteriosis outbreaks were investigated. In the exposure assessment, the prevalence of Campylobacter spp. on ham was evaluated, and the probabilistic distributions for the temperature of ham surfaces in retail markets and home refrigerators were prepared. In addition, the raw data from the Korea National Health and Nutrition Examination Survey (KNHNES) 2012 were used to estimate the consumption amount and frequency of ham. In the hazard characterization, the Beta Poisson model for Campylobacter spp. infection was used. For risk characterization, a simulation model was developed using the collected data, and the risk of Campylobacter spp. on ham was estimated with @RISK. The Campylobacter spp. cell counts on ham samples were below the detection limit (<0.70 Log CFU/g). The daily consumption of ham was 23.93 g per person, and the consumption frequency was 11.57%. The simulated mean value of the initial contamination level of Campylobacter spp. on ham was -3.95 Log CFU/g, and the mean value of ham for probable risk per person per day was 2.20*10(-12). It is considered that the risk of foodborne illness for Campylobacter spp. was low. Furthermore, these results indicate that the microbial risk assessment of Campylobacter spp. in this study should be useful in providing scientific evidence to set up the criteria of Campylobacter spp.. PMID- 26761896 TI - Occurrence and Antibiotic Susceptibility of Listeria Species in Turkey Meats. AB - The aims of this study were to investigate the occurrence of Listeria species in turkey meats and to check the antimicrobial susceptibility of the isolated strains. Hundred and fifteen raw turkey meat samples were randomly collected from the supermarkets, butchers and restaurants. Strain isolation and identification were made according to the ISO11290-1 method. Antimicrobial susceptibility was determined by the standard disc diffusion method. A total of 47 Listeria spp. were isolated from 115 (40.9%) raw turkey meat samples. The isolates were distributed between L. monocytogenes (25.53%), L. innocua (34.04%), L. grayi (31.91%) and L. welshimeri (8.51%). A total of 55.3 % of Listeria spp. isolates were multi-resistant to at least 3 of the antimicrobial agent tested. The level of multi-resistance was higher in L. monocytogenes strains (66.7%) than in L. innocua (62.5%) and L. grayi (53.3%). Listeria spp. isolates were highly resistant to ampicillin, cephalothin, penicillin, meticillin, oxacillin, and trimethoprime-sulfamethoxazole. The isolates particularly L. monocytogenes are increasingly resistant to one or more antibiotics and may represent a potential risk for public health because these antibiotics are common used in treatment of listeriosis. The correct and controlled use of antibiotics in veterinary medicine is important to the emergence of resistant strains. PMID- 26761898 TI - Identification of Coccoidal Bacteria in Traditional Fermented Milk Products from Mongolia, and the Fermentation Properties of the Predominant Species, Streptococcus thermophilus. AB - The objective of this study was to identify the coccoidal bacteria present in 188 samples of fermented yaks', mares' and cows' milk products collected from 12 different regions in Mongolia. Furthermore, we evaluated the fermentation properties of ten selected isolates of the predominant species, Streptococcus (S.) thermophiles, during the process of milk fermentation and subsequent storage of the resulting yoghurt at 4C. Overall, 159 isolates were obtained from 188 samples using M17 agar. These isolates were presumed to be lactic acid bacteria based on their gram-positive and catalase-negative properties, and were identified to species level using 16S rRNA gene sequence analysis. These coccoid isolates were distributed in four genera and six species: Enterococcus (E.) durans, Enterococcus (E.) faecalis, Lactococcus (Lac.) subsp. lactis, Leuconostoc (Leuc.) lactis, Leuconostoc (Leuc.) mesenteroides. subsp. mesenteroides and S. thermophilus. Among these S. thermophilus was the most common species in most samples. From evaluation of the fermentation characteristics (viable counts, pH, titratable acidity [TA]) of ten selected S. thermophilus isolates we could identify four isolates (IMAU 20246, IMAU20764, IMAU20729 and IMAU20738) that were fast acid producers. IMAU20246 produced the highest concentrations of lactic acid and formic acid. These isolates have potential as starter cultures for yoghurt production. PMID- 26761899 TI - Quantitative Proteogenomics and the Reconstruction of the Metabolic Pathway in Lactobacillus mucosae LM1. AB - Lactobacillus mucosae is a natural resident of the gastrointestinal tract of humans and animals and a potential probiotic bacterium. To understand the global protein expression profile and metabolic features of L. mucosae LM1 in the early stationary phase, the QExactive(TM) Hybrid Quadrupole-Orbitrap Mass Spectrometer was used. Characterization of the intracellular proteome identified 842 proteins, accounting for approximately 35% of the 2,404 protein-coding sequences in the complete genome of L. mucosae LM1. Proteome quantification using QExactive(TM) Orbitrap MS detected 19 highly abundant proteins (> 1.0% of the intracellular proteome), including CysK (cysteine synthase, 5.41%) and EF-Tu (elongation factor Tu, 4.91%), which are involved in cell survival against environmental stresses. Metabolic pathway annotation of LM1 proteome using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database showed that half of the proteins expressed are important for basic metabolic and biosynthetic processes, and the other half might be structurally important or involved in basic cellular processes. In addition, glycogen biosynthesis was activated in the early stationary phase, which is important for energy storage and maintenance. The proteogenomic data presented in this study provide a suitable reference to understand the protein expression pattern of lactobacilli in standard conditions. PMID- 26761900 TI - Color Developing Capacity of Plasma-treated Water as a Source of Nitrite for Meat Curing. AB - The interaction of plasma with liquid generates nitrogen species including nitrite (NO(-) 2). Therefore, the color developing capacity of plasma-treated water (PTW) as a nitrite source for meat curing was investigated in this study. PTW, which is generated by surface dielectric barrier discharge in air, and the increase of plasma treatment time resulted in increase of nitrite concentration in PTW. The PTW used in this study contains 46 ppm nitrite after plasma treatment for 30 min. To evaluate the effect of PTW on the cured meat color, meat batters were prepared under three different conditions (control, non-cured meat batter; PTW, meat batter cured with PTW; Sodium nitrite, meat batter cured with sodium nitrite). The meat batters were vacuum-packaged and cooked in a water-bath at 80C for 30 min. The typical color of cured meat developed in cooked meat batter treated with sodium nitrite or PTW. The lightness (L*) and yellowness (b*) values were similar in all conditions, whereas, the redness (a*) values of cooked meat batter with PTW and sodium nitrite (p<0.05) were significantly higher than the control. These data indicate that PTW can be used as a nitrite source in the curing process of meat without addition of other nitrite sources. PMID- 26761901 TI - Whitening Effect of Watersoluble Royal Jelly from South Korea. AB - Royal jelly has been widely used as a health supplement worldwide. However, royal jelly has been implicated in allergic reactions, and we developed a water-soluble royal jelly (WSRJ) without the allergy inducing protein. In this study, we aimed to identify the anti-melanogenic efficacy of WSRJ. B16F1 melanoma cells were first treated with 10 nM alpha-melanocyte stimulating hormone (alpha-MSH) and then with various doses of WSRJ. In addition, we investigated the mRNA and protein expression of melanogenesis-related genes such as tyrosinase, tyrosinase related protein-1 (TRP-1) and TRP-2 by reverse transcription-polymerase chain reaction and western blotting. WSRJ directly inhibited tyrosinase and cellular tyrosinase activity, which decreased melanin synthesis in alpha-MSH stimulated B16F1 melanoma cells a level comparable to that observed with arbutin. WSRJ decreased the mRNA and protein expressions of tyrosinase, TRP-1, and TRP-2, which was comparable to that observed with arbutin. WSRJ has strong anti-melanogenic activity, which invoice direct inhibition of tyrosinase enzyme activity and suppression of expression of melanogenesis related genes. Results from this study suggests that WSRJ is a potential candidate for the treatment of skin pigmentation. PMID- 26761902 TI - Lower Extremity Lateral Skin Stretch Perception for Haptic Feedback. AB - Tactile feedback in recent decades has allowed humans to receive information through technology beyond traditional visual and auditory senses. Lateral skin stretch has the potential to be a mode of tactile feedback, reliably enabling the perception of directional cues through the use of a single actuator. Experiments were conducted to explore sensitivity to skin stretch on nine locations on the human lower leg. Thirty-two stimuli were presented to subjects, exploring effects of displacement (from 0.2-2.0 mm) and speed (from 0.5-4.0 mm/s) on the perception of left and right directions. Higher accuracy came from stimuli having higher displacements and speeds. Three of the locations: soleus, calcaneal tendon (upper), and fibularis longus (lower) all had a mean accuracy of at least 85 percent and are suitable locations for a skin stretch tactile feedback device. PMID- 26761903 TI - Learning to Predict Sequences of Human Visual Fixations. AB - Most state-of-the-art visual attention models estimate the probability distribution of fixating the eyes in a location of the image, the so-called saliency maps. Yet, these models do not predict the temporal sequence of eye fixations, which may be valuable for better predicting the human eye fixations, as well as for understanding the role of the different cues during visual exploration. In this paper, we present a method for predicting the sequence of human eye fixations, which is learned from the recorded human eye-tracking data. We use least-squares policy iteration (LSPI) to learn a visual exploration policy that mimics the recorded eye-fixation examples. The model uses a different set of parameters for the different stages of visual exploration that capture the importance of the cues during the scanpath. In a series of experiments, we demonstrate the effectiveness of using LSPI for combining multiple cues at different stages of the scanpath. The learned parameters suggest that the low level and high-level cues (semantics) are similarly important at the first eye fixation of the scanpath, and the contribution of high-level cues keeps increasing during the visual exploration. Results show that our approach obtains the state-of-the-art performances on two challenging data sets: 1) OSIE data set and 2) MIT data set. PMID- 26761904 TI - Directional Clustering Through Matrix Factorization. AB - This paper deals with a clustering problem where feature vectors are clustered depending on the angle between feature vectors, that is, feature vectors are grouped together if they point roughly in the same direction. This directional distance measure arises in several applications, including document classification and human brain imaging. Using ideas from the field of constrained low-rank matrix factorization and sparse approximation, a novel approach is presented that differs from classical clustering methods, such as seminonnegative matrix factorization, K -EVD, or k -means clustering, yet combines some aspects of all these. As in nonnegative matrix factorization and K -EVD, the matrix decomposition is iteratively refined to optimize a data fidelity term; however, no positivity constraint is enforced directly nor do we need to explicitly compute eigenvectors. As in k -means and K -EVD, each optimization step is followed by a hard cluster assignment. This leads to an efficient algorithm that is shown here to outperform common competitors in terms of clustering performance and/or computation speed. In addition to a detailed theoretical analysis of some of the algorithm's main properties, the approach is empirically evaluated on a range of toy problems, several standard text clustering data sets, and a high dimensional problem in brain imaging, where functional magnetic resonance imaging data are used to partition the human cerebral cortex into distinct functional regions. PMID- 26761905 TI - Extended Dissipative State Estimation for Markov Jump Neural Networks With Unreliable Links. AB - This paper is concerned with the problem of extended dissipativity-based state estimation for discrete-time Markov jump neural networks (NNs), where the variation of the piecewise time-varying transition probabilities of Markov chain is subject to a set of switching signals satisfying an average dwell-time property. The communication links between the NNs and the estimator are assumed to be imperfect, where the phenomena of signal quantization and data packet dropouts occur simultaneously. The aim of this paper is to contribute with a Markov switching estimator design method, which ensures that the resulting error system is extended stochastically dissipative, in the simultaneous presences of packet dropouts and signal quantization stemmed from unreliable communication links. Sufficient conditions for the solvability of such a problem are established. Based on the derived conditions, an explicit expression of the desired Markov switching estimator is presented. Finally, two illustrated examples are given to show the effectiveness of the proposed design method. PMID- 26761906 TI - Neural Network-Based DOBC for a Class of Nonlinear Systems With Unmatched Disturbances. AB - In this brief, the problem of composite anti-disturbance tracking control for a class of strict-feedback systems with unmatched unknown nonlinear functions and external disturbances is investigated. A disturbance-observer-based control (DOBC) in combination with a neural network scheme and back-stepping method is developed to achieve a composite anti-disturbance controller design that provides guaranteed performance. In the proposed method, a conventional disturbance observer and a radial basis function neural network (RBFNN) are combined into a new disturbance observer to estimate the unmatched disturbances. As compared with conventional DOBC methods, the primary merit of the proposed method is that the unknown nonlinear functions are approximated using the RBFNN technique, and not regarded as part of the disturbances or estimated by a conventional disturbance observer. Hence, the proposed method can obtain higher control accuracy than the conventional DOBC methods. This advantage is validated by simulation studies. PMID- 26761907 TI - Landslide Displacement Prediction With Uncertainty Based on Neural Networks With Random Hidden Weights. AB - In this paper, we propose a new approach to establish a landslide displacement forecasting model based on artificial neural networks (ANNs) with random hidden weights. To quantify the uncertainty associated with the predictions, a framework for probabilistic forecasting of landslide displacement is developed. The aim of this paper is to construct prediction intervals (PIs) instead of deterministic forecasting. A lower-upper bound estimation (LUBE) method is adopted to construct ANN-based PIs, while a new single hidden layer feedforward ANN with random hidden weights for LUBE is proposed. Unlike the original implementation of LUBE, the input weights and hidden biases of the ANN are randomly chosen, and only the output weights need to be adjusted. Combining particle swarm optimization (PSO) and gravitational search algorithm (GSA), a hybrid evolutionary algorithm, PSOGSA, is utilized to optimize the output weights. Furthermore, a new ANN objective function, which combines a modified combinational coverage width-based criterion with one-norm regularization, is proposed. Two benchmark data sets and two real-world landslide data sets are presented to illustrate the capability and merit of our method. Experimental results reveal that the proposed method can construct high-quality PIs. PMID- 26761908 TI - Assessment of Vascular Health With Photoplethysmographic Waveforms From the Fingertip. AB - Although the flow-mediated dilation (FMD) index is considered the most reliable indicator of vascular endothelial function, previous studies have proved that the dilatation index (DI) measured by the highly reproducible air pressure sensing system (APSS) is just as accurate in effectively determining endothelial function. Besides, not only is APSS cheaper than the instrument for FMD ratio measurement, but operation of the former is also simple to facilitate its domestic use. However, APSS had the pitfall of being time consuming because of the large amount of computation involved. This paper attempted to validate a new self-developed endothelial function screening (EFS) device that utilized the photoplethysmography (PPG) system for acquiring PPG waveform signals from the index finger through an infrared sensor and a pressure cuff for applying pressure on ipsilateral upper arm for eliciting reactive hyperemic response to assess vascular health. The mean peak amplitude of the signals during the hyperemic phase was divided by that of the baseline to produce an EFS ratio. About 52 volunteers of age 34.76 +/- 15.23 years without history of cardiovascular diseases were recruited for vascular endothelial function evaluation using the EFS device and the APSS. Bland-Altman analysis showed good consistency between the EFS ratio and DI. Besides, linear regression analysis demonstrated highly significant correlation between the two sets of data (p < 0.001, r2 = 0.6261) In conclusion, this paper, which attempted to validate a self-developed, economical, and time-efficient device that can be operated in a domestic setting, demonstrated that the EFS device yielded consistent results on vascular endothelial function comparable to those acquired through APSS. PMID- 26761909 TI - SMURC: High-Dimension Small-Sample Multivariate Regression With Covariance Estimation. AB - We consider a high-dimension low sample-size multivariate regression problem that accounts for correlation of the response variables. The system is underdetermined as there are more parameters than samples. We show that the maximum likelihood approach with covariance estimation is senseless because the likelihood diverges. We subsequently propose a normalization of the likelihood function that guarantees convergence. We call this method small-sample multivariate regression with covariance (SMURC) estimation. We derive an optimization problem and its convex approximation to compute SMURC. Simulation results show that the proposed algorithm outperforms the regularized likelihood estimator with known covariance matrix and the sparse conditional Gaussian graphical model. We also apply SMURC to the inference of the wing-muscle gene network of the Drosophila melanogaster (fruit fly). PMID- 26761910 TI - The Changing Face of Pediatric Orthopedics. PMID- 26761911 TI - Female Athletes: Unique Challenges Facing Women Warriors. PMID- 26761912 TI - Complete Closing Wedge Osteotomy for Correction of Blount Disease (Tibia Vara): A Technique. AB - Treatment of Blount disease (tibia vara) can be daunting in adolescents because of their obesity. The goals in performing osteotomy for Blount disease are to correct the deformity, restore joint alignment, preserve leg length, and prevent recurrent deformity and other complications, such as neurovascular injury, nonunion, and infection. In this article, we report on our treatment of 9 limbs in 8 patients (age range, 13-17 years) with Blount disease. In each case, we performed an oblique complete closing wedge osteotomy of the tibia fixed with a compression plate with oblique screw and a fibular osteotomy. Mean body mass index was 38. In 2 patients, an external fixator (instead of a cast) was used after surgery to increase stability. Mean correction was 26 degrees . The cast was removed at 6 weeks. A hinged knee brace was worn for another 6 weeks. Return to normal activities was allowed after 4 months. The described method, using a closing wedge tibial osteotomy and an oblique fibular osteotomy, is practical and safe and has reproducible results. PMID- 26761913 TI - Compartment Syndrome in Children: Diagnosis and Management. AB - Compartment syndrome (CS) can present differently in children than in adults. Increased need for analgesics is the first sign of evolving CS in children. Children with supracondylar humeral fractures, floating elbow injuries, operatively treated forearm fractures, and tibial fractures are at high risk for CS. Elbow flexion beyond 90 degrees in supracondylar humeral fractures and closed treatment of forearm fractures in floating elbow injuries are associated with increased risk for CS. Prompt diagnosis and treatment with fasciotomy in children result in excellent long-term outcomes. PMID- 26761914 TI - Pigmented Villonodular Synovitis of the Hip: A Systematic Review. AB - Pigmented villonodular synovitis is a rare proliferative condition of the synovium that affects large joints. The primary treatment options are synovectomy and a combination of synovectomy and arthroplasty. We performed a systematic review of the literature, excluding all nonclinical and review articles with follow-up of less than 2 years. Primary outcomes reported were disease recurrence, symptom progression, and revision surgery. Student t tests were used to compare outcomes after synovectomy with outcomes after synovectomy combined with arthroplasty. Twenty-one studies (82 patients) were included. All represented level IV or V evidence. Fifty-one patients (59.3%) were female. Mean (SD) age was 33.2 (12.6) years. Synovectomy alone was performed in 45 patients (54.9%), and synovectomy with arthroplasty was performed in 37 patients (45.1%). Mean (SD) follow-up was 8.4 (5.9) years. The groups' revision rates were not significantly different (26.2% vs 24.3%; P = .17). Mean (SD) time to revision was significantly (P = .02) longer in the synovectomy-with-arthroplasty group, 11.8 (4.5) years, than in the synovectomy-only group, 6.5 (3.9) years. Study results showed revisions are common after surgery for hip pigmented villonodular synovitis, affecting 1 in 4 patients regardless of which surgery they have-either synovectomy alone or synovectomy combined with arthroplasty. Revision is required sooner in synovectomy-only patients than in patients who also undergo arthroplasty. PMID- 26761915 TI - Radiofrequency Microtenotomy for Elbow Epicondylitis: Midterm Results. AB - We conducted a prospective, nonrandomized, single-center clinical study to evaluate the safety and midterm effectiveness of microtenotomy using a radiofrequency probe to treat chronic tendinosis of the elbow. All patients had failed conservative treatment for 6 months. The radiofrequency-based microtenotomy was performed using the Topaz Microdebrider (ArthroCare). Patients were followed annually for up to 9 years postoperatively. Pain status was documented using a visual analog scale self-reported measure. Eighty consecutive patients with tendinosis of the elbow were enrolled; 69 patients were treated for lateral epicondylitis and 11 for medial epicondylitis. The duration of follow-up ranged from 6 months to 9 years (mean, 2.5 years). Ninety-one percent of the patients reported a successful outcome. Within the lateral epicondylitis group, the preoperative visual analog scale improved from 6.9 to 1.3 postoperatively and demonstrated an 81% improvement (P <= .01). For the medial epicondylitis patients, the preoperative visual analog scale improved from 6.1 to 1.3 after surgery, a 79% improvement (P <= .01). No complications were reported. Radiofrequency-based microtenotomy is a safe and effective procedure for elbow epicondylitis. The results are durable with successful outcomes observed at 9 years after surgery. PMID- 26761916 TI - Concomitant Ulnar Styloid Fracture and Distal Radius Fracture Portend Poorer Outcome. AB - The literature on the effect of ulnar styloid fractures (USFs) on concomitant distal radius fractures (DRFs) is mixed. We conducted a study to determine if associated ipsilateral USFs affect outcomes of DRFs. We retrospectively evaluated 315 DRFs treated (184 operatively, 131 nonoperatively) over a 7-year period. Concomitant USFs were identified. Mean follow-up was 12 months. Disabilities of the Arm, Shoulder, and Hand (DASH) and 36-Item Short Form Health Survey (SF-36) outcome scores, and grip strength and wrist range of motion data, were collected. Statistical analysis was performed with Student t test and analysis of variance. Incidence of concomitant USF and DRF was higher (P < .0002) in the operative group (64.6%) than in the nonoperative group (39.1%). Patients with USFs had worse mean (SD) pain score, 1.80 (2.43) versus 0.80 (1.55) (P = .0001), DASH score, 17.03 (18.94) versus 9.21 (14.06) (P = .001), and SF-36 score, 77.16 (17.69) versus 82.68 (16.10) (P = .022). In the operative group, patients with USFs had more pain and poorer DASH Functional scores than patients without USFs. Results were similar in the nonoperative group. There was no difference in healing time between intra-articular and extra-articular fractures or between presence and absence of USFs. Concomitant occurrence of USFs and DRFs-which is associated with worse pain scores and lower functioning compared with USFs without DRFs-should prompt clinicians to counsel patients about delayed recovery. PMID- 26761917 TI - Giant Bone Island of the Tibia in a Child. AB - Giant bone islands have been previously diagnosed only in adults. A symptomatic giant bone island of the tibial diaphysis in a 10-year-old boy is presented in this case report. Imaging investigation included plain radiographs, scintigraphy, computed tomography, and magnetic resonance imaging. Although the findings suggested a giant bone island, the appearance of several atypical imaging features necessitated an open biopsy. Histology confirmed the diagnosis of a giant bone island. Its length, which exceeded 10.8 cm, is the longest reported in the literature. No additional surgical intervention was required. The clinical symptoms and signs, as well as the radiographic appearance of the lesion, were not changed after 15-year follow-up. PMID- 26761918 TI - Isolated Brachialis Muscle Atrophy. AB - solated brachialis muscle atrophy, a rare entity with few reported cases in the literature, is explained by a variety of etiologies. We present a case of unilateral, isolated brachialis muscle atrophy that likely resulted from neuralgic amyotrophy. PMID- 26761919 TI - Patient-Directed Valgus Stress Radiograph of the Knee: A New and Novel Technique. AB - The radiographic investigation of patients with medial-compartment osteoarthritis of the knee is a critical element in the decision-making process of determining whether the patient is a candidate for unicompartmental or total knee arthroplasty. A valgus stress radiograph of the affected knee is an essential part of this radiographic investigation. Historically, this has been performed with manual stress applied by the surgeon or the radiologic technologist; thus, this examination requires 2 individuals to complete. In addition to being inefficient, 1 individual is exposed to radiation, which can be undesirable over many exposures and in a long career. For these reasons, we instituted a quality improvement project to develop a method of obtaining the valgus stress view with 1 technologist that would obviate these concerns. Of 78 examinations performed, 5 studies did not show complete correction of the varus deformity. Of these, 3 showed complete correction on a manual valgus stress radiograph, and 2 did not. Three patients displayed collapse of the lateral compartment, indicating a nonfunctional lateral compartment. The remaining 70 patients had identical radiographic results with both the manual and patient-directed valgus stress. PMID- 26761920 TI - A Bariatric Surgery Primer for Orthopedic Surgeons. AB - Increasing numbers of patients who have undergone bariatric surgery are now presenting to orthopedic surgeons for elective arthroplasties. In addition, orthopedic surgeons themselves are referring more patients for consideration of bariatric surgery in anticipation of future elective procedures. Although the full effects of bariatric surgery on metabolism are not yet known, the altered digestion associated with these surgeries poses several issues for orthopedic surgeons. In this article, we address 3 aspects of care of this class of patient: review of the most commonly performed procedures and their metabolic consequences; suggested preoperative assessment of bariatric patients for any conditions that should be corrected before surgery; and evaluation of outcomes of elective procedures performed after bariatric surgery. Awareness of the unique characteristics of this group of patients helps minimize the potential for complications of planned orthopedic surgeries. PMID- 26761922 TI - Web Page Content and Quality Assessed for Shoulder Replacement. AB - The Internet has become a major source for obtaining health-related information. This study assesses and compares the quality of information available online for shoulder replacement using medical (total shoulder arthroplasty [TSA]) and nontechnical (shoulder replacement [SR]) terminology. Three evaluators reviewed 90 websites for each search term across 3 search engines (Google, Yahoo, and Bing). Websites were grouped into categories, identified as commercial or noncommercial, and evaluated with the DISCERN questionnaire. Total shoulder arthroplasty provided 53 unique sites compared to 38 websites for SR. Of the 53 TSA websites, 30% were health professional-oriented websites versus 18% of SR websites. Shoulder replacement websites provided more patient-oriented information at 48%, versus 45% of TSA websites. In total, SR websites provided 47% (42/90) noncommercial websites, with the highest number seen in Yahoo, compared with TSA at 37% (33/90), with Google providing 13 of the 33 websites (39%). Using the nonmedical terminology with Yahoo's search engine returned the most noncommercial and patient-oriented websites. However, the quality of information found online was highly variable, with most websites being unreliable and incomplete, regardless of search term. PMID- 26761921 TI - Incidence, Risk Factors, and Outcome Trends of Acute Kidney Injury in Elective Total Hip and Knee Arthroplasty. AB - Over the past decade, there has been a marked increase in the number of primary and revision total hip and knee arthroplasties performed in the United States. Acute kidney injury (AKI) is a common complication of these procedures; however, little is known about its epidemiology in the elective arthroplasty population. We conducted a study to determine the incidence, risk factors, and outcomes of AKI after elective joint arthroplasty. Drawing on the Nationwide Inpatient Sample database, we found that the proportion of hospitalizations complicated by AKI increased rapidly from 0.5% in 2002 to 1.8% to 1.9% in 2012. Multivariate analysis revealed that the key risk factors for AKI were chronic kidney disease and the postoperative events of sepsis, acute myocardial infarction, and blood transfusion. Moreover, codiagnosis with chronic kidney disease increased the risk for AKI associated with all 3 postoperative events. After adjusting for confounders, we found an association between AKI and a significantly increased risk for in-hospital mortality and discharge to long-term facilities. AKI serves as an important quality indicator in elective hip and knee surgeries. With elective arthroplasties expected to rise, carefully planned approach to interdisciplinary perioperative care is essential to reduce both the risk and consequences of AKI. PMID- 26761923 TI - Phenotype HNPP (Hereditary Neuropathy With Liability to Pressure Palsies) Induced by Medical Procedures. AB - The phenotype HNPP (hereditary neuropathy with liability to pressure palsies) is caused by heterozygous deletion of the PMP22 gene. HNPP is clinically characterized by asymmetric focal sensory loss and muscle weakness. Reports of HNPP have been rare. In this article, we report the case of an asymptomatic woman with the HNPP mutation. After undergoing total knee arthroplasty, she developed a footdrop with prolonged recovery. We concluded (a) that the HNPP mutation may carry a high risk for certain surgical procedures not expected to cause neurologic deficits in normal patients and (b) that humans with the HNPP mutation can be asymptomatic. Lack of symptoms can contribute to underrecognition of the disease. PMID- 26761924 TI - Pure Intrathoracic Scapular Dislocation. AB - Scapular dislocation, also known as locked scapula or scapulothoracic dislocation, is a rare entity that can be identified as extrathoracic or intrathoracic dislocation, depending on the penetration of the scapula into the thoracic cavity. The 3 reported cases of intrathoracic scapular dislocations in the literature are associated with a preexisting condition, such as sternoclavicular separation, prior rib fracture, thoracotomy for a lung transplant procedure, or surgical resection of superior ribs during breast or pulmonary tumor excisions. There are also 3 published cases of intrathoracic scapular impaction, involving comminuted scapular fractures with intrathoracic impaction of the inferior fragment through intercostal space. We report an intrathoracic scapular dislocation that was not associated with fracture of the scapula or predisposing factors. To our knowledge, this is the first case of pure intrathoracic dislocation. PMID- 26761925 TI - Combined Tibial Tubercle Avulsion Fracture and Patellar Avulsion Fracture: An Unusual Variant in an Adolescent Patient. AB - Traumatic extensor dysfunction of the knee in children is a rare injury, with the majority resulting from tibial tubercle avulsion fracture or patellar sleeve fracture. We report a rare case of combined patellar avulsion fracture and tibial tubercle fracture. With open anatomic reduction, both injuries were successfully treated. While many variations of tibial tubercle fracture have been reported, the authors believe this to be the first report in the English-language literature of this particular combined injury to the knee extensor mechanism in an adolescent. Advanced imaging with computed tomography provided vital information to aid with operative planning, especially since the majority of the unossified tubercle was not seen on plain radiographs, and all fracture fragments were originally believed to be from the tibial tubercle. Computed tomography distinguished the patellar fracture from the tibial tubercle fragments, verifying preoperatively the complexity of the injury. PMID- 26761926 TI - Definitive Fixation of Hand and Wrist Fractures in the Emergency Department. PMID- 26761927 TI - Reconstructive Shelf Arthroplasty as a Salvage Procedure for Complex Fifth Tarsometatarsal Joint Complex Injuries: A Case Review and Discussion. AB - High-energy cuboid fractures are rare injuries that are commonly associated with other midfoot trauma. With displacement, operative intervention is critical to restore articular congruity and the length of the lateral column. Failure to achieve this predisposes patients to posttraumatic arthritis and deformity, often necessitating secondary procedures. Although primary open reduction and internal fixation is the standard of care for these injuries, at times the traditional principles of fracture fixation cannot be applied to cuboid fractures. We describe the case of a 45-year-old woman who underwent a reconstructive shelf arthroplasty of the cuboid and fifth tarsometatarsal joint for a severe injury to the lateral column of the midfoot. PMID- 26761928 TI - Analysis of Direct Costs of Outpatient Arthroscopic Rotator Cuff Repair. AB - Arthroscopic rotator cuff surgery is one of the most commonly performed orthopedic surgical procedures. We conducted a study to calculate the direct cost of arthroscopic repair of rotator cuff tears confirmed by magnetic resonance imaging. Twenty-eight shoulders in 26 patients (mean age, 54.5 years) underwent primary rotator cuff repair by a single fellowship-trained arthroscopic surgeon in the outpatient surgery center of a major academic medical center. All patients had interscalene blocks placed while in the preoperative holding area. Direct costs of this cycle of care were calculated using the time-driven activity-based costing algorithm. Mean time in operating room was 148 minutes; mean time in recovery was 105 minutes. Calculated surgical cost for this process cycle was $5904.21. Among material costs, suture anchor costs were the main cost driver. Preoperative bloodwork was obtained in 23 cases, adding a mean cost of $111.04. Our findings provide important preliminary information regarding the direct economic costs of rotator cuff surgery and may be useful to hospitals and surgery centers negotiating procedural reimbursement for the increased cost of repairing complex tears. PMID- 26761930 TI - Inside out or outside in: does atopic dermatitis disrupt barrier function or does disruption of barrier function trigger atopic dermatitis? PMID- 26761931 TI - Documentation for Mohs surgery. PMID- 26761929 TI - Effects of Thyroid Autoimmunity on Early Atherosclerosis in Euthyroid Girls with Hashimoto's Thyroiditis. AB - OBJECTIVE: In the current study, we aimed to investigate whether thyroid autoimmunity (TA) had any effect on carotid intima-media thickness (cIMT) and enhanced the risk of cardiovascular disease (CVD) independent of thyroid function (TF) in pubertal girls with Hashimoto's thyroiditis (HT). METHODS: Sixty-six newly diagnosed euthyroid girls with HT with a mean age of 14.4+/-2.4 years were included in the study. The control group consisted of 41 age- and body mass index (BMI)-matched healthy girls. At enrollment, all subjects underwent physical examination including blood pressure, standing height, weight, waist circumference (WC), and hip circumference measurements. The lipid profile, high sensitivity C-reactive protein (hs-CRP), homocysteine, blood glucose, insulin, TF, and thyroid antibodies were measured, and thyroid ultrasound and cIMT were performed. RESULTS: There were no significant differences in anthropometric variables between the two groups, but the patients with HT had significantly higher waist-to-hip ratio (WHR). Thyroid hormones, insulin, homocysteine, and homeostatic model assessment-insulin resistance were not different between the two groups. Serum hs-CRP levels were significantly higher in patients than controls (3.4 ng/mL vs. 2.03 ng/mL), (p<0.001). Patients were also characterized by significantly higher total cholesterol (166.4+/-27 mg/dL vs. 151+/-22 mg/dL), (p<0.01) and low-density cholesterol (95.8+/-24.4 mg/dL vs. 82.6+/-20.7 mg/dL), (p<0.01) levels. Patients, regardless of TF, had significantly increased cIMT compared with controls [0.28 mm vs. 0.25 mm, (p<0.001)], and cIMT was correlated with weight-standard deviation score (SDS), BMI-SDS, WC-SDS, and WHR. This increase in cIMT was associated independently with BMI-SDS and hs-CRP levels. CONCLUSION: TA may be related to chronic inflammation, which may cause endothelial dysfunction, a promoter of atherosclerosis in girls with HT. cIMT is a good tool for the early detection and the monitoring of early atherosclerosis in euthyroid patients with HT. Early detection of risk factors of CVD, may be helpful for planning treatment and interventions, so as to prevent complications from the disease in adulthood. PMID- 26761932 TI - Status report from the American Acne & Rosacea Society on medical management of acne in adult women, part 3: oral therapies. AB - Parts 1 and 2 of this 3-part series provided an overview of the epidemiology, visible patterns, and important considerations for clinical and laboratory evaluation of acne vulgaris (AV) in adult women and reviewed the role of proper skin care and topical therapies in this patient population. In Part 3, oral therapies including combination oral contraceptives, spironolactone, antibiotics, and isotretinoin are discussed along with important considerations that clinicians should keep in mind when selecting oral agents for management of AV in adult women. PMID- 26761934 TI - A review of patient adherence to topical therapies for treatment of atopic dermatitis. AB - Atopic dermatitis (AD) is one of the most commonly diagnosed dermatologic conditions in the United States. Topical agents are the mainstay of treatment for AD, and when used correctly, these therapies generally are straightforward and efficacious. However, poor adherence to treatment can prevent patients from achieving disease control. This article provides a review of the literature on patient adherence to topical therapies for AD as well as a discussion of methods to improve patient adherence to treatment in the clinical setting. PMID- 26761933 TI - Acquired port-wine stain with superimposed eczema following penetrating abdominal trauma. AB - Port-wine stains (PWSs), or capillary malformations, are common congenital lesions, but acquired lesions rarely present in the setting of trauma. We present the case of an 18-year-old man who developed a PWS and associated localized eczema following penetrating trauma to the left abdomen. The diagnoses were confirmed on biopsy. The patient's eczema improved with topical steroids. Magnetic resonance imaging of PWSs is recommended in order to rule out deeper arteriovenous malformations. More research is needed to elucidate the connection between PWS pathophysiology and the development of eczema. PMID- 26761935 TI - What is your diagnosis? Herpes zoster. PMID- 26761936 TI - Cutaneous leishmaniasis. PMID- 26761937 TI - Differentiation of latex allergy from irritant contact dermatitis. AB - The term latex allergy refers to a hypersensitivity to products containing natural rubber latex. Individuals with true latex allergy have developed type I (immediate) hypersensitivity due to previous sensitization and production of immunoglobulin E antibodies. Other forms of adverse reactions to latex-containing products may develop, including irritant contact dermatitis and type IV (delayed) hypersensitivity reactions, although they do not indicate true latex allergy. Several diagnostic tests are available to differentiate true latex allergy from irritant contact dermatitis and allergic contact dermatitis. It is crucial to determine the type of hypersensitivity in patients labeled with "latex allergy" in order to establish the most effective treatment regimen. PMID- 26761938 TI - Scaly plaque with pustules and anonychia on the middle finger. PMID- 26761939 TI - Resident guide to advocacy in dermatology. AB - Many opportunities exist for residents to get involved in advocacy in dermatology, from national to grassroots levels. Residents also should be aware of opportunities to get involved in patient advocacy and become familiar with the myriad of patient advocacy groups that exist. These groups offer support and education for patients and initiate research efforts for specific dermatologic conditions that provide support for patients beyond what can be offered during a standard office visit. The value of resident involvement in advocacy also is discussed. PMID- 26761940 TI - Recalcitrant Hailey-Hailey disease responds to oral tacrolimus and botulinum toxin type A. PMID- 26761941 TI - Purpura fulminans in the setting of Escherichia coli septicemia. PMID- 26761942 TI - Erythematous scaly papules on the shins and calves. PMID- 26761943 TI - Histologic correlation of dermoscopy findings in a sebaceous nevus. PMID- 26761944 TI - Assessment of Anti-Mullerian Hormone Level in Management of Adolescents with Polycystic Ovary Syndrome. AB - OBJECTIVE: This study was oriented to investigate the benefit of anti-Mullerian hormone (AMH) level in the management of polycystic ovary syndrome (PCOS). To assess the impact of metformin and oral contraceptives (OC) on serum AMH levels in a cohort of adolescents with PCOS. METHODS: Forty-nine adolescents with PCOS were recruited to the study. Twenty-nine patients without insulin resistance were treated with OC (group 1), and 20 patients with insulin resistance were treated with metformin and OC (group 2). AMH and androgen levels were measured prior to and 6 months after the initiation of treatment. RESULTS: AMH levels were significantly decreased with treatment in both group 1 (p=0.006) and group 2 (p=0.0048). There was a significant correlation between pre- and post-treatment AMH and left ovarian volume (pretreatment: rho=0.336, p=0.018; post-treatment: rho=0.310, p=0.034). CONCLUSION: This study investigated two different treatment regimens in adolescents with PCOS and revealed that AMH levels decreased with treatment. AMH levels were correlated with ovarian volume. PMID- 26761946 TI - Homozygous Ala65Pro Mutation with V89L Polymorphism in SRD5A2 Deficiency. AB - OBJECTIVE: Deficiency of steroid 5-alpha reductase type 2 (5alphaRD2) is a rare autosomal recessive disorder caused by mutations in the SRD5A2 gene. A defect in the 5-alpha reductase enzyme, which ensures conversion of testosterone into dihydrotestosterone, leads to disorders of sex development. This study presents the clinical and genetic results of patients with 5alphaRD2 deficiency. METHODS: 5alphaRD2 deficiency was detected in 6 different patients from 3 unrelated families. All patients were reared as girls. Two of the patients presented with primary amenorrhea, one with primary amenorrhea and rejection of female gender, and the others with masses in their inguinal canals. Chromosome and sex determining region Y (SRY) gene analyses were performed in all patients. Additionally, five exons of the SRD5A2 gene were amplified with polymerase chain reaction in the obtained DNA samples and evaluated. RESULTS: While 46,XY was identified in 5 patients, 47,XXY was detected in one patient. The SRY gene was positive in all patients. The p.Ala65Pro (c193G>C) mutation and V89L polymorphism were observed in exon 1 of the SRD5A2 gene in all patients. CONCLUSION: Identification of this mutation and polymorphism is a significant indicator of presence of 5alphaRD2 deficiency in Southeastern Turkey, a geographical region where consanguineous marriages are also highly common. PMID- 26761945 TI - A Newly-Discovered Mutation in the RFX6 Gene of the Rare Mitchell-Riley Syndrome. AB - Mitchell-Riley syndrome is a genetic disorder characterized by neonatal diabetes, pancreatic hypoplasia, intestinal atresia and/or malrotation, biliary atresia, and gallbladder aplasia or hypoplasia. It was considered a variant of the Martinez-Frias syndrome with similar phenotypic characteristics, except for neonatal diabetes and tracheoesophageal fistula. However, the genetic mutation in (regulatory factor X on chromosome 6) RFX6 was only detected in babies who had diabetes, making it different from the previously known mutations for the disease. This is the first reported case of a classical Mitchell-Riley syndrome in the Arab peninsula along with additional features and novel mutations in the RFX6 gene. PMID- 26761947 TI - A Novel Mutation in Thyroid Peroxidase Gene Causing Congenital Goitrous Hypothyroidism in a German-Thai Patient. AB - Thyroid dyshormonogenesis is responsible for 10-15% of all cases of congenital hypothyroidism and is usually inherited. We report a 26-year-old German-Thai male with congenital hypothyroidism caused by a compound heterozygous mutation in the thyroid peroxidase (TPO) gene. He was diagnosed with congenital goitrous hypothyroidism at 4 months of age and had been treated with levothyroxine replacement therapy. His goiter size had increased due to poor compliance to treatment. Ultrasonography of the thyroid gland showed a pattern suspicious for malignancy. The patient later underwent near-total thyroidectomy. Pathologic examination results were consistent with a multinodular goiter and no malignancy. Genetic analyses by direct sequencing of the entire exons and flanking regions of the TPO gene were performed in the index case and family members. The analyses revealed a compound heterozygote of novel TPO mutation of c.1727C>T in exon 10 resulting in amino acid substitution (p.Ala576Val) and c.2268_2269insT in exon 13 causing a frameshift mutation which introduced a stop codon after the insertion site. The latter has been reported in Chinese subjects. However, there is no previous report of c.1727C>T mutation in the literature. We found the allele contained a novel exon 10 mutation inherited from the patient's German mother and an exon 13 mutation from his Thai father. Analysis using two bioinformatic software programs indicated that this variant was likely to cause damage in the resulting protein molecule. The present report emphasizes the importance of regular follow-up and patient compliance to levothyroxine replacement in patients with goitrous congenital hypothyroidism to avoid prolonged stimulation of thyroid tissue by thyroid-stimulating hormone. PMID- 26761948 TI - Thyroid Function and Thyroid Autoimmunity in Relation to Weight Status and Cardiovascular Risk Factors in Children and Adolescents: A Population-Based Study. AB - OBJECTIVE: In obese subjects, slight increases have been observed in thyrotropin [thyroid-stimulating hormone (TSH)] levels, but data in children are scarce. The aim of this study was to evaluate whether thyroid function and autoimmunity vary with weight status in a healthy population of children and adolescents and to determine whether hyperthyrotropinemia is associated with any cardiovascular risk factor. METHODS: This cross-sectional epidemiological study was conducted in Almeria (Spain) on a representative sample of 1317 healthy subjects aged 2-16 years. Thyroid function, thyroid autoimmunity and cardiovascular risk factors were measured. Chi-square test, analysis of variance and multiple linear regression were used in the statistical analyses. RESULTS: The obese children and adolescents had thyrotropin levels (mean +/- standard deviation) of 3.12+/-2.44 mU/L. These levels were higher than those of overweight subjects (2.79+/-1.51 mU/L) and of normal weight subjects (2.73+/-1.30 mU/L) (p=0.02). Levels of free thyroxine and urinary iodine did not differ significantly between the groups. The prevalence (95% confidence interval) of thyroid autoimmunity was lower in the individuals with normal weight (2.9%; 2.0-4.2) than in the overweight (6.3%; 3.9 9.9) and obese subjects (5.6%, 2.5-11.3) (p=0.02). TSH levels were associated with obesity (beta=0.36; p<0.001) and thyroid autoimmunity (beta=1.10; p<0.001). They were not associated with any cardiovascular risk factor. CONCLUSION: Obese children and adolescents had higher levels of thyrotropin than those who were overweight and of normal weight. The differences among the groups were of very little clinical significance and could possibly be linked to the higher prevalence of thyroid autoimmunity in obese subjects. The hyperthyrotropinemia in these subjects was not associated with any cardiovascular risk factor. PMID- 26761951 TI - Fabrication of PDMS Nanocomposite Materials and Nanostructures for Biomedical Nanosystems. AB - Recent applications of PDMS nanocomposite materials and nanostructures have dramatically increased in biomedical fields due to optical, mechanical and electrical properties that are controllable by nanoengineering fabrication processes. These applications include biomedical imaging, biosensing, and cellular bioengineering studies using PDMS engineered structures with nanoparticles, nanopillars and functional nanoporous membranes. This article reviews the recent progress of PDMS nanocomposite materials and nanostructures and provides descriptions of various fabrication techniques. Together with these fabrication techniques, we discuss how these nanocomposite PDMS biomedical devices are revolutionizing biomedical science and engineering fields. PMID- 26761953 TI - Errata: Vol. 64, No. 17. PMID- 26761949 TI - Sex Hormone-Binding Globulin in Children and Adolescents. AB - Sex hormone-binding globulin (SHBG) is a circulating glycoprotein that transports testosterone and other steroids in the blood. Interest in SHBG has escalated in recent years because of its inverse association with obesity and insulin resistance, and because many studies have linked lower circulating levels of SHBG to metabolic syndrome, type 2 diabetes, nonalcoholic fatty liver disease, polycystic ovary syndrome, and early puberty. The purpose of this review is to summarize molecular, clinical, endocrine, and epidemiological findings to illustrate how measurement of plasma SHBG may be useful in clinical medicine in children. PMID- 26761952 TI - Single Cell Mass Measurement Using Drag Force Inside Lab-on-Chip Microfluidics System. AB - Single cell mass (SCM) is an intrinsic property of single cell, it arouses a great interest among scientists as cell mass depends on the synthesis of proteins, DNA replication, cell wall stiffness, cell cytoplasm density, cell growth, ribosome, and other analogous of organisms. To date, several great strides have been taken to the advancements of SCM measurement techniques. Nevertheless, more works are required to enable the technology to push frontier in deep analysis of SCM measurement, hence to elucidate intracellular properties. In this paper, we present a lab-on-chip microfluidics system for SCM measurement, related with the force required to drag a single cell and Newton's law of motion inside microfluidics channel. Drag force on the cell was generated by a pressure driven syringe micropump and the motion of the cell was measured using optical observation under an inverted microscope. This approach of measuring SCM was calibrated using known mass (77.3 pg) of a polystyrene particle of 5.2 MUm diameter. Furthermore, we used Saccharomyces cerevisiae baker's yeast cells of different sizes ([Formula: see text] diameter) for SCM measurement. Mass of 4.4 MUm diameter of single yeast cell was measured as 2.12 pg which is in the range of previously reported single yeast cell mass (2-3 pg). In addition, we also studied the relation between SCM and single cell size. Results showed that single yeast cell mass increases exponentially with the increasing of single cell size. PMID- 26761954 TI - [Radiotherapy of malignant tumors]. PMID- 26761955 TI - Automobile or Other Conveyance and Adaptive Equipment Certificate of Eligibility for Veterans or Members of the Armed Forces With Amyotrophic Lateral Sclerosis Connected to Military Service. Final rule. AB - The Department of Veterans Affairs (VA) published an Interim Final Rule on February 25, 2015, to amend its adjudication regulations to provide a certificate of eligibility for financial assistance in the purchase of an automobile or other conveyance and adaptive equipment for all veterans with service-connected amyotrophic lateral sclerosis (ALS) and servicemembers serving on active duty with ALS. The amendment authorized automatic issuance of a certificate of eligibility for financial assistance in the purchase of an automobile or other conveyance and adaptive equipment to all veterans with service-connected ALS and members of the Armed Forces serving on active duty with ALS. The intent of this final rule is to confirm the amendment made by the interim final rule without change. PMID- 26761956 TI - Increased Transparency and Consumer Protections for 2016 Marketplace Plans. AB - The open enrollment period that ends in December 2015 for coverage begin-ning January 2016 marks the third year of the health care exchanges or marketplaces and of coverage through new qualified health plans. This issue brief investigates several key changes to the qualified health plans, with a focus on increased transparency and consumer protections. A new out-of-pocket costs calculator, requirements regarding provider networks, and prescription drug cost-sharing requirements should serve to better inform and improve consumer selection. In addition, several policy changes will help individuals with more severe health needs. These include: improved prescription drug coverage for HIV/ AIDS and other conditions, allowing prescription drugs that are obtained through the "exceptions" process to count toward the out-of-pocket spending cap, more comprehensive and consistent habilitative coverage, and an individual out-of pocket spending cap within the family out-of-pocket maximum. PMID- 26761957 TI - Consumer Cost-Sharing in Marketplace vs. Employer Health Insurance Plans, 2015. AB - Using data from 49 states and Washington, D.C., we analyzed changes in cost sharing under health plans offered to individuals and families through state and federal exchanges from 2014 to 2015. We examined eight vehicles for cost-sharing, including deductibles, copayments, coinsurance, and out-of-pocket limits, and compared findings with cost-sharing under employer-based insurance. We found cost sharing under marketplace plans remained essentially unchanged from 2014 to 2015. Stable premiums during that period do not reflect greater costs borne by enrollees. Further, 56 percent of enrollees in marketplace plans attained cost sharing reductions in 2015. However, for people without cost-sharing reductions, average copayments, deductibles, and out-of-pocket limits under catastrophic, bronze, and silver plans are considerably higher than under employer-based plans on average, while cost-sharing under gold plans is similar employer-based plans on average. Marketplace plans are far more likely than employer-based plans to require enrollees to meet deductibles before they receive coverage for prescription drugs. PMID- 26761950 TI - Histopathological evaluation of thrombus in patients presenting with stent thrombosis. A multicenter European study: a report of the prevention of late stent thrombosis by an interdisciplinary global European effort consortium. AB - BACKGROUND: Stent thrombosis (ST) is a rare but serious complication following percutaneous coronary intervention. Analysis of thrombus composition from patients undergoing catheter thrombectomy may provide important insights into the pathological processes leading to thrombus formation. We performed a large-scale multicentre study to evaluate thrombus specimens in patients with ST across Europe. METHODS: Patients presenting with ST and undergoing thrombus aspiration were eligible for inclusion. Thrombus collection was performed according to a standardized protocol and specimens were analysed histologically at a core laboratory. Serial tissue cross sections were stained with haematoxylin-eosin (H&E), Carstairs and Luna. Immunohistochemistry was performed to identify leukocyte subsets, prothrombotic neutrophil extracellular traps (NETs), erythrocytes, platelets, and fibrinogen. RESULTS: Overall 253 thrombus specimens were analysed; 79 (31.2%) from patients presenting with early ST, 174 (68.8%) from late ST; 79 (31.2%) were from bare metal stents, 166 (65.6%) from drug eluting stents, 8 (3.2%) were from stents of unknown type. Thrombus specimens displayed heterogeneous morphology with platelet-rich thrombus and fibrin/fibrinogen fragments most abundant; mean platelet coverage was 57% of thrombus area. Leukocyte infiltrations were hallmarks of both early and late ST (early: 2260 +/- 1550 per mm(2) vs. late: 2485 +/- 1778 per mm(2); P = 0.44); neutrophils represented the most prominent subset (early: 1364 +/- 923 per mm(2) vs. late: 1428 +/- 1023 per mm(2); P = 0.81). Leukocyte counts were significantly higher compared with a control group of patients with thrombus aspiration in spontaneous myocardial infarction. Neutrophil extracellular traps were observed in 23% of samples. Eosinophils were present in all stent types, with higher numbers in patients with late ST in sirolimus-and everolimus-eluting stents. CONCLUSION: In a large-scale study of histological thrombus analysis from patients presenting with ST, thrombus specimens displayed heterogeneous morphology. Recruitment of leukocytes, particularly neutrophils, appears to be a hallmark of ST. The presence of NETs supports their pathophysiological relevance. Eosinophil recruitment suggests an allergic component to the process of ST. PMID- 26761958 TI - Challenges of Forecasting Physician Workforce Needs Amid Delivery System Transformation. AB - As population growth and the aging of the overall population increase demand for health care, policymakers and analysts grapple with whether sufficient health care providers, particularly physicians, will be available to meet that demand. Some argue there are too few physicians already; others say our current supply demand problems lie with efficiency. But suppose both are correct? Perhaps the real challenge is to understand how the provision of health care services is changing in response to market forces such as payment changes, patients' expectations, provider distributions, and technology innovations. This issue brief revisits what is known about evolving practice organizations, professional mixes, information technology support, and the implications of these and other factors for physician workforce policies. PMID- 26761961 TI - What I Learned at SAWC Fall 2015. PMID- 26761960 TI - Manual Lymph Drainage in a Patient with Congestive Heart Failure: A Case Study. AB - A variety of conditions result in lower extremity edema, such as deep vein thrombosis, cellulitis, venous stasis insufficiency, and congestive heart failure (CHF). A case study is presented to illustrate the dynamics of the lymphatic system, the pathology of CHF, the importance of obtaining a pretreatment differential diagnosis, and how to implement a safe treatment plan. The patient was a 69-year-old overweight woman with bilateral lower extremity lymphedema of almost equal volume (~9,100 mL) of >2 months' duration. She had 11 draining wounds and a reported history of chronic obstructive pulmonary disease (COPD) but no cardiac dysfunction. Treatment consisted of 6 sessions of manual lymph drainage (MLD), remedial exercises, and compression wrapping and weekly volumetric measurements over a period of 3 weeks. A 4-L decrease in lower extremity edema volume was noted, but fatigue and shortness of breath increased markedly. Treatment was discontinued and the patient was referred back to her physician for cardiac evaluation and treatment. The literature suggests patients, as well as health care professionals, do not always distinguish CHF symptoms from COPD. Proper assessment, monitoring, and lymphedema treatment adjustments are paramount to providing safe care for patients with signs and symptoms of COPD and suspected CHF. More research to elucidate best practice approaches in patients with lymphedema and concurrent CHF/COPD before the start of MLD treatment is warranted. PMID- 26761962 TI - Making An Innovation Stick. PMID- 26761963 TI - Honey-impregnated Dressings for Treating Challenging Dehisced Surgical Wounds. PMID- 26761964 TI - Introduction to Special Issue on "Fluorescence-Based Sensing Technologies". PMID- 26761965 TI - [Assessment of Coronary Plaques in Patients With Acute Coronary Syndrome Without Persistent ST-Segment Elevation]. AB - AIM: to analyze morphological features of atherosclerotic plaques in culprit and non-culprit coronary lesions in patients with non ST-elevation acute coronary syndrome (NSTE-ACS) by multidetector spiral computed tomography (MDCT). RESULTS. In culprit lesions (n = 70) compared to non-culprit lesions (n = 144) frequency of soft plaques (60 vs 43%, p = 0.003), positive remodeling (70.2 vs 54.3%, p = 0.03) and uneven contour (91.7 vs 68.7%, p = 0.0002) were significantly higher. Minimal plaque density was significantly lower and length of plaque was significantly higher in culprit coronary segments (40.1 +/- 25.3 vs 74.1 +/- 116.8 Hounsfield units [HU], p = 0.02 and 16.8 +/- 13.4 vs 13.2 +/- 6.9 mm, p = 0.01, respectively). Receiver-operator characteristic curve analysis identified optimal cutoff value of minimum plaque density and length for discrimination between culprit and non-culprit lesion as 40 HU and 13.5 mm, respectively. The combination of soft plaque with a minimal density < 40 HU and uneven contour occurred in one third of culprit lesions and almost two times less in non-culprit (31.67 and 17.91%, respectively, p = 0.04) and was characterized by high specificity (82.1%) and negative predictive value (72.7%). CONCLUSION: The most specific features of culprit lesions in patients with NSTE-ACS were positive vascular remodeling, length > 13.5 mm, minimal CT-density < 40 HU, soft plaque's type and presence of uneven contour, as well as a combination of the last 3 features. PMID- 26761967 TI - [Evaluation of Anti-Ischemic and Cardioprotective Effects of Nicorandil in Patients With Stable Angina]. AB - The aim of our study was to assess the anti-ischemic and cardiouprotective efficiency of the activator of potassium channels nicorandil in patients with stable angina during long-term intake on the background of standard therapy of coronary heart disease (CHD), including aspirin, rosuvastatin, valsartan and bisoprolol in comparison with standard therapy and long-acting form of nitrates. We compared the dynamics of nitroglycerine consumption, frequency of angina attacks, carried veloergometry, daily monitoring of an electrocardiogram by Holter, echocardiography, assess the state of lipid and carbohydrate metabolism, were determined concentrations of certain markers of systemic inflammation. The results showed that the inclusion of nicorandil into the standard therapy CHD leads to more significant changes in indicators of clinical evaluation of angina pectoris, myocardial remodeling, inflammatory markers. PMID- 26761966 TI - [The State of Hemostasis and Immune System in Patients' With Acute Coronary Syndrome Combined With Anxiety-Depressive Disorder]. AB - Anxiety-depressive disorders (ADD) have a negative impact on the course and prognosis of patients with ischemic heart disease, but the mechanisms of their correlation are not studied enough. The purpose of this study was to elucidate special characteristics of hemostasis and immune system in patients with acute coronary syndrome (ACS) combined with ADD. We included into the study 60 patients during first 24 hours of ACS. ADD was identified in 27 patients (45%). Parameters of plasma and vascular-platelet hemostasis and phenotype of lymphocytes were determined in samples of blood taken during first 24 hours and on day 10 of hospitalization. We found that patients with ACS combined with ADD had procoagulant state of hemostasis, increased platelet aggregation, decreased content of lymphocytes and augmented immunoregulatory induction of inflammatory processes. PMID- 26761968 TI - [Thiotriazoline in the Treatment of Stable Angina Pectoris of II-III Functional Class]. AB - Trimetazidine is a metabolic agent of proven efficacy in improving myocardial ischemia and angina. A comparative international multicenter randomized trial, assessed anti-anginal anti ischemic efficacy and safety of Trimetazidine (60 mg/d) and Thiotriazoline (600 mg/d) in symptomatic patients with chronic ischemic heart disease receiving the first line therapy. The study assessed the efficacy of the two drugs on total exercise duration, time to 1-mm ST segment depression, the number of angina attacks and nitroglycerin tablets consumed amount. Both drugs have demonstrated clinical efficacy equal for all primary and secondary endpoints. PMID- 26761969 TI - [New Oral Anticoagulants During Catheter Ablation of Atrial Fibrillation. Experience With Rivaroxaban]. AB - Until recently, anticoagulant therapy after catheter ablation of atrial fibrillation, were connected with vitamin K antagonists and drugs of heparin series. New era of novel anticoagulants--dabigatran, rivaroxaban and apixaban is coming up. Our own experience of use in clinical practice of rivoroxaban for patient undergoing catheter ablation of atrial fibrillation will be discussed in this article. PMID- 26761970 TI - [Effects of Meldonium in Early Postmyocardial Infarction Period]. AB - The aim of PMICS (Postmyocardial Infarction Cardiosclerosis) patients therapy within the dispensary supervision is CCI (Chronic Cardio Insufficiency) progression prevention, life quality improvement, hospitalization number decrease and life prognosis improvement. Despite the developed approaches to the given patients treatment, CCI progression prevention, the main disease treatment ensuring and prognosis assessment are not always as much as possible effective. The search of methods improving the given patients prognosis is highly actual. THE AIM: To evaluate the meldonium clinical effectiveness in the early postmyocardial infarction period. MATERIALS AND METHODS: 67 patients were included in investigation, their age ranged from 40 to 70. They survived myocardial infarction (MI) and were discharged for further ambulatory supervision. The patients were randomized into two groups: the first one consisting of 32 patients got basic therapy for ischemic heart disease (IHD). The second group consisting of 35 patients besides basic therapy got mildronate during 12 weeks. RESULTS: meldonium included in standard ischemic heart disease therapy in early postmyocardial infarction cardiosclerosis reduces the rate of angina pectoris attacks (p = 0.001), decreased the number of epiventricular extrasystoles (p = 0.002) and the number of paroxysmal rhythm disturbances (p = 0.001), decreased arterial blood pressure (middle SAP and DAP) p = 0.001, improves life quality and lowered the level of anxiety (p = 0.001). CONCLUSION: The results received are likely to depend on the use of energetically advantageous pyruvate in glycolytic cycle due to restoration of equilibrium in processes of oxygen supply and its consumption, prevention of ATA (adenozine tryphosphoric acid) transport disturbances, elimination of toxic metabolic products accumulation. No side effects were registered during the course of mildronate treatment. PMID- 26761971 TI - [Cardio-Nephroprotection--the Most Important Goal of Antihypertensive Therapy in Patients With Type 2 Diabetes]. AB - AIM: to study the opportunities for cardio and nephroprotection by 6-month combined antihypertensive therapy with lisinopril and amlodipine in hypertensive patients with diabetes mellitus (DM) type 2. MATERIALS AND METHODS: 30 patients with arterial hypertension (AH) stage II-III, chronic kidney disease (CKD) stages 2-3 and type 2 DM were included in to research. We evaluated the results of the physical examination, blood pressure monitoring (ABPM), structural and functional state of the heart and kidneys. Combined analysis the risk of progression of CKD and cardiovascular complications (CVC) depending on the glomerular filtration rate (GFR) and albuminuria (AU) was performed. We also studied carbohydrate and lipid metabolism and estimated the severity of insulin resistance (IR). RESULTS: Against the background of long-term therapy by Equator 100% of patients had achieved target BP values. The circadian BP profile was significantly improved. There was a significant decrease in the index of left ventricular mass by 8.0%, a decline of PU by 58% and AU by 43.6%, respectively. There was the redistribution of patients to assess the combined risk of CKD progression and CVC: 50% of patients in the group crossed a moderate risk by reducing the percentage of patients at high and very high risk of 36.7% and 13.4%, respectively (p < 0.001), as well as significant improvement in metabolic parameters and reduction in IR. A statistically significant correlation between IR and condition of the heart and kidney was determined. CONCLUSION: Long-term combined therapy with lisinopril and amlodipine fully meets the modern requirements for antihypertensive therapy--it leads to a significant reduction in the risk of progression of CKD and development of the CVC and is metabolically neutral. The decrease in the combined risk of CKD progression and development CVC was associated with cardio and nephroprotective action of the Equator, as well as with a reduction in the negative impact of IR in patients with AH and type 2 DM. PMID- 26761972 TI - [Valuing the Lipid Marker of Lipoprotein (a) in the Diagnosis of Patients With Coronary Heart Disease]. PMID- 26761973 TI - [Results of the International Forum of Cardiologists and Internists]. PMID- 26761974 TI - [Heart Rate and Cardioprotection: New Data and Perspectives]. AB - The article presents the results of new experimental and clinical studies of selective inhibitor of If-channel, ivabradine confirming the feasibility of its use in coronary heart disease and chronic heart failure. We discuss some of the pleiotropic effects of ivabradine. Ivabradine may be useful in therapeutic areas outside those where it has previously demonstrated clinical efficacy. PMID- 26761975 TI - [Clinical Value of Left Ventricular Hypertrophy in Arterial Hypertension]. AB - In this review article we present data on prevalence of left ventricular hypertrophy in patients with arterial hypertension, on predictors of its development, methods of detection, and diagnostic criteria. PMID- 26761976 TI - [Potential and Paradoxes of Home Blood Pressure Variability]. AB - We present in this review data on home blood pressure variability (HBPV) with consideration of its definition and threshold values. We also present own classification and discuss analysis of results of HBPV and their interpretation in observational and clinical studies, including own data. Experience in this area accumulated during last 30 years, information on pathophysiological mechanisms, prognostic properties of HBPV may be useful for a physician from practical point of view. PMID- 26761977 TI - [Dystrophic Mineralization of Soft Tissues: Parallels in Formation of Dysfunctions of Cardiac Valves, Calcified Aortic Stenosis, and Atherosclerosis]. PMID- 26761978 TI - [Ventricular Tachycardia as a First Manifestation of Myotonic Dystrophy]. AB - We report a case of bundle-branch reentrant ventricular tachycardia as a first and severe manifestation of myotonic dystrophy. Progressive cardiac conduction disturbances and cardiac arrhythmias are well-known features of myotonic dystrophy, although they are commonly found in late stage of disease in patients with established diagnosis. We review clinical manifestations, diagnostics, management, and prognostic value of cardiac involvement in myotonic dystrophy. PMID- 26761979 TI - Guest Editorial. PMID- 26761980 TI - Dental attendance, perceptions of cost and self-care of school year 12 and 13 students: A focus on Southland, New Zealand. AB - BACKGROUND AND OBJECTIVES: Adolescents and emerging adults can provide dentists with many challenges. Little information is available on their perceptions of dental costs once they turn 18 and dentistry is no longer State-funded. The aim of this study was to explore the use of dental care by Southland students in years 12 and 13, their perceptions of the cost of four common dental procedures, self-related oral health and dental self-care habits, time off school related to dental problems, and knowledge and views regarding fluoride. METHODS: After ethical approval, a 26-question survey was conducted of all Southland students in years 12 and 13. Data were statistically analysed in SPSS version 20 with the alpha value set at 0.05. RESULTS: The participation rate was 49.6%. Regular attendance for examinations was reported by 77.5% with non-attendance mainly related to attitudes around lack of importance or necessity. Reported dental attendance varied according to gender, ethnicity and decile rating of school attended. Although some were accurate in their estimations of dental costs, the standard deviation for all procedures was large. The majority thought that costs put people off going to the dentist. While 74.8% brushed their teeth at least twice daily, only 26.6% flossed regularly. Knowledge regarding fluoride was lacking. CONCLUSIONS: It may be advantageous to include education regarding costs of dental care with patients of this age. This may motivate them to improve their self-care and ensure that their oral health is of a high standard before their dental needs are no longer State-funded. PMID- 26761982 TI - A cautionary tale; squamous cell carcinoma of the gingiva. AB - BACKGROUND AND OBJECTIVES: Oral squamous cell carcinoma is characterised by varied clinical manifestations and is often diagnosed at an advanced stage. This article highlights a case of gingival squamous cell carcinoma which was initially diagnosed and treated as localised periodontitis. METHODS: A 64-year-old Caucasian male had a 2-year history of discomfort and swelling around his upper anterior teeth. His dentist diagnosed localised periodontitis around tooth 11. The patient was treated with regular scaling but showed no improvement. Teeth 11 and 21 were subsequently extracted. He returned later with a swelling in his anterior maxilla and was referred to the Whangarei Hospital Dental Department. RESULTS: The histopathological report confirmed a diagnosis of squamous cell carcinoma. The patient was referred to Auckland for treatment and underwent a tracheostomy, maxillectomy, bilateral selective neck dissection and fibula free flap reconstruction. All lymph nodes retrieved and margins of the lesion were clear, and the patient did not require radiotherapy. He will be monitored over the next 5 years for recurrence. CONCLUSIONS: Gingival squamous cell carcinoma can be easily misdiagnosed. Suspicious lesions which are non-responsive to conventional therapy should be biopsied, even if they are not in the classic high risk anatomical areas of the oral cavity. PMID- 26761983 TI - JOHN ARTHUR SKEGG 1930-2015. PMID- 26761981 TI - The use of radiography in the diagnosis of oral conditions in children and adolescents. AB - Radiography can serve as a useful aid in the diagnosis of numerous oral conditions, with a place in nearly all of the disciplines of dentistry. As such it can have a beneficial role in caring for the oral health of children and adolescents. The following review discusses the use of radiography in the diagnosis of oral conditions in children and adolescents, with particular reference to the diagnosis of dental caries, dental trauma, growth and development and in other dental scenarios, along with the importance of incidental findings. The risks associated with radiation exposure from the use of radiography are discussed, how these need to be balanced with the possible benefits associated with such use, as well as how risks could be minimised. Summary recommendations are also presented, providing an overview of the use of radiography for oral diagnosis in various clinical scenarios for children and adolescents. PMID- 26761984 TI - ELLIOTT THOMAS LANG 1924-2015. PMID- 26761985 TI - GRACE WEBSTER SUCKLING. PMID- 26761986 TI - ROBIN ALAN WRIGHT. PMID- 26761987 TI - Keeping It All Straight...and Together. PMID- 26761988 TI - Advanced Practice Ownership: Is It Right For You? PMID- 26761990 TI - The Importance of Evidence-Based Practice. PMID- 26761991 TI - Collaboration: Not Always a Good Thing. PMID- 26761989 TI - Life is a Journey. PMID- 26761992 TI - Disaster Prevention. PMID- 26761993 TI - Conscientious Objection. When Care Collides with Nurses' Morals, Ethics. PMID- 26761994 TI - [BASELINE SCREENING USING INTERFERON-GAMMA RELEASE ASSAY SUGGESTS AN INCREASED RISK OF MYCOBACTERIUM TUBERCULOSIS INFECTION AMONG EMPLOYEES IN A JAPANESE GENERAL HOSPITAL]. AB - OBJECTIVES: This retrospective study aimed to assess the risk of tuberculosis infection for the employees of a Japanese hospital using baseline interferon gamma release assay (IGRA). The risk was defined as exposure to the hospital environment. METHODS: In total, 870 hospital employees including 161 new employees, 582 for baseline assay, and 127 for contact examination (709 subjects in the post-employment group) were examined from December 2010 to April 2012. The new employees were considered as the "non-exposure" group, whereas the post employment group was considered as the "exposure" group. Multiple logistic regression analyses were used to calculate the odds ratio (OR) for IGRA positivity, adjusted for gender, smoking history, and alcohol intake (model 1), and for years of employment (model 2). RESULTS: The exposure group was significantly associated with an increased risk of positive IGRA results, even when adjusted for years of employment (OR: 4.1; 95% confidence interval: 1.4 17.6; P = 0.007). Subgroup analyses stratified by profession indicated a significantly increased OR for laboratory technicians, doctors, and nurses in both models. No correlation was observed between the length of employment and IGRA positivity. CONCLUSION: Exposure to the hospital environment increased the risk of tuberculosis infection for employees irrespective of the length of employment. Laboratory technicians, doctors, and nurses were at the highest risk of infection. PMID- 26761996 TI - [A CASE OF SPINAL TUBERCULOSIS WITH NEUROPATHY AMELIORATED BY DRAINING A TUBERCULOUS ILIOPSOAS ABSCESS WITHOUT SPINAL SURGERY]. AB - A 75-year-old woman was referred to our hospital after a health check-up disclosed abnormal shadows in the bilateral lungs. The patient was admitted to our hospital after being diagnosed with pulmonary tuberculosis. A physical examination showed a mass in the left inguinal area. Enhanced computed tomography revealed that the tuberculosis involved several regions including the lumber vertebrae, iliopsoas muscles, and left inguinal area. A therapeutic regimen consisting of INH, RFP, EB, and PZA was begun. Neuropathy in the lower extremities and dysuria indicated a spinal lesion, and spinal surgery was considered. However, the patient's history indicated that these symptoms were likely due to an iliopsoas abscess rather than a spinal lesion. This hypothesis was confirmed when the patient's symptoms improved with no sequelae after the abscess was drained. Our case demonstrates that spinal lesions as well as iliopsoas abscesses can cause neuropathy, and underscores the importance of obtaining a patient's history to correctly diagnose the disease and determine the appropriate treatment options. PMID- 26761995 TI - [PULMONARY AND INTESTINAL TUBERCULOSIS DEVELOPING ACUTE TUBERCULOUS PERFORATION OF THE INTESTINE DURING ANTITUBERCULOSIS THERAPY]. AB - Intestinal tuberculosis (TB) was recognized as the most common complication with a high frequency of active pulmonary TB during the TB epidemic period. However, intestinal TB has become a rare disease, and intestinal perforation due to intestinal TB is extremely rare. We herein report two cases of tuberculous intestinal perforation. CASE 1: A 41-year-old man was admitted to our hospital complaining of persistent cough and anorexia. He was in poor nutritional condition, and his body mass index (BMI) and prognostic nutrition index (PNI) were 13.4 and 36.4, respectively. He was diagnosed with pulmonary TB and received anti-TB therapy. On the 51st day of hospitalization, he developed intestinal perforation. Pathologically caseating epithelioid granulomas were noted at the ulcer lesion. CASE 2: A 61-year-old man was admitted to our hospital due to miliary TB caused by intestinal TB. He had taken oral immunosuppressive drugs and steroids for dermatomyositis over the previous eight years and had a poor nutritional condition, with a BMI of 13.4 and a PNI of 14.4. While receiving anti TB therapy, he developed intestinal perforation on the 97th day of hospitalization. The patient's poor nutritional condition and immune reconstitution may have contributed to the intestinal perforation. PMID- 26761998 TI - HOLIDAY PRESENTS. Reflecting on the gifts of life, understanding & leadership. PMID- 26761997 TI - [NINETY YEARS OF THE JAPANESE SOCIETY FOR TUBERCULOSIS--Back to the Future for Research and Control of Tuberculosis]. AB - The 90 years since the foundation of the Japanese Society for Tuberculosis in 1923 can be divided into three periods by three turning points, i.e., epidemiological transitions: 1911-1950 (the first period), 1953-1980 (the second period) and 1980-present (the third period). The progress of the Society is overviewed for each of these periods, and the several specific areas of research and control efforts are discussed. The first period might be viewed as a preparatory phase during which various tremendous efforts were made in basic, clinical, and epidemiological research that would bear fruit during the second period. Following this period, modern technologies were introduced into the national tuberculosis control program accompanied by related basic research, including the development and evolution of the theory of TB pathogenesis, X-ray diagnosis, and clinical trials of chemotherapy, of which the Society has been very proud. The problems of activities in the second period were carried over into the third period, together with the epidemiological challenge of the slowing of epidemiological improvement. For this period, the bibliometric technique was applied in the trial of objectively analyzing the trends of research, activities in publication. In addition, the USA's efforts to maintain awareness of TB, after the unexpected upsurge of TB during 1980s-90s due to its neglect in the past, were cited as lessons Japan should now learn. PMID- 26762000 TI - COMMON TRAITS. Seven habits for highly effective EMS leaders. PMID- 26761999 TI - PRO BONO > CPR CERTIFICATION LIABILITIES. PMID- 26762001 TI - KID CARDIOVERSION. Policy leads to shock of conscious boy with an AED. PMID- 26762002 TI - NITRO EFFECTS. Study assesses nitroglycerin's risk of hypotension in STEMI patients. PMID- 26762004 TI - COMMUNITY EFFORT. How Centre LifeLink EMS increased cardiac arrest survival rate in State College, Pa., from 4% to 20%. PMID- 26762003 TI - SMARTPHONE SAVES. A literature review of mobile phone use in out-of-hospital cardiac arrest. PMID- 26762005 TI - MORNING EMERGENCIES. A guide to wake-up ischemic strokes Morning emergencies. PMID- 26762006 TI - MEASURING UP. EMS agencies must use the right metrics to track improvement efforts. PMID- 26762007 TI - ON LAND & SEA. Beach2Battleship Triathlon highlights importance of preparedness for medical response team. PMID- 26762010 TI - Boots on the ground. Alameda County, Calif., community paramedics curb hospital readmissions & non-emergent 9-1-1 use. PMID- 26762009 TI - MEDICAL MISSIONARIES. Waves of Health helps establish EMS system in Dominican Republic region. PMID- 26762008 TI - Inside the world's largest collection of model ambulances. PMID- 26762011 TI - LIT FUSE. Cardiac emergencies require efficient & rapid care for survival. PMID- 26762012 TI - FREE AT LAST. Freestanding EDs offer alternative patient destinations. PMID- 26762013 TI - From the President. PMID- 26762014 TI - Healthy Eating During Shifts. PMID- 26762015 TI - DNPs: Collaboration and Practice. PMID- 26762016 TI - ANA Ethics Symposium: A Time of Recognition, Celebration, and Reflection. PMID- 26762017 TI - Who Was Dorothy Cornelius and What Did She Mean for Nursing? PMID- 26762018 TI - All For One, One For All. Interprofessional Education Aims at Fostering Teamwork, Quality Care. PMID- 26762019 TI - Interprofessional Education to Promote Collaboration. PMID- 26762020 TI - [Microbial degradation of 3-phenoxybenzoic acid--A review]. AB - 3-phenoxybenzoic acid (3-PBA) with estrogen toxicity is one of the intermediate products of most pyrethroid pesticides. 3-PBA is difficult to degrade in the natural environment, and threatens food safety and human health. Microbial degradation of pyrethroids and their intermediate product (3-PBA) has become a hot topic in recent years. Here, we reviewed microbial species, degrading enzymes and degradation genes, degradation pathways of 3-PBA degrading and the application of 3-PBA degradation strains. This article provides references for the study of 3-PBA degradation by microorganisms. PMID- 26762021 TI - [Progress in microbial co-culture--A review]. AB - We reviewed the history and applications of microorganism co-cultivation in food, agriculture, industry and sewage purification, and summarized ecology relationships between co-culture microorganisms. Joint mixed culture, sequence mixed culture and immobilized cells mixed culture have been used widely and lots of achievements have been made, for example, obtaining metabolites that are difficult to achieve or too low production in pure culture, transforming traditional fermentation industry, producing energy substance, improving substrate utilization ratio, expanding the scope of substrates and degrading toxic substances. Research reports indicate there are many ecology relationships between microorganisms, such as collaborative metabolism, induction effect, quorum sensing and gene transfer. The ecological interplay mechanism of co culture microorganisms should have a further research, which will lay the foundation for developing applications of microorganism co-culture. PMID- 26762022 TI - [Effects of global climate change on the ecological characteristics and biogeochemical significance of marine viruses--A review]. AB - As the most abundance biological agents in the oceans, viruses can influence the physiological and ecological characteristics of host cells through viral infections and lysis, and affect the nutrient and energy cycles of the marine food chain. Thus, they are the major players in the ocean biogeochemical processes. The problems caused by global climate changes, such as sea-surface warming, acidification, nutrients availability, and deoxygenation, have the potential effects on marine viruses and subsequently their ecological and biogeochemical function in the ocean. Here, we reviewed the potential impacts of global climate change on the ecological characteristics (e. g. abundance, distribution, life cycle and the host-virus interactions) and biogeochemical significance (e. g. carbon cycling) of marine viruses. We proposed that marine viruses should not be ignored in the global climate change study. PMID- 26762023 TI - [Genetic diversity of the Rhizobia and screening of high-efficient growth promoting strains isolated from Sesbania cannabina in Rudong County]. AB - OBJECTIVE: To study the genetic diversity and phylogeny of Rhizobia isolated from Sesbania cannabina growing on the tidal flat in Rudong County and screen high efficient growth-promoting strains as Rhizobia inoculator to S. cannabina. METHODS: Phylogenetic analyses were based on 16S rRNA gene, housekeeping genes (recA, atpD, glnII) and symbiotic genes (nodA, nifH). The growth-promoting efficiency was tested by plant inoculation assay on S. cannabina in greenhouse. RESULTS: The 32 isolates belonged to Ensifer, Neorhizobium, Rhizobium, and most closely related to E. meliloti, N. huautlense, R. pusense. The phylogenies of nodA and nifH were congruent, and most closely related to E. saheli. The 7 representative isolates were resistant to high concentration of NaCl (5%, W/V), and YIC5082 grew well in TY medium with 6% NaCl. In plant inoculation assay, all the 7 representative isolates were effective on symbiotic nitrogen fixation, and 6 out of the 7 isolates significantly enhanced the fresh weight and height of plants. CONCLUSION: Rhizobia isolated from S. cannabina growing on the tidal flat in Rudong County showed rich genetic diversity. N. huautlense and E. meliloti were the dominant species. Most of the isolates showed fine growth-promoting efficiency and salt tolerance. YIC5077 showed the best growth-promoting efficiency, good nodulation and nitrogen fixation abilities, which has promising potential applications as Rhizobia inoculator to S. cannabina. PMID- 26762024 TI - [Isolation and identification of thermophilic bacteria for efficient dead-pig composting]. AB - OBJECTIVE: To isolate thermophilic bacteria to degrade organic substances of dead pig. METHODS: Primary screening was done by using diluted plate count and selective medium, and then enzyme activity was measured for secondary screening. Two thermophilic bacterial strains N-3 and Y-3 were isolated, and could degrade protein and lipids. To test their effect, the isolates were mixed (V: V = 1:1, the number of bacteria was 10(8) CFU/mL) and inoculated in dead-pigs and sawdust composting with different doses (0%, 0.3%, 0.6% and 0.9% of the wet weight of fermentation materials). RESULTS: Strain N-3 was identified as Bacillus aestuarii and Y-3 as Geobacillus thermodenitrificans, based on their 16S rDNA gene sequences. The composting temperature of the 0.3%, 0.6% and 0.9% inoculation group could reach 60 degrees C and maintain at the high temperature for about 10 d, which is higher than control (P < 0.01). At the end of composting, the dead pig degradation rate of the (0%, 0.3%, 0.6% and 0.9% inoculation groups were 71.2%, 75.7%, 96.7% and 97.1%, respectively. The groups of 0.6% and 0.9% were significantly higher than the control (P < 0.01). CONCLUSION: Sufficient amount inoculation of thermophilic bacteria (> 0.6%) could effectively increase composting temperature, maintain thermophilic stage for longer time, and accelerate degradation of dead-pig by composting. PMID- 26762025 TI - [Screening and identification of a bacterium capable of converting agar to neoagaro oligosaccharides]. AB - OBJECTIVE: To screen and identify a bacterium capable of converting agar to neoagaro oligosaccharides. METHODS: We took samples of porphyra haitanensis and nearby seawater, and then used the medium containing 1 per thousand agar to enrich the target bacteria. The target isolates were obtained by dilution-plate method, of which crude enzymes were further obtained by liquid culture. We adopted DNS method to determine the target bacteria which can convert agar to neoagaro oligosaccharides. The phylogenetics was identified by analyzing 16S rDNA sequence and combining the strain's morphological and bacterial colonial physiological biochemical characteristics. RESULTS: We isolated a gram-negative bacterial strain HJPHYXJ-1 capable of transforming agar to neoagaro oligosaccharides. Basic Local Alignment Search Tool (BLAST) search of HJPHYXJ-1's 16S rDNA sequence on GenBank suggested that the similarity between this strain and Vibrio natriegens reached 99% . In addition, the morphological and physiological biochemical characteristics of HJPHYXJ-1 also showed highly similarity to Vibrio natriegens. So we identified HJPHYXJ-1 as Vibrio natriegens. The results of HPLC suggested that the metabolite of enzymatic degradation was neoagaro oligosaccharides. CONCLUSIONS: HJPHYXJ-1 or the new isolate of Vibrio natriegens was capable of converting agar to neoagaro oligosaccharides. PMID- 26762026 TI - [Screening and antibacterial function of Bacillus amyloliquefaciens X030]. AB - OBJECTIVE: We isolated 339 bacillus strains from 72 soil samples all over the country, then purified their antimicrobial compounds and studied the antibacterial activity, to enrich bacillus resources and explore their second metabolites. METHODS: A bacillus strain with strong antibacterial activity was selected by dilution plate and water bath heating from a soil sample from a peanut plantation in Henan Province; this strain was identified according to morphological observation, physiological and biochemical characteristics, and consequences of 16S rRNA homologous analysis. Antibacterial compound from the identified strain, Bacillus amyloliquefaciens X030, was separated and purified by acetone precipitation, Sephadex chromatography, C18 reverse phase column chromatography. Its molecular weight was analyzed by LC-MS/MS. The antibacterial activity was characterized by disc diffusion and plate two-way cultivation. RESULTS: Bacillus amyloliquefaciens was isolated that not only has antibacterial activity against Staphylococcus aureus, Candida albican and Saccharomycetes; but also against Pyriculariaoryzae, Chili pointed cell anthrax, Gloeosporium eriobotryae speg and Phytophthora parasitica. The compound was confirmed as polypeptide. CONCLUSION: Bacillus amyloliquefaciens X030 can produce a polypeptide that inhibits pathogenic bacteria and plant pathogenic fungi. PMID- 26762027 TI - [Transcriptional regulation of aco gene cluster in Bacillus thuringiensis]. AB - OBJECTIVE: We analyzed the transcriptional regulation of aco gene cluster and the phenotype of acoR mutant, to determine the effect of acoR deletion on sporulation efficiency and Cry protein production. METHODS: Sequence of aco gene cluster in Bacillus thuringiensis was analyzed by sequence alignment. RT-PCR was carried out to reveal the transcriptional units of the aco gene cluster. acoR insertion mutant was constructed by homologous recombination. Transcriptional activity was analyzed by promoter fusions with lacZ gene. Comparison of the Cry1Ac protein production was determined by protein quantitation. RESULTS: The aco gene cluster was composed of four genes. The acoABCL formed one transcriptional unit. The transcriptional activity of acoA promoter sharply decreased in sigL and acoR mutants, respectively. Deletion of acoR had no effect on growth and Cry protein production, but decreased the motility of cells and sporulation efficiency. CONCLUSION: The aco gene cluster is controlled by Sigma 54 and activated by AcoR. Deletion of acoR has no effect on Cry protein production, but decreased the motility of the cells. PMID- 26762028 TI - [Construction and characterization of Salmonella Pathogenicity Island 2 (SPI-2) deletion mutant of Salmonella Pullorum S06004]. AB - OBJECTIVE: To research the pathogenicity of Salmonella Pathogenicity Island 2 (SPI-2) deletion mutant of Salmonella Pullorum and preliminary explore the feasibility of developing safe attenuated Salmonella Pullorum candidate vaccine strain. METHODS: The SPI-2 (-40 kb) deletion mutant of Salmonella Pullorum S06004 was constructed using the lambda-red recombinant system. Then the biological characteristics such as growth rate, biochemical properties, genetic stability and virulence were evaluated between the deletion mutant strain S06004DeltaSPI2 and its parent strain S06004. RESULTS: S06004DeltaSPI2 was successfully constructed. The growth rate and biochemical properties of S06004DeltaSPI2 were consistent with those of its parent strain S06004. The mutant was stable with the deletion of SPI-2. Chicken lethal test showed that the LD50 of S06004DeltaSPI2 was 252 times higher than the parent strain S06004. CONCLUSION: The virulence of S06004DeltaSPI2 was obviously attenuated. This study provided basic data for further study of the functions of SPI-2, and implied its potential to develop attenuated Salmonella vaccine. PMID- 26762030 TI - [High expression of agarase AgaD in Escherichia coli]. AB - OBJECTIVE: We constructed highly efficient expression systems for agarase AgaD and optimized its culture conditions. METHODS: First, the codon usage of AgaD was optimized to make it suitable for expression in E. coli. Then, the gene expression vector was transformed into different E. coli hosts. According to the "N-end rule" that is related to the in vivo half-life of a protein, a mutant was constructed. Finally, the effects of CaCl2 and glycine on enzyme production were evaluated. RESULTS: A highly efficient expression system of agarase AgaD was constructed, named pET-22b (+)-optagaDx-AD494 ( E3). Replacing N-terminal second amino acid phenylalanine with alanine significantly improved agarase production and shortened the fermentation period. The extracellular enzyme activity was further up-regulated by CaCll and glycine. After optimization, the extracellular enzyme production raised from 20 U/L to 11300 U/L, more than 500 folds. CONCLUSION: The high expression system of AgaD provides good basis for further studying agarases. PMID- 26762029 TI - [Microbiological characteristics of a Lysinibacillus strain isolated from Populous euphratica]. AB - OBJECTIVE: The aim of this study was to identify the microbiological characteristics of a Lysinibacillus strain isolated from storage liquid in the stems of Populus euphratica trees. METHODS: Bacterial morphology and cultivation characteristics were studied by conventional cultivation and dyeing method. Biochemical characteristics, fatty acid components, menaquinone, polar lipids, phylogenetic analyses of 16S rRNA, determination of (G + C) mol% content and DNA- DNA hybridization were studied by polyphasic taxonomic approach. RESULTS: Strain ML-64 is Gram-positive, endospore-forming and rod-shaped. Colonies are pale yellow, circular and entire margin. Temperature range for growth is between 10 and 45 degrees C (optimum at 37 degrees C ). The pH range for growth is between 6. 0 and 9.0 (optimum at 7.0). NaCl concentration range for growth is between 0 and 6% (optimum 3% ). Cells were positive for lipid esterase, Arginine dihydrolase, urease and Voges-Proskauer test. No sugars were fermented in the API 50CH strips. L-Serine, Methyl Pyruvate, alpha-Keto-Butyric, Acetoacetic Acid were oxidized. Resistant to polymyxin b (30 MUg), novobiocin (30 MUg), peillin G (10 U). 16S rRNA gene sequence demonstrated that strain ML-64 was closely related to Lysinibacillus chungkukjangi 2RL3-2T (100%) , Lysinibacillus sinduriensis BLB-1T (99.1%). DNA-DNA relatedness were 82% and 50. 9% with Lysinibacillus chungkukjangi 2RL3-2T and Lysinibacillus massiliensis CIP108446T, respectively. The genomic DNA G + C content of strain ML-64 was 36. 8% (mol). Major fatty acids were iso-C,,, (55. 05% ) and anteiso-C15,0 (20. 70% ). The predominant menaquinone is MK-7. Based on the phenotypic phylogenetic and genotypic analyses, the strain ML-64 is concluded to represent a new mutant strain of the Lysinibacillus chungkukjangi species, GenBank accession number is KC609752. CONCLUSION: As an endophytic bacterium of Populus euphratica, genomic structure of the strain ML-64 was greatly differentiated from the closest strain L. chungkukjangi, and suitably adapted to the endophytic environment of Populus euphratica. PMID- 26762031 TI - [Relationship between bacterial community and its environmental in Zuohai Lake, China]. AB - OBJECTIVE: To reveal the relationship between bacterial community and the environmental in Zuohai lake, Fuzhou City. METHODS: The abundance of total bacteria was studied using DAPI staining; the composition, distribution and the dynamics of bacterial community were examined using both the denaturing gradient gel electrophoresis (DGGE) and the 16S rRNA gene clone library analyses over a 2 year periods from October 2011 to August 2013. Moreover, multivariate statistical analysis was used to analyze the relationship between bacterial community and environmental factors. RESULTS: The total numbers of bacteria ranging from 4.91 x 10(6) cells/mL to 18.71 x 10(6) cells/mL, and the seasonal variation of bacterial abundance was obviously stronger than the spatial heterogeneity. DGGE and clone library analysis revealed that bacterial communities were mainly affected by temporal changes. Phylogenetic analysis showed that bacteria belonging to 11 phyla were identified. Members of 3-Proteobacteria and Cyanobacteria group were the predominated lineage, followed by a-Proteo bacteria, Actinobacteria and Bacteroidetes. Redundancy analysis (RDA) suggested that water temperature, pH, total nitrogen, total phosphorus and chlorophyll a content contributed significantly to the bacteria-environment relationship. CONCLUSION: There is rich bacterial diversity in Zuohai lake, the patterns of change in bacterial communities showed that the seasonal difference might have a significant impact on structuring the bacterial communities in the lake. PMID- 26762032 TI - [Community diversity of ammonia-oxidizing bacteria of three plants rhizosphere in Ebinur Lake wetland]. AB - OBJECTIVE: In order to study the community diversity of rhizosphere soil ammonia oxidizing bacteria, Halocnemum strobilaceum, Reed and Salicornia in Ebinur Lake Wetland were investigated. METHODS: The clone libraries of amoA gene were constructed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and phylogenetics were analyzed. To explore the community structure of rhizosphere amomonia-oxidizing bacteria, we combined rhizosphere physicochemical factors of the three plants. RESULTS: Phylogenetic analysis of the amoA gene fragments showed that all of AOB sequences from shrimp of three plants rhizosphere were affiliated with Nitrosomonas or Nitrosomonas-like phyla, Nitrosospira phyla was not discovered. Three plants rhizosphere composition includes 9 OTUs,12 OTUs and 7 OTUs respectively. Coverages of all libraries of the three plants rhizosphere were over 99% and strongly representative. The richness index, chao1 index, ACE index and Shannon index of the three libraries were as follows, Reed rhizosphere AOB was much higher than Halocnemum strobilaceum rhizosphere AOB, and Salicornia rhizosphere AOB was the lowest. CONCLUSION: This study provides a basis for understanding the community diversity and structure of rhizosphere soil ammonia-oxidizing bacteria in Ebinur Lake wetland. PMID- 26762033 TI - [Expression of Edwardsiella tarda luxS gene at different growth stage]. AB - OBJECTIVE: Purpose of this work was to explore the distribution of LuxS/AI-2 quorum sensing system in Edwardsiella, and analyze expression characteristics and biological function of the key gene luxS accompanying the growth of Edwardsiella. METHODS: The full-length of AI-2/LuxS of Edwardsiella tarda was cloned by PCR based on the sequence on NCBI, then characteristics and conservative structure of this protein-coding gene were analyzed using web database and bioinformatics tools. The anti-rabbits serum was prepared after this protein was purified through prokaryotic expression. The expression level of luxS gene was analyzed during different growth stages using Western blot and further the distribution of luxS gene in Edwardsiella tarda was studied by this technique. To explore whether the specific LuxS is AI-2 dependent we used the method of antibody neutralization to analyze the effect of the anti-rabbits serum on the growth of Edwardsiella tarda. RESULTS] The luxS gene was obtained by PCR, its length was 516 bp, and the sequence was highly conserved in Edwardsiella tarda. Results of Western blot analysis showed that LuxS expression level was the lowest in the lag phase and began increasing when entered index phase. It reached the peak in the late index phase and decreased in decline phase. Moreover, Antibody neutralization results showed that, it can elongate the growth plateau phase, but it has no significant effect on bacterial growth. CONCLUSION: The key gene of luxS was highly conserved, and LuxS/AI-2 was widely distributed among Edwardsiella tarda. The expression level of luxS gene was different during every growth period, expression of LuxS protein reached the highest level in the late index phase. PMID- 26762035 TI - [Antibiotics-resistance and pulsed-field gel electrophoresis patterns of Shigella sonnei from different regions]. AB - OBJECTIVE: To understand the epidemic tendency and antibiotics-resistance among Shigella sonnei isolates collected from different regions by antibiotic susceptibility testing, PCR amplification of the resistance genes and genotyping. METHODS: The susceptibilities to 21 antibiotics of 54 S. sonnei strains were determined by broth microdilution using a 96-well microtiter plate. The amplification of resistance genes was performed by PCR. Pulsed field gel electrophoresis genotyping method was applied to analyze their genetic relationships, and BioNumerics software was used to analyze the PFGE patterns. RESULTS: All tested S. sonnei strains were resistant to Trimethoprim/Sulfamethoxazole, Tetracycline, Ticarcillin, Ampicillin and Gentamicin, whereas sensitive to Imipenem, Cefepime, Levofloxacin, Norfloxacin and Amikacin. A total of 7 different antibiotic resistance genes including blaTEM, blaCTX and intI were identified in the multidrug-resistant S. sonneis strains. PFGE patterns of all the isolates showed a high genetic homology. CONCLUSION: It is of great importance to strengthen the surveillance of S. sonnei from different regions in order to reduce the prevalence of multidrug-resistant strains. PMID- 26762036 TI - [Progress in transcriptional studies]. AB - Gene expression exhibits temporal and spatial patterns to response environmental changes and growth cycle. Gene expression is under strict control at different levels among which control at transcription level is the predominant mode, especially in prokaryotes. In this review, we summarized the new developments of methods used in transcriptional studies, including modifications and improvements of the classic methods, such as gel-shift assay, DNA foot printing, and in vivo reporter system. In addition, we introduced examples to apply new methods, such as surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) to characterize protein-DNA, ligand-protein, and ligand-protein-DNA interactions. The collection of these methods and their application could guide and accelerate relevant studies. PMID- 26762034 TI - [Vacuolating autotransporter toxin affects biological characteristics and pathogenicity of avian pathogenic Escherichia coli]. AB - OBJECTIVE: To determined the role of vacuolating autotransporter toxin (vat) gene in avian pathogenic Escherichia coli (APEC), we detected the biological characteristics and pathogenicity of vat gene mutant strain of APEC-O1. METHODS: We constructed the vat mutant and complementary strain of APEC-O1 by the Red recombination system and plasmid pSTV28. Then we compared the growth curve, motility, agglutination, biofilm formation and pathogenicity of mutant strain, wild-type strain and complementary strain. RESULTS: The vat mutant did not affect the growth and resistance to environment stress of APEC. However, inactivation of APEC-O1 vat gene resulted in enhanced motility, diminished agglutination, decreased biofilm formation and attenuated virulence in ducks. CONCLUSION: These data indicated that Vat affect the motility, agglutination, biofilm formation and virulence of APEC-O1, which help us to understand the role of the Vat in the APEC pathogenicity. PMID- 26762037 TI - [Pathway modification of industrial microorganisms to improve acid-stress tolerance]. AB - Different types of acids from fermentation environment or industrial microorganisms exist during fermentation process. Acids may inhibit growth and metabolism of industrial strains, namely acid stress. The tolerance mechanisms of acid stress include regulation of intracellular proton concentration, protection and restoration of intracellular macromolecules, changes in cell membrane composition and acid stress response at whole cell level. Screening and modification methods have been applied to improve acid-stress tolerance of industrial strains for decades. In this review, we provide insights into acid stress tolerance of industrial microorganisms and address the modification of microbial pathways to improve acid-stress tolerance. PMID- 26762038 TI - [Advances in genetic modification technologies]. AB - Genetic modification technology is a new molecular tool for targeted genome modification. It includes zinc finger nucleases (ZFN) technology, transcription activator-like effector nucleases (TALEN) technology and clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) (CRISPR-Cas) nucleases technology. All of these nucleases create DNA double-strand breaks (DSB) at chromosomal targeted sites and induce cell endogenous mechanisms that are primarily repaired by the non-homologous end joining (NHEJ) or homologous recombination (HR) pathway, resulting in targeted endogenous gene knock-out or exogenous gene insertion. In recent years, genetic modification technologies have been successfully applied to bacteria, yeast, human cells, fruit fly, zebra fish, mouse, rat, livestock, cynomolgus monkey, Arabidopsis, rice, tobacco, maize, sorghum, wheat, barley and other organisms, showing its enormous advantage in gene editing field. Especially, the newly developed CRISPR-Cas9 system arose more attention because of its low cost, high effectiveness, simplicity and easiness. We reviewed the principles and the latest research progress of these three technologies, as well as prospect of future research and applications. PMID- 26762040 TI - [Characterization of L-aspartate-alpha-decarboxylase from Bacillus subtilis]. AB - As an important material in pharmaceutical and chemical industry, beta-alanine was mainly produced by chemical methods. L-aspartate-alpha-decarboxylase could catalyze the alpha-decarboxylation from L-aspartate to beta-alanine. Determinations for specific activities of PanDs from Escherichia coli, Corynebacterium glutamicum and Bacillus subtilis were performed in this study (0.98 U/mg, 7.52 U/mg and 8.4 U/mg respectively). The optimal temperature and pH of PanDs from C. glutamicum and B. subtilis were 65 degrees C, pH 6.5 and 60 degrees C, pH 6.5 respectively. According to our research, PanD from B. subtilis could be more appropriate for industrial application because of the higher activity and thermostability when compared to PanDs from E. coli and C. glutamicum which had been the most studied. We also analyzed and discussed the special post-translation self-cleavage phenomenon and the mechanism based inactivation. PMID- 26762039 TI - [Expression of neuropeptide Y and long leptin receptor in gastrointestinal tract of giant panda]. AB - To study the expression and distribution of neuropeptide Y (NPY) and long leptin receptor (OB-Rb) in the gastrointestinal tract of giant panda, samples of three animals were collected from the key laboratory for reproduction and conservation genetics of endangered wildlife of Sichuan province, China conservation and research center for the giant panda. Paraffin sections of giant panda gastrointestinal tissue samples were observed using hematoxylin-eosin staining (HE) and strept actividin-biotin complex immunohistochemical staining (IHC). The results show that the intestinal histology of three pandas was normal and no pathological changes, and there were rich single-cell and multi-cell mucous glands, long intestinal villi and thick muscularis mucosa and muscle layer. Positive cells expressing NPY and OB-Rb were widely detected in the gastrointestinal tract by IHC methods. NPY positive nerve fibers and neuronal cell were widely distributed in submucosal plexus and myenteric plexus, especially in the former. They were arranged beaded or point-like shape. NPY positive cells were observed in the shape of ellipse and polygon and mainly located in the mucous layer and intestinal glands. OB-Rb positive cells were mainly distributed in the mucous layer and the laminae propria, especially the latter. These results confirmed that NPY and OB-Rb are widely distributed in the gut of the giant panda, which provide strong reference for the research between growth and development, digestion and absorption, and immune function. PMID- 26762041 TI - [Identification and characterization of partner proteins interacting with fatty acid activation enzyme Slr1609 in Synechocystis sp. PCC 6803]. AB - To understand molecular modules related to polyunsaturated fatty acids (PUFA) synthesis and eventually produce PUFA at high efficiency, we developed a protein complex analysis technology in Synechocystis sp. PCC 6803, and applied it to identify possible partner proteins interacting with the key enzymes that catalyze PUFA biosynthesis. We first constructed a recombinant expression of protein of slr1609 encoding the fatty acid activation enzyme, by fusing 3xFLAG tag with the target protein. Then we verified its expression by Western blotting targeting 3xFLAG tag. To maximize purification of Slr1609 protein complex, we optimized the protein expression conditions of Slr1609 in Synechocystis in a 5 L fermenter by monitoring its gene expression using RT-qPCR. The purification of the Slr1609 protein complexes was demonstrated by a Native-PAGE analysis. Finally, LC-MS/MS proteomic analysis allowed identification of the possible partner proteins interacting with Slr1609. PMID- 26762042 TI - [Construction of an integration vector carrying hygromycin B resistance gene and its genetic transformation in Rhizopus oryzae]. AB - To construct a system of genetic transformation suitable for Rhizopus oryzae, we constructed a single-exchange vector pBS-hygro carrying hygromycin B resistance gene (hph) as its selective marker using gene splicing by overlap extension PCR (SOE PCR) technique. We introduced this recombinant vector into Rhizopus oryzae AS 3.819 by PEG/CaCl2-mediated transformation of protoplast, electroporation of protoplast and germinated spores; and we studied the effects of hydrolysis time, field strength and spore germination time on transformation frequency. We conducted quantitative real-time PCR (qPCR) assay to determine the gene copy number of ldhA integrated in the genome of R. oryzae transformants and its effect on the stability of transformants. We successfully achieved R. oryzae transformants integrated with pBS-hygro-ldhA vector. The optimal hydrolysis time for protoplast production was 140 min, and the optimal field strength of electroporation pulse for protoplast was 13 kV/cm. The optimal germination time of spores for electroporation was 2.5 h, and the optimal field strength of electroporation pulse was 14 kV/cm. The transformation frequency of method based on germinated spores was generally higher than the methods based on protoplast. The qPCR test results suggested that transformants with high copy number of integration in a certain range were relatively stable. Our results provided basis and support for metabolic regulation and genetic engineering breeding of R. oryzae. PMID- 26762043 TI - [Effects of light intensity on associated enzyme activity and gene expression during callus formation of Vitis vinifera]. AB - We analyzed the best light intensity for callus induction and maintenance in Vitis vinifera and explored the mechanism of grape callus browning. Tender stem segments of grape cultivar "gold finger" were used to study the effects of different light intensities (0, 500, 1 000, 1 500, 2 000, 2 500, 3 000 and 4 000 Lx) on the induction rate, browning rate and associated enzyme activity and gene expression during Vitis vinifera callus formation. The callus induction rate under 0, 500, 1 000 and 1 500 Lx was more than 92%, significantly higher than in other treatments (P < 0.05). A lower browning rate and better callus growth were also observed during subculture under 1 000 and 1 500 Lx treatments. We found that chlorogenic acid, caffeic acid, p-hydroxybenzoic acid and coumaric acid contents were correlated with the browning rate of callus, among which chlorogenic acid content was positively correlated with the browning rate (P < 0.05). Peroxidase (POD) and polyphenol oxidase (PPO) activities were negatively correlated with the browning rate of callus (P < 0.01). The POD, PPO and phenylalanine ammonialyase (PAL) expression levels were positively correlated with the browning rate at P < 0.05 or P < 0.01. An appropriate light intensity for the tissue culture of Vitis vinifera was 1 000-1 500 Lx, higher or lower light intensities significantly impaired normal callus growth. PMID- 26762044 TI - [Preparation of a novel AAV-ITR gene expression mini vector in Sf9 insect cells via baculovirus]. AB - AAV-ITR gene expression mini vector is a double-strand or single-strand DNA that only contains inverted terminal repeats of adeno-associated virus, cis-elements and gene of interest and does not contain any other foreign DNA sequences. We prepared Bac-ITR-EGFP and Bac-inrep. Spodoptera frugiperda cells were infected with Bac-ITR-EGFP (P3) and Bac-inrep (P3). Up to 100 MUg of AAV-ITR-EGFP gene expression mini vectors were extracted from 2 x 10(7) cells of Sf9 72 h after infection. The gel electrophoresis analysis shows that most forms of AAV-ITR-EGFP gene expression mini vector were monomer and dimer. The mini vector expression efficacy was examined in vitro with HEK 293T cells. The EGFP expression was observed at 24 h after transfection, and the positive ratio reached 65% at 48 h after transfection. PMID- 26762045 TI - [Efficacy of RNA interference mediated by cationic liposomes]. AB - To investigate the cytotoxicity of the homemade peptide cationic liposome CDO14 and its efficacy of RNA interference (RNAi). MTT method was used to determine the cytotoxicity of the liposome to a human lung cancer cell line Luc-A549 that can express luciferase stably. Luciferase siRNA (Luc-siRNA) was transfected into Luc A549 cells by CDO14. Contents of luciferase in the transfected cells were detected by luminous instrument and contents of total protein in these cells were detected by BCA method. Nude mice were inoculated with Luc-A549 cells in axilla to establish xenograft tumor model. Complexes of Luc-siRNA and the cationic liposomes were injected into the modeling mice via tail vein. Contents of luciferase in the transfected mice were detected by the whole body imaging system. The cytotoxicity of the homemade cationic liposome was similar to that of commercial liposome DOTAP, and lower than that of Lipo2000. The siRNA transfection efficacy mediated by CDO14 was higher than that mediated by DOTAP. The homemade peptide cationic liposome CDO14 is expected to serve as delivery vector in gene therapy because of its low cytotoxicity and high transfection efficiency. PMID- 26762046 TI - [Interaction of Flightless I with Nup88 and Importin beta]. AB - High expression of Fightless I (FLII) is associated to multiple tumors. Based on our previous study that FLII might be involved in the nuclear export, we assessed the possible interaction of FLII with the nuclear envelop associating proteins Importin beta and Nup88. We first constructed GST-FLII, GST-LRR recombinant plasmids and transformed them into the Rosetta strain to produce GST-FLII, GST LRR fusion protein. After purification of these proteins, GST-pull down, as well as co-immunoprecipitation, were used to test the interaction of FLII with Importin beta and Nup88. FLII interacted with Importin beta and Nup88, and FLII LRR domain is responsible for these interactions. Thus, FLII may play a role in nuclear export through interaction with Importin beta and Nup88. PMID- 26762047 TI - [Yeast expression and application of an antifreeze protein from the desert beetle Microdera punctipennis]. AB - Insect antifreeze protein (AFP) has high antifreeze activity. Antifreeze proteins can be used in cryopreservation of biological tissues and cells. We expressed an antifreeze protein from the desert beetle Microdera punctipennis in yeast and determined the function of the protein at low temperatures. Yeast expression vector, pPIC9K-Mpafp698, was constructed and transformed into Pichia pastoris GS115. The expression of MpAFP698 was induced by methanol, and identified by tricine SDS-PAGE and Western blotting. Mpafp698 gene was inserted into the genome of the host yeast strain GS115, and correctly expressed. Hardly any yeast's own protein was secreted into the media. Cryoprotective experiments showed that MpAFP698 can significantly protect mouse liver as well as other mouse organs from cold damage compared with those in the control of Bovine serum albumin (BSA) addition. Besides, the hemolysis of blood cells protected by MpAFP698 at 4 degrees C was reduced and the survival rate of SF9 cells protected by MpAFP698 after freezing and thawing was increased compared to those of the control with BSA addition. Our results showed that MpAFP698 can be expressed in yeast, which allows a convenient purification of the MpAFP protein that has the cryoprotective effect. PMID- 26762048 TI - [Fungal Disease Survey and Pathogen Identification on Codonopsis tangshen in Chongqing]. AB - OBJECTIVE: To confirm the current major diseases and corresponding pathogens of Codonopsis tangshen in Chongqing. METHODS: The main cultivation regions of Codonopsis tangshen in Chongqing were systematically investigated, and the pathogens of the obtained specimens were isolated and identified. RESULTS: Totally, five fungal diseases in Codonopsis tangshen were identified, including rust disease (Puccinia campanumoeae Pat.), root rot (Fusarium oxysporum Schl.), violet root rot (Helicobasidium mompa Tanaka), powdery mildew (Sphaerotheca codonopsis (Golov.) Z. Y. Zhao), and blight (Septoria codonopsidis Ziling). Currently, the diseases with the serious damage on Codonopsis tangshen included rust disease, root rot and violet root rot. CONCLUSION: Rust disease, the severest disease,whose incidence reaches 100%, is an urgent problem waiting to be solved effectively in Codonopsis tangshen cultivation. PMID- 26762049 TI - [Study on Genetic Stablity of Cryopreservation Regeneration Plant of Gentiana straminea with ISSR-PCR]. AB - OBJECTIVE: To establish ISSR-PCR system of cryopreservation regeneration plant of Gentiana straminea, and to select appropriate primers and analyze the genetic stability. METHODS: DNA was extracted by CTAB, the optimal ISSR-PCR system was established by orthogonal experiment,and genetic stability was analyzed. RESULTS: The optimal ISSR-PCR system (25 MUL) was established: dNTPs 0.50 MUL, Mg2+ 1.00 MUL, 10 x PCR Buffer 2.00 MUL, primer 0.60 MUL, Taq DNA polymerase 1.25 MUL, template DNA 1.30 MUL, and ddH2O 18.35 MUL. The amplification program was devised: 94 degrees C for 5 min, denaturing at 94 degrees C for 30 s, annealing of 1 min due to denaturing temperature of different primer,extension at 72 degrees C for 1.5 min, 35 cycles, last extension at 72 degrees C for 7 min, conservation at 4 degrees C . The DNA mutation rate of cryopreservation regeneration plant of Gentiana straminea was 1.05%. CONCLUSION: The cryopreservation regeneration plant of Gentiana straminea retains very good genetic stability, there is little variation between each plant, so the cryopreservation can be used as a feasible method for resource protection of Gentiana straminea. PMID- 26762050 TI - [Biological Characteristics and Pollen Morphology of Different Chaenomeles Species in Flowering Stage]. AB - OBJECTIVE: The biological characteristics and pollen morphology of different Chaenomeles species in the flowering stage were studied,in order to provide a theoretical basis to discriminate the germplasm resources and new cultivars selection. METHODS: Field research and scanning electron were used for the research of the biological characteristics and pollen morphology of Chaenomeles species. RESULTS: The differences were significant both in the size of petal and the quantity of stamen in different kinds of Chaenomeles species. The pollen of Chaenomeles speciosa and Chaenomeles japonica were perprolate, and the ratio of the length between poles and diameter of the equator was more than two. The ratio of Chaenomeles sinensis, Chaenomeles cathayensis and Chaenomeles thibeticae ranged from 1.87 to 1.93 and they were prolate. The characteristics,such as the length between poles of pollen grain,diameter of the equator, the ratio of the length between poles and diameter of the equator, surface ornamentation and tectum perforation, had close genetic relationship with Chaenomeles species. CONCLUSION: Biological characteristics and pollen morphology could be the value reference to identify different kinds of Chaenomeles species. PMID- 26762051 TI - [Study on Reproductive Performance of Hirudio nipponica]. AB - OBJECTIVE: To investigate the reproductive performance of Hirudo nipponica under artificial cultivation, in order to provide reference for the commercial rearing and breeding industry of this species. METHODS: The mean number of cocoons, cocoon weight, hatching numbers of cocoons, and the effect of parent leeches weight and density on reproductive performance were investigated. RESULTS: The mean number of cocoons produced by parent leeches was 0.9000 +/- 0.5525, the range was from 0 to 2. The hatching number of cocoons were between 3 and 21, and the weight of cocoons were from 0.05 to 0.25 g. Length of newly hatched juvenile was 1.21 +/- 0.22 cm, and the range was from 0.82 to 1.55 cm. It was found that the parent leeches weight, density and the cocoons weight were positively correlated to the reproductive performance of Hirudio nipponica. CONCLUSION: In artificial cultivation, moderate weight, age and density of parent leeches is necessary to be chose for increasing the reproductive performance of Hirudio nipponica. PMID- 26762052 TI - [Quality Analysis and Evaluation of Anemarrhena asphodeloides Rhizome from Different Habitats]. AB - tive: To compare and analyze the quality of Anemarrhena asphodeloides rhizome from different habitats. METHODS: Simultaneous determination of nine components in Anemarrhena asphodeloides rhizome by UPLC-TQ/MS was performed on a Phenomenex Kinetex XB-C18 (100 mm x 2.1 mm, 1.7 MUm) column with the mobile phase consisted of 0.1% formic acid-acetonitrile (gradient elution) at the flow rate of 0.4 mL/min and thecolumn temperature at 35 degrees C. Multiple reaction mode detection (MRM) in mode was used in this assay. RESULTS: Nine components were separated totally within 15 min. Good correlation were found between the investigated compounds concentrations and their peak areas within the test ranges with the correlation coefficient from 0.9917 to 0.9992. The average recoveries were from 98.1% to 103.7%, and the RSD of precision was in the range of 1.7% - 4.7%. 0.074-3.620 mg/g for sarsasapogenin, 0.042-2.530 mg/g for timosaponin A III, 22.1- 50.4 mg/g for timosaponon B II, 0.10 -8.28 mg/g for officinalisinin II, 0.64 -7.29 mg/g for anemarsaponin B III, 3.28 -27.40 mg/g for mangiferin, 1.83 - 7.21 mg/g for isomangiferin, 0.36 -9.25 mg/g for neomangiferin and 4.72 x 10(-5) - 1.38 x 10(-3) mg/g for baohuoside I in Anemarrhena asphodeloides rhizome from different habitats were detected. CONCLUSION: The method is rapid, accurate and can be used for quality evaluation of Anemarrhena asphodeloides rhizome. The quality of Anemarrhena asphodeloides rhizome from different habitats are different. The saponins content of Anemarrhena asphodeloides rhizome in Hebei is higher than that of the others. PMID- 26762053 TI - [Flow Cytometric Analysis of Genome Size in Atractylodes lancea]. AB - OBJECTIVE: To develop a rapid analytical method for the determination of genome size of Atractylodes lancea by flow cytometry (FCM), and to estimate genome size of five typical plant types of cultivated Atractylodes lancea. METHODS: The fresh young leaves of Atractylodes lancea were used for the preparation of nuclear suspension with two-step protocol. After staining with propidium iodide, the mixture was analyzed by flow cytometry. Zea mays 'CE-777' or Vicafaba 'Inorce' was used for DNA reference standard. RESULTS: The flow cytometric method was developed after screening internal standard, optimizing sample preparation and FCM setups. The narrow leaf type of Atractylodes lancea got the biggest genome size, whereas the smallest one was fasciated stem type. It was suggested that parted leaf might be caused by genome size decrease. CONCLUSION: The methodology presented in this study is suitable for measuring the genome size of Atractylodes lancea. This study also provides useful information on population variation, evaluation of germplasm resources, and breeding of Atractylodes lancea. PMID- 26762054 TI - [Effects of Oxygen Carriers on Submerged Fermentation of Poria cocos]. AB - OBJECTIVE: To explore the regulation effects of oxygen carriers on Poria cocos submerged fermentation system which usually can be seriously inhibited by dissolved oxygen limitation. METHODS: One-factor-at-a-time design was employed to determine the oxygen carrier addition strategy through analyzing the effects of different oxygen carries, concentration and adding time of oxygen carrier on Poria cocos submerged fermentation. Then the oxygen carrier addition strategy was established and the metabolic processes of Poria cocos submerged fermentation were investigated comprehensively. RESULTS: The optimal oxygen carrier addition strategy was adding 1% (V/V) Tween-80 at 48 h after inoculation. Under this optimized condition, dry cell weight of Poria cocos reached 13.43 g/L in a 10 L bioreactor, while yields of exopolysaccharides and pachymic acid were 8.58 g/L and 989.52 MUg/L, respectively, which exhibited obvious promoting effects compared with no addition oxygen carrier fermentation process. CONCLUSION: Tween 80 can remarkably increase the levels of cell growth, exopolysaccharides biosynthesis and pachymic acid in Poria cocos submerged fermentation system, which may provide new reference for further exploring dissolved oxygen limitation in high density fermentation of medical fungi efficiently. PMID- 26762055 TI - [Fingerprint of Vinegar Processed Genkwa Flos Based on Improving Euclidean Distance]. AB - OBJECTIVE: To improve the traditional fingerprint method to distinguish vinegar processed Genkwa Flos from raw Genkwa Flos. METHODS: Ten batches of Genkwa Flos were collected, processed with vinegar through a standard method, and then analyzed under the optimum HPLC condition. Based on the chromatographic data obtained, a common model of vinegar processed Genkwa Flos fingerprints, including 11 common peaks and the components genkwanin, hydroxygenkwanin, luteolin, apigenin and yuanhuacin were identified, was established. The peak of baicalein, an exogenous component added quantitatively to the samples as an internal standard, was served as the reference peak. The similarity between the test samples and the common model was computed using the improved Euclidean distance method developed in this paper. RESULTS: The similarities between vinegar processed Genkwa Flos samples and the common model were higher than 0.9, whereas those between raw Genkwa Flos and the common model were lower than 0.9. CONCLUSION: The proposed method thus effectively provides a clear distinction between vinegar processed and raw Genkwa Flos samples. The result is helpful to ensure the safe clinical use of the plant and expand the application field of fingerprinting technology. PMID- 26762056 TI - [Changes of Furan Constituents in Rhizome of Three Species of Polygonatum Before and After Processing]. AB - OBJECTIVE: To establish a rapid analytical method for furan components before and after processing of Polygonatum rhizome by static headspace injection GC-MS. METHODS: The volatile components were extracted by headspace injection technique and analyzed by GC-MS, and the furan components of three species of Polygonatum rhizome before and after processing were determined by semi quantitative GC-MS. RESULTS: Three species of Polygonatum rhizome had significant differences in furan components contents, Polygonatum cyrtonema ~ Polygonatum kingianum > Polygonatum sibiricum. Each species of Polygonatum rhizome had a corresponding increase in almost all of the nine kinds of furan components after processing, steamed products > stewed products. CONCLUSION: This study provides a theoretical basis for further study of processing of Polygonatum rhizome. PMID- 26762057 TI - [Study on Genuineness Recognition of "Jiang Aurantii Fructus" by Analyzing Fingerprint Similarity Using Information Entropy Theory]. AB - OBJECTIVE: To study the genuineness recognition of traditional Chinese medicine by analyzing fingerprint similarity using information entropy theory, Aurantii Fructus was used as the model drug. METHODS: Fingerprints of different sources of Aurantii Fructus were analyzed by HPLC. "Jiang Aurantii Fructus" genuineness was evaluated by analyzing fingerprint similarity using information entropy theory and compared with the results of traditional calculated methods. RESULTS: The new method obviously improved the effect of genuineness recognition of "Jiang Aurantii Fructus". CONCLUSION: This method provides scientific reference for "Jiang Aurantii Fructus" genuineness identification. PMID- 26762058 TI - [HPLC Fingerprints of Clerodendrum lindleyi]. AB - OBJECTIVE: To establish the HPLC fingerprint of Clerodendrum lindleyi in order to provide the basis for its quality standard. METHODS: The chromatographic fingerprint was obtained with Angilent Zorbax C18 (250 mm x 4.6 mm, 5 MUm) column and gradiently eluted with acetonitrile-0.1% phosphoric acid solution. The column temperature was maintained at 35 degrees C. The flow rate was 1.0 mL/min and the detection wavelength was 327 nm. RESULTS: HPLC fingerprint of Clerodendrum lindleyi was established and 21 common peaks from 11 batches of samples were found. CONCLUSION: The method has good precision, stability and repeatability, which can provide reliable basis for quality evaluation of Clerodendrum lindleyi. PMID- 26762059 TI - [Chemical Constituents from Salvia przewalskii Root]. AB - OBJECTIVE: To study the chemical constituents of the root of Salvia przewalakii. METHODS: The chemical constituents were isolated and purified by means of chromatographic techniques and their structures were elucidated by spectroscopic methods. RESULTS: 17 compounds were isolated and identified as danshenxinkun B (1), danshenol C (2), isotanshinone (3), 1,2-dihydroisodihydrotanshinone-I (4), isotanshinone-II A (5), dihydrotanshinone-I (6), tanshinlactone (7), danshenol B (8), tanshinone-I (9), danshenspiroketallactone (10), ferrugino (11), epi danshenspiroketallactone (12), danshenxinkun A (13), sapriolactone (14), 12 hydroxy-6,7-secoabieta-8,11,13-trien-6,7-diol (15), 6alpha-hydroxysugiol (16) and hypargenin B (17). CONCLUSION: Compounds 1 - 8 are isolated from this plant for the first time. PMID- 26762060 TI - [Lignans from Stem Bark of Styrax perkinsiae]. AB - OBJECTIVE: To study the chemical constituents in the stem bark of Styrax perkinsiae. METHODS: The chemical constituents were separated and purified by chromatographic methods after solvent extraction and identified by spectroscopic analyses. RESULTS: Ten lignans were isolated from the stem bark of Styrax perkinsiae and identified as following: pinoresinol 4-O-beta-D-glucopyranoside (1), matairesinoside (2), styraxlignolide B (3), 3- (beta-D glucopyranosyloxymethyl)-2-(4-hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl )-7 methoxy-(2R , 3S) -dihydrobenzofuran (4), burselignan (5), (+) -neo-olivil (6), threo-1-(4-hydroxy-3-methoxyphenyl )-2-[ 4-(3-hydroxypropyl)-2-methoxyphenoxy]-1, 3-propanediol (7), erythro-1-(4-hydroxy-3-methoxyphenyl )-2-[ 4-(3-hydroxypropyl )-2-methoxyphenoxy ] -1 ,3-propanediol (8), isolariciresinol(9) and (+) lariciresinol (10). CONCLUSION: Compounds 5 - 10 are isolated from the plants of Styrax genus for the first time. PMID- 26762061 TI - [Steroidal Glycoside Constituents from Solanum cumingii]. AB - OBJECTIVE: To investigate the steroidal glycoside constituents of Solanum cumingii. METHODS: The compounds were isolated by silica gel, Sephadex LH-20, RP C18 column and Pre-HPLC chromatography. Their structures were identified by ESI MS and NMR. RESULTS: Six known compounds including torvoside K (1), torvoside J (2), torvoside L (3), khasianine (4), aculeatiside A (5) and solamargine (6) were isolated from Solanum cumingii. CONCLUSION: All compounds are isolated from Solanum cumingii for the first time. PMID- 26762062 TI - [Chemical Constituents From Rhus chinensis Fruit Dregs]. AB - OBJECTIVE: To isolate and elucidate the constituents from the fruit dregs of Rhus chinensis. METHODS: The constituents were isolated and purified by chromatography on silica gel,Sephadex LH-20, RP-C18 gel and recrystallization. The structures were elucidated on the basis of the chemical evidence and spectroscopic data. RESULTS: Ten compounds were obtained: beta-sitosterol (1), morolic acid (2), (2S) -1-O-heptatriacontanoyl glycerol (3), alpha-monpalmitin (4), palmitic acid (5), gallic acid (6), methyl gallate (7), ethyl gallate (8), propyl gallate (9), and protocatechuic acid (10). CONCLUSION: Compounds 3, 4 and 9 are isolated from the plants of Rhus genus for the first time. PMID- 26762063 TI - [Comparative Study on Volatile Oil Composition of Chuanxiong Rhizoma, Angelicae Sinensis Radix and Ligustici Rhizoma et Radix]. AB - OBJECTIVE: To identify Chuanxiong Rhizoma,Angelicae Sinensis Radix and Ligustici Rhizoma et Radix by establishing the HPLC specific chromatograms of their volatile oil and to compare their specific peaks. METHODS: The HPLC method used methanol-water as mobile phase. Their specific peaks were analysed by HPLC-MS. RESULTS: Under the selected spectrum condition, their HPLC specific chromatograms were established. Senkyunolide A, butylphalide, coniferylferulate, E-ligustilide, Z-ligustilide, neocnidilide and E-butylidenephthalide were identified as specific peaks in chromatograms based on their MS data. CONCLUSION: This method is simple, accurate and available to identify Chuanxiong Rhizoma, Angelicae Sinensis Radix and Ligustici Rhizoma et Radix. It provides reference for quality control of their medicinal materials and Chinese Patent Medicine. PMID- 26762064 TI - [Protective Effect of Total Saponins of Panax japonicus Against H2O2-Induced Oxidative Stress Damage]. AB - OBJECTIVE: To investigate the protective effects of total saponins of Panax japonicus (TSPJ) on H2O2-induced oxidative stress damage in SH-SY5Y cells, and to explore the underlying mechanism. METHODS: SH-SY5Y cells were incubated with 600 MUmol/L H2O2 for 12 h, then treated with various concentrations of TSPJ (0.1, 1, 5 and 20 MUg/mL) for 12 h,and then incubated with 600 MUmol/ L H2O2 for 12 h. Cell viability was detected by MTT assay. Superoxide dicmutase (SOD) activities and malondialdehyde( MDA) contents were measured by biochemical assay kits. Protein levels of Nrf2,p-ERK, and p-P38 were detected by Western blotting. Levels of NQO1 and GCLC mRNA expression were determined by real-time PCR. RESULTS: Compared with control group, H2O2 stimulated the decrease of cell viability and SOD activities as well as the increase of MDA contents, which were reversed by TSPJ treatment. Furthermore, TSPJ treatment up-regulated not only the decreased protein expressions of Nrf2 and p-ERK but also the decreased mRNA expression of NQO1 and GCLC. CONCLUSION: TSPJ can protect SH-SY5Y cells from H2O2-induced oxidative stress damage. The mechanism may be related to up-regulating the phosphorylation of ERK thereby promoting the Nrf2 nuclear translocation and increasing the mRNA expression of antioxidant genes such as NQO1 and GCLC. PMID- 26762065 TI - [Cardioprotective Effect and Its Mechanism of Total Saponins of Panacis Majoris Rhizoma in Myocardial Infarction Rats]. AB - OBJECTIVE: To explore the cardioprotective effect and its mechanism of total saponins of Panacis Majoris Rhizoma in myocardial infarction (MI) rats. METHODS: The MI model rats induced by ligating anterior descending branch of coronary artery were randomly divided into four group:model group, total saponins of Panacis Majoris Rhizoma (100 and 200 mg/kg) groups and compound Danshen dripping pills group. The rats were orally administrated with drugs once a day for four weeks. Another rats were selected as sham operation group. After four weeks intervention, cardiac function was examined, the serum levels of TNF-alpha, IL 1beta, IL-6 and IL-8 were measured by using ELISA, respectively. The myocardial hypertrophy index was investigated, the myocardial infarct size, degree of ventricular dilatation, myocardial interstitial collagen volume fraction and tissue morphology were investigated by HE, Masson, picric acid-sirius red staining and observing with alight microscope and electron microscope. Protein expressions of phosphorylation IkappaB-alpha( pIkappaB-alpha) and NF-kappaB p65 in heart tissue were detected by Western blotting. RESULTS: Total saponins of Panacis Majoris Rhizoma might significantly decrease the levels of serum TNF alpha, IL-1beta, IL-6 and IL-8; decrease myocardial hypertrophy indexes, myocardial infarct size, degree of ventricular dilatation and myocardial interstitial collagen volume fraction; improve heart tissue morphology and cardiac function; downregulate protein expression of pIkappaB-alpha and NF kappaBp65; and upregulate protein expression of SIRT1. The aforementioned action effects of total saponins of Panacis Majoris Rhizoma (200 mg/kg) were similar with compound Danshen dripping pills. CONCLUSION: Total saponins of Panacis Majoris Rhizoma possesses cardioprotective effect against ligating left anterior descending branch induced MI in rats. The mechanism may be related to strengthening SIRT1 expression, inhibiting the phosphorylation of IkappaB-alpha, and finally inhibiting the activation of NF-kappaB and proinflammatory production. PMID- 26762066 TI - [Effect of Jinlida on DGAT1 in Skeletal Muscle in Fat-Induced Insulin Resistance ApoE -/- Mice]. AB - OBJECTIVE: To investigate the effect of Jinlida on DGAT1 in skeletal muscle in fat-induced insulin resistance ApoE-/- mice. METHODS: Eight male C57BL/6J mice were used as normal group. 40 male ApoE -/- mice were fed high-fat diet for 16 weeks and divided into five groups: control group, rosiglitazone group, and Jinlida low, middle and high dose groups. Then corresponding drugs were administrated intragastrically for eight weeks. TG content in skeletal muscle was measured by enzymic enzymatic, Glucose tolerance test (OGTT) was used to evaluate the degree of insulin resistance in mice. The mRNA and protein expression of insulin receptor substrate (IRS-1) and diacylglycerol acyltransferase 1 (DGAT1) in skeletal muscle were measured by real-time quantitative reverse transcription PCR (RT-PCR)and Western blot. RESULTS: Jinlida particles reduced fasting blood glucose (FBG) cholesterol (TC), triglyceride (TG), free fatty acid (FFA)and fasting insulin (FIns) levels, raised insulin sensitive index (ISI), improved glucose tolerance, and reduced skeletal muscle lipid deposition in ApoE -/- mice significantly. Jinlida particles increased the expression of IRS-1 mRNA and protein, and reduced DGAT1. CONCLUSION: Jinlida can alleviate the expression of DGAT in skeletal muscle in fat-induced insulin resistance ApoE-/- mice. PMID- 26762067 TI - [Protective Effect of Lycium ruthenicum on Peripheral Blood System Against Radiation Injury in Mice]. AB - OBJECTIVE: To study the protective effect of Lycium ruthenicum on peripheral blood system against radiation injury in mice. METHODS: Kunming mice were randomly divided into control group, model group, positive group and Lycium ruthenicum high dose (8 g/kg), middle dose (4 g/kg) and low dose (2 g/kg)treatment groups that experimented three days after irradiation. In the same way, groups were set at 7 days and 14 days after irradiation respectively. Lycium ruthenicum extract were administered orally to the mice in the three Lycium ruthenicum treatment groups and normal saline were administered orally to the mice in control group and model group for 14 days. Positive group were treated with radioprotective agent amifostine (WR-2721) at 30 min before irradiation. Except control group, mice in other groups received quantity of 5 Gy X-radiation whole body evenly with one time. Hemogram, organ index, DNA, Caspase-3, Caspase-6 and P53 contents were observed at the 3rd, 7th and 14th day after irradiation. RESULTS: Lycium ruthenicum significantly increased the total red blood cell count, hemoglobin count, the indexes of spleen and thymus and bone marrow DNA contents (P < 0.05), as well as decreased Caspase-3 and Caspase-6 contents in serum and the expression of P53 in intestinal crypt epithelial cells. CONCLUSION: The results showed that Lycium ruthenicum had protective effects on peripheral blood system against radiation injury in mice. PMID- 26762068 TI - [Effect of Viqi Chutan Recipe on Caspase-4 and DNA-PK of Cell Apoptosis Approach in Transplanted Lung Cancer A549 Cells in Nude Mice]. AB - OBJECTIVE: To study the inhibitory effect of Yiqi Chutan Recipe on the transplanted tumor through endoplasmic reticulum UPR-mediated approach. METHODS: 40 lung cancer A549 cells models transplanted in nude mice were established. On the 7th day of inoculation, mice were randomly divided into model group( saline group) , Cisplatin group (0.002 g/kg), Yiqi Chutan Recipe low dose group (3.0 g/kg), Yiqi Chutan Recipe high dose group(6. 0 g/kg)and Yiqi Chutan Recipe (3.0 g/kg)with Cisplatin group (0.002 g/kg). Each aforementioned group had eight mice. Mice were treated by Yiqi Chutan Recipe to gavage one time a day, for 21 days, and by Cisplatin Injection to intraperitoneal injection one time a day, for 7 days. On the 22th day, all mice were executed to death. Then each tumor's weight and volume were measured, and the expression of Caspase-4 and DNA-PK protein were detected through immunohistochemical method and Western blot method. RESULTS: Compared with model group, the tumors' volume and weight of Yiqi Chutan Recipe high dose group and Yiqi Chutan Recipe with Cisplatin group were decreased, but the expressions of Caspase-4 and DNA-PK protein in tumors were increased (P < 0.01). Yiqi Chutan Recipe with Cisplatin Group had the better effect (P < 0.05). CONCLUSION: Yiqi Chutan Recipe has a certain inhibitory effect on A549 lung cancer in mice and its possible mechanism is relevant to the increase of expression of Caspase-4 and DNA-PK protein. PMID- 26762069 TI - [Optimization of Polysaccharide Extraction from Spirodela polyrrhiza by Plackett Burman Design Combined with Box-Behnken Response Surface Methodology]. AB - OBJECTIVE: To optimize the processing of polysaccharide extraction from Spirodela polyrrhiza. METHODS: Five factors related to extraction rate of polysaccharide were optimized by the Plackett-Burman design. Based on this study, three factors, including alcohol volume fraction, extraction temperature and ratio of material to liquid, were regarded as investigation factors by Box-Behnken response surface methodology. RESULTS: The effect order of three factors on the extraction rate of polysaccharide from Spirodela polyrrhiza were as follows: extraction temperature, alcohol volume fraction,ratio of material to liquid. According to Box-Behnken response, the best extraction conditions were: alcohol volume fraction of 81%, ratio of material to liquid of 1:42, extraction temperature of 100 degrees C, extraction time of 60 min for four times. CONCLUSION: Plackett-Burman design and Box-Behnken response surface methodology used to optimize the extraction process for the polysaccharide in this study is effective and stable. PMID- 26762070 TI - [Rapid Identification of Chemical Components in Polygonum multiflorum Formula Granules by UPLC/Q-TOF MS]. AB - OBJECTIVE: To establish a simple and reliable method for rapid separation and identification of chemical components in Polygonum multiflorum Formula Granules. METHODS: An ultra-performance liquid chromatography tandem quadrupole time-of flight mass spectrometric method( UPLC/Q-TOF MS) was used. The separation was performed on an Agilent Eclipse Plus C18 RRHD(100 mm x 2.1 mm, 1.8 MUm) column with a mobile phase of water and acetonitrile in a gradient elution mode. The flow rate was 0.4 mL/min and the column temperature was maintained at 25 degrees C. TOF MS was applied for qualitative analysis under positive ion mode. RESULTS: Five compounds were identified by the time of flight mass spectrometry and literature data. CONCLUSION: This method is accurate, rapid and sensitive, it can provide reference for the quality control of Polygonum multiflorum Formula Granules. PMID- 26762071 TI - [Preparation of Oenothera biennis Oil Solid Lipid Nanoparticles Based on Microemulsion Technique]. AB - OBJECTIVE: To study the preparation of Oenothera biennis oil solid lipid nanoparticles and its quality evaluation. METHODS: The solid lipid nanoparticles were prepared by microemulsion technique. The optimum condition was performed based on the orthogonal design to examine the entrapment efficiency, the mean diameter of the particles and so on. RESULTS: The optimal preparation of Oenothera biennis oil solid lipid nanoparticles was as follows: Oenothera biennis dosage 300 mg, glycerol monostearate-Oenothera biennis (2: 3), Oenothera biennis RH/40/PEG-400 (1: 2), RH-40/PEG-400 (1: 2). The resulting nanoparticles average encapsulation efficiency was (89.89 +/- 0.71)%, the average particle size was 44.43 +/- 0.08 nm, and the Zeta potential was 64.72 +/- 1.24 mV. CONCLUSION: The preparation process is simple, stable and feasible. PMID- 26762072 TI - [Accelerated postoperative rehabilitation: multidisciplinary issue (Part 1)]. AB - AIM: To discuss the main aspects of multimodal method of accelerated postoperative rehabilitation (fast track surgery). MATERIAL AND METHODS: The program of accelerated rehabilitation consists of minimization of surgical treatment's stressful influence on patient's organism in perioperative period. The method implies use of efficient preoperative management, minimally invasive operations, regional anesthesia and short-acting anesthetics, early postoperative rehabilitation. RESULTS: The program improves the results of surgical treatment, reduces number of complications and cost of treatment, improves the "quality" of hospital stay. PMID- 26762073 TI - The diagnosis and surgical treatment of cardiac pseudotumors. AB - AIM: Investigation of clinical-diagnostic, surgical and morphological features of cardiac pseudotumors. MATERIAL AND METHODS: Acad. B.V. Petrovskiy Russian Research Center for Surgery has experience of surgical treatment of 336 patients with cardiac pseudotumors followed from December 1962 to December 2014. Morphologically verified primary cardiac tumors were diagnosed in 269 (80.1%) patients. In this study it was analyzed the results of survey and treatment of 67 patients with cardiac pseudotumors who were under observation in institution since February 1970 to December 2014. There were 36 men and 31 women aged 2.2-74 years (mean age 34.1+/-2.1 years). RESULTS: Overall 1- and 24-year survival without hospital mortality according to Kaplan-Meier test was 100 and 94.3% respectively. Patients' life quality in the remote period significantly improved. Good postoperative results were obtained in 62.8% of cases, satisfactory--in 31.4% of patients, unsatisfactory--in 5.8% of survivors. Medical tactics in patients with morphologically unidentified cardiac neoplasms (29.9%) was determined by their small sizes (0.4-1 cm), absence of displaceability followed by risk of embolic syndrome, homogenous echogenicity and clear outlines, absence of hemodynamic disorders and clinical manifestations. CONCLUSION: Analysis showed that timely diagnosis of pseudotumors and morphologically unidentified cardiac neoplasms is very difficult. Successful operations require normothermic or hypothermic perfusion and pharmaco-cold cardioplegia to provide convenient exposure and adequate myocardial protection, prevention of neoplasm fragmentation with following embolism, correction of concomitant valve diseases, congenital heart diseases and coronary heart disease. PMID- 26762074 TI - [Surgical treatment for fibro-muscular dysplasia]. AB - AIM: To present the results of surgical treatment of patients with fibro-muscular dysplasia. MATERIAL AND METHODS: Our experience of treatment of 144 patients with fibro-muscular dysplasia is presented in the article. 118 (82%) patients suffered from stenoses, kinking and aneurysms of internal carotid arteries, 21 (14.5%) patients had lesion of renal arteries, 5 (3.5%) patients--azygous visceral arteries lesion. It was performed 157 reconstructive operations in the Department of cardiac surgery N(o)1 (aortic surgery) of acad. B.V. Petrovskiy Russian Research Center for Surgery for the period from 1993 to 2014. Clinical features of fibro-muscular dysplasia, surgical tactics and technique depending to the localization of lesion are described. RESULTS: Immediate and remote surgical results were studied. There were no any severe intraoperative and immediate postoperative complications. Follow-up after carotid surgery was 104.49+/-68.68 months (6-247 months). Strokes were not observed. Hemodynamically insignificant re-stenoses were diagnosed in 7 (5.5%) cases. Mean follow-up after renal reconstructions was 139.24+/-63.96 months (28-239 months). Persistent blood pressure normalization was achieved in 11 (73.3%) cases. Patients with azygous visceral arteries dysplasia have been examined for the period of 103.4+/-69.6 months (35-205 months). There were no recurrent aneurysms and abdominal ischemia in the remote postoperative period. Hospital and remote mortality was absent. Based on own experience and colleagues' data we consider that surgical treatment of patients with some forms of fibro-muscular dysplasia provides satisfactory results if advisable strategy is selected. PMID- 26762075 TI - [Cardiovascular disorders in case of acute gastrointestinal bleeding in patients with arterial hypertension]. AB - AIM: To investigate the blood pressure changes and electrocardiogram parameters for the 1st day after acute gastrointestinal bleeding in patients with arterial hypertension. MATERIAL AND METHODS: Indexes of blood pressure monitoring and electrocardiogram in case of acute gastrointestinal bleeding in patients with arterial hypertension were studied. 45 patients with arterial hypertension and acute gastrointestinal bleeding, 63 patients in acute stage of bleeding without hypertension and 48 patients suffering from hypertension without gastrointestinal bleeding were studied. Parallel simple open controlled investigation included blood pressure monitoring and Holter monitoring. RESULTS: Circadian dynamics of blood pressure in patients with arterial hypertension on the background of gastrointestinal bleeding was noted by reduced variability and insufficient reduction of pressure at night. Diastolic pressure decreased in accordance with severity of blood loss. Holter monitoring revealed high incidence of supraventricular ectopic activity, sinus arrhythmia and significant elongation of the ventricular electrical systole. PMID- 26762076 TI - [An experience of single lung resection and pneumonectomy after contralateral lung resection in treatment of tuberculosis]. AB - AIM: To improve the efficiency of treatment of single lung destructive tuberculosis. MATERIAL AND METHODS: 15-year experience of operations for destructive tuberculosis performed by the same surgeon including 18 resections of the single lung and 19 pneumonectomies after previous partial lung resection is presented in the article. RESULTS: Surgical management of patients with destructive tuberculosis of single lung provides positive results in more than 90% of cases. However the frequency of its application is still low according to literature data. In case of destructive tuberculosis of single lung partial resection is more frequently indicated if fibrous-cavernous tuberculosis of the upper lung (up to 4 damaged segments), persistent bacterial excretion on the background of adequate chemotherapy and pathogen's drug resistance are present. PMID- 26762077 TI - [Transarterial therapy for hepatocellular cancer]. AB - AIM: To estimate treatment of patients with hepatocellular cancer after transarterial chemoembolization as independent curative method, "bridge" to liver transplantation and in the context of combined therapy. MATERIAL AND METHODS: We presented an experience of transarterial chemoembolization in treatment of 29 patients with hepatocellular cancer. Curative procedures were performed in the context of independent therapy, "bridge" to liver transplantation and combined treatment. It was performed 48 procedures in all. 44.9% of patients underwent one and two procedures, 10.2%--three performances. Mean interval between procedures was 76.2+/-116.2 days (range 8-139 days). RESULTS: Post-embolization syndrome including fervescence, nausea and pain was observed in 24.1% after 1st stage, in 50% and 33.3% after 2nd and 3rd stages respectively. Mean time of expectation of liver transplantation in bridge therapy group was 8.5+/-6.8 months (range 1-20 months). Median survival after transarterial chemoembolization in monotherapy group was 9 months. PMID- 26762078 TI - [Robot-assisted pancreatoduodenectomy]. AB - AIM: To compare the results of robot-assisted and conventional techniques of pancreatoduodenectomy. MATERIAL AND METHODS: It was performed the retrospective investigation of results of robot-assisted and conventional pylorus-preserving pancreatoduodenectomy in 7 and 7 patients respectively. RESULTS: Duration of robot-assisted and conventional surgery was 460.71+/-119.77 and 288.57+/-62.2 minutes, volume of blood loss--414.28+/-285.36 and 400+/-163.30 ml respectively. Postoperative complications after robot-assisted technique were classified as Grade I according to Clavien-Dindo classification. Pancreatic fistulae were absent (ISGPF (2005)). Lower duration of abdominal drainage and opioid analgesia were observed. Also narcotic drugs were required by not all patients after robot assisted surgery. Histological study revealed the large number of excised lymphatic nodes. CONCLUSION: Obvious advantage of robot-assisted operation was precision of great vessels and lymphatic nodes dissection, performing anastomoses. Robot-assisted pancreatoduodenectomy corresponds to all requirements inherent to radical cancer surgery. PMID- 26762079 TI - [Jejunogastroplasty as an alternative method of gastrointestinal tract reconstruction after gastrectomy]. AB - AIM: To prove the surgical safety and functional efficiency of jejunogastroplasty with duodenal passage preservation as an alternative method of gastrointestinal tract reconstruction after gastrectomy. MATERIAL AND METHODS: It was analyzed the results of treatment of 60 patients who underwent gastrectomy for stomach cancer for the period from September 2009 to May 2013. Two congeneric groups by 30 patients who underwent Roux-en-Y reconstruction (control group) and jejunogastroplasty (comparison group) were prospectively compared. RESULTS: Immediate results did not significantly differ in the both groups. Blood loss was 528+/-61.0 and 507+/-71.2 ml, incidence of complications--20.0 and 6.7%, frequency of esophagostomy failure--3.3% and 0, postoperative mortality rate- 3.3% and 0, duration of postoperative hospital-stay--12.4+/-1.3 and 10.9+/-1.2 days respectively (p<0.05). In remote postoperative period the number of patients with stable body mass index or its positive changes was 52.9 and 81.8% in control and main groups, with dumping syndrome--47.1 and 9.1%, with diarrhea--35.3 and 4.5% respectively (p<0.05). Index of good state of health in main group was 68.2%, in control group--17.6% (p<0.05). In authors' opinion safety and physiological efficiency of jejunogastroplasty allow you considering its priority for primary reconstruction after gastrectomy and alternativeness to Roux-en-Y technique. PMID- 26762080 TI - [Laser doppler flowmetry in esophagogastroplasty]. AB - AIM: To present the results of laser Doppler flowmetry for assessment of gastric wall microcirculation. MATERIAL AND METHODS: The study enrolled 22 patients who underwent esophagogastroplasty. The changes in gastric microvasculature during tubular isoperistaltic transplant formation are described. Significant markers of impaired circulation in stomach transplant 5-6 cm apart from right gastroepiploic artery termination were revealed. RESULTS: Esophagogastrostomy at this level and more proximally increases the risk of anastomosis failure and cicatrical stenosis. PMID- 26762081 TI - [Thoracoscopic operations for neurogenic tumors in children]. AB - AIM: To present an overall experience of endoscopic operations in children with neurogenic tumors in two medical institutions. MATERIAL AND METHODS: Thoracoscopic excision of tumors was performed in 19 children aged 1 month-7.5 years (mean 1.5 years) in two clinics for the period 2010-2014. In 9 children (47.3%) age did not exceed 1 year. In our study ganglioneuroma was diagnosed in 9 cases, ganglioneuroblastoma--in 2 patients, neuroblastoma stage I--in 8 cases. All patients were under observation and treated according to NB2004 protocol. Tumor's diameter ranged from 1 to 6 cm (mean 4.9+/-1.9 cm). Mean duration of surgery was 62+/-22 minutes. There were no any intraoperative complications. Early postoperative period in all patients after endoscopic surgery was more favorable than in those after open operations. Any local recurrences were not observed for the follow-up period. RESULTS: Thoracoscopic operations can become more preferable method in treatment of children with neurogenic tumors if great vessels are not involved into neoplastic process and limited volume of tumor is absent. PMID- 26762083 TI - [Abdominal aortic replacement on background of acute intestinal obstruction]. PMID- 26762082 TI - [Features of application of Factor Xa inhibitor at patients with damages of large segments of the lower extremities]. AB - One of the complications of injuries due to the orthopedic manipulation is the development of venous thromboembolism. This article represents data from a study whose purpose was to conduct a comparative assessment of the effectiveness of rivaroxaban and enoxaparin for the prevention of thrombosis in patients after the blocked intramedullary nailing (BIOS), as well as to assess the patients' adherence to anticoagulant therapy. In a prospective study we examined the results of the treatment of 98 patients with fractures of the tibia or femur. The two groups of patients were assigned to thromboprophylaxis with rivaroxaban (58 patients), 10 mg once daily or enoxaparin (40 patients), 40 mg once a day. The effectiveness criteria of the therapy were diagnosed venous thromboembolisms. Adherence to treatment was assessed as the proportions of patients adhere to prescribed drug regimen. Venous thromboembolic events were observed in two patients (2%) (one per group of rivaroxaban and enoxaparin), p>0.05. Assessment of adherence: in the rivaroxaban group 47 (81%) patients were adherent, in the enoxaparin group--6 patients (15%), p<0.05. This study demonstrates that in clinical practice rivaroxaban can be an effective alternative to low molecular weight heparin to prevent thrombosis in patients after the conducted BIOS. Patients adherence of oral anticoagulant therapy significantly higher. PMID- 26762084 TI - [Underlay-plasty for strangulated umbilical hernia in patient with obesity]. PMID- 26762085 TI - [Hybrid surgery on background of idiopathic thrombocytopenic purpura]. PMID- 26762086 TI - [Optimization of treatment and prevention of scars]. PMID- 26762087 TI - [Mechanisms of development and correction of immune and oxidative disorders in case of peritonitis]. PMID- 26762088 TI - [Structural Features of Cysteine-Stabilized Polypeptides from Sea Anemones Venoms]. AB - Nowadays, venom-based drug discovery becomes popular again: pharmaceutical companies evaluate animal venom potential as a combinatory library of biologically-active compounds. Collaborations with research groups from academia are intensified, new toxins are being investigated, among which polypeptides are of paramount importance. Sea anemones produce the most diversified, from structural point of view, polypep- tide venom components among other animals. This particular review considers known polypeptide toxins from sea anemones, basically taking into account its classification by primary structural features. The most important functional characteristics are analyzed in each structural class. PMID- 26762089 TI - [Octarphin--Nonopioid Peptide of the Opioid Origin]. AB - The data on the properties and mechanism of action of the peptide octarphin (TPLVTLFK, the fragment 12-19 of beta-endorphin)--a selective agonist of nonopioid (insensitive to the action of the opioid antagonist naloxone) beta endorphin receptor found on n immune cells (peritoneal macrophages, T and B lymphocytes of spleen and blood), endocrine (adrenal cortex, hypothalamus), cardiovascular (cardiomyocytes) systems are analyzed and systematized. Binding to the receptor octarphin increases increases the mitogen-induced pro- liferation of human and mouse T and B lymphocytes in vitro, activates murine peritoneal macrophages in vitro and in vivo, stimulates growth of human T-lymphoblast cell lines Jurkat and MT-4, inhibits adenylate cyclase activity of rat adrenal cortex membranes and suppresses the secretion of glucocorticoids from the adrenal gland into the blood. It was shown that in a concentration range of 1-1000 nM the peptide increases the activity of inducible NO-synthase (iNOS), and the content of NO and cGMP in lipopolysaccharide-activated murine peritoneal macrophages. Taking into account that NO acts as a primary activator of soluble guanylate cyclase (sGC), it can be assumed that the activating effect of octarphin on macrophages is realized in the following way: increase in th iNOS expression --> increase in the NO production --> increase in the sGC activity --> increase in intracellular levels of cGMP. PMID- 26762090 TI - [Tyrosyl-DNA Phosphodiesterase 1 Is a New Player in Repair of Apurinic/Apyrimidinic Sites]. AB - Genomic DNA is constantly damaged by the action of exogenous factors and endogenous reactive metabolites. Apurinic/apyrimidinic sites (AP sites), which occur as a result of DNA glycosylase induced or spontaneous hydrolysis of the N glycosidic bonds, are the most common damages of DNA. The chemical reactivity of AP sites is the cause of DNA breaks, and DNA-protein and DNA-DNA crosslinks. Repair of AP sites is one of the most important mechanisms for maintaining genome stability. Despite the fact that the main participants of the AP site repair are very well studied, the new proteins that could be involved potentially in this process as "back up" players or perform certain specialized functions are being found. This review is dedicated to one of these proteins, tyrosyl-DNA phosphodiesterase 1 (Tdp1), for which we have recently shown that in addition to its main activity of specific cleavage of the tyrosyl-DNA bond formed via a covalent attachment of topoisomerase 1 (Top1) to DNA, Tdp1 is able to initiate the cleavage of the internal AP sites in DNA and their following repair. Tdp1 was discovered in Saccharomyces cerevisiae yeast as an enzyme hydrolyzing the covalent bond between tyrosyl residue of topoisomerase 1 and 3'-phosphate group in DNA. Tdp1 is the major enzyme which carries out the repair of the irreversible complexes of DNA and topoisomerase 1, which appear. in the presence of Top 1 inhibitors, such as camptothecin, therefore Tdp1 is a very important target for the development of inhibitors--anticancer drugs. Besides, Tdp1 hydrolyzes a wide range of 3'-terminal DNA modifications and the 3'-end nucleosides and its derivatives to form a 3'-phosphate. Tdp1 ability to cleave AP sites suggests its involvement in the base excision repair as an alternative enzyme to cleave AP sites instead of AP endonuclease 1--the major enzyme hydrolyzing AP sites in DNA repair process. PMID- 26762091 TI - [Supramolecular Agents for Theranostics]. AB - This mini-review summarizes recent data obtained in the process of creation of a versatile module platform suitable for construction of supramolecular theranostic agents. As an example, we consider multifunctional hybrid agents for imaging and elimination of cancer cells. The use of an adapter protein system barnase:barstar for producing targeted multifunctional hybrid structures on the basis of highly specific peptides and mini-antibodies as addressing modules and recombinant proteins and/or nanoparticles of different nature (quantum dots, nanogold, magnetic nanoparticles, nanodiamonds, upconverting nanophosphores, polymer nanoparticles) as agents visualizing and damaging cancer cells is described. New perspectives for creation of selective and highly effective compounds for theranostics and personified medicine are contemplated. PMID- 26762093 TI - [Identification of Target Extracellular Proteases--Activators of Proteins of Haemostasis System Produced by Micromycetes Aspergillus ochraceus and Aspergillus terreus]. AB - Effects of extracellular proteases of Aspergillus ochraceus and Aspergillus terreus on plasma hemostasis proteins, consist of initiating the activation of prothrombin complex proteins, was detected. Was discovered, that A. ochraceus proteases have a direct influence on protein C and coagulation factor X, and A. terreus proteases causes their activation indirectly through kallikrein system stimulation. The ability of extracellular proteases of micromycetes activate prekallikrein in human blood plasma on the example of A. terreus was first demonstrated. PMID- 26762092 TI - [Affine Haemosorbents Based on Aromatic Peptides for Binding of the Immunoglobulin G]. AB - Affinity haemoadsorbents based on WY, WTY, WNY ligands and polysaccharide matrix were developed for the human immunoglobulin G binding. The characteristics of new sorbents such as the binding of total IgG and binding of IgG subclasses were compared. It was found that all new sorbents well extract the IgG from the blood plasma. It was evidenced that WNY-based sorbent is more effective for binding of IgG subclass 3. The determination of physic-chemical characteristics of IgG binding revealed that desorption constants for IgG are 10 +/- 3, 28 +/- 4 and 13 +/- 3 uM for WY, WTY, WNY based sorbents respectively. Maximum sorption capacities for IgG are 43 +/- 2, 45 +/- 3 and 46 +/- 3 mg IgG per ml of sorbent for WY, WTY, WNY based sorbents respectively. Also it was shown that the new sorbents are compatible with blood and are suitable for the medical purposes. PMID- 26762094 TI - [Streptokinase and Staphylokinase: Differences in the Kinetics and Mechanism of Their Interaction with Plasminogen, Inhibitors and Fibrin]. AB - Comparative in vitro study of the kinetics of various reactions involved in the process of thrombolysis initiated by streptokinase (SK) and staphylokinase (STA) was carried out. It was shown that at the interaction of an equimolar ratio of plasminogen (Pg) with SK or STA the rate of formation and the specific esterase activity of the complex plasmin (Pm) . SK are higher than those of the complex Pm . STA. The catalytic efficiency (kcat/Km) of hydrolysis of the chromogenic plasmin substrates by Pm . SK complex was 2 times higher than by Pm . STA complex. In the absence of fibrin catalytic efficiency (kPg/K(Pg)) of activation of Glu-plasminogen and Lys-plasminogen glycoform II by Pm . SK complex was higher than by Pm . STA complex, but the pres- ence of fibrin increased kPg/K(Pg)) activation of both plasminogens by Pm . STA complex significantly stronger than by Pm . SK complex due to the decrease in K(Pg)). In contrast to STA (15.5 kDa), SK molecule (47 kDa) creates significant steric hindrances for the interaction of plasmin in Pm . SK complex with protein inhibi- tors. In addition, SK caused greater fibrinogen degradation than STA. It is shown that Pm . SK and Pm . STA complexes lyse fibrin clots in buffer with similar rates, while the rate of lysis of plasma clots, immersed in plas- ma, by Pm . STA complex are significantly higher than those by Pm . SK complex. It was revealed that the species specificity of STA and S K is determined mainly by the rate of formation and the efficiency of Pm . SK and Pm . STA complexes in the activation of autologous plasminogen. The lysis efficiency of plasma clots of mammals fell in the series: human > dog > rabbit for SK and the dog > human > rabbit for STA. The results show that in the purified system SK is a more effective activator of plasminogen than STA. In the system con- taining fibrin and alpha2-AP, the activator and fibrinolytic activities of STA are higher than those of SK, due to the increased stability in plasma and fibrin specificity of STA, the fast reaction of the complex Pm . STA with alpha2AP and the ability of the STA to recyclization in the presence of alpha2AP. PMID- 26762095 TI - [The Effect of Mutations in the Inserted Domain of ATP-Dependent Lon Protease from E. coli on the Enzyme Function]. AB - ATP-Dependent protease LonA from E. coli (Ec-Lon), belonging to the superfamily of AAA+ proteins, is a key member of the protein quality control system in bacterial cells. Ec-Lon functions as homohexamer and degrades abnormal and defective polypeptides as well as a number of regulatory proteins by the processive mechanism. Ec-Lon subunit includes--the both ATPase and proteolytic components (AAA+ module and P domain) in addition to the unique non-catalytic region formed by the N-terminal (N) and the inserted c-helical (HI(CC)) domains. The mutant forms Lon-R164A, Lon-R192A and Lon-Y294A have been obtained and characterized in order to reveal the role of the HI (CC) domain for the enzyme functioning. C-Terminal part of the HI (CC) domain is shown to display an allosteric effect on the efficiency of the enzyme ATPase and proteolytic sites while its coiled-coil (CC) region is involved in the interaction with the protein substrate. PMID- 26762096 TI - [Differences of Nonsense-Mediated mRNA Degradation Activity in Mammalian Cell Lines Revealed by a Fluorescence Reporter]. AB - Activity of nonsense-mediated mRNA degradation (NMD) was studied in several mammalian cell cultures using recently developed genetically encoded fluorescence sensor [Pereverzev et al., Sci. Rep., 2015, vol. 5, p. 7729]. This NMD reporter enables measurement of NMD activity in single live cells using ratio of green and red fluorescent proteins signals. The following cell lines were analyzed: mouse colon carcinoma CT26, mouse Lewis lung carcinoma LLC, human T-cell leukemia Jurkat, and spontaneously immortalized human keratinocytes HaCaT. These cell lines demonstrated very different NMD activities. In CT26, NMD activity was low, whereas in LLC it was high (8.5-fold higher than in CT26). Jurkat and HaCaT cells possessed strong heterogeneity and consisted of two cell subpopulations with high and low NMD activities. In addition, we detected high NMD activity in primary culture of mouse embryonic hippocampal neurons. PMID- 26762097 TI - [Radioligand Method of Assessment of beta-Adrenoceptor's Activity on Human T Lymphocytes]. AB - We proposed a new method of evaluation of beta-receptor's activity on the surface of human T-lymphocytes based on the radioligand method. Optimal conditions for evaluation of specific binding to beta2-adrenoceptors of 0.5 fmol ligand per 1 million cells using [125I]-cyanopindolol were found. The possibility of using of beta2-adrenoceptor's activity assessment in clinical settings was demonstrated on human T-lymphocyte. PMID- 26762098 TI - [Targeted Delivery of Quantum Dots to HER2-Expressing Tumor Using Recombinant Antibodies]. AB - Targeted delivery of semiconductor quantum dots (Q Ds) to tumors overexpressing HER2 cancer marker has been. demonstrated on immunocompromised mice bearing human breast cancer xenografts. To obtain targeted QDs complexes we applied the approach based on the use of protein adaptor system, RNAase barnase and its inhibitor barstar. Specific binding to target cancer marker was achieved through bivalent fusion protein containing two fragments of4D5scFv recombinant antibody and a fragment of barnase. QDs were conjugated to barstar, and final assembly of targeted complexes was obtained through non-covalent specific interaction of barstar, attached to QD, and barnase, that is part of the recombinant targeting protein. The efficient delivery of QDs to HER2-expressing tumor demonstrates the possibilities and prospects of the approach for targeted delivery of nanoparticles to cancer cells in vivo as the way to improve the efficiency of diagnosis and promote development of therapies based on the use of nanoparticles. PMID- 26762099 TI - [The Biological Activity of the Sevanol and Its Analogues]. AB - Previously, from the plant Thymus armeniacus a new lignan sevanol was isolated, it's structure was elucidated and was shown that it effectively inhibits the acid sensing channel ASIC3 and also exhibits a pronounced analgesic and anti inflammatory effect. In this work biological activity of the sevanol analog obtained by chemical synthesis from simple precursors, the stereoisomer of sevanol and a precursor molecule represents a half of sevanol was measured in electrophysiological experiments on human ASIC3 channels expressed in Xenopus laevis oocytes. Measured inhibitory activity of a synthetic analogue coincided with the activity ofthe natural molecule. Stereoisomer showed inhibitory activity drop by about a third part, and the precursor molecule showed much less significant activity. In result the significance of functional groups and a spatial configuration of sevanol in order to biological activity was shown that is important to take into account for the optimal synthesis design as well as for new drugs development on its base. PMID- 26762100 TI - [Enantioselective Synthesis of (R)- and (S)-3-Methylspermidines]. AB - Earlier unknown enantiomerically pure (R)- and (S)-1,8-diamino-3-methyl-4 azaoctane's (3-MeSpd's) were synthesized with high overall yields and optical purity starting from commercially available R- and S-isomers of N-Boc-2 aminopropanol-1. Application of R- and S-isomers of 3-MeSpd for the investigation of the stereospecificity of spermidine transporter and peculiarities of deoxyhypusine synthase reaction are discussed. PMID- 26762101 TI - SYNTHESIS AND BIOLOGICAL EFFICACY OF NOVEL PIPERAZINE ANALOGUES BEARING QUINOLINE AND PYRIDINE MOIETIES. AB - A series of novel piperazine analogues bearing quinolin-8-yloxy-butan- ones/pyridin-2-yloxy-ethanones were synthesized by a simple and convenient approach based on various substituted piperazine incorporating quinoline and pyridine moieties. The analogues were evaluated for in vitro antioxidant activity against 2,2-diphenyl-1-picryl-hydrazyl (DPPH) and ferrous ion radical scavenging activities and anti-inflammatory activity by inhibition of Vipera russelli venom (PLA2) and gastric K+/H(+)-ATPase activities. Most of the title compounds exhibited promising activity. Best antioxidant and PLA2-inhibiting activities were found for piperazine analogues with phenyl and nitro phenyl groups, whereas methoxy group on phenyl piperazine indicated selectivity for the H+/K(+)-ATPase. PMID- 26762102 TI - SYNTHESIS AND CHARACTERIZATION OF POLYSIALIC ACID/CARBOXYMETHYL CHITOSAN HYDROGEL WITH POTENTIAL FOR DRUG DELIVERY. AB - A novel hydrogel was prepared from polysialic acid (PSA) and carboxymethyl chitosan (CMCS) using glutaraldehyde as the cross-linking agent. The resulting PSA-CMCS hydrogel exhibited pH sensitivity, in which the swelling ratio under acidic conditions was higher than those under neutral or alkaline conditions. The swelling ratio of PSA-CMCS hydrogel at equilibrium depended on the medium pH, the cross-linking agent concentration, and the ratio of PSA to CMCS (w/w). Bovine serum albumin (BSA) and 5-fluorouracil (5-FU) were used as model drugs to prepare hydrogel delivery systems. The loading efficiencies of the hydrogel for BSA and 5 FU were 26.25 and 36.74%, respectively. Release behaviors of BSA and 5-FU were influenced by the pH. MTT assays confirmed that PSA-CMCS hydrogel has no cytotoxicity toward the NIH-3T3 cell line; in fact, the 100% aqueous extract of the PSA-CMCS hydrogel enhanced cell growth. These results suggest that PSA-CMCS hydrogel may be a promising pH-sensitive delivery system, especially for hydrophobic chemicals. PMID- 26762103 TI - Relationship of cell-free urine MicroRNA with lupus nephritis in children. AB - BACKGROUND: MicroRNAs (miRNAs) are involved in the post-transcriptional regulation of genes. The objective of this study was to investigate whether select urinary cell-free microRNA's may serve as biomarkers in children with active lupus nephritis (LN) and to assess their relationship to the recently identified combinatorial urine biomarkers, a.k.a. the LN-Panel (neutrophil gelatinase associated lipocalin, monocyte chemotactic protein 1, transferrin, and beta-trace protein). METHODS: miRNAs (125a, 127, 146a, 150 and 155) were measured using real-time polymerase chain reaction in the urine pellet (PEL) and supernatant (SUP) in 14 patients with active LN, 10 patients with active extra renal lupus, and 10 controls. The concentrations of the LN-Panel biomarkers (neutrophil gelatinase associated lipocalin, monocyte chemotactic protein-1, transferrin, beta-trace protein) was assayed. Traditional laboratory and clinical measures of LN and lupus (complements, protein to creatinine ratio; Systemic Lupus Erythematosus Disease Activity Index) were also measured. RESULTS: All tested miRNAs in the SUP, but not the PEL, were associated with the LN-Panel biomarkers (0.3 < |r Pearson| < 0.73; p < 0.05), miRNA125a, miRNA127,miRNA146a also with C3 and dsDNA antibody levels (|r Pearson| > 0.24; p < 0.05), and miRNA146a with the renal domain of the SLEDAI (|r Pearson| = 0.32; p < 0.05). Mean miRNA levels of patients with active LN did not statistically (P > 0.05) differ from those of SLE patients without LN or controls. CONCLUSION: Levels of cell-free miR-125a, miR-150, and miR-155 in the urine supernatant are associated with the expression of LN-Panel biomarkers and some LN measures. These miRNA's may complement, but are unlikely superior to the LN-Panel for estimating concurrent LN activity. PMID- 26762104 TI - Corticospinal tract modeling for neurosurgical planning by tracking through regions of peritumoral edema and crossing fibers using two-tensor unscented Kalman filter tractography. AB - PURPOSE: The aim of this study was to present a tractography algorithm using a two-tensor unscented Kalman filter (UKF) to improve the modeling of the corticospinal tract (CST) by tracking through regions of peritumoral edema and crossing fibers. METHODS: Ten patients with brain tumors in the vicinity of motor cortex and evidence of significant peritumoral edema were retrospectively selected for the study. All patients underwent 3-T magnetic resonance imaging (MRI) including functional MRI (fMRI) and a diffusion-weighted data set with 31 directions. Fiber tracking was performed using both single-tensor streamline and two-tensor UKF tractography methods. A two-region-of-interest approach was used to delineate the CST. Results from the two tractography methods were compared visually and quantitatively. fMRI was applied to identify the functional fiber tracts. RESULTS: Single-tensor streamline tractography underestimated the extent of tracts running through the edematous areas and could only track the medial projections of the CST. In contrast, two-tensor UKF tractography tracked fanning projections of the CST despite peritumoral edema and crossing fibers. Based on visual inspection, the two-tensor UKF tractography delineated tracts that were closer to motor fMRI activations, and it was apparently more sensitive than single-tensor streamline tractography to define the tracts directed to the motor sites. The volume of the CST was significantly larger on two-tensor UKF than on single-tensor streamline tractography ([Formula: see text]). CONCLUSION: Two tensor UKF tractography tracks a larger volume CST than single-tensor streamline tractography in the setting of peritumoral edema and crossing fibers in brain tumor patients. PMID- 26762107 TI - Clinical and investigative critical care medicine in Japan. PMID- 26762108 TI - Response to: Protocols: help for improvement but beware of regression to the mean and mediocrity. PMID- 26762106 TI - How should clinicians respond to requests for potentially inappropriate treatment? PMID- 26762105 TI - Integration of high-resolution data for temporal bone surgical simulations. AB - PURPOSE: To report on the state of the art in obtaining high-resolution 3D data of the microanatomy of the temporal bone and to process that data for integration into a surgical simulator. Specifically, we report on our experience in this area and discuss the issues involved to further the field. DATA SOURCES: Current temporal bone image acquisition and image processing established in the literature as well as in house methodological development. REVIEW METHODS: We reviewed the current English literature for the techniques used in computer-based temporal bone simulation systems to obtain and process anatomical data for use within the simulation. Search terms included "temporal bone simulation, surgical simulation, temporal bone." Articles were chosen and reviewed that directly addressed data acquisition and processing/segmentation and enhancement with emphasis given to computer-based systems. We present the results from this review in relationship to our approach. CONCLUSIONS: High-resolution CT imaging ([Formula: see text] voxel resolution), along with unique image processing and rendering algorithms, and structure-specific enhancement are needed for high level training and assessment using temporal bone surgical simulators. Higher resolution clinical scanning and automated processes that run in efficient time frames are needed before these systems can routinely support pre-surgical planning. Additionally, protocols such as that provided in this manuscript need to be disseminated to increase the number and variety of virtual temporal bones available for training and performance assessment. PMID- 26762109 TI - Stop smoking services are under threat owing to budget cuts. PMID- 26762110 TI - The Loneliness Questionnaire: Establishing Measurement Invariance Across Ethnic Groups. AB - A state of loneliness describes an individual's perception of having dissatisfying social connections to others. Though it is notable across the life span, it may have particularly deleterious effects in childhood and adolescence, leading to increased risk of emotional impairment. The current study evaluates a widely used test of loneliness, the Loneliness Questionnaire, for measurement invariance across ethnic groups in a large, representative sample of youth in the 2nd to 12th grades ( N = 12,344; 41% African American) in Mississippi. Analyses were conducted using multigroup confirmatory factor analysis following a published, sequential method to examine invariance in form, factor loadings, and item intercepts. Overall, our results indicated that the instrument was invariant across ethnicities, suggesting that youth with equivalent manifest scores can be discerned as having comparable levels of latent loneliness. The loneliness scores also corresponded significantly with depression and anxiety scores for most subsamples, with one exception. These findings are discussed in the context of previous results comparing levels of loneliness across ethnicities. Additionally, the broader context of the need to expand invariance studies in instrumentation work is highlighted. PMID- 26762112 TI - The Need for New Emphasis on Batterers Intervention Programs. AB - Although Batterers' Intervention Programs (BIPs) remain a crucial part of victim safety and coordinated community responses, they have received less support and less attention by scholars than other parts of the domestic violence system. Research on BIPs also suggests that they have not been particularly effective at preventing recidivism, are prone to attrition, and increasingly lack the support and confidence of the courts. Nevertheless, BIPs remain one of the few viable alternatives to incarceration for perpetrators of domestic violence. This article examines the historical and empirical reasons for the apparent lack of effectiveness of BIPs. New research suggests avenues for improvement. This begins with incorporating existing research findings, consistency in implementation of best practice models, better diagnosis of personality characteristics of perpetrators and of types of violence that characterize their relationships as well as better funding and support for research. In addition, differentiated treatment approaches tailored to the abuser and their particular types of violence may hold promise-and require increased support by the research and practice communities. PMID- 26762111 TI - Yin Yang 1 promotes mTORC2-mediated AKT phosphorylation. AB - Yin Yang 1 (YY1) regulates both gene expression and protein modifications, and has shown a proliferative role in cancers. In this study, we demonstrate that YY1 promotes AKT phosphorylation at S473, a marker of AKT activation. YY1 expression positively correlated with AKT(S473) phosphorylation in a tissue microarray and cultured cells of breast cancer, but negatively associated with the distant metastasis-free survival of 166 breast cancer patients. YY1 promotes AKT phosphorylation at S473 through direct interaction with AKT, and the AKT-binding site is mapped to the residues G201-S226 on YY1. These residues are also involved in YY1 interaction with Mdm2, Ezh2, and E1A, and thus are designated as the oncogene protein binding (OPB) domain. YY1-promoted AKT phosphorylation relies on the OPB domain but is independent of either transcriptional activity of YY1 or the activity of phosphoinositide-3-kinases. We also determine that YY1-promoted mTORC2 access to AKT leads to its phosphorylation at S473. Importantly, a peptide based on the OPB domain blocks YY1 interaction with AKT and reduces AKT phosphorylation and cell proliferation. Thus, we demonstrate for the first time that YY1 promotes mTORC2-mediated AKT activation and disrupting YY1-AKT interaction by OPB domain-based peptide may represent a potential strategy for cancer therapy. PMID- 26762113 TI - Parent Expectations Mediate Outcomes for Young Adults with Autism Spectrum Disorder. AB - Understanding the complex relationships among factors that may predict the outcomes of young adults with autism spectrum disorder (ASD) is of utmost importance given the increasing population undergoing and anticipating the transition to adulthood. With a sample of youth with ASD (n = 1170) from the National Longitudinal Transition Study-2, structural equation modeling techniques were used to test parent expectations as a mediator of young adult outcomes (i.e., employment, residential independence, social participation) in a longitudinal analysis. The mediation hypothesis was confirmed; family background and functional performance variables significantly predicted parent expectations which significantly predicted outcomes. These findings add context to previous studies examining the role of parent expectations on young adult outcomes and inform directions for family-centered interventions and future research. PMID- 26762114 TI - Exploring What's Missing: What Do Target Absent Trials Reveal About Autism Search Superiority? AB - We used eye-tracking to investigate the roles of enhanced discrimination and peripheral selection in superior visual search in autism spectrum disorder (ASD). Children with ASD were faster at visual search than their typically developing peers. However, group differences in performance and eye-movements did not vary with the level of difficulty of discrimination or selection. Rather, consistent with prior ASD research, group differences were mainly the effect of faster performance on target-absent trials. Eye-tracking revealed a lack of left-visual field search asymmetry in ASD, which may confer an additional advantage when the target is absent. Lastly, ASD symptomatology was positively associated with search superiority, the mechanisms of which may shed light on the atypical brain organization that underlies social-communicative impairment in ASD. PMID- 26762115 TI - Emergency Department Use Among Adults with Autism Spectrum Disorders (ASD). AB - A cross-sectional analyses using Nationwide Emergency Department Sample (2006 2011) was conducted to examine the trends, type of ED visits, and mean total ED charges for adults aged 22-64 years with and without ASD (matched 1:3). Around 0.4% ED visits (n = 25,527) were associated with any ASD and rates of such visits more than doubled from 2006 to 2011 (2549-6087 per 100,000 admissions). Adults with ASD visited ED for: primary psychiatric disorder (15%ASD vs. 4.2%noASD), primary non-psychiatric disorder (16%ASD vs. 14%noASD), and any injury (24%ASD vs. 28%noASD). Mean total ED charges for adults with ASD were 2.3 times higher than for adults without ASD. Findings emphasize the need to examine the extent of frequent ED use in this population. PMID- 26762117 TI - Expanding the diversity of DNA base modifications with N6-methyldeoxyadenosine. AB - Vertebrate DNA is subjected to epigenetic base modifications that have been thought to be limited to methylated and other modified forms of cytidine. A recent study shows that methylation of adenine to form N (6)-methyladenine is a rare but readily detectable modification that can be mapped to distinct genomic sites in vertebrates. PMID- 26762116 TI - Broncholaveolar lavage to detect cytomegalovirus infection, latency, and reactivation in immune competent hosts. AB - Roughly 1/3rd of immune competent patients will reactivate latent cytomegalovirus (CMV) during critical illness. There are no standard methods to detect reactivation, and some investigators have postulated that presence of DNA in BAL fluid is indicative of viral replication. To test this hypothesis, we used a murine model that allows inclusion of matched healthy controls which is not possible in human studies. BALB/c mice infected with Smith-murine CMV or PBS (mock) had BAL evaluated 7, 14, or 21 days after acute infections, during latency, or during bacterial sepsis. Plaque assay, PCR, and rtPCR were performed on BALs and concomitantly obtained lung tissue. BAL cellular compositions, including tetramer evaluation of CMV-specific T cells were evaluated by flow cytometry. CMV DNA were detected in BAL at all time-points during acute infection, becoming undetectable in all mice during latency, then were detected again during bacterial sepsis, peaking 3 weeks after onset. mCMV specific T-cells were most numerous in BAL after acute viral infections, decreasing to low levels during latency, then fluctuating during bacterial sepsis. Specifically, mCMV specific T-cells contracted at sepsis onset, expanding 2-4 weeks post-sepsis, presumably in response to increased viral loads at that time point. Altogether, our results support the use of BAL PCR for the diagnosis of CMV replication in immune competent hosts. Additionally, we demonstrate dynamic changes in CMV specific T cells that occur in BAL during CMV infection and during sepsis induced viral reactivation. J. Med. Virol. 88:1408-1416, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26762118 TI - Echocardiographic evaluation of the early cardiotoxic effect of hematopoietic stem cell transplantation in patients with hematologic malignancies. AB - The purpose was to evaluate the early cardiotoxic effects of the treatment in the course of hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. The studies were conducted on 47 patients qualified for the HSCT. Echocardiography was carried out prior to the HSCT and after the HSCT. It was shown that higher age, administration of cyclophosphamide and higher glucose concentrations represented independent risk factors for the worsening of left ventricular diastolic function. Higher cumulative dose of anthracyclines in the previous cytostatic treatment, higher age and administration of cyclophosphamide represented independent risk factors for worsening of left ventricular systolic function. Peri-transplant therapy in the course of HSCT in patients with hematologic malignancies gives the negative effect on the diastolic and systolic left ventricular function, however, previous treatment is of importance, as higher cumulative dose of anthracyclines represents an independent risk factor for the worsening of left ventricular systolic function. PMID- 26762119 TI - Stroke Serum Priming Modulates Characteristics of Mesenchymal Stromal Cells by Controlling the Expression miRNA-20a. AB - Transplantation of mesenchymal stem cells (MSCs) expanded with fetal bovine serum (FBS) has some limitations, including the requirement of a long culture period to obtain a sufficient amount of stem cells. Priming of MSCs with serum from patients with ischemic stroke (stroke serum) increased the proliferation rate and the neurorestorative capacity of MSCs. We hypothesized that this novel priming method increases the proliferation rate of MSCs via the regulation of microRNAs (miRs). Thus, we investigated miR profiling in stroke serum-primed MSCs and tested whether the regulation of certain miRs may affect the proliferation rate of rat MSCs. The proliferation rate of MSCs cultured with stroke serum was higher than that of MSCs cultured with normal serum or FBS. Using miR microarray analysis, we compared the miR expression profiles between MSCs cultured in FBS and in stroke serum. Among miRs associated with cell proliferation, miR-20a was most significantly increased. Similarly, miR-20a was increased in MSCs obtained from the bone marrow of stroke rats compared with MSCs from normal rats. Furthermore, the deregulation of miR-20a by the transfection of MSCs with pre-miR 20a or anti-miR-20a was significantly correlated with the increased proliferation rate of MSCs. The overexpression of miR-20a in MSCs cultured in FBS improved the proliferation rate, while the knockdown of endogenous miR-20a decreased the proliferation rate. In addition, miR-20a promoted proliferation by suppressing the expression of p21 cyclin-dependent kinase inhibitor 1 (CDKN1A). A dual luciferase reporter assay showed that CDKN1A is a target of miR-20a. Our findings indicate that stroke serum priming upregulated the expression of miR-20a, which promoted MSC proliferation by regulating the cell cycle inhibitor p21 CDKN1A, and suggest the possible roles of priming methods in modulating the characteristics of MSCs by controlling the expression of miR in MSCs. PMID- 26762120 TI - The C-terminal region of human eukaryotic elongation factor 1Bdelta. PMID- 26762121 TI - Perceived Close Relationships With Parents, Teachers, and Peers: Predictors of Social, Emotional, and Behavioral Features in Adolescents With LD or Comorbid LD and ADHD. AB - This study examined the role of adolescents' perceived close relationships with significant others (attachment relationships with mothers/fathers, appraisal of homeroom teacher as secure base, and quality of peer friendship) in explaining differences in their socioemotional and behavioral functioning (peer-network/peer dyadic loneliness, positive/negative affect, and externalizing/internalizing problems), among adolescents with learning disabilities (LD), with comorbid LD and attention-deficit/hyperactivity disorder (ADHD), or with typical development (TD). Participants were 280 adolescents in Grades 10 through 11 in three groups: LD (n = 90), comorbid LD and ADHD (n = 91), and TD (n = 98). Preliminary analyses yielded significant group differences on most socioemotional and behavioral measures. Structural equation modeling (SEM) analysis indicated high fit between the theoretical model and empirical findings and partially different patterns of relationships among the model's components for the three populations. The discussion focuses on the possible unique value of close relationships with each significant attachment figure for adolescents with LD, comorbid LD-ADHD, and TD. PMID- 26762122 TI - Eye Movements and Articulations During a Letter Naming Speed Task. AB - Naming speed (NS) refers to how quickly and accurately participants name a set of familiar stimuli (e.g., letters). NS is an established predictor of reading ability, but controversy remains over why it is related to reading. We used three techniques (stimulus manipulations to emphasize phonological and/or visual aspects, decomposition of NS times into pause and articulation components, and analysis of eye movements during task performance) with three groups of participants (children with dyslexia, ages 9-10; chronological-age [CA] controls, ages 9-10; reading-level [RL] controls, ages 6-7) to examine NS and the NS reading relationship. Results indicated (a) for all groups, increasing visual similarity of the letters decreased letter naming efficiency and increased naming errors, saccades, regressions (rapid eye movements back to letters already fixated), pause times, and fixation durations; (b) children with dyslexia performed like RL controls and were less efficient, had longer articulation times, pause times, fixation durations, and made more errors and regressions than CA controls; and (c) pause time and fixation duration were the most powerful predictors of reading. We conclude that NS is related to reading via fixation durations and pause times: Longer fixation durations and pause times reflect the greater amount of time needed to acquire visual/orthographic information from stimuli and prepare the correct response. PMID- 26762123 TI - Effect of virtual reality exposure therapy on social participation in people with a psychotic disorder (VRETp): study protocol for a randomized controlled trial. AB - BACKGROUND: Many patients with a psychotic disorder participate poorly in society. When psychotic disorders are in partial remission, feelings of paranoia, delusions of reference, social anxiety and self-stigmatization often remain at diminished severity and may lead to avoidance of places and people. Virtual reality exposure therapy (VRET) is an evidence-based treatment for several anxiety disorders. For patients with a psychotic disorder, the VRETp was developed to help them experience exposure to feared social situations. The present study aims to investigate the effects of VRETp on social participation in real life among patients with a psychotic disorder. METHODS/DESIGN: The study is a single-blind randomized controlled trial with two conditions: the active condition, in which participants receive the virtual reality treatment together with treatment as usual (TAU), and the waiting list condition, in which participants receive TAU only. The two groups are compared at baseline, at 3 months posttreatment and at 6 months follow-up. All participants on the waiting list are also offered the virtual reality treatment after the follow-up measurements are completed. The primary outcome is social participation. Secondary outcomes are quality of life, interaction anxiety, depression and social functioning in general. Moderator and mediator analyses are conducted with stigma, cognitive schemata, cognitive biases, medication adherence, simulator sickness and presence in virtual reality. If effective, a cost-effectiveness analysis will be conducted. DISCUSSION: Results from the posttreatment measurement can be considered strong empirical indicators of the effectiveness of VRETp. The 6-month follow-up data may provide reliable documentation of the long term effects of the treatment on the outcome variables. Data from pre-treatment and mid-treatment can be used to reveal possible pathways of change. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN12929657 . Date of registration: 8 September 2015. PMID- 26762126 TI - In response: B Vinay et al.: Fall in inspired oxygen and anaesthetic agent concentrations during change of soda lime absorber, J Clin Monit Comput (2015) Jun; 29 (3):373-376. PMID- 26762124 TI - Physician trust moderates the relationship between intolerance of uncertainty and cancer worry interference among women with Lynch syndrome. AB - This study investigated the extent to which intolerance of uncertainty was associated with cancer worry interference, anxiety and depression among women with Lynch syndrome (LS), and whether having greater trust in one's physician moderated those relationships. Women with confirmed LS (N = 128) were recruited from a high-risk of cancer registry and completed a one-time self-report questionnaire. Women who reported greater intolerance of uncertainty and more trust in their physician reported less cancer worry interference compared to women who had greater intolerance of uncertainty and less trust in their physician, who reported the highest worry interference, b = -1.39, t(99) = -2.27, p = .03. No moderation effect of trust in physician was found for anxiety or depression. Trust in one's physician buffered the impact of high intolerance of uncertainty on cancer worry interference, underscoring the need for supportive provider-patient relationships, particularly for LS patients. PMID- 26762127 TI - Assessing the effect of preoperative levosimendan on renal function in patients with right ventricular dysfunction. AB - The Acute Kidney Injury Network (AKIN) classification considers SCr values, urea and urine output in order to improve timely diagnose ARF and improve patient prognosis by early treatment. Preoperative levosimendan is a new way for cardiac and kidney protection, we try to evaluate this drug in fifteen patients comparing values of AKIN scale parameters pre and post cardiac surgery in patients with right ventricle dysfunction. PMID- 26762125 TI - Process evaluation of a knowledge translation intervention using facilitation of local stakeholder groups to improve neonatal survival in the Quang Ninh province, Vietnam. AB - BACKGROUND: Annually, 2.8 million neonatal deaths occur worldwide, despite the fact that three-quarters of them could be prevented if available evidence-based interventions were used. Facilitation of community groups has been recognized as a promising method to translate knowledge into practice. In northern Vietnam, the Neonatal Health - Knowledge Into Practice trial evaluated facilitation of community groups (2008-2011) and succeeded in reducing the neonatal mortality rate (adjusted odds ratio, 0.51; 95 % confidence interval 0.30-0.89). The aim of this paper is to report on the process (implementation and mechanism of impact) of this intervention. METHODS: Process data were excerpted from diary information from meetings with facilitators and intervention groups, and from supervisor records of monthly meetings with facilitators. Data were analyzed using descriptive statistics. An evaluation including attributes and skills of facilitators (e.g., group management, communication, and commitment) was performed at the end of the intervention using a six-item instrument. Odds ratios were analyzed, adjusted for cluster randomization using general linear mixed models. RESULTS: To ensure eight active facilitators over 3 years, 11 Women's Union representatives were recruited and trained. Of the 44 intervention groups, composed of health staff and commune stakeholders, 43 completed their activities until the end of the study. In total, 95 % (n = 1508) of the intended monthly meetings with an intervention group and a facilitator were conducted. The overall attendance of intervention group members was 86 %. The groups identified 32 unique problems and implemented 39 unique actions. The identified problems targeted health issues concerning both women and neonates. Actions implemented were mainly communication activities. Communes supported by a group with a facilitator who was rated high on attributes and skills (n = 27) had lower odds of neonatal mortality (odds ratio, 0.37; 95 % confidence interval, 0.19-0.73) than control communes (n = 46). CONCLUSIONS: This evaluation identified several factors that might have influenced the outcomes of the trial: continuity of intervention groups' work, adequate attributes and skills of facilitators, and targeting problems along a continuum of care. Such factors are important to consider in scaling-up efforts. TRIAL REGISTRATION: ISRCTN ISRCTN44599712 . PMID- 26762128 TI - Culturally adaptive storytelling method to improve hypertension control in Vietnam - "We talk about our hypertension": study protocol for a feasibility cluster-randomized controlled trial. AB - BACKGROUND: Vietnam is experiencing an epidemiologic transition with an increased prevalence of non-communicable diseases. At present, the major risk factors for cardiovascular disease (CVD) are either on the rise or at alarming levels in Vietnam; inasmuch, the burden of CVD will continue to increase in this country unless effective prevention and control measures are put in place. A national survey in 2008 found that the prevalence of hypertension (HTN) was approximately 25 % among Vietnamese adults and it increased with advancing age. Therefore, novel, large-scale, and sustainable interventions for public health education to promote engagement in the process of detecting and treating HTN in Vietnam are urgently needed. METHODS: A feasibility randomized trial will be conducted in Hung Yen province, Vietnam to evaluate the feasibility and acceptability of a novel community-based intervention using the "storytelling" method to enhance the control of HTN in adults residing in four rural communities. The intervention will center on stories about living with HTN, with patients speaking in their own words. The stories will be obtained from particularly eloquent patients, or "video stars," identified during Story Development Groups. The study will involve two phases: (i) developing a HTN intervention using the storytelling method, which is designed to empower patients to facilitate changes in their lifestyle practices, and (ii) conducting a feasibility cluster-randomized trial to investigate the feasibility, acceptability, and potential efficacy of the intervention compared with usual care in HTN control among rural residents. The trial will be conducted at four communes, and within each commune, 25 individuals 50 years or older with HTN will be enrolled in the trial resulting in a total sample size of 100 patients. DISCUSSION: This feasibility trial will provide the necessary groundwork for a subsequent large-scale, fully powered, cluster randomized controlled trial to test the efficacy of our novel community-based intervention. Results from the full-scale trial will provide health policy makers with practical evidence on how to combat a key risk factor for CVD using a feasible, sustainable, and cost-effective intervention that could be used as a national program for controlling HTN in Vietnam and other developing countries. TRIAL REGISTRATION: ClinicalTrials.gov. REGISTRATION NUMBER: https://clinicaltrials.gov/ct2/show/NCT02483780 (registration date June 22, 2015). PMID- 26762129 TI - Quantitative genetics of circulating Dickkopf-related protein 1 (DKK1) in community-based sample of UK twins. AB - Dickkopf-related protein 1 (DKK1) is a major inhibitor of Wnt signalling pathway but also plays an important role in bone formation. Its circulating levels appear to correlate significantly with plasma levels of inflammatory factors, fractalkine and IL-6. This study, using a large sample of UK twins, showed that the variation of each of these factors and correlation between them was explained by the genetic factors, and indicated possible association with DKK1 gene variants. INTRODUCTION: DKK1 is involved in the development of several inflammatory conditions related to bone and joint degradation. Our objectives were to explore the genetic contribution (heritability) to circulating DKK1 variation and its correlation with other inflammatory cytokines, interleukin 6 (IL-6) and fractalkine, and to test whether the DKK1 heritability could be attributable to single nucleotide polymorphisms (SNPs) mapped to DKK1, IL-6 and FRCT genes. METHODS: The study included a large community-based sample of 4939 women drawn from the general UK population. Plasma samples were analysed for circulating levels of DKK1, IL-6 and fractalkine (FRCT); 65 SNPs of DKK1, IL-6 and FRCT candidate genes, with MAF >0.1, were examined. We applied variance component analysis to evaluate contribution of putative genetic (including above SNPs) and environmental factors to variation of DKK1, and its correlation with IL 6 and FRCT. RESULTS: Putative genetic factors explained 42.2 +/- 2 % of the total variation of circulating DKK1 levels, and were also significant for fractalkine and IL-6 variations. Most importantly, we report significant phenotypic (0.208 +/ 0.006-0.459 +/- 0.007) and genetic (0.338 +/- 0.069-0.617 +/- 0.033) correlations between these molecules. We found evidence suggestive of association between the DKK1 and its structural genes variants. CONCLUSIONS: Circulating DKK1 levels correlated significantly with levels of IL-6 and FRCT, known risk factors for several inflammatory processes suggesting a potential role of DKK1 in inflammation and tissue injury. Our results suggest the contribution of genetic factors in inter-individual variation of DKK1 levels in human population. However, further studies are required to determine genetic polymorphisms affecting DKK1 variation and its correlation with IL-6 and FRCT. PMID- 26762132 TI - From information to knowledge. PMID- 26762131 TI - Full endoscopic endonasal transsellar-transclival approach: the modularity concept. AB - BACKGROUND: Endoscopic endonasal approaches (EEAs) constitute a reasonable option for the treatment of lesions that involve the sellar and clival regions. METHODS: We describe, step by step, the full EEA expanded to the middle and lower clivus for the treatment of perisellar lesions. Delimiting different modules around the sellar region is useful in establishing the best endoscopic approach for each tumor. A craniopharyngioma (CP) with clival extension will be used as an illustrative example of the modularity concept of these approaches. CONCLUSIONS: Transsellar-transclival EEA allows complete resection of lesions located in the sellar and infrasellar region with a low rate of complications. PMID- 26762130 TI - The level of FoxO1 and IL-15 in skeletal muscle, serum and synovial fluid in people with knee osteoarthritis: a case control study. AB - The molecular regulation of muscle function in knee osteoarthritis is unclear. Elevated muscle atrophy regulation marker expression was associated with reduced muscle strength in knee osteoarthritis. The level of protein expression appears to be different between muscle, knee joint and serum, suggesting that inflammation is regulated differently within these tissues. INTRODUCTION: Impaired muscle function is common in knee osteoarthritis (OA). Numerous biochemical molecules have been implicated in the development of OA; however, these have only been identified in the joint and serum. We compared the expression of interleukin-15 (IL-15) and Forkhead box protein-O1 (FoxO1) in muscle of patients with knee OA and asymptomatic individuals and examined whether IL-15 was also present in the joint and serum. METHODS: Muscle and blood samples were collected from 19 patients with knee OA and 10 age-matched asymptomatic individuals. Synovial fluid and muscle biopsies were collected from the OA group during knee replacement surgery. IL-15 and FoxO1 were measured in the skeletal muscle. IL-15 abundance was also analysed in the serum of both groups and synovial fluid from the OA group. Knee extensor strength was measured and correlated with IL-15 and FoxO1 in the muscle. RESULTS: FoxO1 protein expression was higher (p = 0.04), whereas IL-15 expression was lower (p = 0.02) in the muscle of the OA group. Strength was also lower in the OA group and was inversely correlated with FoxO1 expression. No correlation was found between IL-15 in the joint, muscle or serum. CONCLUSION: Skeletal muscle, particularly the quadriceps, is affected in people with knee OA where elevated FoxO1 protein expression was associated with reduced muscle strength. While IL-15 protein expression in the muscle was lower in the knee OA group, no correlation was found between the expression of IL-15 protein in the muscle, joint and serum, which suggests that inflammation is regulated differently within these tissues. Australian Clinical Trials Registry (ACTR) number: ACTRN12613000467730 ( http://www.anzctr.org.au/TrialSearch.aspx?searchTxt=ACTRN12613000467730&isBasic=T ue ). PMID- 26762134 TI - International Perspectives on General Internal Medicine. PMID- 26762135 TI - [Role of coronary intervention after successful cardiopulmonary resuscitation]. AB - Immediate coronary angiography and intervention in suitable stenoses in patients resuscitated from cardiac arrest of presumed coronary origin and return of spontaneous circulation is widely established in interventional centers. The procedure is based on the analogy of positive results achieved with coronary intervention in many forms of acute coronary syndromes on the one hand and otherwise from registries showing promising data from coronary intervention of resuscitated patients. Results from randomized controlled studies, however, are not yet available. With respect to ST-elevation myocardial infarction, the diagnostic reliability of an ECG registered shortly after cardiopulmonary resuscitation is sufficient. The results of the registries are specifically promising for patients with ST-elevation myocardial infarction but less favorable for other forms of acute coronary syndromes. Moreover, insight into the results of the registries reveals that patients with the best prognostic conditions were preferentially selected for coronary intervention (e.g., younger patients, those with an initially shockable arrhythmia, bystander resuscitation), whereas those, for example, with cardiac or renal failure were excluded. For better definition of the actual benefit of coronary intervention after resuscitation from cardiac arrest and the optimal target groups, randomized controlled studies on patients with ST-elevation myocardial infarction are desirable, while for other forms of acute coronary syndromes these studies are essential. PMID- 26762133 TI - The effects of switching daily teriparatide to oral bisphosphonates or denosumab in patients with primary osteoporosis. AB - The aim of this 12-month, observational study was to compare the effects of switching daily teriparatide (TPTD) to oral bisphosphonates (BP) therapy or denosumab (DMAb) therapy in patients with primary osteoporosis. Patients [n = 78; 71 postmenopausal women and seven men; mean age 76.3 (64-94) years; mean duration of prior daily TPTD therapy 20.1 (6-24) months] were allocated to either the (1) "switch-to-BP" group [n = 36; weekly alendronate 35 mg (n = 19), weekly risedronate 17.5 mg (n = 12), monthly minodronate 50 mg (n = 5)]; or (2) "switch to-DMAb" group (n = 42; 60 mg sc every 6 months) based on each physicians' decision. Changes in bone mineral density (BMD) and serum bone turnover markers were monitored every 6 months. No significant difference was observed in baseline clinical characteristics between the groups. After 12 months, the increase in BMD was significantly greater in the switch-to-DMAb group compared to the switch-to BP group: lumbar spine (6.2 vs. 2.6 %; P < 0.01), total hip (4.2 vs. 1.1 %; P < 0.05), and femoral neck (3.5 vs. 1.4 %; P < 0.05). In addition, the patients in the switch-to-DMAb group showed a significant decrease compared to those in the switch-to-BP group in TRACP-5b (-55.8 vs. -32.8 %; P < 0.01) and ucOC (-85.5 vs. 65.0 %; P < 0.001), while no significant difference was observed in PINP (-67.5 vs. -62.1 %). Switching daily TPTD to DMAb significantly increased BMD and decreased bone resorption marker compared to switching to oral BP at 12 months, and thus may provide an effective sequential treatment option after daily TPTD treatment. PMID- 26762136 TI - Incident Reporting by Health-Care Workers in Noninstitutional Care Settings. AB - Patient-perpetrated violence and aggression toward health-care workers, specifically in noninstitutional health-care settings, cause concerns for both health-care providers and the clients whom they serve. Consequentially, this presents a public affairs problem for the entire health-care system, which the current research has failed to adequately address. While the literature overwhelmingly supports the assertion that accurate incident reporting is critical to fully understanding patient violence and aggression toward health care providers, there is limited research examining provider decision making related to reporting incidents of patient violence and aggression targeted toward the provider. There is an even greater paucity of research specifically examining this issue in noninstitutional health-care settings. It is therefore the objective of this review to examine this phenomenon across disciplines and service settings in order to offer a comprehensive review of incident reporting and to examine rationales for providers reporting or failing to report instances of patient violence and aggression toward health-care providers. PMID- 26762137 TI - Vascular complications in plating of the proximal femur: review. AB - INTRODUCTION: Plating of the proximal femur represents a standard fixation method in orthopedic and trauma surgery. Vascular lesions are uncommon but potentially life-threatening. With the increasing number of hip surgery also more of these complications have to be anticipated. The purpose of this study was to evaluate the most common types and locations of vascular lesions after plating of the proximal femur as well as the most important causes. MATERIALS AND METHODS: A literature research was undertaken of the English and german literature on vascular complications after plating of the proximal femur following a structured search protocol. RESULTS: 62 cases with vascular compromise after plating of the proximal femur revealed significantly more iatrogenic origin (n = 41/62) was observed than lesions caused by fracture fragments (n = 11/62) (p = 0.0001); most iatrogenic reasons (n = 28/62) were related to the insertion of plate screws (PS). Lesions were significantly more often located (57/62) in the deep femoral artery (DFA) system than in other vascular systems (n = 5/62) (p = 0.0001). Vascular damages represented significantly more often pseudoaneurysms (PA) (42/62) than major lesions in the vessel wall with acute bleeding (17/62) or vascular occlusions (3/62); (p = 0.0001). PA cases also revealed a significantly longer diagnostic delay than other lesions (36 days vs. 2 days, p = 0.0064). Among clinical symptoms swelling of the thigh (57/62), local pains (42/62) and anemia (26/62) were most often observed. Swelling and pains were significantly more often reported in PAs (p = 0.0338; p = 0.0003). Most patients achieved full functional recovery (n = 41/62), but over-all complication rate was quite high (n = 18/62). CONCLUSIONS: Vascular compromise in plate osteosynthesis of the proximal femur affects significantly more often the DFA system and represents most often PA. As the majority of cases revealed iatrogenic origin, a thorough surgical technique and awareness can help to avoid these complications. PMID- 26762138 TI - Factors associated with utilization of maternal serum screening for Down syndrome in mainland China: a cross-sectional study. AB - BACKGROUND: Knowledge of the factors that influence maternal serum screening (MSS) service utilization can be used to develop health policies to promote equitable access to MSS and further diagnostic tests. The purpose of this study was to find the factors associated with utilization of MSS as well as the current status of service utilization in mainland China. METHODS: This was a hospital based cross-sectional study with respondents interviewed with a questionnaire designed based on Andersen's behavioral model. Descriptive statistics, univariate analysis, and multilevel logistic regression analysis were used to identify the factors associated with MSS utilization, and to explore potential methods to improve screening uptake. RESULTS: A total of 8110 women who had given birth within the previous 7 days in one of 111 participating institutions from six provinces in mainland China were interviewed. Approximately 36% of the participants had used MSS. Women between 20 and 35 years, who resided in urban areas, were educated, were in a stable occupation, who had health knowledge, who attended maternal preparation classes, who had received eight or more prenatal checkups, who were from a region of higher social economic status, and who delivered in a tertiary healthcare institution were significantly more likely to use MSS than their counterparts. As compared with other factors, insufficient education is the single most important demographic factor for service underutilization. CONCLUSIONS: Efforts should not only be made to target the population that underuses MSS, but the overall organization of MSS service delivery should be assessed during policy development to make access to MSS equitable to the entire population of mainland China. PMID- 26762139 TI - The intersection of health and wealth: association between personal bankruptcy and myocardial infarction rates in Canada. AB - BACKGROUND: We examined the association between personal bankruptcy filing and acute myocardial infarction (AMI) rates in Canada. METHODS: Between 2002 and 2009, aggregate and yearly bankruptcy and AMI rates were estimated for 1,155 forward sortation areas of Canada. Scatter plot and correlations were used to assess the association of the aggregate rates. Cross-lagged structural equation models were used to explore the longitudinal relationship between bankruptcy and AMI after adjustment for socio-economic factors. RESULTS: A cross-lagged structural equation model estimated that on average, an increase of 100 in bankruptcy filing count is associated with an increase of 1.5 (p = 0.02) in AMI count in the following year, and an increase of 100 in AMI count is associated with an increase of 7 (p < 0.01) in bankruptcy filing count. CONCLUSIONS: We found that regions with higher rates of AMI corresponded to those with higher levels of economic and financial stress, as indicated by personal bankruptcy rate, and vice-versa. PMID- 26762142 TI - Frozen faecal matter works as well as fresh for transplantation in C difficile patients. PMID- 26762141 TI - Use of cryoablation beyond the prostate. AB - Cryoablation has been used for many years as a surgical ablation technique in the prostate and kidney. However, since the introduction of high-intensity focused ultrasound (HIFU) and robotic surgery for prostate tumours, its popularity in the urologic community has declined. In the early 2000s, innovations in cryoablation technology allowed the use of thinner probes, which were suitable for percutaneous application. As a result, radiologists began using cryoablation, first in the liver, and then in other organs or tissues such as the kidney, lung, breast, pancreas, bone, and soft tissue. In most of these locations, cryoablation has great potential given its inherent advantages, including the use of local anaesthesia, little or no pain during and after the procedure, real-time monitoring of the ablation area on US, CT or MRI, the potential for ablation of large tumours with multiple probes, and the ability to change the shape of the ablation in non-spherical tumours. Yet despite these advantages, the use of percutaneous cryoablation among radiologists appears to be far lower than that of heat-based ablation techniques. The aim of this article is to outline specific aspects of cryoablation and to illustrate its potential clinical applications with case presentations. KEY POINTS: * Recent advances have made cryoablation suitable for percutaneous use by radiologists with image guidance. * Cryoablation has distinct advantages over heat-based ablation techniques. * Cryoablation is becoming increasingly popular for lung, breast, kidney, bone, and soft tissue tumours. PMID- 26762140 TI - Association of MMP-2 gene haplotypes with thoracic aortic dissection in chinese han population. AB - BACKGROUND: Thoracic aortic dissection (TAD) is the most common life-threatening disorder, and MMP-2 is involved in TAD pathogenesis. Our purpose is to systematically evaluate the association of the MMP-2 gene with TAD risk in Chinese Han population. METHODS: In our case-control study, we recruited 755 unrelated participants: 315 case participants with TAD and 440 controls. Twenty two tag SNPs were selected from MMP-2 gene and were genotyped. Genotype data were analyzed by logistic regression. RESULTS: Although we did not find any significant association for MMP-2 SNPs using single-marker analysis, we identified many windows with haplotype frequencies significantly different between case participants and control participants using a variable-sized sliding window strategy. In particular, the most significant association was shown by a 2 SNP window consisting of rs2241145 and rs9928731 (omnibus test: asymptotic Pasym = 7.48 * 10 (-5) and empirical Pemp = 0.001867). There were two protective haplotypes: CT (Pasym = 0.00303; odds ratio [OR], 0.403) and GC (Pasym = 0.000976; OR, 0.448). CONCLUSIONS: MMP-2 haplotypes are associated with genetic susceptibility to thoracic aortic dissection in Chinese Han population. PMID- 26762143 TI - Tubular Pyloric Gland Adenoma of the Left and Right Hepatic Ducts: Report of a Unique Case With Immunohistochemical and Molecular Studies. AB - Pyloric gland adenomas (PGAs) of the extrahepatic biliary system are rare lesions. We report a case of a tubular PGA that led to biliary obstruction. The tumor was located at the confluence of the right and left hepatic ducts, extending to the left hepatic duct. The tumor cells expressed MUC6 and MUC5AC. MUC1 and CD10 were focally positive. MUC2, p53, and CDX2 were not expressed. The Ki67 positivity was estimated at <15%. None of the KRAS, NRAS, BRAF, EGFR coding regions resulted in clinically relevant amino acid substitutions. SNP rs1050171 (EGFR p.Q787Q, silent mutation) corresponding to c.2361G>A transition in exon 20 was noticed. Awareness of this rare lesion is important for pathologists and clinicians alike, because it may cause significant morphologic and clinical difficulties, especially when presenting as an obstructive mass. Because of the possible risk of evolving malignancy, surgical resection is recommended whenever possible. PMID- 26762144 TI - Hidden Voices: Disabled Women's Experiences of Violence and Support Over the Life Course. AB - Violence against women is a worldwide social and human rights problem that cuts across cultural, geographic, religious, social, and economic boundaries. It affects women in countries around the world, regardless of class, religion, disability, age, or sexual identity. International evidence shows that approximately three in five women experienced physical and/or sexual violence by an intimate partner. However, across the globe, women and girls with impairments or life-limiting illnesses are more susceptible to different forms of violence across a range of environments and by different perpetrators including professionals and family members as well as partners. However, they are likely to be seriously disadvantaged in gaining information and support to escape the abusive relationships. This article stems from the United Kingdom part of a comparative study with three other countries (Austria, Germany, and Iceland) funded by the European Commission (EC; 2013-2015). It presents preliminary findings, generated from life history interviews, about disabled women's experiences of violence and access to support (both formal and informal) over their life course and their aspirations for the prevention of violence in the future. The article includes examples of impairment-specific violence that non disabled women do not experience. By bringing the voices of disabled women into the public domain, the article will facilitate a historically marginalized group to contribute to the debate about disability, violence, and support. PMID- 26762146 TI - Outcome-based health equity across different social health insurance schemes for the elderly in China. AB - BACKGROUND: Against the achievement of nearly universal coverage for social health insurance for the elderly in China, a problem of inequity among different insurance schemes on health outcomes is still a big challenge for the health care system. Whether various health insurance schemes have divergent effects on health outcome is still a puzzle. Empirical evidence will be investigated in this study. METHODS: This study employs a nationally representative survey database, the National Survey of the Aged Population in Urban/Rural China, to compare the changes of health outcomes among the elderly before and after the reform. A one way ANOVA is utilized to detect disparities in health care expenditures and health status among different health insurance schemes. Multiple Linear Regression is applied later to examine the further effects of different insurance plans on health outcomes while controlling for other social determinants. RESULTS: The one-way ANOVA result illustrates that although the gaps in insurance reimbursements between the Urban Employee Basic Medical Insurance (UEBMI) and the other schemes, the New Rural Cooperative Medical Scheme (NCMS) and Urban Residents Basic Medical Insurance (URBMI) decreased, out-of-pocket spending accounts for a larger proportion of total health care expenditures, and the disparities among different insurances enlarged. Results of the Multiple Linear Regression suggest that UEBMI participants have better self-reported health status, physical functions and psychological wellbeing than URBMI and NCMS participants, and those uninsured. URBMI participants report better self-reported health than NCMS ones and uninsured people, while having worse psychological wellbeing compared with their NCMS counterparts. CONCLUSIONS: This research contributes to a transformation in health insurance studies from an emphasis on the opportunity-oriented health equity measured by coverage and healthcare accessibility to concern with outcome-based equity composed of health expenditure and health status. The results indicate that fragmented health insurance schemes generate inequitable health care utilization and health outcomes for the elderly. This study re-emphasizes the importance of reforming health insurance systems based on their health outcome rather than entitlement, which will particularly benefit the most vulnerable older groups. PMID- 26762145 TI - Enhancement of HIV-1 infection and intestinal CD4+ T cell depletion ex vivo by gut microbes altered during chronic HIV-1 infection. AB - BACKGROUND: Early HIV-1 infection is characterized by high levels of HIV-1 replication and substantial CD4 T cell depletion in the intestinal mucosa, intestinal epithelial barrier breakdown, and microbial translocation. HIV-1 induced disruption of intestinal homeostasis has also been associated with changes in the intestinal microbiome that are linked to mucosal and systemic immune activation. In this study, we investigated the impact of representative bacterial species that were altered in the colonic mucosa of viremic HIV-1 infected individuals (HIV-altered mucosal bacteria; HAMB) on intestinal CD4 T cell function, infection by HIV-1, and survival in vitro. Lamina propria (LP) mononuclear cells were infected with CCR5-tropic HIV-1BaL or mock infected, exposed to high (3 gram-negative) or low (2 gram-positive) abundance HAMB or control gram-negative Escherichia coli and levels of productive HIV-1 infection and CD4 T cell depletion assessed. HAMB-associated changes in LP CD4 T cell activation, proliferation and HIV-1 co-receptor expression were also evaluated. RESULTS: The majority of HAMB increased HIV-1 infection and depletion of LP CD4 T cells, but gram-negative HAMB enhanced CD4 T cell infection to a greater degree than gram-positive HAMB. Most gram-negative HAMB enhanced T cell infection to levels similar to that induced by gram-negative E. coli despite lower induction of T cell activation and proliferation by HAMB. Both gram-negative HAMB and E. coli significantly increased expression of HIV-1 co-receptor CCR5 on LP CD4 T cells. Lipopolysaccharide, a gram-negative bacteria cell wall component, up regulated CCR5 expression on LP CD4 T cells whereas gram-positive cell wall lipoteichoic acid did not. Upregulation of CCR5 by gram-negative HAMB was largely abrogated in CD4 T cell-enriched cultures suggesting an indirect mode of stimulation. CONCLUSIONS: Gram-negative commensal bacteria that are altered in abundance in the colonic mucosa of HIV-1 infected individuals have the capacity to enhance CCR5-tropic HIV-1 productive infection and depletion of LP CD4 T cells in vitro. Enhanced infection appears to be primarily mediated indirectly through increased expression of CCR5 on LP CD4 T cells without concomitant large scale T cell activation. This represents a novel mechanism potentially linking intestinal dysbiosis to HIV-1 mucosal pathogenesis. PMID- 26762148 TI - Why 'Universal Precautions' are needed for medication lists. PMID- 26762147 TI - Lay perceptions of risk factors for Rift Valley fever in a pastoral community in northeastern Kenya. AB - BACKGROUND: Human behavioral factors have been found to be central in the transmission of Rift Valley fever. Consumption of contaminated meat and milk in particular have been identified as one of the key risk factors for the transmission of Rift Valley fever in humans. In pastoral communities, livestock is the main source of livelihood from which many benefits such as food as well as economic and cultural services are derived. Zoonotic diseases therefore have a great impact on pastoral communities livelihoods. However, lay perceptions regarding the transmission of these diseases including Rift Valley fever hampers their effective control. This study investigated the lay perceptions of risks for Rift Valley fever transmission in a pastoral community in northeastern Kenya. METHODS: A qualitative study was carried out in Ijara district, Kenya which was one of the hotspots of Rift Valley during the 2006/2007 outbreak. Data were collected using focus group discussions and narratives guided by checklists. Eight focus group discussions consisting of 83 participants and six narratives were conducted. Data was transcribed, coded and analysed according to Emergent themes. RESULTS: The participants reported that they had experienced Rift Valley fever in their livestock especially sheep and in humans both in 1997/1998 and 2006/2007. However, they believed that infections in humans occurred as a result of mosquito bites and had little to do with their consumption of meat, milk and blood from infected livestock. The participants in this study indicated that they had heard of the risks of acquiring the disease through consumption of livestock products but their experiences did not tally with the information they had received hence to them, Rift Valley fever was not transmissible through their dietary practices. CONCLUSIONS: Though the communities in this region were aware of Rift Valley fever, they did not have elaborate information regarding the disease transmission dynamics to humans. To avoid misconception about transmission of the disease, intervention strategies, require to be accompanied by comprehensive explanations of the dynamics of its transmission. It is necessary to develop appropriate interventions that take into consideration, lay perceptions of risk factors for the disease and communities' livelihood strategies. PMID- 26762149 TI - Balancing quality of care and resource utilisation in acute care hospitals. PMID- 26762151 TI - Sociocultural determinants of anticipated oral cholera vaccine acceptance in three African settings: a meta-analytic approach. AB - BACKGROUND: Controlling cholera remains a significant challenge in Sub-Saharan Africa. In areas where access to safe water and sanitation are limited, oral cholera vaccine (OCV) can save lives. Establishment of a global stockpile for OCV reflects increasing priority for use of cholera vaccines in endemic settings. Community acceptance of vaccines, however, is critical and sociocultural features of acceptance require attention for effective implementation. This study identifies and compares sociocultural determinants of anticipated OCV acceptance across populations in Southeastern Democratic Republic of Congo, Western Kenya and Zanzibar. METHODS: Cross-sectional studies were conducted using similar but locally-adapted semistructured interviews among 1095 respondents in three African settings. Logistic regression models identified sociocultural determinants of OCV acceptance from these studies in endemic areas of Southeastern Democratic Republic of Congo (SE-DRC), Western Kenya (W-Kenya) and Zanzibar. Meta-analytic techniques highlighted common and distinctive determinants in the three settings. RESULTS: Anticipated OCV acceptance was high in all settings. More than 93% of community respondents overall indicated interest in a no-cost vaccine. Higher anticipated acceptance was observed in areas with less access to public health facilities. In all settings awareness of cholera prevention methods (safe food consumption and garbage disposal) and relating ingestion to cholera causation were associated with greater acceptance. Higher age, larger households, lack of education, social vulnerability and knowledge of oral rehydration solution for self-treatment were negatively associated with anticipated OCV acceptance. Setting-specific determinants of acceptance included reporting a reliable income (W-Kenya and Zanzibar, not SE-DRC). In SE-DRC, intention to purchase an OCV appeared unrelated to ability to pay. Rural residents were less likely than urban counterparts to accept an OCV in W-Kenya, but more likely in Zanzibar. Prayer as a form of self-treatment was associated with vaccine acceptance in SE-DRC and W Kenya, but not in Zanzibar. CONCLUSIONS: These cholera-endemic African communities are especially interested in no-cost OCVs. Health education and attention to local social and cultural features of cholera and vaccines would likely increase vaccine coverage. High demand and absence of insurmountable sociocultural barriers to vaccination with OCVs indicate potential for mass vaccination in planning for comprehensive control or elimination. PMID- 26762150 TI - Effect of a patient decision aid (PDA) for type 2 diabetes on knowledge, decisional self-efficacy, and decisional conflict. AB - BACKGROUND: Patients with type 2 diabetes (T2DM) often have poor glycemic control on first-line pharmacologic therapy and require treatment intensification. Intensification decisions can be difficult because of many available options and their many benefits and risks. The American Diabetes Association recommends patient-centered, evidence-based tools supporting shared decision-making between patients and clinicians. We developed a patient decision aid (PDA) targeting decisions about treatment intensification for T2DM. Our objective was to determine the effectiveness of this PDA for patients with T2DM on metformin who require treatment intensification. METHODS: This study was a pragmatic randomized controlled trial conducted in 27 US primary care and endocrinology clinics. Subjects were English-speaking adults with T2DM receiving metformin with persistent hyperglycemia who were recommended to consider medication intensification. Subjects were randomized to receive either the PDA or usual care (UC). Main outcome measures were change in knowledge, decisional self-efficacy, and decisional conflict. RESULTS: Of 225 subjects enrolled, 114 were randomized to the PDA and 111 to UC. Mean [SD] age was 52 [1] years, time since T2DM diagnosis was 6 [+/-6] years, 45.3% were male, and most (55.5%) were non Caucasian. Compared to UC, PDA users had significantly larger knowledge gains (35.0% [22.3] vs 9.9% [22.2]; P < 0.0001) and larger improvements in self efficacy (3.7 [16.7] vs-3.9 [19.2]; P < 0.0001) and decisional conflict (-22.2 [20.6] vs-7.5 [16.6]; P < 0.0001). CONCLUSIONS: The PDA resulted in substantial and significant improvements in knowledge, decisional conflict and decisional self-efficacy. Decisional conflict scores after PDA use were within the range that correlates with effective decision-making. This PDA has the potential to facilitate shared-decision-making for patients with T2DM. TRIAL REGISTRATION: NCT02110979. PMID- 26762152 TI - Tocolysis for inhibiting preterm birth in extremely preterm birth, multiple gestations and in growth-restricted fetuses: a systematic review and meta analysis. AB - This systematic review was to identify available evidence on the effectiveness of tocolysis in inhibiting preterm delivery for women with threatened extremely preterm birth, multiple gestations, and growth-restricted babies, and their infants' outcomes. A comprehensive search using MEDLINE, Embase, the Cochrane Library, CINAHL, POPLINE and the WHO Global Health Library databases was conducted on 14 February 2014. For selection criteria, randomized controlled trials and non-randomized studies that compared tocolysis treatment to placebo or no treatment were considered. Selection of eligible studies, critical appraisal of the included studies, data collection, meta-analyses, and assessment of evidence quality were performed in accordance with the Cochrane Collaboration's guidance and validated assessment criteria. The search identified seven studies for extremely preterm birth, in which three were randomized controlled trials (RCTs) and four were non-randomized studies (non-RCTs). There were no eligible studies identified for women with multiple pregnancy and growth-restricted fetuses. Meta-analyses indicated no significant difference was found for the relative effectiveness of tocolytics versus placebo for prolonging pregnancy in women with extremely preterm birth (RR 1.04, 95% CI 0.83 to 1.31) or reducing the rate of perinatal deaths (RR 2.22, 95% CI 0.26 to 19.24). In summary, there is no evidence to draw conclusions on the effectiveness of tocolytic therapy for women with threatened extremely preterm birth, multiple gestations, and growth restricted babies. PMID- 26762153 TI - Identification of three new isolates of Tomato spotted wilt virus from different hosts in China: molecular diversity, phylogenetic and recombination analyses. AB - BACKGROUND: Destructive diseases caused by Tomato spotted wilt virus (TSWV) have been reported associated with many important plants worldwide. Recently, TSWV was reported to infect different hosts in China. It is of value to clone TSWV isolates from different hosts and examine diversity and evolution among different TSWV isolates in China as well as worldwide. METHODS: RT-PCR was used to clone the full-length genome (L, M and S segments) of three new isolates of TSWV that infected different hosts (tobacco, red pepper and green pepper) in China. Identity of nucleotide and amino acid sequences among TSWV isolates were analyzed by DNAMAN. MEGA 5.0 was used to construct phylogenetic trees. RDP4 was used to detect recombination events during evolution of these isolates. RESULTS: Whole genome sequences of three new TSWV isolates in China were determined. Together with other available isolates, 29 RNA L, 62 RNA M and 66 RNA S of TSWV isolates were analyzed for molecular diversity, phylogenetic and recombination events. This analysis revealed that the entire TSWV genome, especially the M and S RNAs, had major variations in genomic size that mainly involve the A-U rich intergenic region (IGR). Phylogenetic analyses on TSWV isolates worldwide revealed evidence for frequent reassortments in the evolution of tripartite negative-sense RNA genome. Significant numbers of recombination events with apparent 5' regional preference were detected among TSWV isolates worldwide. Moreover, TSWV isolates with similar recombination events usually had closer relationships in phylogenetic trees. CONCLUSIONS: All five Chinese TSWV isolates including three TSWV isolates of this study and previously reported two isolates can be divided into two groups with different origins based on molecular diversity and phylogenetic analysis. During their evolution, both reassortment and recombination played roles. These results suggest that recombination could be an important mechanism in the evolution of multipartite RNA viruses, even negative sense RNA viruses. PMID- 26762154 TI - Qualitative European survey of patients with idiopathic pulmonary fibrosis: patients' perspectives of the disease and treatment. AB - BACKGROUND: 'Living with IPF and an exploration of Esbriet(r) - a new treatment' was an exploratory, qualitative, real-world survey of European patients with idiopathic pulmonary fibrosis (IPF) who were receiving treatment with pirfenidone prior to its commercial availability. The aim of the survey was to probe the impact of IPF on patients' quality of life; the role of healthcare professionals and caregivers; the information needs of both patients and their caregivers; and patients' perceptions of pirfenidone as a new treatment option for IPF. METHODS: Patients from the UK, Germany and Italy, with a diagnosis of IPF (duration >3 months), who were being treated with pirfenidone, were recruited from patient support groups, specialist centres and advocacy groups. Semi-structured, qualitative, in-depth patient interviews of 1-h duration were conducted by an independent researcher. Patients were initially asked about their experiences of living with IPF and then prompted to describe their experiences of taking pirfenidone. Techniques utilised included: the bubble-speech technique; the icon cards projective exercise; and the free association exercise. All interviews were transcribed and analysed by an independent researcher. RESULTS: Forty-five patients (71% male) were interviewed (mean age 68.5 years; mean time since diagnosis 3.5 years); 87% of patients reported that diagnosis took >1 year. Patients reported that IPF had a significant physical and emotional impact on their quality of life. The beneficial role played by caregivers and interstitial lung disease specialist nurses (where available) was specifically highlighted. Although most patients were keen for information on IPF, this was often of poor quality, out of date, or in English only. Patients' perceptions of pirfenidone were largely positive and associated with 'hope' but were also influenced by the level of side effects experienced. CONCLUSIONS: This survey highlights the impact of IPF on patients' lives, and the need to adequately support both patients and their caregivers. These findings demonstrate the value of seeking patients' perspectives of a chronic disease such as IPF and how this information can be used to guide improvements in care, to best support the needs of patients with this devastating condition. PMID- 26762155 TI - Syphilitic orchitis mimicking a testicular tumor in a clinically occult HIV infected young man: a case report with emphasis on a challenging pathological diagnosis. AB - BACKGROUND: Syphilitic orchitis is a rare manifestation of gumma in tertiary syphilis, microscopically typically characterized by multiple discrete granulomas with central necrosis and peripheral fibrosis. We report a case of syphilitic orchitis mimicking a testicular tumor with atypical histological features. CASE PRESENTATION: A 33-year-old clinically occult HIV-infected man had a testicular tumor. A radical orchiectomy was performed, and a histological examination showed an acute and chronic interstitial inflammatory lesion as well as spindle cell proliferation, without typical gumma formation, necessitating the differential diagnosis having to be made from a panel of etiological factors. Syphilitic orchitis was confirmed by both an immunohistochemical study and PCR testing for the Treponema pallidum DNA polymerase I gene using paraffin-embedded tissues. However, serology tests, including both the Venereal Disease Research Laboratory (VDRL) test and Treponema pallidum partical agglutination (TTPA), demonstrated false-negative results. CONCLUSION: Syphilitic orchitis may present atypical and unusual histological features, and should be included in the differential diagnoses of nonspecific interstitial inflammatory lesions of the testes by pathologists, especially in immunocompromised patients. PMID- 26762157 TI - US president endorses "moonshot" effort to cure cancer. PMID- 26762156 TI - Childhood asthma prevalence and risk factors in three Eastern European countries- the Belarus, Ukraine, Poland Asthma Study (BUPAS): an international prevalence study. AB - BACKGROUND: The prevalence of asthma and other allergic diseases among children living in Eastern is not well described. Our objective was to estimate and compare the prevalence of asthma, respiratory symptoms and allergic diseases in children in Belarus, Ukraine, and Poland as well as to identify risk factors for these conditions. We also sought to profile and compare children with asthma between locations. METHODS: Data were collected as a part of an international, multicenter, cross-sectional study of childhood asthma: The Belarus Ukraine Poland Asthma Study (BUPAS). Subjects were children aged 7-13 years attending primary and secondary schools in the urban and surrounding rural area of Grodno (Belarus), Ternopil (Ukraine) and Silesia Region (Poland). Physician-diagnosed respiratory diseases and symptoms as well as allergic diseases were ascertained using the ISAAC questionnaire completed by the parents. RESULTS: In total there were 4019 children from Belarus (rural: 2018, urban: 2001), 4493 from Ukraine (1972; 2521), and 4036 from Poland (2002, 2034). The overall response rate was 76.7%. Groups were similar in case of gender and age (p > 0.05). Almost all analyzed respiratory and allergic conditions differed significantly between countries including asthma [Poland (rural, urban): 3.5%, 4.1%; Ukraine: 1.4%, 2.1%; Belarus: 1.4%, 1.5%], spastic bronchitis (Poland: 2.7%, 3.2%; Ukraine: 7.5%, 6.5%; Belarus: 6.4%, 7.9%), and chest wheeze in the last year (Poland: 4.8%, 5.2%; Ukraine: 11.5%, 13.0%; Belarus: 10.7%, 10.0%). These differences remained after adjustment for potential confounders. Risk factor associations were generally similar between outcomes. Symptom characteristics of children with asthma between countries were not consistent. The ratio of current wheeze:diagnosis of asthma differed by country: (Rural areas: Belarus: 10.9:1, Ukraine: 17.3:1, Poland: 2.4:1; Urban areas: Belarus: 8.1:1, Ukraine: 7.3:1 Poland: 1.9:1). CONCLUSIONS: The findings show large between-country differences and relatively low prevalence of asthma and allergic diseases in children of Western Belarus and Ukraine. There is evidence for underdiagnosis of asthma in these regions. PMID- 26762158 TI - 60 YEARS OF POMC: From the prohormone theory to pro-opiomelanocortin and to proprotein convertases (PCSK1 to PCSK9). AB - Pro-opiomelanocortin (POMC), is a polyprotein expressed in the pituitary and the brain where it is proteolytically processed into peptide hormones and neuropeptides with distinct biological activities. It is the prototype of multipotent prohormones. The prohormone theory was first suggested in 1967 when Chretien and Li discovered gamma-lipotropin and observed that (i) it was part of beta-lipotropin (beta-LPH), a larger polypeptide characterized 2 years earlier and (ii) its C-terminus was beta-melanocyte-stimulating hormone (beta-MSH). This discovery led them to propose that the lipotropins might be related biosynthetically to the biologically active beta-MSH in a precursor to end product relationship. The theory was widely confirmed in subsequent years. As we celebrate the 50th anniversary of the sequencing of beta-LPH, we reflect over the lessons learned from the sequencing of those proteins; we explain their extension to the larger POMC precursor; we examine how the theory of precursor endoproteolysis they inspired became relevant for vast fields in biology; and how it led, after a long and arduous search, to the novel proteolytic enzymes called proprotein convertases. This family of nine enzymes plays multifaceted functions in growth, development, metabolism, endocrine, and brain functions. Their genetics has provided many insights into health and disease. Their therapeutic targeting is foreseeable in the near future. Thus, what started five decades ago as a theory based on POMC fragments, has opened up novel and productive avenues of biological and medical research, including, for our own current interest, a highly intriguing hypocholesterolemic Gln152His PCSK9 mutation in French-Canadian families. PMID- 26762160 TI - Involvement of the multidisciplinary team and outcomes in inpatient rehabilitation among patients with inflammatory rheumatic disease. AB - BACKGROUND: The last decades have for patients with inflammatory rheumatic diseases seen a shift towards more physically active rehabilitation programs, often provided as out-patients with less use of inpatient facilities. There is little research on which effect the multidisciplinary team has on health outcomes for patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and connective tissue disease. This study examined patient reported outcomes for patients with inflammatory rheumatic diseases receiving rehabilitation care as inpatients in departments of rheumatology, and studied how number of consultations with the multidisciplinary team affected these clinical outcomes. METHODS: Patients with inflammatory rheumatic diseases were included in a multi-center prospective observational study if rehabilitation was considered a focus during an inpatient stay at four departments of rheumatology. At admission, discharge, and after 3 and 6 months, 317 patients were assessed with patients reported outcomes (PRO) including health assessment questionnaire (HAQ), short form 36 (SF-36), pain, fatigue, patient global assessment of disease activity, self-efficacy scales, rheumatoid arthritis disease activity index (RADAI), and SF 6D utility. Patients stated consultations with the multidisciplinary team. RESULTS: Improvements were short-lived, and at 6 months follow-up period only mental health, pain and utility remained improved with small effect sizes. Extensive involvement of health professionals was not associated with improved outcomes. CONCLUSIONS: Patients with inflammatory rheumatic disease receiving inpatient multidisciplinary rehabilitation had small and mainly short-term improvements in most PROs. High use of the multidisciplinary team did not enhance or preserve rehabilitation outcomes in inflammatory rheumatic conditions when admitted as inpatients. PMID- 26762159 TI - Ethnobotanical survey of medicinal plant species used by communities around Mabira Central Forest Reserve, Uganda. AB - BACKGROUND: An ethnobotanical study of medicinal plants was carried out in 14 villages adjacent to Mabira Central Forest Reserve (CFR) in Central Uganda between August 2013 and March 2014. METHODS: Information was obtained through interviews using semi- structured questionnaires. Field excursions with traditional healers and herbal medicine collectors were carried out. Descriptive statistics were used to present the data. Fidelity ratios and Informant consensus agreements were calculated. RESULTS: A total of 190 plant species in 61 families and 152 genera were reported in the treatment of various health conditions. Family Fabaceae was dominant representing 14 % of the plant species documented. Vernonia amygdalina was the preferred species for treating malaria. Leaves (68 %) were the most frequently used parts in preparing herbal remedies. Decoctions (29 %) and oral route (53 %) of administration were commonly used method of herbal medicine preparation and administration respectively. Fifty-eight health conditions grouped in 25 categories were treated using medicinal plants. Informant consensus agreement was highest for blood system disorders (0.9) that included anaemia, hypertension and blood cleansing indicating homogeneity of informant's knowledge about remedies used. Vernonia amygdalina and Erythrina abyssinica had 100 % fidelity level for treatment of malaria and vomiting respectively. CONCLUSION: The diversity of medicinal plant species used and the associated indigenous knowledge are of great value to the local community and their conservation and preservation is paramount. The therapeutic uses of the documented plants provides basic data for further research focused on pharmacological studies and conservation of the most important species. PMID- 26762162 TI - Patient perspectives of methadone formulation change in British Columbia, Canada: outcomes of a provincial survey. AB - BACKGROUND: In British Columbia, Canada, methadone maintenance treatment formulation transitioned from the oral liquid compound TangTM-flavoured methadone to the ten-times more concentrated cherry-flavoured MethadoseTM in February 2014. We quantitatively describe perceptions and reported consequences among a sample of patients on methadone maintenance treatment following this transition. METHODS: A province-wide survey was used. Bivariable analyses utilized independent samples t-tests, Phi associations, and Chi-square tests. Multivariable logistic regression analyses evaluated factors related to dependent variables - namely, increases in dose, pain, dope sickness, and the need to supplement with additional opioids. RESULTS: Four hundred five methadone maintenance treatment patients from fifty harm reduction sites across British Columbia reported transitioning to MethadoseTM in February 2014. The majority (n = 258; 73.1 %) heard about the formulation change from their methadone provider or pharmacist. Adjusted models show worse taste was positively associated with reporting an increasing dose (OR = 2.46; CI:1.31-4.61), feeling more dope sick (OR = 3.39; CI:1.88-6.12), and worsening pain (OR = 4.65; CI:2.45-8.80). Feeling more dope sick was positively associated with dose increase (OR = 2.24; CI:1.37 3.66), and supplementing with opioids (OR = 8.81; CI:5.16-15.05). CONCLUSIONS: Methadone maintenance treatment policy changes in British Columbia affect a structurally vulnerable population who may be less able to cope with transitions and loss of autonomy. There may be a psychosocial component contributing to the perception of MethadoseTM tasting worse, and increased dope sickness, pain, and dose. Our study shows the pronounced negative impacts medication changes can have on patients without informed, coordinated efforts. We stress the need to engage all stakeholders allowing for communication about the reasons, risks and consequences of medication policy changes and provision of additional psychosocial support. PMID- 26762163 TI - EM Talk: communication skills training for emergency medicine patients with serious illness. AB - The emergency department visit for a patient with serious illness represents a sentinel event, signalling a change in the illness trajectory. By better understanding patient and family wishes, emergency physicians can reinforce advance care plans and ensure the hospital care provided matches the patient's values. Despite their importance in care at the end of life, emergency physicians have received little training on how to talk to seriously ill patients and their families about goals of care. To expand communication skills training to emergency medicine, we developed a programme to give emergency medicine physicians the ability to empathically deliver serious news and to talk about goals of care. We have built on lessons from prior studies to design an intervention employing the most effective pedagogical techniques, including the use of simulated patients/families, role-playing and small group learning with constructive feedback from master clinicians. Here, we describe our evidence based communication skills training course EM Talk using simulation, reflective feedback and deliberate practice. PMID- 26762164 TI - Identification of novel in vivo obligate GroEL/ES substrates based on data from a cell-free proteomics approach. AB - Chaperones are essential to maintain the proper folding of various proteins in vivo. The Escherichia coli chaperonin GroEL/GroES (GroE) is one of the best studied chaperones, and its in vivo substrates have been identified, mainly by mass spectrometry-based proteomic studies. Here, we newly identified 20 in vivo obligate GroE substrates with the aid of data from an in vitro comprehensive analysis. The newly identified substrates have similar physicochemical properties to the known substrates, but their expression levels in vivo were significantly lower. Information from the in vitro comprehensive analysis has the potential to compensate for limitations of the MS-based proteomic approaches. PMID- 26762161 TI - The NHS Health Check in England: an evaluation of the first 4 years. AB - OBJECTIVES: To describe implementation of a new national preventive programme to reduce cardiovascular morbidity. DESIGN: Observational study over 4 years (April 2009--March 2013). SETTING: 655 general practices across England from the QResearch database. PARTICIPANTS: Eligible adults aged 40-74 years including attendees at a National Health Service (NHS) Health Check. INTERVENTION: NHS Health Check: routine structured cardiovascular check with support for behavioural change and in those at highest risk, treatment of risk factors and newly identified comorbidity. RESULTS: Of 1.68 million people eligible for an NHS Health Check, 214 295 attended in the period 2009-12. Attendance quadrupled as the programme progressed; 5.8% in 2010 to 30.1% in 2012. Attendance was relatively higher among older people, of whom 19.6% of those eligible at age 60 74 years attended and 9.0% at age 40-59 years. Attendance by population groups at higher cardiovascular disease (CVD) risk, such as the more socially disadvantaged 14.9%, was higher than that of the more affluent 12.3%. Among attendees 7844 new cases of hypertension (38/1000 Checks), 1934 new cases of type 2 diabetes (9/1000 Checks) and 807 new cases of chronic kidney disease (4/1000 Checks) were identified. Of the 27,624 people found to be at high CVD risk (20% or more 10 year risk) when attending an NHS Health Check, 19.3% (5325) were newly prescribed statins and 8.8% (2438) were newly prescribed antihypertensive therapy. CONCLUSIONS: NHS Health Check coverage was lower than expected but showed year-on year improvement. Newly identified comorbidities were an important feature of the NHS Health Checks. Statin treatment at national scale for 1 in 5 attendees at highest CVD risk is likely to have contributed to important reductions in their CVD events. PMID- 26762165 TI - Anti-HLA donor-specific antibodies are not created equally. Don't forget the flow.... PMID- 26762167 TI - Erythematous Plaques and Violaceous Nodules on Extensor Surfaces. PMID- 26762169 TI - An evaluation of orthopaedic nurses' participation in an educational intervention promoting research usage--a triangulation convergence model. AB - AIMS AND OBJECTIVES: To describe the orthopaedic nurses' experiences regarding the relevance of an educational intervention and their personal and contextual barriers to participation in the intervention. BACKGROUND: One of the largest barriers against nurses' research usage in clinical practice is the lack of participation. A previous survey identified 32 orthopaedic nurses as interested in participating in nursing research. An educational intervention was conducted to increase the orthopaedic nurses' research knowledge and competencies. However, only an average of six nurses participated. DESIGN: A triangulation convergence model was applied through a mixed methods design to combine quantitative results and qualitative findings for evaluation. METHODS: Data were collected from 2013 2014 from 32 orthopaedic nurses in a Danish regional hospital through a newly developed 21-item questionnaire and two focus group sessions. Data were first analysed using descriptive statistics (stata 12.0) and qualitative manifest content analysis. Second, the results were compared, contrasted and interpreted using international literature. RESULTS: The nurses experienced the intervention as a new way to focus on nursing research in practice. However, some nurses were not able to see the relevance of research usage in clinical practice. Nursing research was not a top priority for the nurses and their personal barriers for research usage during their working day were prioritising patients' and colleagues' well-being. Their colleagues' and head section nurses' lack of acceptance regarding participation in the teaching session was a contextual barrier for the nurses. CONCLUSION: The nurses were interested in participating in the intervention. However, some felt restricted by the research-practice gap and by diverse personal and contextual barriers. RELEVANCE TO CLINICAL PRACTICE: The knowledge derived from this study has high clinical and practical relevance and is currently used to facilitate the nurses' research usage in the orthopaedic department setting, by working around the perceived barriers. PMID- 26762166 TI - Molecular changes indicative of cartilage degeneration and osteoarthritis development in patients with anterior cruciate ligament injury. AB - BACKGROUND: Anterior cruciate ligament (ACL) tear is considered a risk factor for osteoarthritis development. The purpose of our study was to investigate the expression levels of the apoptotic enzyme caspase 3, pro-inflammatory cytokines interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) and degrading enzyme matrix metalloproteinase 13 (MMP-13), all indicative of cartilage degeneration and osteoarthritis development in patients' chondrocytes after ACL rupture. METHODS: We investigated the correlation between grade of cartilage degradation and time from injury or patients' age. IL-1beta, IL-6 and MMP-13 mRNA expression levels were investigated in normal (n = 4) and chondrocytes from patients with ACL rupture (n = 33) using real-time polymerase chain reaction (PCR). Moreover, MMP 13 and caspase-3 protein expression levels were evaluated by western blot analysis. Trend analysis and correlation coefficient were performed to derive the relations between gene expression (MMP13, IL-6, IL-1beta) and grading of cartilage defects and between gene expression (MMP13, IL-6, IL-1beta) and patients' age, respectively. RESULTS: Correlations were established between grade of cartilage degradation and time from injury. MMP-13, IL-6, IL-1beta and caspase 3 expression levels were significantly upregulated in chondrocytes from ACL deficient knee compared to normal. Among the patients with ACL-deficient knees, a significant upregulation of MMP-13 was observed in patients with ACL-rupture > 18 months from the time of injury to arthroscopy compared to patients with ACL injury up to 18 months, whereas IL-6 and IL-1beta expression was higher in chondrocytes from patients with more than 10 months ACL injury compared to those that underwent surgery within the first 10 months after injury. Nuomicron association was observed between IL-1beta, IL-6 and MMP-13 expression levels and cartilage defects or patients' age. CONCLUSION: Our results showed that increased levels of apoptotic, inflammatory and catabolic factors in chondrocytes are associated with time from injury and could contribute to cartilage degradation and osteoarthritis development after ACL rupture. PMID- 26762168 TI - Characterization of a new low-dose 6-hydroxydopamine model of Parkinson's disease in rat. AB - Intrastriatal administration of 6-hydroxydopamine (6-OHDA) induces partial degeneration of the nigrostriatal pathway, mimicking the pathology of Parkinson's disease (PD). Setting up the partial lesion model can be challenging because a number of experimental settings can be altered. This study compares seven experimental settings in a single study on d-amphetamine-induced rotations, tyrosine hydroxylase (TH)-positive neurites in the striatum, dopamine transporter (DAT)-positive neurites in the striatum, and TH-positive cells in the substantia nigra pars compacta (SNpc) in rats. Moreover, we validate a new algorithm for estimating the number of TH-positive cells. We show that the behavior and immunoreactivity vary greatly depending on the injection settings, and we categorize the lesions as progressive, stable, or regressive based on d amphetamine-induced rotations. The rotation behavior correlated with the degree of the lesion, analyzed by immunohistochemistry; the largest lesions were in the progressive group, and the smallest lesions were in the regressive group. We establish a new low-dose partial 6-OHDA lesion model in which a total of 6 MUg was distributed evenly to three sites in the striatum at a 10 degrees angle. The administration of low-dose 6-OHDA produced stable and reliable rotation behavior and induced partial loss of striatal TH-positive and DAT-positive neurites and TH positive cells in the SNpc. This model is highly suitable for neurorestoration studies in the search for new therapies for PD, and the new algorithm increases the efficacy for estimating the number of dopamine neurons. This study can be extremely useful for laboratories setting up the partial 6-OHDA model. PMID- 26762171 TI - Dielectric Engineering of a Boron Nitride/Hafnium Oxide Heterostructure for High Performance 2D Field Effect Transistors. AB - A unique design of a hexagonal boron nitride (h-BN)/HfO2 dielectric heterostructure stack is demonstrated, with few-layer h-BN to alleviate the surface optical phonon scattering, followed by high-kappa HfO2 deposition to suppress Coulombic impurity scattering so that high-performance top-gated two dimensional semiconductor transistors are achieved. Furthermore, this dielectric stack can also be extended to GaN-based transistors to enhance their performance. PMID- 26762170 TI - Counter-regulatory paracrine actions of FGF-23 and 1,25(OH)2 D in macrophages. AB - Mechanisms underlying the association between fibroblastic growth factor 23 (FGF 23) and inflammation are uncertain. We found that FGF-23 was markedly up regulated in LPS/INF-gamma-induced proinflammatory M1 macrophages and Hyp mouse derived peritoneal macrophages, but not in IL-4-induced M2 anti-inflammatory macrophages. NF-KB and JAK/STAT1 pathways mediated the increased transcription of FGF-23 in response to M1 polarization. FGF-23 stimulated TNF-alpha, but not IL-6, expression in M0 macrophages and suppressed Arginase-1 expression in M2 macrophages through FGFR-mediated mechanisms. 1,25(OH)2 D stimulated Arginase-1 expression and inhibited FGF-23 stimulation of TNF-alpha. FGF-23 has proinflammatory paracrine functions and counter-regulatory actions to 1,25(OH)2 D on innate immune responses. PMID- 26762173 TI - O-Glycan analysis of cellobiohydrolase I from Neurospora crassa. AB - We describe here the composition of the O-linked glycans on the Neurospora crassa cellobiohydrolase I (CBHI), which accounts for approximately 40% of the protein secreted by cells growing in the presence of cellulose. CBHI is O-glycosylated with six types of linear, and three types of branched, O-glycans containing approximately equal amounts of mannose and galactose. In addition to the classic fungal O-glycans with reducing end mannoses, we also identified reducing end galactoses which suggest the existence of a protein-O-galactosyltransferase in N. crassa Because of the excellent genetic resources available for N. crassa, the knowledge of the CBHI O-glycans may enable the future evaluation of the role of O glycosylation on cellulase function and the development of directed O glycan/cellulase engineering. PMID- 26762172 TI - Kinetic analysis and molecular modeling of the inhibition mechanism of roneparstat (SST0001) on human heparanase. AB - Heparanase is a beta-d-glucuronidase which cleaves heparan sulfate chains in the extracellular matrix and on cellular membranes. A dysregulated heparanase activity is intimately associated with cell invasion, tumor metastasis and angiogenesis, making heparanase an attractive target for the development of anticancer therapies. SST0001 (roneparstat; Sigma-Tau Research Switzerland S.A.) is a non-anticoagulant 100% N-acetylated and glycol-split heparin acting as a potent heparanase inhibitor, currently in phase I in advanced multiple myeloma. Herein, the kinetics of heparanase inhibition by roneparstat is reported. The analysis of dose-inhibition curves confirmed the high potency of roneparstat (IC50 ~ 3 nM) and showed, at higher concentrations, a Hill coefficient consistent with the engagement of two molecules of inhibitor. A homology model of human heparanase GS3 construct was built and used for docking experiments with inhibitor fragments. The model has high structural similarity with the recently reported crystal structure of human heparanase. Different interaction schemes are proposed, which support the hypothesis of a complex binding mechanism involving the recruitment of one or multiple roneparstat chains, depending on its concentration. In particular, docking solutions were obtained in which (i) a single roneparstat molecule interacts with both heparin-binding domains (HBDs) of heparanase or (ii) two fragments of roneparstat interact with either HBD-1 or HBD 2, consistent with the possibility of different inhibitor:enzyme binding stoichiometries. This study provides unique insights into the mode of action of roneparstat as well as clues of its interaction with heparanase at a molecular level, which could be exploited to design novel potential inhibitor molecules. PMID- 26762174 TI - The Chihuahua dog: A new animal model for neuronal ceroid lipofuscinosis CLN7 disease? AB - Neuronal ceroid lipofuscinoses (NCLs) are a group of incurable lysosomal storage disorders characterized by neurodegeneration and accumulation of lipopigments mainly within the neurons. We studied two littermate Chihuahua dogs presenting with progressive signs of blindness, ataxia, pacing, and cognitive impairment from 1 year of age. Because of worsening of clinical signs, both dogs were euthanized at about 2 years of age. Postmortem examination revealed marked accumulation of autofluorescent intracellular inclusions within the brain, characteristic of NCL. Whole-genome sequencing was performed on one of the affected dogs. After sequence alignment and variant calling against the canine reference genome, variants were identified in the coding region or splicing regions of four previously known NCL genes (CLN6, ARSG, CLN2 [=TPP1], and CLN7 [=MFSD8]). Subsequent segregation analysis within the family (two affected dogs, both parents, and three relatives) identified MFSD8:p.Phe282Leufs13*, which had previously been identified in one Chinese crested dog with no available ancestries, as the causal mutation. Because of the similarities of the clinical signs and histopathological changes with the human form of the disease, we propose that the Chihuahua dog could be a good animal model of CLN7 disease. PMID- 26762176 TI - Intensive care unit staff will not go back to restricted visiting hours. PMID- 26762175 TI - Computer-assisted total knee arthroplasty using mini midvastus or medial parapatellar approach technique: A prospective, randomized, international multicentre trial. AB - BACKGROUND: Despite the growing evidence in the literature there is still a lack of consensus regarding the use of minimally invasive surgical technique (MIS) in total knee arthroplasty (TKA). METHODS: A prospective, randomized, international multicentre trial including 69 patients was performed to compare computer assisted TKA (CAS-TKA) using either mini-midvastus (MIS group) or standard medial parapatellar approach (conventional group). Patients from 3 centers (Maastricht, Zwickau, Adelaide) with end-stage osteoarthritis of the knee were randomized to either an MIS group with dedicated instrumentation or a conventional group to receive cruciate retaining CAS-TKA without patella resurfacing. The primary outcome was to compare post operative pain and range of motion (ROM). The secondary outcome was to measure the duration of surgery, blood loss, chair rise test, quadriceps strength, anterior knee pain, Knee Society Score (KSS),WOMAC scores, mechanical leg axis and component alignment. RESULTS: Patients in the MIS group (3.97 +/- 2.16) had significant more pain at 2 weeks than patients in the conventional group (2.77 +/- 1.43) p = 0.003. There was no significant difference in any of the other primary outcome parameters. Surgery time was significantly longer (p < 0.001) and there were significantly higher blood loss (p = 0.002) in the MIS group as compared to the conventional group. The difference of the mean mechanical leg alignment between the groups was not statistically significant ( 0.43 degrees (95% CI -1.50-0.64); p = 0.43). There was no significant difference of component alignment between the two surgical groups with respect to flexion/extension (p = 0.269), varus/valgus (p = 0.653) or rotational alignment (p = 0.485) of the femur component and varus valgus alignment (p = 0.778) or posterior slope (p = 0.164) of the tibial component. CONCLUSION: There was no advantage of the MIS approach compared to a conventional approach CAS-TKA in any of the primary outcome measurements assessed, however the MIS approach was associated with longer surgical time and greater blood loss. MIS-TKA in combination with computer navigation is safe in terms of implant positioning. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02625311 8 December 2015. PMID- 26762177 TI - Adolescents' experiences on coping with parental multiple sclerosis: a grounded theory study. AB - AIMS AND OBJECTIVES: To gain insight into what adolescents see as their main concern when having parents who suffer from multiple sclerosis, and develop concepts and theory that may explain how they cope with this concern. BACKGROUND: Health professionals have a special responsibility towards children of parents with chronic diseases, including multiple sclerosis. Few studies show the perspective of the adolescents themselves, and point out that further knowledge is needed. Previous research supports the need for intervention at a youth, parent and family level. DESIGN: Grounded theory. METHODS: We used grounded theory with a generative and constant comparative approach. Data were collected through fifteen individual semi-structured interviews with adolescents aged 12-18 years who had a parent diagnosed with multiple sclerosis. RESULTS: The adolescents' main concern was identified to be preserving control in an uncertain everyday life. This concern was resolved by 'balancing needs', implying the pattern of (1) reflecting, (2) adjusting, (3) taking responsibility and (4) seeking respite. These were used interchangeably in the adolescents' effort to solve their main concern. CONCLUSION: Openness within the family and outwards to the network, is essential for the well-being of the adolescents, and relies on knowledge about the disease, family functioning and support from health professionals. Thus, long-term intervention programs offering information and guidance should be offered. RELEVANCE TO CLINICAL PRACTICE: Understanding the impact of multiple sclerosis on the family from the perspective of the adolescents, gives a basis for health professionals when planning the best possible support for these adolescents. School nurses may play an active role in ensuring a high quality of this work. PMID- 26762178 TI - A novel bipartite UNC-101/AP-1 MU1 binding signal mediates KVS-4/Kv2.1 somatodendritic distribution in Caenorhabditis elegans. AB - Potassium channels such as Kv2.1 are targeted to specific subcellular compartments to fulfill various functions. However, the mechanisms for their localization are poorly understood. Here, we show that KVS-4/Kv2.1 somatodendritic localization in Caenorhabditis elegansDA9 neuron requires UNC 101(AP-1 MU subunit). We define a bipartite sorting signal within KVS-4 consisting of a C-terminal EQMIL and N-terminal WNIIE motifs. The bipartite signal is sufficient to target nonpolarized transmembrane protein MIG-13 into DA9 somatodendritic compartments. Furthermore, we found that AP-1 interacts with the bipartite signal through UNC-101/AP-1 MU N-terminal predicted Longin-like domain. Our results provide new insight into the mechanisms of Kv2.1 post-Golgi sorting and targeting. PMID- 26762181 TI - Movement impairment: Focus on the brain. AB - The saying "mens sana in corpore sano" has a particular resonance these days because, for the majority who have a very sedentary occupation, the everyday rhythms of life do not compel us to do much physical exercise. Recently published data indicate that exercise can counteract the effects of neurological diseases such as Alzheimer's disease and have prompted research on the beneficial effects of movement on the brain and brain neurogenesis. This might lead us to hypothesize that the absence or reduction of movements, especially those with antigravity effects, could induce a deterioration of the brain. This Review discusses current knowledge of the relationship between neurogenic capacity and the lack of motor activity in human and animal models. PMID- 26762179 TI - Twin machines validation for VMAT treatments using electronic portal-imaging device: a multicenter study. AB - PURPOSE: To verify the accuracy of volumetric arc therapy (VMAT) using the RapidArcTM device when switching patients from one single linear accelerator (linac) to a paired energy and mechanics "twin" linac without reoptimization of the original treatment plan. PATIENTS AND METHODS: Four centers using 8 linacs were involved in this study. Seventy-four patients previously treated with the 6MV photon RapidArcTM technique were selected for analysis, using 242 measurements. In each institution, all patients were planned on linac A, and their plans were verified both on linac A and on the twin linac B. Verifications were done using the amorphous silicium electronic portal imager (EPID) of the linacs and were analyzed with the EpiQa software (Epidos, Bratislavia, Slovakia). The gamma index formalism was used for validation with a double threshold of 3 % and 3 mm with a measurement resolution of 0.39 mm/pixel, and a smoothed resolution of approximately 2.5 mm. RESULTS: The number of points passing the gamma criteria between the measured and computed doses was 94.79 +/- 2.57 % for linac A and 94.61 +/- 2.46 % for linac B. Concerning the smoothed measurement analysis, 98.67 +/- 1.26 % and 98.59 +/- 1.20 % points passing the threshold were obtained for linacs A and B, respectively. The difference between the 2 dose matrices acquired on the EPID was very small, with 99.92 +/- 0.06 % of the points passing the criteria. CONCLUSION: For linacs sharing the same mechanical and energy parameters, this study tends to indicate that patients may be safely switched from treatment with one linac to treatment with its twin linac using the same VMAT plan. PMID- 26762182 TI - The two-process model of sleep regulation: a reappraisal. AB - In the last three decades the two-process model of sleep regulation has served as a major conceptual framework in sleep research. It has been applied widely in studies on fatigue and performance and to dissect individual differences in sleep regulation. The model posits that a homeostatic process (Process S) interacts with a process controlled by the circadian pacemaker (Process C), with time courses derived from physiological and behavioural variables. The model simulates successfully the timing and intensity of sleep in diverse experimental protocols. Electrophysiological recordings from the suprachiasmatic nuclei (SCN) suggest that S and C interact continuously. Oscillators outside the SCN that are linked to energy metabolism are evident in SCN-lesioned arrhythmic animals subjected to restricted feeding or methamphetamine administration, as well as in human subjects during internal desynchronization. In intact animals these peripheral oscillators may dissociate from the central pacemaker rhythm. A sleep/fast and wake/feed phase segregate antagonistic anabolic and catabolic metabolic processes in peripheral tissues. A deficiency of Process S was proposed to account for both depressive sleep disturbances and the antidepressant effect of sleep deprivation. The model supported the development of novel non-pharmacological treatment paradigms in psychiatry, based on manipulating circadian phase, sleep and light exposure. In conclusion, the model remains conceptually useful for promoting the integration of sleep and circadian rhythm research. Sleep appears to have not only a short-term, use-dependent function; it also serves to enforce rest and fasting, thereby supporting the optimization of metabolic processes at the appropriate phase of the 24-h cycle. PMID- 26762183 TI - Characterization of the interaction between Trypanosoma brucei Pex5p and its receptor Pex14p. AB - The interaction of Trypanosoma brucei (Tb) Pex5p and its receptor TbPex14p is essential for the translocation of newly synthesized matrix proteins into the glycosome. Here, we reveal that only the third WXXXF/Y motif of TbPex5p is involved in the interaction and that negative charge of the fourth amino acid is important. We suggest that Phe35 and Phe52 of TbPex14p interact with Trp318 and Phe322 in the third motif and that the Lys56 adjacent to Phe35/Phe52 associates with the fourth Glu in the motif to make the complex. This information is expected to be useful for developing anti-trypanosomal drugs. PMID- 26762185 TI - The effects of an 8-week stabilization exercise program on lumbar movement sense in patients with low back pain. AB - BACKGROUND: Lumbar stabilization exercises have gained popularity and credibility in patients with non-acute low back pain. Previous research provides more support to strength/resistance and coordination/stabilisation programs. Some authors also suggest adding strength/resistance training following motor control exercises. However, the effect of such a lumbar stabilization program on lumbar proprioception has never been tested so far. The present study investigated the effects of an 8-week stabilization exercise program on lumbar proprioception in patients with low back pain (LBP) and assessed the 8-week test-retest reliability of lumbar proprioception in control subjects. METHODS: Lumbar proprioception was measured before and after an 8-week lumbar stabilization exercise program for patients with LBP. Control subjects participated in the same protocol but received no treatment. RESULTS: The lumbar proprioception measure showed moderate reliability. Patients with LBP and control subjects demonstrated no differences in lumbar proprioception at baseline. Participants from both groups showed better proprioception following the 8-week interval, demonstrating the presence of learning between testing days. CONCLUSIONS: The improvement of lumbar proprioception seen in both groups was ascribed to motor learning of the test itself. The effect of lumbar stabilization exercises on lumbar proprioception remains unknown because the LBP group did not show lumbar proprioception impairments. PMID- 26762187 TI - Review: radiolabeled polymers containing covalently bound (3) H and (14) C. AB - Radiolabeled compounds are invaluable tools used to study synthetic and biological processes. Radiolabeled polymers find uses in mechanistic pathway elucidation, bioincorporation studies, biodegradation studies, and drug delivery applications. This literature review examines the syntheses (or biosyntheses), physical properties, and applications of radiolabeled polymers which contain covalently bound tritium and carbon-14 atoms. PMID- 26762186 TI - Novel Base-Free Catalytic Wittig Reaction for the Synthesis of Highly Functionalized Alkenes. AB - A highly efficient catalyst system for base-free catalytic Wittig reactions has been developed and optimized. Initially, several potential (pre)catalysts as well as different silanes as reducing agents were screened. A system based on a readily available phosphine oxide as precatalyst and trimethoxy silane as reducing agent proved to be optimal. The effect of various Bronsted acidic additives was studied. Subsequently, the reaction conditions were optimized and standard reaction conditions were determined. Under these conditions the scope of this new protocol was evaluated. Nine activated olefins and 33 aldehydes were converted into 42 highly functionalized alkenes. Notably, aromatic, aliphatic as well as heteroaromatic aldehydes could be converted, giving the desired products in isolated yields up to 99 % and with good to excellent E/Z selectivities. These results underline the remarkable efficiency of this protocol considering the complexity of the reaction mixture and the four reaction steps that proceed in parallel in one pot. PMID- 26762184 TI - Diagnostic efficiency of the SDQ for parents to identify ADHD in the UK: a ROC analysis. AB - Early, accurate identification of ADHD would improve outcomes while avoiding unnecessary medication exposure for non-ADHD youths, but is challenging, especially in primary care. The aim of this paper is to test the Strengths and Difficulties Questionnaire (SDQ) using a nationally representative sample to develop scoring weights for clinical use. The British Child and Adolescent Mental Health Survey (N = 18,232 youths 5-15 years old) included semi-structured interview DSM-IV diagnoses and parent-rated SDQ scores. Areas under the curve for SDQ subscales were good (0.81) to excellent (0.96) across sex and age groups. Hyperactivity/inattention scale scores of 10+ increased odds of ADHD by 21.3*. For discriminating ADHD from other diagnoses, accuracy was fair (<0.70) to good (0.88); Hyperactivity/inattention scale scores of 10+ increased odds of ADHD by 4.47*. The SDQ is free, easy to score, and provides clinically meaningful changes in odds of ADHD that can guide clinical decision-making in an evidence-based medicine framework. PMID- 26762188 TI - EEG spectral power in phasic and tonic REM sleep: different patterns in young adults and children. AB - Rapid eye movement sleep is composed of phasic and tonic periods, two distinguishable microstates in terms of arousal thresholds and sensory processing. Background electroencephalogram oscillations are also different between periods with (phasic state) and periods without (tonic state) eye movements. In Study 1, previous findings analysing electroencephalogram spectral power in phasic and tonic rapid eye movement sleep were replicated, and analyses extended to the high gamma range (52-90 Hz). In Study 2, phasic and tonic spectral power differences within a group of 4-8-year-old children were examined. Based on the polysomnographic data of 20 young adults, the phasic state yielded increased delta and theta power in anterior sites, as well as generally decreased high alpha and beta power in comparison to the tonic state. Moreover, phasic periods exhibited greater spectral power in the lower and the higher gamma band. Interestingly, children (n = 18) exhibited a different pattern, showing increased activity in the low alpha range during phasic periods. Moreover, during phasic in contrast to tonic rapid eye movement sleep, increased low and high gamma and enhanced low gamma band power emerged in anterior and posterior regions, respectively. The current findings show that spectral activity within the high gamma range substantially contributes to the differences between phasic and tonic rapid eye movement sleep, especially in adults. Moreover, the current data underscore the heterogeneity of rapid eye movement sleep, and point to marked differences between young adults and children regarding phasic/tonic electroencephalogram spectral power. These results suggest that the differentiation between phasic and tonic rapid eye movement periods undergoes maturation. PMID- 26762189 TI - Acid-base chemistry of frustrated water at protein interfaces. AB - Water molecules at a protein interface are often frustrated in hydrogen-bonding opportunities due to subnanoscale confinement. As shown, this condition makes them behave as a general base that may titrate side-chain ammonium and guanidinium cations. Frustration-based chemistry is captured by a quantum mechanical treatment of proton transference and shown to remove same-charge uncompensated anticontacts at the interface found in the crystallographic record and in other spectroscopic information on the aqueous interface. Such observations are untenable within classical arguments, as hydronium is a stronger acid than ammonium or guanidinium. Frustration enables a directed Grotthuss mechanism for proton transference stabilizing same-charge anticontacts. PMID- 26762191 TI - Highly Luminescent Linear Complex Arrays of up to Eight Cuprous Centers. AB - Linearly arranged metal atoms that are embedded in discrete molecules have fascinated scientists across various disciplines for decades; this is attributed to their potential use in microelectronic devices on a submicroscopic scale. Luminescent oligonuclear Group 11 metal complexes are of particular interest for applications in molecular light-emitting devices. Herein, we describe the synthesis and characterization of a rare, homoleptic, and neutral linearly arranged tetranuclear Cu(I) complex that is helically bent, thus representing a molecular coil in the solid state. This tetracuprous arrangement dimerizes into a unique octanuclear assembly bearing a linear array of six Cu(I) centers with two additional bridging cuprous ions that constitute a central pseudo-rhombic Cu(I) 4 cluster. The crystal structure determinations of both complexes reveal close d(10) ???d(10) contacts between all cuprous ions that are adjacent to each other. The dynamic behavior in solution, DFT calculations, and the luminescence properties of these remarkable complexes are also discussed. PMID- 26762190 TI - Study of transpedicular screw fixation on spine development in a piglet model. AB - BACKGROUND: Transpedicular screws may cause damage to the cartilage in the neural arch of the vertebra, and give continuous pressure to the skeleton besides the vertebral body. The aim of this study is to examine the morphological change of the vertebral body at fixation sites and development of the vertebral body after fixation. METHODS: A piglet model was used to study the influence of transpedicular screw fixation on spine development. Transpedicular screw fixation was adjusted to meet specific requirements of surgery on piglet. The screws and plates were placed at L1-L3 vertebral plates via routine surgical approach. Scoliosis and kyphosis Cobb angles were measured. RESULTS: Anatomical characteristics of 6-week-old piglets fit the transpedicular screw system, and can meet the requirements of related studies. Transpedicular screw fixation system has no significant influence on the development of canalis vertebralis. Fixation did not cause developmental stenosis of canalis vertebralis and damage to spinal cord or nerve root. However, transpedicular screw fixation significantly impacted the development of the spine: it shortened the spine by curtailing the length of the vertebral body and intervertebral space. Our results also suggested that slow growth of epiphyseal plate may contribute to the shortening of the vertebral body. CONCLUSION: Transpedicular screw fixation system is beneficial for fixation of the developing spine. It may not cause scoliosis but could lead to change of cervical curvature. PMID- 26762192 TI - Isoindoline Derivatives of alpha-Amino Acids as Cyclooxygenase 1 and 2 Inhibitors. AB - IC50 values were obtained for two series of isoindolines derived from alpha-amino acids over cyclooxygenase 1 and 2 (COX-1 and COX-2). In order to explain the biological activity observed, a structure-activity relationship (SAR) model was achieved for the tested compounds and 19 reference compounds with known selective inhibitory activity, through the correlation of the binding energies calculated from rigid docking of the best conformations into the catalytic sites of COX-1 and COX-2, as well as their molecular descriptors: Log P, molecular weight (MW), volume (V), and solvation energy (Esol) versus their experimental IC50 values by MLR and LS-SVM methods. The model probed whether the COX-1 and COX-2 inhibitory activities of the isoindolines correlate with steric, hydrophobic, and thermodynamic parameters. The correlation values with MLR for COX-1 and COX-2 (r(2) = 0.4193 and r(2) = 0.5929) were optimized with LS-SVM until r(2) = 0.6818 for COX-1 and r(2) = 0.8985 for COX-2, resulting in a good predictive ability for COX-1 and -2 inhibition with this model. In conclusion, the data suggests that the physicochemical descriptors evaluated have an impact on the inhibitory activity and selectivity of isoindolines over COX-1 and COX-2. PMID- 26762193 TI - Disturbed sleep in attention-deficit hyperactivity disorder (ADHD) is not a question of psychiatric comorbidity or ADHD presentation. AB - Attention-deficit hyperactivity disorder (ADHD) is a heterogeneous psychiatric disorder with three different presentations and high levels of psychiatric comorbidity. Serious sleep complaints are also common, but the role of the presentations and comorbidity in sleep is under-investigated in ADHD. Consequently, the goal of the study was to investigate sleep problems in medicine naive school-aged children (mean age = 9.6 years) with ADHD compared to controls using objective methods and to examine the role of comorbidity and presentations. Ambulatory polysomnography results suggested that children with ADHD (n = 76) had significantly more sleep disturbances than controls (n = 25), including a larger percentage of rapid eye movement (REM) sleep and more sleep cycles, as well as lower mean sleep efficiency, mean non-REM (NREM) sleep stage 1 and mean NREM sleep stage 3. No significant between-group differences were found on the multiple sleep latency test. Stratifying for comorbidity in the ADHD group did not reveal major differences between groups, but mean sleep latency was significantly longer in children with ADHD and no comorbidity compared to controls (36.1 min; SD = 30.1 versus 22.6 min; SD = 15.2). No differences were found between ADHD presentations. Our results support the presence of night-time sleep disturbances in children with ADHD. Poor sleep does not appear to be attributable to comorbidity alone, nor do sleep disturbances differ within ADHD presentations. PMID- 26762194 TI - House dust mite: a new player in intestinal inflammation? PMID- 26762195 TI - Activated Schwann cells in pancreatic cancer are linked to analgesia via suppression of spinal astroglia and microglia. AB - OBJECTIVE: The impact of glia cells during GI carcinogenesis and in cancer pain is unknown. Here, we demonstrate a novel mechanism how Schwann cells (SCs) become activated in the pancreatic cancer (PCa) microenvironment and influence spinal activity and pain sensation. DESIGN: Human SCs were exposed to hypoxia, to pancreatic cancer cells (PCCs) and/or to T-lymphocytes. Both SC and intrapancreatic nerves of patients with PCa with known pain severity were assessed for glial intermediate filament and hypoxia marker expression, proliferation and for transcriptional alterations of pain-related targets. In conditional PCa mouse models with selective in vivo blockade of interleukin (IL) 6 signalling (Ptf1a-Cre;LSL-Kras(G12D)/KC interbred with IL6(-/-) or sgp130(tg) mice), SC reactivity, abdominal mechanosensitivity and spinal glial/neuronal activity were quantified. RESULTS: Tumour hypoxia, PCC and/or T-lymphocytes activated SC via IL-6-signalling in vitro. Blockade of the IL-6-signalling suppressed SC activation around PCa precursor lesions (pancreatic intraepithelial neoplasia (PanIN)) in KC;IL6(-/-) (32.06%+/-5.25% of PanINs) and KC;sgp130(tg) (55.84%+/-5.51%) mouse models compared with KC mice (78.27%+/-3.91%). Activated SCs were associated with less pain in human PCa and with decreased abdominal mechanosensitivity in KC mice (von Frey score of KC: 3.9+/-0.5 vs KC;IL6(-/-) mice: 5.9+/-0.9; and KC;sgp130(tg): 10.21+/-1.4) parallel to attenuation of spinal astroglial and/or microglial activity. Activated SC exhibited a transcriptomic profile with anti-inflammatory and anti-nociceptive features. CONCLUSIONS: Activated SC in PCa recapitulate the hallmarks of 'reactive gliosis' and contribute to analgesia due to suppression of spinal glia. Our findings propose a mechanism for how cancer might remain pain-free via the SC-central glia interplay during cancer progression. PMID- 26762196 TI - Analysis of the effectiveness and safety of rituximab in patients with refractory lupus nephritis: a chart review. AB - Lupus nephritis is a life-threatening complication of systemic lupus erythematosus. The standard treatment for this condition, including corticosteroids and cyclophosphamide, results in a 70 % remission rate at 12 months, but it is also associated with significant morbidity. Rituximab, a chimeric anti-CD20 antibody, could be useful, given the central role of B cells in the pathogenesis of systemic lupus erythematosus. Case reports and retrospective series have reported that rituximab is effective for refractory lupus nephritis. However, the double-blind, placebo-controlled LUNAR trial failed to meet its end point. We studied clinical, biological, and immunological data on 17 patients who received rituximab as an induction treatment for refractory lupus nephritis at the University Hospital Center of Bordeaux. A complete treatment response was defined as a normal serum creatinine with inactive urinary sediment and 24-h urinary albumin <0.5 g and a partial response (PR) as a >50 % improvement in all of the renal parameters that were abnormal at baseline, with no deterioration in any parameter. Seventeen patients received rituximab as induction treatment for lupus nephritis refractory to standard treatment by cyclophosphamide. After a follow-up of 12 months, complete or partial renal remission was achieved in 53 % patients. Rituximab therapy resulted in a significant improvement in proteinuria and steroid dose tapering in all patients. Rituximab should be considered as a treatment option for refractory lupus glomerulonephritis. PMID- 26762199 TI - Association of Dermatology Consultation With Accuracy of Cutaneous Disorder Diagnoses in Hospitalized Patients: A Multicenter Analysis. PMID- 26762200 TI - Severe invasive streptococcal infection by Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis. AB - Streptococcus pyogenes, a group A Streptococcus (GAS), has been recognized as the causative pathogen in patients with severe invasive streptococcal infection with or without necrotizing fasciitis. In recent epidemiological studies, Streptococcus dysgalactiae subsp. equisimilis (SDSE) has been isolated from severe invasive streptococcal infection. Complete genome sequence showed that SDSE is the closest bacterial species to GAS, with approximately 70% of genome coverage. SDSE, however, lacks several key virulence factors present in GAS, such as SPE-B, the hyaluronan synthesis operon and active superantigen against human immune cells. A key event in the ability of GAS to cause severe invasive streptococcal infection was shown to be the acquisition of novel genetic traits such as phages. Strikingly, however, during severe invasive infection, GAS destroys its own covRS two-component system, which negatively regulates many virulence factor genes, resulting in a hyper-virulent phenotype. In contrast, this phenomenon has not been observed in SDSE. The present review describes the epidemiology of severe invasive streptococcal infection and the detailed pathogenic mechanisms of GAS and SDSE, emphasizing findings from their genome sequences and analyses of gene expression. PMID- 26762198 TI - Medicaid Expansions from 1997 to 2009 Increased Coverage and Improved Access and Mental Health Outcomes for Low-Income Parents. AB - OBJECTIVE: To assess the effects of past Medicaid eligibility expansions to parents on coverage, access to care, out-of-pocket (OOP) spending, and mental health outcomes, and consider implications for the Affordable Care Act (ACA) Medicaid expansion. DATA SOURCES: Person-level data from the National Health Interview Survey (1998-2010) is used to measure insurance coverage and related outcomes for low-income parents. Using state identifiers available at the National Center for Health Statistics Research Data Center, we attach state Medicaid eligibility thresholds for parents collected from a variety of sources to NHIS observations. STUDY DESIGN: We use changes in the Medicaid eligibility threshold for parents within states over time to identify the effects of changes in eligibility on low-income parents. PRINCIPAL FINDINGS: We find that expanding Medicaid eligibility increases insurance coverage, reduces unmet needs due to cost and OOP spending, and improves mental health status among low-income parents. Moreover, our findings suggest that uninsured populations in states not currently participating in the ACA Medicaid expansion would experience even larger improvements in coverage and related outcomes than those in participating states if they chose to expand eligibility. CONCLUSIONS: The ACA Medicaid expansion has the potential to improve a wide variety of coverage, access, financial, and health outcomes for uninsured parents in states that choose to expand coverage. PMID- 26762197 TI - What are we measuring? A critique of range of motion methods currently in use for Dupuytren's disease and recommendations for practice. AB - BACKGROUND: Range of motion is the most frequently reported measure used in practice to evaluate outcomes. A goniometer is the most reliable tool to assess range of motion yet, the lack of consistency in reporting prevents comparison between studies. The aim of this study is to identify how range of motion is currently assessed and reported in Dupuytren's disease literature. Following analysis recommendations for practice will be made to enable consistency in future studies for comparability. This paper highlights the variation in range of motion reporting in Dupuytren's disease. METHODS: A Participants, Intervention, Comparison, Outcomes and Study design format was used for the search strategy and search terms. Surgery, needle fasciotomy or collagenase injection for primary or recurrent Dupuytren's disease in adults were included if outcomes were monitored using range of motion to record change. A literature search was performed in May 2013 using subject heading and free-text terms to also capture electronic publications ahead of print. In total 638 publications were identified and following screening 90 articles met the inclusion criteria. Data was extracted and entered onto a spreadsheet for analysis. A thematic analysis was carried out to establish any duplication, resulting in the final range of motion measures identified. RESULTS: Range of motion measurement lacked clarity, with goniometry reportedly used in only 43 of the 90 studies, 16 stated the use of a range of motion protocol. A total of 24 different descriptors were identified describing range of motion in the 90 studies. While some studies reported active range of motion, others reported passive or were unclear. Eight of the 24 categories were identified through thematic analysis as possibly describing the same measure, 'lack of joint extension' and accounted for the most frequently used. CONCLUSIONS: Published studies lacked clarity in reporting range of motion, preventing data comparison and meta-analysis. Percentage change lacks context and without access to raw data, does not allow direct comparison of baseline characteristics. A clear description of what is being measured within each study was required. It is recommended that range of motion measuring and reporting for Dupuytren's disease requires consistency to address issues that fall into 3 main categories: Definition of terms, Protocol statement, Outcome reporting. PMID- 26762201 TI - Unusual Fragmentation and Transformation of an N-Heterocyclic Carbene by a Stable Phosphonium-Borane peri-Functionalized Naphthalene. AB - A 1-phosphonium-8-borane-decorated naphthalene molecule 2 has been found to react with N,N'-dimethylimidazol-2-ylidene (IMe), a popular member of the N heterocyclic carbene (NHC) family, which converts it into two vinyl-amine fragments one of which is trapped between the phosphonium and borane unit by the formation of a C-C and a B-N bond. The same reactivity was not observed for larger NHC molecules. Control experiments and mechanistic studies have established the involvement of an ylide-borane molecule and an imidazolium salt in addition to IMe carbene in this new transformation of an NHC. PMID- 26762202 TI - X-ray therapy promotes structural regeneration after spinal cord injury in a rat model. AB - OBJECTIVE: This study aims to investigate the therapeutic effects and mechanisms of x-ray treatment on rats following spinal cord injury (SCI). METHODS: Forty-six female Sprague-Dawley rats were subjected to spinal cord injury using the modified Allen weight-drop method. The animals were randomly divided into six groups. Two of the animal groups were irradiated with 10 Gy at the lesion site; another two groups were irradiated with 20 Gy; and the last two groups without irradiation were regarded as the sham group. One of the each of two animal groups was euthanized at different time points at 4 and 12 weeks, respectively, after irradiation. Spinal cord calluses were assessed using kinology and electrophysiology and histology methods. RESULTS: In all of the groups, the neurofilament (NF) counts at 14 weeks were found to be higher than that at 6 weeks after SCI. Both 10-Gy irradiated and 20-Gy irradiated groups were higher than those of the sham group at each time point (P < 0.05). The myelin basic protein (MBP) count decreased at 14 weeks after SCI in the irradiated groups (P < 0.05) but increased at 14 weeks in the sham group (P < 0.05). Furthermore, the MBP count of the irradiated groups was lower than that of the sham group at 14 weeks (P < 0.05). The glial fibrillary acidic protein (GFAP) and Nogo-A counts at 14 weeks were higher than those at 6 weeks in all the groups (P < 0.05), and there was no statistical significance with kinology and electrophysiology tests in all groups. CONCLUSIONS: A self-repair mechanism exists after spinal cord injury, which lasts at least 14 weeks. X-ray therapy promotes the regeneration of the spinal cord system after injury. PMID- 26762203 TI - Visual processing of emotional dynamic faces in 22q11.2 deletion syndrome. AB - INTRODUCTION: The 22q11.2 deletion syndrome (22q11DS) is a neurogenetic syndrome. Individuals affected by this syndrome present poor social functioning and a high risk for the development of psychiatric disorders. Accurate emotion recognition and visual exploration of faces represent important skills for appropriate development of social cognition in individuals with 22q11DS. For these reasons, there is elevated interest in establishing relevant ways to test the mechanisms associated with emotion recognition in patients with 22q11DS. METHODS: This study investigated emotional recognition and visual exploration of emotional faces in persons with 22q11DS, with a dynamic emotion task using an eye-tracking device. To our knowledge, no previous studies have used emotional dynamic stimuli with 22q11DS, despite improved ecological validity of dynamic stimuli compared with static images. Furthermore, these stimuli provide the opportunity to collect reaction times, as indicators of the emotional intensity necessary for identifying each emotion. RESULTS: In our task, we observed comparable accuracy in emotion recognition in the 22q11DS and healthy control groups. However, individuals with 22q11DS were slower to recognise the emotions. They also spent less time looking at the nose during happy and fearful faces. CONCLUSIONS: These results suggest that individuals with 22q11DS may need either more time or more pronounced emotional cues to correctly label facial expressions. PMID- 26762204 TI - Identification of Patients with Recurrent Glioblastoma Who May Benefit from Combined Bevacizumab and CCNU Therapy: A Report from the BELOB Trial. AB - The results from the randomized phase II BELOB trial provided evidence for a potential benefit of bevacizumab (beva), a humanized monoclonal antibody against circulating VEGF-A, when added to CCNU chemotherapy in patients with recurrent glioblastoma (GBM). In this study, we performed gene expression profiling (DASL and RNA-seq) of formalin-fixed, paraffin-embedded tumor material from participants of the BELOB trial to identify patients with recurrent GBM who benefitted most from beva+CCNU treatment. We demonstrate that tumors assigned to the IGS-18 or "classical" subtype and treated with beva+CCNU showed a significant benefit in progression-free survival and a trend toward benefit in overall survival, whereas other subtypes did not exhibit such benefit. In particular, expression of FMO4 and OSBPL3 was associated with treatment response. Importantly, the improved outcome in the beva+CCNU treatment arm was not explained by an uneven distribution of prognostically favorable subtypes as all molecular glioma subtypes were evenly distributed along the different study arms. The RNA-seq analysis also highlighted genetic alterations, including mutations, gene fusions, and copy number changes, within this well-defined cohort of tumors that may serve as useful predictive or prognostic biomarkers of patient outcome. Further validation of the identified molecular markers may enable the future stratification of recurrent GBM patients into appropriate treatment regimens. PMID- 26762205 TI - Impacts on Emergency Department Visits from Personal Responsibility Provisions: Evidence from West Virginia's Medicaid Redesign. AB - OBJECTIVE: To examine the impact of a 2007 redesign of West Virginia's Medicaid program, which included an incentive and "nudging" scheme intended to encourage better health care behaviors and reduce Emergency Department (ED) visits. DATA SOURCES: West Virginia Medicaid enrollment and claims data from 2005 to 2010. STUDY DESIGN: We utilized a "differences in differences" technique with individual and time fixed effects to assess the impact of redesign on ED visits. Starting in 2007, categorically eligible Medicaid beneficiaries were moved from traditional Medicaid to the new Mountain Health Choices (MHC) Program on a rolling basis, approximating a natural experiment. Members chose between a Basic plan, which was less generous than traditional Medicaid, or an Enhanced plan, which was more generous but required additional enrollment steps. DATA COLLECTION: Data were obtained from the West Virginia Bureau for Medical Services. PRINCIPAL FINDINGS: We found that contrary to intentions, the MHC program increased ED visits. Those who selected or defaulted into the Basic plan experienced increased overall and preventable ED visits, while those who selected the Enhanced plan experienced a slight reduction in preventable ED visits; the net effect was an increase in ED visits, as most individuals enrolled in the Basic plan. PMID- 26762206 TI - Effect of Microneedle Pretreatment on Topical Anesthesia: A Randomized Clinical Trial. PMID- 26762207 TI - Triptycene-Roofed Quinoxaline Cavitands for the Supramolecular Detection of BTEX in Air. AB - Two novel triptycene quinoxaline cavitands (DiTriptyQxCav and MonoTriptyQxCav) have been designed, synthesized, and applied in the supramolecular detection of benzene, toluene, ethylbenzene, and xylenes (BTEX) in air. The complexation properties of the two cavitands towards aromatics in the solid state are strengthened by the presence of the triptycene moieties at the upper rim of the tetraquinoxaline walls, promoting the confinement of the aromatic hydrocarbons within the cavity. The two cavitands were used as fiber coatings for solid-phase microextraction (SPME) BTEX monitoring in air. The best performances in terms of enrichment factors, selectivity, and LOD (limit of detection) values were obtained by using the DiTriptyQxCav coating. The corresponding SPME fiber was successfully tested under real urban monitoring conditions, outperforming the commercial divinylbenzene-Carboxen-polydimethylsiloxane (DVB-CAR-PDMS) fiber in BTEX adsorption. PMID- 26762209 TI - FGFR Inhibitor Ameliorates Hypophosphatemia and Impaired Engrailed-1/Wnt Signaling in FGF2 High Molecular Weight Isoform Transgenic Mice. AB - High molecular weight FGF2 transgenic (HMWTg) mouse phenocopies the Hyp mouse, homolog of human X-linked hypophosphatemic rickets with hypophosphatemis, and abnormal FGF23, FGFR, Klotho signaling in kidney. Since abnormal Wnt signaling was reported in Hyp mice we assessed whether Wnt signaling was impaired in HMWTg kidneys and the effect of blocking FGF receptor (FGFR) signaling. Bone mineral density and bone mineral content in female HMWTg mice were significantly reduced. HMWTg mice were gavaged with FGFR inhibitor NVP-BGJ398, or vehicle and were euthanized 24 h post treatment. Serum phosphate was significantly reduced and urine phosphate was significantly increased in HMWTg and was rescued by NVP BGJ398. Analysis of kidneys revealed a significant reduction in Npt2a mRNA in HMWTg that was significantly increased by NVP-BGJ398. Increased FGFR1, KLOTHO, P ERK1/2, and decreased NPT2a protein in HMWTg were rescued by NVP-BGJ398. Wnt inhibitor Engrailed-1 mRNA and protein was increased in HMWTg and was decreased by BGJ398. Akt mRNA and protein was decreased in HMWTg and was increased by NVP BGJ398. The active form of glycogen synthase 3 beta (pGSK3-beta) and phosphor beta-catenin were increased in HMWTg and were both decreased by NVP-BGJ398 while decreased active-beta-catenin in HMWTg was increased by NVP-BGJ398. We conclude that FGFR blockade rescued hypophosphatemia by regulating FGF and WNT signaling in HMWTg kidneys. J. Cell. Biochem. 117: 1991-2000, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26762208 TI - Atypical and malignant granular cell tumors in Japan: a Japanese Musculoskeletal Oncology Group (JMOG) study. AB - BACKGROUND: Malignant granular cell tumors (MGCTs) are extremely rare neoplasms with only a limited number of studies published to date. The aim of this study is to elucidate the clinicopathological characteristics and prognostic factors of MGCTs. METHODS: This is a multi-institutional retrospective study of MGCTs with a central pathological review. A total of 18 cases were retrieved. Specimens were blindly reviewed by two pathologists based on the diagnostic criteria by Fanburg Smith et al. Kaplan-Meier survival probabilities were calculated, and risk factors for poor prognosis were evaluated. RESULTS: Three and fifteen cases were diagnosed as atypical GCTs (AGCTs) and mGCTs according to the Fanburg-Smith et al. classification, respectively. Four (one atypical and three malignant) cases had metastasis at the first presentation, including lymph node metastasis. Three out of ten cases treated with wide resection developed local recurrence. Although prolonged static disease periods of >=1 year were observed in four cases receiving chemotherapy, all cases with local recurrence or metastasis, including two atypical cases, eventually died of disease. The 5- and 10-year overall survival rates for localized MGCTs were 69.2 and 34.6 %, respectively. The presence of necrosis was revealed as a risk factor associated with adverse clinical outcomes. CONCLUSIONS: MGCTs have high rates of recurrence and metastasis including lymph node metastasis. As histologically atypical cases also have metastatic potential, close attention should be paid to AGCTs. The combination of histological evaluation and tumor size may lead to more accurate diagnosis of this rare neoplasm. PMID- 26762211 TI - Carboxylic Carbon Quantum Dots as a Fluorescent Sensing Platform for DNA Detection. AB - The demand for simple, sensitive, affordable, and selective DNA biosensors is ubiquitous, due to the important role that DNA detection performs in the areas of disease diagnostics, environment monitoring, and food safety. A novel application of carboxylic carbon quantum dots (cCQD) is highlighted in this study. Herein, cCQD function as a nanoquencher in the detection of nucleic acid based on a homogeneous fluorescent assay. To that purpose, the performance of two types of cCQD, namely, citric acid QD and malic acid QD, is evaluated. The principle behind the sensing of nucleic acid lies in the different propensity of single stranded DNA and double-stranded DNA to adsorb onto the surface of cCQD. For both types of cCQD, a superior range of detection of at least 3 orders of magnitude is achieved, and the potential to distinguish single-base mismatch is also exhibited. These findings are anticipated to provide valuable insights on the employment of cCQD for the fabrication of future DNA biosensors. PMID- 26762210 TI - Foot and ankle characteristics associated with falls in adults with established rheumatoid arthritis: a cross-sectional study. AB - BACKGROUND: People with rheumatoid arthritis (RA) have an increased risk of falls. The foot is a common site of pathology in RA and foot problems are reported in up to 90% of patients with established disease. The aim of this study was to determine whether foot and ankle characteristics are associated with falls in people with RA. METHODS: Adults with RA were recruited from rheumatology outpatient clinics in Auckland, New Zealand. Participants reported whether they had fallen in the preceding year, and the number of falls. Clinical characteristics, common fall risk factors, and foot and ankle variables were measured. Univariate parametric and non-parametric analysis compared fallers and non-fallers on all variables to determine significant differences. Logistic regression analysis identified variables independently associated with falls. RESULTS: Two hundred and one participants were prospectively recruited. At least one fall in the preceding 12-months was reported by 119 (59%) participants. Univariate analysis showed that fallers had significantly longer mean disease duration, more co-morbid conditions, an increase in lower limb tender joints, higher midfoot peak plantar pressures and were more likely to have a history of vascular disease than non-fallers. Fallers also reported greater difficulty with activities of daily living, increased fear of falling and greater self-reported foot impairment. Logistic regression analysis revealed that increased midfoot peak plantar pressures (odds ratio (OR) 1.12 [for each 20 kPa increase], 95% confidence interval (CI) 1.00-1.25), self-reported foot impairment (OR 1.17 [for each three point increase], 95% CI 1.05-1.31) and history of vascular disease (OR 3.22, 95% CI 1.17-8.88) were independently associated with a fall in the preceding 12 months. CONCLUSIONS: Elevated midfoot peak plantar pressures, self reported foot impairment and vascular disease are associated with falls in people with RA. Assessment of foot deformity, foot function and self-reported foot impairment may be of benefit when considering falls prevention strategies in people with RA. TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry (trial ACTRN12612000597897). PMID- 26762212 TI - Testing the Validity of Primary Care Physicians' Self-Reported Acceptance of New Patients by Insurance Status. AB - OBJECTIVE: To compare physicians' self-reported willingness to provide new patient appointments with the experience of research assistants posing as either a Medicaid beneficiary or privately insured person seeking a new patient appointment. DATA SOURCES/STUDY SETTING: Survey administered to California physicians and telephone calls placed to a subsample of respondents. STUDY DESIGN: Cross-sectional comparison. DATA COLLECTION/EXTRACTION METHODS: All physicians whose California licenses were due for renewal in June or July 2013 were mailed a survey, which included questions about acceptance of new Medicaid and new privately insured patients. Subsequently, research assistants using a script called the practices of a stratified random sample of 209 primary care physician respondents in an attempt to obtain a new patient appointment. By design, half of the physicians selected for the telephone validation reported on the survey that they accepted new Medicaid patients and half indicated that they did not. PRINCIPAL FINDINGS: The percentage of callers posing as Medicaid patients who could schedule new patient appointments was 18 percentage points lower than the percentage of physicians who self-reported on the survey that they accept new Medicaid patients. Callers were also less likely to obtain appointments when they posed as patients with private insurance. CONCLUSIONS: Physicians overestimate the extent to which their practices are accepting new patients, regardless of insurance status. PMID- 26762214 TI - Necrobiotic Xanthogranuloma Treated With Topical Nitrogen Mustard (Mechlorethamine). PMID- 26762213 TI - What are the important surgical factors affecting the wound healing after primary total knee arthroplasty? AB - BACKGROUND: Wound condition after primary total knee arthroplasty (TKA) is an important issue to avoid any postoperative adverse events. Our purpose was to investigate and to clarify the important surgical factors affecting wound score after TKA. METHODS: A total of 139 knees in 128 patients (mean 73 years) without severe comorbidity were enrolled in the present study. All primary unilateral or bilateral TKAs were done using the same skin incision line, measured resection technique, and wound closure technique using unidirectional barbed suture. In terms of the wound healing, Hollander Wound Evaluation Score (HWES) was assessed on postoperative day 14. We performed multiple regression analysis using stepwise method to identify the factors affecting HWES. Variables considered in the analysis were age, sex, body mass index (kg/m(2)), HbA1C (%), femorotibial angle (degrees) on plain radiographs, intraoperative patella eversion during the cutting phase of the femur and the tibia in knee flexion, intraoperative anterior translation of the tibia, patella resurfacing, surgical time (min), tourniquet time (min), length of skin incision (cm), postoperative drainage (ml), patellar height on postoperative lateral radiographs, and HWES. HWES was treated as a dependent variable, and others were as independent variables. RESULTS: The average HWES was 5.0 +/- 0.8 point. According to stepwise forward regression test, patella eversion during the cutting phase of the femur and the tibia in knee flexion and anterior translation of the tibia were entered in this model, while other factors were not entered. Standardized partial regression coefficient was as follows: 0.57 in anterior translation of the tibia and 0.38 in patella eversion. CONCLUSIONS: Fortunately, in the present study using the unidirectional barbed suture, major wound healing problem did not occur. As to the surgical technique, intraoperative patella eversion and anterior translation of the tibia should be avoided for quality cosmesis in primary TKA. PMID- 26762215 TI - Pacific lamprey (Entosphenus tridentatus) ammocoetes exposed to contaminated Portland Harbor sediments: Method development and effects on survival, growth, and behavior. AB - Many anthropogenic disturbances have contributed to the decline of Pacific lampreys (Entosphenus tridentatus), but potential negative effects of contaminants on lampreys are unclear. Lamprey ammocoetes are the only detritivorous fish in the lower Willamette River, Oregon, USA, and have been observed in Portland Harbor sediments. Their long benthic larval stage places them at risk from the effects of contaminated sediment. The authors developed experimental methods to assess the effects of contaminated sediment on the growth and behavior of field-collected ammocoetes reared in a laboratory. Specifically, they developed methods to assess individual growth and burrowing behavior. Burrowing performance demonstrated high variability among contaminated sediments; however, ammocoetes presented with noncontaminated reference sediment initiated burrowing more rapidly and completed it faster. Ammocoete reemergence from contaminated sediments suggests avoidance of some chemical compounds. The authors conducted long-term exposure experiments on individually held ammocoetes using sediment collected from their native Siletz River, which included the following: contaminated sediments collected from 9 sites within Portland Harbor, 2 uncontaminated reference sediments collected upstream, 1 uncontaminated sediment with characteristics similar to Portland Harbor sediments, and clean sand. They determined that a 24-h depuration period was sufficient to evaluate weight changes and observed no mortality or growth effects in fish exposed to any of the contaminated sediments. However, the effect on burrowing behavior appeared to be a sensitive endpoint, with potentially significant implications for predator avoidance. Environ Toxicol Chem 2016;35:2092-2102. (c) 2016 SETAC. PMID- 26762216 TI - Changed nursing scheduling for improved safety culture and working conditions - patients' and nurses' perspectives. AB - AIM: To evaluate fixed scheduling compared with self-scheduling for nursing staff in oncological inpatient care with regard to patient and staff outcomes. BACKGROUND: Various scheduling models have been tested to attract and retain nursing staff. Little is known about how these schedules affect staff and patients. Fixed scheduling and self-scheduling have been studied to a small extent, solely from a staff perspective. METHOD: We implemented fixed scheduling on two of four oncological inpatient wards. Two wards kept self-scheduling. Through a quasi-experimental design, baseline and follow-up measurements were collected among staff and patients. The Safety Attitudes Questionnaire was used among staff, as well as study-specific questions for patients and staff. RESULTS: Fixed scheduling was associated with less overtime and fewer possibilities to change shifts. Self-scheduling was associated with more requests from management for short notice shift changes. The type of scheduling did not affect patient reported outcomes. CONCLUSIONS: Fixed scheduling should be considered in order to lower overtime. Further research is necessary and should explore patient outcomes to a greater extent. IMPLICATIONS FOR NURSING MANAGEMENT: Scheduling is a core task for nurse managers. Our study suggests fixed scheduling as a strategy for managers to improve the effective use of resources and safety. PMID- 26762217 TI - Development and validation of an atlas-based finite element brain model. AB - Traumatic brain injury is a leading cause of disability and injury-related death. To enhance our ability to prevent such injuries, brain response can be studied using validated finite element (FE) models. In the current study, a high resolution, anatomically accurate FE model was developed from the International Consortium for Brain Mapping brain atlas. Due to wide variation in published brain material parameters, optimal brain properties were identified using a technique called Latin hypercube sampling, which optimized material properties against three experimental cadaver tests to achieve ideal biomechanics. Additionally, falx pretension and thickness were varied in a lateral impact variation. The atlas-based brain model (ABM) was subjected to the boundary conditions from three high-rate experimental cadaver tests with different material parameter combinations. Local displacements, determined experimentally using neutral density targets, were compared to displacements predicted by the ABM at the same locations. Error between the observed and predicted displacements was quantified using CORrelation and Analysis (CORA), an objective signal rating method that evaluates the correlation of two curves. An average CORA score was computed for each variation and maximized to identify the optimal combination of parameters. The strongest relationships between CORA and material parameters were observed for the shear parameters. Using properties obtained through the described multiobjective optimization, the ABM was validated in three impact configurations and shows good agreement with experimental data. The final model developed in this study consists of optimized brain material properties and was validated in three cadaver impacts against local brain displacement data. PMID- 26762218 TI - Examining subjective and physiological responses to norm violation using text based vignettes. AB - In this article, we describe a paradigm using text-based vignettes for the study of social and cultural norm violation. Towards this aim, a range of scenarios depicting instances of norm violations was generated and tested with respect to their ability in evoking subjective and physiological responses. In Experiment 1, participants evaluated 29 vignettes on how upsetting, excusable and realistic the described behaviour appeared to be. Based on those ratings we selected and extended three norm violation vignettes for Experiment 2 in which participants' physiological responses were obtained in addition to their subjective ratings. In both studies, the vignettes were successful in eliciting negative responses to norm violations and were significantly affected by the perceivers' level of ethnocultural empathy. The trait measure of cultural empathy further predicted facial electromyography (EMG) activity at muscle sites associated with disgust (M. Levator Labii), thereby suggesting a potential moral response to norm violating scenarios. We discuss the methodological merits and implications of this vignettes paradigm for investigating perceived norm transgressions and make recommendations for future work. PMID- 26762220 TI - Surgical treatment of Peyronie's disease with autologous tunica vaginalis of testis. AB - BACKGROUND: To investigate the feasibility and safety of surgical treatment for Peyronie's disease (PD) by excising and repairing plaque using autologous tunica vaginalis of testis. METHODS: From March 2007 to December 2012, total 19 patients with PD underwent surgical treatment at our center. All patients had significant phallocampsis during erection. All patients complained of decreased sexual function. During the operation, the fibrotic plaque was excised and neurovascular bundle (NVB) was spared. A size-matching autologous tunica vaginalis of testis was harvested as the graft and patched to the defect. All patients received follow up every 3 months in the first year and 6 months in the following years. Data on sexual function before and after the operation was collected and compared. RESULTS: All operations were completed successfully without serious complications. The mean operative time was 74 min. The mean size of excised plaque was 3.0 cm(2). Postoperative pathological studies revealed the fibroplastic hyperplasia of excised tissue. All patients had satisfactory correction of penile appearance. The erectile penile length between pre- and post operation didn't show significant difference. Postoperative intercourse satisfaction and overall satisfaction measured by IIEF-5 were significant improved. CONCLUSIONS: Our surgical treatment is feasible and safe for patients with PD. It can effectively improve the penile cosmetic appearance and patients' intercourse/overall satisfaction on sexual life. PMID- 26762221 TI - Chemo- and Regioselective Reduction of 5,15-Diazaporphyrins Providing Antiaromatic Azaporphyrinoids. AB - Reagent-controlled chemo- and regioselective reduction of 5,15-diazaporphyrins has been developed. The selective reduction of carbon-carbon double bonds of diazaporphyrins provides 18 pi aromatic isobacteriochlorin-type products, whereas the reduction of carbon-nitrogen double bonds leads to selective formation of 20 pi N,N'-dihydrodiazaporphyrins in excellent yields. The distinct antiaromatic character of N,N'-dihydrodiazaporphyrins has been revealed. The free-base N,N' dihydrodiazaporphyrin exhibits slower inner NH tautomerism than that in the corresponding 18 pi porphyrins. PMID- 26762219 TI - Risk Factors for Cutaneous Squamous Cell Carcinoma Recurrence, Metastasis, and Disease-Specific Death: A Systematic Review and Meta-analysis. AB - IMPORTANCE: To date, the magnitude of association and the quality of evidence for cutaneous squamous cell carcinoma (cSCC) and risk factors for outcomes have not been reviewed and analyzed systematically. OBJECTIVE: To systematically analyze all published data on risk factors for recurrence, metastasis, and disease specific death (DSD) of cSCC. DATA SOURCES: Comprehensive search of Ovid MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus, from each database's inception to May 14, 2015. STUDY SELECTION: Inclusion criteria were studies of at least 10 patients, comparative data for at least 1 cSCC risk factor, and an outcome of interest. Exclusion criteria were noncutaneous squamous cell carcinoma (SCC), anogenital SCC, inability to extract cSCC data from other malignancy data, SCC in situ, Marjolin ulcer, and genetic disorders predisposing to cSCC. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently abstracted the data. Meta-analysis was performed using the random effects model. Risk of bias was assessed by the Newcastle-Ottawa Scale. MAIN OUTCOMES AND MEASURES: A priori outcomes were recurrence, metastasis, and DSD. RESULTS: Thirty-six studies (17 248 patients with 23 421 cSCCs) were included. Significant risk factors for recurrence were the following: Breslow thickness exceeding 2 mm (risk ratio [RR], 9.64; 95% CI, 1.30-71.52), invasion beyond subcutaneous fat (RR, 7.61; 95% CI, 4.17-13.88), Breslow thickness exceeding 6 mm (RR, 7.13; 95% CI, 3.04-16.72), perineural invasion (RR, 4.30; 95% CI, 2.80 6.60), diameter exceeding 20 mm (RR, 3.22; 95% CI, 1.91-5.45), location on the temple (RR, 3.20; 95% CI, 1.12-9.15), and poor differentiation (RR, 2.66; 95% CI, 1.72-4.14). Significant risk factors for metastasis were: invasion beyond subcutaneous fat (RR, 11.21; 95% CI, 3.59-34.97), Breslow thickness exceeding 2 mm (RR, 10.76; 95% CI, 2.55-45.31), Breslow thickness exceeding 6 mm (RR, 6.93; 95% CI, 4.02-11.94), diameter exceeding 20 mm (RR, 6.15; 95% CI, 3.56-10.65), poor differentiation (RR, 4.98; 95% CI, 3.30-7.49), perineural invasion (RR, 2.95; 95% CI, 2.31-3.75), immunosuppression (RR, 1.59; 95% CI, 1.07-2.37), and location on the temple (RR, 2.82; 95% CI, 1.72-4.63), ear (RR, 2.33; 95% CI, 1.67 3.23), or lip (RR, 2.28; 95% CI, 1.54-3.37). Significant risk factors for DSD were: diameter exceeding 20 mm (RR, 19.10; 95% CI, 5.80-62.95), poor differentiation (RR, 5.65; 95% CI, 1.76-18.20), location on the ear (RR, 4.67; 95% CI, 1.28-17.12) or lip (RR, 4.55; 95% CI, 1.41-14.69), invasion beyond subcutaneous fat (RR, 4.49; 95% CI, 2.05-9.82), and perineural invasion (RR, 4.06; 95% CI, 3.10-5.32). Evidence quality was considered low to moderate. CONCLUSIONS AND RELEVANCE: Tumor depth is associated with the highest RR of local recurrence and metastasis of cSCC, and tumor diameter exceeding 20 mm is associated with the highest RR of DSD. Unified, consistent collection and reporting of risk factors in a prospective, multicentered effort are needed to further understand the increasing incidence of cSCC. PMID- 26762222 TI - Effect of bioconcentration and trophic transfer on realized exposure to oxazepam in 2 predators, the dragonfly larvae (Aeshna grandis) and the Eurasian perch (Perca fluviatilis). AB - Psychoactive substances are used worldwide and constitute one of the most common groups of pharmaceutical contaminants in surface waters. Although these pharmaceuticals are designed to be efficiently eliminated from the human body, very little is known about their trophic-transfer potential in aquatic wildlife. Therefore, the goal of the present study was to quantify and compare uptake of an anxiolytic (oxazepam) from water (bioconcentration) and via the consumption of contaminated diet (trophic transfer) in 2 common freshwater predators: Eurasian perch (Perca fluviatilis) and the dragonfly larvae Aeshna grandis. Bioconcentration and trophic transfer of oxazepam were found in both predator species. However, higher bioconcentrations were observed for perch (bioconcentration factor [BCF], 3.7) than for dragonfly larvae (BCF, 0.5). Perch also retained more oxazepam from consumed prey (41%) than dragonfly larvae (10%), whereas the relative contribution via prey consumption was 14% and 42% for perch and dragonflies, respectively. In addition, bioconcentration was negatively correlated with perch weight, indicating that exposure levels in natural contaminated environments differ between individuals of different size or between different developmental stages. Hence, trophic transfer of pharmaceuticals may indeed occur, and estimates of environmental exposures that do not consider intake via food or size-dependent bioconcentration may therefore lead to wrongful estimations of realized exposure levels in natural contaminated ecosystems. PMID- 26762223 TI - Frontline nurse managers' confidence and self-efficacy. AB - AIM: This study was focused on determining relationships between confidence levels and self-efficacy among nurse managers. BACKGROUND: Frontline nurse managers have a pivotal role in delivering high-quality patient care while managing the associated costs and resources. The competency and skill of nurse managers affect every aspect of patient care and staff well-being as nurse managers are largely responsible for creating work environments in which clinical nurses are able to provide high-quality, patient-centred, holistic care. METHOD: A descriptive, correlational survey design was used; 85 nurse managers participated. RESULTS: Years in a formal leadership role and confidence scores were found to be significant predictors of self-efficacy scores. CONCLUSIONS: Experience as a nurse manager is an important component of confidence and self efficacy. IMPLICATIONS FOR NURSING MANAGEMENT: There is a need to develop educational programmes for nurse managers to enhance their self-confidence and self-efficacy, and to maintain experienced nurse managers in the role. PMID- 26762225 TI - The impact of balance-focused attitudes on job stress: Gender differences evidenced in American and Chinese samples. AB - Based on gender role expectations model, we examined how balance-focused attitudes would affect job stress by influencing individuals' perceptions of family interference with work (FIW), and investigated whether a gender difference would exist in the relationships among balance-focused attitudes, FIW and job stress. Using two independent samples from the United States and China, we found support for the indirect influence of balance-focused attitudes on job stress, through FIW. Participants with balance-focused attitudes experienced lower levels of job stress as they perceived less interference from family to work. As expected, such indirect effect was more pronounce among male participants, meaning that the male participants benefited more from having balance-focused attitudes. Discussion, theoretical and practical implications are provided. PMID- 26762224 TI - Video-assisted thoracic surgery for primary myelolipoma of the posterior mediastinum. AB - BACKGROUND: Myelolipoma is an uncommon tumor comprising adipose tissue and normal hematopoietic cells and mainly occurs in the adrenal cortex. Mediastinal myelolipoma is very rare; we report a case of posterior mediastinal myelolipoma that required surgical resection. CASE PRESENTATION: A 56-year-old male was diagnosed with a posterior mediastinal tumor by computed tomography. The tumor was originally noted in 2005, and during follow-up in March 2014, it was found to have increased in size. During consultation at our hospital, on magnetic resonance imaging (MRI), we considered the possibility that the tumor was malignant. Consequently, we resected the tumor by video-assisted thoracic surgery (VATS). The histopathological findings revealed that the tumor had undergone intrathoracic extramedullary hematopoiesis. However, after considering the patient's background and histopathological findings, we diagnosed the tumor as a thoracic extra-adrenal myelolipoma. CONCLUSIONS: Pathological analysis was instrumental in clarifying the diagnosis. We recommend surgery as a treatment option for posterior mediastinal tumors. PMID- 26762226 TI - Transgender Patients, Isotretinoin, and US Food and Drug Administration-Mandated Risk Evaluation and Mitigation Strategies: A Prescription for Inclusion. PMID- 26762227 TI - Beyond the Dimer and Trimer: Tetraspiro[2.1.2(5).1.2(9).1.2(13).1(3)] hexadecane 1,3,5,7-tetraone--the Cyclic Tetramer of Carbonylcyclopropane. AB - Tetraspiro[2.1.2(5).1.2(9).1.2(13).1(3)]hexadecane-1,3,5,7-tetraone 4, a unique tetraketone containing a cyclooctane core and four spiroannelated cyclopropane moieties, represents the previously unknown cyclotetramer of carbonylcyclopropane. For this purpose oxidation of the parent polyspirocyclic hydrocarbon was examined under various oxidative conditions, and the reactivity of oxidants towards methylene groups of the eight-membered cycle, activated by adjacent spirocyclopropane rings, was evaluated and contrasted. Whereas the treatment of tetraspirohexadecane with ozone resulted in monooxidation, its reaction with methyl(trifluoromethyl)dioxirane afforded the product of four-fold oxidation, triketoalcohol 10. Subsequent oxidation of the latter with Dess-Martin periodinane gave the target tetraketone 4. PMID- 26762228 TI - Dehydroepiandrosterone triggers autophagic cell death in human hepatoma cell line HepG2 via JNK-mediated p62/SQSTM1 expression. AB - Autophagy is a catabolic process that cancer cells usually exploit during stress conditions to provide energy by recycling organelles and proteins. Beyond its prosurvival role, it is well accepted that occurrence of autophagy is often associated with a particular type of programmed cell death known as autophagic cell death (ACD). Dehydroepiandrosterone (DHEA) is an endogenous hormone showing anticancer properties even if the underlying mechanisms are not fully clear yet. Here, we provide evidence that DHEA induces ACD in human hepatoma cell line, HepG2. Indeed, autophagy inhibitors (i.e. 3-methyladenine or Atg5 siRNA) significantly reduced the percentage of dead cells. DHEA induces p62-dependent autophagy, which turns detrimental and brings about death. DHEA stimulates reactive oxygen species-independent jun N-terminal kinase (JNK) phosphoactivation and the treatment with JNK inhibitor reduces p62 mRNA levels, as well as DHEA induced ACD. The transcription factor nuclear factor (erythroid-derived-2)-like-2 (Nrf2) constitutes the link between JNK and p62 since its migration to the nucleus is suppressed by JNK inhibitor and its inhibition through a dominant negative Nrf2 plasmid transfection decreases p62 protein levels. Overall, our data indicate that DHEA induces ACD in HepG2 via a JNK-Nrf2-p62 axis. Thus, DHEA could represent a new appealing drug for eliminating tumor cells through autophagy particularly in apoptosis-resistant cases. PMID- 26762230 TI - Chronic exposure to mono-(2-ethylhexyl)-phthalate causes endocrine disruption and reproductive dysfunction in zebrafish. AB - Phthalic acid esters are frequently detected in aquatic environments. In the present study, zebrafish were exposed to low concentrations (0 ug/L, 0.46 ug/L, 4.0 ug/L, and 37.5 ug/L) of mono-(2-ethylhexyl) phthalate (MEHP) for 81 d, and the effects on reproduction, gamete quality, plasma vitellogenin (VTG), sex steroids, and transcriptional profiles of key genes involved in steroidogenesis were investigated. The results demonstrated that egg production and sperm quality were decreased after exposure to MEHP, which also resulted in reduced egg diameter and eggshell as well as decreased egg protein content. Significant inductions in plasma testosterone and 17beta-estradiol (E2) were observed in females, which might have resulted from up-regulation of CYP19a and 17beta-HSD gene transcription in the ovary. A significant increase in plasma E2 along with a decrease in plasma 11-keto testosterone was also observed in males, which was accompanied by up-regulation of CYP19a and inhibition of CYP11b transcription in the testis. In addition, plasma vitellogenin levels were significantly increased after MEHP exposure in both sexes. Moreover, continuous MEHP exposure in the F1 embryos resulted in worse hatching rates and increased malformation rates compared with embryos without MEHP exposure. Taken together, these results demonstrate that MEHP has the potential to cause reproductive dysfunction and impair the development of offspring. However, it should be noted that most of the significant effects were observed at higher concentrations, and MEHP at typically measured concentrations may not have major effects on fish reproduction and development. Environ Toxicol Chem 2016;35:2117-2124. (c) 2016 SETAC. PMID- 26762232 TI - Growing Vertical in the Flatland. AB - The world of two-dimensional (2D) heterostructures continues to expand at a rate much greater than anyone could have predicted 10 years ago, but if we are to make the leap from science to technology, many materials challenges must still be overcome. Recent advances, such as those by Liu et al. in this issue of ACS Nano, demonstrate that it is possible to grow rotationally commensurate 2D heterostructures, which could pave the way toward single crystal van der Waals solids. In this Perspective, I provide some insight into a few of the challenges associated with growth of heterostructures, and discuss some of the recent works that help us better understand synthetic realization of 2D heterostructures. PMID- 26762231 TI - Influence of physical assessment of different light-curing units on irradiance and composite microhardness top/bottom ratio. AB - The aim of this study was to evaluate the influence of the physical assessment of different light-curing units from 55 dental offices on the irradiance and composite microhardness top/bottom ratio, and the influence of the radiometers for LED or QTH light sources on irradiance measurement. The irradiance of each light-curing unit was evaluated with two radiometers, either for LED or QTH light. A questionnaire regarding the type of source (LED or QTH), time of use, date of last maintenance and light-curing performance assessment applied. The physical assessments were evaluated regarding damage or debris on the light tip. For each light-curing unit, three composite specimens were made (diameter = 7 mm; thickness = 2 mm) with polymerizing time of 20 s, in order to perform the microhardness (Knoop) test. Data were analyzed by Kruskal-Wallis and Dunn test (alpha = 0.01). There was wide variation in irradiance (0-1000 mW/cm(2)). Approximately 50 % of the light-curing units presented radiation lower than 300 mW/cm(2); 10 % of light-curing units, especially those with LED source, presented values higher than 800 mW/cm(2), and 43 % of light-curing units worked with adequate irradiance between 301 and 800 mW/cm(2). In almost 60 % of cases, no maintenance of light-curing units was performed in a period of 3 to 10 years. The age of the light-curing units and the use of inadequate tips interfered negatively in irradiance. The data emphasize the importance of periodic maintenance of light-polymerizing, light-curing units. PMID- 26762229 TI - Mucins and Wnt/beta-catenin signaling in gastrointestinal cancers: an unholy nexus. AB - The Wnt/beta-catenin signaling pathway is indispensable for embryonic development, maintenance of adult tissue homeostasis and repair of epithelial injury. Unsurprisingly, aberrations in this pathway occur frequently in many cancers and often result in increased nuclear beta-catenin. While mutations in key pathway members, such as beta-catenin and adenomatous polyposis coli, are early and frequent occurrences in most colorectal cancers (CRC), mutations in canonical pathway members are rare in pancreatic ductal adenocarcinoma (PDAC). Instead, in the majority of PDACs, indirect mechanisms such as promoter methylation, increased ligand secretion and decreased pathway inhibitor secretion work in concert to promote aberrant cytosolic/nuclear localization of beta catenin. Concomitant with alterations in beta-catenin localization, changes in mucin expression and localization have been documented in multiple malignancies. Indeed, numerous studies over the years suggest an intricate and mutually regulatory relationship between mucins (MUCs) and beta-catenin. In the current review, we summarize several studies that describe the relationship between mucins and beta-catenin in gastrointestinal malignancies, with particular emphasis upon colorectal and pancreatic cancer. PMID- 26762233 TI - Bidirectional semantic associations between social power and weight. AB - Two experiments were conducted to examine bidirectional semantic associations between power and weight using a priming paradigm. Bidirectionality in the relationship between power and weight was demonstrated, utilising tasks that were identical except that the orders in which the stimuli were presented were reversed. In Experiment 1, an empty scale leaning either leftward or rightward was used as a priming stimulus, and a scale that appeared in equilibrium with a pair of power words was used as a target stimulus. In Experiment 2, a scale with a pair of words that appeared in equilibrium was used as a priming stimulus, and an empty scale leaning either leftward or rightward was used as a target stimulus. We identified interaction effects between power and weight in both experiments. Associations between power and weight provide evidence for both conceptual metaphor views and evolutionary theory. The bidirectionality of metaphorical effects is in line with the strong version of metaphoric structuring. Both language and experiential correlations play important roles in the development of the mapping between power and weight. PMID- 26762235 TI - Pharmacokinetic and Pharmacodynamic Interaction of Boswellic Acids and Andrographolide with Glyburide in Diabetic Rats: Including Its PK/PD Modeling. AB - The effect of boswellic acids (BA) and andrographolide (AD) on the pharmacokinetics and pharmacodynamics of glyburide in normal as well as in streptozotocin-induced diabetic rats was studied. In normal and diabetic rats, the combination of glyburide with BA or AD increased significantly (p < 0.01) all the pharmacokinetic parameters, such as Cmax, AUC0-n, AUCtotal, t1/2, and mean residence time, and decreased the clearance, Vd, markedly as compared with the control group. In rat liver, microsomes BA and AD have shown CYP3A4 inhibitory activity significantly (p < 0.01), compared with the vehicle group. The increase in hypoglycemic action by concomitant administration of glyburide with BA or AD was more in diabetic rats than when the drugs were used singly and with the control group, which suggests the enhancement of glucose reduction capacity of glyburide in diabetic rats along with BA or AD. In PK/PD modeling of BA and AD with glyburide, the predicted PK and PD parameters are in line with the observed PK and PD parameters. The results revealed that BA and AD led to the PK/PD changes because of glyburide-increased bioavailability and because of the inhibition of CYP3A4 enzyme. In conclusion, add-on preparations containing BA or AD may increase the bioavailability of glyburide, and hence the dose should be monitored. PMID- 26762236 TI - Synergistic effect of piperonyl butoxide on acute toxicity of pyrethrins to Hyalella azteca. AB - A series of acute toxicity tests with the amphipod Hyalella azteca was performed to quantify the synergistic effect of piperonyl butoxide (PBO) on pyrethrin toxicity. Concentrations of PBO <4 ug/L caused no toxicity enhancement, whereas toxicity increased with PBO concentrations between 4 ug/L and 15 ug/L. Additive toxicity calculations showed that true synergism accounted for an increase in pyrethrin toxicity (decrease in median lethal concentration) of 1.4-fold to 1.6 fold and varied only slightly between 4 ug/L and 15 ug/L PBO, whereas direct toxicity of PBO accounted for an additional increase in mixture toxicity (up to 3.2-fold) that was proportional to PBO concentration. The results can be used to assess the risk of measured or predicted co-occurring concentrations of PBO and pyrethrins in surface waters. Environ Toxicol Chem 2016;35:2111-2116. (c) 2016 SETAC. PMID- 26762237 TI - Role of molecular testing in the multidisciplinary diagnostic approach of ichthyosis. AB - BACKGROUND: The term ichthyosis describes a generalized disorder of cornification characterized by scaling and/or hyperkeratosis of different skin regions. Mutations in a broad group of genes related to keratinocyte differentiation and epidermal barrier function have been demonstrated to play a causative role in disease development. Ichthyosis may be classified in syndromic or non-syndromic forms based on the occurrence or absence of extracutaneous signs. In this setting, the diagnosis of ichthyosis is an integrated multistep process requiring a multidisciplinary approach in order to formulate the appropriate diagnostic hypothesis and to address the genetic testing. METHODS: Due to the complex features of the different ichthyoses and the high number of genes involved we have investigated a group of 64 patients, affected by syndromic and non-syndromic diseases, using Next Generation Sequencing as a new tool for the molecular diagnosis. RESULTS: Using this innovative molecular approach we were able to find pathogenic mutations in 53 out of 64 patients resulting in 82.8 % total detection rate. An interesting result from the analysis of the data is the high rate of novel sequence variations found compared to known mutations and the relevant rate of homozygous mutations. CONCLUSIONS: The possibility to analyze a large number of genes associated with various diseases allows to study cases with phenotypes not well-determined, giving the opportunity to make new genotype-phenotype correlation. In some cases there were discrepancies between clinical features and histology or electron microscopy and only molecular analysis allowed to definitively resolve the diagnostic dilemma. The genetic diagnosis of ichthyosis leads to a more accurate and effective genetic counseling, allowing correct evaluation of the risk of recurrence, particularly in families with consanguineous background. PMID- 26762238 TI - Effect of levosimendan therapy on myocardial infarct size and left ventricular function after acute coronary occlusion. AB - BACKGROUND: Levosimendan is an inotropic agent with cardioprotective and vasodilating properties used for the management of acutely decompensated heart failure. We studied the effects of levosimendan treatment on the size of myocardial infarction (MI) and left ventricular (LV) function in experimental pig model of post MI heart failure. METHODS: After occlusion of the left anterior descending (LAD) coronary artery, animals received levosimendan 5 mg/kg/day orally for 8 weeks (n=7) or no treatment (n=18). One week after stopping treatment, transthoracic echocardiography, CT scan and positron emission tomography were performed to evaluate myocardial function, perfusion and oxidative metabolism. Histology was used to confirm the size of MI and features of LV remodelling. RESULTS: The size of MI was significantly smaller in the levosimendan group than in the controls (12+/-13% vs 27+/-15% of the LV, p=0.03). End-diastolic volume (EDV) and end-systolic volume (ESV) were smaller in the levosimendan than in the control group (EDV 161+/-29 mL vs 245+/-84 mL, p=0.06; ESV 81+/-18 mL vs 149+/-67 mL, p=0.03), whereas ejection fraction tended to be higher in the levosimendan group (50+/-6% vs 41+/-8%, p=0.06). CONCLUSIONS: Eight weeks of levosimendan therapy after recent LAD occlusion decreases the size of MI and leads to better preservation of LV function as well as reduced LV remodelling. PMID- 26762239 TI - The pulmonary artery wedge pressure response to sustained exercise is time variant in healthy adults. AB - OBJECTIVES: The clinical and prognostic significance of 'exaggerated' elevations in pulmonary artery wedge pressure (PAWP) during symptom-limited exercise testing is increasingly recognised. However, the paucity of normative data makes the identification of abnormal responses challenging. Our objectives was to describe haemodynamic responses that reflect normal adaptation to submaximal exercise in a group of community-dwelling, older, non-dyspnoeic adults. METHODS: Twenty-eight healthy volunteers (16 men/12 women; 55+/-6 years) were studied during rest and two consecutive stages of cycle ergometry, at targeted heart rates of 100 bpm (light exercise) and 120 bpm (moderate exercise). Right-heart catheterisation was performed to measure pulmonary artery pressures, both early (2 min) and after sustained (7 min) exercise at each intensity. RESULTS: End-expiratory PAWP at baseline was 11+/-3 mm Hg and increased to 22+/-5 mm Hg at early-light exercise (p<0.01). At sustained-light exercise, PAWP declined to 17+/-5 mm Hg, remaining elevated versus baseline (p<0.01). PAWP increased again at early-moderate exercise to 20+/-6 mm Hg but did not exceed the values observed at early-light exercise, and declined further to 15+/-5 mm Hg at sustained-moderate exercise (p<0.01 vs baseline). When analysed at 30 s intervals, mean and diastolic pulmonary artery pressures peaked at 180 (IQR=30) s and 130 (IQR=90) s, respectively, and both declined significantly by 420 (IQR=30) s (both p<0.01) of light exercise. Similar temporal patterns were observed at moderate exercise. CONCLUSIONS: The range of PAWP responses to submaximal exercise is broad in health, but also time-variant. PAWP may routinely exceed 20 mm Hg early in exercise. Initial increases in PAWP and mean pulmonary artery pressures do not necessarily reflect abnormal cardiopulmonary physiology, as pressures may normalise within a period of minutes. PMID- 26762240 TI - Right ventricular longitudinal strain for risk stratification in low-flow, low gradient aortic stenosis with low ejection fraction. AB - BACKGROUND: Left ventricular global longitudinal strain (LVLS) is a powerful predictor of outcome in patients with low-flow, low-gradient aortic stenosis (LF LG AS) and low LV ejection fraction (LVEF). However, the impact of right ventricular (RV) function on the outcome of these patients remains unknown. OBJECTIVES: The aim of this study was to examine the impact of RV function as evaluated by RV free wall longitudinal strain (RVLS) on mortality in patients with LF-LG AS and low LVEF. METHODS: 211 patients with LF-LG AS (mean gradient < 40 mm Hg and indexed aortic valve area (AVA) <= 0.6 cm2/m2) and low LVEF (<= 40%)) were prospectively recruited in the True or Pseudo-severe Aortic Stenosis study. AS severity was assessed using the projected AVA (AVAproj) at normal flow rate. Among the 211 patients, 128 had RVLS measurement available at rest and were included in this analysis. RVLS measurement at dobutamine stress echocardiography (DSE) was available in 58 of the 128 patients. RESULTS: Two-year survival was lower in patients with RVLS < |13|% (53% +/- 9%) compared with those with RVLS > |13|% (69% +/- 5%) (p = 0.04). In multivariable Cox analysis stratified for the type of treatment (aortic valve replacement vs conservative) and adjusted for age, AS severity, previous myocardial infarction and LVLS, rest RVLS < |13|% (HR = 2.70; 95% CI 1.19 to 6.11; p = 0.018) was independently associated with all cause mortality. RVLS had incremental prognostic value over baseline risk factors and LVLS (chi2 = 20.13 vs 13.56; p = 0.01). Reduced stress RVLS was also associated with increased risk of mortality (stress RVLS <| 14|%: HR = 2.98; 95% CI 1.30 to 6.52; p = 0.01). In multivariable Cox analysis, stress RVLS < |14|% remained independently associated with mortality (HR = 2.94; 95% CI 1.23 to 7.02; p = 0.015). After further adjustment for rest RVLS, stress RVLS < |14|% remained independently associated with mortality (HR = 3.29; 95% CI 1.17 to 9.25; p = 0.024), whereas rest RVLS was not (p > 0.05). CONCLUSIONS: In this series of patients with LF-LG AS and low LVEF, reduced RVLS was independently associated with increased risk of mortality. Furthermore, stress RVLS provided incremental prognostic value beyond that obtained from rest RVLS. Thus, RVLS measurement at rest and at DSE may be helpful to enhance risk stratification in this high-risk population. TRIAL REGISTRATION NUMBER: NCT01835028; Results. PMID- 26762241 TI - A case of dyspnoea and visible neck pulsations. PMID- 26762243 TI - Twisted MoSe2 Bilayers with Variable Local Stacking and Interlayer Coupling Revealed by Low-Frequency Raman Spectroscopy. AB - Unique twisted bilayers of MoSe2 with multiple stacking orientations and interlayer couplings in the narrow range of twist angles, 60 +/- 3 degrees , are revealed by low-frequency Raman spectroscopy and theoretical analysis. The slight deviation from 60 degrees allows the concomitant presence of patches featuring all three high-symmetry stacking configurations (2H or AA', AB', and A'B) in one unique bilayer system. In this case, the periodic arrangement of the patches and their size strongly depend on the twist angle. Ab initio modeling predicts significant changes in frequencies and intensities of low-frequency modes versus stacking and twist angle. Experimentally, the variable stacking and coupling across the interface are revealed by the appearance of two breathing modes, corresponding to the mixture of the high-symmetry stacking configurations and unaligned regions of monolayers. Only one breathing mode is observed outside the narrow range of twist angles. This indicates a stacking transition to unaligned monolayers with mismatched atom registry without the in-plane restoring force required to generate a shear mode. The variable interlayer coupling and spacing in transition metal dichalcogenide bilayers revealed in this study may provide an interesting platform for optoelectronic applications of these materials. PMID- 26762245 TI - A special year for light. PMID- 26762242 TI - Intrinsic Astrocyte Heterogeneity Influences Tumor Growth in Glioma Mouse Models. AB - The influence of cellular origin on glioma pathogenesis remains elusive. We previously showed that mutations inactivating Rb and Pten and activating Kras transform astrocytes and induce tumorigenesis throughout the adult mouse brain. However, it remained unclear whether astrocyte subpopulations were susceptible to these mutations. We therefore used genetic lineage tracing and fate mapping in adult conditional, inducible genetically engineered mice to monitor transformation of glial fibrillary acidic protein (GFAP) and glutamate aspartate transporter (GLAST) astrocytes and immunofluorescence to monitor cellular composition of the tumor microenvironment over time. Because considerable regional heterogeneity exists among astrocytes, we also examined the influence of brain region on tumor growth. GFAP astrocyte transformation induced uniformly rapid, regionally independent tumor growth, but transformation of GLAST astrocytes induced slowly growing tumors with significant regional bias. Transformed GLAST astrocytes had reduced proliferative response in culture and in vivo and malignant progression was delayed in these tumors. Recruited glial cells, including proliferating astrocytes, oligodendrocyte progenitors and microglia, were the majority of GLAST, but not GFAP astrocyte-derived tumors and their abundance dynamically changed over time. These results suggest that intrinsic astrocyte heterogeneity, and perhaps regional brain microenvironment, significantly contributes to glioma pathogenesis. PMID- 26762246 TI - Accelerated image reconstruction in fluorescence molecular tomography using a nonuniform updating scheme with momentum and ordered subsets methods. PMID- 26762244 TI - Minimizing the effects of magnetization transfer asymmetry on inhomogeneous magnetization transfer (ihMT) at ultra-high magnetic field (11.75 T). AB - OBJECTIVES: The recently reported inhomogeneous magnetization transfer technique (ihMT) has been proposed for specific imaging of inhomogeneously broadened lines, and has shown great promise for characterizing myelinated tissues. The ihMT contrast is obtained by subtracting magnetization transfer images obtained with simultaneous saturation at positive and negative frequency offsets (dual frequency saturation experiment, MT (+/-)) from those obtained with single frequency saturation (MT (+)) at the same total power. Hence, ihMT may be biased by MT-asymmetry, especially at ultra-high magnetic field. Use of the average of single positive and negative frequency offset saturation MT images, i.e., (MT (+)+MT (-)) has been proposed to correct the ihMT signal from MT-asymmetry signal. MATERIALS AND METHODS: The efficiency of this correction method was experimentally assessed in this study, performed at 11.75 T on mice. Quantitative corrected ihMT and MT-asymmetry ratios (ihMTR and MTRasym) were measured in mouse brain structures for several MT-asymmetry magnitudes and different saturation parameter sets. RESULTS: Our results indicated a "safe" range of magnitudes (/MTRasym/<4 %) for which MT-asymmetry signal did not bias the corrected ihMT signal. Moreover, experimental evidence of the different natures of both MT asymmetry and inhomogeneous MT contrasts were provided. In particular, non-zero ihMT ratios were obtained at zero MTRasym values. CONCLUSION: MTRasym is not a confounding factor for ihMT quantification, even at ultra-high field, as long as MTRasym is restricted to +/-4 %. PMID- 26762247 TI - Intraoral photobiomodulation-induced orthodontic tooth alignment: a preliminary study. AB - BACKGROUND: Numerous strategies have been proposed to decrease orthodontic treatment time. Photobiomodulation (PBM) has previously been demonstrated to assist in this objective. The aim of this study was to test if intraoral PBM increases the rate of tooth alignment and reduces the time required to resolve anterior dental crowding. METHODS: Nineteen orthodontic subjects with Class I or Class II malocclusion and Little's Irregularity Index (LII) >= 3 mm were selected from a pool of applicants, providing 28 total arches. No cases required extraction. The test group (N = 11, 18 arches, 10 upper, 8 lower) received daily PBM treatment with an intraoral LED device (OrthoPulseTM, Biolux Research Ltd.) during orthodontic treatment, while the control group (N = 8, 10 arches, 3 upper, 7 lower) received only orthodontic treatment. The PBM device exposed the buccal side of the gums to near-infrared light with a continuous 850-nm wavelength, generating an average daily energy density of 9.5 J/cm(2). LII was measured at the start (T0) of orthodontic treatment until alignment was reached (T1, where LII <= 1 mm). The control group was mostly bonded with 0.018-in slot self ligating SPEED brackets (Hespeler Orthodontics, Cambridge, ON. Canada), while conventionally-ligating Ormco Mini-Diamond twins were used on the PBM group (Ormco, Glendora, Calif. USA). Both groups progressed through alignment with NiTi arch-wires from 0.014-in through to 0.018-in (Ormco), with identical arch-wire changes. The rate of anterior alignment, in LII mm/week, and total treatment time was collected for both groups. Cox proportional hazards models were used to compare groups and while considering age, sex, ethnicity, arch and degree of crowding. RESULTS: The mean alignment rate for the PBM group was significantly higher than that of the control group, with an LII change rate of 1.27 mm/week (SD 0.53, 95 % CI +/- 0.26) versus 0.44 mm/week (SD 0.20, 95 % CI +/- 0.12), respectively (p = 0.0002). The treatment time to alignment was significantly smaller for the PBM group, which achieved alignment in 48 days (SD 39, 95 % CI +/ 39), while the control group took 104 days (SD 55, 95 % CI +/-19, p = 0.0053) on average. These results demonstrated that intraoral PBM increased the average rate of tooth movement by 2.9-fold, resulting in a 54 % average decrease in alignment duration versus control. The average PBM compliance to daily treatments was 93 % during alignment. CONCLUSIONS: Under the limitations of this study, the findings suggest that intraoral PBM could be used to decrease anterior alignment treatment time, which could consequently decrease full orthodontic treatment time. However, due to its limitations, further research in the form of a large, randomized trial is needed. TRIAL REGISTRATION: ClinicalTrials.gov NCT02267837 . Registered 10 October 2014. PMID- 26762248 TI - New Findings on the Effects of Tannic Acid: Inhibition of L-Type Calcium Channels, Calcium Transient and Contractility in Rat Ventricular Myocytes. AB - Tannic acid (TA) is a group of water-soluble polyphenolic compounds that occur mainly in plant-derived feeds, food grains and fruits. Many studies have explored its biomedical properties, such as anticancer, antibacterial, antimutagenic, antioxidant, antidiabetic, antiinflammatory and antihypertensive activities. However, the effects of TA on the L-type Ca(2+) current (ICa-L) of cardiomyocytes remain undefined. The present study examined the effects of TA on ICa-L using the whole-cell patch-clamp technique and on intracellular Ca(2+) handling and cell contractility in rat ventricular myocytes with the aid of a video-based edge detection system. Exposure to TA resulted in a concentration- and voltage dependent blockade of ICa-L, with the half maximal inhibitory concentration of 1.69 MUM and the maximal inhibitory effect of 46.15%. Moreover, TA significantly inhibited the amplitude of myocyte shortening and peak value of Ca(2+) transient and increased the time to 10% of the peak. These findings provide new experimental evidence for the cellular mechanism of action of TA and may help to expand clinical treatments for cardiovascular disease. PMID- 26762249 TI - Modeling the Cost-Effectiveness of Doula Care Associated with Reductions in Preterm Birth and Cesarean Delivery. AB - BACKGROUND: One in nine US infants is born before 37 weeks' gestation, incurring medical costs 10 times higher than full-term infants. One in three infants is born by cesarean; cesarean births cost twice as much as vaginal births. We compared rates of preterm and cesarean birth among Medicaid recipients with prenatal access to doula care (nonmedical maternal support) with similar women regionally. We used data on this association to mathematically model the potential cost-effectiveness of Medicaid coverage of doula services. METHODS: Data came from two sources: all Medicaid-funded, singleton births at hospitals in the West North Central and East North Central US (n = 65,147) in the 2012 Nationwide Inpatient Sample, and all Medicaid-funded singleton births (n = 1,935) supported by a community-based doula organization in the Upper Midwest from 2010 to 2014. We analyzed routinely collected, de-identified administrative data. Multivariable regression analysis was used to estimate associations between doula care and outcomes. A probabilistic decision-analytic model was used for cost effectiveness estimates. RESULTS: Women who received doula support had lower preterm and cesarean birth rates than Medicaid beneficiaries regionally (4.7 vs 6.3%, and 20.4 vs 34.2%). After adjustment for covariates, women with doula care had 22 percent lower odds of preterm birth (AOR 0.77 [95% CI 0.61-0.96]). Cost effectiveness analyses indicate potential savings associated with doula support reimbursed at an average of $986 (ranging from $929 to $1,047 across states). CONCLUSIONS: Based on associations between doula care and preterm and cesarean birth, coverage reimbursement for doula services would likely be cost saving or cost-effective for state Medicaid programs. PMID- 26762250 TI - A Tri-Stimuli-Responsive Shape-Memory Material Using Host-Guest Interactions as Molecular Switches. AB - A thermo-, photo- and chemoresponsive shape-memory material is successfully prepared by introducing alpha-cyclodextrin (alphaCD) and azobenzene (Azo) into a poly(acrylate acid)/alginate (PAA/Alg) network. The tri-stimuli-responsive formation/dissociation of alphaCD-Azo acts as molecular switches freezing or increasing the molecular mobility. The resulting film herein can be processed into temporary shapes as needed and recovers its initial shape upon the application of light irradiation, heating, or chemical agent independently. Furthermore, the agar diffusion test suggests that the alpha-CD-Alg/Azo-PAA has good biocompatibility for L929 fibroblast-like cells. PMID- 26762251 TI - Organization of projection neurons and local neurons of the primary auditory center in the fruit fly Drosophila melanogaster. AB - Acoustic communication between insects serves as an excellent model system for analyzing the neuronal mechanisms underlying auditory information processing. The detailed organization of auditory neural circuits in the brain has not yet been described. To understand the central auditory pathways, we used the brain of the fruit fly Drosophila melanogaster as a model and performed a large-scale analysis of the interneurons associated with the primary auditory center. By screening expression driver strains and performing single-cell labeling of these strains, we identified 44 types of interneurons innervating the primary auditory center. Five types were local interneurons whereas the other 39 types were projection interneurons connecting the primary auditory center with other brain regions. The projection neurons comprised three frequency-selective pathways and two frequency embracive pathways. Mapping of their connection targets revealed that five neuropils in the brain-the wedge (WED), anterior ventrolateral protocerebrum, posterior ventrolateral protocerebrum (PVLP), saddle (SAD), and gnathal ganglia (GNG)-were intensively connected with the primary auditory center. In addition, several other neuropils, including visual and olfactory centers in the brain, were directly connected to the primary auditory center. The distribution patterns of the spines and boutons of the identified neurons suggest that auditory information is sent mainly from the primary auditory center to the PVLP, WED, SAD, GNG, and thoracico-abdominal ganglia. Based on these findings, we established the first comprehensive map of secondary auditory interneurons, which indicates the downstream information flow to parallel ascending pathways, multimodal pathways, and descending pathways. PMID- 26762254 TI - Remembering the Pioneers of Topical Agents. PMID- 26762252 TI - The leukemogenic fusion gene MLL-AF9 alters microRNA expression pattern and inhibits monoblastic differentiation via miR-511 repression. AB - BACKGROUND: In this study we explored the role of microRNAs (miRNAs) as mediators of leukemogenic effects of the fusion gene MLL-AF9, which results from a frequent chromosomal translocation in infant and monoblastic acute myeloid leukemia (AML). METHODS: We performed a specific and efficient knockdown of endogenous MLL-AF9 in the human monoblastic AML cell line THP1. RESULTS: The knockdown associated miRNA expression profile revealed 21 MLL-AF9 dependently expressed miRNAs. Gene ontology analyses of target genes suggested an impact of these miRNAs on downstream gene regulation via targeting of transcriptional modulators as well as involvement in many functions important for leukemia maintenance as e.g. myeloid differentiation, cell cycle and stem cell maintenance. Furthermore, we identified one of the most intensely repressed miRNAs, miR-511, to raise CCL2 expression (a chemokine ligand important for immunosurveillance), directly target cyclin D1, inhibit cell cycle progression, increase cellular migration and promote monoblastic differentiation. With these effects, miR-511 may have a therapeutic potential as a pro-differentiation agent as well as in leukemia vaccination approaches. CONCLUSIONS: Our study provides new insights into the understanding of miRNAs as functional mediators of the leukemogenic fusion gene MLL-AF9 and opens new opportunities to further investigate specific therapeutic options for AML via the miRNA level. PMID- 26762255 TI - Nicknames of Dermatologic Fame. PMID- 26762257 TI - Association of Google Search Volume Index Peaks for Skin Cancer With Skin Cancer Awareness Month. PMID- 26762259 TI - Incorrect Affilation. PMID- 26762258 TI - Association of Google Search Volume Index Peaks for Skin Cancer With Skin Cancer Awareness Month--Reply. PMID- 26762260 TI - Pockmarked. PMID- 26762261 TI - [Health care economic guidance in Germany from the example Morbi-RSA]. AB - Increasing costs in health care represent still a major challenge in most industrial contries. A lot of attempts especially in Germany have been made to manage such problems and for a fair allocation oft he underlying resources. One of this ist the Morbi-RSA. The current review reflects all historical, medical and economical aspects of the Morbi-RSA and gives a perspective to possible future developments. PMID- 26762262 TI - Unilateral unique Lupus tumidus: pathogenetic mystery and diagnostic problem. AB - Lupus tumidus is a rare immunological disorder whose pathogenesis is not fully understood. Although on the one hand there are some differences in (1) the clinical morphology of lesions, (2) the histopathology picture, as well as in (3) serological profile of lupus tumidus patients at the current moment, the disease is regarded as a subform of chronic cutaneous lupus erythematosus. Differential diagnosis requires the exclusion of many diseases such as Jessner Kanoff lymphocytic infiltration, polymorphous light eruption, and reticular erythematous mucinosis. Differentiation between them is not always easy. The standard treatment regimen of patients with lupus tumidus is based on local and systemic application of corticosteroids, azathioprin, dapsone, mepacrine, chloroquine, and hydroxychloroquine. Modern treatment options include the use of pulsed dye laser, tacrolimus 0.1 % ointment and photophoresis. We present a 42-year-old patient with unilateral atypical form of lupus tumidus who was successfully treated with systematically administration of hydroxychloroquine in combination with sunscreen SPF 50. After a 2-month course of treatment with hydroxychloroquine dosage of 200 mg per day and a break of 3 months between courses, we observed a complete remission. PMID- 26762263 TI - Application of Cryopreserved Fibroblast Culture with Au Nanoparticles to Treat Burns. AB - The aim was to investigate a possibility of using the cryopreserved human culture of fibroblasts (CrHFC) with gold nanoparticles (AuNPs) to treat experimental burns in rats.The third-degree burns were modeled in white male rats. All the animals with burns were divided into three experimental groups: control group with no wound treatment; group 1 was composed of animals with CrHFC application; and group 2 consisted of those with CrHFC and AuNPs (6 MUg/ml) application to a burn surface the next day after the injury. The CrHFC was applied to the methylcellulose gel in a dose of 5 * 10(4) of viable cells per 1 cm(2) of the burn. The animals were removed from the experiment on day 21 after the treatment.The CrHFC use alone and with AuNPs to the surface of burns stimulated the wound healing compared with the control. The effect of using CrHFC was less pronounced compared to the CrHFC application with AuNPs. It was reflected in a slower recovery of burns and moderate lymphocytic infiltration of granulation tissue. Immunofluorescent analysis emphasized that the use of CrHFC with AuNPs accelerated the skin synthetic processes and was helpful in recovering type I and III collagen content on day 21 after therapy.The results were likely related primarily to the unique structure and antimicrobial properties of AuNPs. Our experimental study of the effect of CrHFC with AuNPs application on regenerative processes in burns gives some pre-conditions to the following advanced bio- and nanotechnology developments. PMID- 26762264 TI - Magnetic States in Ensemble of Ferromagnetic Nanoparticles in Cu-Mn-Al Alloy. AB - Two Cu-Mn-Al samples of different compositions were studied: one exhibiting martensitic transformation, another without structural transition. X-ray diffraction and magnetic measurements demonstrate that different magnetic behaviors of alloys originate from different concentrations and sizes of ferromagnetic nanoparticles, which appear after solid solution decomposition.Estimation of magnetic moments of ferromagnetic nanoparticles from magnetization curves was performed using Langevin function and compared to those obtained from X-ray examination. Granular systems are known to show giant magnetoresistance. Therefore, magnetoresistance of Cu-Mn-Al melt-spun ribbons after different aging times was measured. The study has shown that increase in the concentration of Mn atoms and time of aging in Cu-Mn-Al alloy leads to an increase in the amount of precipitated phase appearing as ferromagnetic nanoparticles. PMID- 26762265 TI - Iron-Doped (La,Sr)MnO3 Manganites as Promising Mediators of Self-Controlled Magnetic Nanohyperthermia. AB - Fe-doped La0.77Sr0.23Mn1 - y Fe y O3 nanoparticles have been synthesized by sol gel method, and ceramic samples based on them were sintered at 1613 K. Crystallographic and magnetic properties of obtained nanoparticles and ceramic samples have been studied. It has been established that cell volume for nanoparticles increases with growing of iron content, while this dependence displays an opposite trend in the case of ceramic samples. Mossbauer investigations have shown that in all samples, the oxidation state of iron is +3. According to magnetic studies, at room temperature, both nanoparticles and ceramic samples with y <= 0.06 display superparamagnetic properties and samples with y >= 0.08 are paramagnetic. Magnetic fluids based on La0.77Sr0.23Mn1 - y Fe y O3 nanoparticles and aqua solution of agarose have been prepared. It has been established that heating efficiency of nanoparticles under an alternating magnetic field decreases with growing of iron content. PMID- 26762266 TI - "Sometimes we can't fix things": a qualitative study of health care professionals' perceptions of end of life care for patients with heart failure. AB - BACKGROUND: Although heart failure has a worse prognosis than some cancers, patients often have restricted access to well-developed end of life (EoL) models of care. Studies show that patients with advanced heart failure may have a poor understanding of their condition and its outcome and, therefore, miss opportunities to discuss their wishes for EoL care and preferred place of death. We aimed to explore the perceptions and experiences of health care professionals (HCPs) working with patients with heart failure around EoL care. METHODS: A qualitative in-depth interview study nested in a wider ethnographic study of unplanned admissions in patients with heart failure (HoldFAST). We interviewed 24 HCPs across primary, secondary and community care in three locations in England, UK - the Midlands, South Central and South West. RESULTS: The study revealed three issues impacting on EoL care for heart failure patients. Firstly, HCPs discussed approaches to communicating with patients about death and highlighted the challenges involved. HCPs would like to have conversations with patients and families about death and dying but are aware that patient preferences are not easy to predict. Secondly, professionals acknowledged difficulties recognising when patients have reached the end of their life. Lack of communication between patients and professionals can result in situations where inappropriate treatment takes place at the end of patients' lives. Thirdly, HCPs discussed the struggle to find alternatives to hospital admission for patients at the end of their life. Patients may be hospitalised because of a lack of planning which would enable them to die at home, if they so wished. CONCLUSIONS: The HCPs regarded opportunities for patients with heart failure to have ongoing discussions about their EoL care with clinicians they know as essential. These key professionals can help co-ordinate care and support in the terminal phase of the condition. Links between heart failure teams and specialist palliative care services appear to benefit patients, and further sharing of expertise between teams is recommended. Further research is needed to develop prognostic models to indicate when a transition to palliation is required and to evaluate specialist palliative care services where heart failure patients are included. PMID- 26762267 TI - MiR-548c impairs migration and invasion of endometrial and ovarian cancer cells via downregulation of Twist. AB - BACKGROUND: MicroRNAs (miRNAs) are a class of small non-coding RNAs, which post transcriptionally repress the expression of genes involved in cancer initiation and progression. Although some miRNAs that target many signaling pathways (also called universe miRNAs) are supposed to play a global role in diverse human tumors, their regulatory functions in gynecological cancers remain largely unknown. We investigated the biological role and underlying mechanism of miR-548c (one universe miRNA) in endometrial and ovarian cancer. METHODS: The effects of miR-548c overexpression on cell proliferation, migration and invasion were studied in endometrial and ovarian cancer cells. TWIST1 (Twist) was identified as a direct miR-548c target by western blot analysis and luciferase activity assay. The expression of miR-548c and Twist were examined by qRT-PCR in endometrial and ovarian cancer tissues. RESULTS: Here, we report that miR-548c is down-regulated in endometrial and ovarian cancer tissues when compared to normal tissues, and our meta-analysis reveal that decreased miR-548c expression correlates with poor prognosis in endometrial cancer patients. We show that in endometrial and ovarian cancer cells, ectopic expression of miR-548c significantly inhibits whereas knockdown of miR-548c dramatically induces cancer cell proliferation, migration and invasion. By using luciferase reporter assay, we demonstrate that Twist, a known oncogene in endometrial and ovarian cancers, is a direct target of miR 548c. Furthermore, the expression of Twist partially abrogates the tumor suppressive effects of miR-548c on cell migration and invasion. CONCLUSION: These findings suggest that miR-548c directly downregulates Twist, and provide a novel mechanism for Twist upregulation in both endometrial and ovarian cancers. The use of miR-548c may hold therapeutic potential for the treatment of Twist overexpressing tumors. PMID- 26762268 TI - Sphingosine-1-phosphate reduces ischaemia-reperfusion injury by phosphorylating the gap junction protein Connexin43. AB - AIM: Increasing evidence points to lipoprotein composition rather than reverse cholesterol transport in the cardioprotective properties of high-density lipoproteins (HDLs). HDL binding to receptors at the surface of cardiomyocytes activates signalling pathways promoting survival, but downstream targets are largely unknown. Here, we investigate the pathways by which the sphingosine-1 phosphate (S1P) constituent of HDL limits cell death induced by cardiac ischaemia reperfusion (I/R). METHODS AND RESULTS: Apolipoprotein M (ApoM) transgenic (Apom Tg) mice, in which plasma S1P is increased by 296%, and wild-type (WT) mice were subjected to in vivo I/R. Infarct size, neutrophil infiltration into the infarcted area, and serum Troponin I were less pronounced in Apom-Tg mice. In vitro experiments suggest that this cardioprotection depends on direct effects of S1P on cardiomyocytes, whereas leucocyte recruitment seems only indirectly affected. Importantly, short-term S1P treatment at the onset of reperfusion was sufficient to reduce I/R injury in isolated perfused hearts. Mechanistic in vitro and ex vivo studies revealed that 5 min of S1P treatment induced phosphorylation of the gap junction protein Connexin43 (Cx43) on Serine368 (S368), which was mediated by S1P2 and S1P3, but not by S1P1, receptors in cardiomyocytes. Finally, S1P-induced reduction of infarct size after ex vivo I/R was lost in hearts of mice with a truncated C-terminus of Cx43 (Cx43(K258/KO)) or in which the S368 is mutated to a non-phosphorylatable alanine (Cx43(S368A/S368A)). CONCLUSION: Our study reveals an important molecular pathway by which modulating the apoM/S1P axis has a therapeutic potential in the fight against I/R injury in the heart. PMID- 26762269 TI - TBX5 mutations contribute to early-onset atrial fibrillation in Chinese and Caucasians. AB - AIMS: Atrial fibrillation (AF) is a common arrhythmia with an important heritable aspect. The genetic factors underlying AF have not been fully elucidated. METHODS AND RESULTS: We screened six candidate genes (CAV1, KCNJ2, KCNQ1, NKX2.5, PITX2, and TBX5) for novel mutations in 139 patients of Chinese descent with early-onset AF and 576 controls. Four missense TBX5 mutations, p.R355C, p.Q376R, p.A428S, and p.S372L, were identified in evolutionarily conserved regions. We did not find any mutations in CAV1, KCNJ2, KCNQ1, NKX2.5, and PITX2. These mutations increased the expression of atrial natriuretic peptide (ANP) and connexin-40 (CX40) in the primarily cultured rat atrial myocytes but did not alter the expression of cardiac structural genes, atrial myosin heavy chain-alpha (MHC-alpha) and myosin light chain-2alpha (MLC-2alpha). Overexpression of p.R355C developed an atrial arrhythmia suggestive of paroxysmal AF in the zebrafish model. To replicate our findings, we screened TBX5 in 527 early-onset AF cases from the Massachusetts General Hospital AF study. A novel TBX5 deletion (DeltaAsp118, p.D118del) was identified, while no TBX5 mutations were identified in 1176 control subjects. CONCLUSION: Our results provide both genetic and functional evidence to support the contribution of TBX5 gene in the pathogenesis of AF. The potential mechanism of arrhythmia may be due in part to the disturbed expression of ANP and CX40. PMID- 26762271 TI - Solitary Lymph Node Recurrence of Esophageal Squamous Cell Carcinoma: Surgical Failure or Systemic Disease? AB - BACKGROUND: Post-surgical solitary lymph node recurrence (SLNR) may be a characteristic of esophageal squamous cell carcinoma (ESCC). METHODS: Among 402 patients who underwent curative resection for ESCC between 2003 and 2010, we retrospectively reviewed the cases of 148 patients who developed disease recurrence. RESULTS: Among the 148 reviewed cases, 24 patients (16.2 %) developed SLNR and 124 (83.8 %) developed non-SLNR. Clinicopathological background did not differ between the two groups. Five-year overall survival was 37.8 % among the 22 patients with SLNR who received local treatment (surgery or radiation) with or without systemic chemotherapy, compared with only 2.5 % among patients with non SLNR (p = 0.0002). Among the 24 cases of SLNR, 18 were localized inside the surgical field (i.e. the standard three-field regional lymph nodes), while six occurred outside of the surgical field (abdominal para-aortic nodes in four cases and mediastinum in two cases). Notably, of the six patients with SLNR outside of the surgical field, four survived without additional recurrence after SLNR development. Among patients with SLNR, survival was not associated with tumor location, tumor size, or time to recurrence. Initial tumor stage was not associated with SLNR incidence but was identified as a predictor of long-term survival among patients with SLNR. CONCLUSIONS: SLNR developed inside and outside of the surgical field, showing a relatively favorable prognosis with local treatment regardless of location. SLNR outside of the surgical field may actually be localized disease in ESCC. PMID- 26762273 TI - Metformin as firstline treatment for type 2 diabetes: are we sure? PMID- 26762272 TI - Risk Factors for the Loss of Lean Body Mass After Gastrectomy for Gastric Cancer. AB - BACKGROUND: Lean body mass loss after surgery, which decreases the compliance of adjuvant chemotherapy, is frequently observed in gastric cancer patients who undergo gastrectomy for gastric cancer. However, the risk factors for loss of lean body mass remain unclear. METHODS: The current study retrospectively examined the patients who underwent curative gastrectomy for gastric cancer between June 2010 and March 2014 at Kanagawa Cancer Center. All the patients received perioperative care for enhanced recovery after surgery. The percentage of lean body mass loss was calculated by the percentile of lean body mass 1 month after surgery to preoperative lean body mass. Severe lean body mass loss was defined as a lean body mass loss greater than 5 %. Risk factors for severe lean body mass loss were determined by both uni- and multivariate logistic regression analyses. RESULTS: This study examined 485 patients. The median loss of lean body mass was 4.7 %. A lean body mass loss of 5 % or more occurred for 225 patients (46.4 %). Both uni- and multivariate logistic analyses demonstrated that the significant independent risk factors for severe lean body mass loss were surgical complications with infection or fasting (odds ratio [OR] 3.576; p = 0.001), total gastrectomy (OR 2.522; p = 0.0001), and gender (OR 1.928; p = 0.001). CONCLUSIONS: Nutritional intervention or control of surgical invasion should be tested in future clinical trials for gastric cancer patients with these risk factors to maintain lean body mass after gastrectomy. PMID- 26762274 TI - Sampling large geographic areas for rare species using environmental DNA: a study of bull trout Salvelinus confluentus occupancy in western Montana. AB - This study tested the efficacy of environmental DNA (eDNA) sampling to delineate the distribution of bull trout Salvelinus confluentus in headwater streams in western Montana, U.S.A. Surveys proved fast, reliable and sensitive: 124 samples were collected across five basins by a single crew in c. 8 days. Results were largely consistent with past electrofishing, but, in a basin where S. confluentus were known to be scarce, eDNA samples indicated that S. confluentus were more broadly distributed than previously thought. PMID- 26762275 TI - Development and learning of saccadic eye movements in 7- to 42-month-old children. AB - From birth, infants move their eyes to explore their environment, interact with it, and progressively develop a multitude of motor and cognitive abilities. The characteristics and development of oculomotor control in early childhood remain poorly understood today. Here, we examined reaction time and amplitude of saccadic eye movements in 93 7- to 42-month-old children while they oriented toward visual animated cartoon characters appearing at unpredictable locations on a computer screen over 140 trials. Results revealed that saccade performance is immature in children compared to a group of adults: Saccade reaction times were longer, and saccade amplitude relative to target location (10 degrees eccentricity) was shorter. Results also indicated that performance is flexible in children. Although saccade reaction time decreased as age increased, suggesting developmental improvements in saccade control, saccade amplitude gradually improved over trials. Moreover, similar to adults, children were able to modify saccade amplitude based on the visual error made in the previous trial. This second set of results suggests that short visual experience and/or rapid sensorimotor learning are functional in children and can also affect saccade performance. PMID- 26762270 TI - Atrial remodelling in atrial fibrillation: CaMKII as a nodal proarrhythmic signal. AB - CaMKII is a serine-threonine protein kinase that is abundant in myocardium. Emergent evidence suggests that CaMKII may play an important role in promoting atrial fibrillation (AF) by targeting a diverse array of proteins involved in membrane excitability, cell survival, calcium homeostasis, matrix remodelling, inflammation, and metabolism. Furthermore, CaMKII inhibition appears to protect against AF in animal models and correct proarrhythmic, defective intracellular Ca(2+) homeostasis in fibrillating human atrial cells. This review considers current concepts and evidence from animal and human studies on the role of CaMKII in AF. PMID- 26762278 TI - Sources of bias in the perception of heading in the presence of moving objects: Object-based and border-based discrepancies. AB - The focus of expansion (FoE) specifies the heading direction of an observer during self-motion, and experiments show that humans can accurately perceive their heading from optic flow. However, when the environment contains an independently moving object, heading judgments may be biased. When objects approach the observer in depth, the heading bias may be due to discrepant optic flow within the contours of the object that radiates from a secondary FoE (object based discrepancy) or by motion contrast at the borders of the object (border based discrepancy). In Experiments 1 and 2, we manipulated the object's path angle and distance from the observer to test whether the heading bias induced by moving objects is entirely due to object-based discrepancies. The results showed consistent bias even at large path angles and when the object moved far in depth, which is difficult to reconcile with the influence of discrepant optic flow within the object. In Experiment 3, we found strong evidence that the misperception of heading can also result from a specific border-based discrepancy ("pseudo FoE") that emerges from the relative motion between the object and background at the trailing edge of the object. Taken together, the results from the present study support the idea that when moving objects are present, heading perception is biased in some conditions by discrepant optic flow within the contours of the object and in other conditions by motion contrast at the border (the pseudo FoE). Center-weighted spatial pooling mechanisms in MSTd may account for both effects. PMID- 26762277 TI - Ocular-following responses to white noise stimuli in humans reveal a novel nonlinearity that results from temporal sampling. AB - White noise stimuli are frequently used to study the visual processing of broadband images in the laboratory. A common goal is to describe how responses are derived from Fourier components in the image. We investigated this issue by recording the ocular-following responses (OFRs) to white noise stimuli in human subjects. For a given speed we compared OFRs to unfiltered white noise with those to noise filtered with band-pass filters and notch filters. Removing components with low spatial frequency (SF) reduced OFR magnitudes, and the SF associated with the greatest reduction matched the SF that produced the maximal response when presented alone. This reduction declined rapidly with SF, compatible with a winner-take-all operation. Removing higher SF components increased OFR magnitudes. For higher speeds this effect became larger and propagated toward lower SFs. All of these effects were quantitatively well described by a model that combined two factors: (a) an excitatory drive that reflected the OFRs to individual Fourier components and (b) a suppression by higher SF channels where the temporal sampling of the display led to flicker. This nonlinear interaction has an important practical implication: Even with high refresh rates (150 Hz), the temporal sampling introduced by visual displays has a significant impact on visual processing. For instance, we show that this distorts speed tuning curves, shifting the peak to lower speeds. Careful attention to spectral content, in the light of this nonlinearity, is necessary to minimize the resulting artifact when using white noise patterns undergoing apparent motion. PMID- 26762276 TI - Disparity vergence responses before versus after repetitive vergence therapy in binocularly normal controls. AB - This study sought to determine whether significant changes would be observed between vergence eye movements before and after 12 hr of repetitive vergence therapy (1 hr per day on different days) in subjects with normal binocular vision compared to controls. Disparity vergence responses from 23 subjects were studied. An assessment protocol that minimized the influence of the near dissociated phoria on the disparity vergence system was designed. The following parameters were quantified for the responses: latency, time to peak velocity, settling time, peak velocity, and accuracy (difference between the response and stimulus amplitudes). The following outcomes were observed when comparing the results after vergence therapy to the baseline measurements: (a) near point of convergence and near dissociated phoria did not significantly change (p > 0.15); (b) latency, time to peak velocity, and settling time significantly decreased (p <= 0.01); and (c) accuracy significantly improved (p < 0.01). Results support that vergence peak velocity is dependent on the subject's near dissociated phoria. The accuracy and temporal properties of vergence eye movement responses from subjects with normal binocular vision can be improved after vergence therapy. These methods can be utilized within future studies to quantitatively assess vergence therapy techniques for patients with binocular dysfunction. PMID- 26762279 TI - Modular Design of Poly(norbornenes) for Organelle-Specific Imaging in Tumor Cells. AB - Through modular ROMP (ring-opening metathesis polymerization) directly from monomeric norbornenes of bioactive peptides, rhodamine B chromophore, and PEG solubilizer, we designed and synthesized a series of water-soluble poly(norbornenes) with organelle-specific imaging capability in tumor cells. For the selection of FxrFxK, TAT, and SV40 peptide sequences, these fluorescence probes exhibited different targeting specificity toward mitochondria, lysosome, and nucleolus, respectively, based on the same poly(norbornene) backbonds. More importantly, the ROMP strategy enables selective combination from various monomers and allows programmable biofunctionalization via peptide sequence permutations, which would greatly extend the biomedical applications such as imaging, diagnosis, and therapy for these synthetic polymers. PMID- 26762280 TI - Validity and Clinical Utility of Subtyping by the Beck Depression Inventory in Women Seeking Gastric Bypass Surgery. AB - BACKGROUND: The Beck Depression Inventory (BDI) is commonly used in the screening and evaluation process with bariatric surgery candidates despite relatively limited psychometric evidence in this patient group. We examined the validity of the BDI and its clinical utility for subtyping women seeking gastric bypass surgery. METHODS: One hundred twenty-four women evaluated for gastric bypass surgery were administered the Structured Clinical Interview for DSM-IV (SCID-I/P) and completed a self-report battery of psychosocial measures including the BDI. RESULTS: Based on the SCID-I/P, 12.9 % (n = 16) met criteria for current mood disorder. Receiver operating characteristic (ROC) curve analysis revealed the BDI had a good area under the curve (0.788) for predicting SCID-I/P mood disorder diagnosis; BDI score of >15 optimized both sensitivity and specificity. Patients diagnosed with SCID-I/P mood disorders had significantly higher levels of eating disorder psychopathology, self-esteem, and shame, than those without mood disorders. Based on a BDI cut-off score of >15, 41.9 % (n = 52) were categorized as high-BDI and 58.1 % (n = 72) as low-BDI. Patients characterized as high-BDI also had significantly higher levels of all associated measures than those with low-BDI; effect sizes for the differences by BDI subtyping were generally 2-3 times greater than those observed when comparing SCID-I/P-based mood versus no mood disorder subgroups. CONCLUSIONS: In women seeking gastric bypass surgery, the BDI demonstrated limited acceptability efficiency for identifying mood disorders with a cut-point score of >15. When identifying clinical severity, however, subtyping women by BDI scores of >15 may identify a significantly more disturbed subgroup than relying on a SCID-I/P-generated mood disorder diagnosis. PMID- 26762281 TI - Proton Pump Inhibitor Prophylaxis After Gastric Bypass Does Not Cause Hypomagnesemia. AB - Proton pump inhibitor (PPI)-induced hypomagnesemia is currently a major topic. Patients undergoing Roux-en-Y gastric bypass are generally prescribed PPI prophylaxis after surgery. We investigated the prevalence of hypomagnesemia in our bariatric population. We reviewed the files of 1000 postoperative patients for serum magnesium level during PPI use. We found only five cases of hypomagnesemia, none of which was evidently related to PPI use. We conclude that the risk of hypomagnesemia during 1 year of prophylactic PPI use after Roux-en-Y gastric bypass (RYGB) is minimal and laboratory screening is probably not necessary. PMID- 26762283 TI - Nanoliposomal Growth Hormone and Sodium Nitrite Release from Silicone Fibers Reduces Thrombus Formation Under Flow. AB - Biocompatibility of artificial lungs can be improved by endothelialization of hollow fibers. Bioavailability of growth-inducing and anti-thrombotic agents on the hollow fiber-blood interface inhibits thrombosis. We investigated if nanoliposomal growth-inducing growth hormone (nGH) and anti-thrombotic sodium nitrite (nNitrite) incorporation into collagen-coating on silicone hollow fibers improves blood biocompatibility by increasing endothelial cell growth and nitrite bioavailability under flow. Nitrite production rate was assessed under varying flow conditions. Finite element (FE) modeling was used to simulate nitrite transport within the parallel-plate flow chamber, and nitrite bioavailability on the fiber-blood interface at 1-30 dyn/cm(2) shear stress. Endothelial cell number on fibers coated with nNitrite-nGH-collagen conjugate was 1.5-fold higher than on collagen-coated fibers. For collagen-coated fibers, nitrite production reached a maximum at 18 dyn/cm(2) shear stress. When fibers were coated with nNitrite-nGH collagen conjugate, nitrite production increased continuously by increasing shear stress. FE modeling revealed that nitrite concentrations at the fiber-blood interface were affected by shear stress-induced nitrite production, and diffusion/convection-induced nitrite removal. Highest nitrite concentrations and lowest thrombus deposition were observed on fibers coated with nNitrite-nGH collagen conjugate exposed to 6-12 dyn/cm(2) shear stress. In conclusion, our results suggest that nNitrite-nGH-Col conjugate coatings promote endothelialization of silicone hollow fibers in biohybrid artificial lungs. PMID- 26762284 TI - Preperitoneal pelvic packing in patients with hemodynamic instability due to severe pelvic fracture: early experience in a Korean trauma center. AB - BACKGROUND: The mortality rate of patients with hemodynamic instability due to severe pelvic fracture is reported to be 40-60% despite a multidisciplinary treatment approach. Angioembolization and external fixation of the pelvis are the main procedures used to control bleeding in these patients. Several studies have shown that preperitoneal pelvic packing (PPP) is effective for hemorrhage control, despite being small and observational in nature. The purpose of this study was to describe a Korean trauma center's early experience with PPP in unstable patients with pelvic fractures and to evaluate its effectiveness. METHODS: Between January 2012 and May 2015, 30 patients with hemodynamic instability caused by pelvic fracture were enrolled in this study. PPP has been performed in 14 patients since May 2014. Data of pelvic fracture patients with hemodynamic instability were selected from Wonju Severance Christian Hospital Pelvic Trauma Database and were analyzed retrospectively. RESULTS: Mean age and mean ISS were 60.4 +/- 18.8 years and 39.2 +/- 8.1 in 30 unstable patients with pelvic fracture. Mean SBP was 89.1 +/- 24.7 mmHg, and mean hemoglobin was 10.6 +/ 2.3 g/dL. When the non-PPP group (16 patients) and the PPP group (14 patients) were compared, there was no significant difference in the age, gender, ISS, and occurrence of associated injury (p = 0.82, p = 0.23, p = 0.92, and p = 0.60, respectively). Mortality rate due to acute hemorrhage were 37.5% in the non-PPP group and 14.3% in the PPP group. In the PPP group, three patients underwent PPP in the hybrid operating room, and a laparotomy was performed in three patients. Mean systolic blood pressure increased significantly after PPP (71.6 +/- 9.8 vs. 132.2 +/- 36.4 mmHg, p = 0.002). CONCLUSIONS: In unstable patients with pelvic fractures, PPP can be used as an effective treatment, complementary to AE, to control pelvic bleeding. PMID- 26762282 TI - The effect of Sailuotong (SLT) on neurocognitive and cardiovascular function in healthy adults: a randomised, double-blind, placebo controlled crossover pilot trial. AB - BACKGROUND: Sailuotong (SLT) is a standardised herbal medicine formula consisting of Panax ginseng, Ginkgo biloba, and Crocus sativus, and has been designed to enhance cognitive and cardiovascular function. METHODS: Using a randomised, double-blind, placebo controlled crossover design, this pilot study assessed the effect of treatment for 1 week with SLT and placebo (1 week washout period) on neurocognitive and cardiovascular function in healthy adults. Sixteen adults completed a computerised neuropsychological test battery (Compass), and had their electroencephalographic (EEG) activity and cardiovascular system function assessed. Primary outcome measures were cognitive test scores and oddball task event-related potential (ERP) component amplitudes. Secondary outcome measures were resting EEG spectral band amplitudes, and cardiovascular parameters. RESULTS: Treatment with SLT, compared to placebo, resulted in small improvements in working memory, a slight increase in auditory target (cf. nontarget) P3a amplitude, and a decrease in auditory N1 target (cf. nontarget) amplitude. There was no effect of SLT on EEG amplitude in delta, theta, alpha, or beta bands in both eyes open and eyes closed resting conditions, or on aortic and peripheral pulse pressure, and resting heartrate. CONCLUSIONS: Findings suggest that SLT has the potential to improve working memory performance in healthy adults; a larger sample size is needed to confirm this. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry Trial Registration Id: ACTRN12610000947000 . PMID- 26762285 TI - Five minutes with . . . Norman Lamb. PMID- 26762286 TI - Reproductive strategies in two inseminating species of Glandulocaudini, Mimagoniates microlepis and Mimagoniates rheocharis (Characiformes: Characidae: Stevardiinae). AB - The reproductive biology of two inseminating Glandulocaudini species, Mimagoniates microlepis and Mimagoniates rheocharis, was investigated and compared with reproductive patterns described for other inseminating and non inseminating characids, hypothesizing the evolutionary history of these reproductive traits. The long reproductive period, with higher activity in colder months, distinguishes the reproductive strategy of these species when compared with most characiforms. The M. rheocharis population was structured in two groups of males throughout the year, mature males with high gonado-somatic index (IG = 2.0 and 4.4) and immature and maturing males with low IG values (0.0 and 1.2). Mimagoniates rheocharis and M. microlepis showed the lowest absolute mean fecundities known for characids, indicating that inseminating species allocate less energy to oocyte production and reinforcing the hypothesis that insemination has an adaptive advantage, which provides a higher chance of fertilization. PMID- 26762288 TI - Proanthocyanidins in health and disease. AB - Proanthocyanidins (PAs) are the most abundant flavonoids in the human diet. Several epidemiological studies connect PA consumption and health benefits and the designation of PAs as healthy compounds started at the early stages of the 20th century. The beneficial health properties of PAs are attributed to their conjugated and colonic metabolites. Therefore, gut microbial compositions can determine the effectiveness of PAs. Reciprocally, dietary polyphenols can act as prebiotics. Recently, it has also been described that PAs modulate the circadian rhythm. Biochemical and epigenetic mechanisms, including the modulation of microRNAs, allow PAs to modulate cell functionality. PA effects in metabolic diseases are also reviewed. PMID- 26762289 TI - Validation of Procedural Codes to Identify Infants Evaluated for Serious Bacterial Infection. AB - OBJECTIVE: To validate a novel coding method using Current Procedural Terminology, Fourth Edition (CPT-4) codes for identifying infants who underwent a full evaluation for serious bacterial infection (SBI). METHODS: We performed a multicenter, retrospective examination to determine the accuracy of a combination of CPT-4 codes for blood, cerebrospinal fluid (CSF), and urine cultures to identify previously healthy infants <=90 days old admitted to a general care floor and fully evaluated for SBI. Full SBI evaluation was defined as blood, CSF, and urine cultures performed during the emergency department encounter or corresponding hospitalization. Cases were defined as infants who had codes for blood, CSF, and urine cultures (87040, 87070, and either 87086 or 87088), and these were compared with all other encounters. We validated these findings by comparing medical record documentation of blood, CSF, and urine cultures to the corresponding CPT-4 codes, with calculation of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: We identified 8548 qualifying encounters, and 347 (4%) had a combination of CPT-4 codes 87040, 87070, and either 87086 or 87088. This combination had a sensitivity of 100% (95% confidence interval, 98.9-100) and specificity of 98.2% (95% confidence interval, 97.3-98.8) for identifying infants who underwent full SBI evaluation for an unknown source. CONCLUSIONS: CPT-4 codes provide an accurate means to identify infants who underwent complete SBI evaluation. PMID- 26762290 TI - Hydrogel for Simultaneous Tunable Growth Factor Delivery and Enhanced Viability of Encapsulated Cells in Vitro. AB - Poor cell survival in vitro and in vivo is one of the key challenges in tissue engineering. Prosurvival therapeutic proteins, such as insulin-like growth factor 1 (IGF-1), can promote cell viability but require controlled delivery systems due to their short half-lives and rapid clearance. Biocompatible materials are commonly used for drug delivery platforms or to encapsulate cells for increased viability, but few materials have been used for both applications simultaneously. In this work, we present a dual-use platform. A blend of hyaluronan and methylcellulose, known to promote cell survival, was covalently modified with Src homology 3 (SH3)-binding peptides and demonstrated tunable, affinity-based release of the prosurvival fusion protein SH3-IGF-1. The material also significantly increased the viability of retinal pigment epithelium cells under anchorage-independent conditions. This novel platform is applicable to a broad range of cells and protein therapeutics and is a promising drug delivery/cell transplantation strategy to increase the viability of both exogenous and endogenous cells in tissue engineering applications. PMID- 26762287 TI - Knowledge and factors determining choice of contraception among Singaporean women. AB - INTRODUCTION: The study aimed to assess the level of awareness and knowledge of contraception among women in Singapore, and identify the factors that influence contraception choice. METHODS: We conducted a cross-sectional survey of 259 female patients, aged 21-49 years, who attended the Obstetrics and Gynaecology Clinic at National University Hospital, Singapore. An original questionnaire on nine contraceptive methods was used. Respondents who had >= 2 correct answers for a method (out of four questions) were considered to have good knowledge of the method. Participants were asked to rate factors known to influence contraceptive choice as important or not important. RESULTS: Awareness of the following methods was high: condom (100.0%), oral contraception pill (89.2%), tubal ligation (73.0%) and copper intrauterine device (IUD) (72.2%). The women were least aware of hormonal IUD (24.3%). Women who were parous, had a previous abortion, had completed their family or used contraception previously were more likely to have a higher awareness of contraception. 89.2% of the women had good knowledge of the condom; among those aware of hormonal IUD, only 46.0% had good knowledge of it. Women who had used hormonal IUD and the condom were more likely to have good knowledge of them. Many rated efficacy (90.5%) and a healthcare professional's advice (90.1%) as important in contraceptive choice. Few considered peer influence (21.0%) and cultural practices (16.3%) to be important. CONCLUSION: Women in Singapore have poor awareness and knowledge of contraception, especially long-acting reversible methods. More effective ways are needed to educate women about contraceptive methods. PMID- 26762291 TI - Venous access for hematopoietic progenitor cell collection: An international survey by the ASFA HPC donor subcommittee. AB - PURPOSE: Hematopoietic Progenitor Cell (HPC) collection by apheresis is performed in patients and donors to obtain HPCs for transplantation. Although studies have shown these procedures to be safe, successful collection cannot be performed without establishment of venous access. This project's objective was to ascertain the current practices of donor vein assessment and central venous catheter (CVC) usage. METHODS: The American Society for Apheresis (ASFA) HPC subcommittee created an electronic survey about precollection vein assessment and line placement, care, and removal in autologous and allogeneic donors. It was distributed to >5,000 possible participants, with one response analyzed per institution. RESULTS: One hundred centers performing autologous and/or allogeneic procedures provided adequate responses for analysis. Donor vein assessment is most often performed by apheresis staff more than 1 week prior to collection. For patients with questionable access, the next step performed most often is secondary assessment for autologous procedures and CVC placement for allogeneic procedures. Most centers use interventional radiology to place CVCs in jugular veins on collection day with placement verification through electronic medical records. Verbal and written postinsertion CVC care instructions are routinely provided. The apheresis team frequently provides postinsertion CVC care for autologous patients. Heparin is used most often for CVC lock. When used, tissue plasminogen activator is usually instilled for up to 60 min. CONCLUSION: These data summarize the largest single survey of donor vein assessment at institutions performing HPC collections by apheresis. The variations identified in donor venous access practice warrant further investigation and consensus to establish best practices. J. Clin. Apheresis 31:529-534, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26762294 TI - AFLP-Based Analysis of Genetic Diversity, Population Structure, and Relationships with Agronomic Traits in Rice Germplasm from North Region of Iran and World Core Germplasm Set. AB - Analysis of the genetic diversity and population structure of crops is very important for use in breeding programs and for genetic resources conservation. We analyzed the genetic diversity and population structure of 47 rice genotypes from diverse origins using amplified fragment length polymorphism (AFLP) markers and morphological characters. The 47 genotypes, which were composed of four populations: Iranian native varieties, Iranian improved varieties, International Rice Research Institute (IRRI) rice varieties, and world rice collections, were analyzed using ten primer combinations. A total of 221 scorable bands were produced with an average of 22.1 alleles per pair of primers, of which 120 (54.30%) were polymorphic. The polymorphism information content (PIC) values varied from 0.32 to 0.41 with an average of 0.35. The high percentage of polymorphic bands (%PB) was found to be 64.71 and the resolving power (R p) collections were 63.36. UPGMA clustering based on numerical data from AFLP patterns clustered all 47 genotypes into three large groups. The genetic similarity between individuals ranged from 0.54 to 0.94 with an average of 0.74. Population genetic tree showed that Iranian native cultivars formed far distant cluster from the other populations, which may indicate that these varieties had minimal genetic change over time. Analysis of molecular variance (AMOVA) revealed that the largest proportion of the variation (84%) to be within populations showing the inbreeding nature of rice. Therefore, Iranian native varieties (landraces) may have unique genes, which can be used for future breeding programs and there is a need to conserve this unique diversity. Furthermore, crossing of Iranian genotypes with the genetically distant genotypes in the other three populations may result in useful combinations, which can be used as varieties and/or lines for future rice breeding programs. PMID- 26762293 TI - Microfluidic Controlled Mass-Transfer and Buckling for Easy Fabrication of Polymeric Helical Fibers. AB - Microfluidic fabrication of helical microfibers is still a big challenge. The reason is that this always includes designing the necessary geometrical channels and chemical conditions to first form a flowing liquid jet, which has to be continually reacting and rapidly evolving in time from viscous liquid to a flexible solid to maintain the helical structure inside the microfluidic channels. In this report, dextran aqueous solution and liquid PEG400 are infused separately into the inner and outer channels of a simple single emulsion microfluidic device, respectively. The formed two phase stream then enters a widening collection tube, where automatically formation of dextran helical fiber happened due to water shifting and widening of the channel cooperatively induced buckling. Various experimental conditions that influence the amplitudes, wavelengths, and diameters of the formed helical fibers are discussed. PMID- 26762292 TI - How do case presentation teaching methods affect learning outcomes?--SNAPPS and the One-Minute preceptor. AB - BACKGROUND: Various techniques have been developed to enable preceptors to teach residents effectively in outpatient settings to promote active learning, including SNAPPS and the One-Minute Preceptor (OMP). This study aimed to ascertain the differences between SNAPPS and the OMP in case presentation content and learner evaluation when used to teach residents about case presentation. METHODS: From 2011 to 2013, participants were 71 junior clinical residents employed in two hospitals for clinical training. They were randomly allocated to two groups, one using SNAPPS and the other the OMP. From recorded discussions, the "differential diagnoses", "questions and uncertainties", "treatment plans", and "learning issues" were counted. Also, a self-evaluation form was distributed at the end of the study to evaluate the residents' satisfaction with the case presentation. RESULTS: Members of the SNAPPS group used significantly more meaning units related to questions and uncertainties compared with those of the OMP group (P < 0.001). Self-evaluation sheets revealed that members of the SNAPPS group had significantly higher positive responses than those of the OMP group in terms of the following evaluations: "It was easy to bring up questions and uncertainties" (P = 0.046), "It was easy to present the case efficiently" (P = 0.002), "It was easy to present the case in the sequence given" (P = 0.029), and "I was able to give an in-depth case presentation" (P = 0.005). CONCLUSIONS: SNAPPS may induce more meaning units related to questions and uncertainties and give more satisfaction to residents than the OMP. PMID- 26762296 TI - Sixty seconds on . . . alcohol guidelines. PMID- 26762295 TI - Differential responses to environmental challenge by common carp Cyprinus carpio highlight the importance of coping style in integrative physiology. AB - Common carp Cyprinus carpio displaying proactive or reactive stress coping styles were acclimated to two environmental regimes (low oxygen and low temperature), and selected groups were tested for response to an inflammatory challenge (Escherichia coli lipopolysaccharide, LPS). Plasma glucose and lactate levels were measured, as were selected C. carpio-specific messenger (m)RNA transcript abundance, including cortisol receptor (CR), enolase (ENO), glyceraldehyde 3 phosphate dehydrogenase (GAPDH) and interleukin-1-beta (IL1beta) was measured in individual whole brain samples. Basal levels (in sham injected fish held in normoxic conditions at 25 degrees C) of plasma lactate and glucose differed between coping styles, being significantly lower in proactive individuals. Both variables increased in response to LPS challenge, with the exception of plasma glucose in reactive fish held in hypoxia. Baseline levels of gene expression under control conditions were significantly different for GAPDH between behavioural phenotypes. The responses to experimental challenge were sometimes diametrically opposed between stress-coping styles in a transcript-specific manner. For CR and GAPDH, for example, the response to LPS injection in hypoxia were opposite between proactive and reactive animals. Proactive fish showed decreased CR and increased GAPDH, whereas reactive showed the opposite response. These results further highlight that screening for stress-coping styles prior to experiments in adaptive physiology can significantly affect the interpretation of data obtained. Further, this leads to a more finely tuned analytical output providing an improved understanding of variation in individual responses to both environmental and inflammatory challenge. PMID- 26762297 TI - Extracellular calcium regulates protein tyrosine phosphorylation through calcium sensing receptor (CaSR) in stallion sperm. AB - Protein tyrosine phosphorylation (PY), a hallmark of sperm capacitation, is inhibited by extracellular calcium in stallion sperm. The objective of this study was to determine the presence and influence of the calcium-sensing receptor (CaSR) in this phenomenon. First, the presence of the CaSR was demonstrated in stallion sperm. We then tested its function in these gametes using its inhibitor NPS2143 or its agonist AC34356. Sperm were capacitated for 4 hr in modified Whitten's medium with 25 mM bicarbonate plus NPS2143 and 2.4 mM calcium or AC34356 alone, followed by analysis of PY. Inhibition of CaSR with NPS2143 prevented the calcium-dependent PY inhibition in a dose-dependent manner (5, 10, and 15 MUM) whereas AC34356 (100 MUM) inhibited PY similarly to calcium. Stallion sperm motility and viability significantly decreased in presence of 15 MUM of NPS2143 whereas only sperm motility decreased with 100 MUM of AC34356. CaSR function was also studied in the complete absence of calcium by including 2 mM ethylene glycol tetraacetic acid (EGTA); under these conditions, AC34356 again inhibited PY, but this time induced a significant increase in sperm motility. Inhibition of calmodulin by W-7 did not recover the AC34356-mediated PY inhibition. When stallion sperm were incubated under capacitating conditions (calcium, bicarbonate, plus bovine serum albumin) at elevated pH (7.9 or 8.5) AC34356 did not block PY. These results thus elucidate the effect of extracellular conditions on the regulation of CaSR, and point to its modulatory role on stallion sperm PY, motility, and viability. Mol. Reprod. Dev. 83: 236 245, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26762298 TI - CORR Insights(r): What Are the Long-term Results of MUTARS(r) Modular Endoprostheses for Reconstruction of Tumor Resection of the Distal Femur and Proximal Tibia? PMID- 26762300 TI - Large-magnitude Pelvic and Retroperitoneal Tissue Damage Predicts Organ Failure. AB - BACKGROUND: Pelvic and retroperitoneal trauma is a major cause of morbidity and mortality in multiply injured patients. The Injury Severity Score (ISS) has been criticized for underrepresenting and inaccurately defining mechanical injury. The influence of pelvic injury volume on organ dysfunction and multiple organ failure (MOF) has not been described. Through the use of CT, this investigation sought to precisely define volumes of mechanical tissue damage by anatomic region and examine its impact on organ failure. QUESTIONS/PURPOSES: (1) Do patients with MOF have a greater volume of pelvic and retroperitoneal tissue damage when compared with those without MOF? (2) In patients who sustained pelvic trauma, does the magnitude of pelvic injury differ in patients with MOF? (3) Does the magnitude of organ dysfunction correlate with pelvic tissue damage volume? METHODS: Seventy four multiply injured patients aged 18 to 65 years with an ISS >= 18 admitted to the intensive care unit for a minimum of 6 days with complete admission CT scans were analyzed. Each identifiable injury in the head/neck, chest, abdomen, and pelvis underwent volumetric determination using CT to generate regional tissue damage volume scores. Primary outcomes were the development of MOF as measured by the Denver MOF score and the degree of organ dysfunction by utilization of the Sequential Organ Failure Assessment (SOFA) score. Mean pelvic and retroperitoneal tissue damage volumes were compared in patients who developed MOF and those who did not develop MOF using Student's t-test. Among patients who sustained pelvic injuries, we compared mean volume of tissue damaged in patients who developed MOF and those who did not. We assessed whether there was a correlation between organ dysfunction, as measured by the SOFA score as a continuous variable, and the volume of pelvic and retroperitoneal tissue damage using the Pearson product moment correlation coefficient. RESULTS: The average volume of tissue damage was greater in patients with MOF when compared with those without (MOF: 685.667 +/- 1081.344; non-MOF: 195.511 +/- 381.436; mean difference 490.156 cc [95% confidence interval {CI}, 50.076-930.237 cc], p = 0.030). Among patients who sustained pelvic injuries, those with MOF had higher average tissue damage volumes than those without MOF (MOF: 1322.000 +/- 1197.050; non-MOF: 382.750 +/- 465.005; mean difference 939.250 [95% CI, 229.267-1649.233], p = 0.013). Organ dysfunction (SOFA score) correlated with higher volumes of pelvic tissue damage (r = 0.570, p < 0.001). CONCLUSIONS: This investigation demonstrated that greater degrees of pelvic and retroperitoneal tissue damage calculated from injury CT scans in multiply injured patients is associated with more severe organ dysfunction and an increased risk of developing MOF. Early identification of polytrauma patients at risk of MOF allows clinicians to implement appropriate resuscitative strategies early in the disease course. Improved stratification of injury severity and a patient's anticipated clinical course may aid in the planning and execution of staged orthopaedic interventions. Future avenues of study should incorporate the ischemic/hypoperfusion component of pelvic injury in conjunction with the mechanical component presented here for improved stratification of multiply injured patients at higher risk of MOF. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 26762299 TI - What Is the Frequency of Noise Generation in Modern Knee Arthroplasty and Is It Associated With Residual Symptoms? AB - BACKGROUND: Prior investigations have recognized the presence of patient perceived noise generation after total knee arthroplasty (TKA). However, questions remain regarding its overall frequency after both TKA and unicompartmental knee arthroplasty (UKA) as well as with respect to its association with demographic and prosthesis-related factors and its association with patient-reported outcomes. QUESTIONS/PURPOSES: The purposes of this study were (1) to determine the frequency with which patients report noise coming from the knee after TKA or UKA; (2) to identify patient and prosthesis-related factors associated with noise generation; and (3) to ascertain whether noise coming from the knee is associated with residual symptoms after knee arthroplasty. METHODS: A five-center survey study was designed to identify patient-perceived noise and to quantify the degree of residual symptoms and functional deficits in patients after TKA or UKA. Data were collected by an independent, third-party survey center, which administered questions about residual symptoms, function, and pre- and postoperative activity levels. Patients meeting prespecified inclusion criteria were specifically questioned regarding perceived noises from their knee within the last 30 days; those who reported hearing noises sometimes, often, or extremely often were categorized as positive. We retrospectively identified 2671 patients who underwent TKA and 744 patients who underwent UKA and who met inclusion criteria; the final survey population included 1580 patients who underwent TKA and 476 patients who underwent UKA (68% response rate). TKA implant types included cruciate-retaining (59%), posterior-stabilized (16%), rotating platform (13%), gender-specific (7%), and high-flex (5%). Differences in baseline demographic variables were accounted for using multiple logistic regression statistical analyses. Chi square analyses were used to compare the frequency of residual symptoms in those patients with and without noise generation. RESULTS: Overall, 27% (557 of 2056; 95% confidence interval [CI], 25-29) of all patients undergoing knee arthroplasty reported hearing grinding, popping, or clicking from their operative knee in the last 30 days. Men (odds ratio [OR], 1.3; 95% CI, 1.0 1.6; p = 0.02) and younger patients (chi2 [df = 7] = 67.3; p < 0.001) were more likely to report noise generation. After controlling for potential confounding variables, noise generation was more common after TKA (29%) than UKA (21%; OR, 1.5; 95% CI, 1.2-2.0; p < 0.001). Among TKA designs, the likelihood of noise generation was greater in posterior-stabilized (41%; OR, 2.5; 95% CI, 1.8-3.7; p < 0.001), rotating-platform (45%; OR, 2.8; 95% CI, 1.9-4.2; p < 0.001), and gender-specific (36%; OR, 2.0; 95% CI, 1.2-3.2; p = 0.007) designs than in cruciate-retaining (23%) knees. Patient-perceived noise generation was associated with residual symptoms, including difficulty getting in and out of a chair (38% versus 25%, p < 0.001), limp (39% versus 25%, p < 0.001), swelling (42% versus 24%, p < 0.001), and stiffness (40% versus 23%, p < 0.001) compared with those who did not report noise generation after TKA. CONCLUSIONS: Patients frequently perceive noises coming from the knee after arthroplasty, more so in TKA than UKA. Patients reporting noises from the knee were more likely to report functional limitations and the presence of a limp, swelling, and stiffness. Surgeons should inform patients preoperatively of this possibility, because unmet patient expectations are known to negatively impact patient satisfaction after surgery. Subsequent investigations should focus on determining if there is a causal relationship between noise generation and residual symptoms after knee arthroplasty. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26762303 TI - Trophic ecology of yellownose skate Zearaja chilensis, a top predator in the south-western Atlantic Ocean. AB - The diet and trophic level (TL ) of the yellownose skate Zearaja chilensis in the south-western Atlantic Ocean (35 degrees -54 degrees S), and how these varied in relation to body size, sex, maturity stage, depth and region were determined by analysis of stomach contents. From 776 specimens analysed, 671 (86.5%) ranging from 180 to 1190 mm total length (LT ) had prey in their stomachs. The diet was dominated by fishes, mainly the notothenioid Patagonotothen ramsayi and the Argentine hake Merluccius hubbsi. The consumption of fishes and crabs increased with increasing predator size, and these preys were more important in the north than in the south. Isopods and other crustaceans were consumed more in the south and their consumption decreased as the size of Z. chilensis increased. The TL of Z. chilensis increased with LT from 4.29 to 4.59 (mean 4.53), confirming their ecological role as a top predator. The small and large size classes exhibited a low diet overlap and the highest spatial segregation, whereas medium and large specimens had higher co-occurrence and dietary overlap indices. A clear distinction in tooth shape was noted between sexes in adult specimens, with males having longer cusps. This sexual heterodonty may be related to reproductive behaviour, increasing the grasping ability of males during courtship, because there were no differences in diet between the sexes. PMID- 26762304 TI - The effect of electronic health records adoption on patient visit volume at an academic ophthalmology department. AB - BACKGROUND: Electronic health records (EHRs) have become a mandated part of delivering health care in the United States. The purpose of this study is to report patient volume before and after the transition to EHR in an academic outpatient ophthalmology practice. METHODS: Review of patient visits per half-day and number of support staff for established faculty ophthalmologists between July and October for five consecutive years beginning the year before EHR implementation. RESULTS: Eight physicians met inclusion criteria for the study. The number of patient visits was lower in each year after EHR adoption compared to baseline p <= 0.027). Patient volume per provider was reduced an average of 16.9% over the 4 years (range 15.3-18.5%), and during the final year studied, no provider had returned to the pre-EHR number of patients per clinic session. Support staffing was unchanged (p > 0.2). CONCLUSIONS: Adoption of EHR was associated with a significantly reduced number of patient visits per clinic session in an academic setting in which support staffing remained stable. Maintaining clinic volume and access in similar settings may require use of additional staffing. PMID- 26762305 TI - Burnout among after-hours home visit doctors in Australia. AB - BACKGROUND: No previous study had ever looked at Burnout among medical practitioners involved in after-hours house calls (AHHC) in Australia. The growing popularity of AHHC and the high number of overseas-trained doctors involved in it make this a subject of both local and international significance. This study aims to assess the levels of burnout among Australian-based doctors involved in the service. METHODS: This is a quantitative, questionnaire-based survey of all the 300 doctors engaged in AHHC through the National Home Doctor Service (NHDS), Australia's largest home doctor-visit service providers. The study looked at experiences of the participants over the 12-months period from October 2013 to September 2014. The main outcome measure was the 22-item Maslach Burnout Inventory (MBI). Results were presented as Means and Frequency Percentages. RESULTS: A total of 168 valid questionnaires out of 300 were returned, giving a 56.0 % response rate. The Total Maslach Mean Scores (MMS) obtained were 15.97 for Emotional Exhaustion (EE), 3.15 for Depersonalization (DP) and 40.39 for Personal Accomplishment (PA), signifying low-level burnouts in all three dimensions of the MBI. This pattern was equally reflected when the Frequency Percentages were analyzed. With this approach, a majority (56.8%) of the responses were low-level burnout on the EE dimension, while 23.4 and 19.8% respectively reported medium and high level burnouts. On the DP dimension, 87.6, 6.3 and 6.1% of the responses were low, moderate and high level burnouts respectively, while the PA dimension recorded 86.4, 9.6 and 4.0 % respectively. Given that on the MBI scale, perceived personal accomplishment has an inverse relationship with burnout, the low-level MMS finding on the PA dimension therefore indicate a commensurate high perception of personal accomplishments. CONCLUSIONS: Burnout levels are low while perceived achievements are high among doctors involved in after-hours house calls in Australia. The survey recommends that future studies be designed to explore the real reasons behind these findings. PMID- 26762301 TI - Hedgehog signaling pathway: a novel model and molecular mechanisms of signal transduction. AB - The Hedgehog (Hh) signaling pathway has numerous roles in the control of cell proliferation, tissue patterning and stem cell maintenance. In spite of intensive study, the mechanisms of Hh signal transduction are not completely understood. Here I review published data and present a novel model of vertebrate Hh signaling suggesting that Smoothened (Smo) functions as a G-protein-coupled receptor in cilia. This is the first model to propose molecular mechanisms for the major steps of Hh signaling, including inhibition of Smo by Patched, Smo activation, and signal transduction from active Smo to Gli transcription factors. It also suggests a novel role for the negative pathway regulators Sufu and PKA in these processes. PMID- 26762306 TI - Biotinylation of the Fcgamma receptor ectodomains by mammalian cell co transfection: application to the development of a surface plasmon resonance-based assay. AB - We here report the production of four biotinylated Fcgamma receptor (FcgammaR) ectodomains and their subsequent stable capture on streptavidin-biosensor surfaces. For receptor biotinylation, we first describe an in-cell protocol based on the co-transfection of two plasmids corresponding to one of the FcgammaR ectodomains and the BirA enzyme in mammalian cells. This strategy is compared with a standard sequential in vitro enzymatic biotinylation with respect to biotinylation level and yield. Biotinylated FcgammaR ectodomains that have been prepared with both strategies are then compared by analytical ultracentrifugation and surface plasmon resonance (SPR) analyses. Overall, we demonstrate that in cell biotinylation is an interesting alternative to standard biotinylation protocol, as it requires less purification steps while yielding higher titers. Finally, biotin-tagged FcgammaRs produced with the in-cell approach are successfully applied to the development of SPR-based assays to evaluate the impact of the glycosylation pattern of monoclonal antibodies on their interaction with CD16a and CD64. In that endeavor, we unambiguously observe that highly galactosylated trastuzumab (TZM-gal), non-glycosylated trastuzumab (TZM-NG), and reference trastuzumab are characterized by different kinetic profiles upon binding to CD16a and CD64 that had been captured at the biosensor surface via their biotin tag. More precisely, while TZM-NG binding to CD16a was not detected, TZM-gal formed a more stable complex with CD16a than our reference TZM. In contrast, both glycosylated TZM bound to captured CD64 in a stable and similar fashion, whereas the interaction of their non-glycosylated form with CD64 was characterized by a higher dissociation rate. PMID- 26762302 TI - Decision for cell fate: deubiquitinating enzymes in cell cycle checkpoint. AB - All organs consisting of single cells are consistently maintaining homeostasis in response to stimuli such as free oxygen, DNA damage, inflammation, and microorganisms. The cell cycle of all mammalian cells is regulated by protein expression in the right phase to respond to proliferation and apoptosis signals. Post-translational modifications (PTMs) of proteins by several protein-editing enzymes are associated with cell cycle regulation by their enzymatic functions. Ubiquitination, one of the PTMs, is also strongly related to cell cycle regulation by protein degradation or signal transduction. The importance of deubiquitinating enzymes (DUBs), which have a reversible function for ubiquitination, has recently suggested that the function of DUBs is also important for determining the fate of proteins during cell cycle processing. This article reviews and summarizes the diverse roles of DUBs, including DNA damage, cell cycle processing, and regulation of histone proteins, and also suggests the possibility for therapeutic targets. PMID- 26762309 TI - The problem of accessing psychotherapies for depression in the UK. PMID- 26762308 TI - Cardiorespiratory fitness is related to metabolic risk independent of physical activity in boys but not girls from Southern Brazil. AB - OBJECTIVE: Our aim was to determine the relationship between cardiorespiratory fitness (CRF) and metabolic risk in adolescents from Southern Brazil. METHODS: We performed a school-based cross-sectional study in 1,037 adolescents (436 boys) aged 10-16 years from Londrina, PR, Brazil. CRF was determined by 20-m shuttle run test. A continuous metabolic risk score was obtained from the mean of fasting glucose, triglycerides, high density lipoprotein, blood pressure, and waist circumference z-scores. Age, physical activity (Baecke questionnaire), body mass index (BMI; weight/stature(2) ), and somatic maturity (Mirwald method) were included as covariates in multiple linear regression analyses. RESULTS: CRF was related to metabolic risk in boys (beta = -0.02, P < 0.01) and girls (beta = 0.01, P = 0.02) after adjusting for chronological age, BMI, and somatic maturity. However, when adjusted for physical activity, CRF failed to explain metabolic risk in girls (beta = -0.01, P = 0.24). CONCLUSION: We conclude that CRF is independently and inversely related to metabolic risk in boys, but physical activity either mediates or confounds the association between CRF and metabolic risk in girls. Am. J. Hum. Biol. 28:534-538, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26762307 TI - Clinically advanced and metastatic pure mucinous carcinoma of the breast: a comprehensive genomic profiling study. AB - PURPOSE: Pure mucinous breast carcinoma (pmucBC) is a distinctive variant of breast cancer (BC) featuring an excellent overall prognosis. However, on rare occasions, pmucBC pursues an aggressive clinical course. We queried whether comprehensive genomic profiling (CGP) would uncover clinically relevant genomic alterations (CRGA) that could lead to targeted therapy treatment for patients with an advanced and metastatic form of pmucBC. METHODS: From a series of 51,238 total cancer samples, which included 5605 cases of clinically advanced BC and 22 cases of stage IV pmucBC, DNA was extracted from 40 microns of FFPE sections. Comprehensive genomic profiling was performed using a hybrid-capture, adaptor ligation-based next generation sequencing assay to a mean coverage depth of 564X. The results were analyzed for all classes of genomic alterations (GA) including base substitutions, insertions and deletions, select rearrangements, and copy number changes. Clinically relevant genomic alterations were defined as those indicating possible treatment with anti-cancer drugs on the market or in registered clinical trials. RESULTS: Samples were obtained from breast (11), lymph nodes (3), chest wall (2), liver (2), soft tissue (2), bone (1), and pleura (1). The median age of the 22 pmucBC patients was 57 years (range 32-79 years). Three pmucBCs were grade 1, 17 were grade 2, and 2 were grade 3. Twenty-one (95 %) pmucBC were ER+, 18 (82 %) were PR+, and 3 (14 %) were HER2+ by IHC and/or FISH. A total of 132 GA were identified (6.0 GA per tumor), including 53 CRGA, for a mean of 2.4 GA per tumor. Amplification of FGFR1 or ZNF703, located within the same amplicon, was found in 8 of 22 cases (36 %). This enrichment of FGFR1 amplification in 36 % of pmucBC versus 11 % of non-mucinous ER+ BC (601 cases) was significant (p < 0.005). Other frequently altered genes of interest in pmucBC were CCND1 and the FGF3/FGF4/FGF19 amplicon (27 %), often co-amplified together. ERBB2/HER2 alterations were identified in 5 pmucBC (23 %): ERBB2 amplification was found in 3 of 3 cases (100 %) that were HER2+ by IHC and/or FISH; 1 pmucBC was negative for HER2 overexpression by IHC, but positive for amplification by CGP; and 2 pmucBC harbored the ERBB2 substitutions D769Y and V777L (one sample also featured ERBB2 amplification). The enrichment of ERBB2 GA in metastatic pmucBC versus non-metastatic primary pmucBC was significant (p = 0.03). CRGA were also found in 20 additional genes including PIK3CA (5), BRCA1 (1), TSC2 (1), STK11 (1), AKT3 (1), and ESR1 (1). CONCLUSIONS: Metastatic pmucBC is a distinct form of breast cancer that features a relatively high frequency of CRGA, including a significant enrichment of FGFR1 alterations and a high frequency of ERBB2 alterations when compared with non-metastatic pmucBC. These findings suggest that CGP can identify a variety of known and emerging therapy targets that have the potential to improve outcomes for patients with clinically advanced and metastatic forms of this disease. PMID- 26762310 TI - Long-lasting deficits in hedonic and nucleus accumbens reactivity to sweet rewards by sugar overconsumption during adolescence. AB - Adolescence is a critical period characterized by major neurobiological changes. Chronic stimulation of the reward system might constitute an important factor in vulnerability to pathological development. In spite of the dramatic increase in the consumption of sweet palatable foods during adolescence in our modern societies, the long-term consequences of such exposure on brain reward processing remain poorly understood. Here, we investigated in rats the long-lasting effects of sugar overconsumption during their adolescence on their adult reactivity to the hedonic properties of sweet rewards. Adolescent rats with continuous access to 5% sucrose solution (from postnatal day 30-46) showed escalating intake. At adulthood (post-natal day 70), using two-bottle free choice tests, sucrose exposed rats showed lower intake than non-exposed rats suggesting decreased sensitivity to the rewarding properties of sucrose. In Experiment 1, we tested their hedonic-related orofacial reactions to intraoral infusion of tasty solutions. We showed that sucrose-exposed rats presented less hedonic reactions in response to sweet tastes leaving the reactivity to water or quinine unaltered. Hence, in Experiment 2, we observed that this hedonic deficit is associated with lower c-Fos expression levels in the nucleus accumbens, a brain region known to play a central role in hedonic processing. These findings demonstrate that a history of high sucrose intake during the critical period of adolescence induces long-lasting deficits in hedonic treatment that may contribute to reward-related disorders. PMID- 26762311 TI - Sequence homology of parathyroid hormone against amyloidogenic regions of proteins. PMID- 26762312 TI - Annual trauma load of the world's largest indoor skiing center. AB - PURPOSE: There is limited data on the trauma load caused by indoor skiing centers. Therefore, all patients treated at the accident and emergency department of our level I trauma center who sustained injuries at the world's largest indoor skiing center were analyzed during a 3-year period. METHODS: Business intelligence was used to identify all patients who sustained injury at SnowWorld, Landgraaf, The Netherlands, and were seen at the accident and emergency department of the Zuyderland Medical Center from January 1, 2012 till December 31, 2014. Data were collected on patient characteristics, trauma mechanism, transportation, admission, diagnostics, injury and its severity, and treatment. RESULTS: Of the 732 patients seen, 305 had a fracture and 80 a dislocation. Most patients were male snowboarders and most injuries were sustained during winter. More than 2000 X-rays and 100 CT scans were required. Seventy-two patients were admitted and immediate surgery was performed in 21 patients. Ten patients had Injury Severity Scores of 10 or higher. Snowboarders differed significantly from skiers on several parameters, e.g., 1 in 4 snowboarders seen had sustained a distal radius fracture compared to 1 in 100 skiers. CONCLUSION: Acquiring more insight into the characteristics of this specific patient population could benefit clinical care and help clinicians identify and target preventive strategies. LEVEL OF EVIDENCE: IV. PMID- 26762313 TI - Epidemiology and outcome of penetrating injuries in a Western European urban region. AB - PURPOSE: Severe life-threatening injuries in Western Europe are mostly caused by blunt trauma. However, penetrating trauma might be more common in urban regions, but their characteristics have not been fully elucidated. METHODS: Retrospective analysis of data from patients admitted to our urban university level I trauma center between 2008 and 2013 with suspicion of severe multiple injuries. Collection of data was performed prospectively using a PC-supported online documentation program including epidemiological, clinical and outcome parameters. RESULTS: Out of 2095 trauma room patients admitted over the 6-year time period 194 (9.3 %) suffered from penetrating trauma. The mean Injury Severity Score (ISS) was 12.3 +/- 14.1 points. In 62.4 % (n = 121) the penetrating injuries were caused by interpersonal violence or attempted suicide, 98 of these by stabbing and 23 by firearms. We observed a widespread injury pattern where mainly head, thorax and abdomen were afflicted. Subgroup analysis for self-inflicted injuries showed higher ISS (19.8 +/- 21.8 points) than for blunt trauma (15.5 +/- 14.6 points). In 82.5 % of all penetrating trauma a surgical treatment was performed, 43.8 % of the patients received intensive care unit treatment with mean duration of 7.4 +/- 9.3 days. Immediate emergency surgical treatment had to be performed in 8.0 vs. 2.3 % in blunt trauma (p < 0.001). Infectious complications of the penetrating wounds were observed in 7.8 %. CONCLUSIONS: Specific characteristics of penetrating trauma in urban regions can be identified. Compared to nationwide data, penetrating trauma was more frequent in our collective (9.3 vs. 5.0 %), which may be due to higher crime rates in urban areas. Especially, self-inflicted penetrating trauma often results in most severe injuries. PMID- 26762314 TI - Soft matrices inhibit cell proliferation and inactivate the fibrotic phenotype of deep endometriotic stromal cells in vitro. AB - STUDY QUESTION: Can deep infiltrating endometriotic stromal cells (DES) sense changes in extracellular matrix (ECM) stiffness and respond to them? SUMMARY ANSWER: Soft matrices inhibit cell proliferation and inactivate the fibrotic phenotype of DES in vitro. WHAT IS KNOWN ALREADY: Deep infiltrating endometriosis (DIE) is characterized histologically by dense fibrous tissue. Tissue stiffening is a hallmark of fibrosis. Studies show that matrix stiffness is involved in the progression of numerous diseases, including cancer and fibrosis. However, no studies to date have investigated whether tissue stiffening could influence cell behavior in DIE. Previous in vitro studies typically analyzed cells grown on rigid plastic or glass substrates with stiffness in the gigapascal (gPa) range, which is much stiffer than that occurring in vivo. To investigate how changes in ECM stiffness affect the behavior of DES, it is critical to model in vivo tissue compliance conditions in vitro. STUDY DESIGN, SIZE, DURATION: For this laboratory study, paired endometrial and endometriotic samples from 40 patients who had histological evidence of DIE and endometrial samples from 23 patients without endometriosis were analyzed (uterine fibroma: n = 10, tubal infertility: n = 13). PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants were 20-37 years old and had regular menstrual cycles of 26-32 days. The abundance of F-actin, alpha smooth muscle actin (alphaSMA), Ki67, and procollagen type I in DES and endometrial stromal cells (EES) on polyacrylamide gel substrates of varying stiffness (2, 4, 8, 16 and/or 30 kPa) was determined by immunofluorescence confocal microscopy. mRNA level of type I collagen, matrix metalloproteinase-1 (MMP-1), MMP-14 and cyclin D1 was measured by real-time PCR. The cellular proliferation index (CPI), assessed as the percentage of Ki67-positive cells among the total number of nuclei stained by 4',6-diamidino-2-phenylindole (DAPI) was determined. MAIN RESULTS AND THE ROLE OF CHANCE: Increased matrix stiffness induced F-actin stress fiber formation in both EES and DES, whereas alphaSMA containing stress fibers were induced only in DES. Furthermore, increased stiffness increased the CPI in both EES (16 or 30 kPa versus 2 kPa, P < 0.05) and DES (16 or 30 kPa versus 2, 4 or 8 kPa, P < 0.05). Increased stiffness increased the percentage of procollagen I-positive cells as well as mRNA levels of type I collagen in both EES and DES in a matrix stiffness-dependent manner (2, 8 and 30 kPa) (P < 0.05). Increased stiffness also increased MMP-14 mRNA levels in EES (30 versus 2 kPa, P < 0.05), but decreased MMP-1 mRNA levels in DES in a matrix stiffness-dependent manner (2, 8 and 30 kPa; P < 0.05). Treatment with transforming growth factor (TGF)-beta1 further increased type I collagen mRNA levels in both EES and DES when compared with cells grown on a substrate of the same stiffness (2, 8 or 30 kPa, with versus without TGF-beta1, P < 0.05). Treatment with TGF-beta1 also increased MMP-1 (8 or 30 kPa, P < 0.05 versus no TGF-beta1) and MMP-14 mRNA levels (2, 8 or 30 kPa, P < 0.05 versus no TGF-beta1) in EES, but decreased MMP-1 mRNA levels (2, 8 or 30 kPa, P < 0.05 versus no TGF beta1) in DES. On a soft substrate (2 kPa), both EES and DES exhibited a small rounded morphology with diffuse labeling for F-actin. No F-actin-positive stress fibers were observed in either EES or DES grown on 2 kPa substrates. There were more Ki67-positive EES when grown on 2, 4 or 8 kPa compared with Ki67-positive DES (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: A tremendous gap exists between the present in vitro model and in vivo deep endometriotic tissues. Cell culture systems that more closely mimic the cellular complexity typical of in vivo endometriotic tissues are required to develop novel strategies for treatment of DIE. A disadvantage of polyacrylamide is its cytotoxicity but in the two dimensional culture models used here, where cells are seeded above the polyacrylamide gel, this should not have a major impact. Finally, the soft substrates we used in vitro (2 and 4 kPa) may represent the elasticity of the endometrium in vivo, however, currently there are no data regarding tissue stiffness in DIE in vivo. WIDER IMPLICATIONS OF THE FINDINGS: Hormonal suppressive therapy is not usually effective for treating DIE. Interrupting the mechanical interactions between endometriotic fibroblasts and aberrant ECM may be a novel strategy for treatment of DIE. STUDY FUNDING/COMPETING INTERESTS: This study was supported in part by Karl Storz Endoscopy & GmbH (Tuttlingen, Germany). No competing interests are declared. PMID- 26762315 TI - Does age of the sperm donor influence live birth outcome in assisted reproduction? AB - STUDY QUESTION: Does age of the sperm donor have an effect on reproductive outcomes (live birth rate and miscarriage occurrence) of donor insemination or in vitro fertilization treatment using donated sperm? SUMMARY ANSWER: Live birth and miscarriage occurrence in assisted reproduction treatment using donor sperms was not found to be affected by the age of sperm donors up to 45 years old. WHAT IS ALREADY KNOWN: Literature on the effect of sperm donor age on outcome of medically assisted reproduction is scarce. Most researchers agree that semen parameters deteriorate with increasing paternal age. However, there is no substantial evidence to suggest that this deterioration adversely affects the reproductive outcomes in couples undergoing medically assisted reproduction. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study analysed 46 078 first donor insemination treatments and fresh in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles using donated sperm from 1991 to 2012. PARTICIPANTS/ DURATION/METHODS: The first fresh donor insemination and IVF/ICSI treatment cycles (46 078 treatment cycles) using donated sperm from the long-term anonymized data registry from 1991 to 2012 of the HFEA, the UK regulator, were analysed by the binary logistic modelling technique for association between sperm donor age and reproductive outcomes (live birth occurrence and miscarriage occurrence). The statistical package SPSS (version 21) was used for analysis and results were considered to be statistically significant if the P-value was <0.05. MAIN RESULTS AND THE ROLE OF CHANCE: Of 46 078 women, 84.6% (N = 38 974) underwent donor insemination treatment and the remainder, 15.4% (N = 7104), had IVF/ICSI treatment with donor sperm. The live birth occurrence decreased with increasing female age in both treatment groups; In the donor insemination treatment group, it was 11.1% in 18-34 year old women, 8.3% in 35-37 year old women and 4.7% in 38-50 year old women. The corresponding figures in the IVF/ICSI treatment group were 28.9, 22.0 and 12.9% respectively. In each of these subgroups, no evidence of declining likelihood of live birth with increasing sperm donor age was found (P > 0.05). The miscarriage occurrence (i.e. number of miscarriages per 100 women commencing treatment) was 1.3% in 18-34 year old women, 1.9% in 35-37 year old women and 1.9% in 38-50 year old women undergoing donor insemination treatment. In the sperm donation IVF/ICSI treatment group, these figures were 5.7, 8.4 and 6.8% respectively. The results were not suggestive of any unfavourable effect of advancing sperm donor age on the odds of miscarriage occurrence (P > 0.05). LIMITATIONS, REASONS FOR CAUTION: As sperm donors are a select population based on good semen indices, the generalization of results to the paternal population at large may not be possible. Although the study subgroups were controlled for female age, treatment modality and effect of previous treatment cycles, adjustments for certain potential compounding factors, such as smoking status, BMI of women and stimulation protocol used in IVF/ICSI treatment cycles, were not possible. WIDER IMPLICATIONS OF THE FINDINGS: Live birth and miscarriage occurrence following assisted reproduction weren't adversely affected by increasing sperm donor age up to 45 years. In view of the increasing demand for donor sperm, further studies may be required to ascertain the safe upper age limit for sperm donors. STUDY FUNDING/COMPETING INTERESTS: No funding was received from any individual or funding agency. NG was on a Commonwealth Scholarship for the duration of the study. The authors do not have any conflicts of interest to declare. PMID- 26762319 TI - Approach to diagnosing Lyme disease misses a large proportion of cases. PMID- 26762316 TI - i-Scan detection of minimal change esophagitis in dyspeptic patients with or without Gastroesophageal Reflux disease. AB - BACKGROUND: The association of minimal change esophagitis (MCE) with GERD is controversial. i-Scan endoscopy (SE) provides high resolution and modulation of images that may improve minimal change lesion (MCL) detection. We aimed to assess the efficacy of SE in detecting MCL in dyspeptic patients with GERD compared with patients without GERD by GerdQ or by endoscopy with 24-h pH monitoring (PHM) and in normal volunteers. METHODS: This is a cohort study conducted at a tertiary center. All dyspeptic patients were prospectively recruited. All patients completed a validated Thai version of GerdQ and then underwent endoscopy. Forty normal volunteers as a control group were recruited for endoscopy. The distal esophagus was examined by high definition endoscopy and SE sequentially. All had PHM done. GERD was diagnosed by Los Angeles classification A-D and/or by a positive PHM. MCE was diagnosed when MCL or combination of MCL was present. RESULTS: Of 174 patients, 144 completed the study protocol. After the exclusion of 6 patients, 138 remained for analysis. Overlapping GERD symptoms were found in 44.2 % and 26.8 % had confirmed GERD. Group A was comprised of 61 patients with a positive GerdQ and 77 patients in group B had a negative GerdQ. Twenty-four in group A, 28 in group B and 7 in the control group had MCE that was not significantly different. MCE in GERD was significantly higher (51.45 %) than in non-GERD (32.7 %) (p = 0.047) and in the control group (20.58 %) (p = 0.007). The sensitivity, specificity, positive predictive value, and negative predictive value of SE were 51.35 %, 67.33 %, 36.54 % and 79.06 %, respectively. CONCLUSION: In dyspeptic patients, SE detected more MCE in GERD than in non-GERD patients and in the control group. TRIAL REGISTRATION: ClinicalTrials.gov number NCT01742377. PMID- 26762317 TI - Distribution and accumulation of mercury and copper in mangrove sediments in Shenzhen, the world's most rapid urbanized city. AB - To investigate the influence of mangrove forest on heavy metal accumulation and storage in intertidal sediments, core sediments from natural mangrove, restored mangrove, and adjacent mud flat spanning the intertidal zone along the south coastline of the most heavily urbanized Deep bay, Guangdong province, China were analyzed. The average concentrations of mercury (Hg) in surface sediments of natural mangrove and restored mangrove were 172 and 151 ng g(-1), whereas those of copper (Cu) were 75 and 50 MUg g(-1), respectively. Compared to those from other typical mangrove wetlands of the world, the metal levels in Shenzhen were at median to high levels, which is consistent with the fact that Shenzhen is in high exploitation and its mangrove suffer intensive impact from human activities. Hg and Cu concentration profiles indicated a higher metal accumulation in surface layers of sediments, in agreement with enrichment of organic matter contents. Maximum concentration, enrichment factors, and excess (background-deducted) concentration inventories of metals (Hg and Cu) were substantially different between environments, decreasing from natural mangrove sediments to restored mangrove sediments to mud flat. Furthermore, metal inputs to Futian mangrove decreased in the order natural mangrove > restored mangrove > mud flat, indicating that mangrove facilitated the accumulation and storage of Hg and Cu in sediment layers. PMID- 26762321 TI - Effect of the early temperature on the growth of larvae and postlarvae turbot, Scophthalmus maximus L.: muscle structural and ultrastructural study. AB - Turbot specimens were kept at three temperatures (T s ): warm (W) (21-22 degrees C), ambient (A) (17-18 degrees C) and cold (C) (13-14 degrees C) during the larval and early postlarval stages. At 90 days posthatching (dph), all of them were transferred to ambient T until 190 dph. At 2-3 dph, the specimens showed a monolayer of red muscle and immature white fibres; external or dermomyotome cells (presumptive myogenic cells) were observed on the surface of the red muscle. In the following stages, many myogenic cells and presumptive myogenic precursors were observed within the myotome, presumably derived of the dermomyotome. When comparing the growth at the same age (2, 10, 25, 37 dph), the body length and the muscle growth were positively influenced by the warm T, being the hyperplasia the muscle parameter more significantly influenced. The development rate was also positively correlated with the high T: the beginning of the metamorphosis took place at 15, 23 and 25 dph at W, A and C temperatures, respectively, with the highest body length values at ambient temperature. The metamorphosis finished at 25, 30 and 37 dph at W, A and C temperatures, respectively, with the highest body length values at warm temperature. However, the muscle cellularity was similar in all the groups at the end of the metamorphosis. At 90 and 190 dph, the largest body length was observed at W temperature. However, the muscle cellularity was similar between A and W; the number of fibres was similar in all the groups at 190 dph, which shows the beginning of a compensatory muscle growth in A and C, mainly in A. PMID- 26762322 TI - Key Structural Motifs To Predict the Cage Topology in Endohedral Metallofullerenes. AB - We show that the relative isomer stability of fullerene anions is essentially governed by a few simple structural motifs, requiring only the connectivity information between atoms. Relative energies of a large number of isomers of fullerene anions, C(2n)(q) (2n = 68-104; q = -2, -4, -6), can be satisfactorily reproduced by merely counting the numbers of seven kinds of hexagon-based motifs. The dependence of stability on these motifs varies with the charge state, which reflects the fact that the isomeric form of the carbon cage in endohedral metallofullerenes (EMFs) often differs from that in neutral empty fullerenes. The chemical origin of the stabilization differences between motifs is discussed on the basis of electronic and strain effects as well as aromaticity. On the basis of this simple model, the extraordinary abundance of the icosahedral C80 cage in EMFs can be easily understood. We also provide an explanation for why the well known isolated pentagon rule is often violated in smaller EMFs. Finally, simple topological indices are proposed for quantitatively predicting the relative stability of fullerene anions, allowing a rapid determination of suitable hosting cages in EMFs by just counting three simple structural motifs. PMID- 26762320 TI - Pancreatic hamartoma: a case report and literature review. AB - BACKGROUND: Pancreatic hamartoma is an extremely rare benign disease of the pancreas. Only 30 cases have been reported to date. CASE PRESENTATION: A 68-year old man presented with an asymptomatic solid and multi-cystic lesion in the uncus of the pancreas, incidentally detected on abdominal enhanced computed tomography. The tumor was found to be a well-demarcated solid and multi-cystic lesion without any enhancement, measuring 4 cm in diameter. After 28 months of follow-up, the tumor enlarged. At 31 months after initial diagnosis, the patient underwent surgical resection because it was difficult to clinically determine whether the tumor was malignant or not. Macroscopically, the solid tumor consisted of yellow adipose tissue with a smooth thin capsule confined to the pancreatic uncus. The inner structure of the tumor consisted of multiple cysts with a white nodule between the cysts. Histologically, the solid part and the multi-cystic portion consisted of mature adipose tissue and colonization of dilated pancreatic ducts with mild fibrosis, respectively. Immunohistochemical findings revealed cytokeratin 7 and 19 positive staining in the epithelial cells of the ducts. Adipose tissue showed positive staining for S-100 protein and there were only a few MIB-1 positive cells. The tumor was then diagnosed as a pancreatic hamartoma. CONCLUSION: Beside on the above findings, we suggest that the term "well demarcated solid and cystic lesion with chronological morphological changes" could be a clinical keyword to describe pancreatic hamartomas. PMID- 26762323 TI - How should we measure proportionality on relative gene expression data? AB - Correlation is ubiquitously used in gene expression analysis although its validity as an objective criterion is often questionable. If no normalization reflecting the original mRNA counts in the cells is available, correlation between genes becomes spurious. Yet the need for normalization can be bypassed using a relative analysis approach called log-ratio analysis. This approach can be used to identify proportional gene pairs, i.e. a subset of pairs whose correlation can be inferred correctly from unnormalized data due to their vanishing log-ratio variance. To interpret the size of non-zero log-ratio variances, a proposal for a scaling with respect to the variance of one member of the gene pair was recently made by Lovell et al. Here we derive analytically how spurious proportionality is introduced when using a scaling. We base our analysis on a symmetric proportionality coefficient (briefly mentioned in Lovell et al.) that has a number of advantages over their statistic. We show in detail how the choice of reference needed for the scaling determines which gene pairs are identified as proportional. We demonstrate that using an unchanged gene as a reference has huge advantages in terms of sensitivity. We also explore the link between proportionality and partial correlation and derive expressions for a partial proportionality coefficient. A brief data-analysis part puts the discussed concepts into practice. PMID- 26762324 TI - [Mechanical thrombectomy - technique]. AB - Mechanical thrombectomy with stent retrievers in acute stroke has emerged as the technique with the highest recanalization rate of therapeutic procedures available so far. Recently it was demonstrated that compared to intravenous rTPA alone, mechanical thrombectomy improves outcomes of patients with acute occlusions of intracranial arteries of the anterior circulation in several randomized clinical trials. In this article we will give an overview of the steps required for the thrombectomy procedure. PMID- 26762325 TI - Could campaigns like Dry January do more harm than good? PMID- 26762326 TI - Switching the Spin State of Diphenylcarbene via Halogen Bonding. AB - The interactions between diphenylcarbene DPC and the halogen bond donors CF3I and CF3Br were investigated using matrix isolation spectroscopy (IR, UV-vis, and EPR) in combination with QM and QM/MM calculations. Both halogen bond donors CF3X form very strong complexes with the singlet state of DPC, but only weakly interact with triplet DPC. This results in a switching of the spin state of DPC, the singlet complexes becoming more stable than the triplet complexes. CF3I forms a second complex (type II) with DPC that is thermodynamically slightly more stable. Calculations predict that in this second complex the DPC...I distance is shorter than the F3C...I distance, whereas in the first (type I) complex the DPC...I distance is, as expected, longer. CF3Br only forms the type I complex. Upon irradiation I or Br, respectively, are transferred to the DPC carbene center and radical pairs are formed. Finally, on annealing, the formal C-X insertion product of DPC is observed. Thus, halogen bonding is a powerful new principle to control the spin state of reactive carbenes. PMID- 26762327 TI - Wrist fractures and their impact in daily living functionality on elderly people: a prospective cohort study. AB - BACKGROUND: Wrist fractures are the most common arm fractures in older adults. The impact of wrist fractures on daily functionality has been less studied than that of other types and so, less is known about the complexity of factors related to the functional impact of these fractures. This study is aimed to assess the role of individual and health care factors and its association with daily living functional changes after a wrist fracture. METHODS: A prospective cohort of patients aged 65 or more, affected by a fracture due to a fall, was conducted. These patients were identified at the emergency rooms of the six participating hospitals. As independent factors, the following were studied: socio-demographic data, characteristics of the fracture, health-related quality of life, wrist function and provided treatment. The main outcome was functional status measured by the Barthel Index for daily living basic activities and the Lawton Instrumental Activities of Daily Living (IADL) Scale for daily living instrumental activities. Data were collected at baseline just after the fall and after six months of follow-up. Patients were considered to have deteriorated if their functional status as measured by Barthel Index or Lawton IADL scores decreased in a significant way during the six months of follow up. RESULTS: Barthel Index and/or Lawton IADL scores fell at six months after the fracture in 33% of participants. This functional decline was more frequent in patients with comorbidity (p < 0.0001), polypharmacy (p < 0.0001), low health-related quality of life prior to the fall (p < 0.0001) and lower educational level (p = 0.009). The derived multivariate models show that patients that become dependent six months after the fall, have advanced age, severe chronic diseases, low functional performance prior to the fracture, and repeated episodes of accidental falls. This profile is consistent with a frailty phenotype. CONCLUSIONS: Wrist fractures are associated to the occurrence of dependence, especially in frail patients. These patients could benefit from being identified at the time the fracture is treated, in order to tackle their complex needs and so, prevent some of the burden of dependence generated by these fractures. PMID- 26762329 TI - Serum Vitamin D Status and Outcome among Critically Ill Children Admitted to the Pediatric Intensive Care Unit in South India: Authors' Reply. PMID- 26762330 TI - Pediatric Interventional Radiology: Non-Vascular Interventions. AB - Pediatric interventional radiology (PIR), which includes variety of procedures done under image guidance has emerged as an essential adjunct to various surgical and medical conditions, plays a significant role in the delivery of safe and effective care by reducing surgical risks, decreasing the length of hospital stay and reducing costs. The application of interventional techniques in children has been delayed over years as compared to adults due to lack of special hardwares/equipments, lack of adequately trained physicians and also the lack of awareness among the pediatric practitioners. This situation is gradually changing now owing to the advancements in technology. In this review, authors will discuss various non-vascular interventional procedures undertaken in pediatric patients. PMID- 26762328 TI - Small molecule distribution in rat lung: a comparison of various cryoprotectants as inflation media and their applicability to MSI. AB - Given the recent explosion of mass spectrometric imaging (MSI), it has become easier to assess drug tissue localisation without the use of radiolabeling and other more complex methods (such as PET and MRI). For MSI tissue preparation is of utmost importance, however, the lung in particular does pose some difficulties with imaging since it is made up of a number of air-filled alveoli. These organs are known to collapse when the thoracic cavity is pierced, losing its structural integrity and giving poor histological representation for drug distribution analysis. The use of cryoprotectants as a tissue inflation media will aid in the preservation of the lung's structural integrity during MSI experiments involving small molecule distribution. Various established cryoprotectants (DMSO, PvP, ethylene glycol, sucrose, DMEM, control serum, OCT) were selected as lung inflation media for MSI analysis of gatifloxacin (GAT). Female Sprague-Dawley rats were treated with GAT (10 mg/kg b.w) via i.p. injection. After 15 min the animals were terminated by halothane overdose, and each set of tissue inflated with a specific agent. Cryosections were made and MSI conducted to determine drug tissue distribution. During the early stages of the experimental procedure some crypreservatives were eliminated due to difficulties with sample preparation. While others displayed excellent preservation of the tissue structure and integrity. Following MSI analysis, some agents showed homogenous drug distribution while some displayed heterogeneous distribution favoring the basal periphery. Taking into account the physiology of the lung and previous MRI investigations of its perfusion, it is expected that a systemically administered drug would localize in the basal areas. DMSO and DMEM proved to display this distribution pattern while keeping structural integrity intact. However, the later was ruled out since it showed complete suppression of GAT in solution. From the cryoprotectants selected for this study, DMSO is the most promising lung inflation media focusing on small molecule distribution via MSI. PMID- 26762331 TI - Serum Vitamin D Status and Outcome among Critically Ill Children Admitted to the Pediatric Intensive Care Unit in South India: Correspondence. PMID- 26762332 TI - Ingestion of Phenol (Carbolic Acid) Leading to Ventricular Fibrillation. PMID- 26762333 TI - Bmal1 is required for beta cell compensatory expansion, survival and metabolic adaptation to diet-induced obesity in mice. AB - AIMS/HYPOTHESIS: Obesity and consequent insulin resistance are known risk factors for type 2 diabetes. A compensatory increase in beta cell function and mass in response to insulin resistance permits maintenance of normal glucose homeostasis, whereas failure to do so results in beta cell failure and type 2 diabetes. Recent evidence suggests that the circadian system is essential for proper metabolic control and regulation of beta cell function. We set out to address the hypothesis that the beta cell circadian clock is essential for the appropriate functional and morphological beta cell response to insulin resistance. METHODS: We employed conditional deletion of the Bmal1 (also known as Arntl) gene (encoding a key circadian clock transcription factor) in beta cells using the tamoxifen-inducible CreER(T) recombination system. Upon adulthood, Bmal1 deletion in beta cells was achieved and mice were exposed to either chow or high fat diet (HFD). Changes in diurnal glycaemia, glucose tolerance and insulin secretion were longitudinally monitored in vivo and islet morphology and turnover assessed by immunofluorescence. Isolated islet experiments in vitro were performed to delineate changes in beta cell function and transcriptional regulation of cell proliferation. RESULTS: Adult Bmal1 deletion in beta cells resulted in failed metabolic adaptation to HFD characterised by fasting and diurnal hyperglycaemia, glucose intolerance and loss of glucose-stimulated insulin secretion. Importantly, HFD-induced beta cell expansion was absent following beta cell Bmal1 deletion indicating impaired beta cell proliferative and regenerative potential, which was confirmed by assessment of transcriptional profiles in isolated islets. CONCLUSION/INTERPRETATION: Results of the study suggest that the beta cell circadian clock is a novel regulator of compensatory beta cell expansion and function in response to increased insulin demand associated with diet-induced obesity. PMID- 26762335 TI - Sudden cardiac death in heart failure with preserved ejection fraction: a target for therapy? AB - The incidence and mechanisms of sudden cardiac death (SCD) among patients with heart failure with reduced ejection fraction have been well characterized. Conversely, limited data are available exploring the landscape of SCD in patients with heart failure with preserved ejection fraction (HFpEF). HFpEF is a heterogeneous clinical syndrome of increasing prevalence and is associated with substantial morbidity and mortality. This review will aim to contextualize recent data regarding rates and predictors of SCD in this growing population and to discuss the potential role of pharmacologic and device therapy for prevention of SCD within the at-risk HFpEF subset. PMID- 26762334 TI - Cognitive training can reduce the rate of cognitive aging: a neuroimaging cohort study. AB - BACKGROUND: The neural mechanisms underlying the restorative effects of cognitive training on aging brains remain unclear. To address this issue, we examined the relationship between changes in spontaneous brain activity and cognitive performance that occur after cognitive training. METHODS: Participants were older adults who were part of a randomized control trial within a larger longitudinal cognitive training study. We conducted single-domain and multi-domain cognitive training in two respective intervention groups. Participants were trained for 1 h, twice a week, for 12 weeks. Cognition was assessed in all participants and magnetic resonance images were obtained at baseline and 1 year after training. To assess spontaneous fluctuations in brain activity, we acquired resting-state fMRI data. Two indices-functional entropy and time-domain entropy-were used to measure the effects of training. Functional entropy increases with aging, and indicates disruptions in functional conectivity. Time-domain entropy decreases with aging, and indicates structural alterations in the brain and blood-flow reduction. RESULTS: Seventy participants completed the study: 26 in the multi-domain cognitive training group (70.38 +/- 3.30 yrs), 27 in single-domain group (70.48 +/- 3.93 yrs), and 17 in a control group (68.59 +/- 3.24 yrs). Functional entropy increased significantly less in the multi-domain (p = 0.047) and single-domain groups (p = 9.51 * 10(-4)) compared with the control group. In the multi-domain group, this was true in the paracentral lobule (p = 0.004, Bonferroni corrected p < 0.05). Time-domain entropy also improved with training. Compared with controls, time-domain entropy in the multi-domain group decreased less in the inferior frontal gyrus pars opercularis (p = 3.59 * 10(-4)), the medial part of superior frontal gyrus (p = 1.17 * 10(-5)), and the thalamus (p = 4.72 * 10(-5)), while that in the single-domain group decreased less in the cuneus (p = 2.58 * 10(-4), Bonferroni corrected p < 0.05). Additionally, changes in regional entropy for some regions such as hippocampus significantly correlated with improvements in cognitive performance. CONCLUSIONS: Cognitive training can induce plastic changes in neural functional connectivity of healthy older people, and these changes may underlie the positive effect of cognitive training. TRIAL REGISTRATION: ChiCTR TRC-08000732 (Date of registration: 5th November, 2008). PMID- 26762337 TI - Calm down everyone: Keogh's action is not explosive stuff. PMID- 26762338 TI - A Multi-laboratory in Vitro Study to Compare Data from Abbreviated and Pharmacopeial Impactor Measurements for Orally Inhaled Products: a Report of the European Aerosol Group (EPAG). AB - Fine particle dose (FPD) is a critical quality attribute for orally inhaled products (OIPs). The abbreviated impactor measurement (AIM) concept simplifies its measurement, provided there is a validated understanding of the relationship with the full resolution pharmacopoeial impactor (PIM) data for a given product. This multi-center study compared fine particle dose determined using AIM and PIM for five dry powder inhaler (DPIs) and two pressurized metered-dose inhaler (pMDI) products, one of which included a valved holding chamber (VHC). Reference measurements of FPDPIM were made by each organization using either the full resolution Andersen 8-stage non-viable impactor (ACI) or Next Generation Impactor (NGI). FPDAIM was determined for the same OIP(s) with their choice of abbreviated impactor (fast screening impactor (FSI), fast screening Andersen (FSA), or reduced NGI (rNGI)). Each organization used its validated assay method(s) for the active pharmaceutical ingredient(s) (APIs) involved. Ten replicate measurements were made by each procedure. The upper size limit for FPDAIM varied from 4.4 to 5.0 MUm aerodynamic diameter, depending upon flow rate and AIM apparatus; the corresponding size limit for FPDPIM was fixed at 5 MUm in accordance with the European Pharmacopoeia. The 90% confidence interval for the ratio [FPDAIM/FPDPIM], expressed as a percentage, was contained in the predetermined 85 118% acceptance interval for nine of the ten comparisons of FPD. The average value of this ratio was 105% across all OIPs and apparatuses. The findings from this investigation support the equivalence of AIM and PIM for determination of FPD across a wide range of OIP platforms and measurement techniques. PMID- 26762340 TI - Junior doctors' contract talks will resume on Thursday. PMID- 26762339 TI - Regulating the Skin Permeation Rate of Escitalopram by Ion-pair Formation with Organic Acids. AB - In order to regulate the skin permeation rate (flux) of escitalopram (ESP), ion pair strategy was used in our work. Five organic acids with different physicochemical properties, benzoic acid (BA), ibuprofen (IB), salicylic acid (SA), benzenesulfonic acid (BSA), and p-aminobenzoic acid (PABA), were employed as counter-ions to regulate the permeation rate of ESP across the rabbit abdominal skin in vitro. The interaction between ESP and organic acids was characterized by FTIR and 13C NMR spectroscopy. Results showed that all organic acids investigated in this study performed a controlling effect on ESP flux. To further analyze the factors concerned with the permeation capability of ESP-acid complex, a multiple linear regression model was used. It is concluded that the steady-state flux (J) of ESP-acid complexes had a positive correlation with log K o/w (the n-octanol/water partition coefficient of ion-pair complex) and pK a (the acidity of organic acid counter-ion), but a negative correlation with MW (the molecular weight of ion-pair complex). The logK o/w of ion-pair complex is the primary one in all the factors that influence the skin permeation rate of ESP. The results demonstrated that organic acid with appropriate physicochemical properties can be considered as suitable candidate for the transdermal drug delivery of escitalopram. PMID- 26762341 TI - The use of matrigel has no influence on tumor development or PET imaging in FaDu human head and neck cancer xenografts. AB - BACKGROUND: In preclinical research Matrixgel(TM) Basement Membrane Matrix (MG) is used frequently for the establishment of syngeneic and xenograft cancer models. Limited information on its influence on parameters including; tumor growth, vascularization, hypoxia and imaging characteristics is currently available. This study evaluates the potential effect of matrigel use in a human head and neck cancer xenograft model (FaDu; hypopharyngeal carcinoma) in NMRI nude mice. The FaDu cell line was chosen based on its frequent use in studies of cancer imaging and tumor microenvironment. METHODS: NMRI nude mice (n = 34) were divided into two groups and subcutaneously injected with FaDu cells in medium either including (+MG) or excluding matrigel (-MG). In sub study I seven mice from each group (+MG, n = 7; -MG, n = 7) were (18)F- fluorodeoxyglucose ((18)F FDG) PET/CT scanned on Day 5, 8, 12, 15, and 19. In sub study II ten mice from each group (+MG, n = 10; -MG, n = 10) were included and tumors collected for immunohistochemistry (IHC) analysis of tumor microenvironment including; proliferation ratio, micro vessel density, average vessel area, hypoxia, nuclear density, and necrosis. Tumors for IHC were collected according to size (200-400 mm(3), 500-700 mm(3), 800-1100 mm(3)). RESULTS: FDG uptake and tumor growth was statistically compatible for the tumors established with or without MG. The IHC analysis on all parameters only identified a significantly higher micro vessel density for tumor size 500-700 mm(3) and 800-1100 mm(3) and average vessel area for tumor size 500-700 mm(3) in the -MG group. Comparable variations were observed for tumors of both the +MG and -MG groups. No difference in tumor take rate was observed between groups in study. CONCLUSIONS: Matrigel did not affect tumor growth or tumor take for the FaDu xenograft model evaluated. Tumors in the MG group displayed increased angiogenesis compared to the +MG tumors. No difference in (18)F-FDG PET uptake for tumors of different groups was found. Based on these observations the influence of matrigel on tumor imaging and tumor microenvironment seems minor for this particular xenograft model. PMID- 26762336 TI - Neutrophils influx and proinflammatory cytokines inhibition by sodium salicylate, unlike aspirin, in Candida albicans-induced peritonitis model. AB - Sodium salicylate (NaS) and aspirin (ASA) are known to have a variety of effects on microorganisms, such as fungus (C. albicans and C. neoformans), moreover, it have effects in leukocyte adhesion and migration in vitro. In this report, we investigated the effect of ASA and NaS in neutrophil migration and cytokine production in C. albicans-induced peritonitis murine model. For this, mice were treated intraperitoneally (i.p) or orally (po) with NaS or ASA; after they were stimulated i.p. with C. albicans, the cellular migration was evaluated 24 h after stimulation. NaS, in mice treated i.p., unlike ASA, was able to inhibit the neutrophil migration and proinflammatory cytokine production induced by C. albicans, such as TNF-alpha, IL-1, IFN-gamma, IL-12, and IL-10, but did not alter the IL-4 levels in these animals. However, the po treatment with same the dose of NaS or ASA did not affect the influx of this cell for inflammatory site. These results suggest that the NaS inhibits cellular migration and proinflammatory cytokine by different anti-inflammatory mechanism compared to ASA. PMID- 26762343 TI - Panel's questions will delay large cigarette packet warnings, says expert. PMID- 26762342 TI - Salidroside Protects Against 6-Hydroxydopamine-Induced Cytotoxicity by Attenuating ER Stress. AB - Parkinson's disease (PD) is a neurodegenerative disease characterized by a persistent decline of dopaminergic (DA) neurons in the substantia nigra pars compacta. Despite its frequency, effective therapeutic strategies that halt the neurodegenerative processes are lacking, reinforcing the need to better understand the molecular drivers of this disease. Importantly, increasing evidence suggests that the endoplasmic reticulum (ER) stress-induced unfolded protein response is likely involved in DA neuronal death. Salidroside, a major compound isolated from Rhodiola rosea L., possesses potent anti-oxidative stress properties and protects against DA neuronal death. However, the underlying mechanisms are not well understood. In the present study, we demonstrate that salidroside prevents 6-hydroxydopamine (6-OHDA)-induced cytotoxicity by attenuating ER stress. Furthermore, treatment of a DA neuronal cell line (SN4741) and primary cortical neurons with salidroside significantly reduced neurotoxin induced increases in cytoplasmic reactive oxygen species and calcium, both of which cause ER stress, and cleaved caspase-12, which is responsible for ER stress induced cell death. Together, these results suggest that salidroside protects SN4741 cells and primary cortical neurons from 6-OHDA-induced neurotoxicity by attenuating ER stress. This provides a rationale for the investigation of salidroside as a potential therapeutic agent in animal models of PD. PMID- 26762344 TI - Illegal intra-corporeal packets: can dual energy CT be used for the evaluation of cocaine concentration? A cross sectional study. AB - BACKGROUND: The recent implementation of the dual energy technology on CT scanners has opened new perspectives in tissue and material characterization. This study aims to evaluate whether dual energy CT can be used to assess the concentration of cocaine of intra-intestinal illegal packets. METHODS: The study was approved by the institutional review board of our institution (CER 13_027_R). From November 2010 to May 2013, all consecutive conveyors in whom a low-dose abdominal CT (LDCT) revealed the presence of illegal intra-corporeal drug packets underwent a dual energy CT series (gemstone spectral imaging) targeted on one container. The mean radiological density (HU) of these packets was measured on the LDCT series, and on the monochromatic dual energy series, at 40 and 140 keV. The difference between the HU at 40 and 140 keV was reported as ?HU. The effective atomic number Z(eff) was also measured on the monochromatic series. A chemical analysis was performed after expulsion to select cocaine containing packets, and to determine their cocaine concentrations. A correlation analysis was performed between HU, ?HU and Z(eff), with regard to the percentage of cocaine. RESULTS: Fifty-four cocaine conveyors were included. The mean cocaine content of the packets was 36.8% (range 11.2-80, SD 15.4), the mean radiologic density 105 HU, the mean Z(eff) 8.7 and the mean ?HU 163. The cocaine content was correlated with the ?HU (0.57, p < 0.001), with the Z(eff) (r = 0.56, p < 0.001) but not with radiologic density (r = 0.25, p = 0.064). ?HU >200 was 0.9 (9 of 10) sensitive and 0.82 (36 of 44) specific to predict a cocaine concentration higher than 50%. CONCLUSION: Measuring ?HU or Z(eff) on dual energy monochromatic CT series can be used to detect ingested packets with cocaine concentration >50%. PMID- 26762346 TI - Simultaneous ACL-PCL reconstructions with high tibial osteotomy: salvage for an unstable arthritic knee. AB - We present a case of a 28-year-old man with a severe osteoarthritic varus knee after a neglected multiligamentous injury sustained 10 years prior. Simultaneous anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) reconstructions with high tibial osteotomy (HTO) were performed at a single stage. Five years after surgery, there were no signs of effusion and no instability, and the patient could easily kneel down without any discomfort. We think that salvage procedures and biological reconstructions would be the primary choice of surgical treatment in young patients to delay arthroplasty, and it is possible to perform simultaneous reconstructions of ACL and PCL with HTO in a single stage. PMID- 26762347 TI - An unusual cause of cerebellovestibular symptoms. AB - Hashimoto encephalopathy (HE) is a controversial autoimmune disorder, probably underdiagnosed, that causes a wide variety of neurological manifestations. Symptoms differ among patients and may be very severe in some cases. However, it can be treated, with a very good prognosis. In our case, a teenaged girl with a family history of migraine, vitiligo and benign paroxysmal positional vertigo presented with severe ataxia, vomiting and hypotension. She had a history of similar, but milder, symptoms and was misdiagnosed several times. She had subclinical hypothyroidism, and high levels of antithyroid antibodies. There were abnormal MRI and visual evoked potential findings. After excluding other more common causes, we diagnosed her as having 'Hashimoto Encephalopathy', and started treatment with corticosteroids, on which she showed dramatic improvement. After about 2 years of presentation, the patient is able to continue her life independently. PMID- 26762345 TI - Antithrombotic and antiplatelet activities of pelargonidin in vivo and in vitro. AB - Pelargonidin is a well-known red pigment found in plants, and has been reported as having important biological activities that are potentially beneficial for human health. However, the possible roles of pelargonidin as an anticoagulant and the underlying mechanism have not yet been elucidated. We tested the effect of pelargonidin and its glucoside-conjugated form, pelargonidin-3-glucoside, on the clotting times, such as activated partial thromboplastin time (aPTT) and prothrombin time (PT), and the activities and productions of thrombin and activated factor X (FXa). Furthermore, the effects of pelargonidin on the fibrin polymerization, platelet aggregation, and the ratio of plasminogen activator inhibitor-1 (PAI-1) to tissue plasminogen activator were determined. Pelargonidin, but not pelargonidin-3-glucoside, prolonged the aPTT and PT, and inhibited the activity and production of thrombin and FXa in human umbilical vein endothelial cells. Furthermore, pelargonidin inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation and elicited anticoagulant effects in mice. In addition, pelargonidin significantly reduced PAI-1 to t-PA ratio. Collectively, these results indicate that the anthocyanin pelargonidin possesses antithrombotic activity, and can be beneficial in preventing thrombus formation, thus improving blood circulation. PMID- 26762348 TI - Bilateral femoral head avascular necrosis with a very low dose of oral corticosteroid used for panhypopituitarism. AB - Avascular necrosis (AVN) of the femoral head is a rare complication related to glucocorticoid administration and traditionally has been associated with high doses and/or prolonged therapy. Occurrence of osteonecrosis with a physiological replacement dose of glucocorticoids has not been reported previously. We report a 38-year-old man with non-secreting pituitary adenoma who developed bilateral AVN while on a very small dose of oral prednisolone for secondary adrenal insufficiency after surgery for pituitary adenoma. The patient was switched to hydrocortisone. Zolindronic acid was administered and the patient underwent bilateral core decompressive surgery resulting in a reduction of hip pain and improvement. When last evaluated, 2 years after diagnosis of AVN, the patient was functionally independent, and was able to do his routine activities with mild pain. The report intends to highlight the occurrence of AVN of the femur even with a very small dose of prednisolone used for treatment of panhypopituitarism. Glucocorticoids may have to be continued in the lowest possible dose using the most physiological preparation such as hydrocortisone when stoppage is not possible. PMID- 26762349 TI - Acute suppurative thyroiditis secondary to urinary tract infection by E. coli: a rare clinical scenario. AB - A 60-year-old woman with diabetes and symptomatic urinary tract infection presented to us with a painful neck swelling for 2 weeks. We discuss diagnostic and management issues in acute suppurative thyroiditis caused by Escherichia coli. PMID- 26762350 TI - CT images of enterohaemorrhagic Escherichia coli colitis. PMID- 26762351 TI - Varicella zoster virus: a rare cause of acute pancreatitis in an immunocompetent child. AB - A 15-year-old girl with a diagnosis of varicella zoster virus (VZV) presented to hospital with severe abdominal pain. This patient was immunocompetent and found to have acute pancreatitis in association with VZV. She responded well to intravenous acyclovir and supportive treatment. A review of the literature for the management of pancreatitis associated with VZV suggests treatment with acyclovir, as it appears to reduce hospital stay and symptoms. The exact benefit is yet to be quantified. Importantly, this diagnosis should be considered in children who have VZV associated with abdominal pain. PMID- 26762352 TI - Birt-Hogg-Dube syndrome: identifying patients at risk of renal cell carcinoma, pulmonary cysts and pneumothoraces. PMID- 26762353 TI - Gastric volvulus: an easily missed diagnosis of chest pain in the emergency room. PMID- 26762354 TI - Uncommon association of cerebral meningioma, parathyroid adenoma and papillary thyroid carcinoma in a patient harbouring a rare germline variant in the CDKN1B gene. AB - Multiple endocrine neoplasia type 4 (MEN 4) is a novel form of multiple endocrine neoplasia caused by mutations in the CDKN1B gene. Its clinical presentation includes MEN 1-related tumours such as parathyroid and anterior pituitary tumours in possible association with gonadal, adrenal, renal and thyroid tumours as well as facial angiofibromas, colagenomas and meningiomas. We describe the case of a patient with meningioma, papillary thyroid carcinoma, parathyroid adenoma and, additionally, Hurthle cell adenoma, cholesteatoma and uterine leiomyomas. Considering that this association could represent a MEN 4-like phenotype, we looked for germline mutations in the CDKN1B gene. A rare heterozygous single nucleotide substitution c.397C>A was identified. Its role as a susceptibility factor remains to be established. PMID- 26762355 TI - Stomal varices: a cause for intermittent haematuria post-radical cystectomy. PMID- 26762356 TI - Amyloid plaques are still main target for Alzheimer's drugs. PMID- 26762357 TI - Classification of fibroglandular tissue distribution in the breast based on radiotherapy planning CT. AB - BACKGROUND: Accurate segmentation of breast tissues is required for a number of applications such as model based deformable registration in breast radiotherapy. The accuracy of breast tissue segmentation is affected by the spatial distribution (or pattern) of fibroglandular tissue (FT). The goal of this study was to develop and evaluate texture features, determined from planning computed tomography (CT) data, to classify the spatial distribution of FT in the breast. METHODS: Planning CT data of 23 patients were evaluated in this study. Texture features were derived from the radial glandular fraction (RGF), which described the distribution of FT within three breast regions (posterior, middle, and anterior). Using visual assessment, experts grouped patients according to FT spatial distribution: sparse or non-sparse. Differences in the features between the two groups were investigated using the Wilcoxon rank test. Classification performance of the features was evaluated for a range of support vector machine (SVM) classifiers. RESULTS: Experts found eight patients and 15 patients had sparse and non-sparse spatial distribution of FT, respectively. A large proportion of features (>9 of 13) from the individual breast regions had significant differences (p <0.05) between the sparse and non-sparse group. The features from middle region had most significant differences and gave the highest classification accuracy for all the SVM kernels investigated. Overall, the features from middle breast region achieved highest accuracy (91%) with the linear SVM kernel. CONCLUSION: This study found that features based on radial glandular fraction provide a means for discriminating between fibroglandular tissue distributions and could achieve a classification accuracy of 91%. PMID- 26762358 TI - Unwarranted variation of coronary stent choice in The Netherlands. PMID- 26762360 TI - The mystery of the fourth beat. PMID- 26762359 TI - Treatment variation in stent choice in patients with stable or unstable coronary artery disease. AB - AIM: Variations in treatment are the result of differences in demographic and clinical factors (e.g. anatomy), but physician and hospital factors may also contribute to treatment variation. The choice of treatment is considered important since it could lead to differences in long-term outcomes. This study explores the associations with stent choice: i.e. drug-eluting stent (DES) versus bare-metal stents (BMS) for Dutch patients diagnosed with stable or unstable coronary artery disease (CAD). METHODS & RESULTS: Associations with treatment decisions were based on a prospective cohort of 692 patients with stable or unstable CAD. Of those patients, 442 patients were treated with BMS or DES. Multiple logistic regression analyses were performed to identify variables associated with stent choice. Bivariate analyses showed that NYHA class, number of diseased vessels, previous percutaneous coronary intervention, smoking, diabetes, and the treating hospital were associated with stent type. After correcting for other associations the treating hospital remained significantly associated with stent type in the stable CAD population. CONCLUSIONS: This study showed that several factors were associated with stent choice. While patients generally appear to receive the most optimal stent given their clinical characteristics, stent choice seems partially determined by the treating hospital, which may lead to differences in long-term outcomes. PMID- 26762361 TI - How Jeremy Hunt derailed clinician led progress towards a seven day NHS. PMID- 26762363 TI - Correlates of Protection against Influenza in the Elderly: Results from an Influenza Vaccine Efficacy Trial. AB - Although a number of studies have investigated and quantified immune correlates of protection against influenza in adults and children, data on immune protection in the elderly are sparse. A recent vaccine efficacy trial comparing standard dose with high-dose inactivated influenza vaccine in persons 65 years of age and older provided the opportunity to examine the relationship between values of three immunologic assays and protection against community-acquired A/H3N2 influenza illness. The high-dose vaccine induced significantly higher antibody titers than the standard-dose vaccine for all assays. For the hemagglutination inhibition assay, a titer of 40 was found to correspond with 50% protection when the assay virus was antigenically well matched to the circulating virus--the same titer as is generally recognized for 50% protection in younger adults. A dramatically higher titer was required for 50% protection when the assay virus was a poor match to the circulating virus. With the well-matched virus, some protection was seen at the lowest titers; with the poorly matched virus, high levels of protection were not achieved even at the highest titers. Strong associations were also seen between virus neutralization test titers and protection, but reliable estimates for 50% protection were not obtained. An association was seen between titers of an enzyme-linked lectin assay for antineuraminidase N2 antibodies and protection; in particular, the proportion of treatment effect explained by assay titer in models that included both this assay and one of the other assays was consistently higher than in models that included either assay alone. (This study has been registered at ClinicalTrials.gov under registration no. NCT01427309.). PMID- 26762364 TI - Re-exploring Tumor Necrosis Factor Alpha as a Target for Therapy in Intracerebral Hemorrhage. AB - Intracerebral hemorrhage (ICH) is a perplexing condition with high mortality and no treatment beyond supportive care. A major portion of the injurious process is takes place during the hours following the development of hematoma. This so called secondary injury is characterized by an inflammatory cascade that involves a variety of cytokines, including tumor necrosis factor (TNF)-alpha. Several studies in the rodent model of ICH have shown a rapid increase in brain concentrations of TNF-alpha following hematoma induction. There is a reasonable body of evidence from experimental models of ICH suggesting that upregulation of TNF-alpha adjacent to the hematoma is associated with increased peri-hematomal edema, and that inhibition of TNF-alpha attenuates the formation and progression of this edema and ultimately improves outcomes. Unfortunately, efforts to expand upon these findings have interminably stalled at the pre-clinical phase. A robust clinical study to validate serum TNF-alpha as a marker for secondary injury in ICH patients is yet to materialize. PMID- 26762362 TI - Enriched Flavonoid Fraction from Cecropia pachystachya Trecul Leaves Exerts Antidepressant-like Behavior and Protects Brain Against Oxidative Stress in Rats Subjected to Chronic Mild Stress. AB - The purpose of this study was to assess the effect of an enriched C-glycosyl flavonoids fraction (EFF-Cp) from Cecropia Pachystachya leaves on behavior, mitochondrial chain function, and oxidative balance in the brain of rats subjected to chronic mild stress. Male Wistar rats were divided into experimental groups (saline/no stress, saline/stress, EFF-Cp/no stress, and EFF-Cp/stress). ECM groups were submitted to stress for 40 days. On the 35th ECM day, EFF-Cp (50 mg/kg) or saline was administrated and the treatments lasted until the 42nd day. On the 41st and 42nd days, the animals were submitted to the splash test and the forced swim test. After these behavioral tests, the enzymatic activity of mitochondrial chain complexes and oxidative stress were analyzed. EFF-Cp reversed the depressive-like behavior induced by ECM. It also reversed the increase in thiobarbituric acid reactive species, myeloperoxidase activity, and nitrite/nitrate concentrations in some brain regions. The reduced activities of the antioxidants superoxide dismutase and catalase in some brain regions were also reversed by EFF-Cp. The most pronounced effect of EFF-Cp on mitochondrial complexes was an increase in complex IV activity in all studied regions. Thus, it is can be concluded that EFF-Cp exerts an antidepressant-like effect and that oxidative balance may be an important physiological process underlying these effects. PMID- 26762366 TI - Analysis of Advantages, Limitations, and Barriers of Genetic Counseling Service Delivery Models. AB - Previous studies on genetic counseling service delivery models (SDMs) have shown that genetic counselors (GCs) are incorporating alternate models to address growing service demand and improve access to genetic services. This study sought to identify barriers, limitations and advantages to previously identified genetic counseling SDMs. A qualitative research design was employed, in which 20 practicing GCs who utilize a variety of SDMs were interviewed using an email interview format. Interview transcripts were analyzed using a thematic analysis to identify themes related to implementation and utilization of SDMs. Factors that led GCs to implement SDMs other than in-person genetic counseling included: 1) travel distance, 2) wait time and 3) convenience. Logistical issues such as billing and reimbursement, equipment set up, making arrangements for genetic testing and the inability to see the patient are major limitations to alternative genetic counseling SDMs in clinical practice. However, GCs interviewed stated that the convenience to the patient and genetic counselor of alternative SDMs outweighed these limitations. More research is needed to assess the outcomes of SDMs in practice to demonstrate an impact on the identified barriers of travel distance, wait time and convenience. PMID- 26762365 TI - The effects of neoadjuvant chemoradiotherapy and an in-hospital exercise training programme on physical fitness and quality of life in locally advanced rectal cancer patients (The EMPOWER Trial): study protocol for a randomised controlled trial. AB - BACKGROUND: The standard treatment pathway for locally advanced rectal cancer is neoadjuvant chemoradiotherapy (CRT) followed by surgery. Neoadjuvant CRT has been shown to decrease physical fitness, and this decrease is associated with increased post-operative morbidity. Exercise training can stimulate skeletal muscle adaptations such as increased mitochondrial content and improved oxygen uptake capacity, both of which are contributors to physical fitness. The aims of the EMPOWER trial are to assess the effects of neoadjuvant CRT and an in-hospital exercise training programme on physical fitness, health-related quality of life (HRQoL), and physical activity levels, as well as post-operative morbidity and cancer staging. METHODS/DESIGN: The EMPOWER Trial is a randomised controlled trial with a planned recruitment of 46 patients with locally advanced rectal cancer and who are undergoing neoadjuvant CRT and surgery. Following completion of the neoadjuvant CRT (week 0) prior to surgery, patients are randomised to an in-hospital exercise training programme (aerobic interval training for 6 to 9 weeks) or a usual care control group (usual care and no formal exercise training). The primary endpoint is oxygen uptake at lactate threshold ([Formula: see text] at [Formula: see text]) measured using cardiopulmonary exercise testing assessed over several time points throughout the study. Secondary endpoints include HRQoL, assessed using semi-structured interviews and questionnaires, and physical activity levels assessed using activity monitors. Exploratory endpoints include post-operative morbidity, assessed using the Post-Operative Morbidity Survey (POMS), and cancer staging, assessed by using magnetic resonance tumour regression grading. DISCUSSION: The EMPOWER trial is the first randomised controlled trial comparing an in-hospital exercise training group with a usual care control group in patients with locally advanced rectal cancer. This trial will allow us to determine whether exercise training following neoadjuvant CRT can improve physical fitness and activity levels, as well as other important clinical outcome measures such as HRQoL and post-operative morbidity. These results will aid the design of a large, multi-centre trial to determine whether an increase in physical fitness improves clinically relevant post-operative outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01914068 (received: 7 June 2013). SPONSOR: University Hospital Southampton NHS Foundation Trust. PMID- 26762367 TI - Attitudes Towards Gambling, Gambling Problems, and Treatment Among Hispanics in Imperial County, CA. AB - Gambling problems are associated with a wide range of serious negative personal, social, health, and mental health consequences and are an important public health concern. Some data suggest that gambling problems may be more prevalent among Hispanics, but few studies have been conducted in this community. The aim of the current study was to gather community-based, gambling-related data in order to increase understanding of gambling problems and their treatment in the Hispanic community. We conducted a mixed-methods study of gambling behavior and attitudes towards gambling, those with gambling problems, and professional treatment for gambling problems in a publicly funded health center serving a primarily Hispanic clientele. Study participants included clinic staff and clinic patients. All participants completed a brief, self-report survey; however, staff participated in a focus group on gambling issues and patients were interviewed individually about gambling issues. Nearly 80 % of patients had gambled in the past month, as compared to about 36 % of clinic staff. Survey data showed that patients had many risk factors for gambling problems. Focus group and interview information indicated that most viewed gambling problems as a form of addiction, the elderly were seen as being at increased risk for gambling problems, and gambling outings represented one of the few recreational opportunities in the region. The majority of both staff and patients believed that there was a need for gambling-related treatment services in the county; however, a notable minority of patients said that they would first seek help from a trusted relative or family member. Possible avenues to increase awareness of, screening for, and treatment for gambling problems may include collaborations with publicly funded health care centers and the training of promotoras to serve as an interface between health services and the community. PMID- 26762368 TI - Jejunal feeding is followed by a greater rise in plasma cholecystokinin, peptide YY, glucagon-like peptide 1, and glucagon-like peptide 2 concentrations compared with gastric feeding in vivo in humans: a randomized trial. AB - BACKGROUND: Jejunal feeding is preferred instead of gastric feeding in patients who are intolerant to gastric feeding or at risk of aspiration. However, the impact of gastric feeding compared with that of jejunal feeding on postprandial circulating plasma glucose and amino acid concentrations and the associated endocrine response in vivo in humans remains largely unexplored. OBJECTIVE: We compared the impact of administering enteral nutrition as either gastric feeding or jejunal feeding on endocrine responses in vivo in humans. DESIGN: In a randomized, crossover study design, 12 healthy young men (mean +/- SD age: 21 +/- 2 y) received continuous enteral nutrition that contained noncoagulating proteins for 12 h via a nasogastric tube or a nasojejunal tube placed 30-40 cm distal to the ligament of Treitz. Blood samples were collected during the 12-h postprandial period to assess the rise in plasma glucose, amino acid, and gastrointestinal hormone concentrations. RESULTS: No differences were observed in the postprandial rise in circulating plasma amino acid and glucose concentrations between regimens. Jejunal feeding resulted in higher peak plasma insulin concentrations than did gastric feeding (392 +/- 53 compared with 326 +/- 54 pmol/L, respectively; P < 0.05). The postprandial rise in plasma cholecystokinin, peptide YY (PYY), glucagon-like peptide 1 (GLP-1), and glucagon-like peptide 2 (GLP-2) concentrations was greater after jejunal feeding than after gastric feeding, with higher peak concentrations and a greater postprandial incremental AUC for GLP-1 and cholecystokinin (all P < 0.05). Plasma ghrelin concentrations did not differ between regimens. CONCLUSIONS: Enteral nutrition with gastric or jejunal feeding in healthy young men results in similar postprandial plasma amino acid and glucose concentrations. However, the endocrine response differs substantially, with higher peak plasma cholecystokinin, PYY, GLP-1, and GLP-2 concentrations being attained after jejunal feeding. This effect may result in an improved anabolic response, greater insulin sensitivity, and an improved intestinotropic effect. Nevertheless, it may also lead to delayed gastric emptying. This trial was registered at trialregister.nl as NTR2801. PMID- 26762370 TI - How sweet is acute exercise after pure fructose ingestion? PMID- 26762369 TI - Long-term risk of type 2 diabetes in relation to habitual iron intake in women with a history of gestational diabetes: a prospective cohort study. AB - BACKGROUND: An iron overload may induce pancreatic islet damage and increase risk of diabetes. Women with a history of gestational diabetes mellitus (GDM) are at high risk of developing type 2 diabetes mellitus (T2DM) after pregnancy. OBJECTIVE: We aimed to examine the association of habitual iron intake with long term risk of T2DM in this high-risk population. DESIGN: We included 3976 women with a history of GDM from the Nurses' Health Study II cohort as part of the ongoing Diabetes & Women's Health Study. The women were followed up through 2009. Iron intake was assessed with the use of a validated food-frequency questionnaire in 1991 and every 4 y thereafter. We used Cox proportional hazards models to estimate HRs and 95% CIs. RESULTS: We documented 641 incident T2DM cases during 57,683 person-years of observation. Adjusted HRs for T2DM for the highest quartile compared with the lowest quartile were 1.64 (95% CI: 1.20, 2.25; P-trend = 0.02) for total iron intake and 1.80 (95% CI: 1.18, 2.74; P-trend = 0.005) for dietary heme iron intake. In addition, women who consumed >=30.0 mg supplemental Fe/d, compared with nonusers, had an adjusted HR of 1.83 (95% CI: 1.25, 2.70; P trend = 0.002). CONCLUSION: In women with a history of GDM, greater intakes of total iron, dietary heme iron, and supplemental iron were associated with higher risk of T2DM. PMID- 26762371 TI - Synthetic folic acid intakes and status in children living in Ireland exposed to voluntary fortification. AB - BACKGROUND: In the context of mandatory and voluntary folic acid fortification, the exposure of children to folic acid has been a focus of concern, particularly regarding the possibility of whether any potentially adverse effects will emerge in the future. OBJECTIVE: We explored concentrations of fasting unmetabolized folic acid (UFA) in the circulation of children living in Ireland who were exposed to the voluntary folic acid-fortification regimen in place in Ireland. DESIGN: Healthy children who were attending Our Lady's Children's Hospital, Crumlin, for routine minor surgery were recruited to provide a fasting 3-mL blood sample that was taken while a general anesthetic was administered. The samples were analyzed for plasma folate, red blood cell folate, and UFA concentrations. A short dietary questionnaire that captured recent and habitual intakes of folic acid, both as supplements and as fortified foods, was completed face to face with parents. RESULTS: We collected fasting samples (n = 68) and completed questionnaires that captured recent and habitual daily folic acid intakes of children grouped as follows: 0-5 y of age: 6 girls and 21 boys (27 children total); 6-10 y of age: 10 girls and 10 boys (20 children total); and 11-16 y of age: 10 girls and 11 boys (21 children total). UFA was detected in 10.3% of the samples tested (range: 0.5-1.3 nmol/L). Mean plasma folate and red blood cell folate concentrations were 35.1 nmol/L (range: 21-47 nmol/L) and 956 nmol/L (range: 305-2319 nmol/L), respectively. Mean daily intake of folic acid from fortified foods and supplements was 109 MUg (range: 0-767 MUg). CONCLUSIONS: We showed that there was UFA in the plasma of just >10% of the children sampled after an overnight fast. These findings should be considered by policy makers who are responsible for folic acid fortification. This trial was registered at www.isrctn.com as ISRCTN90038765. PMID- 26762372 TI - The effects of lutein on cardiometabolic health across the life course: a systematic review and meta-analysis. AB - BACKGROUND: The antioxidant lutein is suggested as being beneficial to cardiometabolic health because of its protective effect against oxidative stress, but evidence has not systematically been evaluated. OBJECTIVE: We aimed to evaluate systematically the effects of lutein (intake or concentrations) on cardiometabolic outcomes in different life stages. DESIGN: This is a systematic review with meta-analysis of literature published in MEDLINE, Embase, Cochrane Central, Web of Science, PubMed, and Google Scholar up to August 2014. Included were trials and cohort, case-control, and cross-sectional studies in which the association between lutein concentrations, dietary intake, or supplements and cardiometabolic outcomes was reported. Two independent investigators reviewed the articles. RESULTS: Seventy-one relevant articles were identified that included a total of 387,569 participants. Only 1 article investigated the effects of lutein during pregnancy, and 3 studied lutein in children. Furthermore, 31 longitudinal, 33 cross-sectional, and 3 intervention studies were conducted in adults. Meta analysis showed a lower risk of coronary heart disease (pooled RR: 0.88; 95% CI: 0.80, 0.98) and stroke (pooled RR: 0.82; 95% CI: 0.72, 0.93) for the highest compared with the lowest tertile of lutein blood concentration or intake. There was no significant association with type 2 diabetes mellitus (pooled RR: 0.97; 95% CI: 0.77, 1.22), but higher lutein was associated with a lower risk of metabolic syndrome (pooled RR: 0.75; 95% CI: 0.60, 0.92) for the highest compared with the lowest tertile. The literature on risk factors for cardiometabolic diseases showed that lutein might be beneficial for atherosclerosis and inflammatory markers, but there were inconsistent associations with blood pressure, adiposity, insulin resistance, and blood lipids. CONCLUSIONS: Our findings suggest that higher dietary intake and higher blood concentrations of lutein are generally associated with better cardiometabolic health. However, evidence mainly comes from observational studies in adults, whereas large-scale intervention studies and studies of lutein during pregnancy and childhood are scarce. PMID- 26762373 TI - Dietary flavonoid intake and incidence of erectile dysfunction. AB - BACKGROUND: The predominant etiology for erectile dysfunction (ED) is vascular, but limited data are available on the role of diet. A higher intake of several flavonoids reduces diabetes and cardiovascular disease risk, but no studies have examined associations between flavonoids and erectile function. OBJECTIVE: This study examined the relation between habitual flavonoid subclass intakes and incidence of ED. DESIGN: We conducted a prospective study among 25,096 men from the Health Professionals Follow-Up Study. Total flavonoid and subclass intakes were calculated from food-frequency questionnaires collected every 4 y. Participants rated their erectile function in 2000 (with historical reporting from 1986) and again in 2004 and 2008. RESULTS: During 10 y of follow-up, 35.6% reported incident ED. After multivariate adjustment, including classic cardiovascular disease risk factors, several subclasses were associated with reduced ED incidence, specifically flavones (RR = 0.91; 95% CI: 0.85, 0.97; P trend = 0.006), flavanones (RR = 0.89; 95% CI: 0.83, 0.95; P-trend = 0.0009), and anthocyanins (RR = 0.91; 95% CI: 0.85, 0.98; P-trend = 0.002) comparing extreme intakes. The results remained statistically significant after additional adjustment for a composite dietary intake score. In analyses stratified by age, a higher intake of flavanones, anthocyanins, and flavones was significantly associated with a reduction in risk of ED only in men <70 y old and not older men (11-16% reduction in risk; P-interaction = 0.002, 0.03, and 0.007 for flavones, flavanones, and anthocyanins, respectively). In food-based analysis, higher total intake of fruit, a major source of anthocyanins and flavanones, was associated with a 14% reduction in risk of ED (RR = 0.86; 95% CI: 0.79, 0.92; P = 0.002). CONCLUSIONS: These data suggest that a higher habitual intake of specific flavonoid-rich foods is associated with reduced ED incidence. Intervention trials are needed to further examine the impact of increasing intakes of commonly consumed flavonoid-rich foods on men's health. PMID- 26762374 TI - Dietary plant stanol ester consumption improves immune function in asthma patients: results of a randomized, double-blind clinical trial. AB - BACKGROUND: In vitro and ex vivo studies have suggested that plant sterols and stanols can shift the T helper (Th) 1/Th2 balance toward a Th1-type immune response, which may be beneficial in Th2-dominant conditions such as asthma and allergies. OBJECTIVE: We evaluated in vivo whether plant stanol esters affect the immune response in asthma patients. DESIGN: Fifty-eight asthma patients participated in a randomized, double-blind, placebo-controlled intervention study. All subjects started with a 2-wk run-in period in which they consumed 150 mL control soy-based yogurt without added plant stanol esters/d. Next, an 8-wk experimental period was started in which one-half of the participants received plant stanol enriched soy-based yogurts (4.0 g plant stanols/d), whereas the other one-half of subjects continued the consumption of control yogurts. After 4 wk of daily plant stanol consumption, all participants were vaccinated against hepatitis A virus (HAV), and the increase of antibody titres was monitored weekly until 4 wk after vaccination. RESULTS: Asthma patients in the plant stanol ester group showed higher antibody titres against HAV 3 and 4 wk after vaccination [19% (P = 0.037) and 22% (P = 0.030), respectively]. Also, substantial reductions in plasma total immunoglobulin E, interleukin (IL)-1beta, and tumor necrosis factor alpha were shown in the plant stanol ester group. The increase in serum plant stanol concentrations was correlated significantly with the decrease in IL-13 concentrations and the Th1 switch in the Th1/Th2 balance. However, no absolute differences in cytokine production between the plant stanol ester group and the control group were shown. CONCLUSION: To the best of our knowledge, we are among the first authors to show that plant stanol ester consumption improves the immune function in vivo in asthma patients. This trial was registered at clinicaltrials.gov as NCT01715675. PMID- 26762375 TI - Effectiveness of Parent-Child Mediation in Improving Family Functioning and Reducing Adolescent Problem Behavior: Results from a Pilot Randomized Controlled Trial. AB - Parent-child mediation programs are intended to resolve or manage disputes and improve family functioning, but rigorous evaluations of their effectiveness are lacking. Families referred to a community-based mediation program (N = 111) were randomized to an intervention or wait-list control group, and completed three surveys over a 12-week period. With the exception of parent-reported child delinquency (which decreased more in the intervention group), this evaluation provides little support for the short-term effectiveness of parent-child mediation for improving family functioning and reducing child problem behaviors in general. Given that this is the first randomized controlled trial of a parent child mediation program, additional evaluations involving larger samples and longer follow-ups are needed before firm conclusions can be drawn about the effectiveness of this intervention. PMID- 26762377 TI - Amylibacter ulvae sp. nov., a new alphaproteobacterium isolated from the Pacific green alga Ulva fenestrata. AB - A strictly aerobic, Gram-stain-negative, rod-shaped and non-motile bacterium, designated strain 6Alg 255(T), was isolated from the green alga Ulva fenestrata. Phylogenetic analysis based on 16S rRNA gene sequencing revealed that the novel strain affiliated to the family Rhodobacteraceae of the class Alphaproteobacteria being most closely related to Amylibacter marinus LMG 28364(T) with 16S rRNA gene sequence similarity of 97.2 %. Strain 6Alg 255(T) grew with 0.5-6.0 % NaCl and at 4-33 degrees C, hydrolysed aesculin, casein, gelatin and urea. The DNA G + C content was 50.4 mol%. The prevalent fatty acids were C18:1 omega7c and C16:0. The polar lipid profile was characterized by the presence of phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine and unidentified aminolipid. The major respiratory quinone was Q-10. The significant molecular distinctiveness between the novel isolate and its nearest neighbour was strongly supported by the differences in physiological and biochemical tests. Therefore, strain 6Alg 255(T) represents a novel species of the genus Amylibacter, for which the name Amylibacter ulvae sp. nov. is proposed. The type strain is 6Alg 255(T) (=KCTC 32465(T) = KMM 6515(T)). PMID- 26762376 TI - Skin Conductance Level Reactivity Moderates the Association Between Parental Psychological Control and Relational Aggression in Emerging Adulthood. AB - When studying factors that may heighten risk for relational aggression in youth, it is important to consider characteristics of both the individual and their environment. This research examined the associations between parental psychological control and reactive and proactive relational aggression in emerging adults in college. Given that sympathetic nervous system (SNS) activation may underlie differences between reactive and proactive aggression and has been shown to moderate the effects of parenting on youth development, the moderating role of SNS reactivity [indexed by skin conductance level reactivity (SCLR)] was also examined. Emerging adults (N = 180; 77.2 % female) self-reported on perceptions of parental psychological control and reactive and proactive relational aggression. SCLR was assessed in response to an interpersonal laboratory challenge task. Parental psychological control was positively associated with reactive relational aggression only for emerging adults who exhibited high SCLR. Parental psychological control was positively associated with proactive relational aggression only among emerging adults who showed low SCLR. This study extends previous research on parenting and aggression and suggests that parental psychological control is differentially associated with reactive versus proactive relational aggression, depending on emerging adults' SCLR to interpersonal stress. PMID- 26762378 TI - Effects of propranolol on conversational reciprocity in autism spectrum disorder: a pilot, double-blind, single-dose psychopharmacological challenge study. AB - RATIONALE: Pharmacological intervention for autism spectrum disorder (ASD) is an important addition to treatment, yet currently available agents target co-morbid psychiatric concerns, such as aggression and irritability. Propranolol, a beta adrenergic antagonist with anxiolytic effects, has been shown to improve verbal fluency and working memory in adults and adolescents with ASD in single-dose challenges. OBJECTIVES: The present pilot study explores the acute effects of propranolol on a measure of conversational reciprocity in this population. We also examined whether autonomic activity and anxiety moderate or mediate response to the drug, given relationships between these variables and ASD, as well as the drug's effects. METHODS: In a within-subject crossover design, 20 individuals with ASD received a single dose of propranolol or placebo during two sessions in a double-blinded, counterbalanced manner. After drug administration, participants performed a conversational reciprocity task by engaging in a short conversation with the researcher. Measurements of autonomic activity and anxiety were obtained before and after drug administration. RESULTS: Propranolol significantly improved performance on the conversational reciprocity task total [d = 0.40] and nonverbal communication domain scores when compared to the placebo condition. However, neither autonomic activity nor anxiety was significantly associated with drug response. CONCLUSIONS: Acute propranolol administration improved conversational reciprocity in ASD. Further exploration of these preliminary findings, as well as other potential treatment response predictors, with serial doses is warranted. PMID- 26762379 TI - When the party is over: depressive-like states in rats following termination of cortical D1 receptor overexpression. AB - RATIONALE: Increased activity of prefrontal D1 dopamine receptors (D1R) is involved in reward-related behavior found in bipolar disorder and drug addiction. While the effects of elevated D1R are known, depressive-like behaviors also occur in these disorders after reward-seeking ends. OBJECTIVES: The goal is to characterize how termination of D1R overexpression influences depressive-like behaviors. METHODS: An inducible (Tet.On), lentiviral vector was used to manipulate the expression of the DRD1 gene in glutamate neurons within the prefrontal cortex in male, adult rats. Sexual activity and sucrose preference were studied in both D1R elevated ON and relatively reduced OFF states. Following termination of the D1R ON state, depressive-like behavior was determined in the OFF state. Expression of the transcriptional regulator, cyclic AMP-responsive element-binding protein (CREB), was used as an indication of downstream effects in the nucleus accumbens (NA). RESULTS: ON D1R expression increased sexual activity that returned to baseline in the OFF state. Sucrose preferences increased ~6 % in ON state but fell 11 % below control levels when OFF. Consistent with a depressive-like phenotype, D1R OFF decreased activity by 40 %, impaired the ability to control (43 %) and motivation to escape shock (27 % more impaired) relative to dsRed OFF. CREB increased 29 % in the NA in the D1R OFF state relative to the ON state. CONCLUSIONS: This novel approach demonstrates that elevated D1R expression increased hedonic behavior, whereas the termination of D1R overexpression often resulted in depressive-like behavior. These observations support a role for D1R expression cycling in bipolar-associated behaviors and addiction. PMID- 26762380 TI - CYP1A2 genotype affects carbamazepine pharmacokinetics in children with epilepsy. AB - PURPOSE: The purpose of this study is to investigate the effect of two of the most important functional CYP1A2 variations -3860G > A and -163C > A on carbamazepine pharmacokinetics in Serbian pediatric epileptic patients. METHODS: The study involved 40 Serbian pediatric epileptic patients on steady-state carbamazepine treatment. Genotyping for -3860G > A and -163C > A was carried out using PCR-RFLP method, and carbamazepine plasma concentrations were determined by high pressure liquid chromatography (HPLC) method. For pharmacokinetic analysis, NONMEM software with implementation of ADVAN 1 subroutine was used. RESULTS: CYP1A2 polymorphism -163C > A was found at the frequency of 65.0 %, while -3860G > A was not detected. The correlation between weight-adjusted carbamazepine dose and carbamazepine concentration after dose adjustment was significant only in carriers of -163C/C and C/A genotypes (r = 0.68, p = 0.0004). The equation that described population clearance (CL) was CL (l/h) = 0.176 + 0.0484 * SEX + 0.019 * CYP1A2 + 0.000156 * DD, where SEX has a value of 1 if male and 0 if female, CYP1A2 has a value of 1 if -163A/A and 0 if -163C/C or C/A, and DD is the total carbamazepine daily dose (mg/day). CONCLUSIONS: CYP1A2 -163A/A genotype influence carbamazepine pharmacokinetics. In addition to sex and total carbamazepine daily dose, -163C > A CYP1A2 polymorphism should be considered as a predictor of carbamazepine clearance. PMID- 26762381 TI - Treatment with subcutaneous and transdermal fentanyl: results from a population pharmacokinetic study in cancer patients. AB - PURPOSE: Transdermal fentanyl is effective for the treatment of moderate to severe cancer-related pain but is unsuitable for fast titration. In this setting, continuous subcutaneous fentanyl may be used. As data on the pharmacokinetics of continuous subcutaneous fentanyl are lacking, we studied the pharmacokinetics of subcutaneous and transdermal fentanyl. Furthermore, we evaluated rotations from the subcutaneous to the transdermal route. METHODS: Fifty-two patients treated with subcutaneous and/or transdermal fentanyl for moderate to severe cancer related pain participated. A population pharmacokinetic model was developed and evaluated using non-linear mixed-effects modelling. For rotations from subcutaneous to transdermal fentanyl, a 1:1 dose conversion ratio was used while the subcutaneous infusion was continued for 12 h (with a 50 % tapering after 6 h). A 6-h scheme with 50 % tapering after 3 h was simulated using the final model. RESULTS: A one-compartment model with first-order elimination and separate first-order absorption processes for each route adequately described the data. The estimated apparent clearance of fentanyl was 49.6 L/h; the absorption rate constant for subcutaneous and transdermal fentanyl was 0.0358 and 0.0135 h(-1), respectively. Moderate to large inter-individual and inter-occasion variability was found. Around rotation from subcutaneous to transdermal fentanyl, measured and simulated plasma fentanyl concentrations rose and increasing side effects were observed. CONCLUSIONS: We describe the pharmacokinetics of subcutaneous and transdermal fentanyl in one patient cohort and report several findings that are relevant for clinical practice. Further research is warranted to study the optimal scheme for rotations from the subcutaneous to the transdermal route. PMID- 26762382 TI - Effects of Phospholipase A2 Inhibitors on Bilayer Lipid Membranes. AB - The work examines the effect of inhibitors of cytosolic Ca(2+)-dependent and Ca(2+)-independent phospholipases A2 on bilayer lipid membranes. It was established that trifluoroperazine (TFP) and, to a lesser extent, arachidonyl trifluoromethyl ketone (AACOCF3) and palmitoyl trifluoromethyl ketone (PACOCF3) were able to permeabilize artificial lipid membranes (BLM and liposomes). It was shown that AACOCF3 lowered the temperature of phase transition of DMPC liposomes, inducing disordering of the hydrophobic region of lipid bilayer. TFP disordered membranes both in the hydrophobic region and in the region of hydrophilic heads, this being accompanied by changes in the membrane permeability: appearance of a channel-like BLM activity and leakage of sulforhodamine B from liposomes. In contrast to AACOCF3 and TFP, PACOCF3 increased membrane orderliness in the hydrophobic region (heightened the temperature of phase transition of DMPC liposomes) and in the region of lipid heads. The effectiveness of AACOCF3 and PACOCF3 as inductors of BLM and liposome permeabilization was considerably lower comparatively to TFP. As revealed by dynamic light scattering, incorporation of TFP, AACOCF3 and PACOCF3 into the membrane of liposomes resulted in the increase of the average size of particles in the suspension, presumably due to their aggregation or fusion. The paper discusses possible mechanisms of the influence of phospholipase A2 inhibitors on bilayer lipid membranes. PMID- 26762383 TI - Extraction of Phospholipids from Human Erythrocyte Membranes by Hemoglobin Oxidation Products. AB - This investigation examines oxidation conditions under which hemoglobin extracts membrane phospholipid from erythrocytes and model membranes. In erythrocytes made echinocytic with exogenous phospholipid, addition of hemoglobin oxidized with hydrogen peroxide (H2O2) or Vitamin C (conditions that result in the formation of significant quantities of choleglobin), but not ferricyanide (which produces predominantly methemoglobin), induced dose-dependent shape reversion to less echinocytic forms, consistent with extraction of phospholipids from the exofacial side of the membrane. Erythrocytes preloaded with radiolabeled phosphatidylcholine or NBD-labeled phosphatidylcholine, phosphatidylglycerol or phosphatidic acid, exhibited greatest extraction of radiolabel or fluorescence signal with exogenous hemoglobin oxidized via H2O2 or Vitamin C, but not ferricyanide. However, with NBD-phosphatidylserine (a preferential inner monolayer intercalator), significantly less extraction of labeled lipid occurred with oxidized hemoglobin prepared under all three oxidizing conditions. In dimyristoylphosphatidylcholine liposomes containing radiolabeled phosphatidylcholine, phosphatidylserine or phosphatidylethanolamine, subsequent addition of hemoglobin oxidized with H2O2 or Vitamin C extracted radiolabeled lipid with significantly greater efficiency than ferricyanide-treated hemoglobin, with enhanced extraction detectable at levels approaching physiological plasma oxidant concentrations. Radiolabeled lipid extraction was comparable for phospholipids containing saturated acyl chains between 12 and 18 carbons but diminished significantly for oleoyl-containing phospholipids. Hemoglobin dimerization occurred at very low levels with H2O2 treatment, and even lower levels with Vitamin C treatment, and thus did not correlate to the high efficiency and consistent levels of lipid extraction observed with these treatments. These findings indicate that choleglobin extracts lipids from cell membranes regardless of headgroup or acyl chain length, through a process of direct hydrophobic interaction with the membrane surface. PMID- 26762384 TI - Is fetal manipulation during shoulder dystocia management associated with severe maternal and neonatal morbidities? AB - PURPOSE: There is a lack of data regarding maternal morbidity and neonatal hypoxia associated with shoulder dystocia (SD), particularly with respect to whether SD is managed with our without fetal manipulation (FM). Our main objective was to compare severe maternal and neonatal morbidities associated with SD according to FM execution. METHODS: We conducted a retrospective study based on a medical record analysis that included all SD cases from 2007 to 2012. SD was considered when additional maneuvers were required to complete a delivery. Severe maternal morbidity was defined as the occurrence of an obstetric anal sphincter injury. Severe neonatal morbidity was defined as the occurrence of one of these complications: permanent brachial plexus palsy, arterial cord pH < 7.1, Apgar score < 7 at 5 min. We compared severe maternal and neonatal morbidities in the FM and the no-FM group. RESULTS: We report an SD incidence of 2.4 % (n = 227) with 93.8 % of patients treated without FM. We identified two cases of permanent brachial plexus palsy, fifteen cases of arterial cord pH < 7.1 and six cases with an Apgar score < 7 at 5 min; all of them were from the no-FM group. There were more cases of OASI in the FM group (odd ratio = 9.2 [1.32-50.71]). No statistical differences between these groups were observed with respect to severe neonatal morbidity. CONCLUSIONS: Severe neonatal morbidity does not appear to be associated with FM during SD management, but severe maternal morbidity is associated with FM execution. PMID- 26762387 TI - In response to: Predictors for outcome of paper patch myringoplasty in patients with chronic tympanic membrane perforations. PMID- 26762388 TI - Clostridium thermocellum releases coumaric acid during degradation of untreated grasses by the action of an unknown enzyme. AB - Clostridium thermocellum is an anaerobic thermophile with the ability to digest lignocellulosic biomass that has not been pretreated with high temperatures. Thermophilic anaerobes have previously been shown to more readily degrade grasses than wood. Part of the explanation for this may be the presence of relatively large amounts of coumaric acid in grasses, with linkages to both hemicellulose and lignin. We found that C. thermocellum and cell-free cellulase preparations both release coumaric acid from bagasse and switchgrass. Cellulase preparations from a mutant strain lacking the scaffoldin cipA still showed activity, though diminished. Deletion of all three proteins in C. thermocellum with ferulic acid esterase domains, either singly or in combination, did not eliminate the activity. Further work will be needed to identify the novel enzyme(s) responsible for the release of coumaric acid from grasses and to determine whether these enzymes are important factors of microbial biomass degradation. PMID- 26762386 TI - Polymorphisms of the immune-modulating receptor dectin-1 in pigs: their functional influence and distribution in pig populations. AB - Dectin-1, a C-type lectin receptor that recognizes fungal beta-glucans, is involved in antifungal immunity and the regulation of intestinal immune homeostasis. Dectin-1 is involved in both synthesis and maturation of interleukin 1beta, a key pro-inflammatory cytokine in immunity. Here, we assessed the genetic diversity in the gene encoding dectin-1 (CLEC7A) within various pig populations and examined the influence of these polymorphisms on the two different signaling pathways after ligand recognition. An amino-acid polymorphism located in the carbohydrate-recognition domain, leucine to serine at position 138 (L138S), which occurred exclusively in Japanese wild boars at low frequency, significantly increased NF-kappaB induction but not caspase-8 activity after stimulation with zymosan. In contrast, other amino-acid polymorphisms present at comparatively high frequency in commercial pig populations had little influence on ligand recognition. These results suggest that functionally neutral polymorphisms in dectin-1 are widespread in pig populations. PMID- 26762389 TI - Simultaneous biological removal of phenol, sulfide, and nitrate using expanded granular sludge bed reactor. AB - Biological removal of sulfide, nitrate, and phenol at loading rates of 600 g S/(m(3) day), 900 g N/(m(3) day), and 450 g C/(m(3) day), respectively, from synthetic wastewaters was achieved in an expanded granular sludge bed (EGSB) reactor, whose rates are much higher than literature works and are considered feasible for handling high-strength petrochemical wastewaters without dilution. Effects of C/S ratio (2-2.5:1) on EGSB performance were noted insignificantly. The strains Bacillus sp., Thauera sp., and Pseudomonas sp. were the heterotrophic denitrifiers and the strains Thiobacillus sp., Azoarcus sp., and Sulfurovum sp. were the autotrophic denitrifiers in the EGSB granules. The EGSB reactor experienced biological breakdown at loadings higher than 1200 g S/(m(3) day), 1800 g N/(m(3) day), and 900 g C/(m(3) day) by the following mechanism: high sulfide first inhibits heterotrophic denitrifies (Bacillus sp. and Pseudomonas sp.), thereby accumulating nitrite in the system; then, the accumulated nitrite inhibits autotrophic denitrifiers (Thiobacillus sp., Azoarcus sp., and Sulfurovum sp.) to complete breakdown of the system. PMID- 26762390 TI - A novel heterotrophic nitrifying and aerobic denitrifying bacterium, Zobellella taiwanensis DN-7, can remove high-strength ammonium. AB - A novel heterotrophic bacterium capable of heterotrophic nitrification and aerobic denitrification was isolated from ammonium contaminated landfill leachate and physiochemical and phylogenetically identified as Zobellella taiwanensis DN 7. DN-7 converted nitrate, nitrate, and ammonium to N2 as the primary end product. Single factor experiments suggested that the optimal conditions for ammonium removal were trisodium citrate as carbon source, C/N ratio 8, pH 8.0 10.0, salinity less than 3 %, temperature 30 degrees C, and rotation speed more than 150 rpm. Specifically, DN-7 could remove 1000.0 and 2000.0 mg/L NH4 (+)-N completely within 96 and 216 h, with maximum removal rates of 19.6 and 17.3 mg L( 1) h(-1), respectively. These results demonstrated that DN-7 is a promising candidate for application of high-strength ammonium wastewater treatments. PMID- 26762391 TI - Enhanced reduction of Fe(III) oxides and methyl orange by Klebsiella oxytoca in presence of anthraquinone-2-disulfonate. AB - Klebsiella oxytoca GS-4-08 is capable of azo dye reduction, but its quinone respiration and Fe(III) reduction abilities have not been reported so far. In this study, the abilities of this strain were reported in detail for the first time. As the biotic reduction of Fe(III) plays an important role in the biogeochemical cycles, two amorphous Fe(III) oxides were tested as the sole electron acceptor during the anaerobic respiration of strain GS-4-08. For the reduction of goethite and hematite, the biogenic Fe(II) concentrations reached 0.06 and 0.15 mM, respectively. Humic acid analog anthraquinone-2-disulfonate (AQS) was found to serve as an electron shuttle to increase the reduction of both methyl orange (MO) and amorphous Fe(III) oxides, and improve the dye tolerance of the strain. However, the formation of Fe(II) was not accelerated by biologically reduced AQS (B-AH2QS) because of the high bioavailability of soluble Fe(III). For the K. oxytoca strain, high soluble Fe(III) concentrations (above 1 mM) limit its growth and decolorization ability, while lower soluble Fe(III) concentrations produce an electron competition with MO initially, and then stimulate the decolorization after the electron couples of Fe(III)/Fe(II) are formed. With the ability to respire both soluble Fe(III) and insoluble Fe(III) oxides, this formerly known azo-reducer may be used as a promising model organism for the study of the interaction of these potentially competing processes in contaminated environments. PMID- 26762392 TI - Hydrogen production under salt stress conditions by a freshwater Rhodopseudomonas palustris strain. AB - Hydrogen represents a possible alternative energy carrier to face the growing request for energy and the shortage of fossil fuels. Photofermentation for the production of H2 constitutes a promising way for integrating the production of energy with waste treatments. Many wastes are characterized by high salinity, and polluted seawater can as well be considered as a substrate. Moreover, the application of seawater for bacterial culturing is considered cost-effective. The aims of this study were to assess the capability of the metabolically versatile freshwater Rhodopseudomonas palustris 42OL of producing hydrogen on salt containing substrates and to investigate its salt stress response strategy, never described before. R. palustris 42OL was able to produce hydrogen in media containing up to 3 % added salt concentration and to grow in media containing up to 4.5 % salinity without the addition of exogenous osmoprotectants. While the hydrogen production performances in absence of sea salts were higher than in their presence, there was no significant difference in performances between 1 and 2 % of added sea salts. Nitrogenase expression levels indicated that the enzyme was not directly inhibited during salt stress, but a regulation of its expression may have occurred in response to salt concentration increase. During cell growth and hydrogen production in the presence of salts, trehalose was accumulated as a compatible solute; it protected the enzymatic functionality against salt stress, thus allowing hydrogen production. The possibility of producing hydrogen on salt containing substrates widens the range of wastes that can be efficiently used in production processes. PMID- 26762393 TI - The biology and ecology of Necrodes littoralis, a species of forensic interest in Europe. AB - Necrodes littoralis (Linnaeus, 1758) (Coleoptera: Silphidae), also known as the "shore sexton beetle," is a common silphid beetle that visits and breeds on large vertebrate cadavers. This study describes, for the first time, the involvement of N. littoralis on human corpses based on a large dataset of 154 French forensic cases. Various parameters regarding corpse location, decomposition stages, and entomofauna were extracted from each file. Compared to all of the forensic entomology cases analyzed between 1990 and 2013 (1028), N. littoralis was observed, on average, in one case out of eight; most of these cases occurred during spring and summer (73.5%). More than 90% of the cases were located outdoors, especially in woodlands, bushes, and fields. The decomposition stage of the corpse varied among cases, with more than 50% in the advanced decomposition stage, 36% in the early decomposition stage, and less than 10% in the fresh, mummified, or skeletonized stages. Regarding other necrophagous species sampled with N. littoralis, Calliphorid flies were found in 94% of the cases and Fanniidae/Muscidae in 65% of the cases. Chrysomya albiceps, a heliophilic species mostly located in the Mediterranean area, was present in 34% of the cases (only 20% in the whole dataset). The most common coleopteran species were Necrobia spp. (Coleoptera: Cleridae) and Creophilus maxillosus (Coleoptera: Staphylinidae); these beetles were observed in 27% of the cases. The over-representation of these species is likely due to similar requirements regarding the climate and decomposition stage. As N. littoralis is frequently observed and tends to become more common, we conclude that the developmental data for this species would be a precious tool for forensic entomologists in Europe. PMID- 26762394 TI - Motor network structure and function are associated with motor performance in Huntington's disease. AB - In Huntington's disease, the relationship of brain structure, brain function and clinical measures remains incompletely understood. We asked how sensory-motor network brain structure and neural activity relate to each other and to motor performance. Thirty-four early stage HD and 32 age- and sex-matched healthy control participants underwent structural magnetic resonance imaging (MRI), diffusion tensor, and intrinsic functional connectivity MRI. Diffusivity patterns were assessed in the cortico-spinal tract and the thalamus-somatosensory cortex tract. For the motor network connectivity analyses the dominant M1 motor cortex region and for the basal ganglia-thalamic network the thalamus were used as seeds. Region to region structural and functional connectivity was examined between thalamus and somatosensory cortex. Fractional anisotropy (FA) was higher in HD than controls in the basal ganglia, and lower in the external and internal capsule, in the thalamus, and in subcortical white matter. Between-group axial and radial diffusivity differences were more prominent than differences in FA, and correlated with motor performance. Within the motor network, the insula was less connected in HD than in controls, with the degree of connection correlating with motor scores. The basal ganglia-thalamic network's connectivity differed in the insula and basal ganglia. Tract specific white matter diffusivity and functional connectivity were not correlated. In HD sensory-motor white matter organization and functional connectivity in a motor network were independently associated with motor performance. The lack of tract-specific association of structure and function suggests that functional adaptation to structural loss differs between participants. PMID- 26762395 TI - Risk profile and treatment options of acute ischemic in-hospital stroke. AB - Despite the potential immediate access to diagnosis and care, in-hospital stroke (IHS) is associated with delay in diagnosis, lower rates of reperfusion treatment, and unfavorable outcome. Endovascular reperfusion therapy has shown promising results in recent trials for community-onset strokes (COS) and is limited by less contraindications than systemic thrombolysis. Thus, endovascular approaches may offer additional acute treatment options for IHS. We performed a retrospective, observational monocentric analysis of patients with acute ischemic stroke between January 2010 and December 2014. Out of 3506 acute ischemic strokes, 331 (9.4%) were IHS. In-hospital mortality (31.4 vs. 8.0%) and duration of stay after stroke (19.5 vs. 12.1 days) were higher in IHS than in COS. Most IHS occurred in cardiologic and cardiosurgical patients after catheterization or surgery. In 111 cases (33.5%) the time of onset could not be established as a result of sedation or delayed referral resulting in delayed symptom recognition. 52 IHS (15.7%) and 828 COS (26.0%, p < 0.001) patients received any kind of reperfusion therapy, of which 59.6% (IHS) and 12.1% (COS) comprised isolated endovascular interventions (p < 0.001). Intra-hospital delays (time to brain imaging, systemic thrombolysis, and angiography) were longer and outcome parameters (mRS d90, in-hospital mortality, length of stay) were worse in IHS, whereas rates of procedural complications and intracranial hemorrhages were similar in both groups. The overall rate of reperfusion treatment is lower in IHS compared to COS, as IHS patients are less likely to be eligible for systemic thrombolysis. Interventional stroke treatment is a safe and feasible therapeutic option for patients who are not eligible for systemic thrombolysis and should be anticipated whenever IHS is diagnosed. PMID- 26762396 TI - Visual Acuity and Self-Reported Vision Status. AB - OBJECTIVES: This study examined the associations of two measures of vision impairment (i.e., a clinical measure of visual acuity and self-reported vision status) and social isolation in a nationally representative sample of Americans aged 60 and older. METHOD: Five cycles of the National Health and Nutrition Examination Survey (NHANES IV; 1999-2008) were used to estimate successive logistic regression models, holding constant demographic characteristics, chronic illness, functional limitations, and disability. RESULTS: Effects of both measures of vision impairment in predicting social isolation were substantially reduced or eliminated in adjusted models. Where significant effects of vision impairment on social isolation remained, a strong effect was found for self reported poor vision (odds ratio = 1.53; 95% confidence interval = [1.08, 2.16]). DISCUSSION: As one of the better vision-related predictors of social isolation, self-reported vision is among the easiest and inexpensive to assess. The use of self-reported vision as a screening criterion for social isolation is discussed. PMID- 26762397 TI - Adult nephron-specific MR-deficient mice develop a severe renal PHA-1 phenotype. AB - Aldosterone is the main mineralocorticoid hormone controlling sodium balance, fluid homeostasis, and blood pressure by regulating sodium reabsorption in the aldosterone-sensitive distal nephron (ASDN). Germline loss-of-function mutations of the mineralocorticoid receptor (MR) in humans and in mice lead to the "renal" form of type 1 pseudohypoaldosteronism (PHA-1), a case of aldosterone resistance characterized by salt wasting, dehydration, failure to thrive, hyperkalemia, and metabolic acidosis. To investigate the importance of MR in adult epithelial cells, we generated nephron-specific MR knockout mice (MR(Pax8/LC1)) using a doxycycline-inducible system. Under standard diet, MR(Pax8/LC1) mice exhibit inability to gain weight and significant weight loss compared to control mice. Interestingly, despite failure to thrive, MR(Pax8/LC1) mice survive but develop a severe PHA-1 phenotype with higher urinary Na(+) levels, decreased plasma Na(+), hyperkalemia, and higher levels of plasma aldosterone. This phenotype further worsens and becomes lethal under a sodium-deficient diet. Na(+)/Cl(-) co transporter (NCC) protein expression and its phosphorylated form are downregulated in the MR(Pax8/LC1) knockouts, as well as the alphaENaC protein expression level, whereas the expression of glucocorticoid receptor (GR) is increased. A diet rich in Na(+) and low in K(+) does not restore plasma aldosterone to control levels but is sufficient to restore body weight, plasma, and urinary electrolytes. In conclusion, MR deletion along the nephron fully recapitulates the features of severe human PHA-1. ENaC protein expression is dependent on MR activity. Suppression of NCC under hyperkalemia predominates in a hypovolemic state. PMID- 26762398 TI - Plasma functionalization of polycarbonaturethane to improve endothelialization- Effect of shear stress as a critical factor for biocompatibility control. AB - Medical devices made of polycarbonaturethane (PCU) combine excellent mechanical properties and little biological degradation, but restricted hemocompatibility. Modifications of PCU might reduce platelet adhesion and promote stable endothelialization. PCU was modified using gas plasma treatment, binding of hydrogels, and coupling of cell-active molecules (modified heparin, anti-thrombin III (ATIII), argatroban, fibronectin, laminin-nonapeptide, peptides with integrin binding arginine-glycine-aspartic acid (RGD) motif). Biocompatibility was verified with static and dynamic cell culture techniques. Blinded analysis focused on improvement in endothelial cell (EC) adhesion/proliferation, anti thrombogenicity, reproducible manufacturing process, and shear stress tolerance of ECs. EC adhesion and antithrombogenicity were achieved with 9/35 modifications. Additionally, 6/9 stimulated EC proliferation and 3/6 modification processes were highly reproducible for endothelialization. The latter modifications comprised immobilization of ATIII (A), polyethyleneglycole-diamine hydrogel (E) and polyethylenimine-hydrogel connected with modified heparin (IH). Under sheer stress, only the IH modification improved EC adhesion within the graft. However, ECs did not arrange in flow direction and cell anchorage was restricted. Despite large variation in surface modification chemistry and improved EC adhesion under static culture conditions, additional introduction of shear stress foiled promising preliminary data. Therefore, biocompatibility testing required not only static tests but also usage of physiological conditions such as shear stress in the case of vascular grafts. PMID- 26762399 TI - A semi-automated measuring system of brain diffusion and perfusion magnetic resonance imaging abnormalities in patients with multiple sclerosis based on the integration of coregistration and tissue segmentation procedures. AB - BACKGROUND: Diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) abnormalities in patients with multiple sclerosis (MS) are currently measured by a complex combination of separate procedures. Therefore, the purpose of this study was to provide a reliable method for reducing analysis complexity and obtaining reproducible results. METHODS: We implemented a semi-automated measuring system in which different well-known software components for magnetic resonance imaging (MRI) analysis are integrated to obtain reliable measurements of DWI and PWI disturbances in MS. RESULTS: We generated the Diffusion/Perfusion Project (DPP) Suite, in which a series of external software programs are managed and harmonically and hierarchically incorporated by in-house developed Matlab software to perform the following processes: 1) image pre-processing, including imaging data anonymization and conversion from DICOM to Nifti format; 2) co registration of 2D and 3D non-enhanced and Gd-enhanced T1-weighted images in fluid-attenuated inversion recovery (FLAIR) space; 3) lesion segmentation and classification, in which FLAIR lesions are at first segmented and then categorized according to their presumed evolution; 4) co-registration of segmented FLAIR lesion in T1 space to obtain the FLAIR lesion mask in the T1 space; 5) normal appearing tissue segmentation, in which T1 lesion mask is used to segment basal ganglia/thalami, normal appearing grey matter (NAGM) and normal appearing white matter (NAWM); 6) DWI and PWI map generation; 7) co-registration of basal ganglia/thalami, NAGM, NAWM, DWI and PWI maps in previously segmented FLAIR space; 8) data analysis. All these steps are automatic, except for lesion segmentation and classification. CONCLUSION: We developed a promising method to limit misclassifications and user errors, providing clinical researchers with a practical and reproducible tool to measure DWI and PWI changes in MS. PMID- 26762400 TI - LPS-mediated effects and spatio-temporal expression of TLR2 and TLR4 in the bovine corpus luteum. AB - When given intravenously (iv), lipopolysaccharide (LPS) transiently suppresses the structure and function of the bovine corpus luteum (CL). This is associated with increased release of prostaglandin (PG) F2alpha metabolite. The underlying regulatory mechanisms of this process remain, however, obscure. Therefore, the aims of this study were: i) to investigate the expression of the LPS receptor toll-like receptor 4 (TLR4) and 2 (TLR2) in the bovine CL during early, mid- and late luteal phases; and ii) to further dissect the mechanisms of LPS-mediated suppression of luteal function. As revealed by semi-quantitative qPCR and immunohistochemistry, both receptors were detectable throughout the luteal lifespan. Their mRNA levels increased from the early toward the mid-luteal phase; no further changes were observed thereafter. The TLR4 protein seemed more highly represented than TLR2. The cellular localization of TLRs was in blood vessels; weaker signals were observed in luteal cells. Additionally, cows were treated either with LPS (iv, 0.5 MUg/kg BW) or with saline on Day 10 after ovulation. Samples were collected 1200 h after treatment and on Day 10 of the respective subsequent (untreated) cycle. The mRNA expression of several possible regulatory factors was investigated, revealing the suppression of PGF2alpha receptor (PTGFR), STAR protein and 3beta-hydroxysteroid dehydrogenase, compared with controls and subsequent cycles. The expression of TLR2 and TLR4, interleukin 1alpha (IL1A) and 1beta (IL1B) and of PGF2alpha and PGE2 synthases (HSD20A and mPTGES respectively) was increased. The results demonstrate the presence of TLR2 and TLR4 in the bovine CL, and implicate their possible involvement in the deleterious effects of LPS on its function. PMID- 26762401 TI - Unequal distribution of 16S mtrRNA at the 2-cell stage regulates cell lineage allocations in mouse embryos. AB - Cell lineage determination during early embryogenesis has profound effects on adult animal development. Pre-patterning of embryos, such as that of Drosophila and Caenorhabditis elegans, is driven by asymmetrically localized maternal or zygotic factors, including mRNA species and RNA binding proteins. However, it is not clear how mammalian early embryogenesis is regulated and what the early cell fate determinants are. Here we show that, in mouse, mitochondrial ribosomal RNAs (mtrRNAs) are differentially distributed between 2-cell sister blastomeres. This distribution pattern is not related to the overall quantity or activity of mitochondria which appears equal between 2-cell sister blastomeres. Like in lower species, 16S mtrRNA is found to localize in the cytoplasm outside of mitochondria in mouse 2-cell embryos. Alterations of 16S mtrRNA levels in one of the 2-cell sister blastomere via microinjection of either sense or anti-sense RNAs drive its progeny into different cell lineages in blastocyst. These results indicate that mtrRNAs are differentially distributed among embryonic cells at the beginning of embryogenesis in mouse and they are functionally involved in the regulation of cell lineage allocations in blastocyst, suggesting an underlying molecular mechanism that regulates pre-implantation embryogenesis in mouse. PMID- 26762402 TI - Obox4-silencing-activated STAT3 and MPF/MAPK signaling accelerate nuclear membrane breakdown in mouse oocytes. AB - Mouse oocytes begin to mature in vitro once liberated from ovarian follicles. Previously, we showed that oocyte-specific homeobox 4 (Obox4) is critical for maintaining the intact nuclear membrane of the germinal vesicle (GV) in oocytes and for completing meiosis at the metaphase I-II (MI-MII) transition. This study further examines the molecular mechanisms of OBOX4 in regulating GV nuclear membrane breakdown. Maturation-promoting factor (MPF) and MAPK are normally inactive in GV stage oocytes but were activated prematurely in arrested GV stage oocytes by 3-isobutyl-1-metyl-xanthine (IBMX) in vitro after Obox4 RNA interference (RNAi). Furthermore, signal transducer and activator of transcription 3 (STAT3) was significantly activated by Obox4 RNAi. We confirmed that this Obox4 RNAi-induced premature STAT3 and MPF/MAPK activation at the GV stage provoked subsequent GV breakdown (GVBD) despite the opposing force of high cAMP in the IBMX-supplemented medium to maintain intact GV. When cumulus-oocyte complexes were exposed to interferon alpha (IFNA), a STAT3 activator, oocytes matured and cumulus cells expanded to resume nuclear maturation in IBMX supplemented medium, suggesting that STAT3 activation is sufficient for stimulating the continuation of meiosis. Using Stattic, a specific STAT3 inhibitor, we confirmed that GVBD involves STAT3 activation in Obox4-silenced oocytes. Based on these findings, we concluded that i) Obox4 is an important upstream regulator of MPF/MAPK and STAT3 signaling, and ii) Obox4 is a key regulator of the GV arrest mechanism in oocytes. PMID- 26762404 TI - Abbreviations, initialism and acronyms: their use in medical physics (THUMP). PMID- 26762403 TI - Understanding and optimizing brain health in HIV now: protocol for a longitudinal cohort study with multiple randomized controlled trials. AB - BACKGROUND: Chronic HIV infection commonly affects both cognition and mental health, even with excellent systemic viral control. The causes of compromised brain health are likely to be a multi-factorial combination of HIV-related biological factors, co-morbidities such as aging and cerebrovascular disease, and the erosion of coping skills, physical health, and social supports resulting from the strains of living with a chronic illness. METHODS/DESIGN: This study aims to provide a better understanding of the relationship between cognitive complaints, depression, and objectively measured cognitive impairment in HIV, and of the key factors, whether biological or personal, which relate to these presentations and to their evolution over time. Characterization of this heterogeneity will permit more focused pathophysiological studies, and allow more targeted interventions. The project makes extensive use of Web-based research and health care delivery tools, aiming to provide cost-effective, "clinic ready" tools to improve brain health in HIV. This project has two overarching aims, reflecting our dual goals of understanding and improving brain health in HIV, focusing on cognitive impairment, its contributors and consequences. The objectives are to contribute evidence for the validity of a brief brain health assessment, to estimate the extent to which HIV-related cognition-relevant clinical factors and patient centered outcomes inter-relate and evolve over time, allowing identification of the mechanisms underpinning longitudinal change in brain health and to contribute evidence for the feasibility, effectiveness potential, acceptability, and underlying mechanisms of promising interventions for optimizing brain health. We adopt a cohort multiple randomized control trials design. A total of 900 participants will be characterized prospectively over a 27-month period to answer questions about the evolution of outcomes of interest. All participants will be offered basic brain health self-management information. Sub-groups will participate in pilot studies of specific, more intensive interventions to provide pragmatic evidence for feasibility, effectiveness, and comparative effectiveness. DISCUSSION: This work will provide needed estimates of the burden, heterogeneity, evolution, and mechanisms underlying compromised brain health in HIV, and test a range of promising non-pharmacological interventions. This is an on-going study; the trials nested within this cohort that are currently recruiting participants were registered on 7 October 2015 (Clinicaltrials.gov NCT02571504 and NCT02571595). PMID- 26762405 TI - Neurologic amebiasis caused by Balamuthia mandrillaris in an Indian flying fox (Pteropus giganteus). AB - A 4-5-month-old intact male Indian flying fox (Pteropus giganteus) was presented to the Baton Rouge Zoo's veterinary hospital with an acute onset of obtundation that was diagnosed with amebic encephalitis. Histologic examination revealed numerous amebic trophozoites within necrotic foci, affecting the occipital cerebrum and surrounding the mesencephalic aqueduct. The etiologic agent, Balamuthia mandrillaris, was determined by multiplex quantitative real-time polymerase chain reaction, immunohistochemistry, and indirect fluorescent antibody test. The current report documented a case of amebic encephalitis within the order Chiroptera. PMID- 26762406 TI - Childbirth and consequent atopic disease: emerging evidence on epigenetic effects based on the hygiene and EPIIC hypotheses. AB - BACKGROUND: In most high and middle income countries across the world, at least 1:4 women give birth by cesarean section. Rates of labour induction and augmentation are rising steeply; and in some countries up to 50% of laboring women and newborns are given antibiotics. Governments and international agencies are increasingly concerned about the clinical, economic and psychosocial effects of these interventions. DISCUSSION: There is emerging evidence that certain intrapartum and early neonatal interventions might affect the neonatal immune response in the longer term, and perhaps trans-generationally. Two theories lead the debate in this area. Those aligned with the hygiene (or 'Old Friends') hypothesis have examined the effect of gut microbiome colonization secondary to mode of birth and intrapartum/neonatal pharmacological interventions on immune response and epigenetic phenomena. Those working with the EPIIC (Epigenetic Impact of Childbirth) hypothesis are concerned with the effects of eustress and dys-stress on the epigenome, secondary to mode of birth and labour interventions. This paper examines the current and emerging findings relating to childbirth and atopic/autoimmune disease from the perspective of both theories, and proposes an alliance of research effort. This is likely to accelerate the discovery of important findings arising from both approaches, and to maximize the timely understanding of the longer-term consequences of childbirth practices. PMID- 26762408 TI - Pretreatment lymphocyte to monocyte ratio as a predictor of prognosis in patients with early-stage triple-negative breast cancer. AB - Recent studies have shown that the lymphocyte to monocyte ratio (LMR) is a useful prognostic factor in various cancers. The purpose of the current study was to investigate the association between pretreatment LMR, disease-free survival (DFS), and overall survival (OS) in patients with early-stage (I to III) triple negative breast cancer (TNBC). Pretreatment LMR with corresponding clinical features from 230 TNBC patients was noted. A receiver operating characteristic (ROC) curve for survival prediction was plotted to verify the optimal cutoff values for LMR, lymphocyte, and monocyte counts. The difference between variables was calculated using chi-square tests. The Kaplan-Meier method and univariate and multivariate Cox regression models were applied to assess OS and DFS. Based on the ROC analysis, the optimal cutoff point for LMR was 4.7. Associations between high LMR (>=4.7) and significantly small tumor size (P = 0.005) and TNM stage (P = 0.013) were found, although there was no significant association for other clinical pathological factors. In the multivariate analysis, LMR was a significant predictive factor for both OS (hazard ratio [HR] = 0.42; 95 % confidence interval [CI], 0.19-0.95; P < 0.001) and DFS (HR = 0.40; 95 % CI, 0.20 0.79; P < 0.001). In addition, the predictive values of the OS and DFS were also observed for absolute counts of lymphocytes (P < 0.001) and monocytes (P < 0.001). Our study suggests that pretreatment LMR may be a predictive factor for long-term survival in patients with early-stage TNBC. PMID- 26762407 TI - Inhibition of carbonic anhydrase potentiates bevacizumab treatment in cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is a unique liver cancer subtype with an increasing incidence globally. The lack of specific symptoms and definite diagnostic markers results in a delayed diagnosis and disease progression. Systemic chemotherapy is commonly selected for advanced CCA even though its advantages remain unknown. Targeted therapy, especially anti-vascular endothelial growth factor (VEGF) therapy, is promising for CCA; however, improvements in the therapeutic regimen are necessary to overcome subsequent resistance. We demonstrated VEGF expression was higher in CCA cell lines than in other liver cancer cells. Secreted VEGFs played roles in the induction of peri- and intra-tumoral vascularization. VEGF neutralization by bevacizumab effectively reduced tumor growth, mainly through the suppression of angiogenesis; however, increases in the expression of hypoxia inducible factor 1alpha (HIF1alpha) and HIF1alpha-responsive genes (such as VEGF, VEGFR1, VEGFR2, carbonic anhydrase (CA) IX and CAXII) indicated the potential for subsequent therapeutic resistance. Supplementation with a carbonic anhydrase inhibitor, acetazolamide, enhanced the anti-CCA effects of bevacizumab. Anti angiogenesis and anti-proliferation were observed with the combination treatment. These results suggested a novel treatment strategy to overcome anti-angiogenesis resistance and the importance of "induced essentiality" in the treatment of CCA. PMID- 26762410 TI - MEF2D/Wnt/beta-catenin pathway regulates the proliferation of gastric cancer cells and is regulated by microRNA-19. AB - The underlying molecular pathogenesis in gastric cancer remains poorly unknown. The transcription factor myocyte enhancer factor 2D (MEF2D) participates in the initiation and development of many human cancers. However, its potential roles in gastric cancer have surprisingly not been studied. In present study, we first explored MEF2's expression in gastric cancer, finding that only MEF2D rather than MEF2A, 2B, or 2C was elevated in gastric cancer clinical specimens. Furthermore, immunohistochemical analysis on the tissue samples obtained from 260 patients with gastric cancer revealed that MEF2D expression was significantly associated with the clinical stage, vascular invasion, metastasis, and tumor size. Gastric cancer patients with MEF2D expression showed a significantly shorter overall survival time compared with that of patients lacking of MEF2D. Multivariate analysis revealed that MEF2D expression was an independent prognostic factor for overall survival. These results indicated that MEF2D was a prognostic marker for gastric cancer. Notably, MEF2D silencing was able to reduce the proliferation and survival of gastric cancer cells. Further study revealed that MEF2D suppression significantly inactivated the oncogenic Wnt/beta-catenin pathway. Downregulation of MEF2D inhibited the tumorigenesis of gastric cancer cells in nude mice. Finally, MEF2D is a direct target of miR-19, which was found to be decreased in gastric cancer clinical specimens. Collectively, we found that miR 19/MEF2D/Wnt/beta-catenin regulatory network contributes to the growth of gastric cancer, hinting a new promising target for gastric cancer treatment. PMID- 26762411 TI - Protein arginine methyltransferase 1 interacts with Gli1 and regulates its transcriptional activity. AB - Protein arginine methylation, which is mediated by the protein arginine methyltransferases (PRMTs), is associated with numerous fundamental cellular processes. Our previous studies have shown that PRMT1 activated Hedgehog signaling in the esophageal squamous cell carcinoma (ESCC) cells and promoted the growth and migration of cancer cells. However, the detailed mechanisms are unknown. In this study, it was found that PRMT1 interacted with the transcriptional factor Gli1 (glioma-associated oncogene homolog 1) in ESCC cells. The DNA-binding domain (DBD) of Gli1 is responsible for its interaction with PRMT1. Moreover, PRMT1 promoted the methylation of Gli1, and knocking down the expression of PRMT1 impaired the transcriptional activity as well as the biological functions of Gli1. Taken together, our study demonstrated that PRMT1 is a positive regulator of Hedgehog signaling, and PRMT1 might be a therapeutic target for ESCC. PMID- 26762409 TI - Secretome profiling of oral squamous cell carcinoma-associated fibroblasts reveals organization and disassembly of extracellular matrix and collagen metabolic process signatures. AB - An important role has been attributed to cancer-associated fibroblasts (CAFs) in the tumorigenesis of oral squamous cell carcinoma (OSCC), the most common tumor of the oral cavity. Previous studies demonstrated that CAF-secreted molecules promote the proliferation and invasion of OSCC cells, inducing a more aggressive phenotype. In this study, we searched for differences in the secretome of CAFs and normal oral fibroblasts (NOF) using mass spectrometry-based proteomics and biological network analysis. Comparison of the secretome profiles revealed that upregulated proteins involved mainly in extracellular matrix organization and disassembly and collagen metabolism. Among the upregulated proteins were fibronectin type III domain-containing 1 (FNDC1), serpin peptidase inhibitor type 1 (SERPINE1), and stanniocalcin 2 (STC2), the upregulation of which was validated by quantitative PCR and ELISA in an independent set of CAF cell lines. The transition of transforming growth factor beta 1 (TGF-beta1)-mediating NOFs into CAFs was accompanied by significant upregulation of FNDC1, SERPINE1, and STC2, confirming the participation of these proteins in the CAF-derived secretome. Type I collagen, the main constituent of the connective tissue, was also associated with several upregulated biological processes. The immunoexpression of type I collagen N-terminal propeptide (PINP) was significantly correlated in vivo with CAFs in the tumor front and was associated with significantly shortened survival of OSCC patients. Presence of CAFs in the tumor stroma was also an independent prognostic factor for OSCC disease-free survival. These results demonstrate the value of secretome profiling for evaluating the role of CAFs in the tumor microenvironment and identify potential novel therapeutic targets such as FNDC1, SERPINE1, and STC2. Furthermore, type I collagen expression by CAFs, represented by PINP levels, may be a prognostic marker of OSCC outcome. PMID- 26762412 TI - Cadherin-12 enhances proliferation in colorectal cancer cells and increases progression by promoting EMT. AB - Cadherin-12 (CDH12) is a subtype of N-cadherin family. In this study, we investigated the expression of CDH12 and the role of CDH12 in prognosis of colorectal cancer (CRC) patients. In addition, we observed the influence of CDH12 on proliferation and progression of CRC cell lines. By using immunohistochemical staining, we analyzed CRC samples and adjacent non-tumor tissues collected from 78 patients who underwent laparoscopic surgery in Shanghai Minimally Invasive Center, China. Statistical analyses were used to analyze relationship between CDH12 and tumor features. Kaplan-Meier method was used to analyze patients' survival. Proliferation ability of CRC cells was tested by CCK-8 assay, and transwell assays were performed to detect migration and invasion ability. Western blot assay was performed to investigate epithelial-mesenchymal transition (EMT) variants. We found that expression of CDH12 in tumor tissue was higher than in adjacent normal tissue. High expression of CDH12 was associated with tumor invasion depth and predicts poor prognosis of CRC patients. Ectopic/repressing expression of CDH12 increased/decreased the proliferation and migration ability of CRC cells. CDH12 is able to increase cancer cell migration and invasion via promoting EMT by targeting transcriptional factor Snail. These findings may conclude that CDH12 may act as a predictor in CRC patients' prognosis and an oncogene in CRC cell proliferation and migration. CDH12 may influence CRC cell progression through promoting EMT by targeting Snail. In addition, CDH12 is promoted by MCP1 through induction of MCPIP. PMID- 26762413 TI - Mutation analysis of EGFR and its correlation with the HPV in Indian cervical cancer patients. AB - Cervical cancer is a major cause of morbidity and mortality particularly in developing countries. Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene is associated with increased sensitivity to tyrosine kinase inhibitors (TKIs). In this study, the presence of EGFR mutations in cervical cancer and its correlation with HPV were identified. EGFR mutations were found in 31 out of 95 patients (32.63 %). Results showed the presence of EGFR mutations in 5.263 % of patients in exon 19. In exon 20, mutations were predominant in 25.26 % patients. While in exon 21, 8.421 % of patients had mutations. HPV, which is associated with cervical cancer development, was found in 95.78 % (HPVL1), 92.63 % (HPV16), and 3.15 % (HPV18) of patients. No correlation was found between HPV16 and EGFR mutations (p = 0.0616). Overall, mutations like V742R, Q787Q, Q849H, E866E, T854A, L858R, E872Q, and E688Q were found. Next, impact of TKI inhibitor (gefitinib) was checked with respect to presence or absence of mutation considering Q787Q mutation in exon 20 (G/A genotype) which is present in 25.2 % patients. Mutated cervical cancer cell lines showed higher sensitivity to gefitinib. Overall, this study suggests the importance of mutations in EGFR gene and indicates their relevance with respect to TKIs treatment in Indian cervical cancer patients. PMID- 26762414 TI - RANK-RANKL interactions are involved in cell adhesion-mediated drug resistance in multiple myeloma cell lines. AB - Interaction between multiple myeloma (MM) cells and the bone marrow microenvironment plays a critical role in MM pathogenesis and the development of drug resistance. Recently, it has been reported that MM cells express the receptor activator of nuclear factor-kappaB (NF-kappaB) (RANK). However, the role of the RANK/RANK ligand (RANKL) system in drug resistance remains unclear. In this study, we demonstrated a novel function of the RANK/RANKL system in promoting drug resistance in MM. We found that RANKL treatment induced drug resistance in RANK-expressing but not RANK-negative cell lines. RANKL stimulation of RANK-expressing cells increased multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), and lung resistance protein 1 (LRP1) expression and decreased Bim expression through various signaling molecules. RNA silencing of Bim expression induced drug resistance, but the RANKL-mediated drug resistance could not be overcome through the RNA silencing of MDR1, BCRP, and LRP1 expression. These results indicate that the RANK/RANKL system induces chemoresistance through the activation of multiple signal transduction pathways and by decreasing Bim expression in RANK-positive MM cells. These findings may prove to be useful in the development of cell adhesion-mediated drug resistance inhibitors in RANK-positive MM cells. PMID- 26762415 TI - Lin28: an emerging important oncogene connecting several aspects of cancer. AB - RNA-binding protein Lin28 was originally found as a heterochronic gene which played a significant role in the development of Caenorhabditis elegans. The tumor suppressor let-7 is a downstream target of Lin28, which has a wide variety of target genes which are involved in many aspects of cellular activities. By inhibition of let-7 and directly binding the target RNAs, Lin28 plays an important role in different biological and pathological processes including differentiation, metabolism, proliferation, pluripotency, and tumorigenesis. Overexpression of Lin28 has been reported in several kinds of cancers and is correlated with poor outcomes. It has been shown that Lin28 could affect the progression of cancers in several ways, such as promoting proliferation, increasing glucose metabolism, and inducing epithelial-mesenchymal transition (EMT) and cancer stem cells. Decrease of Lin28 expression or reactivation of let 7 in cancer cells could induce a reverse effect, indicating their therapeutic values in developing novel strategies for cancer treatment. Here, we will overview the regulatory mechanisms and functions of Lin28 in cancers. PMID- 26762416 TI - ECRG4 as a novel tumor suppressor gene inhibits colorectal cancer cell growth in vitro and in vivo. AB - Esophageal cancer related gene 4 (ECRG4) as a tumor suppressor gene inhibits the growth and development of various tumors. Colorectal cancer (CRC), a common malignant tumor in the digestive tract worldwide, is a leading cause of death. The aim of our study was to assess the tumor-suppressing effect of ECRG4 on CRC and explore its related mechanisms in vitro and in vivo. The expression levels of ECRG4 were measured in colorectal cancer tissues and para-carcinoma tissues. ECRG4 gene was transfected into CRC cells to investigate its effect on cell proliferation by MTT, colony formation assay, and cell cycle analysis. Cell apoptosis was assessed by annexin-V/PI, Hoechst 33342 staining, and analysis of apoptosis-related protein expressions in vitro. The in vivo tumorigenesis assays were performed in nude mice. According to the results, there was a lower expression of ECRG4 in CRC tissues compared with normal tissues, which was strongly associated with histology differentiation and lymph node metastasis. Additionally, overexpression of ECRG4 had a significant inhibitory effect on proliferation and promoted apoptosis in Caco-2 and SW480 cells. Moreover, we found that the overexpression of ECRG4 inhibited tumorigenesis in vivo by diminishing the volume and weight of the tumors and inducing apoptosis of tumor cells. Our study indicates that ECRG4 may be a new potential target and prognostic factor for patients with CRC. PMID- 26762417 TI - Silvestrol induces early autophagy and apoptosis in human melanoma cells. AB - BACKGROUND: Silvestrol is a cyclopenta[b]benzofuran that was isolated from the fruits and twigs of Aglaia foveolata, a plant indigenous to Borneo in Southeast Asia. The purpose of the current study was to determine if inhibition of protein synthesis caused by silvestrol triggers autophagy and apoptosis in cultured human cancer cells derived from solid tumors. METHODS: In vitro cell viability, flow cytometry, fluorescence microscopy, qPCR and immunoblot was used to study the mechanism of action of silvestrol in MDA-MB-435 melanoma cells. RESULTS: By 24 h, a decrease in cyclin B and cyclin D expression was observed in silvestrol-treated cells relative to control. In addition, silvestrol blocked progression through the cell cycle at the G2-phase. In silvestrol-treated cells, DAPI staining of nuclear chromatin displayed nucleosomal fragments. Annexin V staining demonstrated an increase in apoptotic cells after silvestrol treatment. Silvestrol induced caspase-3 activation and apoptotic cell death in a time- and dose-dependent manner. Furthermore, both silvestrol and SAHA enhanced autophagosome formation in MDA-MB-435 cells. MDA-MB-435 cells responded to silvestrol treatment with accumulation of LC3-II and time-dependent p62 degradation. Bafilomycin A, an autophagy inhibitor, resulted in the accumulation of LC3 in cells treated with silvestrol. Silvestrol-mediated cell death was attenuated in ATG7-null mouse embryonic fibroblasts (MEFs) lacking a functional autophagy protein. CONCLUSIONS: Silvestrol potently inhibits cell growth and induces cell death in human melanoma cells through induction of early autophagy and caspase-mediated apoptosis. Silvestrol represents a natural product scaffold that exhibits potent cytotoxic activity and could be used for the further study of autophagy and its relationship to apoptosis in cancer cells. PMID- 26762418 TI - Multiple biomarkers for mortality prediction in peripheral arterial disease. AB - Few studies have assessed which biomarkers influence mortality risk among those with peripheral arterial disease (PAD). We analyzed data from 556 individuals identified to have PAD (i.e. ankle-brachial index ? 0.9) with available measurements of C-reactive protein, the neutrophil-to-lymphocyte ratio (NLR), homocysteine, and the urinary albumin-to-creatinine ratio (UACR) in the 1999-2004 National Health and Nutrition Examination Survey. We investigated whether a combination of these biomarkers improved the prediction of all-cause and cardiovascular mortality beyond conventional risk factors. During follow-up (median, 8.1 years), 277 of 556 participants died; 63 deaths were attributed to cardiovascular disease. After adjusting for conventional risk factors, Cox proportional-hazards models showed the following to be most strongly associated with all-cause mortality (each is followed by the adjusted hazard ratio [HR] per 1 standard deviation increment in the log values): homocysteine (1.31), UACR (1.21), and NLR (1.20). UACR alone significantly predicted cardiovascular mortality (1.53). Persons in the highest quintile of multimarker scores derived from regression coefficients of significant biomarkers had elevated risks of all cause mortality (adjusted HR, 2.45; 95% CI, 1.66-3.62; p for trend, <0.001) and cardiovascular mortality (adjusted HR, 2.20; 95% CI, 1.02-4.71; p for trend, 0.053) compared to those in the lowest two quintiles. The addition of continuous multimarker scores to conventional risk factors improved risk stratification of all-cause mortality (integrated discrimination improvement [IDI], 0.162; p<0.00001) and cardiovascular mortality (IDI, 0.058; p<0.00001). In conclusion, the addition of a continuous multimarker score to conventional risk factors improved mortality prediction among patients with PAD. PMID- 26762421 TI - A secure future. PMID- 26762423 TI - New chemistry revives elementary question. PMID- 26762420 TI - Solving the drink problem. PMID- 26762434 TI - Vietnam begins huge effort to identify war dead. PMID- 26762435 TI - Taiwan's SARS hero poised to be vice-president. PMID- 26762436 TI - Hunt for Ebola's wild hideout takes off as epidemic wanes. PMID- 26762419 TI - In vitro and ex vivo corneal penetration and absorption models. AB - Topical drug administration is the preferred route of drug delivery to the eye despite the poor bioavailability. To develop more efficient drug carriers, reliable in vitro or ex vivo models are required in the early stages of formulation development, with such methods being faster, cheaper, and more ethical alternatives to in vivo studies. In vitro cell culture models are increasingly being used for transcorneal penetration studies, with primary cell cultures and immortalized cell lines now giving way to the development of organotypic corneal constructs for studying ocular drug bioavailability. Artificially cultured human corneal equivalents are still in the early stages of development, but present tremendous potential for corneal penetration studies. Ex vivo models using excised animal tissue are also being used to study corneal penetration with promising results, although significant inter-species variations need to be considered. This review discusses the in vitro and ex vivo models currently being used to study corneal penetration and evaluates their advantages and limitations with a focus on diffusion cell assemblies. In addition to the tissue used, the diffusion cell set-up can significantly influence the penetration profile and should be cautiously adjusted to simulate clinical conditions. PMID- 26762437 TI - Rebooted Kepler spacecraft hauls in the planets. PMID- 26762438 TI - Nuclear rumours delay India's bid for neutrino glory. PMID- 26762439 TI - Corrections. PMID- 26762440 TI - Trouble in Tibet. PMID- 26762441 TI - Why boredom is anything but boring. PMID- 26762442 TI - Policy: Reassess New Mexico's nuclear-waste repository. PMID- 26762446 TI - Geological sites: EU conservation overlooks geology. PMID- 26762447 TI - Environmental hazard: Monitor safety of aged fuel pipelines. PMID- 26762448 TI - Border controls: Refugee fences fragment wildlife. PMID- 26762449 TI - Cachexia: Treat wasting illness on multiple fronts. PMID- 26762450 TI - Research training: Plans for European medical doctorate. PMID- 26762451 TI - Microbiome: Fibre for the future. PMID- 26762452 TI - Cosmology: Photons from dwarf galaxy zap hydrogen. PMID- 26762453 TI - Climate science: Earth's narrow escape from a big freeze. PMID- 26762454 TI - Neurobiology: Pull out the stops for plasticity. PMID- 26762455 TI - Eight per cent leakage of Lyman continuum photons from a compact, star-forming dwarf galaxy. AB - One of the key questions in observational cosmology is the identification of the sources responsible for ionization of the Universe after the cosmic 'Dark Ages', when the baryonic matter was neutral. The currently identified distant galaxies are insufficient to fully reionize the Universe by redshift z ~ 6 (refs 1-3), but low-mass, star-forming galaxies are thought to be responsible for the bulk of the ionizing radiation. As direct observations at high redshift are difficult for a variety of reasons, one solution is to identify local proxies of this galaxy population. Starburst galaxies at low redshifts, however, generally are opaque to Lyman continuum photons. Small escape fractions of about 1 to 3 per cent, insufficient to ionize much surrounding gas, have been detected only in three low redshift galaxies. Here we report far-ultraviolet observations of the nearby low mass star-forming galaxy J0925+1403. The galaxy is leaking ionizing radiation with an escape fraction of about 8 per cent. The total number of photons emitted during the starburst phase is sufficient to ionize intergalactic medium material that is about 40 times as massive as the stellar mass of the galaxy. PMID- 26762456 TI - Iron-catalysed tritiation of pharmaceuticals. AB - A thorough understanding of the pharmacokinetic and pharmacodynamic properties of a drug in animal models is a critical component of drug discovery and development. Such studies are performed in vivo and in vitro at various stages of the development process--ranging from preclinical absorption, distribution, metabolism and excretion (ADME) studies to late-stage human clinical trials--to elucidate a drug molecule's metabolic profile and to assess its toxicity. Radiolabelled compounds, typically those that contain (14)C or (3)H isotopes, are one of the most powerful and widely deployed diagnostics for these studies. The introduction of radiolabels using synthetic chemistry enables the direct tracing of the drug molecule without substantially altering its structure or function. The ubiquity of C-H bonds in drugs and the relative ease and low cost associated with tritium ((3)H) make it an ideal radioisotope with which to conduct ADME studies early in the drug development process. Here we describe an iron-catalysed method for the direct (3)H labelling of pharmaceuticals by hydrogen isotope exchange, using tritium gas as the source of the radioisotope. The site selectivity of the iron catalyst is orthogonal to currently used iridium catalysts and allows isotopic labelling of complementary positions in drug molecules, providing a new diagnostic tool in drug development. PMID- 26762457 TI - Critical insolation-CO2 relation for diagnosing past and future glacial inception. AB - The past rapid growth of Northern Hemisphere continental ice sheets, which terminated warm and stable climate periods, is generally attributed to reduced summer insolation in boreal latitudes. Yet such summer insolation is near to its minimum at present, and there are no signs of a new ice age. This challenges our understanding of the mechanisms driving glacial cycles and our ability to predict the next glacial inception. Here we propose a critical functional relationship between boreal summer insolation and global carbon dioxide (CO2) concentration, which explains the beginning of the past eight glacial cycles and might anticipate future periods of glacial inception. Using an ensemble of simulations generated by an Earth system model of intermediate complexity constrained by palaeoclimatic data, we suggest that glacial inception was narrowly missed before the beginning of the Industrial Revolution. The missed inception can be accounted for by the combined effect of relatively high late-Holocene CO2 concentrations and the low orbital eccentricity of the Earth. Additionally, our analysis suggests that even in the absence of human perturbations no substantial build-up of ice sheets would occur within the next several thousand years and that the current interglacial would probably last for another 50,000 years. However, moderate anthropogenic cumulative CO2 emissions of 1,000 to 1,500 gigatonnes of carbon will postpone the next glacial inception by at least 100,000 years. Our simulations demonstrate that under natural conditions alone the Earth system would be expected to remain in the present delicately balanced interglacial climate state, steering clear of both large-scale glaciation of the Northern Hemisphere and its complete deglaciation, for an unusually long time. PMID- 26762458 TI - Earliest hominin occupation of Sulawesi, Indonesia. AB - Sulawesi is the largest and oldest island within Wallacea, a vast zone of oceanic islands separating continental Asia from the Pleistocene landmass of Australia and Papua (Sahul). By one million years ago an unknown hominin lineage had colonized Flores immediately to the south, and by about 50 thousand years ago, modern humans (Homo sapiens) had crossed to Sahul. On the basis of position, oceanic currents and biogeographical context, Sulawesi probably played a pivotal part in these dispersals. Uranium-series dating of speleothem deposits associated with rock art in the limestone karst region of Maros in southwest Sulawesi has revealed that humans were living on the island at least 40 thousand years ago (ref. 5). Here we report new excavations at Talepu in the Walanae Basin northeast of Maros, where in situ stone artefacts associated with fossil remains of megafauna (Bubalus sp., Stegodon and Celebochoerus) have been recovered from stratified deposits that accumulated from before 200 thousand years ago until about 100 thousand years ago. Our findings suggest that Sulawesi, like Flores, was host to a long-established population of archaic hominins, the ancestral origins and taxonomic status of which remain elusive. PMID- 26762459 TI - Diet-induced extinctions in the gut microbiota compound over generations. AB - The gut is home to trillions of microorganisms that have fundamental roles in many aspects of human biology, including immune function and metabolism. The reduced diversity of the gut microbiota in Western populations compared to that in populations living traditional lifestyles presents the question of which factors have driven microbiota change during modernization. Microbiota-accessible carbohydrates (MACs) found in dietary fibre have a crucial involvement in shaping this microbial ecosystem, and are notably reduced in the Western diet (high in fat and simple carbohydrates, low in fibre) compared with a more traditional diet. Here we show that changes in the microbiota of mice consuming a low-MAC diet and harbouring a human microbiota are largely reversible within a single generation. However, over several generations, a low-MAC diet results in a progressive loss of diversity, which is not recoverable after the reintroduction of dietary MACs. To restore the microbiota to its original state requires the administration of missing taxa in combination with dietary MAC consumption. Our data illustrate that taxa driven to low abundance when dietary MACs are scarce are inefficiently transferred to the next generation, and are at increased risk of becoming extinct within an isolated population. As more diseases are linked to the Western microbiota and the microbiota is targeted therapeutically, microbiota reprogramming may need to involve strategies that incorporate dietary MACs as well as taxa not currently present in the Western gut. PMID- 26762460 TI - Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. AB - Helminth parasitic infections are a major global health and social burden. The host defence against helminths such as Nippostrongylus brasiliensis is orchestrated by type 2 cell-mediated immunity. Induction of type 2 cytokines, including interleukins (IL) IL-4 and IL-13, induce goblet cell hyperplasia with mucus production, ultimately resulting in worm expulsion. However, the mechanisms underlying the initiation of type 2 responses remain incompletely understood. Here we show that tuft cells, a rare epithelial cell type in the steady-state intestinal epithelium, are responsible for initiating type 2 responses to parasites by a cytokine-mediated cellular relay. Tuft cells have a Th2-related gene expression signature and we demonstrate that they undergo a rapid and extensive IL-4Ralpha-dependent amplification following infection with helminth parasites, owing to direct differentiation of epithelial crypt progenitor cells. We find that the Pou2f3 gene is essential for tuft cell specification. Pou2f3(-/ ) mice lack intestinal tuft cells and have defective mucosal type 2 responses to helminth infection; goblet cell hyperplasia is abrogated and worm expulsion is compromised. Notably, IL-4Ralpha signalling is sufficient to induce expansion of the tuft cell lineage, and ectopic stimulation of this signalling cascade obviates the need for tuft cells in the epithelial cell remodelling of the intestine. Moreover, tuft cells secrete IL-25, thereby regulating type 2 immune responses. Our data reveal a novel function of intestinal epithelial tuft cells and demonstrate a cellular relay required for initiating mucosal type 2 immunity to helminth infection. PMID- 26762461 TI - Structures of two distinct conformations of holo-non-ribosomal peptide synthetases. AB - Many important natural products are produced by multidomain non-ribosomal peptide synthetases (NRPSs). During synthesis, intermediates are covalently bound to integrated carrier domains and transported to neighbouring catalytic domains in an assembly line fashion. Understanding the structural basis for catalysis with non-ribosomal peptide synthetases will facilitate bioengineering to create novel products. Here we describe the structures of two different holo-non-ribosomal peptide synthetase modules, each revealing a distinct step in the catalytic cycle. One structure depicts the carrier domain cofactor bound to the peptide bond-forming condensation domain, whereas a second structure captures the installation of the amino acid onto the cofactor within the adenylation domain. These structures demonstrate that a conformational change within the adenylation domain guides transfer of intermediates between domains. Furthermore, one structure shows that the condensation and adenylation domains simultaneously adopt their catalytic conformations, increasing the overall efficiency in a revised structural cycle. These structures and the single-particle electron microscopy analysis demonstrate a highly dynamic domain architecture and provide the foundation for understanding the structural mechanisms that could enable engineering of novel non-ribosomal peptide synthetases. PMID- 26762464 TI - Extremely low frequency electromagnetic fields affect proliferation and mitochondrial activity of human cancer cell lines. AB - PURPOSE: To date, the effects of electromagnetic fields on cell metabolism have been overlooked. The objective of the present study was to investigate the influence of extremely low frequency electromagnetic fields (ELF-EMF) over mitochondrial metabolism and the consequent impact on cancer cell growth. MATERIALS AND METHODS: The effects of ELF-EMF on cancer growth were investigated in several human cancer cell lines by crystal violet assay. The modulation of mitochondrial activity was assessed by cytofluorimetric evaluation of membrane potential and by real-time quantification of mitochondrial transcription. Moreover the expression of several mitochondrial proteins and their levels in the organelle were evaluated. RESULTS: The long-term exposure to ELF-EMF reduced the proliferation of several cancer cell lines and the effect was associated to an increased mitochondrial activity without evident changes in ATP levels. The results of our experiments excluded a transcriptional modulation of mitochondrial respiratory complexes, rather suggesting that ELF-EMF increased the energy demand. The altered mitochondrial metabolism led to changes in mitochondrial protein profile. In fact we found a downregulated expression of mitochondrial phospho-ERK, p53 and cytochrome c. CONCLUSION: The results of the present study indicate that ELF-EMF can negatively modulate cancer cell growth increasing respiratory activity of cells and altering mitochondrial protein expression. PMID- 26762462 TI - Synthetic cycle of the initiation module of a formylating nonribosomal peptide synthetase. AB - Nonribosomal peptide synthetases (NRPSs) are very large proteins that produce small peptide molecules with wide-ranging biological activities, including environmentally friendly chemicals and many widely used therapeutics. NRPSs are macromolecular machines, with modular assembly-line logic, a complex catalytic cycle, moving parts and many active sites. In addition to the core domains required to link the substrates, they often include specialized tailoring domains, which introduce chemical modifications and allow the product to access a large expanse of chemical space. It is still unknown how the NRPS tailoring domains are structurally accommodated into megaenzymes or how they have adapted to function in nonribosomal peptide synthesis. Here we present a series of crystal structures of the initiation module of an antibiotic-producing NRPS, linear gramicidin synthetase. This module includes the specialized tailoring formylation domain, and states are captured that represent every major step of the assembly-line synthesis in the initiation module. The transitions between conformations are large in scale, with both the peptidyl carrier protein domain and the adenylation subdomain undergoing huge movements to transport substrate between distal active sites. The structures highlight the great versatility of NRPSs, as small domains repurpose and recycle their limited interfaces to interact with their various binding partners. Understanding tailoring domains is important if NRPSs are to be utilized in the production of novel therapeutics. PMID- 26762466 TI - Nickel supported on nitrogen-doped carbon nanotubes as hydrogen oxidation reaction catalyst in alkaline electrolyte. AB - The development of a low-cost, high-performance platinum-group-metal-free hydroxide exchange membrane fuel cell is hindered by the lack of a hydrogen oxidation reaction catalyst at the anode. Here we report that a composite catalyst, nickel nanoparticles supported on nitrogen-doped carbon nanotubes, has hydrogen oxidation activity similar to platinum-group metals in alkaline electrolyte. Although nitrogen-doped carbon nanotubes are a very poor hydrogen oxidation catalyst, as a support, it increases the catalytic performance of nickel nanoparticles by a factor of 33 (mass activity) or 21 (exchange current density) relative to unsupported nickel nanoparticles. Density functional theory calculations indicate that the nitrogen-doped support stabilizes the nanoparticle against reconstruction, while nitrogen located at the edge of the nanoparticle tunes local adsorption sites by affecting the d-orbitals of nickel. Owing to its high activity and low cost, our catalyst shows significant potential for use in low-cost, high-performance fuel cells. PMID- 26762468 TI - Reversing left bronchus obstruction by compression of a pulmonary artery stent. AB - We report a case where endovascular stenting as part of the treatment of complex cardiovascular disease led to airway compression. Using a novel technique, this was successfully reversed. Simultaneous inflations of two balloons-one in the obstructed bronchus and one in the aorta combined with external compression of the chest-resulted in compression the stent. This report illustrates that by thinking "out of the box" and bearing in mind spatial relationships inside the chest, it is possible to diminish the anterior-posterior diameters of a stent. This intervention proved to be successful with relief of the left bronchial compression and improvement of chronic airway infection. (c) 2016 Wiley Periodicals, Inc. PMID- 26762469 TI - Decrease in coccolithophore calcification and CO2 since the middle Miocene. AB - Marine algae are instrumental in carbon cycling and atmospheric carbon dioxide (CO2) regulation. One group, coccolithophores, uses carbon to photosynthesize and to calcify, covering their cells with chalk platelets (coccoliths). How ocean acidification influences coccolithophore calcification is strongly debated, and the effects of carbonate chemistry changes in the geological past are poorly understood. This paper relates degree of coccolith calcification to cellular calcification, and presents the first records of size-normalized coccolith thickness spanning the last 14 Myr from tropical oceans. Degree of calcification was highest in the low-pH, high-CO2 Miocene ocean, but decreased significantly between 6 and 4 Myr ago. Based on this and concurrent trends in a new alkenone Ep record, we propose that decreasing CO2 partly drove the observed trend via reduced cellular bicarbonate allocation to calcification. This trend reversed in the late Pleistocene despite low CO2, suggesting an additional regulator of calcification such as alkalinity. PMID- 26762467 TI - pH-Sensitive stimulus-responsive nanocarriers for targeted delivery of therapeutic agents. AB - In recent years miscellaneous smart micro/nanosystems that respond to various exogenous/endogenous stimuli including temperature, magnetic/electric field, mechanical force, ultrasound/light irradiation, redox potentials, and biomolecule concentration have been developed for targeted delivery and release of encapsulated therapeutic agents such as drugs, genes, proteins, and metal ions specifically at their required site of action. Owing to physiological differences between malignant and normal cells, or between tumors and normal tissues, pH sensitive nanosystems represent promising smart delivery vehicles for transport and delivery of anticancer agents. Furthermore, pH-sensitive systems possess applications in delivery of metal ions and biomolecules such as proteins, insulin, etc., as well as co-delivery of cargos, dual pH-sensitive nanocarriers, dual/multi stimuli-responsive nanosystems, and even in the search for new solutions for therapy of diseases such as Alzheimer's. In order to design an optimized system, it is necessary to understand the various pH-responsive micro/nanoparticles and the different mechanisms of pH-sensitive drug release. This should be accompanied by an assessment of the theoretical and practical challenges in the design and use of these carriers. WIREs Nanomed Nanobiotechnol 2016, 8:696-716. doi: 10.1002/wnan.1389 For further resources related to this article, please visit the WIREs website. PMID- 26762470 TI - Alterations of the volatile metabolome in mouse models of Alzheimer's disease. AB - In the present study, we tested whether the volatile metabolome was altered by mutations of the Alzheimer's disease (AD)-implicated amyloid precursor protein gene (APP) and comprehensively examined urinary volatiles that may potentially serve as candidate biomarkers of AD. Establishing additional biomarkers in screening populations for AD will provide enhanced diagnostic specificity and will be critical in evaluating disease-modifying therapies. Having strong evidence of gross changes in the volatile metabolome of one line of APP mice, we utilized three unique mouse lines which over-express human mutations of the APP gene and their respective non-transgenic litter-mates (NTg). Head-space gas chromatography/mass spectrometry (GC/MS) of urinary volatiles uncovered several aberrant chromatographic peak responses. We later employed linear discrimination analysis and found that the GC/MS peak responses provide accurate (>84%) genotype classification of urinary samples. These initial data in animal models show that mutant APP gene expression entails a uniquely identifiable urinary odor, which if uncovered in clinical AD populations, may serve as an additional biomarker for the disease. PMID- 26762472 TI - Successful treatment of severe refractory lupus hepatitis with mycophenolate mofetil. AB - Systemic lupus erythematosus-related hepatitis, known as lupus hepatitis, is a rare manifestation of systemic lupus erythematosus, and is usually subclinical with mild abnormalities of serum liver enzymes. While cases with clinically significant and refractory lupus hepatitis are uncommon, treatment options for lupus hepatitis are to be established. Here, we report the case of a 45-year-old man with progressive lupus hepatitis accompanied by autoimmune haemolytic anaemia. Lupus hepatitis of this patient was refractory to tacrolimus, azathioprine and cyclophosphamide, but was successfully treated by mycophenolate mofetil. Mycophenolate mofetil might be an effective therapeutic option for refractory lupus hepatitis. PMID- 26762473 TI - Association between toll-like receptor polymorphisms and systemic lupus erythematosus: a meta-analysis update. AB - OBJECTIVE: The aim of this study was to determine whether polymorphisms of the Toll-like receptor (TLR) genes are associated with susceptibility to systemic lupus erythematosus (SLE). METHODS: The authors conducted a meta-analysis of the relationship between 12 TLR polymorphisms and SLE susceptibility. RESULTS: In total, 26 studies that involved 11,984 patients and 14,572 controls were included in the meta-analysis. The meta-analysis showed no association between the two alleles of the rs352140, rs5743836, and rs352139 polymorphisms of TLR9 and SLE, but indicated an association between the two alleles of the rs187084 polymorphism (TLR9) and SLE in the overall population (OR = 0.869, 95% CI = 0.762-0.992, P = 0.038). No association was detected between rs3764880 (TLR8) and SLE; however, our meta-analysis indicated an association between rs3764879 (TLR8) and SLE in Caucasians (OR = 1.414, 95% CI = 1.139-1.756, P = 0.002). An association between rs179008 (TLR7) and SLE was found in the African (OR = 0.430, 95% CI = 0.238 0.775, P = 0.005), but not in the Caucasian population (OR = 1.206, 95% CI = 0.932-1.614, P = 0.145). Furthermore, our meta-analysis indicated a significant association between rs3853839 (TLR7) and SLE in the Asian population (OR = 0.773, 95% CI = 0.735, 0.823, P < 1.0 * 10(-9)). No associations were found between rs5744168 (TLR5), rs4986791 (TLR4), rs4986790 (TLR4), and rs3775291 (TLR3) polymorphisms and SLE susceptibility. CONCLUSIONS: Our meta-analysis suggests that TLR7, TLR8, and TLR9 polymorphisms are associated with the development of SLE in Caucasian, Asian, and African populations. PMID- 26762474 TI - Successful percutaneous implantation of symetis ACURATE neo transcatheter aortic bioprosthesis for the treatment of pure aortic regurgitation. AB - Transcatheter aortic valve implantation (TAVI) was initially developed for the treatment of calcific aortic stenosis. In the recent years, however, TAVI has been used to treat selected patients with pure, severe AR. We report successful transfemoral implantation of a Symetis ACURATE neo bioprosthesis in a severely symptomatic, 87-year-old woman with pure AR and major comorbidities. We decided to use the ACURATE neo bioprosthesis for some of its features appeared to us as potentially useful in the setting of pure AR: the stabilization arches ensure perfect coaxial alignment and extreme stability of the device during deployment, and the "waist" and the skirt were considered useful to obtain a good seal in the absence of significant valvular and annular calcifications. Finally, we decided to use a self-expanding valve to minimize the trauma to the aortic annulus. The procedure was successful and the patient was discharged home on postoperative day 3. At the 3-month control echocardiography, there was no residual AR, and the mean transprosthetic gradient was 3 mm Hg. The current case demonstrates that percutaneous TAVI with the ACURATE neo bioprosthesis may be used to treat pure, isolated AR in selected patients. The device has several interesting features that could make it advantageous in this setting. (c) 2016 Wiley Periodicals, Inc. PMID- 26762476 TI - Preface to selected papers from the 6th International Conference on Computational Systems-Biology and Bioinformatics (CSBio2015). PMID- 26762475 TI - A Bayesian approach to analyzing phenotype microarray data enables estimation of microbial growth parameters. AB - Biolog phenotype microarrays (PMs) enable simultaneous, high throughput analysis of cell cultures in different environments. The output is high-density time course data showing redox curves (approximating growth) for each experimental condition. The software provided with the Omnilog incubator/reader summarizes each time-course as a single datum, so most of the information is not used. However, the time courses can be extremely varied and often contain detailed qualitative (shape of curve) and quantitative (values of parameters) information. We present a novel, Bayesian approach to estimating parameters from Phenotype Microarray data, fitting growth models using Markov Chain Monte Carlo (MCMC) methods to enable high throughput estimation of important information, including length of lag phase, maximal "growth" rate and maximum output. We find that the Baranyi model for microbial growth is useful for fitting Biolog data. Moreover, we introduce a new growth model that allows for diauxic growth with a lag phase, which is particularly useful where Phenotype Microarrays have been applied to cells grown in complex mixtures of substrates, for example in industrial or biotechnological applications, such as worts in brewing. Our approach provides more useful information from Biolog data than existing, competing methods, and allows for valuable comparisons between data series and across different models. PMID- 26762471 TI - Chinese SLE Treatment and Research group (CSTAR) registry VII: prevalence and clinical significance of serositis in Chinese patients with systemic lupus erythematosus. AB - OBJECTIVES: To investigate both the prevalence and clinical characteristics of serositis in Chinese patients with systemic lupus erythematosus (SLE) in a large cohort in the Chinese SLE Treatment and Research group (CSTAR) database. METHODS: A prospective cross-sectional study of patients with SLE was conducted based on the data from the CSTAR registry. Serositis was defined according to the 1999 revised American College of Rheumatology (ACR) criteria for SLE - that is, pleuritis/pleural effusion and/or pericarditis/pericardial effusion detected by echocardiography, chest X-ray or chest computerized tomography (CT) scan. Peritonitis/peritoneal effusion were confirmed by abdominal ultrasonography. We analysed the prevalence and clinical associations of serositis with demographic data, organ involvements, laboratory findings and SLE disease activity. RESULTS: Of 2104 patients with SLE, 345 were diagnosed with serositis. The prevalence of lupus nephritis (LN), interstitial lung disease and pulmonary arterial hypertension, as well as the presence of leukocytopenia, thrombocytopenia, hypocomplementemia and anti-dsDNA antibodies was significantly higher in patients with serositis (P < 0.05). Significantly higher SLE disease activity scores were found in patients with serositis compared to those patients without serositis (P < 0.05). Lupus-related peritonitis had similar clinical manifestations and laboratory profiles as serositis caused by SLE. CONCLUSIONS: There is a significant association of nephropathy, interstitial lung disease, pulmonary arterial hypertension, hypocomplementemia, leukocytopenia, thrombocytopenia and elevated anti-dsDNA antibodies with serositis. The results suggest that higher SLE disease activity contributes to serositis development, and should be treated aggressively. PMID- 26762478 TI - Improving Follow-Up for Failed Newborn Hearing Screening in Emirati Infants. AB - This column shares the best evidence-based strategies and innovative ideas on how to facilitate the learning and implementation of EBP principles and processes by clinicians as well as nursing and interprofessional students. Guidelines for submission are available at http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1741-6787. PMID- 26762477 TI - Endogenous sulfur dioxide alleviates collagen remodeling via inhibiting TGF beta/Smad pathway in vascular smooth muscle cells. AB - The study was designed to investigate the role of endogenous sulfur dioxide (SO2) in collagen remodeling and its mechanisms in vascular smooth muscle cells (VSMCs). Overexpression of endogenous SO2 synthase aspartate aminotransferase (AAT) 1 or 2 increased SO2 levels and inhibited collagen I and III expressions induced by transforming growth factor (TGF)-beta1 in VSMCs. In contrast, AAT1 or AAT2 knockdown induced a severe collagen deposition in TGF-beta1-treated VSMCs. Furthermore, AAT1 or AAT2 overexpression suppressed procollagen I and III mRNA, upregulated matrix metalloproteinase (MMP)-13 expression, downregulated tissue inhibitors of MMP-1 level, and vice versa. Mechanistically, AAT1 or AAT2 overexpression inhibited phosphorylation of type I TGF-beta receptor (TbetaRI) and Smad2/3 in TGF-beta1-stimulated VSMCs. Whereas SB431542, an inhibitor of TGF beta1/Smad signaling pathway, attenuated excessive collagen deposition induced by AAT knockdown. Most importantly, ectopically expressing AAT or exogenous addition of 100 MUM SO2 blocked AAT deficiency-aggravated collagen accumulation in TGF beta1-stimulatd VSMCs, while no inhibition was observed at 100 MUM ethyl pyruvate. These findings indicated that endogenous SO2 alleviated collagen remodeling by controlling TGF-beta1/TbetaRI/Smad2/3-mediated modulation of collagen synthesis and degradation. PMID- 26762479 TI - Association between self-reported and clinical oral health status in Belarusian adults. AB - AIM: The aims of the present study were to determine characteristics of self perception of oral health, and to investigate associations between self-reported status and clinical oral health status among Belarusian adults. METHODS: A cross sectional study, including a questionnaire survey and oral health examination, was conducted among 281 dental patients. RESULTS: Of the participants, 74% were women; the mean ages of female and male participants were 35.9 +/- 12.3 and 28.0 +/- 10.3 years (P < 0.001), respectively. More than half of the participants (58%) described their oral health as negative. The number of decayed teeth (P < 0.001), missing teeth (P < 0.001), and teeth with bleeding on probing (P < 0.01) and deep periodontal pockets (P < 0.001) were significantly higher among participants who described their oral health as negative compared to their counterparts. Participants with better agreement between self-reported and clinical number of teeth had significantly lower numbers of decayed and missing teeth (P < 0.01). There was a significant relationship between participants' self reported periodontal status and number of teeth with bleeding on probing and deep periodontal pockets (P < 0.05). CONCLUSIONS: Self-perceived oral health was significantly associated with clinical oral health status in this study. Self reporting methods could be useful for population-based oral health surveys in Belarus. PMID- 26762483 TI - Graphitic carbon nitride catalysed photoacetalization of aldehydes/ketones under ambient conditions. AB - Graphitic-C3N4 is shown for the first time to catalyse photoacetalization of aldehydes/ketones with alcohols to acetals in high yields using visible light under ambient conditions; transient charge separation over the material is effective to catalyse the reaction in the absence of Lewis or Bronsted acids, giving a new green alternative catalyst. PMID- 26762480 TI - Functional anterior pituitary generated in self-organizing culture of human embryonic stem cells. AB - Anterior pituitary is critical for endocrine systems. Its hormonal responses to positive and negative regulators are indispensable for homeostasis. For this reason, generating human anterior pituitary tissue that retains regulatory hormonal control in vitro is an important step for the development of cell transplantation therapy for pituitary diseases. Here we achieve this by recapitulating mouse pituitary development using human embryonic stem cells. We find that anterior pituitary self-forms in vitro following the co-induction of hypothalamic and oral ectoderm. The juxtaposition of these tissues facilitated the formation of pituitary placode, which subsequently differentiated into pituitary hormone-producing cells. They responded normally to both releasing and feedback signals. In addition, after transplantation into hypopituitary mice, the in vitro-generated corticotrophs rescued physical activity levels and survival of the hosts. Thus, we report a useful methodology for the production of regulator responsive human pituitary tissue that may benefit future studies in regenerative medicine. PMID- 26762484 TI - Does heterogeneity of intracellular Ca[Formula: see text] dynamics underlie speed tuning of direction-selective responses in starburst amacrine cells? AB - The starburst amacrine cell (SAC) plays a fundamental role in retinal motion perception. In the vertebrate retina, SAC dendrites have been shown to be directionally selective in terms of their Ca[Formula: see text] responses for stimuli that move centrifugally from the soma. The mechanism by which SACs show Ca[Formula: see text] bias for centrifugal motion is yet to be determined with precision. Recent morphological studies support a presynaptic delay in glutamate receptor activation induced Ca[Formula: see text] release from bipolar cells preferentially contacting SACs. However, bipolar cells are known to be electrotonically coupled so time delays between the bipolar cells that provide input to SACs seem unlikely. Using fluorescent microscopy and imunnostaining, we found that the endoplasmic reticulum (ER) is omnipresent in the soma extending to the distal processes of SACs. Consequently, a working hypothesis on heterogeneity of intracellular Ca[Formula: see text] dynamics from ER is proposed as a possible explanation for the cause of speed tuning of direction-selective Ca[Formula: see text] responses in dendrites of SACs. PMID- 26762481 TI - The safety and effectiveness of bivalirudin in female patients with acute myocardial infarction undergoing primary angioplasty: A subgroup analysis of the BRIGHT trial. AB - BACKGROUND: Being female is an independent predictor of adverse events during percutaneous coronary interventions (PCI). OBJECTIVE: To evaluate the safety and efficiency of bivalirudin during emergency PCI in female patients with acute myocardial infarction (AMI). METHODS: The present study was a subgroup analysis of the randomized Bivalirudin in Acute Myocardial Infarction vs. Heparin and GPI plus Heparin (BRIGHT) trial. A total of 392 female patients enrolled in the BRIGHT trial were assigned to receive bivalirudin with post-procedure dose infusion (n = 127) or heparin with or without tirofiban (n = 265). The primary efficiency endpoint was 30-day net adverse clinical events (NACEs). The secondary efficiency endpoints were 30-day major cardiac and cerebral events (MACCEs) and bleeding events defined according to Bleeding Academic Research Consortium (BARC) definitions. RESULTS: For female patients, bivalirudin treatment was associated with significantly lower incidences of 30-day NACEs (6.3% vs. 21.5%, P < 0.001), any bleeding (2.4% vs. 12.8%, P = 0.001) and BARC 2-5 type bleeding (1.6% vs. 7.2%, P = 0.021) compared with the control regimen. The incidence of MACCEs (3.4% vs. 9.4%, P = 0.055) and stent thrombosis (0% vs. 1.1%, P = 0.229) were comparable between the two groups. Multivariate analysis showed that bivalirudin (OR: 0.245, 95% CI: 0.113-0.532, P < 0.001), transradial access (OR: 0.119, 95% CI: 0.067-0.211, P < 0.001), and statin (OR: 0.254, 95% CI: 0.08-0.807, P = 0.02) were independent protective factors for 30-day NACEs in female patients. CONCLUSIONS: The use of bivalirudin during emergency PCI for AMI in female patients significantly reduced the bleeding risk with anticoagulation effects compared with heparin with or without tirofiban. PMID- 26762485 TI - Affect development as a need to preserve homeostasis. AB - In this review, we aim to present our hypothesis about the neural development of affect. According to this view, affect develops at a multi-layered process, and as a mediator between drives, emotion and cognition. This development is parallel to the evolution of the brain from reptiles to mammals. There are five steps in this process: (1) Because of the various environmental challenges, changes in the autonomic nervous system occur and homeostasis becomes destabilized; (2) Drives arise from the destabilized homeostasis; (3) Drives trigger the neural basis of the basic emotional systems; (4) These basic emotions evolve into affect to find the particular object to invest the emotional energy; and (5) In the final stage, cognition is added to increase the possibility of identifying a particular object. In this paper, we will summarize the rationale behind this view, which is based on neuroscientific proofs, such as evolution of autonomic nervous system, neural basis the raw affective states, the interaction between affect and cognition, related brain areas, related neurotransmitters, as well as some clinical examples. PMID- 26762482 TI - Effect of topical rebamipide on conjunctival goblet cell recovery after vitrectomy. AB - In vitro and in vivo experiments have shown that topical rebamipide will increase the number of goblet cells in the bulbar conjunctiva. The purpose of this study was to determine whether topical rebamipide will enhance the recovery of conjunctival goblet cells that were damaged during vitrectomy. Forty patients who underwent vitrectomy surgery were studied. The 40 patients consisted of 20 with diabetes mellitus (DM) and 20 patients without DM. They were randomized in a 1:1 ratio into groups that were treated or not treated with topical 2% rebamipide after the surgery. Impression cytology was performed at the end of surgery and at 14 days after the surgery. The mean goblet cell density of each specimen was determined by averaging the total number of goblet cells obtained from three consecutive high magnification microscopic images. In patients without DM, the mean goblet cell density at 14 days after the vitrectomy was significantly higher in eyes with topical rebemipide than in eyes without rebemipide (P < 0.01). In patients with DM, a similar tendency was observed but the difference was not significant (P = 0.09). These results suggest that topical rebamipide can be helpful in patients with globlet cell damage that occur during and after vitrectomy. PMID- 26762486 TI - Epithelial ovarian cancer subtypes attributable to smoking in the Norwegian Women and Cancer Study, 2012. AB - Among European women, ovarian cancer is the fifth most common cancer. Smoking is an established risk factor for mucinous tumors. We estimated the impact of smoking in Norwegian women using population attributable fractions (PAFs) of epithelial ovarian cancer (EOC), by invasiveness and by histological subtypes in the Norwegian Women and Cancer Study with an average of 13.2 years of follow-up. During >2 million person-years, a total of 915 incident EOC cases, of which 667 (73%) invasive and 248 (27%) borderline, were identified among 154,234 women aged 34-70 years at enrolment. Compared with never smokers, current smokers had a nonstatistically significant increased risk of mucinous tumors (hazard ratio [HR] = 1.67 [95% confidence interval, (CI), 0.96-2.96]) and more than twice statistically significant risk of borderline mucinous tumors (HR = 2.17 [95% CI, 1.06-4.45]). The corresponding PAF estimates were 16.5% for mucinous and 25% for borderline mucinous. We found that among middle-aged women, one in six mucinous tumors and one in four borderline mucinous tumors could have been prevented if women did not smoke. PMID- 26762487 TI - Shaping the nonlinear near field. AB - Light scattering at plasmonic nanoparticles and their assemblies has led to a wealth of applications in metamaterials and nano-optics. Although shaping of fields around nanostructures is widely studied, the influence of the field inside the nanostructures is often overlooked. The linear field distribution inside the structure taken to the third power causes third-harmonic generation, a nonlinear optical response of matter. Here we demonstrate by a far field Fourier imaging method how this simple fact can be used to shape complex fields around a single particle alone. We employ this scheme to switch the third-harmonic emission from a single point source to two spatially separated but coherent sources, as in Young's double-slit assembly. We envision applications as diverse as coherently feeding antenna arrays and optical spectroscopy of spatially extended electronic states. PMID- 26762489 TI - Masked Hypertension in Low-Income South African Adults. AB - While South Africa has one of the highest hypertension rates globally, there are few data on masked hypertension (MHT) and white-coat hypertension (WCHT). This study measured the frequency of MHT and WCHT in low-income (<$500 US per month) South African adults, evaluating cardiovascular risk by arterial stiffness. Participants (n=101, 50% male; mean age 39.4+/-9.7 years) were recruited from a large North-West Province employer. Clinic and 24-hour blood pressure (BP) and pulse wave analysis were recorded. Clinic BP identified 18% of patients as hypertensive, while 24-hour BP showed that 63% of patients were hypertensive. The frequency of MHT was high (33 of 81, 41%) with only one case of WCHT. In comparison to those with normal clinic and 24-hour BP, augmentation index and pulse wave velocity were significantly higher in those with hypertensive 24-hour BP irrespective of clinic BP, indicating that, in this group, masked and sustained hypertension carry a similar elevated cardiovascular risk. PMID- 26762491 TI - Protect vulnerable patients: phase II. PMID- 26762490 TI - Soil microbial responses to forest floor litter manipulation and nitrogen addition in a mixed-wood forest of northern China. AB - Changes in litterfall dynamics and soil properties due to anthropogenic or natural perturbations have important implications to soil carbon (C) and nutrient cycling via microbial pathway. Here we determine soil microbial responses to contrasting types of litter inputs (leaf vs. fine woody litter) and nitrogen (N) deposition by conducting a multi-year litter manipulation and N addition experiment in a mixed-wood forest. We found significantly higher soil organic C, total N, microbial biomass C (MBC) and N (MBN), microbial activity (MR), and activities of four soil extracellular enzymes, including beta-glucosidase (BG), N acetyl-beta-glucosaminidase (NAG), phenol oxidase (PO), and peroxidase (PER), as well as greater total bacteria biomass and relative abundance of gram-negative bacteria (G-) community, in top soils of plots with presence of leaf litter than of those without litter or with presence of only fine woody litter. No apparent additive or interactive effects of N addition were observed in this study. The occurrence of more labile leaf litter stimulated G-, which may facilitate microbial community growth and soil C stabilization as inferred by findings in literature. A continued treatment with contrasting types of litter inputs is likely to result in divergence in soil microbial community structure and function. PMID- 26762492 TI - Investigating staff knowledge of safeguarding and pressure ulcers in care homes. AB - OBJECTIVE: To investigate whether nursing/care home staff regard pressure ulceration as a safeguarding issue; and to explore reporting mechanisms for pressure ulcers (PUs) in nursing/care homes. METHOD: Within one clinical commissioning group, 65 staff members from 50 homes completed a questionnaire assessing their experiences of avoidable and unavoidable PUs, grading systems, and systems in place for referral to safeguarding teams. Understanding of safeguarding was assessed in depth by interviews with 11 staff members. RESULTS: Staff observed an average of 2.72 PUs in their workplaces over the previous 12 months, judging 45.6% to be avoidable. Only a minority of respondents reported knowledge of a grading system (mostly the EPUAP/NPUAP system). Most respondents would refer PUs to the safeguarding team: the existence of a grading system, or guidance, appeared to increase that likelihood. Safeguarding was considered a priority in most homes; interviewees were familiar with the term safeguarding, but some confusion over its meaning was apparent. Quality of written documentation and verbal communication received before residents returned from hospital was highlighted. However, respondents expressed concern over lack of information regarding skin integrity. Most staff had received education regarding ulcer prevention or wound management during training, but none reported post registration training or formal education programmes; reliance was placed on advice of district nurses or tissue viability specialists. CONCLUSION: Staff within nursing/care homes understand the fundamentals of managing skin integrity and the importance of reporting skin damage; however, national education programmes are needed to develop knowledge and skills to promote patient health related quality of life, and to reduce the health-care costs of pressure damage. Further research to investigate understanding, knowledge and skills of nursing/care home staff concerning pressure ulcer development and safeguarding will become increasingly necessary, as levels of the older population who may require assisted living continue to rise. PMID- 26762493 TI - Microbiology of corneal wounds after cataract surgery: biofilm formation and antibiotic resistance patterns. AB - OBJECTIVE: To evaluate the bacterial flora of corneal wounds at the end of cataract surgery before intracameral antibiotic use and to determine agents to treat postoperative endophthalmitis, the potential for biofilm formation, and antibiotic resistance. METHOD: This cross-sectional clinical study included patients who underwent cataract surgery using the phacoemulsification technique without any complications. The hemifacial skin, periocular area, eyelids and eyelashes were washed with 10% povidone-iodine and the conjunctiva was washed with 5% povidoneiodine before cataract surgery. After uncomplicated surgery, a wipe sample was taken from the bulbar conjunctival surface, corneal surface, and wound rim before administering intracameral antibiotics. All samples were plated on blood agar, MRS agar, M17 agar, calcium-lactate agar, plate-count agar, and Sabouraud-dextrose agar. Biofilm formation was evaluated by microtitre plates and the Congo red-agar method. Antimicrobial resistance patterns of isolates were determined by the agar-disk diffusion method. RESULTS: We recruited 50 patients and studied 55 eyes, obtaining 34 isolates from the cultures of 16 eyes. Isolated organisms were coagulase-negative staphylococci (CoNS) (35.3%), Bacillus cereus (29.4%) and Pseudomonas spp. (5.9%). We obtained isolates from 64% of diabetic cases and 20% of non-diabetic cases, (p=0.002). It was observed that 21 out of 34 isolates produced a weakly positive biofilm, 8 were moderately positive, three were strongly positive, and two isolates were biofilm negative. Of the CoNS strains four of the 11 were resistance to four or more antibiotics. CONCLUSION: Microorganisms that remained at the end of cataract surgery had the capacity to produce biofilm and had high antibiotic resistance. Appropriate preoperative disinfection is very important and adequate disinfection and suitable antibiotics should be kept in mind for avoiding endophthalmitis, especially for diabetic patients. Biofilm is one of the major factors affecting the virulence of bacteria, and further studies into prevention of biofilm formation are required in this area. PMID- 26762494 TI - Cost analysis of gentamicin-impregnated collagen sponges in preventing sternal wound infection post cardiac surgery. AB - OBJECTIVE: The use of antibiotic-impregnated sponges (Collatamp) during cardiac surgery is controversial. We analysed the cost-effectiveness of its selective use in patients at high-risk of sternal wound infection (SWI). METHOD: Postoperative costs were analysed in two groups of patients undergoing heart surgery between 2011 and 2013: those with SWI (group 1) and in high-risk patients without SWI (group 2). The potential cost of gentamicin-impregnated collagen sponges (GCS) use in high-risk patients was compared with our current practice. RESULTS: We identified 1,251 patients with at least one recognised risk factor for developing SWI in this period. Of these, 18 developed SWI (incidence 1.4%). The median postoperative cost per patient without SWI was L9,617. The additional cost per patient incurred by SWI was L4,860.75. The annual additional cost for treating patients with SWI was L43,749. With a 50% reduction in SWI, the annual additional cost of treating these patients would be reduced to L21,873. The cost of GCS is L80 per patient. Adding this to L21,873 gives a potential total cost of L71,913 in the treated high-risk cohort. CONCLUSION: In our practice the annual cost of treating SWI in high-risk patients without use of GCS is lower than the annual cost of using GCS in all high-risk patients (L43,749 versus L71,913) if it produces a 50% reduction in SWI. The reduction in the incidence of SWI poses no economic benefit when the cost of the product is factored in. PMID- 26762488 TI - Alternative splicing within the Wnt signaling pathway: role in cancer development. AB - BACKGROUND: The Wnt signaling cascade plays a fundamental role in embryonic development, adult tissue regeneration, homeostasis and stem cell maintenance. Abnormal Wnt signaling has been found to be prevalent in various human cancers. Also, a role of Wnt signaling in the regulation of alternative splicing of several cancer-related genes has been established. In addition, accumulating evidence suggests the existence of multiple splice isoforms of Wnt signaling cascade components, including Wnt ligands, receptors, components of the destruction complex and transcription activators/suppressors. The presence of multiple Wnt signaling-related isoforms may affect the functionality of the Wnt pathway, including its deregulation in cancer. As such, specific Wnt pathway isoform components may serve as therapeutic targets or as biomarkers for certain human cancers. Here, we review the role of alternative splicing of Wnt signaling components during the onset and progression of cancer. CONCLUSIONS: Splice isoforms of components of the Wnt signaling pathway play distinct roles in cancer development. Isoforms of the same component may function in a tissue- and/or cancer-specific manner. Splice isoform expression analyses along with deregulated Wnt signaling pathway analyses may be of help to design efficient diagnostic and therapeutic strategies. PMID- 26762495 TI - Classification of dependence-related skin lesions: a new proposal. AB - A new theoretical framework on the development of pressure ulcers and other dependence-related lesions requires continued in-depth analysis of their conceptual bases. This study reports the historical background, definitions, and production mechanisms of these lesions, describing the differential pathognomonic features of pressure and/or shear ulcers, moisture-associated skin damage, and lesions from rubbing or friction. It also discusses the combined/multifactorial lesions that can be found in the clinical setting. Finally, it presents the new classification of these lesions proposed by the Spanish Pressure Ulcers and Chronic Wounds Advisory Panel. PMID- 26762496 TI - Fournier's gangrene (necrotising fasciitis) complicated by renal and respiratory insufficiency: a case report. AB - A case report of a 68-year-old male obese diabetic patient with an abscess of left femoral region, and diffuse inflammation of abdominal wall and genital region developing sepsis, respiratory and renal failure. At admission in the regional hospital a diagnosis of polymicrobial necrotising fasciitis with suspected sepsis was declared. The patient was transferred to the special intensive care unit (SICU) of Burns and reconstructive surgery at the Kosice Saca. The patient was treated surgically, with hyperbaric oxygen and pharmacologically to control his diabetes. The main aetiological agent of the condition was identified as Stenotrophomonas maltophilia. In addition to respiratory and metabolic acidosis and gastric bleeding occurred. Due to acute renal failure (day 38) the patient was transferred to clinic of anaesthesiology and the intensive care medicine at the University Hospital in Kosice. The patient was treated by continuous veno-venous haemodialysis, mechanical ventilation and nasogastric nutritional support. On day 48 the conscious sub-febrile patient with healed wounds was transferred back to the regional hospital with ventilation support and continuous renal replacement therapy. His diabetes was uncontrolled, and only kidney parameters remained pathological. The survival of this patient with an extremely poor prognosis was achieved through prompt transfer to a specialised centre, early identification of the aetiological agent and immediate appropriate antibiotic treatment as a result of good cooperation between surgeons and laboratory specialists. PMID- 26762499 TI - The diagnosis of biofilms in wounds. PMID- 26762498 TI - Biomarkers for wound healing and their evaluation. AB - A biological marker (biomarker) is a substance used as an indicator of biological state. Advances in genomics, proteomics and molecular pathology have generated many candidate biomarkers with potential clinical value. Research has identified several cellular events and mediators associated with wound healing that can serve as biomarkers. Macrophages, neutrophils, fibroblasts and platelets release cytokines molecules including TNF-alpha, interleukins (ILs) and growth factors, of which platelet-derived growth factor (PDGF) holds the greatest importance. As a result, various white cells and connective tissue cells release both matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). Studies have demonstrated that IL-1, IL-6, and MMPs, levels above normal, and an abnormally high MMP/TIMP ratio are often present in non-healing wounds. Clinical examination of wounds for these mediators could predict which wounds will heal and which will not, suggesting use of these chemicals as biomarkers of wound healing. There is also evidence that the application of growth factors like PDGF will alleviate the recuperating process of chronic, non healing wounds. Finding a specific biomarker for wound healing status would be a breakthrough in this field and helping treat impaired wound healing. PMID- 26762497 TI - Wound dressing following primary total hip arthroplasty: a prospective randomised controlled trial. AB - OBJECTIVE: This study compared three methods of surgical wound dressing in patients undergoing primary total hip arthroplasty to determine their effect on wound leakage. METHOD: Total hip arthroplasties were randomised to 3 groups: 2 octyl cyanoacrylate (Dermabond-Ethicon Inc, G) with Opsite (Smith & Nephew; O) [G+O], 2-octyl cyanoacrylate with Tegaderm (3M; T) [G+T], and Opsite without 2 octyl cyanoacrylate [O]. Postoperative wound leakage was assessed and graded daily until discharge, the frequency of the dressing changes was also recorded. Patients were clinically reviewed at three months to assess cosmesis of their surgical scar and wound complications. RESULTS: In all 211 total hip arthoplasties were included. A greater proportion of patients' dressings remained dry on day 1 postoperatively in the two groups using 2-octyl cyanoacrylate (G+O and G+T) compared to the no glue group (O; p=0.0001). The G+T group had a significantly lower proportion of patients with increased leakage of wounds on days 2 and 3 postoperatively compared with both G+O and O groups (p=0.0043). The overall rate of dressing change for G+O was 8%, G+T 5%, and O 13%. Overall wound cosmesis was similar in all groups (p=0.690). CONCLUSION: The reduction in frequency of dressing changes coupled with low levels of wound leakage observed using the combination of the glue and nonabsorbent dressings (O+T), makes this combination of wound closing products ideal for facilitating enhanced recovery and early discharge programmes in elective hip arthroplasty. PMID- 26762500 TI - Life cycle assessment of waste prevention in the delivery of pasta, breakfast cereals, and rice. AB - Waste prevention is the top priority of the European waste management strategy. In fact, as indicated in the latest Waste Framework Directive, the best option to deal with waste is not to generate it at all. In this framework, the distribution of loose dry food products through self-dispensing systems (so-called "loose distribution") is being considered worldwide as a practice to reduce the generation of packaging waste. This life cycle assessment (LCA) evaluates the environmental convenience of the loose distribution of dry pasta, breakfast cereals, and rice, in comparison with the traditional method of distribution. For each product, several baseline scenarios based on single-use packaging were compared with different waste prevention scenarios in which the product is distributed loose. The comparison addressed waste generation, 13 impact categories on the environment and human health, and the Cumulative Energy Demand (CED) indicator. The results are significantly different for the 3 products. The loose distribution of pasta allows a 50% waste reduction and a decrease in the potential impacts only when compared with single-use cartonboard boxes. Conversely, when the comparison is made with single-use polypropylene bags, the loose distribution can even cause an increase in waste generation (up to 15%) and in the potential life cycle impacts. For breakfast cereals, the loose distribution allows a significant reduction in both the amount of waste (up to 84%) and the potential impacts, compared to the sale of traditional single-use bag-in-box packages. Finally, the loose distribution of rice permits a reduction in both waste generation (up to 86%) and most of the potential impacts. In particular, the impact reduction is higher when the reference single-use packaging that is replaced includes a cartonboard box. Integr Environ Assess Manag 2016;12:445-458. (c) 2016 SETAC. PMID- 26762501 TI - Escherichia coli N-Acetylglucosamine-1-Phosphate-Uridyltransferase/Glucosamine-1 Phosphate-Acetyltransferase (GlmU) Inhibitory Activity of Terreic Acid Isolated from Aspergillus terreus. AB - Secondary metabolite of Aspergillus terreus, terreic acid, is a reported potent antibacterial that was identified more than 60 years ago, but its cellular target(s) are still unknown. Here we screen its activity against the acetyltransferase domain of a bifunctional enzyme, Escherichia coli N acetylglucosamine-1-phosphate-uridyltransferase/glucosamine-1-phosphate acetyltransferase (GlmU). An absorbance-based assay was used to screen terreic acid against the acetyltransferase activity of E. coli GlmU. Terreic acid was found to inhibit the acetyltransferase domain of E. coli GlmU with an IC50 of 44.24 +/- 1.85 uM. Mode of inhibition studies revealed that terreic acid was competitive with AcCoA and uncompetitive with GlcN-1-P. It also exhibited concentration-dependent killing of E. coli ATCC 25922 up to 4* minimum inhibitory concentration and inhibited the growth of biofilms generated by E. coli. Characterization of resistant mutants established mutation in the acetyltransferase domain of GlmU. Terreic acid was also found to be metabolically stable in the in vitro incubations with rat liver microsome in the presence of a NADPH regenerating system. The studies reported here suggest that terreic acid is a potent antimicrobial agent and support that E. coli GlmU acetyltransferase is a molecular target of terreic acid, resulting in its antibacterial activity. PMID- 26762502 TI - High-Throughput Screening Using a Whole-Cell Virus Replication Reporter Gene Assay to Identify Inhibitory Compounds against Rift Valley Fever Virus Infection. AB - Rift Valley fever virus (RVFV) is an emerging virus that causes serious illness in humans and livestock. There are no approved vaccines or treatments for humans. The purpose of the study was to identify inhibitory compounds of RVFV infection without any preconceived idea of the mechanism of action. A whole-cell-based high throughput drug screening assay was developed to screen 28,437 small chemical compounds targeting RVFV infection. To accomplish both speed and robustness, a replication-competent NSs-deleted RVFV expressing a fluorescent reporter gene was developed. Inhibition of fluorescence intensity was quantified by spectrophotometry and related to virus infection in human lung epithelial cells (A549). Cell toxicity was assessed by the Resazurin cell viability assay. After primary screening, 641 compounds were identified that inhibited RVFV infection by >=80%, with >=50% cell viability at 50 uM concentration. These compounds were subjected to a second screening regarding dose-response profiles, and 63 compounds with >=60% inhibition of RVFV infection at 3.12 uM compound concentration and >=50% cell viability at 25 uM were considered hits. Of these, six compounds with high inhibitory activity were identified. In conclusion, the high-throughput assay could efficiently and safely identify several promising compounds that inhibited RVFV infection. PMID- 26762503 TI - A High-Throughput Screening Platform Targeting PDLIM5 for Pulmonary Hypertension. AB - Pulmonary arterial hypertension is a complex disease with multiple etiologic factors. PDLIM5, a member of the Enigma subfamily of PDZ and LIM domain protein family, contains an N-terminal PDZ domain and three LIM domains at its C terminus. We have previously shown that overexpression of PDLIM5 prevents hypoxia induced pulmonary hypertension (PH), and deletion of PDLIM5 in smooth muscle cells enhances hypoxia-induced PH in vivo. These results suggest that PDLIM5 may be a novel therapeutic target of PH. In this study, we aim to establish a high throughput screening platform for PDLIM5-targeted drug discovery. We generated a stable mink lung epithelial cell line (MLEC) containing a transforming growth factor-beta/Smad luciferase reporter with lentivirus-mediated suppression of PDLIM5 (MLEC-shPDLIM5) and measured levels of Smad2/3 and pSmad2/3. We found that in MLEC, suppression of PDLIM5 decreased Smad-dependent luciferase activity, Smad3, and pSmad3. We used MLEC-shPDLIM5 and a control cell line (MLEC-shCTL) to screen the Prestwick library (1200 compounds) and identified and validated paclitaxel as a PDLIM5 inhibitor in MLEC. Furthermore, we showed that paclitaxel inhibited Smad2 expression and Smad3 phosphorylation in A549 cells. Our study suggests that this system is robust and suitable for PDLIM5-targeted drug discovery. PMID- 26762504 TI - Plasma endostatin may improve acute kidney injury risk prediction in critically ill patients. AB - BACKGROUND: Breakdown of renal endothelial, tubular and glomerular matrix collagen plays a major role in acute kidney injury (AKI) development. Such collagen breakdown releases endostatin into the circulation. The aim of this study was to compare the AKI predictive value of plasma endostatin with two previously suggested biomarkers of AKI, cystatin C and neutrophil gelatinase associated lipocalin (NGAL). METHODS: We studied 93 patients without kidney disease who had a first plasma sample obtained within 48 h of ICU admission. We identified risk factors for AKI within the population and designed a predictive model. The individual ability and net contribution of endostatin, cystatin C and NGAL to predict AKI were evaluated by the area under the receiver operating characteristics curve (AUC), likelihood-ratio test, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: In total, 21 (23 %) patients experienced AKI within 72 h. A three-parameter model (age, illness severity score and early oliguria) predicted AKI with an AUC of 0.759 (95 % CI 0.646-0.872). Adding endostatin to the predictive model significantly (P = 0.04) improved the AUC to 0.839 (95 % CI 0.752-0.925). In addition, endostatin significantly improved risk prediction using the likelihood ratio test (P = 0.005), NRI analysis (0.27; P = 0.04) and IDI analysis (0.07; P = 0.04). In contrast, adding cystatin C or NGAL to the three-parameter model did not improve risk prediction in any of the four analyses. CONCLUSIONS: In this cohort of critically ill patients, plasma endostatin improved AKI prediction based on clinical risk factors, while cystatin C and NGAL did not. PMID- 26762508 TI - BMA disagrees that 15 of 16 junior contract issues are resolved. PMID- 26762505 TI - Analysis of neuron-astrocyte metabolic cooperation in the brain of db/db mice with cognitive decline using 13C NMR spectroscopy. AB - Type 2 diabetes has been linked to cognitive impairment, but its potential metabolic mechanism is still unclear. The present study aimed to explore neuron astrocyte metabolic cooperation in the brain of diabetic (db/db, BKS.Cg-m+/+ Leprdb/J) mice with cognitive decline using 13C NMR technique in combination with intravenous [2-13C]-acetate and [3-13C]-lactate infusions. We found that the 13C enrichment from [2-13C]-acetate into tricarboxylic acid cycle intermediate, succinate, was significantly decreased in db/db mice with cognitive decline compared with wild-type (WT, C57BLKS/J) mice, while an opposite result was obtained after [3-13C]-lactate infusion. Relative to WT mice, db/db mice with cognitive decline had significantly lower 13C labeling percentages in neurotransmitters including glutamine, glutamate, and gamma-aminobutyric acid after [2-13C]-acetate infusion. However, [3-13C]-lactate resulted in increased 13C-enrichments in neurotransmitters in db/db mice with cognitive decline. This may indicate that the disturbance of neurotransmitter metabolism occurred during the development of cognitive decline. In addition, a reduction in 13C-labeling of lactate and an increase in gluconeogenesis were found from both labeled infusions in db/db mice with cognitive decline. Therefore, our results suggest that the development of cognitive decline in type 2 diabetes may be implicated to an unbalanced metabolism in neuron-astrocyte cooperation and an enhancement of gluconeogenesis. PMID- 26762509 TI - Effects of Instant Messaging on School Performance in Adolescents. AB - Instant messaging may compromise sleep quality and school performance in adolescents. We aimed to determine associations between nighttime messaging and daytime sleepiness, self-reported sleep parameters, and/or school performance. Students from 3 high schools in New Jersey completed anonymous questionnaires assessing sleep duration, daytime sleepiness, messaging habits, and academic performance. Of the 2,352 students sampled, 1,537 responses were contrasted among grades, sexes, and messaging duration, both before and after lights out. Students who reported longer duration of messaging after lights out were more likely to report a shorter sleep duration, higher rate of daytime sleepiness, and poorer academic performance. Messaging before lights out was not associated with higher rates of daytime sleepiness or poorer academic performance. Females reported more messaging, more daytime sleepiness, and better academic performance than males. There may be an association between text messaging and school performance in this cohort of students. PMID- 26762506 TI - Deleting IGF-1 receptor from forebrain neurons confers neuroprotection during stroke and upregulates endocrine somatotropin. AB - Insulin-like growth factors control numerous processes, namely somatic growth, metabolism and stress resistance, connecting this pathway to aging and age related diseases. Insulin-like growth factor signaling also impacts on neurogenesis, neuronal survival and structural plasticity. Recent reports demonstrated that diminished insulin-like growth factor signaling confers increased stress resistance in brain and other tissues. To better understand the role of neuronal insulin-like growth factor signaling in neuroprotection, we inactivated insulin-like growth factor type-1-receptor in forebrain neurons using conditional Cre-LoxP-mediated gene targeting. We found that brain structure and function, including memory performance, were preserved in insulin-like growth factor receptor mutants, and that certain characteristics improved, notably synaptic transmission in hippocampal neurons. To reveal stress-related roles of insulin-like growth factor signaling, we challenged the brain using a stroke-like insult. Importantly, when charged with hypoxia-ischemia, mutant brains were broadly protected from cell damage, neuroinflammation and cerebral edema. We also found that in mice with insulin-like growth factor receptor knockout specifically in forebrain neurons, a substantial systemic upregulation of growth hormone and insulin-like growth factor-I occurred, which was associated with significant somatic overgrowth. Collectively, we found strong evidence that blocking neuronal insulin-like growth factor signaling increases peripheral somatotropic tone and simultaneously protects the brain against hypoxic-ischemic injury, findings that may contribute to developing new therapeutic concepts preventing the disabling consequences of stroke. PMID- 26762507 TI - Cerebrovascular and microglial states are not altered by functional neuroinflammatory gene variant. AB - The translocator protein, a microglial-expressed marker of neuroinflammation, has been implicated in Alzheimer's disease, which is characterized by alterations in vascular and inflammatory states. ATSPOvariant, rs6971, determines binding affinity of exogenous radioligandsin vivo; however, the effect of these altered binding characteristics on inflammatory and cerebrovascular biomarkers has not been assessed. In 2345 living subjects (Alzheimer's Disease Neuroimaging Initiative, n = 1330) and postmortem brain samples (Religious Orders Study and Memory and Aging Project, n = 1015), we analyzed effects of rs6971 on white matter hyperintensisites, cerebral infarcts, circulating inflammatory biomarkers, amyloid angiopathy, and microglial activation. We found that rs6971 does not alter translocator protein in a way that impacts cerebrovascular and inflammatory states known to be affected in dementia. PMID- 26762510 TI - Effect of Aging on Periodontal Inflammation, Microbial Colonization, and Disease Susceptibility. AB - Periodontitis is a chronic inflammatory disease induced by a biofilm that forms on the tooth surface. Increased periodontal disease is associated with aging. We investigated the effect of aging on challenge by oral pathogens, examining the host response, colonization, and osteoclast numbers in aged versus young mice. We also compared the results with mice with lineage-specific deletion of the transcription factor FOXO1, which reduces dendritic cell (DC) function. Periodontitis was induced by oral inoculation of Porphyromonas gingivalis and Fusobacterium nucleatum in young (4 to 5 mo) and aged (14 to 15 mo) mice. Aged mice as well as mice with reduced DC function had decreased numbers of DCs in lymph nodes, indicative of a diminished host response. In vitro studies suggest that reduced DC numbers in lymph nodes of aged mice may involve the effect of advanced glycation end products on DC migration. Surprisingly, aged mice but not mice with genetically altered DC function had greater production of antibody to P. gingivalis, greater IL-12 expression, and more plasma cells in lymph nodes following oral inoculation as compared with young mice. The greater adaptive immune response in aged versus young mice was linked to enhanced levels of P. gingivalis and reduced bacterial diversity. Thus, reduced bacterial diversity in aged mice may contribute to increased P. gingivalis colonization following inoculation and increased periodontal disease susceptibility, reflected by higher TNF levels and osteoclast numbers in the periodontium of aged versus young mice. PMID- 26762511 TI - Early Childhood Adversity and Pregnancy Outcomes. AB - OBJECTIVES: To examine the association between adverse childhood experiences (ACEs) and pregnancy outcomes; to explore mediators of this association including psychiatric illness and health habits. METHODS: Exposure to ACEs was determined by the Early Trauma Inventory Self Report Short Form; psychiatric diagnoses were generated by the Composite International Diagnostic Interview administered in a cohort of 2303 pregnant women. Linear regression and structural equation modeling bootstrapping approaches tested for multiple mediators. RESULTS: Each additional ACE decreased birth weight by 16.33 g and decreased gestational age by 0.063. Smoking was the strongest mediator of the effect on gestational age. CONCLUSIONS: ACEs have an enduring effect on maternal reproductive health, as manifested by mothers' delivery of offspring that were of reduced birth weight and shorter gestational age. PMID- 26762513 TI - Erratum to: Analysis of the mitochondrial maxicircle of Trypanosoma lewisi, a neglected human pathogen. PMID- 26762512 TI - Natural human Plasmodium infections in major Anopheles mosquitoes in western Thailand. AB - BACKGROUND: The Thai-Myanmar border is a remaining hotspot for malaria transmission. Malaria transmission in this region continues year-round, with a major peak season in July-August, and a minor peak in October-November. Malaria elimination requires better knowledge of the mosquito community structure, dynamics and vectorial status to support effective vector control. METHODS: Adult Anopheles mosquitoes were collected using CDC light traps and cow bait in 7 villages along the Thai-Myanmar border in January 2011 - March 2013. Mosquitoes were determined to species by morphological characters. Plasmodium-positivity was determined by circumsporozoite protein ELISA. RESULTS: The 2986 Anopheles mosquitoes collected were assigned to 26 species, with Anopheles minimus sensu lato (s.l.) (40.32%), An. maculatus s.l. (21.43%), An. annularis s.l. (14.43%), An. kochi (5.39%), An. tessellatus (5.26%), and An. barbirostris s.l. (3.52%) being the top six most abundant species. Plasmodium-infected mosquitoes were found in 22 positive samples from 2906 pooled samples of abdomens and heads/thoraxes. Four mosquito species were found infected with Plasmodium: An. minimus s.l., An. maculatus s.l., An. annularis s.l. and An. barbirostris s.l. The infectivity rates of these mosquitoes were 0.76, 0.37, 0.72, and 1.74%, respectively. Consistent with a change in malaria epidemiology to the predominance of P. vivax in this area, 20 of the 22 infected mosquito samples were P. vivax-positive. The four potential vector species all displayed apparent seasonality in relative abundance. While An. minimus s.l. was collected through the entire year, its abundance peaked in the season immediately after the wet season. In comparison, An. maculatus s.l. numbers showed a major peak during the wet season. The two potential vector species, An. annularis s.l. and An. barbirostris s.l., both showed peak abundance during the transition from wet to dry season. Moreover, An. minimus s.l. was more abundant in indoor collections, whereas An. annularis s.l. and An. barbirostris s.l. were more abundant in outdoor collections, suggesting their potential role in outdoor malaria transmission. CONCLUSIONS: This survey confirmed the major vector status of An. minimus s.l. and An. maculatus s.l. and identified An. annularis s.l. and An. barbirostris s.l. as additional vectors with potential importance in malaria transmission after the wet season. PMID- 26762514 TI - Culex pipiens and Culex restuans mosquitoes harbor distinct microbiota dominated by few bacterial taxa. AB - BACKGROUND: Mosquitoes host diverse microbial communities that influence many aspects of their biology including reproduction, digestion, and ability to transmit pathogens. Unraveling the composition, structure, and function of these microbiota can provide new opportunities for exploiting microbial function for mosquito-borne disease control. METHODS: MiSeq(r) sequencing of 16S rRNA gene amplicons was used to characterize the microbiota of adult females of Culex pipiens L. and Cx. restuans Theobald collected from nine study sites in central Illinois. RESULTS: Out of 195 bacterial OTUs that were identified, 86 were shared between the two mosquito species while 16 and 93 OTUs were unique to Cx. pipiens and Cx. restuans, respectively. The composition and structure of microbial communities differed significantly between the two mosquito species with Cx. restuans hosting a more diverse bacterial community compared to Cx. pipiens. Wolbachia (OTU836919) was the dominant bacterial species in Cx. pipiens accounting for 91% of total microbiota while Sphingomonas (OTU817982) was the dominant bacterial species in Cx. restuans accounting for 31% of total microbiota. Only 3 and 6 OTUs occurred in over 60% of individuals in Cx. pipiens and Cx. restuans, respectively. There was little effect of study site on bacterial community structure of either mosquito species. CONCLUSION: These results suggest that the two mosquito species support distinct microbial communities that are sparsely distributed between individuals. These findings will allow investigations of the role of identified microbiota on the spatial and temporal heterogeneity in WNV transmission and their potential application in disease control. PMID- 26762515 TI - Ectoparasites may serve as vectors for the white-nose syndrome fungus. AB - BACKGROUND: Vertebrate ectoparasites frequently play a role in transmission of infectious agents. Pseudogymnoascus destructans is a psychrophilic fungus known to cause white-nose syndrome (WNS), an emerging infectious disease of bats. It is transmitted with direct contact between bats or with contaminated environment. The aim of this study was to examine wing mites from the family Spinturnicidae parasitizing hibernating bats for the presence of P. destructans propagules as another possible transmission route. METHODS: Wing mites collected from 33 bats at four hibernation sites in the Czech Republic were inspected for the presence and load of pathogen's DNA using quantitative PCR. Simultaneously, wing damage of inspected bats caused by WNS was quantified using ultraviolet light (UV) transillumination and the relationship between fungal load on wing mites and intensity of infection was subjected to correlation analysis. RESULTS: All samples of wing mites were positive for the presence of DNA of P. destructans, indicating a high probability of their role in the transmission of the pathogen's propagules between bats. CONCLUSIONS: Mechanical transport of adhesive P. destructans spores and mycelium fragments on the body of spinturnicid mites is highly feasible. The specialised lifestyle of mites, i.e., living on bat wing membranes, the sites most typically affected by fungal growth, enables pathogen transport. Moreover, P. destructans metabolic traits suggest an ability to grow and sporulate on a range of organic substrates, including insects, which supports the possibility of growth on bat ectoparasites, at least in periods when bats roost in cold environments and enter torpor. In addition to transport of fungal propagules, mites may facilitate entry of fungal hyphae into the epidermis through injuries caused by biting. PMID- 26762516 TI - MicroRNAs in fibrosis: opportunities and challenges. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that mediate mRNA cleavage, translational repression or mRNA destabilisation and are around 22-25 nucleotides in length via partial complementary binding to the 3' untranslated region in target transcripts. They are master regulators of gene expression. Fibrosis is an important cause of morbidity and mortality in the world, and there are currently no accepted treatments for fibrosis. Many novel miRNAs are now associated with fibrosis, both organ-specific and systemic, as in the prototypical fibrotic disease systemic sclerosis. Recently, the targets of these altered miRNAs have been validated and defined new biochemical pathways. Dysregulated miRNAs are amenable to therapeutic modulation. This review will examine the role of miRNAs in fibrosis and the opportunities and challenges of targeting them. PMID- 26762518 TI - Cue response dissociates inhibitory processes: task identity information is related to backward inhibition but not to competitor rule suppression. AB - In task switching, a conflict between competing task-sets is resolved by inhibiting the interfering task-set. Recent models have proposed a framework of the task-set as composed of two hierarchical components: abstract task identity (e.g., respond to quantity) and more concrete task rules (e.g., category-response rules mapping the categories "one" and "three" to the left and right keys, respectively). The present study explored whether task-set inhibition is the outcome of a general control process or whether it reflects multiple inhibitory processes, each targeting a different component of the competing task-set. To this end, two effects of task-set inhibition were examined: backward inhibition (BI), reflecting the suppression of a just-performed task-set that is no longer relevant; and, competitor rule suppression (CRS), reflecting the suppression of an irrelevant task-set that generates a response conflict. In two task switching experiments, each involving three tasks, we asked participants to make two responses: a cue response, indicating the identity of the relevant task (e.g., "Color"), and a target response requiring the implementation of the task rule (e.g., "Red"). The results demonstrate that BI, but not CRS, appears in cue responses, and thus, suggests that BI reflects inhibition that influences representations related to abstract task identity, rather than (just) competing responses or response rules. These results support a dissociation between inhibitory processes in task switching. The current findings also provide further evidence for a multi-component conceptualization of task-set and task-set inhibition. PMID- 26762517 TI - Application of cell and biomaterial-based tissue engineering methods in the treatment of cartilage, menisci and ligament injuries. AB - Over 20 years ago it was realized that the traditional methods of the treatment of injuries to joint components: cartilage, menisci and ligaments, did not give satisfactory results and so there is a need of employing novel, more effective therapeutic techniques. Recent advances in molecular biology, biotechnology and polymer science have led to both the experimental and clinical application of various cell types, adapting their culture conditions in order to ensure a directed differentiation of the cells into a desired cell type, and employing non toxic and non-immunogenic biomaterial in the treatment of knee joint injuries. In the present review the current state of knowledge regarding novel cell sources, in vitro conditions of cell culture and major important biomaterials, both natural and synthetic, used in cartilage, meniscus and ligament repair by tissue engineering techniques are described, and the assets and drawbacks of their clinical application are critically evaluated. PMID- 26762519 TI - Mechanisms of Very Late Drug-Eluting Stent Thrombosis Assessed by Optical Coherence Tomography. AB - BACKGROUND: The pathomechanisms underlying very late stent thrombosis (VLST) after implantation of drug-eluting stents (DES) are incompletely understood. Using optical coherence tomography, we investigated potential causes of this adverse event. METHODS AND RESULTS: Between August 2010 and December 2014, 64 patients were investigated at the time point of VLST as part of an international optical coherence tomography registry. Optical coherence tomography pullbacks were performed after restoration of flow and analyzed at 0.4 mm. A total of 38 early- and 20 newer-generation drug-eluting stents were suitable for analysis. VLST occurred at a median of 4.7 years (interquartile range, 3.1-7.5 years). An underlying putative cause by optical coherence tomography was identified in 98% of cases. The most frequent findings were strut malapposition (34.5%), neoatherosclerosis (27.6%), uncovered struts (12.1%), and stent underexpansion (6.9%). Uncovered and malapposed struts were more frequent in thrombosed compared with nonthrombosed regions (ratio of percentages, 8.26; 95% confidence interval, 6.82-10.04; P<0.001 and 13.03; 95% confidence interval, 10.13-16.93; P<0.001, respectively). The maximal length of malapposed or uncovered struts (3.40 mm; 95% confidence interval, 2.55-4.25; versus 1.29 mm; 95% confidence interval, 0.81 1.77; P<0.001), but not the maximal or average axial malapposition distance, was greater in thrombosed compared with nonthrombosed segments. The associations of both uncovered and malapposed struts with thrombus were consistent among early- and newer-generation drug-eluting stents. CONCLUSIONS: The leading associated findings in VLST patients in descending order were malapposition, neoatherosclerosis, uncovered struts, and stent underexpansion without differences between patients treated with early- and new-generation drug-eluting stents. The longitudinal extension of malapposed and uncovered stent was the most important correlate of thrombus formation in VLST. PMID- 26762520 TI - Alternative Strategies to Achieve Cardiovascular Mortality Goals in China and India: A Microsimulation of Target- Versus Risk-Based Blood Pressure Treatment. AB - BACKGROUND: The World Health Organization aims to reduce mortality from chronic diseases including cardiovascular disease (CVD) by 25% by 2025. High blood pressure is a leading CVD risk factor. We sought to compare 3 strategies for treating blood pressure in China and India: a treat-to-target (TTT) strategy emphasizing lowering blood pressure to a target, a benefit-based tailored treatment (BTT) strategy emphasizing lowering CVD risk, or a hybrid strategy currently recommended by the World Health Organization. METHODS AND RESULTS: We developed a microsimulation model of adults aged 30 to 70 years in China and in India to compare the 2 treatment approaches across a 10-year policy-planning horizon. In the model, a BTT strategy treating adults with a 10-year CVD event risk of >= 10% used similar financial resources but averted ~ 5 million more disability-adjusted life-years in both China and India than a TTT approach based on current US guidelines. The hybrid strategy in the current World Health Organization guidelines produced no substantial benefits over TTT. BTT was more cost-effective at $205 to $272/disability-adjusted life-year averted, which was $142 to $182 less per disability-adjusted life-year than TTT or hybrid strategies. The comparative effectiveness of BTT was robust to uncertainties in CVD risk estimation and to variations in the age range analyzed, the BTT treatment threshold, or rates of treatment access, adherence, or concurrent statin therapy. CONCLUSIONS: In model-based analyses, a simple BTT strategy was more effective and cost-effective than TTT or hybrid strategies in reducing mortality. PMID- 26762521 TI - Periodontitis Increases the Risk of a First Myocardial Infarction: A Report From the PAROKRANK Study. AB - BACKGROUND: The relationship between periodontitis (PD) and cardiovascular disease is debated. PD is common in patients with cardiovascular disease. It has been postulated that PD could be causally related to the risk for cardiovascular disease, a hypothesis tested in the Periodontitis and Its Relation to Coronary Artery Disease (PAROKRANK) study. METHODS AND RESULTS: Eight hundred five patients (<75 years of age) with a first myocardial infarction (MI) and 805 age- (mean 62+/-8), sex- (male 81%), and area-matched controls without MI underwent standardized dental examination including panoramic x-ray. The periodontal status was defined as healthy (>=80% remaining bone) or as mild-moderate (from 79% to 66%) or severe PD (<66%). Great efforts were made to collect information on possibly related confounders (~100 variables). Statistical comparisons included the Student pairwise t test and the McNemar test in 2*2 contingency tables. Contingency tables exceeding 2*2 with ranked alternatives were tested by Wilcoxon signed rank test. Odds ratios (95% confidence intervals) were calculated by conditional logistic regression. PD was more common (43%) in patients than in controls (33%; P<0.001). There was an increased risk for MI among those with PD (odds ratio, 1.49; 95% confidence interval, 1.21-1.83), which remained significant (odds ratio, 1.28; 95% confidence interval, 1.03-1.60) after adjusting for variables that differed between patients and controls (smoking habits, diabetes mellitus, years of education, and marital status). CONCLUSIONS: In this large case-control study of PD, verified by radiographic bone loss and with a careful consideration of potential confounders, the risk of a first MI was significantly increased in patients with PD even after adjustment for confounding factors. These findings strengthen the possibility of an independent relationship between PD and MI. PMID- 26762522 TI - Increasing Evidence for an Association Between Periodontitis and Cardiovascular Disease. PMID- 26762523 TI - SPS3 Evidence Supports Intensive Blood Pressure Control. PMID- 26762524 TI - Effect of Intensive Versus Usual Blood Pressure Control on Kidney Function Among Individuals With Prior Lacunar Stroke: A Post Hoc Analysis of the Secondary Prevention of Small Subcortical Strokes (SPS3) Randomized Trial. AB - BACKGROUND: The effect of intensive blood pressure (BP) lowering on kidney function among individuals with established cerebrovascular disease and preserved estimated glomerular filtration rate (eGFR) is not established. METHODS AND RESULTS: Among 2610 participants randomized to a lower (<130 mm Hg) versus higher (130-149 mm Hg) systolic BP target with repeated measures of serum creatinine, we evaluated differences by study arm in annualized eGFR decline and rapid decline (eGFR decline >30%) using linear mixed models and logistic regression, respectively. We assessed associations of both treatment and kidney function decline with stroke, major vascular events, and the composite of stroke, death, major vascular events, or myocardial infarction using multivariable Cox regression, separately and jointly including a test for interaction. Analyses were conducted by treatment arm. Mean age was 63+/-11 years; 949 participants (36%) were diabetic; and mean eGFR was 80+/-19 mL.min(-1).1.73 m(-2). At 9 months, achieved systolic BP was 137+/-15 versus 127+/-14 mm Hg in the higher versus lower BP group, and differences were maintained throughout follow-up (mean, 3.2 years). Compared with the higher target, the lower BP target had a 0.50-mL.min(-1).1.73 m(-2) per year (95% confidence interval [CI], -0.79 to 0.21) faster eGFR decline. Differences were most pronounced during the first year (-2.1 mL.min(-1).1.73 m(-2); 95% CI, -0.97 to -3.2), whereas rates of eGFR decline did not differ after year 1 (-0.095; 95% CI, -0.47 to 0.23). A total of 313 patients (24%) in the lower BP group had rapid kidney function decline compared with 247 (19%) in the higher BP group (odds ratio, 1.4; 95% CI, 1.1 1.6). Differences in rapid decline by treatment arm were apparent in the first year (odds ratio, 1.4; 95% CI, 1.1-1.8) but were not significant after year 1 (odds ratio, 1.0; 95% CI, 0.73-1.4). Rapid decline was associated with higher risk for stroke, major vascular events, and composite after full adjustment among individuals randomized to the higher BP target (stroke hazard ratio, 1.93; 95% CI, 1.15-3.21) but not the lower BP arm (stroke hazard ratio, 0.93; 95% CI, 0.50 1.75; all P for interaction <0.06). CONCLUSIONS: In patients with prior lacunar stroke and relatively preserved kidney function, intensive BP lowering was associated with a greater likelihood of rapid kidney function decline. Differences were observed primarily during the first year of antihypertensive treatment. Rapid kidney function decline was not associated with increased risk for clinical events among those undergoing intensive BP lowering. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicalTrials.gov. Unique identifier: NCT00059306. PMID- 26762525 TI - Efficacy and Safety of Cangrelor in Women Versus Men During Percutaneous Coronary Intervention: Insights From the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) Trial. AB - BACKGROUND: Cangrelor is an intravenous ADP receptor antagonist that leads to potent and reversible inhibition of platelet aggregation. The relative safety and efficacy of some antiplatelet drugs in women has been disputed. METHODS AND RESULTS: The Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) trial randomized 11,145 patients undergoing elective or urgent percutaneous coronary intervention to cangrelor or clopidogrel. The primary efficacy end point was the composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was GUSTO severe bleeding at 48 hours. Of subjects analyzed, 3051 (28%) were female. Cangrelor reduced the odds of the primary end point by 35% in women (adjusted odds ratio [OR], 0.65; 95% confidence interval [CI], 0.48-0.89) and by 14% in men (OR, 0.86; 95% CI, 0.70-1.05; P interaction=0.23) compared with clopidogrel. Cangrelor reduced the odds of stent thrombosis by 61% in women (OR, 0.39; 95% CI, 0.20-0.77) and 16% in men (OR, 0.84; 95% CI, 0.53-1.33; P interaction=0.11). The odds of severe bleeding were similar in both women and men treated with cangrelor (0.3% versus 0.2%, P=0.30 [women]; 0.1% versus 0.1%, P=0.41 [men]; P interaction=0.88) versus clopidogrel. Cangrelor increased the odds of moderate bleeding in women (0.9% versus 0.3%, P=0.02), but not in men (0.2% versus 0.2%, P=0.68; P interaction=0.040). The net clinical benefit (primary efficacy and safety end point) favored cangrelor in both women (OR, 0.68; 95% CI, 0.50-0.92) and men (OR, 0.87; 95% CI, 0.71-1.06; P interaction=0.26). CONCLUSIONS: In CHAMPION PHOENIX, cangrelor reduced the odds of major adverse cardiovascular events and stent thrombosis in women and men and appeared to offer greater net clinical benefit than clopidogrel. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01156571. PMID- 26762526 TI - Intrafollicular Epstein-Barr virus-positive large B cell lymphoma. A variant of "germinotropic" lymphoproliferative disorder. AB - Germinotropic lymphoproliferative disorders were previously described as localized disorders associated with coinfection by human herpes virus 8 and Epstein-Barr virus and characterized by good clinical outcome. We report the clinical, morphological, phenotypical, and molecular features of three cases of a hitherto unreported variant of Epstein-Barr virus (EBV)-positive, human herpes virus 8 (HHV8)-negative large B cell lymphoma with exclusive intrafollicular localization. All cases occurred in elderly individuals (63, 77, and 65 years old; one male, two females) without obvious immunedeficiency, who presented with high stage disease. Lymph nodes showed an effaced nodular architecture with abnormal B follicles colonized by EBV+ large, pleomorphic atypical cells, including Reed-Sternberg-like cells, showing an activated B cell phenotype (CD10 FOXP1-Bcl6-IRF4+ or CD10-FOXP1+Bcl6+IRF4+) and intense expression of CD30. No monoclonal light-chain restriction was detected by immunohistochemistry or in situ hybridization, and IGH rearrangement was polyclonal; notably, EBV clonality was detectable in one case. Lymphoma cells in all cases showed diffuse expression of the c-Myc protein, while Bcl2 was dim or negative; moreover, the strong expression of phosphorylated-STAT3 in tumor cell nuclei suggested activation of the JAK-STAT pathway. FISH analysis was performed in two cases and showed no translocations of BCL2, BCL6, MYC, and PAX5 genes. Response to treatment was poor in 2/3 patients: one died after 18 months, one is alive with disease after 12 months. The intrafollicular EBV-positive large B cell lymphoma expands the spectrum of EBV-associated lymphoproliferative disorders in immunocompetent individuals. PMID- 26762527 TI - IL-25 and IL-33 induce Type 2 inflammation in basophils from subjects with allergic asthma. AB - BACKGROUND: The alarmin cytokines IL-25 and IL-33 are key promoters of type 2 inflammation. Basophils respond to alarmin cytokines, however the relationship of these cytokines with basophil activation and recruitment in human studies of allergic asthma has not been well characterized. This study investigated the effect of IL-25 and IL-33 on basophils in a model of allergic asthma. METHODS: 10 mild allergic asthmatics underwent allergen and diluent inhalation challenges. Bone marrow aspirates were collected at pre-challenge and 24 h (h) post challenge. Peripheral blood and sputum samples were collected at pre-challenge, 7 h, and 24 h post-challenge to measure basophil expression of IL-17RB, ST2, and intracellular IL-25. Freshly isolated peripheral blood basophils from allergic donors were incubated overnight with IL-25 and IL-33, or sputum supernatant collected post-allergen to assess pro-inflammatory effects of mediators released in the airways. RESULTS: There were increased percentage of basophils expressing IL-17RB, ST2, and intracellular IL-25 collected from bone marrow, peripheral blood, and sputum after allergen inhalation challenge. In vitro stimulation with IL-25 and IL-33 increased the percentage of basophils expressing intracellular type 2 cytokines and surface activation markers, and primed eotaxin-induced migratory potential of basophils, which was mediated directly through IL-17RB and ST2, respectively. Stimulation of basophils with sputum supernatants collected post-allergen challenge up-regulated the percentage of basophils expressing markers of activation and intracellular type 2 cytokines, which was reversed following blockade of the common beta chain (betac). CONCLUSIONS: Our findings indicate that the alarmin cytokines IL-33 and IL-25 increase basophil activation and migratory potential, and may pose as a novel therapeutic targets for the treatment of allergic asthma. PMID- 26762528 TI - Varicella vaccine without human serum albumin versus licensed varicella vaccine in children during the second year of life: a randomized, double-blind, non inferiority trial. AB - BACKGROUND: GSK's varicella vaccine contains human serum albumin (HSA) which is used to stabilize the virus and prevent immunogens from adhering to the injection vial walls. However, because HSA is derived from human blood, there is a theoretical risk that it might contain infectious agents which could be unsafe for humans. Given this concern, a study was undertaken to compare the immunogenicity and safety of a new formulation without HSA with the currently licensed varicella vaccine in the Czech Republic and Hungary. METHODS: Healthy children aged 11-21 months received two doses of the varicella vaccine either with or without HSA. Antibody titres against varicella-zoster virus (anti-VZV) were measured 42 days after each dose, using an immunofluorescence assay (IFA, cut-off = 4dilution(-1)) and enzyme linked immunosorbent assay (ELISA, cut-off = 25 mIU/ml). Solicited local symptoms were recorded during a 4-day post vaccination follow-up period; solicited general and unsolicited symptoms were recorded during a 43-day post-vaccination follow-up period and serious adverse event (SAEs) were recorded throughout the study. RESULTS: Of 244 children (mean age = 15.2 months [SD = 3.2]) vaccinated in the study, 233 (vaccine without HSA N = 117; vaccine containing HSA N = 116) formed the according-to-protocol immunogenicity cohort. Observed seroconversion/seroresponse rates were >98 and 100 %, 42 days after doses 1 and 2, respectively. The rates were within the same range in both groups, irrespective of the testing assay. The varicella vaccine without HSA was non-inferior to the licensed vaccine in terms of anti-VZV antibody Geometric Mean Titre/Concentration ratio (1.12 [95 % CI:0.86-1.46] by IFA; 1.12 [95 % CI:0.93-1.33] by ELISA) approximately six weeks after the first dose of the 2-dose vaccination course. The incidence of solicited and unsolicited symptoms was similar after both vaccines; low-grade fever was numerically higher after the first dose of the varicella vaccine without HSA. Seven SAEs were reported, none of which were fatal or considered to be vaccine-related. CONCLUSIONS: The first dose of a new varicella vaccine without HSA was immunologically non-inferior to the licensed varicella vaccine. After two doses, both vaccines had acceptable safety profiles in children aged 11-21 months in the Czech Republic and Hungary. TRIAL REGISTRATION: NCT00568334 , registered on 5 December 2007 ( www.clinicaltrials.gov ). PMID- 26762530 TI - Tailoring nutritional and process variables for hyperproduction of catalase from a novel isolated bacterium Geobacillus sp. BSS-7. AB - BACKGROUND: Catalase (EC 1.11.1.6) is one of the important industrial enzyme employed in diagnostic and analytical methods in the form of biomarkers and biosensors in addition to their enormous applications in textile, paper, food and pharmaceutical sectors. The present study demonstrates the utility of a newly isolated and adapted strain of genus Geobacillus possessing unique combination of several industrially important extremophilic properties for the hyper production of catalase. The bacterium can grow over a wide range of pH (3-12) and temperature (10-90 degrees C) with extraordinary capability to produce catalase. RESULTS: A novel extremophilic strain belonging to genus Geobacillus was exploited for the production of catalase by tailoring its nutritional requirements and process variables. One variable at a time traditional approach followed by computational designing was applied to customize the fermentation process. A simple fermentation media containing only three components namely sucrose (0.55 %, w/v), yeast extract (1.0 %, w/v) and BaCl2 (0.08 %, w/v) was designed for the hyperproduction of catalase. A controlled and optimum air supply caused a tremendous increase in the enzyme production on moving the bioprocess from the flask to bioreactor level. The present paper reports high quantum of catalase production (105,000 IU/mg of cells) in a short fermentation time of 12 h. To the best of our knowledge, there is no report in the literature that matches the performance of the developed protocol for the catalase production. This is the first serious study covering intracellular catalase production from thermophilic genus Geobacillus. CONCLUSIONS: An increase in intracellular catalase production by 214.72 % was achieved in the optimized medium when transferred from the shake flask to the fermenter level. The extraordinary high production of catalase from Geobacillus sp. BSS-7 makes the isolated strain a prospective candidate for bulk catalase production on an industrial scale. PMID- 26762529 TI - Downsizing a pullulanase to a small molecule with improved soluble expression and secretion efficiency in Escherichia coli. AB - BACKGROUND: Significant challenges, including low expression and extracellular secretion of soluble protein, are encountered in expressing and purifying Bacillus acidopullulyticus pullulanase (BaPul) in Escherichia coli. METHODS: An N terminal domain truncation was adopted to facilitate BaPul variant expression and/or secretion. RESULTS: BaPul possesses a complex modular architecture that consists of CBM41-X45a-X25-X45b-CBM48-GH13. The activities of M1 (DeltaCBM41) and M5 (DeltaCBM41DeltaX25) variants were 2.9- and 2.4-fold that of wild-type (WT) enzyme, respectively. The enhanced expression of soluble protein is the main reason for these improved activities. PelB-M1 and PelB-M5 were transported to the periplasmic space, where PelB is part of the PelB-pET28a(+) construct, and PelB M3 (DeltaX25) and PelB-WT variants were largely retained in the cytoplasm. After fermentation, about 56.6 and 93.4 % of the total activity of PelB-M1 and PelB-M5 were transferred to the periplasm, respectively, followed by cell lysis and leakage of the partial enzyme into the extracellular medium. The optimal temperature and pH for purified preparations of M1, M3, and M5 were similar to those of the WT enzyme. In a starch saccharification reaction, the dextrose equivalents of M1, M3, and M5 proteins were 94.7, 94.5, and 93.1 %, respectively, which were also essentially identical to that of WT (93.6 %). CONCLUSION: The deletion of CBM41 and/or X25 domain did not affect the enzyme application, and the truncated variants were more highly expressed and secreted in E. coli. Thus, the truncated variants may be more suitable for industrial applications. PMID- 26762531 TI - Butanol production under microaerobic conditions with a symbiotic system of Clostridium acetobutylicum and Bacillus cereus. AB - BACKGROUND: One major problem of ABE (acetone, butanol and ethanol) fermentation is high oxygen sensitivity of Clostridium acetobutylicum. Currently, no single strain has been isolated or genetically engineered to produce butanol effectively under aerobic conditions. In our previous work, a symbiotic system TSH06 has been developed successfully by our group, and two strains, C. acetobutylicum TSH1 and Bacillus cereus TSH2, were isolated from TSH06. RESULTS: Compared with single culture, TSH06 showed promotion on cell growth and solvent accumulation under microaerobic conditions. To simulate TSH06, a new symbiotic system was successfully re-constructed by adding living cells of B. cereus TSH2 into C. acetobutylicum TSH1 cultures. During the fermentation process, the function of B. cereus TSH2 was found to deplete oxygen and provide anaerobic environment for C. acetobutylicum TSH1. Furthermore, inoculation ratio of C. acetobutylicum TSH1 and B. cereus TSH2 affected butanol production. In a batch fermentation with optimized inoculation ratio of 5 % C. acetobutylicum TSH1 and 0.5 % B. cereus TSH2, 11.0 g/L butanol and 18.1 g/L ABE were produced under microaerobic static condition. In contrast to the single culture of C. acetobutylicum TSH1, the symbiotic system became more aerotolerant and was able to produce 11.2 g/L butanol in a 5 L bioreactor even with continuous 0.15 L/min air sparging. In addition, qPCR assay demonstrated that the abundance of B. cereus TSH2 increased quickly at first and then decreased sharply to lower than 1 %, whereas C. acetobutylicum TSH1 accounted for more than 99 % of the whole population in solventogenic phase. CONCLUSIONS: The characterization of a novel symbiotic system on butanol fermentation was studied. The new symbiotic system re constructed by co-culture of C. acetobutylicum TSH1 and B. cereus TSH2 showed excellent performance on butanol production under microaerobic conditions. B. cereus TSH2 was a good partner for C. acetobutylicum TSH1 by providing an anaerobic environment. During fermentation process, the high ratio of Clostridium and low ratio of Bacillus composition indicated that this symbiotic system was an effective and easily controlled cultivation model for ABE fermentation under microaerobic conditions. PMID- 26762533 TI - Iron-catalysed sequential reaction towards alpha-aminonitriles from secondary amines, primary alcohols and trimethylsilyl cyanide. AB - We have developed a one-pot iron-catalysed sequential reaction of secondary amines with primary alcohols, trimethylsilyl cyanide and TBHP under mild reaction conditions to give the corresponding alpha-aminonitriles. PMID- 26762532 TI - A malaria risk map of Kinshasa, Democratic Republic of Congo. AB - BACKGROUND: In Kinshasa, malaria remains a major public health problem but its spatial epidemiology has not been assessed for decades now. The city's growth and transformation, as well as recent control measures, call for an update. To identify highly exposed communities and areas where control measures are less critically needed, detailed risk maps are required to target control and optimize resource allocation. METHODS: In 2009 (end of the dry season) and 2011 (end of the rainy season), two cross-sectional surveys were conducted in Kinshasa to determine malaria prevalence, anaemia, history of fever, bed net ownership and use among children 6-59 months. Geo-referenced data for key parameters were mapped at the level of the health area (HA) by means of a geographic information system (GIS). RESULTS: Among 7517 children aged 6-59 months from 33 health zones (HZs), 6661 (3319 in 2009 and 3342 in 2011) were tested for both malaria (by Rapid Diagnostic Tests) and anaemia, and 856 (845 in 2009 and 11 in 2011) were tested for anaemia only. Fifteen HZs were sampled in 2009, 25 in 2011, with seven HZs sampled in both surveys. Mean prevalence for malaria and anaemia was 6.4% (5.6-7.4) and 65.1% (63.7-66.6) in 2009, and 17.0% (15.7-18.3) and 64.2% (62.6 65.9) in 2011. In two HZs sampled in both surveys, malaria prevalence was 14.1 % and 26.8% in Selembao (peri-urban), in the 2009 dry season and 2011 rainy season respectively, and it was 1.0 % and 0.8% in Ngiri Ngiri (urban). History of fever during the preceding two weeks was 13.2% (12.5-14.3) and 22.3% (20.8-23.4) in 2009 and 2011. Household ownership of at least one insecticide-treated net (ITN) was 78.7% (77.4-80.0) and 65.0% (63.7-66.3) at both time points, while use was 57.7% (56.0-59.9) and 45.0% (43.6-46.8), respectively. CONCLUSIONS: This study presents the first malaria risk map of Kinshasa, a mega city of roughly 10 million inhabitants and located in a highly endemic malaria zone. Prevalence of malaria, anaemia and reported fever was lower in urban areas, whereas low coverage of ITN and sub-optimal net use were frequent in peri-urban areas. PMID- 26762534 TI - Construction of Insulin 18-mer Nanoassemblies Driven by Coordination to Iron(II) and Zinc(II) Ions at Distinct Sites. AB - Controlled self-assembly (SA) of proteins offers the possibility to tune their properties or to create new materials. Herein, we present the synthesis of a modified human insulin (HI) with two distinct metal-ion binding sites, one native, the other abiotic, enabling hierarchical SA through coordination with two different metal ions. Selective attachment of an abiotic 2,2'-bipyridine (bipy) ligand to HI, yielding HI-bipy, enabled Zn(II)-binding hexamers to SA into trimers of hexamers, [[HI-bipy]6]3, driven by octahedral coordination to a Fe(II) ion. The structures were studied in solution by small-angle X-ray scattering and on surfaces with AFM. The abiotic metal ligand had a higher affinity for Fe(II) than Zn(II) ions, enabling control of the hexamer formation with Zn(II) and the formation of trimers of hexamers with Fe(II) ions. This precise control of protein SA to give oligomers of oligomers provides nanoscale structures with potential applications in nanomedicine. PMID- 26762535 TI - Psychosocial and respiratory disease related to severe bladder dysfunction and non-monosymptomatic enuresis. AB - OBJECTIVE: Complicated bladder dysfunctions (BD) (associated with infections/urological complications or irresponsive to treatment) are a small proportion of all cases, but are highly morbid, clinically and psychosocially. Our aim is to describe a cohort of complicated pediatric BD, using subgroup analysis to compare presentations and responses to treatment among genders, age groups, and patients with or without non-monosymptomatic enuresis (NME). We also relate severe BD to other health conditions or to social/behavioral problems and report treatment results. METHOD: Thirty-five cases of complicated BD were reviewed. Neurogenic bladders and anatomical urological problems were excluded. Justifications for referral, comorbidities, and social aspects/familial dynamics were studied. Overactive bladders were primarily treated with oxybutynin. Transcutaneous parasacral neuromodulation was used in case of insufficient response or unbearable side effects. For infrequent voiders, timed voiding and transcutaneous neuromodulation were counseled. RESULTS: Incontinence/enuresis were the motives for referral in only a third of the cases. UTI (42.9%) was the main reason for referral. Hydronephrosis was observed in 8.6% of the children. Respiratory/ENT problems, obesity, and precocious puberty were highly prevalent. Schooling problems and neuropsychiatric disease were common. Social problems were common. Five patients presented urological problems secondary to BD (hydroureteronephrosis, VUR, trabeculated bladder). Twenty percent of cases required high anticholinergic doses and 37.1% transcutaneous electrostimulation. Eight (22.9%) patients abandoned but later resumed therapy, and 14.6% did not follow treatment. Boys tended to be older than girls and presented NME, respiratory, and behavioral problems more often, with a significant difference for asthma and anxiety/depression. Associated health problems and neuropsychiatric treatment tended to be more frequent among those presenting NME. Non-enuretic children tended to show better results from treatment (see Table). CONCLUSION: The social characteristics of our population (severe cases, socially deprived, very poor, not well educated, and with limited access to health care) determine a very specific sampling. Our research demonstrated that even severe cases of BD affecting socially deprived children may be treated, with adhesion to treatment and results comparable with other cohorts of BD, although the children need multidisciplinary attention and close follow-up. Boys, older children, and NME are more difficult to treat and often have other associated health and behavioral problems. Stress-related conditions were common in severe BD. A relatively high occurrence of precocious puberty was an unexpected finding in our research. PMID- 26762536 TI - Shape-based reconstruction of dynamic fluorescent yield with a level set method. AB - BACKGROUND: Fluorescence molecular tomography (FMT) is an optical imaging technique that reveals biological processes within small animals through non invasively reconstructing the distributions of fluorescent agents. The primary problem in FMT with non-stationary fluorescent yield is the increase of the unknown parameters to be reconstructed. In this paper, a method is proposed to reconstruct dynamic fluorescent yield. METHODS: A shape-based reconstruction method that recovers dynamic fluorescent yield with a level set method is proposed for FMT. To reduce the number of unknown parameters, a level set function is introduced to describe the shape of target and a small number of parameters are used to describe the fluorescent yields at different time points. RESULTS: Results of simulations and phantom experiments demonstrate that the proposed method can recover well the dynamic fluorescent yields, shapes and locations of the target. CONCLUSIONS: The proposed method can handle the cases with non-stationary fluorescent yields and recover the fluorescent yields at each projection angle. PMID- 26762537 TI - Revealing Masked Hypertension in People of African Ancestry: We Need to Do Better. PMID- 26762538 TI - Attraction by repulsion: compounds with like charges undergo self-assembly in water that improves in high salt and persists in real biological fluids. AB - We report a family of highly anionic calixarenes that form discrete homo-dimeric assemblies in pure water, that get stronger in high salt solutions, and that remain assembled in complex, denaturing solutions like real urine. The results reveal the potential of like-charged subunits for self-assembly in high-salt solutions and biological fluids. PMID- 26762539 TI - Spontaneous Capture of Carbohydrate Guests through Folding and Zipping of Self Assembled Ribbons. AB - One of the great challenges in molecular self-assembly is how to confer self folding and closing characteristics on flat two-dimensional structures in response to external triggers. Herein, we report a planar ribbon assembly that folds into closed tubules in response to fructose. The ribbons, ~28 nm wide and 3.5 nm thick, consist of 8 laterally-associated elementary fibrils in which disc shaped macrocycle amphiphiles are stacked along their axis. Upon addition of fructose, these flat structures spontaneously fold into closed tubules, with an outer diameter of ~8 nm, through zipping of the two sides of the ribbons. Notably, the folding and then zipping of the flat ribbons is accompanied by spontaneous capture of the fructose molecules inside the tubular cavities. PMID- 26762541 TI - Structure and dynamics of the aliphatic cholesterol side chain in membranes as studied by (2)H NMR spectroscopy and molecular dynamics simulation. AB - Cholesterol is an evolutionarily highly optimized molecule particularly known for its ability to condense the phospholipids in cellular membranes. Until recently, the accompanying increase in the chain order of the surrounding phospholipids was attributed to the planar and rigid tetracyclic ring structure of cholesterol. However, detailed investigations of cholesterol's aliphatic side chain demonstrated that this side chain is responsible for approximately half of the condensation effect. Therefore, we investigated the structure and dynamics of the aliphatic side chain of cholesterol using (2)H solid-state nuclear magnetic resonance (NMR) spectroscopy and microsecond timescale all-atom molecular dynamics (MD) simulations in four different model membranes: POPC, DPPC, PSM, and POPC/PSM (1 : 1 mol/mol) and at three different temperatures: 5 degrees C, 37 degrees C, and 50 degrees C. A cholesterol variant, in which 11 hydrogens of the aliphatic side chain were exchanged for deuterium, was used and the respective (2)H NMR spectra confirmed the axially asymmetric rotational diffusion of cholesterol in DPPC and PSM. Furthermore, NMR spectra indicated that some hydrogens showed an unexpected magnetic inequivalency. This finding was confirmed by all-atom molecular dynamics simulations and detailed analysis revealed that the hydrogens of the methylene groups at C22, C23, and C24 are magnetically inequivalent. This inequivalency is caused by steric clashes of the aliphatic side chain with the ring structure of cholesterol as well as the branched C21 methyl group. These excluded volume effects result in reduced conformational flexibility of the aliphatic side chain of cholesterol and explain its high order (order parameter of 0.78 for chain motions) and large contribution to the condensation effect. Additionally, the motional pattern of the side chain becomes highly anisotropic such that it shows larger fluctuations perpendicular to the ring plane of cholesterol with a biaxiality of the distribution of 0.046. Overall, our results shed light on the mechanism how the aliphatic side chain is able to contribute about half of the condensation effect of cholesterol. PMID- 26762542 TI - Synergistic Rhodium/Phosphoric Acid Catalysis for the Enantioselective Addition of Oxonium Ylides to ortho-Quinone Methides. AB - We report herein a powerful and highly stereoselective protocol for the domino type reaction of diazoesters with ortho-quinone methides generated in situ to furnish densely functionalized chromans with three contiguous stereogenic centers. A transition-metal and a Bronsted acid catalyst were shown to act synergistically to produce a transient oxonium ylide and ortho-quinone methide, respectively, in two distinct cycles. These intermediates underwent subsequent coupling in a conjugate-addition-hemiacetalization event in generally good yield with excellent diastereo- and enantioselectivity. PMID- 26762540 TI - Workplace exposure to diesel and gasoline engine exhausts and the risk of colorectal cancer in Canadian men. AB - BACKGROUND: The International Agency for Research on Cancer (IARC) classified diesel exhaust as carcinogenic to humans (Group 1) and gasoline exhaust as a possible carcinogen (Group 2B) based studies of lung cancer, however the evidence for other sites is limited. We addressed this question by investigating exposure to diesel and gasoline emissions with respect to risk of colorectal cancer in men. METHODS: We used data from a population-based case-control study with incident cases of colon (n = 931) and rectal (n = 840) cancer and 1360 controls from 7 Canadian provinces conducted in 1994-1997. Lifetime occupational history and information on other risk factors was collected. Occupational hygienists, blinded to case-control status, assigned exposures to each job for 3 dimensions: concentration, frequency, and reliability. Logistic regression was used to estimate odds ratios (OR) and their 95 % confidence intervals (CI), adjusted for age, province, use of proxy respondents, smoking, body-mass index, physical activity, intake of alcohol, processed meats, and occupational exposure to asbestos and aromatic amines. RESULTS: Among CRC cases, 638 (36 %) were exposed to diesel and 814 (46 %) were exposed to gasoline emissions. Relative to the unexposed, elevated risks were observed among subjects ever exposed to high concentration levels of diesel emissions for colorectal cancer (OR = 1.65, 95 % CI = 0.98-2.80) and rectal cancer (OR = 1.98, 95 % CI = 1.09-3.60), but not colon cancer. Prolonged (>10 years) exposure at high concentrations was also associated with high risks of rectal cancer (OR = 2.33 95 % CI = 0.94-5.78; p-trend = 0.02). No statistically significant associations were observed for gasoline emissions. CONCLUSIONS: Our findings suggest that sustained high-level exposure diesel emissions may increase the risk of rectal cancer. PMID- 26762543 TI - Caring for Women Experiencing Reproductive Coercion. AB - Reproductive coercion is behavior that interferes with a woman's decision making regarding reproductive health. It may consist of contraception sabotage and/or pressure to either carry a pregnancy to term or to have an abortion. Reproductive coercion may coexist with intimate partner violence and be associated with higher rates of unintended pregnancy. Midwives and other women's health care providers can play an integral role in identifying reproductive coercion and implementing harm-reduction strategies. PMID- 26762545 TI - Carbon dioxide induced bubble formation in a CH4-CO2-H2O ternary system: a molecular dynamics simulation study. AB - The extraction of methane from its hydrates using carbon dioxide involves the decomposition of the hydrate resulting in a CH4-CO2-H2O ternary solution. Using classical molecular dynamics simulations, we investigate the evolution of dissolved gas molecules in the ternary system at different concentrations of CO2. Various compositions considered in the present study resemble the solution formed during the decomposition of methane hydrates at the initial stages of the extraction process. We find that the presence of CO2 aids the formation of CH4 bubbles by causing its early nucleation. Elucidation of the composition of the bubble revealed that in ternary solutions with high concentration of CO2, mixed gas bubbles composed of CO2 and CH4 are formed. To understand the role of CO2 in the nucleation of CH4 bubbles, the structure of the bubble formed was analyzed, which revealed that there is an accumulation of CO2 at the interface of the bubble and the surrounding water. The aggregation of CO2 at the bubble-water interface occurs predominantly when the concentration of CO2 is high. Radial distribution function for the CH4-CO2 pair indicates that there is an increasingly favorable direct contact between dissolved CH4 and CO2 molecules in the bubble-water interface. It is also observed that the presence of CO2 at the interface results in the decrease in surface tension. Thus, CO2 leads to greater stability of the bubble-water interface thereby bringing down the critical size of the bubble nuclei. The results suggest that a rise in concentration of CO2 helps in the removal of dissolved CH4 thereby preventing the accumulation of methane in the liquid phase. Thus, the presence of CO2 is predicted to assist the decomposition of methane hydrates in the initial stages of the replacement process. PMID- 26762544 TI - Inflammatory bowel disease as a disorder of an imbalance between pro- and anti inflammatory molecules and deficiency of resolution bioactive lipids. AB - The inflammatory process seen in inflammatory bowel disease (IBD) is due to excess production of pro-inflammatory cytokines interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-alpha), interferons (IFNs), macrophage migration inhibitory factor (MIF), HMGB1 (high mobility group B1) and possibly, a reduction in anti-inflammatory cytokines IL-10, IL-4, and transforming growth factor-beta (TGF-beta). These pro-inflammatory molecules lead to increased production of reactive oxygen species (ROS) including nitric oxide resulting in target tissue damage. I propose that inadequate production of inflammation resolving molecules lipoxins, resolvins, protectins, maresins and nitrolipids that suppress inflammation, ROS production, enhance wound healing and have cytoprotective properties results in inappropriate inflammation, delay in healing/repair process and so target tissue/organ damage continues in IBD. Hence, suggested therapeutic approach could include administration of stable synthetic analogues of lipoxins, resolvins, protectins, maresins and nitrolipids. This implies that measuring urine, stool and plasma levels of lipoxins, resolvins, protectins, maresins and nitrolipids may be used to detect the onset, progression and response to treatment of IBD. PMID- 26762546 TI - Metal-Metal Interactions in Heterobimetallic Complexes with Dinucleating Redox Active Ligands. AB - The tuning of metal-metal interactions in multinuclear assemblies is a challenge. Selective P coordination of a redox-active PNO ligand to Au(I) followed by homoleptic metalation of the NO pocket with Ni(II) affords a unique trinuclear Au Ni-Au complex. This species features two antiferromagnetically coupled ligand centered radicals and a double intramolecular d(8)-d(10) interaction, as supported by spectroscopic, single-crystal X-ray diffraction, and computational data. A corresponding cationic dinuclear Au-Ni analogue with a stronger d(8) d(10) interaction is also reported. Although both heterobimetallic structures display rich electrochemistry, only the trinuclear Au-Ni-Au complex facilitates electrocatalytic C-X bond activation of alkyl halides in its doubly reduced state. Hence, the presence of a redox-active ligand framework, an available coordination site at gold, and the nature of the nickel-gold interaction appear to be essential for this reactivity. PMID- 26762547 TI - Perineal Massage in Pregnancy. PMID- 26762548 TI - Theoretical study of electron tunneling through the spiral molecule junctions along spiral paths. AB - The electronic transport properties of carbohelicenes and heterohelicenes absorbed between two metal electrodes have been investigated by using the nonequilibrium Green's function in combination with the density function theory. The transport properties of the molecular junctions are mainly dependent on the nature of spiral molecules. The detailed analyses of the transmission spectra, the energy levels as well as the spatial distribution of molecular projected self consistent Hamiltonian explain how the geometry of molecules affects the intra molecular electronic coupling. The spiral current in the configurations can be achieved by tuning the outer edge states of spiral-shaped molecules. Furthermore, the symmetric current-voltage characteristics are investigated with the bias changing for all devices as well as an negative differential resistance behavior is observed. PMID- 26762549 TI - Auricular ossification: A newly recognized feature of osteoprotegerin-deficiency juvenile Paget disease. AB - We report auricular ossification (AO) affecting the elastic cartilage of the ear as a newly recognized feature of osteoprotegerin (OPG)-deficiency juvenile Paget disease (JPD). AO and auricular calcification refer interchangeably to rigid pinnae, sparing the ear lobe, from various etiologies. JPD is a rare Mendelian disorder characterized by elevated serum alkaline phosphatase activity accompanied by skeletal pain and deformity from rapid bone turnover. Autosomal recessive transmission of loss-of-function mutations within TNFRSF11B encoding OPG accounts for most JPD (JPD1). JPD2 results from heterozygous constitutive activation of TNFRSF11A encoding RANK. Other causes of JPD remain unknown. In 2007, we reported a 60-year-old man with JPD1 who described hardening of his external ears at age 45 years, after 4 years of treatment with bisphosphonates (BPs). Subsequently, we noted rigid pinnae in a 17-year-old boy and 14-year-old girl, yet pliable pinnae in a 12-year-old boy, each with JPD1 and several years of BP treatment. Cranial imaging indicated cortical bone within the pinnae of both teenagers. Radiologic studies of our three JPD patients without mutations in TNFRSF11B showed normal auricles. Review of the JPD literature revealed possible AO in several reports. Two of our JPD1 patients had experienced difficult tracheal intubation, raising concern for mineralization of laryngeal elastic cartilage. Thus, AO is a newly recognized feature of JPD1, possibly exacerbated by BP treatment. Elastic cartilage at other sites in JPD1 might also ossify, and warrants investigation. PMID- 26762552 TI - Current Resources for Evidence-Based Practice, January/February 2016. PMID- 26762551 TI - Metal Free Bi(hetero)aryl Synthesis: A Benzyne Truce-Smiles Rearrangement. AB - A new benzyne transformation is described that affords versatile biaryl structures without recourse to transition-metal catalysis or stoichiometric amounts of organometallic building blocks. Aryl sulfonamides add to benzyne upon fluoride activation, and then undergo an aryl Truce-Smiles rearrangement to afford biaryls with sulfur dioxide extrusion. The reaction proceeds under simple reaction conditions and has excellent scope for the synthesis of sterically hindered atropisomeric biaryl amines. PMID- 26762550 TI - Clinical and metabolic characteristics of treated hyperlipidemic patients additionally affected by subclinical hyperglycemia. AB - BACKGROUND: Impaired glucose regulation (IGR) and hyperlipidemia (HL) are associated with an increased risk of developing a cardiovascular disease. Hyperlipidemic patients were shown to bear a greater risk for an increased intima media thickness (IMT). However little is known about differences between treated hyperlipidemic patients (HL) with normal (NGR) or impaired (IGR) glucose regulation. METHODS: We performed a cross-sectional study, involving 96 non diabetic HL patients with IGR (fasting plasma glucose of >= 100 mg/dl and < 126 mg/dl or/and HbA1c-level of >= 5.7 and < 6.5 %) or with NGR (HbA1c-level of < 5.7 % and a fasting glucose < 100 mg/dl). We compared metabolic characteristics and the IMT between the two groups. Insulin sensitivity in fasting conditions was described by HOMA-IR and QUICKI. RESULTS: HL-IGR patients were older (57.6 +/- 10.4 vs. 49.1 +/- 8.7, p < 0.001), had higher carotid IMT measurements (IMT average: 0.68 +/- 0.14 vs. 0.60 +/- 0.09, p = 0.002; IMT right: 0.67 +/- 0.15 vs. 0.60 +/- 0.10, p = 0.013; IMT left: 0.63 vs. 0.57, p = 0.009), as well as a higher chance to exceed a cut-off value of >= 0.8 mm or insignificant stenosis within this investigation (OR: 3.9, 95 % CI: 1.15-13.22, p = 0.029) compared to HL-NGR-patients. Furthermore HL-IGR patients were characterised by a higher waist circumference (100.6 +/- 10.1 vs. 91.6 +/- 13.3, p < 0.001), higher fasting plasma glucose-levels (100.1 +/- 10.8 vs. 88.1 +/- 6.6, p < 0.001), higher HbA1c concentrations (5.8 +/- 0.33 vs. 5.3 +/- 0.24, p < 0.001) and C-peptide levels (2.70 vs. 2.10, p = 0.012). Age and CVD status were in general the only two variables which independently explained IMT. CONCLUSION: Our study showed that among patients with treated hyperlipidemia the presence of IGR characterised subjects who were older and had a significantly higher risk for an increased IMT compared with those maintaining NGR. Further studies are necessary to evaluate if this specific subpopulation with IGR can benefit from a more strict multifactorial management and perhaps from an additional early antihyperglycaemic treatment. PMID- 26762553 TI - Augmented Z scheme blueprint for efficient solar water splitting system using quaternary chalcogenide absorber material. AB - Photoelectrochemical hydrogen (H2) production from water is a key method of addressing energy needs using an environmentally friendly approach. In the last two decades we have witnessed the evolution of many different expensive catalysts, photoelectrodes and related technologies, especially those involving precious metals and use of acidic or basic electrolytes for hydrogen production. Cu2ZnSnS4 (CZTS) is a relatively new candidate in the category of efficient photocathodes, due to its high absorption coefficient and near optimal energy band gap. In this paper, we demonstrate photoelectrochemical viability of CZTS in combination with other photoanodes such as TiO2, BiVO4, and WO3 for H2 production with the use of an electrolyte of near neutral pH, a single redox mediator, and insignificant potential biasing. A systematic study was performed to understand CZTS performance with each photoanode, band energetics of CZTS with other photoanodes, impedance behavior of each photoelectrode, and utility of a CZTS photocell in place of a CZTS photocathode. Our assessment indicates that a protected CZTS photocell performs well when used in a Z-scheme containing TiO2 nanotubular array-CZTS or nanocrystalline WO3-CZTS. Preliminary experiments indicated that apart from band energetics, porosity and effective surface area of the photoanodes play a crucial role in determining the photoelectrochemical performance of the system. PMID- 26762554 TI - Mild and Efficient Palladium-Catalyzed Direct Trifluoroethylation of Aromatic Systems by C-H Activation. AB - The introduction of trifluoroalkyl groups into aromatic molecules is an important transformation in the field of organic and medicinal chemistry. However, the direct installation of fluoroalkyl groups onto aromatic molecules still represents a challenging and highly demanding synthetic task. Herein, a simple trifluoroethylation process that relies on the palladium-catalyzed C-H activation of aromatic compounds is described. With the utilization of a highly active trifluoroethyl(mesityl)iodonium salt, the developed catalytic method enables the first highly efficient and selective trifluoroethylation of aromatic compounds. The robust catalytic procedure provides the desired products in up to 95 % yield at 25 degrees C in 1.5 to 3 hours and tolerates a broad range of functional groups. The utilization of hypervalent reagents opens new synthetic possibilities for direct alkylations and fluoroalkylations in the field of transition-metal catalyzed C-H activation. PMID- 26762555 TI - Should I Have a Cesarean Birth? PMID- 26762556 TI - Electron stimulated hydroxylation of a metal supported silicate film. AB - Water adsorption on a double-layer silicate film was studied by using infrared reflection-absorption spectroscopy, thermal desorption spectroscopy and scanning tunneling microscopy. Under vacuum conditions, small amounts of silanols (Si-OH) could only be formed upon deposition of an ice-like (amorphous solid water, ASW) film and subsequent heating to room temperature. Silanol coverage is considerably enhanced by low-energy electron irradiation of an ASW pre-covered silicate film. The degree of hydroxylation can be tuned by the irradiation parameters (beam energy, exposure) and the ASW film thickness. The results are consistent with a generally accepted picture that hydroxylation occurs through hydrolysis of siloxane (Si-O-Si) bonds in the silica network. Calculations using density functional theory show that this may happen on Si-O-Si bonds, which are either parallel (i.e., in the topmost silicate layer) or vertical to the film surface (i.e., connecting two silicate layers). In the latter case, the mechanism may additionally involve the reaction with a metal support underneath. The observed vibrational spectra are dominated by terminal silanol groups (nu(OD) band at 2763 cm(-1)) formed by hydrolysis of vertical Si-O-Si linkages. Film dehydroxylation fully occurs only upon heating to very high temperatures (~ 1200 K) and is accompanied by substantial film restructuring, and even film dewetting upon cycling hydroxylation/dehydroxylation treatment. PMID- 26762557 TI - Interstitial 10p deletion derived from a maternal ins(16;10)(q22;p13p15.2): Report of the first familial case of 10p monosomy affecting to two familial members of different generations. AB - Monosomy 10p is a rare chromosomal disorder with a prevalence <1/1,000,000, in which a terminal or interstitial distal region of chromosome 10 is deleted resulting in a variable phenotype depending on the size of the deletion. Two main phenotypes have been defined depending on the location of the deletion: HDR syndrome (Hypoparathyroidism, sensorineural Deafness, and Renal disease), and DGS2 (DiGeorge syndrome type 2). The vast majority of cases reported so far have resulted from de novo events. Here, we present the first familial presentation of this contiguous gene deletion syndrome, affecting two family members in different generations: a child and his maternal uncle. In both cases, the deletion was due to a malsegregation of a maternal balanced rearrangement, ins(16;10)(q22;p13p15.2). The identification and characterization of this rearrangement was possible using a combination of different genetic analyses such as karyotype, MLPA, FISH, and array CGH. We underline the importance of the present results in terms of genetic and reproductive counseling for the carriers of the balanced rearrangement within the family, and demonstrate again the utility of expanding the genetic studies to the relatives of the affected patients. PMID- 26762560 TI - Perimeter ring currents in benzenoids from Pauling bond orders. AB - It is shown that the ring currents in perimeter hexagonal rings of Kekulean benzenoids, as estimated within the Randic conjugated-circuit model, can be calculated directly without tedious pairwise comparison of Kekule structures or Kekule counting for cycle-deleted subgraphs. Required are only the Pauling bond orders of perimeter bonds and the number of Kekule structures of the benzenoid, both readily available from the adjacency matrix of the carbon skeleton. This approach provides easy calculation of complete current maps for benzenoids in which every face has at least one bond on the perimeter (as in the example of cata-condensed benzenoids), and allows qualitative evaluation of the main ring current contributions to (1)H chemical shifts in general benzenoids. A combined Randic-Pauling model for correlation of ring current and bond length through bond order is derived and shown to be consistent with resilience of current under bond alternation. PMID- 26762559 TI - Refoldable Foldamers: Global Conformational Switching by Deletion or Insertion of a Single Hydrogen Bond. AB - Small changes in the structure of a foldamer may lead to gross changes in conformational preference. We show that the simple insertion or deletion of a single hydrogen bond by changes in pH or by photochemical deprotection is sufficient to refold a helical oligomer, interconverting M and P screw-sense preference. As a consequence of the switch, information may be transmitted to a remote catalytic site, selectively directing the formation of either of two enantiomeric products by a reaction involving 1,22-remote intermolecular asymmetric induction. PMID- 26762558 TI - Incremental validity of sense of coherence, neuroticism, extraversion, and general self-efficacy: longitudinal prediction of substance use frequency and mental health. AB - BACKGROUND: Several studies have demonstrated the importance of sense of coherence (SOC), neuroticism (N), extraversion (E), and general self-efficacy (GSE) for health, yet the unique utility of these overlapping constructs remains uncertain. The present research aims at exploring incremental validity when predicting (1) substance use specifically and (2) mental health generally among adolescents. METHODS: A prospective and longitudinal design was used to predict (1) initial substance use nine years into the future and (2) mental health one year and four years into the future. Participants were 318 adolescents (age 14 to 15 at the beginning of the study). RESULTS: Structural equation modeling revealed (1) that SOC had long-term incremental validity over N, E, and GSE for tobacco use and alcohol use, whereas cannabis use was predicted by E and GSE; and (2) that long-term mental health after four years was only predicted by SOC. CONCLUSIONS: Two studies provide further evidence for the importance of considering salutogenic factors when forecasting mental health and health-related behavior beyond classical constructs such as N, E, and GSE. Differences in criterion validity reveal that SOC cannot be equated with reversed neuroticism. PMID- 26762561 TI - EZH2 mutation in an adolescent with Weaver syndrome developing acute myeloid leukemia and secondary hemophagocytic lymphohistiocytosis. AB - Weaver syndrome is an overgrowth syndrome characterized by pre- and postnatal overgrowth with distinctive craniofacial appearance. Mutations in the enhancer of zeste homolog 2 (EZH2) gene were found to cause Weaver syndrome, and have been associated with hematologic malignancies, including acute myeloid leukemia (AML). We present the first report of a patient with Weaver syndrome, who developed AML and harbored an EZH2 mutation. The clinical course of the 16-year-old female adolescent patient was complicated by a secondary hemophagocytic lymphohistiocytosis. Genomic DNA was isolated from bone marrow cells at AML diagnosis. Polymerase chain reactions were performed with primers covering all exons of the EZH2 gene. We found a novel heterozygous EZH2 mutation within exon 5 that caused an amino acid change from proline to leucine at position 132 (p.Pro132Leu) within the catalytic D1 domain. Analysis of a remission sample also showed this mutation, indicating a germline mutation. It remains to be elucidated whether EZH2 mutations contribute to disease severity in specific AML cases. PMID- 26762563 TI - Photonic vortices induced in a single-component phototropic liquid crystal. AB - Using the direct coupling mechanism of light with a liquid via molecular absorption, i.e. the opto-thermal effect, we demonstrate the formation of well controlled three-dimensional circular flows, i.e. a toroidal vortex, inside the liquid crystal (LC) droplet placed on a glass plate in its isotropic phase. We investigated the behavior of a droplet formed of a phototropic liquid crystal and composed of a mesogenic azobenzene derivative under the Gaussian beam light illumination in four different geometries. The light-induced liquid flows in the isotropic phase of the LC were visualized by dispersing carbon micro-particles in the volume of the LC. Movements of the particles could be observed under an optical microscope from the top and side views, respectively. The formation of the stable in time toroidal vortex (the photonic vortex) is dependent on laser light illumination geometry, properties of the liquid and substrate but does not depend on gravitational forces being similar for droplets situated either above or below the glass plate. The main mechanism of the indirect conversion of light into mechanical work is related to the temperature induced gradient of surface tension known as the Marangoni effect. PMID- 26762562 TI - Sonic Hedgehog Pathway Activation Is Associated With Resistance to Platinum-Based Chemotherapy in Advanced Non-Small-Cell Lung Carcinoma. AB - INTRODUCTION: Chemoresistance is a major challenge in the treatment of advanced non-small-cell lung cancer (NSCLC). Because the Sonic hedgehog (Shh) pathway is reactivated in NSCLC, we investigated an association between chemoresistance and Shh activation. PATIENTS AND METHODS: From a cohort of 178 patients with advanced NSCLC treated with platinum-based chemotherapy as first-line treatment, we selected all surgical tumor samples at diagnosis (n = 36). Shh activation was evaluated through Gli1 and Gli2 expression using immunohistochemistry (quantitative score). In vitro treatment studies with cisplatin or vismodegib (Shh pathway inhibitor), or both, were performed on NSCLC cell lines (H322 and A549) and primary cultures from patients with sarcomatoid carcinoma (n = 4). RESULTS: Of the 36 patients, 12 had NSCLC refractory to chemotherapy (R-patients, 33.3%) and 24 had controlled disease (C-patients). Gli1 expression did not differ between the R- and C-patients (P = .35). Gli2 expression was more often positive in the R-patients (41.7% vs. 8.3%; P = .02). Progression-free survival (PFS) and overall survival (OS) in patients with a Gli2-positive score was 2.1 and 8.0 months, respectively, compared with 6.7 and 18.0 months for patients with a Gli2 negative score (P = .03 and P = .002, respectively). On multivariate analysis, the Gli2 score correlated independently with PFS (hazard ratio [HR], 2.64; 95% confidence interval [CI], 1.05-6.63; P = .04) and OS (HR, 4.36; 95% CI, 1.67 11.36; P = .003). The sarcomatoid carcinoma cell lines were more resistant to cisplatin than were the H838 and A549 cell lines. The cisplatin-vismodegib combination displayed a synergistic cytotoxic effect in the most chemoresistant cells in vitro. CONCLUSION: The Shh pathway is associated with resistance to platinum-based chemotherapy in NSCLC. PMID- 26762564 TI - Filtration Shell Mediated Power Density Independent Orthogonal Excitations Emissions Upconversion Luminescence. AB - Lanthanide doped core-multishell structured NaGdF4:Yb,Er@NaYF4:Yb@NaGdF4:Yb,Nd@NaYF4@NaGdF4:Yb,Tm@NaYF4 nanoparticles with power-density independent orthogonal excitations-emissions upconversion luminescence (UCL) were fabricated for the first time. The optical properties of these core-multishell structured nanoparticles were related to the absorption filtration effect of the NaGdF4:Yb,Tm layer. By tuning the thickness of the filtration layer, the nanoparticles can exhibit unique two independent groups of UCL: Tm(3+) prominent UV/blue (UV=ultraviolet) UCL under the excitation at 980 nm and Er(3+) prominent green/red UCL under the excitation at 796 nm. The filtration shell mediated orthogonal excitations-emissions UCL are power-density independent. As a proof of concept, the core-multishell nanoparticles are used in multi-dimensional security design and imaging-guided combined photodynamic therapy and chemotherapy. PMID- 26762565 TI - Path Analysis of Acculturative Stress Components and Their Relationship with Depression Among International Students in China. AB - Acculturative stress prevents international students from adapting to the host culture, increasing their risk for depression. International students in China are a growing and at-risk population for acculturative stress and depression. With data from the International Student Health and Behaviour Survey (Yu et al., ) in China, seven acculturative stress components were detected in a previous study (Yu et al., ), including a central component (self-confidence), three distal components (value conflict, identity threat and rejection) and three proximal components (poor cultural competence, opportunity deprivation and homesickness). The current study extended the previous study to investigate the relationship between these components and depression with data also from International Student Health and Behaviour Survey. Participants were 567 students (59% male, 40.4% African, mean age = 22.75, SD = 4.11) recruited in Wuhan, China. The sample scored high on the Acculturative Stress Scale for International Students (M = 92.81, SD = 23.93) and Center for Epidemiologic Studies Short Depression Scale (M = 0.97, SD = 0.53). Acculturative stress was positively associated with depression; the association between the three distal stress components and depression was fully mediated through self-confidence, while the three proximal components had a direct effect and a self-confidence-mediated indirect effect. These findings extended the value of the previous study, highlighted the central role of self-confidence in understanding acculturative stress and depression and provided new data supporting more effective counselling for international students in China. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26762566 TI - Study of smart antibacterial PCL-xFe3 O4 thin films using mouse NIH-3T3 fibroblast cells in vitro. AB - Surface energy plays a major role in prokaryotic and eukaryotic cell interactions with biomedical devices. In the present study, poly(epsilon-caprolactone)-xFe3 O4 nanoparticles (PCL-xFO NPs; x = 0, 10, 20, 30, 40, 60 wt% FO concentration in PCL) composite thin films were developed for skin tissue regeneration. The surface properties in terms of roughness, surface energy, wettability of the thin films were altered with the incorporation of Fe3 O4 NPs. These thin films show antimicrobial properties and cyto-compatibility with NIH 3T3 mouse embryonic fibroblast cells. The porosity and thickness of the films were controlled by varying RPM of the spin coater. Interestingly, at 1000 RPM the roughness of the film decreased with increasing concentrations of FO NPs in PCL, whereas the surface energy increased with increasing FO NPs concentrations. Furthermore, the spreading of NIH-3T3 cells grown on PCL-xFO thin films was less as compared to control (TCPS), however cells overcame this effect after 48 h of seeding and cells spread similarly to those grown on TCPS after 48 h. Also, the incorporation of FO NPs in thin films induced inner membrane permeabilization in E. coli bacteria leading to bacterial cell death. The viability of E. coli bacteria decreased with increasing concentration of FO NPs in PCL. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 795-804, 2017. PMID- 26762568 TI - Free volumes and gas transport in polymers: amine-modified epoxy resins as a case study. AB - The CO2 transport process was studied in a series of amine-modified epoxy resins having different cross-linking densities but the same chemical environment for the penetrant molecules. Positron Annihilation Lifetime Spectroscopy (PALS) was used to monitor the free volume structure of the samples and experimentally evaluate their fractional free volume fh(T) and its temperature evolution. The analysis of the free volume hole size distribution showed that all the holes have a size large enough to accommodate the penetrant molecules at temperatures T above the glass transition temperature Tg. The measured gas diffusion constants at T > Tg have been reproduced in the framework of the free volume theory of diffusion using a novel procedure based on the use of fh(T) as an input experimental parameter. PMID- 26762567 TI - Deciphering the anti-angiogenic effect of endostatin/cyclophosphamide to normalize tumor micrangium through notch signaling pathway in colon cancer. AB - BACKGROUND: The invasion of colon cancer is associated with the tumor angiogenesis. Endostatin is an important anti-angiogenic agent, and the additive effect of endostatin with a chemotherapeutic agent, cyclophosphamide, on micrangium has not been established. METHODS: Male BALB/c strain nude mice were injected with human colorectal carcinoma cells (HCT-116). The mice were divided into four groups (n=15, each group) and were treated with different concentrations of endostatin (15, 10, and 5 mg/kg/day), cyclophosphamide (20, 10, and 5 mg/kg/day), and combination of endostatin/cyclophosphamide (15+20, 15+10, and 15+5 mg/kg/day). The tumor inhibition rate was evaluated, followed by the quantification of messenger ribonucleic acid (mRNA) and protein expression of notch signaling components NOTCH-1, NOTCH-3, NOTCH-4, JAG-1, DLL-4, Hes-1, and Hey-1 using quantitative polymerase chain reaction (qPCR). The protein expression of NOTCH-3, JAG-1, and DLL-4 was confirmed using western blotting. Microvessel density (MVD) was evaluated to detect micrangium following the treatment. RESULTS: The endostatin/cyclophosphamide-treated samples exhibited an additive effect on the tumor inhibition rate and the microvessel count. NOTCH-1, NOTCH-3, NOTCH-4, JAG-1, Hes-1, and Hey-1 expression levels were highly correlated and downregulated in the treated samples, whereas DLL-4 expression was upregulated that accounted for its anti-angiogenic property. CONCLUSIONS: The combination treatment of colon cancer with endostatin and a chemotherapeutic agent, cyclophosphamide proves to be an efficient therapeutic strategy to inhibit the rapid vasculature formation confirmed by the differential expression of notch signaling components. PMID- 26762569 TI - Connecting Active-Site Loop Conformations and Catalysis in Triosephosphate Isomerase: Insights from a Rare Variation at Residue 96 in the Plasmodial Enzyme. AB - Despite extensive research into triosephosphate isomerases (TIMs), there exists a gap in understanding of the remarkable conjunction between catalytic loop-6 (residues 166-176) movement and the conformational flip of Glu165 (catalytic base) upon substrate binding that primes the active site for efficient catalysis. The overwhelming occurrence of serine at position 96 (98% of the 6277 unique TIM sequences), spatially proximal to E165 and the loop-6 residues, raises questions about its role in catalysis. Notably, Plasmodium falciparum TIM has an extremely rare residue--phenylalanine--at this position whereas, curiously, the mutant F96S was catalytically defective. We have obtained insights into the influence of residue 96 on the loop-6 conformational flip and E165 positioning by combining kinetic and structural studies on the PfTIM F96 mutants F96Y, F96A, F96S/S73A, and F96S/L167V with sequence conservation analysis and comparative analysis of the available apo and holo structures of the enzyme from diverse organisms. PMID- 26762570 TI - Addressing potential prior-data conflict when using informative priors in proof of-concept studies. AB - Bayesian methods are increasingly used in proof-of-concept studies. An important benefit of these methods is the potential to use informative priors, thereby reducing sample size. This is particularly relevant for treatment arms where there is a substantial amount of historical information such as placebo and active comparators. One issue with using an informative prior is the possibility of a mismatch between the informative prior and the observed data, referred to as prior-data conflict. We focus on two methods for dealing with this: a testing approach and a mixture prior approach. The testing approach assesses prior-data conflict by comparing the observed data to the prior predictive distribution and resorting to a non-informative prior if prior-data conflict is declared. The mixture prior approach uses a prior with a precise and diffuse component. We assess these approaches for the normal case via simulation and show they have some attractive features as compared with the standard one-component informative prior. For example, when the discrepancy between the prior and the data is sufficiently marked, and intuitively, one feels less certain about the results, both the testing and mixture approaches typically yield wider posterior-credible intervals than when there is no discrepancy. In contrast, when there is no discrepancy, the results of these approaches are typically similar to the standard approach. Whilst for any specific study, the operating characteristics of any selected approach should be assessed and agreed at the design stage; we believe these two approaches are each worthy of consideration. PMID- 26762572 TI - Bevacizumab in Addition to Palliative Chemotherapy for Patients With Peritoneal Carcinomatosis of Colorectal Origin: A Nationwide Population-Based Study. AB - BACKGROUND: Most patients with colorectal cancer (CRC) presenting with peritoneal carcinomatosis (PC) rely on palliative systemic treatment options. However, data on the use and effect of systemic treatment strategies, including targeted agents for the palliative treatment of colorectal PC, are lacking. We conducted a nationwide population-based study with data from the period in which the targeted agent bevacizumab was introduced in the Netherlands. PATIENTS AND METHODS: The present study included all patients diagnosed from 2007 to 2014 with synchronous PC from CRC treated with only palliative systemic therapy. We assessed the use of bevacizumab, the standard choice of targeted treatment, in addition to first-line chemotherapy. Multivariable logistic regression analyses were performed to calculate the predictors for the additional prescription of bevacizumab. Survival estimates were calculated, and multivariable Cox analyses were performed to estimate the hazard ratios (HRs) of death stratified by the treatment received. RESULTS: A total of 1235 patients received palliative chemotherapy, of whom 436 also received bevacizumab (35%). Patients aged >= 75 years and patients with PC from colonic tumors were less likely to receive chemotherapy plus bevacizumab. The addition of bevacizumab to palliative chemotherapy was associated with an improved overall median survival of 7.5 versus 11 months in both patients with isolated PC and those with concomitant extraperitoneal metastases. The improvement remained after adjustment for patient and tumor characteristics (HR, 0.7; 95% confidence interval, 0.64-0.83). CONCLUSION: The results of the present nationwide population-based study support the rationale for bevacizumab in addition to palliative chemotherapy for patients with PC of CRC and underline the need for ongoing efforts to precisely determine the role of targeted therapy in the treatment of PC. PMID- 26762573 TI - Can evidence-based health policy from high-income countries be applied to lower income countries: considering barriers and facilitators to an organ donor registry in Mumbai, India. AB - BACKGROUND: Organ transplantation has become an effective means to extend lives; however, a major obstacle is the lack of availability of cadaveric organs. India has one of the lowest cadaver organ donation rates in the world. If India could increase the donor rate, the demand for many organs could be met. Evidence from high-income countries suggests that an organ donor registry can be a valuable tool for increasing donor rates. The purpose of this study is to determine whether the implementation of an organ donor registry is a feasible and appropriate policy option to enhance cadaver organ donation rates in a lower income country. METHODS: This qualitative policy analysis employs semi-structured interviews with physicians, transplant coordinators, and representatives of organ donation advocacy groups in Mumbai. Interviews were designed to better understand current organ donation procedures and explore key informants' perceptions about Indian government health priorities and the likelihood of an organ donor registry in Mumbai. The 3-i framework (ideas, interests, and institutions) is used to examine how government decisions surrounding organ donation policies are shaped. RESULTS: Findings indicate that organ donation in India is a complex issue due to low public awareness, misperceptions of religious doctrines, the need for family consent, and a nation-wide focus on disease control. Key informants cite social, political, and infrastructural barriers to the implementation of an organ donor registry, including widely held myths about organ donation, competing health priorities, and limited hospital infrastructure. CONCLUSIONS: At present, both the central government and Maharashtra state government struggle to balance international pressures to improve overall population health with the desire to also enhance individual health. Implementing an organ donor registry in Mumbai is not a feasible or appropriate policy option in India's current political and social environment, as the barriers, identified through the 3-i framework lens, may be too difficult to overcome. Despite the evidence supporting the use of donor registries as a means to enhance organ donation rates, it is clear that context is critical and that it is not always practical to apply evidence-based policy solutions from high-income countries to lower-income settings. PMID- 26762571 TI - Aggregate and hospital-level impact of national guidelines on diagnostic resource utilization for children with pneumonia at children's hospitals. AB - BACKGROUND: National guidelines for the management of community-acquired pneumonia (CAP) in children were published in 2011. These guidelines discourage most diagnostic testing for outpatients, as well as repeat testing for hospitalized patients who are improving. We sought to evaluate the temporal trends in diagnostic testing associated with guideline implementation among children with CAP. METHODS: Children 1 to 18 years old who were discharged with pneumonia after emergency department (ED) evaluation or hospitalization from January 1, 2008 to June 30, 2014 at any of 32 children's hospitals participating in the Pediatric Health Information System were included. We excluded children with complex chronic conditions and those requiring intensive care or who underwent early pleural drainage. We compared use of diagnostic testing (blood culture, complete blood count [CBC], C-reactive protein [CRP], and chest radiography [CXR]) before and after release of the guidelines, and assessed for temporal trends using interrupted time series analysis. We also calculated the cost impact of these changes on diagnostic utilization and evaluated the variability of the guideline's impact across hospitals. RESULTS: Overall, 220,539 patients were included; 53% were male and the median age was 4 years (interquartile range, 2-7). For patients discharged from the ED with CAP, diagnostic utilization rates for blood culture, CBC, CRP, and CXR were higher after guideline publication compared with expected utilization rates without guidelines. In contrast, initial testing and repeat testing among patients hospitalized with CAP was lower after guideline publication. There were modest reductions in estimated costs associated with these changes. However, wide variability was observed in the impact of the guidelines across hospitals. CONCLUSIONS: Publication of national pneumonia guidelines in 2011 was associated with modest changes in diagnostic testing for children with CAP. However, the changes varied across hospitals, and the financial impact was modest. Local implementation efforts are warranted to ensure widespread guideline adherence. Journal of Hospital Medicine 2016;11:317-323. (c) 2016 Society of Hospital Medicine. PMID- 26762574 TI - Can the current density map topology be extracted from the nucleus independent chemical shifts? AB - Aromatic compounds are characterised by the presence of a ring current when in a magnetic field. As a consequence, current density maps are used to assess (the degree of) aromaticity of a compound. However, often a more discrete set of so called Nucleus Independent Chemical Shift (NICS) values is used that is derived from the current density. It is shown here that there is no simple one-to-one relationship that allows reconstructing current density maps from only NICS values. NICS values should therefore not be used as aromaticity indices without analysis of the ab initio computed current density map. PMID- 26762575 TI - Molecular Recognition of Parallel DNA Quadruplex d(TTAGGGT)4 by Mitoxantrone: Binding with 1:2 Stoichiometry Leading to Thermal Stabilization and Telomerase Inhibition. AB - The interaction of the anthraquinone derivative mitoxantrone, a semisynthetic anti-cancer drug with two non-planar side chains, with heptamer G-quadruplex d(TTAGGGT)4 , which contains the human telomere DNA sequence, was evaluated by differential scanning calorimetry, fluorescence Job plotting, absorption, and NMR and CD spectroscopy. Binding led to thermal stabilization of DNA (DeltaTm =13-20 degrees C). The spectra revealed that two mitoxantrone molecules bind externally at two sites of the DNA quadruplex as monomers, by partial insertion of the chromophore and side-chain interaction at the grooves. The inhibition of telomerase (IC50 =2 MUM), as determined by a TRAP assay, can be attributed to thermal stabilization of the DNA quadruplex because of the interactions with mitoxantrone. The studies revealed highly specific molecular recognition between a ligand and a parallel-stranded G-quadruplex; this might serve as a platform for the rational design of new drugs. PMID- 26762576 TI - Lean mass predicts conditioned pain modulation in adolescents across weight status. AB - BACKGROUND: There is a wide continuum of conditioned pain modulation (CPM) in adults with older adults experiencing an attenuated CPM response compared with younger adults. Less is known for adolescents and the role of anthropometrics. METHODS: Fifty-six adolescents (15.1 +/- 1.8 years; 32 normal weight and 24 overweight/obese; 27 boys) completed in a CPM session that included anthropometric testing. Pressure pain thresholds were measured at the nailbed and deltoid muscle (test stimuli) with the foot submerged in a cool or ice water bath (conditioning stimulus). Weight status, body composition (Dual-energy X-ray absorptiometry scan), physical activity levels and clinical pain were also evaluated. RESULTS: The CPM response in adolescents was similar across sites (nailbed vs. deltoid), weight status (normal vs. overweight/obese) and sex. CPM measured at the deltoid muscle was positively associated with left arm lean mass but not fat mass; lean mass of the arm uniquely predicted 10% of the CPM magnitude. CPM measured at the nailbed was positively correlated with physical activity levels. CONCLUSIONS: These results suggest that lean mass and physical activity levels may contribute to endogenous pain inhibition in adolescents across weight status. PMID- 26762577 TI - Culture if spikes? Indications and yield of blood cultures in hospitalized medical patients. AB - BACKGROUND: Although optimal utilization of blood cultures has been studied in populations, including emergency room and intensive care patients, less is known about the use of blood cultures in populations consisting exclusively of patients on a medical service. OBJECTIVE: To identify the physician-selected indication and yield of blood cultures ordered after hospitalization to an acute medical service and to identify populations in which blood cultures may not be necessary. DESIGN, SETTING, AND PATIENTS: A prospective cohort study was performed at a single Veterans Affairs Medical Center from October 1, 2014 through April 15, 2015. Participants included all hospitalized patients on a medical service for whom a blood culture was ordered. MEASUREMENTS: The main outcomes were the rate of true positive blood cultures and the predictors of true positive cultures. RESULTS: The true positive rate was 3.6% per order. The most common physician selected indications were fever and leukocytosis, neither of which alone was highly predictive of true positive blood cultures. The only indication significantly associated with a true positive blood culture was "follow-up previous positive" (likelihood ratio [LR]+ 3.4, 95% confidence interval [CI]: 1.8 6.5). The only clinical predictors were a working diagnosis of bacteremia/endocarditis (LR+ 3.7, 95% CI: 2.5-5.7) and absence of antibiotic exposure within 72 hours of the culture (LR+ 2.4, 95% CI: 1.2-4.9). CONCLUSIONS: The rate of true positive blood cultures among patients on a medical service was lower than previously studied. Using objective and easily obtainable clinical characteristics, including antibiotic exposure and working diagnosis, may improve the likelihood of true positive blood cultures. Journal of Hospital Medicine 2016;11:336-340. (c) 2016 Society of Hospital Medicine. PMID- 26762578 TI - Redox potential tuning by redox-inactive cations in nature's water oxidizing catalyst and synthetic analogues. AB - The redox potential of synthetic oligonuclear transition metal complexes has been shown to correlate with the Lewis acidity of a redox-inactive cation connected to the redox-active transition metals of the cluster via oxo or hydroxo bridges. Such heterometallic clusters are important cofactors in many metalloenzymes, where it is speculated that the redox-inactive constituent ion of the cluster serves to optimize its redox potential for electron transfer or catalysis. A principal example is the oxygen-evolving complex in photosystem II of natural photosynthesis, a Mn4CaO5 cofactor that oxidizes water into dioxygen, protons and electrons. Calcium is critical for catalytic function, but its precise role is not yet established. In analogy to synthetic complexes it has been suggested that Ca(2+) fine-tunes the redox potential of the manganese cluster. Here we evaluate this hypothesis by computing the relative redox potentials of substituted derivatives of the oxygen-evolving complex with the cations Sr(2+), Gd(3+), Cd(2+), Zn(2+), Mg(2+), Sc(3+), Na(+) and Y(3+) for two sequential transitions of its catalytic cycle. The theoretical approach is validated with a series of experimentally well-characterized Mn3AO4 cubane complexes that are structural mimics of the enzymatic cluster. Our results reproduce perfectly the experimentally observed correlation between the redox potential and the Lewis acidities of redox-inactive cations for the synthetic complexes. However, it is conclusively demonstrated that this correlation does not hold for the oxygen evolving complex. In the enzyme the redox potential of the cluster only responds to the charge of the redox-inactive cations and remains otherwise insensitive to their precise identity, precluding redox-tuning of the metal cluster as a primary role for Ca(2+) in biological water oxidation. PMID- 26762580 TI - Social environment alters opioid-induced hyperalgesia and antinociceptive tolerance in adolescent mice. AB - BACKGROUND: Chronic opioid treatment is complicated by the development of tolerance and hyperalgesia. Social environment alters both opioid-induced behaviours and nociceptive mechanisms. Our previous studies demonstrated that, in adolescent rodents, the susceptibility to acquire opioid dependence and reward is dependent on the nature of social housing conditions. Specifically, our previous studies demonstrate that housing morphine-treated mice with drug-naive animals mitigates the abuse liability of opioids. Thus, this study tested the effect of social housing conditions on the development of adaptive processes to morphine antinociception. METHOD: Adolescent males were group-housed in different conditions. In the mixed treatment condition, mice treated with 20 mg/kg morphine (i.e. 'morphine cage-mates') and saline (i.e. 'saline cage-mates') were housed together. In the separated treatment conditions, all mice in the cage received morphine (i.e. 'morphine only') or saline (i.e. 'saline only'). All animals were tested for baseline pain sensitivity and for the response to morphine in the tail withdrawal, hot plate, acetone and von Frey filament tests, during and after discontinuation of opioid treatment. RESULTS: Both morphine cage-mate and morphine only animals developed antinociceptive tolerance. However, this effect was more robust and persistent in the morphine only group. Notably, morphine only animals, but not morphine cage-mates, developed opioid-induced hyperalgesia. CONCLUSION: This study demonstrates that housing morphine-treated mice with drug naive animals mitigates the development of opioid-induced hyperalgesia and antinociceptive tolerance. Thus, this study indicates that social environment influences the effectiveness of opioid pain management. PMID- 26762579 TI - Changes in plasma biomarkers following treatment with cabozantinib in metastatic castration-resistant prostate cancer: a post hoc analysis of an extension cohort of a phase II trial. AB - BACKGROUND: Cabozantinib is an orally available inhibitor of tyrosine kinases including VEGFR2 and c-MET. We performed a post hoc analysis to find associations between select plasma biomarkers and treatment response in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) who received cabozantinib 100 mg daily as part of a phase 2 non-randomized expansion cohort (NCT00940225). METHODS: Plasma samples were collected at baseline, 6 weeks and at time of maximal response from 81 mCRPC pts with bone metastases, of which 33 also had measurable soft-tissue disease. Levels of 27 biomarkers were measured in duplicate using enzyme-linked immunosorbent assay. Spearman correlation coefficients were calculated for the association between biomarker levels or their change on treatment and either bone scan response (BSR) or soft tissue response according to RECIST. RESULTS: A BSR and RECIST response were seen in 66/81 pts (81 %) and 6/33 pts (18 %) respectively. No significant associations were found between any biomarker at any time point and either type of response. Plasma concentrations of VEGFA, FLT3L, c-MET, AXL, Gas6A, bone-specific alkaline phosphatase, interleukin-8 and the hypoxia markers CA9 and clusterin significantly increased during treatment with cabozantinib irrespective of response. The plasma concentrations of VEGFR2, Trap5b, Angiopoietin-2, TIMP-2 and TIE-2 significantly decreased during treatment with caboznatinib. CONCLUSIONS: Our data did not reveal plasma biomarkers associated with response to cabozantinib. The observed alterations in several biomarkers during treatment with cabozantinib may provide insights on the effects of cabozantinib on tumor cells and on tumor micro-environment and may help point to potential co-targeting approaches. PMID- 26762581 TI - Spatiotemporal Characterization of the Cellular and Molecular Contributors to Liver Fibrosis in a Murine Hepatotoxic-Injury Model. AB - The interplay between the inflammatory infiltrate and tissue resident cell populations invokes fibrogenesis. However, the temporal and mechanistic contributions of these cells to fibrosis are obscure. To address this issue, liver inflammation, ductular reaction (DR), and fibrosis were induced in C57BL/6 mice by thioacetamide administration for up to 12 weeks. Thioacetamide treatment induced two phases of liver fibrosis. A rapid pericentral inflammatory infiltrate enriched in F4/80(+) monocytes co-localized with SMA(+) myofibroblasts resulted in early collagen deposition, marking the start of an initial fibrotic phase (1 to 6 weeks). An expansion of bone marrow-derived macrophages preceded a second phase, characterized by accelerated progression of fibrosis (>6 weeks) after DR migration from the portal tracts to the centrilobular site of injury, in association with an increase in DR/macrophage interactions. Although chemokine (C C motif) ligand 2 (CCL2) mRNA was induced rapidly in response to thioacetamide, CCL2 deficiency only partially abrogated fibrosis. In contrast, colony stimulating factor 1 receptor blockade diminished C-C chemokine receptor type 2 [CCR2(neg) (Ly6C(lo))] monocytes, attenuated the DR, and significantly reduced fibrosis, illustrating the critical role of colony-stimulating factor 1-dependent monocyte/macrophage differentiation and linking the two phases of injury. In response to liver injury, colony-stimulating factor 1 drives early monocyte mediated myofibroblast activation and collagen deposition, subsequent macrophage differentiation, and their association with the advancing DR, the formation of fibrotic septa, and the progression of liver fibrosis to cirrhosis. PMID- 26762582 TI - En Route to New Therapeutic Options for Iron Overload Diseases: Matriptase-2 as a Target for Kunitz-Type Inhibitors. AB - The cell-surface serine protease matriptase-2 is a critical stimulator of iron absorption by negatively regulating hepcidin, the key hormone of iron homeostasis. Thus, it has attracted much attention as a target in primary and secondary iron overload diseases. Here, we have characterised Kunitz-type inhibitors hepatocyte growth factor activator inhibitor 1 (HAI-1) and HAI-2 as powerful, slow-binding matriptase-2 inhibitors. The binding modes of the matriptase-2-HAI complexes were suggested by molecular modelling. Different assays, including cell-free and cell-based measurements of matriptase-2 activity, determination of inhibition constants and evaluation of matriptase-2 inhibition by analysis of downstream effects in human liver cells, demonstrated that matriptase-2 is an excellent target for Kunitz inhibitors. In particular, HAI-2 is considered a promising scaffold for the design of potent and selective matriptase-2 inhibitors. PMID- 26762584 TI - Care team identification in the electronic health record: A critical first step for patient-centered communication. AB - Patient-centered communication is essential to coordinate care and safely progress patients from admission through discharge. Hospitals struggle with improving the complex and increasingly electronic conversation patterns among care team members, patients, and caregivers to achieve effective patient-centered communication across settings. Accurate and reliable identification of all care team members is a precursor to effective patient-centered communication and ideally should be facilitated by the electronic health record. However, the process of identifying care team members is challenging, and team lists in the electronic health record are typically neither accurate nor reliable. Based on the literature and on experience from 2 initiatives at our institution, we outline strategies to improve care team identification in the electronic health record and discuss potential implications for patient-centered communication. Journal of Hospital Medicine 2016;11:381-385. (c) 2016 Society of Hospital Medicine. PMID- 26762583 TI - Investigation on Toxicity and Teratogenicity in Rats of a Retinoid-Polyamine Conjugate with Potent Anti-Inflammatory Properties. AB - Previous studies have shown that N(1),N(12)-bis(all-trans-retinoyl)spermine (RASP), a retinoid analog, inhibits RNase P activity and angiogenesis in the chicken embryo chorioallantoic membrane, demonstrates anti-tumor activity on prostate cancer cells, and acts as anti-inflammatory agent, being more effective and less toxic than all-trans retinoic acid. In an attempt to further characterize the biological profile of RASP, we tested its effects on organ toxicity and teratogenicity by daily oral gavage of RASP at a level of 50 mg/Kg of body weight in two generations of rats. We found that this compound does not induce changes to the body growth, the appearance of physical features, and the animal's reflexes. Additionally, no substantial histopathological lesions were found in brain, heart, lung, thymus, liver, thyroid gland, adrenal gland, pituitary gland, kidneys, spleen, skin, femora, prostate, testis, epididymis, vagina, uterus, and ovaries of RASP-treated animals. These results suggest RASP, as a promising lead compound for the treatment of several dermatological disorders and certain cancer types, has apparently minimal toxic side-effects as revealed in this two-generation reproduction study in rats. PMID- 26762585 TI - High Frequency (10 kHz) or Burst Spinal Cord Stimulation in Failed Back Surgery Syndrome Patients With Predominant Back Pain: Preliminary Data From a Prospective Observational Study. AB - BACKGROUND: Conventional spinal cord stimulation (SCS) exhibits pain relief and improved quality of life in refractory failed back surgery syndrome. However, patients suffering from predominant back pain failed to achieve a favorable neuromodulation outcome. Currently, two new stimulation concepts, the burst and the HF10 stimulation paradigms successfully suppress intractable back pain levels in this difficult-to-treat subgroup. To date, literature data comparing both stimulation patterns is lacking. METHODS: A prospective, observational study was conducted including 16 refractory Failed-back surgery syndrome (FBSS) patients with previous spine surgery and predominant back pain (70% of overall pain) with or without leg pain eligible for burst or high-frequency SCS. At baseline and at a three-month follow-up the pain intensity (back pain (VASB )/leg pain (VASL ), sleep quality (Pittsburgh Sleep Quality Index [PSQI]), changes in severity of depressive symptoms (Beck Depression Inventory [BDI]) and any adverse event related to the implantation and the stimulation were recorded. RESULTS: Overall baseline VASB was significantly suppressed in 14 FBSS patients (eight burst/six patients with 10 HF10) from baseline 7.9 +/- 0.7 to 2.3 +/- 1 (p < 0.001), while the overall VASL declined significantly from 3.1 +/- 1.5 to 1.9 +/- 0.83 (p < 0.01). The burst patients experienced significant VASL reduction (burst 1.8 +/- 0.7 (p < 0.009) compared to HF10 patients 2.2 +/- 1). Two patients failed 10 HF10 trial. The BDI [23.3 +/- 2.1 to 13.5 +/- 4.5 (p < 0.001)] and the PSQI [7.6 +/- 3.7 to 4.2 +/- 1.4 (p < 0.003)] dropped down significantly for both modalities. No implantation/stimulation-related complications were observed. CONCLUSIONS: Burst and HF10 SCS performed efficiently and safely in intractable FBSS patients with predominant back pain and deserve more refined, specific investigations to determine their efficacy. PMID- 26762587 TI - Improving Patient Care Through Nursing Engagement in Evidence-Based Practice. AB - This column shares the best evidence-based strategies and innovative ideas on how to facilitate the learning of EBP principles and processes by clinicians as well as nursing and interprofessional students. Guidelines for submission are available at http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1741-6787. PMID- 26762588 TI - Weight-based insulin dosing for acute hyperkalemia results in less hypoglycemia. AB - Hyperkalemia treatment with intravenous insulin has been associated with hypoglycemia. This single-center, retrospective study compared the effects on hypoglycemia between weight-based insulin dosing (0.1 U/kg of body weight up to a maximum of 10 U) compared to standard flat doses of 10 U among patients weighing less than 95 kg. Of the 132 charts randomly selected for review, hypoglycemic events (blood glucose <70 mg/dL) were reduced from 27.3% in the 10-U group to 12.1% in the weight-based group (P = 0.05). The number of affected patients was reduced with 19.7% in the 10-U group and 10.6% in the weight-based group (P = 0.22). The potassium-lowering effects of these 2 strategies were similar between groups. Female patients and those with baseline glucose values <140 mg/dL were at increased risk for hypoglycemia. Weight-based insulin dosing (0.1 U/kg) for acute hyperkalemia therapy resulted in less hypoglycemia without impacting potassium lowering. Journal of Hospital Medicine 2016;11:355-357. (c) 2016 Society of Hospital Medicine. PMID- 26762586 TI - Role of a polyphenol-enriched preparation on chemoprevention of mammary carcinoma through cancer stem cells and inflammatory pathways modulation. AB - BACKGROUND: Naturally occurring polyphenolic compounds from fruits, particularly from blueberries, have been reported to be significantly involved in cancer chemoprevention and chemotherapy. Biotransformation of blueberry juice by Serratia vaccinii increases its polyphenolic content and endows it with anti inflammatory properties. METHODS: This study evaluated the effect of a polyphenol enriched blueberry preparation (PEBP) and its non-fermented counterpart (NBJ), on mammary cancer stem cell (CSC) development in in vitro, in vivo and ex vivo settings. Effects of PEBP on cell proliferation, mobility, invasion, and mammosphere formation were measured in vitro in three cell lines: murine 4T1 and human MCF7 and MDA-MB-231. Ex vivo mammosphere formation, tumor growth and metastasis observations were carried out in a BALB/c mouse model. RESULTS: Our research revealed that PEBP influence cellular signaling cascades of breast CSCs, regulating the activity of transcription factors and, consequently, inhibiting tumor growth in vivo by decreasing metastasis and controlling PI3K/AKT, MAPK/ERK, and STAT3 pathways, central nodes in CSC inflammatory signaling. PEBP significantly inhibited cell proliferation of 4T1, MCF-7 and MDA-MB-231. In all cell lines, PEBP reduced mammosphere formation, cell mobility and cell migration. In vivo, PEBP significantly reduced tumor development, inhibited the formation of ex vivo mammospheres, and significantly reduced lung metastasis. CONCLUSIONS: This study showed that polyphenol enrichment of a blueberry preparation by fermentation increases its chemopreventive potential by protecting mice against tumor development, inhibiting the formation of cancer stem cells and reducing lung metastasis. Thus, PEBP may represent a novel complementary alternative medicine therapy and a source for novel therapeutic agents against breast cancer. PMID- 26762589 TI - Inhibition of Somatosensory Evoked Potentials During Different Modalities of Spinal Cord Stimulation: A Case Report. AB - BACKGROUND: Although the number of patients with chronic neuropathic pain treated by spinal cord stimulation (SCS) is continuously increasing, its analgesic mechanism remains to be elucidated. Previous studies have demonstrated that classical SCS (low stimulation frequency evoking paresthesia) inhibits the somatosensory evoked potentials (SEPs). CASE PRESENTATION: We describe here the results of a series of SEPs recordings performed in a female patient with chronic pain, using four different types of SCS: the classical SCS (60 Hz, 250 MUsec) and three paresthesia free SCS modalities: high frequency (10 kHz, 20 MUsec) and two types of high-density SCS (500 Hz, 500 MUsec and 200 Hz, 1000 MUsec). All the tested SCS modalities completely inhibited the SEPs cortical responses, with an immediate recovery of the inhibition after turning the stimulator off. CONCLUSIONS: All the tested SCS modalities are able to inhibit SEPs and thus the lemniscal system. In particular, both paresthesia and paresthesia free SCS affect SEPs in the same manner. The presence of this inhibitory effect during paresthesia free modalities suggests that it is independent from the generation of action potentials, with a probable mechanism acting at the stimulation site. Further studies investigating the relationship between the inhibition of the lemniscal system and the analgesic effect of the SCS are, therefore, warranted. PMID- 26762590 TI - High-Pressure Raman and Calorimetry Studies of Vanadium(III) Alkyl Hydrides for Kubas-Type Hydrogen Storage. AB - Reversible hydrogen storage under ambient conditions has been identified as a major bottleneck in enabling a future hydrogen economy. Herein, we report an amorphous vanadium(III) alkyl hydride gel that binds hydrogen through the Kubas interaction. The material possesses a gravimetric adsorption capacity of 5.42 wt % H2 at 120 bar and 298 K reversibly at saturation with no loss of capacity after ten cycles. This corresponds to a volumetric capacity of 75.4 kgH2 m(-3) . Raman experiments at 100 bar confirm that Kubas binding is involved in the adsorption mechanism. The material possesses an enthalpy of H2 adsorption of +0.52 kJ mol( 1) H2 , as measured directly by calorimetry, and this is practical for use in a vehicles without a complex heat management system. PMID- 26762591 TI - Early detection of colonic dysplasia by magnetic resonance molecular imaging with a contrast agent raised against the colon cancer marker MUC5AC. AB - Human gastric mucin MUC5AC is secreted in the colonic mucus of cancer patients and is a specific marker of precancerous lesions called aberrant crypt foci. Using MUC5AC as a specific marker can improve sensitivity in the detection of early colorectal cancer. Here we demonstrated that the accumulation of MUC5AC in xenograft and mouse stomach can be detected by magnetic resonance imaging (MRI). We used ultrasmall particles of iron oxide (USPIOs) conjugated with disulfide constrained heptapeptide that were identified using a screening phage display. To accomplish this, we employed positive selection of the phage display library on MUC5AC purified from fresh human colonic adenomas in combination with negative selection of the phage library on purified human MUC2, which is predominantly found in normal colorectal tissues. This conjugate was tested on human colorectal cancer cell lines that were either able or unable to secrete MUC5AC, both in vitro and in vivo. MUC5AC-USPIO contrast agent and USPIOs alone were not detected in cell lines unable to secrete MUC5AC. A combination of MRI and microscopy studies was performed to detect a specific accumulation of the contrast agent in vivo. Thus, the MUC5AC contrast agent enabled non-invasive detection of precancerous lesions and colorectal cancer, highlighting its potential use in diagnostics, in the early detection of colorectal cancer recurrences after treatment and in mechanistic studies implicating MUC5AC. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26762592 TI - Investigation of the Effect of Some Optically Active Imine Compounds on the Enzyme Activities of hCA-I and hCA-II under In Vitro Conditions: An Experimental and Theoretical Study. AB - Inhibitors of carbonic anhydrase (hCA; EC 4.2.1.1) are used as medicines for many diseases. Therefore, they are very important. In this study, a known series of Schiff bases were synthesized and their effects on the activities of hCA-I and hCA-II, which are cytosolic isoenzymes of carbonic anhydrase, were investigated under in vitro conditions. The synthesized compounds (H1, H2, H3, and H4) were found to cause inhibition on enzyme activities of hCA-1 and hCA-II. IC50 values of H1, H2, H3, and H4 compounds were 140, 88, 201, and 271 MUM for hCA-I enzyme activity and 134, 251, 79, and 604 MUM for hCA-II enzyme activity, respectively. The synthesized Schiff bases were characterized by several methods, including (1) H NMR, FT-IR, elemental analysis, and polarimetric measurements. Correlation coefficient square values (R(2) ) of comparison of the theoretical and experimental (1) H NMR shifts for H1, H2, H3, and H4 compounds were found as 0.9781, 0.9814, 0.9758, and 0.8635, respectively. PMID- 26762593 TI - Shuttling as a Strategy to Control the Regiochemistry of Bis-Additions on Fullerene Derivatives. AB - The reactivity of a fullerene-stoppered rotaxane, a C60 monoadduct, towards a second cycloaddition reaction is explored. The close proximity of the macrocycle to the fullerene sphere is able to allosterically influence the second cycloaddition reaction, giving rise to a selected mixture of bis-adducts. PMID- 26762594 TI - Exercise induced bronchoconstriction in adults: evidence based diagnosis and management. PMID- 26762595 TI - Adenocarcinoma arising in urinary bladder endocervicosis. AB - Endocervicosis is a rare benign condition characterized by the presence of endocervical-type mucinous glands. Urinary bladder endocervicosis forms an elevated lesion in the posterior wall of the urinary bladder and is sometimes misdiagnosed as a malignant tumor clinically and pathologically. Herein we describe the first case of adenocarcinoma arising in urinary bladder endocervicosis. The patient, a 58-year-old woman, presented with asymptomatic hematuria. Cystoscopy revealed a nodular mass measuring 4 cm in diameter in the posterior wall, and total cystectomy was performed. Histology revealed that the elevated lesion of the bladder wall was composed of haphazard proliferation of cystic glands lined by benign endocervical-type epithelium. An adenocarcinoma arose at the center of this endocervicosis. Mucin histochemistry revealed the presence of sulfomucin in both the endocervicosis and adenocarcinoma components. Immunohistochemically, the endocervicosis was positive for cytokeratin (CK) 7, AE1/AE3, CAM5.2, HBME1, CA19-9, and estrogen receptor (ER), and negative for CK20, CDX2, progesterone receptor (PR), MUC5AC, and beta-catenin. The adenocarcinoma showed similar immunohistochemical results, except for loss of ER expression and a slight increase in the ratio of Ki-67-positive cells. This case indicates that endocervicosis, known as a benign lesion, harbors the possibility of malignant transformation. PMID- 26762596 TI - Genetic model. PMID- 26762597 TI - Editorial Comment. PMID- 26762598 TI - Diffusion of Oligonucleotides from within Iron-Cross-Linked, Polyelectrolyte Modified Alginate Beads: A Model System for Drug Release. AB - An analytical model to describe diffusion of oligonucleotides from stable hydrogel beads is developed and experimentally verified. The synthesized alginate beads are Fe(3+) -cross-linked and polyelectrolyte-doped for uniformity and stability at physiological pH. Data on diffusion of oligonucleotides from inside the beads provide physical insights into the volume nature of the immobilization of a fraction of oligonucleotides due to polyelectrolyte cross-linking, that is, the absence of a surface-layer barrier in this case. Furthermore, the results suggest a new simple approach to measuring the diffusion coefficient of mobile oligonucleotide molecules inside hydrogels. The considered alginate beads provide a model for a well-defined component in drug-release systems and for the oligonucleotide-release transduction steps in drug-delivering and biocomputing applications. This is illustrated by destabilizing the beads with citrate, which induces full oligonucleotide release with nondiffusional kinetics. PMID- 26762599 TI - Early diagnosis of asymptomatic neurocutaneous melanosis (60 month follow-up). AB - Neurocutaneous melanosis (NCM) is a rare, sporadic, congenital neuroectodermal dysplasia. Large congenital melanocytic nevi (CMN) can evolve in a certain percentage of patients to NCM. Meningeal deposits are benign, but can be prone to malignant transformation in some cases. We describe the case of an infant with asymptomatic NCM, and typical magnetic resonance imaging (MRI) findings. The diagnosis was established shortly after delivery, and the patient was followed for 60 months. At that time, the girl did not have any neurologic symptoms; she reached normal developmental milestones and did not show mental retardation and did not develop malignant melanoma; further follow-up will be needed, although there are no reliable guidelines as to the time range of follow up of asymptomatic NCM in the literature. We report the typical MRI signal abnormalities of the brain, and present a review of the literature regarding this rare and mysterious congenital disorder. PMID- 26762600 TI - Novel EGFR inhibitors attenuate cardiac hypertrophy induced by angiotensin II. AB - Cardiac hypertrophy is an important risk factor for heart failure. Epidermal growth factor receptor (EGFR) has been found to play a role in the pathogenesis of various cardiovascular diseases. The aim of this current study was to examine the role of EGFR in angiotensin II (Ang II)-induced cardiac hypertrophy and identify the underlying molecular mechanisms. In this study, we observed that both Ang II and EGF could increase the phospohorylation of EGFR and protein kinase B (AKT)/extracellular signal-regulated kinase (ERK), and then induce cell hypertrophy in H9c2 cells. Both pharmacological inhibitors and genetic silencing significantly reduced Ang II-induced EGFR signalling pathway activation, hypertrophic marker overexpression, and cell hypertrophy. In addition, our results showed that Ang II-induced EGFR activation is mediated by c-Src phosphorylation. In vivo, Ang II treatment significantly led to cardiac remodelling including cardiac hypertrophy, disorganization and fibrosis, accompanied by the activation of EGFR signalling pathway in the heart tissues, while all these molecular and pathological alterations were attenuated by the oral administration with EGFR inhibitors. In conclusion, the c-Src-dependent EGFR activation may play an important role in Ang II-induced cardiac hypertrophy, and inhibition of EGFR by specific molecules may be an effective strategy for the treatment of Ang II-associated cardiac diseases. PMID- 26762602 TI - Poor vision in a patient with white hair and pale skin. PMID- 26762601 TI - Sinusoidal error perturbation reveals multiple coordinate systems for sensorymotor adaptation. AB - A coordinate system is composed of an encoding, defining the dimensions of the space, and an origin. We examine the coordinate encoding used to update motor plans during sensory-motor adaptation to center-out reaches. Adaptation is induced using a novel paradigm in which feedback of reach endpoints is perturbed following a sinewave pattern over trials; the perturbed dimensions of the feedback were the axes of a Cartesian coordinate system in one session and a polar coordinate system in another session. For center-out reaches to randomly chosen target locations, reach errors observed at one target will require different corrections at other targets within Cartesian- and polar-coded systems. The sinewave adaptation technique allowed us to simultaneously adapt both dimensions of each coordinate system (x-y, or reach gain and angle), and identify the contributions of each perturbed dimension by adapting each at a distinct temporal frequency. The efficiency of this technique further allowed us to employ perturbations that were a fraction the size normally used, which avoids confounding automatic adaptive processes with deliberate adjustments made in response to obvious experimental manipulations. Subjects independently corrected errors in each coordinate in both sessions, suggesting that the nervous system encodes both a Cartesian- and polar-coordinate-based internal representation for motor adaptation. The gains and phase lags of the adaptive responses are not readily explained by current theories of sensory-motor adaptation. PMID- 26762603 TI - Identification of internal control genes in milk-derived mammary epithelial cells during lactation cycle of Indian zebu cow. AB - The present study aims to evaluate the suitability of 10 candidate genes, namely GAPDH, ACTB, RPS15A, RPL4, RPS9, RPS23, HMBS, HPRT1, EEF1A1 and UBI as internal control genes (ICG) to normalize the transcriptional data of mammary epithelial cells (MEC) in Indian cows. A total of 52 MEC samples were isolated from milk of Sahiwal cows (major indigenous dairy breed of India) across different stages of lactation: Early (5-15 days), Peak (30-60 days), Mid (100-140 days) and Late (> 240 days). Three different statistical algorithms: geNorm, Normfinder and BestKeeper were used to assess the suitability of these genes. In geNorm analysis, all the genes exhibited expression stability (M) values below 0.5 with EEF1A1 and RPL4 showing the maximum expression stability. Similar to geNorm, Normfinder also identified EEF1A1 and RPL4 as two of the most stable genes. In Bestkeeper algorithm as well, all the 10 genes showed consistent expression levels. The analysis showed that four genes, that is, EEF1A1, RPL4, GAPDH and ACTB exhibited higher coefficient of correlation to the Bestkeeper index, lower coefficient of variance and standard deviation, indicating their superiority to be used as ICG. The present analysis has provided evidence that RPL4, EEF1A1, GAPDH and ACTB could probably act as most suitable genes for normalizing the transcriptional data of milk-derived mammary epithelial cells of Indian cows. PMID- 26762604 TI - Liver Transplantation in a Patient With CD40 Ligand Deficiency and Hyper-IgM Syndrome: Clinical and Immunological Assessments. AB - Monoclonal antibodies that disrupt CD40-CD40 ligand (CD40L) interactions are likely to have use in human transplantation. However, the extent of the immunosuppressive effects of CD40-CD40L blockade in humans is unknown. Hyper-IgM syndrome (HIGM) is a rare primary immunodeficiency syndrome characterized by defects in the CD40-CD40L pathway, severe immune deficiency (IgG), and high or normal IgM levels. However, the effects of CD40L deficiency on T- and natural killer (NK)-cell function is not established. Here, we present a patient with HIGM syndrome who underwent liver transplantation for hepatitis C virus infection. Posttransplantation, NK-cell antibody-dependent cytokine release (gamma-interferon) to alloantigens and T cell responses to viral antigens and mitogens were assessed and showed normal CD4+ , CD8+ , and NK-cell responses. We also examined antibody-dependent cellular cytotoxicity against a CD40+ and HLA expressing cell line. These experiments confirmed that the patient's NK cells were equivalent to those of normal subjects in mediating antibody-dependent cellular cytotoxicity despite the absence of CD40-CD40L interactions. Mitogenic stimulation of the patient's peripheral blood mononuclear cells showed no expression of CD40L on T and NK cells compared with increased expression in normal subjects. Taken together, these data suggest that absence of CD40L expression is responsible for aberrant B cell immunity but had little impact on NK- and T cell immune responses in vitro. PMID- 26762605 TI - The expanding toolbox for hepatitis C virus research. AB - Hepatitis C virus is a major global health concern with 170 million people chronically infected. Despite the availability of potent antiviral agents targeting multiple HCV proteins and cure rates above 90%, global treatment availability, the likelihood of emerging drug-resistant viral variants and the unavailability of a protective vaccine underline the many unresolved questions remaining to be answered. Model systems allowing the dissection of individual HCV life cycle steps have previously been developed and span noninfectious and infectious means of assessing HCV entry and replication, multiple cellular systems enabling host/pathogen interaction studies as well as in vivo model systems for basic as well as translational HCV research. This review provides an overview of available systems and a comparative summary of assays and models. PMID- 26762606 TI - Association of Candidate Removals From the Kidney Transplant Waiting List and Center Performance Oversight. AB - Approximately 59 000 kidney transplant candidates have been removed from the waiting list since 2000 for reasons other than transplantation, death, or transfers. Prior studies indicate that low-performance (LP) center evaluations by the Scientific Registry of Transplant Recipients (SRTR) are associated with reductions in transplant volume. There is limited information to determine whether performance oversight impacts waitlist management. We used national SRTR data to evaluate outcomes of 315 796 candidates on the kidney transplant waiting list (2007-2014). Compared to centers without LP, rates of waitlist removal (WLR) were higher at centers with LP evaluations (44.6/1000 follow-up years, 95% confidence interval [CI] 44.0, 45.1 versus 68.0/1000 follow-up years, 95% CI 66.6, 69.4), respectively, which was consistent after risk adjustment (adjusted hazard ratio [AHR] = 1.59, 95% CI 1.55, 1.63). Candidate mortality following waitlist removal was lower at LP centers (AHR = 0.90, 95% CI 0.87, 0.94). Analyses limited to LP centers indicated a significant increase in WLR (+28.6 removals/1000 follow-up years, p < 0.001), a decrease in transplant rates ( 11.9/1000 follow-up years, p < 0.001) and a decrease in mortality after removal ( 67.5 deaths/1000 follow-up years, p < 0.001) following LP evaluation. There is a significant association between LP evaluations and transplant center processes of care for waitlisted candidates. Further understanding is needed to determine the impact of performance oversight on transplant center quality of care and patient outcomes. PMID- 26762607 TI - Tuberculosis--diagnosis, management, prevention, and control: summary of updated NICE guidance. PMID- 26762608 TI - Evaluating the diagnostic sensitivity of computed diffusion-weighted MR imaging in the detection of breast cancer. AB - PURPOSE: To evaluate the diagnostic sensitivity of computed diffusion-weighted (DW)-MR imaging for the detection of breast cancer. MATERIALS AND METHODS: Local research ethics approval was obtained. A total of 61 women (median 48 years) underwent dynamic contrast enhanced (DCE)- and DW-MR between January 2011 and March 2012, including 27 with breast cancer on core biopsy and 34 normal cases. Standard ADC maps using all four b values (0, 350, 700, 1150) were used to generate computed DW-MR images at b = 1500 s/mm(2) and b = 2000 s/mm(2) . Four image sets were read sequentially by two readers: acquired b = 1150 s/mm(2) , computed b = 1500 s/mm(2) and b = 2000 s/mm(2) , and DCE-MR at an early time point. Cancer detection was rated using a five-point scale; image quality and background suppression were rated using a four-point scale. The diagnostic sensitivity for breast cancer detection was compared using the McNemar test and inter-reader agreement with a Kappa value. RESULTS: Computed DW-MR resulted in higher overall diagnostic sensitivity with b = 2000 s/mm(2) having a mean diagnostic sensitivity of 76% (range 49.8-93.7%) and b = 1500 s/mm(2) having a mean diagnostic sensitivity of 70.3% (range 32-97.7%) compared with 44.4% (range 25.5-64.7%) for acquired b = 1150 s/mm(2) (both p = 0.0001). Computed DW-MR images produced better image quality and background suppression (mean scores for both readers: 2.55 and 2.9 for b 1500 s/mm(2) ; 2.55 and 3.15 for b 2000 s/mm(2) , respectively) than the acquired b value 1150 s/mm(2) images (mean scores for both readers: 2.4 and 2.45, respectively). CONCLUSION: Computed DW-MR imaging has the potential to improve the diagnostic sensitivity of breast cancer detection compared to acquired DW-MR. J. Magn. Reson. Imaging 2016;44:130-137. PMID- 26762609 TI - Soil-plant-atmosphere conditions regulating convective cloud formation above southeastern US pine plantations. AB - Loblolly pine trees (Pinus taeda L.) occupy more than 20% of the forested area in the southern United States, represent more than 50% of the standing pine volume in this region, and remove from the atmosphere about 500 g C m-2 per year through net ecosystem exchange. Hence, their significance as a major regional carbon sink can hardly be disputed. What is disputed is whether the proliferation of young plantations replacing old forest in the southern United States will alter key aspects of the hydrologic cycle, including convective rainfall, which is the focus of the present work. Ecosystem fluxes of sensible (Hs) and latent heat (LE) and large-scale, slowly evolving free atmospheric temperature and water vapor content are known to be first-order controls on the formation of convective clouds in the atmospheric boundary layer. These controlling processes are here described by a zero-order analytical model aimed at assessing how plantations of different ages may regulate the persistence and transition of the atmospheric system between cloudy and cloudless conditions. Using the analytical model together with field observations, the roles of ecosystem Hs and LE on convective cloud formation are explored relative to the entrainment of heat and moisture from the free atmosphere. Our results demonstrate that cloudy-cloudless regimes at the land surface are regulated by a nonlinear relation between the Bowen ratio Bo=Hs/LE and root-zone soil water content, suggesting that young/mature pines ecosystems have the ability to recirculate available water (through rainfall predisposition mechanisms). Such nonlinearity was not detected in a much older pine stand, suggesting a higher tolerance to drought but a limited control on boundary layer dynamics. These results enable the generation of hypotheses about the impacts on convective cloud formation driven by afforestation/deforestation and groundwater depletion projected to increase following increased human population in the southeastern United States. PMID- 26762610 TI - 'Whose failure counts?' A critical reflection on definitions of failure for community health volunteers providing HIV self-testing in a community-based HIV/TB intervention study in urban Malawi. AB - The category of community health worker applied within the context of health intervention trials has been promoted as a cost-effective approach to meeting study objectives across large populations, relying on the promotion of the concept of 'community belonging' to encourage altruistic volunteerism from community members to promote health. This community-based category of individuals is recruited to facilitate externally driven priorities defined by large research teams, outside of the target research environment. An externally defined intervention is then 'brought to' the community through locally recruited community volunteers who form a bridge between the researchers and participants. The specific role of these workers is context-driven and responsive to the needs of the intervention. This paper is based on the findings from an annual evaluation of community health worker performance employed as community counsellors to deliver semi-supervised HIV self-testing (HIVST) at community level of a large HIV/TB intervention trial conducted in urban Blantyre, Malawi. A performance evaluation was conducted to appraise individual service delivery and assess achievements in meeting pre-defined targets for uptake of HIVST with the aim of improving overall uptake of HIVST. Through an empirical 'evaluation of the evaluation' this paper critically reflects on the position of the community volunteer through the analytical lens of 'failure', exploring the tensions in communication and interpretation of intervention delivery between researchers and community volunteers and the differing perspectives on defining failure. It is concluded that community interventions should be developed in collaboration with the population and that information guiding success should be clearly defined. PMID- 26762612 TI - T2 mapping at 7T MRI can quantitatively assess intramyocardial hemorrhage in rats with acute reperfused myocardial infarction in vivo. AB - PURPOSE: To investigate T2 mapping at 7T magnetic resonance imaging (MRI) for the detection and quantification of reperfused intramyocardial hemorrhage (IMH) in a rat model. MATERIALS AND METHODS: Myocardial infarction (MI) was induced in 25 female rats. Rats were scanned at a 7T MRI 48 hours after reperfusion, using T2 mapping and late gadolinium enhancement imaging. Gross sections of the left ventricular myocardium and corresponding hematoxylin and eosin staining were assessed for IMH. T2 mapping images were matched with the gross sections. The IMH volume, expressed as a percentage of the left ventricular myocardial volume, of each heart determined by T2 mapping was compared with that calculated by pathological gross examination. RESULTS: Six rats died. In all, 97 gross sections of the left ventricular myocardium from the 19 rats were matched with T2 mapping images. IMH occurred pathologically in 68 gross sections, which was detected as hypointense cores by T2 mapping in 63 images (93% sensitivity). Three T2 mapping images with hypointense cores showed no hemorrhage on pathological sections (90% specificity). The positive and negative predictive values of hemorrhage on T2 mapping were 95% and 84%, respectively. In terms of the IMH volume, there was no significant difference between T2 mapping and pathological gross measurements (4.8 +/- 2.4% vs. 5.3 +/- 3.2%; P = 0.11). CONCLUSION: T2 mapping at 7T MRI can reliably detect and quantify IMH in rats in vivo. This may be useful as a noninvasive quantitative approach to investigating the mechanisms and evolution of MI and reperfusion injury. J. Magn. Reson. Imaging 2016;44:194-203. PMID- 26762614 TI - Jonty Heaversedge: Conscientious and a little narcissistic. PMID- 26762613 TI - Echinometra sea urchins acclimatized to elevated pCO2 at volcanic vents outperform those under present-day pCO2 conditions. AB - Rising atmospheric CO2 concentrations will significantly reduce ocean pH during the 21st century (ocean acidification, OA). This may hamper calcification in marine organisms such as corals and echinoderms, as shown in many laboratory based experiments. Sea urchins are considered highly vulnerable to OA. We studied an Echinometra species on natural volcanic CO2 vents in Papua New Guinea, where they are CO2 -acclimatized and also subjected to secondary ecological changes from elevated CO2 . Near the vent site, the urchins experienced large daily variations in pH (>1 unit) and pCO2 (>2000 ppm) and average pH values (pHT 7.73) much below those expected under the most pessimistic future emission scenarios. Growth was measured over a 17-month period using tetracycline tagging of the calcareous feeding lanterns. Average-sized urchins grew more than twice as fast at the vent compared with those at an adjacent control site and assumed larger sizes at the vent compared to the control site and two other sites at another reef near-by. A small reduction in gonad weight was detected at the vents, but no differences in mortality, respiration, or degree of test calcification were detected between urchins from vent and control populations. Thus, urchins did not only persist but actually 'thrived' under extreme CO2 conditions. We suggest an ecological basis for this response: Increased algal productivity under increased pCO2 provided more food at the vent, resulting in higher growth rates. The wider implication of our observation is that laboratory studies on non-acclimatized specimens, which typically do not consider ecological changes, can lead to erroneous conclusions on responses to global change. PMID- 26762611 TI - Role of Human Papillomavirus in Penile Carcinomas Worldwide. AB - BACKGROUND: Invasive penile cancer is a rare disease with an approximately 22 000 cases per year. The incidence is higher in less developed countries, where penile cancer can account for up to 10% of cancers among men in some parts of Africa, South America, and Asia. OBJECTIVE: To describe the human papillomavirus (HPV) DNA prevalence, HPV type distribution, and detection of markers of viral activity (ie, E6*I mRNA and p16(INK4a)) in a series of invasive penile cancers and penile high-grade squamous intraepithelial lesions (HGSILs) from 25 countries. A total of 85 penile HGSILs and 1010 penile invasive cancers diagnosed from 1983 to 2011 were included. DESIGN, SETTING, AND PARTICIPANTS: After histopathologic evaluation of formalin-fixed paraffin-embedded samples, HPV DNA detection and genotyping were performed using the SPF-10/DEIA/LiPA25 system, v.1 (Laboratory Biomedical Products, Rijswijk, The Netherlands). HPV DNA-positive cases were additionally tested for oncogene E6*I mRNA and all cases for p16(INK4a) expression, a surrogate marker of oncogenic HPV activity. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: HPV DNA prevalence and type distributions were estimated. RESULTS AND LIMITATIONS: HPV DNA was detected in 33.1% of penile cancers (95% confidence interval [CI], 30.2-36.1) and in 87.1% of HGSILs (95% CI, 78.0-93.4). The warty-basaloid histologic subtype showed the highest HPV DNA prevalence. Among cancers, statistically significant differences in prevalence were observed only by geographic region and not by period or by age at diagnosis. HPV16 was the most frequent HPV type detected in both HPV-positive cancers (68.7%) and HGSILs (79.6%). HPV6 was the second most common type in invasive cancers (3.7%). The p16(INK4a) upregulation and mRNA detection in addition to HPV DNA positivity were observed in 69.3% of HGSILs, and at least one of these HPV activity markers was detected in 85.3% of cases. In penile cancers, these figures were 22.0% and 27.1%, respectively. CONCLUSIONS: About a third to a fourth of penile cancers were related to HPV when considering HPV DNA detection alone or adding an HPV activity marker, respectively. The observed HPV type distribution reinforces the potential benefit of current and new HPV vaccines in the reduction of HPV-related penile neoplastic lesions. PATIENT SUMMARY: About one-third to one quarter of penile cancers were related to human papillomavirus (HPV). The observed HPV type distribution reinforces the potential benefit of current and new HPV vaccines to prevent HPV-related penile neoplastic lesions. PMID- 26762615 TI - Influence of fat on liver T1 measurements using modified Look-Locker inversion recovery (MOLLI) methods at 3T. AB - PURPOSE: To characterize the effect of fat on modified Look-Locker inversion recovery (MOLLI) T1 maps of the liver. The balanced steady-state free precession (bSSFP) sequence causes water and fat signals to have opposite phase when repetition time (TR) = 2.3 msec at 3T. In voxels that contain both fat and water, the MOLLI T1 measurement is influenced by the choice of TR. MATERIALS AND METHODS: MOLLI T1 measurements of the liver were simulated using the Bloch equations while varying the hepatic lipid content (HLC). Phantom scans were performed on margarine phantoms, using both MOLLI and spin echo inversion recovery sequences. MOLLI T1 at 3T and HLC were determined in patients (n = 8) before and after bariatric surgery. RESULTS: At 3T, with HLC in the 0-35% range, higher fat fraction values lead to longer MOLLI T1 values when TR = 2.3 msec. Patients were found to have higher MOLLI T1 at elevated HLC (T1 = 929 +/- 97 msec) than at low HLC (T1 = 870 +/- 44 msec). CONCLUSION: At 3T, MOLLI T1 values are affected by HLC, substantially changing MOLLI T1 in a clinically relevant range of fat content. J. Magn. Reson. Imaging 2016;44:105-111. PMID- 26762616 TI - Unexpected identification of a recurrent mutation in the DLX3 gene causing amelogenesis imperfecta. AB - OBJECTIVE: To identify the molecular genetic aetiology of a family with autosomal dominant amelogenesis imperfecta (AI). SUBJECTS AND METHODS: DNA samples were collected from a six-generation family, and the candidate gene approach was used to screen for the enamelin (ENAM) gene. Whole-exome sequencing and linkage analysis with SNP array data identified linked regions, and candidate gene screening was performed. RESULTS: Mutational analysis revealed a mutation (c.561_562delCT and p.Tyr188Glnfs*13) in the DLX3 gene. After finding a recurrent DLX3 mutation, the clinical phenotype of the family members was re-examined. The proband's mother had pulp elongation in the third molars. The proband had not hair phenotype, but her cousin had curly hair at birth. CONCLUSIONS: In this study, we identified a recurrent 2-bp deletional DLX3 mutation in a new family. The clinical phenotype was the mildest one associated with the DLX3 mutations. These results will advance the understanding of the functional role of DLX3 in developmental processes. PMID- 26762617 TI - Adenosine plasma level correlates with homocysteine and uric acid concentrations in patients with coronary artery disease. AB - The role of hyperhomocysteinemia in coronary artery disease (CAD) patients remains unclear. The present study evaluated the relationship between homocysteine (HCys), adenosine plasma concentration (APC), plasma uric acid, and CAD severity evaluated using the SYNTAX score. We also evaluated in vitro the influence of adenosine on HCys production by hepatoma cultured cells (HuH7). Seventy-eight patients (mean age +/- SD: 66.3 +/- 11.3; mean SYNTAX score: 19.9 +/- 12.3) and 30 healthy subjects (mean age: 61 +/- 13) were included. We incubated HuH7 cells with increasing concentrations of adenosine and addressed the effect on HCys level in cell culture supernatant. Patients vs. controls had higher APC (0.82 +/- 0.5 MUmol/L vs 0.53 +/- 0.14 MUmol/L; p < 0.01), HCys (15 +/ 7.6 MUmol/L vs 6.8 +/- 3 MUmol/L, p < 0.0001), and uric acid (242.6 +/- 97 vs 202 +/- 59, p < 0.05) levels. APC was correlated with HCys and uric acid concentrations in patients (Pearson's R = 0.65 and 0.52; p < 0.0001, respectively). The SYNTAX score was correlated with HCys concentration. Adenosine induced a time- and dose-dependent increase in HCys in cell culture. Our data suggest that high APC is associated with HCys and uric acid concentrations in CAD patients. Whether the increased APC participates in atherosclerosis or, conversely, is part of a protective regulation process needs further investigations. PMID- 26762618 TI - Effect of PCL/PEG-Based Membranes on Actinorhodin Production in Streptomyces coelicolor Cultivations. AB - The actinomycetes, Gram-positive filamentous bacteria, are the most prolific source of natural occurring antibiotics. At an industrial level, antibiotics from actinomycete strains are produced by means of submerged fermentations, where one of the major factors negatively affecting bioproductivity is the pellet-shaped biomass growth. The immobilization of microorganisms on properly chosen supports prevents cell-cell aggregation resulting in improving the biosynthetic capability. Thus, novel porous biopolymer-based devices are developed by combining melt mixing and particulate leaching. In particular, polycaprolactone (PCL), polyethylene glycol (PEG), and sodium chloride (NaCl) with different grain sizes are used to prepare PCL/PEG/NaCl blends in the melt. These blends are then leached to obtain PCL-based porous membranes that are used as solid support for the growth of Streptomyces coelicolor, a model streptomycete used to produce various antibiotics including the blue colored actinorhodin (ACT). Thereafter, the effect of the devices' characteristics on the bacterial growth and on the production ACT is evaluated. The results showed that ACT production is strongly dependent on the pore size distribution of the device. Moreover, membranes with pores ranging from 90 to 110 MUm are able to offer a potential improvement in volumetric productivity of ACT if compared to conventional submerged liquid culture. PMID- 26762619 TI - Europium nanoparticle-based simple to perform dry-reagent immunoassay for the detection of hepatitis B surface antigen. AB - Hepatitis B infection, caused by hepatitis B virus (HBV), presents a huge global health burden. Serological diagnosis of HBV mainly relies on the detection of hepatitis B surface antigen (HBsAg). Although there are high sensitivity commercial HBsAg enzyme immunoassays (EIAs) available, many low-resource laboratories lacking trained technicians continue to use rapid point-of-care assays with low sensitivities for HBsAg detection, due to their simplicity to operate. We developed a time-resolved fluorometric dry-reagent HBsAg immunoassay which meets the detection limit of high sensitivity EIAs but is simple to operate. To develop the assay, anti-HBsAg monoclonal antibody coated on europium nanoparticles was dried atop of biotinylated anti-HBsAg polyclonal antibody immobilized on streptavidin-coated microtiter wells. To test a sample in dry reagent assay, serum sample and assay buffer were added to the wells, incubated, washed and europium signals were measured. The assay showed a detection limit of 0.25 ng/ml using HBsAg spiked in serum sample. When evaluated with 24 HBV positive and 37 negative serum samples, assay showed 100% sensitivity and specificity. Assay wells are stable for at least 26 weeks when stored at 4 degrees C, and can tolerate elevated temperatures of up to 35 degrees C for two weeks. The developed assay has high potential to be used in low-resource laboratories. PMID- 26762620 TI - Epidemiology and outcome analysis of burn patients admitted to an Intensive Care Unit in a University Hospital. AB - OBJECTIVES: To describe the epidemiologic aspects of burn victims who were hospitalized in the Intensive Care Unit (ICU) at the Burn Center in the University Hospital of the State University of Londrina (UEL). METHODS: A longitudinal retrospective study was conducted, involving patients admitted to the Intensive Care Unit of the Burn Center from January 2010 to December 2012. Demographic and diagnostic data including the diagnosis of the extent and causes of the burns, complications resulting from the burns and the need for specific surgical interventions were collected, together with data for the calculation of the Acute Physiology and Chronic Health Evaluation (APACHE II), Sequential Organ Failure Assessment (SOFA), Therapeutic Intervention Scoring System (TISS-28) and Abbreviated Burn Severity Index (ABSI). Data were collected at admission and daily until discharge from the burn Intensive Care Unit. Risk factors for death and the prognostic performance of scores to predict mortality were analyzed. The level of significance was set at 5%. RESULTS: Two hundred ninety-three patients were analyzed in the study; 68.30% were men, with a median age of 38 years (interquartile range: 28-52). The mean total body surface area burned was 26.60+/ 18.05%. Home incidents were the most frequent cause, occurring in 53.90% of the cases. Fire was the most common cause, found in 77.10% of patients. Liquid alcohol was the most common agent and was associated with 51.50% of the cases. The ABSI presented a median of 7, and the area under the ROC curve was 0.890. In multivariate analysis, age (p<0.001), female gender (p=0.02), total body surface area burned (p<0.001), mechanical ventilation (p<0.001) and acute renal failure (p<0.001) were all associated with mortality. ICU mortality was 32.80%, and hospital mortality was 34.10%. CONCLUSION: Burns most often occurred in young adult men in our study. The most common cause was a direct flame. Liquid alcohol was the most frequent accelerating agent. Patients were considered to be severely burned. Most of the samples had a high mean total body surface area burned. The ABSI score showed the best performance in discriminating non-survivors. Hospital mortality rate was high. PMID- 26762621 TI - Melatonin synergistically enhances protective effect of atorvastatin against gentamicin-induced nephrotoxicity in rat kidney. AB - The risk of serious side-effects such as nephrotoxicity is the principal limitation of gentamicin (GEN) therapeutic efficacy. Oxidative stress is considered to be an important mediator of GEN-induced nephrotoxicity. The present study was designed to evaluate the efficacy of the combination of melatonin (MT) plus atorvastatin (ATO) against GEN-induced nephrotoxicity in rats. We utilized 30 male Wistar albino rats allocated in 5 groups, each containing 6 rats: control, GEN (100 mg/kg/day), ATO (10 mg/kg/day) + GEN, MT (20 mg/kg/day) + GEN, and ATO (10 mg/kg/day) plus MT (20 mg/kg/day) + GEN. Kidney weight, serum creatinine and urea concentration, renal ROS, MDA, GSH levels, SOD, and CAT activity were determined. GEN-induced nephrotoxicity was evidenced by marked elevations in serum urea and creatinine, kidney weight, renal ROS, and MDA levels and reduction in renal GSH level, SOD and CAT activity. MT pretreatment significantly lowered the elevated serum creatinine concentration, kidney weight, renal ROS and MDA levels. However ATO could not reduce these parameters, but similarly to MT, it was able to enhance the renal GSH level, CAT and SOD activity. In addition, a combination therapy of MT plus ATO enhanced the beneficial effects of ATO, while not changing the effects of MT effects or even improving them. The present study indicates that a combination therapy of MT plus ATO can attenuate renal injury in rats treated with GEN, possibly by reducing oxidative stress, and it seems that MT can enhance the beneficial effects of ATO. PMID- 26762624 TI - First US case of Zika virus infection is identified in Texas. PMID- 26762622 TI - Validity of ankylosing spondylitis diagnoses in The Health Improvement Network. AB - BACKGROUND/PURPOSE: Because ankylosing spondylitis (AS) is uncommon, large medical record databases offer important opportunities for pharmacoepidemiologic research. However, the validity of AS diagnoses recorded by a general practitioner (GP) is unknown. We assessed the validity of algorithms for identifying AS in The Health Improvement Network (THIN). METHODS: THIN is a database of GP records for over 10 million persons in the UK. In 2014, we administered a questionnaire to GPs of 100 adults for whom an AS diagnosis had been recorded. As high positive predictive value (PPV) is critically important in AS research, we sought to determine the PPV of an AS diagnostic code relative to the GP's clinical impression as the gold standard. Other AS algorithms included: more than one AS diagnostic code, prescription of a nonsteroidal anti inflammatory drug (NSAID), disease modifying anti-rheumatic drug (DMARD) or biologic. RESULTS: In 61 of 85 returned questionnaires, the GP's clinical impression confirmed AS yielding an overall PPV of 72%. PPV was 89% for two AS codes >7 days apart, and was 86% for an AS code plus a DMARD/biologic. Sensitivity was reduced with algorithms requiring two AS codes (64%) and a DMARD/biologic prescription (30%). Algorithms requiring prescription of an NSAID, or the absence of OA or RA had lower PPV (71-75%) and higher sensitivity (95 98%). CONCLUSION: An AS identification algorithm of two AS diagnoses separated by >7 days provided the highest PPV. This algorithm should be used for pharmacoepidemiologic studies in THIN. PMID- 26762623 TI - Hunger and Satiety Mechanisms and Their Potential Exploitation in the Regulation of Food Intake. AB - Effective strategies to combat recent rises in obesity levels are limited. The accumulation of excess body fat results when energy intake exceeds that expended. Energy balance is controlled by hypothalamic responses, but these can be overridden by hedonic/reward brain systems. This override, combined with unprecedented availability of cheap, energy-dense, palatable foods, may partly explain the increase in overweight and obesity. The complexity of the processes that regulate feeding behaviour has driven the need for further fundamental research. Full4Health is an EU-funded project conceived to advance our understanding of hunger and satiety mechanisms. Food intake has an impact on and is also affected by the gut-brain signalling which controls hunger and appetite. This review describes selected recent research from Full4Health and how new mechanistic findings could be exploited to adapt and control our physiological responses to food, potentially providing an alternative solution to addressing the global problems related to positive energy balance. PMID- 26762625 TI - Affect and Health Behavior Co-Occurrence: The Emerging Roles of Transdiagnostic Factors and Sociocultural Factors. AB - The majority of scientific work addressing relations among affective states and health correlates has focused primarily on their co-occurrence and a limited range of health conditions. We have developed a Special Issue to highlight recent advances in this emerging field of work that addresses the nature and interplay between affective states and disorders, in terms of their impact and consequences from health status and behavior. This Special Issue is organized into three parts classified as (a) co-occurrence and interplay between (b) transdiagnostic factors and (c) sociocultural factors. It is hoped that this issue will (a) alert readers to the significance of this work at different levels of analysis, (b) illustrate the many domains currently being explored via innovative approaches, and (c) identify fecund areas for future systematic study. PMID- 26762626 TI - An Evaluation of the Effects of a Mild Delayed Verbal Punisher on Choice of an Immediate Reinforcer by Children With Autism. AB - Different combinations of immediate and delayed consequences differentially affect choice. Basic research has found that nonhuman animals are more likely to choose an alternative that produces an immediate reinforcer that is followed by a delayed punisher as the delay to punishment increases. The purpose of the current effort was to examine the choices of three individuals with autism when they were given the choice between receiving a larger amount of preferred food followed by a mild, delayed verbal punisher and a smaller amount of the preferred food. A secondary purpose was to determine whether signal presence and duration would affect the efficacy of the punisher (i.e., whether children would be more likely to select the smaller reward that was not followed by a delayed punisher). Results were idiosyncratic across children and highlight the need to evaluate choice under multiple arrangements. PMID- 26762627 TI - Evaluation of oxidant and antioxidant status in living donor renal allograft transplant recipients. AB - The objective of this study was to evaluate the oxidant and antioxidant status in living donor renal allograft transplant recipients. Ninety-two renal transplant recipients with mean age of 34.75 +/- 11.22 years were included in the present study. Venous samples of the recipients were drawn: before the transplant (baseline), 5 min after reperfusion, and 2 weeks after transplant. Samples were processed for the measurement of markers of oxidant and antioxidant status viz. malondialdehyde, catalase, glutathione peroxidase, reduced glutathione, ascorbic acid, and total antioxidant system. The mean baseline levels of reduced glutathione, ascorbic acid, and total antioxidant system were 1.61 +/- 0.84 mg/g hemoglobin, 3.64 +/- 1.49 mg/dL, and 1.42 +/- 0.14 mmol/L which decreased at 5 min after reperfusion to 1.32 +/- 0.72 (p = 0.010), 2.96 +/- 1.25 (p = 0.002), and 1.36 +/- 0.12 (p = 0.042), respectively. The malondialdehyde levels increased from a baseline value of 3.11 +/- 1.02 umol/mL to 3.32 +/- 1.09 at 5 min after reperfusion (p = 0.344) and 4.01 +/- 1.21 (p = 0.000) at 2 weeks. Glutathione peroxidase level decreased from 68.59 +/- 32.79 units/g hemoglobin (baseline) to 63.65 +/- 32.92 at 5 min after reperfusion (p = 0.530) and increased significantly at 2 weeks to 86.38 +/- 37.18 (p = 0.00). There was no significant change in the catalase level. In living donor renal transplantation, oxidative stress starts after reperfusion and is reflected by fall in antioxidant factors and enzymes in the early period. Over the next 2 weeks, there is increased oxidative stress and simultaneous strengthening of antioxidant system which is implied by increase in malondialdehyde and improvement in the markers of antioxidant status. PMID- 26762628 TI - Mating Type Gene (MAT) and Itraconazole Susceptibility of Trichophyton tonsurans Strains Isolated in Japan. AB - Infection by Trichophyton tonsurans is an emerging fungal epidemic in Japan. Itraconazole (ITZ) and terbinafine have been used for the treatment of this infection for 15 years. However, patients with T. tonsurans infections have been shown to remain uncured or to become reinfected, suggesting that subclinical infection or polyphyletic strains and/or antifungal drug-resistant strains might be occurring in Japan. In this study, PCR analysis was performed to confirm the presence of the mating type locus MAT in genomic DNA from 60 Japanese clinical isolates of T. tonsurans, and to assess the previously postulated clonal origin of clinical isolates of this species. Antifungal susceptibility testing on isolates also was performed to confirm the absence of strains resistant to ITZ. PCR analysis proved that all 60 strains contained the MAT1-1 allele, while none contained the MAT1-2 allele. As determined by E-test, the mean MIC of ITZ in the 60 strains was 0.023 mg/L (range 0.002-0.125 mg/L). All strains of T. tonsurans isolated in Japan were clonal and were not resistant to ITZ. Therefore, dermatophytosis due to T. tonsurans is expected to respond to ITZ, since clinical isolates of T. tonsurans tested to date have been susceptible to this antifungal. This infection is proliferating as a subclinical infection in Japan. PMID- 26762629 TI - Prior Abdominal Surgery Jeopardizes Quality of Resection in Colorectal Cancer. AB - BACKGROUND: Prior abdominal surgery increases complexity of abdominal operations. Effort to prevent injury during adhesiolysis might result in less extensive bowel resection in colorectal cancer surgery. The aim of this study was to evaluate the effect of prior abdominal surgery on the outcome of colorectal cancer surgery. METHODS: A nationwide prospective database of patients with primary colorectal cancer resection in The Netherlands between 2010 and 2012 was reviewed for histopathology, morbidity and mortality in patients with compared to patients without prior abdominal surgery. RESULTS: 9042 patients with and 17,679 without prior abdominal surgery were analyzed. After prior abdominal surgery 20.7 % had less than 10 lymph nodes in the histopathological specimen compared to 17.8 % without prior abdominal surgery (adjusted OR 1.17, 95 % CI 1.09-1.26). Adjusted ORs for less than 10 and 12 lymph nodes were significant in colon cancer resection and not in rectal cancer resection. Subgroups of patients who had previous hepatobiliary surgery or other abdominal surgery had a higher incidence of inadequate number of harvested lymph nodes. Prior colorectal surgery increased the percentage of positive circumferential rectal resection margin by 64 % (12.5 and 7.6 %; adjusted OR 1.70, 95 % CI 1.21-2.39). For colon cancer morbidity was significantly higher in patients with prior surgery (33.2 and 29.7 %; adjusted OR 1.18, 95 % CI 1.10-1.26), 30-day mortality was comparable (4.7 % prior surgery and 3.8 % without prior surgery; adjusted OR 1.01, 95 % CI 0.88-1.17). CONCLUSIONS: Prior abdominal surgery compromises the quality of resection and increases postoperative morbidity in patients with primary colorectal cancer. PMID- 26762631 TI - Prognosis After Brain Metastasis from Differentiated Thyroid Carcinoma. AB - BACKGROUND: In patients with differentiated thyroid carcinoma (DTC), lung and bone metastasis sometimes occur. However, brain metastasis (BM) is extremely rare. Because most previous reports about BM from DTC included a relatively small number of cases, the clinical characteristics and outcomes of BM are still unclear. PATIENTS AND METHODS: Between 1965 and 2013, among 961 patients who had died because of DTC, 24 patients were diagnosed with BM from DTC. One patient with BM from DTC is still alive. To identify the prognostic factors for longer survival after BM, the medical records of these 25 patients were retrospectively reviewed. RESULTS: The median age at BM diagnosis was 66 years. Typical symptoms associated with BM had appeared in 20 patients (80%). The Karnofsky Performance Status (KPS) was good (>=70) in 10 patients and poor (<=60) in 15 patients. Seven patients had a single intracranial lesion of BM, 6 patients had 2 or 3 lesions, and 9 patients had 4 or more. Eleven patients did not receive any treatment for BM, and 14 patients underwent surgical resection, radiation therapy, or both. One year and 5-year disease-specific survival rates were 28 and 10.6%, respectively. Good KPS (>=70), small number of intracranial lesions (<=3), and treatment for BM were prognostic factors for long survival on univariate analysis (p < 0.05). On multivariate analysis, only treatment for BM was significant. CONCLUSION: Treatment of BM from DTC is indicated in patients who have a good KPS and fewer intracranial lesions, and some of them may achieve long survival. PMID- 26762633 TI - Use of Suture-Mediated Closure Device in Percutaneous Direct Carotid Puncture During Chimney-Thoracic Endovascular Aortic Repair. AB - BACKGROUND: Insertion of a carotid chimney graft during thoracic endovascular aortic repair (Ch-TEVAR) is a recognized technique to extend the proximal landing zone into the aortic arch in the treatment of thoracic aortic disease. Conventional technique requires surgical exposure of the carotid artery for insertion of the carotid chimney graft. METHODOLOGY: We describe our experience in the use of a suture-mediated closure device in percutaneous Ch-TEVAR in four patients. RESULTS: Successful hemostasis was achieved in all four patients. No complications related to the carotid puncture were recorded. CONCLUSION: We conclude that using suture-mediated closure device for carotid closure appears feasible and deserves further studies as a potential alternative to conventional surgical approach. PMID- 26762632 TI - Adjuvant Hepatic Arterial Infusion Chemotherapy After Resection for Pancreatic Cancer Using Coaxial Catheter-Port System Compared with Conventional System. AB - PURPOSE: Previous reports have shown the effectiveness of adjuvant hepatic arterial infusion chemotherapy (HAIC) in pancreatic cancer. However, percutaneous catheter placement is technically difficult after pancreatic surgery. The purpose of this study was to evaluate the feasibility and outcome of HAIC using a coaxial technique compared with conventional technique for postoperative pancreatic cancer. MATERIALS AND METHODS: 93 consecutive patients who received percutaneous catheter-port system placement after pancreatectomy were enrolled. In 58 patients from March 2006 to August 2010 (Group A), a conventional technique with a 5-Fr indwelling catheter was used and in 35 patients from September 2010 to September 2012 (Group B), a coaxial technique with a 2.7-Fr coaxial catheter was used. RESULTS: The overall technical success rates were 97.1 % in Group B and 86.2 % in Group A. In cases with arterial tortuousness and stenosis, the success rate was significantly higher in Group B (91.7 vs. 53.8 %; P = 0.046). Fluoroscopic and total procedure times were significantly shorter in Group B: 14.7 versus 26.7 min (P = 0.001) and 64.8 versus 80.7 min (P = 0.0051), respectively. No differences were seen in the complication rate. The 1 year liver metastasis rates were 9.9 % using the conventional system and 9.1 % using the coaxial system (P = 0.678). The overall median survival time was 44 months. There was no difference in the survival period between two systems (P = 0.312). CONCLUSIONS: The coaxial technique is useful for catheter placement after pancreatectomy, achieving a high success rate and reducing fluoroscopic and procedure times, while maintaining the safety and efficacy for adjuvant HAIC in pancreatic cancer. PMID- 26762634 TI - The exocyst in Candida albicans polarized secretion and filamentation. AB - The exocyst is an octameric complex that orchestrates the docking and tethering of vesicles to the plasma membrane during exocytosis and is fundamental for key biological processes including growth and establishment of cell polarity. Although components of the exocyst are well conserved among fungi, the specific functions of each component of the exocyst complex unique to Candida albicans biology and pathogenesis are not fully understood. This commentary describes recent findings regarding the role of exocyst subunits Sec6 and Sec15 in C. albicans filamentation and virulence. PMID- 26762640 TI - PSA-NCAM positive neural progenitors stably expressing BDNF promote functional recovery in a mouse model of spinal cord injury. AB - BACKGROUND: Neural stem cells for the treatment of spinal cord injury (SCI) are of particular interest for future therapeutic use. However, until now, stem cell therapies are often limited due to the inhibitory environment following the injury. Therefore, in this study, we aimed at testing a combinatorial approach with BDNF (brain-derived neurotrophic factor) overexpressing early neural progenitors derived from mouse embryonic stem cells. BDNF is a neurotrophin, which both facilitates neural differentiation of stem cells and favors regeneration of damaged axons. METHODS: Mouse embryonic stem cells, modified to stably express BDNF-GFP, were differentiated into PSA-NCAM positive progenitors, which were enriched, and SSEA1 depleted by a sequential procedure of magnetic activated and fluorescence-activated cell sorting. Purified cells were injected into the lesion core seven days after contusion injury of the spinal cord in mice, and the Basso mouse scale (BMS) test to evaluate motor function was performed for 5 weeks after transplantation. To analyze axonal regeneration the anterograde tracer biotinylated dextran amine was injected into the sensorimotor cortex two weeks prior to tissue analysis. Cellular differentiation was analyzed by immunohistochemistry of spinal cord sections. RESULTS: Motor function was significantly improved in animals obtaining transplanted BDNF-GFP-overexpressing cells as compared to GFP-expressing cells and vehicle controls. Stem cell differentiation in vivo revealed an increase of neuronal and oligodendrocytic lineage differentiation by BDNF as evaluated by immunohistochemistry of the neuronal marker MAP2 (microtubule associated protein 2) and the oligodendrocytic markers ASPA (aspartoacylase) and Olig2 (oligodendrocyte transcription factor 2). Furthermore, axonal tracing showed a significant increase of biotin dextran amine positive corticospinal tract fibers in BDNF-GFP-cell transplanted animals caudally to the lesion site. CONCLUSIONS: The combinatorial therapy approach by transplanting BDNF-overexpressing neural progenitors improved motor function in a mouse contusion model of SCI. Histologically, we observed enhanced neuronal and oligodendrocytic differentiation of progenitors as well as enhanced axonal regeneration. PMID- 26762641 TI - Full-length amelogenin influences the differentiation of human dental pulp stem cells. AB - BACKGROUND: Amelogenin is an extracellular matrix protein well known for its role in the organization and mineralization of enamel. Clinically, it is used for periodontal regeneration and, due to its finding also in predentin and intercellular spaces of dental pulp cells, it has recently been suggested for pulp capping procedures. The aim of this study was to analyse in vitro the effect of the recombinant human full-length amelogenin on the growth and differentiation of human dental pulp stem cells (hDPSCs). METHODS: Human DPSCs were treated with a supplement of amelogenin at a concentration of 10 ng/ml, 100 ng/ml and 1000 ng/ml. The groups were compared to the unstimulated control in terms of cell morphology and proliferation, mineralization and gene expression for ALP (alkaline phosphatase), DMP1 (dentin matrix protein-1) and DSPP (dentin sialophosphoprotein). RESULTS: Amelogenin affects hDPSCs differently than PDL (periodontal ligament) cells and other cell lines. The proliferation rate at two weeks is significantly reduced in presence of the highest concentration of amelogenin as compared to the unstimulated control. hDPSCs treated with low concentrations present a downregulation of DMP1 and DSPP, which is significant for DSPP (p = 0.011), but not for DMP1 (p = 0.395). CONCLUSIONS: These finding suggest that the role of full-length amelogenin is not restricted to participation in tooth structure. It influences the differentiation of hDPSC according to various concentrations and this might impair the clinical results of pulp capping. PMID- 26762642 TI - Changes in abdominal obesity in Chilean university students stratified by body mass index. AB - BACKGROUND: Studies based on Body Mass Index (BMI) and waist circumference (WC) are generally used to examine the prevalence and tendency of overweight and obesity. These studies help determine the socioeconomic development of a country and improve public health policies. Therefore, the goal of this research was to determine the trend of change in abdominal obesity of Chilean university students according to the Body Mass Index (BMI) measured in intervals of three and six years. METHODS: For this study, a total of 1598 students of both sexes ranging in age from 18 to 26 from a Chilean university were evaluated. Students were assessed commencing in 2007 (372 males and 315 females), 2010 (250 males and 330 females), and ending in 2013 (153 males and 178 females). During the three transversal assessments, weight, height, and waist circumference were evaluated. BMI was calculated for both sexes. RESULTS: No significant differences were found in age and BMI during the three years evaluated (2007, 2010, and 2013). In 2013, waist circumference (WC) increased significantly (p < 0.001 for both sexes). Moreover, in 2013, in all the percentiles evaluated, high values of WC were compared in relation to previous years. Furthermore, in 2013, in all four BMI categories (underweight, normal, overweight, and obese), the university students showed significant increases in WC (Females: p = 0.004; Males: p = 0.035) whereas in 2007 and 2010, the values remained relatively stable. CONCLUSIONS: BMI remained constant during 2007, 2010, and 2013. However, the university students of both sexes showed greater risk of abdominal obesity as a result of increased WC in 2013. PMID- 26762644 TI - LUPUS - 25 years old. PMID- 26762643 TI - Predicting condom use in adolescents: a test of three socio-cognitive models using a structural equation modeling approach. AB - BACKGROUND: The theory of planned behavior (TPB), socio-cognitive model (SCM), and information-motivation-behavioral skills (IMB) model are effective in predicting condom use. However, the adequacy of these three theoretical models in predicting the frequency of condom use (FCU) among young people has not been compared. This cross-sectional study tested the applicability and suitability of these three models in predicting the FCU, and analyzed the relationships among the postulated constructs. METHODS: Sexually experienced adolescents (n = 410) aged 13-18 completed a survey assessing the TPB, SCM, and IMB model constructs. Participants were students recruited from 18 high schools, randomly selected from the north, south, east, and southeast of Spain. A structural equation modelling (SEM) analysis was applied to test TPB, SCM and IBM and constructs relationships of each model using R. RESULTS: The results of SEM demonstrated that behavioral skills predict behavior via motivation as hypothesized by the IMB model, but not directly via knowledge about condom use and sexually transmitted infections (STIs). Cognitive factors, such knowledge about condom use and STIs as well as condom use self-efficacy, directly predicted the FCU when modeled as per the SCM. According to the TPB, condom use intention was the best predictor of the FCU, and condom use intention was predicted by attitudes toward condom use and subjective norms related to condom use, but perceived control was not directly or indirectly related to the FCU. Based on the data, the TPB becomes the best-fit model for predicting the FCU among young people compared to the SCM and IMB model. CONCLUSIONS: From a statistical perspective, the TPB seems to be the most suitable model for predicting the FCU among young people compared to the other models. Overall, key direct predictors of the FCU in adolescents included condom use intention, behavioral skills and cognitive factors, such as STIs knowledge and condom use self-efficacy. The next step should be to test integrative models that include personal, contextual, environmental, and social factors. PMID- 26762645 TI - Autoimmune congenital heart block: complex and unusual situations. AB - Autoimmune congenital heart block (ACHB) is an immune-mediated cardiac disease included among the manifestations collectively referred to as neonatal lupus. The placental transference of maternal Ro/La autoantibodies may damage the conduction tissues during fetal development leading to blocking of signal conduction at the atrioventricular (AV) node in an otherwise structurally normal heart. Irreversible complete AV block is the main cardiac manifestation of ACHB, but some babies may develop endocardial fibroelastosis, valvular insufficiency, and/or frank cardiomyopathies with significantly reduced cardiac function requiring transplant. The severity of ACHB is illustrated by a global mortality rate of 20% and pacemaker rates of at least 64%, often within the first year of life. This review analyses the main complex and/or unusual clinical situations associated with ACHB, including unusual maternal immunological profiles, infrequent maternal autoimmune diseases, cardiac damage unrelated to AV block, fetal invasive management, late complications after birth, risk of congenital heart block (CHB) in ovodonation and in vitro fertilization techniques, the role of maternal features other than autoimmunity, the influence of the birth order or the risk of CHB in twins and triplets. PMID- 26762646 TI - Validation and comparison study of three urbanicity scales in a Thailand context. AB - BACKGROUND: Validity and reliability of an urbanicity scale is of utmost importance in developing effective strategies to minimize adverse social and health consequences of increased urbanization. A number of urbanicity scales for the quantitative assessment of the "static" feature of an urban environment has been invented and validated by the original developers. However, their comparability and robustness when utilized in another study context were not verified. This study aimed to examine the comparability, validity, and reliability of three urbanicity scales proposed by Dahly and Adair, Jones-Smith and Popkin, and Novak et al. in a Thailand context. METHODS: Urban characteristics data for 537 communities throughout Thailand were obtained from authoritative sources, and urbinicity scores were calculated according to the original developers' algorithms with some modifications to accommodate local available data. Comparability, dimensionality, internal consistency, and criterion-related and construct validities of the scores were then determined. RESULTS: All three scales were highly correlated, but Dahly and Adair's and Jones Smith and Popkin's were more comparable. Only Dahly and Adair's scale achieved the unidimensionality assumption. Internal consistency ranged from very poor to high, based on their Chonbach's alpha and the corrected item-scale correlation coefficients. All three scales had good criterion-related validity (when compared against the official urban-rural dichotomy and four-category urbanicity classification) and construct validity (in terms of their relation to the mean per capita monthly income and body mass index). CONCLUSIONS: This study's results ensure the utility of these three urbanicity scales as valid instruments for examining the social and health impacts of urbanicity/urbanization, but caution must be applied with comparisons of urbanicity levels across different studies when different urbanicity scales are applied. PMID- 26762647 TI - Moderate Effects of Same-Sex Legislation on Dependent Employer-Based Insurance Coverage Among Sexual Minorities. AB - A difference-in-difference approach was used to compare the effects of same-sex domestic partnership, civil union, and marriage policies on same- and different sex partners who could have benefitted from their partners' employer-based insurance (EBI) coverage. Same-sex partners had 78% lower odds (Marginal Effect = -21%) of having EBI compared with different-sex partners, adjusting for socioeconomic and health-related factors. Same-sex partners living in states that recognized same-sex marriage or domestic partnership had 89% greater odds of having EBI compared with those in states that did not recognize same-sex unions (ME = 5%). The impact of same-sex legislation on increasing take-up of dependent EBI coverage among lesbians, gay men, and bisexual individuals was modest, and domestic partnership legislation was equally as effective as same-sex marriage in increasing same-sex partner EBI coverage. Extending dependent EBI coverage to same-sex partners can mitigate gaps in coverage for a segment of the lesbians, gay men, and bisexual population but will not eliminate them. PMID- 26762649 TI - Efficient Research Design: Using Value-of-Information Analysis to Estimate the Optimal Mix of Top-down and Bottom-up Costing Approaches in an Economic Evaluation alongside a Clinical Trial. AB - In designing economic evaluations alongside clinical trials, analysts are frequently faced with alternative methods of collecting the same data, the extremes being top-down ("gross costing") and bottom-up ("micro-costing") approaches. A priori, bottom-up approaches may be considered superior to top-down approaches but are also more expensive to collect and analyze. In this article, we use value-of-information analysis to estimate the efficient mix of observations on each method in a proposed clinical trial. By assigning a prior bivariate distribution to the 2 data collection processes, the predicted posterior (i.e., preposterior) mean and variance of the superior process can be calculated from proposed samples using either process. This is then used to calculate the preposterior mean and variance of incremental net benefit and hence the expected net gain of sampling. We apply this method to a previously collected data set to estimate the value of conducting a further trial and identifying the optimal mix of observations on drug costs at 2 levels: by individual item (process A) and by drug class (process B). We find that substituting a number of observations on process A for process B leads to a modest L 35,000 increase in expected net gain of sampling. Drivers of the results are the correlation between the 2 processes and their relative cost. This method has potential use following a pilot study to inform efficient data collection approaches for a subsequent full-scale trial. It provides a formal quantitative approach to inform trialists whether it is efficient to collect resource use data on all patients in a trial or on a subset of patients only or to collect limited data on most and detailed data on a subset. PMID- 26762650 TI - Is a national time target for emergency department stay associated with changes in the quality of care for acute asthma? A multicentre pre-intervention post intervention study. AB - OBJECTIVE: There is debate whether targets for ED length of stay introduced to reduce ED overcrowding are helpful or harmful, as focus on a process target may divert attention from clinical care. Our objective was to investigate the effect of a national ED target in Aotearoa New Zealand on the recommended care for acute asthma as this is known to suffer in overcrowded departments. METHODS: We conducted a retrospective chart review study across four sites from 2006 to 2012 (target introduced mid 2009). The primary outcome was time to steroids in the ED. The secondary outcomes were other aspects of asthma care in ED. We used general linear models or logistic regression as appropriate to assess care before and after the target. RESULTS: Among the 570 (of 1270 randomly selected cases) eligible for analysis, no difference was demonstrated in time to steroids: least square mean (95% CI) = 58.1 (49-67.5) min before and 50.4 (42.9-55.8) min after the target (P = 0.15). More patients received steroids in ED after the target, OR (95% CI) = 2.1 (1.2-4.3). No differences were demonstrated in those receiving steroid prescriptions or re-presentations: OR (95% CI) = 1.3 (0.9-1.96) and 1.1 (0.5-2.3), respectively. Changes in pre-target and post-target ED and hospital length of stay varied between hospitals. CONCLUSION: Introduction of the target was not associated with a change in times to steroids in ED, although more patients received steroids in ED indicating closer adherence to recommended practice. PMID- 26762651 TI - Acquired and Hereditary Hypercoagulable States in Patients with Continuous Flow Left Ventricular Assist Devices: Prevalence and Thrombotic Complications. AB - BACKGROUND: Thrombotic events in patients with continuous flow left ventricular assist devices (CF-LVADs) are associated with significant morbidity and mortality. The objective of this study was to delineate the frequency, clinical characteristics, and outcomes of patients with hypercoagulable states who undergo CF-LVAD implantation. METHODS: We performed a retrospective review of 168 consecutive patients who underwent CF-LVAD implantation between 2010 and 2013. Chart and laboratory data were reviewed for the presence of a hereditary and/or acquired hypercoagulable state. Adverse outcomes were defined as death, confirmed pump thrombosis, aortic root clot, stroke, deep vein thrombosis, and pulmonary embolism. Fisher's exact test and Kaplan-Meier estimate were used to analyze frequency of adverse outcomes and event free survival, respectively. RESULTS: A hypercoagulable state was identified in 20 patients (11.9%). There were 18 patients with acquired, 1 with a congenital, and 1 with both congenital and acquired hypercoagulable states. The median follow-up was 429 days and 475 days in patients with and without hypercoagulable states, respectively. During the study period, 15% (3/20) of the patients with a hypercoagulable state had a diagnosis of deep vein thrombosis vs 3% (4/148) of the patients without a hypercoagulable state (P = .030). Only patients with a hypercoagulable state had a subarachnoid hemorrhage (3/20 vs 0/148; P < .01). The event-free survival was lower in the patients with hypercoagulable states (P = .005). CONCLUSION: Hypercoagulable states are not uncommon in patients with CF-LVADs and may be associated with increased morbidity. Prospective studies are needed to more accurately identify the incidence, prevalence, and significance of hypercoagulable states in patients being considered for CF-LVAD. PMID- 26762648 TI - Impaired mitochondrial function is abrogated by dexrazoxane in doxorubicin treated childhood acute lymphoblastic leukemia survivors. AB - BACKGROUND: Impaired cardiac function in doxorubicin-treated childhood cancer survivors is partly mediated by the disruption of mitochondrial energy production. Doxorubicin intercalates into mitochondrial DNA (mtDNA) and disrupts genes encoding for polypeptides that make adenosine triphosphate. METHODS: This cross-sectional study examined mtDNA copy numbers per cell and oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) in 64 childhood survivors of high-risk acute lymphoblastic leukemia (ALL) who had been treated on Dana-Farber Cancer Institute childhood ALL protocols and had received doxorubicin alone (42%) or doxorubicin with the cardioprotectant dexrazoxane (58%). The number of mtDNA copies per cell and the OXPHOS enzyme activity of nicotinamide adenine dinucleotide dehydrogenase (complex I [CI]) and cytochrome c oxidase (complex IV [CIV]) were measured with quantitative real-time polymerase chain reaction immunoassays and thin-layer chromatography, respectively. RESULTS: At a median follow-up of 7.8 years after treatment, the median number of mtDNA copies per cell for patients treated with doxorubicin alone (1106.3) was significantly higher than the median number for those who had also received dexrazoxane (310.5; P = .001). No significant differences were detected between the groups for CI or CIV activity. CONCLUSIONS: Doxorubicin-treated survivors had an increased number of PBMC mtDNA copies per cell, and concomitant use of dexrazoxane was associated with a lower number of mtDNA copies per cell. Because of a possible compensatory increase in mtDNA copies per cell to maintain mitochondrial function in the setting of mitochondrial dysfunction, overall OXPHOS activity was not different between the groups. The long-term sustainability of this compensatory response in these survivors at risk for cardiac dysfunction over their lifespan is concerning. PMID- 26762652 TI - Weight satisfaction, management strategies and health beliefs in knee osteoarthritis patients attending an outpatient clinic. AB - BACKGROUND: Although weight control is important in managing knee osteoarthritis (OA), it is difficult to achieve. Understanding beliefs regarding weight management in people with knee OA may improve weight control. AIMS: To examine differences in bodyweight satisfaction, weight management strategies and weight related health-beliefs in obese, overweight and normal weight people with knee OA. METHODS: The beliefs and attitudes to weight in 102 people with symptomatic knee OA were ascertained. Participants were classified as being obese, overweight or of normal weight. RESULTS: Although obese and overweight participants were less satisfied with their bodyweight, they were more likely to want to lose weight and to report dieting compared with normal weight participants(P < 0.001 for all) and also more likely to report weight gain in the past 6 months (P < 0.001). While most participants rated food intake to be a main determinant of health, this belief was more common in normal weight participants (P = 0.04). When asked about their own weight gain, obese participants more frequently believed genetic and metabolic factors to be important than normal and overweight participants (P = 0.01). While 51 (53%) believed that increasing activity was more important than dietary change to avoid weight gain, this was more commonly believed by obese and overweight participants (P < 0.05). CONCLUSIONS: Despite desiring and attempting to lose weight, obese people with symptomatic knee OA more commonly reported weight gain. Overweight and obese participants attributed weight gain to non-modifiable factors but believed physical activity is more important than dietary change in weight management. Thus, education regarding the importance of diet as compared with non-modifiable factors and physical activity may improve weight management in obese people with knee OA. PMID- 26762654 TI - Clostridium perfringens type A netF and netE positive and Clostridium difficile co-infection in two adult dogs. AB - The aim of this study was to report two cases of Clostridium perfringens type A and Clostridium difficile co-infection in adult dogs. Both animals were positive for A/B toxin. Toxigenic C. difficile and C. perfringens type A positive for NetE and NetF-encoding genes were isolated. This report reinforces the necessity of studying a possible synergism of C. difficile and C. perfringens in enteric disorders. PMID- 26762653 TI - IgA- and SIgA anti-PR3 antibodies in serum versus organ involvement and disease activity in PR3-ANCA-associated vasculitis. AB - Circulating immunoglobulin (Ig)A class anti-neutrophil cytoplasm antibodies (ANCA) directed against proteinase 3 (PR3) have been reported in ANCA-associated vasculitis (AAV) with mucosal involvement. However, secretory IgA (SIgA) PR3-ANCA has not been reported previously. In this study we compared serum levels of SIgA PR3-ANCA and IgA PR3-ANCA with IgG PR3-ANCA in relation to disease characteristics. Among 73 patients with AAV and PR3-ANCA at diagnosis, 84% tested positive for IgG PR3-ANCA, 47% for IgA-ANCA and 36% for SIgA PR3-ANCA at the time of sampling for the present study. IgA and IgG PR3-ANCA were represented similarly among patients with different organ manifestations, i.e. upper airway, lung or kidney at time of sampling. However, SIgA PR3-ANCA was significantly less represented among patients with upper airway involvement. During active disease, the proportions of IgA PR3-ANCA and SIgA PR3-ANCA-positive patients were significantly higher compared to inactive disease. Eight patients were sampled prospectively during 24 months from onset of active disease. In these patients, IgA PR3-ANCA and SIgA PR3-ANCA turned negative more often after remission induction compared to IgG PR3-ANCA. Our findings suggest that serum IgA PR3-ANCA and SIgA PR3-ANCA are related more closely to disease activity in AAV compared to IgG PR3-ANCA. Further studies are required to reveal if this has implications for disease activity monitoring. The mean number of PR3-ANCA isotypes increased along with disease activity, suggesting a global B cell activation during active disease. PMID- 26762655 TI - Patterns of service utilisation within Australian hepatology clinics: high prevalence of advanced liver disease. AB - BACKGROUND: Liver diseases in Australia are estimated to affect 6 million people with a societal cost of $51 billion annually. Information about utilisation of specialist hepatology care is critical in informing policy makers about the requirements for delivery of hepatology-related healthcare. AIMS: This study examined the aetiology and severity of liver disease seen in a tertiary hospital hepatology clinic, as well as the resource utilisation patterns. METHODS: A longitudinal cohort study included consecutive patients booked in hepatology outpatient clinics during a 3-month period. Subsequent outpatient appointments for these patients over the following 12 months were then recorded. RESULTS: During the initial 3-month period, 1471 appointments were scheduled with a hepatologist, 1136 of which were attended. Twenty-one per cent of patients were 'new cases'. Hepatitis B virus (HBV) was the most common disease aetiology for new cases (37%). Advanced disease at presentation varied between aetiology; only 5% of HBV cases had advanced liver disease at presentation, in contrast with HCV, NAFLD and ALD, in which advanced disease was identified at presentation in 31%, 46% and 72% of cases, respectively. Most patients (83%) attended multiple hepatology appointments, and a range of referral patterns for procedures, investigations and other specialty assessments were observed. CONCLUSIONS: There is a high prevalence of HBV in new case referrals. Patients with HCV infection, NAFLD and ALD have a high prevalence of advanced liver disease at referral, requiring ongoing surveillance for development of decompensated liver disease and liver cancer. These findings that describe the patterns of health service utilisation among patients with liver disease provide useful information for planning sustainable health service provision for this clinical population. PMID- 26762657 TI - SVD analysis of Array transmission and reception and its use for bootstrapping calibration. AB - PURPOSE: Noise-optimal reconstruction of array transmitter calibrations would ideally require knowledge of the receive array sensitivities which can often only be measured once the transmitter is calibrated to provide sufficient coverage. This poses often a problem in bootstrapping transmit-receive arrays particularly at ultrahigh fields. METHODS: Said problem is resolved by formulating the local transmit-receive efficiency of the array setup as a bilinear form and deriving therefrom a noise-optimal, joint reconstruction of the calibration data resulting in the relative sensitivities of the used transmitters and receivers. RESULTS: Retrieval and reconstruction of parallel transmission calibration data in phantoms and in vivo are presented using an eight-channel parallel transmit setup with up to 16 receivers using strip-line TR arrays and parallel transmission by traveling waves. CONCLUSION: Data sets from calibration scans are reconstructed robustly and with optimal signal-to-noise ratio. The found array signal gain is furthermore a direct performance measure for array transmitter and receiver combinations. The concomitantly obtained image was shown to have maximum coverage of the subject. Magn Reson Med 76:1730-1740, 2016. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26762656 TI - Socioeconomic inequalities and determinants of oral hygiene status among Urban Indian adolescents. AB - OBJECTIVES: To assess the socioeconomic inequalities in oral hygiene and to explore the role of various socioeconomic and psychosocial factors as determinants of these inequalities among adolescents residing in Delhi National Capital Territory. METHODS: A cross-sectional study was conducted among 1386 adolescents aged 12-15 years from three different socioeconomic groups according to their area of residence (middle-class areas, resettlement colonies and urban slum colonies). Level of oral hygiene was examined clinically using the Simplified Oral Hygiene Index (OHI-S), and an interviewer-administered questionnaire was used to measure key socio-demographic variables and psychosocial and health-related behaviours. Logistic regression analysis tested the association between area of residence and poor oral hygiene. RESULTS: Poor oral hygiene was observed in 50.2% of the adolescents. There was a socioeconomic gradient in poor oral hygiene, with higher prevalence observed at each level of deprivation. These differences were only partly explained, and the differences between adolescent groups remained statistically significant after adjusting for various demographic variables, standard of living, social capital, social support and health-affecting behaviours (OR: 1.96, 95% CI: 1.30-2.76; and OR: 2.50, 95% CI: 1.60-3.92 for adolescents from resettlement colonies and urban slums, respectively, than middle-class adolescents). CONCLUSION: Area of residence emerged as a strong socioeconomic predictor of prevalence of poor oral hygiene among Indian adolescents. Various material, psychosocial and behavioural factors did not fully explain the observed inequalities in poor oral hygiene among different adolescent groups. PMID- 26762658 TI - [Neurosurgery in the elderly patient: Geriatric neurosurgery]. AB - OBJECTIVE: Between 2000 and 2050, the proportion of the world's population over 60 years will double, and the number of people aged 80 and older will quadruple. Health professional training does not include instructions about specific care for older people. The World Health Organization maintains that all health providers should be trained on ageing issues. Thus, it is proposed to analyse the effect of ageing on Neurosurgery in our country. MATERIAL AND METHOD: A retrospective historical cohort study was performed on individuals age 70 years or older admitted to the Neurosurgery or the Intensive Care Unit of our hospital, with neurosurgical disease, between two periods: 1999-2000 and 2010-2011. An analysis was made on variables such as: age, pathology, length of stay, comorbidity, performance status, re-admissions and mortality. RESULTS: Similar numbers of patients were admitted during the two periods: 409 and 413. However, there was an increase of 77.5% in patients older than 70 years: 80 versus 142. Statistically significant differences were observed in the Charlson Comorbidity Index, the admission Glasgow Coma Scale (GCS) score, length of stay, and re admissions. Comorbidity and admission GCS score were particularly worse in the second period. Nevertheless, the mean length of stay was lower in that period, but showing more hospital re-admissions. After multivariate analysis, it was observed that re-admissions were associated with comorbidity, but not with early hospital discharge. No differences were found in performance status or mortality. CONCLUSIONS: A very considerable increase in percentage of patients older than 70 years old was found. There were no differences in performance status or mortality, which was probably due to the multidisciplinary management of these patients. The results of this study support the development of an interdisciplinary work group dedicated to Geriatric Neurosurgery. PMID- 26762660 TI - Merger of models on clinical instability--misleading for patients and clinicians? PMID- 26762659 TI - [Neuromonitoring of severe craniocerebral trauma in paediatric patients]. AB - INTRODUCTION: Severe craniocerebral trauma is the main cause of morbidity and mortality in children worldwide. Neuromonitoring of these patients in Cuba is not routine in paediatric intensive cares units, and there is no standardised protocol for its use in these units. MATERIALS AND METHODS: A correlational longitudinal prospective study was conducted on all patients admitted to the paediatric intensive care unit with the diagnosis of severe craniocerebral trauma in the period between January 2003 and December 2014. Continuous neuromonitoring of intracranial pressure and cerebral perfusion pressure was carried out. RESULTS: The results showed that there was a correlation between the initial images of CT scan and the grade of shift of the half line structures. There was a direct relationship between intracranial pressure and the outcomes. The use of early decompressive craniectomy facilitated the rapid control of the intracranial hypertension. CONCLUSIONS: Continuous neuromonitoring contributes to adopt a therapeutic posture in the handling of the paediatric patients with severe head trauma. PMID- 26762661 TI - What if we made stratified medicine work for patients? PMID- 26762662 TI - Antibiotic treatment: balancing patients' rights. PMID- 26762663 TI - Drawing breath. PMID- 26762664 TI - Inhaled corticosteroid dose-response on blood eosinophils in asthma - Authors' reply. PMID- 26762665 TI - Inhaled corticosteroid dose-response on blood eosinophils in asthma. PMID- 26762666 TI - The end of diesel-powered cars? PMID- 26762667 TI - Decade of the lung--a call for action to promote lung health globally. PMID- 26762668 TI - Pregnancy in Adolescence: Is It an Obstetrical Risk? AB - STUDY OBJECTIVE: Adolescent pregnancy is an important public health problem worldwide. It is associated with increased risk of maternal and fetal complications. We aimed to investigate whether adolescent pregnancies have an increased risk for perinatal complications. We focused primarily on the relationship between adolescent pregnancy and preterm delivery. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: We used records of 38,646 women who gave birth at our hospital, between January 2008 and December 2009. Five hundred eighty-two randomly selected pregnant adolescents and 2,920 healthy parity and body mass index matched pregnant women 20-34 years of age were included the study. Perinatal outcomes were compared between the groups. RESULTS: The mean gestational ages of the adolescent and control groups at the first prenatal visit were 11.2 (range, 8-31) and 8.5 (range, 7-28) weeks, respectively (P < .001). The risks of preterm delivery (odds ratio, 2.46; 95% confidence interval, 1.80-3.37; P < .001) and preeclampsia (odds ratio, 2.14; 95% confidence interval, 1.30-3.51; P = .002) were significantly greater among the adolescent mothers. In both groups, the most frequent reason was spontaneous preterm delivery. CONCLUSION: As shown in this study, pregnant adolescents present to hospitals for prenatal care at a much more advanced gestational age compared with adults. At the time they present to the hospital, and particularly in the first trimester, they must be advised to undergo an ultrasound scan to determine the gestational age. As such, it would be reasonable to increase the frequency of examinations after the second trimester, because of the increased risk of preterm labor and preterm birth. PMID- 26762669 TI - Exploring the interface between 'physician-assisted death' and palliative care: cross-sectional data from Australasian palliative care specialists. AB - BACKGROUND: Legalisation of physician-assisted dying (PAD) remains a highly contested issue. In the Australasian context, the opinion and perspective of palliative care specialists have not been captured empirically, and are required to inform better the debate around this issue, moving forward. AIM: To identify current attitudes and experiences of palliative care specialists in Australasia regarding requests for physician-assisted suicide and voluntary euthanasia, and to capture the opinion of palliative care specialists on the legalisation of these practices in the Australasian context. METHOD: An anonymous, cross sectional, online survey of Australasian specialists in palliative care, addressing the following six areas: (i) demographics; (ii) frequency of requests, and response given; (iii) understanding of the term 'voluntary euthanasia'; (iv) opinion regarding legalisation of physician-assisted suicide and voluntary euthanasia in Australasia, and willingness to participate if legal; (v) identification of the most important values guiding this opinion; and (vi) anticipated impact that legalisation of assisted death would have on palliative care practice. RESULTS: Important findings include: (i) palliative care specialists are largely opposed to the legalisation of PAD; (ii) the proportional titration of opioids is not understood by any palliative care specialist studied to be 'voluntary euthanasia'; and (iii) there is a wide variation in frequency of requests, and one-third of palliative care specialists express discomfort in dealing with requests for assisted suicide or euthanasia. CONCLUSION: Key areas for future research at the interface between PAD and best practice end-of-life care are identified, including exploration into why palliative care specialists are largely opposed to PAD, and consideration of the impact 'the opioid misconception' may have on the literature informing this debate. PMID- 26762670 TI - Q-space truncation and sampling in diffusion spectrum imaging. AB - PURPOSE: To characterize the q-space truncation and sampling on the spin displacement probability density function (PDF) in diffusion spectrum imaging (DSI). METHODS: DSI data were acquired using the MGH-USC connectome scanner (Gmax = 300 mT/m) with bmax = 30,000 s/mm2 , 17 * 17 * 17, 15 * 15 * 15 and 11 * 11 * 11 grids in ex vivo human brains and bmax = 10,000 s/mm2 , 11 * 11 * 11 grid in vivo. An additional in vivo scan using bmax =7,000 s/mm2 , 11 * 11 * 11 grid was performed with a derated gradient strength of 40 mT/m. PDFs and orientation distribution functions (ODFs) were reconstructed with different q-space filtering and PDF integration lengths, and from down-sampled data by factors of two and three. RESULTS: Both ex vivo and in vivo data showed Gibbs ringing in PDFs, which becomes the main source of artifact in the subsequently reconstructed ODFs. For down-sampled data, PDFs interfere with the first replicas or their ringing, leading to obscured orientations in ODFs. CONCLUSION: The minimum required q space sampling density corresponds to a field-of-view approximately equal to twice the mean displacement distance (MDD) of the tissue. The 11 * 11 * 11 grid is suitable for both ex vivo and in vivo DSI experiments. To minimize the effects of Gibbs ringing, ODFs should be reconstructed from unfiltered q-space data with the integration length over the PDF constrained to around the MDD. Magn Reson Med 76:1750-1763, 2016. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26762673 TI - Solvatofluorochromic, non-centrosymmetric pi-expanded diketopyrrolopyrrole. AB - A novel non-centrosymmetric pi-expanded diketopyrrolopyrrole was designed and synthesized. Strategic placement of tert-butyl groups at the periphery of a diketopyrrolopyrrole allowed us to selectively fuse one moiety via tandem Friedel Crafts-dehydration reactions, resulting in a non-centrosymmetric dye. The structure of the dye was confirmed by X-ray crystallography, revealing that it contains a nearly flat arrangement of four fused rings. Extensive photophysical studies of this new functional dye revealed that the intensity of its emission strongly depends on solvent polarity, which is typical for dipolar chromophores. In non-polar solvents, the fluorescence quantum yield is high whereas in polar solvents such as MeOH, it is 12%. However, upon two-photon excitation the compound behaves like a centrosymmetric dye, showing a two-photon absorption maximum at significantly shorter wavelengths than twice the wavelength of the one photon absorption maximum. PMID- 26762671 TI - Cerebrospinal fluid lipocalin 2 in patients with clinically isolated syndromes and early multiple sclerosis. AB - BACKGROUND: Lipocalin 2 (LCN2) may be involved in the immunopathogenesis of multiple sclerosis (MS) and might further impact on iron homoeostasis. Brain iron accumulates in MS; however, the association to iron-related proteins is still unsolved. OBJECTIVE: To investigate cerebrospinal fluid (CSF) and serum LCN2, transferrin (Trf) and ferritin in early MS in relation to disease evolution and longitudinal brain iron accumulation. METHODS: We analysed CSF and serum LCN2 by enzyme-linked immunosorbent assay (ELISA) and Trf and ferritin by nephelometry in 55 patients (45 clinically isolated syndrome (CIS), 10 MS, median clinical follow up 4.8 years) and 63 controls. In patients, we assessed sub-cortical grey matter iron by 3T magnetic resonance imaging (MRI) R2* relaxometry (median imaging follow-up 2.2 years). RESULTS: Compared to controls serum (p < 0.01), CSF (p < 0.001) LCN2 and CSF Trf (p < 0.001) levels were reduced in the patients. CSF LCN2 correlated with CSF Trf (r = 0.5, p < 0.001). In clinically stable patients, CSF LCN2 levels correlated with basal ganglia iron accumulation (r = 0.5, p < 0.05). In CIS, higher CSF LCN2 levels were associated with conversion to clinically definite MS (p < 0.05). CONCLUSION: We demonstrate altered LCN2 regulation in early MS and provide first evidence for this to be possibly linked to both clinical MS activity and iron accumulation in the basal ganglia. PMID- 26762672 TI - Prolonged-release fampridine in multiple sclerosis: Improved ambulation effected by changes in walking pattern. AB - BACKGROUND: Prolonged-release fampridine (PR-fampridine, 4-aminopyridine) increases walking speed in the timed 25-foot walk test (T25FW) in some patients (timed-walk responders) with multiple sclerosis (MS). OBJECTIVE: To explore the effects of PR-fampridine on different aspects of walking function and to identify associated gait modifications in subjects with MS. METHODS: In this prospective, randomized, placebo-controlled, double-blind, phase II study (FAMPKIN; clinicaltrials.gov, NCT01576354), subjects received a 6-week course of oral placebo or PR-fampridine treatment (10 mg, twice daily) before crossing over. Using 3D-motion-analysis, kinematic and kinetic parameters were assessed during treadmill walking (primary endpoint). Clinical outcome measures included T25FW, 6 minute walk test (6MWT), and balance scales. Physical activity in everyday life was measured with an accelerometer device. RESULTS: Data from 55 patients were suitable for analysis. Seventeen subjects were timed-walk responders under PR fampridine. For the total study population and for responders, a significant increase in walking speed (T25FW) and distance (6MWT) was observed. Gait pattern changes were found at the single-subject level and correlated with improvements in the T25FW and 6MWT. Physical activity was increased in responders. CONCLUSION: PR-fampridine improves walking speed, endurance, and everyday physical activity in a subset of subjects with MS and leads to individual modifications of the gait pattern. PMID- 26762674 TI - An Sb-doped p-type ZnO nanowire based random laser diode. AB - An electrically pumped Sb-doped ZnO nanowire/Ga-doped ZnO p-n homojunction random laser is demonstrated. Catalyst-free Sb-doped ZnO nanowires were grown on a Ga doped ZnO thin film on a Si substrate by chemical vapor deposition. The morphology of the as-grown titled nanowires was observed by scanning electron microscopy. X-ray photoelectron spectroscopy results indicated the incorporation of Sb dopants. Shallow acceptor states of Sb-doped nanowires were confirmed by photoluminescence measurements. Current-voltage measurements of ZnO nanowire structures assembled from p- and n-type materials showed a typical p-n diode characteristic with a threshold voltage of about 7.5 V. Very good photoresponse was observed in the UV region operated at 0 V and different reverse biases. Random lasing behavior with a low-threshold current of around 10 mA was demonstrated at room temperature. The output power was 170 nW at 30 mA. PMID- 26762675 TI - Dynamics of dissipative self-assembly of particles interacting through oscillatory forces. AB - Dissipative self-assembly is the formation of ordered structures far from equilibrium, which continuously uptake energy and dissipate it into the environment. Due to its dynamical nature, dissipative self-assembly can lead to new phenomena and possibilities of self-organization that are unavailable to equilibrium systems. Understanding the dynamics of dissipative self-assembly is required in order to direct the assembly to structures of interest. In the present work, Brownian dynamics simulations and analytical theory were used to study the dynamics of self-assembly of a mixture of particles coated with weak acids and bases under continuous oscillations of the pH. The pH of the system modulates the charge of the particles and, therefore, the interparticle forces oscillate in time. This system produces a variety of self-assembled structures, including colloidal molecules, fibers and different types of crystalline lattices. The most important conclusions of our study are: (i) in the limit of fast oscillations, the whole dynamics (and not only those at the non-equilibrium steady state) of a system of particles interacting through time-oscillating interparticle forces can be described by an effective potential that is the time average of the time-dependent potential over one oscillation period; (ii) the oscillation period is critical to determine the order of the system. In some cases the order is favored by very fast oscillations while in others small oscillation frequencies increase the order. In the latter case, it is shown that slow oscillations remove kinetic traps and, thus, allow the system to evolve towards the most stable non-equilibrium steady state. PMID- 26762676 TI - [Dermoscopy for beginners (i): General information]. AB - The incidence of skin cancer has been gradually increasing worldwide since the 1960s. It is currently a health and economic problem for the different health systems. Dermoscopy is a non-invasive in vivo diagnostic technique, developed to study skin lesions. It improves the diagnostic accuracy of hyperpigmented lesions, as well as an early diagnosis of potentially malignant lesions, especially melanoma. The time spent on physical examination is not significantly increased. New applications have currently been discovered for this technique. Dermoscopy requires a learning process. Due to the complexity of the topic, the text has been divided into 2 parts to try to simplify its presentation. This first part will focus on the more technical aspects and the characteristics of the device called dermoscope. In the second part, 2 diagnostical methods will be presented along with their easy interpretation and usefulness in Primary Care. PMID- 26762677 TI - Genetics of human Bardet-Biedl syndrome, an updates. AB - Bardet-Biedl syndrome (BBS) is an autosomal recessive multisystemic human genetic disorder characterized by six major defects including obesity, mental retardation, renal anomalies, polydactyly, retinal degeneration and hypogenitalism. In several cases of BBS, few other features such as metabolic defects, cardiovascular anomalies, speech deficits, hearing loss, hypertension, hepatic defects and high incidence of diabetes mellitus have been reported as well. The BBS displays extensive genetic heterogeneity. To date, 19 genes have been mapped on different chromosomes causing BBS phenotypes having varied mutational load of each BBS gene. In this review, we have discussed clinical spectrum and genetics of BBS. This report presents a concise overview of the current knowledge on clinical data and its molecular genetics progress upto date. PMID- 26762678 TI - The use of an imagery mnemonic to teach the Krebs cycle. AB - The Krebs Cycle is a highly taught biochemical pathway that is traditionally difficult to learn. Twenty-seven undergraduate students were randomized to a rote memorization arm or to a mnemonic arm. They were given a pre-test, then shown a lecture corresponding to their assigned method, and then given an immediate Week 0 post-test and a Week 4 post-test. Groups scored comparably low on the pre-test (p = 0.7113). Students in the mnemonic arm performed better on the Week 0 post test than those using rote (p = 0.0055). By Week 4, there was evidence of knowledge decay, with both arms' having comparably low scores (mnemonic vs. rote, p = 0.3739). The mnemonic assists in rapid acquisition of knowledge but probably has to be reviewed iteratively over time to demonstrate its full potential over rote memorization. A limited number of students from only one school was used. (c) 2016 by The International Union of Biochemistry and Molecular Biology, 44:224 229, 2016. PMID- 26762679 TI - Budesonide as first-line therapy for non-cirrhotic autoimmune hepatitis in children: a decision analysis. AB - OBJECTIVE: Therapy for autoimmune hepatitis has been prednisone based for decades; however, budesonide may be equally effective with fewer side effects. Our aim was to evaluate quality-adjusted life years and health care costs of three different treatment regimens. MATERIALS AND METHODS: Treatment using prednisone, budesonide or a combination of both over a three-year period in newly diagnosed children with type I autoimmune hepatitis were simulated with a Markov model. Transition probabilities were calculated over consecutive three-month period. Costs were determined from a hospital database and health utilities were estimated from the literature. A Monte Carlo probabilistic sensitivity analysis was used to simulate the outcomes of 5000 patients in each treatment arm. RESULTS: Compared to standard therapy, budesonide leads to a gain of 0.09 quality adjusted life years, costing $17,722 per QALY over a three-year period. Standard therapy led to significantly lower QALY's compared to other strategies (p < 0.001). Health utilities of patients in remission in each treatment group had the greatest impact on the model. Budesonide remained the treatment of choice if the probability of inducing remission was 55% or greater. CONCLUSIONS: Budesonide therapy in non-cirrhotic, treatment naive patients with type I autoimmune hepatitis yielded greater QALY's compared to the current standard therapy with an acceptable increase in costs. PMID- 26762680 TI - Effects of continuous long-term testosterone therapy (TTh) on anthropometric, endocrine and metabolic parameters for up to 10 years in 115 hypogonadal elderly men: real-life experience from an observational registry study. AB - Subnormal levels of testosterone are associated with significant negative health consequences, with higher risks of all-cause and cardiovascular mortality. The numbers of studies reporting on the benefits of normalisation of testosterone is increasing but longer-term data on (elderly) men receiving testosterone treatment are almost nonexistent. In this single-centre, cumulative, prospective, registry study, 115 hypogonadal men (mean age 59.05 years) received injections with testosterone undecanoate in 12-week intervals for up to 10 years. Waist circumference, body weight and mean BMI dropped progressively with statistical significance versus previous year for 7 years and, respectively, 8 years for weight and body mass index. Similarly, fasting glucose displayed a significant decrease after the first year continuing to decrease thereafter. A decline in HbA1c , from 6.4% to 5.6% (mean <6%), was observed from year 2 on, together with a decrease in the ratio of triglycerides:high-density lipoprotein (HDL), a surrogate marker of insulin resistance, with an increase in HDL levels. The total cholesterol:HDL ratio and non-HDL cholesterol declined significantly. A decrease was also observed in systolic and diastolic blood pressure, with a decrease in levels of the inflammation marker C-reactive protein. No major adverse cardiovascular events were observed throughout the study. PMID- 26762683 TI - Meckel's diverticulum enteroliths causing small bowel obstruction. PMID- 26762682 TI - Three new HLA class II alleles: DRB1*08:70, DQA1*01:13 and DQA1*03:01:03. AB - Three novel HLA class II alleles, DRB1*08:70, DQA1*01:13 and DQA1*03:01:03, were characterized. PMID- 26762684 TI - Psychometric properties of the Greek version of Jacelon Attributed Dignity Scale. AB - BACKGROUND: Maintaining dignity is important for successful aging, but there is lack of validated research instruments in the nursing literature to investigate dignity as perceived by the old people. OBJECTIVE: This is a methodological study aiming to investigate the psychometric properties of the Greek version of Jacelon Attributed Dignity Scale as translated in the Greek language. RESEARCH DESIGN: A methodological approach consisting of translation, adaptation, and cross-cultural validation. A sample of 188 Greek-speaking old Cypriot persons drawn from the Hospital outpatient departments was asked to complete the Greek versions of Jacelon Attributed Dignity Scale and the Instrumental Activities of Daily Living. Data analyses included internal consistency reliability (Cronbach's alpha coefficient), item analysis, and exploratory factor analysis using principal component method with orthogonal varimax rotation. Ethical considerations: The study protocol was approved by the National Bioethics committee according to the national legislation. Permission to use the research instrument was granted from the author. Information about the aim and the benefits of the study was included in the information letter. FINDINGS: Cronbach's alpha for Greek version of Jacelon Attributed Dignity Scale was 0.90. Four factors emerged explaining 65.28% of the total variance, and item to total correlation values ranged from 0.25 to 0.74 indicating high internal consistency and homogeneity. Mean item score in Instrumental Activities of Daily Living was 5.6 (standard deviation = 1.7) for men and 6.7 (standard deviation = 1.7) for women, and the correlations between demographics, Instrumental Activities of Daily Living, and the four factors of the Greek version of Jacelon Attributed Dignity Scale were low; also in multiple linear regression, the values of R2 are presented low. DISCUSSION: Demographic characteristics and degree of functionality seem to be associated with some of the dimensions of dignity but with low correlations; therefore, they cannot predict attributed dignity. CONCLUSION: The Greek version of Jacelon Attributed Dignity Scale is a valid and reliable tool to measure attributed dignity in Greek speaking older adults, but further testing of the psychometric properties and other potential factors that may affect the attributed dignity is needed. PMID- 26762681 TI - Graft-versus-Host Disease after HLA-Matched Sibling Bone Marrow or Peripheral Blood Stem Cell Transplantation: Comparison of North American Caucasian and Japanese Populations. AB - The risk of acute graft-versus-host disease (GVHD) after HLA-matched sibling bone marrow transplantation (BMT) is lower in Japanese than in Caucasian patients. However, race may have differential effect on GVHD dependent on the graft source. North American Caucasian and Japanese patients receiving their first allogeneic BMT or peripheral blood stem cell transplantation from an HLA-matched sibling for leukemia were eligible. BMT was performed in 13% of the Caucasian patients and in 53% of the Japanese patients. On multivariate analysis, the interaction term between race and graft source was not significant in any of the models, indicating that graft source does not affect the impact of race on outcomes. The risk of grade III or IV acute GVHD was significantly lower in the Japanese patients compared with the Caucasian patients (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57 to 0.96), which resulted in lower risk of nonrelapse mortality in the Japanese patients (HR, 0.69; 95% CI, 0.54 to 0.89). The risk of relapse was also lower in this group. The lower risks of nonrelapse mortality and relapse resulted in lower overall mortality rates among the Japanese patients. In conclusion, our data indicate that irrespective of graft source, the risk of severe acute GVHD is lower in Japanese patients, resulting in a lower risk of nonrelapse mortality. PMID- 26762685 TI - Synthesis, conformation and antiproliferative activity of isothiazoloisoxazole 1,1-dioxides. AB - Sixteen new isothiazoloisoxazole 1,1-dioxides, one new isothiazolotriazole and one new isothiazolopyrazole have been synthesised by using 1,3-dipolar cycloadditions to isothiazole 1,1-dioxides. One sub-set of these isothiazoloisoxazoles showed low MUM activity against a human breast carcinoma cell line, whilst a second sub-set plus the isothiazolotriazole demonstrated an interesting restricted rotation of sterically hindered bridgehead substituents. A thiazete 1,1-dioxide produced from one of the isothiazole 1,1-dioxides underwent conversion into an unknown 1,2,3-oxathiazolin-2-oxide upon treatment with Lewis acids, but was inert towards 1,3-dipoles and cyclopropenones. Six supporting crystal structures are included. PMID- 26762686 TI - Noninvasive and repetitive measurement of cellular metabolite from human osteosarcoma cells (MG-63) using 3.0 tesla proton (1 H) MR spectroscopy. AB - PURPOSE: This study suggests a noninvasive and repetitive measurement method using 1 H magnetic resonance spectroscopy to monitor changes in cellular metabolites within a single sample. METHODS: Longitudinal acquisition of cellular metabolites from three-dimensional cultured human osteosarcoma (MG-63) cells was conducted using 3.0 Tesla 1 H MRS for 2 weeks at three time points: days 1, 7, and 14. During the MR spectroscopy (MRS) scan, cell specimen temperatures were kept constant at 37 degrees C by a lab-developed magnetic resonance compatible thermostatic device. A DNA assay and live/dead staining of the cell specimens were carried out at each time point to verify the MRS measurements. RESULTS: Cell viability in the proposed device did not significantly differ from that of cells in a conventional incubator (P = 0.946). Cell proliferation and choline concentration increased during the first week, but remained constant during the second week. Lactate did not change during the first week, but increased during the second week. Likewise, cell viability remained constant until day 7, then decreased. CONCLUSION: The proposed MRS technique results in a survivable environment for longitudinal studies of cells and provides a new way to measure metabolomic changes over time in single specimens of cells. Magn Reson Med 76:1912-1918, 2016. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26762687 TI - Enhancement of nucleation of protein crystals on nano-wrinkled surfaces. AB - The synthesis of high quality protein crystals is essential for determining their structure. Hence the development of strategies to facilitate the nucleation of protein crystals is of prime importance. Recently, Ghatak and Ghatak [Langmuir 2013, 29, 4373] reported heterogeneous nucleation of protein crystals on nano wrinkled surfaces. Through a series of experiments on different proteins, they were able to obtain high quality protein crystals even at low protein concentrations and sometimes without the addition of a precipitant. In this study, the mechanism of protein crystal nucleation on nano-wrinkled surfaces is studied through Monte Carlo simulations. The wrinkled surface is modeled by a sinusoidal surface. Free-energy barriers for heterogeneous crystal nucleation on flat and wrinkled surfaces are computed and compared. The study reveals that the enhancement of nucleation is closely related to the two step nucleation process seen during protein crystallization. There is an enhancement of protein concentration near the trough of the sinusoidal surface which aids in nucleation. However, the high curvature at the trough acts as a deterrent to crystal nucleus formation. Hence, significant lowering of the free-energy barrier is seen only if the increase in the protein concentration at the trough is very high. PMID- 26762689 TI - Lycopene reduces mortality in people with systemic lupus erythematosus: A pilot study based on the third national health and nutrition examination survey. AB - INTRODUCTION: Persistent inflammation and oxidative stress are the main mechanisms that increase the risks of cardiovascular disease-related morbidity and mortality in systemic lupus erythematosus (SLE). As a natural antioxidant, lycopene can alleviate oxidative stress and suppress inflammation. We hypothesized that lycopene could have the potential to reduce mortality in SLE. METHOD: Thirty-seven participants with SLE from the NHANES III were divided into two groups (higher level group and lower level group) by rank method according to serum lycopene. These participants were followed-up from the date of interview (1988-1994) to 31 December 2006 for mortality. Mortality rate and survival function were compared between the two SLE groups. RESULTS: The mortality rate was significantly lower in the higher level group (5.3%) than that in the lower level group (33.3%). There was a significant survival difference between the higher level group and the lower level group (Log rank p = 0.0436). In addition, cardiovascular disease-related mortality was dramatically lower in the higher level group than that in the lower level group. CONCLUSIONS: These findings from nationally representative samples indicate that higher serum lycopene has the protective effect on mortality in SLE. Further studies with large sample size are needed to confirm these primary results. PMID- 26762690 TI - Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome. AB - Hunter syndrome or mucopolysaccharidosis type II (MPSII) is caused by pathogenic variants in the IDS gene. This is the first study that examines the mutational spectrum in 25 unrelated Mexican MPSII families. The responsible genotype was identified in 96% of the families (24/25) with 10 novel pathogenic variants: c.133G>C, c.1003C>T, c.1025A>C, c.463_464delinsCCGTATAGCTGG, c.754_767del, c.1132_1133del, c.1463del, c.508-1G>C, c.1006+1G>T and c.(-217_103del). Extensive IDS gene deletions were identified in four patients; using DNA microarray analysis two patients showed the loss of the entire AFF2 gene, and epilepsy developed in only one of them. Wide allelic heterogeneity was noted, with large gene alterations (e.g. IDS/IDSP1 gene inversions, partial to extensive IDS deletions, and one chimeric IDS-IDSP1 allele) that occurred at higher frequencies than previously reported (36% vs 18.9-29%). The frequency of carrier mothers (80%) is consistent with previous descriptions (>70%). Carrier assignment allowed molecular prenatal diagnoses. Notably, somatic and germline mosaicism was identified in one family, and two patients presented thrombocytopenic purpura and pancytopenia after idursulfase enzyme replacement treatment. Our findings suggest a wide allelic heterogeneity in Mexican MPSII patients; DNA microarray analysis contributes to further delineation of the resulting phenotype for IDS and neighboring loci deletions. PMID- 26762691 TI - Methanogens rapidly transition from methane production to iron reduction. AB - Methanogenesis, the microbial methane (CH4 ) production, is traditionally thought to anchor the mineralization of organic matter as the ultimate respiratory process in deep sediments, despite the presence of oxidized mineral phases, such as iron oxides. This process is carried out by archaea that have also been shown to be capable of reducing iron in high levels of electron donors such as hydrogen. The current pure culture study demonstrates that methanogenic archaea (Methanosarcina barkeri) rapidly switch from methanogenesis to iron-oxide reduction close to natural conditions, with nitrogen atmosphere, even when faced with substrate limitations. Intensive, biotic iron reduction was observed following the addition of poorly crystalline ferrihydrite and complex organic matter and was accompanied by inhibition of methane production. The reaction rate of this process was of the first order and was dependent only on the initial iron concentrations. Ferrous iron production did not accelerate significantly with the addition of 9,10-anthraquinone-2,6-disulfonate (AQDS) but increased by 11-28% with the addition of phenazine-1-carboxylate (PCA), suggesting the possible role of methanophenazines in the electron transport. The coupling between ferrous iron and methane production has important global implications. The rapid transition from methanogenesis to reduction of iron-oxides close to the natural conditions in sediments may help to explain the globally-distributed phenomena of increasing ferrous concentrations below the traditional iron reduction zone in the deep 'methanogenic' sediment horizon, with implications for metabolic networking in these subsurface ecosystems and in past geological settings. PMID- 26762692 TI - Ultrasound Image of Poroid Hidradenoma. PMID- 26762688 TI - [Jean-Jacques Lefrere: A miscarried ambition for blood safety in francophone Africa]. AB - The announcement of the death of Professor Jean-Jacques Lefrere caused considerable emotion and surprise within the francophone Africa blood transfusion research network. The group was created in 2007 in Paris. Each member that works within this group wanted to pay their last respects through dedicated publication for a brilliant researcher and writer. The tribute describes the creation of the group, its goals, its operations, its achievements and the prospects of its activities while emphasizing the essential role that Professor Lefrere played within the group. PMID- 26762694 TI - Plasmonic ridge waveguides with deep-subwavelength outside-field confinements. AB - Subwavelength plasmonic waveguides are the most promising candidates for developing planar photonic circuitry platforms. In this study a subwavelength metallic ridge waveguide is numerically and experimentally investigated. Differing from previous plasmonic waveguides, the metallic strip of the subwavelength ridge waveguide is placed on a thick metal film. It is found that the surface-plasmon-polariton (SPP) waveguide modes result from the coupling of the corner modes in the two ridge corners. The bottom metal film has a great influence on the SPP modes, and nearly all the evanescent fields of the SPP modes are tightly confined outside the ridge waveguide. Simulations show that 50% of the total power flow in the SPP mode can be confined outside the ridge waveguide with an area of only about lambda (2)/20. The propagation length is still about 10 times the plasmon wavelength. Through comparison with a metallic strip placed directly on the dielectric substrate, the proposed ridge waveguide exhibits a much higher sensing performance. This plasmonic ridge waveguide with deep subwavelength outside-field confinements is of significance in a range of nano optics applications, especially in nanosensing. PMID- 26762693 TI - Where Should We Position Antimalarial Drug Combinations in the Management of Refractory Cutaneous Lupus Erythematosus? PMID- 26762695 TI - The many lives of SHH in limb development and evolution. AB - The SHH signaling pathway is essential for proper formation of the limb skeleton, as is required for the survival and expansion of distal chondrogenic progenitor cells. At the same time, SHH is important to specify digit identities along the anterior-posterior axis. Upon gain or loss of activity of the SHH pathway, bones are gained, lost or malformed, and such deregulation underlies the aetiology of various human congenital limb defects. Likewise, accumulating evidence suggests that evolutionary tampering with SHH signaling underlies the morphological diversification of the tetrapod appendicular skeleton. This review summarizes the roles of the SHH pathway in the context of limb development and evolution and incorporates recent evidence into a mechanistic view of how the positioning of digit condensations is integrated with the specification of distinct bone morphologies. PMID- 26762696 TI - Sperm forward motility is negatively affected by short-term exposure to altitude hypoxia. AB - Human exposure to altitude is a model to study the role of oxygen in different areas of physiology and pathophysiology. The aim of this study was to evaluate whether a short exposure to hypoxia (5 days) combined with exercise, at altitude ranging from 900 m above sea level to 5895 m above sea level (Kilimanjaro Expedition) can modify seminal and reproductive hormonal parameter levels in human beings. During the ascent, blood oxygen saturation at 3.848 m above sea level was found to be decreased when compared to sea level (P < 0.02). The sperm forward motility at sea level after the expedition showed a significant reduction (P < 0.02). There were no changes in other seminal parameters among those compared. Determination of the hormonal plasma concentrations showed that baseline values of follicle-stimulating hormone, total testosterone, prolactin and oestradiol were unchanged at sea level after the hypoxic experience, with respect to baseline values at sea level. On the other hand, luteinising hormone levels after altitudes trekking significantly increased compared to levels before the expedition (P < 0.05). Because of the short-term exposure, we can assume that the reduced forward motility described here may result from the effects of the acute altitude hypoxia on spermatozoa during the epididymal transit where they mature acquiring their motility. PMID- 26762697 TI - Suicide in older people: Revisioning new approaches. AB - This discussion paper identifies and examines several tensions inherent in traditional approaches to understanding older people's suicide. Predicted future increases in the absolute number of elderly suicides are subject to careful interpretation due to the underreporting of suicides in older age groups. Furthermore, a significant number of studies of older people's death by suicide examine risk factors or a combination of risk factors in retrospect only, while current approaches to suicide prevention in the elderly place disproportionate emphasis on the identification and treatment of depression. Taken together, such tensions give rise to a monologic view of research and practice, ultimately limiting our potential for understanding older people's experience of suicide and suicidal behaviour. New approaches are necessary if we are to move beyond the current narrow focus that prevails. Fresh thinking, which draws on older people's experience of attempting to die by suicide, might offer critical insight into socially-constructed meanings attributed to suicide and suicidal behaviour by older people. Specifically, identification through research into the protective mechanisms that are relevant and available to older people who have been suicidal is urgently needed to effectively guide mental health nurses and health-care professionals in therapeutic engagement and intervention. PMID- 26762699 TI - The effect of acute alcohol on motor-related EEG asymmetries during preparation of approach or avoid alcohol responses. AB - Alcohol-approach tendencies have been associated with heavy drinking and play a role in the transition to alcohol abuse. Such cognitive biases might predict future alcohol use better under a low dose of alcohol. The aim of this prospective study was to investigate both the magnitude and the predictive power of alcohol-induced changes on approach-avoidance bias and bias-related cortical asymmetries during response preparation across heavy and light drinking adolescents. In heavy drinking adolescents greater approach-related asymmetry index in the beta-band was observed for soft-drink cues compared to alcohol ones and this increase was associated with increase in difficulty to regulate alcohol intake. Earlier findings demonstrated that young heavy drinkers hold both positive and negative implicit alcohol associations, reflecting an ambiguity towards alcohol. The increase in approach related beta-lateralization for soft drink cues measured in this study may represent a compensatory effort for the weaker S-R mapping (approaching soft drink). The MRAA findings in this study may highlight a mechanism related to overcompensation due to ambivalent attitudes towards drinking in our heavy drinking sample who had greater problems to limit their alcohol intake compared to light drinkers. Moreover, a relatively strong approach soft-drink and weak approach alcohol reaction-time bias after alcohol predicted decreasing drinking; suggesting that the capacity to control the bias under alcohol could be a protective factor. PMID- 26762698 TI - Transition From Heparin to Citrate Anticoagulation for Continuous Renal Replacement Therapy: Safety, Efficiency, and Cost. AB - Regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT) has recently been recommended as first-line over heparin. Evidence suggests that RCA prolongs filter life and may reduce bleeding risk, but there is little research on the benefits to dialysis dose delivery or cost, or the effectiveness of transitioning to RCA first-line. The aim of the present study was to assess the effect on dialysis delivery, cost and safety when transitioning from systemic heparin to RCA for first-line anticoagulation for CRRT. A single center, retrospective observational study was conducted from 2006 to 2012, during which a transition from heparin to a simplified RCA protocol occurred. Demographic and dialysis data, pathology results and costs were obtained. Data were analyzed for both heparin and RCA, and for before and after the transition. 166 patients had 992 dialysis days (heparin 334 vs. RCA 658); demographics were well matched; RCA used less filters per day (P = 0.03), had more days when prescribed dialysis was achieved (85% vs. 60%, P < 0.001), and less filter "down time" per day (2.4 vs. 6.1 h, P = 0.02). RCA was estimated to cost AU$487 per day, compared to heparin at $479 per day. When the data were analyzed, comparing before and after the transition, these results remained statistically significant. There was no statistical difference in clinical safety events. Transition to first-line RCA was safe, provided more time on filter and consumed less filter circuits using a simple and user friendly protocol. The adjusted cost difference appears negligible. PMID- 26762700 TI - The effect of alexithymia on early visual processing of emotional body postures. AB - Body postures convey emotion and motion-related information useful in social interactions. Early visual encoding of body postures, reflected by the N190 component, is modulated both by motion (i.e., postures implying motion elicit greater N190 amplitudes than static postures) and by emotion-related content (i.e., fearful postures elicit the largest N190 amplitude). At a later stage, there is a fear-related increase in attention, reflected by an early posterior negativity (EPN) (Borhani et al., 2015). Here, we tested whether difficulties in emotional processing (i.e., alexithymia) affect early and late visual processing of body postures. Low alexithymic participants showed emotional modulation of the N190, with fearful postures specifically enhancing N190 amplitude. In contrast, high alexithymic participants showed no emotional modulation of the N190. Both groups showed preserved encoding of the motion content. At a later stage, a fear related modulation of the EPN was found for both groups, suggesting that selective attention to salient stimuli is the same in both low and high alexithymia. PMID- 26762701 TI - Buckling of an elastic fiber with finite length in a soft matrix. AB - Elastic fibers embedded in a soft matrix are frequently encountered in nature and engineering across different length scales, ranging from microtubules in cytosol and filament networks to dissociative slender fish bones in muscles and fiber reinforced soft composites. Fibers may buckle when the composite is subjected to compression; this study investigates this issue through a combination of experiments, finite-element simulations and theoretical analysis. Analysis reveals the important role of the interfacial shear forces and leads to an explicit solution to predict the occurrence of buckling for a slender fiber with finite length. The results reported in this paper will help understand the formation of shapes in some natural systems and provide guidelines for the design of soft biocomposites. PMID- 26762702 TI - Accelerated exponential parameterization of T2 relaxation with model-driven low rank and sparsity priors (MORASA). AB - PURPOSE: This work is to develop a novel image reconstruction method from highly undersampled multichannel acquisition to reduce the scan time of exponential parameterization of T2 relaxation. THEORY AND METHODS: On top of the low-rank and joint-sparsity constraints, we propose to exploit the linear predictability of the T2 exponential decay to further improve the reconstruction of the T2-weighted images from undersampled acquisitions. Specifically, the exact rank prior (i.e., number of non-zero singular values) is adopted to enforce the spatiotemporal low rankness, while the mixed L2-L1 norm of the wavelet coefficients is used to promote joint sparsity, and the Hankel low-rank approximation is used to impose linear predictability, which integrates the exponential behavior of the temporal signal into the reconstruction process. An efficient algorithm is adopted to solve the reconstruction problem, where corresponding nonlinear filtering operations are performed to enforce corresponding priors in an iterative manner. RESULTS: Both simulated and in vivo datasets with multichannel acquisition were used to demonstrate the feasibility of the proposed method. Experimental results have shown that the newly introduced linear predictability prior improves the reconstruction quality of the T2-weighted images and benefits the subsequent T2 mapping by achieving high-speed, high-quality T2 mapping compared with the existing fast T2 mapping methods. CONCLUSION: This work proposes a novel fast T2 mapping method integrating the linear predictable property of the exponential decay into the reconstruction process. The proposed technique can effectively improve the reconstruction quality of the state-of-the-art fast imaging method exploiting image sparsity and spatiotemporal low rankness. Magn Reson Med 76:1865 1878, 2016. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26762703 TI - [Prognostic value of the metabolically active tumour volume]. AB - PURPOSE: The purpose of this study was to assess the prognostic value of different parameters on pretreatment fluorodeoxyglucose [((18)F)-FDG] positron emission tomography-computed tomography (PET-CT) in patients with localized oesophageal cancer. PATIENTS AND METHOD: We retrospectively reviewed 83 cases of localised oesophageal cancer treated in our institution. Patients were treated with curative intent and have received chemoradiotherapy alone or followed by surgery. Different prognostic parameters were correlated to survival: cancer related factors, patient-related factors and parameters derived from PET-CT (maximum standardized uptake value [SUV max], metabolically active tumor volume either measured with an automatic segmentation software ["fuzzy locally adaptive bayesian": MATVFLAB] or with an adaptive threshold method [MATVseuil] and total lesion glycolysis [TLGFLAB and TLGseuil]). RESULTS: The median follow-up was 21.8 months (range: 0.16-104). The median overall survival was 22 months (95% confidence interval [95%CI]: 15.2-28.9). There were 67 deaths: 49 associated with cancer and 18 from intercurrent causes. None of the tested factors was significant on overall survival. In univariate analysis, the following three factors affected the specific survival: MATVFLAB (P=0.025), TLGFLAB (P=0.04) and TLGseuil (P=0.04). In multivariate analysis, only MATVFLAB had a significant impact on specific survival (P=0.049): MATVFLAB<18 cm(3): 31.2 months (95%CI: 21.7-not reached) and MATVFLAB>18 cm(3): 20 months (95%CI: 11.1-228.9). CONCLUSION: The metabolically active tumour volume measured with the automatic segmentation software FLAB on baseline PET-CT was a significant prognostic factor, which should be tested on a larger cohort. PMID- 26762705 TI - Effects of co-ordination number on the nucleation behaviour in many-component self-assembly. AB - We report canonical and grand-canonical lattice Monte Carlo simulations of the self-assembly of addressable structures comprising hundreds of distinct component types. The nucleation behaviour, in the form of free-energy barriers to nucleation, changes significantly as the co-ordination number of the building blocks is changed from 4 to 8 to 12. Unlike tetrahedral structures - which roughly correspond to DNA bricks that have been studied in experiments - the shapes of the free-energy barriers of higher co-ordination structures depend strongly on the supersaturation, and such structures require a very significant driving force for structure growth before nucleation becomes thermally accessible. Although growth at high supersaturation results in more defects during self-assembly, we show that high co-ordination number structures can still be assembled successfully in computer simulations and that they exhibit self assembly behaviour analogous to DNA bricks. In particular, the self-assembly remains modular, enabling in principle a wide variety of nanostructures to be assembled, with a greater spatial resolution than is possible in low co ordination structures. PMID- 26762704 TI - [Neuroendocrine carcinoma of the bladder: A single centre retrospective study]. AB - PURPOSE: Neuroendocrine carcinoma of the bladder is a rare tumour representing 0.5 to 1% of bladder tumours. It is a specific histological entity characterized by rapid metastatic dissemination and poor prognosis. The aim of this study was to describe the epidemiological, clinical, therapeutic modalities and the evolutive aspects of patients receiving a treatment for bladder neuroendocrine carcinoma. PATIENTS AND METHODS: Between January 2004 and January 2014, seven patients received a treatment for a neuroendocrine carcinoma of the bladder, at the department of oncology, Habib-Bourguiba Hospital, in Sfax, Tunisia. RESULTS: The median age was 58 years. All patients were male. Neuroendocrine carcinoma was pure in four cases and associated with urothelial carcinoma in the other three cases. Two patients were diagnosed at a metastatic stage. A cystectomy was performed in two cases. One patient received a chemotherapy and radiotherapy. The other four patients received chemotherapy alone. A single case of complete remission was observed. Median survival was 15 months (5-30 months). One patient is still alive 30 months after diagnosis. CONCLUSION: The management of neuroendocrine carcinoma of the bladder is not standardized and requires a multidisciplinary consultation. PMID- 26762706 TI - Interobserver reliability of the Australian Spasticity Assessment Scale (ASAS). AB - AIM: The aim of this paper is to present the Australian Spasticity Assessment Scale (ASAS) and to report studies of its interrater reliability. The ASAS identifies the presence of spasticity by confirming a velocity-dependent increased response to rapid passive movement and quantifies it using an ordinal scale. METHOD: The rationale and procedure for the ASAS is described. Twenty-two participants with spastic CP (16 males; age range 1y 11mo-15y 3mo) who had not had botulinum neurotoxin-A within 4 months, or bony or soft tissue surgery within 12 months, were recruited from the spasticity management clinic of a tertiary paediatric teaching hospital. Fourteen muscles in each child were assessed by each of three experienced independent raters. ASAS was recorded for all muscles. Interrater reliability was calculated using the weighted kappa statistic (quadratic weighting; kappaqw) for individual muscles, for upper limbs, for lower limbs, and between raters. RESULTS: The weighted kappa ranged between 0.75 and 0.92 for individual muscle groups and was 0.87 between raters. INTERPRETATION: The ASAS complies with the definition of spasticity and is clinically feasible in paediatric settings. Our estimates of interrater reliability for the ASAS exceed that of the most commonly used spasticity scoring systems. PMID- 26762708 TI - Nonodontogenic "tooth pain" of nose and sinus origin. PMID- 26762707 TI - Clinical practice guidelines for oral management of Sjogren disease: Dental caries prevention. AB - BACKGROUND: Salivary dysfunction in Sjogren disease can lead to serious and costly oral health complications. Clinical practice guidelines for caries prevention in Sjogren disease were developed to improve quality and consistency of care. METHODS: A national panel of experts devised clinical questions in a Population, Intervention, Comparison, Outcomes format and included use of fluoride, salivary stimulants, antimicrobial agents, and nonfluoride remineralizing agents. The panel conducted a systematic search of the literature according to pre-established parameters. At least 2 members extracted the data, and the panel rated the strength of the recommendations by using a variation of grading of recommendations, assessment, development, and evaluation. After a Delphi consensus panel was conducted, the experts finalized the recommendations, with a minimum of 75% agreement required. RESULTS: Final recommendations for patients with Sjogren disease with dry mouth were as follows: topical fluoride should be used in all patients (strong); although no study results link improved salivary flow to caries prevention, the oral health community generally accepts that increasing saliva may contribute to decreased caries incidence, so increasing saliva through gustatory, masticatory, or pharmaceutical stimulation may be considered (weak); chlorhexidine administered as varnish, gel, or rinse may be considered (weak); and nonfluoride remineralizing agents may be considered as an adjunct therapy (moderate). CONCLUSIONS AND PRACTICAL IMPLICATIONS: The incidence of caries in patients with Sjogren disease can be reduced with the use of topical fluoride and other preventive strategies. PMID- 26762711 TI - Ammonia gas sensors based on poly (3-hexylthiophene)-molybdenum disulfide film transistors. AB - In this work, in order to enhance the recovery performance of organic thin film transistors (OTFTs) ammonia (NH3) sensors, poly (3-hexylthiophene) (P3HT) and molybdenum disulfide (MoS2) were combined as sensitive materials. Different sensitive film structures as active layers of OTFTs, i.e., P3HT-MoS2 composite film, P3HT/MoS2 bilayer film and MoS2/P3HT bilayer film were fabricated by spray technology. OTFT gas sensors based on P3HT-MoS2 composite film showed a shorter recovery time than others when the ammonia concentration changed from 4 to 20 ppm. Specifically, x-ray diffraction (XRD), Raman and UV-visible absorption were employed to explore the interface properties between P3HT and single-layer MoS2. Through the complementary characterization, a mechanism based on charge transfer is proposed to explain the physical originality of these OTFT gas sensors: closer interlayer d-spacing and better pi-pi stacking of the P3HT chains in composite film have ensured a short recovery time of OTFT gas sensors. Moreover, sensing mechanisms of OTFTs were further studied by comparing the device performance in the presence of nitrogen or dry air as a carrier gas. This work not only strengthens the fundamental understanding of the sensing mechanism, but provides a promising approach to optimizing the OTFT gas sensors. PMID- 26762709 TI - Interleukin-21 administration to aged mice rejuvenates their peripheral T-cell pool by triggering de novo thymopoiesis. AB - The vaccination efficacy in the elderly is significantly reduced compared to younger populations due to thymic involution and age-related intrinsic changes affecting their naive T-cell compartment. Interleukin (IL)-21 was recently shown to display thymostimulatory properties. Therefore, we hypothesized that its administration to ageing hosts may improve T-cell output and thus restore a competent peripheral T-cell compartment. Indeed, an increase in the production of recent thymic emigrants (RTEs) attributable to intrathymic expansion of early thymic progenitors (ETPs), double-negative (DN), and double-positive (DP) thymocytes as well as thymic epithelial cell (TEC) was observed in recombinant (r)IL-21-treated aged mice. In sharp contrast, no alterations in the frequency of bone marrow (BM)-derived progenitors were detected following rIL-21 administration. Enhanced production of naive T cells improved the T-cell receptor (TCR) repertoire diversity and re-established a pool of T cells exhibiting higher levels of miR-181a and diminished amounts of the TCR-inhibiting phosphatases SHP 2 and DUSP5/6. As a result, stimulation of T cells derived from rIL-21-treated aged mice displayed enhanced activation of Lck, ZAP-70, and ERK, which ultimately boosted their IL-2 production, CD25 expression, and proliferation capabilities in comparison with T cells derived from control aged mice. Consequently, aged rIL-21 treated mice vaccinated using a tyrosinase-related protein 2 (Trp2)-derived peptide exhibited a substantial delay in B16 tumor growth and improved survival. The results of this study highlight the immunorestorative function of rIL-21 paving its use as a strategy for the re-establishment of effective immunity in the elderly. PMID- 26762712 TI - Assessing Radiology's Public Perception: Has Dr Emanuel Changed His View of Radiologists? PMID- 26762710 TI - Benefit of adjunctive tacrolimus in connective tissue disease-interstitial lung disease. AB - We evaluated the safety and effectiveness of adjunctive tacrolimus therapy with conventional immunosuppression in patients with severe connective tissue disease related interstitial lung disease (CTD-ILD). We included patients from our interstitial lung disease (ILD) registry with CTD-ILD, in whom tacrolimus was added to corticosteroids and an additional immunosuppressive agent. Demographic data, clinical features, lung function, radiographic images, and pathologic findings were reviewed. Effectiveness was assessed by comparing pulmonary function tests (PFTs) closest to tacrolimus initiation to PFTs approximately 6-12 months later. Corticosteroid dose at these time points was also evaluated. We report adverse events attributed to tacrolimus. Seventeen patients with CTD-ILD were included in adverse event analysis; twelve were included in efficacy analysis. Length of tacrolimus therapy ranged from 6 to 110 months (mean 38.8 months +/- 31.4). The mean improvement in percent predicted total lung capacity was 7.5% +/- 11.7 (p = 0.02). Forced vital capacity mean improvement was 7.4% +/- 12.5 (p = 0.06). The average decrease in corticosteroid dose at follow-up was 20.3 mg +/- 25.2 (p = 0.02) with complete discontinuation in six patients. No patients experienced a life-threatening adverse event attributed to tacrolimus. Tacrolimus can be effective and is well tolerated as an adjunctive therapy and allows tapering of corticosteroids. PMID- 26762713 TI - Duplicate Publication. PMID- 26762714 TI - Re: "Recommend Clinical Correlation: A Common but Meaningless Phrase in Radiology Reporting". PMID- 26762715 TI - "Speaking of Language". PMID- 26762716 TI - Author's Reply. PMID- 26762717 TI - Sticks and Stones Can Break Your Bones, Words Can Also Hurt You. PMID- 26762718 TI - Introduction of Thoracic CT-Guided Fine-Needle Aspiration to a Resource-Limited Radiology Department in Addis Ababa, Ethiopia. PMID- 26762719 TI - Correction of Metabolic Alkalosis and Elevated Calcium Levels by Sodium Chloride in a Hemodialysis Patient With Inadequate Chloride Intake. PMID- 26762720 TI - An improved course of glycaemia after a bread based breakfast is associated with beneficial effects on acute and semi-acute markers of appetite. AB - The prevalence of type 2 diabetes mellitus is rapidly increasing all over the world and a diet promoting reduced glycaemic excursions in the postprandial phase may help to prevent the disease. In the present study guar gum (GG) and whole grain rye flour or high amylose maize starch (HAM) was combined to design bread products giving low and sustained glycaemia. A meal study was performed with young, healthy subjects and in addition to glucose and insulin, also subjective appetite ratings and biomarkers of appetite, voluntary energy intake at a second meal and markers of fermentation were studied. The combination of GG and rye was superior with improvements in subjective appetite whereas both test products lead to improvements in biomarkers of appetite compared to the white wheat bread reference. The inclusion of GG, rye and/or HAM in bread products show great potential in lowering risk factors associated with insulin resistance and improving acute and semi-acute appetite. PMID- 26762721 TI - Accuracy of transcutaneous bilirubin measured by the BiliCare device in late preterm and term neonates. AB - OBJECTIVE: The objective of this study is to explore the accuracy and performance of a new transcutaneous bilirubinometer (TCB) for the screening of jaundice in late preterm and term infants. METHODS: A cross-sectional study was conducted. TCB measurements were performed using the BiliCare(TM) bilirubinometer. Paired TCB and serum bilirubin (SB) measurements were analysed. RESULTS: One hundred and fourteen paired samples were collected from 93 healthy late preterm and term infants. Bilirubin measurements were done at median (interquartile range) of 50.5 (34, 72) hours. The mean (SD) difference between the TCB and SB was 1.87 (1.98) mg/dL. A TCB cut-off level at 8.0 mg/dL provides a sensitivity of 97.3% with a negative predictive value (NPV) of 87.5% to detect a SB level of at least 8.0 mg/dL. For SB levels of at least 10.0 mg/dL, a TCB cut-off at 9.0 mg/dL shows a sensitivity of 97.5%; NPV 95.4%. For a SB level of at least 13.0 mg/dL, a TCB cut off at 12 or 13 mg/dL had a sensitivity of 92.9% and NPV of 98.7%. CONCLUSION: The BiliCare(TM) demonstrated good performance with positive bias for the screening of jaundice in healthy late preterm or term infants. However, if adopted, proper cut-off levels should be chosen because of sub-optimal device precision. PMID- 26762722 TI - Aluminum and bone: Review of new clinical circumstances associated with Al(3+) deposition in the calcified matrix of bone. AB - Several decades ago, aluminum encephalopathy associated with osteomalacia has been recognized as the major complication of chronic renal failure in dialyzed patients. Removal of aluminum from the dialysate has led to a disappearance of the disease. However, aluminum deposit occurs in the hydroxyapatite of the bone matrix in some clinical circumstances that are presented in this review. We have encountered aluminum in bone in patients with an increased intestinal permeability (coeliac disease), or in the case of prolonged administration of aluminum anti-acid drugs. A colocalisation of aluminum with iron was also noted in cases of hemochromatosis and sickle cell anemia. Aluminium was also identified in a series of patients with exostosis, a frequent benign bone tumor. Corrosion of prosthetic implants composed of grade V titanium (TA6V is an alloy containing 6% aluminum and 4% vanadium) was also observed in a series of hip or knee revisions. Aluminum can be identified in undecalcified bone matrix stained by solochrome azurine, a highly specific stain allowing the detection of 0.03 atomic %. Colocalization of aluminum and iron does not seem to be the fruit of chance but the cellular and molecular mechanisms are still poorly understood. Histochemistry is superior to spectroscopic analyses (EDS and WDS in scanning electron microscopy). PMID- 26762724 TI - Usefulness of New-Onset Atrial Fibrillation, as a Strong Predictor of Heart Failure and Death in Patients With Native Left-Sided Infective Endocarditis. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia in adults and has been independently related to increased morbidity and mortality. AF is a frequent arrhythmia in infective endocarditis (IE). Nevertheless, there are no data on how AF affects the clinical outcome of patients with endocarditis. Our purpose was to investigate patient characteristics, microbiology, echocardiographic findings, in hospital course, and prognosis of patients with IE who develop new-onset AF (NAF) and compare them with those who remained in sinus rhythm (SR) or had previous AF (PAF). From 1997 to 2014, 507 consecutive patients with native left-sided IE were prospectively recruited at 3 tertiary care centers. We distinguished 3 groups according to the type of baseline heart rhythm during hospitalization and previous history of AF: NAF group (n = 52), patients with no previous history of AF and who were diagnosed as having NAF during hospitalization; SR group (n = 380), patients who remained in SR; and PAF group (n = 75), patients with PAF. Patients with NAF were older than those who remained in SR (68.3 vs 59.6 years, p <0.001). At admission, heart failure was more common in NAF group (53% vs 34.3%, p <0.001), whereas stroke (p = 0.427) was equally frequent in all groups. During hospitalization, embolic events occurred similarly (p = 0.411). In the multivariate analysis, NAF was independently associated with heart failure (odds ratio 3.56, p <0.01) and mortality (odds ratio 1.91, p = 0.04). In conclusion, the occurrence of NAF in patients with IE was strongly associated with heart failure and higher in-hospital mortality independently from other relevant clinical variables. PMID- 26762723 TI - Use of Coronary Computed Tomographic Angiography Findings to Modify Statin and Aspirin Prescription in Patients With Acute Chest Pain. AB - Coronary CT angiography (CCTA) is used in patients with low-intermediate chest pain presenting to the emergency department for its reliability in excluding acute coronary syndrome (ACS). However, its influence on medication modification in this setting is unclear. We sought to determine whether knowledge of CCTA based coronary artery disease (CAD) was associated with change in statin and aspirin prescription. We used the CCTA arm of the Rule Out Myocardial Infarction using Computed Angiographic Tomography II multicenter, randomized control trial (R-II) and comparison cohort from the observational Rule Out Myocardial Infarction using Computed Angiographic Tomography I cohort (R-I). In R-II, subjects were randomly assigned to CCTA to guide decision making, whereas in R-I patients underwent CCTA with results blinded to caregivers and managed according to standard care. Our final cohort consisted of 277 subjects from R-I and 370 from R-II. ACS rate was similar (6.9% vs 6.2% respectively, p = 0.75). For subjects with CCTA-detected obstructive CAD without ACS, initiation of statin was significantly greater after disclosure of CCTA results (0% in R-I vs 20% in R-II, p = 0.009). Conversely, for subjects without CCTA-detected CAD, aspirin prescription was lower with disclosure of CCTA results (16% in R-I vs 4.8% in R II, p = 0.001). However, only 68% of subjects in R-II with obstructive CAD were discharged on statin and 65% on aspirin. In conclusion, physician knowledge of CCTA results leads to improved alignment of aspirin and statin with the presence and severity of CAD although still many patients with CCTA-detected CAD are not discharged on aspirin or statin. Our findings suggest opportunity for practice improvement when CCTA is performed in the emergency department. PMID- 26762725 TI - Relation of Activated Clotting Times During Percutaneous Coronary Intervention to Outcomes. AB - Monitoring anticoagulation using the activated clotting time (ACT) in patients treated with heparin and undergoing percutaneous coronary intervention (PCI) is one of the most frequently used tests in invasive cardiology. However, despite its widespread use and guideline endorsement, uncertainty remains regarding the association of ACT with outcomes in contemporary practice. We reviewed all PCI procedures performed at the Mayo Clinic (Rochester, Minnesota) from October 2001 to December 2012 and evaluated the association between the ACT before device activation and in-hospital and 1-year outcomes. ACT values were grouped into tertiles for descriptive purposes and analyzed as a continuous variable for assessment of outcomes. We used logistic and Cox proportional hazards regression models to estimate the association of ACT and outcomes. Of the 12,055 patients who underwent PCI with an ACT value before device activation, 3,977 (33.0%) had an ACT <227, 4,046 (33.6%) had an ACT 227 to 285, and 4,032 (33.4%) had an ACT >285. Baseline and procedural characteristics were similar across ACT tertiles. In unadjusted analysis, higher ACT values were associated with death (p <0.001), bleeding (p = 0.024), procedural complication (p <0.001), and higher 1-year events (cardiac death, p <0.001; cardiac death/myocardial infarction, p = 0.022). After multivariable adjustment for baseline and procedural characteristics, ACT was not independently associated with in-hospital or 1-year ischemic, thrombotic, or bleeding outcomes. In conclusion, ACT values before device activation are not independently associated with clinically important outcomes in contemporary PCI practice. PMID- 26762728 TI - Molecular Imaging of Native Low-Density Lipoprotein by Near-Infrared Fluorescent Angioscopy in Human Coronary Plaques. AB - Low-density lipoprotein (LDL) is an important risk factor for coronary artery disease, but its localization within the human coronary arterial wall is poorly understood. Imaging of LDL in 30 coronary arteries excised from 15 subjects who underwent autopsy was performed using near-infrared fluorescent angioscopy system and using indocyanine green dye as a biomarker of LDL. The percentage incidence of LDL in 28 normal segments, 24 white plaques (early stage of plaque growth), and 21 yellow plaques (mature stage of plaque) classified by conventional angioscopy, was 14.2, 79.1 (p <0.01 vs normal segments and p <0.05 vs yellow plaques), and 28.5, respectively. Coronary near-infrared fluorescent angioscopy showed similar results in 7 patients in vivo. Our results suggested that LDL begins to deposit in the human coronary arterial wall in the early stage of atherosclerosis, increasingly deposits with plaque growth and decreases in the mature stage; and therefore, molecular therapy targeting LDL should be started before plaque maturation. PMID- 26762726 TI - Clinical Characteristics, Management, and Outcomes of Acute Coronary Syndrome in Patients With Right Bundle Branch Block on Presentation. AB - We examined the relations between right bundle branch block (RBBB) and clinical characteristics, management, and outcomes among a broad spectrum of patients with acute coronary syndrome (ACS). Admission electrocardiograms of patients enrolled in the Global Registry of Acute Coronary Events (GRACE) electrocardiogram substudy and the Canadian ACS Registry I were analyzed independently at a blinded core laboratory. We performed multivariable logistic regression analysis to assess the independent prognostic significance of admission RBBB on in-hospital and 6-month mortality. Of 11,830 eligible patients with ACS (mean age 65; 66% non ST-elevation ACS), 5% had RBBB. RBBB on admission was associated with older age, male sex, more cardiovascular risk factors, worse Killip class, and higher GRACE risk score (all p <0.01). Patients with RBBB less frequently received in-hospital cardiac catheterization, coronary revascularization, or reperfusion therapy (all p <0.05). The RBBB group had higher unadjusted in-hospital (8.8% vs 3.8%, p <0.001) and 6-month mortality rates (15.1% vs 7.6%, p <0.001). After adjusting for established prognostic factors in the GRACE risk score, RBBB was a significant independent predictor of in-hospital death (odds ratio 1.45, 95% CI 1.02 to 2.07, p = 0.039), but not cumulative 6-month mortality (odds ratio 1.29, 95% CI 0.95 to 1.74, p = 0.098). There was no significant interaction between RBBB and the type of ACS for either in-hospital or 6-month mortality (both p >0.50). In conclusion, across a spectrum of ACS, RBBB was associated with preexisting cardiovascular disease, high-risk clinical features, fewer cardiac interventions, and worse unadjusted outcomes. After adjusting for components of the GRACE risk score, RBBB was a significant independent predictor of early mortality. PMID- 26762727 TI - Three-Year Outcomes of Transcatheter Aortic Valve Implantation in Patients With Varying Levels of Surgical Risk (from the CoreValve ADVANCE Study). AB - This study compared 3-year clinical outcomes of patients who underwent transcatheter aortic valve implantation with the Society of Thoracic Surgeons (STS) score <=7% to those of patients with a score >7%. Data were drawn from the ADVANCE study, a multinational post-market clinical trial that enrolled real world patients with severe aortic stenosis treated with the CoreValve bioprosthesis. Events were independently adjudicated using Valve Academic Research Consortium-1 definitions. A total of 996 patients were implanted: STS <=7% (n = 697, median STS 4.3%, interquartile range 3.1% to 5.4%) and STS >7% (n = 298, median STS 9.7%, interquartile range 8.0% to 12.4%). At 3 years, the STS <=7% group had lower rates of all-cause mortality (28.6 vs 45.9, p <0.01) and cardiovascular mortality (19.0 vs 30.2, p <0.01) than the STS >7% group. No differences were observed in cerebrovascular accidents, vascular complications, bleeding, or myocardial infarction. In patients with STS <=7%, mortality at 3 years was higher in those with moderate or severe aortic regurgitation (AR) at discharge than in those with mild or less AR (39.9% vs 22.9%; hazard ratio 1.98; 95% confidence interval 1.37 to 2.86; p <0.01). Conversely, the severity of AR at discharge did not affect 3-year mortality in patients with STS >7% (42.9% vs 44.6%, moderate/severe vs mild/less; hazard ratio 1.04; 95% confidence interval, 0.62 to 1.75; p = 0.861; p for interaction = 0.047). In conclusion, patients with STS <=7% had lower rates of all-cause and cardiovascular mortality at 3 years after transcatheter aortic valve implantation. Complication rates were low and stable in both groups, demonstrating the safety of this procedure for patients at various levels of surgical risk. PMID- 26762729 TI - Comparison of the Absorbable Polymer Sirolimus-Eluting Stent (MiStent) to the Durable Polymer Everolimus-Eluting Stent (Xience) (from the DESSOLVE I/II and ISAR-TEST-4 Studies). AB - We compared the outcomes of a novel, thin-strut, cobalt-chromium, absorbable, polymer sirolimus-eluting stent (APSES; MiStent) to the durable polymer cobalt chromium everolimus-eluting stent (EES; Xience). A propensity-matched analysis was performed comparing data from the DES With Sirolimus and a Bioabsorbable Polymer for the Treatment of Patients With De Novo Lesions in the Native Coronary Arteries (DESSOLVE) I and II studies, evaluating the APSES to the EES arm of the Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents-4 study. Target lesion failure (TLF) and its components were evaluated at 12 months and annually to 3 years; 805 patients (APSES = 153; EES = 652) were included with propensity matching in 204 patients (APSES = 102; EES = 102). APSES compared with EES had lower TLF at 1 year (3.0% vs 8.0%, p = 0.12) driven by a difference in target lesion revascularization (TLR; 1% vs 6%, p = 0.05), with no difference in target vessel myocardial infarction (p = 0.56) or stent thrombosis (p = 0.31). At 3 years, TLF (5.0% vs 12.5%, p = 0.07) and TLR (2.0% vs 8.4%, p = 0.04) remained lower with APSES. By landmark analysis, there was no significant difference in TLF between 1 and 3 years (p = 0.36). In conclusion, in a propensity-matched analysis, the APSES demonstrated reduced clinically indicated TLR rates at 1 and 3 years compared with the durable polymer EES, with minimal accrual of events between 1 and 3 years. PMID- 26762732 TI - Chloride (Cl(-)) ion-mediated shape control of palladium nanoparticles. AB - The shape control of Pd nanoparticles is investigated using chloride (Cl(-)) ions as capping agents in an aqueous medium in the temperature range of 60-100 degrees C. With weakly adsorbing and strongly etching Cl(-) ions, oxygen plays a crucial role in shape control. The experimental factors considered are the concentration of the capping agents, reaction time and reaction atmosphere. Thus, Pd nanoparticles of various shapes with high selectivity can be synthesized. Moreover, the removal of Cl(-) ions from the nanoparticle surface is easier than that of Br(-) ions (moderately adsorbing and etching) and I(-) ions (strongly adsorbing and weakly etching). The cleaned Cl(-) ion-mediated shape-controlled Pd nanoparticles are electrochemically characterized and the order of the half-wave potential of the oxygen reduction reaction in oxygen-saturated 0.1 M HClO4 solution is of the same order as that observed with single-crystal Pd surfaces. PMID- 26762730 TI - Long-Term Performance of the Riata/ST Implantable Cardioverter-Defibrillator Lead. AB - Riata and Riata ST implantable cardioverter-defibrillator leads are prone to structural and electrical failure (EF). Our objective was to evaluate Riata/ST lead performance over a long-term follow-up. Of 184 patients having undergone Riata/ST and Riata ST Optim lead implantation from September 2003 to June 2008, 154 patients were evaluated for EF and radiographic conductor externalization (CE). Survival analysis for EF was performed for Riata/ST leads, both for failure free lead survival and cumulative hazard. Subanalysis on 7Fr leads was performed to evaluate EF and CE rates both for different Riata ST lead management (monitoring vs proactive) and between Riata ST and Riata ST Optim leads. During a mean follow-up of 7 years, Riata/ST lead EF rate was 13% overall. Similar failure free survival rate was noted for 7Fr as for 8Fr leads (log-rank, p = 0.63). Of all failed leads, 64% failed only after 5 years of follow-up. Compared with the absolute failure rate of 1.84% per device year, cumulative hazard analysis for leads surviving past 5 years revealed an estimated failure rate of 7% per year. No clinical or procedural predictors for EF were found. The subanalysis on 7Fr leads showed an excellent outcome both for a proactive lead management approach as for Optim leads. In conclusion, long-term survival of the Riata/ST lead is impaired with an accelerating EF risk over time. An initial exponential trend was followed by a linear lead failure pattern for leads surviving past 5 years, corresponding to an estimated 7% annual EF rate. These findings may have repercussions on the lead management strategy in patients currently surviving with a Riata/ST lead to prevent significant clinical events like inappropriate shocks or failed device interventions. PMID- 26762734 TI - The Journal of Thoracic Oncology in the Next Decade. PMID- 26762733 TI - Temporal trends in cerebral palsy by impairment severity and birth gestation. AB - AIM: Our aim was to build on previous research indicating that rates of cerebral palsy (CP) in the Australian state of Victoria are declining, and examine whether severity of impairments is also decreasing. METHOD: Data on individuals with CP were extracted from the Victorian Cerebral Palsy Register for birth years 1983 to 2009. The yearly rates of dichotomized categories for gross motor function, motor laterality, intellectual impairment, and epilepsy per 1000 neonatal survivors and proportions in the CP cohort were tabulated and plotted by birth gestation. Linear regression modelling was used to fit prediction curves; likelihood ratio tests were used to test for differences in trends between impairment severity groups. RESULTS: Since the mid-1990s, CP rates declined in neonatal survivors of birth at all gestations. Our data suggest that the decreasing CP rates were associated with relatively greater decreases in the rates of Gross Motor Function Classification System levels III to V, bilateral CP, epilepsy, and intellectual impairment (all p<0.005). Some variation was seen between birth gestation groups. INTERPRETATION: Declines in rates of CP of all levels of severity and complexity from the mid-1990s provides 'real-world' support for the effectiveness of concurrent neuroprotective strategies and continual innovation in perinatal practices. PMID- 26762735 TI - FGFR Signaling as a Target for Lung Cancer Therapy. AB - Lung cancer is the leading cause of cancer-related death in developed countries. Recently, molecular targeted therapies have shown promising results in the management of lung cancer. These therapies require a clear understanding of the relevant pathways that drive carcinogenesis and maintenance of the malignant phenotype. The fibroblast growth factor receptor (FGFR) signaling axis is one such pathway that plays a central role in normal cellular function. Alterations in this pathway have been found in many cancers. In this review article, we focus on the role of this pathway in lung cancer. We present the molecular structure of FGFR, the interaction of the receptor with its ligands (the fibroblast growth factors), its downstream signaling, and aberrations in the FGFR pathway. We also discuss clinical trials involving selective and multikinase FGFR inhibitors in lung cancer treatment. PMID- 26762731 TI - Age-related changes in miR-143-3p:Igfbp5 interactions affect muscle regeneration. AB - A common characteristic of aging is defective regeneration of skeletal muscle. The molecular pathways underlying age-related decline in muscle regenerative potential remain elusive. microRNAs are novel gene regulators controlling development and homeostasis and the regeneration of most tissues, including skeletal muscle. Here, we use satellite cells and primary myoblasts from mice and humans and an in vitro regeneration model, to show that disrupted expression of microRNA-143-3p and its target gene, Igfbp5, plays an important role in muscle regeneration in vitro. We identified miR-143 as a regulator of the insulin growth factor-binding protein 5 (Igfbp5) in primary myoblasts and show that the expression of miR-143 and its target gene is disrupted in satellite cells from old mice. Moreover, we show that downregulation of miR-143 during aging may act as a compensatory mechanism aiming at improving myogenesis efficiency; however, concomitant upregulation of miR-143 target gene, Igfbp5, is associated with increased cell senescence, thus affecting myogenesis. Our data demonstrate that dysregulation of miR-143-3p:Igfbp5 interactions in satellite cells with age may be responsible for age-related changes in satellite cell function. PMID- 26762736 TI - Radiotherapeutic Management of Non-Small Cell Lung Cancer in the Minimal Resource Setting. AB - Lung cancer is the most common cancer worldwide and the fifth most common cause of death globally. Its incidence continues to increase, especially within low- and middle-income countries (LMICs), which have limited capacity to address the growing need for treatment. The standard of care for lung cancer treatment often involves radiation therapy (RT), which plays an important therapeutic role in curative-intent treatment of early-stage to locally advanced disease, as well as in palliation. The infrastructure, equipment, and human resources required for RT may be limited in LMICs. However, this narrative review discusses the scope of the problem of lung cancer in LMICs, the role of RT technologies in lung cancer treatment, and RT capacity in developing countries. Strategies are presented for maximizing the availability and impact of RT in settings with minimal resource availability, and areas for potential future innovation are identified. Priorities for LMICs involve increasing access to RT equipment and trained health care professionals, ensuring quality of care, providing guidance on priority setting with limited resources, and encouraging innovation to increase the economic efficiency of RT delivery. Several international initiatives are currently under way and represent important first steps toward scaling up RT in LMICs to treat lung cancer. PMID- 26762737 TI - Minimally Invasive versus Open Thymectomy for Thymic Malignancies: Systematic Review and Meta-Analysis. AB - Complete resection is the standard of care for treatment of thymic malignancies. The use of minimally invasive surgery remains controversial. We searched online databases and identified studies from 1995 to 2014 that compared minimally invasive to open thymectomy for thymic malignancies. Study end points included operative blood loss, operative time, respiratory complications, cardiac complications, length of hospital stay, R0 resection, and recurrence. We summarized outcomes across studies using random-effects meta-analysis to account for study heterogeneity. We calculated ORs for binary outcomes and standardized mean differences for continuous outcomes. We calculated incidence rate ratios for the number of recurrences, accounting for total person-time observed in each study. Of 516 potential reference studies, 30 with a total of 2038 patients met the inclusion criteria. Patients with Masaoka stage I or II thymic malignancy constituted 94.89% of those in the minimally invasive surgery (MIS) group and 78.62% of those in open thymectomy (open) group. Mean tumor size was 4.09 cm (MIS) versus 4.80 (open). Of the 1355 MIS cases, 32 were converted to open cases. Patients in the MIS group had significantly less blood loss; however, no significant differences in operating time, respiratory complications, cardiac complications, or overall complications were identified. Length of stay was shorter for patients in the MIS group. When patients with Masaoka stage I and II thymic malignancy only were analyzed, there was no difference in rate of R0 resection or overall recurrence rate. One postoperative death occurred in the open group. The results of this unadjusted meta-analysis of published reports comparing minimally invasive with open thymectomy suggest that in selected patients with thymic malignancy, minimally invasive thymectomy is safe and can achieve oncologic outcomes similar to those of open thymectomy. PMID- 26762740 TI - PD-L1 Is Upregulated by Simultaneous Amplification of the PD-L1 and JAK2 Genes in Non-Small Cell Lung Cancer. AB - OBJECTIVES: The programmed death ligand 1(PD-L1)/programmed cell death protein 1 (PD-1) pathway is one of the most important checkpoint pathways for mediating tumor-induced immune suppression through T-cell exhaustion. Recently, targeted therapies using monoclonal antibodies against components of this pathway have been shown to reduce tumor burden in patients with non-small cell lung cancer (NSCLC). However, the prognostic significance of PD-L1 expression is controversial and the precise mechanisms of PD-L1 gene activation in lung cancer have yet to be clarified. METHODS: We investigated copy number alterations (CNAs) in the PD-L1 gene by real-time PCR in 94 surgically resected lung cancer samples to find possible associations between PD-L1 CNA and lung cancer biology. Janus kinase 2 gene (JAK2) CNA and its influence on the PD-L1/PD-1 pathway were also assessed. RESULTS: Five samples were shown to have PD-L1 gene amplification, whereas 89 samples did not. The patients with PD-L1 amplification had worse prognoses than did those without PD-L1 amplification. Genetic amplification of the PD-L1 gene was correlated with JAK2 gene amplification. The lung cancer cell line HCC4006 was found to harbor both JAK2 and PD-L1 amplification. Flow cytometry analyses revealed the level of PD-L1 protein expression to be higher in HCC4006 cells than in other NSCLC cell lines. Expression of the PD-L1 protein was significantly reduced by the JAK2 inhibitor TG-101348 and the signal transducer and activator of transcription 3 (STAT-3) inhibitor BP-1-102, but not by the STAT1 inhibitor fludarabine. CONCLUSIONS: Our data suggest that expression of PD L1 protein is upregulated by the simultaneous amplification of the PD-L1 and JAK2 genes through JAK-STAT signaling in NCSLC. PMID- 26762741 TI - Metabolite Profiles of the Serum of Patients with Non-Small Cell Carcinoma. AB - INTRODUCTION: Alterations of serum metabolites may allow us to identify individuals with lung cancer and advance our understanding of the nature and treatment of their cancer. We aimed to identify serum metabolites that differentiate patients with lung cancer from at-risk controls. METHODS: Serum samples from patients with biopsy-confirmed untreated stage I through stage III non-small cell lung cancer and at-risk controls were divided into fractions for analysis by ultrahigh-performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Compounds were identified by comparison with library entries of purified standards. Differences in concentrations of single metabolites and metabolite ratios were identified. Prediction models were developed. RESULTS: Serum samples from 284 subjects was analyzed. The subjects' mean age was 67 and 48% were female. Ninety-four patients had lung cancer (50 had adenocarcinoma and 44 had squamous cell carcinoma), 44% had stage I disease, 17% had stage II disease, and 39% had stage III disease. The patients with cancer were slightly older than the controls (68.7 versus 66.2 years, p = 0.013). A total of 534 metabolites were identified in eight metabolite superpathways and 73 subpathways. The concentrations of 149 metabolites differed significantly (q values <0.05) between the cancer and control groups (70 were lower in the cancer group and 79 were higher), and 9723 metabolite ratios differed significantly (q values <0.001) between the cancer and control groups. The accuracies of the models (cancer and cancer subtypes versus control) trained on 70% of the subjects and tested on 30% (expressed as C-statistics) ranged from 0.748 to 0.858. CONCLUSIONS: Differences in the serum metabolite profile exist between patients with stage I through stage III non-small cell lung cancer and matched controls. PMID- 26762742 TI - Patients with Advanced Non-Small Cell Lung Cancer: Are Research Biopsies a Barrier to Participation in Clinical Trials? AB - OBJECTIVES: Clinical trials of therapies for non-small cell lung cancer (NSCLC) are increasingly requiring mandatory tumor samples or research biopsies, both of which are potential barriers to trial participation. We assessed the impact of performance of research biopsies on the enrollment of patients with advanced NSCLC in clinical trials. METHODS: The cases of patients with advanced NSCLC who had been evaluated for clinical trials of systemic therapy at the Princess Margaret Cancer Centre from January 2007 to March 2015 were reviewed. RESULTS: Of the 55 clinical trials identified, 38 required tumor samples for enrollment. Six mandated repeat biopsies, whereas 32 permitted use of archival samples. Trial participation was offered to 636 patients at 940 unique study encounters, with some patients enrolling in multiple trials. Of the patients in 549 encounters during which participation in a therapeutic trial was offered, 60% received study treatment. More patients received study treatment (83% versus 55%, p < 0.0001) and study treatment was started earlier (after 9 days versus after 16, p = 0.002) when the trial did not have a mandatory tissue sample requirement. A similar trend was noted for trials permitting use of archival tissue versus mandatory repeat biopsies. The most common barriers to trial enrollment included absence of a required biomarker (34%), withdrawal of consent (20%), deterioration or death (17%), other exclusion criteria (15%), and insufficient biopsy tissue (10%). CONCLUSION: A growing number of NSCLC trials are requiring tumor tissue for treatment eligibility, which appears to be a significant barrier to trial enrollment. Potential solutions include use of available diagnostic samples (e.g., cytology samples), development of peripheral blood assays for molecular markers, faster central laboratory testing turnaround time, and more resources for rapid biopsy. PMID- 26762739 TI - Focused Analysis of Exome Sequencing Data for Rare Germline Mutations in Familial and Sporadic Lung Cancer. AB - INTRODUCTION: The association between smoking-induced chronic obstructive pulmonary disease (COPD) and lung cancer (LC) is well documented. Recent genome wide association studies (GWAS) have identified 28 susceptibility loci for LC, 10 for COPD, 32 for smoking behavior, and 63 for pulmonary function, totaling 107 nonoverlapping loci. Given that common variants have been found to be associated with LC in genome-wide association studies, exome sequencing of these high priority regions has great potential to identify novel rare causal variants. METHODS: To search for disease-causing rare germline mutations, we used a variation of the extreme phenotype approach to select 48 patients with sporadic LC who reported histories of heavy smoking-37 of whom also exhibited carefully documented severe COPD (in whom smoking is considered the overwhelming determinant)-and 54 unique familial LC cases from families with at least three first-degree relatives with LC (who are likely enriched for genomic effects). RESULTS: By focusing on exome profiles of the 107 target loci, we identified two key rare mutations. A heterozygous p.Arg696Cys variant in the coiled-coil domain containing 147 (CCDC147) gene at 10q25.1 was identified in one sporadic and two familial cases. The minor allele frequency (MAF) of this variant in the 1000 Genomes database is 0.0026. The p.Val26Met variant in the dopamine beta hydroxylase (DBH) gene at 9q34.2 was identified in two sporadic cases; the minor allele frequency of this mutation is 0.0034 according to the 1000 Genomes database. We also observed three suggestive rare mutations on 15q25.1: iron responsive element binding protein neuronal 2 (IREB2); cholinergic receptor, nicotinic, alpha 5 (neuronal) (CHRNA5); and cholinergic receptor, nicotinic, beta 4 (CHRNB4). CONCLUSIONS: Our results demonstrated highly disruptive risk conferring CCDC147 and DBH mutations. PMID- 26762738 TI - The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. AB - The IASLC Staging and Prognostic Factors Committee has collected a new database of 94,708 cases donated from 35 sources in 16 countries around the globe. This has now been analysed by our statistical partners at Cancer Research And Biostatistics and, in close collaboration with the members of the committee proposals have been developed for the T, N, and M categories of the 8th edition of the TNM Classification for lung cancer due to be published late 2016. In this publication we describe the methods used to evaluate the resultant Stage groupings and the proposals put forward for the 8th edition. PMID- 26762743 TI - Three-Year Follow-Up of a Randomized Phase II Trial on Refinement of Early-Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed versus Cisplatin and Vinorelbine (the TREAT Study). AB - INTRODUCTION: Adjuvant chemotherapy in non-small cell lung cancer (NSCLC) improves survival but is associated with significant toxicity. The Randomized Phase II Trial on Refinement of Early-Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed versus Cisplatin and Vinorelbine (TREAT study) was designed to test the hypothesis that a protocol with reduced toxicity might improve feasibility of postoperative delivery of adjuvant chemotherapy drugs to patients with NSCLC, thereby improving compliance and, potentially, survival. METHODS: Two adjuvant regimens were evaluated for feasibility in 132 patients with NSCLC: the standard regimen of cisplatin and vinorelbine (CVb) (cisplatin 50 mg/m(2) on day 1 and day 8 and vinorelbine 25 mg/m(2) on days 1, 8, 15, and 22 every 4 weeks) and a regimen consisting of cisplatin and pemetrexed (CPx) (cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 every 3 weeks). The primary end-point analysis showing that CPx is safe and feasible with dose delivery superior to that of CVb has already been published. Here we report the 3 year follow-up results of the secondary efficacy end points-overall, relapse free, distant metastasis-free, and local relapse-free survival-also with regard to histologic diagnosis. RESULTS: After a median of 39 months, no significant differences in any of the outcome parameters between CVb and CPx were observed. Also, histologic diagnosis and tumor size in stage IB did not influence survival in the CPx-treated patients. Yet, Cox regression analyses showed that overall survival at 3 years was significantly correlated with feasibility and the occurrence of dose-limiting toxicity. CONCLUSIONS: Although adjuvant chemotherapy with CPx is safe and characterized by less toxicity and better dose delivery than CVb, overall survival was not influenced by treatment arm in the context of this phase II trial. PMID- 26762745 TI - Lymph Node Dissection in Thymic Malignancies: Implication of the ITMIG Lymph Node Map, TNM Stage Classification, and Recommendations. AB - OBJECTIVES: The aim of this study is to investigate the pattern of lymphatic metastasis and suggest a lymph node dissection (LND) strategy for thymic malignancies. METHODS: We retrospectively reviewed 131 thymic malignancy patients who had undergone LND. The recently introduced nodal map of the International Thymic Malignancy Interest Group/International Association for the Study of Lung Cancer and the TNM (tumor, node, metastasis) stage classification were used for grouping and staging the lymph nodes. The pattern of lymphatic metastasis and factors in lymphatic metastasis were investigated. RESULTS: Node metastasis was detected in 13 patients (N1 in six and N2 in seven). Six N2 patients (86%) had right paratracheal node (RPN) metastases. The rates of node metastasis were 1% at T1 and 37.5% at T2/3 (p < 0.001). The rates of node metastasis were 8% in the M0 and 43% in the M1 (p = 0.03). The rate was higher for thymic carcinoma (25%) than for thymoma (5.1%, p = 0.01), and the rates also differed between the subtypes of thymoma. There was no node metastasis of the A, AB, or B1 types. Tumor size was also a significant factor in node metastasis. The optimal cutoff value for the node metastasis was 6 cm and the specificity was 62%. Only 16% of the patients had received a preoperative histologic diagnosis. All patients with node metastasis had TNM stage II or higher thymic malignancy. The freedom from recurrence rate of the pN1/2 was significantly worse than that of the pN0 (5-year rate 38.5% versus 87.9%, p < 0.001). CONCLUSION: A status of stage II or higher was the most specific predictor of node metastasis, and the RPN was a crucial station for lymphatic metastasis in thymic malignancies. Thus, LND including RPN is recommended in stage II or higher thymic malignancies. PMID- 26762744 TI - Functional Analysis of the Adrenomedullin Pathway in Malignant Pleural Mesothelioma. AB - INTRODUCTION: Malignant pleural mesothelioma (MPM) grows aggressively within the thoracic cavity and has a very low cure rate, thus highlighting the need for identification of new therapeutic targets. Adrenomedullin (AM) is a multifunctional peptide that is highly expressed in several tumors and plays an important role in angiogenesis and tumor growth after binding to its receptors, calcitonin receptor-like receptor/receptor activity-modifying protein 2 (CLR/RAMP2) and calcitonin receptor-like receptor/receptor activity-modifying protein 3 (CLR/RAMP3). METHODS: Real time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was used to assess the steady-state levels of AM, CLR, RAMP2 and RAMP3 messenger RNA (mRNA) transcripts in normal pleural tissue (n=5) and MPM (n=24). The expression of these candidates at protein level was revealed by immunohistochemistry. We also characterized the expression and regulation by hypoxia of AM system in MPM cell lines and MeT-5A cells. In vitro and in vivo studies were performed to determine the functional role of AM system in MPM. RESULTS: In this study, real-time quantitative reverse transcriptase polymerase chain reaction showed twofold to 10-fold higher levels of AM messenger RNA in MPM tissue than in normal pleural tissue. The MPM cell lines H2452, H2052, and human mesothelioma cell line MSTO-211H showed a significant increase in expression of AM messenger RNA under hypoxic conditions. Our results also show that AM stimulates cell proliferation in vitro through the Raf1 proto-oncogene, serine/threonine kinase (CRAF)/ Mitogen-activated protein kinase kinase 1 (MEK)/Extracellular regulated MAPKinase (ERK) pathway. Furthermore, the proliferation, migration, and invasion of MPM cells were decreased after treatment with anti-AM (alphaAM) and anti-AM receptor antibodies, thus indicating that MPM cells are regulated by AM. The action of AM was specific and mediated by CLR/RAMP2 and CLR/RAMP3 receptors. In vivo, alphaAM and AM22-52 antagonist therapies blocked angiogenesis and induced apoptosis in MSTO-211H xenografts, thereby resulting in tumor regression. Histologic examination of tumors treated with AM22-52 and alphaAM antibody showed evidence of disruption of tumor vasculature with depletion of vascular endothelial cells and a significant decrease in lymphatic endothelial cells. CONCLUSIONS: Our findings highlight the importance of the AM pathway in growth of MPM and in neovascularization by supplying and amplifying signals that are essential for pathologic neoangiogenesis and lymphangiogenesis. PMID- 26762746 TI - Are Anthracycline-Based Regimens Truly Indicated To Be the Standard Chemotherapy Regimen for Thymic Carcinoma? AB - INTRODUCTION: Thymic carcinoma (TC) is an exceptionally rare form of tumor that differs from thymoma by virtue of its very poor prognosis. The difficulties associated with conducting prospective trials involving rare diseases such as TC limit the evidence that can be applied to their treatment. To the extent possible, however, all medical treatment should be evidence based. METHODS: We reviewed the clinical results regarding chemotherapy and thymic epithelial malignancies, which include invasive thymoma and TC. We conducted a search of the PubMed database to extract all the chemotherapeutic clinical trials from January 1990 to December 2014. The search included the terms chemotherapy, thymic malignancy, thymoma, and thymic carcinoma and all English-language publications. RESULTS: From the initial total of 248 articles, we excluded articles that were only in abstract form, review articles, and case reports. In addition, to focus on cytotoxic therapies, we excluded articles on molecular target therapy for TC from our study. After the exclusion criteria were applied, 31 articles remained; they included prospective and retrospective trials. CONCLUSIONS: This study assessed the reliable and assessable data on the chemotherapy regimens for TC to identify the evidence-based recommendations. The results indicate that the only recommended anthracycline-containing regimen would be carboplatin plus amrubicin not the combination of cisplatin, doxorubicin, vincristine, and cyclophosphamide and that the recommended regimens without anthracycline would be carboplatin plus paclitaxel and cisplatin plus docetaxel. PMID- 26762748 TI - An Unusual Metastatic Site for Primary Lung Cancer: The Spleen. PMID- 26762747 TI - Clinicopathological Characteristics of RET Rearranged Lung Cancer in European Patients. AB - INTRODUCTION: Rearrangements of RET are rare oncogenic events in patients with non-small cell lung cancer (NSCLC). While the characterization of Asian patients suggests a predominance of nonsmokers of young age in this genetically defined lung cancer subgroup, little is known about the characteristics of non-Asian patients. We present the results of an analysis of a European cohort of patients with RET rearranged NSCLC. METHODS: Nine hundred ninety-seven patients with KRAS/EGFR/ALK wildtype lung adenocarcinomas were analyzed using fluorescence in situ hybridization for RET fusions. Tumor specimens were molecularly profiled and clinicopathological characteristics of the patients were collected. RESULTS: Rearrangements of RET were identified in 22 patients, with a prevalence of 2.2% in the KRAS/EGFR/ALK wildtype subgroup. Co-occurring genetic aberrations were detected in 10 patients, and the majority had mutations in TP53. The median age at diagnosis was 62 years (range, 39-80 years; mean +/- SD, 61 +/- 11.7 years) with a higher proportion of men (59% versus 41%). There was only a slight predominance of nonsmokers (54.5%) compared to current or former smokers (45.5%). CONCLUSIONS: Patients with RET rearranged adenocarcinomas represent a rare and heterogeneous NSCLC subgroup. In some contrast to published data, we see a high prevalence of current and former smokers in our white RET cohort. The significance of co-occurring aberrations, so far, is unclear. PMID- 26762749 TI - Two Cases of Small Cell Lung Cancer Transformation from EGFR Mutant Adenocarcinoma During AZD9291 Treatment. PMID- 26762750 TI - The Frequency of Rare EGFR Mutations Is Higher than that of Classical Ones: How Come? PMID- 26762751 TI - Differences in the Epidemiology of Rare EGFR Mutations in Different Populations. PMID- 26762753 TI - Modeling continuum of epithelial mesenchymal transition plasticity. AB - Living systems respond to ambient pathophysiological changes by altering their phenotype, a phenomenon called 'phenotypic plasticity'. This program contains information about adaptive biological dynamism. Epithelial-mesenchymal transition (EMT) is one such process found to be crucial in development, wound healing, and cancer wherein the epithelial cells with restricted migratory potential develop motile functions by acquiring mesenchymal characteristics. In the present study, phase contrast microscopy images of EMT induced HaCaT cells were acquired at 24 h intervals for 96 h. The expression study of relevant pivotal molecules viz. F actin, vimentin, fibronectin and N-cadherin was carried out to confirm the EMT process. Cells were intuitively categorized into five distinct morphological phenotypes. A population of 500 cells for each temporal point was selected to quantify their frequency of occurrence. The plastic interplay of cell phenotypes from the observations was described as a Markovian process. A model was formulated empirically using simple linear algebra, to depict the possible mechanisms of cellular transformation among the five phenotypes. This work employed qualitative, semi-quantitative and quantitative tools towards illustration and establishment of the EMT continuum. Thus, it provides a newer perspective to understand the embedded plasticity across the EMT spectrum. PMID- 26762754 TI - Improved estimation of MR relaxation parameters using complex-valued data. AB - PURPOSE: In MR image analysis, T1 , T2 , and T2* maps are generally calculated using magnitude MR data. Without knowledge of the underlying noise variance, parameter estimates at low signal to noise ratio (SNR) are usually biased. This leads to confounds in studies that compare parameters across SNRs and or across scanners. This article compares several estimation techniques which use real or complex-valued MR data to achieve unbiased estimation of MR relaxation parameters without the need for additional preprocessing. THEORY AND METHODS: Several existing and new techniques to estimate relaxation parameters using complex valued data were compared with widely used magnitude-based techniques. Their bias, variance and processing times were studied using simulations covering various aspects of parameter variations. Validation on noise-degraded experimental measurements was also performed. RESULTS: Simulations and experiments demonstrated the superior performance of techniques based on complex valued data, even in comparison with magnitude-based techniques that account for Rician noise characteristics. This was achieved with minor modifications to data modeling and at computational costs either comparable to or higher ( ~two fold) than magnitude-based estimators. Theoretical analysis shows that estimators based on complex-valued data are statistically efficient. CONCLUSION: The estimation techniques that use complex-valued data provide minimum variance unbiased estimates of parametric maps and markedly outperform commonly used magnitude based estimators under most conditions. They additionally provide phase maps and field maps, which are unavailable with magnitude-based methods. Magn Reson Med 77:385-397, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26762752 TI - Prevalence, Prognostic Implications, and Survival Modulators of Incompletely Resected Non-Small Cell Lung Cancer in the U.S. National Cancer Data Base. AB - INTRODUCTION: The impact of incomplete lung cancer resection on survival has never been systematically quantified, nor has the value of postoperative adjuvant therapy in this setting been determined. METHODS: We evaluated lung cancer resections in the National Cancer Data Base from 2004 to 2011 to identify factors associated with margin involvement. We compared the survival of patients with and without positive margins and evaluated the impact of postoperative adjuvant therapy. RESULTS: Of 112,998 resections performed during the 8 years, 5,335 (4.7%) had positive margins. Patient demographic and clinical factors associated with an increased adjusted OR of incomplete resection included black race (p = 0.006), age-based Medicare insurance (p = 0.006), urban residence (p = 0.01), histologic diagnosis of squamous cell carcinoma, high tumor grade, tumor overlapping more than one lobe, and advanced pathologic stage (p < 0.001 for all clinical factors). Community cancer programs (p = 0.002), institutions with high proportions of underinsured patients (p = 0.01), and institutions with a lower volume of cancer resections (p = 0.006) also had an increased adjusted OR. The crude 5-year survival rates of patients with complete versus incomplete resections were 58.5% versus 33.8% (log-rank p < 0.001). After an incomplete resection, adjuvant chemotherapy was associated with improved 5-year survival across all stages (p < 0.01); radiotherapy was associated with worse survival in patients with stage I disease (p < 0.001). CONCLUSIONS: Margin involvement significantly impaired survival after lung cancer resection irrespective of stage. Causative institutional and provider practices should be identified to minimize this adverse outcome. Postoperative adjuvant chemotherapy mitigated mortality risk independently of stage, whereas postoperative radiotherapy exacerbated the risk in patients with stage I disease. These findings need validation in prospective trials. PMID- 26762755 TI - Factorial structure of the Health of the Nation Outcome Scales: An ordinal confirmatory factor analysis using a national sample of clinician ratings in England. AB - In the present study, the superior factorial structure of the Health of the Nation Outcome Scales (HoNOS) was investigated. The aims of the study were to test the fit of our new four-factor/subscale structure within and across a wide range of clinical populations compared to competing structures, and to identify any clinical populations where the HoNOS might require modification in order to improve its psychometric properties. Ordinal confirmatory factor analysis was performed for four competing HoNOS subscale structures using a national sample of 80,161 ratings taken at the point of referral to mental health services in England. A new four-factor structure with good/acceptable internal consistency for each of the factors/subscales demonstrated a significantly better fit to the data for 21 of the 24 data groups compared to three competing subscale models. A new four-factor/subscale structure was shown to be the most generalizable subscale structure currently available for HoNOS. However, although superior to other factorial structures, the statistical fit was less than optimal for some clinical populations. Therefore, we would recommend that additional items relevant to all mental health patients are identified and added to the HoNOS in order to allow the development of a single, more generalizable subscale structure, and a much improved version of the HoNOS. PMID- 26762756 TI - Survival estimations at the limit of viability. AB - OBJECTIVE: The purpose of this study was to assess the variability in neonatal survival to discharge from the neonatal unit by using different inclusion criteria. METHODS: An observational and descriptive study was performed between January 2008 and December 2013 which included infants born between 22 weeks and 31 weeks and 6 d of gestation. The rate of survival was calculated using three different inclusion criteria: the total number of preterm births, the number of all preterm live births, and the number of preterm newborns admitted to the neonatal unit. RESULTS: A total of 783 patients met the inclusion criteria. The survival rate for births between 22 and 31 weeks and 6 d of gestation was 72.8% of total births, 82.3% of live births, and 84.0% of all admissions to the neonatal unit. Therefore, we found a significant difference in survival rates according to whether or not foetal mortality (11.6%) and mortality in the delivery room (2.0%) were included. This variation increased with decreasing gestational age: 17,2%, 25%, and 38,4% at 23 weeks gestation. CONCLUSIONS: Late foetal mortality and the mortality in the delivery room affect the survival rates of preterm infants significantly, especially the most immature newborns. PMID- 26762758 TI - United airway disease: a reality in early life? PMID- 26762757 TI - Decrease of the insulin-like growth factor-1 bioavailability in spontaneously hypertensive rats with erectile dysfunction. AB - We investigated the role of insulin-like growth factor-1 (IGF-1) in spontaneously hypertensive rats with erectile dysfunction. Firstly, we evaluated intracavernous pressure. The bioavailability of IGF-1 at both mRNA and protein levels were measured by quantitative real-time PCR and Western blot respectively. Then, cavernous cyclic guanosine monophosphate concentrations were detected by enzyme linked immunosorbent assay. The cavernosal pressure was significantly decreased in the hypertensive and the propranolol treatment groups compared to the normal control group (P < 0.01). Cavernous IGF-1 bioavailability and the concentrations of cavernous cyclic guanosine monophosphate were both significantly decreased in the hypertensive and the propranolol treatment groups compared to the normal control group (P < 0.01). This study suggests that an obvious decrease in cavernous IGF-1 levels might play an important role in spontaneously hypertensive rats with erectile dysfunction. PMID- 26762761 TI - Crack patterns over uneven substrates. AB - Cracks in thin layers are influenced by what lies beneath them. From buried craters to crocodile skin, crack patterns are found over an enormous range of length scales. Regardless of absolute size, their substrates can dramatically influence how cracks form, guiding them in some cases, or shielding regions from them in others. Here we investigate how a substrate's shape affects the appearance of cracks above it, by preparing mud cracks over sinusoidally varying surfaces. We find that as the thickness of the cracking layer increases, the observed crack patterns change from wavy to ladder-like to isotropic. Two order parameters are introduced to measure the relative alignment of these crack networks, and, along with Fourier methods, are used to characterise the transitions between crack pattern types. Finally, we explain these results with a model, based on the Griffith criteria of fracture, that identifies the conditions for which straight or wavy cracks will be seen, and predicts how well-ordered the cracks will be. Our metrics and results can be applied to any situation where connected networks of cracks are expected, or found. PMID- 26762759 TI - Simuliosis--a dermatosis caused by black flies. PMID- 26762760 TI - At the crossroads: communication of bacteria-containing vacuoles with host organelles. AB - Invasive bacterial pathogens are engulfed upon host cell entry in a vacuolar environment called the bacteria-containing vacuole (BCV). BCVs directly contact with numerous host compartments, mainly vesicles of the endocytic pathway, such as endosomes or lysosomes. In addition, they also interact with the endoplasmic reticulum and endomembranes of the secretory pathway. These connections between the pathogen and the host occur either through heterotypic membrane fusions or through membrane contact sites. The precise regulation of BCV contacts with host compartments defines the constitution of the intracellular bacterial niche. It emerges that the associated pathways may control the stability of the BCV resulting either in vacuolar or cytoplasmically growing bacteria. Here, we will portray how the usage of novel proteomics and imaging technologies allows comparison of the communication of different host cell compartments with four relevant intracellular human pathogens, namely Salmonella enterica, Legionella pneumophila, Shigella flexneri and Francisella tularensis. The first two remain mainly within the BCV, and the latter two escape into the cytoplasm. PMID- 26762762 TI - Doping evaluation of InP nanowires for tandem junction solar cells. AB - In order to push the development of nanowire-based solar cells further using optimized nanowire diameter and pitch, a doping evaluation of the nanowire geometry is necessary. We report on a doping evaluation of n-type InP nanowires with diameters optimized for light absorption, grown by the use of metal-organic vapor phase epitaxy in particle-assisted growth mode using tetraethyltin (TESn) as the dopant precursor. The charge carrier concentration was evaluated using four-probe resistivity measurements and spatially resolved Hall measurements. In order to reach the highest possible nanowire doping level, we set the TESn molar fraction at a high constant value throughout growth and varied the trimethylindium (TMIn) molar fraction for different runs. Analysis shows that the charge carrier concentration in nanowires grown with the highest TMIn molar fraction (not leading to kinking nanowires) results in a low carrier concentration of approximately 10(16) cm(-3). By decreasing the molar fraction of TMIn, effectively increasing the IV/III ratio, the carrier concentration increases up to a level of about 10(19) cm(-3), where it seems to saturate. Axial carrier concentration gradients along the nanowires are found, which can be correlated to a combination of changes in the nanowire growth rate, measured in situ by optical reflectometry, and polytypism of the nanowires observed in transmission electron microscopy. PMID- 26762763 TI - Cerebral palsy and perinatal mortality after pregnancy-induced hypertension across the gestational age spectrum: observations of a reconstructed total population cohort. AB - AIM: Pregnancy-induced hypertension/pre-eclampsia (PIH/PE) is associated with cerebral palsy (CP) in term births but if sufficiently severe to necessitate preterm delivery predicts a lower risk of CP than observed in gestational peers. We investigated whether this apparent 'protection' was attributable to inappropriately chosen comparison groups and/or an increased risk of perinatal death. METHOD: Perinatal information was collected from medical records of children with CP, individually matched neonatal survivors without CP, and representative samples of perinatal deaths of Western Australian birth cohorts from 1980 to 1995. Compared with these data, the sensitivity of statutorily collected PIH/PE data was assessed for each outcome group. Using these sensitivities, the estimated risks of death and CP in births to all women with and without PIH/PE were compared. RESULTS: Sensitivity of statutory PIH/PE data decreased with increasingly poor outcome. Reconstructed cohorts showed that PIH/PE increased the risks both of CP and of perinatal death in births at lower gestations except in births <27 weeks, where the risk of perinatal death only increased greatly. INTERPRETATION: PIH/PE does not protect against poor outcome at any gestational age. Previously reported protective effects originate from inappropriate control for gestational age and not from higher gestation-specific perinatal mortality. PMID- 26762764 TI - Fatness rather than leptin sensitivity determines the timing of puberty in female mice. AB - Leptin is a permissive factor for the onset of puberty. However, changes in adiposity frequently influence leptin sensitivity. Thus, the objective of the present study was to investigate how changes in body weight, fatness, leptin levels and leptin sensitivity interact to control the timing of puberty in female mice. Pre-pubertal obesity, induced by raising C57BL/6 mice in small litters, led to an early puberty onset. Inactivation of Socs3 gene in the brain or exclusively in leptin receptor-expressing cells reduced the body weight and leptin levels at pubertal onset, and increased leptin sensitivity. Notably, these female mice exhibited significant delays in vaginal opening, first estrus and onset of estrus cyclicity. In conclusion, our findings suggest that increased leptin sensitivity did not play an important role in favoring pubertal onset in female mice. Rather, changes in pubertal body weight, fatness and/or leptin levels were more important in influencing the timing of puberty. PMID- 26762765 TI - CREB/GSK-3beta signaling pathway regulates the expression of TR4 orphan nuclear receptor gene. AB - In this study, we show that reduction of glucose concentration increases TR4 expression in 3T3-L1 cells via stimulation of the GSK-3beta-CREB pathway. While GSK-3beta and CREB increased TR4 expression in 3T3-L1 cells, inhibition of CREB expression or activity resulted in loss of GSK-3beta-mediated enhancement of TR4 expression. In addition, CREB enhanced murine TR4 promoter activity via direct binding to a cAMP response element located in the promoter, and this CREB effect was further strengthened by GSK-3beta. Moreover, silencing of TR4 expression by a gene-specific microRNA inhibited CREB-induced lipid accumulation in 3T3-L1 adipocytes, suggesting that TR4 could be a key mediator of CREB-induced lipogenesis. PMID- 26762767 TI - Studying complex system: calcium oscillations as attractor of cell differentiation. AB - Biological processes, such as the induction of undifferentiated cells to enable neurogenesis, provide complex mechanisms for study. For further insight, subsets of these processes that are governed by metabolic pathways or key molecules called attractors need to be elucidated. In this review, we have focused on the role of calcium as a driving force of neuronal differentiation. The activity of calcium refers to peaks and waves, whose amplitudes and frequencies in stem and progenitor cells involve the activation of a great variety of signaling pathways that comprise neurotransmitters and their receptors, intracellular signaling factors and transcription factors, which form a complex network. The study of different subsets, from receptor-mediated calcium flux to the activation of transcription factors, can then be combined to understand the process of neuronal differentiation. PMID- 26762766 TI - Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae. AB - Aneuploidy and aging are correlated; however, a causal link between these two phenomena has remained elusive. Here, we show that yeast disomic for a single native yeast chromosome generally have a decreased replicative lifespan. In addition, the extent of this lifespan deficit correlates with the size of the extra chromosome. We identified a mutation in BUL1 that rescues both the lifespan deficit and a protein trafficking defect in yeast disomic for chromosome 5. Bul1 is an E4 ubiquitin ligase adaptor involved in a protein quality control pathway that targets membrane proteins for endocytosis and destruction in the lysosomal vacuole, thereby maintaining protein homeostasis. Concurrent suppression of the aging and trafficking phenotypes suggests that disrupted membrane protein homeostasis in aneuploid yeast may contribute to their accelerated aging. The data reported here demonstrate that aneuploidy can impair protein homeostasis, shorten lifespan, and may contribute to age-associated phenotypes. PMID- 26762770 TI - The association between body mass index and preeclampsia: a meta-analysis. AB - BACKGROUND: Several observational studies have reported a positive association between elevated body mass index (BMI) and preeclampsia, but no meta-analysis has been conducted yet. This meta-analysis was conducted to estimate the overall association between overweight or obesity and preeclampsia. METHODS: Major electronic databases, including PubMed, Web of Science, and Scopus were searched until August 2015. The reference lists of included studies were screened as well. Epidemiological studies addressing the association between BMI and preeclampsia were enrolled. The heterogeneity across studies was explored by Q-test and I(2) statistic. The possibility of publication bias was assessed using Begg's and Egger's tests. The results were reported using odds ratio (OR) estimate with its 95% confidence intervals (CI) using a random-effects model. RESULTS: We identified a total of 1298 references and included 23 studies with 1 387 599 participants. Preeclampsia was associated with overweight (OR = 1.73; 95% CI: 1.59, 1.87; 21 studies; I(2 )=( )62.3%) and obesity (OR = 3.15; 95% CI: 2.96, 3.35; 22 studies; I(2 )=( )36.0%). There was no evidence of publication bias. CONCLUSIONS: There is sufficient evidence that excess body mass index is significantly associated with an increased risk of preeclampsia. Therefore, overweight and obesity can be considered as a predictor of preeclampsia. PMID- 26762768 TI - Molecular and immunological characterization of DNA ligase IV deficiency. AB - DNA ligase IV (LIG4) deficiency is an extremely rare autosomal recessive primary immunodeficiency disease caused by the LIG4 mutation. To date, fewer than 30 cases of patients have been reported worldwide. No reversion mutations have been previously identified in LIG4. This study enrolled seven Chinese patients with LIG4 deficiency who presented with combined immunodeficiency, microcephaly, and growth retardation. One patient (P1) acquired non-Hodgkin lymphoma. Four patients had impaired T cell proliferation function and skewed T cell receptor diversity. Five novel mutations in LIG4 and a potential hotspot mutation (c.833G>T; p.R278L) in the Chinese population were identified. TA cloning analysis of T cells, NK cells, granulocytes, and oral mucosa cells in P6 revealed wild-type clones and clones that contained both maternally and paternally inherited mutations, indicating possible somatic reversion which need further investigation since no functional or protein assays were possible for all the patients died and no cell lines were available. PMID- 26762771 TI - Gradient-based electrical conductivity imaging using MR phase. AB - PURPOSE: To develop a fast, practically applicable, and boundary artifact free electrical conductivity imaging method that does not use transceive phase assumption, and that is more robust against the noise. THEORY: Starting from the Maxwell's equations, a new electrical conductivity imaging method that is based solely on the MR transceive phase has been proposed. Different from the previous phase based electrical properties tomography (EPT) method, a new formulation was derived by including the gradients of the conductivity into the equations. METHODS: The governing partial differential equation, which is in the form of a convection-reaction-diffusion equation, was solved using a three-dimensional finite-difference scheme. To evaluate the performance of the proposed method numerical simulations, phantom and in vivo human experiments have been conducted at 3T. RESULTS: Simulation and experimental results of the proposed method and the conventional phase-based EPT method were illustrated to show the superiority of the proposed method over the conventional method, especially in the transition regions and under noisy data. CONCLUSION: With the contributions of the proposed method to the phase-based EPT approach, a fast and reliable electrical conductivity imaging appears to be feasible, which is promising for clinical diagnoses and local SAR estimation. Magn Reson Med 77:137-150, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26762769 TI - The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies. AB - Multiple Sclerosis (MS) is an autoimmune disease treated by therapies targeting peripheral blood cells. We previously identified that expression of two MS-risk genes, the transcription factors EOMES and TBX21 (ET), was low in blood from MS and stable over time. Here we replicated the low ET expression in a new MS cohort (p<0.0007 for EOMES, p<0.028 for TBX21) and demonstrate longitudinal stability (p<10(-4)) and high heritability (h(2)=0.48 for EOMES) for this molecular phenotype. Genes whose expression correlated with ET, especially those controlling cell migration, further defined the phenotype. CD56+ cells and other subsets expressed lower levels of Eomes or T-bet protein and/or were under represented in MS. EOMES and TBX21 risk SNP genotypes, and serum EBNA-1 titres were not correlated with ET expression, but HLA-DRB1*1501 genotype was. ET expression was normalised to healthy control levels with natalizumab, and was highly variable for glatiramer acetate, fingolimod, interferon-beta, dimethyl fumarate. PMID- 26762772 TI - l-Cysteine improves antioxidant enzyme activity, post-thaw quality and fertility of Nili-Ravi buffalo (Bubalus bubalis) bull spermatozoa. AB - The effects of l-cysteine in extender on antioxidant enzymes profile during cryopreservation, post-thaw quality parameters and in vivo fertility of Nili-Ravi buffalo bull spermatozoa were studied. Semen samples from 4 buffalo bulls were diluted in Tris-citric acid-based extender having different concentrations of l cysteine (0.0, 0.5, 1.0, 2.0 and 3.0 mm) and frozen in 0.5-ml French straws. The antioxidative enzymes [catalase, super oxide dismutase and total glutathione (peroxidase and reductase)] were significantly higher (P < 0.05) at pre-freezing and post-thawing in extender containing 2.0 mm l-cysteine as compared to other groups. Post-thaw total motility (%), progressive motility (%), rapid velocity (%), average path velocity (MUm s-1 ), straight line velocity (MUm s-1 ), curvilinear velocity (MUm s-1 ), beat cross frequency (Hz), viable spermatozoa with intact plasmalemma (%), acrosome and DNA integrity (%) were higher with the addition of 2.0 mm l-cysteine as compared to other groups (P < 0.05). The fertility rates (59 versus 43%) were higher (P < 0.05) in buffaloes inseminated with doses containing 2.0 mm of l-cysteine than in the control. In conclusion, the addition of 2.0 mm l-cysteine in extender improved the antioxidant enzymes profile, post-thaw quality and in vivo fertility of Nili-Ravi buffalo bull spermatozoa. PMID- 26762773 TI - A novel regulatory element (E77) isolated from CHO-K1 genomic DNA enhances stable gene expression in Chinese hamster ovary cells. AB - Vectors flanked by regulatory DNA elements have been used to generate stable cell lines with high productivity and transgene stability; however, regulatory elements in Chinese hamster ovary (CHO) cells, which are the most widely used mammalian cells in biopharmaceutical production, are still poorly understood. We isolated a novel gene regulatory element from CHO-K1 cells, designated E77, which was found to enhance the stable expression of a transgene. A genomic library was constructed by combining CHO-K1 genomic DNA fragments with a CMV promoter-driven GFP expression vector, and the E77 element was isolated by screening. The incorporation of the E77 regulatory element resulted in the generation of an increased number of clones with high expression, thereby enhancing the expression level of the transgene in the stable transfectant cell pool. Interestingly, the E77 element was found to consist of two distinct fragments derived from different locations in the CHO genome shotgun sequence. High and stable transgene expression was obtained in transfected CHO cells by combining these fragments. Additionally, the function of E77 was found to be dependent on its site of insertion and specific orientation in the vector construct. Our findings demonstrate that stable gene expression mediated by the CMV promoter in CHO cells may be improved by the isolated novel gene regulatory element E77 identified in the present study. PMID- 26762774 TI - Care of children with allergic diseases following major disasters. PMID- 26762775 TI - Quantitative assessment of colorectal morphology: Implications for robotic colonoscopy. AB - This paper presents a method of characterizing the distribution of colorectal morphometrics. It uses three-dimensional region growing and topological thinning algorithms to determine and visualize the luminal volume and centreline of the colon, respectively. Total and segmental lengths, diameters, volumes, and tortuosity angles were then quantified. The effects of body orientations on these parameters were also examined. Variations in total length were predominately due to differences in the transverse colon and sigmoid segments, and did not significantly differ between body orientations. The diameter of the proximal colon was significantly larger than the distal colon, with the largest value at the ascending and cecum segments. The volume of the transverse colon was significantly the largest, while those of the descending colon and rectum were the smallest. The prone position showed a higher frequency of high angles and consequently found to be more torturous than the supine position. This study yielded a method for complete segmental measurements of healthy colorectal anatomy and its tortuosity. The transverse and sigmoid colons were the major determinant in tortuosity and morphometrics between body orientations. Quantitative understanding of these parameters may potentially help to facilitate colonoscopy techniques, accuracy of polyp spatial distribution detection, and design of novel endoscopic devices. PMID- 26762776 TI - Pedicle screw cement augmentation. A mechanical pullout study on different cement augmentation techniques. AB - Pedicle screws with polymethyl methacrylate (PMMA) cement augmentation have been shown to significantly improve the fixation strength in a severely osteoporotic spine. However, the efficacy of screw fixation for different cement augmentation techniques remains unknown. This study aimed to determine the difference in pullout strength between different cement augmentation techniques. Uniform synthetic bones simulating severe osteoporosis were used to provide a platform for each augmentation technique. In all cases a polyaxial screw and acrylic cement (PMMA) at medium viscosity were used. Five groups were analyzed: I) only screw without PMMA (control group); II) retrograde cement pre-filling of the tapped area; III) cannulated and fenestrate screw with cement injection through perforation; IV) injection using a standard trocar of PMMA (vertebroplasty) and retrograde pre-filling of the tapped area; V) injection through a fenestrated trocar and retrograde pre-filling of the tapped area. Standard X-rays were taken in order to visualize cement distribution in each group. Pedicle screws at full insertion were then tested for axial pullout failure using a mechanical testing machine. A total of 30 screws were tested. The results of pullout analysis revealed better results of all groups with respect to the control group. In particular the statistical analysis showed a difference of Group V (p = 0.001) with respect to all other groups. These results confirm that the cement augmentation grants better results in pullout axial forces. Moreover they suggest better load resistance to axial forces when the distribution of the PMMA is along all the screw combining fenestration and pre-filling augmentation technique. PMID- 26762777 TI - Correction: Testing and validating electroanalytical simulations. PMID- 26762778 TI - Low-dose, continuous enzyme replacement therapy ameliorates brain pathology in the neurodegenerative lysosomal disorder mucopolysaccharidosis type IIIA. AB - Repeated replacement of sulphamidase via cerebrospinal fluid injection is an effective treatment for pathological changes in the brain in mice and dogs with the lysosomal storage disorder, mucopolysaccharidosis type IIIA (MPS IIIA). Investigational trials of this approach are underway in children with this condition, however, infusions require attendance at a specialist medical facility. We sought to comprehensively evaluate the effectiveness of sustained release (osmotic pump-delivered) enzyme replacement therapy in murine MPS IIIA as this method, if applied to humans, would require only subcutaneous administration of enzyme once the pump was installed. Six-week-old MPS IIIA and unaffected mice were implanted with subcutaneous mini-osmotic pumps connected to an infusion cannula directed at the right lateral ventricle. Either recombinant human sulphamidase or vehicle were infused over the course of 7 weeks, with pumps replaced part-way through the experimental period. We observed near-normalisation of primarily stored substrate (heparan sulphate) in both hemispheres of the MPS IIIA brain and cervical spinal cord, as determined using tandem mass spectrometry. Immunohistochemistry indicated a reduction in secondarily stored GM 3 ganglioside and neuroinflammatory markers. A bias towards the infusion side was seen in some, but not all outcomes. The recombinant enzyme appears stable under pump-like conditions for at least 1 month. Given that infusion pumps are in clinical use in other nervous system disorders, e.g. for treatment of spasticity or brain tumours, this treatment method warrants consideration for testing in large animal models of MPS IIIA and other lysosomal storage disorders that affect the brain. Clinical trials of repeated injection of replacement enzyme into CSF are underway in patients with the inherited neurodegenerative disorder mucopolysaccharidosis type IIIA. In this pre-clinical study, we examined an alternative approach - slow, continual infusion of enzyme using pumps. We observed significant reductions in substrate accumulation and other disease-based lesions in treated mouse brain. Thus, the strategy warrants consideration for testing in large animal models of MPS IIIA and also in other neurodegenerative lysosomal storage disorders. PMID- 26762779 TI - Reply. PMID- 26762780 TI - Comparison of Intraocular Pressure Measurements Obtained by Rebound, Noncontact, and Goldmann Applanation Tonometry in Children. PMID- 26762781 TI - Effects of edge magnetism on the Kohn anomalies of zigzag graphene nanoribbons. AB - The effects of edge magnetism on the Kohn anomaly (KA) of the G-band phonons of zigzag graphene nanoribbons (ZGNRs) are studied using a combination of the tight binding and mean-field Hubbard models. We show that the opening of an energy gap, induced by magnetic ordering, significantly changes the KA effects, particularly for narrow ribbons in which the gap is larger than the phonon energy. Therefore, the G-band phonon frequency and lifetime are altered for a magnetically-ordered edge state with respect to an unpolarized edge state. The effects of temperature, ZGNR width, doping and transverse electric fields are systematically investigated. We propose using this effect to probe the magnetic order of edge states in graphene nanoribbons using Raman spectroscopy. PMID- 26762782 TI - Congenital anomalies in cerebral palsy: where to from here? AB - Proportions of cases of cerebral palsy (CP) with congenital anomalies recorded in Australian CP registers range from 15% to 40%. The anomalies seen in CP are extremely variable. We have identified that CP registers often do not have quality data on congenital anomalies, necessitating linkage with congenital anomaly registers. However, a lack of unified processes and definitions in congenital anomaly registers and data collections means that linkages are complex, need to be carefully planned, and limitations acknowledged. Historically in CP research, congenital anomalies have been classified by International Classification of Disease codes, then combined into brain and other major and minor anomalies. Systems have been developed to classify congenital anomalies into aetiologically related groups, but such a classification has yet to be trialled in CP. It is anticipated that primary prevention of a small proportion of cases of CP is possible through the primary prevention of congenital anomalies, especially those due to teratogens. Owing to the anticipated low prevalence of each subgroup, global collaboration will be required to further these lines of enquiry. PMID- 26762783 TI - Lack of effects on key cellular parameters of MRC-5 human lung fibroblasts exposed to 370 mT static magnetic field. AB - The last decades have seen increased interest toward possible adverse effects arising from exposure to intense static magnetic fields. This concern is mainly due to the wider and wider applications of such fields in industry and clinical practice; among them, Magnetic Resonance Imaging (MRI) facilities are the main sources of exposure to static magnetic fields for both general public (patients) and workers. In recent investigations, exposures to static magnetic fields have been demonstrated to elicit, in different cell models, both permanent and transient modifications in cellular endpoints critical for the carcinogenesis process. The World Health Organization has therefore recommended in vitro investigations as important research need, to be carried out under strictly controlled exposure conditions. Here we report on the absence of effects on cell viability, reactive oxygen species levels and DNA integrity in MRC-5 human foetal lung fibroblasts exposed to 370 mT magnetic induction level, under different exposure regimens. Exposures have been performed by using an experimental apparatus designed and realized for operating with the static magnetic field generated by permanent magnets, and confined in a magnetic circuit, to allow cell cultures exposure in absence of confounding factors like heating or electric field components. PMID- 26762784 TI - Effect of cannabinoids on CGRP release in the isolated rat lumbar spinal cord. AB - Cannabinoids produce analgesia through a variety of mechanisms. It has been proposed that one mechanism is by modulating the release of CGRP in the spinal cord pain pathways. Previous studies have reported that cannabinoids, particularly CB2 receptor agonists, can modulate CGRP release in the isolated rat spinal cord. In our experiments, the TRPV1 agonist capsaicin evoked CGRP release and this was supressed by the TRPV1 antagonist capsazepine and by the opioid receptor agonist DAMGO. However, none of the cannabinoid receptor agonists that we tested were able to modulate evoked CGRP release; including WIN 55,212-2, methanandamide, and GW405833. These results question the role of spinal cord cannabinoid receptors in the regulation of CGRP signaling. PMID- 26762785 TI - The antinociceptive effects of a delta-opioid receptor agonist in mice with painful diabetic neuropathy: Involvement of heme oxygenase 1. AB - Diabetic neuropathy is poorly controlled by classical analgesics and the research of new therapeutic alternatives is indispensable. Our aim is to investigate if treatment with a carbon monoxide-releasing molecule (tricarbonyldichlororuthenium(II) dimer; CORM-2) or an inducible heme oxygenase (HO-1) inducer (cobalt protoporphyrin IX; CoPP) could enhance the antinociceptive effects produced by a delta-opioid receptor (DOR) agonist in mice with painful diabetic neuropathy. In diabetic mice induced by streptozotocin (STZ) injection, the antiallodynic and antihyperalgesic effects produced by the subcutaneous administration of a DOR agonist ([d-Pen(2),d-Pen(5)]-Enkephalin; DPDPE) and the reversion of its effects with the administration of an HO-1 inhibitor (tin protoporphyrin IX; SnPP) were evaluated. Moreover, the antinociceptive effects produced by the intraperitoneal administration of 10mg/kg of CORM-2 or CoPP, alone or combined, with a subanalgesic dose of DPDPE were also assessed. Our results demonstrated that the subcutaneous administration of DPDPE inhibited the mechanical and thermal allodynia as well as the thermal hyperalgesia induced by diabetes in a dose-dependent manner. Moreover, while the antinociceptive effects produced by a low dose of DPDPE were enhanced by CORM-2 or CoPP co-treatments, the inhibitory effects produced by a high dose of DPDPE were completely reversed by the administration of an HO-1 inhibitor, SnPP, indicating the involvement of HO-1 in the antinociceptive effects produced by this DOR agonist during diabetic neuropathic pain in mice. In conclusion, this study shows that the administration of CORM-2 or CoPP combined with a DOR agonist could be an interesting strategy for the treatment of painful diabetic neuropathy. PMID- 26762786 TI - Distinctive sleep problems in children with perinatal moderate or mild hypoxic ischemia. AB - Extensive studies focus on the cognitive and motor impairments after perinatal hypoxic-ischemia (HI). Sleep problems, although reported to be associated with cerebral palsy (CP), are often overlooked in non-severe HI patients. Here, by investigating the sleep qualities of children with different degrees of HI, we discovered that sleep initiation and maintenance, sleep-related breathing problems, or circadian rhythmic issues were highly associated with children of moderate or mild HI, respectively. Follow-up MRI studies in 2-year old patients showed that periventricular white matter lesions including periventricular leukomalacia (PVL) were prevalent in moderate, but not mild, HI children. In contrast, the occurrence of pineal cysts had a high risk in children with mild HI. Our study provides novel insights into the mechanisms of distinctive sleep problems associated with children of different degrees of HI, and therefore sheds light on the studies of targeted therapeutic treatments for sleep disorders in children who suffer from HI. PMID- 26762787 TI - Temporal sequence of recovery-related events following maximal exercise assessed by heart rate variability and blood lactate concentration. AB - PURPOSE: To analyse the temporal sequence of recovery events related to autonomic nervous system and metabolic processes following maximal exercise, applying linear and nonlinear indices of heart rate variability (HRV) and blood lactate concentration. METHODS: On the following day of the maximum oxygen consumption test, 20 participants firstly lay down for 20 min for resting data collection and then underwent the constant velocity exhaustive test, which consisted in running at 100% of maximal velocity reached on the previous day until exhaustion. Immediately after the end of exercise, the participants kept a supine position for 120 min recovering passively. Prior to exercise and at every 10 min during the recovery time, blood samples were collected to determine lactate concentration, and heart rate variability analysis (time and frequency domain indices and recurrence plot variables) was performed. Friedman's test, complemented with Dunn's multiple comparison test, was used to compare recovery moments and baseline values. RESULTS: From 70 min, no significant differences were detected between lactate concentration and baseline. HRV indices were considered recovered at different timings: at 60 min for SD2; at 70 min for SDNN and LF; at 80 min for RMSSD, HF and SD1 and at 90 min for recurrence plot variables. CONCLUSIONS: During passive recovery after maximal exercise, restoration processes seem to comply an order, considering analysed HRV indices and lactate removal: at first, lactate concentration reaches normal values, allowing sympathovagal reorganization, and then, parasympathetic function is able to complete its reestablishment followed by system complexity recovering. PMID- 26762788 TI - Characterization of calcium oxalate crystal-induced changes in the secretome of U937 human monocytes. AB - In kidney stone disease, migratory monocytes have been found to mediate progressive renal inflammation through the secretion of numerous inflammatory mediators. However, whether calcium oxalate monohydrate (COM), which is the major crystalline compound of kidney stones, has any effects on proteins secreted from monocytes remained largely unknown. The present study aimed to characterize changes in the secretome of U937 human monocytes induced by COM crystals. The viability of cells in serum/protein-free medium was serially evaluated and the data revealed that an exposure time of 16 h was optimal for this study, whereas prolonged incubation for 24 h resulted in declined cell viability. Using this optimal time-point, the secreted proteins recovered from serum/protein-free culture supernatants of controlled and COM-treated cells were resolved in 2-DE and stained with Deep Purple fluorescent dye. Quantitative intensity analysis revealed statistically significant changes in levels of 18 secreted proteins (14 increased and 4 decreased) from COM-treated cells. These significantly altered secreted proteins were then identified by Q-TOF MS and/or MS/MS analyses. Among these, the increased levels of secreted heat shock protein 90 (HSP90), HSP70 and beta-actin were confirmed by Western blot analysis. The increased level of extracellular HSP90 was confirmed on the COM-treated cell surface by the immunofluorescence study, whereas the increased secretion of IFN-alpha was validated by ELISA. Global protein network analysis, literature search and bioinformatics revealed that these significantly altered secreted proteins were involved mainly in immune response and cell survival. Therefore, changes in the secretome of monocytes induced by COM crystals may be related, at least in part, to progressive renal inflammation found in kidney stone disease. PMID- 26762789 TI - Ligand-Enabled, Copper-Promoted Regio- and Chemoselective Hydroxylation of Arenes, Aryl Halides, and Aryl Methyl Ethers. AB - We report here a practical method for the ortho C-H hydroxylation of benzamides with inexpensive copper(II) acetate monohydrate and a pyridine ligand. An intra- and intermolecular ligand combination was explored to achieve regio- and chemoselective hydroxylation. Interestingly, typical regiochemical scrambling associated with the C-H activation was further resolved by introducing a ligand directed ortho hydroxylation of haloarenes and aryl methyl ethers. PMID- 26762791 TI - Re: Meckel-Gruber syndrome: prevalence from a hospital based in Oman. PMID- 26762790 TI - Aconitum-Derived Bulleyaconitine A Exhibits Antihypersensitivity Through Direct Stimulating Dynorphin A Expression in Spinal Microglia. AB - Aconitine and its structurally-related diterpenoid alkaloids have been shown to interact differentially with neuronal voltage-dependent sodium channels, which was suggested to be responsible for their analgesia and toxicity. Bulleyaconitine A (BAA) is an aconitine analogue and has been prescribed for the management of pain. The present study aimed to evaluate the inhibitory effects of BAA on pain hypersensitivity and morphine antinociceptive tolerance, and explore whether the expression of dynorphin A in spinal microglia was responsible for its actions. Single intrathecal or subcutaneous (but not intraventricular or local) injection of BAA blocked spinal nerve ligation-induced painful neuropathy, bone cancer induced pain, and formalin-induced tonic pain by 60 to 100% with the median effective dose values of 94 to 126 ng per rat (intrathecal) and 42 to 59 MUg/kg (subcutaneous), respectively. After chronic treatment, BAA did not induce either self-tolerance to antinociception or cross-tolerance to morphine antinociception, and completely inhibited morphine tolerance. The microglial inhibitor minocycline entirely blocked spinal BAA (but not exogenous dynorphin A) antinociception, but failed to attenuate spinal BAA neurotoxicity. In a minocycline-sensitive and lidocaine- or ropivacaine-insensitive manner, BAA stimulated the expression of dynorphin A in the spinal cord, and primary cultures of microglia but not of neurons or astrocytes. The blockade effects of BAA on nociception and morphine tolerance were totally eliminated by the specific dynorphin A antiserum and/or kappa-opioid receptor antagonist. Our results suggest that BAA eliminates pain hypersensitivity and morphine tolerance through directly stimulating dynorphin A expression in spinal microglia, which is not dependent on the interactions with sodium channels. PERSPECTIVE: The newly illustrated mechanisms underlying BAA antinociception help us to better understand and develop novel dynorphin A expression-based painkillers to treat chronic pain. PMID- 26762792 TI - Second-order motion compensated PRESS for cardiac spectroscopy. AB - PURPOSE: Second-order motion compensation for point-resolved spectroscopy (PRESS) is proposed to allow for robust single-voxel cardiac spectroscopy throughout the entire cardiac cycle and at various heart rates. METHODS: Bipolar FID spoiling gradient pairs compensating for first and second-order motion were designed and implemented into a cardiac-triggered PRESS sequence on a clinical MR system. A numerical three-dimensional model of cardiac motion was used to optimize and validate the gradient waveforms. In vivo measurements in healthy volunteers were obtained to assess the signal-to-noise ratio (SNR) and triglyceride-to-water ratio (TG/W). SNR gains and variability of TG/W of the proposed approach were evaluated against a conventional PRESS sequence with optimized gradients. RESULTS: The proposed sequence increases the mean SNR by 32% (W) and 23% (TG) on average with significantly lower variability for different trigger delays. The variability of TG/W quantification over the cardiac cycle is significantly decreased with second-order motion compensated PRESS when compared with conventional PRESS with reduced-spoiler gradients (coefficient of variation: 0.1 +/- 0.02 versus 0.37 +/- 0.26). CONCLUSION: Second-order motion compensated PRESS effectively reduces cardiac motion-induced signal degradation during FID spoiling, providing higher SNR and less variability for TG/W quantification. The sequence is considered promising to assess the TG/W modulation during various interventions including pharmacologically induced stress. Magn Reson Med 77:57 64, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26762793 TI - Effect of noise pollution on testicular tissue and hormonal assessment in rat. AB - Many studies have focused on the effect of noise stress on the health. So far, few studies have been conducted on the effect of noise on reproductive system. The aim of study was to investigate the effect of noise pollution on morphometric parameters of testicular tissue and hormonal assessment (ACTH, cortisol and testosterone). In this study, 40 male rats were exposed to control, 95, 105 and 115 dB noise intensity for sixty days. At the end of study, blood sampling was performed and ACTH, cortisol and testosterone concentrations were assessed. The results showed that noise stress decreased testosterone levels in the 115 dB treated group, while it increased the ACTH and cortisol levels. Histological sections of testis showed that the mean diameter of the seminiferous tubules and thickness of the germinal epithelium reduced compared to the control group. Also the ratio of the interstitial tissue area to the total testicular tissue area was increased significantly. Our study shows that noise stress may have negative influences on male fertility. PMID- 26762794 TI - Exploring mild enzymatic sustainable routes for the synthesis of bio-degradable aromatic-aliphatic oligoesters. AB - The application of Candida antarctica lipase B in enzyme-catalyzed synthesis of aromatic-aliphatic oligoesters is here reported. The aim of the present study is to systematically investigate the most favorable conditions for the enzyme catalyzed synthesis of aromatic-aliphatic oligomers using commercially available monomers. Reaction conditions and enzyme selectivity for polymerization of various commercially available monomers were considered using different inactivated/activated aromatic monomers combined with linear polyols ranging from C2 to C12 . The effect of various reaction solvents in enzymatic polymerization was assessed and toluene allowed to achieve the highest conversions for the reaction of dimethyl isophthalate with 1,4-butanediol and with 1,10-decanediol (88 and 87% monomer conversion respectively). Mw as high as 1512 Da was obtained from the reaction of dimethyl isophthalate with 1,10-decanediol. The obtained oligomers have potential applications as raw materials in personal and home care formulations, for the production of aliphatic-aromatic block co-polymers or can be further functionalized with various moieties for a subsequent photo- or radical polymerization. PMID- 26762795 TI - Hypogammaglobulinemias in infants and toddlers with mastocytosis - a new aspect to analyze? PMID- 26762797 TI - Postural control and freezing of gait in Parkinson's disease. AB - INTRODUCTION: The relationship between freezing of gait (FOG) and postural instability in Parkinson's disease (PD) is unclear. We analyzed the impact of FOG on postural control. METHODS: 31 PD patients with FOG (PD+FOG), 27 PD patients without FOG (PD-FOG) and 22 healthy control (HC) were assessed in the ON state. Postural control was measured with the Fullerton Advanced Balance (FAB) scale and with center of pressure (COP) analysis during quiet stance and maximal voluntary forward/backward leaning. RESULTS: The groups were balanced concerning age, disease duration and disease severity. PD+FOG performed significantly worse in the FAB scale (21.8 +/- 5.8) compared to PD-FOG (25.6 +/- 5.0) and HC (34.9 +/- 2.4) (mean +/- SD, p < 0.01). PD+FOG had impaired ability to voluntary lean forward, difficulties to stand on foam with eyes closed and reduced limits of stability compared to PD-FOG (p < 0.05). During quiet stance the average anterior posterior COP position was significantly displaced towards posterior in PD+FOG in comparison to PD-FOG and HC (p < 0.05). The COP position correlated with severity of FOG (p < 0.01). PD+FOG and PD-FOG did not differ in average COP sway excursion, sway velocity, sway regularity and postural control asymmetry. CONCLUSIONS: PD+FOG have reduced postural control compared to PD-FOG and HC. Our results show a relationship between the anterior-posterior COP position during quiet stance and FOG. The COP shift towards posterior in PD+FOG leads to a restricted precondition to generate forward progression during gait initiation. This may contribute to the occurrence of FOG or might be a compensatory strategy to avoid forward falls. PMID- 26762798 TI - Extended Swan-Neck Catheter With Upper Abdominal Exit-Site Reduces Peritoneal Dialysis-Related Infections. AB - Extended catheters with an upper abdominal exit-site (UAE) are reportedly associated with a lower incidence of peritoneal dialysis (PD)-related infections. However, little information about the optimal peritoneal catheter configuration for UAE is available. In this nonrandomized multicenter trial, 147 consecutive cases of a UAE involving either a conventional straight (CS; 80 cases) or extended swan-neck catheter (SN; 67 cases) were analyzed to compare exit-site and tunnel infections (ESTI), peritonitis, and catheter survival. The ESTI-free and catheter survival rates were significantly lower in the SN than in the CS group (P <0.01). However, the peritonitis-free survival rate was not different (P = 0.26). In terms of analyses for infection rates, fewer episodes of ESTI (1.284 vs 0.608 episodes/patient-year; P <0.01) and peritonitis (0.345 vs 0.152 episodes/patient-year; P = 0.06) were observed in the SN than CS group. Recurrence analyses showed that the mean number of cumulative episodes of ESTI and peritonitis between two groups were significantly different. PMID- 26762799 TI - Broadly Neutralizing Antibody-Guided Carbohydrate-Based HIV Vaccine Design: Challenges and Opportunities. AB - The HIV envelope (Env) is heavily glycosylated, facilitating the spread and survival of HIV in many ways. Some potent broadly neutralizing antibodies (bnAbs) such as 2G12, PG9, PG16, and PGTs can recognize the conserved glycan residues on Env. The bnAbs, which often emerge after many years of chronic infection, provide insight into the vulnerability of HIV and can therefore guide the design of vaccines. Many carbohydrate-conjugated vaccines have been designed to induce bnAb like antibodies, but none have yet been successful. The low antigenicity of these vaccines is one possible explanation. New strategies have been applied to obtain high-affinity antigens of glycan-dependent and other bnAbs. However, when used as immunogens in vivo, high-affinity antigens are still insufficient in eliciting bnAb-like antibodies. bnAbs generally possess some unusual features and may therefore be suppressed by the host immune system. In view of this situation, some immunization regimens based on the affinity maturation of antibodies have been tested. Herein we summarize recent studies into the design of carbohydrate based HIV vaccines and some valuable experiences gained in work with other bnAb based HIV vaccines. PMID- 26762800 TI - Cholinergic excitation from the pedunculopontine tegmental nucleus to the dentate nucleus in the rat. AB - In spite of the existence of pedunculopontine tegmental nucleus (PPTg) projections to cerebellar nuclei, their nature and functional role is unknown. These fibers may play a crucial role in postural control and may be involved in the beneficial effects induced by deep-brain stimulation (DBS) of brainstem structures in motor disorders. We investigated the effects of PPTg microstimulation on single-unit activity of dentate, fastigial and interpositus nuclei. The effects of PPTg stimulation were also studied in rats whose PPTg neurons were destroyed by ibotenic acid and subsequently subjected to iontophoretically applied cholinergic antagonists. The main response recorded in cerebellar nuclei was a short-latency (1.5-2 ms) and brief (13-15 ms) orthodromic activation. The dentate nucleus was the most responsive to PPTg stimulation. The destruction of PPTg cells reduced the occurrence of PPTg-evoked activation of dentate neurons, suggesting that the effect was due to stimulation of cell bodies and not due to fibers passing through or close to the PPTg. Application of cholinergic antagonists reduced or eliminated the PPTg-evoked response recorded in the dentate nucleus. The results show that excitation is exerted by the PPTg on the cerebellar nuclei, in particular on the dentate nucleus. Taken together with the reduction of nicotinamide adenine dinucleotide phosphate-diaphorase positive neurons in lesioned animals, the iontophoretic experiments suggest that the activation of dentate neurons is due to cholinergic fibers. These data help to explain the effects of DBS of the PPTg on axial motor disabilities in neurodegenerative disorders. PMID- 26762801 TI - Dual-task-related neural connectivity changes in patients with Parkinson' disease. AB - BACKGROUND AND OBJECTIVES: Dual-task (DT) gait impairment in people with Parkinson's disease (PD) and specifically in those with freezing of gait (FOG), reflects attentional dependency of movement. This study aimed to elucidate resting-state brain connectivity alterations related to DT gait abnormalities in PD with and without FOG. METHODS: PD patients (n=73) and healthy age-matched controls (n=20) underwent DT gait analysis and resting-state functional Magnetic Resonance Imaging (rs-MRI) while 'off' medication. Patients were classified as freezer (n=13) or non-freezer (n=60). Functional connectivity (FC) alterations between PD and controls and between patient subgroups were assessed in regions of interest (ROIs) within the fronto-parietal and motor network. RESULTS: PD had longer stance times, shorter swing times and more step length asymmetry during DT gait and needed more time and steps during DT turning compared to controls. Additionally, freezers showed similar impairments and longer double support times compared to non-freezers during DT gait. PD demonstrated hyper-connectivity between the inferior parietal lobule and premotor cortex (PMC) and between the cerebellum and the PMC and M1. FOG-specific hypo-connectivity within the striatum and between the caudate and superior temporal lobe and hyper-connectivity between the dorsal putamen and precuneus was correlated with worse DT performance. CONCLUSION: PD showed FC alterations in DT-related networks, which were not correlated to DT performance. However, FOG-specific FC alterations in DT-related regions involving the precuneus and striatum were correlated to worse DT performance, suggesting that the balance between cognitive and motor networks is altered. PMID- 26762803 TI - Major dorsoventral differences in the modulation of the local CA1 hippocampal network by NMDA, mGlu5, adenosine A2A and cannabinoid CB1 receptors. AB - Recent research points to diversification in the local neuronal circuitry between dorsal (DH) and ventral (VH) hippocampus that may be involved in the large-scale functional segregation along the long axis of the hippocampus. Here, using CA1 field recordings from rat hippocampal slices, we show that activation of N-methyl d-aspartate receptors (NMDARs) reduced excitatory transmission more in VH than in DH, with an adenosine A1 receptor-independent mechanism, and reduced inhibition and enhanced postsynaptic excitability only in DH. Strikingly, co-activation of metabotropic glutamate receptor-5 (mGluR5) with NMDAR, by CHPG and NMDA respectively, strongly potentiated the effects of NMDAR in DH but had not any potentiating effect in VH. Furthermore, the synergistic actions in DH were occluded by blockade of adenosine A2A receptors (A2ARs) by their antagonist ZM 241385 demonstrating a tonic action of these receptors in DH. Exogenous activation of A2ARs by 4-[2-[[6-amino-9-(N-ethyl-beta-D-ribofuranuronamidosyl)-9H purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride (CGS 21680) did not change the effects of mGluR5-NMDAR co-activation in either hippocampal pole. Importantly, blockade of cannabinoid CB1 receptors (CB1Rs) by their antagonist 1 (2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3 carboxamide (AM 281) restricted the synergistic actions of mGluR5-NMDARs on excitatory synaptic transmission and postsynaptic excitability and abolished their effect on inhibition. Furthermore, AM 281 increased the excitatory transmission only in DH indicating that CB1Rs were tonically active in DH but not VH. Removing the magnesium ions from the perfusion medium neither stimulated the interaction between mGluR5 and NMDAR in VH nor augmented the synergy of the two receptors in DH. These findings show that the NMDAR-dependent modulation of fundamental parameters of the local neuronal network, by mGluR5, A2AR and CB1R, markedly differs between DH and VH. We propose that the higher modulatory role of A2AR and mGluR5, in combination with the role of CB1Rs, provide DH with higher functional flexibility of its NMDARs, compared with VH. PMID- 26762802 TI - Changes in the disposition of substance P in the rostral ventromedial medulla after inflammatory injury in the rat. AB - This study examined whether peripheral inflammatory injury increases the levels or changes the disposition of substance P (SubP) in the rostral ventromedial medulla (RVM), which serves as a central relay in bulbospinal pathways of pain modulation. Enzyme immunoassay and reverse transcriptase quantitative polymerase chain reaction were used to measure SubP protein and transcript, respectively, in tissue homogenates prepared from the RVM and the periaqueductal gray (PAG) and cuneiform nuclei of rats that had received an intraplantar injection of saline or complete Freund's adjuvant (CFA). Matrix-Assisted Laser Desorption/Ionization Time of Flight analysis confirmed that the RVM does not contain hemokinin-1 (HK 1), which can confound measurements of SubP because it is recognized equally well by commercial antibodies for SubP. Levels of SubP protein in the RVM were unchanged four hours, four days and two weeks after injection of CFA. Tac1 transcripts were similarly unchanged in the RVM four days or two weeks after CFA. In contrast, the density of SubP immunoreactive processes in the RVM increased 2 fold within four hours and 2.7-fold four days after CFA injection; it was unchanged at two weeks. SubP-immunoreactive processes in the RVM include axon terminals of neurons located in the PAG and cuneiform nucleus. SubP content in homogenates of the PAG and cuneiform nucleus was significantly increased four days after CFA, but not at four hours or two weeks. Tac1 transcripts in homogenates of these nuclei were unchanged four days and two weeks after CFA. These findings suggest that there is an increased mobilization of SubP within processes in the RVM shortly after injury accompanied by an increased synthesis of SubP in neurons that project to the RVM. These findings are consonant with the hypothesis that an increase in SubP release in the RVM contributes to the hyperalgesia that develops after peripheral inflammatory injury. PMID- 26762804 TI - Association of myelin peptide with vitamin D prevents autoimmune encephalomyelitis development. AB - Multiple sclerosis is a chronic, inflammatory and demyelinating disease of the central nervous system (CNS). As there is no cure for this disease, new therapeutic strategies and prophylactic measures are necessary. We recently described the therapeutic activity of the association between myelin oligodendrocyte glycoprotein peptide (MOG) and active vitamin D3 (VitD) against experimental autoimmune encephalomyelitis (EAE). The objective of this work was to evaluate the prophylactic potential of this association in EAE. C57BL/6 mice were vaccinated with MOG in the presence of VitD and then subjected to EAE induction. Animals were euthanized 7 and 19days after disease induction and the following parameters were evaluated: body weight, clinical score, inflammatory process in the CNS, amount of dendritic cells (DCs) and regulatory T cells in the spleen and cytokine production by spleen and CNS cell cultures. Vaccination with MOG associated with VitD determined a drastic reduction in clinical score, body weight loss, CNS inflammation, DCs maturation and also in the production of cytokines by CNS and spleen cell cultures. Collectively, our data indicate that this association prevents EAE development. A similar effect from specific self antigens associated with VitD is expected in other autoimmune conditions and deserves to be experimentally appraised. PMID- 26762807 TI - Risk Analysis of Prostate Cancer in PRACTICAL Consortium-Letter. PMID- 26762806 TI - Statin Use and Breast Cancer Risk in the Nurses' Health Study. AB - Preclinical studies support an anticancer effect of statin drugs, yet epidemiologic evidence remains inconsistent regarding their role in breast cancer primary prevention. Here, we report an updated analysis of the association between statin use and breast cancer incidence in the Nurses' Health Study (NHS) cohort. Postmenopausal NHS participants without a cancer history were followed from 2000 until 2012 (n = 79,518). Data on statin use were retrieved from biennial questionnaires. We fit Cox regression models to estimate associations between longitudinal statin use and breast cancer incidence. Over 823,086 person years of follow-up, 3,055 cases of invasive breast cancer occurred. Compared with never users, both former and current statin users had similar rates of invasive breast cancer incidence [former users: HRadj, 0.96; 95% confidence interval (CI), 0.82-1.1; current users: HRadj, 1.1; 95% CI, 0.92-1.3]. Associations did not differ by estrogen receptor (ER) status or histology (ductal vs. lobular carcinoma). Statin use was not associated with risk of invasive breast cancer, irrespective of histologic subtype and ER status. Statin drugs do not appear to modify processes involved in breast cancer initiation. PMID- 26762808 TI - Risk Analysis of Prostate Cancer in PRACTICAL Consortium--Response. PMID- 26762809 TI - Job Talks and Interviews: How to Stand Out and Fit In: A Report from the American Society of Preventive Oncology Junior Members Interest Group. PMID- 26762810 TI - Revisiting the concept of a symmetric index of agreement for continuous datasets. AB - Quantifying how close two datasets are to each other is a common and necessary undertaking in scientific research. The Pearson product-moment correlation coefficient r is a widely used measure of the degree of linear dependence between two data series, but it gives no indication of how similar the values of these series are in magnitude. Although a number of indexes have been proposed to compare a dataset with a reference, only few are available to compare two datasets of equivalent (or unknown) reliability. After a brief review and numerical tests of the metrics designed to accomplish this task, this paper shows how an index proposed by Mielke can, with a minor modification, satisfy a series of desired properties, namely to be adimensional, bounded, symmetric, easy to compute and directly interpretable with respect to r. We thus show that this index can be considered as a natural extension to r that downregulates the value of r according to the bias between analysed datasets. The paper also proposes an effective way to disentangle the systematic and the unsystematic contribution to this agreement based on eigen decompositions. The use and value of the index is also illustrated on synthetic and real datasets. PMID- 26762812 TI - m-CPBA Mediated Metal Free, Rapid Oxidation of Aliphatic Amines to Oximes. AB - An efficient, rapid oxidation of various aliphatic amines to oximes using m-CPBA as an oxidant in ethyl acetate is described. High conversion (100%) with >90% oxime selectivity is achieved at room temperature under catalyst-free conditions. Mild reaction conditions along with an easy work up procedure offer lower byproduct formation and high selectivity for oximes in good yield and purity. PMID- 26762811 TI - Consequences of bilateral cryptorchidism in adults. AB - Bilateral cryptorchidism treatment results are often shadowed by the majority of unilateral cases. We report the long-term follow-up results of boys treated for bilateral cryptorchidism during childhood. Patients treated in two main paediatric surgery centres were selected from medical registries and invited for a clinical examination including scrotal ultrasound, salivary testosterone measurement and a semen sample. Thirty-six men (38.3%) replied to the written invitation, and 21 agreed to be examined. The mean age at orchidopexy was 74 months (range 24-138). Sperm count was 0.42 * 106 (SD +/- 0.64 * 106 ) ml-1 . The correlation between total testicular volume and total sperm count was statistically significant (r = 0.481; P = 0.032). These results show that surgical treatment of bilateral cryptorchidism after the age of 2 years does not prevent infertility. Sperm count and endocrine evaluation advocated after the treatment of bilateral cryptorchidism in all adult patients. PMID- 26762813 TI - Anomalous liquid imbibition at the nanoscale: the critical role of interfacial deformations. AB - We observed that imbibition of various Rhodamine B-doped wetting liquids in an array of different-sized, horizontal, two-dimensional silica nanochannels terminated within the channels as a function of hydraulic diameter and liquid type. This front termination is not predicted by the classic Washburn equation for capillary flow, which establishes diffusive dynamics in horizontal channels. Various explanations for the anomalous static imbibition measurements were negated; hydrodynamics, thermodynamics, surface chemistry and mechanics were all taken into consideration for this analysis. The atypical imbibition data are explained by deformed menisci and decreased effective channel diameters. These occurrences are due to the enhanced influence of the following phenomena at the nanoscale: surface forces at fluid-solid boundaries, the presence of quasi crystalline thin films or boundary regions, and potential solid surface or boundary layer deformation due to meniscus-induced negative pressures (suction). We introduce a phenomenological model which demonstrates how van der Waals forces, common to all interfaces, lead to local menisci deformation and an average reduction in capillary pressure. An expression for the approximate capillary pressure of a symmetric nanoscale meniscus in a cylindrical pore space is derived; its difference from the macroscopic capillary pressure can be expressed by an effective contact angle. Precursor films, adsorbed films and elastocapillary deformation decrease effective diameter, exacerbating meniscus deformation and increases in effective viscosity; we also describe local models and effective values for these phenomena. The findings can be scaled to imbibition and two-phase flow in nanoporous media. PMID- 26762814 TI - Substitutionally doped phosphorene: electronic properties and gas sensing. AB - Phosphorene, a new elemental two-dimensional material, has attracted increasing attention owing to its intriguing electronic properties. In particular, pristine phospohorene, due to its ultrahigh surface-volume ratio and high chemical activity, has been shown to be promising for gas sensing (Abbas et al 2015 ACS Nano 9 5618). To further enhance its sensing ability, we perform first-principles calculations based on density functional theory to study substitutionally doped phosphorene with 17 different atoms, focusing on structures, energetics, electronic properties and gas sensing. Our calculations reveal that anionic X (X = O, C and S) dopants have a large binding energy and highly dispersive electronic states, signifying the formation of covalent X-P bonds and thus strong structural stability. Alkali atom (Li and Na) doping is found to donate most of the electrons in the outer s-orbital by forming ionic bonds with P, and the band gap decreases by pushing down the conduction band, suggesting that the optical and electronic properties of the doped phosphorene can be tailored. For doping with VIIIB-group (Fe, Co and Ni) elements, a strong affinity is predicted and the binding energy and charge transfer are correlated strongly with their electronegativity. By examining NO molecule adsorption, we find that these metal doped phosphorenes (MDPs) in general exhibit a significantly enhanced chemical activity compared with pristine phosphorene. Our study suggests that substitutionally doped phosphorene shows many intriguing electronic and optic properties different from pristine phosphorene and MDPs are promising in chemical applications involving molecular adsorption and desorption processes, such as materials growth, catalysis, gas sensing and storage. PMID- 26762816 TI - Update: Do probiotics prevent or treat pediatric atopic dermatitis? PMID- 26762815 TI - On the accuracy and precision of cardiac magnetic resonance T2 mapping: A high resolution radial study using adiabatic T2 preparation at 3 T. AB - PURPOSE: The goal of this study was to characterize the accuracy and precision of cardiac T2 mapping as a function of different factors including low signal-to noise ratio (SNR), imaging in systole, and off-resonance frequencies. METHODS: Bloch equation and Monte Carlo simulations were used to determine the influence of SNR and the choice of T2 preparation echo time (TET2prep ) increments on the accuracy and precision of high-resolution radial cardiac T2 mapping at 3.0 T. Healthy volunteers were scanned to establish the difference in precision and inter- and intraobserver variability between T2 mapping in diastole and systole, as well as the effect of SNR and off-resonance frequencies on the accuracy of T2 maps. RESULTS: The simulations demonstrated that a TET2prep increment of ~0.75 times the T2 value of interest optimally increases the precision of the T2 fit. Systolic T2 maps were found to have a higher precision (P = 0.002), but similar inter- and intraobserver variability compared with diastolic T2 maps, whereas off resonance frequencies beyond +/- 100 Hz cause a significant decrease in both accuracy and precision (P < 0.05). CONCLUSION: This evaluation of the accuracy and precision of cardiac T2 mapping characterizes the major vulnerabilities of the technique and will help guide protocol definition of studies that include T2 mapping. Magn Reson Med 77:159-169, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26762817 TI - Strabismus, a preventable barrier to social participation: a short report. AB - Isolated strabismus does not significantly impair visual functionality and has traditionally been considered a primarily cosmetic defect of little importance. However, even in the absence of strabismus amblyopia, manifest strabismus and its non-surgical treatments can render the person less socially acceptable, creating a barrier to participation and resulting in psychosocial disadvantage that has been documented in the typically developing population. The Australian Cerebral Palsy Register traditionally recorded strabismus only if it were not accompanied by visual impairment; however, even these data indicate that the proportion of cerebral palsy registrants with strabismus is many times higher than in comparable population samples, compounding their challenges to achieve participation. It is therefore inappropriate to continue to consider strabismus as merely a cosmetic defect, but one that deserves surgical correction early in life. PMID- 26762818 TI - Perceived School Climate and Chinese Adolescents' Suicidal Ideation and Suicide Attempts: The Mediating Role of Sleep Quality. AB - BACKGROUND: School factors play important roles in adolescent suicide. However, little is known about how school climate is associated with adolescent suicide. This study examined the relationship between perceived school climate and adolescent suicidal ideation and suicide attempts, and whether these relations were explained by adolescent sleep quality. METHODS: A total of 1529 Chinese adolescents (mean age = 14.74 years; 52% boys) participated in the study. They provided self-report data on control variables, perceived school climate, sleep quality, suicidal ideation, and suicide attempts. RESULTS: After controlling for sex, age, family structure, socioeconomic status, and parent-adolescent attachment, we found that perceived school climate negatively predicted adolescent suicidal ideation (odds ratio [OR] = 0.66, p < .001) and suicide attempts (OR = 0.72, p < .001). Moreover, perceived school climate positively predicated adolescent sleep quality (beta = 0.13, p < .001), which in turn, negatively predicted adolescent suicidal ideation (OR = 0.75, p < .001) and suicide attempts (OR = 0.76, p < .001). CONCLUSION: These findings, although cross-sectional, indicate that perceived school climate plays an important role in adolescent suicidality. Moreover, the relation between perceived school climate and adolescent suicidality was largely mediated by adolescent sleep quality. PMID- 26762820 TI - Barriers to Addressing Adolescent Substance Use: Perceptions of New York School Based Health Center Providers. AB - BACKGROUND: Adolescent substance use is associated with chronic health conditions, accidents, injury, and school-related problems, including dropping out. Schools have the potential to provide students with substance use prevention and intervention services, albeit with confidentiality challenges. School-based health centers (SBHCs) provide confidentiality, positioning them as ideal settings to provide substance use prevention and intervention. This study identified program directors' and clinicians' barriers to addressing adolescent substance use in SBHCs. METHODS: Between May and June 2013, an electronic survey was distributed to all 162 New York State SBHC program directors and clinicians serving middle and high school students. RESULTS: The most prevalent perceived barriers to discussing substance use with students were time constraints (43%), the belief that students are not honest about their use (43%), and clinicians' lack of training (28%). Both directors and clinicians identified challenges in getting students to return for additional sessions to address their use, and they also indicated that confidentiality was a treatment referral barrier. CONCLUSIONS: This study identified timely opportunities that may be leveraged and unique challenges that may be overcome with targeted dissemination, training, and technical assistance efforts to enable directors and clinicians to routinely address substance use in SBHCs. PMID- 26762821 TI - Individual and School-Level Socioeconomic Gradients in Physical Activity in Australian Schoolchildren. AB - BACKGROUND: We attempted to determine whether there was a socioeconomic gradient in 9- to 11-year-old Australian children's moderate-to-vigorous physical activity (MVPA), and whether school facilities or policies supporting physical activity were associated with school-level socioeconomic status (SES) and MVPA. METHODS: Children (N = 528) from 26 randomly selected schools participated in the International Study of Childhood Obesity, Lifestyle and the Environment. School level SES was determined by the Index of Community Socio-Educational Advantage. MVPA was determined from 7-day, 24-hour accelerometry. School facilities (21 items) were evaluated with an objective school ground audit. School policies related to physical activity were collected (18 items) in a school administrator survey. Relationships among SES, MVPA, school facilities, and policies were examined using bivariate regression, correlation analyses, and analysis of variance. RESULTS: There was a clear SES gradient in daily and in-school MVPA. School facilities or physical activity policies were not associated with SES or in-school MVPA, with the exception of presence of a sports field which was associated with lower SES schools (p = .02) and lower in-school MVPA (p = .001). CONCLUSIONS: School-built, policy, and resource environments are similar across different SES-level schools. Therefore, some other mechanism must be underlying the SES gradients seen in MVPA participation in Australian children. PMID- 26762819 TI - Behaviors and Knowledge of HealthCorps New York City High School Students: Nutrition, Mental Health, and Physical Activity. AB - BACKGROUND: HealthCorps provides school wellness programming using curricula to promote changes in nutrition, mental health, and physical activity behaviors. The research objective was to evaluate effects of implementing its curricula on nutrition, mental health, and physical activity knowledge and behavior. METHODS: Pre- and postsurvey data were collected (N = 2255) during the 2012-2013 academic year from 14 New York City public high schools. An 18-item knowledge questionnaire addressed 3 domains; 26 behavioral items were analyzed by factor analysis to identify 6 behavior domains, breakfast being a seventh 1-item domain. We examined the effects stratified by sex, applying mixed-effects models to take into account clustering effects of schools and participants adjusted for age. RESULTS: The HealthCorps program significantly increased all 3 knowledge domains (p < .05), and significantly changed several key behavioral domains. Boys significantly increased fruits/vegetables intake (p = .03). Girls increased acceptance of new fruits/vegetables (p = .03) and breakfast consumption (p = .04), and decreased sugar-sweetened beverages and energy dense food intake (p = .03). The associations between knowledge and behavior were stronger in boys than girls. CONCLUSION: The HealthCorps program significantly increased participants' knowledge on nutrition, mental health, and physical activity. It also improved several key behavioral domains, which are targets of the 2010 Dietary Guidelines to address obesity in youth. PMID- 26762822 TI - "Reforms Looked Really Good on Paper": Rural Food Service Responses to the Healthy, Hunger-Free Kids Act of 2010. AB - BACKGROUND: The Healthy, Hunger-Free Kids Act of 2010 (HHKA) required schools to make changes to meals provided to children. Rural school districts have limited resources, with increased obesity rates and local food insecurity. In this study we sought to understand the perceptions of rural food service directors and the barriers to implementing the changes. METHODS: Food service directors from rural school districts were invited to complete a semistructured telephone interview and online survey. A total of 51 respondents completed both, 6 completed only the online survey, and 16 completed only the telephone interview. Qualitative interview data were analyzed through open thematic coding; descriptive statistics were calculated for the quantitative data. RESULTS: Food service directors mostly perceived the changes as negative, challenging, and burdensome. They believed that the changes resulted from concern about childhood obesity, which they did not view as a problem for their students. Diverse challenges were reported related to cost, preparation, and student preference. CONCLUSIONS: Food service directors in isolated, rural areas need support to enhance understanding of HHKA requirements, build professional networks to learn from one another, and communicate with students, families, and other stakeholders. Future efforts should focus on changing perceptions and supporting directors in order to make implementation a success. PMID- 26762823 TI - Geographic Disparity in Funding for School Nutrition Environments: Evidence from Mississippi Schools. AB - BACKGROUND: Despite the federal initiatives on equitable provision of school nutrition programs, geographic disparity in childhood obesity persists. It may be partly because built-in school nutrition environments rely on each school's efficient use of existing operational funds or its ability to obtain expanded financial support. This study explores how funding acquisition by schools is determined by local community characteristics and how it relates to healthy school meal offerings. METHODS: Information about food preparation technology and funding in 811 schools in Mississippi was obtained by in-depth phone interviews of district child nutrition directors and school foodservice managers, which was matched to socioeconomic indicators of schools and communities. Probit models were estimated. RESULTS: About 56% of schools in the sample received some funds toward combination oven/steamers in the last few years. Small schools, schools in non-metro counties, and those in low-income minority areas were significantly less likely to be funded. Obtainment of funds was associated with a 45 percentage point reduction in the probability of serving fried foods. CONCLUSIONS: Funds obtained by schools for advanced food preparation technology contributes to creation of healthier nutrition environments for children. However, fund availability is associated with community characteristics, possibly contributing to geographic disparity of child health. PMID- 26762824 TI - The Impact of Tobacco-Free School Policies on Youth Smoking Rates in Florida Public School Districts. AB - BACKGROUND: Developing and implementing policies to curb and prevent youth tobacco use is of the utmost importance. In Florida, public school districts were authorized to develop tobacco-free school policies through an amendment to the Florida Clean Indoor Air Act in 2011. The purpose of this study is to determine the impact of tobacco-free school policies on smoking rates among youth in Florida. METHODS: Analysis of covariance (ANCOVA) and a multiple regression analysis were used to determine whether the comprehensiveness and enforcement of tobacco-free school policies affect the youth smoking rates within Florida public school districts. The 2010 and 2014 youth smoking rates were calculated based on the Florida Youth Tobacco Survey results. RESULTS: The 2010 youth smoking rate and the inclusion of the enforcement component with provision of cessation resources were statistically significant predictors of the 2014 youth smoking rate. However, the comprehensiveness level of a policy and the inclusion of an enforcement component were not statistically significant predictors. CONCLUSIONS: The inclusion of an enforcement component with provision of cessation resources is important in efforts to reduce youth smoking rates. The content of the tobacco free school policies seems to be less relevant to their effectiveness than the enforcement of the policies. PMID- 26762825 TI - Low Frequency of Fruit and Vegetable Consumption Among Canadian Youth: Findings From the 2012/2013 Youth Smoking Survey. AB - BACKGROUND: Frequent fruit and vegetable (FV) consumption is protective against some cancers, cardiovascular disease, and other chronic diseases. This study explores self-reported frequency of FV consumption in a nationally generalizable sample of Canadian youth in grades 6-12. METHODS: Data from grades 6-12 students who participated in the 2012-2013 Youth Smoking Survey (N = 47,203) were used to examine frequency of FV consumption. Logistic regression models were fitted to examine differences in meeting national FV intake recommendations by sociodemographic, student, and regional characteristics. RESULTS: Approximately 10% of Canadian grade 6-12 students met FV recommendations. Students in grades 6 and 7 had significantly higher odds of meeting recommendations relative to students in grades 8-12. Students who reported achieving "mostly As" on their report cards had significantly higher odds of meeting FV recommendations relative to those receiving As and Bs, Bs and Cs, or Cs (OR = 0.71, OR = 0.53, and OR = 0.46, respectively, p < .0001 for each). Students in British Columbia and Ontario had higher odds of meeting recommendations relative to students in Newfoundland, Prince Edward Island, and Nova Scotia. CONCLUSIONS: Only 1 in 10 Canadian youth are meeting FV recommendations. Programs and policies to encourage FV consumption are required to help mitigate future health issues associated with inadequate FV consumption. PMID- 26762827 TI - Should national guidelines continue to recommend fetal scalp blood sampling during labor? AB - Intrapartum fetal scalp blood sampling (FBS) (pH or lactate) has not been shown to reduce emergency cesarean sections or operative vaginal births or improve long term perinatal outcomes. In contrast, it is associated with rare but potentially very serious complications such as leakage of cerebro-spinal fluid (CSF) and perinatal hemorrhagic shock. Therefore, it does not fulfill the "First Do No Harm" principle and its use during labor should be critically re-evaluated. PMID- 26762829 TI - A century later and not much has changed in use of Anatomic Nomenclature: should surgeons and anatomists be speaking the same language? PMID- 26762828 TI - Trends in bariatric surgery from 2008 to 2012. AB - BACKGROUND: Obesity is a global epidemic that has been increasing in prevalence. The only treatment method for durable weight loss is bariatric surgery. The aim of this study was to observe trends in usage and outcomes of bariatric operations used in the United States from 2008 to 2012. METHODS: Analysis was performed on bariatric surgery admissions from 2008 to 2012 based off of the Nationwide Inpatient Sample database. Data were selected from using International Classification of Disease, 9th Revision codes correlating to bariatric procedures for the purpose of obesity. Annual estimates and trends were reviewed for patient demographics, procedure type, patient outcomes, and length of stay (LOS). RESULTS: A total of 598,756 bariatric procedures were examined. Laparoscopic gastric bypass was the most commonly used surgical method in 2008 (58.2%). A decreasing trend in its use, and the use of laparoscopic gastric banding (LGB), was equipoised with increasing use of laparoscopic sleeve gastrectomy (LSG). Use of LSG accounted for 8.2% of procedures in 2011 and 39.6% in 2012. LGB and LSG had the lowest rates of complications, in-hospital morbidity and mortality, and the shortest LOS whereas open bypass and duodenal switch had the highest rates of complications, in-hospital morbidity and mortality, and longest LOSs. Overall rates of venous thromboembolism increased from .08% in 2008 to .215% in 2012. Respiratory complications decreased from 6.1% to 3.9%. There were no observed trends in rates of renal complications, visceral injury, bleeding, and infections. In-hospital morbidity decreased, whereas mortality rates were stable at .1%. CONCLUSIONS: The utilization of bariatric procedures has reached a plateau in the United States. Changes in the composition of procedural types suggest that LSG has become a popular alternative to gastric bypass and LGB. PMID- 26762826 TI - The Role of Physical Education Lessons and Recesses in School Lifestyle of Adolescents. AB - BACKGROUND: This study investigates school lifestyle among adolescents in terms of physical activity (PA) structure: (1) adolescents participating in a physical education lesson (PEL) versus (2) aggregate recess time exceeding 60 minutes. METHODS: The research was conducted in 24 secondary schools in the Czech Republic (boys N = 208, girls N = 433). For the whole day (1-3 days) participants wore the ActiTrainer accelerometer, which monitored PA, and heart rate. A total of 1122 school days were recorded. RESULTS: Both boys and girls participating in a PEL reported significantly better results compared with nonparticipating individuals regarding all indicators of volume and intensity of school PA (SPA). In most SPA indicators, longer aggregate recess time (>60 minutes) had a statistically significant effect, particularly on the volume of SPA. The recommended 500 steps/hours for SPA was achieved by 83% of boys participating in PEL and 69% of girls. In contrast just 32% of nonparticipating boys and 31% of girls reached this level. With longer recess time the recommendation was met by 43% of boys (42% of girls) compared with 26% of boys (23% of girls) with shorter recess time. CONCLUSIONS: An increase in SPA and an improved lifestyle in adolescents on school days are significantly supported more by PELs than by longer recess time. PMID- 26762830 TI - When patients call their surgeon's office: an opportunity to improve the quality of surgical care and prevent readmissions. AB - BACKGROUND: Little is known about care coordination and communication with outpatient endocrine surgery patients. This study evaluated phone calls between office nurses and surgical patients to identify common issues addressed and their effect on patient care. METHODS: Qualitative analysis of preoperative and postoperative phone conversations between office nurses and endocrine surgery patients. RESULTS: We identified 183 thyroidectomy patients with 38% contacting our office before surgery and 54% within 30 days after surgery. Common reasons for preoperative calls included questions about preoperative evaluation (21%), medications (18%), and insurance and/or work paperwork (12%). Postoperatively, common topics included medications (23%), laboratory results (23%), and concerns about wounds (12%). Nursing staff prevented unnecessary readmission in 7 patients (4%) whereas appropriately referring 16 (9%) for early evaluation. CONCLUSIONS: Patients frequently contact their surgeons before and after endocrine surgery cases. Our findings suggest several areas for improving communication with patients. PMID- 26762831 TI - The appropriate measurement of postdischarge readmissions in Medicare colon surgery. AB - BACKGROUND: Readmissions after inpatient care are being used as a metric for clinical outcomes for surgeons and hospitals, but without standardization of the appropriate postdischarge period. METHODS: Elective colon surgery (ECS) for Medicare patients was reviewed to define the frequency and causes of readmission at 30, 60, and 90 days after discharge. Elective, trauma, and cancer readmissions were excluded. A prediction model at 90 days after discharge was designed to identify risk factors that were associated with readmissions. RESULTS: A total of 107,459 live discharges after ECS had 12,746 readmissions at 30 days, 4,601 1st time readmissions at 31 to 60 days, and another 4,042 1st-time readmissions from days 61 to 90; 40% of initial and nearly 50% of all readmissions occurred from days 31 to 90. Primary causes for readmission were gastrointestinal, infectious, and cardiopulmonary events. CONCLUSIONS: The 90-day postdischarge time period provides the most accurate measurement interval for relevant readmissions after ECS. PMID- 26762832 TI - Epidural analgesia utilization rate for hepatic and pancreatic surgery, that low? PMID- 26762833 TI - Reply to: epidural analgesia utilization rate for hepatic and pancreatic surgery, that low? PMID- 26762834 TI - Allosteric inhibitors of Coxsackie virus A24 RNA polymerase. AB - Coxsackie virus A24 (CVA24), a causative agent of acute hemorrhagic conjunctivitis, is a prototype of enterovirus (EV) species C. The RNA polymerase (3D(pol)) of CVA24 can uridylylate the viral peptide linked to the genome (VPg) from distantly related EV and is thus, a good model for studying this reaction. Once UMP is bound, VPgpU primes RNA elongation. Structural and mutation data have identified a conserved binding surface for VPg on the RNA polymerase (3D(pol)), located about 20A from the active site. Here, computational docking of over 60,000 small compounds was used to select those with the lowest (best) specific binding energies (BE) for this allosteric site. Compounds with varying structures and low BE were assayed for their effect on formation of VPgU by CVA24-3D(pol). Two compounds with the lowest specific BE for the site inhibited both uridylylation and formation of VPgpolyU at 10-20MUM. These small molecules can be used to probe the role of this allosteric site in polymerase function, and may be the basis for novel antiviral compounds. PMID- 26762835 TI - Discovery of 2-(1H-indol-5-ylamino)-6-(2,4-difluorophenylsulfonyl)-8 methylpyrido[2,3-d]pyrimidin-7(8H)-one (7ao) as a potent selective inhibitor of Polo like kinase 2 (PLK2). AB - Several families of protein kinases have been shown to play a critical role in the regulation of cell cycle progression, particularly progression through mitosis. These kinase families include the Aurora kinases, the Mps1 gene product and the Polo Like family of protein kinases (PLKs). The PLK family consists of five members and of these, the role of PLK1 in human cancer is well documented. PLK2 (SNK), which is highly homologous to PLK1, has been shown to play a critical role in centriole duplication and is also believed to play a regulatory role in the survival pathway by physically stabilizing the TSC1/2 complex in tumor cells under hypoxic conditions. As a part of our research program, we have developed a library of novel ATP mimetic chemotypes that are cytotoxic against a panel of cancer cell lines. We show that one of these chemotypes, the 6-arylsulfonyl pyridopyrimidinones, induces apoptosis of human tumor cell lines in nanomolar concentrations. The most potent of these compounds, 7ao, was found to be a highly specific inhibitor of PLK2 when profiled against a panel of 288 wild type, 55 mutant and 12 lipid kinases. Here, we describe the synthesis, structure activity relationship, in vitro kinase specificity and biological activity of the lead compound, 7ao. PMID- 26762837 TI - FEASIBILITY FOR ULTRASOUND-GUIDED INJECTION OF THE COLLATERAL LIGAMENTS OF THE DISTAL INTERPHALANGEAL JOINT IN HORSES. AB - Desmitis of the collateral ligament of the distal interphalangeal joint is a cause of lameness in performance horses. The objective of this prospective, experimental, ex vivo feasibility study was to evaluate the success of ultrasound guided injection of the collateral ligaments of the distal interphalangeal joint in the equine forelimb. Seventy-six ultrasound-guided dye injections of the collateral ligament of the distal interphalangeal joint were performed on horses' cadaver limbs. The hooves were sectioned transversely to verify the location of the dye relative to the collateral ligaments and surrounding structures. Evaluations of transverse sections were performed independently by two experienced observers. A scoring system was used to assess injection of the collateral ligament of the distal interphalangeal joint at the proximal, middle, and distal aspect over the length of the ligament. The collateral ligament was injected at any point in 97.4% of cases. The ligament was injected over the entire scored length in 43.2% of cases (32/74), over two scored length areas in 45.9% of cases (34/74), and in one area in 10.8% of cases (8/74). The distal interphalangeal joint and the common digital extensor tendon were also injected in 81.6% (62/76) and 43.4% (33/76) of the cases, respectively. Use of the ultrasound had a positive and negative predictive value of 98% and 9%, respectively. In this study, ultrasound guidance was useful for confirming injection of the collateral ligament of the distal interphalangeal joint but did not prevent injecting the distal interphalangeal joint and the common digital extensor tendon. PMID- 26762836 TI - Hydroxylated chalcones with dual properties: Xanthine oxidase inhibitors and radical scavengers. AB - In this study, we evaluated the abilities of a series of chalcones to inhibit the activity of the enzyme xanthine oxidase (XO) and to scavenge radicals. 20 mono- and polyhydroxylated chalcone derivatives were synthesized by Claisen-Schmidt condensation reactions and then tested for inhibitory potency against XO, a known generator of reactive oxygen species (ROS). In parallel, the ability of the synthesized chalcones to scavenge a stable radical was determined. Structure activity relationship analysis in conjunction with molecular docking indicated that the most active XO inhibitors carried a minimum of three hydroxyl groups. Moreover, the most effective radical scavengers had two neighboring hydroxyl groups on at least one of the two phenyl rings. Since it has been proposed previously that XO inhibition and radical scavenging could be useful properties for reduction of ROS-levels in tissue, we determined the chalcones' effects to rescue neurons subjected to ROS-induced stress created by the addition of beta amyloid peptide. Best protection was provided by chalcones that combined good inhibitory potency with high radical scavenging ability in a single molecule, an observation that points to a potential therapeutic value of this compound class. PMID- 26762838 TI - Tacrolimus vs. anti-tumour necrosis factor agents for moderately to severely active ulcerative colitis: a retrospective observational study. AB - BACKGROUND: There have been no comparative studies of tacrolimus vs. anti-tumour necrosis factor (anti-TNF) agents to determine which treatment is safer or more effective in refractory ulcerative colitis (UC). AIM: To compare short-term safety and efficacy of tacrolimus vs. anti-TNF agents for active UC. METHODS: One hundred patients with moderate-to-severe active UC were studied. Fifty patients were treated with oral tacrolimus (TAC group). The other 50 patients were treated with anti-TNF agents (anti-TNF group): 40 with infliximab and 10 with adalimumab. Primary endpoints were clinical response and remission rates, colectomy rate, and the incidence of adverse events during 12 weeks. RESULTS: The incidence of adverse events was 12% in the TAC vs. 18% in the anti-TNF groups (P = 0.58). At week 12, clinical remission rate was 40% in the TAC vs. 28% in the anti-TNF groups (P = 0.29). Clinical response (including remission) rate was 62% in the TAC vs. 64% in the anti-TNF groups (P > 0.99). Five patients (10%) in the TAC and 8 (16%) in the anti-TNF groups required colectomy (P = 0.55). In a subgroup analysis restricted to severely active UC, the response rate was 50% in the TAC vs. 25% in the anti-TNF groups (P = 0.24). In severely active UC, the response rate tended to be higher in patients treated with tacrolimus, albeit not statistically significant. CONCLUSIONS: Both tacrolimus and anti-TNF agents appeared to be safe and effective in the management of moderate-to-severe active UC. However, randomised controlled trials are warranted to confirm the results obtained in this study. PMID- 26762839 TI - Microsurgical Simulation Exercise for Surgical Training. AB - OBJECTIVE: Initial training for orthopedic surgical residents (postgraduate years 1-5) in microsurgery using the turkey wing model and evaluation of their proficiency. DESIGN: Residents were given a questionnaire on their comfort level with microsurgery and microsurgical knowledge, followed by a lecture on the subject. They watched a surgical dissection and repair of the turkey wing's neurovasculature. Residents performed the dissection and repairs of the artery, vein, and nerve. A postquestionnaire was administered following the simulation exercise. Their performances on repairs were graded and results compared by academic year. SETTING AND PARTICIPANTS: A total of 21 orthopedic surgery residents were recruited from Stony Brook University Medical Center, Stony Brook, NK. RESULTS: This training activity resulted in significant improvements in both microsurgical knowledge (41%) and comfort (37%). Senior residents scored significantly higher than juniors on 6 microsurgical parameters. The largest effect was in nerve repair showing 4 parameters that differed significantly between groups. CONCLUSION: Microsurgical techniques require extensive training to master. The turkey wing model for repair of the artery, vein, and nerve represents a realistic simulation of a human hand artery, vein, and nerve. It provides an inexpensive method for residents to practice on real tissue for improving microsurgical technique. PMID- 26762840 TI - Boosting Affinity by Correct Ligand Preorganization for the S2 Pocket of Thrombin: A Study by Isothermal Titration Calorimetry, Molecular Dynamics, and High-Resolution Crystal Structures. AB - Structural preorganization to fix bioactive conformations at protein binding sites is a popular strategy to enhance binding affinity during late-stage optimization. The rationale for this enhancement relates to entropic advantages assigned to rigidified versus flexible ligands. We analyzed a narrow series of peptidomimetics binding to thrombin. The individual ligands exhibit at P2 a conformationally flexible glycine, more restricted alanine, N-methylglycine, N methylhomoalanine, and largely rigidified proline moiety. Overall, affinity was found to increase by a factor of 1000, explained partly by an entropic advantage. All ligands adopt the same binding mode with small deviations. The residual mobility of the bound ligands is decreased across the series, and a protein side chain differs in its order/disorder behavior along with changes in the surface water network pattern established across the newly generated protein-ligand surfaces. The enthalpy/entropy inventory displays a rather complex picture and emphasizes that thermodynamics can only be compared in terms of relative differences within a structurally similar ligand series. PMID- 26762841 TI - Atrial average conduction velocity in patients with and without paroxysmal atrial fibrillation. AB - OBJECTIVES: To evaluate intra-atrial conduction delay in patients with atrial fibrillation (AF) via calculation of conduction velocities (CVs) of the right and left atria. METHODS: Electroanatomic mapping was performed during sinus rhythm, in the right atrium (RA) in eight patients with paroxysmal AF, in 12 controls with atrioventricular nodal re-entrant tachycardia (AVNRT) and in the left atrium (LA) in additional 16 AF patients. Three-dimensional maps of activation sequences of the RA and LA were obtained. Local CVs were specifically calculated in the direction of wave-front propagation on the activation maps by using 3-dimensional coordinates and local activation times of triads of sites. Average CVs of each atrium and each of 8 predefined RA and LA regions were calculated. RESULTS: During sinus rhythm, the average CVs of the RA were significantly slower (P<0.05) in the AF group (0.60 +/- 0.12 m s-1 ) than in the controls (0.83 +/- 0.13 m s-1 ). The average CVs of the RA basal, septal and annulus regions were significantly slower than the corresponding regions in controls (P<0.05). In patients with AF, the average CV of the LA was 0.51 +/- 0.11 m s-1 , which is significantly slower than that of the RA and than that of LA as previously reported (P<0.05). CONCLUSION: Compared to patients with AVNRT, patients with AF are associated with conduction delay in both atria with the delay being more marked in the LA than in the RA, which suggests the involvement of conduction disturbances in the genesis and/or perpetuation of AF. PMID- 26762842 TI - Bone morphogenetic proteins in inflammation, glucose homeostasis and adipose tissue energy metabolism. AB - Bore morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)-beta superfamily, a group of secreted proteins that regulate embryonic development. This review summarizes the effects of BMPs on physiological processes not exclusively linked to the musculoskeletal system. Specifically, we focus on the involvement of BMPs in inflammatory disorders, e.g. fibrosis, inflammatory bowel disease, anchylosing spondylitis, rheumatoid arthritis. Moreover, we discuss the role of BMPs in the context of vascular disorders, and explore the role of these signalling proteins in iron homeostasis (anaemia, hemochromatosis) and oxidative damage. The second and third parts of this review focus on BMPs in the development of metabolic pathologies such as type-2 diabetes mellitus and obesity. The pancreatic beta cells are the sole source of the hormone insulin and BMPs have recently been implicated in pancreas development as well as control of adult glucose homeostasis. Lastly, we review the recently recognized role of BMPs in brown adipose tissue formation and their consequences for energy expenditure and adiposity. In summary, BMPs play a pivotal role in metabolism beyond their role in skeletal homeostasis. However, increased understanding of these pleiotropic functions also highlights the necessity of tissue-specific strategies when harnessing BMP action as a therapeutic target. PMID- 26762843 TI - Quantitative Detection and Resolution of BRAF V600 Status in Colorectal Cancer Using Droplet Digital PCR and a Novel Wild-Type Negative Assay. AB - A need exists for robust and cost-effective assays to detect a single or small set of actionable point mutations, or a complete set of clinically informative mutant alleles. Knowledge of these mutations can be used to alert the clinician to a rare mutation that might necessitate more aggressive clinical monitoring or a personalized course of treatment. An example is BRAF, a (proto)oncogene susceptible to either common or rare mutations in codon V600 and adjacent codons. We report a diagnostic technology that leverages the unique capabilities of droplet digital PCR to achieve not only accurate and sensitive detection of BRAF(V600E) but also all known somatic point mutations within the BRAF V600 codon. The simple and inexpensive two-well droplet digital PCR assay uses a chimeric locked nucleic acid/DNA probe against wild-type BRAF and a novel wild type-negative screening paradigm. The assay shows complete diagnostic accuracy when applied to formalin-fixed, paraffin-embedded tumor specimens from metastatic colorectal cancer patients deficient for Mut L homologue-1. PMID- 26762844 TI - Immunohistochemical analysis of lichenoid reactions in patients treated with anti PD-L1 and anti-PD-1 therapy. AB - BACKGROUND: Recent advances in the immunotherapeutic treatment of cancer have led to the development of multiple new directed therapies including monoclonal antibodies that block the immune checkpoint T-cell receptor programmed death 1 (PD-1) and the PD-1 ligand, programmed death ligand 1 (PD-L1). Various immune related toxicities have been associated with these drugs including, most commonly, skin rashes. METHODS: Five cases of lichenoid dermatitis, including one case of lichenoid mucositis and one case of lichen sclerosus, associated with anti-PD-L1 and anti-PD1 therapy were compared with three biopsies of non-drug related lichen planus (LP) and three lichen planus-like keratoses (LPLK) used as controls. RESULTS: Histopathologic and immunophenotypic analysis of these lichenoid lesions demonstrated significantly greater histiocytic infiltrates than observed in control lichenoid reactions (p = 0.0134). We also observed increased spongiosis and epidermal necrosis. No significant differences were seen in expression of CD3, CD4:CD8, CD20, PD-1, CD25, Foxp3, CXCL13 and PD-L1 expression. CONCLUSIONS: These findings expand the literature of immune-related toxicities of PD-L1 and PD-1 blockade to include lichenoid dermatitis and lichenoid mucositis. Of note, these cutaneous side effects were amenable to topical treatment, without the need for medication dose reduction or discontinuation. PMID- 26762846 TI - The "Windsock Sign": Intraluminal Duodenal Diverticulum. PMID- 26762847 TI - Editorial for January 2016 for JPC A/B/C. PMID- 26762845 TI - Novel Diet, Drugs, and Gastric Interventions for Gastroparesis. AB - This review of the pathophysiologic basis for gastroparesis and recent advances in the treatment of patients with gastroparesis shows that there are several novel approaches to advance treatment of gastroparesis including diet, novel prokinetics, interventions on the pylorus, and novel forms of gastric electrical stimulation. The field of gastroparesis is likely to advance with further studies, with help from a guidance document from the Food and Drug Administration on gastroparesis, and with recent approval of the stable isotope gastric emptying test to ensure eligibility of participants in multicenter trials. Clinical experience and a formal, randomized, controlled trial provide insights on optimizing dietary interventions in patients with gastroparesis. This review addresses the biologic rationale of these different treatments, based on known physiology and pathophysiology of gastric emptying. The novel medications include the motilin agonist, camicinal; 5-HT4 receptor agonists, such as velusetrag; and the ghrelin agonist, relamorelin. New approaches target pylorospasm by stent placement, endoscopic pyloric myotomy, or laparoscopic pyloroplasty. These approaches offer the opportunity to achieve more permanent reduction of resistance to flow at the pylorus over the intrapyloric injection of botulinum toxin, which typically has to be repeated every few months if it is efficacious. A novel device, deployed in porcine stomach, involved per-endoscopic electrical stimulation. These promising approaches require formal, randomized, controlled trials and deployment in patients. The presence of concomitant antral hypomotility may be a significant factor in the responsiveness to interventions at the pylorus. PMID- 26762848 TI - Arginine vasopressin (AVP): a review of its historical perspectives, current research and multifunctional role in the hypothalamo-hypophysial system. AB - INTRODUCTION: This publication reviews the function of arginine vasopressin and focuses on the morphologic and functional correlation between the hormone and its effect on stress, the hypophysial-adrenocortical axis, neuroimmune responses, renal function and corticotroph pituitary tumors. MATERIALS AND METHODS: A literature review was performed using various search engines for information regarding the morphology and the multifunctional role of arginine vasopressin. RESULTS: Although a large number of studies were published discussing these interactions, there are several important areas that are still obscure. CONCLUSION: The questions of how does arginine vasopressin affect the morphology and function of these various areas, and how does the secretion of ACTH and adrenocortical hormones influence the morphology of arginine vasopressin producing cells and their hormone secretion requires further investigation. PMID- 26762849 TI - Evaluating the effect of clinical care pathways on quality of cancer care: analysis of breast, colon and rectal cancer pathways. AB - PURPOSE: Substantial gaps exist between clinical practice and evidence-based cancer care, potentially leading to adverse clinical outcomes and decreased quality of life for cancer patients. This study aimed to evaluate the usefulness of clinical pathways as a tool for improving quality of cancer care, using breast, colon, and rectal cancer pathways as demonstrations. METHODS: Newly diagnosed patients with invasive breast, colon, and rectal cancer were enrolled as pre-pathway groups, while patients with the same diagnoses treated according to clinical pathways were recruited for post-pathway groups. RESULTS: Compliance with preoperative core biopsy or fine-needle aspiration, utilization of sentinel lymph node biopsy, and proportion of patients whose tumor hormone receptor status was stated in pathology report were significantly increased after implementation of clinical pathway for breast cancer. For colon cancer, compliance with two care processes was significantly improved: surgical resection with anastomosis and resection of at least 12 lymph nodes. Regarding rectal cancer, there was a significant increase in compliance with preoperative evaluation of depth of tumor invasion, total mesorectal excision treatment of middle- or low-position rectal cancer, and proportion of patients who had undergone rectal cancer surgery whose pathology report included margin status. Moreover, total length of hospital stay was decreased remarkably for all three cancer types, and postoperative complications remained unchanged following implementation of the clinical pathways. CONCLUSIONS: Clinical pathways can improve compliance with standard care by implementing evidence-based quality indicators in daily practice, which could serve as a useful tool for narrowing the gap between clinical practice and evidence-based care. PMID- 26762850 TI - Clinical relevance of CD44 surface expression in advanced stage serous epithelial ovarian cancer: a prospective study. AB - PURPOSE: Cluster of differentiation (CD) 44 is a cell surface receptor that correlates with the development of drug resistance in epithelial ovarian cancer (EOC). Here, we prospectively investigated the clinical impact of CD44 expression on the development of chemoresistance, and on disease-free and overall survival in EOC. METHODS: This study included patients with primary serous EOC that was at International Federation of Gynecology and Obstetrics stages IIIB-IVA and tumors that were CD44 positive and negative in a 1:1 ratio. All patients underwent primary surgical cytoreduction, followed by six cycles of combined paclitaxel and carboplatin chemotherapy every 3 weeks. The treatment was considered complete after the chemotherapy had finished. All patients were followed up for 24 months after completing their chemotherapy. RESULTS: Of the 96 patients with serous EOC at stages IIIB-IVA, 51 % of the tumors were negative for the expression of CD44 and 49 % showed variable CD44 expression. Patients who had CD44-positive tumors had statistically significant shorter disease-free (p <= 0.001) and overall survival (p <= 0.001) intervals compared with patients with CD44-negative tumors. The hazard ratio for death was 6.8 (95 % confidence interval 2.4-19.2, p <= 0.001) among the patients with CD44-positive tumors. A multivariate analysis showed that carboplatin-resistant or carboplatin-refractory EOC was the only independent predictive factor for death. CONCLUSIONS: CD44 expression contributes to the development of carboplatin resistance in advanced serous EOC, and it may contribute to worse prognoses for patients, but it is neither an independent predictor of survival nor of recurrence. PMID- 26762851 TI - Simultaneous determination of indoor ammonia pollution and its biological metabolite in the human body with a recyclable nanocrystalline lanthanide functionalized MOF. AB - A Eu(3+) post-functionalized metal-organic framework of nanosized Ga(OH)bpydc(Eu(3+)@Ga(OH)bpydc, 1a) with intense luminescence is synthesized and characterized. Luminescence measurements reveal that 1a can detect ammonia gas selectively and sensitively among various indoor air pollutants. 1a can simultaneously determine a biological ammonia metabolite (urinary urea) in the human body, which is a rare example of a luminescent sensor that can monitor pollutants in the environment and also detect their biological markers. Furthermore, 1a exhibits appealing features including high selectivity and sensitivity, fast response, simple and quick regeneration, and excellent recyclability. PMID- 26762852 TI - Comparative analyses of the proteins from Mycobacterium tuberculosis and human genomes: Identification of potential tuberculosis drug targets. AB - Tuberculosis, one of the major infectious diseases affecting human beings is caused by the bacillus Mycobacterium tuberculosis. Increased resistance to known drugs commonly used for the treatment of tuberculosis has created an urgent need to identify new targets for validation and to develop drugs. In this study, we have used various bioinformatics tools, to compare the protein sequences from twenty-three M. tuberculosis genome strains along with the known human protein sequences, in order to identify the 'conserved' M. tuberculosis proteins absent in human. Further, based on the analysis of protein interaction networks, we selected one-hundred and forty proteins that were predicted as potential M. tuberculosis drug targets and prioritized according to the ranking of 'clusters' of interacting proteins. Comparison of the predicted 140 TB targets with literature indicated that 46 of them were previously reported, thereby increasing the confidence in our predictions of the remaining 94 targets too. The analyses of the structures and functions corresponding to the predicted potential TB drug targets indicated a diverse range of proteins that included ten 'druggable' targets with some of the known drugs. PMID- 26762855 TI - Thermal noise variance of a receive radiofrequency coil as a respiratory motion sensor. AB - PURPOSE: Development of a passive respiratory motion sensor based on the noise variance of the receive coil array. METHODS: Respiratory motion alters the body resistance. The noise variance of an RF coil depends on the body resistance and, thus, is also modulated by respiration. For the noise variance monitoring, the noise samples were acquired without and with MR signal excitation on clinical 1.5/3 T MR scanners. The performance of the noise sensor was compared with the respiratory bellow and with the diaphragm displacement visible on MR images. Several breathing patterns were tested. RESULTS: The noise variance demonstrated a periodic, temporal modulation that was synchronized with the respiratory bellow signal. The modulation depth of the noise variance resulting from the respiration varied between the channels of the array and depended on the channel's location with respect to the body. The noise sensor combined with MR acquisition was able to detect the respiratory motion for every k-space read-out line. CONCLUSION: Within clinical MR systems, the respiratory motion can be detected by the noise in receive array. The noise sensor does not require careful positioning unlike the bellow, any additional hardware, and/or MR acquisition. Magn Reson Med 77:221 228, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26762853 TI - Endothelial Cords Promote Tumor Initial Growth prior to Vascular Function through a Paracrine Mechanism. AB - The angiogenic switch is an important oncogenic step that determines whether microtumors remain dormant or progresses further. It has been generally perceived that the primary function of this tumorgenic event is to supply oxygen and nutrients through blood circulation. Using in vivo imaging of zebrafish and mouse tumor models, we showed that endothelial cords aggressively penetrated into microtumors and remained non-circulatory for several days before undergoing vascular blood perfusion. Unexpectedly, we found that initial tumor growth in both models was significantly reduced if endothelial cords were removed by blocking VEGF-VEGFR2 signaling or using a vascular deficient zebrafish mutant. It was further shown that soluble factors including IL-8, secreted by endothelial cells (ECs) were responsible for stimulating tumor cells proliferation. These findings establish that tumor angiogenesis play a much earlier and broader role in promoting tumor growth, which is independent of vascular circulation. Understanding this novel mechanism of angiogenic tumor progression offers new entry points for cancer therapeutics. PMID- 26762856 TI - Dorsal Forebrain-Specific Deficiency of Reelin-Dab1 Signal Causes Behavioral Abnormalities Related to Psychiatric Disorders. AB - Reelin-Dab1 signaling is involved in brain development and neuronal functions. The abnormalities in the signaling through either reduction of Reelin and Dab1 gene expressions or the genomic mutations in the brain have been reported to be associated with psychiatric disorders. However, it has not been clear if the deficiency in Reelin-Dab1 signaling is responsible for symptoms of the disorders. Here, to examine the function of Reelin-Dab1 signaling in the forebrain, we generated dorsal forebrain-specific Dab1 conditional knockout mouse (Dab1 cKO) and performed a behavioral test battery on the Dab1 cKO mice. Although conventional Dab1 null mutant mice exhibit cerebellar atrophy and cerebellar ataxia, the Dab1 cKO mice had normal cerebellum and showed no motor dysfunction. Dab1 cKO mice exhibited behavioral abnormalities, including hyperactivity, decreased anxiety-like behavior, and impairment of working memory, which are reminiscent of symptoms observed in patients with psychiatric disorders such as schizophrenia and bipolar disorder. These results suggest that deficiency of Reelin-Dab1 signal in the dorsal forebrain is involved in the pathogenesis of some symptoms of human psychiatric disorders. PMID- 26762858 TI - The choice dilemma in chronic hematological conditions: Why choosing is not only a medical issue? A psycho-cognitive perspective. AB - Research in cognitive psychology focused on risk perception and decision making was shown to facilitate treatment choice and patient's satisfaction with decision in a number of medical conditions, increasing perceived alliance between patient and physician, and adherence to treatment. However, this aspect has been mostly neglected in the literature investigating choice of treatment for chronic hematological conditions. In this paper, a patient centered model and a shared decision making (SDM) approach to treatment switch in chronic hematological conditions, in particular chronic myeloid leukemia, atrial fibrillation, and beta thalassemia is proposed. These pathologies have a series of implications requiring important decisions about new available treatments. Although new generation treatments may provide a significant improvement in patient's health and health-related quality of life (HrQoL), a significant percentage of them is uncertain about or refuse treatment switch, even when strongly suggested by healthcare guidelines. Possible cognitive and emotional factors which may influence decision making in this field and may prevent appropriate risk-and benefits evaluation of new treatment approaches are reviewed. Possible adaptive strategies to improve quality of care, patient participation, adherence to treatment and final satisfaction are proposed, and implications relatively to new treatment options available are discussed. PMID- 26762859 TI - Characterising the nanoscale kinetic friction using force-equilibrium and energy conservation models with optical manipulation. AB - SiC nanowires were manipulated under an optic microscope to investigate the nanoscale friction between nanowires and a flat substrate. The deflection of the nanowires was modeled as that of an Euler-Bernoulli beam subjected to a uniformly distributed load. A simple formula was developed to calculate the kinetic friction from the normalized deflections at the two ends of a nanowire. The frictional force per unit area determined ranges from 0.18-0.51 MPa. Both experimental and simulated results demonstrated that the proposed approach was reliable. The results were also compared with those estimated using an energy conservation model, which produced a frictional force ranging from 0.21-0.62 MPa. The results obtained from the two different methods are in excellent agreement. PMID- 26762857 TI - Laminar Differences in Dendritic Structure of Pyramidal Neurons in the Juvenile Rat Somatosensory Cortex. AB - Pyramidal cell structure varies between different cortical areas and species, indicating that the cortical circuits that these cells participate in are likely to be characterized by different functional capabilities. Structural differences between cortical layers have been traditionally reported using either the Golgi method or intracellular labeling, but the structure of pyramidal cells has not previously been systematically analyzed across all cortical layers at a particular age. In the present study, we investigated the dendritic architecture of complete basal arbors of pyramidal neurons in layers II, III, IV, Va, Vb, and VI of the hindlimb somatosensory cortical region of postnatal day 14 rats. We found that the characteristics of basal dendritic morphologies are statistically different in each cortical layer. The variations in size and branching pattern that exist between pyramidal cells of different cortical layers probably reflect the particular functional properties that are characteristic of the cortical circuit in which they participate. This new set of complete basal dendritic arbors of 3D-reconstructed pyramidal cell morphologies across each cortical layer will provide new insights into interlaminar information processing in the cerebral cortex. PMID- 26762860 TI - Repeated early thrombolysis in cervical spinal cord ischemia. AB - Specific therapy of acute spinal ischemia is not established. We report the first case of an MRI-verified cervical spinal ischemia treated by thrombolysis and review the literature. A 72-year old woman with right-sided motor hemiparesis and trunk ataxia was treated by intravenous thrombolysis with full recovery. Three days later she developed again a severe right-sided sensorimotor hemiparesis and a second off-label intravenous thrombolysis was repeated. Magnetic resonance imaging revealed a right-sided posterior-lateral cervical spinal ischemia. Spinal ischemia may clinically present with a cerebral-stroke-like picture challenging diagnostic and therapeutic procedure. Systemic thrombolysis might be a treatment option in acute spinal ischemia. In addition, early repeated systemic thrombolysis may be considered in selected strokes. PMID- 26762861 TI - Toxoplasmosis in the Caribbean islands: literature review, seroprevalence in pregnant women in ten countries, isolation of viable Toxoplasma gondii from dogs from St. Kitts, West Indies with report of new T. gondii genetic types. AB - Little is currently known of clinical toxoplasmosis in humans and animals in the Caribbean. We investigated the prevalence of IgG and IgM antibodies in 437 pregnant women from 10 English speaking Caribbean countries. Overall, antibodies (IgG) to Toxoplasma gondii (modified agglutination test, MAT, cut-off 1:6) were found in 174 (39.8 %) of 437 human sera; specifically 12 of 38 from Antigua Barbuda, 26 of 52 from Belize, 9 of 50 from Bermuda, 29 of 49 from Dominica, 18 of 49 from Grenada, 16 of 47 from Jamaica, 5 of 15 from Montserrat, 8 of 44 from St. Kitts/Nevis, 24 of 45 from St. Lucia, and 27 of 50 from St. Vincent/Grenadines were seropositive. All IgG-positive sera were tested for IgM antibodies using the immunocapture method; all sera were negative for IgM antibodies. Additionally, tissues and sera of 45 dogs from St. Kitts were examined for T. gondii infection. Antibodies (IgG, MAT, 1:>=25) were found in 19 (42.2 %) of 45 dogs. Muscle samples (tongue, leg) of 19 seropositive dogs were digested in pepsin, and homogenates were bioassayed in mice. Viable T. gondii were isolated from 6 dogs. T. gondii isolates were further propagated in cell culture. PCR-RFLP genotyping of cell culture derived tachyzoites using 10 genetic markers, SAG1, SAG2 (5' and 3' SAG2, and alt.SAG2) SAG3, BTUB, GRA6, c22-8, c29 2, L358, PK1, and Apico revealed that 4 isolates were ToxoDB PCR-RFLP genotype #2, and 2 were new genotypes #264 and #265. Review of 22 viable T. gondii isolates from chickens, dogs, and cats from Grenada and St. Kitts revealed that 1 isolate was type II, 13 were type III, and 8 were atypical. Thus, type III strains were predominant. Overall, the study revealed high prevalence of T. gondii in the Caribbean islands. PMID- 26762863 TI - Biological sex and the risk of cerebral palsy in Victoria, Australia. AB - AIM: Males typically outnumber females in cerebral palsy (CP) cohorts. To better understand this 'male disadvantage' and provide insight into causal pathways to CP, this study used 1983 to 2009 Australian CP and population birth cohorts to identify associations and trends with respect to biological sex and CP. METHOD: Within birth gestation groups, sex ratios were calculated to evaluate any male excess in the CP cohort compared with livebirths, neonatal deaths, neonatal mortality and survival rates, neonatal survivors, and CP rates in survivors. Sex- and gestation-specific trends in neonatal mortality, CP rates, and CP sex ratios were assessed by plotting their annual frequencies and fitting quadratic curves. RESULTS: Over-representation of males in preterm live births partly explained the male excess in the CP cohort after preterm birth, especially at 28 to 31 weeks. Higher CP rates in male neonatal survivors also contributed to the male excess in CP, particularly at <28 and 37+ weeks. Higher neonatal mortality rates in males at all gestations had little impact on the CP sex ratio. There was no clearly discernible change over time in the CP sex ratio. INTERPRETATION: Gestation specific associations between sex and CP provide insight into causal pathways to CP and suggest sex-specific differences in response to neuroprotective strategies. PMID- 26762864 TI - Sterol composition of virgin olive oil of forty-three olive cultivars from the World Collection Olive Germplasm Bank of Cordoba. AB - BACKGROUND: In olive oil, sterols constitute the majority of the unsaponifiable fraction. In recent years there has been increased interest in the sterols of olive oil for their health benefits and their importance to virgin olive oil (VOO) quality regulation. RESULTS: Forty-three olive (Olea europaea L.) cultivars from the World Olive Germplasm Bank, IFAPA Centro 'Alameda de Obispo', Cordoba, Spain were studied for their oil sterol composition and total content. The main sterols found in olive oil were beta-sitosterol, Delta(5) -avenasterol, campesterol and stigmasterol, most of them showing high variability. Most cultivars showed total sterol contents within the limits established by EU regulations, although 28% of VOOs analysed were outside the limits established for total content and/or for individual sterols. Over the group of cultivars, total sterol contents ranged from 855 to 2185 mg kg(-1) . CONCLUSION: The high variability observed was due to the genetic component, since other agronomic and technological factors were similar. Because of the high variability, the sterol fraction can be considered as a useful tool to characterize and discriminate monovarietal VOOs. The results can be useful for nutritionists for VOO inclusion in nutrition studies. Furthermore, the variability observed can be applied in olive breeding projects to select the parents of new olive cultivars with an improved sterol fraction. (c) 2016 Society of Chemical Industry. PMID- 26762862 TI - Atrazine reduces the transmission of an amphibian trematode by altering snail and ostracod host-parasite interactions. AB - Trematodes are ubiquitous members of aquatic environments, have many functional roles in ecosystems, and can cause diseases in humans, livestock, and wild animals. Despite their importance and reports of parasite population declines, few studies have concurrently assessed the effects of aquatic contaminants on multiple hosts, multiple parasite life cycle stages, and on transmission-related host-parasite interactions. Here, we test the effects of environmentally relevant concentrations of the herbicide atrazine (0, 3, 30 MUg/L) on the establishment and development of an amphibian trematode (Halipegus eccentricus) in a first intermediate snail host (Physa acuta) and in a second-intermediate ostracod host (Cypridopsis sp.). Additionally, we test the interactive effects of atrazine and parasitism on snail and ostracod survival. Our results indicate that atrazine negatively affects trematode transmission by altering snail and ostracod host parasite interactions. Although atrazine did not affect the survival of uninfected snails alone, atrazine acted synergistically with parasitism to reduce the longevity of infected snails. As a result, the number of cercariae (i.e., larval trematodes) produced by snails was 50.7 % (3 MUg/L) and 14.9 % (30 MUg/L) relative to controls. Atrazine exhibited direct negative effects on ostracod survival at 30 MUg/L. However, when ostracods were also exposed to trematodes, the negative effects of atrazine on survival were diminished. Although infected ostracod survival remained high, trematode development was significantly reduced, resulting in reduced infectivity of metacercariae (i.e., nongravid adult cysts infective to definite host) to 32.2 % (3 MUg/L) and 28.6 % (30 MUg/L) relative to the controls. The combination of reduced cercaria production and reduced metacercarial infectivity in the 3 and 30 MUg/L atrazine treatment groups reduced the net number of infective worms produced to 16.4 and 4.3 % (respectively) relative to the control. These results demonstrate the complex nature of pesticide effects on trematode infections and indicate that trematodes can affect their first- and second-intermediate hosts differently under different pesticide concentrations. Our work has broad implications for parasite transmission and conservation and provides a testable mechanism for understanding trematode population declines in contaminated wetlands. PMID- 26762865 TI - Quantifying Different Tactile Sensations Evoked by Cutaneous Electrical Stimulation Using Electroencephalography Features. AB - Psychophysical tests and standardized questionnaires are often used to analyze tactile sensation based on subjective judgment in conventional studies. In contrast with the subjective evaluation, a novel method based on electroencephalography (EEG) is proposed to explore the possibility of quantifying tactile sensation in an objective way. The proposed experiments adopt cutaneous electrical stimulation to generate two kinds of sensations (vibration and pressure) with three grades (low/medium/strong) on eight subjects. Event related potentials (ERPs) and event-related synchronization/desynchronization (ERS/ERD) are extracted from EEG, which are used as evaluation indexes to distinguish between vibration and pressure, and also to discriminate sensation grades. Results show that five-phase P1-N1-P2-N2-P3 deflection is induced in EEG. Using amplitudes of latter ERP components (N2 and P3), vibration and pressure sensations can be discriminated on both individual and grand-averaged ERP (p < 0.05). The grand-average ERPs can distinguish the three sensations grades, but there is no significant difference on individuals. In addition, ERS/ERD features of mu rhythm (8-13 Hz) are adopted. Vibration and pressure sensations can be discriminated on grand-average ERS/ERD (p < 0.05), but only some individuals show significant difference. The grand-averaged results show that most sensation grades can be differentiated, and most pairwise comparisons show significant difference on individuals (p < 0.05). The work suggests that ERP- and ERS/ERD based EEG features may have potential to quantify tactile sensations for medical diagnosis or engineering applications. PMID- 26762866 TI - Analysis of the Complexity Measures in the EEG of Schizophrenia Patients. AB - Complexity measures have been enormously used in schizophrenia patients to estimate brain dynamics. However, the conflicting results in terms of both increased and reduced complexity values have been reported in these studies depending on the patients' clinical status or symptom severity or medication and age status. The objective of this study is to investigate the nonlinear brain dynamics of chronic and medicated schizophrenia patients using distinct complexity estimators. EEG data were collected from 22 relaxed eyes-closed patients and age-matched healthy controls. A single-trial EEG series of 2 min was partitioned into identical epochs of 20 s intervals. The EEG complexity of participants were investigated and compared using approximate entropy (ApEn), Shannon entropy (ShEn), Kolmogorov complexity (KC) and Lempel-Ziv complexity (LZC). Lower complexity values were obtained in schizophrenia patients. The most significant complexity differences between patients and controls were obtained in especially left frontal (F3) and parietal (P3) regions of the brain when all complexity measures were applied individually. Significantly, we found that KC was more sensitive for detecting EEG complexity of patients than other estimators in all investigated brain regions. Moreover, significant inter-hemispheric complexity differences were found in the frontal and parietal areas of schizophrenics' brain. Our findings demonstrate that the utilizing of sensitive complexity estimators to analyze brain dynamics of patients might be a useful discriminative tool for diagnostic purposes. Therefore, we expect that nonlinear analysis will give us deeper understanding of schizophrenics' brain. PMID- 26762868 TI - Energetic Properties of Rocket Propellants Evaluated through the Computational Determination of Heats of Formation of Nitrogen-Rich Compounds. AB - The use of ab initio and DFT methods to calculate the enthalpies of formation of solid ionic compounds is described. The results obtained from the calculations are then compared with those from experimental measurements on nitrogen-rich salts of the 2,2-dimethyltriazanium cation (DMTZ) synthesized in our laboratory and on other nitrogen-rich ionic compounds. The importance of calculating accurate volumes and lattice enthalpies for the determination of heats of formation is also discussed. Furthermore, the crystal structure and hydrogen bonding networks of the nitroformate salt of the DMTZ cation is described in detail. Lastly, the theoretical heats of formation were used to calculate the specific impulses (Isp ) of the salts of the DMTZ cation in view of a prospective application in propellant formulations. PMID- 26762871 TI - Deciphering the physics and chemistry of perovskites with transmission electron microscopy. AB - Perovskite oxides exhibit rich structural complexity and a broad range of functional properties, including ferroelectricity, ferromagnetism, and superconductivity. The development of aberration correction for the transmission electron microscope and concurrent progress in electron spectroscopy, electron holography, and other techniques has fueled rapid progress in the understanding of the physics and chemistry of these materials. New techniques based on the transmission electron microscope are first surveyed, and the applications of these techniques for the study of the structure, chemistry, electrostatics, and dynamics of perovskite oxides are then explored in detail, with a particular focus on ferroelectric materials. PMID- 26762870 TI - Cutaneous squamous cell carcinoma progression is associated with decreased GATA-3 immunohistochemical staining. AB - BACKGROUND: The GATA family of transcription factors is an essential regulator of cellular proliferation and differentiation. In the skin, GATA-3 is critical for epidermal stratification and maintenance of barrier function. A role for GATA-3 in the development of human cutaneous squamous cell carcinoma (SCC) is not known. Here, we investigated GATA-3 immunohistochemical staining in premalignant and invasive cutaneous SCC from sun-exposed and sun-protected skin. METHODS: GATA-3 immunohistochemistry was performed on actinic keratoses (AK) (n = 19), in situ squamous cell carcinomas with actinic [SCCIS (A)] (n = 9) or bowenoid features [SCCIS (B)] (n = 17), well-, moderately and poorly differentiated SCC (n = 36), Bowenoid papulosis of the perineum (n = 15) and penile SCC (pSCC) (n = 10). RESULTS: We found that GATA-3 immunohistochemical staining is progressively lost in sun-exposed skin as neoplasia progresses from pre-cancerous AK to SCCIS (A), and ultimately, to SCC, which shows near absent GATA-3 staining. This reduction in GATA-3 staining is independent of histological grade in SCC. Only slight down regulation of GATA-3 was seen in all cases of SCCIS (B) and Bowenoid papulosis, while near absent GATA-3 expression was seen in pSCC. CONCLUSION: We propose that decreased GATA-3 immunohistochemical staining is associated with cutaneous SCC progression on both sun-exposed and sun-protected sites. PMID- 26762869 TI - Evaluation of optimal water fluoridation on the incidence and skeletal distribution of naturally arising osteosarcoma in pet dogs. AB - Experimental toxicological studies in laboratory animals and epidemiological human studies have reported a possible association between water fluoridation and osteosarcoma (OSA). To further explore this possibility, a case-control study of individual dogs evaluated by the UC Davis Veterinary Medical Teaching Hospital was conducted using ecologic data on water fluoridation based on the owner's residence. The case group included 161 dogs with OSA diagnosed between 2008-2012. Two cancer control groups included dogs diagnosed with lymphoma (LSA) or hemangiosarcoma (HSA) during the same period (n = 134 and n = 145, respectively). Dogs with OSA were not significantly more likely to live in an area with optimized fluoride in the water than dogs with LSA or HSA. Additional analyses within OSA patients also revealed no significant differences in age, or skeletal distribution of OSA cases relative to fluoride status. Taken together, these analyses do not support the hypothesis that optimal fluoridation of drinking water contributes to naturally occurring OSA in dogs. PMID- 26762872 TI - Many Paths Lead to CV Outcomes: A Potential Need for Image-Guided Precision Medicine. PMID- 26762874 TI - T1 Maps in Nonischemic DCM: Do They Show Us the Way? PMID- 26762873 TI - T1-Mapping and Outcome in Nonischemic Cardiomyopathy: All-Cause Mortality and Heart Failure. AB - OBJECTIVES: The study sought to examine prognostic relevance of T1 mapping parameters (based on a T1 mapping method) in nonischemic dilated cardiomyopathy (NIDCM) and compare them with conventional markers of adverse outcome. BACKGROUND: NIDCM is a recognized cause of poor clinical outcome. NIDCM is characterized by intrinsic myocardial remodeling due to complex pathophysiological processes affecting myocardium diffusely. Lack of accurate and noninvasive characterization of diffuse myocardial disease limits recognition of early cardiomyopathy and effective clinical management in NIDCM. Cardiac magnetic resonance (CMR) supports detection of diffuse myocardial disease by T1 mapping. METHODS: This is a prospective observational multicenter longitudinal study in 637 consecutive patients with dilated NIDCM (mean age 50 years [interquartile range: 37 to 76 years]; 395 males [62%]) undergoing CMR with T1 mapping and late gadolinium enhancement (LGE) at 1.5-T and 3.0-T. The primary endpoint was all cause mortality. A composite of heart failure (HF) mortality and hospitalization was a secondary endpoint. RESULTS: During a median follow-up period of 22 months (interquartile range: 19 to 25 months), we observed a total of 28 deaths (22 cardiac) and 68 composite HF events. T1 mapping indices (native T1 and extracellular volume fraction), as well as the presence and extent of LGE, were predictive of all-cause mortality and HF endpoint (p < 0.001 for all). In multivariable analyses, native T1 was the sole independent predictor of all-cause and HF composite endpoints (hazard ratio: 1.1; 95% confidence interval: 1.06 to 1.15; hazard ratio: 1.1; 95% confidence interval: 1.05 to 1.1; p < 0.001 for both), followed by the models including the extent of LGE and right ventricular ejection fraction, respectively. CONCLUSIONS: Noninvasive measures of diffuse myocardial disease by T1 mapping are significantly predictive of all-cause mortality and HF events in NIDCM. We provide a basis for a novel algorithm of risk stratification in NIDCM using a complementary assessment of diffuse and regional disease by T1 mapping and LGE, respectively. PMID- 26762877 TI - T1 Mapping: Basic Techniques and Clinical Applications. AB - In cardiac magnetic resonance (CMR) imaging, the T1 relaxation time for the 1H magnetization in myocardial tissue may represent a valuable biomarker for a variety of pathological conditions. This possibility has driven the growing interest in quantifying T1, rather than just relying on its effect on image contrast. The techniques have advanced to where pixel-level myocardial T1 mapping has become a routine component of CMR examinations. Combined with the use of contrast agents, T1 mapping has led an expansive investigation of interstitial remodeling in ischemic and nonischemic heart disease. The purpose of this review was to introduce the reader to the physical principles of T1 mapping, the imaging techniques developed for T1 mapping, the pathophysiological markers accessible by T1 mapping, and its clinical uses. PMID- 26762876 TI - Can a MR Imaging Scanner Accurately Measure Hematocrit to Determine ECV Fraction? PMID- 26762878 TI - PET-MR Imaging in Evaluation of Cardiac and Paracardiac Masses With Histopathologic Correlation. PMID- 26762875 TI - Automatic Measurement of the Myocardial Interstitium: Synthetic Extracellular Volume Quantification Without Hematocrit Sampling. AB - OBJECTIVES: The authors sought to generate a synthetic extracellular volume fraction (ECV) from the relationship between hematocrit and longitudinal relaxation rate of blood. BACKGROUND: ECV quantification by cardiac magnetic resonance (CMR) measures diagnostically and prognostically relevant changes in the extracellular space. Current methodologies require blood hematocrit (Hct) measurement-a complication to easy clinical application. We hypothesized that the relationship between Hct and longitudinal relaxation rate of blood (R1 = 1/T1blood) could be calibrated and used to generate a synthetic ECV without Hct that was valid, user-friendly, and prognostic. METHODS: Proof-of-concept: 427 subjects with a wide range of health and disease were divided into derivation (n = 214) and validation (n = 213) cohorts. Histology cohort: 18 patients with severe aortic stenosis with histology obtained during valve replacement. Outcome cohort: For comparison with external outcome data, we applied synthetic ECV to 1,172 consecutive patients (median follow-up 1.7 years; 74 deaths). All underwent CMR scanning at 1.5-T with ECV calculation from pre- and post-contrast T1 (blood and myocardium) and venous Hct. RESULTS: Proof-of-concept: In the derivation cohort, native R1blood and Hct showed a linear relationship (R(2) = 0.51; p < 0.001), which was used to create synthetic Hct and ECV. Synthetic ECV correlated well with conventional ECV (R(2) = 0.97; p < 0.001) without bias. These results were maintained in the validation cohort. Histology cohort: Synthetic and conventional ECV both correlated well with collagen volume fraction measured from histology (R(2) = 0.61 and 0.69, both p < 0.001) with no statistical difference (p = 0.70). Outcome cohort: Synthetic ECV related to all-cause mortality (hazard ratio 1.90; 95% confidence interval 1.55 to 2.31; for every 5% increase in ECV). Finally, we engineered a synthetic ECV tool, generating automatic ECV maps during image acquisition. CONCLUSIONS: Synthetic ECV provides validated noninvasive quantification of the myocardial extracellular space without blood sampling and is associated with cardiovascular outcomes. PMID- 26762879 TI - The Tissue Issue: T1 Mapping and the Myocardium. PMID- 26762880 TI - Nondestructive estimation of growth year in ginseng cultivars using the means of mathematical modeling on the basis of allometry. AB - Growth-year authentication has extraordinary significance for plant growth, structure and development research, and has a wide range of applications in value assessment of economic crops. Panax ginseng is the most commonly used medicinal plant in Asian countries. The fix number of growth-year is an important quality evaluation which is difficult to be obtained accurately in current technical conditions. Preliminary authentication theory for growth-year has been described in previous studies using a short-lived perennial medicinal plant (Paeonia lactiflora pall.) as the research material. In this research, we focused on the growth-year estimation in ginseng cultivars, and attempt to explore the age estimation method for vascular plants according to mathematical simulation of the root structure development. Micro data was obtained from 204 individuals of 3 different kinds of ginseng cultivars, which have a series of gradient age and a clear growth record. Outer diameter of the vascular cambium (b) and the radius of cross section (r) were measured with ordinary stereo microscope. We further designed and established two different kinds of authentication model based on the taproot structure development for growth year authentication (P =beta*M-alpha and M = K*X1 (a) (1) X2 (a) (2) ). Moreover, the models were applied to identify the growth year of ginseng without damage using Micro-CT or DEI reconstruction. A potential method, have been recently described, the age of ginseng can be analyzed by telomere length and telomerase activity. However, we found that there are different results indicated in other species. We concluded that microscopic methods perceived currently were provided a more effective means for growth-year authentication. PMID- 26762882 TI - Cognitive Processes Are Central in Compassion Meditation. PMID- 26762881 TI - Blueberry Component Pterostilbene Protects Corneal Epithelial Cells from Inflammation via Anti-oxidative Pathway. AB - Blueberries have been recognized to possess protective properties from inflammation and various diseases, but not for eye and ocular disorders. This study explores potential benefits of pterostilbene (PS), a natural component of blueberries, in preventing ocular surface inflammation using an in vitro culture model of human corneal epithelial cells (HCECs) exposed to hyperosmotic medium at 450 mOsM. Gene expression was detected by RT-qPCR, and protein production or activity was determined by ELISA, zymography, Western blotting and immunofluorescent staining. Reactive oxygen species (ROS) production was measured using DCFDA kit. The addition of PS significantly reduced the expression of pro inflammatory mediators, TNF-alpha, IL-1 beta, IL-6, MMP-2 and MMP-9 in HCECs exposed to hyperosmotic medium. Pre-treatment with PS (5 to 20 MUM) suppressed ROS overproduction in a dose-dependent manner. Additionally, PS significantly decreased the levels of oxidative damage biomarkers, malondialdehyde (MDA), 4 hydroxynonenal (4-HNE), aconitase-2 and 8-hydroxydeoxyguanosine (8-OHdG). Importantly, PS was found to rebalance homeostasis between oxygenases and anti oxidative enzymes by decreasing cyclooxygenase 2 (COX2) expression and restoring the activity of antioxidant enzymes, superoxide dismutase 1 (SOD1) and peroxiredoxin-4 (PRDX4) during hyperosmotic stress. Our findings demonstrate that PS protects human cornea from hyperosmolarity-induced inflammation and oxidative stress, suggesting protective effects of PS on dry eye. PMID- 26762883 TI - The clinical effectiveness of concise cognitive behavioral therapy with or without pharmacotherapy for depressive and anxiety disorders; a pragmatic randomized controlled equivalence trial in clinical practice. AB - BACKGROUND: Depressive and anxiety disorders contribute to a high disease burden. This paper investigates whether concise formats of cognitive behavioral- and/or pharmacotherapy are equivalent with longer standard care in the treatment of depressive and/or anxiety disorders in secondary mental health care. METHODS: A pragmatic randomized controlled equivalence trial was conducted at five Dutch outpatient Mental Healthcare Centers (MHCs) of the Regional Mental Health Provider (RMHP) 'Rivierduinen'. Patients (aged 18-65 years) with a mild to moderate anxiety and/or depressive disorder, were randomly allocated to concise or standard care. Data were collected at baseline, 3, 6 and 12 months by Routine Outcome Monitoring (ROM). Primary outcomes were the Brief Symptom Inventory (BSI) and the Web Screening Questionnaire (WSQ). We used Generalized Estimating Equations (GEE) to assess outcomes. RESULTS: Between March 2010 and December 2012, 182 patients, were enrolled (n=89 standard care; n=93 concise care). Both intention-to-treat and per-protocol analyses demonstrated equivalence of concise care and standard care at all time points. Severity of illness reduced, and both treatments improved patient's general health status and subdomains of quality of life. Moreover, in concise care, the beneficial effects started earlier. DISCUSSION: Concise care has the potential to be a feasible and promising alternative to longer standard secondary mental health care in the treatment of outpatients with a mild to moderate depressive and/or anxiety disorder. For future research, we recommend adhering more strictly to the concise treatment protocols to further explore the beneficial effects of the concise treatment. The study is registered in the Netherlands Trial Register, number NTR2590. Clinicaltrials.gov identifier: NCT01643642. PMID- 26762884 TI - Self-assembled Micelle Loading Cabazitaxel for therapy of Lung Cancer. AB - Lung cancer is a leading cause of cancer deaths worldwide, chemotherapy has improved overall survival but remains limited at <12 months median overall survival. Cabazitaxel is hopeful to do the same in advanced lung cancer as well as in metastatic prostate cancer. However, its clinical application was restricted due to its high hydrophobicity and severe side effects. To overcome these problems, we developed self-assembled micelle loading cabazitaxel (CBZ-PM) for therapy of lung cancer. The CBZ-PM has high drug loading (10.52%) and encapsulation efficiency (99.30%) with particle size of 28.77 +/- 0.52 nm and polydisperse index of 0.114 +/- 0.012. The transmission electron microscope image presented its spherical and homogeneous appearance. In vitro release profile showed CBZ-PM has a sustained-release behavior. Furthermore, the result of cell proliferation assays proved that CBZ-PM could induce the Lewis lung carcinoma (LLC) cells death through G2/M arrest more effectively than free CBZ. In vivo anti-tumor activity of CBZ-PM was further studied in mice model of LLC. The tumor inhibitory rate of CBZ-PM was more than 50% and the survival time of LLC bearing mice was efficiently prolonged following administration of CBZ-PM. In addition, the immunohistochemical study showed that more apoptosis cells were detected in the tumor tissue of CBZ-PM group than that of the positive control group. All these indicated that CBZ-PM served as a potential anti-lung cancer agent. PMID- 26762885 TI - Implant stability and bone remodeling up to 84 days of implantation with an initial static strain. An in vivo and theoretical investigation. AB - OBJECTIVES: When implants are inserted, the initial implant stability is dependent on the mechanical stability. To increase the initial stability, it was hypothesized that bone condensation implants will enhance the mechanical stability initially and that the moderately rough surface will further contribute to the secondary stability by enhanced osseointegration. It was further hypothesized that as the healing progresses the difference in removal torque will diminish. In addition, a 3D model was developed to simulate the interfacial shear strength. This was converted to a theoretical removal torque that was compared to the removal torque obtained in vivo. MATERIAL AND METHODS: Condensation implants, inducing bone strains of 0.015, were installed into the left tibia of 24 rabbits. Non-condensation implants were installed into the right tibia. All implants had a moderately rough surface. The implants had an implantation time of 7, 28, or 84 days before the removal torque was measured. The interfacial shear strength at different healing time was estimated by the means of finite element method. RESULTS: At 7 days of healing, the condensation implant had an increased removal torque compared to the non-bone-condensation implant. At 28 and 84 days of healing, there was no difference in removal torque. The simulated interfacial shear strength ratios of bone condensation implants at different implantation time were in line with the in vivo data. CONCLUSIONS: Moderately rough implants that initially induce bone strain during installation have increased stability during the early healing period. In addition, the finite element method may be used to evaluate differences in interlocking capacity. PMID- 26762886 TI - Epidemiology and determinants of pruritus in pre-dialysis chronic kidney disease patients. AB - PURPOSE: There are only a few small studies investigating chronic kidney disease associated pruritus (CKD-P) in pre-dialysis chronic kidney disease (CKD). None of these has taken into account the associations of CKD-P with clinical features and laboratory data. We aimed to study prevalence of and clinical and laboratory associates of CKD-P in pre-dialysis CKD patients. METHODS: A total of 402 consecutive stage 2-5 pre-dialysis CKD patients were included in this cross sectional study. Pruritus was scored based on visual analog scale (VAS). Demographic and clinical features, comorbidities, smoking status and current medication use were recorded. 25 (OH) Vitamin D, urea, creatinine, uric acid, calcium, phosphorus, intact parathyroid hormone (PTH), magnesium, albumin, C reactive protein (CRP), complete blood count and differential and other laboratory tests were studied for each participant. RESULTS: This is the largest study conducted in pre-dialysis population with respect to pruritus and associated factors. The prevalence of CKD-P was 18.9%. Hemoglobin level was significantly lower, and eosinophil count and frequency of xerosis cutis were significantly higher in patients with CKD-P than those of patients without pruritus. However, there was no statistical difference between the pruritus and nonpruritus groups regarding vitamin D, PTH, calcium, phosphorus, neutrophil-to lymphocyte ratio (NLR) and CRP. CONCLUSIONS: CKD-P was almost present in one in every five pre-dialysis CKD patients. Interestingly, the prevalence was not affected by the stage of the CKD. For the first time, our results showed a significant association between CKD-P and peripheral eosinophilia and anemia. Besides this, xerosis cutis seems a determinant factor for CKD-P and its severity. PMID- 26762889 TI - The right ingredients in suit therapy? PMID- 26762888 TI - Echocardiographic Laboratory Accreditation: The Pains and Pleasures. PMID- 26762887 TI - MSG-Evoked c-Fos Activity in the Nucleus of the Solitary Tract Is Dependent upon Fluid Delivery and Stimulation Parameters. AB - The marker of neuronal activation, c-Fos, can be used to visualize spatial patterns of neural activity in response to taste stimulation. Because animals will not voluntarily consume aversive tastes, these stimuli are infused directly into the oral cavity via intraoral cannulae, whereas appetitive stimuli are given in drinking bottles. Differences in these 2 methods make comparison of taste evoked brain activity between results that utilize these methods problematic. Surprisingly, the intraoral cannulae experimental conditions that produce a similar pattern of c-Fos activity in response to taste stimulation remain unexplored. Stimulation pattern (e.g., constant/intermittent) and hydration state (e.g., water-restricted/hydrated) are the 2 primary differences between delivering tastes via bottles versus intraoral cannulae. Thus, we quantified monosodium glutamate (MSG)-evoked brain activity, as measured by c-Fos, in the nucleus of the solitary tract (nTS; primary taste nucleus) across several conditions. The number and pattern of c-Fos neurons in the nTS of animals that were water-restricted and received a constant infusion of MSG via intraoral cannula most closely mimicked animals that consumed MSG from a bottle. Therefore, in order to compare c-Fos activity between cannulae-stimulated and bottle stimulated animals, cannulated animals should be water restricted prior to stimulation, and receive taste stimuli at a constant flow. PMID- 26762890 TI - Surface enhanced Raman scattering of gold nanoparticles supported on copper foil with graphene as a nanometer gap. AB - Gaps with single-nanometer dimensions (<10 nm) between metallic nanostructures enable giant local field enhancements for surface enhanced Raman scattering (SERS). Monolayer graphene is an ideal candidate to obtain a sub-nanometer gap between plasmonic nanostructures. In this work, we demonstrate a simple method to achieve a sub-nanometer gap by dewetting a gold film supported on monolayer graphene grown on copper foil. The Cu foil can serve as a low-loss plasmonically active metallic film that supports the imaginary charge oscillations, while the graphene can not only create a stable sub-nanometer gap for massive plasmonic field enhancements but also serve as a chemical enhancer. We obtained higher SERS enhancements in this graphene-gapped configuration compared to those in Au nanoparticles on Cu film or on graphene-SiO2-Si. Also, the Raman signals measured maintained their fine features and intensities over a long time period, indicating the stability of this Au-graphene-Cu hybrid configuration as an SERS substrate. PMID- 26762891 TI - Prophylaxis for hepatitis B reactivation during and after chemotherapy: many questions, some answers. PMID- 26762892 TI - Nitrogen-Doped Graphene for Photocatalytic Hydrogen Generation. AB - Photocatalytic hydrogen (H2 ) generation in a water splitting process has recently attracted tremendous interest because it allows the direct conversion of clean and unlimited solar energy into the ideal energy resource of H2 . For efficient photocatalytic H2 generation, the role of the photocatalyst is critical. With increasing demand for more efficient, sustainable, and cost effective photocatalysts, various types of semiconductor photocatalysts have been intensively developed. In particular, on the basis of its superior catalytic and tunable electronic properties, nitrogen-doped graphene is a potential candidate for a high-performance photocatalyst. Nitrogen-doped graphene also offers additional advantages originating from its unique two-dimensional sp(2) hybridized carbon network including a large specific surface area and exceptional charge transport properties. It has been reported that nitrogen-doped graphene can play diverse but positive functions including photo-induced charge acceptor/meditator, light absorber from UV to visible light, n-type semiconductor, and giant molecular photocatalyst. Herein, we summarize the recent progress and general aspects of nitrogen-doped graphene as a photocatalyst for photocatalytic H2 generation. In addition, challenges and future perspectives in this field are also discussed. PMID- 26762893 TI - Aphasia in Persian: Implications for cognitive models of lexical processing. AB - Current models of oral reading assume that different routes (sublexical, lexical, and semantic) mediate oral reading performance and reliance on different routes during oral reading depends on the characteristics of print to sound mappings. Studies of single cases of acquired dyslexia in aphasia have contributed to the development of such models by revealing patterns of double dissociation in object naming and oral reading skill that follow brain damage in Indo-European and Sino Tibetan languages. Print to sound mapping in Persian varies in transparency because orthography to phonology translation depends uniquely on the presence or absence of vowel letters in print. Here a hypothesis is tested that oral reading in Persian requires a semantic reading pathway that is independent of a direct non-semantic reading pathway, by investigating whether Persian speakers with aphasia show selective impairments to object naming and reading aloud. A sample of 21 Persian speakers with aphasia ranging in age from 18 to 77 (mean = 53, SD = 16.9) was asked to name a same set of 200 objects and to read aloud the printed names of these objects in different sessions. As an additional measure of sublexical reading, patients were asked to read aloud 30 non-word stimuli. Results showed that oral reading is significantly more preserved than object naming in Persian speakers with aphasia. However, more preserved object naming than oral reading was also observed in some cases. There was a moderate positive correlation between picture naming and oral reading success (p < .05). Mixed effects logistic regression revealed that word frequency, age of acquisition and imageability predict success across both tasks and there is an interaction between these variables and orthographic transparency in oral reading. Furthermore, opaque words were read less accurately than transparent words. The results reveal different patterns of acquired dyslexia in some cases that closely resemble phonological, deep, and surface dyslexia in other scripts - reported here in Persian for the first time. PMID- 26762895 TI - Enhanced OCT4 transcriptional activity substitutes for exogenous SOX2 in cellular reprogramming. AB - Adenoviral early region 1A (E1A) is a viral gene that can promote cellular proliferation and de-differentiation in mammalian cells, features required for the reprogramming of somatic cells to a pluripotent state. E1A has been shown to interact with OCT4, and as a consequence, to increase OCT4 transcriptional activity. Indeed, E1A and OCT4 are sufficient to revert neuroepithelial hybrids to pluripotency, as demonstrated in previous cell fusion experiments. However, the role that E1A might play in the generation of induced pluripotent stem cells (iPSCs) has not been investigated yet. In this report, we show that E1A can generate iPSCs in combination with OCT4 and KLF4, thus replacing exogenous SOX2. The generated iPSCs are bona fide pluripotent cells as shown by in vitro and in vivo tests. Overall, our study suggests that E1A might replace SOX2 through enhancing OCT4 transcriptional activity at the early stages of reprogramming. PMID- 26762896 TI - Microbe-based technology ameliorates glandular trichomes, secondary metabolites and antioxidants in Pelargonium graveolens L'Her. AB - BACKGROUND: Despite the vast exploration of microbes for plant health, there is a lack of knowledge about the synergistic effects of specific microorganisms in sustainable agriculture, especially in medicinal plants such as Pelargonium graveolens L'Her. The aim of this study was to evaluate how synergistic microbes Trichoderma harzianum ThU, Glomus intraradices and Bacillus subtilis CIM affected crop productivity, secondary metabolites and glandular trichome number in P. graveolens. RESULTS: The results demonstrated a significant (P < 0.05) increase in plant growth, secondary metabolites, total chlorophyll, carotenoids, carbohydrates, total phenolics, total flavonoids, free radical-scavenging activity and total antioxidant capacity of P. graveolens treated with synergistic bioinoculants as compared with the control. Most interestingly, an increase in essential oil by 32% in the treatment with all three microbes was observed. Furthermore, the principal aroma compounds citronellol and geraniol also increased in the same treatment. A positive and direct correlation was observed between essential oil content and number of glandular trichomes in all treatments. CONCLUSION: The present study highlights an explicit amalgamation of prospective microbes showing potential for synergism that act as biostimulants in enhancing plant production and improving the antioxidant and aroma profile of P. graveolens. (c) 2016 Society of Chemical Industry. PMID- 26762897 TI - Contingency and the order of nature. AB - Many profess faith in the universal rule of deterministic law. I urge remaining agnostic, putting into nature only what we need to account for what we know to be the case: order where, and to the extent that, we see it. Powers and mechanisms can do that job. Embracing contingency and deriving order from powers and mechanisms reduces three kinds of problems: ontological, theological, and epistemological. Ontologically, there is no puzzle about why models from various branches of natural and social science, daily life, and engineering serve us in good stead if all that's happening is physics laws playing themselves out. Also, when universal laws are replaced with a power/mechanism ontology, nothing is set irredeemably by the Big Bang or at some hyper-surface in space-time. What happens can depend on how we arrange things to exploit the powers of their parts. That may be put to significant theological advantage. The epistemological problem comes from philosopher of physics, Erhard Scheibe. Given what we take physics to teach about the universality of interaction, there is just one very large object the entire universe - to be governed by laws of nature. How then do we ever learn those laws? PMID- 26762898 TI - Diagnostic utility of SOX11 immunohistochemistry in differentiating cutaneous spread of mantle cell lymphoma from primary cutaneous B-cell lymphomas. AB - BACKGROUND: Mantle cell lymphoma (MCL) is associated with the worst prognosis among low-grade B-cell lymphomas. While cutaneous involvement by nodal or systemic MCL is uncommon, its differentiation from primary cutaneous B-cell lymphoma (CBCL) or cutaneous involvement by other extra-cutaneous BCL is challenging as neither histomorphology nor immunophenotype can be absolutely specific. We analyzed the diagnostic utility of SOX11 immunohistochemistry in differentiating secondary cutaneous MCL from other low-grade CBCL. METHODS: Immunohistochemical staining with anti-SOX11 antibody was performed on 8 cases of secondary cutaneous MCL, 16 secondary cutaneous CLL, 20 primary cutaneous MZL, 12 cutaneous FCL (6 primary, 6 secondary), 7 primary cutaneous DLBCL, leg type, 5 systemic DLBCL and 3 B-ALL. SOX11 and cyclin D1 staining were compared in secondary cutaneous MCL. RESULTS: Nuclear SOX11 staining was seen in seven of eight cases (88%) of secondary cutaneous MCL, including a case with minimal cyclin D1 expression. All other CBCL lacked detectable nuclear SOX11 expression. The sensitivity and specificity for SOX11 in MCL were 87.5 and 100%, respectively. Both the sensitivity and specificity for combined SOX11 and cyclin D1 immunohistochemistry were 100%. CONCLUSION: SOX11 immunohistochemistry could be a useful adjunct in distinguishing secondary cutaneous MCL from other CBCL. PMID- 26762901 TI - Erratum: Hayward IP, Bridle KR, Campbell GR, Underwood PA, Campbell JH (1995) Effect of Extracellular Matrix Proteins on Vascular Smooth Muscle Cell Phenotype. Cell Biology International 19: 839-846. doi: 10.1006/cbir.1995.1019. AB - The above article, published in print in Cell Biology International in September 1995 and online on 2 January 2013 in Wiley Online Library (http://onlinelibrary.wiley.com/doi/10.1006/cbir.1995.1019/abstract), is an exact duplicate of the article 'Effect of Extracellular Matrix Proteins on Vascular Smooth Muscle Cell Phenotype' (Hayward et al., ), which was published in the previous issue of Cell Biology International (Hayward et al., ). The duplicate publication is the result of an administrative error. The publisher apologises for any inconvenience. PMID- 26762899 TI - The canine prostate cancer cell line CHP-1 shows over-expression of the co chaperone small glutamine-rich tetratricopeptide repeat-containing protein alpha. AB - Although androgen therapy resistance and poor clinical outcomes are seen in most canine prostate cancer cases, there are only a few tools for analysing canine prostate cancer by using a cell biological approach. Therefore, to evaluate androgen-independent neoplastic cell growth, a new canine prostate cancer cell line (CHP-1) was established in this study. CHP-1 over-expressed the co-chaperone small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA), which is over-expressed in human androgen-independent prostate cancer. The CHP-1 xenograft also showed SGTA over-expression. Although CHP-1 shows poor androgen receptor (AR) signalling upon dihydrotestosterone stimulation, forced expression of AR enabled evaluation of AR signalling. Taken together, these results suggest that CHP-1 will be a useful model for investigating the pathogenesis of androgen dependent and androgen-independent canine prostate cancer. PMID- 26762900 TI - Implementing a patient-initiated review system for people with rheumatoid arthritis: a prospective, comparative service evaluation. AB - RATIONALE, AIMS AND OBJECTIVES: The management of rheumatoid arthritis (RA) usually entails regular hospital reviews with a specialist often when the patient is well rather than during a period of exacerbation. An alternative approach where patients initiate appointments when they need them can improve patient satisfaction and resource use whilst being safe. This service evaluation reports a system-wide implementation of a patient-initiated review appointment system called Direct Access (DA) for people with RA. The aim was to establish the impact on patient satisfaction of the new system versus usual care as well as evaluate the implementation processes. METHODS: As all patients could not start on the new system at once, in order to manage the implementation, patients were randomly allocated to DA or to usual care. Instead of regular follow-up appointments, DA comprised an education session and access to a nurse-led telephone advice line where appointments could be accessed within two weeks. Usual care comprised routine follow-ups with the specialist. Data were collected on patient satisfaction, service use and outcomes of any contact to the advice line. RESULTS: Three hundred and eleven patients with RA were assessed as being suitable for DA. In terms of patient satisfaction, between-group differences were found in favour of DA for accessibility and convenience, ease of contacting the nurse and overall satisfaction with the service. Self-reported visits to the general practitioner were also significantly lower. DA resulted in a greater number of telephone contacts (incidence rate ratio = 1.69; 95% confidence interval 1.07 to 2.68). Hospital costs of the two different service models were similar. Mean waiting time for an appointment was 10.8 days CONCLUSION: This service evaluation found that DA could be implemented and it demonstrated patient benefit in a real-world setting. Further research establishing the broader cost consequences across the whole patient pathway would add to our findings. PMID- 26762902 TI - Zhang, Y., Luo, F., Wu, S., Yu, B., Liu, T. and Wu, Y. (2014), Tribbles homolog 3 expression in spermatogonial stem cells of rat testes. Cell Biology International, 38: 1403-1407. doi: 10.1002/cbin.10338. PMID- 26762903 TI - Extraction, chromatographic and mass spectrometric methods for lipid analysis. AB - Lipids make up a diverse subset of biomolecules that are responsible for mediating a variety of structural and functional properties as well as modulating cellular functions such as trafficking, regulation of membrane proteins and subcellular compartmentalization. In particular, phospholipids are the main constituents of biological membranes and play major roles in cellular processes like transmembrane signaling and structural dynamics. The chemical and structural variety of lipids makes analysis using a single experimental approach quite challenging. Research in the field relies on the use of multiple techniques to detect and quantify components of cellular lipidomes as well as determine structural features and cellular organization. Understanding these features can allow researchers to elucidate the biochemical mechanisms by which lipid-lipid and/or lipid-protein interactions take place within the conditions of study. Herein, we provide an overview of essential methods for the examination of lipids, including extraction methods, chromatographic techniques and approaches for mass spectrometric analysis. PMID- 26762905 TI - Progress in Predicting Chronic Total Occlusion Recanalization. PMID- 26762907 TI - Who Is Thrombogenic: The Scaffold or the Doctor? Back to the Future! PMID- 26762906 TI - Scaffold Thrombosis After Percutaneous Coronary Intervention With ABSORB Bioresorbable Vascular Scaffold: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: The aim of this study was to determine the risk of scaffold thrombosis (ST) after percutaneous coronary intervention (PCI) with placement of an ABSORB bioresorbable vascular scaffold (BVS) (Abbott Vascular, Santa Clara, California) by conducting a systematic review and meta-analysis. BACKGROUND: PCI with BVS placement holds great potential, but concern has recently been raised regarding the risk of ST. METHODS: MEDLINE/PubMed, Cochrane CENTRAL, and meeting abstracts were searched for all studies that included outcomes data for patients after PCI with BVS placement. For studies comparing BVSs with drug-eluting stents (DES), pooled estimates of outcomes, presented as odds ratios (ORs) with 95% confidence intervals (CIs), were generated with random-effects models. RESULTS: Our analysis included 10,510 patients (8,351 with a BVS and 2,159 with DES) with a follow-up of 6.4 +/- 5.1 months and 60 +/- 11 years of age; 78% were male, 36% had stable angina, and 59% had acute coronary syndrome (ACS). Among patients with a BVS, cardiovascular death occurred in 0.6%, myocardial infarction (MI) in 2.1%, target lesion revascularization in 2.0%, and definite/probable ST in 1.2% of patients. Of BVS patients, 0.27% had acute ST and 0.57% had subacute ST. Meta analysis demonstrated that patients who received a BVS were at a higher risk of MI (OR: 2.06, 95% CI: 1.31 to 3.22, p = 0.002) and definite/probable ST (OR: 2.06, 95% CI: 1.07 to 3.98, p = 0.03) compared with patients who received DES, whereas there was a trend toward decreased all-cause mortality with a BVS (OR: 0.40, 95% CI: 0.15 to 1.06, p = 0.06). CONCLUSIONS: Patients undergoing PCI with a BVS had increased definite/probable ST and MI during follow-up compared with DES. Further studies with long-term follow-up are needed to assess the risk of ST with a BVS. PMID- 26762904 TI - Development and Validation of a Novel Scoring System for Predicting Technical Success of Chronic Total Occlusion Percutaneous Coronary Interventions: The PROGRESS CTO (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention) Score. AB - OBJECTIVES: This study sought to develop a novel parsimonious score for predicting technical success of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) performed using the hybrid approach. BACKGROUND: Predicting technical success of CTO PCI can facilitate clinical decision making and procedural planning. METHODS: We analyzed clinical and angiographic parameters from 781 CTO PCIs included in PROGRESS CTO (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention) using a derivation and validation cohort (2:1 sampling ratio). Variables with strong association with technical success in multivariable analysis were assigned 1 point, and a 4-point score was developed from summing all points. The PROGRESS CTO score was subsequently compared with the J-CTO (Multicenter Chronic Total Occlusion Registry in Japan) score in the validation cohort. RESULTS: Technical success was 92.9%. On multivariable analysis, factors associated with technical success included proximal cap ambiguity (beta coefficient [b] = 0.88), moderate/severe tortuosity (b = 1.18), circumflex artery CTO (b = 0.99), and absence of "interventional" collaterals (b = 0.88). The resulting score demonstrated good calibration and discriminatory capacity in the derivation (Hosmer-Lemeshow chi-square = 2.633; p = 0.268, and receiver-operator characteristic [ROC] area = 0.778) and validation (Hosmer-Lemeshow chi-square = 5.333; p = 0.070, and ROC area = 0.720) subset. In the validation cohort, the PROGRESS CTO and J-CTO scores performed similarly in predicting technical success (ROC area 0.720 vs. 0.746, area under the curve difference = 0.026, 95% confidence interval = -0.093 to 0.144). CONCLUSIONS: The PROGRESS CTO score is a novel useful tool for estimating technical success in CTO PCI performed using the hybrid approach. PMID- 26762909 TI - The Importance of Subgroup Analysis in Drug-Eluting Stent Trials. PMID- 26762908 TI - Effect of Chronic Kidney Disease in Women Undergoing Percutaneous Coronary Intervention With Drug-Eluting Stents: A Patient-Level Pooled Analysis of Randomized Controlled Trials. AB - OBJECTIVES: This study sought to evaluate: 1) the effect of impaired renal function on long-term clinical outcomes in women undergoing percutaneous coronary intervention (PCI) with drug-eluting stent (DES); and 2) the safety and efficacy of new-generation compared with early-generation DES in women with chronic kidney disease (CKD). BACKGROUND: The prevalence and effect of CKD in women undergoing PCI with DES is unclear. METHODS: We pooled patient-level data for women enrolled in 26 randomized trials. The study population was categorized by creatinine clearance (CrCl) <45 ml/min, 45 to 59 ml/min, and >=60 ml/min. The primary endpoint was the 3-year rate of major adverse cardiovascular events (MACE). Participants for whom baseline creatinine was missing were excluded from the analysis. RESULTS: Of 4,217 women included in the pooled cohort treated with DES and for whom serum creatinine was available, 603 (14%) had a CrCl <45 ml/min, 811 (19%) had a CrCl 45 to 59 ml/min, and 2,803 (66%) had a CrCl >=60 ml/min. A significant stepwise gradient in risk for MACE was observed with worsening renal function (26.6% vs. 15.8% vs. 12.9%; p < 0.01). Following multivariable adjustment, CrCl <45 ml/min was independently associated with a higher risk of MACE (adjusted hazard ratio: 1.56; 95% confidence interval: 1.23 to 1.98) and all cause mortality (adjusted hazard ratio: 2.67; 95% confidence interval: 1.85 to 3.85). Compared with older-generation DES, the use of newer-generation DES was associated with a reduction in the risk of cardiac death, myocardial infarction, or stent thrombosis in women with CKD. The effect of new-generation DES on outcomes was uniform, between women with or without CKD, without evidence of interaction. CONCLUSIONS: Among women undergoing PCI with DES, CKD is a common comorbidity associated with a strong and independent risk for MACE that is durable over 3 years. The benefits of newer-generation DES are uniform in women with or without CKD. PMID- 26762910 TI - A Randomized Comparison of Reservoir-Based Polymer-Free Amphilimus-Eluting Stents Versus Everolimus-Eluting Stents With Durable Polymer in Patients With Diabetes Mellitus: The RESERVOIR Clinical Trial. AB - OBJECTIVES: The aim of this study was to compare the efficacy of amphilimus eluting stents (AES) with that of everolimus-eluting stents (EES) in patients with diabetes mellitus (DM). BACKGROUND: The AES is a polymer-free drug-eluting stent that elutes sirolimus formulated with an amphiphilic carrier from laser-dug wells. This technology could be associated with a high efficacy in patients with DM. METHODS: This was a multicenter, randomized, noninferiority trial. Patients with DM medically treated with oral glucose-lowering agents or insulin and de novo coronary lesions were randomized in a 1:1 fashion to AES or EES. The primary endpoint was the neointimal (NI) volume obstruction assessed by optical coherence tomography at 9-month follow-up. RESULTS: A total of 116 lesions in 112 patients were randomized. Overall, 40% were insulin-treated patients, with a median HbA1c of 7.3% (interquartile range: 6.7% to 8.0%). The primary endpoint, NI volume obstruction, was 11.97 +/- 5.94% for AES versus 16.11 +/- 18.18% for EES, meeting the noninferiority criteria (p = 0.0003). Pre-specified subgroup analyses showed a significant interaction between stent type and glycemic control (p = 0.02), with a significant reduction in NI hyperplasia in the AES group in patients with the higher HbA1c (p = 0.03). By quantitative coronary angiography, in-stent late loss was 0.14 +/- 0.24 for AES versus 0.24 +/- 0.57 mm for EES (p = 0.27), with a larger minimal lumen diameter at follow-up for AES (p = 0.02), mainly driven by 2 cases of occlusive restenosis in the EES group. CONCLUSIONS: AES are noninferior to EES for the coronary revascularization of patients with DM. These results suggest a high efficacy of the AES and may support the potential benefit of this stent in patients with DM. (A Randomized Comparison of Reservoir-Based Polymer Free Amphilimus-Eluting Stents Versus Everolimus-Eluting Stents With Durable Polymer in Patients With Diabetes Mellitus [RESERVOIR]; NCT01710748). PMID- 26762912 TI - The Quest for the Perfect Stent for a Given Patient: Drug-Coated Stents for the Treatment of Coronary Disease. PMID- 26762911 TI - Polymer-Free Biolimus A9-Coated Stents in the Treatment of De Novo Coronary Lesions: 4- and 12-Month Angiographic Follow-Up and Final 5-Year Clinical Outcomes of the Prospective, Multicenter BioFreedom FIM Clinical Trial. AB - OBJECTIVES: The purpose of this study was to evaluate the efficacy and long-term outcomes of a novel polymer/carrier-free drug-coated stent (DCS) in patients with de novo coronary lesions. BACKGROUND: The BioFreedom (BFD) DCS incorporates a low profile, stainless-steel platform, with a surface that has been modified to create a selectively microstructured abluminal surface that allows adhesion and further release of Biolimus A9 (Biosensors Europe SA, Morges, Switzerland). METHODS: A total of 182 patients (183 lesions) were randomized into a 1:1:1 ratio for treatment with BFD "standard dose" (BFD) or BFD "low dose" (BFD-LD) versus first-generation paclitaxel-eluting stents (PES) at 4 sites in Germany. RESULTS: Baseline and procedural characteristics were well matched. At 4-month angiographic follow-up (Cohort 1, n = 75), in-stent late lumen loss (LLL) was significantly lower with BFD and BFD-LD versus PES (0.08 and 0.12 mm vs. 0.37 mm, respectively; p < 0.0001 for BFD vs. PES, and p = 0.002 for BFD-LD vs. PES). At 12 months (Cohort 2, n = 107), in-stent LLL (primary endpoint) was 0.17 mm in BFD versus 0.35 mm in PES (p = 0.001 for noninferiority; p = 0.11 for superiority); however, the BFD-LD (0.22 mm) did not reach noninferiority (p = 0.21). At 5 years (175 of 182), there were no significant differences in major adverse cardiac events (23.8%, 26.4%, and 20.3%) and clinically indicated target lesion revascularization (10.8%, 13.4%, and 10.2%) for BFD, BFD-LD, and PES, respectively; also, there was no definite/probable stent thrombosis reported. CONCLUSIONS: The BFD, but not the BFD-LD, demonstrated noninferiority versus PES in terms of in-stent LLL, a surrogate of neointimal hyperplasia, at 12-month follow-up. At 5 years, clinical event rates were similar, without occurrence of stent thrombosis in all groups. (BioFreedom FIM Clinical Trial; NCT01172119). PMID- 26762914 TI - Next Generation Valves: What Are We Looking for? PMID- 26762913 TI - Prospective Multicenter Evaluation of the Direct Flow Medical Transcatheter Aortic Valve System: 12-Month Outcomes of the Evaluation of the Direct Flow Medical Percutaneous Aortic Valve 18F System for the Treatment of Patients With Severe Aortic Stenosis (DISCOVER) Study. AB - OBJECTIVES: The aim of this study was to assess the 1-year outcome after transcatheter aortic valve replacement (TAVR) of the Direct Flow Medical (DFM) valve in patients with severe symptomatic aortic stenosis who were contraindicated or high risk for surgery. BACKGROUND: The DFM transcatheter heart valve is a new-generation, nonmetallic aortic valve with a pressurized support structure and conformable double-ring annular sealing delivered through an 18-F sheath. The device allows repositioning, retrieval, and assessment of valve performance before permanent implantation. METHODS: A prospective multicenter European registry was set up to determine the safety and performance of the valve in 100 consecutive patients (10 centers). Echocardiographic and angiographic data were evaluated by an independent core laboratory, and adverse events were adjudicated by a clinical events committee using Valve Academic Research Consortium criteria. RESULTS: Patients were 83.1 +/- 5.9 years of age and had a logistic EuroSCORE of 22.5 +/- 11.3% and a Society of Thoracic Surgeons score of 9.7 +/- 8.7%. Correct valve positioning was obtained in 99% of cases with a combined 30-day safety endpoint at 10%, including major stroke in 5.0%, major vascular complications in 2.0%, and death in 1%. At 12 months, 95% of patients were in New York Heart Association functional class I or II. Freedom from any death was 90%, and freedom from any death or major stroke was 85%. Echocardiography demonstrated none/trace to mild aortic regurgitation in 100% of patients and an unchanged mean aortic gradient of 12.2 +/- 6.6 mm Hg and effective orifice area of 1.6 +/- 0.4 cm(2). CONCLUSIONS: At 1 year, the DFM transcatheter heart valve had durable hemodynamics. This study demonstrates that the low rate of early complications and the low risk of significant aortic regurgitation translated into midterm clinical benefit. PMID- 26762916 TI - Transcatheter Versus Surgical Closure of Atrial Septal Defects. PMID- 26762915 TI - Transcatheter Versus Surgical Closure of Atrial Septal Defects in Children: A Value Comparison. AB - OBJECTIVES: The purpose of this study was to determine whether a transcatheter procedure or surgical closure offers a better value proposition for atrial septal defect (ASD) closure. BACKGROUND: Secundum ASDs are common congenital heart defects with both transcatheter and surgical treatment options. Although both options have been shown to have excellent results in children, the relative value of the 2 procedures is unclear. METHODS: Using data from the Pediatric Hospital Information System for 2004 to 2012, we compared the value of transcatheter versus surgical ASD closure for children ages 1 to 17 years, with value being defined as outcomes relative to costs. Total charges for procedure-related encounters were converted to costs using hospital-specific cost-to-charge ratios, and all costs were adjusted for inflation to reflect 2012 dollars. RESULTS: There were 4,606 transcatheter procedures and 3,159 surgeries at 35 children's hospitals. Those undergoing transcatheter closure were more likely to be older (5.6 years vs. 4.5 years, p < 0.0001). There was no mortality in either group. Children with a surgical procedure had a longer length of stay (4.0 days vs. 1.5 days, p < 0.0001), were more likely to have an infection (odds ratio: 3.73, p < 0.0001) or procedural complication (odds ratio: 6.66, p < 0.0001). Costs for transcatheter procedure encounters were lower than costs for surgical encounters (mean of $19,128 vs. $25,359, p < 0.0001). CONCLUSIONS: Both transcatheter and surgical ASD closure had excellent short-term outcomes, but transcatheter procedures had lower lengths of stay, rates of infection, and complications, resulting in lower overall costs. For children who are eligible, transcatheter ASD closure provides better short-term value than surgery. PMID- 26762917 TI - Late False Aneurysm Formation After Transfemoral TAVR. PMID- 26762918 TI - Is Coronary Wedge Pressure a Technique to Identify High-Risk Patients Who May Benefit From Alternative Treatment in Acute Myocardial Infarction?: Is This The Next Step? PMID- 26762919 TI - Personalized Antiplatelet Therapy: The Odyssey Continues. PMID- 26762920 TI - Reply: Is Coronary Wedge Pressure a Technique to Identify High-Risk Patients Who May Benefit From Alternative Treatment in Acute Myocardial Infarction?: Is This The Next Step? PMID- 26762921 TI - Reply: Personalized Antiplatelet Therapy: The Odyssey Continues. PMID- 26762922 TI - Cerebral Embolization After Implantation of a Balloon-Expandable Aortic Valve Without Prior Balloon Valvuloplasty: When Is Doing Less More? PMID- 26762923 TI - Reply: Cerebral Embolization After Implantation of a Balloon-Expandable Aortic Valve Without Prior Balloon Valvuloplasty: When Is Doing Less More? PMID- 26762924 TI - Risk Avoidance: For Whom? PMID- 26762925 TI - Hypertrophic Obstructive Cardiomyopathy and Uncontrolled Hypertension: A Therapeutic Challenge. PMID- 26762926 TI - Use of Bioresorbable Vascular Scaffold in Acute Dissection: Insights From Optical Coherence Tomography. PMID- 26762927 TI - Peripheral neuropathy in genetically characterized patients with mitochondrial disorders: A study from south India. AB - BACKGROUND: There are relatively few studies, which focus on peripheral neuropathy in large cohorts of genetically characterized patients with mitochondrial disorders. This study sought to analyze the pattern of peripheral neuropathy in a cohort of patients with mitochondrial disorders. METHODS: The study subjects were derived from a cohort of 52 patients with a genetic diagnosis of mitochondrial disorders seen over a period of 8 years (2006-2013). All patients underwent nerve conduction studies and those patients with abnormalities suggestive of peripheral neuropathy were included in the study. Their phenotypic features, genotype, pattern of peripheral neuropathy and nerve conduction abnormalities were analyzed retrospectively. RESULTS: The study cohort included 18 patients (age range: 18 months-50 years, M:F- 1.2:1).The genotype included mitochondrial DNA point mutations (n=11), SURF1 mutations (n=4) and POLG1(n=3). Axonal neuropathy was noted in 12 patients (sensori-motor:n=4; sensory:n=4; motor:n=4) and demyelinating neuropathy in 6. Phenotype-genotype correlations revealed predominant axonal neuropathy in mtDNA point mutations and demyelinating neuropathy in SURF1. Patients with POLG related disorders had both sensory ataxic neuropathy and axonal neuropathy. CONCLUSION: A careful analysis of the family history, clinical presentation, biochemical, histochemical and structural analysis may help to bring out the mitochondrial etiology in patients with peripheral neuropathy and may facilitate targeted gene testing. Presence of demyelinating neuropathy in Leigh's syndrome may suggest underlying SURF1 mutations. Sensory ataxic neuropathy with other mitochondrial signatures should raise the possibility of POLG related disorder. PMID- 26762929 TI - Probing weak localization in chemical vapor deposition graphene wide constriction using scanning gate microscopy. AB - Low-temperature scanning gate microscopy (LT-SGM) studies of graphene allow one to obtain important spatial information regarding coherent transport such as weak localization (WL) and universal conductance fluctuations. Although fascinating LT SGM results on pristine graphene prepared by mechanical exfoliation have been reported in the literature, there appears to be a dearth of LT-SGM results on chemical vapor deposition (CVD)-grown graphene whose large scale and flexible substrate transferability make it an ideal candidate for coherent electronic applications. To this end, we have performed LT-SGM studies on CVD-grown graphene wide constriction (0.8 MUm), which can be readily prepared by cost-effective optical lithography fully compatible with those in wafer foundry, in the WL regime. We find that the movable local gate can sensitively modulate the total conductance of the CVD graphene constriction possibly due to the intrinsic grain boundaries and merged domains, a great advantage for applications in coherent electronics. Moreover, such a conductance modulation by LT-SGM provides an additional, approximately magnetic-field-independent probe for studying coherent transport such as WL in graphene and spatial conductance variation. PMID- 26762928 TI - Postoperative mortality 90 days after robot-assisted laparoscopic prostatectomy and retropubic radical prostatectomy: a nationwide population-based study. AB - OBJECTIVE: To assess 90-day postoperative mortality after robot-assisted laparoscopic radical prostatectomy (RARP) and retropubic radical prostatectomy (RRP) using nationwide population-based registry data. PATIENTS AND METHODS: We conducted a cohort study using the National Prostate Cancer Register of Sweden, including 22 344 men with localized prostate cancer of clinical stage T1-T3, whose prostate-specific antigen levels were <50 MUg/mL and who had undergone primary radical prostatectomy in the period 1998-2012. Vital status was ascertained through the Total Population Register. The rates for 90-day postoperative mortality were analysed using logistic regression analysis, and comparisons of 90-day mortality with the background population were made using standardized mortality ratios (SMRs). RESULTS: Of the 14 820 men who underwent RRP, 29 (0.20%) died, and of the 7 524 men who underwent RARP, 10 (0.13%) died. Mortality in the cohort during the 90-day postoperative period was lower than in an age-matched background population: SMR 0.57 (95% confidence interval [CI] 0.39 0.75). There was no statistically significant difference in 90-day mortality according to surgical method: RARP vs RRP odds ratio (OR) 1.14; 95% CI 0.46-2.81. Postoperative 90-day mortality decreased over time: 2008-2012 vs 1998-2007 OR 0.44; 95% CI 0.21-0.95, mainly because of lower mortality after RARP. CONCLUSION: The 90-day postoperative mortality rates were low after RARP and RRP and there was no statistically significant difference between the methods. Given the long life expectancy among men with low- and intermediate-risk prostate cancer, very low postoperative mortality is a prerequisite for RP, which was fulfilled by both RRP and RARP. The selection of healthy men for RP is highlighted by the lower 90 day mortality after RP compared with the background population. PMID- 26762930 TI - A special supplement: findings from the Australian Cerebral Palsy Register, birth years 1993 to 2006. AB - AIM: To briefly outline the strengths and limitations of cerebral palsy (CP) registers, and to report on findings of the Australian Cerebral Palsy Register (ACPR) pertaining to a population cohort of children with CP. METHOD: De identified data were extracted from the ACPR for people with CP in birth years 1993 to 2006, from South Australia, Victoria, and Western Australia. Live birth prevalence of CP was estimated and risk factors described. RESULTS: The overall birth prevalence of CP (including those whose CP was postneonatally acquired) for the 1993 to 2006 birth cohort was 2.1 per 1000 live births (95% confidence interval [CI] 2.0-2.2). Excluding cases with a known postneonatal cause, the birth prevalence for pre/perinatally acquired CP was 2.0 per 1000 live births (95% CI 1.9-2.1). A downward trend in rates of CP in those born extremely preterm was evident over at least three consecutive periods across all three regions. Most (58.6%) children were born at term (>= 37 wks). Male sex, early gestational age, low birthweight, and multiple birth were risk factors for CP. INTERPRETATION: Overall rates of CP did not change during this period. The proportion of those with CP born extremely preterm decreased. The ACPR Group will investigate whether this pattern continues when data pertaining to the next birth cohort for all three regions becomes available. PMID- 26762931 TI - Prognostic value of the combination of serum l-kynurenine level and indoleamine 2,3-dioxygenase mRNA expression in acute myeloid leukemia. PMID- 26762932 TI - Erratum to: Response of invertebrates from the hyporheic zone of chalk rivers to eutrophication and land use. PMID- 26762933 TI - Soil washing in combination with homogeneous Fenton-like oxidation for the removal of 2,4,4'-trichlorodiphenyl from soil contaminated with capacitor oil. AB - Detoxification by chemical oxidation of polychlorinated biphenyls (PCBs) in contaminated soils is very difficult and inefficient because PCBs typically associate with the solid phase or exist as non-aqueous-phase liquids due to their low solubility and slow desorption rates, and thus, they are difficult to remove from soils by using traditional, water-based elution techniques. Surfactant can enhance washing efficiency of PCBs from contaminated soils. This study used Brij 58, Brij 30, Tween 80, and 2-hydroxypropyl-beta-cyclodextrin (HPCD) to solubilize 2,4,4'-trichlorodiphenyl (PCB28) from soil contaminated with capacitor oil into solution. The feasibility of PCB28 oxidation in soil washing wastewater through a Fe(3+)-catalyzed Fenton-like reaction was subsequently examined. Washing with 10 g L(-1) Brij 58 solution showed the highest extraction efficiency (up to 61.5 %) compared with that of the three other surfactants. The total concentration of PCB28 in contaminated soil at 25 degrees C after 48-h extraction was 286 mg L( 1). In contrast to conditions in which no washing agent was added, addition of the four washing agents decreased the efficiency of PCB28 degradation by the Fenton-like reaction, with the decrease due to addition of 10 g L(-1) Brij 58 solution being the smallest. The optimal concentration of H2O2 for preventing its useless decomposition was found to be 50 mM. The efficiency of PCB28 removal was lower when the initial concentration of PCB28 treated in the Fenton-like reaction was higher. The degradation efficiencies of PCB28 at initial concentrations of 0.1, 10, and 176 mg L(-1) in 10 g L(-1) Brij 58 solution at 25 degrees C and pH 3.0 and 9 h of reaction using 50 mM H2O2 were 64.1, 42.0, and 34.6 %, respectively. This result indicates that soil washing combined with Fenton-like oxidation may be a practical approach for the remediation of PCB-contaminated soil. PMID- 26762934 TI - Carbon amendment and soil depth affect the distribution and abundance of denitrifiers in agricultural soils. AB - The nitrite reductase (nirS and nirK) and nitrous oxide reductase-encoding (nosZ) genes of denitrifying populations present in an agricultural grassland soil were quantified using real-time polymerase chain reaction (PCR) assays. Samples from three separate pedological depths at the chosen site were investigated: horizon A (0-10 cm), horizon B (45-55 cm), and horizon C (120-130 cm). The effect of carbon addition (treatment 1, control; treatment 2, glucose-C; treatment 3, dissolved organic carbon (DOC)) on denitrifier gene abundance and N2O and N2 fluxes was determined. In general, denitrifier abundance correlated well with flux measurements; nirS was positively correlated with N2O, and nosZ was positively correlated with N2 (P < 0.03). Denitrifier gene copy concentrations per gram of soil (GCC) varied in response to carbon type amendment (P < 0.01). Denitrifier GCCs were high (ca. 10(7)) and the bac:nirK, bac:nirS, bac:nir (T) , and bac:nosZ ratios were low (ca. 10(-1)/10) in horizon A in all three respective treatments. Glucose-C amendment favored partial denitrification, resulting in higher nir abundance and higher N2O fluxes compared to the control. DOC amendment, by contrast, resulted in relatively higher nosZ abundance and N2 emissions, thus favoring complete denitrification. We also noted soil depth directly affected bacterial, archaeal, and denitrifier abundance, possibly due to changes in soil carbon availability with depth. PMID- 26762935 TI - Biodegradation of antibiotic ciprofloxacin: pathways, influential factors, and bacterial community structure. AB - Antibiotic ciprofloxacin is ubiquitous in the environment. However, little is known about ciprofloxacin dissipation by microbial community. The present study investigated the biodegradation potential of ciprofloxacin by mixed culture and the influential factors and depicted the structure of ciprofloxacin-degrading microbial community. Both the original microbiota from drinking water biofilter and the microbiota previously acclimated to high levels of ciprofloxacin could utilize ciprofloxacin as sole carbon and nitrogen sources, while the acclimated microbiota had a much stronger removal capacity. Temperature rise and the presence of carbon or nitrogen sources favored ciprofloxacin biodegradation. Many novel biotransformation products were identified, and four different metabolic pathways for ciprofloxacin were proposed. Bacterial community structure illustrated a profound shift with ciprofloxacin biodegradation. The ciprofloxacin degrading bacterial community was mainly composed of classes Gammaproteobacteria, Bacteroidia, and Betaproteobacteria. Microorganisms from genera Pseudoxanthomonas, Stenotrophomonas, Phenylobacterium, and Leucobacter might have links with the dissipation of ciprofloxacin. This work can provide some new insights towards ciprofloxacin biodegradation. PMID- 26762936 TI - Solanum torvum Swartz. fruit attenuates cadmium-induced liver and kidney damage through modulation of oxidative stress and glycosylation. AB - Increased levels of environmental pollutants are linked to almost all human disorders; the efficient method to manage the human health is through naturally available dietary molecule. Solanum torvum (ST) Swartz (Solanaceae) commonly called Turkey Berry is found in Africa, Asia, and South America. Its fruit, part of traditional Indian cuisine, is a widely consumed nutritious herb, acclaimed for its medicinal value. ST aqueous extract (STAe) (250, 500, and 1000 mg/kg b.w., 6 days; oral) against acute Cadmium (Cd) (6.3 mg/kg b.w., single dose; oral) toxicity was evaluated in rats. Protective effect was assessed using serum markers, tissue antioxidants, oxidant derivatives, glycoprotein, and histopathological studies. The activities of serum marker enzymes were increased (40-60 %); antioxidant enzymes such as SOD and CAT, GSH, and its metabolic enzyme activities were decreased (50-80 %) in the liver and kidney upon Cd intoxication. During STAe pre-treatment, at doses of 250 and 500 mg/kg b.w., the above changes were brought to near normal (25-63 %). Tissue 4-hydroxynonenal, 3-nitrotyrosine, and protein carbonyls were increased (8-15 fold) in Cd-alone-treated rats, whereas pre-supplementation of STAe significantly decreased their levels and inhibited the protein glycosylation effectively. The pharmacological effect of STAe was confirmed by histopathological observations. Based on previous literature and present investigation, we conclude that ST may serve as a potential functional food against environmental contaminant such as heavy metal induced oxidative stress. PMID- 26762938 TI - The size distribution of organic carbon in headwater streams in the Amazon basin. AB - Despite the strong representativeness of streams in the Amazon basin, their role in the accumulation of coarse particulate organic carbon (CPOC), fine particulate organic carbon (FPOC), and dissolved organic carbon (DOC) in transport, an important energy source in these environments, is poorly known. It is known that the arboreal vegetation in the Amazon basin is influenced by soil fertility and rainfall gradients, but would these gradients promote local differences in organic matter in headwater streams? To answer this question, 14 low-order streams were selected within these gradients along the Amazon basin, with extensions that varied between 4 and 8 km. The efficiency of the transformation of particulate into dissolved carbon fractions was assessed for each stream. The mean monthly benthic organic matter storage ranged between 1.58 and 9.40 t ha(-1) month(-1). In all locations, CPOC was the most abundant fraction in biomass, followed by FPOC and DOC. Rainfall and soil fertility influenced the distribution of the C fraction (p = 0.01), showing differentiated particulate organic carbon (POC) storage and DOC transportation along the basin. Furthermore, the results revealed that carbon quantification at the basin level could be underestimated, ultimately influencing the global carbon calculations for the region. This is especially due to the fact that the majority of studies consider only fine particulate organic matter and dissolved organic matter, which represent less than 50 % of the stored and transported carbon in streambeds. PMID- 26762939 TI - Electrochemical destruction of trans-cinnamic acid by advanced oxidation processes: kinetics, mineralization, and degradation route. AB - Acidic solutions of trans-cinnamic acid at pH 3.0 have been comparatively treated by anodic oxidation with electrogenerated H2O2 (AO-H2O2), electro-Fenton (EF), and photoelectro-Fenton (PEF). The electrolytic experiments were carried out with a boron-doped diamond (BDD)/air-diffusion cell. The substrate was very slowly abated by AO-H2O2 because of its low reaction rate with oxidizing *OH produced from water discharge at the BDD anode. In contrast, its removal was very rapid and at similar rate by EF and PEF due to the additional oxidation by *OH in the bulk, formed from Fenton's reaction between cathodically generated H2O2 and added Fe2+. The AO-H2O2 treatment yielded the lowest mineralization. The EF process led to persistent final products like Fe(III) complexes, which were quickly photolyzed upon UVA irradiation in PEF to give an almost total mineralization with 98 % total organic carbon removal. The effect of current density and substrate concentration on all the mineralization processes was examined. Gas chromatography-mass spectrometry (GC-MS) analysis of electrolyzed solutions allowed identifying five primary aromatics and one heteroaromatic molecule, whereas final carboxylic acids like fumaric, acetic, and oxalic were quantified by ion exclusion high-performance liquid chromatography (HPLC). From all the products detected, a degradation route for trans-cinnamic acid is proposed. PMID- 26762937 TI - Active capping technology: a new environmental remediation of contaminated sediment. AB - The management and treatment of contaminated sediment is a worldwide problem and poses major technical and economic challenges. Nowadays, various attempts have been committed to investigating a cost-effective way in contaminated sediment restoration. Among the remediation options, in situ capping turns out to be a less expensive, less disruptive, and more durable approach. However, by using the low adsorption capacity materials, traditional caps do not always fulfill the reduction of risks that can be destructive for human health, ecosystem, and even natural resources. Active caps, therefore, are designed to employ active materials (activated carbon, apatite, zeolite, organoclay, etc.) to strengthen their adsorption and degradation capacity. The active capping technology promises to be a permanent and cost-efficient solution to contaminated sediments. This paper provides a review on the types of active materials and the ways of these active materials employed in recent active capping studies. Cap design considerations including site-specific conditions, diffusion/advection, erosive forces, and active material selection that should be noticed in an eligible remediation project are also presented. PMID- 26762940 TI - Influence of oxygen transfer on Pseudomonas putida effects on growth rate and biodesulfurization capacity. AB - The growth rate and desulfurization capacity accumulated by the cells during the growth of Pseudomonas putida KTH2 under different oxygen transfer conditions in a stirred and sparged tank bioreactor have been studied. Hydrodynamic conditions were changed using different agitation conditions. During the culture, several magnitudes associated to growth, such as the specific growth rate, the dissolved oxygen concentration and the carbon source consumption have been measured. Experimental results indicate that cultures are influenced by the fluid dynamic conditions into the bioreactor. An increase in the stirrer speed from 400 to 700 rpm has a positive influence on the cell growth rate. Nevertheless, the increase of agitation from 700 to 2000 rpm hardly has any influence on the growth rate. The effect of fluid dynamics on the cells development of the biodesulfurization (BDS) capacity of the cells during growth is different. The activities of the intracellular enzymes involved in the 4S pathway change with dissolved oxygen concentration. The enzyme activities have been evaluated in cells at several growth time and different hydrodynamic conditions. An increase of the agitation from 100 to 300 rpm has a positive influence on the development of the overall BDS capacity of the cells during growth. This capacity shows a decrease for higher stirrer speeds and the activity of the enzymes monooxygenases DszC and DszA decreases dramatically. The highest value of the activity of DszB enzyme was obtained with cells cultured at 100 rpm, while this activity decreases when the stirrer speed was increased higher than this value. PMID- 26762941 TI - Amide Proton Transfer (APT) MR imaging and Magnetization Transfer (MT) MR imaging of pediatric brain development. AB - OBJECTIVES: To quantify the brain maturation process during childhood using combined amide proton transfer (APT) and conventional magnetization transfer (MT) imaging at 3 Tesla. METHODS: Eighty-two neurodevelopmentally normal children (44 males and 38 females; age range, 2-190 months) were imaged using an APT/MT imaging protocol with multiple saturation frequency offsets. The APT-weighted (APTW) and MT ratio (MTR) signals were quantitatively analyzed in multiple brain areas. Age-related changes in MTR and APTW were evaluated with a non-linear regression analysis. RESULTS: The APTW signals followed a decreasing exponential curve with age in all brain regions measured (R(2) = 0.7-0.8 for the corpus callosum, frontal and occipital white matter, and centrum semiovale). The most significant changes appeared within the first year. At maturation, larger decreases in APTW and lower APTW values were found in the white matter. On the contrary, the MTR signals followed an increasing exponential curve with age in the same brain regions measured, with the most significant changes appearing within the initial 2 years. There was an inverse correlation between the MTR and APTW signal intensities during brain maturation. CONCLUSIONS: Together with MT imaging, protein-based APT imaging can provide additional information in assessing brain myelination in the paediatric population. KEY POINTS: * APTW signals followed a decreasing exponential curve with age. * The most significant APTW changes appeared within the first year * At maturation, larger APTW decreases and lower APTW appeared in white matter * MTR signals followed an increasing exponential curve with age. PMID- 26762942 TI - 3D Quantitative tumour burden analysis in patients with hepatocellular carcinoma before TACE: comparing single-lesion vs. multi-lesion imaging biomarkers as predictors of patient survival. AB - OBJECTIVES: To compare the ability of single- vs. multi-lesion assessment on baseline MRI using 1D- and 3D-based measurements to predict overall survival (OS) in patients with hepatocellular carcinoma (HCC) before transarterial chemoembolization (TACE). METHODS: This retrospective analysis included 122 patients. A quantitative 3D analysis was performed on baseline MRI to calculate enhancing tumour volume (ETV [cm(3)]) and enhancing tumour burden (ETB [%]) (ratio between ETV [cm(3)] and liver volume). Furthermore, enhancing and overall tumour diameters were measured. Patients were stratified into two groups using thresholds derived from the BCLC staging system. Statistical analysis included Kaplan-Meier plots, uni- and multivariate cox proportional hazard ratios (HR) and concordances. RESULTS: All methods achieved good separation of the survival curves (p < 0.05). Multivariate analysis showed an HR of 5.2 (95 % CI 3.1-8.8, p < 0.001) for ETV [cm(3)] and HR 6.6 (95 % CI 3.7-11.5, p < 0.001) for ETB [%] vs. HR 2.6 (95 % CI 1.2-5.6, p = 0.012) for overall diameter and HR 3.0 (95 % CI 1.5 6.3, p = 0.003) for enhancing diameter. Concordances were highest for ETB [%], with no added predictive power for multi-lesion assessment (difference between concordances not significant). CONCLUSION: 3D quantitative assessment is a stronger predictor of survival as compared to diameter-based measurements. Assessing multiple lesions provides no substantial improvement in predicting OS than evaluating the dominant lesion alone. KEY POINTS: * 3D quantitative tumour assessment on baseline MRI predicts survival in HCC patients. * 3D quantitative tumour assessment predicts survival better than any current radiological method. * Multiple lesion assessment provides no improvement than evaluating the dominant lesion alone. * Measuring enhancing tumour volume in proportion to liver volume reflects tumour burden. PMID- 26762945 TI - Robust and stable gene selection via Maximum-Minimum Correntropy Criterion. AB - One of the central challenges in cancer research is identifying significant genes among thousands of others on a microarray. Since preventing outbreak and progression of cancer is the ultimate goal in bioinformatics and computational biology, detection of genes that are most involved is vital and crucial. In this article, we propose a Maximum-Minimum Correntropy Criterion (MMCC) approach for selection of informative genes from microarray data sets which is stable, fast and robust against diverse noise and outliers and competitively accurate in comparison with other algorithms. Moreover, via an evolutionary optimization process, the optimal number of features for each data set is determined. Through broad experimental evaluation, MMCC is proved to be significantly better compared to other well-known gene selection algorithms for 25 commonly used microarray data sets. Surprisingly, high accuracy in classification by Support Vector Machine (SVM) is achieved by less than 10 genes selected by MMCC in all of the cases. PMID- 26762943 TI - Which is the best current guideline for the diagnosis and management of cystic pancreatic neoplasms? An appraisal using evidence-based practice methods. AB - BACKGROUND AND AIM: Cystic pancreatic neoplasms (CPNs) are an increasingly diagnosed entity. Their heterogeneity poses complex diagnostic and management challenges. Despite frequently encountering these entities, particularly in the context of the increased imaging of patients in modern medicine, doctors have to rely on incomplete and ambiguous published literature. The aim of this project was to review the guidelines relating to CPNs using evidence-based practice (EBP) methods. METHODS: A search of both the primary and secondary literature was performed. Five sets of guidelines were identified which were then methodologically appraised by the AGREE II instrument, a validated and widely utilised tool for guideline development assessment. RESULTS: The 2014 'Italian consensus guidelines for the diagnostic work-up and follow-up of cystic pancreatic neoplasms' were found to be the most methodologically sound guidelines, on the basis of both the overall score and average weighted domain score. CONCLUSIONS: The current best guidelines were identified. The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument can be used for retrospective review of published guidelines or as a roadmap for guideline writing groups. All guidelines found were methodologically limited. Further longitudinal/prospective studies are required to improve the level of evidence. KEY POINTS: * Cystic pancreatic neoplasms (CPNs) are an increasingly encountered entity in modern medicine. * Clinical uncertainty remains with regard to optimal diagnostic and management strategies. * The Italian consensus guidelines for cystic pancreatic neoplasms are currently the best guidelines. PMID- 26762946 TI - [Contribution to tumor escape and chemotherapy response: A choice between senescence and apoptosis in heterogeneous tumors]. AB - Understanding adaptive signaling pathways in response to chemotherapy is one of the main challenges of cancer treatment. Activated in response to DNA damage, cell cycle and mitotic checkpoints activate the p53-p21 and p16-Rb pathways and induce apoptosis or senescence. Since senescent cells survive and produce a secretome that influences neighbouring cells, it is not particularly clear whether these responses are equivalent and if tumor cells escape these two suppressive pathways to the same extent. Predicting escape is also complicated by the fact that cancer cells adapt to treatments by activating the epithelial mesenchymal transition and by producing clones with cancer-initiating cells features. Dedifferentiation pathways used in stressful conditions reconstitute dividing and sometimes more aggressive populations in response to chemotherapy. These observations illustrate the importance of tumor heterogeneity and the adaptation capacities of different intra-tumoral subclones. Depending on their oncogenic profile, on their localisation within the tumor and on their interaction with stromal cells, these subclones are expected to have different responses and adaptation capacities to chemotherapy. A complete eradication will certainly rely on combination therapies that can kill at the same time the bulk of the sensitive tumor but can also prevent plasticity and the generation of persistent clones. PMID- 26762947 TI - beta-Hairpin Crowding Agents Affect alpha-Helix Stability in Crowded Environments. AB - The dense, heterogeneous cellular environment is known to affect protein stability. It is now recognized that attractive "quinary" interactions with other biomacromolecules in the cell, referred to as the crowding agents, play a significant role in determining the stability of the protein of interest or test protein. These attractive interactions can reduce or overcome the stabilizing effect of the excluded volume of the crowding agents. However, the roles of specific interactions, such as hydrogen bonding and side chain-side chain hydrophobic interactions, are still unclear. Here, we use molecular simulation to investigate the roles played by hydrophobic interactions and hydrogen bonding between a small helical test protein and equally sized crowding agent proteins in a fixed beta-hairpin configuration. The test protein and crowding agents are represented by a coarse-grained protein model, and we use multicanonical molecular dynamics to study the folding thermodynamics of the test protein. Our results confirm that the stability of the test protein depends on the hydrophobicity of the crowding agents and that the stability of the test protein is reduced through favorable side chain-side chain interactions that preferentially stabilize the unfolded states. In addition, we show that when the intermolecular hydrophobic interactions are more favorable than the intramolecular hydrophobic interactions, the beta-rich crowding agents can completely destabilize the test protein, causing it to adopt configurations with increased beta-content and preventing it from forming its native helical state. Similarities between our results and those seen in the formation of amyloid fibrils are also discussed. PMID- 26762949 TI - Safety and tolerability of navigated TMS in healthy volunteers. PMID- 26762948 TI - Abnormal cortical sources of resting state electroencephalographic rhythms in single treatment-naive HIV individuals: A statistical z-score index. AB - OBJECTIVE: This study tested a simple statistical procedure to recognize single treatment-naive HIV individuals having abnormal cortical sources of resting state delta (<4 Hz) and alpha (8-13 Hz) electroencephalographic (EEG) rhythms with reference to a control group of sex-, age-, and education-matched healthy individuals. Compared to the HIV individuals with a statistically normal EEG marker, those with abnormal values were expected to show worse cognitive status. METHODS: Resting state eyes-closed EEG data were recorded in 82 treatment-naive HIV (39.8 ys.+/-1.2 standard error mean, SE) and 59 age-matched cognitively healthy subjects (39 ys.+/-2.2 SE). Low-resolution brain electromagnetic tomography (LORETA) estimated delta and alpha sources in frontal, central, temporal, parietal, and occipital cortical regions. RESULTS: Ratio of the activity of parietal delta and high-frequency alpha sources (EEG marker) showed the maximum difference between the healthy and the treatment-naive HIV group. Z score of the EEG marker was statistically abnormal in 47.6% of treatment-naive HIV individuals with reference to the healthy group (p<0.05). Compared to the HIV individuals with a statistically normal EEG marker, those with abnormal values exhibited lower mini mental state evaluation (MMSE) score, higher CD4 count, and lower viral load (p<0.05). CONCLUSIONS: This statistical procedure permitted for the first time to identify single treatment-naive HIV individuals having abnormal EEG activity. SIGNIFICANCE: This procedure might enrich the detection and monitoring of effects of HIV on brain function in single treatment-naive HIV individuals. PMID- 26762950 TI - Eye closure sensitivity and catamenial nonconvulsive status epilepticus--A case report. PMID- 26762951 TI - When spikes are symmetric, ripples are not: Bilateral spike and wave above 80 Hz in focal and generalized epilepsy. AB - OBJECTIVE: To evaluate scalp ripples distribution in secondary bilateral synchrony as a tool to lateralize the epileptic focus and to differentiate focal from generalized epilepsy. METHODS: Seventeen EEG recordings with bilateral synchronous discharges of focal (focal group-FG: 10) and generalized (generalized group-GG: 7) epilepsy patients were selected for spikes and ripples marking; the spike-normalized ripple rate was calculated in each hemisphere (right/left - anterior/posterior) and a ripple-dominant hemisphere (the one with the highest rate) was identified. Concordance in FG between the ripple dominant hemisphere and the hemisphere of clinical lateralization was evaluated. The ripple dominant/ripple-nondominant spike-normalized ripple rate ratio was studied to compare groups. RESULTS: In FG the hemisphere of clinical lateralization and the ripple-dominant hemisphere were 100% concordant. In GG only 3/7 patients showed ripples (vs 10/10 FG), all with anterior dominance. No difference in hemisphere ripple dominance between groups was found. CONCLUSIONS: Ripples in secondary bilateral synchrony help to lateralize the epileptic focus but do not help to differentiate between focal and generalized epilepsy. This is the first report of visually identified ripples in idiopathic generalized epilepsy. SIGNIFICANCE: Ripples confirm the clinical lateralization of the epileptic focus in secondary bilateral synchrony but cannot distinguish between focal and generalized epilepsy. PMID- 26762952 TI - Safety and tolerability of navigated TMS for preoperative mapping in neurosurgical patients. AB - OBJECTIVE: Navigated transcranial magnetic stimulation (nTMS) is a non-invasive technique for pre-surgical motor and language mapping in patients with brain lesions. This study examines the safety and tolerability of nTMS in a large, multi-center cohort of neurosurgical patients. METHODS: Functional mapping with monopulse and repetitive nTMS was performed in 733 patients. In this cohort, 57% of patients had left-sided tumors, 50% had frontal tumors, and 50% had seizures secondary to the lesion. Side effects and pain intensity related to the procedure were documented. RESULTS: Patients undergoing monopulse stimulation underwent an average of 490 pulses while those undergoing repetitive stimulation received an average of 2268 pulses. During monopulse stimulation, 5.1% reported discomfort (VAS 1-3), and 0.4% reported pain (VAS>3). During repetitive stimulation, 23.4% reported discomfort and 69.5% reported pain. No seizures or other adverse events were observed. CONCLUSIONS: nTMS is safe and well-tolerated in neurosurgical patients. Clinicians should consider expanding nTMS to patients with frequent seizures, but more evaluation is necessary to evaluate this risk fully. SIGNIFICANCE: nTMS is safe and well-tolerated, even in neurosurgical patients with persistent occasional seizure secondary to a lesion. It should be considered in any patient with a lesion in a presumed peri-eloquent or eloquent brain region. PMID- 26762953 TI - Simultaneous determination of four aflatoxins and ochratoxin A in ginger after inoculation with fungi by ultra-fast liquid chromatography-tandem mass spectrometry. AB - BACKGROUND: Aflatoxins (AFs) and ochratoxin A (OTA) have been detected frequently in food, agricultural products and traditional Chinese medicines, and their presence poses serious health and economic problems worldwide. Ginger can easily be polluted with mycotoxins. In this study, ginger samples were cultivated for 15 days after inoculation with fungi and were prepared based on ultrasound-assisted solid-liquid extraction using methanol/water followed by immunoaffinity column clean-up and analysed by ultra-fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) for AFs and OTA. RESULTS: The limits of detection and quantification of AFs and OTA were 0.04-0.30 ug mL(-1) and 0.125-1.0 ug mL(-1) , respectively. The recoveries were 82.0-100.2%. After 15 days' cultivation, no macroscopic mildew was found in ginger. But, the content of AFB1 expressed an increasing trend in ginger, peel [less than the limit of quantification (LOQ)] to the innermost layer (51.86 u mL(-1) ), AFB2 was only detected in the innermost layer at the level of 0.87 u mL(-1) . A small amount (=2000 MET-min-month), as issued by the United States Department of Health and Human Services. In this national sample of older adults, there was some evidence to suggest that physical activity moderates the relationship between multimorbidity and cognitive function. PMID- 26762966 TI - Combination of melatonin and Wnt-4 promotes neural cell differentiation in bovine amniotic epithelial cells and recovery from spinal cord injury. AB - Although melatonin has been shown to exhibit a wide variety of biological functions, its effects on promoting differentiation of neural cells remain unknown. Wnt signaling mediates major developmental processes during embryogenesis and regulates maintenance, self-renewal, and differentiation of adult mammalian stem cells. However, the role of the noncanonical Wnt pathway during neurogenesis remains poorly understood. In this study, the amniotic epithelial cells ( AECs) were isolated from bovine amnion and incubated with various melatonin concentrations (0.01, 0.1, 1, 10, or 100 MUm) and 5 * 10(-5) m all-trans retinoic acid (RA) for screening optimum culture medium of neural differentiation, compared with each groups, 1 MUm melatonin and 5 * 10(-5) m RA were selected to induce neural differentiation of AECs, and then siMT1, siMT2, oWnt-4, and siWnt-4 were expressed in AECs to research role of these genes in neural differentiation. Efficiency of neural differentiation was evaluated after expressed above genes using flow cytometry. Cell function of neural cells was demonstrated in vivo using spinal cord injury model after cell transplantation, and damage repair of spinal cord was assessed using cell tracking and Basso, Beattie, Bresnahan Locomotor Rating Scale scores. Results demonstrated that melatonin stimulated melatonin receptor 1, which subsequently increased bovine amniotic epithelial cell vitality and promoted differentiation into neural cells. This took place through cooperation with Wnt-4. Additionally, following cotreatment with melatonin and Wnt-4, neurogenesis gene expression was significantly altered. Furthermore, single inhibition of melatonin receptor 1 or Wnt-4 expression decreased expression of neurogenesis-related genes, and bovine amniotic epithelial cell-derived neural cells were successfully colonized into injured spinal cord, which suggested participation in tissue repair. PMID- 26762967 TI - Communicating about the management of medications as patients move across transition points of care: an observation and interview study. AB - RATIONALE, AIMS AND OBJECTIVES: As patients move across transition points, effective medication management is critical for patient safety. The aims of this study were to examine how health professionals, patients and family members communicate about managing medications as patients moved across transition points of care and to identify possible sources of communication failure. METHOD: A descriptive approach was used involving observations and interviews. The emergency departments and medical wards of two hospitals were involved. Observations focused on how health professionals managed medications during interactions with other health professionals, patients and family members, as patients moved across clinical settings. Follow-up interviews with participants were also undertaken. Thematic analysis was completed of transcribed data, and descriptive statistics were used to analyse characteristics of communication failure. RESULTS: Three key themes were identified: environmental challenges, interprofessional relationships, and patient and family beliefs and responsibilities. As patients moved between environments, insufficient tracking occurred about medication changes. Before hospital admission, patients participated in self-care medication activities, which did not always involve exemplary behaviours or match the medications that doctors prescribed. During observations, 432 instances of communication failure (42.8%) were detected, which related to purpose, content, audience and occasion of the communication. CONCLUSIONS: Extensive challenges exist involving the management of medications at transition points of care. Bedside handovers and ward rounds can be utilized as patient counselling opportunities about changes in the medication regimen. Greater attention is needed on how patients in the community make medication related decisions. PMID- 26762968 TI - Utilization of polarized microscopy to differentiate deep penetrating nevus from equine type melanomas. AB - Equine type melanoma can mimic deep penetrating nevus (DPN), making histologic diagnosis challenging. We sought to investigate if the pattern of collagen polarization could be helpful in this setting. A total of 52 specimens were reviewed with polarized microscopy to determine whether refractile collagen was present within melanocytic nests vs. surrounding but not within the nests. Seven of eight (87.5%) equine type melanomas demonstrated refractile collagen within melanocytic nests in part or all of the lesion. In contrast, DPN showed no refractile collagen within the melanocytic nests. Instead, 12 (100%) DPNs and 14 of 16 (87.5%) common combined nevi (DPN plus banal nevus) demonstrated refractile collagen only surrounding melanocytic nests. The entrapment of refractile collagen, as seen with polarized microscopy, within melanocytic nests can support a diagnosis of equine type melanoma. PMID- 26762970 TI - The tyrosine kinase inhibitor toceranib in feline injection site sarcoma: efficacy and side effects. AB - Because of their locally invasive growth and high recurrence rate despite of aggressive local therapy, treatment of feline sarcomas is challenging. The tyrosine kinase inhibitor (TKI) toceranib is currently licensed for the treatment of canine mast cell tumours. There are only few reports about TKI usage in cats. Previous studies indicated promising potential of TKI for the treatment of feline injection site sarcoma (FISS). In this prospective clinical trial, 18 cats with unresectable FISS were treated at a target dosage of 3.25 mg kg-1 every other day to evaluate the clinical efficacy and toxicity of toceranib. There was no clinical response measurable. Adverse events were generally mild and temporary. Grade 3 or 4 adverse events developed infrequently and all resolved with drug holidays and dose reductions. PMID- 26762969 TI - Prolactin receptor and osteogenic induction of prolactin in human periodontal ligament fibroblasts. AB - Prolactin is an important hormone involved in the interaction between maternal, extraembryonic, and fetal tissues that remains in high levels during the entire duration of pregnancy. Although many systemic alterations occur during pregnancy, such as hormonal changes, that are known to be associated with periodontitis and tooth loss, PRL function in human periodontal ligament fibroblasts (HPDLF) had never been studied. Herein, we investigated the role of PRL in the regulation of HPDLF proliferation and differentiation. HPDLF were cultured in differentiating medium with various concentrations of PRL. The present study demonstrated that HPDLF and primary human PDL cells that were extracted for orthodontic purpose expressed both short and long isoforms of PRLR mRNA and its proteins. An incubation with of high concentration of PRL (600 and 1,000 ng/mL) modestly decreased the HPDLF number. In contrast, PRL at a non-reproductive level (10 ng/mL) and pregnant level (100 ng/mL) significantly upregulated the markers of osteogenesis, such as RUNX2, BMP2, and POSTN, but not SOX9. Mineral nodule formation was induced, whereas proteoglycan accumulation was reduced by PRL suggesting that HPDLF were undergoing differentiation into preosteoblastic cells. In conclusion, the presence of hPRLR in human PDL together with PRL-induced upregulation of osteogenic markers strongly suggested a direct regulatory role of PRL in PDL and periodontal tissue development. PMID- 26762971 TI - Complete remission following lenalidomide and rituximab in a patient with heavily pretreated nodular lymphocyte predominant Hodgkin lymphoma. PMID- 26762972 TI - Matrix-Assisted Plasma Atomization Emission Spectrometry for Surface Sampling Elemental Analysis. AB - An innovative technology has been developed involving a simple and sensitive optical spectrometric method termed matrix-assisted plasma atomization emission spectrometry (MAPAES) for surface sampling elemental analysis using a piece of filter paper (FP) for sample introduction. MAPAES was carried out by direct interaction of the plasma tail plume with the matrix surface. The FP absorbs energy from the plasma source and releases combustion heating to the analytes originally present on its surface, thus to promote the atomization and excitation process. The matrix-assisted plasma atomization excitation phenomenon was observed for multiple elements. The FP matrix served as the partial energy producer and also the sample substrate to adsorb sample solution. Qualitative and quantitative determinations of metal ions were achieved by atomic emission measurements for elements Ba, Cu, Eu, In, Mn, Ni, Rh and Y. The detection limits were down to pg level with linear correlation coefficients better than 0.99. The proposed MAPAES provides a new way for atomic spectrometry which offers advantages of fast analysis speed, little sample consumption, less sample pretreatment, small size, and cost-effective. PMID- 26762973 TI - The relationship between prior night's sleep and measures of infant imitation. AB - We examined whether sleep quality during the night and naps during the day preceding a learning event are related to memory encoding in human infants. Twenty-four 6- and twenty-four 12-month-old infants' natural sleeping behavior was monitored for 24 hr using actigraphy. After the recording period, encoding was assessed using an imitation paradigm. In an initial baseline phase, infants were allowed to interact with the stimulus to assess spontaneous production of any target actions. Infants then watched an experimenter demonstrate a sequence of three target actions and were immediately given the opportunity to reproduce the demonstrated target actions to assess memory encoding. Analyses revealed significant correlations between nighttime sleep quality variables (sleep efficiency, sleep fragmentation) and immediate imitation in 6-month-olds, but not in 12-month-olds. High sleep quality in the preceding night was thus positively associated with next day's memory encoding in 6-month-old infants. PMID- 26762974 TI - Shwachman-Bodian-Diamond syndrome (SBDS) protein deficiency impairs translation re-initiation from C/EBPalpha and C/EBPbeta mRNAs. AB - Mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene cause Shwachman Diamond Syndrome (SDS), a rare congenital disease characterized by bone marrow failure with neutropenia, exocrine pancreatic dysfunction and skeletal abnormalities. The SBDS protein is important for ribosome maturation and therefore SDS belongs to the ribosomopathies. It is unknown, however, if loss of SBDS functionality affects the translation of specific mRNAs and whether this could play a role in the development of the clinical features of SDS. Here, we report that translation of the C/EBPalpha and -beta mRNAs, that are indispensible regulators of granulocytic differentiation, is altered by SBDS mutations or knockdown. We show that SBDS function is specifically required for efficient translation re-initiation into the protein isoforms C/EBPalpha-p30 and C/EBPbeta LIP, which is controlled by a single cis-regulatory upstream open reading frame (uORF) in the 5' untranslated regions (5' UTRs) of both mRNAs. Furthermore, we show that as a consequence of the C/EBPalpha and -beta deregulation the expression of MYC is decreased with associated reduction in proliferation, suggesting that failure of progenitor proliferation contributes to the haematological phenotype of SDS. Therefore, our study provides the first indication that disturbance of specific translation by loss of SBDS function may contribute to the development of the SDS phenotype. PMID- 26762975 TI - Structural basis of nucleic acid recognition by FK506-binding protein 25 (FKBP25), a nuclear immunophilin. AB - The nuclear immunophilin FKBP25 interacts with chromatin-related proteins and transcription factors and is suggested to interact with nucleic acids. Currently the structural basis of nucleic acid binding by FKBP25 is unknown. Here we determined the nuclear magnetic resonance (NMR) solution structure of full-length human FKBP25 and studied its interaction with DNA. The FKBP25 structure revealed that the N-terminal helix-loop-helix (HLH) domain and C-terminal FK506-binding domain (FKBD) interact with each other and that both of the domains are involved in DNA binding. The HLH domain forms major-groove interactions and the basic FKBD loop cooperates to form interactions with an adjacent minor-groove of DNA. The FKBP25-DNA complex model, supported by NMR and mutational studies, provides structural and mechanistic insights into the nuclear immunophilin-mediated nucleic acid recognition. PMID- 26762976 TI - Analysis of LexA binding sites and transcriptomics in response to genotoxic stress in Leptospira interrogans. AB - We determined the effects of DNA damage caused by ultraviolet radiation on gene expression in Leptospira interrogans using DNA microarrays. These data were integrated with DNA binding in vivo of LexA1, a regulator of the DNA damage response, assessed by chromatin immunoprecipitation and massively parallel DNA sequencing (ChIP-seq). In response to DNA damage, Leptospira induced expression of genes involved in DNA metabolism, in mobile genetic elements and defective prophages. The DNA repair genes involved in removal of photo-damage (e.g. nucleotide excision repair uvrABC, recombinases recBCD and resolvases ruvABC) were not induced. Genes involved in various metabolic pathways were down regulated, including genes involved in cell growth, RNA metabolism and the tricarboxylic acid cycle. From ChIP-seq data, we observed 24 LexA1 binding sites located throughout chromosome 1 and one binding site in chromosome 2. Expression of many, but not all, genes near those sites was increased following DNA damage. Binding sites were found as far as 550 bp upstream from the start codon, or 1 kb into the coding sequence. Our findings indicate that there is a shift in gene expression following DNA damage that represses genes involved in cell growth and virulence, and induces genes involved in mutagenesis and recombination. PMID- 26762977 TI - Selection-free gene repair after adenoviral vector transduction of designer nucleases: rescue of dystrophin synthesis in DMD muscle cell populations. AB - Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle-wasting disorder caused by mutations in the 2.4 Mb dystrophin-encoding DMD gene. The integration of gene delivery and gene editing technologies based on viral vectors and sequence-specific designer nucleases, respectively, constitutes a potential therapeutic modality for permanently repairing defective DMD alleles in patient derived myogenic cells. Therefore, we sought to investigate the feasibility of combining adenoviral vectors (AdVs) with CRISPR/Cas9 RNA-guided nucleases (RGNs) alone or together with transcriptional activator-like effector nucleases (TALENs), for endogenous DMD repair through non-homologous end-joining (NHEJ). The strategies tested involved; incorporating small insertions or deletions at out-of-frame sequences for reading frame resetting, splice acceptor knockout for DNA-level exon skipping, and RGN-RGN or RGN-TALEN multiplexing for targeted exon(s) removal. We demonstrate that genome editing based on the activation and recruitment of the NHEJ DNA repair pathway after AdV delivery of designer nuclease genes, is a versatile and robust approach for repairing DMD mutations in bulk populations of patient-derived muscle progenitor cells (up to 37% of corrected DMD templates). These results open up a DNA-level genetic medicine strategy in which viral vector-mediated transient designer nuclease expression leads to permanent and regulated dystrophin synthesis from corrected native DMD alleles. PMID- 26762979 TI - Chi hotspots trigger a conformational change in the helicase-like domain of AddAB to activate homologous recombination. AB - In bacteria, the repair of double-stranded DNA breaks is modulated by Chi sequences. These are recognised by helicase-nuclease complexes that process DNA ends for homologous recombination. Chi activates recombination by changing the biochemical properties of the helicase-nuclease, transforming it from a destructive exonuclease into a recombination-promoting repair enzyme. This transition is thought to be controlled by the Chi-dependent opening of a molecular latch, which enables part of the DNA substrate to evade degradation beyond Chi. Here, we show that disruption of the latch improves Chi recognition efficiency and stabilizes the interaction of AddAB with Chi, even in mutants that are impaired for Chi binding. Chi recognition elicits a structural change in AddAB that maps to a region of AddB which resembles a helicase domain, and which harbours both the Chi recognition locus and the latch. Mutation of the latch potentiates the change and moderately reduces the duration of a translocation pause at Chi. However, this mutant displays properties of Chi-modified AddAB even in the complete absence of bona fide hotspot sequences. The results are used to develop a model for AddAB regulation in which allosteric communication between Chi binding and latch opening ensures quality control during recombination hotspot recognition. PMID- 26762978 TI - In vivo blunt-end cloning through CRISPR/Cas9-facilitated non-homologous end joining. AB - The CRISPR/Cas9 system facilitates precise DNA modifications by generating RNA guided blunt-ended double-strand breaks. We demonstrate that guide RNA pairs generate deletions that are repaired with a high level of precision by non homologous end-joining in mammalian cells. We present a method called knock-in blunt ligation for exploiting these breaks to insert exogenous PCR-generated sequences in a homology-independent manner without loss of additional nucleotides. This method is useful for making precise additions to the genome such as insertions of marker gene cassettes or functional elements, without the need for homology arms. We successfully utilized this method in human and mouse cells to insert fluorescent protein cassettes into various loci, with efficiencies up to 36% in HEK293 cells without selection. We also created versions of Cas9 fused to the FKBP12-L106P destabilization domain in an effort to improve Cas9 performance. Our in vivo blunt-end cloning method and destabilization-domain-fused Cas9 variant increase the repertoire of precision genome engineering approaches. PMID- 26762980 TI - The exception that confirms the rule: a higher-order telomeric G-quadruplex structure more stable in sodium than in potassium. AB - DNA and RNA guanine-quadruplexes (G4s) are stabilized by several cations, in particular by potassium and sodium ions. Generally, potassium stabilizes guanine quartet assemblies to a larger extent than sodium; in this article we report about a higher-order G4 structure more stable in sodium than in potassium. Repeats of the DNA GGGTTA telomeric motif fold into contiguous G4 units. Using three independent approaches (thermal denaturation experiments, isothermal molecular-beacon and protein-binding assays), we show that the (GGGTTA)7GGG sequence, folding into two contiguous G4 units, exhibits an unusual feature among G4 motifs: despite a lower thermal stability, its sodium conformation is more stable than its potassium counterpart at physiological temperature. Using differential scanning calorimetry and mutated sequences, we show that this switch in the relative stability of the sodium and potassium conformations (occurring around 45 degrees C in 100 mM cation concentration) is the result of a more favorable enthalpy change upon folding in sodium, generated by stabilizing interactions between the two G4 units in the sodium conformation. Our work demonstrates that interactions between G4 structural domains can make a higher order structure more stable in sodium than in potassium, even though its G4 structural domains are individually more stable in potassium than in sodium. PMID- 26762981 TI - The role of MatP, ZapA and ZapB in chromosomal organization and dynamics in Escherichia coli. AB - Despite extensive research over several decades, a comprehensive view of how the Escherichia coli chromosome is organized within the nucleoid, and how two daughter chromosomes segregate has yet to emerge. Here we investigate the role of the MatP, ZapA and ZapB proteins in organizing the replication terminus (Ter) region and in the chromosomal segregation process. Quantitative image analysis of the fluorescently labeled Ter region shows that the replication terminus attaches to the divisome in a single segment along the perimeter of the cell in a MatP, ZapA and ZapB-dependent manner. The attachment does not significantly affect the bulk chromosome segregation in slow growth conditions. With or without the attachment, two chromosomal masses separate from each other at a speed comparable to the cell growth. The separation starts even before the replication terminus region positions itself at the center of the nucleoid. Modeling of the segregation based on conformational entropy correctly predicts the positioning of the replication terminus region within the nucleoid. However, the model produces a distinctly different chromosomal density distribution than the experiment, indicating that the conformational entropy plays a limited role in segregating the chromosomes in the late stages of replication. PMID- 26762984 TI - HIV on the fast-track to sustainability. PMID- 26762982 TI - FRET-based assay to screen inhibitors of HIV-1 reverse transcriptase and nucleocapsid protein. AB - During HIV-1 reverse transcription, the single-stranded RNA genome is converted into proviral double stranded DNA by Reverse Transcriptase (RT) within a reverse transcription complex composed of the genomic RNA and a number of HIV-1 encoded proteins, including the nucleocapsid protein NCp7. Here, we developed a one-step and one-pot RT polymerization assay. In this in vitro assay, RT polymerization is monitored in real-time by Forster resonance energy transfer (FRET) using a commercially available doubly-labeled primer/template DNA. The assay can monitor and quantify RT polymerization activity as well as its promotion by NCp7. Z factor values as high as 0.89 were obtained, indicating that the assay is suitable for high-throughput drug screening. Using Nevirapine and AZT as prototypical RT inhibitors, reliable IC50 values were obtained from the changes in the RT polymerization kinetics. Interestingly, the assay can also detect NCp7 inhibitors, making it suitable for high-throughput screening of drugs targeting RT, NCp7 or simultaneously, both proteins. PMID- 26762985 TI - The importance of replicating results from randomised trials. PMID- 26762983 TI - An essential role for UTX in resolution and activation of bivalent promoters. AB - Trimethylated histone H3 lysine 27 (H3K27me3) is linked to gene silencing, whereas H3K4me3 is associated with gene activation. These two marks frequently co occupy gene promoters, forming bivalent domains. Bivalency signifies repressed but activatable states of gene expression and can be resolved to active, H3K4me3 prevalent states during multiple cellular processes, including differentiation, development and epithelial mesenchymal transition. However, the molecular mechanism underlying bivalency resolution remains largely unknown. Here, we show that the H3K27 demethylase UTX (also called KDM6A) is required for the resolution and activation of numerous retinoic acid (RA)-inducible bivalent genes during the RA-driven differentiation of mouse embryonic stem cells (ESCs). Notably, UTX loss in mouse ESCs inhibited the RA-driven bivalency resolution and activation of most developmentally critical homeobox (Hox) a-d genes. The UTX-mediated resolution and activation of many bivalent Hox genes during mouse ESC differentiation were recapitulated during RA-driven differentiation of human NT2/D1 embryonal carcinoma cells. In support of the importance of UTX in bivalency resolution, Utx null mouse ESCs and UTX-depleted NT2/D1 cells displayed defects in RA-driven cellular differentiation. Our results define UTX as a bivalency-resolving histone modifier necessary for stem cell differentiation. PMID- 26762986 TI - PrEP: why we are waiting. PMID- 26762987 TI - The importance of replicating results from randomised trials - Authors' reply. PMID- 26762988 TI - Efficacy, safety, bone and metabolic effects of HIV nucleoside reverse transcriptase inhibitor BMS-986001 (AI467003): a phase 2b randomised, controlled, partly blinded trial. AB - BACKGROUND: BMS-986001 is a thymidine analogue nucleoside reverse transcriptase inhibitor (NRTI) designed to maintain in-vitro antiviral activity while minimising off-target effects. We assessed the efficacy and safety of BMS-986001 versus tenofovir disoproxil fumarate in treatment-naive patients with HIV-1. METHODS: In this phase 2b, randomised, active-controlled trial (AI467003), we recruited treatment-naive (no current or previous exposure to an antiretroviral drug for >1 week) adults (aged at least 18 years) with HIV-1 from 47 sites across Asia, Australia, Europe, North America, South Africa, and South America. Patients with plasma HIV-1 RNA greater than 5000 copies per mL and CD4 counts greater than 200 cells per MUL were randomly assigned (2:2:2:3) to receive BMS-986001 100 mg, 200 mg, or 400 mg once a day or to receive tenofovir disoproxil fumarate 300 mg once a day; each allocation was given with efavirenz 600 mg once a day and lamivudine 300 mg once a day. Both patients and investigators were masked to BMS 986001 dose (achieved with similar looking placebo tablets), but not allocation up to and including week 48. The primary endpoints were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL and safety events (serious adverse events and adverse events leading to discontinuation) through week 24; the main analysis was with a modified intention-to-treat population. Resistance analysis was a secondary endpoint, and additional safety parameters were exploratory endpoints. This trial is registered with ClinicalTrials.gov, number NCT01489046, and the European Clinical Trials Database, number EudraCT 2011-003329-89. FINDINGS: Patients were recruited between Jan 25, 2012, and Oct 3, 2012; 757 patients were assessed for eligibility and 301 were randomly assigned to receive either BMS-986001 once a day (67 patients to 100 mg, 67 to 200 mg, and 66 to 400 mg) or tenofovir disoproxil fumarate (n=101). 297 patients received at least one dose of study drug. At week 24, 57 (88%) of 65 patients for whom there were data in the 100 mg group, 54 (81%) of 67 in the 200 mg group, 62 (94%) of 66 in the 400 mg group achieved HIV-1 RNA less than 50 copies per mL, compared with 88 (89%) of 99 in the tenofovir disoproxil fumarate group (modified intention-to-treat population). BMS-986001 was generally well tolerated through week 48. Two patients had BMS-986001-related serious adverse events (atypical drug eruption and thrombocytopenia) and two in the tenofovir disoproxil fumarate group had study drug-related serious adverse events (potential drug-induced liver injury and depression or lipodystrophy) that led to discontinuation. NRTI resistance-associated mutations were reported in four (2%) of 198 patients, and non-NRTI mutations in 17 (9%) of 198 patients receiving BMS-986001 versus none of 99 and one (1%) of 99 patients receiving tenofovir disoproxil fumarate, respectively. Compared with tenofovir disoproxil fumarate, individuals in the BMS 986001 groups showed a smaller decrease in lumbar spine and hip bone mineral density but greater accumulation of limb and trunk fat, subcutaneous and visceral adipose tissue, and increased total cholesterol. INTERPRETATION: BMS-986001 had similar efficacy to that of tenofovir disoproxil fumarate and was associated with a smaller decrease in bone mineral density; however, greater resistance and gains in both peripheral and central fat accumulation were recorded for the investigational drug. Bristol-Myers Squibb has discontinued its involvement in the development of BMS-986001, and future decisions on development will be made by Oncolys BioPharma. FUNDING: Bristol-Myers Squibb. PMID- 26762989 TI - Novel antiretroviral agents and universal access to HIV care. PMID- 26762991 TI - Should kidney disease risk affect antiretroviral choice? PMID- 26762992 TI - Perinatal outcomes associated with maternal HIV infection: a systematic review and meta-analysis. AB - BACKGROUND: The HIV pandemic affects 36.9 million people worldwide, of whom 1.5 million are pregnant women. 91% of HIV-positive pregnant women reside in sub Saharan Africa, a region that also has very poor perinatal outcomes. We aimed to establish whether untreated maternal HIV infection is associated with specific perinatal outcomes. METHODS: We did a systematic review and meta-analysis of the scientific literature by searching PubMed, CINAHL (Ebscohost), Global Health (Ovid), EMBASE (Ovid), and the Cochrane Central Register of Controlled Trials and four clinical trial databases (WHO International Clinical Trials Registry Platform, the Pan African Clinical Trials Registry, the ClinicalTrials.gov database, and the ISRCTN Registry) for studies published from Jan 1, 1980, to Dec 7, 2014. Two authors independently reviewed the studies retrieved by the scientific literature search, identified relevant studies, and extracted the data. We investigated the associations between maternal HIV infection in women naive to antiretroviral therapy and 11 perinatal outcomes: preterm birth, very preterm birth, low birthweight, very low birthweight, term low birthweight, preterm low birthweight, small for gestational age, very small for gestational age, miscarriage, stillbirth, and neonatal death. We included prospective and retrospective cohort studies and case-control studies reporting perinatal outcomes in HIV-positive women naive to antiretroviral therapy and HIV-negative controls. We used a random-effects model for the meta-analyses of specific perinatal outcomes. We did subgroup and sensitivity analyses and assessed the effect of adjustment for confounders. This systematic review and meta-analysis is registered with PROSPERO, number CRD42013005638. FINDINGS: Of 60,750 studies identified, we obtained data from 35 studies (20 prospective cohort studies, 12 retrospective cohort studies, and three case-control studies) including 53 623 women. Our meta-analyses of prospective cohort studies show that maternal HIV infection is associated with an increased risk of preterm birth (relative risk 1.50, 95% CI 1.24-1.82), low birthweight (1.62, 1.41-1.86), small for gestational age (1.31, 1.14-1.51), and stillbirth (1.67, 1.05-2.66). Retrospective cohort studies also suggest an increased risk of term low birthweight (2.62, 1.15-5.93) and preterm low birthweight (3.25, 2.12-4.99). The strongest and most consistent evidence for these associations is identified in sub-Saharan Africa. No association was identified between maternal HIV infection and very preterm birth, very small for gestational age, very low birthweight, miscarriage, or neonatal death, although few data were available for these outcomes. Correction for confounders did not affect the significance of these findings. INTERPRETATION: Maternal HIV infection in women who have not received antiretroviral therapy is associated with preterm birth, low birthweight, small for gestational age, and stillbirth, especially in sub-Saharan Africa. Research is needed to assess how antiretroviral therapy regimens affect these perinatal outcomes. FUNDING: None. PMID- 26762994 TI - Beyond prevention of mother-to-child HIV transmission. PMID- 26762993 TI - HIV-1 virological remission lasting more than 12 years after interruption of early antiretroviral therapy in a perinatally infected teenager enrolled in the French ANRS EPF-CO10 paediatric cohort: a case report. AB - BACKGROUND: Durable HIV-1 remission after interruption of combined antiretroviral therapy (ART) has been reported in some adults who started treatment during primary infection; however, whether long-term remission in vertically infected children is possible was unknown. We report a case of a young adult perinatally infected with HIV-1 with viral remission despite long-term treatment interruption. METHODS: The patient was identified in the ANRS EPF-CO10 paediatric cohort among 100 children infected with HIV perinatally who started ART before 6 months of age. HIV RNA viral load and CD4 cell counts were monitored from birth. Ultrasensitive HIV RNA, peripheral blood mononuclear cell (PBMC)-associated HIV DNA, HIV-specific T-cell responses (ie, production of cytokines and capacity to suppress HIV infection), reactivation of the CD4 cell reservoir (measured by p24 ELISA and HIV RNA in supernatants upon phytohaemagglutinin activation of purified CD4 cells), and plasma concentrations of antiretroviral drugs were assessed after 10 years of documented control off therapy. FINDINGS: The infant was born in 1996 to a woman with uncontrolled HIV-1 viraemia and received zidovudine-based prophylaxis for 6 weeks. HIV RNA and DNA were not detected 3 days and 14 days after birth. HIV DNA was detected at 4 weeks of age. HIV RNA reached 2.17* 10(6) copies per mL at 3 months of age and ART was started. HIV RNA was undetectable 1 month later. ART was discontinued by the family at some point between 5.8 and 6.8 years of age. HIV RNA was undetectable at 6.8 years of age and ART was not resumed. HIV RNA has remained below 50 copies per mL and CD4 cell counts stable through to 18.6 years of age. After 11.5 years of control off treatment, HIV RNA was below 4 copies per mL and HIV DNA was 2.2 log10 copies per 10(6) PBMCs. The HLA genotype showed homozygosity at several loci (A*2301-, B*1503/4101, C*0210/0802, DRB1*1101-, and DQB1*0602-). HIV-specific CD8 T-cell responses and T cell activation were weak. INTERPRETATION: Findings from this case suggest that long-term HIV-1 remission is possible in perinatally infected children who receive treatment early, with characteristics similar to those reported in adult HIV post-treatment controllers. Further studies are needed to understand the mechanisms associated with HIV remission and whether early treatment of infected children might favour the conditions needed to achieve HIV control after treatment discontinuation. FUNDING: Agence de recherche ANRS (France Recherche Nord & Sud Sida-HIV Hepatites). PMID- 26762995 TI - Hope of post-treatment control after perinatal infection? PMID- 26762996 TI - Ethics of ART interruption after stem-cell transplantation. PMID- 26762998 TI - Two cases of compartment syndrome of the lower extremities during surgery for gynecological malignancies. AB - Two cases of compartment syndrome of the lower extremities occurring during surgery for gynecological malignancies are reported. In addition to the risk from being in the lithotomy position for over 4 h, these two cases were believed to have been caused by the combined use of a disposable wound retractor and abdominal retractors to secure the operative field. This conclusion is based on the fact that an abrupt increase in partial pressure of end-tidal CO2 (ETCO2) was observed when wound drapes and abdominal retractors were removed approximately 4 h after the start of surgery. Prolonged compression of the external iliac vein by a disposable wound retractor and abdominal retractors is believed to have induced congestion of the lower extremities, eventually resulting in compartment syndrome. To verify this, during subsequent surgeries of the same type, changes in the diameters of femoral arteries and veins when a disposable wound retractor and abdominal retractors were used were monitored using an ultrasound device, and the findings confirmed that changes in vascular diameter do occur. PMID- 26762999 TI - A case of delayed respiratory depression caused by accidental subcutaneous opioid infusion. AB - We report a case of delayed respiratory depression due to accidental subcutaneous opioid infusion. A healthy 33-year-old woman underwent orthopedic surgery under general anesthesia. Before the end of the operation, it was noticed that a part of the opioid infusion had been administered subcutaneously. About 15 min after tracheal extubation, the patient developed respiratory depression and loss of consciousness. The patient recovered with the use of jaw lift together with bag valve-mask ventilation. We believe that accidental subcutaneous opioid accumulation may have caused the respiratory depression. PMID- 26762997 TI - Role of MnSOD in propofol protection of human umbilical vein endothelial cells injured by heat stress. AB - PURPOSE: Heat stress stimulation can cause various injuries in human umbilical vein endothelial cells (HUVEC), including apoptotic cell death and an increase in cell permeability. Propofol (PPF), a commonly used anesthetic, is known to have an important role in antioxidation as well as organ protection. Therefore, our aim is to evaluate the protective effects of PPF on heat stress (HS)-induced oxidative stress injury and its possible mechanism of action. METHODS: For HS + PPF, cells were treated with propofol followed by 2 h heat stress at 43 degrees C and then 4 h incubation under normal conditions. For propofol treatment, HUVEC were cultured in serum-free Dulbecco's modified Eagle medium supplemented with 0, 10, 25, or 50 MUM propofol for 6 h under normal conditions. RESULTS: During the study, we found that, in HS-induced cellular damage, the protective effect of propofol was related closely with its antioxidation properties. We further revealed that heat stress significantly reduced the level of manganese superoxide demutase (MnSOD) and Cu/Zn SOD, but that propofol could inhibit the reduction of MnSOD only. Transfection of HUVEC with MnSOD small interfering RNA (siRNA) markedly decreased the expression of MnSOD, and the protective effect of propofol in the MnSOD siRNA clones was significantly reduced. CONCLUSION: Propofol protected the heat stress-injured cells, at least partly, through upregulating MnSOD expression, effectively reducing the direct or indirect cell damage caused by oxidative stress. PMID- 26763000 TI - Can neoadjuvant chemotherapy reduce the surgical risks for localized neuroblastoma patients with image-defined risk factors at the time of diagnosis? AB - PURPOSE: To date, no detailed study of the changes in the image-defined risk factors (IDRFs) after neoadjuvant chemotherapy has been performed. The aim of this study was to investigate the effect of chemotherapy on IDRFs for stage L2 neuroblastomas. METHODS: Fifteen stage L2 patients treated by neoadjuvant chemotherapy were selected. Changes after chemotherapy in the number of positive IDRFs, tumor size and major surgical complications were evaluated. RESULTS: All IDRFs disappeared after chemotherapy in four patients (group A) and a reduction in the number of IDRFs, but not disappearance, after chemotherapy was observed in five patients (group B). No change in the number of IDRFs after chemotherapy was observed in six patients (group C). All tumors in groups A shrunk to <20 % of the pretreatment volume. Major surgical complications were observed in one of two, two of three and three of five patients who underwent tumor excision in groups A, B and C, respectively. CONCLUSIONS: Only 27 % of the tumors with IDRFs became negative for IDRFs after chemotherapy. For negative IDRFs, tumors should shrink to <20 % of the volume at the time of diagnosis. Stage L2 tumors may have a potential risk for surgery even after neoadjuvant chemotherapy. PMID- 26763001 TI - What factors contribute to the risk of depression in epilepsy?--Tasmanian Epilepsy Register Mood Study (TERMS). AB - OBJECTIVE: To model the factors associated with depression in a community sample of people with epilepsy. The factors investigated were derived from proposed risk factors for depression from patients with epilepsy, other chronic illness, and the general population. METHODS: Multivariate analysis using general linear regression models of factors associated with depression in the Tasmanian Epilepsy Register Mood Study (TERMS), a cross-sectional community sample of 440 patients with epilepsy. RESULTS: A model with acceptable fit was created that explained 66% of the variance of depression. Associated factors included in this model were neuroticism, physical functioning, social support, past history of depression, and stressful life events. SIGNIFICANCE: In this cross-sectional study designed specifically to investigate depression in epilepsy, we showed that general risk factors for depression in other illness and in the general population are also important in patients with epilepsy, with little support for disease-related risk factors. PMID- 26763003 TI - Rifampin-sirolimus-voriconazole interaction in a hematopoietic cell transplant recipient. AB - Purpose Patients undergoing hematopoietic cell transplantation are treated with multiple medications, potentially complicated by drug-drug interactions. Drug interactions with sirolimus, voriconazole, and rifampin are particularly difficult because of the complex and simultaneous enzyme inhibition and induction mechanisms. We report a hematopoietic cell transplantation patient receiving sirolimus and voriconazole who was given rifampin while being treated for presumed methicillin-resistant Staphylococcus aureus meningitis. Summary A 31 year-old female received a nonmyeloablative allogeneic umbilical cord hematopoietic cell transplantation for myelodysplastic syndrome transformed to acute myeloid leukemia (AML). Her graft versus host disease and antifungal prophylaxis included sirolimus and voriconazole, respectively. Therapeutic drug monitoring prior to admission revealed a stable outpatient sirolimus regimen of 0.4 mg orally daily (trough goal 3-12 mcg/L). She was admitted to the inpatient hematopoietic cell transplantation service and diagnosed with methicillin resistant Staphylococcus aureus bacteremia and presumed bacterial meningitis 217 days after transplant. Intravenous rifampin and vancomycin were initiated and voriconazole was changed to micafungin. Sirolimus trough concentrations were undetectable two days after starting rifampin. Therapeutic sirolimus concentrations were achieved four days later, at a sirolimus dose of 16-18 mg orally daily. Rifampin was discontinued after nine days and the sirolimus dose was adjusted accordingly, maintaining therapeutic levels throughout follow-up. The patient suffered a flare of chronic skin graft versus host disease requiring etanercept, high-dose systemic steroids, and topical steroids. Conclusion To the best of our knowledge, this is the first report describing the management of sirolimus during the transition from voriconazole inhibition to rifampin induction. Clinicians should be aware of potential drug-drug interactions. PMID- 26763002 TI - In vitro and in vivo antiherpetic effects of (1R,2R)-1-(5'-methylful-3' yl)propane-1,2,3-triol. AB - In this study, we demonstrated the in vitro and in vivo antiherpetic activities of a stable furan derivative, (1R,2R)-1-(5'-methylful-3'-yl)propane-1,2,3-triol (MFPT), which had originally been isolated from Streptomyces sp. strain FV60. In the present study, we synthesized MFPT from (5-methylfuran-3-yl)methanol in 6 steps for use in the experiments. MFPT showed potent in vitro antiviral activities against two acyclovir (ACV)-sensitive (KOS and HF) strains and an ACV resistant (A4-3) strain of herpes simplex virus type 1 (HSV-1) and an ACV sensitive HSV type 2 (HSV-2) UW 268 strain, their selectivity indices ranging from 310 to 530. By intravaginal application of MFPT to mice, the virus yields decreased dose-dependently against the three strains of HSV-1 and HSV-2. When MFPT was applied at a dose of 1.0 mg/day, the lesion scores, as clinical signs manifested by viral infection, were extensively suppressed in HSV-1-infected mice, whereas the lesion scores in HSV-2-infected mice were not markedly decreased. Interestingly, MFPT exerted an inhibitory effect against ACV-resistant HSV-1 in mice to a similar degree as in ACV-sensitive HSV-1-infected mice. Therefore, the compound might have potential for developing a topical antiviral agent that could be also applied to the infections caused by ACV-resistant viruses. PMID- 26763004 TI - Effects of the leucovorin shortage: Pilot study investigating cost, efficacy, and toxicity comparison of low fixed-dose versus body surface area-adjusted leucovorin dosing in patients with resectable colon or metastatic colorectal cancer. AB - Purpose As a result of the leucovorin shortage, we switched from BSA-adjusted to low fixed-dose leucovorin in patients with colon cancer receiving fluorouracil containing therapy. Methods A retrospective, pilot study of adults receiving intravenous leucovorin as part of a fluorouracil-containing treatment was conducted including individuals with stage II or III colon or newly diagnosed metastatic colorectal cancer. One low fixed-dose (leucovorin 50 mg) patient was matched by the investigator to one BSA-adjusted (leucovorin 200-500 mg/m2/dose) patient on disease stage and age. The objectives were to compare cost of alternative dosing strategies as well as efficacy and adverse event rates. Only patients being treated in the first-line metastatic colorectal cancer setting were included in the efficacy analysis. Results Fifty-eight patients were included. Leucovorin cost was reduced by 7- to 14-fold, and we were able to conserve a total of 1580-3400 doses of leucovorin by changing to fixed-dose (estimated from 200 mg/m2 or 400 mg/m2 dosing strategies, respectively). No statistically significant differences in progression-free survival ( p = 0.254), overall survival ( p = 0.923), or complications resulted. Conclusion Our decision to reduce the dose of leucovorin allowed us to conserve supply and control cost. The small sample size did not allow us to detect differences in efficacy or adverse event rates, and thus a larger study would be required to confirm our findings that efficacy was not compromised nor adverse effects greater. PMID- 26763005 TI - Molecular and morphological analyses confirm Rhizopogon verii as a widely distributed ectomycorrhizal false truffle in Europe, and its presence in South America. AB - The genus Rhizopogon includes species with hypogeous or subepigeus habit, forming ectomycorrhizae with naturally occurring or planted pines (Pinaceae). Species of the genus Rhizopogon can be distinguished easily from the other hypogeous basidiomycetes by their lacunose gleba without columella and their smooth elliptical spores; however, the limit between species is not always easy to establish. Rhizopogon luteolus, the type species of the genus, has been considered one of the species that are more abundant in Europe, as well as it has been cited in pine plantation of North and South America, different parts of Africa, Australia, and New Zealand. However, in this study, based on molecular analyses of the ITS nuclear ribosomal DNA (nrDNA) sequences (19 new sequences; 37 sequences from GenBank/UNITE, including those from type specimens), we prove that many GenBank sequences under R. luteolus were misidentified and correspond to Rhizopogon verii, a species described from Tunisia. Also, we confirm that basidiomes and ectomycorrhizae recently collected in Germany under Pinus sylvestris, as well as specimens from South of Brazil under Pinus taeda belong to R. verii. Thanks to the numerous ectomycorrhizal tips collected in Germany, a complete description of R. verii/P. sylvestris ectomycorrhiza is provided. Moreover, since in this paper the presence of R. verii in South America is here reported for the first time, a short description of basidiomes collected in Brazil, compared with collections located in different European herbaria, is included. PMID- 26763006 TI - Improved survival of patients with colon cancer detected by screening colonoscopy. AB - BACKGROUND: Screening for colon cancer (CC) may not only reduce its occurrence but has also the potential to reduce the overall mortality. So far, there has been little evidence that detection of colon cancer by screening colonoscopy results in different survival rates compared to symptomatic patients. PATIENTS AND METHODS: Clinical, histological, diagnostic, and survival data of 1016 consecutive patients with CC from a prospectively expanded single-institutional database were analyzed for diagnostic, treatment, and prognostic factors. Findings were then stratified according to detection by screening colonoscopy vs. patients who became symptomatic prior to further diagnostic work-up. RESULTS: 7.1 % of all patients were identified by screening colonoscopy for colon cancer. Screened patients were younger (68.2 vs. 64.8 years), had smaller T stage (p = 0.032), lower tumor stage (p = 0.009), and a tendency to less lymph node metastasis. Overall survival was superior in screened patients, and stage specific survival showed a tendency to improved survival, which was not statistically significant. Furthermore, a higher percentage of screened patients underwent adjuvant chemotherapy (84.6 vs. 55.0 %, p = 0.032). CONCLUSION: Survival outcome and enrollment in a multimodal treatment was higher in screening detected patients compared to patients diagnosed after the onset of clinical symptoms. Besides a potential occurrence of lead time bias, these findings strongly support the need for continued improvement of screening programs and the recruitment of more patients for colorectal cancer screening. PMID- 26763007 TI - Misuse of rapid-onset opioids? Misuse of terminology! PMID- 26763008 TI - The Edmonton Symptom Assessment System: Poor performance as screener for major depression in patients with incurable cancer. AB - BACKGROUND: Depressive symptoms are prevalent in patients with advanced cancer, sometimes of a severity that fulfil the criteria for a major depressive episode. AIM: The aim of this study was to investigate how the item on depression in the Edmonton Symptom Assessment System with a 0-10 Numerical Rating Scale performed as a screener for major depressive episode. A possible improved performance by adding the Edmonton Symptom Assessment System-Anxiety item was also examined. DESIGN: An international cross-sectional study including patients with incurable cancer was conducted. The Edmonton Symptom Assessment System score was compared against major depressive episode as assessed by the Patient Health Questionnaire 9. Screening performance was examined by sensitivity, specificity and the kappa coefficient. SETTING: Patients with incurable cancer (n = 969), median age 63 years and from eight nationalities provided report. Median Karnofsky Performance Status was 70. Median survival was 229 days (205-255 days). RESULTS: Patient Health Questionnaire-9 major depressive episode was present in 133 of 969 patients (13.7%). Edmonton Symptom Assessment System-Depression screening ability for Patient Health Questionnaire-9 major depressive episode was limited. Area under the receiver operating characteristic curve was 0.71 (0.66-0.76). Valid detection or exclusion of Patient Health Questionnaire-9 major depressive episode could not be concluded at any Edmonton Symptom Assessment System-Depression cut off; by the cut-off Numerical Rating Scale ? 2, sensitivity was 0.69 and specificity was 0.60. By the cut-off Numerical Rating Scale ? 4, sensitivity was 0.51 and specificity was 0.82. Combined mean ratings by Edmonton Symptom Assessment System-Depression and Edmonton Symptom Assessment System-Anxiety revealed similar limited screening ability. CONCLUSION: The depression and anxiety items of the Edmonton Symptom Assessment System, a frequently used assessment tool in palliative care settings, seem to measure a construct other than major depressive episode as assessed by the Patient Health Questionnaire-9 instrument. PMID- 26763009 TI - Is it enough to stop distal fusion at L3 in adolescent idiopathic scoliosis with major thoracolumbar/lumbar curves? AB - PURPOSE: The choice of distal fusion level in adolescent idiopathic scoliosis (AIS) patients with major thoracolumbar or lumbar (TL/L) curves (Lenke type 3C, 5C, or 6C) remains debatable. One of the most controversial issues involves stopping the distal fusion at L3, which might result in an increased risk of decompensation but save more mobile spinal segments. The purpose of this study was to evaluate and compare the clinical and radiological outcomes of corrective surgery for AIS with major TL/L curves according to the distal fusion level. METHODS: 229 AIS patients with Lenke type 3C, 5C, or 6C curves that underwent corrective surgery were included. Patients were grouped according to distal fusion level, either L3 (group A) or L4 (group B), and followed up for over 2 years. Group A was further divided into lower end vertebra (LEV) and last touching vertebra (LTV). The SRS-22 score was used to assess clinical outcomes. All radiological parameters were assessed pre- and postoperatively by standing anteroposterior whole-spine radiographs. Clinical and radiological parameters were compared between the groups. RESULTS: Postoperative decompensation was found in 4.6 % (9/197) of group A patients and 9.3 % (3/32) of group B patients. This difference was not statistically significant (P = 0.258). No difference was found in the clinical and radiological parameters between the two groups either pre- or postoperatively. Subgroup analysis showed that the scoliosis correction rate and postoperative apical vertebral translation were lower in cases with an LEV <= L4 or LTV = L5 when the fusion stopped at L3 distally. The adjacent disc wedge angle was aggravated postoperatively in these cases, although this did not reach statistical significance. CONCLUSIONS: There is no difference in the radiological and clinical outcomes in AIS according to the distal fusion level. Major TL/L curve correction in AIS may be sufficient distally at L3 in cases with an LEV >= L3 and LTV >= L4. However, stopping fusion at L3 requires caution in LEV <= L4 or LTV = L5 patients, as this correction rate might be suboptimal and causes a possible progression of the adjacent disc wedge angle. PMID- 26763012 TI - Correction. AB - In the article by Guessous et al (Guessous I, Pruijm M, Ponte B, Ackermann D, Ehret G, Ansermot N, Vuistiner P, Staessen J, Gu Y, Paccaud F, Mohaupt M, Vogt B, Pechere-Bertschi A, Martin PY, Burnier M, Eap CB, Bochud M. Associations of ambulatory blood pressure with urinary caffeine and caffeine metabolite excretions. Hypertension. 2015;65:691-696. doi: 10.1161/HYPERTENSIONAHA.114.04512), which published online ahead of print December 8, 2014, and appeared in the March 2015 issue of the journal, a correction was needed.One of the author surnames was misspelled. Antoinette Pechere-Berstchi has been corrected to read Antoinette Pechere-Bertschi.The authors apologize for this error. PMID- 26763010 TI - Identification of head control deficits following anterior cervical discectomy and fusion in patients with cervical spondylotic myelopathy. AB - PURPOSE: To investigate the presence of head control deficits and its course of recovery after anterior cervical discectomy and fusion (ACDF) surgery in cervical spondylotic myelopathy (CSM) patients. METHODS: Thirty-seven CSM patients were assessed for their C2-C7 cervical lordosis, neck Range of Motion (ROM), repositioning accuracy, neck strength as well as surface electromyography of the neck muscle activities during slow head motions. Assessments were performed preoperatively and then at 3- and 6-month postoperatively. RESULTS: No significant difference was found for the C2-C7 cervical lordosis postoperatively at 6-month. ROM was restricted immediately after surgery but recovered over time, however, neck strength remained significantly reduced postoperatively. Reposition accuracy improved immediately after surgery but declined again at 6-month follow up. In addition, muscle activities required to control head motions showed a continuous reduction postoperatively. CONCLUSIONS: Adequate C2-C7 cervical lordosis was maintained in the current study with improvement of slow head motion control and ROM at 6-month. However, improvement in head position sense was not maintained and neck strength showed continuous declination overtime. Assessment and monitoring of head control deficits should be routinely considered in CSM patients. PMID- 26763013 TI - 'You just deal with it. You have to when you've got a child': A narrative analysis of mothers' accounts of how they coped, both during an abusive relationship and after leaving. AB - A narrative analysis explored the accounts of eight mothers, each of whom had left an abusive relationship at least 12 months previously. Existing research investigating the strategies used by women to cope with domestic violence rarely considers women in their capacity as mothers. Furthermore, women's lives after leaving an abusive relationship have received limited research attention. Thus, this study aimed to understand how women described coping with domestic violence and mothering their children, both during an abusive relationship and after leaving. The analysis focused on how the eight participants described their experiences (narrative form) as well as what they talked about (narrative content). Three types of narrative form were identified: (1) 'The story told to help others', (2) 'The story too difficult to tell' and (3) 'Where's my story going?' Each woman spoke about the contextual factors that influenced whether she coped with domestic violence by seeking support from others, changing her thinking or changing her behaviour. Caring for their children was a major source of support for all the women both during their relationship and after leaving. The findings indicate that mothers who have been abused by their intimate partner may come into contact with a wide range of social and emergency support services. Implications for clinical practice, service delivery and service development relate to the different ways of supporting women in talking about abuse and also the need to recognise trauma in parents. PMID- 26763014 TI - Observed callousness as a predictor of treatment outcomes in parent management training. AB - BACKGROUND: The goal of this study was to examine how observed Callous Unemotional (CU) behavior influenced change in externalized and internalized problems, hyperactivity, social competence, and treatment satisfaction following parent management training. METHODS: Three hundred twenty-three children and their families received Parent Management Training-the Oregon model (PMTO). They were compared at intake and after treatment in order to examine differences in 14 treatment outcomes using hierarchical regression analyses. RESULTS: Children with low levels of observed CU showed the greatest gains after PMTO treatment. This was evident in parent, therapist, self, and teacher reports. CONCLUSIONS: The results indicate that it is possible to observe CU behavior among children with conduct problems, and that children with elevated levels of observed CU behavior may be in need of additional treatment or components of treatment or more intense versions of parent management treatment. PMID- 26763015 TI - New publisher, new-year, new decade. PMID- 26763016 TI - The concept of sporadic cerebral small vessel disease: A road map on key definitions and current concepts. AB - Sporadic cerebral small vessel disease is considered to be among the most common known neuropathological processes and has an important role in stroke, cognitive impairment, and functional loss in elderly persons. The term is now commonly used to describe a range of neuroimaging, neuropathological, and associated clinical features, the pathogenesis of which is largely unclear but that are thought to arise from disease affecting the perforating cerebral arterioles, capillaries, and venules. Modern neuroimaging has revolutionized our understanding of the consequences of small vessels disease on the brain parenchyma, even though small arteries, arterioles, capillaries, and venules are difficult to be directly visualized with current techniques used in clinical practice. In this short review, we focus on histopathological and neuroimaging perspectives, basic definitions, and recent advances in the field. PMID- 26763017 TI - Recent advances in carotid angioplasty and stenting. AB - Atherosclerotic carotid stenosis accounts for about 15% of ischemic strokes. Carotid endarterectomy reduces the risk of stroke in patients with severe carotid stenosis. Carotid artery stenting has emerged as a potentially less invasive alternative to carotid endarterectomy. However, randomized clinical trials in patients with symptomatic stenosis have shown that carotid artery stenting is associated with a higher risk of peri-procedural stroke compared with carotid endarterectomy. Carotid artery stenting is associated with a lower risk of peri procedural myocardial infarction and local complications (cranial nerve palsies, access site hematoma) and appears to be as durable as carotid endarterectomy in terms of long-term protection against ipsilateral stroke and risk of restenosis. The main risk factors for peri-procedural stroke in patients treated with carotid artery stenting are age >70 years and high burden of white-matter lesions on brain imaging. Patients with asymptomatic carotid stenosis receiving modern medical treatment have a low risk (<1%/year) of ipsilateral stroke and it is uncertain whether the benefit of revascularization still justifies the procedural risk of stroke or death. In particular, the small excess of procedural risk of stroke associated with carotid artery stenting (compared with carotid endarterectomy) may offset the small benefit (if any) of carotid endarterectomy versus medical therapy in unselected patients. Randomized clinical trials are ongoing to solve this issue. PMID- 26763018 TI - National stroke registries for monitoring and improving the quality of hospital care: A systematic review. AB - BACKGROUND: Routine monitoring of the quality of stroke care is becoming increasingly important since patient outcomes could be improved with better access to proven treatments. It remains unclear how many countries have established a national registry for monitoring stroke care. AIMS: To describe the current status of national, hospital-based stroke registries that have a focus on monitoring access to evidence-based care and patient outcomes and to summarize the main features of these registries. SUMMARY OF REVIEW: We undertook a systematic search of the published literature to identify the registries that are considered in their country to represent a national standardized dataset for acute stroke care and outcomes. Our initial keyword search yielded 5002 potential papers, of which we included 316 publications representing 28 national stroke registries from 26 countries. Where reported, data were most commonly collected with a waiver of patient consent (70%). Most registries used web-based systems for data collection (57%) and 25% used data linkage. Few variables were measured consistently among the registries reflecting their different local priorities. Funding, resource requirements, and coverage also varied. CONCLUSIONS: This review provides an overview of the current use of national stroke registries, a description of their common features relevant to monitoring stroke care in hospitals. Formal registration and description of registries would facilitate better awareness of efforts in this field. PMID- 26763019 TI - Risk of early recurrent stroke in symptomatic carotid stenosis after best medical therapy and before endarterectomy. AB - BACKGROUND: The early recurrence of neurological symptoms (NR) after urgent aggressive best medical therapy (BMT) in symptomatic carotid stenosis is not well documented. AIMS: To investigate the risk of ipsilateral NR after urgent aggressive BMT in patients with symptomatic (50-99%) carotid stenosis up to carotid endarterectomy (CEA), with emphasis on the first 14 days after index event. METHODS: Prospective population based study, covering a period of 41/2 years. NR rate was determined after initiation of urgent aggressive BMT and until CEA and compared to NR up to 90 days prior to index-event. Urgent BMT consisted of loading dose aspirin and clopidogrel thereafter therapy with aspirin and clopidogrel together with a statin. RESULTS: Of 8200 symptomatic patients (ischemic stroke, transient ischemic attack and ocular events), 250 (3%) patients underwent CEA, 47% within 14 days of the index-event and 99% within 14 days of surgical referral. The overall NR from index-event to CEA in symptomatic patients was significantly lower 1.6% (95% CI 0.5-4%) after BMT when compared with NR in the 90 days prior to referral to a stroke clinic 25% (95% CI 20-30%, p < 0.00001). Peri-operative bleeding 5% (95% CI 3-8%) was comparable with other studies. CONCLUSION: Urgent aggressive BMT after index-event is associated with a significant reduction in the risk of early NR in CEA candidates. The early risk of recurrent stroke in patients with symptomatic significant carotid stenosis is dramatically reduced after urgent aggressive BMT in specialised stroke clinics. PMID- 26763020 TI - Trends in risk of recurrence after the first ischemic stroke in adults younger than 55 years of age in Sweden. AB - BACKGROUND: Previous studies on stroke recurrence in younger adults often contain small sample size which makes it difficult to study trends in stroke recurrence over a long period of time. AIMS: The aim of the present study was to investigate temporal trends in the risk of recurrence in younger patients with a first ischemic stroke. METHODS: All men and women aged 18-54 years who had survived at least 28 days after a first ischemic stroke from 1987 to 2006 were identified in the Swedish Inpatient Register. The patients were stratified into four 5-year periods according to their admission period and were followed up for a total of four years after the index event with regard to recurrent ischemic stroke. A Cox regression model was used to analyze the risk of recurrent ischemic stroke. RESULTS: Of the 17,149 ischemic stroke patients who were identified, 2432 (14.2%) had a recurrent ischemic stroke event within four years. From the first to the last periods (1987-1991 versus 2002-2006), the four-year risk of recurrent ischemic stroke decreased by 55% (hazard ratio 0.45, 95% confidence interval 0.39 0.53) in men and 59% (hazard ratio 0.41, 95% confidence interval, 0.33-0.50) in women. The cumulative four-year risk was 11.8% (95% CI 10.55-13.25) in men and 9.8% (95% CI 8.40-11.46) in women during the last five-year period (2002-2006). CONCLUSIONS: The risk of recurrence among younger ischemic stroke patients has decreased over the past 20 years. Despite these improvements, younger patients are still at a high risk for recurrent ischemic stroke. PMID- 26763021 TI - Leukoaraiosis and lacunes are associated with poor clinical outcomes in ischemic stroke patients treated with intravenous thrombolysis. AB - BACKGROUND: The effect of preexisting small vessel disease on outcomes of patients with ischemic stroke treated with i.v. thrombolysis is not fully understood. AIM: We aim to investigate the effect of combined leukoaraiosis and lacunes as detected on unenhanced brain computer tomography at baseline on clinical outcomes after i.v. thrombolysis. METHODS: We analyzed data from the Canadian Alteplase for Stroke Effectiveness Study. Small vessel disease was assessed on baseline computer tomography rating for leukoaraiosis and lacunes. We dichotomized the burden of small vessel disease to "absent or moderate" and "severe." Clinical outcomes at 90 days included excellent outcome (mRS = 0-1), good outcome (mRS = 0-2), and the occurrence of symptomatic intracerebral hemorrhage. Sensitivity analysis was performed on two age groups (<=80 versus >80). We ran logistic regression adjusting for confounders to evaluate independent effect of small vessel disease on outcomes. RESULTS: There were 820 patients with available brain computer tomography with mean age (+/-SD) of 71.3 (+/-13.2), 455 (55.5%) were male. Of these, 123 (15%) patients had severe small vessel disease at baseline. Age group analysis revealed significant associations of small vessel disease only in patients aged <=80. After adjustment for confounders, presence of severe small vessel disease reduced the chances of both excellent (OR = 0.42, 95% CI = 0.24-0.74) and good outcome (OR = 0.35, 95% CI = 0.21-0.58) and with an increased risk of symptomatic intracerebral hemorrhage (OR = 5.91; 95% CI = 2.40-14.57). CONCLUSION: When considered together as radiological expressions of small vessel disease, presence and severity of severe leukoaraiosis and lacunes on baseline computer tomography scan are associated with poor clinical outcomes in patients treated with i.v. thrombolysis. PMID- 26763022 TI - The predictors and clinical impact of intraventricular hemorrhage in patients with aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Intraventricular hemorrhage is known to complicate the course and outcome of aneurysmal subarachnoid hemorrhage. AIMS: To identify independent risk factors for intraventricular hemorrhage development and its severity during aneurysm rupture. METHODS: Six hundred and twenty-five subarachnoid hemorrhage patients treated at our institution between January 2005 and December 2012 were included. The severity of intraventricular hemorrhage was assessed according to the original Graeb score. Clinical and radiographic features of patients present at the bleeding event were tested as potential risk factors for intraventricular hemorrhage. The characteristics of intraventricular hemorrhage were correlated with the clinical course and outcome. RESULTS: Intraventricular hemorrhage was present in 206 patients (33%) and was independently predicted by patient's age (p = 0.001, odds ratio (OR) = 1.02/year of age increase), aneurysm size (p = 0.031, OR = 1.05/mm increase), and location (p < 0.0001, OR = 3.2 for aneurysms of posterior circulation). The severity of intraventricular hemorrhage was predicted by aneurysm size (p = 0.023) and location (higher severity for aneurysms of anterior circulation, p = 0.01). The presence of intraventricular hemorrhage (p < 0.0001, OR = 4.1) and intraventricular hemorrhage severity of >3 points on the Graeb score (p = 0.029, OR = 3.4) was independently associated with poor outcome. Shunt dependency was associated only with the occurrence of intraventricular hemorrhage (p < 0.0001, OR = 2.8) while the severity of intraventricular hemorrhage influenced the timing of shunt placement (p = 0.0156). CONCLUSIONS: Increasing age, aneurysm size, and location in the posterior circulation are the main risk factors for occurrence of aneurysmal intraventricular hemorrhage, which is independently associated with poor outcome. The severity of intraventricular hemorrhage, however, is higher if the aneurysm is located in the anterior circulation and has impact on functional outcome, but not on shunt dependency. PMID- 26763024 TI - Inter-rater agreement analysis of the Precise Diagnostic Score for suspected transient ischemic attack. AB - BACKGROUND: No definitive criteria are available to confirm the diagnosis of transient ischemic attack. Inter-rater agreement between physicians regarding the diagnosis of transient ischemic attack is low, even among vascular neurologists. We developed the Precise Diagnostic Score, a diagnostic score that consists of discrete and well-defined clinical and imaging parameters, and investigated inter rater agreement in patients with suspected transient ischemic attack. METHODS: Fellowship-trained vascular neurologists, blinded to final diagnosis, independently reviewed retrospectively identical history, physical examination, routine diagnostic studies, and brain magnetic resonance imaging (diffusion and perfusion images) from consecutive patients with suspected transient ischemic attack. Each patient was rated using the 8-point Precise Diagnostic Score score, composed of a clinical score (0-4 points) and an imaging score (0-4 points). The composite Precise Diagnostic Score determines a Precise Diagnostic Score Likelihood of Brain Ischemia Scale: 0-1 = unlikely, 2 = possible, 3 = probable, 4 8 = very likely. RESULTS: Three raters reviewed data from 114 patients. Using Precise Diagnostic Score, all three raters scored a similar percentage of the clinical events as being "probable" or "very likely" caused by brain ischemia: 57, 55, and 58%. Agreement was high for both total Precise Diagnostic Score (intraclass correlation coefficient of 0.94) and for the Likelihood of Brain Ischemia Scale (agreement coefficient of 0.84). CONCLUSIONS: Compared with prior studies, inter-rater agreement for the diagnosis of transient brain ischemia appears substantially improved with the Precise Diagnostic Score scoring system. This score is the first to include specific criteria to assess the clinical relevance of diffusion-weighted imaging and perfusion lesions and supports the added value of magnetic resonance imaging for assessing patients with suspected transient ischemic attack. PMID- 26763023 TI - Do cognitive, language, or physical impairments affect participation in a trial of self-management programs for stroke? AB - BACKGROUND: Research studies may have limited generalizability when survivors of stroke with physical, language, or cognitive impairments are excluded. AIMS: To assess whether presence of cognitive, language, or global impairments affects participation in self-management programs. METHODS: Stroke survivors were recruited in South Australia from seven hospitals or via advertisements into a randomized controlled trial (1:1:1 ratio) of a Stroke Self-Management Program, the Stanford chronic condition self-management program, or standard care. Impairment status was measured using: Cognistat (cognition), Frenchay Aphasia assessment (language), modified Rankin Score (mRS; where score 3-5 = global disability). PRIMARY OUTCOMES: participation (i.e. booked, accessed, and completed a program (defined as attending >= 50% of sessions)) and safety (i.e. adverse events). Outcomes were compared by impairment status. RESULTS: Among 315 people screened 143/149 eligible were randomized (median age 71 years; 41% male; with impairments: 62% cognitive, 34% language, 64% global disability). Participation did not differ by cognitive or language impairment status (cognitive 75%, no cognitive 68%, p = 0.54; language 78%, no language 69%, p = 0.42). However, participation did vary by global impairment status (global disability 61%, no disability 96%, p < 0.001). Participants with cognitive impairment experienced more adverse events (severe n = 9 versus no cognitive impairment n = 1). CONCLUSION: Survivors of stroke with cognitive, language, or global impairments are able to participate in self-management programs and should be included in these types of research studies or programs. Reduced participation by those with global disability and the possibility of more adverse events in people with cognitive impairments needs to be considered. PMID- 26763026 TI - Missing voices: Profile and extent of acquired communication disorders in Aboriginal and non-Aboriginal adult stroke survivors in Western Australia using linked administrative records. AB - BACKGROUND: Limited data exist on the extent of specific functional sequelae, including acquired communication disorder, among Aboriginal stroke survivors, making planning of multidisciplinary services difficult. AIMS: To obtain estimates of the extent and profile of acquired communication disorder in Aboriginal and non-Aboriginal adult stroke survivors in Western Australia and investigate potential disparities in receiving in-hospital speech pathology services among survivors with acquired communication disorder. METHODS: Stroke cases surviving their first stroke episode during 2002-2011 were identified using Western Australia-wide person-based linked hospital and mortality data, and their five-year comorbidity profiles determined. The mid-year prevalence of stroke cases with acquired communication disorder was estimated for 2011. Regression methods were used to investigate determinants of receiving speech pathology services among acquired communication disorder cases. RESULTS: Of 14,757 stroke survivors aged 15-79 years admitted in 2002-2011, 33% had acquired communication disorder (22% aphasia/dysphasia) and 777 (5.3%) were Aboriginal. Aboriginal patients were more likely to be younger, live remotely, and have comorbidities. A diagnosis of aphasia was more common in Aboriginal than non-Aboriginal patients 15-44 years (p = 0.003). A minimum of 107 Aboriginal and 2324 non-Aboriginal stroke patients with acquired communication disorder lived in Western Australia in 2011. Aboriginal status was not associated with receiving in-hospital speech services among acquired communication disorder patients in unadjusted or adjusted models. CONCLUSIONS: The relative youth, geographical distribution, high comorbidity prevalence, and cultural needs of Aboriginal stroke patients with acquired communication disorder should inform appropriate service design for speech pathology and rehabilitation. Innovative models are required to address workforce issues, given low patient volumes. PMID- 26763025 TI - Vitamin D deficiency and incident stroke risk in community-living black and white adults. AB - BACKGROUND: Black individuals are at greater risk of stroke and vitamin D deficiency than white individuals. Epidemiologic studies have shown that low 25 hydroxyvitamin D concentrations are associated with increased risk of stroke, but these studies had limited representation of black individuals. METHODS: We examined the association of 25-hydroxyvitamin D with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort of black and white adults >=45 years of age. Using a case-cohort study design, plasma 25-hydroxyvitamin D was measured in 610 participants who developed incident stroke (cases) and in 937 stroke-free individuals from a stratified cohort random sample of REGARDS participants (comparison cohort). RESULTS: In multivariable models adjusted for socio-demographic factors, co-morbidities and laboratory values including parathyroid hormone, lower 25-hydroxyvitamin D concentrations were associated with higher risk of stroke (25-hydroxyvitamin D >30 ng/mL reference; 25-hydroxyvitamin D concentrations 20-30 ng/mL, hazard ratio 1.33, 95% confidence interval (95% CI) 0.89,1.96; 25-hydroxyvitamin D <20 ng/mL, hazard ratio 1.85, 95% CI 1.17, 2.93). There were no statistically significant differences in the association of lower 25-hydroxyvitamin D with higher risk of stroke in black vs. white participants in fully adjusted models (hazard ratio comparing lowest vs. highest 25-hydroxyvitamin D category 2.62, 95% CI 1.18, 5.83 in blacks vs. 1.64, 95% CI 0.83, 3.24 in whites, P(interaction) = 0.82). The associations were qualitatively unchanged when restricted to ischemic or hemorrhagic stroke subtypes or when using race-specific cut-offs for 25 hydroxyvitamin D categories. CONCLUSIONS: Vitamin D deficiency is a risk factor for incident stroke and the strength of this association does not appear to differ by race. PMID- 26763027 TI - Single photon emission computed tomography imaging of cerebral blood flow, blood brain barrier disruption, and apoptosis time course after focal cerebral ischemia in rats. AB - BACKGROUND: Cerebral ischemia is a leading cause of disability worldwide and no other effective therapy has been validated to date than intravenous thrombolysis. In this context, many preclinical models have been developed and recent advances in preclinical imaging represent promising tools. Thus, we proposed here to characterize in vivo time profiles of cerebral blood flow, blood-brain barrier disruption and apoptosis following a transient middle cerebral artery occlusion in rats using SPECT/CT imaging. METHODS: Rats underwent a 1-h middle cerebral artery occlusion followed by reperfusion. Cerebral blood flow, blood-brain barrier disruption and apoptosis were evaluated by SPECT/CT imaging using respectively (99m)Tc-HMPAO, (99m)Tc-DTPA and the experimental (99m)Tc-Annexin V 128, up to 14 days after middle cerebral artery occlusion. Histological evaluation of apoptosis has been performed using TUNEL method to validate the (99m)Tc-Annexin V-128 uptake. RESULTS: (99m)Tc-HMPAO cerebral blood flow evaluation showed hypoperfusion during occlusion, partially restored on days 4 and 7 and sustained up to 14 days after middle cerebral artery occlusion. (99m)Tc DTPA SPECT/CT showed a blood-brain barrier disruption starting on day 1 post middle cerebral artery occlusion, peaking on day 2, with barrier integrity totally restored on day 7. (99m)Tc-Annexin V-128 SPECT/CT imaging showed significant positive correlation with TUNEL immunohistochemistry and allowed ischemic-induced apoptosis to be detected from day 2 to day 7, peaking on day 3 after middle cerebral artery occlusion. CONCLUSIONS: Using SPECT/CT imaging, we showed that after transient middle cerebral artery occlusion in rat there was a sustained decrease in cerebral blood flow followed by blood-brain barrier disruption preceding meanwhile apoptosis. Rodent SPECT/CT imaging of cerebral blood flow, blood-brain barrier disruption and apoptosis appears to be an efficient tool for evaluating neuroprotective drugs and regenerative therapies against cerebral ischemia and time-windows for therapeutic intervention. PMID- 26763028 TI - Magnetic resonance imaging-based endovascular versus medical stroke treatment for symptom onset up to 12 h. AB - BACKGROUND: Recent trials have shown a clear benefit of endovascular therapy for stroke patients presenting within 6 h after stroke onset. Imaging-based selection may identify a cohort with a favorable response to endovascular therapy, in an even later time window. AIMS: We performed an indirect comparison between outcomes seen in DEFUSE 2, a prospective cohort study of patients who received a baseline MRI before endovascular therapy, and a control group from AXIS 2 receiving standard medical care up to 12 h after symptom onset. METHODS: Patients from AXIS 2 with a confirmed large vessel occlusion were selected as a control group for DEFUSE 2-patients. The primary endpoint was good functional outcome at day 90 (Modified Rankin Score 0-2). We performed a stratified analysis based on the presence of the target mismatch for both studies and reperfusion status in DEFUSE 2. RESULTS: We compared good functional outcome in 108 patients from AXIS 2 and 99 patients from DEFUSE 2. In DEFUSE 2-patients with the target mismatch profile in whom reperfusion was achieved, the rate of good functional outcome was increased compared to target mismatch patients in AXIS 2, 54% versus 29% (OR 3.2, 95% CI 1.1-9.4). In target mismatch patients treated between 6 and 12 h after stroke onset, this association between study and good functional outcome remained present (OR 9.0, 95% CI 1.1-75.8). CONCLUSIONS: This indirect comparison suggests that endovascular treatment resulting in substantial reperfusion is associated with improved outcome in target mismatch patients even beyond 6 h after stroke onset. Confirmation is needed from future clinical trials that randomize patients beyond the 6 h time window. PMID- 26763029 TI - Mechanical thrombectomy in acute ischemic stroke: Consensus statement by ESO Karolinska Stroke Update 2014/2015, supported by ESO, ESMINT, ESNR and EAN. AB - The original version of this consensus statement on mechanical thrombectomy was approved at the European Stroke Organisation (ESO)-Karolinska Stroke Update conference in Stockholm, 16-18 November 2014. The statement has later, during 2015, been updated with new clinical trials data in accordance with a decision made at the conference. Revisions have been made at a face-to-face meeting during the ESO Winter School in Berne in February, through email exchanges and the final version has then been approved by each society. The recommendations are identical to the original version with evidence level upgraded by 20 February 2015 and confirmed by 15 May 2015. The purpose of the ESO-Karolinska Stroke Update meetings is to provide updates on recent stroke therapy research and to discuss how the results may be implemented into clinical routine. Selected topics are discussed at consensus sessions, for which a consensus statement is prepared and discussed by the participants at the meeting. The statements are advisory to the ESO guidelines committee. This consensus statement includes recommendations on mechanical thrombectomy after acute stroke. The statement is supported by ESO, European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), and European Academy of Neurology (EAN). PMID- 26763030 TI - Statistical analysis plan for the Sleep Apnea cardioVascular Endpoints study: An international randomised controlled trial to determine whether continuous positive airways pressure treatment for obstructive sleep apnea in patients with CV disease prevents secondary cardiovascular events. AB - RATIONALE: Obstructive sleep apnea (OSA) is associated with increased risk of cardiovascular disease. Continuous positive airway pressure (CPAP) delivered via a nasal mask during sleep immediately alleviates obstructive apneas and improves sleep quality and daytime somnolence. However, there is uncertainty as to whether such treatment can modify CV risk and disease. AIMS: The Sleep Apnea Cardiovascular Endpoints (SAVE) study aims to determine whether CPAP on top of best medical care compared to best medical care alone can reduce the risk of serious CV events in patients with co-morbid OSA and established CV disease. DESIGN: SAVE is an investigator initiated and conducted, international, multicenter, open, blinded endpoint, randomized controlled trial. Participants were randomised to either CPAP or usual care between 2008 and 2013 and will be followed up for an average of approximately 4 years. STUDY OUTCOME: The primary endpoint is a composite of CV death, myocardial infarction (MI, including silent MI), stroke, hospitalisation for heart failure, hospitalisation for an acute ischemic cardiac event (unstable angina) or cerebral event (transient ischemic event [TIA]). DISCUSSION: The pre-specified statistical analysis plan (SAP) for the main analyses is presented. This SAP was finalised before patient follow-up was completed and before any unblinding of the data. The SAP outlines details of the primary, secondary and tertiary outcomes, together with planned subgroup and exploratory analyses. PMID- 26763031 TI - Atte Meretoja. PMID- 26763032 TI - Multiple spontaneous cervical artery dissections: A transient arteriopathy with good long-term prognosis. PMID- 26763033 TI - Impaired everyday gestural communication in apraxia: A reliable and valid short scale. PMID- 26763036 TI - Recovery of an injured corticoreticulospinal tract in a patient with pontine hemorrhage. PMID- 26763034 TI - Thromboembolic events after transcatheter aortic valve implantation. PMID- 26763035 TI - Ischemic stroke, inflammation, iron overload - Connection to a hepcidin. PMID- 26763037 TI - Injury of the thalamocingulate tract in the Papez circuit by ventriculoperitoneal shunt: A case report. PMID- 26763038 TI - Honeycomb-like appearance in the brain of a former boxer with hyperhomocysteinemia, severe carotid disease and hemorrhagic stroke. PMID- 26763039 TI - Post-stroke hypersomnia. PMID- 26763040 TI - The utility of the RoPE score in cryptogenic stroke patients <=50 years in predicting a stroke-related patent foramen ovale. PMID- 26763041 TI - Time is brain: Things hidden under figures. PMID- 26763043 TI - The Impella(r) Recover mechanical assist device in acute cardiogenic shock: a single-centre experience of 66 patients. AB - OBJECTIVES: Short-term ventricular assist devices are more frequently used in patients with acute cardiogenic shock. The aim of this study was to evaluate its effect on haemodynamic parameters, as well as the short- and long-term outcome and complication rate associated with the device. METHODS: All patients treated with the Impella(r) Recover device at our centre from 2003 to 2014 (n = 66) were included in this study, and follow-up time was 2.9 (+/-0.4) years. Data were obtained through patient records and the population register. Patient-related factors, preimplantation and early postimplantation haemodynamic and biochemical parameters were analysed. Characteristics of survivors and non-survivors were compared. RESULTS: The device was implanted in 66 patients and 58% (38/66) were alive at 30 days post-implantation. The mean duration of support was 7.4 (+/-0.8) days. Mean time in the intensive care unit was 24 (+/-4) days. Following device implantation, patients' cardiac index improved from 2.1 l/min/m(2) (+/-0.20) to 3.8 l/min/m(2) (+/-0.20) at Day 7, mixed venous saturation increased from 56% (+/ 2.0) to 68% (+/-1.2) and diuresis increased from 69 ml/h (+/-9) at device insertion to 105 ml/h (+/-19) at Day 7 on support. Central venous pressure, lactate levels and inotropic support decreased on support. No difference between survivors and non-survivors was established. No correlation was established between preimplant parameters and 30-day mortality. CONCLUSIONS: The Impella(r) Recover device improved haemodynamics in patients with acute cardiogenic shock. Still, 30-day mortality remains high and future studies must focus on the optimal timing of placement of the device. PMID- 26763042 TI - Perioperative optimal blood pressure as determined by ultrasound tagged near infrared spectroscopy and its association with postoperative acute kidney injury in cardiac surgery patients. AB - OBJECTIVES: Perioperative blood pressure management by targeting individualized optimal blood pressure, determined by cerebral blood flow autoregulation monitoring, may ensure sufficient renal perfusion. The purpose of this study was to evaluate changes in the optimal blood pressure for individual patients, determined during cardiopulmonary bypass (CPB) and during early postoperative period in intensive care unit (ICU). A secondary aim was to examine if excursions below optimal blood pressure in the ICU are associated with risk of cardiac surgery-associated acute kidney injury (CSA-AKI). METHODS: One hundred and ten patients undergoing cardiac surgery had cerebral blood flow monitored with a novel technology using ultrasound tagged near infrared spectroscopy (UT-NIRS) during CPB and in the first 3 h after surgery in the ICU. The correlation flow index (CFx) was calculated as a moving, linear correlation coefficient between cerebral flow index measured using UT-NIRS and mean arterial pressure (MAP). Optimal blood pressure was defined as the MAP with the lowest CFx. Changes in optimal blood pressure in the perioperative period were observed and the association of blood pressure excursions (magnitude and duration) below the optimal blood pressure [area under the curve (AUC) < OptMAP mmHgxh] with incidence of CSA-AKI (defined using Kidney Disease: Improving Global Outcomes criteria) was examined. RESULTS: Optimal blood pressure during early ICU stay and CPB was correlated (r = 0.46, P < 0.0001), but was significantly higher in the ICU compared with during CPB (75 +/- 8.7 vs 71 +/- 10.3 mmHg, P = 0.0002). Thirty patients (27.3%) developed CSA-AKI within 48 h after the surgery. AUC < OptMAP was associated with CSA-AKI during CPB [median, 13.27 mmHgxh, interquartile range (IQR), 4.63-20.14 vs median, 6.05 mmHgxh, IQR 3.03-12.40, P = 0.008], and in the ICU (13.72 mmHgxh, IQR 5.09-25.54 vs 5.65 mmHgxh, IQR 1.71-13.07, P = 0.022). CONCLUSIONS: Optimal blood pressure during CPB and in the ICU was correlated. Excursions below optimal blood pressure (AUC < OptMAP mmHgXh) during perioperative period are associated with CSA-AKI. Individualized blood pressure management based on cerebral autoregulation monitoring during the perioperative period may help improve CSA-AKI-related outcomes. PMID- 26763044 TI - Laboratory tests of headache disorders - dawn of a new era? AB - Context The classification of headache disorders has improved over the years, but further work is needed to develop and improve headache diagnosis within headache subtypes. The present review is a call for action to implement laboratory tests in the classification and management of primary and some secondary headaches. Background In this narrative review we present and discuss published tests that might be useful in phenotyping and/or diagnosis of long-lasting headache disorders such as migraine, tension-type headache, trigeminal autonomic cephalalgias, trigeminal neuralgia and persisting secondary headaches. Aim The palpometer test, quantitative sensory testing, nociceptive blink reflex and autonomic tests may be valuable to phenotype and/or diagnose subforms of migraine, tension-type headache, cluster headache, trigeminal neuralgia and medication-overuse headache. Provocation tests with glyceryl trinitrate (GTN) and calcitonin gene-related peptide (CGRP) may be valuable in subclassification of migraine and cluster headache. Lumbar pressure monitoring and optical coherence tomography may valuable tools to diagnose and follow patients with chronic headache and raised intracranial pressure. Finding A number of laboratory tests in headache research are presently available, but have primarily been performed in single research studies or a few studies that differ in methods and patient groups. At present, there is no evidence-based strategy for implementing diagnostic tests, but this could be achieved if well-reputed tertiary headache centers commence developing and implementing laboratory tests in order to improve the classification and treatment of headache patients. PMID- 26762990 TI - Cumulative and current exposure to potentially nephrotoxic antiretrovirals and development of chronic kidney disease in HIV-positive individuals with a normal baseline estimated glomerular filtration rate: a prospective international cohort study. AB - BACKGROUND: Whether or not the association between some antiretrovirals used in HIV infection and chronic kidney disease is cumulative is a controversial topic, especially in patients with initially normal renal function. In this study, we aimed to investigate the association between duration of exposure to antiretrovirals and the development of chronic kidney disease in people with initially normal renal function, as measured by estimated glomerular filtration rate (eGFR). METHODS: In this prospective international cohort study, HIV positive adult participants (aged >=16 years) from the D:A:D study (based in Europe, the USA, and Australia) with first eGFR greater than 90 mL/min per 1.73 m(2) were followed from baseline (first eGFR measurement after Jan 1, 2004) until the occurrence of one of the following: chronic kidney disease; last eGFR measurement; Feb 1, 2014; or final visit plus 6 months (whichever occurred first). Chronic kidney disease was defined as confirmed (>3 months apart) eGFR lower than 60 mL/min per 1.73 m(2). The primary outcome was the occurrence of chronic kidney disease. Poisson regression was used to estimate the incidence rate of chronic kidney disease associated with cumulative exposure to tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, ritonavir-boosted lopinavir, other ritonavir-boosted protease inhibitors, or abacavir. FINDINGS: Between Jan 1, 2004, and July 26, 2013, 23,905 eligible individuals from the D:A:D study were included. Participants had a median baseline eGFR of 110 mL/min per 1.73 m(2) (IQR 100-125), a median age of 39 years (33-45), and median CD4 cell count of 441 cells per mm(3) (294-628). During a median follow-up of 7.2 years (IQR 5.1-8.9), 285 (1%) of 23,905 people developed chronic kidney disease (incidence 1.76 per 1000 person-years of follow-up [95% CI 1.56-1.97]). After adjustment, we recorded a significant increase in chronic kidney disease associated with each additional year of exposure to tenofovir disoproxil fumarate (adjusted incidence rate ratio 1.14 [95% CI 1.10-1.19], p<0.0001), ritonavir-boosted atazanavir (1.20 [1.13 1.26], p<0.0001), and ritonavir-boosted lopinavir (1.11 [1.06-1.16], p<0.0001), but not other ritonavir-boosted protease inhibitors or abacavir. INTERPRETATION: In people with normal renal function, the annual incidence of chronic kidney disease increased for up to 6 years of exposure to tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, or ritonavir-boosted lopinavir therapy. Although the absolute number of new cases of chronic kidney disease was modest, treatment with these antiretrovirals might result in an increasing and cumulative risk of chronic kidney disease. Patients on potentially nephrotoxic antiretrovirals or at high risk of chronic kidney disease should be closely monitored. FUNDING: The Highly Active Antiretroviral Therapy Oversight Committee. PMID- 26763045 TI - Early-onset familial hemiplegic migraine due to a novel SCN1A mutation. AB - Introduction Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. The FHM3 subtype is caused by mutations in SCN1A, which is also the most frequent epilepsy gene encoding the voltage-gated Na+ channel NaV1.1. The aim of this study was to explore the clinical, genetic and pathogenetic features of a pure FHM3 family. Methods A three-generation family was enrolled in this study for genetic testing and assessment of clinical features. Whole cell patch-clamp was performed to determine the functions of identified mutant NaV1.1 channels, which were transiently expressed in human tsA201 cells together with beta1 and beta2 subunits. Results and conclusions We identified a novel SCN1A (p.Leu1624Pro) mutation in a pure FHM family with notably early-onset attacks at mean age of 7. L1624P locates in S3 of domain IV, the same domain as two of four known pure FHM3 mutations. Compared to WT channels, L1624P displayed an increased threshold-near persistent current in addition to other gain-of-function features such as: a slowing of fast inactivation, a positive shift in steady-state inactivation, a faster recovery and higher channel availability during repetitive stimulation. Similar to the known FHM3 mutations, this novel mutation predicts hyperexcitability of GABAergic inhibitory neurons. PMID- 26763047 TI - Bloating: Avicenna's Perspective and Modern Medicine. AB - Bloating and abdominal distention are common complaints present in quite a number of organic and functional diseases. An important subject in traditional Persian medicine is digestive disorders, particularly bloating and its etiology. This is a literature review study conducted on The Canon in Medicine written by Avicenna and using the keywords: bloating, gas. In this article, causes for bloating, according to Avicenna, include diet causes, inappropriate lifestyle, gastrointestinal, and miscellaneous reasons. These were compared with causes suggested in modern medicine. Avicenna classifies causes based on the place of origin into upper part of the abdomen (stomach) and intestinal part of the abdomen. Also, 38 medicinal plants used as remedies were listed. Modern scientific data support all bloating causes that have been mentioned in the canon. Obviously, some causes such as uterine disorders and posterior nasal discharge need to be studied further. PMID- 26763046 TI - Parent Reports of Exclusive Breastfeeding After Attending a Combined Midwifery and Chiropractic Feeding Clinic in the United Kingdom: A Cross-Sectional Service Evaluation. AB - This service evaluation investigated an interdisciplinary allied professional health care strategy to address the problem of suboptimal breastfeeding. A clinic of midwives and chiropractors was developed in a university-affiliated clinic in the United Kingdom to care for suboptimal feeding through a multidisciplinary approach. No studies have previously investigated the effect of such an approach. The aim was to assess any impact to the breastfeeding dyad and maternal satisfaction after attending the multidisciplinary clinic through a service evaluation. Eighty-five initial questionnaires were completed and 72 (85%) follow up questionnaires were returned. On follow-up, 93% of mothers reported an improvement in feeding as well as satisfaction with the care provided. Prior to treatment, 26% of the infants were exclusively breastfed. At the follow-up survey, 86% of mothers reported exclusive breastfeeding. The relative risk ratio for exclusive breastfeeding after attending the multidisciplinary clinic was 3.6 (95% confidence interval = 2.4-5.4). PMID- 26763050 TI - Q.E.COSY: determining sign and size of small deuterium residual quadrupolar couplings using an extended E.COSY principle. AB - Residual quadrupolar couplings contain important structural information comparable with residual dipolar couplings. However, the measurement of sign and size of especially small residual quadrupolar couplings is difficult. Here, we present an extension of the E.COSY principle to spin systems consisting of a Spin 1 coupled to a spin 1/2 nucleus, which allows the determination of the sign of the quadrupolar coupling of the Spin 1 nucleus relative to the heteronuclear coupling between the spins. The so-called Q.E.COSY approach is demonstrated with its sign-sensitivity using variable angle NMR, stretched gels and liquid crystalline phases applied to various CD and CD3 groups. Especially the sign sensitive measurement of residual quadrupolar couplings that remain unresolved in conventional deuterium 1D spectra is shown. PMID- 26763052 TI - The Singapore Cancer Network (SCAN) Guidelines: A New Beginning. PMID- 26763053 TI - Singapore Cancer Network (SCAN) Guidelines for Adjuvant Trastuzumab Use in Early Stage HER2 Positive Breast Cancer. AB - INTRODUCTION: The SCAN breast cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for adjuvant trastuzumab use in early stage HER2 positive breast cancer. MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. RESULTS: Five international guidelines were evaluated- those developed by the National Comprehensive Cancer Network (2015), the National Institute of Health and Clinical Excellence (2006, 2009), the European Society of Medical Oncology (2013), the Breast Cancer Disease Site Group in conjunction with the Program in Evidence Based Care and Cancer Care Ontario (2011) and the Scottish Intercollegiate Guidelines Network (2013). Recommendations on suitable candidacy for adjuvant trastuzumab, whether adjuvant trastuzumab should be given concurrently with a taxane or sequentially after completion of adjuvant chemotherapy, the optimal frequency of cardiac monitoring during adjuvant trastuzumab and the optimal duration of adjuvant trastuzumab were developed. CONCLUSION: These adapted guidelines form the SCAN Guidelines 2015 for adjuvant trastuzumab use in early stage HER2 positive breast cancer. PMID- 26763051 TI - Polymicrogyric Cortex may Predispose to Seizures via Abnormal Network Topology: An fMRI Connectomics Study. AB - Polymicrogyria is a significant malformation of cortical development with a high incidence of epilepsy and cognitive deficits. Graph theoretic analysis is a useful approach to studying network organization in brain disorders. In this study, we used task-free functional magnetic resonance imaging (fMRI) data from four patients with polymicrogyria and refractory epilepsy. Gray matter masks from structural MRI data were parcellated into 1,024 network nodes. Functional "connectomes" were obtained based on fMRI time series between the parcellated network nodes; network analysis was conducted using clustering coefficient, path length, node degree, and participation coefficient. These graph metrics were compared between nodes within polymicrogyric cortex and normal brain tissue in contralateral homologous cortical regions. Polymicrogyric nodes showed significantly increased clustering coefficient and characteristic path length. This is the first study using functional connectivity analysis in polymicrogyria- our results indicate a shift toward a regular network topology in polymicrogyric nodes. Regularized network topology has been demonstrated previously in patients with focal epilepsy and during focal seizures. Thus, we postulate that these network alterations predispose to seizures and may be relevant to cognitive deficits in patients with polymicrogyria. PMID- 26763049 TI - Natural environments, nature relatedness and the ecological theater: connecting satellites and sequencing to shinrin-yoku. AB - Recent advances in research concerning the public health value of natural environments have been remarkable. The growing interest in this topic (often housed under terms such as green and/or blue space) has been occurring in parallel with the microbiome revolution and an increased use of remote sensing technology in public health. In the context of biodiversity loss, rapid urbanization, and alarming rates of global non-communicable diseases (many associated with chronic, low-grade inflammation), discussions of natural vis-a vis built environments are not merely fodder for intellectual curiosity. Here, we argue for increased interdisciplinary collaboration with the aim of better understanding the mechanisms-including aerobiological and epigenetic-that might help explain some of the noted positive health outcomes. It is our contention that some of these mechanisms are related to ecodiversity (i.e., the sum of biodiversity and geodiversity, including biotic and abiotic constituents). We also encourage researchers to more closely examine individual nature relatedness and how it might influence many outcomes that are at the interface of lifestyle habits and contact with ecodiversity. PMID- 26763054 TI - Singapore Cancer Network (SCAN) Guidelines for Bisphosphonate Use in the Adjuvant Breast Cancer Setting. AB - INTRODUCTION: The SCAN breast cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines regarding the optimal time-point for initiation of bisphosphonates when using adjuvant aromatase inhibitors (AIs) and provide a consensus for their role in modifying clinical breast cancer outcomes. MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. RESULTS: Six international guidelines were evaluated-those developed by the National Cancer Comprehensive Network (2015), the European Society of Medical Oncology (2014), the National Institute for Clinical Evidence (2012), the Scottish Intercollegiate Guidelines Network (2013), the British Columbia Cancer Agency (2013) and the treatment algorithm based on the National Osteoporosis Foundation guidelines (2006). Recommendations on the use of bisphosphonates in postmenopausal women initiating adjuvant AIs in breast cancer to preserve bone health and the use of adjuvant bisphosphonates to improve breast cancer outcomes were developed. CONCLUSION: These adapted guidelines form the SCAN Guidelines on the use of adjuvant bisphosphonates to influence breast cancer outcomes and maintenance of bone health when on AIs. PMID- 26763055 TI - Singapore Cancer Network (SCAN) Guidelines for Systemic Therapy of Colorectal Cancer. AB - INTRODUCTION: The SCAN colorectal cancer systemic therapy workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy for colorectal cancer in Singapore. MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. RESULTS: Five international guidelines were evaluated-those developed by the National Comprehensive Cancer Network for colon (2014) and rectal (2014) cancer, the European Society of Medical Oncology for advanced (2012) and early (2013) cancer and the National Institute of Clinical Excellence (2011). Recommendations on systemic therapy in colorectal cancer were produced. CONCLUSION: These adapted guidelines form the SCAN Guidelines 2015 for systemic therapy of colorectal cancer. PMID- 26763048 TI - Implementation of integrated stepped care for unhealthy alcohol use in HIV clinics. AB - BACKGROUND: Effective counseling and pharmacotherapy for unhealthy alcohol use are rarely provided in HIV treatment settings to patients. Our goal was to describe factors influencing implementation of a stepped care model to address unhealthy alcohol use in HIV clinics from the perspectives of social workers, psychologists and addiction psychiatrists. METHODS: We conducted two focus groups with Social Workers (n = 4), Psychologists (n = 2), and Addiction Psychiatrists (n = 4) involved in an ongoing randomized controlled trial evaluating the effectiveness of integrated stepped care for unhealthy alcohol use in HIV infected patients at five Veterans Health Administration (VA) HIV clinics. Data collection and analyses were guided by the Consolidated Framework for Implementation Research (CFIR) domains, with a focus on the three domains which we considered to be most relevant: intervention characteristics (i.e. motivational interviewing, pharmacotherapy), the inner setting (i.e. HIV clinics), and characteristics of individuals (i.e. the providers). A multidisciplinary team used directed content analysis to identify major themes. RESULTS: From the providers' perspective, the major implementation themes that emerged by CFIR domain included: (1) Intervention characteristics: providers valued tools and processes for facilitating patient motivation for treatment of unhealthy alcohol use given their perceived lack of motivation, but expressed a desire for greater flexibility; (2) Inner setting: treating unhealthy alcohol use in HIV clinics was perceived by providers to be consistent with VA priorities; and (3) Characteristics of individuals: there was high self-efficacy to conduct the intervention, an expressed need for more consistent utilization to maintain skills, and consideration of alternative models for delivering the components of the intervention. CONCLUSIONS: Use of the CFIR framework reveals that implementation of integrated stepped care for unhealthy alcohol use in HIV clinics is facilitated by tools to help providers enhance patient motivation or address unhealthy alcohol use among patients perceived to be unmotivated. Implementation may be facilitated by its consistency with organizational values and existing models of care and attention to optimizing provider self-efficacy and roles (i.e. approaches to treatment integration). PMID- 26763056 TI - Singapore Cancer Network (SCAN) Guidelines for Systemic Therapy of Pancreatic Adenocarcinoma. AB - INTRODUCTION: The SCAN pancreatic cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy for pancreatic adenocarcinoma in Singapore. MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. RESULTS: Five international guidelines were evaluated- those developed by the National Cancer Comprehensive Network (2014), the European Society of Medical Oncology (2012), Cancer Care Ontario (2013), the Japan Pancreas Society (2013) and the British Society of Gastroenterology, Pancreatic Society of Great Britain and Ireland, and the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (2005). Recommendations on the management of resected, borderline resectable, locally advanced and metastatic pancreatic adenocarcinoma were developed. CONCLUSION: These adapted guidelines form the SCAN Guidelines for systemic therapy for pancreatic adenocarcinoma in Singapore. PMID- 26763057 TI - Singapore Cancer Network (SCAN) Guidelines for the Management of Advanced Castrate-Resistant Prostate Cancer. AB - INTRODUCTION: The SCAN genitourinary cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for the management of advanced castrate-resistant prostate cancer. MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. RESULTS: Five international guidelines were evaluated- those developed by the National Comprehensive Cancer Network (2014), the European Society of Medical Oncology (2013), the American Urological Association (2013), the National Institute of Health and Clinical Excellence (2014) and the American Society of Clinical Oncology and Cancer Care Ontario (2014). Recommendations on the management of advanced castrate-resistant prostate cancer were developed. CONCLUSION: These adapted guidelines form the SCAN Guidelines 2015 for the management of advanced castrate-resistant prostate cancer. PMID- 26763058 TI - Singapore Cancer Network (SCAN) Guidelines for Systemic Therapy of Metastatic Renal Cell Carcinoma (mRCC). AB - INTRODUCTION: The SCAN genitourinary cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy of metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. RESULTS: Six international guidelines were evaluated- those developed by the National Comprehensive Cancer Network (2014), the European Association for Urology (2013), the European Society of Medical Oncology (2012), the National Institute of Health and Clinical Excellence (2011), the Canadian Kidney Cancer Forum (2013) and the Asian Oncology Summit (2012). Recommendations on the first-, second- and third line treatment for mRCC were developed. CONCLUSION: These adapted guidelines form the SCAN Guidelines 2015 for systemic therapy of mRCC. PMID- 26763059 TI - Singapore Cancer Network (SCAN) Guidelines for Neoadjuvant and Adjuvant Chemotherapy for Muscle-invasive Bladder Cancer. AB - INTRODUCTION: The SCAN genitourinary cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. RESULTS: Three international guidelines were evaluated- those developed by the National Comprehensive Cancer Network (2014), the European Society of Medical Oncology (2011) and the European Association of Urology (2013). Recommendations on the use of neoadjuvant and adjuvant chemotherapy in MIBC were developed. CONCLUSION: These adapted guidelines form the SCAN Guidelines 2015 for neoadjuvant and adjuvant chemotherapy in MIBC. PMID- 26763060 TI - Singapore Cancer Network (SCAN) Guidelines for Front-Line Systemic Therapy of Newly Diagnosed Advanced Epithelial Ovarian Cancer. AB - INTRODUCTION: The SCAN gynaecological cancers systemic therapy workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for front line systemic therapy of advanced epithelial ovarian cancer. MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. RESULTS: Five international guidelines were evaluated- those developed by the National Comprehensive Cancer Network (2013), the European Society of Medical Oncology (2013), the National Institute of Health and Clinical Excellence (2011), the Scottish Intercollegiate Guidelines Network (2011) and the Greater Metropolitan Clinical Taskforce (2009). Recommendations on the role of systemic therapy with intravenous chemotherapy, intraperitoneal chemotherapy, anti angiogenic agents and neoadjuvant chemotherapy in newly diagnosed advanced epithelial ovarian cancer were developed. CONCLUSION: These adapted guidelines form the SCAN Guidelines 2015 for front-line systemic therapy of advanced epithelial ovarian cancer. PMID- 26763061 TI - Singapore Cancer Network (SCAN) Guidelines for the Systemic Therapy of Endometrial (Uterine) Cancer. AB - INTRODUCTION: The SCAN gynaecological cancers systemic therapy workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for the systemic therapy of endometrial (uterine) cancer. MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. RESULTS: Three international guidelines were evaluated- those developed by the National Cancer Comprehensive Network (2015), the European Society of Medical Oncology (2013) and the Cancer Council Australia (2011). Recommendations on the role of chemotherapy following surgery in women diagnosed with endometrial cancer, the chemotherapeutic options for women with advanced or recurrent endometrial cancers and the role of chemotherapy in women with uterine papillary serous carcinoma or clear cell carcinoma were developed. CONCLUSION: These adapted guidelines form the SCAN Guidelines 2015 for the systemic therapy of endometrial (uterine) cancer. PMID- 26763062 TI - Singapore Cancer Network (SCAN) Guidelines for Adjuvant Chemotherapy in Resected Non-Small Cell Lung Cancer. AB - INTRODUCTION: The SCAN lung cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for the use of adjuvant systemic therapy for non-small cell lung cancer in Singapore. MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. RESULTS: Five international guidelines were evaluated- those developed by the National Comprehensive Cancer Network (2014), European Society of Medical Oncology (2014), National Institute of Clinical Excellence (2012), Scottish Intercollegiate Guidelines Network (2014), and the Cancer Care Council Australia (2012). Recommendations on the selection of patients, chemotherapy regimen, treatment for stage I disease, treatment for positive margins and treatment options for pN2 disease with negative margins were produced. CONCLUSION: These adapted guidelines form the SCAN Guidelines 2015 for adjuvant systemic therapy of non-small cell lung cancer. PMID- 26763063 TI - Singapore Cancer Network (SCAN) Guidelines for the Use of Systemic Therapy in Advanced Non-Small Cell Lung Cancer. AB - INTRODUCTION: The SCAN lung cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for the use of systemic therapy in advanced non-small cell lung cancer (NSCLC) in Singapore. MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. RESULTS: Five international guidelines were evaluated- those developed by the National Comprehensive Cancer Network (2014), the European Society of Medical Oncology (2014), the National Institute of Clinical Excellence (2012), the Scottish Intercollegiate Guidelines Network (2014) and Cancer Care Council Australia (2012). Recommendations on systemic treatment for advanced NSCLC were produced. CONCLUSION: These adapted guidelines form the SCAN guidelines 2015 for systemic therapy of advanced or metastatic NSCLC. PMID- 26763066 TI - Singapore Cancer Network (SCAN) Guidelines for the Initial Evaluation, Diagnosis and Management of Retroperitoneal Soft Tissue Sarcoma. AB - INTRODUCTION: The SCAN sarcoma workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for the initial evaluation, diagnosis and management of patients with retroperitoneal soft tissue sarcoma. MATERIALS AND METHODS: The workgroup utilised a consensus approach to create high quality evidence-based clinical practice guidelines suited for our local setting. RESULTS: Various international guidelines from the fields of radiology, pathology, surgical, medical and radiation oncology were reviewed. Recommendations on the role of radiological imaging, pathology, surgery, radiotherapy and systemic therapy in the management of retroperitoneal soft tissue sarcoma were developed. CONCLUSION: These guidelines form the SCAN Guidelines 2015 for the diagnosis, staging and optimal management of patients with retroperitoneal soft tissue sarcoma. PMID- 26763064 TI - Singapore Cancer Network (SCAN) Guidelines for Systemic Therapy of High-Grade Glioma. AB - INTRODUCTION: The SCAN Neuro-Oncology workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy for high-grade glioma in Singapore. MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. RESULTS: Six international guidelines were evaluated- those developed by the National Comprehensive Cancer Network (2013), the European Association for Neuro-Oncology (EANO) Task Force on Malignant Glioma (2014), the European Society of Medical Oncology (2014), the Canadian GBM Recommendations Committee (2007) and the Australian Cancer Network (2009). Recommendations on the systemic therapy of high-grade glioma were produced. CONCLUSION: These adapted guidelines form the SCAN Guidelines 2015 for systemic therapy of high-grade glioma. PMID- 26763067 TI - Singapore Cancer Network (SCAN) Guidelines for Referral for Genetic Evaluation of Common Hereditary Cancer Syndromes. AB - INTRODUCTION: The SCAN cancer genetics workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for referral for genetic evaluation of common hereditary cancer syndromes. MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. RESULTS: To formulate referral guidelines for the 3 most commonly encountered hereditary cancer syndromes to guide healthcare providers in Singapore who care for cancer patients and/or their family members, 7, 5, and 3 sets of international guidelines respectively for hereditary breast and ovarian cancer (HBOC) syndrome, Lynch syndrome (LS), and familial adenomatous polyposis (FAP) were evaluated. For each syndrome, the most applicable one was selected, with modifications made such that they would be appropriate to the local context. CONCLUSION: These adapted guidelines form the SCAN Guidelines 2015 for referral for genetic evaluation of common hereditary cancer syndromes. PMID- 26763065 TI - Singapore Cancer Network (SCAN) Guidelines for the Initial Evaluation, Diagnosis, and Management of Extremity Soft Tissue Sarcoma and Osteosarcoma. AB - INTRODUCTION: The SCAN sarcoma workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for the initial evaluation, diagnosis, and management of extremity soft tissue sarcoma and osteosarcoma. MATERIALS AND METHODS: The workgroup utilised a consensus approach to create high quality evidence-based clinical practice guidelines suited for our local setting. RESULTS: Various international guidelines from the fields of radiology, pathology, orthopaedic surgery, medical, radiation and paediatric oncology were reviewed, including those developed by von Mehren Metal (J Natl Compr Canc Netw 2014), the National Collaborating Centre for Cancer (2006), the European Sarcoma Network Working Group (2012) and Grimer RJ et al (Sarcoma 2008). Our clinical practice guidelines contextualised to the local patient will streamline care and improve clinical outcomes for patients with extremity soft tissue and osteosarcoma. CONCLUSION: These guidelines form the SCAN Guidelines 2015 for the initial evaluation, diagnosis, and management of extremity soft tissue sarcoma and osteosarcoma. PMID- 26763068 TI - Di(ethylene glycol) methyl ether methacrylate (DEGMEMA)-derived gels align small organic molecules in methanol. AB - Residual dipolar couplings (RDCs) constitute an important NMR parameter for structural elucidation in all areas of chemistry. In this study, di(ethylene glycol) methyl ether methacrylate (DEGMEMA)-based gels are introduced as alignment media for the measurement of RDCs of small organic molecules in polar solvents such as methanol. The low viscosity of methanol permits the execution of J-scaled BIRD HSQC experiments that yield very sharp lines in anisotropic conditions. The gels have excellent mechanical properties, and their compression and expansion in the swollen state can be reversed and performed multiple times. This process enables the easy loading and release of analytes. The excellent performance of these new aligning gels is demonstrated by analyzing the structure of the alkaloid retrorsine. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26763070 TI - [Sporadic cutaneous lymphosarcoma of T-cell origin with involvement of lymph nodes and internal organs in a Holstein cow]. AB - Sporadic lymphosarcomas in adult cattle are rare entities with an unknown etiology. This case report describes the course of the disease in a 3.5-year-old cow of the breed German Holstein, which was presented to the veterinarian due to multifocal nodular skin lesions. Several superficial lymph nodes (Lymphonodi mandibulares, parotidei and mammariae) were enlarged, had a tight-elastic consistency and were freely movable. The histopathological and immunohistochemical examination of skin biopsies showed the presence of multifocal cutaneous T-cell lymphosarcomas consistent with a skin leukosis. Bovine leukemia virus infection was excluded by serological investigation of a milk sample and virological examination of a tissue sample, respectively. Seven weeks after the first clinical examination, the cow deteriorated rapidly and was euthanized. A post mortem examination revealed the presence of neoplastic cells within lymph nodes (all superficial lymph nodes of the carcass and Lymphonodi pulmonales), kidney and lungs as well as a liver rupture. Additionally, an overview of the case reports of sporadic bovine cutaneous lymphosarcomas published during the previous 15 years will be provided. The legal background for a further utilization of affected animals for milk and meat production will be discussed. This case report illustrates that sporadic bovine leukosis represents an important differential diagnosis for viral-, bacterial- and parasitic-induced skin lesions and enlargement of lymph nodes in adult cattle. PMID- 26763069 TI - Postictal immobility and generalized EEG suppression are associated with the severity of respiratory dysfunction. AB - OBJECTIVE: The pathophysiology of sudden unexpected death in epilepsy (SUDEP) remains undetermined. Seizures are accompanied by respiratory dysfunction (RD). Postictal generalized electroencephalography (EEG) suppression (PGES) may follow generalized tonic-clonic seizures (GTCS). Following GTCS patients have impaired arousal and may be motionless. Patients with SUDEP are usually prone. Postictal immobility (PI) may contribute to SUDEP by not permitting repositioning of the head to allow unimpeded ventilation. To determine whether RD and/or ictal characteristics are associated with PI, we analyzed patients with GTCS in the epilepsy monitoring unit. METHOD: We investigated for associations between PI duration and PGES, ictal/postictal oxygen saturation (SpO2 ), end-tidal CO2 (ETCO2 ), seizure localization, duration, and tonic and total convulsive phase duration. We investigated for linkage between PGES and these measures. RESULTS: Seventy patients with 181 GTCS and available SpO2 and/or ETCO2 data were studied. Simple linear regression analysis by seizures showed that PI duration was associated with peak periictal ETCO2 (p = 0.03), duration of oxygen desaturation (p = 0.005) and with SpO2 nadir (p = 0.02). PI duration was not associated with tonic, convulsive phase or total seizure duration. Analysis by patients also showed significant association of PI with RD. Duration of PI was longer following seizures with PGES (p < 0.001). PGES was not associated with the tonic, convulsive phase or total seizure duration. SpO2 nadir was lower in seizures with PGES (p = 0.046), ETCO2 peak change (p = 0.003) was higher, and duration of ETCO2 elevation (p = 0.03) was longer. Multivariable regression analysis showed that PGES and severe RD were associated with PI duration. SIGNIFICANCE: The duration of PI and presence of PGES are associated with periictal RD. The duration of PI is also associated with the presence of PGES. Seizure duration or duration of the convulsive phase is not associated with PI or PGES. Interventions aimed at reversing impaired arousal and PI may reduce SUDEP risk. PMID- 26763071 TI - Distinguishing rotamers in N-trifluoroacetyl-3-benzazepine derivatives. AB - This paper provides the full (13) C NMR assignments for the trifluoroacetamides of five potentially appetite-reducing 5-HT2C benzazepine receptor agonists and two open-ring synthetic precursors. These compounds exist in solution as mixtures of two rotamers for each of which the (13) C NMR signals have now been assigned with the assistance of 2D NMR experiments and the carbonyl-induced shifts of the neighboring (13) CH2 resonances and long-range (13) C/(19) F couplings. PMID- 26763072 TI - Macrophage response to oncolytic paramyxoviruses potentiates virus-mediated tumor cell killing. AB - Tumor-associated macrophages (TAMs) are known to regulate tumor response to many anti-cancer therapies, including oncolytic virotherapy. Oncolytic virotherapy employing oncolytic paramyxoviruses, such as attenuated measles (MeV) and mumps (MuV) viruses, has demonstrated therapeutic potential against various malignancies. However, the response of TAMs to oncolytic paramyxoviruses and the consequent effect on virotherapeutic efficacy remains to be characterized. Here, we demonstrate that the presence of human monocyte-derived macrophages (MDMs), irrespective of initial polarization state, enhances the virotherapeutic effect of MeV and MuV on breast cancer cells. Notably, our finding contrasts those of several studies involving other oncolytic viruses, which suggest that TAMs negatively impact virotherapeutic efficacy by impeding virus replication and dissemination. We found that the enhanced virotherapeutic effect in the presence of MDMs was due to slightly delayed proliferation and significantly elevated cell death that was not a result of increased virus replication. Instead, we found that the enhanced virotherapeutic effect involved several macrophage-associated anti-tumor mediators, and was associated with the modulation of MDMs towards an anti-tumor phenotype. Our findings present an alternative view on the role of TAMs in oncolytic virotherapy, and highlight the immunotherapeutic potential of oncolytic paramyxoviruses; possibly contributing towards the overall efficacy of oncolytic virotherapy. PMID- 26763073 TI - Screening of PRKAR1A and PDE4D in a Large Italian Series of Patients Clinically Diagnosed With Albright Hereditary Osteodystrophy and/or Pseudohypoparathyroidism. AB - The cyclic adenosine monophosphate (cAMP) intracellular signaling pathway mediates the physiological effects of several hormones and neurotransmitters, acting by the activation of G-protein coupled receptors (GPCRs) and several downstream intracellular effectors, including the heterotrimeric stimulatory G protein (Gs), the cAMP-dependent protein kinase A (PKA), and cAMP-specific phosphodiesterases (PDEs). Defective G-protein-mediated signaling has been associated with an increasing number of disorders, including Albright hereditary osteodistrophy (AHO) and pseudohypoparathyroidism (PHP), a heterogeneous group of rare genetic metabolic disorders resulting from molecular defects at the GNAS locus. Moreover, mutations in PRKAR1A and PDE4D genes have been recently detected in patients with acrodysostosis (ACRDYS), showing a skeletal and endocrinological phenotype partially overlapping with AHO/PHP. Despite the high detection rate of molecular defects by currently available molecular approaches, about 30% of AHO/PHP patients still lack a molecular diagnosis, hence the need to screen patients negative for GNAS epi/genetic defects also for chromosomal regions and genes associated with diseases that undergo differential diagnosis with PHP. According to the growing knowledge on Gsalpha-cAMP signaling-linked disorders, we investigated our series of patients (n = 81) with a clinical diagnosis of PHP/AHO but negative for GNAS anomalies for the presence of novel genetic variants at PRKAR1A and PDE4D genes. Our work allowed the detection of 8 novel missense variants affecting genes so far associated with ACRDYS in 9 patients. Our data further confirm the molecular and clinical overlap among these disorders. We present the data collected from a large series of patients and a brief review of the literature in order to compare our findings with already published data; to look for PRKAR1A/PDE4D mutation spectrum, recurrent mutations, and mutation hot spots; and to identify specific clinical features associated with ACRDYS that deserve surveillance during follow-up. (c) 2016 American Society for Bone and Mineral Research. PMID- 26763074 TI - Diagnostic accuracy of rapid immunoassays for heparin-induced thrombocytopenia. A systematic review and meta-analysis. AB - The platelet factor 4/heparin ELISA has limited specificity for heparin-induced thrombocytopenia (HIT) and frequently does not provide same-day results. Rapid immunoassays (RIs) have been developed which provide results in 30 minutes or less. We conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of RIs for HIT. We searched the literature for studies in which samples from patients with suspected HIT were tested using a RI and a functional assay against which the performance of the RI could be measured. We performed sensitivity analyses of studies that directly compared different RIs with each other and with ELISAs. Estimates of sensitivity and specificity for each RI were calculated. Twenty-three articles, collectively involving six different RIs, met eligibility criteria. All RIs exhibited high sensitivity (0.96 to 1.00); there was wider variability in specificity (0.68 to 0.94). Specificity of the IgG-specific chemiluminescent assay (IgG-CA) was greater than the polyspecific chemiluminescent assay [0.94 (95 %CI 0.89-0.99) vs 0.82 (0.77 0.87)]. The particle gel immunoassay demonstrated greater specificity than the polyspecific ELISA [0.96 (0.95-0.97) vs 0.91 (0.89-0.92)]. The IgG-CA and lateral flow immunoassay [0.94 (0.91-0.97)] exhibited greater specificity than the IgG specific ELISA [0.86 (0.82-0.90)]. Given their high sensitivity and rapid turnaround time, RIs are a reliable means of excluding HIT at the point-of-care in patients with low or intermediate clinical probability. Additionally, some RIs have greater specificity than HIT ELISAs. In summary, IgG-specific RIs appear to have improved diagnostic accuracy compared with ELISAs in patients with suspected HIT and may reduce misdiagnosis and overtreatment. PMID- 26763076 TI - Future potential means of diagnosing gastric subepithelial lesions: Beyond conventional endoscopic ultrasound and endoscopic ultrasound-guided fine-needle aspiration. PMID- 26763075 TI - Antibacterial efficacy and pharmacokinetic evaluation of sanguinarine in common carp (Cyprinus carpio) following a single intraperitoneal administration. AB - Sanguinarine (SA), with antimicrobial and antiparasitic activities against fish pathogens, exhibits great potential commercial use in aquaculture. However, little information on pharmacokinetics of SA restricts further application in aquaculture. In this study, pharmacokinetics of SA in common carp (Cyprinus carpio) following a single intraperitoneal administration [10 mg kg(-1) BW (body weight)] was evaluated by high-performance liquid chromatography (HPLC). The peak concentration (Cmax ) of SA in kidney was 11.8 MUg g(-1) , which was higher than in other tissues and plasma. The terminal half-life in fish tissue and plasma was as follows: 42.3 h (kidney) > 37.2 h (liver) > 20.1 h (gill) > 18.8 h (muscle) > 10.9 h (spleen) > 10.0 h (plasma). Additionally, we determined the bacterial loads in tissues of common carp infected with Aeromonas hydrophila after i.p. administration of SA at 0, 5, 10 and 20 mg kg(-1) BW. The results showed that i.p. administration of SA at 10 mg kg(-1) BW significantly enhanced antibacterial efficacy against A. hydrophila, where the antibacterial ratio in the gill, kidney, spleen and liver on day 5 was 95.13%, 93.33%, 90.09% and 92.82%, respectively. Overall, these results suggested the potential of SA to treat A. hydrophila infection in common carp farming industry. PMID- 26763077 TI - Atrial fibrillation is associated with high levels of monocyte-platelet aggregates and increased CD11b expression in patients with aortic stenosis. AB - A growing body of evidence suggests a pivotal role of inflammatory processes in AF in a bidirectional manner. Infiltrating leukocytes seem to promote both structural and electrical remodelling processes in patients with AF. Monocyte platelets-aggregates (MPAs) are sensitive markers of both platelets and monocyte activation. So far it is not clear whether the content of MPAs is affected by AF. The present study examined the content of MPAs and the activation of monocytes in elderly patients with an aortic stenosis in dependence of AF. These patients are known to have a high prevalence of AF. Flow-cytometric quantification analysis demonstrated that patients with AF have an increased content of MPAs (207 +/- 13 cells/ul vs 307 +/- 21 cells/ul, p< 0.001), and enhanced expression of CD11b on monocytes (p< 0.001), compared to patients in stable sinus rhythm (SR). The number of CD14+/CD16+ monocytes were only slightly elevated in patients with AF. These findings were seen in patients with permanent AF. But also patients with paroxysmal AF, even when presenting in SR, the MPAs were increased by 50 % (p< 0.05) as well as the CD11b expression, which was twice as high (p< 0.05) compared to stable SR. These results demonstrate for the first time a dependency of MPAs and CD11b expression on monocytes in the presence of AF and support the notion of a close relationship between AF, thrombogenesis and inflammation. The content of MPAs and the extent of activation on monocytes appear promising as biomarkers for paroxysmal AF and as possible future targets for developing novel pharmacological therapeutic strategies. PMID- 26763078 TI - Transcriptional regulation of early T-cell development in the thymus. AB - T-cell development occurs in multipotent progenitors arriving in the thymus, which provides a highly specialized microenvironment. Specification and sequential commitment processes to T cells begin in early thymic progenitors upon receiving thymus-specific environmental cues, resulting in the activation of the genetically programmed transcriptional cascade that includes turning on and off numerous transcription factors in a precise manner. Thus, early thymocyte differentiation has been an excellent model system to study cell differentiation processes. This review summarizes recent advances in our knowledge on thymic T cell development from newly arrived multipotent T-cell progenitors to fully committed T-cell precursors, from the transcriptional regulation perspective. PMID- 26763079 TI - Neurotrophin-3 Induces BMP-2 and VEGF Activities and Promotes the Bony Repair of Injured Growth Plate Cartilage and Bone in Rats. AB - Injured growth plate is often repaired by bony tissue causing bone growth defects, for which the mechanisms remain unclear. Because neurotrophins have been implicated in bone fracture repair, here we investigated their potential roles in growth plate bony repair in rats. After a drill-hole injury was made in the tibial growth plate and bone, increased injury site mRNA expression was observed for neurotrophins NGF, BDNF, NT-3, and NT-4 and their Trk receptors. NT-3 and its receptor TrkC showed the highest induction. NT-3 was localized to repairing cells, whereas TrkC was observed in stromal cells, osteoblasts, and blood vessel cells at the injury site. Moreover, systemic NT-3 immunoneutralization reduced bone volume at injury sites and also reduced vascularization at the injured growth plate, whereas recombinant NT-3 treatment promoted bony repair with elevated levels of mRNA for osteogenic markers and bone morphogenetic protein (BMP-2) and increased vascularization and mRNA for vascular endothelial growth factor (VEGF) and endothelial cell marker CD31 at the injured growth plate. When examined in vitro, NT-3 promoted osteogenesis in rat bone marrow stromal cells, induced Erk1/2 and Akt phosphorylation, and enhanced expression of BMPs (particularly BMP-2) and VEGF in the mineralizing cells. It also induced CD31 and VEGF mRNA in rat primary endothelial cell culture. BMP activity appears critical for NT-3 osteogenic effect in vitro because it can be almost completely abrogated by co-addition of the BMP inhibitor noggin. Consistent with its angiogenic effect in vivo, NT-3 promoted angiogenesis in metatarsal bone explants, an effect abolished by co-treatment with anti-VEGF. This study suggests that NT-3 may be an osteogenic and angiogenic factor upstream of BMP-2 and VEGF in bony repair, and further studies are required to investigate whether NT-3 may be a potential target for preventing growth plate faulty bony repair or for promoting bone fracture healing. (c) 2016 American Society for Bone and Mineral Research. PMID- 26763080 TI - Success of Maxillary Alveolar Defect Repair in Rats Using Osteoblast Differentiated Human Deciduous Dental Pulp Stem Cells. AB - PURPOSE: The use of cell-based therapies represents one of the most advanced methods for enhancing the regenerative response in craniofacial abnormalities. The main aim of this study was to evaluate the regenerative potential of human dental pulp stem cells, isolated from deciduous teeth, for reconstructing maxillary alveolar defects in Wistar rats. MATERIALS AND METHODS: Human deciduous dental pulp stem cells were isolated and stimulated to differentiate into osteoblasts in culture media. Maxillary alveolar defects were created in 60 Wistar rats by a surgical procedure. Then, on the basis of the type of graft used to repair the bone defect, the rats were divided into 6 equal groups: groups 1 and 2, transplantation of iliac bone graft; groups 3 and 4, transplantation of stem cells derived from deciduous dental pulp in addition to collagen matrix; groups 5 and 6, transplantation of just collagen matrix. Then, fetal bone formation, granulation tissue, fibrous tissue, and inflammatory tissue were evaluated by hematoxylin-eosin staining at 1 month (groups 1, 3, and 5) and 2 months (groups 2, 4, and 6) after surgery, and data were analyzed and compared using the Fisher exact test. RESULTS: Maximum fetal bone formation occurred in group 2, in which iliac bone graft was inserted into the defect area for 2 months; there also were significant differences among the groups for bone formation (P = .009). In the 1-month groups, there were no significant differences between the control and stem cell-plus-scaffold groups. There were significant differences between the 2-month groups for fetal bone formation only between the control and scaffold groups (P = .026). CONCLUSIONS: The study showed that human dental pulp stem cells are an additional cell resource for repairing maxillary alveolar defects in rats and constitute a promising model for reconstruction of human maxillary alveolar defects in patients with cleft lip and palate. PMID- 26763082 TI - First evidence of infectious hematopoietic necrosis virus (IHNV) in the Netherlands. AB - In spring 2008, infectious hematopoietic necrosis virus (IHNV) was detected for the first time in the Netherlands. The virus was isolated from rainbow trout, Oncorhynchus mykiss (Walbaum), from a put-and-take fishery with angling ponds. IHNV is the causative agent of a serious fish disease, infectious hematopoietic necrosis (IHN). From 2008 to 2011, we diagnosed eight IHNV infections in rainbow trout originating from six put-and-take fisheries (symptomatic and asymptomatic fish), and four IHNV infections from three rainbow trout farms (of which two were co-infected by infectious pancreatic necrosis virus, IPNV), at water temperatures between 5 and 15 degrees C. At least one farm delivered trout to four of these eight IHNV-positive farms. Mortalities related to IHNV were mostly <40%, but increased to nearly 100% in case of IHNV and IPNV co-infection. Subsequent phylogenetic analysis revealed that these 12 isolates clustered into two different monophyletic groups within the European IHNV genogroup E. One of these two groups indicates a virus-introduction event by a German trout import, whereas the second group indicates that IHNV was already (several years) in the Netherlands before its discovery in 2008. PMID- 26763081 TI - Tissue factor associates with survival and regulates tumour progression in osteosarcoma. AB - Osteosarcoma is the most common primary malignant bone tumour. Patients often develop lung metastasis and have a poor prognosis despite extensive chemotherapy and surgical resections. Tissue Factor is associated with poor clinical outcome in a wide range of cancer types, and promotes angiogenesis and metastasis. The role of Tissue Factor in OS tumourigenesis is unknown. Fifty-three osteosarcoma pre-treatment biopsies and four osteosarcoma cell lines were evaluated for Tissue Factor expression, and a possible association with clinical parameters was investigated. Tissue Factor function was inhibited in an osteosarcoma cell line (143B) by shRNA knockdown or specific antibodies, and pro-tumourigenic gene expression, proliferation, matrigel invasion and transwell migration was examined. 143B cells were implanted in mice in the presence of Tissue Factor blocking antibodies, and tumour volume, micro-vessel density and metastases in the lung were evaluated. Tissue Factor was highly expressed in 73.6 % of osteosarcoma biopsies, and expression associated significantly with disease-free survival. Tissue Factor was expressed in all four investigated cell lines. Tissue Factor was knocked down in 143B cells, which led to reduced expression of IL-8, CXCL-1, SNAIL and MMP2, but not MMP9. Tissue Factor knockdown or inhibition with antibodies reduced matrigel invasion. Tissue Factor antibodies limited 143B tumour growth in vivo, and resulted in decreased intra-tumoural micro-vessel density. Furthermore, lung metastasis from the primary tumour was significantly reduced. Thus, Tissue Factor expression in osteosarcoma reduces metastasis-free survival in patients, and increases pro-tumourigenic behaviour both in vitro and in vivo. PMID- 26763084 TI - Do matrix metalloproteinase inhibitors improve the bond durability of universal dental adhesives? AB - The aim of this study was to evaluate the effects of matrix metalloproteinases (MMPs) inhibitors on the microtensile bond strength (MUTBS) and the adhesive dentin interface of two universal dentin bonding agents, Single Bond Universal and All Bond Universal, after 12 months of water storage. Seventy extracted, caries-free, human third molars were used in this study. Of these, 50 were used for MUTBS testing and 20 were used for scanning electron microscopy. The two bonding agents were applied to flat dentin surfaces in five different ways: self etch mode, etch-and-rinse mode with 37% phosphoric acid, etch-and-rinse mode with phosphoric acid containing 1% benzalkonium chloride, etch-and-rinse mode with phosphoric acid and 2% chlorhexidine, and etch-and-rinse mode with 0.5 M ethylenediaminetetraacetic acid (EDTA) (n = 5 for each bonding agent in each group; N = 50). Half the specimens were subjected to MUTBS tests at 24 h, while half were subjected to the tests after 12 months of water storage. For each bonding agent, inhibition, storage, and their interaction effects were tested by two-way analysis of variance and Bonferroni tests. For Single Bond Universal, the benzalkonium chloride (p = 0.024) and chlorhexidine groups (p = 0.033) exhibited significantly higher MUTBS values at 24 h compared with the self-etch group. For All Bond Universal, all groups displayed similar bond strengths at 24 h (p > 0.05). After 12 months of water storage, the MUTBS values decreased significantly in the benzalkonium chloride group for Single Bond Universal (p = 0.001) and the self-etch (p = 0.029), chlorhexidine (p = 0.046), and EDTA (p = 0.032) groups for All Bond Universal. These results suggest that the immediate dentin bond strength increases when universal bonding systems are applied in the etch-and-rinse mode, although the durability decreases. The use of chlorhexidine and EDTA can increase the bond durability of mild adhesives such as Single Bond Universal. SCANNING 38:535-544, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26763083 TI - Relationship between androgen deprivation therapy and community-acquired respiratory infections in patients with prostate cancer. AB - OBJECTIVES: To investigate the dose-dependent effect of androgen deprivation therapy on community-acquired respiratory infections in patients with localized prostate cancer. METHODS: We identified 52 905 men diagnosed with localized prostate cancer within the Surveillance, Epidemiology and End Results-Medicare database between 1991 and 2006. We compared those who did not receive androgen deprivation therapy with those who received androgen deprivation therapy within 2 years of diagnosis, calculated as monthly equivalent doses (<7, 7-11, >11 doses), or orchiectomy. Adjusted Cox hazard models were fitted to predict the risk of community-acquired respiratory infections (acute sinusitis, acute bronchitis, [severe] pneumonia) in patients treated with medical androgen deprivation therapy versus orchiectomy versus none. RESULTS: Overall, 43.4% received medical androgen deprivation therapy. These patients more likely experienced respiratory events compared with those who did not receive androgen deprivation therapy or who underwent orchiectomy (62.2% vs 54.5% vs 47.8%, P < 0.001). The risk of experiencing any respiratory event increased with the number of doses received. For example, men receiving >11 doses of androgen deprivation therapy were at greatest risk of acute sinusitis, acute bronchitis and pneumonia (HR 1.13, 1.26 and 1.15, respectively, all P < 0.001), except severe pneumonia. Furthermore, we did not detect any relationship between orchiectomy and respiratory events. Study limitations include the utilization of a retrospective population-based dataset. CONCLUSIONS: Increased exposure to medical androgen deprivation therapy for men with localized prostate cancer is associated with a higher risk of community acquired respiratory infections. Our results suggest that respiratory complications represent potentially underreported complications of medical androgen deprivation therapy. PMID- 26763085 TI - Inflammation and the coagulation system in tuberculosis: Tissue Factor leads the dance. AB - Mycobacterium tuberculosis, the causative agent of tuberculosis, drives the formation of granulomas, structures in which both immune cells and the bacterial pathogen cohabit. The most abundant cells in granulomas are macrophages, which contribute as both cells with bactericidal activity and as targets for M. tuberculosis infection and proliferation during the entire course of infection. The mechanisms and factors involved in the regulation and control of macrophage microenvironment-specific polarization and plasticity are not well understood, as some granulomas are able to control bacteria growth and others fail to do so, permitting bacterial spread. In this issue of the European Journal of Immunology, Venkatasubramanian et al. [Eur. J. Immunol. 2016. 46: 464-479] show that mice lacking the tissue factor gene in myeloid cells have augmented M. tuberculosis growth and increased inflammation in the lungs. This suggests that tissue factor, an initiator of coagulation, is important for the generation of fibrin, which supports granuloma formation. This article demonstrates for the first time the involvement of tissue factor in inducing effective immunity against M. tuberculosis, and sheds new lights on the complex interplay between host inflammatory response, the coagulation system, and the control of M. tuberculosis infection. PMID- 26763086 TI - Carboxiterminal pro-endothelin-1 as an endothelial cell biomarker in thrombotic thrombocytopenic purpura. AB - Thrombotic thrombocytopenic purpura (TTP) is characterised by the deficiency of the von Willebrand factor (VWF) cleaving protease (ADAMTS-13). Although several observations indicate an important role of endothelial activation in the pathogenesis of TTP, no reliable endothelial activation markers are available in the clinical management of TTP. Our aim was to investigate the presence of endothelial activation in TTP and to determine its connections with disease activity, therapy and complement activation. We enrolled 54 patients (median age 40.5; 44 females) and 57 healthy controls (median age 34; 30 females),VWF antigen, carboxiterminal-pro-endothelin-1 (CT-proET-1), complement Factor H and complement activation products (C3bBbP and SC5b-9) were measured. In both the acute and remission phase of TTP we found increased CT-proET-1 and VWF levels, while Factor H levels decreased compared with healthy controls. In remission, however, the elevated CT-proET-1 levels showed 22 % decrease when compared with the acute phase in paired samples (p=0.0031), whereas no changes for VWF and Factor H levels were observed. We also found positive correlations between CT proET-1 levels and alternative pathway activation markers (C3bBbP; p=0.0360; r=0.4299). The data we present here demonstrate a role of endothelium activation in patients with acute TTP. The finding that CT-proET-1 levels decreased in remission compared with the acute phase further supports endothelial involvement. In addition, we show that endothelial activation also correlated with the activation of the alternative complement pathway. The data suggest that complement and endothelium activation jointly contribute to the development of TTP episodes in patients with predisposition to TTP. PMID- 26763087 TI - Skeletal anomaly assessment in diploid and triploid juvenile Atlantic salmon (Salmo salar L.) and the effect of temperature in freshwater. AB - Triploid Atlantic salmon tend to develop a higher prevalence of skeletal anomalies. This tendency may be exacerbated by an inadequate rearing temperature. Early juvenile all-female diploid and triploid Atlantic salmon were screened for skeletal anomalies in consecutive experiments to include two size ranges: the first tested the effect of ploidy (0.2-8 g) and the second the effect of ploidy, temperature (14 degrees C and 18 degrees C) and their interaction (8-60 g). The first experiment showed that ploidy had no effect on skeletal anomaly prevalence. A high prevalence of opercular shortening was observed (average prevalence in both ploidies 85.8%) and short lower jaws were common (highest prevalence observed 11.3%). In the second experiment, ploidy, but not temperature, affected the prevalence of short lower jaw (diploids > triploids) and lower jaw deformity (triploids > diploids, highest prevalence observed 11.1% triploids and 2.7% diploids) with a trend indicating a possible developmental link between the two jaw anomalies in triploids. A radiological assessment (n = 240 individuals) showed that at both temperatures triploids had a significantly (P < 0.05) lower number of vertebrae and higher prevalence of deformed individuals. These findings (second experiment) suggest ploidy was more influential than temperature in this study. PMID- 26763088 TI - Prediagnostic prostate-specific antigen kinetics and the risk of biopsy progression in active surveillance patients. AB - OBJECTIVE: To analyze the association between prediagnostic prostate-specific antigen kinetics and the risk of biopsy progression in prostate cancer patients on active surveillance, and to study the effect of prediagnostic prostate specific antigen values on the predictive performance of prostate-specific antigen velocity and prostate-specific antigen doubling time. METHODS: The study included 137 active surveillance patients with two or more prediagnostic prostate specific antigen levels measured over a period of at least 3 months. Two sets of analyses were carried out. First, the association between prostate-specific antigen kinetics calculated using only the prediagnostic prostate-specific antigen values and the risk of biopsy progression was studied. Second, using the same cohort of patients, the predictive value of prostate-specific antigen kinetics calculated using only post-diagnostic prostate-specific antigens and compared with that of prostate-specific antigen kinetics based on both pre- and post-diagnostic prostate-specific antigen levels was analyzed. RESULTS: Of 137 patients included in the analysis, 37 (27%) had biopsy progression over a median follow-up period of 3.2 years. Prediagnostic prostate-specific antigen velocity of more than 2 ng/mL/year and 3 ng/mL/year was statistically significantly associated with the risk of future biopsy progression. However, after adjustment for baseline prostate-specific antigen density, these associations were no longer significant. None of the tested prostate-specific antigen kinetics based on combined pre- and post-diagnostic prostate-specific antigen values were statistically significantly associated with the risk of biopsy progression. CONCLUSIONS: Historical prediagnostic prostate-specific antigens seems to be not clinically useful in patients diagnosed with low-risk prostate cancer on active surveillance. PMID- 26763089 TI - Synthesis, characterization, and application of polysodium N-alkylenyl alpha-d glucopyranoside surfactants for micellar electrokinetic chromatography-tandem mass spectrometry. AB - Sugar-based ionic surfactants forming micelles are known to suppress ESI of various compounds due to decrease in surface tension upon micelle formation . For the first time, poly (sodium N-undecylenyl-alpha-d-glucopyranoside 4,6-hydrogen phosphate, (poly-alpha-d-SUGP) based surfactants with different chain lengths and head groups have been successfully synthesized, characterized, and applied as compatible chiral selector for MEKC-ESI-MS/MS. First, the effect of polymerization concentration of the monomer, alpha-d-SUGP, was evaluated by enantioseparation of one anionic compound (1,1'-binaphthyl-2,2'diyl-hydrogen phosphate) and one zwitterionic compound (dansylated phenylalanine) in MEKC-UV to find the optimum molar surfactant concentration for polymerization. Next, MEKC-UV and MEKC-MS were compared for the enantioseparation of 1,1'-binaphthyl-2,2'diyl hydrogen phosphate. The influence of polymeric glucopyranoside based surfactant head groups and carbon chain lengths on chiral Rs was evaluated for two classes of cationic drugs (ephedrine alkaloids and beta-blockers). Finally, enantioselective MEKC-MS of ephedrine alkaloids and beta-blockers were profiled at their optimum pH 5.0 and 7.0, respectively, using 20 mM NH4 OAc, 25 mM poly alpha-d-SUGP at 30 kV and 25 degrees C under optimum spray chamber conditions. The LOD for most of the enantiomers ranges from 10 to 100 ng/mL with S/N of at least >=3.0. PMID- 26763090 TI - Life span and reproductive cost explain interspecific variation in the optimal onset of reproduction. AB - Fitness can be profoundly influenced by the age at first reproduction (AFR), but to date the AFR-fitness relationship only has been investigated intraspecifically. Here, we investigated the relationship between AFR and average lifetime reproductive success (LRS) across 34 bird species. We assessed differences in the deviation of the Optimal AFR (i.e., the species-specific AFR associated with the highest LRS) from the age at sexual maturity, considering potential effects of life history as well as social and ecological factors. Most individuals adopted the species-specific Optimal AFR and both the mean and Optimal AFR of species correlated positively with life span. Interspecific deviations of the Optimal AFR were associated with indices reflecting a change in LRS or survival as a function of AFR: a delayed AFR was beneficial in species where early AFR was associated with a decrease in subsequent survival or reproductive output. Overall, our results suggest that a delayed onset of reproduction beyond maturity is an optimal strategy explained by a long life span and costs of early reproduction. By providing the first empirical confirmations of key predictions of life-history theory across species, this study contributes to a better understanding of life-history evolution. PMID- 26763091 TI - Multi-analyte profiling in human carotid atherosclerosis uncovers pro inflammatory macrophage programming in plaques. AB - Molecular characterisation of vulnerable atherosclerosis is necessary for targeting functional imaging and plaque-stabilising therapeutics. Inflammation has been linked to atherogenesis and the development of high-risk plaques. We set to quantify cytokine, chemokine and matrix metalloproteinase (MMP) protein production in cells derived from carotid plaques to map the inflammatory milieu responsible for instability. Carotid endarterectomies from carefully characterised symptomatic (n=35) and asymptomatic (n=32) patients were enzymatically dissociated producing mixed cell type atheroma cell suspensions which were cultured for 24 hours. Supernatants were interrogated for 45 analytes using the Luminex 100 platform. Twenty-nine of the 45 analytes were reproducibly detectable in the majority of donors. The in vitro production of a specific network of mediators was found to be significantly higher in symptomatic than asymptomatic plaques, including: tumour necrosis factor alpha, interleukin (IL) 1beta, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), CCL5, CCL20, CXCL9, matrix metalloproteinase (MMP)-3 and MMP-9. Ingenuity pathway analysis of differentially expressed analytes between symptomatic and asymptomatic patients identified a number of key biological pathways (p< 10(-25)). In conclusion, the carotid artery plaque culprit of ischaemic neurological symptoms is characterised by an inflammatory milieu favouring inflammatory cell recruitment and pro-inflammatory macrophage polarisation. PMID- 26763092 TI - The Red Queen lives: Epistasis between linked resistance loci. AB - A popular theory explaining the maintenance of genetic recombination (sex) is the Red Queen Theory. This theory revolves around the idea that time-lagged negative frequency-dependent selection by parasites favors rare host genotypes generated through recombination. Although the Red Queen has been studied for decades, one of its key assumptions has remained unsupported. The signature host-parasite specificity underlying the Red Queen, where infection depends on a match between host and parasite genotypes, relies on epistasis between linked resistance loci for which no empirical evidence exists. We performed 13 genetic crosses and tested over 7000 Daphnia magna genotypes for resistance to two strains of the bacterial pathogen Pasteuria ramosa. Results reveal the presence of strong epistasis between three closely linked resistance loci. One locus masks the expression of the other two, while these two interact to produce a single resistance phenotype. Changing a single allele on one of these interacting loci can reverse resistance against the tested parasites. Such a genetic mechanism is consistent with host and parasite specificity assumed by the Red Queen Theory. These results thus provide evidence for a fundamental assumption of this theory and provide a genetic basis for understanding the Red Queen dynamics in the Daphnia-Pasteuria system. PMID- 26763093 TI - Editorial Comment from Dr Minardi and Dr Fulvi to Predictive value of urinary interleukin-6 for symptomatic urinary tract infections in a nursing home population. PMID- 26763094 TI - Membrane supported liquid-liquid-liquid microextraction combined with field amplified sample injection CE-UV for high-sensitivity analysis of six cardiovascular drugs in human urine sample. AB - An effective dual preconcentration method involving off-line membrane supported liquid-liquid-liquid microextraction (MS-LLLME) and on-line field-amplified sample injection (FASI) was proposed for the extraction of six cardiovascular drugs, including mexiletine, xylocaine, propafenone, propranolol, metoprolol, and carvedilol from aqueous solution prior to CE-UV. In MS-LLLME, the analytes were extracted from 9 mL sample solution into toluene, and then back extracted into a drop of acceptor phase of 10 MUL 20 mmol/L acetic acid. After that, the acceptor phase was directly introduced into CE for FASI without any modification. In FASI process, water plug was hydrodynamically injected (50 mbar, 3 s) into the capillary prior to sample injection (+6 kV, 18 s). Six target analytes were separated in less than 10 min at 25 degrees C with a BGE consisting of 70 mmol/L Tris-H3 PO4 (pH 2.2) containing 10% v/v methanol. Under the optimized conditions, LODs obtained by the proposed MS-LLLME-FASI-CE-UV method were in the range of 0.02-0.82 MUg/L (based on S/N = 3) with enrichment factors of 546- to 7300-fold for the target analytes. The RSDs of the developed method were in the range of 6.7-12.9% (n = 7). Good linearity (R(2) = 0.9928-0.9997) was obtained in concentration range of 0.1-100 MUg/L for mexiletine and propranolol, 0.2-100 MUg/L for xylocaine and metoprolol, 0.5-100 MUg/L for propafenone and 2.0-100 MUg/L for carvedilol, respectively. The developed method was successfully applied for real-time determination of metoprolol in human urine samples within 26 h after uptake. PMID- 26763095 TI - Betanodavirus ability to infect juvenile European sea bass, Dicentrarchus labrax, at different water salinity. AB - Viral encephalopathy and retinopathy (VER) is one of the most devastating and economically relevant diseases for marine aquaculture. The presence of betanodavirus in freshwater fish is recorded, but very little is known about VER outbreaks in marine species reared in freshwater. Our study investigated the ability of betanodavirus to cause disease in European sea bass, Dicentrarchus labrax, reared at different salinity levels. Fish were challenged with RGNNV or mock infected by bath at different salinity levels (freshwater, 250/00 and 330/00). Fish were checked twice a day and the dead ones were examined by standard virological techniques, by rRT-PCR and by histochemical and immunohistochemical analyses. All the infected groups showed a significant higher mortality rate than the one of the mock-infected group. VERv presence was confirmed by rRT-PCR. Histochemical and immunohistochemical analyses highlighted the typical lesions associated with VER. Our results highlight that salinity does not affect the ability of betanodavirus to induce clinical signs and mortality in European sea bass infected under experimental conditions. These results underline the great adaptation potential of VERv, which in combination with its already known high environmental resistance and broad host range, may explain the diffusion of this disease and the threat posed to aquaculture worldwide. PMID- 26763098 TI - On genetic canalization, infinitesimal model and whole-genome sequence data. PMID- 26763100 TI - Identification and pathogenicity of Vibrio parahaemolyticus isolates and immune responses of Penaeus (Litopenaeus) vannamei (Boone). AB - Five different Vibrio parahaemolyticus strains (SH8, SH108, SH58, AH5 and GD10) isolated from the hepatopancreas of moribund shrimp in farms of mainland China were identified and capable of inducing massive mortality of Penaeus (Litopenaeus) vannamei. The immersion challenge results with five isolates indicated variance of virulence, while only GD10 caused massive sloughing of tubule epithelial cells which was recognized as the most significant symptom of AHPND. Differences in immune responses were detected of P. vannamei during 48 h post-infection (p.i.) by injection or immersion challenge with V. parahaemolyticus (SH8, SH108 and GD10) isolates. When injected SH8 and SH108 isolates, the expression of lysozyme (LSZ) showing statistically significant upregulation at 16 and 48 h p.i. and that of Toll-like receptors (TLR) showed statistically significant upregulation at 48 h p.i. When immersion challenge with the GD10 isolate, TLR were upregulated after 8 h p.i. challenge with 10(4) cfu mL(-1) ; however, LSZ was downregulated when challenged with 10(3) cfu mL(-1) . The results suggested that LSZ and TLR serve as crucial molecular markers of innate immunity in shrimp against V. parahaemolyticus infection. LSZ is a vital marker for acute bacterial infection, while TLR serves as a crucial marker for chronic infection. PMID- 26763099 TI - Acute-phase glycoprotein N-glycome of ovarian cancer patients analyzed by CE-LIF. AB - Epithelial ovarian cancer (EOC) is the most frequent cause of death from all gynecological malignancies because of its late diagnosis. As N-glycosylation is modified in the course of ovarian cancer, it is a promising source of tumor biomarkers. In this work, serum glycoproteins, depleted from albumin and IgG, were separated by 2DE. Protein spots of acute-phase proteins were identified by peptide mapping and their corresponding glycan moieties were released enzymatically, fluorescently labeled and analyzed by CE-LIF. In the positive acute-phase proteins, haptoglobin, alpha1-antitrypsin, and alpha1 antichymotrypsin, an increase of antennarity and Lewis(X) motif could be measured in EOC patients on tri- and/or tetraantennary N-glycans. Tetraantennary N-glycans containing three Lewis(X) epitopes and triantennary N-glycans containing a beta(1 6) branch and a Lewis(X) epitope were only present in EOC patients. We also showed for the first time that the core-fucosylated biantennary digalactosylated N-glycan of alpha1-acid glycoprotein is a potential biomarker for EOC. To conclude, core-fucosylated biantennary N-glycans on alpha1-acid glycoprotein as well as higher antennarity and increased amounts of Lewis(X) motif on haptoglobin, alpha1-antitrypsin, and alpha1-antichymotrypsin are promising biomarkers for EOC. Nevertheless, their specificity and selectivity for the early detection of EOC should be evaluated in a larger study. PMID- 26763101 TI - The donor OH stretching-libration dynamics of hydrogen-bonded methanol dimers in cryogenic matrices. AB - FTIR spectra of the methanol dimer trapped in neon matrices are presented. The fundamental, overtone and combination bands involving the donor OH libration and stretching motions were observed in order to extract relevant anharmonicity constants. We find a stretching-libration coupling constant of +43(5) cm(-1) and a diagonal librational anharmonicity constant of -71(5) cm(-1). The spectra are compared to a number of VPT2 calculations and a torsionally localized monomer model in order to enhance previous explanations of the observable OH stretching red-shift upon dimerization. PMID- 26763102 TI - Exosomes derived from mineralizing osteoblasts promote ST2 cell osteogenic differentiation by alteration of microRNA expression. AB - Mineralizing osteoblasts (MOBs) can release exosomes, although the functional significance remains unclear. In the present study, we demonstrate that exosomes derived from mineralizing pre-osteoblast MC3T3-E1 cells can promote bone marrow stromal cell (ST2) differentiation to osteoblasts. We reveal that MOB-derived exosomes significantly influence miRNA profiles in recipient ST2 cells, and these changes tend to activate the Wnt signaling pathway by inhibiting Axin1 expression and increasing beta-catenin expression. We also suggest that MOB derived-exosomes partly induce the variation in miRNA expression in recipient ST2 cells by exosomal miRNA transfer. These findings suggest an exosome-mediated mode of cell to-cell communication in the osteogenic microenvironment, and also indicate the potential of MOB exosomes in bone tissue engineering. PMID- 26763103 TI - High frequency of Candida fabianii among clinical isolates biochemically identified as Candida pelliculosa and Candida utilis. AB - Clinical yeast isolates belonging to Candida pelliculosa, Candida utilis and Candida fabianii are difficult to distinguish in a routine mycology laboratory using common biochemical tests. The aims of this study were to determine the prevalence of C. pelliculosa, C. utilis and C. fabianii in clinical samples and to compare their minimum inhibitory concentrations (MICs) to systemic antifungals. Two hundred and forty-eight clinical yeast isolates obtained from eight large hospitals in the Czech Republic were included in this study. Identification was performed biochemically using ID 32C kit and by MALDI-TOF MS. MICs were determined using colorimetric broth dilution Sensititre YeastOne panels. From a total number of 248 isolates, 175 were identified as C. pelliculosa and 73 as C. utilis using the biochemical kit. In contrast, MALDI-TOF MS identified 222 isolates as C. fabianii, 20 as C. pelliculosa and 6 as C. utilis. The highest mean MICs were found in C. fabianii and, regardless of the studied species, in isolates from blood cultures and central venous catheters. MALDI-TOF MS revealed C. fabianii to be most prevalent in clinical samples as compared with the other studied species. Higher MIC values in C. fabianii support the importance of correct identification of this species. PMID- 26763104 TI - Antimicrobial properties of biosynthesized silver nanoparticles studied by flow cytometry and related techniques. AB - This work reports the effect of silver bionanoparticles (Bio(AgNPs) synthesized by Actinobacteria CGG 11n on selected Gram (+) and Gram (-) bacteria. Flow cytometry, classical antibiogram method and fluorescent microscopy approach was used for evaluation of antimicrobial activity of Bio(AgNPs) and their combination with antibiotics. Furthermore, the performed research specified the capacity of flow cytometry method as an alternative to the standard ones and as a complementary method to electromigration techniques. The study showed antibacterial activity of both BioAgNPs and the combination of antibiotics/BioAgNPs against all the tested bacteria strains in comparison with a diffusion, dilution and bioautographic methods. The synergistic effect of antibiotics/BioAgNPs combination (e.g. kanamycin, ampicillin, neomycin and streptomycin) was found to be more notable against Pseudomonas aeruginosa representing a prototype of multi-drug resistant "superbugs" for which effective therapeutic options are very limited. PMID- 26763105 TI - Preservation of cochlear structures and hearing when using the Nucleus Slim Straight (CI422) electrode in children. AB - OBJECTIVE: In cochlear implantation, there are two crucial factors promoting hearing preservation: an atraumatic surgical approach and selection of an electrode that does not damage cochlear structures. This study aimed to evaluate hearing preservation in children implanted with the Nucleus Slim Straight (CI422) electrode. METHODS: Nineteen children aged 6-18 years, with partial deafness, were implanted using the 6-step Skarzynski procedure. Electrode insertion depth was 20-25 mm. Hearing status was assessed with pure tone audiometry before surgery, and at 1, 5, 9, 12 and 24 months after surgery. Electrode placement was confirmed with computed tomography. RESULTS: Mean hearing preservation in the study group at activation of the cochlear implant was 73 per cent (standard deviation = 37 per cent). After 24 months, it was 67 per cent (standard deviation = 45 per cent). On a categorical scale, hearing preservation was possible in 100 per cent of cases. CONCLUSION: Hearing preservation in children implanted with the Nucleus CI422 slim, straight electrode is possible even with 25 mm insertion depth, although the recommended insertion depth is 20 mm. A round window approach using a soft, straight electrode is most conducive to hearing preservation. PMID- 26763106 TI - The pharmacokinetics of intravenous fenoldopam in healthy, awake cats. AB - Fenoldopam is a selective dopamine-1 receptor agonist that improves diuresis by increasing renal blood flow and perfusion and causing peripheral vasodilation. Fenoldopam has been shown to induce diuresis and be well-tolerated in healthy cats. It is used clinically in cats with oliguric kidney injury at doses extrapolated from human medicine and canine studies. The pharmacokinetics in healthy beagle dogs has been reported; however, pharmacokinetic data in cats are lacking. The goal of this study was to determine pharmacokinetic data for healthy, awake cats receiving an infusion of fenoldopam. Six healthy, awake, client-owned cats aged 2-6 years old received a 120-min constant rate infusion of fenoldopam at 0.8 MUg/kg/min followed by a 20-min washout period. Ascorbate stabilized plasma samples were collected during and after the infusion for the measurement of fenoldopam concentration by HPLC with mass spectrometry detection. This study showed that the geometric mean of the volume of distribution, clearance, and half-life (198 mL/kg, 46 mL/kg/min, and 3.0 mins) is similar to pharmacokinetic parameters for humans. No adverse events were noted. Fenoldopam at a constant rate infusion of 0.8 MUg/kg per min was well tolerated in healthy cats. Based on the results, further evaluation of fenoldopam in cats with kidney disease is recommended. PMID- 26763107 TI - A ladder network modelling the electrochemical impedance of the diffusion and reaction processes in semi-infinite space. AB - The Gerischer impedance, i.e., the diffusion-reaction impedance of an ionic species in semi-infinite space, has been modelled by means of a novel simple equivalent ladder electric circuit constituted by a finite number of resistors and capacitors, which corresponds to the Cauer structure obtained from development into continued fractions. The Nyquist plots of the impedance of the ladder network or Cauer circuit and the deviation with respect to the Gerischer impedance have been originally analysed as a function of the number of circuit elements. From the Cauer equivalent circuit, a new and simple expression modelling the Gerischer impedance at the limit of the lowest frequencies has been derived. PMID- 26763109 TI - Psychotic disorder associated with 22q11.2 duplication syndrome. PMID- 26763108 TI - Structural and functional characterization of a small chitin-active lytic polysaccharide monooxygenase domain of a multi-modular chitinase from Jonesia denitrificans. AB - Lytic polysaccharide monooxygenases (LPMOs) boost enzymatic depolymerization of recalcitrant polysaccharides, such as chitin and cellulose. We have studied a chitin-active LPMO domain (JdLPMO10A) that is considerably smaller (15.5 kDa) than all structurally characterized LPMOs so far and that is part of a modular protein containing a GH18 chitinase. The 1.55 A resolution structure revealed deletions of interacting loops that protrude from the core beta-sandwich scaffold in larger LPMO10s. Despite these deletions, the enzyme is active on alpha- and beta-chitin, and the chitin-binding surface previously described for larger LPMOs is fully conserved. JdLPMO10A may represent a minimal scaffold needed to catalyse the powerful LPMO reaction. PMID- 26763110 TI - Personality traits in the differentiation of major depressive disorder and bipolar disorder during a depressive episode. AB - The aim of this study was to determine the differences in personality traits between individuals with Major Depressive Disorder (MDD) and Bipolar Disorder (BD) during a depressive episode, when it can be hard to differentiate them. Data on personality traits (NEO-FFI), mental disorders (Mini International Neuropsychiatric Interview Plus) and socioeconomic variables were collected from 245 respondents who were in a depressive episode. Individuals with MDD (183) and BD (62) diagnosis were compared concerning personality traits, clinical aspects and socioeconomic variables through bivariate analyses (chi-square and ANOVA) and multivariate analysis (logistic regression). There were no differences in the prevalence of the disorders between socioeconomic and clinical variables. As for the personality traits, only the difference in Agreeableness was statistically significant. Considering the control of suicide risk, gender and anxiety comorbidity in the multivariate analysis, the only variable that remained associated was Agreeableness, with an increase in MDD cases. The brief version of the NEO inventories (NEO-FFI) does not allow for the analysis of personality facets. During a depressive episode, high levels of Agreeableness can indicate that MDD is a more likely diagnosis than BD. PMID- 26763111 TI - Near-IR image-guided laser ablation of demineralization on tooth occlusal surfaces. AB - INTRODUCTION: Studies have shown that reflectance images at near-IR wavelengths coincident with higher water absorption are well-suited for image-guided laser ablation of carious lesions since the contrast between sound and demineralized enamel is extremely high and interference from stains is minimized. The objective of this study was to demonstrate that near-IR reflectance images taken at a wavelength range of 1,500-1,700 nm can be used to guide a 9.3 MUm CO(2) laser for the selective ablation of early demineralization on tooth occlusal surfaces. METHODS: The occlusal surfaces of ten sound human molars were used in this in vitro study. Shallow simulated caries lesions with random patterns and varying depth and position were produced on tooth occlusal surfaces. Sequential near-IR reflectance images at 1,500-1,700 nm were used to guide the laser for the selective removal of the demineralized enamel. Digital microscopy and polarization sensitive optical coherence tomography (PS-OCT) were used to assess selectivity. RESULTS: Images taken before and after lesion removal suggest that the demineralized areas were removed with high selectivity. Although the estimated volume of tissue ablated was typically higher than the initial lesion volume measured with PS-OCT, the volume of enamel removed by the laser correlated well with the initial lesion volume. CONCLUSION: Sequential near-IR reflectance images at 1,500-1,700 nm can be used to guide a 9.3 MUm CO(2) laser for the selective ablation of early demineralization on tooth occlusal surfaces. PMID- 26763112 TI - Serum, milk, and tissue monensin concentrations in cattle with adequate and potentially toxic dietary levels of monensin: pharmacokinetics and diagnostic interpretation. AB - Used in both beef cattle and dairy cows, monensin can provide many health benefits but can, when unintended overexposures occur, result in adverse effects. Information on serum and tissue concentrations following overexposure and/or overt toxicosis which may aid in diagnostics and clinical outcome is lacking. The aim of this study was to determine concentrations of monensin in biological specimens following oral exposure for 10 days to an approved dose (1 mg/kg) and a higher dose (5 mg/kg) of monensin given daily on a body weight basis to 10 dairy cows. No deaths were reported; cows receiving 5 mg/kg showed early signs of toxicosis including depression, decreased feed intake, and diarrhea after 4 days of exposure. Histopathological findings were minimal in most cows. Pharmacokinetic modeling of the detected serum concentrations for the 1 and 5 mg/kg dose groups determined the Cmax , Tmax, and t1/2lambda to be 0.87 and 1.68 ng/mL, 2.0 and 1.0 h, and 1.76 and 2.32 days, respectively. Mixed regression models showed that the dose level and days since last dose were significantly associated with monensin concentrations in all four tissues, and with cardiac troponin levels. The high dose resulted in a significant elevation of monensin in tissues at approximately 4.7 times compared to the monensin concentrations in the tissues of animals from the low-dose group. The cTnI concentrations in the high dose group were 2.1 times that of cTnI in the low-dose group. Thus, the ability to diagnose monensin overexposure and/or toxicosis will improve from knowledge of biological monensin concentrations from this study. PMID- 26763113 TI - Solution growth of Ta-doped hematite nanorods for efficient photoelectrochemical water splitting: a tradeoff between electronic structure and nanostructure evolution. AB - Ta-doped hematite (alpha-Fe2O3) nanorod array films were successfully prepared on fluorine-doped tin dioxide (FTO) coated glass substrates via a facile solution growth process with TaCl5 as a Ta doping precursor. Under 1 sun illumination and at an applied potential of 1.0 V vs. Ag/AgCl, the Ta-doped alpha-Fe2O3 photoanode with optimized dopant concentration showed a photocurrent density as high as 0.53 mA cm(-2), which was about 3.5 times higher than that of the undoped sample. As demonstrated by Mott-Schottky and X-ray absorption spectroscopy measurements, considerable increase in photoelectrochemical (PEC) performance achieved for Ta doped alpha-Fe2O3 nanorod films should be mainly attributed to the increased electron donor density induced by Ta doping. However, with superfluous Ta doping, the [110]-oriented nanorod structure was destroyed, which caused greatly restrained photoinduced holes transferring to the surface and retarded surface water oxidation reaction, leading to decreased PEC water splitting activity. This study clearly demonstrated that doping could be effective to enhance the PEC activity of alpha-Fe2O3 nanorods as photoanodes, while it is of great necessity to balance the trade-off between the electronic structure and nanostructure evolution by optimizing the dopant concentration, for increased donor density and meanwhile with the nanorod nanostructure well preserved for directed charge transfer. PMID- 26763114 TI - Plant alpha-glucan phosphatases SEX4 and LSF2 display different affinity for amylopectin and amylose. AB - The plant glucan phosphatases Starch EXcess 4 (SEX4) and Like Sex Four2 (LSF2) apply different starch binding mechanisms. SEX4 contains a carbohydrate binding module, and LSF2 has two surface binding sites (SBSs). We determined KDapp for amylopectin and amylose, and KD for beta-cyclodextrin and validated binding site mutants deploying affinity gel electrophoresis (AGE) and surface plasmon resonance. SEX4 has a higher affinity for amylopectin; LSF2 prefers amylose and beta-cyclodextrin. SEX4 has 50-fold lower KDapp for amylopectin compared to LSF2. Molecular dynamics simulations and AGE data both support long-distance mutual effects of binding at SBSs and the active site in LSF2. PMID- 26763115 TI - Milk production, quality, and consumption in Jimma (Ethiopia): Facts and producers', retailers', and consumers' perspectives. AB - Four studies were performed to quantify milk production, quality and consumption in the town Jimma, Ethiopia. First, 47 dairy farmers and 44 milk retailers were interviewed to gain more insights in dairy farming and marketing, and associated constraints. Second, bulk milk samples (n=188) were collected for 4 consecutive weeks to investigate milk quality [Total Bacterial Counts (TBC), Coliform Counts (CC), Somatic Cell Counts (SCC), and antimicrobial residues]. Third, (bulk) milk samples from 32 farms, 46 milk retailers and the 3 local milk collection centers were collected to determine the presence of oxacillin susceptible-and oxacillin resistant Staphylococcus aureus. Fourth, 208 adult inhabitants were interviewed to gain more insight in milk consumption and associated concerns of consumers. The average dairy farm included in the studies consisted of 5 lactating cows, produced 43 liters of milk per day and was owned by male, literate adults. Milk was sold to retailers (71% of the production) and directly to customers (25%) without any quality control, whereas 4% was self-consumed. Shortage of animal nutrition and adulteration of the milk were the main constraints for farmers and retailers, respectively. The median TBC, CC and SCC were 122,500CFU/mL, 1,005CFU/mL and 609,500cells/mL, respectively. Antimicrobial residues were detected in 20% of all samples. In general, the milk quality was considered to be poor (TBC>10,000CFU/mL, and/or CC>100CFU/mL, and/or SCC>400,000cells/mL and/or presence of antimicrobial residues) in 97% of all samples. S. aureus was isolated from 12 (38%), 13 (33%), and 2 out of 3 of the milk samples originating from the dairy farms, the milk retailers, and the milk collection centers, respectively. Seven (26%) of the isolates were resistant to oxacillin suggesting the presence of MRSA (Lee, 2003). Local milk is occasionally consumed by adults but more frequently by children. Adults mainly drink spontaneously fermented milk (57% of 105 interviewees consuming local milk) whereas most milk for children is boiled (86% of 110 households with children consuming local milk). Most consumers are concerned about adulteration and milk borne diseases but not about antimicrobial residues. Educated consumers (secondary school or higher) were more likely to boil milk for own consumption, to be concerned about antimicrobial residues in milk, to be concerned about milk borne diseases and to be willing to pay more for milk with proven good quality compared to poorly educated consumers. We conclude that milk quality incentives should be introduced in Jimma, and investments should be made in knowledge transfer, training, milk collection systems and a central milk quality lab. PMID- 26763117 TI - Pharmacokinetics of guaifenesin following administration of multiple doses to exercised Thoroughbred horses. AB - Guaifenesin is an expectorant commonly used in performance horses to aid in the clearance of mucus from the airways. Guaifenesin is also a centrally acting skeletal muscle relaxant and as such is a prohibited drug with withdrawal necessary prior to competition. To the authors' knowledge, there are no reports in the literature describing single or multiple oral administrations of guaifenesin in the horse to determine a regulatory threshold and related withdrawal time. Therefore, the objective of the current study was to describe the pharmacokinetics of guaifenesin following oral administration in order to provide data upon which appropriate regulatory recommendations can be established. Nine exercised Thoroughbred horses were administered 2 g of guaifenesin orally BID for a total of five doses. Blood samples were collected immediately prior to drug administration and at various times postadministration. Serum guaifenesin concentrations were determined and pharmacokinetic parameters calculated. Guaifenesin was rapidly absorbed (Tmax of 15 min) following oral administration. The Cmax was 681.3 +/- 323.8 ng/mL and 1080 +/- 732.8 following the first and last dose, respectively. The serum elimination half-life was 2.62 +/- 1.24 h. Average serum guaifenesin concentrations remained above the LOQ of the assay (0.5 ng/mL) by 48 h postadministration of the final dose in 3 of 9 horses. PMID- 26763120 TI - Association of defects in doped non-stoichiometric ceria from first principles. AB - We investigate the interaction and distribution of defects in doped non stoichometric ceria Ce1-xRExO2-x/2-delta (with RE = Lu, Y, Gd, Sm, Nd, and La) by combining DFT+U calculations and Monte Carlo simulations. The concentrated solution of defects in ceria is described by the pair interactions of dopant ions, oxygen vacancies, and small polarons. The calculated interaction energies for polarons and oxygen vacancies are in agreement with experimental results and previously reported calculations. Simulations reveal that in thermodynamic equilibrium the configurational energy decreases with increasing non stoichiometry as well as increasing dopant fraction similar to the observed behavior of the enthalpy of reduction in experiments. This effect is attributed to the attractive interaction of oxygen vacancies with polarons and dopant ions. PMID- 26763118 TI - Structural basis for the endoribonuclease activity of the type III-A CRISPR associated protein Csm6. AB - Prokaryotic CRISPR-Cas systems provide an RNA-guided mechanism for genome defense against mobile genetic elements such as viruses and plasmids. In type III-A CRISPR-Cas systems, the RNA-guided multisubunit Csm effector complex targets both single-stranded RNAs and double-stranded DNAs. In addition to the Csm complex, efficient anti-plasmid immunity mediated by type III-A systems also requires the CRISPR-associated protein Csm6. Here we report the crystal structure of Csm6 from Thermus thermophilus and show that the protein is a ssRNA-specific endoribonuclease. The structure reveals a dimeric architecture generated by interactions involving the N-terminal CARF and C-terminal HEPN domains. HEPN domain dimerization leads to the formation of a composite ribonuclease active site. Consistently, mutations of invariant active site residues impair catalytic activity in vitro. We further show that the ribonuclease activity of Csm6 is conserved across orthologs, suggesting that it plays an important functional role in CRISPR-Cas systems. The dimer interface of the CARF domains features a conserved electropositive pocket that may function as a ligand-binding site for allosteric control of ribonuclease activity. Altogether, our work suggests that Csm6 proteins provide an auxiliary RNA-targeting interference mechanism in type III-A CRISPR-Cas systems that operates in conjunction with the RNA- and DNA targeting endonuclease activities of the Csm effector complex. PMID- 26763119 TI - Recruitment of the 4EHP-GYF2 cap-binding complex to tetraproline motifs of tristetraprolin promotes repression and degradation of mRNAs with AU-rich elements. AB - The zinc finger protein tristetraprolin (TTP) promotes translation repression and degradation of mRNAs containing AU-rich elements (AREs). Although much attention has been directed toward understanding the decay process and machinery involved, the translation repression role of TTP has remained poorly understood. Here we identify the cap-binding translation repression 4EHP-GYF2 complex as a cofactor of TTP. Immunoprecipitation and in vitro pull-down assays demonstrate that TTP associates with the 4EHP-GYF2 complex via direct interaction with GYF2, and mutational analyses show that this interaction occurs via conserved tetraproline motifs of TTP. Mutant TTP with diminished 4EHP-GYF2 binding is impaired in its ability to repress a luciferase reporter ARE-mRNA. 4EHP knockout mouse embryonic fibroblasts (MEFs) display increased induction and slower turnover of TTP-target mRNAs as compared to wild-type MEFs. Our work highlights the function of the conserved tetraproline motifs of TTP and identifies 4EHP-GYF2 as a cofactor in translational repression and mRNA decay by TTP. PMID- 26763122 TI - Cylindromatosis--A Protective Molecule against Liver Diseases. AB - Cylindromatosis (CYLD) is a deubiquitination enzyme involved in the regulation of different cellular processes including inflammation, fibrosis, and cancer. The function of CYLD is via deubiquitination of specific substrates in different signaling pathways including NF-kappaB, Notch, and JNK. CYLD contributes to hepatic homeostasis and restoration upon liver injury. Mutation or disruption of the activity of CYLD in animals aggravates acute as well as chronic liver injury and promotes development and progression of hepatocellular cancer. This is mediated by a shift of the balance toward pro-inflammatory, pro-fibrogenic, and pro-oncogenic pathways. In this review, we will explain the liver-associated signaling pathways that CYLD regulates in hepatocytes and nonparenchymal liver cells under physiological and pathological conditions. We will also describe the most recent findings concerning CYLD-mediated downstream signaling in the liver in situations such as injury, infection, inflammation, and cancer. Furthermore, we will discuss the potential of novel diagnostic tools and treatment strategies utilizing CYLD and its target genes. PMID- 26763116 TI - Multiplexed neurochemical signaling by neurons of the ventral tegmental area. AB - The ventral tegmental area (VTA) is an evolutionarily conserved structure that has roles in reward-seeking, safety-seeking, learning, motivation, and neuropsychiatric disorders such as addiction and depression. The involvement of the VTA in these various behaviors and disorders is paralleled by its diverse signaling mechanisms. Here we review recent advances in our understanding of neuronal diversity in the VTA with a focus on cell phenotypes that participate in 'multiplexed' neurotransmission involving distinct signaling mechanisms. First, we describe the cellular diversity within the VTA, including neurons capable of transmitting dopamine, glutamate or GABA as well as neurons capable of multiplexing combinations of these neurotransmitters. Next, we describe the complex synaptic architecture used by VTA neurons in order to accommodate the transmission of multiple transmitters. We specifically cover recent findings showing that VTA multiplexed neurotransmission may be mediated by either the segregation of dopamine and glutamate into distinct microdomains within a single axon or by the integration of glutamate and GABA into a single axon terminal. In addition, we discuss our current understanding of the functional role that these multiplexed signaling pathways have in the lateral habenula and the nucleus accumbens. Finally, we consider the putative roles of VTA multiplexed neurotransmission in synaptic plasticity and discuss how changes in VTA multiplexed neurons may relate to various psychopathologies including drug addiction and depression. PMID- 26763121 TI - The linker between LOV2-Jalpha and STK plays an essential role in the kinase activation by blue light in Arabidopsis phototropin1, a plant blue light receptor. AB - Phototropin (phot), a blue light receptor in plants, is composed of several domains: LOV1, LOV2, and a serine/threonine kinase (STK). LOV2 is the main regulator of light activation of STK. However, the detailed mechanism remains unclear. In this report, we focused on the linker region between LOV2 and STK excluding the Jalpha-helix. Spectroscopy and a kinase assay for the substituents in the linker region of Arabidopsis phot1 LOV2-STK indicated that the linker is involved in the activation of STK. A putative module in the middle of the linker would be critical for intramolecular signaling and/or regulation of STK. PMID- 26763123 TI - The long-term impacts of Medicaid exposure in early childhood: Evidence from the program's origin. AB - This paper examines the long-term impact of exposure to Medicaid in early childhood on adult health and economic status. The staggered timing of Medicaid's adoption across the states created meaningful variation in cumulative exposure to Medicaid for birth cohorts that are now in adulthood. Analyses of the Panel Study of Income Dynamics suggest exposure to Medicaid in early childhood (age 0-5) is associated with statistically significant and meaningful improvements in adult health (age 25-54), and this effect is only seen in subgroups targeted by the program. Results for economic outcomes are imprecise and we are unable to come to definitive conclusions. Using separate data we find evidence of two mechanisms that could plausibly link Medicaid's introduction to long-term outcomes: contemporaneous increases in health services utilization for children and reductions in family medical debt. PMID- 26763124 TI - Pharmacokinetics and tissue residues of moroxydine hydrochloride in gibel carp, Carassius gibelio after oral administration. AB - The pharmacokinetics and tissue residues of moroxydine hydrochloride were studied in gibel carp at water temperature of 15 and 25 degrees C. Samples (blood, skin, muscle, liver, and kidney) were collected over 10 days after the treatment and analyzed by high-performance liquid chromatography with an ultraviolet detector. The results indicated that the influence of water temperature on the metabolism of the drug was significant. The plasma concentration-time data of moroxydine hydrochloride conformed to single-compartment open model at the two water temperatures. There were higher absorption rate (t1/2ka ) and longer elimination half-lives (t1/2ke ) at 15 degrees C (4.29 and 15.87 h, respectively) compared with those at 25 degrees C (3.02 and 4.22 h, respectively). The maximum plasma concentration (Cmax ) and the time-point of maximum plasma concentration (Tp ) were 2.98 MUg/mL and 10.35 h at 15 degrees C and 3.12 MUg/mL and 4.03 h at 25 degrees C, respectively. The distribution volume (Vd /F) of moroxydine hydrochloride was estimated to be 4.55 L/kg at 15 degrees C and 2.89 L/kg at 25 degrees C. The total body clearance (CLb ) of moroxydine hydrochloride was determined to be 0.25 and 0.49 L/(h.kg) at 15 degrees C and 25 degrees C, respectively; the areas under the concentration-time curve were 75.89 MUg.h/mL at 15 degrees C and 42.33 MUg.h/mL at 25 degrees C. The depletion of moroxydine hydrochloride in gibel carp was slower with a longer half-life period, especially at lower water temperature that was tested. PMID- 26763125 TI - Does the intravenous administration of frusemide reduce endolymphatic hydrops? AB - OBJECTIVE: To verify the hypothesis that intravenous frusemide reduces endolymphatic hydrops, as evaluated by three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging following intratympanic gadolinium administration. METHODS: The study comprised 12 patients (7 females and 5 males, aged 19-74 years) with Meniere's disease. Disease duration ranged from 0.5 to 8 years, with a frequency of 0.5 to 6 vertigo spells per month, as calculated in the last 6 months. Three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging was performed 24 hours after intratympanic injection of gadobutrol diluted eight-fold. Frusemide 20 mg was given intravenously immediately after imaging. Magnetic resonance imaging was repeated after 1 hour, using the same parameters and sequence. RESULTS: All patients showed enhancement defects, indicating endolymphatic hydrops of variable degrees. No modifications occurred at the second magnetic resonance imaging performed 1 hour after frusemide administration. CONCLUSION: There was no evidence of endolymphatic hydrops modification 1 hour after intravenously administered frusemide. Therefore, loop diuretics in Meniere's disease, which are today used on an empirical basis, must be reconsidered. Implications of these outcomes are discussed and related to the role of endolymphatic hydrops in the development of Meniere's disease. PMID- 26763126 TI - Ultrafast carrier dynamics of carbon nanodots in different pH environments. AB - Ultrafast carrier relaxation dynamics in fluorescent carbon nanodots is investigated by femtosecond transient absorption spectra at different pH environments so as to understand the mechanism of fluorescence for the first time. Utilizing multi-wavelength global analysis to fit the measured signal via a sequential model, four different relaxation channels are found, which are attributed to electron-electron scattering and surface state trapping, optical phonon scattering, acoustic phonon scattering and electron-hole recombination respectively. The results reveal that the surface states are mainly composed of different oxygen-containing functional groups (epoxy, carbonyl and carboxyl) and carbon atoms on the edge of the carbon backbone and can effectively trap a large number of photo-excited electrons. The deprotonation of carboxyl groups at high pH will change the distribution of pi electron cloud density between the carbon backbone and surface states and consequently, compared with the excited electrons in the acidic and neutral environments, those in the alkaline environment can be more easily trapped by the surface within 1 ps, thereby giving rise to stronger fluorescence emission. PMID- 26763128 TI - Response of the hepatic transcriptome to aflatoxin B1 in ducklings. AB - This study was conducted to determine the effects of aflatoxin B1 (AFB1) on the hepatic transcriptome in ducklings through RNA-sequencing (RNA-Seq). Twenty four, 1-day-old ducklings were divided into 4 treatment groups. Each group received an oral dose of AFB1 at 0, 10, 20, 40 MUg/kg BW per day for 2 weeks. Administration of 20 and 40 MUg/kg BW of AFB1 significantly decreased body weight, feed intake, serum total protein and albumin, while increasing serum aspartate aminotransferase and alanine aminotransferase activities, and hepatic histopathological lesions. Furthermore, RNA was extracted from the liver of ducklings administrated 0 and 40 MUg/kg BW of AFB1. Two RNA-Seq libraries were created from pooled samples and produced over 149 M reads, totaling 14.9 Gb of sequence. Approximately 96,953 predicted transcripts were assembled, 749 of which had significant differential expressions (>= 2-fold) between the control and AFB1 treatment. GO and KEGG pathway analysis results showed that many genes involved in phase I metabolism, phase II detoxification, oxidation-reduction process, carcinogenesis, apoptosis and cell cycle, and fatty acid metabolism were affected by AFB1 exposure. Conclusion, this study determined the hepatic transcriptome responded to AFB1 exposure, and provide candidate genes can be targeted to prevent and/or reduce aflatoxicosis in ducklings. PMID- 26763129 TI - Biological and Bioelectrochemical Recovery of Critical and Scarce Metals. AB - Metal-bearing solid and liquid wastes are increasingly considered as secondary sources of critical and scarce metals. Undoubtedly, microorganisms are a cost effective resource for extracting and concentrating diffuse elements from secondary sources. Microbial biotechnology for extracting base metals from ores and treatment of metal-laden wastewaters has already been applied at full scale. By contrast, microbe-metal interactions in the recovery of scarce metals and a few critical metals have received attention, whereas the recovery of many others has been barely explored. Therefore, this article explores and details the potential application of microbial biotechnologies in the recovery of critical and scarce metals. In the past decade bioelectrochemical systems have emerged as a new technology platform for metal recovery coupled to the removal of organic matter. PMID- 26763127 TI - Transducin-like enhancer of split-1 is expressed and functional in human macrophages. AB - Macrophages display heterogeneous phenotypes, including the classical M1 proinflammatory and the alternative M2 anti-inflammatory polarization states. The transducin-like enhancer of split-1 (TLE1) is a transcriptional corepressor whose functions in macrophages have not been studied yet. We report that TLE1 is highly expressed in human alternative macrophages in vitro and in atherosclerotic plaques as well as in adipose tissue M1/M2 mixed macrophages. TLE1 silencing in alternative macrophages decreases the expression of the M2 markers IL-1Ra and IL 10, while it exacerbates TNFalpha and CCL3 induction by lipopolysaccharide. Hence, TLE1 is expressed in human macrophages where it has potential anti inflammatory and alternative phenotype promoting properties. PMID- 26763131 TI - Prediction of the residue levels of drugs in eggs, using physicochemical properties and their influence on passive diffusion processes. AB - Based on a physiologically based pharmacokinetic model, describing the relationship between the plasma concentration of a drug and its deposition into eggs, general transport constants into yolk and albumen were derived, for a number of compounds, using experimental data from literature. Using only generally accepted concepts in passive diffusion theory, these transport constants were used to derive and calibrate general equations, describing the transport into yolk and albumen, in terms of the physicochemical properties of a drug. It is shown that, in theory, it is possible to calculate/predict the transport constants, using the physicochemical parameters: pKa and plasma protein binding. For a number of sulfonamides, the model was used to predict their distribution between egg yolk and albumen; the outcome was compared to data found in literature. Within this dataset, the lipophilic nature of a drug does not seem to play a major role in explaining the distribution ratio of a drug between albumen and yolk. PMID- 26763133 TI - Temperature-resolved optical spectroscopy of pentacene polymorphs: variation of herringbone angles in single-crystals and interface-controlled thin films. AB - The polarization-resolved absorption spectra are determined for different pentacene polymorphs, both, for thin films grown on ZnO as well as for free standing single crystals. A clear interrelation between the Davydov splitting of the lowest-energy singlet-exciton type transitions and the herringbone angle of the molecules in the unit cell is found. The variation in oscillator strength of the individual excitonic Davydov components with temperature is explained by a variation of this herringbone angle. The extraordinarily strong variation of the herringbone angle for Campbell phase pentacene films grown on ZnO substrates is attributed to interface-mediated strain due to the different thermal expansion coefficients of the organic and inorganic constituents. PMID- 26763130 TI - Fructose and glucose combined with free fatty acids induce metabolic disorders in HepG2 cell: A new model to study the impacts of high-fructose/sucrose and high fat diets in vitro. AB - SCOPE: This work investigated the underlying mechanism of high-fructose/sucrose and high-fat diets, which rapidly induce metabolic syndrome in vivo, via a new cell model. METHODS AND RESULTS: Glucose and/or fructose were used to induce the human hepatoma cell (HepG2) in the presence of palmitic acid, oleic acid, or combined fatty acids (CFA) for 24 h. The alterations in lipid and uric acid production, glucose metabolism, oxidative status, and related genes and proteins were monitored. The cell model that featured metabolic disorders was established by treatment of 10 mM glucose and 15 mM fructose plus 1 mM CFA. Results showed that palmitic acid mainly induced insulin resistance, oxidative stress, and triglyceride (TG) secretion, whereas oleic acid mainly contributed to intracellular TG. Fructose was mainly responsible for uric acid and cholesterol production. In addition, fructose synergistically elevated the intra- and extracellular TG and extracellular malonaldehyde with glucose and CFA. Regulations of genes and proteins associated with carbohydrate metabolism and lipogenesis partially explained the action of fructose in inducing the metabolic disorders in cell. CONCLUSION: The combination of glucose, fructose, and CFA could successfully induce metabolic disorders in HepG2 cells, including dyslipidemia, insulin resistance, hyperuricemia, and oxidative stress. PMID- 26763132 TI - The potential application of a biomarker approach for the investigation of low calorie sweetener exposure. AB - Low-calorie sweeteners (LCS) are commonly used as sugar substitutes in the diet to provide a desired sweet taste without increased energy intake. The number of LCS available on the market has increased considerably over the years and despite extensive evaluation of their safety prior to approval, debate continues around the effects of consumption on health. In Europe, Member States are obligated to monitor exposure to LCS and methods currently used tend to rely on self-reported dietary intake data alongside LCS concentrations in products. However, the acquisition of accurate data can be costly in terms of resources and time and are inherently imprecise. Although LCS are intensely sweet, they are chemically diverse and a limitation of many studies investigating the health effects of consumption is that they often fail to discern intakes of individual LCS. An approach which objectively assesses intakes of individual LCS would therefore allow robust investigations of their possible effects on health. Biomarker approaches have been utilised for the objective investigation of intakes of a range of dietary components and the feasibility of any such approach depends upon its validity as well as its applicability within the target population. This review aims to provide an overview of current understanding of LCS intake and explore the possibility of implementing a biomarker approach to enhance such understanding. Several commonly used LCS, once absorbed into the body, are excreted via the kidneys; therefore a urinary biomarker approach may be possible for the investigation of short-term exposure to these compounds. PMID- 26763134 TI - Regulation of Bax/mitochondria interaction by AKT. AB - Bax-dependent mitochondrial permeabilization during apoptosis is controlled by multiple factors, including the phosphorylation by the protein kinase AKT. We used the heterologous co-expression of human Bax and AKT1 in yeast to investigate how the kinase modulates the different steps underlying Bax activation. We found that AKT activated Bax and increased its cellular content. Both effects were dependent on Ser184, but a phosphorylation of this residue did not fully explain the effects of AKT. Additional experiments with mutants substituted on Ser184 suggested that the regulation of Bax dynamic equilibrium between the cytosol and mitochondria might be more tightly regulated by Bcl-xL when Bax is phosphorylated. PMID- 26763135 TI - Older (but not younger) preschoolers understand that knowledge differs between people and across time. AB - We examined 3- to 5-year-olds' understanding of general knowledge (e.g., knowing that clocks tell time) by investigating whether (1) they recognize that their own general knowledge has changed over time (i.e., they knew less as babies than they know now), and (2) such intraindividual knowledge differences are easier/harder to understand than interindividual differences (i.e., Do preschoolers understand that a baby knows less than they do?). Forty-eight 3- to 5-year-olds answered questions about their current general knowledge ('self-now'), the general knowledge of a 6-month-old ('baby-now'), and their own general knowledge at 6 months ('self-past'). All age groups were significantly above chance on the self now questions, but only 5-year-olds were significantly above chance on the self past and baby-now questions. Moreover, children's performance on the baby-now and self-past questions did not differ. Our findings suggest that younger preschoolers do not fully appreciate that their past knowledge differs from their current knowledge, and that others may have less knowledge than they do. We situate these findings within the research on knowledge understanding, more specifically, and cognitive development, more broadly. PMID- 26763137 TI - Letter to the Co-Editors-in-Chief, Radiotherapy and Oncology. PMID- 26763136 TI - Significance of histologic tumor grade in rectal cancer treated with preoperative chemoradiotherapy followed by curative surgery: A multi-institutional retrospective study. AB - BACKGROUND AND PURPOSE: To evaluate the pre-treatment clinical factors affecting recurrence and survival in rectal cancer patients who receive preoperative chemoradiotherapy (CRT) and curative surgery. METHODS AND MATERIALS: The clinical data of 1782 patients from 8 institutions in Korea were analyzed. The potential prognostic factors that could be acquired before radical surgery were patient age, gender, clinical T and N stages, tumor size and location, tumor grade, carcinoembryonic antigen (CEA) level, and the concurrent chemotherapy regimen. The relapse-free survival (RFS), overall survival (OS), and cumulative incidence of locoregional and distant recurrence were analyzed according to the clinical factors. RESULTS: Among the pre-treatment clinical factors, tumor grade, pre-CRT CEA level, tumor location, and clinical N stage were significant prognostic factors affecting the RFS. The high-grade tumor was the hazardous factor for RFS on the multivariate analysis [Hazard ratio (HR), 1.83; 95% confidence interval (CI), 1.29-2.58; p=0.001]. The 5-year RFS rate for high-grade tumors was significantly lower than that for low-grade tumors (63.8% vs. 78.8%, p<0.001). The tumor grade was a significant prognostic factor for distant recurrence (HR, 1.83, 95% CI, 1.29-2.58; p<0.001), but not for locoregional recurrence (HR, 1.49, 95% CI, 0.68-3.26; p=0.320) on the multivariate analysis. The 5-year OS rate for high-grade tumors was significantly lower than that for low-grade tumors (70.6% vs. 85.5%, p<0.001). CONCLUSION: The tumor grade is the significant pre-treatment clinical factor for recurrence and survival in rectal cancer patients who receive preoperative CRT and curative surgery. PMID- 26763138 TI - A Transparent Antipeep Piezoelectric Nanogenerator to Harvest Tapping Energy on Screen. AB - Aligning PbZr(0.52)Ti(0.48)O3 (PZT) nanowires in polydimethylsiloxane introduces dielectrophoresis, improving the electromechanical properties of nanogenerators, and the light transmittance of composite films. A novel transparent and antipeep piezoelectric nanogenerator is developed that can be used for harvesting the energy from the light tapping of a finger on a cell phone, with an output current of 0.8 nA. PMID- 26763140 TI - The impact of medetomidine on the protein-binding characteristics of MK-467 in canine plasma. AB - This study determined the unbound fraction of the peripheral alpha2 -adrenoceptor antagonist MK-467 alone and combined with medetomidine. MK-467 (0.1, 1 and 10 MUm) was incubated in canine plasma with and without medetomidine (molar ratio 20:1), with human serum albumin (HSA) and with alpha1-acid glycoprotein (AGP). Rapid equilibrium dialysis was used for the measurement of protein binding. All samples were analysed by liquid chromatography and tandem mass spectrometry to obtain the unbound fraction (fu ) of MK-467. Unbound fractions (fu ) of MK-467 in canine plasma (mean +/- standard deviation) were 27.6 +/- 3.5%, 26.6 +/- 0.9% and 42.4 +/- 1.2% at 0.1, 1.0 and 10 MUm concentrations, respectively. In the presence of medetomidine, fu were 27.5 +/- 0.4%, 26.6 +/- 0.9% and 41.0 +/- 2.4%. The fu of MK-467 in HSA were 50.1 +/- 2.5% at 0.1 MUm, 49.4 +/- 1.2% at 1.0 MUm and 56.7 +/- 0.5% at 10 MUm. fu of MK-467 in AGP was 56.3 +/- 3.7% at 0.1 MUm, 54.6 +/- 5.6% at 1.0 MUm and 65.3 +/- 0.4% at 10 MUm. Protein binding of MK-467 was approximately 70% between 0.1 and 1.0 MUm. Medetomidine had no apparent effect on the protein binding of MK-467. PMID- 26763141 TI - Neural correlates of social exchanges during the Prisoner's Dilemma game in depression. AB - BACKGROUND: Depression is a disabling disorder that significantly impacts on the interpersonal functioning of individuals. However, little is known about the neural substrates of such difficulties. In the last few years neuroeconomics, which combines imaging with multiplayer behavioural economic paradigms, has been used to study the neural substrates of normal and abnormal interpersonal interactions. METHOD: This study used functional magnetic resonance imaging to investigate neural activity in unmedicated depressed participants (n = 25) and matched healthy controls (n = 25). During scanning, participants played a behavioural economic game, the Prisoner's Dilemma. In this game, the participant and a co-player independently choose either to cooperate or not cooperate with each other. RESULTS: Depressed participants reported higher levels of negative feelings (betrayal, guilt) during the game than did controls. Neural activation was compared between 'imbalanced' events [when one of the players cooperated and the other defected ('CD' and 'DC')] and 'draw' events [when both players either cooperated or defected ('CC' and 'DD')]. Participants preferentially activated the anterior insula and the dorsolateral prefrontal cortex (DLPFC), a region implicated in cognitive control and regulation of emotions. Importantly, compared to controls depressed participants showed reduced activation in the left DLPFC, with the extent of signal reduction correlating with increased self-report feelings of guilt associated with DC outcomes. CONCLUSIONS: Our findings suggest that depression is associated with reduced activation of the DLPFC during social events that involve unreciprocated cooperation. This abnormality may underlie anomalies in cognitive control and top-down regulation of emotions during challenging social exchanges. PMID- 26763139 TI - Analgesic Effect of the Newly Developed S(+)-Flurbiprofen Plaster on Inflammatory Pain in a Rat Adjuvant-Induced Arthritis Model. AB - Preclinical Research This article describes the properties of a novel topical NSAID (Nonsteroidal anti-inflammatory drug) patch, SFPP (S(+)-flurbiprofen plaster), containing the potent cyclooxygenase (COX) inhibitor, S(+)-flurbiprofen (SFP). The present studies were conducted to confirm human COX inhibition and absorption of SFP and to evaluate the analgesic efficacy of SFPP in a rat adjuvant-induced arthritis (AIA) model. COX inhibition by SFP, ketoprofen and loxoprofen was evaluated using human recombinant COX proteins. Absorption of SFPP, ketoprofen and loxoprofen from patches through rat skin was assessed 24 h after application. The AIA model was induced by injecting Mycobacterium tuberculosis followed 20 days later by the evaluation of the prostaglandin PGE2 content of the inflamed paw and the pain threshold. SFP exhibited more potent inhibitory activity against COX-1 (IC50 = 8.97 nM) and COX-2 (IC50 = 2.94 nM) than the other NSAIDs evaluated. Absorption of SFP was 92.9%, greater than that of ketoprofen and loxoprofen from their respective patches. Application of SFPP decreased PGE2 content from 15 min to 6 h and reduced paw hyperalgesia compared with the control, ketoprofen and loxoprofen patches. SFPP showed analgesic efficacy, and was superior to the ketoprofen and loxoprofen patches, which could be through the potent COX inhibitory activity of SFP and greater skin absorption. The results suggested SFPP can be expected to exert analgesic effect clinically. PMID- 26763142 TI - Unique Cobalt Sulfide/Reduced Graphene Oxide Composite as an Anode for Sodium-Ion Batteries with Superior Rate Capability and Long Cycling Stability. AB - Exploitation of high-performance anode materials is essential but challenging to the development of sodium-ion batteries (SIBs). Among all proposed anode materials for SIBs, sulfides have been proved promising candidates due to their unique chemical and physical properties. In this work, a facile solvothermal method to in situ decorate cobalt sulfide (CoS) nanoplates on reduced graphene oxide (rGO) to build CoS@rGO composite is described. When evaluated as anode for SIBs, an impressive high specific capacity (540 mAh g(-1) at 1 A g(-1) ), excellent rate capability (636 mAh g(-1) at 0.1 A g(-1) and 306 mAh g(-1) at 10 A g(-1)), and extraordinarily cycle stability (420 mAh g(-1) at 1 A g(-1) after 1000 cycles) have been demonstrated by CoS@rGO composite for sodium storage. The synergetic effect between the CoS nanoplates and rGO matrix contributes to the enhanced electrochemical performance of the hybrid composite. The results provide a facile approach to fabricate promising anode materials for high-performance SIBs. PMID- 26763144 TI - Local structure of the metal-organic perovskite dimethylammonium manganese(ii) formate. AB - We report total neutron scattering measurements on the metal-organic perovskite analogue dimethylammonium manganese(ii) formate, (CD3)2ND2[Mn(DCO2)3]. Reverse Monte Carlo modelling shows that, in both the disordered high-temperature and ordered low-temperature phases, the ammonium moiety forms substantially shorter hydrogen bonds (N...O = 2.4 A and 2.6 A) than are visible in the average crystal structures. These bonds result from a pincer-like motion of two adjacent formate ions about the dimethylammonium ion in such a way that the framework can adjust independently to the positions of nearest-neighbour dimethylammonium ions. At low temperatures the shortest hydrogen bond is less favourable, apparently because it involves a greater distortion of the framework. Furthermore, in the high temperature phase, in addition to the three disordered nitrogen positions expected from the average crystal structure, there appear to be also smaller probability maxima between these positions, corresponding to orientations in which the dimethylammonium is hydrogen-bonded to the two oxygen atoms of a single formate ion. The spontaneous strain across the phase transition reveals a contraction of the framework about the dimethylammonium cation, continuing as the material is cooled below the transition temperature. These results provide direct evidence of the local atomic structure of the guest-framework hydrogen bonding, and in particular the distortions of the framework responsible for the phase transition in this system. PMID- 26763145 TI - Effects of MK-467 on the antinociceptive and sedative actions and pharmacokinetics of medetomidine in dogs. AB - We investigated the influence of the peripherally acting alpha2 -adrenoceptor antagonist MK-467 on the sedative and antinociceptive actions and plasma drug concentrations of medetomidine, an alpha2 -adrenoceptor agonist that is used in veterinary medicine as a sedative and analgesic agent. Eight healthy beagle dogs received intravenous medetomidine (10 MUg/kg) or medetomidine with MK-467 (250 MUg/kg) in a randomized crossover design. A standardized nociceptive pressure stimulus was applied to a nail bed of a hindlimb. Times for withdrawal of the limb and for head lift were measured, and sedation was scored. EEG data were collected prior to and after stimulation. Plasma drug concentrations were measured. Co-administration of MK-467 significantly attenuated medetomidine analgesia, as assessed with limb withdrawal, and also shortened the duration of sedation. The apparent plasma clearance of both enantiomers of medetomidine, dexmedetomidine and levomedetomidine, was more than doubled in the presence of MK 467. Antagonism by MK-467 of medetomidine-evoked vasoconstriction is seen as the mechanism behind this pharmacokinetic drug interaction. Thus, MK-467 attenuated the antinociceptive and sedative effects of medetomidine. This can probably be explained by increased clearance and decreased concentrations of dexmedetomidine in plasma after co-administration of MK-467 with racemic medetomidine. PMID- 26763146 TI - Are invertebrates relevant models in ageing research? Focus on the effects of rapamycin on TOR. AB - Ageing is the organisms increased susceptibility to death, which is linked to accumulated damage in the cells and tissues. Ageing is a complex process regulated by crosstalk of various pathways in the cells. Ageing is highly regulated by the Target of Rapamycin (TOR) pathway activity. TOR is an evolutionary conserved key protein kinase in the TOR pathway that regulates growth, proliferation and cell metabolism in response to nutrients, growth factors and stress. Comparing the ageing process in invertebrate model organisms with relatively short lifespan with mammals provides valuable information about the molecular mechanisms underlying the ageing process faster than mammal systems. Inhibition of the TOR pathway activity via either genetic manipulation or rapamycin increases lifespan profoundly in most invertebrate model organisms. This contribution will review the recent findings in invertebrates concerning the TOR pathway and effects of TOR inhibition by rapamycin on lifespan. Besides some contradictory results, the majority points out that rapamycin induces longevity. This suggests that administration of rapamycin in invertebrates is a promising tool for pursuing the scientific puzzle of lifespan prolongation. PMID- 26763143 TI - Intermediate filament dynamics: What we can see now and why it matters. AB - The mechanical properties of vertebrate cells are largely defined by the system of intermediate filaments (IF). As part of a dense network, IF polymers are constantly rearranged and relocalized in the cell to fulfill their duty as cells change shape, migrate, or divide. With the development of new imaging technologies, such as photoconvertible proteins and super-resolution microscopy, a new appreciation for the complexity of IF dynamics has emerged. This review highlights new findings about the transport of IF, the remodeling of filaments by a process of severing and re-annealing, and the subunit exchange that occurs between filament precursors and a soluble pool of IF. We will also discuss the unique dynamic features of the keratin IF network. Finally, we will speculate about how the dynamic properties of IF are related to their functions. PMID- 26763148 TI - High-level expression and characterization of a glycosylated human cementum protein 1 with lectin activity. AB - This work aims to contribute to the knowledge of human cementum protein 1 (CEMP1), its conformational characteristics and influence during the biomineralization process. The results revealed that hrCEMP1 expressed in Pichia pastoris is a 2.4% glycosylated, thermostable protein which possesses a molecular mass of 28,770 Da. The circular dichroism spectrum indicated a secondary structure content of 28.6% of alpha-helix, 9.9% of beta-sheet and 61.5% of random coil forms. Biological activity assays demonstrated that hrCEMP1 nucleates and regulates hydroxyapatite crystal growth. Hereby, it is demonstrated for the first time that CEMP1 has a (C-type) lectin-like activity and specifically recognizes mannopyranoside. The information produced by this biochemical and structural characterization may contribute to understand more fully the biological functions of CEMP1. PMID- 26763149 TI - PATTERNS OF ONSITE MAGNETIC RESONANCE IMAGING EQUIPMENT AMONG ORTHOPEDIC PRACTICES. AB - BACKGROUND: Despite ongoing policy debate, little is known about the growth in orthopedic surgery practices with onsite magnetic resonance imaging (MRI) capacity, or practice characteristics associated with the acquisition of in office MRI equipment. METHODS: In July 2012, American Academy of Orthopaedic Surgeons (AAOS) member practices received a web-based survey requesting general information about their practice, such as number practice providers authorized to order MRIs, the type of onsite MRI capacity present (if any), and the date of acquisition for the MRI equipment. Survey responses were augmented with county level measures of practice area characteristics as of the year of first onsite MRI acquisition (or 2012 for practices without an onsite MRI). RESULTS: The survey obtained usable responses from 740 orthopedic practices, which were geographically representative of AAOS member practices. Forty percent (298) reported onsite MRI capacity. Onsite MRI acquisition occurred at a steady pace over 2000-2012, with no dramatic increase occurring in any particular year over that period. Multivariate logistic regression indicated that practice size (number of providers) was the most important factor affecting the likelihood of onsite MRI acquisition. There was no association between onsite MRI acquisition and any of the county-level practice area characteristics included in the analysis. CONCLUSIONS: Orthopedic practices acquiring onsite MRI equipment on average are much larger than practices without onsite MRI capacity. Larger practices may be more likely to attain the economies of scale necessary to absorb the fixed costs associated with onsite MRI acquisition. PMID- 26763147 TI - Suppressive effects of sirtinol on human cytomegalovirus (hCMV) infection and hCMV-induced activation of molecular mechanisms of senescence and production of reactive oxygen species. AB - Substantial evidence suggests that chronic human cytomegalovirus (hCMV) infection contributes significantly to T-cell immunosenescence and adverse health outcomes in older adults. As such, it is important to search for compounds with anti-hCMV properties. Studies have shown that resveratrol, a sirtuin activator, suppresses hCMV infection. Here we report suppressive effects of sirtinol, a sirtuin antagonist, on hCMV infection and its cellular and molecular consequences. Human diploid fibroblast WI-38 cells were infected by hCMV Towne strain in the absence or presence of sirtinol. hCMV replication was measured using qPCR. Senescent phenotype was determined by senescence-associated beta galactosidase (SA-beta Gal) activity. Expression of hCMV immediate early (IE) and early (E) proteins and senescence-associated proteins (pRb and Rb, p16(INK4), and p53) and production of reactive oxygen species (ROS) were assessed using standard laboratory assays. The results demonstrated that sirtinol suppressed hCMV infection as well as hCMV induced activation of molecular mechanisms of senescence and ROS production. While underlying molecular mechanisms remain to be elucidated, these findings indicate sirtinol as a novel and potent anti-hCMV agent with the potential to be developed as an effective treatment for chronic hCMV infection and its cellular and molecular consequences that are important to ageing and health of older adults. PMID- 26763151 TI - Advances in organometallic synthesis with mechanochemical methods. AB - Solvent-based syntheses have long been normative in all areas of chemistry, although mechanochemical methods (specifically grinding and milling) have been used to good effect for decades in organic, and to a lesser but growing extent, inorganic coordination chemistry. Organometallic synthesis, in contrast, represents a relatively underdeveloped area for mechanochemical research, and the potential benefits are considerable. From access to new classes of unsolvated complexes, to control over stoichiometries that have not been observed in solution routes, mechanochemical (or 'M-chem') approaches have much to offer the synthetic chemist. It has already become clear that removing the solvent from an organometallic reaction can change reaction pathways considerably, so that prediction of the outcome is not always straightforward. This Perspective reviews recent developments in the field, and describes equipment that can be used in organometallic synthesis. Synthetic chemists are encouraged to add mechanochemical methods to their repertoire in the search for new and highly reactive metal complexes and novel types of organometallic transformations. PMID- 26763150 TI - Electrospun Multiscale Structured Membrane for Efficient Water Collection and Directional Transport. AB - Integrating multiscale structural functions in one device is of great significance in water collection. So a multiscale structured membrane is designed to achieve cycle between water directional collection on the micrometer-sized biomimetic beads and directional transport to the intersection of adjacent fibers, which endows the membrane with high efficiency and continuity in water collection. PMID- 26763152 TI - 41 years into the bronchial tree: a very obstructive cap. AB - Inhaled foreign body, which remains unknown from the childhood until the mid-age is extremely rare. We report the case of a 58-year-old man who was addressed to our department to remove a pen cap, inhaled forty-one years earlier. It was discovered during a routine pre-op check-up for bronchiectasis, caused by the long period of retention into the bronchial tree. The successful removal of the cap changed completely the therapeutic strategy, as there was no indication for surgical resection any more. PMID- 26763153 TI - Versatile method for template-free synthesis of single crystalline metal and metal alloy nanowires. AB - Metal and metal alloy nanowires have applications ranging from spintronics to drug delivery, but high quality, high density single crystalline materials have been surprisingly difficult to fabricate. Here we report a versatile, template free, self-assembly method for fabrication of single crystalline metal and metal alloy nanowires (Co, Ni, NiCo, CoFe, and NiFe) by reduction of metal nitride precursors formed in situ by reaction of metal salts with a nitrogen source. Thiol reduction of the metal nitrides to the metallic phase at 550-600 degrees C results in nanowire growth. In this process, sulfur acts as a uniaxial structure directing agent, passivating the surface of the growing nanowires and preventing radial growth. The versatility of the method is demonstrated by achieving nanowire growth from gas-phase, solution-phase or a combination of gas- and solution-phase precursors. The fabrication method is suited to large-area CVD on a wide range of solid substrates. PMID- 26763154 TI - Dual temporal encoding mechanisms in human auditory cortex: Evidence from MEG and EEG. AB - Current hypotheses about language processing advocate an integral relationship between encoding of temporal information and linguistic processing in the brain. All such explanations must accommodate the evident ability of the perceptual system to process both slow and fast time scales in speech. However most cortical neurons are limited in their capability to precisely synchronise to temporal modulations at rates faster than about 50Hz. Hence, a central question in auditory neurophysiology concerns how the full range of perceptually relevant modulation rates might be encoded in the cerebral cortex. Here we show with concurrent noninvasive magnetoencephalography (MEG) and electroencephalography (EEG) measurements that the human auditory cortex transitions between a phase locked (PL) mode of responding to modulation rates below about 50Hz, and a non phase-locked (NPL) mode at higher rates. Precisely such dual response modes are predictable from the behaviours of single neurons in auditory cortices of non human primates. Our data point to a common mechanistic explanation for the single neuron and MEG/EEG results and support the hypothesis that two distinct types of neuronal encoding mechanisms are employed by the auditory cortex to represent a wide range of temporal modulation rates. This dual encoding model allows slow and fast modulations in speech to be processed in parallel and is therefore consistent with theoretical frameworks in which slow temporal modulations (such as rhythm or syllabic structure) are akin to the contours or edges of visual objects, whereas faster modulations (such as periodicity pitch or phonemic structure) are more like visual texture. PMID- 26763155 TI - Two-year-olds but not younger children comprehend it in ambiguous contexts: Evidence from preferential looking. AB - Children use pronouns in their speech from the earliest word combinations. Yet, it is not clear from these early utterances whether they understand that pronouns are used as substitutes for nouns and entities in the discourse. The aim of this study was to examine whether young children understand the anaphoric function of pronouns, focusing on the interpretation of the pronoun it in English-speaking children at 1;6 and 2;0. We tested whether adults and children would prefer to look at a previously introduced vs. novel visual object depending on the argument form (it, the + noun, a + noun , or silence). Results demonstrate that, like adults, two-year-olds understand that it refers to a previously introduced referent. There is no evidence that this knowledge is established in children at 1;6. This suggests that some time between 1;6 and 2;0 children come to understand that it refers to a highly accessible referent introduced in the prior context. PMID- 26763156 TI - Transition-Metal-Doped p-Type ZnO Nanoparticle-Based Sensory Array for Instant Discrimination of Explosive Vapors. AB - The development of portable, real-time, and cheap platforms to monitor ultratrace levels of explosives is of great urgence and importance due to the threat of terrorism attacks and the need for homeland security. However, most of the previous chemiresistor sensors for explosive detection are suffering from limited responses and long response time. Here, a transition-metal-doping method is presented to remarkably promote the quantity of the surface defect states and to significantly reduce the charge transfer distance by creating a local charge reservoir layer. Thus, the sensor response is greatly enhanced and the response time is remarkably shortened. The resulting sensory array can not only detect military explosives, such as, TNT, DNT, PNT, PA, and RDX with high response, but also can fully distinguish some of the improvised explosive vapors, such as AN and urea, due to the huge response reaching to 100%. Furthermore, this sensory array can discriminate ppb-level TNT and ppt-level RDX from structurally similar and high-concentration interfering aromatic gases in less than 12 s. Through comparison with the previously reported chemiresistor or Schottky sensors for explosive detection, the present transition-metal-doping method resulting ZnO sensor stands out and undoubtedly challenges the best. PMID- 26763157 TI - {Ge9[Si(SiMe3)3]2}(2-): a starting point for mixed substituted metalloid germanium clusters. AB - Deeper investigations on the silylation reaction of the Ge9(4-) Zintl anion are provided. The reaction of K4Ge9 with two equivalents of ClHyp (Hyp = Si(SiMe3)3) gives the metalloid cluster compound [Ge9(Hyp)2](2-). Subsequent reactions with this compound give access to the first mixed trisubstituted metalloid cluster [Ge9(Hyp)2(Hyp(Ph3))](-) (Hyp(Ph3) = Si(SiMe3)2(SiPh3)), opening a way to a variety of mixed substituted Ge9 clusters for future investigations. PMID- 26763158 TI - Nasal saline as a placebo in allergic rhinitis. PMID- 26763159 TI - Evidence for the effect of serotonin receptor 1A gene (HTR1A) polymorphism on tractability in Thoroughbred horses. AB - Tractability, or how easily animals can be trained and controlled, is an important behavioural trait for the management and training of domestic animals, but its genetic basis remains unclear. Polymorphisms in the serotonin receptor 1A gene (HTR1A) have been associated with individual variability in anxiety-related traits in several species. In this study, we examined the association between HTR1A polymorphisms and tractability in Thoroughbred horses. We assessed the tractability of 167 one-year-old horses reared at a training centre for racehorses using a questionnaire consisting of 17 items. A principal components analysis of answers contracted the data to five principal component (PC) scores. We genotyped two non-synonymous single nucleotide polymorphisms (SNPs) in the horse HTR1A coding region. We found that one of the two SNPs, c.709G>A, which causes an amino acid change at the intracellular region of the receptor, was significantly associated with scores of four of five PCs in fillies (all Ps < 0.05) and one PC in colts (P < 0.01). Horses carrying an A allele at c.709G>A showed lower tractability. This result provides the first evidence that a polymorphism in a serotonin-related gene may affect tractability in horses with the effect partially different depending on sex. PMID- 26763160 TI - The albinism of the feral Asinara white donkeys (Equus asinus) is determined by a missense mutation in a highly conserved position of the tyrosinase (TYR) gene deduced protein. AB - A feral donkey population (Equus asinus), living in the Asinara National Park (an island north-west of Sardinia, Italy), includes a unique white albino donkey subpopulation or colour morph that is a major attraction of this park. Disrupting mutations in the tyrosinase (TYR) gene are known to cause recessive albinisms in humans (oculocutaneous albinism Type 1; OCA1) and other species. In this study, we analysed the donkey TYR gene as a strong candidate to identify the causative mutation of the albinism of these donkeys. The TYR gene was sequenced from 13 donkeys (seven Asinara white albino and six coloured animals). Seven single nucleotide polymorphisms were identified. A missense mutation (c.604C>G; p.His202Asp) in a highly conserved amino acid position (even across kingdoms), which disrupts the first copper-binding site (CuA) of functional protein, was identified in the homozygous condition (G/G or D/D) in all Asinara white albino donkeys and in the albino son of a trio (the grey parents had genotype C/G or H/D), supporting the recessive mode of inheritance of this mutation. Genotyping 82 donkeys confirmed that Asinara albino donkeys had genotype G/G whereas all other coloured donkeys had genotype C/C or C/G. Across-population association between the c.604C>G genotypes and the albino coat colour was highly significant (P = 6.17E-18). The identification of the causative mutation of the albinism in the Asinara white donkeys might open new perspectives to study the dynamics of this putative deleterious allele in a feral population and to manage this interesting animal genetic resource. PMID- 26763161 TI - Can antimonide-based nanowires form wurtzite crystal structure? AB - The epitaxial growth of antimonide-based nanowires has become an attractive subject due to their interesting properties required for various applications such as long-wavelength IR detectors. The studies conducted on antimonide-based nanowires indicate that they preferentially crystallize in the zinc blende (ZB) crystal structure rather than wurtzite (WZ), which is common in other III-V nanowire materials. Also, with the addition of small amounts of antimony to arsenide- and phosphide-based nanowires grown under conditions otherwise leading to WZ structure, the crystal structure of the resulting ternary nanowires favors the ZB phase. Therefore, the formation of antimonide-based nanowires with the WZ phase presents fundamental challenges and is yet to be explored, but is particularly interesting for understanding the nanowire crystal phase in general. In this study, we examine the formation of Au-seeded InSb and GaSb nanowires under various growth conditions using metalorganic vapor phase epitaxy. We address the possibility of forming other phases than ZB such as WZ and 4H in binary nanowires and demonstrate the controlled formation of WZ InSb nanowires. We further discuss the fundamental aspects of WZ growth in Au-seeded antimonide based nanowires. PMID- 26763163 TI - Cigarette smoking and testosterone in men and women: A systematic review and meta analysis of observational studies. AB - Recently Health Canada and the Food and Drug Administration warned about the cardiovascular risk of testosterone, making environmental drivers of testosterone potential prevention targets. Cotinine, a tobacco metabolite, inhibits testosterone breakdown. We assessed the association of smoking with testosterone in a systematic review and meta-analysis, searching PubMed and Web of Science through March 2015 using ("testosterone" or "androgen" or "sex hormone") and ("smoking" or "cigarette"). Two reviewers independently searched, selected, assessed quality and abstracted with differences resolved by consensus or reference to a third reviewer. The initial search yielded 2881 studies; 28 met the selection criteria. In 22 studies of 13,317 men, mean age 18-61years, smokers had higher mean testosterone than non-smokers (1.53nmol/L, 95% confidence interval (CI) 1.11 to 1.96) using a random effects model with inverse variance weighting. In 6 studies of 6089 women, mean age 28-62years, smoking was not clearly associated with testosterone (0.11nmol/L, 95% CI -0.08 to 0.30). Fixed effects models provided similar results, but suggested a positive association in women. Whether products which raise cotinine, such as e-cigarettes or nicotine replacement, also raise testosterone, should be investigated, to inform any regulatory action for e-cigarettes, which emit nicotine into the surrounding air, with relevance for both active and passive smokers. PMID- 26763162 TI - Sun-induced chlorophyll fluorescence from high-resolution imaging spectroscopy data to quantify spatio-temporal patterns of photosynthetic function in crop canopies. AB - Passive detection of sun-induced chlorophyll fluorescence (SIF) using spectroscopy has been proposed as a proxy to quantify changes in photochemical efficiency at canopy level under natural light conditions. In this study, we explored the use of imaging spectroscopy to quantify spatio-temporal dynamics of SIF within crop canopies and its sensitivity to track patterns of photosynthetic activity originating from the interaction between vegetation structure and incoming radiation as well as variations in plant function. SIF was retrieved using the Fraunhofer Line Depth (FLD) principle from imaging spectroscopy data acquired at different time scales a few metres above several crop canopies growing under natural illumination. We report the first maps of canopy SIF in high spatial resolution. Changes of SIF were monitored at different time scales ranging from quick variations under induced stress conditions to seasonal dynamics. Natural changes were primarily determined by varying levels and distribution of photosynthetic active radiation (PAR). However, this relationship changed throughout the day demonstrating an additional physiological component modulating spatio-temporal patterns of SIF emission. We successfully used detailed SIF maps to track changes in the canopy's photochemical activity under field conditions, providing a new tool to evaluate complex patterns of photosynthesis within the canopy. PMID- 26763164 TI - The impact of Medicare eligibility on cancer screening behaviors. AB - INTRODUCTION: Lack of health insurance limits access to preventive services, including cancer screening. We examined the effects of Medicare eligibility on the appropriate use of cancer screening services in the United States. METHODS: We performed a cross-sectional analysis of the 2012 Behavioral Risk Factor and Surveillance System (analyzed in 2014). Univariable and logistic regression analyses were performed for participants aged 60-64 and 66-70 to examine the effects of Medicare eligibility on prevalence of self-reported screening for colorectal, breast, and prostate cancers. Sub-analyses were performed among low income (<$25,000 annual/household) individuals. RESULTS: Medicare-eligible individuals were significantly more likely to undergo all examined preventive services (colorectal cancer OR: 1.90; 95% CI 1.79-2.04; prostate cancer OR: 1.29; 95% CI 1.17-1.43; breast cancer OR: 1.23; 95% CI 1.10-1.37) and the effect was most pronounced among low-income individuals (colorectal cancer OR: 2.04; 95% CI 1.8-2.32; prostate cancer OR: 1.39; 95% CI 1.12-1.72; breast cancer OR: 1.42, 95% CI 1.20-1.67). Access to a healthcare provider was the strongest independent predictor of undergoing appropriate screening, ranging from OR 2.73 (95% CI 2.20 3.39) for colorectal cancer screening in the low-income population to OR 4.79 (95% CI 3.95-5.81) for breast cancer screening in the overall cohort. The difference in screening prevalence was most pronounced when comparing Medicare eligible participants to uninsured Medicare-ineligible participants (+33.2%). CONCLUSIONS: Medicare eligibility impacts the prevalence of cancer screening, likely as a result of increased access to primary care. Low-income individuals benefit most from Medicare eligibility. Expanded public insurance coverage to these individuals may improve access to preventive services. PMID- 26763167 TI - The Long and Winding Road to Gamma-Amino-Butyric Acid as Neurotransmitter. AB - This review centers on the discoveries made during more than six decades of neuroscience research on the role of gamma-amino-butyric acid (GABA) as neurotransmitter. In doing so, special emphasis is directed to the significant involvement of Canadian scientists in these advances. Starting with the early studies that established GABA as an inhibitory neurotransmitter at central synapses, we summarize the results pointing at the GABA receptor as a drug target as well as more recent evidence showing that GABAA receptor signaling plays a surprisingly active role in neuronal network synchronization, both during development and in the adult brain. Finally, we briefly address the involvement of GABA in neurological conditions that encompass epileptic disorders and mental retardation. PMID- 26763168 TI - Contributions of inner and outer coordination sphere bonding in determining the strength of substituted phenolic pyrazoles as copper extractants. AB - Alkyl-substituted phenolic pyrazoles such as 4-methyl-2-[5-(n-octyl)-1H-pyrazol-3 yl]phenol (L2H) are shown to function as Cu-extractants, having similar strength and selectivity over Fe(iii) to 5-nonylsalicylaldoxime which is a component of the commercially used ACORGA(r) solvent extraction reagents. Substitution in the phenol ring of the new extractants has a major effect on their strength, e.g. 2 nitro-4-methyl-6-[5-(2,4,4-trimethylpentyl)-1H-pyrazol-3-yl]phenol (L4H) which has a nitro group ortho to the phenolic hydroxyl group unit and has an extraction distribution coefficient for Cu nearly three orders of magnitude higher than its unsubstituted analogue 4-methyl-6-[5-(2,4,4-trimethylpentyl)-1H-pyrazol-3 yl]phenol (L8H). X-ray structure determinations and density functional theory (DFT) calculations confirm that inter-ligand hydrogen bonding between the pyrazole NH group and the phenolate oxygen atom stabilise the Cu-complexes, giving pseudomacrocyclic structures. Electron-accepting groups ortho to the phenol oxygen atoms buttress the inter-ligand H-bonding, enhancing extractant strength but the effectiveness of this is very dependent on steric factors. The correlation between the calculated energies of formation of copper complexes in the gas phase and the observed strength of comparably substituted reagents in solvent extraction experiments is remarkable. Analysis of the energies of formation suggests that big differences in strength of extractants arise principally from a combination of the effects of the substituents on the ease of deprotonation of the proligands and, for the ortho-substituted ligands, their propensity to buttress inter-ligand hydrogen bonding. PMID- 26763165 TI - Effect of appreciation for Indigenous cultures and exposure to racial insults on alcohol and drug use initiation among multiethnic Argentinean youth. AB - OBJECTIVES: This study evaluated the effect of factors reflecting appreciation of Indigenous culture and racial insults on alcohol and drug use initiation among multi-ethnic youth in Jujuy, Argentina. METHODS: Students were surveyed from 27 secondary schools that were randomly selected to represent the province. A total of 3040 eligible students in 10th grade, age 14 to 18years were surveyed in 2006 and 2660 of these same students completed surveys in 11th grade in 2007. Multivariate logistic regression models assessed the effect of appreciation for Indigenous cultures and reported exposure to racial insults in 10th grade on incident current alcohol drinking in previous 30days, binge drinking (>=5 drinks at one sitting), and lifetime drug use (marijuana, inhalants or cocaine) in 11th grade among students not reporting these behaviors in 2006. RESULTS: In 2006, 63% of respondents reported high appreciation for Indigenous cultures and 39% had ever experienced racial insults. In 2007, incident current drinking was 24.4%, binge drinking 14.8%, and any drug use initiation was 4.1%. Exposure to racial insults increased the likelihood of binge drinking (OR=1.6; 95% CI 1.2-2.1) but was not significant for any drug use. Appreciation for Indigenous cultures reduced the risk of any drug use initiation (OR=0.5, 95% CI 0.3-0.7) but had no effect for alcohol drinking outcomes. These effects were independent of Indigenous ethnicity. CONCLUSIONS: Enhancing appreciation for Indigenous cultures and decreasing racial insults are achievable goals that can be incorporated into programs to prevent youth substance use. PMID- 26763166 TI - Enhanced and Differential Capture of Circulating Tumor Cells from Lung Cancer Patients by Microfluidic Assays Using Aptamer Cocktail. AB - Collecting circulating tumor cells (CTCs) shed from solid tumor through a minimally invasive approach provides an opportunity to solve a long-standing oncology problem, the real-time monitoring of tumor state and analysis of tumor heterogeneity. However, efficient capture and detection of CTCs with diverse phenotypes is still challenging. In this work, a microfluidic assay is developed using the rationally-designed aptamer cocktails with synergistic effect. Enhanced and differential capture of CTCs for nonsmall cell lung cancer (NSCLC) patients is achieved. It is also demonstrated that the overall consideration of CTC counts obtained by multiple aptamer combinations can provide more comprehensive information in treatment monitoring. PMID- 26763169 TI - Pulmonary Langerhans cell histiocytosis: radiologic resolution following cessation of second hand smoking. AB - We present a 65-year-old male former smoker with past medical history of renal cell carcinoma. Surveillance chest CT scan showed numerous progressive bilateral upper lobe predominant nodular cystic densities. A Video Assisted Thoracoscopic Surgery lung biopsy was diagnostic of Pulmonary Langerhans Cell Histiocytosis. Further questioning of the patient revealed exposure to second hand smoke from his wife. A repeat chest CT scan 6 months following cessation of all smoking exposure showed near complete resolution of the nodular densities. Our case report highlights the importance of early identification of second hand smoke exposure. Timely elimination of the exposure led to near complete radiologic resolution. PMID- 26763170 TI - A transposable element insertion in APOB causes cholesterol deficiency in Holstein cattle. AB - Cholesterol deficiency, a new autosomal recessive inherited genetic defect in Holstein cattle, has been recently reported to have an influence on the rearing success of calves. The affected animals show unresponsive diarrhea accompanied by hypocholesterolemia and usually die within the first weeks or months of life. Here, we show that whole genome sequencing combined with the knowledge about the pedigree and inbreeding status of a livestock population facilitates the identification of the causative mutation. We resequenced the entire genomes of an affected calf and a healthy partially inbred male carrying one copy of the critical 2.24-Mb chromosome 11 segment in its ancestral state and one copy of the same segment with the cholesterol deficiency mutation. We detected a single structural variant, homozygous in the affected case and heterozygous in the non affected carrier male. The genetic makeup of this key animal provides extremely strong support for the causality of this mutation. The mutation represents a 1.3kb insertion of a transposable LTR element (ERV2-1) in the coding sequence of the APOB gene, which leads to truncated transcripts and aberrant splicing. This finding was further supported by RNA sequencing of the liver transcriptome of an affected calf. The encoded apolipoprotein B is an essential apolipoprotein on chylomicrons and low-density lipoproteins, and therefore, the mutation represents a loss of function mutation similar to autosomal recessive inherited familial hypobetalipoproteinemia-1 (FHBL1) in humans. Our findings provide a direct gene test to improve selection against this deleterious mutation in Holstein cattle. PMID- 26763171 TI - Interaction between hormonal and mitochondrial signalling during growth, development and in plant defence responses. AB - Mitochondria play a central role in plant metabolism as they are a major source of ATP through synthesis by the oxidative phosphorylation pathway and harbour key metabolic reactions such as the TCA cycle. The energy and building blocks produced by mitochondria are essential to drive plant growth and development as well as to provide fuel for responses to abiotic and biotic stresses. The majority of mitochondrial proteins are encoded in the nuclear genome and have to be imported into the organelle. For the regulation of the corresponding genes intricate signalling pathways exist to adjust their expression. Signals directly regulate nuclear gene expression (anterograde signalling) to adjust the protein composition of the mitochondria to the needs of the cell. In parallel, mitochondria communicate back their functional status to the nucleus (retrograde signalling) to prompt transcriptional regulation of responsive genes via largely unknown signalling mechanisms. Plant hormones are the major signalling components regulating all layers of plant development and cellular functions. Increasing evidence is now becoming available that plant hormones are also part of signalling networks controlling mitochondrial function and their biogenesis. This review summarizes recent advances in understanding the interaction of mitochondrial and hormonal signalling pathways. PMID- 26763172 TI - The effect of range of motion exercises on delirium prevention among patients aged 65 and over in intensive care units. AB - The purpose of this study was to determine the effect of range of motion exercises on preventing delirium and shortening the duration of delirium among patients in the intensive care unit who are aged 65 and over. The study was conducted in the intensive care unit on patients with non-invasive mechanical ventilation. The sample size included 47 patients from the intervention group and 47 from the control group. The incidence of delirium was 8.5% in the intervention group and 21.3% in the control group. The duration of delirium was 15 h for patients in the intervention group and 38 h for those in the control group. Although delirium incidence and duration decreased by 2.5-fold in the intervention group compared to the control group; there was no significant relationship between the intervention and control groups. In conclusion, as the decreases in delirium occurrence and duration were not statistically significant, the effect of range of motion exercises was limited. PMID- 26763173 TI - Experimental verification of nanofluid shear-wave reconversion in ultrasonic fields. AB - Here we present the verification of shear-mediated contributions to multiple scattering of ultrasound in suspensions. Acoustic spectroscopy was carried out with suspensions of silica of differing particle sizes and concentrations in water to find the attenuation at a broad range of frequencies. As the particle sizes approach the nanoscale, commonly used multiple scattering models fail to match experimental results. We develop a new model, taking into account shear mediated contributions, and find excellent agreement with the attenuation spectra obtained using two types of spectrometer. The results determine that shear-wave phenomena must be considered in ultrasound characterisation of nanofluids at even relatively low concentrations of scatterers that are smaller than one micrometre in diameter. PMID- 26763174 TI - Structural influence of graft and block polycations on the adsorption of BSA. AB - Protein adsorption is considered as an important factor for the low transfection efficiency of polycations in vivo. In this study, two typical polycations of equal molecular weight with different structures were chosen to investigate their adsorption on bovine serum albumin (BSA), including the block copolymer named poly (N-vinylpyrrolidone)-b-poly (2-dimethylaminoethyl methacrylate) (PVP-b PDMAEMA, i.e. PbP) and graft copolymer named PVP-g-PDMAEMA (PgP), respectively. Fluorescence spectroscopy was used to confirm the binding constants and binding sites between polycations and BSA in static state. The binding constants were 4.1*10(4)M(-1) vs 8.3*10(4)M(-1) and binding sites were 0.3 vs 1.1 for PbP and PgP, respectively, indicating PgP had stronger binding affinity with BSA. Surface plasmon resonance (SPR) was used to study the dynamical non-specific interaction between BSA and polycations as well as the polyplexes. The numbers of both PbP and PgP adsorbed on BSA increased with concentration of polycations increasing, and the number of PgP adsorbed on BSA is higher compared with PbP when their concentration is low. When their concentration is high, the number of PbP adsorbed on BSA is more than that of PgP. However, PgP/DNA polyplexes showed higher adsorption amount compared with PbP/DNA polyplexes at different N/P ratios. PMID- 26763175 TI - The immunological activity of Lycium barbarum polysaccharides liposome in vitro and adjuvanticity against PCV2 in vivo. AB - In previous researches, the results showed that Lycium barbarum polysaccharides (LBP) encapsulated with liposome could enhance the immune activity of LBP. Therefore, the present study was designed to investigate the effects of LBPL on spleen lymphocytes and macrophages of mice in vitro and evaluate the immunological adjuvant activity of PCV2 vaccine in vivo. The results showed that LBPL could significantly promote splenocyte proliferation synergistically with PHA or LPS, increase the ratio of CD4(+) to CD8(+) T cells and promote the cytokine secretion of macrophages; enhance PCV2-specific IgG antibody responses, promote Th1 cytokines (IFN-gamma and TNF-a) and Th2 cytokine (IL-4) secretion. The histomorphological observation of spleen demonstrated that LBPL as a vaccine adjuvant also has good improvement and stimulating effect on the immune organ. PMID- 26763176 TI - Toxicology and immunology of Ganoderma lucidum polysaccharides in Kunming mice and Wistar rats. AB - In the present work, the toxicology and immunology of polysaccharides from fruiting body of Ganoderma lucidum (GPs) were investigated. No abnormal clinical symptoms or deaths and no significant difference in body weight and food in taking rate were found in Wistar rats during the 30-day feeding administration. No significant differences were found in each hematology value, clinical chemistry value and organ/body weight ratio, either. It had no mutagenicity due to the negative experimental results of Ames test, micronucleus test of polychromatic erythrocyte, sperm abnormality test, and chromosome aberration test in Kunming mice, respectively. The immune experiments indicated that high-dose GPs had immune effects in increasing the degree of toe swelling and enhancing the primary immune response to SRBC (P<0.01). But no-significant influence of GPs on the phagocytic function of mononuclear macrophages (MPhi) could be obtained. PMID- 26763177 TI - NADP+ binding effects tryptophan accessibility, folding and stability of recombinant B. malayi G6PD. AB - Brugia malayi Glucose 6-phosphate dehydrogenase apoenzyme (BmG6PD) was expressed and purified by affinity chromatography to study the differences in kinetic properties of enzyme and the effect of the cofactor NADP(+) binding on enzyme stability. The presence of cofactor NADP(+) influenced the tertiary structure of enzyme due to significant differences in the tryptophan microenvironment. However, NADP(+) binding have no effect on secondary structure of the enzyme. Quenching with acrylamide indicated that two or more tryptophan residues became accessible upon cofactor binding. Unfolding and cross linking study of BmG6PD showed that NADP(+) stabilized the protein in presence of high concentration of urea/GdmCl. A homology model of BmG6PD constructed using human G6PD (PDB id: 2BH9) as a template indicated 34% alpha-helix, 19% beta-sheet and 47% random coil conformations in the predicted model of the enzyme. In the predicted model binding of NADP(+) to BmG6PD was less tight with the structural sites (-10.96 kJ/mol binding score) as compared with the coenzyme site (-15.47 kJ/mol binding score). PMID- 26763178 TI - Inorganic UV-Visible-SWIR Broadband Photodetector Based on Monodisperse PbS Nanocrystals. AB - Solution-processed inorganic UV-visible short-wave-infrared photodetectors with light sensitivity from 350 nm to 2000 nm are fabricated using highly monodispersed large PbS NCs. These devices showed detectivity values over 1 * 10(11) Jones from 350 nm to 2000 nm, and a maximum detectivity value of 1.2 * 10(12) Jones at 1800 nm. PMID- 26763179 TI - Evaluation of Manual and Automated Bloodstream Infection Surveillance in Outpatient Dialysis Centers. AB - Outpatient hemodialysis bloodstream infection rates, now used for performance measurement and were significantly higher for manual compared with automated surveillance (P<.001), largely owing to the absence of blood culture data in the dialysis electronic health record. Improvement in data sharing between hospitals and outpatient dialysis centers is necessary. PMID- 26763181 TI - Oxidase-like mimic of Ag@Ag3PO4 microcubes as a smart probe for ultrasensitive and selective Hg(2+) detection. AB - An oxidase-like mimic system based on facilely synthesized Ag@Ag3PO4 microcubes (Ag@Ag3PO4MCs) was designed and utilized to detect mercury ions with high selectivity and ultrasensitivity. Ag@Ag3PO4MCs with an average size of ca. 1.6 MUm were synthesized by the reaction of [Ag(NH3)2](+) complex and Na2HPO4 and subsequent photoreduction under ultraviolet light. The as-prepared Ag@Ag3PO4MCs can effectively catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) and o-phenylenediamine (OPD) in the presence of dissolved oxygen in slightly acidic solution, exhibiting oxidase-like activities rather than peroxidase-like activity. Interestingly, the introduction of Ag nanoparticles (AgNPs) on the surfaces of Ag3PO4MCs can dramatically enhance the oxidase-like activities due to a synergistic effect between AgNPs and Ag3PO4MCs, as evidenced by the faster oxidation speed of TMB and OPD than that of native Ag3PO4MCs in the presence of dissolved oxygen. The enzyme kinetics can be well-explained by the Michaelis Menten equation. As "poisoning" inhibitor, Hg(2+) ions can inhibit the enzyme reaction catalyzed by Ag3PO4MCs or Ag@Ag3PO4MCs. On the basis of this effect, a colorimetric Hg(2+) sensor was developed by the enzyme inhibition reaction of Ag3PO4MCs or Ag@Ag3PO4MCs. The excellent specific interaction of Hg-Ag or Hg(2+) Ag(+) provides high selectivity for Hg(2+) over interfering metal ions. Meanwhile, the sensitivity of this sensor to Hg(2+) is extremely excellent with a limit of detection as low as 0.253 nM for Ag@Ag3PO4MCs. Considering the advantages of low detection limit, low cost, facile preparation, and visualization, the colorimetric Ag@Ag3PO4MCs sensor shows high promise for the testing of Hg(2+) in water samples. PMID- 26763180 TI - Long time enzyme replacement therapy stabilizes obstructive lung disease and alters peripheral immune cell subsets in Fabry patients. AB - BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder, causing accumulation of globotriaosylceramid in different organs. Glycolipids are activators of different immune cell subsets the resulting inflammation is responsible for organ damage. Pulmonary involvement leads to airway inflammation; however, data on severity, as well as the effect of enzyme replacement therapy on lung function parameters and changes in peripheral immune cell subsets on lung involvement are sparse. METHODS: Seven Fabry patients and four carriers underwent detailed clinical examinations screening for pulmonary manifestations. Repetitive measurements were performed on five patients on ERT (average follow-up 5 years). Patients with Fabry disease and control volunteers were included into peripheral blood cell measurements. RESULTS: Lung involvement was present in all patients. Symptoms suggestive for lung disease were mild, however, obstructive ventilatory disorder, dominantly affecting small airways accompanied by hyperinflation was demonstrated in all affected patients. ERT resulted in small improvement of FEV1 in most treated patients. Decreased ratio of myeloid DC, Th17 cells while increase in T helper (Th)1 cells, and no change in Th2 and regulatory T (Treg) cells were detected in Fabry patients. CONCLUSIONS: Fabry disease results mainly in mild symptoms related to lung involvement, characterized by moderate non reversible obstructive ventilatory disorder. Stabilization of airway obstruction during follow-up was observed using ERT in most patients, emphasizing the importance of this treatment in respect of pulmonary manifestations. Changes of immune cell subsets in the peripheral blood might play a role in inflammatory process, including small airways in Fabry patient's lung. PMID- 26763184 TI - Antihyperalgesic Activity of Rhodiola rosea in a Diabetic Rat Model. AB - Preclinical Research Rhodiola rosea L. (Crassulaceae) is used for enhancing physical and mental performance. Recent studies demonstrated that R. rosea had anti-inflammatory activity in animal models, for example, carrageenan- and nystatin-induced edema in rats, possibly by inhibiting phospholipase A2 and cyclooxygenases-1 and -2. In addition, R. rosea had antinociceptive activity in thermal and chemical pain tests as well as mechanical hyperalgesia. The purpose of the present study was to assess the antihyperalgesic effect of an ethanol extract of Rhodiola rosea (R. rosea) in a diabetic rat model. Rats were administered a single dose of streptozotocin (STZ; 50 mg/kg, i.p.) and hyperalgesia was evaluated four weeks later. Formalin-evoked (0.5%) flinching was increased in diabetic rats compared with nondiabetic controls Systemic (1-100 mg/kg, i.p.) and local (0.1-10 mg/paw into the dorsal surface of the right hind paw) administration of R. rosea ethanol extract dose-dependently reduced formalin induced hyperalgesia in diabetic rats. The antihyperalgesic effect of R. rosea was compared with gabapentin. These results suggest that R. rosea ethanol extract may have potential as a treatment for diabetic hyperalgesia. PMID- 26763185 TI - Synthesis and catalytic properties of highly branched palladium nanostructures using seeded growth. AB - In order to develop nanocatalysts with enhanced catalytic performance, it is important to be able to synthesize nanocrystals enclosed by high-index surface facets, due to their high density of low coordinated atoms at step, ledge and kink sites. Here, we report a facile seed-mediated route to the synthesis of highly branched Pd nanostructures with a combination of {113}, {115} and {220} high-index surface planes. The size of these nanostructures is readily controlled by a simple manipulation of the seed concentration. The selective use of oleylamine and oleic acid was also found to be critical to the synthesis of these structures, with Pd icosahedra enclosed by low-index {111} facets being produced when hexadecylamine was employed as capping ligand. The structure-property relationship of these nanostructures as catalysts in Suzuki-cross coupling reactions was then investigated and compared, with the high-index faceted branched Pd nanostructures found to be the most effective catalysts. PMID- 26763187 TI - Plant Polyphenol-Assisted Green Synthesis of Hollow CoPt Alloy Nanoparticles for Dual-Modality Imaging Guided Photothermal Therapy. AB - Theranostic nanomedicines that integrate diagnostic and therapeutic moieties into a single nanoscale platform are playing an increasingly important role in fighting cancer. Here, a facile and green synthetic strategy for hollow CoPt alloy nanoparticles (HCPA-NPs) using plant polyphenols as assisted agents is reported for the first time. This novel strategy enables size-controlled synthesis of HCPA-NPs through the control of the molecular sizes of polyphenols. It is also a versatile strategy for synthesizing other hollow alloy nanoparticles with various metal compositions due to the diverse metal-chelating ability of the polyphenols. Further studies show that HCPA-NPs have good biocompatibility and can be successfully implemented for magnetic resonance and photoacoustic dual modal imaging guided photothermal therapy. This work brings new insights for the green synthesis of hollow nanoparticles and extends these biocompatible nanoparticles for theranostic applications. PMID- 26763186 TI - Risk factors for Group B Streptococcus colonisation and disease in Gambian women and their infants. AB - OBJECTIVES: To determine risk factors for GBS colonisation in Gambian mothers and in their infants from birth to day 60-89 of age. METHODS: Swabs and breastmilk from mothers/infant pairs were collected and cultured on selective agar. Negative samples were analysed for GBS DNA via real-time PCR. Positive isolates were serotyped using multiplex PCR and gel-agarose electrophoresis. RESULTS: Seven hundred and fifty women/infant pairs were recruited. 253 women (33.7%) were GBS colonised at delivery. The predominant serotypes were: V (55%), II (16%), III (10%), Ia (8%) and Ib (8%). 186 infants were colonised (24.8%) at birth, 181 (24.1%) at 6 days and 96 at day 60-89 (14%). Infants born before 34 weeks of gestation and to women with rectovaginal and breastmilk colonisation at delivery had increased odds of GBS colonisation at birth. Season of birth was associated with increased odds of persistent infant GBS colonisation (dry season vs. wet season AOR 2.9; 95% CI 1.6-5.2). CONCLUSION: GBS colonisation is common in Gambian women at delivery and in their infants to day 60-89 and is dominated by serotype V. In addition to maternal colonisation, breastmilk and season of birth are important risk factors for infant GBS colonisation. PMID- 26763189 TI - Documented Transmission of Extended-Spectrum Beta-Lactamase-Producing Klebsiella pneumoniae From Patient to Gastroscope. PMID- 26763188 TI - A novel method for sensitive determination of subclinical right ventricular systolic dysfunction in patients with obstructive sleep apnea. AB - OBJECTIVE: The aim of this study was to evaluate right ventricular (RV) regional systolic function and dyssynchrony in patients with newly diagnosed obstructive sleep apnea using real-time three-dimensional (3D) echocardiography. METHODS: Eighty-two subjects without hypertension, diabetes mellitus or any cardiac or pulmonary disease referred for evaluation of obstructive sleep apnea (OSA) had overnight polysomnography and complete echocardiographic assessment. According to the apnea hypopnea index (AHI), subjects were divided into four groups: group 1: control subjects (AHI < 5, n = 19), group 2: patients with mild OSA (AHI: 5-14, n = 21), group 3: moderate OSA (AHI: 15-30, n = 18), group 4: severe OSA (AHI > 30, n = 24). Real-time three-dimensional echocardiographic images were acquired to obtain RV regional (inflow, body and outflow) ejection fraction (EF) and time to minimum systolic volume in all subjects. RESULTS: Body weight and body mass index were greater in the severe and moderate OSA group than those of mild and controls group (P < 0.05). There was a significant decrease in mean SaO2 and the lowest SaO2 in severe OSA when compared to other groups (P < 0.001). Inflow EF and global EF were significantly lower in moderate and severe OSA patients than in controls (P < 0.05). Inflow EF and global EF were negatively correlated with AHI (r = -0.534 and r = -0.479, respectively, P < 0.001). CONCLUSIONS: In patients with OSA, RV inflow and global systolic function were impaired and were in inverse relationship with AHI. Evaluation of RV regional systolic function using real-time three-dimensional echocardiography may play a potential role in the noninvasive assessment of the severity of OSA. PMID- 26763190 TI - Computational insights into the photophysical and electroluminescence properties of homoleptic fac-Ir(C^N)3 complexes employing different phenyl-derivative featuring phenylimidazole-based ligands for promising phosphors in OLEDs. AB - The electronic structures and photophysical properties of three homoleptic iridium(iii) complexes IrL3 with C^N ligands, including 2a (L = 1-(2,6 diisopropylphenyl)-2-phenyl-1H-imidazole), 5a (L = 1-(2,6-dimethylphenyl)-2 phenyl-1H-imidazole), and 6a (L = 1-(3,5-diisopropylbiphenyl-4-yl)-2-phenyl-1H imidazole), are investigated by means of the density functional method. Furthermore, seven new complexes are theoretically designed, including 1a (L = 1,2-diphenyl-1H-imidazole), 3a (L = 1-(2,6-dimethoxyphenyl)-2-phenyl-1H imidazol), 4a (L = 2-(2-phenyl-1H-imidazol-1-yl)isophthalaldehyde), 1b (L = 2 (biphenyl-3-yl)-1H-imidazole), 2b (L = 2-(2',6'-diisopropylbiphenyl-3-yl)-1H imidazole), 3b (L = 2-(2',6'-dimethoxybiphenyl-3-yl)-1H-imidazole), and 4b (L = 3'-(1H-imidazol-2-yl)biphenyl-2,6-dicarbaldehyde), to explore the influence of different substituents and different substituted positions on the electronic structures, phosphorescence properties, and organic light-emitting diode (OLED) performance. The HOMO-LUMO energy gap is greatly decreased by introduction of the -CHO group into the phenyl ring (4a and 4b see -sketched structures for all the investigated Ir(iii) complexes). As a result, their absorption and emission spectra present red-shifting leading them to be potential red-emitting phosphors. Other complexes are all blue-emitting materials, indicating that the effect of the substituted position on the emitting color is negligible. However, the addition of the substituent on the para-position of the phenyl ring in the phenylimidazole ligand would increase the quantum yield and electroluminescence (EL) performance compared with that on the imidazole ring. PMID- 26763192 TI - Fabrication of poly-crystalline Si-based Mie resonators via amorphous Si on SiO2 dewetting. AB - We report the fabrication of Si-based dielectric Mie resonators via a low cost process based on solid-state dewetting of ultra-thin amorphous Si on SiO2. We investigate the dewetting dynamics of a few nanometer sized layers annealed at high temperature to form submicrometric Si-particles. Morphological and structural characterization reveal the polycrystalline nature of the semiconductor matrix as well as rather irregular morphologies of the dewetted islands. Optical dark field imaging and spectroscopy measurements of the single islands reveal pronounced resonant scattering at visible frequencies. The linewidth of the low-order modes can be ~20 nm in full width at half maximum, leading to a quality factor Q exceeding 25. These values reach the state-of-the art ones obtained for monocrystalline Mie resonators. The simplicity of the dewetting process and its cost-effectiveness opens the route to exploiting it over large scales for applications in silicon-based photonics. PMID- 26763191 TI - [Population impact of a podiatric school health programme]. AB - This article presents an overview of the work done over the past 12 years in a collaboration between the school communities at various primary and secondary schools and the practical experience managers working in the Preventive and Community Podiatry area of the Podiatry degree at the University of Seville (Spain). The article presents several strategies, which were carried out in the fields of Foot Health for All and Preventive and Community Podiatry as part of the Hermes Research Group (CTS-601) aimed at promoting general foot health. Foot examinations were conducted in a total of 4,630 school pupils, with foot problems being confirmed in 677 of them. Some 7,145 members of the school community were also helped, with these people being reached through educational activities around foot care. The aim of the initiative was to prevent foot damage among children, which could have a harmful impact on their quality of life as adults. PMID- 26763193 TI - Synthesis of p-O-Alkyl Salicylanilide Derivatives as Novel EGFR Inhibitors. AB - Preclinical Research Epidermal growth factor receptor (EGFR), a validated target for anticancer drugs, plays a critical role in tumorigenesis and tumor development. A series of p-O-alkyl salicylanilide derivatives were designed and synthesized as novel EGFR inhibitors using a salicylic acid scaffold. A simulated six-membered ring strategy formed through intramolecular hydrogen bonds was employed to mimic the planar quinazoline of the EGFR antagonist, gefitinib. The derived compounds with hydroxyl at the ortho position were more potent than ones with methoxyl group. In particular, compounds 5d and 5b displayed significant EGFR inhibitory (IC50 values = 0.30 and 0.45 MUM, respectively) activity as well as potent antiproliferative activity in A431 and HCT-116 tumor cells. These salicylanilides could be considered as promising lead compounds for developing novel EGFR inhibitors. PMID- 26763194 TI - Association between AUTS2 haplotypes and alcohol dependence in a Japanese population. AB - OBJECTIVE: Recent genome-wide analysis has indicated that the autism susceptibility candidate 2 (AUTS2) gene is involved in the regulation of alcohol consumption. We hypothesised that AUTS2 might be associated with the development of alcohol dependence. Therefore, in this exploratory study, we compared the genotype and allele frequencies of the polymorphisms rs6943555 and rs9886351 in the AUTS2 gene between patients with alcohol dependence and healthy control subjects living in a Japanese provincial prefecture. We also examined whether or not the haplotypes consisting of these polymorphisms are related to alcohol dependence. METHODS: The subjects of this study consisted of 64 patients with alcohol dependence and 75 unrelated healthy people. The AUTS2 genotypes were determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. RESULTS: No significant differences in the genotype and allele frequencies of the polymorphisms AUTS2 rs6943555 and rs9886351 were found between alcohol dependence and control subjects. On the other hand, the frequencies of the AUTS2 haplotypes were significantly different between them, and the rs6943555 and rs9886351 A-A haplotype was associated with alcohol dependence (p=0.0187). CONCLUSION: This suggests that the rs6943555 and rs9886351 A-A haplotype might affect the vulnerability to alcohol dependence pathogenesis. Further studies are needed to confirm the reproducibility of the results of this study with increased numbers of subjects. PMID- 26763195 TI - Hospitalisation of multiethnic older patients with AECOPD: exploration of the occurrence of anxiety, depression and factors associated with short-term hospital readmission. AB - INTRODUCTION: The elderly, with chronic obstructive pulmonary disease (COPD), are at a higher risk of hospitalisation due to acute exacerbation of COPD (AECOPD). They also often encounter multiple co-morbidities. OBJECTIVES: This study was aimed to explore the occurrence of anxiety, depression and to identify the factors associated with hospital readmission among older patients after AECOPD discharge. METHODS: A multicentre prospective study was conducted in Malaysia (from 1st September 2012 till 31st September 2013) among older patients (>=60 years) hospitalised for AECOPD. Anxiety and depression were assessed on discharge using previously validated questionnaires, Generalized Anxiety Disorder-7 (GAD-7 and Geriatric Depression Scale (GDS-15), respectively. Patients were followed up for a period of 3 months after discharge. RESULTS: A total of 81 patients with a median age of 72 years (IQR 66.40-78.00) were recruited. Anxiety was observed in 34.57% while 38.27% had depression. Both anxiety and depression were detected in 25.93% of the patients. A history of frequent AECOPD admissions was found to be associated with developing depressive symptoms, while anxiety scores were associated with severe dyspnoea. Severe depression was more commonly identified among patients aged 60-75 and in those with a history of tuberculosis. A high readmission rate (40.74%) during the 3-month period was noticed. History of frequent AECOPD admissions (OR = 2.87; 95% CI 1.05-7.85, P = 0.040) and ischemic heart disease (IHD) (OR = 4.04; 95% CI 1.1-14.6, P = 0.032) were identified as the factors associated with the risk of hospital readmission. CONCLUSIONS: Anxiety and depression were found to be relatively common among older patients with AECOPD. IHD and history of frequent COPD hospitalisation were associated with short-term readmission among the elderly. PMID- 26763199 TI - Tin-catalyzed hydrophosphination of alkenes. AB - Simple tin derivatives, Cp*2SnCl2 (1) and Ph2SnCl2 (2), catalyze the hydrophosphination of alkene substrates with diphenylphosphine. Competitive dehydrocoupling to give Ph4P2 was observed, but this side reaction can be mitigated when the catalysis is conducted under an H2 atmosphere. Efforts to prepare stable tin bis(phosphido) compounds commonly resulted in decomposition to Ph4P2. Lewis acidic inorganic tin compounds do not show dehydrocoupling reactivity. It was found that the Lewis acid, B(C6F5)3, is able to engage in the hydrophosphination of alkenes, but it is poorly effective under the conditions tested. PMID- 26763198 TI - RESCUE-HF Trial: Retrograde Delivery of Allogeneic Umbilical Cord Lining Subepithelial Cells in Patients With Heart Failure. AB - Cell therapy is an evolving option for patients with end-stage heart failure. First-generation cell therapy trials have had marginal success. Our goal was to evaluate retrograde delivery of allogeneic umbilical cord subepithelial cells (UCSECs) in patients with heart failure. A prospective open-label dose escalation study of the safety and feasibility of UCSECs infused retrogradely into the coronary sinus was performed. Patients received a single dose of either 100 million (M), 200M, or 400M cells. The patients were followed for 2 years. Twenty four patients were successfully enrolled in the study. The patients had UCSEC infusion without procedure-related complications. The ejection fraction in patients receiving UCSECs demonstrated improvement compared to baseline; from 25.4% (+/-5.5) at screening to 34.9% (+/-4.1) at 12 months. End-systolic diameter decreased significantly from 59.9 (+/-5.3) mm to 52.6 (+/-2.7) mm (p < 0.05). Retrograde UCSEC delivery was safe and feasible in all three dosage groups. Patients receiving 200M and 400M UCSECs showed signs of early improvement in left ventricular ejection fraction (LVEF) and remodeling. This study provides the basis for a larger clinical trial in heart failure (HF) patients using the middle or high dose of UCSECs. PMID- 26763197 TI - A Nanoplatform with Precise Control over Release of Cargo for Enhanced Cancer Therapy. AB - The development of a nanocarrier delivery system having both sufficient stability in blood circulation and a rapid drug release profile at target sites remains a major challenge in cancer therapy. Here, a multifunctional star-shaped micellar system with a precisely spatiotemporal control of releasing encapsulated agents is developed by mixing a photoinitiated crosslinking amphiphilic copolymer with a phenylboronic acid (PBA)-functionalized redox-sensitive amphiphilic copolymer for the first time. The combination of the functional polymers effectively resolves the contradiction that the micellar system cannot release the rapid drug release in cells when it possesses an extreme stability that is often required in blood circulation. In this system, the inner core polymers are photo-crosslinked, endowing a stable micelle matrix structure; the end groups of the hydrophilic segments are decorated with PBA ligands, providing an active targeting ability; disulfide bonds in the micellar matrix impart a redox-responsive trigger for the prompt intracellular release of drugs. As a result, with a relatively low DOX dosage (2 mg kg(-1) per injection) the in vivo antitumor effect on H22-bearing BALB/c mice shows that the micelles have a high therapeutic efficacy against solid tumors while minimal side effects against normal tissues. PMID- 26763196 TI - The role of omega-3 polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids in the treatment of major depression and Alzheimer's disease: Acting separately or synergistically? AB - Omega-3 polyunsaturated fatty acids (n-3-PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may improve or prevent some psychiatric and neurodegenerative diseases in both experimental and clinical studies. As important membrane components, these PUFAs benefit brain health by modulating neuroimmune and apoptotic pathways, changing membrane function and/or competing with n-6 PUFAs, the precursors of inflammatory mediators. However, the exact role of each fatty acid in neuroimmune modulation and neurogenesis, the interaction between EPA and DHA, and the best EPA:DHA ratios for improving brain disorders, remain unclear. It is also unknown whether EPA, as a DHA precursor, acts directly or via DHA. Here, we discuss recent evidence of EPA and DHA effects in the treatment of major depression and Alzheimer's disease, as well as their potential synergistic action on anti-inflammatory, antioxidant and neurotrophic processes in the brain. We further analyze the cellular and molecular mechanisms by which EPA, DHA or their combination may benefit these diseases. We also outline the limitations of current studies and suggest new genetic models and novel approaches to overcome these limitations. Finally, we summarize future strategies for translational research in this field. PMID- 26763200 TI - [Early rehospitalization of persons aged 75 years or older admitted to a post emergency general medicine department: Rates and predictive factors]. AB - INTRODUCTION: Given the implications of rehospitalization at the individual and societal level, it seems important to identify elderly persons (EP) at risk. We analyzed the predictive factors of early rehospitalization in EP aged 75 years or more hospitalized in a medicine department. METHODS: A single-center retrospective study that included EP aged 75 years or more hospitalized in a polyvalent medical department following an emergency admission. Patients who died during the hospitalization, who had been transferred or hospitalized during the previous month, were excluded. The impact of sociodemographic, administrative and biomedical data on rehospitalization at one month was analyzed. RESULTS: A total of 319 hospitalizations were collected (mean age of patients: 84.7+/-5.7 years). Most lived at home (80.2%) and among these 8.4% had no home help. The rehospitalization rate was 16.3%, among which 2/3 were related to the reason for the initial hospitalization. Among the predictive factors found in the univariate analysis (male sex, multiple diseases, polypharmacy, multiple hospitalizations, cognitive disorders and calls to emergency services), only the presence of at least two previous hospitalizations in the year (odds ratio [OR]=2.10; 95% confidence interval [95%CI] [1.01-4.39]; P=0.048) and the presence of confusion without dementia (OR=3.78; IC 95% [1.09-13.06]; P=0.04) were significant. Discharge to a rehabilitation unit and increased support at home did not affect the likelihood of rehospitalization. CONCLUSION: The rehospitalization of EP is frequent and difficult to anticipate because there are few predictors and their impact is weak. The most important factors were medical: multiple hospitalizations and confusion without dementia. PMID- 26763201 TI - Metal-semiconductor-metal transition in zigzag carbon nanoscrolls. AB - Similar to rolling up paper, carbon nanoscrolls (CNSs) can be rolled from graphene nanoribbons (GNRs) using physical approaches. Owing to their peculiar one-dimensional nanostructures, CNSs have attracted great attention over the past few years. In this study, we have investigated the effects of bending deformation on the electronic properties of zigzag CNSs (ZCNSs) during the rolling process from zigzag GNRs (ZGNRs) by means of first-principles calculations. It is found that a metal-semiconductor-metal transition is observed. By analyzing charge density and density of states, the origin of this electronic property transition is discussed. Furthermore, we find that the metal-semiconductor-metal transition in ZCNSs is independent of ribbon width as well as spin-orbit interaction. Our results of the metal-semiconductor-metal transition in the ZCNSs are robust and may open potential applications in nano-electromechanical devices based on the ZCNSs. PMID- 26763202 TI - Factors associated with mouth breathing in children with -developmental disabilities. AB - OBJECTIVE: To investigate the prevalence and factors associated with mouth breathing among patients with developmental disabilities of a dental service. METHODS: We analyzed 408 dental records. Mouth breathing was reported by the patients' parents and from direct observation. Other variables were as -follows: history of asthma, bronchitis, palate shape, pacifier use, thumb -sucking, nail biting, use of medications, gastroesophageal reflux, bruxism, gender, age, and diagnosis of the patient. Statistical analysis included descriptive analysis with ratio calculation and multiple logistic regression. Variables with p < 0.25 were included in the model to estimate the adjusted OR (95% CI), calculated by the forward stepwise method. Variables with p < 0.05 were kept in the model. RESULTS: Being male (p = 0.016) and use of centrally acting drugs (p = 0.001) were the variables that remained in the model. CONCLUSION: Among patients with developmental disabilities, boys and psychotropic drug users had a greater chance of being mouth breathers. PMID- 26763203 TI - Cardiac changes in anorexia nervosa. AB - Introduction Anorexia nervosa is an eating disorder, which is associated with many different medical complications as a result of the weight loss and malnutrition that characterise this illness. It has the highest mortality rate of any psychiatric disorder. A large portion of deaths are attributable to the cardiac abnormalities that ensue as a result of the malnutrition associated with anorexia nervosa. In this review, the cardiac complications of anorexia nervosa will be discussed. METHODS: A comprehensive literature review on cardiac changes in anorexia nervosa was carried out. RESULTS: There are structural, functional, and rhythm-type changes that occur in patients with anorexia nervosa. These become progressively significant as ongoing weight loss occurs. CONCLUSION: Cardiac changes are inherent to anorexia nervosa and they become more life threatening and serious as the anorexia nervosa becomes increasingly severe. Weight restoration and attention to these cardiac changes are crucial for a successful treatment outcome. PMID- 26763204 TI - Effective concentration, recovery, and detection of infectious adenoviruses from environmental waters. AB - Current application of fecal indicator bacteria (FIB) as an indicator of sewage contamination has its limitation and other alternative indicator systems are needed for enhanced monitoring of recreational water quality. To explore the potential use of human enteric viruses (HEV) as a potential indicator, human adenovirus type 7 (HAdV-7) was tested in this study as a model virus. Through spiked HAdV-7 into the sample seawater, different procedures for viral concentration and elution were comparatively analyzed in a side-by-side fashion. Nearly 80% infectious viruses were recovered from the spiked seawater with the use of a magnetic stirring method and 1.0 mM NaOH as elution buffer. A viral plaque assay was established with optimized conditions for the detection and quantification of infectious HAdV and used to determine the stability of HAdV-7 in seawater and a possible correlation for HAdV detection between the viral infectivity assay and PCR. Findings from this study suggest it is possible to concentrate and recover infectious HAdV from environmental waters effectively with optimized laboratory conditions, which warrants the future test and establishment of using HEV as an alternative indicator of water quality. PMID- 26763205 TI - Pasteurella multocida toxin: Targeting mast cell secretory granules during kiss and-run secretion. AB - Pasteurella multocida toxin (PMT), a virulence factor of the pathogenic Gram negative bacterium P. multocida, is a 146 kDa protein belonging to the A-B class of toxins. Once inside a target cell, the A domain deamidates the alpha-subunit of heterotrimeric G-proteins, thereby activating downstream signaling cascades. However, little is known about how PMT selects and enters its cellular targets. We therefore studied PMT binding and uptake in porcine cultured intestinal mucosal explants to identify susceptible cells in the epithelium and underlying lamina propria. In comparison with Vibrio cholera B-subunit, a well-known enterotoxin taken up by receptor-mediated endocytosis, PMT binding to the epithelial brush border was scarce, and no uptake into enterocytes was detected by 2h, implying that none of the glycolipids in the brush border are a functional receptor for PMT. However, in the lamina propria, PMT distinctly accumulated in the secretory granules of mast cells. This also occurred at 4 degrees C, ruling out endocytosis, but suggestive of uptake via pores that connect the granules to the cell surface. Mast cell granules are known to secrete their contents by a "kiss-and-run" mechanism, and we propose that PMT may exploit this secretory mechanism to gain entry into this particular cell type. PMID- 26763206 TI - Modular Graphene-Based 3D Covalent Networks: Functional Architectures for Energy Applications. AB - The development of ordered graphene-based materials combining high stability, large surface areas, ability to act as absorbent of relevant chemical species, and solution processability is of significance for energy applications. A poorly explored approach relies on the controlled nanostructuration of graphene into robust and highly ordered 3D networks as a route to further leverage the exceptional properties of this unique material. Here, a simple yet effective and scalable one-step method is reported to prepare graphene-based 3D covalent networks (G3DCNs) with tunable interlayer distance via controlled polymerization of benzidines with graphene oxide at different reaction temperatures under catalyst- and template-free conditions. The reduced form of G3DCNs is used as electrodes in supercapacitors; it reveals a high specific capacitance of 156 F g( 1) at a current density of 1 A g(-1) in a two-electrode configuration and 460 F g(-1) at a current density of 0.5 A g(-1) in a three-electrode configuration, combined with an excellent cycling stability over 5000 cycles. The present study will promote the quantitative understanding of structure-property relationship, for the controlled fabrication of 3D graphene-based multifunctional materials. PMID- 26763207 TI - EPR detection and characterisation of a paramagnetic Mo(iii) dihydride intermediate involved in electrocatalytic hydrogen evolution. AB - EPR spectroscopy and theoretical data show that the slow heterogeneous electron transfer kinetics associated with the reduction of an 18-electron Mo(IV) acetato dihydride are a consequence of an eta(2)-eta(1) rearrangement of the carboxylate ligand which gives a unique paramagnetic 17-electron Mo(III) dihydride. PMID- 26763208 TI - Creating a journal club competition improves paediatric nurses' participation and engagement. AB - BACKGROUND: To improve journal club participation, innovative approaches are required but few have been described. It was unknown if adding an element of competition, to an established journal club, would increase nurses' participation. OBJECTIVE: To explore the impact on attendance and participation in a hospital-wide nursing journal club through the introduction of an element of competition. DESIGN: A descriptive exploratory study. SETTING AND PARTICIPANTS: An Australian specialist tertiary paediatric hospital with over 1600 nurses. METHODS: In 2013, 12 hospital wards/departments were randomly assigned a month each to present journal club. Nurses were supported to evaluate an article according to a published framework. A predetermined rubric guided marking. Post competition, all hospital nurses received an anonymous online survey invitation. Demographic, Likert scale and qualitative data were collected. Questions elicited attitudes and perceived barriers or facilitators to participation in the journal club. RESULTS: Compared to 2012, there was a statistically significant increase in journal club attendance (2013 median=20.5 [IQR=18.2, 27.7] vs. 2012 median=9 [IQR=6.5, 12.5], Mann-Whitney U test, p<0.01). Full online survey responses were received from 289/1674 (response rate 17.3%) of sent invitations (Non-Attendees n=224, Attendees n=65 (including 18 presenters). Overall, Attendees reported journal club had a positive impact on their professional engagement. Presenters rated the journal club format highly as it developed skills and increased their confidence in journal club presentation. Emergent themes were time and location, engagement, topics and content. CONCLUSION: A competition format can increase nurses' journal club attendance and participation. Further work is required to establish applicability of this format to other settings. PMID- 26763209 TI - Evidence of clinical competence by simulation, a hermeneutical observational study. AB - Making the transition from theory to practise easier in nursing education through simulation is widely implemented all over the world, and there is research evidence of the positive effects of simulation. The pre-understanding for this study is based on a definition of clinical competence as encountering, knowing, performing, maturing and developing, and the hypothesis is that these categories should appear in simulated situations. The aim of the study was to explore the forms and expressions of clinical competence in simulated situations and furthermore to explore if and how clinical competence could be developed by simulation. An observational hermeneutic study with a hypothetic-deductive approach was used in 18 simulated situations with 39 bachelor degree nursing students. In the situations, the scenarios, the actors and the plots were described. The story told was "the way from suffering to health" in which three main plots emerged. The first was, doing as performing and knowing, which took the shape of knowing what to do, acting responsibly, using evidence and equipment, appearing confident and feeling comfortable, and sharing work and information with others. The second was, being as encountering the patient, which took the shape of being there for him/her and confirming by listening and answering. The third plot was becoming as maturing and developing which took the shape of learning in co-operation with other students. All the deductive categories, shapes and expressions appeared as dialectic patterns having their negative counterparts. The study showed that clinical competence can be made evident and developed by simulation and that the challenge is in encountering the patient and his/her suffering. PMID- 26763211 TI - Rational synthesis of Pd nanoparticle-embedded reduced graphene oxide frameworks with enhanced selective catalysis in water. AB - A three-dimensional (3D) Pd-reduced graphene oxide framework (Pd-rGOF) with hierarchical macro- and mesoporous structures has been developed via covalence- and coordination-assisted self-assembly approach. In this facile fabrication process, GO was first cross-linked with triethylene tetramine (TETA) to form 3D GOF, in which well-dispersed and ultrasmall Pd nanoparticles (NPs) in situ grew and embedded the framework. The obtained nanopores, 3D Pd-rGOF, can act as nanoreactors to help the reaction substrates thoroughly contact with the surface of Pd NPs, thereby exhibiting high activity and selectivity toward the Tsuji Trost reaction in water, with 99% conversion and selectivity for most substrates. Moreover, the 3D Pd-rGOF catalyst can be reused more than ten times without significant loss of activity, rendering this catalyst long-term stability. The abovementioned observations make the rGOF a universal platform to coordinate other noble metal ions (NM) to construct desired NM-rGOF nanocatalysts with improved activity, selectivity, and durability that can be used in a broad range of practical applications. PMID- 26763210 TI - Nursing student profiles and occurrence of early academic failure: Findings from an explorative European study. AB - BACKGROUND: In the European context regulated by the Bologna Process principles, there is little evidence to date on the different profiles, if any, of nursing students enrolled in the 1st academic year and their academic outcomes. AIMS: To describe and compare the nursing student profiles and their academic outcomes at the end of the 1st year across European Bachelor of Nursing Science (BNS) courses. DESIGN: An exploratory multicentre cohort study involving five countries: Nursing students who were enrolled in nursing programmes for the academic year 2011/2012 in the participating BNS courses, willing to participate and regularly admitted to the 2nd academic year, were included in this study undertaken in 2013. Individual and faculty level variables were collected after having ensured the validity of the tools developed in English and then appropriately translated into the language of each participating country. FINDINGS: A total of 378/710 (53.2%) students participated in the study. They attended from 390 to 810h of lessons, while clinical experience ranged from 162 to 536h. The students reported a mean average age of 21.4 (Confidence of Interval [CI] 95%, 21.0-22.3) and foreign students were limited in number (on average 3.7%). The students reported adopting mainly individual learning strategies (92.9%), duplicating notes or lecture notes prepared by professors (74.4%), and concentrating their study before exams (74.6%). The majority reported experiencing learning difficulties (49.7%) and a lack of academic support (84.9%). Around 33.2% reported economic difficulties and the need to work while studying nursing on average for 24h/week. Personal expectations regarding the nursing role were different (45.6%) than the role encountered during the 1st year, as learning workloads were higher (57.2%) with regard to expectations. Around one-third of students reported the intention to leave nursing education while the proportion of those reporting early academic failure was on average 5.6%. CONCLUSIONS: More strategies aimed at harmonising nursing education across Europe, at supporting nursing students' learning processes during 1st year, and identifying factors influencing their intention to leave and their academic failure, are recommended. PMID- 26763212 TI - The extinct, giant giraffid Sivatherium giganteum: skeletal reconstruction and body mass estimation. AB - Sivatherium giganteum is an extinct giraffid from the Plio-Pleistocene boundary of the Himalayan foothills. To date, there has been no rigorous skeletal reconstruction of this unusual mammal. Historical and contemporary accounts anecdotally state that Sivatherium rivalled the African elephant in terms of its body mass, but this statement has never been tested. Here, we present a three dimensional composite skeletal reconstruction and calculate a representative body mass estimate for this species using a volumetric method. We find that the estimated adult body mass of 1246 kg (857-1812 kg range) does not approach that of an African elephant, but confirms that Sivatherium was certainly a large giraffid, and may have been the largest ruminant mammal that has ever existed. We contrast this volumetric estimate with a bivariate scaling estimate derived from Sivatherium's humeral circumference and find that there is a discrepancy between the two. The difference implies that the humeral circumference of Sivatherium is greater than expected for an animal of this size, and we speculate this may be linked to a cranial shift in centre of mass. PMID- 26763213 TI - Deep genetic structure and ecological divergence in a widespread human commensal toad. AB - The Asian common toad (Duttaphrynus melanostictus) is a human commensal species that occupies a wide variety of habitats across tropical Southeast Asia. We test the hypothesis that genetic variation in D. melanostictus is weakly associated with geography owing to natural and human-mediated dispersal facilitated by its commensal nature. Phylogenetic and population genetic analyses of mitochondrial and nuclear DNA sequence variation, and predictive species distribution modelling, unexpectedly recovered three distinct evolutionary lineages that differ genetically and ecologically, corresponding to the Asian mainland, coastal Myanmar and the Sundaic islands. The persistence of these three divergent lineages, despite ample opportunities for recent human-mediated and geological dispersal, suggests that D. melanostictus actually consists of multiple species, each having narrower geographical ranges and ecological niches, and higher conservation value, than is currently recognized. These findings also have implications for the invasion potential of this human commensal elsewhere, such as in its recently introduced ranges on the islands of Borneo, Sulawesi, Seram and Madagascar. PMID- 26763214 TI - Female in-nest chatter song increases predation. AB - Female song is an ancestral trait in songbirds, yet extant females generally sing less than males. Here, we examine sex differences in the predation cost of singing behaviour. The superb fairy-wren (Malurus cyaneus) is a Southern Hemisphere songbird; males and females provision the brood and produce solo song year-round. Both sexes had higher song rate during the fertile period and lower song rate during incubation and chick feeding. Females were more likely than males to sing close to or inside the nest. For this reason, female but not male song rate predicted egg and nestling predation. This study identifies a high fitness cost of song when a parent bird attends offspring inside a nest and explains gender differences in singing when there are gender differences in parental care. PMID- 26763215 TI - Different food sources elicit fast changes to bacterial virulence. AB - Environmentally transmitted, opportunistic bacterial pathogens have a life cycle that alternates between hosts and environmental reservoirs. Resources are often scarce and fluctuating in the outside-host environment, whereas overcoming the host immune system could allow pathogens to establish a new, resource abundant and stable niche within the host. We tested if short-term exposure to different outside-host resource types and concentrations affect Serratia marcescens (bacterium)'s virulence in Galleria mellonella (moth). As expected, virulence was mostly dictated by the bacterial dose, but we also found a clear increase in virulence when the bacterium had inhabited a low (versus high) resource concentration, or animal-based (versus plant-based) resources for 48 h prior to injection. The results suggest that temporal changes in pathogen's resource environment can induce very rapid changes in virulence and affect infection severity. Such changes could also play an important role in shifts from environmental lifestyle to pathogenicity or switches in host range and have implications for the management of opportunistic pathogens and disease outbreaks. PMID- 26763216 TI - Framing the debate on human-like framing effects in bonobos and chimpanzees: a comment on Krupenye et al. (2015). PMID- 26763218 TI - What's in a frame? Response to Kanngiesser & Woike (2016). PMID- 26763217 TI - Mitochondrial responses to prolonged anoxia in brain of red-eared slider turtles. AB - Mitochondria are central to aerobic energy production and play a key role in neuronal signalling. During anoxia, however, the mitochondria of most vertebrates initiate deleterious cell death cascades. Nonetheless, a handful of vertebrate species, including some freshwater turtles, are remarkably tolerant of low oxygen environments and survive months of anoxia without apparent damage to brain tissue. This tolerance suggests that mitochondria in the brains of such species are adapted to withstand prolonged anoxia, but little is known about potential neuroprotective responses. In this study, we address such mechanisms by comparing mitochondrial function between brain tissues isolated from cold-acclimated red eared slider turtles (Trachemys scripta elegans) exposed to two weeks of either normoxia or anoxia. We found that brain mitochondria from anoxia-acclimated turtles exhibited a unique phenotype of remodelling relative to normoxic controls, including: (i) decreased citrate synthase and F1FO-ATPase activity but maintained protein content, (ii) markedly reduced aerobic capacity, and (iii) mild uncoupling of the mitochondrial proton gradient. These data suggest that turtle brain mitochondria respond to low oxygen stress with a unique suite of changes tailored towards neuroprotection. PMID- 26763219 TI - Sexual harassment induces a temporary fitness cost but does not constrain the acquisition of environmental information in fruit flies. AB - Across animals, sexual harassment induces fitness costs for females and males. However, little is known about the cognitive costs involved, i.e. whether it constrains learning processes, which could ultimately affect an individual's fitness. Here we evaluate the acquisition of environmental information in groups of fruit flies challenged with various levels of male sexual harassment. We show that, although high sexual harassment induces a temporary fitness cost for females, all fly groups of both sexes exhibit similar levels of learning. This suggests that, in fruit flies, the fitness benefits of acquiring environmental information are not affected by the fitness costs of sexual harassment, and that selection may favour cognition even in unfavourable social contexts. Our study provides novel insights into the relationship between sexual conflicts and cognition and the evolution of female counterstrategies against male sexual harassment. PMID- 26763220 TI - Dogs recognize dog and human emotions. AB - The perception of emotional expressions allows animals to evaluate the social intentions and motivations of each other. This usually takes place within species; however, in the case of domestic dogs, it might be advantageous to recognize the emotions of humans as well as other dogs. In this sense, the combination of visual and auditory cues to categorize others' emotions facilitates the information processing and indicates high-level cognitive representations. Using a cross-modal preferential looking paradigm, we presented dogs with either human or dog faces with different emotional valences (happy/playful versus angry/aggressive) paired with a single vocalization from the same individual with either a positive or negative valence or Brownian noise. Dogs looked significantly longer at the face whose expression was congruent to the valence of vocalization, for both conspecifics and heterospecifics, an ability previously known only in humans. These results demonstrate that dogs can extract and integrate bimodal sensory emotional information, and discriminate between positive and negative emotions from both humans and dogs. PMID- 26763221 TI - Lost at sea: ocean acidification undermines larval fish orientation via altered hearing and marine soundscape modification. AB - The dispersal of larvae and their settlement to suitable habitat is fundamental to the replenishment of marine populations and the communities in which they live. Sound plays an important role in this process because for larvae of various species, it acts as an orientational cue towards suitable settlement habitat. Because marine sounds are largely of biological origin, they not only carry information about the location of potential habitat, but also information about the quality of habitat. While ocean acidification is known to affect a wide range of marine organisms and processes, its effect on marine soundscapes and its reception by navigating oceanic larvae remains unknown. Here, we show that ocean acidification causes a switch in role of present-day soundscapes from attractor to repellent in the auditory preferences in a temperate larval fish. Using natural CO2 vents as analogues of future ocean conditions, we further reveal that ocean acidification can impact marine soundscapes by profoundly diminishing their biological sound production. An altered soundscape poorer in biological cues indirectly penalizes oceanic larvae at settlement stage because both control and CO2-treated fish larvae showed lack of any response to such future soundscapes. These indirect and direct effects of ocean acidification put at risk the complex processes of larval dispersal and settlement. PMID- 26763222 TI - Modeling Importations and Exportations of Infectious Diseases via Travelers. AB - This paper is an attempt to estimate the risk of infection importation and exportation by travelers. Two countries are considered: one disease-free country and one visited or source country with a running endemic or epidemic infectious disease. Two models are considered. In the first model (disease importation), susceptible individuals travel from their disease-free home country to the endemic country and come back after some weeks. The risk of infection spreading in their home country is then estimated supposing the visitors are submitted to the same force of infection as the local population but do not contribute to it. In the second model (disease exportation), it is calculated the probability that an individual from the endemic (or epidemic) country travels to a disease-free country in the condition of latent infected and eventually introduces the infection there. The input of both models is the force of infection at the visited/source country, assumed known. The models are deterministic, but a preliminary stochastic formulation is presented as an appendix. The models are exemplified with two distinct real situations: the risk of dengue importation from Thailand to Europe and the risk of Ebola exportation from Liberia to the USA. PMID- 26763223 TI - The Time Intensity of Childcare Provided by Older Immigrant Women in the United States. AB - Older adults comprise an increasing share of new legal admits to the United States. While many are financially dependent on their families, a more complete picture requires taking into account the nonmonetary contributions of this population. Using the American Time Use Survey, this study examines whether older recent immigrant women provide more unpaid childcare than their native-born and more established immigrant counterparts. Results suggest that while older recent immigrant women are more likely to provide unpaid childcare, this effect is eliminated upon controlling for demographic characteristics. However, among those who do provide childcare, older recent immigrant women provide more hours of care even after controlling for demographic and household characteristics. This pattern holds up even after restricting the analysis to women living with young children. These results may signal reciprocal supportive networks. Working-age adults may financially support older recent immigrants, while older recent immigrants provide unremunerated childcare for working-age adults. PMID- 26763224 TI - Effect of Left Atrial Ablation Process and Strategy on Microemboli Formation During Irrigated Radiofrequency Catheter Ablation in an In Vivo Model. AB - BACKGROUND: Formation of microemboli during catheter ablation has been suggested as a cause for asymptomatic cerebral emboli. However, it is unknown which part of the process and ablation setting/strategy is most strongly related to this occurrence. METHODS AND RESULTS: A total of 27 pigs were used. Catheter/sheath manipulations in left atrium were performed in 25 of 27 pigs outfitted with microemboli monitoring systems. Ablations using open-irrigated radiofrequency catheters were performed in 18 of 25 pigs. Two of 27 pigs did not undergo left atrial procedures and were injected with microembolic materials in the carotid artery to serve as positive controls. In total, 334 sheath/catheter manipulations (transseptal puncture, sheath flushing, catheter insertion, pulmonary vein venography, and sheath exchange) and 333 radiofrequency applications (power setting, 30/50 W; point-by-point/drag ablations) were analyzed. High microbubble volume in the extracorporeal circulation loop and a high number of microembolic signals in carotid artery were observed during sheath/catheter manipulations especially in saline/contrast injections at fast speed and ablations with steam pop. Fast sheath flushing produced significantly higher microbubble volume than slow sheath flushing (median, 12 200 versus 121 nL; P<0.0001). A total of 44 of 126 (35%) blood filters in the circulation loop showed microparticles (thrombus/coagulum and tissue). Most of them were seen after radiofrequency application especially in 50-W ablations, drag ablations, and steam pop. Brain magnetic resonance imaging showed positive-embolic lesions in control pigs. CONCLUSIONS: Formation of microbubbles was the greatest during fast saline/contrast injections and steam pops, whereas high-power radiofrequency applications, drag ablations, and steam pops produced most of the microparticles. PMID- 26763225 TI - Uncovering Atrial Fibrillation Beyond Short-Term Monitoring in Cryptogenic Stroke Patients: Three-Year Results From the Cryptogenic Stroke and Underlying Atrial Fibrillation Trial. AB - BACKGROUND: Atrial fibrillation (AF) can be a cause of previously diagnosed cryptogenic stroke. However, AF can be paroxysmal and asymptomatic, thereby making detection with routine ECG methods difficult. Oral anticoagulation is highly effective in reducing recurrent stroke in patients with AF, but its initiation is dependent on the detection of AF. Cryptogenic Stroke and Underlying Atrial Fibrillation (CRYSTAL AF) is the first randomized study to report the detection of AF in cryptogenic stroke patients using continuous long-term monitoring via insertable cardiac monitors (ICM). METHODS AND RESULTS: Patients with prior cryptogenic stroke were randomized to control (n=220) or ICM (n=221) and followed for <=36 months. Cumulative AF detection rates in the ICM arm increased progressively during this period (3.7%, 8.9%, 12.4%, and 30.0% at 1, 6, 12, and 36 months, respectively), but remained low in the control arm (3.0% at 36 months). This resulted in oral anticoagulation prescription in 94.7% of ICM patients with AF detected at 6 months, 96.6% at 12 months, and 90.5% at 36 months. Among ICM patients with AF detected, the median time to AF detection was 8.4 months, 81.0% of first AF episodes were asymptomatic, and 94.9% had at least 1 day with >6 minutes of AF. CONCLUSIONS: Three-year monitoring by ICM in cryptogenic stroke patients demonstrated a significantly higher AF detection rate compared with routine care. Given the frequency of asymptomatic first episodes and the long median time to detection, these findings highlight the limitations of using traditional AF detection methods. The majority of patients with AF were prescribed oral anticoagulation therapy. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov; Unique identifier: NCT00924638. PMID- 26763226 TI - Impact of Complete Versus Incomplete Circumferential Lines Around the Pulmonary Veins During Catheter Ablation of Paroxysmal Atrial Fibrillation: Results From the Gap-Atrial Fibrillation-German Atrial Fibrillation Competence Network 1 Trial. AB - BACKGROUND: Ablation of atrial fibrillation (AF) is an established treatment option for symptomatic patients. It is not known whether complete pulmonary vein isolation (PVI) is superior to incomplete PVI with regard to the patients' clinical outcome. METHODS AND RESULTS: Patients with drug-refractory, symptomatic paroxysmal AF were randomly assigned to either incomplete (group A) or complete PVI (group B). In group A, a persistent gap was intentionally left within the circumferential ablation line, whereas in group B, complete PVI without any gaps was intended. At 3 months, all patients underwent invasive reevaluation to assess the rate of persistent PVI. Clinical follow-up was based on daily 30-s transtelephonic ECG transmissions. Primary study end point was the time to first recurrence of (symptomatic or asymptomatic) AF. A total of 233 patients were enrolled (116 in group A and 117 in group B). AF recurrence within 3 months was observed in a total of 161 patients (136 [84.5%] with symptomatic and 25 [15.5%] with asymptomatic AF); AF recurred in 62.2% of group B patients and 79.2% of group A patients (P<0.001), for a difference in favor of complete PVI of 17.1% (95% confidence interval, 5.3%-28.9%). Invasive restudy in 103 group A patients and 93 group B patients revealed conduction gaps in 92 (89.3%) and 65 (69.9%) patients, respectively. CONCLUSIONS: This study proves the superiority of complete PVI over incomplete PVI with respect to AF recurrence within 3 months. However, the rate of electric reconduction 3 months after PVI is high in patients with initially isolated PVs. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov; Unique identifier: NCT00293943. PMID- 26763228 TI - The Tribulations of Atrial Fibrillation Ablation Trialists. PMID- 26763227 TI - Radiofrequency Ablation of Persistent Atrial Fibrillation: Diagnosis-to-Ablation Time, Markers of Pathways of Atrial Remodeling, and Outcomes. AB - BACKGROUND: Various ablation strategies of persistent atrial fibrillation (PersAF) have had disappointing outcomes, despite concerted clinical and research efforts, which could reflect progressive atrial fibrillation-related atrial remodeling. METHODS AND RESULTS: Two-year outcomes were assessed in 1241 consecutive patients undergoing first-time ablation of PersAF (2005-2012). The time intervals between the first diagnosis of PersAF and the ablation procedures were determined. Patients had echocardiograms and measures of B-type natriuretic peptide and C-reactive protein before the procedures. The median diagnosis-to ablation time was 3 years (25th-75th percentiles 1-6.5). With longer diagnosis-to ablation time (based on quartiles), there was a significant increase in recurrence rates in addition to an increase in B-type natriuretic peptide levels (P=0.01), C-reactive protein levels (P<0.0001), and left atrial size (P=0.03). The arrhythmia recurrence rates over 2 years were 33.6%, 52.6%, 57.1%, and 54.6% in the first, second, third, and fourth quartiles, respectively (P(categorical)<0.0001). In Cox Proportional Hazard analyses, B-type natriuretic peptide levels, C-reactive protein levels, and left atrial size were associated with arrhythmia recurrence. The diagnosis-to-ablation time had the strongest association with the ablation outcomes which persisted in multivariable Cox analyzes (hazard ratio for recurrence per +1Log diagnosis-to-ablation time 1.27, 95% confidence interval 1.14-1.43; P<0.0001; hazard ratio fourth versus first quartile 2.44, 95% confidence interval 1.68-3.65; P(categorical)<0.0001). CONCLUSIONS: In patients with PersAF undergoing ablation, the time interval between the first diagnosis of PersAF and the catheter ablation procedure had a strong association with the ablation outcomes, such as shorter diagnosis-to ablation times were associated with better outcomes and in direct association with markers of atrial remodeling. PMID- 26763229 TI - Mitigating the Risk of Microemboli Formation During Irrigated Radiofrequency Catheter Ablation. PMID- 26763230 TI - Presence of Cryptosporidium parvum and Giardia lamblia in water samples from Southeast Asia: towards an integrated water detection system. AB - BACKGROUND: Access to clean and safe drinking water that is free from pathogenic protozoan parasites, especially Cryptosporidium parvum and Giardia lamblia that cause gastrointestinal illness in humans, is still an issue in Southeast Asia (SEA). This study is the first attempt to detect the aforementioned protozoan parasites in water samples from countries in SEA, using real-time polymerase chain reaction (qPCR) assays. METHODS: A total of 221 water samples of 10 l each were collected between April and October 2013 from Malaysia (53), Thailand (120), the Philippines (33), and Vietnam (15). A physicochemical analysis was conducted. The water samples were processed in accordance with the US Environmental Protection Agency's methods 1622/1623.1, microscopically observed and subsequently screened using qPCR assays. RESULTS: Cryptosporidium oocysts were detected in treated water samples from the Philippines (1/10), with a concentration of 0.06 +/- 0.19 oocyst/L, and untreated water samples from Thailand (25/93), Malaysia (17/44), and the Philippines (11/23), with concentrations ranging from 0.13 +/- 0.18 to 0.57 +/- 1.41 oocyst/L. Giardia cysts were found in treated water samples from the Philippines (1/10), with a concentration of 0.02 +/- 0.06 cyst/L, and in untreated water samples from Thailand (20/93), Vietnam (5/10), Malaysia (22/44), and the Philippines (16/23), with concentrations ranging from 0.12 +/- 0.3 to 8.90 +/- 19.65 cyst/L. The pathogens C. parvum and G. lamblia were detected using using qPCR assays by targeting the 138-bp fragment and the small subunit gene, respectively. C. parvum was detected in untreated water samples from the Philippines (1/23) and Malaysia (2/44), whilst, G. lamblia detected was detected in treated water samples from the Philippines (1/10) and in untreated water samples from Thailand (21/93), Malaysia (12/44), and the Philippines (17/23). Nitrate concentration was found to have a high positive correlation with (oo)cyst (0.993). CONCLUSION: The presence of (oo)cysts in the water samples means that there is potential risk for zoonotic disease transmission in the studied countries. Detection using qPCR is feasible for quantifying both pathogenic C. parvum and G. lamblia in large water samples. PMID- 26763231 TI - How the Linker Connecting the Two Kringles Influences Activation and Conformational Plasticity of Prothrombin. AB - A flexible linker (Lnk2) composed of 26 amino acids connects kringle-1 to kringle 2 in the coagulation factor prothrombin. Recent studies point to Lnk2 as a key determinant of the structure and function of this zymogen. Using a combination of mutagenesis, structural biology, and single molecule spectroscopy, we show how Lnk2 influences activation and conformational plasticity of prothrombin. Scrambling the sequence of Lnk2 is inconsequential on activation, and so is extension by as many as 22 residues. On the other hand, below a critical length of 15 residues, the rate of prothrombin activation increases (10-fold) in the absence of cofactor Va and decreases (3-fold) in the presence of cofactor. Furthermore, activation by prothrombinase takes place without preference along the prethrombin-2 (cleavage at Arg(271) first) or meizothrombin (cleavage at Arg(320) first) pathways. Notably, these transitions in the rate and pathway of activation require the presence of phospholipids, pointing to an important physiological role for Lnk2 when prothrombin is anchored to the membrane. Two new crystal structures of prothrombin lacking 22 (ProTDelta146-167) or 14 (ProTDelta154-167) residues of Lnk2 document striking conformational rearrangements of domains located across this linker. FRET measurements of freely diffusing single molecules prove that these structural transitions are genuine properties of the zymogen in solution. These findings support a molecular model of prothrombin activation where Lnk2 presents the sites of cleavage at Arg(271) and Arg(320) to factor Xa in different orientations by pivoting the C-terminal kringle-2/protease domain pair on the N-terminal Gla domain/kringle-1 pair anchored to the membrane. PMID- 26763232 TI - Docosahexaenoic Acid Promotes Axon Outgrowth by Translational Regulation of Tau and Collapsin Response Mediator Protein 2 Expression. AB - n-3 PUFAs are essential for neuronal development and brain function. However, the molecular mechanisms underlying their biological effects remain unclear. Here we examined the mechanistic action of docosahexaenoic acid (DHA), the most abundant n-3 polyunsaturated fatty acids in the brain. We found that DHA treatment of cortical neurons resulted in enhanced axon outgrowth that was due to increased axon elongation rates. DHA-mediated axon outgrowth was accompanied by the translational up-regulation of Tau and collapsin response mediator protein 2 (CRMP2), two important axon-related proteins, and the activation of Akt and p70 S6 kinase. Consistent with these findings, rapamycin, a potent inhibitor of mammalian target of rapamycin (mTOR), prevented DHA-mediated axon outgrowth and up-regulation of Tau and CRMP2. In addition, DHA-dependent activation of the Akt mTOR-S6K pathway enhanced 5'-terminal oligopyrimidine tract-dependent translation of Tau and CRMP2. Therefore, our results revealed an important role for the Akt mTOR-S6K pathway in DHA-mediated neuronal development. PMID- 26763233 TI - Loss of alpha-Tubulin Acetylation Is Associated with TGF-beta-induced Epithelial Mesenchymal Transition. AB - The epithelial-to-mesenchymal transition (EMT) is a process by which differentiated epithelial cells reprogram gene expression, lose their junctions and polarity, reorganize their cytoskeleton, increase cell motility and assume a mesenchymal morphology. Despite the critical functions of the microtubule (MT) in cytoskeletal organization, how it participates in EMT induction and maintenance remains poorly understood. Here we report that acetylated alpha-tubulin, which plays an important role in microtubule (MT) stabilization and cell morphology, can serve as a novel regulator and marker of EMT. A high level of acetylated alpha-tubulin was correlated with epithelial morphology and it profoundly decreased during TGF-beta-induced EMT. We found that TGF-beta increased the activity of HDAC6, a major deacetylase of alpha-tubulin, without affecting its expression levels. Treatment with HDAC6 inhibitor tubacin or TGF-beta type I receptor inhibitor SB431542 restored the level of acetylated alpha-tubulin and consequently blocked EMT. Our results demonstrate that acetylated alpha-tubulin can serve as a marker of EMT and that HDAC6 represents an important regulator during EMT process. PMID- 26763234 TI - New Family of Ulvan Lyases Identified in Three Isolates from the Alteromonadales Order. AB - Ulvan is the main polysaccharide component of the Ulvales (green seaweed) cell wall. It is composed of disaccharide building blocks comprising 3-sulfated rhamnose linked to d-glucuronic acid (GlcUA), l-iduronic acid (IdoUA), or d xylose (Xyl). The degradation of ulvan requires ulvan lyase, which catalyzes the endolytic cleavage of the glycoside bond between 3-sulfated rhamnose and uronic acid according to a beta-elimination mechanism. The first characterized ulvan lyase was identified in Nonlabens ulvanivorans, an ulvanolytic bacterial isolate. In the current study, we have identified and biochemically characterized novel ulvan lyases from three Alteromonadales isolated bacteria. Two homologous ulvan lyases (long and short) were found in each of the bacterial genomes. The protein sequences have no homology to the previously reported ulvan lyases and therefore are the first representatives of a new family of polysaccharide lyases. The enzymes were heterologously expressed in Escherichia coli to determine their mode of action. The heterologous expressed enzymes were secreted into the milieu subsequent to their signal sequence cleavage. An endolytic mode of action was observed and studied using gel permeation chromatography and (1)H NMR. In contrast to N. ulvanivorans ulvan lyase, cleavage occurred specifically at the GlcUA residues. In light of the genomic context and modular structure of the ulvan lyase families identified to date, we propose that two ulvan degradation pathways evolved independently. PMID- 26763237 TI - Data as the Foundation for Health Policy. PMID- 26763235 TI - Matrix-driven Myosin II Mediates the Pro-fibrotic Fibroblast Phenotype. AB - Pro-fibrotic mesenchymal cells are known to be the key effector cells of fibroproliferative disease, but the specific matrix signals and the induced cellular responses that drive the fibrogenic phenotype remain to be elucidated. The key mediators of the fibroblast fibrogenic phenotype were characterized using a novel assay system that measures fibroblast behavior in response to actual normal and fibrotic lung tissue. Using this system, we demonstrate that normal lung promotes fibroblast motility and polarization, while fibrotic lung immobilizes the fibroblast and promotes myofibroblast differentiation. These context-specific phenotypes are surprisingly both mediated by myosin II. The role of myosin II is supported by the observation of an increase in myosin phosphorylation and a change in intracellular distribution in fibroblasts on fibrotic lung, as compared with normal lung. Moreover, loss of myosin II activity has opposing effects on protrusive activity in fibroblasts on normal and fibrotic lung. Loss of myosin II also selectively inhibits myofibroblast differentiation in fibroblasts on fibrotic lung. Importantly, these findings are recapitulated by varying the matrix stiffness of polyacrylamide gels in the range of normal and fibrotic lung tissue. Comparison of the effects of myosin inhibition on lung tissue with that of polyacrylamide gels suggests that matrix fiber organization drives the fibroblast phenotype under conditions of normal/soft lung, while matrix stiffness drives the phenotype under conditions of fibrotic/stiff lung. This work defines novel roles for myosin II as a key regulatory effector molecule of the pro-fibrotic phenotype, in response to biophysical properties of the matrix. PMID- 26763236 TI - Characterization of the First alpha-(1->3) Branching Sucrases of the GH70 Family. AB - Leuconostoc citreumNRRL B-742 has been known for years to produce a highly alpha (1->3)-branched dextran for which the synthesis had never been elucidated. In this work a gene coding for a putative alpha-transglucosylase of the GH70 family was identified in the reported genome of this bacteria and functionally characterized. From sucrose alone, the corresponding recombinant protein, named BRS-B, mainly catalyzed sucrose hydrolysis and leucrose synthesis. However, in the presence of sucrose and a dextran acceptor, the enzyme efficiently transferred the glucosyl residue from sucrose to linear alpha-(1->6) dextrans through the specific formation of alpha-(1->3) linkages. To date, BRS-B is the first reported alpha-(1->3) branching sucrase. Using a suitable sucrose/dextran ratio, a comb-like dextran with 50% of alpha-(1->3) branching was synthesized, suggesting that BRS-B is likely involved in the comb-like dextran produced byL. citreumNRRL B-742. In addition, data mining based on the search for specific sequence motifs allowed the identification of two genes putatively coding for branching sucrases in the genome ofLeuconostoc fallaxKCTC3537 andLactobacillus kunkeeiEFB6. Biochemical characterization of the corresponding recombinant enzymes confirmed their branching specificity, revealing that branching sucrases are not only found inL. citreumspecies. According to phylogenetic analyses, these enzymes are proposed to constitute a new subgroup of the GH70 family. PMID- 26763240 TI - The Perceived Impact of the Patient Protection and Affordable Care Act on North Carolina's Free Clinics. AB - BACKGROUND: The Patient Protection and Affordable Care Act of 2010 (ACA) may dramatically affect the demographics of the uninsured population and the funding prospects for free health clinics. METHODS: We conducted a cross-sectional survey of 64 of 80 free clinics (80.0% response rate) in North Carolina to assess free clinic directors' knowledge of the ACA and their perceptions of how the ACA would affect clinic operations. RESULTS: Free clinic directors were knowledgeable about well publicized aspects of the ACA (eg, lack of Medicaid expansion in North Carolina), but they were less knowledgeable about provisions such as the Federal Tort Claims Act and high-risk pools, which may have direct and indirect effects on free clinics. Directors expressed concern over the unintended consequences of the ACA, such as reduced funding and reduced volunteerism. Anticipated clinic changes as a result of the ACA include initiation of electronic medical records and, to a lesser extent, a move to become "hybrid" clinics (federally qualified health center look-alikes). LIMITATIONS: This study is focused on North Carolina free clinics that are members of the North Carolina Association of Free Clinics (NCAFC). Findings cannot be generalized to non-NCAFC free clinics or to free clinic networks outside the state. CONCLUSIONS: Despite its effort to expand health insurance coverage, the ACA may have unintended consequences to low-cost free clinics that serve uninsured populations. PMID- 26763238 TI - Fish Consumption Patterns and Mercury Advisory Knowledge Among Fishers in the Haw River Basin. AB - BACKGROUND: Fish consumption has numerous health benefits, with fish providing a source of protein as well as omega-3 fatty acids. However, some fish also contain contaminants that can impair human health. In North Carolina, the Department of Health and Human Services has issued fish consumption advisories due to methylmercury contamination in fish. Little is known about local fishers' consumption patterns and advisory adherence in North Carolina. METHODS: We surveyed a consecutive sample of 50 fishers (74.6% positive response rate) who reported eating fish caught from the Haw River Basin or Jordan Lake. They provided information on demographic characteristics, species caught, and the frequency of local fish consumption. Additionally, fishers provided information on their knowledge of fish consumption advisories and the impact of those advisories on their fishing and fish consumption patterns. RESULTS: The majority of participants were male (n = 44) and reported living in central North Carolina. Catfish, crappie, sunfish, and large-mouth bass were consumed more frequently than other species of fish. Of the fishers surveyed, 8 reported eating more than 1 fish meal high in mercury per week, which exceeds the North Carolina advisory recommendation. Most participants (n = 32) had no knowledge of local fish advisories, and only 4 fishers reported that advisories impacted their fishing practices. LIMITATIONS: We sampled 50 fishers at 11 locations. There is no enumeration of the dynamic population of fishers and no way to assess the representativeness of this sample. CONCLUSIONS: Additional outreach is needed to make local fishers aware of fish consumption advisories and the potential health impacts of eating high-mercury fish, which may also contain other persistent and bioaccumulative toxins. PMID- 26763241 TI - Disability and Exposure to High Levels of Adverse Childhood Experiences: Effect on Health and Risk Behavior. AB - BACKGROUND: Health disparities among persons with disabilities have been previously documented. However, there is little research specific to adverse childhood experiences (ACEs) in this population and how ACE exposure affects health outcomes in adulthood. METHODS: Data from the 2012 North Carolina Behavioral Risk Factor Surveillance System (BRFSS) survey were analyzed to compare the prevalence of ACEs between adults with and without disabilities and high ACE exposure (3-8 ACEs). Adjusted risk ratios of health risks and perceived poor health by disability status were calculated using predicted marginals. RESULTS: A higher percentage of persons with disabilities (36.5%) than those without disabilities (19.6%) reported high ACE exposure. Among those with high ACE exposure, persons with disabilities were more likely to report several ACE categories, particularly childhood sexual abuse. In adjusted analyses, persons with disabilities had an increased risk of smoking (relative risk [RR] = 1.29; 95% CI, 1.10-1.51), poor physical health (RR = 4.34; 95% CI, 3.08-6.11), poor mental health (RR = 4.69; 95% CI, 3.19-6.87), and doctor-diagnosed depression (RR = 2.16; 95% CI, 1.82-2.56) compared to persons without disabilities. LIMITATIONS: The definition of disability derived from the BRFSS survey does not allow for those with disabilities to be categorized according to physical disabilities versus mental or emotional disabilities. In addition, we were unable to determine the timing of ACE exposure in relation to disability onset. CONCLUSIONS: A better understanding of the life course associations between ACEs and disability and the impact of exposure to multiple types of childhood adversity on disability and health is needed to inform research and services specific to this vulnerable population. PMID- 26763239 TI - Estimating the Burden of Pandemic Infectious Disease: The Case of the Second Wave of Pandemic Influenza H1N1 in Forsyth County, North Carolina. AB - BACKGROUND: Understanding the burden of influenza A(H1N1)pdm09 virus during the second wave of 2009-2010 is important for future pandemic planning. METHODS: Persons who presented to the emergency department (ED) or were hospitalized with fever and/or acute respiratory symptoms at the academic medical center in Forsyth County, North Carolina were prospectively enrolled and underwent nasal/throat swab testing for influenza A(H1N1)pdm09. Laboratory-confirmed cases of influenza A(H1N1)pdm09 virus identified through active surveillance were compared by capture-recapture analysis to those identified through independent, passive surveillance (physician-ordered influenza testing). This approach estimated the number of total cases, including those not captured by either surveillance method. A second analysis estimated the total number of influenza A(H1N1)pdm09 cases by multiplying weekly influenza percentages determined via active surveillance by weekly counts of influenza-associated discharge diagnoses from administrative data. Market share adjustments were used to estimate influenza A(H1N1)pdm09 virus ED visits or hospitalizations per 1,000 residents. RESULTS: Capture-recapture analysis estimated that 753 residents (95% confidence interval [CI], 424-2,735) with influenza A(H1N1)pdm09 virus were seen in the academic medical center from September 2009 through mid-April 2010; this result yielded an estimated 4.7 (95% CI, 2.6-16.9) influenza A(H1N1)pdm09 virus ED visits or hospitalizations per 1,000 residents. Similarly, 708 visits were estimated using weekly influenza percentages and influenza-associated discharge diagnoses, yielding an estimated 4.4 influenza A(H1N1)pdm09 virus ED visits or hospitalizations per 1,000 residents. CONCLUSION: This study demonstrates that the burden of influenza A(H1N1)pdm09 virus in ED and inpatient settings by capture-recapture analysis was 4-5 per 1,000 residents; this rate was approximately 8-fold higher than that detected by physician-ordered influenza testing. PMID- 26763242 TI - Association Between Staff Experience and Effective Tuberculosis Contact Tracing in North Carolina, 2008-2009. AB - BACKGROUND: Effective investigation of tuberculosis (TB) contacts is essential for continued progress toward TB elimination. As the incidence of TB declines, staff experience will also decline. Little is known about the association between the experience level of public health TB staff and the quality of contact investigations. METHODS: Contact investigations involving fewer than 30 contacts during the period 2008-2009 were included in this analysis. Multivariable models were used to examine associations between staff TB experience (assessed by a standardized survey) and measures of contact investigation quality: time from case identification to contact identification and number of contacts identified per case investigated. RESULTS: A total of 501 cases and 3,230 contacts met the inclusion criteria. Data were stratified by the number of cases in the county and whether the case was smear-positive or smear-negative. For contacts of smear positive cases, greater staff experience was associated with more rapid contact identification both in counties with high case counts (hazard ratio [HR] = 2.43; 95% CI, 1.79-3.31) and in counties with low case counts (HR = 1.142; 95% CI, 0.95 1.37). However, for smear-negative cases, staff in counties with low case counts identified contacts more slowly as years of experience increased (HR = 0.82; 95% CI, 0.62-1.07). For contacts of smear-negative cases, more contacts (relative risk [RR] = 1.20; 95% CI, 1.07-1.35) were identified per case in high case-count counties (more than 20 cases during 2008-2009). Conversely, in low case-count counties, fewer contacts were identified per case (RR = 0.94; 95% CI, 0.82-1.08); however, this finding was not significant. DISCUSSION: Speed of identification and number of contacts are imperfect surrogates for the most important outcome of contact investigations-that is, the rapid identification and treatment of infected contacts. CONCLUSION: More TB experience was associated with more rapid and thorough TB contact investigations. Retaining experienced staff and mentoring staff new to case management should be high priorities for TB control programs. PMID- 26763243 TI - From Pilot to Practice: A Trainee-Integrated Pharmacy Practice Model in Cardiology. AB - OBJECTIVES: Problems related to medication use portend poor outcomes, but resources for expanding clinical pharmacy services are limited. We conducted a pilot study in the area of cardiology to determine the impact and feasibility of a trainee-integrated pharmacy practice (TIPP) model comprised of pharmacy residents and a clinical pharmacist. METHODS: Coverage of 2 acute care and 1 intensive care team was distributed among 1 clinical pharmacist and 3 pharmacy residents. Patient care services included interdisciplinary rounds, order verification, medication reconciliation, counseling, clinical monitoring, and documentation. A pharmacy technician collected medication histories for newly admitted patients. Data related to medication reconciliation, clinical interventions, and time requirements were collected. Clinical services were compared to historical controls where data were available. RESULTS: Over the 18 day pilot study, the mean daily census consisted of 33.4 +/- 5.3 patients. Admission medication reconciliation was performed on 8.1 patients per day, resulting in the discovery of 3.5 discrepancies per patient. Of 18 patients receiving anticoagulant therapy, 9 were counseled prior to discharge. Compared to historical controls, the number of patients receiving medication reconciliation and discharge counseling improved by 81% and 70%, respectively (both P < .05). A total of 763 clinical interventions were recommended (42.4 per day), with many recognized in peer-reviewed literature as conferring improvements in clinical outcomes. Members of the model were active for a mean of 10-12 hours each day, with 6.3-7.2 hours corresponding to direct patient care. LIMITATIONS: This was a single-arm, observational pilot study. CONCLUSION: Implementation of a TIPP model significantly expanded clinical pharmacy services on an acute care cardiology service, but it required significant time commitments. PMID- 26763245 TI - North Carolina's Operation Medicine Drop: Results From One of the Nation's Largest Drug Disposal Programs. AB - INTRODUCTION: In 2013, a total of 1,085 North Carolina residents died due to unintentional poisoning; 91% of these deaths were attributed to medications or drugs (over-the-counter, prescription, or illicit). Proper disposal of unused, unneeded, and/or expired medications is an essential part of preventing these unintentional deaths, as well as averting the other adverse consequences of these drugs on the environment and population health. METHODS: Operation Medicine Drop is a medication take-back program coordinated by Safe Kids North Carolina, a county-level, coalition-based injury prevention organization. The Operation Medicine Drop program and event registration system were used to review and validate the number of events, the counties where the events were held, and the number of unit doses (pills) collected from March 2010 to June 2014. SAS version 9.4 was used to generate basic counts and frequencies of events and doses, and ArcGIS version 10.0 was used to create the map. RESULTS: From March 2010 to June 2014, Operation Medicine Drop held 1,395 events with 245 different participating law enforcement agencies in 91 counties in North Carolina, and it collected 69.6 million unit doses of medication. More than 60 local Safe Kids North Carolina community coalitions had participated as of June 2014. Every year, Operation Medicine Drop has witnessed increases in events, participating agencies, participating counties, and the number of doses collected. CONCLUSION: Operation Medicine Drop is an excellent example of a successful and ongoing collaboration to improve public health. Medication take-back programs may play an important role in preventing future overdose deaths in North Carolina. PMID- 26763244 TI - Enrollment and Racial Disparities in Cancer Treatment Clinical Trials in North Carolina. AB - BACKGROUND: Clinical trials provide access to innovative, high-quality cancer treatment. Simultaneously, broad access helps to ensure that trials include heterogeneous patient populations, which improves the generalizability of findings and the development of interventions that are effective for diverse populations. We provide updated data describing enrollment into cancer treatment trials in North Carolina. METHODS: For the period 1996-2009, person-level data regarding cancer clinical trial enrollment and cancer incidence were obtained from the North Carolina Central Cancer Registry and the National Cancer Institute (NCI). Enrollment rates were estimated as the ratio of trial enrollment to cancer incidence for race, sex, and year for each county, Area Health Education Center region, and the state overall. Enrollment rates for common cancers are presented. RESULTS: From 1996 to 2009, North Carolina NCI treatment trial enrollment rates were 2.4% and 2.2% for white patients and minority patients, respectively. From 2007 to 2009, rates were 3.8% for white women, 3.5% for minority women, 1.3% for white men, and 1.0% for minority men; there was greater enrollment among more urban populations (2.4%) than among the most rural populations (1.5%). LIMITATIONS: This study is limited to NCI-sponsored treatment trials in North Carolina. Policies governing collection of original data necessitate a delay in data availability. CONCLUSIONS: Effort is needed to ensure trial access and enrollment among all North Carolina populations. Specifically, we identified racial and sex disparities, particularly for certain cancers (eg, breast cancer). Programs in North Carolina and across the nation can use the methods we employed to assess their success in broadening clinical trial enrollment to include diverse populations. PMID- 26763246 TI - Mental Health and Substance Misuse-Related Emergency Department Discharges in Urban Counties of North Carolina. AB - BACKGROUND: National evidence suggests that there is considerable variation between regions in emergency department utilization for routine health care needs. Many emergency departments are poorly equipped to manage the needs of patients with mental health or substance misuse diagnoses, who could often be more effectively managed in other settings. We sought to quantify differences in the frequency of mental health and substance misuse-related emergency department encounters across urban counties in North Carolina. METHODS: Data from the 2010 North Carolina State Emergency Department and Inpatient Databases were analyzed with descriptive, bivariate, and multivariate statistics. Primary discharge diagnoses were classified using the International Classification of Disease, Ninth Revision, Clinical Modification codes included with the databases. RESULTS: The overall rate of mental health and substance misuse encounters in urban counties was 19.1 encounters per 1,000 people (4.5% of all emergency department encounters). This rate ranged from 6.4 encounters per 1,000 people (2.4% of encounters) in Wake County to 30.1 encounters per 1,000 people (6.4%) in Orange County. LIMITATIONS: There is a possibility of nondifferential classification error in the state databases, as coding practices and coding errors may vary between facilities. We were unable to confirm diagnoses through additional clinical information or Diagnostic and Statistical Manual criteria. CONCLUSION: Mental health and substance misuse-related encounters constitute a small percentage of emergency department encounters in North Carolina's urban counties, with significant variation between counties. Diverting some of these encounters to community-based mental health and substance misuse health care providers could reduce emergency department utilization while improving the quality of care delivered to this vulnerable patient population. PMID- 26763247 TI - Hyperbaric Oxygen Therapy: Using Evidence-Based Medicine to Heal Injured Brain Tissue. PMID- 26763248 TI - Molecular Pathways: AXL, a Membrane Receptor Mediator of Resistance to Therapy. AB - AXL is a tyrosine kinase membrane receptor that signals via PI3K, MAPK, and protein kinase C (PKC), among other pathways. AXL has oncogenic potential and interacts with other membrane receptors, depending on their relative abundance and availability. The increased expression of AXL in cancer is often the result of pharmacologic selective pressure to a number of chemotherapies and targeted therapies and acts as a mechanism of acquired drug resistance. This resistance phenotype, frequently accompanied by epithelial-to-mesenchymal transition, can be reversed by AXL inhibition. In tumors with high levels of EGFR, including lung, head and neck, and triple-negative breast cancer, AXL dimerizes with this receptor and initiates signaling that circumvents the antitumor effects of anti EGFR therapies. Likewise, AXL overexpression and dimerization with EGFR can overcome PI3K inhibition by activating the phospholipase C-gamma-PKC cascade that, in turn, sustains mTORC1 activity. The causative role of AXL in inducing drug resistance is underscored by the fact that the suppression of AXL restores sensitivity to these agents. Hence, these observations indicate that AXL is selectively expressed in tumor cells refractory to therapy and that cotargeting AXL in this setting would potentially overcome drug resistance. The use of AXL inhibitors should be considered in the clinic. PMID- 26763249 TI - Adaptation to AI Therapy in Breast Cancer Can Induce Dynamic Alterations in ER Activity Resulting in Estrogen-Independent Metastatic Tumors. AB - PURPOSE: Acquired resistance to aromatase inhibitor (AI) therapy is a major clinical problem in the treatment of breast cancer. The detailed mechanisms of how tumor cells develop this resistance remain unclear. Here, the adapted function of estrogen receptor (ER) to an estrogen-depleted environment following AI treatment is reported. EXPERIMENTAL DESIGN: Global ER chromatin immuno precipitation (ChIP)-seq analysis of AI-resistant cells identified steroid independent ER target genes. Matched patient tumor samples, collected before and after AI treatment, were used to assess ER activity. RESULTS: Maintained ER activity was observed in patient tumors following neoadjuvant AI therapy. Genome wide ER-DNA-binding analysis in AI-resistant cell lines identified a subset of classic ligand-dependent ER target genes that develop steroid independence. The Kaplan-Meier analysis revealed a significant association between tumors, which fail to decrease this steroid-independent ER target gene set in response to neoadjuvant AI therapy, and poor disease-free survival and overall survival (n = 72 matched patient tumor samples, P = 0.00339 and 0.00155, respectively). The adaptive ER response to AI treatment was highlighted by the ER/AIB1 target gene, early growth response 3 (EGR3). Elevated levels of EGR3 were detected in endocrine-resistant local disease recurrent patient tumors in comparison with matched primary tissue. However, evidence from distant metastatic tumors demonstrates that the ER signaling network may undergo further adaptations with disease progression as estrogen-independent ER target gene expression is routinely lost in established metastatic tumors. CONCLUSIONS: Overall, these data provide evidence of a dynamic ER response to endocrine treatment that may provide vital clues for overcoming the clinical issue of therapy resistance. Clin Cancer Res; 22(11); 2765-77. (c)2016 AACR. PMID- 26763250 TI - Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis. AB - PURPOSE: The aim of this study was to confirm the prognostic significance of POLE exonuclease domain mutations (EDM) in endometrial carcinoma patients. In addition, the effect of treatment on POLE-mutated tumors was assessed. EXPERIMENTAL DESIGN: A retrospective patient cohort of 496 endometrial carcinoma patients was identified for targeted sequencing of the POLE exonuclease domain, yielding 406 evaluable tumors. Univariable and multivariable analyses were performed to determine the effect of POLE mutation status on progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS). Combining results from eight studies in a meta-analysis, we computed pooled HR for PFS, DSS, and OS. RESULTS: POLE EDMs were identified in 39 of 406 (9.6%) endometrial carcinomas. Women with POLE-mutated endometrial carcinomas were younger, with stage I (92%) tumors, grade 3 (62%), endometrioid histology (82%), and frequent (49%) lymphovascular invasion. In univariable analysis, POLE-mutated endometrial carcinomas had significantly improved outcomes compared with patients with no EDMs for PFS, DSS, and OS. In multivariable analysis, POLE EDMs were only significantly associated with improved PFS. The effect of adjuvant treatment on POLE-mutated cases could not be determined conclusively; however, both treated and untreated patients with POLE EDMs had good outcomes. Meta-analysis revealed an association between POLE EDMs and improved PFS and DSS with pooled HRs 0.34 [95% confidence interval (CI), 0.15-0.73] and 0.35 (95% CI, 0.13-0.92), respectively. CONCLUSIONS: POLE EDMs are prognostic markers associated with excellent outcomes for endometrial carcinoma patients. Further investigation is needed to conclusively determine if treatment is necessary for this group of women. Clin Cancer Res; 22(12); 2865-73. (c)2016 AACR. PMID- 26763251 TI - Tumor-Infiltrating Plasma Cells Are Associated with Tertiary Lymphoid Structures, Cytolytic T-Cell Responses, and Superior Prognosis in Ovarian Cancer. AB - PURPOSE: CD8(+) tumor-infiltrating lymphocytes (TIL) are key mediators of antitumor immunity and are strongly associated with survival in virtually all solid tumors. However, the prognostic effect of CD8(+) TIL is markedly higher in the presence of CD20(+) B cells, suggesting that cooperative interactions between these lymphocyte subsets lead to more potent antitumor immunity. EXPERIMENTAL DESIGN: We assessed the colocalization patterns, phenotypes, and gene expression profiles of tumor-associated T- and B-lineage cells in high-grade serous ovarian cancer (HGSC) by multicolor IHC, flow cytometry, and bioinformatic analysis of gene expression data from The Cancer Genome Atlas. RESULTS: T cells and B cells colocalized in four types of lymphoid aggregate, ranging from small, diffuse clusters to large, well-organized tertiary lymphoid structures (TLS) resembling activated lymph nodes. TLS were frequently surrounded by dense infiltrates of plasma cells (PC), which comprised up to 90% of tumor stroma. PCs expressed mature, oligoclonal IgG transcripts, indicative of antigen-specific responses. PCs were associated with the highest levels of CD8(+), CD4(+), and CD20(+) TIL, as well as numerous cytotoxicity-related gene products. CD8(+) TIL carried prognostic benefit only in the presence of PCs and these other TIL subsets. PCs were independent of mutation load, BRCA1/2 status, and differentiation antigens but positively associated with cancer-testis antigens. CONCLUSIONS: PCs are associated with the most robust, prognostically favorable CD8(+) TIL responses in HGSC. We propose that TLS facilitate coordinated antitumor responses involving the combined actions of cytolytic T cells and antibody-producing PCs. Clin Cancer Res; 22(12); 3005-15. (c)2016 AACR. PMID- 26763252 TI - Epigenetic Regulation of the Homeobox Gene MSX1 Associates with Platinum Resistant Disease in High-Grade Serous Epithelial Ovarian Cancer. AB - PURPOSE: Although high-grade serous ovarian cancer (HGSOC) is frequently chemoresponsive, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival (PFS) of less than 6 months. Validated predictive biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of intrinsic resistance. Our aim was to identify DNA methylation biomarkers of poor response to chemotherapy and demonstrate involvement of the associated gene in platinum drug cell sensitivity. EXPERIMENTAL DESIGN: DNA methylation was investigated in independent tumor cohorts using Illumina HumanMethylation arrays and gene expression by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction and siRNA knockdown of ovarian cancer cell lines. RESULTS: CpG sites at contiguous genomic locations within the MSX1 gene have significantly lower levels of methylation in independent cohorts of HGSOC patients, which recur by 6 months compared with after 12 months (P < 0.05, q < 0.05, n = 78), have poor RECIST response (P < 0.05, q < 0.05, n = 61), and are associated with PFS in an independent cohort (n = 146). A decrease in methylation at these CpG sites correlates with decreased MSX1 gene expression. MSX1 expression is associated with PFS (HR, 0.92; 95% CI, 0.85-0.99; P = 0.029; n = 309). Cisplatin-resistant ovarian cancer cell lines have reduced MSX1 expression, and MSX1 overexpression leads to cisplatin sensitization, increased apoptosis, and increased cisplatin induced p21 expression. CONCLUSIONS: Hypomethylation of CpG sites within the MSX1 gene is associated with resistant HGSOC disease at presentation and identifies expression of MSX1 as conferring platinum drug sensitivity. Clin Cancer Res; 22(12); 3097-104. (c)2016 AACR. PMID- 26763253 TI - T-Cell Immunoglobulin and ITIM Domain (TIGIT) Associates with CD8+ T-Cell Exhaustion and Poor Clinical Outcome in AML Patients. AB - PURPOSE: T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is a recently identified T-cell coinhibitory receptor. In this study, we aimed to determine the clinical impact of TIGIT in patients with acute myelogenous leukemia (AML) and dissect the role of TIGIT in the pathogenesis of leukemia progression. EXPERIMENTAL DESIGN: TIGIT expression on T cells from peripheral blood collected from patients with AML was examined by flow cytometry. The correlation of TIGIT expression to clinical outcomes, including rate of complete remission and relapse post-allogeneic stem cell transplantation (alloSCT) in AML patients, was analyzed. Phenotypic and functional study (cytokine release, proliferation, killing, and apoptosis) of TIGIT-expressing T cells were performed. Using siRNA to silence TIGIT, we further elucidated the regulatory role of TIGIT in the T-cell immune response by dissecting the effect of TIGIT knockdown on cytokine release and apoptosis of T cells from AML patients. RESULTS: TIGIT expression on CD8(+) T cells is elevated in AML patients and high-TIGIT correlates with primary refractory disease and leukemia relapse post-alloSCT. TIGIT(+) CD8(+) T cells display phenotypic features of exhaustion and exhibit functional impairment manifested by low production of cytokines and high susceptibility to apoptosis. Importantly, their functional defects are reversed by TIGIT knockdown. CONCLUSIONS: TIGIT contributes to functional T-cell impairment and associates with poor clinical outcome in AML. Our study suggests that blockade of TIGIT to restore T-cell function and antitumor immunity may represent a novel effective leukemia therapeutic. Clin Cancer Res; 22(12); 3057 66. (c)2016 AACR. PMID- 26763254 TI - Incorporation of Next-Generation Sequencing into Routine Clinical Care to Direct Treatment of Head and Neck Squamous Cell Carcinoma. AB - PURPOSE: The clinical impact of next-generation sequencing (NGS) in patients with head and neck squamous cell carcinoma (HNSCC) has not been described. We aimed to evaluate the clinical impact of NGS in the routine care of patients with HNSCC and to correlate genomic alterations with clinical outcomes. EXPERIMENTAL DESIGN: Single-center study examining targeted NGS platform used to sequence tumor DNA obtained from 213 HNSCC patients evaluated in outpatient head and neck oncology clinic between August 2011 and December 2014. We correlated tumor genomic profiling results with clinical outcomes. RESULTS: PI3K/RTK pathway activation occurred frequently [activating PIK3CA mutation or amplification (13%), PTEN inactivation (3%), RAS activation (6%), EGFR or ERBB2 activation (9%)]. Alterations in pathways affecting cell-cycle regulation [CCND1 amplification (9%), CDKN2A inactivation (17%), BRCA2 inactivation (2%)] and squamous differentiation [NOTCH1 inactivation (8%) andEP300 inactivation (6%)] were identified. PIK3CA amplification (n = 43), not PIK3CA mutation, was associated with significantly poorer progression-free survival (P = 0.0006). Oncogenic RAS mutations (n = 13) were associated with significantly poorer progression-free survival (P = 0.0001) and lower overall survival (P = 0.003). Eight patients with advanced, treatment-refractory HNSCC enrolled on clinical trials matched to tumor profiling results, and 50% achieved a partial response. CONCLUSIONS: Incorporation of NGS clinical assays into the routine care of patients with HNSCC is feasible and may readily facilitate enrollment into clinical trials of targeted therapy with a higher likelihood of success. Data can be utilized for discovery of genomic biomarkers of outcome. PIK3CA amplification and RAS mutations were frequently identified and associated with poorer prognosis in this cohort. Clin Cancer Res; 22(12); 2939-49. (c)2016 AACR. PMID- 26763256 TI - Propensity Score Analysis Comparing Clinical Outcomes of Drug-Eluting vs Bare Nitinol Stents in Femoropopliteal Lesions. AB - PURPOSE: To present a propensity score matching analysis comparing the 1-year outcomes of de novo femoropopliteal lesions treated with drug-eluting stents (DES) or bare nitinol stents (BNS). METHODS: A retrospective review was conducted of 452 limbs in 389 patients (mean age 74+/-8 years; 284 men) treated with DES implantation and 1808 limbs in 1441 patients (mean age 72+/-9 years; 1023 men) implanted with BNS for de novo femoropopliteal lesions. One-year follow-up data were available on all patients. The primary endpoint was 12-month restenosis assessed by duplex ultrasonography or follow-up angiography within +/-2 months. Secondary endpoint was major adverse limb events (MALE) including major amputation, any reintervention, and restenosis. RESULTS: The BNS group was more likely to have current smoking, chronic total occlusion, and poor below-the-knee runoff. The stratification analysis demonstrated that diabetes mellitus (DM) and reference vessel diameter (RVD) had a significant interaction on the association of DES vs BNS implantation with restenosis (interaction p<0.05). Thus, the population was stratified into 4 subgroups (1: -DM, RVD >=5 mm, 2: +DM, RVD >=5 mm, 3: -DM, RVD <5 mm, and 4: +DM, RVD <5 mm); the RVD threshold was empirically determined. There were no significant intergroup differences in baseline variables after matching. There was no significant difference in restenosis risk between DES and BNS in the RVD >=5 mm subgroup regardless of the presence of DM. The DES group had a significantly higher restenosis risk in the RVD <5 mm subgroup regardless of the presence of DM. No significant difference was observed in the risk of major amputation, reintervention, or MALE in any subgroup. CONCLUSION: These results suggest that a first-generation DES was not superior to a conventional BNS for femoropopliteal lesions. PMID- 26763257 TI - Commentary: Carbon Dioxide Automated Angiography in Patients With a High Risk of Contrast-Induced Nephropathy Who Undergo Percutaneous Interventions for Critical Limb Ischemia. PMID- 26763255 TI - Arrhythmia and Sudden Death in Hemodialysis Patients: Protocol and Baseline Characteristics of the Monitoring in Dialysis Study. AB - BACKGROUND: Dialysis patients have high rates of cardiovascular morbidity and mortality, but data on arrhythmia burden, arrhythmia type, arrhythmia triggers, and the identity of terminal arrhythmias have historically been limited by an inability to monitor heart rhythm for prolonged periods. OBJECTIVES: To investigate arrhythmia and its association with sudden death in dialysis dependent ESRD, describe the potential for implantable devices to advance study of dialysis physiology, review the ethical implications of using implantable devices in clinical studies, and report on the protocol and baseline results of the Monitoring in Dialysis Study (MiD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this multicenter, interventional-observational, prospective cohort study, we placed implantable loop recorders in patients undergoing long term hemodialysis. The proportion of patients experiencing clinically significant arrhythmias was the primary endpoint. For 6 months, we captured detailed data on the primary endpoint, symptomatic arrhythmias, other electrocardiographic variables, dialysis prescription, electrolytes, dialysis-related variables, and vital signs. We collected additional electrocardiographic data for up to 1 year. RESULTS: Overall, 66 patients underwent implantation in sites in the United States and India. Diabetes was present in 63.6% of patients, 12.1% were age >=70 years, 69.7% were men, and 53.0% were black. Primary and secondary endpoint data are expected in 2016. CONCLUSIONS: Cardiac arrhythmia is an important contributor to cardiovascular morbidity and mortality in dialysis patients, but available technology has previously limited the ability to estimate its true burden and triggers and to define terminal rhythms in sudden death. Use of implantable technology in observational studies raises complex issues but may greatly expand understanding of dialysis physiology. The use of implantable loop recorders in MiD is among the first examples of such a trial, and the results are expected to provide novel insights into the nature of arrhythmia in hemodialysis patients. PMID- 26763258 TI - Commentary: Physician-Modified vs Off-the-Shelf Fenestrated and Branched Endografts: Is This a Fair Comparison? PMID- 26763259 TI - Commentary: Computational Biomechanics-Based Rupture Prediction of Abdominal Aortic Aneurysms. PMID- 26763261 TI - Commentary: Cilostazol and Carotid Stenting: A Merry Marriage? PMID- 26763260 TI - AlluraClarity Radiation Dose-Reduction Technology in the Hybrid Operating Room During Endovascular Aneurysm Repair. AB - PURPOSE: To evaluate the effect of radiation dose reduction with the Allura ClarityIQ image processing technology for fixed C-arms in comparison with a mobile C-arm and an Allura fixed C-arm without ClarityIQ technology during endovascular aneurysm repair (EVAR) procedures. METHODS: Radiation dose data from 85 patients (mean age 74.2+/-7.8 years; 68 men) undergoing EVAR with mobile and fixed C-arm fluoroscopy were retrospectively analyzed. The radiation dose parameters included the kerma area product (KAP), fluoroscopic time (FT), and number of digital subtraction angiography (DSA) frames (FrDSA). KAPtotal consisted of KAPfluoro (KAP for fluoroscopic imaging) and KAPDSA (KAP for DSA and single shots). Linear regression analysis was used to explore differences in the association of KAP with the FT, FrDSA, and body mass index (BMI) among the 3 C arms. RESULTS: The mean KAPtotal values for mobile, Allura C-arm, and AlluraClarity C-arm for noncomplex EVARs were 56+/-39, 245+/-142, and 157+/-120 Gy.cm(2) (p<0.001); for complex EVARs, the values were 110+/-43, 874+/-653, and 598+/-319 Gy.cm(2) (p<0.001), respectively. On average, KAPfluoro tripled when the mobile C-arm was replaced by the fixed C-arm. There were no significant differences in the KAPfluoro adjusted for the FT between Allura and AlluraClarity (p=0.69). However, there was a major 61% reduction in KAPDSA from 1.36 Gy.cm(2) per DSA frame for Allura to 0.54 Gy.cm(2) per DSA frame with AlluraClarity (p=0.03). For the mobile C-arm, BMI was not associated with KAP (p=0.13). The associations of BMI with KAPfluoro and KAPDSA were significant for both fixed C arms but were more robust for Allura compared to AlluraClarity (p=0.02 for KAPfluoro and p<0.001 for KAPDSA). CONCLUSION: Changing a mobile C-arm for a fixed C-arm in a hybrid operating suite increased the average intraoperative dose during EVAR. Upgrading the Allura fixed C-arm with ClarityIQ technology resulted in a 61% reduction in the radiation per DSA frame. PMID- 26763262 TI - Commentary: The Zenith t-Branch Endograft: What Have We Learned So Far? PMID- 26763265 TI - Corrigendum. Combined Directional Atherectomy and Drug-Eluting Balloon Angioplasty for Isolated Popliteal Artery Lesions in Patients With Peripheral Artery Disease. PMID- 26763263 TI - Internal Iliac Artery Disease Management: Still Absent in the Update to TASC II (Inter-Society Consensus for the Management of Peripheral Arterial Disease). PMID- 26763267 TI - Semen quality and interval to sterility in tom cats treated with a 9.4 mg deslorelin implant. AB - Objectives Gonadotropin-releasing hormone (GnRH) agonists like deslorelin are being increasingly used in tom cats for their efficacy in controlling reproductive behaviour and fertility. Deslorelin implants have been widely available in Europe since 2008. Little, if anything, is known about the interval between treatment and onset of sterility, as well as semen quality, after treatment in tom cats. The purpose of this study was to investigate semen quality and interval to sterility in tom cats treated with a 9.4 mg deslorelin implant. Methods Fifteen healthy adult tom cats were treated with a 9.4 mg deslorelin implant (Suprelorin 12). For each cat, semen collection and a GnRH stimulation test (intramuscular administration of 50 MUg gonadorelin [Fertagyl], followed by blood sampling 1 h later, to assay serum testosterone) were performed on the first consultation and then repeated every 15 days until complete sterility was achieved. Semen collection was performed by introducing a 14 cm, open-end feline catheter (Argyle) 9 cm into the distal urethra 10 mins after sedation by intramuscular injection of 100 MUg/kg medetomidine (Domitor). Results Semen collection was not successful in all cats at each attempt. In the first month after treatment, the semen of only four cats could be evaluated, while the semen of eight cats could be evaluated during the second and third months of the study. Semen quality (ejaculate volume, progressive motility and morphological abnormalities) improved slightly during the first 19-25 days in 2/4 cats, and in 1/4 cats motility was still very high (80%) 25 days post-treatment (PT), but we have no data regarding fertility prior to treatment in this cat. The last cat never produced spermatozoa. Subsequently, semen quality gradually worsened in all cats from 30 days onwards. At 70 days PT, one cat was still potentially fertile. After 72 days all cats were sterile. Conclusions and relevance Semen quality increased slightly in treated cats during the first month after treatment, and then gradually decreased over the following months. Complete sterility was reached within 40-72 days following implantation. PMID- 26763268 TI - Replantation of digits: a review of predictive factors for survival. AB - The survival of 75 consecutive digital replantations carried out between 2006 and 2010 at a regional hand centre in the United Kingdom was determined. The patient demographics, mechanism of injury, co-morbid factors, operative and post operative details were extracted and reviewed from the medical and hand therapy notes. Predictive factors of survival were determined by using univariate and multivariate statistical analysis. The survival rate was 70%. Arterial thrombosis was the leading cause of replant failure, followed by venous congestion. Smoking, level of amputation, number of nerves repaired, warm ischaemia time and timing of replantation were independent predictors of replant survival. However, only warm ischaemia time less than 6 hours and 30 minutes and replantations done within 'office hours' showed significance on multivariate logistic regression. Our study suggests that replantations done in daylight hours, when feasible, with rested staff and a full complement of the theatre team are likely to have better outcomes. LEVEL OF EVIDENCE: Level IV case series. PMID- 26763270 TI - The correlation of initial radiographic characteristics of distal radius fractures and injuries of the triangular fibrocartilage complex. AB - Our purpose was to determine the correlation of initial radiographic parameters of a distal radius fracture with an injury of the triangular fibrocartilage complex. In a prospective study, 85 patients with surgically treated distal radius fractures were included. Wrist arthroscopy was used to identify and classify triangular fibrocartilage complex lesions. The initial radial length and angulation, dorsal angulation, ulnar variance and distal radioulnar distance were measured. Wrist arthroscopy identified a triangular fibrocartilage complex lesion in 45 patients. Statistical analysis did not identify a correlation with any single radiographic parameter of the distal radius fractures with the associated triangular fibrocartilage complex injuries. The initial radiograph of a distal radius fracture does not predict a triangular fibrocartilage complex injury. LEVEL OF EVIDENCE: III. PMID- 26763269 TI - From the brachial plexus to the hand, multiple connections between the median and ulnar nerves may serve as bypass routes for nerve fibres. AB - Axons from the median and ulnar nerves can pass to each other through aberrant connections between them. Multiple interconnections between the nerves may provide a detour route for nerve fibres going to the hand. We investigated the incidence of variations and the associations between them in 90 cadaveric upper limbs. In 91% of upper limbs, one to five variations were found, with several statistically significant associations. The contribution of the C8 nerve to the lateral cord was positively associated with an accessory contribution of the lateral cord to the ulnar nerve. The latter variation showed positive association with the occurrence of any of the variations in the hand itself. Ulnar innervation of the superficial head of the flexor pollicis brevis was positively associated with the Riche-Cannieu communication. The co-existence of the variations and their associations may be the explanation for unusual clinical findings related to median and ulnar conduction, which appear contrary to anatomical knowledge. PMID- 26763271 TI - Extracorporeal shock wave therapy versus corticosteroid injection in the treatment of trigger finger: a randomized controlled study. AB - : The purpose of this study was to compare the efficacies of extracorporeal shock wave therapy and corticosteroid injection for the management of trigger finger. In this prospective randomized clinical trial, 40 patients with actively correctable trigger fingers were randomly assigned to extracorporeal shock wave therapy (1000 impulses and 2.1 bar) or injection groups. The effectiveness of the treatment was assessed using cure rates, a visual analogue scale, the frequency of triggering, the severity of triggering, the functional impact of triggering, and the Quick-Disabilities of the Arm, Shoulder, and Hand questionnaire at 1, 3, and 6 months after treatment. An intention-to- treat analysis was used in this study. Both groups demonstrated statistically significant improvements in all outcome measures after treatment. The intention-to-treat analyses showed no between-group differences for cure rates, pain, and functional status at follow up. We conclude that extracorporeal shock wave therapy could be a non-invasive option for treating trigger finger, especially for those patients who wish to avoid steroid injections. LEVEL OF EVIDENCE: Level II. PMID- 26763272 TI - Recovery of rock climbing performance after surgical reconstruction of finger pulleys. AB - This study evaluated recovery of sport performance and correction of bowstringing after surgical reconstruction of closed finger pulley rupture in high-level rock climbers. A total of 38 patients treated with an extensor retinaculum graft were assessed. The mean follow-up time was 85 months, and 30 patients returned to their previous climbing level. The mean total active motion score was 96% of the opposite side. All patients had an excellent Buck-Gramcko score. There was no significant difference in grip strength and tip pinch strength in the crimp position between the injured side and the opposite side. A total of 31 patients were examined with ultrasonography. In 18, flexor bowstringing effects had returned to near-normal values. There was an association between rock climbing level recovery and the flexor bowstringing correction (odds ratio, 6.9; 95% confidence interval, 1.1-42.8). If flexor bowstringing was corrected, patients were more likely to regain their preinjury sport performance. The ultrasonography measurement was a useful tool for predicting functional recovery. LEVEL OF EVIDENCE: 4. PMID- 26763273 TI - Anatomy of the deep branch of the ulnar nerve. AB - The aim of this study was to provide a clear description of the course, precise branching pattern and distribution of the deep branch of the ulnar nerve. A total of 36 hands from 18 preserved cadavers were dissected. The vertical distance from the pisoscaphoid line to the crossing points between the deep branch of the ulnar nerve and each metacarpal was about 4 cm. The deep branch of the ulnar nerve gave off two types of muscular branches: (1) trunks that innervate more than two intrinsic hand muscles; and (2) multiple separate branches innervating only a single muscle. The median numbers of trunks and separate branches were 5 and 6, respectively. LEVELS OF EVIDENCE: N/A. PMID- 26763274 TI - Long-term outcome of patients with hereditary transthyretin V30M amyloidosis with polyneuropathy after liver transplantation. AB - BACKGROUND: Liver transplantation halts production of mutated transthyretin (TTR), and thus it is an accepted treatment, with improved survival, in patients with hereditary (familial) amyloidosis with polyneuropathy (FAP). However, the effects of transplantation on the clinical manifestations of FAP have not yet been adequately clarified. This study aimed to investigate whether liver transplantation would improve the long-term clinical manifestations in FAP patients who had undergone transplantations. PATIENTS AND METHODS: We assessed 29 non-transplant and 36 transplant FAP V30M patients using an FAP clinical scoring system. RESULTS: The total clinical score of the non-transplant group increased and was significantly correlated with FAP duration; that of the transplant group increased slowly after transplantation. In patients 5 years or more after FAP onset, the total clinical scores of the transplant group were significantly lower than those of the non-transplant group. In the same patients, scores for sensory, motor, autonomic and organ impairments of the transplant group were significantly lower than those of the non-transplant group. CONCLUSIONS: Liver transplantation had beneficial effects on FAP clinical manifestations in patients with FAP TTR V30M. Liver transplantation should therefore be considered as an effective treatment in the clinical management of patients with FAP TTR V30M. PMID- 26763275 TI - Graphene quantum dots as the electrolyte for solid state supercapacitors. AB - We propose that graphene quantum dots (GQDs) with a sufficient number of acidic oxygen-bearing functional groups such as -COOH and -OH can serve as solution- and solid- type electrolytes for supercapacitors. Moreover, we found that the ionic conductivity and ion-donating ability of the GQDs could be markedly improved by simply neutralizing their acidic functional groups by using KOH. These neutralized GQDs as the solution- or solid-type electrolytes greatly enhanced the capacitive performance and rate capability of the supercapacitors. The reason for the enhancement can be ascribed to the fully ionization of the weak acidic oxygen bearing functional groups after neutralization. PMID- 26763276 TI - Meta-analysis reveals PTPN22 1858C/T polymorphism confers susceptibility to rheumatoid arthritis in Caucasian but not in Asian population. AB - The PTPN22 1858C/T polymorphism is associated with rheumatoid arthritis (RA). However, reports from the Asian populations are conflicting in nature and lacks consensus. The aim of our study was to evaluate the association between the PTPN22 1858C/T polymorphism and RA in Asian and Caucasian subjects by carrying out a meta-analysis of Asian and Caucasian data. A total of 27 205 RA cases and 27 677 controls were considered in the present meta-analysis involving eight Asian and 35 Caucasian studies. The pooled odds ratios (ORs) were performed for the allele, dominant, and recessive genetic model. No statistically significant association was found between the PTPN22 1858C/T polymorphism and risk of RA in Asian population (allele genetic model: OR = 1.217, 95% confidence interval (CI) = 0.99-1.496, p value 0.061; dominant genetic model: OR = 1.238, 95% CI = 0.982 1.562, p value 0.071; recessive genetic model: OR = 1.964, 95% CI = 0.678-5.693, p value 0.213). A significant association with risk of RA in Caucasian population suggesting that T-- allele does confer susceptibility to RA in this subgroup was observed (allele genetic model: OR = 1.638, 95% CI = 1.574-1.705, p value < 0.0001; dominant genetic model: OR = 1.67, 95% CI = 1.598-1.745, p value < 0.0001; recessive genetic model: OR = 2.65, 95% CI = 2.273-3.089, p value < 0.0001). The PTPN22 1858C/T polymorphism is not associated with RA risk in Asian populations. However, our meta-analysis confirms that the PTPN22 1858C/T polymorphism is associated with RA susceptibility in Caucasians. PMID- 26763278 TI - Cystatin C: One more component of the complex cardiorenal interaction in heart failure. PMID- 26763277 TI - Cysteine Dioxygenase Type 1 Inhibits Osteogenesis by Regulating Wnt Signaling in Primary Mouse Bone Marrow Stromal Cells. AB - Mesenchymal stem cells (MSCs) are multipotent cells, which can give rise to variety of cell types, including adipocytes and osteoblasts. Previously, we have shown that cysteine dioxygenase type 1 (Cdo1) promoted adipogenesis of primary mouse bone marrow stromal cells (BMSCs) and 3T3-L1 pre-adipocytes via interaction with Ppargamma. However, the role of Cdo1 in osteogenesis remains unclear. Here, we demonstrated that expression of Cdo1 was elevated during osteoblastic differentiation of BMSCs in vitro. Interestingly, knockdown of Cdo1 by siRNA led to an increased expression of osteogenic related genes, elevated alkaline phosphatase (ALP) activity, and enhanced mineralization. Overexpression of Cdo1 in BMSCs inversely suppressed the osteogenesis. Furthermore, we found that overexpression of Cdo1 impaired Wnt signaling and restricted the Wnt3a induced expression of osteogenic transcriptional factors, such as Runx2 and Dlx5. Collectively, our findings indicate Cdo1 suppresses osteogenic differentiation of BMSCs, through a potential mechanism which involves in Wnt signaling reduction concomitantly. PMID- 26763279 TI - Novel Molecular Imaging Approaches to Abdominal Aortic Aneurysm Risk Stratification. AB - Selection of patients for abdominal aortic aneurysm repair is currently based on aneurysm size, growth rate, and symptoms. Molecular imaging of biological processes associated with aneurysm growth and rupture, for example, inflammation and matrix remodeling, could improve patient risk stratification and lead to a reduction in abdominal aortic aneurysm morbidity and mortality. (18)F fluorodeoxyglucose-positron emission tomography and ultrasmall superparamagnetic particles of iron oxide magnetic resonance imaging are 2 novel approaches to abdominal aortic aneurysm imaging evaluated in clinical trials. A variety of other tracers, including those that target inflammatory cells and proteolytic enzymes (eg, integrin alphavbeta3 and matrix metalloproteinases), have proven effective in preclinical models of abdominal aortic aneurysm and show great potential for clinical translation. PMID- 26763280 TI - Prognosis of Myocardial Damage in Sarcoidosis Patients With Preserved Left Ventricular Ejection Fraction: Risk Stratification Using Cardiovascular Magnetic Resonance. AB - BACKGROUND: Cardiac sarcoidosis is associated with an increased risk of heart failure and sudden death, but its risk in patients with preserved left ventricular ejection fraction is unknown. Using cardiovascular magnetic resonance in patients with extracardiac sarcoidosis and preserved left ventricular ejection fraction, we sought to (1) determine the prevalence of cardiac sarcoidosis or associated myocardial damage, defined by the presence of late gadolinium enhancement (LGE), (2) quantify their risk of death/ventricular tachycardia (VT), and (3) identify imaging-based covariates that predict who is at greatest risk of death/VT. METHODS AND RESULTS: Parameters of left and right ventricular function and LGE burden were measured in 205 patients with left ventricular ejection fraction >50% and extracardiac sarcoidosis who underwent cardiovascular magnetic resonance for LGE evaluation. The association between covariates and death/VT in the entire group and within the LGE+ group was determined using Cox proportional hazard models and time-dependent receiver-operator curves analysis. Forty-one of 205 patients (20%) had LGE; 12 of 205 (6%) died or had VT during follow-up; of these, 10 (83%) were in the LGE+ group. In the LGE+ group (1) the rate of death/VT per year was >20* higher than LGE- (4.9 versus 0.2%, P<0.01); (2) death/VT were associated with a greater burden of LGE (14+/-11 versus 5+/-5%, P<0.01) and right ventricular dysfunction (right ventricular EF 45+/-12 versus 53+/-28%, P=0.04). LGE burden was the best predictor of death/VT (area under the receiver-operating characteristics curve, 0.80); for every 1% increase of LGE burden, the hazard of death/VT increased by 8%. CONCLUSIONS: Sarcoidosis patients with LGE are at significant risk for death/VT, even with preserved left ventricular ejection fraction. Increased LGE burden and right ventricular dysfunction can identify LGE+ patients at highest risk of death/VT. PMID- 26763282 TI - Prognosis of Myocardial Damage in Sarcoidosis Patients With Preserved Left Ventricular Ejection Fraction: Always Look at the Bright Side of Cardiovascular Magnetic Resonance. PMID- 26763283 TI - Intramyocardial Hemorrhage in Acute Myocardial Infarction: Prognostic Biomarker and Treatment Target? PMID- 26763281 TI - Myocardial Hemorrhage After Acute Reperfused ST-Segment-Elevation Myocardial Infarction: Relation to Microvascular Obstruction and Prognostic Significance. AB - BACKGROUND: The success of coronary reperfusion therapy in ST-segment-elevation myocardial infarction (MI) is commonly limited by failure to restore microvascular perfusion. METHODS AND RESULTS: We performed a prospective cohort study in patients with reperfused ST-segment-elevation MI who underwent cardiac magnetic resonance 2 days (n=286) and 6 months (n=228) post MI. A serial imaging time-course study was also performed (n=30 participants; 4 cardiac magnetic resonance scans): 4 to 12 hours, 2 days, 10 days, and 7 months post reperfusion. Myocardial hemorrhage was taken to represent a hypointense infarct core with a T2* value of <20 ms. Microvascular obstruction was assessed with late gadolinium enhancement. Adverse remodeling was defined as an increase in left ventricular end-diastolic volume >=20% at 6 months. Cardiovascular death or heart failure events post discharge were assessed during follow-up. Two hundred forty-five patients had evaluable T2* data (mean+/-age, 58 [11] years; 76% men). Myocardial hemorrhage 2 days post MI was associated with clinical characteristics indicative of MI severity and inflammation. Myocardial hemorrhage was a multivariable associate of adverse remodeling (odds ratio [95% confidence interval]: 2.64 [1.07 6.49]; P=0.035). Ten (4%) patients had a cardiovascular cause of death or experienced a heart failure event post discharge, and myocardial hemorrhage, but not microvascular obstruction, was associated with this composite adverse outcome (hazard ratio, 5.89; 95% confidence interval, 1.25-27.74; P=0.025), including after adjustment for baseline left ventricular end-diastolic volume. In the serial imaging time-course study, myocardial hemorrhage occurred in 7 (23%), 13 (43%), 11 (33%), and 4 (13%) patients 4 to 12 hours, 2 days, 10 days, and 7 months post reperfusion. The amount of hemorrhage (median [interquartile range], 7.0 [4.9-7.5]; % left ventricular mass) peaked on day 2 (P<0.001), whereas microvascular obstruction decreased with time post reperfusion. CONCLUSIONS: Myocardial hemorrhage and microvascular obstruction follow distinct time courses post ST-segment-elevation MI. Myocardial hemorrhage was more closely associated with adverse outcomes than microvascular obstruction. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02072850. PMID- 26763284 TI - Acute hepatotoxicity associated with therapeutic doses of intravenous acetaminophen. AB - BACKGROUND: IV acetaminophen at 4 g per day is considered safe, producing no hepatic failure in more than 1400 cases. Oxidation of acetaminophen forms a reactive intermediate that binds to cellular proteins resulting in acetaminophen protein adducts (APAP-CYS). Serum concentrations of APAP-CYS have been found to correlate with acetaminophen-induced hepatotoxicity. We report a case of hepatotoxicity associated with therapeutic doses of IV acetaminophen, with elevated serum APAP-CYS. CASE DETAILS: The patient was a 92-year-old, 68 kg woman without known hepatic disease or ethanol abuse. On hospital day 3 she underwent laparoscopic reduction of internal hernias under general anesthesia. Surgery was uncomplicated and postoperatively she was treated with subcutaneous heparin and IV acetaminophen, 1 g every 6 h for almost 4 days (total dose = 13 g). At the start of therapy, transaminases were normal. On hospital day 5, she was noted to have marked transaminase elevations (AST: 4698 IU/L; ALT: 3914 IU/L) with increases in INR (1.68), ammonia (60 mcg/dL), and total bilirubin (1.8 mg/dL). Serum acetaminophen concentration was 15.3 mcg/mL 26 h after her last dose. Acetaminophen was discontinued and IV acetylcysteine was given and continued at the second maintenance dose rate for a second 16-hour infusion, at which time transaminases, INR, ammonia and total bilirubin were all improving. The patient was discharged 2 days later. Serum APAP-CYS concentrations in serum samples obtained during her hospitalization were elevated (peak = 4.81 MUM on hospital day 5; expected range for therapeutic dosing <1.1 MUM). CASE DISCUSSION: We have identified a case of acute liver injury associated with therapeutic dosing of IV acetaminophen. The serum APAP-CYS concentrations are consistent with that seen in cases of hepatotoxicity following repeated supratherapeutic acetaminophen ingestion. Several factors that likely contributed to her susceptibility included advanced age, post-operative status, a likely catabolic state and multiple acetaminophen doses over several days. These uncommon circumstances limit the generalizability of risk. We believe the findings are most consistent with acetaminophen-induced liver injury. CONCLUSION: This case illustrates a potential hazard of IV acetaminophen and demonstrates the potential utility of APAP-CYS adducts in evaluating causality in acute liver injury. PMID- 26763286 TI - The Role of Forensic Factors and Potential Harm to the Child in the Decision Not to Act Among Men Sexually Attracted to Children. AB - To date, sexual abuse prevention efforts have largely focused on tertiary prevention strategies designed to prevent recidivism among forensic samples of men with a history of sex offending behavior. The present study used mixed methodology to investigate the role of several forensic and related factors on the decision not to commit a sex offense among two groups of community men who self-reported a sexual attraction to children: those who reported a history of acting on their attractions (Acted, n = 29) and those who reported never acting on their attractions (Not Acted, n = 71). Participants from both groups described in their own words the factors that contributed to their decision not to act on their attractions. They also responded to quantitative and qualitative questions regarding the influence and role of the following factors on their decision not to act: (a) the possibility of jail or punishment, (b) mental health treatment, and (c) not wanting to hurt the child. Results were compared across groups, and across prompted and unprompted responses. Analyses highlighted harm to the child as a particularly salient factor in the decision not to act among men in the community at risk for sexually offending. The present study suggests that investigating potential protective factors may be an important direction for future research among samples of community men at risk for both first-time and repeat offenses against children. PMID- 26763285 TI - Experiences of Discrimination, Harassment, and Violence in a Sample of Italian Transsexuals Who Have Undergone Sex-Reassignment Surgery. AB - The present study aims to provide an overview of experiences of discrimination, harassment, and violence in a sample of Italian transsexuals who have undergone sex-reassignment surgery (SRS). Lack of support for gender transition from family members was also assessed, before and after SRS. Data were collected in the context of a multicentric study (Milan, Florence, and Bari) on SRS outcome. Patients who underwent SRS were contacted and asked to fill out a questionnaire concerning experiences of discrimination, harassment, violence, and crime they might have experienced in previous years. Seventy-two participants took part in the research: 46 were male-to-female (MtF; 64%) and 26 were female-to-male (FtM; 36%). Thirty-six percent of the total sample (with no differences between MtF and FtM) experienced at least one episode of harassment, violence, or discrimination. The workplace was reported to be the social area with the highest risk of discrimination and harassment (22% of participants). Reports of more than one incident of discrimination, harassment, and violence characterized the majority of participants in the MtF sample. Compared with previous studies carried out in other countries, a much larger proportion of participants could count on a supportive family environment before and after transition. Our results show that Italian society at large is prejudiced against transsexuals, but at a more "micro" level, having a trans person as a family member might result in a protective and tolerant attitude. PMID- 26763287 TI - Male Peer Support to Hostile Sexist Attitudes Influences Rape Proclivity. AB - Sexual assault affects a large proportion of women in the world. Although most rapes are committed by one man, the act itself may be influenced by many (e.g., the peer group). Hostile sexism (HS) has repeatedly been associated with men's rape proclivity, but the influence exerted by the HS of the peer group on rape proclivity has not been investigated. In this study, we explored the impact of perceived male peer support to HS on participants' rape proclivity. A sample of Spanish undergraduate students from a university in the south of Spain ( N = 134) completed the Ambivalent Sexism Inventory. Immediately afterwards, they received feedback on the supposed sexist responses of a peer group (high vs. low in HS); we kept the benevolent sexism (BS) of the peer group at medium levels. Next, we assessed participants' rape proclivity using acquaintance rape scenarios. Results showed an interaction between participants' own levels of HS and information about the HS of the peer group. Men high in HS reported higher rape proclivity in the high-HS peer-group condition than in the low-HS peer-group condition. By contrast, information on the peer group did not affect self-reported rape proclivity of men low in HS. Results also corroborated the relationship between participants' levels of HS and rape proclivity, and expanded the literature by revealing an unexpected influence of participants' BS on rape proclivity. PMID- 26763288 TI - Hyperglycemia at presentation is associated with in hospital mortality in non diabetic patient with organophosphate poisoning. AB - AIMS: This study evaluated whether the initial venous glucose level at presentation is associated with fatality in organophosphate (OP)-poisoned patients without diabetes mellitus (DM) and whether the association between glucose and outcome differs depending on the chemical formulation of the OP ingested. METHODS: This retrospective observational case series consisted of 184 patients without DM who had a history of OP poisoning. Initial glucose level at presentation, outcome and general clinical data were recorded. The patients were categorized into the following groups according to their glucose level at presentation: group 1 (<140 mg/dl, n = 63), group 2 (140-200 mg/dl, n = 58), group 3 (200-300 mg/dl, n = 41), and group 4 (>=300 mg/dl, n = 22). The most commonly ingested OPs were dichlorvos (n = 33), fenitrothion (n = 25), and ethyl p-nitrophenol thio-benzene phosphonate (EPN) (n = 24). The primary outcome was case fatality. RESULTS: Group 4 had a higher case fatality than groups 1 (p = 0.003) and 2 (p = 0.015), and group 3 had a higher case fatality than group 1 (p = 0.040). Multivariate analysis revealed that age [odds ratio (OR) 1.065, 95% confidence interval (CI) 1.020-1.112, p = 0.001], being in group 3 (OR 6.997, 95% CI 1.063-46.066, p = 0.043) and being in group 4 (OR 9.101, 95% CI 1.380-60.044, p = 0.022) were associated with case fatality. When using the glucose level at presentation > 233 mg/dl, the dichlorvos group had a higher sensitivity (66.7% vs. 50.0%), specificity (90.0% vs. 86.4%), and positive (40.0% vs. 25.0%) and negative (96.4% vs. 95.0%) predictive values for predicting case fatality than the EPN group. No patient died of fenitrothion poisoning (mean glucose level at presentation = 169.4 +/- 39.6 mg/dl). CONCLUSION: The case fatality risk independently increases as the initial venous glucose level at presentation increases in OP-poisoned patients without DM. However, because the association between the venous glucose level at presentation and case fatality varies according to the type of OP ingested, the chemical identity of the OP should be considered. PMID- 26763289 TI - Benchmarking Deep Networks for Predicting Residue-Specific Quality of Individual Protein Models in CASP11. AB - Quality assessment of a protein model is to predict the absolute or relative quality of a protein model using computational methods before the native structure is available. Single-model methods only need one model as input and can predict the absolute residue-specific quality of an individual model. Here, we have developed four novel single-model methods (Wang_deep_1, Wang_deep_2, Wang_deep_3, and Wang_SVM) based on stacked denoising autoencoders (SdAs) and support vector machines (SVMs). We evaluated these four methods along with six other methods participating in CASP11 at the global and local levels using Pearson's correlation coefficients and ROC analysis. As for residue-specific quality assessment, our four methods achieved better performance than most of the six other CASP11 methods in distinguishing the reliably modeled residues from the unreliable measured by ROC analysis; and our SdA-based method Wang_deep_1 has achieved the highest accuracy, 0.77, compared to SVM-based methods and our ensemble of an SVM and SdAs. However, we found that Wang_deep_2 and Wang_deep_3, both based on an ensemble of multiple SdAs and an SVM, performed slightly better than Wang_deep_1 in terms of ROC analysis, indicating that integrating an SVM with deep networks works well in terms of certain measurements. PMID- 26763291 TI - Encouraging post-stroke patients to be active seems possible: results of an intervention study with knowledge brokers. AB - PURPOSE: Although physical activity and exercise for stroke patients is highly recommended for fast recovery, patients in hospitals and rehabilitation centres are insufficiently encouraged to be physically active. In this study, we investigated the impact of knowledge brokers (KBs), enterprising nurses and therapists, on health professionals' (HP) performance to encourage stroke inpatients to be physically active. METHOD: This multicenter intervention study used a pre-post test design. Two or three KBs were trained in each stroke unit of 12 hospitals and 10 rehabilitation centres in The Netherlands. Questionnaires were completed by patients and HPs before and after the KB-intervention. The primary outcome was encouragement given by HPs to their patients to be physically active, as reported by patients and HPs. RESULTS: After the KB-intervention, many more patients (48%; N=217) reported at least some encouragement by HPs to be physically active than before (26%; N=243, p<0.000). HPs (N=288) on an average reported encouraging patients more often after the intervention, but this difference was significant only for occupational therapists and KBs. CONCLUSIONS: Based on patient's reports of HP behaviour, the KB-intervention appears effective since more patients felt encouraged to be physically active after the intervention compared to before. Replication of this study in an experimental design is needed to allow causal inferences. Implications for rehabilitation We advise rehabilitation teams to make use of knowledge brokers (KBs), since the KB intervention was shown to increase the encouragement felt by stroke patients to be physically active. It seems worthwhile to involve physicians, nurses and patients' families more frequently in efforts to encourage stroke patients to be physically active. PMID- 26763293 TI - Open-Source 3-D Platform for Low-Cost Scientific Instrument Ecosystem. AB - The combination of open-source software and hardware provides technically feasible methods to create low-cost, highly customized scientific research equipment. Open-source 3-D printers have proven useful for fabricating scientific tools. Here the capabilities of an open-source 3-D printer are expanded to become a highly flexible scientific platform. An automated low-cost 3-D motion control platform is presented that has the capacity to perform scientific applications, including (1) 3-D printing of scientific hardware; (2) laboratory auto-stirring, measuring, and probing; (3) automated fluid handling; and (4) shaking and mixing. The open-source 3-D platform not only facilities routine research while radically reducing the cost, but also inspires the creation of a diverse array of custom instruments that can be shared and replicated digitally throughout the world to drive down the cost of research and education further. PMID- 26763290 TI - Chronic Co-Administration of Sepiapterin and L-Citrulline Ameliorates Diabetic Cardiomyopathy and Myocardial Ischemia/Reperfusion Injury in Obese Type 2 Diabetic Mice. AB - BACKGROUND: Diabetic heart disease is associated with tetrahydrobiopterin oxidation and high arginase activity, leading to endothelial nitric oxide synthase dysfunction. Sepiapterin (SEP) is a tetrahydrobiopterin precursor, and L citrulline (L-Cit) is converted to endothelial nitric oxide synthase substrate, L arginine. Whether SEP and L-Cit are effective at reducing diabetic heart disease is not known. The present study examined the effects of SEP and L-Cit on diabetic cardiomyopathy and ischemia/reperfusion injury in obese type 2 diabetic mice. METHODS AND RESULTS: Db/db and C57BLKS/J mice at 6 to 8 weeks of age received vehicle, SEP, or L-Cit orally alone or in combination for 8 weeks. Cardiac function was evaluated with echocardiography. Db/db mice displayed hyperglycemia, obesity, and normal blood pressure and cardiac function compared with C57BLKS/J mice at 6 to 8 weeks of age. After vehicle treatment for 8 weeks, db/db mice had reduced ejection fraction, mitral E/A ratio, endothelium-dependent relaxation of coronary arteries, tetrahydrobiopterin concentrations, ratio of endothelial nitric oxide synthase dimers/monomers, and nitric oxide levels compared with vehicle-treated C57BLKS/J mice. These detrimental effects of diabetes mellitus were abrogated by co-administration of SEP and L-Cit. Myocardial infarct size was increased, and coronary flow rate and +/- dP/dt were decreased during reperfusion in vehicle-treated db/db mice subjected to ischemia/reperfusion injury compared with control mice. Co-administration of SEP and L-Cit decreased infarct size and improved coronary flow rate and cardiac function in both C57BLKS/J and db/db mice. CONCLUSIONS: Co-administration of SEP and L-Cit limits diabetic cardiomyopathy and ischemia/reperfusion injury in db/db mice through a tetrahydrobiopterin/endothelial nitric oxide synthase/nitric oxide pathway. PMID- 26763292 TI - One-Minute Room-Temperature Transfer-Free Production of Mono- and Few-Layer Polycrystalline Graphene on Various Substrates. AB - Graphene deposited on various substrates has attracted the attention of the scientific and technical communities for use in a wide range of applications. Graphene on substrates is commonly produced by two types of methods, namely, methods that require a transfer step and transfer-free methods. Compared with methods that require a transfer step, transfer-free methods have a simpler procedure and a lower cost. Thus, transfer-free methods have considerable potential to meet the industrial and commercial demands of production methods. However, some limitations of the current transfer-free methods must be overcome, such as the high temperatures encountered during production, the relatively long manufacturing times, incompatibilities for both rigid and flexible substrates, and an inability to extend the process to other two-dimensional (2-D) atomic crystals. In this work, a room-temperature rubbing method is developed for the rapid transfer-free production of defect-free polycrystalline graphene on rigid and flexible substrates. Starting with inexpensive commercially obtained graphite powder, mono- and few-layer graphene can be fabricated directly on various substrates, with an average production time of less than one minute (from raw graphite to graphene on the substrate). Importantly, this method can be extended to other 2-D atomic crystals. PMID- 26763294 TI - Open-Source Wax RepRap 3-D Printer for Rapid Prototyping Paper-Based Microfluidics. AB - The open-source release of self-replicating rapid prototypers (RepRaps) has created a rich opportunity for low-cost distributed digital fabrication of complex 3-D objects such as scientific equipment. For example, 3-D printable reactionware devices offer the opportunity to combine open hardware microfluidic handling with lab-on-a-chip reactionware to radically reduce costs and increase the number and complexity of microfluidic applications. To further drive down the cost while improving the performance of lab-on-a-chip paper-based microfluidic prototyping, this study reports on the development of a RepRap upgrade capable of converting a Prusa Mendel RepRap into a wax 3-D printer for paper-based microfluidic applications. An open-source hardware approach is used to demonstrate a 3-D printable upgrade for the 3-D printer, which combines a heated syringe pump with the RepRap/Arduino 3-D control. The bill of materials, designs, basic assembly, and use instructions are provided, along with a completely free and open-source software tool chain. The open-source hardware device described here accelerates the potential of the nascent field of electrochemical detection combined with paper-based microfluidics by dropping the marginal cost of prototyping to nearly zero while accelerating the turnover between paper-based microfluidic designs. PMID- 26763295 TI - Children with congenital limb deficiency in Norway: issues related to school life and health-related quality of life. A cross-sectional study. AB - PURPOSE: To describe clinical features, issues related to school life and health related quality of life (HRQOL) for children with congenital limb deficiency (CLD) and compare these children to Norwegian school children on HRQOL. METHOD: Cross-sectional study. In 2010, a postal questionnaire, designed for this study and the Paediatric Quality of Life Inventory (PedsQL), was sent to 154 eligible parents of children with CLD, aged 6-18 years and registered at TRS National Resource Centre for Rare Disorders in Norway. RESULTS: Response rate 44% (n = 67), median age 11 years, 42% were girls. Of the total group, 46 had unilateral upper limb deficiency (UULD) and 21 had multiple/lower limb deficiency (MLD/LLD). The most common UULD was below-elbow deficiency, of these, 65% used grip improving devices, and 35% used prostheses. Children with UULD-reported PedsQL score similar to Norwegian schoolchildren (NSC). The MLD/LLD group was heterogeneous; most had below-elbow/knee deficiency. In this group, PedsQL scores were reduced for physical and social functioning compared with NSC. Compared with children with UULD, more children with MLD/LLD were restricted in participation because of pain and fewer participated in physical education with peers. CONCLUSIONS: Most children with CLD participated with their peers and managed well in everyday life. Children with MLD/LLD seemed to have more challenges than children with UULD. Approximately one-third of all the children had assistive devices and/or practical assistance in school. Implications for Rehabilitation Most children with upper-limb deficiency (UULD) in Norway manage well in everyday life and have HRQOL equal to other Norwegian children. Many choose grip-improving devices instead of prostheses. Their preferences should be respected and taken into account as the need for new assistive devices arise. For children with pronounced disabilities, access to, and use of, assistive devices, adaptions and practical assistance may be important for participation. Cooperation with the child and the parents is necessary to find useful measures. Physical education and practical subjects may provide special challenges, both for children and their teachers. Children themselves often find good solutions and the tasks should be planned ahead in cooperation with them. PMID- 26763296 TI - Facile Synthesis of Non-Graphitizable Polypyrrole-Derived Carbon/Carbon Nanotubes for Lithium-ion Batteries. AB - Graphite is usually used as an anode material in the commercial lithium ion batteries (LIBs). The relatively low lithium storage capacity of 372 mAh g(-1) and the confined rate capability however limit its large-scale applications in electrical vehicles and hybrid electrical vehicles. As results, exploring novel carbon-based anode materials with improved reversible capacity for high-energy density LIBs is urgent task. Herein we present TNGC/MWCNTs by synthesizing tubular polypyrrole (T-PPy) via a self-assembly process, then carbonizing T-PPy at 900 degrees C under an argon atmosphere (TNGC for short) and finally mixing TNGC with multi-walled carbon nanotubes (MWCNTs). As for TNGC/MWCNTs, the discharge capacity of 561 mAh g(-1) is maintained after 100 cycles at a current density of 100 mA g(-1). Electrochemical results demonstrate that TNGC/MWCNTs can be considered as promising anode materials for high-energy-density LIBs. PMID- 26763297 TI - Socioeconomic correlates of trauma: An analysis of emergency ward patients in Yaounde, Cameroon. AB - INTRODUCTION: Injury is a significant and increasingly common cause of morbidity and mortality in sub-Saharan Africa; however, the social and economic factors underlying these trends are not well understood. We evaluated the relationship between socioeconomic status (SES) and trauma outcomes using a prospective registry of patients presenting to the largest trauma hospital in Yaounde, Cameroon. METHODS: Trauma patients (n=2855) presenting to the emergency ward at Central Hospital, Yaounde between April 15 and October 15, 2009 were surveyed regarding demographic and socioeconomic background, nature and severity of injuries, treatment, and disposition. A wealth score was estimated for each patient, corresponding to an SES index constructed using principle components analysis of the urban Cameroonian Demographic and Health Survey. Logistic regression was used to evaluate the effects of SES on care-seeking behaviour, injury severity, and treatment outcome. MAIN OUTCOME MEASURES: SES wealth score, care-seeking prior to visiting hospital, injury severity, treatment outcome. RESULTS: Patients aged 1-89 presented with road traffic injuries (59.83%), falls (7.76%), and penetrating trauma (6.16%), and had higher SES than the broader urban Cameroonian population. Within the Yaounde sample, being in the lowest SES quintile was associated with an increased likelihood of having sought care elsewhere before presenting to the hospital (aOR=3.28, p<0.001), after controlling for background and injury characteristics. Patients in the lowest SES quintile were also more likely to present with moderate/severe injuries (aOR=4.93, p<0.001), and were more likely to be transferred to the operating room. CONCLUSIONS: Patients presenting to this trauma centre were wealthier than the broader community, suggesting the possibility of barriers to accessing care. Poorer patients were more likely to have severe injuries and more likely to need surgery, but were less likely to seek care from a major trauma centre immediately. Substantial differences in SES between the sample visiting the hospital and the broader community suggest a need for community-based sampling approaches in future trauma research. PMID- 26763298 TI - The treatment of atrophic, recalcitrant long-bone nonunion in the upper extremity with human recombinant bone morphogenetic protein-7 (rhBMP-7) and plate fixation: A retrospective review. AB - INTRODUCTION: Recombinant Human Bone Morphogenetic Protein-7 (rhBMP-7) has been shown to promote fracture healing in both clinical studies and basic science models, however, there is little information from large-scale studies of its use for human nonunion. The purpose of this study was to determine the safety and efficacy of rhBMP-7 in the treatment of atrophic human long-bone nonunions in the upper extremity. PATIENTS AND METHODS: This was a single center, retrospective, longitudinal cohort study of patients treated with compression plating and the application of rhBMP-7 in isolation to a long-bone nonunion. Patients over sixteen years of age with an atrophic, aseptic nonunion of a humerus, radius, ulna or clavicle were eligible for inclusion. RESULTS: We identified seventy eligible patients who were treated with rhBMP-7 for a long-bone nonunion between July 1997 and April 2012. The mean age of the patients at the time of treatment with rhBMP-7 was 50.7 years (range, 20-92 years). Five patients were lost to follow-up prior to definitive clinical or radiographic union. During the one-year post-operative period fifty-six patients had achieved union and two patients developed a stable fibrous union after the index procedure. Two patients had early implant failure and five patients had persistent nonunion. Thus, the union rate following initial surgery was 89% (58/65) and four of the five nonunion patients went on to heal following revision open reduction and internal fixation. CONCLUSION: We found that the application of rhBMP-7 for upper extremity nonunion was an effective method (89% union rate) of treating this challenging pathology. Additionally, if not initially successful, further reconstruction was not compromised by rhBMP-7 use. PMID- 26763301 TI - Combining size-exclusion chromatography with differential hydrogen-deuterium exchange to study protein conformational changes. AB - Methods for protein characterization are being actively developed based on the growing importance of protein therapies and applications. The goal of this study was to demonstrate the use of size-exclusion chromatography (SEC) in combination with differential hydrogen-deuterium exchange (HDX) to compare protein global conformational changes at different solution conditions. Using chaotropic mobile phase additive, differential HDX was used to detect a number of solvent accessible labile protons of protein on-column at pH and temperature conditions which provided unrestricted intrinsic H/D exchange (all-or-nothing approach). Varying SEC on-column conditions allowed for protein conformational changes to be observed. Temperature and pressure were independently studied with regards to their effect on the proteins' (insulin, cytochrome C, ubiquitin, and myoglobin) conformational changes in the solution. The obtained DeltaHDX profiles revealed protein conformational changes in solution under varied conditions manifested as the difference in the number of protons exchanged to deuterons, or vice-versa. The approach described in this manuscript could prove useful for protein batch-to batch comparisons, for optimization of chemical reactions with enzyme as catalyst or for protein chemical modification reactions. PMID- 26763299 TI - Nanofibril scaffold assisted MEMS artificial hydrogel neuromasts for enhanced sensitivity flow sensing. AB - We present the development and testing of superficial neuromast-inspired flow sensors that also attain high sensitivity and resolution through a biomimetic hyaulronic acid-based hydrogel cupula dressing. The inspiration comes from the spatially distributed neuromasts of the blind cavefish that live in completely dark undersea caves; the sensors enable the fish to form three-dimensional flow and object maps, enabling them to maneuver efficiently in cluttered environments. A canopy shaped electrospun nanofibril scaffold, inspired by the cupular fibrils, assists the drop-casting process allowing the formation of a prolate spheroid shaped artificial cupula. Rheological and nanoindentation characterizations showed that the Young's modulus of the artificial cupula closely matches the biological cupula (10-100 Pa). A comparative experimental study conducted to evaluate the sensitivities of the naked hair cell sensor and the cupula-dressed sensor in sensing steady-state flows demonstrated a sensitivity enhancement by 3.5-5 times due to the presence of hydrogel cupula. The novel strategies of sensor development presented in this report are applicable to the design and fabrication of other biomimetic sensors as well. The developed sensors can be used in the navigation and maneuvering of underwater robots, but can also find applications in biomedical and microfluidic devices. PMID- 26763300 TI - Ionic liquids-lithium salts pretreatment followed by ultrasound-assisted extraction of vitexin-4"-O-glucoside, vitexin-2"-O-rhamnoside and vitexin from Phyllostachys edulis leaves. AB - An efficient method for the extraction of vitexin, vitexin-4"-O-glucoside, and vitexin-2"-O-rhamnoside from Phyllostachys edulis leaves comprises heat treatment using an ionic liquid-lithium salt mixture (using 1-butyl-3-methylimidazolium bromide as the solvent and lithium chloride as the additive), followed by ultrasound-assisted extraction. To obtain higher extraction yields, the effects of the relevant experimental parameters (including heat treatment temperature and time, relative amounts of 1-butyl-3-methylimidazolium bromide and lithium chloride, power and time of the ultrasound irradiation, and the liquid-solid ratio) are evaluated and response surface methodology is used to optimize the significant factors. The morphologies of the treated and untreated P. edulis leaves are studied by scanning electron microscopy. The improved extraction method proposed provides high extraction yield, good repeatability and precision, and has wide potential applications in the analysis of plant samples. PMID- 26763302 TI - Sample normalization methods in quantitative metabolomics. AB - To reveal metabolomic changes caused by a biological event in quantitative metabolomics, it is critical to use an analytical tool that can perform accurate and precise quantification to examine the true concentration differences of individual metabolites found in different samples. A number of steps are involved in metabolomic analysis including pre-analytical work (e.g., sample collection and storage), analytical work (e.g., sample analysis) and data analysis (e.g., feature extraction and quantification). Each one of them can influence the quantitative results significantly and thus should be performed with great care. Among them, the total sample amount or concentration of metabolites can be significantly different from one sample to another. Thus, it is critical to reduce or eliminate the effect of total sample amount variation on quantification of individual metabolites. In this review, we describe the importance of sample normalization in the analytical workflow with a focus on mass spectrometry (MS) based platforms, discuss a number of methods recently reported in the literature and comment on their applicability in real world metabolomics applications. Sample normalization has been sometimes ignored in metabolomics, partially due to the lack of a convenient means of performing sample normalization. We show that several methods are now available and sample normalization should be performed in quantitative metabolomics where the analyzed samples have significant variations in total sample amounts. PMID- 26763303 TI - Reproducibility of Intra- and Inter-scanner Measurements of Liver Fat Using Complex Confounder-corrected Chemical Shift Encoded MRI at 3.0 Tesla. AB - The purpose of this study was to prospectively evaluate the reproducibility of the proton density fat-fraction (PDFF) of the liver using the IDEAL algorithm, a quantitative confounder-corrected chemical-shift-encoded MRI method. Data were obtained from 15 volunteers on four different days. The first and the third examinations were conducted on scanner one with one-week intervals, while the second and the fourth tests were performed on scanner two with same time interval. For each test, two MR scans were performed, one before and one after a meal. Regions-of-interest measurements were manually calculated to estimate the PDFF in the right and left lobes on the PDFF images. Reproducibility was measured using the intra-class correlation coefficient (ICC). The ICCs of the PDFF in the right and left lobes were 0.935 and 0.878, respectively. The intra-scanner ICCs of the right lobe before and after a meal or at a one-week interval were 0.924 and 0.953, respectively. The inter-scanner ICCs of PDFF the next day and at a one week interval were 0.920 and 0.864, respectively. The PDFF of liver derived from IDEAL demonstrated high intra- and inter-scanner measurement reproducibility. The PDFF of the right lobe before a meal was more reproducible than after-meal measurements. PMID- 26763305 TI - Clinicians Report Difficulty Limiting Low-Value Services in Daily Practice. AB - Health care services that increase costs but fail to improve health are of low value. Limiting low-value services has potential to decrease health care expenditures by eliminating waste. We examined the opinions of Continuing Medical Education attendees about the "Choosing Wisely" campaign and decreasing use of potentially unnecessary services of low value. We compared our attendees' responses to those of participants who completed a survey a year earlier. Respondents acknowledged waste of resources as a common and serious problem and noted frequent opportunities to address low-value services with their patients. They also reported limited ability to successfully reduce unnecessary services in daily clinical care. Lack of familiarity with "Choosing Wisely" may be related. PMID- 26763304 TI - Changes in Knowledge and Beliefs About Human Papillomavirus and Cervical Cancer Screening Intervals in Low-Income Women After an Educational Intervention. AB - INTRODUCTION: Women have been reluctant to adopt longer than annual intervals for cervical cancer screening, despite guidelines recommending screening every 3 to 5 years. Our study assessed patient knowledge and beliefs about human papillomavirus (HPV) and cervical cancer screening after exposure to an educational intervention, and whether there was a change in time regarding knowledge and beliefs among all study participants in an underserved population. METHOD: The study was conducted in 15 clinics associated with 6 Federally Qualified Health Centers in Illinois, USA. Cervical cancer screening patients (n = 644) completed a baseline and postintervention follow-up survey. The intervention included an HPV test and an educational pamphlet. Significance testing of changes in knowledge and beliefs was conducted with multilevel, mixed effects models adjusting for repeated measures of patients and clustering within clinics. RESULTS: No significant differences in study outcomes were found between the intervention and control groups. Among all women, knowledge of HPV significantly improved over time. At follow-up, fewer women reported that having a co-test is good, wise, will give you peace of mind, will tell you whether you need to worry if Pap is abnormal, is something your doctor thinks you should have, and will give you the best care available. More women said it would be bad, useless, or worrying to wait 3 years for a Pap test at follow-up. CONCLUSION: HPV knowledge improved over time, but the educational intervention utilized in this study was not successful in improving attitudes and beliefs about co-testing and longer screening intervals, and beliefs about HPV co-testing and 3-year screening intervals were less favorable. Having health care providers discuss the consequences of overscreening and the natural history of HPV and cervical cancer with their patients may help increase adherence to longer screening intervals. Further examination of the essential components for educational intervention in this population is warranted. PMID- 26763306 TI - Evaluation of R-wave offset in the left chest leads for estimating the left ventricular activation delay: An evaluation based on coronary sinus electrograms and the 12-lead electrocardiogram. AB - BACKGROUND: The QRS duration does not always reflect the left ventricular (LV) activation delay in patients with ventricular conduction disturbances. The R-wave offset in left chest leads may more closely reflect the LV activation delay than the QRS offset. METHODS: We evaluated 138 cases with left bundle branch block (LBBB, n=11), right BBB (RBBB, n=38), non-specific intraventricular conduction disturbance (n=11), narrow QRS (<120ms, n=56) and right ventricular pacing (n=22). Cases with right axis deviation (120 to 270 degrees) were excluded. The intervals from the QRS onset to the V-waves in coronary sinus bipolar electrograms (QCS) were measured, and the longest interval was defined as the QCSmax. In the 12-lead electrocardiogram, the interval from the QRS onset to the R-wave offset (QR) was measured and then averaged in leads I-aVL, II-III-aVF, V1 V2, V3-V4 and V5-V6. RESULTS: Significant correlations (p<0.05) were found between QCSmax and QR in I-aVL (r=0.83), II-III-aVF (r=0.51) and V5-V6 (r=0.86) in cases with a normal axis (0 to 90 degrees, n=64); and I-aVL (r=0.90), II-III aVF (r=0.31) and V5-V6 (r=0.69) in cases with left axis deviation (-45 to -89 degrees, n=52). Overall, the QRS duration was also correlated with QCSmax (r=0.72, p<0.001); however, this correlation was weaker than the correlation between QCSmax and QR in I-aVL (r=0.89, p<0.001) due to disparities in RBBB (p<0.001). CONCLUSIONS: The interval from the QRS onset to R-wave offset in the left chest leads reflects the degree of LV activation delay regardless of differences in QRS duration and morphology. PMID- 26763308 TI - Is there a relation between genetic susceptibility with cancer? A study about paraoxanase (PON1) enzyme activity in breast cancer cases. AB - Human serum paraoxonase 1 (PON1, EC 3.1.1.2) is a high density lipoprotein (HDL) associated antioxidant enzyme that not only decreases oxidative stress, but it is also implicated in development of many cancers. Genetic information provides a means of identifying people who have an increased risk of cancer, thus this knowledge of cancer genetics helps to identify the ability to characterize malignancies leading to the development of new therapeutic approaches. Because of this reason, in this preliminary study we aimed to investigate the role of human serum PON1 enzyme activity and phenotypic distribution in 32 breast cancer (BC) patients (age range 28-82) and 35 cancer free (CF) control group (age range 21 67). PON1 enzyme was prepared from the serum pool of BC patients using hydrophobic interaction chromatography on L-tyrosine-9-aminophenanthrene-coupled Sepharose 4Bgel. The PON1 enzyme activity towards paraoxon substrate was quantified spectrophotometrically. The basal activity of PON1 was statistically decreased in cancer cases compared to the control group. In addition, individuals were classified according to phenotyping of human PON1 Q and R types. In the cohort of BC patients, an increase in the frequency of the PON homozygote Q (AA) genotype was observed (31% in the BC group versus 14% in the CF controls). The frequency of the PON heterozygote QR (AB) genotype was 34.5% in the patients with BC and 37% in the CF group. The same trend was observed in PON homozygote R (BB) genotype frequency (BC cases 34.5% versus controls 49%). We determined that the kinetic parameters of the purified enzyme by Lineweaver-Burk method. We obtained Km and Vmax values of 0.227 mM and 62 U/mL min for the BC enzyme, compared with 0.775 mM and 206 U/mL min for the CF control enzyme. As a conclusion, it is clear from our results that while the PON1 AA allele frequency in BC cases is much higher, that of BB allele is much lower, in comparison with the control group. The most significant finding of this study is AA allele activity which is low in BC cases was found high. We concluded that decreased AA allele PON1 activity might have a relation with BC. PMID- 26763307 TI - Bioactivity of periodontal ligament stem cells on sodium titanate coated with graphene oxide. AB - As a biocompatible and low cytotoxic nanomaterial, graphene oxide (GO) has captured tremendous interests in tissue engineering. However, little is known about the behavior of dental stem cells on GO. This study was to evaluate the bioactivity of human periodontal ligament stem cells (PDLSCs) on GO coated titanium (GO-Ti) substrate in vitro as compared to sodium titanate (Na-Ti) substrate. By scanning electron microscope (SEM), confocal laser scanning microscope (CLSM), methylthiazol tetrazolium (MTT) assay, alkaline phosphatase (ALP) activity, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis, we investigated the attachment, morphology, proliferation and osteogenic differentiation of PDLSCs on these two substrates. When seeded on GO-Ti substrate, PDLSCs exhibited significantly higher proliferation rate, ALP activity and up-regulated gene expression level of osteogenesis-related markers of collagen type I (COL-I), ALP, bone sialoprotein (BSP), runt related transcription factor 2 (Runx2) and osteocalcin (OCN) compared with those on Na-Ti substrate. Moreover, GO promoted the protein expression of BSP, Runx2 and OCN. These findings suggest that the combination of GO and PDLSCs provides a promising construct for regenerative dentistry. PMID- 26763310 TI - Letter to the editor. PMID- 26763309 TI - Comparative transcriptome and metabolome provides new insights into the regulatory mechanisms of accelerated senescence in litchi fruit after cold storage. AB - Litchi is a non-climacteric subtropical fruit of high commercial value. The shelf life of litchi fruit under ambient conditions (AC) is approximately 4-6 days. Post-harvest cold storage prolongs the life of litchi fruit for up to 30 days with few changes in pericarp browning and total soluble solids. However, the shelf life of litchi fruits at ambient temperatures after pre-cold storage (PCS) is only 1-2 days. To better understand the mechanisms involved in the rapid fruit senescence induced by pre-cold storage, a transcriptome of litchi pericarp was constructed to assemble the reference genes, followed by comparative transcriptomic and metabolomic analyses. Results suggested that the senescence of harvested litchi fruit was likely to be an oxidative process initiated by ABA, including oxidation of lipids, polyphenols and anthocyanins. After cold storage, PCS fruit exhibited energy deficiency, and respiratory burst was elicited through aerobic and anaerobic respiration, which was regulated specifically by an up regulated calcium signal, G-protein-coupled receptor signalling pathway and small GTPase-mediated signal transduction. The respiratory burst was largely associated with increased production of reactive oxygen species, up-regulated peroxidase activity and initiation of the lipoxygenase pathway, which were closely related to the accelerated senescence of PCS fruit. PMID- 26763311 TI - Functionalized mesoporous bioactive glass scaffolds for enhanced bone tissue regeneration. AB - Mesoporous bioactive glass (MBG), which possesses excellent bioactivity, biocompatibility and osteoconductivity, has played an important role in bone tissue regeneration. However, it is difficult to prepare MBG scaffolds with high compressive strength for applications in bone regeneration; this difficulty has greatly hindered its development and use. To solve this problem, a simple powder processing technique has been successfully developed to fabricate a novel type of MBG scaffold (MBGS). Furthermore, amino or carboxylic groups could be successfully grafted onto MBGSs (denoted as N-MBGS and C-MBGS, respectively) through a post-grafting process. It was revealed that both MBGS and the functionalized MBGSs could significantly promote the proliferation and osteogenic differentiation of bMSCs. Due to its positively charged surface, N-MBGS presented the highest in vitro osteogenic capability of the three samples. Moreover, in vivo testing results demonstrated that N-MBGS could promote higher levels of bone regeneration compared with MBGS and C-MBGS. In addition to its surface characteristics, it is believed that the decreased degradation rate of N-MBGS plays a vital role in promoting bone regeneration. These findings indicate that MBGSs are promising materials with potential practical applications in bone regeneration, which can be successfully fabricated by combining a powder processing technique and post-grafting process. PMID- 26763313 TI - Fabrication of in-situ grown graphene reinforced Cu matrix composites. AB - Graphene/Cu composites were fabricated through a graphene in-situ grown approach, which involved ball-milling of Cu powders with PMMA as solid carbon source, in situ growth of graphene on flaky Cu powders and vacuum hot-press sintering. SEM and TEM characterization results indicated that graphene in-situ grown on Cu powders guaranteed a homogeneous dispersion and a good combination between graphene and Cu matrix, as well as the intact structure of graphene, which was beneficial to its strengthening effect. The yield strength of 244 MPa and tensile strength of 274 MPa were achieved in the composite with 0.95 wt.% graphene, which were separately 177% and 27.4% enhancement over pure Cu. Strengthening effect of in-situ grown graphene in the matrix was contributed to load transfer and dislocation strengthening. PMID- 26763312 TI - Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants Exposed to Neonatal Morphine. AB - OBJECTIVE: To examine the relationship between morphine exposure and growth of the cerebellum and cerebrum in very preterm neonates from early in life to term equivalent age, as well as to examine morphine exposure and brain volumes in relation to neurodevelopmental outcomes at 18 months corrected age (CA). STUDY DESIGN: A prospective cohort of 136 very preterm neonates (24-32 weeks gestational age) was serially scanned with magnetic resonance imaging near birth and at term-equivalent age for volumetric measurements of the cerebellum and cerebrum. Motor outcomes were assessed with the Peabody Developmental Motor Scales, Second Edition and cognitive outcomes with the Bayley Scales of Infant and Toddler Development, Third Edition at 18 months CA. Generalized least squares models and linear regression models were used to assess relationships between morphine exposure, brain volumes, and neurodevelopmental outcomes. RESULTS: A 10 fold increase in morphine exposure was associated with a 5.5% decrease in cerebellar volume, after adjustment for multiple clinical confounders and total brain volume (P = .04). When infants exposed to glucocorticoids were excluded, the association of morphine was more pronounced, with an 8.1% decrease in cerebellar volume. Morphine exposure was not associated with cerebral volume (P = .30). Greater morphine exposure also predicted poorer motor (P < .001) and cognitive outcomes (P = .006) at 18 months CA, an association mediated, in part, by slower brain growth. CONCLUSIONS: Morphine exposure in very preterm neonates is independently associated with impaired cerebellar growth in the neonatal period and poorer neurodevelopmental outcomes in early childhood. Alternatives to better manage pain in preterm neonates that optimize brain development and functional outcomes are urgently needed. PMID- 26763314 TI - Purification and Partial Characterization of a Novel Bacteriocin Synthesized by Lactobacillus paracasei HD1-7 Isolated from Chinese Sauerkraut Juice. AB - Bacteriocins have antimicrobial activities against food-spoiling bacteria and food-borne pathogens. Paracin 1.7, a bacteriocin synthesized by Lactobacillus paracasei HD1-7 isolated from Chinese sauerkraut juice, was studied. Following partial purification with ammonium sulfate precipitation, CM Sepharose Fast Flow, and Sephadex G-10 chromatography, the molecular weight of Paracin 1.7 was about 10 kDa based on Tricine-SDS-PAGE results. A 2.87 fold purified bacteriocin was produced, reaching a final yield of 39.93% and the specific activity of 1.56 * 10(3) AU/mg. The N-terminal amino acid sequence of Paracin 1.7 was VSNTFFA, and the LC/LTQ results revealed that the N-terminal amino acid sequence was similar to that of ABC-type oligopeptide transport system protein and N-acetylmuramoyl-L alanine amidase. Paracin 1.7 was sensitive to protease K, had antimicrobial activities at a broad pH range (3.0-8.0), and was heat resistant (121 degrees C for 20 min). Paracin 1.7 from Lactobacillus paracasei HD1-7 is a novel bacteriocin that has potential applications in food preservation. PMID- 26763315 TI - Ballast water sediment elemental analysis. AB - Sediment samples from the ballast water tanks of ships calling at the port of Rijeka in the Northern Adriatic were analysed using X-ray photoelectron spectroscopy (XPS) and secondary ion mass spectroscopy (SIMS) using caesium, argon and oxygen ion beams. The research was carried out in order to determine the sediment composition and relative abundance of the dominant elements. The results indicate that the sediment samples mostly consisted of compounds that originated from the deterioration of tank plates, tank coating residues and ballast operations such as clay, silt, sand and organic materials. No significant heavy metals or highly toxic elements were found. The research revealed some advantages and significant drawbacks of using XPS and SIMS for the routine analysis of sediment composition as a decision supporting tool for ballast water and sediment management. PMID- 26763316 TI - Coral microbial community dynamics in response to anthropogenic impacts near a major city in the central Red Sea. AB - Coral-associated bacteria play an increasingly recognized part in coral health. We investigated the effect of local anthropogenic impacts on coral microbial communities on reefs near Jeddah, the largest city on the Saudi Arabian coast of the central Red Sea. We analyzed the bacterial community structure of water and corals (Pocillopora verrucosa and Acropora hemprichii) at sites that were relatively unimpacted, exposed to sedimentation & local sewage, or in the discharge area of municipal wastewaters. Coral microbial communities were significantly different at impacted sites: in both corals the main symbiotic taxon decreased in abundance. In contrast, opportunistic bacterial families, such as e.g. Vibrionaceae and Rhodobacteraceae, were more abundant in corals at impacted sites. In conclusion, microbial community response revealed a measurable footprint of anthropogenic impacts to coral ecosystems close to Jeddah, even though the corals appeared visually healthy. PMID- 26763317 TI - Assessment of trace element contamination and bioaccumulation in algae (Ulva lactuca), mussels (Perna perna), shrimp (Penaeus kerathurus), and fish (Mugil cephalus, Saratherondon melanotheron) along the Senegalese coast. AB - Concentrations of 11 elements were quantified in five marine species from different trophic levels of a food web (algae, mussel, shrimp and fish), representative for shallow Senegalese coastal waters, and including species of commercial importance. Significant differences in element concentrations and bioaccumulation were demonstrated, revealing the utility of employing a suite of organisms as bioindicators to monitor metal contamination in coastal areas. There was no clear seasonal pattern in concentration of elements, however inter-site differences were observed. Calculations of transfer factors for all the studied elements showed that transfer factors from water were greater than those from sediments. For shrimp and mussel, the concentrations of Pb and Cd were below the EU's maximum level for human consumption, however high concentrations of arsenic in shrimp were recorded at all sites. PMID- 26763318 TI - Application of macrobenthic diversity to estimate ecological health of artificial oyster reef in Yangtze Estuary, China. AB - In this study, several macrobenthic diversity investigations were performed in Yangtze Estuary Oyster Reef, the largest artificial oyster reef in China, from 2012 to 2014. The sampling sites of the south branch showed considerably higher diversity than those of the north branch. The richness measures exhibited a significant increasing trend from low- to high-salinity zone; however, the evenness measures were typically high in the middle-salinity zone. During the past decade, the results were combined with historical data to detect the changes in macrobenthos. The variation in substrate organisms and macrobenthic diversity followed a steady trend after a major fluctuation. Redundancy analysis indicated that the water salinity and substrate factors were the main indicators that influence macrobenthic distribution. All sampling sites in the south branch were protected by a nature reserve. However, the N2 and N6 sites in the north branch were subjected to severe and mild human interventions, respectively. PMID- 26763319 TI - Environmental genotoxicity assessment along the transport routes of chemical munitions leading to the dumping areas in the Baltic Sea. AB - The frequencies of micronuclei (MN), nuclear buds (NB) and nuclear buds on filament (NBf) were examined in 660 specimens of herring (Clupea harengus) collected in 2009-2014 at 65 study stations located mainly along the chemical munition transport routes in the Baltic Sea. The frequency of nuclear abnormalities was strongly increased in herring caught at four stations located close to chemical munition dumping sites, or CWAs - substances (chemical warfare agents) in sediments. Significant increase of MN, NB and NBf was observed in fish caught November 2010-2013 compared to 2009. The most significantly increased genotoxicity responses were recorded in fish caught at stations along CW (chemical weapons) transport routes, close to the Bornholm CW dumping area, in zones with CWAs in sediments and with oil-gas platforms. PMID- 26763320 TI - Environmental assessment of pesticides in the Mondego River Estuary (Portugal). AB - The Mondego River estuary, located on the North Atlantic Ocean Ecoregion, is a basin affected by agricultural run-off with increasing signs of eutrophication. We evaluated the amounts and distribution of 56 priority pesticides belonging to distinct categories (insecticides, herbicides and fungicides). Temporal trends were considered and a total of 42 surface water samples were collected between 2010 and 2011. More than 55% of the GC-MS/MS-quantified pesticides were above the maximum amounts established by the European Directives (98/83/EC and 2013/39/EU). Based on the concentration addition (CA) and independent action (IA) models, we used a two-tiered approach to assess the hazard of the pesticide mixture, at the maximum concentration found, reflecting a potential risk. Short-term exposure using Artemia salina indicated a significant toxic effect where the locomotion of the animals was clearly affected. PMID- 26763321 TI - Ingestion of marine litter by loggerhead sea turtles, Caretta caretta, in Portuguese continental waters. AB - The accumulation of litter in marine and coastal environments is a major threat to marine life. Data on marine litter in the gastrointestinal tract of stranded loggerhead turtles, Caretta caretta, found along the Portuguese continental coast was presented. Out of the 95 analysed loggerheads, litter was present in 56 individuals (59.0%) and most had less than 10 litter items (76.8%) and less than 5 g (dm) (96.8%). Plastic was the main litter category (frequency of occurrence=56.8%), while sheet (45.3%) was the most relevant plastic sub category. There was no influence of loggerhead stranding season, cause of stranding or size on the amount of litter ingested (mean number and dry mass of litter items per turtle). The high ingested litter occurrence frequency in this study supports the use of the loggerhead turtle as a suitable tool to monitor marine litter trends, as required by the European Marine Strategy Framework Directive. PMID- 26763322 TI - Controlling harmful algae blooms using aluminum-modified clay. AB - The performances of aluminum chloride modified clay (AC-MC), aluminum sulfate modified clay (AS-MC) and polyaluminum chloride modified clay (PAC-MC) in the removal of Aureococcus anophagefferens were compared, and the potential mechanisms were analyzed according to the dispersion medium, suspension pH and clay surface charges. The results showed that AC-MC and AS-MC had better efficiencies in removing A.anophagefferens than PAC-MC. The removal mechanisms of the three modified clays varied. At optimal coagulation conditions, the hydrolysates of AC and AS were mainly monomers, and they transformed into Al(OH)3(am) upon their addition to algae culture, with the primary mechanism being sweep flocculation. The PAC mainly hydrolyzed to the polyaluminum compounds, which remained stable when added to the algae culture, and the flocculation mainly occurred through polyaluminum compounds. The suspension pH significantly influenced the aluminum hydrolysate and affected the flocculation between the modified clay and algae cells. PMID- 26763323 TI - Are we eating plastic-ingesting fish? AB - Yes, we are eating plastic-ingesting fish. A baseline assessment of plastic pellet ingestion by two species of important edible fish caught along the eastern coast of Brazil is described. The rate of plastic ingestion by king mackerel (Scomberomorus cavalla) was quite high (62.5%), followed by the Brazilian sharpnose shark (Rhizoprionodon lalandii, 33%). From 2 to 6 plastic resin pellets were encountered in the stomachs of each fish, with sizes of from 1 to 5 mm, and with colors ranging from clear to white and yellowish. Ecological and health related implications are discussed and the potential for transferring these materials through the food-chain are addressed PMID- 26763325 TI - Study on the cumulative impact of reclamation activities on ecosystem health in coastal waters. AB - The purpose of this study is to develop feasible tools to investigate the cumulative impact of reclamations on coastal ecosystem health, so that the strategies of ecosystem-based management can be applied in the coastal zone. An indicator system and model were proposed to assess the cumulative impact synthetically. Two coastal water bodies, namely Laizhou Bay (LZB) and Tianjin coastal waters (TCW), in the Bohai Sea of China were studied and compared, each in a different phase of reclamations. Case studies showed that the indicator scores of coastal ecosystem health in LZB and TCW were 0.75 and 0.68 out of 1.0, respectively. It can be concluded that coastal reclamations have a historically cumulative effect on benthic environment, whose degree is larger than that on aquatic environment. The ecosystem-based management of coastal reclamations should emphasize the spatially and industrially intensive layout. PMID- 26763324 TI - Hydrocarbons and trace metals in mussels in the Macae coast: Preliminary assessment for a coastal zone under influence of offshore oil field exploration in southeastern Brazil. AB - Concentrations of PAHs and metals were obtained from mussels collected in beaches, coastal island and estuary of the Macae coast, the main operational basin for offshore oil exploration in Brazil. This survey provides reference levels for scenarios of increasing exploration, as well as for other areas of the coast undergoing urbanization to support exploration. As expected, urban areas such as the Macae river estuary presented high concentrations of PAHs, although unsuspected sites such the island also presented signs of contamination. PAH in mussels originated from pyrolytic and petrogenic sources. Metals were typical of non-contaminated coastal environments, although Cr concentrations were above Brazilian Reference Levels. PMID- 26763326 TI - Plastic debris in great skua (Stercorarius skua) pellets corresponds to seabird prey species. AB - Plastic is a common item in marine environments. Studies assessing seabird ingestion of plastics have focused on species that ingest plastics mistaken for prey items. Few studies have examined a scavenger and predatory species that are likely to ingest plastics indirectly through their prey items, such as the great skua (Stercorarius skua). We examined 1034 regurgitated pellets from a great skua colony in the Faroe Islands for plastics and found approximately 6% contained plastics. Pellets containing remains of Northern fulmars (Fulmarus glacialis) had the highest prevalence of plastic. Our findings support previous work showing that Northern fulmars have higher loads of plastics than other sympatric species. This study demonstrates that marine plastic debris is transferred from surface feeding seabird species to predatory great skuas. Examination of plastic ingestion in species that do not ingest plastics directly can provide insights into how plastic particles transfer vertically within the food web. PMID- 26763327 TI - The fern cavitation catapult: mechanism and design principles. AB - Leptosporangiate ferns have evolved an ingenious cavitation catapult to disperse their spores. The mechanism relies almost entirely on the annulus, a row of 12-25 cells, which successively: (i) stores energy by evaporation of the cells' content, (ii) triggers the catapult by internal cavitation, and (iii) controls the time scales of energy release to ensure efficient spore ejection. The confluence of these three biomechanical functions within the confines of a single structure suggests a level of sophistication that goes beyond most man-made devices where specific structures or parts rarely serve more than one function. Here, we study in detail the three phases of spore ejection in the sporangia of the fern Polypodium aureum. For each of these phases, we have written the governing equations and measured the key parameters. For the opening of the sporangium, we show that the structural design of the annulus is particularly well suited to inducing bending deformations in response to osmotic volume changes. Moreover, the measured parameters for the osmoelastic design lead to a near-optimal speed of spore ejection (approx. 10 m s(-1)). Our analysis of the trigger mechanism by cavitation points to a critical cavitation pressure of approximately -100 +/- 14 bar, a value that matches the most negative pressures recorded in the xylem of plants. Finally, using high-speed imaging, we elucidated the physics leading to the sharp separation of time scales (30 versus 5000 us) in the closing dynamics. Our results highlight the importance of the precise tuning of the parameters without which the function of the leptosporangium as a catapult would be severely compromised. PMID- 26763329 TI - Role of stag beetle jaw bending and torsion in grip on rivals. AB - In aggressive battles, the extremely large male stag beetle jaws have to withstand strongly elevated bite forces. We found several adaptations of the male Cyclommatus metallifer jaw morphology for enhanced robustness that conspecific females lack. As a result, males improve their grip on opponents and they maintain their safety factor (5.2-7.2) at the same level as that of females (6.8), despite their strongly elevated bite muscle force (3.9 times stronger). Males have a higher second moment of area and torsion constant than females, owing to an enhanced cross-sectional area and shape. These parameters also increase faster with increasing bending moment towards the jaw base in males than in females. Male jaws are more bending resistant against the bite reaction force than against perpendicular forces (which remain lower in battles). Because of the triangular cross section of the male jaw base, it twists more easily than it bends. This torsional flexibility creates a safety system against overload that, at the same time, secures a firm grip on rivals. We found no structural mechanical function of the large teeth halfway along the male jaws. Therefore, it appears that the main purpose of these teeth is a further improvement of grip on rivals. PMID- 26763328 TI - Dissecting the self-assembly kinetics of multimeric pore-forming toxins. AB - Pore-forming toxins are ubiquitous cytotoxins that are exploited by both bacteria and the immune response of eukaryotes. These toxins kill cells by assembling large multimeric pores on the cell membrane. However, a quantitative understanding of the mechanism and kinetics of this self-assembly process is lacking. We propose an analytically solvable kinetic model for stepwise, reversible oligomerization. In biologically relevant limits, we obtain simple algebraic expressions for the rate of pore formation, as well as for the concentration of pores as a function of time. Quantitative agreement is obtained between our model and time-resolved kinetic experiments of Bacillus thuringiensis Cry1Ac (tetrameric pore), aerolysin, Staphylococcus aureus alpha-haemolysin (heptameric pores) and Escherichia coli cytolysin A (dodecameric pore). Furthermore, our model explains how rapid self-assembly can take place with low concentrations of oligomeric intermediates, as observed in recent single-molecule fluorescence experiments of alpha-haemolysin self-assembly. We propose that suppressing the concentration of oligomeric intermediates may be the key to reliable, error-free, self-assembly of pores. PMID- 26763330 TI - Bursting noise in gene expression dynamics: linking microscopic and mesoscopic models. AB - The dynamics of short-lived mRNA results in bursts of protein production in gene regulatory networks. We investigate the propagation of bursting noise between different levels of mathematical modelling and demonstrate that conventional approaches based on diffusion approximations can fail to capture bursting noise. An alternative coarse-grained model, the so-called piecewise deterministic Markov process (PDMP), is seen to outperform the diffusion approximation in biologically relevant parameter regimes. We provide a systematic embedding of the PDMP model into the landscape of existing approaches, and we present analytical methods to calculate its stationary distribution and switching frequencies. PMID- 26763331 TI - Physical limits on bacterial navigation in dynamic environments. AB - Many chemotactic bacteria inhabit environments in which chemicals appear as localized pulses and evolve by processes such as diffusion and mixing. We show that, in such environments, physical limits on the accuracy of temporal gradient sensing govern when and where bacteria can accurately measure the cues they use to navigate. Chemical pulses are surrounded by a predictable dynamic region, outside which bacterial cells cannot resolve gradients above noise. The outer boundary of this region initially expands in proportion to the square root of time before rapidly contracting. Our analysis also reveals how chemokinesis-the increase in swimming speed many bacteria exhibit when absolute chemical concentration exceeds a threshold-may serve to enhance chemotactic accuracy and sensitivity when the chemical landscape is dynamic. More generally, our framework provides a rigorous method for partitioning bacteria into populations that are 'near' and 'far' from chemical hotspots in complex, rapidly evolving environments such as those that dominate aquatic ecosystems. PMID- 26763332 TI - Do terrestrial hermit crabs sniff? Air flow and odorant capture by flicking antennules. AB - Capture of odorant molecules by olfactory organs from the surrounding fluid is the first step of smelling. Sniffing intermittently moves fluid across sensory surfaces, increasing delivery rates of molecules to chemosensory receptors and providing discrete odour samples. Aquatic malacostracan crustaceans sniff by flicking olfactory antennules bearing arrays of chemosensory hairs (aesthetascs), capturing water in the arrays during downstroke and holding the sample during return stroke. Terrestrial malacostracans also flick antennules, but how their flicking affects odour capture from air is not understood. The terrestrial hermit crab, Coenobita rugosus, uses antennules bearing shingle-shaped aesthetascs to capture odours. We used particle image velocimetry to measure fine-scale fluid flow relative to a dynamically scaled physical model of a flicking antennule, and computational simulations to calculate diffusion to aesthetascs by odorant molecules carried in that flow. Air does not flow into the aesthetasc array during flick downstrokes or recovery strokes. Odorants are captured from air flowing around the outside of the array during flick downstrokes, when aesthetascs face upstream and molecule capture rates are 21% higher than for stationary antennules. Bursts of flicking followed by pauses deliver discrete odour samples to olfactory sensors, causing intermittency in odour capture by a different mechanism than aquatic crustaceans use. PMID- 26763333 TI - On the organization of human T-cell receptor loci: log-periodic distribution of T cell receptor gene segments. AB - The human T-cell repertoire is complex and is generated by the rearrangement of variable (V), diversity (D) and joining (J) segments on the T-cell receptor (TCR) loci. The T-cell repertoire demonstrates self-similarity in terms clonal frequencies when defined by V, D and J gene segment usage; therefore to determine whether the structural ordering of these gene segments on the TCR loci contributes to the observed clonal frequencies, the TCR loci were examined for self-similarity and periodicity in terms of gene segment organization. Logarithmic transformation of numeric sequence order demonstrated that the V and J gene segments for both T-cell receptor alpha (TRA) and beta (TRB) loci are arranged in a self-similar manner when the spacing between the adjacent segments was considered as a function of the size of the neighbouring gene segment, with an average fractal dimension of approximately 1.5. Accounting for the gene segments occurring on helical DNA molecules with a logarithmic distribution, sine and cosine functions of the log-transformed angular coordinates of the start and stop nucleotides of successive TCR gene segments showed an ordered progression from the 5' to the 3' end of the locus, supporting a log-periodic organization. T cell clonal frequency estimates, based on V and J segment usage, from normal stem cell donors were plotted against the V and J segment on TRB locus and demonstrated a periodic distribution. We hypothesize that this quasi-periodic variation in gene-segment representation in the T-cell clonal repertoire may be influenced by the location of the gene segments on the periodic-logarithmically scaled TCR loci. Interactions between the two strands of DNA in the double helix may influence the probability of gene segment usage by means of either constructive or destructive interference resulting from the superposition of the two helices. PMID- 26763335 TI - Evolving random fractal Cantor superlattices for the infrared using a genetic algorithm. AB - Ordered and chaotic superlattices have been identified in Nature that give rise to a variety of colours reflected by the skin of various organisms. In particular, organisms such as silvery fish possess superlattices that reflect a broad range of light from the visible to the UV. Such superlattices have previously been identified as 'chaotic', but we propose that apparent 'chaotic' natural structures, which have been previously modelled as completely random structures, should have an underlying fractal geometry. Fractal geometry, often described as the geometry of Nature, can be used to mimic structures found in Nature, but deterministic fractals produce structures that are too 'perfect' to appear natural. Introducing variability into fractals produces structures that appear more natural. We suggest that the 'chaotic' (purely random) superlattices identified in Nature are more accurately modelled by multi-generator fractals. Furthermore, we introduce fractal random Cantor bars as a candidate for generating both ordered and 'chaotic' superlattices, such as the ones found in silvery fish. A genetic algorithm is used to evolve optimal fractal random Cantor bars with multiple generators targeting several desired optical functions in the mid-infrared and the near-infrared. We present optimized superlattices demonstrating broadband reflection as well as single and multiple pass bands in the near-infrared regime. PMID- 26763334 TI - Type-III secretion filaments as scaffolds for inorganic nanostructures. AB - Nanostructured materials exhibit unique magnetic, electrical and catalytic properties. These characteristics are determined by the chemical composition, size and shape of the nanostructured components, which are challenging to modulate on such small size scales and to interface with living cells. To address this problem, we are using a self-assembling filament protein, PrgI, as a scaffold for bottom-up inorganic nanostructure synthesis. PrgI is a small protein (80 amino acids) that oligomerizes to form the type-III secretion system needle of Salmonella enterica. We demonstrate that purified PrgI monomers also spontaneously self-assemble into long filaments and that high-affinity peptide tags specific for attachment to functionalized particles can be integrated into the N-terminal region of PrgI. The resulting filaments selectively bind to gold, whether the filaments are assembled in vitro, sheared from cells or remain attached to live S. enterica cell membranes. Chemical reduction of the gold modified PrgI variants results in structures that are several micrometres in length and which incorporate a contiguous gold surface. Mutant strains with genomically incorporated metal-binding tags retain the secretion phenotype. We anticipate that self-assembled, cell-tethered protein/metal filamentous structures have applications in sensing and energy transduction in vivo. PMID- 26763336 TI - Role of vaccination-induced immunity and antigenic distance in the transmission dynamics of highly pathogenic avian influenza H5N1. AB - Highly pathogenic avian influenza (HPAI) H5N1 epidemics in poultry cause huge economic losses as well as sporadic human morbidity and mortality. Vaccination in poultry has often been reported as being ineffective in preventing transmission and as a potential driving force in the selection of immune escape mutants. We conducted transmission experiments to evaluate the transmission dynamics of HPAI H5N1 strains in chickens vaccinated with high and low doses of immune escape mutants we have previously selected, and analysed the data using mathematical models. Remarkably, we demonstrate that the effect of antigenic distances between the vaccine and challenge strains used in this study is too small to influence the transmission dynamics of the strains used. This is because the effect of a sufficient vaccine dose on antibody levels against the challenge viruses is large enough to compensate for any decrease in antibody titres due to antigenic differences between vaccine and challenge strains. Our results show that at least under experimental conditions, vaccination will remain effective even after antigenic changes as may be caused by the initial selection in vaccinated birds. PMID- 26763338 TI - Lower third clivus and foramen magnum intradural tumor removal: The plea for a simple posterolateral approach. AB - BACKGROUND: Anterior or anterolateral lesions of the lower third clivus and/or foramen magnum require a surgical exposure that provides a clear visualization of both pathological and normal anatomy without retraction of neural or vascular structures. The posterolateral approach permits access to the anterolateral intradural aspect of the brainstem. The aim of this study was to stress that there is no need for vertebral artery transposition, occipital condyle drilling, occipitocervical fixation or trans-oro-pharyngeal access to remove these lesions. METHODS: All five consecutive patients treated surgically for an intradural foramen magnum lesion in the Department of Neurosurgery at Angers University Hospital, between May 2012 and January 2015, were included in this retrospective study. In 4 cases, patients were referred to us for a second opinion after an initial surgical proposal at another institution. For all patients, the data collected were age at diagnosis, clinical signs, and quality of rostral and caudal exposure of the lesion, quality of resection, complications and postoperative neurological deficits. RESULTS: All patients were operated on with a control of the rostrocaudal part of the lesion, without touching the vertebral artery, or the use of occipital condyle drilling. There was no need for occipitocervical fixation. Total resection was achieved in 4 cases, subtotal resection in one. All had watertight dural closure with no dural patch, or postoperative neurological deficits. No recurrence occurred between 6 and 30 months after surgery. CONCLUSION: Based on these results, the posterolateral approach was a simple, effective and safe procedure for anterior and anterolateral intradural lesion of the foramen magnum. PMID- 26763337 TI - Combinatorial Treatment with Apelin-13 Enhances the Therapeutic Efficacy of a Preconditioned Cell-Based Therapy for Peripheral Ischemia. AB - Hypoxic pretreatment of peripheral blood mononuclear cells (PBMNCs) enhances therapeutic angiogenesis in ischemic tissues after cell transplantation. However, newly formed vessels generated using this approach are immature and insufficient for promoting functional recovery from severe ischemia. In this study, we examined whether apelin-13, a regulator of vessel maturation, could be an effective promoter of therapeutic angiogenesis, following severe limb ischemia. Combinatorial treatment of hypoxic preconditioned PBMNCs with apelin-13 resulted in increased blood perfusion and vascular reactivity in ischemic mouse hindlimbs compared with a monotherapy comprising each factor. Apelin-13 upregulated expression of PDGF-BB and TGF-beta1 in hypoxic PBMNCs, as well as that of PDGFR beta in vascular smooth muscle cells (VSMCs). Proliferation and migration of VSMCs treated with apelin-13 was accelerated in the presence of PDGF-BB. Interestingly, expression of an apelin receptor, APJ, in PBMNC was increased under hypoxia but not under normoxia. In addition, an in vitro angiogenesis assay using a co-culture model comprising mouse thoracic aorta, hypoxic PBMNCs, and apelin-13 demonstrated that combinatorial treatment recruited mural cells to sprouted vessel outgrowths from the aortic ring, thereby promoting neovessel maturation. Thus, combinatorial injection of hypoxic PBMNCs and apelin-13 could be an effective therapeutic strategy for patients with severe ischemic diseases. PMID- 26763339 TI - Retrospective Analysis of the Medication Utilization and Clinical Outcomes of Patients Treated with Various Regimens for Hepatitis C Infection. AB - BACKGROUND: The hepatitis C virus (HCV) is the most common chronic blood-borne infection and the leading cause of liver transplantation in the United States. There are approximately 3.2 million people currently infected with HCV in the United States. In late 2013, the introduction of sofosbuvir and simeprevir represented a critical advancement in the treatment of HCV by improving sustained virologic response (SVR) rates. PURPOSE: The purpose of this study was to evaluate medication utilization and clinical outcomes of patients with HCV who were treated with any Food and Drug Administration-approved combination of ribavirin, peginterferon products, simeprevir, and sofosbuvir. METHODS: Prescription records and clinical assessment forms of patients who started HCV therapy and were eligible for SVR between January 1, 2014, and December 31, 2014, were retrospectively reviewed. Data collection included patient demographics, genotype, SVR, patient-reported adverse events, discontinuations, and adherence markers. RESULTS: A total of 367 eligible patients were identified who had initiated treatment during the study period. Genotype 1 was the most common genotype, and an overall SVR rate of 86.9% was observed. Results were similar to those seen in phase III clinical trials. In addition, adverse events of these medications were more tolerable, and discontinuation rates were lower than with previous therapies. PMID- 26763340 TI - Practice Patterns and Opinions on Current Clinical Practice Guidelines Regarding the Management of Delirium in the Intensive Care Unit. AB - OBJECTIVE: The aim of this study was to determine current delirium practices in the intensive care unit (ICU) setting and evaluate awareness and adoption of the 2013 Pain, Agitation, and Delirium (PAD) guidelines with emphasis on delirium management. DESIGN, SETTING, AND PARTICIPANTS: A large-scale, multidisciplinary, online survey was administered to physician, pharmacist, nurse, and mid-level practitioner members of the Society of Critical Care Medicine (SCCM) between September 2014 and October 2014. A total of 635 respondents completed the survey. MEASUREMENTS AND MAIN RESULTS: Nonpharmacologic interventions such as early mobilization were used in most ICUs (83%) for prevention of delirium. A majority of respondents (97%) reported using pharmacologic agents to treat hyperactive delirium. Ninety percent of the respondents answered that they were aware of the 2013 PAD guidelines, and 75% of respondents felt that their delirium practices have been changed as a result of the new guidelines. In addition, logistic regression analysis of this study showed that respondents who use delirium screening tools were twice more likely to be fully aware of key components of the updated guidelines (odds ratio [OR] = 2.07, 95% confidence interval [CI] = 1.20 3.60). CONCLUSIONS: Most critical care practitioners are fully aware and knowledgeable of key recommendations in the new guidelines and have changed their delirium practices accordingly. PMID- 26763341 TI - Possible Hepatotoxicity Associated With Daptomycin: A Case Report and Literature Review. AB - PURPOSE: To report a case of isolated daptomycin-induced acute liver injury without elevations in creatine kinase (CK) levels or kidney dysfunction. SUMMARY: A 49-year-old female with a history of pancreatitis, lupus, diabetes, congestive heart failure, hypertension, and chronic pain syndrome presented to the emergency department with alteration in mental status and acute liver failure. The patient had been treated with daptomycin for methicillin-resistant Staphylococcus aureus (MRSA) endocarditis for 3 weeks. After ruling out other possible etiologies, daptomycin was suspected as a cause of acute liver failure. Her liver failure resolved gradually following withdrawal of daptomycin. CONCLUSION: Although hepatic abnormalities caused by daptomycin are rare, a handful of cases with daptomycin-induced liver injury have been reported in the literature. Of note, in most cases, patients on daptomycin therapy developed liver damage with elevations in CK levels. Our case report suggests possible severe liver injury associated with high-dose and long-term daptomycin treatment in the absence of rhabdomyolysis. Future research is warranted to further investigate the relationship between daptomycin use and liver injury, yet it is reasonable to monitor liver function tests at baseline and weekly thereafter along with CK levels, especially in patients requiring long-term daptomycin therapy. PMID- 26763342 TI - Should We be Worried About QTc Prolongation Using Citalopram? A Review. AB - PURPOSE: Summarize available information regarding clinical impact of citalopram on the QTc interval. METHODS: A literature search was conducted in Pubmed, EMBASE, and Cochrane databases using the MeSH term "long QT syndrome" and key word "citalopram" on July 11, 2014. RESULTS: Thirty-one studies were evaluated with 4 included in this review. Studies were excluded if they reported acute overdoses of citalopram or did not report on patient-specific risk factors for long QT syndrome (eg, hypokalemia, bradycardia, and increased age). The majority of the available data is derived from case reports. A number of confounders complicate the determination of a causal link between QTc prolongation and citalopram. Of the 4 studies included for review, none identified significant QTc prolongation in patients taking citalopram 20 to 60 mg daily without the patients having one or more patient-specific risk factors for prolonged QTc. CONCLUSION: There is insufficient evidence to establish a causal link between citalopram 20 to 60 mg orally daily and increased risk of TdP. Further research is required to determine the clinical impact and association between citalopram 20 to 60 mg daily and QTc prolongation. PMID- 26763343 TI - Cervical pessaries to prevent preterm birth in women with a multiple pregnancy: a per-protocol analysis of a randomized clinical trial. AB - INTRODUCTION: We recently showed that a cervical pessary prevents preterm birth and reduces poor neonatal outcomes in women with a twin pregnancy and a short cervix (<38 mm). The objective of this study was to evaluate the full potential treatment effect of the pessary in the whole group and in women with a short cervix. MATERIAL AND METHODS: We performed a per-protocol analysis of a multicenter randomized controlled trial (ProTWIN trial, NTR1858) where we excluded women who were allocated to the pessary but never had it placed. Women who had the pessary removed before 36 gestational weeks and did not deliver within 7 days after removal, were excluded. Analyses were performed on all women and in those with a cervical length <38 mm. RESULTS: In 23 (6%) women the pessary was not placed. In women with a cervical length <38 mm (25th percentile) the pessary reduced poor perinatal outcome (relative risk 0.32, 95% confidence interval 0.13-0.78) and birth at <32 weeks (relative risk 0.41, 95% confidence interval 0.20-0.87). After excluding 47 (12%) women, the time to delivery was longer in the pessary group than in the control group (whole group: hazard ratio 0.68, 95% confidence interval 0.55-0.82, cervical length <38 mm: hazard ratio 0.35, 95% confidence interval 0.22-0.57). CONCLUSIONS: The analysis confirms the principal findings of the intention-to-treat analysis. Time to delivery was longer in the pessary group than in the control group when censored data were used. This implies the pessary should not be removed until labor is evident. PMID- 26763344 TI - The Notch pathway regulates both the proliferation and differentiation of follicular cells in the panoistic ovary of Blattella germanica. AB - The Notch pathway is an essential regulator of cell proliferation and differentiation during development. Its involvement in insect oogenesis has been examined in insect species with meroistic ovaries, and it is known to play a fundamental role in cell fate decisions and the induction of the mitosis-to endocycle switch in follicular cells (FCs). This work reports the functions of the main components of the Notch pathway (Notch and its ligands Delta and Serrate) during oogenesis in Blattella germanica, a phylogenetically basal species with panoistic ovary. As is revealed by RNAi-based analyses, Notch and Delta were found to contribute towards maintaining the FCs in an immature, non apoptotic state. This ancestral function of Notch appears in opposition to the induction of transition from mitosis to endocycle that Notch exerts in Drosophila melanogaster, a change in the Notch function that might be in agreement with the evolution of the insect ovary types. Notch was also shown to play an active role in inducing ovarian follicle elongation via the regulation of the cytoskeleton. In addition, Delta and Notch interactions were seen to determine the differentiation of the posterior population of FCs. Serrate levels were found to be Notch-dependent and are involved in the control of the FC programme, although they would appear to play no crucial role in panoistic ovary oogenesis. PMID- 26763345 TI - Overlap of copper and iron uptake systems in mitochondria in Saccharomyces cerevisiae. AB - In Saccharomyces cerevisiae, the mitochondrial carrier family protein Pic2 imports copper into the matrix. Deletion of PIC2 causes defects in mitochondrial copper uptake and copper-dependent growth phenotypes owing to decreased cytochrome c oxidase activity. However, copper import is not completely eliminated in this mutant, so alternative transport systems must exist. Deletion of MRS3, a component of the iron import machinery, also causes a copper-dependent growth defect on non-fermentable carbon. Deletion of both PIC2 and MRS3 led to a more severe respiratory growth defect than either individual mutant. In addition, MRS3 expressed from a high copy number vector was able to suppress the oxygen consumption and copper uptake defects of a strain lacking PIC2. When expressed in Lactococcus lactis, Mrs3 mediated copper and iron import. Finally, a PIC2 and MRS3 double mutant prevented the copper-dependent activation of a heterologously expressed copper sensor in the mitochondrial intermembrane space. Taken together, these data support a role for the iron transporter Mrs3 in copper import into the mitochondrial matrix. PMID- 26763346 TI - Early immune recovery after autologous transplantation in non-Hodgkin lymphoma patients: predictive factors and clinical significance. AB - Limited data is available about the factors affecting early immune recovery or its clinical significance after autologous stem cell transplantation (auto-SCT). We prospectively analyzed factors affecting early immune recovery and outcome among 72 non-Hodgkin lymphoma (NHL) patients. Absolute lymphocyte count 15 d after auto-SCT (ALC-15) >= 0.5 * 10(9)/L was associated with the use of plerixafor (p = 0.004), the number of CD34(+) cells (p = 0.015), and CD34(+) CD38(-) cells (p = 0.005) in the grafts. ALC-15 >= 0.5 * 10(9)/L was associated with improved overall survival (p = 0.021). In patients with aggressive histology, ALC-15 >= 0.5 * 10(9)/L was beneficial in regard to both progression free survival (p = 0.015) and overall survival (p = 0.002). Early immune recovery seems to be important in transplanted patients with NHL and, therefore, an easy and affordable method for disease-related risk analysis. Patients with aggressive histology and slow immune recovery may need additional post-transplant treatment. PMID- 26763347 TI - Six-year follow-up of patients treated with oncoplastic reduction mammoplasty: A cohort study. AB - BACKGROUND: Current evidence for the oncological safety of oncoplastic breast conservation is poor as it is based mostly on short-term follow-up data. Hence, we report long-term recurrence rates in patients treated with oncoplastic reduction mammoplasty (ORM). METHODS: A prospectively maintained database was searched to identify patients who underwent ORM between 2005 and 2010. A retrospective review of medical records was carried out, including patients with ductal carcinoma in situ and invasive breast cancer. RESULTS: Follow-up data from 65 consecutive patients with ORM were reviewed, of which 50 patients were eligible to measure long-term recurrence rates. The average weight of the resected tissue was 272 g altogether. The mean preoperative tumour size was 2.95 cm on imaging. 64% of patients had stage II - III cancers. Incomplete excision rate after ORM was 16.1%, completion mastectomy rate was 10.7%. During a median follow-up of 72 months, 2% local, 6% distant recurrence rates were detected. The breast cancer-specific survival rate was 96% per cent. CONCLUSIONS: Based on these long-term follow-up data, ORM is an oncologically safe treatment option. PMID- 26763348 TI - Clinicopathological significance of SIRT1 expression in colorectal cancer: A systematic review and meta analysis. AB - PURPOSE: The relationship between SIRT1 and clinicopathological parameters of colorectal cancer (CRC) is controversial. To evaluate the clinicopathological and prognostic value of silent mating type information regulation 2 homolog-1 (SIRT1) expressions in patients with CRC, a meta-analysis was performed. METHODS: We conducted a meta-analysis to investigate the impact of SIRT1 on clinicopathological parameters and prognosis in CRC patients. Studies assessing the relationship between these parameters and SIRT1 expression in CRC were identified up to September, 2015. RESULTS: Seven studies met the inclusion criteria. Our results showed that SIRT1 expression was correlated with depth of invasion (OR = 0.922, 95% CI: 0.646-1.316, P = 0.005), lymph node metastasis (OR = 1.001, 95% CI: 0.781-1.283, P = 0.000) and TNM stage (OR = 1.103, 95% CI: 0.892 1.365, P = 0.008). Furthermore, we found that SIRT1 expression predicted a poor overall survival (OS) in CRC patients (OR = 1.220, 95% CI: 0.955-1.558, P = 0.037, fixed-effect). CONCLUSIONS: The overall data of the present meta-analysis showed that SIRT1 expression was not correlated with clinicopathological features except for depth of invasion, lymph node metastasis and TNM stage. Simultaneously, SIRT1 overexpression predicted a poor OS in CRC patients, and SIRT1 is a candidate negative prognostic biomarker for CRC patients. PMID- 26763352 TI - 2 Gy * 2 for palliative treatment of mantle cell lymphoma. PMID- 26763349 TI - Safety and efficacy of different lenalidomide starting doses in patients with relapsed or refractory chronic lymphocytic leukemia: results of an international multicenter double-blinded randomized phase II trial. AB - The objective of this study was to evaluate the safety and efficacy of different lenalidomide starting doses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). CLL patients were randomized to receive lenalidomide at initial doses of 5, 10, or 15 mg/d (N = 103). Doses were escalated by 5 mg every 28-d up to a maximum of 25 mg/d; dose reductions in up to 5 mg decrements were permitted. The most common grade >=3 adverse events (AEs) were neutropenia and thrombocytopenia. Ten patients died during therapy (four deaths considered as related to lenalidomide); 12 patients experienced second primary malignancies. The most common cause for treatment discontinuation was AEs. Overall response rates were similar across arms. Progression-free survival and overall survival rates were longer in patients who escalated treatment (to 15 or 20 mg/d) versus those who did not. Lower starting doses allowed subsequent dose escalation of lenalidomide while maintaining an acceptable tolerability profile in patients with relapsed/refractory CLL. PMID- 26763351 TI - Systematic Analysis of the Risk Factors Affecting the Recurrence of Traumatic Carotid-Cavernous Sinus Fistula. AB - OBJECTIVE: The current therapies for traumatic carotid-cavernous sinus fistula (tCCF) yield a variable rate of recurrence and produce different results. We analyzed factors among traumatic head injury to identify the risk factors in recurrent tCCFs. METHODS: We retrospectively reviewed patients who were diagnosed with tCCFs from January 2004 to December 2014 in a tertiary referral center. The factors that were analyzed included age, sex, associated injury, clinical presentation, interval from injury to interventions, interventions for tCCFs, and pathologic characters of tCCFs under digital subtraction angiography. RESULTS: A total of 55 patients with 56 tCCFs (1 bilateral tCCF) were included. Thirty-nine patients (40 tCCFs) were treated successfully in single session of a procedure, whereas 16 patients (16 tCCFs) experienced a recurrence of tCCF. In multivariate analysis, we found that the involvement of C2 or C4 segments (Debrun classification) of intracavernous internal carotid artery is an independent risk factor (hazard ratio [HR] 2.95, 95% confidence interval [95% CI] 1.34-6.52; P < 0.01) for the recurrence of tCCFs. Endovascular coil embolization demonstrated superior efficacy in successful interventions of tCCFs compared with detachable balloons (HR 2.63, 95% CI 1.06-6.57; P < 0.05) and other modalities (HR 3.06, 95% CI: 1.27-7.37; P < 0.05). CONCLUSIONS: A detachable coil is a favorable approach in the management of tCCFs when considering the rate of recurrence. In addition, the involvement of C2 or C4 segments (Debrun classification) served as an independent risk factor of the recurrence of tCCFs. PMID- 26763350 TI - Bone mineral density, osteoporosis, and fractures among people with eating disorders: a systematic review and meta-analysis. AB - OBJECTIVE: To provide meta-analytical evidence of bone mineral density (BMD), fractures, and osteoporosis rates in eating disorders (ED) vs. healthy controls (HCs). METHOD: Three independent authors searched major electronic databases from inception till August 2015 for cross-sectional studies reporting BMD in people with ED (anorexia nervosa, (AN); bulimia nervosa, (BN); eating disorders not otherwise specified, (EDNOS)) vs. HCs. Standardized mean differences (SMDs) +/ 95% and confidence intervals (CIs) were calculated for BMD, and odds ratios (ORs) for osteopenia, osteoporosis, and fractures. RESULTS: Overall, 57 studies were eligible, including 21 607 participants (ED = 6485, HCs = 15 122). Compared to HC, AN subjects had significantly lower BMD values at lumbar spine (SMD = -1.51, 95% CI = -1.75, -1.27, studies = 42), total hip (SMD = -1.56, 95%CI = -1.84, 1.28, studies = 23), intertrochanteric region (SMD = -1.80, 95%CI = -2.46, -1.14, studies = 7), trochanteric region (SMD = -1.05, 95%CI = -1.44, -0.66, studies = 7), and femoral neck (SMD = -0.98, 95%CI = -1.12, -0.77, studies = 20). Reduced BMD was moderated by ED illness duration and amenorrhea (P < 0.05). AN was associated with an increased likelihood of osteoporosis (OR = 12.59, 95%CI = 3.30 47.9, P < 0.001, studies = 4) and fractures (OR = 1.84, 95% CI = 1.17-2.89, I(2) = 56, studies = 6). No difference in BMD was found between BN and EDNOS vs. HC. CONCLUSION: People with AN have reduced BMD, increased odds of osteoporosis and risk of fractures. Proactive monitoring and interventions are required to ameliorate bone loss in AN. PMID- 26763353 TI - A systematic review and meta-analysis of the long-term overall outcome of autism spectrum disorders in adolescence and adulthood. AB - OBJECTIVE: A systematic review and meta-analysis of studies reporting on the overall outcome in terms of a global measure of adjustment in children with autistic disorders followed up in adolescence and adulthood. METHOD: PubMed, PsycINFO, and EMBASE were systematically searched on 3rd of August 2015. Included studies were analyzed using random-effects models estimating event rates (%) and 95% confidence intervals (95%CI). RESULTS: From 4350 records identified in the search, 15 studies covering 12 unique samples and a total of N = 828 individuals with autistic disorders were included in the analyses. An estimated 19.7% (95%CI: 14.2-26.6) had a good outcome, 31.1% (95%CI: 23.2-40.4%) a fair outcome, and 47.7% (95%CI: 36.6-59.0) a poor outcome. The meta-analysis showed strong evidence for heterogeneity. The subtype of childhood autism is a significant moderating factor on the risk of having a poor outcome at follow-up, whereas age at follow up showed statistically significant but inconsistent associations with outcome status. CONCLUSION: The long-term outcome of almost half of all individuals with autistic disorders is poor. The subtype of autism in childhood may be a predictor for specific long-term outcomes, but in general, little is known about the pathways and predictors. PMID- 26763354 TI - Polyomavirus JC microRNA expression after infection in vitro. AB - The in vitro expression of the Polyomavirus JC (JCPyV) microRNAs, JC-miRNA-3p and -5p, at early time points post-infection was investigated. The expression of the JCPyV microRNAs was monitored in hematopoietic progenitor KG-1 cells and in kidney fibroblast-like COS-7 cells transformed with SV40 after infection with a JCPyV CY archetype viral clone. The JCPyV DNA viral load was low in KG-1 cells compared with that in COS-7 cells, which showed productive viral replication. The expression of the JCPyV microRNAs was observed from 12h after the viral infection of both cell types and in the exosomes present in their cell supernatant. Additionally, this study verified that the JCPyV microRNAs in the exosomes present in the supernatants produced by the infected cells might be carried into uninfected cells. These findings suggest that additional investigations of the expression of JCPyV microRNAs and their presence in exosomes are necessary to shed light on their regulatory role during viral reactivation. PMID- 26763355 TI - Production of infectious ferret hepatitis E virus in a human hepatocarcinoma cell line PLC/PRF/5. AB - A strain of ferret hepatitis E virus (HEV), sF4370, isolated from an imported ferret was used to inoculate a human hepatocarcinoma cell line, PLC/PRF/5. The virus genome and capsid protein were detected in the cell culture supernatant. Immunofluorescence microscopy indicated that the capsid protein was located in the cytoplasm. The virus particles were purified from the culture supernatant by sucrose gradient ultracentrifugation. The capsid protein with molecular mass of ~72 kDa was detected in fractions with density of 1.150-1.162 g/cm(3), and particles of ferret HEV was associated with cell membrane. The virus recovered from the supernatant was serially passaged with PLC/PRF/5 cells and had the ability to infect ferrets by oral inoculation, indicating that the ferret HEV grown in PLC/PRF/5 was infectious. The establishment of ferret HEV cell culture system might be useful to understand the life cycle, mechanism of infection and replication of ferret HEV. PMID- 26763356 TI - Low-density-solvent-based air-assisted liquid-liquid microextraction followed by gas chromatography with flame ionization detection for the determination of synthetic phenolic antioxidants in milk samples. AB - A simple and rapid sample pretreatment technique termed low-density-solvent-based air-assisted liquid-liquid microextraction has been developed for the extraction and preconcentration of three synthetic phenolic antioxidants including butylated hydroxyanisole, butylated hydroxytoluene, and tert-butyl hydroquinone from milk samples prior to their analysis by gas chromatography with flame ionization detection. In this method, initially trichloroacetic acid as a proteins precipitation agent is added to the sample, and then it is sonicated and centrifuged. The obtained aqueous phase is removed and the analytes extracted by the proposed method using a low-density organic solvent. Some important parameters such as type and volume of extraction solvent, ionic strength, pH, and centrifugation rate and time were studied. Under the optimum conditions, enrichment factors were obtained in the range of 501-614. LODs and quantification were between 0.76-1.16 and 2.66-3.96 ng mL(-1) , respectively. This method is rapid and requires less than 15 min for sample preparation. PMID- 26763358 TI - Interim prosthesis preventing tongue protrusion following mandibular alveolar ridge and lower lip resection in a surgically compromised patient. AB - Carcinomas of the mandibular buccogingival region being aggressive rapidly destroy the supporting bone and adjacent soft tissues, making it mandatory for the oncosurgeon to resect substantial amounts of involved hard and soft tissues. Segmental mandibulectomy -followed by immediate bony and soft tissue reconstruction is the most acceptable approach. However, immediate reconstruction may not always be feasible or possible due to high recurrences potential of lesion, inaccessible residual pathology, or systemic -conditions that pose a risk for graft inosculation. In certain cases, where large portion of lower lip also needs to be sacrificed with alveolar resection, protrusion of tongue through the defect beyond the lip confines leads to drooling of saliva, difficulty in speech and worsening of esthetic appearance, social isolation, and compromised quality of life. So, pending reconstruction and definitive rehabilitation, patients would require provisional treatment to control some of the ill effects. This article presents a simple technique for fabrication of a provisional prosthesis for preventing tongue protrusion, salivary drooling following mandibular alveolar ridge and lip resection. PMID- 26763357 TI - Prognostic impact of serial measurements of serum-free light chain assay throughout the course of newly diagnosed multiple myeloma treated with bortezomib based regimens. AB - We retrospectively investigated the role of serial serum-free light chain (sFLC) evaluations in 150 multiple myeloma (MM) patients treated with first-line bortezomib-based regimens. Baseline sFLC ratio (sFLCR) identified three groups of patients - normal, lightly abnormal (<100), and highly abnormal (>=100) - with different progression-free survival (PFS: 3-year estimate 72% versus 61% versus 44%, respectively, p = 0.03). Moreover, the achievement of a normal sFLCR correlated with extended PFS (49 versus 17 months, p < 0.0001) and overall survival (75 versus 43 months, p < 0.0001) as compared with abnormal sFLCR, a gain maintained in a multivariate analysis for PFS. At relapse, a high sFLCR was associated with earlier start of salvage therapy compared with sFLCR <100 (3 month probability: 89% versus 64%, p = 0.0426). In 20% of patients, sFLC escape preceded the conventional relapse by a median of 3.8 months. Our results highlight the role of sFLC assay in the prognosis and follow-up of MM. PMID- 26763359 TI - CD200 Expression on Plasma Cell Myeloma Cells is Associated with the Efficacies of Bortezomib, Lenalidomide and Thalidomide. AB - Plasma cell myeloma (PCM) is a devastating disease with a highly heterogeneous outcome, with survival ranging from a few months to longer than 10 years. Treatment of multiple myeloma has changed markedly in the past decade due to the development of new drugs such as bortezomib, lenalidomide and thalidomide, which have greatly improved the outcome of PCM. The clinical and prognostic value of immunophenotyping in PCM remains questionable. The aim of this study was to determine the diagnostic and prognostic significance of CD200 expression in newly diagnosed PCM. We retrospectively reviewed the records of 107 patients newly diagnosed with PCM at Showa University Hospital between January 2004 and September 2013. Expression of CD200 was studied by immunohistochemistry. Clinical and pathological parameters were compared between CD200-positive and CD200 negative cases. CD200-positive PCM cases had lower serum albumin (p = 0.0001) compared to those without CD200 expression. Our results showed no significant difference in median overall survival between patients with CD200-positive and CD200-negative PCM. However, there was a strong correlation between CD200 expression and serum albumin level. In the CD200-negative group, median overall survival was significantly longer in patients who received new drug treatment. These findings suggest that CD200 expression is a useful marker for evaluation of the severity of PCM and that lack of CD200 expression may improve the sensitivity of PCM to therapy with new drugs. PMID- 26763360 TI - Plasmacytoid Dendritic Cells Producing Interferon-alpha (IFN-alpha) and Inducing Mx1 Play an Important Role for CD4(+) Cells and CD8(+) Cells in Necrotizing Lymphadenitis. AB - We confirmed the characteristic clinical features of necrotizing lymphadenitis (NEL) in 66 cases (23 male, 43 female) in Japan, which included high fever (38-40 degrees ), painful cervical lymphadenopathy (62/66, 93.9%), and leukopenia (under 4,000/mm(3)) (25/53, 47.2%), without seasonal occurrence, in a clinicopathological, immunohistochemical, electron microscopic serological study. Patient age varied from 3-55 years, and 72.7% (44/66) of patients were younger than 30 years. Histopathology of NEL was characterized by the presence of CD8(+) immunoblasts, CD123(+) cells (plasmacytoid dendritic cells; PDCs), histiocytes and macrophages phagocytizing CD4(+) apoptotic lymphocytes, but no granulocytes or bacteria. The number of PDCs and CD8(+) cells in lesions tended to increase with time, and PDCs tended to be larger and irregular in the lesions compared with the non-lesion tissue of the lymph nodes. In addition, PDCs showed no temporal morphological change in the lymph nodes. The number of CD4(+) cells in the lymph node lesions sharply decreased from the 2nd to the 4th week, and then tended to increase; however, CD4(+) cells gradually decreased with time in non lesion tissue. PDCs may produce interferon-alpha (IFN-alpha), which induces Mx1 expression. Strong Mx1 immunoreactivity is indicative of IFN-alpha production. IFN-alpha induces transformation of CD8(+) cells into immunoblasts, as well as phagocytosis of apoptotic cells derived from CD4(+) cells by macrophages. Thus, PDCs may play an important role with immune cells, including CD8(+) and CD4(+) cells, in necrotizing lymphadenitis. PMID- 26763361 TI - Cytogenetic Study and Analysis of Protein Expression in Plasma Cell Myeloma with t(11;14)(q13;q32): Absence of BCL6 and SOX11, and Infrequent Expression of CD20 and PAX5. AB - The t(11;14)(q13;q32) translocation is the most common chromosomal translocation in plasma cell myeloma (PCM), but the cytogenetic and immunophenotypic features of PCM with t(11;14)(q13;q32) remain to be fully elucidated. To address the issue, we retrospectively analyzed 21 newly diagnosed PCM patients with the t(11;14)(q13;q32) translocation in our institute. CD20 is a B-cell-specific transmembrane protein that is the topic of much focus as a potential target in immunotherapy. We observed a low incidence of CD20 expression (2 of 21 patients, 11%), although the expression of CD20 was previously reported to be associated with t(11;14)(q13;q32). PAX5 is an essential transcriptional factor involved in B cell development and commitment, and is down-regulated upon plasma cell differentiation. We observed one patient (6%) with expression of PAX5. The expression of CD19, CD56, and CD138 was detected in one (0.7%), nine (60%), and 13 patients (87%), respectively. Cyclin D1, CD38, and BCL2 were detected in all patients; on the other hand, neither BCL6 nor SOX11 was detected in any of the evaluated patients. Abnormalities of chromosome 13 were detected in six patients (38%), but deletion of TP53 was not observed in any of the evaluated patients. Our results suggest the absence of BCL6 and SOX11 expression, and infrequent expression of CD20, PAX5, and CD56 in PCM with t(11;14)(q13;q32), in contrast to the findings of earlier reports. PMID- 26763362 TI - TET2 Mutation in Adult T-Cell Leukemia/Lymphoma. AB - Loss-of-function of ten-eleven translocation-2 (TET2) is a common event in myeloid malignancies, and plays pleiotropic roles, including augmenting stem cell self-renewal and skewing hematopoietic cells to the myeloid lineage. TET2 mutation has also been reported in lymphoid malignancies; 5.7~12% of diffuse large B-cell lymphomas and 18~83% of angioimmunoblastic T-cell lymphomas had TET2 mutations. We investigated TET2 mutations in 22 adult T-cell leukemia/lymphoma (ATLL) patients and identified a missense mutation in 3 cases (14%). TET2 mutation occurred in a number of ATLL patients and was likely involved in their leukemogenesis. PMID- 26763363 TI - Spontaneous Regression of Intravascular Large B-Cell Lymphoma and Apoptosis of Lymphoma Cells: A Case Report. AB - A 61-year-old Japanese woman presented with hemophagocytic syndrome (HPS) and suffered from intravascular large B-cell lymphoma (IVLBCL). After a few days of supportive care, her condition improved without any anti-cancer drugs or steroids. She experienced recurrences of HPS at 15 mon and 21 mon after first presentation, but lymphoma cells were not observed. Relapse of IVLBCL with pulmonary involvement occurred 27 mon after first presentation. She underwent R CHOP therapy followed by autologous stem cell transplantation. She is currently alive and without lymphoma. Immunostaining by anti-ssDNA suggested that spontaneous regression may have been due to apoptosis of the lymphoma cells. PMID- 26763364 TI - Intraocular Relapse with Hypopyon and Retinal Infiltrates after Chemotherapy and Peripheral Blood Stem Cell Transplantation for Extranodal NK/T-Cell Lymphoma. AB - We report a case of intraocular relapse of extranodal NK/T-cell lymphoma with anterior chamber hypopyon and retinal infiltrates. A 55-year-old man developed fever, malaise, anorexia, and hepatosplenomegaly, and was diagnosed with NK/T cell lymphoma by liver biopsy. He underwent 2 courses of SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy, followed by myeloablative peripheral blood stem cell transplantation, donated by his brother. Two months later, he developed high-grade fever, hepatosplenomegaly, and peritoneal lymphadenopathy, and the relapse with hemophagocytic syndrome was diagnosed by bone marrow biopsy. He underwent 2 courses of SMILE salvage chemotherapy, followed by non-myeloablative peripheral blood stem cell transplantation, donated by his son. Two months later, he noticed blurred vision in both eyes. The right eye had aqueous cells and keratic precipitates, but no retinal lesions. The left eye had hypopyon in the anterior chamber with numerous aqueous cells, and retinal white infiltrates with retinal hemorrhages. The aqueous cells, obtained by anterior chamber paracentesis, were positive for CD3, CD56, and Epstein-Barr virus-encoded RNA, but negative for CD20 by immunocytochemical staining. Head magnetic resonance imaging demonstrated white matter lesions in the anterior to parietal lobes on the right side. The patient underwent intrathecal methotrexate injection and external beam radiation at 40 Gy, covering the entire brain and both eyes. The retinal lesions and hypopyon disappeared. Two months later, the patient died of renal failure, and autopsy demonstrated multi-organ involvement of lymphoma cells. In conclusion, we report a case of NK/T-cell lymphoma relapse with intraocular lesions, after combined chemotherapy and hematopoietic stem cell transplantation. PMID- 26763365 TI - Early-Onset Severe Diffuse Alveolar Hemorrhage after Bortezomib Administration Suggestive of Pulmonary Involvement of Myeloma Cells. AB - Severe acute lung injury is a rare but life-threatening complication associated with bortezomib. We report a patient with multiple myeloma who developed a severe diffuse alveolar hemorrhage (DAH) immediately after the first bortezomib administration. The patient was suspected to have pulmonary involvement of myeloma, which caused DAH after rapidly eradicating myeloma cells in the lungs with bortezomib. Rechallenge with bortezomib was performed without recurrent DAH. In patients with multiple myeloma who manifest abnormal pulmonary shadow, we should be aware of early-onset severe DAH after bortezomib administration, which might be due to pulmonary involvement of myeloma cells. PMID- 26763366 TI - Peripheral T-Cell Lymphoma, Not Otherwise Specified and Concurrent Seminoma in Testis. AB - Concurrent seminoma and malignant lymphoma of the testis is rare. We present a case of concurrent seminoma and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) in a 54-year-old man who complained of painless left testicular enlargement. Radical left orchiectomy was performed. Macroscopically, the tumor (4.0 * 3.0 cm) was creamy, soft, and homogeneous, and microscopic evaluation revealed an alveolar structure of large cells that formed sheets, as well as colonization by other abnormal cells in a 1.0 * 1.0 cm area. The portion of the tumor comprising large abnormal cells was diagnosed as a seminoma, which was positive for c-kit by immunohistochemistry; the other portion was diagnosed as CD3/CD8, TIA, and granzyme B-positive PTCL-NOS. These two portions were clearly differentiated from one another. The patient received CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) therapy and achieved complete response for 50 months. To our knowledge, this is the first reported case of synchronous advanced seminoma and PTCL. PMID- 26763367 TI - Nodal Marginal Zone Large B-Cell Lymphoma with Burkitt Translocation and Complex Chromosomal Changes Associated with Overexpression of BCL2, MYC, and BCL6. AB - We report the first case of a nodal marginal zone large B-cell lymphoma and the first with MYC rearrangement. This high proliferation rate lymphoma (40% of cells) occurred in the bilateral cervical, axillary, and para-aortic lymph nodes of an 82 year old woman. It involved extensively her bone marrow, and was lethal. Malignant B-cells were CD10 negative, harbored Burkitt translocation, and multiple chromosomal changes including trisomies of chromosomes 3 and 18, and three copies of 8q with an intact q24 cytoband (in addition to MYC rearrangement), associated with overexpression of BCL6, BCL2, and MYC respectively. We suggest that in aggressive nodular marginal zone lymphomas (clinical picture or high proliferation rate of lymphoma cells), fluorescence in situ hybridization analysis for MYC rearrangement, with break-apart probe, and for MYC/IGH translocation, in addition to chromosome analysis, should be performed. MYC rearrangement associated with a more rapid progression of the neoplasia, might warrant a more aggressive treatment. PMID- 26763368 TI - Coexistent t(8;21)(q22;q22) Translocation and 5q Deletion in Acute Myeloid Leukemia. AB - The t(8;21)(q22;q22) translocation is specifically observed in acute myeloid leukemia (AML) M2 subtype, whereas del(5q) is one of the most common cytogenetic aberrations in myelodysplastic syndromes (MDS). Thus, t(8;21)(q22;q22) and del(5q) appear to be mutually exclusive, and the association between them has not been characterized yet. Here, we report an 81-year-old woman with coexistent t(8;21)(q22;q22) and del(5q) at initial diagnosis. The bone marrow was infiltrated with 18.4% myeloblasts, and showed marked myeloid and erythroid dysplasia. Myeloblasts were positive for CD19 and CD56 as well as CD13, CD33, CD34 and HLA-DR. G-banding and spectral karyotyping showed 46,XX,del(5)(q?),t(8;21)(q22;q22)[18]/46,XX[2]. Both del(5)(q?) and t(8;21)(q22;q22) were present in a single clone. Fluorescence in situ hybridization (FISH) on metaphase spreads detected a RUNX1/RUNX1T1 fusion signal on the der(8)t(8;21)(q22;q22), and confirmed deletion of CSF1R signaling at 5q33 q34 on the del(5)(q?). Furthermore, FISH on interphase nuclei revealed that the RUNX1/RUNX1T1 fusion signal and deletion of CSF1R signaling were found in 66.0% and 58.0% of interphase cells, respectively, suggesting that del(5)(q?) occurred in cells with RUNX1/RUNX1T1. These results indicated a diagnosis of AML with t(8;21)(q22;q22)/RUNX1/RUNX1T1 rather than MDS, even though the percentage of bone marrow myeloblasts was less than 20%. Based on these findings, together with those of other reported cases, del(5q) seems to be an extremely rare but recurrent secondary aberration in AML with t(8;21)(q22;q22). PMID- 26763369 TI - Proposal for a risk banding framework for inhaled low aspect ratio nanoparticles based on physicochemical properties. AB - We present a conceptual framework that can be used to assign risk bands to inhaled low aspect ratio nanoparticles starting from exposure bands assigned to a specific exposure situation. The framework mimics a basic physiological scheme that captures the essential mechanisms of fate and toxicity of inhaled nanoparticles and is composed of several models and rules that estimate the result of the following processes: the deposition of particles in the respiratory tract, their (de-)agglomeration, lung burden and clearance, their diffusion through the lung mucus layer, translocation and cellular uptake and local and systemic toxicity. Each model is based on a set of particle's physicochemical properties, including the size and size distribution(s), the zeta potential (or net charge at a specific pH), the surface hydrophobicity or hydrophilicity, the conduction band energy (for metals, metal oxides, quantum dots, etc.) and the solubility at a specific pH. The framework takes the exposure bands as input and predicts, using the above-mentioned models, an internal dose band (module 1). Module 2 assigns a relative hazard ranking depending on the region of particle deposition in the respiratory tract, the likelihood of uptake and whether the toxicological effects are assumed to be local and/or systemic. By combining the results of Module 1 and 2, the framework provides a relative risk ranking. PMID- 26763370 TI - Potential of monitoring isotopologues by quantitative gas chromatography with time-of-flight mass spectrometry for metabolomic assay. AB - Because of the extreme complexity of metabolomic samples, the effectiveness of quantitative gas chromatography with time-of-flight mass spectrometry depends substantially on the expansion of the linear dynamic range. Facing the existence of numerous saturated detector signals, a data processing method based on monitoring isotopologues has been developed. The monoisotopic ion kept the high mass spectrometry sensitivity, and the less abundant isotopologue ions extended the linear dynamic range. This alternative method was proved to extend the linear dynamic range to five orders of magnitude successfully and overcome the quantitative problems induced by the ion detector saturation. Finally, to validate the applicability, the method was applied to a metabolomic assay of Alzheimer's disease. Comparing with the traditional monoisotopic method, the use of monitoring isotopologues helped us to discover an additional eight metabolites with significant difference and to conduct a more reliable principal component analysis as well. The results demonstrated that monitoring isotopologues in quantitative gas chromatography with time-of-flight mass spectrometry could improve the authenticity of metabolomic analysis. PMID- 26763371 TI - Improved performance of SrFe12O19 bulk magnets through bottom-up nanostructuring. AB - The influence of synthesis and compaction parameters is investigated with regards to formation of high performance SrFe12O19 bulk magnets. The produced magnets consist of highly aligned, single-magnetic domain nanoplatelets of SrFe12O19. The relationship between the magnetic performance of the samples and their structural features is established through systematic characterization by Vibrating Sample Magnetometry (VSM) and Rietveld refinement of powder X-ray diffraction data (PXRD). The analysis is supported by complementary techniques including Transmission Electron Microscopy (TEM), Atomic Force Microscopy (AFM) and X-ray pole figure measurements. SrFe12O19 hexagonal nanoplatelets with various sizes are synthesized by a supercritical hydrothermal flow method. The crystallite sizes are tuned by varying the Fe/Sr ratio in the precursor solution. Compaction of SrFe12O19 nanoplatelets into bulk magnets is performed by Spark Plasma Sintering (SPS). Rietveld refinement of the pressed pellets and texture analysis of pole figure measurements reveal that SPS pressing produces a high degree of alignment of the nanoplatelets, achieved without applying any magnetic field prior or during compaction. The highly aligned nanocrystallites combined with crystal growth during SPS give rise to an enormous enhancement of the magnetic properties compared to the as-synthesized powders, leading to high performance bulk magnets with energy products of 26 kJ m(-3). PMID- 26763372 TI - Recurrent VTE in a heterozygote of the fibrinogen Aalpha IVS4+1G>T and Aalpha p.Arg168Ter mutation. PMID- 26763373 TI - Surface-modified yeast cells: A novel eukaryotic carrier for oral application. AB - The effective targeting and subsequent binding of particulate carriers to M cells in Peyer's patches of the gut is a prerequisite for the development of oral delivery systems. We have established a novel carrier system based on cell surface expression of the beta1-integrin binding domain of invasins derived from Yersinia enterocolitica and Yersinia pseudotuberculosis on the yeast Saccharomyces cerevisiae. All invasin derivatives were shown to be effectively expressed on the cell surface and recombinant yeast cells showed improved binding to both human HEp-2 cells and M-like cells in vitro. Among the different derivatives tested, the integrin-binding domain of Y. enterocolitica invasin proved to be the most effective and was able to target Peyer's patches in vivo. In conclusion, cell surface-modified yeasts might provide a novel bioadhesive, eukaryotic carrier system for efficient and targeted delivery of either antigens or drugs via the oral route. PMID- 26763374 TI - A unified multicomponent stress-diffusion model of drug release from non biodegradable polymeric matrix tablets. AB - We propose a new transport model of drug release from hydrophilic polymeric matrices, based on Stefan-Maxwell flux laws for multicomponent transport. Polymer stress is incorporated in the total mixing free energy, which contributes directly to the diffusion driving force while leading to time-dependent boundary conditions at the tablet interface. Given that hydrated matrix tablets are dense multicomponent systems, extended Stefan-Maxwell (ESM) flux laws are adopted to ensure consistency with the Onsager reciprocity principle and the Gibbs-Duhem thermodynamic constraint. The ESM flux law for any given component takes into account the friction exerted by all other species and is invariant with respect to reference velocity, thus satisfying Galilean translational invariance. Our model demonstrates that penetrant-induced plasticization of polymer chains partially or even entirely offsets the steady decline of chemical potential gradients at the tablet-medium interface that drive drug release. Utilizing a Flory-Huggins thermodynamic model, a modified form of the upper convected Maxwell constitutive equation for polymer stress and a Fujita-type dependence of mutual diffusivities on composition, depending on parameters, Fickian, anomalous or case II drug transport arises naturally from the model, which are characterized by quasi-power-law release profiles with exponents ranging from 0.5 to 1, respectively. A necessary requirement for non-Fickian release in our model is that the matrix stress relaxation time is comparable to the time scale for water diffusion. Mutual diffusivities and their composition dependence are the most decisive factors in controlling drug release characteristics in our model. Regression of the experimental polymer dissolution and drug release profiles in a system of Theophylline/cellulose (K15M) demonstrate that API-water mutual diffusivity in the presence of excipient cannot generally be taken as a constant. PMID- 26763375 TI - Short-range cytokine gradients to mimic paracrine cell interactions in vitro. AB - Cell fate decisions in many physiological processes, including embryogenesis, stem cell niche homeostasis and wound healing, are regulated by secretion of small signaling proteins, called cytokines, from source cells to their neighbors or into the environment. Concentration level and steepness of the resulting paracrine gradients elicit different cell responses, including proliferation, differentiation or chemotaxis. For an in-depth analysis of underlying mechanisms, in vitro models are required to mimic in vivo cytokine gradients. We set up a microparticle-based system to establish short-range cytokine gradients in a three dimensional extracellular matrix context. To provide native binding sites for cytokines, agarose microparticles were functionalized with different glycosaminoglycans (GAG). After protein was loaded onto microparticles, its slow release was quantified by confocal microscopy and fluorescence correlation spectroscopy. Besides the model protein lysozyme, SDF-1 was used as a relevant chemokine for hematopoietic stem and progenitor cell (HSPC) chemotaxis. For both proteins we found gradients ranging up to 50MUm from the microparticle surface and concentrations in the order of nM to pM in dependence on loading concentration and affinity modulation by the GAG functionalization. Directed chemotactic migration of cells from a hematopoietic cell line (FDCPmix) and primary murine HSPC (Sca-1(+) CD150(+) CD48(-)) toward the SDF-1-laden microparticles proved functional short-range gradients in a two-dimensional and three-dimensional setting over time periods of many hours. The approach has the potential to be applied to other cytokines mimicking paracrine cell-cell interactions in vitro. PMID- 26763376 TI - Biodegradable poly(lactic-co-glycolic acid) microspheres loaded with S-nitroso-N acetyl-D-penicillamine for controlled nitric oxide delivery. AB - Nitric oxide (NO) is a fascinating and important endogenous free-radical gas with potent antimicrobial, vasodilating, smooth muscle relaxant, and growth factor stimulating effects. However, its wider biomedical applicability is hindered by its cumbersome administration, since NO is unstable especially in biological environments. In this work, to ultimately develop site-specific controlled release vehicles for NO, the NO donor S-nitroso-N-acetyl-D-penicillamine (SNAP) was encapsulated within poly(lactic-co-glycolic acid) 50:50 (PLGA) microspheres by using a solid-in-oil-in-water emulsion solvent evaporation method. The highest payload was 0.56(+/-0.01) MUmol SNAP/mg microspheres. The in vitro release kinetics of the donor were controlled by the bioerosion of the PLGA microspheres. By using an uncapped PLGA (Mw=24,000-38,000) SNAP was slowly released for over 10days, whereas by using the ester capped PLGA (Mw=38,000-54,000) the release lasted for over 4weeks. The presence of copper ions and/or ascorbate in solution was necessary to efficiently decompose the released NO donor and obtain sustained NO release. It was also demonstrated that light can be used to induce rapid NO release from the microspheres over several hours. SNAP exhibited excellent storage stability when encapsulated in the PLGA microspheres. These new microsphere formulations may be useful for site-specific administration and treatment of pathologies associated with dysfunction in endogenous NO production, e.g. treatment of diabetic wounds, or in diseases involving other biological functions of NO including vasodilation, antimicrobial, anticancer, and neurotransmission. PMID- 26763377 TI - Identification of pancreatic tumors in vivo with ligand-targeted, pH responsive mesoporous silica nanoparticles by multispectral optoacoustic tomography. AB - Despite significant efforts to translate nanotechnology for cancer application, lack of identification of biodistribution/accumulation of these nanovehicles in vivo remains a substantial barrier for successful implementation of theranostic nanoparticles in the clinic. The purpose of the study was to develop a tumor targeted theranostic nanovehicle for pancreatic cancer detectable by multispectral optoacoustic tomography (MSOT). To improve the tumor specificity of our mesoporous silica nanoparticle (MSN), we utilized a dual targeting strategy: 1) an elevated tumor receptor, urokinase plasminogen activator receptor (UPAR), and 2) the acidic tumor microenvironment. The tumor specificity of the MSN particle was improved with the addition of both chitosan, targeting acidic pH, and urokinase plasminogen activator (UPA), targeting UPAR. Drug release assays confirmed pH responsive release of gemcitabine in vitro. The UPAR specific binding of MSN-UPA nanoparticles was confirmed by reduction in fluorescence signal following MSN-UPA nanoparticle treatment in UPAR positive cells blocked with a UPAR-blocking antibody. Based upon Indocyanine Green encapsulation within the nanoparticles, UPA ligand targeted MSNs demonstrated increased intensity compared to untargeted MSNs at both pH7.4 (7*) and 6.5 (20*); however the signal was much more pronounced at a pH of 6.5 using tissue phantoms (p<0.05). In vivo, MSN-UPA particles demonstrated orthotopic pancreatic tumor specific accumulation compared to liver or kidney as identified using multispectral optoacoustic tomography (p<0.05) and confirmed by ex vivo analysis. By tracking in vivo nanoparticle biodistribution with MSOT, it was shown that pH responsive, ligand targeted MSNs preferentially bind to pancreatic tumors for payload delivery. PMID- 26763378 TI - Bleeding risk assessment in patients undergoing elective cardiac surgery using ROTEM((r)) platelet and Multiplate((r)) impedance aggregometry. AB - Impaired platelet function is a major risk factor for peri-operative bleeding and transfusion. This prospective, observational study enrolled 101 consecutive patients undergoing elective cardiac surgery with cardiopulmonary bypass. Platelet function was assessed by two whole blood impedance aggregometers (ROTEM((r)) platelet and Multiplate((r)) ), using three different activators (arachidonic acid, adenosine diphosphate and thrombin receptor-activating peptide 6), at three peri-operative time points (before anaesthesia, after aortic declamping and 5-10 min after protamine administration). Platelet function was impaired over the time-course in all assays. Results after protamine administration demonstrated the best correlation with postoperative chest tube drainage. Patients with a chest tube drainage exceeding the 75th percentile of the entire study population, during the first 24 postoperative hours, were characterised to have excessive bleeding. Both devices provided similar predictability for postoperative chest tube drainage and red blood cell transfusion requirements. The latter was associated with the degree of platelet inhibition and the number of pathways inhibited determined respective cut-off values. PMID- 26763379 TI - Long-Term Results From Tonsillectomy in Adults. AB - BACKGROUND: Tonsillectomy is performed more than 400 000 times in the European Union each year, making it one of the most common operations. Nonetheless, there have been only a few long-term studies of quality of life after tonsillectomy. METHODS: In 2004, data on the quality of life after tonsillectomy were obtained from adult German-speaking tonsillectomy patients by means of the Glasgow Benefit Inventory and a questionnaire specifically designed for that study. The present study concerns the further followup of these patients, sometimes many years later. 114 patients with recurrent tonsillitis were included in this descriptive study. RESULTS: Of the 114 patients, 97 (85%) provided further data at 14 months, and 71 (62%) at ca. 7 years. The Glasgow Benefit Inventory revealed postoperative improvement of quality of life at 14 months and at 7 years, with median values of 16.67 points (quartile 11.11/25) and 13.89 points (quartile 8.33/25) (p=0.168). The mean number of annual episodes of sore throat fell from 10 preoperatively to 2 postoperatively (p=0.0001). The number of visits to the doctor, the intake of analgesic drugs and antibiotics, and the number of medical absences from work also declined significantly over the period of observation. CONCLUSION: Tonsillectomy was associated with a longlasting improvement of health and quality of life, and with lower utilization of medical resources. The 62% response rate at 7 years leaves the question open whether patients with a favorable postoperative course may have been more likely than others to participate in the study. PMID- 26763383 TI - What Makes Nursing Work? PMID- 26763380 TI - Cardioversion in Non-Valvular Atrial Fibrillation. AB - BACKGROUND: Atrial fibrillation is the most common type of cardiac arrhythmia and is associated with elevated rates of stroke, heart failure, hospital admission, and death. Its prevalence in the overall population is 1.5% to 2%. To convert atrial fibrillation to sinus rhythm, cardioversion is needed. METHODS: This review is based on pertinent articles published from 2004 to December 2014 that were retrieved by a selective PubMed search employing the terms "atrial fibrillation" and "cardioversion." RESULTS: In electrical cardioversion, a defibrillator is used to pass a pulse of current between two electrodes. In pharmacological cardioversion, antiarrhythmic drugs are given intravenously or orally. Electrical cardioversion results in sinus rhythm in more than 85% of patients; pharmacological cardioversion results in sinus rhythm in about 70% of patients with recent-onset atrial fibrillation. As a rule, cardioversion should be carried out only under effective therapeutic anticoagulation with heparin, a vitamin K antagonist, or a new oral anticoagulant drug. If atrial fibrillation has been present for more than 48 hours, cardioversion must be preceded by transesophageal echocardiography to rule out blood clot in the left atrium, or else the patient is pretreated with an anticoagulant drug for at least 3 weeks. As cardioversion can transiently impair left atrial pumping function, anticoagulation is usually maintained for 4 weeks after the procedure. The decision whether to continue anticoagulation beyond this point is based on the risk of stroke, as assessed with the CHA2DS2-VASc score. CONCLUSION: The main risks of cardioversion-thrombo--embolism and clinically significant hemorrhage- occur in 1% of cases or less (in the first 30 days after treatment) if the procedure is carried out as recommended in therapeutic guidelines. Serious complications still occur, but they are rare. PMID- 26763382 TI - Malocclusion and the need for orthodontic treatment in 8-year-old children with Down syndrome: a cross-sectional population-based study. AB - OBJECTIVES: To describe the arch morphology and the prevalence and severity of malocclusions in 8-year-old children with DS, and to evaluate their need for treatment using the Norwegian Need for Orthodontic Treatment Index (NOTI), and comparing the findings with a control group. MATERIALS AND METHODS: This population-based cross-sectional study was part of a national prospective study evaluating upper airway function, hearing, dental, and craniofacial characteristics in a cohort of children with DS in Norway. The cohort consisted of 32 children with DS and represented 57% of all children born with DS in Norway in 2002. Dental arch morphology and malocclusion were assessed on dental casts. Data were collected prospectively at the TAKO-centre, National Resource Center for Oral Health in Rare Medical Conditions. RESULTS: All the children with DS (100%) had objectively assessed needs for orthodontic treatment, compared with 30% of the normative comparison group. Among the children with DS, 68% were objectively categorized as being in "great need" (Category B) for treatment and the 75% were categorized as having "obvious need" (Category C). In comparison, only 20% of children without DS were in Category B, and 44% were in Category C. CONCLUSION: This study indicates significantly higher prevalence and severity of malocclusions in 8-year-old children with DS compared with control group. PMID- 26763384 TI - HIV-1 low copy viral sequencing-A prototype assay. AB - In HIV-1 patients with low viral burden, sequencing is often problematic, yet important. This study presents a sensitive, sub-type independent system for sequencing of low level viremia. Sequencing data from 32 HIV-1 infected patients with low level viremia were collected longitudinally. A combination of ViroSeq(r) HIV-1 Genotyping System and an in-house nesting protocol was used. Eight sub types were represented. The success-rate of amplification of both PR and RT in the same sample was 100% in samples with viral loads above 100 copies/ml. Below 100 copies/ml, this study managed to amplify both regions in 7/13 (54%) samples. The assays were able to amplify either PR or RT in all sub-types included but one sub-type A specimen. In conclusion, this study presents a promising, simple assay to increase the ability to perform HIV-1 resistance testing at low level viremia. This is a prototype assay and the method needs further testing to evaluate clinical performance. PMID- 26763381 TI - Palliative Care of Adult Patients With Cancer. AB - BACKGROUND: In Germany, the annual mortality rate from cancer in the year 2011 was 269.9 deaths per 100 000 persons; every fourth death was due to cancer. A central objective of palliative care is to maintain the best possible quality of life for cancer patients right up to the end of their lives. METHODS: The PubMed, Embase, and Cochrane Library databases were systematically searched for pertinent publications, and the ones that were selected were assessed as recommended by the Scottish Intercollegiate Guidelines Network. As part of the German Guideline Program in Oncology, recommendations for the S3 Guideline on Palliative Care concerning seven different topics in the management of adult patients with incurable cancer were developed by a representative expert panel employing a consensus process. RESULTS: Opioids are the drugs of first choice for severe and moderately severe cancer-related pain, and for breathlessness. No clinically relevant respiratory depression was observed in any study. When opioids are used, accompanying medication to prevent constipation is recommended. Drugs other than opioids are ineffective against breathlessness, but clinical experience has shown that benzodiazepines and opioids can be used in combination in advanced stages of disease, or if the patient suffers from marked anxiety. Depression should be treated even in patients with a short life expectancy; psychotherapy is indicated, and antidepressant medication is indicated as well if depression is at least moderately severe. Communication skills, an essential component of palliative care, play a major role in conversations between the physician and the patient about the diagnosis, the prognosis, and the patient's wish to hasten death. When the dying phase begins, tumor-specific treatments should be stopped. CONCLUSION: Palliative care should be offered to cancer patients with incurable disease. Generalist and specialist palliative care constitute a central component of patient care, with the goal of achieving the best possible quality of life for the patient. PMID- 26763386 TI - The importance of obstructive sleep apnoea management in peri-operative medicine. PMID- 26763385 TI - Diagnosis and Management of Iron Deficiency in CKD: A Summary of the NICE Guideline Recommendations and Their Rationale. AB - The UK-based National Institute for Health and Care Excellence (NICE) has updated its guidance on iron deficiency and anemia management in chronic kidney disease. This report outlines the recommendations regarding iron deficiency and their rationale. Serum ferritin alone or transferrin saturation alone are no longer recommended as diagnostic tests to assess iron deficiency. Red blood cell markers (percentage hypochromic red blood cells, reticulocyte hemoglobin content, or reticulocyte hemoglobin equivalent) are better than ferritin level alone at predicting responsiveness to intravenous iron. When red blood cell markers are not available, a combination of transferrin saturation < 20% and ferritin level < 100ng/mL is an alternative. In comparisons of the cost-effectiveness of different iron status testing and treatment strategies, using percentage hypochromic red blood cells > 6% was the most cost-effective strategy for both hemodialysis and nonhemodialysis patients. A trial of oral iron replacement is recommended in people not receiving an erythropoiesis-stimulating agent (ESA) and not on hemodialysis therapy. For children receiving ESAs, but not treated by hemodialysis, oral iron should be considered. In adults and children receiving ESAs and/or on hemodialysis therapy, intravenous iron should be offered. When giving intravenous iron, high-dose low-frequency administration is recommended. For all children and for adults receiving in-center hemodialysis, low-dose high frequency administration may be more appropriate. PMID- 26763387 TI - Xenobiotic metabolism in the zebrafish: a review of the spatiotemporal distribution, modulation and activity of Cytochrome P450 families 1 to 3. AB - The zebrafish (Danio rerio) has been increasingly explored in pharmaceutical research as a promising alternative model for toxicological screens. This necessitates a thorough knowledge on the biotransformation processes for a correct interpretation of pharmacological and toxicological data. Physiologically, cytochrome P450 (CYP) enzymes, specifically CYP families 1-3, play a pivotal role in drug metabolism. And yet, information regarding activity of CYP, its isoforms, and conjugation enzymes in zebrafish is either scarce or conflicting. To account for this discrepancy, the available spatiotemporal, modulation and activity data on zebrafish CYP 1-3 families are reviewed in this paper and compared with human CYP data. The CYP genetic features and synteny are well characterized, as is their expression in different organ systems. Moreover, several substrates metabolized by humans also show metabolism in zebrafish, with other CYP isoforms possibly involved. Altogether, the five CYP1 members, 41 CYP2 members and five CYP3 members in zebrafish show distinct evolutionary and orthological similarities with humans. PMID- 26763388 TI - Identification of sheep red blood cell (SRBC) surface immune-responsive peptides detected by antisera from SRBC-immunized rats. AB - To identify the sheep red blood cell (SRBC) surface immune-responsive peptides, immuno-reactive fraction of SRBC was detected by SDS-PAGE and western blot analysis with antisera from SRBC-immunized rats. Then the most intense immuno reactive band on SDS-PAGE was subjected to nanoLC-ESI-MS/MS analysis, and 17 proteins were identified including membrane proteins of erythrocytes such as band 3 anion transport protein isoform 1 (Anion exchange protein 1; AE-1, CD233), Ammonium transporter Rh type A (Rh type A glycoprotein, CD241) and Ankyrin-1 (ANK 1), Spectrin beta chain. Among them, plasma protein AE-1 (CD233) and Rh type A glycoprotein (CD241) have transmembrane domain and correspond to extracellular region in their sequences. These extracellular regions of the plasma membrane proteins are supposed to be major immune-responsive peptides of SRBC in rats. These peptides are promising for the construction of an ELISA system which does not require the processing of SRBC membrane ghosts. PMID- 26763389 TI - Acute pulmonary toxicity and inflammation induced by combined exposure to didecyldimethylammonium chloride and ethylene glycol in rats. AB - Didecyldimethylammonium chloride (DDAC), an antimicrobial agent, has been reported to induce pulmonary toxicity in animal studies. DDAC is frequently used in spray-form household products in combination with ethylene glycol (EG). The purpose of this study was to evaluate the toxic interaction between DDAC and EG in the lung. DDAC at a sub-toxic dose (100 MUg/kg body weight) was mixed with a non-toxic dose of EG (100 or 200 MUg/kg body weight), and was administrated to rats via intratracheal instillation. Lactate dehydrogenase activity and total protein content in the bronchoalveolar lavage fluid (BALF) were not changed by singly treated DDAC or EG, but significantly enhanced at 1 d after treatment with the mixture, with the effect dependent on the dose of EG. Total cell count in BALF was largely increased and polymorphonuclear leukocytes were predominantly recruited to the lung in rats administrated with the mixture. Inflammatory cytokines, tumor necrosis factor-alpha and interleukin-6 also appeared to be increased by the mixture of DDAC and EG (200 MUg/kg body weight) at 1 d post exposure, which might be associated with the increase in inflammatory cells in lung. BALF protein content and inflammatory cell recruitment in the lung still remained elevated at 7 d after the administration of DDAC with the higher dose of EG. These results suggest that the combination of DDAC and EG can synergistically induce pulmonary cytotoxicity and inflammation, and EG appears to amplify the harmful effects of DDAC on the lung. Therefore pulmonary exposure to these two chemicals commonly found in commercial products can be a potential hazard to human health. PMID- 26763390 TI - MEIS3 is repressed in A549 lung epithelial cells by deoxynivalenol and the repression contributes to the deleterious effect. AB - Deoxynivalenol (DON) is an important Fusarium toxin of concern for food safety. The inhalation of powder contaminated with DON is possible and may cause lung toxicity. In this study, we analyzed the gene expression profile of A549 cells treated for 24 hr with 0.2 ug/mL DON by microarray analysis. In total, 16 genes and 5 noncoding RNAs were significantly affected by DON treatment. The repression of B3GALT4, MEIS3, AK7, SEMA3A, KCNMB4, and SCARA5 was confirmed by quantitative PCR. We investigated the DON toxicity on A549 cells that exogenously expressed these 6 genes. The result indicated that A549 cells that transiently expressed MEIS3 were tolerant to the deleterious effects of DON. Our data show that DON affected the expression of genes with various functions, and suggest that the repression of MEIS3 plays roles in the deleterious effect of DON in A549 lung epithelial cells. PMID- 26763391 TI - Safety evaluation of a newly-developed dietary fiber: resistant glucan mixture. AB - Resistant glucan mixture (RGM), a water-soluble dietary fiber produced by the random polymerization of glucose with activated carbon as a catalyst at a high temperature, has been recently developed by our group. There has been little physiological and safety research into RGM and therefore we now present our research into its safety. A reverse mutation assay indicated that RGM is not mutagenic either with or without metabolic activation. We conducted a 90-day subchronic oral toxicity study in rats. Male and female rats fed either a 3% or 5% w/w RGM diet had no muddy or watery stools, and there was no RGM-related death in any group. Although some parameters in the 3% and 5% w/w groups were significantly different from those in the control group, these changes were not due to any toxicity from RGM. The results indicated that the No Observed Adverse Effect Level (NOAEL) of RGM was 3.3 and 3.9 g/kg body weight (BW) per day in male and female rats, respectively. We then studied the gastrointestinal effects of RGM in healthy adult humans. Gastrointestinal symptoms, such as gurgling sounds, flatus and tenesmus, were mild and transient. In men and women, the maximum no effect dose for diarrhea was more than 0.9 g RGM /kg BW. The results of our current safety assessment studies suggest that RGM is safe for human consumption. PMID- 26763392 TI - shRNA-mediated AMBRA1 knockdown reduces the cisplatin-induced autophagy and sensitizes ovarian cancer cells to cisplatin. AB - Recent research has revealed a role for Ambra1, an autophagy-related gene-related (ATG) protein, in the autophagic pro-survival response, and Ambra1 has been shown to regulate Beclin1 and Beclin1-dependent autophagy in embryonic stem cells and cancer cells. However, whether Ambra1 plays an important role in the autophagy pathway in ovarian cancer cells is unknown. In this study, we hypothesized that Ambra1 is an important regulator of autophagy and apoptosis in ovarian cancer cells. We firstly confirmed autophagic activity in ovarian cancer OVCAR-3 cells which were treated with cisplatin by assessing endogenous microtubule-associated protein 1 light chain 3 (LC3) localization and the presence of autophagosomes and LC3 protein levels in OVCAR-3 cells. Cell apoptosis and viability were measured by annexin-V and PI staining and MTT assays. We then knocked down Ambra1 expression with transfection with the plasmid expressing the small hairpin RNA (shRNA) targeting AMBRA1, then re-evaluated autophagy in the OVCAR-3 cells subject to cisplatin treatment, and re-determined the sensitivity of OVCAR-3 cells to cisplatin. Results demonstrated that cisplatin treatment induced autophagy in OVCAR-3 cells in association with Ambra1 upregulation in the ovarian cancer cells. When Ambra1 expression was reduced by shRNA, the ovarian cancer cells were more sensitive to cisplatin. In conclusion, Ambra1 is a crucial regulator of autophagy and apoptosis in ovarian cancer cells subject to cisplatin to maintain the balance between autophagy and apoptosis. And the Ambra1-targeting inhibition might be an effective method to sensitize ovarian cancer cells to chemotherapy. PMID- 26763393 TI - Carbon tetrachloride-induced lethality in mouse is prevented by multiple pretreatment with zinc sulfate. AB - Carbon tetrachloride (CCl4) is commonly used as a chemical inducer of experimental liver injury. Several compounds have been demonstrated to attenuate the hepatic damage caused by sublethal doses of CCl4. However, rescue from lethal toxicity of CCl4 has not been reported. In the present study, we evaluated the protective effect of metallothionein (MT), an endogenous scavenger of free radicals, on CCl4-induced lethal toxicity of mice. To induce MT production in male ddY mice, we administered Zn (as ZnSO4) at 50 mg/kg as a once-daily subcutaneous injection for 3 days prior to a single intraperitoneal administration of 4 g/kg CCl4. Animals were observed for mortality every 3 hr for 24 hr after CCl4 injection. Liver damage was assessed by determining (in a subset of these mice) blood levels of alanine aminotransferase (ALT; a marker of liver injury) and liver histopathology at 6 hr after CCl4 injection. Our results showed that three times pretreatment with Zn yielded > 40-fold induction of hepatic MT protein levels compared to control group. Zn pretreatment completely abolished the CCl4-induced mortality of mice. We also found that pretreatment of mice with Zn significantly decreased the ALT levels and reduced the histological liver damage as assessed at 6 hr post-CCl4. These findings suggest that prophylaxis with Zn protects mice from CCl4-induced acute hepatic toxicity and mortality, presumably by induction of radical-scavenging MT. PMID- 26763394 TI - Molecular identification of poisonous mushrooms using nuclear ITS region and peptide toxins: a retrospective study on fatal cases in Thailand. AB - Cases of mushroom poisoning in Thailand have increased annually. During 2008 to 2014, the cases reported to the National Institute of Health included 57 deaths; at least 15 died after ingestion of amanitas, the most common lethal wild mushrooms inhabited. Hence, the aims of this study were to identify mushroom samples from nine clinically reported cases during the 7-year study period based on nuclear ITS sequence data and diagnose lethal peptide toxins using a reversed phase LC-MS method. Nucleotide similarity was identified using BLAST search of the NCBI database and the Barcode of Life Database (BOLD). Clade characterization was performed by maximum likelihood and Bayesian phylogenetic approaches. Based on BLAST and BOLD reference databases our results yielded high nucleotide similarities of poisonous mushroom samples to A. exitialis and A. fuliginea. Detailed phylogenetic analyses showed that all mushroom samples fall into their current classification. Detection of the peptide toxins revealed the presence of amatoxins and phallotoxins in A. exitialis and A. fuliginea. In addition, toxic alpha-amanitin was identified in a new provisional species, Amanita sp.1, with the highest toxin quantity. Molecular identification confirmed that the mushrooms ingested by the patients were members of the lethal amanitas in the sections Amanita and Phalloideae. In Thailand, the presence of A. exitialis was reported here for the first time and all three poisonous mushroom species provided new and informative data for clinical studies. PMID- 26763395 TI - Cigarette smoke extract-induced interleukin-6 expression is regulated by phospholipase D1 in human bronchial epithelial cells. AB - Cigarette smoking is known to be associated with various kinds of diseases, including atherosclerotic cardiovascular disease, cancer, and chronic obstructive pulmonary disease (COPD). Many of the diseases associated with cigarette smoking are also associated with changes in interleukin-6 (IL-6) expression. In this study, we investigated the role of phospholipase D1 (PLD1) in IL-6 expression induced by cigarette smoke extract (CSE). Treatment with CSE increased PLD1 and IL-6 expressions in human bronchial epithelial (BEAS-2B) cells. In addition, CSE treatment activated PLC, PKC, and MAPK pathway through the Gi protein-coupled receptor. Pertussis toxin (PTX, Gi protein-coupled receptor inhibitor), PAO (PLC inhibitor), Go6976 (PKC inhibitor) and SB203580 (p38MAPK inhibitor) decreased CSE induced PLD1 expression. The results show that Gi protein, PLC, PKC, and p38MAPK act as upstream regulators of PLD1 in CSE-treated BEAS-2B cells. Moreover, PLD1 siRNA transfection decreased CSE-induced ATF2 phosphorylation and IL-6 expression. In addition, inhibitors of Gi protein, PLC, PKC, and p38MAPK, and ATF2 siRNA transfection decreased CSE-induced IL-6 expression, suggesting that CSE-induced IL-6 expression is regulated via Gi protein/PLC/PKC/p38MAPK/PLD1/ATF2 pathway. Taken together, the results suggest that PLD1 is an important regulator of IL-6 expression induced by CSE in BEAS-2B cells. PMID- 26763396 TI - Disruption of spindle checkpoint function in rats following 28 days of repeated administration of renal carcinogens. AB - We previously reported that 28-day exposure to hepatocarcinogens that facilitate cell proliferation specifically alters the expression of G1/S checkpoint-related genes and proteins, induces aberrant early expression of ubiquitin D (UBD) at the G2 phase, and increases apoptosis in the rat liver, indicating G1/S and spindle checkpoint dysfunction. The present study aimed to determine the time of onset of carcinogen-specific cell-cycle disruption after repeated administration of renal carcinogens for up to 28 days. Rats were orally administered the renal carcinogens nitrofurantoin (NFT), 1-amino-2,4-dibromoantraquinone (ADAQ), and 1,2,3-trichloropropane (TCP) or the non-carcinogenic renal toxicants 1-chloro-2 propanol, triamterene, and carboxin for 3, 7 or 28 days. Both immunohistochemical single-molecule analysis and real-time RT-PCR analysis revealed that carcinogen specific expression changes were not observed after 28 days of administration. However, the renal carcinogens ADAQ and TCP specifically reduced the number of cells expressing phosphorylated-histone H3 at Ser10 in both UBD(+) cells and proliferating cells, suggestive of insufficient UBD expression at the M phase and early transition of proliferating cells from the M phase, without increasing apoptosis, after 28 days of administration. In contrast, NFT, which has marginal carcinogenic potential, did not induce such cellular responses. These results suggest that it may take 28 days to induce spindle checkpoint dysfunction by renal carcinogens; however, induction of apoptosis may not be essential. Thus, induction of spindle checkpoint dysfunction may be dependent on carcinogenic potential of carcinogen examined, and marginal carcinogens may not exert sufficient responses even after 28 days of administration. PMID- 26763398 TI - Antiviral drug vidarabine possessing cardiac type 5 adenylyl cyclase inhibitory property did not affect cardiohemodynamic or electrophysiological variables in the halothane-anesthetized dogs. AB - Vidarabine has been used for the treatment of patients with local and systemic herpes virus infection; moreover, it was recently reported that it inhibits cardiac type 5 adenylyl cyclase. Furthermore, vidarabine has been shown to suppress atrial fibrillation and improve congestive heart failure in experimental models of mice induced by the isoproterenol infusion. Since information that can explain its experimentally demonstrated efficacy against congestive heart failure and atrial fibrillation remains limited, in this study we precisely assessed cardio-electropharmacological effect using the halothane-anesthetized canine model. Vidarabine was intravenously administrated in three escalating doses of 1, 10, 100 mg/kg over 10 min with a pause between the doses (n = 4). Meanwhile, the vehicle dimethyl sulfoxide in volumes of 0.033, 0.033 and 0.33 mL/kg was intravenously administrated in the same manner as was vidarabine (n = 4). No significant difference was detected in any cardiohemodynamic or electrophysiological variables between the vehicle- and vidarabine-treated groups, which indicates that effective doses of vidarabine adequately inhibiting type 5 adenylyl cyclase did not affect the cardiovascular variables in vivo at all, showing its cardiac safety profile under physiological condition. Thus, the clinical utility of vidarabine might be limited to the pathological situation including congestive heart failure with increased adrenergic tone and/or sympathetic nerve-dependent atrial fibrillation. PMID- 26763397 TI - Arsenic acid inhibits proliferation of skin fibroblasts, and increases cellular senescence through ROS mediated MST1-FOXO signaling pathway. AB - Arsenic exposure through drinking water is a major public health problem. It causes a number of toxic effects on skin. Arsenic has been reported to inhibit cell proliferation in in vitro conditions. However, reports about the molecular mechanisms are limited. Here, we investigated the mechanism involved in arsenic acid-mediated inhibition of cell proliferation using mouse skin fibroblast cell line. The present study found that 10 ppm arsenic acid inhibited cell proliferation, without any effect on cell death. Arsenic acid induced the generation of reactive oxygen species (ROS), resulting in oxidative stress to DNA. It also activated the mammalian Ste20-like protein kinase 1 (MST1); however the serine/threonine kinase Akt was downregulated. Forkhead box O (FOXO) transcription factors are activated through phosphorylation by MST1 under stress conditions. They are inhibited by phosphorylation by Akt through external and internal stimuli. Activation of FOXOs results in their nuclear localization, followed by an increase in transcriptional activity. Our results showed that arsenic induced the nuclear translocation of FOXO1 and FOXO3a, and altered the cell cycle, with cells accumulating at the G2/M phase. These effects caused cellular senescence. Taken together, our results indicate that arsenic acid inhibited cell proliferation through cellular senescence process regulated by MST1-FOXO signaling pathway. PMID- 26763399 TI - Paraphenylene diamine exacerbates platelet aggregation and thrombus formation in response to a low dose of collagen. AB - Paraphenylene daimine (PPD) is an aromatic amine that is widely used in several industrial products; however, its toxicity has been reported in several cases of cardiac arrests. As platelets play a key role in cardiovascular diseases, we aimed to determine the impact of PPD in vitro and in vivo on platelet function. Our findings demonstrated that platelet activation and aggregation were strongly enhanced by PPD. Treatment with PPD primed human platelets that became more reactive in response to low doses of collagen. Furthermore, PPD exacerbated thrombus formation in rats in comparison with those untreated. Our results suggest that PPD is an important platelet primer predisposing platelets to promote thrombus formation in response to vascular injury. This should prompt the authorities to consider controlling the marketing of this product. PMID- 26763401 TI - Effect of penicillin-based antibiotics, amoxicillin, ampicillin, and piperacillin, on drug-metabolizing activities of human hepatic cytochromes P450. AB - The effects of three kinds of penicillin-based antibiotics, amoxicillin, ampicillin, and piperacillin, on drug-metabolizing activity of human hepatic cytochrome P450 (P450 or CYP) were investigated. Metabolic activities of P450s expressed in recombinant Escherichia coli at substrate concentrations around the Michaelis constant were compared in the presence or absence of the antibiotics. Amoxicillin, ampicillin, and piperacillin at 0.5 or 1 mM concentrations neither inhibited nor stimulated CYP2C9-mediated tolbutamide methylhydroxylation, CYP2D6 mediated dopamine formation from p-tyramine, or CYP3A4- or CYP3A5-mediated testosterone 6beta-hydroxylation. However, amoxicillin and piperacillin inhibited CYP2C8-mediated aminopyrine N-demethylation at 50% inhibitory concentration of 0.83 and 1.14 mM, respectively. These results suggest that piperacillin might inhibit CYP2C8 clinically, although the interactions between these three penicillin-based antibiotics and other drugs that are metabolized by P450s investigated would not be clinically significant. PMID- 26763400 TI - Development of an in vitro photosensitization test based on changes of cell surface thiols and amines as biomarkers: the photo-SH/NH2 test. AB - As a part of our studies to develop a cell-based in vitro photosensitization assay, we examined whether changes of cell-surface thiols and amines on human monocytic cell line THP-1 could be used to predict photosensitizing potential of chemicals. First, we identified a suitable ultraviolet A (UV-A) irradiation dose to be 5.0 J/cm(2) by investigating the effect of UV-A on the levels of cell surface thiols and amines in ketoprofen (KP; a representative photoallergen) treated THP-1 cells. Next, we confirmed that phenol red, a known photoirritant used as a pH indicator in the culture medium, did not affect the KP-induced changes of cell-surface thiols and amines. Using the criterion of more than 15% change of cell-surface thiols and/or amines in response to UV-A irradiation, 22 of 26 known photosensitizers (15 of 18 photoallergens, 7 of 8 photoirritants) were judged positive. Seven of 7 known non-phototoxins did not alter cell-surface thiols or amines. The accuracy for predicting photosensitizers was 87.9% (sensitivity/specificity; 84.6%/100%), and the accuracy for predicting photoallergens was 69.7% (sensitivity/specificity; 83.3%/53.3%). Our results suggest that changes of cell-surface thiols and/or amines may be useful biomarkers for predicting photosensitization potential, including photoallergenicity, of compounds. We designate this test as the photo-SH/NH2 test. PMID- 26763402 TI - Upregulations of metallothionein gene expressions and tolerance to heavy metal toxicity by three dimensional cultivation of HepG2 cells on VECELL 3-D inserts. AB - The VECELL 3-D insert is a new culture scaffold consisting of collagen-coated ePTFE (expanded polytetrafluoroethylene) mesh. We analyzed the effects of VECELL 3-D inserts on the functionality of HepG2, a human hepatocellular carcinoma cell line. HepG2 cells cultured on VECELL 3-D inserts maintained a round shape, while those cultured on a standard culture plate or collagen-coated cell culture plate showed a flattened and cubic epithelial-like shape. HepG2 cells cultured on VECELL 3-D inserts had showed upregulated expression of metallothionein genes and in turn a higher tolerance to toxicity induced by heavy metals. These results suggest that HepG2 cell functions were changed by the cell morphology that is induced by culturing on a VECELL 3-D insert. PMID- 26763403 TI - Detection of metabolic activation leading to drug-induced phospholipidosis in rat hepatocyte spheroids. AB - Drug-induced phospholipidosis (PLD) is one of the adverse reactions to treatment with cationic amphiphilic drugs. Recently, simple and reliable evaluation methods for PLD have been reported. However, the predictive power of these methods for in vivo PLD induction is insufficient in some cases. To accurately predict PLD, we focused on drug metabolism and used three-dimensional cultures of hepatocytes known as spheroids. Here we used the fluorescent phospholipid dye N-(7-nitrobenz 2-oxa-1,3-diazol-4-yl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine (NBD PE) to detect PLD induction. After 48 hr exposure to 20 uM amiodarone and amitriptyline, PLD inducers, NBD-PE fluorescence in the spheroids was significantly higher than that in the control. In contrast, 1 mM acetaminophen, as a negative control, did not increase fluorescence. Furthermore, the combination of NBD-PE fluorescence and LysoTracker Red fluorescence and the accumulation of intrinsic phospholipids reflected PLD induction in spheroids. To evaluate metabolic activation, we assessed PLD induction by loratadine. NBD-PE fluorescence intensity was significantly increased by 50 uM loratadine treatment. However, the fluorescence was markedly decreased by co-treatment with 500 uM 1 aminobenzotriazole, a broad cytochrome P450 inhibitor. The formation of desloratadine, a metabolite of loratadine, was observed in spheroids after treatment with loratadine alone. These results showed that metabolic activation is the key factor in PLD induction by treatment with loratadine. We demonstrated that rat primary hepatocyte spheroid culture is a useful model for evaluating drug-induced PLD induction mediated by metabolic activation of the drug using the fluorescence probe technique. PMID- 26763404 TI - Protective effects of geniposide against Tripterygium glycosides (TG)-induced liver injury and its mechanisms. AB - Tripterygium glycosides (TG) are commonly used for basic medicine in curing rheumatoid arthritis but with a high incidence of liver injury. Geniposide (GP) has broad and diverse bioactivities, but until now it is still unknown whether GP can protect against TG-induced liver injury. This study, for the first time, observed the possible protection of GP against TG-induced liver injury in mice and its mechanisms underlying. Oral administration of TG (270 mg/kg) induced significant elevation in the levels of serum alanine / aspartate transaminase (ALT/AST), hepatic malondialdehyde (MDA) and pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) (all P < 0.01). On the other hand, remarkably decreased biomarkers, including hepatic glutathione (GSH) level, activities of glutathione transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT), and anti-inflammatory cytokine interleukin (IL)-10, were observed following TG exposure (all P < 0.01). Nevertheless, all of these phenotypes were evidently reversed by pre-administration of GP for 7 continuous days. Further analysis showed that the mRNA expression of hepatic growth factor beta1 (TGF-beta1), one of tissue repair and regeneration cytokines, was enhanced by GP. Taken together, the current research suggests that GP protects against TG induced liver injury in mice probably involved during attenuating oxidative stress and inflammation, and promoting tissue repair and regeneration. PMID- 26763405 TI - Orofacial amyloidosis--unusual -presentation of a rare condition: A case report. AB - Orofacial amyloidosis is an extremely rare and generally a benign condition. In contrast to systemic amyloidosis, other organs are not involved; however, extensive investigations are recommended to intercept any systemic involvement. Diagnosis is confirmed by histological examination and Congo red staining. This condition does not have a known etiology, and hence no general consensus exists regarding its management. We are presenting a case of a 65-year-old female patient with orofacial amyloidosis having ocular and extensive oral involvement. PMID- 26763406 TI - Chinese hamster ovary-sphingomyelin synthase2 biospecific extraction and liquid chromatography with tandem mass spectrometry analysis for the prediction of bioactive components of Rhizoma Polygoni Cuspidati. AB - A novel strategy for predicting bioactive components in traditional Chinese medicines using Chinese hamster ovary-sphingomyelin synthase2 (CHO-SMS2 ) cell biospecific extraction and high-performance liquid chromatography with diode array detection and tandem mass spectrometry analysis was proposed. The hypothesis is that when cells are incubated with the extract of traditional Chinese medicines, the potential bioactive components in the traditional Chinese medicines should selectively combine with the cells, while the cell-combining components would be detectable in the extract of denatured cells. The identities of the cell-combining components could be determined by liquid chromatography with tandem mass spectrometry. Using the proposed approach, the potential bioactive components of Rhizoma Polygoni Cuspidati, a commonly used traditional Chinese medicine for atherosclerosis, were detected and identified. Eight compounds in the extract of Rhizoma Polygoni Cuspidati were detected as the components selectively combined with CHO-SMS2 cells, which is a stable cell line that highly expresses sphingomyelin synthases, it was found that piceid, resveratrol, emodin-8-beta-d-glucoside, physcion-8-beta-d-glucoside, emodin, physcion, 3,5,4'-trihydroxystilbene-3-O-(6"-galloyl)-glucoside, and emodin-1-O glucoside combined specifically with CHO-SMS2 cells. The results indicate that the proposed approach may be applied to predict the bioactive candidates in traditional Chinese medicines. PMID- 26763407 TI - Vibrational spectroscopy and imaging for concurrent cellular trafficking of co localized doxorubicin and deuterated phospholipid vesicles. AB - Simultaneous tracking of nanoparticles and encapsulated payload is of great importance and visualizing their activity is arduous. Here we use vibrational spectroscopy to study the in vitro tracking of co-localized lipid nanoparticles and encapsulated drug employing a model system derived from doxorubicin encapsulated deuterated phospholipid (dodecyl phosphocholine-d38) single tailed phospholipid vesicles. PMID- 26763409 TI - Microparticles as intercellular carriers of the microRNA signal: insights for novel diagnostic and therapeutic approaches. PMID- 26763410 TI - Early deaths in bloodstream infections: a population-based case series. AB - A notable portion of deaths in bloodstream infections (BSI) have previously been shown to occur within 2 days after taking the first positive blood culture specimen. The aim of this study was to analyse patients' characteristics and causative pathogens of BSIs, leading to early deaths in order to explore possibilities for prevention. Patients with BSI in Helsinki and Uusimaa region (population = 1.5 million) in 2007 were identified from the National Infectious Disease Register (n = 2181) and their deaths within 2 days after the first positive blood culture from the Population Information System (n = 76). Of the early fatal BSIs, 42 (55%) were community-acquired (CA-BSI) and 34 (45%) healthcare-associated (HA-BSI). Charlson comorbidity index was moderate-to-high (index >= 3) in 71% of HA-BSIs and 60% of CA-BSIs. The most common pathogens in CA-BSIs were Streptococcus pneumoniae (29%) and Escherichia coli (24%) and in HA BSIs Pseudomonas aeruginosa (24%) and Staphylococcus aureus (18%). The respiratory tract (50%) was the most common focus of infection. Empiric antimicrobial treatment was more often appropriate in CA-BSIs vs HA-BSIs (81% vs 41%, p < 0.001), but treatment delays were longer in CA-BSIs. The majority of the BSI patients who died early had severe comorbidities. S. pneumoniae accounted for one third of CA-BSIs, highlighting the potential role of pneumococcal vaccines in prevention. Early recognition of BSI and its origin (CA-BSI vs HA-BSI) is crucial. Continuous surveillance data on causative microbes and resistance trends in hospitals is needed to propose guidelines for empiric antimicrobial therapy of BSIs. PMID- 26763412 TI - Intrinsic non-ohmic electronic transport properties of the transparent In-Zn-O compound nanobelts under ohmic contact and out of the space charge limited transport region. AB - It is generally accepted that the nonlinear I-V characteristics for semiconductor nanostructures are mainly induced by the Schottky contacts or by the space charge limited transport mechanism. We perform I-V measurements on undoped and doped In Zn-O compound nanobelts and confirm that their intrinsic non-ohmic transport behaviors are not caused by these mechanisms. A model based on the hopping assisted trap state electrons transport process is introduced to explain the nonlinear I-V characteristics and to extract their electrical parameters. An understanding of this trap-state influenced carrier transport can advance the progress of nanomaterials applications and enable us to distinguish their intrinsic transport behaviors from contact effects. The results also indicate that the material has good electrical properties and can be used as a potential substitute for In2O3. PMID- 26763411 TI - Prospective evaluation of radiation-induced skin toxicity in a race/ethnically diverse breast cancer population. AB - We evaluated predictors of radiation-induced skin toxicity in a prospective study of a tri-racial/ethnic breast cancer population. We evaluated patient demographics, tumor characteristics, and treatment variables in the first 392 patients in a prospective study assessing radiation-induced skin toxicity. Logistic regression analyses were conducted to evaluate potential predictors of skin toxicity. The study consists of 59 non-Hispanic whites (NHW; 15%), 241 Hispanic Whites (HW; 62%), 79 black or African Americans (AA; 20%), and 13 others (3%). Overall, 48% developed grade 0-1 skin toxicity, 49.8% grade 2, and 2.2% grade 3 by the National Cancer Institute's Common Toxicity Criteria for Adverse Events (CTCAE) scale. Twenty-one percent developed moist desquamation. In multivariate analysis, higher body mass index (BMI; OR = 2.09; 95%CI = 1.15, 3.82), higher disease stage (OR = 1.82; 95%CI = 1.06, 3.11), ER-positive/PR negative status (OR = 2.74; 95%CI = 1.26, 5.98), and conventionally fractionated regimens (OR = 3.25; 95%CI = 1.76, 6.01) were significantly associated with higher skin toxicity grade after adjustment for age, race, ethnicity, ER status, and breast volume. B MI specifically predicted for moist desquamation, but not degree of erythema. In this racially and ethnically diverse cohort of breast cancer patients receiving radiation to the intact breast, risk factors including BMI, disease stage, and conventionally fractionated radiation predicted for higher skin toxicity grade, whereas age, race, ethnicity, and breast volume did not. BMI specifically predicted for moist desquamation, suggesting that preventive measures to address this particular outcome should be investigated. PMID- 26763413 TI - Our Future Workforce: Who, Where, Doing What? PMID- 26763414 TI - Putting the Human Hair Follicle Cycle on the Map. AB - A detailed characterization of the normal (in situ) human hair follicle cycle, supplemented with expressional data on specific hair follicle markers, has been awaited by basic hair researchers and dermatologists. Combining this hair cycle guide, together with a thorough analysis of the human-on-mouse hair xenograft model, provides solid ground for examining human hair cycle biology and pathology and for hair cycle-related pharmacological testing. PMID- 26763415 TI - Measuring the Impact of Vitiligo: Behind the White Spots. AB - The impact of vitiligo is generally believed to be underestimated. Salzes et al. propose a questionnaire to measure the actual burden of vitiligo. Using a stepwise approach they constructed and validated this instrument taking into account the differences between fair and dark skin phototypes. It is a promising approach that can be implemented on an international scale. PMID- 26763416 TI - An Unexpected Role for TRPV4 in Serotonin-Mediated Itch. AB - Previous studies have revealed that TRPV1 and TRPA1 function downstream of many itch receptors, where they mediate inward current to trigger action potentials in primary afferents. Although other TRP channels, such as TRPV4, are expressed in primary afferents, whether or not they play an analogous role in itch was previously unknown. Now, Akiyama et al. provide evidence that TRPV4 is a key mediator of serotonin-induced itch. This finding is important because it uncovers an unanticipated role for TRPV4 in itch, thereby identifying a novel therapeutic target. PMID- 26763417 TI - TIGIT-CD155 Interactions in Melanoma: A Novel Co-Inhibitory Pathway with Potential for Clinical Intervention. AB - Inozume et al. describe a novel immunosuppressive mechanism in melanoma that is triggered by the interaction between CD155 (expressed by melanomas) and T-cell Ig and ITIM domain (TIGIT) (expressed by tumor infiltrating lymphocytes). This pathway exists in addition to the "classical" co-inhibitory PD-1-PD-L1 pathway. Hence, the combinatorial blockage of both pathways by specific antibodies resulted in the greatly enhanced effector function of melanoma-specific cytotoxic T cells. Given that CD155-TIGIT signaling exerts potent inhibitory action in different subsets of immune cells and that CD155 is expressed broadly in several tumor entities, this report points toward a novel and promising therapeutic strategy to combine different checkpoint blocking agents for greater success in antitumor therapy. PMID- 26763408 TI - Matricellular proteins in drug delivery: Therapeutic targets, active agents, and therapeutic localization. AB - Extracellular matrix is composed of a complex array of molecules that together provide structural and functional support to cells. These properties are mainly mediated by the activity of collagenous and elastic fibers, proteoglycans, and proteins such as fibronectin and laminin. ECM composition is tissue-specific and could include matricellular proteins whose primary role is to modulate cell matrix interactions. In adults, matricellular proteins are primarily expressed during injury, inflammation and disease. Particularly, they are closely associated with the progression and prognosis of cardiovascular and fibrotic diseases, and cancer. This review aims to provide an overview of the potential use of matricellular proteins in drug delivery including the generation of therapeutic agents based on the properties and structures of these proteins as well as their utility as biomarkers for specific diseases. PMID- 26763418 TI - Mind the Gap: Sex Bias in Basic Skin Research. AB - Given the recent National Institutes of Health proposal for balanced use of male and female cells and animals in preclinical studies, we explored whether sex bias exists in skin research. We surveyed 802 dermatological research articles from 2012 through 2013. No information about the sex of studied cells or animals was provided in 60% of papers. Among keratinocytes of known sex, 70% were male. Few studies compared male versus female cells or animals. Disclosure of sex and comparative studies contribute to our understanding of the biologic basis of sex differences. Addressing sex-specific differences in preclinical research informs subsequent clinical trial design and promotes individualized therapy. PMID- 26763419 TI - Molecular Genetics of the PI3K-AKT-mTOR Pathway in Genodermatoses: Diagnostic Implications and Treatment Opportunities. AB - A number of critical signaling pathways are required for homeostatic regulation of cell survival, differentiation, and proliferation during organogenesis. One of them is the PI3K-AKT-mTOR pathway consisting of a cascade of inhibitor/activator molecules. Recently, a number of heritable diseases with skin involvement, manifesting particularly with tissue overgrowth, have been shown to result from mutations in the genes in the PI3K-AKT-mTOR and interacting intracellular pathways. Many of these conditions represent an overlapping spectrum of phenotypic manifestations forming a basis for novel, unifying classifications. Identification of the mutant genes and specific mutations in these patients has implications for diagnostics and genetic counseling and provides a rational basis for the development of novel treatment modalities for this currently intractable group of disorders. PMID- 26763420 TI - Epidermolysis Bullosa Acquisita: From Pathophysiology to Novel Therapeutic Options. AB - Epidermolysis bullosa acquisita (EBA) is a prototypic organ-specific autoimmune disease induced by autoantibodies to type VII collagen causing mucocutaneous blisters. In the inflammatory (bullous pemphigoid-like) EBA variant, autoantibody binding is followed by a lesional inflammatory cell infiltration, and the overall clinical picture may be indistinguishable from that of bullous pemphigoid, the latter being the most common autoimmune bullous disease. The last decade witnessed the development of several mouse models of inflammatory EBA that facilitated the elucidation of the pathogenesis of autoantibody-induced, cell mediated subepidermal blistering diseases and identified new therapeutic targets for these and possibly other autoantibody-driven disorders. PMID- 26763423 TI - The Vitiligo Impact Patient Scale (VIPs): Development and Validation of a Vitiligo Burden Assessment Tool. AB - Vitiligo has a major impact on health-related quality of life. Although a few vitiligo-specific quality of life instruments exist, there is no specific vitiligo burden tool. We developed and validated a specific vitiligo burden tool according to skin phototype. In total, 301 patients completed 35 items of the Vitiligo Impact Patient scale, of whom 235 were of skin phototype I to III and 66 of phototype IV to VI. The dimensionality of the items was evaluated using factor analyses, with results suggesting three factors in fair- and dark-skinned patients ("Psychological effects on daily life," "Relationships and Sexuality," and "Economic Constraints, Care & Management of Disease"). Unidimensionality was confirmed by higher order factor analysis. Cronbach's alpha were high-and intradimensional coherences all demonstrated good reliability (alpha > 0.8). The final instrument consists of 29 items (19 items common to all patients, 3 specific to fair skin, and 7 to dark skin). The test-retest reliability demonstrated very good reproducibility. The intraclass correlation of each dimension was greater than 0.90 for each population. External validity was confirmed by the correlation coefficients and Bland and Altman plots of the Vitiligo Impact Patient scale-Fair Skin and Vitiligo Impact Patient scale-Dark Skin versus the Short-Form-12, PVC Metra, Body Image States Scale, and Daily Life Quality Index assessment tools. PMID- 26763422 TI - Correction of Hair Shaft Defects through Allele-Specific Silencing of Mutant Krt75. AB - Dominant mutations in keratin genes can cause a number of inheritable skin disorders characterized by intraepidermal blistering, epidermal hyperkeratosis, or abnormalities in skin appendages, such as nail plate dystrophy and structural defects in hair. Allele-specific silencing of mutant keratins through RNA interference is a promising therapeutic approach for suppressing the expression of mutant keratins and related phenotypes in the epidermis. However, its effectiveness on skin appendages remains to be confirmed in vivo. In this study, we developed allele-specific small interfering RNAs capable of selectively suppressing the expression of a mutant Krt75, which causes hair shaft structural defects characterized by the development of blebs along the hair shaft in mice. Hair regenerated from epidermal keratinocyte progenitor cells isolated from mutant Krt75 mouse models reproduced the blebbing phenotype when grafted in vivo. In contrast, mutant cells manipulated with a lentiviral vector expressing mutant Krt75-specific short hairpin RNA (shRNA) persistently suppressed this phenotype. The phenotypic correction was associated with a significant reduction of mutant Krt75 mRNA in the skin grafts. Thus, data obtained from this study demonstrated the feasibility of utilizing RNA interference to achieve durable correction of hair structural phenotypes through allele-specific silencing of mutant keratin genes. PMID- 26763421 TI - A Guide to Studying Human Hair Follicle Cycling In Vivo. AB - Hair follicles (HFs) undergo lifelong cyclical transformations, progressing through stages of rapid growth (anagen), regression (catagen), and relative "quiescence" (telogen). Given that HF cycling abnormalities underlie many human hair growth disorders, the accurate classification of individual cycle stages within skin biopsies is clinically important and essential for hair research. For preclinical human hair research purposes, human scalp skin can be xenografted onto immunocompromised mice to study human HF cycling and manipulate long-lasting anagen in vivo. Although available for mice, a comprehensive guide on how to recognize different human hair cycle stages in vivo is lacking. In this article, we present such a guide, which uses objective, well-defined, and reproducible criteria, and integrates simple morphological indicators with advanced, (immuno) histochemical markers. This guide also characterizes human HF cycling in xenografts and highlights the utility of this model for in vivo hair research. Detailed schematic drawings and representative micrographs provide examples of how best to identify human HF stages, even in suboptimally sectioned tissue, and practical recommendations are given for designing human-on-mouse hair cycle experiments. Thus, this guide seeks to offer a benchmark for human hair cycle stage classification, for both hair research experts and newcomers to the field. PMID- 26763424 TI - Super-Resolution Microscopy Reveals Altered Desmosomal Protein Organization in Tissue from Patients with Pemphigus Vulgaris. AB - Pemphigus vulgaris (PV) is an autoimmune epidermal blistering disease in which autoantibodies (IgG) are directed against the desmosomal cadherin desmoglein 3. To better understand how PV IgG alters desmosome morphology and function in vivo, biopsies from patients with PV were analyzed by structured illumination microscopy, a form of superresolution fluorescence microscopy. In patient tissue, desmosomal proteins were aberrantly clustered and patient IgG colocalized with markers for lipid rafts and endosomes. Additionally, steady-state levels of desmoglein 3 were decreased and desmosomes were reduced in size in patient tissue. Desmosomes at blister sites were occasionally split, with PV IgG decorating the extracellular faces of split desmosomes. Desmosome splitting was recapitulated in vitro by exposing cultured keratinocytes both to PV IgG and to mechanical stress, demonstrating that splitting at the blister interface in patient tissue is due to compromised desmosomal adhesive function. These findings indicate that desmoglein 3 clustering and endocytosis are associated with reduced desmosome size and adhesion defects in tissue of patients with PV. Further, this study reveals that superresolution optical imaging is a powerful approach for studying epidermal adhesion structures in normal and diseased skin. PMID- 26763426 TI - Type VI Collagen Regulates Dermal Matrix Assembly and Fibroblast Motility. AB - Type VI collagen is a nonfibrillar collagen expressed in many connective tissues and implicated in extracellular matrix (ECM) organization. We hypothesized that type VI collagen regulates matrix assembly and cell function within the dermis of the skin. In the present study we examined the expression pattern of type VI collagen in normal and wounded skin and investigated its specific function in new matrix deposition by human dermal fibroblasts. Type VI collagen was expressed throughout the dermis of intact human skin, at the expanding margins of human keloid samples, and in the granulation tissue of newly deposited ECM in a mouse model of wound healing. Generation of cell-derived matrices (CDMs) by human dermal fibroblasts with stable knockdown of COL6A1 revealed that type VI collagen deficient matrices were significantly thinner and contained more aligned, thicker, and widely spaced fibers than CDMs produced by normal fibroblasts. In addition, there was significantly less total collagen and sulfated proteoglycans present in the type VI collagen-depleted matrices. Normal fibroblasts cultured on de-cellularized CDMs lacking type VI collagen displayed increased cell spreading, migration speed, and persistence. Taken together, these findings indicate that type VI collagen is a key regulator of dermal matrix assembly, composition, and fibroblast behavior and may play an important role in wound healing and tissue regeneration. PMID- 26763425 TI - Characterization of Lipoprotein Composition and Function in Pediatric Psoriasis Reveals a More Atherogenic Profile. AB - Psoriasis is associated with increased cardiovascular disease in adults, but the risk profile of children with psoriasis remains to be fully characterized. We measured lipoprotein composition and function in 44 patients with pediatric psoriasis and 44 age- and sex-matched healthy controls, using nuclear magnetic resonance spectroscopy and a validated ex vivo assay of high-density lipoprotein cholesterol efflux capacity. The mean age of the patients was 13 years and the population was ethnically diverse. Children with psoriasis had higher waist-to hip ratios (0.85 vs. 0.80; P < 0.002) and insulin resistance measures (log transformed homeostasis model assessment of insulin resistance 0.65 vs. 0.41; P = 0.07). Despite comparable traditional lipid values, having psoriasis was associated with higher apolipoprotein B concentrations (72.4 vs. 64.6; P = 0.02), decreased large high-density lipoprotein particles (5.3 vs. 6.7; P < 0.01), and reduced cholesterol efflux capacity after adjusting for age, sex, fasting glucose, homeostasis model assessment of insulin resistance, systolic blood pressure, body mass index, apolipoprotein A-1, and high-density lipoprotein cholesterol concentration (beta -0.22; P = 0.02). Patients with pediatric psoriasis have a more atherogenic cardiometabolic risk profile, with evidence of insulin resistance and lipoprotein dysfunction by particle size, number, and functional assessment. These findings may provide a basis for the observed link later in life between psoriasis and cardiovascular disease, and support the need to screen and educate young patients to minimize later complications. PMID- 26763428 TI - Risk of Multiple Sclerosis in Patients with Psoriasis: A Danish Nationwide Cohort Study. AB - Psoriasis and multiple sclerosis (MS) are inflammatory disorders with similarities in genetic risk variants and inflammatory pathways. Limited evidence is available on the relationship between the two diseases. We therefore investigated the risk of incident (new-onset) MS in patients with mild and severe psoriasis, respectively. All Danish citizens aged >= 18 years from 1 January 1997 to 31 December 2011 were identified by linkage of nationwide registries at the individual level. We estimated incidence rate ratios (IRRs) adjusted for age, gender, socioeconomic status, smoking, medication, comorbidity, and UV phototherapy by Poisson regression. There were 58,628 and 9,952 cases of mild and severe psoriasis, respectively, and 9,713 cases of MS. Incidence rates of MS per 10,000 person-years for the reference population, mild psoriasis, and severe psoriasis were 1.78, 3.22, and 4.55, respectively. Adjusted IRRs of MS were 1.84 (95% confidence interval [CI], 1.46-2.30) and 2.61 (95% CI, 1.44-4.74) in mild and severe psoriasis, respectively. Similar results were observed when adjustment for family history of MS was included in the analyses. Psoriasis may confer a disease severity-dependent risk of MS. Further studies are warranted to establish the mechanisms underlying this relationship and its potential clinical consequences. PMID- 26763427 TI - Longitudinal, 3D Imaging of Collagen Remodeling in Murine Hypertrophic Scars In Vivo Using Polarization-Sensitive Optical Frequency Domain Imaging. AB - Hypertrophic scars (HTS), frequently seen after traumatic injuries and surgery, remain a major clinical challenge because of the limited success of existing therapies. A significant obstacle to understanding HTS etiology is the lack of tools to monitor scar remodeling longitudinally and noninvasively. We present an in vivo, label-free technique using polarization-sensitive optical frequency domain imaging for the 3D, longitudinal assessment of collagen remodeling in murine HTS. In this study, HTS was induced with a mechanical tension device for 4 10 days on incisional wounds and imaged up to 1 month after device removal; an excisional HTS model was also imaged at 6 months after injury to investigate deeper and more mature scars. We showed that local retardation and degree of polarization provide a robust signature for HTS. Compared with normal skin with heterogeneous local retardation and low degree of polarization, HTS was characterized by an initially low local retardation, which increased as collagen fibers remodeled, and a persistently high degree of polarization. This study demonstrates that polarization-sensitive optical frequency domain imaging offers a powerful tool to gain significant biological insights into HTS remodeling by enabling longitudinal assessment of collagen in vivo, which is critical to elucidating HTS etiology and developing more effective HTS therapies. PMID- 26763429 TI - Increased Bacterial Load and Expression of Antimicrobial Peptides in Skin of Barrier-Deficient Mice with Reduced Cancer Susceptibility. AB - Mice lacking three epidermal barrier proteins-envoplakin, periplakin, and involucrin (EPI-/- mice)-have a defective cornified layer, reduced epidermal gammadelta T cells, and increased dermal CD4(+) T cells. They are also resistant to developing skin tumors. The tumor-protective mechanism involves signaling between Rae-1 expressing keratinocytes and the natural killer group 2D receptor on immune cells, which also plays a role in host defenses against infection. Given the emerging link between bacteria and cancer, we investigated whether EPI /- mice have an altered skin microbiota. The bacterial phyla were similar in wild type and EPI-/- skin. However, bacteria were threefold more abundant in EPI-/- skin and penetrated deeper into the epidermis. The major epithelial defense mechanism against bacteria is production of antimicrobial proteins (AMPs). EPI-/- skin exhibited enhanced expression of antimicrobial peptides. However, reducing the bacterial load by antibiotic treatment or breeding mice under specific pathogen-free conditions did not reduce AMP expression or alleviate the abnormalities in T-cell populations. We conclude that the atopic characteristics of EPI-/- skin are a consequence of the defective barrier rather than a response to the increased bacterial load. It is therefore unlikely that the increase in skin microbiota contributes directly to the observed cancer resistance. PMID- 26763430 TI - Immunomodulatory Activities of the Benzoxathiole Derivative BOT-4-One Ameliorate Pathogenic Skin Inflammation in Mice. AB - T-cell-mediated immune responses play an important role in body protection. However, aberrantly activated immune responses are responsible for inflammatory and autoimmune diseases. The regulation of pathologic immune responses may be a potential therapeutic strategy for the treatment of these diseases. Despite that multiple pharmacologic properties of benzoxathiole derivatives have been defined, the molecular mechanisms underlying these properties remain to be clarified. Here, we demonstrated the benzoxathiole derivative 2-cyclohexylimino-6-methyl-6,7 dihydro-5H-benzo[1,3]oxathiol-4-one (BOT-4-one) regulated immune responses and ameliorated experimentally induced inflammatory skin diseases both in vitro and in vivo. BOT-4-one inhibited the differentiation of CD4(+) T-cell subsets by regulating the expression and production of T-cell lineage-specific master transcription factors and cytokines and activating the signal transducer and activator of transcription proteins. In addition, BOT-4-one inhibited TCR mediated Akt and NF-kappaB signaling. Topical application of BOT-4-one ameliorated experimentally induced inflammatory skin diseases in mice models such as 2,4,6-trinitrochlorobenzene-induced contact and atopic dermatitis and IL-23 induced psoriasis-like skin inflammation. Our study demonstrated that BOT-4-one ameliorates inflammatory skin diseases by suppressing the pathogenic CD4(+) T cell differentiation and overall immune responses. PMID- 26763431 TI - Dimethylfumarate Impairs Neutrophil Functions. AB - Host defense against pathogens relies on neutrophil activation. Inadequate neutrophil activation is often associated with chronic inflammatory diseases. Neutrophils also constitute a significant portion of infiltrating cells in chronic inflammatory diseases, for example, psoriasis and multiple sclerosis. Fumarates improve the latter diseases, which so far has been attributed to the effects on lymphocytes and dendritic cells. Here, we focused on the effects of dimethylfumarate (DMF) on neutrophils. In vitro, DMF inhibited neutrophil activation, including changes in surface marker expression, reactive oxygen species production, formation of neutrophil extracellular traps, and migration. Phagocytic ability and autoantibody-induced, neutrophil-dependent tissue injury ex vivo was also impaired by DMF. Regarding the mode of action, DMF modulates-in a stimulus-dependent manner-neutrophil activation using the phosphoinositide 3 kinase/Akt-p38 mitogen-activated protein kinase and extracellular signal regulated kinase 1/2 pathways. For in vivo validation, mouse models of epidermolysis bullosa acquisita, an organ-specific autoimmune disease caused by autoantibodies to type VII collagen, were employed. In the presence of DMF, blistering induced by injection of anti-type VII collagen antibodies into mice was significantly impaired. DMF treatment of mice with clinically already manifested epidermolysis bullosa acquisita led to disease improvement. Collectively, we demonstrate a profound inhibitory activity of DMF on neutrophil functions. These findings encourage wider use of DMF in patients with neutrophil mediated diseases. PMID- 26763432 TI - Skin pH Is the Master Switch of Kallikrein 5-Mediated Skin Barrier Destruction in a Murine Atopic Dermatitis Model. AB - Elevated skin surface pH has been reported in patients with atopic dermatitis. In this study, we explored the role of skin pH in the pathogenesis of atopic dermatitis using the NC/Tnd murine atopic dermatitis model. Alkalinization of the skin of asymptomatic NC/Tnd mice housed in specific pathogen-free conditions induced kallikrein 5 and activated protease-activated receptor 2, resulting in thymic stromal lymphopoietin secretion and a cutaneous T-helper 2 allergic response. This was associated with increased transepidermal water loss and development of eczematous lesions in these specific pathogen-free NC/Tnd mice, which normally do not suffer from atopic dermatitis. Injection of recombinant thymic stromal lymphopoietin also induced scratching behavior in the specific pathogen-free NC/Tnd mice. Thymic stromal lymphopoietin production and dermatitis induced by alkalinization of the skin could be blocked by the protease-activated receptor 2 antagonist ENMD-1068. In contrast, weak acidification of eczematous skin in conventionally housed NC/Tnd mice reduced kallikrein 5 activity and ameliorated the dermatitis. Onset of the dermatitis was associated with increased epidermal filaggrin expression and impaired activity of the sodium/hydrogen exchanger 1, a known regulator of skin pH. We conclude that alterations in skin pH directly modulate kallikrein 5 activity leading to skin barrier dysfunction, itch, and dermatitis via the protease-activated receptor 2-thymic stromal lymphopoietin pathway. PMID- 26763433 TI - Differential Features between Chronic Skin Inflammatory Diseases Revealed in Skin Humanized Psoriasis and Atopic Dermatitis Mouse Models. AB - Psoriasis and atopic dermatitis are chronic and relapsing inflammatory diseases of the skin affecting a large number of patients worldwide. Psoriasis is characterized by a T helper type 1 and/or T helper type 17 immunological response, whereas acute atopic dermatitis lesions exhibit T helper type 2 dominant inflammation. Current single gene and signaling pathways-based models of inflammatory skin diseases are incomplete. Previous work allowed us to model psoriasis in skin-humanized mice through proper combinations of inflammatory cell components and disruption of barrier function. Herein, we describe and characterize an animal model for atopic dermatitis using similar bioengineered based approaches, by intradermal injection of human T helper type 2 lymphocytes in regenerated human skin after partial removal of stratum corneum. In this work, we have extensively compared this model with the previous and an improved version of the psoriasis model, in which T helper type 1 and/or T helper type 17 lymphocytes replace exogenous cytokines. Comparative expression analyses revealed marked differences in specific epidermal proliferation and differentiation markers and immune-related molecules, including antimicrobial peptides. Likewise, the composition of the dermal inflammatory infiltrate presented important differences. The availability of accurate and reliable animal models for these diseases will contribute to the understanding of the pathogenesis and provide valuable tools for drug development and testing. PMID- 26763434 TI - Early Tumor-Infiltrating Dendritic Cells Change their Characteristics Drastically in Association with Murine Melanoma Progression. AB - Dendritic cells (DCs) have a critical effect on the outcome of adaptive immune responses against growing tumors. Tumor-infiltrating dendritic cells (TIDCs) play diverse roles in the regulation of tumor regression or growth, but the characteristics that distinguish those effects are obscure. In this study, we investigated the frequency, phenotype, and function of TIDCs over time from early stages of melanoma growth in mice. Flow cytometric analysis revealed that the tumors were infiltrated by a significant population of CD11c(+) major histocompatibility complex II(+) DCs, especially at an early stage of tumor growth. The allogeneic stimulatory capacity of TIDCs increased with tumor growth, whereas this capacity of DCs in lymph nodes decreased. TIDCs harvested at an early stage of melanoma (early TIDCs) accelerated tumor growth, but those harvested at a late stage (late TIDCs) delayed tumor progression when they were coinjected with melanoma cells. Furthermore, coinjection of early TIDCs failed to induce full immunocompetent maturation of CD8(+) T cells, with much lower expression of IFN-gamma, granzyme B, and perforin within the tumor microenvironment. In conclusion, TIDCs change their characteristics from an immunoinhibitory to an immunostimulatory phenotype over time in association with tumor progression. PMID- 26763437 TI - Prevention and Mitigation of Experimental Autoimmune Encephalomyelitis by Murine beta-Defensins via Induction of Regulatory T Cells. AB - The antimicrobial peptide murine beta-defensin-14 (mBD14) was found to exert, in addition to its antimicrobial activity, the capacity to induce regulatory T cells as demonstrated in the model of contact hypersensitivity. Because it is induced by ultraviolet radiation, mBD14 may contribute to the antigen-specific immunosuppression by ultraviolet radiation. To prove whether this applies also for other immunologic models and because ultraviolet radiation appears to have beneficial effects on multiple sclerosis, we utilized the model of experimental autoimmune encephalomyelitis. Injection of mBD14 into mice before immunization with myelin oligodendrocyte glycoprotein caused amelioration of the disease with less central nervous system inflammation and decreased levels of proinflammatory cytokines and cytotoxic T cells. The beneficial effect was due to Foxp3(+) regulatory T cells because it was lost on in vivo depletion of regulatory T cells. mBD14, however, also acts in a therapeutic setting, because injection of mBD14 into mice with clinical features of experimental autoimmune encephalomyelitis reduced the clinical score significantly. Human beta-defensin 3, the human orthologue of mBD14, induced in vitro regulatory T cell-specific markers in CD4(+)CD25(-) T cells, shifting these nonregulatory cells into a regulatory phenotype with suppressive features. Thus, defensins may represent candidates worth being further pursued for the therapy of multiple sclerosis. PMID- 26763435 TI - Involvement of TRPV4 in Serotonin-Evoked Scratching. AB - Several thermosensitive transient receptor potential channels (transient receptor potential vanilloid type-1, -3; transient receptor potential cation channel, subfamily A, member 1) have been implicated in itch. In contrast, the role of transient receptor potential vanilloid type-4 (TRPV4) in itch is unknown. Therefore, we investigated if TRPV4, a temperature-sensitive cation channel, plays an important role in acute itch in mice. Four different pruritogens, including serotonin (5-hydroxytryptamine [5-HT]), histamine, SLIGRL (protease activated receptors 2/mas-related G-protein-coupled receptor C11 agonist), and chloroquine (mas-related G-protein-coupled receptor A3 agonist), were intradermally injected into mice and itch-related scratching behavior was assessed. TRPV4 knockout mice exhibited significantly fewer 5-HT-evoked scratching bouts compared with wild-type mice. Notably, no differences between TRPV4 knockout and wild-type mice were observed in the number of scratch bouts elicited by SLIGRL and histamine. Pretreatment with a TRPV4 antagonist significantly attenuated 5-HT-evoked scratching in vivo. Using calcium imaging in cultured primary murine dorsal root ganglion neurons, the response of neurons after 5-HT application, but not other pruritogens, was significantly lower in TRPV4 knockout compared with wild-type mice. A TRPV4 antagonist significantly suppressed 5-HT-evoked responses in dorsal root ganglion cells from wild-type mice. Approximately 90% of 5-HT-sensitive dorsal root ganglion neurons were immunoreactive for an antibody to TRPV4, as assessed by calcium imaging. These results indicate that 5-HT-induced itch is linked to TRPV4. PMID- 26763436 TI - Molecular Phenotyping Small (Asian) versus Large (Western) Plaque Psoriasis Shows Common Activation of IL-17 Pathway Genes but Different Regulatory Gene Sets. AB - Psoriasis is present in all racial groups, but in varying frequencies and severity. Considering that small plaque psoriasis is specific to the Asian population and severe psoriasis is more predominant in the Western population, we defined Asian small and intermediate plaque psoriasis as psoriasis subtypes and compared their molecular signatures with the classic subtype of Western large plaque psoriasis. Two different characteristics of psoriatic spreading-vertical growth and radial expansion-were contrasted between subtypes, and genomic data were correlated to histologic and clinical measurements. Compared with Western large plaque psoriasis, Asian small plaque psoriasis revealed limited psoriasis spreading, but IL-17A and IL-17-regulated proinflammatory cytokines were highly expressed. Paradoxically, IL-17A and IL-17-regulated proinflammatory cytokines were lower in Western large plaque psoriasis, whereas T cells and dendritic cells in total psoriatic skin area were exponentially increased. Negative immune regulators, such as CD69 and FAS, were decreased in both Western large plaque psoriasis and psoriasis with accompanying arthritis or obesity, and their expression was correlated with psoriasis severity index. Based on the disease subtype comparisons, we propose that dysregulation of T-cell expansion enabled by downregulation of immune negative regulators is the main mechanism for development of large plaque psoriasis subtypes. PMID- 26763439 TI - Spleen Tyrosine Kinase Mediates EGFR Signaling to Regulate Keratinocyte Terminal Differentiation. AB - Spleen tyrosine kinase (Syk), a nonreceptor tyrosine kinase, was initially identified as a crucial regulator in proximal immunoreceptor signaling. Additional studies have revealed its pleiotropic roles, and drugs targeting Syk are under development for inflammatory diseases. Syk expression in the skin has been detected, but its functions in the skin are still unknown. Here, we found that Syk phosphorylation and expression in primary human keratinocytes decreased gradually along with terminal differentiation. Human skin specimens showed similar in vivo patterns. Syk inhibitors or knockdown of Syk increased the expression of differentiation markers under in vitro differentiation models. Furthermore, EGFR activation prominently induced Syk phosphorylation, which could be inhibited by the EGFR inhibitor gefitinib or knockdown of EGFR. The Src inhibitor also partially attenuated EGF-induced phosphorylation of Syk. However, Syk inhibition suppressed EGF-induced phosphorylation of EGFR. Immunoprecipitation and confocal microscopy further revealed the increased molecular interaction between EGFR and Syk after EGF stimulation. This study unravels the role of Syk in EGFR-mediated signaling and reveals regulatory roles of Syk in keratinocyte differentiation, suggesting the clinical potential of topical or systemic Syk inhibitors in the treatment of skin diseases with aberrant differentiation. PMID- 26763438 TI - Galectin-7 Regulates Keratinocyte Proliferation and Differentiation through JNK miR-203-p63 Signaling. AB - Galectin-7, a member of the beta-galactoside-binding protein family, is primarily expressed in stratified epithelial cells, including keratinocytes. There is information in the literature suggesting a role for this protein in regulation of keratinocyte survival and growth, but the underlying mechanism remains relatively unknown. Moreover, its expression pattern in the epidermis suggests that it is also involved in the regulation of keratinocyte differentiation. Here, we demonstrate that galectin-7 knockdown results in reduced differentiation and increased proliferation of keratinocytes. Using microarray and deep-sequencing analyses, we found that galectin-7 positively and negatively regulates microRNA (miR)-203 and miR-146a expression, respectively. We show that galectin-7 regulates keratinocyte differentiation and proliferation through miR-203 but not miR-146a. A knockdown of either galectin-7 or miR-203 in keratinocytes increases expression of p63, an essential transcription factor involved in skin development. Rescue of miR-203 expression in a galectin-7 knockdown model reduces p63 expression to baseline. Increased galectin-7 expression upregulates c-Jun N terminal kinase (JNK) protein levels, which is required for miR-203 expression. Finally, we establish that galectin-7 can be associated with JNK1 and protect it from ubiquitination and degradation. Thus, our data suggest an intracellular function of galectin-7: regulation of keratinocyte proliferation and differentiation through the JNK1-miR-203-p63 pathway. PMID- 26763440 TI - Keratin Isotypes Control Desmosome Stability and Dynamics through PKCalpha. AB - Expression and interaction of desmosomal components and keratins provide stable cell cohesion and protect the epidermis against various types of stress. The differentiation-specific isotype composition of the keratin cytoskeleton and desmosomes is regarded as a major determinant of adhesive strength. In support, wound healing is characterized by a transient decrease in desmosomal adhesion accompanied by increased expression of keratins K6/K16/K17 at the expense of K1/K10. The significance of altered keratin expression for desmosomal composition and adhesion remains incompletely understood at a mechanistic and functional level. Here, we investigated the respective contribution of K5/K14 or K6/K17 to desmosome adhesion, on their stable re-expression in keratinocytes lacking all keratins. This revealed that K5/K14 filaments support stable desmosomes, whereas "wound healing" keratins K6/K17 induce elevated protein kinase C alpha-mediated desmosome disassembly and subsequent destabilization of epithelial sheets. Moreover, our data suggest that K5/K14 sequester protein kinase C alpha in the cytoplasm, whereas K6/K17 or the absence of all keratins enables protein kinase C alpha translocation to the plasma membrane and induction of desmosome disassembly. Gain- and loss-of-function experiments support a major role of K5 in desmosome stability control via protein kinase C alpha. Our data show that keratin isotypes differently and specifically regulate wound healing and invasion by modulating intercellular adhesion. PMID- 26763441 TI - MEP50/PRMT5 Reduces Gene Expression by Histone Arginine Methylation and this Is Reversed by PKCdelta/p38delta Signaling. AB - Protein kinase C delta (PKCdelta) and p38delta are key proteins in a cascade that stimulates keratinocyte differentiation. This cascade activates transcription of involucrin (hINV) and other genes associated with differentiation. Protein arginine methyltransferase 5 (PRMT5) is an arginine methyltransferase that symmetrically dimethylates arginine residues. This protein interacts with a cofactor, methylosome protein 50 (MEP50), and symmetrically dimethylates arginine eight of histone 3 (H3R8me2s) and arginine three of histone 4 (H4R3me2s) to silence gene expression. We use the hINV gene as a tool to understand the relationship between PKCdelta/p38delta and PRMT5/MEP50 signaling. MEP50 suppresses hINV mRNA level and promoter activity. This is associated with increased arginine dimethylation of hINV gene-associated H3/H4. We further show that the PKCdelta/p38delta keratinocyte differentiation cascade reduces PRMT5 and MEP50 expression, association with the hINV gene promoter, and H3R8me2s and H4R2me2s formation. We propose that PRMT5/MEP50-dependent methylation is an epigenetic mechanism that assists in silencing of hINV expression, and that PKCdelta signaling activates gene expression by directly activating transcription and by suppressing PRMT5/MEP50-dependent arginine dimethylation of promoter associated histones. This is an example of crosstalk between PKCdelta/p38delta signaling and PRMT5/MEP50 epigenetic silencing. PMID- 26763442 TI - Connexin26 Mutations Causing Palmoplantar Keratoderma and Deafness Interact with Connexin43, Modifying Gap Junction and Hemichannel Properties. AB - Mutations in GJB2 (connexin [Cx]26) cause either deafness or deafness associated with skin diseases. That different disorders can be caused by distinct mutations within the same gene suggests that unique channel activities are influenced by each class of mutation. We have examined the functional characteristics of two human mutations, Cx26-H73R and Cx26-S183F, causing palmoplantar keratoderma (PPK) and deafness. Both failed to form gap junction channels or hemichannels when expressed alone. Coexpression of the mutants with wild-type Cx43 showed a transdominant inhibition of Cx43 gap junction channels, without reductions in Cx43 protein synthesis. In addition, the presence of mutant Cx26 shifted Cx43 channel gating and kinetics toward a more Cx26-like behavior. Coimmunoprecipitation showed Cx43 being pulled down more efficiently with mutant Cx26 than wild-type, confirming the enhanced formation of heteromeric connexons. Finally, the formation of heteromeric connexons resulted in significantly increased Cx43 hemichannel activity in the presence of Cx26 mutants. These findings suggest a common mechanism whereby Cx26 mutations causing PPK and deafness transdominantly influence multiple functions of wild-type Cx43. They also implicate a role for aberrant hemichannel activity in the pathogenesis of PPK and further highlight an emerging role for Cx43 in genetic skin diseases. PMID- 26763443 TI - Secreted Frizzled-Related Protein 2 (sFRP2) Functions as a Melanogenic Stimulator; the Role of sFRP2 in UV-Induced Hyperpigmentary Disorders. AB - In this study, we found that secreted frizzled-related protein 2 (sFRP2) is overexpressed in the hyperpigmentary skin of melasma and solar lentigo and in acutely UV-irradiated skin. To investigate the effect of sFRP2 on melanogenesis, normal human melanocytes were infected with sFRP2-lentivirus or sh-sFRP2. It was found that sFRP2 stimulates melanogenesis through microphthalmia-associated transcription factor and/or tyrosinase upregulation via beta-catenin signaling. The stimulatory action of sFRP2 in pigmentation was further confirmed in melanocytes cocultured with fibroblasts and in ex vivo cultured skin. The findings suggest that sFRP2 functions as a melanogenic stimulator and that it plays a role in the development of UV-induced hyperpigmentary disorders. PMID- 26763444 TI - Identification, Review, and Systematic Cross-Validation of microRNA Prognostic Signatures in Metastatic Melanoma. AB - In metastatic melanoma, it is vital to identify and validate biomarkers of prognosis. Previous studies have systematically evaluated protein biomarkers or mRNA-based expression signatures. No such analyses have been applied to microRNA (miRNA)-based prognostic signatures. As a first step, we identified two prognostic miRNA signatures from publicly available data sets (Gene Expression Omnibus/The Cancer Genome Atlas) of global miRNA expression profiling information. A 12-miRNA signature predicted longer survival after surgery for resection of American Joint Committee on Cancer stage III disease (>4 years, no sign of relapse) and outperformed American Joint Committee on Cancer standard-of care prognostic markers in leave-one-out cross-validation analysis (error rates 34% and 38%, respectively). A similar 15-miRNA biomarker derived from The Cancer Genome Atlas miRNA-seq data performed slightly worse (39%) than these current biomarkers. Both signatures were then assessed for replication in two independent data sets and subjected to systematic cross-validation together with the three other miRNA-based prognostic signatures proposed in the literature to date. Five miRNAs (miR-142-5p, miR-150-5p, miR-342-3p, miR-155-5p, and miR-146b-5p) were reproducibly associated with patient outcome and have the greatest potential for application in the clinic. Our extensive validation approach highlighted among multiple independent cohorts the translational potential and limitations of miRNA signatures, and pointed to future directions in the analysis of this emerging class of markers. PMID- 26763445 TI - Melanoma Cells Control Antimelanoma CTL Responses via Interaction between TIGIT and CD155 in the Effector Phase. AB - Recently, T-cell immunoreceptor with Ig and ITIM domains (TIGIT) was reported as a candidate for novel immune checkpoints. However, the impact of TIGIT on melanoma-specific cytotoxic T lymphocytes in the effector phase remains unclear. In this study, we demonstrated that melanoma cells control antimelanoma cytotoxic T lymphocyte responses via the TIGIT-CD155 interaction in the effector phase. TIGIT is an inhibitory receptor expressed on T cells, and CD155 is one of the cognate ligands expressed on the tumor cells or antigen-presenting cells. First, we confirmed that CD155 was constitutively expressed on melanoma cells. We then demonstrated that CD155 on melanoma cells suppressed cytokine release from melanoma-specific cytotoxic T lymphocytes via interaction with TIGIT. Overexpression of CD155 enhanced and its downregulation attenuated the suppressive effect. This suggested that antimelanoma cytotoxic T lymphocyte responses are controlled not only by an imbalance in CD226 (an activating molecule that binds to CD155) and TIGIT expression on T cells but also by the expression levels of CD155 on melanoma cells. In addition, the co-blockade of TIGIT and PD-1 signals synergistically elicited a response of tumor-infiltrating lymphocytes on autologous melanoma cells. These results suggest that the CD155 TIGIT interaction should be blocked for enhancement of antimelanoma immune responses. PMID- 26763446 TI - RanBP3 Regulates Melanoma Cell Proliferation via Selective Control of Nuclear Export. AB - Chromosome region maintenance 1-mediated nucleocytoplasmic transport has been shown as a potential anticancer target in various malignancies. However, the role of the most characterized chromosome region maintenance 1 cofactor ran binding protein 3 (RanBP3) in cancer cell biology has never been investigated. Utilizing a loss-of-function experimental setting in a vast collection of genetically varied melanoma cell lines, we observed the requirement of RanBP3 in melanoma cell proliferation and survival. Mechanistically, we suggest the reinstatement of transforming growth factor-beta (TGF-beta)-Smad2/3-p21(Cip1) tumor-suppressor axis as part of the RanBP3 silencing-associated antiproliferative program. Employing extensive nuclear export sequence analyses and immunofluorescence-based protein localization studies, we further present evidence suggesting the requirement of RanBP3 function for the nuclear exit of the weak nuclear export sequence-harboring extracellular signal-regulated kinase protein, although it is dispensable for general CRM1-mediated nuclear export of strong nuclear export sequence-harboring cargoes. Rendering mechanistic support to RanBP3 silencing mediated apoptosis, consequent to extracellular signal-regulated kinase nuclear entrapment, we observed increased levels of cytoplasmically restricted nonphosphorylated/active proapoptotic Bcl-2-antagonist of cell death (BAD) protein. Last, we present evidence suggesting the frequently activated mitogen activated protein kinase signaling in melanoma as a potential founding basis for a deregulated post-translational control of RanBP3 activity. Collectively, the presented data suggest RanBP3 as a potential target for therapeutic intervention in human melanoma. PMID- 26763447 TI - Dual Effects of Bisphosphonates on Ectopic Skin and Vascular Soft Tissue Mineralization versus Bone Microarchitecture in a Mouse Model of Generalized Arterial Calcification of Infancy. AB - Generalized arterial calcification of infancy is an intractable ectopic mineralization disorder caused by mutations in the ENPP1 gene, resulting in reduced plasma inorganic pyrophosphate (PPi) levels. We previously characterized the Enpp1(asj) mutant mouse as a model of generalized arterial calcification of infancy, and we have now explored the potential efficacy of bisphosphonates, nonhydrolyzable PPi analogs, in preventing ectopic mineralization in these mice. The mice were maintained on either basic diet (control) or diets containing etidronate or alendronate in three different concentrations (experimental). Considering low bioavailability of bisphosphonates when administered orally, subsequent studies tested the mice with subcutaneous injections of etidronate. The treatments were initiated at 4 weeks of age, and the degree of mineralization was assessed at 12 weeks of age by quantitation of calcium deposits in the muzzle skin containing dermal sheath of vibrissae and in aorta. We found that bisphosphonate treatments significantly reduced mineralization in skin and aorta. These changes in treated mice were accompanied with restoration of their bone microarchitecture, determined by microcomputed tomography. The inhibitory capacity of bisphosphonates, with mechanistic implications, was confirmed in a cell-based mineralization assay in vitro. Collectively, these results suggest that bisphosphonate treatment may be beneficial by a dual effect for preventing ectopic soft tissue mineralization while correcting decreased bone mineralization in generalized arterial calcification of infancy caused by ENPP1 mutations. PMID- 26763449 TI - Mesenchymal Stromal Cell-Derived PTX3 Promotes Wound Healing via Fibrin Remodeling. AB - Although mesenchymal stromal cells (MSCs) can promote wound healing in different clinical settings, the underlying mechanism of MSC-mediated tissue repair has yet to be determined. Because a nonredundant role of pentraxin 3 (PTX3) in tissue repair and remodeling has been recently described, here we sought to determine whether MSC-derived PTX3 might play a role in wound healing. Using a murine model of skin repair, we found that Ptx3-deficient (Ptx3(-/-)) MSCs delayed wound closure and reduced granulation tissue formation compared with wt MSCs. At day 2, confocal microscopy revealed a dramatic reduction in green fluorescent protein (GFP)-expressing Ptx3(-/-) MSCs recruited to the wound, where they appeared to be not only poorly organized in bundles but also scattered in the extracellular matrix. These findings were further confirmed by quantitative biochemical analysis of GFP content in wound extracts. Furthermore, Ptx3(-/-) MSC-treated skins displayed increased levels of fibrin and lower levels of D-dimer, suggesting delayed fibrin-rich matrix remodeling compared with control skins. Consistently, both pericellular fibrinolysis and migration through fibrin were found to be severely affected in Ptx3(-/-) MSCs. Overall, our findings identify an essential role of MSC-derived PTX3 in wound repair underscoring the beneficial potential of MSC-based therapy in the management of intractable wounds. PMID- 26763448 TI - Lentiviral Engineered Fibroblasts Expressing Codon-Optimized COL7A1 Restore Anchoring Fibrils in RDEB. AB - Cells therapies, engineered to secrete replacement proteins, are being developed to ameliorate otherwise debilitating diseases. Recessive dystrophic epidermolysis bullosa (RDEB) is caused by defects of type VII collagen, a protein essential for anchoring fibril formation at the dermal-epidermal junction. Whereas allogeneic fibroblasts injected directly into the dermis can mediate transient disease modulation, autologous gene-modified fibroblasts should evade immunological rejection and support sustained delivery of type VII collagen at the dermal epidermal junction. We demonstrate the feasibility of such an approach using a therapeutic grade, self-inactivating-lentiviral vector, encoding codon-optimized COL7A1, to transduce RDEB fibroblasts under conditions suitable for clinical application. Expression and secretion of type VII collagen was confirmed with transduced cells exhibiting supranormal levels of protein expression, and ex vivo migration of fibroblasts was restored in functional assays. Gene-modified RDEB fibroblasts also deposited type VII collagen at the dermal-epidermal junction of human RDEB skin xenografts placed on NOD-scid IL2Rgamma(null) recipients, with reconstruction of human epidermal structure and regeneration of anchoring fibrils at the dermal-epidermal junction. Fibroblast-mediated restoration of protein and structural defects in this RDEB model strongly supports proposed therapeutic applications in man. PMID- 26763450 TI - Desmoglein 3-Dependent Signaling Regulates Keratinocyte Migration and Wound Healing. AB - The desmosomal transmembrane adhesion molecules desmoglein 3 (Dsg3) and desmocollin 3 (Dsc3) are required for strong keratinocyte cohesion. Recently, we have shown that Dsg3 associates with p38 mitogen-activated protein kinase (p38MAPK) and suppresses its activity. Here, we further investigated the role of Dsg3-dependent control of p38MAPK function. Dsg3-deficient mice display recurrent spontaneously healing skin erosions. In lesional and perilesional biopsies, p38MAPK activation was detectable compared with control animals. This led us to speculate that Dsg3 regulates wound repair in a p38MAPK-dependent manner. Indeed, scratch-wounded keratinocyte monolayers exhibited p38MAPK activation and loss of Dsg3 in cells lining the wound edge. Human keratinocytes after silencing of Dsg3 as well as primary cells isolated from Dsg3 knockout animals exhibited accelerated migration, which was further corroborated in an ex vivo skin outgrowth assay. Importantly, migration was efficiently blocked by inhibition of p38MAPK, indicating that p38MAPK mediates the effects observed upon loss of Dsg3. In line with this, we show that levels of active p38MAPK associated with Dsc3 are increased in Dsg3-deficient cells. These data indicate that Dsg3 controls a switch from an adhesive to a migratory keratinocyte phenotype via p38MAPK inhibition. Thus, loss of Dsg3 adhesion may foster wound closure by allowing p38MAPK-dependent migration. PMID- 26763451 TI - Degradation Mechanism Induced by Psoriasis in Human Fingernails: A Different Approach. PMID- 26763452 TI - Functional Interpretation of Genome-Wide Association Study Evidence in Alopecia Areata. PMID- 26763453 TI - Expression of Sezary Biomarkers in the Blood of Patients with Erythrodermic Mycosis Fungoides. PMID- 26763455 TI - Validity of Self-Reported Psoriasis in a General Population: The HUNT Study, Norway. PMID- 26763454 TI - Epidermolysis Bullosa Acquisita Develops in Dominant Dystrophic Epidermolysis Bullosa. PMID- 26763456 TI - Identification and Characterization of a Recessive Missense Mutation p.P277L in SERPINB7 in Nagashima-Type Palmoplantar Keratosis. PMID- 26763457 TI - Elevated Galectin-10 Expression of IL-22-Producing T Cells in Patients with Atopic Dermatitis. PMID- 26763458 TI - Sub6 (Tri r 2), an Onychomycosis Marker Revealed by Proteomics Analysis of Trichophyton rubrum Secreted Proteins in Patient Nail Samples. PMID- 26763459 TI - Gnaq(M1J): An ENU-Induced Mutant Allele Affecting Pigmentation in the Mouse. PMID- 26763460 TI - BRAFV600E and NRASQ61R Homogeneity in Melanoma Tumors. PMID- 26763461 TI - Telomerase Expression by Aberrant Methylation of the TERT Promoter in Melanoma Arising in Giant Congenital Nevi. PMID- 26763463 TI - Research Techniques Made Simple: Techniques to Assess Cell Proliferation. AB - Cell proliferation is commonly assayed in the laboratory for research purposes, but is increasingly used clinically to gauge tumor aggressiveness and potentially guide care. Therefore, both researchers and clinicians should have a basic understanding of techniques used to assess cell proliferation. Multiple cell proliferation assays exist, and the choice of method depends on the laboratory resources available, the types of cells/tissues to be studied, and the specific experimental goals. In this article, we identify four overarching categories of cell proliferation assays that signify various stages of the cell cycle: nucleoside-analog incorporation, cell cycle-associated protein detection, use of cytoplasmic proliferation dyes, and indirect measures of cell proliferation. Each method has strengths and limitations that should guide the dermatology investigator's choice of assay. PMID- 26763462 TI - Diabetic Wounds Exhibit Distinct Microstructural and Metabolic Heterogeneity through Label-Free Multiphoton Microscopy. PMID- 26763464 TI - Rosacea or photodamaged skin? Use of brimonidine gel in differentiating erythema in the two conditions. AB - In this case report, we detail the response of a 37-year-old Caucasian man with an overlap of erythematotelangiectatic rosacea and telangiectatic photoaging to brimonidine tartrate gel. With the application of brimonidine only on half of his face, skin analysis images, clinician's and patient's assessment showed that there was significant improvement in the erythema. This case has lent insight into how brimonidine can be used to assess the extent of photoaging by eliminating the erythema of rosacea to some degree. We propose that it can be used as a non-invasive test to differentiate between the two conditions, sparing patients from skin biopsies and molecular analysis. PMID- 26763465 TI - Oral Health-related quality of life in pediatric patients with cystic fibrosis. AB - PURPOSE: To compare the oral health-related quality of life (OHRQoL) of 8- to 12 year-old children and 13- to 17-year-old adolescents diagnosed with cystic fibrosis (CF). MATERIALS AND METHODS: Participants were recruited from a Midwest CF center. Parents provided demographic information and their assessment of the child's health. Patients completed the Child Oral Health Impact Profile (COHIP). RESULTS: Thirty-nine child-parent pairs participated. Fifty four percent of the patients were male, 87% Caucasian, and 56% adolescent, with 66% of families reporting an annual income of over $100,000. Excellent or very good health, including oral health, was reported by 67% of the patients. Individuals taking 10 or more medications reported better OHRQoL while Caucasians reported better oral health and total scores than other races. Adolescents had poorer total COHIP, social-emotional well-being, and self-image scores. CONCLUSION: Although most patients reported good or excellent oral health, adolescents reported a poorer OHRQoL than younger patients. PMID- 26763466 TI - Triple Antithrombotic Therapy - Always One Too Many? PMID- 26763467 TI - Pearls and Pitfalls in Catheter Ablation of Persistent Atrial Fibrillation. AB - Catheter ablation of atrial fibrillation (AF) has evolved over the past 20 years from being a novel, unproven procedure to a commonly performed procedure. Triggers are important for the initiation of AF and a suitable substrate is important for perpetuation of AF. Remodeling, including electrical and structural remodeling, is common in patients with persistent AF. Therefore, targeting the remodeled atrium is a critical issue during persistent AF ablation. However, ablation outcomes remain suboptimal despite aggressive substrate modification. Empirical linear ablation is not recommended because of the difficulty in achieving complete linear block and it is recommended only if macroreentry tachycardia develops during the procedure. Complex fractionated atrial electrogram (CFAE) ablation is recommended in the Heart Rhythm Society Consensus Document but efficacy has been limited in long-term follow-up studies. Rotor ablation is controversial. A combined approach using CFAE, similarity and phase mappings with rotor identification may be helpful in searching for AF sources and subsequent substrate ablation. Nevertheless, more prospective randomized studies are required to validate efficacy and safety. PMID- 26763468 TI - Role of Coronary Microvascular Dysfunction in Takotsubo Cardiomyopathy. AB - Takotsubo cardiomyopathy (TTC) is a relatively frequent acute cardiac condition, but its pathogenesis has not been established as yet. Since the first descriptions of TTC, microvascular dysfunction has been advocated as a possible pathophysiological mechanism underlying the left ventricular wall motion abnormalities that characterize the syndrome. Several noninvasive and invasive methods have confirmed the involvement of coronary microvascular abnormalities in the pathogenesis of TTC, but whether microvascular dysfunction is the primary cause or a secondary phenomenon is still debated. The greater prevalence of TTC among postmenopausal women, along with the relationship identified between physical and emotional triggers and other "neuro-cardiac" mechanisms, suggest that increased microvascular reactivity, possibly sympathetically mediated, may play a pathogenic role in susceptible individuals. This review critically evaluates the possible role of microvascular dysfunction in the development of TTC. PMID- 26763469 TI - Stuck at work? Quantitative proteomics of environmental wine yeast strains reveals the natural mechanism of overcoming stuck fermentation. AB - During fermentation oenological yeast cells are subjected to a number of different stress conditions and must respond rapidly to the continuously changing environment of this harsh ecological niche. In this study we gained more insights into the cell adaptation mechanisms by linking proteome monitoring with knowledge on physiological behaviour of different strains during fermentation under model winemaking conditions. We used 2D-DIGE technology to monitor the proteome evolution of two newly discovered environmental yeast strains Saccharomyces bayanus and triple hybrid Saccharomyces cerevisiae * Saccharomyces kudriavzevii * S. bayanus and compared them to data obtained for the commercially available S. cerevisiae strain. All strains examined showed (i) different fermentative behaviour, (ii) stress resistance as well as (iii) susceptibility to stuck fermentation which was reflected in significant differences in protein expression levels. During our research we identified differentially expressed proteins in 155 gel spots which correspond to 70 different protein functions. Differences of expression between strains were observed mainly among proteins involved in stress response, proteins degradation pathways, cell redox homeostasis and amino acids biosynthesis. Interestingly, the newly discovered triple hybrid S. cerevisiae * S. kudriavzevii * S. bayanus strain which has the ability to naturally restart stuck fermentation showed a very strong induction of expression of two proteolytic enzymes: Pep4 and Prc1 that appear as numerous isoforms on the gel image and which may be the key to its unique properties. This study is an important step towards the better understanding of wine fermentations at a molecular level. PMID- 26763470 TI - Highly selective luminescent nanostructures for mitochondrial imaging and targeting. AB - Here a luminescent hybrid nanostructure based on functionalized quantum dots (QDs) is used as a fluorescent imaging agent able to target selectively mitochondria thanks to the molecular recognition of the translocator protein (TSPO). The selective targeting of such an 18 kDa protein mainly located in the outer mitochondrial membrane and overexpressed in several pathological states including neurodegenerative diseases and cancers may provide valuable information for the early diagnosis and therapy of human disorders. In particular, the rational design of amino functionalized luminescent silica coated QD nanoparticles (QD@SiO2 NPs) provides a versatile nanoplatform to anchor a potent and selective TSPO ligand, characterized by a 2-phenyl-imidazo[1,2-a]pyridine acetamide structure along with a derivatizable carboxylic end group, useful to conjugate the TSPO ligand and achieve TSPO-QD@SiO2 NPs by means of a covalent amide bond. The colloidal stability and optical properties of the proposed nanomaterials are comprehensively investigated and their potential as mitochondrial imaging agents is fully assessed. Sub-cellular fractionation, together with confocal laser scanning fluorescence microscopy and co-localization analysis of targeted TSPO-QD@SiO2 NPs in C6 glioma cells overexpressing the TSPO, proves the great potential of these multifunctional nanosystems as in vitro selective mitochondrial imaging agents. PMID- 26763471 TI - Postprandial appetite ratings are reproducible and moderately related to total day energy intakes, but not ad libitum lunch energy intakes, in healthy young women. AB - Reproducibility and validity testing of appetite ratings and energy intakes are needed in experimental and natural settings. Eighteen healthy young women ate a standardized breakfast for 8 days. Days 1 and 8, they rated their appetite (Hunger, Fullness, Desire to Eat, Prospective Food Consumption (PFC)) over a 3.5 h period using visual analogue scales, consumed an ad libitum lunch, left the research center and recorded food intake for the remainder of the day. Days 2-7, participants rated their at-home Hunger at 0 and 30 min post-breakfast and recorded food intake for the day. Total area under the curve (AUC) over the 180 min period before lunch, and energy intakes were calculated. Reproducibility of satiety measures between days was evaluated using coefficients of repeatability (CR), coefficients of variation (CV) and intra-class coefficients (ri). Correlation analysis was used to examine validity between satiety measures. AUCs for Hunger, Desire to Eat and PFC (ri = 0.73-0.78), ad libitum energy intakes (ri = 0.81) and total day energy intakes (ri = 0.48) were reproducible; fasted ratings were not. Average AUCs for Hunger, Desire to Eat and PFC, Desire to Eat at nadir and PFC at fasting, nadir and 180 min were correlated to total day energy intakes (r = 0.50-0.77, P < 0.05), but no ratings were correlated to lunch consumption. At-home Hunger ratings were weakly reproducible but not correlated to reported total energy intakes. Satiety ratings did not concur with next meal intake but PFC ratings may be useful predictors of intake. Overall, this study adds to the limited satiety research on women and challenges the accepted measures of satiety in an experimental setting. PMID- 26763472 TI - [Computed tomographic anatomy of the salivary glands in the cat]. AB - OBJECTIVE: The aim of the study was to define anatomical characteristics of the feline salivary glands in cross-sectional images obtained by unenhanced computed tomography (CT) and to describe landmarks for a reliable identification. MATERIAL AND METHODS: Heads of adult normocephalic cats without indications of cephalic disease were examined. Cats were included in the prospective part of the study when examined no later than 1 hour post mortem (n = 16). In the retrospective part of the study, previous CT-studies were evaluated (n = 25). The results of both groups were evaluated separately. Initially, the possibility of identifying and delineating the salivary glands from the surrounding tissue was assessed. Anatomical structures of the head were then defined as landmarks. Dimensions and density (Hounsfield units, HU) of the salivary glands were determined based on transversal and reconstructed sagittal images. RESULTS: In total, 94.3% of the parotid glands, 90.7% of the mandibular glands and 96.8% of the zygomatic glands could be delineated. The remaining salivary glands could not be identified. Anatomical landmarks, including the external ear canal, the musculus (M.) masseter, the M. pterygoideus medialis and the bulbus oculi facilitated the identification. Comparing the size of the salivary glands of both groups revealed differences (measured lateromedially and rostrocaudally) in size of <= 2 mm. The definable salivary glands varied significantly in their density. The mean density of the glandula (Gl.) parotis was 65 HU, of the Gl. mandibularis 62 HU and of the Gl. zygomatica 57 HU. The comparisons of densities of both sides of the glands did not show statistically significant differences. CONCLUSIONS: The large salivary glands (Gl. parotis and Gl. mandibularis) and the Gl. zygomatica of the cat can be reliably identified in CT-images. CT landmarks and data regarding the size and density of each gland could be gathered. The remaining minor salivary glands could not be delineated accurately. The difference in depicting the glands can be explained mainly by a lack of contrast with the surrounding tissue. PMID- 26763473 TI - Transparent resistive switching memory using aluminum oxide on a flexible substrate. AB - Resistive switching memory (ReRAM) has attracted much attention in recent times owing to its fast switching, simple structure, and non-volatility. Flexible and transparent electronic devices have also attracted considerable attention. We therefore fabricated an Al2O3-based ReRAM with transparent indium-zinc-oxide (IZO) electrodes on a flexible substrate. The device transmittance was found to be higher than 80% in the visible region (400-800 nm). Bended states (radius = 10 mm) of the device also did not affect the memory performance because of the flexibility of the two transparent IZO electrodes and the thin Al2O3 layer. The conduction mechanism of the resistive switching of our device was explained by ohmic conduction and a Poole-Frenkel emission model. The conduction mechanism was proved by oxygen vacancies in the Al2O3 layer, as analyzed by x-ray photoelectron spectroscopy analysis. These results encourage the application of ReRAM in flexible and transparent electronic devices. PMID- 26763481 TI - Corrigendum. PMID- 26763474 TI - Bloodstream infections caused by multi-drug resistant Proteus mirabilis: Epidemiology, risk factors and impact of multi-drug resistance. AB - BACKGROUND: The prevalence of antimicrobial co-resistance among ESBL-producing Enterobactereaceae is extremely high in Israel. Multidrug-resistant Proteus mirabilis strains (MDR-PM), resistant to almost all antibiotic classes have been described. The aim was to determine the risk factors for bloodstream infections caused by MDR-PM and clinical outcomes. METHODS: A retrospective case-control study. Adult patients with PM bacteremia during 7 years were identified retrospectively and their files reviewed for demographics, underlying diseases, Charlson Comorbidity Index, treatment and outcome. RESULTS: One hundred and eighty patients with PM-bloodstream infection (BSI) were included; 90 cases with MDR-PM and 90 controls with sensitive PM (S-PM). Compared to controls, cases more frequently were from nursing homes, had recurrent hospital admissions in the past year and received antibiotic therapy in the previous 3 months, were bedridden and suffered from peripheral vascular disease and peptic ulcer disease (p < 0.001). Two-thirds of the MDR-PM isolates were ESBL-producers vs 4.4% of S-PM isolates (p < 0.001, OR = 47.6, 95% CI = 15.9-142.6). In-hospital crude mortality rate of patients with MDR-PM BSI was 37.7% vs 23.3% in those with S-PM BSI (p = 0.0359, OR = 2, 95% CI = 1.4-3.81). CONCLUSIONS: PM bacteremia in elderly and functionally-dependent patients is likely to be caused by nearly pan-resistant PM strains in the institution; 51.8% of the patients received inappropriate empiric antibiotic treatment. The crude mortality rate of patients with MDR-PM BSI was significantly higher than that of patients with S-PM BSI. PMID- 26763482 TI - Catalytic Asymmetric Ring-Opening Reactions of Aziridines with 3-Aryl-Oxindoles. AB - A highly enantioselective ring-opening alkylation reaction between 3-aryl oxindole and N-(2-picolinoyl) aziridine has been realized for the first time. The reaction is efficiently mediated by a simple in-situ-generated magnesium catalyst and 3,3'-fluorinated-BINOL (BINOL=1,1'-binaphthalene-2,2'-diol) has been identified as a powerful chiral ligand. Notably, the fluorine atom on the chiral ligand plays a key role in providing the desired chiral 3-alkyl-3-aryl oxindoles with excellent enantioselectivities. PMID- 26763484 TI - Chronic hepatitis C virus infection, a new cardiovascular risk factor? AB - Among the large scope of extrahepatic manifestations related to hepatitis C virus (HCV) infection, many studies recently evaluated the frequency and characteristics of cardiovascular involvement. To assess the current published data on HCV infection and cardiovascular diseases. Published studies on cardiovascular disease, i.e. cerebrovascular accident and ischaemic heart disease in subjects with HCV infection were analysed from literature databases. Subjects with HCV chronic infection have an increased prevalence of carotid atherosclerosis and increased intima-media thickness compared to healthy controls or those with hepatitis B or non-alcoholic steatohepatitis. Active chronic HCV infection appears as an independent risk factor for ischaemic cerebrovascular accidents. Active chronic HCV infection is associated with increased risk of ischaemic heart disease. In some studies, successful interferon-based therapy showed a beneficial impact on the cardiovascular risk. The risk of major cardiovascular events is higher in patients with HCV infection compared to controls, independent of the severity of the liver disease or the common cardiovascular risk factors. The beneficial impact of interferon-based therapy needs to be confirmed with new direct antiviral interferon-free agents in prospective studies with extended follow-up. PMID- 26763485 TI - Impact of induced joy on literacy in children: does the nature of the task make a difference? AB - This research examined whether induced joy influences fifth graders' performance in literacy tasks. Children were asked to recall a joyful experience, used as a joy induction, before completing either a grammar (Study 1) or textual comprehension task (Study 2). The grammar task involved understanding at the surface level and retrieval of appropriate declarative and procedural knowledge, but limited elaboration unlike the textual comprehension task, which tackled inference generation. By differentiating tasks based on depth of processing required for completion we aimed at testing the validity of two concurrent hypotheses: that of a facilitating effect and that of a detrimental effect of induced joy. Compared to controls, joy induced children showed better performance on the grammar task - specifically children with lower language ability. No differences across groups emerged as a function of joy induction on the text comprehension task. Results are discussed with respect to emotion effects on cognition. PMID- 26763483 TI - Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors. AB - Dopamine is critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in appetitive tasks. A parallel and growing literature indicates that dopamine signaling is involved in consolidation of memories into stable representations in aversive tasks such as fear conditioning. Relatively little is known about how dopamine may modulate memories that form during extinction, when organisms learn that the relation between previously associated events is severed. We investigated whether fear and reward extinction share common mechanisms that could be enhanced with dopamine D1/5 receptor activation. Pharmacological activation of dopamine D1/5 receptors (with SKF 81297) enhanced extinction of both cued and contextual fear. These effects also occurred in the extinction of cocaine-induced conditioned place preference, suggesting that the observed effects on extinction were not specific to a particular type of procedure (aversive or appetitive). A cAMP/PKA biased D1 agonist (SKF 83959) did not affect fear extinction, whereas a broadly efficacious D1 agonist (SKF 83822) promoted fear extinction. Together, these findings show that dopamine D1/5 receptor activation is a target for the enhancement of fear or reward extinction. PMID- 26763487 TI - Sharing Core Facilities and Research Resources--An Investment in Accelerating Scientific Discoveries. PMID- 26763486 TI - Sp1-mediated ectopic expression of T-cell lymphoma invasion and metastasis 2 in hepatocellular carcinoma. AB - T-cell lymphoma invasion and metastasis 2 (TIAM2) is a neuron-specific protein that has been found ectopically expressed in hepatocellular carcinoma (HCC). Results from clinical specimens and cellular and animal models have shown that the short form of TIAM2 (TIAM2S) functions as an oncogene in the tumorigenesis of liver cancer. However, the regulation of TIAM2S ectopic expression in HCC cells remains largely unknown. This study aimed to identify the mechanism underlying the ectopic expression of TIAM2S in liver cancer cells. In this report, we provide evidence illustrating that Sp1 binds directly to the GC box located in the TIAM2S core promoter. We further demonstrated that overexpression of Sp1 in HepaRG cells promotes endogenous TIAM2S mRNA and protein expressions, and knockdown of Sp1 in 2 HCC cell lines, HepG2 and PLC/PRF/5, led to a substantial reduction in TIAM2S mRNA and protein in these cells. Of 60 paired HCC samples, 70% showed a significant increase (from 1.1- to 3.6-fold) in Sp1 protein expression in the tumor cells. The elevated Sp1 expression was highly correlated with both TIAM2S mRNA and protein expressions in these samples. Together, these results illustrate that Sp1 positively controls TIAM2S transcription and that Sp1 mediated transcriptional activation is essential for TIAM2S ectopic expression in liver cancer cells. PMID- 26763488 TI - Long-Term Predictors of Thromboembolic Events in Nonvalvular Atrial Fibrillation Patients Undergoing Electrical Cardioversion. AB - BACKGROUND: Patients with nonvalvular atrial fibrillation (AF) who undergo electrical cardioversion (ECV) tend to be younger and have less comorbidity. Long term anticoagulation after ECV should be based on thromboembolic risk. We sought to study the long-term incidence of thromboembolic events (TE), factors related to TE and compare the predictive value of the CHADS2and CHA2DS2-VASc scores in this particular population. METHODS AND RESULTS: From January 2008 to June 2012, 571 ECV were performed in 406 consecutive patients with nonvalvular AF. Risk factors for TE and factors related to anticoagulation therapy after ECV were registered. During a follow-up of approximately 2 years, the annual incidence of TE was 1.9%. Factors associated with TE were: poor quality anticoagulation control (hazard ratio [HR]: 2.91; 95% confidence interval [CI]: 1.10-7.80; P=0.03), cessation of anticoagulation after ECV (HR: 8.80; 95% CI: 3.11-25.10; P<0.001), age >=65 years (HR: 13.65; 95% CI: 1.74-107.16; P=0.01), CHADS2score (HR: 1.59; 95% CI: 1.10-2.29; P=0.01) and CHA2DS2-VASc score (HR: 1.67; 95% CI: 1.30-2.22; P<0.001). Both risk scores predicted TE [c-statistic for CHADS2: 0.68 (95% CI: 0.62-0.74; P=0.005), for CHA2DS2-VASc: 0.75 (95% CI: 0.70-0.80; P<0.001)]. Based on c-statistics, the predictive accuracy of CHA2DS2-VASc was superior (difference between areas: 0.064+/-0.031; P=0.0403). CONCLUSIONS: Important determinants of long-term occurrence of TE after ECV were related to anticoagulant therapy (poor quality anticoagulation and cessation of this therapy over follow-up). The CHA2DS2-VASc score successfully predicts TE after ECV, having better predictive accuracy than the CHADS2score. (Circ J 2016; 80: 605 612). PMID- 26763489 TI - Heart Rate Control With If Inhibitor, Ivabradine, in Japanese Patients With Chronic Heart Failure - A Randomized, Double-Blind, Placebo-Controlled Phase II Study. AB - BACKGROUND: Elevated heart rate (HR) is an independent risk factor for cardiovascular outcomes in various cardiac diseases, including heart failure (HF). METHODS AND RESULTS: Randomized placebo-controlled study was conducted to evaluate the effects of ivabradine, an Ifinhibitor, on the resting HR in 126 Japanese symptomatic HF patients with left ventricular ejection fraction <=35%, resting HR >=75 beats/min in sinus rhythm, and stable, optimal background treatment. Patients were randomly allocated into 3 groups: placebo; starting dose of ivabradine 2.5 mg twice daily (BID; 2.5 mg group); 5 mg BID group. The dose was increased up to 7.5 mg BID according to dose-adjustment criteria. After the 6 week treatment, the reductions in resting HR were significant in both the 2.5-mg (16.6+/-8.1 beats/min) and 5-mg (16.4+/-9.6 beats/min) groups (P<0.0001 for both groups) compared with placebo (1.7+/-8.7 beats/min). The most frequent side effect of ivabradine was phosphenes, but all were mild. Treatment was discontinued in 1 patient due to HF in the 5 mg group. CONCLUSIONS: Ivabradine starting at 2.5 or 5 mg BID effectively reduced resting HR in Japanese HF patients. Ivabradine at the starting dose of 2.5 mg BID could be safer than 5 mg BID. (Circ J 2016; 80: 668-676). PMID- 26763490 TI - Effect of carrageenan addition on the rennet-induced gelation of skim milk. AB - BACKGROUND: Carrageenan (CG) (kappa-CG, iota-CG and lambda-CG) was added to skim milk and the rennet-induced aggregation was studied. Caseinomacropeptide (CMP) release, diffusing wave spectroscopy (DWS) and rheology were used to follow the structural dynamics of casein micelles during gelation. The influence of carrageenan on the nature of protein interactions in the gels was investigated using a combination of ultracentrifugation and specific dissociating agents. RESULTS: For the recombined samples containing kappa-CG and low concentrations of iota-CG and lambda-CG, the CMP release was slowed down; however, the development of DWS and rheological parameters was similar to that of the control sample, and the increase in the incorporation of proteins through calcium bridges and hydrophobic interactions may be the most likely contributors. For the recombined samples containing high concentrations of iota-CG and lambda-CG, other factors may impede the gel formation process. CONCLUSION: High concentrations of iota-CG and lambda-CG strongly interfered with the rennet-induced aggregation, interrupted the interaction of caseins and therefore may contribute to good quality of low-fat cheese. (c) 2016 Society of Chemical Industry. PMID- 26763491 TI - Femoral and sciatic nerve blockades and incision site infiltration in rabbits undergoing stifle joint arthrotomy. AB - This study was designed to determine whether perineural injections of local anaesthetics decreases intraoperative nociception and improves postoperative analgesia in New Zealand White rabbits undergoing experimental stifle arthrotomy. All animals were anaesthetized using isoflurane and received morphine intramuscularly. The sciatic and femoral nerves of the leg to be operated on were located using a nerve stimulator (1 Hz, 0.5 mA). Rabbits were assigned to a treatment group (LB; n = 12) or a placebo group (P; n = 12) in a randomized blinded fashion. Group LB received lidocaine 2% (1 mg/kg) combined with bupivacaine 0.5% (0.25 mg/kg) injections around the sciatic and femoral nerves (0.1 mL/kg total volume per site) and subcutaneous infiltration of the incision site with lidocaine 1% (1.25 mg/kg). Group P received the same volume of 0.9% NaCl. Rabbits in group P required higher doses of intraoperative fentanyl and propofol to reduce heart rate and suppress increase in systolic blood pressure, and maintain an adequate anaesthetic plane. Interventional analgesia (buprenorphine and carprofen) was required significantly earlier in rabbits in group P (2 and 6 h after the first nerve blockade, respectively) based on assessment of their pain-related behaviour and range of motion. Using a visual analogue scale (0 mm= no pain to 100 mm= maximal possible pain), rabbits in group LB were judged to show significantly less pain compared with rabbits in group P (14 +/- 10 mm and 37 +/- 25 mm, respectively) 2 h after nerve blockade. In conclusion, this technique of perineural analgesia combined with incision site infiltration reduced intraoperative fentanyl requirements and improved postoperative analgesia in rabbits. PMID- 26763492 TI - Normal ultrasonographic images of reproductive organs of female Japanese quails ( Coturnix coturnix japonica): a laboratory animal model. AB - Certain special biological characteristics of Japanese quails ( Coturnix coturnix japonica) could enable quicker and less expensive laboratory experiments than similar studies using mice or chickens. Moreover, due to some physiological similarities with humans, quails have been recognized as an ideal laboratory model for experiments in some fields such as immunology, endocrinology, and reproductive biology. The aim of this study was to acquire normal ultrasonographic images of reproductive organs of female Japanese quails in order to facilitate laboratory experiments on reproductive biology and to determine a non-invasive in-life alternative to carcass analysis. Thirty female Japanese quails of different ages were used for ultrasound scanning of ovaries, follicles, ova, oviducts and eggs. In addition, five quails were euthanized for experiments using a direct standoff imaging technique. It was possible to identify different sizes of follicles ranging from small white follicles (0.14 cm) to large yellow follicles (2.57 cm), post-ovulatory follicles (POFs), ova at various stages of development, oviducts, and also eggs within the oviducts. These findings demonstrate that ultrasound scanning of female Japanese quail reproductive organs might be a beneficial diagnostic tool for applications such as studying reproductive physiology, anticipating the beginning or the end of the breeding season, detecting any pathological disorders easily, and identifying non productive females which could lead to more cost-efficient laboratory procedures. PMID- 26763493 TI - Parent Training for Children With or at Risk for Developmental Delay: The Role of Parental Homework Completion. AB - This study investigated the extent to which parental homework completion during behavioral parent training (BPT) for children with or at risk for developmental delay contributed to parenting and child outcomes. Parents of 48 children (Mage=44.17 months, SD=14.29; 73% male; 72% White) with developmental delay (IQ<75) or at risk for developmental delay (due to premature birth) with co occurring clinically elevated externalizing behavior problems received Parent Child Interaction Therapy (PCIT) as part of two previously completed randomized controlled trials. Parental homework completion was measured using parental report of home practice of treatment skills collected weekly by therapists. Parents also reported on child externalizing behavior problems and levels of parenting stress, while parenting skills were observed during a 5-min child directed play and child compliance was observed during a 5-min cleanup situation. Results indicated that higher rates of parental homework completion predicted parenting outcomes (i.e., increased positive parenting skills and decreased levels of parenting stress) and child outcomes (i.e., lower levels of externalizing behavior problems). Additionally, although limited by temporal precedence, there was an indirect effect of reductions in parenting stress on the negative association between parental homework completion and child externalizing behavior problems. These findings highlight the importance of parents practicing skills learned during BPT for optimizing treatment outcome. Parenting stress was also identified as a potential mechanism by which high levels of parental homework completion contributed to reductions in child externalizing behavior problems. PMID- 26763494 TI - Does Worrying Mean Caring Too Much? Interpersonal Prototypicality of Dimensional Worry Controlling for Social Anxiety and Depressive Symptoms. AB - Worry, social anxiety, and depressive symptoms are dimensions that have each been linked to heterogeneous problems in interpersonal functioning. However, the relationships between these symptoms and interpersonal difficulties remain unclear given that most studies have examined diagnostic categories, not accounted for symptoms' shared variability due to general distress, and investigated only interpersonal problems (neglecting interpersonal traits, interpersonal goals, social behavior in daily life, and reports of significant others). To address these issues, students (Study 1; N=282) endorsed symptoms and interpersonal circumplex measures of traits and problems, as well as event contingent social behaviors during one week of naturalistic daily interactions (N=184; 7,036 records). Additionally, depressed and anxious patients (N=47) reported symptoms and interpersonal goals in a dyadic relationship, and significant others rated patients' interpersonal goals and impact (Study 2). We derived hypotheses about prototypical interpersonal features from theories about the functions of particular symptoms and social behaviors. As expected, worry was uniquely associated with prototypically affiliative tendencies across all self report measures in both samples, but predicted impacting significant others in unaffiliative ways. As also hypothesized, social anxiety was uniquely and prototypically associated with low dominance across measures, and general distress was associated with cold-submissive tendencies. Findings for depressive symptoms provided less consistent evidence for unique prototypical interpersonal features. Overall, results suggest the importance of multimethod assessment and accounting for general distress in interpersonal models of worry, social anxiety, and depressive symptoms. PMID- 26763495 TI - An Empirical Examination of Symptom Substitution Associated With Behavior Therapy for Tourette's Disorder. AB - Over the past six decades, behavior therapy has been a major contributor to the development of evidence-based psychotherapy treatments. However, a long-standing concern with behavior therapy among many nonbehavioral clinicians has been the potential risk for symptom substitution. Few studies have been conducted to evaluate symptom substitution in response to behavioral treatments, largely due to measurement and definitional challenges associated with treated psychiatric symptoms. Given the overt motor and vocal tics associated with Tourette's disorder, it presents an excellent opportunity to empirically evaluate the potential risk for symptom substitution associated with behavior therapy. The present study examined the possible presence of symptom substitution using four methods: (a) the onset of new tic symptoms, (b) the occurrence of adverse events, (c) change in tic medications, and (d) worsening of co-occurring psychiatric symptoms. Two hundred twenty-eight participants with Tourette's disorder or persistent motor or vocal tic disorders were randomly assigned to receive behavioral therapy or supportive therapy for tics. Both therapies consisted of eight sessions over 10 weeks. Results indicated that participants treated with behavior therapy were not more likely to have an onset of new tic symptoms, experience adverse events, increase tic medications, or have an exacerbation in co-occurring psychiatric symptoms relative to participants treated with supportive therapy. Further analysis suggested that the emergence of new tics was attributed with the normal waxing and waning nature of Tourette's disorder. Findings provide empirical support to counter the long-standing concern of symptom substitution in response to behavior therapy for individuals with Tourette's disorder. PMID- 26763496 TI - Intolerance of Uncertainty Is Associated With Increased Threat Appraisal and Negative Affect Under Ambiguity but Not Uncertainty. AB - Intolerance of Uncertainty (IU) has gained increasing interest as a vulnerability factor for worry in Generalized Anxiety Disorder and other emotional disorders. We extended the procedure of Grupe and Nitschke (2011) to compare threat processing in High IU (n=29) and Low IU (n=26) participants. Participants viewed four cues: two reference cues that preceded aversive pictures on 100% or 0% of trials, and a target cue that preceded aversive pictures on 50% of trials (Uncertain condition). Participants were instructed about these probabilities in advance. In addition, we surprised participants with a second target cue that also preceded aversive pictures on 50% of trials but that had not been mentioned in the instructions (Ambiguous condition). Results provided preliminary evidence that High IU participants showed greater online threat expectancy, postexperimental covariation estimates and negative mood for the target cues compared to the reference cues. The results also suggest that among high IU individuals, ambiguity, rather than uncertainty per se, may be a particularly powerful trigger for biased threat appraisal and negative affect. Clinically, the results suggest that patients with high IU may benefit from interventions to help them calibrate the degree of risk in situations involving ambiguous threat. PMID- 26763497 TI - Pilot Cases of Combined Cognitive Processing Therapy and Smoking Cessation for Smokers With Posttraumatic Stress Disorder. AB - Posttraumatic stress disorder (PTSD) and smoking are often comorbid, and both problems are in need of improved access to evidence-based treatment. The combined approach could address two high-priority problems and increase patient access to both treatments, but research is needed to determine whether this is feasible and has promise for addressing both PTSD and smoking. We collected data from 15 test cases that received a treatment combining two evidence-based treatments: cognitive processing therapy-cognitive version (CPT-C) for PTSD and integrated care for smoking cessation (ICSC). We explored two combined treatment protocols including a brief (six-session) CPT-C with five follow-up in-person sessions focused on smoking cessation (n=9) and a full 12-session CPT-C protocol with ICSC (n=6). The combined interventions were feasible and acceptable to patients with PTSD making a quit attempt. Initial positive benefits of the combined treatments were observed. The six-session dose of CPT-C and smoking cessation resulted in 6 month bioverified smoking abstinence in two of nine participants, with clinically meaningful PTSD symptom reduction in three of nine participants. In the second cohort (full CPT-C and smoking treatment), both smoking and PTSD symptoms were improved, with three of six participants abstinent from smoking and four of six participants reporting clinically meaningful reduction in PTSD symptoms. Results suggested that individuals with PTSD who smoke are willing to engage in concurrent treatment of these problems and that combined treatment is feasible. PMID- 26763498 TI - Mechanisms of Change in Written Exposure Treatment of Posttraumatic Stress Disorder. AB - Although the effectiveness of exposure therapy for PTSD is recognized, treatment mechanisms are not well understood. Emotional processing theory (EPT) posits that fear reduction within and between sessions creates new learning, but evidence is limited by self-report assessments and inclusion of treatment components other than exposure. We examined trajectories of physiological arousal and their relation to PTSD treatment outcome in a randomized controlled trial of written exposure treatment, a protocol focused on exposure to trauma memories. Hierarchical linear modeling was used to model reduction in Clinician Administered PTSD Scale score as a predictor of initial activation and within- and between-session change in physiological arousal. Treatment gains were significantly associated with initial physiological activation, but not with within- or between-session changes in physiological arousal. Treatment gains were associated with larger between-session reductions in self-reported arousal. These findings highlight the importance of multimethod arousal assessment and add to a growing literature suggesting refinements of EPT. PMID- 26763499 TI - Clinical Feedback About Empirically Supported Treatments for Obsessive-Compulsive Disorder. AB - Previous evidence for the treatment of obsessive-compulsive disorder (OCD) has been derived principally from randomized controlled trials. As such, evidence about the treatment of OCD has unilaterally flowed from researchers to clinicians. Despite often having decades of experience treating OCD, clinicians' feedback on their clinical observations in using these treatments has not been solicited. The current study contacted clinicians for their clinical observations on empirically supported treatments for OCD to identify commonly used cognitive behavioral techniques and their limitations in their practices. One hundred eighty-one psychotherapists completed an online survey. The average participant practiced psychotherapy for 15 years, worked in private practice, held a doctorate, and treated an average of 25 clients with OCD in their lifetime. In regard to the most common techniques, behavioral strategies involving exposure to a feared outcome and prevention of a compulsive ritual were the most frequent group of interventions, followed by techniques that attempted to identify and challenge irrational thoughts. However, the majority of participants also reported incorporating mindfulness or acceptance-based methods. Based on therapists' reports, the most common barriers to the efficacy of cognitive behavioral interventions included limited premorbid functioning, chaotic lifestyles, controlling and critical families, OCD symptom severity, OCD symptom chronicity, and comorbidities. This study provides insight into common practices and limitations in clinical practice to inform future clinically relevant treatment research. PMID- 26763500 TI - Anxiety and Related Disorders and Concealment in Sexual Minority Young Adults. AB - Sexual minorities face greater exposure to discrimination and rejection than heterosexuals. Given these threats, sexual minorities may engage in sexual orientation concealment in order to avoid danger. This social stigma and minority stress places sexual minorities at risk for anxiety and related disorders. Given that three fourths of anxiety disorder onset occurs before the age of 24, the current study investigated the symptoms of generalized anxiety disorder, social phobia, panic disorder, posttraumatic stress disorder, and depression in sexual minority young adults relative to their heterosexual peers. Secondarily, the study investigated sexual orientation concealment as a predictor of anxiety and related disorders. A sample of 157 sexual minority and 157 heterosexual young adults matched on age and gender completed self-report measures of the aforementioned disorders, and indicated their level of sexual orientation concealment. Results revealed that sexual minority young adults reported greater symptoms relative to heterosexuals across all outcome measures. There were no interactions between sexual minority status and gender, however, women had higher symptoms across all disorders. Sexual minority young women appeared to be at the most risk for clinical levels of anxiety and related disorders. In addition, concealment of sexual orientation significantly predicted symptoms of social phobia. Implications are offered for the cognitive and behavioral treatment of anxiety and related disorders in this population. PMID- 26763501 TI - Change in Dysfunctional Beliefs About Sleep in Behavior Therapy, Cognitive Therapy, and Cognitive-Behavioral Therapy for Insomnia. AB - As part of a larger randomized controlled trial, 188 participants were randomized to behavior therapy (BT), cognitive therapy (CT), or cognitive-behavioral therapy (CBT) for insomnia. The aims of this study were threefold: (a) to determine whether change in dysfunctional beliefs about sleep was related to change in sleep, insomnia symptoms, and impairment following treatment; (b) to determine whether BT, CT, and CBT differ in their effects on dysfunctional beliefs; and (c) to determine whether the treatments differ in their effects on particular kinds of dysfunctional beliefs. Beliefs, sleep, insomnia symptoms, and sleep-related psychosocial impairment were assessed at pretreatment, posttreatment, and 6- and 12-month follow-up. Greater change in dysfunctional beliefs occurring over the course of BT, CT, or CBT was associated with greater improvement in insomnia symptoms and impairment at posttreatment and both follow-ups. All groups experienced a significant decrease in dysfunctional beliefs during treatment, which were sustained through 6- and 12-month follow-up. Compared with the BT group, a greater proportion of participants in the CT and/or CBT groups endorsed dysfunctional beliefs below a level considered clinically significant at posttreatment and 12-month follow-up. The results demonstrate the importance of targeting dysfunctional beliefs in insomnia treatment, suggest that beliefs may be significantly modified with BT alone, and indicate that cognitive interventions may be particularly powerful in enhancing belief change. PMID- 26763502 TI - An Experimental Investigation of the Effect of Stress on Saving and Acquiring Behavioral Tendencies: The Role of Distress Tolerance and Negative Urgency. AB - Stress has been implicated as a risk factor for hoarding, although past research has relied on cross-sectional and self-report designs. Using experimental methods and objective hypothetical behavioral hoarding paradigms, we investigated the direct effect of stress on in-the-moment saving and acquiring behavioral tendencies. We also evaluated whether distress tolerance (DT) and negative urgency interacted with stress to predict saving and acquiring behavioral tendencies. A sample of young adults (N=80) completed questionnaires about DT and negative urgency. Participants were randomized to either a psychosocial stressor or nonstressful control task prior to completing two hypothetical behavioral hoarding paradigms. The discarding task asked participants to choose between saving and disposing of items. For the acquiring task, participants completed a computer-simulated shopping spree that measured items acquired. Unexpectedly, participants in the stress condition saved and acquired fewer items than those in the control condition. As hypothesized, stress interacted with DT to predict saving tendencies. The current study should be replicated in a clinical sample. Longitudinal studies are needed to further examine the long-term effect of stress on hoarding. This is the first examination of the direct effect of stress on saving and acquiring tendencies. Although some study hypotheses were not supported, several results are consistent with our predictions and suggest a complex relationship between stress and hoarding. If findings are replicated in a clinical sample, it may be that hoarding patients could benefit from treatments incorporating DT strategies. PMID- 26763503 TI - Generalization on the Basis of Prior Experience Is Predicted by Individual Differences in Working Memory. AB - Generalization on the basis of prior experience is a central feature of human and nonhuman behavior, and anomalies in generalization can give rise to a wide array of problems. For instance, elevated levels of generalization have been shown in individuals suffering from an anxiety disorder. Identifying the individual difference variables that influence the extent to which behavior generalizes to novel stimuli may help our understanding of generalization and its potential maladaptive consequences. In this study, we first present an index of generalization that captures individual differences in generalization in a single continuous measure, thereby surpassing problems associated with traditional analyzing techniques. Further, we investigate whether generalization is predicted by working memory capacity. More precisely, it is hypothesized that generalization is a function of individual differences in the capacity to compare the current situation with previous learning experiences in working memory, and to adjust subsequent behavior accordingly. In a community sample, we found higher levels of generalization in individuals who were less efficient at filtering out irrelevant information from access to working memory. These results suggest that working memory impairments may contribute to elevated and potentially maladaptive levels of generalization. PMID- 26763504 TI - The role of childhood trauma in bipolar disorders. AB - This review will discuss the role of childhood trauma in bipolar disorders. Relevant studies were identified via Medline (PubMed) and PsycINFO databases published up to and including July 2015. This review contributes to a new understanding of the negative consequences of early life stress, as well as setting childhood trauma in a biological context of susceptibility and discussing novel long-term pathophysiological consequences in bipolar disorders. Childhood traumatic events are risk factors for developing bipolar disorders, in addition to a more severe clinical presentation over time (primarily an earlier age at onset and an increased risk of suicide attempt and substance misuse). Childhood trauma leads to alterations of affect regulation, impulse control, and cognitive functioning that might decrease the ability to cope with later stressors. Childhood trauma interacts with several genes belonging to several different biological pathways [Hypothalamic-pituitary-adrenal (HPA) axis, serotonergic transmission, neuroplasticity, immunity, calcium signaling, and circadian rhythms] to decrease the age at the onset of the disorder or increase the risk of suicide. Epigenetic factors may also be involved in the neurobiological consequences of childhood trauma in bipolar disorder. Biological sequelae such as chronic inflammation, sleep disturbance, or telomere shortening are potential mediators of the negative effects of childhood trauma in bipolar disorders, in particular with regard to physical health. The main clinical implication is to systematically assess childhood trauma in patients with bipolar disorders, or at least in those with a severe or instable course. The challenge for the next years will be to fill the gap between clinical and fundamental research and routine practice, since recommendations for managing this specific population are lacking. In particular, little is known on which psychotherapies should be provided or which targets therapists should focus on, as well as how childhood trauma could explain the resistance to mood stabilizers. PMID- 26763505 TI - Circadian rhythmicity in emerging mood disorders: state or trait marker? AB - BACKGROUND: Circadian rhythm disturbances overlap with the symptoms of mood episodes and may trigger or prolong mood symptoms. There is limited research on the role of circadian disturbances in mood disorders in young people and/or first episode cases of unipolar and bipolar disorders. METHODS: Actigraphy was undertaken for about 14 days in 63 post-pubertal individuals aged 13-25 years with a recent onset of a mood disorder meeting recognised diagnostic criteria. We examined associations between three easily interpretable markers of circadian rhythm activity (amplitude, acrophase and rhythmicity index) and demography and clinical characteristics. Then, circadian markers were compared between diagnostic groups, controlling for potential confounders. RESULTS: Longer duration of illness was correlated with reduced circadian rhythmicity and lower levels of activity over 24 h. A delay in the timing of maximum activity was associated with the level of manic but not depressive symptoms. The circadian rhythmicity index differentiated unipolar from bipolar cases, and in bipolar but not unipolar disorder, the rhythmicity was less robust in those with more severe manic or depressive symptoms. CONCLUSIONS: Less robust circadian rhythmicity, especially associated with increasing symptom severity, may represent a more specific or a trait marker of young people with mood disorders who are at higher risk of a bipolar course of illness. PMID- 26763506 TI - Comparison of Analytical and Clinical Performance of HPV 9G DNA Chip, PANArray HPV Genotyping Chip, and Hybrid-Capture II Assay in Cervicovaginal Swabs. AB - BACKGROUND: Human papillomavirus (HPV) infection can be detected by using several molecular methods, including Hybrid-Capture II (HC2) assay and variable HPV DNA chip tests, although each method has different sensitivities and specificities. METHODS: We performed HPV 9G DNA Chip (9G) and PANArray HPV Genotyping Chip (PANArray) tests on 118 cervicovaginal swabs and compared the results with HC2, cytology, histology, and direct sequencing results. RESULTS: The overall and high risk HPV (HR-HPV) positivity rates were 62.7% and 44.9% using 9G, and 61.0% and 30.5% using PANArray, respectively. The positivity rates for HR-HPV with these two chips were significantly lower than 55.1% when HC2 was used. The sensitivity of overall HPV positivity in detecting histologically confirmed low-grade cervical squamous intraepithelial lesions or higher was 88.7% for all three tests. The specificity was 58.5% for 9G and 61.5% for PANArray, which was significantly lower than the 72.3% for HC2. With the HR-HPV(+) genotype threshold, the sensitivity decreased to 75.5% for 9G and 52.8% for PANArray, which was significantly lower than the 88.7% for HC2. Comparison of the two chips showed concordant results in 55.1% of the samples, compatible results in 16.9%, and discordant results in 28.0%, exhibiting poor agreement in detecting certain HPV genotypes. Compared with direct sequencing, 9G yielded no discordant results, whereas PANArray yielded 31 discordant results (26.7%). CONCLUSIONS: Compared with HC2, the HPV genotyping tests showed lower sensitivity in histologic correlation. When the two chips were compared, the 9G was more sensitive and accurate for detecting HR-HPV than the PANArray. PMID- 26763507 TI - 2,4-Toluene diisocyanate detection in liquid and gas environments through electrochemical oxidation in an ionic liquid. AB - The electrochemical oxidation of 2,4-toluene diisocyanate (2,4-TDI) in an ionic liquid (IL) has been systematically characterized to determine plausible electrochemical and chemical reaction mechanisms and to define the optimal detection methods for such a highly significant analyte. It has been found that the use of an IL as the electrolyte allows the oxidation of 2,4-TDI to occur at a less positive anodic potential with no side reactions as compared to traditional acetonitrile based electrolytes. UV-Vis, FT-IR, cyclic voltammetry and Electrochemical Impedance Spectroscopy (EIS) studies have revealed the unique mechanisms of dimerization of 2,4-TDI at the electrode interface by self-addition reactions, which can be utilized to improve the selectivity of detection. The study of 2,4-TDI redox chemistry further facilitates the development of a robust amperometric sensing methodology by selecting a hydrophobic IL ([C4mpy][NTf2]) and by restricting the potential window to only include the oxidation process. Thus, this innovative electrochemical sensor is capable of avoiding the two most ubiquitous interferents in ambient conditions (i.e. humidity and oxygen), thereby enhancing the sensor performance and reliability for real world applications. The method was established to detect 2,4-TDI in both liquid and gas phases. The limits of detection (LOD) values were 130.2 ppm and 0.7862 ppm, respectively, for the two phases, and are comparable to the safety standards reported by NIOSH. The as-developed 2.4-TDI amperometric sensor exhibits a sensitivity of 1.939 MUA ppm( 1). Moreover, due to the simplicity of design and the use of an IL both as a solvent and non-volatile electrolyte, the sensor has the potential to be miniaturized for smart sensing protocols in distributed sensor applications. PMID- 26763508 TI - Contemporary Trends in Radical Prostatectomy in the United States: Open vs Minimally Invasive Surgery. PMID- 26763509 TI - Celebrating Mayo Clinic Proceedings' 90th Anniversary: A Story of Longevity and Progression of Mission. PMID- 26763510 TI - Radical Prostatectomy Trends in the United States: 1998 to 2011. AB - OBJECTIVE: To determine the incidence and distribution of radical prostatectomy (RP) in the United States over time. PATIENTS AND METHODS: We conducted a serial cross-sectional analysis of time trends using the Nationwide Inpatient Sample of adult men older than 45 years who underwent RP between January 1, 1998, and December 31, 2011. RESULTS: Weighted estimates revealed that 962,917 men underwent RP during the study period. The annual rate of RP remained relatively stable, from 1425 RPs per million in the period 1998 to 1999 to 1330 RPs per million in the period 2010 to 2011 (7% decrease; P=.90). The annual rate of open RP decreased from 1424 per million to 435 per million (P<.001), whereas the annual rate of minimally invasive RP increased from less than 1 per million to 895 per million (P<.001). Since 2006, hospitals providing open RP decreased by 18% (from 2288 to 1870; P<.001), whereas hospitals providing minimally invasive RP increased by 191% (from 341 to 993; P<.001). The median open RP caseload per hospital decreased by 7% (from 68 to 63; P<.001), whereas the median caseload for hospitals providing minimally invasive RP declined by 17% (from 122 to 101; P<.001). The hospitals providing fewer than 50 minimally invasive RPs per year increased from 12% to 26% (from 144 of 1240 to 3020 of 11,644; P<.001). CONCLUSION: Per capita utilization of RP in the United States has remained stable from 1998 to 2011. Rapid expansion of the use of minimally invasive RP has reduced open RP utilization rates and median annual hospital caseload. PMID- 26763511 TI - Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers in Patients Without Heart Failure? Insights From 254,301 Patients From Randomized Trials. AB - OBJECTIVES: To compare the efficacy and safety of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) in patients without heart failure. PATIENTS AND METHODS: Meta-analysis of randomized trials identified using PubMed, Embase, and Cochrane Central Register of Controlled Trials searches from January 1, 1980, through April 13, 2015, of ACEis and ARBs compared with placebo or active controls and corroborated with head-to-head trials of ARBs vs ACEis. Outcomes were all-cause mortality, cardiovascular death, myocardial infarction (MI), angina, stroke, heart failure, revascularization, and new-onset diabetes. RESULTS: Our search yielded 106 randomized trials that enrolled 254,301 patients. Compared with placebo, ACEis but not ARBs reduced the outcomes of all-cause mortality (ACEis vs placebo: relative risk [RR], 0.89; 95% CI, 0.80-1.00; ARBs vs placebo: RR, 1.01; 95% CI, 0.96-1.06; Pinteraction=.04), cardiovascular death (RR, 0.83; 95% CI, 0.70-0.99 and RR, 1.02; 95% CI, 0.92 1.14; Pinteraction=.05), and MI (RR, 0.83; 95% CI, 0.78-0.90 and RR, 0.93; 95% CI, 0.85-1.03; Pinteraction=.06). The meta-regression analysis revealed that the difference between ACEis and ARBs compared with placebo was due to a higher placebo event rate in the ACEis trials (most of these trials were conducted a decade earlier than the ARB trials) for the outcome of all-cause mortality (P=.001), cardiovascular death (P<.001), and MI (P=.02). Sensitivity analyses restricted to trials published after 2000 revealed similar outcomes with ACEis vs placebo and ARBs vs placebo (Pinteraction>.05). Head-to-head comparison trials of ARBs vs ACEis exhibited no difference in outcomes except for a lower risk of drug withdrawal due to adverse effects with ARBs (RR, 0.72; 95% CI, 0.65-0.81). CONCLUSION: In patients without heart failure, evidence from placebo-controlled trials (restricted to trials after 2000), active controlled trials, and head-to head randomized trials all suggest ARBs to be as efficacious and safe as ACEis, with the added advantage of better tolerability. PMID- 26763513 TI - 77-Year-Old Man With Hypothyroidism, Right Upper Quadrant Pain, and Diarrhea. PMID- 26763512 TI - Disclosure of Industry Payments to Physicians: An Epidemiologic Analysis of Early Data From the Open Payments Program. AB - The Centers for Medicare and Medicaid Services' Open Payments program implements Section 6002 of the Affordable Care Act requiring medical product manufacturers to report payments made to physicians or teaching hospitals as well as ownership or investment interests held by physicians in the manufacturer. To determine the characteristics and distribution of these industry payments by specialty, we analyzed physician payments made between August 1, 2013, and December 31, 2013, that were publicly disclosed by Open Payments. We compared payments between specialty types (medical, surgical, and other) and across specialties within each type using the Pearson chi(2) test and the Kruskal-Wallis test. The number of physicians receiving payments was compared with the total number of active physicians in each specialty in 2012. We also analyzed physician ownership interests. Allopathic and osteopathic physicians received 2.43 million payments totaling $475 million. General payments represented 90% of payments by total value ($430 million) (per-physician median, $100; interquartile range [IQR], $31 $273; mean +/- SD, $1407+/-$23,766), with the remaining 10% ($45 million) as research payments (median, $2365; IQR, $592-$8550; mean +/- SD, $12,880+/ $66,743). Physicians most likely to receive general payments were cardiovascular specialists (78%) and neurosurgeons (77%); those least likely were pathologists (9%). Reports of ownership interest in reporting entities included $310 million in dollar amount invested and $447 million in value of interest held by 2093 physicians. In conclusion, the distribution and characteristics of industry payments to physicians varied widely by specialty during the first half-year of Open Payments reporting. PMID- 26763515 TI - Is There a Need for "Bias Police" in Industry-Sponsored Research? PMID- 26763516 TI - In Reply--Is There a Need for "Bias Police" in Industry-Sponsored Research? PMID- 26763514 TI - Multiple Myeloma: Diagnosis and Treatment. AB - The diagnosis and treatment of multiple myeloma has changed dramatically in the past decade. The disease definition has been updated to include highly specific biomarkers in addition to established markers of end-organ damage. The staging system has been revised to combine both measures of tumor burden and disease biology. Advances in therapy have resulted in a marked improvement in overall survival. New drugs introduced in the past few years include carfilzomib, pomalidomide, panobinostat, ixazomib, elotuzumab, and daratumumab. In this review, we outline the current approach to the diagnosis, prognosis, and management of multiple myeloma. PMID- 26763518 TI - Radiation Therapy in Gastric and Ocular Marginal Zone Lymphomas. PMID- 26763517 TI - Incidence of Infective Endocarditis in Patients With Bicuspid Aortic Valves in the Community. PMID- 26763519 TI - Split Hand Syndrome and Syndrome of Inappropriate Antidiuretic Hormone. PMID- 26763520 TI - 69-Year-Old Woman With Confusion and Fatigue. PMID- 26763521 TI - Baron Takaki and the Mayo Family: The Long-Lasting Bond Between Japan and Mayo Clinic. PMID- 26763522 TI - Pancreatic Tumor in a Patient With Parathyroid and Pituitary Disease. PMID- 26763524 TI - Role of Hormone Therapy After Primary Surgery for Endometrioma: A Multicenter Retrospective Cohort Study. AB - Endometriosis is a major cause of disability in women, and 40% to 50% of patients experience disease recurrence by 5 years after surgery. This multicenter retrospective cohort study (N = 588) determined the rate and risk factors for recurrent endometrioma after primary surgery and examined the role of postoperative hormone therapy. When recurrence was defined by sonographic identification of the endometrioma (>=20 mm in size), 61 (10.4%) patients experienced disease recurrence. The cumulative recurrence rates at 1, 2, 3, and 5 years after surgery were 2.2%, 4.9%, 6.9%, and 9.8%, respectively. To determine the risk factors for recurrence, the clinical factors of patients with and without recurrence were compared. There was a significantly increased risk of recurrence with posterior cul-de-sac (PCDS) obliteration (P = .031) and higher serum cancer antigen 125 (CA125) level (P = .005). A longer postoperative hormonal therapy duration (P < .01), absence of PCDS obliteration (P = .036), and lower serum CA125 level (P = .014) were associated with longer recurrence-free interval on multivariate analysis using the Cox regression model. Postoperative hormone therapy prolonged the interval from the time of surgery to the first recurrence. However, it did not prolong the interval from the end of treatment to the first recurrence. Our results indicate that although long-term postoperative hormone therapy might maintain minimal disease status, it does not control residual disease. Therefore, persistent hormone suppression should be used to prevent disease recurrence. PMID- 26763525 TI - Comparative Characterization of Vaginal Cells Derived From Premenopausal Women With and Without Severe Pelvic Organ Prolapse. AB - BACKGROUND: This study tested a hypothesis that primary human vaginal cells derived from tissue of premenopausal women with severe pelvic organ prolapse (POP HVCs) would display differential functional characteristics as compared to vaginal cells derived from asymptomatic women with normal pelvic floor support (control-HVCs). METHODS: Vaginal tissue biopsies were collected from premenopausal patients with POP (n = 8) and asymptomatic controls (n = 7) during vaginal hysterectomy or repair. Primary vaginal cells were isolated by enzymatic digestion and characterized by immunocytochemistry. Cell attachment and proliferation on different matrices (collagen I, collagen II, collagen IV, fibronectin, laminin, tenascin, and vitronectin) were compared between POP-HVCs and control-HVCs. RNA was extracted, and the expression of 84 genes was screened using Human Extracellular Matrix and Adhesion Molecules RT(2) Profiler PCR array. The expression of selected genes was verified by quantitative reverse transcription-polymerase chain reaction. RESULTS: (1) Control-HVCs attached to collagen IV more efficiently than POP-HVCs; (2) control-HVCs and POP-HVCs show a similar proliferation rate when plated on proNectin and collagen I; (3) when seeded on collagen I, resting POP-HVCs expressed significantly (P < .05) increased transcript levels of collagen VII, multiple matrix metalloproteinases (MMP3, MMP7, MMP10, MMP12, MMP13, and MMP14), integrins (ITGA1, ITGA4, ITGA6, ITGA8, ITGB1, ITGB2, and ITGB3), and cell adhesion molecules as compared to control-HVCs. Collagen XV and tissue inhibitors of MMPs (TIMP1 and TIMP2) as well as genes involved in the biogenesis and maturation of collagen and elastin fibers (LOX, LOXL1-LOXL3, BMP1, and ADAMTS2) were significantly downregulated in POP HVCs versus control-HVCs (P < .05). CONCLUSIONS: Resting primary POP-HVCs in vitro show altered cellular characteristics as compared to control-HVCs, which may influence their dynamic responses to external mechanical or hormonal stimuli. PMID- 26763526 TI - [Subcutaneous Taenia crassiceps-cysticercosis in a dog with Cushing's syndrome]. AB - A male, 12-year-old Cairn terrier suffering from Cushing's syndrome with two therapy-resistant inflammatory subcutaneous lesions was examined pathomorphologically and parasitologically. Within the subcutaneous tissue, there was a suppurative to necrotizing and histiocytic inflammation present with the formation of caverns. Intralesional whitish-grey cysts with a diameter of 1-4 mm were detected. Molecular investigations of the cysts confirmed the preliminary morphological identification as Cysticercus longicollis. The adenohypophysis showed an infiltrative growing carcinoma. Cysticercus longicollis is the metacestode of Taenia (T.) crassiceps, a tapeworm of foxes and coyotes. Small rodents are typical intermediate hosts, in which the metacestode develops within the body cavities as well as in the subcutis. Subcutaneous cysticercosis after infection with eggs of T. crassiceps is also described in different domestic animal species and in humans, who represent aberrant intermediate hosts. Immunosuppression due to Cushing's syndrome, probably caused by the tumor of the adenohypophysis, may have played a role in the pathogenesis of the present case. PMID- 26763527 TI - Biodegradable poly-3-hydroxybutyrate as a fertiliser carrier. AB - BACKGROUND: Increasing use of mineral fertilisers can lead to accumulation of fertilisers in soil, water and foodstuffs. One of the approaches to preventing these problems is to develop controlled release forms of fertilisers. RESULTS: Experimental formulations of the nitrogen fertiliser urea loaded in a degradable matrix of the natural polymer poly-3-hydroxybutyrate (P3HB) in the form of films, pellets and coated granules were constructed and investigated. Nitrogen release into soil occurred as the polymer was degraded, and it was dependent on the geometry of the carrier and the amount of nitrogen loaded in it, showing that nitrogen release can last for 30 days or longer and that release rates can be controlled by varying the fabrication technique employed. P3HB/urea formulations have a favourable effect on the soil microbial community. The use of embedded urea has a beneficial influence on the growth of creeping bentgrass (Agrostis stolonifera) and lettuce (Latuca sativa) and reduces removal of nitrogen with drain water. CONCLUSION: The slow-release nitrogen formulations developed in this study can be buried in soil together with seeds preventing nitrogen deficiency. The use of such slow-release formulations can decrease the amounts of chemicals in the environment and prevent their adverse effects on the biosphere. (c) 2016 Society of Chemical Industry. PMID- 26763530 TI - Palladium-Catalyzed Site-Selective C-H Functionalization of Weakly Coordinating Sulfonamides: Synthesis of Biaryl Sulfonamides. AB - A novel and site selective C-H functionalization of unsubstituted sulfonamides has been developed for the synthesis of ortho aryl sulfonamides. The reaction involves highly regioselective ortho mono arylation of weakly coordinating SO2 NH2 directing group by means of aryl iodides. Palladium acetate in the presence of silver(I) oxide is found to be the most effective catalytic system. PMID- 26763529 TI - Evaluation of surface roughness of the bracket slot floor--a 3D perspective study. AB - BACKGROUND: An important constituent of an orthodontic appliance is orthodontic brackets. It is either the bracket or the archwire that slides through the bracket slot, during sliding mechanics. Overcoming the friction between the two surfaces demands an important consideration in an appliance design. The present study investigated the surface roughness of four different commercially available stainless steel brackets. METHODS: All tests were carried out to analyse quantitatively the morphological surface of the bracket slot floor with the help of scanning electron microscope (SEM) machine and to qualitatively analyse the average surface roughness (Sa) of the bracket slot floor with the help of a three dimensional (3D) non-contact optical surface profilometer machine. RESULTS: The SEM microphotographs were evaluated with the help of visual analogue scale, the surface roughness for group A = 0-very rough surface, group C = 1--rough surface, group B = 2--smooth surface, and group D = 3-very smooth surface. Surface roughness evaluation with the 3D non-contact optical surface profilometer machine was highest for group A, followed by group C, group B and group D. Groups B and D provided smooth surface roughness; however, group D had the very smooth surface with values 0.74 and 0.75 for mesial and distal slots, respectively. CONCLUSIONS: Evaluation of surface roughness of the bracket slot floor with both SEM and profilometer machine led to the conclusion that the average surface roughness was highest for group A, followed by group C, group B and group D. PMID- 26763528 TI - Surgical treatment of adolescent internal condylar resorption (AICR) with articular disc repositioning and orthognathic surgery in the growing patient--a pilot study. AB - BACKGROUND: The aim of this study was to better understand how surgical repositioning and stabilization of anteriorly displaced articular discs using the Mitek mini-anchor technique affects condylar growth in growing patients with adolescent internal condylar resorption (AICR). METHODS: Twenty-two adolescent patients diagnosed with AICR and anterior temporomandibular disc displacement were compared to untreated control subjects without AICR matched for age, sex, and Angle classification. Pre-surgical (T1 and T2) and post-surgical (T3 and T4) mandibular tracings were superimposed on natural stable structures to evaluate the horizontal, vertical, and total changes in the position of condylion. RESULTS: The treated group showed an overall decrease in condylar height pre surgically and statistically significant changes in condylar growth direction between the pre- and post-surgical observation periods. Pre-surgically, the treated group showed significantly more posterior condylar growth than the control group; they also showed inferior condylar growth, while the controls showed superior growth. Controls and patients in the treated group showed no significant differences in condylar growth post-surgically. CONCLUSIONS: Adolescent patients diagnosed with AICR and anterior disc displacement treated with mandibular ramus and maxillary osteotomies, along with Mitek anchors to reposition internally deranged discs, showed post-surgical normalization of condylar growth. PMID- 26763531 TI - Nutritional effects on reproductive performance of captive adult female coyotes (Canis latrans). AB - Interactions between animals and their environment are fundamental to ecological research. Field studies of coyote (Canis latrans) reproductive performance suggest mean litter size changes in response to prey abundance. However, this relationship has been assessed primarily by using carcasses collected from trappers. The objective of this study was to assess whether nutritional manipulation prior to mating affected reproduction in adult female coyotes. We examined the effects of caloric restriction during the 7 months prior to estrus on the reproductive rates of 11 captive female coyotes and the subsequent initial survival of pups through two reproductive cycles. This was a 2-year study with a cross-over design so each female was monitored for reproductive performance on each of the two diet treatments. We assessed the number of implantation scars, number of pups born, sex ratios of pups, average pup weight at birth and 2- and 6 weeks of age, and the survival rates between implantation and 2-weeks of age for two diet treatments. We found the mean number of implantation sites and pups whelped during a reproductive cycle was influenced by food-intake prior to conception. Additionally, we found evidence suggesting the effects of nutritional stress may persist for additional breeding cycles. We also provided evidence suggesting well-fed females tended to have more male pups. Understanding how environmental factors influence reproductive output may improve model predictions of coyote population dynamics. PMID- 26763532 TI - Leucine-enkephalin promotes wound repair through the regulation of hemidesmosome dynamics and matrix metalloprotease. AB - The skin responds to environmental stressors by coordinated actions of neuropeptides and their receptors. An endogenous peptide for delta-opioid receptor (DOPr), Leu-enkephalin (L-ENK), is expressed in the skin and its expression is altered in pathological conditions. Although the importance of DOPr is rapidly gaining recognition, the molecular mechanisms underlying its effects on wound healing are largely undefined. We show here that L-ENK induced activation of Erk, P90(RSK), and Elk-1 and promoted the disruption of hemidesmosomes and the expression of matrix metalloprotease (MMP)-2 and MMP-9, important processes for wound healing. Treatment with Erk inhibitor blocked activation of P90(RSK) and Elk-1 and significantly blunted wound repair. Therefore, our results suggest that activation of Erk and its downstream effectors, P90(RSK) and Elk-1, are critical for DOPr-mediated skin homeostasis. PMID- 26763534 TI - Simulated Patients and Scenarios to Assess and Teach Psychiatry Residents. PMID- 26763535 TI - Discrepancy between the composition of some commercial cat foods and their package labelling and suitability for meeting nutritional requirements. AB - OBJECTIVE: To investigate if the label information and nutrient composition of commercial cat foods are accurate and compliant with the Australian Standard (AS 5812-2011) and if they meet the nutritional requirements of an adult cat. METHODS: A chemical analysis of 10 wet and 10 dry commercial cat foods labelled as 'nutritionally complete' for the adult cat was performed. The results were compared with the package composition values, the Australian Standard and the unique dietary requirements of the cat. In addition, the results of the chemical analysis were compared with the nutrient requirements published by the Association of the American Feed Control Officials and the National Research Council. RESULTS: When compared with the Australian Standard, 9 of the 20 cat foods did not adhere to their 'guaranteed analysis' and 8 did not adhere to the standards for nutrient composition. Also, various deficiencies and excesses of crude protein, crude fat, fatty acid and amino acid were observed in the majority of the cat foods. CONCLUSIONS: The results of this study highlight a need for an improved method of ensuring that label information and nutrient composition are accurate and comply with the Australian Standard (AS 5812-2011) to ensure the adult cat's unique dietary requirements are being met by commercial adult cat food. PMID- 26763536 TI - Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma. AB - Increased lipid droplet number and fatty acid synthesis allow glioblastoma multiforme, the most common and aggressive type of brain cancer, to withstand accelerated metabolic rates and resist therapeutic treatments. Lipid droplets are postulated to sequester hydrophobic therapeutic agents, thereby reducing drug effectiveness. We hypothesized that the inhibition of lipid droplet accumulation in glioblastoma cells using pyrrolidine-2, a cytoplasmic phospholipase A2 alpha inhibitor, can sensitize cancer cells to the killing effect of curcumin, a promising anticancer agent isolated from the turmeric spice. We observed that curcumin localized in the lipid droplets of human U251N glioblastoma cells. Reduction of lipid droplet number using pyrrolidine-2 drastically enhanced the therapeutic effect of curcumin in both 2D and 3D glioblastoma cell models. The mode of cell death involved was found to be mediated by caspase-3. Comparatively, the current clinical chemotherapeutic standard, temozolomide, was significantly less effective in inducing glioblastoma cell death. Together, our results suggest that the inhibition of lipid droplet accumulation is an effective way to enhance the chemotherapeutic effect of curcumin against glioblastoma multiforme. PMID- 26763537 TI - Dyslipidaemia in 2015: Advances in treatment of dyslipidaemia. PMID- 26763538 TI - Cardiac resuscitation in 2015: Improving outcomes after OHCA--targeting the layperson. PMID- 26763539 TI - Genetics of CVD in 2015: Using genomic approaches to identify CVD-causing variants. PMID- 26763540 TI - Coronary intervention in 2015: Improvement of long-term outcomes after PCI. PMID- 26763541 TI - Testing of candidate single nucleotide variants associated with paclitaxel neuropathy in the trial NCCTG N08C1 (Alliance). AB - Paclitaxel-induced peripheral neuropathy (PIPN) cannot be predicted from clinical parameters and might have a pharmacogenomic basis. Previous studies identified single nucleotide variants (SNV) associated with PIPN. However, only a subset of findings has been confirmed to date in more than one study, suggesting a need for further re-testing and validation in additional clinical cohorts. Candidate PIPN associated SNVs were identified from the literature. SNVs were retested in 119 patients selected by extreme phenotyping from 269 in NCCTG N08C1 (Alliance) as previously reported. SNV genotyping was performed by a combination of short-read sequencing analysis and Taqman PCR. These 22 candidate PIPN SNVs were genotyped. Two of these, rs7349683 in the EPHA5 and rs3213619 in ABCB1 were found to be significantly associated with PIPN with an Odds ratios OR = 2.07 (P = 0.02) and OR = 0.12 (P = 0.03), respectively. In addition, three SNVs showed a trend toward a risk- or protective effect that was consistent with previous reports. The rs10509681 and rs11572080 in the gene CYP2C8*3 showed risk effect with an OR = 1.49 and rs1056836 in CYP1B1 showed a protective effect with an OR = 0.66. None of the other results supported the previously reported associations, including some SNVs displaying an opposite direction of effect from previous reports, including rs1058930 in CYP2C8, rs17222723 and rs8187710 in ABCC2, rs10771973 in FGD4, rs16916932 in CACNB2 and rs16948748 in PITPNA. Alliance N08C1 validated or supported a minority of previously reported SNV-PIPN associations. Associations previously reported by multiple studies appeared to have a higher likelihood to be validated by Alliance N08C1. PMID- 26763542 TI - Couple's infertility in relation to male smoking in a Chinese rural area. AB - Smoking is a well-known risk factor of reproductive health. However, the effect of paternal smoking on fertility has been less extensively examined. We conducted a cross-sectional study in a mountainous area of South-West China to assess the effect of male smoking on couples' fertility. A total of 8200 couples aged 18-49 years in the study area were invited to participate in the study. An in-person interview was performed to collect demographic characteristics of the couples, and husbands' life style factors including smoking and drinking habits. Information on time to pregnancy (TTP) was collected retrospectively. Infertility was defined as failure to achieve clinical pregnancy after regular unprotected intercourse for >=12 months. Logistic regression model was used to estimate the association between male smoking and infertility. A total of 7025 couples were included in the final analysis. After adjusting for potential confounders, the couples were more likely to suffer from infertility if the husbands smoked (adjusted odds ratio [aOR] =1.28, 95% CI: 1.08-1.52) before the first pregnancy. After the analyses were performed according to husbands' smoking duration, an increased risk started at a relatively longer smoking duration of 5-10 years (aOR = 1.58, 95% CI: 1.26-1.99) and a stronger association (aOR = 3.34, 95% CI: 2.45 4.56) was observed in the group of >=10 years. Similar patterns were found for the number of cigarettes smoked per day and the total amount of cigarettes smoked. From our findings, we conclude that male smoking may have an adverse impact on couples' infertility. PMID- 26763543 TI - beta-defensins and the epididymis: contrasting influences of prenatal, postnatal, and adult scenarios. AB - beta-defensins are components of host defense, with antimicrobial and pleiotropic immuno-modulatory properties. Research over the last 15 years has demonstrated abundant expression of a variety of beta-defensins in the postnatal epididymis of different species. A gradient of region- and cell-specific expression of these proteins is observed in the epithelium of the postnatal epididymis. Their secretion into the luminal fluid and binding to spermatozoa as they travel along the epididymis has suggested their involvement in reproduction-specific tasks. Therefore, continuous attention has been given to various beta-defensins for their role in sperm function and fertility. Although beta-defensins are largely dependent on androgens, the underlying mechanisms regulating their expression and function in the epididymis are not well understood. Recent investigation has pointed out to a new and interesting scenario where beta-defensins emerge with a different expression pattern in the Wolffian duct, the embryonic precursor of the epididymis, as opposed to the adult epididymis, thereby redefining the concept concerning the multifunctional roles of beta-defensins in the developing epididymis. In this review, we summarize some current views of beta-defensins in the epididymis highlighting our most recent data and speculations on their role in the developing epididymis during the prenatal-to-postnatal transition, bringing attention to the many unanswered questions in this research area that may contribute to a better understanding of epididymal biology and male fertility. PMID- 26763544 TI - Potential role of punicalagin against oxidative stress induced testicular damage. AB - Punicalagin is isolated from pomegranate and widely used for the treatment of different diseases in Chinese traditional medicine. This study aimed to evaluate the effect of Punicalagin (purity >=98%) on oxidative stress induced testicular damage and its effect on fertility. We detected the antioxidant potential of punicalagin in lipopolysaccharide (LPS) induced oxidative stress damage in testes, also tried to uncover the boosting fertility effect of Punicalagin (PU) against oxidative stress-induced infertility. Results demonstrated that 9 mg kg-1 for 7 days treatment significantly decreases LPS induced oxidative damage in testes and nitric oxide production. The administration of oxidative stress resulted in a significant reduction in testes antioxidants GSH, T-SOD, and CAT raised LPO, but treatment with punicalagin for 7 days increased antioxidant defense GSH, T-SOD, and CAT by the end of the experiment and reduced LPO level as well. PU also significantly activates Nrf2, which is involved in regulation of antioxidant defense systems. Hence, the present research categorically elucidates the protective effect of punicalagin against LPS induced oxidative stress induced perturbation in the process of spermatogenesis and significantly increased sperm health and number. Moreover, fertility success significantly decreased in LPS injected mice compared to controls. Mice injected with LPS had fertility indices of 12.5%, while others treated with a combination of PU + LPS exhibited 75% indices. By promoting fertility and eliminating oxidative stress and inflammation, PU may be a useful nutrient for the treatment of infertility. PMID- 26763545 TI - Two paths for stabilization of ERG in prostate carcinogenesis: TMPRSS2-ERG fusions and speckle-type pox virus and zinc finger protein mutations. PMID- 26763546 TI - Effects of obstructive sleep apnea and its treatment over the erectile function: a systematic review. AB - Erectile dysfunction (ED) is considered a condition with a broad range of etiologies. Obstructive sleep apnea (OSA) syndrome is one of the lesser studied risk factors for ED. We intend to summarize the current evidence on the relationship between OSA and sexual impairment, focusing on the results in terms of erectile function of the different therapies offered to OSA patients. A systematic review was conducted, selecting articles related to the physiology of OSA and ED, and to the treatments of OSA syndrome and their reported outcomes in erectile and sexual function. Higher prevalences of ED in the OSA groups have been published. However, whether this effect on the erectile function occurs in the entire range of OSA severities remains unclear. Several hypotheses were proposed to explain the physiology of this association. Continuous Positive Airway Pressure as a treatment for OSA patients with ED has achieved a significative improvement in the sexual parameters in most of the studies. Phosphodiesterase type 5 inhibitors (iPDE5) on demand are useful as a treatment for ED in this subgroup of patients, with high satisfaction rates. The surgical treatment for the OSA evidenced benefits over the erectile function, and the effect on the sexual satisfaction of the therapy using Mandibular Advancement Devices is still undefined. PMID- 26763547 TI - Dietary n-6:n-3 ratio and Vitamin E improve motility characteristics in association with membrane properties of boar spermatozoa. AB - This study was aimed to evaluate the effects of dietary n-6:n-3 ratio and Vitamin E on the membrane properties and motility characteristics of spermatozoa in boars. Forty Duroc boars were randomly distributed in a 2 * 2 factorial design with two n-6:n-3 ratios (14.4 and 6.6) and two Vitamin E levels (200 and 400 mg kg-1 ). During 16 weeks of treatment, fresh semen was collected at weeks 0, 8, 12, and 16 for measurements of motility characteristics, contents of fatty acids, membrane properties (membrane fluidity and membrane integrity), and lipid peroxidation of the spermatozoa. The semen was diluted in Beltsville Thawing Solution (BTS) extender and stored at 17 degrees C, and the sperm motility was assessed at 12, 36, 72, and 120 h of storage. The 6.6 n-6:n-3 dietary ratio increased the contents of n-3 polyunsaturated fatty acids (PUFAs) and docosahexaenoic acid (DHA) and improved the membrane integrity and membrane fluidity of the spermatozoa, resulting in notably increased total motility, sperm progressive motility, and velocity parameters of fresh semen. Feeding diet with Vitamin E (400 mg kg-1 ) prevented sperm lipid peroxidation, and resulted in higher total motility and sperm progressive motility in fresh and liquid stored semen. In conclusion, the adjustment of n-6:n-3 ratio (6.6) and supply of Vitamin E (400 mg kg-1 ) successfully improved sperm motility characteristics and thus may be beneficial to the fertility of boars, which might be due to the modification of the physical and functional properties of spermatozoa membrane in response to dietary supplementation. PMID- 26763548 TI - A possible relationship between serum sex hormones and benign prostatic hyperplasia/lower urinary tract symptoms in men who underwent transurethral prostate resection. AB - In this study, we examined the relationship between sex hormone levels and lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) who underwent transurethral surgery. The study was conducted in 158 patients who came to our hospital for surgery. Clinical conditions were assessed by body mass index (BMI), digital rectal examination, International Prostate Symptom Score (IPSS) and transrectal ultrasound (TRUS). The levels of sex hormones (including total testosterone (TT), estradiol (E 2 ), progesterone (P), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL)) and prostate-specific antigen (PSA) were reviewed. Correlations were determined through statistical analysis. The mean age was 72.06 +/- 8.68 years. The total IPSS was significantly associated with the TT level (r = -0.21, P= 0.01). Other sex hormone levels were not correlated with total IPSS. However, some ratios such as E 2 / TT (r = 0.23, P= 0.00) and FSH/LH (r = -0.17, P = 0.04) were associated with total IPSS. Further analysis showed that the nocturia was associated with age (r = 0.16, P= 0.04), BMI (r = 0.21, P = 0.01), and TT (r = -0.19, P= 0.02). Moreover, we divided the patients into two subgroups based on IPSS severity (<20 or >=20). The mean TT level was in the normal range, but it was significantly related to the presence of severe LUTS. In summary, our study has shown that the severity of LUTS is associated with TT, E 2 / TT and FSH/LH in men who underwent prostate surgery. Increasing nocturia was observed in lower testosterone patients. Additional larger studies are needed to elucidate the potential mechanisms. PMID- 26763549 TI - An update on the role of medical treatment including antioxidant therapy in varicocele. AB - Varicocele-associated male infertility has classically been managed using surgery or assisted reproductive techniques. With increasing evidence of oxidative stress as a pathophysiological factor in varicocele-associated infertility, medical therapy especially antioxidants might become a treatment option with lower risks. We reviewed the existing literature on the role of various medical agents in the management of male infertility attributed to varicoceles. Medical therapy is typically evaluated in three different situations such as (a) comparison of two drugs or one drug with placebo, (b) comparison of drugs versus surgery, and (c) comparison of drugs as adjuvant therapy with surgery versus drug therapy alone. Due to heterogeneity of data and lack of well-conducted studies, there is insufficient data to recommend routine use of medical therapy for men with varicocele-associated infertility and surgery remains the treatment of choice. Pregnancy and live birth rates are usually not reported in most studies and mere improvement in sperm parameters or antioxidant capacity is insufficient to support its routine use. Antioxidant therapy is a potential option due to its theoretical benefit, data from preclinical studies, and lack of major side effects. Adjuvant therapy with antioxidants after surgical repair of varicocele may improve the outcome and is a potential area for further research. PMID- 26763550 TI - Antegrade scrotal sclerotherapy of internal spermatic veins for varicocele treatment: technique, complications, and results. AB - Varicocele repair is mainly indicated in young adult patients with clinical palpable varicocele and abnormal semen parameters. Varicocele treatment is associated with a significant improvement in sperm concentration, motility, morphology, and pregnancy rate. Antegrade scrotal sclerotherapy (ASS) represented one of the main alternatives to the traditional inguinal or suprainguinal surgical ligation. This article reviews the use of ASS for varicocele treatment. We provide a brief overview of the history of the procedure and present our methods used in ASS. In addition, we review complication and success of ASS, including our own retrospective data of treating 674 patients over the last 17 years. Herein, we analyzed step by step the ASS technique and described our results with an original modified technique with a long follow-up. Between December 1997 and December 2014, we performed 674 ASS. Mean operative time was 14 min (range 9 to 50 min). No significant intraoperative complications were reported. Within 90 days from the procedure, postoperative complications were recorded in overall 49 (7.2%) patients. No major complications were recorded. A persistent/recurrent varicocele was detected in 40 (5.9%) cases. In 32/40 (80%) cases, patients showed preoperative grade III varicoceles. In patients with a low sperm number before surgery, sperm count improved from 13 * 10 6 to 21 * 10 6 ml 1 (P < 0.001). The median value of the percentage of progressive motile forms at 1 h improved from 25% to 45% (P < 0.001). Percentage of normal forms increased from 17% before surgery to 35% 1 year after the procedure (P < 0.001). In the subgroup of the 168 infertile patients, 52 (31%) fathered offspring at a 12-month minimum follow-up. Therefore, ASS is an effective minimal invasive treatment for varicocele with low recurrence/persistence rate. PMID- 26763551 TI - Epidemiology of varicocele. AB - Varicocele is a common problem in reproductive medicine practice. A varicocele is identified in 15% of healthy men and up to 35% of men with primary infertility. The exact pathophysiology of varicoceles is not very well understood, especially regarding its effect on male infertility. We have conducted a systematic review of studies evaluating the epidemiology of varicocele in the general population and in men presenting with infertility. In this article, we have identified some of the factors that can influence the epidemiological aspects of varicoceles. We also recognize that varicocele epidemiology remains incompletely understood, and there is a need for well-designed, large-scale studies to fully define the epidemiological aspects of this condition. PMID- 26763552 TI - Age-Specific Normal Reference Range for Serum Anti-Mullerian Hormone in Healthy Chinese Han Women: A nationwide Population-Based Study. AB - BACKGROUND: The increasing use of anti-Mullerian hormone (AMH) in clinic has raised concerns regarding the reliable reference range for this test. However, the reference range for AMH in normal Chinese female population has not been established. Furthermore, relationship between AMH and other clinical markers such as body mass index (BMI) and antral follicle counts (AFCs) and other sex related hormones have not been examined in normal population-based women. OBJECTIVE: We aimed to determine the age-specific reference range for serum AMH in healthy Chinese women throughout reproductive age to menopause and to estimate relationship between AMH and other clinical markers in healthy women. STUDY DESIGN: In this multicenter and nationwide study, advertisements were used to recruit 2055 women, aged 20 to 55 years, from 6 different regions in China; 1590 (77.37%) women met the inclusion criteria for the reference range population. We measured the baseline serum AMH levels using new Beckman Coulter Gen II assay. Serum concentration of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), testosterone (T), prolactin (PRL), progesterone (PRG), and AFCs were also determined in the follicular phase. MAIN OUTCOME MEASURES: The AMH Age nomogram and AMH levels of different age-groups and the relationship between AMH and other clinical markers. RESULTS: Serum AMH concentrations declined progressively with age. A quadratic model defined as log (AMH) = (-1.970 + 0.296 * Age - 0.006 * Age(2)) fitted best the decline of AMH with age. The median AMH levels were 6.23, 5.65, 4.55, 3.74, 2.78, and 1.09 ng/mL for the 20 <= age < 25, 25 <= age < 30, 30 <= age < 33, 33 <= age < 37, 37 <= age < 40, and 40 <= age < 55 groups, respectively. The 5th to 95th percentiles of the AMH levels, as the reference range, were 2.06 to 12.66, 1.77 to 13.83, 1.48 to 11.45, 0.87 to 9.76, 0.56 to 9.49, and 0.08 to 5.70 ng/mL for each age-group. The AMH levels were positively correlated with AFCs and T, LH, PRL and PRG levels and negatively correlated with BMI and FSH levels and were not significantly correlated with E2 levels. The relationship between AMH and other variables remain unchanged except for PRL, which was not significantly correlated with AMH levels after controlling for both age and BMI. CONCLUSIONS: This study determined the normal reference ranges for serum AMH levels in a large population-based sample of healthy Chinese women. PMID- 26763553 TI - Overexpression of HOXC8 is Associated With Poor Prognosis in Epithelial Ovarian Cancer. AB - Homeobox C8 (HOXC8) is a transcription factor that has been reported as a potential driver oncogene in several tumors and involved in the regulation of many cancer-related proteins. In this study, we investigated the expression and role of HOXC8 in ovarian cancer. Western blot and immunohistochemistry analyses were performed to detect the expression of HOXC8. Kaplan-Meier curve showed that high expression of HOXC8 was related to poor prognosis of patients with epithelial ovarian cancer (EOC). Starvation and refeeding assay were used to assess cell cycle, suggesting that HOXC8 played a critical role in EOC cell proliferation. HOXC8 depletion by small interfering RNA inhibited cell proliferation, migration, and induced apoptosis in EOC cells. Moreover, HOXC8 knockdown increased the expression of ZAC1. Owing to the overexpression of HOXC8, our findings implied that HOXC8 is involved in the progression of EOC and could be a potential therapeutical approach of EOC. PMID- 26763554 TI - MicroRNA Expression is Altered in Granulosa Cells of Ovarian Hyperresponders. AB - Controlled ovarian stimulation plays an integral role in assisted reproduction technology, but individual patients have different responses to exogenous gonadotropins. In order to determine whether microRNAs (miRNAs) have a regulatory role in ovarian response, we profiled the expression of microRNAs in isolated ovarian granulosa cells collected from ovarian hyperresponders and normal responders using microarrays and validated the expression of selected miRNAs using quantitative polymerase chain reaction (PCR). There were 81 miRNAs differentially expressed between the 2 groups, with 45 increased and 36 decreased in the high response group. Bioinformatics analysis of these altered miRNAs and their target genes revealed some significantly enriched pathways, including regulation of the cell cycle, transcription, cell proliferation, and gonadotrophin releasing hormone signaling pathway. The expression of hsa-miR-513a 5p, hsa-miR-27b-3p, hsa-miR-19b-3p, hsa-miR-3201, hsa-miR-423-5p, hsa-miR-193b 5p, and hsa-miR-202-3p was validated by real-time PCR. Hsa-miR-423-5p, predicted to target anti-Mullerian hormone, cytochrome P450, family 19, subfamily A, polypeptide 1, methylenetetrahydrofolate reductase, progesterone receptor, and follicle stimulating hormone, beta-polypeptide was found to have significantly decreased expression in the hyperresponders (P = .023). Hsa-miR-193b-5p also showed a tendency to be significantly decreased in the hyperresponders (P = .093). In conclusion, our findings provide evidence for altered miRNA expression in granulosa cells of women with ovarian hyperresponse, suggesting a role of miRNAs in regulating ovarian response to gonadotropins. PMID- 26763555 TI - The role of habit in recurrent pressure ulcers following spinal cord injury. AB - BACKGROUND: Despite the existence of numerous prevention strategies, pressure ulcers remain highly prevalent in those with spinal cord injury (SCI). The concept of habit, broadly defined, may help understand the persistence of this problem and offer strategies for its mitigation by occupational therapy. AIM: The aim of this paper is to describe the relationship between habits established prior to sustaining an SCI and post-injury habits that impacted on pressure ulcer risk. METHODS: Secondary analysis of qualitative data collected during an ethnographic study of community-dwelling adults with SCI. RESULTS: Participants' habits appeared to substantially affect their risk of developing pressure ulcers. Habits established before incurring the SCI either facilitated or hindered the acquisition of new habits intended to prevent pressure ulcers. CONCLUSIONS: An understanding of the individual's pre-existing habits may be important when designing a rehabilitation programme intended to minimize risk of pressure ulcer development following SCI. Habit-change strategies could be used to supplement education in pressure ulcer prevention techniques. SIGNIFICANCE: Occupational therapists have a longstanding interest in habit. A more comprehensive understanding of this concept may provide important insights into the persistence and management of pressure ulcers following SCI. PMID- 26763557 TI - Interlayer electronic hybridization leads to exceptional thickness-dependent vibrational properties in few-layer black phosphorus. AB - Stacking two-dimensional (2D) materials into multi-layers or heterostructures, known as van der Waals (vdW) epitaxy, is an essential degree of freedom for tuning their properties on demand. Few-layer black phosphorus (FLBP), a material with high potential for nano- and optoelectronics applications, appears to have interlayer couplings much stronger than graphene and other 2D systems. Indeed, these couplings call into question whether the stacking of FLBP can be governed only by vdW interactions, which is of crucial importance for epitaxy and property refinement. Here, we perform a theoretical investigation of the vibrational properties of FLBP, which reflect directly its interlayer coupling, by discussing six Raman-observable phonons, including three optical, one breathing and two shear modes. With increasing sample thickness, we find anomalous redshifts of the frequencies for each optical mode but a blueshift for the armchair shear mode. Our calculations also show splitting of the phonon branches, due to anomalous surface phenomena, and strong phonon-phonon coupling. By computing uniaxial stress effects, inter-atomic force constants and electron densities, we provide a compelling demonstration that these properties are the consequence of strong and highly directional interlayer interactions arising from the electronic hybridization of the lone electron-pairs of FLBP, rather than from vdW interactions. This exceptional interlayer coupling mechanism controls the stacking stability of BP layers and thus opens a new avenue beyond vdW epitaxy for understanding the design of 2D heterostructures. PMID- 26763556 TI - Evaluating predictors of competing risk outcomes when censoring depends on time dependent covariates, with application to safety and efficacy of HIV treatment. AB - We propose a prediction model for the cumulative incidence functions of competing risks, based on a logit link. Because of a concern about censoring potentially depending on time-varying covariates in our motivating human immunodeficiency virus (HIV) application, we describe an approach for estimating the parameters in the prediction models using inverse probability of censoring weighting under a missingness at random assumption. We then illustrate the application of this methodology to identify predictors of the competing outcomes of virologic failure, an efficacy outcome, and treatment limiting adverse event, a safety outcome, among human immunodeficiency virus-infected patients first starting antiretroviral treatment. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26763559 TI - [Twenty years of progress in wound care]. PMID- 26763558 TI - The interpretation of hepatic venous pressure gradient tracings - excellent interobserver agreement unrelated to experience. AB - BACKGROUND AND AIMS: The hepatic venous pressure gradient (HVPG) plays an important role in the diagnosis, prognosis and therapy of patients with cirrhosis and portal hypertension. One barrier to its widespread use is the potential for a low reproducibility. We aimed to evaluate the interobserver agreement in the interpretation of optimally acquired HVPG tracings from patients with cirrhosis and different degrees of portal hypertension. METHODS: Two hundred and fifteen tracings obtained from 51 patients with cirrhosis in a single centre were interpreted independently by two hepatologists: one experienced observer and one inexperienced observer. Correlation was performed by Pearson linear regression and the intraclass correlation coefficient (ICC). A Bland-Altman plot was constructed to visualize how the differences between observers compared across the range of measurements. Logistic regression was used to identify predictors of >=10% variation between observers' readings. RESULTS: There was a significant linear relationship between observers' readings r = 0.98 (P = 0.001). The ICC between observers (interobserver agreement) was also excellent at 0.991 (P = 0.001). Using the Bland-Altman technique, the mean difference between the observers' readings was 0.2 mmHg (95% CI: -1.2 mmHg to 1.6 mmHg). Thirteen per cent of all readings and 9% of readings with an HVPG of >=10 mmHg differed by >=10%. As expected, a lower baseline HVPG was a predictor of this variability. CONCLUSIONS: Interobserver reproducibility in the assessment of optimally acquired HVPG tracings is excellent without differences related to experience. The data provide further support that the HVPG can be used accurately in clinical and research settings. PMID- 26763560 TI - [Cross-disciplinary support for a patient at the end of life]. AB - A follow-up and rehabilitation care team implemented concerted, cross disciplinary support with a patient nearing the end of her life. Working closely with the patient and her family, caregivers provided personalised palliative care. This account by members of the team shows the importance of the technical and relational dimensions in this context. PMID- 26763561 TI - [Professionalizing the management of strokes]. AB - A stroke is a life threatening emergency requiring fast access to medical care and to a technical support centre. Health professionals are trained in the complexity of this care. Preventive care and educational activities are developed in emergency departments, notably in neurovascular units, thereby contributing to the prevention of complications and the risk of repeat strokes. PMID- 26763562 TI - [Choosing the proper dressing, a nursing approach]. PMID- 26763563 TI - [Hydrocellular dressings, 25 years of evolution]. AB - Hydrocellular dressings have evolved considerably over the last 25 years. Manufacturers have worked to increase their absorbency, to make them easier for caregivers to use and to improve their comfort for the patients. This class now comprises a diverse range of dressings. Their inclusion on the list of products and services approved for reimbursement, given the low level of evidence provided by the clinical studies currently available, depends on their technical characteristics assessed in vitro. PMID- 26763564 TI - [Debridement dressings]. AB - For any wound, necrosis is an obstacle to the formation of granulation tissue and creates an environment which is particularly favourable to the proliferation of bacteria. Mechanical debridement, carried out by a doctor or nurse, or surgical debridement, is usually necessary. It is completed by autolytic debridement using technical dressings. Among the many modern dressings designed on the principle of the moist healing environment, some are more adapted to the debridement phase and are recommended by the French National Authority for Health. PMID- 26763565 TI - [Neutral and impregnated dressings and products]. AB - Dressings without active ingredients are adapted to each stage of healing, depending on their degree of moisture, their absorption capacity and their non traumatic character. Impregnated and mechanical dressings are also available. They are indicated for preventing or treating a symptom or a complication, or for "boosting" healing, in the form of a sequential treatment. Understanding their composition enables their indications to be better targeted thereby improving the efficacy of the overall wound management. PMID- 26763566 TI - [Dressings for superficial wounds]. AB - The main dressings for superficial wounds are hydrocolloids, interfaces, greasy dressings, hydrocellular dressings, metalloprotease inhibitors and hyaluronic acid dressings. There are pros and cons specific to each type and their use depends on the particularities of the superficial wounds. PMID- 26763567 TI - [Dressings for malodorous wounds]. AB - While sensitivity to odours varies from one individual to another, bad smells can instinctively and uncontrollably induce nausea and revulsion. Different treatment strategies can be implemented. They consist in neutralising the odours, adding more pleasant smells and/or targeting the bacteria. The management of odours remains a complex problem without any universal or single solution. Odour control must not be used as a replacement for adapted hygiene and wound care. PMID- 26763569 TI - [The prescribing of dressings]. AB - Dressings must be prescribed as accurately as possible, whether the prescription is written by a nurse or by a doctor. The pharmacist is then able to dispense the exact product prescribed. Knowledge of the different classes of dressings and their indications ensures the adapted management of chronic and acute wounds. PMID- 26763568 TI - [Negative pressure wound therapy dressings]. AB - There are many different forms of negative pressure wound therapy dressings and it is important to distinguish clearly between each type. They enable the treatment to be adapted to the shape and depth of the wound, its degree of exudation and the persistence of the fibrinous areas on the surface. The machine's traction capacity, measured in mm of mercury (Hg), must be controlled to establish the healing profile: the more powerful the machine and the more contact there is between the foam and the wound, the faster the formation of the granulation tissue. There are many different solutions which are implemented in accordance with the clinical assessment of the wound. PMID- 26763570 TI - [Secondary dressings]. AB - Wound management imposes a defined approach to each phase of healing and thereby the need for in-depth knowledge of the various medical devices available: primary and secondary dressings. Secondary dressings are essential as they have an impact on the efficacy of the primary dressing. Their role is to protect, reinforce and cover the primary dressing. In practice, it is usually nurses who have the responsibility of selecting and prescribing the most suitable dressing for the wound. PMID- 26763571 TI - [Improper use of dressings]. AB - Neither nurses nor doctors receive initial training in wounds and the use of dressings. They are however required in their daily practice to provide this type of care. Advances in wound healing techniques and the appearance of "modern" dressings offer a wide range of solutions to caregivers. Professionals must acquire skills in this area and make the best possible use of the dressings at their disposal to optimise the controlled wound healing. PMID- 26763572 TI - [Dressings of the future]. PMID- 26763573 TI - [Meta-synthesis]. AB - Nursing science's body of knowledge is mainly composed of the results of qualitative studies which, since the 1970s, have contributed notably to improving understanding of patients' experiences. This abundant scientific literature enables reviews to be carried out with the aim of producing solid theories. Meta synthesis is a methodology which was created for this purpose. The theories which it produces constitute reference frameworks for researchers wishing to develop innovative nursing procedures and to test them within the context of clinical studies. PMID- 26763574 TI - An Improved Suture Technique for Perform Biliary Reconstruction in Orthotopic Liver Transplantation. AB - BACKGROUND: The biliary anastomosis remains to be the Achilles' heel of liver transplantation. The incidence of biliary complications (e.g., stenosis and leakage) is immanent and the optimal type of reconstruction is unclear. The aim of this study was to compare 2 different bile duct suture techniques regarding their benefits in the prevention of biliary complications. MATERIAL AND METHODS: From 1992 to 2012, the transplanted patients (n=394) of our center were analyzed retrospectively in terms of suture techniques and consecutive biliary complications. Secondary, possible risk factors (cold ischemic time, donor age, and preoperative liver function) were examined. An end-to-end choledocho choledochostomy without T-tube was performed during orthotopic liver transplantation whenever possible. In group 1 (n=123) the biliary reconstruction was performed completely by continuous-suture technique. In group 2 (n=164) continuous-suture technique was also performed in posterior wall of the bile duct, but the anterior wall was closed by interrupted-suture technique. RESULTS: The overall biliary complication rate was 19.6%. There were no significant differences in biliary complications between the groups. Analysis of risk factors showed no influence on the complication rate. CONCLUSIONS: The argument for the interrupted-suture technique is a better overview and a lower risk to grab the posterior wall during the anastomotic realization. The threads of the anterior wall can be presented individually and then be knotted. PMID- 26763575 TI - Determination of the ratio of fluorophore/nanoparticle for fluorescence-labelled nanoparticles. AB - Optical analysis based on fluorescence labeling has been extensively used for the selective tagging of a wide range of biomedical important targets or for sensing purposes. Fluorescent nanoparticles (NPs) offer interesting properties as labels, as they can be also used as active labels that change their properties upon changes in the environment, such as pH- or distance-dependent fluorescence. In case NPs are not intrinsically fluorescent, they can be made fluorescent by attaching fluorophores to their volume and/or surface. Dye-labelled NPs can produce a highly amplified optical signal compared to a single dye molecule, as there are many dye molecule attached to each NP, providing a great improvement in analytical sensitivity. However, an appropriate control to quantify the fluorophore/NP ratio is required to succeed in the preparation of quantitative platforms matching the required application. Here a methodology to determine such parameter, the fluorophore/NP ratio, is presented. The methodology combines data obtained from UV/Vis absorption spectroscopy for determination of the dye concentration and inductively coupled plasma-mass spectrometry (ICP-MS) analysis for determination of the NP concentration. To validate the approach, it has been applied to the analysis of different sets of fluorophore-NP conjugates prepared using diverse fluorescent dyes (i.e. fluorophores with different structures and emissions) and several types of NPs (i.e. PbS QDs, Au NPs and FePt NPs). The fluorophore-NP conjugates hereby were designed to incorporate the dye directly into an amphiphilic polymer coating. The developed methodology allows for quantification of fluorophore-NP coupling, and therefore, opens up the possibility of selecting controlled conjugates. PMID- 26763576 TI - A Method to Evaluate Critical Factors for Successful Implementation of Clinical Pathways. AB - OBJECTIVE: Clinical pathways (CPs) have been viewed as a multidisciplinary tool to improve the quality and efficiency of evidence-based care. Despite widespread enthusiasm for CPs, research has shown that many CP initiatives are unsuccessful. To this end, this study provides a methodology to evaluate critical success factors (CSFs) that can aid healthcare organizations to achieve successful CP implementation. DESIGN: This study presents a new approach to evaluate CP implementation CSFs, with the aims being: (1) to identify CSFs for implementation of CPs through a comprehensive literature review and interviews with collaborative experts; (2) to use a filed study data with a robust fuzzy DEMATEL (the decision making trial and evaluation laboratory) approach to visualize the structure of complicated causal relationships between CSFs and obtain the influence level of these factors. PARTICIPANTS: The filed study data is provided by ten clinical experts of a Chinese hospital. RESULTS: 23 identified CSF factors which are initially identified through a review of the literature and interviews with collaborative experts. Then, a number of direct and indirect relationships are derived from the data such that different perceptions can be integrated into a compromised cause and effect model of CP implementation. CONCLUSIONS: The results indicate that the proposed approach can systematically evaluate CSFs and realize the importance of each factor such that the most common causes of failure of CP implementation could be eliminated or avoided. Therefore, the tool proposed would help healthcare organizations to manage CP implementation in a more effective and proactive way. PMID- 26763578 TI - The role of the SIBLING, Bone Sialoprotein in skeletal biology - Contribution of mouse experimental genetics. AB - Bone Sialoprotein (BSP) is a member of the "Small Integrin-Binding Ligand N linked Glycoproteins" (SIBLING) extracellular matrix protein family of mineralized tissues. BSP has been less studied than other SIBLING proteins such as Osteopontin (OPN), which is coexpressed with it in several skeletal cell types. Here we review the contribution of genetically engineered mice (BSP gene knockout and overexpression) to the understanding of the role of BSP in the bone organ. The studies made so far highlight the role of BSP in skeletal mineralization, as well as its importance for proper osteoblast and osteoclast differentiation and activity, most prominently in primary/repair bone. The absence of BSP also affects the local environment of the bone tissue, in particular hematopoiesis and vascularization. Interestingly, lack of BSP induces an overexpression of OPN, and the cognate protein could be responsible for some aspects of the BSP gene knockout skeletal phenotype, while replacing BSP for some of its functions. Such interplay between the partly overlapping functions of SIBLING proteins, as well as the network of cross-regulations in which they are involved should now be the focus of further work. PMID- 26763577 TI - Maternal protein restriction during pregnancy and lactation alters central leptin signalling, increases food intake, and decreases bone mass in 1 year old rat offspring. AB - The effects of perinatal nutrition on offspring physiology have mostly been examined in young adult animals. Aging constitutes a risk factor for the progressive loss of metabolic flexibility and development of disease. Few studies have examined whether the phenotype programmed by perinatal nutrition persists in aging offspring. Persistence of detrimental phenotypes and their accumulative metabolic effects are important for disease causality. This study determined the effects of maternal protein restriction during pregnancy and lactation on food consumption, central leptin sensitivity, bone health, and susceptibility to high fat diet-induced adiposity in 1-year-old male offspring. Sprague-Dawley rats received either a control or a protein restricted diet throughout pregnancy and lactation and pups were weaned onto laboratory chow. One-year-old low protein (LP) offspring exhibited hyperphagia. The inability of an intraperitoneal (i.p.) leptin injection to reduce food intake indicated that the hyperphagia was mediated by decreased central leptin sensitivity. Hyperphagia was accompanied by lower body weight suggesting increased energy expenditure in LP offspring. Bone density and bone mineral content that are negatively regulated by leptin acting via the sympathetic nervous system (SNS), were decreased in LP offspring. LP offspring did not exhibit increased susceptibility to high fat diet induced metabolic effects or adiposity. The results presented here indicate that the programming effects of perinatal protein restriction are mediated by specific decreases in central leptin signalling to pathways involved in the regulation of food intake along with possible enhancement of different CNS leptin signalling pathways acting via the SNS to regulate bone mass and energy expenditure. PMID- 26763579 TI - Congenital nasal neuroglial heterotopia and encephaloceles: An update on current evaluation and management. AB - OBJECTIVES/HYPOTHESIS: To describe our experience and current management approach for congenital nasal neuroglial heterotopia (NGH) and encephaloceles. STUDY DESIGN: Retrospective chart review at a tertiary pediatric hospital from 1970 to 2013. METHODS: Thirty patients met inclusion criteria: 21 NGH and nine encephaloceles. Data including demographics, pathology, imaging modality, surgical approach, resection extent, outcomes, and complications were analyzed. RESULTS: Fourteen NGH patients (67%) presented with an internal nasal mass and nasal obstruction. Three patients (14%) presented with an external nasal mass and four (19%) had a mixed lesion. Median age at surgery was 0.51 years (interquartile range 1.32 years). Thirteen (62%) had an intranasal endoscopic approach. Median operative time was 1.6 hours (interquartile range 1.2 hours), and there were no major complications. Nine patients with encephalocele were identified: six (67%) presented with transethmoidal encephaloceles, two (22%) presented with nasoethmoidal encephaloceles, and one (11%) presented with a nasofrontal lesion. The median age at surgery was 1.25 years (interquartile range 1.4 years). All patients required a craniotomy for intracranial extension. Median operative time was 5 hours (interquartile range 1.9 hours), and eight patients (88%) had a total resection. Length of stay ranged from 3 to 14 days. CONCLUSION: Nasal neuroglial heterotopia and encephaloceles are very rare lesions that require multidisciplinary evaluation and management. At our institution, there has been a shift to magnetic resonance imaging alone for the evaluation of NGH to avoid radiation exposure. Endoscopic extracranial resection is feasible for most intranasal and mixed NGH without an increase in operative time, residual disease, or complications. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2161-2167, 2016. PMID- 26763581 TI - Identification and characterization of novel HLA alleles: Utility of next generation sequencing methods. AB - The HLA genes are the most polymorphic of the human genome, and novel HLA alleles are continuously identified, often by clinical Sanger sequencing-based typing (SBT) assays. Introduction of next-generation sequencing (NGS) technologies for clinical HLA typing may significantly improve this process. Here we compare four cases of novel HLA alleles identified and characterized by both SBT and NGS. The tested NGS system sequenced broader regions of the HLA loci, and identified novel polymorphisms undetected by SBT. Subsequent characterization of the novel alleles in isolation of coencoded alleles by SBT required custom-designed primers, while the NGS system was able to sequence both alleles in phase. However, the tested assay was unable to amplify buccal cell DNA for subsequent NGS sequencing, presumably due to the lower quality of these samples. While NGS assays will undoubtedly increase novel allele identification, more stringent DNA sample requirements may be necessary for this new technology. PMID- 26763580 TI - Concise Review: Paracrine Role of Stem Cells in Pituitary Tumors: A Focus on Adamantinomatous Craniopharyngioma. AB - The existence of tissue-specific progenitor/stem cells in the adult pituitary gland of the mouse has been demonstrated recently using genetic tracing experiments. These cells have the capacity to differentiate into all of the different cell lineages of the anterior pituitary and self-propagate in vitro and can therefore contribute to normal homeostasis of the gland. In addition, they play a critical role in tumor formation, specifically in the etiology of human adamantinomatous craniopharyngioma, a clinically relevant tumor that is associated with mutations in CTNNB1 (gene encoding beta-catenin). Mouse studies have shown that only pituitary embryonic precursors or adult stem cells are able to generate tumors when targeted with oncogenic beta-catenin, suggesting that the cell context is critical for mutant beta-catenin to exert its oncogenic effect. Surprisingly, the bulk of the tumor cells are not derived from the mutant progenitor/stem cells, suggesting that tumors are induced in a paracrine manner. Therefore, the cell sustaining the mutation in beta-catenin and the cell-of origin of the tumors are different. In this review, we will discuss the in vitro and in vivo evidence demonstrating the presence of stem cells in the adult pituitary and analyze the evidence showing a potential role of these stem cells in pituitary tumors. PMID- 26763583 TI - [Restrictive ventricular septal defect in a dwarf rabbit]. AB - A 9-week-old intact female dwarf rabbit was presented for evaluation of a heart murmur. Physical examination revealed a grade IV/VI systolic heart murmur with the maximal intensity over the right heart base. Evidence for a left-sided cardiomegaly was present on lateral and dorsoventral radiographs. An electrocardiogram was recorded in right lateral recumbency, which revealed a sinus tachycardia with a heart rate of 360 beats/minute. Echocardiography showed normal dimensions for the atria and ventricles. Two-dimensional echocardiography confirmed the presence of a perimembranous ventricular septal defect (VSD) with a diameter of 0.8 mm. Identification of the VSD was possible from a right (long and short axes) and a left parasternal window. Peak flow velocity of the systolic left to right shunt was 5.2 m/s. Additionally, a relative pulmonic stenosis (peak flow in the pulmonary artery of 1.02 m/s, pulsed-wave Doppler) was present. According to these findings, the VSD was classified as restrictive. At this time point, medical treatment was unnecessary. The re-examination after 7 weeks revealed unchanged morphological and haemodynamic findings. The VSD in this dwarf rabbit displayed both in the physical and echocardiographic examinations typical features as seen in dogs and cats as well as in one New Zealand white rabbit. PMID- 26763582 TI - Culturally and linguistically diverse (CALD) carers' perceptions of oral care in residential aged care settings in Perth, Western Australia. AB - OBJECTIVE: The aims of the study were twofold: to explore African migrant carers' perceptions of oral health who worked in residential aged care and to investigate their perspectives of oral care for aged care residents. BACKGROUND: Culturally and linguistically diverse (CALD) carers are strongly represented in Australian residential aged care facilities. METHODS: Exploratory qualitative research targeted carers from African backgrounds working in residential aged care facilities in Perth, Western Australia. Fifteen African carers were recruited through community networks and participated in semistructured interviews. Data were analysed for key themes related to the study's aims noting similarities and differences between participants. RESULTS: All participants considered oral health important to individual well-being and quality of life. Most had limited knowledge of prevention and early detection of oral disease resulting from regular dental check-ups with the majority visiting dental professionals only for dental pain. Yet participants considered oral health care for residents needed improvement. Suggestions included dental professionals on staff and training and professional development for all staff not just in oral health care but also in working respectfully and sensitively with residents and staff from CALD backgrounds. CONCLUSION: Our findings suggest that, to ensure residents receive high quality oral health care, ongoing professional development is required, not only for CALD carers in oral health but also for non-CALD staff in care that is respectful of cultural differences. PMID- 26763584 TI - Autologous bone marrow stromal cell transplantation as a treatment for acute radiation enteritis induced by a moderate dose of radiation in dogs. AB - Radiation enteritis is one of the most common complications of cancer radiotherapy, and the development of new and effective measures for its prevention and treatment is of great importance. Adult bone marrow stromal stem cells (ABMSCs) are capable of self-renewal and exhibit low immunogenicity. In this study, we investigated ABMSC transplantation as a treatment for acute radiation enteritis. We developed a dog model of acute radiation enteritis using abdominal intensity-modulated radiation therapy in a single X-ray dose of 14 Gy. ABMSCs were cultured in vitro, identified via immunofluorescence and flow cytometry, and double labeled with CM-Dil and superparamagnetic iron oxide (SPIO) before transplantation, which took place 48 hours after abdominal irradiation in a single fraction. The dog model of acute radiation enteritis was transplanted with cultured ABMSCs labeled with CM-Dil and SPIO into the mesenteric artery through the femoral artery. Compared with untreated control groups, dogs treated with ABMSCs exhibited substantially longer survival time and improved relief of clinical symptoms. ABMSC transplantation induced the regeneration of the intestinal epithelium and the recovery of intestinal function. Furthermore, ABMSC transplantation resulted in elevated serum levels of the anti-inflammatory cytokine interleukin-11 (IL10) and intestinal radioprotective factors, such as keratinocyte growth factor, basic fibroblast growth factor-2, and platelet derived growth factor-B while reducing the serum level of the inflammatory cytokine IL17. ABMSCs induced the regeneration of the intestinal epithelium and regulated the secretion of serum cytokines and the expression of radioprotective proteins and thus could be beneficial in the development of novel and effective mitigators of and protectors against acute radiation enteritis. PMID- 26763585 TI - Magnetic resonance imaging as a potential biomarker for Parkinson's disease. AB - Although a magnetic resonance imaging (MRI) biomarker for Parkinson's disease (PD) remains an unfulfilled objective, there have been numerous developments in MRI methodology and some of these have shown promise for PD. With funding from the National Institutes of Health and the Michael J Fox Foundation there will be further validation of structural, diffusion-based, and iron-focused MRI methods as possible biomarkers for PD. In this review, these methods and other strategies such as neurochemical and metabolic MRI have been covered. One of the challenges in establishing a biomarker is in the selection of individuals as PD is a heterogeneous disease with varying clinical features, different etiologies, and a range of pathologic changes. Additionally, longitudinal studies are needed of individuals with clinically diagnosed PD and cohorts of individuals who are at great risk for developing PD to validate methods. Ultimately an MRI biomarker will be useful in the diagnosis of PD, predicting the course of PD, providing a means to track its course, and provide an approach to select and monitor treatments. PMID- 26763586 TI - Controlled multi-arm platform design using predictive probability. AB - The process of screening agents one-at-a-time under the current clinical trials system suffers from several deficiencies that could be addressed in order to extend financial and patient resources. In this article, we introduce a statistical framework for designing and conducting randomized multi-arm screening platforms with binary endpoints using Bayesian modeling. In essence, the proposed platform design consolidates inter-study control arms, enables investigators to assign more new patients to novel therapies, and accommodates mid-trial modifications to the study arms that allow both dropping poorly performing agents as well as incorporating new candidate agents. When compared to sequentially conducted randomized two-arm trials, screening platform designs have the potential to yield considerable reductions in cost, alleviate the bottleneck between phase I and II, eliminate bias stemming from inter-trial heterogeneity, and control for multiplicity over a sequence of a priori planned studies. When screening five experimental agents, our results suggest that platform designs have the potential to reduce the mean total sample size by as much as 40% and boost the mean overall response rate by as much as 15%. We explain how to design and conduct platform designs to achieve the aforementioned aims and preserve desirable frequentist properties for the treatment comparisons. In addition, we demonstrate how to conduct a platform design using look-up tables that can be generated in advance of the study. The gains in efficiency facilitated by platform design could prove to be consequential in oncologic settings, wherein trials often lack a proper control, and drug development suffers from low enrollment, long inter-trial latency periods, and an unacceptably high rate of failure in phase III. PMID- 26763587 TI - Endocytic function is critical for influenza A virus infection via DC-SIGN and L SIGN. AB - The ubiquitous presence of cell-surface sialic acid (SIA) has complicated efforts to identify specific transmembrane glycoproteins that function as bone fide entry receptors for influenza A virus (IAV) infection. The C-type lectin receptors (CLRs) DC-SIGN (CD209) and L-SIGN (CD209L) enhance IAV infection however it is not known if they act as attachment factors, passing virions to other unknown receptors for virus entry, or as authentic entry receptors for CLR-mediated virus uptake and infection. Sialic acid-deficient Lec2 Chinese Hamster Ovary (CHO) cell lines were resistant to IAV infection whereas expression of DC-SIGN/L-SIGN restored susceptibility of Lec2 cells to pH- and dynamin-dependent infection. Moreover, Lec2 cells expressing endocytosis-defective DC-SIGN/L-SIGN retained capacity to bind IAV but showed reduced susceptibility to infection. These studies confirm that DC-SIGN and L-SIGN are authentic endocytic receptors for IAV entry and infection. PMID- 26763589 TI - Multiplex surface plasmon resonance biosensing and its transferability towards imaging nanoplasmonics for detection of mycotoxins in barley. AB - A 6-plex competitive inhibition immunoassay for mycotoxins in barley was developed on a prototype portable nanostructured imaging surface plasmon resonance (iSPR) instrument, also referred to as imaging nanoplasmonics. As a benchmark for the prototype nanoplasmonics instrument, first a double 3-plex assay was developed for the detection of deoxynivalenol (DON), zearalenone (ZEA), T-2 toxin (T-2), ochratoxin A (OTA), fumonisin B1 (FB1) and aflatoxin B1 (AFB1) using a well-established benchtop SPR instrument and two biosensor chips. To this end, ovalbumin (OVA) conjugates of mycotoxins were immobilized on the chip via amine coupling. The SPR response was then recorded upon injection of a mixture of antibodies at a fixed concentration and the sample (or matrix-matched standard) over a chip with immobilized mycotoxin-OVA conjugates. The chips were regenerated after each sample using 10 mM HCl and 20 mM NaOH and could be used for at least 60 cycles. The limits of detection in barley (in MUg kg(-1)) were determined to be 26 for DON, 6 for ZEA, 0.6 for T-2, 3 for OTA, 2 for FB1 and 0.6 for AFB1. Preliminary in-house validation showed that DON, T-2, ZEA and FB1 can be detected at the European Union regulatory limits, while for OTA and AFB1 sensitivities should be improved. Furthermore, measurement of naturally contaminated barley showed that the assay can be used as a semi-quantitative screening method for mycotoxins prior to liquid chromatography tandem mass spectrometry (LC-MS/MS). Finally, using the same bio-reagents the assay was transferred to a 6-plex format in the nanoplasmonics instrument and subsequently the two assays were compared. Although less sensitive, the 6-plex portable iSPR assay still allowed detection of DON, T-2, ZEA and FB1 at relevant levels. Therefore, the prototype iSPR shows potential for future applications in rapid in-field and at-line screening of multiple mycotoxins. PMID- 26763588 TI - Three-dimensional microtissues essentially contribute to preclinical validations of therapeutic targets in breast cancer. AB - A 3D microtissues using T47D and JIMT-1 cells were generated to analyze tissue like response of breast cancer cells after combined human epidermal growth factor receptor 2 (HER2)-targeted treatment and radiation. Following lentiviral knockdown of HER2, we compared growth rate alterations using 2D monolayers, 3D microtissues, and mouse xenografts. Additionally, to model combined therapeutic strategies, we treated HER2-depleted T47D cells and 3D microtissues using trastuzumab (anti-HER2 antibody) in combination with irradiation. Comparison of HER2 knockdown with corresponding controls revealed growth impairment due to HER2 knockdown in T47D 2D monolayers, 3D microtissues, and xenografts (after 2, 12, and >=40 days, respectively). In contrast, HER2 knockdown was less effective in inhibiting growth of trastuzumab-resistant JIMT-1 cells in vitro and in vivo. Combined administration of trastuzumab and radiation treatment was also analyzed using T47D 3D microtissues. Administration of both, radiation (5 Gy) and trastuzumab, significantly enhanced the growth inhibiting effect in 3D microtissues. To improve the predictive power of potential drugs--as single agents or in combination--here, we show that regarding tumor growth analyses, 3D microtissues are highly comparable to outcomes derived from xenografts. Considering increased limitations for animal experiments on the one hand and strong need of novel drugs on the other hand, it is indispensable to include highly reproducible 3D microtissue platform in preclinical analyses to validate more accurately the capacity of future drug-combined radiotherapy. PMID- 26763590 TI - Oral Biology and Chicago. PMID- 26763591 TI - A three dimensional free body analysis describing variation in the musculoskeletal configuration of the cynodont lower jaw. AB - The evolution of the middle ear from the cynodont craniomandibular bones is one of the key mammalian innovations, and the mechanics underlying this anatomical transformation represents an intriguing paradox. Because the jaw joint of nonmammalian cynodonts was functionally coupled to the inner ear, auditory performance would favor low joint reaction forces. However, this could not be achieved at the expense of feeding performance, favoring high bite forces. The balance of these two seemingly incompatible performance criteria in the context of the morphological diversity of the cynodont lower jaw is poorly understood. Here we derive a series of equations using three dimensional free body analysis that describe the relationship between the orientation and position of the jaw elevator muscles, the position of the jaw articulation relative to the bite point, the joint reaction forces and the bite force in the lower jaw of the nonmammalian cynodont Probainognathus. These equations permit the effects of variation in each variable to be tested independently, yielding three terms that act to limit joint reaction forces without substantially impacting bite force: the reorientation of the resultant muscle force more vertically, shifting the position of the bite point medial to the jaw articulation, and elevating the jaw articulation above the level with the tooth row only when the muscles are oriented principally in the anterior direction. The predictions from our equations provide insights for functional interpretations of patterns of morphological diversity in the cynodont fossil record. They also illustrate that the musculoskeletal configuration of the cynodont lower jaw can be evolutionarily labile without negatively impacting the dual performance criteria of the auditory and feeding system. PMID- 26763592 TI - Structure and scale of the mechanics of mammalian dental enamel viewed from an evolutionary perspective. AB - Mammalian enamel, the contact dental tissue, is something of an enigma. It is almost entirely made of hydroxyapatite, yet exhibits very different mechanical behavior to a homogeneous block of the same mineral. Recent approaches suggest that its hierarchical composite form, similar to other biological hard tissues, leads to a mechanical performance that depends very much on the scale of measurement. The stiffness of the material is predicted to be highest at the nanoscale, being sacrificed to produce a high toughness at the largest scale, that is, at the level of the tooth crown itself. Yet because virtually all this research has been conducted only on human (or sometimes "bovine") enamel, there has been little regard for structural variation of the tissue considered as evolutionary adaptation to diet. What is mammalian enamel optimized for? We suggest that there are competing selective pressures. We suggest that the structural characteristics that optimize enamel to resist large-scale fractures, such as crown failures, are very different to those that resist wear (small-scale fracture). While enamel is always designed for damage tolerance, this may be suboptimal in the enamel of some species, including modern humans (which have been the target of most investigations), in order to counteract wear. The experimental part of this study introduces novel techniques that help to assess resistance at the nanoscale. PMID- 26763593 TI - Nucleation-mediated synthesis and enhanced catalytic properties of Au-Pd bimetallic tripods and bipyramids with twinned structures and high-energy facets. AB - The Au-Pd alloy has been proved to be an excellent catalyst in many applications, such as the electro-oxidation of formic acid, CO oxidation and oxidation of alcohols to aldehydes. However, most of the research has been focused on the shape-controlled Au-Pd alloy NCs with a single-crystal structure. Due to the existence of high-energy atoms on the twin defects, twinned structures usually will further increase their catalytic activities. It is necessary to develop a method to prepare the Au-Pd alloy with twinned structures and investigate their catalytic properties. Herein, we successfully synthesized Au-Pd alloy tripods and bipyramids with twinned structures by the cooperation of cetyltrimethyl ammonium chloride (CTAC) and cetyltrimethyl ammonium bromide (CTAB). The tripods contain one twin plane, while the bipyramids consist of a fivefold-twinned structure. In addition, the tripods and bipyramids are both exposed by high-energy facets. We proposed that the tripods and bipyramids are evolved from bipyramid seeds and fivefold twinned seeds, respectively. The as-prepared Au-Pd tripods and bipyramids performed better activity for electrocatalytic oxidation of formic acid compared to the cubic Au-Pd nanoparticles. PMID- 26763594 TI - Using Top-down and Bottom-up Costing Approaches in LMICs: The Case for Using Both to Assess the Incremental Costs of New Technologies at Scale. AB - PURPOSE: Estimating the incremental costs of scaling-up novel technologies in low income and middle-income countries is a methodologically challenging and substantial empirical undertaking, in the absence of routine cost data collection. We demonstrate a best practice pragmatic approach to estimate the incremental costs of new technologies in low-income and middle-income countries, using the example of costing the scale-up of Xpert Mycobacterium tuberculosis (MTB)/resistance to riframpicin (RIF) in South Africa. MATERIALS AND METHODS: We estimate costs, by applying two distinct approaches of bottom-up and top-down costing, together with an assessment of processes and capacity. RESULTS: The unit costs measured using the different methods of bottom-up and top-down costing, respectively, are $US16.9 and $US33.5 for Xpert MTB/RIF, and $US6.3 and $US8.5 for microscopy. The incremental cost of Xpert MTB/RIF is estimated to be between $US14.7 and $US17.7. While the average cost of Xpert MTB/RIF was higher than previous studies using standard methods, the incremental cost of Xpert MTB/RIF was found to be lower. CONCLUSION: Costs estimates are highly dependent on the method used, so an approach, which clearly identifies resource-use data collected from a bottom-up or top-down perspective, together with capacity measurement, is recommended as a pragmatic approach to capture true incremental cost where routine cost data are scarce. PMID- 26763595 TI - Contribution of domain 30 of tropoelastin to elastic fiber formation and material elasticity. AB - Elastin is a fibrous structural protein of the extracellular matrix that provides reversible elastic recoil to vertebrate tissues such as arterial vessels, lung, and skin. The elastin monomer, tropoelastin, contains a large proportion of intrinsically disordered and flexible hydrophobic sequences that collectively are responsible for the initial phase separation of monomers during assembly, and are essential for driving elastic recoil. While structural disorder of hydrophobic sequences is controlled by a high proline and glycine residue composition, hydrophobic domain 30 of human tropoelastin is atypically proline-poor, and forms beta-sheet amyloid-like fibrils as an individual peptide. We explored the contribution of confined regions of secondary structure at the location of domain 30 in human tropoelastin to fiber assembly and mechanical properties using a set of mutations designed to inhibit or enhance the propensity of beta-sheet formation at this location. Our data support a dual role for confined beta-sheet secondary structure in domain 30 of tropoelastin in guiding the formation of fibers, and as a determinant of stiffness and viscoelastic properties of cross linked materials. Together, these results suggest a mechanism for specificity in fiber assembly, and elucidate structure-function relationships for the rational design of elastomeric biomaterials with defined mechanical properties. PMID- 26763597 TI - Can we improve adolescent adherence? AB - Adherence has been defined as the extent to which a person's action and behaviour matches the agreed recommendations from a clinician.(1,2) It is a continuous and dynamic process influenced by many factors, including the disease, the treatments, the healthcare team and system, social and economic factors, as well as patient-related factors.(1) Non-adherence may adversely affect clinical outcomes and lead to increased healthcare costs.(1-3) Reported rates of adherence are around 50% for people with long-term conditions, and may be as low as 30% among adolescents (aged 10-19 years).(1,3,4) Around 20% of those aged under 18 years have a chronic illness and treatment often requires long-term cumbersome regimens including multiple daily medicines, making adherence challenging.(1,3,5) It is important to distinguish between intentional and non-intentional adherence and to tailor interventions to the individual, using every healthcare contact as an opportunity to discuss adherence.(1) Here we consider the challenges faced by healthcare professionals in encouraging adolescents to adhere to treatment regimens (in particular taking medicines) and some strategies that may help. PMID- 26763596 TI - Low Expression of Mir-137 Predicts Poor Prognosis in Cutaneous Melanoma Patients. AB - BACKGROUND: The present study aimed to measure miR-137 expression in patients with cutaneous melanoma (CM) and to estimate the correlation of miR-137 expression and the prognosis of CM patients. MATERIAL/METHODS: The expression level of miR-137 was assayed by quantitative real-time PCR (qRT-PCR) and presented as mean +/-SD. Chi-square was used to evaluate the relationship between miR-137 expression and clinical characteristics. We used a Kaplan-Meier survival curve to determine the overall survival rate of CM patients. Moreover, the correlation between miR-137 expression and the prognosis of CM patients was confirmed by Cox regression analysis. RESULTS: The relative expression of miR-137 in CM tissue was 1.59+/-0.43, while that in paired normal tissue was 2.41+/-0.54, which was significantly higher. Chi-square analysis showed statistical significance between miR-137 expression and clinical characteristics such as TNM stage, ulcer, and occurrence site (P<0.05). However, no association was found between miR-137 expression and age, sex, or family history (P>0.05). According to the survival curve outcome, patients with low miR-137 expression showed relatively higher mortality (P=0.000) and multivariate analysis verified that low expression of miR-137 predicted poor prognosis of CM patients (HR=8.531, 95% CI=2.950-24.668, P=0.000). CONCLUSIONS: Compared with paired normal tissues, miR 137 expression was lower in CM tissues. Patients with low miR-137 expression had higher mortality than those with high miR-137 expression, suggesting that low miR 137 expression indicated poor prognosis for CM patients. PMID- 26763598 TI - The management of dry eye. AB - Dry eye disease (also called keratoconjunctivitis sicca) is a common condition, with a prevalence ranging from 8-34%, depending on the criteria used.(1) It becomes more common with increasing age and affects more women than men. Artificial tears and ocular lubricants are considered the mainstay of treatment and there is a very wide range of these products available. In England in 2014, over 6.4 million prescription items for artificial tears, ocular lubricants and astringents were dispensed in the community at a cost to the NHS of over L27 million.(2) In this article we review the management of dry eye disease, focusing on artificial tears and ocular lubricants. PMID- 26763599 TI - Acute severe male hypo-testosteronemia affects central motor command in humans. AB - PURPOSE: To indirectly evaluate the effect of androgens on neuromuscular system in humans we analyzed if an induced short-term hypogonadal state (serum total testosterone-TT<2.3ng/ml) may affect central drive to skeletal muscle and/or muscle neuro-mechanical performance. METHODS: We compared voluntary and electrically evoked muscle sEMG signals from biceps brachii in nine hypogonadal male volunteers (Hypo) and in ten healthy controls (Cont). Serum TT and dihydrotestosterone (DHT) were assayed. RESULTS: With respect to Hypo, Cont exhibited significantly higher median frequency content (MDF) at any angular velocity; normalized MDF [95.9% (SD=23.3) vs 73.8% (SD=9.3)]; muscle fiber conduction velocity (CV) from lowest to highest angular velocities; initial MDF at fatigue test [91.78Hz (SD=22.03) vs 70.94Hz (SD=11.06)] as well as was the normalized slope [-0.64 (SD=0.14 vs -0.5 (SD=0.11)]. In the non-fatigued state, Hypo showed a slower single twitches time to peak (TTP). In Cont, half relaxation time (HRT) decreased after fatigue while increased in Hypo (p<0.05 between groups). A significant correlation between both TT and dihydrotestosterone with MDF and CV was found during voluntary contractions only. CONCLUSIONS: A brief exposure to very low serum TT concentration in males seem to determine a reduced excitability of the NM system which, in turn, would favor a predominant recruitment of slow twitch MUs. PMID- 26763601 TI - Effects of scapular upward rotation exercises on alignment of scapula and clavicle and strength of scapular upward rotators in subjects with scapular downward rotation syndrome. AB - The purpose of this study was to investigate the effects of a 6-week scapular upward rotation exercise (SURE) on scapular and clavicular alignment and scapular upward rotators strength in subjects with scapular downward rotation syndrome (SDRS). Seventeen volunteer subjects with SDRS were recruited from university populations. The alignment of the scapula and clavicle was measured using radiographic analysis and compared in subjects before and after a 6-week self SURE program. A hand-held dynamometer was used to measure the strength of the scapular upward rotators. The subjects were instructed how to perform the self SURE program at home. The 6-week self-SURE program was divided into two sections (the first section with non-resistive SURE during weeks 1-3, and the second section with resistive SURE using thera-band during weeks 4-6). The significance of the difference between pre- and post-program was assessed using a paired t test, with the level of statistical significance set at p<0.05. Significant differences between pre- and post-program were found for scapular and clavicular alignment (p<0.05). Additionally, the comparison between pre- and post-program measurements of the strength of the scapular upward rotators showed significant differences (p<0.05). The results of this study showed that a 6-week self-SURE program is effective for improving scapular and clavicular alignment and increasing the strength of scapular upward rotator muscles in subjects with SDRS. PMID- 26763600 TI - Surface electromyography in animal biomechanics: A systematic review. AB - The study of muscle activity using surface electromyography (sEMG) is commonly used for investigations of the neuromuscular system in man. Although sEMG has faced methodological challenges, considerable technical advances have been made in the last few decades. Similarly, the field of animal biomechanics, including sEMG, has grown despite being confronted with often complex experimental conditions. In human sEMG research, standardised protocols have been developed, however these are lacking in animal sEMG. Before standards can be proposed in this population group, the existing research in animal sEMG should be collated and evaluated. Therefore the aim of this review is to systematically identify and summarise the literature in animal sEMG focussing on (1) species, breeds, activities and muscles investigated, and (2) electrode placement and normalisation methods used. The databases PubMed, Web of Science, Scopus, and Vetmed Resource were searched systematically for sEMG studies in animals and 38 articles were included in the final review. Data on methodological quality was collected and summarised. The findings from this systematic review indicate the divergence in animal sEMG methodology and as a result, future steps required to develop standardisation in animal sEMG are proposed. PMID- 26763602 TI - TLR signalling can modify the mineralization of tooth germ. AB - OBJECTIVE: The aim of this work is to investigate the possible role of Toll-like receptor 4 (TLR4) during the development of mouse tooth germ. TLR4 is well known to inhibit mineralization and cause inflammation in mature odontoblasts and dental pulp cells. However, unlike these pathological functions of TLR4, little is known about the developmental function(s) of TLR4 during tooth development. MATERIALS AND METHODS: TLR4 expression was studied via Western blot in developing lower mouse incisors from E13.5 to E18.5. To generate functional data about the effects of TLR4, a specific agonist (LPS) was applied to the medium of in vitro tooth germ cultures, followed by Western blot, histochemical staining, ELISA assay, in situ hybridization and RT-qPCR. RESULTS: Increased accumulation of biotin-labelled LPS was detected in the enamel organ and in preodontoblasts. LPS treatment induced degradation of the inhibitor molecule (IkappaB) of the NF kappaB signalling pathway. However, no morphological alterations were detected in cultured tissue after LPS addition at the applied dosage. Activation of TLR4 inhibited the mineralization of enamel and dentin, as demonstrated by alizarin red staining and as decreased levels of collagen type X. mRNA expression of ameloblastin was elevated after LPS administration. CONCLUSION: These results demonstrate that TLR4 may decrease the mineralization of hard tissues of the tooth germ and may trigger the maturation of ameloblasts; it can give valuable information to understand better congenital tooth abnormalities. PMID- 26763604 TI - Prospective evaluation of patient-reported quality of life outcomes after external beam radiation treatment for prostate cancer in Victoria: A cohort study by the Victorian Prostate Cancer Registry. AB - INTRODUCTION: External beam radiation treatment (EBRT) for prostate cancer (CaP) can cause adverse effects on bowel, bladder and sexual function. We aimed to use CaP clinical registry data to evaluate variation in patient adverse effects after EBRT in Victoria. METHODS: Study subjects were men diagnosed with primary CaP between 2009 and 2014, treated with EBRT in metropolitan Melbourne, or in one of three regional integrated cancer service (ICS) regions. Information on change in general and disease-specific health outcome 12 and 24 months after the initial diagnosis were obtained using a modified Expanded CaP index composite (EPIC)-26 survey and there was no variation of follow up between ICSs. RESULTS: The proportion of men with 'big bother' (the most troublesome category) was compared between the ICS regions in Victoria (n = 1,825). There was no difference in big bother in urinary and sexual function across the regions at 24 months. However, patients treated in one regional cancer service had a higher proportion with 'big bother' (11.1%) compared with the rest of the Victoria (4.8%); (chi(2) = 4.85; P = 0.02). The only significant factor for this was the location of EBRT (odds ratio = 2.6; 95% confidence interval: 1.12-6.04; P = 0.02). There was no association over time in that region with change in EBRT technique from 3-D conformal radiation therapy to intensity-modulated radiation therapy (z-test for proportion: 0.77; P: 0.44). CONCLUSION: A comprehensive clinical cancer registry system, can be used to benchmark outcomes for men diagnosed with CaP and may detect clinically relevant variations that require further detailed evaluation and response. PMID- 26763603 TI - Mild systemic inflammation and moderate hypoxia transiently alter neuronal excitability in mouse somatosensory cortex. AB - During the perinatal period, the brain is highly vulnerable to hypoxia and inflammation, which often cause white matter injury and long-term neuronal dysfunction such as motor and cognitive deficits or epileptic seizures. We studied the effects of moderate hypoxia (HYPO), mild systemic inflammation (INFL), or the combination of both (HYPO+INFL) in mouse somatosensory cortex induced during the first postnatal week on network activity and compared it to activity in SHAM control animals. By performing in vitro electrophysiological recordings with multi-electrode arrays from slices prepared directly after injury (P8-10), one week after injury (P13-16), or in young adults (P28-30), we investigated how the neocortical network developed following these insults. No significant difference was observed between the four groups in an extracellular solution close to physiological conditions. In extracellular 8mM potassium solution, slices from the HYPO, INFL, and HYPO+INFL group were more excitable than SHAM at P8-10 and P13-16. In these two age groups, the number and frequency of spontaneous epileptiform events were significantly increased compared to SHAM. The frequency of epileptiform events was significantly reduced by the NMDA antagonist D-APV in HYPO, INFL, and HYPO+INFL, but not in SHAM, indicating a contribution of NMDA receptors to this pathophysiological activity. In addition, the AMPA/kainate receptor antagonist CNQX suppressed the remaining epileptiform activity. Electrical stimulation evoked prominent epileptiform activity in slices from HYPO, INFL and HYPO+INFL animals. Stimulation threshold to elicit epileptiform events was lower in these groups than in SHAM. Evoked events spread over larger areas and lasted longer in treated animals than in SHAM. In addition, the evoked epileptiform activity was reduced in the older (P28-30) group indicating that cortical dysfunction induced by hypoxia and inflammation was transient and compensated during early development. PMID- 26763605 TI - Optical frequency domain imaging vs. intravascular ultrasound in percutaneous coronary intervention (OPINION trial): Study protocol for a randomized controlled trial. AB - BACKGROUND: Optical coherence tomography is becoming increasingly widespread as an adjunctive intravascular diagnostic technique in percutaneous coronary intervention (PCI), because of its ability to visualize coronary structures at high resolution. Several studies have reported that intravascular ultrasound (IVUS) guidance in PCI might be helpful to reduce subsequent stent thrombosis, restenosis, repeat revascularization, myocardial infarction, and cardiac death. The OPtical frequency domain imaging vs. INtravascular ultrasound in percutaneous coronary InterventiON (OPINION) trial is aimed at evaluating the impact of optical frequency domain imaging (OFDI) guidance in PCI on clinical outcomes compared with IVUS guidance. METHODS AND DESIGN: The OPINION trial is a multicenter, prospective, randomized, controlled, open-label, parallel group, non inferiority trial in Japan. The eligible patients are randomly assigned to receive either OFDI-guided PCI or IVUS-guided PCI. PCI is performed using the biolimus-eluting stent in accordance with a certain criteria of OFDI and IVUS for optimal stent deployment. All patients will undergo a follow-up angiography at 8 months. The primary endpoint is target vessel failure composed of cardiac death, myocardial infarction attributed to the target vessel, and clinically-driven target vessel revascularization at 12 months. CONCLUSION: When completed, the OPINION trial will contribute to define the clinical value of the OFDI guidance in PCI. PMID- 26763606 TI - Dielectric and Thermodynamic Signatures of Low-Temperature Glassy Dynamics in the Hybrid Perovskites CH3NH3PbI3 and HC(NH2)2PbI3. AB - Hybrid main group halide perovskites hold great technological promise in optoelectronic applications and present rich and complex evolution of structure and dynamics. Here we present low-temperature dielectric measurements and calorimetry of APbI3 [A = CH3NH3(+), HC(NH2)2(+)] that suggest glassy behavior on cooling. In both compounds, the dielectric loss displays frequency-dependent peaks below 100 K characteristic of a glassy slowing of relaxation dynamics, with HC(NH2)2PbI3 exhibiting greater glass fragility. Consistent with quenched disorder, the low-temperature heat capacity of both perovskites deviates substantially from the ~T(3) acoustic phonon contribution predicted by the Debye model. We suggest that static disorder of the A-site molecular cation, potentially coupled to local distortions of the Pb-I sublattice, is responsible for these phenomena. The distinct low-temperature dynamics observed in these two perovskites suggest qualitative differences in the interaction between the molecular cation and the surrounding inorganic framework, with potential implications for defect screening and device performance at ambient temperatures. PMID- 26763607 TI - Laryngology litigation in the United States: Thirty years in review. AB - OBJECTIVES/HYPOTHESIS: Malpractice claims pertaining to laryngology procedures are a potentially important source of information that could be used to minimize the risk of future litigation and improve patient care. STUDY DESIGN: A retrospective review of two publicly available databases containing jury verdicts and settlements. METHODS: The LexisNexis Jury Verdicts and Settlements and WestlawNext legal databases were reviewed for all lawsuits and out-of-court adjudications related to the practice of laryngology. Data including patient demographics, type of surgery performed, plaintiff allegation, nature of injury, outcomes, and indemnities were collected and analyzed. RESULTS: Of 87 cases meeting inclusion criteria, 56 were decided by a jury and 31 were adjudicated out of court. Vocal cord surgery was the most commonly litigated surgery. The two most commonly cited legal allegations were physical injury and negligence. No statistical difference for legal outcome was found when death or vocal cord injuries occurred. Complications in procedures that utilized a laser predicted an unfavorable outcome (P = 0.013). A payout was made in over one-half of cases, but defendants were favored in over two-thirds of cases decided by a jury. The average indemnities were significant for both jury verdicts ($4.6 million) and out-of-court settlements ($0.9 million). CONCLUSION: An awareness of laryngology malpractice litigation has the potential to provide better patient care and help laryngologists avoid potential risks for litigation. The factors determining legal responsibility in laryngology cases underscore the importance of close communication with anesthesiologists and careful evaluation of hoarseness in all patients regardless of risk factors. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:2301-2304, 2016. PMID- 26763609 TI - Curcumin attenuates Mancozeb-induced toxicity in rat thymocytes through mitochondrial survival pathway. AB - The widely used fungicide Mancozeb (Man) has been shown to cause genotoxic effects in rodents and toxicological manifestations in different cells, mainly by altering the antioxidant defense in cells. On the other hand, curcumin (Cur), a natural phenolic compound, is thought to possess anti-inflammatory and antioxidant properties. Here, we investigated the possible protective role of Cur on Man-induced toxicity in rat thymocytes and potential mechanism involved. Rat thymocytes were treated with Man(0.01 MUg/ml) and/or increasing Cur(0.3, 1, 3 MUM) concentrations and levels of cell viability, apoptosis, mitochondrial membrane potential (MMP),Bcl-2, Bax protein expression, caspase-3 and -9 activity and p38 MAPK signaling involvement were examined. Cells treated with Man displayed increased cell toxicity, hypodiploid cells, caspase-3 and -9 activity, Bax protein expression, followed with decreased MMP and Bcl-2 protein expression. Inhibition of p38 MAPK signaling pathway markedly reduced apoptosis rate and caspase-3 activity in thymocytes exposed to Man. Application of increasing Cur (1, 3 MUM) concentrations resulted with significantly reduced cytotoxicity, apoptosis, caspase-3, -9 activity, Bax protein expression, together with increased MMP and Bcl-2 protein expression in rat thymocytes. These result suggest that certain Cur concentrations may mediate Man-induced rat thymocytes toxicity through mitochondrial survival pathway, which may be useful in preventing possible secondary immunological consequences induced by Man. PMID- 26763610 TI - Consumption of hair dye products by the French women population: Usage pattern and exposure assessment. AB - Only few published data are available in the literature about consumption and exposure, for hair dye products. The aim of this study was to assess the use of 10 different hair dye products in French Women with a focus on consumption of hair dye in different places of use (at home and at the hairdressers) in order to assess the corresponding dermal exposures. The assessment was performed on a total of 4237 women older than 15 years old, thanks to three national web surveys. The percentage of hair dye users among the French women population was about 64%.The mean frequency of use ranged between 2.23 and 14.22 times per year depending on the studied product and age category of women. This study provided the first data available for exposure to hair dye products with mean exposures ranging between 1.48 and 6.49 mg/kg bw/day depending on the product studied and age category of women. Moreover, consumption data obtained in this study might be useful to perform safety assessment of hair dye products thanks to the knowledge of the age categories of the population having the highest percentage of users and/or frequency of use. PMID- 26763611 TI - Prioritisation of allergenic foods with respect to public health relevance: Report from an ILSI Europe Food Allergy Task Force Expert Group. AB - Regulators and risk managers in general need to decide whether an allergenic food or ingredient is of such public health importance that it needs to be actively managed. There is therefore a need to scale the relative allergenicity of foods and ingredients according to the hazards they pose. Objective criteria increase transparency and trust in this decision-making process and its conclusions. This paper proposes a framework that allows categorisation and prioritisation of allergenic foods according to their public health importance. The challenge is to find a basis on which the allergenicity of foods can best be described and a method to combine the relevant measures of allergenicity into a scoring system that prioritises allergenic foods on the basis of their public health relevance. The framework is designed in accordance with the generic risk analysis principles used in food safety and can be used by regulators to decide whether or not a specific allergenic food or ingredient is of sufficient public health importance that it warrants regulation (i.e. mandatory labelling) when used in the production of food products. PMID- 26763608 TI - Maturation and electrophysiological properties of human pluripotent stem cell derived oligodendrocytes. AB - Rodent-based studies have shown that the membrane properties of oligodendrocytes play prominent roles in their physiology and shift markedly during their maturation from the oligodendrocyte precursor cell (OPC) stage. However, the conservation of these properties and maturation processes in human oligodendrocytes remains unknown, despite their dysfunction being implicated in human neurodegenerative diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Here, we have defined the membrane properties of human oligodendrocytes derived from pluripotent stem cells as they mature from the OPC stage, and have identified strong conservation of maturation-specific physiological characteristics reported in rodent systems. We find that as human oligodendrocytes develop and express maturation markers, they exhibit a progressive decrease in voltage-gated sodium and potassium channels and a loss of tetrodotoxin-sensitive spiking activity. Concomitant with this is an increase in inwardly rectifying potassium channel activity, as well as a characteristic switch in AMPA receptor composition. All these steps mirror the developmental trajectory observed in rodent systems. Oligodendrocytes derived from mutant C9ORF72-carryng ALS patient induced pluripotent stem cells did not exhibit impairment to maturation and maintain viability with respect to control lines despite the presence of RNA foci, suggesting that maturation defects may not be a primary feature of this mutation. Thus, we have established that the development of human oligodendroglia membrane properties closely resemble those found in rodent cells and have generated a platform to enable the impact of human neurodegenerative disease-causing mutations on oligodendrocyte maturation to be studied. PMID- 26763612 TI - Evaluation of the effectiveness of a chamomile (Matricaria chamomilla) and linseed (Linum usitatissimum) saliva substitute in the relief of xerostomia in elders. AB - OBJECTIVE: The aim of this study was to determine the efficacy of a chamomile (Matricaria chamomilla) and linseed (Linum usitatissimum) saliva substitute in the relief of xerostomia in older participants. BACKGROUND: In elders, xerostomia is a permanent and progressive condition that significantly affects their quality of life. The treatment for progressive xerostomia is currently restricted to palliative measures, and saliva substitutes are indicated. A lack of evidence on the effectiveness of the saliva substitutes in the relief of symptoms of xerostomia has been reported. MATERIALS AND METHODS: Seventy-four elderly participants presenting xerostomia of diverse origin were selected. Herbal saliva substitute and carboxymethyl cellulose conventional saliva substitute were tested using a double-blind, randomised, cross-sectional clinical trial. RESULTS: Every participant of the study exhibited dry mouth sensation. A sensation of thick saliva was described in 59.5% of the participants. The need for liquid intake to swallow food, the sensation of difficulty in swallowing and the burning sensation in the tongue were observed in 54.1, 56.8 and 27.0% of the participants, respectively. The most prevalent diseases were hypertension, depressive symptoms and arthritis. Results of the clinical tests showed that the herbal saliva substitute produced a greater relief of dry mouth symptoms, thick saliva sensation and the sensation of difficulty in swallowing than the conventional substitute (Wilcoxon test p < 0.05). CONCLUSIONS: New chamomile- and linseed based saliva substitute was effective in relieving xerostomia symptoms in older participants of this study. PMID- 26763613 TI - Characteristics of 1-day postoperative mortality: a comparison with 2- to 7-day postoperative mortality. AB - BACKGROUND: The purpose of this study was to determine causes and characteristics of early postoperative mortality focusing on postoperative day 1 (POD 1). METHODS: We reviewed the electronic medical records of patients who died within 7 days after surgery under anesthesia at a tertiary university hospital from January 2004 to December 2014. Postoperative mortalities were divided into POD 1 group and POD 7 group, which included death that occurred from days 2 to 7 after surgery. Characteristics of POD 1 group were compared with those of POD 7 group. RESULTS: The mortality rates of POD 1 and POD 7 groups were 3.6 and 7.8 per 10,000 anesthesia, respectively. The incidence of POD 1 mortality is higher than any other day of the week of surgery. The incidences of massive transfusion, intraoperative cardiac arrest, and intraoperative use of epinephrine were higher in POD 1 group than in POD 7 group. In adults, the proportion of emergency operations was higher in POD 1 group than in POD 7 group. The leading cause of death in POD 1 group was hypovolemic and cardiogenic shock, whereas that in POD 7 group was distributive shock. Human factor-related mortality was more frequent in POD 1 group (15.3%) compared with POD 7 group (6.1%). CONCLUSIONS: The characteristics of POD 1 mortality were different from those of POD 2-7 mortality. A large proportion of early postoperative deaths were due to POD 1 mortality. Human factor-related causes were more associated with POD 1 mortality, indicating much room for improvement. PMID- 26763614 TI - Evaluating Appropriate Blood Transfusion in Cancer Surgery. PMID- 26763615 TI - Mining molecular structure databases: Identification of small molecules based on fragmentation mass spectrometry data. AB - Mass spectrometry (MS) is a key technology for the analysis of small molecules. For the identification and structural elucidation of novel molecules, new approaches beyond straightforward spectral comparison are required. In this review, we will cover computational methods that help with the identification of small molecules by analyzing fragmentation MS data. We focus on the four main approaches to mine a database of metabolite structures, that is rule-based fragmentation spectrum prediction, combinatorial fragmentation, competitive fragmentation modeling, and molecular fingerprint prediction. (c) 2016 Wiley Periodicals, Inc. Mass Spec Rev 36:624-633, 2017. PMID- 26763618 TI - Non-toxigenic Clostridium difficile to prevent recurrent C. difficile infection. PMID- 26763616 TI - Smartphones and Patient Care: Exploring the Use of Text-Based Messaging for Patient-Related Communication. AB - Background Text messaging (texting) has become a routine medium of communication in society. However, its use among clinicians has not been fully characterized. We explored general surgery residents' practices and views on texting for patient related communication. Methods An email survey was distributed to all general surgery residents at a large Canadian medical school. Results Overall, 46 (57%) of those surveyed responded. All used texting for patient-related communication. Eleven percent of residents did not have a password on their cell phone and 89% did not have encrypted phones. Texting was the most common way (41%) by which residents communicated routine patient-related information with staff physicians. Most (85%) residents agreed that texting enhances patient care. The majority (66%) did not know if their hospital had a policy on texting and were unaware of legislation surrounding texting in patient care (89%). Conclusions Most general surgery residents use texting for communication of routine patient-related care issues. However, they acknowledge concerns regarding the security of this medium. PMID- 26763619 TI - RETRACTED: Relationship Between Aldosterone Synthase CYP1A1 MspI Gene Polymorphism and Prostate Cancer Risk. PMID- 26763620 TI - Application of FDM three-dimensional printing technology in the digital manufacture of custom edentulous mandible trays. AB - The objective was to establish and evaluate a method for manufacture of custom trays for edentulous jaws using computer aided design and fused deposition modeling (FDM) technologies. A digital method for design the custom trays for edentulous jaws was established. The tissue surface data of ten standard mandibular edentulous plaster models, which was used to design the digital custom tray in a reverse engineering software, were obtained using a 3D scanner. The designed tray was printed by a 3D FDM printing device. Another ten hand-made custom trays were produced as control. The 3-dimentional surface data of models and custom trays was scanned to evaluate the accuracy of reserved impression space, while the difference between digitally made trays and hand-made trays were analyzed. The digitally made custom trays achieved a good matching with the mandibular model, showing higher accuracy than the hand-made ones. There was no significant difference of the reserved space between different models and its matched digitally made trays. With 3D scanning, CAD and FDM technology, an efficient method of custom tray production was established, which achieved a high reproducibility and accuracy. PMID- 26763621 TI - Study of clinical characteristics in young subjects with Developmental coordination disorder. AB - BACKGROUND: Developmental Coordination Disorder (DCD) is a chronic neurological disorder observed in children. DCD is characterized by slowness in activities and motor impairment that affects the children's daily living and academic achievements, and later their professional and social behavior. Our aim in this work was to report characteristics frequencies in a group of children with DCD and to propose a subtyping of DCD characteristics. METHODS: Thirty three clinical DCD characteristics, the mostly reported in the literature, were assessed in 129 patients, boys and girls aged from 4years to 18years, and their subtyping was proposed. The statistical analyses were carried out with the Chi square, the t test and the correlation for the statistical differences, and with the Ward clustering method for subtyping. RESULTS: We found that there were 3.17 boys for one girl, all patients were characterized as slow, 47% were left-handers or ambidextrous, 36% and 26% had orofacial and verbal dyspraxia, respectively, 83% were found anxious, and 84% were described as being clumsy. CONCLUSIONS: It appears from these results that a child with DCD expresses more than a single difficulty. Three subtypes emerged from the statistical analysis in this study: (1) clumsiness and other characteristics except language difficulties; (2) self esteem and peer relation without clumsiness and language difficulties; (3) language difficulties and orofacial dyspraxia. PMID- 26763622 TI - Predictive and prognostic values of ERCC1 and XRCC1 in biliary tract cancers. AB - AIMS: To investigate the predictive and prognostic values of DNA repair genes excision repair cross-complementation group 1 (ERCC1) and X-ray repair cross complementing group 1 (XRCC1) in tumour samples from patients with a diagnosis of biliary tract cancer (BTC). METHODS: Expressions of ERCC1 and XRCC1 were determined by immunohistochemistry (IHC) for 160 patients with BTC and association with clinicopathological features and patient survival was performed to evaluate their predictive and prognostic values. RESULTS: Neoplastic tissue showed much lower nuclear expression compared with non-neoplastic tissue for ERCC1 (median immunostaining score (IS)=0.7 (95% CI 0.2 to 1.3) vs 8.0 (95% CI 5.5 to 8.0), p<0.001) and XRCC1 (median IS=4.0 (95% CI 3.0 to 5.5) vs 8.0 (95% CI 8.0 to 12.0), p<0.001). High nuclear expression of both proteins was able to predict better overall survival (OS) in patients with gallbladder adenocarcinoma, distal bile duct and perihilar cholangiocarcinoma undergoing gemcitabine as adjuvant therapy (ERCC1: median OS estimate=39.7 vs 22.9 months, p=0.011; XRCC1: median OS estimate=33.8 vs 14.6 months, p=0.005). Intense cytoplasmic expression of XRCC1 was found in 12 patients; these patients had significantly more frequent lymph node metastasis (90.0% vs 48.1%, p=0.017) and worse OS (median estimate=12.6 months vs 25.6 months, p=0.004) and recurrence-free survival (median estimate=5.7 months vs 15.1 months, p=0.011). Vascular invasion was significantly more frequent in patients with low nuclear expression for ERCC1 (58.7% vs 20.9%, p<0.001) and XRCC1 (69.6% vs 30.3%, p=0.001). CONCLUSIONS: IHC expression of ERCC1 and XRCC1 has some predictive and prognostic values in patients with BTC. Nuclear expression of ERCC1 and XRCC1 may be used to predict therapeutic response in patients undergoing gemcitabine monotherapy. PMID- 26763623 TI - Quality by design approach: antioxidant activity of the tablets containing cornelian cherry fruits in relation to their composition and physical properties. AB - The aim of this study was to prepare tablets containing ground fruits of cornelian cherry (Cornus mas L.) with high antioxidant capacity. The experiment was planned and evaluated on Design of Experiment (DoE) principle using Multivariate Data Analysis (MVA) as modern tools used in Quality by Design (QbD) approach. Various tableting mixtures with three different particle sizes of the plant material (up to 800 MUm, more than 800 MUm and their mixture) and percentage of silicon dioxide (1, 3 and 5%) were prepared. Tablets with a diameter of 10 mm and mass of 400 mg were subsequently produced from these mixtures using two compression forces (C1=7 kN and C2=14 kN). Principal Component Analysis (PCA) and Multiple Linear Regression (MLR) with response surface methodology were used to find the influential process-formulation parameters and describe their optimal settings. Finally, it is possible to say that the increasing level of silicon dioxide and the decreasing particle size of ground cornelian cherry lead to prolongation of disintegration time and increase of radial hardness and abrasion loss. Maximal antioxidant activity was obtained using 5% amount of silicon dioxide, the largest particle size and the low compression force. PMID- 26763624 TI - Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis. AB - Molecular, genetic and pathological evidence suggests that deficits in GABAergic parvalbumin-positive interneurons contribute to schizophrenia pathophysiology through alterations in the brain's excitation-inhibition balance that result in impaired behaviour and cognition. Although the factors that trigger these deficits are diverse, there is increasing evidence that they converge on a common pathological hub that involves NMDA receptor hypofunction and oxidative stress. These factors have been separately linked to schizophrenia pathogenesis, but evidence now suggests that they are mechanistically interdependent and contribute to a common schizophrenia-associated pathology. PMID- 26763625 TI - Relationship Between Health Literacy and Unintentional and Intentional Medication Nonadherence in Medically Underserved Patients With Type 2 Diabetes. AB - PURPOSE: The purpose of this study was to investigate the relationship between health literacy and overall medication nonadherence, unintentional nonadherence, and intentional nonadherence. Limited health literacy may be associated with worse diabetes outcomes, but the literature shows mixed results, and mechanisms remain unclear. Medication adherence is associated with diabetes outcomes and may be a mediating factor. Distinguishing between unintentional and intentional nonadherence may elucidate the relationship between health literacy and nonadherence in patients with type 2 diabetes. METHODS: Cross-sectional study of 208 patients with type 2 diabetes recruited from a primary care clinic in St. Louis, Missouri. Information was obtained from written questionnaire and patient medical records. Bivariate and multivariable regression were used to examine predictors of medication nonadherence. RESULTS: The majority of patients in the study were low income, publicly insured, and African American, with limited health literacy and a high school/GED education or less. In multivariable models, limited health literacy was significantly associated with increased unintentional nonadherence but not intentional nonadherence. CONCLUSIONS: Results suggest differences in factors affecting intentional and unintentional nonadherence. The findings also suggest interventions are needed to decrease unintentional nonadherence among patients with type 2 diabetes and limited health literacy. Efforts to address unintentional medication nonadherence among patients with type 2 diabetes with limited health literacy may improve patient health. PMID- 26763626 TI - Development of new host-specific Bacteroides qPCRs for the identification of fecal contamination sources in water. AB - Bacteroides spp. have been proposed as indicators of fecal contamination in microbial source tracking (MST) methodologies. The aim of this study was to develop new qPCR assays that target host-specific Bacteroidal 16S ribosomal RNA genes, to determine the source of fecal contamination in water. Denaturing gradient gel electrophoresis (DGGE) was used to select for host-specific bands of Bacteroides associated with a fecal pollution source and later to design four qPCR host-specific assays. A set of common primers for Bacteroides spp., four different Bacteroides spp. host-associated hydrolysis probes (human, cattle, pig, and poultry), and one hydrolysis probe for the Bacteroides genus were designed. This set of qPCR assays together with other previously developed Bacteroidetes MST targets were used to analyze water samples with fecal contamination from the four sources studied. The host-specific Bacteroides qPCRs designed for human (HMprobeBac), pig (PGprobeBac), and poultry (PLprobeBac) were highly specific for its sources (1.0, 0.97, and 1.0, respectively) although its sensitivity was lower (0.45, 0.50, and 0.73, respectively). The cattle-specific qPCR was totally unspecific and was discarded for future experiments. When compared to previously designed assays, the human and pig qPCRs showed better accuracies (0.86 and 0.84) than their counterparts HF183 and Pig-2-Bac (0.38 and 0.65). Thus, the newly designed human, pig, and poultry qPCR assays outperform other methods developed until date and may be useful for source tracking purposes. PMID- 26763627 TI - Association Patterns in Open Data to Explore Ciprofloxacin Adverse Events. AB - BACKGROUND: Ciprofloxacin is one of the main drugs to treat bacterial infections. Bacterial infections can lead to high morbidity, mortality, and costs of treatment in the world. In this study, an analysis was conducted using the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database on the adverse events of ciprofloxacin. OBJECTIVES: The aim of this study was to explore unknown associations among the adverse events of ciprofloxacin, patient demographics and adverse event outcomes. METHODS: A search of FDA AERS reports was performed and some statistics was highlighted. The most frequent adverse events and event outcomes of ciprofloxacin were listed, age and gender specific distribution of adverse events are reported, then the apriori algorithm was applied to the dataset to obtain some association rules and objective measures were used to select interesting ones. Furthermore, the results were compared against classical data mining algorithms and discussed. RESULTS: The search resulted in 6 531 reports. The reports included within the dataset consist of 3 585 (55.8%) female and 2 884 (44.1%) male patients. The mean age of patients is 54.59 years. Preschool child, middle aged and aged groups have most adverse events reports in all groups. Pyrexia has the highest frequency with ciprofloxacin, followed by pain, diarrhoea, and anxiety in this order and the most frequent adverse event outcome is hospitalization. Age and gender based differences in the events in patients were found. In addition, some of the interesting associations obtained from the Apriori algorithm include not only psychiatric disorders but specifically their manifestation in specific gender groups. CONCLUSIONS: The FDA AERS offers an important data resource to identify new or unknown adverse events of drugs in the biomedical domain. The results that were obtained in this study can provide valuable information for medical researchers and decision makers at the pharmaceutical research field. PMID- 26763628 TI - Inefficient effort allocation and negative symptoms in individuals with schizophrenia. AB - Negative symptoms like avolition and anhedonia are thought to involve difficulties with reward processing and motivation. The current study aimed to replicate and extend prior findings that individuals with schizophrenia display reduced willingness to expend effort for rewards and that such reduced effort is associated with negative symptoms, poor functioning, and cognitive impairment. The present study compared the effortful decision making of individuals with schizophrenia (n=48) and healthy controls (n=27) on the Effort Expenditure for Rewards Task (EEfRT). Individuals with schizophrenia chose a smaller proportion of hard tasks than healthy controls across all probability and reward levels with the exception of trials with a 12% probability and low or medium reward magnitude wherein both groups chose similarly few hard tasks. Contrary to expectations, in individuals with schizophrenia, greater negative symptoms were associated with making more effortful choices. Effortful decision making was unrelated to positive symptoms, depression, cognition, and functioning in individuals with schizophrenia. Our results are consistent with prior findings that revealed a pattern of inefficient decision making in individuals with schizophrenia relative to healthy controls. However the results did not support the hypothesized association of negative symptoms and reduced effort in schizophrenia and highlight prior inconsistencies in this literature. Future research is needed to understand what factors may be related to diminished effortful decision making in schizophrenia and the clinical significance of such performance deficits. PMID- 26763629 TI - A Three-Dimensional Scaffold-Based System for Modeling the Bone Marrow Tissue. AB - Hematopoietic stem and progenitor cells (HPC) niche, consisting of HPC and their surrounding stromal components, is the fundamental unit for bone marrow (BM) tissue engineering. Previously, mouse BM-derived cell complexes with HPC niche unit properties called "niche-like units" were isolated and characterized. This study was aimed to evaluate the possibility of bioengineering marrow tissue in heterotypic sites using niche-like units in combination with three-dimensional scaffolds. BM niche-like units were isolated from GFP-transgenic C57BL/6 mice and seeded on electrospun poly (L-lactide) nanofiber scaffolds, which were then roll folded and aseptically implanted into the peritoneal cavity of irradiated wild type mice. One month after implantation, donor-derived cells were detected in peripheral blood of the recipients and contributed to restoration of all blood lineages. The transplanted bioengineered tissue histologically resembled native BM structure and was connected to the mouse systemic circulation. Long-term self renewal was confirmed by serial transplantation into tertiary recipients. In conclusion, this study establishes a novel system for BM tissue engineering, which can be used to improve the HPC transplantation outcomes especially in cases where HPC niche is damaged and also as an in vivo model to test the effects of different factors on hematopoiesis. PMID- 26763630 TI - Breast feeding could reduce the risk of childhood leukaemias. PMID- 26763631 TI - A Military-Specific Injury Scoring System to Aid in Understanding the Golden Hour. PMID- 26763632 TI - Antioxidant responses to drought in sunflower and sorghum seedlings. AB - To determine if antioxidant responses to drought differ between C3 and C4 plants, we grew Sorghum bicolor (C4 ) and Helianthus annuus (C3 ) under either watered or dry conditions in a growth chamber. Levels of leaf enzymatic antioxidants (ascorbate peroxidase, catalase, guaiacol peroxidase, dehydroascorbate reductase, monodehydroascorbate reductase, glutathione reductase and superoxide dismutase), nonenzymatic antioxidants (ascorbate, glutathione and carotenoids) and stress parameters (Chl and malondialdehyde [MDA]) were determined. Under watered and drought conditions, Chl contents and leaf relative water contents (RWC) were higher in sorghum than in sunflower; however, MDA levels were higher in sunflower than in sorghum. Under watered conditions, inherent levels of antioxidants were not consistently higher or lower in sorghum than in sunflower. In response to drought, levels of antioxidants, Chl and MDA showed increase, decrease or remained unchanged depending on crop, duration of drought and kind of antioxidants. Duration of drought was divided arbitrarily into three stages. At an early stage of drought (watering had stopped for 3-4 d) when soil water content (WC) and leaf RWC had decreased only in sunflower, drought generally did not affect levels of antioxidants and stress parameters. At a middle stage of drought (watering had stopped for 5-6 d) when soil WC had decreased for both sorghum and sunflower but leaf WC and RWC had decreased only in sunflower, drought changed levels of some antioxidants in sunflower and sorghum. At a late stage of drought (watering had stopped for 7-8 d) when soil WC, leaf WC and RWC had decreased in sorghum and sunflower, most parameters studied were affected by drought. Because of the differential effect of drought, levels of antioxidants were not consistently higher or lower in sorghum than in sunflower under drought. These results show that, under both drought and watered conditions, sorghum does not have consistently higher or lower antioxidant levels than sunflower, and that antioxidant responses to drought differ in C3 and C4 plants. PMID- 26763633 TI - Ammonium assimilation by young plants of Hordeum vulgare in light and darkness: effects on respiratory oxygen consumption by roots. AB - Barley plants (Hordeum vutgare L.) grown for 10 d in nitrogen-free hydroponic culture, after a rapid initial phase absorbed supplied NH4 (+) at a constant rate of 15.1 +/-1.2 MU mol h(-1) g(-1) f. wt in the light, arid at a rate of 13.81 +/- 1.6 MU mol h(-1) g(-1) f. wt in darkness. Ammonium-grown plants assimilated NH4 (+) at a rate of 7.5 +/- 0.33 MUmol h-1 g(-1) f. wt and at a 50% lower rate in darkness. Nitrogen-free grown plants showed low concentrations of free amino acids in both root and shoot tissues. Supplying NH4 (+) caused an immediate increase in the concentration of free amino in the root tissues of both illuminated and darkened plants over a 120 mm period. The increase in concentration of glutamine then exhibited a lag period of 120 min, after which it resumed, but to a very small extent. Glutamine also accumulated in shoot tissue of illuminated plants at increasing rates, attaining a concentration which, 8 h after NH4 (+) supply, was 1.61-fold greater than that attained in the roots. In shoots of darkened plants, by contrast, the concentration of glutamine increased slowly and was always smaller than that in the root tissue. Overall formation of glutamine (in shoots and roots) occurred at decreasing rates during the first 4 h, and then at increasing rates. The increase was more pronounced in illuminated plants than in darkened plants, liven 24 h after NH4 (+) was supplied, glutamine content in root tissue was lower than that in shoot tissue. However, 48 h later, the concentrations of glutamine in root and shoot were similar, attaining values that were almost 47-fold (in root) and 134-fold (in shoot) greater than initial values. Significant levels of asparagine were detected in the root and in the shoot 24 h after adding NH4 (+) . These increased further during the succeeding period. Ammonium supply caused a transitory drop in the concentration of ATP in root tissue, along with noticeable transitory variations in glucose-6-P concentration. A permanent decrease in free glucose concentration was also detected. Addition of NH4 (+) caused 2- and 1.43-fold increases in respiratory oxygen consumption by roots of illuminated and darkened plants, respectively. Both in the light and in the dark, the root tissue accumulated methylammonium up to a concentration of 55-67 MUmol h(-1) g(-1) f. wt. Methylammonium was never found in shoot tissue of either illuminated or darkened plants. Methylammonium stimulated respiration of root barley plants by a factor of 1.2. Regulatory aspects of NH4 (+) metabolism are discussed. PMID- 26763634 TI - The phosphorus requirement of N2 -fixing and urea-fed Acacia mangium. AB - The fast-growing leguminous tree Acacia mangium Willd, was grown for at least 22 wk in aerated solution culture either under N2 -fixing conditions or with 2 mmol urea per plant per wk. Inorganic phosphorus was supplied at between 1 and 100 MUmol P(1) per plant per wk: the latter was determined to be the optimum P supply for growth. The external P requirement for growth and the efficiency of utilization of internal P were similar for both N sources. However, shoot growth and the concentrations of N and P in leaves were decreased by P deficiency to a slightly higher extent in N2 -fixing plants than in urea-fed plants. Even though P deficiency limited nodule growth more drastically than it did shoot growth, the fraction of P allocated to both nodules and nodule nitrogenase activity (acetylene reduction) increased with P deficiency. It is concluded that this increase in nitrogenase activity reflects a higher N requirement per unit nodule mass in P-deficient plants and that, once nodules are fully functional the efficiency of utilization of internal P in N2 -fixing A. mangium is high compared with that of other N2 -fixing legumes. PMID- 26763635 TI - Effects of elevated CO2 , nitrogen form and concentration on growth and photosynthesis of a fast- and slow-growing grass. AB - Growth and photosynthesis of Agrostis capillaris L. and Nardus stricta L. were measured for plants grown under ambient and elevated concentrations of CO2 (340 and 550 MUl CO2 l(-1) respectively) and a range of nitrogen concentrations (0.01, 0.1, 1 and 5 mg N l(-1) ) supplied as either ammonium sulphate or sodium nitrate. After 42 d of growth for A. capillaris and 49 d of growth for N. stricta, the higher nitrogen concentrations resulted in stimulation of growth. The form of nitrogen did not affect the total dry weight attained by A. capillaris. However, ammonium-grown N. stricta attained a greater total dry weight than did nitrate grown plants. Nitrogen form influenced leaf area ratio, which was greater in nitrate-grown A. capillaris and in ammonium-grown N. stricta. At the two lowest nitrogen concentrations there was no effect of elevated CO2 on total dry weight in either species, whilst at the two highest nitrogen concentrations positive growth responses to elevated C02 were observed. Photosynthetic capacity and carboxylation efficiency were lower in plants grown in elevated CO2 at the two lowest nitrogen concentrations, and were associated with greater leaf soluble carbohydrate content and lower foliar nitrogen concentrations. By contrast, the CO2 treatment did not affect these parameters at the two highest nitrogen concentrations employed. PMID- 26763636 TI - Effects of elevated CO2 and nutrient supply on the seasonal growth and morphology of Agrostis capillaris. AB - Responses to elevated CO2 have been studied using an upland grass species, Agrostis capillaris L. The plants were grown in sand culture with a range of N, P and K concentrations, in 'Solardome' growth chambers with either ambient air or a CO2 concentration of 250MUmol CO2 mol(-1) above ambient The interactive effects of high CO2 and nutrient supply (in plant growth and morphology were monitored throughout the growing season. A. capillaris exhibited positive growth responses to enhanced CO2 even at limiting supplies of N and P. Moreover, greater shoot mass at elevated CO2 was attributed to disproportionate increases in leaf and tiller number, resulting in an increase in the average leaf number per tiller. However, total leaf area remained unaffected, indicating that leaf size was reduced. There was no evidence of any acclimation in the growth response of A. capillaris to additional CO2 , even in N and P-stressed plants. On the contrary, a stimulation in leaf production was observed later in the growing season. A consistent interaction was observed between N and P concentrations, whereby the response to one element was greater at higher concentrations of the other. In addition, there were indications of competition among the three elements for uptake at the root. These findings indicate the importance of multifactorial nutrient experiments in developing an understanding of the complex relationships during CO2 enrichment. PMID- 26763637 TI - Effects of elevated carbon dioxide and arbuscular mycorrhizal infection on Trifolium repens. AB - Trifolium repens L. cv. aran was grown for 58 d at ambient (350 MUol mol(-1) ) and elevated (700 MUol mol(-1) ) atmospheric CO2 , wish and without the arbuscular mycorrhizal fungus Glomus mosseae (Nicol. & Gerd.) Gerd. & Trappe cv. YV. Plant biomass, mycorrhizal infection, non-structural carbohydrates, C, N and P content were examined. Elevated CO2 (a) significantly increased above- and below-ground biomass, (b) decreased specific leaf area and specific root length, (c) decreased tissue %N and increased the C:N ratio, and (d) significantly increased total non-structural carbohydrates. Inoculating T. ripens with Glomus mosseae (a) significantly increased above- and below-ground biomass. (b) increased the total root length and total leaf area, and (c) significantly decreased tissue of Evidence of an increased influence of mycorrhiza on the P nutrition of T. repens at elevated CO2 was found in the 22%, increase in leaf total P (P < 005) of mycorrhizal plants grown at elevated CO2 compared with non mycorrhizal plants. No significant interactions were found between CO2 and mycorrhiza treatments. The proportion of T. repens root length colonized by Glomus mosseae was not affected by CO2 concentration. The percentage mycorrhizal infection was 29% at ambient CO2 and 35%, et al elevated CO2 . However, exposure to elevated CO2 significantly increased the total mycorrhizal foot length from 3.4 to 6.1 m per plant. The results show little evidence that the role of arbuscular mycorrhiza in the growth and nutrition of T. repens would increase if atmospheric CO2 were to increase as predicted. PMID- 26763638 TI - Photosynthesis and nutrient-use efficiency of barley in response to low arbuscular mycorrhizal colonization and addition of phosphorus. AB - The effects of arbuscular mycorrhizal infection by Glomus mosseae (Nicol. & Gerd.) Gerd. & Trappe on growth and photosynthesis of barley (Hordeum vulgare L. cv. Manitou) were investigated in sand culture at five levels of calcium phosphate (50, 100, 200, 400 and 800 mg P kg(-1) ). Mycorrhizal infection was low and varied with P supply, declining from 3.3% at 50 mg P kg(-1) to 1.5% at the highest P concentration. In general, there were small differences in biomass between mycorrhizal (+AM) and non-mycorrhizal (-AM) barley but a significant reduction in dry mass of senesced leaves occurred in the +AM plants. Leaf P concentrations increased with P application, but did not differ between + AM and AM plants. Although there were no differences in dry mass between + AM and -AM plants at 50 mg P kg(-1) , it was at this lowest P supply that +AM plants had higher rates of photosynthesis and greater P-use and N-use efficiencies. The mycorrhizal enhancement of maximum photosynthetic rate at the lowest P level was associated with a higher stomatal conductance, but was not related to increased leaf P or to changes in photon yield or the ratio of variable (FV) to maximum (FM) chlorophyll fluorescence. PMID- 26763639 TI - Phosphodiesterase as mycorrhizal P sources: I. Phosphodiesterase production and the utilization of DNA as a phosphorus source by the ericoid mycorrhizal fungus Hymenoscyphus ericae. AB - These results provide the first account of the breakdown and utilization of DNA by an ericoid mycorrhizal fungus, and of its phosphodiesterase activity in vitro. Hymenoscyphus ericae (Read) Korf & Kernan grew well on DNA as a sole source of phosphorus (P), achieving greater mycelium dry weight than on an equivalent concentration of P supplied as orthophosphate. Some characteristics of the production and activity of extracellular (culture filtrate) and cell-wall bound phosphodiesterase in H. ericae are reported. At least part of the phosphodiesterase activity is attributed to the exonuclease F nucleotide diesterase on the basis of its high affinity for a specific substrate of this enzyme, The pH optima for extra-cellular and cell-wall-bound diesterase are acidic (pH 4.0-5.5), with considerable activity maintained in the pH range typical of organic soils under ericaceous plants (pH 3.0-4.5). The production of phosphodiesterase was not substrate-induced, since highest specific activity for wall-bound enzyme was found in culture grown without organic or inorganic P. The results are discussed in relation to the ecology and biology of acid organic soils on which ericaceous plants are dominant. PMID- 26763640 TI - Phosphodiesters as mycorrhizal P sources: II. Ericoid mycorrhiza and the utilization of nuclei as a phosphorus and nitrogen source by Vaccinium macrocarpon. AB - Mycorrhizal plants of Vaccinium mocrocarpon Aiton used nuclei from salmon sperm as a sole source of phosphorus (P) and achieved similar yields, P content and P concentration to plants crown with orthophosphate. Mycorrhizal infection significantly increased the effectiveness of utilization of both inorganic and organic (nuclei) sources of P by Vaccinium but in the case of the organic source this involved providing access to P which was completely unavailable to the uninfected plants. The results provide further support for the view that ericoid mycorrhizas have a crucial role in direct recycling of nutrients from organic matter, independent of the mineralizing activities of saprotrophic micro organisms. PMID- 26763641 TI - Effects of Ascochyta caulina on photosynthesis of leaves of Chenopodium album. AB - The effect of leaf necrosis caused by Ascochyta caulina (P. Karst.) v.d. Aa & v Kest. on photosynthesis of leaves of Chenopodium album L. was studied in growth chambers. Fully expanded leaves of young plants were sprayed with a suspension of pycnidiospores, or with a spore-free control solution. Subsequently, leaves were exposed to high humidity for 6, 18, or 24 h to promote different levels of necrosis. Individual leaves were assessed for proportion of necrotic leaf area and net photosynthetic rate (npr) 3, 4 and 7 d after treatment. The npr of leaves decreased with increasing proportion of necrotic leaf area. The relationship between the two was linear in five of six regression analyses carried out. The observed linearity indicates that necrotic leaf tissue hardly affected the surrounding healthy leaf tissue. The proportion of necrotic leaf area that caused a npr of zero was on average 0.4, ranging from 0.2 to 0.5. PMID- 26763642 TI - Regional and local patterns in the spatial distribution of the flower-infecting smut fungus Sporisorium amphilophis in natural populations of its host Bothriochloa macra. AB - Regional variation in the incidence of the systemic floral-smut fungus Sparisorium amphilophis (Syd.) Langdon & Fullerton an the perennial grass Bothriochloa macra (Steud.) S. T. Blake was investigated through three surveys over a 12 yr period (1981-93). In all three surveys a marked north-south trend in percentage of infection was detected with a greater proportion of plants in northerly populations being infected than in populations located to the south. The incidence of disease in populations was negatively correlated with the frequency of days with temperatures <0 degrees C in winter. Detailed exploration of local variation in a subset of five populations showed that the incidence of S. amphilophis was density-dependent and was greater in the edge areas of host populations than in the less disturbed core areas. Smut prevented seed production and negatively affected different aspects of the morphology of the plants, such as the height and basal diameter. Infection also significantly increased the number of inflorescences per plant. These field results were complemented by glasshouse-based competition experiments which indicated that, despite causing reductions in size, S. amphilophis only affected the competitive ability of infected plants grown under sub-optimal conditions. The results of this study indicate that an interplay between physical and biotic aspects of the environment determines regional and local levels of disease. PMID- 26763643 TI - The physiology of basidiomycete linear organs: III. Uptake and translocation of radiocaesium within differentiated mycelia of Armillaria spp. growing in microcosms and in the field. AB - Autoradiography and quantitative image analysis were used to measure (137) Cs distribution and translocation through mycelia of A. gallica Marxmuller & Romagn. and A. ostoyae (Romagn.) Herink growing in small microcosms in the laboratory. Rhizomorphs of A. gallica were labelled with (134) Cs in the field, and the translation of radiolabel measured after excavation and destructive harvesting. The flux of radiocaesium through rhizomorphs was estimated to be greater than through undifferentiated hyphae, and greater through rhizomorphs growing in the field than through rhizomorphs grown across homogeneous media in the laboratory'. Differentiation within mycelia resulting in melanization or rhizomorph formation cave rise to increased heterogeneity in the (137) Cs distribution through laboratory microcosms compared with that through microcosms containing undifferentiated mycelia. Radiocaesium leaked from undifferentiated hyphae into the surrounding medium, but melanized regions of the mycelium appeared to be conservative for radiocaesium. These findings provide further evidence for the importance of filamentous fungi in determining the distribution and rate of release of radiocaesium currently present in the environment as a result of weapons testing and the accident at the Chernobyl nuclear reactor. PMID- 26763644 TI - Catechin, proanthocyanidin and lignin contents of loblolly pine (Pinus taeda) needles after chronic exposure to ozone. AB - Concentrations of soluble and bound phenolic compounds were measured in needles of 3-yr-old loblolly pine (Pinus taeda L.) trees exposed from May to November 1993 to a range of ozone (O3 ) concentrations in open-top field chambers, The treatments were charcoal-filtered air (CF). non-filtered air (NF), and NF air with O2 added at 1.5 times (NF 1.5) and 2(1 times (NF 2.0) the ambient O., concentration for 12 h daily. Average daily (0800-2000 hours) O3 concentrations in the CF. NF. NF 1.5 and NF 20 treatments were. 29. 47, 76 and 98 nl 1(-1) . respectively, for the 140 d treatment period. At the end of the treatment period, total phenolic and proanthocyanidin concentrations in the previous year's needles were 25-29% higher in the NF 2.0 treatment compared with the lower O3 treatments. Catechin concentration increased in the previous year's needles by as much as 81 % between the NF 2.0 treatment and the lower O3 treatments. Catechin is an effective antioxidant, and elevated levels might confer some protection against O3 injury. No significant differences in total phenolics and proanthocyanidins in the previous year's needles were detected among the remaining treatments, or among any O3 treatment for the current year's needles. Lignin content in needles of both years was not significantly affected by O3 exposure. Chances in the phenolic content of older needles in response to elevated O3 could alter plant pathogen interactions and slow down microbiol decomposition, which could contribute to a decline in site soil quality. PMID- 26763645 TI - The effects of different ozone exposures on three contrasting populations of Plantago major. AB - Plantago major grows throughout Britain in a range of ozone climates. Because populations have been shown to differ in ozone resistance, the aim of the experiment was to compare the reaction of populations from contrasting ozone climates to different types of ozone exposure. Three populations were grown under controlled conditions in five different ozone treatments (including controls for 10 wk. Development, growth, stomatal conductance and seed production were recorded. Populations were from the south coast of England (Lullington), near a mountain summit (Great Dun Fell) and lowland Scotland (Bush). Ozone treatments were: charcoal and Purafil filtered air (CF); 35 nl l(-1) for 24 h every day: 70 nl l(-1) h for 7 h everyday: CF then three episodes each week of 70 nl l(-1) for 7 h; and 35 nl l(-1) continuously plus three 7 h episodes each week of 70 nl l( 1) . The different ozone treatments resulted in different responses in each population. Ozone promoted senescence in the Great Dun Fell population but not in the others; it reduced root growth more in the Lullington population than in the others but those from Lullington and Great Dun Fell maintained seed production to a much greater extent than the Bush population. The reproductive effort (number of seeds g(-1) of vegetative weight) actually increased in ozone in the Lullington and Great Dun Fell populations. It is suggested that this might he a general stress response rather than being specifically related to ozone. Effects on stomatal conductance were similar to those previously reported and the converse of effects on seed production. The relative responses of the populations varied according to the ozone treatment. Continuous exposure to 35 n1 l(-l) reduced leaf size only in the Great Dun Fell population, but seed output was reduced in the Bush population. In some cases, giving 3-d episodes of 70 n1 l(-1) had a greater effect than giving the dose every day but the effects varied with the population. This greater effect was considered to be a result of the time it takes for a plant to develop maximum anti-oxidant defence, which is lost when the ozone decreases after the episode. A plant exposed to episodes might have to re induce defence with each exposure. Although it is reported frequently that ozone favours allocation of resources to the shoot over the root, it is concluded that this is an over-simplification of the response. Even within a species there is a complex suite of responses that varies with the population and with ozone exposure. Describing a population as resistant or sensitive is also an over simplification. PMID- 26763646 TI - Effects of emissions from copper-nickel smelters on the frost hardiness of Finns sylvestris needles in the subarctic region. AB - It has been proposed that freezing injuries play an important role in the forest decline phenomenon. In this study, the effect of emissions from the copper-nickel smelters in Monchegorsk and Nikel-Zapolyarnyi in the Kola Peninsula, south-west Russia, on seasonal changes in the frost hardiness of Pinus sylvestris L. needles were studied. The frost hardiness of current-year needles during autumn, winter, spring and early summer in 1991-1993 was estimated by the electrolyte leakage method and by visual estimation of the proportion of damaged needles at nine sites in Finnish Lapland, at five sites in the vicinity of Monchegorsk and at two sites in Norway, in the vicinity of Nikel. The foliar S, Cu, and Ni concentrations also analysed. There were no significant differences at any time of the year between the frost hardiness of pine needles at the sites in Norway and Finnish Lapland. However, in the winter, the degree of visual damage at -45 degrees C, the temperature close to the lowest recorded temperature in this area, was slightly higher at the sites near to Nikel than at the sites in Finnish Lapland. In the Kola Peninsula the frost hardiness was consistently lower at the sites located 10 km to the south and 36 km to the south-west of Monchegorsk than at the other sites (48-110 km to the south-west). The differences were greatest in early June, 1991, when frost hardiness was -2 degrees C and -8 degrees C at the sites closest to Monchegorsk. At the same time, the frost hardiness at the other sites was e.-20 degrees C. There were slight differences between years, but the trends were the same. A clearly increasing gradient in the S, Cu and Ni concentrations was observed on moving towards the emission point source at Monchegorsk. Highly elevated concentrations were found within 40 km of the smelter. The results suggest that air pollutants from the copper-nickel smelter have predisposed the pines to freezing injuries, rhus contributing to forest decline in the Kola Peninsula. PMID- 26763647 TI - Ion compartmentation in the red alga Caloglossa leprieurii in response to salinity changes: freeze-substitution and X-ray microanalysis. AB - The elemental content of cell compartments in the euryhaline red macroalga Caloglossa leprieurii (Montague) J. Agardh subjected to different salinities, was determined by X-ray microanalysis of freeze-substituted thin sections. Duty are given for three compartments; cell wall, vacuole and cytoplasm. The most abundant elements detected were potassium, sodium and chlorine, with a Sulphur peak in the cell wall indicating the presence of sulphated polysaccharides. With salinity upshock the cytoplasm is maintained low in K, Na and Cl, whereas in the vacuoles they increased. High levels of K and Na located in the cell wall reflect cation binding to negatively charged polysaccharides. Hyposaline shock resulted in decreased K, Na and Cl levels in all compartments, though K was retained in the cytoplasm. Results are discussed with regard to the role of ion compartmentation in the salt tolerance of this alga, and the cation exchange properties of the cell wall are emphasized. PMID- 26763648 TI - Cation ratios in Cladonia portentosa as indices of precipitation acidity in the British Isles. AB - The relationship between rainfall chemistry and the concentrations of potassium, calcium and magnesium in the apices (top 5 mm) of the cushion-forming; lichen Cladonia portentosa (Dufour) Coem was investigated. Lichen samples, together with underlying topsoil, were collected from heathlands in close proximity to rain gauges in the UK Acid Deposition Monitoring Network, located in rural areas of the British Isles, which provide wet deposition data based on weekly bulk samples. The ratios K(+) : Mg(2+) and extracellular Mg(2+) : intracellular Mg(2+) in the lichen apices were strongly correlated with H(+) concentration in precipitation. It is suggested that shifts in these ratios occur owing to enhanced displacement of extracellular Mg(2+) by elevated H(+) concentration in acid rain. By contrast, there was no indication of any relationship between total acid deposition and lichen chemistry. The concentration of Mg(2+) in the lichen was weakly correlated with that in soil, whereas lichen Ca(2+) content was not correlated with either precipitation or soil chemistry. It is concluded that these ratios describing changes in lichen Mg(2+) content provide good biomarkers for wet-deposited acidity. PMID- 26763649 TI - Vasopressin-induced changes in splanchnic blood flow and hepatic and portal venous pressures in liver resection. AB - BACKGROUND: To minimize blood loss during hepatic surgery, various methods are used to reduce pressure and flow within the hepato-splanchnic circulation. In this study, the effect of low- to moderate doses of vasopressin, a potent splanchnic vasoconstrictor, on changes in portal and hepatic venous pressures and splanchnic and hepato-splanchnic blood flows were assessed in elective liver resection surgery. METHODS: Twelve patients were studied. Cardiac output (CO), stroke volume (SV), mean arterial (MAP), central venous (CVP), portal venous (PVP) and hepatic venous pressures (HVP) were measured, intraoperatively, at baseline and during vasopressin infusion at two infusion rates (2.4 and 4.8 U/h). From arterial and venous blood gases, the portal (splanchnic) and hepato splanchnic blood flow changes were calculated, using Fick's equation. RESULTS: CO, SV, MAP and CVP increased slightly, but significantly, while systemic vascular resistance and heart rate remained unchanged at the highest infusion rate of vasopressin. PVP was not affected by vasopressin, while HVP increased slightly. Vasopressin infusion at 2.4 and 4.8 U/h reduced portal blood flow (-26% and -37%, respectively) and to a lesser extent hepato-splanchnic blood flow (-9% and -14%, respectively). The arterial-portal vein lactate gradient was not significantly affected by vasopressin. Postoperative serum creatinine was not affected by vasopressin. CONCLUSION: Short-term low to moderate infusion rates of vasopressin induced a splanchnic vasoconstriction without metabolic signs of splanchnic hypoperfusion or subsequent renal impairment. Vasopressin caused a centralization of blood volume and increased cardiac output. Vasopressin does not lower portal or hepatic venous pressures in this clinical setting. PMID- 26763651 TI - Structure and Properties of Egyptian Blue Monolayer Family: XCuSi4O10 (X = Ca, Sr, and Ba). AB - Motivated by the recent experimental advances in exfoliating Egyptian blue monolayers, we have carried out extensive calculations using density functional theory to understand their geometry, stability, mechanical properties, electronic structures, and magnetism. Upon exfoliation from the bulk, XCuSi4O10 (X = Ca, Sr, and Ba) monolayers are found to change symmetry from tetragonal to orthorhombic. They all satisfy Born criteria and are mechanically stable. Each Cu site carries a magnetic moment of 1.0 MUB but with degenerate ferromagnetic and antiferromagnetic coupling states. From Ca to Sr and Ba, as the atomic number increases, the thickness, elastic constants, Young's moduli, and Poisson's ratios of the monolayers increase, while the band gaps decrease. Applying strain can tune the magnitude of energy band gaps, but the direct gap feature remains. Complementing the widely studied graphene, MXenes, black phosphorus, and dichalcogenide sheets, the Egyptian blue monolayers add additional features to the family of two-dimensional materials. PMID- 26763650 TI - Chemokine CCL15 Mediates Migration of Human Bone Marrow-Derived Mesenchymal Stem Cells Toward Hepatocellular Carcinoma. AB - Mesenchymal stem cells (MSCs) possess the ability to migrate toward tumor sites and are regarded as promising gene delivery vehicles for cancer therapeutics. However, the factors that mediate this tropism have yet to be completely elucidated. In this study, through cytokine array analysis, chemokine CCL15 was found to be the most abundant protein differentially expressed in hepatocellular carcinoma (HCC) cell lines compared with a normal liver cell line. Serum CCL15 levels in HCC patients determined by enzyme linked immunosorbent assay were shown to be profoundly elevated compared with healthy controls. Immunohistochemical analysis indicated that CCL15 expression was much stronger in HCC tumor tissues than in adjacent nontumor tissues. Transwell migration assay suggested that CCL15 may be involved in chemotaxis of human MSCs (hMSCs) toward HCC in vitro and that this chemotactic effect of CCL15 is mediated via CCR1 receptors on hMSCs. Orthotopic animal models of HCC were established to investigate the role of CCL15 in hMSCs migration toward HCC in vivo. Both histological and flow cytometric analysis showed that significantly fewer hMSCs localized within 97H-CCL15-shRNA xenografts compared with 97H-green fluorescent protein xenografts after intravenous delivery. Finally, the possible effects of hMSCs on HCC tumor growth were also evaluated. Coculture experiments showed that hMSCs had no apparent effect on the proliferation of HCC cells in vitro In addition, systemic administration of hMSCs did not affect HCC tumor progression in vivo. Our data in this study help to elucidate the mechanism underlying the homing capacity of hMSCs toward HCC. PMID- 26763653 TI - Evolution of a pentameral body plan was not linked to translocation of anterior Hox genes: the echinoderm HOX cluster revisited. AB - Echinodermata is a large phylum of marine invertebrates characterized by an adult, pentameral body plan. This morphology is clearly derived as all members of Deuterostomia (the superphylum to which they belong) have a bilateral body plan. The origin of the pentameral plan has been the subject of intense debate. It is clear that the ancestor of Echinodermata had a bilateral plan but how this ancestor transformed its body "architecture" in such a drastic manner is not clear. Data from the fossil record and ontogeny are sparse and, so far, not very informative. The sequencing of the sea urchin genome a decade ago opened the possibility that the pentameral body plan was a consequence of a broken Hox cluster and a series of papers dwelt on the putative relationship between Hox gene arrangements in the chromosomes and the origin of pentamery. This relationship, sound as it was, is challenged by the revelation that the sea star HOX cluster is, in fact, intact, thus falsifying the hypothesis of a direct relationship between HOX cluster arrangement and the origin of the pentameral body plan. Here, we explore the relationship between Hox gene arrangements and echinoderm body "architecture," the expression of Hox genes in development and alternative scenarios for the origin of pentamery, with putative roles for signaling centers in generating multiple axes. PMID- 26763652 TI - What Determines HIV Prevention Costs at Scale? Evidence from the Avahan Programme in India. AB - Expanding essential health services through non-government organisations (NGOs) is a central strategy for achieving universal health coverage in many low-income and middle-income countries. Human immunodeficiency virus (HIV) prevention services for key populations are commonly delivered through NGOs and have been demonstrated to be cost-effective and of substantial global public health importance. However, funding for HIV prevention remains scarce, and there are growing calls internationally to improve the efficiency of HIV prevention programmes as a key strategy to reach global HIV targets. To date, there is limited evidence on the determinants of costs of HIV prevention delivered through NGOs; and thus, policymakers have little guidance in how best to design programmes that are both effective and efficient. We collected economic costs from the Indian Avahan initiative, the largest HIV prevention project conducted globally, during the first 4 years of its implementation. We use a fixed-effect panel estimator and a random-intercept model to investigate the determinants of average cost. We find that programme design choices such as NGO scale, the extent of community involvement, the way in which support is offered to NGOs and how clinical services are organised substantially impact average cost in a grant based payment setting. PMID- 26763654 TI - Long noncoding RNA GAS5 can predict metastasis and poor prognosis: a meta analysis. AB - INTRODUCTION: Growth arrest-specific 5 (GAS5), a newly discovered long-noncoding RNAs (lncRNAs), has been reported to be down-regulated in multiple cancers. This meta-analysis aims to identify the potential value of GAS5 as a biomarker of cancer metastasis and prognosis. EVIDENCE ACQUISITION: We searched the MEDLINE, EMBASE and Cochrane Library databases. This meta-analysis collected all relevant studies and explored the association of lncRNA GAS5 with overall survival (OS), lymphnode metastasis (LNM), and distant metastasis (DM). EVIDENCE SYNTHESIS: Four studies were eligible for analysis, which included 328 patients. Meta-analysis revealed that low levels of GAS5 expression could predict poor OS in multiple cancers (pooled Hazard Ratio [HR]: 0.38, 95% confidence interval [CI]: 0.26-0.54, P<0.00001). Moreover, compared with high GAS5 expression, low GAS5 expression was correlated with LNM (pooled HR: 4.03, 95% CI: 1.93-8.41, P=0.0002) and DM (pooled HR: 10.17, 95% CI: 1.26-82.31, P=0.03). CONCLUSIONS: lncRNA GAS5 may potentially serve as a novel biomarker for cancer metastasis and prognosis. PMID- 26763655 TI - Neurological complications of cardiac disease (heart brain disorders). AB - BACKGROUND: Heart disease is a frequent cause of cerebral compromise. This review aimed at summarising and discussing available data about heart brain disorders. METHODS: We performed a literature search in conventional databases. RESULTS: Frequent cerebral complications of cardiac disease include embolic stroke, syncope, and intracerebral bleeding. Rare complications are watershed infarction, brain abscess, meningitis, metastasis, dementia, or aneurysm formation. The most frequent and most well-known cardiac cause of neurological complications is cardiac embolism. Cardiac emboli can be of different material and derive from the left atrium, left atrial appendage, left ventricle, or the mitral or aortic valves. Also arrhythmias such as atrial fibrillation or atrial flutter may give rise to thrombus formation. Heart failure, myocardial infarction, myocardial aneurysm, endocarditis/myocarditis, and noncompaction are further causes of cerebral embolism. Another cardiac cause of neurological complications is low output failure due to systolic dysfunction, arrhythmias, or valve stenosis. Arrhythmias are not only associated with intra-cardiac thrombus formation but may also lead to low output failure and consecutively to watershed infarction, vertigo, fainting, or syncope. Valve abnormalities can be another source of neurological disease. CONCLUSIONS: The cardiologist must know about the neurological complications of heart disease and the neurologist must know about the cardiac causes of cerebral abnormalities. Heart-brain disorders require a bidisciplinary diagnostic and therapeutic approach. PMID- 26763656 TI - N-Doped graphene frameworks with superhigh surface area: excellent electrocatalytic performance for oxygen reduction. AB - N-Doped carbon materials are promising candidates as alternative catalysts to noble metals in promoting the oxygen reduction reaction (ORR) in fuel cells. However, methods to further reduce the ORR overpotential and improve related kinetics remain to be developed. This study reports that N-doped graphene frameworks (NGFs) synthesized from the rapid pyrolysis of solid glycine particles in the presence of sodium carbonate, display an extremely large specific surface area (1760 m(2) g(-1)) and a graphitic-N-dominant C-N configuration. The NGFs can efficiently catalyze the electrochemical reduction of molecular oxygen into water following a 4e pathway, with a low overpotential (0.98 V of onset potential vs. RHE), very high kinetic limiting current density (16.06 mA cm(-2)), and turnover frequency (121 s(-1)), much better than the commercial Pt/C catalyst. PMID- 26763657 TI - Conformations of Low-Molecular-Weight Lignin Polymers in Water. AB - Low-molecular-weight lignin binds to cellulose during the thermochemical pretreatment of biomass for biofuel production, which prevents the efficient hydrolysis of the cellulose to sugars. The binding properties of lignin are influenced strongly by the conformations it adopts. Here, we use molecular dynamics simulations in aqueous solution to investigate the dependence of the shape of lignin polymers on chain length and temperature. Lignin is found to adopt collapsed conformations in water at 300 and 500 K. However, at 300 K, a discontinuous transition is found in the shape of the polymer as a function of the chain length. Below a critical degree of polymerization, Nc =15, the polymer adopts less spherical conformations than above Nc. The transition disappears at high temperatures (500 K) at which only spherical shapes are adopted. An implication relevant to cellulosic biofuel production is that lignin will self aggregate even at high pretreatment temperatures. PMID- 26763660 TI - Highly sensitive broadband flexible photodetectors based on a blend film with zinc octaethylporphyrin long nanowires embedded in an insulating polymer. AB - Blend films with long nanowires of zinc octaethylporphyrin (ZnOEP) embedded in an insulating polymer of poly(methyl methacrylate) (PMMA) have been successfully fabricated by a one-step spin-coating process. Concerning photoactive blends based on small-molecule semiconductors, this is quite a novel strategy and allows us to greatly reduce the issues related to low device performance, such as phase separation, poor connectivity of the semiconducting layer, and higher densities of interfacial defects. Intensive studies on the correlation between the film morphology and device performance have revealed that excellent photodetector performance is derived from efficient charge transport and good connectivity observed in highly crystalline, interconnected ZnOEP nanowires embedded in an insulating PMMA matrix. To the best of our knowledge, this is the first demonstration of a blend-film-based organic photodetector, which exhibits high sensitivity, high stability, high I(on)/I(off) ratio, excellent mechanical flexibility, and a broadband responsivity region extending up to 1050 nm. The unique characteristics of facile fabrication, high sensitivity, excellent mechanical stability, and broadband responsivity can make the blend film of ZnOEP and PMMA promising in large-area flexible photodetectors. PMID- 26763658 TI - DNA co-methylation modules in postmortem prefrontal cortex tissues of European Australians with alcohol use disorders. AB - DNA methylome alterations in the prefrontal cortex (PFC) may contribute to risk for alcohol use disorders (AUDs). We examined postmortem PFC DNA methylomes of 16 male and seven female pairs of AUD and control subjects using Illumina's HumanMethylation450 BeadChip assays. In male AUD subjects, 1,812 CpGs (1,099 genes) were differentially methylated (9.5 * 10(-9) <= Pnominal <= 7.2 * 10(-4), q < 0.05). In females, no CpGs were associated with AUDs after multiple testing correction (q > 0.05). Twenty-one AUD-associated co-methylation modules were identified in males by co-methylation analysis. The 1,812 CpGs were over presented by two AUD-associated co-methylation modules (Mturquoise: 1,048 CpGs/683 genes; Mblue: 429 CpGs/304 genes) (Phyper <= 0.001). Biological processes enriched for genes in these two modules included neural development and transcriptional regulation. Genes mapped by CpGs in these two modules were enriched in genome-wide association study-identified genes with variants associated with four substance dependence phenotypes or five psychiatric disorders. Additionally, 106 of the 1,812 CpGs were mapped to 93 genes (e.g., AUD associated genes GRIK3, GRIN2C, and GABRA1) with differential expression in postmortem PFC of male AUD subjects. Our study demonstrates that DNA methylation alterations in the PFC are associated with (and might result in) increased risk of AUDs, and there was a complex DNA methylation-gene expression relationship. PMID- 26763659 TI - Oscillations and Episodic Memory: Addressing the Synchronization/Desynchronization Conundrum. AB - Brain oscillations are one of the core mechanisms underlying episodic memory. However, while some studies highlight the role of synchronized oscillatory activity, others highlight the role of desynchronized activity. We here describe a framework to resolve this conundrum and integrate these two opposing oscillatory behaviors. Specifically, we argue that the synchronization and desynchronization reflect a division of labor between a hippocampal and a neocortical system, respectively. We describe a novel oscillatory framework that integrates synchronization and desynchronization mechanisms to explain how the two systems interact in the service of episodic memory. PMID- 26763661 TI - Recent advances in mass spectrometric analysis of protein deamidation. AB - Protein deamidation has been proposed to represent a "molecular clock" that progressively disrupts protein structure and function in human degenerative diseases and natural aging. Importantly, this spontaneous process can also modify therapeutic proteins by altering their purity, stability, bioactivity, and antigenicity during drug synthesis and storage. Deamidation occurs non enzymatically in vivo, but can also take place spontaneously in vitro, hence artificial deamidation during proteomic sample preparation can hamper efforts to identify and quantify endogenous deamidation of complex proteomes. To overcome this, mass spectrometry (MS) can be used to conduct rigorous site-specific characterization of protein deamidation due to the high sensitivity, speed, and specificity offered by this technique. This article reviews recent progress in MS analysis of protein deamidation and discusses the strengths and limitations of common "top-down" and "bottom-up" approaches. Recent advances in sample preparation methods, chromatographic separation, MS technology, and data processing have for the first time enabled the accurate and reliable characterization of protein modifications in complex biological samples, yielding important new data on how deamidation occurs across the entire proteome of human cells and tissues. These technological advances will lead to a better understanding of how deamidation contributes to the pathology of biological aging and major degenerative diseases. (c) 2016 Wiley Periodicals, Inc. Mass Spec Rev 36:677-692, 2017. PMID- 26763663 TI - Evaluations of imidazolium ionic liquids as novel skin permeation enhancers for drug transdermal delivery. AB - In this work, imidazolium ionic liquids (imidazolium ILs) were employed as the novel chemical permeation enhancers (CPEs) and their performances and mechanisms of action were deeply investigated. Testosterone was used as a model drug to investigate the transdermal delivery enhancement of twenty imdidazolium ILs. The results suggested that the promotion activity connected to the structure and composition of the ILs. The quantitative structure-activity relationship (QSAR) model revealed a good linearity between the electronic properties of ILs and their enhancements. Furthermore, the transepidermal water loss (TEWL) and scanning laser confocal microscope (CLSM) examinations showed the strong improvement of ILs on skin barrier permeability, which were well correlated with the drug penetration profiles. The total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and atomic force microscope (AFM) evaluations of skins indicated that the ILs can disrupt the regular and compact arrangements of the corneocytes, change the surface properties of stratum corneum, and make the skin structure more permeable. Our work demonstrated the significant skin permeation promotion profiles of the imidazolium ILs, which are of great potential in transdermal drug delivery systems. PMID- 26763662 TI - The Association Between Bleeding and the Incidence of Warfarin Discontinuation in Patients with Atrial Fibrillation. AB - AIM: While bleeding is a well-known complication of warfarin use and is thought to be a contributory cause of treatment discontinuation, studies quantifying this association are limited. The objective of this study was to quantify the association between bleeding events and subsequent warfarin discontinuation in patients with nonvalvular atrial fibrillation (NVAF). METHODS: A nested case control analysis was conducted within a cohort of patients with NVAF newly treated with warfarin. All patients who discontinued warfarin (at least 60 days from last day of warfarin supply) during follow-up were identified as cases and matched with up to 10 controls on age, sex, and duration of follow-up. The index date was defined as the date of warfarin treatment discontinuation of the cases. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of warfarin treatment discontinuation associated with a bleeding event in the 60 days before the index date. RESULTS: The cohort included 24,243 patients who initiated warfarin treatment, of whom 13,482 discontinued treatment during follow-up (cases). Bleeding was associated with an increased risk of warfarin treatment discontinuation (3.55% vs. 0.85%; OR, 4.31; 95% CI, 3.87-4.81). When including only bleeds as the first listed diagnosis, the unadjusted OR was 4.64 (95% CI, 4.10-5.26), and the adjusted OR was 4.65 (95% CI, 4.10-5.27). CONCLUSIONS: Bleeding was significantly associated with warfarin discontinuation, and thus, the selection of an effective treatment regimen associated with a lower bleeding rate could be a desirable treatment approach. PMID- 26763664 TI - Medication errors with antituberculosis therapy in an inpatient, academic setting: forgotten but not gone. AB - WHAT IS KNOWN AND OBJECTIVE: Tuberculosis, an infectious disease caused by the bacteria Mycobacterium tuberculosis, has significant public health implications. Despite the decreasing prevalence of tuberculosis cases and the availability of well-established treatment guidelines, errors with antituberculosis medications remain a concern as clinician experience with the infection has waned and the goal of eradicating tuberculosis has remained unfulfilled. Whereas inappropriate use of other anti-infective classes has been extensively studied, the evaluation of medication errors associated with antituberculosis therapy has been limited to a small number of studies conducted more than two decades ago. This study evaluated the prevalence of inpatient medication errors with antituberculosis therapy in patients with suspected or confirmed tuberculosis disease. METHODS: All admitted patients treated with at least one antituberculosis medication between July 2010 and June 2013 were evaluated for inclusion in the retrospective study. Multidrug antituberculosis regimens were reviewed for medication errors, which were categorized as dosing errors, drug interactions, omission of therapy and inappropriate continuation of therapy in the presence of drug toxicity. Appropriate management was determined in accordance with the national guidelines for the treatment of tuberculosis, as well as guidelines on the use of antiretroviral agents for patients with both human immunodeficiency virus (HIV) infection and tuberculosis disease. The impact of infectious diseases and pulmonary consultation on the prevalence of medication errors was also examined. RESULTS AND DISCUSSION: More than half of all study patients (44/72, 61%) experienced at least one medication error associated with antituberculosis therapy. Dosing errors were the most common type of medication error identified and were predominantly related to weight-based dosing. Seven dosing errors were related to drug interactions between rifamycins and antiretroviral therapy in HIV infected patients. Medication error rates were similar between patients receiving consultation from infectious diseases and/or pulmonary specialties and those without consultation. The large majority of antituberculosis medication errors (56/66 errors, 85%) remained uncorrected during the patient's hospital admission. WHAT IS NEW AND CONCLUSION: Medication errors associated with antituberculosis therapy remain a common occurrence in the current clinical practice setting. Greater vigilance when prescribing medications for tuberculosis disease is needed. PMID- 26763665 TI - Glass-ceramics bonding in geriatric patients: comparison with young teeth. AB - OBJECTIVE: The aim of the study was to assess whether in geriatric patients, the shear bond strength (SBS) of glass-ceramics differed when compared to young controls. BACKGROUND: In the need of aesthetic restorations for geriatric patients, reliable bonding of glass-ceramics should be accomplished; however, glass-ceramics bonding on aged tooth structures is still unclear. MATERIALS AND METHODS: Sixty extracted molars from young and geriatric patients [18-25 (Y), and 65-80 (O)] were cut buccolingually to prepare enamel (E) and dentin (D) surfaces. Both surfaces were randomly divided into three groups according to the resin cements: Variolink II (V); Superbond (S); and Clearfil Esthetic Cement (C) (n = 10). Disc-shaped glass-ceramics (IPS E-max Press) (n = 120) were prepared. Specimens were bonded and subjected to thermocycling. SBS test was performed using a universal testing machine (0.5 mm/min). After debonding, the surfaces were examined using stereomicroscope and scanning electron microscope. Data were statistically analysed with Kolmogorov-Smirnov, Levene, anova and Bonferroni tests (p = 0.05). RESULTS: There were no significant differences between the old and young teeth surfaces. V showed the highest SBS [MPa(SD)] on both enamel and dentin [36.7 (6.5) (YE), 23.2 (13.2) (YD), 32.1 (16.2) (OE), 25.5 (8.6) (OD), respectively]. Significant differences were observed between resin cements (p < 0.05). The failure types were 43% adhesive between tooth and cement, 48% mix, 9% adhesive between cement and ceramic, regardless of cement type. CONCLUSION: In geriatric patients, the shear bond strength of glass-ceramics did not differ when compared to that of young controls. On the dentin surface, etch-rinse resin cements appear to be more appropriate for glass-ceramics bonding. PMID- 26763666 TI - [Post-traumatic femoral arteriovenous fistula, endovascular treatment]. AB - BACKGROUND: Arteriovenous fistulas secondary to gunshot wounds have been increasing due to military activities, with endovascular treatment showing better results in haemodynamically stable patients. CLINICAL CASE: A 16 year-old male with diagnosis of femoral arteriovenous fistula in the left lower extremity was admitted to general surgery for endovascular management. A procedure with stent was performed without complications, and is currently on anticoagulant and antiplatelet treatment. CONCLUSION: Arteriovenous fistulas under the inguinal region can be safely treated with endovascular treatment (embolisation or stent) on stable patients. The objective of this therapy is to close the defect between artery and vein. This is the case of a patient with great results due to endovascular treatment, decreasing complications of the surgical treatment. PMID- 26763667 TI - Spontaneous Formation of Extensive Vessel-Like Structures in Murine Engineered Heart Tissue. AB - Engineered heart tissue (EHT) from primary heart cells contains endothelial cells (ECs), but the extent to which ECs organize into vessel-like structures or even functional vessels remains unknown and is difficult to study by conventional methods. In this study, we generated fibrin-based mini-EHTs from a transgenic mouse line (Cdh5-CreERT2 * Rosa26-LacZ), in which ECs were specifically and inducibly labeled by applying tamoxifen (EC(iLacZ)). EHTs were generated from an unpurified cell mix of newborn mouse hearts and were cultured under standard serum-containing conditions. Cre expression in 15-day-old EHTs was induced by addition of o-hydroxytamoxifen to the culture medium for 48 h, and ECs were visualized by X-gal staining. EC(iLacZ) EHTs showed a dense X-gal-positive vessel like network with distinct tubular structures. Immunofluorescence revealed that ECs were mainly associated with cardiomyocytes within the EHT. EC(iLacZ) EHT developed spontaneous and regular contractility with forces up to 0.1 mN. Coherent contractility and the presence of an extensive vessel-like network were both dependent on the presence of animal sera in the culture medium. Contractile EC(iLacZ) EHTs successfully served as grafts in implantation studies onto the hearts of immunodeficient mice. Four weeks after implantation, EHTs showed X-gal positive lumen-forming vessel structures connected to the host myocardium circulation as they contained erythrocytes on a regular basis. Taken together, genetic labeling of ECs revealed the extensive formation of vessel-like structures in EHTs in vitro. The EC(iLacZ) EHT model could help simultaneously study biological effects of compounds on cardiomyocyte function and tissue vascularization. PMID- 26763668 TI - Documentation of preventive care for pressure ulcers initiated during annual evaluations in SCI. AB - OBJECTIVE: Community-acquired pressure ulcers (PrUs) are a frequent cause of hospitalization of Veterans with spinal cord injury (SCI). The Veterans Health Administration (VHA) recommends that SCI annual evaluations include assessment of PrU risk factors, a thorough skin inspection and sharing of recommendations for PrU prevention strategies. We characterized consistency of preventive skin care during annual evaluations for Veterans with SCI as a first step in identifying strategies to more actively promote PrU prevention care in other healthcare encounters. DESIGN/SETTING/PARTICIPANTS: Retrospective cross-sectional observational design, including review of electronic medical records for 206 Veterans with SCI admitted to 2 VA SCI centers from January-December, 2011. OUTCOME MEASURES: Proportion of applicable skin health elements documented (number of applicable elements/skin health elements documented). RESULTS: Our sample was primarily white (78%) male (96.1%), and mean age = 61 years. 40% of participants' were hospitalized for PrU treatment, with a mean of 294 days (median = 345 days) from annual evaluation to the index admission. On average, Veterans received an average of 75.5% (IQR 68-86%) of applicable skin health elements. Documentation of applicable skin health elements was significantly higher during inpatient vs. outpatient annual evaluations (mean elements received = 80.3% and 64.3%, respectively, P > 0.001). No significant differences were observed in documentation of skin health elements by Veterans at high vs. low PrU risk. CONCLUSION: Additional PrU preventive care in the VHA outpatient setting may increase identification and detection of PrU risk factors and early PrU damage for Veterans with SCI in the community, allowing for earlier intervention. PMID- 26763670 TI - Primary seroresponses to double-dose compared with standard-dose hepatitis B vaccination in patients with chronic kidney disease: a systematic review and meta analysis. AB - Background: Clinical guidelines recommend double-dose hepatitis B vaccination for patients requiring dialysis, due to an increased risk of hepatitis B infection and reduced vaccine responsiveness. There are no recommendations for patients with chronic kidney disease (CKD) prior to dialysis. Methods: We performed a systematic review and meta-analysis of randomized and quasi-randomized trials comparing efficacy (seroresponses) and harms of double-dose compared with standard-dose hepatitis B vaccination in patients with CKD, including those requiring dialysis. A systematic literature search (CENTRAL, MEDLINE and EMBASE) was performed using a predetermined search strategy. Relative risks were calculated from pooled data using a random-effects model with subgroup analysis by dialysis requirement and vaccine type. Results: Seven studies (501 patients) fulfilled review criteria: four in patients receiving dialysis and three in patients not receiving dialysis. The incidence of seroconversion was not increased with double-dose vaccination overall [risk ratio (RR) 1.17, 95% confidence interval (CI) 0.98-1.39], by dialysis requirement or vaccine type. The incidence of seroprotection (reported by only four studies) was increased with double-dose vaccination overall (RR 1.53, 95% CI 1.17-2.00) but not by dialysis requirement. Adverse events were not reported by treatment arm, precluding comparison. The overall quality of included studies was moderate to low. Conclusions: The current data do not support clinical guideline recommendations for administering double-dose vaccination for patients with CKD as seroconversion was not improved and seroprotection was inadequately assessed. Large high-quality studies are required to overcome the current evidence gap regarding vaccine dosing in CKD. PMID- 26763671 TI - Highlights of the 2015 ERA-EDTA Congress--glomerular diseases. AB - The present paper summarizes highlights in the field of glomerular diseases presented at the 2015 European Renal Association congress in London. Topics covered include a European survey on renal biopsy practice and indications, the STOP-IgAN randomized controlled trial in patients with IgA-nephropathy, B-cell- targeting therapies in minimal change nephropathy and focal segmental glomerulosclerosis (FSGS), novel insights into the action of glucocorticosteroids in glomerular crescent and scar (FSGS) formation, the immunoproteasome in IgA nephropathy, socio-economic factors and glomerular disease progression, glomerular CD80 (B7-1) expression in FSGS patients and aldosterone-antagonism in proteinuric renal diseases. PMID- 26763672 TI - Timing of start of dialysis in diabetes mellitus patients: a systematic literature review. AB - BACKGROUND: Diabetes mellitus is a frequent cause of the need for renal replacement therapy (RRT). Historically, RRT was started earlier in patients with diabetes, in an attempt to prevent complications of uraemia and diabetes. We did a systematic review to find support for this earlier start of dialysis in patients with versus without diabetes. METHODS: The MEDLINE, EMBASE and CENTRAL databases were searched for articles about the timing of dialysis initiation in (subgroups of) patients with diabetes and CKD Stage 5. RESULTS: A total of 340 papers were screened and 11 papers were selected to be reviewed. Only three studies showed data of at least one subgroup of patients with diabetes. Two observational studies concluded that start of dialysis with a higher estimated glomerular filtration rate (eGFR) is beneficial with regard to survival, one did not find a difference and six observational studies concluded that start of dialysis with a lower eGFR is associated with better survival in patients with diabetes. The effect of timing of initiation of dialysis did not differ between patients with versus without diabetes. Lastly, one randomized controlled trial (two papers) reported that there was no difference in survival between start at higher versus lower eGFR overall and a P-value for the interaction with diabetes of P = 0.63, indicating no difference between patients with versus without diabetes with regard to the timing of start of dialysis and subsequent mortality on dialysis. CONCLUSIONS: There is no difference between early (eGFR) and late (lower eGFR) start of RRT with regard to mortality in patients with versus without diabetes. RRT should thus be initiated based on the same criteria in all patients, irrespective of the presence or absence of diabetes. PMID- 26763673 TI - Core-Fluorinated Naphthalene Diimides: Synthesis, Characterization, and Application in n-Type Organic Field-Effect Transistors. AB - A series of difluoro- and tetrafluoro-substituted naphthalene diimides (NDIs) were synthesized by halogen exchange reactions of corresponding bromo-NDIs with CsF in dioxane. Two strong electron acceptor molecules 6 and 8 with low-lying LUMO energy levels of -4.27 and -4.54 eV were obtained, starting from tetrafluoro NDI. Organic field-effect transistors (OFETs) based on these fluorinated NDIs were fabricated by vapor deposition, exhibiting n-channel field-effect character under ambient conditions with the highest mobility of 0.1 cm(2) V(-1) s(-1). PMID- 26763674 TI - A Military-Specific Injury Scoring System to Aid in Understanding the Golden Hour Reply. PMID- 26763669 TI - The DESCARTES-Nantes survey of kidney transplant recipients displaying clinical operational tolerance identifies 35 new tolerant patients and 34 almost tolerant patients. AB - BACKGROUND: Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive drugs and without evidence of rejection are supposed to be exceptional. The ERA-EDTA-DESCARTES working group together with Nantes University launched a European-wide survey to identify new patients, describe them and estimate their frequency for the first time. METHODS: Seventeen coordinators distributed a questionnaire in 256 transplant centres and 28 countries in order to report as many 'operationally tolerant' patients (TOL; defined as having a serum creatinine <1.7 mg/dL and proteinuria <1 g/day or g/g creatinine despite at least 1 year without any immunosuppressive drug) and 'almost tolerant' patients (minimally immunosuppressed patients (MIS) receiving low-dose steroids) as possible. We reported their number and the total number of kidney transplants performed at each centre to calculate their frequency. RESULTS: One hundred and forty-seven questionnaires were returned and we identified 66 TOL (61 with complete data) and 34 MIS patients. Of the 61 TOL patients, 26 were previously described by the Nantes group and 35 new patients are presented here. Most of them were noncompliant patients. At data collection, 31/35 patients were alive and 22/31 still operationally tolerant. For the remaining 9/31, 2 were restarted on immunosuppressive drugs and 7 had rising creatinine of whom 3 resumed dialysis. Considering all patients, 10-year death censored graft survival post-immunosuppression weaning reached 85% in TOL patients and 100% in MIS patients. With 218 913 kidney recipients surveyed, cumulative incidences of operational tolerance and almost tolerance were estimated at 3 and 1.5 per 10 000 kidney recipients, respectively. CONCLUSIONS: In kidney transplantation, operational tolerance and almost tolerance are infrequent findings associated with excellent long-term death-censored graft survival. PMID- 26763675 TI - Generalised anxiety disorder in children and adolescents. AB - INTRODUCTION: Generalised anxiety disorder (GAD) in a child or adolescent is excessive worry and tension about everyday events that the child or adolescent cannot control and that is expressed on most days for at least 6 months, to the extent that there is distress or difficulty in performing day-to-day tasks. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of pharmacological treatments for generalised anxiety disorder in children and adolescents? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). RESULTS: At this update, searching of electronic databases retrieved 949 studies. After deduplication and removal of conference abstracts, 417 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 310 studies and the further review of 107 full publications. Of the 107 full articles evaluated, one systematic review was added at this update. We performed a GRADE evaluation for six PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for six interventions based on information about the effectiveness and safety of antidepressants, antipsychotics, benzodiazepines, buspirone, hydroxyzine, and pregabalin. PMID- 26763677 TI - A novel mechanism to explain success of invasive herbaceous species at the expense of natives in eastern hardwood forests. PMID- 26763676 TI - Wilson's disease with and without rapid eye movement sleep behavior disorder compared to healthy matched controls. AB - OBJECTIVE: Quantitative data are reported on rapid eye movement (REM) sleep behavior disorder (RBD) in a cohort of predominantly neurological Wilson's disease (WD). METHODS: A total of 41 patients with WD and 41 healthy, age- and gender-matched controls were studied by conducting face-to-face interviews, neurological and clinical examinations, laboratory tests, and WD- and RBD specific scales. Video-polysomnography and quantification of REM sleep without atonia (RWA) were conducted in 35 patients and 41 controls. RESULTS: Patients with WD showed significantly worse sleep quality, less sleep efficiency, increased wakefulness after sleep onset, and more arousals compared to healthy controls. Five patients with WD (four women) fulfilled the diagnostic criteria for RBD with significantly higher values in RWA, RBD Questionnaire-Hong Kong, and RBD Screening Questionnaire compared to patients with WD without RBD. In three patients with WD, RBD had manifested before any other symptom that could be attributed to WD. Percentage of RWA was significantly lower in WD without RBD than in WD with RBD, but still significantly increased compared to controls. CONCLUSIONS: RBD can be comorbid with WD. RWA is commonly present in WD, both in the presence or absence of clinical RBD. A causal connection is possible, though retrospective determination of RBD onset and the low number of patients do not allow a definitive conclusion at this point. However, screening for WD in idiopathic RBD is available at low cost and is recommended. Early-stage copper chelation therapy provides a highly effective treatment to prevent further WD manifestations and might also control the comorbid RBD. PMID- 26763678 TI - Disentangling the factors shaping microbiota composition across the plant holobiont. PMID- 26763679 TI - Bacterial RNA - a new MAMP on the block? PMID- 26763681 TI - Corrigendum. Standards for plant synthetic biology: a common syntax for exchanges of DNA parts. PMID- 26763680 TI - Genetic control of mesophyll conductance in common wheat. PMID- 26763682 TI - Corrigendum. ZmpTAC12 binds single-stranded nucleic acids and is essential for accumulation of the plastid-encoded polymerase complex in maize. PMID- 26763683 TI - Cell cycle, proliferation and apoptosis in erythroblasts cultured from patients with beta-thalassaemia major. PMID- 26763685 TI - Sperm Accumulated Against Surface: A novel alternative bioassay for environmental monitoring. AB - Forecasting the impacts of changes in water quality on broadcast spawning aquatic organisms is a key aspect of environmental monitoring. Rapid assays of reproductive potential are central to this monitoring, and there is a need to develop a variety of methods to identify responses. Here, we report a proof-of concept study that assesses whether quantification of "Sperm Accumulated Against Surface" (SAAS) of tissue culture well-plates could be a rapid and simple proxy measure of fertilisation success. Our results confirm that motile sperm (but not immotile sperm) actively accumulate at surfaces and that the pattern of accumulation reflects fertilisation success in the model oyster species Crassostrea gigas. Furthermore, we confirm these patterns of SAAS for another marine species, the polychaete Galeolaria caespitosa, as well as for a freshwater species, the fish Gasterosteus aculeatus. For all species considered, SAAS reflected changes in sperm performance caused by experimentally manipulated differences in water quality (here, salinity). These findings indicate that SAAS could be applied easily to a range of species when examining the effects of water quality. Measurement of SAAS could, therefore, form the basis of a rapid and reliable assay for bioassessments of broadcast spawning aquatic organisms. PMID- 26763684 TI - Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia. AB - AIM(S): Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxic ischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients METHODS: Demographic, clinical and laboratory data of patients included in a multicentre prospective observational cohort study (the 'PharmaCool Study') were collected. A non-linear mixed-effects regression analysis (nonmem(r)) was performed to describe the population PK of gentamicin. The most optimal dosing regimen was evaluated based on simulations of the final model. RESULTS: A total of 47 patients receiving gentamicin were included in the analysis. The PK were best described by an allometric two compartment model with gestational age (GA) as a covariate on clearance (CL). During hypothermia the CL of a typical patient (3 kg, GA 40 weeks, 2 days post-natal age (PNA)) was 0.06 l kg-1 h-1 (inter individual variability (IIV) 26.6%) and volume of distribution of the central compartment (Vc) was 0.46 l kg-1 (IIV 40.8%). CL was constant during hypothermia and rewarming, but increased by 29% after reaching normothermia (>96 h PNA). CONCLUSIONS: This study describes the PK of gentamicin in neonates undergoing controlled hypothermia. The 29% higher CL in the normothermic phase compared with the preceding phases suggests a delay in normalization of CL after rewarming has occurred. Based on simulations we recommend an empiric dose of 5 mg kg-1 every 36 h or every 24 h for patients with GA 36-40 weeks and GA 42 weeks, respectively. PMID- 26763686 TI - The flip-or-flop boutique: Marine debris on the shores of St Brandon's rock, an isolated tropical atoll in the Indian Ocean. AB - Isolated coral atolls are not immune from marine debris accumulation. We identified Southeast Asia, the Indian sub-continent, and the countries on the Arabian Sea as most probable source areas of 50 000 items on the shores of St. Brandon's Rock (SBR), Indian Ocean. 79% of the debris was plastics. Flip-flops, energy drink bottles, and compact fluorescent lights (CFLs) were notable item types. The density of debris (0.74 m(-)(1) shore length) is comparable to similar islands but less than mainland sites. Intact CFLs suggests product-facilitated long-range transport of mercury. We suspect that aggregated marine debris, scavenged by the islands from currents and gyres, could re-concentrate pollutants. SBR islets accumulated debris types in different proportions suggesting that many factors act variably on different debris types. Regular cleaning of selected islets will take care of most of the accumulated debris and may improve the ecology and tourism potential. However, arrangements and logistics require more study. PMID- 26763687 TI - Etomidate exposure in early infant mice (P10) does not induce apoptosis or affect behaviour. AB - BACKGROUND: Numerous animal studies have shown that all commonly used intravenous anaesthetic drugs and volatile agents may cause neuronal apoptosis following exposure in early life. Most studies have focussed on detecting increased apoptosis but their methods are not always readily transferrable to humans. The lipid formulation of etomidate represents an alternative to the currently established intravenous anaesthetic agents but there is no animal or human data on apoptosis or long-term behavioural changes. The aim of our study was to investigate the effects of etomidate on cerebral neuronal apoptosis and long-term behavioural effects using an established mouse model that represents the clinically relevant period of anaesthesia during early infancy in humans. METHODS: Six groups of 10 day old mice (P10) were injected with either etomidate 0.3, 3 or 10 mg/kg, propofol 60 mg/kg, ketamine 50 mg/kg or placebo only. Apoptosis in the cerebral cortex and hippocampus was assessed 24 h after treatment (activated caspase-3). Late behavioural effects were tested at 2 months of age (spontaneous activity in a new environment). RESULTS: No evidence was found of differences in activated caspase 3-concentrations among the study groups. Significant late behavioural changes were only observed in the ketamine group. CONCLUSION: A single dose of etomidate in early infant mice at P10 did not produce evidence of cerebral apoptosis or impaired adult motor behaviour. PMID- 26763689 TI - Evolution of the YABBY gene family in seed plants. AB - Members of the YABBY gene family of transcription factors in angiosperms have been shown to be involved in the initiation of outgrowth of the lamina, the maintenance of polarity, and establishment of the leaf margin. Although most of the dorsal-ventral polarity genes in seed plants have homologs in non spermatophyte lineages, the presence of YABBY genes is restricted to seed plants. To gain insight into the origin and diversification of this gene family, we reconstructed the evolutionary history of YABBY gene lineages in seed plants. Our findings suggest that either one or two YABBY genes were present in the last common ancestor of extant seed plants. We also examined the expression of YABBY genes in the gymnosperms Ephedra distachya (Gnetales), Ginkgo biloba (Ginkgoales), and Pseudotsuga menziesii (Coniferales). Our data indicate that some YABBY genes are expressed in a polar (abaxial) manner in leaves and female cones in gymnosperms. We propose that YABBY genes already acted as polarity genes in the last common ancestor of extant seed plants. PMID- 26763688 TI - HTA Implementation Roadmap in Central and Eastern European Countries. AB - The opportunity cost of inappropriate health policy decisions is greater in Central and Eastern European (CEE) compared with Western European (WE) countries because of poorer population health and more limited healthcare resources. Application of health technology assessment (HTA) prior to healthcare financing decisions can improve the allocative efficiency of scarce resources. However, few CEE countries have a clear roadmap for HTA implementation. Examples from high income countries may not be directly relevant, as CEE countries cannot allocate so much financial and human resources for substantiating policy decisions with evidence. Our objective was to describe the main HTA implementation scenarios in CEE countries and summarize the most important questions related to capacity building, financing HTA research, process and organizational structure for HTA, standardization of HTA methodology, use of local data, scope of mandatory HTA, decision criteria, and international collaboration in HTA. Although HTA implementation strategies from the region can be relevant examples for other CEE countries with similar cultural environment and economic status, HTA roadmaps are not still fully transferable without taking into account country-specific aspects, such as country size, gross domestic product per capita, major social values, public health priorities, and fragmentation of healthcare financing. PMID- 26763690 TI - Photoinduced charge generation rates in soluble P3HT : PCBM nano-aggregates predict the solvent-dependent film morphology. AB - The device efficiency of bulk heterojunction (BHJ) solar cells is critically dependent on the nano-morphology of the solution-processed polymer : fullerene blend. Active control on blend morphology can only emanate from a detailed understanding of solution structures during the film casting process. Here we use photoinduced charge transfer (CT) rates to probe the effective length scale of the pre-formed solution structures and their energy disorder arising from a mixture of poly(3-hexylthiophene-2,5-diyl) (P3HT) and [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) in three different organic solvents. The observed solvent-dependent ultrafast biphasic rise of the transient polaron state in solution along with changes detected in the C=C stretching frequency of bound PCBM provides direct evidence for film-like P3HT : PCBM interfaces in solution. Using the diffusive component of the charge transfer rate, we deduce ~3-times larger functional nano-domain size in toluene than in chlorobenzene thereby correctly predicting the relative polymer nanofiber widths observed in annealed films. We thus provide first experimental evidence for the postulated polymer : fullerene : solvent ternary phase that seeds the eventual morphology in spin-cast films. Our work motivates the design of new chemical additives to tune the grain size of the evolving polymer : fullerene domains within the solution phase. PMID- 26763691 TI - Lung cancer incidence and mortality in China, 2010. AB - BACKGROUND: The National Central Cancer Registry of China (NCCR) is responsible for cancer surveillance. Local cancer registries in each province submit data for annual publication. The incidence and mortality of lung cancer in China in 2010 by age, gender, and area is reported in this article. METHODS: In 2013, 145 of 219 population-based cancer registries' 2010 data were selected after quality evaluation. Classification included Western, Middle, and Eastern areas, and the crude incidence and mortality rates of lung cancer were calculated by age, gender, and urban and rural. Age-standardized rates were determined by China and World standard population data. The 6th National Population Census data of China was used, combined with the registries' data to estimate the lung cancer burden in China in 2010. RESULTS: Lung cancer had the highest incidence and mortality in China for men and women. It was estimated that 605 946 lung cancer cases were diagnosed in China in 2010, with a crude incidence rate of 46.08/100 000, and 486 555 patients died from lung cancer, with a crude mortality rate of 37.00/100 000. Age-standardized rates for incidence were 35.23/100 000 and 35.04/100 000, respectively. Incidence and mortality rates for lung cancer were higher in men and urban areas than those in women and rural areas, reaching a peak for subjects of 80-84 years old. CONCLUSION: Lung cancer has the highest incidence and mortality of all cancers in China, especially for males in urban areas. Our findings justify the need to plan and develop effective interventions, such as air pollution control and smoking deterrents, to control and prevent the spread of lung cancer in China. PMID- 26763692 TI - Vitamin B12 deficiency among asymptomatic healthy infants: its impact on the immune system. AB - AIM: The immunomodulatory effects of vitamin B12 deficiency in children have not yet been established in the literature. In the current study, the effects of vitamin B12 on the immune system in asymptomatic and otherwise healthy infants have been studied. METHODS: The study was conducted at Marmara University, "well child" outpatient clinic. Vitamin B12 level was measured in a cohort of 611 healthy term infants, followed regularly for at least 6 months. Immunoglobulin measurements, lymphocyte subset analysis, cytokine production analysis, lymphocyte proliferation assays and evaluation of lymphocyte apoptosis were performed in a subset of 60 infants. RESULTS: In this cohort, one out of three babies displayed vitamin B12 deficiency. The percentage of CD4+CD25+ regulatory T cells (Tregs) was lower in vitamin B12 deficient babies than in controls. Although the percentage of Tregs increased after treatment, the change was not significant. There was no difference of cytokine levels between vitamin B12 deficient and control groups. However, proinflammatory cytokines were reduced after treatment. No significant difference was observed for immunoglobulins, early apoptosis and lymphocyte proliferation. CONCLUSION: Vitamin B12 deficiency is an underestimated health problem among the developing countries. The clinical consequences of the decreased percentage of Tregs associated with ?vitamin B12 deficiency, and reduction of proinflammatory cytokines after vitamin supplementation needs to be further studied, especially in terms of emerging allergies, autoimmune disorders and anti-inflammatory effects. PMID- 26763693 TI - Mammalian development does not recapitulate suspected key transformations in the evolutionary detachment of the mammalian middle ear. AB - The ectotympanic, malleus and incus of the developing mammalian middle ear (ME) are initially attached to the dentary via Meckel's cartilage, betraying their origins from the primary jaw joint of land vertebrates. This recapitulation has prompted mostly unquantified suggestions that several suspected--but similarly unquantified--key evolutionary transformations leading to the mammalian ME are recapitulated in development, through negative allometry and posterior/medial displacement of ME bones relative to the jaw joint. Here we show, using uCT reconstructions, that neither allometric nor topological change is quantifiable in the pre-detachment ME development of six marsupials and two monotremes. Also, differential ME positioning in the two monotreme species is not recapitulated. This challenges the developmental prerequisites of widely cited evolutionary scenarios of definitive mammalian middle ear (DMME) evolution, highlighting the requirement for further fossil evidence to test these hypotheses. Possible association between rear molar eruption, full ME ossification and ME detachment in marsupials suggests functional divergence between dentary and ME as a trigger for developmental, and possibly also evolutionary, ME detachment. The stable positioning of the dentary and ME supports suggestions that a 'partial mammalian middle ear' as found in many mammaliaforms--probably with a cartilaginous Meckel's cartilage--represents the only developmentally plausible evolutionary DMME precursor. PMID- 26763694 TI - Replicated divergence in cichlid radiations mirrors a major vertebrate innovation. AB - Decoupling of the upper jaw bones--jaw kinesis--is a distinctive feature of the ray-finned fishes, but it is not clear how the innovation is related to the extraordinary diversity of feeding behaviours and feeding ecology in this group. We address this issue in a lineage of ray-finned fishes that is well known for its ecological and functional diversity--African rift lake cichlids. We sequenced ultraconserved elements to generate a phylogenomic tree of the Lake Tanganyika and Lake Malawi cichlid radiations. We filmed a diverse array of over 50 cichlid species capturing live prey and quantified the extent of jaw kinesis in the premaxillary and maxillary bones. Our combination of phylogenomic and kinematic data reveals a strong association between biting modes of feeding and reduced jaw kinesis, suggesting that the contrasting demands of biting and suction feeding have strongly influenced cranial evolution in both cichlid radiations. PMID- 26763696 TI - Colony pace: a life-history trait affecting social insect epidemiology. AB - Among colonies of social insects, the worker turnover rate (colony 'pace') typically shows considerable variation. This has epidemiological consequences for parasites, because in 'fast-paced' colonies, with short-lived workers, the time of parasite residence in a given host will be reduced, and further transmission may thus get less likely. Here, we test this idea and ask whether pace is a life history strategy against infectious parasites. We infected bumblebees (Bombus terrestris) with the infectious gut parasite Crithidia bombi, and experimentally manipulated birth and death rates to mimic slow and fast pace. We found that fewer workers and, importantly, fewer last-generation workers that are responsible for rearing sexuals were infected in colonies with faster pace. This translates into increased fitness in fast-paced colonies, as daughter queens exposed to fewer infected workers in the nest are less likely to become infected themselves, and have a higher chance of founding their own colonies in the next year. High worker turnover rate can thus act as a strategy of defence against a spreading infection in social insect colonies. PMID- 26763695 TI - Irrational time allocation in decision-making. AB - Time is an extremely valuable resource but little is known about the efficiency of time allocation in decision-making. Empirical evidence suggests that in many ecologically relevant situations, decision difficulty and the relative reward from making a correct choice, compared to an incorrect one, are inversely linked, implying that it is optimal to use relatively less time for difficult choice problems. This applies, in particular, to value-based choices, in which the relative reward from choosing the higher valued item shrinks as the values of the other options get closer to the best option and are thus more difficult to discriminate. Here, we experimentally show that people behave sub-optimally in such contexts. They do not respond to incentives that favour the allocation of time to choice problems in which the relative reward for choosing the best option is high; instead they spend too much time on problems in which the reward difference between the options is low. We demonstrate this by showing that it is possible to improve subjects' time allocation with a simple intervention that cuts them off when their decisions take too long. Thus, we provide a novel form of evidence that organisms systematically spend their valuable time in an inefficient way, and simultaneously offer a potential solution to the problem. PMID- 26763697 TI - Resilience and stability of a pelagic marine ecosystem. AB - The accelerating loss of biodiversity and ecosystem services worldwide has accentuated a long-standing debate on the role of diversity in stabilizing ecological communities and has given rise to a field of research on biodiversity and ecosystem functioning (BEF). Although broad consensus has been reached regarding the positive BEF relationship, a number of important challenges remain unanswered. These primarily concern the underlying mechanisms by which diversity increases resilience and community stability, particularly the relative importance of statistical averaging and functional complementarity. Our understanding of these mechanisms relies heavily on theoretical and experimental studies, yet the degree to which theory adequately explains the dynamics and stability of natural ecosystems is largely unknown, especially in marine ecosystems. Using modelling and a unique 60-year dataset covering multiple trophic levels, we show that the pronounced multi-decadal variability of the Southern California Current System (SCCS) does not represent fundamental changes in ecosystem functioning, but a linear response to key environmental drivers channelled through bottom-up and physical control. Furthermore, we show strong temporal asynchrony between key species or functional groups within multiple trophic levels caused by opposite responses to these drivers. We argue that functional complementarity is the primary mechanism reducing community variability and promoting resilience and stability in the SCCS. PMID- 26763698 TI - Moa diet fits the bill: virtual reconstruction incorporating mummified remains and prediction of biomechanical performance in avian giants. AB - The moa (Dinornithiformes) are large to gigantic extinct terrestrial birds of New Zealand. Knowledge about niche partitioning, feeding mode and preference among moa species is limited, hampering palaeoecological reconstruction and evaluation of the impacts of their extinction on remnant native biota, or the viability of exotic species as proposed ecological 'surrogates'. Here we apply three dimensional finite-element analysis to compare the biomechanical performance of skulls from five of the six moa genera, and two extant ratites, to predict the range of moa feeding behaviours relative to each other and to living relatives. Mechanical performance during biting was compared using simulations of the birds clipping twigs based on muscle reconstruction of mummified moa remains. Other simulated food acquisition strategies included lateral shaking, pullback and dorsoventral movement of the skull. We found evidence for limited overlap in biomechanical performance between the extant emu (Dromaius novaehollandiae) and extinct upland moa (Megalapteryx didinus) based on similarities in mandibular stress distribution in two loading cases, but overall our findings suggest that moa species exploited their habitats in different ways, relative to both each other and extant ratites. The broad range of feeding strategies used by moa, as inferred from interspecific differences in biomechanical performance of the skull, provides insight into mechanisms that facilitated high diversities of these avian herbivores in prehistoric New Zealand. PMID- 26763699 TI - Evolutionary origins of germline segregation in Metazoa: evidence for a germ stem cell lineage in the coral Orbicella faveolata (Cnidaria, Anthozoa). AB - The ability to segregate a committed germ stem cell (GSC) lineage distinct from somatic cell lineages is a characteristic of bilaterian Metazoans. However, the occurrence of GSC lineage specification in basally branching Metazoan phyla, such as Cnidaria, is uncertain. Without an independently segregated GSC lineage, germ cells and their precursors must be specified throughout adulthood from continuously dividing somatic stem cells, generating the risk of propagating somatic mutations within the individual and its gametes. To address the potential for existence of a GSC lineage in Anthozoa, the sister-group to all remaining Cnidaria, we identified moderate- to high-frequency somatic mutations and their potential for gametic transfer in the long-lived coral Orbicella faveolata (Anthozoa, Cnidaria) using a 2b-RAD sequencing approach. Our results demonstrate that somatic mutations can drift to high frequencies (up to 50%) and can also generate substantial intracolonial genetic diversity. However, these somatic mutations are not transferable to gametes, signifying the potential for an independently segregated GSC lineage in O. faveolata. In conjunction with previous research on germ cell development in other basally branching Metazoan species, our results suggest that the GSC system may be a Eumetazoan characteristic that evolved in association with the emergence of greater complexity in animal body plan organization and greater specificity of stem cell functions. PMID- 26763700 TI - Tracking and forecasting ecosystem interactions in real time. AB - Evidence shows that species interactions are not constant but change as the ecosystem shifts to new states. Although controlled experiments and model investigations demonstrate how nonlinear interactions can arise in principle, empirical tools to track and predict them in nature are lacking. Here we present a practical method, using available time-series data, to measure and forecast changing interactions in real systems, and identify the underlying mechanisms. The method is illustrated with model data from a marine mesocosm experiment and limnologic field data from Sparkling Lake, WI, USA. From simple to complex, these examples demonstrate the feasibility of quantifying, predicting and understanding state-dependent, nonlinear interactions as they occur in situ and in real time--a requirement for managing resources in a nonlinear, non-equilibrium world. PMID- 26763702 TI - Rugged adaptive landscapes shape a complex, sympatric radiation. AB - Strong disruptive ecological selection can initiate speciation, even in the absence of physical isolation of diverging populations. Species evolving under disruptive ecological selection are expected to be ecologically distinct but, at least initially, genetically weakly differentiated. Strong selection and the associated fitness advantages of narrowly adapted individuals, coupled with assortative mating, are predicted to overcome the homogenizing effects of gene flow. Theoretical plausibility is, however, contrasted by limited evidence for the existence of rugged adaptive landscapes in nature. We found evidence for multiple, disruptive ecological selection regimes that have promoted divergence in the sympatric, incipient radiation of 'sharpfin' sailfin silverside fishes in ancient Lake Matano (Sulawesi, Indonesia). Various modes of ecological specialization have led to adaptive morphological differences between the species, and differently adapted morphs display significant but incomplete reproductive isolation. Individual fitness and variation in morphological key characters show that disruptive selection shapes a rugged adaptive landscape in this small but complex incipient lake fish radiation. PMID- 26763701 TI - The pertussis enigma: reconciling epidemiology, immunology and evolution. AB - Pertussis, a highly contagious respiratory infection, remains a public health priority despite the availability of vaccines for 70 years. Still a leading cause of mortality in developing countries, pertussis has re-emerged in several developed countries with high vaccination coverage. Resurgence of pertussis in these countries has routinely been attributed to increased awareness of the disease, imperfect vaccinal protection or high infection rates in adults. In this review, we first present 1980-2012 incidence data from 63 countries and show that pertussis resurgence is not universal. We further argue that the large geographical variation in trends probably precludes a simple explanation, such as the transition from whole-cell to acellular pertussis vaccines. Reviewing available evidence, we then propose that prevailing views on pertussis epidemiology are inconsistent with both historical and contemporary data. Indeed, we summarize epidemiological evidence showing that natural infection and vaccination both appear to provide long-term protection against transmission and disease, so that previously infected or vaccinated adults contribute little to overall transmission at a population level. Finally, we identify several promising avenues that may lead to a consistent explanation of global pertussis epidemiology and to more effective control strategies. PMID- 26763703 TI - Ambient temperature influences tolerance to plant secondary compounds in a mammalian herbivore. AB - Growing evidence suggests that plant secondary compounds (PSCs) ingested by mammals become more toxic at elevated ambient temperatures, a phenomenon known as temperature-dependent toxicity. We investigated temperature-dependent toxicity in the desert woodrat (Neotoma lepida), a herbivorous rodent that naturally encounters PSCs in creosote bush (Larrea tridentata), which is a major component of its diet. First, we determined the maximum dose of creosote resin ingested by woodrats at warm (28-29 degrees C) or cool (21-22 degrees C) temperatures. Second, we controlled the daily dose of creosote resin ingested at warm, cool and room (25 degrees C) temperatures, and measured persistence in feeding trials. At the warm temperature, woodrats ingested significantly less creosote resin; their maximum dose was two-thirds that of animals at the cool temperature. Moreover, woodrats at warm and room temperatures could not persist on the same dose of creosote resin as woodrats at the cool temperature. Our findings demonstrate that warmer temperatures reduce PSC intake and tolerance in herbivorous rodents, highlighting the potentially adverse consequences of temperature-dependent toxicity. These results will advance the field of herbivore ecology and may hone predictions of mammalian responses to climate change. PMID- 26763704 TI - Pleiotropic effects of juvenile hormone in ant queens and the escape from the reproduction-immunocompetence trade-off. AB - The ubiquitous trade-off between survival and costly reproduction is one of the most fundamental constraints governing life-history evolution. In numerous animals, gonadotropic hormones antagonistically suppressing immunocompetence cause this trade-off. The queens of many social insects defy the reproduction survival trade-off, achieving both an extraordinarily long life and high reproductive output, but how they achieve this is unknown. Here we show experimentally, by integrating quantification of gene expression, physiology and behaviour, that the long-lived queens of the ant Lasius niger have escaped the reproduction-immunocompetence trade-off by decoupling the effects of a key endocrine regulator of fertility and immunocompetence in solitary insects, juvenile hormone (JH). This modification of the regulatory architecture enables queens to sustain a high reproductive output without elevated JH titres and suppressed immunocompetence, providing an escape from the reproduction immunocompetence trade-off that may contribute to the extraordinary lifespan of many social insect queens. PMID- 26763705 TI - Experimental macroevolution. AB - The convergence of several disparate research programmes raises the possibility that the long-term evolutionary processes of innovation and radiation may become amenable to laboratory experimentation. Ancestors might be resurrected directly from naturally stored propagules or tissues, or indirectly from the expression of ancestral genes in contemporary genomes. New kinds of organisms might be evolved through artificial selection of major developmental genes. Adaptive radiation can be studied by mimicking major ecological transitions in the laboratory. All of these possibilities are subject to severe quantitative and qualitative limitations. In some cases, however, laboratory experiments may be capable of illuminating the processes responsible for the evolution of new kinds of organisms. PMID- 26763706 TI - Fitness costs of worker specialization for ant societies. AB - Division of labour is of fundamental importance for the success of societies, yet little is known about how individual specialization affects the fitness of the group as a whole. While specialized workers may be more efficient in the tasks they perform than generalists, they may also lack the flexibility to respond to rapid shifts in task needs. Such rigidity could impose fitness costs when societies face dynamic and unpredictable events, such as an attack by socially parasitic slavemakers. Here, we experimentally assess the colony-level fitness consequences of behavioural specialization in Temnothorax longispinosus ants that are attacked by the slavemaker ant T. americanus. We manipulated the social organization of 102 T. longispinosus colonies, based on the behavioural responses of all 3842 workers. We find that strict specialization is disadvantageous for a colony's annual reproduction and growth during slave raids. These fitness costs may favour generalist strategies in dynamic environments, as we also demonstrate that societies exposed to slavemakers in the field show a lower degree of specialization than those originating from slavemaker-free populations. Our findings provide an explanation for the ubiquity of generalists and highlight their importance for the flexibility and functional robustness of entire societies. PMID- 26763707 TI - Presence of a loner strain maintains cooperation and diversity in well-mixed bacterial communities. AB - Cooperation and diversity abound in nature despite cooperators risking exploitation from defectors and superior competitors displacing weaker ones. Understanding the persistence of cooperation and diversity is therefore a major problem for evolutionary ecology, especially in the context of well-mixed populations, where the potential for exploitation and displacement is greatest. Here, we demonstrate that a 'loner effect', described by economic game theorists, can maintain cooperation and diversity in real-world biological settings. We use mathematical models of public-good-producing bacteria to show that the presence of a loner strain, which produces an independent but relatively inefficient good, can lead to rock-paper-scissor dynamics, whereby cooperators outcompete loners, defectors outcompete cooperators and loners outcompete defectors. These model predictions are supported by our observations of evolutionary dynamics in well mixed experimental communities of the bacterium Pseudomonas aeruginosa. We find that the coexistence of cooperators and defectors that produce and exploit, respectively, the iron-scavenging siderophore pyoverdine, is stabilized by the presence of loners with an independent iron-uptake mechanism. Our results establish the loner effect as a simple and general driver of cooperation and diversity in environments that would otherwise favour defection and the erosion of diversity. PMID- 26763709 TI - Heritable variation in heat shock gene expression: a potential mechanism for adaptation to thermal stress in embryos of sea turtles. AB - The capacity of species to respond adaptively to warming temperatures will be key to their survival in the Anthropocene. The embryos of egg-laying species such as sea turtles have limited behavioural means for avoiding high nest temperatures, and responses at the physiological level may be critical to coping with predicted global temperature increases. Using the loggerhead sea turtle (Caretta caretta) as a model, we used quantitative PCR to characterise variation in the expression response of heat-shock genes (hsp60, hsp70 and hsp90; molecular chaperones involved in cellular stress response) to an acute non-lethal heat shock. We show significant variation in gene expression at the clutch and population levels for some, but not all hsp genes. Using pedigree information, we estimated heritabilities of the expression response of hsp genes to heat shock and demonstrated both maternal and additive genetic effects. This is the first evidence that the heat-shock response is heritable in sea turtles and operates at the embryonic stage in any reptile. The presence of heritable variation in the expression of key thermotolerance genes is necessary for sea turtles to adapt at a molecular level to warming incubation environments. PMID- 26763710 TI - The genomic basis of adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa. AB - Antibiotic resistance carries a fitness cost that must be overcome in order for resistance to persist over the long term. Compensatory mutations that recover the functional defects associated with resistance mutations have been argued to play a key role in overcoming the cost of resistance, but compensatory mutations are expected to be rare relative to generally beneficial mutations that increase fitness, irrespective of antibiotic resistance. Given this asymmetry, population genetics theory predicts that populations should adapt by compensatory mutations when the cost of resistance is large, whereas generally beneficial mutations should drive adaptation when the cost of resistance is small. We tested this prediction by determining the genomic mechanisms underpinning adaptation to antibiotic-free conditions in populations of the pathogenic bacterium Pseudomonas aeruginosa that carry costly antibiotic resistance mutations. Whole-genome sequencing revealed that populations founded by high-cost rifampicin-resistant mutants adapted via compensatory mutations in three genes of the RNA polymerase core enzyme, whereas populations founded by low-cost mutants adapted by generally beneficial mutations, predominantly in the quorum-sensing transcriptional regulator gene lasR. Even though the importance of compensatory evolution in maintaining resistance has been widely recognized, our study shows that the roles of general adaptation in maintaining resistance should not be underestimated and highlights the need to understand how selection at other sites in the genome influences the dynamics of resistance alleles in clinical settings. PMID- 26763712 TI - In vitro antimicrobial susceptibility of Alloscardovia omnicolens and molecular mechanisms of acquired resistance. AB - All the 31 isolates of Alloscardovia omnicolens exhibited low MICs for beta lactams, glycopeptides, linezolid, tetracyclines, and cotrimoxazole. One strain showed MICs >=256MUg/mL for both erythromycin and clindamycin with a single point mutation in 23S rRNA. One strain likely had acquired fluoroquinolone resistance associated with a unique mutation in ParC. PMID- 26763711 TI - Diversity and evolution of the primate skin microbiome. AB - Skin microbes play a role in human body odour, health and disease. Compared with gut microbes, we know little about the changes in the composition of skin microbes in response to evolutionary changes in hosts, or more recent behavioural and cultural changes in humans. No studies have used sequence-based approaches to consider the skin microbe communities of gorillas and chimpanzees, for example. Comparison of the microbial associates of non-human primates with those of humans offers unique insights into both the ancient and modern features of our skin associated microbes. Here we describe the microbes found on the skin of humans, chimpanzees, gorillas, rhesus macaques and baboons. We focus on the bacterial and archaeal residents in the axilla using high-throughput sequencing of the 16S rRNA gene. We find that human skin microbial communities are unique relative to those of other primates, in terms of both their diversity and their composition. These differences appear to reflect both ancient shifts during millions of years of primate evolution and more recent changes due to modern hygiene. PMID- 26763713 TI - Utility of in-house fluconazole disk diffusion susceptibility testing in the treatment of candidemia. AB - Among 302 first candidemia episodes, 210 (69.6%) were initially treated with an echinocandin or polyene (E/P) antifungal drug. In 137 (72.5%) patients with fluconazole-susceptible isolates, treatment was changed to fluconazole based on disk diffusion susceptibility testing. Clinical outcomes were not compromised in patients receiving E/P who were de-escalated to fluconazole for treatment of candidemia based on disk diffusion results. PMID- 26763714 TI - Palladium on Nitrogen-Doped Mesoporous Carbon: A Bifunctional Catalyst for Formate-Based, Carbon-Neutral Hydrogen Storage. AB - The lack of safe, efficient, and economical hydrogen storage technologies is a hindrance to the realization of the hydrogen economy. Reported herein is a reversible formate-based carbon-neutral hydrogen storage system that is established over a novel catalyst comprising palladium nanoparticles supported on nitrogen-doped mesoporous carbon. The support was fabricated by a hard template method and nitridated under a flow of ammonia. Detailed analyses demonstrate that this bicarbonate/formate redox equilibrium is promoted by the cooperative role of the doped nitrogen functionalities and the well-dispersed, electron-enriched palladium nanoparticles. PMID- 26763719 TI - Bonding and Anti-bonding Modes of Plasmon Coupling Effects in TiO2-Ag Core-shell Dimers. AB - Bonding and anti-bonding modes of plasmon coupling effects are numerically investigated in TiO2-Ag core-shell nano dimers. First, splitting phenomena of the coupled anti-bonding modes are observed under the longitudinal polarization when the distance between the monomers decreases to a certain level. Second, one of the split resonance modes is identified to be formed by the dipole anti-bonding mode of the monomers from charge density distribution patterns. Those split modes have similar redshift behaviors as the coupled dipole bonding modes in the same situations. Furthermore, the intensities of those anti-bonding modes weaken with decreasing distance between the monomers, because of the interaction of the induced dipole moment in the monomers and the charge distribution variation on the facing surfaces of the gap by the coulomb attraction. Other split bands are the higher-order mode (octupole-like or triakontadipole-like), which do not have obvious peak-shift behavior, and the intensities have very little attenuation with decreasing distance. Finally, the coupling of the bonding and anti-bonding modes under the longitudinal polarization is symmetric (bonding). PMID- 26763715 TI - Infrainguinal Endovascular Recanalization: Risk Factors for Arterial Thromboembolic Occlusions and Efficacy of Percutaneous Aspiration Thrombectomy. AB - PURPOSE: To investigate factors predictive of thromboembolic occlusions and evaluate the efficacy of percutaneous aspiration thrombectomy (PAT) for infrainguinal thromboembolic occlusions in patients undergoing endovascular recanalization (EVR). MATERIALS AND METHODS: In this single-center retrospective study, 23 patients who underwent PAT for thromboembolism during EVR and 237 patients who underwent successful EVR without thromboembolic occlusions (control group) were enrolled. Immediate posttreatment and follow-up outcomes between groups were compared. Multivariate analysis was performed to identify factors predictive of thromboembolic occlusions. Technical success of PAT was defined as achievement of < 30% residual stenosis and restoration of modified thrombolysis in myocardial infarction grade 3 flow. RESULTS: The technical success rate was 95.7% in the PAT group. After intervention, ankle brachial index (ABI), restoration of blood flow, and improvement in dorsal/plantar arterial pulse score showed no significant differences between the PAT and control groups. During follow-up, no significant differences were observed between groups in improvement of sustained ABI and maximum walking distance, ulcer healing, restenosis/occlusion and limb salvage rates, and pain relief in patients with critical ischemia. Stenosis greater than 90% with lesion occlusion (odds ratio, 12.891; 95% confidence interval, 1.676-99.161; P = .014) and intraluminal angioplasty (odds ratio, 18.423; 95% confidence interval, 2.408-140.942; P = .005) were associated with a high incidence of thromboembolism. CONCLUSIONS: Stenosis greater than 90% with lesion occlusion and intraluminal angioplasty may be factors predictive of thromboembolic occlusions. PAT is a safe and effective treatment for thromboembolism during infrainguinal arterial EVR. PMID- 26763720 TI - Revealing the ultrafast charge carrier dynamics in organo metal halide perovskite solar cell materials using time resolved THz spectroscopy. AB - Ultrafast charge carrier dynamics in organo metal halide perovskite has been probed using time resolved terahertz (THz) spectroscopy (TRTS). Current literature on its early time characteristics is unanimous: sub-ps charge carrier generation, highly mobile charges and very slow recombination rationalizing the exceptionally high power conversion efficiency for a solution processed solar cell material. Electron injection from MAPbI3 to nanoparticles (NP) of TiO2 is found to be sub-ps while Al2O3 NPs do not alter charge dynamics. Charge transfer to organic electrodes, Spiro-OMeTAD and PCBM, is sub-ps and few hundreds of ps respectively, which is influenced by the alignment of energy bands. It is surmised that minimizing defects/trap states is key in optimizing charge carrier extraction from these materials. PMID- 26763721 TI - Sex Differences in the Embryonic Development of the Central Oxytocin System in Mice. AB - Recent studies suggest that oxytocin (OXT) may be important for organising the neural circuitry that underlies adult social behaviour. Although most of the work exploring these effects has focused on early postnatal development, there is evidence that OXT may also be important during foetal development. However, without an understanding of how the OXT system develops, the ability to functionally link OXT in foetal life to adult behaviour is limited. To understand where and when OXT could be acting during embryonic development to affect the organisation of neural substrates, we examined the development of the mouse OXT system from embryonic day (E) 12.5 through postnatal day (PND) 2 using OXT receptor (OXTR) binding and a quantitative polymerase chain reaction. In both males and females, OXTR binding was observed by E16.5 in the ventricular and subventricular zones, as well as the developing amygdala. In males, OXT mRNA was not detectable until PND2, whereas it was detectable by E16.5 in females. OXTR mRNA was detected by E12.5 in both sexes, although females appear to have more OXTR mRNA during foetal development than males. The present study is significant because it is the first to reveal an unexpected sex difference in the development of the OXT system and supports the possibility that OXT during foetal development may contribute to sex differences in adult behaviour. PMID- 26763722 TI - Systematic Review and Meta-Analysis: Serum Infliximab Levels During Maintenance Therapy and Outcomes in Inflammatory Bowel Disease. AB - BACKGROUND AND AIMS: A number of observational studies have reported an association between serum levels of infliximab [IFX] at various thresholds, and clinical outcomes in inflammatory bowel disease [IBD]. This association has not previously been systematically analysed. METHODS: Systematic review of studies that reported serum infliximab levels according to outcomes in IBD. Primary outcome was clinical remission, and secondary outcomes included endoscopic remission, C-reactive protein [CRP] levels, and colectomy. Meta-analysis of raw data was performed where appropriate. A quality assessment was also undertaken. RESULTS: A total of 22 studies met the inclusion criteria, including 3483 patients; 12 studies reported IFX levels in a manner suitable for determining effect estimates. During maintenance therapy, patients in clinical remission had significantly higher mean trough IFX levels than patients not in remission: 3.1 ug/ml versus 0.9 ug/ml. The standardised mean difference in serum IFX levels between groups was 0.6 ug/ml (95% confidence interval [CI] 0.4-0.9, p = 0.0002]. Patients with an IFX level > 2 ug/ml were more likely to be in clinical remission (risk ratio [RR] 2.9, 95% CI 1.8-4.7, p < 0.001], or achieve endoscopic remission [RR 3, 95% CI 1.4-6.5, p = 0.004] than patients with levels < 2 ug/ml. CONCLUSIONS: There is a significant difference between serum infliximab levels in patients with IBD in remission, compared with those who relapse. A trough threshold during maintenance > 2 ug/ml is associated with a greater probability of clinical remission and mucosal healing. PMID- 26763723 TI - Patient engagement in clinical communication: an exploratory study. AB - AIM: Existing practice strategies for actively involving patients in care during hospitalisation are poorly understood. The aim of this study was to explore how healthcare professionals engaged patients in communication associated with care transitions. METHOD: An instrumental, collective case study approach was used to generate empirical data about patient transitions in care. A purposive sample of key stakeholders representing (i) patients and their families; (ii) hospital discharge planning team members; and (iii) healthcare professionals was recruited in five Australian health services. Individual and group semi-structured interviews were conducted to elicit detailed explanations of patient engagement in transition planning. Interviews lasted between 30 and 60 minutes and were digitally recorded and transcribed verbatim. Data collection and analysis were conducted simultaneously and continued until saturation was achieved. Thematic analysis was undertaken. RESULTS: Five themes emerged as follows: (i) organisational commitment to patient engagement; (ii) the influence of hierarchical culture and professional norms on patient engagement; (iii) condoning individual healthcare professionals' orientations and actions; (iv) understanding and negotiating patient preferences; and (v) enacting information sharing and communication strategies. Most themes illustrated how patient engagement was enabled; however, barriers also existed. CONCLUSION: Our findings show that strong organisational and professional commitment to patient-centred care throughout the organisation was a consistent feature of health services that actively engaged patients in clinical communication. Understanding patients' needs and preferences and having both formal and informal strategies to engage patients in clinical communication were important in how this involvement occurred. PMID- 26763724 TI - Epidemiological analysis of human fascioliasis in northeastern Punjab, Pakistan. AB - A coprological study was performed to assess human fascioliasis in 7200 subjects inhabiting rural communities of localities close to the capital city of Lahore in the northeastern part of the very highly populated Punjab province, Pakistan, a country where human infection had never been reported before 2005. The analysis of 1200 subjects including 50 subjects/month throughout a two-year study in each of six localities surveyed provided an overall prevalence of 1.18%, with a range between 0.67% and 1.75% according to localities. Infection rates did not differ according to gender, excepting a higher rate in females (1.13% vs 0.77%) in one locality. Prevalences according to age groups proved to be higher in 11-20 years with 1.57%, followed by 1.18% in 0-10 years and 0.47% in 21-30 years, while no infection above 30 years. Seasonal prevalences proved to be significantly different when comparing summer and autumn with winter and spring. Monthly prevalences showed two peaks, the highest in August (4.67%) and another in January (2.17%). Correlation studies of monthly prevalences with temperature, humidity, rainfall, and pan evaporation showed significant results only with humidity. Despite prevalences being low, the very high number of inhabitants and population densities of the areas surveyed suggest a wide public health problem potentially infecting up to 150,000 rural people, children included, only in the respective districts. Additionally, the situation becomes of more concern when considering the present climate change trend affecting the Punjab, which indicates a progressively increasing fascioliasis transmission risk in that animal endemic area in the near future. PMID- 26763725 TI - Delayed-onset cerebral infarction after cosmetic facial injection using hyaluronic acid. PMID- 26763726 TI - An observational retrospective evaluation of 79 young men with long-term adverse effects after use of finasteride against androgenetic alopecia. AB - Concern regarding adverse effects of finasteride is increasing. We aimed to determine the type and frequency of symptoms in men having long-term sexual and non-sexual side effects after finasteride treatment (a condition recently called post-finasteride syndrome, PFS) against androgenetic alopecia (AGA). Subjects were recruited at the Urology Unit of the Trieste University-Hospital, and from a dedicated website. Out of 79 participants, 34% were white Italians, mean age was 33.4 +/- 7.60 years, mean duration of finasteride use was 27.3 +/- 33.21 months; mean time from finasteride discontinuation was 44.1 +/- 34.20 months. Symptoms were investigated by an ad hoc 100 questions' questionnaire, and by validated Arizona Sexual Experience Scale (ASEX) and Aging Male Symptom Scale (AMS) questionnaires. By ASEX questionnaire, 40.5% of participants declared getting and keeping erection very difficult, and 3.8% never achieved; reaching orgasm was declared very difficult by 16.5%, and never achieved by 2.5%. By the ad hoc questionnaire, the most frequent sexual symptoms referred were loss of penis sensitivity (87.3%), decreased ejaculatory force (82.3%), and low penile temperature (78.5%). The most frequent non-sexual symptoms were reduced feeling of life pleasure or emotions (anhedonia) (75.9%); lack of mental concentration (72.2%), and loss of muscle tone/mass (51.9%). We contributed to inform about symptoms of PFS patients; unexpectedly loss of penis sensitivity was more frequent than severe erectile dysfunction and loss of muscle tone/mass was affecting half of the subjects. Further studies are necessary to investigate the pathophysiological and biochemical pathways leading to the post-finasteride syndrome. PMID- 26763727 TI - Ticagrelor vs clopidogrel followed by ticagrelor re-loading in patients with ST segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: A randomized, pharmacodynamic comparison. AB - Among patients allocated to ticagrelor in the primary percutaneous coronary intervention (PCI) cohort of Platelet Inhibition and Patient Outcomes (PLATO) trial, 40.7% had received pre-randomization 600 mg of clopidogrel. This scenario is frequently employed in real-world practice. In a prospective, three-center, single-blind, parallel design study, 74 P2Y12 inhibitor-naive patients undergoing primary PCI were randomized (Hour 0) to ticagrelor 180 mg loading dose (LD) vs clopidogrel 600 mg LD followed after 2 h by ticagrelor 180 mg re-LD. Platelet reactivity (VerifyNow, in PRU) was assessed at Hour 0, 2, 4, 6, and 24. The primary comparison was non-inferiority of ticagrelor to clopidogrel followed by ticagrelor re-LD regarding platelet reactivity at 24 h using a prespecified margin of <35 PRU for the upper bound of the one-sided 97.5% confidence interval (CI). Ticagrelor was proven non-inferior to clopidogrel followed by ticagrelor re LD with a difference between arms of 13.5 PRU (28.8 upper 97.5% CI), p = 0.001. At Hour 2, platelet reactivity was lower in ticagrelor only vs clopidogrel followed by ticagrelor re-LD groups with least square estimate mean difference (95% CI) -105.7 (-140.6 to -70.8), p < 0.001, without significant difference thereafter. In conclusion, in patients undergoing primary PCI, a strategy of ticagrelor LD only was proven non-inferior to clopidogrel LD followed by ticagrelor re-LD, in terms of antiplatelet efficacy at 24 h post-randomization and provided an earlier onset of platelet inhibition. PMID- 26763729 TI - Privacy, anonymity and subjectivity in genomic research. AB - The use of non-anonymized human genome data is becoming increasingly popular in research. Here we review the proceedings of a special meeting on this topic that took place at European Molecular Biology Organization (EMBO) in December 2014. The main points discussed centered on how to achieve 'anonymity,' 'trust,' and 'protection of data' in relation to new genomic technologies and research. Following our report of this meeting, we also raise three further issues for future consideration: the harmonization of international law in relation to genetic data protection; the complex issues around the 'dividual' nature of genetic data; and the growing commercial value of personal data. In conclusion, we stress the importance of scientists working in the area of genomic research engaging in interdisciplinary collaborations with humanities and social science scholars and addressing these complicated issues. PMID- 26763728 TI - Blockade of IL-18 signaling diminished neuropathic pain and enhanced the efficacy of morphine and buprenorphine. AB - Currently, the low efficacy of antinociceptive drugs for the treatment of neuropathic pain is a major therapeutic problem. Here, we show the potential role of interleukin (IL)-18 signaling in this phenomenon. IL-18 is an important molecule that performs various crucial functions, including the alteration of nociceptive transmission in response to neuropathic pain. We have studied the changes in the mRNA and protein levels (qRT-PCR and Western blot analysis, respectively) of IL-18, IL-18-binding protein (IL-18BP) and the IL-18 receptor (IL-18R) over time in rats following chronic constriction injury (CCI) of the sciatic nerve. Our study demonstrated that the spinal levels of IL-18BP were slightly downregulated at days 7 and 14 in the rats subjected to CCI. In contrast, the IL-18 and IL-18R mRNA expression and protein levels were elevated in the ipsilateral spinal cord on days 2, 7 and 14. Moreover, in rats exposed to a single intrathecal administration of IL-18BP (50 and 100 ng) 7 or 14 days following CCI, symptoms of neuropathic pain were attenuated, and the analgesia pursuant to morphine and buprenorphine (0.5 and 2.5 MUg) was enhanced. In summary, the restoration of the analgesic activity of morphine and buprenorphine via the blockade of IL-18 signaling suggests that increased IL-18 pathway may account for the decreased analgesic efficacy of opioids for neuropathic pain. PMID- 26763730 TI - Inflammation in rheumatology in 2015: New tools to tackle inflammatory arthritis. PMID- 26763731 TI - Rheumatoid arthritis: Missed opportunities in the 2015 ACR guideline for RA treatment. PMID- 26763732 TI - Distribution of crystalloid fluid changes with the rate of infusion: a population based study. AB - BACKGROUND: Crystalloid fluid requires 30 min for complete distribution throughout the extracellular fluid space and tends to cause long-standing peripheral edema. A kinetic analysis of the distribution of Ringer's acetate with increasing infusion rates was performed to obtain a better understanding of these characteristics of crystalloids. METHODS: Data were retrieved from six studies in which 76 volunteers and preoperative patients had received between 300 ml and 2375 ml of Ringer's acetate solution at a rate of 20-80 ml/min (0.33-0.83 ml/min/kg). Serial measurements of the blood hemoglobin concentration were used as inputs in a kinetic analysis based on a two-volume model with micro-constants, using software for nonlinear mixed effects. RESULTS: The micro-constants describing distribution (k12) and elimination (k10) were unchanged when the rate of infusion increased, with half-times of 16 and 26 min, respectively. In contrast, the micro-constant describing how rapidly the already distributed fluid left the peripheral space (k21) decreased by 90% when the fluid was infused more rapidly, corresponding to an increase in the half-time from 3 to 30 min. The central volume of distribution (V(c)) doubled. CONCLUSION: The return of Ringer's acetate from the peripheral fluid compartment to the plasma was slower with high than with low infusion rates. Edema is a normal consequence of plasma volume expansion with this fluid, even in healthy volunteers. The results are consistent with the view that the viscoelastic properties of the interstitial matrix are responsible for the distribution and redistribution characteristics of crystalloid fluid. PMID- 26763734 TI - Development of self-assembling peptide nanovesicle with bilayers for enhanced EGFR-targeted drug and gene delivery. AB - Development of rational vectors for efficient drug and gene delivery is crucial for cancer treatment. In this study, epidermal growth factor receptor (EGFR) binding peptide amphiphile (PA) were used as the primary bilayer skeleton material to construct ultra-stable self-assembling peptide nanovesicle (SPV). The resulted EGFR-targeted SPV (ESPV) could efficiently encapsulate therapeutic cargos (drugs or small interfering RNAs [siRNAs]) or labelled fluorescent cargo (quantum dots [QDs]) and exhibited excellent affinity for EGFR-positive cancer cells. Moreover, ESPV could deliver more drug or plasmid DNA to tumour sites and promote gene expression (a three-fold ratio of ESPVs vs cationic liposomes). Notably, the individual delivery or co-delivery of doxorubicin (DOX) and the acetylcholinesterase (AChE) gene via the ESPVs resulted in excellent drug/gene delivery both in vitro and in vivo and exerted a significant growth-suppressing effect on a liver cancer xenograft. This nanoscale, targeted cargo-packaging technology may provide a new strategy for the design of highly targeted cancer therapy vectors. PMID- 26763735 TI - Human stem cell decorated nanocellulose threads for biomedical applications. AB - Upon surgery, local inflammatory reactions and postoperative infections cause complications, morbidity, and mortality. Delivery of human adipose mesenchymal stem cells (hASC) into the wounds is an efficient and safe means to reduce inflammation and promote wound healing. However, administration of stem cells by injection often results in low cell retention, and the cells deposit in other organs, reducing the efficiency of the therapy. Thus, it is essential to improve cell delivery to the target area using carriers to which the cells have a high affinity. Moreover, the application of hASC in surgery has typically relied on animal-origin components, which may induce immune reactions or even transmit infections due to pathogens. To solve these issues, we first show that native cellulose nanofibers (nanofibrillated cellulose, NFC) extracted from plants allow preparation of glutaraldehyde cross-linked threads (NFC-X) with high mechanical strength even under the wet cell culture or surgery conditions, characteristically challenging for cellulosic materials. Secondly, using a xenogeneic free protocol for isolation and maintenance of hASC, we demonstrate that cells adhere, migrate and proliferate on the NFC-X, even without surface modifiers. Cross-linked threads were not found to induce toxicity on the cells and, importantly, hASC attached on NFC-X maintained their undifferentiated state and preserved their bioactivity. After intradermal suturing with the hASC decorated NFC-X threads in an ex vivo experiment, cells remained attached to the multifilament sutures without displaying morphological changes or reducing their metabolic activity. Finally, as NFC-X optionally allows facile surface tailoring if needed, we anticipate that stem-cell-decorated NFC-X opens a versatile generic platform as a surgical bionanomaterial for fighting postoperative inflammation and chronic wound healing problems. PMID- 26763733 TI - Folate-targeted pH-responsive calcium zoledronate nanoscale metal-organic frameworks: Turning a bone antiresorptive agent into an anticancer therapeutic. AB - Zoledronate (Zol) is a third-generation bisphosphonate that is widely used as an anti-resorptive agent for the treatment of cancer bone metastasis. While there is preclinical data indicating that bisphosphonates such as Zol have direct cytotoxic effects on cancer cells, such effect has not been firmly established in the clinical setting. This is likely due to the rapid absorption of bisphosphonates by the skeleton after intravenous (i.v.) administration. Herein, we report the reformulation of Zol using nanotechnology and evaluation of this novel nanoscale metal-organic frameworks (nMOFs) formulation of Zol as an anticancer agent. The nMOF formulation is comprised of a calcium zoledronate (CaZol) core and a polyethylene glycol (PEG) surface. To preferentially deliver CaZol nMOFs to tumors as well as facilitate cellular uptake of Zol, we incorporated folate (Fol)-targeted ligands on the nMOFs. The folate receptor (FR) is known to be overexpressed in several tumor types, including head-and-neck, prostate, and non-small cell lung cancers. We demonstrated that these targeted CaZol nMOFs possess excellent chemical and colloidal stability in physiological conditions. The release of encapsulated Zol from the nMOFs occurs in the mid endosomes during nMOF endocytosis. In vitro toxicity studies demonstrated that Fol-targeted CaZol nMOFs are more efficient than small molecule Zol in inhibiting cell proliferation and inducing apoptosis in FR-overexpressing H460 non-small cell lung and PC3 prostate cancer cells. Our findings were further validated in vivo using mouse xenograft models of H460 and PC3. We demonstrated that Fol targeted CaZol nMOFs are effective anticancer agents and increase the direct antitumor activity of Zol by 80-85% in vivo through inhibition of tumor neovasculature, and inhibiting cell proliferation and inducing apoptosis. PMID- 26763737 TI - In Reply. PMID- 26763736 TI - Systemic delivery of messenger RNA for the treatment of pancreatic cancer using polyplex nanomicelles with a cholesterol moiety. AB - Systemic delivery of messenger RNA (mRNA) is technically challenging because mRNA is highly susceptible to enzymatic degradation in the blood circulation. In this study, we used a nanomicelle-based platform, prepared from mRNA and poly(ethylene glycol) (PEG)-polycation block copolymers. A cholesterol (Chol) moiety was attached to the omega-terminus of the block copolymer to increase the stability of the nanomicelle by hydrophobic interaction. After in vitro screening, polyaspartamide with four aminoethylene repeats in its side chain (PAsp(TEP)) was selected as the cationic segment of the block copolymer, because it contributes to enhance nuclease resistance and high protein expression from the mRNA. After intravenous injection, PEG-PAsp(TEP)-Chol nanomicelles showed significantly enhanced blood retention of mRNA in comparison to nanomicelles without Chol. We used the nanomicelles for treating intractable pancreatic cancer in a subcutaneous inoculation mouse model through the delivery of mRNA encoding an anti-angiogenic protein (sFlt-1). PEG-PAsp(TEP)-Chol nanomicelles generated efficient protein expression from the delivered mRNA in tumor tissue, resulting in remarkable inhibition of the tumor growth, whereas nanomicelles without Chol failed to show a detectable therapeutic effect. In conclusion, the stabilized nanomicelle system led to the successful systemic delivery of mRNA in therapeutic application, holding great promise for the treatment of various diseases. PMID- 26763738 TI - Correlates of self-rated attachment in patients with cancer and their caregivers: a systematic review and meta-analysis. AB - BACKGROUND: This study aimed to evaluate the association between an anxious/avoidant attachment style and psychosocial variables in patients with cancer and their caregivers. METHODS: PsycINFO, PubMed, Google Scholar, and SCOPUS were searched for empirical studies published in peer-reviewed journals between 1994 and 2015, and unpublished data from one cohort were added. Meta analyses synthesized results from studies investigating the correlates of attachment styles, measured with validated scales, among patients with cancer or their caregivers. RESULTS: Thirteen studies (k = 13) were included in the quantitative synthesis (including unpublished data from one cohort). Anxious attachment was associated with depression (r = 0.29, CI 0.19-0.38, I(2) = 76%), anxiety (r = 0.34, CI 0.13-0.52, I(2) = 69%), and social support (r = -0.39, CI 0.55-0.21, I(2) = 87%). Avoidant attachment was associated with depressive symptoms (r = 0.20, CI 0.15-0.25, I(2) = 16%), anxiety (r = 0.13, CI 0.01-0.24, I(2) = 4%), and social support (r = -0.28, CI -0.42-0.14, I(2) = 75%). CONCLUSIONS: Patients with cancer and their caregivers showing high levels of insecure attachment are at risk of experiencing higher levels of depressive symptoms, anxiety, and poor social support. Findings suggest that clinicians' awareness of attachment styles may serve as important clinical insight to improve treatment outcomes. Large-scale studies and longitudinal studies are required to investigate distinct longitudinal pathways in cancer-related distress across different attachment styles Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26763739 TI - Aligned platinum nanowire networks from surface-oriented lipid cubic phase templates. AB - Mesoporous metal structures featuring a bicontinuous cubic morphology have a wide range of potential applications and novel opto-electronic properties, often orientation-dependent. We describe the production of nanostructured metal films 1 2 microns thick featuring 3D-periodic 'single diamond' morphology that show high out-of-plane alignment, with the (111) plane oriented parallel to the substrate. These are produced by electrodeposition of platinum through a lipid cubic phase (Q(II)) template. Further investigation into the mechanism for the orientation revealed the surprising result that the Q(II) template, which is tens of microns thick, is polydomain with no overall orientation. When thicker platinum films are grown, they also show increased orientational disorder. These results suggest that polydomain Q(II) samples display a region of uniaxial orientation at the lipid/substrate interface up to approximately 2.8 +/- 0.3 MUm away from the solid surface. Our approach gives previously unavailable information on the arrangement of cubic phases at solid interfaces, which is important for many applications of Q(II) phases. Most significantly, we have produced a previously unreported class of oriented nanomaterial, with potential applications including metamaterials and lithographic masks. PMID- 26763741 TI - High VEGF-A level at baseline predicts poor treatment effect of bevacizumab-based chemotherapy in metastatic colorectal cancer: a meta-analysis. AB - INTRODUCTION: Bevacizumab (BEV) improves survival of metastatic colorectal cancer (mCRC) patients, but no specific biomarkers can predict which patients will benefit from bevacizumab (BEV). This meta-analysis aimed to evaluate the predictive significance of plasma/intratumoral vascular endothelial growth factor A (VEGF-A) at baseline in the effectiveness of BEV-based treatment in mCRC. EVIDENCE ACQUISITION: The PubMed, Medline, and Embase were searched to identify eligible studies. The association of high/low VEGF-A level at baseline with progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) were analyzed. Subgroup analysis based on sample and chemotherapy was also conducted. The pooled hazard ratio (HR), risk ratio (RR) and 95% confidence interval (95% CI) were calculated to estimate the effects. EVIDENCE SYNTHESIS: Eleven eligible studies were included. This meta-analysis showed that high VEGF-A level at baseline was associated with poor PFS (HR=1.26, 95% CI [1.12, 1.42], P=0.0001) and OS (HR=1.30, 95% CI [1.15, 1.46], P<0.0001) of mCRC patients following BEV-based chemotherapy compared to low VEGF-A level. Subgroup analysis showed that the pooled results of PFS (blood and tumor tissue subgroup) and OS (blood subgroup) were similar to that of overall analysis. However, there was no significant difference in ORR between high and low VEGF-A level in tumor tissue subgroup (RR=0.95, 95% CI [0.53, 1.71], P=0.87). Moreover, the predictive role of high VEGF-A level at baseline was not impacted by various chemotherapies. CONCLUSIONS: This meta-analysis indicated that high plasma/intratumoral VEGF-A level at baseline could predict poor treatment effect (depressed PFS and OS) of BEV-based chemotherapy in mCRC, although there was no correlation between intratumoral VEGF-A level and ORR following BEV-based treatment. PMID- 26763742 TI - Monitoring of beta cell replacement outcomes. AB - Pancreatic islet transplantation is a promising beta cell replacement treatment for patients with "brittle" type 1 diabetes (T1D) or intractable chronic pancreatitis to restore or preserve pancreatic endocrine function. Early after transplant, a significant islet mass is lost due to an innate inflammatory response, and further loss of the islet graft occurs over time due to immune response, drug toxicity, or metabolic exhaustion. Thus, clinically feasible techniques are essential to monitor islet graft function and survival to maintain appropriate therapy. Currently, islet graft function is monitored using blood glucose levels, insulin and C-peptide levels, and islet imaging. However, these tests are influenced by physiological changes, including beta cell stimulation. Biomarkers that are independent of metabolic stimuli would be more accurate and reliable in detecting islet damage. Antibodies against islet autoantigens are useful but not reliable markers of islet injury due to their presence during the pretransplant period. Several islet-specific proteins such as Glutamate decarboxylase-65, doublecortin, protein phosphatase 1, regulatory (inhibitor) subunit 1A, ubiquitin C-terminal hydrolase-L1, and the high-mobility group box-1 protein have been proposed as candidates to monitor islet damage, but these biomarkers have short half-lives and unreliable detection. Unmethylated insulin DNA has been studied in T1D patients and has been documented as a highly correlative and selective biomarker for beta cell death. More recently, microRNAs (miRNAs) that are selectively expressed in islets have been shown to provide sensitive and accurate quantification of islet damage. Analysis of plasma samples from autologous and allogeneic islet transplant patients has demonstrated the value of miRNA-375 as a specific biomarker to accurately assess islet damage. Use of selective, sensitive, and measurably reproducible biomarkers of islets will lead to effective monitoring of beta cell replacement therapy and may also lead to development of preventative and interventional treatment strategies to improve outcomes. PMID- 26763740 TI - Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease. AB - Sclerostin is a potent inhibitor of osteoblastogenesis. Interestingly, newly diagnosed multiple myeloma (MM) patients have high levels of circulating sclerostin that correlate with disease stage and fractures. However, the source and impact of sclerostin in MM remains to be defined. Our goal was to determine the role of sclerostin in the biology of MM and its bone microenvironment as well as investigate the effect of targeting sclerostin with a neutralizing antibody (scl-Ab) in MM bone disease. Here we confirm increased sclerostin levels in MM compared with precursor disease states like monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM. Furthermore, we found that a humanized MM xenograft mouse model bearing human MM cells (NOD-SCID.CB17 male mice injected intravenously with 2.5 million of MM1.S-Luc-GFP cells) demonstrated significantly higher concentrations of mouse-derived sclerostin, suggesting a microenvironmental source of sclerostin. Associated with the increased sclerostin levels, activated beta-catenin expression levels were lower than normal in MM mouse bone marrow. Importantly, a high-affinity grade scl-Ab reversed osteolytic bone disease in this animal model. Because scl-Ab did not demonstrate significant in vitro anti-MM activity, we combined it with the proteasome inhibitor carfilzomib. Our data demonstrated that this combination therapy significantly inhibited tumor burden and improved bone disease in our in vivo MM mouse model. In agreement with our in vivo data, sclerostin expression was noted in marrow stromal cells and osteoblasts of MM patient bone marrow samples. Moreover, MM cells stimulated sclerostin expression in immature osteoblasts while inhibiting osteoblast differentiation in vitro. This was in part regulated by Dkk-1 secreted by MM cells and is a potential mechanism contributing to the osteoblast dysfunction noted in MM. Our data confirm the role of sclerostin as a potential therapeutic target in MM bone disease and provides the rationale for studying scl Ab combined with proteasome inhibitors in MM. (c) 2016 American Society for Bone and Mineral Research. PMID- 26763743 TI - Review: In vivo and postmortem effects of feed antioxidants in livestock: a review of the implications on authorization of antioxidant feed additives. AB - The pivotal roles of regulatory jurisdictions in the feed additive sector cannot be over-emphasized. In the European Union (EU), antioxidant substances are authorized as feed additives for prolonging the shelf life of feedstuffs based on their effect for preventing lipid peroxidation. However, the efficacy of antioxidants transcends their functional use as technological additives in animal feeds. Promising research results have revealed the in vivo efficacy of dietary antioxidants for combating oxidative stress in production animals. The in vivo effect of antioxidants is significant for enhancing animal health and welfare. Similarly, postmortem effect of dietary antioxidants has been demonstrated to improve the nutritional, organoleptic and shelf-life qualities of animal products. In practice, dietary antioxidants have been traditionally used by farmers for these benefits in livestock production. However, some antioxidants particularly when supplemented in excess could act as prooxidants and exert detrimental effects on animal well-being and product quality. Presently, there is no exclusive legislation in the EU to justify the authorization of antioxidant products for these in vivo and postmortem efficacy claims. To indicate these efficacy claims and appropriate dosage on product labels, it is important to broaden the authorization status of antioxidants through the appraisal of existing EU legislations on feed additives. Such regulatory review will have major impact on the legislative categorization of antioxidants and the efficacy assessment in the technical dossier application. The present review harnesses the scientific investigations of these efficacy claims in production animals and, proposes potential categorization and appraisal of in vivo methodologies for efficacy assessment of antioxidants. This review further elucidates the implication of such regulatory review on the practical application of antioxidants as feed additives in livestock production. Effecting these regulatory changes will stimulate the innovation of more potent antioxidant products and create potential new markets that will have profound economic impacts on the feed additive industry. Based on the in vivo efficacy claims, antioxidants may have to contend with the legislative controversy of either to be considered as veterinary drugs or feed additives. In this scenario, antioxidants are not intended to diagnose or cure diseases as ascribed to veterinary products. This twisted distinction can be logically debated with reference to the stipulated status of feed additives in Commission Regulation (EC) No 1831/2003. Nonetheless, it is imperative for relevant stakeholders in the feed additive industry to lobby for the review of existing EU legislations for authorization of antioxidants for these efficacy claims. PMID- 26763745 TI - Anomalous Origin of the Left Coronary Artery From the Pulmonary Artery in an Infant and Adult: Intraoperative Echocardiographic Comparison. PMID- 26763744 TI - Prognosis after surgical treatment for pancreatic cancer in patients aged 80 years or older: a multicenter study. AB - BACKGROUND: The optimal therapeutic strategy for very elderly pancreatic cancer patients remains to be determined. The aim of this study was to clarify the role of pancreatic resection in patients 80 years of age or older. METHODS: A retrospective multicenter analysis of 1401 patients who had undergone pancreatic resection for pancreatic cancer was performed. The patients aged >= 80 years (n = 99) were compared with a control group <80 years of age (n = 1302). RESULTS: There were no significant differences in the postoperative complications and mortality between the two groups. However, the prognosis of octogenarians was poorer than that of younger patients for both resectable and borderline resectable tumors. Importantly, there were few long-term survivors in the elderly group, especially among those with borderline resectable pancreatic cancer. A multivariate analysis of the prognostic factors in the very elderly patients indicated that the completion of adjuvant chemotherapy was the only significant factor. In addition, preoperative albumin level was the only independent risk factor for a failure to complete adjuvant chemotherapy. CONCLUSION: This study demonstrates that the postoperative prognosis in octogenarian patients was not good as that in younger patients possibly due to less frequent completion of adjuvant chemotherapy. PMID- 26763746 TI - Primary pulmonary collision tumor with three components in the underlying interstitial lung disease. AB - A collision tumor of the lung is relatively rare. We report a case of a 72-year old man with a collision tumor consisting of three neoplastic components in the underlying interstitial lung disease. Computed tomography showed a parenchymal lesion with an air bronchogram. Transthoracic needle lung biopsy showed chronic inflammation, however, a malignant pulmonary tumor was clinically suspected. The patient underwent a right lower lobectomy with mediastinal lymph node dissection. The histological features of the surgical specimen showed lung cancer with three neoplastic components, which were squamous cell carcinoma, invasive mucinous adenocarcinoma, and invasive non-mucinous adenocarcinoma. To the best of our knowledge, this is the first documentation of a collision lung tumor with three components. PMID- 26763747 TI - Transcriptome responses in alfalfa associated with tolerance to intensive animal grazing. AB - Tolerance of alfalfa (Medicago sativa L.) to animal grazing varies widely within the species. However, the molecular mechanisms influencing the grazing tolerant phenotype remain uncharacterized. The objective of this study was to identify genes and pathways that control grazing response in alfalfa. We analyzed whole plant de novo transcriptomes from grazing tolerant and intolerant populations of M. sativa ssp. falcata subjected to grazing by sheep. Among the Gene Ontology terms which were identified as grazing responsive in the tolerant plants and differentially enriched between the tolerant and intolerant populations (both grazed), most were associated with the ribosome and translation-related activities, cell wall processes, and response to oxygen levels. Twenty-one grazing responsive pathways were identified that also exhibited differential expression between the tolerant and intolerant populations. These pathways were associated with secondary metabolite production, primary carbohydrate metabolic pathways, shikimate derivative dependent pathways, ribosomal subunit composition, hormone signaling, wound response, cell wall formation, and anti-oxidant defense. Sequence polymorphisms were detected among several differentially expressed homologous transcripts between the tolerant and intolerant populations. These differentially responsive genes and pathways constitute potential response mechanisms for grazing tolerance in alfalfa. They also provide potential targets for molecular breeding efforts to develop grazing-tolerant cultivars of alfalfa. PMID- 26763748 TI - Synthesis and anti-tubercular activity of N(2)-arylbenzo[g]isoquinoline-5,10 dione-3-iminium bromides. AB - Tuberculosis has remained a challenge for medicinal chemists worldwide. In the framework of a collaborative program to identify and evaluate novel antitubercular candidate compounds, the biological properties of benzo[g]isoquinoline-5,10-diones have been found to be very promising. In this paper we have further expanded the library by incorporation of an amidinium moiety into the benzo[g]isoquinoline-5,10-dione scaffold. The presence of this functional group also increased the solubility of the quinones in polar solvents. To this purpose N(2)-arylbenzo[g]isoquinoline-5,10-dione-3-iminium bromides were synthesized in a straightforward way by means of a reaction of anilines with 2 (bromomethyl)-3-(cyanomethyl)-1,4-dimethoxynaphthalene. Following the biological evaluation, N(2)-(4-chlorophenyl)-5,10-dioxobenzo[g]isoquinoline-3(2H)-iminium bromide (MIC = 1.16 MUM, CC50 = 28.51 MUM, SI = 24.58) was selected as the most promising representative. Apart from the nano-molar anti-mycobacterial activity, the compound was able to target intracellular residing Mycobacterium tuberculosis and the susceptibility of a multi-drug-resistant strain towards the compound was confirmed. PMID- 26763751 TI - The penetration of acoustic cavitation bubbles into micrometer-scale cavities. AB - The penetration of acoustically induced cavitation bubbles in micrometer-scale cavities is investigated experimentally by means of high-speed photography and acoustic measurements. Micrometer-scale cavities of different dimensions (width=40 MUm, 80 MUm, 10 mm and depth=50 MUm) are designed to replicate the cross section of microvias in a PCB. The aim here is to present a method for enhancing mass transfer due to the penetration of bubbles in such narrow geometries under the action of ultrasound. The micrometer-scale cavities are placed in a test-cell filled with water and subjected to an ultrasound excitation at 75 kHz. A cavitation bubble cluster is generated at the mouth of the cavity which acts as a continuous source of bubbles that penetrate into the cavity. The radial oscillation characteristics and translation of these bubbles are investigated in detail here. It is observed that the bubbles arrange themselves into streamer-like structures inside the cavity. Parameters such as bubble population and size distribution and their correlation with the phase of the incident ultrasound radiation are investigated in detail here. This provides a valuable insight into the dynamics of bubbles in narrow confined spaces. Mass transfer investigations show that fresh liquid can be continuously introduced in the cavities under the action of ultrasound. Our findings may have important consequences in optimizing the filling processes for microvias with high aspect ratios. PMID- 26763750 TI - Infections due to Elizabethkingia meningoseptica in critically injured trauma patients: a seven-year study. AB - Elizabethkingia meningoseptica is an infrequent cause of hospital-acquired infections. The clinical and microbiological profiles of infections due to E. meningoseptica over a seven-year period at a Level-I trauma centre are reported in this study. Medical records of patients from whose clinical samples E. meningoseptica was isolated on more than one occasion were reviewed. A total of 21 cases were observed during the study, 16 (76.2%) of which exhibited multidrug resistance. The observed in-hospital mortality rate was 47.6%. A high index of clinical suspicion and effective detection of E. meningoseptica in clinical samples are requisite for improved clinical outcome. PMID- 26763749 TI - Bioengineering of noncoding RNAs for research agents and therapeutics. AB - The discovery of functional small noncoding RNAs (ncRNAs), such as microRNAs and small interfering RNAs, in the control of human cellular processes has opened new avenues to develop RNA-based therapies for various diseases including viral infections and cancers. However, studying ncRNA functions and developing RNA based therapeutics relies on access to large quantities of affordable ncRNA agents. Currently, synthetic RNAs account for the major source of agents for RNA research and development, yet carry artificial modifications on the ribose ring and phosphate backbone in sharp contrast to posttranscriptional modifications present on the nucleobases or unmodified natural RNA molecules produced within cells. Therefore, large efforts have been made in recent years to develop recombinant RNA techniques to cost-effectively produce biological RNA agents that may better capture the structure, function, and safety properties of natural RNAs. In this article, we summarize and compare current in vitro and in vivo methods for the production of RNA agents including chemical synthesis, in vitro transcription, and bioengineering approaches. We highlight the latest recombinant RNA approaches using transfer RNA (tRNA), ribosomal RNA (rRNA), and optimal ncRNA scaffold (OnRS), and discuss the applications of bioengineered ncRNA agents (BERAs) that should facilitate RNA research and development. PMID- 26763752 TI - Application of diffusion-edited and solvent suppression 1H-NMR to the direct analysis of markers in valerian-hop liquid herbal products. AB - INTRODUCTION: The rising trend to consume herbal products for the treatment and/or prevention of minor ailments together with their chemical and pharmacological complexity means there is an urgent need to develop new approaches to their quality and stability. OBJECTIVES: This work looks at the application of one-dimensional diffusion-edited (1)H-NMR spectroscopy (1D DOSY) and (1)H-NMR with suppression of the ethanol and water signals to the characterisation of quality and stability markers in multi-component herbal medicines/food supplements. MATERIAL AND METHODS: The experiments were performed with commercial tinctures of Valeriana officinalis L. (valerian), expired and non expired, as well as its combination with Hummulus lupulus L. (hops), which is one of the most popular blends of relaxant herbs. These techniques did not require purification or evaporation of components for the qualitative analysis of the mixture, but only the addition of D2 O and TSP. RESULTS: The best diagnostic signals were found at delta 7 ppm (H-11, valerenic acid), delta 4.2 ppm (H-1, hydroxyvalerenic acid) and delta 1.5-1.8 ppm (methyl groups in prenylated moieties, alpha-acids/prenylated flavones). CONCLUSION: This work concludes on the potential value of 1D DOSY (1)H-NMR to provide additional assurance of quality in complex natural mixtures. PMID- 26763753 TI - Incidence and Predictors of Cardiomyocyte Injury in Elective Coronary Angiography. AB - OBJECTIVE: Coronary angiography is considered to be a safe tool for the evaluation of coronary artery disease and performed in approximately 12 million patients each year worldwide. The aim of our study was to investigate the frequency and predictors of cardiomyocyte injury in patients undergoing elective coronary angiography. METHODS: A total of 749 consecutive patients who were scheduled to undergo elective coronary angiography were prospectively analyzed. High-sensitivity cardiac troponin T concentrations were measured both before and after elective coronary angiography (without intervention). Acute cardiomyocyte injury was predefined as an absolute increase in high-sensitivity cardiac troponin T of at least 7 ng/L (if also fulfilling a relative change of >20%). RESULTS: Acute cardiomyocyte injury was observed in 101 patients (13.5%, 95% confidence interval [CI], 11.1-16.2). It was independently associated with aortic valve stenosis (odds ratio [OR], 5.4; 95% CI, 3.0-9.8; P <.001), age (OR, 1.05; 95% CI, 1.02-1.08; P <.001), female sex (OR, 3.5; 95% CI, 1.8-6.8; P <.001), contrast volume (OR, 1.006; 95% CI, 1.001-1.012; P = .019 per 10 mL of contrast volume), documented cardiomyopathy (OR, 2.5; 95% CI, 1.0-6.0; P = .045), and mitral regurgitation (OR, 2.3; CI, 1.0-4.9; P = .033). In contrast, operator experience and extent of coronary artery disease were not found to be associated with acute cardiomyocyte injury. CONCLUSIONS: Cardiomyocyte injury accompanies elective coronary angiography in 1 of 8 patients. Sex, age, contrast agent volume, and ventricular disease, rather than the extent of coronary artery disease, independently predict cardiomyocyte injury. Further research aiming to reduce the incidence of cardiomyocyte injury seems warranted. PMID- 26763755 TI - Rash and Fever: Clues to an Elusive Hematologic Malignancy. PMID- 26763754 TI - Impact on Long-Term Mortality of Presence of Obstructive Coronary Artery Disease and Classification of Myocardial Infarction. AB - BACKGROUND: In contrast to the associated-with-thromboembolic-event type 1 myocardial infarction, type 2 myocardial infarction is caused by acute imbalance between oxygen supply and demand of myocardium. Type 2 myocardial infarction may be present in patients with or without obstructive coronary artery disease, but knowledge about patient characteristics, treatments, and outcome in relation to coronary artery status is lacking. We aimed to compare background characteristics, triggering mechanisms, treatment, and long-term prognosis in a large real-life cohort of patients with type 1 and type 2 myocardial infarction with and without obstructive coronary artery disease. METHODS: All 41,817 consecutive patients with type 1 and type 2 myocardial infarction registered in the Swedish myocardial infarction registry (SWEDEHEART) who underwent coronary angiography between January 1, 2011 and December 31, 2013, with the last follow up on December 31, 2014, were studied. RESULTS: In 92.8% of 40,501 patients classified as type 1 and in 52.5% of patients classified as type 2 myocardial infarction, presence of an obstructive coronary artery disease could be shown. Within the patients with obstructive coronary artery disease, those with type 2 myocardial infarction were older, and had more comorbidities and smaller necrosis as compared with type 1 myocardial infarction. In contrast, there was almost no difference in risk profile and extent of myocardial infarction between type 1 and type 2 myocardial infarction patients with nonobstructive coronary artery stenosis. The crude long-term mortality was higher in type 2 as compared with type 1 myocardial infarction with obstructive coronary artery disease (hazard ratio [HR] 1.72; 95% confidence interval [CI], 1.45-2.03), but was lower after adjustment (HR 0.76; 95% CI, 0.61-0.94). In myocardial infarction patients with nonobstructive coronary artery stenosis, the mortality risk was similar regardless of the clinical myocardial infarction type (crude HR 1.14; 95% CI, 0.84-1.55; adjusted HR 0.82; 95% CI, 0.52-1.29). CONCLUSIONS: The substantial differences in risk factors, treatment, and outcome in patients with type 1 and type 2 myocardial infarction with obstructive coronary artery disease supports the relevance of the division between type 1 and type 2 in this population. On the contrary, in patients with nonobstructive coronary artery stenosis, irrespective of the clinical type, a similar risk profile, extent of necrosis, and long-term prognosis were observed, indicating that distinction between type 1 and type 2 myocardial infarction in these patients seems to be inappropriate. PMID- 26763756 TI - Prognostic Impact of Myocardial Injury Related to Various Cardiac and Noncardiac Conditions. AB - BACKGROUND: Elevated cardiac troponins in clinical conditions other than myocardial infarction are well known. For such occurrences, the term "myocardial injury" has been proposed. The long-term outcome in patients with myocardial injury related to various cardiac and noncardiac clinical disorders is unknown. METHODS: During January 2010 to January 2011, we prospectively studied hospitalized patients who had cardiac troponin I measured on clinical indication. Patients with cardiac troponin I values >30 ng/L and no evidence of myocardial ischemia were diagnosed as having myocardial injury. Patients were classified into 5 categories of plausible related conditions: cardiac ischemic, cardiac nonischemic, noncardiac, multifactorial, or indeterminate. Follow-up was a minimum of 3 years, with all-cause mortality as the single end-point. RESULTS: A total of 3762 patients were considered, of whom 1089 (29%) had myocardial injury. The most common associated conditions were noncardiac (n = 346) or multifactorial (n = 359). Cardiac ischemic (n = 183) and cardiac nonischemic (n = 134) conditions occurred less frequently. After a median of 3.2 years, 645 patients (59%) had died. A multivariate Cox regression analysis showed no difference in mortality between patients with cardiac ischemic and cardiac nonischemic conditions (hazard ratio [HR] 0.75; 95% confidence interval [CI], 0.50-1.13; P = .2). Patients with noncardiac or multifactorial disorders, however, had significantly higher mortality than those with associated cardiac ischemic conditions (HR 1.39; 95% CI, 1.06-1.80; P = .02, and HR 1.94; 95% CI, 1.50-2.51; P <.001), respectively. CONCLUSIONS: In patients with myocardial injury, the most common associated conditions were noncardiac or multifactorial. Of notice, these patients had significantly higher long-term mortality when compared with those with associated cardiac conditions. PMID- 26763757 TI - Navigating in an unpredictable daily life: a metasynthesis on children's experiences living with a parent with severe mental illness. AB - A large group of individuals suffering from mental illness are parents living with their children. These children are invisible in the health care even though at risk for illhealth. The aim of this metasynthesis was to advance knowledge of how children of parents with mental illness experience their lives, thus contributing to the evidence of this phenomenon. The metasynthesis is following Sandelowski and Barroso's guidelines. Literature searches covering the years 2000 to 2013 resulted in 22 reports which were synthesised into the theme 'navigating in an unpredictable everyday life' and the metaphor compass. Children of parents with mental illness irrespective of age are responsible, loving and worrying children who want to do everything to help and support. Children feel shame when the parent behaves differently, and they conceal their family life being afraid of stigmatisation and bullying. When their parent becomes ill, they distance to protect themselves. The children cope through information, knowledge, frankness and trustful relationships. These children need support from healthcare services because they subjugate own needs in favour of the parental needs, they should be encouraged to talk about their family situation, and especially, young children should to be child-like, playing and seeing friends. PMID- 26763758 TI - The sibling species Leptidea juvernica and L. sinapis (Lepidoptera, Pieridae) in the Balkan Peninsula: ecology, genetic structure, and morphological variation. AB - The wood white butterfly Leptidea sinapis and its more recently discovered sibling species L. reali and L. juvernica have emerged as a model system for studying the speciation and evolution of cryptic species, as well as their ecological interactions in conditions of sympatry. Leptidea sinapis is widely distributed from Western Europe to Central Asia while the synmorphic L. juvernica and L. reali have allopatric distributions, both occurring in sympatry with L. sinapis and exhibiting an intricate, regionally variable ecological niche separation. Until now, the Balkan Peninsula remained one of the major unknowns in terms of distribution, genetic structure, and ecological preferences of the Leptidea triplet in Europe. We present new molecular and morphological data from a detailed survey of the region. Our DNA analysis suggests that the Balkan populations belong only to L. sinapis and L. juvernica, and that they are not genetically differentiated from other mainland populations. The distribution data reveal that L. sinapis is a widespread habitat generalist, while L. juvernica exhibits a transition from a habitat generalist in the western Balkans to a localised habitat specialist, confined to humid mountain habitats, in the east. The morphometric analysis of male genitalia and a comparison to data from other parts of the species' ranges suggest an interesting mosaic of regional morphological variation that is likely linked to environmental and ecological factors. We also demonstrate the usefulness of the genitalia scaling relations for analysing the morphological variation and discuss the implications for species identification. PMID- 26763759 TI - Undulation frequency affects burial performance in living and model flatfishes. AB - Flatfishes bury themselves under a thin layer of sand to hide from predators or to ambush prey. We investigated the role of undulation frequency of the body in burial in five species of flatfishes (Isopsetta isolepis, Lepidopsetta bilineata, Hippoglossoides elassodon, Parophrys vetulus, and Psettichthys melanostictus). High-speed videos show that undulations begin cranially and pass caudally while burying, as in forward swimming in many other fishes. The flatfishes also flick the posterior edge of their dorsal and anal fins during burial, which may increase the total surface area covered by substrate. We built a simple physical model - a flexible, oval silicone plate with a motorized, variable-speed actuator - to isolate the effect of undulation frequency on burial. In both the model and actuated dead flatfish, increased undulation frequency resulted in an increase in the area of sand coverage. Complete coverage required an undulation frequency of no more than 10Hz for our models, and that was also sufficient for live flatfishes. The model shows that undulation is sufficient to bury the animal, but live flatfishes showed a superior ability to bury, which we attribute to the action of the median fins. PMID- 26763760 TI - Functional allele and genotype frequencies of CYP1A2, CYP2B6 and iNOS among mainland Chinese Tibetan, Mongolian, Uygur and Han populations. AB - WHAT IS KNOWN AND OBJECTIVE: Cytochrome P450 1A2 (CYP1A2), CYP2B6 and inducible nitric oxide synthase (iNOS) are involved in the metabolism and action of many important therapeutic drugs, and genetic variants have been associated with interethnic differences in response to treatment, including chemotherapy. METHODS: Eight hundred and forty-two unrelated Chinese healthy subjects (323 Tibetan, 134 Mongolian, 162 Uygur and 223 Han) were recruited for genotyping. Frequencies of CYP1A2 -163C>A, CYP2B6 516G>T and iNOS -954G>C were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. RESULTS AND DISCUSSION: The frequency of CYP1A2-163A was higher in Chinese Mongolian (0.698) than in Chinese Tibetan (0.633), Uygur (0.633) and Han populations (0.608, P < 0.05), respectively. The frequency of CYP1A2-163A in the Chinese population (total, 0.636) was intermediate between those reported in Caucasians (0.682, P < 0.05) and Africans (0.549, P < 0.01). The frequency of CYP2B6 516T in Chinese Uygur (0.287) was significantly higher than those in Chinese Tibetan (0.147, P < 0.01) and Mongolian (0.179, P < 0.01), respectively, but was similar to the frequency in Chinese Han (0.226). The frequencies of CYP2B6 516T were in the order of Africans (0.500) > Caucasians (0.286) > Chinese (0.200). The variant iNOS-954C was rare in Chinese Tibetan (0.005), Mongolian (0.004), Uygur (0.000) and Han (0.007), respectively, but showed higher frequencies in African ethnic groups. The frequencies of iNOS-954C were in the order of Africans (0.098) > Chinese (0.004) > Caucasians (0.000). WHAT IS NEW AND CONCLUSION: This is the first report of the distribution frequencies of functional CYP1A2, CYP2B6 and iNOS genes among mainland Chinese Tibetan, Mongolian, Uygur and Han populations. These results should help inform studies of interethnic differences in disease susceptibility or drug responses. PMID- 26763761 TI - Tetracycline hydrochloride: A potential clinical drug for radioprotection. AB - Radiation exposure in planned scenario necessarily requires radioprotector for protection against radiation injuries in tissues and organs. A large number of potential radioprotectors have been investigated but no approved radioprotector is available. Hence, in quest for radioprotector, repurposing of clinical drug is an approach which aims at finding the radioprotective potential of known drugs so that in case of untoward accident the knowledge could be translated to drug usage. In this study, we have investigated the radical scavenging properties of tetracycline pertaining to radioprotection. Our study suggests that tetracycline hydrochloride efficiently scavenges free radicals in ABTS (2,2'-azino-bis(3 ethylbenzothiazoline-6-sulphonic acid), DPPH (2,2-diphenyl-1-picrylhydrazyl) and FRAP (ferric reducing antioxidant power) assays. Hydroxyl radical scavenging assay has demonstrated its ability to scavenge gamma radiation induced free radicals by lowering the formation of malondialdehyde. Radiation causes damage to macromolecules and hence the protection offered by tetracycline hydrochloride to DNA and protein shows its radioprotective potential. Plasmid DNA relaxation study with pBR322 has shown that tetracycline hydrochloride confers dose modification factor (DMF) of 2 and 4 at 100 MUM and 250 MUM concentration respectively. Tetracycline hydrochloride has also protected bovine serum albumin (BSA) from radiation induced degradation. The ex vivo studies for lipid peroxidation and mitochondrial membrane potential further substantiate our findings. The whole body animal survival study has shown the drug to offer 20% protection at a lethal radiation dose of 9 Gy. This study demonstrates the radioprotective potential of the drug by providing some insight into ex vivo and in vivo efficacy. PMID- 26763762 TI - Gene cloning, functional expression and characterisation of a novel type I pullulanase from Paenibacillus barengoltzii and its application in resistant starch production. AB - A novel pullulanase gene (PbPulA) from Paenibacillus barengoltzii was cloned. PbPulA has an open reading frame of 2028 bp encoding 675 amino acids. It was heterologously expressed in Escherichia coli as an intracellular soluble protein. The recombinant pullulanase (PbPulA) was purified to homogeneity with a molecular mass of about 75 kDa on SDS-PAGE. PbPulA was optimally active at pH 5.5 and 50 degrees C. It was stable within pH 5.5-10.5. The enzyme exhibited strict substrate specificity towards pullulan, but showed relatively low activity towards amylopectin and no activity towards other tested polysaccharides. The Km and Vmax values of the enzyme on pullulan were 2.94 mg/mL and 280.5 MUmol/min/mg, respectively. The addition of PbPulA in gelatinized rice and maize starches significantly increased the resistant starch type 3 (RS3) yields. Final yields from rice and maize starches were 10.82 g/100 g and 11.41 g/100 g, respectively. These properties make PbPulA useful in starch industries. PMID- 26763763 TI - Enzymatic dehairing of goat skins using alkaline protease from Bacillus sp. SB12. AB - The present paper reports the production, purification and biochemical characterization of an extracellular alkaline protease from Bacillus sp. SB12. The enzyme has been used as an alternative to conventional chemicals treatment for dehairing of goat skins. The protease was optimally active at 37 degrees C and pH 9. Starch at 2% (w/v) was used as the best carbon source and the addition of yeast extract and peptone at 1% each supported the maximum level of protease production in the presence of 5 mM Ca(2+). Protease purification was performed with ammonium sulphate precipitation at 70% saturated fraction followed by dialysis and gel filtration chromatography using Sephadex G-100. The purified enzyme was homogeneous on non-denaturing PAGE and appeared as a single band with an apparent molecular weight of 41 kDa. This enzyme was moderately thermostable and has a wide pH stability range extending from pH 7 to 11. It showed high tolerance toward surfactants agents and organic solvents while it was completely inhibited by PMSF indicating the serine protease type. Purified protease was used to remove hair from goat skin proving its potential application in leather processing industry. The results revealed that the protease has enhanced the quality and physico-chemical properties of the skins while reducing the pollution. PMID- 26763764 TI - Switching Opioid-Dependent Patients From Methadone to Morphine: Safety, Tolerability, and Methadone Pharmacokinetics. AB - The aim of this study was to switch patients established on methadone opioid substitution therapy (OST) to morphine over 1 week. Subjects established on daily methadone OST (mean dose 60 mg/day) were switched to morphine slow-release capsules, dosed at 4* the previous total daily methadone dose, for 6 days, then given morphine syrup dosed q3h. All 27 subjects enrolled in this study completed the switch from methadone to morphine. Opioid withdrawal symptoms (OWS) peaked within 12-24 hours of starting morphine, and 24/27 subjects required higher daily morphine doses (mean 5.2* multiple). Pharmacokinetic evaluation showed that 91% of methadone was cleared during this time, with a mean elimination half-life of 59 hours. The most frequent treatment-emergent non-OWS adverse events were headache, nausea, constipation, and neck pain. The method described here appears to be a safe and acceptable approach to switch subjects from methadone to morphine. PMID- 26763765 TI - Blood Transfusion in Major Abdominal Surgery for Malignant Tumors: A Trend Analysis Using the National Surgical Quality Improvement Program. AB - IMPORTANCE: Blood transfusion can be a lifesaving treatment for the surgical patient, yet transfusion-related immunomodulation may underlie the association of allogeneic transfusion with increased perioperative morbidity and possibly poorer long-term oncologic outcomes. OBJECTIVE: To evaluate trends in transfusion rates for major abdominal oncologic resections to assess changes in recent clinical practice (given the accumulating evidence of the deleterious effects of blood transfusion). DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of a population-based registry of all hospitals participating in the American College of Surgeons National Surgical Quality Improvement Project (2005-2013 Participant Use Data Files), which was queried for patients who underwent major resection of a pancreatic, hepatic, or gastric malignant tumor. Data analysis was performed from July to August 2015. MAIN OUTCOME AND MEASURES: The primary outcome was the transfusion of any quantity of packed red blood cells. Transfusion rates were calculated for the perioperative period, which was defined as the time from the start of surgery to 72 hours after surgery. Secondary outcomes included wound infection, myocardial infarction, and renal insufficiency, and the rates of these complications were calculated as well. Trend analysis was performed for each year of data to evaluate for changes over the study period. RESULTS: A total of 19 680 patients (median age, 65.0 years [interquartile range, 57.0-73.0 years]) were identified, of whom 5900 (30.0%) received a blood transfusion (of 13 657 patients who underwent a pancreatic resection, 4074 required transfusion [29.8%]; of 1605 patients who underwent a gastric resection, 378 required transfusion [23.6%]; and of 4418 patients who underwent a hepatic resection, 1448 required transfusion [32.8%]). There was a significant trend toward decreasing rates of transfusion during the study period (z = -7.89, P < .001), which corresponded to an absolute 6.1% decrease in the rate of transfusion of packed red blood cells from 2005 to 2013 (ie, from 32.8% to 26.7%). There was no significant change in the rates of postoperative wound infection or renal insufficiency during this time period, but there was an increased rate of perioperative myocardial infarction during the study period (0.33% absolute increase; z = 3.15, P = .002). CONCLUSIONS AND RELEVANCE: Over 9 years of contemporary practice, a trend of less perioperative blood transfusions for oncologic abdominal surgery was observed. Further studies are needed to assess whether these trends reflect changes in operative techniques, hospital cohorts, or transfusion thresholds. PMID- 26763766 TI - Ribosomal RNA analysis in the diagnosis of Diamond-Blackfan Anaemia. AB - Diamond-Blackfan anaemia (DBA) is an inherited disease characterized by pure erythroid aplasia that has been tagged as a 'ribosomopathy'. We report a multi centre study focused on the analysis of rRNA processing of 53 Italian DBA patients using capillary electrophoresis analysis of rRNA maturation of the 40S and 60S ribosomal subunits. The ratio of 28S/18S rRNA was higher in patients with mutated ribosomal proteins (RPs) of the small ribosomal subunit. In contrast, patients with mutated RPs of the large ribosomal subunit (RPLs) had a lower 28S/18S ratio. The assay reported here would be amenable for development as a diagnostic tool. PMID- 26763767 TI - Mediterranean dietary pattern in pregnant women and offspring risk of overweight and abdominal obesity in early childhood: the INMA birth cohort study. AB - BACKGROUND: Animal models have suggested that maternal diet quality may reduce offspring obesity risk regardless of maternal body weight; however, evidence from human studies is scarce. OBJECTIVE: The aim of this study was to evaluate associations between adherence to the Mediterranean diet (MD) during pregnancy and childhood overweight and abdominal obesity risk at 4 years of age. METHODS: We analysed 1827 mother-child pairs from the Spanish 'Infancia y Medio Ambiente' cohort study, recruited between 2003 and 2008. Diet was assessed during pregnancy using a food frequency questionnaire and MD adherence by the relative Mediterranean diet score (rMED). Overweight (including obesity) was defined as an age-specific and sex-specific body mass index >=85th percentile (World Health Organization referent), and abdominal obesity as a waist circumference (WC) >90th percentile. Multivariate adjusted linear and logistic regression models were used to evaluate associations between pregnancy rMED and offspring overweight and abdominal obesity. RESULT: There was no association between rMED and body mass index z-score, whereas there was a significant association between higher adherence to MD and lower WC (beta of high vs. low rMED: -0.62 cm; 95% confidence interval: -1.10, -0.14 cm, P for trend = 0.009). CONCLUSION: Pregnancy adherence to the MD was not associated with childhood overweight risk, but it was associated with lower WC, a marker of abdominal obesity. PMID- 26763768 TI - Novel heart valve prosthesis with self-endothelialization potential made of modified polyhedral oligomeric silsesquioxane-nanocomposite material. AB - In the cardiovascular system, the endothelial layer provides a natural antithrombogenic surface on the inner portion of the heart and associated vessels. For a synthetic material therefore, the ability to attract and retain endothelial or endothelial progenitor cells (EPCs), ultimately creating a single endothelial layer on its surface, is of prime importance. The authors have developed a nanocomposite polymer, based on a combination of polyhedral oligomeric silsesquioxane nanoparticles and polycarbonate urea urethane (POSS PCU), which is biocompatible and has been used in human for the world's first synthetic trachea, tear duct, and bypass graft. In this study, the authors modified the surface of this casted nanocomposite by grafting fibronectin derived bioactive peptides [glycine-arginine-glycine-aspartic acid-glycine (GRGDG) and lauric acid conjugated GRGDG (GRGDG-LA)] to enhance the endothelialization for using heart valves leaflets from circulating EPCs. Human peripheral blood mononuclear cells were separated using Ficoll-Paque centrifugation, with harvested EPCs purified using CD34 microbead labeling and magnetic-activated cell sorting. Cells were seeded onto 96 well plates coated with POSS-PCU, GRGDG/GRGDG LA modified POSS-PCU and PCU polymers, for a period of 21 days. Cells were studied under light, confocal, and scanning electron microscope (SEM). Fluorescence-activated cell sorting was used to analyze cell surface markers. Cell attachment and proliferation was observed in all POSS-PCU samples, significantly higher than the activity seen within the control PCU polymers (p < 0.05). Microscopic examination revealed clonal expansion and morphological changes in cells seeded on POSS-PCU. The cells expressed increasing levels of mature endothelial cell markers over time with a concurrent reduction in hematopoietic stem cell marker expression. SEM showed a mixed population of morphologically differentiated endothelial cells and EPCs. These results support the use of heart valve made with the POSS-PCU polymer and demonstrate that suitable chemical modification of this nanocomposite could increase self endothelialization potential and reduce associated thrombotic events. PMID- 26763769 TI - Antimicrobial properties of platelet-rich preparations. A systematic review of the current pre-clinical evidence. AB - In recent years autologous platelet concentrates (APCs) have become popular in several medicine fields, representing a valuable adjunct to regenerative surgical procedures. Beneficial effects in the control of postsurgical discomfort and infection have also been frequently reported, suggesting that APC may possess anti-inflammatory and antimicrobial properties. The aim of the present review was to summarize the current evidence regarding the antimicrobial effects of platelet concentrates, investigated by in vitro and animal studies. This review was conducted following a systematic approach. An electronic search was performed on MEDLINE, EMBASE and Scopus databases using appropriate search terms, without language or time restrictions. Preclinical studies assessing the antimicrobial activity of APC were included and divided according to the experimental design. Twenty in vitro studies and four animal studies, investigating APC effects on a broad range of microorganisms, were included. In in vitro studies APC reduced the growth of microorganisms during the first hours of incubation, while they could not completely break down the microbial load. In fact, over time a recovery of bacterial growth was always observed, suggesting that APCs display a bacteriostatic rather than a microbicidal activity. All animal studies showed that APC administered by local injections were able to reduce the infection caused by different microorganisms, although to a lesser extent compared to antibiotics. In conclusion, although the exact action mechanisms of interaction with microbial pathogens need further investigation, platelet concentrates proved to have antimicrobial properties, and therefore could represent a useful natural substance for controlling postoperative infections at surgical sites. PMID- 26763770 TI - Advances in the clinicopathological and molecular classification of cutaneous mesenchymal neoplasms. AB - In recent years, there have been several important refinements in the classification of cutaneous mesenchymal neoplasms, including the description of new tumour types, along with the identification of novel and recurrent molecular genetic findings. In addition to providing new insights into tumour biology, many of these advances have had significant clinical consequences with regard to diagnostics, management, and prognostication. Newly described entities include pseudomyogenic haemangioendothelioma, haemosiderotic fibrolipomatous tumour, and fibroblastic connective tissue naevus, which are reviewed in the context of the principal differential diagnoses and significant clinical implications. Genetic characterization of several soft tissue tumour types that occur in the skin has resulted in the identification of diagnostically useful markers: ALK gene rearrangement with corresponding ALK protein expression by immunohistochemistry in epithelioid fibrous histiocytoma; the WWTR1-CAMTA1 fusion gene with CAMTA1 protein expression in epithelioid haemangioendothelioma; MYC amplification and overexpression in radiation-associated angiosarcoma; and EWSR1 gene rearrangement in cutaneous myoepithelial tumours. Finally, the classification of intradermal smooth muscle tumours and unclassified/pleomorphic dermal sarcoma has been refined, resulting in both improved classification and improved prognostication. Many of the tumour types listed above are encountered not only by specialist dermatopathologists, but also by practising general surgical pathologists, and this review should therefore provide a widely applicable update on the histological and molecular classification of cutaneous mesenchymal neoplasms, along with the appropriate use of ancillary diagnostic tests, in particular immunohistochemistry, in the evaluation of such lesions and their histological mimics. PMID- 26763772 TI - Intubation Checklists: Expanding Beyond Single Centers. PMID- 26763771 TI - Perampanel as add-on treatment in refractory focal epilepsy. The Dianalund experience. AB - BACKGROUND: Perampanel (PER) is an antagonist of AMPA receptors that has been approved for adjunctive treatment of partial-onset seizures. AIMS: To evaluate effectiveness and safety of PER as add-on treatment in patients with severely refractory focal epilepsy. METHODS: PER was introduced as add-on treatment in 22 consecutive patients with drug-resistant focal epilepsy. PER was started with 2 mg/day at bedtime and was up-titrated by 2 mg/day every 2-4 weeks. RESULTS: All patients suffered from severely refractory focal epilepsy (86% took 2 or more AEDs prior PER initiation; 40% had been submitted to surgery or were surgery candidates; 7 had VNS). After 12 months since PER initiation, the retention rate was 54.5% and the responder rate was 27.2%, including 9.1% seizure-free patients. Mean PER dose in the responders was 8 mg/day (range 4-10). Most common side effects were tiredness, behavioral changes (primarily aggressivity), dizziness and were reported in 59.1% of patients, leading to PER discontinuation in 31.8% of subjects. CONCLUSIONS: PER as add-on treatment can achieve clinically meaningful improvement in patients suffering from severely refractory focal epilepses. Further studies are warranted to explore the tolerability profile, with particular focus on psychiatric adverse events. PMID- 26763773 TI - A randomised, double-blinded study comparing giving etoricoxib vs. placebo to female patients with fibromyalgia. AB - OBJECTIVES: Current therapeutic approaches to fibromyalgia syndrome (FMS) do not provide satisfactory pain control to a high percentage of patients. This unmet need constantly fuels the pursuit for new modalities for pain relief. This randomised, double-blind, controlled study assessed the efficacy and safety of adding etoricoxib vs. placebo to the current therapeutic regimen of female patients with FMS. METHODS: In this double-blind, placebo-controlled study, female patients were randomised to receive either 90 mg etoricoxib once daily or placebo for 6 weeks. Several physical and mental parameters were assessed throughout the study. The primary end-point was the response to treatment, defined as >= 30% reduction in the average Brief Pain Inventory score. Secondary outcomes were changes in the Fibromyalgia Impact Questionnaire, SF-36 Quality of Life assessment questionnaire and Hamilton rating scales for anxiety and depression. RESULTS: Overall, 73 patients were recruited. Although many outcome measures improved throughout the study, no difference was recorded between the etoricoxib- and placebo-treated groups. The Brief Pain Inventory, Fibromyalgia Impact Questionnaire, The Hamilton Anxiety and Depression scores did not differ between the two groups. CONCLUSIONS: This is the first randomised, double-blind study assessing the effect of adding etoricoxib to pre-existing medications for female patients with FMS. Although being mildly underpowered this study clearly has shown that etoricoxib did not improve pain scores and did not lead to any beneficial mental or physical effects. PMID- 26763774 TI - Web-based cognitive training for breast cancer survivors with cognitive complaints-a randomized controlled trial. AB - BACKGROUND: Cognitive complaints are common amongst breast cancer survivors, and no standard treatment exists. The present study evaluates whether web-based cognitive training can alleviate subjectively reported and objectively assessed cognitive complaints in a sample of breast cancer survivors. The primary and secondary outcomes were an objective measure of working memory and a measure of perceived cognitive functioning. Additional outcomes were neuropsychological tests of memory, executive function, working memory and questionnaire-based assessment of anxiety, depression and somatization. METHODS: A total of 157 female breast cancer survivors were recruited from an existing cohort and through announcements in open access cancer-related Internet fora and randomly allocated to either web-based cognitive training (eCogT) with telephone support (n = 94) or a waitlist control (WLC) condition (n = 63). eCogT encompassed 30 training sessions over 6 weeks. Neuropsychological assessments were undertaken over the telephone, and questionnaire data was collected online. Data was collected at baseline, post-intervention and at 5-month follow-up. RESULTS: Mixed linear models revealed no statistically significant change in primary or secondary outcome at follow-up in either group. Statistically significant improvements (p 0.040-0.043) were found in the eCogT group for verbal learning and on a working memory test. CONCLUSIONS: Web-based cognitive training did not result in improvements of the primary or secondary outcome. Improved performance was observed on verbal learning and working memory. These effects were observed at 5 month follow-up, indicating long-term effects of training. The intervention may be applied in a clinical setting at low cost and without risk of adverse effects.(c) 2016 The Authors Psycho-Oncology Published by John Wiley & Sons Ltd. PMID- 26763775 TI - A behaviorally related developmental switch in nitrergic modulation of locomotor rhythmogenesis in larval Xenopus tadpoles. AB - Locomotor control requires functional flexibility to support an animal's full behavioral repertoire. This flexibility is partly endowed by neuromodulators, allowing neural networks to generate a range of motor output configurations. In hatchling Xenopus tadpoles, before the onset of free-swimming behavior, the gaseous modulator nitric oxide (NO) inhibits locomotor output, shortening swim episodes and decreasing swim cycle frequency. While populations of nitrergic neurons are already present in the tadpole's brain stem at hatching, neurons positive for the NO-synthetic enzyme, NO synthase, subsequently appear in the spinal cord, suggesting additional as yet unidentified roles for NO during larval development. Here, we first describe the expression of locomotor behavior during the animal's change from an early sessile to a later free-swimming lifestyle and then compare the effects of NO throughout tadpole development. We identify a discrete switch in nitrergic modulation from net inhibition to overall excitation, coincident with the transition to free-swimming locomotion. Additionally, we show in isolated brain stem-spinal cord preparations of older larvae that NO's excitatory effects are manifested as an increase in the probability of spontaneous swim episode occurrence, as found previously for the neurotransmitter dopamine, but that these effects are mediated within the brain stem. Moreover, while the effects of NO and dopamine are similar, the two modulators act in parallel rather than NO operating serially by modulating dopaminergic signaling. Finally, NO's activation of neurons in the brain stem also leads to the release of NO in the spinal cord that subsequently contributes to NO's facilitation of swimming. PMID- 26763776 TI - Tactile texture signals in primate primary somatosensory cortex and their relation to subjective roughness intensity. AB - This study investigated the hypothesis that a simple intensive code, based on mean firing rate, could explain the cortical representation of subjective roughness intensity and its invariance with scanning speed. We examined the sensitivity of neurons in the cutaneous, finger representation of primary somatosensory cortex (S1) to a wide range of textures [1 mm high, raised-dot surfaces; spatial periods (SPs), 1.5-8.5 mm], scanned under the digit tips at different speeds (40-115 mm/s). Since subjective roughness estimates show a monotonic increase over this range and are independent of speed, we predicted that the mean firing rate of a subgroup of S1 neurons would share these properties. Single-unit recordings were made in four alert macaques (areas 3b, 1 and 2). Cells whose discharge rate showed a monotonic increase with SP, independent of speed, were particularly concentrated in area 3b. Area 2 was characterized by a high proportion of cells sensitive to speed, with or without texture sensitivity. Area 1 had intermediate properties. We suggest that area 3b and most likely area 1 play a key role in signaling roughness intensity, and that a mean rate code, signaled by both slowly and rapidly adapting neurons, is present at the level of area 3b. Finally, the substantial proportion of neurons that showed a monotonic change in discharge limited to a small range of SPs (often independent of response saturation) could play a role in discriminating smaller changes in SP. PMID- 26763777 TI - A quantitative confidence signal detection model: 1. Fitting psychometric functions. AB - Perceptual thresholds are commonly assayed in the laboratory and clinic. When precision and accuracy are required, thresholds are quantified by fitting a psychometric function to forced-choice data. The primary shortcoming of this approach is that it typically requires 100 trials or more to yield accurate (i.e., small bias) and precise (i.e., small variance) psychometric parameter estimates. We show that confidence probability judgments combined with a model of confidence can yield psychometric parameter estimates that are markedly more precise and/or markedly more efficient than conventional methods. Specifically, both human data and simulations show that including confidence probability judgments for just 20 trials can yield psychometric parameter estimates that match the precision of those obtained from 100 trials using conventional analyses. Such an efficiency advantage would be especially beneficial for tasks (e.g., taste, smell, and vestibular assays) that require more than a few seconds for each trial, but this potential benefit could accrue for many other tasks. PMID- 26763778 TI - Electroresponsive properties of rat central medial thalamic neurons. AB - The central medial thalamic (CMT) nucleus is a poorly known component of the middle thalamic complex that relays nociceptive inputs to the basolateral amygdala and cingulate cortex and plays a critical role in the control of awareness. The present study was undertaken to characterize the electroresponsive properties of CMT neurons. Similar to relay neurons found throughout the dorsal thalamus, CMT cells assumed tonic or burst-firing modes, depending on their membrane potentials (Vm). However, they showed little evidence of the hyperpolarization-activated mixed cationic conductance (IH)-mediated inward rectification usually displayed by dorsal thalamic relay cells at hyperpolarized Vm Two subtypes of CMT neurons were identified when comparing their responses with depolarization applied from negative potentials. Some cells generated a low threshold spike burst followed by tonic firing, whereas others remained silent after the initial burst, irrespective of the amount of depolarizing current injected. Equal proportions of the two cell types were found among neurons retrogradely labeled from the basolateral amygdala. Their morphological properties were heterogeneous but distinct from the classical bushy relay cell type that prevails in most of the dorsal thalamus. We propose that the marginal influence of IHin CMT relative to other dorsal thalamic nuclei has significant network-level consequences. Because IHpromotes the genesis of highly coherent delta oscillations in thalamocortical networks during sleep, these oscillations may be weaker or less coherent in CMT. Consequently, delta oscillations would be more easily disrupted by peripheral inputs, providing a potential mechanism for the reported role of CMT in eliciting arousal from sleep or anesthesia. PMID- 26763779 TI - Temporal correlations among functionally specialized striatal neural ensembles in reward-conditioned mice. AB - As the major input to the basal ganglia, the striatum is innervated by a wide range of other areas. Overlapping input from these regions is speculated to influence temporal correlations among striatal ensembles. However, the network dynamics among behaviorally related neural populations in the striatum has not been extensively studied. We used large-scale neural recordings to monitor activity from striatal ensembles in mice undergoing Pavlovian reward conditioning. A subpopulation of putative medium spiny projection neurons (MSNs) was found to discriminate between cues that predicted the delivery of a reward and cues that predicted no specific outcome. These cells were preferentially located in lateral subregions of the striatum. Discriminating MSNs were more spontaneously active and more correlated than their nondiscriminating counterparts. Furthermore, discriminating fast spiking interneurons (FSIs) represented a highly prevalent group in the recordings, which formed a strongly correlated network with discriminating MSNs. Spike time cross-correlation analysis showed the existence of synchronized activity among FSIs and feedforward inhibitory modulation of MSN spiking by FSIs. These findings suggest that populations of functionally specialized (cue-discriminating) striatal neurons have distinct network dynamics that sets them apart from nondiscriminating cells, potentially to facilitate accurate behavioral responding during associative reward learning. PMID- 26763780 TI - A population of gap junction-coupled neurons drives recurrent network activity in a developing visual circuit. AB - In many regions of the vertebrate brain, microcircuits generate local recurrent activity that aids in the processing and encoding of incoming afferent inputs. Local recurrent activity can amplify, filter, and temporally and spatially parse out incoming input. Determining how these microcircuits function is of great interest because it provides glimpses into fundamental processes underlying brain computation. Within the Xenopus tadpole optic tectum, deep layer neurons display robust recurrent activity. Although the development and plasticity of this local recurrent activity has been well described, the underlying microcircuitry is not well understood. Here, using a whole brain preparation that allows for whole cell recording from neurons of the superficial tectal layers, we identified a physiologically distinct population of excitatory neurons that are gap junctionally coupled and through this coupling gate local recurrent network activity. Our findings provide a novel role for neuronal coupling among excitatory interneurons in the temporal processing of visual stimuli. PMID- 26763781 TI - The neural dynamics of somatosensory processing and adaptation across childhood: a high-density electrical mapping study. AB - Young children are often hyperreactive to somatosensory inputs hardly noticed by adults, as exemplified by irritation to seams or labels in clothing. The neurodevelopmental mechanisms underlying changes in sensory reactivity are not well understood. Based on the idea that neurodevelopmental changes in somatosensory processing and/or changes in sensory adaptation might underlie developmental differences in somatosensory reactivity, high-density electroencephalography was used to examine how the nervous system responds and adapts to repeated vibrotactile stimulation over childhood. Participants aged 6 18 yr old were presented with 50-ms vibrotactile stimuli to the right wrist over the median nerve at 5 blocked interstimulus intervals (ranging from ~7 to ~1 stimulus per second). Somatosensory evoked potentials (SEPs) revealed three major phases of activation within the first 200 ms, with scalp topographies suggestive of neural generators in contralateral somatosensory cortex. Although overall SEPs were highly similar for younger, middle, and older age groups (6.1-9.8, 10.0 12.9, and 13.0-17.8 yr old), there were significant age-related amplitude differences in initial and later phases of the SEP. In contrast, robust adaptation effects for fast vs. slow presentation rates were observed that did not differ as a function of age. A greater amplitude response in the later portion of the SEP was observed for the youngest group and may be related to developmental changes in responsivity to somatosensory stimuli. These data suggest the protracted development of the somatosensory system over childhood, whereas adaptation, as assayed in this study, is largely in place by ~7 yr of age. PMID- 26763784 TI - Functional connectivity as a means to delineate differences between treatment resistant and treatment-responsive schizophrenia. AB - It has been estimated that one-third of schizophrenia patients are treatment resistant (TRS). Recent studies have shown that functional connectivity (FC) can be used for measuring connections between brain regions in diseased states. White, Wigton, Joyce, Collier, Fornito, and Shergill (Neuropsychopharmacology First published September 9, 2015; doi:10.1038/npp.2015.277) used FC to identify differences between schizophrenia patients responding to antipsychotic treatment and TRS patients. Their results support the idea that the groups differ not only in treatment response but also neurophysiologically through differences in FC. PMID- 26763783 TI - Repetition priming-induced changes in sensorimotor transmission. AB - When a behavior is repeated performance often improves, i.e., repetition priming occurs. Although repetition priming is ubiquitous, mediating mechanisms are poorly understood. We address this issue in the feeding network ofAplysia Similar to the priming observed elsewhere, priming inAplysiais stimulus specific, i.e., it can be either "ingestive" or "egestive." Previous studies demonstrated that priming alters motor and premotor activity. Here we sought to determine whether sensorimotor transmission is also modified. We report that changes in sensorimotor transmission do occur. We ask how they are mediated and obtain data that strongly suggest a presynaptic mechanism that involves changes in the "background" intracellular Ca(2+)concentration ([Ca(2+)]i) in primary afferents themselves. This form of plasticity has previously been described and generated interest due to its potentially graded nature. Manipulations that alter the magnitude of the [Ca(2+)]iimpact the efficacy of synaptic transmission. It is, however, unclear how graded control is exerted under physiologically relevant conditions. In the feeding system changes in the background [Ca(2+)]iare mediated by the induction of a nifedipine-sensitive current. We demonstrate that the extent to which this current is induced is altered by peptides (i.e., increased by a peptide released during the repetition priming of ingestive activity and decreased by a peptide released during the repetition priming of egestive activity). We suggest that this constitutes a behaviorally relevant mechanism for the graded control of synaptic transmission via the regulation of the [Ca(2+)]iin a neuron. PMID- 26763785 TI - Pseudahrensia todarodis sp. nov., isolated from the gut of a Japanese flying squid, Todarodes pacificus. AB - A novel Gram-stain-negative, non-motile, non-spore-forming, non-flagellated, aerobic, beige-coloured and rod-shaped bacterium, designated strain KHS02T, was isolated from the intestinal tract of a Japanese flying squid, Todarodes pacificus, which was collected from the East Sea, Korea. Phylogenetic analysis of 16S rRNA gene sequences revealed that strain KHS02T formed a monophyletic clade with Pseudahrensia aquimaris HDW-32T, with which it had the highest sequence similarity (98.67 %). Strain KHS02T grew optimally at pH 7 with 2 % (w/v) NaCl at 25 degrees C on marine broth 2216, but could not grow without Na+. The predominant isoprenoid quinone was ubiquinone-10 (Q-10). The major fatty acids (>10 % of the total) were summed feature 8 (C18 : 1omega6c and/or C18 : 1omega7c) and 11-methyl C18 : 1omega7c. The polar lipids of strain KHS02T comprised phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, two unidentified aminolipids, an unidentified phospholipid and an unidentified lipid. The genomic DNA G+C content was 58.6 mol%. DNA-DNA hybridization showed that the isolate shared 16.2 +/- 1.3 % (reciprocal, 15.7 +/- 2.8 %) genomic relatedness with the type strain of the closest species. In conclusion, this isolate is suggested to represent a novel species of the genus Pseudahrensia, for which the name Pseudahrensia todarodis is proposed. The type strain is KHS02T ( = KACC 18257T = JCM 30419T). PMID- 26763782 TI - KV1 channels identified in rodent myelinated axons, linked to Cx29 in innermost myelin: support for electrically active myelin in mammalian saltatory conduction. AB - Saltatory conduction in mammalian myelinated axons was thought to be well understood before recent discoveries revealed unexpected subcellular distributions and molecular identities of the K(+)-conductance pathways that provide for rapid axonal repolarization. In this study, we visualize, identify, localize, quantify, and ultrastructurally characterize axonal KV1.1/KV1.2 channels in sciatic nerves of rodents. With the use of light microscopic immunocytochemistry and freeze-fracture replica immunogold labeling electron microscopy, KV1.1/KV1.2 channels are localized to three anatomically and compositionally distinct domains in the internodal axolemmas of large myelinated axons, where they form densely packed "rosettes" of 9-nm intramembrane particles. These axolemmal KV1.1/KV1.2 rosettes are precisely aligned with and ultrastructurally coupled to connexin29 (Cx29) channels, also in matching rosettes, in the surrounding juxtaparanodal myelin collars and along the inner mesaxon. As >98% of transmembrane proteins large enough to represent ion channels in these specialized domains, ~500,000 KV1.1/KV1.2 channels define the paired juxtaparanodal regions as exclusive membrane domains for the voltage-gated K(+)conductance that underlies rapid axonal repolarization in mammals. The 1:1 molecular linkage of KV1 channels to Cx29 channels in the apposed juxtaparanodal collars, plus their linkage to an additional 250,000-400,000 Cx29 channels along each inner mesaxon in every large-diameter myelinated axon examined, supports previously proposed K(+)conductance directly from juxtaparanodal axoplasm into juxtaparanodal myeloplasm in mammalian axons. With neither Cx29 protein nor myelin rosettes detectable in frog myelinated axons, these data showing axon-to myelin linkage by abundant KV1/Cx29 channels in rodent axons support renewed consideration of an electrically active role for myelin in increasing both saltatory conduction velocity and maximum propagation frequency in mammalian myelinated axons. PMID- 26763786 TI - Von Hippel-Lindau disease: an evaluation of natural history and functional disability. AB - BACKGROUND: Although many studies have been published about specific lesions characterizing von Hippel-Lindau(VHL) disease, none have dealt with the natural history of the whole disease and the consequent disabilities. We aim to define the comprehensive natural history of VHL disease and to describe the functional disabilities and their impact upon patients' quality of life, thereby tailoring the follow-up schedule accordingly. METHODS: We performed a prospective analysis on 128 VHL-affected patients beginning in 1996. For each affected organ, we defined intervals between the first and subsequent VHL-related manifestations and compared them with current VHL surveillance protocols. We looked for any association of the number of involved organs with age, sex, type of VHL gene mutation, and functional domain mutation. Ultimately, we assessed the organ specific disabilities caused by VHL disease. RESULTS: Hemangioblastomas show different patterns of progression depending on their location, whereas both renal cysts and carcinomas have similar progression rates. Surgery for pheochromocytoma and CNS hemangioblastoma is performed earlier than for pancreatic or renal cancer. The number of involved organs is associated with age but not with sex, type of VHL gene mutation, or functional domain mutation. A thorough analysis of functional disabilities showed that age is related to the first-appearing functional impairment, but it is not predictive of the final number of disabilities. CONCLUSIONS: Our study defines the disease progression and provides a comprehensive view of the syndrome over time. We analyzed for the first time the functional disability of VHL patients, assessing the progression for each function. PMID- 26763788 TI - JNIS podcasts: the early part of our journey. AB - Podcasts are an area of innovation in the neurointerventional space that has the potential to convey information in ways that traditional journal articles in peer reviewed journals do not. BMJ maintains an archive of all of its podcasts on the Journal of NeuroInterventional Surgery (JNIS) website. We sought to analyze this early JNIS podcast experience and assess the impact of content elements and an increased presence in social media. PMID- 26763787 TI - Alternative Splicing in CKD. AB - Alternative splicing (AS) has emerged in the postgenomic era as one of the main drivers of proteome diversity, with >=94% of multiexon genes alternatively spliced in humans. AS is therefore one of the main control mechanisms for cell phenotype, and is a process deregulated in disease. Numerous reports describe pathogenic mutations in splice factors, splice sites, or regulatory sequences. Additionally, compared with the physiologic state, disease often associates with an abnormal proportion of splice isoforms (or novel isoforms), without an apparent driver mutation. It is therefore essential to study how AS is regulated in physiology, how it contributes to pathogenesis, and whether we can manipulate faulty splicing for therapeutic advantage. Although the disease most commonly linked to deregulation of AS in several genes is cancer, many reports detail pathogenic splice variants in diseases ranging from neuromuscular disorders to diabetes or cardiomyopathies. A plethora of splice variants have been implicated in CKDs as well. In this review, we describe examples of these CKD-associated splice variants and ideas on how to manipulate them for therapeutic benefit. PMID- 26763789 TI - New psychoactive substances as part of polydrug abuse within opioid maintenance treatment revealed by comprehensive high-resolution mass spectrometric urine drug screening. AB - OBJECTIVE: At present, polydrug abuse comprises, besides traditional illicit drugs, new psychoactive substances (NPS) and non-prescribed psychotropic medicines (N-PPM). Polydrug abuse was comprehensively evaluated among opioid dependent patients undergoing opioid maintenance treatment (OMT). METHODS: Two hundred consecutively collected urine samples from 82 OMT patients (52 male) treated with methadone or buprenorphine-naloxone medication were studied using a liquid chromatography/time-of-flight mass spectrometry screening method. The method enables simultaneous detection of hundreds of abused substances covering the traditional drugs of abuse and many NPS as well as N-PPM. RESULTS: Ninety-two (45.8%) samples were positive for the abused substances. Benzodiazepines (29.0%), amphetamines (19.5%), cannabinoids (17.0%), NPS (13.0%), N-PPM (9.0%), and opioids (9.0%) were detected in different combinations. The simultaneous occurrence of up to three groups of abused substances was common (40.0%), and in one sample, all six groups were found. The stimulant NPS alpha pyrrolidinovalerophenone was found in 10.0% and the sedative N-PPM pregabalin in 4.0% of the samples. The patients were seldom aware of what particular NPS they had abused. CONCLUSIONS: A widespread occurrence of abused substances beyond the ordinary was revealed. Identifying these patients is essential as polydrug abuse is a safety risk to the patient and may cause attrition from OMT. PMID- 26763791 TI - Should we screen for hypothyroidism in patients with cardiovascular disease? PMID- 26763792 TI - Characterization of multifunctional beta-NaEuF4/NaGdF4 core-shell nanoparticles with narrow size distribution. AB - The properties of beta-NaEuF4/NaGdF4 core-shell nanocrystals have been thoroughly investigated. Nanoparticles with narrow size distribution and an overall diameter of ~22 nm have been produced with either small beta-NaEuF4 cores (~3 nm diameter) or large beta-NaEuF4 cores (~18 nm diameter). The structural properties and core shell formation are investigated by X-ray diffraction, transmission electron microscopy and electron paramagnetic resonance, respectively. Optical luminescence measurements and X-ray photoelectron spectroscopy are employed to gain information about the optical emission bands and valence states of the rare earth constituents. Magnetic characterization is performed by SQUID and X-ray magnetic circular dichroism measurements at the rare earth M(4,5) edges. The characterization of the core-shell nanoparticles by means of these complementary techniques demonstrates that partial intermixing of core and shell materials takes place, and a significant fraction of europium is present in the divalent state which has significant influence on the magnetic properties. Hence, we obtained a combination of red emitting Eu(3+) ions and paramagnetic Gd(3+) ions, which may be highly valuable for potential future applications. PMID- 26763790 TI - Coronary plaque quantification and fractional flow reserve by coronary computed tomography angiography identify ischaemia-causing lesions. AB - AIMS: Coronary plaque characteristics are associated with ischaemia. Differences in plaque volumes and composition may explain the discordance between coronary stenosis severity and ischaemia. We evaluated the association between coronary stenosis severity, plaque characteristics, coronary computed tomography angiography (CTA)-derived fractional flow reserve (FFRCT), and lesion-specific ischaemia identified by FFR in a substudy of the NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps). METHODS AND RESULTS: Coronary CTA stenosis, plaque volumes, FFRCT, and FFR were assessed in 484 vessels from 254 patients. Stenosis >50% was considered obstructive. Plaque volumes (non-calcified plaque [NCP], low-density NCP [LD-NCP], and calcified plaque [CP]) were quantified using semi-automated software. Optimal thresholds of quantitative plaque variables were defined by area under the receiver-operating characteristics curve (AUC) analysis. Ischaemia was defined by FFR or FFRCT <=0.80. Plaque volumes were inversely related to FFR irrespective of stenosis severity. Relative risk (95% confidence interval) for prediction of ischaemia for stenosis >50%, NCP >=185 mm(3), LD-NCP >=30 mm(3), CP >=9 mm(3), and FFRCT <=0.80 were 5.0 (3.0-8.3), 3.7 (2.4-5.6), 4.6 (2.9-7.4), 1.4 (1.0-2.0), and 13.6 (8.4 21.9), respectively. Low-density NCP predicted ischaemia independent of other plaque characteristics. Low-density NCP and FFRCT yielded diagnostic improvement over stenosis assessment with AUCs increasing from 0.71 by stenosis >50% to 0.79 and 0.90 when adding LD-NCP >=30 mm(3) and LD-NCP >=30 mm(3) + FFRCT <=0.80, respectively. CONCLUSION: Stenosis severity, plaque characteristics, and FFRCT predict lesion-specific ischaemia. Plaque assessment and FFRCT provide improved discrimination of ischaemia compared with stenosis assessment alone. PMID- 26763793 TI - A highly penetrant form of childhood apraxia of speech due to deletion of 16p11.2. PMID- 26763794 TI - Adjuvant systemic chemotherapy with or without bevacizumab in patients with resected pulmonary metastases from colorectal cancer. AB - INTRODUCTION: We investigated the impact of modern chemotherapy regimens and bevacizumab following pulmonary metastasectomy (PM) from metastatic colorectal cancer (CRC). METHODS: A total of 122 consecutive patients who were curatively resected for pulmonary metastases of CRC in twelve oncology centers were retrospectively analysed between January 2000 and April 2012. RESULTS: Of 122 patients, 14 did not receive any treatment following PM. The remaining 108 patients received fluoropyrimidine-based (n = 12), irinotecan-based (n = 56) and oxaliplatin-based (n = 40) chemotherapy combinations. Among these, 52 patients received bevacizumab (BEV) while 56 did not (NoBEV). Median recurrence-free survival (RFS) was 17 months and median overall survival (OS) has not been reached at a median follow-up of 25 months after PM. Three and five-year OS rates were 66% and 53%, respectively. RFS and OS were similar, irrespective of the chemotherapy regimen or BEV use. Positive pulmonary margin, KRAS mutation status, and previous liver metastasectomy were negative independent prognostic factors for RFS, while pathologically confirmed thoracic lymph node involvement was the only negative independent prognostic for OS in multivariate analysis. CONCLUSIONS: No significant RFS or OS difference was observed in respect to chemotherapy regimens with or without BEV in patients with pulmonary metastases of CRC following curative resection. PMID- 26763796 TI - Violence and HIV. PMID- 26763795 TI - Prevalence of Substance Use in an HIV Primary Care Safety Net Clinic: A Call for Screening. AB - Substance use complicates HIV care and prevention. Primary care clinics are an ideal setting to screen for and offer interventions for unhealthy alcohol and drug use; however, few HIV clinics routinely screen for substance use. We enrolled 208 clinic patients at an urban underserved HIV primary care clinic. We screened the patients for substance use with the Alcohol, Smoking, and Substance Involvement Score Test and measured urine toxicology. Of the 168 participants who completed screening, the majority reported tobacco or nonprescribed substance use in the previous 3 months. More African American participants reported low or no risk amphetamine use compared to Hispanic, White, or Other race participants (p < .001). Implementing standard clinic practice for screening and assessing substance use in HIV primary care clinics is needed. PMID- 26763799 TI - How to use the medical subject headings (MeSH). AB - BACKGROUND: A thorough understanding of the National Library of Medicine's Medical Subject Headings can increase the efficiency and precision of one's literature searching skills using the Medline database. AIMS: To describe how to use the Medical Subject Headings to conduct a search for literature, and how to write up a description of the search strategy. MATERIALS AND METHODS: The author interprets National Library of Medicine documentation to describe Medical Subject Headings, and shares strategies from daily literature searching. CONCLUSION: Knowing how to use Medical Subject Headings improves the efficiency and quality of one's literature searches. PMID- 26763797 TI - The Importance of Global Health Experiences in the Development of New Cardiologists. AB - As the global burden of cardiovascular disease continues to increase worldwide, nurturing the development of early-career cardiologists interested in global health is essential to create a cadre of providers with the skill set to prevent and treat cardiovascular diseases in international settings. As such, interest in global health has increased among cardiology trainees and early-career cardiologists over the past decade. International clinical and research experiences abroad present an additional opportunity for growth and development beyond traditional cardiovascular training. We describe the American College of Cardiology International Cardiovascular Exchange Database, a new resource for cardiologists interested in pursuing short-term clinical exchange opportunities abroad, and report some of the benefits and challenges of global health cardiovascular training in both resource-limited and resource-abundant settings. PMID- 26763798 TI - Ruthenium(II) Complexes with 2-Phenylimidazo[4,5-f][1,10]phenanthroline Derivatives that Strongly Combat Cisplatin-Resistant Tumor Cells. AB - Cisplatin was the first metal-based therapeutic agent approved for the treatment of human cancers, but its clinical activity is greatly limited by tumor drug resistance. This work utilized the parent complex [Ru(phen)2(PIP)](2+) (1) to develop three Ru(II) complexes (2-4) with different positional modifications. These compounds exhibited similar or superior cytotoxicities compared to cisplatin in HeLa, A549 and multidrug-resistant (A549R) tumor cell lines. Complex 4, the most potent member of the series, was highly active against A549R cancer cells (IC50 = 0.8 MUM). This complex exhibited 178-fold better activity than cisplatin (IC50 = 142.5 MUM) in A549R cells. 3D multicellular A549R tumor spheroids were also used to confirm the high proliferative and cytotoxic activity of complex 4. Complex 4 had the greatest cellular uptake and had a tendency to accumulate in the mitochondria of A549R cells. Further mechanistic studies showed that complex 4 induced A549R cell apoptosis via inhibition of thioredoxin reductase (TrxR), elevated intracellular ROS levels, mitochondrial dysfunction and cell cycle arrest, making it an outstanding candidate for overcoming cisplatin resistance. PMID- 26763800 TI - Rabbit dietary supplementation with pale purple coneflower. 1. Effects on the reproductive performance and immune parameters of does. AB - Echinacea pallida (EPAL), also known as pale purple coneflower, is a herbaceous flowering plant with immune-enhancement and antioxidative properties. The effect of EPAL on the reproductive performance, serum biochemistry and haematological parameters of rabbit does has been studied here. A total of 100, 21-week-old Grimaud rabbit does, were randomly assigned to two groups. One group was fed a basal diet supplemented with 3 g EPAL/kg diet (Echinacea group, E), while the other was fed the basal diet without the supplementation (control group, C). The reproductive performance of the does was not affected by the treatment (P>0.05). The haematological parameters of pregnant rabbits showed that there was no interaction between gestation day and treatment. The EPAL supplementation induced a reduction (-47.3%) in the basophil cell rate (0.55% and 0.29%, for the control and treatment groups, respectively; P=0.049). The gestation day significantly affected most of the haematological parameters (P<0.05). The white blood cell counts declined progressively after day 14. The mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, red cell distribution width, mean platelet volume and eosinophils increased steadily throughout the study, and reached a maximum value on day 28. The red blood cells, haemoglobin, haematocrit, mean corpuscular volume and neutrophils increased slightly up to day 14, and then subsequently decreased progressively until day 28. The lymphocytes and platelet distribution width decreased until day 14, and then increased to a maximum value on day 28. No significant effect of gestation day or treatment was observed on the blood serum chemistry. As far as the immune parameters are concerned, no significant differences were observed between groups, while a significant effect of gestation day was observed for lysozymes (6.02 v. 7.99 v. 1.91; for 0, 14 and 28 days, respectively; P=0.014). In conclusion, a lack of effect of EPAL has been observed. In fact, no impacts of EPAL have been observed on the reproductive or haematological parameters of the does. The effects of dietary supplementation with EPAL on the performances, bacterial community, blood parameters and immunity in growing rabbits are reported in the second part of this study. PMID- 26763801 TI - Lateral collateral ligament deficiency of the elbow joint: A modeling approach. AB - A computational model capable of predicting the effects of lateral collateral ligament deficiency of the elbow joint would be a valuable tool for surgical planning and prediction of the long-term consequences of ligament deficiency. The purpose of this study was to simulate lateral collateral ligament deficiency during passive flexion using a computational multibody elbow joint model and investigate the effects of ligament insufficiency on the kinematics, ligament loads, and articular contact characteristics (area, pressure). The elbow was placed initially at approximately 20 degrees of flexion and a 345 mm vertical downward motion profile was applied over 40 s to the humerus head. The vertical displacement induced flexion from the initial position to a maximum flexion angle of 135 degrees . The study included simulations for intact, radial collateral ligament deficient, lateral ulnar collateral ligament deficient, and combined radial and lateral ulnar collateral ligament deficient elbow. For each condition, relative bone kinematics, contact pressure, contact area, and intact ligament forces were predicted. Intact and isolated radial collateral ligament deficient elbow simulations were almost identical for all observed outcomes. Minor differences in kinematics, contact area and pressure were observed for the isolated lateral ulnar collateral ligament deficient elbow compared to the intact elbow, but no elbow dislocation was detected. However, sectioning both ligaments together induced substantial differences in kinematics, contact area, and contact pressure, and caused complete dislocation of the elbow joint. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1645-1655, 2016. PMID- 26763803 TI - Lung cancer screening in Australia: progress or procrastination? PMID- 26763805 TI - Improving health literacy in refugee populations. PMID- 26763806 TI - Cost-effectiveness of screening for bowel cancer. PMID- 26763807 TI - Electronic cigarettes: what can we learn from the UK experience? PMID- 26763808 TI - Therapeutic drug safety for Indigenous Australians: how do we close the gap? PMID- 26763809 TI - Vitamin D testing: new targeted guidelines stem the overtesting tide. PMID- 26763810 TI - Pharmaceutical industry exposure in our hospitals: the final frontier. AB - Despite recent changes in attitudes, most hospitals continue to experience pharmaceutical industry presence. Pharmaceutical industry presence may be necessary and beneficial in the context of sponsorship of clinical trials with appropriate governance. Doctors continue to hold positive attitudes towards market-oriented activities of the pharmaceutical and medical device industries. Despite evidence to the contrary, doctors believe they are able to effectively manage pharmaceutical sales representative interactions such that their own prescribing is not adversely impacted. Doctors also share a belief that small gifts and benefits are harmless. There may be significant financial burden associated with divestment of such sponsorship by hospitals. Change requires education and effective policies to manage pharmaceutical industry relationships and conflicts of interest. We discuss case studies involving students and public hospital doctors to show that divestment is possible without significant financial detriment. Health services need to be proactive in transitioning financial and cultural reliance on pharmaceutical industry sponsorship to other potentially less harmful sources. PMID- 26763811 TI - Are general practice characteristics predictors of good glycaemic control in patients with diabetes? A cross-sectional study. AB - OBJECTIVES: To determine whether certain characteristics of general practices are associated with good glycaemic control in patients with diabetes and with completing an annual cycle of care (ACC). RESEARCH DESIGN AND METHODS: Our cross sectional analysis used baseline data from the Australian Diabetes Care Project conducted between 2011 and 2014. Practice characteristics were self-reported. Characteristics of the patients that were assessed included glycaemic control (HbA1c level <= 53 mmol/mol), age, sex, duration of diabetes, socio-economic disadvantage (SEIFA) score, the complexity of the patient's condition, and whether the patient had completed an ACC for diabetes in the past 18 months. Clustered logistic regression was used to establish predictors of glycaemic control and a completed ACC. RESULTS: Data were available from 147 general practices and 5455 patients with established type 1 or type 2 diabetes in three Australian states. After adjustment for other patient characteristics, only the patient completing an ACC was statistically significant as a predictor of glycaemic control (P = 0.011). In a multivariate model, the practice having a chronic disease-focused practice nurse (P = 0.036) and running educational events for patients with diabetes (P = 0.004) were statistically significant predictors of the patient having complete an ACC. CONCLUSIONS: Patient characteristics are moderately good predictors of whether the patient is in glycaemic control, whereas practice characteristics appear to predict only the likelihood of patients completing an ACC. The ACC is an established indicator of good diabetes management. This is the first study to report a positive association between having completed an ACC and the patient being in glycaemic control. PMID- 26763812 TI - Reporting of health practitioners by their treating practitioner under Australia's national mandatory reporting law. AB - OBJECTIVE: To describe the frequency, nature and outcomes of reports about health practitioners made by their treating practitioners under Australia's new mandatory reporting system. DESIGN AND SETTING: Retrospective case file review and analysis of treating practitioner reports received by the Australian Health Practitioner Regulation Agency between 1 November 2011 and 31 January 2013, and of the outcomes of the completed investigations of these reports to November 2014. MAIN OUTCOME MEASURES: Characteristics of treating practitioners and reported practitioners; nature of the care relationship; grounds for report; regulatory action taken in response to report. RESULTS: Of 846 mandatory reports about medical practitioners, 64 (8%) were by treating practitioners. A minority of reports (14 of 64) were made by a practitioner-patient's regular care provider; most (50 of 64) arose from an encounter during an acute admission, first assessment or informal corridor consultation. The reported practitioner patients were typically being treated for mental illness (28 of 64) or substance misuse (25 of 64). In 80% of reports (50 of 64), reporters described practitioner patients who exhibited diminished insight, dishonesty, disregard for patient safety, or an intention to self-harm. CONCLUSIONS: The nature and circumstances of the typical treating practitioner report challenge assumptions expressed in policy debates about the merits of the new mandatory reporting law. Mandatory reports by treating practitioners are rare. The typical report is about substance misuse or mental illness, is made by a doctor who is not the patient's regular care provider, and identifies an impediment to safely managing the risk posed by the practitioner-patient within the confines of the treating relationship. PMID- 26763813 TI - Natural history and long-term impact of dental fluorosis: a prospective cohort study. AB - OBJECTIVE: The study assessed longitudinal changes in the presentation of dental fluorosis and evaluated the impact of fluorosis on the perception of oral health among young adults. DESIGN AND SETTING: Prospective follow-up study during 2011 12 of a population-based study in South Australia conducted between 2003 and 2004. PARTICIPANTS: 8-13-year-old children initially examined in 2003 and 2004. MAIN OUTCOMES: Dental fluorosis was assessed with the Thylstrup and Fejerskov (TF) Index. The impact on perceptions of oral health by the study participants and their parents was assessed with the Global Rating of Oral Health (GROH). Pairwise comparative analysis of the presentation of fluorosis was conducted at the individual and tooth levels. Multivariable models of changes in fluorosis were generated. An ordinal logistic regression model was used to evaluate the association between GROH with dental fluorosis, caries and other factors. RESULT: A total of 314 participants completed the follow-up questionnaires and dental examination. Over 60% of teeth scored as TF 1 at baseline were scored as TF 0 at follow-up; 66% of teeth scored as TF 2 or 3 at baseline were scored as TF 0 or 1 at follow-up. In multivariable models, changes in fluorosis were not significantly associated with socio-economic factors or oral health behaviours, confirming that they were the result of a natural process. Perceptions of poor oral health were significantly associated with the number of untreated decayed tooth surfaces at follow-up, but not with fluorosis. CONCLUSION: Very mild and mild dental fluorosis diminished with time. Dental fluorosis did not have a negative impact on perceptions of oral health. PMID- 26763814 TI - "Sorry, I'm not a dentist": perspectives of rural GPs on oral health in the bush. AB - OBJECTIVE: To examine the provision of oral health and oral health service in rural areas from the perspective of general practitioners working in communities without resident dentists. DESIGN, SETTING AND PARTICIPANTS: A qualitative approach using face-to-face, semi-structured interviews with 30 GPs from rural Queensland, Tasmania and South Australia, conducted between October 2013 and October 2014. RESULTS: Four major themes emerged from the interviews: rural oral health, managing oral health presentations, barriers to patients seeing a dentist, and improving oral health. Rural GPs saw patients with a range of oral health problems, including toothache, abscesses and trauma, and observed poor oral health in their communities. Some acknowledged that they were not confident when dealing with oral health problems; they typically provided short-term pain relief, prescriptions for antibiotics, and advised patients to see a dentist. Participants noted that rural patients may not see a dentist when advised to do so because symptoms had abated, oral health was regarded as a low priority, or the costs of travelling to and seeing a dentist discouraged them. The interviewees recommended building the capacity of GPs to better care for patients with oral health problems, establishing more effective communication and referral pathways between GPs and dentists, focusing on preventive dental care, and delivering dental services in more flexible and consistent ways that better meet the needs of the communities. CONCLUSIONS: Rural oral health could be improved by several approaches, including additional training for GPs in oral health care, primary prevention activities in communities, and improving the access to dental services. PMID- 26763815 TI - Not just a cosmetic problem: facial papules in Birt-Hogg-Dube syndrome. PMID- 26763816 TI - Fulminant liver failure and transplantation after use of dietary supplements. PMID- 26763819 TI - Priscilla Kincaid-Smith. PMID- 26763818 TI - Compensated transnational surrogacy in Australia: time for a comprehensive review. AB - Commercial or compensated surrogacy involves providing payment for a woman to gestate a fetus to term and then hand over the child to commissioning parent(s). Compensated surrogacy is currently restricted by law or regulation in all Australian states and territories. New South Wales, Queensland and the Australian Capital Territory also restrict commissioning transnational compensated surrogacy, although there is evidence that this is not acting as a deterrent. Ethical issues arising in transnational compensated surrogacy include concerns relating to exploitation, commodification and welfare. The current status quo is unsatisfactory on legal, ethical and practical grounds. It is time to openly debate how Australia should balance the desire for childbearing through surrogacy with the limited domestic availability of women willing to act as surrogates. PMID- 26763822 TI - Single nucleotide polymorphisms in the Trx2/TXNIP and TrxR2 genes of the mitochondrial thioredoxin antioxidant system and the risk of diabetic retinopathy in patients with Type 2 diabetes mellitus. AB - BACKGROUND: Oxidative stress plays an important role in the pathogenesis of diabetes and its complications. The aim of this study was to examine the possible association between seven single nucleotide polymorphisms (SNPs) of the Trx2/TXNIP and TrxR2 genes encoding proteins involved in the thioredoxin antioxidant defence system and the risk of diabetic retinopthy (DR). DESIGN: Cross-sectional case-control study. PARTICIPANTS: A total of 802 Slovenian patients with Type 2 diabetes mellitus; 277 patients with DR and 525 with no DR were enrolled. METHODS: Patients genotypes of the SNPs; including rs8140110, rs7211, rs7212, rs4755, rs1548357, rs4485648 and rs5748469 were determined by the competitive allele specific PCR method. MAIN OUTCOME MEASURES: Each genotype of examined SNPs was regressed in a logistic model, assuming the co-dominant, dominant and the recessive models of inheritance with covariates of duration of diabetes, HbA1c, insulin therapy, total cholesterol and LDL cholesterol levels. RESULTS: In the present study, for the first time we identified an association between the rs4485648 polymorphism of the TrxR2 gene and DR in Caucasians with Type 2 DM. The estimated ORs of adjusted logistic regression models were found to be as follows: 4.4 for CT heterozygotes, 4.3 for TT homozygotes (co-dominant genetic model) and 4.4 for CT+TT genotypes (dominant genetic model). CONCLUSIONS: In our case-control study we were not able to demonstrate any association between rs8140110, rs7211, rs7212, rs4755, rs1548357, and rs5748469 and DR, however, our findings provide evidence that the rs4485648 polymorphism of the TrxR2 gene might exert an independent effect on the development of DR. PMID- 26763823 TI - Costs of ED episodes of care in the United States. AB - BACKGROUND: Emergency department (ED) care is a focus of cost reduction efforts. Costs for acute care originating in the ED, including outpatient and inpatient encounters (i.e. ED episodes), have not been estimated. OBJECTIVE: We estimate total US costs of ED episodes, potentially avoidable costs, and proportional costs of national health expenditures (NHEs). METHODS: We conducted a secondary analysis of 2010 data from the Medical Expenditure Panel Survey, National Hospital Ambulatory Medical Care Survey, and the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample. Outpatient ED encounters were categorized based on the New York University algorithm and admissions by ambulatory care sensitive condition (ACSC) vs non-ACSC. Potentially avoidable encounters were nonemergent ED visits and ACSC hospital admissions. Using the Medical Expenditure Panel Survey, we determined mean per-visit payments for each visit type. Using the National Hospital Ambulatory Medical Care Survey and Nationwide Inpatient Sample, we estimated aggregate expenditures and proportional costs of NHE by visit category. RESULTS: Emergency department episodes of care accounted for $328.1 billion in payments in 2010. This represented 12.5% of NHE; ED admissions were 8.3% and outpatient ED care was 4.2%. Nonemergent outpatient visits were the most common, comprising 30.4% of ED episodes, and non-ACSC admissions were the most costly at $188.3 billion. Potentially avoidable encounters accounted for $64.4 billion, 19.6% of ED episodes, and 2.4% of NHE. CONCLUSIONS: More than 1 in 10 health care dollars is spent on ED episodes of care. Of this, less than 1 in 5 dollars is potentially avoidable; therefore, efforts to reduce ED visits through improved primary care may have little impact on overall costs. PMID- 26763824 TI - The prehospital and hospital costs of emergency care for frequent ED patients. AB - INTRODUCTION: Frequent emergency department (ED) use has been identified as a cause of ED overcrowding and increasing health care costs. Studies have examined the expense of frequent patients (FPs) to hospitals but have not added the cost Emergency Medical Services (EMS) to estimate the total cost of this pattern of care. METHODS: Data on 2012 ED visits to a rural Level I Trauma Center and public safety net hospital were collected through a deidentified patient database. Transport data and 2012 Medicare Reimbursement Schedules were used to estimate the cost of EMS transport. Health information, outcomes, and costs were compared to find differences between the FP and non-FP group. RESULTS: This study identified 1242 FPs who visited the ED 5 or more times in 2012. Frequent patients comprised 3.25% of ED patients but accounted for 17% of ED visits and 13.7% of hospital costs. Frequent patients had higher rates of chronic disease, severity scores, and mortality. Frequent patients arrived more often via ambulance and accounted for 32% of total transports at an estimated cost of $2.5-$3.2 million. Hospital costs attributable to FPs were $29.1 million, bringing the total cost of emergency care to $31.6-$32.3 million, approximately $25,000 per patient. CONCLUSIONS: This study demonstrates that the inclusion of a prehospital cost estimate adds approximately 10% to the cost of care for the FP population. In addition to improving care for a sick population of patients, programs that reduce frequent EMS and ED use have the potential to produce a favorable cost benefit to communities and health systems. PMID- 26763825 TI - Identifying the optimal hand placement site for chest compression by measuring hand width and sternal length in young adults. AB - OBJECTIVE: There are no specific guidelines regarding the exact hand placement location for effective chest compressions. This study was designed to identify the optimal hand placement site over the chest during cardiopulmonary resuscitation (CPR). METHODS: The sternal length (SL) of young Korean adults was measured as the distance from the suprasternal notch (SN) to the lower end of the sternum. In addition, the heel width of the hand (H) was measured 1 cm (H1) and 2 cm (H2) distal to the proximal end of the carpal bones. RESULTS: A total of 300 men and 300 women were enrolled. SL positively correlated with height (R(2)=14.2), weight (R(2)=15.3), BMI (R(2)=10.3), H1 (R(2) =3.4), and H2 (R(2) = 5.0). Mean H2 and half of the SL (SL/2) for the subgroups were M 8.4 and 10.1 cm, M' 8.3 and 9.7 cm, W 7.6 and 10.1 cm, and W' 7.4 and 9.5 cm, respectively (M, men taller than the mean; M', men shorter than the mean; W, women taller than the mean; W', women shorter than the mean). Mean H2 in men was 1.1 to 1.6 cm shorter than SL/2, whereas mean H2 in women was 2.2 to 2.9 cm shorter than SL/2. CONCLUSIONS: To find the most optimal chest compression point, from the patients' left side, CPR providers need to palpate the SN using the right little finger and placing the left heel one heel width (H2) from the SN. From the patient's right side, CPR providers should use the left little finger to palpate the SN and place the right heel one heel width (H2) from the SN. PMID- 26763826 TI - Painless acrocyanosis: Paget-Schroetter syndrome secondary to thoracic outlet obstruction from muscle hypertrophy. PMID- 26763832 TI - Rabbit dietary supplementation with pale purple coneflower. 2. Effects on the performances, bacterial community, blood parameters and immunity of growing rabbits. AB - Echinacea pallida (EPAL), a herbaceous flowering plant with immunomodulatory properties, has been chosen to determine the pre- and post-supplementary effects on the growth performances, bacterial community, blood parameters and immunity of growing rabbits. The same Grimaud does (14-week-old) from the studied in the first part of this study were randomly divided into two groups (n=50/group). The first group was fed a basal diet without supplementation (Control group, C) while the another group was fed a basal diet supplemented with 3 g EPAL/kg diet (Echinacea group, E). From the second parturition, 80 weaned kits (40 from the C does and 40 from the E does) were randomly assigned to four groups of 20 animals each and were fed a growing commercial diet supplemented with or without a 3 g EPAL/kg diet: the CC group (rabbits from the C does fed the control diet), CE group (rabbits from the C does fed the supplemented diet), EC (rabbits from the E does fed the control diet) and EE group (rabbits from the E does fed the supplemented diet). The dietary EPAL treatment did not affect the growth performance. Ten fattening rabbits from each group were selected to evaluate the bacterial community and blood parameters, while the remaining rabbits (n=10/group) were used to study phagocytosis and the humoral immune response. The variability was evaluated from hard faeces at 35, 49 and 89 days, and the caecal content at 89 days. The variability of the bacterial community of the EE group was higher than that of the other groups. The phagocytic activity was higher in the CE and EE groups than in the CC and EC ones (30.9 and 29.7 v. 21.2 and 21.8%; P<0.05), whereas no statistically significant difference was observed for the blood parameters or humoral immune response against vaccination (rabbit haemorrhagic disease virus) at 95 days old which the serum was collected at 88, 102, 109, 116 and 123 days old. In conclusion, no impact of EPAL dietary supplementation has been observed on the growth performances, bacterial community, blood parameters or humoral immune responses in growing rabbits, except for an increase in phagocytic activities. PMID- 26763833 TI - Quadriceps function relates to muscle size following ACL reconstruction. AB - It remains unclear what role reduced volume and cross-section area (CSA) of individual quadriceps muscles may play in persistent quadriceps weakness and more global dysfunction following ACL reconstruction (ACLR). The purpose of this investigation was to establish the relationship between cross-sectional area of the quadriceps muscle group and measures of knee related and quadriceps function following ACLR. Thirty participants with a history of primary, unilateral ACLR experiencing persistent quadriceps activation failure participated in this cohort study. Clinical factors including International Knee Documentation Committee (IKDC) score, normalized knee extension MVIC torque (Nm/kg) and quadriceps central activation ratio (CAR, %) were assessed in addition to CSA. Quadriceps CSA was measured via magnetic resonance imaging (MRI; Siemens Avanto 1.5T). Quadriceps CSA (cm(2) ) and quadriceps volume (cm(3) ) as well as individual muscle estimates were identified within a 10 cm mid-thigh capture area. Pearson's product-moment correlation coefficients (r) established relationships between CSA and all other variables. Stepwise linear regression established which CSA factors were able to successfully predict clinical factors. Knee extension MVIC torque was strongly correlated with Vastus Intermedius (VI; r = 0.857, p < 0.001) CSA as well as partial VI (r = 0.849, p < 0.001) and quadriceps (r = 0.830, p < 0.001) volume. Partial VI (r = 0.365, p = 0.047) volume was weakly correlated with IKDC score. Knee extension MVIC torque was strongly predicted using VI CSA alone (R(2) = 0.725) or in combination with Vastus Medialis CSA (VM; R(2) = 0.756). Statement of Clinical Significance: Atrophy of the VI and VM muscles negatively impacts knee extension strength following ACLR. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1656-1662, 2016. PMID- 26763827 TI - A wearable multiplexed silicon nonvolatile memory array using nanocrystal charge confinement. AB - Strategies for efficient charge confinement in nanocrystal floating gates to realize high-performance memory devices have been investigated intensively. However, few studies have reported nanoscale experimental validations of charge confinement in closely packed uniform nanocrystals and related device performance characterization. Furthermore, the system-level integration of the resulting devices with wearable silicon electronics has not yet been realized. We introduce a wearable, fully multiplexed silicon nonvolatile memory array with nanocrystal floating gates. The nanocrystal monolayer is assembled over a large area using the Langmuir-Blodgett method. Efficient particle-level charge confinement is verified with the modified atomic force microscopy technique. Uniform nanocrystal charge traps evidently improve the memory window margin and retention performance. Furthermore, the multiplexing of memory devices in conjunction with the amplification of sensor signals based on ultrathin silicon nanomembrane circuits in stretchable layouts enables wearable healthcare applications such as long-term data storage of monitored heart rates. PMID- 26763834 TI - Comparison of FIB-4 index, NAFLD fibrosis score and BARD score for prediction of advanced fibrosis in adult patients with non-alcoholic fatty liver disease: A meta-analysis study. AB - AIM: Non-alcoholic fatty liver disease (NAFLD)-related advanced hepatic fibrosis is associated with liver and cardiovascular morbidity and mortality. This study aims to compare the FIB-4 index, NAFLD fibrosis score (NFS) and BARD score for prediction of advanced liver fibrosis. METHODS: Pooled sensitivity, specificity, diagnostic odds ratio (DOR), summary receiver-operator curves (SROC) and Spearman's rank correlation coefficient were used to examine the accuracy of each non-invasive scoring system for predicting NAFLD-related advanced fibrosis. RESULTS: Four studies with 1038 adult patients were included in this meta analysis. A total of 135 patients (13.0%) had advanced fibrosis. In the FIB-4 index group, pooled sensitivity and specificity with 95% confidence interval (CI), and the area under the ROC (AUROC) were 0.844 (0.772-0.901), 0.685 (0.654 0.716) and 0.8496 +/- 0.0680, respectively, at a cut-off of 1.30. At a threshold of 3.25, the same parameters were 0.38 (0.30-0.47), 0.96 (0.95-0.98) and 0.8445 +/- 0.0981. At a cut-off of -1.455, values were 0.77 (0.69-0.84), 0.70 (0.67 0.73) and 0.8355 +/- 0.0667, respectively. At a 0.676 cut-off, pooled sensitivity and specificity with 95% CI were 0.27 (0.19-0.35) and 0.98 (0.96-0.98), respectively; and the AUROC was 0.647 +/- 0.2208. In the BARD score group, pooled sensitivity and specificity with 95% CI were 0.74 (0.66-0.81) and 0.66 (0.63 0.69), respectively; and the AUROC was 0.7625 +/- 0.0285. CONCLUSION: FIB-4 index with a 1.30 cut-off has better diagnostic accuracy than the FIB-4 index with a 3.25 cut-off, NFS and BARD score, despite showing its limited value for predicting NAFLD-related advanced fibrosis. PMID- 26763836 TI - Does the Use of Diagnostic Imaging Reduce the Rate of Negative Appendectomy? AB - BACKGROUND: In February 2010, the Dutch Society of Surgeons introduced a guideline for diagnosis and treatment of acute appendicitis. This guideline suggests that, with the standardized use of imaging (ultrasound and computed tomography), the percentage of negative appendectomies can be reduced. With this study we evaluated the effect of the implementation of this guideline. Primary outcome is the percentage of negative appendectomies. Diagnostic imaging might result in a delay of surgery and a higher rate of perforated appendices. Therefore, our secondary outcome is the perforation rate. METHODS: Retrospectively all pathology results in our hospital were studied, which were classified as "appendicitis acuta" or "appendix sana" from January 2007 until October 2012. To evaluate the perforation rate in acute appendicitis, surgery reports of all patients included in the study were studied. Both percentages of negative appendectomies and perforation rate were compared for the periods before and after the introduction of the new guideline (i.e. 2007-2009 vs. 2010-2012). RESULTS: A significant decline in the percentage of negative appendectomies was found from an average of 18.0% before implementation of the guideline towards an average of 9.2% after implementation of the guideline (p<0.001). The percentage of patients with appendicitis in which the appendix perforated remained about the same; 20.9% before implementation of the guideline compared to 19.2% after implementation of the guideline (p=0.527). CONCLUSIONS: Our data show a significant decline in negative appendectomies without an increase of perforation rate after introduction of the new diagnostic guideline for acute appendicitis. PMID- 26763835 TI - The Validity of the Distress Thermometer in Greek Colon Cancer Patients. AB - BACKGROUND: Although screening for distress is a crucial part of psycho-social care for cancer patients, there has not been a validation study for this purpose in Greece. The purpose of this study was to evaluate for the first time the psychometric properties of the Greek translation of the Distress Thermometer (DT) and Problem List (PL) in Greek colorectal cancer patients (CRC). METHODS: Participants were 84 CRC inpatients of the 1st Surgical Propedeutic Department of the Aristotle University of Thessaloniki with a mean age of 70.8+/-9.5 years. Participants completed the DT, PL and the Hospital Anxiety and -Depression Scale (HADS). RESULTS: The Cronbach's alpha coefficient in the DT was 0.795. Patients' mean score in the DT was 5.7+/-2.74, while the mean number of the reported problems in the PL was 18.85+/-5.50 and the mean total score of the HADS was 15.61+/-6.95. ROC-analysis supported that a cut-off score of 7 gives the optimal sensitivity and specificity for the DT. CONCLUSION: The index sample has manifested high levels of distress, which correspond to high need for support and improvement of the patient-provider relationship. This is probably a difficult task, since the Greek healthcare system has minimal experience of providing psycho-oncology care. The present study has indicated that the DT can be reliably used in the Greek clinical setting. Future studies, along with state provision, are essential in order to offer Greek cancer patients state-of-the-art and comprehensive care. PMID- 26763837 TI - Mechanical Bowel Obstruction--Changes in Aetiology over the Past 145 Years: A Single Centre Retrospective Cohort Study. AB - INTRODUCTION: Mechanical bowel obstruction (MBO) remains one of the most common abdominal surgical emergencies. The aetiology of MBO depends on the population demographics and period of time in which a given population was studied. We are presenting the results of an analysis covering 145 years of observations based on patients operated in our department. METHODS: The single centre retrospective analysis included 1825 patients with MBO. They were divided into 4 groups depending on the years in which they were treated : group 1 (1868-1898), group 2 (1956-1970), group 3 (1987-1999), group 4 (2000-2013). The analysis covered the sex distribution, the mean age of patients versus the life expectancy and changes in MBO aetiology in every period. RESULTS: We noticed an increase in the mean age and the growing divergence between life expectancy. Additionally, an increasing percentage of women were observed. There were also significant changes in the aetiology. An increase in MBO caused by cancer was observed. The rate of strangulated hernias doubled in the second period of time, and then it gradually decreased. Intestinal volvulus was common in the first period and became one of the rarest causes of MBO in the subsequent periods. MBO due to adhesions remained at the same level. It became, however, the most common cause in the last period. CONCLUSIONS: Within nearly 150 years significant changes occurred in the demographics and aetiology of MBO. Currently, the most common cause is peritoneal adhesions after previous surgeries. Although our results represent a single centre experience, they may reflect changing patterns in MBO in the Polish population over time. PMID- 26763838 TI - Endovascular Aneurysm Repair (EVAR) : A Ten-Year Retrospective Study in a Low Volume Center. AB - BACKGROUND: We evaluated clinical outcomes of EVAR procedures at a low-volume center in Belgium. We also analyzed the time before endoleak appeared. METHODS: We reviewed 77 EVAR procedures performed over 10 years in a low-volume center. Patients were reviewed at intervals of 1, 3, 6, 12, 24 and 36 months. RESULTS: The deployment of the endograft was successful for 76 of the 77 patients (98.7%). Perioperative mortality was 1.3%. Cardiac infarctus was reported in 5.19% of patients, 1.3% suffered hematoma, 1.3% renal insufficiency, 7.8%-respiratory diseases, and 2.6% strokes. The mortality rate during the first postoperative year was 9% and none of these deaths were AAA related. One endograft thrombosis was reported (1.3%) and there were no cases of endograft migration. Type 1 endoleak occurred in 3.9% of patients, and Type 2 in 22.1%. No other type of endoleak was reported. The mean period before endoleak diagnosis was 9.8 months. Two patients needed to be re-operated for a Type 1 endoleak. CONCLUSION: Performing EVAR procedures in a low-volume center did not increase morbidity and mortality risks. This is probably because the primary factor is the volume of procedures carried out by the surgeon, rather than the institution. EVAR follow up is needed to diagnose endoleak, which can appear several months after. PMID- 26763839 TI - The Usefulness of Early Surgical Rib Stabilization in Flail Chest. AB - BACKGROUND: Flail chest is a clinical condition observed in patients with blunt thorax trauma. Surgical stabilization methods performed on selected patients shorten the durations of mechanical ventilation and intensive care monitoring and significantly reduce the rates of ventilator-associated morbidity and mortality. MATERIAL AND METHOD: Patients treated and diagnosed with flail chest between 2009 and 2014 were studied retrospectively. RESULTS: There were two groups: 10 patients in the group treated surgically and 10 patients in the group treated non surgically. The groups were similar in terms of age, ISS score, degree of pulmonary contusion, number of rib fractures and location of flail chest. There were no significant differences between the stabilization and non-surgical therapy groups in hospitalization and mechanical ventilation period, tracheostomies, hospital costs and mortality. However, there were significant differences in the intensive care period. The number of the patients who developed pneumonia was significantly lower in the stabilization group, and the difference was statistically significant. CONCLUSION: Early surgical rib stabilization in flail chest is a safe treatment method which has a low complication rate and can reduce the morbidity and mortality which develop from mechanical ventilation. PMID- 26763840 TI - Epidemiological Study of Thyroid Pathology in a University Hospital. AB - OBJECTIVES: The incidence of papillary thyroid carcinoma increased in several countries. The purpose of this study was to quantify the changes in thyroid carcinomas in our University Hospital. STUDY DESIGN: Retrospective study. METHODS: All 1.927 thyroidectomy cases studied in the Pathology Department of Hotel-Dieu de France Hospital (Beirut, Lebanon), between 2003 and 2013, were included. RESULTS: The Female/Male Sex Ratio of the studied population was 3.7/1. The mean age of female patients was significantly lower than that of male patients. The most frequent diagnoses were multinodular goiter (78%) and papillary-carcinoma (26%). 337 cases had a single lesion on gross examination. 21 of them were diagnosed with follicular carcinoma and 59 with follicular adenoma. A statistically significant correlation was found between the unicity of the lesion on gross examination and the final diagnosis of a follicular neoplasm. Thyroid carcinoma was multifocal in 33% of the cases and bilateral in 24%. A statistically significant increase in thyroid carcinoma proportion (from 15% in 2003 to 44% in 2013) was found. Among all thyroid carcinomas, the proportion of papillary type increased from 65% in 2003 to 94% in 2013 ; this increase remained statistically significant after the exclusion of papillary micro-carcinomas, whose proportion was stable throughout the 11 years. CONCLUSIONS: In this study, we noted a statistically significant increase in the frequency of thyroid carcinoma, especially of the papillary type. The unicity of the lesion on gross examination is significantly associated with a follicular neoplasm. PMID- 26763841 TI - A Rare Presternal Soft Tissue Tumor: Ectopic Hamartomatous Thymoma (Branchial Anlage Mixed Tumor). AB - Ectopic hamartomatous thymoma is a rare benign tumor in adults, mostly located in the lower neck region. It was first reported in 1982 by Smith and McClure. Histopathologically these tumors are typically well marginated and composed of a mixture of spindle cells, mature adipose tissue, and epithelial cells, including both glandular and squamous elements. The histogenesis of this tumor is controversial. Recently, an origin from a remnant of the cervical sinus of His was proposed. Ectopic hamartomatous thymoma needs to be differentiated from malignant lesions such as synovial sarcomas or malignant peripheral nerve sheath tumors. These tumors can have similar clinical features and radiologic images. Recognition of this tumor is important because it follows a benign clinical course and conservative surgical excision is the treatment of choice. To our knowledge, 61 cases have previously been reported. We present the case of a 45 year-old women with an uncomplicated presternal located ectopic hamartomatous thymoma. The morphological and immunohistochemical findings are discussed and a review of literature is made. PMID- 26763842 TI - Malignant Gastrocolic Fistula: Review of the Literature and Report of a Case. AB - Nowadays the development of a gastro-colic fistula is usually due to malignant disease in the gastro-intestinal tract. The symptoms can vary extensively and establishing the diagnosis quite challenging. We describe the case of a gastro colic fistula with a complicated course and review the literature. PMID- 26763843 TI - Aggressive Serous Peritoneal Psammocarcinoma: a Case Report. AB - Serous peritoneal psammocarcinoma is a rare primitive surface tumour. First time, it has been described in 1916. Only 30 cases have been reported in the literature. The tumour mimics an ovarian serous papillary adenocarcinoma and is characterized by dystrophic calcifications called psammoma bodies. Aggressive debulking surgery has been the initial treatment modality. The evolution of the disease is mostly favourable except in a few cases with a more aggressive course. We report the case of an initially well differentiated psammocarcinoma with a further unfavourable evolution. PMID- 26763844 TI - Single-incision Laparoscopic Intragastric Surgery for a Pancreatic Pseudocyst. AB - Single-incision Laparoscopic Surgery is an emerging laparoscopic technique that aims for a minimal invasive approach. Several cases and series have been reported in literature for a wide variety of pathologies, such as appendectomy, cholecystectomy, bariatric procedures and colonic surgery. We report the case of an intragastric cystogastrostomy performed by SILS in a patient with a symptomatic pseudocyst of the pancreas. With this case we would like to demonstrate the feasibility and safety of the procedure. PMID- 26763845 TI - Conservative Treatment of Left Ventricular Free Wall Rupture. AB - We present a case of post-infarction Left Ventricular Free Wall Rupture (LVFWR), in which conservative treatment was successfully applied. A 48-year old male patient presented at our emergency department with abdominal pain and a clinical presentation of shock. There had been an episode of chest pain three days before admission. Electrocardiogram was suggestive for old myocardial infarction. Coronarography revealed an occlusion of a diagonal branch. Computed Tomography scan was performed to exclude a rupturing aortic aneurysm, but a large pericardial effusion was seen. Echocardiography confirmed the diagnosis of cardiac tamponade and pericardiocentesis was performed. Conservative treatment consisting of bed rest, blood pressure control and beta-blocker therapy was applied, allowing the patient to be discharged after 10 days. The diagnosis of LVFWR was confirmed by cardiac magnetic resonance imaging.Surgery is considered as the golden standard in treatment of LVFWR. This case illustrates that in selected patients conservative treatment is possible. PMID- 26763847 TI - What is the benefit of renal denervation? PMID- 26763846 TI - Reversal of right ventricular remodeling by dichloroacetate is related to inhibition of mitochondria-dependent apoptosis. AB - Most patients with pulmonary arterial hypertension die from right ventricular failure (RVF). Right ventricular (RV) myocardial apoptosis has an important role in RVF and is regulated by the mitochondria. Dichloroacetate (DCA) can improve cardiac function in RVF, but whether it can regulate myocardial apoptosis via mitochondria is still unknown. In this study, we investigated the effects of DCA on myocardial mitochondria, the mitochondrial apoptosis and other aspects of RV remodeling, including fibrosis and capillary rarefaction. RVF was induced in rats by a single s.c. injection of monocrotaline. After 4 weeks, DCA treatment was started with i.p. injection of 50, 150 or 2007 mg kg(-1) per day during 14 days. Compared with saline-treated RVF animals, treatment with DCA resulted in decreased mean pulmonary arterial pressure and total pulmonary resistance (TPR), and increased cardiac output. The expression of pyruvate dehydrogenase kinase was suppressed, while pyruvate dehydrogenase expression was upregulated with DCA application. DCA treatment was also associated with restored RV mitochondrial function and a reduction in RV hypertrophy, fibrosis, capillary rarefaction and apoptosis. Mitochondria-dependent apoptosis was involved in DCA regulation of RV. The absent correlation between TPR and main parameters in RV suggests that the effects of DCA in the two organ systems are independent. We conclude that DCA improves cardiac function in experimental RVF partly by reversing RV remodeling, restoring mitochondrial function and regulating mitochondria-dependent apoptosis. The study shows that a fear for increased RV apoptosis with DCA treatment is unnecessary and suggests a potential role of DCA in the treatment of RVF. PMID- 26763848 TI - Relationship between outpatient visit frequency and hypertension control: a 9 year occupational cohort study. AB - The purpose of this study was to investigate the relationship between the frequency of outpatient visits and hypertension control as determined from health insurance records. This 9-year cohort study in Japan was based on 518 participants with hypertension who underwent health checkups in 2004. Participants were aged 35-56 years and none had a history of cardiovascular or cerebrovascular disease. All were covered by the same employee health insurer. Mean annual outpatient visit days at a hospital/clinic during the 9-year period were classified within four quartiles (Q1, Q2, Q3, Q4). Uncontrolled hypertension was defined as a systolic blood pressure (BP) ?140 mm Hg and a diastolic BP ?90 mm Hg. Logistic regression analysis was used to estimate the multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the prevalence of uncontrolled hypertension in groups Q1, Q2 and Q3 vs. Q4. The median (25th 75th percentile) annual outpatient visit days was 9.4 (4.0-15.5). Uncontrolled hypertension was observed in 62.4% of the participants in 2013. The multivariable adjusted ORs and 95% CIs for uncontrolled hypertension in Q1, Q2 and Q3 vs. Q4 were 4.03 (2.28-7.12), 1.67 (0.99-2.81) and 1.44 (0.86-2.41), respectively. Uncontrolled hypertension increased significantly as the number of outpatient visits decreased (P for trend <0.001). This tendency was maintained when participants taking antihypertensive agents at baseline were excluded. Our study showed an inverse relationship between outpatient visit frequency and uncontrolled hypertension. PMID- 26763849 TI - The angiotensin II receptor antagonist, losartan, enhances regulator of G protein signaling 2 mRNA expression in vascular smooth muscle cells of Wistar rats. AB - Angiotensin II (Ang II) reportedly enhances regulator of G-protein signaling 2 (RGS2), thus making a negative feedback loop for Ang II signal transduction. However, few studies have reported whether Ang II receptor (ATR) antagonists influence RGS2 mRNA expression. We investigated RGS2 mRNA expression when Ang II binding to ATR was blocked with Ang II subtype-1 receptor (AT1R) blockers using vascular smooth muscle cells from the thoracic aorta of male Wistar rats. RGS2 mRNA expression significantly increased with Ang II stimulation, and this increase was almost completely abolished by olmesartan, a potent AT1R-specific blocker. Ang II subtype-2 receptor (AT2R) was not involved in Ang II-mediated RGS expression. In contrast, the AT1R blocker, losartan, partially decreased Ang II mediated RGS2 mRNA expression because this antagonist directly stimulated RGS2 mRNA expression in Ang II-free medium. EXP3174, which is an active metabolite of losartan, almost completely blunted Ang II-mediated RGS2 mRNA expression without direct stimulation of RGS2 mRNA expression. Moreover, pretreatment with olmesartan abolished Ang II-mediated RGS2 mRNA expression. Treatment with a protein kinase C inhibitor partially decreased losartan-mediated RGS2 mRNA expression. These results suggest that AT1R blockers inhibit RGS2 mRNA expression in response to Ang II via an AT1R-mediated mechanism. However, the AT1R blocker, losartan, behaves as a direct agonist for RGS2 mRNA expression via AT1R through protein kinase C-dependent and -independent pathways. In conclusion, losartan exhibits dual effects on RGS2 mRNA expression, and the direct upregulation of RGS2 mRNA expression may provide a new strategy for the treatment of hypertension. PMID- 26763850 TI - Ca2+ -regulated lysosome fusion mediates angiotensin II-induced lipid raft clustering in mesenteric endothelial cells. AB - It has been reported that intracellular Ca2+ is involved in lysosome fusion and membrane repair in skeletal cells. Given that angiotensin II (Ang II) elicits an increase in intracellular Ca2+ and that lysosome fusion is a crucial mediator of lipid raft (LR) clustering, we hypothesized that Ang II induces lysosome fusion and activates LR formation in rat mesenteric endothelial cells (MECs). We found that Ang II acutely increased intracellular Ca2+ content, an effect that was inhibited by the extracellular Ca2+ chelator ethylene glycol tetraacetic acid (EGTA) and the inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release inhibitor 2-aminoethoxydiphenyl borate (2-APB). Further study showed that EGTA almost completely blocked Ang II-induced lysosome fusion, the translocation of acid sphingomyelinase (ASMase) to LR clusters, ASMase activation and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase activation. In contrast, 2 APB had a slight inhibitory effect. Functionally, both the lysosome inhibitor bafilomycin A1 and the ASMase inhibitor amitriptyline reversed Ang II-induced impairment of vasodilation. We conclude that Ca2+ -regulated lysosome fusion mediates the Ang II-induced regulation of the LR-redox signaling pathway and mesenteric endothelial dysfunction. PMID- 26763852 TI - Biomarkers of lipid peroxidation related to hypertension in aging. AB - The aim of this clinical study was to evaluate the influence of aging on the levels of lipid peroxidation (quantified as thiobarbituric acid-reactive substances (TBARS) content), lipid hydroperoxide (LOOH), hexanoyl lysine (HEL), 8 iso-prostaglandin F2alpha (8-iso-PGF2alpha) and total antioxidant capacity (TAC), and determine their relationships to the demographic and cardiovascular risk factors in elderly hypertensive (HT) patients. This study consisted of four groups: two elderly groups with 30 HT patients (11 males, 19 females) and 30 normotensive healthy volunteers (15 males, 15 females), and two young groups with 30 HT patients (13 males, 17 females) and 30 normotensive healthy volunteers (12 males, 18 females). In the elderly control group, the TBARS, LOOH, HEL and 8-iso PGF2alpha levels, and the carotid intima media thickness (CIMT) were significantly higher than in the young control group. The TBARS, LOOH, HEL and 8 iso-PGF2alpha levels and the CIMT measurements were significantly higher in the elderly HT group than in the young HT group. In addition, the TAC levels were significantly lower in the elderly and young HT groups than in the elderly and young control groups. The CIMT was significantly positively correlated with TBARS (r=0.40, P<0.001), HEL (r= 0.30, P=0.001), LOOH (r= 0.44, P<0.001) and 8-iso PGF2alpha (r= 0.32, P<0.001) in all of the HT groups. It seems that in elderly patients, the LOOH and TBARS are better biomarkers of lipid peroxidation in hypertension in terms of sensitivity. In all of the HT groups, 8-iso-PGF2alpha had the highest sensitivity. Hypertension is associated with lipid peroxidation due to an impaired oxidant/antioxidant status. Increased lipid peroxidation and decreased antioxidants with aging indicate that peroxidative damage further increases with higher blood pressure and the aging process. PMID- 26763853 TI - Association of body composition and blood pressure categories with retinal vessel diameters in primary school children. AB - Alterations in retinal vessel diameters have been shown to be predictive of cardiovascular risk in adults and children. The aim of our study was to examine the association of body composition and blood pressure (BP) categories with retinal vessel diameters in school children. We examined anthropometric parameters, BP and retinal arteriolar (CRAE) and venular (CRVE) diameters as well as the arteriolar-to-venular diameter ratio (AVR) in 391 children (age: 7.3, s.d. 0.4). Differences between the lowest and highest BP quartiles indicated that higher systolic and diastolic BP were associated with narrower CRAE (P<0.001 for both). Children in the highest weight quartile had narrower CRAE compared with the lowest quartile (P=0.05). In the regression analysis, systolic and diastolic BP were associated with arteriolar narrowing (-0.4 measuring units (mu) per mm Hg, 95% confidence interval: [-0.6; -0.3] and -0.6 mu per mm Hg [-0.7; -0.4], respectively; P<0.001 for both). An independent association was found for diastolic BP only. Compared with normotensives (NT; 74.4% of cohort), arteriolar narrowing was already seen in children categorized as pre-hypertensive (PHT) (11.5% of cohort), which was similar to HT children (14.1% of cohort) (NT: mean 207.2 [205.6; 208.7] mu; PHT: 201.7 [197.8; 205.7] mu; HT: 199.7 [196.2; 203.3] mu; P=0.01 for PHT vs. NT and P<0.001 for HT vs. NT in systolic BP). Our results suggest that systolic and diastolic BP are main determinants of retinal arteriolar diameters; and therefore, microvascular health in young children. Pre hypertension seems to be associated with retinal microvascular alterations early in life. PMID- 26763851 TI - Effects of antihypertensive drugs losartan and levamlodipine besylate on insulin resistance in patients with essential hypertension combined with isolated impaired fasting glucose. AB - The objective of this study was to observe the antihypertensive effect of losartan and levamlodipine besylate on insulin resistance in patients with essential hypertension (EH) combined with isolated impaired fasting glucose (i IFG). Patients (n=244) were randomly assigned to losartan potassium tablets (50 100 mg per day) or levamlodipine besylate tablets (2.5-5.0 mg per day) for intensive antihypertensive treatment with no lifestyle interventions for 3 years. The changes in fasting plasma glucose, fasting insulin (FINS) and insulin sensitivity index (ISI) from before to after treatment were observed. Blood pressure (BP) in each group was significantly reduced by treatment (P<0.05). After 12 months of treatment, the FINS level in the losartan potassium group was significantly decreased and ISI was significantly increased compared with before treatment (P<0.05) and compared with the levamlodipine besylate group (P<0.05). After 24 and 36 months of treatment, FINS was significantly decreased and ISI was significantly improved in both groups compared with baseline (P<0.05), and there was no difference between the groups (P>0.05). The incidence of new-onset diabetes mellitus was not significantly different between two groups. The antihypertensive effect of losartan and levamlodipine besylate could amoliorate insulin resistance in patients with EH combined with i-IFG. The improvement of insulin resistance by losartan potassium at 12 months might be better than that by levamlodipine besylate; however, after 24 and 36 months of follow-up, both agents significantly alleviated insulin resistance. These results suggest that the effects of these two drugs on insulin resistance are not significantly different. PMID- 26763854 TI - Effects on carotid-femoral pulse wave velocity 24 h post exercise in young healthy adults. AB - Arterial stiffness, often measured by carotid-femoral pulse wave velocity (cfPWV), is a subclinical marker of cardiovascular disease that is known to be reduced by exercise training. Exercise is also known to have acute vascular effects, yet it is unclear whether exercise 24 h before cfPWV testing influences this outcome. Thirty healthy, young adults completed a supervised, 30-min bout of moderate-to-vigorous intensity treadmill running. cfPWV, systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured both before (after 48 h of abstaining from exercise) and 24 h after (with no additional exercise) the exercise session. From pre-exercise to 24 h post exercise, cfPWV decreased from 6.05+/-0.82 to 5.84+/-0.87 m s(-1) (P=0.02), SBP from 119.7+/-13.8 to 116.8+/-11.4 mm Hg (P=0.03) and DBP from 65.1+/-5.7 to 63.2+/-5.4 mm Hg (P=0.02), with no significant changes in HR. cfPWV was positively correlated with SBP pre-exercise (r=0.54, P<0.01) and post exercise (r=0.53, P<0.01). Changes in blood pressure explained 4-5% of the variability in cfPWV change; adjustments slightly attenuated the 24-h effects of exercise on cfPWV. Some evidence of gender differences was observed with higher cfPWV in males across assessments (P<0.05) and statistically significant reductions in cfPWV in males (-0.36+/-0.54 m s(-1) (P=0.02)) but not in females (-0.07+/-0.31 m s(-1) (P=0.41)). In conclusion, cfPWV decreased 24 h after an exercise bout, suggesting that exercise completed in the past 24 h should be considered before cfPWV testing. PMID- 26763856 TI - Propionibacterium acnes in shoulder surgery: is loss of hair protective for infection? AB - BACKGROUND: Propionibacterium acnes (P acnes) has been linked to chronic infections in shoulder surgery. It was recently observed during first-time shoulder surgery in healthy patients at a rate between 36% and 56%. Male gender and the anterolateral approach were reported risk factors. Because the skin biology greatly differs, we aimed to correlate skin complaints with P acnes positive intraoperative cultures from different tissue layer samples in patients undergoing shoulder surgery for the first time. METHODS: Intraoperative samples (1 skin, 1 superficial, 1 deep tissue, and 1 control sample) from 112 patients (70 men, 42 women; aged 59.2 years) were cultured. The association between the presence of P acnes in the deep or superficial tissue, or both, and 10 items of a validated preoperative questionnaire for skin pathology was explored. RESULTS: The cultures were positive for P acnes in 38.4% (n = 43) of the cases. Skin samples were positive for P acnes in 8% (n = 9), superficial samples were positive in 23% (n = 26), and deep samples were positive in 30% (n = 34). Self reported "loss of hair" was significantly negatively associated with the presence of P acnes in the superficial or deep tissue sample (P = .00028). DISCUSSION: Patients who report having "loss of hair" show fewer P acnes-positive cultures in intraoperative tissue samples taken during open shoulder surgery. Whether this subgroup is at a lesser risk for P acnes infections remains to be substantiated. LEVEL OF EVIDENCE: Basic Science Study; Microbiology. PMID- 26763855 TI - Immune activation during the implantation phase causes preeclampsia-like symptoms via the CD40-CD40 ligand pathway in pregnant mice. AB - The CD40 ligand (CD40L) is expressed by T cells and has a critical role in immune system regulation. Interventions targeting CD40L interactions following embryo implantation represent an approach to preventing preeclampsia (PE). To better understand the role of CD40L in PE, we developed a PE mouse model in which we examined how CD40L-induced immune activation affects embryo implantation. Blastocysts were incubated with CD40L-expressing adenovirus and then were transferred into the uterine horns of pseudopregnant ICR mice. Histology, biochemistry and flow cytometry experiments were performed to examine the characteristics of the mouse model. In early pregnancy, decidualization and spiral artery remodeling were reduced in CD40L-transfected mice (CD40L mice) compared with control mice. Hematoxylin-eosin (HE) staining revealed hemorrhaging and excess fibrin deposition at the labyrinth layer-junctional zone interface of the placenta, and PAS staining demonstrated prominent focal and segmental sclerosis with collapsed glomerular capillaries in the kidneys of the CD40L mice. Flow cytometry data showed that interferon-gamma production derived from CD4(+) T cells was elevated in the splenic cells of CD40L mice. Blood pressure (measured by the tail-cuff method) and urine albumin concentrations were significantly increased in CD40L mice compared with control mice. Furthermore, the plasma concentrations of soluble Flt-1 and soluble endoglin were increased in CD40L mice, as occurs in human patients with PE. Thus, CD40L-induced T-helper cell type 1 differentiation during embryo implantation may have a critical role in the pathogenesis of a PE-like presentation in a novel mouse model of PE. PMID- 26763857 TI - Noncontrast Brain Computed Tomography Findings of Spontaneous Intracranial Hypotension in the Emergency Department Setting. AB - BACKGROUND: Spontaneous intracranial hypotension (SIH) is a difficult diagnosis, especially in an emergency department (ED) setting where magnetic resonance imaging (MRI) is usually not available. OBJECTIVES: To emphasize the presence of a very frequent but unnoticed tentorial subdural hygroma among a number of recognized noncontrast brain computed tomography (CT) findings in patients with spontaneous intracranial hypotension. METHODS: This is a case series study of 7 consecutive patients with orthostatic headache who were admitted to the ED and finally diagnosed as SIH, and of 11 women who underwent brain CT due to very severe orthostatic headache after epidural anesthesia. We evaluated the CT findings of patients with SIH and further compared each patient's CT findings with their respective MRI and with the brain CT of women with postepidural anesthesia orthostatic headache. RESULTS: Noncontrast brain CT was abnormal in five out of seven (71%) SIH cases: tentorial subdural hygroma was found in four (57%) cases; supratentorial subdural hygroma and cervical spinal venous engorgement were found in two (29%) cases, and subdural hematoma was found in one case. All women with severe orthostatic headache after epidural anesthesia had CT findings similar to those of spontaneous intracranial hypotension patients. CONCLUSIONS: The presence of a tentorial subdural hygroma on brain CT in a patient with orthostatic headache may strongly suggest the diagnosis of intracranial hypotension. This finding can be of high clinical significance in an emergency setting, avoiding additional invasive or expensive procedures. PMID- 26763858 TI - Influenza in the Emergency Department: Vaccination, Diagnosis, and Treatment: Clinical Practice Paper Approved by American Academy of Emergency Medicine Clinical Guidelines Committee. AB - BACKGROUND: Influenza is an acute respiratory virus that results in significant worldwide morbidity and mortality each year. As emergency physicians, we are often the first to encounter patients with seasonal influenza. It is therefore critical that we draw on the most recent and relevant research when we make clinical decisions regarding the diagnosis, treatment, and prophylaxis of this disease. METHODS: A MEDLINE literature search from August 2009 to August 2015 was performed using the keywords influenza vaccination efficacy AND systematic, influenza AND rapid antigen testing, and Oseltamivir AND systematic, while limiting the search to human studies written in the English language. General review articles and case reports were omitted. Each of the selected articles then underwent a structured review. RESULTS: We identified 163 articles through our literature search, of which 68 were found to be relevant to our clinical questions. These studies then underwent a rigorous review from which recommendations were given. CONCLUSIONS: Influenza vaccine efficacy continues to range between 40% and 80%. Vaccination has the potential to decrease disease severity and is recommended for individuals older than 6 months of age. If resources permit, vaccination can be offered to patients presenting to the emergency department. Rapid antigen detection for influenza is a simple bedside test with high specificity, but generally low sensitivity. If a patient presents with a syndrome consistent with influenza and has negative rapid antigen detection, they should either receive a confirmatory reverse transcriptase polymerase chain reaction or be treated as if they have influenza. Treatment with neuraminidase inhibitors can decrease the duration of influenza and is recommended in hospitalized patients, or in those with high risk of complications. PMID- 26763859 TI - How to Delineate Pericardial Effusion from Pleural Effusion on Bedside Ultrasound. PMID- 26763860 TI - Authentic learning in anatomy: A primer on pragmatism. PMID- 26763865 TI - Characteristics of non-obese non-alcoholic fatty liver disease: Effect of genetic and environmental factors. AB - AIM: There are a considerable number of patients with non-obese non-alcoholic fatty liver disease (NAFLD). However, the clinical characteristics of non-obese NAFLD is not fully understood. We investigated genetic and other clinical parameters in non-obese and obese NAFLD. METHODS: The single nucleotide polymorphism rs738409 in the patatin-like phospholipase 3 gene (PNPLA3) was genotyped by the Invader assay in 540 NAFLD patients (134 non-obese and 406 obese) and 1012 control subjects (782 non-obese and 230 obese). All NAFLD patients underwent liver biopsy. Odds ratios were calculated by multiple logistic regression analysis using age, sex, body mass index (BMI), type 2 diabetes mellitus (T2DM) and rs738409 genotype as explanatory variables. RESULTS: Non obese NAFLD subjects had a higher rs738409 GG genotype than obese NAFLD. Multiple logistic regression analysis indicated that the odds ratios of T2DM and rs738409 GG genotype for NAFLD were higher in non-obese than in obese groups. In non-obese NAFLD, rs738409 GG genotype was associated with lobular inflammation, hepatocyte ballooning and NAFLD activity score. In obese NAFLD, BMI and T2DM but not rs738409 GG genotype were associated with severity of histology. CONCLUSION: We demonstrated that the risk factors for the development and progression of NAFLD were different between non-obese and obese patients and that PNPLA3 rs738409 was strongly associated with the development and progression of non-obese NAFLD. PMID- 26763863 TI - Stabilizing Off-pathway Oligomers by Polyphenol Nanoassemblies for IAPP Aggregation Inhibition. AB - Experimental studies have shown that many naturally occurring polyphenols have inhibitory effect on the aggregation of several proteins. Here, we use discrete molecular dynamics (DMD) simulations and high-throughput dynamic light scattering (DLS) experiments to study the anti-aggregation effects of two polyphenols, curcumin and resveratrol, on the aggregation of islet amyloid polypeptide (IAPP or amylin). Our DMD simulations suggest that the aggregation inhibition is caused by stabilization of small molecular weight IAPP off-pathway oligomers by the polyphenols. Our analysis indicates that IAPP-polyphenol hydrogen bonds and pi-pi stacking combined with hydrophobic interactions are responsible for the stabilization of oligomers. The presence of small oligomers is confirmed with DLS measurements in which nanometer-sized oligomers are found to be stable for up to 7.5 hours, the time frame within which IAPP aggregates in the absence of polyphenols. Our study offers a general anti-aggregation mechanism for polyphenols, and further provides a computational framework for the future design of anti-amyloid aggregation therapeutics. PMID- 26763866 TI - Heterochromia of the Hair and Eyelashes with Blaschkoid Dyspigmentation. AB - Heterochromia of the hair involves the presence of two distinctive colors of scalp hair in one individual. We report the case of a 4-year-old girl with reddish streaks of scalp hair, heterochromia of the eyelashes, and cutaneous hypopigmentation following the lines of Blaschko. PMID- 26763867 TI - The GAO Report: Funding, Challenges, and Solutions for Regenerative Medicine. PMID- 26763864 TI - Reduced interleukin-2 responsiveness impairs the ability of Treg cells to compete for IL-2 in nonobese diabetic mice. AB - Enhancement of regulatory T cell (Treg cell) frequency and function is the goal of many therapeutic strategies aimed at treating type 1 diabetes (T1D). The interleukin-2 (IL-2) pathway, which has been strongly implicated in T1D susceptibility in both humans and mice, is a master regulator of Treg cell homeostasis and function. We investigated how IL-2 pathway defects impact Treg cells in T1D-susceptible nonobese diabetic (NOD) mice in comparison with protected C57BL/6 and NOD congenic mice. NOD Treg cells were reduced in frequency specifically in the lymph nodes and expressed lower levels of CD25 and CD39/CD73 immunosuppressive molecules. In the spleen and blood, Treg cell frequency was preserved through expansion of CD25(low), effector phenotype Treg cells. Reduced CD25 expression led to decreased IL-2 signaling in NOD Treg cells. In vivo, treatment with IL-2-anti-IL-2 antibody complexes led to effective upregulation of suppressive molecules on NOD Treg cells in the spleen and blood, but had reduced efficacy on lymph node Treg cells. In contrast, NOD CD8(+) and CD4(+) effector T cells were not impaired in their response to IL-2 therapy. We conclude that NOD Treg cells have an impaired responsiveness to IL-2 that reduces their ability to compete for a limited supply of IL-2. PMID- 26763868 TI - A Multicenter, Retrospective Study of Early Weightbearing for Modified Lapidus Arthrodesis. AB - The modified Lapidus arthrodesis is a long-established surgical technique for management of hallux valgus that provides reproducible results and quality patient outcomes. The data from 367 consecutive patients undergoing unilateral modified Lapidus arthrodesis from January 1, 2007 to December 31, 2008 at participating centers were retrospectively evaluated. The included patients were categorized into early weightbearing (<= 21 days) and delayed weightbearing (> 21 days) groups. A total of 24 nonunions (6.5%) were identified, with 13 (7.1%) in the early weightbearing group and 11 (6.0%) in the delayed weightbearing group. To date, the present study is the largest multicenter investigation to evaluate early weightbearing after modified Lapidus arthrodesis and the only large study to directly compare early and delayed weightbearing. The findings of the present study have shown that early weightbearing for modified Lapidus arthrodesis does not increase the risk of nonunion when evaluating various fixation constructs. PMID- 26763869 TI - Effectiveness of family involvement in newly diagnosed type 2 diabetes patients: a follow-up study. AB - OBJECTIVE: To investigate the effects of family-involvement on health education for T2DM from the aspects of knowledge, attitude and practice (KAP), health related quality of life (HRQoL), body mass index (BMI) and glucose control. METHODS: A follow-up study was performed and patients with newly diagnosed T2DM were divided into family-involved group (FIG, n=60) and single-involved group (SIG, n=60). Hierarchical linear models were used to assess within-group changes and between-group differences in the glycosylated hemoglobin A1c (HbA1c), KAP, SF 36 and BMI. RESULTS: Significant improvements in FIG along with significant differences between-group were seen for HbA1c levels (9.73, 8.92, 5.55, 5.79, 5.30 vs. 10.05, 9.53, 6.36, 8.41, 6.58) in baseline, M3, M6, M12, M24 compared with SIG, respectively (all P<=0.001). Significant improvements in FIG along with significant differences between-group were seen for KAP (16.23, 46.98, 48.93 vs. 16.65, 29.07, 37.62), SF-36 (78.04, 92.68, 92.34 vs. 74.96, 77.03, 78.25), and BMI (24.74, 23.46, 22.96 vs. 24.00, 23.45, 23.50) in baseline, M12 and M24, respectively (all P<=0.05). CONCLUSION: Family involvement is beneficial to the control of T2DM and should be suggested for T2DM newly diagnosed. PRACTICE IMPLICATIONS: Health education should encourage the family to participate in the whole process to improve the efficacy of education. PMID- 26763870 TI - The discordance of information needs between cancer patients and their families in China. AB - OBJECTIVE: We aimed at studying information needs of patients and their families, and their attitude towards the counterparts' information needs. Factors influencing psychological status of patients were investigated. METHODS: Self designed questionnaires for information needs and attitude were delivered to participants. Patient Health Questionnaire 9-item and Generalized Anxiety Disorder 7-item scale were used to evaluate psychological status of patients. RESULTS: 183 eligible pairs of patients and families were involved. Except for the patients' expected life span, most patients and families needed information for all other subscales of disease-related information. Most patients wished families know more information; however, caregivers tended to prevent this. The occurrence of patients' psychiatric disorders was related to their needs for expected life span (OR 3.06 95%CI 1.36-6.93), as well as the attitude of caregivers about whether to provide more information about treatment outcomes (OR 0.24 95% CI 0.10-0.63). CONCLUSIONS: Information discordance between cancer patients and their families tended to happen when it came to patients' prognostic information. The psychological status of cancer patients was found in association with their information needs and families' attitude towards it. PRACTICE IMPLICATIONS: To guide oncology professionals and cancer patients' families for information provision. PMID- 26763871 TI - Expert and patient consensus on a dynamic model for shared decision-making in frail older patients. AB - OBJECTIVE: Shared decision-making (SDM) is widely recommended as a way to support patients in making healthcare choices. Due to an ageing population, the number of older patients will increase. Existing models for SDM are not sufficient for this patient group, due to their multi-morbidity, the lack of guidelines and evidence applicable to the numerous combinations of diseases. The aim of this study was to gain consensus on a model for SDM in frail older patients with multiple morbidities. METHODS: We used a three-round Delphi study to reach consensus on a model for SDM in older patients with multiple morbidities. The expert panel consisted of 16 patients (round 1), and 59 professionals (rounds 1-3). In round 1, the SDM model was introduced, rounds 2 and 3 were used to validate the importance and feasibility of the SDM model. RESULTS: Consensus for the proposed SDM model as a whole was achieved for both importance (91% panel agreement) and feasibility (76% panel agreement). CONCLUSIONS: SDM in older patients with multiple morbidities is a dynamic process. It requires a continuous counselling dialogue between professional and patient or proxy decision maker. PRACTICE IMPLICATIONS: The developed model for SDM in clinical practice may help professionals to apply SDM in the complex situation of the care for older patients. PMID- 26763872 TI - Teratocarcinomas Arising from Allogeneic Induced Pluripotent Stem Cell-Derived Cardiac Tissue Constructs Provoked Host Immune Rejection in Mice. AB - Transplantation of induced pluripotent stem cell-derived cardiac tissue constructs is a promising regenerative treatment for cardiac failure: however, its tumourigenic potential is concerning. We hypothesised that the tumourigenic potential may be eliminated by the host immune response after allogeneic cell transplantation. Scaffold-free iPSC-derived cardaic tissue sheets of C57BL/6 mouse origin were transplanted into the cardiac surface of syngeneic C57BL/6 mice and allogeneic BALB/c mice with or without tacrolimus injection. Syngeneic mice and tacrolimus-injected immunosuppressed allogeneic mice formed teratocarcinomas with identical phenotypes, characteristic, and time courses, as assessed by imaging tools including (18)F-fluorodeoxyglucose-positron emission tomography. In contrast, temporarily immunosuppressed allogeneic mice, following cessation of tacrolimus injection displayed diminished progression of the teratocarcinoma, accompanied by an accumulation of CD4/CD8-positive T cells, and finally achieved complete elimination of the teratocarcinoma. Our results indicated that malignant teratocarcinomas arising from induced pluripotent stem cell-derived cardiac tissue constructs provoked T cell-related host immune rejection to arrest tumour growth in murine allogeneic transplantation models. PMID- 26763873 TI - Effect of obesity on the association between MYL2 (rs3782889) and high-density lipoprotein cholesterol among Korean men. AB - High-density lipoprotein (HDL) cholesterol levels are associated with a decreased risk of coronary artery disease. Several genome-wide association studies that have examined HDL cholesterol levels have implicated myosin light chain 2 regulatory cardiac slow (MYL2) as a possible causal factor. Herein, the association between the rs3782889 single-nucleotide polymorphism (SNP) in the MYL2 gene and HDL cholesterol levels was tested in the Korean population. A total of 4294 individuals were included in a replication study with MYL2 SNP rs3782889. SNP rs3782889 in the MYL2 gene was associated with mean HDL cholesterol level (effect per allele, -1.055 mg dl(-1), P=0.0005). Subjects with the CT/CC genotype had a 1.43-fold (range 1.19-1.73-fold) higher risk of an abnormal HDL cholesterol level (<40 mg dl(-1)) than subjects with the TT genotype. When analyzed by sex, the MYL2 association was stronger in men than that in women. When analyzed by body mass index (BMI), the MYL2 association was much stronger in male subjects with BMI ?26.44 kg m(-2) (odds ratio (OR)=2.68; 95% confidence interval (CI)=1.87 3.84; P<0.0001) than that in male subjects with BMI <26.44 kg m(-2). When compared with subjects having the TT genotype and BMI <26.44 kg m(-2), ORs (95% CI) were 3.30 (2.41-4.50) in subjects having the CT/CC genotype and BMI ?26.44 kg m(-2) (P for interaction <0.0001). Our results clearly demonstrate that genetic variants in MYL2 influence HDL cholesterol levels in Korean obese male subjects. PMID- 26763874 TI - Genome-wide association study reveals sex-specific selection signals against autosomal nucleotide variants. AB - A genome-wide association study (GWAS) was conducted to examine genetic associations of common autosomal nucleotide variants with sex in a Korean population with 4183 males and 4659 females. Nine genetic association signals were identified in four intragenic and five intergenic regions (P<5 * 10(-8)). Further analysis with an independent data set confirmed two intragenic association signals in the genes encoding protein phosphatase 1, regulatory subunit 12B (PPP1R12B, intron 12, rs1819043) and dynein, axonemal, heavy chain 11 (DNAH11, intron 61, rs10255013), which are directly involved in the reproductive system. This study revealed autosomal genetic variants associated with sex ratio by GWAS for the first time. This implies that genetic variants in proximity to the association signals may influence sex-specific selection and contribute to sex ratio variation. Further studies are required to reveal the mechanisms underlying sex-specific selection. PMID- 26763875 TI - Identification of a novel mutation confirms the implication of IFT172 (BBS20) in Bardet-Biedl syndrome. AB - Bardet-Biedl syndrome (BBS; MIM 209900) is a recessive heterogeneous ciliopathy characterized by retinitis pigmentosa (RP), postaxial polydactyly, obesity, hypogonadism, cognitive impairment and kidney dysfunction. So far, 20 BBS genes have been identified, with the last reported ones being found in one or very few families. Whole-exome sequencing was performed in a consanguineous family in which two affected children presented typical BBS features (retinitis pigmentosa, postaxial polydactyly, obesity, hypogonadism and cognitive impairment) without any mutation identified in known BBS genes at the time of the study. We identified a homozygous splice-site mutation (NM_015662.2: c.4428+3A>G) in both affected siblings in the last reported BBS gene, namely, Intraflagellar Transport 172 Homolog (IFT172). Familial mutation segregation was consistent with autosomal recessive inheritance. IFT172 mutations were initially reported in Jeune and Mainzer-Saldino syndromes. Recently, mutations have also been found in isolated RP and Bardet-Biedl-like ciliopathy. This is the second report of IFT172 mutations in BBS patients validating IFT172 as the twentieth BBS gene (BBS20). Moreover, another IFT gene, IFT27, was already associated with BBS, confirming the implication of IFT genes in the pathogenesis of BBS. PMID- 26763876 TI - Familial retinoblastoma due to intronic LINE-1 insertion causes aberrant and noncanonical mRNA splicing of the RB1 gene. AB - Retinoblastoma (RB, MIM 180200) is the paradigm of hereditary cancer. Individuals harboring a constitutional mutation in one allele of the RB1 gene have a high predisposition to develop RB. Here, we present the first case of familial RB caused by a de novo insertion of a full-length long interspersed element-1 (LINE 1) into intron 14 of the RB1 gene that caused a highly heterogeneous splicing pattern of RB1 mRNA. LINE-1 insertion was inferred by mRNA studies and full length sequenced by massive parallel sequencing. Some of the aberrant mRNAs were produced by noncanonical acceptor splice sites, a new finding that up to date has not been described to occur upon LINE-1 retrotransposition. Our results clearly show that RNA-based strategies have the potential to detect disease-causing transposon insertions. It also confirms that the incorporation of new genetic approaches, such as massive parallel sequencing, contributes to characterize at the sequence level these unique and exceptional genetic alterations. PMID- 26763877 TI - An effective screening strategy for deafness in combination with a next generation sequencing platform: a consecutive analysis. AB - The diagnosis of the genetic etiology of deafness contributes to the clinical management of patients. We performed the following four genetic tests in three stages for 52 consecutive deafness subjects in one facility. We used the Invader assay for 46 mutations in 13 genes and Sanger sequencing for the GJB2 gene or SLC26A4 gene in the first-stage test, the TaqMan genotyping assay in the second stage test and targeted exon sequencing using massively parallel DNA sequencing in the third-stage test. Overall, we identified the genetic cause in 40% (21/52) of patients. The diagnostic rates of autosomal dominant, autosomal recessive and sporadic cases were 50%, 60% and 34%, respectively. When the sporadic cases with congenital and severe hearing loss were selected, the diagnostic rate rose to 48%. The combination approach using these genetic tests appears to be useful as a diagnostic tool for deafness patients. We recommended that genetic testing for the screening of common mutations in deafness genes using the Invader assay or TaqMan genotyping assay be performed as the initial evaluation. For the remaining undiagnosed cases, targeted exon sequencing using massively parallel DNA sequencing is clinically and economically beneficial. PMID- 26763878 TI - De novo missense mutations in NALCN cause developmental and intellectual impairment with hypotonia. AB - Three recessive mutations in the sodium leak channel, nonselective (NALCN) have been reported to cause intellectual disability and hypotonia. In addition, 14 de novo heterozygous mutations have been identified in 15 patients with arthrogryposis and neurodevelopmental impairment. Here, we report three patients with neurodevelopmental disease and hypotonia, harboring one recurrent (p.R1181Q) and two novel mutations (p.L312V and p.V1020F) occurring de novo in NALCN. Mutation p.L312 is located in the pore forming S6 region of domain I and p.V1020F in the S5 region of domain III. Mutation p.R1181Q is in a linker region. Mapping these three mutations to a model of NALCN showed p.Leu312 and p.Val1020 positioned in the hydrophobic core of the pore modules, indicating these two mutations may affect the gating function of NALCN. Although p.R1181Q is unlikely to affect the ion channel structure, previous studies have shown that an analogous mutation in Caenorhabditis elegans produced a phenotype with a coiling locomotion, suggesting that p.R1181Q could also affect NALCN function. Our three patients showed profound intellectual disability and growth delay, facial dysmorphologies and hypotonia. The present data support previous work suggesting heterozygous NALCN mutations lead to syndromic neurodevelopmental impairment. PMID- 26763879 TI - A novel de novo POGZ mutation in a patient with intellectual disability. AB - POGZ, the gene encoding pogo transposable element-derived protein with zinc finger domain, has been implicated in autism spectrum disorder and it is widely expressed in the human tissues, including the brain. Intellectual disability (ID) is highly heterogeneous neurodevelopment disorder and affects ~2-3% of the general population. Here we report the identification of a novel frameshift mutation in the coding region of the POGZ gene (c.1277_1278insC), which occurred de novo in a Chinese patient with ID. In silico analysis and western blotting revealed this frameshift mutation generating truncated protein in peripheral blood lymphocytes, and this may disrupt several important domains of POGZ gene. Our finding broadens the spectrum of POGZ mutations and may help to understand the molecular basis of ID and aid genetic counseling. PMID- 26763880 TI - KOHBRA BRCA risk calculator (KOHCal): a model for predicting BRCA1 and BRCA2 mutations in Korean breast cancer patients. AB - The widely used Western BRCA mutation prediction models underestimated the risk of having a BRCA mutation in Korean breast cancer patients. This study aimed to identify predictive factors for BRCA1/2 mutations and to develop a Korean BRCA risk calculator. The model was constructed by logistic regression model, and it was based on the Korean Hereditary Breast Cancer study, in which 1669 female patients were enrolled between May 2007 and December 2010. A separate data set of 402 patients, who were enrolled from Jan 2011 to August 2012, was used to test the performance of our model. In total, 264 (15.8%) and 67 (16.7%) BRCA mutation carriers were identified in the model and validation set, respectively. Multivariate analysis showed that age at breast cancer diagnosis, bilateral breast cancer, triple-negative breast cancer (TNBC) and the number of relatives with breast or ovarian cancer within third-degree relatives were independent predictors of the BRCA mutation among familial breast cancer patients. An age <35 years at diagnosis, bilateral breast cancer, both breast and ovarian cancer and TNBC remained significant predictors in non-familial breast cancer cases. Our model was developed based on logistic regression models. The validation results showed no differences between the observed and expected carrier probabilities. This model will be a useful tool for providing genetic risk assessments in Korean populations. PMID- 26763881 TI - Genome-wide association study of serum lipids confirms previously reported associations as well as new associations of common SNPs within PCSK7 gene with triglyceride. AB - Previous reports including genome-wide association studies (GWASs) have described associations of serum lipids with genomic variations. In the present study, we examined the association of ~2.5 million single-nucleotide polymorphisms (SNPs) from 3041 Japanese healthy volunteers obtained from the Japan Pharmacogenomics Data Science Consortium (JPDSC) database with serum lipids. We confirmed the previously reported associations of 14 SNPs in 5 regions for low-density lipoprotein (LDL) cholesterol, 23 SNPs in 12 regions for high-density lipoprotein (HDL) cholesterol, 16 SNPs in 6 regions for triglyceride and 5 SNPs in 1 region for phospholipid. Furthermore, we identified 16 possible novel candidate genes associated with LDL cholesterol, HDL cholesterol or triglycerides, where SNPs had P-values of <1 * 10(-5). Further replication analyses of these genes with Korean data revealed significant associations of SNPs located within the PCSK7 gene and triglyceride (Pmeta=7.98 * 10(-9) and 1.91 * 10(-8) for rs508487 and rs236911, respectively). These associations remained significant even by the conditional analysis adjusting for three neighboring variations associated with triglyceride. Our present data suggest that PCSK7 as well as PCSK9 may be associated with lipids, especially triglyceride, and may serve as a candidate for a new drug target to treat lipid abnormality syndromes. PMID- 26763882 TI - Mosaic 13q14 deletions in peripheral leukocytes of non-hematologic cancer cases and healthy controls. AB - Loss of 13q14.3 is a chromosomal event found in ~50% of B-cell chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL) cases. Surveys of somatic alterations in solid tumors have shown sporadic 13q14.3 loss in many different tumor types, but not at high frequency in any specific tumor type. In our recent survey of the single-nucleotide polymorphism (SNP) microarray data from 127 000 cancer-free or solid tumor cases, we observed mosaic 13q14.3 loss as common autosomal somatic large structural events (>2 Mb in size) in blood and buccal-derived DNA. Herein, we examined this region more closely investigating structural mosaic events <2 Mb using SNP microarray data in 46 254 non-hematologic cancer cases and 36 229 controls. We detected 60 individuals with 13q14.3 mosaic loss, 1 mosaic copy neutral uniparental disomy and 13 individuals with homozygosity. Although 13q14.3 loss size was variable, the minimally deleted region (MDR) (chr13: 49 590 000-49 983 100; GRCh36) was comparable to what is classically reported in MBL and CLL. Breakpoint analysis of the estimated boundaries reveals enrichment for genes and open chromatin. The frequency of 13q14.3 loss significantly increases with increasing age (P-value=0.028), but was not significantly different between non-hematological cancer cases and controls (0.084% versus 0.058%; P-value=0.19). These findings suggest that mosaic 13q14.3 losses accumulate with age. Individuals with detected mosaic 13q14.3 deletions may be early, undetected cases of MBL or CLL, but not necessarily all will develop MBL and CLL. PMID- 26763884 TI - Breast Hypoplasia as a Complication of an Untreated Infantile Hemangioma. AB - We report the case of a mixed infantile hemangioma (IH) involving the right breast that resulted in pronounced hypoplasia of the affected breast, which became apparent after breast development at puberty. No treatment had been performed in infancy or childhood. This case demonstrates that the presence of an IH may affect development of the mammary gland bud and that systemic therapy should be considered in an attempt to minimize this adverse sequela. PMID- 26763883 TI - Variable expressivity of the phenotype in two families with brachydactyly type E, craniofacial dysmorphism, short stature and delayed bone age caused by novel heterozygous mutations in the PTHLH gene. AB - Brachydactyly refers to shortening of digits due to hypoplasia or aplasia of bones forming the hands and/or feet. Isolated brachydactyly type E (BDE), which is characterized by shortened metacarpals and/or metatarsals, results in a small proportion of patients from HOXD13 or PTHLH mutations, although in the majority of cases molecular lesion remains unknown. BDE, like other brachydactylies, shows clinical heterogeneity with highly variable intrafamilial and interindividual expressivity. In this study, we investigated two Polish cases (one familial and one sporadic) presenting with BDE and additional symptoms due to novel PTHLH mutations. Apart from BDE, the affected family showed short stature, mild craniofacial dysmorphism and delayed bone age. Sanger sequencing of PTHLH revealed a novel heterozygous frameshift mutation c.258delC(p.N87Tfs*18) in two affected individuals and one relative manifesting mild brachydactyly. The sporadic patient, in addition to BDE, presented with craniofacial dysmorphism, normal stature and bone age, and was demonstrated to carry a de novo heterozygous c.166C>T(p.R56*) mutation. Our paper reports on the two novel truncating PTHLH variants, resulting in variable combination of BDE and other symptoms. Data shown here expand the knowledge on the phenotypic presentation of PTHLH mutations, highlighting significant clinical variability and incomplete penetrance of the PTHLH-related symptoms. PMID- 26763885 TI - BMI1 Regulation of Self-Renewal and Multipotency in Human Mesenchymal Stem Cells. AB - We have previously described generation of mesenchymal stem cells (MSCs) from human embryonic and induced pluripotent stem cells. One of the central questions in stem cell biology is to understand how stem cells regulate the decision to self-renew vs. differentiate, at the molecular level. In the current studies we used loss-of-function and gain-of-function analyses in primary human MSCs to demonstrate that BMI1 is a critical regulator for self-renewal and multipotency in this interesting cell type. Knockdown of BMI1 in MSCs reduced self-renewal by upregulation of p16(INK4A) and increased apoptosis. Knockdown of p16(INK4A) partially rescued the self-renewal defect in MSCs with loss of BMI1. Overexpressed BMI1 reduced apoptosis and increased cell proliferation by repressing p16(INK4A). Loss of BMI1 resulted in deregulation of PPARgamma, an adipogenic factor, and imprinted gene network (IGN), which blocks osteogenesis. Knockdown of PPARgamma or IGN in BMI1 defect models restored osteogenesis. Overexpression of BMI1 repressed transcripts of RUNX2 and PPARgamma, in osteogenesis and adipogenesis, respectively, which lead to decreased lineage specification potential in MSCs. These data show that BMI1 regulates cell proliferation, apoptosis, and differentiation of human MSCs. PMID- 26763886 TI - Neurogenic plasticity of mesenchymal stem cell, an alluring cellular replacement for traumatic brain injury. AB - Traumatic brain injury (TBI) imposes horrendous neurophysiological alterations leading to most devastating forms of neuro-disability. Which includes impaired cognition, distorted locomotors activity and psychosomatic disability in both youths and adults. Emerging evidence from recent studies has identified mesenchymal stem cells (MSCs) as one of the promising category of stem cells having excellent neuroregenerative capability in TBI victims. Some of the clinical and animal studies reported that MSCs transplantation could cure neuronal damage as well as improve cognitive and locomotors behaviors in TBI. However, mechanism behind their broad spectrum neuroregenerative potential in TBI has not been reviewed yet. Therefore, in the present article, we present a comprehensive data on the important attributes of MSCs, such as neurotransdifferentiation, neuroprotection, axonal repair and plasticity, maintenance of blood-brain integrity, reduction of reactive oxygen species (ROS) and immunomodulation. We have reviewed in detail the crucial neurogenic capabilities of MSCs in vivo and provided consolidated knowledge regarding their cellular remodeling in TBI for future therapeutic implications. PMID- 26763888 TI - Lymphomatoid Papulosis Type D: Report of a Case in a Child and Review of the Literature. AB - Lymphomatoid papulosis (LyP) is a cutaneous CD30-positive T-cell lymphoproliferative disorder that occurs primarily in adults and presents with crops of papules that become necrotic and spontaneously regress. It is classified according to the histopathologic findings; currently recognized subtypes include A, B, C, D, and E. LyP is uncommon in children. Herein we describe a child with an unusual clinical presentation of LyP type D and review the literature of reported cases in children. PMID- 26763887 TI - Age- and gender-specific associations between sleep duration and incident hypertension in a Chinese population: the Kailuan study. AB - The objective of this study was to explore the age- and sex-dependent association between sleep duration and incident hypertension in a Chinese population. The Kailuan prospective cohort study recruited 101 510 participants. Those participants were followed for an average of 3.98 years and the data obtained from 32 137 participants out of 101 510 were analyzed in this study. Sleep duration was categorized as five groups of?5, 6, 7, 8 and ?9 h. Cox proportional hazards models were used to analyze the association of sleep duration with incident hypertension. The 3.98 years' follow-up data showed that 12 732 out of 32 137 participants developed hypertension. Short duration of sleep (?5 h per night) was associated with an increased risk of hypertension in woman (hazard ratio (HR) 1.27; 95% confidence interval (CI) 1.02 to 1.58) and participants aged <60 years (HR 1.11; 95% CI 1.02-1.21), when compared with the group reported with 7 h of sleep per day. This study suggested that short sleep duration could cause an increased risk of hypertension in Chinese females and population aged <60 years. PMID- 26763889 TI - The use of genomic coancestry matrices in the optimisation of contributions to maintain genetic diversity at specific regions of the genome. AB - BACKGROUND: Optimal contribution methods have proved to be very efficient for controlling the rates at which coancestry and inbreeding increase and therefore, for maintaining genetic diversity. These methods have usually relied on pedigree information for estimating genetic relationships between animals. However, with the large amount of genomic information now available such as high-density single nucleotide polymorphism (SNP) chips that contain thousands of SNPs, it becomes possible to calculate more accurate estimates of relationships and to target specific regions in the genome where there is a particular interest in maximising genetic diversity. The objective of this study was to investigate the effectiveness of using genomic coancestry matrices for: (1) minimising the loss of genetic variability at specific genomic regions while restricting the overall loss in the rest of the genome; or (2) maximising the overall genetic diversity while restricting the loss of diversity at specific genomic regions. RESULTS: Our study shows that the use of genomic coancestry was very successful at minimising the loss of diversity and outperformed the use of pedigree-based coancestry (genetic diversity even increased in some scenarios). The results also show that genomic information allows a targeted optimisation to maintain diversity at specific genomic regions, whether they are linked or not. The level of variability maintained increased when the targeted regions were closely linked. However, such targeted management leads to an important loss of diversity in the rest of the genome and, thus, it is necessary to take further actions to constrain this loss. Optimal contribution methods also proved to be effective at restricting the loss of diversity in the rest of the genome, although the resulting rate of coancestry was higher than the constraint imposed. CONCLUSIONS: The use of genomic matrices when optimising contributions permits the control of genetic diversity and inbreeding at specific regions of the genome through the minimisation of partial genomic coancestry matrices. The formula used to predict coancestry in the next generation produces biased results and therefore it is necessary to refine the theory of genetic contributions when genomic matrices are used to optimise contributions. PMID- 26763890 TI - A new format for the journal and a farewell. PMID- 26763892 TI - Variable selection for binary classification using error rate p-values applied to metabolomics data. AB - BACKGROUND: Metabolomics datasets are often high-dimensional though only a limited number of variables are expected to be informative given a specific research question. The important task of selecting informative variables can therefore become complex. In this paper we look at discriminating between two groups. Two tasks need to be performed: (i) finding variables which differ between the two groups; and (ii) determining how the selected variables can be used to classify new subjects. We introduce an approach using minimum classification error rates as test statistics to find discriminatory and therefore informative variables. The thresholds resulting in the minimum error rates can be used to classify new subjects. This approach transforms error rates into p-values and is referred to as ERp. RESULTS: We show that non-parametric hypothesis testing, based on minimum classification error rates as test statistics, can find statistically significantly shifted variables. The discriminatory ability of variables becomes more apparent when error rates are evaluated based on their corresponding p-values, as relatively high error rates can still be statistically significant. ERp can handle unequal and small group sizes, as well as account for the cost of misclassification. ERp retains (if known) or reveals (if unknown) the shift direction, aiding in biological interpretation. The threshold resulting in the minimum error rate can immediately be used to classify new subjects. We use NMR generated metabolomics data to illustrate how ERp is able to discriminate subjects diagnosed with Mycobacterium tuberculosis infected meningitis from a control group. The list of discriminatory variables produced by ERp contains all biologically relevant variables with appropriate shift directions discussed in the original paper from which this data is taken. CONCLUSIONS: ERp performs variable selection and classification, is non parametric and aids biological interpretation while handling unequal group sizes and misclassification costs. All this is achieved by a single approach which is easy to perform and interpret. ERp has the potential to address many other characteristics of metabolomics data. Future research aims to extend ERp to account for a large proportion of observations below the detection limit, as well as expand on interactions between variables. PMID- 26763891 TI - Significance of myocardial tenascin-C expression in left ventricular remodelling and long-term outcome in patients with dilated cardiomyopathy. AB - AIM: Dilated cardiomyopathy (DCM) has a variety of causes, and no useful approach to predict left ventricular (LV) remodelling and long-term outcome has yet been established. Myocardial tenascin-C (TNC) is known to appear under pathological conditions, possibly to regulate cardiac remodelling. The aim of this study was to clarify the significance of myocardial TNC expression in LV remodelling and the long-term outcome in DCM. METHODS AND RESULTS: One hundred and twenty-three consecutive DCM patients who underwent endomyocardial biopsy for initial diagnosis were studied. Expression of TNC in biopsy sections was analysed immunohistochemically to quantify the ratio of the TNC-positive area to the whole myocardial tissue area (TNC area). Clinical parameters associated with TNC area were investigated. The patients were divided into two groups based on receiver operating characteristic analysis of TNC area to predict death: high TNC group with TNC area >=2.3% (22 patients) and low TNC group with TNC area <2.3% (101 patients). High TNC was associated with diabetes mellitus. Comparing echocardiographic findings between before and 9 months after endomyocardial biopsy, the low TNC group was associated with decreased LV end-diastolic diameter and increased LV ejection fraction, whereas the high TNC group was not. Survival analysis revealed a worse outcome in the high TNC group than in the low TNC group (P < 0.001). Multivariable Cox regression analysis revealed that TNC area was independently associated with poor outcome (HR = 1.347, P = 0.032). CONCLUSIONS: Increased myocardial TNC expression was associated with worse LV remodeling and long-term outcome in DCM. PMID- 26763894 TI - NOBLE - Flexible concept recognition for large-scale biomedical natural language processing. AB - BACKGROUND: Natural language processing (NLP) applications are increasingly important in biomedical data analysis, knowledge engineering, and decision support. Concept recognition is an important component task for NLP pipelines, and can be either general-purpose or domain-specific. We describe a novel, flexible, and general-purpose concept recognition component for NLP pipelines, and compare its speed and accuracy against five commonly used alternatives on both a biological and clinical corpus. NOBLE Coder implements a general algorithm for matching terms to concepts from an arbitrary vocabulary set. The system's matching options can be configured individually or in combination to yield specific system behavior for a variety of NLP tasks. The software is open source, freely available, and easily integrated into UIMA or GATE. We benchmarked speed and accuracy of the system against the CRAFT and ShARe corpora as reference standards and compared it to MMTx, MGrep, Concept Mapper, cTAKES Dictionary Lookup Annotator, and cTAKES Fast Dictionary Lookup Annotator. RESULTS: We describe key advantages of the NOBLE Coder system and associated tools, including its greedy algorithm, configurable matching strategies, and multiple terminology input formats. These features provide unique functionality when compared with existing alternatives, including state-of-the-art systems. On two benchmarking tasks, NOBLE's performance exceeded commonly used alternatives, performing almost as well as the most advanced systems. Error analysis revealed differences in error profiles among systems. CONCLUSION: NOBLE Coder is comparable to other widely used concept recognition systems in terms of accuracy and speed. Advantages of NOBLE Coder include its interactive terminology builder tool, ease of configuration, and adaptability to various domains and tasks. NOBLE provides a term-to-concept matching system suitable for general concept recognition in biomedical NLP pipelines. PMID- 26763895 TI - Statins and oxidative stress in chronic heart failure. AB - Statins are the most commonly prescribed drugs for the treatment of dyslipidemia. They are also recommended in primary and secondary prevention of cardiovascular disease. In addition to decreasing cholesterol synthesis, statins interfere with the synthesis of isoprenoid intermediates, which may explain many of their pleiotropic properties, including their antioxidant effects. Oxidative stress is defined as an imbalance between the synthesis of reactive oxygen species and their elimination by antioxidant defense systems, with a prevailing pro-oxidant status that results in macromolecular damage and disruption of cellular redox signaling. Reactive oxygen species interfere with various processes that affect cardiac structure and function, contributing to the contractile dysfunction, myocardial hypertrophy and fibrosis observed in the pathophysiology of heart failure. By regulating several molecular pathways that control nicotinamide adenine dinucleotide phosphate oxidase and endothelial nitric oxide synthase activity, statins help restore redox homeostasis. These drugs also contribute to the control of inflammation and appear to have a protective role in various diseases. The results of observational studies and clinical trials with statins in heart failure have not been consensual. This review aims to analyze the role of oxidative stress in heart failure and the molecular mechanisms underlying statins' antioxidant properties. It also examines current scientific evidence on the use of these drugs as a specific treatment for heart failure. PMID- 26763893 TI - Hypochloraemia is strongly and independently associated with mortality in patients with chronic heart failure. AB - AIMS: Hyponatraemia is strongly associated with adverse outcomes in heart failure. However, accumulating evidence suggests that chloride may play an important role in renal salt sensing and regulation of neurohormonal and sodium conserving pathways. Our objective was to determine the prognostic importance of hypochloraemia in patients with heart failure. METHODS AND RESULTS: Patients in the BEST trial with baseline serum chloride values were evaluated (n = 2699). Hypochloraemia was defined as a serum chloride <=96 mmol/L and hyponatraemia as serum sodium <=135 mmol/L. Hypochloraemia was present in 13.0% and hyponatraemia in 13.7% of the population. Chloride and sodium were only modestly correlated (r = 0.53), resulting in only 48.7% of hypochloraemic patients having concurrent hyponatraemia. Both hyponatraemia and hypochloraemia identified a population with greater disease severity; however, renal function tended to be worse and loop diuretic doses higher with hypochloraemia. In univariate analysis, lower serum sodium or serum chloride as continuous parameters were each strongly associated with mortality (P < 0.001). However, when both parameters were included in the same model, serum chloride remained strongly associated with mortality [hazard ratio (HR) 1.3 per standard deviation decrease, 95% confidence interval (CI) 1.18 1.42, P < 0.001], whereas sodium was not (HR 0.97 per standard deviation decrease, 95% CI 0.89-1.06, P = 0.52). CONCLUSION: Serum chloride is strongly and independently associated with worsened survival in patients with chronic heart failure and accounted for the majority of the risk otherwise attributable to hyponatraemia. Given the critical role of chloride in a number of regulatory pathways central to heart failure pathophysiology, additional research is warranted in this area. PMID- 26763896 TI - Is a Stem Version on the Crosstable Lateral Radiograph Accurate in Total Hip Arthroplasty? AB - BACKGROUND: In contrast to the acetabular cup version (CV), stem version (SV) measurement on the crosstable lateral radiograph has not been validated. We, therefore, investigated: (1) the difference of SV on the crosstable lateral radiograph from that measured using computed tomography data and (2) the reliability of SV measurement on the crosstable lateral radiograph. METHODS: We examined the correlations of the crosstable-CV and crosstable-SV with true-CV (operative cup anteversion) and true-SV (neck version relative to the posterior condylar line) obtained using computed tomography data from 103 patients. We also produced the digital reconstructed crosstable lateral radiograph with adjusted hip flexion and rotation and defined SV on this image as the true-crosstable SV. RESULTS: Significant positive correlations were noted between the crosstable-CV and true-CV, with a correlation coefficient of 0.79. In contrast, the correlation between the crosstable-SV and true-SV was very low (r = 0.30), with significantly higher deviation from the true-SV values when compared with the crosstable-CV (standard deviation, 11.6 degrees vs 6.5 degrees , P < .001). The true crosstable SV was correlated with true-SV (r = 0.81); however, the average difference was 23.5 degrees +/- 8.9 degrees . CONCLUSION: Crosstable-SV differed from true-SV in the measurement plane and did not correlate well with the true SV, suggesting the unreliability of its measurements. Therefore, the crosstable SV is not recommended for clinical use. PMID- 26763897 TI - Comparison of Antagonist Muscle Activity During Walking Between Total Knee Replacement and Control Subjects Using Unnormalized Electromyography. AB - BACKGROUND: Although satisfactory outcomes have been reported after total knee replacement (TKR), full recovery of muscle strength and physical function is rare. We developed a relative activation index (RAI) to compare leg muscle activity from unnormalized surface electromyography (sEMG) between TKR and control subjects. METHODS: Nineteen TKR and 19 control subjects underwent gait analysis and sEMG. RAIs were calculated by dividing the average sEMG for 2 consecutive subphases of stance defined by the direction of the external sagittal plane moment (flexion or extension). RESULTS: RAIs and external moments indicate TKR subjects have less initial stance antagonist rectus femoris activity (P = .004), greater middle stance antagonist biceps femoris activity (P < .001), and less late stance agonist biceps femoris activity (P < .001) than control subjects. Individuals with TKR demonstrate increased flexor muscle activation during weight bearing, potentially contributing to altered gait patterns found during the stance phase of gait. CONCLUSION: The RAI helps detail whether decreased external moments correspond to less agonist or more antagonist muscle activity to determine true muscle activity differences between subject groups. Identifying the mechanisms underlying altered muscle function both before and after TKR is critical for developing rehabilitation strategies to address functional deficits and disability found in this patient population. PMID- 26763899 TI - Thermally triggered phononic gaps in liquids at THz scale. AB - In this paper we present inelastic X-ray scattering experiments in a diamond anvil cell and molecular dynamic simulations to investigate the behavior of phononic excitations in liquid Ar. The spectra calculated using molecular dynamics were found to be in a good agreement with the experimental data. Furthermore, we observe that, upon temperature increases, a low-frequency transverse phononic gap emerges while high-frequency propagating modes become evanescent at the THz scale. The effect of strong localization of a longitudinal phononic mode in the supercritical phase is observed for the first time. The evidence for the high-frequency transverse phononic gap due to the transition from an oscillatory to a ballistic dynamic regimes of motion is presented and supported by molecular dynamics simulations. This transition takes place across the Frenkel line thermodynamic limit which demarcates compressed liquid and non compressed fluid domains on the phase diagram and is supported by calculations within the Green-Kubo phenomenological formalism. These results are crucial to advance the development of novel terahertz thermal devices, phononic lenses, mirrors, and other THz metamaterials. PMID- 26763898 TI - A comprehensive benchmarking study of protocols and sequencing platforms for 16S rRNA community profiling. AB - BACKGROUND: In the last 5 years, the rapid pace of innovations and improvements in sequencing technologies has completely changed the landscape of metagenomic and metagenetic experiments. Therefore, it is critical to benchmark the various methodologies for interrogating the composition of microbial communities, so that we can assess their strengths and limitations. The most common phylogenetic marker for microbial community diversity studies is the 16S ribosomal RNA gene and in the last 10 years the field has moved from sequencing a small number of amplicons and samples to more complex studies where thousands of samples and multiple different gene regions are interrogated. RESULTS: We assembled 2 synthetic communities with an even (EM) and uneven (UM) distribution of archaeal and bacterial strains and species, as metagenomic control material, to assess performance of different experimental strategies. The 2 synthetic communities were used in this study, to highlight the limitations and the advantages of the leading sequencing platforms: MiSeq (Illumina), The Pacific Biosciences RSII, 454 GS-FLX/+ (Roche), and IonTorrent (Life Technologies). We describe an extensive survey based on synthetic communities using 3 experimental designs (fusion primers, universal tailed tag, ligated adaptors) across the 9 hypervariable 16S rDNA regions. We demonstrate that library preparation methodology can affect data interpretation due to different error and chimera rates generated during the procedure. The observed community composition was always biased, to a degree that depended on the platform, sequenced region and primer choice. However, crucially, our analysis suggests that 16S rRNA sequencing is still quantitative, in that relative changes in abundance of taxa between samples can be recovered, despite these biases. CONCLUSION: We have assessed a range of experimental conditions across several next generation sequencing platforms using the most up-to-date configurations. We propose that the choice of sequencing platform and experimental design needs to be taken into consideration in the early stage of a project by running a small trial consisting of several hypervariable regions to quantify the discriminatory power of each region. We also suggest that the use of a synthetic community as a positive control would be beneficial to identify the potential biases and procedural drawbacks that may lead to data misinterpretation. The results of this study will serve as a guideline for making decisions on which experimental condition and sequencing platform to consider to achieve the best microbial profiling. PMID- 26763901 TI - Cumulative social risk and type 2 diabetes in US adults: The National Health and Nutrition Examination Survey (NHANES) 1999-2006. AB - BACKGROUND: The cumulative effects of adverse social factors on the diabetes risk remains to be clarified. DESIGN: Cross-sectional analysis of the US National Health and Nutrition Examination Survey (NHANES) 1999-2006. METHODS: We included 10,276 adults aged >=20 years. Diabetes mellitus was defined by physician diagnosis or fasting plasma glucose (>=126 mg/dl) or glycated hemoglobin (>=6.5%). Social risk factors (low family income, low education level, minority racial/ethnic group status, and single-living status) and health-related behaviors (physical activity and dietary intake) were self-reported. Social risk factors were combined in a cumulative social risk index (range 0 to >=3) and logistic regression used to assess the association of cumulative social risk and diabetes, taking into account complex survey design and sampling weights. RESULTS: Of 10,276 participants, 1515 (weighted proportion - 10%) had diabetes, 3295 (32.3%) and 1830 (9.0%) were exposed to >=1 adverse social risk factor and >=3 social risk factors, respectively. Diabetes was associated with increasing cumulative social risk in a graded manner (p for trend <0.001). Compared with a cumulative social risk score of 0, the age- and sex-adjusted diabetes odds for a cumulative social risk score of >=3 was 2.84 (95% confidence interval: 2.23 3.62), and 2.72 (95% confidence interval: 2.05-3.60) after further adjustment for family history of diabetes, body mass index, smoking, dietary intake and leisure time physical activity. Health behaviors and adiposity only partially influenced the cumulative social risk and diabetes relationship. CONCLUSIONS: Simultaneous exposure to several adverse social risk factors significantly influences the odds of diabetes. Better prevention and control of diabetes needs accounting for all aspects of social disadvantage. PMID- 26763902 TI - CREATION OF FEMALE COMPUTATIONAL PHANTOMS FOR CALIBRATION OF LUNG COUNTERS. AB - Plutonium isotopes are of high concern because they lead to high doses. In case of contamination, the activity burden inside the lungs should be assessed accurately. Many studies showed that the presence of breasts has a substantial influence on lung counting efficiencies. Currently, the calibration of most lung counting systems is done by means of physical phantoms representing only male chests. A set of female computational phantoms has been developed in order to provide gender-specific efficiency calibrations for the (241)Am gamma emission (59.54 keV). The phantoms were created starting from a library of female chest phantoms provided by Institut de radioprotection et de surete nucleaire (IRSN) (Farah, J. Amelioration des mesures anthroporadiametriques personnalisees assistees par calcul Monte Carlo: optimisation des temps de calculs et methodologie de mesure pour l'etablissement de la repartition d'activite. PhD Thesis, 2011). While the IRSN phantoms represent a supine measurement position, the SCK*CEN lung counter set-up requires the persons to be sitting in a chair. Using open-source software, the breast shapes of the original phantoms have been recreated to simulate the drooping of breasts in vertical sitting position. A Monte Carlo approach was chosen for calculating calibration coefficients for female lung counting. The results obtained with MCNPx 2.7 simulations showed a significant decrease in the detection efficiency. For bigger bust and breast sizes, the detection efficiency showed to be up to 10 times lower than the ones measured with the Livermore male torso phantom. PMID- 26763900 TI - Reconstruction of temporal activity of microRNAs from gene expression data in breast cancer cell line. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs that regulate genes at the post-transcriptional level in spatiotemporal manner. Several miRNAs are identified as prognostic and diagnostic markers in many human cancers. Estimation of the temporal activities of the miRNAs is an important step in the way to understand the complex interactions of these important regulatory elements with transcription factors (TFs) and target genes (TGs). However, current research on miRNA activities excludes network dynamics from the studies, disregarding the important element of time in the regulatory network analysis. RESULTS: In the current study, we combined experimentally verified miRNA-TG interactions with breast cancer microarray TG expression data to identify key miRNAs and compute their temporal activity using network component analysis (NCA). The computed activities showed that miRNAs were regulated in a time dependent manner. Our results allowed constructing a synergistic network of miRNAs using the computed miRNA activities and their shared regulation of TGs. We further extended this network by incorporating miRNA-TG, miRNA-TF, TF-miRNA and TF-TG regulations in the context of breast cancer. Our integrated network identified several miRNAs known to be involved in breast cancer regulation and revealed several novel miRNAs. Our further analysis detected substantial involvement of the miRNAs miR 324, miR-93, miR-615 and miR-1 in breast cancer, which was not known previously. Next, combining our integrated networks with functional annotation of differentially expressed genes resulted in new sub-networks. These sub-networks allowed us to identify the key miRNAs and their interactions with TFs and TGs of several biological processes involved in breast cancer. The identified markers are validated for their potential as prognostic markers for breast cancer through survival analysis. CONCLUSIONS: Our dynamical analysis of the miRNA interactions greatly helps to discover new network based markers, and is highly applicable (but not limited) to cancer research. PMID- 26763903 TI - THE RESULTS OF THE EURADOS INTERCOMPARISON IC2014 FOR WHOLE-BODY DOSEMETERS IN PHOTON FIELDS. AB - The European Dosimetry Group (EURADOS) first started performing international intercomparisons for whole-body dosemeters for individual monitoring services in 1998. Since 2008, these whole-body intercomparisons have been performed on a regular basis. In this latest intercomparison (IC2014), 96 monitoring services from 35 countries (mostly European) participated with 112 dosimetry systems. Unlike in the previous intercomparisons, the whole registration, communication and data exchange process was handled by a new on-line platform. All dosemeter irradiations were carried out in the Seibersdorf accredited dosimetry laboratory. The irradiation plan consisted of nine irradiation setups with five different photon radiation qualities (S-Cs, S-Co, RQR7, W-80 and W-150) and two different angles of radiation incidence (0 degrees and 60 degrees ). The paper describes and analyses the individual results for the personal dose equivalent quantities Hp(10) and if requested, Hp(0.07), for all participating systems and compares these results with the ISO 14146 'trumpet curve' performance criteria. The results show that 100 systems (89 % of all systems) do fulfil the general ISO 14146 performance criteria. This paper gives an overview on the performance of the participating individual monitoring services and the influence of the dosemeter type on the observed response values. PMID- 26763904 TI - A SURVEY ON THE ACCURACY OF WHOLE-BODY COUNTERS OPERATED IN FUKUSHIMA AFTER THE NUCLEAR DISASTER. AB - To check internal contamination, whole-body counters (WBCs) have been used continuously in Fukushima prefecture since the 2011 disaster. Many WBCs have been installed recently. The accuracy of these WBCs has been tested with bottle manikin absorption phantoms. No significant problems with the performance or accuracy of the WBCs have been found. PMID- 26763905 TI - EURADOS PROGRAMME OF INTERCOMPARISONS FOR INDIVIDUAL MONITORING SERVICES: SEVEN YEARS OF DEVELOPMENT AND FUTURE PLANS. AB - In 2008 the European Radiation Dosimetry Group (EURADOS) started a new programme of intercomparisons for individual monitoring services (IMS). The aim was to provide the possibility to IMS in Europe to participate in dosimetry intercomparions with regular time intervals with all types of dosemeter systems that are used routinely to monitor workers for exposure to external radiation. A self-evaluation of the programme shows that, apart from a few problems encountered, the programme can be judged as fit for its purpose. The results of a questionnaire among the participants support this conclusion. The conclusions encourage EURADOS to continue this programme of self-sustained intercomparisons for IMS. PMID- 26763906 TI - Asanoa endophytica sp. nov., an endophytic actinomycete isolated from the rhizome of Boesenbergia rotunda. AB - A novel Gram-stain-positive, non-motile, endophytic actinomycete, designated strain BR3-1T, which produced spore chains borne on the tips of short sporophores, was isolated from the rhizome of Boesenbergia rotunda collected from Udon Thani province, Thailand. This strain was investigated for its taxonomic position using a polyphasic approach. The strain contained 3 hydroxydiaminopimelic acid and meso-diaminopimelic acid in the cell-wall peptidoglycan. The whole-cell sugars comprised glucose, mannose, rhamnose, ribose and xylose. Phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol and phosphatidylinositol mannosides were found as the characteristic phospholipids. The predominant menaquinones were MK-10(H8) and MK-10(H6). The major cellular fatty acids were iso-C16 : 0, iso-C15 : 0 and anteiso-C15 : 0. The G+C content of the genomic DNA was 71.4 mol%. 16S rRNA gene sequence analysis revealed that strain BR3-1T belonged to the genus Asanoa and was most closely related to Asanoa ishikariensis (99.39 %), Asanoa iriomotensis (99.31 %), Asanoa siamensis (99.17 %), Asanoa ferruginea (98.84 %) and Asanoa hainanensis (98.71 %). The DNA-DNA relatedness value between strain BR3-1T and its phylogenetically closest relatives was in the range of 15.4 % +/- 1.2 to 45.8 % +/- 2.6. In addition, some physiological and biochemical properties indicated that strain BR3-1T could be readily distinguished from all type strains in the genus Asanoa. Thus, strain BR3-1T should be classified as a representative of a novel species, for which the name Asanoa endophytica sp. nov. is proposed. The type strain is BR3-1T ( = BCC 66355T = NBRC 110002T). PMID- 26763907 TI - Lysobacter terricola sp. nov., isolated from greenhouse soil. AB - Strain 5GH22-11T, which was isolated from greenhouse soil in the Yangpyeong region, Gyeonggi province, Republic of Korea, was characterized to be an aerobic, Gram-stain-negative, flagellated, rod-shaped bacterium. It could grow at temperatures from 10 to 33 degrees C (optimum of 28-30 degrees C), in the pH range of 6.0-10.0 (optimum of pH 7.0) and without NaCl. 16S rRNA gene sequence analysis showed that strain 5GH18-14T showed the highest sequence similarities with Lysobacter niabensis GH34-4T (98.6 %), Lysobacter yangpyeongensis GH19-3T (98.1 %), 'Lysobacter fragariae' THG-DN8.7 (97.9 %), Lysobacter terrae THG-A13T (97.3 %), 'Lysobacter rhizosphaerae' THG-DN8.3 (97.2 %), 'Lysobacter tyrosinelyticus' THG-DN8.2 (97.2 %) and Lysobacter oryzae YC6269T (97.2 %), revealing less than 95.5 % sequence similarities with all other species with validly published names. Phylogenetic trees also indicated that strain 5GH18-14T formed a compact subcluster with L. niabensis GH34-4T, L. yangpyeongensis GH19 3T, L. terrae THG-A13T and L. oryzae YC6269T within the genus Lysobacter. The predominant quinone of strain 5GH18-14T was Q-8. The polar lipids were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol and phosphatidylmonomethylethanolamine in large amounts, and moderate or small amounts of three unknown phospholipids and two unknown aminophospholipids. DNA DNA hybridization values with closely related species were below 70 %. The DNA G+C content was 65.9 mol%. Based on the phylogenetic, physiological and chemotaxonomic data, it has been demonstrated that strain 5GH18-14T represents a novel species of the genus Lysobacter, for which the name Lysobacter terricola sp. nov. is proposed. The type strain is 5GH18-14T ( = KACC 16954T = JCM 30862T). PMID- 26763908 TI - Evidence for a dual role of actin in regulating chromosome organization and dynamics in yeast. AB - Eukaryotic chromosomes undergo movements that are involved in the regulation of functional processes such as DNA repair. To better understand the origin of these movements, we used fluorescence microscopy, image analysis and chromosome conformation capture to quantify the actin contribution to chromosome movements and interactions in budding yeast. We show that both the cytoskeletal and nuclear actin drive local chromosome movements, independently of Csm4, a putative LINC protein. Inhibition of actin polymerization reduces subtelomere dynamics, resulting in more confined territories and enrichment in subtelomeric contacts. Artificial tethering of actin to nuclear pores increased both nuclear pore complex (NPC) and subtelomere motion. Chromosome loci that were positioned away from telomeres exhibited reduced motion in the presence of an actin polymerization inhibitor but were unaffected by the lack of Csm4. We further show that actin was required for locus mobility that was induced by targeting the chromatin-remodeling protein Ino80. Correlated with this, DNA repair by homologous recombination was less efficient. Overall, interphase chromosome dynamics are modulated by the additive effects of cytoskeletal actin through forces mediated by the nuclear envelope and nuclear actin, probably through the function of actin in chromatin-remodeling complexes. PMID- 26763909 TI - Coordination of autophagosome-lysosome fusion and transport by a Klp98A-Rab14 complex in Drosophila. AB - Degradation of cellular material by autophagy is essential for cell survival and homeostasis, and requires intracellular transport of autophagosomes to encounter acidic lysosomes through unknown mechanisms. Here, we identify the PX-domain containing kinesin Klp98A as a new regulator of autophagosome formation, transport and maturation in Drosophila. Depletion of Klp98A caused abnormal clustering of autophagosomes and lysosomes at the cell center and reduced the formation of starvation-induced autophagic vesicles. Reciprocally, overexpression of Klp98A redistributed autophagic vesicles towards the cell periphery. These effects were accompanied by reduced autophagosome-lysosome fusion and autophagic degradation. In contrast, depletion of the conventional kinesin heavy chain caused a similar mislocalization of autophagosomes without perturbing their fusion with lysosomes, indicating that vesicle fusion and localization are separable and independent events. Klp98A-mediated fusion required the endolysosomal GTPase Rab14, which interacted and colocalized with Klp98A, and required Klp98A for normal localization. Thus, Klp98A coordinates the movement and fusion of autophagic vesicles by regulating their positioning and interaction with the endolysosomal compartment. PMID- 26763910 TI - Pellicle formation in the malaria parasite. AB - The intraerythrocytic developmental cycle of Plasmodium falciparum is completed with the release of up to 32 invasive daughter cells, the merozoites, into the blood stream. Before release, the final step of merozoite development is the assembly of the cortical pellicle, a multi-layered membrane structure. This unique apicomplexan feature includes the inner membrane complex (IMC) and the parasite's plasma membrane. A dynamic ring structure, referred to as the basal complex, is part of the IMC and helps to divide organelles and abscises in the maturing daughter cells. Here, we analyze the dynamics of the basal complex of P. falciparum. We report on a novel transmembrane protein of the basal complex termed BTP1, which is specific to the genus Plasmodium. It colocalizes with the known basal complex marker protein MORN1 and shows distinct dynamics as well as localization when compared to other IMC proteins during schizogony. Using a parasite plasma membrane marker cell line, we correlate dynamics of the basal complex with the acquisition of the maternal membrane. We show that plasma membrane invagination and IMC propagation are interlinked during the final steps of cell division. PMID- 26763912 TI - Sphingosine kinase 2 as the promising target for stroke research. PMID- 26763913 TI - Early tracheostomy in ventilated stroke patients: Study protocol of the international multicentre randomized trial SETPOINT2 (Stroke-related Early Tracheostomy vs. Prolonged Orotracheal Intubation in Neurocritical care Trial 2). AB - BACKGROUND: Tracheostomy is a common procedure in long-term ventilated critical care patients and frequently necessary in those with severe stroke. The optimal timing for tracheostomy is still unknown, and it is controversial whether early tracheostomy impacts upon functional outcome. METHOD: The Stroke-related Early Tracheostomy vs. Prolonged Orotracheal Intubation in Neurocritical care Trial 2 (SETPOINT2) is a multicentre, prospective, randomized, open-blinded endpoint (PROBE-design) trial. Patients with acute ischemic stroke, intracerebral hemorrhage or subarachnoid hemorrhage who are so severely affected that two weeks of ventilation are presumed necessary based on a prediction score are eligible. It is intended to enroll 190 patients per group (n = 380). Patients are randomized to either percutaneous tracheostomy within the first five days after intubation or to ongoing orotracheal intubation with consecutive weaning and extubation and, if the latter failed, to percutaneous tracheostomy from day 10 after intubation. The primary endpoint is functional outcome defined by the modified Rankin Scale (mRS, 0-4 (favorable) vs. 5 + 6 (unfavorable)) after six months; secondary endpoints are mortality and cause of mortality during intensive care unit-stay and within six months from admission, intensive care unit-length of stay, duration of sedation, duration of ventilation and weaning, timing and reasons for withdrawal of life support measures, relevant intracranial pressure rises before and after tracheostomy. CONCLUSION: The necessity and optimal timing of tracheostomy in ventilated stroke patients need to be identified. SETPOINT2 should clarify whether benefits in functional outcome can be achieved by early tracheostomy in these patients. PMID- 26763914 TI - Penetrating arteries of the cerebral white matter: The importance of vascular territories of delivering arteries and completeness of circle of Willis. PMID- 26763915 TI - Off-label use of novel anticoagulants for treatment of cerebral venous thrombosis: A Canadian survey. PMID- 26763911 TI - Neuropeptides CRH, SP, HK-1, and Inflammatory Cytokines IL-6 and TNF Are Increased in Serum of Patients with Fibromyalgia Syndrome, Implicating Mast Cells. AB - Fibromyalgia syndrome (FMS) is a chronic, idiopathic condition of widespread musculoskeletal pain affecting more women than men. Even though clinical studies have provided evidence of altered central pain pathways, the lack of definitive pathogenesis or reliable objective markers has hampered development of effective treatments. Here we report that the neuropeptides corticotropin-releasing hormone (CRH), substance P (SP), and SP-structurally-related hemokinin-1 (HK-1) were significantly (P = 0.026, P < 0.0001, and P = 0.002, respectively) elevated (0.82 +/- 0.57 ng/ml, 0.39 +/- 0.18 ng/ml, and 7.98 +/- 3.12 ng/ml, respectively) in the serum of patients with FMS compared with healthy controls (0.49 +/- 0.26 ng/ml, 0.12 +/- 0.1 ng/ml, and 5.71 +/- 1.08 ng/ml, respectively). Moreover, SP and HK-1 levels were positively correlated (Pearson r = 0.45, P = 0.002) in FMS. The serum concentrations of the inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF) were also significantly (P = 0.029 and P = 0.006, respectively) higher (2.97 +/- 2.35 pg/ml and 0.92 +/- 0.31 pg/ml, respectively) in the FMS group compared with healthy subjects (1.79 +/- 0.62 pg/ml and 0.69 +/- 0.16 pg/ml, respectively). In contrast, serum IL-31 and IL-33 levels were significantly lower (P = 0.0001 and P = 0.044, respectively) in the FMS patients (849.5 +/- 1005 pg/ml and 923.2 +/- 1284 pg/ml, respectively) in comparison with healthy controls (1281 +/- 806.4 pg/ml and 3149 +/- 4073 pg/ml, respectively). FMS serum levels of neurotensin were not different from controls. We had previously shown that CRH and SP stimulate IL-6 and TNF release from mast cells (MCs). Our current results indicate that neuropeptides could stimulate MCs to secrete inflammatory cytokines that contribute importantly to the symptoms of FMS. Treatment directed at preventing the secretion or antagonizing these elevated neuroimmune markers, both centrally and peripherally, may prove to be useful in the management of FMS. PMID- 26763916 TI - Cost-effectiveness of an insertable cardiac monitor to detect atrial fibrillation in patients with cryptogenic stroke. AB - BACKGROUND AND AIMS: Documentation of atrial fibrillation is required to initiate oral anticoagulation therapy for recurrent stroke prevention. Atrial fibrillation often goes undetected with traditional electrocardiogram monitoring techniques. We evaluated whether atrial fibrillation detection using continuous long-term monitoring with an insertable cardiac monitor is cost-effective for preventing recurrent stroke in patients with cryptogenic stroke, in comparison to the standard of care. METHODS: A lifetime Markov model was developed to estimate the cost-effectiveness of insertable cardiac monitors from a UK National Health Service perspective using data from the randomized CRYSTAL-AF trial and other published literature. We also conducted scenario analyses (CHADS2 score) and probabilistic sensitivity analyses. All costs and benefits were discounted at 3.5%. RESULTS: Monitoring cryptogenic stroke patients with an insertable cardiac monitor was associated with fewer recurrent strokes and increased quality adjusted life years compared to the standard of care (7.37 vs 7.22). Stroke related costs were reduced in insertable cardiac monitor patients, but overall costs remained higher than the standard of care (L19,631 vs L17,045). The incremental cost-effectiveness ratio was L17,175 per quality-adjusted life years gained, compared to standard of care in the base-case scenario, which is below established quality-adjusted life years willingness-to-pay thresholds. When warfarin replaced non-vitamin-K oral anticoagulants as the main anticoagulation therapy, the incremental cost-effectiveness ratio was L13,296 per quality adjusted life years gained. CONCLUSION: Insertable cardiac monitors are a cost effective diagnostic tool for the prevention of recurrent stroke in patients with cryptogenic stroke. The cost-effectiveness results have relevance for the UK and across value-based healthcare systems that assess costs relative to outcomes. PMID- 26763917 TI - Protocol for the comparison of triflusal and clopidogrel in secondary prevention of stroke based on cytochrome P450 2C19 genotyping (MASETRO study): A multicenter, randomized, open-label, parallel-group trial. AB - RATIONALE AND AIM: The antiplatelet effect of clopidogrel is reportedly influenced by cytochrome P450 2C19 (CYP2C19) polymorphisms. However, there is no data concerning the relationship between stroke recurrence and CYP2C19 polymorphisms in patients treated with clopidogrel for secondary prevention of ischemic stroke. Triflusal may be an alternative therapy for clopidogrel in patients with poor genotype. The Comparison of Triflusal and Clopidogrel Effects in Secondary Prevention of Stroke Based on Cytochrome P450 2C19 Genotyping (MAESTRO) study will investigate the effect of antiplatelet agents based on CYP2C19 polymorphisms in secondary prevention of ischemic stroke. SAMPLE SIZE AND DESIGN: Assuming that 55% of patients belong to the poor genotype group, the required sample size is 1080 patients with at least 24 months of follow-up. This study is designed as a prospective, multicenter, randomized, parallel-group, open label, and blind genotype trial. Patients who experience their first non cardiogenic ischemic stroke within 30 days prior to screening are eligible. Patients received 300 mg triflusal twice a day or 75 mg clopidogrel once daily during the trial. The study is registered with ClinicalTrials.gov (NCT01174693). STUDY OUTCOME: The primary outcome is recurrent ischemic stroke or hemorrhagic stroke. Secondary outcomes consist of composite major vascular events including stroke, myocardial infarction, coronary revascularization, or vascular death. DISCUSSION: Personalized medicine may be essential for patients according to individual drug metabolism abilities. MAESTRO is the first prospective study designed to evaluate the effect of CYP2C19 polymorphism in secondary stroke prevention and will resolve several questions regarding preventive antiplatelet agents for recurrent stroke. PMID- 26763918 TI - Care-limiting decisions in acute stroke and association with survival: analyses of UK national quality register data. AB - BACKGROUND: Prognosis after intracerebral hemorrhage (ICH) is poor and care limiting decisions may worsen outcomes. AIMS: To determine whether in current UK stroke practice, key acute care decisions are associated with stroke subtype (ICH/ischemic) and whether these decisions are independently associated with survival. METHODS: We extracted data describing all stroke patients included in a UK quality register between 1 April 2013 and 31 March 2014. Key care decisions in our analyses were transfer to higher level care on admission and palliation in the first 72 h. We used multivariable regression models to test for associations between stroke subtype (ICH/ischemic), key care decisions, and survival. RESULTS: A total of 65,818 patients were included in the final analysis. After ICH (n = 7020/65,818, 10.7%), 10.5% were palliated on the day of admission and 19.3% by 72 h (vs. 0.7% and 3.3% for ischemic stroke). Although a greater proportion were admitted directly to higher level care after ICH (3.7% vs. 1.5% for ischemic stroke), ICH was not independently associated with the decision to admit to higher level care (adjusted odds ratio (OR): 1.12, 95% confidence interval (95%CI): 0.95-1.31, p = 0.183). However, ICH was strongly associated with the decision to commence palliative care on the day of admission (OR: 7.27, 95%CI: 6.31-8.37, p < 0.001). Palliative care was independently associated with risk of death by 30 days regardless of stroke subtype. CONCLUSIONS: When compared to ischemic stroke, patients with ICH are much more likely to commence palliative care during the first 72 h of their care, independent of level of consciousness, age, and premorbid health. PMID- 26763919 TI - What is the relationship among penumbra volume, collaterals, and time since onset in the first 6 h after acute ischemic stroke? AB - BACKGROUND: The steep, time-dependent loss of benefit from reperfusion in clinical trials is consistent with loss of penumbra over the early hours of ischemia, as observed in animal models. Human imaging studies, however, show persistent penumbra for up to 48 h. We investigated core and penumbra volumes and collateral status in relation to time after stroke onset within the first 6 h. METHODS: Using data from three multimodal computer tomography-based studies in acute ischemic stroke patients <6 h after onset, we measured core and penumbra volumes, collateral status, and target mismatch (defined as core volume < 50 ml, perfusion lesion volume > 15 ml, mismatch ratio > 1.8). Patients were grouped by onset to imaging time (<3, 3-4.5, 4.5-6 h). We explored correlates of penumbra proportion by multivariable linear regression. RESULTS: Analysis included 144 subjects. Across time epochs, neither proportions of penumbra (59%, 64%, 75% at <3, 3-4.5, >4. 5 h, respectively, p = 0.4) nor poor collaterals (15/56 (27%), 14/47 (30%), 4/15 (27%) at <3, 3-4.5, >4.5 h, p = 0.9) differed significantly. Penumbra proportion was not clearly related to time to imaging (R(2) = 0.003; p = 0.5) but a trend for divergent effects by collateral status was seen (slight increase in penumbra over time with good collaterals versus reduced with poor, interaction = 0.08). The proportion of patients with target mismatch did not vary by time (56%, 74%, and 67% at <3, 3-4.5, >4.5 h, p = 0.09). CONCLUSIONS: In a cross-sectional sample imaged within 6 h, neither the proportions of penumbral tissue nor "target mismatch" varied by time from onset. A trend for reducing penumbra proportion only among those with poor collaterals may have pathophysiological and therapeutic importance. PMID- 26763920 TI - Beauty parlor stroke revisited: An 11-year single-center consecutive series. AB - BACKGROUND: Hairdresser-related ischemic cerebrovascular events (HICE) are attributed to compression of vertebral arteries or cervical artery dissections. We determined their frequency, mechanisms, localization and outcome in a pre specified study. METHODS: We prospectively collected ischemic strokes and transient ischemic attacks occurring in relation to a hairdresser visit from 2002 to 2013, using consecutive data from an ischemic stroke registry (ASTRAL). HICE were compared to all other acute ischemic strokes in ASTRAL. RESULTS: We identified 10 HICE (9 strokes and 1 transient ischemic attack). Age and anterior posterior distribution were similar with a significantly higher rate of females (90% vs. 43%, p = 0.02) in the HICE group compared to ASTRAL. Patients with HICE had significantly lower incidence of hyperlipidemia (30% vs. 73%) and diabetes (0% vs. 19%). The mechanisms of HICE were diverse: carotid artery dissection (n = 2), cardiac (n = 2), lacunar (n = 2), other determined (n = 2) and unknown etiology (n = 2). Two HICE with atherosclerotic intracranial disease were possibly caused by acute hemodynamic changes related to systemic hypotension during hot air hair drying. Unadjusted favorable outcome at three months seemed to be better in HICE (90% vs. 57%), and 12-month mortality and recurrences were similar. CONCLUSIONS: HICE may occur frequently in females without a predilection for the posterior circulation. Although some HICE may occur by chance (pseudo HICE), hairdresser visits may have a causal role in some cases, including cervical artery dissection or hemodynamic compromise related to pre-existing arterial disease (true HICE). Available data are insufficient for specific preventive recommendations. PMID- 26763922 TI - Response to letter: And yet it moves - AVERT enlightens translations stroke research. PMID- 26763921 TI - And yet it moves--AVERT enlightens translational stroke research. PMID- 26763923 TI - Response to letter: Vrselja et al. PMID- 26763924 TI - Serum hepcidin levels and stroke in thalassemia patients. PMID- 26763925 TI - Cerebrolysin dose-dependently improves neurological outcome in rats after acute stroke: A prospective, randomized, blinded, and placebo-controlled study. AB - BACKGROUND: Cerebrolysin is a mixture of neuropeptides and free amino acids that is clinically used for the treatment of stroke. To further standardize treatment schemes, we assessed the dose response of Cerebrolysin on sensorimotor outcome in a rat model of ischemic stroke. METHODS: This study was a prospective, blinded, placebo-controlled, preclinical experiment. Male and female Wistar rats, subjected to embolic middle cerebral artery occlusion, were randomly treated with Cerebrolysin doses of 0.8, 2.5, 5.0, 7.5 ml/kg or placebo, 4 h after middle cerebral artery occlusion for a total of 10 consecutive days. RESULTS: The primary outcome was neurologic improvement at day 28, lesion volume, mortality, and animal weight were secondary and safety outcomes, respectively. There was a significant (p < 0.001) dose effect of Cerebrolysin on neurological outcome. Cerebrolysin at a dose of >= 2.5 ml/kg significantly (p < 0.001) improved neurological outcome (Mean Estimate (95% CL): 0.8 ml/kg: 6.2 (-6.0/18.4), 2.5 ml/kg: -28.9 (-41.6/-16.2), 5.0 ml/kg: -33.4 (-45.0/-21.7), 7.5 ml/kg: -36.3 ( 48.2/-24.4). Higher doses (>= 2.5 ml/kg) resulted in better recovery; however, differences between effective doses were not significant. Treatment with 5 ml/kg reduced lesion volume (p = 0.016). No treatment gender interactions were found and there were no differences in death or weight loss. CONCLUSION: Collectively, these data on Cerebrolysin efficacy demonstrate the feasibility of a preclinical study setup following a randomized, placebo-controlled, and blinded design with a clinical relevant treatment scheme. Cerebrolysin at doses of >= 2.5 ml/kg improved functional outcome and at a dose of 5 ml/kg reduced infarct volume. PMID- 26763926 TI - Quality of life of stroke survivors and their primary caregivers in Pakistan. PMID- 26763929 TI - The parasitic worm-derived immunomodulator, ES-62 and its drug-like small molecule analogues exhibit therapeutic potential in a model of chronic asthma. AB - Chronic asthma is associated with persistent lung inflammation and long-term remodelling of the airways that have proved refractory to conventional treatments such as steroids, despite their efficacy in controlling acute airway contraction and bronchial inflammation. As its recent dramatic increase in industrialised countries has not been mirrored in developing regions, it has been suggested that helminth infection may protect humans against developing asthma. Consistent with this, ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, can prevent pathology associated with chronic asthma (cellular infiltration of the lungs, particularly neutrophils and mast cells, mucus hyper production and airway thickening) in an experimental mouse model. Importantly, ES 62 can act even after airway remodelling has been established, arresting pathogenesis and ameliorating the inflammatory flares resulting from repeated exposure to allergen that are a debilitating feature of severe chronic asthma. Moreover, two chemical analogues of ES-62, 11a and 12b mimic its therapeutic actions in restoring levels of regulatory B cells and suppressing neutrophil and mast cell responses. These studies therefore provide a platform for developing ES 62-based drugs, with compounds 11a and 12b representing the first step in the development of a novel class of drugs to combat the hitherto intractable disorder of chronic asthma. PMID- 26763930 TI - DNA supercoiling, a critical signal regulating the basal expression of the lac operon in Escherichia coli. AB - Escherichia coli lac repressor (LacI) is a paradigmatic transcriptional factor that controls the expression of lacZYA in the lac operon. This tetrameric protein specifically binds to the O1, O2 and O3 operators of the lac operon and forms a DNA loop to repress transcription from the adjacent lac promoter. In this article, we demonstrate that upon binding to the O1 and O2 operators at their native positions LacI constrains three (-) supercoils within the 401-bp DNA loop of the lac promoter and forms a topological barrier. The stability of LacI mediated DNA topological barriers is directly proportional to its DNA binding affinity. However, we find that DNA supercoiling modulates the basal expression from the lac operon in E. coli. Our results are consistent with the hypothesis that LacI functions as a topological barrier to constrain free, unconstrained (-) supercoils within the 401-bp DNA loop of the lac promoter. These constrained (-) supercoils enhance LacI's DNA-binding affinity and thereby the repression of the promoter. Thus, LacI binding is superhelically modulated to control the expression of lacZYA in the lac operon under varying growth conditions. PMID- 26763931 TI - Modular structure of brain functional networks: breaking the resolution limit by Surprise. AB - The modular organization of brain networks has been widely investigated using graph theoretical approaches. Recently, it has been demonstrated that graph partitioning methods based on the maximization of global fitness functions, like Newman's Modularity, suffer from a resolution limit, as they fail to detect modules that are smaller than a scale determined by the size of the entire network. Here we explore the effects of this limitation on the study of brain connectivity networks. We demonstrate that the resolution limit prevents detection of important details of the brain modular structure, thus hampering the ability to appreciate differences between networks and to assess the topological roles of nodes. We show that Surprise, a recently proposed fitness function based on probability theory, does not suffer from these limitations. Surprise maximization in brain co-activation and functional connectivity resting state networks reveals the presence of a rich structure of heterogeneously distributed modules, and differences in networks' partitions that are undetectable by resolution-limited methods. Moreover, Surprise leads to a more accurate identification of the network's connector hubs, the elements that integrate the brain modules into a cohesive structure. PMID- 26763933 TI - METTL13 is downregulated in bladder carcinoma and suppresses cell proliferation, migration and invasion. AB - The incidence of bladder cancer has increased in the last few decades, thus novel markers for early diagnosis and more efficacious treatment are urgently needed. It found that METTTL13 protein is aberrant expression in variety of human cancers and METTL13 was involved in oncogenic pathways. However, the role of METTL13 has been unexplored in bladder cancer to date. Here, expression of METTL13 was lower in bladder cancer tissue samples and cancer cell lines than in normal bladder tissue and cell lines. METTL13 was downregulated in the late stages of the disease and was maintained at low level throughout the tumor progression process based on tumor node metastasis (TNM) staging. Further research suggested that METTL13 negatively regulates cell proliferation in bladder cancer and reinstates G1/S checkpoint via the coordinated downregulation of CDK6, CDK4 and CCND1, decreased phosphorylation of Rb and subsequent delayed cell cycle progression. Moreover, METTL13-dependent inhibition of bladder cancer cell migration and invasion is mediated by downregulation of FAK (Focal adhesion kinase) phosphorylation, AKT (v-akt murine thymoma viral oncogene) phosphorylation, beta catenin expression and MMP-9 expression. These integrated efforts have identified METTL13 as a tumor suppressor and might provide promising approaches for bladder cancer treatment and prevention. PMID- 26763932 TI - Radiation-induced alternative transcription and splicing events and their applicability to practical biodosimetry. AB - Accurate assessment of the individual exposure dose based on easily accessible samples (e.g. blood) immediately following a radiological accident is crucial. We aimed at developing a robust transcription-based signature for biodosimetry from human peripheral blood mononuclear cells irradiated with different doses of X rays (0.1 and 1.0 Gy) at a dose rate of 0.26 Gy/min. Genome-wide radiation induced changes in mRNA expression were evaluated at both gene and exon level. Using exon-specific qRT-PCR, we confirmed that several biomarker genes are alternatively spliced or transcribed after irradiation and that different exons of these genes exhibit significantly different levels of induction. Moreover, a significant number of radiation-responsive genes were found to be genomic neighbors. Using three different classification models we found that gene and exon signatures performed equally well on dose prediction, as long as more than 10 features are included. Together, our results highlight the necessity of evaluating gene expression at the level of single exons for radiation biodosimetry in particular and transcriptional biomarker research in general. This approach is especially advisable for practical gene expression-based biodosimetry, for which primer- or probe-based techniques would be the method of choice. PMID- 26763934 TI - Antinociceptive effects of vitexin in a mouse model of postoperative pain. AB - Vitexin, a C-glycosylated flavone present in several medicinal herbs, has showed various pharmacological activities including antinociception. The present study investigated the antinociceptive effects of vitexin in a mouse model of postoperative pain. This model was prepared by making a surgical incision on the right hindpaw and von Frey filament test was used to assess mechanical hyperalgesia. Isobolographical analysis method was used to examine the interaction between vitexin and acetaminophen. A reliable mechanical hyperalgesia was observed at 2 h post-surgery and lasted for 4 days. Acute vitexin administration (3-10 mg/kg, i.p.) dose-dependently relieved this hyperalgesia, which was also observed from 1 to 3 days post-surgery during repeated daily treatment. However, repeated vitexin administration prior to surgery had no preventive value. The 10 mg/kg vitexin-induced antinociception was blocked by the opioid receptor antagonist naltrexone or the GABAA receptor antagonist bicuculline. The doses of vitexin used did not significantly suppress the locomotor activity. In addition, the combination of vitexin and acetaminophen produced an infra-additive effect in postoperative pain. Together, though vitexin acetaminophen combination may not be useful for treating postoperative pain, vitexin exerts behaviorally-specific antinociception against postoperative pain mediated through opioid receptors and GABAA receptors, suggesting that vitexin may be useful for the control of postoperative pain. PMID- 26763936 TI - Protein aggregate turbidity: Simulation of turbidity profiles for mixed aggregation reactions. AB - Due to their colloidal nature, all protein aggregates scatter light in the visible wavelength region when formed in aqueous solution. This phenomenon makes solution turbidity, a quantity proportional to the relative loss in forward intensity of scattered light, a convenient method for monitoring protein aggregation in biochemical assays. Although turbidity is often taken to be a linear descriptor of the progress of aggregation reactions, this assumption is usually made without performing the necessary checks to provide it with a firm underlying basis. In this article, we outline utilitarian methods for simulating the turbidity generated by homogeneous and mixed-protein aggregation reactions containing fibrous, amorphous, and crystalline structures. The approach is based on a combination of Rayleigh-Gans-Debye theory and approximate forms of the Mie scattering equations. PMID- 26763935 TI - Calcium-chelating alizarin and other anthraquinones inhibit biofilm formation and the hemolytic activity of Staphylococcus aureus. AB - Staphylococcal biofilms are problematic and play a critical role in the persistence of chronic infections because of their abilities to tolerate antimicrobial agents. Thus, the inhibitions of biofilm formation and/or toxin production are viewed as alternative means of controlling Staphylococcus aureus infections. Here, the antibiofilm activities of 560 purified phytochemicals were examined. Alizarin at 10 MUg/ml was found to efficiently inhibit biofilm formation by three S. aureus strains and a Staphylococcus epidermidis strain. In addition, two other anthraquinones purpurin and quinalizarin were found to have antibiofilm activity. Binding of Ca(2+) by alizarin decreased S. aureus biofilm formation and a calcium-specific chelating agent suppressed the effect of calcium. These three anthraquinones also markedly inhibited the hemolytic activity of S. aureus, and in-line with their antibiofilm activities, increased cell aggregation. A chemical structure-activity relationship study revealed that two hydroxyl units at the C-1 and C-2 positions of anthraquinone play important roles in antibiofilm and anti-hemolytic activities. Transcriptional analyses showed that alizarin repressed the alpha-hemolysin hla gene, biofilm-related genes (psmalpha, rbf, and spa), and modulated the expressions of cid/lrg genes (the holin/antiholin system). These findings suggest anthraquinones, especially alizarin, are potentially useful for controlling biofilm formation and the virulence of S. aureus. PMID- 26763937 TI - Geometry Dependent Evolution of the Resonant Mode in ZnO Elongated Hexagonal Microcavity. AB - We have developed a novel but simple approach to obtain ZnO microcombs with parallelogram stems and elongated hexagonal branches. We found that the present elongated hexagonal microcavity exhibited quite different features for its optical resonant modes due to the broken hexagonal symmetry. The resonant mode evolution of such microcavity was investigated systemically by using a spatially resolved spectroscopic technique. Theoretical analyses based on the plane wave mode and FEM simulations agreed well with the experimental results. We believe that our research allows us to have a deeper understanding of the controllable growth of novel optical cavities and the shape-dependent optical resonant modes. PMID- 26763938 TI - OUTCOME OF DOGS WITH INTRANASAL LYMPHOMA TREATED WITH VARIOUS RADIATION AND CHEMOTHERAPY PROTOCOLS: 24 CASES. AB - Tumors of the nasal cavity comprise approximately 1% of all neoplasms in dogs. Canine intranasal lymphoma is rare and reports evaluating the outcome of treatment are lacking. The goal of this observational, descriptive, multi institutional study was to evaluate the overall median survival times (MSTs) in a group of dogs with intranasal lymphoma that were treated with irradiation and/or chemotherapy. Dogs meeting these inclusion criteria were retrospectively recruited from medical archives at multiple institutions. Eighteen cases of intermediate to high grade intranasal lymphoma and six cases of low-grade intranasal lymphoma were identified. The date of diagnosis, method of diagnosis, treatment received (radiation and/or chemotherapy protocols), and date of death were recorded. Kaplan-Meier survival analysis was performed on the intermediate to high grade group to calculate overall MST. Log-rank tests were performed to compare effects of treatment with radiation therapy +/- chemotherapy and chemotherapy alone. Kaplan-Meier survival analysis was performed separately on the low-grade group. The overall MST was 375 days for the intermediate to high grade group. Cases treated with radiation +/- chemotherapy had an MST of 455 days (n = 12) and those treated with chemotherapy alone (n = 6) had an MST of 157 days in the intermediate to high grade group. The MST was 823 days for the low-grade group. Results support the use of radiation therapy for treatment of canine intranasal lymphoma, however a randomized, controlled, clinical trial would be needed for more definitive recommendations. The role of adjunctive chemotherapy also may require further investigation. PMID- 26763939 TI - The Impact of Cognitive Stressors in the Emergency Department on Physician Implicit Racial Bias. AB - OBJECTIVES: The emergency department (ED) is characterized by stressors (e.g., fatigue, stress, time pressure, and complex decision-making) that can pose challenges to delivering high-quality, equitable care. Although it has been suggested that characteristics of the ED may exacerbate reliance on cognitive heuristics, no research has directly investigated whether stressors in the ED impact physician racial bias, a common heuristic. We seek to determine if physicians have different levels of implicit racial bias post-ED shift versus preshift and to examine associations between demographics and cognitive stressors with bias. METHODS: This repeated-measures study of resident physicians in a pediatric ED used electronic pre- and postshift assessments of implicit racial bias, demographics, and cognitive stressors. Implicit bias was measured using the Race Implicit Association Test (IAT). Linear regression models compared differences in IAT scores pre- to postshift and determined associations between participant demographics and cognitive stressors with postshift IAT and pre- to postshift difference scores. RESULTS: Participants (n = 91) displayed moderate prowhite/antiblack bias on preshift (mean +/- SD = 0.50 +/- 0.34, d = 1.48) and postshift (mean +/- SD = 0.55 +/- 0.39, d = 1.40) IAT scores. Overall, IAT scores did not differ preshift to postshift (mean increase = 0.05, 95% CI = -0.02 to 0.14, d = 0.13). Subanalyses revealed increased pre- to postshift bias among participants working when the ED was more overcrowded (mean increase = 0.09, 95% CI = 0.01 to 0.17, d = 0.24) and among those caring for >10 patients (mean increase = 0.17, 95% CI = 0.05 to 0.27, d = 0.47). Residents' demographics (including specialty), fatigue, busyness, stressfulness, and number of shifts were not associated with postshift IAT or difference scores. In multivariable models, ED overcrowding was associated with greater postshift bias (coefficient = 0.11 per 1 unit of NEDOCS score, SE = 0.05, 95% CI = 0.00 to 0.21). CONCLUSIONS: While resident implicit bias remained stable overall preshift to postshift, cognitive stressors (overcrowding and patient load) were associated with increased implicit bias. Physicians in the ED should be aware of how cognitive stressors may exacerbate implicit racial bias. PMID- 26763941 TI - Effects of myosin light chain phosphorylation on length-dependent myosin kinetics in skinned rat myocardium. AB - Myosin force production is Ca(2+)-regulated by thin-filament proteins and sarcomere length, which together determine the number of cross-bridge interactions throughout a heartbeat. Ventricular myosin regulatory light chain-2 (RLC) binds to the neck of myosin and modulates contraction via its phosphorylation state. Previous studies reported regional variations in RLC phosphorylation across the left ventricle wall, suggesting that RLC phosphorylation could alter myosin behavior throughout the heart. We found that RLC phosphorylation varied across the left ventricle wall and that RLC phosphorylation was greater in the right vs. left ventricle. We also assessed functional consequences of RLC phosphorylation on Ca(2+)-regulated contractility as sarcomere length varied in skinned rat papillary muscle strips. Increases in RLC phosphorylation and sarcomere length both led to increased Ca(2+)-sensitivity of the force-pCa relationship, and both slowed cross-bridge detachment rate. RLC phosphorylation slowed cross-bridge rates of MgADP release (~30%) and MgATP binding (~50%) at 1.9 MUm sarcomere length, whereas RLC phosphorylation only slowed cross-bridge MgATP binding rate (~55%) at 2.2 MUm sarcomere length. These findings suggest that RLC phosphorylation influences cross-bridge kinetics differently as sarcomere length varies and support the idea that RLC phosphorylation could vary throughout the heart to meet different contractile demands between the left and right ventricles. PMID- 26763942 TI - DNA aptamer release from the DNA-SWNT hybrid by protein recognition. AB - Here we show the formation of the complex between a DNA aptamer and a single walled carbon nanotube (SWNT) and its reaction with its target protein. The aptamer, which is specifically bound with thrombin, the target protein in this study, easily wraps and disperses the SWNT by noncovalent pi-pi stacking. PMID- 26763940 TI - Experimental Model for Successful Liver Cell Therapy by Lenti TTR-YapERT2 Transduced Hepatocytes with Tamoxifen Control of Yap Subcellular Location. AB - Liver repopulation by transplanted hepatocytes has not been achieved previously in a normal liver microenvironment. Here we report that adult rat hepatocytes transduced ex vivo with a lentivirus expressing a human YapERT2 fusion protein (hYapERT2) under control of the hepatocyte-specific transthyretin (TTR) promoter repopulate normal rat liver in a tamoxifen-dependent manner. Transplanted hepatocytes expand very slowly but progressively to produce 10% repopulation at 6 months, showing clusters of mature hepatocytes that are fully integrated into hepatic parenchyma, with no evidence for dedifferentiation, dysplasia or malignant transformation. Thus, we have developed the first vector designed to regulate the growth control properties of Yap that renders it capable of producing effective cell therapy. The level of liver repopulation achieved has significant translational implications, as it is 2-3x the level required to cure many monogenic disorders of liver function that have no underlying hepatic pathology and is potentially applicable to diseases of other tissues and organs. PMID- 26763943 TI - The Importance of Toll-like Receptors in NF-kappaB Signaling Pathway Activation by Helicobacter pylori Infection and the Regulators of this Response. AB - Helicobacter pylori (H. pylori) is a common pathogenic bacterium in the stomach that infects almost half of the population worldwide and is closely related to gastric diseases and some extragastric diseases, including iron-deficiency anemia and idiopathic thrombocytopenic purpura. Both the Maastricht IV/Florence consensus report and the Kyoto global consensus report have proposed the eradication of H. pylori to prevent gastric cancer as H.pylori has been shown to be a major cause of gastric carcinogenesis. The interactions between H. pylori and host receptors induce the release of the proinflammatory cytokines by activating proinflammatory signaling pathways such as nuclear factor kappa B (NF kappaB), which plays a central role in inflammation, immune response, and carcinogenesis. Among these receptors, Toll-like receptors (TLRs) are classical pattern recognition receptors in the recognition of H. pylori and the mediation of the host inflammatory and immune responses to H. pylori. TLR polymorphisms also contribute to the clinical consequences of H. pylori infection. In this review, we focus on the functions of TLRs in the NF-kappaB signaling pathway activated by H. pylori, the regulators modulating this response, and the functions of TLR polymorphisms in H.pylori-related diseases. PMID- 26763944 TI - PATHOLOGIC BASIS FOR RIM ENHANCEMENT OBSERVED IN COMPUTED TOMOGRAPHIC IMAGES OF FELINE NASOPHARYNGEAL POLYPS. AB - In postcontrast computed tomographic (CT) images, feline nasopharyngeal polyps typically demonstrate enhancement of the peripheral rim. Computed tomographic images and histologic specimens of a case series of 22 cats with surgically removed nasopharyngeal polyps were reviewed retrospectively in an attempt to elucidate the origin of rim enhancement. Polyps were present in the tympanic cavity in 15 (68%) cats (three with extension into the nasopharynx), only in the nasopharynx in four (18%) cats, and only in the external ear canal in the remaining three (14%) cats. All polyps had variable degrees of epithelial injury. Hemorrhage and inflammatory infiltration were significantly more marked in the superficial stroma whereas edema was significantly more marked in the core stroma. In noncontrast CT images (n = 22), the tympanic bulla was thickened in all 15 cats with a polyp in the tympanic cavity and enlarged in eight (53%) of these cats. In postcontrast CT images (n = 15), an outer zone of relatively increased attenuation compatible with a rim was observed in 11 (73%) polyps. The magnitude and extent of rim enhancement in CT images was positively correlated with the histologic grade of inflammation in the superficial stroma and negatively correlated with the grade of edema in the superficial stroma. It appears that inflammation is the major determinant of contrast medium accumulation in feline nasopharyngeal polyps, and the tendency for inflammation to affect predominantly the superficial layers explains the frequent observation of a rim in postcontrast CT images. PMID- 26763946 TI - Lower Amplitude of the Hoffmann Reflex in Women With Patellofemoral Pain: Thinking Beyond Proximal, Local, and Distal Factors. AB - OBJECTIVES: To investigate whether vastus medialis (VM) Hoffmann reflexes (H reflexes) differ on the basis of the presence or absence of patellofemoral pain (PFP) and to assess the capability of VM H-reflex measurements in accurately discriminating between women with and without PFP. DESIGN: Cross-sectional study. SETTING: Laboratory of biomechanics and motor control. PARTICIPANTS: Women (N=30) aged 18 to 35 years were recruited, consisting of 2 groups: women with PFP (n=15) and asymptomatic controls (n=15). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Maximum evoked responses were obtained by electrical stimulation applied to the femoral nerve, and peak-to-peak amplitudes of maximal Hoffmann reflex (Hmax) and maximal motor wave (Mmax) ratios were calculated. Independent samples t tests were performed to identify differences between groups, and a receiver operating characteristic curve was constructed to assess the discriminatory capability of VM H-reflex measurements. RESULTS: VM Hmax/Mmax ratios were significantly lower in participants with PFP than in pain-free participants (P=.007). In addition, the VM Hmax/Mmax ratios presented large and balanced discriminatory capability values (sensitivity, 73%; specificity, 67%). CONCLUSIONS: This study is the first to show that VM H-reflexes are lower in women with PFP than in asymptomatic controls. Therefore, increasing the excitation of the spinal cord in PFP participants may be essential to maintaining the gains acquired during the rehabilitation programs. PMID- 26763945 TI - Focal Adhesion Kinase Regulates Fibroblast Migration via Integrin beta-1 and Plays a Central Role in Fibrosis. AB - Lung fibrosis is a major medical problem for the aging population worldwide. Fibroblast migration plays an important role in fibrosis. Focal Adhesion Kinase (FAK) senses the extracellular stimuli and initiates signaling cascades that promote cell migration. This study first examined the dose and time responses of FAK activation in human lung fibroblasts treated with platelet derived growth factor BB (PDGF-BB). The data indicate that FAK is directly recruited by integrin beta1 and the subsequent FAK activation is required for fibroblast migration on fibronectin. In addition, the study has identified that alpha5beta1 and alpha4beta1 are the major integrins for FAK-mediated fibroblast migration on fibronect. In contrast, integrins alphavbeta3, alphavbeta6, and alphavbeta8 play a minor but distinct role in fibroblast migration on fibronectin. FAK inhibitor significantly reduces PDGF-BB stimulated fibroblast migration. Importantly, FAK inhibitor protects bleomycin-induced lung fibrosis in mice. FAK inhibitor blocks FAK activation and significantly reduces signaling cascade of fibroblast migration in bleomycin-challenged mice. Furthermore, FAK inhibitor decreases lung fibrotic score, collagen accumulation, fibronectin production, and myofibroblast differentiation in in bleomycin-challenged mice. These data demonstrate that FAK mediates fibroblast migration mainly via integrin beta1. Furthermore, the findings suggest that targeting FAK signaling is an effective therapeutic strategy against fibrosis. PMID- 26763948 TI - Wearable Vibrotactile Biofeedback Device Allowing Identification of Different Floor Conditions for Lower-Limb Amputees. AB - OBJECTIVE: To evaluate a newly developed biofeedback device enabling lower-limb amputees to identify various floor conditions. DESIGN: Self-control with repeated measures (with and without the biofeedback device) within the amputee group, and group control comparing between amputee and nonamputee groups. SETTING: University locomotion laboratory. PARTICIPANTS: Five lower-limb amputees and 8 nonamputees (N=13). INTERVENTIONS: A wearable biofeedback device, which identified different floor conditions by analyzing the force patterns under the prosthetic feet and provided vibration cues in response to different floor conditions, was provided to the amputees. MAIN OUTCOME MEASURES: The subjects stepped on a foam platform concealing a small object or no object at 1 of the 4 locations of the foot sole. Subjects were asked whether there was a small object under their feet and the location of the object if it existed. The test was repeated with 4 different object types and 4 object locations. The success rate of floor identification was evaluated. RESULTS: Without the biofeedback device, nonamputee subjects (76.56%) identified floor conditions better than amputees (22.5%) significantly (P<.001). On using the biofeedback device, the amputees significantly improved (P<.01) their success rate showing no significant difference (P=.746) compared with the nonamputees. No significant differences were found among object types (P=.689). CONCLUSIONS: Amputees performed significantly worse than nonamputees in recognizing the different floor conditions used in this experiment. With the biofeedback device, amputees significantly improved their abilities in identifying different floor conditions. Future attempts could configure the device to allow it to provide warning signals in response to fall-inducing conditions. PMID- 26763947 TI - Effects of Leg-Press Training With Moderate Vibration on Muscle Strength, Pain, and Function After Total Knee Arthroplasty: A Randomized Controlled Trial. AB - OBJECTIVES: To examine the effects of a time-saving leg-press training program with moderate vibration on strength parameters, pain, and functional outcomes of patients after total knee arthroplasty (TKA) in comparison with functional physiotherapy. DESIGN: Randomized controlled trial. SETTING: Outpatient rehabilitation department at a university teaching hospital. PARTICIPANTS: Patients (N=55) with TKA were randomly allocated into 2 rehabilitation groups. INTERVENTIONS: Six weeks after TKA, participants either underwent isokinetic leg press training combined with moderate vibration (n=26) of 15 minutes per session or functional physiotherapy (n=29) of 30 minutes per session. Both groups received therapy twice a week for a period of 6 weeks. Participants were evaluated at baseline (6wk after TKA) and after the 6-week rehabilitation program. MAIN OUTCOME MEASURES: The main outcome measure was maximal voluntary contraction (MVC) of the involved leg. Secondary outcome measures were pain assessed with a visual analog scale (VAS), range of motion, stair test, timed Up and Go test, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). RESULTS: Both groups showed statistically significant improvements in MVC of knee extensors measured on the knee dynamometer (leg-press group: from 0.8+/-.06 to 1+/-.09Nm/kg body weight [BW], physiotherapy group: from 0.7+/-.06 to 0.9+/-.06Nm/kg BW; P<.05) and in closed kinetic chain on the leg press (leg press group: from 8.9+/-.77 to 10.3+/-1.06N/kg BW, physiotherapy group: from 6.7+/-.54 to 9.1+/-.70N/kg BW; P<.05) and in pain at rest (leg-press group: from 2+/-.36 to 1.3+/-.36 on the VAS, physiotherapy group: from 1.2+/-.28 to 1.1+/ .31; P<.05), WOMAC scores, and functional measurements after 6 weeks of training. There was no significant difference between the 2 groups concerning strength, pain, and functional outcomes after training (P>.05). CONCLUSIONS: Isokinetic leg press training with moderate vibration and functional physiotherapy are both effective in regaining muscle strength and function after TKA; however, isokinetic leg-press training is considerably less time consuming. PMID- 26763949 TI - Exercise Induces Peripheral Muscle But Not Cardiac Adaptations After Stroke: A Randomized Controlled Pilot Trial. AB - OBJECTIVE: To explore the physiological factors affecting exercise-induced changes in peak oxygen consumption and function poststroke. DESIGN: Single center, single-blind, randomized controlled pilot trial. SETTING: Community stroke services. PARTICIPANTS: Adults (N=40; age>50y; independent with/without stick) with stroke (diagnosed >6 mo previously) were recruited from 117 eligible participants. Twenty participants were randomized to the intervention group and 20 to the control group. No dropouts or adverse events were reported. INTERVENTIONS: Intervention group: 19-week (3 times/wk) progressive mixed (aerobic/strength/balance/flexibility) community group exercise program. Control group: Matched duration home stretching program. MAIN OUTCOME MEASURES: (1) Pre- and postintervention: maximal cardiopulmonary exercise testing with noninvasive (bioreactance) cardiac output measurements; and (2) functional outcome measures: 6-minute walk test; timed Up and Go test, and Berg Balance Scale. RESULTS: Exercise improved peak oxygen consumption (18+/-5 to 21+/-5 mL/(kg?min); P<.01) and peak arterial-venous oxygen difference (9.2+/-2.7 to 11.4+/-2.9 mL of O2/100 mL of blood; P<.01), but did not alter cardiac output (17.2+/-4 to 17.7+/-4.2 L/min; P=.44) or cardiac power output (4.8+/-1.3 to 5.0+/-1.35 W; P=.45). A significant relation existed between change in peak oxygen consumption and change in peak arterial-venous oxygen difference (r=.507; P<.05), but not with cardiac output. Change in peak oxygen consumption did not strongly correlate with change in function. CONCLUSIONS: Exercise induced peripheral muscle, but not cardiac output, adaptations after stroke. Implications for stroke clinical care should be explored further in a broader cohort. PMID- 26763950 TI - Shoulder Strength Changes One Year After Axillary Lymph Node Dissection or Sentinel Lymph Node Biopsy in Patients With Breast Cancer. AB - OBJECTIVES: To assess the changes in shoulder strength of patients with breast cancer during the first year after surgery; and to compare the effect of sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) on shoulder strength. DESIGN: Prospective longitudinal observational study from presurgery to 1 year after. SETTING: Tertiary hospital. PARTICIPANTS: Of 129 consecutive patients examined for eligibility, a sample of women (N=112) with breast cancer were included (44 underwent ALND, and 68 underwent SLNB). INTERVENTIONS: Not applicable. MAIN OUTCOMES MEASURES: Difference between the affected and unaffected arm in strength of shoulder external rotators, internal rotators, abductors, and serratus anterior, measured by dynamometry. Evaluations were performed prior to surgery and at 1, 6, and 12 months after surgery. RESULTS: After breast cancer ALND surgery, strength decreased significantly at the first month for internal rotators, without having recovered presurgery values after 1 year of follow-up, with a mean difference of 2.26kg (P=.011). There was no significant loss of strength for patients treated with SLNB. The loss of shoulder range of motion was only significant the first month for the ALND group. The factors identified as associated with strength loss in the general estimating equation models were the ALND surgery and having received physical/occupational therapy during follow-up. CONCLUSIONS: One year after breast cancer surgery, patients treated with ALND had not recovered their previous shoulder internal rotators strength, whereas those who underwent SLNB presented no significant loss of strength. This provides important information for designing rehabilitation programs targeted specifically at the affected muscle group after nodal surgical approach. PMID- 26763951 TI - ASSOCIATIONS BETWEEN DUAL-PHASE COMPUTED TOMOGRAPHY FEATURES AND HISTOPATHOLOGIC DIAGNOSES IN 52 DOGS WITH HEPATIC OR SPLENIC MASSES. AB - Ability to noninvasively differentiate malignant from nonmalignant abdominal masses would aid clinical decision making. The aim of this retrospective, cross sectional study was to identify features in dual-phase computed tomographic (CT) studies that could be used to distinguish malignant from nonmalignant hepatic and splenic masses in dogs. Medical records were searched for dogs that had an abdominal dual-phase CT examination, a hepatic or splenic mass, and subsequent histopathologic diagnosis. Computed tomographic images for all included dogs were acquired prior to and <30 s (early phase) and >60 s (delayed phase) after intravenous contrast administration. Fifty-two dogs with 55 masses were studied: 24 hepatic, including 14 (58%) malignant and 10 (42%) non-malignant; 31 splenic, including 18 (58%) malignant and 13 (42%) nonmalignant. There was substantial overlap in the pre- and postcontrast CT features of malignant and nonmalignant hepatic and splenic masses. Regardless of histologic diagnosis, hepatic masses most frequently showed marked, generalized enhancement in early phase images that persisted in the delayed phase. Splenic hemangiosarcoma and nodular hyperplastic lesions most frequently showed marked, generalized enhancement in early phase images that persisted in delayed images whereas most splenic hematomas had slight enhancement in early phase images. All splenic hematomas and 77% of the hemangiosarcomas had contrast accumulation compatible with active hemorrhage. There were no other significant differences in quantitative or categorical CT data between malignant and nonmalignant hepatic or splenic masses. Dual-phase CT of dogs with hepatic or splenic masses provides limited specific diagnostic information. PMID- 26763953 TI - Massive preparation of pitch-based organic microporous polymers for gas storage. AB - A general challenge for preparing organic microporous polymers (MOPs) is to use cheap and sustainable building blocks while retaining the advanced functions. We demonstrate a strategy to massively prepare pitch-based MOPs, which are thermally and chemically stable. A maximum BET surface area of 758 m(2) g(-1) and high gas storage capacity were achieved. PMID- 26763952 TI - Geographic origin and evolutionary history of China's two predominant HIV-1 circulating recombinant forms, CRF07_BC and CRF08_BC. AB - To determine the origin and evolutionary history of two predominant and closely related circulating recombinant forms (CRF07_BC and CRF08_BC), recombinant structures and phylogenies of 7 unique recombinant forms comprised of subtypes of B' (Thai B linage) and C (designated URFs_BC) from archival specimens of injection drug users (IDUs) collected in 1996 to 1998 from western Yunnan and 4 circulating recombinant forms with B'/C recombinants recently identified (designated nCRFs_BC) in China were compared with those of CRF07_BC and CRF08_BC. The results showed that 5 of 7 URFs_BC and all the nCRFs_BC shared recombination breakpoints with CRF07_BC and/or CRF08_BC. Yunnan URFs_BC consistently occupied the basal branch positions compared with CRF07_BC, CRF08_BC, and nCRFs_BC in phylogenetic trees. The estimated most recent common ancestors (tMRCA) for Yunnan URFs_BC were from ~1987, approximately half a decade earlier than those for CRF07_BC (~1994) and CRF08_BC (~1992). Discrete phylogeographic and spatial diffusion analysis revealed that both CRF07_BC and CRF08 BC came from western Yunnan in the early 1990s. Our results provide compelling evidence for western Yunnan as the geographic origin of CRF07_BC and CRF08_BC, which emerged from a swarm of URFs_BC by a series of recombination events in western Yunnan in the early 1990s. PMID- 26763955 TI - Pretreatment of Bronchoalveolar Lavage Fluid Samples with SLsolution Leads to False-Negative Aspergillus Galactomannan Levels. PMID- 26763954 TI - The effect of transcranial direct current stimulation on contrast sensitivity and visual evoked potential amplitude in adults with amblyopia. AB - Amblyopia is a neurodevelopmental disorder of vision that occurs when the visual cortex receives decorrelated inputs from the two eyes during an early critical period of development. Amblyopic eyes are subject to suppression from the fellow eye, generate weaker visual evoked potentials (VEPs) than fellow eyes and have multiple visual deficits including impairments in visual acuity and contrast sensitivity. Primate models and human psychophysics indicate that stronger suppression is associated with greater deficits in amblyopic eye contrast sensitivity and visual acuity. We tested whether transcranial direct current stimulation (tDCS) of the visual cortex would modulate VEP amplitude and contrast sensitivity in adults with amblyopia. tDCS can transiently alter cortical excitability and may influence suppressive neural interactions. Twenty-one patients with amblyopia and twenty-seven controls completed separate sessions of anodal (a-), cathodal (c-) and sham (s-) visual cortex tDCS. A-tDCS transiently and significantly increased VEP amplitudes for amblyopic, fellow and control eyes and contrast sensitivity for amblyopic and control eyes. C-tDCS decreased VEP amplitude and contrast sensitivity and s-tDCS had no effect. These results suggest that tDCS can modulate visual cortex responses to information from adult amblyopic eyes and provide a foundation for future clinical studies of tDCS in adults with amblyopia. PMID- 26763956 TI - Automated Broad-Range Molecular Detection of Bacteria in Clinical Samples. AB - Molecular detection methods, such as quantitative PCR (qPCR), have found their way into clinical microbiology laboratories for the detection of an array of pathogens. Most routinely used methods, however, are directed at specific species. Thus, anything that is not explicitly searched for will be missed. This greatly limits the flexibility and universal application of these techniques. We investigated the application of a rapid universal bacterial molecular identification method, IS-pro, to routine patient samples received in a clinical microbiology laboratory. IS-pro is a eubacterial technique based on the detection and categorization of 16S-23S rRNA gene interspace regions with lengths that are specific for each microbial species. As this is an open technique, clinicians do not need to decide in advance what to look for. We compared routine culture to IS pro using 66 samples sent in for routine bacterial diagnostic testing. The samples were obtained from patients with infections in normally sterile sites (without a resident microbiota). The results were identical in 20 (30%) samples, IS-pro detected more bacterial species than culture in 31 (47%) samples, and five of the 10 culture-negative samples were positive with IS-pro. The case histories of the five patients from whom these culture-negative/IS-pro-positive samples were obtained suggest that the IS-pro findings are highly clinically relevant. Our findings indicate that an open molecular approach, such as IS-pro, may have a high added value for clinical practice. PMID- 26763958 TI - Restricted Identification of Clinical Pathogens Categorized as Biothreats by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry. PMID- 26763959 TI - Effects of Treated versus Untreated Polystyrene on Caspofungin In Vitro Activity against Candida Species. AB - Significant interlaboratory variability is observed in testing the caspofungin susceptibility of Candida species by both the CLSI and EUCAST broth microdilution methodologies. We evaluated the influence of treated versus untreated polystyrene microtiter trays on caspofungin MICs using 209 isolates of four Candida species, including 16 C. albicans and 11 C. glabrata isolates with defined FKS mutations. Caspofungin MICs were also determined using the commercially available YeastOne and Etest assays and 102 isolates. All C. glabrata isolates had caspofungin MICs of >=0.5 MUg/ml, the clinical breakpoint for caspofungin resistance in this species, measured using trays made of treated polystyrene, regardless of the FKS status. In contrast, susceptible isolates could readily be distinguished from resistant/non-wild-type isolates when caspofungin MICs were measured using untreated polystyrene trays and both the YeastOne and Etest assays. Similar results were also observed for C. krusei isolates, as all isolates had caspofungin MICs above the threshold for resistance measured using treated polystyrene trays. In contrast, C. albicans isolates could be correctly identified as susceptible or resistant when caspofungin MICs were measured with treated or untreated trays and with the YeastOne and Etest assays. MICs falsely elevated above the resistance breakpoint were also not observed for C. tropicalis isolates. These results demonstrated that the use of treated polystyrene may be one factor that leads to falsely elevated caspofungin in vitro susceptibility results and that this may also be a greater issue for some Candida species than for others. PMID- 26763957 TI - Gyrase Mutations Are Associated with Variable Levels of Fluoroquinolone Resistance in Mycobacterium tuberculosis. AB - Molecular diagnostics that rapidly and accurately predict resistance to fluoroquinolone drugs and especially later-generation agents promise to improve treatment outcomes for patients with multidrug-resistant tuberculosis and prevent the spread of disease. Mutations in the gyr genes are known to confer most fluoroquinolone resistance, but knowledge about the effects of gyr mutations on susceptibility to early- versus later-generation fluoroquinolones and about the role of mutation-mutation interactions is limited. Here, we sequenced the full gyrA and gyrB open reading frames in 240 multidrug-resistant and extensively drug resistant tuberculosis strains and quantified their ofloxacin and moxifloxacin MIC by testing growth at six concentrations for each drug. We constructed a multivariate regression model to assess both the individual mutation effects and interactions on the drug MICs. We found that gyrB mutations contribute to fluoroquinolone resistance both individually and through interactions with gyrA mutations. These effects were statistically significant. In these clinical isolates, several gyrA and gyrB mutations conferred different levels of resistance to ofloxacin and moxifloxacin. Consideration of gyr mutation combinations during the interpretation of molecular test results may improve the accuracy of predicting the fluoroquinolone resistance phenotype. Further, the differential effects of gyr mutations on the activity of early- and later generation fluoroquinolones requires further investigation and could inform the selection of a fluoroquinolone for treatment. PMID- 26763960 TI - Detection and Prevalence of Penicillin-Susceptible Staphylococcus aureus in the United States in 2013. AB - Using blaZ PCR as the "gold standard," the sensitivities of CLSI penicillin zone edge and nitrocefin-based tests for beta-lactamase production in Staphylococcus aureus were 64.5% and 35.5%, respectively, with specificity of 99.8% for both methods. In 2013, 13.5% of 3,083 S. aureus isolates from 31 U.S. centers were penicillin susceptible. PMID- 26763961 TI - Rapid Detection of Vancomycin-Intermediate Staphylococcus aureus by Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry. AB - Vancomycin is the standard of care for the treatment of invasive methicillin resistantStaphylococcus aureus(MRSA) infections. Infections with vancomycin nonsusceptible MRSA, including vancomycin-intermediateS. aureus(VISA) and heterogeneous VISA (hVISA), are clinically challenging and are associated with poor patient outcomes. The identification of VISA in the clinical laboratory depends on standard susceptibility testing, which takes at least 24 h to complete after isolate subculture, whereas hVISA is not routinely detected in clinical labs. We therefore sought to determine whether VISA and hVISA can be differentiated from vancomycin-susceptibleS. aureus(VSSA) using the spectra produced by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Strains of MRSA were characterized for vancomycin susceptibility phenotype by broth microdilution and modified population analysis. We tested 21 VISA, 21 hVISA, and 38 VSSA isolates by MALDI-TOF MS. Susceptibility phenotypes were separated by using a support vector machine (SVM) machine learning algorithm. The resulting model was validated by leave-one-out cross validation. Models were developed and validated by using spectral profiles generated under various subculture conditions, as well as with and without hVISA strains. Using SVM, we correctly identified 100% of the VISA and 97% of the VSSA isolates with an overall classification accuracy of 98%. Addition of hVISA to the model resulted in 76% hVISA identification, 100% VISA identification, and 89% VSSA identification, for an overall classification accuracy of 89%. We conclude that VISA/hVISA and VSSA isolates are separable by MALDI-TOF MS with SVM analysis. PMID- 26763962 TI - Phenotypic, Genotypic, and Antimicrobial Characteristics of Streptococcus halichoeri Isolates from Humans, Proposal To Rename Streptococcus halichoeri as Streptococcus halichoeri subsp. halichoeri, and Description of Streptococcus halichoeri subsp. hominis subsp. nov., a Bacterium Associated with Human Clinical Infections. AB - Phenotypic, genotypic, and antimicrobial characteristics of six phenotypically distinct human clinical isolates that most closely resembled the type strain of Streptococcus halichoeri isolated from a seal are presented. Sequencing of the 16S rRNA, rpoB, sodA, and recN genes; comparative whole-genome analysis; conventional biochemical and Rapid ID 32 Strep identification methods; and antimicrobial susceptibility testing were performed on the human isolates, the type strain of S. halichoeri, and type strains of closely related species. The six human clinical isolates were biochemically indistinguishable from each other and showed 100% 16S rRNA, rpoB, sodA, and recN gene sequence similarity. Comparative 16S rRNA gene sequencing analysis revealed 98.6% similarity to S. halichoeri CCUG 48324(T), 97.9% similarity to S. canis ATCC 43496(T), and 97.8% similarity to S. ictaluri ATCC BAA-1300(T). A 3,530-bp fragment of the rpoB gene was 98.8% similar to the S. halichoeri type strain, 84.6% to the S. canis type strain, and 83.8% to the S. ictaluri type strain. The S. halichoeri type strain and the human clinical isolates were susceptible to the antimicrobials tested based on CLSI guidelines for Streptococcus species viridans group with the exception of tetracycline and erythromycin. The human isolates were phenotypically distinct from the type strain isolated from a seal; comparative whole-genome sequence analysis confirmed that the human isolates were S. halichoeri. On the basis of these results, a novel subspecies, Streptococcus halichoeri subsp. hominis, is proposed for the human isolates and Streptococcus halichoeri subsp. halichoeri is proposed for the gray seal isolates. The type strain of the novel subspecies is SS1844(T) = CCUG 67100(T) = LMG 28801(T). PMID- 26763963 TI - Evaluation of Xpert MTB/RIF for Detection of Mycobacterium tuberculosis in Cerebrospinal Fluid. AB - Studies investigating Xpert MTB/RIF diagnostic performance on cerebrospinal fluid (CSF) samples are lacking in resource-rich settings. Xpert MTB/RIF results for 740 CSF samples from 698 patients across England were retrospectively compared with the results of culture of the same and contemporary samples. The overall sensitivity was calculated at 55%. PMID- 26763964 TI - Fifteen-Minute Detection of Streptococcus pyogenes in Throat Swabs by Use of a Commercially Available Point-of-Care PCR Assay. PMID- 26763965 TI - What's in a Name? The Impact of Accurate Staphylococcus pseudintermedius Identification on Appropriate Antimicrobial Susceptibility Testing. AB - Bacteria in the Staphylococcus intermedius group, including Staphylococcus pseudintermedius, often encode mecA-mediated methicillin resistance. Reliable detection of this phenotype for proper treatment and infection control decisions requires that these coagulase-positive staphylococci are accurately identified and specifically that they are not misidentified as S. aureus. As correct species level bacterial identification becomes more commonplace in clinical laboratories, one can expect to see changes in guidance for antimicrobial susceptibility testing and interpretation. The study by Wu et al. in this issue (M. T. Wu, C.-A. D. Burnham, L. F. Westblade, J. Dien Bard, S. D. Lawhon, M. A. Wallace, T. Stanley, E. Burd, J. Hindler, R. M. Humphries, J Clin Microbiol 54:535-542, 2016, http://dx.doi.org/10.1128/JCM.02864-15) highlights the impact of robust identification of S. intermedius group organisms on the selection of appropriate antimicrobial susceptibility testing methods and interpretation. PMID- 26763966 TI - Depletion of Human DNA in Spiked Clinical Specimens for Improvement of Sensitivity of Pathogen Detection by Next-Generation Sequencing. AB - Next-generation sequencing (NGS) technology has shown promise for the detection of human pathogens from clinical samples. However, one of the major obstacles to the use of NGS in diagnostic microbiology is the low ratio of pathogen DNA to human DNA in most clinical specimens. In this study, we aimed to develop a specimen-processing protocol to remove human DNA and enrich specimens for bacterial and viral DNA for shotgun metagenomic sequencing. Cerebrospinal fluid (CSF) and nasopharyngeal aspirate (NPA) specimens, spiked with control bacterial and viral pathogens, were processed using either a commercially available kit (MolYsis) or various detergents followed by DNase prior to the extraction of DNA. Relative quantities of human DNA and pathogen DNA were determined by real-time PCR. The MolYsis kit did not improve the pathogen-to-human DNA ratio, but significant reductions (>95%;P< 0.001) in human DNA with minimal effect on pathogen DNA were achieved in samples that were treated with 0.025% saponin, a nonionic surfactant. Specimen preprocessing significantly decreased NGS reads mapped to the human genome (P< 0.05) and improved the sensitivity of pathogen detection (P< 0.01), with a 20- to 650-fold increase in the ratio of microbial reads to human reads. Preprocessing also permitted the detection of pathogens that were undetectable in the unprocessed samples. Our results demonstrate a simple method for the reduction of background human DNA for metagenomic detection for a broad range of pathogens in clinical samples. PMID- 26763967 TI - Evaluation of a New Device for Simplifying and Standardizing Stool Sample Preparation for Viral Molecular Testing with Limited Hands-On Time. AB - Sensitive molecular assays have greatly improved the diagnosis of viral gastroenteritis. However, the proper preparation of stool samples for clinical testing remains an issue. bioMerieux has developed a stool preprocessing device (SPD) that includes a spoon for calibrated sampling and a vial containing buffer, glass beads, and two filters. The resulting stool filtrate is used for nucleic acid extraction. The purpose of this study was to evaluate the performance of the SPD for the quantification of human adenovirus (HAdV) DNA in stool samples collected from hematopoietic stem cell transplant (HSCT) recipients. HAdV DNA was quantified with the Adenovirus R-gene kit. The suitability of the device to reproducibly quantify HAdV DNA in stools using different extraction platforms (easyMAG and QIAsymphony) was determined using archived HAdV-positive stool samples. Coefficients of variation of HAdV DNA quantifications ranged from 1.79% to 1.83%, and no difference in quantification was observed between the two extraction systems. The HAdV DNA limit of quantification using the SPD was 3.75 log10copies/g of stool. HAdV DNA quantification using the SPD was then compared to that of the routine preprocessing technique on 75 fresh stool samples collected prospectively from pediatric HSCT recipients at risk for HAdV infections. Thirty-eight samples were HAdV DNA positive with both the SPD and routine preprocessing methods. HAdV DNA loads were on average 1.14-log10copies/g of stool higher with the SPD (P< 0.0001) than with routine methods. This new device enabled a standardized preparation of stool samples in <5 min and a reproducible and sensitive quantification of HAdV DNA. The use of the SPD for the detection of other gastrointestinal infections warrants further evaluation. PMID- 26763969 TI - Interferon Gamma Release Assays for Latent Tuberculosis: What Are the Sources of Variability? AB - Interferon gamma release assays (IGRAs) are blood-based tests intended for diagnosis of latent tuberculosis infection (LTBI). IGRAs offer logistical advantages and are supposed to offer improved specificity over the tuberculin skin test (TST). However, recent serial testing studies of low-risk individuals have revealed higher false conversion rates with IGRAs than with TST. Reproducibility studies have identified various sources of variability that contribute to nonreproducible results. Sources of variability can be broadly classified as preanalytical, analytical, postanalytical, manufacturing, and immunological. In this minireview, we summarize known sources of variability and their impact on IGRA results. We also provide recommendations on how to minimize sources of IGRA variability. PMID- 26763968 TI - Novel Assays for Measurement of Total Cell-Associated HIV-1 DNA and RNA. AB - Although a number of PCR-based quantitative assays for measuring HIV-1 persistence during suppressive antiretroviral therapy (ART) have been reported, a simple, sensitive, reproducible method is needed for application to large clinical trials. We developed novel quantitative PCR assays for cell-associated (CA) HIV-1 DNA and RNA, targeting a highly conserved region in HIV-1pol, with sensitivities of 3 to 5 copies/1 million cells. We evaluated the performance characteristics of the assays using peripheral blood mononuclear cells (PBMCs) from 5 viremic patients and 20 patients receiving effective ART. Total and resting CD4(+)T cells were isolated from a subset of patients and tested for comparison with PBMCs. The estimated standard deviations including interassay variability and intra-assay variability of the assays were modest, i.e., 0.15 and 0.10 log10copies/10(6)PBMCs, respectively, for CA HIV-1 DNA and 0.40 and 0.19 log10copies/10(6)PBMCs for CA HIV-1 RNA. Testing of longitudinally obtained PBMC samples showed little variation for either viremic patients (median fold differences of 0.80 and 0.88 for CA HIV-1 DNA and RNA, respectively) or virologically suppressed patients (median fold differences of 1.14 and 0.97, respectively). CA HIV-1 DNA and RNA levels were strongly correlated (r= 0.77 to 1;P= 0.0001 to 0.037) for assays performed using PBMCs from different sources (phlebotomy versus leukapheresis) or using total or resting CD4(+)T cells purified by either bead selection or flow cytometric sorting. Their sensitivity, reproducibility, and broad applicability to small numbers of mononuclear cells make these assays useful for observational and interventional studies that examine longitudinal changes in the numbers of HIV-1-infected cells and their levels of transcription. PMID- 26763970 TI - Field Evaluation of Four Rapid Tests for Diagnosis of HIV Infection in Panama. AB - Four HIV rapid tests were subjected to field validation in Panama and compared to an enzyme-linked immunosorbent assay/Multispot-based testing algorithm. The sensitivities of Determine, Uni-Gold, SD Bioline, and INSTI were 99.8%. The specificities of Determine, SD-Bioline, and Uni-Gold were 100%, and the specificity of INSTI was 99.8%. On the basis of these data, we determined that these rapid tests can be used in an appropriate algorithm to diagnose HIV infection and are suitable for use in testing and counseling settings in Panama. PMID- 26763972 TI - Identification of Neisseria gonorrhoeae by the Bruker Biotyper Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry System Is Improved by a Database Extension. AB - Identification ofNeisseria gonorrhoeaeby the Bruker matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) system may be affected by "B consistency categorization." A supplementary database of 17N. gonorrhoeaemain spectra was constructed. Twelve of 64N. gonorrhoeaeidentifications were categorized with B consistency, which disappeared using the supplementary database. Database extension did not result in misidentification ofNeisseria meningitidis. PMID- 26763971 TI - MTBDRplus and MTBDRsl Assays: Absence of Wild-Type Probe Hybridization and Implications for Detection of Drug-Resistant Tuberculosis. AB - Accurate identification of drug-resistantMycobacterium tuberculosisis imperative for effective treatment and subsequent reduction in disease transmission. Line probe assays rapidly detect mutations associated with resistance and wild-type sequences associated with susceptibility. Examination of molecular-level performance is necessary for improved assay result interpretation and for continued diagnostic development. Using data collected from a large, multisite diagnostic study, probe hybridization results from line probe assays, MTBDRplusand MTBDRsl, were compared to those of sequencing, and the diagnostic performance of each individual mutation and wild-type probe was assessed. Line probe assay results classified as resistant due to the absence of wild-type probe hybridization were compared to those of sequencing to determine if novel mutations were inhibiting wild-type probe hybridization. The contribution of absent wild-type probe hybridization to the detection of drug resistance was assessed via comparison to a phenotypic reference standard. In our study, mutation probes demonstrated significantly higher specificities than wild-type probes and wild-type probes demonstrated marginally higher sensitivities than mutation probes, an ideal combination for detecting the presence of resistance conferring mutations while yielding the fewest number of false-positive results. The absence of wild-type probe hybridization without mutation probe hybridization was determined to be primarily the result of failure of mutation probe hybridization and not the result of novel or rare mutations. Compared to phenotypic culture-based drug susceptibility testing, the absence of wild-type probe hybridization without mutation probe hybridization significantly contributed to the detection of phenotypic rifampin and fluoroquinolone resistance with negligible increases in false-positive results. PMID- 26763973 TI - Water as an agent for the morphology modification of metal oxalate materials on the nanoscale: from sheets to rods. AB - A number of approaches have been used to control the shape of metal oxalates, which often used as precursors for metal oxide nanomaterials. However, attempts to use water as a regulator have not been reported. Here in we report systematic studies on related topics: nanosheets, composed of 1-dimensional [M(C2O4)(EG)] (M = Zn or Co) polymeric structure, could be transformed into nanorods by using water as a shape-shifting agent because water can readily substitute EG ligand, leading alternation of inter-chain hydrogen bonding interactions. In addition, heat-treatment of these nanomaterials with diverse morphologies resulted in porous metal oxides with high degrees of shape retention. PMID- 26763974 TI - The influence of a school-based intervention programme regarding adherence to a healthy diet in children and adolescents from disadvantaged areas in Greece: the DIATROFI study. AB - BACKGROUND: To evaluate the effects, via a cohort study, of a food aid and promotion of healthy nutrition programme, implemented in areas of low socioeconomic status (SES) in Greece, on students' diet quality. METHODS: From a total of 162 schools participating in the programme during the 2012-2013 school year, we collected 3941 individually linked questionnaires at baseline and at the end of the intervention, recording sociodemographic characteristics, lifestyle parameters and dietary habits of the students. For the assessment of diet quality, the KIDMED score was computed, along with food frequency consumption data regarding milk, fruits, vegetables and whole grain products. Pre-post intervention values were compared using non-parametric tests. Generalised estimating equations were used to explore the factors that influence changes in dietary habits. RESULTS: By the end of the intervention, favourable changes were observed regarding healthy eating; KIDMED increased statistically significantly in adolescent girls (p=0.042), while the consumption frequency of all foods promoted by the intervention, namely, milk, fruits, vegetables and whole grain products, increased for children and adolescents, boys and girls (p<=0.002). Factors indicating lower SES, such as foreign country of birth, lower education level, no income source and high levels of food insecurity, were associated with lower diet quality. CONCLUSIONS: As low SES groups tend to adopt unhealthier dietary choices, it is of the outmost importance to take action for the promotion of healthy eating, directed especially to these at risk populations. School-based nutritional programmes can be considered as an effective policy measure towards this direction. PMID- 26763975 TI - Modulation of miR156 to identify traits associated with vegetative phase change in tobacco (Nicotiana tabacum). AB - After germination, plants progress through juvenile and adult phases of vegetative development before entering the reproductive phase. The character and timing of these phases vary significantly between different plant species, which makes it difficult to know whether temporal variations in various vegetative traits represent the same, or different, developmental processes. miR156 has been shown to be the master regulator of vegetative development in plants. Overexpression of miR156 prolongs the juvenile phase of development, whereas knocking-down the level of miR156 promotes the adult phase of development. Therefore, artificial modulation of miR156 expression is expected to cause corresponding changes in vegetative-specific traits in different plant species, particularly in those showing no substantial difference in morphology during vegetative development. To identify specific traits associated with the juvenile to-adult transition in tobacco, we examined the phenotype of transgenic tobacco plants with elevated or reduced levels of miR156. We found that leaf shape, the density of abaxial trichomes, the number of leaf veins, the number of stomata, the size and density of epidermal cells, patterns of epidermal cell staining, the content of chlorophyll and the rate of photosynthesis, are all affected by miR156. These newly identified miR156-regulated traits therefore can be used to distinguish between juvenile and adult phases of development in tobacco, and provide a starting point for future studies of vegetative phase change in the family Solanaceae. PMID- 26763977 TI - Methanosarcina flavescens sp. nov., a methanogenic archaeon isolated from a full scale anaerobic digester. AB - A novel, strictly anaerobic, methanogenic archaeon, strain E03.2T, was isolated from a full-scale biogas plant in Germany. Cells were non-motile sarcina-like cocci, occurring in aggregates. Strain E03.2T grew autotrophically on H2 plus CO2, and additionally cells could utilize acetate, methanol, moni-, di- and trimethylamine as carbon and energy sources; however, growth or methanogenesis on formate was not observed. Yeast extract and vitamins stimulated growth but were not mandatory. The optimal growth temperature of strain E03.2T was approximately 45 degrees C; maximal growth rates were obtained at about pH 7.0 in the presence of approximately 6.8 mM NaCl. The DNA G+C content of strain E03.2T was 41.3 mol%. Phylogenetic analyses based on 16S rRNA gene and mcrA sequences placed strain E03.2T within the genus Methanosarcina. Based on 16S rRNA gene sequence similarity strain E03.2T was related to seven different species of the genus Methanosarcina, but most closely related to Methanosarcina thermophila TM-1T. Phenotypic, physiological and genomic characteristics indicated that strain E03.2T represents a novel species of the genus Methanosarcina, for which the name Methanosarcina flavescens sp. nov. is proposed. The type strain is E03.2T ( = DSM 100822T = JCM 30921T). PMID- 26763976 TI - FRAMA: from RNA-seq data to annotated mRNA assemblies. AB - BACKGROUND: Advances in second-generation sequencing of RNA made a near-complete characterization of transcriptomes affordable. However, the reconstruction of full-length mRNAs via de novo RNA-seq assembly is still difficult due to the complexity of eukaryote transcriptomes with highly similar paralogs and multiple alternative splice variants. Here, we present FRAMA, a genome-independent annotation tool for de novo mRNA assemblies that addresses several post-assembly tasks, such as reduction of contig redundancy, ortholog assignment, correction of misassembled transcripts, scaffolding of fragmented transcripts and coding sequence identification. RESULTS: We applied FRAMA to assemble and annotate the transcriptome of the naked mole-rat and assess the quality of the obtained compilation of transcripts with the aid of publicy available naked mole-rat gene annotations. Based on a de novo transcriptome assembly (Trinity), FRAMA annotated 21,984 naked mole-rat mRNAs (12,100 full-length CDSs), corresponding to 16,887 genes. The scaffolding of 3488 genes increased the median sequence information 1.27-fold. In total, FRAMA detected and corrected 4774 misassembled genes, which were predominantly caused by fusion of genes. A comparison with three different sources of naked mole-rat transcripts reveals that FRAMA's gene models are better supported by RNA-seq data than any other transcript set. Further, our results demonstrate the competitiveness of FRAMA to state of the art genome-based transcript reconstruction approaches. CONCLUSION: FRAMA realizes the de novo construction of a low-redundant transcript catalog for eukaryotes, including the extension and refinement of transcripts. Thereby, results delivered by FRAMA provide the basis for comprehensive downstream analyses like gene expression studies or comparative transcriptomics. FRAMA is available at https://github.com/gengit/FRAMA . PMID- 26763978 TI - Ehrlichia minasensis sp. nov., isolated from the tick Rhipicephalus microplus. AB - Recently, we obtained a rickettsial isolate (Ehrlichia sp. UFMG-EVT) from the haemolymph of engorged Rhipicephalus microplus tick females. On the basis of maximum-likelihood phylogenetic analysis using 16S rRNA gene, groEL, dsb, gltA and trp36 sequences we showed that Ehrlichia sp. UFMG-EVT belongs to the alpha Proteobacteria, family Anaplasmataceae, genus Ehrlichia. Ehrlichia sp. UFMG-EVT is a sister taxon of Ehrlichia canis with 16S rRNA gene, groEL, dsb, gltA and trp36 sequence similarities of 98.3 %, 97.2 %, 94.7 %, 94.3 % and 49.1 %, respectively. Ehrlichia sp. UFMG-EVT has been maintained in the laboratory by continuous passage in the IDE8 tick cell line where the ultrastructure was characterized using electron microscopy and was found to resemble that of E. canis, Ehrlichia muris and Ehrlichia chaffeensis, but not Ehrlichia ruminantium and Ehrlichia ewingii. We propose the name Ehrlichia minasensis sp. nov. for this bacterium to acknowledge the place from where it was initially isolated, Minas Gerais, Brazil. The type strain is strain Ehrlichia sp. UFMG-EVT ( = DSM 100393T = TCB-TBB-0018T). PMID- 26763979 TI - Inter-segment complementarity in orbiviruses: a driver for co-ordinated genome packaging in the Reoviridae? AB - The process by which eukaryotic viruses with segmented genomes select a complete set of genome segments for packaging into progeny virus particles is not understood. In this study a model based on the association of genome segments through specific RNA-RNA interactions driven by base pairing was formalized and tested in the Orbivirus genus of the Reoviridae family. A strategy combining screening of the genomic sequences for inter-segment complementarity with direct functional testing of inter-segment RNA-RNA interactions using reverse genetics is described in the type species of the Orbivirus genus, Bluetongue virus (BTV). Two examples, involving four of the ten BTV genomic segments, of specific inter segment interaction motifs whose maintenance is essential for the generation of infectious virus, were identified. Equivalent inter-segment complementarities were found between the identified regions of the orthologous genome segments of all orbiviruses, including phylogenetically distant species. Specific interaction of the participating RNA segments was confirmed in vitro using electrophoretic mobility shift assays, with the interactions inhibited using oligonucleotides complementary to the interaction motif of one of the interacting partners, and also through mutagenesis of the motifs. In each example, the base pairing rather than the absolute sequence was critical to the formation of a functional inter segment interaction, with mutations only being tolerated in rescued virus if compensating changes were made in the interacting partner to restore uninterrupted base pairing. The absolute sequence of the complementarity motifs varied between species, indicating that this newly identified phenomenon may contribute to the observed lack of reassortment between Orbivirus species. PMID- 26763981 TI - Use of a venting PEG tube in the management of recurrent acute gastric dilatation associated with Prader-Willi syndrome. AB - A patient with Prader-Willi Syndrome was admitted to the ICU with features of recurrent acute gastric dilatation, aspiration pneumonia and a massive pulmonary embolus. He was initially managed with intubation, assisted ventilation, intravenous fluids and anticoagulation. Decompression of the stomach was achieved with a nasogastric tube. After ventilator weaning, he did not tolerate the nasogastric intubation that led to a further episode of aspiration pneumonia as a result of non-resolving gastric dilatation. He required readmission to intensive care for a further period of ventilatory support. While the patient was sedated and ventilated, a venting percutaneous endoscopic gastrostomy (PEG) with a jejunal feeding extension was placed, permitting both continued decompression of the stomach and enteral feeding. The patient tolerated the PEG-J well and his nutritional needs were successfully addressed. Oral intake was slowly re established with ongoing decompression of the stomach with the PEG. He was discharged from hospital with the PEG in place. PMID- 26763982 TI - 21st Century Genetics: Mass Spectrometry of Yeast Telomerase. AB - Telomerase is a specialized reverse transcriptase that maintains the ends of chromosomes in almost all eukaryotes. The core of telomerase consists of telomerase RNA and the reverse transcriptase that uses a short segment without the RNA to template the addition of telomeric repeats. In addition, one or more accessory proteins are required for telomerase action in vivo. The best-studied accessory protein is Est1, which is conserved from yeasts to humans. In budding yeast, Est1 has two critical in vivo functions: By interaction with Cdc13, a telomere-binding protein, it recruits telomerase to telomeres, and it also increases telomerase activity. Although budding yeast telomerase is highly regulated by the cell cycle, Est1 is the only telomerase subunit whose abundance is cell cycle-regulated. Close to 400 yeast genes are reported to affect telomere length, although the specific function of most of them is unknown. With the goal of identifying novel telomerase regulators by mass spectrometry, we developed methods for purifying yeast telomerase and its associated proteins. We summarize the methods we used and describe the experiments that show that four telomerase associated proteins identified by mass spectrometry, none of which had been linked previously to telomeres, affect telomere length and cell cycle regulation of telomerase by controlling Est1 abundance. PMID- 26763980 TI - Beyond the inflammasome: regulatory NOD-like receptor modulation of the host immune response following virus exposure. AB - A complex interaction exists between elements of the host innate immune system and viral pathogens. It is essential that the host mount a robust immune response during viral infection and effectively resolve inflammation once the pathogen has been eliminated. Members of the nucleotide-binding domain leucine-rich repeat [NBD-LRR; known as NOD-like receptor (NLR)] family of cytosolic pattern recognition receptors are essential components of these immunological processes and have diverse functions in the host antiviral immune response. NLRs can be subgrouped based on their general function. The inflammasome-forming subgroup of NLRs are the best-characterized family members, and several have been found to modulate the maturation of IL-1beta and IL-18 following virus exposure. However, the members of the regulatory NLR subgroups are significantly less characterized. These NLRs uniquely function to modulate signalling pathways initiated by other families of pattern-recognition receptors, such as Toll-like receptors and/or Rig I-like helicase receptors. Regulatory NLRs that augment pro-inflammatory pathways include nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and NOD2, which have been shown to form a multiprotein complex termed the NODosome that significantly modulates IFN and NF-kappaB signalling following viral infection. Conversely, a second subgroup of regulatory NLRs functions to negatively regulate inflammation. These inhibitory NLRs include NLRX1, NLRP12 and NLRC3, which have been shown to interact with TRAF molecules and various kinases to modulate diverse cellular processes. Targeting NLR signalling following infection with a virus represents a novel and promising therapeutic strategy. However, significant effort is still required to translate the current understanding of NLR biology into effective therapies. PMID- 26763983 TI - Transposable Elements, Polydactyl Proteins, and the Genesis of Human-Specific Transcription Networks. AB - Transposable elements (TEs) may account for up to two-thirds of the human genome, and as genomic threats they are subjected to epigenetic control mechanisms engaged from the earliest stages of embryonic development. We previously determined that an important component of this process is the sequence-specific recognition of TEs by KRAB (Kruppel-associated box)-containing zinc-finger proteins (KRAB-ZFPs), a large family of tetrapod-restricted transcription factors that act by recruiting inducers of heterochromatin formation and DNA methylation. We further showed that KRAB-ZFPs and their cofactor KAP1 exert a marked influence on the transcription dynamics of embryonic stem cells via their docking of repressor complexes at TE-contained regulatory sequences. It is generally held that, beyond this early embryonic period, TEs become permanently silenced, and that the evolutionary selection of KRAB-ZFPs and other TE controllers is the result of a simple evolutionary arms race between the host and these genetics invaders. Here, I discuss recent evidence that invalidates this dual assumption and instead suggests that KRAB-ZFPs are the instruments of a massive enterprise of TE domestication, whereby transposon-based regulatory sequences and their cellular ligands establish species-specific transcription regulation networks that influence multiple aspects of human development and physiology. PMID- 26763985 TI - Erase-Maintain-Establish: Natural Reprogramming of the Mammalian Epigenome. AB - The genetic information is largely identical across most cell types in a given organism but the epigenome, which controls expression of the genome, is cell type and context-dependent. Although most mature mammalian cells appear to have a stable, heritable epigenome, a dynamic intricate process reshapes it as these cells transition from soma to germline and back again. During normal embryogenesis, primordial germ cells, of somatic origin, are set aside to become gametes. In doing so their genome is reprogrammed-that is, the epigenome of specific regions is replaced in a sex-specific fashion as they terminally differentiate into oocytes or spermatocytes in the gonads. Upon union of these gametes, reprogramming of the new organism's epigenome is initiated, which eventually leads, through pluripotent cells, to the cell lineages required for proper embryonic development to a sexually mature adult. This never-ending cycle of birth and rebirth is accomplished through methylation and demethylation of specific genomic sites within the gametes and pluripotent cells of an organism. This enigmatic process of natural epigenomic reprogramming is now being dissected in vivo, focusing on specific genomic regions-that is, imprinted genes and retrotransposons, where TRIM28 molecular complexes appear to guide the transition from gamete to embryo. PMID- 26763988 TI - Occupational contact allergy to the epoxy resin hardener 2-methylpentane-1,5 diamine. PMID- 26763984 TI - Imaging Transcription: Past, Present, and Future. AB - Transcription, the first step of gene expression, is exquisitely regulated in higher eukaryotes to ensure correct development and homeostasis. Traditional biochemical, genetic, and genomic approaches have proved successful at identifying factors, regulatory sequences, and potential pathways that modulate transcription. However, they typically only provide snapshots or population averages of the highly dynamic, stochastic biochemical processes involved in transcriptional regulation. Single-molecule live-cell imaging has, therefore, emerged as a complementary approach capable of circumventing these limitations. By observing sequences of molecular events in real time as they occur in their native context, imaging has the power to derive cause-and-effect relationships and quantitative kinetics to build predictive models of transcription. Ongoing progress in fluorescence imaging technology has brought new microscopes and labeling technologies that now make it possible to visualize and quantify the transcription process with single-molecule resolution in living cells and animals. Here we provide an overview of the evolution and current state of transcription imaging technologies. We discuss some of the important concepts they uncovered and present possible future developments that might solve long standing questions in transcriptional regulation. PMID- 26763989 TI - How should we advise patients with allergic contact dermatitis caused by (meth )acrylates about future dental work? PMID- 26763986 TI - Reduced intensity VEPEMB regimen compared with standard ABVD in elderly Hodgkin lymphoma patients: results from a randomized trial on behalf of the Fondazione Italiana Linfomi (FIL). AB - Survival rates for elderly Hodgkin Lymphoma (HL) have not improved substantially in recent years, mainly because of a lack of prospective randomized studies, due to difficulties in enrolling patients. Between 2002 and 2006, 54 untreated HL patients, aged between 65 and 80 years and considered 'non-frail' according to a comprehensive geriatric evaluation, were enrolled into a phase III randomized trial to compare a reduced-intensity regimen (vinblastine, cyclophosphamide, procarbazine, prednisone, etoposide, mitoxantrone, bleomycin; VEPEMB) with standard ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Primary endpoint was progression-free survival (PFS). Seventeen patients were in early stage (I IIA), while 37 were advanced stage. Median age was 72 years and median follow-up was 76 months. Five-year PFS rates were 48% vs. 70% [adjusted Hazard ratio (HR) = 2.19, 95% confidence interval (CI) = 0.94-5.10, P = 0.068] and 5-year overall survival (OS) rates were 63% vs. 77% (adjusted HR = 1.67, 95% CI = 0.69-4.03, P = 0.254) for VEPEMB compared to ABVD. Overall treatment-related mortality was 4%. World Health Organization grade 4 cardiac and lung toxicity occurred in four patients treated with ABVD versus no cases in the VEPEMB arm. Standard ABVD regimen resulted in better PFS and OS than the VEPEMB, although the differences were not statistically significant. The low toxicity of both treatments was probably attributable to stringent selection of patients based on a Comprehensive Geriatric Assessment that excluded frail patients. PMID- 26763990 TI - Occupational periorbital allergic contact dermatitis caused by antioxidants in black rubber in an otorhinolaryngologist using an otomicroscope. PMID- 26763991 TI - Contact allergy resulting from the use of acrylate nails is increasing in both users and those who are occupationally exposed. PMID- 26763992 TI - Airborne allergic contact dermatitis caused by Apuleia leiocarpa in a parquet fitter. PMID- 26763993 TI - Sensitization to cyanoacrylates caused by prolonged exposure to a glucose sensor set in a diabetic child. PMID- 26763994 TI - Two unusual cases of allergic contact stomatitis caused by methacrylates. PMID- 26763995 TI - PTBP-FR and TRUE Test(r). PMID- 26763996 TI - Trichoplusia ni Kinesin-1 Associates with Autographa californica Multiple Nucleopolyhedrovirus Nucleocapsid Proteins and Is Required for Production of Budded Virus. AB - The mechanism by which nucleocapsids of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) egress from the nucleus to the plasma membrane, leading to the formation of budded virus (BV), is not known. AC141 is a nucleocapsid-associated protein required for BV egress and has previously been shown to be associated with beta-tubulin. In addition, AC141 and VP39 were previously shown by fluorescence resonance energy transfer by fluorescence lifetime imaging to interact directly with the Drosophila melanogaster kinesin-1 light chain (KLC) tetratricopeptide repeat (TPR) domain. These results suggested that microtubule transport systems may be involved in baculovirus nucleocapsid egress and BV formation. In this study, we investigated the role of lepidopteran microtubule transport using coimmunoprecipitation, colocalization, yeast two hybrid, and small interfering RNA (siRNA) analyses. We show that nucleocapsid AC141 associates with the lepidopteran Trichoplusia ni KLC and kinesin-1 heavy chain (KHC) by coimmunoprecipitation and colocalization. Kinesin-1, AC141, and microtubules colocalized predominantly at the plasma membrane. In addition, the nucleocapsid proteins VP39, FP25, and BV/ODV-C42 were also coimmunoprecipitated with T. ni KLC. Direct analysis of the role of T. ni kinesin-1 by downregulation of KLC by siRNA resulted in a significant decrease in BV production. Nucleocapsids labeled with VP39 fused with three copies of the mCherry fluorescent protein also colocalized with microtubules. Yeast two-hybrid analysis showed no evidence of a direct interaction between kinesin-1 and AC141 or VP39, suggesting that either other nucleocapsid proteins or adaptor proteins may be required. These results further support the conclusion that microtubule transport is required for AcMNPV BV formation. IMPORTANCE: In two key processes of the replication cycle of the baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV), nucleocapsids are transported through the cell. These include (i) entry of budded virus (BV) into the host cell and (ii) egress and budding of nucleocapsids newly produced from the plasma membrane. Prior studies have shown that the entry of nucleocapsids involves the polymerization of actin to propel nucleocapsids to nuclear pores and entry into the nucleus. For the spread of infection, progeny viruses must rapidly exit the infected cells, but the mechanism by which AcMNPV nucleocapsids traverse the cytoplasm is unknown. In this study, we examined whether nucleocapsids interact with lepidopteran kinesin-1 motor molecules and are potentially carried as cargo on microtubules to the plasma membrane in AcMNPV-infected cells. This study indicates that microtubule transport is utilized for the production of budded virus. PMID- 26763997 TI - Acidianus Tailed Spindle Virus: a New Archaeal Large Tailed Spindle Virus Discovered by Culture-Independent Methods. AB - The field of viral metagenomics has expanded our understanding of viral diversity from all three domains of life (Archaea, Bacteria, and Eukarya). Traditionally, viral metagenomic studies provide information about viral gene content but rarely provide knowledge about virion morphology and/or cellular host identity. Here we describe a new virus, Acidianus tailed spindle virus (ATSV), initially identified by bioinformatic analysis of viral metagenomic data sets from a high-temperature (80 degrees C) acidic (pH 2) hot spring located in Yellowstone National Park, followed by more detailed characterization using only environmental samples without dependency on culturing. Characterization included the identification of the large tailed spindle virion morphology, determination of the complete 70.8-kb circular double-stranded DNA (dsDNA) viral genome content, and identification of its cellular host. Annotation of the ATSV genome revealed a potential three domain gene product containing an N-terminal leucine-rich repeat domain, followed by a likely posttranslation regulatory region consisting of high serine and threonine content, and a C-terminal ESCRT-III domain, suggesting interplay with the host ESCRT system. The host of ATSV, which is most closely related to Acidianus hospitalis, was determined by a combination of analysis of cellular clustered regularly interspaced short palindromic repeat (CRISPR)/Cas loci and dual viral and cellular fluorescence in situ hybridization (viral FISH) analysis of environmental samples and confirmed by culture-based infection studies. This work provides an expanded pathway for the discovery, isolation, and characterization of new viruses using culture-independent approaches and provides a platform for predicting and confirming virus hosts. IMPORTANCE: Virus discovery and characterization have been traditionally accomplished by using culture-based methods. While a valuable approach, it is limited by the availability of culturable hosts. In this research, we report a virus-centered approach to virus discovery and characterization, linking viral metagenomic sequences to a virus particle, its sequenced genome, and its host directly in environmental samples, without using culture-dependent methods. This approach provides a pathway for the discovery, isolation, and characterization of new viruses. While this study used an acidic hot spring environment to characterize a new archaeal virus, Acidianus tailed spindle virus (ATSV), the approach can be generally applied to any environment to expand knowledge of virus diversity in all three domains of life. PMID- 26763998 TI - ISG15 Is Upregulated in Respiratory Syncytial Virus Infection and Reduces Virus Growth through Protein ISGylation. AB - Human respiratory syncytial virus (RSV), for which neither a vaccine nor an effective therapeutic treatment is currently available, is the leading cause of severe lower respiratory tract infections in children. Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like protein that is highly increased during viral infections and has been reported to have an antiviral or a proviral activity, depending on the virus. Previous studies from our laboratory demonstrated strong ISG15 upregulation during RSV infection in vitro. In this study, an in-depth analysis of the role of ISG15 in RSV infection is presented. ISG15 overexpression and small interfering RNA (siRNA)-silencing experiments, along with ISG15 knockout (ISG15(-/-)) cells, revealed an anti-RSV effect of the molecule. Conjugation inhibition assays demonstrated that ISG15 exerts its antiviral activity via protein ISGylation. This antiviral activity requires high levels of ISG15 to be present in the cells before RSV infection. Finally, ISG15 is also upregulated in human respiratory pseudostratified epithelia and in nasopharyngeal washes from infants infected with RSV, pointing to a possible antiviral role of the molecule in vivo. These results advance our understanding of the innate immune response elicited by RSV and open new possibilities to control infections by the virus. IMPORTANCE: At present, no vaccine or effective treatment for human respiratory syncytial virus (RSV) is available. This study shows that interferon stimulated gene 15 (ISG15) lowers RSV growth through protein ISGylation. In addition, ISG15 accumulation highly correlates with the RSV load in nasopharyngeal washes from children, indicating that ISG15 may also have an antiviral role in vivo. These results improve our understanding of the innate immune response to RSV and identify ISG15 as a potential target for virus control. PMID- 26764000 TI - Mononucleated Blood Cell Populations Display Different Abilities To Transmit Prion Disease by the Transfusion Route. AB - Previous experiments carried out in a sheep scrapie model demonstrated that the transfusion of 200 MUl of prion-infected whole blood has an apparent 100% efficacy for disease transmission. These experiments also indicated that, despite the apparent low infectious titer, the intravenous administration of white blood cells (WBC) resulted in efficient disease transmission. In the study presented here, using the same transmissible spongiform encephalopathy (TSE) animal model, our aim was to determine the minimal number of white blood cells and the specific abilities of mononucleated cell populations to transmit scrapie by the transfusion route. Our results confirmed that the transfusion of 100 MUl, but not 10 MUl, of fresh whole blood collected in asymptomatic scrapie-infected donor sheep can transmit the disease. The data also show that the intravenous administration of 10(5) WBCs is sufficient to cause scrapie in recipient sheep. Cell-sorted CD45R(+) (predominantly B lymphocytes), CD4(+)/CD8(+) (T lymphocytes), and CD14(+) (monocytes/macrophages) blood cell subpopulations all were shown to contain prion infectivity by bioassays in ovine PrP transgenic mice. However, while the intravenous administration of 10(6) CD45(+) or CD4(+)/8(+) living cells was able to transmit the disease, similar numbers of CD14(+) cells failed to infect the recipients. These data support the contention that mononucleated blood cell populations display different abilities to transmit TSE by the transfusion route. They also represent an important input for the risk assessment of blood-borne prion disease transmission and for refining the target performance of leukoreduction processes that currently are applied to mitigate the transmission risk in transfusion medicine. IMPORTANCE: Interindividual variant Creutzfeldt-Jakob disease (vCJD) transmission through blood and blood derived products is considered a major public health issue in transfusion medicine. Over the last decade, TSE in sheep has emerged as a relevant model for assessing the blood-borne vCJD transmission risk. In this study, using a sheep TSE model, we characterized the ability of different peripheral blood mononucleated cell populations to infect TSE-free recipients by the transfusion route. Our results indicate that as little as 10(5) WBC and 100 MUl of blood collected from asymptomatic scrapie infected animals can transmit the disease. They also demonstrate unambiguously that peripheral blood mononuclear cell subpopulations display dramatically different abilities to transmit the disease. These data represent an important input for the risk assessment of blood-borne prion disease transmission and for refining the target performance of leukoreduction processes that currently are applied to mitigate the transmission risk in transfusion medicine. PMID- 26763999 TI - Conformational Epitope-Specific Broadly Neutralizing Plasma Antibodies Obtained from an HIV-1 Clade C-Infected Elite Neutralizer Mediate Autologous Virus Escape through Mutations in the V1 Loop. AB - Broadly neutralizing antibodies isolated from infected patients who are elite neutralizers have identified targets on HIV-1 envelope (Env) glycoprotein that are vulnerable to antibody neutralization; however, it is not known whether infection established by the majority of the circulating clade C strains in Indian patients elicit neutralizing antibody responses against any of the known targets. In the present study, we examined the specificity of a broad and potent cross-neutralizing plasma obtained from an Indian elite neutralizer infected with HIV-1 clade C. This plasma neutralized 53/57 (93%) HIV pseudoviruses prepared with Env from distinct HIV clades of different geographical origins. Mapping studies using gp120 core protein, single-residue knockout mutants, and chimeric viruses revealed that G37080 broadly cross-neutralizing (BCN) plasma lacks specificities to the CD4 binding site, gp41 membrane-proximal external region, N160 and N332 glycans, and R166 and K169 in the V1-V3 region and are known predominant targets for BCN antibodies. Depletion of G37080 plasma with soluble trimeric BG505-SOSIP.664 Env (but with neither monomeric gp120 nor clade C membrane-proximal external region peptides) resulted in significant reduction of virus neutralization, suggesting that G37080 BCN antibodies mainly target epitopes on cleaved trimeric Env. Further examination of autologous circulating Envs revealed the association of mutation of residues in the V1 loop that contributed to neutralization resistance. In summary, we report the identification of plasma antibodies from a clade C-infected elite neutralizer that mediate neutralization breadth via epitopes on trimeric gp120 not yet reported and confer autologous neutralization escape via mutation of residues in the V1 loop. IMPORTANCE: A preventive vaccine to protect against HIV-1 is urgently needed. HIV-1 envelope glycoproteins are targets of neutralizing antibodies and represent a key component for immunogen design. The mapping of epitopes on viral envelopes vulnerable to immune evasion will aid in defining targets of vaccine immunogens. We identified novel conformational epitopes on the viral envelope targeted by broadly cross-neutralizing antibodies elicited in natural infection in an elite neutralizer infected with HIV-1 clade C. Our data extend our knowledge on neutralizing epitopes associated with virus escape and potentially contribute to immunogen design and antibody-based prophylactic therapy. PMID- 26764001 TI - Secreted Oral Epithelial Cell Membrane Vesicles Induce Epstein-Barr Virus Reactivation in Latently Infected B Cells. AB - In the oral epithelium, peripheral stores of Epstein-Barr virus (EBV) are transmitted from infiltrating B cells to epithelial cells. Once the virus is transmitted to epithelial cells, the highly permissive nature of this cell type for lytic replication allows virus amplification and exchange to other hosts. Since the initial transfer of EBV from B cells to epithelial cells requires transitioning of the B-cell to a state that induces virus reactivation, we hypothesized that there might be epithelium-specific signals that allow the infiltrating B cells to sense the appropriate environment to initiate reactivation and begin this exchange process. We previously found that the epithelium-specific miR-200 family of microRNAs promotes EBV lytic replication. Here we show that there are high levels of miR-200 family members in oral and tonsillar epithelia and in saliva. Analysis of cultured oral epithelial cells (OKF6) showed that they actively secrete membrane vesicles (exosomes) that are enriched with miR-200 family members. Coculturing of EBV-positive B cells with OKF6 cells induced viral reactivation. Further, treatment of EBV-positive B cells with OKF6 cell-derived membrane vesicles promoted reactivation. Using a cell system that does not naturally express miR-200 family members, we found that enforced expression of a miR-200 family member produced membrane vesicles that were able to induce the lytic cascade in EBV-positive B cells. We propose that membrane vesicles secreted by oral and tonsillar epithelial cells may serve as a tissue-specific environmental cue that initiates reactivation in B cells, promoting the transfer of virus from peripheral B-cell stores to the oral epithelium to facilitate virus amplification and exchange to other hosts. IMPORTANCE: Epstein-Barr virus (EBV) is an important human pathogen that is causally associated with several lymphomas and carcinomas. The switch from latency to the lytic cycle is critical for successful host infection and for EBV pathogenesis. Although the EBV lytic cycle can be triggered by certain agents in vitro, the mechanisms that signal reactivation in vivo are poorly understood. We previously reported that endogenously expressed miR-200 family members likely play a role in facilitating the lytic tendencies of EBV in epithelial cells. Here we show that membrane vesicles secreted from oral epithelial cells contain miR 200 family members and that they can be transmitted to proximal EBV-positive B cells, where they trigger reactivation. We propose that this intercellular communication pathway may serve as a sensor mechanism for infiltrating B cells to recognize an appropriate environment to initiate reactivation, thereby allowing the exchange of virus to the oral epithelium. PMID- 26764002 TI - Infectivity and Transmissibility of Avian H9N2 Influenza Viruses in Pigs. AB - The H9N2 influenza viruses that are enzootic in terrestrial poultry in China pose a persistent pandemic threat to humans. To investigate whether the continuous circulation and adaptation of these viruses in terrestrial poultry increased their infectivity to pigs, we conducted a serological survey in pig herds with H9N2 viruses selected from the aquatic avian gene pool (Y439 lineage) and the enzootic terrestrial poultry viruses (G1 and Y280 lineages). We also compared the infectivity and transmissibility of these viruses in pigs. It was found that more than 15% of the pigs sampled from 2010 to 2012 in southern China were seropositive to either G1 or Y280 lineage viruses, but none of the sera were positive to the H9 viruses from the Y439 lineage. Viruses of the G1 and Y280 lineages were able to infect experimental pigs, with detectable nasal shedding of the viruses and seroconversion, whereas viruses of the Y439 lineage did not cause a productive infection in pigs. Thus, adaptation and prevalence in terrestrial poultry could lead to interspecies transmission of H9N2 viruses from birds to pigs. Although H9N2 viruses do not appear to be continuously transmissible among pigs, repeated introductions of H9 viruses to pigs naturally increase the risk of generating mammalian-adapted or reassorted variants that are potentially infectious to humans. This study highlights the importance of monitoring the activity of H9N2 viruses in terrestrial poultry and pigs. IMPORTANCE: H9N2 subtype of influenza viruses has repeatedly been introduced into mammalian hosts, including humans and pigs, so awareness of their activity and evolution is important for influenza pandemic preparedness. However, since H9N2 viruses usually cause mild or even asymptomatic infections in mammalian hosts, they may be overlooked in influenza surveillance. Here, we found that the H9N2 viruses established in terrestrial poultry had higher infectivity in pigs than those from aquatic birds, which suggests that adaptation of the H9N2 viruses in terrestrial poultry might have increased the infectivity of the virus to mammals. Therefore, monitoring the prevalence and evolution of H9 viruses prevalent in terrestrial birds and conducting risk assessment of their threat to mammals are critical for evaluating the pandemic potential of this virus. PMID- 26764003 TI - Five of Five VHHs Neutralizing Poliovirus Bind the Receptor-Binding Site. AB - Nanobodies, or VHHs, that recognize poliovirus type 1 have previously been selected and characterized as candidates for antiviral agents or reagents for standardization of vaccine quality control. In this study, we present high resolution cryo-electron microscopy reconstructions of poliovirus with five neutralizing VHHs. All VHHs bind the capsid in the canyon at sites that extensively overlap the poliovirus receptor-binding site. In contrast, the interaction involves a unique (and surprisingly extensive) surface for each of the five VHHs. Five regions of the capsid were found to participate in binding with all five VHHs. Four of these five regions are known to alter during the expansion of the capsid associated with viral entry. Interestingly, binding of one of the VHHs, PVSS21E, resulted in significant changes of the capsid structure and thus seems to trap the virus in an early stage of expansion. IMPORTANCE: We describe the cryo-electron microscopy structures of complexes of five neutralizing VHHs with the Mahoney strain of type 1 poliovirus at resolutions ranging from 3.8 to 6.3A. All five VHHs bind deep in the virus canyon at similar sites that overlap extensively with the binding site for the receptor (CD155). The binding surfaces on the VHHs are surprisingly extensive, but despite the use of similar binding surfaces on the virus, the binding surface on the VHHs is unique for each VHH. In four of the five complexes, the virus remains essentially unchanged, but for the fifth there are significant changes reminiscent of but smaller in magnitude than the changes associated with cell entry, suggesting that this VHH traps the virus in a previously undescribed early intermediate state. The neutralizing mechanisms of the VHHs and their potential use as quality control agents for the end game of poliovirus eradication are discussed. PMID- 26764004 TI - Equine Arteritis Virus Uses Equine CXCL16 as an Entry Receptor. AB - Previous studies in our laboratory have identified equine CXCL16 (EqCXCL16) to be a candidate molecule and possible cell entry receptor for equine arteritis virus (EAV). In horses, the CXCL16 gene is located on equine chromosome 11 (ECA11) and encodes a glycosylated, type I transmembrane protein with 247 amino acids. Stable transfection of HEK-293T cells with plasmid DNA carrying EqCXCL16 (HEK-EqCXCL16 cells) increased the proportion of the cell population permissive to EAV infection from <3% to almost 100%. The increase in permissiveness was blocked either by transfection of HEK-EqCXCL16 cells with small interfering RNAs (siRNAs) directed against EqCXCL16 or by pretreatment with guinea pig polyclonal antibody against EqCXCL16 protein (Gp anti-EqCXCL16 pAb). Furthermore, using a virus overlay protein-binding assay (VOPBA) in combination with far-Western blotting, gradient-purified EAV particles were shown to bind directly to the EqCXCL16 protein in vitro. The binding of biotinylated virulent EAV strain Bucyrus at 4 degrees C was significantly higher in HEK-EqCXCL16 cells than nontransfected HEK 293T cells. Finally, the results demonstrated that EAV preferentially infects subpopulations of horse CD14(+) monocytes expressing EqCXCL16 and that infection of these cells is significantly reduced by pretreatment with Gp anti-EqCXCL16 pAb. The collective data from this study provide confirmatory evidence that the transmembrane form of EqCXCL16 likely plays a major role in EAV host cell entry processes, possibly acting as a primary receptor molecule for this virus. IMPORTANCE: Outbreaks of EVA can be a source of significant economic loss for the equine industry from high rates of abortion in pregnant mares, death in young foals, establishment of the carrier state in stallions, and trade restrictions imposed by various countries. Similar to other arteriviruses, EAV primarily targets cells of the monocyte/macrophage lineage, which, when infected, are believed to play a critical role in EVA pathogenesis. To this point, however, the host-specified molecules involved in EAV binding and entry into monocytes/macrophages have not been identified. Identification of the cellular receptors for EAV may provide insights to design antivirals and better prophylactic reagents. In this study, we have demonstrated that EqCXCL16 acts as an EAV entry receptor in EAV-susceptible cells, equine monocytes. These findings represent a significant advance in our understanding of the fundamental mechanisms associated with the entry of EAV into susceptible cells. PMID- 26764005 TI - Ecotropic Murine Leukemia Virus Infection of Glial Progenitors Interferes with Oligodendrocyte Differentiation: Implications for Neurovirulence. AB - Certain murine leukemia viruses (MLVs) are capable of inducing fatal progressive spongiform motor neuron disease in mice that is largely mediated by viral Env glycoprotein expression within central nervous system (CNS) glia. While the etiologic mechanisms and the glial subtypes involved remain unresolved, infection of NG2 glia was recently observed to correlate spatially and temporally with altered neuronal physiology and spongiogenesis. Since one role of NG2 cells is to serve as oligodendrocyte (OL) progenitor cells (OPCs), we examined here whether their infection by neurovirulent (FrCasE) or nonneurovirulent (Fr57E) ecotropic MLVs influenced their viability and/or differentiation. Here, we demonstrate that OPCs, but not OLs, are major CNS targets of both FrCasE and Fr57E. We also show that MLV infection of neural progenitor cells (NPCs) in culture did not affect survival, proliferation, or OPC progenitor marker expression but suppressed certain glial differentiation markers. Assessment of glial differentiation in vivo using transplanted transgenic NPCs showed that, while MLVs did not affect cellular engraftment or survival, they did inhibit OL differentiation, irrespective of MLV neurovirulence. In addition, in chimeric brains, where FrCasE infected NPC transplants caused neurodegeneration, the transplanted NPCs proliferated. These results suggest that MLV infection is not directly cytotoxic to OPCs but rather acts to interfere with OL differentiation. Since both FrCasE and Fr57E viruses restrict OL differentiation but only FrCasE induces overt neurodegeneration, restriction of OL maturation alone cannot account for neuropathogenesis. Instead neurodegeneration may involve a two-hit scenario where interference with OPC differentiation combined with glial Env-induced neuronal hyperexcitability precipitates disease. IMPORTANCE: A variety of human and animal retroviruses are capable of causing central nervous system (CNS) neurodegeneration manifested as motor and cognitive deficits. These retroviruses infect a variety of CNS cell types; however, the specific role each cell type plays in neuropathogenesis remains to be established. The NG2 glia, whose CNS functions are only now emerging, are a newly appreciated viral target in murine leukemia virus (MLV)-induced neurodegeneration. Since one role of NG2 glia is that of oligodendrocyte progenitor cells (OPCs), we investigated here whether their infection by the neurovirulent MLV FrCasE contributed to neurodegeneration by affecting OPC viability and/or development. Our results show that both neurovirulent and nonneurovirulent MLVs interfere with oligodendrocyte differentiation. Thus, NG2 glial infection could contribute to neurodegeneration by preventing myelin formation and/or repair and by suspending OPCs in a state of persistent susceptibility to excitotoxic insult mediated by neurovirulent virus effects on other glial subtypes. PMID- 26764006 TI - Involvement of the N-Terminal Deubiquitinating Protease Domain of Human Cytomegalovirus UL48 Tegument Protein in Autoubiquitination, Virion Stability, and Virus Entry. AB - Human cytomegalovirus (HCMV) protein pUL48 is closely associated with the capsid and has a deubiquitinating protease (DUB) activity in its N-terminal region. Although this DUB activity moderately increases virus replication in cultured fibroblast cells, the requirements of the N-terminal region of pUL48 in the viral replication cycle are not fully understood. In this study, we characterized the recombinant viruses encoding UL48(DeltaDUB/NLS), which lacks the DUB domain and the adjacent nuclear localization signal (NLS), UL48(DeltaDUB), which lacks only the DUB, and UL48(Delta360-1200), which lacks the internal region (amino acids 360 to 1200) downstream of the DUB/NLS. While DeltaDUB/NLS and Delta360-1200 mutant viruses did not grow in fibroblasts, the DeltaDUB virus replicated to titers 100-fold lower than those for wild-type virus and showed substantially reduced viral gene expression at low multiplicities of infection. The DUB domain contained ubiquitination sites, and DUB activity reduced its own proteasomal degradation in trans. Deletion of the DUB domain did not affect the nuclear and cytoplasmic localization of pUL48, whereas the internal region (360-1200) was necessary for cytoplasmic distribution. In coimmunoprecipitation assays, pUL48 interacted with three tegument proteins (pUL47, pUL45, and pUL88) and two capsid proteins (pUL77 and pUL85) but the DUB domain contributed to only pUL85 binding. Furthermore, we found that the DeltaDUB virus showed reduced virion stability and less efficiently delivered its genome into the cell than the wild-type virus. Collectively, our results demonstrate that the N-terminal DUB domain of pUL48 contributes to efficient viral growth by regulating its own stability and promoting virion stabilization and virus entry. IMPORTANCE: HCMV pUL48 and its herpesvirus homologs play key roles in virus entry, regulation of immune signaling pathways, and virion assembly. The N terminus of pUL48 contains the DUB domain, which is well conserved among all herpesviruses. Although studies using the active-site mutant viruses revealed that the DUB activity promotes viral growth, the exact role of this region in the viral life cycle is not fully understood. In this study, using the mutant virus lacking the entire DUB domain, we demonstrate that the DUB domain of pUL48 contributes to viral growth by regulating its own stability via autodeubiquitination and promoting virion stability and virus entry. This report is the first to demonstrate the characteristics of the mutant virus with the entire DUB domain deleted, which, along with information on the functions of this region, is useful in dissecting the functions associated with pUL48. PMID- 26764007 TI - TRIM5alpha Degradation via Autophagy Is Not Required for Retroviral Restriction. AB - TRIM5alpha is an interferon-inducible retroviral restriction factor that prevents infection by inducing the abortive disassembly of capsid cores recognized by its C-terminal PRY/SPRY domain. The mechanism by which TRIM5alpha mediates the disassembly of viral cores is poorly understood. Previous studies demonstrated that proteasome inhibitors abrogate the ability of TRIM5alpha to induce premature core disassembly and prevent reverse transcription; however, viral infection is still inhibited, indicating that the proteasome is partially involved in the restriction process. Alternatively, we and others have observed that TRIM5alpha associates with proteins involved in autophagic degradation pathways, and one recent study found that autophagic degradation is required for the restriction of retroviruses by TRIM5alpha. Here, we show that TRIM5alpha is basally degraded via autophagy in the absence of restriction-sensitive virus. We observe that the autophagy markers LC3b and lysosome-associated membrane protein 2A (LAMP2A) localize to a subset of TRIM5alpha cytoplasmic bodies, and inhibition of lysosomal degradation with bafilomycin A1 increases this association. To test the requirement for macroautophagy in restriction, we examined the ability of TRIM5alpha to restrict retroviral infection in cells depleted of the autophagic mediators ATG5, Beclin1, and p62. In all cases, restriction of retroviruses by human TRIM5alpha, rhesus macaque TRIM5alpha, and owl monkey TRIM-Cyp remained potent in cells depleted of these autophagic effectors by small interfering RNA (siRNA) knockdown or clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 genome editing. Collectively, these results are consistent with observations that the turnover of TRIM5alpha proteins is sensitive to autophagy inhibition; however, the data presented here do not support observations that the inhibition of autophagy abrogates retroviral restriction by TRIM5 proteins. IMPORTANCE: Restriction factors are a class of proteins that inhibit viral replication. Following fusion of a retrovirus with a host cell membrane, the retroviral capsid is released into the cytoplasm of the target cell. TRIM5alpha inhibits retroviral infection by promoting the abortive disassembly of incoming retroviral capsid cores; as a result, the retroviral genome is unable to traffic to the nucleus, and the viral life cycle is extinguished. In the process of restriction, TRIM5alpha itself is degraded by the proteasome. However, in the present study, we have shown that in the absence of a restriction-sensitive virus, TRIM5alpha is degraded by both proteasomal and autophagic degradation pathways. Notably, we observed that restriction of retroviruses by TRIM5alpha does not require autophagic machinery. These data indicate that the effector functions of TRIM5alpha can be separated from its degradation and may have further implications for understanding the mechanisms of other TRIM family members. PMID- 26764009 TI - Influenza A Viruses Expressing Intra- or Intergroup Chimeric Hemagglutinins. AB - A panel of influenza A viruses expressing chimeric hemagglutinins (cHA) with intragroup or intergroup head/stalk combinations was generated. Viruses were characterized for growth kinetics and preservation of stalk epitopes. With a few notable exceptions, cHA viruses behaved similarly to wild-type viruses and maintained stalk epitopes, which indicated their potential as vaccine candidates to induce stalk-specific antibodies. PMID- 26764008 TI - Morphological, Biochemical, and Functional Study of Viral Replication Compartments Isolated from Adenovirus-Infected Cells. AB - Adenovirus (Ad) replication compartments (RC) are nuclear microenvironments where the viral genome is replicated and a coordinated program of late gene expression is established. These virus-induced nuclear sites seem to behave as central hubs for the regulation of virus-host cell interactions, since proteins that promote efficient viral replication as well as factors that participate in the antiviral response are coopted and concentrated there. To gain further insight into the activities of viral RC, here we report, for the first time, the morphology, composition, and activities of RC isolated from Ad-infected cells. Morphological analyses of isolated RC particles by superresolution microscopy showed that they were indistinguishable from RC within infected cells and that they displayed a dynamic compartmentalization. Furthermore, the RC-containing fractions (RCf) proved to be functional, as they directed de novo synthesis of viral DNA and RNA as well as RNA splicing, activities that are associated with RC in vivo. A detailed analysis of the production of viral late mRNA from RCf at different times postinfection revealed that viral mRNA splicing occurs in RC and that the synthesis, posttranscriptional processing, and release from RC to the nucleoplasm of individual viral late transcripts are spatiotemporally separate events. The results presented here demonstrate that RCf are a powerful system for detailed study into RC structure, composition, and activities and, as a result, the determination of the molecular mechanisms that induce the formation of these viral sites of adenoviruses and other nuclear-replicating viruses. IMPORTANCE: RC may represent molecular hubs where many aspects of virus-host cell interaction are controlled. Here, we show by superresolution microscopy that RCf have morphologies similar to those of RC within Ad-infected cells and that they appear to be compartmentalized, as nucleolin and DBP display different localization in the periphery of these viral sites. RCf proved to be functional, as they direct de novo synthesis of viral DNA and mRNA, allowing the detailed study of the regulation of viral genome replication and expression. Furthermore, we show that the synthesis and splicing of individual viral late mRNA occurs in RC and that they are subject to different temporal patterns of regulation, from their synthesis to their splicing and release from RC to the nucleoplasm. Hence, RCf represent a novel system to study molecular mechanisms that are orchestrated in viral RC to take control of the infected cell and promote an efficient viral replication cycle. PMID- 26764010 TI - Proteomic Analysis of Epithelial to Mesenchymal Transition (EMT) Reveals Cross talk between SNAIL and HDAC1 Proteins in Breast Cancer Cells. AB - Epithelial to mesenchymal transition (EMT)(1) occurs naturally during embryogenesis, tissue repair, cancer progression, and metastasis. EMT induces cellular and microenvironmental changes resulting in loss of epithelial and acquisition of mesenchymal phenotypes, which promotes cellular invasive and migratory capabilities. EMT can be triggered by extracellular factors, including TGF-beta, HGF, and EGF. Overexpression of transcription factors, such as SNAIL, SLUG, ZEB1/2, and TWIST1, also induces EMT and is correlated to cancer aggressiveness. Here, the breast adenocarcinoma cell line MCF7 was transduced with SNAIL to identify specific mechanisms controlled by this transcription factor during EMT. Overexpression of SNAIL led to EMT, which was thoroughly validated by molecular, morphological, and functional experiments. Subcellular proteome enrichment followed by GEL-LC-MS/MS was performed to provide extensive protein fractionation and in-depth proteomic analysis. Quantitative analysis relied on a SILAC strategy, using the invasive breast cancer cell line MDA-MB-231 as a reference for quantitation. Subsets of proteins enriched in each subcellular compartment led to a complementary list of 4289 proteins identified with high confidence. A subset of differentially expressed proteins was validated by Western blot, including regulation in specific cellular compartments, potentially caused by protein translocation. Protein network analysis highlighted complexes involved in cell cycle control and epigenetic regulation. Flow cytometry analysis indicated that SNAIL overexpression led to cell cycle arrest in G0/G1 phases. Furthermore, down-regulation of HDAC1 was observed, supporting the involvement of epigenetic processes in SNAIL-induced EMT. When HDAC1 activity was inhibited, MCF7 not only apparently initiated EMT but also up-regulated SNAIL, indicating the cross-talk between these two proteins. Both HDAC1 inhibition and SNAIL overexpression activated the AKT pathway. These molecular mechanisms appear to be essential to EMT and therefore for cancer metastasis. Specific control of such epigenetic processes might then represent effective approaches for clinical management of metastatic cancer. PMID- 26764013 TI - Teaching mandibular implant-Supported overdentures in dental schools in North America - a survey. AB - INTRODUCTION: Mandibular two-implant overdentures are considered the minimum standard of care for edentulous patients and provide an excellent performance, as well as satisfaction to the patients. Dental schools are required to promote the teaching of current treatment options in order to enable students to master state of-the-art procedures. AIMS: The purpose of this study was to examine how the theoretical and practical aspects of mandibular two-implant overdentures are taught in dental schools in North America. METHODS: Data were collected via an online questionnaire that included questions regarding the theoretical and clinical courses, surgical procedure and imaging method. RESULTS: Of 75 schools, 36 responded to the survey. Almost all the schools teach the subject theoretically, but it is not mandatory for students to perform in most of the schools. Only a minority (23%) of the mandibular dentures made by students are implant-supported. Almost all of the schools (94%) use two implants to support overdentures, and Locator abutment is used almost exclusively. The prevalent imaging for the surgical procedure is CT scans, although 30% of the schools use panoramic radiograph. None of the schools loads the implants immediately after surgery. CONCLUSION: Some clear trends are apparent in the current survey: the use of two implants, no use of bar connectors and delayed loading of the implants. It is likely that graduates will not have sufficient clinical skills and will need continuing education to be familiar with the required procedures, both surgical and prosthetic. PMID- 26764011 TI - Mapping the O-Mannose Glycoproteome in Saccharomyces cerevisiae. AB - O-Mannosylation is a vital protein modification conserved from fungi to humans. Yeast is a perfect model to study this post-translational modification, because in contrast to mammalsO-mannosylation is the only type ofO-glycosylation. In an essential step toward the full understanding of proteinO-mannosylation we mapped theO-mannose glycoproteome in baker's yeast. Taking advantage of anO-glycan elongation deficient yeast strain to simplify sample complexity, we identified over 500O-glycoproteins from all subcellular compartments for which over 2300O mannosylation sites were mapped by electron-transfer dissociation (ETD)-based MS/MS. In this study, we focus on the 293O-glycoproteins (over 1900 glycosylation sites identified by ETD-MS/MS) that enter the secretory pathway and are targets of ER-localized proteinO-mannosyltransferases. We find thatO-mannosylation is not only a prominent modification of cell wall and plasma membrane proteins, but also of a large number of proteins from the secretory pathway with crucial functions in protein glycosylation, folding, quality control, and trafficking. The analysis of glycosylation sites revealed thatO-mannosylation is favored in unstructured regions and beta-strands. Furthermore,O-mannosylation is impeded in the proximity ofN-glycosylation sites suggesting the interplay of these types of post translational modifications. The detailed knowledge of the target proteins and theirO-mannosylation sites opens for discovery of new roles of this essential modification in eukaryotes, and for a first glance on the evolution of different types ofO-glycosylation from yeast to mammals. PMID- 26764012 TI - Sampling From the Proteome to the Human Leukocyte Antigen-DR (HLA-DR) Ligandome Proceeds Via High Specificity. AB - Comprehensive analysis of the complex nature of the Human Leukocyte Antigen (HLA) class II ligandome is of utmost importance to understand the basis for CD4(+)T cell mediated immunity and tolerance. Here, we implemented important improvements in the analysis of the repertoire of HLA-DR-presented peptides, using hybrid mass spectrometry-based peptide fragmentation techniques on a ligandome sample isolated from matured human monocyte-derived dendritic cells (DC). The reported data set constitutes nearly 14 thousand unique high-confident peptides,i.e.the largest single inventory of human DC derived HLA-DR ligands to date. From a technical viewpoint the most prominent finding is that no single peptide fragmentation technique could elucidate the majority of HLA-DR ligands, because of the wide range of physical chemical properties displayed by the HLA-DR ligandome. Our in-depth profiling allowed us to reveal a strikingly poor correlation between the source proteins identified in the HLA class II ligandome and the DC cellular proteome. Important selective sieving from the sampled proteome to the ligandome was evidenced by specificity in the sequences of the core regions both at their N- and C- termini, hence not only reflecting binding motifs but also dominant protease activity associated to the endolysosomal compartments. Moreover, we demonstrate that the HLA-DR ligandome reflects a surface representation of cell-compartments specific for biological events linked to the maturation of monocytes into antigen presenting cells. Our results present new perspectives into the complex nature of the HLA class II system and will aid future immunological studies in characterizing the full breadth of potential CD4(+)T cell epitopes relevant in health and disease. PMID- 26764014 TI - Incidence and predictors of early adulthood pre-diabetes/type 2 diabetes, among Iranian adolescents: the Tehran Lipid and Glucose Study. AB - PURPOSE: To evaluate the incidence and predictors of early adulthood pre diabetes/type 2 diabetes (T2D) among Iranian adolescents during a median follow up of 9.2 yr. METHOD: A total of 2563 subjects aged 10-19 yr, without pre diabetes/T2D at baseline, were entered in the study. Pre-diabetes was defined as those with fasting plasma glucose (FPG) 5.6 to <7 mmol/L. T2D was defined as anti T2D drug consumption or FPG >=7 mmol/L. Multivariate Cox-proportional analysis was applied to examine the association between different risk factors that showed attained statistical significance < 0.2 in univariate analysis, with incident pre diabetes/T2D. Same method was repeated on 1803 subjects with complete parental data to find the relation between parental risk factors and pre-diabetes/T2D. RESULT: The mean age of participants was 14.45 +/- 2.78 yr, and 53.6% were female. During follow-up 208 cases of pre-diabetes/T2D occurred, resulting in an incidence rate of 9.61 per 1000 person-years. Multivariate-adjusted hazard ratios (HRs) for incident pre-diabetes/T2D showed significant risk for 1 standard deviation increase in FPG and body mass index with corresponding HR of 1.89 (1.6 2.23) and 1.435 (1.080-1.905), respectively. Among parental potential risk factors, the paternal history of T2D was independently associated with increased risk for pre-diabetes/T2D in the adolescence (HR = 1.63(1.02-2.60)). CONCLUSION: About 1% of Iranian adolescents developed pre-diabetes/T2D each year. Among the non-modifiable risk factors paternal history of T2D and, among modifiable risk factors, the presence of general adiposity as well as the higher level of FPG should be considered among adolescents for development of pre-diabetes/T2D later in the young adulthood. PMID- 26764016 TI - Posterior reversible encephalopathy syndrome complicating diabetic ketoacidosis; an important treatable complication. AB - Development of acute neurological symptoms secondary to cerebral oedema is well described in diabetic ketoacidosis (DKA) and often has a poor prognosis. We present the clinical and radiological data of a 17-yr-old girl who developed cortical blindness, progressive encephalopathy, and seizures caused by posterior reversible encephalopathy syndrome (PRES) that developed after her DKA had resolved. Vasogenic oedema in PRES resolves if the underlying trigger is identified and eliminated. In this case, hypertension was identified as the likely precipitating factor and following treatment her vision and neurological symptoms rapidly improved. We suggest how recent DKA may have contributed to the development of PRES in this patient. PMID- 26764018 TI - Light-Directed Dynamic Chirality Inversion in Functional Self-Organized Helical Superstructures. AB - Helical superstructures are widely observed in nature, in synthetic polymers, and in supramolecular assemblies. Controlling the chirality (the handedness) of dynamic helical superstructures of molecular and macromolecular systems by external stimuli is a challenging task, but is of great fundamental significance with appealing morphology-dependent applications. Light-driven chirality inversion in self-organized helical superstructures (i.e. cholesteric, chiral nematic liquid crystals) is currently in the limelight because inversion of the handedness alters the chirality of the circularly polarized light that they selectively reflect, which has wide potential for application. Here we discuss the recent developments toward inversion of the handedness of cholesteric liquid crystals enabled by photoisomerizable chiral molecular switches or motors. Different classes of chiral photoresponsive dopants (guests) capable of conferring light-driven reversible chirality inversion of helical superstructures fabricated from different nematic hosts are discussed. Rational molecular designs of chiral molecular switches toward endowing handedness inversion to the induced helical superstructures of cholesteric liquid crystals are highlighted. This Review is concluded by throwing light on the challenges and opportunities in this emerging frontier, and it is expected to provide useful guidelines toward the development of self-organized soft materials with stimuli-directed chirality inversion capability and multifunctional host-guest systems. PMID- 26764019 TI - Catalytic Enantioselective Functionalization of Unactivated Terminal Alkenes. AB - Terminal alkenes are readily available functional groups which appear in alpha olefins produced by the chemical industry, and they appear in the products of many contemporary synthetic reactions. While the organic transformations that apply to alkenes are amongst the most studied reactions in all of chemical synthesis, the number of reactions that apply to nonactivated terminal alkenes in a catalytic enantioselective fashion is small in number. This Minireview highlights the cases where stereocontrol in catalytic reactions of 1-alkenes is high enough to be useful for asymmetric synthesis. PMID- 26764020 TI - cnvScan: a CNV screening and annotation tool to improve the clinical utility of computational CNV prediction from exome sequencing data. AB - BACKGROUND: With advances in next generation sequencing technology and analysis methods, single nucleotide variants (SNVs) and indels can be detected with high sensitivity and specificity in exome sequencing data. Recent studies have demonstrated the ability to detect disease-causing copy number variants (CNVs) in exome sequencing data. However, exonic CNV prediction programs have shown high false positive CNV counts, which is the major limiting factor for the applicability of these programs in clinical studies. RESULTS: We have developed a tool (cnvScan) to improve the clinical utility of computational CNV prediction in exome data. cnvScan can accept input from any CNV prediction program. cnvScan consists of two steps: CNV screening and CNV annotation. CNV screening evaluates CNV prediction using quality scores and refines this using an in-house CNV database, which greatly reduces the false positive rate. The annotation step provides functionally and clinically relevant information using multiple source datasets. We assessed the performance of cnvScan on CNV predictions from five different prediction programs using 64 exomes from Primary Immunodeficiency (PIDD) patients, and identified PIDD-causing CNVs in three individuals from two different families. CONCLUSIONS: In summary, cnvScan reduces the time and effort required to detect disease-causing CNVs by reducing the false positive count and providing annotation. This improves the clinical utility of CNV detection in exome data. PMID- 26764021 TI - Genomic and metagenomic analysis of microbes in a soil environment affected by the 2011 Great East Japan Earthquake tsunami. AB - BACKGROUND: The Great East Japan Earthquake of 2011 triggered large tsunami waves, which flooded broad areas of land along the Pacific coast of eastern Japan and changed the soil environment drastically. However, the microbial characteristics of tsunami-affected soil at the genomic level remain largely unknown. In this study, we isolated microbes from a soil sample using general low nutrient and seawater-based media to investigate microbial characteristics in tsunami-affected soil. RESULTS: As expected, a greater proportion of strains isolated from the tsunami-affected soil than the unaffected soil grew in the seawater-based medium. Cultivable strains in both the general low-nutrient and seawater-based media were distributed in the genus Arthrobacter. Most importantly, whole-genome sequencing of four of the isolated Arthrobacter strains revealed independent losses of siderophore-synthesis genes from their genomes. Siderophores are low-molecular-weight, iron-chelating compounds that are secreted for iron uptake; thus, the loss of siderophore-synthesis genes indicates that these strains have adapted to environments with high-iron concentrations. Indeed, chemical analysis confirmed the investigated soil samples to be rich in iron, and culture experiments confirmed weak cultivability of some of these strains in iron limited media. Furthermore, metagenomic analyses demonstrated over-representation of denitrification-related genes in the tsunami-affected soil sample, as well as the presence of pathogenic and marine-living genera and genes related to salt tolerance. CONCLUSIONS: Collectively, the present results would provide an example of microbial characteristics of soil disturbed by the tsunami, which may give an insight into microbial adaptation to drastic environmental changes. Further analyses on microbial ecology after a tsunami are envisioned to develop a deeper understanding of the recovery processes of terrestrial microbial ecosystems. PMID- 26764017 TI - Bacterial Transcription as a Target for Antibacterial Drug Development. AB - Transcription, the first step of gene expression, is carried out by the enzyme RNA polymerase (RNAP) and is regulated through interaction with a series of protein transcription factors. RNAP and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. Despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. The determination of the three-dimensional structures of RNAP and transcription complexes at high resolution over the last 15 years has led to renewed interest in targeting this essential process for antibiotic development by utilizing rational structure-based approaches. In this review, we describe the inhibition of the bacterial transcription process with respect to structural studies of RNAP, highlight recent progress toward the discovery of novel transcription inhibitors, and suggest additional potential antibacterial targets for rational drug design. PMID- 26764023 TI - Modulation of apoptosis and viral latency - an axis to be well understood for successful cure of human immunodeficiency virus. AB - Human immunodeficiency virus (HIV) is the causative agent of the deadly disease AIDS, which is characterized by the progressive decline of CD4(+)T-cells. HIV-1 encoded proteins such as envelope gp120 (glycoprotein gp120), Tat (trans activator of transcription), Nef (negative regulatory factor), Vpr (viral protein R), Vpu (viral protein unique) and protease are known to be effective in modulating host cell signalling pathways that lead to an alteration in apoptosis of both HIV-infected and uninfected bystander cells. Depending on the stage of the virus life cycle and host cell type, these viral proteins act as mediators of pro- or anti-apoptotic signals. HIV latency in viral reservoirs is a persistent phenomenon that has remained beyond the control of the human immune system. To cure HIV infections completely, it is crucial to reactivate latent HIV from cellular pools and to drive these apoptosis-resistant cells towards death. Several previous studies have reported the role of HIV-encoded proteins in apoptosis modulation, but the molecular basis for apoptosis evasion of some chronically HIV-infected cells and reactivated latently HIV-infected cells still needs to be elucidated. The current review summarizes our present understanding of apoptosis modulation in HIV-infected cells, uninfected bystander cells and latently infected cells, with a focus on highlighting strategies to activate the apoptotic pathway to kill latently infected cells. PMID- 26764022 TI - Pateamine A-sensitive ribosome profiling reveals the scope of translation in mouse embryonic stem cells. AB - BACKGROUND: Open reading frames are common in long noncoding RNAs (lncRNAs) and 5'UTRs of protein coding transcripts (uORFs). The question of whether those ORFs are translated was recently addressed by several groups using ribosome profiling. Most of those studies concluded that certain lncRNAs and uORFs are translated, essentially based on computational analysis of ribosome footprints. However, major discrepancies remain on the scope of translation and the translational status of individual ORFs. In consequence, further criteria are required to reliably identify translated ORFs from ribosome profiling data. RESULTS: We examined the effect of the translation inhibitors pateamine A, harringtonine and puromycin on murine ES cell ribosome footprints. We found that pateamine A, a drug that targets eIF4A, allows a far more accurate identification of translated sequences than previously used drugs and computational scoring schemes. Our data show that at least one third but less than two thirds of ES cell lncRNAs are translated. We also identified translated uORFs in hundreds of annotated coding transcripts including key pluripotency transcripts, such as dicer, lin28, trim71, and ctcf. CONCLUSION: Pateamine A inhibition data clearly increase the precision of the detection of translated ORFs in ribosome profiling experiments. Our data show that translation of lncRNAs and uORFs in murine ES cells is rather common although less pervasive than previously suggested. The observation of translated uORFs in several key pluripotency transcripts suggests that translational regulation by uORFs might be part of the network that defines mammalian stem cell identity. PMID- 26764024 TI - Helicobacter pullorum induces nitric oxide release in murine macrophages that promotes phagocytosis and killing. AB - Helicobacter pullorum is an avian enterohepatic species that, more recently, has also been found as a naturally acquired infection in mice and rats, and isolated from patients with gastrointestinal and hepatobiliary diseases. In this work, the interaction between H. pullorum and murine macrophages was examined. Firstly, the impact of nitric oxide, which is an antimicrobial produced by mammalian macrophages, on H. pullorum 6350-92 viability and morphology was studied by colony-forming assays and light microscopy, respectively. Exposure to nitric oxide lowered H. pullorum viability, in a growth-phase-dependent manner, and decreased the mean cell size. However, the number of coccoid forms remained low, contrasting with what has been observed for other Helicobacter species. Confocal microscopy showed that H. pullorum is internalized by murine macrophages, triggering nitric oxide production that promotes phagocytosis and killing of the pathogen. Interaction between H. pullorum and macrophages stimulated secretion of pro-inflammatory cytokines, such as TNF-alpha, IL-1beta, IL-6 and MIP-2. These results show that H. pullorum is able to infect mammalian murine cells triggering an inflammatory response. PMID- 26764025 TI - Mandibular dysfunction as a reflection of bulbar involvement in SMA type 2 and 3. AB - OBJECTIVE: In a cross-sectional study, we aimed to determine (1) the effect of spinal muscular atrophy (SMA) type 2 and 3 on mandibular function reflected as masticatory performance, mandibular range of motion, and bite force and (2) the predictors of mandibular dysfunction. METHODS: Sixty patients with SMA type 2 and 3 (mean age 32.3 years, SD 17.4 years) and 60 age-matched controls filled out questionnaires about impairments of mandibular function. All participants underwent detailed clinical examination to document the mandibular range of motion including maximal mouth opening, bite force, and masticatory function. RESULTS: All mandibular movements, including mouth opening, lateral range of motion, and protrusion of the mandible, were reduced in patients with SMA type 2 and 3 compared to healthy controls (p < 0.001). Maximal bite force was 19% lower in patients than controls, and more in patients with SMA type 2 than type 3. The strongest predictive factor was SMA type for impairment of mandibular range of motion (R(2) = 0.82) and weakness of neck muscles for bite force (R(2) = 0.47). CONCLUSIONS: Reduced mandibular mobility and bite force are common complications in SMA. SMA type and neck muscle strength are important correlates of these complications. We provide further evidence for clinically relevant bulbar involvement in patients with SMA. PMID- 26764026 TI - Early- vs late-onset subcortical vascular cognitive impairment. AB - OBJECTIVE: To evaluate the differences between early-onset subcortical vascular cognitive impairment (EO-SVCI) and late-onset subcortical vascular cognitive impairment (LO-SVCI) with regard to pathologic burden, structural changes, and cognitive function. METHODS: We prospectively recruited 142 patients from a single referral center. Patients were divided into EO-SVCI (n = 30, age at onset <65 years) and LO-SVCI (n = 112, age at onset >= 65 years) groups. All patients underwent neuropsychological tests, 3T brain MRI, and [(11)C] Pittsburgh compound B (PiB)-PET. We compared pathologic burden such as small vessel disease and amyloid burden; structural changes such as structural network, cortical thickness, and hippocampal volume; and cognitive function between EO-SVCI and LO SVCI. RESULTS: EO-SVCI patients had more lacunes, while LO-SVCI patients had higher PiB standardized uptake value ratios. EO-SVCI patients exhibited more severe structural network disruptions in the frontal area, while LO-SVCI patients exhibited more severe cortical and hippocampal atrophy. Although disease severity did not differ between the 2 groups, frontal-executive dysfunction was more severe in EO-SVCI patients. CONCLUSIONS: EO-SVCI patients showed more vascular related factors, while LO-SVCI patients exhibited more Alzheimer disease-related characteristics. The greater number of lacunes in EO-SVCI might account for the more severe frontal network disruption and frontal-executive dysfunction, while the greater amyloid burden in LO-SVCI might account for the more severe cortical and hippocampal atrophy. Our findings suggest that the age at onset is a crucial factor that determines distinct features in SVCI patients, such as pathologic burden, structural changes, and cognitive function. PMID- 26764027 TI - A nonsense mutation in CHCHD2 in a patient with Parkinson disease. PMID- 26764028 TI - Accuracy of clinical diagnosis of Parkinson disease: A systematic review and meta analysis. AB - OBJECTIVE: To evaluate the diagnostic accuracy of clinical diagnosis of Parkinson disease (PD) reported in the last 25 years by a systematic review and meta analysis. METHODS: We searched for articles published between 1988 and August 2014. Studies were included if reporting diagnostic parameters regarding clinical diagnosis of PD or crude data. The selected studies were subclassified based on different study setting, type of test diagnosis, and gold standard. Bayesian meta analyses of available data were performed. RESULTS: We selected 20 studies, including 11 using pathologic examination as gold standard. Considering only these 11 studies, the pooled diagnostic accuracy was 80.6% (95% credible interval [CrI] 75.2%-85.3%). Accuracy was 73.8% (95% CrI 67.8%-79.6%) for clinical diagnosis performed mainly by nonexperts. Accuracy of clinical diagnosis performed by movement disorders experts rose from 79.6% (95% CrI 46%-95.1%) of initial assessment to 83.9% (95% CrI 69.7%-92.6%) of refined diagnosis after follow-up. Using UK Parkinson's Disease Society Brain Bank Research Center criteria, the pooled diagnostic accuracy was 82.7% (95% CrI 62.6%-93%). CONCLUSION: The overall validity of clinical diagnosis of PD is not satisfying. The accuracy did not significantly improve in the last 25 years, particularly in the early stages of disease, where response to dopaminergic treatment is less defined and hallmarks of alternative diagnoses such as atypical parkinsonism may not have emerged. Misclassification rate should be considered to calculate the sample size both in observational studies and randomized controlled trials. Imaging and biomarkers are urgently needed to improve the accuracy of clinical diagnosis in vivo. PMID- 26764030 TI - Whole-brain MRI phenotyping in dysplasia-related frontal lobe epilepsy. AB - OBJECTIVE: To perform whole-brain morphometry in patients with frontal lobe epilepsy and evaluate the utility of group-level patterns for individualized diagnosis and prognosis. METHODS: We compared MRI-based cortical thickness and folding complexity between 2 frontal lobe epilepsy cohorts with histologically verified focal cortical dysplasia (FCD) (13 type I; 28 type II) and 41 closely matched controls. Pattern learning algorithms evaluated the utility of group level findings to predict histologic FCD subtype, the side of the seizure focus, and postsurgical seizure outcome in single individuals. RESULTS: Relative to controls, FCD type I displayed multilobar cortical thinning that was most marked in ipsilateral frontal cortices. Conversely, type II showed thickening in temporal and postcentral cortices. Cortical folding also diverged, with increased complexity in prefrontal cortices in type I and decreases in type II. Group-level findings successfully guided automated FCD subtype classification (type I: 100%; type II: 96%), seizure focus lateralization (type I: 92%; type II: 86%), and outcome prediction (type I: 92%; type II: 82%). CONCLUSION: FCD subtypes relate to diverse whole-brain structural phenotypes. While cortical thickening in type II may indicate delayed pruning, a thin cortex in type I likely results from combined effects of seizure excitotoxicity and the primary malformation. Group level patterns have a high translational value in guiding individualized diagnostics. PMID- 26764032 TI - Comment: Whole-brain structural changes in extratemporal, nonlesional epilepsy. PMID- 26764031 TI - Time for a new March of Dimes. PMID- 26764029 TI - Prospective study of plasma urate and risk of Parkinson disease in men and women. AB - OBJECTIVE: To examine whether higher plasma urate concentrations are associated with a lower risk of developing Parkinson disease (PD) and whether there is a sex difference in the potential urate-PD relationship. METHODS: We conducted a nested case-control study based on 90,214 participants of 3 ongoing US cohorts. We identified 388 new PD cases (202 men and 186 women) since blood collection, which were then matched to 1,267 controls. PD cases were confirmed by medical record review. Conditional logistic regression estimated relative risks (RRs) and 95% confidence intervals (95% CIs), after adjustment for age, smoking, caffeine intake, plasma concentrations of cholesterol and ferritin, and other covariates. We also conducted a meta-analysis to combine our study with 3 previously published prospective studies on urate and PD risk. RESULTS: In the present nested case-control study, the multivariate-adjusted RRs of PD comparing extreme quartiles of urate were 0.63 (95% CI 0.35, 1.10; ptrend = 0.049) in men and 1.04 (95% CI 0.61, 1.78; ptrend = 0.44) in women (pheterogeneity = 0.001). In the meta analysis, the pooled RRs comparing 2 extreme quartiles of urate were 0.63 (95% CI 0.42, 0.95) in men and 0.89 (95% CI 0.57, 1.40) in women. CONCLUSION: We observed that men, but not women, with higher urate concentrations had a lower future risk of developing PD, suggesting that urate could be protective against PD risk or could slow disease progression during the preclinical stage of disease. PMID- 26764033 TI - The Neonatal CD8+ T Cell Repertoire Rapidly Diversifies during Persistent Viral Infection. AB - CMV is the most common congenital infection in the United States. The major target of congenital CMV is the brain, with clinical manifestations including mental retardation, vision impairment, and sensorineural hearing loss. Previous reports have shown that CD8(+) T cells are required to control viral replication and significant numbers of CMV-specific CD8(+) T cells persist in the brain even after the initial infection has been cleared. However, the dynamics of CD8(+) T cells in the brain during latency remain largely undefined. In this report, we used TCR sequencing to track the development and maintenance of neonatal clonotypes in the brain and spleen of mice during chronic infection. Given the discontinuous nature of tissue-resident memory CD8(+) T cells, we hypothesized that neonatal TCR clonotypes would be locked in the brain and persist into adulthood. Surprisingly, we found that the Ag-specific T cell repertoire in neonatal-infected mice diversified during persistent infection in both the brain and spleen, while maintaining substantial similarity between the CD8(+) T cell populations in the brain and spleen in both early and late infection. However, despite the diversification of, and potential interchange between, the spleen and brain Ag-specific T cell repertoires, we observed that germline-encoded TCR clonotypes, characteristic of neonatal infection, persisted in the brain, albeit sometimes in low abundance. These results provide valuable insights into the evolution of CD8(+) T cell repertoires following neonatal CMV infection and thus have important implications for the development of therapeutic strategies to control CMV in early life. PMID- 26764035 TI - Autoreactive CD19+CD20- Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis. AB - The contribution of autoantibody-producing plasma cells in multiple sclerosis (MS) remains unclear. Anti-CD20 B cell depletion effectively reduces disease activity in MS patients, but it has a minimal effect on circulating autoantibodies and oligoclonal bands in the cerebrospinal fluid. Recently we reported that MEDI551, an anti-CD19 mAb, therapeutically ameliorates experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. MEDI551 potently inhibits pathogenic adaptive immune responses, including depleting autoantibody producing plasma cells. In the present study, we demonstrated that CD19 mAb treatment ameliorates EAE more effectively than does CD20 mAb. Myelin oligodendrocyte glycoprotein-specific Abs and short-lived and long-lived autoantibody-secreting cells were nearly undetectable in the CD19 mAb-treated mice, but they remained detectable in the CD20 mAb-treated mice. Interestingly, residual disease severity in the CD20 mAb-treated animals positively correlated with the frequency of treatment-resistant plasma cells in the bone marrow. Of note, treatment-resistant plasma cells contained a substantial proportion of CD19(+)CD20(-) plasma cells, which would have otherwise been targeted by CD19 mAb. These data suggested that CD19(+)CD20(-) plasma cells spared by anti-CD20 therapy likely contribute to residual EAE severity by producing autoreactive Abs. In patients with MS, we also identified a population of CD19(+)CD20(-) B cells in the cerebrospinal fluid that would be resistant to CD20 mAb treatment. PMID- 26764034 TI - Memory Stem T Cells in Autoimmune Disease: High Frequency of Circulating CD8+ Memory Stem Cells in Acquired Aplastic Anemia. AB - Memory stem T cells (TSCMs) constitute a long-lived, self-renewing lymphocyte population essential for the maintenance of functional immunity. Hallmarks of autoimmune disease pathogenesis are abnormal CD4(+) and CD8(+) T cell activation. We investigated the TSCM subset in 55, 34, 43, and 5 patients with acquired aplastic anemia (AA), autoimmune uveitis, systemic lupus erythematosus, and sickle cell disease, respectively, as well as in 41 age-matched healthy controls. CD8(+) TSCM frequency was significantly increased in AA compared with healthy controls. An increased CD8(+) TSCM frequency at diagnosis was associated with responsiveness to immunosuppressive therapy, and an elevated CD8(+) TSCM population after immunosuppressive therapy correlated with treatment failure or relapse in AA patients. IFN-gamma and IL-2 production was significantly increased in various CD8(+) and CD4(+) T cell subsets in AA patients, including CD8(+) and CD4(+) TSCMs. CD8(+) TSCM frequency was also increased in patients with autoimmune uveitis or sickle cell disease. A positive correlation between CD4(+) and CD8(+) TSCM frequencies was found in AA, autoimmune uveitis, and systemic lupus erythematosus. Evaluation of PD-1, CD160, and CD244 expression revealed that TSCMs were less exhausted compared with other types of memory T cells. Our results suggest that the CD8(+) TSCM subset is a novel biomarker and a potential therapeutic target for AA. PMID- 26764037 TI - Structural Illumination of Equine MHC Class I Molecules Highlights Unconventional Epitope Presentation Manner That Is Evolved in Equine Leukocyte Antigen Alleles. AB - MHC class I (MHC I)-restricted virus-specific CTLs are implicated as critical components in the control of this naturally occurring lentivirus and in the protective immune response to the successfully applied attenuated equine infectious anemia virus vaccine in the horse. Nevertheless, the structural basis for how the equine MHC I presents epitope peptides remains unknown. In this study, we investigated the binding of several equine infectious anemia virus derived epitope peptides by the ability to refold recombinant molecules and by thermal stability, and then by determining the x-ray structure of five peptide MHC I complexes: equine MHC class I allele (Eqca)-N*00602/Env-RW12, Eqca N*00602/Gag-GW12, Eqca-N*00602/Rev-QW11, Eqca-N*00602/Gag-CF9, and Eqca N*00601/Gag-GW12. Although Eqca-N*00601 and Eqca-N*00602 differ by a single amino acid, Eqca-N*00601 exhibited a drastically different peptide presentation when binding a similar CTL epitope, Gag-GW12; the result makes the previously reported function clear to be non-cross-recognition between these two alleles. The structures plus Eqca-N*00602 complexed with a 9-mer peptide are particularly noteworthy in that we illuminated differences in apparent flexibility in the center of the epitope peptides for the complexes with Gag-GW12 as compared with Env-RW12, and a strict selection of epitope peptides with normal length. The featured preferences and unconventional presentations of long peptides by equine MHC I molecules provide structural bases to explain the exceptional anti lentivirus immunity in the horse. We think that the beneficial reference points could serve as an initial platform for other human or animal lentiviruses. PMID- 26764038 TI - Metastatic HPV-related head and neck squamous cell carcinoma to the lung and mediastinal lymph nodes in aspirated cytology material: A diagnostic pitfall. AB - BACKGROUND: Although HPV-related head and neck squamous cell carcinoma (HNSCC) has good prognosis, a small proportion of patients develop distant metastases and have worse outcomes. Such metastases can be particularly difficult to diagnose in the lung and mediastinum, where they show extensive morphologic overlap with primary pulmonary neoplasms. This case series discusses metastatic HPV-related HNSCC in lung and mediastinal fine needle aspiration (FNA) cytology. METHODS: The cytopathology archives were searched for lung and mediastinal FNA specimens of patients with HNSCC. Specimens were included if either the index FNA or the patient's original HNSCC was positive for HPV by DNA in-situ hybridization (ISH). Ten such cases were identified. Patient demographics and primary tumor details were tabulated from the electronic medical record. All FNA slides and stains were reviewed. RESULTS: The ten patients (mean age of 58.2 years) included 4 smokers. Smears from all cases were hypercellular and hyperchromatic, with focal keratinization in 6/10 (60%). Core biopsies and cell blocks showed basaloid morphology with variable amounts of necrosis. All ten FNAs were diffusely positive for p16 (100%) and 7/9 cases stained (77.8%) were positive for HPV DNA ISH. CONCLUSIONS: Metastatic HPV-related HNSCC to the lung and mediastinal lymph nodes share the characteristic basaloid, minimally keratinizing morphology seen in Primary HNSCC cytology. Poorly differentiated pulmonary squamous cell carcinoma and neuroendocrine carcinomas are the primary differentials. Although primary lung neoplasms are not HPV-related, p16 positivity can be seen in both squamous cell and small cell lung carcinomas. HPV ISH allows definitive diagnosis of metastatic HPV-related HNSCC. PMID- 26764036 TI - HIV-1 Env Glycoprotein Phenotype along with Immune Activation Determines CD4 T Cell Loss in HIV Patients. AB - The mechanism behind the selective depletion of CD4(+) cells in HIV infections remains undetermined. Although HIV selectively infects CD4(+) cells, the relatively few infected cells in vivo cannot account for the extent of CD4(+) T cell depletion, suggesting indirect or bystander mechanisms. The role of virus replication, Env glycoprotein phenotype, and immune activation (IA) in this bystander phenomenon remains controversial. Using samples derived from HIV infected patients, we demonstrate that, although IA in both CD4(+) and CD8(+) subsets correlates with CD4 decline, apoptosis in CD4(+) and not CD8(+) cells is associated with disease progression. Because HIV-1 Env glycoprotein has been implicated in bystander apoptosis, we cloned full-length Envs from plasma of viremic patients and tested their apoptosis-inducing potential (AIP). Interestingly, AIP of HIV-1 Env glycoproteins were found to correlate inversely with CD4:CD8 ratios, suggesting a role of Env phenotype in disease progression. In vitro mitogenic stimulation of PBMCs resulted in upregulation of IA markers but failed to alter the CD4:CD8 ratio. However, coculture of normal PBMCs with Env-expressing cells resulted in selective CD4 loss that was significantly enhanced by IA. Our study demonstrates that AIP of HIV-1 Env and IA collectively determine CD4 loss in HIV infection. PMID- 26764039 TI - Pulmonary nocardiosis in fine-needle aspiration cytology smears: Report of four cases. AB - Nocardia has been recognized as a significant opportunistic pathogen in organ transplant patients; however, it is an uncommon pathogen in immunocompetent patients. It may mimic other infectious diseases both clinically and radiologically. We report four cases of pulmonary nocardiosis in three immunocompromised and one immunocompetent patients on fine-needle aspiration cytology (FNAC). Two patients presented with lung consolidation while two had cavitatory lesions. FNAC smears showed inflammatory cells composed of polymorphs and histiocytes along with necrosis. Occasional epithelioid cell granuloma was seen in one case. Modified Ziehl-Neelsen (ZN) stain was performed which highlighted long slender filamentous branching organisms conforming to the morphology of Nocardia. Thus, a suspicion for nocardiosis should be kept while assessing cytologic material especially in immunocompromised individuals. The diagnosis can be confirmed by special stains and culture studies; however, a high index of clinical suspicion is required so that appropriate culture media can be used for high diagnostic yield. FNAC is of help in providing immediate and accurate diagnosis of nocardiosis, thus helping in appropriate medical management. PMID- 26764041 TI - Expecting a child: pregnancy in light of an ontological health model. AB - AIM: To make visible the existential character of pregnancy by searching for its health dimensions as it is described in the ontological health model. METHOD: Eight women were interviewed two or three times during their pregnancy and one time shortly after birth. The women have taken part in the routine programme that constitutes maternity care in Sweden. A hermeneutic approach inspired by Gadamer was used to analyse the data. An ontological health model was used to interpret the findings. FINDINGS: Nine themes on a rational and a contextual level were clustered to three themes on an existential level: A new life stage, The new life takes shape and Health is jeopardised. Contents of these themes were interpreted together with an ontological health model. Expecting a child means to do, be and become in expectation of the new life. Suffering and health are two different dimensions in a woman's life during pregnancy; they are integrated with one another and ever-present. It is in the meeting with the inevitable, life-changing gravidity and vulnerability that the integrative movement creates the new. Longing is the desire that provides motivation to continue. PMID- 26764040 TI - Associations of human retinal very long-chain polyunsaturated fatty acids with dietary lipid biomarkers. AB - The human retina is well-known to have unique lipid profiles enriched in long chain polyunsaturated fatty acids (LC-PUFAs) and very long-chain polyunsaturated fatty acids (VLC-PUFAs) that appear to promote normal retinal structure and function, but the influence of diet on retinal lipid profiles in health and disease remains controversial. In this study, we examined two independent cohorts of donor eyes and related their retinal lipid profiles with systemic biomarkers of lipid intake. We found that serum and red blood cell lipids, and to a lesser extent orbital fat, are indeed excellent biomarkers of retinal lipid content and n-3/n-6 ratios in both the LC-PUFA and VLC-PUFA series. Eyes from age-related macular degeneration (AMD) donors have significantly decreased levels of VLC PUFAs and low n-3/n-6 ratios. These results are consistent with the protective role of dietary n-3 LC-PUFAs against AMD and emphasize the importance of monitoring systemic biomarkers of lipid intake when undertaking clinical trials of lipid supplements for prevention and treatment of retinal disease. PMID- 26764043 TI - Granulocyte-colony stimulating factor induces disseminated intravascular coagulation in dormant acute promyelocytic leukemia. PMID- 26764042 TI - Host sphingomyelin increases West Nile virus infection in vivo. AB - Flaviviruses, such as the dengue virus and the West Nile virus (WNV), are arthropod-borne viruses that represent a global health problem. The flavivirus lifecycle is intimately connected to cellular lipids. Among the lipids co-opted by flaviviruses, we have focused on SM, an important component of cellular membranes particularly enriched in the nervous system. After infection with the neurotropic WNV, mice deficient in acid sphingomyelinase (ASM), which accumulate high levels of SM in their tissues, displayed exacerbated infection. In addition, WNV multiplication was enhanced in cells from human patients with Niemann-Pick type A, a disease caused by a deficiency of ASM activity resulting in SM accumulation. Furthermore, the addition of SM to cultured cells also increased WNV infection, whereas treatment with pharmacological inhibitors of SM synthesis reduced WNV infection. Confocal microscopy analyses confirmed the association of SM with viral replication sites within infected cells. Our results unveil that SM metabolism regulates flavivirus infection in vivo and propose SM as a suitable target for antiviral design against WNV. PMID- 26764045 TI - Prognostic impact of immunophenotypic complete response in patients with multiple myeloma achieving better than complete response. AB - To investigate the impact of immunophenotypic complete response [iCR, <=10(-4) multiple myeloma (MM) cells defined by multicolor flow cytometry (MFC)] on survival in patients with MM, we retrospectively analyzed 78 patients that obtained conventional CR at our hospital. Survivals were landmarked at achievement of CR. The rate of stringent CR (sCR) among patients with CR was 88%, and iCR for CR and sCR patients were 44% and 49%, respectively. Achievement of iCR was associated with significantly longer disease-free survival (DFS) not only in CR patients (p = 0.009) but also in sCR patients (p = 0.002), while sCR attainment per se did not have statistically significant impact on DFS (p = 0.06) or overall survival (OS) (p = 0.587). Univariate and multivariate analyses indicated that attainment of iCR was independently associated with longer 2-year DFS in addition to creatinine (<=2.0 mg/dL) and maintenance therapy. This study highlights the importance of pursuing iCR even in patients with sCR. PMID- 26764044 TI - Elevated PIM2 gene expression is associated with poor survival of patients with acute myeloid leukemia. AB - The PIM2 gene encodes the serine/threonine kinase involved in cell survival and apoptosis. The aim of the study was to evaluate the expression of the PIM2 gene in acute myeloid leukemia (AML) and to examine its role in apoptosis of the blastic cells. We analyzed the PIM2 expression in 148 patients: 91 with AML, 57 with acute lymphoblastic leukemia and 24 healthy controls by Real-Time PCR and Western blot. Inhibition of the PIM2 gene in human leukemic HL60 cell line was performed with RNAi and apoptosis rate was analyzed. Our results indicate that overexpression of PIM2 in AML is associated with low complete remission rate, high-risk cytogenetics, shorter leukemia-free survival, and event-free survival. Cytometric analysis of HL60/PAC-GFP and HL60/PAC-GFP-shPIM2 cells revealed an increase in the number of apoptotic cells after inhibition of PIM2 gene. In summary, the elevated expression of PIM2 in blastic cells is associated with poor prognosis of AML patients and their resistance to induction therapy. PMID- 26764048 TI - Oxygen sensing by the carotid body: mechanisms and role in adaptation to hypoxia. AB - Oxygen (O2) is fundamental for cell and whole-body homeostasis. Our understanding of the adaptive processes that take place in response to a lack of O2(hypoxia) has progressed significantly in recent years. The carotid body (CB) is the main arterial chemoreceptor that mediates the acute cardiorespiratory reflexes (hyperventilation and sympathetic activation) triggered by hypoxia. The CB is composed of clusters of cells (glomeruli) in close contact with blood vessels and nerve fibers. Glomus cells, the O2-sensitive elements in the CB, are neuron-like cells that contain O2-sensitive K(+)channels, which are inhibited by hypoxia. This leads to cell depolarization, Ca(2+)entry, and the release of transmitters to activate sensory fibers terminating at the respiratory center. The mechanism whereby O2modulates K(+)channels has remained elusive, although several appealing hypotheses have been postulated. Recent data suggest that mitochondria complex I signaling to membrane K(+)channels plays a fundamental role in acute O2sensing. CB activation during exposure to low Po2is also necessary for acclimatization to chronic hypoxia. CB growth during sustained hypoxia depends on the activation of a resident population of stem cells, which are also activated by transmitters released from the O2-sensitive glomus cells. These advances should foster further studies on the role of CB dysfunction in the pathogenesis of highly prevalent human diseases. PMID- 26764051 TI - Triacylglyceride physiology in the short-finned eel, Anguilla australis--the effects of androgen. AB - The importance of androgens (especially 11-ketotestosterone) during previtellogenesis in eels is well established. In wild pubertal migrants, circulating 11-ketotestosterone levels correlate with a number of morphological and molecular changes. Here, we test the prediction that this correlation represents a causal relationship by artificially raising the levels of circulating 11-ketotestosterone in prepubertal nonmigratory female and pubertal, migratory male short-finned eels (Anguilla australis) using sustained-release hormone implants. In females, increases in hepatosomatic index and transcript copy numbers of hepatic apolipoprotein B and microsomal triacylglyceride transfer protein indicated increased repackaging of endogenously sourced triacylglycerides. These changes in liver measures were reflected in increased concentrations of serum triacylglycerides. However, despite a small increase in gonadosomatic index, ovarian lipoprotein receptor transcript abundances were not affected by 11-ketotestosterone. Interestingly, no such changes in hepatic gene expression were detected in a dose-response experiment using males. We propose that the androgens are inducing the observed changes in previtellogenic females, although it remains unclear to what extent these effects are direct or indirect. PMID- 26764049 TI - The role of STIM and ORAI proteins in phagocytic immune cells. AB - Phagocytic cells, such as neutrophils, macrophages, and dendritic cells, migrate to sites of infection or damage and are integral to innate immunity through two main mechanisms. The first is to directly neutralize foreign agents and damaged or infected cells by secreting toxic substances or ingesting them through phagocytosis. The second is to alert the adaptive immune system through the secretion of cytokines and the presentation of the ingested materials as antigens, inducing T cell maturation into helper, cytotoxic, or regulatory phenotypes. While calcium signaling has been implicated in numerous phagocyte functions, including differentiation, maturation, migration, secretion, and phagocytosis, the molecular components that mediate these Ca(2+) signals have been elusive. The discovery of the STIM and ORAI proteins has allowed researchers to begin clarifying the mechanisms and physiological impact of store-operated Ca(2+) entry, the major pathway for generating calcium signals in innate immune cells. Here, we review evidence from cell lines and mouse models linking STIM and ORAI proteins to the control of specific innate immune functions of neutrophils, macrophages, and dendritic cells. PMID- 26764050 TI - Heat shock protein 70 regulates platelet integrin activation, granule secretion and aggregation. AB - Molecular chaperones that support protein quality control, including heat shock protein 70 (Hsp70), participate in diverse aspects of cellular and physiological function. Recent studies have reported roles for specific chaperone activities in blood platelets in maintaining hemostasis; however, the functions of Hsp70 in platelet physiology remain uninvestigated. Here we characterize roles for Hsp70 activity in platelet activation and function. In vitro biochemical, microscopy, flow cytometry, and aggregometry assays of platelet function, as well as ex vivo analyses of platelet aggregate formation in whole blood under shear, were carried out under Hsp70-inhibited conditions. Inhibition of platelet Hsp70 blocked platelet aggregation and granule secretion in response to collagen-related peptide (CRP), which engages the immunoreceptor tyrosine-based activation motif bearing collagen receptor glycoprotein VI (GPVI)-Fc receptor-gamma chain complex. Hsp70 inhibition also reduced platelet integrin-alphaIIbbeta3 activation downstream of GPVI, as Hsp70-inhibited platelets showed reduced PAC-1 and fibrinogen binding. Ex vivo, pharmacological inhibition of Hsp70 in human whole blood prevented the formation of platelet aggregates on collagen under shear. Biochemical studies supported a role for Hsp70 in maintaining the assembly of the linker for activation of T cells signalosome, which couples GPVI-initiated signaling to integrin activation, secretion, and platelet function. Together, our results suggest that Hsp70 regulates platelet activation and function by supporting linker for activation of T cells-associated signaling events downstream of platelet GPVI engagement, suggesting a role for Hsp70 in the intracellular organization of signaling systems that mediate platelet secretion, "inside-out" activation of platelet integrin-alphaIIbbeta3, platelet-platelet aggregation, and, ultimately, hemostatic plug and thrombus formation. PMID- 26764053 TI - LA and ALA prevent glucose intolerance in obese male rats without reducing reactive lipid content, but cause tissue-specific changes in fatty acid composition. AB - While the cause of Type 2 diabetes remains poorly defined, the accumulation of reactive lipids within white adipose tissue, skeletal muscle, and liver have been repeatedly implicated as underlying mechanisms. The ability of polyunsaturated fatty acids (PUFAs) to prevent the development of insulin resistance has gained considerable interest in recent years; however, the mechanisms-of-action remain poorly described. Therefore, we determined the efficacy of diets supplemented with either linoleic acid (LA) or alpha-linolenic acid (ALA) in preventing insulin resistance and reactive lipid accumulation in key metabolic tissues of the obese Zucker rat. Obese Zucker rats displayed impaired glucose homeostasis and reduced n-3 and n-6 PUFA content in the liver and epididymal white adipose tissue (EWAT). After the 12-wk feeding intervention, both LA- and ALA supplemented diets prevented whole body glucose and insulin intolerance; however, ALA had a more pronounced effect. These changes occurred in association with n-3 and n-6 accumulation in all tissues studied, albeit to different extents (EWAT > liver > muscle). Triacylglycerol (TAG), diacylglycerol (DAG), ceramide, and sphingolipid accumulation were not attenuated in obese animals supplemented with either LA or ALA, suggesting that preservation of glucose homeostasis occurred independent of changes in reactive lipid content. However, PUFA-supplemented diets differentially altered the fatty acid composition of TAGs, DAGs, and PLs in a tissue-specific manner, suggesting essential fatty acid metabolism differs between tissues. Together, our results indicate that remodeling of the fatty acid composition of various lipid fractions may contribute to the improved glucose tolerance observed in obese rats fed PUFA-supplemented diets. PMID- 26764052 TI - Diminished anabolic signaling response to insulin induced by intramuscular lipid accumulation is associated with inflammation in aging but not obesity. AB - The loss of skeletal muscle mass is observed in many pathophysiological conditions, including aging and obesity. The loss of muscle mass and function with aging is defined as sarcopenia and is characterized by a mismatch between skeletal muscle protein synthesis and breakdown. Characteristic metabolic features of both aging and obesity are increases in intramyocellular lipid (IMCL) content in muscle. IMCL accumulation may play a mechanistic role in the development of anabolic resistance and the progression of muscle atrophy in aging and obesity. In the present study, aged and high-fat fed mice were used to determine mechanisms leading to muscle loss. We hypothesized the accumulation of bioactive lipids in skeletal muscle, such as ceramide or diacylglycerols, leads to insulin resistance with aging and obesity and the inability to activate protein synthesis, contributing to skeletal muscle loss. We report a positive association between bioactive lipid accumulation and the loss of lean mass and muscle strength. Obese and aged animals had significantly higher storage of ceramide and diacylglycerol compared with young. Furthermore, there was an attenuated insulin response in components of the mTOR anabolic signaling pathway. We also observed differential increases in the expression of inflammatory cytokines and the phosphorylation of IkappaBalpha with aging and obesity. These data challenge the accepted role of increased inflammation in obesity-induced insulin resistance in skeletal muscle. Furthermore, we have now established IkappaBalpha with a novel function in aging-associated muscle loss that may be independent of its previously understood role as an NF-kappaB inhibitor. PMID- 26764054 TI - Delayed growth, motor function and learning in preterm pigs during early postnatal life. AB - Preterm birth interrupts normal fetal growth with consequences for postnatal growth and organ development. In preterm infants, many physiological deficits adapt and disappear with advancing postnatal age, but some may persist into childhood. We hypothesized that preterm birth would induce impaired organ growth and function during the first postnatal week in pigs, while motor abilities and behavioral characteristics would show more persistent developmental delay. Cesarean-delivered preterm (n = 112, 90% gestation) or term (n = 56, 100% gestation) piglets were reared under identical conditions and euthanized for blood and organ collection on postnatal days 0, 5, or 26. Body weight gain remained lower in preterm vs. term pigs up to day 26 (25.5 +/- 1.5 vs. 31.0 +/- 0.5 g.kg(-1).day(-1), P < 0.01) when relative weights were higher for brain and kidneys and reduced for liver and spleen. Neonatal preterm pigs had reduced values for blood pH, Po2, glucose, lactate, hematocrit, and cortisol, but at day 26, most values were normalized, although plasma serotonin and IGF 1 levels remained reduced. Preterm pigs showed delayed neonatal arousal and impaired physical activity, coordination, exploration, and learning, relative to term pigs (all P < 0.05). Supplementation of parenteral nutrition during the first 5 days with an enteral milk diet did not affect later outcomes. In preterm pigs, many physiological characteristics of immaturity disappeared by 4 wk, while some neurodevelopmental deficits remained. The preterm pig is a relevant animal model to study early dietary and pharmacological interventions that support postnatal maturation and neurodevelopment in preterm infants. PMID- 26764055 TI - The effect of plasma osmolality and baroreceptor loading status on postexercise heat loss responses. AB - We examined the separate and combined effects of plasma osmolality and baroreceptor loading status on postexercise heat loss responses. Nine young males completed a 45-min treadmill exercise protocol at 58 +/- 2% Vo2 peak, followed by a 60-min recovery. On separate days, participants received 0.9% NaCl (ISO), 3.0% NaCl (HYP), or no infusion (natural recovery) throughout exercise. In two additional sessions (no infusion), lower-body negative (LBNP) or positive (LBPP) pressure was applied throughout the final 45 min of recovery. Local sweat rate (LSR; ventilated capsule: chest, forearm, upper back, forehead) and skin blood flow (SkBF; laser-Doppler flowmetry: forearm, upper back) were continuously measured. During HYP, upper back LSR was attenuated from end-exercise to 10 min of recovery by ~0.35 +/- 0.10 mg.min(-1).cm(-2) and during the last 20 min of recovery by ~0.13 +/- 0.03 mg.min(-1).cm(-2), while chest LSR was lower by 0.18 +/- 0.06 mg.min(-1).cm(-2) at 50 min of recovery compared with natural recovery (all P < 0.05). Forearm and forehead LSRs were not affected by plasma hyperosmolality during HYP (all P > 0.28), which suggests regional differences in the osmotic modulation of postexercise LSR. Furthermore, LBPP application attenuated LSR by ~0.07-0.28 mg.min(-1).cm(-2) during the last 30 min of recovery at all sites except the forehead compared with natural recovery (all P < 0.05). Relative to natural recovery, forearm and upper back SkBF were elevated during LBPP, ISO, and HYP by ~6-10% by the end of recovery (all P < 0.05). We conclude that 1) hyperosmolality attenuates postexercise sweating heterogeneously among skin regions, and 2) baroreceptor loading modulates postexercise SkBF independently of changes in plasma osmolality without regional differences. PMID- 26764056 TI - Comprehensive assessment of the global and regional vascular responses to food ingestion in humans using novel rapid MRI. AB - Ingestion of food is known to increase mesenteric blood flow. It is not clear whether this increased flow demand is compensated by a rise in cardiac output (CO) alone or by redistribution of blood flow from other organs. We used a new comprehensive imaging method to assess the human cardiovascular response to food ingestion. Following a 12-h fast, blood flow in segments of the aorta and in organ-specific arteries, and ventricular volumes were assessed in 20 healthy adults using MRI at rest and following ingestion of a high-energy liquid meal. Systemic vascular resistance (SVR) fell substantially and CO rose significantly. Blood pressure remained stable. These changes were predominantly driven by a rapid fall in mesenteric vascular resistance, resulting in over four times more intestinal blood flow. Renal vascular resistance also declined but less dramatically. No changes in blood flow to the celiac territory, the brain, or the limbs were observed. In conclusion, this is the first study to fully characterize systemic and regional changes in vascular resistance after food ingestion in humans. Our findings show that the postprandial drop in SVR is fully compensated for by increased CO and not by redistribution of blood from other organs. With the exception of a modest increase in renal blood flow, there was no evidence of altered blood flow to nondigestive organs. The proposed oral food challenge protocol can be applied safely in an MRI environment and may be useful for studying the involvement of the gut in systemic or cardiovascular disease. PMID- 26764058 TI - Nitric oxide availability in deeply hypoxic crucian carp: acute and chronic changes and utilization of ambient nitrite reservoirs. AB - Recent research suggest that anoxia-tolerant fish transfer extracellular nitrite into the tissues, where it is used for nitric oxide (NO) generation, iron nitrosylation, and S-nitrosation of proteins, as part of the cytoprotective response toward prolonged hypoxia and subsequent reoxygenation. We hypothesized that crucian carp take up ambient nitrite and use it as a source of cellular NO availability during hypoxia. Fish were exposed for 1 day to normoxia (Po2 > 140 mmHg) and deep hypoxia (1 < Po2 < 3 mmHg) at both low (< 0.2 MUM) and moderately elevated (10 MUM) ambient [nitrite] to decipher NO metabolites in plasma and several tissues. We also compared NO metabolite changes during acute (10 min) and chronic (1 day) exposures to three different O2 levels. Plasma [nitrite] decreased with decreasing [O2], while the cellular concentrations of nitrite and nitros(yl)ated compounds either increased or stayed constant, depending on O2 level and tissue type. Nitrite was notably increased in the heart during deep hypoxia, and the increase was amplified by elevated ambient [nitrite]. Raised nitrite also increased gill [nitrite] and decreased mRNA expression of an inducible nitric oxide synthase-2 gene variant. The data support that ambient nitrite is taken up across the gills to be distributed via the blood to the tissues, particularly the heart, where it assists in cytoprotection and other functions. Cardiac nitrite was not elevated in acutely exposed fish, revealing that the response requires time. NO metabolite levels were higher during acute than chronic exposures, possibly caused by increased swimming activity and stress in acutely exposed fish. PMID- 26764057 TI - A case of mistaken identity: are reactive oxygen species actually reactive sulfide species? AB - Stepwise one-electron reduction of oxygen to water produces reactive oxygen species (ROS) that are chemically and biochemically similar to reactive sulfide species (RSS) derived from one-electron oxidations of hydrogen sulfide to elemental sulfur. Both ROS and RSS are endogenously generated and signal via protein thiols. Given the similarities between ROS and RSS, we wondered whether extant methods for measuring the former would also detect the latter. Here, we compared ROS to RSS sensitivity of five common ROS methods: redox-sensitive green fluorescent protein (roGFP), 2', 7'-dihydrodichlorofluorescein, MitoSox Red, Amplex Red, and amperometric electrodes. All methods detected RSS and were as, or more, sensitive to RSS than to ROS. roGFP, arguably the "gold standard" for ROS measurement, was more than 200-fold more sensitive to the mixed polysulfide H2Sn(n = 1-8) than to H2O2 These findings suggest that RSS may be far more prevalent in intracellular signaling than previously appreciated and that the contribution of ROS may be overestimated. This conclusion is further supported by the observation that estimated daily sulfur metabolism and ROS production are approximately equal and the fact that both RSS and antioxidant mechanisms have been present since the origin of life, nearly 4 billion years ago, long before the rise in environmental oxygen 600 million years ago. Although ROS are assumed to be the most biologically relevant oxidants, our results question this paradigm. We also anticipate our findings will direct attention toward development of novel and clinically relevant anti-(RSS)-oxidants. PMID- 26764059 TI - Exercise-Based Cardiac Rehabilitation for Coronary Heart Disease: Cochrane Systematic Review and Meta-Analysis. AB - BACKGROUND: Although recommended in guidelines for the management of coronary heart disease (CHD), concerns have been raised about the applicability of evidence from existing meta-analyses of exercise-based cardiac rehabilitation (CR). OBJECTIVES: The goal of this study is to update the Cochrane systematic review and meta-analysis of exercise-based CR for CHD. METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, and Science Citation Index Expanded were searched to July 2014. Retrieved papers, systematic reviews, and trial registries were hand-searched. We included randomized controlled trials with at least 6 months of follow-up, comparing CR to no exercise controls following myocardial infarction or revascularization, or with a diagnosis of angina pectoris or CHD defined by angiography. Two authors screened titles for inclusion, extracted data, and assessed risk of bias. Studies were pooled using random effects meta-analysis, and stratified analyses were undertaken to examine potential treatment effect modifiers. RESULTS: A total of 63 studies with 14,486 participants with median follow-up of 12 months were included. Overall, CR led to a reduction in cardiovascular mortality (relative risk: 0.74; 95% confidence interval: 0.64 to 0.86) and the risk of hospital admissions (relative risk: 0.82; 95% confidence interval: 0.70 to 0.96). There was no significant effect on total mortality, myocardial infarction, or revascularization. The majority of studies (14 of 20) showed higher levels of health-related quality of life in 1 or more domains following exercise-based CR compared with control subjects. CONCLUSIONS: This study confirms that exercise based CR reduces cardiovascular mortality and provides important data showing reductions in hospital admissions and improvements in quality of life. These benefits appear to be consistent across patients and intervention types and were independent of study quality, setting, and publication date. PMID- 26764060 TI - Cardiac Rehabilitation and Healthy Life-Style Interventions: Rectifying Program Deficiencies to Improve Patient Outcomes. PMID- 26764061 TI - Coronary CT Angiography for Suspected ACS in the Era of High-Sensitivity Troponins: Randomized Multicenter Study. AB - BACKGROUND: It is uncertain whether a diagnostic strategy supplemented by early coronary computed tomography angiography (CCTA) is superior to contemporary standard optimal care (SOC) encompassing high-sensitivity troponin assays (hs troponins) for patients suspected of acute coronary syndrome (ACS) in the emergency department (ED). OBJECTIVES: This study assessed whether a diagnostic strategy supplemented by early CCTA improves clinical effectiveness compared with contemporary SOC. METHODS: In a prospective, open-label, multicenter, randomized trial, we enrolled patients presenting with symptoms suggestive of an ACS at the ED of 5 community and 2 university hospitals in the Netherlands. Exclusion criteria included the need for urgent cardiac catheterization and history of ACS or coronary revascularization. The primary endpoint was the number of patients identified with significant coronary artery disease requiring revascularization within 30 days. RESULTS: The study population consisted of 500 patients, of whom 236 (47%) were women (mean age 54 +/- 10 years). There was no difference in the primary endpoint (22 [9%] patients underwent coronary revascularization within 30 days in the CCTA group and 17 [7%] in the SOC group [p = 0.40]). Discharge from the ED was not more frequent after CCTA (65% vs. 59%, p = 0.16), and length of stay was similar (6.3 h in both groups; p = 0.80). The CCTA group had lower direct medical costs (?337 vs. ?511, p < 0.01) and less outpatient testing after the index ED visit (10 [4%] vs. 26 [10%], p < 0.01). There was no difference in incidence of undetected ACS. CONCLUSIONS: CCTA, applied early in the work-up of suspected ACS, is safe and associated with less outpatient testing and lower costs. However, in the era of hs-troponins, CCTA does not identify more patients with significant CAD requiring coronary revascularization, shorten hospital stay, or allow for more direct discharge from the ED. (Better Evaluation of Acute Chest Pain with Computed Tomography Angiography [BEACON]; NCT01413282). PMID- 26764062 TI - The Management of Acute Chest Pain: What Lies Beyond the Emergency Department Doors? PMID- 26764063 TI - Cost-Effectiveness of Transcatheter Aortic Valve Replacement With a Self Expanding Prosthesis Versus Surgical Aortic Valve Replacement. AB - BACKGROUND: Previous studies of the cost-effectiveness of transcatheter aortic valve replacement (TAVR) have been based primarily on a single balloon-expandable system. OBJECTIVES: The goal of this study was to evaluate the cost-effectiveness of TAVR with a self-expanding prosthesis compared with surgical aortic valve replacement (SAVR) for patients with severe aortic stenosis and high surgical risk. METHODS: We performed a formal economic analysis on the basis of individual, patient-level data from the CoreValve U.S. High Risk Pivotal Trial. Empirical data regarding survival and quality of life over 2 years, and medical resource use and hospital costs through 12 months were used to project life expectancy, quality-adjusted life expectancy, and lifetime medical costs in order to estimate the incremental cost-effectiveness of TAVR versus SAVR from a U.S. RESULTS: Relative to SAVR, TAVR reduced initial length of stay an average of 4.4 days, decreased the need for rehabilitation services at discharge, and resulted in superior 1-month quality of life. Index admission and projected lifetime costs were higher with TAVR than with SAVR (differences $11,260 and $17,849 per patient, respectively), whereas TAVR was projected to provide a lifetime gain of 0.32 quality-adjusted life-years ([QALY]; 0.41 LY) with 3% discounting. Lifetime incremental cost-effectiveness ratios were $55,090 per QALY gained and $43,114 per LY gained. Sensitivity analyses indicated that a reduction in the initial cost of TAVR by ~$1,650 would lead to an incremental cost-effectiveness ratio <$50,000/QALY gained. CONCLUSIONS: In a high-risk clinical trial population, TAVR with a self-expanding prosthesis provided meaningful clinical benefits compared with SAVR, with incremental costs considered acceptable by current U.S. STANDARDS: With expected modest reductions in the cost of index TAVR admissions, the value of TAVR compared with SAVR in this patient population would become high. (Safety and Efficacy Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement [Medtronic CoreValve U.S. Pivotal Trial]; NCT01240902). PMID- 26764064 TI - The Core Value of Cost-Effectiveness Analyses. PMID- 26764065 TI - Causes of Death Following PCI Versus CABG in Complex CAD: 5-Year Follow-Up of SYNTAX. AB - BACKGROUND: There are no data available on specific causes of death from randomized trials that have compared coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI). OBJECTIVES: The purpose of this study was to investigate specific causes of death, and its predictors, after revascularization for complex coronary disease in patients. METHODS: An independent Clinical Events Committee consisting of expert physicians who were blinded to the study treatment subclassified causes of death as cardiovascular (cardiac and vascular), noncardiovascular, or undetermined according to the trial protocol. Cardiac deaths were classified as sudden cardiac, related to myocardial infarction (MI), and other cardiac deaths. RESULTS: In the randomized cohort, there were 97 deaths after CABG and 123 deaths after PCI during a 5-year follow up. After CABG, 49.4% of deaths were cardiovascular, with the greatest cause being heart failure, arrhythmia, or other causes (24.6%), whereas after PCI, the majority of deaths were cardiovascular (67.5%) and as a result of MI (29.3%). The cumulative incidence rates of all-cause death were not significantly different between CABG and PCI (11.4% vs. 13.9%, respectively; p = 0.10), whereas there were significant differences in terms of cardiovascular (5.8% vs. 9.6%, respectively; p = 0.008) and cardiac death (5.3% vs. 9.0%, respectively; p = 0.003), which were caused primarily by a reduction in MI-related death with CABG compared with PCI (0.4% vs. 4.1%, respectively; p <0.0001). Treatment with PCI versus CABG was an independent predictor of cardiac death (hazard ratio: 1.55; 95% confidence interval: 1.09 to 2.33; p = 0.045). The difference in MI-related death was seen largely in patients with diabetes, 3-vessel disease, or high SYNTAX (TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries) trial scores. CONCLUSIONS: During a 5-year follow up, CABG in comparison with PCI was associated with a significantly reduced rate of MI-related death, which was the leading cause of death after PCI. Treatments following PCI should target reducing post-revascularization spontaneous MI. Furthermore, secondary preventive medication remains essential in reducing events post-revascularization. (TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries [SYNTAX]; NCT00114972). PMID- 26764066 TI - CABG for Complex CAD: When Will Evidence-Based Practice Align With Evidence-Based Medicine? PMID- 26764067 TI - Impact of Bleeding on Quality of Life in Patients on DAPT: Insights From TRANSLATE-ACS. AB - BACKGROUND: Prolonged dual antiplatelet therapy (DAPT) is recommended after an acute myocardial infarction (AMI) to reduce ischemic events but is associated with increased rates of major and minor bleeding. OBJECTIVES: This study sought to determine the incidence of post-percutaneous coronary intervention (PCI) bleeding that occurs on contemporary DAPT and its impact on quality of life (QOL). METHODS: We studied 9,290 AMI patients treated with PCI and discharged alive between April 2010 and September 2012. Post-discharge bleeding was categorized according to the Bleeding Academic Research Consortium (BARC) definition. The primary outcome was the 6-month Euro QOL-5 Dimension (EQ-5D) index score (a measure of health utility); a secondary outcome was the EQ-5D visual analog scale (VAS) at 6 months. RESULTS: Of the 9,290 patients with AMI, bleeding events occurred as follows: any BARC bleeding: 24.2%; BARC 1: 9.1%; BARC 2: 13.8%; BARC 3: 1.1%; BARC 4: 0.03%; and BARC 5: 0%. Those who experienced any BARC bleeding had lower scores across all 5 EQ-5D domains (mobility, self-care, usual activities, pain, and anxiety), as well as lower EQ-5D VAS and EQ-5D index scores. After clinical risk adjustment, any BARC bleeding was independently associated with 6-month EQ-5D index score (p < 0.0001) and lower QOL (p < 0.001). Both the EQ-5D index and the VAS score declined in a stepwise fashion with increasing BARC severity. CONCLUSIONS: Among patients undergoing PCI for AMI, bleeding during follow-up was associated with worse 6-month utility and QOL. Although even minor bleeding was associated with impaired health status and QOL, the degree of impairment increased in a stepwise fashion with bleeding severity. PMID- 26764068 TI - Bleeding and Quality of Life. PMID- 26764070 TI - Calcification and Inflammation in Atherosclerosis: Which Is the Chicken, and Which Is the Egg? PMID- 26764069 TI - Does Vascular Calcification Accelerate Inflammation?: A Substudy of the dal PLAQUE Trial. AB - BACKGROUND: Atherosclerosis is an inflammatory condition with calcification apparent late in the disease process. The extent and progression of coronary calcification predict cardiovascular events. Relatively little is known about noncoronary vascular calcification. OBJECTIVES: This study investigated noncoronary vascular calcification and its influence on changes in vascular inflammation. METHODS: A total of 130 participants in the dal-PLAQUE (Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging) study underwent fluorodeoxyglucose positron emission tomography/computed tomography at entry and at 6 months. Calcification of the ascending aorta, arch, carotid, and coronary arteries was quantified. Cardiovascular risk factors were related to arterial calcification. The influences of baseline calcification and drug therapy (dalcetrapib vs. placebo) on progression of calcification were determined. Finally, baseline calcification was related to changes in vascular inflammation. RESULTS: Age >65 years old was consistently associated with higher baseline calcium scores. Arch calcification trended to progress more in those with calcification at baseline (p = 0.055). There were no significant differences between progression of vascular calcification with dalcetrapib compared to that with placebo. Average carotid target-to-background ratio indexes declined over 6 months if carotid calcium was absent (single hottest slice [p = 0.037], mean of maximum target-to-background ratio [p = 0.010], and mean most diseased segment [p < 0.001]), but did not significantly change if calcification was present at baseline. CONCLUSIONS: Across multiple arterial regions, higher age is consistently associated with higher calcium scores. The presence of vascular calcification at baseline is associated with progressive calcification; in the carotid arteries, calcification appears to influence vascular inflammation. Dalcetrapib therapy did not affect vascular calcification. PMID- 26764072 TI - The American College of Cardiology Ventures Into Medical Research and Innovation Policy. PMID- 26764071 TI - A Tale of 2 Diseases: The History of Long-QT Syndrome and Brugada Syndrome. AB - The Brugada syndrome (BrS) and long-QT syndrome (LQTS) present as congenital or acquired disorders with diagnostic electrocardiograms (ST-segment elevation and prolonged QT interval, respectively) and increased risk for malignant arrhythmias. Our understanding of the 2 disease forms (congenital vs. acquired) differs. A female patient on quinidine for atrial fibrillation who develops ventricular fibrillation is diagnosed with "acquired LQTS" and is discharged with no therapy other than instructions to avoid QT-prolonging medications. In contrast, an asymptomatic male patient who develops a Brugada electrocardiogram on flecainide is diagnosed with "asymptomatic BrS" and could be referred for an electrophysiological evaluation that could result in defibrillator implantation. The typical patient undergoing defibrillator implantation for BrS is asymptomatic but has a Brugada electrocardiogram provoked by a drug. The authors describe how the histories of LQTS and BrS went through the same stages, but in different sequences, leading to different conclusions. PMID- 26764073 TI - Passions and Realities of Training in Cardiology: Challenges for Fellows-in Training. PMID- 26764074 TI - Atrogin-1 Pathway Activation in Cushing Syndrome Cardiomyopathy. PMID- 26764075 TI - Time Course of Change in Ectopic Fat Stores After Bariatric Surgery. PMID- 26764076 TI - Getting What the Guidelines Stated Matters. PMID- 26764077 TI - Reply: Getting What the Guidelines Stated Matters. PMID- 26764078 TI - Reconsidering the Impact of Pre-Operative Malperfusion on Acute Type A Dissection: The Modified Penn Classification. PMID- 26764079 TI - Reply: Reconsidering the Impact of Pre-Operative Malperfusion on Acute Type A Dissection: The Modified Penn Classification. PMID- 26764080 TI - Left Atrial Appendage Occlusion Device Societal Overview: The Surgeon's Comment. PMID- 26764081 TI - Reply: Left Atrial Appendage Occlusion Device Societal Overview: The Surgeon's Comment. PMID- 26764082 TI - Eruptive Penile Syringomas in an Adolescent: Novel Approach with Serial Microexcisions and Suture-Adhesive Repair. AB - Penile syringomas are benign adnexal tumors that are usually asymptomatic but can be cosmetically distressing. Because of the delicate nature of skin in this region, treatment is difficult, and there are few case reports of procedural destruction of these tumors. We report a case of successful surgical excision using Castroviejo ophthalmic scissors followed by primary closure with fast absorbing plain gut suture and a cyanoacrylate adhesive application. This procedure was well tolerated and had an impressive cosmetic outcome. PMID- 26764083 TI - Disease severity scoring system for non-transfusion-dependent thalassemia. PMID- 26764084 TI - High on-aspirin platelet reactivity predicts cardiac death in acute coronary syndrome patients undergoing PCI. PMID- 26764086 TI - Periungual Bowen's Disease in a 12-Year-Old Boy Treated with Photodynamic Therapy. AB - Bowen's disease (BD) usually occurs on sun-exposed areas in elderly patients. BD rarely occurs in childhood and lesions of the nail unit and periungual area are likely associated with human papillomavirus infection. Herein, we report a case of BD presenting on the periungual area in a 12-year-old boy which was successfully treated with two sessions of photodynamic therapy. PMID- 26764085 TI - Microarray profiling analysis of long non-coding RNAs expression in tendinopathy: identification for potential biomarkers and mechanisms. AB - The role of lncRNAs in pathologies of tendinopathy has not been researched so far, this study aims to identify the role and potent mechanism of lncRNAs in tendinopathy with a bioinformatic analysis. The gene profile of GSE26051 based on the platform of Affymetrix Human Genome U133B Array condensed was downloaded from Gene Expression Omnibus. A total of 46 specimens (including 23 normal samples and 23 tendinopathy specimens) were available. Compared with the control samples, differentially expressed genes (DEGs) of tendinopathy was identified the by packages in R. The selected DEGs were further analysed using bioinformatics methods including co-expression and enrichment analysis to detect the potential role of lncRNAs. A total of 40 different expressed lncRNAs were identified. However, most of the identified lncRNAs have not been researched before. And this study only annotate one of the identified lncRNAs successfully, the LOC100507027 (myoregulin), with the potential role in regulating skeletal muscle tissue development and skeletal muscle organ development. PMID- 26764087 TI - Mallotus roxburghianus modulates antioxidant responses in pancreas of diabetic rats. AB - Mallotus roxburghianus has long been used by Mizo tribal people for the treatment of diabetes. Scientific validation at known doses may provide information about its safety and efficacy. Methanolic leaf extract of M. roxburghianus (MRME 100 and 400mg/kg) was tested in comparison with normal and alloxan diabetic rats for 28 days p.o. in terms of body and pancreatic weight, blood glucose level, antioxidant enzymes, expression of visfatin and PCNA, histopathology and histomorphometric measurements of pancreas. The results were evaluated statistically using ANOVA, correlation and regression and Principal component analysis (PCO). MRME (100 and 400mg/kg) treatment significantly (p<0.0001) decreased the body weight, blood glucose level, improved the mass and size of pancreas, elevated the levels of antioxidant enzymes and up regulate the expression of visfatin and PCNA. PCO analysis was good to fitness and prediction distinguishes the therapeutic effects of M. roxburghianus from the alloxan induced diabetic rats. MRME has significant role in protecting animals from alloxan-induced diabetic oxidative stress in pancreas and exhibited promising antihyperglycaemic and antioxidant activities along with significant reversal of disturbed antioxidant status and lipid peroxidative damage. Pancreatic architecture and physiology under diabetic oxidative stress have been significantly modulated by MRME and validated as a drug candidate for antidiabetic treatment. M. roxburghianus treatment restores the antioxidant enzyme system and rejuvenates the islets mass in alloxanized rat by accelerating visfatin and PCNA expression in pancreatic tissue. PMID- 26764089 TI - Myonuclear transcription is responsive to mechanical load and DNA content but uncoupled from cell size during hypertrophy. AB - Myofibers increase size and DNA content in response to a hypertrophic stimulus, thus providing a physiological model with which to study how these factors affect global transcription. Using 5-ethynyl uridine (EU) to metabolically label nascent RNA, we measured a sevenfold increase in myofiber transcription during early hypertrophy before a change in cell size and DNA content. The typical increase in myofiber DNA content observed at the later stage of hypertrophy was associated with a significant decrease in the percentage of EU-positive myonuclei; however, when DNA content was held constant by preventing myonuclear accretion via satellite cell depletion, both the number of transcriptionally active myonuclei and the amount of RNA generated by each myonucleus increased. During late hypertrophy, transcription did not scale with cell size, as smaller myofibers (<1000 MUm(2)) demonstrated the highest transcriptional activity. Finally, transcription was primarily responsible for changes in the expression of genes known to regulate myofiber size. These findings show that resident myonuclei possess a significant reserve capacity to up-regulate transcription during hypertrophy and that myofiber transcription is responsive to DNA content but uncoupled from cell size during hypertrophy. PMID- 26764088 TI - Mitochondrial anchorage and fusion contribute to mitochondrial inheritance and quality control in the budding yeast Saccharomyces cerevisiae. AB - Higher-functioning mitochondria that are more reduced and have less ROS are anchored in the yeast bud tip by the Dsl1-family protein Mmr1p. Here we report a role for mitochondrial fusion in bud-tip anchorage of mitochondria. Fluorescence loss in photobleaching (FLIP) and network analysis experiments revealed that mitochondria in large buds are a continuous reticulum that is physically distinct from mitochondria in mother cells. FLIP studies also showed that mitochondria that enter the bud can fuse with mitochondria that are anchored in the bud tip. In addition, loss of fusion and mitochondrial DNA (mtDNA) by deletion of mitochondrial outer or inner membrane fusion proteins (Fzo1p or Mgm1p) leads to decreased accumulation of mitochondria at the bud tip and inheritance of fitter mitochondria by buds compared with cells with no mtDNA. Conversely, increasing the accumulation and anchorage of mitochondria in the bud tip by overexpression of MMR1 results in inheritance of less-fit mitochondria by buds and decreased replicative lifespan and healthspan. Thus quantity and quality of mitochondrial inheritance are ensured by two opposing processes: bud-tip anchorage by mitochondrial fusion and Mmr1p, which favors bulk inheritance; and quality control mechanisms that promote segregation of fitter mitochondria to the bud. PMID- 26764090 TI - LIN-41 inactivation leads to delayed centrosome elimination and abnormal chromosome behavior during female meiosis in Caenorhabditis elegans. AB - During oogenesis, two successive meiotic cell divisions occur without functional centrosomes because of the inactivation and subsequent elimination of maternal centrosomes during the diplotene stage of meiosis I. Despite being a conserved phenomenon in most metazoans, the means by which this centrosome behavior is controlled during female meiosis remain elusive. Here, we conducted a targeted RNAi screening in the Caenorhabditis elegans gonad to identify novel regulators of centrosome behavior during oogenesis. We screened 513 genes known to be essential for embryo production and directly visualized GFP-gamma-tubulin to monitor centrosome behavior at all stages of oogenesis. In the screening, we found that RNAi-mediated inactivation of 33 genes delayed the elimination of GFP gamma-tubulin at centrosomes during oogenesis, whereas inactivation of nine genes accelerated the process. Depletion of the TRIM-NHL protein LIN-41 led to a significant delay in centrosome elimination and to the separation and reactivation of centrosomes during oogenesis. Upon LIN-41 depletion, meiotic chromosomes were abnormally condensed and pulled toward one of the two spindle poles around late pachytene even though the spindle microtubules emanated from both centrosomes. Overall, our work provides new insights into the regulation of centrosome behavior to ensure critical meiotic events and the generation of intact oocytes. PMID- 26764091 TI - Geminin deletion in mouse oocytes results in impaired embryo development and reduced fertility. AB - Geminin controls proper centrosome duplication, cell division, and differentiation. We investigated the function of geminin in oogenesis, fertilization, and early embryo development by deleting the geminin gene in oocytes from the primordial follicle stage. Oocyte-specific disruption of geminin results in low fertility in mice. Even though there was no evident anomaly of oogenesis, oocyte meiotic maturation, natural ovulation, or fertilization, early embryo development and implantation were impaired. The fertilized eggs derived from mutant mice showed developmental delay, and many were blocked at the late zygote stage. Cdt1 protein was decreased, whereas Chk1 and H2AX phosphorylation was increased, in fertilized eggs after geminin depletion. Our results suggest that disruption of maternal geminin may decrease Cdt1 expression and cause DNA rereplication, which then activates the cell cycle checkpoint and DNA damage repair and thus impairs early embryo development. PMID- 26764092 TI - A novel imaging method for quantitative Golgi localization reveals differential intra-Golgi trafficking of secretory cargoes. AB - Cellular functions of the Golgi are determined by the unique distribution of its resident proteins. Currently, electron microscopy is required for the localization of a Golgi protein at the sub-Golgi level. We developed a quantitative sub-Golgi localization method based on centers of fluorescence masses of nocodazole-induced Golgi ministacks under conventional optical microscopy. Our method is rapid, convenient, and quantitative, and it yields a practical localization resolution of ~ 30 nm. The method was validated by the previous electron microscopy data. We quantitatively studied the intra-Golgi trafficking of synchronized secretory membrane cargoes and directly demonstrated the cisternal progression of cargoes from the cis- to the trans-Golgi. Our data suggest that the constitutive efflux of secretory cargoes could be restricted at the Golgi stack, and the entry of the trans-Golgi network in secretory pathway could be signal dependent. PMID- 26764093 TI - Common formin-regulating sequences in Smy1 and Bud14 are required for the control of actin cable assembly in vivo. AB - Formins comprise a large family of proteins with diverse roles in remodeling the actin cytoskeleton. However, the spatiotemporal mechanisms used by cells to control formin activities are only beginning to be understood. Here we dissected Smy1, which has dual roles in regulating formins and myosin. Using mutagenesis, we identified specific sequences in Smy1 critical for its in vitro inhibitory effects on the FH2 domain of the formin Bnr1. By integrating smy1 alleles targeting those sequences, we genetically uncoupled Smy1's functions in regulating formins and myosin. Quantitative imaging analysis further demonstrated that the ability of Smy1 to directly control Bnr1 activity is crucial in vivo for proper actin cable length, shape, and velocity and, in turn, efficient secretory vesicle transport. A Smy1-like sequence motif was also identified in a different Bnr1 regulator, Bud14, and found to be essential for Bud14 functions in regulating actin cable architecture and function in vivo. Together these observations reveal unanticipated mechanistic ties between two distinct formin regulators. Further, they emphasize the importance of tightly controlling formin activities in vivo to generate specialized geometries and dynamics of actin structures tailored to their physiological roles. PMID- 26764094 TI - The glucose metabolite methylglyoxal inhibits expression of the glucose transporter genes by inactivating the cell surface glucose sensors Rgt2 and Snf3 in yeast. AB - Methylglyoxal (MG) is a cytotoxic by-product of glycolysis. MG has inhibitory effect on the growth of cells ranging from microorganisms to higher eukaryotes, but its molecular targets are largely unknown. The yeast cell-surface glucose sensors Rgt2 and Snf3 function as glucose receptors that sense extracellular glucose and generate a signal for induction of expression of genes encoding glucose transporters (HXTs). Here we provide evidence that these glucose sensors are primary targets of MG in yeast. MG inhibits the growth of glucose-fermenting yeast cells by inducing endocytosis and degradation of the glucose sensors. However, the glucose sensors with mutations at their putative ubiquitin-acceptor lysine residues are resistant to MG-induced degradation. These results suggest that the glucose sensors are inactivated through ubiquitin-mediated endocytosis and degraded in the presence of MG. In addition, the inhibitory effect of MG on the glucose sensors is greatly enhanced in cells lacking Glo1, a key component of the MG detoxification system. Thus the stability of these glucose sensors seems to be critically regulated by intracellular MG levels. Taken together, these findings suggest that MG attenuates glycolysis by promoting degradation of the cell-surface glucose sensors and thus identify MG as a potential glycolytic inhibitor. PMID- 26764095 TI - A NIMA-related kinase, CNK4, regulates ciliary stability and length. AB - NIMA-related kinases (Nrks or Neks) have emerged as key regulators of ciliogenesis. In human, mutations in Nek1 and Nek8 cause cilia-related disorders. The ciliary functions of Nrks are mostly revealed by genetic studies; however, the underlying mechanisms are not well understood. Here we show that a Chlamydomonas Nrk, CNK4, regulates ciliary stability and length. CNK4 is localized to the basal body region and the flagella. The cnk4-null mutant exhibited long flagella, with formation of flagellar bulges. The flagella gradually became curled at the bulge formation site, leading to flagellar loss. Electron microscopy shows that the curled flagella involved curling and degeneration of axonemal microtubules. cnk4 mutation resulted in flagellar increases of IFT trains, as well as its accumulation at the flagellar bulges. IFT speeds were not affected, however, IFT trains frequently stalled, leading to reduced IFT frequencies. These data are consistent with a model in which CNK4 regulates microtubule dynamics and IFT to control flagellar stability and length. PMID- 26764097 TI - Identification of DPY19L3 as the C-mannosyltransferase of R-spondin1 in human cells. AB - R-spondin1 (Rspo1) is a secreted protein that enhances Wnt signaling, which has crucial functions in embryonic development and several cancers. C-mannosylation is a rare type of glycosylation and might regulate secretion, protein-protein interactions, and enzymatic activity. Although human Rspo1 contains 2 predicted C mannosylation sites, C-mannosylation of Rspo1 has not been reported, nor have its functional effects on this protein. In this study, we demonstrate by mass spectrometry that Rspo1 is C-mannosylated at W(153) and W(156). Using Lec15.2 cells, which lack dolichol-phosphate-mannose synthesis activity, and mutant Rspo1 expressing cells that replace W(153) and W(156) by alanine residues, we observed that C-mannosylation of Rspo1 is required for its secretion. Further, the enhancement of canonical Wnt signaling by Rspo1 is regulated by C-mannosylation. Recently DPY19 was reported to be a C-mannosyltransferase in Caenorhabditis elegans, but no C-mannosyltransferases have been identified in any other organism. In gain- and loss-of-function experiments, human DPY19L3 selectively modified Rspo1 at W(156) but not W(153) based on mass spectrometry. Moreover, knockdown of DPY19L3 inhibited the secretion of Rspo1. In conclusion, we identified DPY19L3 as the C-mannosyltransferase of Rspo1 at W(156) and found that DPY19L3-mediated C-mannosylation of Rspo1 at W(156) is required for its secretion. PMID- 26764096 TI - Augmin shapes the anaphase spindle for efficient cytokinetic furrow ingression and abscission. AB - During anaphase, distinct populations of microtubules (MTs) form by either centrosome-dependent or augmin-dependent nucleation. It remains largely unknown whether these different MT populations contribute distinct functions to cytokinesis. Here we show that augmin-dependent MTs are required for the progression of both furrow ingression and abscission. Augmin depletion reduced the accumulation of anillin, a contractile ring regulator at the cell equator, yet centrosomal MTs were sufficient to mediate RhoA activation at the furrow. This defect in contractile ring organization, combined with incomplete spindle pole separation during anaphase, led to impaired furrow ingression. During the late stages of cytokinesis, astral MTs formed bundles in the intercellular bridge, but these failed to assemble a focused midbody structure and did not establish tight linkage to the plasma membrane, resulting in furrow regression. Thus augmin-dependent acentrosomal MTs and centrosomal MTs contribute to nonredundant targeting mechanisms of different cytokinesis factors, which are required for the formation of a functional contractile ring and midbody. PMID- 26764100 TI - Langmuir films study on lipid-containing artificial tears. AB - Lipid-containing artificial tears are a type of artificial tears that use lipid components in order to restore the lipid layer of the tear film. One of these components is lecithin which can be applied in spray solutions containing lecithin liposomes. In this work the behavior of three of these commercial tears based on lecithin, Innoxa, Opticalm and Optrex, are studied using the Langmuir technique. The obtained isotherms are presented, discussed and compared. This technique seems useful in order to see the film behavior of the lipid components of these tears and determine some important parameters such as fluidity and extension at the air-water interface, and allows us to discern differences between these commercial tears. Innoxa and Optrex tears are more similar to each other than to Opticalm tears. Opticalm presents more fluidity, probably due to the presence of more insaturations in the fatty acid chains of the phospholipids of the lecithin used in fabrication. PMID- 26764099 TI - Poly(L-histidine) based copolymers: Effect of the chemically substituted L histidine on the physio-chemical properties of the micelles and in vivo biodistribution. AB - Even though the Poly(l-histidine) (PHis) based copolymers have been well studied, the effect of the chemically substituted l-histidine on the physio-chemical and biological properties of the micelles has never been elucidated to date. To address this issue, triblock copolymer of poly(ethylene glycol)-poly(D,L-lactide) poly(2,4-dinitrophenol-L-histidine)(mPEG-b-PLA-b-DNP-PHis) with DNP group substituted to the saturated nitrogen of l-histidine were synthesized. The pH sensitive properties of the copolymer micelles were characterized using an acid base titration method, fluorescene probe technique, DLS observation, in vitro drug release and cytotoxicity against MCF-7 cells under different pH conditions, respectively. The results suggest that mPEG-b-PLA-b-DNP-PHis copolymers showed similar micellar stability for DOX loaded micelles, increased particle size, and similar pH responsive properties with mPEG-b-PLA-b-PHis copolymers. The subcellular distribution observation demonstrated that mPEG-b-PLA-b-DNP-PHis micelles showed a slightly compromised endo-lysosmal escape of doxorubicin as compared to mPEG-b-PLA-b-PHis micelles. The mPEG-b-PLA-b-DNP-PHis micelles showed higher cellular uptake by MCF-7 cells than mPEG-b-PLA-b-PHis micelles due to the different uptake pathways. Effect of DNP substitution on the in vivo distribution of the copolymer micelles was studied using non-invasive near-infrared fluorescence (NIRF) imaging with mPEG-b-PLA-b-PHis micelles as control. The results indicate that the mPEG-b-PLA-b-DNP-PHis micelles showed a reduced passive targeting to the tumor due to the larger particle size. These results suggest that saturated nitrogen of PHis may serve as a valuable site for chemical modification of the PHis based copolymers because of the little effect on the pH responsive properties. However, selection of the substitution group needs to be considered due to the possible increase of micellar particle size of the micelles, leading to compromised passive targeting. PMID- 26764098 TI - Inhibition of the FKBP family of peptidyl prolyl isomerases induces abortive translocation and degradation of the cellular prion protein. AB - Prion diseases are fatal neurodegenerative disorders for which there is no effective treatment. Because the cellular prion protein (PrP(C)) is required for propagation of the infectious scrapie form of the protein, one therapeutic strategy is to reduce PrP(C) expression. Recently FK506, an inhibitor of the FKBP family of peptidyl prolyl isomerases, was shown to increase survival in animal models of prion disease, with proposed mechanisms including calcineurin inhibition, induction of autophagy, and reduced PrP(C) expression. We show that FK506 treatment results in a profound reduction in PrP(C) expression due to a defect in the translocation of PrP(C) into the endoplasmic reticulum with subsequent degradation by the proteasome. These phenotypes could be bypassed by replacing the PrP(C) signal sequence with that of prolactin or osteopontin. In mouse cells, depletion of ER luminal FKBP10 was almost as potent as FK506 in attenuating expression of PrP(C). However, this occurred at a later stage, after translocation of PrP(C) into the ER. Both FK506 treatment and FKBP10 depletion were effective in reducing PrP(Sc) propagation in cell models. These findings show the involvement of FKBP proteins at different stages of PrP(C) biogenesis and identify FKBP10 as a potential therapeutic target for the treatment of prion diseases. PMID- 26764101 TI - Erythrocyte aggregation under high pressure studied by laser photometry and mathematical analysis. AB - The effects of hydrostatic pressure on erythrocyte aggregation have been studied by laser photometry and analysis based on a phenomenological theory. Samples were prepared by suspending swine erythrocytes in their own plasma. A high-pressure vessel consisting of a stainless-steel block with a hole to hold a sample cell and two sapphire windows to allows the passage of a He-Ne laser beam was used in the experimental setup. The suspension was stirred at 1500 rpm to disperse the erythrocytes homogeneously. Immediately after reducing the stirring rate from 1500 rpm to 300 rpm, the transmitted light intensity (I) was recorded every 10 ms under a high pressure of 40-200 MPa. The value of I increased with time (t) owing to erythrocyte aggregation. From the phenomenological theory, the equation DeltaI(t)=DeltaIeq[1-e(-Kt)/(1-B(1-e(-Kt)))] was derived for the change in the transmitted light intensity (DeltaI) due to erythrocyte aggregation, where DeltaIeq is the transmitted light intensity in the steady state, K is a time constant and B is a constant that represents the ratio of the number of interaction sites on erythrocyte aggregates at time t to that in the steady state. The observed time courses of DeltaI obtained at all pressures could be closely fitted to the theoretical equation. DeltaIeq roughly increased with increasing pressure. On the other hand, K and B abruptly decreased above 120 MPa. The growth rate of aggregates decreased above 120 MPa. These results suggest a change in the mechanism of erythrocyte aggregation at approximately 120 MPa. We discuss the physical meaning of the parameters. PMID- 26764102 TI - Non-invasive topical drug delivery to spinal cord with carboxyl-modified trifunctional copolymer of ethylene oxide and propylene oxide. AB - In this study the effect of oxidative modification on micellar and drug delivery properties of copolymers of ethylene oxide (EO) and propylene oxide (PO) was investigated. Carboxylated trifunctional copolymers were synthesized in the reaction with chromium(VI) oxide. We found that carboxylation significantly improved the uniformity and stability of polymeric micelles by inhibiting the microphase transition. The cytotoxicity of copolymers was studied in relation to their aggregative state on two cell types (cancer line vs. primary fibroblasts). The accumulation of rhodamine 123 in neuroblastoma SH-SY5Y cells was dramatically increased in the presence of the oxidized block copolymer with the number of PO and EO units of 83.5 and 24.2, respectively. The copolymer was also tested as an enhancer for topical drug delivery to the spinal cord when applied subdurally. The oxidized copolymer facilitated the penetration of rhodamine 123 across spinal cord tissues and increased its intraspinal accumulation. These results show the potential of using oxidized EO/PO based polymers for non-invasive delivery of protective drugs after spinal cord injury. PMID- 26764103 TI - Transport of stearic acid-based solid lipid nanoparticles (SLNs) into human epithelial cells. AB - Development of drug delivery systems, as much as the drug molecule itself, is an important consideration for improving drug absorption and bioavailability. The mechanisms by which drug carriers enter target cells can differ depending on their size, surface properties and components. Solid lipid nanoparticles (SLNs) have gained an increased attention in recent years and are the drug carriers of interest in this paper. They are known to breach the cell-membrane barrier and have been actively sought to transport biomolecules. Previous studies by our group, and also other groups, provided an extensive characterization of SLNs. However, few studies have investigated the uptake of SLNs and these have had limited mechanistic focus. The aim of this work was to investigate the pathway of uptake of SLNs by human epithelial cells i.e., lung A549 and cervical HeLa cells. To the best of our knowledge, this is first study that investigates the cellular uptake of SLNs by human epithelial cells. The mechanism of cellular uptake was deciphered using pharmacologic inhibitors (sucrose, potassium-free buffer, filipin and cytochalasin B). Imaging techniques and flow assisted cell sorting (FACS) were used to assess the cellular uptake of SLNs loaded with rhodamine 123 as a fluorescent probe. This study provided evidence that the cellular uptake of SLNs was energy-dependent, and the endocytosis of SLNs was mainly dependent on clathrin-mediated mechanisms. The establishment of entry mechanism of SLNs is of fundamental importance for future facilitation of SLNs as biological or drug carriers. PMID- 26764104 TI - Cytotoxicity of folic acid conjugated hollow silica nanoparticles toward Caco2 and 3T3 cells, with and without encapsulated DOX. AB - Hollow silica nanoparticles of two sizes with and without a folic acid targeting ligand were synthesized. Fickian diffusion of the antitumor drug doxorubicin hydrochloride (DOX) was demonstrated by the produced nanoparticles, achieving a cumulative release of 73% and 45% for 215 nm and 430 nm particles respectively over a period of 500 h. The hollow silica nanoparticles presented a time and dose dependent toxicity, selective to human epithelial colorectal adenocarcinoma (Caco2) cells, over mouse embryonic fibroblast (3T3) cells. At 24h Caco2 cell viability was reduced to 66% using pure hollow silica at a concentration of 50 MUg mL(-1), while that of 3T3 cells remained at 94% under the same conditions. The selective cytotoxicity of hollow silica nanoparticles was further enhanced by conjugation of folic acid and incorporation of DOX: at 24h and an equivalent DOX concentration of 0.5 MUg mL(-1), viable Caco2 cells were reduced to 45% while 3T3 cells were reduced to 83%. Interestingly the equivalent dose of free DOX was more toxic to 3T3 than to Caco2 cells, reducing the 3T3 viability to 72% and the Caco2 viability to 80%, which is likely due to the presence of the p-glycoprotein pumps in Caco2 cells. Folic acid conjugation served to enhance the viability of both cell lines in this work. Careful optimization of the folate content should further improve the cell specificity of the hollow silica nanoparticles, thus providing a viable targeting platform for cancer therapy. PMID- 26764105 TI - Physicochemical characterization and in vivo evaluation of triamcinolone acetonide-loaded hydroxyapatite nanocomposites for treatment of rheumatoid arthritis. AB - The current study was aimed to investigate the anti-inflammatory effect of triamcinolone acetonide-loaded hydroxyapatite (TA-loaded HAp) nanocomposites in the arthritic rat model. The HAp nanocomposites were synthesized through a chemical precipitation method and the drug was subsequently incorporated into the nanocomposites using an impregnation method. The physicochemical properties as well as cytotoxicity of the prepared nanoformulation were examined as well. To evaluate the therapeutic efficacy of the prepared nanoformulation, the various parameters such as paw volume, haematological parameters and histological studies were assessed in the arthritic rats. The nanocomposites with the particle size of 70.45 nm, pore size of 2.71 nm and drug loading of 41.94% were obtained in this study. The specific surface area (aBET) as well as the volume of nitrogen adsorbed on one gram of HAp to complete the monolayer adsorption (Vm) were decreased after the drug loading process. The prepared nanoformulation revealed the slower drug release profile compared to the pure drug. Furthermore, the obtained data from MTT assay showed that the TA-loaded nanocomposites had a lower cytotoxic effect on NIH-3T3 and CAOV-4 cell lines as compared to the pure drug. Furthermore, TA-loaded HAp nanocomposites demonstrated favorable effects on the paw volume as well as the haematological and histopathological abnormalities in the adjuvant-induced arthritic rats. Therefore, TA-loaded HAp nanocomposites are potentially suggested for treatment of rheumatoid arthritis after further required evaluations. PMID- 26764106 TI - Detection of adenosine triphosphate in HeLa cell using capillary electrophoresis laser induced fluorescence detection based on aptamer and graphene oxide. AB - A method for ATP quantification based on dye-labeled aptamer/graphene oxide (aptamer/GO) using capillary electrophoresis-laser induced fluorescence (CE-LIF) detecting technique has been established. In this method, the carboxyfluorescein (FAM)-labelled ATP aptamers were adsorbed onto the surface of GO, leading to the fluorescence quenching of FAM; after the incubation with a limited amount of ATP, stronger affinity between ATP aptamer and ATP resulted in the desorption of aptamers and the fluorescence restoration of FAM. Then, aptamer-ATP complex and excess of aptamer/GO and GO were separated and quantified by CE-LIF detection. It was shown that a linear relation was existing in the CE-LIF peak intensity of aptamer-ATP and ATP concentration in range of 10-700 MUM, the regression equation was F=1.50+0.0470C(ATP) (R(2)=0.990), and the limit of detection was 1.28 MUM (3S/N, n=5), which was one order magnitude lower than that of detection in solution by fluorescence method. The approach with excellent specificity and reproducibility has been successfully applied to detecting concentration of ATP in HeLa cell. PMID- 26764107 TI - Omega-3 fatty acids incorporated colloidal systems for the delivery of Angelica gigas Nakai extract. AB - Omega-3 (omega-3) fish oil-enriched colloidal systems were developed for the oral delivery of Angelica gigas Nakai (AGN) extract (ext). By constructing a pseudo ternary phase diagram, the composition of oil-in-water (o/w) microemulsion (ME) systems based on omega-3 (oil), Labrasol (surfactant), and water was determined. AGN ext was dissolved into the ME system and d-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS) was added to the ME formulation in order to enhance the mucosal absorption of the pharmacologically active ingredients in the AGN ext. The droplet size of AGN-loaded MEs was 205-277 nm and their morphology was spherical. The release of major components of AGN, decursin (D) and decursinol angelate (DA), from ME formulations in pH 1.2 and 6.8 buffers was significantly greater (P<0.05) than that from the AGN suspension group. The pharmacokinetic properties of AGN-loaded MEs in rats were evaluated by measuring decursinol (DOH) concentrations in plasma after oral administration. TPGS-included ME (F2) resulted in significantly greater (P<0.05) systemic exposure of DOH than that with ME without TPGS (F1), AGN ext+TPGS, and AGN in suspension. Severe toxicity of F1 and F2 on the intestinal epithelium was not observed by histological staining. The colloidal carriers described herein are promising delivery systems for oral administration of AGN ext. PMID- 26764108 TI - alpha-Tocopherol succinate improves encapsulation and anticancer activity of doxorubicin loaded in solid lipid nanoparticles. AB - This work aimed to develop solid lipid nanoparticles (SLN) co-loaded with doxorubicin and alpha-tocopheryl succinate (TS), a succinic acid ester of alpha tocopherol that exhibits anticancer actions, evaluating the influence of TS on drug encapsulation efficiency. The SLN were characterized for size, zeta potential, entrapment efficiency (EE), and drug release. Studies of in vitro anticancer activity were also conducted. The EE was significantly improved from 30 +/- 1% to 96 +/- 2% for SLN without and with TS at 0.4%, respectively. In contrast, a reduction in particle size from 298 +/- 1 to 79 +/- 1 nm was observed for SLN without and with TS respectively. The doxorubicin release data show that SLN provide a controlled drug release. The in vitro studies showed higher cytotoxicity for doxorubicin-TS-loaded SLN than for free doxorubicin in breast cancer cells. These findings suggest that TS-doxorubicin-loaded SLN is a promising alternative for the treatment of cancer. PMID- 26764109 TI - Coating morphology and surface composition of acrylic terpolymers with pendant catechol, OEG and perfluoroalkyl groups in varying ratio and the effect on protein adsorption. AB - This work aims at developing versatile low-biofouling polymeric coatings by using acrylic terpolymers (DOFs) that bear pendant catechol (D), oligo(ethylene glycol) (O), and perfluoroalkyl (F) groups in varying ratios. The polymers were endowed with the ability to form firmly coatings on virtually any surfaces and undergo surface microphase separation and self-assembly, as revealed by the surface enrichment of F pendants and the morphology variation from irregular solid domains to discrete crater-type aggregates of different size. The effect on protein adsorption was investigated using bovine serum albumin (BSA) and adhesive fibrinogen (Fib) as model proteins. The coating of DOF164 (low F content), which has morphology of discrete crater-type aggregates of ~ 400 nm in size, adsorbed a least amount of protein but with a highest protein unit activity as determined by SPR and immunosorbent assay; whereas the coating of DOF1612 (high F content) showed a 12.3-fold higher adsorption capacity toward Fib. Interestingly, a 2.2 fold lower adsorption amount but with a 1.8-fold higher unit activity was found for Fib adsorbed on the DOF164 surface than on DOF250 (without F fraction), whose OEG segments being a widely recognized protein compatible material. The features of the DOF164 terpolymer presenting a robust coating ability and a minimal protein adsorption capacity while with a high protein unit activity suggest its potential application as a non-fouling surface-modifier for medical antifouling coatings and as a matrix material for selective protein immobilization and activity preservation in biosensor construction. PMID- 26764110 TI - Structural, biocomplexation and gene delivery properties of hydroxyethylated gemini surfactants with varied spacer length. AB - Gemini surfactants with hexadecyl tails and hydroxyethylated head groups bridged with tetramethylene (G4), hexamethylene (G6) and dodecamethylene (G12) spacers were shown to self-assemble at the lower critical micelle concentration compared to their conventional m-s-m analogs. The lipoplex formation and the plasmid DNA transfer into different kinds of host cells were studied. In the case of eukaryotic cells, high transfection efficacy has been demonstrated for DNA-gemini complexes, which increased as follows: G6G4>G12 has been obtained in the case of transformation of bacterial cells with plasmid DNA-gemini complexes, mediated by electroporation technique. Solely G6 shows transformation efficacy exceeding the control result (uncomplexed DNA), while the inhibitory effect occurs for G4 and G12. Analysis of physico chemical features of single surfactants and lipoplexes shows that compaction and condensation effects change as follows: G62-fold) of the IgG1 subtype in serum from TD boys (n = 60) compared to ASD boys (n = 74), as well as compared to older adult males (n = 53). Together these data suggest that ASD boys have reduced levels (>50%) of an IgG1 antibody, which resembles the level found normally with advanced age. In this discovery study, the ASD1 peptoid was 66% accurate in predicting ASD. PMID- 26764138 TI - Histone acetylation and methylation significantly change with severity of atherosclerosis in human carotid plaques. AB - BACKGROUND: The aim of the study was to analyze histone acetylation, methylation, and the expression of their corresponding transferases in atherosclerotic plaques of patients with carotid artery stenosis. METHODS: Atherosclerotic tissue from our biobank (n=80) was divided into various segments covering all plaque stages and classified according to the American Heart Association. The plaques were assigned to early (types I-III) or advanced (types V-VII) stage group of atherosclerosis. Ten healthy carotid arteries from transplant donors served as controls. The expression of histone acetyltransferases (GNAT group: GCN5L, P300/CBP group: P300, MYST group: MYST1 and MYST2) and histone methyltransferases (H3K4: MLL2/4, SET7/9, and hSET1A; H3K9: SUV39H1, SUV39H2, ESET/SETDB1, and EHMT1; H3K27: EZH2 and G9a) was analyzed by SYBR-green-based real-time polymerase chain reaction. Histone acetylation/methylation in the cells within atherosclerotic plaques was determined by immunohistochemistry. RESULTS: Increased histone acetylation was observed on H3K9 and H3K27 in smooth muscle cells (SMCs) in advanced atherosclerotic lesions compared to healthy vessels (P=.002 and .034). H3K9 acetylation in SMCs and macrophages was associated with plaque severity of atherosclerosis (P=.048 and <.001). Expression of GCN5L and MYST1 also correlated with the severity of atherosclerosis (P<.001). Methylation of H3K9 and H3K27 was significantly reduced in atherosclerotic plaques in SMCs and inflammatory cells (P<.001 and .026). Methylation on H3K4 was significantly associated with the severity of atherosclerosis. Expression of methyltransferase MLL2/4 was increased in advanced stages of atherosclerosis (P<.001). CONCLUSIONS: Histone acetylation and methylation seem to play a decisive role in atherosclerosis, showing significant differences between healthy vessels and vessels at different stages of atherosclerosis. PMID- 26764139 TI - Fulminant Peripartum myocarditis associated with sudden cardiac death: a case report. AB - Myocarditis is an inflammatory disease of myocardium, associated with nonischemic necrosis and degeneration of myocytes. Although the clinical course is rapid, myocarditis can lead to dilated cardiomyopathy with chambers dilatation and ventricular dysfunction. The pathophysiology of myocarditis in humans is not completely understood. There are several etiological agents implicated, mainly viral agents. The clinical presentation is extremely various, with nonspecific systemic symptoms until sudden death. The great variability of symptoms makes the diagnosis, therefore, extremely difficult. We report the case of a 40-year-old woman who developed, after childbirth, hyperthermia associated with neck and left arm pain; initially treated with acetaminophen, without any benefit, the young woman, after few days, died suddenly. The autopsy documented the presence of edematous lungs and enlarged and congested liver. The microbiological tests performed 4 days after death were negative. The heart was normal in shape and volume; a section of the left ventricle wall showed subendocardial discromic areas histologically characterized by multifocal perivascular and interstitial inflammatory infiltrates. These infiltrates consisted mainly of neutrophils with eosinophil component associated with myocyte necrosis and hemorrhagic interstitial infiltration. PMID- 26764140 TI - Immunoglobulin G4-related disease: some missing pieces in a still unsolved complex puzzle. PMID- 26764142 TI - Neonatal multiple blood cysts of heart valves. AB - The female neonate, 27 days, 53 cm, 3450 g, was found dead in early morning hours. Baby was healthy, well nourished, and not neglected, up to the day before when she started to cough and scheduled for next-day regular pediatrician visit. Due to unexpected death, the autopsy was performed. Multiple oval, blood cysts, up to 0.5 cm, were found on the free valvular margins of the mitral valve, tricuspid valve, and aortic valve. The blood cysts were unilocular, filled with blood, and lined with flattened endothelial cells. The surrounding stroma was slightly edematous but without myxoid changes. PMID- 26764141 TI - Dynamic monitoring of oxidative DNA double-strand break and repair in cardiomyocytes. AB - DNA double-strand breaks (DSBs) are most dangerous lesions. To determine whether oxidative stress can induce DSBs and how they are repaired in cardiomyocytes (CMs), cultured neonatal rat CMs were treated with different doses of H2O2 and followed for up to 72 h for monitoring the spatiotemporal dynamics of DNA repair protein assembly/disassembly at DSB foci. The protein levels and foci numbers of histone H2AX phosphorylated at serine 139 (gamma-H2AX) increased proportionally to 50, 100, and 200 MUmol/L H2O2 after 30 min treatment. When H2O2 was at or above 400 MUmol/L, gamma-H2AX became predominantly pannuclear. After 30 min, 200 MUmol/L of H2O2 treatment, gamma-H2AX levels were highest within the first hour and then gradually declined during the recovery and returned to basal levels at 48 h. Among DNA damage transducer kinases, ataxia telangiectasia mutated (ATM) was significantly activated by H2O2 in contrast to mild activation of ATR (ATM and Rad3-related). A DSB binding protein, p53 binding protein 1, formed distinct nuclear foci that colocalized with gamma-H2AX foci and phosphorylated ATM. Our findings indicate that DSBs can be induced by H2O2 and ATM is the main kinase to mediate DSB repair in CMs. Therefore, monitoring DSB repair can assess oxidative injury and response in CMs. PMID- 26764144 TI - Segmental arterial mediolysis and fibromuscular dysplasia: what comes first, the chicken or the egg? AB - Segmental arterial mediolysis (SAM) is a rare vasculopathy characterized by lysis of the outer media in splanchnic arteries and formation of dissecting pseudoaneurysms that may spontaneously rupture, leading to massive and often fatal intraabdominal hemorrhage. The pathogenesis of SAM is poorly understood. Healed SAM lesions closely resemble fibromuscular dysplasia (FMD), leading some authors to postulate that SAM represents a precursor to FMD despite distinct clinical differences between these two disorders. Herein, we present a 61-year old woman with fatal SAM who showed histologic features in her aorta suggesting the opposite pathogenetic relationship, with an unclassified "FMD-like" arteriopathy preceding development of SAM. PMID- 26764143 TI - Impaired mitochondrial biogenesis is a common feature to myocardial hypertrophy and end-stage ischemic heart failure. AB - Mitochondrial (mt) DNA depletion and oxidative mtDNA damage have been implicated in the process of pathological cardiac remodeling. Whether these features are present in the early phase of maladaptive cardiac remodeling, that is, during compensated cardiac hypertrophy, is still unknown. We compared the morphologic and molecular features of mt biogenesis and markers of oxidative stress in human heart from adult subjects with compensated hypertrophic cardiomyopathy and heart failure. We have shown that mtDNA depletion is a constant feature of both conditions. A quantitative loss of mtDNA content was associated with significant down-regulation of selected modulators of mt biogenesis and decreased expression of proteins involved in mtDNA maintenance. Interestingly, mtDNA depletion characterized also the end-stage phase of cardiomyopathies due to a primary mtDNA defect. Oxidative stress damage was detected only in failing myocardium. PMID- 26764145 TI - Resveratrol improves vasoprotective effects of captopril on aortic remodeling and fibrosis triggered by renovascular hypertension. AB - BACKGROUND: Renin-angiotensin system triggers vascular remodeling and fibrosis during the renovascular hypertensive two-kidney, one-clip (2K1C) model by oxidative-stress-mediated mechanisms. Thus, we hypothesized that the chronic treatment with the polyphenolic antioxidant resveratrol would improve the vasoprotective effects promoted by the chronic treatment with the angiotensin converting enzyme inhibitor (ACEi) captopril in 2K1C hypertensive rats. Our main objective was to evaluate the effects of the combined treatment with resveratrol and captopril on vascular remodeling and fibrosis in 2K1C rats. METHODS: Male Wistar rats underwent to unilateral renal stenosis by 2K1C Goldblatt model. Six weeks after surgery, rat systolic blood pressure (SBP) was measured by indirect tail-cuff plethysmography. 2K1C rats were considered hypertensive when presenting SBP higher than 160 mmHg and underwent resveratrol (20 mg/kg), captopril (6 or 12 mg/kg), or resveratrol (20 mg/kg) combined with captopril (6 or 12 mg/kg) treatment for 3 weeks. Nine weeks after surgery, rat SBP was measured, and rat thoracic aorta was isolated for histological assays with hematoxylin/eosin or Picrosirius Red to evaluate aortic remodeling and fibrosis, respectively. RESULTS: Oral treatment of 2K1C hypertensive rats with resveratrol (20 mg/kg) combined with the dose-dependent ACEi captopril (6 and 12 mg/kg) resulted in lesser aortic thickening and reduced aortic fibrosis. Resveratrol (20 mg/kg) promoted a more expressive hypotensive effect with captopril (12 mg/kg) in 2K1C rats than the treatment with isolated captopril (12 mg/kg). CONCLUSION: Resveratrol improves the vasoprotective effects promoted by captopril on aortic remodeling and fibrosis during renovascular hypertension probably by synergic mechanisms involving antioxidant actions and nitric oxide generation. PMID- 26764146 TI - Argonaute proteins in cardiac tissue contribute to the heart injury during viral myocarditis. AB - MicroRNAs (miRNAs) are a group of short, noncoding, regulatory RNA molecules the dysregulation of which contributes to the pathogenesis of myocarditis. Argonaute proteins are essential components of miRNA-induced silencing complex and play important roles during miRNA biogenesis and function. However, the expression pattern of four AGO family members has not yet been detected in the coxsackievirus B3 (CVB3)-induced myocarditis tissue samples. In this study, we detected the expression of four AGOs in the CVB3-infected mouse heart tissues and found that AGO1 and AGO3 up-regulated significantly at 4 and 8h after CVB3 infection. Further in vitro research indicated that up-regulated AGO1 and AGO3 are related to the down-regulated TNFAIP3, which is a negative regulator of NF kappaB pathway. Subsequently, we confirmed that TNFAIP3 is a direct target of miR 19a/b, and during CVB3 infection, the expression of miR-19a/b and miR-125a/b is not significantly changed. TNFAIP3 level is mainly reduced by up-regulated AGO1 and AGO3. This research sheds light on the relationship between overexpressed AGO proteins and CVB3-induced myocarditis, and this provides potential therapeutic target for viral myocarditis. PMID- 26764149 TI - The electrical heart: 25 years of discovery in cardiac electrophysiology, arrhythmias and sudden death. AB - This review summarizes progress in the fields of cardiac electrophysiology, arrhythmias and sudden death made in the 25-year interval between 1992 and 2016 during which time Cardiovascular Pathology has been published. Organized along clinical lines, it considers the major heart rhythm disorders underlying atrial, atrioventricular and ventricular arrhythmias, and sudden cardiac death. There is a strong focus on the remarkable advances in understanding the genetic basis for cardiac rhythm disturbances and elucidating fundamental mechanisms of abnormal conduction and impulse formation. During this 25-year period, our understanding of how altered tissue structure (classical pathology) contributes to arrhythmias and sudden death has undergone continuous refinement as new insights have been gained about arrhythmia mechanisms and the dynamic interplay between anatomic substrates and triggers of the major heart rhythm disorders. PMID- 26764148 TI - Ventricular myocarditis coincides with atrial myocarditis in patients. AB - INTRODUCTION: Atrial fibrillation (AF) is a common complication in myocarditis. Atrial inflammation has been suggested to play an important role in the pathophysiology of AF. However, little is known about the occurrence of atrial inflammation in myocarditis patients. Here, we analyzed inflammatory cell numbers in the atria of myocarditis patients without symptomatic AF. METHODS: Cardiac tissue was obtained postmortem from lymphocytic myocarditis patients (n=6), catecholamine-induced myocarditis patients (n=5), and control patients without pathological evidence of heart disease (n=5). Tissue sections of left and right ventricle and left and right atrium were stained for myeloperoxidase (neutrophilic granulocytes), CD45 (lymphocytes), and CD68 (macrophages). These cells were subsequently quantified in atrial and ventricular myocardium and atrial adipose tissue. RESULTS: In lymphocytic myocarditis patients, a significant increase was observed for lymphocytes in the left atrial adipose tissue. In catecholamine-induced myocarditis patients, significant increases were found in the atria for all three inflammatory cell types. Infiltrating inflammatory cell numbers in the atrial myocardium correlated positively with those in the ventricles, especially in catecholamine-induced myocarditis patients. CONCLUSIONS: To a varying extent, atrial myocarditis occurs concurrently with ventricular myocarditis in patients diagnosed with myocarditis of different etiology. This provides a substrate that potentially predisposes myocarditis patients to the development of AF and subsequent complications such as sudden cardiac death and heart failure. PMID- 26764150 TI - Improved fertility in suckled beef cows ovulating large follicles or supplemented with long-acting progesterone after timed-AI. AB - We aimed to evaluate the effects and the interaction of size of the preovulatory follicle (POF) and long-acting progesterone (P4) supplementation after timed-AI on CL function and pregnancy success in beef cows. In experiment 1, ovulations of beef cows were synchronized starting on Day -10, and cows were split to receive sodium cloprostenol (large follicle group; LF; n = 31) or nothing (small follicle group; SF; n = 35). Ovulations were induced on Day 0, and cows were inseminated. Ovulated cows were assigned to receive placebo (LF/control group, n = 14; and SF/control group, n = 9) or 150 mg of long-acting P4 on Day 4.5 (LF/P4 group, n = 13; and SF/P4 group, n = 12). Diameter of POF, blood flow in POF wall, ovulation rate, and size and vascularization of CL were greater (P < 0.05) in LF group. In experiments 2 (unknown cyclic status) and 4 (noncycling), ovulations were synchronized, and beef cows received placebo or 150 mg of long-acting P4 on Day 4 after timed-artificial insemination. In experiment 2, pregnancy/AI (P/AI) did not differ (P > 0.1) between P4-treated (53.2%; 209/393) and control cows (56.2%; 219/390), but P/AI was greater in cows with a CL < 0.9 cm(2) on Day 4 that were P4-treated (57.9%, 22/38) versus placebo-treated (40.4%, 21/52; P < 0.05). In Experiment 4, P/AI was greater (P < 0.05) in P4-treated cows (55.6%, 105/189 vs. 46.0%, 86/187). In Experiment 3, cyclic-suckled beef cows were treated as described in Experiment 1 to generate animals with small (SF; n = 111) or large POF (LF; n = 109), and subdivided to receive placebo or P4 on Day 4. POF size, ovulation rate, CL area, and P/AI were greater (P < 0.007) in the LF group. Pregnancy/AI in ovulated cows were lower (P = 0.05) in the SF/control group (41.5%, 17/41) compared to LF/control group (62%, 31/50) and were similar for the SF/P4 group (55.6%, 25/45) and LF/P4 group (57%, 28/49) compared to others. In summary, smaller and less vascularized POF results in less functional CL and reduces ovulatory rate and P/AI in cyclic beef cows; the long-acting P4 injection on Day 4 after timed-artificial insemination may attenuate the negative effects of small POF/CL; and postovulatory P4 supplementation improved fertility in anestrous beef cattle. PMID- 26764147 TI - Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1. AB - The muscle-specific ubiquitin ligase muscle ring finger-1 (MuRF1) is critical in regulating both pathological and physiological cardiac hypertrophy in vivo. Previous work from our group has identified MuRF1's ability to inhibit serum response factor and insulin-like growth factor-1 signaling pathways (via targeted inhibition of cJun as underlying mechanisms). More recently, we have identified that MuRF1 inhibits fatty acid metabolism by targeting peroxisome proliferator activated receptor alpha (PPARalpha) for nuclear export via mono-ubiquitination. Since MuRF1-/- mice have an estimated fivefold increase in PPARalpha activity, we sought to determine how challenge with the PPARalpha agonist fenofibrate, a PPARalpha ligand, would affect the heart physiologically. In as little as 3 weeks, feeding with fenofibrate/chow (0.05% wt/wt) induced unexpected pathological cardiac hypertrophy not present in age-matched sibling wild-type (MuRF1+/+) mice, identified by echocardiography, cardiomyocyte cross-sectional area, and increased beta-myosin heavy chain, brain natriuretic peptide, and skeletal muscle alpha-actin mRNA. In addition to pathological hypertrophy, MuRF1 /- mice had an unexpected differential expression in genes associated with the pleiotropic effects of fenofibrate involved in the extracellular matrix, protease inhibition, hemostasis, and the sarcomere. At both 3 and 8 weeks of fenofibrate treatment, the differentially expressed MuRF1-/- genes most commonly had SREBP-1 and E2F1/E2F promoter regions by TRANSFAC analysis (54 and 50 genes, respectively, of the 111 of the genes >4 and <-4 log fold change; P <= .0004). These studies identify MuRF1's unexpected regulation of fenofibrate's pleiotropic effects and bridges, for the first time, MuRF1's regulation of PPARalpha, cardiac hypertrophy, and hemostasis. PMID- 26764151 TI - Effect of colloid (Androcoll-Bear, Percoll, and PureSperm) selection on the freezability of brown bear (Ursus arctos) sperm. AB - The development of a species-specific conservation protocol that involves artificial insemination with frozen semen needs to validate an effective methodology for freezing semen. Colloid centrifugation has been suggested and widely applied as an effective tool for selecting animal spermatozoa for artificial breeding. The objective of the present study was to compare different methods of centrifugation, single layer using Androcoll-Bear and Percoll and double layer using PureSperm 100 (in two different discontinuous gradients 40% 80% and 45%-90%), for the selection of fresh brown bear sperm samples. In the before freezing group, all selected samples showed a higher progressive motility and viability (except Percoll for motility 43.0 +/- 5.3 [P < 0.05]); all colloids except PureSperm 45/90% rendered samples with fewer damaged acrosomes. In the after thawing group, all tested centrifugation colloids showed a good capacity to decrease the number of damaged acrosomes. Furthermore, PureSperm treatment (45/90%) resulted in an increase in apoptotic-like changes not only immediately after thawing but also after the incubation test, leading us to suggest that this gradient could induce some kind of deleterious effects on the sperm samples. On the other hand, PureSperm treatment (40/80%) yielded a quality preservation capacity similar to Androcoll-Bear in number of damaged acrosomes, different relative to the control (control, 5.3 +/- 0.6; PureSperm 80, 2.0 +/- 0.3; Androcoll, 2.1 +/- 0.9 [P < 0.05]) but a decrease in the number of viable spermatozoa recovered after thawing relative to the control (control, 21.2 +/- 3.1; PureSperm 80, 13.7 +/- 2.7 [P < 0.05]). In conclusion, Androcoll-Bear constitutes a useful tool for handling of brown bear ejaculates owing to its simple handling and procedure with a reliable sperm selection and freezability. This colloid yielded an improvement in several sperm parameters in brown bear frozen-thawed semen; the selected spermatozoa of fresh samples with this colloid showed a better resistance to freezing compared with the control sample not only for motility but also for viability. PMID- 26764152 TI - Diagnosis and effects of urine contamination in cooled-extended stallion semen. AB - Urospermia is known to affect semen quality in many mammals, including stallions. Determinations of semen pH and creatinine and urea concentrations have been used to diagnose urine contamination in raw stallion semen. Unfortunately, practitioners suspecting urine contamination in cooled-shipped samples have no proven means to confirm the presence of urine. Therefore, the objectives of this study were (1) to assess the effects of urine contamination on sperm motility of extended fresh and cooled-stored stallion semen, (2) to evaluate the usefulness of semen color, odor, pH, and creatinine and urea concentrations for urospermia diagnosis, and (3) to evaluate the accuracy of a commercial blood urea nitrogen test strip in diagnosing urine contamination in extended-cooled stallion semen. Thirty-seven ejaculates were obtained from 11 stallions with no history of urospermia before division into 5 mL aliquots, and contamination with stallion urine. Each resulting sample was assessed for sperm motility, color, odor, pH, creatinine, and urea nitrogen concentration using both a semiquantitative test strip (Azostix), and a quantitative automated analyzer before and after cooling for 24 hour. Sperm motility parameters, pH, and creatinine and urea concentrations were analyzed using mixed models. Urine contamination decreased total and progressive motility in all samples before and after cooling (P < 0.05). Mean control total motility was 80% at 0 hour and 67% at 24 hours, whereas urine-contaminated samples ranged from 30% to 71% at 0 hour and 27% to 61% at 24 hours. Control mean urea (29 mg/dL) and creatinine (0.6 mg/dL) concentrations were significantly different (P < 0.05) from all urine-contaminated samples (158 mg/dL and 11.6 mg/dL, respectively) at 0 hour. Similarly, control mean urea (8 mg/dL) and creatinine (0.9 mg/dL) concentrations were significantly different than all urine-contaminated samples at 24 hours. Odor assessment presented moderate sensitivity (65%) and high specificity (100%), while color assessment presented low sensitivity (47%) and moderate specificity (79%) for urine in extended semen. Azostix strips were highly sensitive (95%) and specific (97%). Assessment of color, odor, and pH are not reliable methods to diagnose urine in experimentally contaminated cooled-stored stallion semen. Sperm motility parameters (in raw and cooled semen) are significantly reduced by the presence of urine in a concentration dependent. The results of the present study indicated that determination of urea and creatinine concentrations can be used to diagnose urospermia and that Azostix can be used as a point care method for diagnosing urine contamination in extended cooled stallion semen. PMID- 26764153 TI - Erratum for the Research Article: "CMV-specific T cells generated from naive T cells recognize atypical epitopes and may be protective in vivo" by P. J. Hanley, J. J. Melenhorst, S. Nikiforow, P. Scheinberg, J. W. Blaney, G. Demmler-Harrison, C. R. Cruz, S. Lam, R. A. Krance, K. S. Leung, C. A. Martinez, H. Liu, D. C. Douek, H. E. Heslop, C. M. Rooney, E. J. Shpall, A. J. Barrett, J. R. Rodgers, C. M. Bollard. PMID- 26764154 TI - Clinical trials for neurodevelopmental disorders: At a therapeutic frontier. AB - A well-powered clinical trial that failed to replicate promising results in animal models of fragile X syndrome yields important lessons for clinical trial design (Berry-Kravis et al., this issue). PMID- 26764155 TI - Personalized medical education: Reappraising clinician-scientist training. AB - Revitalizing the Oslerian ideal of the clinician-scientist-teacher may help in the training of the next generation of translational researchers. PMID- 26764156 TI - Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials. AB - Fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autistic spectrum disorder, is typically caused by transcriptional silencing of the X-linked FMR1 gene. Work in animal models has described altered synaptic plasticity, a result of the up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling, as a putative downstream effect. Post hoc analysis of a randomized, placebo-controlled, crossover phase 2 trial suggested that the selective mGluR5 antagonist mavoglurant improved behavioral symptoms in FXS patients with completely methylated FMR1 genes. We present the results of two phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel group studies of mavoglurant in FXS, designed to confirm this result in adults (n = 175, aged 18 to 45 years) and adolescents (n = 139, aged 12 to 17 years). In both trials, participants were stratified by methylation status and randomized to receive mavoglurant (25, 50, or 100 mg twice daily) or placebo over 12 weeks. Neither of the studies achieved the primary efficacy end point of improvement on behavioral symptoms measured by the Aberrant Behavior Checklist-Community Edition using the FXS-specific algorithm (ABC-C(FX)) after 12 weeks of treatment with mavoglurant. The safety and tolerability profile of mavoglurant was as previously described, with few adverse events. Therefore, under the conditions of our study, we could not confirm the mGluR theory of FXS nor the ability of the methylation state of the FMR1 promoter to predict mavoglurant efficacy. Preclinical results suggest that future clinical trials might profitably explore initiating treatment in a younger population with longer treatment duration and longer placebo run-ins and identifying new markers to better assess behavioral and cognitive benefits. PMID- 26764157 TI - Repetitive blast exposure in mice and combat veterans causes persistent cerebellar dysfunction. AB - Blast exposure can cause mild traumatic brain injury (TBI) in mice and other mammals. However, there are important gaps in our understanding of the neuropathology underlying repetitive blast exposure in animal models compared to the neuroimaging abnormalities observed in blast-exposed veterans. Moreover, how an increase in the number of blast exposures affects neuroimaging endpoints in blast-exposed humans is not well understood. We asked whether there is a dose response relationship between the number of blast-related mild TBIs and uptake of (18)F-fluorodeoxyglucose (FDG), a commonly used indicator of neuronal activity, in the brains of blast-exposed veterans with mild TBI. We found that the number of blast exposures correlated with FDG uptake in the cerebellum of veterans. In mice, blast exposure produced microlesions in the blood-brain barrier (BBB) predominantly in the ventral cerebellum. Purkinje cells associated with these BBB microlesions displayed plasma membrane disruptions and aberrant expression of phosphorylated tau protein. Purkinje cell loss was most pronounced in the ventral cerebellar lobules, suggesting that early-stage breakdown of BBB integrity may be an important factor driving long-term brain changes. Blast exposure caused reactive gliosis in mouse cerebellum, particularly in the deep cerebellar nuclei. Diffusion tensor imaging tractography of the cerebellum of blast-exposed veterans revealed that mean diffusivity correlated negatively with the number of blast related mild TBIs. Together, these results argue that the cerebellum is vulnerable to repetitive mild TBI in both mice and humans. PMID- 26764159 TI - Cord blood monocyte-derived inflammatory cytokines suppress IL-2 and induce nonclassic "T(H)2-type" immunity associated with development of food allergy. AB - Food allergy is a major health burden in early childhood. Infants who develop food allergy display a proinflammatory immune profile in cord blood, but how this is related to interleukin-4 (IL-4)/T helper 2 (T(H)2)-type immunity characteristic of allergy is unknown. In a general population-derived birth cohort, we found that in infants who developed food allergy, cord blood displayed a higher monocyte to CD4(+) T cell ratio and a lower proportion of natural regulatory T cell (nT(reg)) in relation to duration of labor. CD14(+) monocytes of food-allergic infants secreted higher amounts of inflammatory cytokines (IL 1beta, IL-6, and tumor necrosis factor-alpha) in response to lipopolysaccharide. In the presence of the mucosal cytokine transforming growth factor-beta, these inflammatory cytokines suppressed IL-2 expression by CD4(+) T cells. In the absence of IL-2, inflammatory cytokines decreased the number of activated nT(reg) and diverted the differentiation of both nT(reg) and naive CD4(+) T cells toward an IL-4-expressing nonclassical TH2 phenotype. These findings provide a mechanistic explanation for susceptibility to food allergy in infants and suggest anti-inflammatory approaches to its prevention. PMID- 26764158 TI - Inhibition of diacylglycerol kinase alpha restores restimulation-induced cell death and reduces immunopathology in XLP-1. AB - X-linked lymphoproliferative disease (XLP-1) is an often-fatal primary immunodeficiency associated with the exuberant expansion of activated CD8(+) T cells after Epstein-Barr virus (EBV) infection. XLP-1 is caused by defects in signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), an adaptor protein that modulates T cell receptor (TCR)-induced signaling. SAP deficient T cells exhibit impaired TCR restimulation-induced cell death (RICD) and diminished TCR-induced inhibition of diacylglycerol kinase alpha (DGKalpha), leading to increased diacylglycerol metabolism and decreased signaling through Ras and PKCtheta (protein kinase Ctheta). We show that down-regulation of DGKalpha activity in SAP-deficient T cells restores diacylglycerol signaling at the immune synapse and rescues RICD via induction of the proapoptotic proteins NUR77 and NOR1. Pharmacological inhibition of DGKalpha prevents the excessive CD8(+) T cell expansion and interferon-gamma production that occur in SAP deficient mice after lymphocytic choriomeningitis virus infection without impairing lytic activity. Collectively, these data highlight DGKalpha as a viable therapeutic target to reverse the life-threatening EBV-associated immunopathology that occurs in XLP-1 patients. PMID- 26764161 TI - Spectrum of Clinical Responses to Therapies in Infantile Bullous Pemphigoid. AB - Infantile bullous pemphigoid (BP) is a rare autoimmune dermatosis characterized by the presence of antibodies against basal membrane zone proteins. Histologic and immunologic features are similar to those of the adult disease, but its clinical features may vary in children. We report here four cases of infantile BP whose atypical presentation or progression shed new light on the disease. PMID- 26764162 TI - An efficient strategy to assemble water soluble histidine-perylene diimide and graphene oxide for the detection of PPi in physiological conditions and in vitro. AB - A strategy to develop water soluble, biocompatible nanocomposite probe for the detection of pyrophosphate (PPi) in physiological conditions and in in vitro live melanoma cancer cells (B16F10) is reported. The self-assembled nanocomposite probe comprised of amino acid (histidine) functionalized perylenediimide (PDI HIS), copper ion and graphene oxide (GO) and that could be utilized as a highly effective sensing platform in biological conditions and cellular environment via fluorescence "turn-on" for PPi detection. This controlled fabrication of metal organic self-assembled spheres along with GO proved very valuable for the detection of PPi in unprecedented sensitivity over other competing ions. The PDI HIS-Cu-GO (PCG) nanocomposite sensor provides a unique platform for the fluorogenic detection of PPi having a very low limit of detection (LOD) of 0.60*10-7M based on the strong affinity (1.0*106M-1) between the copper complex of PDI-HIS receptor and PPi. The intracellular detection of PPi using PCG also carried out in B16F10 cells where >10 times observed as compared to the PDI HIS+Cu2+ complex. Thus early cancer detection via PPi recognition in physiological conditions and in live cells was possible using PCG. Furthermore, the fabrication of PDI-HIS and PCG with PVA hydrogel films and on thin layer chromatography plates demonstrated the practical utility for the detection of PPi anions by "off-on" response rapidly in a label free manner. PMID- 26764160 TI - 267 Spanish Exomes Reveal Population-Specific Differences in Disease-Related Genetic Variation. AB - Recent results from large-scale genomic projects suggest that allele frequencies, which are highly relevant for medical purposes, differ considerably across different populations. The need for a detailed catalog of local variability motivated the whole-exome sequencing of 267 unrelated individuals, representative of the healthy Spanish population. Like in other studies, a considerable number of rare variants were found (almost one-third of the described variants). There were also relevant differences in allelic frequencies in polymorphic variants, including ~10,000 polymorphisms private to the Spanish population. The allelic frequencies of variants conferring susceptibility to complex diseases (including cancer, schizophrenia, Alzheimer disease, type 2 diabetes, and other pathologies) were overall similar to those of other populations. However, the trend is the opposite for variants linked to Mendelian and rare diseases (including several retinal degenerative dystrophies and cardiomyopathies) that show marked frequency differences between populations. Interestingly, a correspondence between differences in allelic frequencies and disease prevalence was found, highlighting the relevance of frequency differences in disease risk. These differences are also observed in variants that disrupt known drug binding sites, suggesting an important role for local variability in population-specific drug resistances or adverse effects. We have made the Spanish population variant server web page that contains population frequency information for the complete list of 170,888 variant positions we found publicly available (http://spv.babelomics.org/), We show that it if fundamental to determine population-specific variant frequencies to distinguish real disease associations from population-specific polymorphisms. PMID- 26764163 TI - Prognosis of Brief Psychotic Episodes: A Meta-analysis. AB - IMPORTANCE: The prognostic significance of competing constructs and operationalizations for brief psychotic episodes (acute and transient psychotic disorder [ATPD], brief psychotic disorder [BPD], brief intermittent psychotic symptoms [BIPS], and brief limited intermittent psychotic symptoms [BLIPS]) is unknown. OBJECTIVE: To provide a meta-analytical prognosis of the risk of psychotic recurrence in patients with remitted first-episode ATPD, BPD, BIPS, and BLIPS and in a benchmark group of patients with remitted first-episode schizophrenia (FES). We hypothesized a differential risk: FES > ATPD > BPD > BIPS > BLIPS. DATA SOURCES: The Web of Knowledge and Scopus databases were searched up to May 18, 2015; the articles identified were reviewed as well as citations of previous publications and results of a manual search of the reference lists of retrieved articles. STUDY SELECTION: We included original articles that reported the risk of psychotic recurrence at follow-up for patients in remission from first-episode ATPD, BPD, BLIPS, BIPS, and FES. DATA EXTRACTION AND SYNTHESIS: Independent extraction by multiple observers. Random-effects meta-analysis was performed, and moderators were tested with meta-regression analyses, Bonferroni corrected. Heterogeneity was assessed with the I2 index. Sensitivity analyses tested the robustness of the results. Publication bias was assessed with funnel plots and the Egger test. MAIN OUTCOMES AND MEASURES: Proportion of patients with baseline ATPD, BPD, BLIPS, and BIPS who had any psychotic recurrence at 6, 12, 24, and 36 or more months of follow-up. RESULTS: Eighty-two independent studies comprising up to 11,133 patients were included. There was no prognostic difference in risk of psychotic recurrence between ATPD, BPD, BLIPS, and BIPS at any follow-up (P > .03). In the long-term analysis, risk of psychotic recurrence (reported as mean [95% CI]) was significantly higher in the FES group (0.78 [0.58 0.93] at 24 months and 0.84 [0.70-0.94] at >= 36 months; P < .02 and P < .001, respectively) compared with the other 4 groups (0.39 [0.32-0.47] at 24 months and 0.51 [0.41-0.61] at >= 36 months). There were no publication biases. Sex and exposure to antipsychotic medication modulated the meta-analytical estimates (.002 < P < .03). CONCLUSIONS AND RELEVANCE: There are no prognostic differences in risk of psychotic recurrence between ATPD, BPD, BLIPS, and BIPS constructs of brief psychotic episodes. Conversely, there is consistent meta-analytical evidence for better long-term prognosis of brief psychotic episodes compared with remitted first-episode schizophrenia. These findings should influence the diagnostic practice and clinical services in the management of early psychosis. PMID- 26764164 TI - Transparent superwetting nanofilms with enhanced durability at model physiological condition. AB - There have been many studies on superwetting surfaces owing to the variety of their potential applications. There are some drawbacks to developing these films for biomedical applications, such as the fragility of the microscopic roughness feature that is vital to ensure superwettability. But, there are still only a few studies that have shown an enhanced durability of nanoscale superwetting films at certain extreme environment. In this study, we fabricated intrinsically stable superwetting films using the organosilicate based layer-by-layer (LbL) self assembly method in order to control nano-sized roughness of the multilayer structures. In order to develop mechanically and chemically robust surfaces, we successfully introduced polymeric silsesquioxane as a building block for LbL assembly with desired fashion. Even in the case that the superhydrophobic outer layers were damaged, the films maintained their superhydrophobicity because of the hydrophobic nature of their inner layers. As a result, we successfully fabricated superwetting nano-films and evaluated their robustness and stability. PMID- 26764166 TI - Surgical treatment of Cesarean scar ectopic pregnancy: efficacy and safety of ultrasound-guided suction curettage. AB - OBJECTIVES: To assess the efficacy of ultrasound-guided suction curettage for management of pregnancies implanted into the lower uterine segment Cesarean section scar. METHODS: This was a retrospective study including women diagnosed with Cesarean section scar pregnancy at two large tertiary referral early pregnancy units between 1997 and 2014. Surgical evacuation was offered to selected women presenting in the first trimester <= 14 weeks' gestation. All procedures were performed transcervically under ultrasound guidance using suction curettage. A modified Shirodkar cervical suture was used in women who required additional measures to secure hemostasis. RESULTS: A total of 232 women with Cesarean section scar pregnancy were seen at the referral units; 191/232 (82.3%) women were treated surgically. The median intraoperative blood loss was 100 mL (range, 10-3000 mL); 9/191 (4.7% (95% CI, 1.7-7.7%)) women required blood transfusion and, in one (0.5% (95% CI, 0-1.5%)), life-saving hysterectomy had to be performed because of uncontrollable intraoperative bleeding. Of the women who attended for follow-up, 7/116 (6.0% (95% CI, 1.7-10.3%)) required a repeat surgical procedure because of retained products of conception. Multivariable analysis showed that the gestational sac diameter (odds ratio (OR), 1.10 (95% CI, 1.03-1.17)) and pregnancy vascularity on Doppler examination (OR, 3.41 (95% CI, 1.39-8.33)) were significant predictors of heavy intraoperative blood loss (> 1000 mL). CONCLUSIONS: Ultrasound-guided suction curettage is an effective method for the treatment of pregnancies implanted into a lower uterine segment Cesarean section scar and is associated with a low risk of blood transfusion and hysterectomy. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26764165 TI - Genotoxic mode of action predictions from a multiplexed flow cytometric assay and a machine learning approach. AB - Several endpoints associated with cellular responses to DNA damage as well as overt cytotoxicity were multiplexed into a miniaturized, "add and read" type flow cytometric assay. Reagents included a detergent to liberate nuclei, RNase and propidium iodide to serve as a pan-DNA dye, fluorescent antibodies against gammaH2AX, phospho-histone H3, and p53, and fluorescent microspheres for absolute nuclei counts. The assay was applied to TK6 cells and 67 diverse reference chemicals that served as a training set. Exposure was for 24 hrs in 96-well plates, and unless precipitation or foreknowledge about cytotoxicity suggested otherwise, the highest concentration was 1 mM. At 4- and 24-hrs aliquots were removed and added to microtiter plates containing the reagent mix. Following a brief incubation period robotic sampling facilitated walk-away data acquisition. Univariate analyses identified biomarkers and time points that were valuable for classifying agents into one of three groups: clastogenic, aneugenic, or non genotoxic. These mode of action predictions were optimized with a forward stepping process that considered Wald test p-values, receiver operator characteristic curves, and pseudo R(2) values, among others. A particularly high performing multinomial logistic regression model was comprised of four factors: 4 hr gammaH2AX and phospho-histone H3 values, and 24 hr p53 and polyploidy values. For the training set chemicals, the four-factor model resulted in 94% concordance with our a priori classifications. Cross validation occurred via a leave-one-out approach, and in this case 91% concordance was observed. A test set of 17 chemicals that were not used to construct the model were evaluated, some of which utilized a short-term treatment in the presence of a metabolic activation system, and in 16 cases mode of action was correctly predicted. These initial results are encouraging as they suggest a machine learning strategy can be used to rapidly and reliably predict new chemicals' genotoxic mode of action based on data from an efficient and highly scalable multiplexed assay. PMID- 26764169 TI - IDENTIFICATION OF PROTEASOME ALPHA6 SUBUNIT ASSOCIATED WITH DELTAMETHRIN RESISTANCE IN Drosophila melanogaster Kc CELLS. AB - Differential expression of the proteasome alpha6 (prosalpha6) was previously reported between Plutella xylostella strains that are resistant or susceptible to the pesticide deltamethrin (DM). This finding indicated that the prosalpha6 may be involved in DM resistance. In this article, qPCR analysis revealed that the prosalpha6 was also significantly upregulated in Drosophila Kc cells treated with DM. To better understand the contribution of prosalpha6 in DM resistance, RNA interference, heterologous expression, and a proteasome inhibitor (MG-132) were used. MG-132 was used to suppress proteasomal activity, and the dsRNA was designed to block the function of prosalpha6. The results indicated that both MG 132 and prosalpha6 knockdown decreased the cellular viability following DM treatment. Prosalpha6 was cloned and transfected into Drosophila Kc cells. The result showed that overexpression of prosalpha6 in Drosophila Kc cells conferred some protection against DM. Taken together, our results indicate that prosalpha6 is involved in Drosophila cells DM resistance. PMID- 26764170 TI - Large Controlled Observational Study on Remote Monitoring of Pacemakers and Implantable Cardiac Defibrillators: A Clinical, Economic, and Organizational Evaluation. AB - BACKGROUND: Patients with implantable devices such as pacemakers (PMs) and implantable cardiac defibrillators (ICDs) should be followed up every 3-12 months, which traditionally required in-clinic visits. Innovative devices allow data transmission and technical or medical alerts to be sent from the patient's home to the physician (remote monitoring). A number of studies have shown its effectiveness in timely detection and management of both clinical and technical events, and endorsed its adoption. Unfortunately, in daily practice, remote monitoring has been implemented in uncoordinated and rather fragmented ways, calling for a more strategic approach. OBJECTIVE: The objective of the study was to analyze the impact of remote monitoring for PM and ICD in a "real world" context compared with in-clinic follow-up. The evaluation focuses on how this service is carried out by Local Health Authorities, the impact on the cardiology unit and the health system, and organizational features promoting or hindering its effectiveness and efficiency. METHODS: A multi-center, multi-vendor, controlled, observational, prospective study was conducted to analyze the impact of remote monitoring implementation. A total of 2101 patients were enrolled in the study: 1871 patients were followed through remote monitoring of PM/ICD (I group) and 230 through in-clinic visits (U-group). The follow-up period was 12 months. RESULTS: In-clinic device follow-ups and cardiac visits were significantly lower in the I-group compared with the U-group, respectively: PM, I group = 0.43, U-group = 1.07, P<.001; ICD, I-group = 0.98, U-group = 2.14, P<.001. PM, I-group = 0.37, U-group = 0.85, P<.001; ICD, I-group = 1.58, U-group = 1.69, P=.01. Hospitalizations for any cause were significantly lower in the I group for PM patients only (I-group = 0.37, U-group = 0.50, P=.005). There were no significant differences regarding use of the emergency department for both PM and ICD patients. In the I-group, 0.30 (PM) and 0.37 (ICD) real clinical events per patient per year were detected within a mean (SD) time of 1.18 (2.08) days. Mean time spent by physicians to treat a patient was lower in the I-group compared to the U-group (-4.1 minutes PM; -13.7 minutes ICD). Organizational analysis showed that remote monitoring implementation was rather haphazard and fragmented. From a health care system perspective, the economic analysis showed statistically significant gains (P<.001) for the I-group using PM. CONCLUSIONS: This study contributes to build solid evidence regarding the usefulness of RM in detecting and managing clinical and technical events with limited use of manpower and other health care resources. To fully gain the benefits of RM of PM/ICD, it is vital that organizational processes be streamlined and standardized within an overarching strategy. PMID- 26764172 TI - Effect of carboidiimide on thermal denaturation temperature of dentin collagen. AB - OBJECTIVES: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) has been shown to cross-link dentin type I collagen. Increased cross-linking usually elevates the glass transition temperature of polymers. The aim of this study was to evaluate the cross-linking reaction promoted by EDC in different aqueous concentrations by measuring the thermal denaturation temperature (Td) of human dentin collagen. METHODS: The Td of dehydrated collagen and of insoluble dentin matrix collagen immersed in 0.5M or 1M EDC aqueous solution for different treatment times was obtained using a Differential Scanning Calorimeter (DSC). Specimens were also analyzed by Energy Dispersive X-Ray Spectroscopy. RESULTS: EDC-treated dentin collagen showed a significantly higher Td than the untreated specimens when immersed in either 0.5M EDC or 1M EDC for 10min or longer (p<0.05). EDC-treated dentin collagen showed an increase of sulfur and chloride, not detectable in EDC-untreated dentin specimens. Conversely, the relative amount of carbon, nitrogen and oxygen was not modified by treatments. SIGNIFICANCE: EDC treated dentin collagen showed a higher Td than the untreated control at all tested concentrations and immersion times. A higher Td can be considered an indirect indicator of a more resistant and highly cross-linked collagen network. More data are needed to confirm these results. PMID- 26764171 TI - Probing the dual function of a novel tertiary amine compound in dentin adhesive formulations. AB - OBJECTIVES: A novel tertiary amine compound containing three methacrylate urethane groups was synthesized for application in dentin adhesives. The synthesis, photopolymerization kinetics, and leaching were examined in an earlier study using this novel compound as the co-initiator (0.5 and 1.75wt% based on the total resin mass). The objective of this work was to investigate the potential of TUMA (8-(2-(((2-(methacryloyloxy)ethyl)carbamoyl)oxy)propyl)-6,10-dimethyl-4,12 dioxo-5,11-dioxa-3,8,13-triazapentadecane-1,15-diyl bis(2-methylacrylate)) to serve simultaneously as a co-initiator and co-monomer (15-45wt% based on the total resin mass) in dentin adhesive formulations. The polymerization kinetics, water sorption and dynamic mechanical properties of these novel formulations were determined. MATERIALS AND METHOD: The monomer system contained Bisphenol A glycerolate dimethacrylate (BisGMA), 2-hydroxyethylmethacrylate (HEMA) and TUMA (synthesized in our lab) at the mass ratio of 45/(55-x)/x. Two photoinitiator (PI) systems were compared. One initiator system contains three components: camphorquinone (CQ), diphenyliodonium hexafluorophosphate (DPIHP) and ethyl-4 (dimethylamino) benzoate (EDMAB) and the second initiator system contains CQ and DPIHP. The control adhesive formulations are: C0-3: HEMA/BisGMA 45/55 (w/w) and 3 component PI and C0-2: HEMA/BisGMA 45/55 (w/w) and 2-component PI. These controls were used as a comparison to the experimental adhesive resins (Ex-3 or Ex-2), in which x represents the weight percentage of synthesized co-monomer (TUMA) to replace part of BisGMA. The control and experimental adhesive formulations were photo-polymerized and compared with regard to the degree of conversion (DC), polymerization rate (Rp), water sorption and dynamic mechanical analysis (DMA) under both dry and wet conditions. RESULTS: C0-3 and Ex-3 formulations had similar DC, while the DC of Ex-2 formulation was higher than C0-2. The DC was similar when comparing the two- component with the three-component photoinitiator system when TUMA was used at the same concentration. DMA under dry conditions shows higher rubbery storage modulus for all experimental formulations, while storage modulus at rubbery region under wet conditions was decreased as compared with control (C0-3). There was no statistically significant difference for the DMA results under both dry and wet conditions when comparing two- and three component initiator systems with the same TUMA concentration. SIGNIFICANCE: The newly synthesized TUMA could serve simultaneously as a co-monomer and co initiator in the absence of commercial co-initiator. This study provides information for the future development of new co-monomer/co-initiator for dentin adhesives and dental composites. PMID- 26764174 TI - Poly(propylene glycol) and urethane dimethacrylates improve conversion of dental composites and reveal complexity of cytocompatibility testing. AB - OBJECTIVES: To determine the effects of various monomers on conversion and cytocompatibility of dental composites and to improve these properties without detrimentally affecting mechanical properties, depth of cure and shrinkage. METHODS: Composites containing urethane dimethacrylate (UDMA) or bisphenol A glycidyl methacrylate (Bis-GMA) with poly(propylene glycol) dimethacrylate (PPGDMA) or triethylene glycol dimethacrylate (TEGDMA) were characterized using the following techniques: conversion (FTIR at 1 and 4mm depths), depth of cure (BS EN ISO 4049:2009 and FTIR), shrinkage (BS EN ISO 17304:2013 and FTIR), strength and modulus (biaxial flexural test) and water sorption. Cytocompatibility of composites and their liquid phase components was assessed using three assays (resazurin, WST-8 and MTS). RESULTS: UDMA significantly improved conversion, BFS and depth of cure compared to Bis-GMA, without increasing shrinkage. UDMA was cytotoxic at lower concentrations than Bis-GMA, but extracts of Bis-GMA-containing composites were less cytocompatible than of those containing UDMA. PPGDMA improved conversion and depth of cure compared to TEGDMA, without detrimentally affecting shrinkage. TEGDMA was shown by all assays to be highly toxic. Resazurin, but not WST-8 and MTS, suggested that PPGDMA exhibited improved cytocompatibility compared to TEGDMA. SIGNIFICANCE: The use of UDMA and PPGDMA results in composites with excellent conversion, depth of cure and mechanical properties, without increasing shrinkage. Composites containing UDMA appear to be slightly more cytocompatible than those containing Bis-GMA. These monomers may therefore improve the material properties of dental restorations, particularly bulk fill materials. The effect of diluent monomer on cytocompatibility requires further investigation. PMID- 26764173 TI - Characterization of methacrylate-based composites containing thio-urethane oligomers. AB - OBJECTIVE: To evaluate the ability of thio-urethane oligomers to improve the properties of restorative composite resins. METHODS: Oligomers were synthesized by combining 1,6-hexanediol-diissocyante (aliphatic) with pentaerythritol tetra-3 mercaptopropionate (PETMP) or 1,3-bis(1-isocyanato-1-methylethyl)benzene (aromatic) with trimethylol-tris-3-mercaptopropionate (TMP), at 1:2 isocyanate:thiol, leaving pendant thiols. Oligomers were added at 0-20 wt% to BisGMA-TEGDMA (70-30 wt%). Silanated inorganic fillers were added (70 wt%). Materials were photoactivated at 800 mW/cm(2) filtered to 320-500 nm. Near-IR was used to follow degree of methacrylate conversion (DC). Mechanical properties were evaluated in three-point bending with 2 mm * 2 mm * 25 mm bars for flexural strength/modulus and toughness (FS/E, and T) according to ISO 4049, and 2 mm * 5 mm * 25 mm notched specimens for fracture toughness (KIC). Polymerization stress (PS) was measured on the Bioman. Results were analyzed with ANOVA/Tukey's test (alpha=5%). RESULTS: Significant increase in DC was observed in thio-urethane containing materials especially for the group with 20 wt% of aliphatic version. Materials composed by oligomers also promoted higher FS, E, and KIC in comparison to controls irrespective of thio-urethane type. A significant increase in toughness was detected by ANOVA, but not distinguished in the groups. The PS was significantly reduced by the presence of thio-urethane for almost all groups. CONCLUSIONS: The use of thio-urethane oligomer to compose methacrylate-based restorative composite promote increase in DC, FS, E and KIC while significant reduces PS. SIGNIFICANCE: A simple additive was shown to reduce stress while increasing convrersion and mechanical properties, mainly fracture toughness. This has he potential of increasing the service life of dental composites, without changing current operatory procedures. PMID- 26764175 TI - Strontium effects on root dentin tubule occlusion and nanomechanical properties. AB - OBJECTIVES: Dentin hypersensitivity often is treated by promotion of dentin tubule occlusion. In this in vitro study we evaluated nanomechanical properties and degree of tubule occlusion conferred to sound and demineralized human root dentin following treatment with a 10% (w/w) strontium acetate solution and its relation to the treatment duration and delivery method. METHODS: 24 human cervical root dentin disks (8 groups of 3) were polished through 0.25 MUm. 12 disks were subjected to an acid challenge (1% citric acid, pH 3.8) for 2 min. The specimens were incubated in artificial saliva, treated by soaking or brushing with deionized (DI) water or a solution of 10% strontium acetate for 2 min twice a day for 28 days. The occlusion percent and nanomechanical properties were determined at the baseline, 5, 14 and 28 days. Cross-sectioned specimens were prepared to evaluate the depth affected by strontium acetate / dentin interaction by SEM. Statistical analysis was performed using linear mixed effects models. RESULTS: A 10% strontium acetate treatment over 5-28 days significantly increased tubule occlusion for normal root dentin and to a lesser extent for demineralized dentin and increased the AFM based nanomechanical properties of demineralized dentin. Brushing was more effective than soaking in recovery of properties of demineralized dentin when treated with strontium. No difference in tubuleocclusion was found between the two delivery methods. SIGNIFICANCE: Strontium acetate itself proved to have the ability to occlude dentin tubules and result in small changes in the mechanical properties of dentin. PMID- 26764176 TI - Mechanical reliability of air-abraded and acid-etched bonded feldspar ceramic. AB - OBJECTIVES: This study investigated the effect of surface treatment (air-abrasion with alumina or hydrofluoric acid-etching) on feldspar ceramic mechanical strength and initial reliability (24h) before/after adhesive luting. METHODS: Ceramic discs (VITA) were tested as monolithic specimens (Acid; Abrasion), luted bilayers (Acid+luting agent; Abrasion+luting agent), or untreated (Control). Luted groups were coated using resin-based agent (RelyX Veneer, 3M ESPE). Biaxial flexural test with ball-on-ring setup was carried out (n=30). Biaxial flexural strength (sigmabf, MPa), characteristic strength (sigma0, MPa), and Weibull modulus (m) were calculated for axial positions z=0 (ceramic surface) and z=-t2 (luting agent surface). For each condition, 95% confidence intervals were calculated. Scanning electron microscopy was used for topography and fractography analyses. RESULTS: At z=0, sigmabf and sigma0 of luted specimens were higher than of monolithic specimens for both surface treatments. Groups Acid and Abrasion had lower sigmabf and sigma0 than Control. Group Abrasion had poorer mechanical strength. Similar structural reliability was observed for all conditions except for the group Abrasion+luting agent, which had lower m than all other groups. At z=-t2, no significant differences between luted groups were observed for mechanical strength and reliability. A more irregular surface topography with more sharp angles was left by air-abrasion than etching. Monolithic specimens failed from surface pores at the tensile area, whereas failure in luted specimens originated from pores below the resin-ceramic interface. SIGNIFICANCE: Air abrasion yielded lower mechanical strength and initial reliability than acid etching. Presence of a resin-based luting agent layer bonded to ceramic significantly increased its mechanical strength. PMID- 26764177 TI - Use of crosslinkers to inactivate dentin MMPs. AB - OBJECTIVES: This study evaluated the endogenous matrix metalloproteinase (MMP) activity of demineralized dentin matrix following 1 or 5 min pretreatment by various collagen crosslinkers. Generic MMP activity assay, total protein analysis, in situ zymography, gelatin zymography and multiplex bead technology were used to evaluate matrix-bound MMP activity. METHODS: Six different crosslinkers; glutaraldehyde, riboflavin/UVA, riboflavin-5-monophospate/UVA, sumac berry extract, grape seed extract, and curcumin were used. Demineralized dentin beams were pretreated with respective crosslinkers for 1 or 5 min. Demineralized dentin beams with no crosslinker pretreatment served as control. The reduction in the total activity of dentin matrices were measured using generic MMP activity assay. Dentin slabs were used for in situ zymography and evaluated by using hydrolysis of self-quenched fluorescein-conjugated gelatin under confocal microscopy. Dentin beam extracts were used for total protein assay and multiplex analysis and powder extracts were used for gelatin zymography. RESULTS: MMP activity in crosslinker pretreated samples decreased significantly between 21% and 70%, whereas untreated control samples' activity increased up to 84%. Zymograms confirmed a decrease in the gelatinolytic activity and in the amount of extractable total protein content. Multiplex analysis of extracts of crosslinker-treated dentin showed a reduction in the MMP-8, MMP-2 and MMP-9 release. SIGNIFICANCE: The result of this work suggests that the effect of the crosslinkers is source-dependent. The use of crosslinkers for as little as 1min on demineralized dentin can inactivate the endogenous protease activity of dentin matrices. PMID- 26764178 TI - Survival of resin infiltrated ceramics under influence of fatigue. AB - PURPOSE: to evaluate influence of cyclic fatigue on two resin infiltrated ceramics and three all-ceramic crowns manufactured using CAD/CAM technology. MATERIALS AND METHODS: CAD/CAM anatomically shaped crowns were manufactured using two resin infiltrated ceramics (Lava Ultimate and Vita Enamic), two reinforced glass ceramic milling blocks ((IPS)Empress CAD and (IPS)e.max CAD) and a veneered zirconia core ((IPS)Zir CAD). (IPS)e.max CAD and (IPS)Zir CAD were milled into 0.5mm thick anatomically shaped core structure which received standardized press on veneer ceramic. The manufactured crowns were cemented on standardized resin dies using a resin adhesive (Panavia F2.0). Initial fracture strength of half of the specimens was calculated using one cycle load to failure in a universal testing machine. The remaining crowns were subjected to 3.7 million chewing cycles (load range 50-200N at 3s interval) in a custom made pneumatic fatigue tester. Survival statistics were calculated and Weibull modulus was measured from fitted load-cycle-failure diagrams. Scanning electron microscopy was performed to fractographically analyze fractured surfaces. Data were analyzed using two way analysis of variance and Bonferroni post hoc tests (alpha=0.05). RESULTS: Dynamic fatigue resulted in significant reduction (F=7.54, P<0.005) of the initial fracture strength of the tested specimens. Zirconia showed the highest deterioration percent (34% reduction in strength) followed by (IPS)Empress (32.2%), (IPS)e.max (27.1%) while Lava Ultimate and Vita Enamic showed the lowest percent of reduction in strength. The two types of resin infiltrated ceramics and (IPS)Empress demonstrated the highest percent of fracture incidences under the influence of fatigue (35-45% splitting). None of the tested veneered zirconia restorations were fractured during testing, however, chipping of the veneer ceramics was observed in 6 crowns. The lowest percent of failure was observed for (IPS)e.max crowns manifested as 3 cases of minor chipping in addition to two complete fracture incidences. SEM images demonstrated the internal structure of the tested materials and detected location and size of the critical crack. CONCLUSION: The internal structure of the tested materials significantly influenced their fatigue behavior. Resin infiltrated ceramics were least influenced by fatigue while the characteristic strength of zirconia prevented core fracture but failure still occurred from the weaker veneer ceramic. PMID- 26764179 TI - Examining Minority Attrition Among Women in Longitudinal Trauma Research. AB - Research suggests that racial and ethnic minorities are more likely to attrit from longitudinal trauma studies than non-Hispanic Whites. Yet, little is known about how the loss of minority participants influences longitudinal findings as well as internal and external validity of study findings. Thus, the present study examined the effects of race/ethnicity on attrition in a longitudinal trauma study of women (minority = 223, non-Hispanic White or majority = 459) exposed to a campus shooting. Survival analyses were used to compare the attrition rates of minority participants to majority participants and assess the extent to which race/ethnicity, among other variables, predicted attrition. Minority participants were more likely to attrit than majority participants, hazard ratio (HR) = 0.69, 95% CI [0.48, 0.99], even after adjusting for study variables. A main effect was also found for age, HR = 1.06, 95% CI [1.01, 1.12]. Race/ethnicity did not interact with other study variables to influence attrition. The findings underscored the importance of assessing the effects of attrition on longitudinal findings and external validity. PMID- 26764180 TI - Skin dose differences between intensity-modulated radiation therapy and volumetric-modulated arc therapy and between boost and integrated treatment regimens for treating head and neck and other cancer sites in patients. AB - The purpose of this study was (1) to evaluate dose to skin between volumetric modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) treatment techniques for target sites in the head and neck, pelvis, and brain and (2) to determine if the treatment dose and fractionation regimen affect the skin dose between traditional sequential boost and integrated boost regimens for patients with head and neck cancer. A total of 19 patients and 48 plans were evaluated. The Eclipse (v11) treatment planning system was used to plan therapy in 9 patients with head and neck cancer, 5 patients with prostate cancer, and 5 patients with brain cancer with VMAT and static-field IMRT. The mean skin dose and the maximum dose to a contiguous volume of 2cm(3) for head and neck plans and brain plans and a contiguous volume of 5cm(3) for pelvis plans were compared for each treatment technique. Of the 9 patients with head and neck cancer, 3 underwent an integrated boost regimen. One integrated boost plan was replanned with IMRT and VMAT using a traditional boost regimen. For target sites located in the head and neck, VMAT reduced the mean dose and contiguous hot spot most noticeably in the shoulder region by 5.6% and 5.4%, respectively. When using an integrated boost regimen, the contiguous hot spot skin dose in the shoulder was larger on average than a traditional boost pattern by 26.5% and the mean skin dose was larger by 1.7%. VMAT techniques largely decrease the contiguous hot spot in the skin in the pelvis by an average of 36% compared with IMRT. For the same target coverage, VMAT can reduce the skin dose in all the regions of the body, but more noticeably in the shoulders in patients with head and neck and pelvis cancer. We also found that using integrated boost regimens in patients with head and neck cancer leads to higher shoulder skin doses compared with traditional boost regimens. PMID- 26764181 TI - Establishing and Governing e-Mental Health Care in Australia: A Systematic Review of Challenges and A Call For Policy-Focussed Research. AB - BACKGROUND: Growing evidence attests to the efficacy of e-mental health services. There is less evidence on how to facilitate the safe, effective, and sustainable implementation of these services. OBJECTIVE: We conducted a systematic review on e-mental health service use for depressive and anxiety disorders to inform policy development and identify policy-relevant gaps in the evidence base. METHODS: Following the PRISMA protocol, we identified research (1) conducted in Australia, (2) on e-mental health services, (3) for depressive or anxiety disorders, and (4) on e-mental health usage, such as barriers and facilitators to use. Databases searched included Cochrane, PubMed, PsycINFO, CINAHL, Embase, ProQuest Social Science, and Google Scholar. Sources were assessed according to area and level of policy relevance. RESULTS: The search yielded 1081 studies; 30 studies were included for analysis. Most reported on self-selected samples and samples of online help-seekers. Studies indicate that e-mental health services are predominantly used by females, and those who are more educated and socioeconomically advantaged. Ethnicity was infrequently reported on. Studies examining consumer preferences found a preference for face-to-face therapy over e therapies, but not an aversion to e-therapy. Content relevant to governance was predominantly related to the organizational dimensions of e-mental health services, followed by implications for community education. Financing and payment for e-services and governance of the information communication technology were least commonly discussed. CONCLUSIONS: Little research focuses explicitly on policy development and implementation planning; most research provides an e services perspective. Research is needed to provide community and policy-maker perspectives. General population studies of prospective treatment seekers that include ethnicity and socioeconomic status and quantify relative preferences for all treatment modalities are necessary. PMID- 26764182 TI - Intensive Enteral Nutrition Is Ineffective for Patients With Severe Alcoholic Hepatitis Treated With Corticosteroids. AB - BACKGROUND & AIMS: Severe alcoholic hepatitis (AH) is a life-threatening disease for which adequate oral nutritional support is recommended. We performed a randomized controlled trial to determine whether the combination of corticosteroid and intensive enteral nutrition therapy is more effective than corticosteroid therapy alone in patients with severe AH. METHODS: We enrolled 136 heavy consumers of alcohol (age, 18-75 y) with recent onset of jaundice and biopsy-proven severe AH in our study, performed at 18 hospitals in Belgium and 2 in France, from February 2010 through February 2013. Subjects were assigned randomly (1:1) to groups that received either intensive enteral nutrition plus methylprednisolone or conventional nutrition plus methylprednisolone (controls). In the intensive enteral nutrition group, enteral nutrition was given via feeding tube for 14 days. The primary end point was patient survival for 6 months. RESULTS: In an intention-to-treat analysis, we found no significant difference between groups in 6-month cumulative mortality: 44.4% of patients died in the intensive enteral nutrition group (95% confidence interval [CI], 32.2%-55.9%) and 52.1% of controls died (95% CI, 39.4%-63.4%) (P = .406). The enteral feeding tube was withdrawn prematurely from 48.5% of patients, and serious adverse events considered to be related to enteral nutrition occurred in 5 patients. Regardless of group, a greater proportion of patients with a daily calorie intake less than 21.5 kcal/kg/day died (65.8%; 95% CI, 48.8-78.4) than patients with a higher intake of calories (33.1%; 95% CI, 23.1%-43.4%) (P < .001). CONCLUSIONS: In a randomized trial of patients with severe AH treated with corticosteroids, we found that intensive enteral nutrition was difficult to implement and did not increase survival. However, low daily energy intake was associated with greater mortality, so adequate nutritional intake should be a main goal for treatment. ClinicalTrials.gov number: NCT01801332. PMID- 26764184 TI - Lipid-Induced Signaling Causes Release of Inflammatory Extracellular Vesicles From Hepatocytes. AB - BACKGROUND & AIMS: Hepatocyte cellular dysfunction and death induced by lipids and macrophage-associated inflammation are characteristics of nonalcoholic steatohepatitis (NASH). The fatty acid palmitate can activate death receptor 5 (DR5) on hepatocytes, leading to their death, but little is known about how this process contributes to macrophage-associated inflammation. We investigated whether lipid-induced DR5 signaling results in the release of extracellular vesicles (EVs) from hepatocytes, and whether these can induce an inflammatory macrophage phenotype. METHODS: Primary mouse and human hepatocytes and Huh7 cells were incubated with palmitate, its metabolite lysophosphatidylcholine, or diluent (control). The released EV were isolated, characterized, quantified, and applied to macrophages. C57BL/6 mice were placed on chow or a diet high in fat, fructose, and cholesterol to induce NASH. Some mice also were given the ROCK1 inhibitor fasudil; 2 weeks later, serum EVs were isolated and characterized by immunoblot and nanoparticle-tracking analyses. Livers were collected and analyzed by histology, immunohistochemistry, and quantitative polymerase chain reaction. RESULTS: Incubation of primary hepatocytes and Huh7 cells with palmitate or lysophosphatidylcholine increased their release of EVs, compared with control cells. This release was reduced by inactivating mediators of the DR5 signaling pathway or rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) inhibition. Hepatocyte-derived EVs contained tumor necrosis factor-related apoptosis-inducing ligand and induced expression of interleukin 1beta and interleukin 6 messenger RNAs in mouse bone marrow-derived macrophages. Activation of macrophages required DR5 and receptor-interacting protein kinase 1. Administration of the ROCK1 inhibitor fasudil to mice with NASH reduced serum levels of EVs; this reduction was associated with decreased liver injury, inflammation, and fibrosis. CONCLUSIONS: Lipids, which stimulate DR5, induce release of hepatocyte EVs, which activate an inflammatory phenotype in macrophages. Strategies to inhibit ROCK1-dependent release of EVs by hepatocytes might be developed for the treatment of patients with NASH. PMID- 26764183 TI - Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers. AB - BACKGROUND & AIMS: A long duration of inflammatory bowel disease (IBD) increases the risk for colorectal cancer. Mutation analysis of limited numbers of genes has indicated that colorectal tumors that develop in patients with IBD differ from those of patients without IBD. We performed whole-exome sequencing analyses to characterize the genetic landscape of these tumors. METHODS: We collected colorectal tumor and non-neoplastic tissues from 31 patients with IBD and colorectal cancer (15 with ulcerative colitis, 14 with Crohn's disease, and 2 with indeterminate colitis) and performed whole-exome sequencing analyses of the microdissected tumor and matched nontumor tissues. We identified somatic alterations by comparing matched specimens. The prevalence of mutations in sporadic colorectal tumors was obtained from previously published exome sequencing studies. RESULTS: Two specimens had somatic mutations in the DNA proofreading or mismatch repair genes POLE, MLH1, and MSH6 and the tumor cells had a hypermutable phenotype. The remaining tumors had, on average, 71 alterations per sample. TP53 was the most commonly mutated gene, with prevalence similar to that of sporadic colorectal tumors (63% of cases). However, tumors from the patients with IBD had a different mutation spectrum. APC and KRAS were mutated at significantly lower rates in tumors from patients with IBD than in sporadic colorectal tumors (13% and 20% of cases, respectively). Several genes were mutated more frequently or uniquely in tumors from patients with IBD, including SOX9 and EP300 (which encode proteins in the WNT pathway), NRG1 (which encodes an ERBB ligand), and IL16 (which encodes a cytokine). Our study also revealed recurrent mutations in components of the Rho and Rac GTPase network, indicating a role for noncanonical WNT signaling in development of colorectal tumors in patients with IBD. CONCLUSIONS: Colorectal tumors that develop in patients with IBD have distinct genetic features from sporadic colorectal tumors. These findings could be used to develop disease-specific markers for diagnosis and treatment of patients with IBD and colorectal cancer. PMID- 26764185 TI - Familial Liability for Eating Disorders and Suicide Attempts: Evidence From a Population Registry in Sweden. AB - IMPORTANCE: Suicide attempts are common in individuals with eating disorders. More precise understanding of the mechanisms underlying their concomitant occurrence is needed. OBJECTIVE: To examine the association between eating disorders and suicide attempts and whether familial risk factors contribute to the association. DESIGN, SETTING, AND PARTICIPANTS: A Swedish birth cohort including individuals born in Sweden between January 1, 1979, and December 31, 2001, was followed up from age 6 years to December 31, 2009 (N = 2,268,786). Information was acquired from Swedish national registers. All individuals were linked to their biological full siblings, maternal half siblings, paternal half siblings, full cousins, and half cousins. Data analysis was conducted from October 5, 2014, to April 28, 2015. MAIN OUTCOMES AND MEASURES: Eating disorders were captured by 3 variables (any eating disorder, anorexia nervosa, and bulimia nervosa) identified by any lifetime diagnoses recorded in the registers. Suicide attempts were defined as any suicide attempts, including death by suicide, recorded in the registers. We examined the association between eating disorders and death by suicide separately, but the study was underpowered to explore familial liability for this association. RESULTS: Of 2,268,786 individuals, 15,457 females (1.40% of all females) and 991 males (0.09% of all males) had any eating disorder, 7680 females (0.70%) and 453 males (0.04%) had anorexia nervosa, and 3349 females (0.30%), and 61 males (0.01%) had bulimia nervosa. Individuals with any eating disorder had an increased risk (reported as odds ratio [95% CI]) of suicide attempts (5.28 [5.04-5.54]) and death by suicide (5.39 [4.00-7.25]). The risks were attenuated but remained significant after adjusting for comorbid major depressive disorder, anxiety disorder, and substance use disorder (suicide attempts: 1.82 [1.72-1.93]; death by suicide: 2.04 [1.49-2.80]). Similar results were found for anorexia nervosa (suicide attempts: crude, 4.42 [4.12-4.74] vs adjusted, 1.70 [1.56-1.85]; death by suicide: crude, 6.46 [4.38-9.54] vs adjusted, 2.67 [1.78-4.01]) and bulimia nervosa (suicide attempts: crude, 6.26 [5.73-6.85] vs adjusted, 1.88 [1.68-2.10]; death by suicide: crude, 4.45 [2.44 8.11] vs adjusted, 1.48 [0.81-2.72]). Individuals (index) who had a full sibling with any eating disorder had an increased risk of suicide attempts (1.41 [1.29 1.53]). The risk was attenuated for any eating disorder in more-distant relatives (maternal half siblings, 1.10 [0.90-1.34]; paternal half siblings, 1.21 [0.98 1.49]; full cousins, 1.11 [1.06-1.18]; half cousins, 0.90 [0.78-1.03]). This familial pattern remained stable after adjusting for the index individuals' eating disorders. Similar patterns were found for anorexia nervosa and bulimia nervosa. CONCLUSIONS AND RELEVANCE: These results suggest an increased risk of suicide attempts in individuals with lifetime eating disorders and their relatives. The pattern of familial coaggregation suggests familial liability for the association between eating disorders and suicide. Psychiatric comorbidities partially explain this association, suggesting particularly high-risk presentations. PMID- 26764187 TI - Performance of ultrasound-based endometriosis staging system (UBESS) for predicting level of complexity of laparoscopic surgery for endometriosis. AB - OBJECTIVE: To develop and assess the performance of a preoperative ultrasound based endometriosis staging system (UBESS) to predict the level of complexity of laparoscopic surgery for endometriosis. METHODS: This was a multicenter prospective and retrospective cohort study on consecutive women with suspected endometriosis who underwent laparoscopy between June 2009 and July 2013. Each woman underwent a systematic transvaginal ultrasound evaluation to assess the pelvis for different phenotypes of endometriosis, and the diagnostic performance of ultrasound for these different phenotypes was evaluated relative to the gold standard, laparoscopy. A three-stage preoperative UBESS was developed to assess the severity of pelvic endometriosis, based on the histological phenotypes of endometriosis, the anatomical locations of deep infiltrating endometriosis and their sonographic markers of local invasiveness. The three stages of UBESS (I III) were then correlated with the three levels of complexity of laparoscopic surgery for endometriosis described by the Royal College of Obstetricians and Gynaecologists (Levels 1-3). The end-points were the diagnostic performance of UBESS to predict the level of complexity of laparoscopic surgery for endometriosis, i.e. UBESS stage I to predict Level-1 laparoscopic surgery, UBESS stage II to predict Level-2 laparoscopic surgery and UBESS stage III to predict Level-3 laparoscopic surgery. RESULTS: The analysis included 192 women, with a mean +/- SD age at diagnosis of endometriosis of 23.7 +/- 9.3 years and a mean duration of symptoms prior to presentation of 42 months. Predominant reported locations of pelvic pain were left iliac fossa (32%), right iliac fossa (29.5%) and lower abdomen (61%) and predominant symptoms included dyspareunia (57.5%), dysmenorrhea (58.5%) and dyschezia (41.5%). The accuracy, sensitivity, specificity, positive and negative predictive values and positive and negative likelihood ratios of UBESS I for predicting a requirement for Level-1 laparoscopic surgery were: 87.5%, 83.3%, 91.7%, 90.9%, 84.6%, 10 and 0.182; those of UBESS II for predicting Level-2 surgery were: 87.0%, 73.7%, 90.3%, 65.1%, 93.3%, 7.6 and 0.292; and those of UBESS III for predicting Level-3 surgery were: 95.3%, 94.8%, 95.5%, 90.2%, 97.7%, 21.2 and 0.054, respectively. CONCLUSION: UBESS could be utilized to predict the level of complexity of laparoscopic surgery for endometriosis. It has the potential to facilitate the triage of women with suspected endometriosis to the most appropriate surgical expertise required for laparoscopic endometriosis surgery. UBESS needs to be validated externally in multiple centers to assess its general applicability. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26764186 TI - SGEF Is Regulated via TWEAK/Fn14/NF-kappaB Signaling and Promotes Survival by Modulation of the DNA Repair Response to Temozolomide. AB - Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors. Despite surgical removal followed by concomitant radiation and chemotherapy with the alkylating agent temozolomide, GB tumors develop treatment resistance and ultimately recur. Impaired response to treatment occurs rapidly, conferring a median survival of just fifteen months. Thus, it is necessary to identify the genetic and signaling mechanisms that promote tumor resistance to develop targeted therapies to combat this refractory disease. Previous observations indicated that SGEF (ARHGEF26), a RhoG-specific guanine nucleotide exchange factor (GEF), is overexpressed in GB tumors and plays a role in promoting TWEAK-Fn14-mediated glioma invasion. Here, further investigation revealed an important role for SGEF in glioma cell survival. SGEF expression is upregulated by TWEAK-Fn14 signaling via NF-kappaB activity while shRNA-mediated reduction of SGEF expression sensitizes glioma cells to temozolomide-induced apoptosis and suppresses colony formation following temozolomide treatment. Nuclear SGEF is activated following temozolomide exposure and complexes with the DNA damage repair (DDR) protein BRCA1. Moreover, BRCA1 phosphorylation in response to temozolomide treatment is hindered by SGEF knockdown. The role of SGEF in promoting chemotherapeutic resistance highlights a heretofore unappreciated driver, and suggests its candidacy for development of novel targeted therapeutics for temozolomide-refractory, invasive GB cells. IMPLICATION: SGEF, as a dual process modulator of cell survival and invasion, represents a novel target for treatment refractory glioblastoma. PMID- 26764189 TI - 3D-QSAR, molecular dynamics simulations and molecular docking studies of benzoxazepine moiety as mTOR inhibitor for the treatment of lung cancer. AB - According to WHO statistics, lung cancer is one of the leading causes of death among all other types of cancer. Many genes get mutated in lung cancer but involvement of EGFR and KRAS are more common. Unavailability of drugs or resistance to the available drugs is the major problem in the treatment of lung cancer. In the present research, mTOR was selected as an alternative target for the treatment of lung cancer which involves PI3K/AKT/mTOR pathway. 28 synthetic mTOR inhibitors were selected from the literature. Ligand based approach (CoMFA and CoMSIA) and structure based approach (molecular dynamics simulations assisted molecular docking study) were applied for the identification of important features of benzoxazepine moiety, responsible for mTOR inhibition. Three different alignments were tried to obtain best QSAR model, of which, distil was found to be the best method, as it gave good statistical results. In CoMFA, Leave One Out (LOO) cross validated coefficients (q(2)), conventional coefficient (r(2)) and predicted correlation coefficient (r(2)pred) values were found to be 0.615, 0.990 and 0.930, respectively. Similarly in CoMSIA, q(2), r(2)ncv and r(2)pred values were found to be 0.748, 0.986 and 0.933, respectively. Molecular dynamics and simulations study revealed that B-chain of mTOR protein was stable at and above 500 FS with respect to temperature (at and above 298 K), Potential energy (at and above 7669.72 kJ/mol) and kinetic energy (at and above 4009.77 kJ/mol). Molecular docking study was performed on simulated protein of mTOR which helped to correlate interactions of amino acids surrounded to the ligand with contour maps generated by QSAR method. Important features of benzoxazepine were identified by contour maps and molecular docking study which would be useful to design novel molecules as mTOR inhibitors for the treatment of lung cancer. PMID- 26764188 TI - Amphiphilic nanoparticles of resveratrol-norcantharidin to enhance the toxicity in zebrafish embryo. AB - Direct coupling of a hydrophobic drug and a hydrophilic natural product via an ester bond produced an amphiphilic adduct that formed liposomes. Liposomes of resveratrol-norcantharidin adduct are capable of forming a tadpole-like nanoparticle and exhibited high toxicity in zebrafish embryos to give the better transportation and the effective concentration into cells. Using fluorescent chromophore showed the liposome in the stomach and intestinal villi rather than in the skin and muscle. This result may provide an insight into the mechanism of action of traditional Chinese medicines, which often contain a significant amount of flavonoids and polyphenol analogs. PMID- 26764190 TI - Peptide-based inhibitors of protein-protein interactions. AB - Protein-protein interactions (PPIs) are key elements of several important biological processes and have emerged as valuable targets in medicinal chemistry. Importantly, numerous specific protein-protein interactions (e.g., p53-HDM2 and Bcl-2-BH3 domains) were found to be involved in the development of several diseases, including various types of cancer. In general, the discovery of new synthetic PPI inhibitors is a challenging task because protein surfaces have not evolved in a manner that allows for specific binding of low molecular weight compounds. Here, we review the discovery strategies for peptide-based PPI inhibitors. Although peptide-based drug candidates exhibit significant drawbacks (in particular, low proteolytic stability), modifications of either the side chains or backbone could provide molecules of interest. Moreover, due to the large molecular size of peptide-based compounds, the discovery of molecules that specifically interact with extended protein surfaces is possible. Two major strategies for constructing peptide-based PPI inhibitors are as follows: (a) cyclization (e.g., stapled peptides) and (b) modification of the backbone structure (e.g., beta-peptides and peptoids). These approaches for constructing PPI inhibitors enhance both the inhibitory activity and pharmacokinetic properties compared with non-modified alpha-peptides. PMID- 26764191 TI - Discovery of potent aryl-substituted 3-[(3-methylpyridine-2-carbonyl) amino]-2,4 dimethyl-benzoic acid EP4 antagonists with improved pharmacokinetic profile. AB - Two new series of EP4 antagonists containing a 3-methylaryl-2-carbonyl core have been identified. One series has a 3-substituted-phenyl core, while the other one incorporates a 3-substituted pyridine. Both series led to compounds with potent activity in functional and human whole blood (hWB) assays. In the pyridine series, compound 7a was found to be a highly potent and selective EP4 antagonist, with suitable rat and dog pharmacokinetic profiles. PMID- 26764193 TI - Website Sharing in Online Health Communities: A Descriptive Analysis. AB - BACKGROUND: An increasing number of people visit online health communities to seek health information. In these communities, people share experiences and information with others, often complemented with links to different websites. Understanding how people share websites can help us understand patients' needs in online health communities and improve how peer patients share health information online. OBJECTIVE: Our goal was to understand (1) what kinds of websites are shared, (2) information quality of the shared websites, (3) who shares websites, (4) community differences in website-sharing behavior, and (5) the contexts in which patients share websites. We aimed to find practical applications and implications of website-sharing practices in online health communities. METHODS: We used regular expressions to extract URLs from 10 WebMD online health communities. We then categorized the URLs based on their top-level domains. We counted the number of trust codes (eg, accredited agencies' formal evaluation and PubMed authors' institutions) for each website to assess information quality. We used descriptive statistics to determine website-sharing activities. To understand the context of the URL being discussed, we conducted a simple random selection of 5 threads that contained at least one post with URLs from each community. Gathering all other posts in these threads resulted in 387 posts for open coding analysis with the goal of understanding motivations and situations in which website sharing occurred. RESULTS: We extracted a total of 25,448 websites. The majority of the shared websites were .com (59.16%, 15,056/25,448) and WebMD internal (23.2%, 5905/25,448) websites; the least shared websites were social media websites (0.15%, 39/25,448). High-posting community members and moderators posted more websites with trust codes than low-posting community members did. The heart disease community had the highest percentage of websites containing trust codes compared to other communities. Members used websites to disseminate information, supportive evidence, resources for social support, and other ways to communicate. CONCLUSIONS: Online health communities can be used as important health care information resources for patients and caregivers. Our findings inform patients' health information-sharing activities. This information assists health care providers, informaticians, and online health information entrepreneurs and developers in helping patients and caregivers make informed choices. PMID- 26764192 TI - Synthesis, anti-inflammatory, ulcerogenic and cyclooxygenase activities of indenopyrimidine derivatives. AB - Objective of the present work was to evaluate the anti-inflammatory, ulcerogenicity and cyclooxygenase activity of indenopyrimidine derivatives. Anti inflammatory activity of the tested compounds is investigated by carrageenan induced rat paw edema assay. Compounds A1, A6, A7 and A12 exhibit the comparable anti-inflammatory activity (79.33-81.33%) to the standard drug diclofenac sodium (85.33%), while A6, A7, A9, A12 and A14 show better ulcer index than the reference standard diclofenac sodium. To rationalize the anti-inflammatory activity, docking experiments are performed to study the ability of these compounds to bind into the active site of COX-2 enzyme. PMID- 26764194 TI - EUS-guided gallbladder drainage for rescue treatment of malignant distal biliary obstruction after unsuccessful ERCP. AB - BACKGROUND AND AIMS: EUS-guided bile duct drainage (EUS-BD) is a well-recognized rescue biliary drainage method after unsuccessful ERCP. EUS-guided gallbladder drainage (EUS-GBD) was recently used to treat acute cholecystitis. The aim of this study was to assess the efficacy and safety of EUS-GBD for malignant biliary stricture-induced obstructive jaundice after unsuccessful ERCP as well as unsuccessful or impractical EUS-BD. METHODS: Between January 2006 and October 2014, 12 patients with obstructive jaundice due to unresectable malignant distal biliary stricture underwent EUS-GBD after ERCP failed. EUS-GBD was performed under the guidance of EUS and fluoroscopy by puncturing the gallbladder with a needle, inserting a guidewire, dilating the puncture hole, and placing a stent. The technical and functional success rates, adverse events rate, overall patient survival time, and stent dysfunction rate during patient survival were measured. RESULTS: The rates of technical success, functional success, adverse events, and stent dysfunction were 100%, 91.7%, 16.7%, and 8.3%, respectively. The median survival time after EUS-GBD was 105 days (range 15 - 236 days). CONCLUSIONS: EUS GBD is a possible alternative route for decompression of the biliary system when ERCP is unsuccessful. PMID- 26764195 TI - Usefulness of single-operator cholangioscopy-guided laser lithotripsy in patients with Mirizzi syndrome and cystic duct stones: experience at a tertiary care center. AB - BACKGROUND AND AIMS: ERCP is an established technique for the management of bile duct stones. Large bile duct stones (>1.2 cm) require additional techniques such as mechanical lithotripsy and balloon sphincteroplasty for ductal clearance. The literature on endoscopic management of cystic duct stones (CDSs) and Mirizzi syndrome (MS) is limited. We report our experience with cholangioscopy-assisted extraction of CDSs and MS in patients in whom conventional endoscopic and surgical techniques failed. METHODS: Between August 2011 and August 2014, 50 patients (15 males) diagnosed with MS (n = 40) and CDSs (n = 10) were recruited for the study. MRCP was the preferred diagnostic modality to outline the biliary anatomy. ERCP was performed by using an Olympus TJF 160/180 duodenoscope (Olympus, Tokyo, Japan). Cholangioscopy was performed by using the Spyglass system (Boston Scientific, Marlborough, Mass). Holmium laser lithotripsy (LL) was performed when conventional stone extraction techniques failed. RESULTS: Cholangioscopy-guided LL was required in 34 of 50 patients (68%) with MS and CDSs. Stone extractions using conventional endoscopy techniques were successful in 8 patients and with surgery in another 8 patients, and these patients were excluded from the final statistical analysis. The mean stone size for MS was 21 mm (range 15-41 mm), and the CDS size was 8 mm (range 6-12 mm). Single-session ductal clearance could be achieved in 32 patients (94%). Adverse events were mild and included fever (2 patients), transient abdominal pain (2 patients), and self limited pancreatitis (2 patients). CONCLUSIONS: Cholangioscopy-guided LL is a useful technique for extraction of CDSs and in MS with high single-session success rates. It is also a rescue technique in patients in whom surgical stone extraction failed. PMID- 26764196 TI - Retrospective Appraisals Mediate the Effects of Combat Experiences on PTS and Depression Symptoms in U.S. Army Medics. AB - A life-threatening traumatic experience can cause physical and psychological distress, but it can also be remembered with pride from having demonstrated one's courage and abilities under severe circumstances. Characteristics of the event, early response, as well as later personal reflection, together determine the individual's response to a traumatic event. We investigated how traumatic combat experiences and retrospective appraisals of those experiences affected reports of symptoms of posttraumatic stress and depression in 324 U.S. Army medics. Higher levels of combat experiences were associated with both appraisals of threat to life (r = .40) and appraisals of personal benefit of the deployment (r = .15). Threat appraisals were associated with increases (r = .33 and .29), whereas benefit appraisals were associated with decreases (r = -.28 and -.30, respectfully), in symptoms of posttraumatic stress and depression. These opposing mediation pathways led to weak or nonsignificant total effects, which concealed the effects of combat intensity on posttraumatic stress (R(2) = .28) and depression (R(2) = .24). Acknowledging the beneficial effects that a combat experience had on one's life was associated with less intense behavioral health symptoms and offset the detrimental effects of traumatic combat experiences. PMID- 26764197 TI - The risk factors and prevalence of upper extremity impairments and an analysis of effects of lymphoedema and other impairments on the quality of life of breast cancer patients. AB - This study aimed to determine the prevalence and identify the risk factors associated with upper extremity impairments (UEIs) in breast cancer patients and to investigate the degree to which these impairments and other characteristics influence quality of life (QoL). A total of 201 women over the age of 18 who underwent breast cancer treatment at least 6 months were included in this cross sectional study. All of the patients were evaluated for the presence of lymphoedema and any UEIs. UEIs divided into five subgroups: pain, restriction of shoulder range of motion (ROM), numbness and heaviness, loss of strength, and sensory deficit. QoL of the patients was evaluated by SF-36. The prevalence of the upper extremity impairments was as follows: pain 31.8%, restriction of shoulder ROM 23.9%, numbness and heaviness 35.3%, loss of strength 8.5%, and sensory deficit 18.4%. Furthermore, lymphoedema was seen in 41.3% of patients. The multivariate model showed that lymphoedema is the only statistically significant risk factor that affects the development of UEIs (P = 0.001). However, it also revealed that lymphoedema (P = 0.001) and increased age negatively affect QoL, whereas prolongation of the follow-up period has a favourable impact (P = 0.016). Therefore, lymphoedema diminishes QoL via an increased number of UEIs. PMID- 26764198 TI - Perioperative outcomes of video- and robot-assisted segmentectomies. AB - OBJECTIVE: Video-assisted thoracic surgery appears to be technically difficult for segmentectomy. Conversely, robotic surgery could facilitate the performance of segmentectomy. The aim of this study was to compare the early results of video and robot-assisted segmentectomies. METHODS: Data were collected prospectively on videothoracoscopy from 2010 and on robotic procedures from 2013. Fifty-one patients who were candidates for minimally invasive segmentectomy were included in the study. Perioperative outcomes of video-assisted and robotic segmentectomies were compared. RESULTS: The minimally invasive segmentectomies included 32 video- and 16 robot-assisted procedures; 3 segmentectomies (2 video assisted and 1 robot-assisted) were converted to lobectomies. Four conversions to thoracotomy were necessary for anatomical reason or arterial injury, with no uncontrolled bleeding in the robotic arm. There were 7 benign or infectious lesions, 9 pre-invasive lesions, 25 lung cancers, and 10 metastatic diseases. Patient characteristics, type of segment, conversion to thoracotomy, conversion to lobectomy, operative time, postoperative complications, chest tube duration, postoperative stay, and histology were similar in the video and robot groups. Estimated blood loss was significantly higher in the video group (100 vs. 50 mL, p = 0.028). CONCLUSIONS: The morbidity rate of minimally invasive segmentectomy was low. The short-term results of video-assisted and robot-assisted segmentectomies were similar, and more data are required to show any advantages between the two techniques. Long-term oncologic outcomes are necessary to evaluate these new surgical practices. PMID- 26764199 TI - Emphysematous lungs do not affect visibility of virtual-assisted lung mapping. AB - BACKGROUND: It has recently been suggested that virtual-assisted lung mapping may enable safer and more reliable intraoperative navigation compared to conventional preoperative lung marking strategies. This study aimed to examine the relationship between emphysematous lungs and the intraoperative visibility of virtual-assisted lung mapping markings. METHODS: We retrospectively analyzed the data of 21 patients who underwent virtual-assisted lung mapping followed by lung resection between October 2013 and May 2015. The visibility of the intraoperative lung markings was graded. The degree of pulmonary emphysema was assessed by the percentage of low attenuation area on computed tomography. We elucidated the associations between the marking grade and other factors such as patient age or sex, pulmonary lobe mapped, marking operator, Brinkman index, and percentage of low attenuation area of the pulmonary lobe. RESULTS: In Spearman rank correlation analysis, there was no correlation between the Brinkman index and the percentage of low attenuation area (n = 26, r = -0.016, p = 0.937). In stepwise multivariate regression analysis, the marking grade correlated with the marking operator (p < 0.001) and the Brinkman index (p = 0.008), but not with patient age or sex, the pulmonary lobe mapped, or degree of pulmonary emphysema. CONCLUSION: The skill of the marking operator and the patient's smoking history had significant effects on the intraoperative visibility of markings made by virtual-assisted lung mapping, whereas emphysematous lungs did not affect the intraoperative visibility of lung markings. PMID- 26764200 TI - Nitric oxide inhibits basolateral 10-pS Cl- channels through the cGMP/PKG signaling pathway in the thick ascending limb of C57BL/6 mice. AB - We used patch-clamp techniques to examine whether nitric oxide (NO) decreases NaCl reabsorption by suppressing basolateral 10-pS Cl- channels in the thick ascending limb (TAL). Both the NO synthase substrate l-arginine (l-Arg) and the NO donor S-nitroso-N-acetylpenicillamine significantly inhibited 10-pS Cl- channel activity in the TAL. The inhibitory effect of l-Arg on Cl- channels was completely abolished in the presence of the NO synthase inhibitor or NO scavenger. Moreover, inhibition of soluble guanylyl cyclase abrogated the effect of l-Arg on Cl- channels, whereas the cGMP analog 8-bromo-cGMP (8-BrcGMP) mimicked the effect of l-Arg and significantly decreased 10-pS Cl- channel activity, indicating that NO inhibits basolateral Cl- channels by increasing cGMP production. Furthermore, treatment of the TAL with a PKG inhibitor blocked the effect of l-Arg and 8-BrcGMP on Cl- channels, respectively. In contrast, a phosphodiesterase 2 inhibitor had no significant effect on l-Arg or 8-BrcGMP induced inhibition of Cl- channels. Therefore, we conclude that NO decreases basolateral 10-pS Cl- channel activity through a cGMP-dependent PKG pathway, which may contribute to the natriuretic and diuretic effects of NO in vivo. PMID- 26764201 TI - Mesenchymal stem cell transplantation inhibited high salt-induced activation of the NLRP3 inflammasome in the renal medulla in Dahl S rats. AB - Inflammasomes activate caspase-1 to produce interleukin (IL)-1beta. Activation of the NLRP3 inflammasome is involved in various renal pathological conditions. It remains unknown whether the NLRP3 inflammasome activation participates in the abnormal renal response to high-salt (HS) diet in Dahl salt-sensitive (S) rats. In addition, our lab recently showed that transplantation of mesenchymal stem cells (MSCs) attenuated HS-induced inflammation in the renal medulla in Dahl S rat. However, it is unclear whether the anti-inflammatory action of MSCs is associated with inhibition of the NLRP3 inflammasome. The present study determined the response of the NLRP3 inflammasome to HS intake and the effect of MSC transplantation on the NLRP3 inflammasome in the renal medulla in Dahl S rats. Immunostaining showed that the inflammasome components NLRP3, ASC, and caspase-1 were mainly present in distal tubules and collecting ducts. Interestingly, the renal medullary levels of these inflammasome components were remarkably increased after a HS diet in Dahl S rats, while remaining unchanged in normal rats. This HS-induced activation of the NLRP3 inflammasome was significantly blocked by MSC transplantation into the renal medulla in Dahl S rats. Furthermore, infusion of a caspase-1 inhibitor into the renal medulla significantly attenuated HS-induced hypertension in Dahl S rats. These data suggest that HS-induced activation of the NLRP3 inflammasome may contribute to renal medullary dysfunction in Dahl S rats and that inhibition of inflammasome activation may be one of the mechanisms for the anti-inflammatory and anti hypertensive effects of stem cells in the renal medulla in Dahl S rats. PMID- 26764202 TI - Reactive oxygen species-initiated autophagy opposes aldosterone-induced podocyte injury. AB - Evidence has demonstrated that aldosterone (Aldo) is involved in the development and progression of chronic kidney diseases. The purpose of the present study was to investigate the role of autophagy in Aldo-induced podocyte damage and the underlying mechanism. Mouse podocytes were treated with Aldo in the presence or absence of 3-methyladenine and N-acetylcysteine. Cell apoptosis was investigated by detecting annexin V conjugates, apoptotic bodies, caspase-3 activity, and alterations of the podocyte protein nephrin. Autophagy was evaluated by measuring the expressions of light chain 3, p62, beclin-1, and autophagy-related gene 5. Aldo (10-7 mol/l) induced podocyte apoptosis, autophagy, and downregulation of nephrin protein in a time-dependent manner. Aldo-induced apoptosis was further promoted by the inhibition of autophagy via 3-methyladenine and autophagy-related gene 5 small interfering RNA pretreatment. Moreover, Aldo time dependently increased ROS generation, and H2O2 (10-4 mol/l) application remarkably elevated podocyte autophagy. After treatment with N-acetylcysteine, the autophagy induced by Aldo or H2O2 was markedly attenuated, suggesting a key role of ROS in mediating autophagy formation in podocytes. Inhibition of ROS could also lessen Aldo-induced podocyte injury. Taken together, our findings suggest that ROS triggered autophagy played a protective role against Aldo-induced podocyte injury, and targeting autophagy in podocytes may represent a new therapeutic strategy for the treatment of podocytopathy. PMID- 26764203 TI - Heparan sulfate 6-O-endosulfatases, Sulf1 and Sulf2, regulate glomerular integrity by modulating growth factor signaling. AB - Glomerular integrity and functions are maintained by growth factor signaling. Heparan sulfate, the major component of glomerular extracellular matrixes, modulates growth factor signaling, but its roles in glomerular homeostasis are unknown. We investigated the roles of heparan sulfate 6-O-endosulfatases, sulfatase (Sulf)1 and Sulf2, in glomerular homeostasis. Both Sulf1 and Sulf2 were expressed in the glomeruli of wild-type (WT) mice. Sulf1 and Sulf2 double knockout (DKO) mice showed glomerular hypercellularity, matrix accumulation, mesangiolysis, and glomerular basement membrane irregularity. Platelet-derived growth factor (PDGF)-B and PDGF receptor-beta were upregulated in Sulf1 and Sulf2 DKO mice compared with WT mice. Glomeruli from Sulf1 and Sulf2 DKO mice in vitro stimulated by either PDGF-B, VEGF, or transforming growth factor-beta similarly showed reduction of phospho-Akt, phospho-Erk1/2, and phospho-Smad2/3, respectively. Since glomerular lesions in Sulf1 and Sulf2 DKO mice were reminiscent of diabetic nephropathy, we examined the effects of Sulf1 and Sulf2 gene disruption in streptozotocin-induced diabetes. Diabetic WT mice showed an upregulation of glomerular Sulf1 and Sulf2 mRNA by in situ hybridization. Diabetic DKO mice showed significant increases in albuminuria and serum creatinine and an acceleration of glomerular pathology without glomerular hypertrophy; those were associated with a reduction of glomerular phospho-Akt. In conclusion, Sulf1 and Sulf2 play indispensable roles to maintain glomerular integrity and protective roles in diabetic nephropathy, probably by growth factor modulation. PMID- 26764205 TI - Increased carbamylation level of HDL in end-stage renal disease: carbamylated-HDL attenuated endothelial cell function. AB - It is thought that carbamylated modification plays a crucial role in the development and progression of cardiovascular disease (CVD) in patients with end stage renal disease (ESRD). However, information on the biological effects of carbamylated high-density lipoprotein (C-HDL) in ESRD is poor. The present study investigated the carbamylation level of HDL in ESRD and the effects of C-HDL on endothelial repair properties. HDL was isolated from healthy control subjects (n = 22) and patients with ESRD (n = 30). The carbamylation level of HDL was detected using ELISA. Isolated C-HDL for use in tissue culture experiments was carbamylated in vitro to a similar extent to that observed in ESRD. Human arterial endothelial cells were treated with C-HDL or native HDL to assess their migration, proliferation, and angiogenesis properties. HDL-associated paraoxonase 1 activity was also determined by spectrophotometry assay. Compared with healthy control subjects, the carbamylation level of HDL in ESRD patients was increased and positively correlated with blood urea concentration. In vitro, C-HDL significantly inhibited migration, angiogenesis, and proliferation in endothelial cells. Mechanistic studies revealed that HDL-associated paraoxonase 1 activity was decreased and negatively correlated with the carbamylation level of HDL in ESRD patients. In addition, C-HDL suppressed the expression of VEGF receptor 2 and scavenger receptor class B type I signaling pathways in endothelial cells. In conclusion, the present study identified a significantly increased carbamylation level of HDL in ESRD. Furthermore, C-HDL inhibited endothelial cell repair functions. PMID- 26764204 TI - Oxalate-induced chronic kidney disease with its uremic and cardiovascular complications in C57BL/6 mice. AB - Chronic kidney disease (CKD) research is limited by the lack of convenient inducible models mimicking human CKD and its complications in experimental animals. We demonstrate that a soluble oxalate-rich diet induces stable stages of CKD in male and female C57BL/6 mice. Renal histology is characterized by tubular damage, remnant atubular glomeruli, interstitial inflammation, and fibrosis, with the extent of tissue involvement depending on the duration of oxalate feeding. Expression profiling of markers and magnetic resonance imaging findings established to reflect inflammation and fibrosis parallel the histological changes. Within 3 wk, the mice reproducibly develop normochromic anemia, metabolic acidosis, hyperkalemia, FGF23 activation, hyperphosphatemia, and hyperparathyroidism. In addition, the model is characterized by profound arterial hypertension as well as cardiac fibrosis that persist following the switch to a control diet. Together, this new model of inducible CKD overcomes a number of previous experimental limitations and should serve useful in research related to CKD and its complications. PMID- 26764206 TI - Novel application of complementary imaging techniques to examine in vivo glucose metabolism in the kidney. AB - The metabolic status of the kidney is a determinant of injury susceptibility and a measure of progression for many disease processes; however, noninvasive modalities to assess kidney metabolism are lacking. In this study, we employed positron emission tomography (PET) and intravital multiphoton microscopy (MPM) to assess cortical and proximal tubule glucose tracer uptake, respectively, following experimental perturbations of kidney metabolism. Applying dynamic image acquisition PET with 2-18fluoro-2-deoxyglucose (18F-FDG) and tracer kinetic modeling, we found that an intracellular compartment in the cortex of the kidney could be distinguished from the blood and urine compartments in animals. Given emerging literature that the tumor suppressor protein p53 is an important regulator of cellular metabolism, we demonstrated that PET imaging was able to discern a threefold increase in cortical 18F-FDG uptake following the pharmacological inhibition of p53 in animals. Intravital MPM with the fluorescent glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2 NBDG) provided increased resolution and corroborated these findings at the level of the proximal tubule. Extending our observation of p53 inhibition on proximal tubule glucose tracer uptake, we demonstrated by intravital MPM that pharmacological inhibition of p53 diminishes mitochondrial potential difference. We provide additional evidence that inhibition of p53 alters key metabolic enzymes regulating glycolysis and increases intermediates of glycolysis. In summary, we provide evidence that PET is a valuable tool for examining kidney metabolism in preclinical and clinical studies, intravital MPM is a powerful adjunct to PET in preclinical studies of metabolism, and p53 inhibition alters basal kidney metabolism. PMID- 26764209 TI - Heuristic Evaluation of Ehealth Interventions: Establishing Standards That Relate to the Therapeutic Process Perspective. AB - In recent years, the number of available eHealth interventions aimed at treating behavioral and mental health challenges has been growing. From the perspective of health care providers, there is a need for eHealth interventions to be evaluated prior to clinical trials and for the limited resources allocated to empirical research to be invested in the most promising products. Following a literature review, a gap was found in the availability of eHealth interventions evaluation principles related to the patient experience of the therapeutic process. This paper introduces principles and concepts for the evaluation of eHealth interventions developed as a first step in a process to outline general evaluation guidelines that relate to the clinical context from health care providers' perspective. Our approach was to conduct a review of literature that relates to the examination of eHealth interventions. We identified the literature that was most relevant to our study and used it to define guidelines that relate to the clinical context. We then compiled a list of heuristics we found to be useful for the evaluation of eHealth intervention products' suitability for empirical examination. Four heuristics were identified with respect to the therapeutic process: (1) the product's ease of use (ie, usability), (2) the eHealth intervention's compatibility with the clinical setting, (3) the presence of tools that make it easier for the user to engage in therapeutic activities, and (4) the provision of a feasible therapeutic pathway to growth. We then used this set of heuristics to conduct a detailed examination of MyFitnessPal. This line of work could help to set the bar higher for product developers and to inform health care providers about preferred eHealth intervention designs. PMID- 26764207 TI - Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron. AB - Diabetes increases the reabsorption of Na(+) (TNa) and glucose via the sodium glucose cotransporter SGLT2 in the early proximal tubule (S1-S2 segments) of the renal cortex. SGLT2 inhibitors enhance glucose excretion and lower hyperglycemia in diabetes. We aimed to investigate how diabetes and SGLT2 inhibition affect TNa and sodium transport-dependent oxygen consumption [Formula: see text] along the whole nephron. To do so, we developed a mathematical model of water and solute transport from the Bowman space to the papillary tip of a superficial nephron of the rat kidney. Model simulations indicate that, in the nondiabetic kidney, acute and chronic SGLT2 inhibition enhances active TNa in all nephron segments, thereby raising [Formula: see text] by 5-12% in the cortex and medulla. Diabetes increases overall TNa and [Formula: see text] by ~50 and 100%, mainly because it enhances glomerular filtration rate (GFR) and transport load. In diabetes, acute and chronic SGLT2 inhibition lowers [Formula: see text] in the cortex by ~30%, due to GFR reduction that lowers proximal tubule active TNa, but raises [Formula: see text] in the medulla by ~7%. In the medulla specifically, chronic SGLT2 inhibition is predicted to increase [Formula: see text] by 26% in late proximal tubules (S3 segments), by 2% in medullary thick ascending limbs (mTAL), and by 9 and 21% in outer and inner medullary collecting ducts (OMCD and IMCD), respectively. Additional blockade of SGLT1 in S3 segments enhances glucose excretion, reduces [Formula: see text] by 33% in S3 segments, and raises [Formula: see text] by <1% in mTAL, OMCD, and IMCD. In summary, the model predicts that SGLT2 blockade in diabetes lowers cortical [Formula: see text] and raises medullary [Formula: see text], particularly in S3 segments. PMID- 26764208 TI - A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease. AB - Autosomal-dominant polycystic kidney disease (ADPKD) is a common cause of end stage renal disease, and no approved treatment is available in the United States to slow disease progression. The mammalian target of rapamycin (mTOR) signaling pathway is aberrantly activated in renal cysts, and while mTOR inhibitors are highly effective in rodent models, clinical trials in ADPKD have been disappointing due to dose-limiting extrarenal side effects. Since mTOR is known to be regulated by nutrients and cellular energy status, we hypothesized that dietary restriction may affect renal cyst growth. Here, we show that reduced food intake (RFI) by 23% profoundly affects polycystic kidneys in an orthologous mouse model of ADPKD with a mosaic conditional knockout of PKD1. This mild level of RFI does not affect normal body weight gain, cause malnutrition, or have any other apparent side effects. RFI substantially slows disease progression: relative kidney weight increase was 41 vs. 151% in controls, and proliferation of cyst lining cells was 7.7 vs. 15.9% in controls. Mice on an RFI diet maintained kidney function and did not progress to end-stage renal disease. The two major branches of mTORC1 signaling, S6 and 4EBP1, are both suppressed in cyst-lining cells by RFI, suggesting that this dietary regimen may be more broadly effective than pharmacological mTOR inhibition with rapalogs, which primarily affects the S6 branch. These results indicate that polycystic kidneys are exquisitely sensitive to minor reductions in nutrient supply or energy status. This study suggests that a mild decrease in food intake represents a potential therapeutic intervention to slow disease progression in ADPKD patients. PMID- 26764210 TI - Task management skills and their deficiencies during care delivery in simulated medical emergency situation: A classification. AB - OBJECTIVES: Our objective was to develop the analysis of task management skills by proposing a framework classifying task management stages and deficiencies. Few studies of non-technical skills have detailed the components of task management skills through behavioural markers, despite their central role in care delivery. RESEARCH METHODOLOGY/DESIGN: A post hoc qualitative behavioural analysis was performed of recordings made of professional training sessions based upon simulated scenarios. SETTING: Four recorded sessions in a high-fidelity simulation setting were observed and recorded. Two scenarios were used (cardiac arrest and respiratory failure), and there were two training sessions per scenario. MAIN OUTCOMES MEASURES: Four types of task management deficiencies were identified with regards to task constraints: constraint relaxation, unsatisfied constraints, additional constraints and constraint transgression. Both equipment and space constraints were also identified. RESULTS: The lack of prerequisite actions when preparing the environment, corequisite actions for equipment and protocol monitoring, or postrequisite actions to restore the environment were associated with task management deficiencies. CONCLUSION: Deficiencies in task management behaviours can be identified in simulated as well as actual medical emergency settings. This framework opens perspectives for both training caregivers and designing ergonomic work situations. PMID- 26764211 TI - The emergence of the vasopressin and oxytocin hormone receptor gene family lineage: Clues from the characterization of vasotocin receptors in the sea lamprey (Petromyzon marinus). AB - The sea lamprey (Petromyzon marinus) is a jawless vertebrate at an evolutionary nexus between invertebrates and jawed vertebrates. Lampreys are known to possess the arginine vasotocin (AVT) hormone utilized by all non-mammalian vertebrates. We postulated that the lamprey would possess AVT receptor orthologs of predecessors to the arginine vasopressin (AVP)/oxytocin (OXT) family of G protein coupled receptors found in mammals, providing insights into the origins of the mammalian V1A, V1B, V2 and OXT receptors. Among the earliest animals to diverge from the vertebrate lineage in which these receptors are characterized is the jawed, cartilaginous elephant shark, which has genes orthologous to all four mammalian receptor types. Therefore, our work was aimed at helping resolve the critical gap concerning the outcomes of hypothesized large-scale (whole-genome) duplication events. We sequenced one partial and four full-length putative lamprey AVT receptor genes and determined their mRNA expression patterns in 15 distinct tissues. Phylogenetically, three of the full-coding genes possess structural characteristics of the V1 clade containing the V1A, V1B and OXT receptors. Another full-length coding gene and the partial sequence are part of the V2 clade and appear to be most closely related to the newly established V2B and V2C receptor subtypes. Our synteny analysis also utilizing the Japanese lamprey (Lethenteron japonicum) genome supports the recent proposal that jawless and jawed vertebrates shared one-round (1R) of WGD as the most likely scenario. PMID- 26764212 TI - Retinoic acid triggers meiosis initiation via stra8-dependent pathway in Southern catfish, Silurus meridionalis. AB - Existing studies demonstrated that retinoic acid (RA) regulates meiotic initiation via stra8-independent pathway in teleosts which lack stra8 in their genomes. However, stra8 was recently identified from several fish species including Southern catfish (Silurus meridionalis). To explore the existence of stra8-dependent pathway in RA mediated meiotic initiation in fishes, in the present study, the genes encoding RA synthase aldh1a2 and catabolic enzyme cyp26a1 and cyp26b1 were cloned from the Southern catfish. By immunohistochemistry, Aldh1a2 signal was observed in gonads of both sexes during the meiotic initiation period. By real-time PCR, differentially expressed gene was observed for cyp26a1, but not for cyp26b1, in gonads during the meiotic initiation. Administration of exogenous RA or inhibition of endogenous RA degradation by either KET (RA catabolic enzyme inhibitor) or cyp26a1 knockdown using CRISPR/Cas9 induced advanced meiotic initiation in the ovaries as demonstrated by increased Stra8/stra8 expression and appearance of oocytes. In contrast, treatment with RA synthase inhibitor DEAB resulted in delayed meiotic initiation and Stra8/stra8 expression in the ovaries, which was rescued by exogenous RA administration. These results indicated that (1) RA triggers the onset of meiosis via stra8-dependent pathway in stra8 existing teleosts, as it does in tetrapods; (2) exogenous RA can rescue the endogenous RA deficiency; (3) Cyp26a1, instead of Cyp26b1, is the key catabolic enzyme involved in meiosis initiation in teleosts. Taken together, RA might trigger meiotic initiation via stra8-dependent and -independent pathway in different teleosts. PMID- 26764213 TI - Stimulation of food intake after central administration of gonadotropin inhibitory hormone is similar in genetically selected low and high body weight lines of chickens. AB - Gonadotropin-inhibitory hormone (GnIH), first isolated from the brain of the Japanese quail (Coturnix japonica), when centrally administered exerts orexigenic effects in birds. However, the precise mechanisms mediating this effect are poorly understood and limited information is available on this effect in models of body weight dysfunction. Thus, the purpose of the present study was to investigate appetite-associated effects of GnIH in chicks from lines that have been selected for either low or high body weight, and are anorexic or become obese, respectively. Central GnIH injection increased food intake in both lines with a similar magnitude of response. There was no effect on water intake. Hypothalamic GnIH mRNA was greater in the low than high weight lines and was greater in the fasted than fed chicks. GnIH receptor mRNA was similarly expressed in both lines, and was greater in fed than fasted chicks. Thus, although selection for body weight did not alter the effect of GnIH on feeding, fasting increased GnIH mRNA in both lines implying that it is an innate hunger factor. PMID- 26764214 TI - Changes in gene expression and cellular localization of insulin-like growth factors 1 and 2 in the ovaries during ovary development of the yellowtail, Seriola quinqueradiata. AB - A method of controlling the somatic growth and reproduction of yellowtail fish (Seriola quinqueradiata) is needed in order to establish methods for the efficient aquaculture production of the species. However, little information about the hormonal interactions between somatic growth and reproduction is available for marine teleosts. There is accumulating evidence that insulin-like growth factor (IGF), a major hormone related somatic growth, plays an important role in fish reproduction. As the first step toward understanding the physiological role of IGF in the development of yellowtail ovaries, we characterized the expression and cellular localization of IGF-1 and IGF-2 in the ovary during development. We histologically classified the maturity of two-year old females with ovaries at various developmental stages into the perinucleolar (Pn), yolk vesicle (Yv), primary yolk (Py), secondary yolk and tertiary yolk (Ty) stages, according to the most advanced type of oocyte present. The IGF-1 gene expression showed constitutively high levels at the different developmental stages, although IGF-1 mRNA levels tended to increase from the Py to the Ty stage with vitellogenesis, reaching maximum levels during the Ty stage. The IGF-2 mRNA levels increased as ovarian development advanced. Using immunohistochemistry methods, immunoreactive IGF-1 was mainly detected in the theca cells of ovarian follicles during late secondary oocyte growth, and in part of the granulosa cells of Ty stage oocytes. IGF-2 immunoreactivity was observed in all granulosa cells in layer in Ty stage oocytes. These results indicate that follicular IGFs may be involved in yellowtail reproduction via autocrine/paracrine mechanisms. PMID- 26764216 TI - Research awareness, attitudes and barriers among clinical staff in a regional cancer centre. Part 1: a quantitative analysis. AB - Research is of key importance in delivering high-quality patient care through evidence-based practice. Attitude towards research and barriers to research can have an impact on research activity. A survey was conducted to establish the levels of research awareness and attitudes among clinical staff groups in this regional cancer centre and identify any barriers to participation in research. The survey consisted of 26 questions and was distributed electronically and completed online. The response rate was 22.3% (n = 123). All participants felt that clinical research will help the regional cancer centre develop and progress treatments in the future. A positive attitude towards research was evident and consistent across professional groups. The main identified barriers to research included lacking the required knowledge, skills and training, lacking support from managers, and lack of opportunity or time to be involved in research, in particular for allied health professionals. However, there appears to be the foundation of a healthy research culture for nurses supported by management. The results of the survey support the implementation of an action plan based on the recommendations of this journal article. PMID- 26764215 TI - Long-Term Trajectories of PTSD in Vietnam-Era Veterans: The Course and Consequences of PTSD in Twins. AB - We estimated the temporal course of posttraumatic stress disorder (PTSD) in Vietnam-era veterans using a national sample of male twins with a 20-year follow up. The complete sample included those twins with a PTSD diagnostic assessment in 1992 and who completed a DSM-IV PTSD diagnostic assessment and a self-report PTSD checklist in 2012 (n = 4,138). Using PTSD diagnostic data, we classified veterans into 5 mutually exclusive groups, including those who never had PTSD, and 4 PTSD trajectory groups: (a) early recovery, (b) late recovery, (c) late onset, and (d) chronic. The majority of veterans remained unaffected by PTSD throughout their lives (79.05% of those with theater service, 90.85% of those with nontheater service); however, an important minority (10.50% of theater veterans, 4.45% of nontheater veterans) in 2012 had current PTSD that was either late onset (6.55% theater, 3.29% nontheater) or chronic (3.95% theater, 1.16% nontheater). The distribution of trajectories was significantly different by theater service (p < .001). PTSD remains a prominent issue for many Vietnam-era veterans, especially for those who served in Vietnam. PMID- 26764217 TI - Pharmacological stimulation of GAL1R but not GAL2R attenuates kainic acid-induced neuronal cell death in the rat hippocampus. AB - The neuropeptide galanin is widely distributed in the central and peripheral nervous systems and part of a bigger family of bioactive peptides. Galanin exerts its biological activity through three G-protein coupled receptor subtypes, GAL1 3R. Throughout the last 20years, data has accumulated that galanin can have a neuroprotective effect presumably mediated through the activation of GAL1R and GAL2R. In order to test the pharmaceutical potential of galanin receptor subtype selective ligands to inhibit excitotoxic cell death, the GAL1R selective ligand M617 and the GAL2R selective ligand M1145 were compared to the novel GAL1/2R ligand M1154, in their ability to reduce the excitotoxic effects of intracerebroventricular injected kainate acid in rats. The peptide ligands were evaluated in vitro for their binding preference in a competitive (125)I-galanin receptor subtype binding assay, and G-protein signaling was evaluated using both classical signaling and a label-free real-time technique. Even though there was no significant difference in the time course or severity of the kainic acid induced epileptic behavior in vivo, administration of either M617 or M1154 before kainic acid administration significantly attenuated the neuronal cell death in the hippocampus. Our results indicate the potential therapeutic value of agonists selective for GAL1R in the prevention of neuronal cell death. PMID- 26764219 TI - Experiences of cancer patients in Poland throughout diagnosis and treatment. AB - Previous studies have failed to explain why the mortality rate of cancer patients is higher in Poland than other countries in the European Union. We aimed to evaluate the health care system in Poland during the diagnosis and treatment of cancer. In this multicentre study, 125 cancer patients treated at 15 centres across Poland participated in focus group interviews in 2014. We identified and assessed crucial elements that affect a patients' experience from the early onset of symptoms, through to diagnosis and treatment. We found that the majority of patients were dissatisfied with the length of time taken to diagnose cancer. Throughout diagnosis, treatment and follow-up, patients reported a lack of communication from health care professionals. While dealings with oncologists and medical staff were viewed favourably, patients felt the cancer centres were not well organised. Patients recommended that having one doctor in charge of an individual's treatment and follow-up would improve patient care and well-being. A late cancer diagnosis may be contributing to the high mortality rate observed in Poland. In the future, new policies should be developed to reduce the time to cancer diagnosis, increase communication with health care professionals and improve the organisation of cancer care for patients. PMID- 26764218 TI - Online Support Program for Parents of Children With a Chronic Kidney Disease Using Intervention Mapping: A Development and Evaluation Protocol. AB - BACKGROUND: The care for children with a chronic kidney disease (CKD) is complex. Parents of these children may experience high levels of stress in managing their child's disease, potentially leading to negative effects on their child's health outcomes. Although the experienced problems are well known, adequate (online) support for these parents is lacking. OBJECTIVE: The objective of the study is to describe the systematic development of an online support program for parents of children with CKD, and how this program will be evaluated. METHODS: Intervention Mapping (IM) was used for the development of the program. After conducting a needs assessment, defining program objectives, searching for theories, and selecting practical applications, the online program e-Powered Parents was developed. e-Powered Parents consist of three parts: (1) an informative part with information about CKD and treatments, (2) an interactive part where parents can communicate with other parents and health care professionals by chat, private messages, and a forum, and (3) a training platform consisting of four modules: Managing stress, Setting limits, Communication, and Coping with emotions. In a feasibility study, the potential effectiveness and effect size of e-Powered Parents will be evaluated using an explorative randomized controlled trial with parents of 120 families. The outcomes will be the child's quality of life, parental stress and fatigue, self-efficacy in the communication with health care professionals, and family management. A process evaluation will provide insight in parents' experiences, including their experienced level of support. RESULTS: Study results are expected to be published in the summer of 2016. CONCLUSIONS: Although the development of e-Powered Parents using IM was time-consuming, IM has been a useful protocol. IM provided us with a systematic framework for structuring the development process. The participatory planning group was valuable as well; knowledge, experiences, and visions were shared, ensuring us that parents and health care professionals support the program. TRIAL REGISTRATION: Dutch Trial Registration: NTR4808; www.trialregister.nl (Archived by WebCite at http://www.webcitation.org/6cfAYHcYb). PMID- 26764220 TI - Non-coding RNAs as modulators of the cardiac fibroblast phenotype. AB - Cardiac fibroblasts represent one of the most frequent cell type in the heart of rodents and humans and alterations of their phenotype have a great impact on cardiac function. Due to aging, ischemic injuries, valvular dysfunctions, hypertension and aortic stenosis, multiple signals trigger the accumulation of extracellular matrix in the cardiac interstitium and perivascular space, leading to structural and functional detrimental changes in the heart. Cardiac fibroblasts are the principal orchestrators of matrix formation and degradation and indirectly regulate cardiac hypertrophy and inflammation. Understanding the molecular bases of their action could provide tools for the treatment of cardiac remodeling. This review summarizes recent evidences on non-coding RNAs, including microRNAs and long non-coding RNAs that modulate the phenotype of cardiac fibroblasts and may serve in the future as targets for novel therapeutic strategies against cardiac fibrosis. PMID- 26764221 TI - A novel PI3K axis selective molecule exhibits potent tumor inhibition in colorectal carcinogenesis. AB - Phosphatidylinositol-3-kinase (PI3K) pathway deregulation is responsible for initiation, chemo-resistance, and poor prognosis of colorectal cancer (CRC). Therefore, PI3K pathway inhibition can provide a plausible way of attaining CRC treatment. We report PI3K target specific synthesis and selection of a potent molecule, that is, 2,3-dihydro-2-(naphthalene-1-yl) quinazolin-4(1H)-one (DHNQ) from quinazolinone series based on the structural activity relationship after evaluation in diverse cancers. This molecule inhibited the PI3K enzyme activity and transcriptional as well as translational expression levels in colorectal cancer (CRC) models. This was associated with subsequent decrease in phosphorylation of its downstream effector proteins, that is, p-Akt(Ser-473) and p-mTORC1(Ser-2448) and decreased ERK signaling. Furthermore, DHNQ decreased expression of cyclins that caused G1 arrest and decreased Bcl-2/Bax ratio after mitochondrial membrane potential loss, reactive oxygen species generation, and an increase in cytosolic Ca2+ loads that is responsible for the decreased CRC cell proliferation and survival. These biochemical changes triggered apoptotic cell death with altered autophagic Beclin-1 and LC3beta expression. It seemed that the PI3K-Akt signaling regulated apoptosis and autophagy through different mechanisms but mTORC1 mediated autophagy appeared not to be involved in the cell death induction by DHNQ. The molecule also showed significant anticancer efficacy in in vivo tumor models without any mortality indicating its non-toxic nature with possible clinical significance. Overall, the selective elucidation of DHNQ molecular mechanism will provide the possible strategies for the clinical development in CRC that may respond to this specific, potent and novel P13K inhibitor. (c) 2016 Wiley Periodicals, Inc. PMID- 26764222 TI - Elevated absolute monocyte count predicts unfavorable outcomes in patients with angioimmunoblastic T-cell lymphoma. AB - This study was aimed at investigating the prognostic significance of the absolute monocyte count (AMC) in peripheral blood in patients with newly diagnosed angioimmunoblastic T cell lymphoma (AITL). AMC was performed in 73 therapy-naive patients with AITL in 2 institutions during 2008-2015, and higher AMC was observed in those with extranodal sites >1, bone marrow involvement, high lactate dehydrogenase level, the EBV infection, no response to treatment and high IPI, PIT, PIAI score group. The best AMC cut-off level at diagnosis was 0.8 * 10(9)/L and the 3-year overall survival (OS) was 64% for patients with low AMC group (<= 0.8 * 10(9)/L) compared to 10% in high AMC group (>0.8 * 10(9)/L) (P<0.001). Multivariate analysis showed that elevated AMC remained an adverse prognostic parameter. Our results suggest that AMC is an independent prognostic parameter for OS in patients with AITL, and AMC >0.8 * 10(9)/L can routinely be used to identify high-risk patients with unfavorable survival. PMID- 26764223 TI - Therapy for relapsed acute lymphoblastic leukemia: Still a role for standard chemotherapy regimens? PMID- 26764225 TI - Resolutions for 2016. PMID- 26764226 TI - The potential role of pharmacists in chronic disease screening. PMID- 26764224 TI - Male Pattern Baldness in Relation to Prostate Cancer-Specific Mortality: A Prospective Analysis in the NHANES I Epidemiologic Follow-up Study. AB - We used male pattern baldness as a proxy for long-term androgen exposure and investigated the association of dermatologist-assessed hair loss with prostate cancer-specific mortality in the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. From the baseline survey (1971-1974), we included 4,316 men who were 25-74 years of age and had no prior cancer diagnosis. We estimated hazard ratios and used Cox proportional hazards regressions with age as the time metric and baseline hazard stratified by baseline age. A hybrid framework was used to account for stratification and clustering of the sample design, with adjustment for the variables used to calculate sample weights. During follow-up (median, 21 years), 3,284 deaths occurred; prostate cancer was the underlying cause of 107. In multivariable models, compared with no balding, any baldness was associated with a 56% higher risk of fatal prostate cancer (hazard ratio = 1.56; 95% confidence interval: 1.02, 2.37), and moderate balding specifically was associated with an 83% higher risk (hazard ratio = 1.83; 95% confidence interval: 1.15, 2.92). Conversely, patterned hair loss was not statistically significantly associated with all-cause mortality. Our analysis suggests that patterned hair loss is associated with a higher risk of fatal prostate cancer and supports the hypothesis of overlapping pathophysiological mechanisms. PMID- 26764227 TI - The need to incorporate generic medicines topic in the curriculum of Yemeni pharmacy colleges. PMID- 26764229 TI - Editorial: Listening, learning and acting: working with people who use services to plan and undertake research. PMID- 26764228 TI - Pathways to Specialized Ribosomes: The Brussels Lecture. AB - "Specialized ribosomes" is a topic of intense debate and research whose provenance can be traced to the earliest days of molecular biology. Here, the history of this idea is reviewed, and critical literature in which the specialized ribosomes have come to be presently defined is discussed. An argument supporting the evolution of a variety of ribosomes with specialized functions as a consequence of selective pressures acting on a near-infinite set of possible ribosomes is presented, leading to a discussion of how this may also serve as a biological buffering mechanism. The possible relationship between specialized ribosomes and human health is explored. A set of criteria and possible approaches are also presented to help guide the definitive identification of "specialized" ribosomes, and this is followed by a discussion of how synthetic biology approaches might be used to create new types of special ribosomes. PMID- 26764230 TI - Myostatin propeptide gene delivery by gene gun ameliorates muscle atrophy in a rat model of botulinum toxin-induced nerve denervation. AB - AIM: Muscle atrophy is a common symptom after nerve denervation. Myostatin propeptide, a precursor of myostatin, has been documented to improve muscle growth. However, the mechanism underlying the muscle atrophy attenuation effects of myostatin propeptide in muscles and the changes in gene expression are not well established. We investigated the possible underlying mechanisms associated with myostatin propeptide gene delivery by gene gun in a rat denervation muscle atrophy model, and evaluated gene expression patterns. MAIN METHODS: In a rat botulinum toxin-induced nerve denervation muscle atrophy model, we evaluated the effects of wild-type (MSPP) and mutant-type (MSPPD75A) of myostatin propeptide gene delivery, and observed changes in gene activation associated with the neuromuscular junction, muscle and nerve. KEY FINDINGS: Muscle mass and muscle fiber size was moderately increased in myostatin propeptide treated muscles (p<0.05). And enhancement of the gene expression of the muscle regulatory factors, neurite outgrowth factors (IGF-1, GAP43) and acetylcholine receptors was observed. Our results demonstrate that myostatin propeptide gene delivery, especially the mutant-type of MSPPD75A, attenuates muscle atrophy through myogenic regulatory factors and acetylcholine receptor regulation. SIGNIFICANCE: Our data concluded that myostatin propeptide gene therapy may be a promising treatment for nerve denervation induced muscle atrophy. PMID- 26764231 TI - Effects of short term and long term Extremely Low Frequency Magnetic Field on depressive disorder in mice: Involvement of nitric oxide pathway. AB - AIMS: Previous reports on the possible effects of Extremely Low Frequency Magnetic Fields (ELF MF) on mood have been paradoxical in different settings while no study has yet been conducted on animal behavior. In addition, it was shown that ELF MF exposure makes an increase in brain nitric oxide level. Therefore, in the current study, we aimed to assess the possible effect(s) of ELF MF exposure on mice Forced Swimming Test (FST) and evaluate the probable role of the increased level of nitric oxide in the observed behavior. MAIN METHODS: Male adult mice NMRI were recruited to investigate the short term and long term ELF MF exposure (0.5 mT and 50 Hz, single 2h and 2 weeks 2h a day). Locomotor behavior was assessed by using open-field test (OFT) followed by FST to evaluate the immobility time. Accordingly, NOmega-nitro-l-arginine methyl ester 30 mg/kg was used to exert anti-depressant like effect. KEY FINDINGS: According to the results, short term exposure did not alter the immobility time, whereas long term exposure significantly reduces immobility time (p<0.01). However, it was revealed that the locomotion did not differ among all experimental groups. Short term exposure reversed the anti-depressant like effect resulting from 30 mg/kg of NOmega-nitro-l-arginine methyl ester (p<0.01). SIGNIFICANCE: It has been concluded that long term exposure could alter the depressive disorder in mice, whereas short term exposure has no significant effect. Also, reversing the anti depressant activity of L-NAME indicates a probable increase in the brain nitric oxide. PMID- 26764232 TI - Suppression of Kv1.5 protects against endothelial apoptosis induced by palmitate and in type 2 diabetes mice. AB - AIMS: Palmitate, a common saturated free fatty acid, induces endothelial apoptosis in vitro in culture endothelial cells and in vivo in type 2 diabetes mellitus (T2DM) patients. The present study aimed to investigate whether Kv1.5 regulates palmitate-induced endothelial apoptosis and endothelial dysfunction in T2DM. MAIN METHODS: In vitro experiments were carried out in primary human HUVECs. Apoptosis was analyzed by flow cytometry. Cell viability was determined by Cell Counting Assay Kit-8. The siRNA transfection was employed to knockdown Kv1.5 protein expression. Intracellular and mitochondrial ROS, and mitochondrial membrane potential were detected using fluorescent probes. Male C57BL/6 mice fed with high-sucrose/fat diet were injected with streptozotocin (35mg/kg body weight) to establish T2DM animal model. KEY FINDINGS: We found that palmitate induced endothelial apoptosis was parallel to a significant increase in endogenous Kv1.5 protein expression in endothelial cells. Silencing of Kv1.5 with siRNA reduced palmitate-induced endothelial apoptosis, intracellular ROS generation, mitochondrial ROS generation and membrane potential (Deltapsim) alteration and cleaved caspase-3 protein expression; while increased cell viability and ratio of Bcl-2/Bax. Furthermore, we observed that Kv1.5 protein expression increased in endothelial cells of thoracic aorta of T2DM mice. Silencing of Kv1.5 significantly improved the endothelium-dependent vasodilation in thoracic aortic rings of T2DM mice. SIGNIFICANCE: These results demonstrate that suppression of Kv1.5 protects endothelial cells against palmitate-induced apoptosis via inhibiting mitochondria-mediated excessive ROS generation and apoptotic signaling pathway, suggesting that Kv1.5 may serve as a therapeutic target of treatment for endothelial dysfunction induced by palmitate and lipid metabolism in T2DM patients. PMID- 26764233 TI - NF-kappaB mediates the antiproliferative and proapoptotic effects of bergamot juice in HepG2 cells. AB - AIMS: Among cancers, hepatocellular carcinoma is one of the commonest worldwide, and its incidence is increasing around the world. A lot of evidence underlines that natural substances usually consumed in the diet can have an important role in the prevention of cancer. In this study we investigated the molecular mechanisms underlying the antiproliferative activity of Citrus bergamia (bergamot) juice (BJ) in human hepatocellular carcinoma HepG2 cells. MAIN METHODS: HepG2 cells were exposed to BJ and then cell proliferation, cell cycle progression, apoptosis and NF-kappaB nuclear translocation were evaluated. KEY FINDINGS: Here we present results demonstrating that BJ reduced the growth rate of human hepatocellular carcinoma HepG2 cells in a time- and concentration dependent manner, by a mechanism involving the activation of apoptotic machinery via both intrinsic and extrinsic pathways. Moreover, BJ increased expression of P53 and P21 proteins that may be responsible for the HepG2 cell cycle arrest in G2 phase. In addition, BJ reduced NF-kappaB nuclear translocation. SIGNIFICANCE: Our data demonstrate the ability of BJ in reducing the growth of HepG2 cells, revealing its mechanism of action and suggesting a promising role as anticancer drugs. PMID- 26764234 TI - Very low protein diet enhances inflammation, malnutrition, and vascular calcification in uremic rats. AB - AIMS: Clinical studies have shown that very low protein diet (VLPD) has negative effects on long-term survival. It remains unclear why VLPD induces premature death. The present study determined the underlying mechanism whereby VLPD exerts its harmful effects on uremic rats. MAIN METHODS: Rats were divided into four groups and fed a normal diet or diets containing 0.3% adenine and low/normal protein with high/low phosphate. After 6 weeks, body weight, urinary biochemistry (creatinine and phosphate), serum biochemical parameters (urea, creatinine, fibroblast growth factor 23, albumin, and fetuin-A), systemic inflammatory markers (serum tumor necrosis factor-alpha and urinary 8-hydroxy-2' deoxyguanosine), calcium content in the aorta, and serum calcium-phosphate precipitates were evaluated. Hepatic mRNA levels were also determined. KEY FINDINGS: Rats fed the diet containing 0.3% adenine developed severe azotemia. Rats fed VLPD developed malnutrition (decreases in body weight, serum albumin and fetuin-A levels, and urinary creatinine excretion) and systemic inflammation (increases in serum tumor necrosis factor-alpha and urinary 8-hydroxy-2' deoxyguanosine) independent of phosphate status. VLPD decreased the serum fetuin A level and hepatic fetuin-A synthesis and increased serum calcium-phosphate precipitates, a marker of calciprotein particle. A high-phosphate diet induced arterial medial calcification, which was enhanced by VLPD. Serum calcium phosphate precipitate levels were correlated with the degree of inflammation, malnutrition, and aortic calcium content. Dietary phosphate restriction prevented VLPD-enhanced vascular calcification, but could not halt inflammation and malnutrition induced by VLPD. SIGNIFICANCE: VLPD enhances inflammation, malnutrition, and vascular calcification in uremic rats, among which only vascular calcification is prevented by dietary phosphate restriction. PMID- 26764235 TI - Ligands for cannabinoid receptors, promising anticancer agents. AB - Cannabinoid compounds are unique to cannabis and provide some interesting biological properties. These compounds along with endocannabinoids, a group of neuromodulator compounds in the body especially in brain, express their effects by activation of G-protein-coupled cannabinoid receptors, CB1 and CB2. There are several physiological properties attributed to the endocannabinoids including pain relief, enhancement of appetite, blood pressure lowering during shock, embryonic development, and blocking of working memory. On the other hand, activation of endocannabinoid system may be suppresses evolution and progression of several types of cancer. According to the results of recent studies, CB receptors are over-expressed in cancer cell lines and application of multiple cannabinoid or cannabis-derived compounds reduce tumor size through decrease of cell proliferation or induction of cell cycle arrest and apoptosis along with desirable effect on decrease of tumor-evoked pain. Therefore, modulation of endocannabinoid system by inhibition of fatty acid amide hydrolase (FAAH), the enzyme, which metabolized endocannabinoids, or application of multiple cannabinoid or cannabis-derived compounds, may be appropriate for the treatment of several cancer subtypes. This review focuses on how cannabinoid affect different types of cancers. PMID- 26764236 TI - Thyroid hormones effects on oxidative stress and cardiac remodeling in the right ventricle of infarcted rats. AB - Right ventricle (RV) dysfunction post-myocardial infarction (MI) was associated with a worsened prognosis. In this scenario, reactive oxygen species (ROS) are related with the progression from MI to heart failure. Previous work showed that thyroid hormones (TH) are cardioprotective after MI. AIMS: This study aims to investigate the effect of T3 and T4 administration on oxidative stress and angiogenesis parameters in the RV after MI. MAIN METHODS: Wistar rats were allocated into four groups: Sham-operated (SHAM), infarcted (AMI), sham-operated + TH (SHAMT), and infarcted+TH (AMIT). The treated groups received T3 (2 MUg/100g/day) and T4 (8 MUg/100g/day) by gavage for 26 days. After this, echocardiographic analysis was performed and the RV was collected to western blot and biochemical analysis. KEY FINDINGS: Infarcted treated rats showed RV hypertrophy compared with AMI and SHAMT. Hydrogen peroxide levels were decrease and SOD activity and expression were increased in the infarcted treated rats. Besides that, the hormonal administration increased eNOS expression and prevented the reduction of VEGF levels in AMIT rats. SIGNIFICANCE: In conclusion, TH seems to improve oxidative stress parameters, to promote physiological hypertrophy and to increase the expression of proteins involved with angiogenesis in the right heart. PMID- 26764237 TI - Return-to-Play Outcomes in Professional Baseball Players After Medial Ulnar Collateral Ligament Injuries: Comparison of Operative Versus Nonoperative Treatment Based on Magnetic Resonance Imaging Findings. AB - BACKGROUND: The medial ulnar collateral ligament (UCL) is the primary static stabilizer to valgus stress of the elbow. Injuries to the UCL are common in baseball pitchers. In the 1970s, reconstructive surgery was developed. Return-to play (RTP) rates of 67% to 95% after reconstruction have been reported. There is a paucity of published studies among professional baseball players reporting RTP with nonoperative treatment. PURPOSE: To identify professional baseball players' ability to RTP after the nonoperative treatment of UCL injuries based on the magnetic resonance imaging (MRI) grade. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A review of elbow injuries among a professional baseball organization from 2006 to 2011 was performed. MRI was performed on all players. Forty-three UCL injuries were diagnosed. Treatment included rehabilitation, surgery, or both. Rates of RTP and return to the same level of play or higher (RTSP) were calculated and correlated with the MRI grade, location of injury, and player position. MRI grading was as follows: I, intact ligament with or without edema; IIA, partial tear; IIB, chronic healed injury; and III, complete tear. RESULTS: Forty-three UCL injuries in 43 players were diagnosed. Eight had complete tears (grade III), were treated operatively with UCL reconstruction, and had an RTP rate of 75% and RTSP rate of 63% (5/8 returned to the same level and 1 to a lower level). All 8 were pitchers. The remaining 35 players had incomplete injuries (4 grade I, 8 grade IIA, and 23 grade IIB), consisting of 24 pitchers and 11 positional players. Of these 35 players, 1 underwent surgery without attempted rehabilitation, 3 initiated rehabilitation until MRI was performed and then underwent surgery, and 3 underwent surgery after failed rehabilitation. The 7 players who underwent UCL reconstruction surgery had an RTP rate of 100% and RTSP rate of 86% (6/7 returned to the same level and 1 to a lower level). The remaining 28 with nonoperative treatment had both RTP and RTSP rates of 93% (26/28 returned to the same level and 0 to a lower level). Of these, 10 were positional players with an RTSP rate of 90%, and 18 were pitchers with an RTSP rate of 94%. Of all players with incomplete UCL injuries who completed nonoperative rehabilitative treatment (n = 31), 26 had a successful RTSP (84%). CONCLUSION: Incomplete UCL injuries in professional baseball players can be successfully treated nonoperatively in the majority of cases. Pitchers are more likely to have complete tears leading to surgery. MRI grading of UCL injuries can help predict RTP and the need for surgery. PMID- 26764238 TI - Emergency Contraceptives and the Beginning of Human Animals. AB - Emergency contraceptives may sometimes prevent implantation, thereby causing the death of the embryo. According to some positions contrary to abortion, because the embryo is a human animal, there are usually decisive moral reasons not to use them. In this article, I will show that objecting to the use of emergency contraceptives on those grounds is unjustified. If organisms are real existents, then according to the most plausible conception of what is required for a group of cells to compose one, the embryo cannot qualify as a single organism. On the other hand, if organisms are virtual objects, then whether or not the embryo qualifies as one is morally irrelevant. I conclude that even if those positions are right about the morality of abortion, they are not entitled to oppose the use of emergency contraceptives. PMID- 26764239 TI - Functional up-regulation of Nav1.8 sodium channel on dorsal root ganglia neurons contributes to the induction of scorpion sting pain. AB - BmK I, purified from the venom of scorpion Buthus martensi Karsch (BmK), is a receptor site-3-specific modulator of voltage-gated sodium channels (VGSCs) and can induce pain-related behaviors in rats. The tetrodotoxin-resistant (TTX-R) sodium channel Nav1.8 contributes to most of the sodium current underlying the action potential upstroke in dorsal root ganglia (DRG) neurons and may serve as a critical ion channel targeted by BmK I. Herein, using electrophysiological, molecular, and behavioral approaches, we investigated whether the aberrant expression of Nav1.8 in DRG contributes to generation of pain induced by BmK I. The expression of Nav1.8 was found to be significantly increased at both mRNA and protein levels following intraplantar injection of BmK I in rats. In addition, the current density of TTX-R Nav1.8 sodium channel is significantly increased and the gating kinetics of Nav1.8 is also altered in DRG neurons from BmK I-treated rats. Furthermore, spontaneous pain and mechanical allodynia, but not thermal hyperalgesia induced by BmK I, are significantly alleviated through either blockade of the Nav1.8 sodium channel by its selective blocker A-803467 or knockdown of the Nav1.8 expression in DRG by antisense oligodeoxynucleotide (AS ODN) targeting Nav1.8 in rats. Finally, BmK I was shown to induce enhanced pain behaviors in complete freund's adjuvant (CFA)-inflamed rats, which was partly due to the over-expression of Nav1.8 in DRG. Our results suggest that functional up regulation of Nav1.8 channel on DRG neurons contributes to the development of BmK I-induced pain in rats. PMID- 26764241 TI - Genetic dysfunction of serotonin 2A receptor hampers response to antidepressant drugs: A translational approach. AB - Pharmacological studies have yielded valuable insights into the role of the serotonin 2A (5-HT2A) receptor in major depressive disorder (MDD) and antidepressant drugs (ADs) response. However, it is still unknown whether genetic variants in the HTR2A gene affect the therapeutic outcome of ADs and the mechanism underlying the regulation of such response remains poorly described. In this context, a translational human-mouse study offers a unique opportunity to address the possibility that variations in the HTR2A gene may represent a relevant marker to predict the efficacy of ADs. In a first part of this study, we investigated in depressed patients the effect of three HTR2A single nucleotide polymorphisms (SNPs), selected for their potential functional consequences on 5 HT2A receptor (rs6313, rs6314 and rs7333412), on response and remission rates after 3 months of antidepressant treatments. We also explored the consequences of the constitutive genetic inactivation of the 5-HT2A receptor (i.e. in 5-HT2A(-/-) mice) on the activity of acute and prolonged administration of SSRIs. Our clinical data indicate that GG patients for the rs7333412 SNP were less prone to respond to ADs than AA/AG patients. In the preclinical study, we demonstrated that the 5-HT2A receptor exerts an inhibitory influence on the neuronal activity of the serotonergic system after acute administration of SSRIs. However, while the chronic administration of the SSRIs escitalopram or fluoxetine elicited a progressive increased in the firing rate of 5-HT neurons in 5-HT2A(+/+) mice, it failed to do so in 5-HT2A(-/-) mutants. These electrophysiological impairments were associated with a decreased ability of the chronic administration of fluoxetine to stimulate hippocampal plasticity and to produce antidepressant-like activities. Genetic loss of the 5-HT2A receptor compromised the activity of chronic treatment with SSRIs, making this receptor a putative marker to predict ADs response. PMID- 26764242 TI - Genistein improves sensorimotor gating: Mechanisms related to its neuroprotective effects on the striatum. AB - Huntington's disease (HD) is a neurodegenerative disorder, characterized by selective atrophy in the striatum, particularly the medium spiny GABAergic efferent neurons. This results in striatal sensorimotor gating deficits. Systemic administration of 3-nitropropionic acid (3-NPA) produces selective lesions mimicking those of HD. Males were found to be more susceptible to 3-NPA-induced neurotoxicity than females, suggesting neuroprotective effects of estrogens. Phytoestrogens, including genistein, are good estrogenic alternatives that keep their beneficial effects on non-reproductive organs and lack the potential hazardous side effects. The current study was designed to investigate the potential beneficial effects of genistein in 3-NPA-induced HD in ovariectomized rats. Results showed that 3-NPA (20 mg/kg) administration caused significant disruption of the rats' locomotor activity and prepulse inhibition. In addition, it decreased striatal ATP levels and increased oxidative stress, inflammatory and apoptotic markers with striatal focal hemorrhage and gliosis. Pretreatment with 17beta-estradiol (2.5 mg/kg) or genistein (20 mg/kg) led to a significant improvement of behavioral parameters, increased ATP production, decreased oxidative stress, attenuated inflammation and apoptosis. Therefore, this study suggests potential neuroprotective effects of genistein in ovariectomized rats challenged with 3-NPA. PMID- 26764243 TI - Expression profile and prognostic value of glypican-3 in post-operative South Korean hepatocellular carcinoma patients. AB - Hepatocellular carcinoma (HCC) patients commonly experience poor overall survival (OS) and disease-free survival (DFS) after curative surgical resection. Glypican 3 (GPC3) has been suggested as a prognostic biomarker for post-operative survival. However, few to none of these studies have included South Korean patients. This study aimed to determine GPC3 expression rate, clinical correlation, and post-operative prognostic value in South Korean HCC patients who underwent curative surgical resection. Surgically resected tissues from 185 HCC patients were collected and assembled into tissue microarrays (TMAs), which were stained for GPC3 by immunohistochemistry. GPC3 expression rates were correlated with clinicopathological information, and survival analyses were performed to assess the prognostic value of GPC3. GPC3 expression was present in 153 patients (82.7%). GPC3-positive patients were younger with higher frequencies of microvascular invasion and higher AFP levels than GPC3-negative patients. There was no significant difference in survival between GPC3-negative and GPC3-positive patients. Based on multivariate analysis, GPC3 expression was not a prognostic marker for post-operative survival. In South Korean HCC patients, GPC3 expression was more frequent in HCCs with aggressive features, but it was not an independent prognostic biomarker. PMID- 26764244 TI - Wishful Thinking? Inside the Black Box of Exposure Assessment. AB - BACKGROUND: Decision-making processes used by experts when undertaking occupational exposure assessment are relatively unknown, but it is often assumed that there is a common underlying method that experts employ. However, differences in training and experience of assessors make it unlikely that one general method for expert assessment would exist. Therefore, there are concerns about formalizing, validating, and comparing expert estimates within and between studies that are difficult, if not impossible, to characterize. Heuristics on the other hand (the processes involved in decision making) have been extensively studied. Heuristics are deployed by everyone as short-cuts to make the often complex process of decision-making simpler, quicker, and less burdensome. Experts' assessments are often subject to various simplifying heuristics as a way to reach a decision in the absence of sufficient data. Therefore, investigating the underlying heuristics or decision-making processes involved may help to shed light on the 'black box' of exposure assessment. METHODS: A mixed method study was conducted utilizing both a web-based exposure assessment exercise incorporating quantitative and semiqualitative elements of data collection, and qualitative semi-structured interviews with exposure assessors. Qualitative data were analyzed using thematic analysis. RESULTS: Twenty-five experts completed the web-based exposure assessment exercise and 8 of these 25 were randomly selected to participate in the follow-up interview. Familiar key themes relating to the exposure assessment exercise emerged; 'intensity'; 'probability'; 'agent'; 'process'; and 'duration' of exposure. However, an important aspect of the detailed follow-up interviews revealed a lack of structure and order with which participants described their decision making. Participants mostly described some form of an iterative process, heavily relying on the anchoring and adjustment heuristic, which differed between experts. CONCLUSION: In spite of having undertaken comparable training (in occupational hygiene or exposure assessment), experts use different methods to assess exposure. Decision making appears to be an iterative process with heavy reliance on the key heuristic of anchoring and adjustment. Using multiple experts to assess exposure while providing some form of anchoring scenario to build from, and additional training in understanding the impact of simple heuristics on the process of decision making, is likely to produce a more methodical approach to assessment; thereby improving consistency and transparency in expert exposure assessment. PMID- 26764240 TI - Targeting AMPK signaling in combating ovarian cancers: opportunities and challenges. AB - The development and strategic application of effective anticancer therapies have turned out to be one of the most critical approaches of managing human cancers. Nevertheless, drug resistance is the major obstacle for clinical management of these diseases especially ovarian cancer. In the past years, substantial studies have been carried out with the aim of exploring alternative therapeutic approaches to enhance efficacy of current chemotherapeutic regimes and reduce the side effects caused in order to produce significant advantages in overall survival and to improve patients' quality of life. Targeting cancer cell metabolism by the application of AMP-activated protein kinase (AMPK)-activating agents is believed to be one of the most plausible attempts. AMPK activators such as 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside, A23187, metformin, and bitter melon extract not only prevent cancer progression and metastasis but can also be applied as a supplement to enhance the efficacy of cisplatin-based chemotherapy in human cancers such as ovarian cancer. However, because of the undesirable outcomes along with the frequent toxic side effects of most pharmaceutical AMPK activators that have been utilized in clinical trials, attentions of current studies have been aimed at the identification of replaceable reagents from nutraceuticals or traditional medicines. However, the underlying molecular mechanisms of many nutraceuticals in anticancer still remain obscure. Therefore, better understanding of the functional characterization and regulatory mechanism of natural AMPK activators would help pharmaceutical development in opening an area to intervene ovarian cancer and other human cancers. PMID- 26764247 TI - Erratum. PMID- 26764245 TI - Cell line modeling to study biomarker panel in prostate cancer. AB - BACKGROUND: African-American men with prostate cancer (PCa) present with higher grade and -stage tumors compared to Caucasians. While the disparity may result from multiple factors, a biological basis is often strongly suspected. Currently, few well-characterized experimental model systems are available to study the biological basis of racial disparity in PCa. We report a validated in vitro cell line model system that could be used for the purpose. METHODS: We assembled a PCa cell line model that included currently available African-American PCa cell lines and LNCaP (androgen-dependent) and C4-2 (castration-resistant) Caucasian PCa cells. The utility of the cell lines in studying the biological basis of variance in a malignant phenotype was explored using a multiplex biomarker panel consisting of proteins that have been proven to play a role in the progression of PCa. The panel expression was evaluated by Western blot and RT-PCR in cell lines and validated in human PCa tissues by RT-PCR. As proof-of-principle to demonstrate the utility of our model in functional studies, we performed MTS viability assays and molecular studies. RESULTS: The dysregulation of the multiplex biomarker panel in primary African-American cell line (E006AA) was similar to metastatic Caucasian cell lines, which would suggest that the cell line model could be used to study an inherent aggressive phenotype in African American men with PCa. We had previously demonstrated that Protein kinase D1 (PKD1) is a novel kinase that is down regulated in advanced prostate cancer. We established the functional relevance by over expressing PKD1, which resulted in decreased proliferation and epithelial mesenchymal transition (EMT) in PCa cells. Moreover, we established the feasibility of studying the expression of the multiplex biomarker panel in archived human PCa tissue from African-Americans and Caucasians as a prelude to future translational studies. CONCLUSION: We have characterized a novel in vitro cell line model that could be used to study the biological basis of disparity in PCa between African-Americans and Caucasians. PMID- 26764246 TI - Cytoplasmic accumulation of ELAVL1 is an independent predictor of biochemical recurrence associated with genomic instability in prostate cancer. AB - BACKGROUND: ELAVL1 is an RNA binding protein involved in translation control, which might have a regulatory role in prostate cancer progress. METHODS: To evaluate its impact and relationship with key genomic alterations, ELAVL1 expression was analyzed by immunohistochemistry on a tissue microarray containing 12,427 prostate cancers. RESULTS: The analysis revealed a mild to moderate predominantly nuclear immunostaining in normal prostate epithelium and an often higher both cytoplasmic and nuclear expression in cancer cells. Weak, moderate, and strong cytoplasmic ELAVL1 staining was found in 43%, 18%, and 3% of 10,478 interpretable tumors. Strong ELAVL1 staining was linked to high Gleason grade, advanced pathological tumor stage, positive nodal status, and PSA recurrence (P < 0.0001 each). A combined analysis of the effect of nuclear and cytoplasmic ELAVL1 expression on PSA recurrence revealed that the association with patient outcome was entirely driven by cytoplasmic staining. ELAVL1 positivity was more frequent in cancers harboring TMPRSS2:ERG fusions found by FISH (78%) or showing immunohistochemical ERG expression (74%) than in cancers without ERG rearrangement (63%) or ERG expression (58%, P < 0.0001 each). Strong cytoplasmic ELAVL1 staining was further linked to presence of PTEN, 5q21, 6q15, and 3p13 deletions (P < 0.0001 each), an observation consistent with cytoplasmic ELAVL1 accumulation in case of genomic instability. The prognostic role of ELAVL1 expression was independent of Gleason grade, T stage, N stage, surgical margin status, and preoperative PSA, irrespective of whether preoperative or postoperative variables were used for modeling. CONCLUSION: Our study identifies cytoplasmic accumulation of ELAVL1 as a predictor of adverse clinical behavior of prostate cancer independent of established clinico-pathological parameters. PMID- 26764248 TI - Stereotactic Radiotherapy for Stage I Small Cell Lung Cancer. PMID- 26764249 TI - The Rationale for Targeted Therapies and Stereotactic Radiosurgery in the Treatment of Brain Metastases. AB - Brain metastases are the most common intracranial malignancy. Many approaches, including radiation therapy, surgery, and cytotoxic chemotherapy, have been used to treat patients with brain metastases depending on the patient's disease burden and symptoms. However, stereotactic surgery (SRS) has revolutionized local treatment of brain metastases. Likewise, targeted therapies, including small molecule inhibitors and monoclonal antibodies that target cancer cell metabolism or angiogenesis, have transformed managing systemic disease. Prospective data on combining these treatments for synergistic effect are limited, but early data show favorable safety and efficacy profiles. The combination of SRS and targeted therapy will further individualize treatment, potentially obviating the need for cytotoxic chemotherapy or whole-brain radiation. There is a great need to pursue research into these exciting modalities and novel combinations to further improve the treatment of patients with brain metastases. This article discusses reported and ongoing clinical trials assessing the safety and efficacy of targeted therapy during SRS. IMPLICATIONS FOR PRACTICE: Treatment of patients with brain metastases requires a multidisciplinary approach. Stereotactic radiosurgery is increasingly used in the upfront setting to treat new brain metastasis. Targeted therapies have revolutionized systemic treatment of many malignancies and may sometimes be used as initial treatment in metastatic patients. There is sparse literature regarding safety and efficacy of combining these two treatment modalities. This article summarizes the supporting literature and highlights ongoing clinical trials in combining radiosurgery with targeted therapy. PMID- 26764250 TI - Optimizing the G8 Screening Tool for Older Patients With Cancer: Diagnostic Performance and Validation of a Six-Item Version. AB - BACKGROUND: A multidimensional geriatric assessment (GA) is recommended in older cancer patients to inventory health problems and tailor treatment decisions accordingly but requires considerable time and human resources. The G8 is among the most sensitive screening tools for selecting patients warranting a full GA but has limited specificity. We sought to develop and validate an optimized version of the G8. PATIENTS AND METHODS: We used a prospective cohort of cancer patients aged >= 70 years referred to geriatricians for GA (2007-2012: n = 729 [training set]; 2012-2014: n = 414 [validation set]). Abnormal GA was defined as at least one impaired domain across seven validated tests. Multiple correspondence analysis, multivariate logistic regression, and bootstrapped internal validation were performed sequentially. RESULTS: The final model included six independent predictors for abnormal GA: weight loss, cognition/mood, performance status, self-rated health status, polypharmacy (>= 6 medications per day), and history of heart failure/coronary heart disease. For the original G8, sensitivity was 87.2% (95% confidence interval, 84.3-89.7), specificity 57.7% (47.3-67.7), and area under the receiver-operating characteristic curve (AUROC) 86.5% (83.5-89.6). The modified G8 had corresponding values of 89.2% (86.5-91.5), 79.0% (69.4-86.6), and 91.6% (89.3; 93.9), with higher AUROC values for all tumor sites and stable properties on the validation set. CONCLUSION: A modified G8 screening tool exhibited better diagnostic performance with greater uniformity across cancer sites and required only six items. If these features are confirmed in other settings, the modified tool may facilitate selection for a full GA in older patients with cancer. IMPLICATIONS FOR PRACTICE: Several screening tools have been developed to identify older patients with cancer likely to benefit from a complete geriatric assessment, but none combines appropriate sensitivity and specificity. Based on a large prospective cohort study, an optimized G8 tool was developed, combining a systematic statistical approach with expert judgment to ensure optimal discriminative power and clinical relevance. The improved screening tool achieves high sensitivity, high specificity, better homogeneity across cancer types, and greater parsimony with only six items needed, facilitating selection for a full geriatric assessment. PMID- 26764252 TI - Association Between Decreased Serum Albumin With Risk of Venous Thromboembolism and Mortality in Cancer Patients. AB - BACKGROUND: In cancer patients, reduced serum albumin has been described as a marker for global declining health and poor prognosis. Our aim was to investigate the association of albumin concentrations with the occurrence of venous thromboembolism (VTE) and mortality in patients with cancer. METHODS: This investigation was performed in the framework of the Vienna Cancer and Thrombosis Study (CATS), a prospective observational cohort study. We included 1,070 patients with active cancer and assayed serum albumin from venous blood taken at study inclusion. Risk for occurrence of VTE was calculated in a proportional subdistribution hazard regression model with respect to competing risk of death and adjusted for cancer site, leukocyte count, estimated glomerular filtration rate, and cholinesterase. RESULTS: Patients (630 males [58.9%] and 440 females [41.1%]) were observed for a median of 723 days. During follow-up, 90 VTE events (8.4%) and 396 deaths (37.0%) occurred. The median albumin was 41.3 g/L (25th 75th percentile, 37.6-44.2). Patients with albumin levels below the 75th percentile had a 2.2-fold increased risk of VTE (95% confidence interval [CI] 1.09-4.32), as well as a 2.3-fold increased risk of death (95% CI 1.68-3.20) compared with patients with albumin above the 75th percentile. CONCLUSION: Decreased serum albumin levels in cancer patients were significantly associated with increased risk of VTE and mortality. Serum albumin, a marker of a cancer patient's overall prognosis, could be considered for risk assessment of important clinical outcomes such as VTE and mortality. IMPLICATIONS FOR PRACTICE: Cancer patients are at increased risk of venous thromboembolism (VTE). In this prospective cohort study of 1,070 cancer patients, decreased serum albumin was a marker for risk of VTE and mortality, independent of kidney or liver function and inflammation markers. The study identified a group of patients with high risk of cancer-associated VTE and a reduced prognosis who may benefit from supportive therapy such as primary VTE prophylaxis. PMID- 26764251 TI - Ventricular-Arterial Coupling in Breast Cancer Patients After Treatment With Anthracycline-Containing Adjuvant Chemotherapy. AB - BACKGROUND: Anthracycline-containing chemotherapy (Anth-C) is associated with long-term cardiovascular mortality. Although cardiovascular risk assessment has traditionally focused on the heart, evidence has demonstrated that vascular dysfunction also occurs during and up to 1 year following Anth-C. Whether vascular dysfunction persists long-term or negatively influences cardiac function remains unknown. Hence, the present study evaluated ventricular-arterial coupling, in concert with measures of vascular structure and function, in the years following Anth-C. METHODS: Arterial elastance (Ea), end-systolic elastance (Ees), and ventricular-arterial coupling (Ea/Ees) were measured during rest and exercise using echocardiography. Resting vascular function (flow-mediated dilation) and structure (carotid intima-media thickness, arterial stiffness) were also measured. RESULTS: Thirty breast cancer survivors (6.5 +/- 3.6 years after Anth-C) with normal left ventricular ejection fraction (LVEF) (60% +/- 6%) and 30 matched controls were studied. At rest, no differences were found in Ea, Ees, Ea/Ees, or LVEF between groups. The normal exercise-induced increase in Ees was attenuated in survivors at 50% and 75% of maximal workload (p < .01). Ea/Ees was also higher at all workloads in the survivors compared with the controls (p < .01). No differences in vascular structure and function were observed between the two groups (p > .05). CONCLUSION: In the years after Anth-C, ventricular-arterial coupling was significantly attenuated during exercise, primarily owing to decreased LV contractility (indicated by a reduced Ees). This subclinical dysfunction appears to be isolated to the heart, as no differences in Ea were observed. The previously reported adverse effects of Anth-C on the vasculature appear to not persist in the years after treatment, as vascular structure and function were comparable to controls. IMPLICATIONS FOR PRACTICE: Anthracycline induced cardiotoxicity results in significantly impaired ventricular-arterial coupling in the years following chemotherapy, owing specifically to decreased left ventricular contractility. This subclinical dysfunction was identified only under exercise stress. A comprehensive evaluation of vascular structure and function yielded no differences between those treated with anthracyclines and controls. Combined with a stress stimulus, ventricular-arterial coupling might hold significant value beyond characterization of integrative cardiovascular function, in particular as a part of a risk-stratification strategy after anthracycline-containing chemotherapy. Although vascular function and structure were not different in this cohort, this does not undermine the importance of identifying vascular (dys)function in this population, because increases in net arterial load during exercise might amplify the effect of reductions in contractility on cardiovascular function after anthracycline-containing chemotherapy. PMID- 26764253 TI - Development of prenatal screening--A historical overview. AB - The first prenatal screening test to be introduced was based on a single maternal serum marker of neural tube defects. Since then various prenatal screening concepts have been developed, the most successful being Down syndrome risk estimation using multiple serum and ultrasound markers. Today a completely new approach to aneuploidy screening is available based on maternal plasma cell-free DNA testing. This has the potential to markedly improve screening performance but routine testing is currently too expensive in a public health setting. However, it can be cost-effective when used in combination with existing multi-maker tests. Some are beginning to broaden prenatal screening to include pregnancy complications such as pre-eclampsia that can be prevented using soluble low-dose aspirin treatment started before 16 weeks of gestation. Prenatal screening for cardiac abnormalities, fragile X syndrome and recessive genetic disorders is underutilized and public health planners should considered a more widespread application of available methods. PMID- 26764254 TI - Unplanned early return to the emergency department by older patients: the Safe Elderly Emergency Department Discharge (SEED) project. AB - BACKGROUND: an emergency department (ED) visit is a sentinel event for an older person, with increased likelihood of adverse outcomes post-discharge including early re-presentation. OBJECTIVES: to determine factors associated with early re presentation. METHODS: prospective cohort study conducted in the ED of a large acute Melbourne tertiary hospital. Community-dwelling patients >=65 years were interviewed including comprehensive assessment of cognitive and functional status, and mood. Logistic regression was used to identify risk factors for return within 30 days. RESULTS: nine hundred and fifty-nine patients, median age 77 years, were recruited. One hundred and forty patients (14.6%) re-presented within 30 days, including 22 patients (2.3%) on >=2 occasions and 75 patients (7.8%) within 7 days. Risk factors for re-presentation included depressive symptoms, cognitive impairment, co-morbidity, triaged as less urgent (ATS 4) and attendance in the previous 12 months, with a decline in risk after 85 years of age. Logistic regression identified chronic obstructive pulmonary disease (OR 1.78, 95% CI 1.02-3.11), moderate cognitive impairment (OR 2.07, 95% CI 1.09 3.90), previous ED visit (OR 2.11, 95% CI 1.43-3.12) and ATS 4 (OR 2.34, 95% CI 1.10-4.99) as independent risk factors for re-presentation. Age >=85 years was associated with reduced risk (OR 0.81, 95% CI 0.70-0.93). CONCLUSION: older discharged patients had a high rate of early re-presentation. Previously identified risk factors-increased age, living alone, functional dependence and polypharmacy-were not associated with early return in this study. It is not clear whether these inconsistencies represent a change in patient case-mix or strategies implemented to reduce re-attendance. This remains an important area for future research. PMID- 26764255 TI - Adolescent Rats Self-Administer Less Nicotine Than Adults at Low Doses. AB - INTRODUCTION: Although nearly 90% of current smokers initiated tobacco use during adolescence, little is known about reinforcement by nicotine in adolescents. Researchers are currently investigating whether a potential public health policy setting a tobacco product standard with very low nicotine levels would improve public health, and it is essential to understand whether data generated in adults translates to adolescents, particularly as it relates to the threshold dose of nicotine required to support smoking. The present study compared self administration of low doses of nicotine between adolescent and adult rats. METHODS: Adolescent (postnatal day [P] 30) and adult (P90) male and female rats were allowed to nosepoke to receive intravenous infusions of nicotine (3-100 MUg/kg/infusion) during 16 daily 1-hour sessions. RESULTS: At 10 MUg/kg/infusion nicotine, adolescent rats earned significantly fewer infusions than adults. When responding for 30 MUg/kg/infusion nicotine, rats of both ages earned a similar number of infusions; however, there were subtle differences in the distribution of infusions across the 1-hour session. No sex differences were apparent in either age group at any dose. CONCLUSIONS: These results demonstrate that adolescent rats are less sensitive than adults to the primary reinforcing effects of nicotine. However, at nicotine doses that support self-administration in both age groups, adolescent and adult rats do not differ in acquisition or number of infusions earned. These results suggest that reducing nicotine levels in cigarettes to a level that does not support smoking in adults may be sufficient to reduce the acquisition of smoking in adolescents. IMPLICATIONS: The results of the present studies demonstrate that adolescent rats are less sensitive than adults to the primary reinforcing effects of nicotine. These results suggest that reducing nicotine levels in cigarettes to a level that does not support smoking in adults will be sufficient to reduce the acquisition of smoking in adolescents. PMID- 26764257 TI - Social Disparities in Unaided Quit Attempts Among Daily Current and Former Smokers: Results From the 2010-2011 Tobacco Use Supplement to the Current Population Survey. AB - INTRODUCTION: There are well-documented inverse relationships between smoking and smoking cessation with measures of socioeconomic status. This study used nationally representative data to examine unaided quit attempts and their sociodemographic determinants among daily current and former smokers who made a quit attempt in the last 12 months. METHODS: We used data from the 2010-2011 Tobacco Use Supplement to the Current Population Survey. We limited the analysis to current daily smokers who made a quit attempt in the past year and former smokers who were daily smokers 1 year prior to the survey (N = 8201). RESULTS: Nearly 62% (n = 5078) of the sample made an unaided quit attempt. Adjusted results indicated unaided quit attempts were more likely among males compared to females (P < .001), younger age groups compared to older age groups (P < .001), non-Hispanic blacks compared to non-Hispanic whites (P < .001), among people with lower income compared to people with higher income (P < .001), and among people with lower nicotine dependence compared to those with higher nicotine dependence (P < .001). CONCLUSIONS: Most quit attempts were unaided and there were significant sociodemographic disparities in unaided quit attempts. Considering that cessation aids enhance the likelihood of quitting, policies and programs should target populations which are more likely to attempt quitting without an aid and encourage them to use or provide subsidized cessation aids. Healthcare providers should advise their patients about approaches to quitting. IMPLICATIONS: This study used the most recent nationally representative data for the United States to examine sociodemographic disparities in unaided quitting among current and former daily smokers who made a quit attempt in the last 12 months. Most quit attempts were unaided. People who were male, younger, non Hispanic black, had lower nicotine dependence, and those who were low income were more likely to make an unaided quit attempt. These results could be used by policy makers and program planners to develop cessation interventions directed at specific populations to improve smoking cessation rates. PMID- 26764256 TI - Changes Over Time in Absolute and Relative Socioeconomic Differences in Smoking: A Comparison of Cohort Studies From Britain, Finland, and Japan. AB - INTRODUCTION: Socioeconomic differences in smoking over time and across national contexts are poorly understood. We assessed the magnitude of relative and absolute social class differences in smoking in cohorts from Britain, Finland, and Japan over 5-7 years. METHODS: The British Whitehall II study (n = 4350), Finnish Helsinki Health Study (n = 6328), and Japanese Civil Servants Study (n = 1993) all included employed men and women aged 35-68 at baseline in 1997-2002. Follow-up was in 2003-2007 (mean follow-up 5.1, 6.5, and 3.6 years, respectively). Occupational social class (managers, professionals and clerical employees) was measured at baseline. Current smoking and covariates (age, marital status, body mass index, and self-rated health) were measured at baseline and follow-up. We assessed relative social class differences using the Relative Index of Inequality and absolute differences using the Slope Index of Inequality. RESULTS: Social class differences in smoking were found in Britain and Finland, but not in Japan. Age-adjusted relative differences at baseline ranged from Relative Index of Inequality 3.08 (95% confidence interval 1.99-4.78) among Finnish men to 2.32 (1.24-4.32) among British women, with differences at follow up greater by 8%-58%. Absolute differences remained stable and varied from Slope Index of Inequality 0.27 (0.15-0.40) among Finnish men to 0.10 (0.03-0.16) among British women. Further adjustment for covariates had modest effects on inequality indices. CONCLUSIONS: Large social class differences in smoking persisted among British and Finnish men and women, with widening tendencies in relative differences over time. No differences could be confirmed among Japanese men or women. IMPLICATIONS: Changes over time in social class differences in smoking are poorly understood across countries. Our study focused on employees from Britain, Finland and Japan, and found relative and absolute and class differences among British and Finnish men and women. Key covariates had modest effects on the differences. Relative differences tended to widen over the 4- to 7-year follow up, whereas absolute differences remained stable. In contrast, class differences in smoking among Japanese men or women were not found. Britain and Finland are at the late stage of the smoking epidemic model, whereas Japan may not follow the same model. PMID- 26764258 TI - A Risk-Continuum Categorization of Product Use Among US Youth Tobacco Users. AB - INTRODUCTION: To examine prevalence and correlates of five mutually exclusive tobacco-use patterns among US youth tobacco users. METHODS: A nationally representative sample of tobacco users (N = 3202, 9-17 years) was classified into five product-use patterns. Weighted multinominal and multivariate logistic regression models were used to examine prevalence of product-use patterns by gender, race and ethnicity, and grade level; and associations between product-use patterns and perceived accessibility of tobacco products, exposure and receptivity to pro-tobacco marketing, social benefits of smoking, and tobacco associated risks. RESULTS: Dual use (ie, use of two product categories) was the most prevalent pattern (30.5%), followed by non-cigarette combustible only (26.7%), polytobacco (ie, use of three product categories; 17.5%), cigarette only (14.9%), and noncombustible only (10.4%) use. Product-use patterns differed by gender, race, and ethnicity. Compared to cigarette only users, dual and polytobacco users were more likely to be exposed to and be receptive to pro tobacco marketing, and were less likely to acknowledge tobacco-use related risks (Ps < .05). CONCLUSIONS: Curbing tobacco use warrants research on users of more than one tobacco-product categories according to the risk-continuum categorization. IMPLICATIONS: We present a risk-continuum categorization of product-use patterns among tobacco users not older than 17 years. We classify tobacco users into five mutually exclusive product-use patterns: cigarette only users, non-cigarette combustible only users, noncombustible only users, dual use, and polytobacco use. This categorization overcomes limitations in current literature on tobacco-use patterns, which include exclusion of certain products (eg, e-cigarettes) and product-use patterns (eg, exclusive users of non-cigarette products), and inconsistent classification of tobacco users. It is parsimonious yet complex enough to retain differential characteristics of sub-tobacco users based on number (single, dual, polytobacco) and categories (cigarettes, non cigarette combustibles, noncombustibles) of tobacco products consumed. PMID- 26764259 TI - Adolescents' and Young Adults' Knowledge and Beliefs About Constituents in Novel Tobacco Products. AB - INTRODUCTION: Novel tobacco products, such as little cigars, cigarillos, hookah, and e-cigarettes, and their smoke or aerosol contain chemicals which the FDA has determined to be Harmful or Potentially Harmful Constituents. We explored adolescents' and young adults' knowledge and beliefs about constituents in novel tobacco products and their smoke or aerosol, in order to inform risk communication messages. METHODS: Seventy-seven adolescents and young adults (ages 13-25) participated in 10 focus groups, including 47 novel tobacco product users and 30 susceptible nonusers. Participants were asked to discuss 10 pre-selected constituents found in novel tobacco products and their smoke or aerosol. The first author analyzed the discussion for emergent themes. RESULTS: Participants were generally familiar with arsenic, carbon monoxide, formaldehyde, and nicotine, but unfamiliar with acetaldehyde, acrolein, 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanon (NNK), and N-nitrosonornicotine (NNN). All participants had negative beliefs about most constituents, although users had positive beliefs about nicotine. "Unfamiliar" constituents were associated with similarly-sounding words (eg, acetaldehyde sounds like acetaminophen), and some participants recognized words in the chemical names of NNK/NNN (eg, "nitro"). "Familiar" constituents were associated with negative health effects and other common products the constituents are found in. All participants wanted more information about the constituents' health effects, toxicity, and other common products. Most participants were unaware the constituents discussed are in novel tobacco products and their smoke or aerosol. CONCLUSIONS: Risk communication messages could capitalize on negative associations with familiar constituents, or attempt to educate about unfamiliar constituents, to discourage novel tobacco product use among adolescents and young adults. IMPLICATIONS: The results of this study have implications for how the FDA and other agencies can communicate about the risks of novel tobacco products to the general public, which will be particularly important once the Deeming Rule is finalized. Our findings suggest it may be effective to capitalize on the public's negative beliefs about and associations with familiar constituents, or to educate about unfamiliar constituents and their health effects, their concentration and toxicity in novel tobacco products and their smoke or aerosol, and other products they are found in. PMID- 26764260 TI - Disease activity-guided dose optimisation of adalimumab and etanercept is a cost effective strategy compared with non-tapering tight control rheumatoid arthritis care: analyses of the DRESS study. AB - BACKGROUND: A disease activity-guided dose optimisation strategy of adalimumab or etanercept (TNFi (tumour necrosis factor inhibitors)) has shown to be non inferior in maintaining disease control in patients with rheumatoid arthritis (RA) compared with usual care. However, the cost-effectiveness of this strategy is still unknown. METHOD: This is a preplanned cost-effectiveness analysis of the Dose REduction Strategy of Subcutaneous TNF inhibitors (DRESS) study, a randomised controlled, open-label, non-inferiority trial performed in two Dutch rheumatology outpatient clinics. Patients with low disease activity using TNF inhibitors were included. Total healthcare costs were measured and quality adjusted life years (QALY) were based on EQ5D utility scores. Decremental cost effectiveness analyses were performed using bootstrap analyses; incremental net monetary benefit (iNMB) was used to express cost-effectiveness. RESULTS: 180 patients were included, and 121 were allocated to the dose optimisation strategy and 59 to control. The dose optimisation strategy resulted in a mean cost saving of -?12 280 (95 percentile -?10 502; -?14 104) per patient per 18 months. There is an 84% chance that the dose optimisation strategy results in a QALY loss with a mean QALY loss of -0.02 (-0.07 to 0.02). The decremental cost-effectiveness ratio (DCER) was ?390 493 (?5 085 184; dominant) of savings per QALY lost. The mean iNMB was ?10 467 (?6553-?14 037). Sensitivity analyses using 30% and 50% lower prices for TNFi remained cost-effective. CONCLUSIONS: Disease activity guided dose optimisation of TNFi results in considerable cost savings while no relevant loss of quality of life was observed. When the minimal QALY loss is compensated with the upper limit of what society is willing to pay or accept in the Netherlands, the net savings are still high. TRIAL REGISTRATION NUMBER: NTR3216; Post-results. PMID- 26764261 TI - Microautologous Fat Transplantation for Primary Augmentation Rhinoplasty: Long Term Monitoring of 198 Asian Patients. AB - BACKGROUND: Numerous techniques and materials are available for increasing the dorsal height and length of the nose. Microautologous fat transplantation (MAFT) may be an appropriate strategy for augmentation rhinoplasty. OBJECTIVES: The authors sought to determine the long-term results of MAFT with the so-called one third maneuver in Asian patients who underwent augmentation rhinoplasty. METHODS: A total of 198 patients who underwent primary augmentation rhinoplasty with MAFT were evaluated in a retrospective study. Fat was harvested by liposuction and was processed and refined by centrifugation. Minute parcels of purified fat were transplanted to the nasal dorsum with a MAFT-Gun. Patient satisfaction was scored with a 5-point Likert scale, and aesthetic outcomes were validated with pre- and postoperative photographs. RESULTS: The mean age of the patients was 45.5 years. The mean operating time for MAFT was 25 minutes, and patients underwent 1-3 MAFT sessions. The mean volume of fat delivered per session was 3.4 mL (range, 2.0-5.5 mL). Patients received follow-up for an average of 19 months (range, 6-42 months). Overall, 125 of 198 patients (63.1%) indicated that they were satisfied with the results of 1-3 sessions of MAFT. There were no major complications. CONCLUSIONS: The results of this study support MAFT as an appropriate fat transfer strategy for Asian patients undergoing primary augmentation rhinoplasty. LEVEL OF EVIDENCE 4: Therapeutic. PMID- 26764263 TI - The behaviours that dementia care home staff in South Africa find challenging: An exploratory study. AB - Background Behavioural and psychological symptoms of dementia are often the reasons for moving to a care home. Care staff, often with limited dementia training, may have to support residents with distressed behaviour on a daily basis. Evidence about the support of residents with distressed or challenging behaviour in the South African context is lacking. This exploratory study aimed to gain an understanding of what care home staff perceived to be distressed behaviour, their coping strategies and how they learned to work with residents with behavioural symptoms of dementia. Methods An exploratory study was conducted among 17 participants working in four care homes in the Western Cape province of South Africa in 2014. Semi-structured interviews were audio-recorded. Data were analysed thematically. Findings Findings reflected the literature with regard to examples of behavioural symptoms of people with dementia that staff find challenging to manage. Overall, the majority of staff reported holding positive feelings about working with people with dementia. All preferred interpersonal approaches to manage distressed behaviour above medication although a small minority noted the use of medication in some cases. Dementia training was considered by most participants as an unmet need. Conclusion This exploratory study identified care home workers' desires for training about dementia and their preferences for interpersonal as opposed to pharmacological approaches to managing residents' distressed behaviour. The legacy of race and cultural perspectives in South Africa appears to still influence care practice and provision. Staff commitment, their interest in advancing their practice and their aspirations to offer more person-centred care were evident. Dementia training was identified as potentially helpful to care home staff who manage residents' distressed behaviour. Training should be developed in South Africa to promote good practice. PMID- 26764264 TI - Do physical environmental changes make a difference? Supporting person-centered care at mealtimes in nursing homes. AB - Purpose Drawing on therapeutic physical environmental design principles and Kitwood's theoretical view of person-centered care, this study examined the impact of environmental renovations in dining spaces of a long-term care facility on residents' mealtime experience and staff practice in two care units. Method The research design involved pre- and post-renovation ethnographic observations in the dining spaces of the care units and a post-renovation staff survey. The objective physical environmental features pre- and post-renovations were assessed with a newly developed tool titled Dining Environment Audit Protocol. We collected observational data from 10 residents and survey responses from 17 care aides and nurses. Findings Based on a systematic analysis of observational data and staff survey responses, five themes were identified: (a) autonomy and personal control, (b) comfort of homelike environment, (c) conducive to social interaction, (d) increased personal support, and (e) effective teamwork. Implications Although the physical environment can play an influential role in enhancing the dining experience of residents, the variability in staff practices reveals the complexity of mealtime environment and points to the necessity of a systemic approach to foster meaningful culture change. PMID- 26764262 TI - Improvements in Vertebral-Column Angles and Psychological Metrics After Abdominoplasty With Rectus Plication. AB - BACKGROUND: Substantial fluctuations in body weight can result in diastasis recti and weakening of the connections between the lateral abdominal muscles and the rectus sheath. OBJECTIVES: The authors sought to determine the postural and psychological effects of abdominoplasty with vertical rectus plication. METHODS: Forty women with substantial back and lumbar pain owing to abdominal lipodystrophy were evaluated in a prospective study. Preoperatively and 6 months postoperatively, patients underwent bidirectional radiography of the thoracic and lumbar regions. A visual analog scale (VAS), the Beck Depression Inventory (BDI), and the Nottingham Health Profile (NHP) were applied to assess physical, psychological, and quality-of-life changes following surgery. RESULTS: Significant improvements in posture, assessed in terms of lumbar lordosis, thoracic kyphosis, and the lumbosacral angle, were observed 6 months after abdominoplasty with rectus plication. Results of the VAS and BDI indicated significant improvements in pain and quality of life, respectively. Results of the NHP indicated significant postoperative improvements in fatigue, pain, and sleep. CONCLUSIONS: Abdominoplasty with rectus plication improves posture by tightening the thoracolumbar fascia. In selected patients, abdominoplasty can reduce back and lumbar pain, thereby improving quality of life. PMID- 26764265 TI - How people come to recognise a problem and seek medical help for a person showing early signs of dementia: A systematic review and meta-ethnography. AB - Evidence suggests that there is usually a long delay between noticing first signs of dementia and seeking medical help. We conducted a systematic review of what people experience and how they make decisions during this time, and used a meta ethnographic approach to synthesise the findings. Screening and quality assessment resulted in nine studies eligible for inclusion. People with dementia mainly report experiencing memory lapses, while carers focus on more subtle changes in personality. People respond to these changes in one of three ways: 1) they discount them as normal; 2) they reserve judgement as to their cause and significance, or 3) they misattribute them. Pivotal events can finally trigger help seeking. Active reflection and seeking of further evidence may lead to earlier recognition of the possibility of dementia and the need to seek help; it also reduces the risk of a pivotal event. Public education should aim to improve recognition of more subtle signs and to encourage repeated evaluation and reflection. PMID- 26764266 TI - BDKRB2 +9/-9 bp polymorphisms influence BDKRB2 expression levels and NO production in knee osteoarthritis. AB - The bradykinin B2 receptor (BDKRB2) plays a key role in the inflammation process of osteoarthritis. Nitric oxide has also long been considered to be a catabolic factor that contributes to inflammatory response and the osteoarthritis disease pathology. Several studies have reported that the BDKRB2 +9/-9 bp polymorphisms are associated with transcription of the receptor. However, the roles of BDKRB2 polymorphisms in inflammation in osteoarthritis remain unclear. This study enrolled 156 subjects with primary knee osteoarthritis and 58 healthy volunteers. BDKRB2 polymorphisms were genotyped, and the mRNA and protein levels of BDKRB2 in synovial tissues from osteoarthritis patients were measured by quantitative real time polymerase chain reaction and western blot analysis, respectively. Nitric oxide production in serum from patients with osteoarthritis was measured using a nitric oxide assay kit. We found that the mean BDKRB2 mRNA levels were significantly higher in Kallgren-Lawrence grade-4 osteoarthritis patients than patients with lower grade osteoarthritis. The +9/-9 bp polymorphisms significantly affected the BDKRB2 mRNA and protein expression levels in synovial tissues from osteoarthritis subjects. Osteoarthritis patients with +9/-9 and -9/ 9 genotypes had higher BDKRB2 expression levels in synovial tissue and nitric oxide production in serum. Moreover, positive correlation was found between the BDKRB2 levels in synovial tissue and nitric oxide production. Compared with health controls, significant increases of nitric oxide production in osteoarthritis were detected which were associated with increasing severity of osteoarthritis. Multiple linear regression analysis (adjusted for gender and age) showed serum nitric oxide level was positively associated with BDKRB2 polymorphism and Kallgren-Lawrence grade and was inversely associated with obesity. Our findings showed that the BDKRB2 +9/-9 bp polymorphisms affected the gene expression and nitric oxide production, which were associated with radiographic severity of osteoarthritis, suggesting that the BDKRB2 +9/ -9 bp polymorphisms may act as a genetic modulator of osteoarthritis, and play an essential role in inflammatory process in osteoarthritis. PMID- 26764267 TI - The effect of music during bronchoscopy: A meta-analysis. AB - Bronchoscopy is considered a stressful procedure performed on patients. Hence, the use of music to ease the anxiety of patients has been examined in various studies, but the results have been inconclusive. The aim of this review is to synthesize the findings of previous studies on the effects of music therapy on the physiological outcomes of patients undergoing bronchoscopy. An electronic database search was performed to identify the literature. Random-effects model was used to combine the results, and meta-regression was used to explore the heterogeneity. Seven studies with 829 subjects were included. Results showed that the combined mean differences (95% confidence interval) for systolic and diastolic blood pressure were -11.99 (-15.82, -6.57) and -4.84 (-7.78, -1.90) mm Hg, respectively, whereas that for heart rate was -10.57 (-16.63, -4.51) beats per minute. In conclusion, listening to music reduced blood pressure and heart rate among patients undergoing bronchoscopy. PMID- 26764268 TI - Costs of leaf reinforcement in response to winter cold in evergreen species. AB - The competitive equilibrium between deciduous and evergreen plant species to a large extent depends on the intensity of the reduction in carbon gain undergone by evergreen leaves, associated with the leaf traits that confer resistance to stressful conditions during the unfavourable part of the year. This study explores the effects of winter harshness on the resistance traits of evergreen leaves. Leaf mass per unit area (LMA), leaf thickness and the concentrations of fibre, nitrogen (N), phosphorus (P), soluble protein, chlorophyll and ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) were determined in three evergreen and two deciduous species along a winter temperature gradient. In the evergreen species, LMA, thickness, and P and structural carbohydrate concentrations increased with the decrease in winter temperatures. Nitrogen and lignin concentrations did not show definite patterns in this regard. Chlorophyll, soluble proteins and Rubisco decreased with the increase in winter harshness. Our results suggest that an increase in LMA and in the concentration of structural carbohydrates would be a requirement for the leaves to cope with low winter temperatures. The evergreen habit would be associated with higher costs at cooler sites, because the cold resistance traits imply additional maintenance costs and reduced N allocation to the photosynthetic machinery, associated with structural reinforcement at colder sites. PMID- 26764269 TI - A montane Mediterranean climate supports year-round photosynthesis and high forest biomass. AB - The mid-elevation forest of California's Sierra Nevada poses a bioclimatic paradox. Mid-elevation trees experience a montane Mediterranean climate, with near-freezing winter days and rain-free summers. The asynchrony between warmth and water input suggests low primary production, limited by photosynthetic dormancy in winter cold, and again in summer and early autumn with drought, yet this forest is characterized by tall trees and high biomass. We used eddy covariance in a mid-elevation Sierra stand to understand how winter cold and summer drought limit canopy photosynthesis and production. The trees exhibited canopy photosynthesis year-round. Trees avoided winter dormancy, and daytime CO2uptake continued despite a deep snowpack and near-freezing temperatures. Photosynthesis on sunny days continued at half of maximum rates when air temperature was 0 degrees C. Likewise, the vegetation avoided summer drought dormancy, and high rates of daytime CO2uptake and transpiration continued despite a 5-month period with only negligible water input. We attribute this drought avoidance to deep rooting and availability of deep soil water. Year-round photosynthesis helps explain the large biomass observed in the Sierra Nevada, and implies adaptive strategies that may contribute to the resiliency or vulnerability of Sierran vegetation to climate change. PMID- 26764270 TI - Integrated physiological and hormonal profile of heat-induced thermotolerance in Pinus radiata. AB - Despite great interest, not only from the economic point of view but also in terms of basic science, research on heat stress tolerance in conifers remains scarce. To fill this gap, a time-course experiment using expected temperature increase was performed aiming to identify physiological and biochemical traits that allow the characterization of heat-induced thermotolerance and recovery in Pinus radiata D. Don plants. Several physiological parameters were assessed during heat exposure and after recovery, and multiple phytohormones-abscisic acid (ABA), indole-3-acetic acid (IAA), cytokinins (CKs), gibberellins, jasmonic acid, salicylic acid (SA) and brassinosteroids-were quantified by ultra-performance liquid chromatography-mass spectrometry from unique sample. Furthermore, tissue specific stress-signaling was monitored by IAA and ABA immunolocalization. Multivariate statistical analysis of the data enabled clustering of the shorter- and longer-term effects of heat stress exposure. Two sequential physiological responses were identified: an immediate and a delayed response, essentially determined by specific phytohormones, proline, malondialdehyde and total soluble sugar patterns. Results showed that ABA and SA play a crucial role in the first stage of response to heat stress, probably due to the plant's urgent need to regulate stomatal closure and counteract the increase in oxidative membrane damage demonstrated in shorter-term exposures. However, in longer exposures and recovery, proline, total sugars, IAA and CKs seem to be more relevant. This integrated approach pinpointed some basic mechanisms of P. radiata physiological responses underlying thermotolerance processes and after recovery. PMID- 26764271 TI - Learning from the Melbourne experience: How reliable are cancer registry data for hepatocellular carcinoma? PMID- 26764272 TI - Evaluation of Nutritional Status in Children during Predialysis, or Treated By Peritoneal Dialysis or Hemodialysis. AB - OBJECTIVE: Malnutrition is one of the major causes of morbidity and mortality in children with chronic kidney disease (CKD). The objective of this study was to evaluate nutritional status of children with stage 3-4 CKD and treated by peritoneal dialysis or hemodialysis using anthropometric measurements, biochemical parameters and bioelectrical impedance analysis. PATIENTS AND METHODS: The study included a total of 52 patients and 46 healthy children. RESULTS: In anthropometric evaluation, the children with CKD had lower values for standard deviation score for weight, height, body mass index, skinfold thickness and mid-arm circumference than those of healthy children (p < 0.05). The fat mass (%) and the body cell mass (%) measurements performed by bioelectrical impedance analysis were lower compared with the control group (p < 0.05). CONCLUSION: It is considered that bioelectrical impedance analysis measurement should be used with anthropometric measurements, which are easy to perform, to achieve more accurate nutritional evaluation in children. PMID- 26764273 TI - A comprehensive comparison of tools for differential ChIP-seq analysis. AB - ChIP-seq has become a widely adopted genomic assay in recent years to determine binding sites for transcription factors or enrichments for specific histone modifications. Beside detection of enriched or bound regions, an important question is to determine differences between conditions. While this is a common analysis for gene expression, for which a large number of computational approaches have been validated, the same question for ChIP-seq is particularly challenging owing to the complexity of ChIP-seq data in terms of noisiness and variability. Many different tools have been developed and published in recent years. However, a comprehensive comparison and review of these tools is still missing. Here, we have reviewed 14 tools, which have been developed to determine differential enrichment between two conditions. They differ in their algorithmic setups, and also in the range of applicability. Hence, we have benchmarked these tools on real data sets for transcription factors and histone modifications, as well as on simulated data sets to quantitatively evaluate their performance. Overall, there is a great variety in the type of signal detected by these tools with a surprisingly low level of agreement. Depending on the type of analysis performed, the choice of method will crucially impact the outcome. PMID- 26764274 TI - A study of bias and increasing organismal complexity from their post translational modifications and reaction site interplays. AB - Post-translational modifications (PTMs) are important steps in the biosynthesis of proteins. Aside from their integral contributions to protein development, i.e. perform specialized proteolytic cleavage of regulatory subunits, the covalent addition of functional groups of proteins or the degradation of entire proteins, PTMs are also involved in enabling proteins to withstand and recover from temporary environmental stresses (heat shock, microgravity and many others). The literature supports evidence of thousands of recently discovered PTMs, many of which may likely contribute similarly (perhaps, even, interchangeably) to protein stress response. Although there are many PTM actors on the biological stage, our study determines that these PTMs are generally cast into organism-specific, preferential roles. In this work, we study the PTM compositions across the mitochondrial (Mt) and non-Mt proteomes of 11 diverse organisms to illustrate that each organism appears to have a unique list of PTMs, and an equally unique list of PTM-associated residue reaction sites (RSs), where PTMs interact with protein. Despite the present limitation of available PTM data across different species, we apply existing and current protein data to illustrate particular organismal biases. We explore the relative frequencies of observed PTMs, the RSs and general amino-acid compositions of Mt and non-Mt proteomes. We apply these data to create networks and heatmaps to illustrate the evidence of bias. We show that the number of PTMs and RSs appears to grow along with organismal complexity, which may imply that environmental stress could play a role in this bias. PMID- 26764275 TI - Extracranial Carotid Artery Disease: Risk Factors and Outcomes in Patients With Acute Critical Hemispheric Ischemic Stroke. AB - OBJECTIVES: The prevalence of carotid disease in stroke patients has been underestimated because most stroke patients who receive carotid sonography have already survived the acute event. Little is known about the extracranial carotid arteries of patients with acute stroke who need intensive care. This study reviewed color-coded carotid duplex sonographic examinations of the extracranial carotid arteries of patients with acute critical hemispheric ischemic stroke. METHODS: We retrospectively reviewed 30 consecutive patients who had acute critical hemispheric ischemic stroke and received color-coded carotid duplex sonography in the intensive care unit. The presence of occlusive carotid artery disease was correlated with clinical features, vascular risk factors, and outcomes. RESULTS: Overall, 57% of the patients (17 of 30) had an occlusive internal carotid artery, and 44% of patients with atrial fibrillation (7 of 16) also had occlusive carotid disease. Eventually, 73% of the patients (21 of 30) had poor outcomes, and 57% (17 of 30) died. The contributing factors to a poor outcome were older age, an initial conscious disturbance, endotracheal intubation, and occlusive carotid disease, with the most significant factor being older age (P = .022; odds ratio, 27.76). The factors contributing to death were endotracheal intubation, occlusive carotid disease, and reversed ophthalmic flow, with the most significant factor being occlusive carotid disease (P = .014; odds ratio, 11.38). Soft homogeneously echogenic thrombi filling the lumen of the internal carotid artery and moving forward and backward with the carotid pulse were found in 3 patients. A small segment of ruptured plaque that was floating forward and backward with pulsation was found in 1 patient. CONCLUSIONS: Occlusive carotid artery disease is not uncommon among Chinese patients who have had an acute critical hemispheric infarction. Older age is the factor most significantly correlated with a poor outcome, and occlusive carotid disease is the factor most significantly correlated with death. PMID- 26764277 TI - M.mode.ify: A Free Online Tool to Generate Post Hoc M-Mode Images From Any Ultrasound Clip. AB - We present a software tool designed to generate an M-mode image post hoc from any B-mode ultrasound clip, along any possible axis. M.mode.ify works by breaking down an ultrasound clip into individual frames. It then rotates and crops these frames by using a user-selected M-mode line. The post hoc M-mode image is created by splicing these frames together. Users can measure time and distance after proper calibration through the M.mode.ify interface. This tool opens up new possibilities for clinical application, quality assurance, and research. It is available free for public use at http://www.ultrasoundoftheweek.com/M.mode.ify/. PMID- 26764276 TI - Do Anesthetic Techniques Influence the Threshold for Glomerular Capillary Hemorrhage Induced in Rats by Contrast-Enhanced Diagnostic Ultrasound? AB - OBJECTIVES: Glomerular capillary hemorrhage can be induced by ultrasonic cavitation during contrast-enhanced diagnostic ultrasound (US) exposure, an important nonthermal US bioeffect. Recent studies of pulmonary US exposure have shown that thresholds for another nonthermal bioeffect of US, pulmonary capillary hemorrhage, is strongly influenced by whether xylazine is included in the specific anesthetic technique. The objective of this study was to determine the influence of xylazine on contrast-enhanced diagnostic US-induced glomerular capillary hemorrhage. METHODS: In this study, anesthesia with ketamine only was compared to ketamine plus xylazine for induction of glomerular capillary hemorrhage in rats by 1.6-MHz intermittent diagnostic US with a microsphere contrast agent (similar to Definity; Lantheus Medical Imaging, Inc, North Billerica, MA). Glomerular capillary hemorrhage was measured as a percentage of glomeruli with hemorrhage found in histologic sections for groups of rats scanned at different peak rarefactional pressure amplitudes. RESULTS: There was a significant difference between the magnitude of the glomerular capillary hemorrhage between the anesthetics at 2.3 MPa, with 45.6% hemorrhage for ketamine only, increasing to 63.2% hemorrhage for ketamine plus xylazine (P < .001). However, the thresholds for the two anesthetic methods were virtually identical at 1.0 MPa, based on linear regression of the exposure response data. CONCLUSIONS: Thresholds for contrast-enhanced diagnostic US-induced injury of the microvasculature appear to be minimally affected by anesthetic methods. PMID- 26764278 TI - Integration of Ultrasound in Undergraduate Medical Education at the California Medical Schools: A Discussion of Common Challenges and Strategies From the UMeCali Experience. AB - Since the first medical student ultrasound electives became available more than a decade ago, ultrasound in undergraduate medical education has gained increasing popularity. More than a dozen medical schools have fully integrated ultrasound education in their curricula, with several dozen more institutions planning to follow suit. Starting in June 2012, a working group of emergency ultrasound faculty at the California medical schools began to meet to discuss barriers as well as innovative approaches to implementing ultrasound education in undergraduate medical education. It became clear that an ongoing collaborative could be formed to discuss barriers, exchange ideas, and lend support for this initiative. The group, termed Ultrasound in Medical Education, California (UMeCali), was formed with 2 main goals: to exchange ideas and resources in facilitating ultrasound education and to develop a white paper to discuss our experiences. Five common themes integral to successful ultrasound education in undergraduate medical education are discussed in this article: (1) initiating an ultrasound education program; (2) the role of medical student involvement; (3) integration of ultrasound in the preclinical years; (4) developing longitudinal ultrasound education; and (5) addressing competency. PMID- 26764279 TI - Contemporary Treatment of Acute Heart Failure. AB - Heart failure (HF) is a rapidly growing global pandemic. A consequence of the increased prevalence of HF has been an increase in hospitalizations due to acute HF (AHF) in the United States and in many other countries around the world. Despite advances in treatment, morbidity and mortality rates in the post discharge period after an AHF admission remain unacceptably high. The occurrence of an AHF episode poses a major clinical challenge since current therapeutic options are limited to providing mostly short-term symptomatic relief. Diuretics to relieve congestion, inotropic agents to maintain tissue perfusion and vasodilators to reduce the load on the heart are the primary drug approaches for treating AHF. Determining the most effective way of using these agents has been the focus of several recently completed studies, but success in altering outcomes has proved to be elusive. Results from studies using new experimental agents such as ularitide and serelaxin, however, have been promising and ongoing. Phase 3 clinical trials will determine their role in the therapeutic regimen. This manuscript reviews aspects of medical therapy of AHF for which new insights are available and describes pathophysiologic abnormalities that appear to be amenable to treatment with both currently available therapies and novel agents that are being developed. PMID- 26764280 TI - Palatal lesions: discriminative value of conventional MRI and diffusion weighted imaging. AB - OBJECTIVE: To evaluate and compare the ability of conventional MRI, diffusion weighted imaging (DWI) and a combination of both MRI techniques to differentiate malignant and benign palatal lesions. METHODS: A retrospective review of MRI findings was performed in patients with pathologically confirmed palatal lesions between January 2012 and December 2014. Each lesion was evaluated with conventional MRI characteristics, including enhancement, inner texture, margin, adjacent soft-tissue involvement and cervical lymph node, and/or apparent diffusion coefficient (ADC) value. Statistical analyses were performed to assess the differential performance of each parameter separately and together. RESULTS: A total of 42 patients (24 males, 18 females; age: 54.9 +/- 16.4 years) were investigated. The optimal cut-off ADC value to distinguish malignant from benign lesions was 1.02 * 10(-3) mm(2) s(-1), with a sensitivity of 87.5% and a specificity of 75.0%. Conventional MRI showed a sensitivity of 87.1% and a specificity of 63.6%. Combination of conventional MRI and ADC scores increased sensitivity to 100% and specificity to 75.0%. The AUCs did not differ significantly between conventional MRI alone, DWI alone and integration of both. CONCLUSION: Additional DWI does not substantially improve differential ability of conventional MRI. However, combining ADC values with conventional MRI improves both sensitivity and specificity, which is of worth to be further validated in prospective studies with larger sample sizes. ADVANCES IN KNOWLEDGE: Combination of conventional MRI and ADC scores could increase the ability to differentiate malignant from benign palatal lesions, with a sensitivity of 100% and specificity of 75.0%, although without statistical significance. PMID- 26764281 TI - New advances in lower gastrointestinal bleeding management with embolotherapy. AB - Lower gastrointestinal bleeding (LGIB) is associated with high morbidity and mortality. Embolization is currently proposed as the first step in the treatment of acute, life-threatening LGIB, when endoscopic approach is not possible or is unsuccessful. Like most procedures performed in emergency setting, time represents a significant factor influencing outcome. Modern tools permit identifying and reaching the bleeding site faster than two-dimensional angiography. Non-selective cone-beam CT arteriography can identify a damaged vessel. Moreover, sophisticated software able to detect the vessel may facilitate direct placement of a microcatheter into the culprit vessel without the need for sequential angiography. A further important aspect is the use of an appropriate technique of embolization and a safe and effective embolic agent. Current evidence shows the use of detachable coils (with or without a triaxial system) and liquid embolics has proven advantages compared with other embolic agents. The present article analyses these modern tools, making embolization of acute LGIB safer and more effective. PMID- 26764282 TI - The significance of PTV dose coverage on cancer control outcomes in early stage non-small cell lung cancer patients treated with highly ablative stereotactic body radiation therapy. AB - OBJECTIVE: We evaluated whether patients with early-stage non-small-cell lung cancers (NSCLCs) treated with stereotactic body radiation therapy (SBRT) without full prescription dose coverage of the planning target volume (PTV) had inferior outcomes. METHODS: The SBRT regimen was 54 Gy in three fractions. Dosimetric constraints were as per the Radiation Therapy Oncology Group 0236 guidelines. All patients underwent four-dimensional CT (4D-CT) simulation. The internal target volume (ITV) was defined using 4D-CT, and the PTV was defined as a 6-mm longitudinal and a 3-mm axial expansion from the ITV. If normal tissue constraints were beyond tolerance, ITV-based dosing was employed where priority was made for full ITV coverage at the expense of PTV coverage. Patients with and without full PTV dose coverage were compared, and control rates were estimated using Kaplan-Meier analysis. RESULTS: 120 NSCLC cases were evaluated with 81% having adequate PTV dose coverage. ITV and PTV were significantly larger in the cohort with inadequate PTV dose coverage (p = 0.0085 and p = 0.0038, respectively), and the mean ITV and PTV doses were higher in patients with adequate PTV dose coverage (p = 0.002 and p < 0.0001, respectively). The 3-year local control rate was 100% for both cohorts. There was no difference in 3-year regional control (p = 0.36), disease-specific survival (p = 0.79) or overall survival (p = 0.73). CONCLUSION: When delivering a highly ablative SBRT regimen for early-stage NSCLC, full-dose coverage of the ITV is sufficient for local control. ADVANCES IN KNOWLEDGE: Our data are among the first to evaluate the utility of PTV margins in a highly ablative SBRT regimen and suggest that when dosing constraints cannot be met, full tumouricidal dose coverage of the ITV is sufficient for local control. PMID- 26764283 TI - Emergency radiology: straightening of the cervical spine in MDCT after trauma--a sign of injury or normal variant? AB - OBJECTIVE: To evaluate whether straightening of the cervical spine (C-spine) alignment after trauma can be considered a significant multidetector CT (MDCT) finding. METHODS: 160 consecutive patients after C-spine trauma admitted to a Level 1 trauma centre received MDCT according to Canadian Cervical Spine Rule and National Emergency X-Radiography Utilization Study indication rule; subgroups with and without cervical collar immobilization (CCI +/-) were compared with a control group (n = 20) of non-traumatized patients. Two independent readers evaluated retrospectively the alignment, determined the absolute rotational angle of the posterior surface of C2 and C7 (ARA C2-7) and grouped the results for lordosis (<-13 degrees ), straight (-13 to +6 degrees ) and kyphosis (>+6 degrees ). RESULTS: In the two CCI-/CCI+ study groups, the straight or kyphotic alignment significantly (p = 0.001) predominated over lordosis. The number of patients with straight C-spine alignment was higher in the CCI+ group (CCI+ 69% vs CCI- 49%, p = 0.05). A comparison of the CCI+ group vs the CCI- group revealed a slightly smaller number of kyphotic (10% vs 18%, p = 0.34) and lordotic (21% vs 33%, p = 0.33) alignments. Statistically, however, the differences were of no significance. The control group revealed no significant differences. CONCLUSION: Straightening of the C-spine alone is not a definitive sign of injury but is a biomechanical variation due to CCI and neck positioning during MDCT or active patient control. ADVANCES IN KNOWLEDGE: Straightening of the C-spine alignment in MDCT alone is not a definitive sign of injury. Straightening of the C-spine alignment is related to neck positioning and active patient control. CCI has a straightening effect on the cervical alignment. PMID- 26764284 TI - Biomarkers of susceptibility following benzene exposure: influence of genetic polymorphisms on benzene metabolism and health effects. AB - Benzene is a ubiquitous occupational and environmental pollutant. Improved industrial hygiene allowed airborne concentrations close to the environmental context (1-1000 ug/m(3)). Conversely, new limits for benzene levels in urban air were set (5 ug/m(3)). The biomonitoring of exposure to such low benzene concentrations are performed measuring specific and sensitive biomarkers such as S-phenylmercapturic acid, trans, trans-muconic acid and urinary benzene: many studies referred high variability in the levels of these biomarkers, suggesting the involvement of polymorphic metabolic genes in the individual susceptibility to benzene toxicity. We reviewed the influence of metabolic polymorphisms on the biomarkers levels of benzene exposure and effect, in order to understand the real impact of benzene exposure on subjects with increased susceptibility. PMID- 26764285 TI - Copenhagen uPAR prostate cancer (CuPCa) database: protocol and early results. AB - AIM: Urokinase plasminogen activator receptor (uPAR) plays a central role during cancer invasion by facilitating pericellular proteolysis. We initiated the prospective 'Copenhagen uPAR Prostate Cancer' study to investigate the significance of uPAR levels in prostate cancer (PCa) patients. METHODS: Plasma samples and clinical data from patients with newly diagnosed PCa have been collected prospectively. The uPAR forms have been measured in plasma using time resolved fluorescence immunoassays. RESULTS: The level of intact uPAR(I-III) did not differ. Plasma uPAR(I-III) + uPAR(II-III) levels and uPAR(I) levels were significantly higher in hormone-naive and castrate-resistant patients compared with patients with localized disease (both: p < 0.0001). CONCLUSION: Our results show that cleaved uPAR forms are significantly increased in patients with advanced PCa. PMID- 26764286 TI - Biomarkers in the clinical development of asthma therapies. AB - Here we review how biomarkers have been used in the design, execution and interpretation of recent clinical studies of therapeutic candidates targeting cytokine-mediated inflammatory pathways in asthma. This review focuses on type 2 inflammation, as there are multiple therapeutics and/or clinical studies that can be compared within that specific pathway. Comparative analyses of data from these clinical studies illustrate the utility of biomarkers to quantify pharmacodynamic effects, clarify mechanism of action and stratify patients, which may facilitate the interpretation of outcomes in the development of molecularly targeted therapies. These case examples provide a basis for biomarker considerations in the design of future studies in the asthma setting. PMID- 26764287 TI - Psychiatry's Social Control and Patients' Rights. PMID- 26764288 TI - Six-month Follow-up of Cognitive Impairment and Depressive Symptoms in Late-onset Depression. AB - OBJECTIVE: To assess cognitive performance in elderly depressed patients following treatment for 6 months. Remission rate of depression after 6 months of treatment was calculated. METHODS: The study was performed in a consecutive group of patients aged >= 65 years with late-onset depression. Severity of depression was assessed by the Hamilton Depression Scale, cognitive performance by the Hong Kong Montreal Cognitive Assessment, and functional level by the Instrumental Activities of Daily Living Scale. RESULTS: A total of 52 patients were recruited. In all, 28 (53.8%) were found to have cognitive impairment at baseline and 8 (28.6%) of them had improvement after 6 months. This cognitively impaired group was older and had a lower Instrumental Activities of Daily Living Scale score. The remission rate of depression was 61.5%. CONCLUSIONS: Cognitive impairment constituted a stable feature in a considerable number of elderly patients with depression. About two-thirds of patients achieved remission of depression after 6 months of treatment. PMID- 26764289 TI - Prevalence of Psychiatric Morbidity in Chinese Subjects with Knee Osteoarthritis in a Hong Kong Orthopaedic Clinic. AB - OBJECTIVES: To identify the prevalence and associated factors of psychiatric morbidities and to evaluate the effectiveness of the Hospital Anxiety and Depression Scale (HADS) in screening for psychiatric morbidity in patients with knee osteoarthritis in a local orthopaedic clinic. METHODS: A cross-sectional study was conducted from October 2013 to June 2014 to examine patients with knee osteoarthritis at a specialist orthopaedic clinic. They were evaluated for psychiatric diagnoses using the Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID-I). Socio-demographic and clinical characteristics were compared between patients with and without psychiatric morbidity. Patients were also assessed using the HADS with accuracy compared with the psychiatric diagnoses made by the SCID-I. RESULTS: Of the 115 patients, 39% had current psychiatric disorders. Logistic regression analysis revealed that limitation of physical activity, perceived absence of confidant, a history of psychiatric illness, and follow-up in orthopaedic clinic for >= 5 years were independent factors associated with psychiatric disorders. CONCLUSIONS: The prevalence of psychiatric morbidity in patients with knee osteoarthritis was significant. Recognition of independent associated factors can aid in early identification and intervention in patients who are at risk of developing psychiatric morbidity. The HADS is a useful means to screen for psychiatric morbidity in these patients. PMID- 26764290 TI - Burden Assessment, Psychiatric Morbidity, and Their Correlates in Caregivers of Patients with Intellectual Disability. AB - OBJECTIVE: Intellectual disability in a child places great stress on a family and caregiver and this leads to significant socio-occupational dysfunction and impaired quality of life for caregivers. This study aimed to assess socio demographic characteristics, burden, and psychiatric morbidity of the caregivers of persons with intellectual disability, as well as to determine the variables that correlated with burden and psychiatric morbidity. METHODS: An observational study was carried out in an outpatient psychiatric unit of a tertiary care teaching hospital in India from October 2014 to April 2015. A total of 100 caregivers of intellectually impaired individuals were assessed for burden and psychiatric morbidity. RESULTS: In all, 39% of the caregivers had a high burden score, 46% perceived mild-to-moderate burden severity, and 15% perceived no to mild burden. Mild-to-moderate depressive symptoms were present in 23% and 16% had severe-to-extremely severe depressive symptoms. Mild-to-moderate anxiety symptoms were evident in 19% of caregivers and a further 19% had severe-to-extremely severe anxiety symptoms. CONCLUSION: Routine assessment of burden and psychiatric morbidity in the caregiver will help to reduce their burden and thus help them care for their children more appropriately and efficiently. PMID- 26764291 TI - Neutropenia and Agranulocytosis in Chinese Patients Prescribed Clozapine. AB - OBJECTIVES: To examine the rate of neutropenia and agranulocytosis, and the pattern of development of these 2 disorders among Chinese patients prescribed clozapine treatment in a local psychiatric unit. METHODS: Patients who were receiving clozapine when they were under the care of Pamela Youde Nethersole Eastern Hospital Psychiatric Unit, Hong Kong, from 1 January 1997 to 31 December 2012 and who developed neutropenia and agranulocytosis from 1 January 1997 to 30 June 2013 were retrospectively reviewed. RESULTS: A total of 13 patients out of 980 clozapine recipients developed neutropenia and 3 developed agranulocytosis during treatment. Half of them were aged > 50 years and three quarters were female. The majority of patients who developed neutropenia and agranulocytosis were prescribed > 1 psychotropic medication in addition to clozapine. Half of the incidents occurred in the first 18 weeks of clozapine treatment. CONCLUSION: Long term monitoring of white cell count is necessary during clozapine treatment. The concurrent use of clozapine with other potentially leukopenic psychotropic drugs should be limited. PMID- 26764292 TI - A 17-Month Review of the Care Model, Service Structure, and Design of THRIVE, a Community Mental Health Initiative in Northern Singapore. AB - Effective delivery of psychiatric care requires the development of a range of services. The existing Singapore health care system provides a comprehensive range of psychiatric services based in restructured hospitals. The Ministry of Health Community Mental Health Masterplan (2012-2017) aims to build novel services for the community. This Masterplan envisions the development of ASCATs (Assessment Shared Care Teams) and COMITs (Community Intervention Teams) to build the capacity and capability for psychiatric care to be delivered outside the hospital in the community. A community mental health plan comprising a fast access clinic, internet-delivered self-help and building a community network of providers was devised for the North of Singapore through the THRIVE (Total Health Rich In Vitality and Energy) programme. This article provides an introduction to the care model, service structure and design of the THRIVE, and reviews its milestones and achievements from its inception in August 2012 until December 2013. PMID- 26764293 TI - CRP and a biomarker of type I collagen degradation, C1M, can differentiate anti inflammatory treatment response in ankylosing spondylitis. AB - AIM: To investigate if tissue turnover biomarkers were efficacy biomarkers in ankylosing spondylitis and if the biomarkers at baseline predicted a good outcome (BASDAI50). PATIENTS & METHODS: Twenty-two etanercept treated ankylosing spondylitis patients were investigated for inflammation (CRP, ESR, CRPM) and tissue turnover (C1M, C2M, C3M) during the first year of treatment. Biomarkers profiles and treatment response were investigated. RESULTS: ESR, CRP, BASDAI and C1M were decreased with treatment (p <= 0.04). C1M and CRP segregated patients into two populations predicting treatment efficacy. CONCLUSION: C1M and CRP were efficacy biomarkers and baseline biomarkers could select who benefited (by biomarkers) from treatment. C1M was not superior to CRP, but the biomarkers evaluate different pathologic events, indicating that C1M and CRP identify different events. PMID- 26764294 TI - The challenge of small lung nodules identified in CT screening: can biomarkers assist diagnosis? AB - Various biomarkers have been developed as noninvasive tests to indicate the presence of lung cancer in asymptomatic persons, and in particular to provide evidence as to whether indeterminate lung nodules detected by screening are malignant. We performed an overview of the range of biomarkers reported in the literature and described those that can complement low-dose computed tomography screening. Several have promising sensitivity and specificity. However to our knowledge, only three techniques have reached the prospective screening phase (phase 4) of the five-phase biomarker development process. Two miRNA signatures (the miR-Test for serum and the miRNA signature classifier test for plasma) are being assessed in prospective screening trials, as is the EarlyCDT-Lung test based on autoantibodies. All will need to undergo prospective studies to determine their ability to improve outcomes before they can become an established adjunct to lung cancer control strategies. PMID- 26764295 TI - [Current Status of Genetic Diagnosis of Charcot-Marie-Tooth Disease: Variety of the Disease-causing Genes]. AB - At least 40 genes have been associated with Charcot-Marie-Tooth disease (CMT) and the related inherited neuropathies. Genetic studies have revealed the following factors as causes of inherited neuropathies: myelin components, transcription factors for myelination, myelin maintenance systems, differentiation factors of the peripheral nerve, neurofilaments, protein transfer systems, mitochondrial proteins, DNA repair, RNA/protein synthesis, ion channels, and aminoacyl-tRNA synthetases. Since 2007, we have tried to screen for mutations in CMT patients using microarrays or next generation sequencers. As a result, the detection rate of gene mutations has improved to about 25%. In this study, we applied target resequencing to 72 genes. From the negative examples, we identified the cases based on clinical course, family history, and electrophysiological findings, and then performed exome analysis. We then tried to identify novel causative genes by analyzing the enormous data obtained from our exome analysis. PMID- 26764297 TI - [Phenotypes of Charcot-Marie-Tooth Syndrome and Differential Diagnosis Focused in Inflammatory Neuropathies]. AB - Charcot-Marie-Tooth disease (CMT), the most frequent form of inherited neuropathy, is a genetically heterogeneous syndrome of the peripheral nervous system with a rather homologous clinical phenotype (slowly progressive distal weakness and muscle atrophy, skeletal deformities, and areflexia in each limb). CMT1 is the autosomal-dominant demyelinating form, and CMT1A (mostly PMP22 duplication) is the most frequent subtype, followed by CMTX1, HNPP (hereditary neuropathy with liability to pressure palsies), CMT1B, or CMT2. As CMT is characterized by slowly progressive motor and sensory disturbances in each limb, it could be misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP) occasionally. Some points can distinguish demyelinating CMT from CIDP. CMT1 patients do not show the conduction block that is frequent in CIDP. In addition, ultrasonographic findings are useful because CMT1 suggests diffuse enlargement of peripheral nerves, whereas CIDP is characterized by asymmetrical or focal enlargement of peripheral nerves. Some CMT1 cases show favorable responses to immunomodulating therapeutics such as corticosteroids, IVIg, and plasma exchange. Such CIDP-like CMT1 (especially CMT1B or CMT2A) shows moderate to high levels of cerebrospinal fluid protein and infiltrated inflammatory macrophages. PMID- 26764296 TI - [Pathology of Charcot-Marie-Tooth Disease]. AB - Although genetic testing is available, nerve biopsy is useful in selected patients for the diagnosis of Charcot-Marie-Tooth disease (CMT). These are sporadic cases of hereditary neuropathy, or familial cases in which genetic testing is negative. CMT is caused by mutations of various genes. The pathological features of CMT have mostly been investigated using nerve biopsy, which may shed light on the presumed functions of mutated gene products. PMP22 duplication in CMT1A induces numerous large onion bulb lesions (OB). Compared to chronic inflammatory demyelinating polyradiculoneuropathy, the differential features of CMT1A are patchy distribution of OB and non-inflammatory lesions. CMT1B also manifests as OB, but presents abnormal compaction of myelin sheaths caused by uncompacted myelin or excessive myelin folding. CMT2 includes axonal neuropathies and many causative genes have been found. CMT2A (MFN2 mutation) shows abnormal mitochondria with a spherical morphology instead of tubular in the longitudinal direction. CMT4 consists of autosomal recessive forms with demyelinating pathology. Most subtypes have mutations of genes relating to myelin maintenance, and pathologically, they show abnormal folding of the myelin structure. PMID- 26764298 TI - [Therapy for Charcot-Marie-Tooth Disease: From the Standpoint of Neurologists]. AB - To date, there is no approved pharmacologic treatment for any form of Charcot Marie-Tooth disease (CMT). However, some clinical or preclinical trials for CMT1A have been undertaken, for example Neurotrophin-3, PXT3003, and neuregulin-1. Gene therapy for CMT1X, CMT2F and Giant axonal neuropathy using animal model or culture cells have been reported with some interesting results. Stem cell research for example iPS cells derived from patients with CMT2A or CMT2E, is being conducted to clarify the mechanism of CMT and find therapeutic clues. The development of new surrogate markers for clinical trials is also needed. Additionally, steps should be taken to improve the quality of life of patients with CMT, including pain control and life style enhancement. PMID- 26764299 TI - [Treatment for Patients with Charcot-Marie-Tooth Disease: Orthopaedic Aspects]. AB - The orthopedic manifestations in patients with Charcot-Marie-Tooth disease include deformity and dysfunction of the extremities and spine. Conservative treatment is the first choice. Orthosis and rehabilitation can improve function, and are important for the prevention of joint contractures. Foot problems are most commonly observed and require surgical treatment. Foot deformities include pes cavus, cavovarus, claw toes, or drop foot. Single or combined surgeries selected for soft tissues are plantar release, tendon transfer, or Achilles tendon lengthening, and those for bones are osteotomies and joint fusions. The upper limb initially demonstrates loss of power of the intrinsic hand muscles followed by symmetrical atrophy of the forearm muscle groups. The typical hand deformity is claw hand. Tendon transfer, joint fusion, soft tissue release, or nerve decompression procedures are performed for correction of hand deformities. Acetabular dysplasia in the hip joints is sometimes observed and osteotomy is selected as surgical treatment in such cases. The associated spinal deformity is scoliosis with or without kyphosis. Similar to treatment of idiopathic scoliosis, posterior spinal fusion is performed in patients with progressive spinal deformities. PMID- 26764300 TI - [Rehabilitation of Charcot-Marie-Tooth Disease]. AB - Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited neuromuscular diseases causing progressive muscle weakness; contracture; deformity in the feet, legs, and hands; and impairments of ambulation and handgrip. Reduced physical ability can be attributed not only to the disease but also to physical deconditioning. Previously, most physicians in the field of rehabilitation were anxious about the hypothesis of overwork weakness in CMT, and did not conduct intensive exercise programs for patients with CMT. However, recent studies have reported that progressive resistance strengthening programs for lower extremities are feasible, safe, beneficial, and improve exercise intolerance and undue fatigue in patients with CMT. Although the improvement in exercise tolerance may be partly due to the reversal of deconditioning effect of related sedentary lifestyle, progressive resistance training and physical fitness can improve walking function, activities of daily living, and subjective perception of pain and fatigue in patients with CMT. To increase the daily physical function, some studies described the potential benefits of ankle-foot orthoses (AFOs); however, no control study supported it. So far, the training programs on CMT have been dependent on the exercise programs for able-bodied individuals. To increase the effects of rehabilitation, optimal programs that combine the training protocol and AFO strategies will have to be designed for patients with CMT. PMID- 26764301 TI - [Scans without Evidence of Dopamine Deficit (SWEDDs)]. AB - Dopamine transporter (DaT) single-photon emission computed tomography (SPECT) and [18F]fluoro-L-DOPA ([18F]DOPA) positron emission tomography (PET) facilitate the investigation of dopaminergic hypofunction in neurodegenerative diseases. DaT SPECT and [18F]DOPA PET have been adopted as survey tools in clinical trials. In a large study on Parkinson's disease, 4-15% of subjects clinically diagnosed with early-stage Parkinson's disease had normal dopaminergic functional imaging scans. These are called Scans without Evidence of Dopamine Deficit (SWEDDs), and are considered to represent a state different from Parkinson's disease. Neurological diseases that exhibit parkinsonism and have normal dopaminergic cells in the nigrostriatal system (e.g., essential tremor, psychogenic parkinsonism, DOPA responsive dystonia, vascular parkinsonism, drug-induced parkinsonism, manganism, brain tumor, myoclonus-dystonia (DYT11), and fragile X syndrome) might be diagnosed with SWEDDs. True bradykinesia with fatigue or decrement may be useful for distinguishing between Parkinson's disease and SWEDDs. However, because SWEDDs encompass many diseases, their properties may not be uniform. In this review, we discuss DaT SPECT, the concept of SWEDDs, and differential diagnosis. PMID- 26764302 TI - [Axonal Regeneration-related Molecules as Biomarkers for Multiple Sclerosis]. AB - Abnormalities in both the nervous and immune systems are thought to be relevant to the pathogenesis of multiple sclerosis (MS). Several functional molecules closely related to axonal regeneration play an important role in not only the nervous system, but also the immune system. Many recent studies revealed that these molecules are associated with the neurological and immunological aspects of the pathogenesis of MS. Therefore, we focused on these molecules as promising biomarkers for MS. Nogo protein and its receptor (Nogo receptor-1; NgR1) are well known representative molecules that prevent axonal regeneration, and we identified lateral olfactory tract usher substance (LOTUS) as an endogenous antagonist of NgR1. We found that LOTUS expression was decreased in the spinal cord in an experimental autoimmune encephalomyelitis mouse model and that variations in LOTUS concentration in the cerebrospinal fluid correlated well with disease activity in MS patients. On the other hand, previous studies have shown that repulsive guidance molecule-a and semaphorins, known to be involved in axonal guidance and regeneration, play a role in MS pathogenesis. We review the association of these molecules with the neurological and immunological aspects of MS pathogenesis, and we show that they are promising, clinically-relevant biomarkers for MS. PMID- 26764303 TI - [A Case of Anti-GQ1b Antibody Syndrome Associated with Pure Bilateral Adie's Pupils]. AB - A 37 year-old Japanese male felt photophobia of both eyes one week following the onset of the common cold. His neurological examination revealed bilateral Adie's tonic pupils, no extraocular movement disorder, normal deep tendon reflexes, and no cerebellar signs. Based on markedly increased blood levels of anti-GQ1b IgG and anti-GT1a IgG antibodies, we diagnosed him as anti-GQ1b antibody syndrome. Bilateral Adie's tonic pupils were improved by IVIg drip infusion and methylprednisolone pulse therapy. This case suggests that we need to investigate anti ganglioside antibody when a patient presents with bilateral Adie's tonic pupils. PMID- 26764304 TI - [Intravascular Large B Cell Lymphoma with Cauda Equina Syndrome: A Case Report and Review of the Literature]. AB - A 62-year-old man complained of gait disturbance, bladder and bowel dysfunction and paresthesia of both legs one month before admission. His symptoms were suggestive of cauda equina syndrome. After admission, he developed rapid progressive numbness and weakness of both legs and a disturbance of consciousness. A random skin biopsy was performed and a histological diagnosis of intravascular large B cell lymphoma (IVLBCL) was reached. His symptoms were improved after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy. PMID- 26764306 TI - Probing the stability of insulin oligomers using electrospray ionization ion mobility mass spectrometry. AB - The peptide hormone insulin is central to regulating carbohydrate and fat metabolism in the body by controlling blood sugar levels. Insulin's most active form is the monomer and the extent of insulin oligomerization is related to insulin's activity of controlling blood sugar levels. Electrospray ionization (ESI) of human insulin produced a series of oligomers from the monomer to the undecamer identified using quadrupole ion mobility time-of-flight mass spectrometry. Previous research suggested that only the monomer, dimer and hexamer are native forms of insulin in solution and the range of oligomers observed in the gas-phase are ESI artifacts. Here the properties of three distinct oligomer bands I, II and III, where both the charge state and number of insulin units of the oligomer increase incrementally, were investigated. When Zn(ii) was added to the insulin sample the same oligomers were observed but with 0-6 Zn(ii) ions bound to each of the oligomers. The oligomers of bands I, II and III were characterized by comparing their drift times, collision cross- sections, relative intensities, collision-induced dissociation (CID) patterns and relative breakdown energies. Insulin oligomers of band I dissociated primarily by releasing either the 2+ or 3+ monomer accompanied by an oligomer that conserved the mass, charge and Zn(ii) of the precursor. Insulin oligomers of bands II and III dissociated primarily by releasing the 2+ monomer accompanied by an oligomer which conserved the mass, charge and Zn(ii) of the precursor. Comparison of CID patterns and breakdown energies showed all the oligomers in band II required higher collision energies to dissociate than the oligomers in band I, and the oligomers of band III required higher energies to dissociate than oligomers of band II. These results show that the amount of excess charge on the oligomer in respect to the number of insulin monomers in the oligomer affects their stability. PMID- 26764305 TI - Fragile lifespan expansion by dietary mitohormesis in C. elegans. AB - Mitochondrial function is central to longevity and an imbalance in mitonuclear protein homeostasis activates a protective response called the mitochondrial unfolded protein response (UPRmt). Toxic compounds damaging mitochondria trigger the UPRmt, but at sublethal doses these insults extend lifespan in simple animals like C. elegans. Mitochondria are the main energy suppliers in eukaryotes, but it is not known if diet influences the UPRmt. High dietary glucose reduces lifespan in worms, and we show that high dietary glucose activates the UPRmt to protect against lifespan reduction. While lifelong exposure to glucose reduces lifespan, glucose exposure restricted to developing animals extends lifespan and requires the UPRmt. However, this lifespan extension is abolished by further mitochondrial stress in adult animals. We demonstrate that dietary conditions regulate mitochondrial homeostasis, where induction of the UPRmt during development extends lifespan, but prolonged activation into adulthood reduces lifespan. PMID- 26764307 TI - Analysis of illicit drugs by direct ablation of solid samples. AB - Analysis of illicit drugs arises as an important field of work given the high social impacts presented by drugs in the modern society. Direct laser ablation of solid compounds allows their analysis without sampling or preparation procedures. For that purpose, an experimental set-up that combines laser ablation with time of- flight mass spectrometry has been constructed very recently to perform studies on the mass spectra of such drugs as 3,4-methylenedioxy-N methylamphetamine, commonly known as MDMA or ecstasy. Analysis of the observed fragmentation pattern in mass spectra may elucidate the ablation-induced photofragmentation phenomena produced, which differ from those previously observed with conventional ionization methods. PMID- 26764308 TI - Characterization of isomeric VX nerve agent adducts on albumin in human plasma using liquid chromatography-tandem mass spectrometry. AB - This study includes the characterization of isomeric VX organophosphorus adducts on albumin in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). VX or its structural isomers were spiked into a vial containing plasma in order to obtain phosphorylated albumin. After pronase and trypsin digestion, the resulting solutions were analyzed to confirm adduct formation with the amino acid tyrosine on the albumin in human plasma. The LC-MS/MS experiments show that VX and its isomers can be attached to tyrosine on the albumin in human blood. Mass spectrometric studies revealed some interesting fragmentation pathways during the ionization process, such as ethylene, formic acid and ammonia elimination and an intermolecular electrophilic aromatic substitution reaction. The proposed mechanisms for the formation of the fragments were confirmed through the analysis of fragments of deuterated adducts. PMID- 26764309 TI - Mass spectral studies on vinylic degradation products of sulfur mustards under gas chromatography/mass spectrometry conditions. AB - Sulfur mustards are a class of vesicant chemical warfare agents that rapidly degrade in environmental samples. The most feasible degradation products of sulfur mustards are chloroethyl vinylic compounds and divinylic compounds, which are formed by the elimination of one and two HCl molecules from sulfur mustards, respectively. The detection and characterization of these degradation products in environmental samples are an important proof for the verification of sulfur mustard usage. In this study, we synthesized a set of sulfur mustard degradation products, i.e., divinylic compounds (1-7) and chloroethyl vinylic compounds (8 14), and characterized using gas chromatography/mass spectrometry (GC/MS) under electron ionization (EI) and chemical ionization (CI) (methane) conditions. The EI mass spectra of the studied compounds mainly included the fragment ions that resulted from homolytic cleavages with or without hydrogen migrations. The divinylic compounds (1-7) showed [M-SH](+) ions, whereas the chloroethylvinyl compounds (8-14) showed [M-Cl](+) and [M-CH2CH2Cl](+) ions. Methane/CI mass spectra showed [M+H](+) ions and provided molecular weight information. The GC retention index (RI) values were also calculated for the studied compounds. The EI and CI mass spectral data together with RI values are extremely useful for off site analysis for the verification of the chemical weapons convention and also to participate in official Organization for the Prohibition of Chemical Weapons proficiency tests. PMID- 26764311 TI - Letter: Compact analyzer for a laser time-of-flight mass spectrometer. AB - Aspects of a new type of laser time-of-flight mass spectrometer are described in this letter. It is based on a wedge-shaped reflecting mirror and is used as an ion analyzer. The analyzer provides time focusing by both energy and a divergence angle of ions. Time focusing of good quality is acquired in the energy range of +/-20% of the average ion energy, which is, at least, two times wider than the energy range of the known ion optical systems for similar applications. The mass resolution of the analyzer is ~600, while overall dimensions are very small (10 * 10 * 5 cm). PMID- 26764310 TI - Rapid comparison of metabolites in humans and rats of different sexes using untargeted UPLC-TOFMS and an in-house software platform. AB - Metabolite differences between sexes have rarely been observed in a global manner, but it has recently been made possible by the advancement in metabolomics techniques. In this study, untargeted ultraperformance liquid chromatography coupled to time-of-flight mass spectrometry and an in-house software platform were used for a rapid comparison of sex differences in urinary metabolites in humans and in urinary and serum metabolites in Sprague Dawley (SD) rats. In addition, the species differences of urinary metabolites between humans and SD rats were also observed. Principle component analysis showed that all the observed metabolite sex differences were more distinct in SD rats than in humans, indicating that the sex differences of human urinary metabolites is small compared with that of SD rats. In SD rats, the observed metabolite sex differences were more distinct in urine than in serum, indicating the importance of urine analysis for metabolomics studies. The species differences in the urinary metabolites of humans and SD rats were much more distinct than any of the observed sex differences. Many sex- and species-related markers were discovered and putatively identified. In both humans and SD rats, steroid metabolites appeared to constitute a major sex difference in urinary metabolites. This provides new proof of the special importance of steroid metabolites in sex differences from an untargeted metabolomics investigation, which is rare for sex differences. Contrary patterns involving adrenocortical activity appeared to exist between rodents and humans, which agrees with previous reports. In the serum metabolites of SD rats, sex differences in ascorbic acid or its isomer and pantothenic acid or its isomer, but not in steroid metabolites, were prominent. Human-specific alpha-N- phenylacetyl-l-glutamine and androsterone glucuronide were among the putative identities of the markers discriminating humans and SD rats. This study demonstrated the feasibility of an in-house software platform and provides metabolite-related information on sex and species differences. PMID- 26764312 TI - Letter: Comparison of pyridine and pyrazine derivatives distributions in exhaled breath and exhaled breath condensate after smoking. AB - Molecular mass distributions of series of compounds found in exhaled breath after smoking are compared between the direct-breath analysis by extractive electrospray ionization and the analysis of exhaled breath condensate by direct infusion electrospray ionization mass spectrometry. Although all the analyzed series of compounds are detected by both methods, their relative abundances are different. A number-average mass is used as a quantitative characteristic of the series. It is shown that this value is close for the distributions of the series of compounds in the mass spectrum of exhaled breath condensate and the mass spectrum obtained by summation of direct mass spectra over the breathing time. PMID- 26764313 TI - 'Hard' crystalline lattice in the Weyl semimetal NbAs. AB - We report the effect of hydrostatic pressure on the magnetotransport properties of the Weyl semimetal NbAs. Subtle changes can be seen in the rho(xx)(T) profiles with pressure up to 2.31 GPa. The Fermi surfaces undergo an anisotropic evolution under pressure: the extremal areas slightly increase in the k(x)-k(y) plane, but decrease in the k(z)-k(y)(k(x)) plane. The topological features of the two pockets observed at atmospheric pressure, however, remain unchanged at 2.31 GPa. No superconductivity can be seen down to 0.3 K for all the pressures measured. By fitting the temperature dependence of specific heat to the Debye model, we obtain a small Sommerfeld coefficient gamma(0) = 0.09(1) mJ (mol.K(2))(-1) and a large Debye temperature, Theta(D) = 450(9) K, confirming a 'hard' crystalline lattice that is stable under pressure. We also studied the Kadowaki-Woods ratio of this low-carrier-density massless system, R(KW) = 3.2 * 10(4) MUOmega cm mol(2) K(2) J(-2). After accounting for the small carrier density in NbAs, this R(KW) indicates a suppressed transport scattering rate relative to other metals. PMID- 26764314 TI - Salvage of Severe Foot and Ankle Trauma With a 3D Printed Scaffold. PMID- 26764315 TI - An immune regulatory CCT repeat containing oligodeoxynucleotide capable of causing hair loss in male mice. AB - An oligodeoxynucleotide with CCT repeats (CCT ODN) has been found in our previous study to selectively downregulate Toll-like receptor 7/9 (TLR7/9)-mediated immune responses both in vitro and in vivo. In this study, we unexpectedly found that CCT ODN induced severe patchy hair loss around the mouth in male F1 mice (female Balb/c * male C57BL/6) with lupus-like nephritis induced by injecting allogenic lymphocytes and also in male Balb/c mice, but not in female F1 mice and Balb/c mice and either gender of C57BL/6 mice. Increased infiltration of natural killer group 2, member D (NKG2D+) cells in hair loss skin and upregulated interferon gamma (IFN-gamma) messenger RNA expression in cultured splenocytes were observed in male Balb/c mice. The CCT ODN-conditioned supernatants of cultured mouse splenocytes caused catagen-like changes to hair follicles (HFs). We hypothesized that the CCT ODN could induce patchy hair loss in the male mice with certain genetic traits by mobilizing NKG2D+ cells to HFs and by inducing the production of IFN-gamma from immune cells. Taken together these data indicated that a gender and genetic preference of immune-regulatory oligonucleotides is causing unexpected clinical situations such as hair loss. PMID- 26764317 TI - Energy and Protein Supplementation Does Not Affect Protein and Amino Acid Kinetics or Pregnancy Outcomes in Underweight Indian Women. AB - BACKGROUND: In India, the prevalence of low birth weight is high in women with a low body mass index (BMI), suggesting that underweight women are not capable of providing adequate energy and protein for fetal growth. Furthermore, as pregnancy progresses, there is increased need to provide methyl groups for methylation reactions associated with the synthesis of new proteins and, unlike normal-BMI American women, low-BMI Indian women are unable to increase methionine transmethylation and remethylation rates as pregnancy progresses from trimester 1 to 3. This also negatively influences birth weight. OBJECTIVE: The aim was to determine the effect of dietary supplementation with energy and protein from 12 +/- 1 wk of gestation to time of delivery compared with no supplement on pregnancy outcomes, protein kinetics, and the fluxes of the methyl group donors serine and glycine. METHODS: Protein kinetics and serine and glycine fluxes were measured by using standard stable isotope tracer methods in the fasting and postprandial states in 24 pregnant women aged 22.9 +/- 0.7 y with low BMIs [BMI (in kg/m(2)) <=18.5] at 12 +/- 1 wk (trimester 1) and 30 +/- 1 wk (trimester 3) of gestation. After the first measurement, subjects were randomly assigned to either receive the supplement (300 kcal/d, 15 g protein/d) or no supplement. RESULTS: Supplementation had no significant effect on any variable of pregnancy outcome, and except for fasting state decreases in leucine flux (125 +/- 7.14 compared with 113 +/- 5.06 MUmol ? kg(-1) ? h(-1); P = 0.04) and nonoxidative disposal (110 +/- 6.97 compared with 101 +/- 3.69 MUmol ? kg(-1) ? h(-1); P = 0.02) from trimesters 1 to 3, it had no effect on any other leucine kinetic variable or urea, glycine, and serine fluxes. CONCLUSION: We conclude that in Indian women with a low BMI, supplementation with energy and protein from week 12 of pregnancy to time of delivery does not improve pregnancy outcome, whole-body protein kinetics, or serine and glycine fluxes. PMID- 26764316 TI - High Fiber and Low Starch Intakes Are Associated with Circulating Intermediate Biomarkers of Type 2 Diabetes among Women. AB - BACKGROUND: Carbohydrate quality has been consistently related to the risk of type 2 diabetes (T2D). However, limited information is available about the effect of carbohydrate quality on biomarkers related to T2D. OBJECTIVE: We examined the associations of carbohydrate quality measures (CQMs) including carbohydrate intake; starch intake; glycemic index; glycemic load; total, cereal, fruit, and vegetable fiber intakes; and different combinations of these nutrients with plasma concentrations of adiponectin, C-reactive protein (CRP), and glycated hemoglobin (HbA1c). METHODS: This is a cross-sectional analysis of 2458 diabetes free women, ages 43-70 y, in the Nurses Health Study. CQMs were estimated from food-frequency questionnaires, and averages from 1984, 1986, and 1990 were used. Plasma biomarkers were collected in 1990. Multiple linear regression models were used to assess the associations between CQMs and biomarkers. RESULTS: After age, body mass index, lifestyle, and dietary variables were adjusted, 1) total fiber intake was positively associated with adiponectin (P-trend = 0.004); 2) cereal fiber intake was positively associated with adiponectin and inversely associated with CRP, and fruit fiber intake was negatively associated with HbA1c concentrations (all P-trend < 0.03); 3) starch intake was inversely associated with adiponectin (P-trend = 0.02); 4) a higher glycemic index was associated with lower adiponectin and higher HbA1c (both P-trend < 0.05); 5) a higher carbohydrate-to-total fiber intake ratio was associated with lower adiponectin (P trend = 0.005); 6) a higher starch-to-total fiber intake ratio was associated with lower adiponectin and higher HbA1c (both P-trend < 0.05); and 7) a higher starch-to-cereal fiber intake ratio was associated with lower adiponectin (P trend = 0.002). CONCLUSIONS: A greater fiber intake and a lower starch-to-fiber intake ratio are favorably associated with adiponectin and HbA1c, but only cereal fiber intake was associated with CRP in women. Further research is warranted to understand the potential mechanism of these associations in early progression of T2D. PMID- 26764318 TI - Adiposity and Chronic Inflammation in Young Women Predict Inflammation during Normal Pregnancy in the Philippines. AB - BACKGROUND: Rates of overweight and obesity are on the rise globally, and excess adipose tissue may contribute to elevations in inflammation during pregnancy, leading to pregnancy complications and adverse birth outcomes. OBJECTIVE: The purpose of this study was to evaluate adiposity and inflammation in young women as predictors of inflammation in the third trimester of pregnancy in a community based sample of healthy women. METHODS: Female participants (24-30 y) in a prospective observational cohort study (Cebu Longitudinal Health and Nutrition Survey) were contacted between 2009 and 2014 to identify new pregnancies. A total of 309 women provided data from 409 pregnancies. An in-home interview was scheduled for the third trimester to collect pregnancy information, anthropometric measurements, and a blood sample. Circulating C-reactive protein (CRP) was measured with a high-sensitivity immunoassay. Data collected from assessments in 2005 and 2009 were used to assess body mass index (BMI) and CRP in young adulthood, before pregnancy. Robust regression models were implemented to evaluate BMI and CRP in young adulthood as predictors of pregnancy CRP. RESULTS: Pre-pregnancy BMI was a stronger predictor of third-trimester circulating CRP than BMI in the third trimester. No association was found between pregnancy weight gain and CRP. Pre-pregnancy CRP was a significant predictor of CRP in pregnancy, independent of BMI. CONCLUSIONS: Levels of overweight/obesity and inflammation in young adulthood, before pregnancy, are important predictors of inflammation in the third trimester of pregnancy. These results may have implications for addressing the growing concern about the contribution of obesity to adverse birth outcomes, and they suggest that factors that influence the regulation of inflammation, before pregnancy and independent of adiposity, may be important in shaping the inflammatory response to pregnancy. PMID- 26764319 TI - Validation of Reported Whole-Grain Intake from a Web-Based Dietary Record against Plasma Alkylresorcinol Concentrations in 8- to 11-Year-Olds Participating in a Randomized Controlled Trial. AB - BACKGROUND: Whole-grain (WG) intake is important for human health, but accurate intake estimation is challenging. Use of a biomarker for WG intake provides a possible way to validate dietary assessment methods. OBJECTIVE: Our aim was to validate WG intake from 2 diets reported by children, using plasma alkylresorcinol (AR) concentrations, and to investigate the 3-mo reproducibility of AR concentrations and reported WG intake. METHODS: AR concentrations were analyzed in fasting blood plasma samples, and WG intake was estimated in a 7-d web-based diary by 750 participants aged 8-11 y in a 2 school meal * 3 mo crossover trial. Reported WG intake and plasma AR concentrations were compared when children ate their usual bread-based lunch (UBL) and when served a hot lunch meal (HLM). Correlations and cross-classification were used to rank subjects according to intake. The intraclass correlation coefficients (ICCs) between subjects' measurements at baseline and after the UBL were used to assess reproducibility. RESULTS: Correlations between reported WG wheat + rye intake and plasma AR were 0.40 and 0.37 (P < 0.001) for the UBL and the HLM diets, and 78% and 77% were classified in the same or adjacent quartiles for the UBL and HLM diets, respectively. The ICC over 3 mo was 0.47 (95% CI: 0.38, 0.55) for plasma total ARs and 0.64 (95% CI: 0.58, 0.70) for reported WG intake. Correlations were higher when using the AR C17:0 homolog as a biomarker, reflecting rye intake instead of plasma total ARs [UBL: r = 0.47; HLM: r = 0.43, P < 0.001; ICC = 0.51 (95% CI: 0.43, 0.59)]. CONCLUSIONS: Self-reported WG wheat + rye intake among children showed moderate correlations with plasma AR concentrations. Substantial intraindividual variation was found in WG intake and plasma AR concentrations. The AR homolog C17:0 may be used as a biomarker for WG intake when the WG intake primarily comes from rye as in the present study. This trial was registered at clinicaltrials.gov as NCT01457794. PMID- 26764322 TI - Aged Garlic Extract Reduces Low Attenuation Plaque in Coronary Arteries of Patients with Metabolic Syndrome in a Prospective Randomized Double-Blind Study. AB - BACKGROUND: Although several previous studies have demonstrated that aged garlic extract (AGE) inhibits the progression of coronary artery calcification, its effect on noncalcified plaque (NCP) has been unclear. OBJECTIVE: This study investigated whether AGE reduces coronary plaque volume measured by cardiac computed tomography angiography (CCTA) in patients with metabolic syndrome (MetS). METHODS: Fifty-five patients with MetS (mean +/- SD age: 58.7 +/- 6.7 y; 71% men) were prospectively assigned to consume 2400 mg AGE/d (27 patients) or placebo (28 patients) orally. Both groups underwent CCTA at baseline and follow up 354 +/- 41 d apart. Coronary plaque volume, including total plaque volume (TPV), dense calcium (DC), NCP, and low-attenuation plaque (LAP), were measured based upon predefined intensity cutoff values. Multivariable linear regression analysis, adjusted for age, gender, number of risk factors, hyperlipidemia medications, history of coronary artery disease, scan interval time, and baseline %TPV, was performed to examine whether AGE affected each plaque change. RESULTS: The %LAP change was significantly reduced in the AGE group compared with the placebo group (-1.5% +/- 2.3% compared with 0.2% +/- 2.0%, P = 0.0049). In contrast, no difference was observed in %TPV change (0.3% +/- 3.3% compared with 1.6% +/- 3.0%, P = 0.13), %NCP change (0.2% +/- 3.3% compared with 1.4% +/- 2.9%, P = 0.14), and %DC change (0.2% +/- 1.4%, compared with 0.2% +/- 1.7%, P = 0.99). Multivariable linear regression analysis found a beneficial effect of AGE on %LAP regression (beta: -1.61; 95% CI: -2.79, -0.43; P = 0.008). CONCLUSIONS: This study indicates that the %LAP change was significantly greater in the AGE group than in the placebo group. Further studies are needed to evaluate whether AGE has the ability to stabilize vulnerable plaque and decrease adverse cardiovascular events. This trial was registered at clinicaltrials.gov as NCT01534910. PMID- 26764323 TI - Bioavailability of Alfrutamide and Caffedymine and Their P-Selectin Suppression and Platelet-Leukocyte Aggregation Mechanisms in Mice. AB - BACKGROUND: Alfrutamide and caffedymine are phenolic amides found in plants, including garlic and cocoa. However, the bioavailability of alfrutamide and caffedymine and their effects on cardiovascular diseases (CVDs), particularly via effects on P-selectin expression(PSE) and platelet-leukocyte aggregation (PLA), are unknown. OBJECTIVE: The objective of this study was to investigate the bioavailability of alfrutamide and caffedymine and their effects on PSE and PLA, which are frequently involved in the progression of CVDs. METHODS: Cyclooxygenase (COX) I and COX-II activities and cAMP were determined by using COX and cAMP kits. Bioavailability was determined by HPLC analysis of plasma samples from Swiss Webster mice orally administered alfrutamide and caffedymine (10 MUg each). PSE and PLA were also measured by flow cytometry using blood samples from the same mice. RESULTS: At 0.05 MUmol/L, alfrutamide and caffedymine inhibited COX-I and COX-II by 20-40% (P < 0.05) and 16-33% (P < 0.05), respectively, compared with the control. At 0.1 MUmol/L, the 2 compounds also inhibited platelet PSE by 28% (P < 0.05) and 35% (P < 0.05), respectively, compared with the control. The beta2-adrenoceptor antagonists ICI118551 and butoxamine partially suppressed the inhibition of PSE by caffedymine, suggesting that beta2 receptors are involved in inhibition by caffedymine but not by alfrutamide. At the same concentration (0.1 MUmol/L), however, these 2 compounds inhibited PLA by 24-32% (P < 0.05) compared with the control. In addition, mice administered caffedymine and alfrutamide orally (10 MUg/35 g body weight) exhibited maximum concentrations >0.6 MUmol/L and significant inhibition of PSE by 23-34% (P < 0.05) and PLA by 20-27% (P < 0.05) compared with control mice. CONCLUSIONS: These data show the adequate bioavailability of alfrutamide and caffedymine and their different mechanisms of suppressing PSE and PLA: alfrutamide exerts its effects only via COX inhibition, whereas caffedymine works through both COX inhibition and cAMP amplification. PMID- 26764321 TI - Late-Pregnancy Salivary Cortisol Concentrations of Ghanaian Women Participating in a Randomized Controlled Trial of Prenatal Lipid-Based Nutrient Supplements. AB - BACKGROUND: High circulating cortisol is associated with miscarriage, preterm birth, and low birth weight. Research in nonpregnant individuals suggests that improved nutrition may lower cortisol concentrations. It is unknown whether nutritional supplementation during pregnancy lowers cortisol. OBJECTIVE: Our objective was to determine whether women receiving a lipid-based nutrient supplement (LNS) throughout pregnancy would have lower salivary cortisol at 36 wk gestation compared with women receiving other nutrient supplements. METHODS: We conducted a randomized controlled trial in 1320 pregnant Ghanaian women at <=20 wk gestation who were assigned to receive daily throughout pregnancy: 1) 60 mg iron + 400 MUg folic acid (IFA), 2) multiple micronutrients (MMNs), or 3) 20 g LNS (containing 118 kcal, 22 micronutrients, and protein). Morning salivary cortisol was collected from a subsample at baseline and at 28 and 36 wk gestation. RESULTS: A total of 758 women had cortisol measurements at 28 or 36 wk gestation. Salivary cortisol at 36 wk gestation did not differ between groups and was (mean +/- SE) 7.97 +/- 0.199 in the IFA group, 7.84 +/- 0.191 in the MMN group, and 7.77 +/- 0.199 nmol/L in the LNS group, when adjusted for baseline cortisol, time of waking, and time between waking and saliva collection (P = 0.67). There was an interaction between supplementation group and women's age (continuous variable, P-interaction = 0.03); and when age was dichotomized by the median, significant differences in salivary cortisol concentrations between groups were seen in women <=26 y of age (IFA = 8.23 +/- 0.284 nmol/L, MMN = 8.20 +/- 0.274 nmol/L, and LNS = 7.44 +/- 0.284 nmol/L; P = 0.03) but not in women >26 y old (IFA = 7.71 +/- 0.281 nmol/L, MMN = 7.50 +/- 0.274 nmol/L, and LNS = 8.08 +/- 0.281 nmol/L; P = 0.13). CONCLUSIONS: We conclude that supplementation with LNSs or MMNs during pregnancy did not affect the cortisol concentration in the study population as a whole, in comparison with IFA, but that LNS consumption among younger women may lead to lower cortisol at 36 wk gestation. This trial was registered at clinicaltrials.gov as NCT00970866. PMID- 26764324 TI - Aged Garlic Extract Inhibits Human Platelet Aggregation by Altering Intracellular Signaling and Platelet Shape Change. AB - BACKGROUND: Increased platelet aggregation plays a pivotal role in the etiology of cardiovascular disease. Upon platelet aggregation, an increase in free cytoplasmic Ca(2+) results in the inhibition of soluble guanylyl cyclase (sGC) and adenylyl cyclase (AC), leading to a decrease in cyclic guaninosine-5' monophosphate (cGMP) and cAMP, respectively. This leads to the activation of the glycoprotein IIb/IIIa (GPIIb/IIIa) fibrinogen receptor, resulting in platelet shape change. Aged garlic extract (AGE) decreases platelet aggregation; however, the mechanisms involved are not clearly defined. OBJECTIVE: Our objective was to investigate the effects of AGE on intraplatelet cell signaling and platelet shape change. METHODS: Platelets from 14 participants were studied. Platelet aggregation was induced by ADP in the presence of AGE up to a concentration of 6.25% (vol:vol) alone or in combination with 3-morpholinosydnonimine (Sin-1), a nitric oxide donor. The experiments with AGE were repeated in the presence of 3 isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor. In a series of separate experiments, platelet aggregation was induced in the presence of either 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an sGC inhibitor, or 9 (tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22536), an AC inhibitor, or a combination of both in the presence of IBMX and AGE. Intraplatelet cGMP and cAMP were measured. The platelets were also subjected to scanning electron microscopic analysis, and their binding to fibrinogen was determined. RESULTS: AGE decreased platelet aggregation at all concentrations tested; this decrease was more marked in the presence of Sin-1 and ranged between 15% and 67%.The presence of IBMX also led to a decrease (17-35%) in platelet aggregation at all AGE concentrations and a significant decrease in the amounts of cGMP (24-41%) and cAMP (19-70%), respectively, in the presence of ODQ and SQ22536. The presence of AGE significantly inhibited the binding of activated platelets to fibrinogen, preventing changes in platelet shape. CONCLUSION: These results indicate that AGE inhibits platelet aggregation by increasing cyclic nucleotides and inhibiting fibrinogen binding and platelet shape change. PMID- 26764325 TI - Pharmacokinetics of S-Allyl-l-cysteine in Rats Is Characterized by High Oral Absorption and Extensive Renal Reabsorption. AB - BACKGROUND: S-Allylcysteine (SAC) is a key component of aged garlic extract, one of many garlic products. However, information on its pharmacokinetics has been scant except for data from a few animal studies. OBJECTIVE: We designed this study to determine the overall pharmacokinetics of SAC in rats. METHODS: After oral or intravenous administration of SAC to rats at a dose of 5 mg/kg, the plasma concentration-time profile of SAC and its metabolites, as well as the amounts excreted in bile and urine, were analyzed by using liquid chromatography tandem mass spectrometry. RESULTS: After oral administration, SAC was well absorbed with a bioavailability of 98%. Two major metabolites of SAC, N-acetyl-S allylcysteine (NAc-SAC) and N-acetyl-S-allylcysteine sulfoxide (NAc-SACS), were detected in plasma, but their concentrations were markedly lower than those of SAC. SAC was metabolized to a limited extent, but most of the orally absorbed SAC was excreted into urine in the form of its N-acetylated metabolites. The amounts of SAC, NAc-SAC, and NAc-SACS excreted in urine over 24 h were 2.9%, 80%, and 11% of the orally administered SAC, respectively. The very low renal clearance (0.016 L ? h(-1) ? kg(-1)) of SAC indicated that it undergoes extensive renal reabsorption. These results collectively suggested that SAC was ultimately metabolized to NAc-SAC and NAc-SACS through the cycles of urinary excretion, renal reabsorption, and systemic recirculation. CONCLUSION: The pharmacokinetics of SAC in rats were characterized by high oral absorption, limited metabolism, and extensive renal reabsorption, all of which potentially contribute to its high and relatively long-lasting plasma concentrations. PMID- 26764326 TI - Garlic Lowers Blood Pressure in Hypertensive Individuals, Regulates Serum Cholesterol, and Stimulates Immunity: An Updated Meta-analysis and Review. AB - BACKGROUND: Garlic has been shown to have cardiovascular protective and immunomodulatory properties. OBJECTIVES: We updated a previous meta-analysis on the effect of garlic on blood pressure and reviewed the effect of garlic on cholesterol and immunity. METHODS: We searched the Medline database for randomized controlled trials (RCTs) published between 1955 and December 2013 on the effect of garlic preparations on blood pressure. In addition, we reviewed the effect of garlic on cholesterol and immunity. RESULTS: Our updated meta-analysis on the effect of garlic on blood pressure, which included 20 trials with 970 participants, showed a mean +/- SE decrease in systolic blood pressure (SBP) of 5.1 +/- 2.2 mm Hg (P < 0.001) and a mean +/- SE decrease in diastolic blood pressure (DBP) of 2.5 +/- 1.6 mm Hg (P < 0.002) compared with placebo. Subgroup analysis of trials in hypertensive subjects (SBP/DBP >=140/90 mm Hg) at baseline revealed a larger significant reduction in SBP of 8.7 +/- 2.2 mm Hg (P < 0.001; n = 10) and in DBP of 6.1 +/- 1.3 mm Hg (P < 0.001; n = 6). A previously published meta-analysis on the effect of garlic on blood lipids, which included 39 primary RCTs and 2300 adults treated for a minimum of 2 wk, suggested garlic to be effective in reducing total and LDL cholesterol by 10% if taken for >2 mo by individuals with slightly elevated concentrations [e.g., total cholesterol >200 mg/dL (>5.5 mmol/L)]. Garlic has immunomodulating effects by increasing macrophage activity, natural killer cells, and the production of T and B cells. Clinical trials have shown garlic to significantly reduce the number, duration, and severity of upper respiratory infections. CONCLUSIONS: Our review suggests that garlic supplements have the potential to lower blood pressure in hypertensive individuals, to regulate slightly elevated cholesterol concentrations, and to stimulate the immune system. Garlic supplements are highly tolerated and may be considered as a complementary treatment option for hypertension, slightly elevated cholesterol, and stimulation of immunity. Future long-term trials are needed to elucidate the effect of garlic on cardiovascular morbidity and mortality. PMID- 26764327 TI - Garlic and Heart Disease. AB - BACKGROUND: Thousands of studies have been published based on animal and human studies evaluating garlic's effects and safety. OBJECTIVE: We reviewed the available literature investigating the effects of garlic supplements on hypertension, hypercholesterolemia, C-reactive protein (CRP), pulse wave velocity (PWV), and coronary artery calcium (CAC), as well as available data on side effects. METHODS: We searched PubMed for all human studies using medical subject heading words through 30 May 2013 and assessed relevant review articles and original studies. Only double-blind, randomized, controlled trials and meta analyses of double-blind, randomized, controlled trials were included. The review of articles and data extraction were performed by 2 independent authors, with any disagreements resolved by consensus. RESULTS: Garlic supplementation reduced blood pressure by 7-16 mm Hg (systolic) and 5-9 mm Hg (diastolic) (4 meta analyses and 2 original studies). It reduced total cholesterol by 7.4-29.8 mg/dL (8 meta-analyses). The most consistent benefits were shown in studies that used aged garlic extract (AGE). A few small studies that used AGE also showed favorable effects on CAC, CRP, and PWV. Although garlic is generally safe, rare adverse reactions have been documented with limited causality established. CONCLUSION: We conclude that garlic supplementation has the potential for cardiovascular protection based on risk factor reduction (hypertension and total cholesterol) and surrogate markers (CRP, PWV, and CAC) of atherosclerosis. Larger studies are warranted to evaluate these effects further. PMID- 26764328 TI - Garlic Influences Gene Expression In Vivo and In Vitro. AB - There is a large body of preclinical research aimed at understanding the roles of garlic and garlic-derived preparations in the promotion of human health. Most of this research has targeted the possible functions of garlic in maintaining cardiovascular health and in preventing and treating cancer. A wide range of outcome variables has been used to investigate the bioactivity of garlic, ranging from direct measures of health status such as cholesterol concentrations, blood pressure, and changes in tumor size and number, to molecular and biochemical measures such as mRNA gene expression, protein concentration, enzyme activity, and histone acetylation status. Determination of how garlic influences mRNA gene expression has proven to be a valuable approach to elucidating the mechanisms of garlic bioactivity. Preclinical studies investigating the health benefits of garlic far outnumber human studies and have made frequent use of mRNA gene expression measurement. There is an immediate need to understand mRNA gene expression in humans as well. Although safety and ethical constraints limit the types of available human tissue, peripheral whole blood is readily accessible, and measuring mRNA gene expression in whole blood may provide a unique window to understanding how garlic intake affects human health. PMID- 26764329 TI - Aged Garlic Extract Suppresses the Development of Atherosclerosis in Apolipoprotein E-Knockout Mice. AB - BACKGROUND: Aged garlic extract (AGE) has been shown to retard the progression of coronary calcification in patients with coronary artery disease. OBJECTIVE: To clarify the mechanism of AGE's action to retard atherosclerosis, we investigated whether AGE suppresses the formation and progression of atherosclerosis in Apolipoprotein E (Apoe)-knockout (ApoE-KO) mice. METHODS: Male C57BL/6J mice (control mice, 5 wk old) were fed a standard diet, whereas male ApoE-KO mice (5 wk old) were fed a standard diet with or without 3% AGE for 12 or 24 wk. After the treatment, blood samples, aortas, and spleens were collected from all mice. Concentrations of total cholesterol (TC), HDL cholesterol, and triglycerides (TGs) in serum were measured. The area of atherosclerotic lesion in the aorta was examined by Oil Red O staining. The relative abundances of monocytes plus macrophages (CD11b(+) cells) and interferon-gamma-producing CD4(+) T cells in spleen were assessed by flow cytometric analysis. RESULTS: The atherosclerotic lesion areas in the aortas of ApoE-KO mice were 87 and 114 times as great (P < 0.01) as those in control mice at 12 and 24 wk, respectively. AGE feeding significantly inhibited the progression of atherosclerotic lesion area in ApoE-KO mice by 22% (P < 0.05) at 12 wk. In addition, serum concentrations of TC and TGs in ApoE-KO mice were significantly higher than those in control mice at 12 and 24 wk. Treatment with AGE significantly suppressed the increases in serum concentrations of TC and TGs in ApoE-KO mice by 21% (P < 0.05) and 19% (P < 0.05) at 24 wk, respectively, and reduced the relative abundance of CD11b(+) cells in ApoE-KO mice by 24% (P < 0.05) at 12 wk. CONCLUSION: These data suggest that the antiatherosclerotic activity of AGE is at least partly due to the suppression of inflammation and lipid deposition in the vessels during the early stage of atherosclerotic development in ApoE-KO mice. PMID- 26764320 TI - Role of Ingested Amino Acids and Protein in the Promotion of Resistance Exercise Induced Muscle Protein Anabolism. AB - The goal of this critical review is to comprehensively assess the evidence for the molecular, physiologic, and phenotypic skeletal muscle responses to resistance exercise (RE) combined with the nutritional intervention of protein and/or amino acid (AA) ingestion in young adults. We gathered the literature regarding the translational response in human skeletal muscle to acute exposure to RE and protein/AA supplements and the literature describing the phenotypic skeletal muscle adaptation to RE and nutritional interventions. Supplementation of protein/AAs with RE exhibited clear protein dose-dependent effects on translational regulation (protein synthesis) through mammalian target of rapamycin complex 1 (mTORC1) signaling, which was most apparent through increases in p70 ribosomal protein S6 kinase 1 (S6K1) phosphorylation, compared with postexercise recovery in the fasted or carbohydrate-fed state. These acute findings were critically tested via long-term exposure to RE training (RET) and protein/AA supplementation, and it was determined that a diminishing protein/AA supplement effect occurs over a prolonged exposure stimulus after exercise training. Furthermore, we found that protein/AA supplements, combined with RET, produced a positive, albeit minor, effect on the promotion of lean mass growth (when assessed in >20 participants/treatment); a negligible effect on muscle mass; and a negligible to no additional effect on strength. A potential concern we discovered was that the majority of the exercise training studies were underpowered in their ability to discern effects of protein/AA supplementation. Regardless, even when using optimal methodology and large sample sizes, it is clear that the effect size for protein/AA supplementation is low and likely limited to a subset of individuals because the individual variability is high. With regard to nutritional intakes, total protein intake per day, rather than protein timing or quality, appears to be more of a factor on this effect during long-term exercise interventions. There were no differences in strength or mass/muscle mass on RET outcomes between protein types when a leucine threshold (>2 g/dose) was reached. Future research with larger sample sizes and more homogeneity in design is necessary to understand the underlying adaptations and to better evaluate the individual variability in the muscle-adaptive response to protein/AA supplementation during RET. PMID- 26764330 TI - Development of an Analytic Method for Sulfur Compounds in Aged Garlic Extract with the Use of a Postcolumn High Performance Liquid Chromatography Method with Sulfur-Specific Detection. AB - BACKGROUND: Garlic and its processed preparations contain numerous sulfur compounds that are difficult to analyze in a single run using HPLC. OBJECTIVE: The aim of this study was to develop a rapid and convenient sulfur-specific HPLC method to analyze sulfur compounds in aged garlic extract (AGE). METHODS: We modified a conventional postcolumn HPLC method by employing a hexaiodoplatinate reagent. Identification and structural analysis of sulfur compounds were conducted by LC-mass spectrometry (LC-MS) and nuclear magnetic resonance. The production mechanisms of cis-S-1-propenylcysteine (cis-S1PC) and S allylmercaptocysteine (SAMC) were examined by model reactions. RESULTS: Our method has the following advantages: less interference from nonsulfur compounds, high sensitivity, good correlation coefficients (r > 0.98), and high resolution that can separate >20 sulfur compounds, including several isomers, in garlic preparations in a single run. This method was adapted for LC-MS analysis. We identified cis-S1PC and gamma-glutamyl-S-allyl-mercaptocysteine in AGE. The results of model reactions suggest that cis-S1PC is produced from trans-S1PC through an isomerization reaction and that SAMC is produced by a reaction involving S-allylcysteine/S1PC and diallyldisulfide during the aging period. CONCLUSION: We developed a rapid postcolumn HPLC method for both qualitative and quantitative analyses of sulfur compounds, and this method helped elucidate a potential mechanism of cis-S1PC and SAMC action in AGE. PMID- 26764331 TI - The Role of Adiponectin in Cardiometabolic Diseases: Effects of Nutritional Interventions. AB - Adiponectin is an adipocyte-derived hormone abundantly present in plasma that exerts its effects through the activation of 3 receptors. Its concentrations are negatively regulated by the accumulation of visceral fat, and clinical studies implicate hypoadiponectinemia in the pathogenesis of diabetes mellitus type 2, coronary artery disease, hypertension, and left ventricular hypertrophy. In contrast, high concentrations of adiponectin are associated with a decreased risk of coronary artery disease, with an improvement in the differentiation of preadipocytes into adipocytes, and with increased endothelial nitric oxide production. Therefore, adiponectin appears to be an important molecule involved in limiting the pathogenesis of obesity-linked disorders, and it may have potential benefits in the treatment and prevention of cardiovascular disease. Caloric restriction, moderate alcohol consumption, and consuming a Mediterranean diet increase adiponectin concentrations, and current evidence suggests a positive, dose-dependent relation between omega-3 (n-3) fatty acid intake and circulating concentrations of adiponectin. Recently, it was reported that the administration of aged garlic extract and a single food intervention with pistachios can increase adiponectin concentrations in individuals with metabolic syndrome. Moreover, the Mediterranean diet is associated with higher adiponectin concentrations. Additional studies are needed to evaluate the potential benefits of increasing adiponectin by nutritional interventions in the treatment and prevention of cardiometabolic diseases. PMID- 26764332 TI - Aged Garlic Extract Modifies Human Immunity. AB - Garlic contains numerous compounds that have the potential to influence immunity. Immune cells, especially innate immune cells, are responsible for the inflammation necessary to kill pathogens. Two innate lymphocytes, gammadelta-T and natural killer (NK) cells, appear to be susceptible to diet modification. The purpose of this review was to summarize the influence of aged garlic extract (AGE) on the immune system. The author's laboratory is interested in AGE's effects on cell proliferation and activation and inflammation and to learn whether those changes might affect the occurrence and severity of colds and flu. Healthy human participants (n = 120), between 21 and 50 y of age, were recruited for a randomized, double-blind, placebo-controlled parallel-intervention study to consume 2.56 g AGE/d or placebo supplements for 90 d during the cold and flu season. Peripheral blood mononuclear cells were isolated before and after consumption, and gammadelta-T and NK cell function was assessed by flow cytometry. The effect on cold and flu symptoms was determined by using daily diary records of self-reported illnesses. After 45 d of AGE consumption, gammadelta-T and NK cells proliferated better and were more activated than cells from the placebo group. After 90 d, although the number of illnesses was not significantly different, the AGE group showed reduced cold and flu severity, with a reduction in the number of symptoms, the number of days participants functioned suboptimally, and the number of work/school days missed. These results suggest that AGE supplementation may enhance immune cell function and may be partly responsible for the reduced severity of colds and flu reported. The results also suggest that the immune system functions well with AGE supplementation, perhaps with less accompanying inflammation. This trial was registered at clinicaltrials.gov as NCT01390116. PMID- 26764333 TI - Chemical Assignment of Structural Isomers of Sulfur-Containing Metabolites in Garlic by Liquid Chromatography-Fourier Transform Ion Cyclotron Resonance-Mass Spectrometry. AB - BACKGROUND: The chemical assignment of metabolites is crucial to understanding the relation between food composition and biological activity. OBJECTIVE: This study was designed to detect and chemically assign sulfur-containing metabolites by using LC-Fourier transform ion cyclotron resonance-mass spectrometry (FTICR MS) in Allium plants. METHODS: Ultrahigh resolution (>250,000 full width at half maximum) and mass accuracy (<1 mDa) by FTICR-MS allowed us to distinguish ions containing sulfur isotopes ((32)S and (34)S). RESULTS: Putative 69 S-containing monoisotopic ions (S-ions) were extracted from the metabolome data of onion (Allium cepa), green onion (Allium fistulosum), and garlic (Allium sativum) on the basis of theoretical mass differences between (32)S-ions and their (34)S substituted counterparts and on the natural abundance of (34)S. Eight S-ions were chemically assigned by using the reference data according to the guidelines of the Metabolomics Standards Initiative. Three ions detected in garlic were assigned as derived from the isomers gamma-glutamyl-S-1-propenylcysteine and gamma-glutamyl-S-2-propenylcysteine and as S-2-propenylmercaptoglutathione on the basis of differences in key product ions identified in reference tandem MS spectra. CONCLUSION: The ability to discriminate between such geometric isomers will be extremely useful for the chemical assignment of unknown metabolites in MS based metabolomics. PMID- 26764334 TI - Fibroblast Growth Factor 21 (Fgf21) Gene Expression Is Elevated in the Liver of Mice Fed a High-Carbohydrate Liquid Diet and Attenuated by a Lipid Emulsion but Is Not Upregulated in the Liver of Mice Fed a High-Fat Obesogenic Diet. AB - BACKGROUND: Fibroblast growth factor 21 (FGF21) is a regulator of carbohydrate and lipid metabolism; however, the regulation of Fgf21 gene expression by diet remains incompletely understood. OBJECTIVE: We investigated the effect of a high carbohydrate (HC) liquid diet, with and without supplementation with a lipid emulsion (LE), and of a high-fat diet (HFD) compared with a low-fat diet (LFD) on the regulation of Fgf21 gene expression in the liver of intact mice. METHODS: C57BL/6 male mice were fed standard feed pellets (SFPs), a purified HC liquid diet (adequate in calories and protein), or an HC liquid diet containing an LE at either 4% or 13.5% of energy for 5 wk (Expt. 1) or 1 wk (Expt. 2). In Expt. 3, mice were fed a purified LFD (~10% fat) or HFD (~60% fat) or were fed an HFD and given access to a running wheel for voluntary exercise for 16 wk. RESULTS: Fgf21 mRNA in liver and FGF21 protein in plasma were increased by 3.5- to 7-fold in HC mice compared with SFP mice (P < 0.001), whereas the LE dose-dependently attenuated the induction of Fgf21 expression (P < 0.05). After 16 wk, hepatic Fgf21 mRNA did not differ between LFD and HFD mice but was dramatically reduced in the HFD+exercise group to <20% of the level in the HFD group (P < 0.0001). CONCLUSIONS: In mice, hepatic Fgf21 expression was upregulated by 1 and 5 wk of feeding a lipogenic HC diet but not by 16 wk of feeding an obesogenic HFD, whereas the addition of fat as an LE to the HC formula significantly reduced Fgf21 gene expression and the plasma FGF21 protein concentration. Our results support a strong and reversible response of hepatic Fgf21 expression to shifts in dietary glucose intake. PMID- 26764336 TI - Evaluating Sativex(r) in Neuropathic Pain Management: A Clinical and Neurophysiological Assessment in Multiple Sclerosis. AB - OBJECTIVE: The aim of our study was to better investigate the role of Sativex((r)) in improving pain in multiple sclerosis (MS) patients by means of either clinical or neurophysiological assessment. SETTING: Pain is a common symptom of MS, affecting up to 70% of patients. Pain treatment is often unsatisfactory, although emerging drugs (including cannabinoids) are giving encouraging results. Clinical pain assessment in MS is very difficult, and more objective tools are necessary to better quantify this symptom and its potential response to the treatments. SUBJECTS AND METHODS: We enrolled 20 MS patients (10 with and 10 without neuropathic pain), who underwent a specific clinical (such as visual analog scale) and neurophysiological assessment (by means of laser-evoked potentials and transcranial magnetic stimulation), before and after 4 weeks of Sativex administration. RESULTS: One month of drug administration in MS patients with neuropathic pain successfully reduced pain rating and improved quality of life. Interestingly, such effects were paralleled by an increase of fronto central gamma-band oscillation and of pain-motor integration strength. CONCLUSIONS: Our data suggest that Sativex may be effective in improving MS related neuropathic pain, maybe through its action on specific cortical pathways. PMID- 26764337 TI - Salivary Alpha-Amylase Correlates with Subjective Heat Pain Perception. AB - OBJECTIVE: Self-reports of pain are important for an adequate therapy. This is a problem with patients and infants who are restricted in providing an accurate verbal estimation of their pain. Reliable, real-time, economical, and non invasive physiological correlates might contribute to a more comprehensive description of pain. Salivary alpha-amylase constitutes one candidate biomarker, which reflects predominantly sympathetic nervous system alterations under stressful conditions and can be measured non-invasively. The current study investigated the effects of acute heat pain on salivary alpha-amylase activity. METHODS: Heat pain tolerance was measured on the non-dominant forearm. Participants completed visual analog scales on pain intensity and unpleasantness. Saliva samples were collected directly after pain induction. SUBJECTS: Twenty seven healthy volunteers were recruited for this study. RESULTS: While salivary alpha-amylase levels correlated positively with intensity and unpleasantness ratings in response to acute heat pain stimuli, there was no corresponding association with pain tolerance. CONCLUSIONS: Salivary alpha-amylase is suggested to be an indirect physiologic correlate of subjective heat pain perception. Future studies should address the role of salivary alpha-amylase depending on the origin of pain, the concerned tissue, and other pain assessment methods. PMID- 26764335 TI - Garlic-Derived Organic Polysulfides and Myocardial Protection. AB - For centuries, garlic has been shown to exert substantial medicinal effects and is considered to be one of the best disease-preventative foods. Diet is important in the maintenance of health and prevention of many diseases including cardiovascular disease (CVD). Preclinical and clinical evidence has shown that garlic reduces risks associated with CVD by lowering cholesterol, inhibiting platelet aggregation, and lowering blood pressure. In recent years, emerging evidence has shown that hydrogen sulfide (H2S) has cardioprotective and cytoprotective properties. The active metabolite in garlic, allicin, is readily degraded into organic diallyl polysulfides that are potent H2S donors in the presence of thiols. Preclinical studies have shown that enhancement of endogenous H2S has an impact on vascular reactivity. In CVD models, the administration of H2S prevents myocardial injury and dysfunction. It is hypothesized that these beneficial effects of garlic may be mediated by H2S-dependent mechanisms. This review evaluates the current knowledge concerning the cardioprotective effects of garlic-derived diallyl polysulfides. PMID- 26764338 TI - Safety of Lumbar Spine Radiofrequency Procedures in Patients Who Have Posterior Spinal Hardware. AB - OBJECTIVE: The purpose of this study was to determine whether the energy generated by an active radiofrequency (RF) cannula adjacent to lumbar spine hardware could result in heating of the hardware. DESIGN: Prospective study. SETTING: Tertiary care medical center. SUBJECTS: Six patients with lumbar facet joint pain at the level adjacent to lumbar spine fusion hardware were studied. METHODS: A total of 10 lumbar medial branch nerve radiofrequency lesion procedures were performed on six patients. A temperature probe was placed on the fusion hardware to continuously monitor the temperature of the hardware throughout the RF procedure. RESULTS: The temperature of the fusion hardware increased in six of the 10 RF lesion procedures. During two of the procedures, the temperature rose rapidly to 42 degrees C, at which time the procedure was ceased at that level. CONCLUSION: This study demonstrated that radiofrequency lesioning to treat symptomatic facet joint pain in patients who have adjacent posterior lumbar fusion hardware may result in heat energy being transferred to the adjacent hardware. This may increase the risk of injury to the patient. Monitoring for a temperature increase is easily accomplished by inserting a temperature probe onto the surface of the hardware. PMID- 26764339 TI - The EJCTS publication family is growing: the appointment of new editors for ICVTS and MMCTS. PMID- 26764340 TI - Pharmacokinetics of Intraperitoneal Cefalothin and Cefazolin in Patients Being Treated for Peritoneal Dialysis-Associated Peritonitis. AB - ? BACKGROUND: The standard treatment of peritoneal dialysis (PD)-associated peritonitis (PD-peritonitis) is intraperitoneal (IP) administration of antibiotics. Only limited data on the pharmacokinetics and appropriateness of contemporary dose recommendations of IP cefalothin and cefazolin exist. The aim of this study was to describe the pharmacokinetics of IP cefalothin and cefazolin in patients treated for PD-peritonitis. ? METHODS: As per international guidelines, IP cefalothin or cefazolin 15 mg/kg once daily was dosed with gentamicin in a 6-hour dwell to patients with PD-peritonitis during routine care. Serial plasma and PD effluent samples were collected over the first 24 hours of therapy. Antibiotic concentrations were quantified using a validated chromatographic method with pharmacokinetic analysis performed using a non compartmental approach. ? RESULTS: Nineteen patients were included (cefalothin n = 8, cefazolin n = 11). The median bioavailability for both antibiotics exceeded 92%, but other pharmacokinetic parameters varied markedly between antibiotics. Both antibiotics achieved high PD effluent concentrations throughout the antibiotic dwell. Cefazolin had a smaller volume of distribution compared with cefalothin (14 vs 40 L, p = 0.003). The median trough total plasma antibiotic concentration for cefazolin and cefalothin during the dwell differed (plasma 56 vs 13 mg/L, p < 0.0001) despite a similar concentration in PD effluent (37 vs 38 mg/L, p = 0.58). Lower antibiotic concentrations were noted during PD dwells not containing antibiotic, particularly cefalothin, which was frequently undetectable in plasma and PD effluent. The median duration that the unbound antibiotic concentration was above the minimum inhibitory concentration (MIC) was approximately 13% (plasma) and 25% (IP) for cefalothin, and 100% (plasma and IP) for cefazolin, of the dosing interval. ? CONCLUSIONS: When IP cefalothin or cefazolin is allowed to dwell for 6 hours, sufficient PD effluent concentrations are present for common pathogens during this time. However, with once-daily IP dosing, in contrast to cefazolin, there is a risk of subtherapeutic plasma and PD effluent cefalothin concentrations, so more frequent dosing may be required. PMID- 26764341 TI - Center-Specific Factors Associated with Peritonitis Risk-A Multi-Center Registry Analysis. AB - ? BACKGROUND: Previous studies have reported significant variation in peritonitis rates across dialysis centers. Limited evidence is available to explain this variability. The aim of this study was to assess center-level predictors of peritonitis and their relationship with peritonitis rate variations. ? METHODS: All incident peritoneal dialysis (PD) patients treated in Australia between October 2003 and December 2013 were included. Data were accessed through the Australia and New Zealand Dialysis and Transplant Registry. The primary outcome was peritonitis rate, evaluated in a mixed effects negative binomial regression model. Peritonitis-free survival was assessed as a secondary outcome in a Cox proportional hazards model. ? RESULTS: Overall, 8,711 incident PD patients from 51 dialysis centers were included in the study. Center-level predictors of lower peritonitis rates included smaller center size, high proportion of PD, low peritoneal equilibration test use at PD start, and low proportion of hospitalization for peritonitis. In contrast, a low proportion of automated PD exposure, high icodextrin exposure and low or high use of antifungal prophylaxis at the time of peritonitis were associated with a higher peritonitis rate. Similar results were obtained for peritonitis-free survival. Overall, accounting for center-level characteristics appreciably decreased peritonitis variability among dialysis centers (p = 0.02). ? CONCLUSION: This study identified specific center-level characteristics associated with the variation in peritonitis risk. Whether these factors are directly related to peritonitis risk or surrogate markers for other center characteristics is uncertain and should be validated in further studies. PMID- 26764342 TI - Analysis of Ultrafiltration Failure Diagnosed at the Initiation of Peritoneal Dialysis with the Help of Peritoneal Equilibration Tests with Complete Drainage at Sixty Minutes. A Longitudinal Study. AB - ? BACKGROUND: Ultrafiltration failure (UFF) diagnosed at the initiation of peritoneal dialysis (PD) has been insufficiently characterized. In particular, few longitudinal studies have analyzed the time course of water transport in patients with this complication. ? OBJECTIVE: To investigate the time course of peritoneal water transport during the first year on PD in patients presenting UFF since the initiation of this therapy (study group). ? METHOD: Prospective, observational, single-center design. We analyzed, at baseline and after 1 year of follow-up, peritoneal water transport in 19 patients incident on PD with UFF. We used incident patients without UFF as a control group. Water transport was characterized with the help of 3.86/4.25% dextrose-based peritoneal equilibration tests (PETs) with complete drainage at 60 minutes. ? RESULTS: The study group revealed a disorder of water transport affecting both small-pore ultrafiltration (SPUF) (p = 0.054 vs incident without UFF) and free water transport (FWT) (p = 0.001). After 1 year of follow-up, FWT displayed a general increasing trend in the study group (mean variation 48.9 mL, 95% confidence interval [CI] 15.5, 82.2, p = 0.012), while the behavior of SPUF was less predictable (-4.8 mL, 95% CI 61.4, 71.1, p = 0.85). These changes were not observed in incident patients without UFF. Neither initial clinical characteristics, baseline PET-derived parameters, or suffering peritoneal infections during the first year predicted the time course of the capacity of UF in the study group. Recovery from incident UFF was apparently linked to improvement of SPUF. ? CONCLUSIONS: Patients with UFF at the start of PD suffer a disorder of peritoneal water transport affecting both FWT and SPUF. Free water transport increases systematically in these patients after 1 year of follow-up. The evolution of SPUF is less predictable, and improvement of this parameter marks reversibility of this complication. PMID- 26764343 TI - A Survey of Hospice Volunteer Coordinators: Training Methods and Objectives of Current Hospice Volunteer Training Programs. AB - INTRODUCTION: Currently more than 5800 hospice organizations operate in the United States.1 Hospice organizations are required by the Centers for Medicare and Medicaid Services (CMS) to use volunteers for services provided to patients.2 Although CMS regulates the amount of hours hospice volunteers should provide, there are currently no national requirements for objectives of training.3 The purpose of this study was to gather information from a sample of hospices regarding volunteer coordinator background, current training for volunteers, importance of training objectives, and any comments regarding additional objectives. METHODS: Representative state hospice organizations were contacted by e-mail requesting their participation and distribution of the survey throughout their member hospices. The survey asked demographical questions, along with ratings of training components based on perceived level of importance and time spent on each objective. RESULTS: A total of 90 surveys were received, and the response rate was undeterminable. Results showed the majority of hospices were nonprofit, had less than 100 currently trained volunteers, and maintained an average daily patient census of less than 50. Questions regarding training programs indicated that most use live lecture methods of approximately 19 hours or less in duration. Overall, responding hospice organizations agreed that all objectives surveyed were important in training volunteers. CONCLUSION: The small number of respondents to this survey makes generalization nationwide difficult, however it is a strong starting point for the development of further surveys on hospice volunteer training and achieving a standardized set of training objectives and delivery methods. PMID- 26764344 TI - Development of a Scale to Assess Physician Advance Care Planning Self-Efficacy. AB - BACKGROUND: Although patients prefer that physicians initiate advance care planning (ACP) conversations, few physicians regularly do so. Physicians may be reluctant to initiate ACP conversations because they lack self-efficacy in their skills. Yet, no validated scale on self-efficacy for ACP exists. Our objective was to develop a scale that measures physicians' ACP self-efficacy (ACP-SE) and to investigate the validity of the tool. METHODS: Electronic questionnaires were administered to a random sample of family medicine physicians (n = 188). Exploratory factor analysis was performed to determine whether the scale was multidimensional. An initial assessment of the scale's validity was also conducted. RESULTS: The exploratory factor analysis indicated that a single factor was appropriate using all 17 items. A single, unidimensional scale was created by averaging the 17 items, yielding good internal consistency (Cronbach alpha = 0.95). The average scale score was 3.94 (standard deviation = 0.71) on a scale from 1 to 5. The scale was moderately correlated with a global single-item measure of self-efficacy for ACP ( r = .79, P < .001), and the scale differentiated between physician groups based on how much ACP they were doing, how recently they had an ACP conversation, formal training on ACP, and knowledge of ACP. In a multivariate analysis, the ACP-SE scale was a strong predictor of the percentage of patients with chronic life-limiting diseases with whom the physician discussed ACP. CONCLUSION: The final ACP-SE scale included 17 items and demonstrated high internal consistency. PMID- 26764345 TI - Effectiveness of Percutaneous Celiac Plexus Ablation in the Treatment of Severe Cancer Pain in Upper Abdomen and Evaluation of Health Economics. AB - OBJECTIVE: To compare the effectiveness, adverse effects, and cost-effectiveness of percutaneous neurolytic celiac plexus block (NCPB) versus traditional medication strategies for the treatment of patients with advanced cancer having severe upper abdominal cancer pain. METHODS: This retrospective study included 81 patients with advanced upper abdominal cancer admitted to The Sixth People's Hospital Affiliated to Shanghai Jiaotong University between January 2013 and July 2014. The patients were divided into percutaneous NCPB (treatment) and medication for pain (control) groups. The outcomes were measured in terms of Numeric Rating Scale (NRS) score and Karnofsky Performance Status (KPS) score before treatment and on the 3rd, 7th, 14th, and 28th days posttreatment. The effectiveness and cost-effectiveness of the therapy were assessed using analysis of the health economics. RESULTS: The improvements in NRS score (1.42 +/- 1.09 vs 4.03 +/- 0.96, P < .01) and KPS score (65.55 +/- 9.09 vs 63.03 +/- 8.961, P < .01) in the treatment group were significantly superior compared to the control group on the 7th day of treatment, followed by no significant difference between the 2 groups on the 14th and the 28th day of treatment. Health economics evaluation revealed that the medicine-specific costs and total health care costs were significantly reduced in the treatment group compared to the control group ( P < .05), but no significant differences between the 2 groups ( P > .05) were seen in the costs of hospitalization, examinations, and treatment. CONCLUSION: The percutaneous NCPB method shows promising results and better cost-effectiveness for treating patients with advanced cancer having severe upper abdominal pain. PMID- 26764346 TI - "I Told Myself to Stay Positive" Perceptions of Coping Among Latinos With a Cancer Diagnosis Living in the United States. AB - PURPOSE: This study contributes to the sparse body of literature examining perceptions of coping among Latino men and women with a cancer diagnosis living in the United States. There are currently 50 million Latinos in the United States and, by 2050, projected to grow to 128 million. Although some research indicates that Latinos have unique sociocultural beliefs that influence their cancer care, very little is known about their perceptions of coping after being diagnosed with cancer. We examined Latino men and women's perceptions of coping to understand the meaning of their experience with cancer Method: Using criterion sampling technique, 60 immigrant and migrant Latino men and women diagnosed with cancer within the past 5 years were recruited from community-based organizations, clinics, and churches. The study consisted of 60- to 90-minute semistructured interviews asking open-ended questions pertaining to coping. The qualitative design facilitated an understanding of coping within the participants' social and cultural contexts. RESULTS: Median age of the participants was 55 years. Among the women, 80% had breast cancer; 12% had ovarian cancer; and 8% had throat, thyroid, stomach, or skin cancers. Among the men, 94% had prostate cancer and 6% had brain, colorectal, or lung cancers. Emerging themes associated with the development of coping strategies involved positive reframing, family support, religion and spirituality, and support from health care providers. The term "positive reframing" relates to finding meaning and positive emotions that help sustain the coping process, despite having a cancer diagnosis. In addition, when medical and helping professionals provided tangible support, participants engaged in meaning-based coping. CONCLUSION: This study provides insights regarding the existing coping strategies which Latinos utilize and provides clinician-tangible information pertaining to participant's engagement in meaning-based coping. Family support facilitated coping among the Latino men and women. The role of religion and spirituality in the lives of the participants enabled them to cope with the cancer diagnosis. Future research is necessary to examine coping strategies regarding specific cancers at end of life. PMID- 26764347 TI - Human Endometrial Exosomes Contain Hormone-Specific Cargo Modulating Trophoblast Adhesive Capacity: Insights into Endometrial-Embryo Interactions. AB - Embryo implantation into receptive endometrium requires synergistic endometrial blastocyst interactions within the uterine cavity and is essential for establishing pregnancy. We demonstrate that exosomes (40-150 nm nanovesicles) released from endometrial epithelial cells are an important component of these interactions. We defined the proteome of purified endometrial epithelial-derived exosomes (Exos) influenced by menstrual cycle hormones estrogen (E; proliferative phase) and estrogen plus progesterone (EP; receptive phase) and examined their potential to modify trophoblast function. E-/EP-Exos were uniquely enriched with 254 and 126 proteins, respectively, with 35% newly identified proteins not previously reported in exosome databases. Importantly, EP-Exos protein cargo was related to fundamental changes in implantation: adhesion, migration, invasion, and extracellular matrix remodeling. These findings from hormonally treated ECC1 endometrial cancer cells were validated in human primary uterine epithelial cell derived exosomes. Functionally, exosomes were internalized by human trophoblast cells and enhanced their adhesive capacity, a response mediated partially through active focal adhesion kinase (FAK) signaling. Thus, exosomes contribute to the endometrial-embryo interactions within the human uterine microenvironment essential for successful implantation. PMID- 26764348 TI - Maternal Smoke Exposure Impairs the Long-Term Fertility of Female Offspring in a Murine Model. AB - The theory of fetal origins of adult disease was first proposed in 1989, and in the decades since, a wide range of other diseases from obesity to asthma have been found to originate in early development. Because mammalian oocyte development begins in fetal life it has been suggested that environmental and lifestyle factors of the mother could directly impact the fertility of subsequent generations. Cigarette smoke is a known ovotoxicant in active smokers, yet disturbingly 13% of Australian and 12% of US women continue to smoke throughout pregnancy. The focus of our investigation was to characterize the adverse effects of smoking on ovary and oocyte quality in female offspring exposed in utero. Pregnant mice were nasally exposed to cigarette smoke for 12 wk throughout pregnancy/lactation, and ovary and oocyte quality of the F1 (maternal smoke exposed) generation was examined. Neonatal ovaries displayed abnormal somatic cell proliferation and increased apoptosis, leading to a reduction in follicle numbers. Further investigation found that altered somatic cell proliferation and reduced follicle number continued into adulthood; however, apoptosis did not. This reduction in follicles resulted in decreased oocyte numbers, with these oocytes found to have elevated levels of oxidative stress, altered metaphase II spindle, and reduced sperm-egg interaction. These ovarian and oocyte changes ultimately lead to subfertility, with maternal smoke-exposed animals having smaller litters and also taking longer to conceive. In conclusion, our results demonstrate that in utero and lactational exposure to cigarette smoke can have long-lasting effects on the fertility of the next generation of females. PMID- 26764349 TI - Assisted Reproduction Causes Reduced Fetal Growth Associated with Downregulation of Paternally Expressed Imprinted Genes That Enhance Fetal Growth in Mice. AB - Alteration of intrauterine growth trajectory is linked to metabolic diseases in adulthood. In mammalian and, specifically, human species, pregnancies through assisted reproductive technology (ART) are associated with changes in intrauterine growth trajectory. However, it is still unclear how ART alters intrauterine growth trajectory, especially reduced fetal growth in early to midgestation. In this study, using a mouse model, it was found that ART procedures reduce fetal and placental growth at Embryonic Day 10.5. Furthermore, ART leads to decreased methylation levels at H19, KvDMR1, and Snrpn imprinting control regions in the placentae, instead of fetuses. Furthermore, in the placenta, ART downregulated a majority of parentally expressed imprinted genes, which enhance fetal growth, whereas it upregulated a majority of maternally expressed genes which repress fetal growth. Additionally, the expression of genes that regulate placental development was also affected by ART. ART also downregulated a majority of placental nutrient transporters. Disruption of genomic imprinting and abnormal expression of developmentally and functionally relevant genes in placenta may influence the placental development and function, which affect fetal growth and reprogramming. PMID- 26764351 TI - Tibial lengthening over intramedullary nails: A matched case comparison with Ilizarov tibial lengthening. AB - OBJECTIVES: The purpose of this study was to compare the results and complications of tibial lengthening over an intramedullary nail with treatment using the traditional Ilizarov method. METHODS: In this matched case study, 16 adult patients underwent 19 tibial lengthening over nails (LON) procedures. For the matched case group, 17 patients who underwent 19 Ilizarov tibial lengthenings were retrospectively matched to the LON group. RESULTS: The mean external fixation time for the LON group was 2.6 months and for the matched case group was 7.6 months. The mean lengthening amounts for the LON and the matched case groups were 5.2 cm and 4.9 cm, respectively. The radiographic consolidation time in the LON group was 6.6 months and in the matched case group 7.6 months. Using a clinical and radiographic outcome score that was designed for this study, the outcome was determined to be excellent in 17 and good in two patients for the LON group. The outcome was excellent in 14 and good in five patients in the matched case group. The LON group had increased blood loss and increased cost. The LON group had four deep infections; the matched case group did not have any deep infections. CONCLUSIONS: The outcomes in the LON group were comparable with the outcomes in the matched case group. The LON group had a shorter external fixation time but experienced increased blood loss, increased cost, and four cases of deep infection. The advantage of reducing external fixation treatment time may outweigh these disadvantages in patients who have a healthy soft-tissue envelope.Cite this article: J. E. Herzenberg. Tibial lengthening over intramedullary nails: A matched case comparison with Ilizarov tibial lengthening. Bone Joint Res 2016;5:1-10. doi: 10.1302/2046-3758.51.2000577. PMID- 26764353 TI - 'Sideline Guidelines' by Cleveland Clinic Innovations: a smartphone application for the on-field healthcare practitioner. PMID- 26764350 TI - Ggnbp2 Is Essential for Pregnancy Success via Regulation of Mouse Trophoblast Stem Cell Proliferation and Differentiation. AB - The Ggnbp2 null mutant embryos died in utero between Embryonic Days 13.5 to 15.5 with dysmorphic placentae, characterized by excessive nonvascular cell nests consisting of proliferative trophoblastic tissue and abundant trophoblast stem cells (TSCs) in the labyrinth. Lethality of Ggnbp2 null embryos was caused by insufficient placental perfusion as a result of remarkable decreases in both fetal and maternal blood vessels in the labyrinth. These defects were accompanied by a significant elevation of c-Met expression and phosphorylation and its downstream effector Stat3 activation. Knockdown of Ggnbp2 in wild-type TSCs in vitro provoked the proliferation but delayed the differentiation with an upregulation of c-Met expression and an enhanced phosphorylation of c-Met and Stat3. In contrast, overexpression of Ggnbp2 in wild-type TSCs exhibited completely opposite effects compared to knockdown TSCs. These results suggest that loss of GGNBP2 in the placenta aberrantly overactivates c-Met-Stat3 signaling, alters TSC proliferation and differentiation, and ultimately compromises the structure of placental vascular labyrinth. Our studies for the first time demonstrate that GGNBP2 is an essential factor for pregnancy success acting through the maintenance of a balance of TSC proliferation and differentiation during placental development. PMID- 26764355 TI - Postibrutinib outcomes in patients with mantle cell lymphoma. AB - Despite unprecedented clinical activity in mantle cell lymphoma (MCL), primary and acquired resistance to ibrutinib is common. The outcomes and ideal management of patients who experience ibrutinib failure are unclear. We performed a retrospective cohort study of all patients with MCL who experienced disease progression while receiving ibrutinib across 15 international sites. Medical records were evaluated for clinical characteristics, pathological and radiological data, and therapies used pre- and postibrutinib. A total of 114 subjects met eligibility criteria. The median number of prior therapies was 3 (range, 0-10). The Mantle Cell Lymphoma International Prognostic Index (MIPI) scores at the start of ibrutinib were low, intermediate, and high in 46%, 31%, and 23% of patients, respectively. Of patients with available data prior to ibrutinib and postibrutinib, 34 of 47 and 11 of 12 had a Ki67 >30%. The median time on ibrutinib was 4.7 months (range 0.7-43.6). The median overall survival (OS) following cessation of ibrutinib was 2.9 months (95% confidence interval [CI], 1.6-4.9). Of the 104 patients with data available, 73 underwent subsequent treatment an average of 0.3 months after stopping ibrutinib with a median OS of 5.8 months (95% CI, 3.7-10.4). Multivariate Cox regression analysis of MIPI before postibrutinib treatment, and subsequent treatment with bendamustine, cytarabine, or lenalidomide failed to reveal any association with OS. Poor clinical outcomes were noted in the majority of patients with primary or secondary ibrutinib resistance. We could not identify treatments that clearly improved outcomes. Future trials should focus on understanding the mechanisms of ibrutinib resistance and on treatment after ibrutinib. PMID- 26764354 TI - Timing of the loss of Pten protein determines disease severity in a mouse model of myeloid malignancy. AB - Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric mixed myelodysplastic/myeloproliferative neoplasm (MDS/MPN). JMML leukemogenesis is linked to a hyperactivated RAS pathway, with driver mutations in the KRAS, NRAS, NF1, PTPN11, or CBL genes. Previous murine models demonstrated how those genes contributed to the selective hypersensitivity of JMML cells to granulocyte macrophage-colony-stimulating factor (GM-CSF), a unifying characteristic in the disease. However, it is unclear what causes the early death in children with JMML, because transformation to acute leukemia is rare. Here, we demonstrate that loss of Pten (phosphatase and tensin homolog) protein at postnatal day 8 in mice harboring Nf1 haploinsufficiency results in an aggressive MPN with death at a murine prepubertal age of 20 to 35 days (equivalent to an early juvenile age in JMML patients). The death in the mice was due to organ infiltration with monocytes/macrophages. There were elevated activities of protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) in cells at physiological concentrations of GM-CSF. These were more pronounced in mice with Nf1 haploinsufficiency than in littermates with wild-type Nf1,but this model is insufficient to cause cells to be GM-CSF hypersensitive. This new model represents a murine MPN model with features of a pediatric unclassifiable mixed MDS/MPN and mimics many clinical manifestations of JMML in terms of age of onset, aggressiveness, and organ infiltration with monocytes/macrophages. Our data suggest that the timing of the loss of PTEN protein plays a critical role in determining the disease severity in myeloid malignancies. This model may be useful for studying the pathogenesis of pediatric diseases with alterations in the Ras pathway. PMID- 26764356 TI - Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. AB - The cumulative incidence of National Institutes of Health (NIH)-defined chronic graft-versus-host disease (GVHD) requiring systemic treatment is ~35% at 1 year after transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized blood cells from HLA-matched related or unrelated donors. We hypothesized that high-dose cyclophosphamide given after G-CSF-mobilized blood cell transplantation would reduce the cumulative 1-year incidence of chronic GVHD to 15% or less. Forty-three patients with high-risk hematologic malignancies (median age, 43 years) were enrolled between December 2011 and September 2013. Twelve (28%) received grafts from related donors, and 31 (72%) received grafts from unrelated donors. Pretransplant conditioning consisted of fludarabine and targeted busulfan (n = 25) or total body irradiation (>=12 Gy; n = 18). Cyclophosphamide was given at 50 mg/kg per day on days 3 and 4 after transplantation, followed by cyclosporine starting on day 5. The cumulative 1-year incidence of NIH-defined chronic GVHD was 16% (95% confidence interval, 5-28%). The cumulative incidence estimates of grades 2-4 and 3-4 acute GVHD were 77% and 0%, respectively. At 2 years, the cumulative incidence estimates of nonrelapse mortality and recurrent malignancy were 14% and 17%, respectively, and overall survival was projected at 70%. Of the 42 patients followed for >=1 year, 21 (50%) were relapse-free and alive without systemic immunosuppression at 1 year after transplantation. Thus, myeloablative pretransplant conditioning can be safely combined with high-dose cyclophosphamide after transplantation, and the risk of chronic GVHD associated with HLA-matched mobilized blood cell grafts can be substantially reduced. This trial was registered at www.clinicaltrials.gov as #NCT01427881. PMID- 26764358 TI - Human amniotic membrane grafts in therapy of chronic non-healing wounds. AB - BACKGROUND: Human amniotic membrane (HAM) has been embraced as a natural wound dressing almost exclusively in ophthalmology. Only recently, emergence of commercial HAM products prompted its use in growing range of indications, especially treatment of chronic non-healing wounds. SOURCES OF DATA: ClinicalTrials.gov database and International Clinical Trials Registry Platform searched with key words 'human amniotic membrane' and 'chronic wounds'. AREAS OF AGREEMENT: HAM can be successfully used as a natural wound dressing to promote healing. AREAS OF CONTROVERSY: It is still unclear, which preparation is more advantageous, cryopreserved HAM or dehydrated HAM. GROWING POINTS: There are an increasing number of commercial HAM products and clinical trials for a variety of dermatological diagnoses. AREAS TIMELY FOR DEVELOPING RESEARCH: In spite of easy procurement and low production costs, to our knowledge, there are currently only a few manufacturers of commercial HAM products tested in clinical trials for cutaneous wounds and all of them are located in the USA. PMID- 26764359 TI - Coils implanted into lungs show promise for emphysema. PMID- 26764357 TI - Influence of immunoglobulin isotype on therapeutic antibody function. AB - Monoclonal antibody (mAb) therapeutics are revolutionizing cancer treatment; however, not all tumors respond, and agent optimization is essential to improve outcome. It has become clear over recent years that isotype choice is vital to therapeutic success with agents that work through different mechanisms, direct tumor targeting, agonistic receptor engagement, or receptor-ligand blockade, having contrasting requirements. Here we summarize how isotype dictates mAb activity and discuss ways in which this information can be used for the development of enhanced therapeutics. PMID- 26764360 TI - Perinatal Risk Factors for Feeding and Eating Disorders in Children Aged 0 to 3 Years. AB - OBJECTIVE: To describe the incidence, age at diagnosis, and associations between perinatal risk factors of feeding and eating disorders (FED) diagnosed at hospital in children aged 0 to 3 years. METHODS: A nationwide cohort of 901 227 children was followed until 48 months of age in the national registers from 1997 to 2010. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) for FED diagnosis according to the International Classification of Diseases and associations with perinatal risk factors. RESULTS: A total of 1365 children (53% girls) were diagnosed with FED at hospital, corresponding to a cumulative incidence of 1.6 per 1000 live births. High risk of FED was seen in children born before gestational week 28 (HR, 3.52; 95% confidence interval [CI], 2.15-5.78). HRs were 3.74 for children small for gestational age <=3 SD (95% CI, 2.71-5.17) and 4.71 in those with congenital malformations (95% CI, 3.86-5.74). Increased risk of FED was associated with female gender (HR, 1.2; 95% CI, 1.08-1.34), maternal smoking in pregnancy (HR, 1.24; 95% CI, 1.08-1.42), immigrant status (HR, 2.24; 95% CI, 1.92-2.61), and being the firstborn (HR, 1.33; 95% CI, 1.19-1.50). CONCLUSIONS: FED in referred children aged 0 to 3 years are associated with perinatal adversities, female gender, maternal smoking in pregnancy, being firstborn, and having immigrant parents. The results suggest complex causal mechanisms of FED and underscore the need for a multidisciplinary approach in the clinical management of young children with persistent problems of feeding, eating, and weight faltering. PMID- 26764361 TI - US Poison Control Center Calls for Infants 6 Months of Age and Younger. AB - BACKGROUND: Anticipatory guidance and prevention efforts to decrease poisonings in young children have historically focused on restricting access to minimize exploratory ingestions. Because infants through 6 months of age have limited mobility, such exposures are expected to be less frequent and therapeutic (or dosing) errors should be more frequent. Although recent prevention efforts target some types of therapeutic errors, the epidemiology of these exposures is not well characterized in this age group. This could have important implications for the effectiveness of current prevention efforts. METHODS: A 10-year (2004-2013) retrospective review of exposure calls for infants through 6 months of age was conducted on National Poison Data System files. RESULTS: A total of 271 513 exposures were reported, of which 96.7% were unintentional. Of these, the most common reasons were general unintentional (50.7%), which includes exploratory exposures, and therapeutic error (36.7%). Among the latter, 47.0% involved quantitative dosing errors (a different amount than intended) and 42.8% involved nonquantitative dosing errors (a medication given twice or too soon, the wrong medication, or wrong route). Most exposures (97.5%)occurred in the home but only 85.2% of calls came from the home;80.4% ofself-referrals to a healthcare facility were not admitted. CONCLUSIONS: General unintentional (including exploratory) exposures and therapeutic errors both comprise a large proportion of calls in this age group. Among therapeutic errors, quantitative and nonquantitative dosing errors are equally concerning. There areappreciablenumbers of patients presenting to healthcare prior topoison centerconsultation. These data can help target future anticipatory guidance and prevention measures. PMID- 26764362 TI - Desirable Information of Opioids for Families of Patients With Terminal Cancer. AB - OBJECTIVE: The aims of this study are to clarify the state of information regarding opioids for families and what kinds of experiences they had with opioids while the patient was followed as an outpatient and inpatient. PARTICIPANTS: This study was part of a cross-sectional nationwide survey of bereaved families of patients with cancer, namely, the Japan Hospice and Palliative Care Evaluation 2 study. The participants in this study comprised 572 bereaved families who had experienced the death of a family member during the period from January 2008 to December 2009 at 1 of 103 certificated palliative care units. MAIN OUTCOME MEASURES: In response to the question of "how much improvement was needed for information regarding opioids," 41% answered "improvement is not necessary at all," 43% answered "improvement is slightly necessary," 14% answered "improvement is necessary," and 2% answered "improvement is extremely necessary." Regarding anxiety about the use of opioid, it was found that 14% of respondents indicated "opioids are very safe," 65% of respondents indicated "opioids are relatively safe," 19% of respondents indicated "opioids are not so safe," and 2% of respondents indicated "opioids are not so safe at all." from the information obtained for opioids. It was found that 90% of families agreed with the item, "I would like to be clearly explained that drugs for medical purposes are safe and that the patient will not develop a drug addiction and their life expectancy will not be reduced." CONCLUSION: From this study, it is important for families of patients with cancer to be explained profound and careful information of opioid. PMID- 26764363 TI - Timing and Outcome of Referral to the First Stand-Alone Palliative Care Center in the Eastern Mediterranean Region, the Palliative Care Center of Kuwait. AB - BACKGROUND: Compared to other regions of the world, palliative care (PC) in the Eastern Mediterranean region is at an earlier stage of development. The Palliative Care Center of Kuwait (PCC-K) was established a few years ago as the first stand-alone PC center in the region. This study was conducted to investigate the timing of referral to the PCC-K and its outcome. METHODS: Retrospective review of referrals to the PCC-K during its first 3 years of action. Late referral was defined as referral during the last 30 days of life. RESULTS: During the 3-year period, 498 patients with cancer were referred to the PCC-K of whom 467 were eligible for analysis. Referral was considered late in 58% of patients. Nononcology facilities were more likely to refer patients late when compared to oncology facilities ( P = .033). The palliative performance scale (PPS) was <=30 in 59% of late referrals and 21% in earlier referrals ( P < .001). Among 467 referred patients, 342 (73%) were eligible for transfer to the PCC-K, 102 (22%) were ineligible, and 23 (5%) died before assessment by the PCC-K consultation team. From the 342 eligible patients, the family caregivers refused the transfer of 64 (19%) patients to the PCC-K. CONCLUSION: Patients are frequently referred late to the PCC-K. Further research to identify barriers to PC and its early integration in Kuwait is required. The PPS may be useful in identifying late referrals. PMID- 26764365 TI - Short-Term Prognosis of Juvenile Myocardial Infarction: Role of Plasma Viscosity. PMID- 26764364 TI - TGFbeta1-Smad3-Jagged1-Notch1-Slug signaling pathway takes part in tumorigenesis and progress of tongue squamous cell carcinoma. AB - BACKGROUND: TGFbeta1 and Smad3 play an important role in the process of EMT. TGFbeta1 regulates the expression of Jagged1 by modulating Notch signaling. Jagged1 is related to tumor invasion, metastasis, chemotherapy resistance, and tumor immune escape. The aims of this study are to examine deregulation of TGFbeta1-Smad3-Jagged1-Notch1-Slug signaling in TSCC and to investigate its roles in TSCC progression. MATERIALS AND METHODS: Notch1, Smad3, Jagged1 and Slug proteins and mRNA expression were detected in specimens from 89 cases of patients. We analyzed the correlation between their expressions and histological grade, clinical stage and lymph node metastasis. RESULTS: Notch1, Smad3, Jagged1 and Slug mRNA expressions in TSCC were higher than normal tissue (P <0.05). The protein expression of Notch1 and Smad3 in TSCC were higher (chi(2) =7.30, P <0.01 and chi(2) = 5.84, P <0.05). Notch1 and Smad3 expressions were correlated with clinical stage (chi(2) =18.81, P<0.01; chi(2) =22.29, P<0.01), but not Jagged1 (chi(2) =0.53, P>0.05). The Slug protein expression was correlated with clinical stage. The positive rate of Notch1 was higher in lymph node metastases positive cases (chi(2) =7.30, P<0.01). Moreover, higher expression of Jagged1 was found in lymph node positive cases (chi(2) =10.82, P<0.01). CONCLUSIONS: The key protein expression in TGFbeta1-Smad3-Jagged1-Notch1-Slug signaling pathway significantly correlated with the clinicopathological features of TSCC patients. It's potential as a biomarker and a novel therapeutic target for TSCC patients at risk of metastasis. It may play an irreplaceable role in TSCC progression which may attribute to promoting EMT which enhances cell migration, invasion and metastasis. PMID- 26764366 TI - MyoK+ardial Infarction: Potassium Levels and Outcomes Following Acute Myocardial Infarction. PMID- 26764367 TI - Low Rates of Revascularization and High In-Hospital Mortality in Patients With Ischemic Lower Limb Amputation: Morbidity and Mortality of Ischemic Amputation. AB - BACKGROUND: To assess the nationwide contemporary burden of cardiovascular risk factors, comorbidities, and in-hospital mortality in patients with lower limb amputation (LLA) due to peripheral arterial disease and critical limb ischemia (CLI) in Germany. METHODS: German nationwide data for 2005 and 2009 were analyzed regarding in-hospital rates of major and minor ischemic LLA, risk factors, comorbidities, surgical and endovascular revascularizations, and in-hospital mortality. RESULTS: In 2005, a total of 22 479 major (7.8%) and 28 262 minor (9.8%) LLAs were performed with a relative decrease of -21.8% in major LLA, yet with a relative increase of +2% in minor LLA rate in 2009. The overall revascularization rate before amputation was 46% in 2005 and 57% in 2009. In hospital mortality for non-CLI, minor, and major amputees was 3.3%, 4.6%, and 19.8%, respectively (P < .001 for major vs minor LLA and non-CLI). CONCLUSION: The total number of ischemic LLA and amputation-related in-hospital mortality remains high in Germany in the 21st century. The poor outcome of patients with CLI might in part be due to underuse of revascularizations prior to amputation. PMID- 26764368 TI - Australian Aboriginal perspectives of attention deficit hyperactivity disorder. PMID- 26764369 TI - Large reductions in depression and anxiety via low-intensity cognitive behavioural therapy delivered by novice coach. PMID- 26764370 TI - Risk factors for repetition of a deliberate self-harm episode within seven days in adolescents and young adults: A population-level record linkage study in Western Australia. AB - OBJECTIVE: The risk of repetition of deliberate self-harm peaks in the first 7 days after a deliberate self-harm episode. However, thus far no studies have examined the risk factors for repeating deliberate self-harm during this short term period. We aimed to investigate the effects of socio-demographic factors, self-harm method and mental health factors in adolescents (10-19 years old) and young adults (20-29 years old). METHODS: We used data linkage of population-wide administrative records from hospital inpatients and emergency departments to identify all the deliberate self-harm-related episodes that occurred in adolescents and young adults in Western Australia from 2000 to 2011. Logistic regression with generalised estimating equations was used for the analyses. RESULTS: The incidence of repeating deliberate self-harm within the first 7 days after an index episode was 6% (403/6,768) in adolescents and 8% (842/10,198) in young adults. Socio-demographic risk factors included female gender and socioeconomic disadvantage. Compared with non-poisoning, self-poisoning predicted increased risk of having a repeated deliberate self-harm episode in males, but not in females. Borderline personality, impulse-control and substance use disorders diagnosed within one week before and one week after an index deliberate self-harm episode conferred the highest risk, followed by depressive and anxiety disorders. Having a preceding deliberate self-harm episode up to 7 days before an index episode was a strong predictor for the future repetition of a deliberate self-harm episode. CONCLUSION: Having a repeated deliberate self-harm episode within the first 7 days was related to a wide range of factors present at an index deliberate self-harm episode including socio-demographic characteristics, deliberate self-harm method and co-existing psychiatric conditions. These factors can inform risk assessments tailored to adolescents and young adults respectively to reduce the repetition of deliberate self-harm within a short but critical period, potentially contributing to reduce the repetition of deliberate self-harm in the long term. PMID- 26764372 TI - How common is bipolar disorder in general primary care attendees? A systematic review and meta-analysis investigating prevalence determined according to structured clinical assessments. AB - OBJECTIVE: There are mounting calls for bipolar disorder to be managed in primary care, yet the exact prevalence remains unclear. We conducted a meta-analysis to investigate the prevalence of bipolar disorder in general primary care attendees without other comorbid psychiatric diagnosis. METHOD: We systematically searched major electronic databases from inception till 03/2015. Articles were included that reported the prevalence of bipolar disorder determined in line with structured clinical assessment in primary care settings. Two independent authors conducted searches, completed methodological appraisal and extracted data. A random effects meta-analysis and meta-regression were performed. RESULTS: Sixteen studies were included accounting for 425,691 participants (mean age = 41.1 years [standard deviation = 7.2 years] 33.3% males). Overall, the global prevalence of bipolar disorder was 1.9% (95% confidence interval = [0.6, 5.4]). The prevalence of bipolar disorder in studies recording a current diagnosis was 3.7% (95% confidence interval = [1.9, 6.0]) and 0.7% (95% confidence interval = [0.2, 1.5]) in studies considering a 12-month period. A diagnosis of bipolar disorder appeared higher in North America (3.7%, 95% confidence interval = [0.9, 8.1]) compared to Europe (0.8%, 95% confidence interval = [0.3, 1.5]). Meta-regression suggests that a more recent publication date (co-efficient = 0.089, 95% confidence interval = [0.0173, 0.1654], z = 2.19, p = 0.01, R(2) = 0.21) and younger age of participants (co-efficient -0.0851, 95% confidence interval = [ 0.1696, 0.005], z = -1.97, p = 0.04, R(2) = 0.24) moderated a higher prevalence of bipolar disorder. CONCLUSION: The global prevalence of bipolar disorder in primary care is 1.9%, with potentially higher prevalence rates in North America compared to Europe. A more recent study publication date is a significant predictor of higher prevalence of bipolar disorder. Potential reasons/drivers of this are considered within the text. PMID- 26764371 TI - Suicidal behaviours: Prevalence estimates from the second Australian Child and Adolescent Survey of Mental Health and Wellbeing. AB - OBJECTIVE: To (1) estimate the lifetime and 12-month prevalence of suicidal behaviours in Australian young people aged 12-17 years, (2) describe their co morbidity with mental illness and (3) describe the co-variation of these estimates with social and demographic variables. METHOD: A national random sample of children aged 4-17 years was recruited in 2013-2014. The response rate to the survey was 55% with 6310 parents and carers of eligible households participating. In addition, of the 2967 young people aged 11-17 years in these households, 89% (2653) of the 12- to 17-year-olds completed a self-report questionnaire that included questions about suicidal behaviour. RESULTS: In any 12-month period, about 2.4% or 41,400 young people would have made a suicide attempt. About 7.5% of 12- to 17-year-olds report having suicidal ideation, 5.2% making a plan and less than 1% (0.6%) receiving medical treatment for an attempt. The presence of a mental disorder shows the largest significant association with lifetime and 12 month suicidal behaviour, along with age, gender, sole parent family status and poor family functioning. Of young people with a major depressive disorder, 19.7% reported making a suicide attempt within the previous 12 months. There are also significant elevations in the proportions of young people reporting suicidal behaviour who have anxiety and conduct disorders. CONCLUSION: Mental disorders should be a leading intervention point for suicide prevention both in the primary health sector and in the mental health sector specifically. The associations examined here also suggest that efforts to assist sole parent and/or dysfunctional families would be worthy areas in which to target these efforts. PMID- 26764373 TI - Cultural Influences in Women-Friendly Labor-Saving Hand Tool Designs: The Milk Churner Case. AB - OBJECTIVE: The aim of this study was to highlight the importance of culture in sustainable, labor-saving solutions design for women in low-resource settings. BACKGROUND: One of the reasons behind the gender asset gap among Sub-Saharan African women is the higher labor burden these women face, making it difficult for them to produce for the home and markets. Hand tools are the simplest form and therefore the best first step to address this problem. But designing women friendly (sustainable) hand tools calls for better understanding of the low resource settings where these women reside. METHOD: A milk churner was redesigned using a human-centered (participatory) approach with groups of women from two dominant ethnolinguistic groups of Bantu and Nilotic of Uganda, and its usability was tested. RESULTS: The churner reduced labor up to eightfold and has potential to expand the range of uses to include children and husbands due to its simplicity. Also, the churner significantly reduced undesirable health effects, like pain in knee joints. Based on the experience with the churner, a six-item "survival guide" is proposed to complement human-centered design guiding principles for facilitating the generation of solutions in low-resource settings. CONCLUSION: By paying great attention to culture in relation to human factors, a labor-reducing churner has been successfully introduced among Ugandan women. The ultimate goal is to make the churner available to female smallholder dairy farming households throughout Sub-Saharan Africa. APPLICATIONS: This study provides a survival guide for generating solutions to problems from low-resource settings. PMID- 26764376 TI - The Transmembrane Region of Guard Cell SLAC1 Channels Perceives CO2 Signals via an ABA-Independent Pathway in Arabidopsis. AB - The guard cell S-type anion channel, SLOW ANION CHANNEL1 (SLAC1), a key component in the control of stomatal movements, is activated in response to CO2 and abscisic acid (ABA). Several amino acids existing in the N-terminal region of SLAC1 are involved in regulating its activity via phosphorylation in the ABA response. However, little is known about sites involved in CO2 signal perception. To dissect sites that are necessary for the stomatal CO2 response, we performed slac1 complementation experiments using transgenic plants expressing truncated SLAC1 proteins. Measurements of gas exchange and stomatal apertures in the truncated transgenic lines in response to CO2 and ABA revealed that sites involved in the stomatal CO2 response exist in the transmembrane region and do not require the SLAC1 N and C termini. CO2 and ABA regulation of S-type anion channel activity in guard cells of the transgenic lines confirmed these results. In vivo site-directed mutagenesis experiments targeted to amino acids within the transmembrane region of SLAC1 raise the possibility that two tyrosine residues exposed on the membrane are involved in the stomatal CO2 response. PMID- 26764375 TI - Reconstitution of CO2 Regulation of SLAC1 Anion Channel and Function of CO2 Permeable PIP2;1 Aquaporin as CARBONIC ANHYDRASE4 Interactor. AB - Dark respiration causes an increase in leaf CO2 concentration (Ci), and the continuing increases in atmospheric [CO2] further increases Ci. Elevated leaf CO2 concentration causes stomatal pores to close. Here, we demonstrate that high intracellular CO2/HCO3 (-) enhances currents mediated by the Arabidopsis thaliana guard cell S-type anion channel SLAC1 upon coexpression of any one of the Arabidopsis protein kinases OST1, CPK6, or CPK23 in Xenopus laevis oocytes. Split ubiquitin screening identified the PIP2;1 aquaporin as an interactor of the betaCA4 carbonic anhydrase, which was confirmed in split luciferase, bimolecular fluorescence complementation, and coimmunoprecipitation experiments. PIP2;1 exhibited CO2 permeability. Mutation of PIP2;1 in planta alone was insufficient to impair CO2- and abscisic acid-induced stomatal closing, likely due to redundancy. Interestingly, coexpression of betaCA4 and PIP2;1 with OST1-SLAC1 or CPK6/23-SLAC1 in oocytes enabled extracellular CO2 enhancement of SLAC1 anion channel activity. An inactive PIP2;1 point mutation was identified that abrogated water and CO2 permeability and extracellular CO2 regulation of SLAC1 activity. These findings identify the CO2-permeable PIP2;1 as key interactor of betaCA4 and demonstrate functional reconstitution of extracellular CO2 signaling to ion channel regulation upon coexpression of PIP2;1, betaCA4, SLAC1, and protein kinases. These data further implicate SLAC1 as a bicarbonate-responsive protein contributing to CO2 regulation of S-type anion channels. PMID- 26764374 TI - An Indexed, Mapped Mutant Library Enables Reverse Genetics Studies of Biological Processes in Chlamydomonas reinhardtii. AB - The green alga Chlamydomonas reinhardtii is a leading unicellular model for dissecting biological processes in photosynthetic eukaryotes. However, its usefulness has been limited by difficulties in obtaining mutants in specific genes of interest. To allow generation of large numbers of mapped mutants, we developed high-throughput methods that (1) enable easy maintenance of tens of thousands of Chlamydomonas strains by propagation on agar media and by cryogenic storage, (2) identify mutagenic insertion sites and physical coordinates in these collections, and (3) validate the insertion sites in pools of mutants by obtaining >500 bp of flanking genomic sequences. We used these approaches to construct a stably maintained library of 1935 mapped mutants, representing disruptions in 1562 genes. We further characterized randomly selected mutants and found that 33 out of 44 insertion sites (75%) could be confirmed by PCR, and 17 out of 23 mutants (74%) contained a single insertion. To demonstrate the power of this library for elucidating biological processes, we analyzed the lipid content of mutants disrupted in genes encoding proteins of the algal lipid droplet proteome. This study revealed a central role of the long-chain acyl-CoA synthetase LCS2 in the production of triacylglycerol from de novo-synthesized fatty acids. PMID- 26764379 TI - Self-esteem, social participation, and quality of life in patients with multiple sclerosis. AB - The aim of this study is to explore whether self-esteem and social participation are associated with the physical and mental quality of life (Physical Component Summary, Mental Component Summary) and whether self-esteem can mediate the association between these variables. We collected information from 118 consecutive multiple sclerosis patients. Age, gender, disease duration, disability status, and participation were significant predictors of Physical Component Summary, explaining 55.4 percent of the total variance. Self-esteem fully mediated the association between social participation and Mental Component Summary (estimate/standard error = -4.872; p < 0.001) and along with disability status explained 48.3 percent of the variance in Mental Component Summary. These results can be used in intervention and educational programs. PMID- 26764378 TI - Arabidopsis RNASE THREE LIKE2 Modulates the Expression of Protein-Coding Genes via 24-Nucleotide Small Interfering RNA-Directed DNA Methylation. AB - RNaseIII enzymes catalyze the cleavage of double-stranded RNA (dsRNA) and have diverse functions in RNA maturation. Arabidopsis thaliana RNASE THREE LIKE2 (RTL2), which carries one RNaseIII and two dsRNA binding (DRB) domains, is a unique Arabidopsis RNaseIII enzyme resembling the budding yeast small interfering RNA (siRNA)-producing Dcr1 enzyme. Here, we show that RTL2 modulates the production of a subset of small RNAs and that this activity depends on both its RNaseIII and DRB domains. However, the mode of action of RTL2 differs from that of Dcr1. Whereas Dcr1 directly cleaves dsRNAs into 23-nucleotide siRNAs, RTL2 likely cleaves dsRNAs into longer molecules, which are subsequently processed into small RNAs by the DICER-LIKE enzymes. Depending on the dsRNA considered, RTL2-mediated maturation either improves (RTL2-dependent loci) or reduces (RTL2 sensitive loci) the production of small RNAs. Because the vast majority of RTL2 regulated loci correspond to transposons and intergenic regions producing 24 nucleotide siRNAs that guide DNA methylation, RTL2 depletion modifies DNA methylation in these regions. Nevertheless, 13% of RTL2-regulated loci correspond to protein-coding genes. We show that changes in 24-nucleotide siRNA levels also affect DNA methylation levels at such loci and inversely correlate with mRNA steady state levels, thus implicating RTL2 in the regulation of protein-coding gene expression. PMID- 26764377 TI - The LSM1-7 Complex Differentially Regulates Arabidopsis Tolerance to Abiotic Stress Conditions by Promoting Selective mRNA Decapping. AB - In eukaryotes, the decapping machinery is highly conserved and plays an essential role in controlling mRNA stability, a key step in the regulation of gene expression. Yet, the role of mRNA decapping in shaping gene expression profiles in response to environmental cues and the operating molecular mechanisms are poorly understood. Here, we provide genetic and molecular evidence that a component of the decapping machinery, the LSM1-7 complex, plays a critical role in plant tolerance to abiotic stresses. Our results demonstrate that, depending on the stress, the complex from Arabidopsis thaliana interacts with different selected stress-inducible transcripts targeting them for decapping and subsequent degradation. This interaction ensures the correct turnover of the target transcripts and, consequently, the appropriate patterns of downstream stress responsive gene expression that are required for plant adaptation. Remarkably, among the selected target transcripts of the LSM1-7 complex are those encoding NCED3 and NCED5, two key enzymes in abscisic acid (ABA) biosynthesis. We demonstrate that the complex modulates ABA levels in Arabidopsis exposed to cold and high salt by differentially controlling NCED3 and NCED5 mRNA turnover, which represents a new layer of regulation in ABA biosynthesis in response to abiotic stress. Our findings uncover an unanticipated functional plasticity of the mRNA decapping machinery to modulate the relationship between plants and their environment. PMID- 26764380 TI - H3K36ac Is an Evolutionary Conserved Plant Histone Modification That Marks Active Genes. AB - In eukaryotic cells, histones are subject to a large number of posttranslational modifications whose sequential or combinatorial action affects chromatin structure and genome function. We identified acetylation at Lys-36 in histone H3 (H3K36ac) as a new chromatin modification in plants. The H3K36ac modification is evolutionary conserved in seed plants, including the gymnosperm Norway spruce (Picea abies) and the angiosperms rice (Oryza sativa), tobacco (Nicotiana tabacum), and Arabidopsis (Arabidopsis thaliana). In Arabidopsis, H3K36ac is highly enriched in euchromatin but not in heterochromatin. Genome-wide chromatin immunoprecipitation sequencing experiments revealed that H3K36ac peaks at the 5' end of genes, mainly on the two nucleosomes immediately distal to the transcription start site, independently of gene length. H3K36ac overlaps with H3K4me3 and the H2A.Z histone variant. The histone acetyl transferase GCN5 and the histone deacetylase HDA19 are required for H3K36ac homeostasis. H3K36ac and H3K36me3 show negative crosstalk, which is mediated by GCN5 and the histone methyl transferase SDG8. Although H3K36ac is associated with gene activity, we did not find a linear relationship between H3K36ac and transcript levels, suggesting that H3K36ac is a binary indicator of transcription. PMID- 26764382 TI - Utilization of a photoactivatable antigen system to examine B-cell probing termination and the B-cell receptor sorting mechanisms during B-cell activation. AB - Antigen binding to the B-cell receptor (BCR) induces several responses, resulting in B-cell activation, proliferation, and differentiation. However, it has been difficult to study these responses due to their dynamic, fast, and transient nature. Here, we attempted to solve this problem by developing a controllable trigger point for BCR and antigen recognition through the construction of a photoactivatable antigen, caged 4-hydroxy-3-nitrophenyl acetyl (caged-NP). This photoactivatable antigen system in combination with live cell and single molecule imaging techniques enabled us to illuminate the previously unidentified B-cell probing termination behaviors and the precise BCR sorting mechanisms during B cell activation. B cells in contact with caged-NP exhibited probing behaviors as defined by the unceasing extension of membrane pseudopods in random directions. Further analyses showed that such probing behaviors are cell intrinsic with strict dependence on F-actin remodeling but not on tonic BCR signaling. B-cell probing behaviors were terminated within 4 s after photoactivation, suggesting that this response was sensitive and specific to BCR engagement. The termination of B-cell probing was concomitant with the accumulation response of the BCRs into the BCR microclusters. We also determined the Brownian diffusion coefficient of BCRs from the same B cells before and after BCR engagement. The analysis of temporally segregated single molecule images of both BCR and major histocompatibility complex class I (MHC-I) demonstrated that antigen binding induced trapping of BCRs into the BCR microclusters is a fundamental mechanism for B cells to acquire antigens. PMID- 26764381 TI - Transcription factor 7-like 1 is involved in hypothalamo-pituitary axis development in mice and humans. AB - Aberrant embryonic development of the hypothalamus and/or pituitary gland in humans results in congenital hypopituitarism (CH). Transcription factor 7-like 1 (TCF7L1), an important regulator of the WNT/beta-catenin signaling pathway, is expressed in the developing forebrain and pituitary gland, but its role during hypothalamo-pituitary (HP) axis formation or involvement in human CH remains elusive. Using a conditional genetic approach in the mouse, we first demonstrate that TCF7L1 is required in the prospective hypothalamus to maintain normal expression of the hypothalamic signals involved in the induction and subsequent expansion of Rathke's pouch progenitors. Next, we reveal that the function of TCF7L1 during HP axis development depends exclusively on the repressing activity of TCF7L1 and does not require its interaction with beta-catenin. Finally, we report the identification of two independent missense variants in human TCF7L1, p.R92P and p.R400Q, in a cohort of patients with forebrain and/or pituitary defects. We demonstrate that these variants exhibit reduced repressing activity in vitro and in vivo relative to wild-type TCF7L1. Together, our data provide support for a conserved molecular function of TCF7L1 as a transcriptional repressor during HP axis development in mammals and identify variants in this transcription factor that are likely to contribute to the etiology of CH. PMID- 26764386 TI - Community-based interventions for older people with complex needs: time to think again? PMID- 26764383 TI - Directional memory arises from long-lived cytoskeletal asymmetries in polarized chemotactic cells. AB - Chemotaxis, the directional migration of cells in a chemical gradient, is robust to fluctuations associated with low chemical concentrations and dynamically changing gradients as well as high saturating chemical concentrations. Although a number of reports have identified cellular behavior consistent with a directional memory that could account for behavior in these complex environments, the quantitative and molecular details of such a memory process remain unknown. Using microfluidics to confine cellular motion to a 1D channel and control chemoattractant exposure, we observed directional memory in chemotactic neutrophil-like cells. We modeled this directional memory as a long-lived intracellular asymmetry that decays slower than observed membrane phospholipid signaling. Measurements of intracellular dynamics revealed that moesin at the cell rear is a long-lived element that when inhibited, results in a reduction of memory. Inhibition of ROCK (Rho-associated protein kinase), downstream of RhoA (Ras homolog gene family, member A), stabilized moesin and directional memory while depolymerization of microtubules (MTs) disoriented moesin deposition and also reduced directional memory. Our study reveals that long-lived polarized cytoskeletal structures, specifically moesin, actomyosin, and MTs, provide a directional memory in neutrophil-like cells even as they respond on short time scales to external chemical cues. PMID- 26764387 TI - Decreased mortality during inpatient care in The Netherlands: what are the keys to further improve health care for elderly patients? PMID- 26764384 TI - The LMO2 oncogene regulates DNA replication in hematopoietic cells. AB - Oncogenic transcription factors are commonly activated in acute leukemias and subvert normal gene expression networks to reprogram hematopoietic progenitors into preleukemic stem cells, as exemplified by LIM-only 2 (LMO2) in T-cell acute lymphoblastic leukemia (T-ALL). Whether or not these oncoproteins interfere with other DNA-dependent processes is largely unexplored. Here, we show that LMO2 is recruited to DNA replication origins by interaction with three essential replication enzymes: DNA polymerase delta (POLD1), DNA primase (PRIM1), and minichromosome 6 (MCM6). Furthermore, tethering LMO2 to synthetic DNA sequences is sufficient to transform these sequences into origins of replication. We next addressed the importance of LMO2 in erythroid and thymocyte development, two lineages in which cell cycle and differentiation are tightly coordinated. Lowering LMO2 levels in erythroid progenitors delays G1-S progression and arrests erythropoietin-dependent cell growth while favoring terminal differentiation. Conversely, ectopic expression in thymocytes induces DNA replication and drives these cells into cell cycle, causing differentiation blockade. Our results define a novel role for LMO2 in directly promoting DNA synthesis and G1-S progression. PMID- 26764388 TI - Advanced nurse practitioners in the care of frail older people: a challenge for geriatricians? PMID- 26764389 TI - Pain management in long-term care: are we finally on the right track? PMID- 26764390 TI - Predicting delirium: time to use delirium risk scores in routine practice? PMID- 26764391 TI - The risk of overweight/obesity in mid-life and late life for the development of dementia: a systematic review and meta-analysis of longitudinal studies. AB - SCOPE: it has been suggested that overweight/obesity as a risk factor for incident dementia differs between mid-life and later life. We performed a systematic review and meta-analysis of the up-to-date current literature to assess this. SEARCH METHODS: inclusion criteria included epidemiological longitudinal studies published up to September 2014, in participants without cognitive impairment based on evidence of cognitive assessment and aged 30 or over at baseline assessment with at least 2 years of follow-up. Pubmed, Medline, EMBASE, PsychInfo and the Cochrane Library were searched using combinations of the search terms: Dementia, Alzheimer disease, Vascular Dementia, Multi-Infarct Dementia, Cognitive decline, Cognitive impairment, Mild Cognitive Impairment/Obesity, Overweight, Adiposity, Waist circumference (limits: humans, English language). Handsearching of all papers meeting the inclusion criteria was performed. A random-effects model was used for the meta-analysis. RESULTS: of the 1,612 abstracts identified and reviewed, 21 completely met the inclusion criteria. Being obese below the age of 65 years had a positive association on incident dementia with a risk ratio (RR) 1.41 (95% confidence interval, CI: 1.20 1.66), but the opposite was seen in those aged 65 and over, RR 0.83 (95% CI: 0.74 0.94). CONCLUSIONS: this systematic review and meta-analysis suggests a positive association between obesity in mid-life and later dementia but the opposite in late life. Whether weight reduction in mid-life reduces risk is worthy of further study. PMID- 26764392 TI - Effectiveness and cost-effectiveness of a proactive, goal-oriented, integrated care model in general practice for older people. A cluster randomised controlled trial: Integrated Systematic Care for older People--the ISCOPE study. AB - BACKGROUND: older people often experience complex problems. Because of multiple problems, care for older people in general practice needs to shift from a 'problem-based, disease-oriented' care aiming at improvement of outcomes per disease to a 'goal-oriented care', aiming at improvement of functioning and personal quality of life, integrating all healthcare providers. Feasibility and cost-effectiveness of this proactive and integrated way of working are not yet established. DESIGN: cluster randomised trial. PARTICIPANTS: all persons aged >=75 in 59 general practices (30 intervention, 29 control), with a combination of problems, as identified with a structured postal questionnaire with 21 questions on four health domains. INTERVENTION: for participants with problems on >=3 domains, general practitioners (GPs) made an integrated care plan using a functional geriatric approach. Control practices: care as usual. OUTCOME MEASURES: (i) quality of life (QoL), (ii) activities of daily living, (iii) satisfaction with delivered health care and (iv) cost-effectiveness of the intervention at 1-year follow-up. TRIAL REGISTRATION: Netherlands trial register, NTR1946. RESULTS: of the 11,476 registered eligible older persons, 7,285 (63%) participated in the screening. One thousand nine hundred and twenty-one (26%) had problems on >=3 health domains. For 225 randomly chosen persons, a care plan was made. No beneficial effects were found on QoL, patients' functioning or healthcare use/costs. GPs experienced better overview of the care and stability, e.g. less unexpected demands, in the care. CONCLUSIONS: GPs prefer proactive integrated care. 'Horizontal' care using care plans for older people with complex problems can be a valuable tool in general practice. However, no direct beneficial effect was found for older persons. PMID- 26764393 TI - Changes in the in-hospital mortality and 30-day post-discharge mortality in acutely admitted older patients: retrospective observational study. AB - OBJECTIVES: to compare changes over time in the in-hospital mortality and the mortality from discharge to 30 days post-discharge for six highly prevalent discharge diagnoses in acutely admitted older patients as well as to assess the effect of separately analysing the in-hospital mortality and the mortality from discharge to 30 days post-discharge. STUDY DESIGN AND SETTING: retrospective analysis of Dutch hospital and mortality data collected between 2000 and 2010. SUBJECTS: the participants included 263,746 people, aged 65 years and above, who were acutely admitted for acute myocardial infarction (AMI), heart failure (HF), stroke, chronic obstructive pulmonary disease, pneumonia or hip fracture. METHODS: we compared changes in the in-hospital mortality and mortality from discharge to 30 days post-discharge in the Netherlands using a logistic- and a multinomial regression model. RESULTS: for all six diagnoses, the mortality from admission to 30 days post-discharge declined between 2000 and 2009. The decline ranged from a relative risk ratio (RRR) of 0.41 [95% confidence interval (CI) 0.38-0.45] for AMI to 0.77 [0.73-0.82] for HF. In separate analyses, the in hospital mortality decreased for all six diagnoses. The mortality from discharge to 30 days post-discharge in 2009 compared to 2000 depended on the diagnosis, and either declined, remained unchanged or increased. CONCLUSIONS: the decline in hospital mortality in acutely admitted older patients was largely attributable to the lower in-hospital mortality, while the change in the mortality from discharge to 30 days post-discharge depended on the diagnosis. Separately reporting the two rate estimates might be more informative than providing an overall hospital mortality rate. PMID- 26764394 TI - Development of a curriculum for advanced nurse practitioners working with older people with frailty in the acute hospital through a modified Delphi process. AB - BACKGROUND: advanced nurse practitioners (ANPs) are experienced nurses who undertake some activities traditionally performed by medical staff. There are four pillars of advanced practice: advanced clinical skills, leadership, education and research. ANPs are starting to specialise in the management of older adults with frailty in the acute hospital. However, the role and competencies required for this have not been well defined. This study aimed to establish an expert consensus on the role description and essential competencies for ANPs working with older people with frailty to develop a curriculum. METHODS: a literature review and workshops including multi-professional and lay representatives generated a role description and a list of 69 competencies. A modified Delphi process was then conducted with three rounds involving a panel of 31 experts including representatives from the RCN, BGS Education and Training Committee, BGS Senior Nurses and Practitioners Group, Chartered Society of Physiotherapy Older People Network, College of Occupational Therapists Older People Specialist Section and lay representatives. Consensus on the statements was established by 70% panel agreement. RESULTS: the role description reached 100% agreement within three rounds. Twenty-five essential competencies were agreed after Round 1, increasing to 43 after Round 2 and 49 after Round 3. CONCLUSION: this Delphi study has allowed, for the first time, a national panel of clinical experts and lay representatives to refine and agree a set of competencies for ANPs working with older people with frailty. It is the first step towards ensuring consistency in the training of ANPs in geriatric medicine. PMID- 26764395 TI - Analgesic prescribing patterns in Norwegian nursing homes from 2000 to 2011: trend analyses of four data samples. AB - BACKGROUND: the analgesic drug use has been reported to increase in general in nursing home patients. However, there is insufficient evidence in terms of what agents are used, variations of use over time and to whom these drugs are prescribed. OBJECTIVE: we investigated the prescribing patterns of scheduled analgesic drugs in Norwegian nursing home patients from 2000 to 2011, with the association to age, gender, cognitive function and type of nursing home unit. DESIGN: secondary analyses of four study samples (three observational studies and one randomised controlled trial). SETTING AND SUBJECTS: nursing home patients included in study samples from 2000 (n = 1,926), 2004 (n = 1,163), 2009 (n = 850) and 2011 (n = 1,858) located in 14 Norwegian counties. METHODS: trend analyses of analgesic drug prescriptions. Percentages were described using t-test, chi(2) and Mann-Whitney U test and multivariate logistic regression. RESULTS: the odds ratio for receiving any pain medication in 2011 compared with 2000 was 2.6 (95% CI 2.23 2.91), this is corresponding to a 65% increase from 34.9 to 57.6%. The paracetamol prescription increased by 113%, from 22.7% in 2000 to 48.4% in 2011. Strong opioids (fentanyl, buprenorphine, morphine, oxycodone) increased from 1.9% in 2000 to 17.9% in 2011 (P < 0.001), whereas non-steroidal anti-inflammatory drug prescription decreased, from 6.8 to 3.2%. In 2000, 2004 and 2009, people with dementia received fewer analgesics compared with patients without dementia; no differences in analgesic drug use between the groups were found in 2011. CONCLUSIONS: the analgesic drug prescription increased significantly from 2000 to 2011, especially the use of paracetamol and strong opioids. We also highlight a possible change from under-prescription of analgesic medication in people with dementia, to an equal amount compared with patients without cognitive impairment. PMID- 26764396 TI - Delirium risk stratification in consecutive unselected admissions to acute medicine: validation of externally derived risk scores. AB - BACKGROUND: reliable delirium risk stratification will aid recognition, anticipation and prevention and will facilitate targeting of resources in clinical practice as well as identification of at-risk patients for research. Delirium risk scores have been derived for acute medicine, but none has been prospectively validated in external cohorts. We therefore aimed to determine the reliability of externally derived risk scores in a consecutive cohort of older acute medicine patients. METHODS: consecutive patients aged >=65 over two 8-week periods (2010, 2012) were screened prospectively for delirium using the Confusion Assessment Method (CAM), and delirium was diagnosed using the DSM IV criteria. The reliability of existing delirium risk scores derived in acute medicine cohorts and simplified for use in routine clinical practice (USA, n = 2; Spain, n = 1; Indonesia, n = 1) was determined by the area under the receiver operating characteristic curve (AUC). Delirium was defined as prevalent (on admission), incident (occurring during admission) and any (prevalent + incident) delirium. RESULTS: among 308 consecutive patients aged >=65 (mean age/SD = 81/8 years, 164 (54%) female), existing delirium risk scores had AUCs for delirium similar to those reported in their original internal validations ranging from 0.69 to 0.76 for any delirium and 0.73 to 0.83 for incident delirium. All scores performed better than chance but no one score was clearly superior. CONCLUSIONS: externally derived delirium risk scores performed well in our independent acute medicine population with reliability unaffected by simplification and might therefore facilitate targeting of multicomponent interventions in routine clinical practice. PMID- 26764397 TI - Cardiovascular risk profile and use of statins at the age of 70 years: a comparison of two Finnish birth cohorts born 20 years apart. AB - OBJECTIVE: to compare cardiovascular morbidity and risk factor profiles of two 70 year-old cohorts of Finns examined in 1991 and 2011 and to describe prevalence of statin use according to cardiovascular risk in the later cohort. METHODS: 1920 born cohort of community-dwelling 70-year-old persons (n = 1032) participated in comprehensive health surveys, physical and laboratory examinations in the Turku Elderly Study (TUVA) during 1991-92. In 2011, identical examination pattern was performed, in a 1940-born cohort of 70-year-old persons (n = 956) from the same area. Prevalence of cardiovascular diseases (CVD) and risk factors in the two cohorts was compared. Further, each cohort was divided into three cardiovascular risk groups (high, moderate and low) based on their estimated risk. Prevalence of statin use was calculated among each risk group in the 1940 cohort. RESULTS: coronary heart disease (25 versus 11%) and peripheral artery disease (9 versus 2%) were more common in the 1920 than 1940 cohort, respectively. Lipid profile was worse and blood pressure higher in the earlier cohort, whereas use of statins and antihypertensives was more common in the later cohort. Forty-two per cent of the 1920 cohort and 29% of the 1940 cohort were estimated to have high cardiovascular risk. In the 1940 cohort, a total of 36% used statins. Statin use was most common among high-risk persons. CONCLUSIONS: seventy-year olds examined in 2011 had less CVD morbidity than their counterparts 20 years earlier, and their cardiovascular risk factors were better controlled which is reflected in higher use of preventive medications, such as statins and antihypertensives. PMID- 26764399 TI - Beyond METs: types of physical activity and depression among older adults. AB - BACKGROUND/OBJECTIVES: physical activity may be beneficial in reducing depression incidence among the elderly. A key unanswered question is whether certain types of physical activity are particularly associated with decreased depression incidence. We examined the relationship between quantity and type of physical activity and subsequent depression using longitudinal data from elderly adults in New York City (NYC). METHODS: we followed 3,497 adults aged 65-75 living in NYC for three years. Total physical activity was measured using the Physical Activity Scale for the Elderly (PASE) and type of physical activity was measured using a latent class analysis of PASE item responses. We used generalised estimating equations to measure the relationship between quantity and latent class of physical activity at waves 1-2 and depression at waves 2-3, controlling for wave 1 depression. RESULTS: individuals in the second highest quartile (50-75%) (odds ratio (OR) = 0.45; 95% confidence interval (CI) = 0.23, 0.88) and highest quartile of activity (OR = 0.31; 95% CI = 0.16, 0.63) had lower odds of depression. Among all subjects, athletic types (OR = 0.25; 95% CI = 0.12, 0.51) and walker types (OR = 0.58; 95% CI = 0.34, 0.99) had lower odds of depression. Among non-disabled participants, walkers (OR = 0.36; 95% CI = 0.18, 0.73), athletic types (OR = 0.14; 95% CI = 0.06, 0.32), domestic/gardening types (OR = 0.29; 95% CI = 0.12, 0.73) and domestic/gardening athletic types (OR = 0.13; 95% CI = 0.02, 0.75) had lower odds of depression. CONCLUSION: respondents who practised the highest levels of physical activity and who performed athletic activities were at lower risk for depression. Interventions aimed at promoting athletic physical activity among older adults may generate benefits for mental health. PMID- 26764400 TI - Long-term physical activity is associated with reduced arterial stiffness in older adults: longitudinal results of the SAPALDIA cohort study. AB - BACKGROUND: longitudinal analyses of physical activity (PA) and arterial stiffness in populations of older adults are scarce. We examined associations between long-term change of PA and arterial stiffness in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA). METHODS: we assessed PA in SAPALDIA 2 (2001-03) and SAPALDIA 3 (2010-11) using a short questionnaire with a cut-off of at least 150 min of moderate-to-vigorous PA per week for sufficient activity. Arterial stiffness was measured oscillometrically by means of the brachial-ankle pulse wave velocity (baPWV) in SAPALDIA 3. We used multivariable mixed linear regression models adjusted for several potential confounders in 2,605 persons aged 50-81. RESULTS: adjusted means of baPWV were significantly lower in persons with sufficient moderate-to-vigorous PA (i) in SAPALDIA 2 but not in SAPALDIA 3 (P = 0.048) and (ii) in both surveys (P = 0.001) compared with persons with insufficient activity in both surveys. There was a significant interaction between sex and the level of change in PA concerning baPWV (P = 0.03). The triples of parameter estimates describing the association between level of PA change and baPWV were not significantly different between the two sex-specific models (P = 0.07). CONCLUSIONS: keeping up or adopting a physically active lifestyle was associated with lower arterial stiffness in older adults after a follow-up of almost a decade. Increasing the proportion of older adults adhering to PA recommendations incorporating also vigorous PA may have a considerable impact on vascular health at older age and may contribute to healthy ageing in general. PMID- 26764398 TI - The Multidimensional Prognostic Index predicts in-hospital length of stay in older patients: a multicentre prospective study. AB - BACKGROUND: prediction of length of stay (LOS) may be useful to optimise care plans to reduce the negative outcomes related to hospitalisation. OBJECTIVE: to evaluate whether the Multidimensional Prognostic Index (MPI), based on a Comprehensive Geriatric Assessment (CGA), may predict LOS in hospitalised older patients. DESIGN: prospective multicentre cohort study. SETTING: twenty Geriatrics Units. PARTICIPANTS: patients aged 65 and older consecutively admitted to Geriatrics Units. MEASUREMENT: at admission, the CGA-based MPI was calculated by using a validated algorithm that included information on basal and instrumental activities of daily living, cognitive status, nutritional status, the risk of pressures sores, co-morbidity, number of drugs and co-habitation status. According to validated cut-offs, subjects were divided into three groups of risk, i.e. MPI-1 low risk (value <=0.33), MPI-2 moderate risk (value 0.34 0.66) and MPI-3 severe risk of mortality (value >=0.67). RESULTS: two thousand and thirty-three patients were included; 1,159 were women (57.0%). Age- and sex adjusted mean LOS in patients divided according to the MPI grade was MPI-1 = 10.1 (95% CI 8.6-11.8), MPI-2 = 12.47 (95% CI 10.7-14.68) and MPI-3 = 13.41 (95% CI 11.5-15.7) days (P for trend <0.001). The overall accuracy of the MPI to predict LOS was good (C-statistic 0.74, 95% CI 0.72-0.76). Moreover, a statistically significant trend of LOS means was found even in patients stratified according to their International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) main diagnosis. CONCLUSIONS: the MPI is an accurate predictor of LOS in older patients hospitalised with the most frequent diseases. PMID- 26764401 TI - Race and fall risk: data from the National Health and Aging Trends Study (NHATS). AB - OBJECTIVES: the objective of this study was to explore whether race-based difference in fall risk may be mediated by environmental and physical performance risk factors. METHODS: using data from a nationally representative longitudinal survey of 7,609 community-dwelling participants in the National Health and Aging Trends Study (NHATS), we evaluated whether racial differences in fall risk may be explained by physical performance level (measured by the Short Physical Performance Battery), mobility disability, physical activity level and likelihood of living alone. Multivariate Poisson regression and mediation models were used in analyses. RESULTS: in whites and blacks, the annual incidence of 'any fall' was 33.8 and 27.1%, respectively, and the annual incidence of 'recurrent falls' was 15.5 and 12.3%, respectively. Compared with whites, blacks had relative risks of 0.7 (95% confidence interval 0.6-0.8) and 0.6 (0.5-0.8) for sustaining any fall and recurrent falls, respectively, in adjusted analyses. Blacks had poorer performance on the SPPB (P < 0.001), higher levels of mobility disability (P < 0.001), similar levels of physical activity (P = 0.19) and were equally likely to live alone relative to whites (P = 0.77). Mediation analysis revealed that these risk factors collectively acted as suppressors and none of these factors accounted for the racial differences in fall risk observed. CONCLUSIONS: relative to whites, blacks were at 30 and 40% decreased risk of sustaining any fall and recurrent falls, respectively. This difference in risk remains unexplained. PMID- 26764402 TI - Links between depressive symptoms and unmet health and social care needs among older prisoners. AB - BACKGROUND: absolute numbers of older prisoners and their proportion of the total prison population are increasing. They have multiple health and social care needs that are prominent on entry into prison. No previous studies have identified older prisoners' health and social care needs at this crucial point. OBJECTIVE: to examine unmet health and social care needs among older men entering prison and their links with depressive symptoms. METHODS: a cross-sectional survey across nine prisons in the North of England was completed. One hundred male prisoners aged between 60 and 81 were interviewed, using the Camberwell Assessment of Need Forensic short version (CANFOR-S) and Geriatric Depression Scale-Short Form (GDS 15). Descriptive statistics were generated and chi(2) tests performed. RESULTS: participants reported high levels of unmet needs as measured with the CANFOR-S, notably in the domains of knowledge about their condition and treatment (38%); psychological distress (34%); daytime activities (29%); benefits (28%); food (22%) and physical health (21%). The mean total number of unmet needs was 2.74, with a median of 2.0. More than half the sample (56%, 95% CI 45-66%) exhibited clinical signs of depression. A significant association between depressive symptomology and an unmet physical health need, as measured by the CANFOR-S, was detected (chi(2) = 6.76, df = 1, P < 0.01). CONCLUSIONS: high levels of depressive symptoms were experienced by older prisoners on entry into prison. Personalised health and social care needs assessment and discrete depression screening are required on prison entry to facilitate effective management of unmet needs. PMID- 26764403 TI - The facilitators of communication with people with dementia in a care setting: an interview study with healthcare workers. AB - OBJECTIVES: to describe the views of healthcare workers on the facilitators of communication with people with dementia in a care setting. DESIGN: thematic analysis of semi-structured interviews. SETTING: all participants were interviewed in their place of work. PARTICIPANTS: sixteen healthcare workers whose daily work involves interacting with people with dementia. RESULTS: four overarching categories of themes were identified from the interviews that impact on communication: the attributes of a care worker, communication strategies used, organisational factors and the physical characteristics of the care environment. CONCLUSION: many strategies used by healthcare workers to facilitate communication have not yet been studied in the research literature. Participants' views on training should be incorporated into future dementia training programmes. PMID- 26764404 TI - Femoral nerve palsy associated with bilateral spontaneous iliopsoas haematomas: a complication of venous thromboembolism therapy. AB - We report a case of femoral nerve palsy occurring as a result of spontaneous bilateral iliopsoas haematomas in an elderly patient on treatment dose dalteparin for a suspected pulmonary embolus. There are limited case reports in the literature relating to this rare problem, and their management is controversial. We advocate non-operative treatment in the instance of a delayed presentation in a frail elderly patient with a subsequent good functional outcome. PMID- 26764405 TI - Front door geriatrics has much to offer. PMID- 26764406 TI - Re: Front door geriatrics has much to offer. PMID- 26764407 TI - Disease causing mutations in inverted formin 2 regulate its binding to G-actin, F actin capping protein (CapZ alpha-1) and profilin 2. AB - Focal segmental glomerulosclerosis (FSGS) is a devastating form of nephrotic syndrome which ultimately leads to end stage renal failure (ESRF). Mutations in inverted formin 2 (INF2), a member of the formin family of actin-regulating proteins, have recently been associated with a familial cause of nephrotic syndrome characterized by FSGS. INF2 is a unique formin that can both polymerize and depolymerize actin filaments. How mutations in INF2 lead to disease is unknown. In the present study, we show that three mutations associated with FSGS, E184K, S186P and R218Q, reduce INF2 auto-inhibition and increase association with monomeric actin. Furthermore using a combination of GFP-INF2 expression in human podocytes and GFP-Trap purification coupled with MS we demonstrate that INF2 interacts with profilin 2 and the F-actin capping protein, CapZ alpha-1. These interactions are increased by the presence of the disease causing mutations. Since both these proteins are involved in the dynamic turnover and restructuring of the actin cytoskeleton these changes strengthen the evidence that aberrant regulation of actin dynamics underlies the pathogenesis of disease. PMID- 26764409 TI - Mimics and chameleons of optic neuritis. AB - Optic neuritis is a common problem and most neurologists are familiar with it. Recent studies have suggested that it can be overdiagnosed in as many as 10% of cases. The major reasons for this relate to confusion regarding terminology and lack of familiarity with common mimics. This article covers typical 'idiopathic' demyelinating optic neuropathy (IDON) and several possible variations in the way it can present (chameleons). We then discuss several conditions that can mimic IDON, including neuromyelitis optica, sarcoidosis, chronic relapsing inflammatory optic neuropathy, anterior ischaemic optic neuropathy, infectious/parainfectious optic neuropathy, neuroretinitis, Leber's hereditary optic neuropathy, and some 'ocular' mimics including autoimmune retinopathy and central serous choroidoretinopathy. PMID- 26764408 TI - Intracellular NAD+ levels are associated with LPS-induced TNF-alpha release in pro-inflammatory macrophages. AB - Metabolism and immune responses have been shown to be closely linked and as our understanding increases, so do the intricacies of the level of linkage. NAD(+) has previously been shown to regulate tumour necrosis factor-alpha (TNF-alpha) synthesis and TNF-alpha has been shown to regulate NAD(+) homoeostasis providing a link between a pro-inflammatory response and redox status. In the present study, we have used THP-1 differentiation into pro- (M1-like) and anti- (M2-like) inflammatory macrophage subset models to investigate this link further. Pro- and anti-inflammatory macrophages showed different resting NAD(+) levels and expression levels of NAD(+) homoeostasis enzymes. Challenge with bacterial lipopolysaccharide, a pro-inflammatory stimulus for macrophages, caused a large, biphasic and transient increase in NAD(+) levels in pro- but not anti inflammatory macrophages that were correlated with TNF-alpha release and inhibition of certain NAD(+) synthesis pathways blocked TNF-alpha release. Lipopolysaccharide stimulation also caused changes in mRNA levels of some NAD(+) homoeostasis enzymes in M1-like cells. Surprisingly, despite M2-like cells not releasing TNF-alpha or changing NAD(+) levels in response to lipopolysaccharide, they showed similar mRNA changes compared with M1-like cells. These data further strengthen the link between pro-inflammatory responses in macrophages and NAD(+). The agonist-induced rise in NAD(+) shows striking parallels to well-known second messengers and raises the possibility that NAD(+) is acting in a similar manner in this model. PMID- 26764410 TI - Promiscuous tumor targeting phage proteins. AB - Cancer cell-specific targeting ligands against numerous cancer cell lines have been selected previously and used as ligands for cell-specific delivery of chemotherapies and various nanomedicines. However, tumor heterogeneity is one recognized problem hampering clinical translation of targeted anti-cancer medicines. Therefore, a novel class of targeting ligands is required that recognize receptors expressed between a variety of cancer phenotypes, identified here as 'promiscuous' ligands. In this work, promiscuous phage fusion proteins were first identified by a novel selection scheme to enrich for pan-cancer cell binding abilities, as indicated by conserved structural motifs identified previously in other cancer types. Additionally, peptide sequences containing a combination of motifs were identified to modulate binding. A panel of phage fusion proteins was studied for their specificity and selectivity for lung and pancreatic cancer cells. Phage displaying the fusion peptides GSLEEVSTL or GEFDELMTM, the two predominate clones with greatest binding ability, were used to modify preformed, doxorubicin-loaded, liposomes. These modified liposomes increased cytotoxicity up to 8.1-fold in several cancer cell lines when compared with unmodified liposomal doxorubicin. Taken together, these data indicate that promiscuous phage proteins, selected against different cancer cell lines, can be used as targeting ligands for treatment of heterogeneous tumor populations. PMID- 26764411 TI - Lifestyle Changes in Young Adulthood and Middle Age and Risk of Cardiovascular Disease and All-Cause Mortality: The Doetinchem Cohort Study. AB - BACKGROUND: The associations between overall lifestyle profile and cardiovascular disease (CVD) and death have been mainly investigated in cross-sectional studies. The full benefits of a healthy lifestyle may therefore be underestimated, and the magnitude of benefits associated with changes in lifestyle remains unclear. We quantified the association of changes in lifestyle profiles over 5 years with risk of CVD and all-cause mortality. METHODS AND RESULTS: Lifestyle factors (ie, diet, physical activity, smoking, alcohol consumption) and body mass index were assessed and dichotomized as healthy/unhealthy among 5263 adults ages 26 to 66 in 1993-1997 and 5 years later (1998-2002). Multivariable-adjusted hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were estimated to quantify associations of change in lifestyle with fatal/nonfatal CVD and all-cause mortality that occurred 8 to 15 years after 1998-2002. Independent of baseline lifestyles, each decrement in number of healthy lifestyle factors was, on average, associated with 35% higher risk of CVD (HR, 1.35; 95% CI, 1.12-1.63) and 37% higher risk of all-cause mortality (HR, 1.37; 95% CI, 1.10-1.70); no association was noted with increase in the number of healthy lifestyle factors (P>0.5). Individuals who maintained 4 to 5 healthy lifestyle factors had 2.5 times lower risk of CVD (HR, 0.43; 95% CI, 0.25-0.63) and all-cause mortality (HR, 0.40; 95% CI, 0.22-0.73) than those who maintained only 0 to 1 healthy lifestyle factor. CONCLUSIONS: Our findings suggest that the benefits of healthy lifestyles may be easier lost than gained over a 5-year period. This underscores the need for efforts to promote maintenance of healthy lifestyles throughout the life course. PMID- 26764412 TI - Association of Digoxin With Interstage Mortality: Results From the Pediatric Heart Network Single Ventricle Reconstruction Trial Public Use Dataset. AB - BACKGROUND: Mortality for infants with single ventricle congenital heart disease remains as high as 8% to 12% during the interstage period, the time between discharge after the Norwood procedure and before the stage II palliation. The objective of our study was to determine the association between digoxin use and interstage mortality in these infants. METHODS AND RESULTS: We conducted a retrospective cohort study using the Pediatric Heart Network Single Ventricle Reconstruction Trial public use dataset, which includes data on infants with single right ventricle congenital heart disease randomized to receive either a Blalock-Taussig shunt or right ventricle-to-pulmonary artery shunt during the Norwood procedure at 15 institutions in North America from 2005 to 2008. Parametric survival models were used to compare the risk of interstage mortality between those discharged to home on digoxin versus those discharged to home not on digoxin, adjusting for center volume, ascending aorta diameter, shunt type, and socioeconomic status. Of the 330 infants eligible for this study, 102 (31%) were discharged home on digoxin. Interstage mortality for those not on digoxin was 12.3%, compared to 2.9% among those on digoxin, with an adjusted hazard ratio of 3.5 (95% CI, 1.1-11.7; P=0.04). The number needed to treat to prevent 1 death was 11 patients. There were no differences in complications between the 2 groups during the interstage period. CONCLUSIONS: Digoxin use in infants with single ventricle congenital heart disease is associated with significantly reduced interstage mortality. PMID- 26764415 TI - Non-intubated uniportal lung surgery?. AB - Uniportal video-assisted thoracoscopic surgery (uniVATS) is currently being used to diagnose and treat several intrathoracic conditions with minimal morbidity and reduced hospital stay compared with standard multiport VATS surgery. The potential advantages of uniVATS can be also enhanced by the adoption of loco regional anaesthesiological techniques in non-intubated or awake patients yielding the possibility of performing an ever larger proportion of thoracic surgical procedures in an outpatient setting. This review will look at organizational and technical aspects of implementing a non-intubated uniVATS program. PMID- 26764413 TI - Preserved Autonomic Cardiovascular Regulation With Cardiac Pacemaker Inhibition: A Crossover Trial Using High-Fidelity Cardiovascular Phenotyping. AB - BACKGROUND: Sympathetic and parasympathetic influences on heart rate (HR), which are governed by baroreflex mechanisms, are integrated at the cardiac sinus node through hyperpolarization-activated cyclic nucleotide-gated channels (HCN4). We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact. METHODS AND RESULTS: We treated 21 healthy men with 2*7.5 mg ivabradine or placebo in a randomized crossover fashion. We recorded electrocardiogram, blood pressure, and muscle sympathetic nerve activity at rest and during pharmacological baroreflex testing. Ivabradine reduced normalized HR from 65.9+/-8.1 to 58.4+/-6.2 beats per minute (P<0.001) with unaffected blood pressure and muscle sympathetic nerve activity. On ivabradine, cardiac and sympathetic baroreflex gains and blood pressure responses to vasoactive drugs were unchanged. Ivabradine aggravated bradycardia during baroreflex loading. CONCLUSIONS: HCN4 blockade with ivabradine reduced HR, leaving physiological regulation of HR and muscle sympathetic nerve activity as well as baroreflex blood pressure buffering intact. Ivabradine could aggravate bradycardia during parasympathetic activation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865917. PMID- 26764414 TI - Blood Pressure Reactivity to Psychological Stress in Young Adults and Cognition in Midlife: The Coronary Artery Risk Development in Young Adults (CARDIA) Study. AB - BACKGROUND: The classic view of blood pressure (BP) reactivity to psychological stress in relation to cardiovascular risks assumes that excess reactivity is worse and lower reactivity is better. Evidence addressing how stress-induced BP reactivity in young adults is associated with midlife cognitive function is sparse. METHODS AND RESULTS: We assessed BP reactivity during a star tracing task and a video game in adults aged 20 to 32 years. Twenty-three years later, cognitive function was assessed with use of the Digit Symbol Substitution Test (a psychomotor speed test), the Rey Auditory Verbal Learning Test (a verbal memory test), and the modified Stroop test (an executive function test). At the time of follow-up, participants (n=3021) had a mean age of 50.2 years; 56% were women, and 44% were black. In linear regression models adjusted for demographic and clinical characteristics including baseline and follow-up resting BP, lower systolic BP (SBP) reactivity during the star tracing and video game was associated with worse Digit Symbol Substitution Test scores (beta [SE]: 0.11 [0.02] and 0.05 [0.02], respectively) and worse performance on the Stroop test (beta [SE]: -0.06 [0.02] and -0.05 [0.02]; all P<0.01). SBP reactivity was more consistently associated than diastolic BP reactivity with cognitive function scores. The associations between SBP reactivity and cognitive function were mostly similar between blacks and whites. CONCLUSIONS: Lower psychological stress induced SBP reactivity in younger adults was associated with lower cognitive function in midlife. BP reactivity to psychological stressors may have different associations with target organs in hypertension. PMID- 26764417 TI - The placebo effect in thyroid cancer: a meta-analysis. AB - CONTEXT: The natural history of advanced thyroid malignancies is largely unknown. The outcome of patients included in the placebo arm of clinical trials could be reflective of their therapy-free evolution. OBJECTIVE: To analyze the response rate, symptoms and adverse effects of locally advanced or metastatic differentiated (DTC) and medullary thyroid cancer (MTC) in patients treated with placebo in clinical trials. DESIGN: PubMed (MEDLINE) and SCOPUS databases were searched through September 2015 to identify high-quality randomized controlled clinical trials. We included studies that recruited patients with DTC or MTC with a placebo arm. METHODS: We conducted a meta-analysis for each category of response rate, adherence to treatment, and adverse events. An empirical Bayesian random-effect model was used. RESULTS: We identified five clinical trials. DTC and MTC were independently analyzed. In the placebo arm, no complete response was observed; partial response occurred in 1.6% (0.6-3) and 6.4% (3.4-10.3) of DTC and MTC respectively; stable disease was described in 40.5% (34.6-46.9) and 53.9% (44.3-64.4) of DTC and MTC respectively. DTC reached a disease control rate of 42.3% (36.2-48.9) and MTC of 60.2 (50.1-71.4). Treatment discontinuation rate was 3.5% (1.9-5.5) in DTC and 5.7% (3.0-9.4) in MTC. Rate of dose reduction was 7.3% (4.8-10.5) in DTC and 6.2% (3.3-10.0) in MTC. CONCLUSIONS: This meta-analysis provides extensive data on the response rate and adverse effects of locally advanced or metastatic DTC and MTC in patients treated with placebo. These results may be used for comparisons with results from clinical trials without a placebo arm. PMID- 26764416 TI - Single-port video-assisted thoracic surgery in 1063 cases: a single-institution experience?. AB - OBJECTIVES: Single-port video-assisted thoracic surgery (VATS) technique has been used for thoracic diseases. There was no report about single-port VATS in large series. Outcomes following single-port VATS were analysed to determine its efficacy and safety. METHODS: From June 2012 to June 2014, 1063 single-port VATSs were performed by four surgeons. Patient demographics, perioperative parameters, histopathology and outcomes were analysed. RESULTS: There were 1063 patients (524 men and 539 women). The median age was 56.1 +/- 8.7 years (range, 15-86 years). Lobectomy was performed in 569 patients, segmentectomy in 162, wedge resection in 264, pleural biopsy in 7, drainage of effusion in 20, pleural tumour resection in 5, mediastinal tumour resection in 54, mediastinal tumour biopsy in 2, bilobectomy in 7, sleeve lobectomy in 3 and pneumonectomy in 2. Synchronous bilateral single-port VATS was performed in 27 cases, whereas metachronous bilateral single-port VATS was performed in 5 cases. Pathological diagnoses included primary lung cancer in 635 cases, metastatic lung cancer in 19, mediastinal tumour in 56, pleural disease in 32 and benign pulmonary conditions in 353. Fifteen intraoperative vascular injuries were identified in 15 patients. The total conversion rate was 4.6%. The average operation time was 135 +/- 31 min (range, 30-230 min), and the average blood loss was 117 +/- 47 ml (range, 50-2000 ml). The median intensive care unit stay was 1 day (0-4 days). The postoperative hospital stay was 6.2 +/- 2.6 days on average. There was no operative death, and operative complications occurred in 59 patients (5.6%). The 1-year overall survival and 1-year disease-free survival for the primary lung cancer group were 98 and 96%, respectively. CONCLUSIONS: Our findings indicate that single-port VATS for thoracic diseases is safe and feasible. PMID- 26764418 TI - Novel calcium-sensing receptor cytoplasmic tail deletion mutation causing autosomal dominant hypocalcemia: molecular and clinical study. AB - OBJECTIVE: Autosomal dominant hypocalcemia (ADH) is a rare disorder caused by activating mutations of the calcium-sensing receptor (CASR). The treatment of ADH patients with 1alpha-hydroxylated vitamin D derivatives can cause hypercalciuria leading to nephrocalcinosis. DESIGN AND METHODS: We studied a girl who presented with hypoparathyroidism and asymptomatic hypocalcemia at age 2.5 years. Mutations of CASR were investigated by DNA sequencing. Functional analyses of mutant and WT CASRs were done in transiently transfected human embryonic kidney (HEK293) cells. RESULTS: The proband and her father are heterozygous for an eight-nucleotide deletion c.2703_2710delCCTTGGAG in the CASR encoding the intracellular domain of the protein. Transient expression of CASR constructs in kidney cells in vitro suggested greater cell surface expression of the mutant receptor with a left shifted extracellular calcium dose-response curve relative to that of the WT receptor consistent with gain of function. Initial treatment of the patient with calcitriol led to increased urinary calcium excretion. Evaluation for mosaicism in the paternal grandparents of the proband was negative. CONCLUSIONS: We describe a novel naturally occurring deletion mutation within the CASR that apparently arose de novo in the father of the ADH proband. Functional analysis suggests that the cytoplasmic tail of the CASR contains determinants that regulate the attenuation of signal transduction. Early molecular analysis of the CASR gene in patients with isolated idiopathic hypoparathyroidism is recommended because of its relevance to clinical outcome and treatment choice. In ADH patients, calcium supplementation and low-dose cholecalciferol avoids hypocalcemic symptoms without compromising renal function. PMID- 26764419 TI - The effect of GH treatment on serum FGF23 and Klotho in GH-deficient children. AB - BACKGROUND: Normal phosphate homeostasis is essential for normal linear growth. The phosphaturic fibroblast growth factor 23 (FGF23)/Klotho axis is a major regulator of phosphate homeostasis; therefore, an intact FGF23/Klotho axis is important for normal linear growth. On the other hand, GH/IGF1 axis has opposing effects on phosphate homeostasis, but the underline mechanisms remain unclear. AIM: The main objective of this study was to investigate the possible interactions of FGF23 and its co-receptor Klotho, with growth hormone (GH)/IGF1 axis in the regulation of phosphate metabolism in GH-deficient children under GH treatment. METHODS: We studied 23 GH-deficient children, before and 3 months after the onset of GH treatment. Anthropometry and assessment of biochemical parameters were performed, as well as measurement of FGF23 (intact FGF23/iFGF23 and C-terminal FGF23/cFGF23) and soluble alpha-Klotho (sKlotho) levels. RESULTS: After 3 months on GH treatment, the elevation of serum phosphate and TmPO4/GFR (P<0.0001 and P<0.01 respectively) was accompanied by a significant increase in cFGF23 (P<0.01), iFGF23 (P<0.0001), sKlotho (P<0.0001) and IGF1 (P<0.0001). Serum phosphate and TmPO4/GFR were positively associated with iFGF23 (P<0.01 and P<0.05) and IGF1 (P<0.05 and P<0.05). iFGF23 levels were positively correlated with sKlotho (P<0.001), IGF1 (P<0.0001) and height SDS (P<0.0001), whereas sKlotho was positively associated with IGF1 (P<0.0001) and height SDS (P<0.001). CONCLUSION: The increase in serum phosphate, which we found in GH-deficient children under GH treatment, is not associated with suppression but rather than with upregulation of the phosphaturic FGF23/Klotho axis. PMID- 26764420 TI - Vasa vasorum and coronary artery disease progression: optical coherence tomography findings. PMID- 26764422 TI - Podcasting in the STEM disciplines: the implications of supplementary lecture recording and 'lecture flipping'. AB - Lecture capture or 'podcasting' technology offers a new and engaging format of learning materials that can be used to increase the flexibility and interactivity of learning and teaching environments. Here we discuss different ways that these recordings can be incorporated into STEM discipline teaching, and the impact this can have on students' learning. PMID- 26764423 TI - Simultaneous saccharification and fermentation of dilute alkaline-pretreated corn stover for enhanced butanol production by Clostridium saccharobutylicum DSM 13864. AB - Simultaneous saccharification and fermentation (SSF) process was applied for biobutanol production by Clostridium saccharobutylicum DSM 13864 from corn stover (CS). The key influential factors in SSF process, including corn steep liquor concentration, dry biomass and enzyme loading, SSF temperature, inoculation size and pre-hydrolysis time were optimized. In 5-L bioreactor with SSF process, butanol titer and productivity of 12.3 g/L and 0.257 g/L/h were achieved at 48 h, which were 20.6% and 21.2% higher than those in separate hydrolysis and fermentation (SHF), respectively. The butanol yield reached 0.175 g/g pretreated CS in SSF, representing 50.9% increase than that in SHF (0.116 g/g pretreated CS). This study proves the feasibility of efficient and economic production of biobutanol from CS by SSF. PMID- 26764421 TI - Methylated circulating tumor DNA in blood: power in cancer prognosis and response. AB - Circulating tumor DNA (ctDNA) in the plasma or serum of cancer patients provides an opportunity for non-invasive sampling of tumor DNA. This 'liquid biopsy' allows for interrogations of DNA such as quantity, chromosomal alterations, sequence mutations and epigenetic changes, and can be used to guide and improve treatment throughout the course of the disease. This tremendous potential for real-time 'tracking' in a cancer patient has led to substantial research efforts in the ctDNA field. ctDNA can be distinguished from non-tumor DNA by the presence of tumor-specific mutations and copy number variations, and also by aberrant DNA methylation, with both DNA sequence and methylation changes corresponding to those found in the tumor. Aberrant methylation of specific promoter regions can be a very consistent feature of cancer, in contrast to mutations, which typically occur at a wide range of sites. This consistency makes ctDNA methylation amenable to the design of widely applicable clinical assays. In this review, we examine ctDNA methylation in the context of monitoring disease status, treatment response and determining the prognosis of cancer patients. PMID- 26764424 TI - Comparing the temporal colonization and microbial diversity of showerhead biofilms in Hawai'i and Colorado. AB - The household is a potential source of opportunistic pathogens to humans, a particularly critical issue for immunodeficient individuals. An important human microbe interface is the biofilm that develops on showerhead surfaces. Once microbe-laden biofilms become aerosolized, they can potentially be inhaled into the lungs. Understanding how quickly a new showerhead becomes colonized would provide useful information to minimize exposure to potentially pathogenic environmental microbes. High school scientists sampled the inner surfaces of pre existing and newly fitted showerheads monthly over a nine-month period and applied standard microbiologic culture techniques to qualitatively assess microbial growth. Water chemistry was also monitored using commercial test strips. Sampling was performed in households on Oahu, Hawai'i and Denver, Colorado, representing warm/humid and cold/arid environments, respectively. Pre existing showerheads in Hawai'i showed more diverse microbial growth and significantly greater microbial numbers than a comparable showerhead from Colorado. New, chrome-plated or plastic showerheads in Hawai'i showed diverse and abundant growth one month after installment compared to new showerheads from Colorado. The pH, total chlorine and water hardness levels varied significantly between the Hawai'i and Colorado samples. Enthusiastic student and teacher participation allowed us to answer long-standing questions regarding the temporal colonization of microbial biofilms on pre-existing and new showerhead surfaces. PMID- 26764425 TI - Fungal denitrification: Bipolaris sorokiniana exclusively denitrifies inorganic nitrogen in the presence and absence of oxygen. AB - Fungi may play an important role in the production of the greenhouse gas nitrous oxide (N2O). Bipolaris sorokiniana is a ubiquitous saprobe found in soils worldwide, yet denitrification by this fungal strain has not previously been reported. We aimed to test if B. sorokiniana would produce N2O and CO2 in the presence of organic and inorganic forms of nitrogen (N) under microaerobic and anaerobic conditions. Nitrogen source (organic-N, inorganic-N, no-N control) significantly affected N2O and CO2 production both in the presence and absence of oxygen, which contrasts with bacterial denitrification. Inorganic N addition increased denitrification of N2O (from 0 to 0.3 MUg N20-N h(-1) g(-1) biomass) and reduced respiration of CO2 (from 0.1 to 0.02 mg CO2 h(-1) g(-1) biomass). Isotope analyses indicated that nitrite, rather than ammonium or glutamine, was transformed to N2O. Results suggest the source of N may play a larger role in fungal N2O production than oxygen status. PMID- 26764426 TI - The outcome of prenatal identification of sex chromosome abnormalities. AB - OBJECTIVE: The outcome of a pregnancy following identification of a sex chromosome abnormality (SCA) is unclear. The aims of this study were to ascertain the prevalence of SCA detected prenatally in Scotland and to determine the outcomes for these cases. DESIGN: Following retrospective identification of all prenatal karyotypes performed in Scotland between 2000 and 2012, data linkage was performed to obtain information regarding maternal characteristics and pregnancy outcomes. Detailed outcome data were also collected for all affected offspring in the West of Scotland and Grampian regions within Scotland. RESULTS: Of the 28 145 pregnancies that had a karyotype over the study period, records were available for 27 152 (96%). Karyotype abnormalities were identified in 2139 (8%), with SCA being identified in 321(1%) tests. 45,X was identified as the commonest SCA in 135 pregnancies. Of 121 pregnancies with SCA in the West of Scotland and Grampian, 64 (53%), 52 (43%) and 5 (4%) led to a live birth, termination and intrauterine death, respectively. Of the 64 live births, 21 (33%) had a postnatal karyotype and 35 (54%) received specialist follow-up for the SCA that was identified prenatally. CONCLUSIONS: Abnormalities of sex chromosomes are identified in approximately 1% of all pregnancies that undergo a prenatal karyotype. There is a need to review the prenatal as well as postnatal care of the affected mother and offspring. PMID- 26764428 TI - Obituary--Giovanni Esposito M.D., PhD (1926-2015). PMID- 26764429 TI - Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. PMID- 26764427 TI - Recent Mobility of Casposons, Self-Synthesizing Transposons at the Origin of the CRISPR-Cas Immunity. AB - Casposons are a superfamily of putative self-synthesizing transposable elements that are predicted to employ a homolog of Cas1 protein as a recombinase and could have contributed to the origin of the CRISPR-Cas adaptive immunity systems in archaea and bacteria. Casposons remain uncharacterized experimentally, except for the recent demonstration of the integrase activity of the Cas1 homolog, and given their relative rarity in archaea and bacteria, original comparative genomic analysis has not provided direct indications of their mobility. Here, we report evidence of casposon mobility obtained by comparison of the genomes of 62 strains of the archaeon Methanosarcina mazei. In these genomes, casposons are variably inserted in three distinct sites indicative of multiple, recent gains, and losses. Some casposons are inserted into other mobile genetic elements that might provide vehicles for horizontal transfer of the casposons. Additionally, many M. mazei genomes contain previously undetected solo terminal inverted repeats that apparently are derived from casposons and could resemble intermediates in CRISPR evolution. We further demonstrate the sequence specificity of casposon insertion and note clear parallels with the adaptation mechanism of CRISPR-Cas. Finally, besides identifying additional representatives in each of the three originally defined families, we describe a new, fourth, family of casposons. PMID- 26764430 TI - Corrigendum to ''Patient-controlled intranasal fentanyl analgesia: a pilot study to assess practicality and tolerability during childbirth'' Int J Obstet Anesth 2015; 24: 117-23. PMID- 26764431 TI - Reply by Author. PMID- 26764432 TI - Reply by Author. PMID- 26764434 TI - The IOC relative energy deficiency in sport clinical assessment tool (RED-S CAT). PMID- 26764435 TI - Preface. PMID- 26764436 TI - [Bart B. Ya. (To the 80th Birthday)]. PMID- 26764437 TI - [Vladimir Petrovitch Pomerantsev]. PMID- 26764465 TI - Electrophysiological Evidence for Intrinsic Pacemaker Currents in Crayfish Parasol Cells. AB - I used sharp intracellular electrodes to record from parasol cells in the semi isolated crayfish brain to investigate pacemaker currents. Evidence for the presence of the hyperpolarization-activated inward rectifier potassium current was obtained in about half of the parasol cells examined, where strong, prolonged hyperpolarizing currents generated a slowly-rising voltage sag, and a post hyperpolarization rebound. The amplitudes of both the sag voltage and the depolarizing rebound were dependent upon the strength of the hyperpolarizing current. The voltage sag showed a definite threshold and was non-inactivating. The voltage sag and rebound depolarization evoked by hyperpolarization were blocked by the presence of 5-10 mM Cs2+ ions, 10 mM tetraethyl ammonium chloride, and 10 mM cobalt chloride in the bathing medium, but not by the drug ZD 7288. Cs+ ions in normal saline in some cells caused a slight increase in mean resting potential and a reduction in spontaneous burst frequency. Many of the neurons expressing the hyperpolarization-activated inward potassium current also provided evidence for the presence of the transient potassium current IA, which was inferred from experimental observations of an increased latency of post hyperpolarization response to a depolarizing step, compared to the response latency to the depolarization alone. The latency increase was reduced in the presence of 4-aminopyridine (4-AP), a specific blocker of IA. The presence of 4 AP in normal saline also induced spontaneous bursting in parasol cells. It is conjectured that, under normal physiological conditions, these two potassium currents help to regulate burst generation in parasol cells, respectively, by helping to maintain the resting membrane potential near a threshold level for burst generation, and by regulating the rate of rise of membrane depolarizing events leading to burst generation. The presence of post-burst hyperpolarization may depend upon IA channels in parasol cells. PMID- 26764468 TI - Systems-Level Nutrition Approaches to Define Phenotypes Resulting from Complex Gene-Environment Interactions. AB - High-throughput metabolomic, proteomic, and genomic technologies have delivered 21st-century data showing that humans cannot be randomized into groups: individuals are genetically and biochemically distinct. Gene-environment interactions caused by unique dietary and lifestyle factors contribute to the heterogeneity in physiologies observed in human studies. The risk factors determined for populations (i.e. the population-attributable risk) cannot be applied to the individual. Developing individual risk/benefit factors in light of the genetic diversity of human populations, the complexity of foods, culture and lifestyle, and the variety in metabolic processes that lead to health or disease are significant challenges for personalizing dietary advice for healthy or diseased individuals. PMID- 26764466 TI - Brain Connectivity Dissociates Responsiveness from Drug Exposure during Propofol Induced Transitions of Consciousness. AB - Accurately measuring the neural correlates of consciousness is a grand challenge for neuroscience. Despite theoretical advances, developing reliable brain measures to track the loss of reportable consciousness during sedation is hampered by significant individual variability in susceptibility to anaesthetics. We addressed this challenge using high-density electroencephalography to characterise changes in brain networks during propofol sedation. Assessments of spectral connectivity networks before, during and after sedation were combined with measurements of behavioural responsiveness and drug concentrations in blood. Strikingly, we found that participants who had weaker alpha band networks at baseline were more likely to become unresponsive during sedation, despite registering similar levels of drug in blood. In contrast, phase-amplitude coupling between slow and alpha oscillations correlated with drug concentrations in blood. Our findings highlight novel markers that prognosticate individual differences in susceptibility to propofol and track drug exposure. These advances could inform accurate drug titration and brain state monitoring during anaesthesia. PMID- 26764467 TI - Human Rights Violations among Men Who Have Sex with Men in Southern Africa: Comparisons between Legal Contexts. AB - In 1994, South Africa approved a constitution providing freedom from discrimination based on sexual orientation. Other Southern African countries, including Botswana, Malawi, and Namibia, criminalize same-sex behavior. Men who have sex with men (MSM) have been shown to experience high levels of stigma and discrimination, increasing their vulnerability to negative health and other outcomes. This paper examines the relationship between criminalization of same sex behavior and experiences of human rights abuses by MSM. It compares the extent to which MSM in peri-urban Cape Town experience human rights abuses with that of MSM in Gaborone, Botswana; Blantyre and Lilongwe, Malawi; and Windhoek, Namibia. In 2008, 737 MSM participated in a cross-sectional study using a structured survey collecting data regarding demographics, human rights, HIV status, and risk behavior. Participants accrued in each site were compared using bivariate and multivariate logistic regression. Encouragingly, the results indicate MSM in Cape Town were more likely to disclose their sexual orientation to family or healthcare workers and less likely to be blackmailed or feel afraid in their communities than MSM in Botswana, Malawi, or Namibia. However, South African MSM were not statistically significantly less likely experience a human rights abuse than their peers in cities in other study countries, showing that while legal protections may reduce experiences of certain abuses, legislative changes alone are insufficient for protecting MSM. A comprehensive approach with interventions at multiple levels in multiple sectors is needed to create the legal and social change necessary to address attitudes, discrimination, and violence affecting MSM. PMID- 26764469 TI - Applications of Nutritional Biomarkers in Global Health Settings. AB - In global health settings, there are three generic areas that require reliable biomarkers of nutritional status and function. Population surveillance needs to identify key nutrient deficiencies (or excesses) to monitor progress towards elimination of nutritional imbalances and to stratify populations into groups especially 'at risk' to whom public health resources can be focused. Clinical interventions need biomarkers to help identify disease pathways, to assist in targeting nutrient prescriptions, and to avoid potential harm (e.g. in the case of iron). Discovery science requires biomarkers in many domains, but especially in the study of nutrient-gene interactions and regarding the effects of nutritional status on the epigenome. Each of these applications imposes different constraints on the methodology though in all cases the optimum biomarker would have high sensitivity and specificity, would capture variation of functional significance, and would be cheap and easy to apply. These attributes are hard to achieve, and recent progress towards next-generation biomarkers, though holding much promise, has not yet delivered significant breakthroughs in the global health setting. Recent efforts to overcome these problems by two initiatives (BOND and INSPIRE) are highlighted as exemplars of a route map to progress. PMID- 26764470 TI - Next-Generation Biomarkers of Health. AB - Current biomarkers used in health care and in nutrition and health research are based on quantifying disease onset and its progress. Yet, both health care and nutrition should focus on maintaining optimal health, where the related biology is essentially differing from biomedical science. Health is characterized by the ability to continuously adapt in varying circumstances where multiple mechanisms of systems flexibility are involved. A new generation of biomarkers is needed that quantifies all aspects of systems flexibility, opening the door to real lifestyle-related health optimization, self-empowerment, and related products and services. PMID- 26764471 TI - Bioinformatics: Novel Insights from Genomic Information. AB - While scientific methods have dominated research approaches in biology over the past decades, it is increasingly recognized that the complexity of biological systems must be addressed by a different approach, namely unbiased research involving the collection of large amounts of genome-wide information. To enable analysis of this information we and others are developing a variety of computational tools that allow bioinformaticists and wet laboratory biologists to extract novel patterns of data from these results and generate novel biological insights while generating new hypotheses for testing in the laboratory. There are two types of critical tools, databases to collate all information on biomolecules, especially interactions, and tools that reorganize information in a supervised (e.g. pathway analysis or gene ontology) or unsupervised (nonhierarchical clustering and network analysis) manner. Here we describe some of the tools we have developed and how we have used these to gain new ideas in the general area of infection and innate immunity/inflammation. In particular, it is illustrated how such analyses enable novel hypotheses about mechanisms associated with diseases and the mechanisms of action of immunomodulatory and other interventions, the definition of mechanism-based biomarkers/diagnostics, and prospective new interventions based on drug repurposing. PMID- 26764473 TI - Biomarkers in Pediatric Liver Disease. AB - The chronic nature of liver diseases in children and adults merits close follow up for disease progression and/or treatment evaluation. Disease progression involves injury to liver cells resulting in cell death, varying degrees of inflammation, steatosis depending on the insult, oxidative stress, and eventually fibrosis and cirrhosis unless the process is modified with treatment or spontaneous recovery. Inflammation, cell death, and fibrosis are the three major processes that determine the outcome of liver disease irrespective of the etiology. Markers to measure the activity or status of these parameters in a dynamic way, particularly via noninvasive methods, are urgently required. In this chapter, we summarize recent advances in the identification of biomarkers of liver diseases: biomarkers corresponding to inflammation, cell death, fibrosis, and the development of malignancy. PMID- 26764472 TI - Summary on Methodologies: Global Epidemiology. PMID- 26764474 TI - Next-Generation Biomarkers for Iron Status. AB - Iron is needed for oxygen transport, muscle activity, mitochondrial function, DNA synthesis, and sensing of hypoxia. The hierarchical master determinant of dietary iron absorption and iron distribution within the body is the peptide hormone hepcidin. Hepcidin itself is regulated by a combination of signals derived from iron stores, inflammation, and erythropoietic expansion. Iron deficiency and iron deficiency anemia are common and important conditions that can be treated with iron preparations. However, other factors besides iron deficiency can cause anemia, especially inflammation, which responds poorly to iron treatment, and inherited disorders of red blood cells, which are associated with accumulation of excess pathogenic iron. Assessment of iron status is challenging, and indices such as serum ferritin, soluble transferrin receptor, and zinc protoporphyrin have specific weaknesses. Moreover, a diagnosis of iron deficiency or iron deficiency anemia is most useful if the diagnosis also leads to effective treatment. Low levels of hepcidin allow iron absorption and effective iron incorporation into red blood cells. The best 'biomarker' to guide treatment may therefore be the physiological 'determinant' of iron utilization. Iron is also important in transplantation medicine and influences clinical outcome of arterial pulmonary hypertension; here too, biomarkers including hepcidin may be useful to actively and beneficially manage iron status. PMID- 26764475 TI - The Search for Biomarkers of Long-Term Outcome after Preterm Birth. AB - Preterm birth and survival rates are rising globally, and consequently there is a growing necessity to safeguard life-long health. Epidemiological and other studies from around the world point to a higher risk of adverse adult health outcomes following preterm birth. These reports encompass morbidities in multiple domains, poorer reproductive health, and reduced longevity. The contributions of genetic inheritance, intrauterine exposures, and postnatal care practices to this altered adult phenotype are not known. Early detection is essential to implement preventive measures and to test protective antenatal and neonatal interventions to attenuate aberrant health trajectories. A satisfactory biomarker of outcome must be predictive of later functional health and ideally remain stable over the period from infancy to childhood and adult life. To date, blood pressure is the index that best fulfils these criteria. High throughput 'omic' technologies may identify biomarkers of later outcome and health risk. However, their potential can only be realized with initial investment in large, longitudinal cohort studies, which couple serial metabolomic profiling with functional health assessments across the life course. PMID- 26764476 TI - Beyond Cholesterol - New Cardiovascular Biomarkers. AB - Atherosclerosis (AS) is the primary pathological result of obesity. Vulnerable AS plaques cause fatal clinical end points such as myocardial infarction and stroke. To prevent this, improvements in early diagnosis and treatment are essential. Because vulnerable AS plaques are frequently nonstenotic, they are preclinically undetectable using conventional imaging. Levels of blood lipids, C-reactive protein, and interleukin-6 are increased, but are insufficient to indicate the process of critical perpetuation before the end points present. More specific biomarkers (e.g. troponin, copetin, natriuretic peptides, growth differentiation factor-15, or soluble ST2) indicate the acute coronary syndrome or cardiac insufficiency, but not a critical destabilization of AS lesions in coronary or carotid arteries. Thus, valuable time (months to years) that could be used to treat the patient is wasted. An improved management of this dilemma may involve better detection of variations in degrees of immune inflammation in plaques by using new biomarkers in blood and/or within the lesion (molecular imaging). Macrophage and T-cell polarization, and innate and adaptive immune responses (e.g. Toll-like receptors) are involved in this critical process. New biomarkers in these mechanisms include pentraxin 3, calprotectins S100A8/S100A9, myeloperoxidase, adiponectin, interleukins, and chemokines. These proteins may also be candidates for molecular imaging using nuclear (magnetic resonance) imaging tools. Nevertheless, the main challenge remains: which asymptomatic individual should be screened? At which time interval? Intense interdisciplinary research in laboratory medicine (biomarkers), nanomedicine (nanoparticle development), and radiology (molecular imaging) will hopefully address these questions. PMID- 26764477 TI - Summary on Applications/End Users. PMID- 26764478 TI - Stratified Medicine: Maximizing Clinical Benefit by Biomarker-Driven Health Care. AB - Stratified medicine involves the use of biomarkers to differentiate patient populations into subsets that provide more detailed information about the specific causes of conditions, and predict how patients will respond to a given drug or combination of drugs. Biomarker-driven patient stratification can empower clinicians by providing accurate assessments of patient status (diagnostic and prognostic utility) in order to strategize treatment planning and delivery (predictive and monitoring utility) based on information extracted from biomarker profiles. This approach may also help presymptomatic individuals by delaying the onset of disease, minimize the severity of the disease, or possibly prevent disease occurrence. Patients and clinicians may benefit from this approach as it may allow for the transformation of current empirical 'medical practice' to efficient data-driven 'individualized therapeutic strategies' with a low risk of medical error. The health care industry may also benefit from this approach by designing clinical trials based on appropriate patient stratification. Here, recent advances in the field of stratified medicine are highlighted in the context of our efforts to integrate this rapidly evolving concept into our research, and to ultimately develop potential diagnostic/prognostic/predictive products and nutritional solutions for individual patients and consumers. PMID- 26764480 TI - The Scientific Challenge of Expanding the Frontiers of Nutrition. AB - Nutritional research is entering a paradigm shift which necessitates the modeling of complex interactions between diet, genetics, lifestyle, and environmental factors. This requires the development of analytical and processing capabilities for multiple data and information sources to be able to improve targeted and personalized nutritional approaches for the maintenance of health. Ideally, such knowledge will be employed to underpin the development of concepts that combine consumer and medical nutrition with diagnostic targeting for early intervention designed to maintain proper metabolic homeostasis and delay the onset of chronic diseases. Nutritional status is fundamental to any description of health, and when combined with other data on lifestyle, environment, and genetics, it can be used to drive stratified or even personalized nutritional strategies for health maintenance and preventive medicine. In this work, we will discuss the importance of developing new nutrient assessment methods and diagnostic capabilities for nutritional status to generate scientific hypotheses and actionable concepts from which to develop targeted and eventually personalized nutritional solutions for health protection. We describe efforts to develop algorithms for dietary nutrient intake and a holistic nutritional profiling platform as the basis of understanding the complex nutrition and health interactome. PMID- 26764479 TI - The Gut Microbiome, Its Metabolome, and Their Relationship to Health and Disease. AB - Despite its importance in maintaining the health of the host, growing evidence suggests that gut microbiota may also be an important factor in the pathogenesis of various diseases. The composition of the microbiota can be influenced by many factors, including age, genetics, host environment, and diet. There are epidemiologic data associating diet with the development of inflammatory bowel disease as well as evidence that diet can influence both the form and the function of the microbiome. Based on this evidence, studies are now underway to examine the effect of defined formula diets, an effective therapeutic modality in Crohn's disease, on both the gut microbiome and its metabolome as a therapeutic probe. Diet has an impact upon both the composition and the function of the microbiota in part through small-molecule production that may influence the development of both immune-mediated and metabolic diseases. By comparing dietary intake, the gut microbiota, and the plasma metabolome in omnivores versus vegans, we provide evidence that the production of certain bacterial metabolites is constrained by the composition of the gut microbiota. In total, these results demonstrate the potential promise of dietary manipulation of the gut microbiota and its metabolome as a modality to both maintain health and treat disease. PMID- 26764481 TI - Summary on Future Horizons. PMID- 26764482 TI - Myocardial KChIP2 Expression in Guinea Pig Resolves an Expanded Electrophysiologic Role. AB - Cardiac ion channels and their respective accessory subunits are critical in maintaining proper electrical activity of the heart. Studies have indicated that the K+ channel interacting protein 2 (KChIP2), originally identified as an auxiliary subunit for the channel Kv4, a component of the transient outward K+ channel (Ito), is a Ca2+ binding protein whose regulatory function does not appear restricted to Kv4 modulation. Indeed, the guinea pig myocardium does not express Kv4, yet we show that it still maintains expression of KChIP2, suggesting roles for KChIP2 beyond this canonical auxiliary interaction with Kv4 to modulate Ito. In this study, we capitalize on the guinea pig as a system for investigating how KChIP2 influences the cardiac action potential, independent of effects otherwise attributed to Ito, given the endogenous absence of the current in this species. By performing whole cell patch clamp recordings on isolated adult guinea pig myocytes, we observe that knock down of KChIP2 significantly prolongs the cardiac action potential. This prolongation was not attributed to compromised repolarizing currents, as IKr and IKs were unchanged, but was the result of enhanced L-type Ca2+ current due to an increase in Cav1.2 protein. In addition, cells with reduced KChIP2 also displayed lowered INa from reduced Nav1.5 protein. Historically, rodent models have been used to investigate the role of KChIP2, where dramatic changes to the primary repolarizing current Ito may mask more subtle effects of KChIP2. Evaluation in the guinea pig where Ito is absent, has unveiled additional functions for KChIP2 beyond its canonical regulation of Ito, which defines KChIP2 as a master regulator of cardiac repolarization and depolarization. PMID- 26764483 TI - Acute Kidney Injury: Tubular Markers and Risk for Chronic Kidney Disease and End Stage Kidney Failure. AB - Acute kidney injury (AKI) is a common clinical syndrome directly related to patient short-term and long-term morbidity and mortality. Over the last decade, the occurrence rate of AKI has been increasing, and there has also been a growing epidemic of chronic kidney diseases (CKD) and end-stage kidney disease (ESRD) linked to severe and repeated episodes of AKIs. The detection and management of AKI are currently far from satisfactory. A large proportion of AKI patients, especially those with preexisting CKD, are at an increased risk of non-resolving AKI and progressing to CKD and ESRD. Proposed pathological processes that contribute to the transition of AKI to CKD and ESRD include severity and frequency of kidney injury, alterations of tubular cell phenotype with cells predominantly in the G2/M phase, interstitial fibrosis and microvascular rarification related to loss of endothelial-pericyte interactions and pericyte dedifferentiation. Innate immune responses, especially dendritic cell responses related to inadequate adenosine receptor (2a)-mediated signals, autophagic insufficiency and renin-angiotensin system activation have also been implicated in the progression of AKI and transitions from AKI to CKD and ESRD. Although promising advances have been made in understanding the pathophysiology of AKI and AKI consequences, much more work needs to be done in developing biomarkers for detecting early kidney injury, prognosticating kidney disease progression and developing strategies to effectively treat AKI and to minimize AKI progression to CKD and ESRD. PMID- 26764485 TI - Decompressive Hemicraniectomy in a South American Population--Morbidity and Outcomes Analysis. AB - BACKGROUND: Malignant cerebral artery strokes have a poor prognosis, with nearly 80% of mortality in some series despite intensive care. After a large randomized trial, decompressive hemicraniectomy has been performed more often in stroke patients. Here, we describe patients in a tertiary teaching hospital in Brazil, emphasizing the impact of age on outcomes. METHODS: A retrospective cohort of patients, with malignant strokes which received a decompressive hemicraniectomy, from paper and electronic medical records, from January 2010 to December 2013 was divided into two groups according to age. RESULTS: The final analysis included 60 patients. The overall mortality was higher among patients older than 60 yrs (67% vs. 41%; p = 0.039), whose group also had a worse outcome (76% with mRS 5 or 6) at 90 days (OR 3.91 CI95% 1.30-11.74), whereas only 24% had mRS of 0-4 (p = 0.015). All patients who presented with sepsis died (p = 0.003). The incidence of pulmonary infection was very high in the elderly group (76%) with significant intergroup differences (p = 0.027, OR 8.32 CI95% 0.70-98.48). CONCLUSIONS: Older patients present more commonly with infections, more disabilities and a higher mortality, highlighting very poor results in elderly population. These results should be proved with a South American trial, and if confirmed, it can impact on future decisions regarding decompressive craniectomy for acute ischemic stroke in our region. PMID- 26764484 TI - Antibiotic and Antiinflammatory Therapy Transiently Reduces Inflammation and Hypercoagulation in Acutely SIV-Infected Pigtailed Macaques. AB - Increased chronic immune activation and inflammation are hallmarks of HIV/SIV infection and are highly correlated with progression to AIDS and development of non-AIDS comorbidities, such as hypercoagulability and cardiovascular disease. Intestinal dysfunction resulting in microbial translocation has been proposed as a lead cause of systemic immune activation and hypercoagulability in HIV/SIV infection. Our goal was to assess the biological and clinical impact of a therapeutic strategy designed to reduce microbial translocation through reduction of the microbial content of the intestine (Rifaximin-RFX) and of gut inflammation (Sulfasalazine-SFZ). RFX is an intraluminal antibiotic that was successfully used in patients with hepatic encephalopathy. SFZ is an antiinflammatory drug successfully used in patients with mild to moderate inflammatory bowel disease. Both these clinical conditions are associated with increased microbial translocation, similar to HIV-infected patients. Treatment was administered for 90 days to five acutely SIV-infected pigtailed macaques (PTMs) starting at the time of infection; seven untreated SIVsab-infected PTMs were used as controls. RFX+SFZ were also administered for 90 days to three chronically SIVsab-infected PTMs. RFX+SFZ administration during acute SIVsab infection of PTMs resulted in: significantly lower microbial translocation, lower systemic immune activation, lower viral replication, better preservation of mucosal CD4+ T cells and significantly lower levels of hypercoagulation biomarkers. This effect was clear during the first 40 days of treatment and was lost during the last stages of treatment. Administration of RFX+SFZ to chronically SIVsab-infected PTMs had no discernible effect on infection. Our data thus indicate that early RFX+SFZ administration transiently improves the natural history of acute and postacute SIV infection, but has no effect during chronic infection. PMID- 26764486 TI - A Single 9-Colour Flow Cytometric Method to Characterise Major Leukocyte Populations in the Rat: Validation in a Model of LPS-Induced Pulmonary Inflammation. AB - The rat is a commonly used model for immunological investigation. Yet basic research and characterisation of leukocyte populations and sub-sets lags far behind murine research, with inconsistency on reported leukocyte markers and their overlap. These shortcomings limit the opportunity for more complex and advanced rat immunology research. In this study, we developed a robust 9-colour flow-cytometric protocol to elucidate the major blood and tissue rat leukocyte populations, and validated it in a model of LPS-induced pulmonary inflammation. Blood and tissues (lung, BALF, spleen, liver, bone marrow) from naive Sprague Dawley rats were collected and analysed by flow cytometry (FCM). Rats were exposed to aerosolised saline or LPS (1 mg/mL), at 3 and 24 hrs thereafter blood, lung and BALF were collected and analysed using FCM and ELISA. Neutrophils, two monocyte subsets, NK Cells, B Cells, CD4+, CD8+ T Cells and alveolar macrophages can be identified simultaneously across different tissues using a 9-colour panel. Neutrophils and monocytes can be distinguished based upon differential expression of CD43 and His48. Neutrophils and CD43Lo/His48Hi monocyte-macrophages are elevated in the lung at 3 and 24 hrs during LPS-induced pulmonary inflammation. This validated method for leukocyte enumeration will offer a platform for greater consistency in future rat immunology and inflammation research. PMID- 26764487 TI - Chicken scFvs with an Artificial Cysteine for Site-Directed Conjugation. AB - For the site-directed conjugation of chemicals and radioisotopes to the chicken derived single-chain variable fragment (scFv), we investigated amino acid residues replaceable with cysteine. By replacing each amino acid of the 157 chicken variable region framework residues (FR, 82 residues on VH and 75 on VL) with cysteine, 157 artificial cysteine mutants were generated and characterized. At least 27 residues on VL and 37 on VH could be replaced with cysteine while retaining the binding activity of the original scFv. We prepared three VL (L5, L6 and L7) and two VH (H13 and H16) mutants as scFv-Ckappa fusion proteins and showed that PEG-conjugation to the sulfhydryl group of the artificial cysteine was achievable in all five mutants. Because the charge around the cysteine residue affects the in vivo stability of thiol-maleimide conjugation, we prepared 16 charge-variant artificial cysteine mutants by replacing the flanking residues of H13 with charged amino acids and determined that the binding activity was not affected in any of the mutants except one. We prepared four charge-variant H13 artificial cysteine mutants (RCK, DCE, ECD and ECE) as scFv-Ckappa fusion proteins and confirmed that the reactivity of the sulfhydryl group on cysteine is active and their binding activity is retained after the conjugation process. PMID- 26764488 TI - Assessment of Median Nerve Mobility by Ultrasound Dynamic Imaging for Diagnosing Carpal Tunnel Syndrome. AB - Carpal tunnel syndrome (CTS) is the most common peripheral neuropathy and is characterized by median nerve entrapment at the wrist and the resulting median nerve dysfunction. CTS is diagnosed clinically as the gold standard and confirmed with nerve conduction studies (NCS). Complementing NCS, ultrasound imaging could provide additional anatomical information on pathological and motion changes of the median nerve. The purpose of this study was to estimate the transverse sliding patterns of the median nerve during finger movements by analyzing ultrasound dynamic images to distinguish between normal subjects and CTS patients. Transverse ultrasound images were acquired, and a speckle-tracking algorithm was used to determine the lateral displacements of the median nerve in radial-ulnar plane in B-mode images utilizing the multilevel block-sum pyramid algorithm and averaging. All of the averaged lateral displacements at separate acquisition times within a single flexion-extension cycle were accumulated to obtain the cumulative lateral displacements, which were curve-fitted with a second-order polynomial function. The fitted curve was regarded as the transverse sliding pattern of the median nerve. The R2 value, curvature, and amplitude of the fitted curves were computed to evaluate the goodness, variation and maximum value of the fit, respectively. Box plots, the receiver operating characteristic (ROC) curve, and a fuzzy c-means clustering algorithm were utilized for statistical analysis. The transverse sliding of the median nerve during finger movements was greater and had a steeper fitted curve in the normal subjects than in the patients with mild or severe CTS. The temporal changes in transverse sliding of the median nerve within the carpal tunnel were found to be correlated with the presence of CTS and its severity. The representative transverse sliding patterns of the median nerve during finger movements were demonstrated to be useful for quantitatively estimating median nerve dysfunction in CTS patients. PMID- 26764527 TI - A phase I trial of the intravenous Hsp90 inhibitor alvespimycin (17-DMAG) in patients with relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. PMID- 26764528 TI - Management of pancreatic trauma: A pancreatic surgeon's point of view. AB - BACKGROUND: Pancreatic trauma occurs in 0.2% of patients with blunt trauma and 1 12% of patients with penetrating trauma. Traumatic pancreatic injuries are characterised by high morbidity and mortality, which further increase with delayed diagnoses. The diagnosis of pancreatic trauma is challenging. Signs and symptoms can be non-specific or even absent. METHODS: A critical review of studies reporting the management and outcomes of pancreatic trauma was performed. RESULTS: The management of pancreatic trauma depends on the haemodynamic stability of the patient, the degree and location of parenchymal injury, the integrity of the main pancreatic duct, and the associated injuries to other organs. Nevertheless, the involvement of the main pancreatic duct is the most important predictive factor of the outcome. The majority of pancreatic traumas are managed by medical treatment (parenteral nutrition, antibiotic therapy and somatostatin analogues), haemostasis, debridement of devitalised tissue and closed external drainage. If a proximal duct injury is diagnosed, endoscopic transpapillary stent insertion can be a viable option, while surgical resection by pancreaticoduodenectomy is restricted to an extremely small number of selected cases. Injuries of the distal parenchyma or distal duct may be managed with distal pancreatectomy with spleen preservation. At the pancreatic neck, when pancreatic transection occurs without damage to the parenchyma, a parenchyma sparing procedure is feasible. CONCLUSION: The management of pancreatic injuries is complex and often requires a multidisciplinary approach. Here, we propose a management algorithm that is based on parenchymal damage and the site of duct injury. PMID- 26764529 TI - Bariatric Surgery and the Neuro-Ophthalmologist. AB - BACKGROUND: As the prevalence of obesity increases, so, too, do the prevalences of weight-related diseases and surgical procedures to promote weight loss. It is important for neuro-ophthalmologists to be familiar with these procedures and possible downstream effects on afferent and efferent visual function. EVIDENCE ACQUISITION: Review of ophthalmology, neurology, general surgery, obesity, endocrinology, nutrition, psychiatry, and neurosurgery literature. RESULTS: Bariatric surgery is a safe and effective treatment for weight loss in obese individuals. There is Level IV evidence that it is associated with improvement in idiopathic intracranial hypertension (IIH). Laboratory nutrient deficiencies are common following some types of bariatric procedures. Symptomatic deficiencies are less common but can be devastating. Thiamine deficiency can cause nystagmus and other symptoms in weeks to months after surgery, whereas B12 or copper deficiency can cause optic neuropathy in years to decades following bariatric surgery. CONCLUSIONS: Bariatric surgery is a potential treatment for IIH. Postoperative vitamin deficiencies may cause nystagmus, optic neuropathy, nyctalopia, and/or ophthalmoparesis weeks to years after surgery. PMID- 26764531 TI - Birthdate of parvalbumin-neurons in the Parvafox-nucleus of the lateral hypothalamus. AB - The Parvafox-nucleus in the lateral hypothalamus is characterized by the presence of two distinct neural populations, the Parvalbumin (Parv) and the Foxb1 expressing ones. Foxb1-neurons are born at day 10 in the subventricular zone of the mouse mammillary region. It would be interesting to know if the subpopulation of Parv- neurons develop independently at different times and then meet the Foxb1 expressing neurons in the lateral hypothalamus, their final settling place. The aim of this study was to define the period of birth of the Parv-positive neurons using an in-vivo Bromodeoxyuridine-based method in rats. Parv-neurons are generated from embryonic day 10 to day 13, with a peak at day 12. Thus, it appears that the birthdates of the two subpopulations in these two species is similar, perhaps suggesting that they are born from the same neuroepithelial region. PMID- 26764532 TI - Increased expression of Slit2 and its receptors Robo1 and Robo4 in reactive astrocytes of the rat hippocampus after transient forebrain ischemia. AB - Slit2 is a secreted glycoprotein that was originally identified as a chemorepulsive factor in the developing brain; however, it was recently reported that Slit2 is associated with adult neuronal function including a variety of pathophysiological processes. To elucidate whether Slit2 is implicated in the pathophysiology of ischemic injury, we investigated the temporal changes and cellular localization of Slit2 and its predominant receptors, Robo1 and Robo4, for 28 days after transient forebrain ischemia. Slit2 and its receptors had similar overall expression patterns in the control and ischemic hippocampi. The ligand and receptors were constitutively expressed in hippocampal neurons in control animals; however, in animals with ischemic injury, their upregulation was detected in reactive astrocytes, but not in neurons or activated microglia, in the CA1 region. Astroglial induction of Slit2 and its receptors occurred by day 3 after reperfusion, and appeared to increase progressively until the final time point on day 28. Their temporal expression patterns overlapped with the time period in which reactive astrocytes undergo dynamic structural changes and appear hypertrophic in the ischemic hippocampus. The immunohistochemical data were consistent with the results of the immunoblot analyses, indicating that the expression of Slit2 and Robo increased progressively over the relatively long period of 28 days examined here. Collectively, these results suggest that Slit2/Robo signaling may be involved in regulating the astroglial reaction via autocrine or paracrine mechanisms in post-ischemic processes. Moreover, this may contribute to the dynamic morphological changes that occur in astrocytes in response to ischemic injury. PMID- 26764533 TI - Amitriptyline induces brain-derived neurotrophic factor (BDNF) mRNA expression through ERK-dependent modulation of multiple BDNF mRNA variants in primary cultured rat cortical astrocytes and microglia. AB - A significant role of brain-derived neurotrophic factor (BDNF) has been previously implicated in the therapeutic effect of antidepressants. To ascertain the contribution of specific cell types in the brain that produce BDNF following antidepressant treatment, the effects of the tricyclic antidepressant amitriptyline on rat primary neuronal, astrocytic and microglial cortical cultures were examined. Amitriptyline increased the expression of BDNF mRNA in astrocytic and microglial cultures but not neuronal cultures. Antidepressants with distinct mechanisms of action, such as clomipramine, duloxetine and fluvoxamine, also increased BDNF mRNA expression in astrocytic and microglial cultures. There are multiple BDNF mRNA variants (exon I, IIA, IV and VI) expressed in astrocytes and microglia and the variant induced by antidepressants has yet to be elaborated. Treatment with antidepressants increased the expression of exon I, IV and VI in astrocyte and microglia. Clomipramine alone significantly upregulated expression of exon IIA. The amitriptyline-induced expression of both total and individual BDNF mRNA variants (exon I, IV and VI) were blocked by MEK inhibitor U0126, indicating MEK/ERK signaling is required in the expression of BDNF. These findings indicate that non-neural cells are a significant target of antidepressants and further support the contention that glial production of BDNF is crucial role in the therapeutic effect of antidepressants. The current data suggest that targeting of glial function could lead to the development of antidepressants with a truly novel mechanism of action. PMID- 26764534 TI - Relationship between seizure frequency and number of neuronal and non-neuronal cells in the hippocampus throughout the life of rats with epilepsy. AB - The relationship between seizure frequency and cell death has been a subject of controversy. To tackle this issue, we determined the frequency of seizures and the total number of hippocampal cells throughout the life of rats with epilepsy using the pilocarpine model. Seizure frequency varied in animals with epilepsy according to which period of life they were in, with a progressive increase in the number of seizures until 180 days (sixth months) of epileptic life followed by a decrease (330 days-eleventh month) and subsequently stabilization of seizures. Cell counts by means of isotropic fractionation showed a reduction in the number of hippocampal neuronal cells following 30, 90, 180 and 360 days of spontaneous recurrent seizures (SRS) in rats compared to their controls (about 25%-30% of neuronal cell reduction). In addition, animals with 360 days of SRS showed a reduction in the number of neuronal cells when compared with animals with 90 and 180 days of seizures. The total number of hippocampal non-neuronal cells was reduced in rats with epilepsy after 30 days of SRS, but no significant alteration was observed on the 90th, 180th and 360th days. The total number of neuronal cells was negatively correlated with seizure frequency, indicating an association between occurrence of epileptic seizures throughout life and neuronal loss. In sum, our results add novel data to the literature concerning the time course of SRS and hippocampal cell number throughout epileptic life. PMID- 26764535 TI - The Radical SAM Enzyme HydG Requires Cysteine and a Dangler Iron for Generating an Organometallic Precursor to the [FeFe]-Hydrogenase H-Cluster. AB - Three maturase enzymes-HydE, HydF, and HydG-synthesize and insert the organometallic component of the [FeFe]-hydrogenase active site (the H-cluster). HydG generates the first organometallic intermediates in this process, ultimately producing an [Fe(CO)2(CN)] complex. A limitation in understanding the mechanism by which this complex forms has been uncertainty regarding the precise metallocluster composition of HydG that comprises active enzyme. We herein show that the HydG auxiliary cluster must bind both l-cysteine and a dangler Fe in order to generate the [Fe(CO)2(CN)] product. These findings support a mechanistic framework in which a [(Cys)Fe(CO)2(CN)](-) species is a key intermediate in H cluster maturation. PMID- 26764536 TI - A novel label-free fluorescence strategy for methyltransferase activity assay based on dsDNA-templated copper nanoparticles coupled with an endonuclease assisted signal transduction system. AB - Evaluating DNA methyltransferase (MTase) activity has received considerable attention due to its significance in the fields of early cancer clinical diagnostics and drug discovery. Herein, we proposed a novel label-free fluorescence method for MTase activity assay by coupling double-stranded DNA (dsDNA)-templated copper nanoparticles (CuNPs) with an endonuclease-assisted signal transduction system. In this strategy, dsDNA molecules were first methylated by DNA adenine methylation (Dam) MTase and then cleaved by the methylation-sensitive restriction endonuclease DpnI. The cleaved DNA fragments could not act as efficient templates for the formation of fluorescent CuNPs and thus no fluorescence signal was produced. Under optimized experimental conditions, the developed strategy exhibited a sensitive fluorescence response to Dam MTase activity. This strategy was also demonstrated to provide an excellent platform to the inhibitor screening for Dam MTase. These results demonstrated the great potential for the practical applications of the proposed strategy for Dam MTase activity assay. PMID- 26764537 TI - Transition-metal catalysed C-N bond activation. AB - Transition-metal catalysed C-N bond activation has attracted much attention and become one of the most promising bond disconnection and formation strategies that encompass a broad spectrum of applications in many reactions. In this tutorial review, efficient strategies for catalytic cleavage of C(sp)-N, C(sp(2))-N and C(sp(3))-N bonds and their applications in new C-C and C-N bond formation reactions are summarized. PMID- 26764538 TI - Shock tubes and blast injury modeling. AB - Explosive blast injury has become the most prevalent injury in recent military conflicts and terrorist attacks. The magnitude of this kind of polytrauma is complex due to the basic physics of blast and the surrounding environments. Therefore, development of stable, reproducible and controllable animal model using an ideal blast simulation device is the key of blast injury research. The present review addresses the modeling of blast injury and applications of shock tubes. PMID- 26764539 TI - The past and present of blast injury research in China. AB - With the increasing incidence of blast injury, the research on its mechanisms and protective measures draws more and more attention. Blast injury has many characteristics different from general war injuries or trauma. For example, soldiers often have various degrees of visceral injury without significant surface damage, combined injuries and arterial air embolism. Researchers in China began to investigate blast injury later than the United States and Sweden, but the development is so fast that lots of achievements have been gained, including the development of biological shock tube, the mechanisms and characteristics of blast injury in various organs, as well as protective measures under special environments. This article reviews the past and current situation of blast injury research in China. PMID- 26764540 TI - Blast-induced traumatic brain injury: a new trend of blast injury research. AB - Blast injury has become the major life- and function-threatening injuries in recent warfares. There is increased research interest in the mental disorders caused by blast-induced traumatic brain injury (bTBI), which has been proved as one of the "signature wounds" in modern battlefield. We reviewed the recent progresses in bTBI-related researches and concluded that the new era of blast injury research has shifted from the traditional physical impairments to cognitive dysfunctional/mental disorders that are proved to be more related to the outcome of combat casualty care. PMID- 26764541 TI - Chronic caffeine exposure attenuates blast-induced memory deficit in mice. AB - OBJECTIVE: To investigate the effects of three different ways of chronic caffeine administration on blast- induced memory dysfunction and to explore the underlying mechanisms. METHODS: Adult male C57BL/6 mice were used and randomly divided into five groups: control: without blast exposure, con-water: administrated with water continuously before and after blast-induced traumatic brain injury (bTBI), con caffeine: administrated with caffeine continuously for 1 month before and after bTBI, pre-caffeine: chronically administrated with caffeine for 1 month before bTBI and withdrawal after bTBI, post-caffeine: chronically administrated with caffeine after bTBI. After being subjected to moderate intensity of blast injury, mice were recorded for learning and memory performance using Morris water maze (MWM) paradigms at 1, 4, and 8 weeks post-blast injury. Neurological deficit scoring, glutamate concentration, proinflammatory cytokines production, and neuropathological changes at 24 h, 1, 4, and 8 weeks post-bTBI were examined to evaluate the brain injury in early and prolonged stages. Adenosine A1 receptor expression was detected using qPCR. RESULTS: All of the three ways of chronic caffeine exposure ameliorated blast-induced memory deficit, which is correlated with the neuroprotective effects against excitotoxicity, inflammation, astrogliosis and neuronal loss at different stages of injury. Continuous caffeine treatment played positive roles in both early and prolonged stages of bTBI; pre bTBI and post-bTBI treatment of caffeine tended to exert neuroprotective effects at early and prolonged stages of bTBI respectively. Up-regulation of adenosine A1 receptor expression might contribute to the favorable effects of chronic caffeine consumption. CONCLUSION: Since caffeinated beverages are widely consumed in both civilian and military personnel and are convenient to get, the results may provide a promising prophylactic strategy for blast-induced neurotrauma and the consequent cognitive impairment. PMID- 26764542 TI - Stromal vascular fraction combined with silicone rubber chamber improves sciatic nerve regeneration in diabetes. AB - PURPOSE: To study the effects of transplantation of characterized uncultured stromal vascular fraction (SVF) on sciatic nerve regeneration. METHODS: A 10-mm sciatic nerve defect was bridged using a silicone conduit filled with SVF. In control group, silicone conduit was filled with phosphate-buffered saline alone. In sham-operated group, the sciatic nerve was only exposed and manipulated. The regenerated nerve fibers were studied 8 and 12 weeks after surgery. RESULTS: Behavioral and functional studies confirmed faster recovery of regenerated axons in SVF transplanted animals than in control group (p<0.05). Gastrocnemius muscle mass in SVF transplanted animal was found to be significantly more than that in control group. Morphometric indices of the regenerated fibers showed the number and diameter of the myelinated fibers to be significantly higher in SVF transplanted animals than in control group. In immunohistochemistry, the location of reactions to S- 100 in SVF transplanted animals was clearly more positive than that in control group. CONCLUSION: SVF transplantation combined with silicone conduit could be considered as a readily accessible source of stromal cells that improves functional recovery of sciatic nerve. It may have clinical implications for the surgical management of acute diabetic patients after facial nerve transection. PMID- 26764543 TI - Comparison of closed reduction and expert tibial nailing with open reduction and plate and screw fixation in the treatment of two segmental tibial fractures. AB - PURPOSE: To compare the outcomes of closed reduction and expert tibial nailing (ETN) versus open reduction and plate and screw fixation in treating two segmental tibial fractures. METHODS: This study included 53 cases of two segmental fractures of the tibial shaft. They were admitted to our department between March 2010 and June 2013 and treated respectively by closed reduction and ETN (ETN group, n=31) or open reduction fixation with plate and screws (PS group, n=22). The general data of two groups including gender, age, injury cause, fracture type, etc showed no significant difference (p>0.05). To compare the therapeutic effects between two groups, the intraoperative condition, post- operative function and related complications were investigated. RESULTS: All the patients were successfully followed up. The period was 19.2 months for ETN group and 20.5 months for PS group. All the fractures in ETN group had union without complications such as malunion, infection, or osteofascial compartment syndrome; whereas there were 3 cases of superficial infection cured by repeated dressing change and 2 cases of delayed union in PS group. The total incidence of complication in PS group was 22.7% (5/22), much higher than that in ETN group (p<0.05). Moreover, ETN group showed a better result in terms of intraoperative blood loss, operation time, postoperative weight bearing time and fracture union time. In ETN group, at one-year follow-up, Johner-Wruhs' criteria was adopted to assess the postoperative function, which was reported as excellent in 18 cases, good in 10 cases and fair in 3 cases in ETN group (100% excellent-good rate). While in PS group, the result was excellent in 10 cases, good in 7 cases, fair in 3 cases and poor in 2 cases (77.3% excellent-good rate). The comparison was insignificant (p>0.05). CONCLUSION: Compared with plate and screw fixation, ETN fixation has the advantages of fewer complications, shorter operation time, being less invasive, earlier postoperative rehabilitation and weight bearing, quicker fracture union and better functional recovery, thus being an effective way to treat two segmental tibial fractures. PMID- 26764544 TI - Role of speckle tracking imaging in the assessment of myocardial regional ventricular function in experimental blunt cardiac injury. AB - PURPOSE: To evaluate the usefulness and information collecting ability of speckle tracking imaging techniques in the assessment of myocardial regional ventricular contractility in a rabbit model with blunt cardiac injury. METHODS: Fifteen healthy New Zealand rabbits weighing (2.70 +/-0.28) kg were anesthetized (3% pentobarbital sodium/i.v) and impacted using the BIM-II biological impact machine to induce myocardial contusion (MC). Hemodynamic parameters, such as heart rate, systolic pressure, mean arterial pressure, diastolic pressure and central venous pressure, were determined before and after MC. Further, parameters reflecting left ventricular functions, such as left ventricular end systolic pressure, left ventricular end diastolic pressure, isovolumic pressure (IP) and the maximal increasing/decreasing rate of left intraventricular pressure (+/-dp/dtmax), were also determined before and after MC. Left ventricular functions were determined either by two dimensional transthoracic echocardiography or by speckle tracking imaging for segmental abnormal ventricular wall motions. RESULTS: Heart rate, systolic pressure, diastolic pressure and mean arterial pressure decreased significantly but transiently, while central venous pressure markedly increased after MC. In contrast to significant changes in diastolic functions, there was no significant change in cardiac systolic functions after MC. The speckle tracking imaging demonstrated that strain values of different myocardial segment significantly decreased post impact, and that of the ventricular segment decreased from segment to segment. CONCLUSION: Speckle tracking imaging is useful and informative to assess myocardial regional dysfunctions post MC. PMID- 26764545 TI - Does pelvic injury trigger erectile dysfunction in men? AB - PURPOSE: Pelvic ring fractures constitute 3%-8% of all fractures of the skeletal system and are generally related with high energy trauma. Sexual dysfunction following pelvic fracture has a high incidence, and affects the male patients both physically and psychologically. In this study, we aimed to investigate the impact and frequencies of comorbidities such as erectile dysfunction (ED) with adverse sociocultural and psychological consequences for the patient who had a pelvic ring fracture. METHODS: This study included 26 men who corresponded to the inclusion criteria and agreed to participate our study. RESULTS: According to fracture types, most of our cases were Tile type A1 and type A2. Severe and moderate ED were detected in 46.1% (12/26) of these patients via the International Index of Erectile Function-5 questionnaire. CONCLUSION: ED develops following pelvic fractures, especially in Tile type B and C pelvic fractures. PMID- 26764546 TI - Simultaneous extraarticular fracture of the base of the first metacarpal and dislocation of the metacarpophalangeal joint of the thumb: A case report. AB - Double fracture-dislocations of the thumb are rare. Only a single case report of a simultaneous extra- articular fracture of the base of the first metacarpal and dislocation of the metacarpophalangeal joint has been previously reported. We report the second case report of this injury in a 20-year-old man. The patient had an excellent outcome after treatment. PMID- 26764547 TI - Invading of intrauterine contraceptive device into the sigmoid colon through uterine perforation caused by a blunt trauma. AB - Intrauterine contraceptive device (IUCD) is relatively safe but still with some serious risks. Uterus perforation is rare and would be fatal. A case of Cu-7 IUCD invading into the sigmoid colon through uterine perforation caused by a pelvic blunt trauma was presented. Our case showed that uterus perforation by an IUCD could induce utero-sigmoid fistula which is likely to be missed. Imaging is required when the patients with IUCD present abdominal pain, particularly with a history of trauma. PMID- 26764548 TI - Proximal tibial and fibular physeal fracture causing popliteal artery injury and peroneal nerve injury: A case report and review of literature. AB - Either proximal tibial or tibial physeal injuries are rare. The combination of both is even rarer, let alone causes a vascular injury. Early intervention is the key for management. We hereby present an interesting case of simultaneous proximal tibiofibular physeal injury with popliteal arterial occlusion and common peroneal nerve injury. The present case is important in two aspects: firstly it reports a very rare occurrence of simultaneous proximal tibiofibular physeal injury associated with vascular insult and common peroneal nerve injury; secondly it highlights that with timely intervention excellent results can be achieved in paediatric patients. PMID- 26764549 TI - Dislocation of a constrained total knee arthroplasty with patellar tendon rupture after trivial trauma. AB - Constrained total knee prostheses are used in knees with severe deformities and insufficiency of collaterals to provide stable and mobile knees. Dislocation after constrained knee prosthesis is an extremely rare and dreaded complication. When dislocation is associated with patellar tendon rupture, the management includes restoration of the extensor apparatus along with a stable knee. Repair of the patellar tendon is challenging due to poor soft tissue coverage in the area and a bulky repair can put tension on the wound closure. Ideal method of restoration of the extensor apparatus is a matter of debate. There are various modalities used ranging from primary end-to-end repair, augmentation by medial gastrocnemius flap, semitendinosus and synthetic implants and allograft tendoachilles. We report a rare case of a posterior dislocation of a constrained total knee arthroplasty in association with patellar tendon rupture due to a minor fall after a few weeks of surgery. The first episode was managed by reposition of the dislocation and V-Y plasty of the quadriceps and primary repair. The second episode of dislocation with re-rupture needed augmentation by semitendinosus along with the insertion of the thicker insert. The management of this complex problem along with the review of literature is discussed in this case report. PMID- 26764550 TI - Manubriosternal dislocation with spinal fracture: A rare cause for delayed haemothorax. AB - Type 2 manubriosternal dislocations with concomitant spinal fracture are rare and may be associated with thoracic visceral injuries. The complication of delayed haemothorax has not been reported yet. We report a case of a young male who suffered manubriosternal dislocation with chance type thoracic spine fracture due to fall of a tree branch over his back. The haemothorax presented late on day three. The possible injury mechanism is discussed along with review of literature. We conclude that a lateral chest radiograph is indicated in spinal fracture patients complaining of midsternal pain. Computerized axial tomography scan of chest with contrast is indicated to rule out visceral injuries and a chest radiograph should be repeated before the patient is discharged to look for delayed haemothorax. PMID- 26764552 TI - A Methodological Study On The Evaluation Of Learning From Story Narratives. AB - Exploratory multidimensional scaling and confirmatory nonparametric procedures (Hubert and Levin, 1976) were used to represent data from similarity rating and sorting tasks performed on nine animal names. Confirmatory procedures demonstrated that the organization of the data from the two tasks was similar. Analyses of data from sorting tasks performed after reading two stories with the nine animals as main characters (Bisanz, LaParte, Vesonder, and Voss, 1978) suggested a change from pre-reading organization that was similar to the organization of the characters intended by the authors in one of the two stories. One of the two dimensions used to write the second story appeared not to be salient to the readers. PMID- 26764551 TI - Validity, reliability and responsiveness of the Body Image Quality of Life Inventory in patients treated for infective endocarditis. AB - RATIONALE AND OBJECTIVES: Suffering through infective endocarditis (IE) can drastically alter a person's physical appearance, and body image-related concerns have been reported by patients. The extent and severity of the phenomenon has not previously been explored, as no quantitative measure has been validated in this patient population. The purpose of this study was thus to assess the validity, reliability and responsiveness of the Danish Body Image Quality of Life Inventory (BIQLI-DA) on patients treated for IE. METHODS: We evaluated the psychometric properties of the BIQLI-DA on data obtained in the CopenHeart IE trial, which is a randomised clinical trial evaluating the effects of comprehensive cardiac rehabilitation for patients treated for IE. We administered the BIQLI-DA as part of data collection at baseline and 6 months. We examined the psychometric properties through correlations to other measures, including body mass index, Medical Outcome Short Form 36 and Hospital Anxiety and Depression Scale. In addition, we examined internal consistency on item and scale level and performed anova group-by-time interaction to test for responsiveness. RESULTS AND STUDY LIMITATION: Participants were seventy patients with a mean age of 58 years and of which 83% were men. Results indicated convergent construct validity by confirming hypothesised associations to potentially related constructs. The BIQLI-DA was found to be highly internally consistent with a Cronbach's alpha of 0.96. Instrument responsiveness was indicated by a significant group-by-time interaction. Support for the validity of the BIQLI-DA might have been strengthened by a larger sample with more women. A more optimal design for testing responsiveness would possibly have allowed for clearer conclusions. CONCLUSIONS: The BIQLI-DA may be applicable in healthcare research as it seems to be valid, reliable and responsive; however, evidence should be strengthened through further exploration of instrument performance, particularly regarding responsiveness. PMID- 26764553 TI - The Construct Heuristic Applied To The Measurement Of Psychopathology. AB - Three samples consisting of normal adults (n=182), psychiatric patients (n=352) and high school students (n=1,485) were used to evaluate the empirical item structure of the Basic Personality Inventory. Using a principal components model with a confirmatory rotation, 96, 99, and 98 percent of the items loaded appropriately on their respective scales. No items were found to load inappropriately across all three samples, 219 of 220 items loaded appropriately across two samples, and 205 of 220 items loaded appropriately across all three samples. The empirical item structure was found to be congruent with the hypothesized structure, with keyed items showing much higher loadings than non keyed items. All results indicated a substantial improvement over that expected by chance. These results were interpreted as providing evidence for the efficiency of the construct-oriented heuristic. PMID- 26764554 TI - Multivariate Relationships Between Job Characteristics And Job Satisfaction In The Public Sector: A Triple Cross-Validation Study. AB - This study investigated multivariate relationships between task characteristics, measured by the Job Diagnostic Survey, and satisfaction with work outcomes, measured by the Triple Audit Opinion Survey, for 1,972 workers in the public sector. The obtained canonical correlations were high and stable across independent samples of public employees as indicated by a triple cross-validation design. The results support the predictions derived from the Hackman and Oldham model that job characteristics are more important for feelings of intrinsic job satisfaction than feelings of extrinsic job satisfaction, and that job characteristic - job satisfaction relationships are higher for high self actualization need strength employees than for low self-actualization need strength employees. It was concluded that previous job characteristic - job satisfaction relationships established for private sector employees can be generalized to public sector employees. PMID- 26764555 TI - Aggregation (Composition) Schema For Eigenvector Scaling Of Criteria Priorities In Hierarchical Structures. AB - An eigenvector approach to scaling of choice alternatives based upon multiple attributes evaluated on a relative basis by paired comparisons is reviewed. It is shown that neither compensatory aggregation (composition) nor noncompensatory models may be consistent or appropriate for an individual's utility. An alternative approach, where the individual (judge) evaluates all attributes simultaneously, and thereby, performs a subjective aggregation (composition) across all attributes simultaneously, is proposed. Eigenvector scaling may then be used to "prioritize" choice alternatives based upon aggregated pairwise comparisons. PMID- 26764556 TI - Method Of Complete Triads: An Investigation Of Unreliability In Multidimensional Perception Of Nations. AB - In many instances investigators are hesitant to use "too many" objects or stimuli in a multidimensional scaling study using the method of complete triads. One of the major reasons for this is that such use is postulated to lead to subject fatigue/boredom effects or practice effects which may produce unreliability in the judgments. In the present study an experimental design was constructed in an attempt (a) to investigate the presence of subject fatigue/boredom effects or practice effects and (b) to assess the influence of these effects on the configurations and distances resulting from multidimensional scaling of nations. The results showed that the postulated effects were present, but they did not influence the multidimensional scaling solutions. PMID- 26764557 TI - Generalized Discriminant Analysis: Some Illustrations. AB - The versatility of discriminant analysis as a technique to obtain more parsimonious descriptions in multivariate studies has not been fully exploited. Although the technique has been commonly proposed and used for multivariate analysis of variance studies, there have been few applications for other models and effects of current interest in the behavioral sciences. This article briefly reviews generalized discriminant analysis as a descriptive technique associated with the multivariate general linear model, and then presents results for several example analyses. The examples, based on real data, include contextual effects analyses using multilevel models and an aptitude-treatment-interaction analysis. It is argued that discriminant analysis has the most value as a descriptive technique when used in the spirit of an "external factor analysis." PMID- 26764558 TI - Some Cautions Concerning The Application Of Causal Modeling Methods. AB - Literal acceptance of the results of fitting "causal" models to correlational data can lead to conclusions that are of questionable value. The long-established principles of scientific inference must still be applied. In particular, the possible influence of variables that are not observed must be considered; the well-known difference between correlation and causation is still relevant, even when variables are separated in time; the distinction between measured variables and their theoretical counterparts still exists; and ex post facto analyses are not tests of models. There seems to be some danger of overlooking these principles when complex computer programs are used to analyze. correlational data, even though these new methods provide great increases in the rigor with which correlational data can be analyzed. PMID- 26764559 TI - The risk of respiratory symptoms on allergen exposure increases with increasing specific IgE levels. AB - BACKGROUND: The relation between IgE sensitization and allergic respiratory symptoms has usually been evaluated by dichotomizing specific IgE levels. The aim of this study was to evaluate the association between specific IgE levels and risk of symptoms on allergen-related exposure, with special reference to allergen related asthma-rhinitis comorbidity. METHODS: We considered 6391 subjects enrolled within the European Community Respiratory Health Survey 2, having information on cat/grass/D. pteronyssinus IgE levels and symptoms on exposure to animals/pollen/dust. The risk of oculonasal/asthmalike/both symptoms was evaluated by a multinomial logistic model. RESULTS: A clear positive association was observed between specific IgE levels to cat/grass/mite and the risk of symptoms on each allergen-related exposure (test for trend with P < 0.001). This trend was particularly pronounced when considering the coexistence of asthmalike and oculonasal symptoms. Compared to non-sensitized subjects, subjects with specific IgE to cat >= 3.5 kU/l presented relative risk ratios of 11.4 (95% CI 6.7-19.2), 18.8 (8.2-42.8), and 55.3 (30.5-100.2) when considering, respectively, only oculonasal symptoms, only asthmalike symptoms, or both. A similar pattern was observed when considering specific IgE to grass/mite and symptoms on exposure to pollen/dust. Also the proportion of people using inhaled medicines or visiting a general practitioner for breathing problems in the previous year increased with increasing sum of specific IgE to cat/grass/mite. CONCLUSION: Specific IgE level is the most important predictor of allergen-related symptoms. The risk of both oculonasal/asthmalike symptoms increases with specific IgE levels, suggesting that specific IgE contributes to the 'united airways disease'. PMID- 26764560 TI - Platelet activation at the onset of human endotoxemia is undetectable in vivo. AB - Infection induces platelet activation and consumption, which leads to thrombocytopenia, enhances microvascular thrombosis, impairs microcirculation and eventually triggers disseminated intravascular coagulation (DIC). It is well characterized that endotoxemia results in a pro-inflammatory and pro-coagulatory state, which favors platelet activation. However the early, direct effects of endotoxemia on platelets have not been investigated so far. Therefore we aimed to determine the early effects of the endotoxin lipopolysaccharide (LPS) on platelet function in vivo. In a human endotoxemia model, 15 healthy volunteers were stimulated with LPS (2 ng/kg). Blood was drawn before, 10, 30 and 60 min after LPS challenge and platelet activation analyzed by flow cytometry (GPIIb/IIIa activation, surface CD62P and CD40L, intraplatelet reactive oxygen formation and platelet-leukocyte aggregates) and ELISA (sCD40L, sCD62P and CXCL4). In parallel, blood samples and platelets were spiked with LPS (50 pg/ml) in vitro and monitored over 60 min for the same platelet activation markers. In vitro platelet stimulation with LPS activated platelets independent of the presence of leukocytes and enhanced their adhesion to endothelial cells. In contrast, in vivo no increase in GPIIb/IIIa activation or surface expression of CD62P was observed. However, endotoxemia resulted in a significant drop in platelet count and elevated the plasma CXCL4 levels already 10 min after the LPS challenge. These data indicate that LPS rapidly activates platelets, leading to alpha-granule release and endothelial adhesion. This might explain the drop in platelet count observed at the onset of endotoxemia. PMID- 26764562 TI - Solution synthesis of telluride-based nano-barbell structures coated with PEDOT:PSS for spray-printed thermoelectric generators. AB - Solution-processable telluride-based heterostructures coated with poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (Te-Bi2Te3/PEDOT:PSS) were synthesized through a solution-phase reaction at low temperatures. The water based synthesis yielded PEDOT: PSS-coated Te-Bi2Te3 nano-barbell structures with a high Seebeck coefficient that can be stably dispersed in water. These hybrid solutions were deposited onto a substrate by the spray-printing method to prepare thermoelectric generators. The thermoelectric properties of the Te Bi2Te3/PEDOT:PSS hybrid films were significantly enhanced by a simple acid treatment due to the increased electrical conductivity, and the power factor of those materials can be effectively tuned over a wide range depending on the acid concentration of the treatment. The power factors of the synthesized Te Bi2Te3/PEDOT:PSS hybrids were optimized to 60.05 MUW m(-1) K(-2) with a Seebeck coefficient of 93.63 MUV K(-1) and an electrical conductivity of 69.99 S cm(-1). The flexible thermoelectric generator fabricated by spray-printing Te Bi2Te3/PEDOT:PSS hybrid solutions showed an open-circuit voltage of 1.54 mV with six legs at DeltaT = 10 degrees C. This approach presents the potential for realizing printing-processable hybrid thermoelectric materials for application in flexible thermoelectric generators. PMID- 26764561 TI - Effect of High Pressure Homogenization and Dimethyl Dicarbonate (DMDC) on Microbial and Physicochemical Qualities of Mulberry Juice. AB - In this study, the effect of high pressure homogenization (HPH) and dimethyl dicarbonate (DMDC) on microbial and nutrient qualities of mulberry juice was evaluated. Results showed that repeated HPH passes at 200 MPa or adding DMDC at 250 mg/L significantly inactivated the indigenous microorganisms in mulberry juice (P < 0.05), whereas some surviving microorganisms recovered to grow during storage of 4 degrees C. The combined treatment with 3 passes of HPH and 250 mg/L of DMDC (HPH-DMDC) decreased the population of surviving indigenous microorganisms to the level attained by heat treatment at 95 degrees C for 1 min (HT) with no significant increase (P > 0.05) in the population of microorganisms during subsequent storage at 4 degrees C. Moreover, no significant changes (P > 0.05) in the physical attributes, including pH, TSS ((o) Brix), L*, a*, and b* values were observed in the samples treated by the HPH-DMDC or by HT. Compared with HT, HPH-DMDC treatment resulted in a higher degree of retention in total phenolics, and alpha-glucosidase inhibitory activity, although the treatment led to higher losses in cyanidin 3-glucoside, cyanidin 3-rutinoside, and antioxidant capacity. Overall, HPH-DMDC treatment can be a useful alternative to conventional thermal pasteurization of mulberry juice, considering its ability to inactive, and inhibit indigenous microorganisms. PMID- 26764563 TI - Black Carbon Emissions from Associated Natural Gas Flaring. AB - Approximately 150 billion cubic meters (BCM) of natural gas is flared and vented in the world annually, emitting greenhouse gases and other pollutants with no energy benefit. About 7 BCM per year is flared in the United States, and half is from North Dakota alone. There are few emission measurements from associated gas flares and limited black carbon (BC) emission factors have been previously reported from the field. Emission plumes from 26 individual flares in the Bakken formation in North Dakota were sampled. Methane, carbon dioxide, and BC were measured simultaneously, allowing the calculation of BC mass emission factors using the carbon balance method. Particle optical absorption was measured using a three-wavelength particle soot absorption photometer (PSAP) and BC particle number and mass concentrations were measured with a single particle soot photometer. The BC emission factors varied over 2 orders of magnitude, with an average and uncertainty range of 0.14 +/- 0.12 g/kg hydrocarbons in associated gas and a median of 0.07 g/kg which represents a lower bound on these measurements. An estimation of the BC emission factor derived from PSAP absorption provides an upper bound at 3.1 g/kg. These results are lower than previous estimations and laboratory measurements. The BC mass absorption cross section was 16 +/- 12 m(2)/g BC at 530 nm. The average absorption Angstrom exponent was 1.2 +/- 0.8, suggesting that most of the light absorbing aerosol measured was black carbon and the contribution of light absorbing organic carbon was small. PMID- 26764564 TI - The Changing Landscape of Pediatric Low-Grade Gliomas: Clinical Challenges and Emerging Therapies. AB - Pediatric low-grade gliomas (PLGGs) are the most common brain tumors in children. Though histologically benign and associated with excellent outcome, patients with unresectable lesions--mostly young children with midline tumors--experience multiple progressions and are at increased risk for long-term neurological sequelae. PLGGs in children with underlying genetic predisposition syndromes- especially neurofibromatosis type 1 and tuberous sclerosis--have a distinct natural history and biology with important treatment implications. Given the complexity of medical issues, optimal management requires a large network of health care providers; treatment decisions must address both tumor control and potential side effects of the therapy. Current treatment strategies often fail to induce sustained tumor regression and many children require several lines of therapy, highlighting the need for novel therapies. Here, we review the current management of PLGG and discuss how new molecular targets--in particular alterations of the Ras/MAPK pathway--are rapidly changing our approach to PLGG. PMID- 26764566 TI - Introduction to the special issue on "The Last Word on Prevention". PMID- 26764565 TI - Reconsidering the Resources Needed for Multiple Casualty Events: Lessons Learned From the Crash of Asiana Airlines Flight 214. AB - IMPORTANCE: To date, a substantial portion of multiple casualty incident literature has focused exclusively on prehospital and emergency department resources needed for optimal disaster response. Thus, inpatient resources required to care for individuals injured in multiple casualty events are not well described. OBJECTIVE: To highlight the resources beyond initial emergency department triage needed for multiple casualty events, using one of the largest commercial aviation disasters in modern US history as a case study. DESIGN, SETTING, AND PARTICIPANTS: Prospective case series of injured individuals treated at an urban level I trauma center following the crash of Asiana Airlines flight 214 on July 6, 2013. This analysis was conducted between June 1, 2014, and December 1, 2015. EXPOSURE: Commercial jetliner crash. MAIN OUTCOMES AND MEASURES: Medical records, imaging data, nursing overtime, blood bank records, and trauma registry data were analyzed. Disaster logs, patient injuries, and blood product data were prospectively collected during the incident. RESULTS: Among 307 people aboard the flight, 192 were injured; 63 of the injured patients were initially evaluated at San Francisco General Hospital and Trauma Center (the highest number at any of the receiving medical facilities; age range, 4-74 years [23 were aged <17 years and 3 were aged >60 years]; median injury severity score of 19 admitted patients, 9 [range, 9-45]), including the highest number of critically injured patients (10 of 12). Despite the high impact of the crash, only 3 persons (<1%) died, including 1 in-hospital death. Among the 63 patients, 32 (50.8%) underwent a computed tomographic imaging study, with imaging of the abdomen and pelvis being the most common. Sixteen of the 32 patients undergoing computed tomography (50.0%) had a positive finding on at least 1 scan. Nineteen patients had major injuries and required admission, with 5 taken directly from the emergency department to the operating room. The most frequent injury was spinal fracture (13 patients). In the first 48 hours, 15 operations were performed and 117 total units of blood products were transfused. A total of 370 nursing overtime hours were required to treat the injured patients on the day of the event. CONCLUSIONS AND RELEVANCE: Proper disaster preparedness requires attention to hospital-level needs beyond initial emergency department triage. The Asiana Airlines flight 214 crash highlights the need to plan for high use of advanced imaging, blood products, operating room availability, nursing resources, and management of inpatient hospital beds. PMID- 26764567 TI - Atomic scale insights into urea-peptide interactions in solution. AB - The mechanism by which proteins are denatured by urea is still not well understood, especially on the atomic scale where these interactions occur in vivo. In this study, the structure of the peptide GPG has been investigated in aqueous urea solutions in order to understand the combination of roles that both urea and water play in protein unfolding. Using a combination of neutron diffraction enhanced by isotopic substitution and computer simulations, it was found, in opposition with previous simulations studies, that urea is preferred over water around polar and charged portions of the peptides. Further, it appears that while urea directly replaces water around the nitrogen groups on GPG that urea and water occupy different positions around the peptide bond carbonyl groups. This suggests that urea may in fact weaken the peptide bond, disrupting the peptide backbone, thus ultimately causing denaturation. PMID- 26764568 TI - Radiation-induced autophagy: mechanisms and consequences. AB - Autophagy is an evolutionary conserved, indispensable, lysosome-mediated degradation process, which helps in maintaining homeostasis during various cellular traumas. During stress, a context-dependent role of autophagy has been observed which drives the cell towards survival or death depending upon the type, time, and extent of the damage. The process of autophagy is stimulated during various cellular insults, e.g. oxidative stress, endoplasmic reticulum stress, imbalances in calcium homeostasis, and altered mitochondrial potential. Ionizing radiation causes ROS-dependent as well as ROS-independent damage in cells that involve macromolecular (mainly DNA) damage, as well as ER stress induction, both capable of inducing autophagy. This review summarizes the current understanding on the roles of oxidative stress, ER stress, DNA damage, altered mitochondrial potential, and calcium imbalance in radiation-induced autophagy as well as the merits and limitations of targeting autophagy as an approach for radioprotection and radiosensitization. PMID- 26764569 TI - In their own words: A qualitative study of the psychosocial concerns of posttreatment and long-term lung cancer survivors. AB - Although lung cancer is the deadliest type of cancer, survival rates are improving. To address the dearth of literature about the concerns of lung cancer survivors, the authors conducted 21 in-depth interviews with lung cancer survivors that focused on experiences during diagnosis, treatment, and long-term survivorship. Emergent themes included feeling blamed for having caused their cancer, being stigmatized as throwaways, and long-term survivors' experiencing surprise that they are still alive, given poor overall survival rates. Survivors also desired increased public support. It is imperative for healthcare and public health professionals to learn more about needs of this population. PMID- 26764570 TI - Electrochemical examination of ability of dsDNA/PAM composites for storing and releasing of doxorubicin. AB - Composites consisting of ss- and ds-DNA strands and polyacrylamide (PAM) hydrogel have been synthesized. DNA was entrapped non-covalently. The obtained DNA biomaterial exhibited a strong increase in guanine and adenine anodic currents when temperature reached the physiological level. This increase was related to the unique oligonucleotide structural changes in the composite. The structural alterations in the PAM lattices were employed for the release of the drug accumulated in the composite. Doxorubicin (Dox) was selected as the drug; it was accumulated by intercalation to dsDNA and was slowly released from the dsDNA/PAM system by using a minor temperature increase (up to 40/45 degrees C) as it is routinely done in hyperthermia. The applied release temperature was either constant or oscillating. The binding strength, the rate of Dox release and the properties of the composite were examined using voltammetry, SEM and ICP-MS. PMID- 26764571 TI - Comparison of various advanced oxidation processes for the degradation of phenylurea herbicides. AB - Various types of advanced oxidation processes (AOPs), such as UV photolysis, ozonation, heterogeneous photocatalysis and their combinations were comparatively examined at the same energy input in a home-made reactor. The oxidative transformations of the phenylurea herbicides fenuron, monuron and diuron were investigated. The initial rates of transformation demonstrated that UV photolysis was highly efficient in the cases of diuron and monuron. Ozonation proved to be much more effective in the transformation of fenuron than in those of the chlorine containing monuron and diuron. In heterogeneous photocatalysis, the rate of decomposition decreased with increase of the number of chlorine atoms in the target molecule. Addition of ozone to UV-irradiated solutions and/or TiO2 containing suspensions markedly increased the initial rates of degradation. Dehalogenation of monuron and diuron showed that each of these procedures is suitable for the simultaneous removal of chlorinated pesticides and their chlorinated intermediates. Heterogeneous photocatalysis was found to be effective in the mineralization. PMID- 26764574 TI - Solidification of nanosuspensions for the production of solid oral dosage forms and inhalable dry powders. AB - INTRODUCTION: Nanosuspensions combine the advantages of nanotherapeutics (e.g. increased dissolution rate and saturation solubility) with ease of commercialisation. Transformation of nanosuspensions to solid oral and inhalable dosage forms minimises the physical instability associated with their liquid state, enhances patient compliance and enables targeted oral and pulmonary drug delivery. AREAS COVERED: This review outlines solidification methods for nanosuspensions. It includes spray and freeze drying as the most widely used techniques. Fluidised-bed coating, granulation and pelletisation are also discussed as they yield nanocrystalline formulations with more straightforward downstream processing to tablets or capsules. Spray-freeze drying, aerosol flow reactor and printing of nanosuspensions are also presented as promising alternative solidification techniques. Results regarding the solid state, in vitro dissolution and/or aerosolisation efficiency of the nanocrystalline formulations are given and combined with available in vivo data. Focus is placed on the redispersibility of the solid nanocrystalline formulations, which is a prerequisite for their clinical application. EXPERT OPINION: A few solidified nanocrystalline products are already on the market and many more are in development. Oral and inhalable nanoparticle formulations are expected to have great potential especially in the areas of personalised medicine and delivery of high drug doses (e.g. antibiotics) to the lungs, respectively. PMID- 26764572 TI - FoxO3 suppresses Myc-driven lymphomagenesis. AB - This study demonstrates, for the first time, that loss of a single forkhead box class O (FoxO) transcription factor, can promote lymphomagenesis. Using two different mouse models, we show that FoxO3 has a significant tumour-suppressor function in the context of Myc-driven lymphomagenesis. Loss of FoxO3 significantly accelerated myeloid tumorigenesis in vavP-MYC10 transgenic mice and B lymphomagenesis in EMU-myc transgenic mice. Tumour analysis indicated that the selective pressure for mutation of the p53 pathway during EMU-myc lymphomagenesis was not altered. Frank tumours were preceded by elevated macrophage numbers in FoxO3(-/-) vavP-MYC10 mice but, surprisingly, pre-B-cell numbers were relatively normal in healthy young FoxO3(-/-)EMU-myc mice. In vitro assays revealed enhanced survival capacity of Myc-driven cells lacking FoxO3, but no change in cell cycling was detected. The loss of FoxO3 may also be affecting other tumour suppressive functions for which FoxO1/4 cannot fully compensate. PMID- 26764573 TI - An immediate transcriptional signature associated with response to the histone deacetylase inhibitor Givinostat in T acute lymphoblastic leukemia xenografts. AB - Despite some success with certain hematological malignancies and in contrast with the strong pro-apoptotic effects measured in vitro, the overall response rate of acute lymphoblastic leukemia (ALL) to histone deacetylase inhibitors (HDACis) is low. With the aim to improve the understanding of how HDACis work in vivo, we investigated the therapeutic efficacy of the clinically approved HDACi Givinostat in a collection of nine pediatric human T-ALL engrafted systemically in NOD/SCID mice. We observed highly heterogeneous antileukemia responses to Givinostat, associated with reduction of the percentage of infiltrating blasts in target organs, induction of apoptosis and differentiation. These effects were not associated with the T-ALL cytogenetic subgroup. Transcriptome analysis disclosed an immediate transcriptional signature enriched in genes involved in cell-cycle regulation and DNA repair, which was validated by quantitative RT-PCR and was associated with in vivo response to this HDACi. Increased phospho-H2AX levels, a marker of DNA damage, were measured in T-ALL cells from Givinostat responders. These results indicate that the induction of the DNA damage response could be an early biomarker of the therapeutic effects of Givinostat in T-ALL models. This information should be considered in the design of future clinical trials with HDACis in acute leukemia. PMID- 26764575 TI - Anatomical Relationship Between the Kidney Collecting System and the Intrarenal Arteries in the Sheep: Contribution for a New Urological Model. AB - Previous studies have demonstrated that the pig collecting system heals after partial nephrectomy without closure. Recently, a study in sheep showed that partial nephrectomy without closure of the collecting system resulted in urinary leakage and urinoma. The aim of this study was to present detailed anatomical findings on the intrarenal anatomy of the sheep. Forty two kidneys were used to produce tridimensional endocasts of the collecting system together with the intrarenal arteries. A renal pelvis which displayed 11-19 (mean of 16) renal recesses was present. There were no calices present. The renal artery was singular in each kidney and gave two primary branches one to the dorsal surface and one to ventral surface. Dorsal and ventral branches of the renal artery were classified based on the relationship between their branching pattern and the collecting system as: type I (cranial and caudal segmental arteries), type II (cranial, middle and caudal segmental arteries) or type III (cranial, cranial middle, caudal middle, and caudal segmental arteries). Type I was the most common branching pattern for the dorsal and ventral branches of the renal artery. The arterial supply of the caudal pole of the sheep kidney supports its use as an experimental model due to the similarity to the human kidney. However, the lack of a retropelvic artery discourages the use of the cranial pole in experiments in which the arteries are an important aspect to be considered. PMID- 26764576 TI - Identification of smoking using Medicare data--a validation study of claims-based algorithms. AB - PURPOSE: This study examined the accuracy of claims-based algorithms to identify smoking against self-reported smoking data. METHODS: Medicare patients enrolled in the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study were identified. For each patient, self-reported smoking status was extracted from Women's Hospital Rheumatoid Arthritis Sequential Study and the date of this measurement was defined as the index-date. Two algorithms identified smoking in Medicare claims: (i) only using diagnoses and procedure codes and (ii) using anti smoking prescriptions in addition to diagnoses and procedure codes. Both algorithms were implemented: first, only using 365-days pre-index claims and then using all available pre-index claims. Considering self-reported smoking status as the gold standard, we calculated specificity, sensitivity, positive predictive value, negative predictive value (NPV), and area under the curve (AUC). RESULTS: A total of 128 patients were included in this study, of which 48% reported smoking. The algorithm only using diagnosis and procedure codes had the lowest sensitivity (9.8%, 95%CI 2.4%-17.3%), NPV (54.9%, 95%CI 46.1%-63.9%), and AUC (0.55, 95%CI 0.51-0.59) when applied in the period of 365 days pre-index. Incorporating pharmacy claims and using all available pre-index information improved the sensitivity (27.9%, 95%CI 16.6%-39.1%), NPV (60.4%, 95%CI 51.3% 69.5%), and AUC (0.64, 95%CI 0.58-0.70). The specificity and positive predictive value was 100% for all the algorithms tested. CONCLUSION: Claims-based algorithms can identify smokers with limited sensitivity but very high specificity. In the absence of other reliable means, use of a claims-based algorithm to identify smoking could be cautiously considered in observational studies. PMID- 26764577 TI - Extent of pleural effusion on chest radiograph is associated with failure of high flow nasal cannula oxygen therapy. AB - PURPOSE: The purpose of the study was to determine whether pleural effusion (PE) is associated with a failure of high-flow nasal cannula (HFNC) therapy. MATERIALS AND METHODS: We conducted a single-center retrospective study. Seventy-three patients with acute respiratory failure given HFNC therapy between January 2012 and December 2014 were reviewed. HFNC failure was defined as intubation or noninvasive positive pressure ventilation following HFNC therapy. The numbers of quadrants with consolidation or ground glass opacity were counted on chest radiographs performed within 24 hours before starting HFNC therapy, and the PE score was calculated. PE score was the original score, verified by the computed tomographic images of some of the study patients. RESULTS: Overall, 29 of 73 experienced HFNC failure. PE score was significantly greater in the HFNC failure group, but the number of quadrants with opacity was not significantly different. Age and Sequential Organ Failure Assessment (SOFA) score were significantly greater in the HFNC failure group. The PE (odds ratio, 1.49; 95% confidence interval, 1.10-2.02; P = .01) and SOFA (odds ratio, 1.33; 95% confidence interval, 1.05-1.68; P = .02) scores were independently associated with HFNC failure in multivariate analysis. CONCLUSIONS: The extent of PE on chest radiograph and SOFA score were associated with HFNC failure. PMID- 26764578 TI - Delayed anticoagulation is associated with poor outcomes in high-risk acute pulmonary embolism. AB - PURPOSE: Early diagnosis and timely treatment are essential to improve the outcomes of pulmonary embolism (PE), but no study has investigated the impact of anticoagulation timing on clinical outcomes in high-risk acute PE patients. We analyzed the relationship between early anticoagulation initiation and in hospital mortality in high-risk acute PE patients at the intensive care unit (ICU) of a teaching hospital. MATERIALS AND METHODS: Seventy-three PE patients admitted to the ICU were included in this retrospective study. Demographic, clinical, radiological, and therapeutic data were collected on ICU admission, and the timings of diagnosis and anticoagulation initiation were analyzed. RESULTS: The number of survivors was 67. The median time from hospital arrival to the start of anticoagulation therapy was significantly lower in survivors (3.6 [2.6 5.0] hours) than nonsurvivors (5.7 [4.5-14.9] hours; P = .03). However, the median time required to achieve a therapeutic anticoagulation level was comparable between survivors and nonsurvivors (12.0 [9.5-19.5] vs 16.4 [10.7 27.4] hours; P = .488). Ventilatory support and vasopressor use were found to be associated with higher in-hospital mortality. CONCLUSIONS: Delayed anticoagulation is an important prognostic factor of poor outcomes in high-risk acute PE patients. PMID- 26764579 TI - Clinical equipoise on prophylaxis against catheter-associated thrombosis in critically ill children. AB - PURPOSE: In preparation for a randomized controlled trial of prophylaxis against catheter-associated deep venous thrombosis in critically ill children, we aimed to determine clinical equipoise, defined as willingness to randomize children, among pediatric critical care physicians. MATERIALS AND METHODS: We conducted a cross-sectional, self-administered electronic survey of pediatric critical care physicians in the United States. The survey focused on the effect of child's age, presence of a central venous catheter, and risk (ie, presence of coagulopathy or recent surgery) and presence of bleeding on their willingness to randomize children to an anticoagulant or placebo. RESULTS: Responses from 239 (33.0%) of 725 physicians were analyzed. Respondents were willing to randomize children 1 month or older in the presence of a catheter but only those older than 13 years in the absence of a catheter. For children with coagulopathy, they would randomize those with international normalized ratio less than or equal to 2.0, partial thromboplastin time less than or equal to 50 seconds, and platelet count greater than or equal to 50000/mm(3). Respondents were willing to randomize children 2 days after most types of surgery and after 1 to 5 days of a bleeding event. CONCLUSIONS: Clinical equipoise on prophylaxis against catheter-associated thrombosis exists among pediatric critical care physicians, which ethically justifies conducting a randomized controlled trial. PMID- 26764582 TI - The effects of device position on the operator's radiation dose when using a handheld portable X-ray device. AB - INTRODUCTION: Handheld X-ray devices are now offered in dental practice. Handheld X-ray units challenge the concept of a restricted access to the "controlled area" as they are held by the operator. Although an integral lead shield is provided, the distance from the body is variable, dependent on how the device is held. The aim of this article was to investigate the level of operator dose when using a handheld X-ray device in various positions. MATERIAL AND METHODS: A NOMAD ProTM Handheld X-ray system (Aribex Inc., Charlotte, NC) fitted with a remote control and mounted on a tripod was used in this study. A maxillofacial phantom ATOM((r)) Max Dental and Diagnostic Phantom, model 711 HN (CIRS Inc., Norfolk, VA) was used to simulate the patient's head position. A mannequin was used to represent the operator. Pre-calibrated thermoluminescent dosemeters (TLDs) (Qados, Agar Scientific, Stansted, UK) were placed on the mannequin close to the eyes and at the level of thyroid, trunk, waist, hand (right finger + left palm) and feet, and three TLDs were used for background radiation. Three test scenarios were investigated; Position 1, close to operators' body and parallel to the ground; Position 2, away from the body with the arms fully extended (approximately 40 cm distance) and parallel to the ground; Position 3, perpendicular to the ground while the arms are partially extended. 30 exposures each of 1 s were performed in each test. RESULTS: Background radiation was measured at 0.0110 mGy. The highest exposure after subtracting background radiation was recorded on the palm of the left hand (0.0310 mGy) at Position 3. The estimated dose to the operator was calculated based on an average workload of 100 intraoral radiographs weekly for a dental practitioner working 46 weeks a year. CONCLUSIONS: There is a negligible increase in operator exposure levels using handheld X-ray devices which remain well below the recommended levels of the Ionizing Radiation Regulations 1999. They could however represent an increase from what should be a nil exposure when using a wall-mounted machine. The position of the device relative to the operator has a significant effect on the overall operator's radiation exposure. The use of personal dosemeters is highly recommended to ensure a continuity of low radiation dose exposure. Furthermore, guidance, training and protocols on usage must be in place, strictly adhered to and regular audits are necessary to ensure compliance. PMID- 26764583 TI - A comparative study of new and current methods for dental micro-CT image denoising. AB - OBJECTIVES: The aim of the current study was to evaluate the application of two advanced noise-reduction algorithms for dental micro-CT images and to implement a comparative analysis of the performance of new and current denoising algorithms. METHODS: Denoising was performed using gaussian and median filters as the current filtering approaches and the block-matching and three-dimensional (BM3D) method and total variation method as the proposed new filtering techniques. The performance of the denoising methods was evaluated quantitatively using contrast to-noise ratio (CNR), edge preserving index (EPI) and blurring indexes, as well as qualitatively using the double-stimulus continuous quality scale procedure. RESULTS: The BM3D method had the best performance with regard to preservation of fine textural features (CNREdge), non-blurring of the whole image (blurring index), the clinical visual score in images with very fine features and the overall visual score for all types of images. On the other hand, the total variation method provided the best results with regard to smoothing of images in texture-free areas (CNRTex-free) and in preserving the edges and borders of image features (EPI). CONCLUSIONS: The BM3D method is the most reliable technique for denoising dental micro-CT images with very fine textural details, such as shallow enamel lesions, in which the preservation of the texture and fine features is of the greatest importance. On the other hand, the total variation method is the technique of choice for denoising images without very fine textural details in which the clinician or researcher is interested mainly in anatomical features and structural measurements. PMID- 26764584 TI - Ultrasonographic localization of the thyroid gland for its optimal shielding prior to lateral cephalometric radiography: a pilot study. AB - OBJECTIVES: Lateral cephalometric radiography is a common radiographic examination technique in children. The exclusion of the thyroid gland from the primary X-ray beam is important especially with children. However, patient treatment might require displaying the four most cranial cervical vertebrae (C1 C4) for the assessment of cervical vertebral maturation. Our aim was to present a safe way to display C1-C4 and exclude the thyroid gland from the X-ray beam during lateral cephalometric radiography. METHODS: The thyroid glands of 25, 7- to 12-year-old patients were localized by ultrasound examination and shielded prior to lateral cephalometric radiography. A roentgen-positive mark was taped on the patient's skin at the level of most cranial level of the thyroid gland in the midsagittal plane. After exposure, each lateral cephalometric radiograph (LCR) was analyzed for the visibility of the cervical vertebrae. The distance between the ear post and the highest edge of the thyroid shield (TS) at the lateral part of the neck was measured and compared with the distance between the centre of the radiological external auditory meatus, and a roentgen-positive mark was made on the LCR. RESULTS: 68% of the LCRs displayed C1-C4, and the rest of them displayed C1-C3. In all of the patients, the highest edge of the TS in the lateral parts of the neck was located in a higher position than the actual most cranial level of the thyroid gland. CONCLUSIONS: Despite localizing the thyroid gland prior to lateral cephalometric radiography, simultaneous visualization of C1-C4 and exclusion of the thyroid gland from the primary X-ray beam during lateral cephalometric radiography might not be completely possible in children because of the design and poor fitness of the TS. PMID- 26764585 TI - Facets of clinicians' anxiety and the delivery of cognitive behavioral therapy. AB - Psychological therapists commonly fail to adhere to treatment protocols in everyday clinical practice. In part, this pattern of drift is attributable to anxious therapists being less likely to undertake some elements of evidence-based therapies - particularly the exposure-based elements. This study considers what facets of anxiety (cognitive, behavioral, physiological) are related to junior clinicians' reported use of cognitive-behavioral therapy techniques. Thirty-two clinicians (mean age = 28.9 years; mean length of CBT experience = 1.5 years; 23 female, nine male) who offered CBT were assessed for their cognitive, behavioral and physiological characteristics (Intolerance of Uncertainty scale; risk taking; skin conductance response and heart rate variability). While the three different facets of anxiety were relatively poorly associated with each other, as is usual in this literature, each facet was linked differently to the reported delivery of CBT techniques (P < .05). Overall, higher anxiety levels were associated with a poorer use of exposure methods or with a greater use of other behavioral or cognitive methods. Of the three facets of anxiety, only physiological reactivity showed an association with the clinicians' temporal characteristics, with more experienced therapists being more likely to have greater skin conductance responses to positive and negative outcomes. These findings suggest that clinicians who are more anxious are less likely to deliver the full evidence based form of CBT and to focus instead on less challenging elements of the therapy. Potential ways of overcoming this limitation are discussed. PMID- 26764587 TI - Directly Binding Rather than Induced-Fit Dominated Binding Affinity Difference in (S)- and (R)-Crizotinib Bound MTH1. AB - As one of the most successful anticancer drugs, crizotinib is found to be efficient in the suppression of MTH1, a new therapeutic target for RAS-dependent cancers. Deep analysis shows that stereospecificity is prevalent in the binding of crizotinib to MTH1, where the target is more preferred to bind with the (S) enantiomer of crizotinib. Surprisingly, very similar binding modes were found for the two enantiomers (Huber et al. Nature 2014, 508, 222-227), which puzzled us to ask a question as to why such a subtle structural variation could lead to so large of a binding affinity difference. Thereafter, by using advanced all-atom molecular dynamics simulations, we characterized the free energy surfaces of the binding/unbinding processes of the (S) and (R)-crizotinib enantiomers to/from MTH1. Interestingly, we found that rather than the induced-fit process, which is prevalent in drug selectivity and specificity (Wilson et al. Science 2015, 347, 882-886), the directly binding process has dominated impact on the binding affinity difference of the enantiomers, implying a common mechanism of stereoselectivity of enantiomers. PMID- 26764586 TI - Dialectical behavior therapy and domains of functioning over two years. AB - Individuals diagnosed with borderline personality disorder (BPD) tend to have a significant degree of functional impairment across a range of social and occupational spheres including difficulty finding and maintaining satisfying employment, housing, or relationships. Understanding what factors are associated with functional impairment will enable treatment providers to move those diagnosed with BPD beyond symptomatic recovery and toward a life worth living. This paper investigated the trajectories and predictors of functional outcomes for suicidal women with BPD (N = 99) during a treatment outcome study of Dialectical Behavior Therapy (DBT). Results revealed that participants had statistical and clinical improvements in functioning. Individuals with high emotion dysregulation displayed poorer psychosocial functioning at the subsequent assessment period and slower rates of change, which was also seen in reverse for one psychosocial functioning variable. Skills use was not related to individual trajectories in functioning. This study highlights the relationship of emotion dysregulation to functioning within a sample of suicidal women with BPD as well as the importance researching multiple domains in functioning. PMID- 26764588 TI - Metformin Joins Forces with Microbes. AB - The gut microbiota is a key player regulating human physiology and can adjust its structure and metabolic activity in response to host health. A recent Nature paper by Forslund et al. (2015) reveals that microbiota adaptation to metformin treatment are responsible for the drug's therapeutic effects against type 2 diabetes. PMID- 26764589 TI - Acute Gastroenteritis Leaves a Lasting Impression. AB - Host immunity shapes intestinal microbiota composition, influencing health and disease. In this issue of Cell Host & Microbe,Kamdar et al. (2016) demonstrate that an aberrant acute inflammatory response to Yersinia enterocolitica infection leads to long-lasting shifts in commensal communities and renders the host susceptible to chronic inflammation despite pathogen clearance. PMID- 26764590 TI - H. pylori's BabA Embraces Change. AB - Long before the cause was discovered, peptic ulcers were known to occur preferentially in individuals of certain blood groups. In this issue of Cell Host & Microbe, Moonens et al. (2016) perform structural analyses of the Helicobacter pylori adhesin BabA to determine how the bacteria discriminately bind different blood group glycans. PMID- 26764591 TI - MAPping the Function of Phytopathogen Effectors. AB - Pseudomonas syringae secretes effectors from its type III secretion system to infect plants. In this issue of Cell Host & Microbe, Guo et al. (2016) determine that the T3SS effector, HopE1, targets calmodulin and the microtubule-associated protein MAP65-1 to subvert plant immunity. PMID- 26764592 TI - Autophagy Snuffs a Macrophage's Inner Fire. AB - Autophagy is a well-known cell-intrinsic antiviral defense mechanism. Two new studies published in this issue of Cell Host & Microbe (Lu et al., 2016; Park et al., 2016) demonstrate that deletion of autophagy in myeloid cells leads paradoxically to better control of viral infection in vivo through enhanced inflammation, leading to antiviral resistance. PMID- 26764593 TI - Taking it Personally: Personalized Utilization of the Human Microbiome in Health and Disease. AB - The genomic revolution enabled the clinical inclusion of an immense body of person-specific information to an extent that is revolutionizing medicine and science. The gut microbiome, our "second genome," dynamically integrates signals from the host and its environment, impacting health and risk of disease. Herein, we summarize how individualized characterization of the microbiome composition and function may assist in personalized diagnostic assessment, risk stratification, disease prevention, treatment decision-making, and patients' follow up. We further discuss the limitations, pitfalls, and challenges that the microbiome field faces in integrating patient-specific microbial data into the clinical realm. Finally, we highlight how recent insights into personalized modulation of the microbiome, by nutritional and pre-, pro-, and post-biotic intervention, may lead to development of individualized approaches that may enable us to harness the microbiome as a central precision medicine target. PMID- 26764594 TI - Genetic and Metabolic Signals during Acute Enteric Bacterial Infection Alter the Microbiota and Drive Progression to Chronic Inflammatory Disease. AB - Chronic inflammatory disorders are thought to arise due to an interplay between predisposing host genetics and environmental factors. For example, the onset of inflammatory bowel disease is associated with enteric proteobacterial infection, yet the mechanistic basis for this association is unclear. We have shown previously that genetic defiency in TLR1 promotes acute enteric infection by the proteobacteria Yersinia enterocolitica. Examining that model further, we uncovered an altered cellular immune response that promotes the recruitment of neutrophils which in turn increases metabolism of the respiratory electron acceptor tetrathionate by Yersinia. These events drive permanent alterations in anti-commensal immunity, microbiota composition, and chronic inflammation, which persist long after Yersinia clearence. Deletion of the bacterial genes involved in tetrathionate respiration or treatment using targeted probiotics could prevent microbiota alterations and inflammation. Thus, acute infection can drive long term immune and microbiota alterations leading to chronic inflammatory disease in genetically predisposed individuals. PMID- 26764595 TI - The Host Shapes the Gut Microbiota via Fecal MicroRNA. AB - The host gut microbiota varies across species and individuals but is relatively stable over time within an individual. How the host selectively shapes the microbiota is largely unclear. Here, we show that fecal microRNA (miRNA)-mediated inter-species gene regulation facilitates host control of the gut microbiota. miRNAs are abundant in mouse and human fecal samples and present within extracellular vesicles. Cell-specific loss of the miRNA-processing enzyme, Dicer, identified intestinal epithelial cells (IEC) and Hopx-positive cells as predominant fecal miRNA sources. These miRNAs can enter bacteria, such as F. nucleatum and E. coli, specifically regulate bacterial gene transcripts, and affect bacterial growth. IEC-miRNA-deficient (Dicer1(DeltaIEC)) mice exhibit uncontrolled gut microbiota and exacerbated colitis, and WT fecal miRNA transplantation restores fecal microbes and ameliorates colitis. These findings identify both a physiologic role by which fecal miRNA shapes the gut microbiota and a potential strategy for manipulating the microbiome. PMID- 26764596 TI - Antigen Export Reduces Antigen Presentation and Limits T Cell Control of M. tuberculosis. AB - Persistence of Mycobacterium tuberculosis results from bacterial strategies that manipulate host adaptive immune responses. Infected dendritic cells (DCs) transport M. tuberculosis to local lymph nodes but activate CD4 T cells poorly, suggesting bacterial manipulation of antigen presentation. However, M. tuberculosis antigens are also exported from infected DCs and taken up and presented by uninfected DCs, possibly overcoming this blockade of antigen presentation by infected cells. Here we show that the first stage of this antigen transfer, antigen export, benefits M. tuberculosis by diverting bacterial proteins from the antigen presentation pathway. Kinesin-2 is required for antigen export and depletion of this microtubule-based motor increases activation of antigen-specific CD4 T cells by infected cells and improves control of intracellular infection. Thus, although antigen transfer enables presentation by bystander cells, it does not compensate for reduced antigen presentation by infected cells and represents a bacterial strategy for CD4 T cell evasion. PMID- 26764598 TI - A Bacterial Effector Co-opts Calmodulin to Target the Plant Microtubule Network. AB - The bacterial pathogen Pseudomonas syringae depends on effector proteins secreted by its type III secretion system for the pathogenesis of plants. The majority of these effector proteins are known suppressors of immunity, but their plant targets remain elusive. Using Arabidopsis thaliana as a model host, we report that the HopE1 effector uses the host calcium sensor, calmodulin (CaM), as a co factor to target the microtubule-associated protein 65 (MAP65), an important component of the microtubule network. HopE1 interacted with MAP65 in a CaM dependent manner, resulting in MAP65-GFP dissociation from microtubules. Transgenic Arabidopsis expressing HopE1 had reduced secretion of the immunity protein PR-1 compared to wild-type plants. Additionally, Arabidopsis map65-1 mutants were immune deficient and were more susceptible to P. syringae. Our results suggest a virulence strategy in which a pathogen effector is activated by host calmodulin to target MAP65 and the microtubule network, thereby inhibiting cell wall-based extracellular immunity. PMID- 26764597 TI - Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori. AB - The Helicobacter pylori adhesin BabA binds mucosal ABO/Le(b) blood group (bg) carbohydrates. BabA facilitates bacterial attachment to gastric surfaces, increasing strain virulence and forming a recognized risk factor for peptic ulcers and gastric cancer. High sequence variation causes BabA functional diversity, but the underlying structural-molecular determinants are unknown. We generated X-ray structures of representative BabA isoforms that reveal a polymorphic, three-pronged Le(b) binding site. Two diversity loops, DL1 and DL2, provide adaptive control to binding affinity, notably ABO versus O bg preference. H. pylori strains can switch bg preference with single DL1 amino acid substitutions, and can coexpress functionally divergent BabA isoforms. The anchor point for receptor binding is the embrace of an ABO fucose residue by a disulfide clasped loop, which is inactivated by reduction. Treatment with the redox-active pharmaceutic N-acetylcysteine lowers gastric mucosal neutrophil infiltration in H. pylori-infected Le(b)-expressing mice, providing perspectives on possible H. pylori eradication therapies. PMID- 26764601 TI - Pre-Emptive Avoidance Strategy (P.E.A.S.) - addressing allergic contact dermatitis in pediatric populations. AB - Pediatric allergic contact dermatitis (ACD) has been increasingly recognized in the United States. Reported rates of positive patch tests in children referred for suspected ACD range between 27 and 95.6%. Many young children are becoming sensitized to contact allergens found in personal hygiene products. We reviewed five recent pediatric patch test studies to determine the top allergens associated with this source of ACD in children. The top ten allergens were neomycin, balsam of Peru, fragrance mix, lanolin, cocamidopropylbetaine, formaldehyde, corticosteroids, methylchlorisothiazolinone (MCI)/methylisothiazolinone (MI), propylene glycol, and benzalkonium chloride. We estimate that one third of children suffering from ACD could potentially benefit from a 'pre-emptive avoidance strategy' (P.E.A.S.) of the stated top 10 allergens. PMID- 26764602 TI - The developmental origins of complex behavior and neuropsychiatric disease. PMID- 26764599 TI - Autophagy Genes Enhance Murine Gammaherpesvirus 68 Reactivation from Latency by Preventing Virus-Induced Systemic Inflammation. AB - Host genes that regulate systemic inflammation upon chronic viral infection are incompletely understood. Murine gammaherpesvirus 68 (MHV68) infection is characterized by latency in macrophages, and reactivation is inhibited by interferon-gamma (IFN-gamma). Using a lysozyme-M-cre (LysMcre) expression system, we show that deletion of autophagy-related (Atg) genes Fip200, beclin 1, Atg14, Atg16l1, Atg7, Atg3, and Atg5, in the myeloid compartment, inhibited MHV68 reactivation in macrophages. Atg5 deficiency did not alter reactivation from B cells, and effects on reactivation from macrophages were not explained by alterations in productive viral replication or the establishment of latency. Rather, chronic MHV68 infection triggered increased systemic inflammation, increased T cell production of IFN-gamma, and an IFN-gamma-induced transcriptional signature in macrophages from Atg gene-deficient mice. The Atg5 related reactivation defect was partially reversed by neutralization of IFN gamma. Thus Atg genes in myeloid cells dampen virus-induced systemic inflammation, creating an environment that fosters efficient MHV68 reactivation from latency. PMID- 26764603 TI - Estimating the prevalence of Parkinson's disease (PD) and proportions of patients with associated dementia and depression among the older adults based on secondary claims data. AB - OBJECTIVES: While the epidemiology of Parkinson's disease (PD) has been extensively studied, data on the prevalence of PD among the older adults in Germany are scarce, based on small samples, and limited to primary data designs. This study estimated the PD prevalence among the older adults in Germany in 2006 using secondary data. METHODS: We included 815,573 health insurance members aged >=65 years from all regions in Germany. PD was identified in case of at least one inpatient or outpatient diagnosis. An outpatient diagnosis had to be confirmed by either a subsequent diagnosis or an antiparkinsonian drug within 12 months. PD was also assumed if a first prescription was confirmed by a diagnosis within 12 months. Cases were checked for a diagnosis of dementia or depression. RESULTS: The standardized prevalence of PD was 1680 (95% confidence interval (CI): 1644 1716) cases per 100,000 persons. The prevalence increased with age and peaked in the age group of >=90 years (4633 cases; 95% CI: 4227-5068) with higher rates in men (1729; 95% CI: 1684-1776) than in women (1644; 95% CI: 1593-1697). Dementia and depression occurred in 26.6% (95% CI: 25.8-27.5) and 32.6 (95% CI: 31.7-33.5) of PD cases, respectively. CONCLUSIONS: The age-related increase of PD prevalence and the age-specific prevalence estimates are in line with other European studies, stressing the public health relevance related to PD. In addition to the minimization of biases that might occur in primary data studies, further strengths of our findings are the large underlying sample size and the coverage of Germany. PMID- 26764604 TI - Rethinking cataract surgery benchmarking, key performance indicators and maintaining professional standards in Australia. PMID- 26764600 TI - Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis. AB - Mutations in the autophagy gene EPG5 are linked to the multisystem human disease Vici syndrome, which is characterized in part by pulmonary abnormalities, including recurrent infections. We found that Epg5-deficient mice exhibited elevated baseline innate immune cellular and cytokine-based lung inflammation and were resistant to lethal influenza virus infection. Lung transcriptomics, bone marrow transplantation experiments, and analysis of cellular cytokine expression indicated that Epg5 plays a role in lung physiology through its function in macrophages. Deletion of other autophagy genes including Atg14, Fip200, Atg5, and Atg7 in myeloid cells also led to elevated basal lung inflammation and influenza resistance. This suggests that Epg5 and other Atg genes function in macrophages to limit innate immune inflammation in the lung. Disruption of this normal homeostatic dampening of lung inflammation results in increased resistance to influenza, suggesting that normal homeostatic mechanisms that limit basal tissue inflammation support some infectious diseases. PMID- 26764606 TI - Coping with Labor Pain. PMID- 26764605 TI - Whole mitochondrial DNA sequencing in Alpine populations and the genetic history of the Neolithic Tyrolean Iceman. AB - The Tyrolean Iceman is an extraordinarily well-preserved natural mummy that lived south of the Alpine ridge ~5,200 years before present (ybp), during the Copper Age. Despite studies that have investigated his genetic profile, the relation of the Iceman's maternal lineage with present-day mitochondrial variation remains elusive. Studies of the Iceman have shown that his mitochondrial DNA (mtDNA) belongs to a novel lineage of haplogroup K1 (K1f) not found in extant populations. We analyzed the complete mtDNA sequences of 42 haplogroup K bearing individuals from populations of the Eastern Italian Alps - putatively in genetic continuity with the Tyrolean Iceman-and compared his mitogenome with a large dataset of worldwide K1 sequences. Our results allow a re-definition of the K1 phylogeny, and indicate that the K1f haplogroup is absent or rare in present-day populations. We suggest that mtDNA Iceman's lineage could have disappeared during demographic events starting in Europe from ~5,000 ybp. Based on the comparison of our results with published data, we propose a scenario that could explain the apparent contrast between the phylogeographic features of maternal and paternal lineages of the Tyrolean Iceman within the context of the demographic dynamics happening in Europe from 8,000 ybp. PMID- 26764608 TI - Michaelis-Menten reaction scheme as a unified approach towards the optimal restart problem. AB - We study the effect of restart, and retry, on the mean completion time of a generic process. The need to do so arises in various branches of the sciences and we show that it can naturally be addressed by taking advantage of the classical reaction scheme of Michaelis and Menten. Stopping a process in its midst-only to start it all over again-may prolong, leave unchanged, or even shorten the time taken for its completion. Here we are interested in the optimal restart problem, i.e., in finding a restart rate which brings the mean completion time of a process to a minimum. We derive the governing equation for this problem and show that it is exactly solvable in cases of particular interest. We then continue to discover regimes at which solutions to the problem take on universal, details independent forms which further give rise to optimal scaling laws. The formalism we develop, and the results obtained, can be utilized when optimizing stochastic search processes and randomized computer algorithms. An immediate connection with kinetic proofreading is also noted and discussed. PMID- 26764609 TI - Optimal control in nonequilibrium systems: Dynamic Riemannian geometry of the Ising model. AB - A general understanding of optimal control in nonequilibrium systems would illuminate the operational principles of biological and artificial nanoscale machines. Recent work has shown that a system driven out of equilibrium by a linear response protocol is endowed with a Riemannian metric related to generalized susceptibilities, and that geodesics on this manifold are the nonequilibrium control protocols with the lowest achievable dissipation. While this elegant mathematical framework has inspired numerous studies of exactly solvable systems, no description of the thermodynamic geometry yet exists when the metric cannot be derived analytically. Herein, we numerically construct the dynamic metric of the two-dimensional Ising model in order to study optimal protocols for reversing the net magnetization. PMID- 26764610 TI - Temperature inversion of the thermal polarization of water. AB - Temperature gradients polarize water, a nonequilibrium effect that may result in significant electrostatic fields for strong thermal gradients. Using nonequilibrium molecular dynamics simulations, we show that the thermal polarization features a significant dependence with temperature that ultimately leads to an inversion phenomenon, whereby the polarization field reverses its sign at a specific temperature. Temperature inversion effects have been reported before in the Soret coefficient of aqueous solutions, where the solution changes from thermophobic to thermophilic at specific temperatures. We show that a similar inversion behavior is observed in pure water. Microscopically, the inversion is the result of a balance of dipolar and quadrupolar contributions and the strong temperature dependence of the quadrupolar contribution, which is determined by the thermal expansion of the liquid. PMID- 26764607 TI - In vitro release and In vivo biocompatibility studies of biomimetic multilayered alginate-chitosan/beta-TCP scaffold for osteochondral tissue. AB - Biomimetic three-layered monolithic scaffold (TLS) intended for the treatment of osteocondral defects was prepared by using alginate, chitosan and beta-tricalcium phosphate (beta-TCP) to study drug release behavior of the alternative drug delivery system and to investigate the therapeutic efficacy of the scaffold. Dexamethasone sodium phosphate (Dex) as a model drug was incorporated into the scaffold by solvent sorption method and in vitro release studies were conducted. In addition, the scaffold was implanted into the defects formed in the trochlea of Sprague-Dawley rats to assess the healing potential of the TLS on the osteochondral defect against reference Maioregen(r) comparatively. The release studies showed that after an initial burst at 3rd h, dexamethasone is released slowly during a 72-h period. In vivo studies indicated that the TLS has good tissue biocompatibility and biodegradation rate and showed better results during osteochondral healing process compared to the reference. All results demonstrated that the alginate-chitosan/beta-TCP scaffold could be evaluated as a good candidate for osteochondral tissue applications. PMID- 26764611 TI - Stick-slip behavior in a continuum-granular experiment. AB - We report moment distribution results from a laboratory experiment, similar in character to an isolated strike-slip earthquake fault, consisting of sheared elastic plates separated by a narrow gap filled with a two-dimensional granular medium. Local measurement of strain displacements of the plates at 203 spatial points located adjacent to the gap allows direct determination of the event moments and their spatial and temporal distributions. We show that events consist of spatially coherent, larger motions and spatially extended (noncoherent), smaller events. The noncoherent events have a probability distribution of event moment consistent with an M(-3/2) power law scaling with Poisson-distributed recurrence times. Coherent events have a log-normal moment distribution and mean temporal recurrence. As the applied normal pressure increases, there are more coherent events and their log-normal distribution broadens and shifts to larger average moment. PMID- 26764612 TI - Wall slip across the jamming transition of soft thermoresponsive particles. AB - Flows of suspensions are often affected by wall slip, that is, the fluid velocity v(f) in the vicinity of a boundary differs from the wall velocity v(w) due to the presence of a lubrication layer. While the slip velocity v(s)=|v(f)-v(w)| robustly scales linearly with the stress sigma at the wall in dilute suspensions, there is no consensus regarding denser suspensions that are sheared in the bulk, for which slip velocities have been reported to scale as a v(s)?sigma(p) with exponents p inconsistently ranging between 0 and 2. Here we focus on a suspension of soft thermoresponsive particles and show that v(s)) actually scales as a power law of the viscous stress sigma-sigma(c), where sigma(c) denotes the yield stress of the bulk material. By tuning the temperature across the jamming transition, we further demonstrate that this scaling holds true over a large range of packing fractions phi on both sides of the jamming point and that the exponent p increases continuously with phi, from p=1 in the case of dilute suspensions to p=2 for jammed assemblies. These results allow us to successfully revisit inconsistent data from the literature and pave the way for a continuous description of wall slip above and below jamming. PMID- 26764613 TI - Grain-boundary-induced melting in quenched polycrystalline monolayers. AB - Melting in two dimensions can successfully be explained with the Kosterlitz Thouless-Halperin-Nelson-Young (KTHNY) scenario which describes the formation of the high-symmetry phase with the thermal activation of topological defects within an (ideally) infinite monodomain. With all state variables being well defined, it should hold also as freezing scenario where oppositely charged topological defects annihilate. The Kibble-Zurek mechanism, on the other hand, shows that spontaneous symmetry breaking alongside a continuous phase transition cannot support an infinite monodomain but leads to polycrystallinity. For any nonzero cooling rate, critical fluctuations will be frozen out in the vicinity of the transition temperature. This leads to domains with different director of the broken symmetry, separated by a defect structure, e.g., grain boundaries in crystalline systems. After instantaneously quenching a colloidal monolayer from a polycrystalline to the isotropic fluid state, we show that such grain boundaries increase the probability for the formation of dislocations. In addition, we determine the temporal decay of defect core energies during the first few Brownian times after the quench. Despite the fact that the KTHNY scenario describes a continuous phase transition and phase equilibrium does not exist, melting in polycrystalline samples starts at grain boundaries similar to first order phase transitions. PMID- 26764614 TI - Suppression and promotion of charge inversion in the presence of multivalent coions. AB - We report charge inversion using Monte Carlo calculations for a negatively charged surface in aqueous solutions involving coions of different charges and monovalent counterions. It is shown that a rise in the valence of coions at moderate concentrations can substantially promote charge inversion for the surface charge values of biological relevance, regardless of the representation of surface charges but dependent in a nontrivial way on polarization effects resulting from dielectric discontinuity. These obtained characteristics challenge the traditional belief that the coions are generally considered to suppress charge inversion and expose the important role of coions of higher valence in tailoring the effective interactions of biomolecules with the cell membrane. PMID- 26764615 TI - Dendrite fragmentation in alloy solidification due to sidearm pinch-off. AB - Dendrite sidebranch detachment is an important fragmentation mechanism during the solidification of alloys. The detachment occurs at the junction between a sidearm and its parent stem. While this pinching process is driven by capillarity, the presence of solidification opposes the instability. Using a simple numerical model of a single sidearm, we are able to capture the essential dynamics of dendrite sidebranch development and the resulting morphological transitions. While shortly before pinch-off the neck itself obeys well-known universal scaling relations, the overall evolution of the sidearm shape sensitively depends on its initial geometry and the rate of solidification. It is found that pinch-off only occurs over limited ranges of geometrical parameters and cooling rates and is generally bounded by sidearm retraction and coalescence regimes. Simple scaling relations are identified that provide the bounds for the pinch-off regime. Pinching at the branching point is shown to be faster than the Rayleigh-Plateau instability of an infinitely long cylinder. PMID- 26764617 TI - Dynamics of a polymer in an active and viscoelastic bath. AB - We study the dynamics of an ideal polymer chain in a viscoelastic medium and in the presence of active forces. The motion of the center of mass and of individual monomers is calculated. On time scales that are comparable to the persistence time of the active forces, monomers can move superdiffusively, while on larger time scales subdiffusive behavior occurs. The difference between this subdiffusion and that in the absence of active forces is quantified. We show that the polymer swells in response to active processes and determine how this swelling depends on the viscoelastic properties of the environment. Our results are compared to recent experiments on the motion of chromosomal loci in bacteria. PMID- 26764616 TI - Hysteresis, reentrance, and glassy dynamics in systems of self-propelled rods. AB - Nonequilibrium active matter made up of self-driven particles with short-range repulsive interactions is a useful minimal system to study active matter as the system exhibits collective motion and nonequilibrium order-disorder transitions. We studied high-aspect-ratio self-propelled rods over a wide range of packing fractions and driving to determine the nonequilibrium state diagram and dynamic properties. Flocking and nematic-laning states occupy much of the parameter space. In the flocking state, the average internal pressure is high and structural and mechanical relaxation times are long, suggesting that rods in flocks are in a translating glassy state despite overall flock motion. In contrast, the nematic-laning state shows fluidlike behavior. The flocking state occupies regions of the state diagram at both low and high packing fraction separated by nematic-laning at low driving and a history-dependent region at higher driving; the nematic-laning state transitions to the flocking state for both compression and expansion. We propose that the laning-flocking transitions are a type of glass transition that, in contrast to other glass-forming systems, can show fluidization as density increases. The fluid internal dynamics and ballistic transport of the nematic-laning state may promote collective dynamics of rod-shaped micro-organisms. PMID- 26764618 TI - Curvature-induced crosshatched order in two-dimensional semiflexible polymer networks. AB - A recurring motif in the organization of biological tissues are networks of long, fibrillar protein strands effectively confined to cylindrical surfaces. Often, the fibers in such curved, quasi-two-dimensional (2D) geometries adopt a characteristic order: the fibers wrap around the central axis at an angle which varies with radius and, in several cases, is strongly bimodally distributed. In this Rapid Communication, we investigate the general problem of a 2D crosslinked network of semiflexible fibers confined to a cylindrical substrate, and demonstrate that in such systems the trade-off between bending and stretching energies, very generically, gives rise to crosshatched order. We discuss its general dependency on the radius of the confining cylinder, and present an intuitive model that illustrates the basic physical principle of curvature induced order. Our findings shed new light on the potential origin of some curiously universal fiber orientational distributions in tissue biology, and suggests novel ways in which synthetic polymeric soft materials may be instructed or programmed to exhibit preselected macromolecular ordering. PMID- 26764619 TI - Phase diagram of the ground states of DNA condensates. AB - The phase diagram of the ground states of DNA in a bad solvent is studied for a semiflexible polymer model with a generalized local elastic bending potential characterized by a nonlinearity parameter x and effective self-attraction promoting compaction. x=1 corresponds to the wormlike chain model. Surprisingly, the phase diagram as well as the transition lines between the ground states are found to be a function of x. The model provides a simple explanation for the results of prior experimental and computational studies and makes predictions for the specific geometries of the ground states. The results underscore the impact of the form of the microscopic bending energy at macroscopic observable scales. PMID- 26764621 TI - Persistent chimera states in nonlocally coupled phase oscillators. AB - Chimera states in the systems of nonlocally coupled phase oscillators are considered stable in the continuous limit of spatially distributed oscillators. However, it is reported that in the numerical simulations without taking such limit, chimera states are chaotic transient and finally collapse into the completely synchronous solution. In this Rapid Communication, we numerically study chimera states by using the coupling function different from the previous studies and obtain the result that chimera states can be stable even without taking the continuous limit, which we call the persistent chimera state. PMID- 26764620 TI - Modularity and the spread of perturbations in complex dynamical systems. AB - We propose a method to decompose dynamical systems based on the idea that modules constrain the spread of perturbations. We find partitions of system variables that maximize "perturbation modularity," defined as the autocovariance of coarse grained perturbed trajectories. The measure effectively separates the fast intramodular from the slow intermodular dynamics of perturbation spreading (in this respect, it is a generalization of the "Markov stability" method of network community detection). Our approach captures variation of modular organization across different system states, time scales, and in response to different kinds of perturbations: aspects of modularity which are all relevant to real-world dynamical systems. It offers a principled alternative to detecting communities in networks of statistical dependencies between system variables (e.g., "relevance networks" or "functional networks"). Using coupled logistic maps, we demonstrate that the method uncovers hierarchical modular organization planted in a system's coupling matrix. Additionally, in homogeneously coupled map lattices, it identifies the presence of self-organized modularity that depends on the initial state, dynamical parameters, and type of perturbations. Our approach offers a powerful tool for exploring the modular organization of complex dynamical systems. PMID- 26764622 TI - Helicity conservation under quantum reconnection of vortex rings. AB - Here we show that under quantum reconnection, simulated by using the three dimensional Gross-Pitaevskii equation, self-helicity of a system of two interacting vortex rings remains conserved. By resolving the fine structure of the vortex cores, we demonstrate that the total length of the vortex system reaches a maximum at the reconnection time, while both writhe helicity and twist helicity remain separately unchanged throughout the process. Self-helicity is computed by two independent methods, and topological information is based on the extraction and analysis of geometric quantities such as writhe, total torsion, and intrinsic twist of the reconnecting vortex rings. PMID- 26764623 TI - Fully nonlinear dynamics of stochastic thin-film dewetting. AB - The spontaneous formation of droplets via dewetting of a thin fluid film from a solid substrate allows materials nanostructuring. Often, it is crucial to be able to control the evolution, and to produce patterns characterized by regularly spaced droplets. While thermal fluctuations are expected to play a role in the dewetting process, their relevance has remained poorly understood, particularly during the nonlinear stages of evolution that involve droplet formation. Within a stochastic lubrication framework, we show that thermal noise substantially influences the process of droplets formation. Stochastic systems feature a smaller number of droplets with a larger variability in size and space distribution, when compared to their deterministic counterparts. Finally, we discuss the influence of stochasticity on droplet coarsening for asymptotically long times. PMID- 26764624 TI - Self-similar pinch-off mechanism and scaling of ferrofluid drops. AB - The pinch off of heterogeneous ferrofluid drops at a nozzle in air was experimentally investigated with a magnetic field (downward or upward) and without a magnetic field. Compared to homogeneous drops, the self-similarity and universal scaling law were verified through modifying the initial conditions, such as the nozzle diameter, flow rate, and magnitude and direction of the magnetic fields. Two pinch-off points were observed, and the two consecutive pinch-off dynamics were characterized through scaling laws. Here our scaling exponent remains within the scope of (0.70-0.80) for the primary whereas it remains within the scope of (0.60-0.70) for the secondary pinch off, respectively, comparable to the classic range from 2/3 to 1 for homogeneous drops. The gravity-compensating and gravity-superimposing magnetic fields display a negligible effect on the exponent but determine the sequence of double pinch offs. The universal character of the self-similar pinch off is extended to a heterogeneous fluid. PMID- 26764625 TI - Entropic lattice Boltzmann model for compressible flows. AB - We present a lattice Boltzmann model (LBM) that covers the entire range of fluid flows, from low Mach weakly compressible to transonic and supersonic flows. One of the most restrictive limitations of the lattice Boltzmann method, the low Mach number limit, is overcome here by three fundamental changes to the LBM scheme: use of an appropriately chosen multispeed lattice, accurate evaluation of the equilibrium, and the entropic relaxation for the collision. The range of applications is demonstrated through the simulation of a bow shock in front of an airfoil and the simulation of decaying compressible turbulence with shocklets. PMID- 26764626 TI - Small quantum absorption refrigerator in the transient regime: Time scales, enhanced cooling, and entanglement. AB - A small quantum absorption refrigerator, consisting of three qubits, is discussed in the transient regime. We discuss time scales for coherent dynamics, damping, and approach to the steady state, and we study cooling and entanglement. We observe that cooling can be enhanced in the transient regime, in the sense that lower temperatures can be achieved compared to the steady-state regime. This is a consequence of coherent dynamics but can occur even when this dynamics is strongly damped by the dissipative thermal environment, and we note that precise control over couplings or timing is not needed to achieve enhanced cooling. We also show that the amount of entanglement present in the refrigerator can be much larger in the transient regime compared to the steady state. These results are of relevance to future implementations of quantum thermal machines. PMID- 26764628 TI - Kubo formulas for dispersion in heterogeneous periodic nonequilibrium systems. AB - We consider the dispersion properties of tracer particles moving in nonequilibrium heterogeneous periodic media. The tracer motion is described by a Fokker-Planck equation with arbitrary spatially periodic (but constant in time) local diffusion tensors and drifts, eventually with the presence of obstacles. We derive a Kubo-like formula for the time-dependent effective diffusion tensor valid in any dimension. From this general formula, we derive expressions for the late time effective diffusion tensor and drift in these systems. In addition, we find an explicit formula for the late finite-time corrections to these transport coefficients. In one dimension, we give a closed analytical formula for the transport coefficients. The formulas derived here are very general and provide a straightforward method to compute the dispersion properties in arbitrary nonequilibrium periodic advection-diffusion systems. PMID- 26764627 TI - Absorbing phase transition in a conserved lattice gas model with next-nearest neighbor hopping in one dimension. AB - The absorbing phase transition of the modified conserved lattice gas (m-CLG) model was investigated in one dimension. The m-CLG model was modified from the conserved lattice gas (CLG) model in such a way that each active particle hops to one of the nearest-neighbor and next-nearest-neighbor empty sites. The order parameter exponent, the dynamic exponent, and the correlation length exponent were estimated from the power-law behavior and finite-size scaling of the active particle densities. The exponents were found to differ considerably from those of the ordinary CLG model and were also distinct from those of the Manna model, suggesting that next-nearest-neighbor hopping is a relevant factor that alters the critical behavior in the one-dimensional CLG model. PMID- 26764629 TI - Effective stochastic generators for conditioned dynamics at an atypical reaction diffusion current. AB - We consider the fluctuations of a time-integrated particle current around an atypical value in a generic stochastic Markov process involving classical particles with two-site interaction and hard-core repulsion on a finite one dimensional lattice with open boundaries. We address the question of which interactions one has to impose on such a process to make the atypical value of the current typical. It is known that a corresponding effective stochastic Markov process might exist whose typical current value is equal to the atypical current value in the original process within a time-translational invariant regime. This effective process has, in principle, nonlocal transition rates. Nevertheless, it turns out that under some conditions, the stochastic generator of the effective process has the same dynamical rules as the stochastic generator of the original process. We find these conditions and show that our approach can be generalized to any time-integrated observable. PMID- 26764630 TI - Dynamics of Brownian particles in three-dimensional ordered porous media subject to an oscillatory force. AB - Brownian dynamics simulation has been employed to study the dynamic behavior of particles in three-dimensional ordered porous media subject to a sinusoidal force field. The media comprises interconnected spherical cavities arranged in a simple cubic lattice. The thermal noise assists the particles to undergo cavity hopping, leading to a displacement behavior analogous to stochastic resonance, when the imposed field is strong enough but not aligned with the aperture lines, and the oscillation frequency is not too high. The periodic mean trajectory depends on the strength, frequency, and orientation of the imposed field. At sufficiently large field strength, the periodic particle displacement can become nonsinusoidal due to the strong hindrance and pinning effect of the cavity wall. PMID- 26764631 TI - Broadband boundary effects on Brownian motion. AB - Brownian motion of particles in confined fluids is important for many applications, yet the effects of the boundary over a wide range of time scales are still not well understood. We report high-bandwidth, comprehensive measurements of Brownian motion of an optically trapped micrometer-sized silica sphere in water near an approximately flat wall. At short distances we observe anisotropic Brownian motion with respect to the wall. We find that surface confinement not only occurs in the long time scale diffusive regime but also in the short time scale ballistic regime, and the velocity autocorrelation function of the Brownian particle decays faster than that of a particle in bulk fluid. Furthermore, at low frequencies the thermal force loses its color due to the reflected flow from the no-slip boundary. The power spectrum of the thermal force on the particle near a no-slip boundary becomes flat at low frequencies. This detailed understanding of boundary effects on Brownian motion opens a door to developing a 3D microscope using particles as remote sensors. PMID- 26764632 TI - Off-equilibrium scaling behaviors across first-order transitions. AB - We study off-equilibrium behaviors at first-order transitions (FOTs) driven by a time dependence of the temperature across the transition point T(c), such as the linear behavior T(t)/T(c)=1+/-t/t(s) where t(s) is a time scale. In particular, we investigate the possibility of nontrivial off-equilibrium scaling behaviors in the regime of slow changes, corresponding to large t(s). We consider the two dimensional Potts models, which provide an ideal theoretical laboratory to investigate issues related to FOTs driven by thermal fluctuations. We put forward general ansatzes for off-equilibrium scaling behaviors around the time t=0 corresponding to T(c). Then we present numerical results for the q=10 and 20 Potts models. We show that off-equilibrium scaling behaviors emerge at FOTs with relaxational dynamics, when appropriate boundary conditions are considered, such as mixed boundary conditions favoring different phases at the opposite sides of the system, which enforce an interface in the system. PMID- 26764633 TI - Anomalous dynamical scaling in anharmonic chains and plasma models with multiparticle collisions. AB - We study the anomalous dynamical scaling of equilibrium correlations in one dimensional systems. Two different models are compared: the Fermi-Pasta-Ulam chain with cubic and quartic nonlinearity and a gas of point particles interacting stochastically through multiparticle collision dynamics. For both models-that admit three conservation laws-by means of detailed numerical simulations we verify the predictions of nonlinear fluctuating hydrodynamics for the structure factors of density and energy fluctuations at equilibrium. Despite this, violations of the expected scaling in the currents correlation are found in some regimes, hindering the observation of the asymptotic scaling predicted by the theory. In the case of the gas model this crossover is clearly demonstrated upon changing the coupling constant. PMID- 26764634 TI - Thermodynamics of the noninteracting Bose gas in a two-dimensional box. AB - Bose-Einstein condensation (BEC) of a noninteracting Bose gas of N particles in a two-dimensional box with Dirichlet boundary conditions is studied. Confirming previous work, we find that BEC occurs at finite N at low temperatures T without the occurrence of a phase transition. The conventionally-defined transition temperature T(E) for an infinite three-dimensional (3D) system is shown to correspond in a 2D system with finite N to a crossover temperature between a slow and rapid increase in the fractional boson occupation N(0)/N of the ground state with decreasing T. We further show that T(E)~1/logN at fixed area per boson, so in the thermodynamic limit there is no significant BEC in 2D at finite T. Thus, paradoxically, BEC only occurs in 2D at finite N with no phase transition associated with it. Calculations of thermodynamic properties versus T and area A are presented, including Helmholtz free energy, entropy S, pressure p, ratio of p to the energy density U/A, heat capacity at constant volume (area) C(V) and at constant pressure C(p), isothermal compressibility kappa(T) and thermal expansion coefficient alpha(p), obtained using both the grand-canonical ensemble (GCE) and canonical ensemble (CE) formalisms. The GCE formalism gives acceptable predictions for S, p, p/(U/A), kappa(T) and alpha(p) at large N, T and A but fails for smaller values of these three parameters for which BEC becomes significant, whereas the CE formalism gives accurate results for all thermodynamic properties of finite systems even at low T and/or A where BEC occurs. PMID- 26764635 TI - Brownian colloids in underdamped and overdamped regimes with nonhomogeneous temperature. AB - The motion of Brownian particles when temperature is spatially dependent is studied by stochastic simulations and theoretical analysis. Nonequilibrium steady probability distributions P(st)(z,v) for both underdamped and overdamped regimes are analyzed. The existence of local kinetic energy equipartition theorem is also discussed. The transition between both regimes is characterized by a dimensionless friction parameter. This study is applied to three physical systems of colloidal particles. PMID- 26764636 TI - Pattern formation in flocking models: A hydrodynamic description. AB - We study in detail the hydrodynamic theories describing the transition to collective motion in polar active matter, exemplified by the Vicsek and active Ising models. Using a simple phenomenological theory, we show the existence of an infinity of propagative solutions, describing both phase and microphase separation, that we fully characterize. We also show that the same results hold specifically in the hydrodynamic equations derived in the literature for the active Ising model and for a simplified version of the Vicsek model. We then study numerically the linear stability of these solutions. We show that stable ones constitute only a small fraction of them, which, however, includes all existing types. We further argue that, in practice, a coarsening mechanism leads towards phase-separated solutions. Finally, we construct the phase diagrams of the hydrodynamic equations proposed to qualitatively describe the Vicsek and active Ising models and connect our results to the phenomenology of the corresponding microscopic models. PMID- 26764637 TI - Mesoscopic description of random walks on combs. AB - Combs are a simple caricature of various types of natural branched structures, which belong to the category of loopless graphs and consist of a backbone and branches. We study continuous time random walks on combs and present a generic method to obtain their transport properties. The random walk along the branches may be biased, and we account for the effect of the branches by renormalizing the waiting time probability distribution function for the motion along the backbone. We analyze the overall diffusion properties along the backbone and find normal diffusion, anomalous diffusion, and stochastic localization (diffusion failure), respectively, depending on the characteristics of the continuous time random walk along the branches, and compare our analytical results with stochastic simulations. PMID- 26764638 TI - Nonequilibrium quasi-long-range order of a driven random-field O(N) model. AB - We investigate three-dimensional O(N) spin models driven with a uniform velocity over a random field. Within a spin-wave approximation, it is shown that in the strong driving regime the model with N=2 exhibits a quasi-long-range order in which the spatial correlation function decays in a power-law form. Furthermore, for the cases that N=2 and 3, we numerically demonstrate a nonequilibrium phase transition between the quasi-long-range order phase and the disordered phase, which turns out to resemble the Kosterlitz-Thouless transition in the two dimensional pure XY model in equilibrium. PMID- 26764639 TI - Understanding the mechanisms of solid-water reactions through analysis of surface topography. AB - The topography of a reactive surface contains information about the reactions that form or modify the surface and, therefore, it should be possible to characterize reactivity using topography parameters such as surface area, roughness, or fractal dimension. As a test of this idea, we consider a two dimensional (2D) lattice model for crystal dissolution and examine a suite of topography parameters to determine which may be useful for predicting rates and mechanisms of dissolution. The model is based on the assumption that the reactivity of a surface site decreases with the number of nearest neighbors. We show that the steady-state surface topography in our model system is a function of, at most, two variables: the ratio of the rate of loss of sites with two neighbors versus three neighbors (d(2)/d(3)) and the ratio of the rate of loss of sites with one neighbor versus three neighbors (d(1)/d(3)). This means that relative rates can be determined from two parameters characterizing the topography of a surface provided that the two parameters are independent of one another. It also means that absolute rates cannot be determined from measurements of surface topography alone. To identify independent sets of topography parameters, we simulated surfaces from a broad range of d(1)/d(3) and d(2)/d(3) and computed a suite of common topography parameters for each surface. Our results indicate that the fractal dimension D and the average spacing between steps, E[s], can serve to uniquely determine d(1)/d(3) and d(2)/d(3) provided that sufficiently strong correlations exist between the steps. Sufficiently strong correlations exist in our model system when D>1.5 (which corresponds to D>2.5 for real 3D reactive surfaces). When steps are uncorrelated, surface topography becomes independent of step retreat rate and D is equal to 1.5. Under these conditions, measures of surface topography are not independent and any single topography parameter contains all of the available mechanistic information about the surface. Our results also indicate that root-mean-square roughness cannot be used to reliably characterize the surface topography of fractal surfaces because it is an inherently noisy parameter for such surfaces with the scale of the noise being independent of length scale. PMID- 26764640 TI - Phase transitions in optimal search times: How random walkers should combine resetting and flight scales. AB - Recent works have explored the properties of Levy flights with resetting in one dimensional domains and have reported the existence of phase transitions in the phase space of parameters which minimizes the mean first passage time (MFPT) through the origin [L. Kusmierz et al., Phys. Rev. Lett. 113, 220602 (2014)]. Here, we show how actually an interesting dynamics, including also phase transitions for the minimization of the MFPT, can also be obtained without invoking the use of Levy statistics but for the simpler case of random walks with exponentially distributed flights of constant speed. We explore this dynamics both in the case of finite and infinite domains, and for different implementations of the resetting mechanism to show that different ways to introduce resetting consistently lead to a quite similar dynamics. The use of exponential flights has the strong advantage that exact solutions can be obtained easily for the MFPT through the origin, so a complete analytical characterization of the system dynamics can be provided. Furthermore, we discuss in detail how the phase transitions observed in random walks with resetting are closely related to several ideas recurrently used in the field of random search theory, in particular, to other mechanisms proposed to understand random search in space as mortal random walks or multiscale random walks. As a whole, we corroborate that one of the essential ingredients behind MFPT minimization lies in the combination of multiple movement scales (regardless of their specific origin). PMID- 26764641 TI - Jamming and percolation in generalized models of random sequential adsorption of linear k-mers on a square lattice. AB - The jamming and percolation for two generalized models of random sequential adsorption (RSA) of linear k-mers (particles occupying k adjacent sites) on a square lattice are studied by means of Monte Carlo simulation. The classical RSA model assumes the absence of overlapping of the new incoming particle with the previously deposited ones. The first model is a generalized variant of the RSA model for both k-mers and a lattice with defects. Some of the occupying k adjacent sites are considered as insulating and some of the lattice sites are occupied by defects (impurities). For this model even a small concentration of defects can inhibit percolation for relatively long k-mers. The second model is the cooperative sequential adsorption one where, for each new k-mer, only a restricted number of lateral contacts z with previously deposited k-mers is allowed. Deposition occurs in the case when z<=(1-d)z(m) where z(m)=2(k+1) is the maximum numbers of the contacts of k-mer, and d is the fraction of forbidden contacts. Percolation is observed only at some interval k(min)<=k<=k(max) where the values k(min) and k(max) depend upon the fraction of forbidden contacts d. The value k(max) decreases as d increases. A logarithmic dependence of the type log(10)(k(max))=a+bd, where a=4.04+/-0.22,b=-4.93+/-0.57, is obtained. PMID- 26764642 TI - Stochastically gated diffusion-limited reactions for a small target in a bounded domain. AB - We calculate the reaction rate for stochastically gated ligands diffusing in a two-dimensional and a three-dimensional bounded domain with a single small target. Each ligand independently switches between an open and a closed state according to a two-state Markov process; a reaction between ligand and target can only occur when the former is an open state. In the large-time limit the reaction rate is an exponentially decaying function of time, whose rate of decay is given by the principal eigenvalue of the Laplacian. We calculate the principal eigenvalue using matched asymptotics and determine the leading-order reduction in the reaction rate due to stochastic gating. We also develop a probabilistic interpretation of the reaction rate in terms of the first-passage time density to the target. PMID- 26764643 TI - Mean-field approach for diffusion of interacting particles. AB - A nonlinear Fokker-Planck equation is obtained in the continuous limit of a one dimensional lattice with an energy landscape of wells and barriers. Interaction is possible among particles in the same energy well. A parameter gamma, related to the barrier's heights, is introduced. Its value is determinant for the functional dependence of the mobility and diffusion coefficient on particle concentration, but has no influence on the equilibrium solution. A relation between the mean-field potential and the microscopic interaction energy is derived. The results are illustrated with classical particles with interactions that reproduce fermion and boson statistics. PMID- 26764644 TI - Nonequilibrium steady states of ideal bosonic and fermionic quantum gases. AB - We investigate nonequilibrium steady states of driven-dissipative ideal quantum gases of both bosons and fermions. We focus on systems of sharp particle number that are driven out of equilibrium either by the coupling to several heat baths of different temperature or by time-periodic driving in combination with the coupling to a heat bath. Within the framework of (Floquet-)Born-Markov theory, several analytical and numerical methods are described in detail. This includes a mean-field theory in terms of occupation numbers, an augmented mean-field theory taking into account also nontrivial two-particle correlations, and quantum-jump type Monte Carlo simulations. For the case of the ideal Fermi gas, these methods are applied to simple lattice models and the possibility of achieving exotic states via bath engineering is pointed out. The largest part of this work is devoted to bosonic quantum gases and the phenomenon of Bose selection, a nonequilibrium generalization of Bose condensation, where multiple single particle states are selected to acquire a large occupation [Phys. Rev. Lett. 111, 240405 (2013)]. In this context, among others, we provide a theory for transitions where the set of selected states changes, describe an efficient algorithm for finding the set of selected states, investigate beyond-mean-field effects, and identify the dominant mechanisms for heat transport in the Bose selected state. PMID- 26764645 TI - Thermal rectification in anharmonic chains under an energy-conserving noise. AB - Systems in which the heat flux depends on the direction of the flow are said to present thermal rectification. This effect has attracted much theoretical and experimental interest in recent years. However, in most theoretical models the effect is found to vanish in the thermodynamic limit, in disagreement with experiment. The purpose of this paper is to show that the rectification may be restored by including an energy-conserving noise which randomly flips the velocity of the particles with a certain rate lambda. It is shown that as long as lambda is nonzero, the rectification remains finite in the thermodynamic limit. This is illustrated in a classical harmonic chain subject to a quartic pinning potential (the Phi(4) model) and coupled to heat baths by Langevin equations. PMID- 26764646 TI - Critical nonequilibrium relaxation in the Swendsen-Wang algorithm in the Berezinsky-Kosterlitz-Thouless and weak first-order phase transitions. AB - Recently we showed that the critical nonequilibrium relaxation in the Swendsen Wang algorithm is widely described by the stretched-exponential relaxation of physical quantities in the Ising or Heisenberg models. Here we make a similar analysis in the Berezinsky-Kosterlitz-Thouless phase transition in the two dimensional (2D) XY model and in the first-order phase transition in the 2D q=5 Potts model and find that these phase transitions are described by the simple exponential relaxation and power-law relaxation of physical quantities, respectively. We compare the relaxation behaviors of these phase transitions with those of the second-order phase transition in the three- and four-dimensional XY models and in the 2D q-state Potts models for 2<=q<=4 and show that the species of phase transitions can be clearly characterized by the present analysis. We also compare the size dependence of relaxation behaviors of the first-order phase transition in the 2D q=5 and 6 Potts models and propose a quantitative criterion on "weakness" of the first-order phase transition. PMID- 26764647 TI - Inflexibility and independence: Phase transitions in the majority-rule model. AB - In this work we study opinion formation in a population participating in a public debate with two distinct choices. We consider three distinct mechanisms of social interactions and individuals' behavior: conformity, nonconformity, and inflexibility. The conformity is ruled by the majority-rule dynamics, whereas the nonconformity is introduced in the population as an independent behavior, implying the failure of attempted group influence. Finally, the inflexible agents are introduced in the population with a given density. These individuals present a singular behavior, in a way that their stubbornness makes them reluctant to change their opinions. We consider these effects separately and all together, with the aim to analyze the critical behavior of the system. We perform numerical simulations in some lattice structures and for distinct population sizes. Our results suggest that the different formulations of the model undergo order disorder phase transitions in the same universality class as the Ising model. Some of our results are complemented by analytical calculations. PMID- 26764649 TI - Speed of evolution on graphs. AB - The likelihood that a mutant fixates in the wild population, i.e., fixation probability, has been intensively studied in evolutionary game theory, where individuals' fitness is frequency dependent. However, it is of limited interest when it takes long to take over. Thus the speed of evolution becomes an important issue. In general, it is still unclear how fixation times are affected by the population structure, although the fixation times have already been addressed in the well-mixed populations. Here we theoretically address this issue by pair approximation and diffusion approximation on regular graphs. It is shown (i) that under neutral selection, both unconditional and conditional fixation time are shortened by increasing the number of neighbors; (ii) that under weak selection, for the simplified prisoner's dilemma game, if benefit-to-cost ratio exceeds the degree of the graph, then the unconditional fixation time of a single cooperator is slower than that in the neutral case; and (iii) that under weak selection, for the conditional fixation time, limited neighbor size dilutes the counterintuitive stochastic slowdown which was found in well-mixed populations. Interestingly, we find that all of our results can be interpreted as that in the well-mixed population with a transformed payoff matrix. This interpretation is also valid for both death-birth and birth-death processes on graphs. This interpretation bridges the fixation time in the structured population and that in the well-mixed population. Thus it opens the avenue to investigate the challenging fixation time in structured populations by the known results in well-mixed populations. PMID- 26764648 TI - Charge-regulation phase transition on surface lattices of titratable sites adjacent to electrolyte solutions: An analog of the Ising antiferromagnet in a magnetic field. AB - We report a charge-patterning phase transition on two-dimensional square lattices of titratable sites, here regarded as protonation sites, placed in a low dielectric medium just below the planar interface between this medium and a salt solution. We calculate the work-of-charging matrix of the lattice with use of a linear Debye-Huckel model, as input to a grand-canonical partition function for the distribution of occupancy patterns. For a large range of parameter values, this model exhibits an approximate inverse cubic power-law decrease of the voltage produced by an individual charge, as a function of its in-lattice separation from neighboring titratable sites. Thus, the charge coupling voltage biases the local probabilities of proton binding as a function of the occupancy of sites for many neighbors beyond the nearest ones. We find that even in the presence of these longer-range interactions, the site couplings give rise to a phase transition in which the site occupancies exhibit an alternating, checkerboard pattern that is an analog of antiferromagnetic ordering. The overall strength W of this canonical charge coupling voltage, per unit charge, is a function of the Debye length, the charge depth, the Bjerrum length, and the dielectric coefficients of the medium and the solvent. The alternating occupancy transition occurs above a curve of thermodynamic critical points in the (pH-pK,W) plane, the curve representing a charge-regulation analog of variation of the Neel temperature of an Ising antiferromagnet as a function of an applied, uniform magnetic field. The analog of a uniform magnetic field in the antiferromagnet problem is a combination of pH-pK and W, and 1/W is the analog of the temperature in the antiferromagnet problem. We use Monte Carlo simulations to study the occupancy patterns of the titratable sites, including interactions out to the 37th nearest-neighbor category (a distance of ?74 lattice constants), first validating simulations through comparison with exact and approximate results for the nearest-neighbor case. We then use the simulations to map the charge patterning phase boundary in the (pH-pK,W) plane. The physical parameters that determine W provide a framework for identifying and designing real surfaces that could exhibit charge-patterning phase transitions. PMID- 26764650 TI - How an autonomous quantum Maxwell demon can harness correlated information. AB - We study an autonomous quantum system which exhibits refrigeration under an information-work trade-off like a Maxwell demon. The system becomes correlated as a single "demon" qubit interacts sequentially with memory qubits while in contact with two heat reservoirs of different temperatures. Using strong subadditivity of the von Neumann entropy, we derive a global Clausius inequality to show thermodynamic advantages from access to correlated information. It is demonstrated, in a matrix product density operator formalism, that our demon can simultaneously realize refrigeration against a thermal gradient and erasure of information from its memory, which is impossible without correlations. The phenomenon can be even enhanced by the presence of quantum coherence. PMID- 26764651 TI - Generic finite size scaling for discontinuous nonequilibrium phase transitions into absorbing states. AB - Based on quasistationary distribution ideas, a general finite size scaling theory is proposed for discontinuous nonequilibrium phase transitions into absorbing states. Analogously to the equilibrium case, we show that quantities such as response functions, cumulants, and equal area probability distributions all scale with the volume, thus allowing proper estimates for the thermodynamic limit. To illustrate these results, five very distinct lattice models displaying nonequilibrium transitions-to single and infinitely many absorbing states-are investigated. The innate difficulties in analyzing absorbing phase transitions are circumvented through quasistationary simulation methods. Our findings (allied to numerical studies in the literature) strongly point to a unifying discontinuous phase transition scaling behavior for equilibrium and this important class of nonequilibrium systems. PMID- 26764652 TI - Self-organized anomalous aggregation of particles performing nonlinear and non Markovian random walks. AB - We present a nonlinear and non-Markovian random walks model for stochastic movement and the spatial aggregation of living organisms that have the ability to sense population density. We take into account social crowding effects for which the dispersal rate is a decreasing function of the population density and residence time. We perform stochastic simulations of random walks and discover the phenomenon of self-organized anomaly (SOA), which leads to a collapse of stationary aggregation pattern. This anomalous regime is self-organized and arises without the need for a heavy tailed waiting time distribution from the inception. Conditions have been found under which the nonlinear random walk evolves into anomalous state when all particles aggregate inside a tiny domain (anomalous aggregation). We obtain power-law stationary density-dependent survival function and define the critical condition for SOA as the divergence of mean residence time. The role of the initial conditions in different SOA scenarios is discussed. We observe phenomenon of transient anomalous bimodal aggregation. PMID- 26764653 TI - Rapid spatial equilibration of a particle in a box. AB - We study the equilibration behavior of a quantum particle in a one-dimensional box, with respect to a coarse-grained position measurement (whether it lies in a certain spatial window or not). We show that equilibration in this context indeed takes place and does so very rapidly, in a time comparable to the time for the initial wave packet to reach the edges of the box. We also show that, for this situation, the equilibration behavior is relatively insensitive to the precise choice of position measurements or initial condition. PMID- 26764654 TI - Anomalous free energy changes induced by topology. AB - We report that nontrivial topology of a driven Brownian particle restricted on a ring leads to anomalous behaviors on free energy change. Starting from steady states with identical distribution and current on the ring, free energy changes are distinct and nonperiodic after the system is driven by the same periodic force protocol. We demonstrate our observation in examples through both exact solutions and numerical simulations. The free energy calculated here can be measured in recent experimental systems. PMID- 26764655 TI - Multifractal to monofractal evolution of the London street network. AB - We perform a multifractal analysis of the evolution of London's street network from 1786 to 2010. First, we show that a single fractal dimension, commonly associated with the morphological description of cities, does not suffice to capture the dynamics of the system. Instead, for a proper characterization of such a dynamics, the multifractal spectrum needs to be considered. Our analysis reveals that London evolves from an inhomogeneous fractal structure, which can be described in terms of a multifractal, to a homogeneous one, which converges to monofractality. We argue that London's multifractal to monofractal evolution might be a special outcome of the constraint imposed on its growth by a green belt. Through a series of simulations, we show that multifractal objects, constructed through diffusion limited aggregation, evolve toward monofractality if their growth is constrained by a nonpermeable boundary. PMID- 26764656 TI - Successively thresholded domain boundary roughening driven by pinning centers and missing bonds: Hard-spin mean-field theory applied to d=3 Ising magnets. AB - Hard-spin mean-field theory has recently been applied to Ising magnets, correctly yielding the absence and presence of an interface roughening transition respectively in d=2 and d=3 dimensions and producing the ordering-roughening phase diagram for isotropic and anisotropic systems. The approach has now been extended to the effects of quenched random pinning centers and missing bonds on the interface of isotropic and anisotropic Ising models in d=3. We find that these frozen impurities cause domain boundary roughening that exhibits consecutive thresholding transitions as a function of interaction anisotropy. For both missing-bond and pinning-center impurities, for moderately large values of the anisotropy, the systems saturate to the "solid-on-solid" limit, exhibiting a single universal curve for the domain boundary width as a function of impurity concentration. PMID- 26764657 TI - Diffusion of a massive particle in a periodic potential: Application to adiabatic ratchets. AB - We generalize a theory of diffusion of a massive particle by the way in which transport characteristics are described by analytical expressions that formally coincide with those for the overdamped massless case but contain a factor comprising the particle mass which can be calculated in terms of Risken's matrix continued fraction method (MCFM). Using this generalization, we aim to elucidate how large gradients of a periodic potential affect the current in a tilted periodic potential and the average current of adiabatically driven on-off flashing ratchets. For this reason, we perform calculations for a sawtooth potential of the period L with an arbitrary sawtooth length (l0 which appears due to the inertial effect. Analysis of the temperature dependences of the quantities under study reveals the dominant role of inertia in the high-temperature region. In particular, we show, by the analytical strong-inertia approach developed for this region, that the temperature-dependent contribution to the mobility at zero force and to the related effective diffusion coefficient are proportional to T(-3/2) and T(-1/2), respectively, and have a logarithmic singularity at l->0. PMID- 26764658 TI - Phase transitions and order in two-dimensional generalized nonlinear sigma models. AB - We study phase transitions and the nature of order in a class of classical generalized O(N) nonlinear sigma models (NLS) constructed by minimally coupling pure NLS with additional degrees of freedom in the form of (i) Ising ferromagnetic spins, (ii) an advective Stokesian velocity, and (iii) multiplicative noises. In examples (i) and (ii), and also (iii) with the associated multiplicative noise being not sufficiently long-ranged, we show that the models may display a class of unusual phase transitions between stiff and soft phases, where the effective spin stiffness respectively diverges and vanishes in the long wavelength limit at two dimensions (2D), unlike in pure NLS. In the stiff phase, in the thermodynamic limit the variance of the transverse spin (or, the Goldstone mode) fluctuations are found to scale with the system size L in 2D as lnlnL with a model-dependent amplitude, which is markedly weaker than the well-known lnL dependence of the variance of the broken symmetry modes in models that display quasi-long-range order in 2D. Equivalently, for N=2 at 2D the equal-time spin-spin correlations decay in powers of inverse logarithm of the spatial separation with model-dependent exponents. These transitions are controlled by the model parameters those couple the O(N) spins with the additional variables. In the presence of long-range noises in example (iii), true long-range order may set in 2D, depending upon the specific details of the underlying dynamics. Our results should be useful in understanding phase transitions in equilibrium and nonequilibrium low-dimensional systems with continuous symmetries in general. PMID- 26764659 TI - Topological-distance-dependent transition in flocks with binary interactions. AB - We have studied a flocking model with binary interactions (binary flock), where the velocity of an agent depends on the velocity of only another agent and its own velocity, topped by the angular noise. The other agent is selected as the nth topological neighbor; the specific value of n being a fixed parameter of the problem. On the basis of extensive numerical simulation results, we argue that for n = 1, the phase transition from the ordered to the disordered phase of the flock is a special kind of discontinuous transition. Here, the order parameter does not flip-flop between multiple metastable states. It continues its initial disordered state for a period t(c), then switches over to the ordered state and remains in this state ever after. For n = 2, it is the usual discontinuous transition between two metastable states. Beyond this range, the continuous transitions are observed for n>=3. Such a system of binary flocks has been further studied using the hydrodynamic equations of motion. Linear stability analysis of the homogeneous polarized state shows that such a state is unstable close to the critical point and above some critical speed, which increases as we increase n. The critical noise strengths, which depend on the average correlation between a pair of topological neighbors, are estimated for five different values of n, which match well with their simulated values. PMID- 26764660 TI - Efficient search of multiple types of targets. AB - Random searches often take place in fragmented landscapes. Also, in many instances like animal foraging, significant benefits to the searcher arise from visits to a large diversity of patches with a well-balanced distribution of targets found. Up to date, such aspects have been widely ignored in the usual single-objective analysis of search efficiency, in which one seeks to maximize just the number of targets found per distance traversed. Here we address the problem of determining the best strategies for the random search when these multiple-objective factors play a key role in the process. We consider a figure of merit (efficiency function), which properly "scores" the mentioned tasks. By considering random walk searchers with a power-law asymptotic Levy distribution of step lengths, p(l)~l(-MU), with 10, an expression for the heat current obtained previously under assumption of the thermodynamic limit is reproduced. The energy current between two platinum nanoparticles mediated by a carbon oxide molecule is considered as an application of the developed model. PMID- 26764664 TI - Scaling exponents for ordered maxima. AB - We study extreme value statistics of multiple sequences of random variables. For each sequence with N variables, independently drawn from the same distribution, the running maximum is defined as the largest variable to date. We compare the running maxima of m independent sequences and investigate the probability S(N) that the maxima are perfectly ordered, that is, the running maximum of the first sequence is always larger than that of the second sequence, which is always larger than the running maximum of the third sequence, and so on. The probability S(N) is universal: it does not depend on the distribution from which the random variables are drawn. For two sequences, S(N)~N(-1/2), and in general, the decay is algebraic, S(N)~N(-sigma(m)), for large N. We analytically obtain the exponent sigma(3)?1.302931 as root of a transcendental equation. Furthermore, the exponents sigma(m) grow with m, and we show that sigma(m)~m for large m. PMID- 26764665 TI - Particle coupled to a heat bath in non-Abelian gauge potentials. AB - We derive the quantum Langevin equation (QLE) for a harmonically single trapped cold atom subjected to artificial non-Abelian gauge potentials and linearly coupled to a heat bath. The independent-oscillator (IO) and the momentum-momenta coupling models are studied. In each case, the non-Abelian effect on the QLE is pointed out for a U(2) gauge transformation. For the IO model, only the generalized Lorentz force is modified by the appearance of an additive term. For the momentum-momenta coupling model, the generalized Lorentz force as well as the friction force are subjected to modifications. The dependence of the system on the magnetic field is explicit even if the gauge potential is uniform in space. PMID- 26764666 TI - Finite-temperature buckling of an extensible rod. AB - Thermal fluctuations can play an important role in the buckling of elastic objects at small scales, such as polymers or nanotubes. In this paper, we study the finite-temperature buckling transition of an extensible rod by analyzing fluctuation corrections to the elasticity of the rod. We find that, in both two and three dimensions, thermal fluctuations delay the buckling transition, and near the transition, there is a critical regime in which fluctuations are prominent and make a contribution to the effective force that is of order ?T. We verify our theoretical prediction of the phase diagram with Monte Carlo simulations. PMID- 26764667 TI - Percolation and jamming of linear k-mers on a square lattice with defects: Effect of anisotropy. AB - Using the Monte Carlo simulation, we study the percolation and jamming of oriented linear k-mers on a square lattice that contains defects. The point defects with a concentration d are placed randomly and uniformly on the substrate before deposition of the k-mers. The general case of unequal probabilities for orientation of depositing of k-mers along different directions of the lattice is analyzed. Two different relaxation models of deposition that preserve the predetermined order parameter s are used. In the relaxation random sequential adsorption (RRSA) model, the deposition of k-mers is distributed over different sites on the substrate. In the single-cluster relaxation (RSC) model, the single cluster grows by the random accumulation of k-mers on the boundary of the cluster (Eden-like model). For both models, a suppression of growth of the infinite (percolation) cluster at some critical concentration of defects d(c) is observed. In the zero-defect lattices, the jamming concentration p(j) (RRSA model) and the density of single clusters p(s) (RSC model) decrease with increasing length k mers and with a decrease in the order parameter. For the RRSA model, the value of d(c) decreases for short k-mers (k<16) as the value of s increases. For k=16 and 32, the value of d(c) is almost independent of s. Moreover, for short k-mers, the percolation threshold is almost insensitive to the defect concentration for all values of s. For the RSC model, the growth of clusters with ellipselike shapes is observed for nonzero values of s. The density of the clusters p(s) at the critical concentration of defects d(c) depends in a complex manner on the values of s and k. An interesting finding for disordered systems (s=0) is that the value of p(s) tends towards zero in the limits of the very long k-mers, k->infinity, and very small critical concentrations d(c)->0. In this case, the introduction of defects results in a suppression of k-mer stacking and in the formation of empty or loose clusters with very low density. On the other hand, denser clusters are formed for ordered systems with p(s)~0.065 at s=0.5 and p(s)~0.38 at s=1.0. PMID- 26764668 TI - Identifying a correlated spin fluctuation in an entangled spin chain subject to a quantum phase transition. AB - This paper presents a theoretical framework for analyzing the quantum fluctuation properties of a quantum spin chain subject to a quantum phase transition. We can quantify the fluctuation properties by examining the correlation between the fluctuations of two neighboring spins subject to the quantum uncertainty. To do this, we first compute the reduced density matrix rho of the spin pair from the ground state |Psi? of a spin chain, and then identify the quantum correlation part rho(q) embedded in rho. If the spin chain is translationally symmetric and characterized by a nearest-neighbor two-body spin interaction, we can determine uniquely the form of rho(q) as W|Phi>. We demonstrate the framework for a transverse-field quantum Ising spin chain and indicate its validity for more general spin chain models. PMID- 26764669 TI - Self-similar nonequilibrium dynamics of a many-body system with power-law interactions. AB - The influence of power-law interactions on the dynamics of many-body systems far from equilibrium is much less explored than their effect on static and thermodynamic properties. To gain insight into this problem we introduce and analyze here an out-of-equilibrium deposition process in which the deposition rate of a given particle depends as a power law on the distance to previously deposited particles. This model draws its relevance from recent experimental progress in the domain of cold atomic gases, which are studied in a setting where atoms that are excited to high-lying Rydberg states interact through power-law potentials that translate into power-law excitation rates. The out-of-equilibrium dynamics of this system turns out to be surprisingly rich. It features a self similar evolution which leads to a characteristic power-law time dependence of observables such as the particle concentration, and results in a scale invariance of the structure factor. Our findings show that in dissipative Rydberg gases out of equilibrium the characteristic distance among excitations-often referred to as the blockade radius-is not a static but rather a dynamic quantity. PMID- 26764670 TI - Thermostatistics of a damped bimodal particle. AB - We study the thermostatistics of a damped bimodal particle, i.e., a particle of mass m subject to a work reservoir that is analytically represented by the telegraph noise. Because of the colored nature of the noise, it does not fit the Levy-Ito class of stochastic processes, making this system an instance of a nonequilibrium system in contact with a non-Gaussian external reservoir. We obtain the statistical description of the position and velocity, namely in the stationary state, as well as the (time-dependent) statistics of the energy fluxes in the system considering no constraints on the telegraph noise features. With that result we are able to give an account of the statistical properties of the large deviations of the injected and dissipated power that can change from sub Gaussianity to super-Gaussianity depending on the color of the noise. By properly defining an effective temperature for this system, T, we are capable of obtaining an equivalent entropy production-exchange rate equal to the ratio between the dissipation of the medium, gamma, and the mass of the particle, m, a relation that concurs with the case of a standard thermal reservoir at temperature, T=T. PMID- 26764671 TI - Effective degrees of freedom of a random walk on a fractal. AB - We argue that a non-Markovian random walk on a fractal can be treated as a Markovian process in a fractional dimensional space with a suitable metric. This allows us to define the fractional dimensional space allied to the fractal as the nu-dimensional space F(nu) equipped with the metric induced by the fractal topology. The relation between the number of effective spatial degrees of freedom of walkers on the fractal (nu) and fractal dimensionalities is deduced. The intrinsic time of random walk in F(nu) is inferred. The Laplacian operator in F(nu) is constructed. This allows us to map physical problems on fractals into the corresponding problems in F(nu). In this way, essential features of physics on fractals are revealed. Particularly, subdiffusion on path-connected fractals is elucidated. The Coulomb potential of a point charge on a fractal embedded in the Euclidean space is derived. Intriguing attributes of some types of fractals are highlighted. PMID- 26764672 TI - Dynamic stabilization of a coupled ultracold atom-molecule system. AB - We numerically demonstrate the dynamic stabilization of a strongly interacting many-body bosonic system which can be realized by coupled ultracold atom-molecule gases. The system is initialized to an unstable equilibrium state corresponding to a saddle point in the classical phase space, where subsequent free evolution gives rise to atom-molecule conversion. To control and stabilize the system, periodic modulation is applied that suddenly shifts the relative phase between the atomic and the molecular modes and limits their further interconversion. The stability diagram for the range of modulation amplitudes and periods that stabilize the dynamics is given. The validity of the phase diagram obtained from the time-average calculation is discussed by using the orbit tracking method, and the difference in contrast with the maximum absolute deviation analysis is shown as well. A brief quantum analysis shows that quantum fluctuations can put serious limitations on the applicability of the mean-field results. PMID- 26764673 TI - Large deviations for Markov processes with resetting. AB - Markov processes restarted or reset at random times to a fixed state or region in space have been actively studied recently in connection with random searches, foraging, and population dynamics. Here we study the large deviations of time additive functions or observables of Markov processes with resetting. By deriving a renewal formula linking generating functions with and without resetting, we are able to obtain the rate function of such observables, characterizing the likelihood of their fluctuations in the long-time limit. We consider as an illustration the large deviations of the area of the Ornstein-Uhlenbeck process with resetting. Other applications involving diffusions, random walks, and jump processes with resetting or catastrophes are discussed. PMID- 26764674 TI - Critical behavior of a fixed-energy Manna sandpile model for regular initial conditions in one dimension. AB - For a fixed-energy (FE) Manna sandpile model in one dimension, we investigate the critical behavior for regular initial conditions in which activities are distributed at regular intervals on average. The FE Manna model conserves the density rho of total particles and undergoes an absorbing phase transition at a critical rho(c). For the regular initial conditions, we show via extensive simulations that the dynamical scaling behaviors differ from those of the random and the natural initial conditions. Off-critical scaling exponents beta and nu(?) are also measured and shown to agree well with the values of the directed percolation (DP) class as reported by Basu et al. [Phys. Rev. Lett. 109, 015702 (2012)]. Our results suggest that the dynamical scaling behaviors depend on the characteristics of initial conditions, but the off-critical scaling behaviors in the steady state are independent of initial conditions and belong to the DP class. PMID- 26764675 TI - Dynamical arrest with zero complexity: The unusual behavior of the spherical Blume-Emery-Griffiths disordered model. AB - The short- and long-time dynamics of model systems undergoing a glass transition with apparent inversion of Kauzmann and dynamical arrest glass transition lines is investigated. These models belong to the class of the spherical mean-field approximation of a spin-1 model with p-body quenched disordered interaction, with p>2, termed spherical Blume-Emery-Griffiths models. Depending on temperature and chemical potential the system is found in a paramagnetic or in a glassy phase and the transition between these phases can be of a different nature. In specific regions of the phase diagram coexistence of low-density and high-density paramagnets can occur, as well as the coexistence of spin-glass and paramagnetic phases. The exact static solution for the glassy phase is known to be obtained by the one-step replica symmetry breaking ansatz. Different scenarios arise for both the dynamic and the thermodynamic transitions. These include: (i) the usual random first-order transition (Kauzmann-like) for mean-field glasses preceded by a dynamic transition, (ii) a thermodynamic first-order transition with phase coexistence and latent heat, and (iii) a regime of apparent inversion of static transition line and dynamic transition lines, the latter defined as a nonzero complexity line. The latter inversion, though, turns out to be preceded by a dynamical arrest line at higher temperature. Crossover between different regimes is analyzed by solving mode-coupling-theory equations near the boundaries of paramagnetic solutions and the relationship with the underlying statics is discussed. PMID- 26764676 TI - Nonlinear low-to-high-frequency energy cascades in diatomic granular crystals. AB - We study wave propagation in strongly nonlinear one-dimensional diatomic granular crystals under an impact load. Depending on the mass ratio of the "light" to "heavy" beads, this system exhibits rich wave dynamics from highly localized traveling waves to highly dispersive waves featuring strong attenuation. We demonstrate experimentally the nonlinear resonant and antiresonant interactions of particles, and we verify that the nonlinear resonance results in strong wave attenuation, leading to highly efficient nonlinear energy cascading without relying on material damping. In this process, mechanical energy is transferred from low to high frequencies, while propagating waves emerge in both ordered and chaotic waveforms via a distinctive spatial cascading. This energy transfer mechanism from lower to higher frequencies and wave numbers is of particular significance toward the design of novel nonlinear acoustic metamaterials with inherently passive energy redistribution properties. PMID- 26764677 TI - Influence of rough and smooth walls on macroscale flows in tumblers. AB - Walls in discrete element method simulations of granular flows are sometimes modeled as a closely packed monolayer of fixed particles, resulting in a rough wall rather than a geometrically smooth wall. An implicit assumption is that the resulting rough wall differs from a smooth wall only locally at the particle scale. Here we test this assumption by considering the impact of the wall roughness at the periphery of the flowing layer on the flow of monodisperse particles in a rotating spherical tumbler. We find that varying the wall roughness significantly alters average particle trajectories even far from the wall. Rough walls induce greater poleward axial drift of particles near the flowing layer surface but decrease the curvature of the trajectories. Increasing the volume fill level in the tumbler has little effect on the axial drift for rough walls but increases the drift while reducing curvature of the particle trajectories for smooth walls. The mechanism for these effects is related to the degree of local slip at the bounding wall, which alters the flowing layer thickness near the walls, affecting the particle trajectories even far from the walls near the equator of the tumbler. Thus, the proper choice of wall conditions is important in the accurate simulation of granular flows, even far from the bounding wall. PMID- 26764678 TI - Structural characterization of the packings of granular regular polygons. AB - By using a recently developed method for discrete modeling of nonspherical particles, we simulate the random packings of granular regular polygons with three to 11 edges under gravity. The effects of shape and friction on the packing structures are investigated by various structural parameters, including packing fraction, the radial distribution function, coordination number, Voronoi tessellation, and bond-orientational order. We find that packing fraction is generally higher for geometrically nonfrustrated regular polygons, and can be increased by the increase of edge number and decrease of friction. The changes of packing fraction are linked with those of the microstructures, such as the variations of the translational and orientational orders and local configurations. In particular, the free areas of Voronoi tessellations (which are related to local packing fractions) can be described by log-normal distributions for all polygons. The quantitative analyses establish a clearer picture for the packings of regular polygons. PMID- 26764679 TI - Discharge flow of a bidisperse granular media from a silo: Discrete particle simulations. AB - Discrete particle simulations are used to study two-dimensional discharge flow from a silo using both monodisperse and bidisperse mixtures. The density and the velocity profiles through the aperture are measured. In the monodisperse case, two particles' diameters are studied for different outlet diameters. In the bidisperse case, we varied the fine mass fraction of the mixture. In all cases, the density and the velocity profiles are found to follow the same self-similar law. Based on these observations and the previous work of Benyamine et al., a physical model is proposed to describe the flow of bidisperse mixtures giving an explicit expression for the flow rate that is in good agreement with the results. PMID- 26764680 TI - Transition to a labyrinthine phase in a driven granular medium. AB - Labyrinthine patterns arise in two-dimensional physical systems submitted to competing interactions, in fields ranging from solid-state physics to hydrodynamics. For systems of interacting particles, labyrinthine and stripe phases were studied in the context of colloidal particles confined into a monolayer, both numerically by means of Monte Carlo simulations and experimentally using superparamagnetic particles. Here we report an experimental observation of a labyrinthine phase in an out-of-equilibrium system constituted of macroscopic particles. Once sufficiently magnetized, they organize into short chains of particles in contact and randomly orientated. We characterize the transition from a granular gas state towards a solid labyrinthine phase, as a function of the ratio of the interaction strength to the kinetic agitation. The spatial local structure is analyzed by means of accurate particle tracking. Moreover, we explain the formation of these chains using a simple model. PMID- 26764681 TI - Mechanisms for impulsive energy dissipation and small-scale effects in microgranular media. AB - We study impulse response in one-dimensional homogeneous microgranular chains on a linear elastic substrate. Microgranular interactions are analytically described by the Schwarz contact model which includes nonlinear compressive as well as snap to and from-contact adhesive effects forming a hysteretic loop in the force deformation relationship. We observe complex transient dynamics, including disintegration of solitary pulses, local clustering, and low-to-high-frequency energy transfers resulting in enhanced energy dissipation. We study in detail the underlying dynamics of cluster formation in the impulsively loaded medium and relate enhanced energy dissipation to the rate of cluster formation. These unusual and interesting dynamical phenomena are shown to be robust over a range of physically feasible conditions and are solely scale effects since they are attributed to surface forces, which have no effect at the macroscale. We establish a universal relation between the reclustering rate and the effective damping in these systems. Our findings demonstrate that scale effects generating new nonlinear features can drastically affect the dynamics and acoustics of microgranular materials. PMID- 26764682 TI - Confined disordered strictly jammed binary sphere packings. AB - Disordered jammed packings under confinement have received considerably less attention than their bulk counterparts and yet arise in a variety of practical situations. In this work, we study binary sphere packings that are confined between two parallel hard planes and generalize the Torquato-Jiao (TJ) sequential linear programming algorithm [Phys. Rev. E 82, 061302 (2010)] to obtain putative maximally random jammed (MRJ) packings that are exactly isostatic with high fidelity over a large range of plane separation distances H, small to large sphere radius ratio alpha, and small sphere relative concentration x. We find that packing characteristics can be substantially different from their bulk analogs, which is due to what we term "confinement frustration." Rattlers in confined packings are generally more prevalent than those in their bulk counterparts. We observe that packing fraction, rattler fraction, and degree of disorder of MRJ packings generally increase with H, though exceptions exist. Discontinuities in the packing characteristics as H varies in the vicinity of certain values of H are due to associated discontinuous transitions between different jammed states. When the plane separation distance is on the order of two large-sphere diameters or less, the packings exhibit salient two-dimensional features; when the plane separation distance exceeds about 30 large-sphere diameters, the packings approach three-dimensional bulk packings. As the size contrast increases (as alpha decreases), the rattler fraction dramatically increases due to what we call "size-disparity" frustration. We find that at intermediate alpha and when x is about 0.5 (50-50 mixture), the disorder of packings is maximized, as measured by an order metric psi that is based on the number density fluctuations in the direction perpendicular to the hard walls. We also apply the local volume-fraction variance sigma(tau)(2)(R) to characterize confined packings and find that these packings possess essentially the same level of hyperuniformity as their bulk counterparts. Our findings are generally relevant to confined packings that arise in biology (e.g., structural color in birds and insects) and may have implications for the creation of high-density powders and improved battery designs. PMID- 26764683 TI - Order-disorder transitions in a sheared many-body system. AB - Motivated by experiments on sheared suspensions that show a transition between ordered and disordered phases, we here study the long-time behavior of a sheared and overdamped two-dimensional system of particles interacting by repulsive forces. As a function of interaction strength and shear rate we find transitions between phases with vanishing and large single-particle diffusion. In the phases with vanishing single-particle diffusion, the system evolves towards regular lattices, usually on very slow time scales. Different lattices can be approached, depending on interaction strength and forcing amplitude. The disordered state appears in parameter regions where the regular lattices are unstable. Correlation functions between the particles reveal the formation of shear bands. In contrast to single-particle densities, the spatially resolved two-particle correlation functions vary with time and allow to determine the phase within a period. As in the case of the suspensions, motion in the state with low diffusivity is essentially reversible, whereas in the state with strong diffusion it is not. PMID- 26764684 TI - Survey of shock-wave structures of smooth-particle granular flows. AB - We show the effects of simulated supersonic granular flow made up of smooth particles passing over two prototypical bodies: a wedge and a disk. We describe a way of computationally identifying shock wave locations in granular flows and tabulate the shock wave locations for flow over wedges and disks. We quantify the shock structure in terms of oblique shock angle for wedge impediments and shock standoff distance for disk impediments. We vary granular flow parameters including upstream volume fraction, average upstream velocity, granular temperature, and the collision coefficient of restitution. Both wedges and disks have been used in the aerospace community as prototypical impediments to flowing air in order to investigate the fundamentally different shock structures emanating from sharp and blunt bodies, and we present these results in order to increase the understanding of the fundamental behavior of supersonic granular flow. PMID- 26764685 TI - Gas-induced fluidization of mobile liquid-saturated grains. AB - Gas invasion in liquid-saturated sands exhibits different morphologies and dynamics. For mobile beds, the repeated rise of gas through the layer leads to the growth of a fluidized zone, which reaches a stationary shape. Here, we present experimental results characterizing the evolution of the fluidized region as a function of the gas-flow rate and grain size. We introduce a new observable, the flow density, which quantifies the motion of the grains in the system. The growth of the fluidized zone is characterized by a spatiotemporal analysis, which provides the stabilization time, tau(s). In the stationary regime, we report two main contributions to motion in the fluidized region: the central gas rise and a convective granular motion. Interestingly, a static model with a fixed porous network accounts for the final shape of the invasion zone. We propose an explanation where the initial gas invasion weakens the system and fixes since the early stage the morphology of the fluidized zone. PMID- 26764686 TI - Laser-induced bubble generation on a gold nanoparticle: A nonsymmetrical description. AB - The modeling of bubbles initiated by laser-irradiated nanoparticles is of interest for many applications. There is at present no comprehensive physical picture for all the stages of the process. We present an alternative approach with a key assumption: the vapor bubble evolves adjacent to the nanoparticle. To take into account the irreversible evolution, the statistical rate theory was used, thus avoiding the introduction of extra ad hoc parameters. Model results agree well with published data and our measurements. The only free parameter, the thermal boundary conductance, can be obtained by adjusting the model to the experimental data. PMID- 26764687 TI - Stochastic approach to plasticity and yield in amorphous solids. AB - We focus on the probability distribution function (PDF) P(Deltagamma;gamma) where Deltagamma are the measured strain intervals between plastic events in a athermal strained amorphous solids, and gamma measures the accumulated strain. The tail of this distribution as Deltagamma->0 (in the thermodynamic limit) scales like Deltagamma(eta). The exponent eta is related via scaling relations to the tail of the PDF of the eigenvalues of the plastic modes of the Hessian matrix P(lambda) which scales like lambda(theta), eta=(theta-1)/2. The numerical values of eta or theta can be determined easily in the unstrained material and in the yielded state of plastic flow. Special care is called for in the determination of these exponents between these states as gamma increases. Determining the gamma dependence of the PDF P(Deltagamma;gamma) can shed important light on plasticity and yield. We conclude that the PDF's of both Deltagamma and lambda are not continuous functions of gamma. In slowly quenched amorphous solids they undergo two discontinuous transitions, first at gamma=0(+) and then at the yield point gamma=gamma(Y) to plastic flow. In quickly quenched amorphous solids the second transition is smeared out due to the nonexisting stress peak before yield. The nature of these transitions and scaling relations with the system size dependence of are discussed. PMID- 26764688 TI - Dynamics of prolate spheroidal elastic particles in confined shear flow. AB - We investigate through numerical simulations the dynamics of a neo-Hookean elastic prolate spheroid suspended in a Newtonian fluid under shear flow. Both initial orientations of the particle within and outside the shear plane and both unbounded and confined flow geometries are considered. In unbounded flow, when the particle starts on the shear plane, two stable regimes of motion are found, i.e., trembling, where the particle shape periodically elongates and compresses in the shear plane and the angle between its major semiaxis and the flow direction oscillates around a positive mean value, and tumbling, where the particle shape periodically changes and its major axis performs complete revolutions around the vorticity axis. When the particle is initially oriented out of the shear plane, more complex dynamics arise. Geometric confinement of the particle between the moving walls also influences its deformation and regime of motion. In addition, when the particle is initially located in an asymmetric position with respect to the moving walls, particle lateral migration is detected. The effects on the particle dynamics of the geometric and physical parameters that rule the system are investigated. PMID- 26764689 TI - Qualitative change in structural dynamics of some glass-forming systems. AB - Analysis of the temperature dependence of the structural relaxation time tau(alpha)(T) in supercooled liquids revealed a qualitatively distinct feature-a sharp, cusplike maximum in the second derivative of logtau(alpha)(T)at some T(max). It suggests that the super-Arrhenius temperature dependence of tau(alpha)(T) in glass-forming liquids eventually crosses over to an Arrhenius behavior at Tinfinity); until now, there was a large deviation for (sufficiently) colored noises. The present study shows that H provides us with ideal conditions for studying the corresponding Carr-Helfrich theory considering pure multiplicative noise. PMID- 26764709 TI - Twist, tilt, and orientational order at the nematic to twist-bend nematic phase transition of 1",9"-bis(4-cyanobiphenyl-4'-yl) nonane: A dielectric, (2)H NMR, and calorimetric study. AB - The nature of the nematic-nematic phase transition in the liquid crystal dimer 1",9"-bis(4-cyanobiphenyl-4'-yl) nonane (CB9CB) has been investigated using techniques of calorimetry, dynamic dielectric response measurements, and (2)H NMR spectroscopy. The experimental results for CB9CB show that, like the shorter homologue CB7CB, the studied material exhibits a normal nematic phase, which on cooling undergoes a transition to the twist-bend nematic phase (N(TB)), a uniaxial nematic phase, promoted by the average bent molecular shape, in which the director tilts and precesses describing a conical helix. Modulated differential scanning calorimetry has been used to analyze the nature of the N(TB)-N phase transition, which is found to be weakly first order, but close to tricritical. Additionally broadband dielectric spectroscopy and (2)H magnetic resonance studies have revealed information on the structural characteristics of the recently discovered twist-bend nematic phase. Analysis of the dynamic dielectric response in both nematic phases has provided an estimate of the conical angle of the heliconical structure for the N(TB) phase. Capacitance measurements of the electric-field realignment of the director in initially planar aligned cells have yielded values for the splay and bend elastic constants in the high temperature nematic phase. The bend elastic constant is small and decreases with decreasing temperature as the twist-bend phase is approached. This behavior is expected theoretically and has been observed in materials that form the twist-bend nematic phase. (2)H NMR measurements characterize the chiral helical twist identified in the twist-bend nematic phase and also allow the determination of the temperature dependence of the conical angle and the orientational order parameter with respect to the director. PMID- 26764710 TI - Phase behavior of shape-changing spheroids. AB - We introduce a simple model for a biaxial nematic liquid crystal. This consists of hard spheroids that can switch shape between prolate (rodlike) and oblate (platelike) subject to an energy penalty Deltaepsilon. The spheroids are approximated as hard Gaussian overlap particles and are treated at the level of Onsager's second-virial description. We use both bifurcation analysis and a numerical minimization of the free energy to show that, for additive particle shapes, (i) there is no stable biaxial phase even for Deltaepsilon=0 (although there is a metastable biaxial phase in the same density range as the stable uniaxial phase) and (ii) the isotropic-to-nematic transition is into either one of two degenerate uniaxial phases, rod rich or plate rich. We confirm that even a small amount of shape nonadditivity may stabilize the biaxial nematic phase. PMID- 26764711 TI - Nematic droplets on fibers. AB - The emergence of new techniques for the fabrication of nematic droplets with nontrivial topology provides new routes for the assembly of responsive devices. Here we explore some of the properties of nematic droplets on fibers, which constitute the basic units of a type of device that is able to respond to external stimuli, including the detection of gases. We perform a numerical study of spherical nematic droplets on fibers. We analyze the equilibrium textures for homogeneous and hybrid boundary conditions and find that in some cases the nematic avoids the nucleation of topological defects, which would provide a different optical response. We consider in detail a homeotropic nematic droplet wrapped around a fiber with planar anchoring. We investigate the effect of an electric field on the texture of this droplet. In the presence of a dc field, the system undergoes an orientational transition above a given threshold E(c), for which a ring defect is transformed into a figure-eight defect. We also consider ac fields, at high and low frequencies, and find that the textures are similar to those observed for static fields, in contrast with recently reported experiments. PMID- 26764712 TI - Viscoelasticity of a homeotropic nematic slab. AB - The viscoelastic behavior of a homeotropic nematic slab is studied when it is subjected to a (dilation-compression) sinusoidal deformation of small amplitude (linear regime). I show that the nematic phase behaves as an isotropic liquid of viscosity eta(c) (nu(3)) at low (high) frequency, where eta(c) is the third Miesowicz viscosity and nu(3) a smaller viscosity first introduced by Martin, Parodi, and Pershan. The crossover frequency f(?) between these two asymptotic regimes scales as h(2)/D, where h is the sample thickness and D=K(3)/gamma(1) is the orientational diffusivity (with K(3) the bend constant and gamma(1) the rotational viscosity). Between these two limits the sample behaves as a viscoelastic fluid whose elastic and loss moduli G' and G" are calculated. These predictions are tested experimentally with a piezoelectric rheometer. PMID- 26764713 TI - Field-driven dynamics of nematic microcapillaries. AB - Polymer-dispersed liquid-crystal (PDLC) composites long have been a focus of study for their unique electro-optical properties which have resulted in various applications such as switchable (transparent or translucent) windows. These composites are manufactured using desirable "bottom-up" techniques, such as phase separation of a liquid-crystal-polymer mixture, which enable production of PDLC films at very large scales. LC domains within PDLCs are typically spheroidal, as opposed to rectangular for an LCD panel, and thus exhibit substantially different behavior in the presence of an external field. The fundamental difference between spheroidal and rectangular nematic domains is that the former results in the presence of nanoscale orientational defects in LC order while the latter does not. Progress in the development and optimization of PDLC electro-optical properties has progressed at a relatively slow pace due to this increased complexity. In this work, continuum simulations are performed in order to capture the complex formation and electric field-driven switching dynamics of approximations of PDLC domains. Using a simplified elliptic cylinder (microcapillary) geometry as an approximation of spheroidal PDLC domains, the effects of geometry (aspect ratio), surface anchoring, and external field strength are studied through the use of the Landau-de Gennes model of the nematic LC phase. PMID- 26764714 TI - Spatiotemporal complexity of electroconvection patterns in nematic liquid crystals. AB - We investigate a number of complex patterns driven by the electroconvection instability in a planarly aligned layer of a nematic liquid crystal. They are traced back to various secondary instabilities of the ideal roll patterns bifurcating at onset of convection, whereby the basic nematohydrodynamic equations are solved by common Galerkin expansion methods. Alternatively these equations are systematically approximated by a set of coupled amplitude equations. They describe slow modulations of the convection roll amplitudes, which are coupled to a flow field component with finite vorticity perpendicular to the layer and to a quasihomogeneous in-plane rotation of the director. It is demonstrated that the Galerkin stability diagram of the convection rolls is well reproduced by the corresponding one based on the amplitude equations. The main purpose of the paper is, however, to demonstrate that their direct numerical simulations match surprisingly well new experiments, which serves as a convincing test of our theoretical approach. PMID- 26764716 TI - Droplet relaxation in Hele-Shaw geometry: Application to the measurement of the nematic-isotropic surface tension. AB - Shape measurements after the coalescence of isotropic droplets embedded in a thin sample of a homeotropic nematic phase provides a tool to measure the nematic isotropic surface tension. In addition, this experiment allows us to check the scaling laws recently given by Brun et al. [P.-T. Brun, M. Nagel, and F. Gallaire, Phys. Rev. E 88, 043009 (2013)] to explain the relaxation of ellipsoidal droplets in a Hele-Shaw cell. PMID- 26764715 TI - Visualization, coarsening, and flow dynamics of focal conic domains in simulated smectic-A liquid crystals. AB - Smectic liquid crystals vividly illustrate the subtle interplay of broken translational and orientational symmetries, by exhibiting defect structures forming geometrically perfect confocal ellipses and hyperbolas. Here, we develop and numerically implement an effective theory to study the dynamics of focal conic domains in smectic-A liquid crystals. We use the information about the smectic's structure and energy density provided by our simulations to develop several novel visualization tools for the focal conics. Our simulations accurately describe both simple and extensional shear, which we compare to experiments, and provide additional insight into the coarsening dynamics of focal conic domains. PMID- 26764717 TI - Substrate-induced gliding in a nematic liquid crystal layer. AB - We consider the interaction between nematic liquid crystals (NLCs) and polymer substrates. Such substrates can interact with NLCs, exhibiting a phenomenon known as director gliding: the preferred orientation of the NLC molecules at the interface changes on time scales that are slow relative to the elastic relaxation time scale of the NLC. We present two models for gliding, inspired by experiments that investigate the interaction between the NLC and a polymer substrate. These models, though simple, lead to nontrivial results, including loss of bistability under gliding. Perhaps surprisingly, we find that externally imposed switching between the steady states of a bistable system may reverse the effect of gliding, preventing loss of bistability if switching is sufficiently frequent. Our findings may be of relevance to a variety of technological applications involving liquid crystal devices, and particularly to a new generation of flexible liquid crystal displays that implement polymeric substrates. PMID- 26764719 TI - Long polymers near wedges and cones. AB - We perform a Monte Carlo study of N-step self-avoiding walks, attached to the corner of an impenetrable wedge in two dimensions (d=2), or the tip of an impenetrable cone in d=3, of sizes ranging up to N=10(6) steps. We find that the critical exponent gamma(alpha), which determines the dependence of the number of available conformations on N for a cone or wedge with opening angle alpha, is in good agreement with the theory for d=2. We study the end-point distribution of the walks in the allowed space and find similarities to the known behavior of random walks (ideal polymers) in the same geometry. For example, the ratio between the mean square end-to-end distances of a polymer near the cone or wedge and a polymer in free space depends linearly on gamma(alpha), as is known for ideal polymers. We show that the end-point distribution of polymers attached to a wedge does not separate into a product of angular and radial functions, as it does for ideal polymers in the same geometry. The angular dependence of the end position of polymers near the wedge differs from theoretical predictions. PMID- 26764718 TI - Finite-size corrections for confined polymers in the extended de Gennes regime. AB - Theoretical results for the extension of a polymer confined to a channel are usually derived in the limit of infinite contour length. But experimental studies and simulations of DNA molecules confined to nanochannels are not necessarily in this asymptotic limit. We calculate the statistics of the span and the end-to-end distance of a semiflexible polymer of finite length in the extended de Gennes regime, exploiting the fact that the problem can be mapped to a one-dimensional weakly self-avoiding random walk. The results thus obtained compare favorably with pruned-enriched Rosenbluth method (PERM) simulations of a three-dimensional discrete wormlike chain model of DNA confined in a nanochannel. We discuss the implications for experimental studies of linear lambda-DNA confined to nanochannels at the high ionic strengths used in many experiments. PMID- 26764720 TI - Dynamics and relaxation of charge carriers in poly(methylmethacrylate)-based polymer electrolytes embedded with ionic liquid. AB - In the present paper, we have studied dynamics and relaxation of the charge carriers in polymethylmethacrylate-lithium bis(trifluoromethane sulfonyl)imide polymer electrolytes embedded with 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide ionic liquid. We have analyzed the frequency dependent conductivity spectra using the random free-energy barrier model coupled with the contribution of electrode polarization in the low frequency region. The temperature dependence of ionic conductivity, and relaxation time obtained from the analysis of the spectra exhibits Vogel-Tammann-Fulcher type behavior. The Barton-Nakajima-Namikawa relation is consistent with the results obtained from the random free-energy barrier model. The scaling of ac conductivity spectra has been performed to understand the effect of temperature as well as the composition on the relaxation mechanism. The analysis of the ac conductivity also clearly indicates the existence of a nearly constant loss phenomenon at low temperatures or at high frequencies. PMID- 26764721 TI - Extension of nanoconfined DNA: Quantitative comparison between experiment and theory. AB - The extension of DNA confined to nanochannels has been studied intensively and in detail. However, quantitative comparisons between experiments and model calculations are difficult because most theoretical predictions involve undetermined prefactors, and because the model parameters (contour length, Kuhn length, effective width) are difficult to compute reliably, leading to substantial uncertainties. Here we use a recent asymptotically exact theory for the DNA extension in the "extended de Gennes regime" that allows us to compare experimental results with theory. For this purpose, we performed experiments measuring the mean DNA extension and its standard deviation while varying the channel geometry, dye intercalation ratio, and ionic strength of the buffer. The experimental results agree very well with theory at high ionic strengths, indicating that the model parameters are reliable. At low ionic strengths, the agreement is less good. We discuss possible reasons. In principle, our approach allows us to measure the Kuhn length and the effective width of a single DNA molecule and more generally of semiflexible polymers in solution. PMID- 26764722 TI - Wavelet-based multiscale analysis of bioimpedance data measured by electric cell substrate impedance sensing for classification of cancerous and normal cells. AB - The paper presents a study to differentiate normal and cancerous cells using label-free bioimpedance signal measured by electric cell-substrate impedance sensing. The real-time-measured bioimpedance data of human breast cancer cells and human epithelial normal cells employs fluctuations of impedance value due to cellular micromotions resulting from dynamic structural rearrangement of membrane protrusions under nonagitated condition. Here, a wavelet-based multiscale quantitative analysis technique has been applied to analyze the fluctuations in bioimpedance. The study demonstrates a method to classify cancerous and normal cells from the signature of their impedance fluctuations. The fluctuations associated with cellular micromotion are quantified in terms of cellular energy, cellular power dissipation, and cellular moments. The cellular energy and power dissipation are found higher for cancerous cells associated with higher micromotions in cancer cells. The initial study suggests that proposed wavelet based quantitative technique promises to be an effective method to analyze real time bioimpedance signal for distinguishing cancer and normal cells. PMID- 26764723 TI - Analytical approach to an integrate-and-fire model with spike-triggered adaptation. AB - The calculation of the steady-state probability density for multidimensional stochastic systems that do not obey detailed balance is a difficult problem. Here we present the analytical derivation of the stationary joint and various marginal probability densities for a stochastic neuron model with adaptation current. Our approach assumes weak noise but is valid for arbitrary adaptation strength and time scale. The theory predicts several effects of adaptation on the statistics of the membrane potential of a tonically firing neuron: (i) a membrane potential distribution with a convex shape, (ii) a strongly increased probability of hyperpolarized membrane potentials induced by strong and fast adaptation, and (iii) a maximized variability associated with the adaptation current at a finite adaptation time scale. PMID- 26764724 TI - Simplest relationship between local field potential and intracellular signals in layered neural tissue. AB - The relationship between the extracellularly measured electric field potential resulting from synaptic activity in an ensemble of neurons and intracellular signals in these neurons is an important but still open question. Based on a model neuron with a cylindrical dendrite and lumped soma, we derive a formula that substantiates a proportionality between the local field potential and the total somatic transmembrane current that emerges from the difference between the somatic and dendritic membrane potentials. The formula is tested by intra- and extracellular recordings of evoked synaptic responses in hippocampal slices. Additionally, the contribution of different membrane currents to the field potential is demonstrated in a two-population mean-field model. Our formalism, which allows for a simple estimation of unknown dendritic currents directly from somatic measurements, provides an interpretation of the local field potential in terms of intracellularly measurable synaptic signals. It is also applicable to the study of cortical activity using two-compartment neuronal population models. PMID- 26764725 TI - Computational study of stability of an H-H-type pseudoknot motif. AB - Motifs in RNA tertiary structures are important to their structural organizations and biological functions. Here we consider an H-H-type pseudoknot (HHpk) motif that consists of two hairpins connected by a junction loop and with kissing interactions between the two hairpin loops. Such a tertiary structural motif is recurrently found in RNA tertiary structures, but is difficult to predict computationally. So it is important to understand the mechanism of its formation and stability. Here we investigate the stability of the HHpk tertiary structure by using an all-atom molecular dynamics simulation. The results indicate that the HHpk tertiary structure is stable. However, it is found that this stability is not due to the helix-helix packing, as is usually expected, but is maintained by the combined action of the kissing hairpin loops and junctions, although the former plays the main role. Stable HHpk motifs may form structural platforms for the molecules to realize their biological functions. These results are useful for understanding the construction principle of RNA tertiary structures and structure prediction. PMID- 26764726 TI - Nontoxic colloidal particles impede antibiotic resistance of swarming bacteria by disrupting collective motion and speed. AB - A monolayer of swarming B. subtilis on semisolid agar is shown to display enhanced resistance against antibacterial drugs due to their collective behavior and motility. The dynamics of swarming motion, visualized in real time using time lapse microscopy, prevents the bacteria from prolonged exposure to lethal drug concentrations. The elevated drug resistance is significantly reduced when the collective motion of bacteria is judiciously disrupted using nontoxic polystyrene colloidal particles immobilized on the agar surface. The colloidal particles block and hinder the motion of the cells, and force large swarming rafts to break up into smaller packs in order to maneuver across narrow spaces between densely packed particles. In this manner, cohesive rafts rapidly lose their collectivity, speed, and group dynamics, and the cells become vulnerable to the drugs. The antibiotic resistance capability of swarming B. subtilis is experimentally observed to be negatively correlated with the number density of colloidal particles on the engineered surface. This relationship is further tested using an improved self-propelled particle model that takes into account interparticle alignment and hard-core repulsion. This work has pertinent implications on the design of optimal methods to treat drug resistant bacteria commonly found in swarming colonies. PMID- 26764728 TI - Effect of elastic colored noise in the hopping dynamics of single molecules in stretching experiments. AB - The influence of colored noise induced by elastic fluctuations in single-molecule stretching experiments is theoretically and numerically studied. Unlike in the thermal white noise case currently considered in the literature, elastically induced hopping dynamics between folded and unfolded states is manifested through critical oscillations showing smaller end-to-end distance fluctuations (deltax~1.25nm) within the free energy wells corresponding to both states. Our results are derived by analyzing the elastic coupling between the Handle-Molecule Handle system and the laser optical tweezers (LOT) array. It is shown that an Ornstein-Uhlenbeck process related to this elastic coupling may trigger the hopping transitions via a colored noise with an intensity proportional to the elastic constant of the LOT array. Evolution equations of the variables of the system were derived by using the irreversible thermodynamics of small systems recently proposed. Theoretical expressions for the corresponding stationary probability densities are provided and the viability of inferring the shape of the free energy from direct measurements is discussed. PMID- 26764727 TI - Input nonlinearities can shape beyond-pairwise correlations and improve information transmission by neural populations. AB - While recent recordings from neural populations show beyond-pairwise, or higher order, correlations (HOC), we have little understanding of how HOC arise from network interactions and of how they impact encoded information. Here, we show that input nonlinearities imply HOC in spin-glass-type statistical models. We then discuss one such model with parametrized pairwise- and higher-order interactions, revealing conditions under which beyond-pairwise interactions increase the mutual information between a given stimulus type and the population responses. For jointly Gaussian stimuli, coding performance is improved by shaping output HOC only when neural firing rates are constrained to be low. For stimuli with skewed probability distributions (like natural image luminances), performance improves for all firing rates. Our work suggests surprising connections between nonlinear integration of neural inputs, stimulus statistics, and normative theories of population coding. Moreover, it suggests that the inclusion of beyond-pairwise interactions could improve the performance of Boltzmann machines for machine learning and signal processing applications. PMID- 26764730 TI - Effects of dynamic synapses on noise-delayed response latency of a single neuron. AB - The noise-delayed decay (NDD) phenomenon emerges when the first-spike latency of a periodically forced stochastic neuron exhibits a maximum for a particular range of noise intensity. Here, we investigate the latency response dynamics of a single Hodgkin-Huxley neuron that is subject to both a suprathreshold periodic stimulus and a background activity arriving through dynamic synapses. We study the first-spike latency response as a function of the presynaptic firing rate f. This constitutes a more realistic scenario than previous works, since f provides a suitable biophysically realistic parameter to control the level of activity in actual neural systems. We first report on the emergence of classical NDD behavior as a function of f for the limit of static synapses. Second, we show that when short-term depression and facilitation mechanisms are included at the synapses, different NDD features can be found due to their modulatory effect on synaptic current fluctuations. For example, an intriguing double NDD (DNDD) behavior occurs for different sets of relevant synaptic parameters. Moreover, depending on the balance between synaptic depression and synaptic facilitation, single NDD or DNDD can prevail, in such a way that synaptic facilitation favors the emergence of DNDD whereas synaptic depression favors the existence of single NDD. Here we report the existence of the DNDD effect in the response latency dynamics of a neuron. PMID- 26764729 TI - Multiscale modeling and simulation of microtubule-motor-protein assemblies. AB - Microtubules and motor proteins self-organize into biologically important assemblies including the mitotic spindle and the centrosomal microtubule array. Outside of cells, microtubule-motor mixtures can form novel active liquid crystalline materials driven out of equilibrium by adenosine triphosphate consuming motor proteins. Microscopic motor activity causes polarity-dependent interactions between motor proteins and microtubules, but how these interactions yield larger-scale dynamical behavior such as complex flows and defect dynamics is not well understood. We develop a multiscale theory for microtubule-motor systems in which Brownian dynamics simulations of polar microtubules driven by motors are used to study microscopic organization and stresses created by motor mediated microtubule interactions. We identify polarity-sorting and crosslink tether relaxation as two polar-specific sources of active destabilizing stress. We then develop a continuum Doi-Onsager model that captures polarity sorting and the hydrodynamic flows generated by these polar-specific active stresses. In simulations of active nematic flows on immersed surfaces, the active stresses drive turbulent flow dynamics and continuous generation and annihilation of disclination defects. The dynamics follow from two instabilities, and accounting for the immersed nature of the experiment yields unambiguous characteristic length and time scales. When turning off the hydrodynamics in the Doi-Onsager model, we capture formation of polar lanes as observed in the Brownian dynamics simulation. PMID- 26764731 TI - Wrinkling of a spherical lipid interface induced by actomyosin cortex. AB - Actomyosin actively generates contractile forces that provide the plasma membrane with the deformation stresses essential to carry out biological processes. Although the contractile property of purified actomyosin has been extensively studied, to understand the physical contribution of the actomyosin contractile force on a deformable membrane is still a challenging problem and of great interest in the field of biophysics. Here, we reconstitute a model system with a cell-sized deformable interface that exhibits anomalous curvature-dependent wrinkling caused by the actomyosin cortex underneath the spherical closed interface. Through a shape analysis of the wrinkling deformation, we find that the dominant contributor to the wrinkled shape changes from bending elasticity to stretching elasticity of the reconstituted cortex upon increasing the droplet curvature radius of the order of the cell size, i.e., tens of micrometers. The observed curvature dependence is explained by the theoretical description of the cortex elasticity and contractility. Our present results provide a fundamental insight into the deformation of a curved membrane induced by the actomyosin cortex. PMID- 26764733 TI - Coupling between pore formation and phase separation in charged lipid membranes. AB - We investigated the effect of charge on the membrane morphology of giant unilamellar vesicles (GUVs) composed of various mixtures containing charged lipids. We observed the membrane morphologies by fluorescent and confocal laser microscopy in lipid mixtures consisting of a neutral unsaturated lipid [dioleoylphosphatidylcholine (DOPC)], a neutral saturated lipid [dipalmitoylphosphatidylcholine (DPPC)], a charged unsaturated lipid [dioleoylphosphatidylglycerol (DOPG((-)))], a charged saturated lipid [dipalmitoylphosphatidylglycerol (DPPG((-)))], and cholesterol (Chol). In binary mixtures of neutral DOPC-DPPC and charged DOPC-DPPG((-))), spherical vesicles were formed. On the other hand, pore formation was often observed with GUVs consisting of DOPG((-))) and DPPC. In a DPPC-DPPG((-)))-Chol ternary mixture, pore-formed vesicles were also frequently observed. The percentage of pore-formed vesicles increased with the DPPG((-))) concentration. Moreover, when the head group charges of charged lipids were screened by the addition of salt, pore formed vesicles were suppressed in both the binary and ternary charged lipid mixtures. We discuss the mechanisms of pore formation in charged lipid mixtures and the relationship between phase separation and the membrane morphology. Finally, we reproduce the results seen in experimental systems by using coarse grained molecular dynamics simulations. PMID- 26764734 TI - Fock space, symbolic algebra, and analytical solutions for small stochastic systems. AB - Randomness is ubiquitous in nature. From single-molecule biochemical reactions to macroscale biological systems, stochasticity permeates individual interactions and often regulates emergent properties of the system. While such systems are regularly studied from a modeling viewpoint using stochastic simulation algorithms, numerous potential analytical tools can be inherited from statistical and quantum physics, replacing randomness due to quantum fluctuations with low copy-number stochasticity. Nevertheless, classical studies remained limited to the abstract level, demonstrating a more general applicability and equivalence between systems in physics and biology rather than exploiting the physics tools to study biological systems. Here the Fock space representation, used in quantum mechanics, is combined with the symbolic algebra of creation and annihilation operators to consider explicit solutions for the chemical master equations describing small, well-mixed, biochemical, or biological systems. This is illustrated with an exact solution for a Michaelis-Menten single enzyme interacting with limited substrate, including a consideration of very short time scales, which emphasizes when stiffness is present even for small copy numbers. Furthermore, we present a general matrix representation for Michaelis-Menten kinetics with an arbitrary number of enzymes and substrates that, following diagonalization, leads to the solution of this ubiquitous, nonlinear enzyme kinetics problem. For this, a flexible symbolic maple code is provided, demonstrating the prospective advantages of this framework compared to stochastic simulation algorithms. This further highlights the possibilities for analytically based studies of stochastic systems in biology and chemistry using tools from theoretical quantum physics. PMID- 26764735 TI - Polymer ejection from strong spherical confinement. AB - We examine the ejection of an initially strongly confined flexible polymer from a spherical capsid through a nanoscale pore. We use molecular dynamics for unprecedentedly high initial monomer densities. We show that the time for an individual monomer to eject grows exponentially with the number of ejected monomers. By measurements of the force at the pore we show this dependence to be a consequence of the excess free energy of the polymer due to confinement growing exponentially with the number of monomers initially inside the capsid. This growth relates closely to the divergence of mixing energy in the Flory-Huggins theory at large concentration. We show that the pressure inside the capsid driving the ejection dominates the process that is characterized by the ejection time growing linearly with the lengths of different polymers. Waiting time profiles would indicate that the superlinear dependence obtained for polymers amenable to computer simulations results from a finite-size effect due to the final retraction of polymers' tails from capsids. PMID- 26764732 TI - Role of DNA binding sites and slow unbinding kinetics in titration-based oscillators. AB - Genetic oscillators, such as circadian clocks, are constantly perturbed by molecular noise arising from the small number of molecules involved in gene regulation. One of the strongest sources of stochasticity is the binary noise that arises from the binding of a regulatory protein to a promoter in the chromosomal DNA. In this study, we focus on two minimal oscillators based on activator titration and repressor titration to understand the key parameters that are important for oscillations and for overcoming binary noise. We show that the rate of unbinding from the DNA, despite traditionally being considered a fast parameter, needs to be slow to broaden the space of oscillatory solutions. The addition of multiple, independent DNA binding sites further expands the oscillatory parameter space for the repressor-titration oscillator and lengthens the period of both oscillators. This effect is a combination of increased effective delay of the unbinding kinetics due to multiple binding sites and increased promoter ultrasensitivity that is specific for repression. We then use stochastic simulation to show that multiple binding sites increase the coherence of oscillations by mitigating the binary noise. Slow values of DNA unbinding rate are also effective in alleviating molecular noise due to the increased distance from the bifurcation point. Our work demonstrates how the number of DNA binding sites and slow unbinding kinetics, which are often omitted in biophysical models of gene circuits, can have a significant impact on the temporal and stochastic dynamics of genetic oscillators. PMID- 26764736 TI - Optimality and adaptation of phenotypically switching cells in fluctuating environments. AB - Stochastic switching between alternative phenotypic states is a common cellular survival strategy during unforeseen environmental fluctuations. Cells can switch between different subpopulations that proliferate at different rates in different environments. Optimal population growth is typically assumed to occur when phenotypic switching rates match environmental switching rates. However, it is not well understood how this optimum behaves as a function of the growth rates of phenotypically different cells. In this study, we use mathematical and computational models to test how the actual parameters associated with optimal population growth differ from those assumed to be optimal. We find that the predicted optimum is practically always valid if the environmental durations are long. However, the regime of validity narrows as environmental durations shorten, especially if subpopulation growth rate differences differ from each other (are asymmetric) in two environments. Furthermore, we study the fate of mutants with switching rates previously predicted to be optimal. We find that mutants which match their phenotypic switching rates with the environmental ones can only sweep the population if the assumed optimum is valid, but not otherwise. PMID- 26764737 TI - Dynamics of simple gene-network motifs subject to extrinsic fluctuations. AB - Cellular processes do not follow deterministic rules; even in identical environments genetically identical cells can make random choices leading to different phenotypes. This randomness originates from fluctuations present in the biomolecular interaction networks. Most previous work has been focused on the intrinsic noise (IN) of these networks. Yet, especially for high-copy-number biomolecules, extrinsic or environmental noise (EN) has been experimentally shown to dominate the variation. Here, we develop an analytical formalism that allows for calculation of the effect of EN on gene-expression motifs. We introduce a method for modeling bounded EN as an auxiliary species in the master equation. The method is fully generic and is not limited to systems with small EN magnitudes. We focus our study on motifs that can be viewed as the building blocks of genetic switches: a nonregulated gene, a self-inhibiting gene, and a self-promoting gene. The role of the EN properties (magnitude, correlation time, and distribution) on the statistics of interest are systematically investigated, and the effect of fluctuations in different reaction rates is compared. Due to its analytical nature, our formalism can be used to quantify the effect of EN on the dynamics of biochemical networks and can also be used to improve the interpretation of data from single-cell gene-expression experiments. PMID- 26764739 TI - Liquidity crises on different time scales. AB - We present an empirical analysis of the microstructure of financial markets and, in particular, of the static and dynamic properties of liquidity. We find that on relatively large time scales (15 min) large price fluctuations are connected to the failure of the subtle mechanism of compensation between the flows of market and limit orders: in other words, the missed revelation of the latent order book breaks the dynamical equilibrium between the flows, triggering the large price jumps. On smaller time scales (30 s), instead, the static depletion of the limit order book is an indicator of an intrinsic fragility of the system, which is related to a strongly nonlinear enhancement of the response. In order to quantify this phenomenon we introduce a measure of the liquidity imbalance present in the book and we show that it is correlated to both the sign and the magnitude of the next price movement. These findings provide a quantitative definition of the effective liquidity, which proves to be strongly dependent on the considered time scales. PMID- 26764738 TI - Optimal synchronization of Kuramoto oscillators: A dimensional reduction approach. AB - A recently proposed dimensional reduction approach for studying synchronization in the Kuramoto model is employed to build optimal network topologies to favor or to suppress synchronization. The approach is based in the introduction of a collective coordinate for the time evolution of the phase locked oscillators, in the spirit of the Ott-Antonsen ansatz. We show that the optimal synchronization of a Kuramoto network demands the maximization of the quadratic function omega(T)Lomega, where omega stands for the vector of the natural frequencies of the oscillators and L for the network Laplacian matrix. Many recently obtained numerical results can be reobtained analytically and in a simpler way from our maximization condition. A computationally efficient hill climb rewiring algorithm is proposed to generate networks with optimal synchronization properties. Our approach can be easily adapted to the case of the Kuramoto models with both attractive and repulsive interactions, and again many recent numerical results can be rederived in a simpler and clearer analytical manner. PMID- 26764740 TI - Internal character dictates transition dynamics between isolation and cohesive grouping. AB - We show that accounting for internal character among interacting heterogeneous entities generates rich transition behavior between isolation and cohesive dynamical grouping. Our analytical and numerical calculations reveal different critical points arising for different character-dependent grouping mechanisms. These critical points move in opposite directions as the population's diversity decreases. Our analytical theory may help explain why a particular class of universality is so common in the real world, despite the fundamental differences in the underlying entities. It also correctly predicts the nonmonotonic temporal variation in connectivity observed recently in one such system. PMID- 26764741 TI - Fragility of network-forming glasses: A universal dependence on the topological connectivity. AB - The fragilities of over 150 different network-forming glass melts are shown to conform to a common dependence on just one parameter: the connectivity of the weakest network structure present in the associated glass solid. This includes both nonoxide network-forming chalcogenide melts as well as a variety of alkali oxide glasses, and spans a broad range of connectivity, phi, from polymeric structures (phi=2) to overconstrained random networks with connectivities well in excess of the rigidity threshold (phi(C)=2.4). A theoretical framework for the origin of this universal pattern is offered within the context of entropic models of the glass transition. PMID- 26764742 TI - Critical tipping point distinguishing two types of transitions in modular network structures. AB - Modularity is a key organizing principle in real-world large-scale complex networks. The relatively sparse interactions between modules are critical to the functionality of the system and are often the first to fail. We model such failures as site percolation targeting interconnected nodes, those connecting between modules. We find, using percolation theory and simulations, that they lead to a "tipping point" between two distinct regimes. In one regime, removal of interconnected nodes fragments the modules internally and causes the system to collapse. In contrast, in the other regime, while only attacking a small fraction of nodes, the modules remain but become disconnected, breaking the entire system. We show that networks with broader degree distribution might be highly vulnerable to such attacks since only few nodes are needed to interconnect the modules, consequently putting the entire system at high risk. Our model has the potential to shed light on many real-world phenomena, and we briefly consider its implications on recent advances in the understanding of several neurocognitive processes and diseases. PMID- 26764744 TI - General and exact approach to percolation on random graphs. AB - We present a comprehensive and versatile theoretical framework to study site and bond percolation on clustered and correlated random graphs. Our contribution can be summarized in three main points. (i) We introduce a set of iterative equations that solve the exact distribution of the size and composition of components in finite-size quenched or random multitype graphs. (ii) We define a very general random graph ensemble that encompasses most of the models published to this day and also makes it possible to model structural properties not yet included in a theoretical framework. Site and bond percolation on this ensemble is solved exactly in the infinite-size limit using probability generating functions [i.e., the percolation threshold, the size, and the composition of the giant (extensive) and small components]. Several examples and applications are also provided. (iii) Our approach can be adapted to model interdependent graphs-whose most striking feature is the emergence of an extensive component via a discontinuous phase transition-in an equally general fashion. We show how a graph can successively undergo a continuous then a discontinuous phase transition, and preliminary results suggest that clustering increases the amplitude of the discontinuity at the transition. PMID- 26764743 TI - Approximating frustration scores in complex networks via perturbed Laplacian spectra. AB - Systems of many interacting components, as found in physics, biology, infrastructure, and the social sciences, are often modeled by simple networks of nodes and edges. The real-world systems frequently confront outside intervention or internal damage whose impact must be predicted or minimized, and such perturbations are then mimicked in the models by altering nodes or edges. This leads to the broad issue of how to best quantify changes in a model network after some type of perturbation. In the case of node removal there are many centrality metrics which associate a scalar quantity with the removed node, but it can be difficult to associate the quantities with some intuitive aspect of physical behavior in the network. This presents a serious hurdle to the application of network theory: real-world utility networks are rarely altered according to theoretic principles unless the kinetic impact on the network's users are fully appreciated beforehand. In pursuit of a kinetically interpretable centrality score, we discuss the f-score, or frustration score. Each f-score quantifies whether a selected node accelerates or inhibits global mean first passage times to a second, independently selected target node. We show that this is a natural way of revealing the dynamical importance of a node in some networks. After discussing merits of the f-score metric, we combine spectral and Laplacian matrix theory in order to quickly approximate the exact f-score values, which can otherwise be expensive to compute. Following tests on both synthetic and real medium-sized networks, we report f-score runtime improvements over exact brute force approaches in the range of 0 to 400% with low error (<3%). PMID- 26764745 TI - Approximate solution for frequency synchronization in a finite-size Kuramoto model. AB - Scientists have been considering the Kuramoto model to understand the mechanism behind the appearance of collective behavior, such as frequency synchronization (FS) as a paradigm, in real-world networks with a finite number of oscillators. A major current challenge is to obtain an analytical solution for the phase angles. Here, we provide an approximate analytical solution for this problem by deriving a master solution for the finite-size Kuramoto model, with arbitrary finite variance distribution of the natural frequencies of the oscillators. The master solution embodies all particular solutions of the finite-size Kuramoto model for any frequency distribution and coupling strength larger than the critical one. Furthermore, we present a criterion to determine the stability of the FS solution. This allows one to analytically infer the relationship between the physical parameters and the stable behavior of networks. PMID- 26764746 TI - Complex networks as an emerging property of hierarchical preferential attachment. AB - Real complex systems are not rigidly structured; no clear rules or blueprints exist for their construction. Yet, amidst their apparent randomness, complex structural properties universally emerge. We propose that an important class of complex systems can be modeled as an organization of many embedded levels (potentially infinite in number), all of them following the same universal growth principle known as preferential attachment. We give examples of such hierarchy in real systems, for instance, in the pyramid of production entities of the film industry. More importantly, we show how real complex networks can be interpreted as a projection of our model, from which their scale independence, their clustering, their hierarchy, their fractality, and their navigability naturally emerge. Our results suggest that complex networks, viewed as growing systems, can be quite simple, and that the apparent complexity of their structure is largely a reflection of their unobserved hierarchical nature. PMID- 26764747 TI - Network-based model of the growth of termite nests. AB - We present a model for the growth of the transportation network inside nests of the social insect subfamily Termitinae (Isoptera, termitidae). These nests consist of large chambers (nodes) connected by tunnels (edges). The model based on the empirical analysis of the real nest networks combined with pruning (edge removal, either random or weighted by betweenness centrality) and a memory effect (preferential growth from the latest added chambers) successfully predicts emergent nest properties (degree distribution, size of the largest connected component, average path lengths, backbone link ratios, and local graph redundancy). The two pruning alternatives can be associated with different genuses in the subfamily. A sensitivity analysis on the pruning and memory parameters indicates that Termitinae networks favor fast internal transportation over efficient defense strategies against ant predators. Our results provide an example of how complex network organization and efficient network properties can be generated from simple building rules based on local interactions and contribute to our understanding of the mechanisms that come into play for the formation of termite networks and of biological transportation networks in general. PMID- 26764748 TI - Demography-based adaptive network model reproduces the spatial organization of human linguistic groups. AB - The distribution of human linguistic groups presents a number of interesting and nontrivial patterns. The distributions of the number of speakers per language and the area each group covers follow log-normal distributions, while population and area fulfill an allometric relationship. The topology of networks of spatial contacts between different linguistic groups has been recently characterized, showing atypical properties of the degree distribution and clustering, among others. Human demography, spatial conflicts, and the construction of networks of contacts between linguistic groups are mutually dependent processes. Here we introduce an adaptive network model that takes all of them into account and successfully reproduces, using only four model parameters, not only those features of linguistic groups already described in the literature, but also correlations between demographic and topological properties uncovered in this work. Besides their relevance when modeling and understanding processes related to human biogeography, our adaptive network model admits a number of generalizations that broaden its scope and make it suitable to represent interactions between agents based on population dynamics and competition for space. PMID- 26764749 TI - Growing multiplex networks with arbitrary number of layers. AB - This paper focuses on the problem of growing multiplex networks. Currently, the results on the joint degree distribution of growing multiplex networks present in the literature pertain to the case of two layers and are confined to the special case of homogeneous growth and are limited to the state state (that is, the limit of infinite size). In the present paper, we first obtain closed-form solutions for the joint degree distribution of heterogeneously growing multiplex networks with arbitrary number of layers in the steady state. Heterogeneous growth means that each incoming node establishes different numbers of links in different layers. We consider both uniform and preferential growth. We then extend the analysis of the uniform growth mechanism to arbitrary times. We obtain a closed form solution for the time-dependent joint degree distribution of a growing multiplex network with arbitrary initial conditions. Throughout, theoretical findings are corroborated with Monte Carlo simulations. The results shed light on the effects of the initial network on the transient dynamics of growing multiplex networks and takes a step towards characterizing the temporal variations of the connectivity of growing multiplex networks, as well as predicting their future structural properties. PMID- 26764750 TI - Mean-field dynamics of a random neural network with noise. AB - We consider a network of randomly coupled rate-based neurons influenced by external and internal noise. We derive a second-order stochastic mean-field model for the network dynamics and use it to analyze the stability and bifurcations in the thermodynamic limit, as well as to study the fluctuations due to the finite size effect. It is demonstrated that the two types of noise have substantially different impact on the network dynamics. While both sources of noise give rise to stochastic fluctuations in the case of the finite-size network, only the external noise affects the stationary activity levels of the network in the thermodynamic limit. We compare the theoretical predictions with the direct simulation results and show that they agree for large enough network sizes and for parameter domains sufficiently away from bifurcations. PMID- 26764751 TI - Effects of local and global network connectivity on synergistic epidemics. AB - Epidemics in networks can be affected by cooperation in transmission of infection and also connectivity between nodes. An interplay between these two properties and their influence on epidemic spread are addressed in the paper. A particular type of cooperative effects (called synergy effects) is considered, where the transmission rate between a pair of nodes depends on the number of infected neighbors. The connectivity effects are studied by constructing networks of different topology, starting with lattices with only local connectivity and then with networks that have both local and global connectivity obtained by random bond-rewiring to nodes within a certain distance. The susceptible-infected removed epidemics were found to exhibit several interesting effects: (i) for epidemics with strong constructive synergy spreading in networks with high local connectivity, the bond rewiring has a negative role in epidemic spread, i.e., it reduces invasion probability; (ii) in contrast, for epidemics with destructive or weak constructive synergy spreading on networks of arbitrary local connectivity, rewiring helps epidemics to spread; (iii) and, finally, rewiring always enhances the spread of epidemics, independent of synergy, if the local connectivity is low. PMID- 26764752 TI - Universal bursty behavior in the air transportation system. AB - Social activities display bursty behavior characterized by heavy-tailed interevent time distributions. We examine the bursty behavior of airplanes' arrivals in hub airports. The analysis indicates that the air transportation system universally follows a power-law interarrival time distribution with an exponent alpha=2.5 and an exponential cutoff. Moreover, we investigate the mechanism of this bursty behavior by introducing a simple model to describe it. In addition, we compare the extent of the hub-and-spoke structure and the burstiness of various airline networks in the system. Remarkably, the results suggest that the hub-and-spoke network of the system and the carriers' strategy to facilitate transit are the origins of this universality. PMID- 26764753 TI - Extreme fluctuations in stochastic network coordination with time delays. AB - We study the effects of uniform time delays on the extreme fluctuations in stochastic synchronization and coordination problems with linear couplings in complex networks. We obtain the average size of the fluctuations at the nodes from the behavior of the underlying modes of the network. We then obtain the scaling behavior of the extreme fluctuations with system size, as well as the distribution of the extremes on complex networks, and compare them to those on regular one-dimensional lattices. For large complex networks, when the delay is not too close to the critical one, fluctuations at the nodes effectively decouple, and the limit distributions converge to the Fisher-Tippett-Gumbel density. In contrast, fluctuations in low-dimensional spatial graphs are strongly correlated, and the limit distribution of the extremes is the Airy density. Finally, we also explore the effects of nonlinear couplings on the stability and on the extremes of the synchronization landscapes. PMID- 26764755 TI - Critical space-time networks and geometric phase transitions from frustrated edge antiferromagnetism. AB - Recently I proposed a simple dynamical network model for discrete space-time that self-organizes as a graph with Hausdorff dimension d(H)=4. The model has a geometric quantum phase transition with disorder parameter (d(H)-d(s)), where d(s) is the spectral dimension of the dynamical graph. Self-organization in this network model is based on a competition between a ferromagnetic Ising model for vertices and an antiferromagnetic Ising model for edges. In this paper I solve a toy version of this model defined on a bipartite graph in the mean-field approximation. I show that the geometric phase transition corresponds exactly to the antiferromagnetic transition for edges, the dimensional disorder parameter of the former being mapped to the staggered magnetization order parameter of the latter. The model has a critical point with long-range correlations between edges, where a continuum random geometry can be defined, exactly as in Kazakov's famed 2D random lattice Ising model but now in any number of dimensions. PMID- 26764754 TI - Experimental proof of faster-is-slower in systems of frictional particles flowing through constrictions. AB - The "faster-is-slower" (FIS) effect was first predicted by computer simulations of the egress of pedestrians through a narrow exit [D. Helbing, I. J. Farkas, and T. Vicsek, Nature (London) 407, 487 (2000)]. FIS refers to the finding that, under certain conditions, an excess of the individuals' vigor in the attempt to exit causes a decrease in the flow rate. In general, this effect is identified by the appearance of a minimum when plotting the total evacuation time of a crowd as a function of the pedestrian desired velocity. Here, we experimentally show that the FIS effect indeed occurs in three different systems of discrete particles flowing through a constriction: (a) humans evacuating a room, (b) a herd of sheep entering a barn, and (c) grains flowing out a 2D hopper over a vibrated incline. This finding suggests that FIS is a universal phenomenon for active matter passing through a narrowing. PMID- 26764756 TI - Synchronization in dynamical networks with unconstrained structure switching. AB - We provide a rigorous solution to the problem of constructing a structural evolution for a network of coupled identical dynamical units that switches between specified topologies without constraints on their structure. The evolution of the structure is determined indirectly from a carefully built transformation of the eigenvector matrices of the coupling Laplacians, which are guaranteed to change smoothly in time. In turn, this allows one to extend the master stability function formalism, which can be used to assess the stability of a synchronized state. This approach is independent from the particular topologies that the network visits, and is not restricted to commuting structures. Also, it does not depend on the time scale of the evolution, which can be faster than, comparable to, or even secular with respect to the dynamics of the units. PMID- 26764757 TI - Effective centrality and explosive synchronization in complex networks. AB - Synchronization of networked oscillators is known to depend fundamentally on the interplay between the dynamics of the graph's units and the microscopic arrangement of the network's structure. We here propose an effective network whose topological properties reflect the interplay between the topology and dynamics of the original network. On that basis, we are able to introduce the effective centrality, a measure that quantifies the role and importance of each network's node in the synchronization process. In particular, in the context of explosive synchronization, we use such a measure to assess the propensity of a graph to sustain an irreversible transition to synchronization. We furthermore discuss a strategy to induce the explosive behavior in a generic network, by acting only upon a fraction of its nodes. PMID- 26764758 TI - Emergence of long-range correlations and bursty activity patterns in online communication. AB - Research has suggested that the activity occurring in a variety of social, economic, and technological systems exhibits long-range fluctuations in time. Pronounced levels of rapidly occurring events are typically observed over short periods of time, followed by long periods of inactivity. Relatively few studies, however, have shed light on the degree to which inhomogeneous temporal processes can be detected at, and emerge from, different levels of analysis. Here we investigate patterns of human activity within an online forum in which communication can be assessed at three intertwined levels: the micro level of the individual users; the meso level of discussion groups and continuous sessions; and the macro level of the whole system. To uncover the relation between different levels, we conduct a number of numerical simulations of a zero-crossing model in which users' behavior is constrained by progressively richer and more realistic rules of social interaction. Results indicate that, when users are solipsistic, their bursty behavior is not sufficient for generating heavy-tailed interevent time distributions at a higher level. However, when users are socially interdependent, the power spectra and interevent time distributions of the simulated and real forums are remarkably similar at all levels of analysis. Social interaction is responsible for the aggregation of multiple bursty activities at the micro level into an emergent bursty activity pattern at a higher level. We discuss the implications of the findings for an emergentist account of burstiness in complex systems. PMID- 26764759 TI - Low-rank network decomposition reveals structural characteristics of small-world networks. AB - Small-world networks occur naturally throughout biological, technological, and social systems. With their prevalence, it is particularly important to prudently identify small-world networks and further characterize their unique connection structure with respect to network function. In this work we develop a formalism for classifying networks and identifying small-world structure using a decomposition of network connectivity matrices into low-rank and sparse components, corresponding to connections within clusters of highly connected nodes and sparse interconnections between clusters, respectively. We show that the network decomposition is independent of node indexing and define associated bounded measures of connectivity structure, which provide insight into the clustering and regularity of network connections. While many existing network characterizations rely on constructing benchmark networks for comparison or fail to describe the structural properties of relatively densely connected networks, our classification relies only on the intrinsic network structure and is quite robust with respect to changes in connection density, producing stable results across network realizations. Using this framework, we analyze several real-world networks and reveal new structural properties, which are often indiscernible by previously established characterizations of network connectivity. PMID- 26764760 TI - Trend-driven information cascades on random networks. AB - Threshold models of global cascades have been extensively used to model real world collective behavior, such as the contagious spread of fads and the adoption of new technologies. A common property of those cascade models is that a vanishingly small seed fraction can spread to a finite fraction of an infinitely large network through local infections. In social and economic networks, however, individuals' behavior is often influenced not only by what their direct neighbors are doing, but also by what the majority of people are doing as a trend. A trend affects individuals' behavior while individuals' behavior creates a trend. To analyze such a complex interplay between local- and global-scale phenomena, I generalize the standard threshold model by introducing a type of node called global nodes (or trend followers), whose activation probability depends on a global-scale trend, specifically the percentage of activated nodes in the population. The model shows that global nodes play a role as accelerating cascades once a trend emerges while reducing the probability of a trend emerging. Global nodes thus either facilitate or inhibit cascades, suggesting that a moderate share of trend followers may maximize the average size of cascades. PMID- 26764761 TI - Memory-induced mechanism for self-sustaining activity in networks. AB - We study a mechanism of activity sustaining on networks inspired by a well-known model of neuronal dynamics. Our primary focus is the emergence of self-sustaining collective activity patterns, where no single node can stay active by itself, but the activity provided initially is sustained within the collective of interacting agents. In contrast to existing models of self-sustaining activity that are caused by (long) loops present in the network, here we focus on treelike structures and examine activation mechanisms that are due to temporal memory of the nodes. This approach is motivated by applications in social media, where long network loops are rare or absent. Our results suggest that under a weak behavioral noise, the nodes robustly split into several clusters, with partial synchronization of nodes within each cluster. We also study the randomly weighted version of the models where the nodes are allowed to change their connection strength (this can model attention redistribution) and show that it does facilitate the self-sustained activity. PMID- 26764762 TI - Hierarchical mutual information for the comparison of hierarchical community structures in complex networks. AB - The quest for a quantitative characterization of community and modular structure of complex networks produced a variety of methods and algorithms to classify different networks. However, it is not clear if such methods provide consistent, robust, and meaningful results when considering hierarchies as a whole. Part of the problem is the lack of a similarity measure for the comparison of hierarchical community structures. In this work we give a contribution by introducing the hierarchical mutual information, which is a generalization of the traditional mutual information and makes it possible to compare hierarchical partitions and hierarchical community structures. The normalized version of the hierarchical mutual information should behave analogously to the traditional normalized mutual information. Here the correct behavior of the hierarchical mutual information is corroborated on an extensive battery of numerical experiments. The experiments are performed on artificial hierarchies and on the hierarchical community structure of artificial and empirical networks. Furthermore, the experiments illustrate some of the practical applications of the hierarchical mutual information, namely the comparison of different community detection methods and the study of the consistency, robustness, and temporal evolution of the hierarchical modular structure of networks. PMID- 26764763 TI - Testing validity of the Kirkwood approximation using an extended Sznajd model. AB - We revisit the deduction of the exit probability of the one-dimensional Sznajd model through the Kirkwood approximation [F. Slanina et al., Europhys. Lett. 82, 18006 (2008)]. This approximation is peculiar in that, in spite of the agreement with simulation results [F. Slanina et al., Europhys. Lett. 82, 18006 (2008); R. Lambiotte and S. Redner, Europhys. Lett. 82, 18007 (2008); A. M. Timpanaro and C. P. C. Prado, Phys. Rev. E 89, 052808 (2014)], the hypothesis about the correlation lengths behind it are inconsistent and fixing these inconsistencies leads to the same results as a simple mean field. We use an extended version of the Sznajd model to test the Kirkwood approximation in a wider context. This model includes the voter, Sznajd, and "United we stand, divided we fall" models [R. A. Holley and T. M. Liggett, Ann. Prob. 3, 643 (1975); K. Sznajd-Weron and J. Sznajd, Int. J. Mod. Phys. C 11, 1157 (2000)] as different parameter combinations, meaning that some analytical results from these models can be used to evaluate the performance of the Kirkwood approximation. We also compare the predicted exit probability with simulation results for networks with 10(3) sites. The results show clearly the regions in parameter space where the approximation gives accurate predictions, as well as where it starts failing, leading to a better understanding of its reliability. PMID- 26764764 TI - Microscopic theory of traffic-flow instability governing traffic breakdown at highway bottlenecks: Growing wave of increase in speed in synchronized flow. AB - We have revealed a growing local speed wave of increase in speed that can randomly occur in synchronized flow (S) at a highway bottleneck. The development of such a traffic flow instability leads to free flow (F) at the bottleneck; therefore, we call this instability an S->F instability. Whereas the S->F instability leads to a local increase in speed (growing acceleration wave), in contrast, the classical traffic flow instability introduced in the 1950s-1960s and incorporated later in a huge number of traffic flow models leads to a growing wave of a local decrease in speed (growing deceleration wave). We have found that the S->F instability can occur only if there is a finite time delay in driver overacceleration. The initial speed disturbance of increase in speed (called "speed peak") that initiates the S->F instability occurs usually at the downstream front of synchronized flow at the bottleneck. There can be many speed peaks with random amplitudes that occur randomly over time. It has been found that the S->F instability exhibits a nucleation nature: Only when a speed peak amplitude is large enough can the S->F instability occur; in contrast, speed peaks of smaller amplitudes cause dissolving speed waves of a local increase in speed (dissolving acceleration waves) in synchronized flow. We have found that the S->F instability governs traffic breakdown-a phase transition from free flow to synchronized flow (F->S transition) at the bottleneck: The nucleation nature of the S->F instability explains the metastability of free flow with respect to an F->S transition at the bottleneck. PMID- 26764765 TI - Currency target-zone modeling: An interplay between physics and economics. AB - We study the performance of the euro-Swiss franc exchange rate in the extraordinary period from September 6, 2011 to January 15, 2015 when the Swiss National Bank enforced a minimum exchange rate of 1.20 Swiss francs per euro. Within the general framework built on geometric Brownian motions and based on the analogy between Brownian motion in finance and physics, the first-order effect of such a steric constraint would enter a priori in the form of a repulsive entropic force associated with the paths crossing the barrier that are forbidden. Nonparametric empirical estimates of drift and volatility show that the predicted first-order analogy between economics and physics is incorrect. The clue is to realize that the random-walk nature of financial prices results from the continuous anticipation of traders about future opportunities, whose aggregate actions translate into an approximate efficient market with almost no arbitrage opportunities. With the Swiss National Bank's stated commitment to enforce the barrier, traders' anticipation of this action leads to a vanishing drift together with a volatility of the exchange rate that depends on the distance to the barrier. This effect is described by Krugman's model [P. R. Krugman, Target zones and exchange rate dynamics, Q. J. Econ. 106, 669 (1991)]. We present direct quantitative empirical evidence that Krugman's theoretical model provides an accurate description of the euro-Swiss franc target zone. Motivated by the insights from the economic model, we revise the initial economics-physics analogy and show that, within the context of hindered diffusion, the two systems can be described with the same mathematics after all. Using a recently proposed extended analogy in terms of a colloidal Brownian particle embedded in a fluid of molecules associated with the underlying order book, we derive that, close to the restricting boundary, the dynamics of both systems is described by a stochastic differential equation with a very small constant drift and a linear diffusion coefficient. As a side result, we present a simplified derivation of the linear hydrodynamic diffusion coefficient of a Brownian particle close to a wall. PMID- 26764766 TI - Quantifying information transfer and mediation along causal pathways in complex systems. AB - Measures of information transfer have become a popular approach to analyze interactions in complex systems such as the Earth or the human brain from measured time series. Recent work has focused on causal definitions of information transfer aimed at decompositions of predictive information about a target variable, while excluding effects of common drivers and indirect influences. While common drivers clearly constitute a spurious causality, the aim of the present article is to develop measures quantifying different notions of the strength of information transfer along indirect causal paths, based on first reconstructing the multivariate causal network. Another class of novel measures quantifies to what extent different intermediate processes on causal paths contribute to an interaction mechanism to determine pathways of causal information transfer. The proposed framework complements predictive decomposition schemes by focusing more on the interaction mechanism between multiple processes. A rigorous mathematical framework allows for a clear information-theoretic interpretation that can also be related to the underlying dynamics as proven for certain classes of processes. Generally, however, estimates of information transfer remain hard to interpret for nonlinearly intertwined complex systems. But if experiments or mathematical models are not available, then measuring pathways of information transfer within the causal dependency structure allows at least for an abstraction of the dynamics. The measures are illustrated on a climatological example to disentangle pathways of atmospheric flow over Europe. PMID- 26764767 TI - Flow instability originating from particle configurations using the two dimensional optimal velocity model. AB - The two-dimensional optimal velocity model has potential applications to pedestrian dynamics and the collective motion of animals. In this paper, we extend the linear stability analysis presented in a previous paper [A Nakayama et al., Phys. Rev. E. 77, 016105 (2008)] and investigate the effects of particle configuration on the stability of several wave modes of collective oscillations of moving particles. We find that, when a particle moves without interacting with particles that are positioned in a diagonally forward or backward direction, the stable region of the particle flow is completely removed by the elliptically polarized mode. PMID- 26764768 TI - Compounding approach for univariate time series with nonstationary variances. AB - A defining feature of nonstationary systems is the time dependence of their statistical parameters. Measured time series may exhibit Gaussian statistics on short time horizons, due to the central limit theorem. The sample statistics for long time horizons, however, averages over the time-dependent variances. To model the long-term statistical behavior, we compound the local distribution with the distribution of its parameters. Here, we consider two concrete, but diverse, examples of such nonstationary systems: the turbulent air flow of a fan and a time series of foreign exchange rates. Our main focus is to empirically determine the appropriate parameter distribution for the compounding approach. To this end, we extract the relevant time scales by decomposing the time signals into windows and determine the distribution function of the thus obtained local variances. PMID- 26764769 TI - Detecting deterministic nature of pressure measurements from a turbulent combustor. AB - Identifying nonlinear structures in a time series, acquired from real-world systems, is essential to characterize the dynamics of the system under study. A single time series alone might be available in most experimental situations. In addition to this, conventional techniques such as power spectral analysis might not be sufficient to characterize a time series if it is acquired from a complex system such as a thermoacoustic system. In this study, we analyze the unsteady pressure signal acquired from a turbulent combustor with bluff-body and swirler as flame holding devices. The fractal features in the unsteady pressure signal are identified using the singularity spectrum. Further, we employ surrogate methods, with translational error and permutation entropy as discriminating statistics, to test for determinism visible in the observed time series. In addition to this, permutation spectrum test could prove to be a robust technique to characterize the dynamical nature of the pressure time series acquired from experiments. Further, measures such as correlation dimension and correlation entropy are adopted to qualitatively detect noise contamination in the pressure measurements acquired during the state of combustion noise. These ensemble of measures is necessary to identify the features of a time series acquired from a system as complex as a turbulent combustor. Using these measures, we show that the pressure fluctuations during combustion noise has the features of a high dimensional chaotic data contaminated with white and colored noise. PMID- 26764770 TI - Absolute negative mobility induced by potential phase modulation. AB - We investigate the transport properties of a particle subjected to a deterministic inertial rocking system, under a constant bias, for which the phase of the symmetric spatial potential used is time modulated. We show that this modulated phase, assisted by a periodic driving force, can lead to the occurrence of the so-called absolute negative mobility (ANM), the phenomenon in which the particle surprisingly moves against the bias. Furthermore, we discover that ANM predominantly originates from chaotic-periodic transitions. While a detailed mechanism of ANM remains unclear, we show that one can manipulate the control parameters, i.e., the amplitude and the frequency of the phase, in order to enforce the motion of the particle in a given direction. Finally, for this experimentally realizable system, we devise a two-parameter current plot which may be a good guide for controlling ANM. PMID- 26764771 TI - Oscillation of a rotating levitated droplet: Analysis with a mechanical model. AB - A droplet of millimeter-to-centimeter scale can exhibit electrostatic levitation, and such levitated droplets can be used for the measurement of the surface tension of the liquids by observing the characteristic frequency of oscillatory deformation. In the present study, a simple mechanical model is proposed by considering a single mode of oscillation in the ellipsoidal deformation of a levitated rotating droplet. By measuring the oscillation frequency with respect to the rotational speed and oscillation amplitude, it is expected that the accuracy of the surface tension measurement could be improved. Using the proposed model, the dependences of the characteristic frequency of oscillatory deformation and the averaged aspect ratio are calculated with respect to the rotational angular velocity of a rotating droplet. These dependences are found to be consistent with the experimental observations. PMID- 26764772 TI - Cycles of self-pulsations in a photonic integrated circuit. AB - We report experimentally on the bifurcation cascade leading to the appearance of self-pulsation in a photonic integrated circuit in which a laser diode is subjected to delayed optical feedback. We study the evolution of the self-pulsing frequency with the increase of both the feedback strength and the injection current. Experimental observations show good qualitative accordance with numerical results carried out with the Lang-Kobayashi rate equation model. We explain the mechanism underlying the self-pulsations by a phenomenon of beating between successive pairs of external cavity modes and antimodes. PMID- 26764773 TI - Manifesting the evolution of eigenstates from quantum billiards to singular billiards in the strongly coupled limit with a truncated basis by using RLC networks. AB - The coupling interaction between the driving source and the RLC network is explored and characterized as the effective impedance. The mathematical form of the derived effective impedance is verified to be identical to the meromorphic function of the singular billiards with a truncated basis. By using the derived impedance function, the resonant modes of the RLC network can be divided into the open-circuit and short-circuit states to manifest the evolution of eigenvalues and eigenstates from closed quantum billiards to the singular billiards with a truncated basis in the strongly coupled limit. The substantial differences of the wave patterns between the uncoupled and strongly coupled eigenmodes in the two dimensional wave systems can be clearly revealed with the RLC network. Finally, the short-circuit resonant states are exploited to confirm that the experimental Chladni nodal-line patterns in the vibrating plate are the resonant modes subject to the strong coupling between the oscillation system and the driving source. PMID- 26764774 TI - Periodic mean-field solutions and the spectra of discrete bosonic fields: Trace formula for Bose-Hubbard models. AB - We consider the many-body spectra of interacting bosonic quantum fields on a lattice in the semiclassical limit of large particle number N. We show that the many-body density of states can be expressed as a coherent sum over oscillating long-wavelength contributions given by periodic, nonperturbative solutions of the, typically nonlinear, wave equation of the classical (mean-field) limit. To this end, we construct the semiclassical approximation for both the smooth and oscillatory parts of the many-body density of states in terms of a trace formula starting from the exact path integral form of the propagator between many-body quadrature states. We therefore avoid the use of a complexified classical limit characteristic of the coherent state representation. While quantum effects such as vacuum fluctuations and gauge invariance are exactly accounted for, our semiclassical approach captures quantum interference and therefore is valid well beyond the Ehrenfest time where naive quantum-classical correspondence breaks down. Remarkably, due to a special feature of harmonic systems with incommensurable frequencies, our formulas are generically valid also in the free field case of noninteracting bosons. PMID- 26764775 TI - Critical phenomena of dynamical delocalization in a quantum Anderson map. AB - Using a quantum map version of the one-dimensional Anderson model, the localization-delocalization transition of quantum diffusion induced by coherent dynamical perturbation is investigated in comparison with the quantum standard map. Existence of critical phenomena, which depends on the number of frequency component M, is demonstrated. Diffusion exponents agree with theoretical prediction for the transition, but the critical exponent of the localization length deviates from it with increase in the M. The critical power epsilon(c) of the normalized perturbation at the transition point remarkably decreases as epsilon(c)~(M-1)(-1). PMID- 26764776 TI - Two-dimensional solitons in conservative and parity-time-symmetric triple-core waveguides with cubic-quintic nonlinearity. AB - We analyze a system of three two-dimensional nonlinear Schrodinger equations coupled by linear terms and with the cubic-quintic (focusing-defocusing) nonlinearity. We consider two versions of the model: conservative and parity-time (PT) symmetric. These models describe triple-core nonlinear optical waveguides, with balanced gain and losses in the PT-symmetric case. We obtain families of soliton solutions and discuss their stability. The latter study is performed using a linear stability analysis and checked with direct numerical simulations of the evolutional system of equations. Stable solitons are found in the conservative and PT-symmetric cases. Interactions and collisions between the conservative and PT-symmetric solitons are briefly investigated, as well. PMID- 26764777 TI - Synchronization dynamics in diverse ensemble of noisy phase oscillators with asynchronous phase updates. AB - Decentralized control of autonomous phase oscillators integrated into networked systems is of great interest for many technological applications, from clock synchronization in sensor nets to coordinated motion in swarm robotics. In the simplest distributed synchronization scheme, each oscillator updates its phase from time to time to a new value equal to the average of its present phase and the phases of its neighbors. Here we describe the resulting synchronization dynamics within a mean-field model where the update actions of different oscillators are completely asynchronous. In particular, it is shown how the steady-state level of synchrony depends on noise intensity and frequency diversity for any given rate of updates. The central part of the analysis is devoted to the case when the correction rate positively correlates with the degree of macroscopic coherence. We demonstrate that depending on relation between correction rate and phase coherence the oscillators may exhibit both continuous and discontinuous transition from incoherence to synchrony upon the change of interaction constant. To illustrate our analytical results, numerical simulations have been performed for a large population of phase oscillators with the proposed type of coupling. PMID- 26764778 TI - Activation process in excitable systems with multiple noise sources: One and two interacting units. AB - We consider the coaction of two distinct noise sources on the activation process of a single excitable unit and two interacting excitable units, which are mathematically described by the Fitzhugh-Nagumo equations. We determine the most probable activation paths around which the corresponding stochastic trajectories are clustered. The key point lies in introducing appropriate boundary conditions that are relevant for a class II excitable unit, which can be immediately generalized also to scenarios involving two coupled units. We analyze the effects of the two noise sources on the statistical features of the activation process, in particular demonstrating how these are modified due to the linear or nonlinear form of interactions. Universal properties of the activation process are qualitatively discussed in the light of a stochastic bifurcation that underlies the transition from a stochastically stable fixed point to continuous oscillations. PMID- 26764779 TI - Activation process in excitable systems with multiple noise sources: Large number of units. AB - We study the activation process in large assemblies of type II excitable units whose dynamics is influenced by two independent noise terms. The mean-field approach is applied to explicitly demonstrate that the assembly of excitable units can itself exhibit macroscopic excitable behavior. In order to facilitate the comparison between the excitable dynamics of a single unit and an assembly, we introduce three distinct formulations of the assembly activation event. Each formulation treats different aspects of the relevant phenomena, including the thresholdlike behavior and the role of coherence of individual spikes. Statistical properties of the assembly activation process, such as the mean time to-first pulse and the associated coefficient of variation, are found to be qualitatively analogous for all three formulations, as well as to resemble the results for a single unit. These analogies are shown to derive from the fact that global variables undergo a stochastic bifurcation from the stochastically stable fixed point to continuous oscillations. Local activation processes are analyzed in the light of the competition between the noise-led and the relaxation-driven dynamics. We also briefly report on a system-size antiresonant effect displayed by the mean time-to-first pulse. PMID- 26764780 TI - Energy-exchange collisions of dark-bright-bright vector solitons. AB - We find a dark component guiding the practically interesting bright-bright vector one-soliton to two different parametric domains giving rise to different physical situations by constructing a more general form of three-component dark-bright bright mixed vector one-soliton solution of the generalized Manakov model with nine free real parameters. Moreover our main investigation of the collision dynamics of such mixed vector solitons by constructing the multisoliton solution of the generalized Manakov model with the help of Hirota technique reveals that the dark-bright-bright vector two-soliton supports energy-exchange collision dynamics. In particular the dark component preserves its initial form and the energy-exchange collision property of the bright-bright vector two-soliton solution of the Manakov model during collision. In addition the interactions between bound state dark-bright-bright vector solitons reveal oscillations in their amplitudes. A similar kind of breathing effect was also experimentally observed in the Bose-Einstein condensates. Some possible ways are theoretically suggested not only to control this breathing effect but also to manage the beating, bouncing, jumping, and attraction effects in the collision dynamics of dark-bright-bright vector solitons. The role of multiple free parameters in our solution is examined to define polarization vector, envelope speed, envelope width, envelope amplitude, grayness, and complex modulation of our solution. It is interesting to note that the polarization vector of our mixed vector one soliton evolves in sphere or hyperboloid depending upon the initial parametric choices. PMID- 26764781 TI - Dynamics of phase slips in systems with time-periodic modulation. AB - The Adler equation with time-periodic frequency modulation is studied. A series of resonances between the period of the frequency modulation and the time scale for the generation of a phase slip is identified. The resulting parameter space structure is determined using a combination of numerical continuation, time simulations, and asymptotic methods. Regions with an integer number of phase slips per period are separated by regions with noninteger numbers of phase slips and include canard trajectories that drift along unstable equilibria. Both high- and low-frequency modulation is considered. An adiabatic description of the low frequency modulation regime is found to be accurate over a large range of modulation periods. PMID- 26764782 TI - Exponential system-size dependence of the lifetime of transient spiral chaos in excitable and oscillatory media. AB - Excitable media can develop spiral chaos, in which the number of spirals changes chaotically with time. Depending on parameter values in dynamical equations, spiral chaos may permanently persist or spontaneously arrive at a steady state after a transient time, referred to as the lifetime. Previous numerical studies have demonstrated that the lifetime of transient spiral chaos increases exponentially with system size to a good approximation. In this study, using the fact that the number of spirals obeys a Gaussian distribution, we provide a general expression for the system size dependence of the lifetime for large system sizes, which is indeed exponential. We confirm that the expression is in good agreement with numerically obtained lifetimes for both excitable and oscillatory media with parameter sets near the onset of transient chaos. The expression we develop for the lifetime is expected to be useful for predicting lifetimes in large systems. PMID- 26764783 TI - Amplified response in coupled chaotic oscillators by induced heterogeneity. AB - The phenomenon of emergent amplified response is reported in two unidirectionally coupled identical chaotic systems when heterogeneity as a parameter mismatch is introduced in a state of complete synchrony. The amplified response emerges from the interplay of heterogeneity and a type of cross-feedback coupling. It is reflected as an expansion of the response attractor in some directions in the state space of the coupled system. The synchronization manifold is simply rotated by the parameter detuning while its stability in the transverse direction is still maintained. The amplification factor is linearly related to the amount of parameter detuning. The phenomenon is elaborated with examples of the paradigmatic Lorenz system, the Shimizu-Morioka single-mode laser model, the Rossler system, and a Sprott system. Experimental evidence of the phenomenon is obtained in an electronic circuit. The method may provide an engineering tool for distortion-free amplification of chaotic signals. PMID- 26764785 TI - Synchronization and plateau splitting of coupled oscillators with long-range power-law interactions. AB - We investigate synchronization and plateau splitting of coupled oscillators on a one-dimensional lattice with long-range interactions that decay over distance as a power law. We show that in the thermodynamic limit the dynamics of systems of coupled oscillators with power-law exponent alpha<=1 is identical to that of the all-to-all coupling case. For alpha>1, oscillatory behavior of the phase coherence appears as a result of single plateau splitting into multiple plateaus. A coarse-graining method is used to investigate the onset of plateau splitting. We analyze a simple oscillatory state formed by two plateaus in detail and propose a systematic approach to predict the onset of plateau splitting. The prediction of breaking points of plateau splitting is in quantitatively good agreement with numerical simulations. PMID- 26764784 TI - Nature of short, high-amplitude compressive stress pulses in a periodic dissipative laminate. AB - We study the evolution of high-amplitude stress pulses in periodic dissipative laminates taking into account the nonlinear constitutive equations of the components and their dissipative behavior. Aluminum-tungsten laminate was selected due to the large difference in acoustic impedances of components, the significant nonlinearity of the aluminum constitutive equation at the investigated range of stresses, and its possible practical applications. Laminates with different cell size, which controls the internal time scale, impacted by plates with different thicknesses that determine the incoming pulse duration, were investigated. It has been observed that the ratio of the duration of the incoming pulse to the internal characteristic time determines the nature of the high-amplitude dissipative propagating waves-a triangular oscillatory shock-like profile, a train of localized pulses, or a single localized pulse. These localized quasistationary waves resemble solitary waves even in the presence of dissipation: The similar pulses emerged from different initial conditions, indicating that they are inherent properties of the corresponding laminates; their characteristic length scale is determined by the scale of mesostructure, nonlinear properties of materials, and the stress amplitude; and a linear relationship exists between their speed and amplitude. They mostly recover their shapes after collision with phase shift. A theoretical description approximating the shape, length scale, and speed of these high-amplitude dissipative pulses was proposed based on the Korteweg-de Vries equation with a dispersive term determined by the mesostructure and a nonlinear term derived using Hugoniot curves of components. PMID- 26764786 TI - Advantage of four-electrode over two-electrode defibrillators. AB - Defibrillation is the standard clinical treatment used to stop ventricular fibrillation. An electrical device delivers a controlled amount of electrical energy via a pair of electrodes in order to reestablish a normal heart rate. We propose a technique that is a combination of biphasic shocks applied with a four electrode system rather than the standard two-electrode system. We use a numerical model of a one-dimensional ring of cardiac tissue in order to test and evaluate the benefit of this technique. We compare three different shock protocols, namely a monophasic and two types of biphasic shocks. The results obtained by using a four-electrode system are compared quantitatively with those obtained with the standard two-electrode system. We find that a huge reduction in defibrillation threshold is achieved with the four-electrode system. For the most efficient protocol (asymmetric biphasic), we obtain a reduction in excess of 80% in the energy required for a defibrillation success rate of 90%. The mechanisms of successful defibrillation are also analyzed. This reveals that the advantage of asymmetric biphasic shocks with four electrodes lies in the duration of the cathodal and anodal phase of the shock. PMID- 26764787 TI - Chimeralike states in a network of oscillators under attractive and repulsive global coupling. AB - We report chimeralike states in an ensemble of oscillators using a type of global coupling consisting of two components: attractive and repulsive mean-field feedback. We identify the existence of two types of chimeralike states in a bistable Lienard system; in one type, both the coherent and the incoherent populations are in chaotic states (which we refer to as chaos-chaos chimeralike states) and, in another type, the incoherent population is in periodic state while the coherent population has irregular small oscillation. We find a metastable state in a parameter regime of the Lienard system where the coherent and noncoherent states migrate in time from one to another subpopulation. The relative size of the incoherent subpopulation, in the chimeralike states, remains almost stable with increasing size of the network. The generality of the coupling configuration in the origin of the chimeralike states is tested, using a second example of bistable system, the van der Pol-Duffing oscillator where the chimeralike states emerge as weakly chaotic in the coherent subpopulation and chaotic in the incoherent subpopulation. Furthermore, we apply the coupling, in a simplified form, to form a network of the chaotic Rossler system where both the noncoherent and the coherent subpopulations show chaotic dynamics. PMID- 26764788 TI - Dissipative dynamics of a particle in a vibrating periodic potential: Chaos and control. AB - The dissipative chaotic dynamics of a particle subjected to a horizontally vibrating periodic potential is characterized theoretically and confirmed numerically in the case of an external chaos-controlling periodic excitation also acting on the particle. Theoretical predictions concerning the chaotic threshold in parameter space are deduced from the application of Melnikov's method that fully determine the chaos-control scenario. Also, the structure of diverse regularization regions in parameter space is explained theoretically with the aid of an energy analysis. It was found that the phase difference between the two periodic excitations involved plays a crucial role in the chaos-control scenario, with the particular feature that its optimal value depends upon the ratio between the damping coefficient and the excitation frequency. This constitutes a genuine feature of the chaos-control scenario associated with nonsteady potentials which is in contrast to the case of steady potentials. Additionally, we demonstrate the robustness of the chaos-control scenario against the presence of low-intensity Gaussian noise and reshaping of chaos-suppressing excitations. PMID- 26764789 TI - Neighborhoods of periodic orbits and the stationary distribution of a noisy chaotic system. AB - The finest state-space resolution that can be achieved in a physical dynamical system is limited by the presence of noise. In the weak-noise approximation, the stochastic neighborhoods of deterministic periodic orbits can be computed from distributions stationary under the action of a local Fokker-Planck operator and its adjoint. We derive explicit formulas for widths of these distributions in the case of chaotic dynamics, when the periodic orbits are hyperbolic. The resulting neighborhoods form a basis for functions on the attractor. The global stationary distribution, needed for calculation of long-time expectation values of observables, can be expressed in this basis. PMID- 26764791 TI - Quantum signatures of chimera states. AB - Chimera states are complex spatiotemporal patterns in networks of identical oscillators, characterized by the coexistence of synchronized and desynchronized dynamics. Here we propose to extend the phenomenon of chimera states to the quantum regime, and uncover intriguing quantum signatures of these states. We calculate the quantum fluctuations about semiclassical trajectories and demonstrate that chimera states in the quantum regime can be characterized by bosonic squeezing, weighted quantum correlations, and measures of mutual information. Our findings reveal the relation of chimera states to quantum information theory, and give promising directions for experimental realization of chimera states in quantum systems. PMID- 26764790 TI - Quantum manifestations of classical nonlinear resonances. AB - When an integrable classical system is perturbed, nonlinear resonances are born, grow, and eventually disappear due to chaos. In this paper the quantum manifestations of such a transition are studied in the standard map. We show that nonlinear resonances act as a perturbation that break eigenphase degeneracies for unperturbed states with quantum numbers that differ in a multiple of the order of the resonance. We show that the eigenphase splittings are well described by a semiclassical expression based on an integrable approximation of the Hamiltonian in the vicinity of the resonance. The morphology in phase space of these states is also studied. We show that the nonlinear resonance imprints a systematic influence in their localization properties. PMID- 26764792 TI - Power-law ansatz in complex systems: Excessive loss of information. AB - The ubiquity of power-law relations in empirical data displays physicists' love of simple laws and uncovering common causes among seemingly unrelated phenomena. However, many reported power laws lack statistical support and mechanistic backings, not to mention discrepancies with real data are often explained away as corrections due to finite size or other variables. We propose a simple experiment and rigorous statistical procedures to look into these issues. Making use of the fact that the occurrence rate and pulse intensity of crumple sound obey a power law with an exponent that varies with material, we simulate a complex system with two driving mechanisms by crumpling two different sheets together. The probability function of the crumple sound is found to transit from two power-law terms to a bona fide power law as compaction increases. In addition to showing the vicinity of these two distributions in the phase space, this observation nicely demonstrates the effect of interactions to bring about a subtle change in macroscopic behavior and more information may be retrieved if the data are subject to sorting. Our analyses are based on the Akaike information criterion that is a direct measurement of information loss and emphasizes the need to strike a balance between model simplicity and goodness of fit. As a show of force, the Akaike information criterion also found the Gutenberg-Richter law for earthquakes and the scale-free model for a brain functional network, a two dimensional sandpile, and solar flare intensity to suffer an excessive loss of information. They resemble more the crumpled-together ball at low compactions in that there appear to be two driving mechanisms that take turns occurring. PMID- 26764793 TI - Solitons in a forced nonlinear Schrodinger equation with the pseudo-Raman effect. AB - The dynamics of solitons is considered in the framework of an extended nonlinear Schrodinger equation (NLSE), which is derived from a Zakharov-type model for wind driven high-frequency surface waves in the ocean, coupled to damped low-frequency internal waves. The drive gives rise to a convective (but not absolute) instability in the system. The resulting NLSE includes a pseudo-stimulated-Raman scattering (pseudo-SRS) term, which is a spatial-domain counterpart of the SRS term, a well-known ingredient of the temporal-domain NLSE in optics. Analysis of the field-momentum balance and direct simulations demonstrates that wave-number downshift by the pseudo-SRS may be compensated by the upshift induced by the wind traction, thus maintaining robust bright solitons in both stationary and oscillatory forms; in particular, they are not destroyed by the underlying convective instability. Analytical soliton solutions are found in an approximate form and are verified by numerical simulations. Solutions for soliton pairs are obtained in the numerical form. PMID- 26764794 TI - Conservative perturbation theory for nonconservative systems. AB - In this paper, we show how to use canonical perturbation theory for dissipative dynamical systems capable of showing limit-cycle oscillations. Thus, our work surmounts the hitherto perceived barrier for canonical perturbation theory that it can be applied only to a class of conservative systems, viz., Hamiltonian systems. In the process, we also find Hamiltonian structure for an important subset of Lienard system-a paradigmatic system for modeling isolated and asymptotic oscillatory state. We discuss the possibility of extending our method to encompass an even wider range of nonconservative systems. PMID- 26764795 TI - Forecasting critical transitions using data-driven nonstationary dynamical modeling. AB - An approach to predicting critical transitions from time series is introduced. A nonstationary low-order stochastic dynamical model of appropriate complexity to capture the transition mechanism under consideration is estimated from data. In the simplest case, the model is a one-dimensional effective Langevin equation, but also higher-dimensional dynamical reconstructions based on time-delay embedding and local modeling are considered. Integrations with the nonstationary models are performed beyond the learning data window to predict the nature and timing of critical transitions. The technique is generic, not requiring detailed a priori knowledge about the underlying dynamics of the system. The method is demonstrated to successfully predict a fold and a Hopf bifurcation well beyond the learning data window. PMID- 26764796 TI - Chaotic properties of spin lattices near second-order phase transitions. AB - We perform a numerical investigation of the Lyapunov spectra of chaotic dynamics in lattices of classical spins in the vicinity of second-order ferromagnetic and antiferromagnetic phase transitions. On the basis of this investigation, we identify a characteristic of the shape of the Lyapunov spectra, the "G-index," which exhibits a sharp peak as a function of temperature at the phase transition, provided the order parameter is capable of sufficiently strong dynamic fluctuations. As part of this work, we also propose a general numerical algorithm for determining the temperature in many-particle systems, where kinetic energy is not defined. PMID- 26764797 TI - Predator-prey model for the self-organization of stochastic oscillators in dual populations. AB - A predator-prey model of dual populations with stochastic oscillators is presented. A linear cross-coupling between the two populations is introduced following the coupling between the motions of a Wilberforce pendulum in two dimensions: one in the longitudinal and the other in torsional plain. Within each population a Kuramoto-type competition between the phases is assumed. Thus, the synchronization state of the whole system is controlled by these two types of competitions. The results of the numerical simulations show that by adding the linear cross-coupling interactions predator-prey oscillations between the two populations appear, which results in self-regulation of the system by a transfer of synchrony between the two populations. The model represents several important features of the dynamical interplay between the drift wave and zonal flow turbulence in magnetically confined plasmas, and a novel interpretation of the coupled dynamics of drift wave-zonal flow turbulence using synchronization of stochastic oscillator is discussed. PMID- 26764798 TI - Confinement effects on liquid-flow characteristics in carbon nanotubes. AB - Liquid flow dynamics through the armchair (6,6)-(160,160) carbon nanotubes (CNTs) is elucidated by molecular dynamics simulations. The liquid is modeled by nonpolar argon atoms to understand the fundamental flow physics. The velocity profiles and slip lengths are discussed considering the radial distributions of the fluid density by the presently proposed finite difference-based velocity fitting method. It is found that as the CNT diameter D increases, the slip length and the flow rate enhancement show three-step transitional profiles in the region of D<=2.3 nm. The slip length and the flow rate stepwise increase at the first transition while they drop at the second and third transitions. The first transition corresponds to the structural change from the single-file chain to single-ring structures of the molecule cluster. The second and third transitions take place when the ring structure starts to develop another inner layer. PMID- 26764799 TI - Small- and large-scale characterization and mixing properties in a thermally driven thin liquid film. AB - We study aqueous, freestanding, thin films stabilized by a surfactant with respect to mixing and dynamical systems properties. With this special setup, a two-dimensional fluid can be realized experimentally. The physics of the system involves a complex interplay of thermal convection and interface and gravitational forces. Methodologically, we characterize the system using two classical dynamical systems properties: Lyapunov exponents and entropies. Our experimental setup produces convection with two stable eddies by applying a temperature gradient in one spot that yields weakly turbulent mixing. From dynamical systems theory, one expects a relation of entropies, Lyapunov exponents, a prediction with little experimental support. We can confirm the corresponding statements experimentally, on different scales using different methods. On the small scale the motion and deformation of fluid filaments of equal size (color imaging velocimetry) are used to compute Lyapunov exponents. On the large scale, entropy is computed by tracking the left-right motion of the center fluid jet at the separatrix between the two convection rolls. We thus combine here dynamical systems methods with a concrete application of mixing in a nanoscale freestanding thin film. PMID- 26764800 TI - Mathematical model for logarithmic scaling of velocity fluctuations in wall turbulence. AB - For wall turbulence, moments of velocity fluctuations are known to be logarithmic functions of the height from the wall. This logarithmic scaling is due to the existence of a characteristic velocity and to the nonexistence of any characteristic height in the range of the scaling. By using the mathematics of random variables, we obtain its necessary and sufficient conditions. They are compared with characteristics of a phenomenological model of eddies attached to the wall and also with those of the logarithmic scaling of the mean velocity. PMID- 26764801 TI - Effect of vorticity flip-over on the premixed flame structure: Experimental observation of type-I inflection flames. AB - Premixed flames propagating in horizontal tubes are observed to take on a convex shape towards the fresh mixture, which is commonly explained as a buoyancy effect. A recent rigorous analysis has shown, on the contrary, that this process is driven by the balance of vorticity generated by a curved flame front with the baroclinic vorticity, and predicted existence of a regime in which the leading edge of the flame front is concave. We report experimental realization of this regime. Our experiments on ethane and n-butane mixtures with air show that flames with an inflection point on the front are regularly produced in lean mixtures, provided that a sufficiently weak ignition is used. The observed flame shape perfectly agrees with that theoretically predicted. PMID- 26764802 TI - Frozen reaction fronts in steady flows: A burning-invariant-manifold perspective. AB - The dynamics of fronts, such as chemical reaction fronts, propagating in two dimensional fluid flows can be remarkably rich and varied. For time-invariant flows, the front dynamics may simplify, settling in to a steady state in which the reacted domain is static, and the front appears "frozen." Our central result is that these frozen fronts in the two-dimensional fluid are composed of segments of burning invariant manifolds, invariant manifolds of front-element dynamics in xytheta space, where theta is the front orientation. Burning invariant manifolds (BIMs) have been identified previously as important local barriers to front propagation in fluid flows. The relevance of BIMs for frozen fronts rests in their ability, under appropriate conditions, to form global barriers, separating reacted domains from nonreacted domains for all time. The second main result of this paper is an understanding of bifurcations that lead from a nonfrozen state to a frozen state, as well as bifurcations that change the topological structure of the frozen front. Although the primary results of this study apply to general fluid flows, our analysis focuses on a chain of vortices in a channel flow with an imposed wind. For this system, we present both experimental and numerical studies that support the theoretical analysis developed here. PMID- 26764803 TI - Phenomenological Blasius-type friction equation for turbulent power-law fluid flows. AB - We propose a friction formula for turbulent power-law fluid flows, a class of purely viscous non-Newtonian fluids commonly found in applications. Our model is derived through an extension of the friction factor analysis based on Kolmogorov's phenomenology, recently proposed by Gioia and Chakraborty. Tests against classical empirical data show excellent agreement over a significant range of Reynolds number. Limits of the model are also discussed. PMID- 26764804 TI - Cross-diffusion-driven hydrodynamic instabilities in a double-layer system: General classification and nonlinear simulations. AB - Cross diffusion, whereby a flux of a given species entrains the diffusive transport of another species, can trigger buoyancy-driven hydrodynamic instabilities at the interface of initially stable stratifications. Starting from a simple three-component case, we introduce a theoretical framework to classify cross-diffusion-induced hydrodynamic phenomena in two-layer stratifications under the action of the gravitational field. A cross-diffusion-convection (CDC) model is derived by coupling the fickian diffusion formalism to Stokes equations. In order to isolate the effect of cross-diffusion in the convective destabilization of a double-layer system, we impose a starting concentration jump of one species in the bottom layer while the other one is homogeneously distributed over the spatial domain. This initial configuration avoids the concurrence of classic Rayleigh-Taylor or differential-diffusion convective instabilities, and it also allows us to activate selectively the cross-diffusion feedback by which the heterogeneously distributed species influences the diffusive transport of the other species. We identify two types of hydrodynamic modes [the negative cross diffusion-driven convection (NCC) and the positive cross-diffusion-driven convection (PCC)], corresponding to the sign of this operational cross-diffusion term. By studying the space-time density profiles along the gravitational axis we obtain analytical conditions for the onset of convection in terms of two important parameters only: the operational cross-diffusivity and the buoyancy ratio, giving the relative contribution of the two species to the global density. The general classification of the NCC and PCC scenarios in such parameter space is supported by numerical simulations of the fully nonlinear CDC problem. The resulting convective patterns compare favorably with recent experimental results found in microemulsion systems. PMID- 26764805 TI - Between giant oscillations and uniform distribution of droplets: The role of varying lumen of channels in microfluidic networks. AB - The simplest microfluidic network (a loop) comprises two parallel channels with a common inlet and a common outlet. Recent studies that assumed a constant cross section of the channels along their length have shown that the sequence of droplets entering the left (L) or right (R) arm of the loop can present either a uniform distribution of choices (e.g., RLRLRL...) or long sequences of repeated choices (RRR...LLL), with all the intermediate permutations being dynamically equivalent and virtually equally probable to be observed. We use experiments and computer simulations to show that even small variation of the cross section along channels completely shifts the dynamics either into the strong preference for highly grouped patterns (RRR...LLL) that generate system-size oscillations in flow or just the opposite-to patterns that distribute the droplets homogeneously between the arms of the loop. We also show the importance of noise in the process of self-organization of the spatiotemporal patterns of droplets. Our results provide guidelines for rational design of systems that reproducibly produce either grouped or homogeneous sequences of droplets flowing in microfluidic networks. PMID- 26764806 TI - Sedimentation of an oblate ellipsoid in narrow tubes. AB - Sedimentation behaviors of an oblate ellipsoidal particle inside narrow [R/a?(1.2,2.0)] infinitely long circular tubes are studied by the lattice Boltzmann method, where R and a are the radius of the tube and the length of the semimajor axis of the ellipsoid, respectively. The Archimedes numbers (Ar) up to 70 are considered. Four periodic and two steady sedimentation modes are identified. It is the first time that the anomalous mode has been found in a circular tube for an ellipsoidal particle. The phase diagram of the modes as a function of Ar and R/a is obtained. The anomalous mode is observed in the larger R/a and lower-Ar regime. Through comparisons between the anomalous and oscillatory modes, it is found that R/a plays a critical role for the anomalous mode. Some constrained cases with two steady modes are simulated. It is found that the particle settles faster in the unconstrained modes than in the corresponding constrained modes. This might inspire further study on why the particle adopts a specific mode under a certain circumstance. PMID- 26764807 TI - Stability of a flow down an incline with respect to two-dimensional and three dimensional disturbances for Newtonian and non-Newtonian fluids. AB - Squire's theorem, which states that the two-dimensional instabilities are more dangerous than the three-dimensional instabilities, is revisited here for a flow down an incline, making use of numerical stability analysis and Squire relationships when available. For flows down inclined planes, one of these Squire relationships involves the slopes of the inclines. This means that the Reynolds number associated with a two-dimensional wave can be shown to be smaller than that for an oblique wave, but this oblique wave being obtained for a larger slope. Physically speaking, this prevents the possibility to directly compare the thresholds at a given slope. The goal of the paper is then to reach a conclusion about the predominance or not of two-dimensional instabilities at a given slope, which is of practical interest for industrial or environmental applications. For a Newtonian fluid, it is shown that, for a given slope, oblique wave instabilities are never the dominant instabilities. Both the Squire relationships and the particular variations of the two-dimensional wave critical curve with regard to the inclination angle are involved in the proof of this result. For a generalized Newtonian fluid, a similar result can only be obtained for a reduced stability problem where some term connected to the perturbation of viscosity is neglected. For the general stability problem, however, no Squire relationships can be derived and the numerical stability results show that the thresholds for oblique waves can be smaller than the thresholds for two-dimensional waves at a given slope, particularly for large obliquity angles and strong shear-thinning behaviors. The conclusion is then completely different in that case: the dominant instability for a generalized Newtonian fluid flowing down an inclined plane with a given slope can be three dimensional. PMID- 26764808 TI - Flow of a circulating tumor cell and red blood cells in microvessels. AB - Quantifying the behavior of circulating tumor cells (CTCs) in the blood stream is of fundamental importance for understanding metastasis. Here, we investigate the flow mode and velocity of CTCs interacting with red blood cells (RBCs) in various sized microvessels. The flow of leukocytes in microvessels has been described previously; a leukocyte forms a train with RBCs in small microvessels and exhibits margination in large microvessels. Important differences in the physical properties of leukocytes and CTCs result from size. The dimensions of leukocytes are similar to those of RBCs, but CTCs are significantly larger. We investigate numerically the size effects on the flow mode and the cell velocity, and we identify similarities and differences between leukocytes and CTCs. We find that a transition from train formation to margination occurs when (R-a)/t(R)~1, where R is the vessel radius, a is the cell radius, and t(R) is the thickness of RBCs, but that the motion of RBCs differs from the case of leukocytes. Our results also show that the velocities of CTCs and leukocytes are larger than the average blood velocity, but only CTCs move faster than RBCs for microvessels of R/a~1.5-2.0. These findings are expected to be useful not only for understanding metastasis, but also for developing microfluidic devices. PMID- 26764809 TI - Mobility of power-law and Carreau fluids through fibrous media. AB - The flow of generalized Newtonian fluids with a rate-dependent viscosity through fibrous media is studied, with a focus on developing relationships for evaluating the effective fluid mobility. Three methods are used here: (i) a numerical solution of the Cauchy momentum equation with the Carreau or power-law constitutive equations for pressure-driven flow in a fiber bed consisting of a periodic array of cylindrical fibers, (ii) an analytical solution for a unit cell model representing the flow characteristics of a periodic fibrous medium, and (iii) a scaling analysis of characteristic bulk parameters such as the effective shear rate, the effective viscosity, geometrical parameters of the system, and the fluid rheology. Our scaling analysis yields simple expressions for evaluating the transverse mobility functions for each model, which can be used for a wide range of medium porosity and fluid rheological parameters. While the dimensionless mobility is, in general, a function of the Carreau number and the medium porosity, our results show that for porosities less than E?0.65, the dimensionless mobility becomes independent of the Carreau number and the mobility function exhibits power-law characteristics as a result of the high shear rates at the pore scale. We derive a suitable criterion for determining the flow regime and the transition from a constant viscosity Newtonian response to a power-law regime in terms of a new Carreau number rescaled with a dimensionless function which incorporates the medium porosity and the arrangement of fibers. PMID- 26764810 TI - Dynamical features of the wake behind a pitching foil. AB - As an extension of the previous study on the three-dimensional transition of the wake behind a pitching foil [Deng and Caulfield, Phys. Rev. E 91, 043017 (2015)], this investigation draws a comprehensive map on the pitching frequency-amplitude phase space. First, by fixing the Reynolds number at Re=1700 and varying the pitching frequency and amplitude, we identify three key dynamical features of the wake: first, the transition from Benard-von Karman (BvK) vortex streets to reverse BvK vortex streets, and second, the symmetry breaking of this reverse BvK wake leading to a deflected wake, and a further transition from two-dimensional (2D) wakes to three-dimensional (3D) wakes. The transition boundary between the 2D and 3D wakes lies top right of the wake deflection boundary, implying a correlation between the wake deflection and the 2D to 3D wake transition, confirming that this transition occurs after the wake deflection. This paper supports the previous extensive numerical studies under two-dimensional assumption at low Reynolds number, since it is indeed two dimensional except for the cases at very high pitching frequencies or large amplitudes. Furthermore, by three-dimensional direct numerical simulations (DNSs), we confirm the previous statement about the physical realizability of the short wavelength mode at beta=30 (or lambda(z)=0.21) for Re=1500. By comparing the three-dimensional vortical structures by DNSs with that from the reconstruction of Floquet modes, we find a good consistency between them, both exhibiting clear streamwise structures in the wake. PMID- 26764811 TI - Swimming of a deformable slab in a viscous incompressible fluid with inertia. AB - The swimming of a deformable planar slab in a viscous incompressible fluid is studied on the basis of the Navier-Stokes equations. A continuum of plane wave displacements, symmetric on both sides of the slab and characterized by a polarization angle, allows optimization of the swimming efficiency with respect to polarization. The mean swimming velocity and mean rate of dissipation are calculated to second order in the amplitude of the stroke. The optimum efficiency depends on the ratio of viscosity and mass density of the fluid. For high viscosity a stroke is found with significantly higher efficiency than Taylor's solution for a waving sheet. For low viscosity the efficiency is optimal for a nearly irrotational flow pattern. PMID- 26764812 TI - Role of boundary conditions in helicoidal flow collimation: Consequences for the von Karman sodium dynamo experiment. AB - We present hydrodynamic and magnetohydrodynamic (MHD) simulations of liquid sodium flow with the PLUTO compressible MHD code to investigate influence of magnetic boundary conditions on the collimation of helicoidal motions. We use a simplified cartesian geometry to represent the flow dynamics in the vicinity of one cavity of a multiblades impeller inspired by those used in the Von-Karman sodium (VKS) experiment. We show that the impinging of the large-scale flow upon the impeller generates a coherent helicoidal vortex inside the blades, located at a distance from the upstream blade piloted by the incident angle of the flow. This vortex collimates any existing magnetic field lines leading to an enhancement of the radial magnetic field that is stronger for ferromagnetic than for conducting blades. The induced magnetic field modifies locally the velocity fluctuations, resulting in an enhanced helicity. This process possibly explains why dynamo action is more easily triggered in the VKS experiment when using soft iron impellers. PMID- 26764813 TI - Hydrodynamic analysis of flagellated bacteria swimming in corners of rectangular channels. AB - The influence of nearby solid surfaces on the motility of bacteria is of fundamental importance as these interactions govern the ability of the microorganisms to explore their environment and form sessile colonies. Reducing biofouling in medical implants and controlling the transport of bacterial cells in a microfluidic device are two applications that could benefit from a detailed understanding of swimming in microchannels. In this study, we investigate the self-propelled motion of a model bacterium, driven by rotating a single helical flagellum, in such an environment. In particular, we focus on the corner region of a large channel modeled as two perpendicular sections of no-slip planes joined with a rounded corner. We numerically solve the equations of Stokes flow using the boundary element method to obtain the swimming velocities at different positions and orientations relative to the channel corner. From these velocities, we construct many trajectories to ascertain the general behavior of the swimmers. Considering only hydrodynamic interactions between the bacterium and the channel walls, we show that some swimmers can become trapped near the corner while moving, on average, along the axis of the channel. This result suggests that such bacteria may be found at much higher densities in corners than in other parts of the channel. Another implication is that these corner accumulating bacteria may travel quickly through channels since they are guided directly along the corner and do not turn back or swim transversely across the channel. PMID- 26764814 TI - Weakly nonlinear analysis of Rayleigh-Benard convection in a non-Newtonian fluid between plates of finite conductivity: Influence of shear-thinning effects. AB - Finite-amplitude thermal convection in a shear-thinning fluid layer between two horizontal plates of finite thermal conductivity is considered. Weakly nonlinear analysis is adopted as a first approach to investigate nonlinear effects. The rheological behavior of the fluid is described by the Carreau model. As a first step, the critical conditions for the onset of convection are computed as a function of the ratio xi of the thermal conductivity of the plates to the thermal conductivity of the fluid. In agreement with the literature, the critical Rayleigh number Ra(c) and the critical wave number k(c) decrease from 1708 to 720 and from 3.11 to 0, when xi decreases from infinity to zero. In the second step, the critical value alpha(c) of the shear-thinning degree above which the bifurcation becomes subcritical is determined. It is shown that alpha(c) increases with decreasing xi. The stability of rolls and squares is then investigated as a function of xi and the rheological parameters. The limit value xi(c), below which squares are stable, decreases with increasing shear-thinning effects. This is related to the fact that shear-thinning effects increase the nonlinear interactions between sets of rolls that constitute the square patterns [M. Bouteraa et al., J. Fluid Mech. 767, 696 (2015)]. For a significant deviation from the critical conditions, nonlinear convection terms and nonlinear viscous terms become stronger, leading to a further diminution of xi(c). The dependency of the heat transfer on xi and the rheological parameters is reported. It is consistent with the maximum heat transfer principle. Finally, the flow structure and the viscosity field are represented for weakly and highly conducting plates. PMID- 26764815 TI - Theoretical study of time-dependent, ultrasound-induced acoustic streaming in microchannels. AB - Based on first- and second-order perturbation theory, we present a numerical study of the temporal buildup and decay of unsteady acoustic fields and acoustic streaming flows actuated by vibrating walls in the transverse cross-sectional plane of a long straight microchannel under adiabatic conditions and assuming temperature-independent material parameters. The unsteady streaming flow is obtained by averaging the time-dependent velocity field over one oscillation period, and as time increases, it is shown to converge towards the well-known steady time-averaged solution calculated in the frequency domain. Scaling analysis reveals that the acoustic resonance builds up much faster than the acoustic streaming, implying that the radiation force may dominate over the drag force from streaming even for small particles. However, our numerical time dependent analysis indicates that pulsed actuation does not reduce streaming significantly due to its slow decay. Our analysis also shows that for an acoustic resonance with a quality factor Q, the amplitude of the oscillating second-order velocity component is Q times larger than the usual second-order steady time averaged velocity component. Consequently, the well-known criterion v(1)?c(s) for the validity of the perturbation expansion is replaced by the more restrictive criterion v(1)?c(s)/Q. Our numerical model is available as supplemental material in the form of comsol model files and matlab scripts. PMID- 26764816 TI - Flagellar swimmers oscillate between pusher- and puller-type swimming. AB - Self-propulsion of cellular microswimmers generates flow signatures, commonly classified as pusher and puller type, which characterize hydrodynamic interactions with other cells or boundaries. Using experimentally measured beat patterns, we compute that the flagellated green alga Chlamydomonas oscillates between pusher and puller, rendering it an approximately neutral swimmer, when averaging over its full beat cycle. Beyond a typical distance of 100MUm from the cell, inertia attenuates oscillatory microflows. We show that hydrodynamic interactions between cells oscillate in time and are of similar magnitude as stochastic swimming fluctuations. From our analysis, we also find that the rate of hydrodynamic dissipation varies in time, which implies that flagellar beat patterns are not optimized with respect to this measure. PMID- 26764817 TI - Osmotic pressure of ionic liquids in an electric double layer: Prediction based on a continuum model. AB - An analysis has been performed for the osmotic pressure of ionic liquids in the electric double layer (EDL). By using the electromechanical approach, we first derive a differential equation that is valid for computing the osmotic pressure in the continuum limit of any incompressible fluid in EDL. Then a specific model for ionic liquids proposed by Bazant et al. [M. Z. Bazant, B. D. Storey, and A. A. Kornyshev, Phys. Rev. Lett. 106, 046102 (2011)] is adopted for more detailed computation of the osmotic pressure. Ionic liquids are characterized by the correlation and the steric effects of ions and their effects are analyzed. In the low voltage cases, the correlation effect is dominant and the problem becomes linear. For this low voltage limit, a closed form formula is derived for predicting the osmotic pressure in EDL with no overlapping. It is found that the osmotic pressure decreases as the correlation effect increases. The osmotic pressures at the nanoslit surface and nanoslit centerline are also obtained for the low voltage limit. For the cases of moderately high voltage with high correlation factor, approximate formulas are derived for estimating osmotic pressure values based on the concept of a condensed layer near the electrode. In order to corroborate the results predicted by analytical studies, the full nonlinear model has been solved numerically. PMID- 26764818 TI - Metal pad instabilities in liquid metal batteries. AB - A mechanical analogy is used to analyze the interaction between the magnetic field, electric current, and deformation of interfaces in liquid metal batteries. In the framework of a low-mode, nondissipative, linear stability model, it is found that, during charging or discharging, a sufficiently large battery is prone to instabilities of two types. One is similar to the metal pad instability known to exist in the aluminum reduction cells. Another type is new. It is related to the destabilizing effect of the Lorentz force formed by the azimuthal magnetic field induced by the base current, and the current perturbations caused by the local variations of the thickness of the electrolyte layer. PMID- 26764819 TI - Numerical analysis of the angular motion of a neutrally buoyant spheroid in shear flow at small Reynolds numbers. AB - We numerically analyze the rotation of a neutrally buoyant spheroid in a shear flow at small shear Reynolds number. Using direct numerical stability analysis of the coupled nonlinear particle-flow problem, we compute the linear stability of the log-rolling orbit at small shear Reynolds number Re(a). As Re(a)->0 and as the box size of the system tends to infinity, we find good agreement between the numerical results and earlier analytical predictions valid to linear order in Re(a) for the case of an unbounded shear. The numerical stability analysis indicates that there are substantial finite-size corrections to the analytical results obtained for the unbounded system. We also compare the analytical results to results of lattice Boltzmann simulations to analyze the stability of the tumbling orbit at shear Reynolds numbers of order unity. Theory for an unbounded system at infinitesimal shear Reynolds number predicts a bifurcation of the tumbling orbit at aspect ratio lambda(c)~0.137 below which tumbling is stable (as well as log rolling). The simulation results show a bifurcation line in the lambda-Re(a) plane that reaches lambda~0.1275 at the smallest shear Reynolds number (Re(a)=1) at which we could simulate with the lattice Boltzmann code, in qualitative agreement with the analytical results. PMID- 26764820 TI - Capillary saturation and desaturation. AB - Capillary desaturation experiments produce disconnected (trapped) ganglia of mesoscopic sizes intermediate between pore size and system size. Experimental evidence for interactions between these mesoscale clusters during desaturation is analyzed and discussed within the established microscopic and macroscopic laws of Newton, Young-Laplace, and Darcy. A theoretical expression for capillary number correlations is introduced that seems to have remained unnoticed. It expresses capillary desaturation curves in terms of stationary capillary pressures and relative permeabilities. The theoretical expression shows that the plateau saturation in capillary desaturation curves may in general differ from the residual nonwetting saturation defined through the saturation limit of the main hysteresis loop. Hysteresis effects as well as the difference between wetting and nonwetting fluids are introduced into the analysis of capillary desaturation experiments. The article examines experiments with different desaturation protocols and discusses the existence of a mesoscopic length scale intermediate between pore scale and sample scale. The theoretical expression is derived entirely within the existing traditional theory of two-phase flow in porous media and compared to a recent experiment. PMID- 26764821 TI - Refined similarity hypothesis using three-dimensional local averages. AB - The refined similarity hypotheses of Kolmogorov, regarded as an important ingredient of intermittent turbulence, has been tested in the past using one dimensional data and plausible surrogates of energy dissipation. We employ data from direct numerical simulations, at the microscale Reynolds number R(lambda)~650, on a periodic box of 4096(3) grid points to test the hypotheses using three-dimensional averages. In particular, we study the small-scale properties of the stochastic variable V=Deltau(r)/(repsilon(r))(1/3), where Deltau(r) is the longitudinal velocity increment and epsilon(r) is the dissipation rate averaged over a three-dimensional volume of linear size r. We show that V is universal in the inertial subrange. In the dissipation range, the statistics of V are shown to depend solely on a local Reynolds number. PMID- 26764822 TI - Solitary solutions including spatially localized chaos and their interactions in two-dimensional Kolmogorov flow. AB - Two-dimensional Kolmogorov flow in wide periodic boxes is numerically investigated. It is shown that the total flow rate in the direction perpendicular to the force controls the characteristics of the flow, especially the existence of spatially localized solitary solutions such as traveling waves, periodic solutions, and chaotic solutions, which can behave as elementary components of the flow. We propose a procedure to construct approximate solutions consisting of solitary solutions. It is confirmed by direct numerical simulations that these solutions are stable and represent interactions between elementary components such as collisions, coexistence, and collapse of chaos. PMID- 26764823 TI - Shape matters: Near-field fluid mechanics dominate the collective motions of ellipsoidal squirmers. AB - Microswimmers show a variety of collective motions. Despite extensive study, questions remain regarding the role of near-field fluid mechanics in collective motion. In this paper, we describe precisely the Stokes flow around hydrodynamically interacting ellipsoidal squirmers in a monolayer suspension. The results showed that various collective motions, such as ordering, aggregation, and whirls, are dominated by the swimming mode and the aspect ratio. The collective motions are mainly induced by near-field fluid mechanics, despite Stokes flow propagation over a long range. These results emphasize the importance of particle shape in collective motion. PMID- 26764824 TI - Fractal flame structure due to the hydrodynamic Darrieus-Landau instability. AB - By using large scale numerical simulations, we obtain fractal structure, which develops at originally planar flame fronts due to the hydrodynamic Darrieus Landau (DL) instability bending the fronts. We clarify some important issues regarding the DL fractal flames, which have been debated for a long time. We demonstrate an increase of the flame propagation speed with the hypothetic channel width, which controls the length scale of the instability development. We show that this increase may be fitted by a power law indicating the mean fractal properties of the flame front structure. The power exponent in this law is found to be not a universal constant, rather it depends on the flame properties-on the density drop at the front. Using box counting on the simulated flame front shapes we show the fractal flame dimension at the intermediate scale is smaller than the one given by the power law, but it has a similar dependency on the density drop. We also obtain a formation of pockets at the DL fractal flame fronts, which previously has been associated only with turbulent burning. PMID- 26764825 TI - Hydrodynamic interactions between pairs of capsules and drops in a simple shear: Effects of viscosity ratio and heterogeneous collision. AB - Hydrodynamic interactions between a pair of capsules in simple shear are numerically investigated using a front-tracking finite difference method. The membrane of the capsule is modeled using different hyperelastic constitutive relations. We also compare the pair interactions between drops to those between capsules. An increased viscosity ratio leads to a reduced net cross-stream separation between capsules as well as drops after collision. At low viscosity ratios, for the same capillary number drop-pairs show higher cross-stream separation than those for capsule-pairs, while substantially large viscosity ratios result in almost the same value for both cases. We investigate pair collisions between two heterogeneous capsules C(1) and C(2) with two different capillary numbers. The maximum deformation of C(1) was seen to increase with increasing stiffness (decreasing capillary number) of C(2), even though the stiffness of C(1) was kept fixed. The findings are similar for a drop-pair, however, with a smaller maximum deformation for the same combinations of capillary numbers. The final cross-stream drift of the trajectory of C(1) decreases with the increasing stiffness of C(2), but the relative trajectory between the capsules remains unchanged. The maximum deformation and the cross stream drift of the trajectory of C(1) are shown to approximately vary with power law functions of the ratio of the capillary numbers of C(1) and C(2). An analytical explanation of the dependence on the two capillary numbers is offered. Different membrane constitutive laws result in similar deformation and drift in trajectory. PMID- 26764826 TI - Wake control with permeable multilayer structures: The spherical symmetry case. AB - We explore the possibility of controlling the wake and drag of a spherical object independently of each other, using radial distributions of permeability in the Brinkman-Stokes formalism. By discretizing a graded-permeability shell into discrete, macroscopically homogeneous layers, we are able to sample the entire functional space of spherically-symmetric permeabilities and observe quick convergence to a certain manifold in the wake-drag coordinates. Monte Carlo samplings with 10^{4}-10^{5} points have become possible thanks to our new algorithm, which is based on exact analytical solutions for the Stokes flow through an arbitrary multilayer porous sphere. The algorithm is not restricted to the Brinkman-Stokes equation and can be modified to account for other types of scattering problems for spherically-symmetric systems with arbitrary radial complexity. Our main practical finding for Stokes flow is that it is possible to reduce a certain measure of wake of a spherical object without any energy penalty and without active (power-consuming) force generation. PMID- 26764827 TI - Thermophoretic motion behavior of submicron particles in boundary-layer separation flow around a droplet. AB - As a key mechanism of submicron particle capture in wet deposition and wet scrubbing processes, thermophoresis is influenced by the flow and temperature fields. Three-dimensional direct numerical simulations were conducted to quantify the characteristics of the flow and temperature fields around a droplet at three droplet Reynolds numbers (Re) that correspond to three typical boundary-layer separation flows (steady axisymmetric, steady plane-symmetric, and unsteady plane symmetric flows). The thermophoretic motion of submicron particles was simulated in these cases. Numerical results show that the motion of submicron particles around the droplet and the deposition distribution exhibit different characteristics under three typical flow forms. The motion patterns of particles are dependent on their initial positions in the upstream and flow forms. The patterns of particle motion and deposition are diversified as Re increases. The particle motion pattern, initial position of captured particles, and capture efficiency change periodically, especially during periodic vortex shedding. The key effects of flow forms on particle motion are the shape and stability of the wake behind the droplet. The drag force of fluid and the thermophoretic force in the wake contribute jointly to the deposition of submicron particles after the boundary-layer separation around a droplet. PMID- 26764828 TI - Formation of bubbly horizon in liquid-saturated porous medium by surface temperature oscillation. AB - We study nonisothermal diffusion transport of a weakly soluble substance in a liquid-saturated porous medium in contact with a reservoir of this substance. The surface temperature of the porous medium half-space oscillates in time, which results in a decaying solubility wave propagating deep into the porous medium. In this system, zones of saturated solution and nondissolved phase coexist with ones of undersaturated solution. The effect is first considered for the case of annual oscillation of the surface temperature of water-saturated ground in contact with the atmosphere. We reveal the phenomenon of formation of a near-surface bubbly horizon due to temperature oscillation. An analytical theory of the phenomenon is developed. Further, the treatment is extended to the case of higher frequency oscillations and the case of weakly soluble solids and liquids. PMID- 26764829 TI - Radiation-pressure-induced nonlinearity in microdroplets. AB - High quality (Q) factor whispering gallery modes (WGMs) can induce nonlinear effects in liquid droplets through mechanisms such as radiation pressure, Kerr nonlinearity, and thermal effects. However, such nonlinear effects, especially those due to radiation pressure, have yet to be thoroughly investigated and compared in the literature. In this study, we present an analytical approach that can exactly calculate the droplet deformation induced by the radiation pressure. The accuracy of the analytical approach is confirmed through numerical analyses based on the boundary element method. We show that the nonlinear optofluidic effect induced by the radiation pressure is stronger than the Kerr effect and the thermal effect under a large variety of realistic conditions. Using liquids with ultralow and experimentally attainable interfacial tension, we further confirm the prediction that it may only take a few photons to produce measurable WGM resonance shift through radiation-pressure-induced droplet deformation. PMID- 26764830 TI - Numerical simulation of gas flow and heat transfer in a rough microchannel using the lattice Boltzmann method. AB - In microfluidics, two important factors responsible for the differences between the characteristics of the flow and heat transfer in microchannels and conventional channels are rarefaction and surface roughness which are studied in the present work. An incompressible gas flow in a microchannel is simulated two dimensionally using the lattice Boltzmann method. The flow is in the slip regime and surface roughness is modeled by both regular and Gaussian random distribution of rectangular modules. The effects of relative surface roughness height and Knudsen number on gaseous flow and heat transfer are studied. It was shown that as the relative roughness height increases, the Poiseuille number increases and the Nusselt number has a decreasing or increasing trend, depending on the degree of rarefaction. A comparison between the flow and heat transfer characteristics in regular and random distribution of surface roughness demonstrates that in regular roughness, circular flows are more pronounced; Poiseuille number is higher and Nusselt number is lower than that of its equivalent random roughness. PMID- 26764832 TI - Uniform heating of materials into the warm dense matter regime with laser-driven quasimonoenergetic ion beams. AB - In a recent experiment at the Trident laser facility, a laser-driven beam of quasimonoenergetic aluminum ions was used to heat solid gold and diamond foils isochorically to 5.5 and 1.7 eV, respectively. Here theoretical calculations are presented that suggest the gold and diamond were heated uniformly by these laser driven ion beams. According to calculations and SESAME equation-of-state tables, laser-driven aluminum ion beams achievable at Trident, with a finite energy spread of DeltaE/E~20%, are expected to heat the targets more uniformly than a beam of 140-MeV aluminum ions with zero energy spread. The robustness of the expected heating uniformity relative to the changes in the incident ion energy spectra is evaluated, and expected plasma temperatures of various target materials achievable with the current experimental platform are presented. PMID- 26764831 TI - Low-Reynolds-number predator. AB - To generalize simple bead-linker model of swimmers to higher dimensions and to demonstrate the chemotaxis ability of such swimmers, here we introduce a low Reynolds predator, using a two-dimensional triangular bead-spring model. Two state linkers as mechanochemical enzymes expand as a result of interaction with particular activator substances in the environment, causing the whole body to translate and rotate. The concentration of the chemical stimulator controls expansion versus the contraction rate of each arm and so affects the ability of the body for diffusive movements; also the variation of activator substance's concentration in the environment breaks the symmetry of linkers' preferred state, resulting in the drift of the random walker along the gradient of the density of activators. External food or danger sources may attract or repel the body by producing or consuming the chemical activators of the organism's enzymes, inducing chemotaxis behavior. Generalization of the model to three dimensions is straightforward. PMID- 26764833 TI - Small-scale behavior of Hall magnetohydrodynamic turbulence. AB - Decaying Hall magnetohydrodynamic (HMHD) turbulence is studied using three dimensional (3D) direct numerical simulations with grids up to 768(3) points and two different types of initial conditions. Results are compared to analogous magnetohydrodynamic (MHD) runs and both Laplacian and Laplacian-squared dissipative operators are examined. At scales below the ion inertial length, the ratio of magnetic to kinetic energy as a function of wave number transitions to a magnetically dominated state. The transition in behavior is associated with the advection term in the momentum equation becoming subdominant to dissipation. Examination of autocorrelation functions reveals that, while current and vorticity structures are similarly sized in MHD, HMHD current structures are narrower and vorticity structures are wider. The electric field autocorrelation function is significantly narrower in HMHD than in MHD and is similar to the HMHD current autocorrelation function at small separations. HMHD current structures are found to be significantly more intense than in MHD and appear to have an enhanced association with strong alignment between the current and magnetic field, which may be important in collisionless plasmas where field-aligned currents can be unstable. When hyperdiffusivity is used, a longer region consistent with a k(-7/3) scaling is present for right-polarized fluctuations when compared to Laplacian dissipation runs. PMID- 26764834 TI - Approximants to the Tonks-Langmuir theory for a collisionless annular plasma. AB - Maclaurin series approximant and Pade rational approximant are used to solve the Tonks-Langmuir theory for an annular plasma and investigate the radial transport behavior of charged particles. Coefficients of the well-known Maclaurin approximant are given in a novel form of recurrence relations which are convenient for computation and present a lower limit for the annular ratio of inner radius to outer radius (i.e., this approximant is not applicable to annular geometries with small inner radii). The newly introduced Pade approximant extrapolates the annular ratio limit determined by the Maclaurin approximant to a lower value and hence is applicable to most annular geometries. General radial profiles of the normalized plasma density and mean drift velocity of ions are given across the annulus and they are independent of the gas type and the Paschen number of the discharge. The annular modeling is applied to an argon plasma and obtains the electron temperature as a function of the Paschen number for different annular geometries. PMID- 26764835 TI - Beltrami state in black-hole accretion disk: A magnetofluid approach. AB - Using the magnetofluid unification framework, we show that the accretion disk plasma (embedded in the background geometry of a black hole) can relax to a class of states known as the Beltrami-Bernoulli (BB) equilibria. Modeling the disk plasma as a Hall magnetohydrodynamics (MHD) system, we find that the space-time curvature can significantly alter the magnetic (velocity) decay rates as we move away from the compact object; the velocity profiles in BB states, for example, deviate substantially from the predicted corresponding geodesic velocity profiles. These departures imply a rich interplay of plasma dynamics and general relativity revealed by examining the corresponding Bernoulli condition representing "homogeneity" of total energy. The relaxed states have their origin in the constraints provided by the two helicity invariants of Hall MHD. These helicities conspire to introduce an oscillatory length scale into the system that is strongly influenced by relativistic and thermal effects. PMID- 26764836 TI - Effect of correlations on heat transport in a magnetized strongly coupled plasma. AB - In a classical ideal plasma, a magnetic field is known to reduce the heat conductivity perpendicular to the field, whereas it does not alter the one along the field. Here we show that, in strongly correlated plasmas that are observed at high pressure and/or low temperature, a magnetic field reduces the perpendicular heat transport much less and even enhances the parallel transport. These surprising observations are explained by the competition of kinetic, potential, and collisional contributions to the heat conductivity. Our results are based on first-principle molecular dynamics simulations of a one-component plasma. PMID- 26764837 TI - Helicity-based particle-relabeling operator and normal mode expansion of the dissipationless incompressible Hall magnetohydrodynamics. AB - The dynamics of an incompressible, dissipationless Hall magnetohydrodynamic medium are investigated from Lagrangian mechanical viewpoint. The hybrid and magnetic helicities are shown to emerge, respectively, from the application of the particle relabeling symmetry for ion and electron flows to Noether's first theorem, while the constant of motion associated with the theorem is generally given by their arbitrary linear combination. Furthermore, integral path variation associated with the invariant action is expressed by the operation of an integrodifferential operator on the reference path. The eigenfunctions of this operator are double Beltrami flows, i.e., force-free stationary solutions to the equation of motion and provide a family of orthogonal function bases that yields the spectral representation of the equation of motion with a remarkably simple form. Among the double Beltrami flows, considering the influence of a uniform background magnetic field and the Hall term effect vanishing limit, the generalized Elsasser variables are found to be the most suitable for avoiding problems with singularities in the standard magnetohydrodynamic limit. PMID- 26764838 TI - Collision of ion acoustic solitary waves in a magnetized plasma: Effect of dust grains and trapped electrons. AB - The head-on collision of two ion acoustic solitary waves is investigated in a magnetized plasma containing trapped electrons and dust grains. For completeness, the fluctuations in dust grain charge are taken into account. By using the extended Poincare-Lighthill-Kuo (PLK) perturbation method, an analytical expression is obtained for the phase shift that takes place due to the collision of the waves. How the phase shift behaves under the combined effect of trapped electrons and dust grains along with the finite temperature of ions is examined. A focus is given to uncover the situations of fluctuating charge and fixed charge on the dust grains in the plasma. Interestingly, the solitary waves acquire a larger phase shift and are delayed more in the case of dust grains having a fluctuating charge. PMID- 26764839 TI - Experimental and ab initio investigations of microscopic properties of laser shocked Ge-doped ablator. AB - Plastic materials (CH) doped with mid-Z elements are used as ablators in inertial confinement fusion (ICF) capsules and in their surrogates. Hugoniot equation of state (EOS) and electronic properties of CH doped with germanium (at 2.5% and 13% dopant fractions) are investigated experimentally up to 7 Mbar using velocity and reflectivity measurements of shock fronts on the GEKKO laser at Osaka University. Reflectivity and temperature measurements were updated using a quartz standard. Shocked quartz reflectivity was measured at 532 and 1064 nm. Theoretical investigation of shock pressure and reflectivity was then carried out by ab initio simulations using the quantum molecular dynamics (QMD) code abinit and compared with tabulated average atom EOS models. We find that shock states calculated by QMD are in better agreement with experimental data than EOS models because of a more accurate description of ionic structure. We finally discuss electronic properties by comparing reflectivity data to a semiconductor gap closure model and to QMD simulations. PMID- 26764840 TI - Raman amplification in the coherent wave-breaking regime. AB - In regimes far beyond the wave-breaking threshold of Raman amplification, we show that significant amplification can occur after the onset of wave breaking, before phase mixing destroys the coherent coupling between pump, probe, and plasma wave. Amplification in this regime is therefore a transient effect, with the higher efficiency "coherent wave-breaking" (CWB) regime accessed by using a short, intense probe. Parameter scans illustrate the marked difference in behavior between below wave breaking, in which the energy-transfer efficiency is high but total energy transfer is low, wave breaking, in which efficiency is low, and CWB, in which moderate efficiencies allow the highest total energy transfer. PMID- 26764841 TI - Nonlinear Landau damping and modulation of electrostatic waves in a nonextensive electron-positron-pair plasma. AB - The nonlinear theory of amplitude modulation of electrostatic wave envelopes in a collisionless electron-positron (EP) pair plasma is studied by using a set of Vlasov-Poisson equations in the context of Tsallis' q-nonextensive statistics. In particular, the previous linear theory of Langmuir oscillations in EP plasmas [Saberian and Esfandyari-Kalejahi, Phys. Rev. E 87, 053112 (2013)] is rectified and modified. Applying the multiple scale technique (MST), it is shown that the evolution of electrostatic wave envelopes is governed by a nonlinear Schrodinger (NLS) equation with a nonlocal nonlinear term ?P?|phi(xi',tau)|(2)dxi'phi/(xi xi') [where P denotes the Cauchy principal value, phi is the small-amplitude electrostatic (complex) potential, and xi and tau are the stretched coordinates in MST], which appears due to the wave-particle resonance. It is found that a subregion 1/310 Yrs) Outcome of the Laparoscopic Biliopancreatic Diversion With Duodenal Switch. AB - OBJECTIVE: The aim of the study was to report 10+ year outcome of laparoscopic biliopancreatic diversion with duodenal switch (LDS), with special focus on quality of life. BACKGROUND:: Reports on long-term morbidity and quality of life after LDS are rare. METHODS: Records of all patients who underwent LDS 10+ years ago were analyzed. Patients were contacted to answer a questionnaire based on Bariatric Analysis and Reporting Outcome System. Blood work was reported when performed within the past year. RESULTS: Of the 153 patients who underwent LDS, follow-up was available for 113 patients (78.5%). Mean follow-up was 130.2 +/- 4.6 months. Percentage total weight loss was 40.7 +/- 10.8%. Weight loss was greatest in the super obese category (BMI > 50 kg/m). Remission rate for type 2 diabetes was 87.5% (21/24) and for arterial hypertension 80.9% (38/47). Dyslipidemia remission rates were 93.3% (28/30) for total cholesterol, 89.7% (26/29) for triglycerides, and 95.0% (19/20) for low-density lipoprotein cholesterol. However, 42.5% of the patients needed reoperation, including 10.6% for correction of protein malnutrition, the latter exclusively in non-super obese individuals. Most common deficiencies concerned vitamin A and D, iron, and zinc. De novo gastroesophageal reflux disease was reported in 43.8%. The Bariatric Analysis and Reporting Outcome System score was good at 4.9 +/- 2.2, and 82.3% of participants would choose the procedure again. CONCLUSIONS: LDS is a very effective metabolic procedure, at the cost of occasional protein and other nutritional deficiencies. Outcome in the long term is best in super obese patients. Overall quality of life is good. The high reoperation rate and incidence of gastroesophageal reflux disease are concerning. PMID- 26764872 TI - Prevention of Atrial Fibrillation in High-risk Patients Undergoing Lung Cancer Surgery: The PRESAGE Trial. AB - OBJECTIVE: We performed a prospective, randomized clinical study to assess whether prophylactic treatment with metoprolol or losartan, initiated soon after lung cancer surgery in patients with elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, reduces the incidence of postoperative atrial fibrillation. BACKGROUND: Postoperative atrial fibrillation is a well recognized complication after lung cancer surgery, with an incidence as high as 30%. Perioperative increase of NT-proBNP has been demonstrated to be a strong independent predictor of postoperative atrial fibrillation in this setting. METHODS: NT-proBNP concentration was measured 24 hours before surgery and soon after surgery in 1116 patients. Three hundred twenty (29%) patients showed a high NT-proBNP value and were enrolled: 108 were assigned to the metoprolol group, 102 to the losartan group, and 110 to the control group. RESULTS: Overall, the incidence of postoperative atrial fibrillation was 20% (n = 64); it was significantly lower in the metoprolol and losartan groups compared with the control group [6%, 12%, and 40%, respectively; relative risk 0.19, 95% confidence intervals (CIs), 0.09-0.37; P < 0.001 in the metoprolol group; and 0.29, 95% CI, 0.16-0.52; P < 0.001 in the losartan group). No significant difference was found when the metoprolol and losartan groups were directly compared (P = 0.21). CONCLUSIONS: A prophylactic treatment with metoprolol or losartan, initiated soon after lung cancer surgery in patients with high NT-proBNP levels, significantly reduced the occurrence of postoperative atrial fibrillation. PMID- 26764873 TI - Surgical Comanagement by Hospitalists Improves Patient Outcomes: A Propensity Score Analysis. AB - OBJECTIVE: The aim of the study was to examine the impact of a surgical comanagement (SCM) hospitalist program on patient outcomes at an academic institution. BACKGROUND: Prior studies may have underestimated the impact of SCM due to methodological shortcomings. METHODS: This is a retrospective study utilizing a propensity score-weighted intervention (n = 16,930) and control group (n = 3695). Patients were admitted between January 2009 to July 2012 (pre-SCM) and September 2012 to September 2013 (post-SCM) to Orthopedic or Neurosurgery at our institution. Using propensity score methods, linear regression, and a difference-in-difference approach, we estimated changes in outcomes between pre and post periods, while adjusting for confounding patient characteristics. RESULTS: The SCM intervention was associated with a significant differential decrease in the proportion of patients with at least 1 medical complication [odds ratio (OR) 0.86; 95% confidence interval (CI), 0.74-0.96; P = 0.008), the proportion of patients with length of stay at least 5 days (OR 0.75; 95% CI, 0.67 0.84; P < 0.001), 30-day readmission rate for medical cause (OR 0.67; 95% CI, 0.52-0.81; P < 0.001), and the proportion of patients with at least 2 medical consultants (OR 0.55; 95% CI, 0.49-0.63; P < 0.001). There was no significant change in patient satisfaction (OR 1.08; 95% CI, 0.87-1.33; P = 0.507). We estimated average savings of $2642 to $4303 per patient in the post-SCM group. The overall provider satisfaction with SCM was 88.3%. CONCLUSIONS: The SCM intervention reduces medical complications, length of stay, 30-day readmissions, number of consultants, and cost of care. PMID- 26764874 TI - Too Many Languages in the ALPPS: Preventing Another Tower of Babel? AB - OBJECTIVES: To establish a "consensus" terminology of many variants of the ALPPS procedure. BACKROUND: The rapid development and dissemination of ALPPS with the availability of many variants has led to numerous neologisms, also leading to confusion and difficulties in comparing various experiences. The first expert meeting in February 2015 in Hamburg concluded that the development of a common terminology of procedures, summarized under the acronym ALPPS, is needed. METHODS: The current literature on ALPPS and the International ALPPS registry, including more than 600 cases, were reviewed to identify all the acronyms related to ALPPS. A logical nomenclature system was proposed by founding members of the registry and subsequently submitted to each center registered in the ALPPS registry (n = 209) to reach a consensus. RESULTS: The many identified ALPPS terms were classified according to their application (e.g. surgical access such as laparoscopy, transection variants etc.). These variants were subsequently placed in form of prepositions before ALPPS following a defined order: strategy, stage of the procedure, access, portal vein embolization, if used, types of transection and hepatectomy. The principles for the terminology and specific application were eventually commented and approved by each center registered in the registry. CONCLUSIONS: The proposed "consensus" terminology should enable to better compare the many variants of ALPPS, and was also designed to implement future developments due to the readily applicable principles. PMID- 26764877 TI - Optimum force system for intrusion and extrusion of maxillary central incisor in labial and lingual orthodontics. AB - BACKGROUND: The objective of the present study was to specify an optimum force system for intrusion and extrusion of maxillary central incisor and to compare the effects of bracket positioning at different heights from the incisal edge in Labial Orthodontics (LaO) and Lingual Orthodontics (LiO). METHODS: A mathematical model of maxillary central incisor with normal inclination was developed. Four cases of heights of bracket slot from incisal edge were considered both in LaO and LiO viz. 3mm, 4mm, 5mm and 6mm. Based on a mathematical model, an optimum force system consisting of an intrusive or extrusive force (F) and a moment (M) was devised and moment (M) to force (F) ratio (M:F ratio) was estimated in each case. Then, three-dimensional Computer Aided Design (CAD) models of incisor and surrounding structures were prepared. To validate an optimum force system, finite element analysis was carried out and force system with derived M:F ratio was applied in each case. RESULTS: In finite element analysis, results were shown in the form of vector graph of nodal displacements along with undeformed and deformed models. The desired intrusion or extrusion of incisor was observed. Thus, force system devised from a mathematical model was validated with finite element analysis in each case. CONCLUSION: To achieve intrusion or extrusion, M:F ratios required in LaO were same i.e. 8:1 for aforementioned heights of bracket slot from incisal edge but different in LiO i.e. 0:1, 1:1, 2:1 and 3:1 for the heights of 3mm, 4mm, 5mm and 6mm respectively. PMID- 26764878 TI - Shifting Trends in Bacterial Keratitis in Taiwan: A 10-Year Review in a Tertiary Care Hospital. AB - PURPOSE: To investigate the distribution, current trends, and antibiotic susceptibility profiles of bacterial keratitis isolates over 10 years. METHODS: We retrospectively reviewed the microbiology records of all corneal scrapings undertaken for cultures at Chang Gung Memorial Hospital from 2003 through 2012. We identified bacterial isolates and verified antibiotic susceptibilities by using the disk diffusion method. The Mantel-Haenszel linear-by-linear association chi test was used to detect the trends. RESULTS: We collected 2012 corneal scrapings, and the culture was positive in 992 samples (49.3%), yielding 1282 isolates. Bacterial isolates were identified for 1039 isolates (81.1%), including 533 gram-positive and 506 gram-negative isolates. An increase in the percentage of gram-positive isolates was significant (P = 0.008), as was a decrease in that of gram-negative isolates (P = 0.002). The most common bacterial isolates were Pseudomonas aeruginosa (24.4%) and coagulase-negative Staphylococcus (16.6%). For gram-positive organisms, the susceptibilities were as follows: vancomycin 100%, ciprofloxacin 88.9%, sulfamethoxazole-trimethoprim 86.8%, clindamycin 73.2%, and oxacillin 56.5%. The susceptibility of gram-positive bacteria to clindamycin and oxacillin increased significantly (P = 0.009 and P = 0.001). For gram-negative organisms, the susceptibilities were as follows: ciprofloxacin 93.7%, piperacillin 91.9%, ceftazidime 90.9%, amikacin 88.3%, and gentamicin 84.7%. No change in trend occurred. CONCLUSIONS: In Taiwan, we documented an increasing trend in the percentage of gram-positive bacteria. Methicillin-resistant microorganisms accounted for 43.5% of all gram-positive bacteria, but the trend of resistance to oxacillin and clindamycin significantly decreased. Ciprofloxacin continued to be a good empiric antibiotic for treating bacterial keratitis. PMID- 26764879 TI - Comparison of Long-Term Outcomes of Femtosecond Laser-Assisted Keratoplasty with Conventional Keratoplasty. AB - PURPOSE: Astigmatism is a significant problem in penetrating keratoplasty. Lower astigmatism and better visual outcomes had been expected from laser-assisted penetrating keratoplasty, that is, from the top-hat, mushroom, or zig-zag cutting profiles. We report the long-term outcomes of 141 femtosecond laser-assisted penetrating keratoplasties retrospectively. We compare these outcomes with those of penetrating keratoplasty using the guided trephine system (GTS). METHODS: In all, 141 femtosecond laser-assisted penetrating keratoplasties had been performed in 119 patients. The results were compared with those of conventional keratoplasty (n = 1254; visual and refractive outcomes, graft rejections, and graft failure). RESULTS: Follow-up averaged 33 months. In eyes with keratoconus, the time to achieve a visual acuity of 10/20 (Snellen) was shorter in the mushroom than in the GTS group. However, there was no relevant long-term difference. Graft astigmatism was higher in the laser groups [keratometric astigmatism at the end of follow-up: -4.5 +/- 4 (GTS), -5.8 +/- 3.3 (top-hat), 5.9 +/- 3.2 D (mushroom); P < 0.01]. In eyes with keratoconus, rates of graft rejection were highest in the mushroom group (55%). In the other groups, top-hat keratoplasty resulted in lower rates of rejection than GTS keratoplasty (31%). CONCLUSIONS: There is no significant difference in the refractive and visual outcomes after femtosecond laser-assisted penetrating keratoplasty compared with GTS keratoplasty. The benefits from the use of the femtosecond laser may be limited and should be weighed against an increased risk of immune reactions, higher surgical complexity, and higher costs. PMID- 26764880 TI - High-Resolution Optical Coherence Tomography Findings of Lisch Epithelial Corneal Dystrophy. AB - PURPOSE: To describe a case of Lisch epithelial corneal dystrophy (LECD) and present its unique characteristics on high-resolution optical coherence tomography (HR-OCT). METHODS: A 78-year-old man with whorled corneal epithelial opacities in the right eye was referred for the evaluation of ocular surface squamous neoplasia. Clinical evaluation, photographs, and HR-OCT images of the cornea involved were obtained and scrapings of the affected cornea were sent for histopathologic analysis. RESULTS: Clinically, the patient presented with an opalescent whirling epithelium in a linear pattern encroaching on the visual axis. HR-OCT showed normal thickness epithelial hyperreflectivity of involved cornea without stromal involvement, along with sharply demarcated borders of unaffected tissue. Histopathologic findings demonstrated vacuolated periodic acid Schiff (PAS) positive cells throughout the epithelial layers consistent with LECD. CONCLUSIONS: HR-OCT was able to provide useful information to rule out ocular surface squamous neoplasia and confirm the clinical impression of LECD at the time of clinical examination. HR-OCT shows promise as an adjunctive diagnostic tool for ocular surface lesions and pathologies. PMID- 26764881 TI - Rate and Localization of Graft Detachment in Descemet Membrane Endothelial Keratoplasty. AB - PURPOSE: To investigate the rate and localization of graft detachment after Descemet membrane endothelial keratoplasty. METHODS: Sixty-six consecutive cases operated between June and August 2014 at the Charite-Universitatsmedizin Berlin were examined prospectively 1 week postoperatively. A single masked observer analyzed the rate and localization of graft detachment using optical coherence tomography (OCT), and the rebubbling rate was measured. Localization of graft detachment was correlated to the incision approach. Preoperative data were correlated to the rate of graft detachment and rebubbling. RESULTS: Graft detachment occurred in more than 2 clock hours and with postoperative corneal edema in 33.3% and required rebubbling. In 33.3%, graft detachment occurred in more than 2 clock hours and with postoperative corneal edema and required rebubbling. The mean graft detachment rate was 8.3% per clock hour. A significantly higher graft detachment rate was noted in the inferior clock hours (21.1%, P < 0.0001, 16.7%, P = 0.003). Only higher age of the patient correlated to a higher rate of graft detachment (P = 0.022). No correlation was found between localization of graft detachment and the incision approach (P = 0.615). CONCLUSIONS: The graft detachment rate is high after Descemet membrane endothelial keratoplasty, but detachment is usually peripheral, partial and mainly inferior and involves only a few clock hours. Only higher age of the patient is strongly associated with a higher rate of graft detachment. The incision approach is not significantly correlated with the localization of graft detachment. Therefore, the postoperative supine position of the patient seems to be of major importance.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02020044. PMID- 26764882 TI - Application of the SMILE-Derived Glued Lenticule Patch Graft in Microperforations and Partial-Thickness Corneal Defects. AB - PURPOSE: To report the initial clinical outcomes of the small incision lenticule extraction (SMILE)-derived glued lenticule patch graft for management of microperforations and complicated corneal tears. METHODS: In this single-center case series, 7 eyes (of 7 patients) that presented with microperforations, partial-thickness corneal defect, and traumatic complicated corneal tear were repaired with a lenticule patch graft obtained from Refractive Lenticule Extraction (ReLEx) with the SMILE procedure. The patch was secured to the recipient eye using fibrin glue. Preoperatively, anterior segment optical coherence tomography was used to assess the depth of the defect and to decide the thickness of the lenticule. Patients were followed up on days 1, 7, and 15 and at 1 and 3 months postoperatively. Main outcome parameters measured were best corrected visual acuity, clarity of the graft, and restoration of optical and tectonic integrity. RESULTS: All surgeries were uneventful. Significant improvement in visual acuity was seen from 15 days onward in 5 of 7 eyes. The lenticule graft was well apposed and remained clear until the last follow-up visit in all eyes treated. CONCLUSIONS: The patch graft from the SMILE-derived lenticule using fibrin glue seems to serve as a safe, feasible, and inexpensive surgical option for the management of microperforations and complicated corneal tears, especially in centers that perform the SMILE procedure in large numbers. PMID- 26764883 TI - Scleritis Due to Histoplasmosis. AB - PURPOSE: To describe the first-documented case of histoplasma scleritis in an immunocompetent patient. METHODS: Medical and pathological records of the patient described were reviewed. RESULTS: A 77-year-old immunocompetent man presented with necrotizing scleritis. Biopsy was consistent with histoplasma species, and culture results confirmed a causative agent of Histoplasma capsulatum. The patient required a long course of treatment, which included topical voriconazole and amphotericin, oral itraconazole and voriconazole, intravenous amphotericin, and periocular voriconazole and amphotericin. After 8 months of treatment, the patient's scleritis resolved, and he maintained good visual acuity. CONCLUSIONS: To our knowledge, this is the second report of histoplasma scleritis in the literature and the first report in an immunocompetent patient. PMID- 26764884 TI - Ocular Surface Changes With Sofosbuvir in Egyptian Patients With Hepatitis C Virus Infection. AB - PURPOSE: To evaluate the effect of oral sofosbuvir on the ocular surface of Egyptian patients with chronic hepatitis C virus infection. METHODS: This prospective randomized comparative study was performed on 300 eyes undergoing sofosbuvir therapy with peginterferon and ribavirin and on 300 eyes undergoing treatment with only peginterferon and ribavirin. Patients were evaluated for dry eye subjectively (Ocular Surface Disease Index questionnaire) and objectively, Schirmer test, tear film breakup time, and conjunctival nucleus/cytoplasm ratio by impression cytology. RESULTS: The Ocular Surface Disease Index score significantly changed from 3.1 +/- 2.8 at baseline to 11.9 +/- 4.1 and 15.2 +/- 3.8 after 1 and 3 months of therapy, respectively, in the sofosbuvir group but had decreased to 7.6 +/- 6.2 by 3 months after cessation of therapy. Mean Schirmer test values showed a significant change in the sofosbuvir group from 17.5 +/- 2.7 mm at baseline to 10.8 +/- 1.4 and 7.0 +/- 2.5 mm after 1 and 3 months, respectively, and started returning to normal (11.0 +/- 3.3 mm) after 1 month of treatment and mean tear film breakup time varied from 11.0 +/- 5.2 seconds at baseline to 9.2 +/- 2.6 and 6.1 +/- 1.2 seconds at 1 and 3 months, respectively (P < 0.001). The mean nucleus/cytoplasm ratio was significantly different from 1/1.5 at baseline to 1/1.9 and 1/2.4 at 1 and 3 months, respectively, and persisted 3 months after discontinuation of therapy (nucleus/cytoplasm ratio 1/2.0). These changes were not the same in the non sofosbuvir group. CONCLUSIONS: Impairment of tear function and squamous metaplastic changes in the ocular surface occurred in patients with chronic hepatitis C treated with sofosbuvir combined with other antivirals. PMID- 26764885 TI - Microbial Keratitis and Endophthalmitis After the Boston Type 1 Keratoprosthesis. AB - PURPOSE: To determine the incidence, ocular surface disease associations, microbiological profile, and clinical course of postoperative infections after implantation of the Boston type 1 keratoprosthesis (KPro-1). METHODS: A retrospective chart review was conducted of all cases of the KPro-1 performed at a tertiary eye care center between January 1, 2008, and December 31, 2014. RESULTS: Seventy-five KPro-1 procedures were included in the analysis. Postoperative infections occurred in 13 eyes (17.3%) with an incidence of 0.064 cases per eye-year. The Kaplan-Meier probability of an infection-free graft was 0.96, 0.90, 0.88, 0.87, and 0.86 at years 1 through 5, respectively. The rate of infections was greater in eyes with ocular surface disease (26.3% vs. 8.1%, P = 0.06), especially in those with a history of chemical or thermal injury or herpes zoster keratopathy (P = 0.001). There were 8 cases (10.7%) of microbial keratitis due to either fungi (5 cases) or bacteria (3 cases). There were 7 cases (9.3%) of endophthalmitis due to bacteria (5 cases) or intraocular extension of fungal keratitis (2 cases). The incidence of microbial keratitis and endophthalmitis was 0.034 and 0.03 cases per eye-year, respectively. Therapeutic management of the infected eyes required graft and device removal in 7 eyes (53.8%). After completion of microbiologic treatment, 7 eyes (53.8%) had lost more than 2 lines of the best-corrected preinfection visual acuity, including 5 eyes with endophthalmitis that had hand motion vision or worse. CONCLUSIONS: Postoperative infections are a serious issue that compromises device retention and visual outcomes after keratoprosthesis implantation. PMID- 26764886 TI - In Response to "Letter to Editor: Evidence Suggesting That the Keratinized Portions of the Upper and Lower Lid Margins Do Not Make Complete Contact During Deliberate Blinking". PMID- 26764887 TI - Dermatofibrosarcoma Protuberans: The role of tissue expansion in reconstructive surgery of the scalp. AB - INTRODUCTION: Dermatofibrosarcoma Protuberans is an uncommon tumour, making up less than 0.1% of all malignancies. With regards to soft tissue tumours; this pathology is thought to make up less than 2% of the sum total. Traditionally treatment has been wide local excision, with or without adjuvant radiotherapy. PRESENTATION OF CASE: We present a case of a 42 year old man referred by his GP with a lump on the right parietal region of the scalp. An USS done by his GP revealed a complex hypoechoic cystic mass, some 2cm*1cm*2cm. Excision biopsy was performed and on review of the pathology it was noted that the lesion was a Dermatofibrosarcoma Protuberans. Due to the relatively low grade of this sarcoma, it was decided to treat with wide local excision with 2-4cm margins. The expected residual scalp defect would be difficult to close with local flaps. To facilitate closure tissue expansion was undertaken for 6 weeks prior to definitive surgery. DISCUSSION: With regards to tumours of the head and neck, use of a tissue expander has been recommended to improve cosmetic outcomes following respective surgery with wide margins. Ultimately the timing of tissue expansion i.e. before/after resection of the tumour, must weight the risk of delayed resective surgery on prognosis against the benefits of this reconstructive technique. CONCLUSION: Head and neck tumours requiring careful reconstruction may benefit from tissue expansion to provide adequate volumes of matching soft tissue, as shown in this case. PMID- 26764888 TI - Spontaneous rupture of a giant renal angiomyolipoma-Wunderlich's syndrome: Report of a case. AB - INTRODUCTION: Herein we present a rare case of pontaneous rupture of a giant renal angiomyolipoma (AML), with symptoms of hypovolemic shock (Wunderlich's syndrome), which was managed by urgent total nephrectomy. PRESENTATION OF CASE: A 53 year old female was transferred to the emergency room with progressive acute painful swelling of the left lateral abdominal area, duration of 5h. An emergent ultrasonic examination, revealed a heterogeneous-solid mass with maximum diameter of 23cm, with probable origin from the left kidney. Due to worsening of the clinical status (hypovolemic shock), loss of consciousness and acute drop of haematocrit level to 17.8%, the patient was urgently intubated in the emergency room and transferred to the operating theater. A giant haemorrhagic mass was found originating from the left kidney, which removed en-block with the left kidney. The patient was transferred to the intensive care unit. Her recovery was uneventful. The histopathologic examination revealed a giant renal angiomyolipoma (25*18*8cm) with extensive bleeding. DISCUSSION: Enlarged renal AMLs can rupture. This can be sudden and painful with manifestations of hypovolemic shock. The management of AMLs has been correlated with symptoms. Patients with life threatening retroperitoneal haemorrhage, require urgent exploration as retroperitoneal bleeding can lead to severe complications, increasing morbidity. CONCLUSION: In case of giant angiomyolipoma with intratumoral haemorrhage, and symptoms of Wunderlich's syndrome, partial or total nephrectomy is a good treatment option in order to save the patient's life. PMID- 26764889 TI - A rare cause of small bowel obstruction due to bezoar in a virgin abdomen. AB - INTRODUCTION: Bezoar is an unusual cause of small bowel obstruction accounting for 0.4-4% of all mechanical bowel obstruction. The common site of obstruction is terminal ileum. CASE REPORT: A 28-year-old male with no past surgical history, known to have severe mental retardation presented with anorexia. CT scan demonstrated dilated small bowel loops and intraluminal ileal mass with mottled appearance. At exploratory laparotomy, a bezoar was found impacted in the terminal ileum 5-6 inches away from the ileocecal valve and was removed through an enterotomy. DISCUSSION: Bezoars are concretions of fibers or foreign bodies in the alimentary tract. Small bowel obstruction is one of common clinical symptoms. The typical finding of well-defined intraluminal mass with mottled gas pattern in CT scan is suggestive of an intestinal bezoar. The treatment option of bezoar is surgery including manual fragmentation of bezoar and pushing it toward cecum, enterotomy or segmental bowel resection. Thorough exploration of abdominal cavity should be done to exclude the presence of concomitant bezoars. Recurrence is common unless underlying predisposing condition is corrected. CONCLUSIONS: Bezoar induced small bowel obstruction remains an uncommon diagnosis. It should be suspected in patients with an increased risk of bezoar formation, such as in the presence of previous gastric surgery, a history suggestive of increased fiber intake, or patient with psychiatric disorders. CT scan is helpful for preoperative diagnosis. PMID- 26764890 TI - Organized hematoma mimicking retroperitoneal cystic tumors. AB - INTRODUCTION: Isolated retroperitoneal cysts are uncommon with an estimated incidence of 1/5750-1/250,000. In women they occur about 1.5-2 times more often than in men. The largest numbers of patients are young or middle aged (20-50 years). Lack of knowledge about the causes of these rare entities and asymptomatic clinical picture often leads to diagnostic and tactical mistakes. METHODS: The medical history of 54-year old male patient B., who has been hospitalized at Surgical Department No1 of Danylo Halytsky Lviv National Medical University (Surgical Department of Lviv Regional Clinical Hospital), was processed retrospectively. RESULT: Diagnosing of retroperitoneal organized hematoma in the early stages is not always possible, because exploration of retroperitoneal space can be difficult. General tests and tumor markers are usually normal range and not prognostically informative in this case. Decisively important were imaging diagnostic methods-USG and CT. As clinical cases of organized hematoma are quite rare, finding out retroperitoneal formation with irregular contours and infiltrative component indicates for retroperitoneal tumors. Thus, this formation accumulated contrast that says for increased vascularization. Intraoperative: formation with thick walls and heterogeneous structure. Histological diagnosis: hematoma in a phase of deep organization. On our opinion, taking into account location and structure of tumors, laparoscopic intervention was not appropriate, open surgery was reasonable approach. Preoperative biopsy has a crucial role to set preliminary diagnosis. CONCLUSION: Despite the fact that organized retroperitoneal hematomas are quite rare, their diagnosis requires detailed examination and histological verification. PMID- 26764891 TI - Looking back to inform the future: Lesson learned from survivors of childhood cancer. PMID- 26764892 TI - Controlled and Extended In Vitro Release of Bioactive Anti-Vascular Endothelial Growth Factors from a Microsphere-Hydrogel Drug Delivery System. AB - PURPOSE: To demonstrate controlled and extended release of bioactive anti vascular endothelial growth factor (VEGF) agents (ranibizumab or aflibercept) from an injectable microsphere-hydrogel drug delivery system (DDS). METHODS: Anti VEGF agents were radiolabeled with iodine-125 and loaded into poly(lactic-co glycolic acid) (PLGA) 75:25 microspheres using a modified double-emulsion, solvent evaporation technique. Microspheres were then suspended in an injectable poly(N-isopropylacrylamide)-based thermo-responsive hydrogel to create a microsphere-hydrogel DDS. Release profiles were performed in phosphate buffered saline at 37 degrees C and at predetermined intervals, release samples were collected. Microspheres were also made using non-radiolabeled anti-VEGFs to determine the bioactivity of the DDS throughout release. Bioactivity and cytotoxicity of release samples were determined using human umbilical vascular endothelial cells (HUVECs) under VEGF-induced proliferation. RESULTS: The DDS is capable of releasing either ranibizumab or aflibercept for 196 days with an initial burst (first 24 h) of 22.2 +/- 2.2 and 13.1 +/- 0.5 MUg, respectively, followed by controlled release of 0.153 and 0.065 MUg/day, respectively. Release samples showed no toxicity in HUVECs at any time. Both anti-VEGFs remained bioactive throughout release with significant inhibition of HUVEC proliferation compared to the drug-free DDS, which showed no inhibitory effect on HUVEC proliferation. CONCLUSIONS: Controlled, extended, and bioactive release for approximately 200 days was achieved for both ranibizumab and aflibercept in vitro. The use of anti-VEGF-loaded microspheres suspended within an injectable, thermo-responsive hydrogel may be an advantageous ocular DDS with the potential to improve upon current therapies. PMID- 26764893 TI - Tailoring structure formation and mechanical properties of particle brush solids via homopolymer addition. AB - Recent progress in the area of surface-initiated controlled radical polymerization (SI-CRP) has enabled the synthesis of polymer-grafted colloids with precise control over the architecture of grafted chains. The resulting 'particle brush materials' are of interest both from a fundamental as well as applied perspective because structural frustrations (associated with the tethering of chains to a curved surface) imply a sensitive dependence of the interactions between brush particles on the architecture of surface-tethered chains that offers new opportunities to design hybrid materials with novel functionalities. An important prerequisite for establishing structure-property relations in particle brush materials is to understand the role of homopolymer impurities that form, for example, by thermal self-initiation. This contribution presents a detailed discussion of the role of homopolymer additives on the structure and mechanical properties of particle brush materials. The results suggest that the dissolution of homopolymer fillers follows a two-step mechanism comprised of the initial segregation of homopolymer to the interstitial regions within the array and the subsequent swelling of the particle brush (depending on the respective degree of polymerization of brush and linear chains). Addition of even small amounts of homopolymer is found to significantly increase the fracture toughness of particle brush assembly structures. The increased resistance to failure could enable the synthesis of robust colloidal crystal type materials that can be processed into complex shapes using 'classical' polymer forming techniques such as molding or extrusion. PMID- 26764894 TI - Assessing Fluid Responsiveness in Spontaneously Breathing Patients. AB - OBJECTIVES: The primary objective of this study was to test if fasting volunteers exhibit fluid responsiveness using noninvasive hemodynamic measurements. The secondary objective was to test a passive leg raise (PLR) maneuver as a diagnostic predictor of fluid responsiveness. METHODS: This was a quasi experimental design involving healthy volunteers. Subjects were excluded for pregnancy and congestive heart failure. Following a 12-hour fast, subjects had baseline hemodynamic monitoring recorded using noninvasive, continuous pulse contour analysis. Subjects then had a PLR maneuver performed, followed by an intravenous bolus of crystalloid. A rise in stroke volume >= 10% from baseline with the bolus was considered consistent with fluid responsiveness, and the same rise with a PLR was consistent with a positive PLR maneuver. The primary outcome was the change in stroke volume with a fluid bolus. Univariate analysis assessed changes in hemodynamic parameters. Logistic regression analysis determined the test characteristics of the PLR in predicting subjects who were ultimately fluid responsive. RESULTS: Forty subjects completed the study. The mean change in stroke volume with a crystalloid bolus was 19% (95% confidence interval [CI] = 16% to 21%). Thirty-six (90%) subjects were fluid responsive. The mean PLR response for the overall cohort was 16% (95% CI = 12% to 19%), and 26 (65%) subjects had a positive PLR maneuver. The PLR was 72% sensitive (95% CI = 55% to 85%) and 100% specific (95% CI = 40% to 100%) for predicting the presence of fluid responsiveness. CONCLUSIONS: Noninvasive assessment of fluid responsiveness in healthy volunteers and prediction of this response with a PLR maneuver is achievable. Further work is indicated to test these methods in acutely ill patients. PMID- 26764895 TI - Ventilator-assisted preoxygenation: Protocol for combining non-invasive ventilation and apnoeic oxygenation using a portable ventilator. AB - OBJECTIVE: To describe a simple protocol for ventilator-assisted preoxygenation (VAPOX) prior to rapid sequence intubation in the ED using a Hamilton T1 ventilator in an effort to further reduce the incidence of transient and critical hypoxaemia. METHODS: Ventilator-assisted preoxygenation includes the following steps; preparation for rapid sequence intubation as per institutional protocols, including departmental checklists. Hamilton T1 ventilator is setup in non invasive spontaneous/timed mode with settings as described. The patient is optimally positioned and nasal cannula applied with an oxygen flow rate of 15 L/min. A face mask is applied with the jaw pulled forward using a two-handed thenar eminence grip and the ventilator is started. Preoxygenation occurs for 3 min. Drugs including neuromuscular blockers are administered, while the operator ensures the airway remains patent. The ventilator transitions into Pressure Controlled Ventilation once apnoea ensues. Nasal oxygen continues until endotracheal tube is successfully secured. RESULTS: We describe a case series of the first eight consecutive adult patients on who VAPOX was applied. All eight patients were clinically deemed at high risk of oxygen desaturation. No clinically significant hypoxia occurred, and the lowest oxyhaemoglobin desaturation was 92%. CONCLUSION: Preoxygenation using a ventilator with an open valve system may allow safe combination of non-invasive ventilation, pressure controlled ventilation and apnoeic oxygenation using nasal cannula. VAPOX may be the technique of choice to preoxygenate and apnoeic oxygenate many patients who undergo rapid sequence intubation in the ED equipped with these ventilators. PMID- 26764896 TI - Early Intervention for Children with Intellectual Disabilities: An Update. AB - This article provides an update on advances in both developmental and intervention science that have occurred in the field of early intervention for children with developmental delays in the past decade. From the perspective of developmental science, findings related to multiple and reciprocal pathways of influence on the development of children with delays that can inform early intervention practice are discussed. This is followed by a review of two prominent lines of early intervention research: promoting children's developm-ent by enhancing parent-sensitive responsiveness and improving children's cognitive and social outcomes in inclusive preschool settings. Merging policy initiati-ves with our knowledge of developmental processes is discussed as the key to accelerating progress in the development of comprehensive early intervention systems. PMID- 26764897 TI - Role of an Absolutely Conserved Tryptophan Pair in the Extracellular Domain of Cys-Loop Receptors. AB - Cys-loop receptors mediate fast synaptic transmission in the nervous system, and their dysfunction is associated with a number of diseases. While some sequence variability is essential to ensure specific recognition of a chemically diverse set of ligands, other parts of the underlying amino acid sequences show a high degree of conservation, possibly to preserve the overall structural fold across the protein family. In this study, we focus on the only two absolutely conserved residues across the Cys-loop receptor family, two Trp side chains in the WXD motif of Loop D and in the WXPD motif of Loop A. Using a combination of conventional mutagenesis, unnatural amino acid incorporation, immunohistochemistry and MD simulations, we demonstrate the crucial contributions of these two Trp residues to receptor expression and function in two prototypical Cys-loop receptors, the anion-selective GlyR alpha1 and the cation-selective nAChR alpha7. Specifically, our results rule out possible electrostatic contributions of these Trp side chains and instead suggest that the overall size and shape of this aromatic pair is required in stabilizing the Cys-loop receptor extracellular domain. PMID- 26764898 TI - Ranitidine-induced anaphylaxis: clinical features, cross-reactivity, and skin testing. AB - BACKGROUND: Histamine H2 receptor antagonists are commonly prescribed medications and are known to be well tolerated. However, 99 cases of ranitidine-induced anaphylaxis occurred in Korea from 2007 to 2014. OBJECTIVE: The purpose of this study was to determine the incidence, clinical features, and diagnostic methods for ranitidine-induced anaphylaxis. METHODS: Ranitidine-related pharmacovigilance data from 2007 to 2014 were reviewed. Adverse drug reactions with causal relationships were selected, and clinical manifestations, outcomes, and drug related information were assessed. For further investigation, 8 years of pharmacovigilance data were collected at a single centre. Twenty-three patients participated in in vivo and in vitro studies. Skin tests, oral provocation tests, and laboratory tests were performed, including tests using other kinds of histamine H2 receptor antagonists. RESULTS: Over 7 years, 584 patients suffered adverse reactions to ranitidine. The most common manifestation was cutaneous symptoms. Among them, 99 patients (17.0%) experienced anaphylaxis. In a single centre study, skin prick tests were positive in 91.7% of ranitidine-induced anaphylaxis patients (11/12); the optimal concentration was 20 mg/mL. Detection of ranitidine-specific immunoglobulin E failed. Cimetidine and proton pump inhibitors showed no cross-reactivity with ranitidine based on the skin prick test, oral provocation test, or clinical determination. Surprisingly, 82.6% of patients reintroduced ranitidine and re-experienced the same adverse reactions because ranitidine was not considered the culprit drug. CONCLUSIONS AND CLINICAL RELEVANCE: Although ranitidine is known as a safe drug, it can also cause diverse adverse reactions, including anaphylaxis. This study demonstrates the need to pay attention to adverse reactions to ranitidine and consider ranitidine as a cause of anaphylaxis. PMID- 26764899 TI - Differential response in allergen-specific IgE, IgGs, and IgA levels for predicting outcome of oral immunotherapy. AB - BACKGROUND: Oral immunotherapy (OIT) induces desensitization and/or tolerance in patients with persistent food allergy, but the biomarkers of clinical outcomes remain obscure. Although OIT-induced changes in serum allergen-specific IgE and IgG4 levels have been investigated, the response of other allergen-specific IgG subclasses and IgA during OIT remains obscure. METHODS: A pilot study was conducted to investigate egg OIT-induced changes in allergen-specific IgE, IgG subclasses, and IgA levels and search for possible prediction biomarkers of desensitization. We measured serum levels of egg white-, ovomucoid-, and ovalbumin-specific IgE, IgA, and IgG subclasses by high-sensitivity allergen microarray in 26 children with egg allergy who received rush OIT. RESULTS: Allergen-specific IgE gradually decreased while IgG4 increased during 12-month OIT. Serum levels of IgG1, IgG3, and IgA increased significantly after the rush phase, then decreased during the maintenance phase. IgG2 levels changed in a manner similar to that of IgG4. In particular, significantly high fold increases in egg white-specific IgG1, relative to baseline, after the rush phase and high IgA levels before OIT were observed in responders, compared with low-responders to OIT. Patients who could not keep desensitization showed relatively small changes in all immunoglobulin levels during OIT. CONCLUSION: The response to OIT was associated with significant increases in serum allergen-specific IgG1 levels after rush phase and high baseline IgA levels, compared with small changes in immunoglobulin response in low-responders. The characteristic IgG1 changes and IgA levels in the responders could be potentially useful biomarkers for the prediction of positive clinical response to OIT. PMID- 26764900 TI - Ultrasound morphological changes in the carotid wall of Takayasu's arteritis: monitor of disease progression. AB - BACKGROUND: The aims of this study were to examine ultrasound morphological changes in the carotid wall in cases of Takayasu's arteritis and to thereby determine the value of ultrasound for assessments of Takayasu's arteritis disease activity and follow-up studies. METHODS: We used high-frequency ultrasound to analyze morphological changes in 51 Takayasu's arteritis patients and compared the findings with clinical and laboratory parameters. A follow-up study of 20 patients was performed. RESULTS: Five types of ultrasonographic images were observed in the carotid walls of Takayasu's arteritis patients. Type III and type IV images were observed in younger patients; smaller wall thicknesses and less luminal stenosis were observed in these images. Type II and type IV images were more frequently obtained in cases involving active patients, whereas type I and type III images were more often acquired in cases involving inactive patients with significantly lower Indian Takayasu clinical activity scores. During follow up, the wall thickness and outer diameter of the carotid increased in patients who relapsed and decreased in patients who remained in remission. CONCLUSIONS: The five types of carotid ultrasound images reveal Takayasu's arteritis-related morphological changes in the vessel wall, which reflect anatomical changes. Carotid ultrasound should play a central role in monitoring the progression of Takayasu's arteritis. PMID- 26764901 TI - Effects of prepartum oilseed supplements on subclinical endometritis, pro- and anti-inflammatory cytokine transcripts in endometrial cells and postpartum ovarian function in dairy cows. AB - Postpartum uterine infections affect ovarian function and delay ovulation in cattle. As dietary fats can affect immune cell function, we investigated the influence of prepartum diets on postpartum uterine inflammatory status (UIS) as assessed 25+/-1 days postpartum by endometrial cytology (normal: <=8% polymorphonuclear cells (PMN) vs subclinical endometritis (SCE): >8% PMN) and associations between SCE, pro- and anti-inflammatory cytokine gene expression and ovarian function. During the last 5 weeks of gestation, dairy cows received a diet supplemented with 8% rolled sunflower (n=10) or canola seed (n=9) or no oilseed (n=9). Ovaries were scanned until 35 days postpartum. Prepartum diets did not influence SCE, but a preovulatory-size follicle developed sooner (P<=0.05), the interval to first ovulation was shorter and the proportion of cows ovulating within 35 days postpartum was greater in the sunflower seed group. Although mRNA expression of cytokines was not affected by diet, cows with SCE had higher (P<=0.05) expression of interleukin-1beta (IL1B), interleukin-8 (CXCL8), IL10 and tumour necrosis factor-alpha (TNF) than normal cows. The interval (mean +/- s.e.m.) from calving to preovulatory-size follicle was shorter (P<=0.05) in normal (13.2+/-0.9 days) than SCE cows (18.7+/-1.4 days). In summary, a prepartum diet supplemented with sunflower seed positively influenced postpartum ovarian function without affecting UIS or pro- and anti-inflammatory cytokine gene expression in endometrial cells. PMID- 26764903 TI - [Study Quality and its Influence on Treatment Outcome in Studies on the Effectiveness of Inpatient Psychotherapy - A Meta-Analysis]. AB - INTRODUCTION: It is widely accepted that the quality of a study may affect its results. A possible influence of the studies' quality on the heterogeneity of the treatment effects will therefore be examined on the basis of studies being included in a recent meta-analysis on inpatient psychotherapy in German speaking countries. MATERIAL AND METHODS: The quality of the 103 included studies was assessed by means of 19 criteria addressing general study quality as well as internal and external validity. We examined the relation between study quality and treatment outcome (quantified by effect size Hedges' g either for the Global Severity Index of the Symptom Checklist (SCL GSI) or for an overall outcome calculated across various measures) with univariate correlation analyses as well as metaregression. RESULTS: Study quality varies considerably between the included studies but also between the different quality criteria. On average, the included studies show a medium quality. Most quality criteria do not correlate significantly with the treatment effects. Studies of higher quality tend to show higher treatment effects. DISCUSSION: The operationalization of single quality items is still worthy of discussion since some criteria are hardly ever while others are always fulfilled. The study quality does not appear to be a homogenous concept, but there are positive as well as negative correlations between single criteria and treatment outcome. Accordingly, the calculation of a total quality score does not seem feasible. CONCLUSION: Regarding the present meta-analysis on the effectiveness of psychotherapeutic hospital treatment, a systematic overestimation due to the inclusion of some studies with lower quality is not to be assumed. PMID- 26764904 TI - [The Phase Model of Psychotherapeutic Outcome: Validation of the "Questionnaire for the Evaluation of Psychotherapeutic Change Processes" (FEP)]. AB - Sufficiently theoretically founded and validated measures in German language to assess psychotherapeutic change are rare. The German Questionnaire for the Evaluation of Psychotherapeutic Change Processes (FEP) was designed on the basis of the Phase model of psychotherapeutic outcome. In the present study, the psychometric properties of the FEP and especially its factorial structure are validated. Psychometric values were calculated and confirmatory factor analyses were performed (outpatient sample, N=427). Itemindices, reliability - with exception of retest-reliability - and validity reached overall good to very good values. The best model-fit indices were obtained for the 3-factor-structure corresponding to the FEP-subscales Well-being, Symptoms and Interpersonal relations which represent the dimensions postulated by the Phase model. The FEP proved to be a psychometrically well-founded transdiagnostic measure of outcome and change which represents multidimensional phases of change. Its application in outcome monitoring is recommended. PMID- 26764902 TI - [What do Patients Experience between Group Sessions during Inpatient Psychotherapy? An Application of the Inter-Session-Questionnaire in Psychotherapeutic Hospitals]. AB - The study describes an application of the Inter-Session-Questionnaire (ISF) related to inpatient group psychotherapy. The instrument should be tested with the extension of differentiating intersession experiences related to the person of the therapist as well as the group. In a cross sectional study performed in 13 different hospitals, 702 patients were assessed. These patients were treated in rehab hospitals, acute hospitals as well as special hospitals providing treatment for eating disorders. The sample should be relatively representative for psychosomatic and psychotherapeutic hospitals in Germany. Besides the type of the hospital, we also analysed the influence of group characteristics (size of group, type of group and number of completed sessions) as well as the patients' sex. Surprisingly, there were almost no marked differences of inter-session experiences related to the the therapist or the group. The profiles of the item judgements of the ISF were similar to those reported for outpatient and day treatment samples. Inter-session-experiences differed in part according to our expectation depending on the variables mentioned above which suggests to use the ISF in specific studies dealing with the process and outcome of inpatient group psychotherapy as well as the differentiation of relevant subgroups. PMID- 26764905 TI - Optimal Population-Level Infection Detection Strategies for Malaria Control and Elimination in a Spatial Model of Malaria Transmission. AB - Mass campaigns with antimalarial drugs are potentially a powerful tool for local elimination of malaria, yet current diagnostic technologies are insufficiently sensitive to identify all individuals who harbor infections. At the same time, overtreatment of uninfected individuals increases the risk of accelerating emergence of drug resistance and losing community acceptance. Local heterogeneity in transmission intensity may allow campaign strategies that respond to index cases to successfully target subpatent infections while simultaneously limiting overtreatment. While selective targeting of hotspots of transmission has been proposed as a strategy for malaria control, such targeting has not been tested in the context of malaria elimination. Using household locations, demographics, and prevalence data from a survey of four health facility catchment areas in southern Zambia and an agent-based model of malaria transmission and immunity acquisition, a transmission intensity was fit to each household based on neighborhood age dependent malaria prevalence. A set of individual infection trajectories was constructed for every household in each catchment area, accounting for heterogeneous exposure and immunity. Various campaign strategies-mass drug administration, mass screen and treat, focal mass drug administration, snowball reactive case detection, pooled sampling, and a hypothetical serological diagnostic-were simulated and evaluated for performance at finding infections, minimizing overtreatment, reducing clinical case counts, and interrupting transmission. For malaria control, presumptive treatment leads to substantial overtreatment without additional morbidity reduction under all but the highest transmission conditions. Compared with untargeted approaches, selective targeting of hotspots with drug campaigns is an ineffective tool for elimination due to limited sensitivity of available field diagnostics. Serological diagnosis is potentially an effective tool for malaria elimination but requires higher coverage to achieve similar results to mass distribution of presumptive treatment. PMID- 26764906 TI - Dominant Expression of DCLK1 in Human Pancreatic Cancer Stem Cells Accelerates Tumor Invasion and Metastasis. AB - Patients with pancreatic cancer typically develop tumor invasion and metastasis in the early stage. These malignant behaviors might be originated from cancer stem cells (CSCs), but the responsible target is less known about invisible CSCs especially for invasion and metastasis. We previously examined the proteasome activity of CSCs and constructed a real-time visualization system for human pancreatic CSCs. In the present study, we found that CSCs were highly metastatic and dominantly localized at the invading tumor margins in a liver metastasis model. Microarray and siRNA screening assays showed that doublecortin-like kinase 1 (DCLK1) was predominantly expressed with histone modification in pancreatic CSCs with invasive and metastatic potential. Overexpression of DCLK1 led to amoeboid morphology, which promotes the migration of pancreatic cancer cells. Knockdown of DCLK1 profoundly suppressed in vivo liver metastasis of pancreatic CSCs. Clinically, DCLK1 was overexpressed in the metastatic tumors in patients with pancreatic cancer. Our studies revealed that DCLK1 is essential for the invasive and metastatic properties of CSCs and may be a promising epigenetic and therapeutic target in human pancreatic cancer. PMID- 26764907 TI - In Vitro Cultivation of 'Unculturable' Oral Bacteria, Facilitated by Community Culture and Media Supplementation with Siderophores. AB - Over a third of oral bacteria are as-yet-uncultivated in-vitro. Siderophores have been previously shown to enable in-vitro growth of previously uncultivated bacteria. The objective of this study was to cultivate novel oral bacteria in siderophore-supplemented culture media. Various compounds with siderophore activity, including pyoverdines-Fe-complex, desferricoprogen and salicylic acid, were found to stimulate the growth of difficult-to-culture strains Prevotella sp. HOT-376 and Fretibacterium fastidiosum. Furthermore, pyrosequencing analysis demonstrated increased proportions of the as-yet-uncultivated phylotypes Dialister sp. HOT-119 and Megasphaera sp. HOT-123 on mixed culture plates supplemented with siderophores. Therefore a culture model was developed, which incorporated 15 MUg siderophore (pyoverdines-Fe-complex or desferricoprogen) or 150 MUl neat subgingival-plaque suspension into a central well on agar plates that were inoculated with heavily-diluted subgingival-plaque samples from subjects with periodontitis. Colonies showing satellitism were passaged onto fresh plates in co-culture with selected helper strains. Five novel strains, representatives of three previously-uncultivated taxa (Anaerolineae bacterium HOT 439, the first oral taxon from the Chloroflexi phylum to have been cultivated; Bacteroidetes bacterium HOT-365; and Peptostreptococcaceae bacterium HOT-091) were successfully isolated. All novel isolates required helper strains for growth, implying dependence on a biofilm lifestyle. Their characterisation will further our understanding of the human oral microbiome. PMID- 26764908 TI - Polymer Coated Urea in Turfgrass Maintains Vigor and Mitigates Nitrogen's Environmental Impacts. AB - Polymer coated urea (PCU) is a N fertilizer which, when added to moist soil, uses temperature-controlled diffusion to regulate N release in matching plant demand and mitigate environmental losses. Uncoated urea and PCU were compared for their effects on gaseous (N2O and NH3) and aqueous (NO3(-)) N environmental losses in cool season turfgrass over the entire PCU N-release period. Field studies were conducted on established turfgrass sites with mixtures of Kentucky bluegrass (Poa pratensis L.) and perennial ryegrass (Lolium perenne L.) in sand and loam soils. Each study compared 0 kg N ha(-1) (control) to 200 kg N ha(-1) applied as either urea or PCU (Duration 45CR(r)). Application of urea resulted in 127-476% more evolution of measured N2O into the atmosphere, whereas PCU was similar to background emission levels from the control. Compared to urea, PCU reduced NH3 emissions by 41-49% and N2O emissions by 45-73%, while improving growth and verdure compared to the control. Differences in leachate NO3(-) among urea, PCU and control were inconclusive. This improvement in N management to ameliorate atmospheric losses of N using PCU will contribute to conserving natural resources and mitigating environmental impacts of N fertilization in turfgrass. PMID- 26764910 TI - Correction: General Validity of Levelt's Propositions Reveals Common Computational Mechanisms for Visual Rivalry. PMID- 26764909 TI - Broad Range of Hepatitis B Virus (HBV) Patterns, Dual Circulation of Quasi Subgenotype A3 and HBV/E and Heterogeneous HBV Mutations in HIV-Positive Patients in Gabon. AB - Integrated data on hepatitis B virus (HBV) patterns, HBV genotypes and mutations are lacking in human immunodeficiency virus type 1 (HIV-1) co-infected patients from Africa. This survey was conducted in 2010-2013 among 762 HIV-1-positive adults from Gabon who were predominantly treated with 3TC-based antiretroviral treatment. HBV patterns were identified using immunoassays detecting total antibody to hepatitis B core antigen (HBcAb), hepatitis B surface antigen (HBsAg), IgM HBcAb, hepatitis B e antigen (HBeAg), antibody to HBsAg (HBsAb) and an in-house real-time PCR test for HBV DNA quantification. Occult hepatitis B (OBI) was defined by the presence of isolated anti-HBc with detectable serum HBV DNA. HBV genotypes and HBV mutations were analyzed by PCR-direct sequencing method. Seventy-one (9.3%) patients tested positive for HBsAg, including one with acute hepatitis B (0.1%; 95% CI, 0.0%-0.2%), nine with HBeAg-positive chronic hepatitis B (CHB) (1.2%; 95% CI, 0.6%-2.2%), 16 with HBeAg-negative CHB (2.1%; 95% CI, 1.2%-3.3%) and 45 inactive HBV carriers (5.9%; 95% CI, 4.4%-7.8%). Sixty one (8.0%; 95% CI, 6.2%-10.1%) patients showed OBI. Treated patients showed similar HBV DNA levels to those obtained in untreated patients, regardless of HBV patterns. Around 15.0% of OBI patients showed high (>1,000 UI/mL) viremia. The mutation M204V/I conferring resistance to 3TC was more common in HBV/A (47.4%) than in HBV/E isolates (0%) (P = .04). Our findings encouraged clinicians to promote HBV vaccination in patients with no exposure to HBV and to switch 3TC to universal TDF in those with CHB. PMID- 26764911 TI - Heterogeneous Ensemble Combination Search Using Genetic Algorithm for Class Imbalanced Data Classification. AB - Classification of datasets with imbalanced sample distributions has always been a challenge. In general, a popular approach for enhancing classification performance is the construction of an ensemble of classifiers. However, the performance of an ensemble is dependent on the choice of constituent base classifiers. Therefore, we propose a genetic algorithm-based search method for finding the optimum combination from a pool of base classifiers to form a heterogeneous ensemble. The algorithm, called GA-EoC, utilises 10 fold-cross validation on training data for evaluating the quality of each candidate ensembles. In order to combine the base classifiers decision into ensemble's output, we used the simple and widely used majority voting approach. The proposed algorithm, along with the random sub-sampling approach to balance the class distribution, has been used for classifying class-imbalanced datasets. Additionally, if a feature set was not available, we used the (alpha, beta) - k Feature Set method to select a better subset of features for classification. We have tested GA-EoC with three benchmarking datasets from the UCI-Machine Learning repository, one Alzheimer's disease dataset and a subset of the PubFig database of Columbia University. In general, the performance of the proposed method on the chosen datasets is robust and better than that of the constituent base classifiers and many other well-known ensembles. Based on our empirical study we claim that a genetic algorithm is a superior and reliable approach to heterogeneous ensemble construction and we expect that the proposed GA-EoC would perform consistently in other cases. PMID- 26764913 TI - Various Effects of Sandblasting of Dental Restorative Materials. AB - BACKGROUND: Sandblasting particles which remain on the surfaces of dental restorations are removed prior to cementation. It is probable that adhesive strength between luting material and sandblasting particle remnants might exceed that with restorative material. If that being the case, blasting particles adhere to sandblasted material surface could be instrumental to increasing adhesive strength like underlying bonding mechanism between luting material and silanized particles of tribochemical silica coating-treated surface. We hypothesize that ultrasonic cleaning of bonding surfaces, which were pretreated with sandblasting, may affect adhesive strength of a resin luting material to dental restorative materials. METHODS: We therefore observed adhesive strength of resin luting material to aluminum oxide was greater than those to zirconia ceramic and cobalt chromium alloy beforehand. To measure the shear bond strengths of resin luting material to zirconia ceramic and cobalt-chromium alloy, forty specimens of each restorative material were prepared. Bonding surfaces were polished with silicon abrasive paper and then treated with sandblasting. For each restorative material, 40 sandblasted specimens were equally divided into two groups: ultrasonic cleaning (USC) group and non-ultrasonic cleaning (NUSC) group. After resin luting material was polymerized on bonding surface, shear test was performed to evaluate effect of ultrasonic cleaning of bonding surfaces pretreated with sandblasting on bond strength. RESULTS: For both zirconia ceramic and cobalt-chromium alloy, NUSC group showed significantly higher shear bond strength than USC group. CONCLUSIONS: Ultrasonic cleaning of dental restorations after sandblasting should be avoided to retain improved bonding between these materials. PMID- 26764912 TI - Medically Relevant Acinetobacter Species Require a Type II Secretion System and Specific Membrane-Associated Chaperones for the Export of Multiple Substrates and Full Virulence. AB - Acinetobacter baumannii, A. nosocomialis, and A. pittii have recently emerged as opportunistic human pathogens capable of causing severe human disease; however, the molecular mechanisms employed by Acinetobacter to cause disease remain poorly understood. Many pathogenic members of the genus Acinetobacter contain genes predicted to encode proteins required for the biogenesis of a type II secretion system (T2SS), which have been shown to mediate virulence in many Gram-negative organisms. Here we demonstrate that Acinetobacter nosocomialis strain M2 produces a functional T2SS, which is required for full virulence in both the Galleria mellonella and murine pulmonary infection models. Importantly, this is the first bona fide secretion system shown to be required for virulence in Acinetobacter. Using bioinformatics, proteomics, and mutational analyses, we show that Acinetobacter employs its T2SS to export multiple substrates, including the lipases LipA and LipH as well as the protease CpaA. Furthermore, the Acinetobacter T2SS, which is found scattered amongst five distinct loci, does not contain a dedicated pseudopilin peptidase, but instead relies on the type IV prepilin peptidase, reinforcing the common ancestry of these two systems. Lastly, two of the three secreted proteins characterized in this study require specific chaperones for secretion. These chaperones contain an N-terminal transmembrane domain, are encoded adjacently to their cognate effector, and their disruption abolishes type II secretion of their cognate effector. Bioinformatic analysis identified putative chaperones located adjacent to multiple previously known type II effectors from several Gram-negative bacteria, which suggests that T2SS chaperones constitute a separate class of membrane-associated chaperones mediating type II secretion. PMID- 26764940 TI - A high or a reasonably-reactively elevated platelet-to-lymphocyte ratio, which plays the role? PMID- 26764914 TI - Profile of mood states and quality of life of Chinese postmastectomy women in Hong Kong: Integrating variable- and person-centered approaches. AB - Understanding the mood state and its relationship with quality of life (QOL) of mastectomy recipients can serve as baseline within which a sound rehabilitation program can be developed. This study therefore was conducted to facilitate a better understanding of participants' postmastectomy mood states, identify their potential predictors, identify clusters of mood profiles, and clarify between cluster differences in terms of QOL. Hong Kong mastectomy patients completed the Profile of Mood States and Ferrans and Powers Quality of Life Index. We extended the complementary strengths of the application of both variable- and person centered approaches to clarify relationships and to identify profiles of mood states in relation to QOL in a sample of 200 women who had undergone a mastectomy in Hong Kong. Simultaneous regression identified age and educational attainment as predictors of mood states, and cluster analysis identified three distinct mood profiles that are able to explain differences in various measures of QOL after mastectomy. Implications for future research and practice are discussed. PMID- 26764941 TI - High Resolution Chest Computerized Tomography in the Diagnosis of Ocular Sarcoidosis in a High TB Endemic Population. AB - PURPOSE: To review the role of high resolution chest computed tomography (HRCT) in ocular sarcoidosis in a high TB endemic population. METHODS: This was a retrospective study. RESULTS: Out of 140 cases, 54 had ocular sarcoidosis, while 86 cases had ocular tuberculosis. Abnormal HRCT findings was noted in 52 cases (96.3%) of ocular sarcoidosis compared with 55 cases (64.7%) of ocular tuberculosis (p = 0.001). Mediastinal lymphadenopathy was the most common finding in both groups (p = 0.544). Hilar lymphadenopathy and fissural nodules were significantly seen in ocular sarcoidosis (p = 0.001). Necrosis was seen in three cases of ocular sarcoidosis. In nearly half of the cases, it was not possible to differentiate between sarcoidosis and tuberculosis on HRCT. CONCLUSIONS: HRCT is a useful diagnostic tool in ocular sarcoidosis. Bilateral hilar lymphadenopathy and fissural nodules are significant findings in ocular sarcoidosis. A confident diagnosis of ocular sarcoidosis is made by the amalgamation of results of clinical, radiologic, and other laboratory investigations. PMID- 26764942 TI - How Do People Think About Intelligence? AB - Two studies are reported concerning implicit theories of intelligence. The first study replicated procedures employed by Sternberg, Conway, Ketron, and Bernstein (1981). Factor analysis of importance ratings of intelligent and unintelligent behaviors suggested a simpler model of implicit theories than suggested by Sternberg et al. However, the use of importance ratings for examining implicit theories was challenged because the results proved ambiguous. The second study used a sorting procedure to produce similarity data. Multidimensional and tree scaling solutions indicated that the primary distinction in implicit theories was between intelligent and unintelligent behaviors and that important distinctions were not made among intelligent behaviors. In general, the data suggested that implicit theories of intelligence are much simpler than most formal theories used in psychology. PMID- 26764943 TI - Eyseneck Personality Inventory Item Factor Structure. AB - The Eysenck Personality Inventory (EPI) was administered to a sample of 583 Australians. Responses to the 57 items were intercorrelated and factor analyzed by three different methods: (a) extract two principal factors and rotate them by varimax; (b) extract as many factors as possible by the minimum residual method, determine the correct number of factors using the Tandem Criteria method and then rotate that number of factors by the Tandem Criterion I method; (c) using ones in the diagonals, extract all factors with positive eigen values and rotate these factors by varimax. All three methods obtained major Neuroticism and Extraversion factors but the third method gave the poorest confirmation of the expected factor structure for these items. Of the remaining two methods, the second is preferred for testing the expected underlying factor structure for these items since it permits items to remain on the same factor only if they are correlated with each other and it reveals what other constructs may be required in addition to those hypothesized to account for all the common factor variance. PMID- 26764944 TI - Limited Information Parameter Estimates for Latent or Mixed Manifest and Latent Variable Models. AB - We argue for separate analyses of the measurement and structural portions of latent or mixed manifest and latent variable models. We present limited information (single equation) procedures for estimating parameters in the structural portion of these models. These include parameter estimation procedures for recursive or nonrecursive relations, and procedures for testing zero-effect hypotheses. We then compare full and limited information estimates in a Monte Carlo analysis of sample correlation matrices that contained structural model misspecifications. Both full and limited information estimates identified misspecified nonzero effects reasonably well. However, limited information estimates were far superior in detecting misspecified zero-effect hypotheses. We recommend limited information parameter estimation procedures over full information techniques for (a) testing specific causal hypotheses and (b) locating specific structural model misspecifications. PMID- 26764945 TI - Evaluating Outlier Identification Tests: Mahalanobis D Squared and Comrey Dk. AB - Comrey (1985) presented a statistic, Dk, to detect outliers. Its purported advantage over the more well-known Mahalanobis D squared is that it might be more sensitive to outliers that distort the correlation coefficient. The present study used a Monte Carlo simulation to compare Dk and D squared in terms of their hit and false alarm rates, their extent of overlap, and their effect on correlation coefficients resulting from outlier removal. The results indicated that D squared had a higher hit rate than Dk with approximately the same false alarm rate. The statistics identified the same cases as outliers 19 to 55 percent of the time. Surprising, the average correlations that resulted from outlier removal by D squared were closer to the population correlations than were those resulting from outlier removal by Dk. Under the conditions investigated, D squared was preferable to Dk as an outlier removal statistic. PMID- 26764946 TI - Clustering Seven Data Sets by Means of Some or All of Seven Clustering Methods. AB - Seven data sets, one artificially contrived, the others real data from different areas of psychology and sociology but mainly concerned with children, were subjected to clustering by seven different algorithms. These methods are for the most part rather well known: Holzinger and Harman's (1941) B-coefficient, Overall and Klett's (1972) Linear Typal Analysis, McQuitty and Koch's (1974a, b) elementary linkage analysis, Rohlf and his colleagues' (Rohlf, Kishpaugh, & Kirk, 1971) Numerical Taxonomy System, the Statistical Analysis System (SAS Institute, 1982) hierarchical clustering (Cluster) method, Cattell and Coulter's (1966) Taxonome, and one not very well known, Bolz's (1978) Type Analysis. Insofar as possible, all methods were run on all sets of data on the computer with appropriate adjustments to the respective programs. With the B-coefficient both hand and machine calculations were carried out. Statistical and logical comparisons were made among the different methods used on the data sets. All methods had their strengths and weaknesses, some being more adequate with some data sets and others with others. Surprisingly, the B-coefficient, at least with smaller sets compared favorably with other methods, even though it is scarcely known to modern clustering literature. PMID- 26764947 TI - Omega: A General Formulation of the Rand Index of Cluster Recovery Suitable for Non-disjoint Solutions. AB - Cluster recovery indices are more important than ever, because of the necessity for comparing the large number of clustering procedures available today. Of the cluster recovery indices prominent in contemporary literature, the Hubert and Arabie (1985) adjustment to the Rand index (1971) has been demonstrated to have the most desirable properties (Milligan & Cooper, 1986). However, use of the Hubert and Arabie adjustment to the Rand index is limited to cluster solutions involving non-overlapping, or disjoint, clusters. The present paper introduces a generalization of the Hubert and Arabie adjusted Rand index. This generalization, called the Omega index, can be applied to situations where both, one, or neither of the solutions being compared is non-disjoint. In the special case where both solutions are disjoint, the Omega index is equivalent to the Hubert and Arabie adjusted Rand index. PMID- 26764949 TI - COSAN: Convariance Structure Analysis. PMID- 26764948 TI - Categorical Variables in Multiple Regression: Some Cautions. AB - Various methods of coding categorical variables for use as predictors in multiple regression analyses have been presented in the literature. The limitations of two oft-discussed methods -- dummy coding and nonsense coding -- are detailed for several frequently-used regression designs. Two examples involving potentially inappropriate interpretations of the results of analyses involving dummy coding are presented. Researchers are cautioned that the parameter estimate or estimates and test of significance associated with a predictor variable or set of predictor variables in an equation which involves dummy- and/or nonsense-coded predictors represent an effect of interest only in a limited set of circumstances. PMID- 26764950 TI - NOHARM: Least Squares Item Factor Analysis. PMID- 26764952 TI - MISS: Analysis of Incomplete Data. PMID- 26764953 TI - SETCORAN: Multivariate Set Correlation. PMID- 26764951 TI - LINCS: Linear Convariance Structure Analysis. PMID- 26764954 TI - TETRAD: Discovering Causal Structure. PMID- 26764955 TI - Aspects of Person-Machine Communication in Structural Modeling of Correlations and Covariances. AB - Analysis of covariance or correlation structure is characterized, unfortunately, by repetitive suboptimal communication between persons and/or computer programs. After analyzing some aspects of this suboptimality, I suggest some approaches to improving the situation. PMID- 26764956 TI - The onset of lipid peroxidation in rheumatoid arthritis: consequences and monitoring. AB - Several epidemiological studies propose the association of rheumatoid arthritis (RA) with oxidative stress. The aim of this study was to estimate the possible onset of systemic lipid peroxidation in RA patients and its relevance for pathophysiology and monitoring of RA. Seventy-three patients with RA and 73 healthy subjects were included in the study. Lipid peroxidation was estimated by the measurement of 4-hydroxynonenal (4-HNE), 4-hydroxyhexenal, malondialdehyde, acrolein, crotonaldehyde, 4-oxononenal, and isoprostanes (8-isoPGF(2alpha)) levels. Cytosolic phospholipase A(2) (cPLA(2)), platelet-activating factor acetylhydrolase (PAF-AH) and glutathione peroxidase (GSH-Px) activities and vitamin E levels were also determined. In parallel, the plasma levels of phospholipid arachidonic acid (AA), linoleic acid (LA), and 4-HNE-protein adducts were monitored. Plasma of RA patients had increased vitamin E levels, but decreased GSH-Px activity and phospholipid AA and LA levels when compared to levels of the healthy subjects. The levels of aldehydes were significantly increased in the plasma of the RA patients and even more in urine. Significant increases in HNE-modified protein adducts was observed for the first time in plasma of RA patients, while the activities of PAF-AH and cPLA(2) were decreased. The 8-isoPGF(2alpha) levels were 9-fold higher in plasma and 3-fold higher in urine of RA patients and were related to the severity of disease. The levels of lipid peroxidation products in plasma and in urine suggest the relationship between lipid peroxidation and the development of RA. Additionally, urine 8 isoPGF(2alpha), plasma 4-HNE and 4-HNE-protein adducts appear to be convenient biomarkers to monitor progression of this autoimmune disease. PMID- 26764957 TI - Environmental sustainability in European public healthcare. AB - Purpose - The purpose of this paper is to enlarge the debate concerning the influence of leadership on environmental sustainability implementation in European public healthcare organisations. Design/methodology/approach - This paper is a viewpoint. It is based on preliminary analysis of European standards dedicated to environmental sustainability and their spread across Europe in public healthcare organisations. Viewpoints concerning leadership are then discussed and asserted. Findings - This paper found a limited implementation of standards such as Green Public Procurement criteria, Eco-Management and Audit Scheme and ISO 14001 in public healthcare. Some clues indicate that the lack of implementation is related to leadership and management commitment. Originality/value - For the first time, this paper investigates relationships between leadership and environmental sustainability in European public healthcare opening further avenues of research on the subject. PMID- 26764958 TI - LEAN thinking in Finnish healthcare. AB - Purpose - The purpose of this study is to evaluate how LEAN thinking is used as a management and development tool in the Finnish public healthcare system and what kind of outcomes have been achieved or expected by using it. The main focus is in managing and developing patient and treatment processes. Design/methodology/approach - A mixed-method approach incorporating the Webropol survey was used. Findings - LEAN is quite a new concept in Finnish public healthcare. It is mainly used as a development tool to seek financial savings and to improve the efficiency of patient processes, but has not yet been deeply implemented. However, the experiences from LEAN initiatives have been positive, and the methodology is already quite well-known. It can be concluded that, because of positive experiences from LEAN, the environment in Finnish healthcare is ready for the deeper implementation of LEAN. Originality/value - This paper evaluates the usage of LEAN thinking for the first time in the public healthcare system of Finland as a development tool and a management system. It highlights the implementation and achieved results of LEAN thinking when used in the healthcare environment. It also highlights the expectations for LEAN thinking in Finnish public healthcare. PMID- 26764959 TI - Exploring senior nurses' experiences of leading organizational change. AB - Purpose - The aim of this paper is to explore Senior nurses' experiences of leading organizational change. There is a substantial literature reporting middle level nurse managers' experiences of change; however, there is less evidence concerning senior nurses' perspectives. In view of this, interview data collected from senior nurses, as part of a study of major organizational change, were analysed to redress this imbalance. Design/methodology/approach - In-depth semi structured interviews (n = 14) were conducted with senior nurses (between 2009 and 2012). Findings - Senior nurses' activity centred on leadership and workforce issues, internal influences and external pressures. In periods of change, appropriate leadership was vital, and "weak" leaders were considered to have an adverse effect on teams. Concerns were expressed about financial strictures and their impact on patient care and service provision. The senior nurses were striving to provide the best quality of service delivery with the limited resources available. Concentration on operational matters was necessary to maintain stability in periods of change. However, this prevented senior nurses from influencing strategic decision-making in their organizations. Practical implications - If senior nurses are to realise their potential to operate at a strategic level, they need to be given time and support to lead, rather than just react to change. This research emphasises the importance of a "nursing voice" to inform board-level decisions and maintain a focus on patient care. Originality/value - This research sheds light on the work of a key group of staff in health-care organizations. Understanding senior nurses' experience of and contribution to change is a useful contribution to health services research. PMID- 26764960 TI - Performance management in healthcare: a critical analysis. AB - Purpose - The purpose of this paper is to explore the underlying theoretical assumptions and implications of current micro-level performance management and evaluation (PME) practices, specifically within health-care organizations. PME encompasses all activities that are designed and conducted to align employee outputs with organizational goals. Design/methodology/approach - PME, in the context of healthcare, is analyzed through the lens of critical theory. Specifically, Habermas' theory of communicative action is used to highlight some of the questions that arise in looking critically at PME. To provide a richer definition of key theoretical concepts, the authors conducted a preliminary, exploratory hermeneutic semantic analysis of the key words "performance" and "management" and of the term "performance management". Findings - Analysis reveals that existing micro-level PME systems in health-care organizations have the potential to create a workforce that is compliant, dependent, technically oriented and passive, and to support health-care systems in which inequalities and power imbalances are perpetually reinforced. Practical implications - At a time when the health-care system is under increasing pressure to provide high quality, affordable services with fewer resources, it may be wise to investigate new sector-specific ways of evaluating and managing performance. Originality/value - In this paper, written for health-care leaders and health human resource specialists, the theoretical assumptions and implications of current PME practices within health-care organizations are explored. It is hoped that readers will be inspired to support innovative PME practices within their organizations that encourage peak performance among health-care professionals. PMID- 26764961 TI - Measuring communication competence and effectiveness of ASHAs (accredited social health activist) in their leadership role at rural settings of Uttar Pradesh (India). AB - Purpose - This paper aims to find out accredited social health activists' (ASHA) communication competence and effectiveness while working as leaders with groups in the rural setting. ASHA, as the "first point of contact" for pregnant women in rural areas, plays a significant role in building awareness and disseminating key information at critical times (e.g. antenatal and post-natal period), promotes healthy maternal and newborn care practices and facilitates identification and referral of maternal and newborn complications. ASHA plays critical role of a leader in bridging the gap between health system and community. In the entire process, effective communication competency is the key to her effectiveness. Design/methodology/approach - The study adopts seven items from the farmers communication (FACOM) scale of communication measures developed by Udai Pareek and Y.P Singh. Preliminary editing of the items was done keeping certain points in mind such as the items should not be judgemental, should be acts of behaviour, should be observable and should be simple. This scale was adopted for the study, as it was designed to measure farmers' communication competence and suited the context. The evaluation criteria included the seven essential elements of communication identified in the FACOM scale. Findings - Results from the study identified a need to sensitise ASHAs on the critical role of effective communication and need for investing more in building her capacity for health communication. The trainings being imparted to ASHAs have to be strengthened in terms of communication skills. They should focus upon developing all three variables of communication skills equally and integrating them to get desired results. Research limitations/implications - The study was conducted in one state while the programme is running across the country. The sample size was small. Practical implications - The learning of the study will help in developing a better understanding of the beneficiaries' perspectives and their expectations regarding ASHAs communication process in the leadership role which she performs. Such understanding will not only be instructive but may also prove transformative for the benefit of both ASHAs and her community, whose support is critical to the success of the programme. This learning will feed into the policy planning and communication and capacity building strategy of the ASHA programme and may lead to better and more effective strategies and tools of communication. Originality/value - Research study is original. Keeping the observers' status in mind, questionnaire was translated in Hindi language. Twenty ASHAs were selected randomly from small villages of Uttar Pradesh, the largest state in India. The scale was presented to at least five observers (all females) for one ASHA. These observers/judges were the ones who knew ASHA well and with whom she had communicated at some point of time as part of her work. PMID- 26764962 TI - Organizing principles and management climate in high-performing municipal elderly care. AB - Purpose - Previous research has shown that user-oriented care predicts older persons' satisfaction with care. What is yet to be researched is how senior management facilitates the implementation of user-oriented care. The purpose of this study is to investigate the organizing principles and management climate characterizing successful elderly care. Design/methodology/approach - The department in one highly ranked municipality was selected and compared with a more average municipality. On-site in-depth semi-structured interviews with department managers and participatory observations at managers' meetings were conducted in both municipalities. Findings - Results revealed three key principles for successful elderly care: organizing care from the viewpoint of the older person; recruiting and training competent and autonomous employees; instilling a vision for the mission that guides operations at all levels in the organization. Furthermore, using climate theory to interpret the empirical material, in the highly successful municipality the management climate was characterized by affective support and cognitive autonomy, in contrast to a more instrumental work climate primarily focusing on organizational structure and doing the right things characterizing the more average municipality. Originality/value - The authors suggest that guiding organizing principles are intertwined with management climate and that there are multiple perspectives that must be considered by the management, that is, the views of the older persons, the co-workers and the mission. These results can guide future care quality developments, and increase the understanding of the importance of organizational climate at the senior management level. PMID- 26764963 TI - Management and leadership competence in hospitals: a systematic literature review. AB - Purpose - The purpose of this study is to describe the characteristics of management and leadership competence of health-care leaders and managers, especially in the hospital environment. Health-care leaders and managers in this study were both nursing and physician managers. Competence was assessed by evaluating the knowledge, skills, attitudes and abilities that enable management and leadership tasks. Design/methodology/approach - A systematic literature review was performed to find articles that identify and describe the characteristics of management and leadership competence. Searches of electronic databases were conducted using set criteria for article selection. Altogether, 13 papers underwent an inductive content analysis. Findings - The characteristics of management and leadership competence were categorized into the following groups: health-care-context-related, operational and general. Research limitations/implications - One limitation of the study is that only 13 articles were found in the literature regarding the characteristics of management and leadership competence. However, the search terms were relevant, and the search process was endorsed by an information specialist. The study findings imply the need to shift away from the individual approach to leadership and management competence. Management and leadership need to be assessed more frequently from a holistic perspective, and not merely on the basis of position in the organizational hierarchy or of profession in health care. Originality/value - The authors' evaluation of the characteristics of management and leadership competence without a concentrated profession-based approach is original. PMID- 26764964 TI - Constructing professional and organisational fields. AB - Purpose - The purpose of this paper is to fill an apparent gap in the literature addressing issues of leadership and change - the development and activities of constructing and leading sports sciences and medicine professions, and similarly, the construction and leadership of multidisciplinary/inter-disciplinary organisations that practice sports sciences and medicine. Design/methodology/approach - This study incorporated explorations through conducting both interviews and survey questionnaires with members of Sports Medicine Australia (SMA). The interviews (qualitative) were semi-structured and asked questions addressing what changed, why change and how change was implemented. Findings - The health sciences and medicine professions moving to specialised sports sciences and medicine disciplines and SMA, evolved through forces driving the need for change (legitimacy, resource dependency, positioning and core competencies). Practical implications - The knowledge developed from understanding activities of change that traditional professions conducted to become specialised Disciplines and parallel changes in a single Discipline organisation evolving to an umbrella organisation (SMA), comprised a membership of specialised Disciplines, can act as a catalyst for inquiry by other professional and organisational groups. Originality/value - The findings of this study contributes to the literature investigating change in professional and organisations fields. More specifically, this study promotes inquiry into leadership practices of sports sciences and medicine, as contributors to the field of health services. PMID- 26764965 TI - Effect of Subgingival Irrigation with Different Substances in the Treatment of Periodontal Disease. A Histometric Study in Rats. AB - The aim of this study was to evaluate the histometric effects of subgingival irrigation with different solutions as adjuvant for the treatment of periodontal disease in rats. Periodontal disease was induced by ligature in the first lower molars of 91 Wistar rats over the course of 28 days. After removal of the ligatures, the animals were subjected to scaling and root planing, followed by subgingival irrigation with different solutions (0.9% saline, 0.2% chlorhexidine, 0.1% and 0.5% sodium hypochlorite and 11% propolis extract). The animals were sacrificed 7 and 14 days after the treatment and tissue was processed for histometric analysis for evaluation of bone support and epithelial migration. The histometric analysis showed no statistically significant differences between the group treated with scaling and groups treated with subgingival irrigation (p > 0.05) regarding bone support and epithelial migration. Similarly, significant differences were not found among the different solutions used for subgingival irrigation. This study agrees with the position of the American Academy of Periodontology, which states that there is insufficient evidence to indicate the routine use of subgingival irrigation as adjuvant to periodontal treatment. PMID- 26764966 TI - Comparative Evaluation of Coronally Advanced Flap with and without Bioactive Glass Putty in the Management of Gingival Recession Defects: A Randomized Controlled Clinical Trial. AB - BACKGROUND: The need-of-the-hour is a material that can support coronally advanced flap (CAF) procedures in treatment of gingival recession. Recent literature shows that various bone substitutes are being used for this procedure. This study clinically evaluates the outcomes of CAF with and without bioactive glass putty (NovaBone(r)) in terms of root coverage, gains in keratinized tissue height, and root coverage esthetic score in multiple gingival recession defects. METHODS: Ten healthy patients (age range 18-45 years) with multiple bilateral (n = 40 test 20; control 20) and comparable Miller's Class I or Class II gingival recession defects were selected. The defects were randomly assigned by a computer generated list to either test (CAF + bioactive glass putty) or control (CAF alone) groups. Clinical parameters included gingival recession (GR), probing pocket depth (PPD), clinical attachment level (CAL), keratinized tissue height (KTH), root coverage esthetic score (RES) evaluated at baseline and at 6 months post-surgery CAF with or without bioactive glass putty. RESULTS: Six months post surgery all clinical parameters showed significant reductions. Gingival recession showed significant reduction both in test and control groups (2.0 +/- 0.47 mm and 2.3 +/- 0.48 mm, respectively; p < 0.05) with no intergroup difference. The exposed root was covered by 72% (test) and 79% (control). CAL gain was also significant in both groups (test: 2.7 +/- 0.67 mm; control: 2.8 +/- 0.78 mm; p < 0.05) with no intergroup difference. Keratinized tissue height gain was significant in both the groups (test group: 1.2 +/- 0.42 mm; control group: 0.9 +/- 0.57 mm) with no intergroup difference. Also, the RES was significant for both the test and control groups (7.2 +/- 2.78 and 7.7 +/- 1.41 respectively) with no intergroup differences. CONCLUSIONS: In isolated Class I/II GR defects, CAF associated with bioactive glass putty provided no significant difference in root coverage, CAL, KTH or RES compared to CAF alone. However, statistically significant gains were seen in all the parameters in both groups as compared to baseline. We refute the claims of the recent studies using a bone substitute for root coverage. Further long-term clinical trials are warranted to substantiate our results. PMID- 26764967 TI - Periodontal and Restorative Treatment of Gingival Recession Associated with Non Carious Cervical Lesions: Case Study. AB - The association between the presence of gingival recession and non-carious cervical lesions is a common finding in dentistry. These diseases have multifactorial etiology and the treatment should be multidisciplinary. Although traditionally the majority of professionals treat non-carious cervical lesions only with conventional restorative procedures, in most cases a combination of periodontal and restorative treatments provides the best functional and esthetic results. Thus, the objective of this case report was to present a new option for treatment, which consists of a subepithelial connective tissue graft associated with a coronally advanced flap placed on dentin and non-carious cervical lesions restored with lithium disilicate partial veneers. A patient complaining about the esthetic aspects of her teeth and cervical dentin hypersensitivity was submitted to occlusal adjustments and daily diet analysis in order to manage etiologic factors. Experienced operators then performed restorative and surgical treatments. Periodontal clinical attachment level (probing depth + gingival margin), bleeding on probing, plaque index, and the integrity of the restorations were observed. During the monitoring period, the treatment was effective, with good functional and esthetic results. The hypersensitivity disappeared, and neither inflammatory characteristics in gingival tissue nor failures in restorations were noted. It might be concluded that treatment with a combination of techniques can be effective and predictable for patients with gingival recession and non-carious cervical lesions that may or may not require restorative procedures under controlled conditions. PMID- 26764968 TI - Association between Acute Myocardial Infarction and Periodontitis: A Review of the Literature. AB - BACKGROUND: Cardiovascular disease (CVD), particularly acute myocardial infarction (AMI), is the leading cause of death worldwide. In India, myocardial events are expected to be the fastest growing cause of death between 2005 and 2015. Thus, in order to prevent and manage the onset of the prevailing AMI epidemic, there is a crucial need to explore different dependent and independent risk factors of AMI, as well as its relationship with other systemic diseases and ill health conditions. One such possible relationship could be an association between AMI and periodontal diseases. OBJECTIVES AND METHODOLOGY: The aim of this study was to review the existing literature to assess the strength of association between AMI and periodontitis in the context of Indian, particularly North Indian, populations and to outline key knowledge gaps in this field. FINDINGS: Review of the literature clearly indicates that evidence on the association between periodontitis and AMI in Indian populations, as well as other populations worldwide, is limited. The number of studies done so far is relatively low. Further, inadequate sample size, retrospective data analyses, potential residual confounding factors, inconsistent definitions of exposure and outcome variables, and reported diversity in results, are some of the other key limitations. CONCLUSIONS: Insufficient evidence is available to justify that periodontal interventions can prevent the onset or progression of acute myocardial events. More longitudinal clinical trials and case-control studies with well controlled confounding factors and valid outcome and exposure measures are needed for determining the true association between the conditions. PMID- 26764970 TI - Con-Current versus Counter-Current Dialysate Flow during CVVHD. A Comparative Study for Creatinine and Urea Removal. AB - BACKGROUND: Dialysate fluid connection to the membrane in continuous dialysis may affect solute clearance. Although circuit connections are routinely made counter current to blood flow in intermittent dialysis, no study has assessed the effect of this dialysate fluid flow direction on removal of small solutes creatinine and urea during treatment using continuous veno-venous haemodialysis (CVVHD). AIMS: To assess if dialysate flow direction during CVVHD affects small solute removal. METHODS: This ethics-approved study recruited a convenience sample of 26 adult ICU patients requiring continuous dialysis to assess urea and creatinine removal for con-current vs. counter-current dialysate flow direction. The circuit was adjusted from continuous veno-venous haemodiafiltration to CVVHD 20 min prior to sampling with no fluid removal. Blood (b) and spent dialysate fluid (f) were taken in both concurrent and counter-current fluid flow at 1 (T1) and 4 (T4) hours with a new treatment. Blood flow was 200 ml/min. Dialysate flow 33 ml/min. Removal of urea and creatinine was expressed as the diafiltrate/plasma concentration ratio: Uf/b and Cf/b respectively. Data lacking normal distribution are presented as median with 25th and 75th interquartile ranges (IQR), otherwise as mean with SD and assessed with the independent t test for paired data. p < 0.5 was considered significant. RESULTS: Fifteen male patients were included with a median (IQR) age of 67 years (52-75), and APACHE x0399;x0399; score 17 (14-19) with all patients meeting RIFLE criteria 'F'. At both times, the counter-current dialysate flow was associated with higher mean (SD) diafiltrate/plasma concentration ratios: T1 0.87 (0.16) vs. 0.77 (0.10), p = 0.006; T2 0.96 (0.16) vs. 0.76 (0.09), p < 0.001 for creatinine and T1 0.98 (0.09) vs. 0.81 (0.09), p < 0.001; T2 0.99 (0.07) vs. 0.82 (0.08), p < 0.001 for urea. CONCLUSION: Counter current dialysate flow during CVVHD for ICU patients is associated with an approximately 20% increase in removal of small solutes creatinine and urea. Video Journal Club 'Cappuccino with Claudio Ronco' at http://www.karger.com/?doi=441270. PMID- 26764972 TI - Safety profiles of old and new antimicrobials for the treatment of MRSA infections. AB - INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of severe nosocomial and community-acquired infections. Various adverse effects have been associated with compounds that are commonly used in the treatment of MRSA. AREAS COVERED: Prolonged use of high-dose vancomycin has been linked with nephrotoxicity. Linezolid use has been associated with lactic acidosis in regimens longer than 14 days and occurrence of thrombocytopenia in patients with renal impairment. Daptomycin use correlates with reversible and often asymptomatic myopathy. Among new compounds, telavancin has shown increased toxicity compared to vancomycin, especially in patients with severe renal impairment, while a low rate of adverse effects was reported others glycolipopeptides such as dalbavancin and oritavancin and for new cephalosporins. Recently studied oxazolidinones (tedizolid and radezolid) also showed mild adverse effects in Phase 2 and 3 clinical trials. EXPERT OPINION: Due to the constant increase in antimicrobial resistance, the use of higher doses and prolonged regimens of antibiotics employed in the treatment of Gram-positive infections has become more common and linked to increased toxicity. Furthermore, new compounds with MRSA activity have been recently approved and will be regularly employed in clinical practice. The knowledge of the adverse effects and risk factors for the development of toxicity associated with anti-MRSA antimicrobials is paramount for the correct use of old and new compounds, especially in the treatment of severe infections. PMID- 26764969 TI - Outcome of Surgical or Endovascular Treatment of Giant Intracranial Aneurysms, with Emphasis on Age, Aneurysm Location, and Unruptured Aneuryms--A Systematic Review and Meta-Analysis. AB - BACKGROUND: Designing treatment strategies for unruptured giant intracranial aneurysms (GIA) is difficult as evidence of large clinical trials is lacking. We examined the outcome following surgical or endovascular GIA treatment focusing on patient age, GIA location and unruptured GIA. METHODS: Medline and Embase were searched for studies reporting on GIA treatment outcome published after January 2000. We calculated the proportion of good outcome (PGO) for all included GIA and for unruptured GIA by meta-analysis using a random effects model. RESULTS: We included 54 studies containing 64 study populations with 1,269 GIA at a median follow-up time (FU-T) of 26.4 months (95% CI 10.8-42.0). PGO was 80.9% (77.4 84.4) in the analysis of all GIA compared to 81.2% (75.3-86.1) in the separate analysis of unruptured GIA. For each year added to patient age, PGO decreased by 0.8%, both for all GIA and unruptured GIA. For all GIA, surgical treatment resulted in a PGO of 80.3% (95% CI 76.0-84.6) compared to 84.2% (78.5-89.8, p = 0.27) after endovascular treatment. In unruptured GIA, PGO was 79.7% (95% CI 71.5 87.8) after surgical treatment and 84.9% (79.1-90.7, p = 0.54) after endovascular treatment. PGO was lower in high quality studies and in studies presenting aggregate instead of individual patient data. In unruptured GIA, the OR for good treatment outcome was 5.2 (95% CI 2.0-13.0) at the internal carotid artery compared to 0.1 (0.1-0.3, p < 0.1) in the posterior circulation. Patient sex, FU T and prevalence of ruptured GIA were not associated with PGO. CONCLUSIONS: We found that the chances of good outcome after surgical or endovascular GIA treatment mainly depend on patient age and aneurysm location rather than on the type of treatment conducted. Our analysis may inform future research on GIA. PMID- 26764971 TI - Servier's pipeline in oncology: moving from research to patients. PMID- 26764974 TI - Formation and Dynamics of Antiferromagnetic Correlations in Tunable Optical Lattices. AB - We report on the observation of antiferromagnetic correlations of ultracold fermions in a variety of optical lattice geometries that are well described by the Hubbard model, including dimers, 1D chains, ladders, isolated and coupled honeycomb planes, as well as square and cubic lattices. The dependence of the strength of spin correlations on the specific geometry is experimentally studied by measuring the correlations along different lattice tunneling links, where a redistribution of correlations between the different lattice links is observed. By measuring the correlations in a crossover between distinct geometries, we demonstrate an effective reduction of the dimensionality for our atom numbers and temperatures. We also investigate the formation and redistribution time of spin correlations by dynamically changing the lattice geometry and studying the time evolution of the system. Time scales ranging from a sudden quench of the lattice geometry to an adiabatic evolution are probed. PMID- 26764973 TI - Preparation, characterization, and in vitro drug release behavior of glutathione sensitive long-circulation micelles based on polyethylene glycol prodrug. AB - In this paper, a kind of glutathione-sensitive polymeric micelles was prepared through assembling in aqueous solution of an amphiphilic polymeric prodrug which was synthesized by linkage of 6-mercaptopurine (6-MP) and polyethylene glycol monomethyl ether using propiolic acid as a connecting arm. The glutathione (GSH) sensitive strategy is based on a Michael addition-elimination reaction, that is the amphiphilic polymeric prodrug which contains alpha, beta-unsaturated carbonyl group acts as a Michael acceptor to receive the attack of nucleophile - glutathione, and undergoes elimination reaction to release the original drug. Transmission electron microscope observation showed that the polymeric micelles (PMs) had a spherical-like morphology with a mean diameter of 28 +/- 3.2 nm. The dynamic light scattering investigation data exhibited that the size and distribution changes of PMs are negligible after being placed for 15 days. In vitro drug release study indicated that only less than 13% of 6-MP was released from the micelles under GSH stimulation at micromolar level, while 34.5, 53.7, and 77.8% accumulative release rates were achieved under GSH stimulation at millimolar level (1, 2 and 10 mM), respectively. The cell inhibition rate of PM solution against HL-60 cells carried out by MTT method reached 85%. The cellular uptake and the intracellular drug release of PMs in HL-60 cells were observed through determining the intracellular 6-MP content by UV-vis spectrophotometer. In vitro macrophage uptake study showed a low phagocytosis rate, indicating the long-circulation ability of the PMs. PMID- 26764975 TI - Experimental Greenberger-Horne-Zeilinger-Type Six-Photon Quantum Nonlocality. AB - Quantum nonlocality gives us deeper insight into quantum physics. In addition, quantum nonlocality has been further recognized as an essential resource for device-independent quantum information processing in recent years. Most experiments of nonlocality are performed using a photonic system. However, until now, photonic experiments of nonlocality have involved at most four photons. Here, for the first time, we experimentally demonstrate the six-photon quantum nonlocality in an all-versus-nothing manner based on a high-fidelity (88.4%) six photon Greenberger-Horne-Zeilinger state. Our experiment pushes multiphoton nonlocality studies forward to the six-photon region and might provide a larger photonic system for device-independent quantum information protocols. PMID- 26764976 TI - Quantum Delayed-Choice Experiment with a Beam Splitter in a Quantum Superposition. AB - A quantum system can behave as a wave or as a particle, depending on the experimental arrangement. When, for example, measuring a photon using a Mach Zehnder interferometer, the photon acts as a wave if the second beam splitter is inserted, but as a particle if this beam splitter is omitted. The decision of whether or not to insert this beam splitter can be made after the photon has entered the interferometer, as in Wheeler's famous delayed-choice thought experiment. In recent quantum versions of this experiment, this decision is controlled by a quantum ancilla, while the beam splitter is itself still a classical object. Here, we propose and realize a variant of the quantum delayed choice experiment. We configure a superconducting quantum circuit as a Ramsey interferometer, where the element that acts as the first beam splitter can be put in a quantum superposition of its active and inactive states, as verified by the negative values of its Wigner function. We show that this enables the wave and particle aspects of the system to be observed with a single setup, without involving an ancilla that is not itself a part of the interferometer. We also study the transition of this quantum beam splitter from a quantum to a classical object due to decoherence, as observed by monitoring the interferometer output. PMID- 26764977 TI - "Photonic" Cat States from Strongly Interacting Matter Waves. AB - We consider ultracold quantum gases of scalar bosons residing in a coupling strength-density regime in which they constitute a twofold fragmented condensate trapped in a single well. It is shown that the corresponding quantum states are, in the appropriate Fock space basis, identical to the photon cat states familiar in quantum optics, which correspond to superpositions of coherent states of the light field with a phase difference of pi. In marked distinction to photon cat states, however, the very existence of matter-wave cat states crucially depends on the many-body correlations of the constituent bosons. We consequently establish that the quadratures of the effective "photons," expressing the highly nonclassical nature of the macroscopic matter-wave superposition state, can be experimentally accessed by measuring the density-density correlations of the interacting quantum gas. PMID- 26764978 TI - Quantum Fidelity for Arbitrary Gaussian States. AB - We derive a computable analytical formula for the quantum fidelity between two arbitrary multimode Gaussian states which is simply expressed in terms of their first- and second-order statistical moments. We also show how such a formula can be written in terms of symplectic invariants and used to derive closed forms for a variety of basic quantities and tools, such as the Bures metric, the quantum Fisher information, and various fidelity-based bounds. Our result can be used to extend the study of continuous-variable protocols, such as quantum teleportation and cloning, beyond the current one-mode or two-mode analyses, and paves the way to solve general problems in quantum metrology and quantum hypothesis testing with arbitrary multimode Gaussian resources. PMID- 26764979 TI - Work Fluctuation-Dissipation Trade-Off in Heat Engines. AB - Reducing work fluctuation and dissipation in heat engines or, more generally, information heat engines that perform feedback control, is vital to maximize their efficiency. The same problem arises when we attempt to maximize the efficiency of a given thermodynamic task that undergoes nonequilibrium processes for arbitrary initial and final states. We find that the most general trade-off relation between work fluctuation and dissipation applicable to arbitrary nonequilibrium processes is bounded from below by the information distance characterizing how far the system is from thermal equilibrium. The minimum amount of dissipation is found to be given in terms of the relative entropy and the Renyi divergence, both of which quantify the information distance between the state of the system and the canonical distribution. We give an explicit protocol that achieves the fundamental lower bound of the trade-off relation. PMID- 26764980 TI - On-Chip Maxwell's Demon as an Information-Powered Refrigerator. AB - We present an experimental realization of an autonomous Maxwell's demon, which extracts microscopic information from a system and reduces its entropy by applying feedback. It is based on two capacitively coupled single-electron devices, both integrated on the same electronic circuit. This setup allows a detailed analysis of the thermodynamics of both the demon and the system as well as their mutual information exchange. The operation of the demon is directly observed as a temperature drop in the system. We also observe a simultaneous temperature rise in the demon arising from the thermodynamic cost of generating the mutual information. PMID- 26764981 TI - Dissipation Bound for Thermodynamic Control. AB - Biological and engineered systems operate by coupling function to the transfer of heat and/or particles down a thermal or chemical gradient. In idealized deterministically driven systems, thermodynamic control can be exerted reversibly, with no entropy production, as long as the rate of the protocol is made slow compared to the equilibration time of the system. Here we consider fully realizable, entropically driven systems where the control parameters themselves obey rules that are reversible and that acquire directionality in time solely through dissipation. We show that when such a system moves in a directed way through thermodynamic space, it must produce entropy that is on average larger than its generalized displacement as measured by the Fisher information metric. This distance measure is subextensive but cannot be made small by slowing the rate of the protocol. PMID- 26764982 TI - Testing Einstein's Equivalence Principle With Fast Radio Bursts. AB - The accuracy of Einstein's equivalence principle (EEP) can be tested with the observed time delays between correlated particles or photons that are emitted from astronomical sources. Assuming as a lower limit that the time delays are caused mainly by the gravitational potential of the Milky Way, we prove that fast radio bursts (FRBs) of cosmological origin can be used to constrain the EEP with high accuracy. Taking FRB 110220 and two possible FRB/gamma-ray burst (GRB) association systems (FRB/GRB 101011A and FRB/GRB 100704A) as examples, we obtain a strict upper limit on the differences of the parametrized post-Newtonian parameter gamma values as low as [gamma(1.23 GHz)-gamma(1.45 GHz)]<4.36*10(-9). This provides the most stringent limit up to date on the EEP through the relative differential variations of the gamma parameter at radio energies, improving by 1 to 2 orders of magnitude the previous results at other energies based on supernova 1987A and GRBs. PMID- 26764983 TI - Taking the Universe's Temperature with Spectral Distortions of the Cosmic Microwave Background. AB - The cosmic microwave background (CMB) energy spectrum is a near-perfect blackbody. The standard model of cosmology predicts small spectral distortions to this form, but no such distortion of the sky-averaged CMB spectrum has yet been measured. We calculate the largest expected distortion, which arises from the inverse Compton scattering of CMB photons off hot, free electrons, known as the thermal Sunyaev-Zel'dovich (TSZ) effect. We show that the predicted signal is roughly one order of magnitude below the current bound from the COBE-FIRAS experiment, but it can be detected at enormous significance (?1000sigma) by the proposed Primordial Inflation Explorer (PIXIE). Although cosmic variance reduces the effective signal-to-noise ratio to 230sigma, this measurement will still yield a subpercent constraint on the total thermal energy of electrons in the observable Universe. Furthermore, we show that PIXIE can detect subtle relativistic effects in the sky-averaged TSZ signal at 30sigma, which directly probe moments of the optical depth-weighted intracluster medium electron temperature distribution. These effects break the degeneracy between the electron density and the temperature in the mean TSZ signal, allowing a direct inference of the mean baryon density at low redshift. Future spectral distortion probes will thus determine the global thermodynamic properties of ionized gas in the Universe with unprecedented precision. These measurements will impose a fundamental "integral constraint" on models of galaxy formation and the injection of feedback energy over cosmic time. PMID- 26764984 TI - How to Recover a Qubit That Has Fallen into a Black Hole. AB - We demonstrate an algorithm for the retrieval of a qubit, encoded in spin angular momentum, that has been dropped into a no-firewall black hole. Retrieval is achieved analogously to quantum teleportation by collecting Hawking radiation and performing measurements on the black hole. Importantly, these methods require only the ability to perform measurements from outside the event horizon. PMID- 26764985 TI - Precision Test of Gauge-Gravity Duality with Flavor. AB - We put AdS/CFT dualities involving probe branes to a precision test. On the holographic side we use a new class of supersymmetric D7-brane embeddings into AdS(5)*S(5), which allow us to describe N=4 super Yang-Mills theory coupled to massive N=2 supersymmetric flavors on S(4). With these embeddings we can compare holographic results to a field theory analysis of the free energy using supersymmetric localization. Localization allows us to get results at strong coupling, and hence to compare in detail to AdS/CFT. We find analytically matching results: a phase transition at the same critical mass in both calculations and matching free energies up to a scheme-dependent constant in both phases. PMID- 26764986 TI - Distance between Quantum States and Gauge-Gravity Duality. AB - We study a quantum information metric (or fidelity susceptibility) in conformal field theories with respect to a small perturbation by a primary operator. We argue that its gravity dual is approximately given by a volume of maximal time slice in an anti-de Sitter spacetime when the perturbation is exactly marginal. We confirm our claim in several examples. PMID- 26764988 TI - Microscopic Observation of Pauli Blocking in Degenerate Fermionic Lattice Gases. AB - The Pauli exclusion principle is one of the most fundamental manifestations of quantum statistics. Here, we report on its local observation in a spin-polarized degenerate gas of fermions in an optical lattice. We probe the gas with single site resolution using a new generation quantum gas microscope avoiding the common problem of light induced losses. In the band insulating regime, we measure a strong local suppression of particle number fluctuations and a low local entropy per atom. Our work opens a new avenue for studying quantum correlations in fermionic quantum matter both in and out of equilibrium. PMID- 26764992 TI - Mechanism of Partial Flame Propagation and Extinction in a Strong Gravitational Field. AB - A theory of partial flame propagation driven by the gravitational field is developed. Using the on-shell approach, equations for the gas velocity distributions and the front shape of a steady flame are obtained and solved numerically. It is found that the solutions describing upward flame propagation come in pairs having close propagation speeds, and that the effect of strong gravity is to reverse the burnt gas velocity profile generated by the flame. On the basis of these results, a complete explanation is given of the intricate observed behavior of flames near the limits of inflammability, including the dependence of the inflammability range on the size of the combustion domain, the large distances of partial flame propagation, and the progression of flame extinction. PMID- 26764989 TI - Exact Potential Driving the Electron Dynamics in Enhanced Ionization of H(2)(+). AB - It was recently shown that the exact factorization of the electron-nuclear wave function allows the construction of a Schrodinger equation for the electronic system, in which the potential contains exactly the effect of coupling to the nuclear degrees of freedom and any external fields. Here we study the exact potential acting on the electron in charge-resonance enhanced ionization in a model one-dimensional H(2)(+) molecule. We show there can be significant differences between the exact potential and that used in the traditional quasistatic analyses, arising from nonadiabatic coupling to the nuclear system, and that these are crucial to include for accurate simulations of time-resolved ionization dynamics and predictions of the ionization yield. PMID- 26764991 TI - Optimal Frames for Polarization State Reconstruction. AB - Complete determination of the polarization state of light requires at least four distinct projective measurements of the associated Stokes vector. Stability of state reconstruction, however, hinges on the condition number kappa of the corresponding instrument matrix. Optimization of redundant measurement frames with an arbitrary number of analysis states, m, is considered in this Letter in the sense of minimization of kappa. The minimum achievable kappa is analytically found and shown to be independent of m, except for m=5 where this minimum is unachievable. Distribution of the optimal analysis states over the Poincare sphere is found to be described by spherical 2 designs, including the Platonic solids as special cases. Higher order polarization properties also play a key role in nonlinear, stochastic, and quantum processes. Optimal measurement schemes for nonlinear measurands of degree t are hence also considered and found to correspond to spherical 2t designs, thereby constituting a generalization of the concept of mutually unbiased bases. PMID- 26764994 TI - Condensation of Coherent Structures in Turbulent Flows. AB - Coherent structures are ubiquitous in turbulent flows and play a key role in transport. The most important coherent structures in thermal turbulence are plumes. Despite being the primary heat carriers, the potential of manipulating thermal plumes to transport more heat has been overlooked so far. Unlike some other forms of energy transport, such as electromagnetic or sound waves, heat flow in fluids is generally difficult to manipulate, as it is associated with the random motion of molecules and atoms. Here we report how a simple geometrical confinement can lead to the condensation of elementary plumes. The result is the formation of highly coherent system-sized plumes and the emergence of a new regime of convective thermal turbulence characterized by universal temperature profiles and significantly enhanced heat transfer. It is also found that the universality of the temperature profiles and heat transport originate from the geometrical properties of the coherent structures, i.e., the thermal plumes. Therefore, in contrast to the classical regime, boundary layers in this plume controlled regime are being controlled, rather than controlling. PMID- 26764990 TI - Paraxial Theory of Direct Electro-optic Sampling of the Quantum Vacuum. AB - Direct detection of vacuum fluctuations and analysis of subcycle quantum properties of the electric field are explored by a paraxial quantum theory of ultrafast electro-optic sampling. The feasibility of such experiments is demonstrated by realistic calculations adopting a thin ZnTe electro-optic crystal and stable few-femtosecond laser pulses. We show that nonlinear mixing of a short near-infrared probe pulse with the multiterahertz vacuum field leads to an increase of the signal variance with respect to the shot noise level. The vacuum contribution increases significantly for appropriate length of the nonlinear crystal, short pulse duration, tight focusing, and a sufficiently large number of photons per probe pulse. If the vacuum input is squeezed, the signal variance depends on the probe delay. Temporal positions with a noise level below the pure vacuum may be traced with subcycle resolution. PMID- 26764993 TI - Turbulence on a Fractal Fourier Set. AB - A novel investigation of the nature of intermittency in incompressible, homogeneous, and isotropic turbulence is performed by a numerical study of the Navier-Stokes equations constrained on a fractal Fourier set. The robustness of the energy transfer and of the vortex stretching mechanisms is tested by changing the fractal dimension D from the original three dimensional case to a strongly decimated system with D=2.5, where only about 3% of the Fourier modes interact. This is a unique methodology to probe the statistical properties of the turbulent energy cascade, without breaking any of the original symmetries of the equations. While the direct energy cascade persists, deviations from the Kolmogorov scaling are observed in the kinetic energy spectra. A model in terms of a correction with a linear dependency on the codimension of the fractal set E(k)~k(-5/3+3-D) explains the results. At small scales, the intermittency of the vorticity field is observed to be quasisingular as a function of the fractal mode reduction, leading to an almost Gaussian statistics already at D~2.98. These effects must be connected to a genuine modification in the triad-to-triad nonlinear energy transfer mechanism. PMID- 26764997 TI - Ultrafast Time-Resolved Photoelectric Emission. AB - The emission times of laser-triggered electrons from a sharp tungsten tip are directly characterized under ultrafast, near-infrared laser excitation at Keldysh parameters of 6.61:8. In multivariate models, factors associated with NEP initiation (p < .05) were attending shooting galleries (Adjusted Relative Risk [ARR]: 1.54); arrest for track-marks (ARR: 1.38); having a family member that ever used drugs (ARR: 1.37); and having a larger PWID network (ARR: 1.01 per 10 persons). NEP initiation was inversely associated with obtaining syringes at pharmacies (ARR: .56); earning >2500 pesos/month (ARR: .66); and reporting needle sharing (ARR: .71). CONCLUSIONS: Uptake of NEP expansion in Tijuana was vigorous among PWID. We identified a range of factors that influenced the likelihood of NEP initiation, including police interaction. These findings have important implications for the scale-up of NEP in Mexico. PMID- 26765075 TI - Active music therapy for persons with dementia and their family caregivers. PMID- 26765076 TI - Using Medication to Cope with Labor Pain. PMID- 26765078 TI - Tool use in left brain damage and Alzheimer's disease: What about function and manipulation knowledge? AB - Tool use disorders are usually associated with difficulties in retrieving function and manipulation knowledge. Here, we investigate tool use (Real Tool Use, RTU), function (Functional Association, FA) and manipulation knowledge (Gesture Recognition, GR) in 17 left-brain-damaged (LBD) patients and 14 AD patients (Alzheimer disease). LBD group exhibited predicted deficit on RTU but not on FA and GR while AD patients showed deficits on GR and FA with preserved tool use skills. These findings question the role played by function and manipulation knowledge in actual tool use. PMID- 26765077 TI - An accessible pharmacodynamic transcriptional biomarker for notch target engagement. AB - gamma-Secretase mediates amyloid production in Alzheimer's disease (AD) and oncogenic activity of Notch. gamma-Secretase inhibitors (GSIs) are thus of interest for AD and oncology. A peripheral biomarker of Notch activity would aid determination of the therapeutic window and dosing regimen for GSIs, given toxicities associated with chronic Notch inhibition. This study examined the effects of GSI MK-0752 on blood and hair follicle transcriptomes in healthy volunteers. The effects of a structurally diverse GSI on rhesus blood and hair follicles were also compared. Significant dose-related effects of MK-0752 on transcription were observed in hair follicles, but not blood. The GSI biomarker identified in follicles exhibited 100% accuracy in a clinical test cohort, and was regulated in rhesus by a structurally diverse GSI. This study identified a translatable, accessible pharmacodynamic biomarker of GSI target engagement and provides proof of concept of hair follicle RNA as a translatable biomarker source. PMID- 26765079 TI - Forage yields and feeding value of small grain winter cereals for lambs. AB - BACKGROUND: An understanding of the dynamics that affect the nutrient content of forages with advancing growth stages is critical for designing equally dynamic feeding programmes. This study compared the agronomic characteristic and feeding values of forages from barley, rye, wheat, oats and triticale weekly from tillering (Z 24-25) to dough stages of maturity (Z 83-87). RESULT: Digestible dry matter yield of cereal species increased rapidly (P < 0.05) from 1.9 t ha(-1) at tillering to 7.8 t ha(-1) at ear emergence (Z 50-55) and remained stable (P > 0.05) until the dough stage when it increased to 10.4 t ha(-1) . The nutritive quality of cereal species decreased with advancing growth stages, and this was more pronounced in barley and rye with rapid reductions in their energy and digestibility values. Changes in the nutritive value of cereal forages indicated a strong relationship (P < 0.05) with the leaf-stem ratio of the plants. The animal response reflected the changes in feeding value of cereal species with advancing growth stages. The average live weight gain of lambs decreased (P < 0.05) from an average of 203 g d(-1) on 2 May to 142 g d(-1) on the 13 June. CONCLUSION: Wheat and oats, and to a lesser extent triticale, provided higher quality forages than barley and rye. All cereal species had poor feeding qualities between ear emergence and milk stages (Z 71-75). (c) 2016 Society of Chemical Industry. PMID- 26765081 TI - 'I Know it was Every Week, but I Can't be Sure if it was Every Day: Domestic Violence and Women with Learning Disabilities. AB - BACKGROUND: Domestic violence against women is well researched in the general population, but much less so in relation to women with learning disabilities. This qualitative research study interviewed 15 women with learning disabilities who had experienced domestic violence about their experiences, the impact of the violence on them and their children, their coping strategies and help seeking behaviour. MATERIALS AND METHODS: Semistructured in-depth interviews were conducted. Data were analysed using Inter-pretive Phenomenological Analysis. A service user advisory group helped at particular stages, notably at the formative stage and with dissemination, especially the production of accessible materials, including a DVD. RESULTS: The violence experienced by many of the women was severe and frequent. It impacted negatively on their physical and psychological well-being. The women's awareness of refuges and others sources of help was generally low. CONCLUSIONS: Healthcare and social care professionals have a clear remit to help women with learning disabilities to avoid and escape violent relationships. PMID- 26765080 TI - Comparison of Four Bleeding Risk Scores to Identify Rivaroxaban-treated Patients With Venous Thromboembolism at Low Risk for Major Bleeding. AB - OBJECTIVES: Outpatient treatment of acute venous thromboembolism (VTE) requires the selection of patients with a low risk of bleeding during the first few weeks of anticoagulation. The accuracy of four systems, originally derived for predicting bleeding in VTE treated with vitamin K antagonists (VKAs), was assessed in VTE patients treated with rivaroxaban. METHODS: All patients treated with rivaroxaban in the multinational EINSTEIN deep vein thrombosis (DVT) and pulmonary embolism (PE) trials were included. Major bleeding was defined as >=2 g/dL drop in hemoglobin or >=2-unit blood transfusion, bleeding in critical area, or bleeding contributing to death. The authors examined the incidence of major bleeding in patients with low-risk assignment by the systems of Ruiz-Gimenez et al. (score = 0 to 1), Beyth et al. (score = 0), Kuijer et al. (score = 0), and Landefeld and Goldman. (score = 0). For clinical relevance, the definition of low risk for all scores except Kuijer includes all patients < 65 years with no prior bleeding history and no comorbid conditions (current cancer, renal insufficiency, diabetes mellitus, anemia, prior stroke, or myocardial infarction). RESULTS: A total of 4,130 patients (1,731 with DVT only, 2,399 with PE with or without DVT) were treated with rivaroxaban for a mean (+/-SD) duration of 207.6 (+/-95.9) days. Major bleeding occurred in 1.0% (40 of 4,130; 95% confidence interval [CI] = 0.7% to 1.3%) overall. Rates of major bleeding for low-risk patients during the entire treatment period were similar: Ruiz-Gimenez et al., 12 of 2,622 (0.5%; 95% CI = 0.2% to 0.8%); Beyth et al., nine of 2,249 (0.4%; 95% CI = 0.2% to 0.8%); Kuijer et al., four of 1,186 (0.3%; 95% CI = 0.1% to 0.9%); and Landefeld and Goldman, 11 of 2,407 (0.5%; 95% CI = 0.2% to 0.8%). At 30 days, major bleed rates for low-risk patients were as follows: Ruiz-Gimenez et al., five of 2,622 (0.2%; 95% CI = 0.1% to 0.4%); Beyth et al., five of 2,249 (0.2%; 95% CI = 0.1% to 0.5%); Kuijer et al., three of 1,186 (0.3%; 95% CI = 0.1% to 0.7%); and Landefeld and Goldman, seven of 2,407 (0.3%; 95% CI = 0.1% to 0.6%). No low-risk patient had a fatal bleed. CONCLUSIONS: Four scoring systems that use criteria obtained in routine clinical practice, derived to predict low bleeding risk with VKA treatment for VTE, identified patients with less than a 1% risk of major bleeding during full-course treatment with rivaroxaban. PMID- 26765082 TI - Thunderstorm-related asthma: what happens and why. AB - The fifth report issued by the Intergovernmental Panel on Climate Change forecasts that greenhouse gases will increase the global temperature as well as the frequency of extreme weather phenomena. An increasing body of evidence shows the occurrence of severe asthma epidemics during thunderstorms in the pollen season, in various geographical zones. The main hypotheses explaining association between thunderstorms and asthma claim that thunderstorms can concentrate pollen grains at ground level which may then release allergenic particles of respirable size in the atmosphere after their rupture by osmotic shock. During the first 20 30 min of a thunderstorm, patients suffering from pollen allergies may inhale a high concentration of the allergenic material that is dispersed into the atmosphere, which in turn can induce asthmatic reactions, often severe. Subjects without asthma symptoms, but affected by seasonal rhinitis can also experience an asthma attack. All subjects affected by pollen allergy should be alerted to the danger of being outdoors during a thunderstorm in the pollen season, as such events may be an important cause of severe exacerbations. In light of these observations, it is useful to predict thunderstorms and thus minimize thunderstorm-related events. PMID- 26765083 TI - Zinc acclimation mitigated high zinc induced oxidative stress by enhancing antioxidant defenses in large yellow croaker Pseudosciaena crocea. AB - The hypothesis tested in the present study was that Zn acclimation will alleviate high Zn induced oxidative stress in large yellow croaker Pseudosciaena crocea. To the end, fish were pre-exposed to 0 and 2mgZnL(-1) for 48h and then exposed to 0 and 10mgZnL(-1) for 48h. Lipid peroxidation, activities and mRNA levels of antioxidant enzyme genes (Cu/Zn-SOD, CAT, GPx and GR), and gene expressions of Nrf2-Keap1 signaling molecules at different exposure time (12h, 24h and 48h) were determined in the liver and spleen of large yellow croaker. 10mgZnL(-1) exposure alone enhanced lipid peroxidation in the liver during 12-48h and in the spleen during 24-48h. Although 2mgZnL(-1) pre-exposure did not affect lipid peroxidation, 2mgZnL(-1) pre-exposure mitigated high Zn induced oxidative stress. The positive effect of Zn acclimation could be attributed to the up-regulated expression and activities of antioxidant enzyme genes under high Zn stress. Obtained results also showed a coordinated transcriptional regulation of antioxidant genes, suggesting that Nrf2 is required for the protracted induction of these genes. Besides, the sharp increase in Keap1 expression levels would support its role in switching off Nrf2 response. In conclusion, Zn acclimation mitigated high Zn-induced oxidative stress in large yellow croker, emphasizing a central role of transcription factor Nrf2 in the process. PMID- 26765084 TI - Differential responses of female and male brains to hypoxia in the marine medaka Oryzias melastigma. AB - Hypoxia, an endocrine disruptor, affects synthesis and balance of sex steroid hormones, leading to reproductive impairment in both female and male fish. Cumulating reports demonstrated the alternation of hypothalamus-pituitary-gonad axis (HPG-axis) by hypoxia. However, the detail mechanism underlying how hypoxia may alter other brain functions remains largely unknown. In this report, we used marine medaka as a model and conducted a high-throughput RNA sequencing followed by bioinformatics analysis on hypoxia-exposed brain tissues, aiming to determine the change of transcriptional signature and to unravel the pathways that are induced by hypoxia. We found that hypoxia lead to dysregulation of brain functions (including synaptic transmission, axon guidance, potassium ion transport, neuron differentiation, and development of brain and pituitary gland), and also signaling pathways (e.g., gap junction, calcium signaling pathway, and GnRH signaling pathway). Our results further demonstrate gender-specific responses to hypoxia in female and male fish's brains, which provides novel insights into the mechanism underlying the hypoxia induced sex specific brain functions impairments. PMID- 26765085 TI - Thyroid disruption in zebrafish (Danio rerio) larvae: Different molecular response patterns lead to impaired eye development and visual functions. AB - The vertebrate thyroid system is important for multiple developmental processes, including eye development. Thus, its environmentally induced disruption may impact important fitness-related parameters like visual capacities and behaviour. The present study investigated the relation between molecular effects of thyroid disruption and morphological and physiological changes of eye development in zebrafish (Danio rerio). Two test compounds representing different molecular modes of thyroid disruption were used: propylthiouracil (PTU), which is an enzyme inhibitor of thyroid hormone synthesis, and tetrabromobisphenol A (TBBPA), which interacts with the thyroid hormone receptors. Both chemicals significantly altered transcript levels of thyroid system-related genes (TRalpha, TRbeta, TPO, TSH, DIO1, DIO2 and DIO3) in a compound-specific way. Despite these different molecular response patterns, both treatments resulted in similar pathological alterations of the eyes such as reduced size, RPE cell diameter and pigmentation, which were concentration-dependent. The morphological changes translated into impaired visual performance of the larvae: the optokinetic response was significantly and concentration-dependently decreased in both treatments, together with a significant increase of light preference of PTU-treated larvae. In addition, swimming activity was impacted. This study provides first evidence that different modes of molecular action of the thyroid disruptors can be associated with uniform apical responses. Furthermore, this study is the first to show that pathological eye development, as it can be induced by exposure to thyroid disruptors, indeed translates into impaired visual capacities of zebrafish early life stages. PMID- 26765086 TI - Low levels of chemical anthropogenic pollution may threaten amphibians by impairing predator recognition. AB - Recent studies suggest that direct mortality and physiological effects caused by pollutants are major contributing factors to global amphibian decline. However, even sublethal concentrations of pollutants could be harmful if they combined with other factors to cause high mortality in amphibians. Here we show that sublethal concentrations of pollutants can disrupt the ability of amphibian larvae to recognize predators, hence increasing their risk of predation. This effect is indeed much more important since very low amounts of pollutants are ubiquitous, and environmental efforts are mostly directed towards preventing lethal spills. We analyzed the effects of two common contaminants (humic acid and ammonium nitrate) on the ability of tadpoles of the western spadefoot toad (Pelobates cultripes) to recognize chemical cues from a common predator, nymphs of the dragonfly Anax imperator. We compared the swimming activity of tadpoles in the presence and absence of water-borne chemical cues from dragonflies at different concentrations of humic acid and ammonium nitrate. Tadpoles reduced swimming activity in response to predator cues in the absence of pollutants, whereas they remained unresponsive to these cues when either humic acid or ammonium nitrate was added to the water, even at low concentrations. Moreover, changes in tadpole activity associated with the pollutants themselves were non significant, indicating no toxic effect. Alteration of the natural chemical environment of aquatic systems by pollutants may be an important contributing cause for declines in amphibian populations, even at sublethal concentrations. PMID- 26765087 TI - Bisphenol A exposure may increase the risk of development of atopic disorders in children. AB - BACKGROUND: Little is known about the effect of Bisphenol A (BPA) on atopic disorders. OBJECTIVE: To investigated the associations (i) between postnatal BPA exposure and allergic diseases in children; (ii) between BPA and IgE levels for the possible disease pathogenesis; and (iii) gender-based differences. METHODS: A total of 453 children from Childhood Environment and Allergic Diseases Study cohort with urine and blood samples were recruited in Taiwan. Urinary BPA glucoronide (BPAG) levels were measured by UPLC-MS/MS at ages 3 and 6 years. The associations between BPAG levels at different ages and IgE levels and the development of allergic diseases were evaluated by multivariate linear regression and logistic regression. A mediation analysis was also conducted to evaluate how much risk of allergic diseases in relation to BPA exposure is explained by IgE changes. RESULTS: The BPAG levels at age 3 were positively associated with IgE levels at age 3 (beta=64.85kU/l per ln-unit increase BPAG level; 95% CI, 14.59 115.11kU/l). Stratified by gender, BPAG levels at age 3 were positively associated with IgE levels at age 3, particularly in girls (beta=139.23kU/l; 95% CI, 57.38-221.09kU/l). Similar results were also found at age 6. Urinary BPAG levels at age 3 were significantly associated with asthma at ages 3 and 6, with OR (95%CI) of 1.29(1.08-1.55) and 1.27(1.04-1.55). We estimated that 70% of the total effect of BPA exposure on asthma is mediated by IgE levels. CONCLUSIONS: BPA exposures were associated with IgE levels and may increase the risk of development of allergic diseases in children particularly in girls. PMID- 26765088 TI - Improving microcystin monitoring relevance in recreative waters: A regional case study (Brittany, Western France, Europe). AB - Cyanobacteria and their toxins are known as a health hazard in recreative and distributed waters. Monitoring data from 2004 to 2011 were collected at regional scale to characterize exposition parameters to microcystins in Brittany (Western France). The data show that cyanobacteria populations are experiencing a composition shift leading to a longer duration of cell densities higher than WHO alert levels 2 and 3. Microcystins however appear to be more frequently detected with subacute concentrations in low cell density samples than in high cell density samples or during bloom episodes. Positive relations are described between microcystin concentrations, detection frequencies and cyanobacteria biovolumes, allowing for a novel definition of alert levels and decision framework following WHO recommendations. PMID- 26765089 TI - [The Most Cited Articles in Volume 40 of Psychiatrische Praxis- Congratulations!]. PMID- 26765090 TI - [Being Creative to Stay Alive]. PMID- 26765091 TI - ["Should Danger to Third Parties Justify Involuntary Admission to Psychiatric Hospitals Under Public Law?"--Pro]. PMID- 26765092 TI - ["Should Danger to Third Parties Justify Involuntary Admission to Psychiatric Hospitals Under Public Law?"--Contra]. PMID- 26765093 TI - [In Process Citation]. PMID- 26765094 TI - Estimation of the synthetic routes of seized methamphetamines using GC-MS and multivariate analysis. AB - One hundred and twenty six seized methamphetamine (MA) samples were analyzed using GC-MS. All the peaks that appeared in the chromatograms were investigated and 61 impurities including n-octacosane (internal standard) were identified. Among them, 37 impurities were already known or newly identified by comparing with commercial library entries and 18 impurities were detected for the first time. To estimate the synthetic routes of MA samples, route specific impurities had to be selected for each method. Two naphthalenes, 1,3-dimethyl-2 phenylnaphthalene and 1-benzyl-3-methylnaphthalene were selected as Nagai route specific impurities and three diasteromers, UK-19.62(58_165_178) I, UK 19.95(58_165_178) II, UK-20.49(58_165_178) III were also selected not only for their high frequency detection only in Nagai samples but also for the high principal component analysis (PCA) correlation values. For the Emde route, N,N dimethyl-3,4-diphenylhexane-2,5-diamine and N-methyl-1-{4-[2 (methylamino)propyl]phenyl}-1-phenylpropan-2-amine were selected as route specific impurities, and N,N-di(beta-phenylisopropyl)amine I (DPIA I), N,N di(beta-phenylisopropyl)amine II (DPIA II), N,N-di(beta phenylisopropyl)methylamine I (DPIMA I) and N,N-di(beta phenylisopropyl)methylamine II (DPIMA II) were selected for the Leuckart route. With these route specific impurities, synthetic routes could be identified for 78 of the 126 samples. The 61 impurities were registered in AMDIS target component library and the GC-MS data were deconvoluted. After AMDIS deconvolution, a matrix file was composed and then multivariate analyses were performed to estimate the synthetic route for unknown samples. The unsupervised methods, hierarchical clustering analysis (HCA) and PCA clustered the samples according to the closeness between samples. Two classification functions were obtained from discriminant analysis (DA) and the synthetic routes of the unknown samples were predicted using these two functions. PMID- 26765096 TI - Reference ranges of 17-hydroxyprogesterone, DHEA, DHEAS, androstenedione, total and free testosterone determined by TurboFlow-LC-MS/MS and associations to health markers in 304 men. AB - We report reference ranges based on LC-MS/MS for testosterone (T), free testosterone (FT) and its precursors, i.e. 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEAS) and androstenedione (Adione), in relation to different health markers and lifestyle factors. The study was based on 304 healthy men aged 30-61 years participating in a population-based cross-sectional study (Health2008). Examination program consisted of a clinical examination, completion of a self-administered questionnaire and blood sampling. Steroid metabolites were measured by a validated and sensitive LC-MS/MS method. Older age-groups were significantly associated with decreased concentrations of DHEA, DHEAS, Adione, and FT, while no significant associations with age were shown for 17-OHP or T. Participants with BMI>=30 kg/m(2) had lower age-related steroid metabolite z-scores compared to participants with BMI<30 kg/m(2), i.e. 17 OHP: -0.51 vs. 0.08 (p<0.001); DHEA: -0.27 vs. 0.09 (p=0.014); Adione: -0.29 vs. 0.09 (p=0.012); T: -0.99 vs. 0.14 (p<0.001); and FT -0.55 vs. 0.05 (p<0.001), respectively. In conclusion, this large study on serum steroid metabolites and concomitant assessment of health markers in healthy men provides age-related reference ranges, and furthermore evaluates the impact of lifestyle factors and metabolic syndrome on androgen metabolite levels. PMID- 26765095 TI - Genetic variants within telomere-associated genes, leukocyte telomere length and the risk of acute coronary syndrome in Czech women. AB - The association between leukocyte telomere length (LTL) and cardiovascular disease (CVD) has been published in many reports, although almost exclusively in men. In our study we analysed the association between LTL and five selected variants within three candidate genes (TERC rs12696304; TERF2IP rs3784929 and rs8053257; UCP2 rs659366 and rs622064), which are not only involved in telomere length maintenance but also potentially associated with higher risk of acute coronary syndrome (ACS) in Czech women (505 cases and 642 controls). We detected significantly shorter LTL in women with ACS (P<0.001), but the difference disappeared after multiple adjustments. We did not find any significant associations between analysed variants and LTL, except for rs622064 within the UCP2 gene, in which case AA homozygotes had a higher LTL (P<0.04). Genotype frequencies of the analysed SNPs did not differ between controls and women with ACS. Variants within UCP2 (rs622064; CC vs. A allele carriers OR=1.61; 95% CI: 1.21-2.15, P<0.002) and within TERF2IP (rs8053257; A allele carriers vs. GG, OR=1.78; 95% CI: 1.07-3.18, P<0.03) were associated with increased risk of type 2 diabetes mellitus (T2DM). Analysed polymorphisms were not major determinants of telomere length or ACS risk in Czech females. PMID- 26765098 TI - Outcomes of vascular intervention and use of perioperative medications for nonpulmonary aneurysms in Behcet disease. AB - BACKGROUND: Aneurysms attributable to Behcet disease (BD) are not common but are associated with a poor prognosis because of a high risk of rupture. Special considerations are required for vascular intervention, because the intense local inflammation may increase complications. The aim of this study was to assess the outcome of operative intervention and the use of perioperative medical therapy for aneurysms in patients with BD. MATERIALS AND METHODS: We reviewed retrospectively the medical records of patients with BD admitted to Peking Union Medical College Hospital between January 1995 and January 2015. RESULTS: Among 874 patients diagnosed with BD, 176 patients had vascular involvement, of whom 59 had arterial aneurysms. Thirty-six patients with 51 arterial aneurysms underwent operative intervention. The 51 primary operative interventions included 20 open operations and 31 endovascular interventions. Eleven (22 %) recurrent aneurysms developed in 10 patients and 5 (10%) thrombosis occurred in 5 patients. Of the 19 endovascular stents placed for aortic aneurysms, 1 type I endoleak, 1 graft occlusion, 3 recurrent aneurysms, and 1 recurrent aneurysmal rupture occurred. Among the revascularization procedures for extremity arteries, there were more complications with endovascular intervention than with open surgery. The cumulative risk of recurrent aneurysmal formation at the operative site was significantly less in patients treated with operative intervention combined with use of immunosuppressants than those treated with operative intervention alone (P = .01). CONCLUSION: In patients with BD, an endovascular approach is feasible and effective for aortic aneurysms, whereas bypass surgery appears to provide better outcomes for extremity arterial aneurysms than placement of endovascular stents. The administration of corticosteroids combined with cyclophosphamide perioperatively decreases the cumulative risk of recurrent aneurysm. PMID- 26765099 TI - Discrete emotion-congruent false memories in the DRM paradigm. AB - Research has shown that false-memory production is enhanced for material that is emotionally congruent with the mood of the participant at the time of encoding. So far this research has only been conducted to examine the influence of generic negative affective mood states and generic negative stimuli on false-memory production. In addition, much of the research is limited as it focuses on valence and arousal dimensions, and fails to take into account the more comprehensive nature of emotions. The current study demonstrates that this effect goes beyond general negative or positive moods and acts at a more discrete emotional level. Participants underwent a standard emotion-induction procedure before listening to negative emotional or neutral associative word lists. The emotions induced, negative word lists, and associated nonpresented critical lures, were related to either fear or anger, 2 negative valence emotions that are also both high in arousal. Results showed that when valence and arousal are controlled for, false memories are more likely to be produced for discrete emotionally congruent compared with incongruent materials. These results support spreading activation theories of false remembering and add to our understanding of the adaptive nature of false-memory production. (PsycINFO Database Record PMID- 26765097 TI - Validation of research trajectory 1 of an Exposome framework: Exposure to benzo(a)pyrene confers enhanced susceptibility to bacterial infection. AB - The exposome provides a framework for understanding elucidation of an uncharacterized molecular mechanism conferring enhanced susceptibility of macrophage membranes to bacterial infection after exposure to the environmental contaminant benzo(a)pyrene, [B(a)P]. The fundamental requirement in activation of macrophage effector functions is the binding of immunoglobulins to Fc receptors. FcgammaRIIa (CD32a), a member of the Fc family of immunoreceptors with low affinity for immunoglobulin G, has been reported to bind preferentially to IgG within lipid rafts. Previous research suggested that exposure to B(a)P suppressed macrophage effector functions but the molecular mechanisms remain elusive. The goal of this study was to elucidate the mechanism(s) of B(a)P-exposure induced suppression of macrophage function by examining the resultant effects of exposure induced insult on CD32-lipid raft interactions in the regulation of IgG binding to CD32. The results demonstrate that exposure of macrophages to B(a)P alters lipid raft integrity by decreasing membrane cholesterol 25% while increasing CD32 into non-lipid raft fractions. This robust diminution in membrane cholesterol and 30% exclusion of CD32 from lipid rafts causes a significant reduction in CD32 mediated IgG binding to suppress essential macrophage effector functions. Such exposures across the lifespan would have the potential to induce immunosuppressive endophenotypes in vulnerable populations. PMID- 26765100 TI - Socioemotional flexibility in mother-daughter dyads: Riding the emotional rollercoaster across positive and negative contexts. AB - Socioemotional flexibility is a dyad-level indicator of adaptive interpersonal emotion regulation, and involves the temporal dynamics of shifting in and out of emotion states over time and the range of emotional states expressed during interpersonal interactions. Higher flexibility is associated with better psychosocial adjustment. In line with the Flex3 model, flexibility during interactions between 96 mothers and their adolescent daughters (Mage = 13.99 years) at 2 different time scales were examined in the current study: (a) within positive and negative emotional contexts (dynamic flexibility); and (b) between positive and negative emotional contexts (reactive flexibility). Mothers and daughters completed the emotional rollercoaster task-a series of 5 3-min discussions on times they felt the following strong emotions toward each other: (a) happy/excited, (b) worried/sad, (c) proud, (d) frustrated/annoyed, and (e) grateful. In general, higher dynamic (within-discussion) flexibility and moderate levels of flexibility across discussions were associated with lower internalizing symptoms and higher relationship quality. Results support the Flex3 model and also suggest that in addition to emotional valence (positive vs. negative), specific emotion contexts (e.g., sad vs. frustrated) differentially influence socioemotional flexibility in mother-daughter dyads. PMID- 26765101 TI - Photoprotection by dietary phenolics against melanogenesis induced by UVA through Nrf2-dependent antioxidant responses. AB - Dietary phenolics may play a protective role in UV-mediated skin pigmentation through their antioxidant and UV-absorbing actions. In this study, we investigated whether genetic silencing of Nrf2, regulating the transcription of antioxidant genes, affected melanogenesis in primary human epidermal melanocytes (HEMn) and B16F10 melanoma cells subjected to UVA (8J/cm(2)) exposure. Then, we explored the antimelanogenic actions of phenolics; caffeic acid (CA) and ferulic acid (FA) providing partial UVA protection; quercetin (QU) and rutin (RU) providing strong UVA protection and; avobenzone (AV), an efficient UVA filter, in association with modulation of Nrf2-mediated antioxidant defenses in response to UVA insults in B16F10 cells. Upon oxidative insults, Nrf2 silencing promoted melanogenesis in both HEMn and B16F10 cells irradiated with UVA. Stimulation of melanogenesis by UVA correlated with increased ROS and oxidative DNA damage (8 OHdG), GSH depletion as well as a transient downregulation of Nrf2 nuclear translocation and of Nrf2-ARE signaling in B16F10 cells. All test compounds exerted antimelanogenic effects with respect to their abilities to reverse UVA mediated oxidative damage as well as downregulation of Nrf2 activity and its target antioxidants (GCLC, GST and NQO1) in B16F10 cells. In conclusion, defective Nrf2 may promote melanogenesis under UVA irradiation through oxidative stress mechanisms. Compounds with antioxidant and/or UVA absorption properties could protect against UVA-induced melanogenesis through indirect regulatory effect on Nrf2-ARE pathway. PMID- 26765102 TI - Immune-related adverse events with immune checkpoint blockade: a comprehensive review. AB - Cancer immunotherapy is coming of age; it has prompted a paradigm shift in oncology, in which therapeutic agents are used to target immune cells rather than cancer cells. The first generation of new immunotherapies corresponds to antagonistic antibodies that block specific immune checkpoint molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand PD-L1. Targeting these checkpoints in patients living with cancer had led to long-lasting tumour responses. By unbalancing the immune system, these new immunotherapies also generate dysimmune toxicities, called immune-related adverse events (IRAEs) that mainly involve the gut, skin, endocrine glands, liver, and lung but can potentially affect any tissue. In view of their undisputed clinical efficacy, anti-CTLA-4 and anti-PD-1 antibodies are entering in the routine oncological practice, and the number of patients exposed to these drugs will increase dramatically in the near future. Although steroids can be used to treat these IRAEs, the associated immunosuppression may compromise the antitumour response. Oncologists must be ready to detect and manage these new types of adverse events. This review focuses on the mechanisms of IRAE generation, putative relationship between dysimmune toxicity and antitumour efficacy, as a basis for management guidelines. PMID- 26765104 TI - Retention in care among HIV-positive patients initiating second-line antiretroviral therapy: a retrospective study from an Ethiopian public hospital clinic. AB - BACKGROUND: Access to second-line antiretroviral therapy (ART) for HIV-positive patients remains limited in sub-Saharan Africa. Furthermore, outcomes of second line ART may be compromised by mortality and loss to follow-up (LTFU). OBJECTIVE: To determine retention in care among patients receiving second-line ART in a public hospital in Ethiopia, and to investigate factors associated with LTFU among adults and adolescents. DESIGN: HIV-positive persons with documented change of first-line ART to a second-line regimen were retrospectively identified from hospital registers, and data were collected at the time of treatment change and subsequent clinic visits. Baseline variables for adults and adolescents were analyzed using multivariate Cox proportional hazards models comparing subjects remaining in care and those LTFU (defined as a missed appointment of >=90 days). RESULTS: A total of 383 persons had started second-line ART (330 adults/adolescents; 53 children) and were followed for a median of 22.2 months (the total follow-up time was 906 person years). At the end of study follow-up, 80.5% of patients remained in care (adults and adolescents 79.8%; children 85.7%). In multivariate analysis, LTFU among adults and adolescents was associated with a baseline CD4 cell count <100 cells/mm(3) and a first-line regimen failure that was not confirmed by HIV RNA testing. CONCLUSIONS: Although retention in care during second-line ART in this cohort was satisfactory, and similar to that reported from first-line ART programs in Ethiopia, our findings suggest the benefit of earlier recognition of patients with first-line ART failure and confirmation of suspected treatment failure by viral load testing. PMID- 26765105 TI - Discrepancies between Patients' Preferences and Educational Programs on Oral Anticoagulant Therapy: A Survey in Community Pharmacies and Hospital Consultations. AB - BACKGROUND: Oral anticoagulation therapy is increasingly used for the prevention and treatment of thromboembolic complications in various clinical situations. Nowadays, education programs for patients treated with anticoagulants constitute an integrated component of their management. However, such programs are usually based on the healthcare providers' perceptions of what patients should know, rather than on patients' preferences. OBJECTIVE: To investigate patients' viewpoints on educational needs and preferred modalities of information delivery. METHODS: We conducted an observational study based on a self-administered questionnaire. To explore several profiles of patients, the study was designed for enrolling patients in two settings: during outpatient consultations in a cardiology department (Saint Antoine Hospital, Paris, France) and in community pharmacies throughout France. RESULTS: Of the 371 patients who completed the questionnaire, 187 (50.4%) were recruited during an outpatient consultation and 184 (49.6%) were recruited in community pharmacies. 84.1% of patients were receiving a vitamin K antagonist and 15.6% a direct oral anticoagulant. Patients ranked 16 of 21 (76.2%) questionnaire items on information about their treatment as important or essential; information on adverse effects of treatment was the highest ranked domain (mean score 2.38, 95% CI 2.30-2.46). Pharmacists (1.69, 1.58-1.80), nurses (1.05, 0.95-1.16), and patient associations (0.36, 0.29-0.44), along with group sessions (0.85, 0.75-0.95), the internet (0.77, 0.67-0.88), and delivery of material at the patient's home (1.26, 1.14-1.38), were ranked poorly in terms of delivering educational material. CONCLUSION: This study revealed substantial discrepancies between patient preferences and current educational programs. These findings should be useful for tailoring future educational programs that are better adapted to patients, with a potential associated enhancement of their effectiveness. PMID- 26765107 TI - The Future of Surgical Oncology: Image-Guided Cancer Surgery. PMID- 26765106 TI - Predictive Values of N-Terminal Pro-B-Type Natriuretic Peptide and Cardiac Troponin I for Myocardial Fibrosis in Hypertrophic Obstructive Cardiomyopathy. AB - BACKGROUND: Both high-sensitivity cardiac troponin T and B-type natriuretic peptide are useful in detecting myocardial fibrosis, as determined by late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR), in patients with non-obstructive hypertrophic cardiomyopathy. However, their values to predict myocardial fibrosis in hypertrophic obstructive cardiomyopathy (HOCM) remain unclear. We investigated the role of N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) and cardiac troponin I (cTnI) to identify LGE-CMR in patients with HOCM. METHODS: Peripheral concentrations of NT-proBNP and cTnI were determined in patients with HOCM (n = 163; age = 47.2 +/- 10.8 years; 38.7% females). Contrast-enhanced CMR was performed to identify and quantify myocardial fibrosis. RESULTS: LGE was detected in 120 of 163 patients (73.6%). Patients with LGE had significantly higher levels of NT-proBNP and cTnI than those without LGE (1386.2 [904.6-2340.8] vs. 866.6 [707.2-1875.2] pmol/L, P = 0.003; 0.024 [0.010 0.049] vs. 0.010 [0.005-0.021] ng/ml, P <0.001, respectively). The extent of LGE was positively correlated with log cTnI (r = 0.371, P <0.001) and log NT-proBNP (r = 0.211, P = 0.007). On multivariable analysis, both log cTnI and maximum wall thickness (MWT) were independent predictors of the presence of LGE (OR = 3.193, P = 0.033; OR = 1.410, P < 0.001, respectively), whereas log NT-proBNP was not. According to the ROC curve analysis, combined measurements of MWT >=21 mm and/or cTnI >=0.025 ng/ml indicated good diagnostic performance for the presence of LGE, with specificity of 95% or sensitivity of 88%. CONCLUSIONS: Serum cTnI is an independent predictor useful for identifying myocardial fibrosis, while plasma NT proBNP is only associated with myocardial fibrosis on univariate analysis. Combined measurements of serum cTnI with MWT further improve its value in detecting myocardial fibrosis in patients with HOCM. PMID- 26765103 TI - A Functionally Conserved Gene Regulatory Network Module Governing Olfactory Neuron Diversity. AB - Sensory neuron diversity is required for organisms to decipher complex environmental cues. In Drosophila, the olfactory environment is detected by 50 different olfactory receptor neuron (ORN) classes that are clustered in combinations within distinct sensilla subtypes. Each sensilla subtype houses stereotypically clustered 1-4 ORN identities that arise through asymmetric divisions from a single multipotent sensory organ precursor (SOP). How each class of SOPs acquires a unique differentiation potential that accounts for ORN diversity is unknown. Previously, we reported a critical component of SOP diversification program, Rotund (Rn), increases ORN diversity by generating novel developmental trajectories from existing precursors within each independent sensilla type lineages. Here, we show that Rn, along with BarH1/H2 (Bar), Bric-a brac (Bab), Apterous (Ap) and Dachshund (Dac), constitutes a transcription factor (TF) network that patterns the developing olfactory tissue. This network was previously shown to pattern the segmentation of the leg, which suggests that this network is functionally conserved. In antennal imaginal discs, precursors with diverse ORN differentiation potentials are selected from concentric rings defined by unique combinations of these TFs along the proximodistal axis of the developing antennal disc. The combinatorial code that demarcates each precursor field is set up by cross-regulatory interactions among different factors within the network. Modifications of this network lead to predictable changes in the diversity of sensilla subtypes and ORN pools. In light of our data, we propose a molecular map that defines each unique SOP fate. Our results highlight the importance of the early prepatterning gene regulatory network as a modulator of SOP and terminally differentiated ORN diversity. Finally, our model illustrates how conserved developmental strategies are used to generate neuronal diversity. PMID- 26765123 TI - Aquaporin-3 Inhibition Reduces the Growth of NSCLC Cells Induced by Hypoxia. AB - BACKGROUND/AIMS: Non-small cell lung cancer (NSCLC) is the leading cause of death worldwide. Although aquaporin-3 (AQP3) is widely distributed in mammalian tissues and over-expressed in NSCLC cells, there are limited studies on the effects of AQP3 knockdown on NSCLC cells under hypoxic conditions. METHODS: The CCK-8 assay was used to calculate cell viability. Scratch-wound healing and transwell assays were used to detect cell migration and invasion. Apoptotic cells were measured by the TUNEL assay. mRNA expression levels were calculated via quantitative RT-PCR. Relative protein levels were determined by immunoblot assays. RESULTS: AQP3 knockdown substantially reduced proliferation, migration, and invasion of A549 and NCI-H460 cells under hypoxic conditions. Moreover, AQP3 knockdown clearly induced cell apoptosis. Further analysis identified levels of HIF-1alpha, VEGF, Raf, phosphor-MEK, and phosphor-ERK, whose activities were significantly attenuated in the AQP3 knockdown group. CONCLUSIONS: These findings indicate that AQP3 knockdown retards the growth of NSCLC cells partially through inhibiting HIF 1alpha/VEGF and Raf/MEK/ERK signalling pathways. PMID- 26765121 TI - Regulation of Asymmetric Division by Atypical Protein Kinase C Influences Early Specification of CD8(+) T Lymphocyte Fates. AB - Naive CD8(+) T lymphocytes responding to microbial pathogens give rise to effector T cells that provide acute defense and memory T cells that provide long lived immunity. Upon activation, CD8(+) T lymphocytes can undergo asymmetric division, unequally distributing factors to the nascent daughter cells that influence their eventual fate towards the effector or memory lineages. Individual loss of either atypical protein kinase C (aPKC) isoform, PKCzeta or PKClambda/iota, partially impairs asymmetric divisions and increases CD8(+) T lymphocyte differentiation toward a long-lived effector fate at the expense of memory T cell formation. Here, we show that deletion of both aPKC isoforms resulted in a deficit in asymmetric divisions, increasing the proportion of daughter cells that inherit high amounts of effector fate-associated molecules, IL-2Ralpha, T-bet, IFNgammaR, and interferon regulatory factor 4 (IRF4). However, unlike CD8(+) T cells deficient in only one aPKC isoform, complete loss of aPKC unexpectedly increased CD8(+) T cell differentiation toward a short-lived, terminal effector fate, as evidenced by increased rates of apoptosis and decreased expression of Eomes and Bcl2 early during the immune response. Together, these results provide evidence for an important role for asymmetric division in CD8(+) T lymphocyte fate specification by regulating the balance between effector and memory precursors at the initiation of the adaptive immune response. PMID- 26765122 TI - The contribution of a collagen-fibrin patch (Tachosil) to prevent the postoperative lymphatic complications after groin lymphadenectomy: a double institution observational study. AB - OBJECTIVE: Postoperative morbidity associated with groin lymphadenectomy remain high and still represents a major concern for this patients. The aim of this study was to confirm the efficacy of TachoSil((r)) in preventing postoperative complications after inguinofemoral lymphadenectomy for gynecological malignancy. STUDY DESIGN: An observational study was conducted to evaluate the incidence of postoperative complications among 49 patients (TachoSil((r)) group=24; control group=25) underwent groin dissection enrolled in two Italian Department of Gynecology Oncology from 2011 to 2014. RESULTS: A total of 74 inguinal dissections were performed. Bilateral groin dissection was performed in 25 patients (Tachosil group=10; group 2=15). Patients in TachoSil((r)) group showed a lower daily drainage volume with a mean volume of 84 ml (range 30-465) vs. 143 ml (range -72 to 413) in the control group (p=.004), and a lower total drainage volume with a mean of 540 ml (range 90-930) vs. 900 ml (range 200-3270) for Tachosil and control group, respectively. A lower incidence of lymphocyst required drainage, cellulitis, wound infection and late lymphedema was observed in TachoSil group even without reaching statistical significance. CONCLUSIONS: This observational study confirmed that the use of TachoSil((r)) seems to be highly effective in reducing the rate of postoperative lymphorrea and postoperative complications after groin dissection in case of gynecological malignancies. Larger multicenter prospective study is advisable to validate our preliminary results. PMID- 26765127 TI - Cutaneous lymphoid hyperplasia following vaccine for pollen hyposensitization. PMID- 26765125 TI - A Blood Test for Methylated BCAT1 and IKZF1 vs. a Fecal Immunochemical Test for Detection of Colorectal Neoplasia. AB - OBJECTIVES: To compare the performance of a new blood test for colorectal cancer (CRC) to an established fecal immunochemical test (FIT) in a study population with the full range of neoplastic and non-neoplastic pathologies encountered in the colon and rectum. METHODS: Volunteers were asked to complete a FIT prior to colonoscopy. Blood was collected after bowel preparation but prior to colonoscopy, and plasma was assayed for the presence of methylated BCAT1 and IKZF1 DNA using a multiplex real-time PCR assay. Sensitivity and specificity estimates for the blood test were calculated from true- and false-positive rates for neoplasia and compared with FIT at a range of fecal hemoglobin (Hb) concentration positivity thresholds. RESULTS: In total, 1,381 volunteers (median age 64 years; 49% male) completed both tests prior to colonoscopy. Estimated sensitivity of the BCAT1/IKZF1 blood test for CRC was 62% (41/66; 95% confidence interval 49-74%) with a specificity of 92% (1207/1315; 90-93%). FIT returned the same specificity at a cutoff of 60 MUg Hb/g, at which its corresponding sensitivity for cancer was 64% (42/66; 51-75%). In the range of commonly used FIT cutoffs, respective cancer sensitivity and specificity estimates with FIT were: 59% (46-71%) and 93% (92-95%) at 80 MUg Hb/g, and 79% (67-88%) and 81% (78-83%) at 10 MUg Hb/g. Although estimated sensitivities were not significantly different between the two tests for any stage of cancer, FIT showed a significantly higher sensitivity for advanced adenoma at the lower cutoffs. Specificity of FIT, but not of the BCAT1/IKZF1 blood test, deteriorated substantially in people with overt blood in the feces. When combining FIT (cutoff 10 MUg Hb/g) with the BCAT1/IKZF1 blood test, sensitivity for cancer was 89% (79-96%) at 74% (72-77%) specificity. CONCLUSIONS: A test based on detection of methylated BCAT1/IKZF1 DNA in blood has comparable sensitivity but better specificity for CRC than FIT at the commonly used positivity threshold of 10 MUg Hb/g. Further evaluation of the new test relative to FIT in the population screening context is now required to fully understand the potential advantages and disadvantages of these biomarkers in screening. PMID- 26765129 TI - Keratosis follicularis spinulosa decalvans. PMID- 26765130 TI - Cutaneous meningioma. PMID- 26765124 TI - Biological Control Activities of Rice-Associated Bacillus sp. Strains against Sheath Blight and Bacterial Panicle Blight of Rice. AB - Potential biological control agents for two major rice diseases, sheath blight and bacterial panicle blight, were isolated from rice plants in this study. Rice associated bacteria (RABs) isolated from rice plants grown in the field were tested for their antagonistic activities against the rice pathogens, Rhizoctonia solani and Burkholderia glumae, which cause sheath blight and bacterial panicle blight, respectively. Twenty-nine RABs were initially screened based on their antagonistic activities against both R. solani and B. glumae. In follow-up retests, 26 RABs of the 29 RABs were confirmed to have antimicrobial activities, but the rest three RABs did not reproduce any observable antagonistic activity against R. solani or B. glumae. According to16S rDNA sequence identity, 12 of the 26 antagonistic RABs were closest to Bacillus amyloliquefaciens, while seven RABs were to B. methylotrophicus and B, subtilis, respectively. The 16S rDNA sequences of the three non-antagonistic RABs were closest to Lysinibacillus sphaericus (RAB1 and RAB12) and Lysinibacillus macroides (RAB5). The five selected RABs showing highest antimicrobial activities (RAB6, RAB9, RAB16, RAB17S, and RAB18) were closest to B. amyloliquefaciens in DNA sequence of 16S rDNA and gyrB, but to B. subtilis in that of recA. These RABs were observed to inhibit the sclerotial germination of R. solani on potato dextrose agar and the lesion development on detached rice leaves by artificial inoculation of R. solani. These antagonistic RABs also significantly suppressed the disease development of sheath blight and bacterial panicle blight in a field condition, suggesting that they can be potential biological control agents for these rice diseases. However, these antagonistic RABs showed diminished disease suppression activities in the repeated field trial conducted in the following year probably due to their reduced antagonistic activities to the pathogens during the long-term storage in 70C, suggesting that development of proper storage methods to maintain antagonistic activity is as crucial as identification of new biological control agents. PMID- 26765132 TI - Erythema gyratum repens associated with cryptogenic organizing pneumonia. PMID- 26765135 TI - Testing Specific Hypotheses Concerning Latent Group Differences in Multi-group Covariance Structure Analysis with Structured Means. AB - This article concerns multi-group covariance structure analysis with structured means. The traditional latent selection model is formulated as a special case of phenotypic selection, that is, selection based not on latent variables, but on observed variables. This formulation has the advantage that it enables one to test very specific hypotheses concerning selection on latent variables. Illustrations are given using simulated and real data. PMID- 26765133 TI - Choroidal Thickness in Eyes with Fuchs Uveitis Syndrome. AB - PURPOSE: This study measured the macular thickness, peripapillary retinal nerve fiber layer (RNFL) thickness, subfoveal choroidal thickness (SFCT), and ganglion cell complex (GCC) thickness in eyes with Fuchs uveitis syndrome (FUS). METHODS: In total, 25 patients with unilateral FUS were enrolled. The diagnosis of FUS was based on the presence of several of the following clinical features: absence of acute symptoms and ciliary injection; small to medium-sized and stellate keratic precipitates (KP) diffusely scattered on the entire corneal endothelium; chronic low-grade anterior chamber inflammation; iris stromal atrophy with or without heterochromia; lack of posterior synechiae; iris nodules; and vitreous cells and debris. Spectral domain optical coherence tomography (SD-OCT; RTVue-100 OCT) was used to obtain the measurements. The SFCT, RNFL thickness, macular retinal thickness, and GCC thickness of the eyes with FUS were measured and compared with those of the uninvolved fellow eyes. A paired samples t-test was used for statistical analyses. A value of p<0.05 was considered to be statistically significant for all analyses. RESULTS: The mean age of the patients was 35.2 +/- 4.8 years. Fifteen patients (60%) were male, and 10 (40%) were female. Small- to medium-sized stellate KPs and mild anterior chamber reactions were seen in all patients. Heterochromia was observed in 24% of the eyes, iris nodules in 36% of the eyes, lens opacity in 44% of the eyes, and vitreous cells and debris in 88% of the eyes. The mean SFCT was significantly thinner in eyes with FUS (296.47 +/- 32.29 um) than in the fellow eyes without FUS (324.47 +/- 26.73 um; p = 0.001). The mean average GCC thickness was found to be 101.09 +/- 5.46 um in eyes with FUS and 103.80 +/- 6.65 um in eyes without FUS (p = 0.023). There were no significant differences in the mean RNFL and macular thickness values. CONCLUSIONS: We detected subfoveal choroidal thinning in eyes with FUS when compared with the uninvolved fellow eyes. In our opinion, thinning of the SFCT in FUS might be associated with autoimmune responses and chronic inflammatory processes. PMID- 26765136 TI - A Unidimensional Latent Trait Model for Continuous Item Responses. AB - A general linear latent trait model for continuous item responses is described. The special unidimensional case for continuous item responses is Joreskog's (1971) model of congeneric item responses. In the context of the unidimensional case model for continuous item responses the concepts of item and test information functions, specific objectivity, item bias, and reliability are discussed; also the application of the model to test construction is shown. Finally, the correspondence with latent trait theory for dichotomous item responses is discussed. PMID- 26765134 TI - Integrity((r)) bare-metal coronary stent-induced platelet and endothelial cell activation results in a higher risk of restenosis compared to Xience((r)) everolimus-eluting stents in stable angina patients. AB - Drug-eluting stenting (DES) has become a reliable tool for coronary stenting; however, its direct effects on platelet and endothelium function differ from those of bare-metal stenting (BMS). This study involved a periprocedural analysis of various biomarkers of cellular activation after elective DES (Xience((r)), Abbott Vascular, Santa Clara, CA, USA) or BMS (Integrity((r)), Medtronic, Minneapolis, MI, USA). Forty-nine stable angina patients were recruited: 28 underwent BMS, and 21 received everolimus-eluting stents. Samples were collected (i) prior to stenting, (ii) at 24 hours after procedure, and (iii) after 1 month of dual antiplatelet therapy. Platelet activation was analyzed by surface P selectin positivity in parallel with plasma levels of soluble P-selectin, CD40L and platelet-derived growth factor (PDGF). Endothelial cell (EC) activation was detected by measuring markers of early (von Willebrand factor) and delayed response (VCAM-1, ICAM-1, E-selectin). Patients were followed for 6 months for the occurrence of restenosis or stent thrombosis. Increased platelet activation was sustained regardless of stent type or antiplatelet medication. Concentrations of most EC markers were more elevated after BMS than after DES. No stent thrombosis was seen, but six BMS subjects displayed restenosis with significantly higher sCD40L (779 [397-899] vs. 381 [229-498] pg/mL; p = 0.032) and sICAM-1 (222 [181-272] vs. 162 [153-223] ng/mL; p = 0.046) levels than in those without complication, while DES patients exhibited significantly decreased PDGF (572 [428 626] vs. 244 [228-311] pg/mL; p = 0.004) after 1 month. Nonresponsiveness to antiplatelet drugs did not influence these changes. In conclusion, the degree of platelet and EC activation suggests that Xience((r)) DES may be regarded a safer coronary intervention than Integrity((r)) BMS, with a lower risk of in-stent restenosis. PMID- 26765137 TI - Estimating and Testing the Sources of Evoked Potentials in the Brain. AB - The source of an event related brain potential (ERP) is estimated from multivariate measurements of this ERP on the head under several mathematical and physical constraints on the parameters of the source model. We will discuss statistical aspects of standard methods to estimate these parameters and their confidence intervals. In addition new principled tests of the goodness of fit as well as of differences between estimated sources are proposed and compared with customary approaches in psychophysiology. Several factors which influence the statistical analysis, in particular the number of measurement leads, will be discussed. PMID- 26765138 TI - Antisocial Behavior, Delinquent Peer Association, and Unsupervised Wandering for Boys: Growth and Change from Childhood to Early Adolescence. AB - Latent growth curve analysis was used to study individual differences in initial status and growth rates of antisocial behavior, delinquent peer association, and unsupervised wandering during the transition from childhood to early adolescence for a sample of 206, primarily working-class, European-American boys. All three constructs showed significant individual differences in initial status at Grade 4 and growth rates from Grade 4 to Grade 8. Wandering and delinquent peer association showed positive mean trends. Linear growth curves adequately described growth for delinquent peer association and antisocial behavior. Growth on wandering was linear up to Grade 7 and then showed positive acceleration from Grade 7 to Grade 8. All three constructs were highly related at the initial assessment point. Individual differences in growth rates were highly correlated on all three constructs. The findings were discussed in terms of the trait confluence model for peer influence on antisocial behavior. PMID- 26765139 TI - Testing for the Factorial Validity, Replication, and Invariance of a Measuring Instrument: A Paradigmatic Application Based on the Maslach Burnout Inventory. AB - The intent of this article is twofold: (a) to report substantive findings from a cross-validated study that tested for the factorial validity and invariance of the Maslach Burnout Inventory (MBI) across gender for elementary (males n = 742; females n = 801) and secondary (males n = 659; females n = 721) teachers, and (b) for purposes of helping readers who may be new to the structural modeling methodology, to provide an example of how these procedures may be applied in testing for the construct validity of a measuring instrument. Unique to this article is the use of multiple model-fitting criteria that address issues related to nonnormality of the data, complexity and replicability of the model, and error of approximation and sampling error in the estimation of fit; other "experimental" indices of fit are also included. Substantively, although results argue generally for the equivalency of the MBI across gender, calibration/validation groups, and teaching panels, they also suggest the need for a reexamination of content and retesting of construct validity related to six of the 22 items. PMID- 26765141 TI - Genetic and infective diversity of the liver fluke Fasciola hepatica (Trematoda: Digenea) from Cuba. AB - In this study we present the first approach to exploration of the genetic diversity of Cuban Fasciola hepatica populations using microsatellite markers, coupled with observed prevalence in slaughterhouses. Nine populations of flukes recovered from cows and buffalos were studied in the central-western region of Cuba. The observed infection rates of definitive hosts (bovines) were 70-100% in most cases. An important amount of polymorphism was found in the four loci explored. However, no apparent genetic differences were found between populations from different provinces or bovine species. The absence of deviations from Hardy Weinberg equilibrium suggests a high rate of cross-fertilization between F. hepatica individuals. This result was confirmed when all multilocus genotypes were tested for clonal reproduction and only four individuals differed statistically (P sex< 0.05). High values of expected heterozygosity coupled with highly probable mixing among strains make the metapopulation genetically diversified but similar in terms of certain alleles (low F ST values). These results suggest a close relationship between parasite diversity and cattle management in Cuba. Our findings should be taken into consideration by veterinary authorities to help mitigate fasciolosis transmission. PMID- 26765142 TI - Novel investigational therapies for onychomycosis: an update. AB - INTRODUCTION: Onychomycosis is an infection of the nail plate that is prevalent among the ageing population. Onychomycosis is difficult to treat with low initial cure rates, high rates of relapse, and reinfection. Present treatment options include oral and topical therapies, with oral therapies yielding better results. However, there has been a greater emphasis on the development of topical antifungal therapies as they have fewer side effects and drug interactions. AREAS COVERED: This review summarizes new and reformulated drugs. Results from in vitro studies to Phase III clinical trials are discussed. Novel drugs include: the oral azole VT-1161, the topical azole efinaconazole, the benzoxaborole tavaborole, reformulations of terbinafine P-3058 and LI-P, novel inhibitor of succinate dehydrogenase ME1111, and off-label use of tazarotene. Enhanced permeation of the morpholine amorolfine through the nail plate is also discussed using ultraviolet (UV) curable gels, and a fractional CO2 laser. EXPERT OPINION: Novel topical antifungals and the reformulation of current antifungals have demonstrated marked improvement in nail penetration. Current research has an emphasis on topical therapies due to their minimized risk for adverse effects and higher patient demand. Nevertheless, few topical agents have surfaced in the past few years and the investigation of efficacious combination therapies may become more important. PMID- 26765140 TI - The Potential Influence of Bumble Bee Visitation on Foraging Behaviors and Assemblages of Honey Bees on Squash Flowers in Highland Agricultural Ecosystems. AB - Bee species interactions can benefit plant pollination through synergistic effects and complementary effects, or can be of detriment to plant pollination through competition effects by reducing visitation by effective pollinators. Since specific bee interactions influence the foraging performance of bees on flowers, they also act as drivers to regulate the assemblage of flower visitors. We selected squash (Cucurbita pepo L.) and its pollinators as a model system to study the foraging response of honey bees to the occurrence of bumble bees at two types of sites surrounded by a high amount of natural habitats (>= 58% of land cover) and a low amount of natural habitats (<= 12% of land cover) in a highland agricultural ecosystem in China. At the individual level, we measured the elapsed time from the departure of prior pollinator(s) to the arrival of another pollinator, the selection of honey bees for flowers occupied by bumble bees, and the length of time used by honey bees to explore floral resources at the two types of sites. At the community level, we explored the effect of bumble bee visitation on the distribution patterns of honey bees on squash flowers. Conclusively, bumble bee visitation caused an increase in elapsed time before flowers were visited again by a honey bee, a behavioral avoidance by a newly arriving honey bee to select flowers occupied by bumble bees, and a shortened length of time the honey bee takes to examine and collect floral resources. The number of overall bumble bees on squash flowers was the most important factor explaining the difference in the distribution patterns of honey bees at the community level. Furthermore, decline in the number of overall bumble bees on the squash flowers resulted in an increase in the number of overall honey bees. Therefore, our study suggests that bee interactions provide an opportunity to enhance the resilience of ecosystem pollination services against the decline in pollinator diversity. PMID- 26765144 TI - Halogenated benzoate derivatives of altholactone with improved anti-fungal activity. AB - Altholactone exhibited the anti-fungal activity with a high MIC value of 128 MUg ml(-1) against Cryptococcus neoformans and Saccharomyces cerevisiae. Fifteen ester derivatives of altholactone 1-15 were modified by esterification and their structures were confirmed by spectroscopic methods. Most of the ester derivatives exhibited stronger anti-fungal activities than that of the precursor altholactone. 3-Bromo- and 2,4-dichlorobenzoates (7 and 15) exhibited the lowest minimal inhibitory concentration (MIC) values against C. neoformans at 16 MUg ml( 1), while the 4-bromo-, 4-iodo-, and 1-bromo-3-chlorobenzoates (11-13) displayed potent activity against S. cerevisiae with MIC values of 1 MUg ml(-1). In conclusion, this analysis indicates that the anti-fungal activity of altholactone is enhanced by addition of halogenated benzoyl group to the 3-OH group. PMID- 26765145 TI - Phenylboronic acid as a glucose-responsive trigger to tune the insulin release of glycopolymer nanoparticles. AB - An amphiphilic glycopolymer, poly(D-gluconamidoethyl methacrylate -r-3 methacrylamido phenylboronic acid), which could self-assemble to form nanoparticles with a narrow size distribution, was synthesized. Transmission electron microscopy showed that the nanoparticles were spherical in shape with diameters of about 120 nm. The phenylboronic acid rendered the glycopolymer nanoparticles glucose sensitive, which was evident from swelling behavior of the nanoparticles at different glucose concentrations and was found to be dependent on the glucose level. Insulin was efficiently encapsulated within the nanoparticles (up to 15%), and the release of insulin increased with an increase in the level of glucose in the medium. Cell viability tests proved that the glycopolymer nanoparticles had good cytocompatibility, due to which the glycopolymers have the potential to be used in biomedical fields. PMID- 26765146 TI - A Comprehensive Assessment of Family Physician Gender and Quality of Care: A Cross-Sectional Analysis in Ontario, Canada. AB - BACKGROUND: Studies evaluating primary care quality across physician gender are limited to primary and secondary prevention. OBJECTIVES: Investigate the relationship between family physician gender and quality of primary care using indicators that cover 5 key dimensions of primary care. RESEARCH DESIGN: Cross sectional analysis using linked health administrative datasets (April 1, 2008 to March 31, 2010). SUBJECTS: All family physicians working in the 3 main primary care models in the province of Ontario (Canada), providing general care and having a panel size >1200. MEASURES: Indicators of cancer screening (3), chronic disease management (9), continuity (2), comprehensiveness (2), and access (5). RESULTS: A total of 4195 physicians (31% female) were eligible. Adjusting for provider and patient factors, patients of female physicians were more likely to have received recommended cancer screening (odds ratios [95% confidence interval (CI)] (OR) range: 1.24 [1.18-1.30], 1.85 [1.78-1.92]) and diabetes management (OR: 1.04 [1.01-1.08], 1.28 [1.05-1.57]). They had fewer emergency room visits (rate ratio [95% CI] (RR) range: 0.83 [0.79-0.87]) and hospitalizations (RR: 0.89 [0.86-0.93]), and higher referrals (RR: 1.12 [1.09-1.14]). There was evidence of effect modification by patient gender (female vs. male) for hospitalization (RR: 0.74 [0.70-0.79] vs. 0.96 [0.90-1.02]) and emergency room visits (RR: 0.84 [0.81 0.88] vs. 0.98 [0.94-1.01]). Lower emergency room visits were also more evident in more complex patients of female physicians. There were no significant differences in the continuity or comprehensiveness measures. CONCLUSIONS: The indicators assessed in this study point to a benefit for patients under the care of female physicians. Potential explanations are discussed. PMID- 26765143 TI - Intradialytic Hypoxemia in Chronic Hemodialysis Patients. AB - When kidney failure occurs, patients are at risk for fluid overload states, which can cause pulmonary edema, pleural effusions, and upper airway obstruction. Kidney disease is also associated with impaired respiratory function, as in central sleep apnea or chronic obstructive pulmonary disease. Hence, respiratory and renal diseases are frequently coexisting. Hypoxemia is the terminal pathway of a multitude of respiratory pathologies. The measurement of oxygen saturation (SO2) is a basic and commonly used tool in clinical practice. Both arterial oxygen saturation (SaO2) and central venous oxygen saturation (ScvO2) can be easily obtained in hemodialysis (HD) patients, SaO2 from an arteriovenous access and ScvO2 from a central catheter. Here, we give a brief overview of the anatomy and physiology of the respiratory system, and the different technologies that are currently available to measure oxygen status in dialysis patients. We then focus on literature regarding intradialytic SaO2 and ScvO2. Lastly, we present clinical vignettes of intradialytic drops in SaO2 and ScvO2 in association with different symptoms and clinical scenarios with an emphasis on the pathophysiology of these cases. Given the fact that in the general population hypoxemia is associated with adverse outcomes, including increased mortality, cardiac arrhythmias and cardiovascular events, we posit that intradialytic SO2 may serve as a potential marker to identify HD patients at increased risk for morbidity and mortality. PMID- 26765147 TI - Do Nursing Home Chain Size and Proprietary Status Affect Experiences With Care? AB - BACKGROUND: In 2012, over half of nursing homes were operated by corporate chains. Facilities owned by the largest for-profit chains were reported to have lower quality of care. However, it is unknown how nursing home chain ownerships are related with experiences of care. OBJECTIVES: To study the relationship between nursing home chain characteristics (chain size and profit status) with patients' family member reported ratings on experiences with care. DATA SOURCES AND STUDY DESIGN: Maryland nursing home care experience reports, the Online Survey, Certification, And Reporting (OSCAR) files, and Area Resource Files are used. Our sample consists of all nongovernmental nursing homes in Maryland from 2007 to 2010. Consumer ratings were reported for: overall care; recommendation of the facility; staff performance; care provided; food and meals; physical environment; and autonomy and personal rights. We identified chain characteristics from OSCAR, and estimated multivariate random effect linear models to test the effects of chain ownership on care experience ratings. RESULTS: Independent nonprofit nursing homes have the highest overall rating score of 8.9, followed by 8.6 for facilities in small nonprofit chains, and 8.5 for independent for-profit facilities. Facilities in small, medium, and large for profit chains have even lower overall ratings of 8.2, 7.9, and 8.0, respectively. We find similar patterns of differences in terms of recommendation rate, and important areas such as staff communication and quality of care. CONCLUSIONS: Evidence suggests that Maryland nursing homes affiliated with large-for-profit and medium-for-profit chains had lower ratings of family reported experience with care. PMID- 26765150 TI - Subnanometer Molybdenum Sulfide on Carbon Nanotubes as a Highly Active and Stable Electrocatalyst for Hydrogen Evolution Reaction. AB - Electrochemically splitting water for hydrogen evolution reaction (HER) has been viewed as a promising approach to produce renewable and clean hydrogen energy. However, searching for cheap and efficient HER electrocatalysts to replace the currently used Pt-based catalysts remains an urgent task. Herein, we develop a one-step carbon nanotube (CNT) assisted synthesis strategy with CNTs' strong adsorbability to mediate the growth of subnanometer-sized MoS(x) on CNTs. The subnanometer MoS(x)-CNT hybrids achieve a low overpotential of 106 mV at 10 mA cm(-2), a small Tafel slope of 37 mV per decade, and an unprecedentedly high turnover frequency value of 18.84 s(-1) at eta = 200 mV among all reported non-Pt catalysts in acidic conditions. The superior performance of the hybrid catalysts benefits from the presence of a higher number of active sites and the abundant exposure of unsaturated S atoms rooted in the subnanometer structure, demonstrating a new class of subnanometer-scale catalysts. PMID- 26765148 TI - ICU Telemedicine and Critical Care Mortality: A National Effectiveness Study. AB - BACKGROUND: Intensive care unit (ICU) telemedicine is an increasingly common strategy for improving the outcome of critical care, but its overall impact is uncertain. OBJECTIVES: To determine the effectiveness of ICU telemedicine in a national sample of hospitals and quantify variation in effectiveness across hospitals. RESEARCH DESIGN: We performed a multicenter retrospective case-control study using 2001-2010 Medicare claims data linked to a national survey identifying US hospitals adopting ICU telemedicine. We matched each adopting hospital (cases) to up to 3 nonadopting hospitals (controls) based on size, case mix, and geographic proximity during the year of adoption. Using ICU admissions from 2 years before and after the adoption date, we compared outcomes between case and control hospitals using a difference-in-differences approach. RESULTS: A total of 132 adopting case hospitals were matched to 389 similar nonadopting control hospitals. The preadoption and postadoption unadjusted 90-day mortality was similar in both case hospitals (24.0% vs. 24.3%, P=0.07) and control hospitals (23.5% vs. 23.7%, P<0.01). In the difference-in-differences analysis, ICU telemedicine adoption was associated with a small relative reduction in 90 day mortality (ratio of odds ratios=0.96; 95% CI, 0.95-0.98; P<0.001). However, there was wide variation in the ICU telemedicine effect across individual hospitals (median ratio of odds ratios=1.01; interquartile range, 0.85-1.12; range, 0.45-2.54). Only 16 case hospitals (12.2%) experienced statistically significant mortality reductions postadoption. Hospitals with a significant mortality reduction were more likely to have large annual admission volumes (P<0.001) and be located in urban areas (P=0.04) compared with other hospitals. CONCLUSIONS: Although ICU telemedicine adoption resulted in a small relative overall mortality reduction, there was heterogeneity in effect across adopting hospitals, with large-volume urban hospitals experiencing the greatest mortality reductions. PMID- 26765151 TI - Empathy and stress in nurses working in haemodialysis: a qualitative study. AB - AIMS: To explore the concepts of empathy and stress in nurses working in haemodialysis units in France and their possible interactions. BACKGROUND: Nurses' work in haemodialysis is rather complex. It requires technical expertise, because of the peculiarity of the treatment, and emotional skills, to care for patients throughout a long-lasting therapy. Empathy is considered as a key in the concept of caring, which allows nurses to give appropriate answers to their patients' needs. In addition, nurses' work environment can generate stress. DESIGN: A qualitative descriptive design. METHOD: Nurses (N = 23) working in haemodialysis units were interviewed in three different sites in 2014. RESULTS: The analysis of nurses' speech emphasized a predominance of the cognitive attributes of empathy: understanding, communication, adjusted response (43%), and a special feature of the relationship due to the chronicity of the care (23%). The main stressors highlighted were time management (14%), emergencies (12%) and technical nature of the task (8%). Nurses' experience in haemodialysis seemed to be a modulating factor regarding empathy and stress. The main stressors highlighted were time management (14%), emergencies (12%) and technical nature of the task (8%). Nurses' experience in haemodialysis seemed to be a modulating factor regarding empathy and stress. CONCLUSION: The results showed the special features of nurses' work in haemodialysis and the need for further studies to investigate these concepts. The influence of stress on empathy needs to be explored more precisely, especially regarding nurses' experience and its impact on patients. PMID- 26765152 TI - Treatment strategies for infertile women with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a common reproductive disorder that can be diagnosed when two of the following three criteria are present: menstrual irregularity, hyperandrogenism and polycystic ovaries. Factors such as the individual's body weight influence the severity of the phenotype and risk of metabolic comorbidities. While anovulatory infertility is a common issue among lean and obese reproductive-aged women with PCOS, obesity is associated with resistance to oral ovulation induction agents, lower pregnancy rates and a higher risk of pregnancy complications. Lifestyle modification is recommended as first line therapy among obese women with PCOS in order to optimize their outcomes. Among lean and obese women with PCOS, ovulation induction can be achieved with aromatase inhibitors, selective estrogen receptor modulators, insulin sensitizing agents, gonadotropins and ovarian drilling with varying rates of ovulation, live birth and multiple gestations. Assisted reproductive technologies are reserved for women who do not conceive despite restoration of ovulation or couples with additional factors contributing to their infertility. This review will outline treatment strategies for achieving a healthy pregnancy among lean and obese women with PCOS and infertility. PMID- 26765153 TI - Raman microscopy at the subcellular level: a study on early apoptosis in endothelial cells induced by Fas ligand and cycloheximide. AB - High spatially resolved Raman microscopy was applied to study the early apoptosis in endothelial cells and chemical and structural changes induced by this process. Application of cluster analysis enabled separation of signals due to various subcellular organelles and compartments such as the nuclei, nucleoli, endoplasmic reticulum or cytoplasm and analysis of alterations locally at the subcellular level. Different stimuli, i.e. Fas ligand, a tumor necrosis factor, and cycloheximide, an inhibitor of eukaryotic protein biosynthesis, were applied to induce apoptotic mechanisms. Due to different mechanisms of action, the changes observed in subcellular structures were different for FasL and cycloheximide. Although in both cases a statistically significant decrease of the protein level was observed in all studied cellular structures, the increase of the nucleic acids content locally in apoptotic nuclei was considerably more pronounced upon FasL-induced apoptosis compared to the cycloheximide one. Additionally, apoptosis invokes also a decrease of the proteins with the alpha-helix protein structure selectively for FasL in the cytoplasm and endoplasmic reticulum. PMID- 26765155 TI - Venous Ulcers, Falls, Balance Confidence, and Strength: Cause and Effect. PMID- 26765154 TI - Efficacy assessment of three inactivated koi herpes virus antigen preparations against experimental challenge virus infection in common carp. PMID- 26765156 TI - The Ups and Downs of the 2016 Medicare Physician Fee Schedule. PMID- 26765157 TI - An Automated and Minimally Invasive Tool for Generating Autologous Viable Epidermal Micrografts. AB - OBJECTIVE: A new epidermal harvesting tool (CelluTome; Kinetic Concepts, Inc, San Antonio, Texas) created epidermal micrografts with minimal donor site damage, increased expansion ratios, and did not require the use of an operating room. The tool, which applies both heat and suction concurrently to normal skin, was used to produce epidermal micrografts that were assessed for uniform viability, donor site healing, and discomfort during and after the epidermal harvesting procedure. DESIGN: This study was a prospective, noncomparative institutional review board approved healthy human study to assess epidermal graft viability, donor-site morbidity, and patient experience. SETTING: These studies were conducted at the multispecialty research facility, Clinical Trials of Texas, Inc, San Antonio. PATIENTS: The participants were 15 healthy human volunteers. RESULTS: The average viability of epidermal micrografts was 99.5%. Skin assessment determined that 76% to 100% of the area of all donor sites was the same in appearance as the surrounding skin within 14 days after epidermal harvest. A mean pain of 1.3 (on a scale of 1 to 5) was reported throughout the harvesting process. CONCLUSIONS: Use of this automated, minimally invasive harvesting system provided a simple, low cost method of producing uniformly viable autologous epidermal micrografts with minimal patient discomfort and superficial donor-site wound healing within 2 weeks. PMID- 26765158 TI - Wound Care Algorithm: Diagnosis and Treatment. AB - There has been a dramatic rise in the incidence of wounds in the United States. Chronic wounds are not only difficult and costly to treat, but also have a devastating impact on the patients, caregivers, and on society as a whole. Many factors influence the etiology of wounds. The goal of this article is to educate all types of healthcare providers on the evaluation process and the various available treatment options of chronic wounds. With the information presented in this article, providers will be able to achieve faster healing and hopefully decrease the total number of chronic and debilitating wounds. PMID- 26765159 TI - Frequent Application of the New Gelatin-Collagen Nonwoven Accelerates Wound Healing. AB - OBJECTIVE: Mortality after chronic wounds is high. Thus, proper and effective therapy is of critical importance. Adult mammalian skin cannot regenerate spontaneously. It heals under scar formation in a process of repair. In general, wound closure is achieved through a combination of contraction, scar formation, and regeneration. To enhance wound healing, research groups are continuously inventing and evaluating novel skin replacement products. A single application of a new gelatin-collagen nonwoven accelerates wound closure of full-thickness skin defects. Therefore, the authors' objective was to evaluate the effect of a higher application frequency of the nonwoven on wound closure in a minipig model. MATERIALS AND METHODS: Four full-thickness skin defects were created surgically on the dorsum of 12 Gottingen minipigs. Next, 3 wounds were treated randomly with a novel gelatin-collagen nonwoven in different thicknesses, while the fourth wound was left untreated and served as the control wound. Moreover, 6 minipigs achieved multiple applications of the wound dressing. During the experimental period of 21 days, a close-up photographic documentation was performed. Finally, the areas of the initial wounds were excised and examined histologically. RESULTS: More frequent application of the nonwoven achieved accelerated wound healing and better epidermis quality compared with a single application. Mean time until wound closure of all wounds treated with a multiple application of the nonwoven was 11.0 (+/- 1.2) days, compared with a single application of the nonwoven with 12.4 (+/- 1.26) days and control wounds with 13.5 (+/- 1.19) days. Furthermore, the epidermal thickness of all wounds treated with multiple applications of the nonwoven was increased by 10.67 MUm (31.89 +/- 8.86 MUm, P = .0007) compared with a single application of the nonwoven and by 6.53 MUm (27.75 +/- 7.24 MUm, P = .0435) compared with the control group. CONCLUSIONS: Multiple applications of the gelatin-collagen nonwoven may be an appropriate treatment for chronic wounds leading to a fast wound closure through a combination of contraction and re-epithelialization. PMID- 26765160 TI - The Effect of Warm Compress Bistage Intervention on the Rate of Episiotomy, Perineal Trauma, and Postpartum Pain Intensity in Primiparous Women with Delayed Valsalva Maneuver Referring to the Selected Hospitals of Shiraz University of Medical Sciences in 2012-2013. AB - BACKGROUND: Genital trauma during vaginal delivery may result from episiotomy, spontaneous perineal tears (perineum, vagina), or both. In 2012, this study aimed to investigate the effect of warm compress bistage intervention on the rate of episiotomy, perineal trauma, and postpartum pain intensity in the primiparous woman with delayed Valsalva maneuver. METHODS: In this randomized clinical trial, which was performed in hospitals in Shiraz, Iran, in 2012-2013, 150 women were randomly divided into 2 groups: 1 intervention and 1 control. The intervention group received warm compress bistage intervention at 7-cm and 10-cm dilatation and zero position during the first and second stages of labor for 15 to 20 minutes, whereas the control group received the hospitals' routine care. After delivery, the prevalence of episiotomy; intact perineum; location, degree, and length of rupture; and postpartum pain intensity were assessed in the 2 groups. Following that, the data were analyzed with SPSS statistical software (version 16) using chi test, t test, and odds ratio. RESULTS: The results revealed a significant difference between the intervention and control groups regarding the frequency of intact perinea (27% vs 6.7%) and the frequency of episiotomy (45% vs 90.70%). In addition, the frequency of the location of rupture (P = .019), mean length of episiotomy incision (P = .02), and mean intensity of pain the day after delivery (P < .001) were significantly lower in the intervention group compared with the control group. However, the rate of ruptures was higher in the intervention group. CONCLUSIONS: Warm compress bistage intervention was effective in reducing episiotomies and the mean length of episiotomy incision, reducing pain after delivery, and increasing the rate of intact perinea. However, the rate of ruptures slightly increased in the intervention group compared with the control group. PMID- 26765161 TI - Falls, Balance Confidence, and Lower-Body Strength in Patients Seeking Outpatient Venous Ulcer Wound Care. AB - PURPOSE & ABSTRACT: To provide information about a quality improvement project examining falls in persons seeking outpatient wound care. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to:1. Describe the scope of the problem and the related quality improvement project. 2. Delineate the results of the project and their implications for treatment of patients with venous ulcers. OBJECTIVE: The authors aim to examine fall occurrence and fall injuries in persons seeking outpatient wound care and to compare falls, balance confidence, and lower-body strength in persons with injection-related venous ulcers (IRVUs) versus persons with venous ulcers (VUs) related to other risk factors besides injection drugs (VUs-other). DESIGN: This quality improvement project used a cross-sectional, comparative design. Participants responded to demographic questions, the Activities-specific Balance Confidence (ABC) Scale, fear of falling, fall numbers, and injuries and performed the 30-second chair rise test. SETTING: Outpatient wound service. PATIENTS: Patients (N = 106; mean age, 59.94 years) included men (66%) and women. RESULTS: Sixty patients reported falling; 47 were recurrent fallers. Twenty patients stated they were injured, but did not go to an emergency department. A higher number of total falls was significantly related to more comorbidities. Total falls were significantly related to fear of falling and ABC Scale scores. Those with VUs-other had significantly more comorbidities and higher body mass index values than those with IRVUs. Those with IRVUs were comparable to those VUs-other on number of falls and fear of falling, respectively. Those with IRVUs (7.30) performed significantly more chair rises than those with VUs-other (4.72). Persons with IRVUs had significantly higher ABC Scale scores (63.24%) than those with VUs other (49.38%). CONCLUSIONS: Falls are a common occurrence in persons seeking outpatient wound care. Despite greater strength sufficient to perform more chair rises among those with IRVUs, fall rates were comparable to those of weaker individuals with other types of VUs. With the high occurrence of falls during the project, long-term risk for fall injury would be high. Further research is needed to clarify interactions between VU risk and patient factors such as strength, age, agility, and impaired cognition. PMID- 26765162 TI - The Strategic View of Modified Stage 2 Meaningful Use: Part 2. PMID- 26765163 TI - Falls, Balance Confidence, and Lower-Body Strength in Patients Seeking Outpatient Venous Ulcer Wound Care. PMID- 26765164 TI - Tuning Ag29 nanocluster light emission from red to blue with one and two-photon excitation. AB - We demonstrate that the tuning of the light emission from red to blue in dihydrolipoic acid (DHLA) capped Ag29 nanoclusters can be trigged with one and two photon excitations. The cluster stoichiometry was determined with mass spectrometry and found to be Ag29(DHLA)12. In a detailed optical investigation, we show that these silver nanoclusters exhibit a strong red photoluminescence visible to the naked eye and characterized by a quantum yield of nearly ~2% upon one-photon excitation. In the nonlinear optical (NLO) study of the properties of the clusters, the two-photon excited fluorescence spectra were recorded and their first hyperpolarizability obtained. The two-photon absorption cross-section at ~800 nm for Ag29(DHLA)12 is higher than 10(4) GM and the hyperpolarizability is 106 * 10(-30) esu at the same excitation wavelength. The two-photon excited fluorescence spectrum appears strongly blue-shifted as compared to the one-photon excited spectrum, displaying a broad band between 400 and 700 nm. The density functional theory (DFT) provides insight into the structural and electronic properties of Ag29(DHLA)12 as well as into interplay between metallic subunit or core and ligands which is responsible for unique optical properties. PMID- 26765166 TI - Transient Ion-Pair Separations for Electrospray Mass Spectrometry. AB - We report a novel ion-pair chromatography (IPC) approach for liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS), where the eluent does not contain any ion-pairing reagent (IPR). The IPR is injected on the column, much like the sample, and moves down the column. Significant amounts of a high retention factor IPR is injected, resulting in a transient but reproducible regional coating that progresses along the column. The sample is injected after a brief interval. The sample components interact with the IPR coated region during their passage; the chosen eluent gradient elutes the analytes of interest into the mass spectrometer before the IPR. Following analyte elution, the gradient is steeply raised, the IPR is washed out, and the effluent is sent to waste via a diverter valve until it is fully removed. As the nature of the analyte retention continuously changes along the column and with time, we call this transient ion pair separation (TIPS). As the IPR never enters the MS, TIPS addresses two major drawbacks of IPC for ESI-MS: it avoids both ion suppression and ion source contamination. The potential of the generic approach for other modes of separation is discussed. An illustrative separation of two small inorganic ions, iodate and nitrate, is demonstrated on a reverse phase column by a transient prior injection of hexadecyltrimethylammonium chloride as IPR. PMID- 26765165 TI - Sensory subtypes and anxiety in older children and adolescents with autism spectrum disorder. AB - This study aimed to identify sensory subtypes in older children and adolescents with Autism Spectrum Disorders (ASD) and examine the relationship of sensory subtypes with anxiety levels in this group. Mothers of 57 children and adolescents with ASD aged 11-17 years (Mean age = 14 years. 2.4 months, SD = 1.81) completed the short sensory profile and Spence anxiety scales. Model-based cluster analysis was applied to sensory profile scores to identify sensory subtypes. Three sensory subtypes, sensory adaptive (N = 19), sensory moderate (N = 29) and sensory severe (N = 9) were identified. The results indicated that the differences between the subtypes were well characterised by the severity of sensory symptoms and were not attributable to sensory modality or varying types of sensory-related behaviors. Children and adolescents from the adaptive subtype had significantly lower anxiety scores when compared with other two subtypes. There were no differences between subtypes based on chronological age, expressive language, or severity of autism diagnostic features as measured by the social communication questionnaire (SCQ total score). This is the first study to identify the existence of sensory subtypes among older children and adolescents with ASD and explore their association with anxiety levels. Autism Res 2016, 9: 1073-1078. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26765168 TI - Correction: Association between Body Mass Index and Prognosis of Colorectal Cancer: A Meta-Analysis of Prospective Cohort Studies. PMID- 26765167 TI - Fatal traumatic brain injuries in the construction industry, 2003-2010. AB - BACKGROUND: Research on fatal work-related traumatic brain injuries (TBIs) is limited. This study describes fatal TBIs in the US construction industry. METHODS: Fatal TBIs were extracted from the Bureau of Labor Statistics Census of Fatal Occupational Injuries. RESULTS: From 2003 to 2010, 2,210 fatal TBIs occurred in construction at a rate of 2.6 per 100,000 full-time equivalent (FTE) workers. Workers aged 65 years and older had the highest fatal TBI rates among all workers (7.9 per 100,000 FTE workers). Falls were the most frequent injury event (n = 1,269, 57%). Structural iron and steel workers and roofers had the highest fatal TBI rate per 100,000 FTE workers (13.7 and 11.2, respectively). Fall-related TBIs were the leading cause of death in these occupations. CONCLUSIONS: A large percentage of TBIs in the construction industry were due to falls. Emphasis on safety interventions is needed to reduce these fall-related TBIs, especially among vulnerable workers. PMID- 26765169 TI - Energetics of Photoinduced Charge Migration within the Tryptophan Tetrad of an Animal (6-4) Photolyase. AB - Cryptochromes and photolyases are flavoproteins that undergo cascades of electron/hole transfers after excitation of the flavin cofactor. It was recently discovered that animal (6-4) photolyases, as well as animal cryptochromes, feature a chain of four tryptophan residues, while other members of the family contain merely a tryptophan triad. Transient absorption spectroscopy measurements on Xenopus laevis (6-4) photolyase have shown that the fourth residue is effectively involved in photoreduction but at the same time could not unequivocally ascertain the final redox state of this residue. In this article, polarizable molecular dynamics simulations and constrained density functional theory calculations are carried out to reveal the energetics of charge migration along the tryptophan tetrad. Migration toward the fourth tryptophan is found to be thermodynamically favorable. Electron transfer mechanisms are sought either through an incoherent hopping mechanism or through a multiple sites tunneling process. The Jortner-Bixon formulation of electron transfer (ET) theory is employed to characterize the hopping mechanism. The interplay between electron transfer and relaxation of protein and solvent is analyzed in detail. Our simulations confirm that ET in (6-4) photolyase proceeds out of equilibrium. Multiple site tunneling is modeled with the recently proposed flickering resonance mechanism. Given the position of energy levels and the distribution of electronic coupling values, tunneling over three tryptophan residues may become competitive in some cases, although a hopping mechanism is likely to be the dominant channel. For both reactive channels, computed rates are very sensitive to the starting protein configuration, suggesting that both can take place and eventually be mixed, depending on the state of the system when photoexcitation takes place. PMID- 26765199 TI - Caregiver burden in family carers of people with dementia with Lewy bodies and Alzheimer's disease. AB - OBJECTIVE: To characterise the differences in caregiver distress between carers of people diagnosed with dementia with Lewy bodies (DLB) and people with Alzheimer's disease (AD), with a view to differentiating and improving support for caregivers. METHODS: This study is a part of two larger Norwegian studies, DemVest (n = 265) and The Norwegian Dementia Register (n = 2220), with data from caregivers and people diagnosed with AD (n = 100) and DLB (n = 86) between 2005 and 2013. The average age was 74.9 years (SD = 7.8). Caregiver distress was rated by the Relative Stress Scale. Diagnosis of the person receiving care was based on a comprehensive standardised assessment program (International Classification of Diseases, Revision 10 or Diagnostic and Statistical Manual for Mental Disorders, fourth edition). Additional data collected from people receiving care were neuropsychiatric symptoms, comorbidity and activities of daily living (ADL) score. Linear regression analyses were applied, first unadjusted and then in stepwise-adjusts in addition to descriptive analyses. RESULTS: Caregivers to people with AD (20.2%) and 40% of caregivers for people with DLB experienced moderate or high caregiver burden with an increased risk of psychiatric disorders in the early stage of dementia. High Relative Stress Scale (RSS) total scores in caregivers was significantly associated with neuropsychiatric symptoms (Neuropsychiatric Inventory, p = 0.004) and also with impaired ADL functioning (Rapid Disability Rating Scale-2, p < 0.0005). CONCLUSION: Caregiver distress differed (RSS total, p = 0.005) between people caring for someone with AD (15.0) and those caring for someone with DLB (19.9). These findings have direct implications for the needs and resources that could be available for these individuals and indicate the need for further research into caregiver burden in carers to people with DLB. Copyright (c) 2016 John Wiley & Sons, Ltd. ETHICS AND DISSEMINATION: Cohorts were ethically approved by the Regional Ethics Committee for Medical Research Ethics in Eastern and Western Norway. PMID- 26765200 TI - SnxTi1-xO2 solid-solution-nanoparticle embedded mesoporous silica (SBA-15) hybrid as an engineered photocatalyst with enhanced activity. AB - Synthesis of hybrids of a porous host-material (with well-dispersed embedded nanoparticles inside the pore), wherein each nanoparticle has precisely controlled properties (size and composition) poses a generic challenge. To this end, a new strategy is proposed to form SnxTi1-xO2 solid-solution-nanoparticles inside the pores of sphere-like mesoporous silica (SBA-15), with different percentages of Sn in the nanoparticle (varying from 5 to 50 at%), for enhanced photocatalysis. X-ray diffraction confirms the formation of solid-solution nanoparticles in the porous silica hybrid, while the location of nanoparticles and elemental composition are identified using electron microscopy. The hybrid with 5 at% of Sn (Sn0.05Ti0.95O2-sphere-like SBA-15) shows the maximum photocatalytic activity for degradation of rhodamine-B dye (first order rate constant for degradation, k = 1.86 h(-1)), compared to both pure TiO2-sphere-like SBA-15 (k = 1.38 h(-1)) or pure SnO2-sphere-like SBA-15 (k = 0.14 h(-1)) or other hybrids in this series. XPS and PL spectra suggest the formation of more oxygen vacancies during the replacement of Ti(4+) with Sn(4+). Electrochemical studies reveal that there is a reduction of charge transfer resistance from 910 kOmega cm(-2) for TiO2-sphere-like SBA-15, to 332 kOmega cm(-2) for Sn0.05Ti0.95O2 sphere-like SBA-15. These results imply that the enhancement in photocatalytic performance is as a result of delay in recombination of charge carriers. Therefore, the approach followed in the present work to form solid-solution nanoparticles inside a porous host without causing pore blockage, would be a promising route towards increasing reaction rates in catalytic applications of hybrid materials. PMID- 26765204 TI - Acantholytic variant of Duhring's disease. PMID- 26765203 TI - Mechanisms of navigating goals after testicular cancer: meaning and emotion regulation. AB - OBJECTIVE: The navigation of major life goals can be challenging to cancer survivors, particularly during young adulthood. This study examined the relationships of goal navigation skills (e.g., goal identification, goal clarification, and goal adjustment) with having a sense of life meaning, emotion regulation coping processes, and physical and psychological health indicators in young adult survivors of testicular cancer. METHODS: Men ages 18 to 29 years (N = 171; M age = 25.2, SD = 3.32) with a history of testicular cancer were recruited via the California State Cancer Registry and completed questionnaire measures including assessments of goal navigation, sense of meaning, emotional approach coping, and indicators of physical and psychological well-being. RESULTS: Goal navigation skills were negatively related to depressive symptoms (r = -0.41, p < 0.01) and positively related to physical functioning (r = 0.28, p < 0.01). Controlling for participant age and months since diagnosis, mediation models revealed significant indirect effects of sense of meaning on depressive symptoms (-0.50, p < 0.05) and physical functioning (0.34, p < 0.05). Similarly, emotion regulating coping had significant indirect effects on depressive symptoms (-0.08, p < 0.05) and physical functioning (0.11, p < 0.05) CONCLUSIONS: Consistent with a self-regulation framework, goal navigation skill is related to physical and psychological well-being via its association with maintenance of a sense of meaning as well as successful attempts at regulation of emotions. The study provides preliminary evidence that these skill-based processes relate to adjustment to cancer in young adults. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26765206 TI - Chemoselectivity and the Chan-Lam Coupling Reaction: Adding Amino Acids to Polymer-Coated Microelectrode Arrays. AB - The placement of a peptide onto a microelectrode array is frequently complicated by the presence of multiple nucleophiles in the peptide. In the work reported here, we have found that the Chan-Lam coupling reactions used to site-selectively place thiol, alcohol, and amine nucleophiles onto diblock-copolymer-coated surfaces are chemoselective for the placement of thiol and alcohol nucleophiles on the arrays. This means that cysteine- and serine-containing peptides can be placed onto an array without any need to protect the N terminus of the peptide. Furthermore, it was found that placement of thiol groups onto an array with the Chan-Lam reaction using optimized reaction times leads to complete coverage of the electrodes. The extent of this coverage can be controlled by varying the reaction time in a manner that allows for the construction of arrays with a gradient of peptide concentrations. PMID- 26765207 TI - Repair of a Large Multisubunit Nasal Defect. PMID- 26765208 TI - Commentary on the Accuracy of Ultrasonography on the Location of Lipomas in the Forehead. PMID- 26765205 TI - Prevalence and associations of gout and hyperuricaemia: results from an Australian population-based study. AB - BACKGROUND: Despite gout and hyperuricaemia being major comorbid health issues worldwide, there is a knowledge gap regarding their impact in the Australian community. AIMS: To determine the prevalence and associations of self-reported medically diagnosed gout and hyperuricaemia in an Australian population-based cohort. METHODS: The North West Adelaide Health Study is a longitudinal cohort study consisting of three stages of data collection. Each stage comprised a self complete questionnaire, clinic assessment and computer-assisted telephone interview. In Stage 3 (2008-2010), participants were asked if a doctor had ever diagnosed them with gout. Additional data included demographics, comorbidities, laboratory data and Short Form 36 (SF-36). Participants were defined as having gout if they had self-reported medically diagnosed gout or were taking any gout specific medication (allopurinol, colchicine, probenecid). Hyperuricaemia was defined as a serum uric acid (SUA) level >0.42 mmol/L in men and >0.34 mmol/L in women. RESULTS: The overall prevalence of gout was 5.2%. Males were significantly more likely to have gout than females (8.5 vs 2.1%, P < 0.001). The overall prevalence of hyperuricaemia was 16.6%, with being male again identified as a significant risk factor (17.8 vs 15.4%, P < 0.01). Both gout and hyperuricaemia were associated with male sex, body mass index and renal disease after multivariable adjustment. There was no significant difference reported in quality of life (mean SF-36) scores in participants with gout compared to unaffected individuals. CONCLUSION: The prevalence of gout and hyperuricaemia is high in the South Australian population. This study emphasises the need for optimal diagnosis and management of gout in Australia. PMID- 26765209 TI - Reconstruction of a Large Defect on the Superior Helical Rim. PMID- 26765211 TI - Metal free earth abundant elemental red phosphorus: a new class of visible light photocatalyst and photoelectrode materials. AB - Developing a high-performance photocatalyst and a photoelectrode with enhanced visible light harvesting properties is essential for practical visible light photocatalytic applications. Noble metal-free, highly visible light-active, elemental red phosphorus (RP) was prepared by a facile mechanical ball milling method, which is a reproducible, low cost and controllable synthesis process. The synthesis used inexpensive and abundant raw materials because most RP hybrids are based on expensive noble-metals. The novel milled RP showed significantly enhanced photocatalytic and photoelectrochemical performances with a lower charge transfer resistance compared to commercial RP under wide visible photoirradiation, making it a feasible alternative for photocatalytic applications. PMID- 26765210 TI - Maternal Pharmacokinetics and Fetal Disposition of (+/-)-Citalopram during Mouse Pregnancy. AB - While selective-serotonin reuptake inhibitor (SSRI) antidepressants are commonly prescribed in the treatment of depression, their use during pregnancy leads to fetal drug exposures. According to recent reports, such exposures could affect fetal development and long-term offspring health. A central question is how pregnancy-induced physical and physiological changes in mothers, fetuses, and the placenta influence fetal SSRI exposures during gestation. In this study, we examined the effects of gestational stage on the maternal pharmacokinetics and fetal disposition of the SSRI (+/-)-citalopram (CIT) in a mouse model. We determined the maternal and fetal CIT serum concentration-time profiles following acute maternal administration on gestational days (GD)14 and GD18, as well as the fetal brain drug disposition. The results show that pregnancy affects the pharmacokinetics of CIT and that maternal drug clearance increases as gestation progresses. The data further show that CIT and its primary metabolite desmethylcitalopram (DCIT) readily cross the placenta into the fetal compartment, and fetal exposure to CIT exceeds that of the mother during gestation 2 h after maternal administration. Enzymatic activity assays revealed that fetal drug metabolic capacity develops in late gestation, resulting in elevated circulating and brain concentrations of DCIT at embryonic day (E)18. Fetal exposure to the SSRI CIT in murine pregnancy is therefore influenced by both maternal gestational stage and embryonic development, suggesting potential time-dependent effects on fetal brain development. PMID- 26765212 TI - Principal Component Analysis of Lipid Molecule Conformational Changes in Molecular Dynamics Simulations. AB - Molecular dynamics simulations of lipid bilayers are ubiquitous nowadays. Usually, either global properties of the bilayer or some particular characteristics of each lipid molecule are evaluated in such simulations, but the structural properties of the molecules as a whole are rarely studied. Here, we show how a comprehensive quantitative description of conformational space and dynamics of a single lipid molecule can be achieved via the principal component analysis (PCA). We illustrate the approach by analyzing and comparing simulations of DOPC bilayers obtained using eight different force fields: all-atom generalized AMBER, CHARMM27, CHARMM36, Lipid14, and Slipids and united-atom Berger, GROMOS43A1-S3, and GROMOS54A7. Similarly to proteins, most of the structural variance of a lipid molecule can be described by only a few principal components. These major components are similar in different simulations, although there are notable distinctions between the older and newer force fields and between the all-atom and united-atom force fields. The DOPC molecules in the simulations generally equilibrate on the time scales of tens to hundreds of nanoseconds. The equilibration is the slowest in the GAFF simulation and the fastest in the Slipids simulation. Somewhat unexpectedly, the equilibration in the united-atom force fields is generally slower than in the all-atom force fields. Overall, there is a clear separation between the more variable previous generation force fields and significantly more similar new generation force fields (CHARMM36, Lipid14, Slipids). We expect that the presented approaches will be useful for quantitative analysis of conformations and dynamics of individual lipid molecules in other simulations of lipid bilayers. PMID- 26765213 TI - Reversible, Selective Trapping of Perchlorate from Water in Record Capacity by a Cationic Metal-Organic Framework. AB - We report the capture of ppm-level aqueous perchlorate in record capacity and kinetics via the complete anion exchange of a cationic metal-organic framework. Ambient conditions were used for both the synthesis of silver 4,4'-bipyridine nitrate (SBN) and the exchange, forming silver 4,4'-bipyridine perchlorate (SBP). The exchange was complete within 90 min, and the capacity was 354 mg/g, representing 99% removal. These values are greater than current anion exchangers such as the resins Amberlite IRA-400 (249 mg/g), Purolite A530E (104 mg/g), and layered double hydroxides (28 mg/g). Moreover, unlike resins and layered double hydroxides, SBN is fully reusable and displays 96% regeneration to SBN in nitrate solution, with new crystal formation allowing the indefinite cycling for perchlorate. We show seven cycles as proof of concept. Perchlorate contamination of water represents a serious health threat because it is a thyroid endocrine disruptor. This noncomplexing anionic pollutant is significantly mobile and environmentally persistent. Removal of other anionic pollutants from water such as chromate, pertechnetate, or arsenate may be possible by this methodology. PMID- 26765220 TI - Bananas, pesticides and health in southwestern Ecuador: A scalar narrative approach to targeting public health responses. AB - Public health responses to agricultural pesticide exposure are often informed by ethnographic or other qualitative studies of pesticide risk perception. In addition to highlighting the importance of structural determinants of exposure, such studies can identify the specific scales at which pesticide-exposed individuals locate responsibility for their health issues, with implications for study and intervention design. In this study, an ethnographic approach was employed to map scalar features within explanatory narratives of pesticides and health in Ecuador's banana-producing El Oro province. Unstructured observation, 14 key informant interviews and 15 in-depth semi-structured interviews were carried out during 8 months of fieldwork in 2011-2013. Analysis of interview data was informed by human geographic literature on the social construction of scale. Individual-focused narratives of some participants highlighted characteristics such as carelessness and ignorance, leading to suggestions for educational interventions. More structural explanations invoked farm-scale processes, such as uncontrolled aerial fumigations on plantations owned by elites. Organization into cooperatives helped to protect small-scale farmers from 'deadly' banana markets, which in turn were linked to the Ecuadorian nation-state and actors in the banana consuming world. These scalar elements interacted in complex ways that appear linked to social class, as more well-off individuals frequently attributed the health problems of other (poorer) people to individual behaviours, while providing more structural explanations of their own difficulties. Such individualizing narratives may help to stabilize inequitable social structures. Research implications of this study include the possibility of using scale focused qualitative research to generate theory and candidate levels for multi level models. Equity implications include a need for public health researchers planning interventions to engage with scale-linked inequities, such as disparities within nation-states. Finally, the prominence of the global North in explanatory narratives is a useful reminder that 'structural factors' prominently include inequities related to the legacies of colonialism. PMID- 26765219 TI - Therapeutic implication of genetic variants of IL13 and STAT4 in airway remodelling with bronchial asthma. AB - BACKGROUND: Several gene variants identified in bronchial asthmatic patients are associated with a decrease in pulmonary function. The effects of this intervention on pulmonary function have not been fully researched. OBJECTIVE: We determined the effects of high-dose inhaled corticosteroids (ICSs) on decreased pulmonary function in asthmatic Japanese patients with variants of IL13 and STAT4 during long-term treatments with low to mild doses of ICS. METHODS: In this study, 411 patients with bronchial asthma who were receiving ICSs and living in Japan were recruited, were genotyped, and underwent pulmonary function tests and fibreoptic examinations. The effects of 2 years of high-dose ICSs administered to asthmatic patients who were homozygous for IL13 AA of rs20541 or STAT4 TT of rs925847 and who progressed to airway remodelling were investigated. RESULTS: High-dose ICS treatment increased the pulmonary function of patients homozygous for IL13 AA of rs20541 but not of patients homozygous for STAT4 TT of rs925847. The increased concentrations of the mediators IL23, IL11, GMCSF, hyaluronic acid, IL24, and CCL8 in bronchial lavage fluid (BLF) were diminished after high-dose ICS treatment in patients homozygous for IL13 AA of rs20541. CONCLUSION AND CLINICAL RELEVANCE: IL13 AA of rs20541 and STAT4 TT of rs925847 are potential genomic biomarkers for predicting lower pulmonary function. The administration of high-dose ICSs to asthmatic patients with genetic variants of IL13 AA may inhibit the advancement of airway remodelling. The genetic variants of STAT4 TT did not respond to high-dose ICSs. Therefore, using medications other than ICSs must be considered even during the initial treatment of bronchial asthma. These genetic variants may aid in the realization of personalized and phenotype-specific therapies for bronchial asthma. PMID- 26765222 TI - Clinical relevance of cyclic GMP modulators: A translational success story of network pharmacology. AB - Therapies that modulate cyclic guanosine-3'-5'-monophosphate (cGMP) have emerged as one of the most successful areas in recent drug discovery and clinical pharmacology. Historically, their focus has been on cardiovascular disease phenotypes; however, cGMP's relevance is likely to go beyond this rather limited organ-based set of indications. Moreover, the multitude of targets and their apparent interchangeability is a proof-of-concept of network pharmacology. PMID- 26765223 TI - Am I in Labor? PMID- 26765221 TI - Economic hardship and biological weathering: The epigenetics of aging in a U.S. sample of black women. AB - BACKGROUND: Past research has linked low socio-economic status (SES) to inflammation, metabolic dysregulation, and various chronic and age-related diseases such as type 2 diabetes, coronary heart disease, stroke, and dementia. These studies suggest that the challenges and adversities associated with low SES may result in premature aging and increased risk of morbidity and mortality. OBJECTIVE: Building upon this research, the present study investigates various avenues whereby low income might accelerate biological aging. METHODS: Structural equation modeling and longitudinal data from a sample of 100 Black, middle-aged women residing in the United States was used to investigate the effect of income on a recently developed epigenetic measure of biological aging. This measure can be used as a "biological clock" to assess, at any point during adulthood, the extent to which an individual is experiencing accelerated or decelerated biological aging. RESULTS: Low income displayed a robust association with accelerated aging that was unaffected after controlling for other SES-related factors such as education, marital status, and childhood adversity. Further, our analyses indicated that the association between income and biological aging was not explained by health-related behaviors such as diet, exercise, smoking, alcohol consumption, or having health insurance. Rather, in large measure, it was financial pressure (difficulty paying bills, buying necessities, or meeting daily expenses) that accounted for the association between low income and accelerated aging. CONCLUSIONS: These findings support the view that chronic financial pressures associated with low income exert a weathering effect that results in premature aging. PMID- 26765227 TI - A one-stop clinic in gastroenterology - Benefits and limitations. AB - Most patients with gastrointestinal conditions may currently be studied and cared for in an outpatient clinic, with no need for hospital admission, when diagnostic procedures such as ultrasounds or endoscopy are properly used. Because of this, the Spanish National Health System must meet a high demand of clinical attendance. PMID- 26765225 TI - Negativity Bias in Dangerous Drivers. AB - The behavioral and cognitive characteristics of dangerous drivers differ significantly from those of safe drivers. However, differences in emotional information processing have seldom been investigated. Previous studies have revealed that drivers with higher anger/anxiety trait scores are more likely to be involved in crashes and that individuals with higher anger traits exhibit stronger negativity biases when processing emotions compared with control groups. However, researchers have not explored the relationship between emotional information processing and driving behavior. In this study, we examined the emotional information processing differences between dangerous drivers and safe drivers. Thirty-eight non-professional drivers were divided into two groups according to the penalty points that they had accrued for traffic violations: 15 drivers with 6 or more points were included in the dangerous driver group, and 23 drivers with 3 or fewer points were included in the safe driver group. The emotional Stroop task was used to measure negativity biases, and both behavioral and electroencephalograph data were recorded. The behavioral results revealed stronger negativity biases in the dangerous drivers than in the safe drivers. The bias score was correlated with self-reported dangerous driving behavior. Drivers with strong negativity biases reported having been involved in mores crashes compared with the less-biased drivers. The event-related potentials (ERPs) revealed that the dangerous drivers exhibited reduced P3 components when responding to negative stimuli, suggesting decreased inhibitory control of information that is task-irrelevant but emotionally salient. The influence of negativity bias provides one possible explanation of the effects of individual differences on dangerous driving behavior and traffic crashes. PMID- 26765226 TI - Beneficial Effect of Bidens pilosa on Body Weight Gain, Food Conversion Ratio, Gut Bacteria and Coccidiosis in Chickens. AB - In the interests of food safety and public health, plants and their compounds are now re-emerging as an alternative approach to treat gastrointestinal diseases in chickens. Here, we studied the impact of the edible medicinal plant, B. pilosa, on growth performance, gut bacteria and coccidiosis in chickens. First, we found that B. pilosa significantly elevated body weight gain and lowered feed conversion ratio in chickens. Next, we showed that B. pilosa reduced cecal damage as evidenced by increased hemorrhage, villus destruction and decreased villus-to crypt ratio in chicken ceca. We also performed pyrosequencing of the PCR ampilcons based on the 16S rRNA genes of gut bacteria in chickens. Metagenomic analysis indicated that the chicken gut bacteria belonged to 6 phyla, 6 classes, 6 orders, 9 families, and 8 genera. More importantly, we found that B. pilosa affected the composition of bacteria. This change in bacteria composition was correlated with body weight gain, feed conversion ratio and gut pathology in chickens. Collectively, this work suggests that B. pilosa has beneficial effects on growth performance and protozoan infection in chickens probably via modulation of gut bacteria. PMID- 26765228 TI - Efficacy of a high-resolution consultation system in gastroenterology at an Andalusian hospital center. AB - BACKGROUND: By high resolution consultation (HRC) we mean an ambulatory process of assistance fulfilled in a single day, by which treatment and diagnosis are established and recorded. OBJECTIVE: To assess to which extent patients with digestive conditions may benefit from a single consultation system. MATERIAL: A descriptive study of 179 first visit events, randomly selected as high-resolution consultations in gastroenterology. We discuss the percentage of patients who benefited from HRC and the complementary tests performed. RESULTS: Most common conditions included dyspepsia (16%), a family history of colon cancer (16%) and gastroesophageal reflux disease (GERD) (16%). Seventy-nine (44%) of all first visits became HRCs and 80 (45%) required a diagnostic test (100% abdominal ultrasound) that was reviewed on the same day. Performing a test on the same day significantly increased the percentage of HRCs (57% vs. 34%, p < 0.002). GERD, dyspepsia, cholelithiasis and chronic liver disease were the subjects most commonly leading to HRC. CONCLUSIONS: Gastroenterology consultations may largely benefit from an HRC system with only organizational changes and no additional costs. PMID- 26765229 TI - Comparative study between open and minimally invasive approach in the surgical management of esophageal leiomyoma. AB - INTRODUCTION: Leiomyomas are the most common benign tumors of the esophagus. Although classically surgical enucleation through thoracotomy or laparotomy has been widely accepted as treatment of choice, development of endoscopic and minimally invasive procedures has completely changed the surgical management of these tumors. MATERIAL AND METHODS: We performed a retrospective review of all esophageal leiomyoma operated at Hospital Universitario Ramon y Cajal (Madrid, Spain) between January 1986 and December 2014, analyzing patients' demographic data, symptomatology, tumor size and location, diagnostic tests, surgical data, complications and postoperative stay. RESULTS: Thirteen patients were found within that period, 8 men and 5 women, with a mean age of 53.62 years (range 35 70 years). Surgical enucleation was achieved in all patients. In 8 cases (61.54%) a thoracic approach was performed (4 thoracotomies and 4 thoracoscopies), and in 5 cases (38.56%) an abdominal approach was performed (3 laparotomies and 2 laparoscopies); enucleation was carried out through a minimally invasive approach in 6 patients (46.15%). There were no cases of endoscopic resection alone. Surgery mean length was 174.38 minutes (range 70-270 minutes) and median postoperative stay was 6.5 days (range 2-27 days). There was neither mortality nor cases of intraoperative complications were described. No postoperative major complications were reported; however one patient presented important pain in his right hemithorax that required management and long term follow-up by the Pain Management Unit. With a mean follow-up of 165.57 months (median 170; range 29-336 months) no recurrences were reported. CONCLUSION: Enucleation is the treatment of choice for the majority of esophageal leiomyomas. In our experience, duration of the surgical procedure through minimally invasive approach was longer than surgery through open approach; however, postoperative stay was shorter in the first group. Paradoxically, incision pain after surgery (thoracic neuralgia) was found to be higher in the minimally invasive approach group. Nevertheless, none of the results obtained in the study reached statistical significance, probably due to the small simple size. PMID- 26765224 TI - Blimp-1-Dependent IL-10 Production by Tr1 Cells Regulates TNF-Mediated Tissue Pathology. AB - Tumor necrosis factor (TNF) is critical for controlling many intracellular infections, but can also contribute to inflammation. It can promote the destruction of important cell populations and trigger dramatic tissue remodeling following establishment of chronic disease. Therefore, a better understanding of TNF regulation is needed to allow pathogen control without causing or exacerbating disease. IL-10 is an important regulatory cytokine with broad activities, including the suppression of inflammation. IL-10 is produced by different immune cells; however, its regulation and function appears to be cell specific and context-dependent. Recently, IL-10 produced by Th1 (Tr1) cells was shown to protect host tissues from inflammation induced following infection. Here, we identify a novel pathway of TNF regulation by IL-10 from Tr1 cells during parasitic infection. We report elevated Blimp-1 mRNA levels in CD4+ T cells from visceral leishmaniasis (VL) patients, and demonstrate IL-12 was essential for Blimp-1 expression and Tr1 cell development in experimental VL. Critically, we show Blimp-1-dependent IL-10 production by Tr1 cells prevents tissue damage caused by IFNgamma-dependent TNF production. Therefore, we identify Blimp-1-dependent IL-10 produced by Tr1 cells as a key regulator of TNF-mediated pathology and identify Tr1 cells as potential therapeutic tools to control inflammation. PMID- 26765231 TI - Duodenal fistula after gastrectomy: Retrospective study of 13 new cases. AB - INTRODUCTION: Duodenal stump fistula (DSF) after gastrectomy has a low incidence but a high morbidity and mortality, and is therefore one of the most aggressive and feared complications of this procedure. MATERIAL AND METHODS: We retrospectively evaluated all DSF occurred at our hospital after carrying out a gastrectomy for gastric cancer, between January 1997 and December 2014. We analyzed demographic, oncologic, and surgical variables, and the evolution in terms of morbidity, mortality and hospital stay. RESULTS: In the period covered in this study, we performed 666 gastrectomies and observed DSF in 13 patients (1.95%). In 8 of the 13 patients (61.5%) surgery was the treatment of choice and in 5 cases (38.5%) conservative treatment was carried out. Postoperative mortality associated with DSF was 46.2% (6 cases). In the surgical group, 3 patients developed severe sepsis with multiple organ failure, 2 patients presented a major hematemesis which required endoscopic haemostasis, 1 patient had an evisceration and another presented a subphrenic abscess requiring percutaneous drainage. Six patients (75%) died despite surgery, with 3 deaths in the first 24 hours of postoperative care. The 2 patients who survived after the second surgical procedure had a hospital stay of 45 and 84 days respectively. In the conservative treatment group the cure rate was 100% with no significant complications and an average postoperative hospital stay of 39.5 days (range, 26 65 days). CONCLUSION: FMD is an unusual complication but it is associated with a high morbidity and mortality. In our experience, conservative management has shown better results compared with surgical treatment. PMID- 26765230 TI - Antibiotic prophylaxis in elective cholecystectomy: Protocol adequacy and related outcomes in a retrospective single-centre analysis. AB - BACKGROUND: Antibiotic prophylaxis is an effective tool to reduce surgical infection rates. However, antibiotic prophylaxis in cholecystectomy is controversial when non-high risk patients are considered. This research aims to evaluate the adherence with antibiotic prophylaxis protocol in patients undergoing cholecystectomy, and its impact in the outcomes of surgical infection. METHODS: This single-center observational and retrospective study analyzed all elective cholecystectomy procedures carried out at the Fundacion Alcorcon University Hospital in the period 2007-2014. Data were recovered from hospital records; rates of adherence to the available hospital protocols were evaluated for choice, initiation, duration, administration route and dosages of antibiotics, and the starting and duration of the prophylaxis. RESULTS: The overall adequacy rate to protocol was 72%. The adherence rates in both the administration route and dose were 100%. The most common violations of the protocol included the choice of antibiotic agent (19%), followed by the moment of initiating its administration (8.9%). The overall wound infection rate was lower in case of laparoscopy than in laparotomy cholecystectomy (1.4% vs. 4.3%, p < 0.05; odds rate [OR] 0.29, 95% confidence interval [CI] 0.1-0.6). No relationship between adequacy of antibiotic prophylaxis and surgical infection rate was documented, neither considering overall gallbladder surgeries (crude OR 0.26, 95% CI 0.1-2.0), nor laparoscopy vs. open surgery (MH adjusted OR 0.24, 95% CI 0.2 2.1). CONCLUSIONS: The overall adequacy rate to antibiotic prophylaxis protocol recommended for elective cholecystectomy in our hospital was high (72%). No significant association between the adequacy or antibiotic prophylaxis and surgical infection was found. PMID- 26765232 TI - Epithelioid angiomyolipoma of the liver: Clinicopathological correlation in a series of 4 cases. AB - Hepatic angiomyolipoma is a rare neoplasm that can be difficult to diagnose in cases of ecoguide biopsy. We studied 4 cases of female patients with a mean age of 51 years. None of the patients presented specific abdominal symptoms, or other tumour masses detected by chance. One of them had relevant personal history: Renal cell carcinoma. This same patient was diagnosed with a contralateral renal angiomyolipoma. None of the patients showed evidence of tuberous sclerosis. Three tumours have been diagnosed by biopsy and only in one patient was decided to completely remove the tumour surgically. None of the patients had evidence of recurrence of disease or an increase in tumour size over an average period of 45 months. Histologically, the tumours have been sub classified into angiomyolipomas epithelioid. In 50% of the cases, extramedullary haematopoiesis was observed. The first diagnostic impression using imaging methods included: Focal nodular hyperplasia, hepatocellular adenoma, hepatocellular carcinoma and metastasis. By immunohistochemistry, it has been demonstrated that all tumours expressing melanocytic markers (HMB45 and Melan A) and markers of smooth muscle cells (smooth muscle actin). The diagnosis of these tumours is increasing due to programmes for early detection of hepatocellular carcinoma in patients with liver cirrhosis. It must be taken into account their broad spectrum of morphological diversity to avoid incorrect diagnosis of a malignant neoplasm. PMID- 26765234 TI - Splenosis: Non-invasive diagnosis of a great mimicker. AB - Splenosis is defined as the location of heterotopic splenic tissue implants in the abdominal cavity or other atypical location. This entity may mimic different benign and malignant processes, which may cause an inappropriate management of the patient. A previous history of splenic trauma or splenectomy should introduce this entity in the differential diagnosis in these patients. CLINICAL CASES: Clinical features and imaging findings of two cases of splenosis are presented and a review of the published literature on this entity is made. RESULTS: Based on the behavior of the lesions in different imaging techniques and taking into account the relevant history of previous splenectomy, it was possible to establish the final diagnosis of intraabdominal splenosis. CONCLUSIONS: Splenosis is an entity that should be considered in the differential diagnosis in patients with prior history of splenectomy and/or spleen trauma to avoid improper handling of them. Imaging techniques are key tools in non-invasive diagnosis of this entity. PMID- 26765233 TI - Anal intraepitelial neoplasia: A narrative review. AB - Anal intraepitelial neoplasia (AIN) constitutes a major health problem in certain risk groups, such as patients with immunosuppression of varied origin, males who have sexual relations with other males, and females with a previous history of vaginal or cervical abnormalities in cytology. Its relationship with the human papillomavirus (HPV) infection has been well documented; however, many of the factors involved in the progression and regression of the viral infection to dysplasia and anal carcinoma are unknown. AIN can be diagnosed through cytology of the anal canal or biopsy guided by high-resolution anoscopy. However, the need for these techniques in high-risk groups remains controversial. Treatment depends on the risk factors and given the high morbidity and high recurrence rates the utility of the different local treatments is still a subject of debate. Surgical biopsy is justified only in the case of progression suggesting lesions. The role of the vaccination in high-risk patients as primary prevention has been debated by different groups. However, there is no general consensus on its use or on the need for screening this population. PMID- 26765236 TI - Pelvic inflammatory myofibroblastic tumor mimicking a rectal cancer. AB - We report a case of a 50-year-old woman who presented to the emergency department with large bowel obstruction and anemia. The initial imaging study suggested an inoperable rectal tumor with involvement of surrounding structures. In this paper we discuss the diagnostic work-up of this patient with a diagnosis of pelvic/perirectal inflammatory myofibroblastic tumor (IMT). IMT is a rare tumor with intermediate malignant potential that frequently mimics clinical and imaging features of malignancy. Additionally, to the best of our knowledge, this is the first case of a pelvic IMT that regressed without surgical excision. PMID- 26765235 TI - Liver abscess secondary to duodenal perforation by fishbone: Report of a case. AB - Liver abscesses usually arise from amoebian or bacterial origin, being rarely secondary to foreign bodies (1-3). We report the case of a 72-years-old female complaining from abdominal pain located in epoigastrium and right hypochondrium during the last 48 hours. Laboratory data revealed leukocytosis with neutrophilia and pain located in the mentioned locations at physical examination. Ultrasonography showed a liver abscess involving segments 2 and 3. CT scan revealed that the abscess was secondary to a fishbone perforating the duodenum and inlaid in the liver (Figure 1). The fishbone was surgically extracted from the hepatic lobe with hemostasia and a duodenal suture with epiploplastia was performed. Antibiotic was added to the treatment. The patient presented an uneventful postoperative course. The intake of foreign bodies is a frequent event, representing bones and fishbones the most frequent foreing bodies in the adults. Sometimes, the diagnosis may be difficult because the symptoms are not specific. Imaging test are very usefol for the diagnosis, as in the case we present. PMID- 26765237 TI - Hemoperitoneum secondary to an spontaneous rupture of the spleen mimmicking a duodenal perforated ulcera: A case report. AB - Spontaneous rupture of the spleen without traumatic cause is an unfrequent entity, usually related with pathologic spleens. We present a case of spontaneous rupture of an histologically normal spleen with splenomegalia secondary to smoking habit. The hemoperitoneum caused by the spontaneous rupture of the spleen mimmicked a hollow viscera perforation. PMID- 26765238 TI - Graft versus host disease as a complication after liver transplantation: A rare but serious association. AB - The graft versus host disease after liver transplant is rare, with an incidence less than 1%, but with a high mortality (75-85%), especially due to infectious complications. It usually affects gastrointestinal tract, skin and blood system in the context of a normal liver graft function. There is no consensus on the most appropriate treatment: some articles support a reduction or even elimination of immunosuppressive drugs, while others published success with a dose increase. CLINICAL CASE: We report a case of a 68 year-old liver transplant recipient with a graft retrieved from an ABO identical cadaveric donor. After an uneventful postoperative period, he was readmitted presenting these symptoms: skin lesions, diarrhea and kidney failure. After ruling out infectious causes or drug toxicity, skin, duodenum and colon biopsies demonstrated characteristic histological changes of graft versus host disease grade III. Initially, supportive treatment along with methylprednisolone bolus were administered with good response. However, as the doses of corticosteroids decreased, the patient worsened again, requiring basiliximab. In spite of that, the patient progressively worsened with hematological involvement and, finally, an alteration of liver function tests prior to decease. The autopsy showed CMV and Herpes virus superinfection. DISCUSSION: We report a new case of graft-versus-host disease after liver transplantation with fatal evolution due to viral superinfection despite the employed measures. PMID- 26765239 TI - Hemoperitoneum secondary to perforated inflammatory myofibroblastic tumor: A case report of an unusual complication. AB - INTRODUCTION: Inflammatory myofibroblastic tumors (IMT) are rare neoplasms characterized by a proliferation of spindle-shaped cells with a stroma infiltrated by macrophages, lymphocytes and plasma cells. CASE REPORT: We report a case of 59 years old male who presented an acute abdomen due to a mass of the mesentery of the terminal ileum, which was perforated with active bleeding. Histopathology reported a low-grade TMI with clear margins. DISCUSSION: Inflammatory myofibroblastic tumors of the mesentery are rare entities whose etio pathogenia remains unclear. It requires a histopathological diagnosis and inmunohistochemical evaluation and its treatment is based on complete resection of the tumor. These type of neoplasms require close monitoring due to local recurrence. PMID- 26765240 TI - Authors' reply: Spanish or English in scientific reporting. AB - We thank Professor Culebras Fernandez his letter and his praise to the content of our recently published narrative review on percutaneous endoscopic gastrostomy. A systematic review of the literature would have required a search in multiple languages, as we recently did for other research. Aware of the diffusivity of English language in Science, an increasing number of professional and scientific journals from varied geographical origin, including many from Arab countries, India and Singapore, have adopted English as language for publication in order to provide their contents with an improving visibility. This same strategy was followed by the Spanish Journal of Gastroenterology (Revista Espanola de Enfermedades Digestivas or REED) for all its contents several decades ago. As a result, the Web of Science search provided by the Professor in his letter reveals that all the documents published on endoscopic gastrostomy in REED since 1993 are written in English. PMID- 26765241 TI - Gastric outlet obstruction: An unusual adverse event of percutaneous endoscopic gastrostomy. AB - Dear Editor, A 75-year-old woman living in a nursing home presented with a 24 hour history of abdominal cramping and vomiting. Medical history was remarkable for dementia and a percutaneous endoscopic gastrostomy (PEG) was performed 3 years earlier. The day before the admission the feeding tube was accidentally pulled out and a Foley catheter was placed in order to avoid stoma closure. On physical examination, there was extravasation of the gastric content through the stoma. The base of the "Y" of the Foley catheter was introduced in the gastric stoma and a pulling sensation was felt when it was mobilized. The remainder abdominal examination was unremarkable. On esophagogastroduodenoscopy the Foley catheter was identified passing the pylorus and pulling duodenal bulb towards the antrum (Figure 1). Advancing the scope through the duodenum, the Foley balloon impacted in the duodenal apex was identified. There was no mucosal injury so the balloon was deflated and the catheter removed. A 14 Fr. Bard PEG tube was latter placed to allow a reduction in the calibre of the stoma. Gastric outlet obstruction is an unusual adverse event of PEG tubes. In adults it is usually related to Foley catheters use as peristalsis can pull the balloon into the duodenum in the absence of an external bumper. A clinical picture of abdominal cramping, vomiting and resistance to the attempt of percutaneous reposition should raise the suspicion of gastrostomy tube migration through the pylorus. Foley catheters are easily available and some may use it to prevent gastrostomy closure after accidentally PEG tube extraction. We have performed more than 800 PEG and assisted several cases of gastric outlet obstruction and even stoma damage in this setting. This case emphasises the importance of receiving an early PEG tube with external bumper replacement to prevent this adverse event. PMID- 26765242 TI - Endoscopic submucosal dissection for a gastric fibrolipoma. AB - Fibrolipoma is one of the uncommon variant of lipomas characterized by the presence of adipose tissue and abundant amounts of fibrous tissues. It is usually encountered in a subdermal location and uncommonly involves the alimentary tract. This letter to editor describes a gastric submucosal mass which was ultimately diagnosed of fibrolipoma. PMID- 26765243 TI - Avr4 promotes Cf-4 receptor-like protein association with the BAK1/SERK3 receptor like kinase to initiate receptor endocytosis and plant immunity. AB - The first layer of plant immunity is activated by cell surface receptor-like kinases (RLKs) and proteins (RLPs) that detect infectious pathogens. Constitutive interaction with the SUPPRESSOR OF BIR1 (SOBIR1) RLK contributes to RLP stability and kinase activity. As RLK activation requires transphosphorylation with a second associated RLK, it remains elusive how RLPs initiate downstream signaling. We employed live-cell imaging, gene silencing and coimmunoprecipitation to investigate the requirement of associated kinases for functioning and ligand induced subcellular trafficking of Cf RLPs that mediate immunity of tomato against Cladosporium fulvum. Our research shows that after elicitation with matching effector ligands Avr4 and Avr9, BRI1-ASSOCIATED KINASE 1/SOMATIC EMBRYOGENESIS RECEPTOR KINASE 3 (BAK1/SERK3) associates with Cf-4 and Cf-9. BAK1/SERK3 is required for the effector-triggered hypersensitive response and resistance of tomato against C. fulvum. Furthermore, Cf-4 interacts with SOBIR1 at the plasma membrane and is recruited to late endosomes upon Avr4 trigger, also depending on BAK1/SERK3. These observations indicate that RLP-mediated resistance and endocytosis require ligand-induced recruitment of BAK1/SERK3, reminiscent of BAK1/SERK3 interaction and subcellular fate of the FLAGELLIN SENSING 2 (FLS2) RLK. This reveals that diverse classes of cell surface immune receptors share common requirements for initiation of resistance and endocytosis. PMID- 26765244 TI - Hypercoagulant Abdominal Swabs in Cardiac Surgery: Potential Problems and Background. AB - Background During cardiac surgery with heart-lung-machine support, abdominal swabs are routinely used to adsorb blood from the operation field. In part, abdominal swabs exhibit procoagulant activity, which is usually considered harmless. However, coagulation induction and abnormal clot formation on the surface of abdominal swabs in the operation field may, if the blood is retransfused into the extracorporeal circuit, lead to severe thromboembolic complications. The aim of the present study was to elucidate the origin of the unexpected blood clotting upon contact with hypercoagulant swabs. Methods The coagulant properties of three abdominal swabs were characterized using a simple clotting test and human whole blood, which was anticoagulated with different heparin concentrations. Eluates prepared from the abdominal swabs and the color stabilizer polydiallyamine (PDAA) were incubated with blood and blood clotting was investigated. Furthermore, the effects of the abdominal swabs on blood clotting time and on heparin were investigated. Results Our data show that the three abdominal swabs as well as the respective eluates exhibit distinctive coagulant properties. The abdominal swab with the highest hypercoagulant effect significantly reduced blood clotting time and also led to a reduction in free heparin. PDAA does not induce activation of the coagulation system. Conclusion The data indicate that the hypercoagulant swab reduces the clotting time and the concentration of free heparin. Abdominal swabs used during complex cardiac surgery with heart-lung-machine support should definitely be tested for their coagulant properties using appropriate tests before clinical applications, as it cannot be specified what leads to their hypercoagulant property. PMID- 26765246 TI - Handoff Practices in Emergency Medicine: Are We Making Progress? AB - OBJECTIVES: Transitions of care present a risk for communication error and may adversely affect patient care. This study addresses the scope of current handoff practices amongst U.S. emergency medicine (EM) residents. In addition, it evaluates current educational and evaluation practices related to handoffs. Given the ever-increasing emphasis on transitions of care in medicine, we sought to determine if interval changes in resident transition of care education, assessment, and proficiency have occurred. METHODS: This was a cross-sectional survey study guided by the Kern model for medical curriculum development. The Council of Residency Directors Listserv provided access to 175 programs. The survey focused on elucidating current practices of handoffs from emergency physicians (EPs) to EPs, including handoff location and duration, use of any assistive tools, and handoff documentation in the emergency department (ED) patient's medical record. Multiple-choice questions were the primary vehicle for the response process. A four-point Likert-type scale was used in questions regarding perceived satisfaction and competency. Respondents were not required to answer all questions. Responses were compared to results from a similar 2011 study for interval changes. RESULTS: A total of 127 of 175 programs responded to the survey, making the overall response rate 72.6%. Over half of respondents (72 of 125, 57.6%) indicated that their ED uses a standardized handoff protocol, which is a significant increase from 43.2% in 2011 (p = 0.018). Of the programs that do have a standardized system, a majority (72 of 113, 63.7%) of resident physicians use it regularly. Significant increases were noted in the number of programs offering formal training during orientation (73.2% from 59.2%; p = 0.015), decreases in the number of programs offering no training (2.4% from 10.2%; p = 0.013), and no assessment of proficiency (51.5% from 69.8%; p = 0.006). No significant interval changes were noted in handoffs being documented in the patient's medical record (57.4%), the percentage of computer/electronic signouts, or the level of dissatisfaction with handoff tools (54.1%). Less than two-thirds of respondents (80 of 126, 63.5%) indicated that their residents were "competent" or "extremely competent" in delivering and receiving handoffs. CONCLUSIONS: An insufficient level of handoff training is currently mandated or available for EM residents, and their handoff skills appear to be developed mostly informally throughout residency training with varying results. Programs that have created a standardized protocol are not ensuring that the protocol is actually being employed in the clinical arena. Handoff proficiency most often goes unevaluated, although it is improved from 2011. PMID- 26765245 TI - Development Pattern on Lymph Node Resection in Minimally Invasive Esophagectomy and 2-year Survival Analysis. AB - Background Thoracoscopic-laparoscopic procedures have been used more in the operations of esophagus cancer; in most times we call it minimally invasive esophagectomy, which is becoming mature. However, the efficacy of minimally invasive esophagectomy is still unclear, especially about the dissection of lymph nodes and survival. Methods A retrospective review was performed. The development process of minimally invasive esophagectomy for esophageal cancer was divided into three stages: the first stage 20, the second stage 37, the third stage 50. Result Total 107 patients underwent minimally invasive esophagectomy between July 2010 and May 2015. The number of lymph node resected during the three stages increased significantly, with a mean of 12.65, 15.91, and 20.16 nodes, respectively (p = 0.0075). The number of lymph nodes dissection greater than or equal to 12 or 18 increased significantly (p = 0.000). The patients from the first and the second stages had the similar 2-year survival rate (p = 0.8618). There is no significant difference in the 2-year disease-free survival rate (p = 0.606). Conclusion Surgeons accumulate experience on lymphadenectomy during minimally invasive esophagectomy as time goes by, and experience on 50 to 60 cases is essential and necessary to accomplish an apparent progress. PMID- 26765248 TI - Self-injury, aggression and destruction in children with severe intellectual disability: Incidence, persistence and novel, predictive behavioural risk markers. AB - BACKGROUND: A risk informed, early intervention strategy for self-injurious, aggressive and destructive behaviours in children with severe intellectual disability is gaining support. The aims of this study were to establish the cumulative incidence and persistence of self-injury, aggression and destruction and the relationship between these behaviours and two potentially predictive behavioural risk markers (repetitive behaviour, and impulsivity and overactivity) in children at high risk. METHODS: In a longitudinal design self-injury, aggression and destruction were assessed by teachers of 417 children with severe intellectual disability on two occasions separated by 15-18 months. RESULTS: Aggression, destruction and self-injury were persistent (69%, 57% and 58% respectively). Repetitive and restricted behaviours and interests (RRBI) and overactivity/impulsivity (O/I) were significantly associated with aggression (O/I OR=1.291, p<.001), destruction (RRBI OR 1.201, p=.013; O/I OR 1.278, p<.001) and/or self-injury (RRBI, OR 1.25, p=.004; O/I OR=1.117, p<.001). The relative risk of the cumulative incidence of self-injury, aggression and destruction was significantly increased by repetitive and restricted behaviours and interests (self-injury 2.66, destruction 2.16) and/or overactivity/impulsivity (aggression 2.42, destruction 2.07). CONCLUSIONS: The results provide evidence that repetitive and restricted behaviours and interests, and overactivity/impulsivity, are risk markers for the onset of self-injury, aggression and destruction within the already high risk group of children with severe intellectual disability. PMID- 26765249 TI - Audiovisual alignment of co-speech gestures to speech supports word learning in 2 year-olds. AB - Analyses of caregiver-child communication suggest that an adult tends to highlight objects in a child's visual scene by moving them in a manner that is temporally aligned with the adult's speech productions. Here, we used the looking while-listening paradigm to examine whether 25-month-olds use audiovisual temporal alignment to disambiguate and learn novel word-referent mappings in a difficult word-learning task. Videos of two equally interesting and animated novel objects were simultaneously presented to children, but the movement of only one of the objects was aligned with an accompanying object-labeling audio track. No social cues (e.g., pointing, eye gaze, touch) were available to the children because the speaker was edited out of the videos. Immediately afterward, toddlers were presented with still images of the two objects and asked to look at one or the other. Toddlers looked reliably longer to the labeled object, demonstrating their acquisition of the novel word-referent mapping. A control condition showed that children's performance was not solely due to the single unambiguous labeling that had occurred at experiment onset. We conclude that the temporal link between a speaker's utterances and the motion they imposed on the referent object helps toddlers to deduce a speaker's intended reference in a difficult word-learning scenario. In combination with our previous work, these findings suggest that intersensory redundancy is a source of information used by language users of all ages. That is, intersensory redundancy is not just a word-learning tool used by young infants. PMID- 26765250 TI - A response to Meakin and Jamieson DNA transfer: Review and implications for casework. PMID- 26765247 TI - Myoglobin-Catalyzed Olefination of Aldehydes. AB - The olefination of aldehydes constitutes a most valuable and widely adopted strategy for constructing carbon-carbon double bonds in organic chemistry. While various synthetic methods have been made available for this purpose, no biocatalysts are known to mediate this transformation. Reported herein is that engineered myoglobin variants can catalyze the olefination of aldehydes in the presence of alpha-diazoesters with high catalytic efficiency (up to 4,900 turnovers) and excellent E diastereoselectivity (92-99.9 % de). This transformation could be applied to the olefination of a variety of substituted benzaldehydes and heteroaromatic aldehydes, also in combination with different alkyl alpha-diazoacetate reagents. This work provides a first example of biocatalytic aldehyde olefination and extends the spectrum of synthetically valuable chemical transformations accessible using metalloprotein-based catalysts. PMID- 26765251 TI - Evaluation of mRNA markers for estimating blood deposition time: Towards alibi testing from human forensic stains with rhythmic biomarkers. AB - Determining the time a biological trace was left at a scene of crime reflects a crucial aspect of forensic investigations as - if possible - it would permit testing the sample donor's alibi directly from the trace evidence, helping to link (or not) the DNA-identified sample donor with the crime event. However, reliable and robust methodology is lacking thus far. In this study, we assessed the suitability of mRNA for the purpose of estimating blood deposition time, and its added value relative to melatonin and cortisol, two circadian hormones we previously introduced for this purpose. By analysing 21 candidate mRNA markers in blood samples from 12 individuals collected around the clock at 2h intervals for 36h under real-life, controlled conditions, we identified 11 mRNAs with statistically significant expression rhythms. We then used these 11 significantly rhythmic mRNA markers, with and without melatonin and cortisol also analysed in these samples, to establish statistical models for predicting day/night time categories. We found that although in general mRNA-based estimation of time categories was less accurate than hormone-based estimation, the use of three mRNA markers HSPA1B, MKNK2 and PER3 together with melatonin and cortisol generally enhanced the time prediction accuracy relative to the use of the two hormones alone. Our data best support a model that by using these five molecular biomarkers estimates three time categories, i.e. night/early morning, morning/noon, and afternoon/evening with prediction accuracies expressed as AUC values of 0.88, 0.88, and 0.95, respectively. For the first time, we demonstrate the value of mRNA for blood deposition timing and introduce a statistical model for estimating day/night time categories based on molecular biomarkers, which shall be further validated with additional samples in the future. Moreover, our work provides new leads for molecular approaches on time of death estimation using the significantly rhythmic mRNA markers established here. PMID- 26765253 TI - If you watch it move, you'll recognize it in 3D: Transfer of depth cues between encoding and retrieval. AB - Viewing objects with stereoscopic displays provides additional depth cues through binocular disparity supporting object recognition. So far, it was unknown whether this results from the representation of specific stereoscopic information in memory or a more general representation of an object's depth structure. Therefore, we investigated whether continuous object rotation acting as depth cue during encoding results in a memory representation that can subsequently be accessed by stereoscopic information during retrieval. In Experiment 1, we found such transfer effects from continuous object rotation during encoding to stereoscopic presentations during retrieval. In Experiments 2a and 2b, we found that the continuity of object rotation is important because only continuous rotation and/or stereoscopic depth but not multiple static snapshots presented without stereoscopic information caused the extraction of an object's depth structure into memory. We conclude that an object's depth structure and not specific depth cues are represented in memory. PMID- 26765252 TI - Teichoic, teichulosonic and teichuronic acids in the cell wall of Brevibacterium aurantiacum VKM Ac-2111(T). AB - Two different teichoic acids, along with a teichulosonic and a teichuronic acids, were identified in the cell wall of Brevibacterium aurantiacum VKM Ac-2111(T). One teichoic acid is 1,3-poly(glycerol phosphate) with 2-acetamido-2-deoxy-alpha D-galactopyranose and L-glutamic acid as non-stoichiometric substituents at O-2 of the glycerol residue. The second one is a poly(glycosylglycerol phosphate) with -4)-alpha-D-Galp-(1 -> 2)-sn-Gro-(3-P- and/or -6)-alpha-D-Galp-(1 -> 2)-sn Gro-(3-P- units in the main chain. The structure of the first has not been reported so far, while the latter one is new for actinobacteria. The teichulosonic acid with alpha-3-deoxy-beta-D-glycero-D-galacto-non-2 ulopyranosonic acid (Kdn) and beta-D-glucopyranose residues in the backbone represents a novel polymer: -> 8)-alpha-Kdn-(2 -> 6)-beta-D-Glcp-(1 ->. The teichuronic acid has also hitherto unknown structure: -> 3)-beta-D-Galf(2OAc)0.3 (1 -> 3)-beta-D-GlcpA-(1 -> and is found in members of the genus Brevibacterium for the first time. The polymer structures were elucidated using 1D- and 2D-NMR spectroscopy: (1)H,(1)H COSY, TOCSY, ROESY, (1)H,(13)C HSQC, HSQC-TOCSY, and (1)H,(13)C and (1)H,(31)P HMBC. PMID- 26765254 TI - Why We Need a Transdiagnostic Staging Approach to Emerging Psychopathology, Early Diagnosis, and Treatment. PMID- 26765256 TI - Comprehensive Identification and Bread-Making Quality Evaluation of Common Wheat Somatic Variation Line AS208 on Glutenin Composition. AB - High molecular weight glutenin subunits (HMW-GSs) are important seed storage proteins in wheat (Triticum aestivum) that determine wheat dough elasticity and processing quality. Clarification of the defined effectiveness of HMW-GSs is very important to breeding efforts aimed at improving wheat quality. To date, there have no report on the expression silencing and quality effects of 1Bx20 and 1By20 at the Glu-B1 locus in wheat. A wheat somatic variation line, AS208, in which both 1Bx20 and 1By20 at Glu-B1 locus were silenced, was developed recently in our laboratory. Evaluation of agronomic traits and seed storage proteins by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and reversed-phase high performance liquid chromatography (RP-HPLC) indicated that AS208 was highly similar to its parental cultivar Lunxuan987 (LX987), with the exception that the composition and expression of HMW-GSs was altered. The 1Bx20 and 1By20 in AS208 were further identified to be missing by polymerase chain reaction (PCR) and quantitative real-time RT-PCR (qRT-PCR) assays. Based on the PCR results for HMW GS genes and their promoters in AS208 compared with LX987, 1Bx20 and 1By20 were speculated to be deleted in AS208 during in vitro culture. Quality analysis of this line with Mixograph, Farinograph, and Extensograph instruments, as well as analysis of bread-making quality traits, demonstrated that the lack of the genes encoding 1Bx20 and 1By20 caused various negative effects on dough processing and bread-making quality traits, including falling number, dough stability time, mixing tolerance index, crude protein values, wet gluten content, bread size, and internal cell structure. AS208 can potentially be used in the functional dissection of other HMW-GSs as a plant material with desirable genetic background, and in biscuit making industry as a high-quality weak gluten wheat source. PMID- 26765255 TI - Quantitative IFN-gamma and IL-2 Response Associated with Latent Tuberculosis Test Discordance in HIV-infected Pregnant Women. AB - RATIONALE: Pregnant women with latent tuberculosis infection (LTBI) are at high risk for development of TB, especially if infected with HIV. OBJECTIVES: To assess the performance of LTBI tests in pregnant and postpartum women infected with HIV, investigate the immunology behind discordance in pregnancy, and explore the implications for the development of postpartum TB. METHODS: We screened pregnant women in their second/third trimester and at delivery for LTBI using the tuberculin skin test (TST) and IFN-gamma release assay (IGRA) (QuantiFERON Gold). A subset of antepartum women had longitudinal testing, with repeat testing at delivery and postpartum and additional cytokines measured from the IGRA supernatant. The kappa statistic and Wilcoxon rank sum test were used to determine agreement and comparison of cytokine concentrations, respectively. MEASUREMENTS AND MAIN RESULTS: Of 252 enrolled, 71 (28%) women had a positive IGRA but only 27 (10%) had a positive TST (P < 0.005). There was 75% agreement (kappa, 0.25). When stratified by pregnancy versus delivery, 20% had IGRA(+)/TST( ) discordance at each time point. A positive IGRA was associated with known TB contact (odds ratio, 3.6; confidence interval, 1.2-11.1; P = 0.02). Compared with IGRA(+)/TST(+), women with IGRA(+)/TST(-) discordance had significantly less IFN gamma (1.85 vs. 3.48 IU/ml; P = 0.02) and IL-2 (46.17 vs. 84.03 pg/ml; P = 0.01). Five developed postpartum TB, of which three had IGRA(+)/TST(-) discordance during pregnancy. CONCLUSIONS: Choice of LTBI test in pregnant women infected with HIV affects results. Pregnant women with IGRA(+)/TST(-) discordance had less IFN-gamma and IL-2 than those with concordant-positive results and may represent an especially high-risk subset for the development of active TB postpartum. PMID- 26765258 TI - Single Sustained Inflation followed by Ventilation Leads to Rapid Cardiorespiratory Recovery but Causes Cerebral Vascular Leakage in Asphyxiated Near-Term Lambs. AB - BACKGROUND: A sustained inflation (SI) rapidly restores cardiac function in asphyxic, bradycardic newborns but its effects on cerebral haemodynamics and brain injury are unknown. We determined the effect of different SI strategies on carotid blood flow (CaBF) and cerebral vascular integrity in asphyxiated near term lambs. METHODS: Lambs were instrumented and delivered at 139 +/- 2 d gestation and asphyxia was induced by delaying ventilation onset. Lambs were randomised to receive 5 consecutive 3 s SI (multiple SI; n = 6), a single 30 s SI (single SI; n = 6) or conventional ventilation (no SI; n = 6). Ventilation continued for 30 min in all lambs while CaBF and respiratory function parameters were recorded. Brains were assessed for gross histopathology and vascular leakage. RESULTS: CaBF increased more rapidly and to a greater extent during a single SI (p = 0.01), which then decreased below both other groups by 10 min, due to a higher cerebral oxygen delivery (p = 0.01). Blood brain barrier disruption was increased in single SI lambs as indicated by increased numbers of blood vessel profiles with plasma protein extravasation (p = 0.001) in the cerebral cortex. There were no differences in CaBF or cerebral oxygen delivery between the multiple SI and no SI lambs. CONCLUSIONS: Ventilation with an initial single 30 s SI improves circulatory recovery, but is associated with greater disruption of blood brain barrier function, which may exacerbate brain injury suffered by asphyxiated newborns. This injury may occur as a direct result of the initial SI or to the higher tidal volumes delivered during subsequent ventilation. PMID- 26765257 TI - A Sensitized Screen for Genes Promoting Invadopodia Function In Vivo: CDC-42 and Rab GDI-1 Direct Distinct Aspects of Invadopodia Formation. AB - Invadopodia are specialized membrane protrusions composed of F-actin, actin regulators, signaling proteins, and a dynamically trafficked invadopodial membrane that drive cell invasion through basement membrane (BM) barriers in development and cancer. Due to the challenges of studying invasion in vivo, mechanisms controlling invadopodia formation in their native environments remain poorly understood. We performed a sensitized genome-wide RNAi screen and identified 13 potential regulators of invadopodia during anchor cell (AC) invasion into the vulval epithelium in C. elegans. Confirming the specificity of this screen, we identified the Rho GTPase cdc-42, which mediates invadopodia formation in many cancer cell lines. Using live-cell imaging, we show that CDC-42 localizes to the AC-BM interface and is activated by an unidentified vulval signal(s) that induces invasion. CDC-42 is required for the invasive membrane localization of WSP-1 (N-WASP), a CDC-42 effector that promotes polymerization of F-actin. Loss of CDC-42 or WSP-1 resulted in fewer invadopodia and delayed BM breaching. We also characterized a novel invadopodia regulator, gdi-1 (Rab GDP dissociation inhibitor), which mediates membrane trafficking. We show that GDI-1 functions in the AC to promote invadopodia formation. In the absence of GDI-1, the specialized invadopodial membrane was no longer trafficked normally to the invasive membrane, and instead was distributed to plasma membrane throughout the cell. Surprisingly, the pro-invasive signal(s) from the vulval cells also controls GDI-1 activity and invadopodial membrane trafficking. These studies represent the first in vivo screen for genes regulating invadopodia and demonstrate that invadopodia formation requires the integration of distinct cellular processes that are coordinated by an extracellular cue. PMID- 26765261 TI - Larval cases of caddisfly (Insecta: Trichoptera) affinity in Early Permian marine environments of Gondwana. AB - Caddisflies (Trichoptera) are small, cosmopolitan insects closely related to the Lepidoptera (moths and butterflies). Most caddisflies construct protective cases during their larval development. Although the earliest recognisable caddisflies date back to the early Mesozoic (Early and Middle Triassic), being particularly numerous and diverse during the Late Jurassic and Early Cretaceous, the first records of their larval case constructions are known exclusively from much younger, Early to Middle Jurassic non-marine deposits in the northern hemisphere. Here we present fossils from the Early Permian (Asselian-Sakmarian) marine deposits of Brazil which have strong morphological and compositional similarity to larval cases of caddisflies. If they are, which is very probable, these finds not only push back the fossil record of true caddisflies, but also indicate that their larvae constructed cases at the very beginning of their evolution in marine environments. Since modern caddisflies that construct larval cases in marine environments are only known from eastern Australia and New Zealand, we suggest that this marine ecology may have first evolved in western Gondwana during the Early Permian and later spread across southern Pangea. PMID- 26765260 TI - Laboratory characterization of invasive Haemophilus influenzae isolates from Nunavut, Canada, 2000-2012. AB - BACKGROUND: With invasive Haemophilus influenzae serotype b (Hib) disease controlled by vaccination with conjugate Hib vaccines, there is concern that invasive disease due to non-serotype b strains may emerge. OBJECTIVE: This study characterized invasive H. influenzae (Hi) isolates from Nunavut, Canada, in the post-Hib vaccine era. METHODS: Invasive H. influenzae isolates were identified by conventional methods at local hospitals; and further characterized at the provincial and federal public health laboratories, including detection of serotype antigens and genes, multi-locus sequence typing and antibiotic susceptibility. RESULTS: Of the 89 invasive H. influenzae cases identified from 2000 to 2012, 71 case isolates were available for study. There were 43 serotype a (Hia), 12 Hib, 2 Hic, 1 Hid, 1 Hie, 2 Hif and 10 were non-typeable (NT). All 43 Hia were biotype II, sequence type (ST)-23. Three related STs were found among the Hib isolates: ST-95 (n=9), ST-635 (n=2) and ST-44 (n=1). Both Hif belonged to ST-124 and the 2 Hic were typed as ST-9. The remaining Hid (ST-1288) and Hie (ST 18) belonged to 2 separate clones. Of the 10 NT strains, 3 were typed as ST-23 and the remaining 7 isolates each belonged to a unique ST. Eight Hib and 1 NT-Hi were found to be resistant to ampicillin due to beta-lactamase production. No resistance to other antibiotics was detected. CONCLUSION: During the period of 2000-2012, Hia was the predominant serotype causing invasive disease in Nunavut. This presents a public health concern due to an emerging clone of Hia as a cause of invasive H. influenzae disease and the lack of published guidelines for the prophylaxis of contacts. The clonal nature of Hia could be the result of spread within an isolated population, and/or unique characteristics of this strain to cause invasive disease. Further study of Hia in other populations may provide important information on this emerging pathogen. No antibiotic resistance was detected among Hia isolates; a small proportion of Hib and NT-Hi isolates demonstrated resistance to ampicillin due to beta-lactamase production. PMID- 26765259 TI - Cancer among circumpolar populations: an emerging public health concern. AB - OBJECTIVES: To determine and compare the incidence of cancer among the 8 Arctic States and their northern regions, with special focus on 3 cross-national indigenous groups--Inuit, Athabaskan Indians and Sami. METHODS: Data were extracted from national and regional statistical agencies and cancer registries, with direct age-standardization of rates to the world standard population. For comparison, the "world average" rates as reported in the GLOBOCAN database were used. FINDINGS: Age-standardized incidence rates by cancer sites were computed for the 8 Arctic States and 20 of their northern regions, averaged over the decade 2000-2009. Cancer of the lung and colon/rectum in both sexes are the commonest in most populations. We combined the Inuit from Alaska, Northwest Territories, Nunavut and Greenland into a "Circumpolar Inuit" group and tracked cancer trends over four 5-year periods from 1989 to 2008. There has been marked increase in lung, colorectal and female breast cancers, while cervical cancer has declined. Compared to the GLOBOCAN world average, Inuit are at extreme high risk for lung and colorectal cancer, and also certain rare cancers such as nasopharyngeal cancer. Athabaskans (from Alaska and Northwest Territories) share some similarities with the Inuit but they are at higher risk for prostate and breast cancer relative to the world average. Among the Sami, published data from 3 cohorts in Norway, Sweden and Finland show generally lower risk of cancer than non-Sami. CONCLUSIONS: Cancer among certain indigenous people in the Arctic is an increasing public health concern, especially lung and colorectal cancer. PMID- 26765262 TI - Involvement of Endoplasmic Reticulum Stress in Uremic Cardiomyopathy: Protective Effects of Tauroursodeoxycholic Acid. AB - BACKGROUND/AIMS: Uremic cardiomyopathy (UCM) is a complication in chronic kidney disease. We investigated if endoplasmic reticulum stress (ERS) is involved in UCM, and determined the efficacy of tauroursodeoxycholic acid (TUDCA) in UCM prevention. METHODS: Mice were divided randomly into three groups: sham (saline, i.p), 5/6 nephrectomized (Nx) (saline, i.p) and Nx+TUDCA (250 mg/kg/day, i.p.). Renal function was assessed by measuring serum creatinine, blood urea nitrogen and by periodic acid-Schiff reagent staining. Histologic examination of cardiac fibrosis and apoptosis was determined by Masson's trichrome and TUNEL assay. Cardiac function was evaluated by echocardiography. Fibrotic factors (transforming growth factor-beta, fibronectin, collagen I/IV) were evaluated by real-time PCR. ERS-related proteins were measured by western blotting. RESULTS: Impaired renal function and cardiac dysfunction were shown in 5/6 nephrectomy mice but were improved significantly by TUDCA. 5/6 nephrectomy mice exhibited marked cardiomyocyte apoptosis, cardiac fibrosis and elevated pro-fibrotic factors. ERS markers (GRP78, GRP94, P-PERK, P-eIF2a) and ERS-induced apoptosis pathways (activation of CHOP and caspase-12) were increased significantly in 5/6 nephrectomy mice, and TUDCA treatment blunted these changes. CONCLUSIONS: ERS has a key role in UCM, and the cardioprotective role of TUDCA is related to inhibition of ERS-induced apoptosis by inhibition of CHOP and caspase-12 pathways. PMID- 26765263 TI - Dual Endothelin Receptor Blockade Abrogates Right Ventricular Remodeling and Biventricular Fibrosis in Isolated Elevated Right Ventricular Afterload. AB - BACKGROUND: Pulmonary arterial hypertension is usually fatal due to right ventricular failure and is frequently associated with co-existing left ventricular dysfunction. Endothelin-1 is a powerful pro-fibrotic mediator and vasoconstrictor that is elevated in pulmonary arterial hypertension. Endothelin receptor blockers are commonly used as pulmonary vasodilators, however their effect on biventricular injury, remodeling and function, despite elevated isolated right ventricular afterload is unknown. METHODS: Elevated right ventricular afterload was induced by progressive pulmonary artery banding. Seven rabbits underwent pulmonary artery banding without macitentan; 13 received pulmonary artery banding + macitentan; and 5 did not undergo inflation of the pulmonary artery band (sham-operated controls). RESULTS: Right and left ventricular collagen content was increased with pulmonary artery banding compared to sham-operated controls and ameliorated by macitentan. Right ventricular fibrosis signaling (connective tissue growth factor and endothelin-1 protein levels); extra-cellular matrix remodeling (matrix-metalloproteinases 2 and 9), apoptosis and apoptosis-related peptides (caspases 3 and 8) were increased with pulmonary artery banding compared with sham-operated controls and decreased with macitentan. CONCLUSION: Isolated right ventricular afterload causes biventricular fibrosis, right ventricular apoptosis and extra cellular matrix remodeling, mediated by up-regulation of endothelin-1 and connective tissue growth factor signaling. These pathological changes are ameliorated by dual endothelin receptor blockade despite persistent elevated right ventricular afterload. PMID- 26765265 TI - Prostaglandin E2 Levels of Aqueous and Vitreous Humor in Ketorolac 0.4% and Nepafenac 0.1% Administered Healthy Rabbits. AB - PURPOSE: To compare the lowering effects of ketorolac 0.4% and nepafenac 0.1% on aqueous and vitreous humor prostaglandin E2 (PGE2) levels in rabbits. METHODS: Ketorolac and nepafenac ophthalmic solutions were administered to the right eyes of 24 healthy rabbits after randomized division into two groups. The left eyes of these rabbits were considered as controls for the two groups. On the 4th day of the experiment, the samples were taken from the aqueous and vitreous humors of the rabbits bilaterally, and PGE2 levels were measured by an enzyme immune assay kit. RESULTS: Ketorolac and nepafenac achieved a statistically significant decrease (p<0.001, for each) in PGE2 levels in the aqueous (11.75 +/- 6.15 and 14.75 +/- 7.60 pg/mL, respectively) and the vitreous humor (6.58 +/- 4.62 and 9.83 +/- 4.55 pg/mL, respectively). CONCLUSIONS: Both ketorolac and nepafenac inhibited PGE2 levels in both the aqueous and vitreous humors of rabbits. Although PGE2-lowering effects were similar in the aqueous humor, nepafenac seemed to be more potent than ketorolac in the vitreous humor. PMID- 26765266 TI - Development and validation of HPLC method with fluorometric detection for quantification of bisnaphthalimidopropyldiaminooctane in animal tissues following administration in polymeric nanoparticles. AB - A simple, sensitive and specific high-performance liquid chromatography method for the quantification of bisnaphthalimidopropyldiaminooctane (BNIPDaoct), a potent anti-Leishmania compound, incorporated into poly(d,l-lactide-co-glycolic acid) (PLGA) nanoparticles was developed and validated toward bioanalysis application. Biological tissue extracts were injected into a reversed-phase monolithic column coupled to a fluorimetric detector (lambdaexc=234nm, lambdaem=394nm), using isocratic elution with aqueous buffer (acetic acid/acetate 0.10M, pH 4.5, 0.010M octanesulfonic acid) and acetonitrile, 60:40 (v/v) at a flow rate of 1.5mLmin(-1). The run time was 6min, with a BNIPDaoct retention time of 3.3min. Calibration curves were linear for BNIPDaoct concentrations ranging from 0.002 to 0.100MUM. Matrix effects were observed and calibration curves were performed using the different organ (spleen, liver, kidney, heart and lung) extracts. The method was found to be specific, accurate (97.3-106.8% of nominal values) and precise for intra-day (RSD<1.9%) and inter-day assays (RSD<7.2%) in all matrices. Stability studies showed that BNIPDaoct was stable in all matrices after standing for 24h at room temperature (20 degrees C) or in the autosampler, and after three freeze-thaw cycles. Mean recoveries of BNIPDaoct spiked in mice organs were >88.4%. The LOD and LOQ for biological matrices were <=0.8 and <=1.8nM, respectively, corresponding to values <=4 and <=9nmolg(-1) in mice organs. The method developed was successfully applied to biodistribution assessment following intravenous administration of BNIPDaoct in solution or incorporated in PLGA nanoparticles. PMID- 26765267 TI - Design of experiments for enantiomeric separation in supercritical fluid chromatography. AB - A new chiral melatoninergic ligand, potentially successor of Valdoxan((r)), presenting an improved pharmacological profile with regard to agomelatine, was chosen as a probe for a supercritical fluid chromatographic separation carried out on an amylose tris[(S)-1-alpha-methylbenzylcarbamate] based stationary phase. The goal of this work was to optimize simultaneously three factors identified to have a significant influence to obtain the best resolution in the shortest analysis time (i.e., retention time of the second eluting enantiomer) for this chiral compound. For this purpose a central circumscribed composite (CCC) design was developed with three factors: the flow-rate, the pressure outlet and the percentage of ethanol to optimize of two responses: shortest analysis time and best resolution. The optimal conditions obtained via the optimizer mode of the software (using the Nelder-Mead method) i.e., CO2/EtOH 86:14 (v:v), 104bar, 3.2mLmin(-1) at 35 degrees C lead to a resolution of 3.27 in less than 6min. These conditions were transposed to a preparative scale where a concentrated methanolic solution of 40mM was injected with a sample loop of 100MUL. This step allowed to separate an amount of around 65mg of racemic melatonin ligand in only 3h with impressive yields (97%) and enantiomeric excess (99.5%). PMID- 26765264 TI - The multiple sclerosis susceptibility genes TAGAP and IL2RA are regulated by vitamin D in CD4+ T cells. AB - Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system that develops in genetically susceptible individuals. The majority of the MS-associated gene variants are located in genetic regions with importance for T-cell differentiation. Vitamin D is a potent immunomodulator, and vitamin D deficiency has been suggested to be associated with increased MS disease susceptibility and activity. In CD4+ T cells, we have analyzed in vitro vitamin D responsiveness of genes that contain an MS-associated single-nucleotide polymorphism (SNP) and with one or more vitamin D response elements in their regulatory regions. We identify IL2RA and TAGAP as novel vitamin D target genes. The vitamin D response is observed in samples from both MS patients and controls, and is not dependent on the genotype of MS-associated SNPs in the respective genes. PMID- 26765268 TI - Chiral separation of new designer drugs (Cathinones) on chiral ion-exchange type stationary phases. AB - We present the enantioseparation of new designer drugs from the cathinone family on structurally different chiral ion-exchange type stationary phases. A novel strong cation-exchange type chiral stationary phase was synthesized and its performance compared with previously reported ion-exchange type chiral stationary phases. The influence of structural elements of the chiral selectors on their chromatographic performance was studied and the possibilities of tuning chromatographic parameters by varying the polarity of the employed mobile phases were determined. Evidence is provided that a change in mobile phase composition strongly influences the solvation shell of the polarized and polarizable units of the selectors and analytes, as well as ionizable mobile phase additives. Furthermore, the structural features of the selectors (e.g. the size of aromatic units and their substitution pattern) are shown to play a key role in the effective formation of diastereomeric complexes with analytes. Thus, we have achieved the enantioseparation of all test analytes with a mass spectrometry compatible mobile phase with a chiral strong cation-exchange type stationary phase. PMID- 26765269 TI - Impact of superior mediastinal metastasis on the prognosis of papillary thyroid carcinoma. AB - The impact of lymph node (LN) metastasis on survival or tumor recurrence in patients with papillary thyroid carcinoma (PTC) is controversial. The objective of this study was to investigate the effect of superior mediastinal metastasis on the prognosis of patients with PTC and to identify any correlations between such metastasis and clinical indicators. Medical records of PTC patients who underwent surgery as their initial treatment between 1981 and 2008 at our institution were retrospectively reviewed. Patients with or without superior mediastinal metastasis were selected. Prognosis was determined using the Kaplan-Meier method and Cox-hazard regression model with the forward stepwise method. Correlations between multiple factors and superior mediastinal metastasis were investigated using a binary logistic regression analysis. The study cohort included 488 patients of whom 75 (15.4%) had superior mediastinal metastasis. The survival differences between patients with superior mediastinal metastasis dissected via the transcervical approach and patients without metastasis were not significant. The prognosis of patients with superior mediastinal metastasis dissected by sternotomy was significantly poorer. As for disease-free survival, significant differences were found between patients with superior mediastinal metastases dissected by either method and patients without metastases. The main variables predicting superior mediastinal metastasis were an age of 45 years or older and the total number of cervical LN metastases. Superior mediastinal metastasis was an independent predictive factor for recurrence-free survival in PTC patients. The main variables predicting superior mediastinal metastasis were being 45 years of age or older, and having a greater total number of cervical LN metastases. PMID- 26765270 TI - A case of lean polycystic ovary syndrome with early stage of type 1 diabetes successfully treated with metformin. AB - Polycystic ovary syndrome (PCOS) is common in obese women with insulin resistant type 2 diabetes for which metformin treatment is getting established in addition to clomiphene. However, lean PCOS patients are sometimes accompanied with type 1 diabetes. It remains unclear whether these patients are insulin resistant and whether metformin is effective for them. A 32-year-old woman, who suffered from acne, hirsutism, and menstrual disorders since age 29, was diagnosed as PCOS by serum high LH levels and polycystic ovary on echography. Interestingly, her body mass index (BMI) had consistently been 21.0 kg/m2 since age 20. She was first treated with clomiphene for one year for infertility but it did not improve her menstrual cycle nor did she get pregnant during that period. She was then assessed with diabetes mellitus and subsequently diagnosed as type 1 diabetes with mild hyperglycemia (HbA1c 6.0%). Since her insulin secretion was still well preserved, to assess insulin sensitivity, hyperinsulinemic-euglycemic clamp test was performed and showed her to be insulin resistant. Low dose insulin and low dose metformin treatment was started without clomiphene. After her ovulation and menstrual cycle were ameliorated only one month later, her treatment was supplemented with clomiphene for the next three months enabling her to at last become pregnant. This report highlights the efficacy of metformin in lean PCOS with type 1 diabetes. Insulin therapy is essential for type 1 diabetes but hyperinsulinemia potentially exacerbates PCOS through hyperandrogenism. Metformin is therefore recommended for treatment of lean PCOS with type 1 diabetes as well as common obese PCOS with type 2 diabetes. PMID- 26765271 TI - Extensive irregular Mongolian blue spots as a clue for GM1 gangliosidosis type 1. PMID- 26765272 TI - Sudden cardiac death in marathons: a systematic review. AB - The aim of this systematic review is to summarise the results of cohort studies that examined the incidence of SCD in marathons and to assess the quality of the methods used. A search of the PROSPERO international database revealed no prospective or published systematic reviews investigating SCD in marathons. The review was conducted using studies that reported and characterised the incidence of SCD in people participating in marathons. Studies were identified via electronic database searches (Medline, CINAHL, SPORTDiscus and Google Scholar) from January 1, 1966 to October 1, 2014 and through manual literature searches. 7 studies met the inclusion criteria and were included in this review. 6 of the studies were conducted in the USA and 1 in the UK. These studies covered a 34 year period involving between 215,413 and 3,949,000 runners. The SCD of between 4 and 28 people are recorded in the papers and the reported estimates of the incidence of SCD in marathons ranged widely from 0.6 to 1.9 per 100,000 runners. The proportion of those suffering SCD who were male ranged from 57.1% to 100% and the mean age reported in the papers, ranged from 37 to 48. This review raises 4 methodological concerns over i) collating reports of SCD in marathons; ii) time of death in relation to the marathon; iii) the use of registrants rather than runners in the estimates of sample size and iv) limited detail on runners exercise history. These four concerns all threaten the reliability and interpretation of any estimate of SCD incidence rates in marathons. This review recommends that the methods used to collect data on SCD in marathons be improved and that a central reporting system be established. PMID- 26765273 TI - Carbon nanotubes implanted manganese-based MOFs for simultaneous detection of biomolecules in body fluids. AB - Metal-organic frameworks (MOFs) have recently attracted much interest in electrochemical fields due to their controlled porosity, large internal surface area, and countless structural topologies. However, the direct application of single component MOFs is limited since they also exhibit poor electronic conductivity, low mechanical stability, and inferior electrocatalytic ability. To overcome these problems, we implanted multi-walled carbon nanotubes (MWCNTs) into manganese-based metal-organic frameworks (Mn-BDC) using a one-step solvothermal method and found that the introduction of MWCNTs can initiate the splitting of bulky Mn-BDC into thin layers. This splitting is highly significant in that it enhances the electronic conductivity and electrocatalytic ability of Mn-BDC. The constructed Mn-BDC@MWCNT composites were utilized as an electrode modifying material in the fabrication of an electrochemical sensor and then were used successfully for the determination of biomolecules in human body fluid. The sensor displayed successful detection performance with wide linear detection ranges (0.1-1150, 0.01-500, and 0.02-1100 MUM for AA, DA and UA, respectively) and low limits of detection (0.01, 0.002, and 0.005 MUM for AA, DA and UA, respectively); thus, this preliminary study presents an electrochemical biosensor constructed with a novel electrode modifying material that exhibits superior potential for the practical detection of AA, DA and UA in urine samples. PMID- 26765279 TI - iCI: Iterative CI toward full CI. AB - It is shown both theoretically and numerically that the minimal multireference configuration interaction (CI) approach [Liu, W.; Hoffmann, M. R. Theor. Chem. Acc. 2014, 133, 1481] converges quickly and monotonically from above to full CI by updating the primary, external, and secondary states that describe the respective static, dynamic, and again static components of correlation iteratively, even when starting with a rather poor description of a strongly correlated system. In short, the iterative CI (iCI) is a very effective means toward highly correlated wave functions and, ultimately, full CI. PMID- 26765274 TI - Finite element simulations of the active stress in the imaginal disc of the Drosophila Melanogaster. AB - During the larval stages of development, the imaginal disc of Drosphila Melanogaster is composed by a monolayer of epithelial cells, which undergo a strain actively produced by the cells themselves. The well-organized collective contraction produces a stress field that seemingly has a double morphogenetic role: it orchestrates the cellular organization towards the macroscopic shape emergence while simultaneously providing a local information on the organ size. Here we perform numerical simulations of such a mechanical control on morphogenesis at a continuum level, using a three-dimensional finite model that accounts for the active cell contraction. The numerical model is able to reproduce the (few) known qualitative characteristics of the tensional patterns within the imaginal disc of the fruit fly. The computed stress components slightly deviate from planarity, thus confirming the previous theoretical assumptions of a nonlinear elastic analytical model, and enforcing the hypothesis that the spatial variation of the mechanical stress may act as a size regulating signal that locally scales with the global dimension of the domain. PMID- 26765281 TI - Perspectives on investigational drugs for acromegaly. PMID- 26765282 TI - Large-scale dynamic assembly of metal nanostructures in plasmofluidic field. AB - We discuss two aspects of the plasmofluidic assembly of plasmonic nanostructures at the metal-fluid interface. First, we experimentally show how three and four spot evanescent-wave excitation can lead to unconventional assembly of plasmonic nanoparticles at the metal-fluid interface. We observed that the pattern of assembly was mainly governed by the plasmon interference pattern at the metal fluid interface, and further led to interesting dynamic effects within the assembly. The interference patterns were corroborated by 3D finite-difference time-domain simulations. Secondly, we show how anisotropic geometry, such as Ag nanowires, can be assembled and aligned in unstructured and structured plasmofluidic fields. We found that by structuring the metal-film, Ag nanowires can be aligned at the metal-fluid interface with a single evanescent-wave excitation, thus highlighting the prospect of assembling plasmonic circuits in a fluid. An interesting aspect of our method is that we obtain the assembly at locations away from the excitation points, thus leading to remote assembly of nanostructures. The results discussed herein may have implications in realizing a platform for reconfigurable plasmonic metamaterials, and a test-bed to understand the effect of plasmon interference on assembly of nanostructures in fluids. PMID- 26765283 TI - A mixed iron-manganese based pyrophosphate cathode, Na2Fe0.5Mn0.5P2O7, for rechargeable sodium ion batteries. AB - The development of secondary batteries based on abundant and cheap elements is vital. Among various alternatives to conventional lithium-ion batteries, sodium ion batteries (SIBs) are promising due to the abundant resources and low cost of sodium. While there are many challenges associated with the SIB system, cathode is an important factor in determining the electrochemical performance of this battery system. Accordingly, ongoing research in the field of SIBs is inclined towards the development of safe, cost effective cathode materials having improved performance. In particular, pyrophosphate cathodes have recently demonstrated decent electrochemical performance and thermal stability. Herein, we report the synthesis, electrochemical properties, and thermal behavior of a novel Na2Fe0.5Mn0.5P2O7 cathode for SIBs. The material was synthesized through a solid state process. The structural analysis reveals that the mixed substitution of manganese and iron has resulted in a triclinic crystal structure (P1[combining macron] space group). Galvanostatic charge/discharge measurements indicate that Na2Fe0.5Mn0.5P2O7 is electrochemically active with a reversible capacity of ~80 mA h g(-1) at a C/20 rate with an average redox potential of 3.2 V. (vs. Na/Na(+)). It is noticed that 84% of initial capacity is preserved over 90 cycles showing promising cyclability. It is also noticed that the rate capability of Na2Fe0.5Mn0.5P2O7 is better than Na2MnP2O7. Ex situ and CV analyses indicate that Na2Fe0.5Mn0.5P2O7 undergoes a single phase reaction rather than a biphasic reaction due to different Na coordination environment and different Na site occupancy when compared to other pyrophosphate materials (Na2FeP2O7 and Na2MnP2O7). Thermogravimetric analysis (25-550 degrees C) confirms good thermal stability of Na2Fe0.5Mn0.5P2O7 with only 2% weight loss. Owing to promising electrochemical properties and decent thermal stability, Na2Fe0.5Mn0.5P2O7, can be an attractive cathode for SIBs. PMID- 26765284 TI - Big Pharma Profits and the Public Loses. PMID- 26765285 TI - Development of Biodegradable Poly(citrate)-Polyhedral Oligomeric Silsesquioxanes Hybrid Elastomers with High Mechanical Properties and Osteogenic Differentiation Activity. AB - Biodegradable elastomeric biomaterials have attracted much attention in tissue engineering due to their biomimetic viscoelastic behavior and biocompatibility. However, the low mechanical stability at hydrated state, fast biodegradation in vivo, and poor osteogenic activity greatly limited bioelastomers applications in bone tissue regeneration. Herein, we develop a series of poly(octanediol citrate) polyhedral oligomeric silsesquioxanes (POC-POSS) hybrids with highly tunable elastomeric behavior (hydrated state) and biodegradation and osteoblasts biocompatibility through a facile one-pot thermal polymerization strategy. POC POSS hybrids show significantly improved stiffness and ductility in either dry or hydrated conditions, as well as good antibiodegradation ability (20-50% weight loss in 3 months). POC-POSS hybrids exhibit significantly enhanced osteogenic differentiation through upregulating alkaline phosphatase (ALP) activity, calcium deposition, and expression of osteogenic markers (ALPL, BGLAP, and Runx2). The high mechanical stability at hydrated state and enhanced osteogenic activity make POC-POSS hybrid elastomers promising as scaffolds and nanoscale vehicles for bone tissue regeneration and drug delivery. This study may also provide a new strategy (controlling the stiffness under hydrated condition) to design advanced hybrid biomaterials with high mechanical properties under physiological condition for tissue regeneration applications. PMID- 26765286 TI - Description of Adults Seeking Hearing Help for the First Time According to Two Health Behavior Change Approaches: Transtheoretical Model (Stages of Change) and Health Belief Model. AB - OBJECTIVES: Several models of health behavior change are commonly used in health psychology. This study applied the constructs delineated by two models-the transtheoretical model (in which readiness for health behavior change can be described with the stages of precontemplation, contemplation and action) and the health belief model (in which susceptibility, severity, benefits, barriers, self efficacy, and cues to action are thought to determine likelihood of health behavior change)-to adults seeking hearing help for the first time. DESIGN: One hundred eighty-two participants (mean age: 69.5 years) were recruited following an initial hearing assessment by an audiologist. Participants' mean four frequency pure-tone average was 35.4 dB HL, with 25.8% having no hearing impairment, 50.5% having a slight impairment, and 23.1% having a moderate or severe impairment using the World Health Organization definition of hearing loss. Participants' hearing-related attitudes and beliefs toward hearing health behaviors were examined using the University of Rhode Island Change Assessment (URICA) and the health beliefs questionnaire (HBQ), which assess the constructs of the transtheoretical model and the health belief model, respectively. Participants also provided demographic information, and completed the hearing handicap inventory (HHI) to assess participation restrictions, and the psychosocial impact of hearing loss (PIHL) to assess the extent to which hearing impacts competence, self-esteem, and adaptability. RESULTS: Degree of hearing impairment was associated with participation restrictions, perceived competence, self-esteem and adaptability, and attitudes and beliefs measured by the URICA and the HBQ. As degree of impairment increased, participation restrictions measured by the HHI, and impacts of hearing loss, as measured by the PIHL, increased. The majority of first-time help seekers in this study were in the action stage of change. Furthermore, relative to individuals with less hearing impairment, individuals with more hearing impairment were at more advanced stages of change as measured by the URICA (i.e., higher contemplation and action scores relative to their precontemplation score), and they perceived fewer barriers and more susceptibility, severity, benefits and cues to action as measured by the HBQ. Multiple regression analyses showed participation restrictions (HHI scores) to be a highly significant predictor of stages of change explaining 30% to 37% of the variance, as were duration of hearing difficulty, and perceived benefits, severity, self-efficacy and cues to action assessed by the HBQ. CONCLUSIONS: The main predictors of stages of change in first-time help seekers were reported participation restrictions and duration of hearing difficulty, with constructs from the health belief model also explaining some of the variance in stages of change scores. The transtheoretical model and the health belief model are valuable for understanding hearing health behaviors and can be applied when developing interventions to promote help seeking. PMID- 26765287 TI - A highly immunogenic vaccine against A/H7N9 influenza virus. AB - Since the first case of human infection in March 2013, continued reports of H7N9 cases highlight a potential pandemic threat. Highly immunogenic vaccines to this virus are urgently needed to protect vulnerable populations who lack protective immunity. In this study, an egg- and adjuvant-independent adenoviral vector based, hemagglutinin H7 subtype influenza vaccine (HAd-H7HA) demonstrated enhanced cell-mediated immunity as well as serum antibody responses in a mouse model. Most importantly, this vaccine provided complete protection against homologous A/H7N9 viral challenge suggesting its potential utility as a pandemic vaccine. PMID- 26765288 TI - Maternal Tdap vaccination: Coverage and acute safety outcomes in the vaccine safety datalink, 2007-2013. AB - INTRODUCTION: Since October 2012, the combined tetanus toxoid, reduced diphtheria toxoid, acellular pertussis vaccine (Tdap) has been recommended in the United States during every pregnancy. METHODS: In this observational study from the Vaccine Safety Datalink, we describe receipt of Tdap during pregnancy among insured women with live births across seven health systems. Using a retrospective matched cohort, we evaluated risks for selected medically attended adverse events in pregnant women, occurring within 42 days of vaccination. Using a generalized estimating equation, we calculated adjusted incident rate ratios (AIRR). RESULTS: Our vaccine coverage cohort included 438,487 live births between January 1, 2007 and November 15, 2013. Across the coverage cohort, 14% received Tdap during pregnancy. By 2013, Tdap was administered during pregnancy in 41.7% of live births, primarily in the 3rd trimester. Our vaccine safety cohort included 53,885 vaccinated and 109,253 matched unvaccinated pregnant women. There was no increased risk for a composite outcome of medically attended acute adverse events within 3 days of vaccination. Similarly, across the safety cohort, over a 42 day window, incident neurologic events, thrombotic events, and new onset proteinuria did not differ by maternal receipt of Tdap. Among women receiving Tdap at 20 weeks gestation or later, as compared to their matched controls, there was no increased risk for gestational diabetes or cardiac events while venous thromboembolic events and thrombocytopenia were diagnosed within 42 days of vaccination at slightly decreased rates. CONCLUSION: Tdap coverage during pregnancy increased from 2007 through 2013, but was still below 50%. No acute maternal safety signals were detected in this large cohort. PMID- 26765290 TI - Expression analysis of BECN1 in acute myeloid leukemia: association with distinct cytogenetic and molecular abnormalities. AB - INTRODUCTION: In acute myeloid leukemia (AML), it has been shown that AML-derived cells often remain sensitive to autophagy-inducing stimuli, leading to the idea that harnessing the autophagy can be pertinent to AML cytotoxic therapy. Despite this promising notion, to date, there is no comprehensive study addressing autophagy-related genes expression status in AML. As a critical mediator, BECN1 influences the onset and advance of autophagy and several studies have pointed to the BECN1 recurrent allelic deletion and expression variation in a broad range of tumors. To explore this caveat, we chose this alteration-prone gene to investigate in our study. METHODS: We have analyzed the expression status of BECN1 in a series of 128 de novo AML patients using real-time quantitative polymerase chain reaction (qRT-PCR). RESULTS: In our favorable subgroup, BECN1 expression did not alter (P = 0.301), but in intermediate and unfavorable patients, we have had BECN1 low expression compared to the normal controls (P = 0.008 and P < 0.001, respectively). We found evidence for the association of reduced expression of BECN1 with FLT3-ITD mutation (19 of 27 patients), monosomal karyotype (all of 11 patients), higher age, and WBC count. CONCLUSION: Overall, remarkable association of reduced expression of BECN1 with FLT3-ITD mutation and monosomal karyotype and their functional relationship is interesting which should be addressed and verified in future studies. PMID- 26765289 TI - NADPH oxidases differentially regulate ROS metabolism and nutrient uptake under cadmium toxicity. AB - The role of NADPH oxidases under cadmium (Cd) toxicity was studied using Arabidopsis thaliana mutants AtrbohC, AtrbohD and AtrbohF, which were grown under hydroponic conditions with 25 and 100 MUM Cd for 1 and 5 days. Cadmium reduced the growth of leaves in WT, AtrbohC and D, but not in AtrbohF. A time-dependent increase in H2 O2 and lipid peroxidation was observed in all genotypes, with AtrbohC showing the smallest increase. An opposite behaviour was observed with NO accumulation. Cadmium increased catalase activity in WT plants and decreased it in Atrboh mutants, while glutathione reductase and glycolate oxidase activities increased in Atrboh mutants, and superoxide dismutases were down-regulated in AtrbohC. The GSH/GSSG and ASA/DHA couples were also affected by the treatment, principally in AtrbohC and AtrbohF, respectively. Cadmium translocation to the leaves was severely reduced in Atrboh mutants after 1 day of treatment and even after 5 days in AtrbohF. Similar results were observed for S, P, Ca, Zn and Fe accumulation, while an opposite trend was observed for K accumulation, except in AtrbohF. Thus, under Cd stress, RBOHs differentially regulate ROS metabolism, redox homeostasis and nutrient balance and could be of potential interest in biotechnology for the phytoremediation of polluted soils. PMID- 26765291 TI - Health and economic benefits of public financing of epilepsy treatment in India: An agent-based simulation model. AB - OBJECTIVE: An estimated 6-10 million people in India live with active epilepsy, and less than half are treated. We analyze the health and economic benefits of three scenarios of publicly financed national epilepsy programs that provide: (1) first-line antiepilepsy drugs (AEDs), (2) first- and second-line AEDs, and (3) first- and second-line AEDs and surgery. METHODS: We model the prevalence and distribution of epilepsy in India using IndiaSim, an agent-based, simulation model of the Indian population. Agents in the model are disease-free or in one of three disease states: untreated with seizures, treated with seizures, and treated without seizures. Outcome measures include the proportion of the population that has epilepsy and is untreated, disability-adjusted life years (DALYs) averted, and cost per DALY averted. Economic benefit measures estimated include out-of pocket (OOP) expenditure averted and money-metric value of insurance. RESULTS: All three scenarios represent a cost-effective use of resources and would avert 800,000-1 million DALYs per year in India relative to the current scenario. However, especially in poor regions and populations, scenario 1 (which publicly finances only first-line therapy) does not decrease the OOP expenditure or provide financial risk protection if we include care-seeking costs. The OOP expenditure averted increases from scenarios 1 through 3, and the money-metric value of insurance follows a similar trend between scenarios and typically decreases with wealth. In the first 10 years of scenarios 2 and 3, households avert on average over US$80 million per year in medical expenditure. SIGNIFICANCE: Expanding and publicly financing epilepsy treatment in India averts substantial disease burden. A universal public finance policy that covers only first-line AEDs may not provide significant financial risk protection. Covering costs for both first- and second-line therapy and other medical costs alleviates the financial burden from epilepsy and is cost-effective across wealth quintiles and in all Indian states. PMID- 26765292 TI - Tunability of 1/f Noise at Multiple Dirac Cones in hBN Encapsulated Graphene Devices. AB - The emergence of multiple Dirac cones in hexagonal boron nitride (hBN)-graphene heterostructures is particularly attractive because it offers potentially better landscape for higher and versatile transport properties than the primary Dirac cone. However, the transport coefficients of the cloned Dirac cones is yet not fully characterized and many open questions, including the evolution of charge dynamics and impurity scattering responsible for them, have remained unexplored. Noise measurements, having the potential to address these questions, have not been performed to date in dual-gated hBN-graphene-hBN devices. Here, we present the low-frequency 1/f noise measurements at multiple Dirac cones in hBN encapsulated single and bilayer graphene in dual-gated geometry. Our results reveal that the low-frequency noise in graphene can be tuned by more than two orders of magnitude by changing carrier concentration as well as by modifying the band structure in bilayer graphene. We find that the noise is surprisingly suppressed at the cloned Dirac cone compared to the primary Dirac cone in single layer graphene device, while it is strongly enhanced for the bilayer graphene with band gap opening. The results are explained with the calculation of dielectric function using tight-binding model. Our results also indicate that the 1/f noise indeed follows the Hooge's empirical formula in hBN-protected devices in dual-gated geometry. We also present for the first time the noise data in bipolar regime of a graphene device. PMID- 26765293 TI - Physalis angulata induces death of promastigotes and amastigotes of Leishmania (Leishmania) amazonensis via the generation of reactive oxygen species. AB - Leishmaniasis are a neglected group of emerging diseases that have been found in 98 countries and are caused by protozoa of the genus Leishmania. The therapy for leishmaniasis causes several side effects and leads to drug-resistant strains. Natural products from plants have exhibited activities against Leishmania in various experimental models. Physalis angulata is a widely used plant in popular medicine, and in the literature it has well-documented leishmanicidal activity. However, its mechanism of action is still unknown. Thus, this study aims to evaluate the mechanism driving the leishmanicidal activity of an aqueous extract of P. angulata root (AEPa). AEPa was effective against both promastigotes and intracellular amastigote forms of Leishmania amazonensis. This effect was mediated by an increase of reactive oxygen species (ROS), but not of nitric oxide (NO). The increased production of ROS induces cell death by phenotypes seems by apoptosis cell death in Leishmania, but not autophagy or necrosis. In addition, morphological analysis of macrophages showed that AEPa induced a high number of cytoplasmic projections, increased the volume of cytoplasm and number of vacuoles, caused cytoskeleton alterations and resulted in high spreading ability. AEPa also promoted superoxide anion (O2(-)) production in both uninfected macrophages and those infected with Leishmania. Therefore, these results revealed that AEPa causes cell death by phenotypes seems by apoptosis cell death in L. amazonensis and modulates macrophage activation through morphofunctional alterations and O2(-) generation to induce Leishmania death. PMID- 26765295 TI - The Perceived Structure Of Social Attitudes And Personality : A Multidimensional Scaling Approach. AB - This study examined the relationships between attitudes inferred from behavior and attitudes implied by item content. 60 subjects judged the similarity between all possible pairs of 18 attitude items and 6 person descriptions designed to reflect three hypothesized dimensions of authoritarian ideology. These interstimulus similarity judgments were subjected t o a multidimensional scaling analysis. Results supported the hypotheses that (a) subsets of attitude statements reflecting hypothesized facets of authoritarian ideology of Superstition, Authoritarian Rejection, and Power and Toughness would be per ceived as representing independent dimensions; and (b) both people and attitude items can be represented cogently by points in a common multidimensional space. PMID- 26765294 TI - Three Factor Analyses Of Electromyographic Data Under Varying Conditions. AB - Electromyographic scores for seven muscles, systolic and diastolic blood pressure, heart rate, and galvanic skin resistance were obtained on 20 male and 24 female psychiatric clinic out-patients during three experimental conditions: rest, white noise, and psychological stress. Subjects also received 6 psychiatric ratings representing their response to the psychological stress. These ratings were included in all three score matrices. A principal component factor matrix was computed ?or each of the conditions; these were rotated both orthogonally and obliquely. Muscles which are in close physical proximity tended to cluster much more on the analyses of scores obtained -during-rest and noise than during psychological stress. The pattern of heart rate and the two blood pressures varied with the conditions. Although the same rating scores were used for the three analyses, their loadings differed. PMID- 26765296 TI - Discriminant Analyses Of Preschool Masculinity And Femininity. AB - The nature of masculinity and femininity in the preschool years was investigated. Four criterion groups, Most Masculine boys, Least Masculine boys, Most Feminine girls, and Least Feminine girls, were selected from teachers' judgments of masculinity and femininity made by the method of pair comparisons. A covariance matrix of the teachers' personality ratings of these children was factor analyzed. Four factors were identified : Extraversion- Introversion, Social Adjustment, Competence, and an unnamed factor. A discriminant analysis on these factors indicated that MM boys were more extraverted, somewhat more competent and slightly more socially adjusted than LM boys. A second discriminant analysis indicated that M F girls were more socially adjusted, somewhat more competent and slightly more introverted than LF girls. The coefficient of congruence between the discriminant pat- terns for masculinity and femininity indicated that these constructs are not opposite ends of a continuum. PMID- 26765297 TI - Predicting Individual Differences By Cluster Analysis : Holzinger Abilities And MMPI Personality Attributes. AB - Prediction of individual differences by cluster analysis procedures is described for the case of Holzinger's 24-variable problem and the case of MMPI item clusters. Comparisons are made between univariate, multiple regression, and person-cluster predictions. The best prediction is from person- clusters, whose score patterns are objectively isolated by BC TRY Computer System programs. The role of chance is objectively assessed by program 4CAST and not by estimation formulations. PMID- 26765298 TI - Proving Causal Propositions : The Foundations Of Program And Experiment Design. AB - Although causal propositions cannot be proven to the point of incorrigibility, they can be disproven (aside from instrument validity problems) or corroborated. Just how one proceeds to such disproof or corroboration depends upon what his interest is in the causes of his dependent variables' values. Testing and qualifying or restricting a specific causal proposition, developing a comprehensive or variance exhaustive linear causal proposition (or multiple regression equation), and mapping or describing the efficacy of a specific set of Treatments imply somewhat,different programs of re- search and experiment designs. Programs and designs for these three interests or strategies are differentiated in terms of a Factor Lattice of all the ex ante relevant variables. The terms of this analysis refer to the regional locations in, density of coverage of, and allocation of replicates to the selected Lattice intersects and the factorial completeness of the design which they constitute, as well as to the type of control exercised over the Factors: production, selection, or stochastic. PMID- 26765299 TI - A Measure Of Similarity Between Individuals When Scoring Directions Of Variables Are Arbitrary. AB - Holley and Guilford have proposed an index, G, originally intended for use in Q type factor analysis when scoring directions are arbitrary. G is appropriate for dichotomous data only. In this paper, a general measure is derived which is identical to G in the case of dichotomous data. The measure is approximately equal to the mean inter-person covariance when all permutations of scoring directions are considered. The measure is also closely connected both with component analysis of individual differences and with the condition of proportionality between two sets of observed values. PMID- 26765301 TI - Erratum. PMID- 26765300 TI - Transformation Methods For Latent Roots And Vectors. AB - Factorial analysis by the principal component method leads to a well- known problem in mathematics, that of the solution of the characteristic equation. One of the solutions widely known to psychologists is that of the Hotelling iterative method. This article presents two transformation methods that possess certain advantages over the Hotelling procedure. PMID- 26765303 TI - The Value of Sonographer Credentialing: An Important First Step. PMID- 26765302 TI - Guidelines for the Use of Echocardiography in the Evaluation of a Cardiac Source of Embolism. AB - Embolism from the heart or the thoracic aorta often leads to clinically significant morbidity and mortality due to transient ischemic attack, stroke or occlusion of peripheral arteries. Transthoracic and transesophageal echocardiography are the key diagnostic modalities for evaluation, diagnosis, and management of stroke, systemic and pulmonary embolism. This document provides comprehensive American Society of Echocardiography guidelines on the use of echocardiography for evaluation of cardiac sources of embolism. It describes general mechanisms of stroke and systemic embolism; the specific role of cardiac and aortic sources in stroke, and systemic and pulmonary embolism; the role of echocardiography in evaluation, diagnosis, and management of cardiac and aortic sources of emboli including the incremental value of contrast and 3D echocardiography; and a brief description of alternative imaging techniques and their role in the evaluation of cardiac sources of emboli. Specific guidelines are provided for each category of embolic sources including the left atrium and left atrial appendage, left ventricle, heart valves, cardiac tumors, and thoracic aorta. In addition, there are recommendation regarding pulmonary embolism, and embolism related to cardiovascular surgery and percutaneous procedures. The guidelines also include a dedicated section on cardiac sources of embolism in pediatric populations. PMID- 26765304 TI - Resolutions-Resolutions. PMID- 26765305 TI - What are Your Resolutions, Professional and Otherwise? PMID- 26765306 TI - Emerging from Two-Dimensional Shadows, the Value of Added Dimensions in the Accurate Assessment of Mitral Regurgitation. PMID- 26765307 TI - Meta analysis on relationship between distributions of C282Y and H63D alleles and genotypes and hepatocellular carcinoma. AB - According to the results of retrieving PubMed/MEDLINE and EMBASE databases, this study summarized distributions of two commonly mutated alleles (C282Y and H63D) and genotypes in HFE gene, and considered odds ratios (ORs) as well as its 95% confidence intervals (95% CIs) as effective variables of the included study itself and after summarizing. In terms of allele, compared with individual carrying wild type (WT) allele, individual carrying C282Y allele was more likely to suffer from liver cancer, with OR and P value of 1.58 (95% CI 1.10-2.27) and 0.01, respectively; no significantly increased risk of liver cancer was found in individual carrying H63D allele, with OR and P value of 1.12 (95% CI 0.89-1.47) and 0.35, respectively. From a perspective of genotype, in comparison with individual carrying WT/WT genotype, risk of individual carried with C282Y/C282Y homozygote genotype suffering from liver cancer increased significantly, with OR and P value of 5.10 (95% CI 2.58-10.09) and less than 0.00001, respectively. Furthermore, OR and P value of individual carrying C282Y/WT heterozygous genotype were 1.28 (95% CI 1.01-1.63) and 0.04 severally; and individual carried with H63D/H63D homozygote genotype was found without obviously increased liver cancer risk, with OR and P value of 1.04 (95% CI 0.63-1.71) and 0.89. Moreover, OR and P value of individual carrying H63D/H63D homozygote genotype or H63D/WT heterozygous genotype were 1.19 (95% CI 0.99-1.37) and 0.07, respectively. Meta analysis revealed that individual carrying C282Y/C282Y homozygote genotype had 5.10 times of liver cancer risk than individual carrying WT/WT genotype, while no significantly increased liver cancer risk was found in individual carrying H63D/H63D homozygote genotype or carrying C282Y/WT and H63D/WT heterozygous genotype. PMID- 26765308 TI - Tissue factor-dependent pathway in severe preeclampsia revisited: a Brazilian cohort study. AB - Previously we investigated the tissue factor (TF)-dependent coagulation pathway and key haemostatic cofactors in white women with preeclampsia (P-EC) and suggested that plasma factor VII (FVII) levels can differentiate women with P-EC from healthy nonpregnant women or normal pregnant women, at the same trimester, with high sensitivity, specificity, positive and negative predictive values. Here we re-examine the TF-dependent pathway in a large cohort of Brazilian women. A total of 240 women were studied. These included healthy nonpregnant women (n = 79), normotensive pregnant women (n = 80) and women with severe P-EC (n = 81). Commercially available enzyme-linked immunosorbent assays were used to measure plasma FVII, activated factor VII (FVIIa), TF and tissue factor pathway inhibitor (TFPI). All study participants were matched for age. Pregnant women (with/without P-EC) were matched for gestational age and parity. Plasma levels of FVII, FVIIa and TFPI were significantly increased in women with severe P-EC compared with healthy nonpregnant women (P < 0.01) or normotensive pregnant women (P < 0.01). FVIIa was also higher in normotensive pregnant women compared with nonpregnant women (P < 0.01). However, no such significant trends were observed for plasma TF levels (P = 0.074). In conclusion, circulating FVII, FVIIa and TFPI were significantly elevated in women with severe P-EC in the absence of comparable changes in plasma TF levels. The present work is in agreement with our previous report on FVII levels in white women with P-EC. Thus, this lends further support to the notion that plasma FVII levels are potentially valuable diagnostic marker for P-EC, irrespective of ethnicity. PMID- 26765309 TI - A Simplified Approach to Risk Assessment Based on System Dynamics: An Industrial Case Study. AB - Seveso plants are complex sociotechnical systems, which makes it appropriate to support any risk assessment with a model of the system. However, more often than not, this step is only partially addressed, simplified, or avoided in safety reports. At the same time, investigations have shown that the complexity of industrial systems is frequently a factor in accidents, due to interactions between their technical, human, and organizational dimensions. In order to handle both this complexity and changes in the system over time, this article proposes an original and simplified qualitative risk evaluation method based on the system dynamics theory developed by Forrester in the early 1960s. The methodology supports the development of a dynamic risk assessment framework dedicated to industrial activities. It consists of 10 complementary steps grouped into two main activities: system dynamics modeling of the sociotechnical system and risk analysis. This system dynamics risk analysis is applied to a case study of a chemical plant and provides a way to assess the technological and organizational components of safety. PMID- 26765310 TI - Gossypol induces pyroptosis in mouse macrophages via a non-canonical inflammasome pathway. AB - Gossypol, a polyphenolic compound isolated from cottonseeds, has been reported to possess many pharmacological activities, but whether it can influence inflammasome activation remains unclear. In this study, we found that in mouse macrophages, gossypol induced cell death characterized by rapid membrane rupture and robust release of HMGB1 and pro-caspase-11 comparable to ATP treatment, suggesting an induction of pyroptotic cell death. Unlike ATP, gossypol induced much low levels of mature interleukin-1beta (IL-1beta) secretion from mouse peritoneal macrophages primed with LPS, although it caused pro-IL-1beta release similar to that of ATP. Consistent with this, activated caspase-1 responsible for pro-IL-1beta maturation was undetectable in gossypol-treated peritoneal macrophages. Besides, RAW 264.7 cells lacking ASC expression and caspase-1 activation also underwent pyroptotic cell death upon gossypol treatment. In further support of pyroptosis induction, both pan-caspase inhibitor and caspase-1 subfamily inhibitor, but not caspase-3 inhibitor, could sharply suppress gossypol induced cell death. Other canonical pyroptotic inhibitors, including potassium chloride and N-acetyl-l-cysteine, could suppress ATP-induced pyroptosis but failed to inhibit or even enhanced gossypol-induced cell death, whereas nonspecific pore-formation inhibitor glycine could attenuate this process, suggesting involvement of a non-canonical pathway. Of note, gossypol treatment eliminated thioglycollate-induced macrophages in the peritoneal cavity with recruitment of other leukocytes. Moreover, gossypol administration markedly decreased the survival of mice in a bacterial sepsis model. Collectively, these results suggested that gossypol induced pyroptosis in mouse macrophages via a non canonical inflammasome pathway, which raises a concern for its in vivo cytotoxicity to macrophages. PMID- 26765311 TI - Root structure-function relationships in 74 species: evidence of a root economics spectrum related to carbon economy. AB - Although fine roots are important components of the global carbon cycle, there is limited understanding of root structure-function relationships among species. We determined whether root respiration rate and decomposability, two key processes driving carbon cycling but always studied separately, varied with root morphological and chemical traits, in a coordinated way that would demonstrate the existence of a root economics spectrum (RES). Twelve traits were measured on fine roots (diameter <= 2 mm) of 74 species (31 graminoids and 43 herbaceous and dwarf shrub eudicots) collected in three biomes. The findings of this study support the existence of a RES representing an axis of trait variation in which root respiration was positively correlated to nitrogen concentration and specific root length and negatively correlated to the root dry matter content, lignin : nitrogen ratio and the remaining mass after decomposition. This pattern of traits was highly consistent within graminoids but less consistent within eudicots, as a result of an uncoupling between decomposability and morphology, and of heterogeneity of individual roots of eudicots within the fine-root pool. The positive relationship found between root respiration and decomposability is essential for a better understanding of vegetation-soil feedbacks and for improving terrestrial biosphere models predicting the consequences of plant community changes for carbon cycling. PMID- 26765313 TI - Flame retardants: Dust - And not food - Might be the risk. AB - Flame retardants (FRs) are used to delay ignition of materials such as furniture and electric and electronic instruments. Many FRs are persistent and end up in the environment. Environmental studies on flame retardants (FRs) took off in the late 1990s. Polybrominated diphenylethers (PBDEs) appeared to be bioaccumulative and were found in many organisms all over the world. When PBDEs were banned or their production voluntarily terminated, alternatives appeared on the market that often had similar properties or were of more concern due to their toxicity such as halogenated phosphorus-based FRs. Here we show that in spite of the ban on PBDEs more brominated FRs are being produced, an increasing number of other FRs is being applied and FR levels in our homes are much higher than in the outdoor environment. While nowadays we live in better isolated houses and sit in front of the computer or television, on flame retarded upholstery, we are at risk due to the toxic effects of a suite of FRs. The high exposure to these substances indoors calls for better risk assessments that include mixture effects. PMID- 26765312 TI - Mechanisms and Treatment of Intradialytic Hypertension. AB - BACKGROUND: Intradialytic hypertension is a condition where there is an increase in blood pressure (BP) from pre- to post-hemodialysis; this condition has been recently identified as an independent mortality risk factor in hypertensive hemodialysis patients. The mechanisms and management of intradialytic hypertension have been explored in numerous research studies over the past few years. SUMMARY: Patients with intradialytic hypertension have been found to be more chronically volume overloaded compared to other hemodialysis patients, although no causal role has been established. Patients with intradialytic hypertension have intradialytic vascular resistance surges that likely explain the BP increase during dialysis. Acute intradialytic changes in endothelial cell function have been proposed as etiologies for the increase in vascular resistance, although it is unclear if endothelin-1 or some other vasoconstrictive peptide is responsible. There is an association between dialysate to serum sodium gradients and BP increase during dialysis in patients with intradialytic hypertension, although it is unclear if this is related to endothelial cell activity or acute osmolar changes. In addition to probing the dry weight of patients with intradialytic hypertension, other management strategies include lowering dialysate sodium and changing antihypertensives to include carvedilol or other poorly dialyzed antihypertensives. KEY MESSAGES: Hemodialysis patients with intradialytic hypertension have an increased mortality risk compared to patients with modest decreases in BP during dialysis. Intradialytic hypertension is associated with extracellular volume overload in addition to acute increases in vascular resistance during dialysis. Management strategies should include reevaluation of dry weight and modification of both the dialysate prescription and medication prescription. PMID- 26765314 TI - Association of ORCA/LRWD1 with repressive histone methyl transferases mediates heterochromatin organization. AB - Heterochromatin mostly constitutes tightly packaged DNA, decorated with repressive histone marks, including histone H3 methylated at lysine 9, histone H4 methylated at lysine 20 and histone H3 methylated at lysine 27. Each of these marks is incorporated by specific histone lysine methyl transferases. While constitutive heterochromatin enriched with H3K9me3 and H4K20me3 occur within repetitive elements, including centromeres and telomeres, the facultative heterochromatin resides on the inactive X-chromosome and contains H3K27me3 mark. Origin recognition complex-associated (ORCA/LRWD1) protein is required for the initiation of DNA replication and also plays crucial roles in heterochromatin organization. ORCA associates with constitutive and facultative heterochromatin in human cells and binds to repressive histone marks. We demonstrate that ORCA binds to multiple repressive histone methyl transferases including G9a, GLP, Suv39h1 (H3K9me2/3), Suv420h1/h2 (H4K20me2/3) and EZH2 (H3K27me3). Removal of ORCA from human cells causes aberrations in the chromatin architecture. We propose that ORCA acts as a scaffold protein that enables the formation of multiple histone lysine methyltransferase complexes at heterochromatic sites thereby facilitating chromatin organization. PMID- 26765316 TI - Clinical Trials of Novel Treatments for Cystic Fibrosis. PMID- 26765315 TI - Effects of Combined Treatment With Arsenic Trioxide and Itraconazole in Patients With Refractory Metastatic Basal Cell Carcinoma. AB - IMPORTANCE: Tumor resistance is an emerging problem for Smoothened (SMO) inhibitor-treated metastatic basal cell carcinoma (BCC). Arsenic trioxide and itraconazole antagonize the hedgehog (HH) pathway at sites distinct from those treated by SMO inhibitors. OBJECTIVE: To determine whether administration of intravenous arsenic trioxide and oral itraconazole in patients with metastatic BCC is associated with a reduction in GLI1 messenger RNA expression in tumor and/or normal skin biopsy samples. DESIGN, SETTING, AND PARTICIPANTS: Five men with metastatic BCC who experienced relapse after SMO inhibitor treatment underwent intravenous arsenic trioxide treatment for 5 days, every 28 days, and oral itraconazole treatment on days 6 to 28. Data were collected from April 10 to November 14, 2013. Follow-up was completed on October 3, 2015, and data were analyzed from June 5 to October 6, 2015. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in messenger RNA levels of the GLI family zinc finger 1 (GLI1) gene (HH-pathway target gene) in biopsy specimens of normal skin or BCC before and after treatment. Secondary objectives were evaluation of tumor response and tolerability. RESULTS: Of the 5 patients (mean [SD] age, 52 [9] years; age range, 43-62 years), 3 completed 3 cycles of treatment and 2 discontinued treatment early owing to disease progression or adverse events. Adverse effects included grade 2 transaminitis and grade 4 leukopenia with a grade 3 infection. Overall, arsenic trioxide and itraconazole reduced GLI1 messenger RNA levels by 75% from baseline (P < .001). The best overall response after 3 treatment cycles was stable disease in 3 patients. CONCLUSIONS AND RELEVANCE: Targeting the HH pathway with sequential arsenic trioxide and itraconazole treatment is a feasible treatment for metastatic BCC. Although some patients experienced stable disease for 3 months, none had tumor shrinkage, which may be owing to transient GLI1 suppression with sequential dosing. Continuous dosing may be required to fully inhibit the HH pathway and achieve clinical response. PMID- 26765318 TI - Should patients newly diagnosed with bladder cancer be screened for lung cancer? PMID- 26765319 TI - Correction: Cytotaxonomy of Eurypyga helias (Gruiformes, Eurypygidae): First Karyotypic Description and Phylogenetic Proximity with Rynochetidae. PMID- 26765317 TI - Predictors of early androgen deprivation treatment failure in prostate cancer with bone metastases. AB - Approximately 15% of men with hormone naive metastatic prostate cancer primarily fail to respond to androgen deprivation treatment (ADT). The reason why the response to ADT differs in this subgroup of men with prostate cancer remains unclear. The aim of this study was to describe the characteristics of these men and to thereby define predictors of early ADT failure in prostate cancer patients with bone metastases. The study was based on 915 men from the prospective randomized multicenter trial (no. 5) conducted by the Scandinavian Prostate Cancer Group comparing parenteral estrogen with total androgen blockade. Early ADT failure was defined as death from metastatic prostate cancer within 12 months after the start of ADT. Multivariate logistic regression models were applied to identify clinical predictors of early ADT failure. Ninety-four (10.3%) men were primarily nonresponders to ADT. Independent predictors of early ADT failure were poor Eastern Cooperative Oncology Group performance status (PS), analgesic consumption, low hemoglobin, and high Soloway score (extent of disease observed on the scan), in where patients with poor PS and/or high analgesic consumption had a threefold risk of early ADT failure. Not significantly factors related to early ADT failure were age, treatment, cardiovascular comorbidity, T category, grade of malignancy, serum estrogen level, and SHBG at enrolment. We analyzed characteristics of a subgroup of patients who primarily failed to respond to ADT. Four independent clinical predictors of early ADT failure could be defined, and men exhibiting these features should be considered for an alternative treatment. PMID- 26765320 TI - Microfluidic Distance Readout Sweet Hydrogel Integrated Paper-Based Analytical Device (MUDiSH-PAD) for Visual Quantitative Point-of-Care Testing. AB - A disposable, equipment-free, versatile point-of-care testing platform, microfluidic distance readout sweet hydrogel integrated paper-based analytical device (MUDiSH-PAD), was developed for portable quantitative detection of different types of targets. The platform relies on a target-responsive aptamer cross-linked hydrogel for target recognition, cascade enzymatic reactions for signal amplification, and microfluidic paper-based analytic devices (MUPADs) for visual distance-based quantitative readout. A "sweet" hydrogel with trapped glucoamylase (GA) was synthesized using an aptamer as a cross-linker. When target is present in the sample, the "sweet" hydrogel collapses and releases enzyme GA into the sample, generating glucose by amylolysis. A hydrophilic channel on the MUPADs is modified with glucose oxidase (GOx) and colorless 3,3'-diaminobenzidine (DAB) as the substrate. When glucose travels along the channel by capillary action, it is converted to H2O2 by GOx. In addition, DAB is converted into brown insoluble poly-3,3'-diaminobenzidine [poly(DAB)] by horseradish peroxidase, producing a visible brown bar, whose length is positively correlated to the concentration of targets. The distance-based visual quantitative platform can detect cocaine in urine with high selectivity, sensitivity, and accuracy. Because the target-induced cascade reaction is triggered by aptamer/target recognition, this method is widely suitable for different kinds of targets. With the advantages of low cost, ease of operation, general applicability, and disposability with quantitative readout, the MUDiSH-PAD holds great potential for portable detection of trace targets in environmental monitoring, security inspection, personalized healthcare, and clinical diagnostics. PMID- 26764987 TI - Determination of the Ratio of b-Quark Fragmentation Fractions f(s)/f(d) in pp Collisions at ?s=7 TeV with the ATLAS Detector. AB - With an integrated luminosity of 2.47 fb(-1) recorded by the ATLAS experiment at the LHC, the exclusive decays B(s)(0)->J/psiphi and B(d)(0)->J/psiK(*0) of B mesons produced in pp collisions at ?s=7 TeV are used to determine the ratio of fragmentation fractions f(s)/f(d). From the observed B(s)(0)->J/psiphi and B(d)(0)->J/psiK(*0) yields, the quantity (f(s)/f(d))[B(B(s)(0) >J/psiphi)/B(B(d)(0)->J/psiK(*0))] is measured to be 0.199+/-0.004(stat)+/ 0.008(syst). Using a recent theory prediction for [B(B(s)(0)->J/psiphi)/B(B(d)(0) >J/psiK(*0))] yields (f(s)/f(d))=0.240+/-0.004(stat)+/-0.010(syst)+/-0.017(th). This result is based on a new approach that provides a significant improvement of the world average. PMID- 26765323 TI - A Mutant with Expression Deletion of Gene Sec-1 in a 1RS.1BL Line and Its Effect on Production Quality of Wheat. AB - The chromosome arm 1RS of rye (Secale cereal L.) has been used worldwide as a source of genes for agronomic and resistant improvement. However, the 1RS arm in wheat has end-use quality defects that are partially attributable to the presence of omega-secalins, which are encoded by genes at the Sec-1 locus. Various attempts in removing the Sec-1 genes from the 1RS.1BL translocation chromosome have been made. In the present study, two new primary 1RS.1BL translocation lines, T917-26 and T917-15, were developed from a cross between wheat variety "A42912" and Chinese local rye "Weining." The lines T917-15 and T917-26 carried a pair of intact and homogeneous 1RS.1BL chromosomes. The line T917-26 also harbored an expression deletion of some genes at the Sec-1 locus, which originated from a mutation that occurred simultaneously with wheat-rye chromosome translocations. These results suggest that the accompanying mutations of the evolutionarily significant translocations are remarkable resources for plant improvement. Comparison of translocation lines with its wheat parent showed improvements in the end-use quality parameters, which included protein content (PC), water absorption (WA), sodium dodecyl sulfate sedimentation (SDSS), wet gluten (WG), dry gluten (DG) and dough stickiness (DS), whereas significant reduction in gluten index (GI) and stability time (ST) were observed. These findings indicate that 1RS in wheat has produced a higher amount of protein, although these comprised worse compositions. However, in the T917-26 line that harbored an expression deletion mutation in the Sec-1 genes, the quality parameters were markedly improved relative to its sister line, T917-15, especially for GI and DS (P < 0.05). These results indicated that expression deletion of Sec-1 genes significantly improves the end-use quality of wheat cultivars harboring the 1RS.1BL translocation. Strategies to remove the Sec-1 genes from the 1RS.1BL translocation in wheat improvement are discussed. PMID- 26765324 TI - Gold-Catalyzed Enantio- and Diastereoselective Syntheses of Left Fragments of Azadirachtin/Meliacarpin-Type Limonoids. AB - Meliacarpin-type limonoids are an important class of organic insecticides. Their syntheses are challenging due to their chemical complexity. Here, we report the highly enantio- and diastereoselective synthesis of the left fragments of azadirachtin I and 1-cinnamoylmelianolone, being two important family members of meliacarpin-type limonoids, via pairwise palladium- and gold-catalyzed cascade reactions. Gold-catalyzed reactions of 1,7-diynes were performed as model studies, and the efficient construction of tetracyclic late-stage intermediates was achieved on the basis of this key transformation. Our unique route gave both of the left fragments in 23 steps from the commercially available chiral starting material (-)-carvone. This study significantly advances research on the synthesis of the meliacarpin-type limonoids. PMID- 26765325 TI - Erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) combined responders to tadalafil after 12 weeks of treatment. AB - OBJECTIVE: To analyse the proportion of men taking tadalafil 5 mg once daily who experience a combined improvement in symptoms of both erectile dysfunction (ED) and lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). MATERIALS AND METHODS: The data from men aged >=45 years randomized to tadalafil 5 mg once daily or placebo enrolled in one of four randomized, placebo-controlled LUTS/BPH clinical trials were analysed (N = 927). A novel classification of 'combined responders' to ED and LUTS/BPH treatment was defined, based on published criteria for men who showed improvement in both International Index of Erectile Function - Erectile Function domain (IIEF-EF) score and total International Prostate Symptom Score (IPSS). Descriptive analyses assessed the covariate distribution by responder status. Unadjusted and adjusted logistic regressions provided odds ratios with 95% confidence intervals comparing combined responders with all others (partial and non-responders). RESULTS: Among men randomized to tadalafil 5 mg, 40.5% were combined responders (n = 189). Among placebo randomized men, 18.3% were combined responders (n = 84). Combined responders, in the total population, had the highest baseline IPSS and lowest baseline IIEF-EF scores, corresponding to the highest level of dysfunction. The majority of men were aged <=65 years, white, non-obese, non-smokers, and regular alcohol consumers. Only treatment, baseline IPSS, baseline IIEF-EF, obesity and psychoactive medication use were significantly associated with responder status (P <= 0.05). Tadalafil-treated men had 2.8 times significantly increased adjusted odds of being combined responders vs non-responders (P < 0.001). For each unit decrease in baseline IIEF-EF or alcoholic drink consumption per week there was a 4% significant increase in the adjusted odds of being a combined responder to tadalafil therapy. CONCLUSIONS: This novel measure of combined response is useful in differentiating patients with clinically relevant symptom improvement for both ED and LUTS/BPH after treatment with tadalafil 5 mg once daily vs placebo. This combined responder measure may be useful in future assessment of treatment benefits across patient groups after various types of treatment intervention (e.g. surgical vs pharmacotherapy vs non-pharmacological intervention). PMID- 26765322 TI - Spatially Resolved Quantification of Chromatin Condensation through Differential Local Rheology in Cell Nuclei Fluorescence Lifetime Imaging. AB - The linear sequence of DNA encodes access to the complete set of proteins that carry out cellular functions. Yet, much of the functionality appropriate for each cell is nested within layers of dynamic regulation and organization, including a hierarchy of chromatin structural states and spatial arrangement within the nucleus. There remain limitations in our understanding of gene expression within the context of nuclear organization from an inability to characterize hierarchical chromatin organization in situ. Here we demonstrate the use of fluorescence lifetime imaging microscopy (FLIM) to quantify and spatially resolve chromatin condensation state using cell-permeable, DNA-binding dyes (Hoechst 33342 and PicoGreen). Through in vitro and in situ experiments we demonstrate the sensitivity of fluorescence lifetime to condensation state through the mechanical effects that accompany the structural changes and are reflected through altered viscosity. The establishment of FLIM for resolving and quantifying chromatin condensation state opens the door for single-measurement mechanical studies of the nucleus and for characterizing the role of genome structure and organization in nuclear processes that accompany physiological and pathological changes. PMID- 26765327 TI - A(2+) Cation Control of Chiral Domain Formation in A(TiO)Cu4(PO4)4 (A = Ba, Sr). AB - Single crystals of two novel tetragonal chiral materials, A(TiO)Cu4(PO4)4 (A = Ba, Sr), were grown from Na2Mo2O7 flux, and their crystal and chiral domain structures were characterized. Polarized-light microscopy studies of the chiral domain structures in the crystals show that Ba(TiO)Cu4(PO4)4 mostly hosts a multidomain state, while a monodomain state predominantly appears in Sr(TiO)Cu4(PO4)4. To explain this striking difference, we quantified the chirality strength of these materials by comparing atomic positions in the chiral and nearest-achiral crystal structures, revealing larger chirality strength in Sr(TiO)Cu4(PO4)4 than in Ba(TiO)Cu4(PO4)4. Our proposed mechanisms linking the chirality strength and domain formation can account for the different occurrence frequency of chiral domains in this system. PMID- 26765331 TI - Scotland's GP Rural Fellowship: an initiative that has impacted on rural recruitment and retention. AB - CONTEXT: In Scotland 20% of the population live in a remote or rural area spread across 94% of the land mass that is defined as remote and rural. NHS Education for Scotland (NES), NHS Scotland's training and education body, works in partnership with territorial health boards and medical schools to address rural recruitment and retention through a variety of initiatives. The longest established of these is the GP Rural Fellowship, which has been in place since 2002. This article describes this program and reports on a survey of the output of the Fellowship from 2002 to 2013. THE RURAL FELLOWSHIP PROGRAM: The Fellowship is aimed at newly qualified GPs, who are offered a further year of training in and exposure to rural medicine. The Fellowship has grown and undergone several modifications since its inception. The current model involves co-funding arrangements between NES and participating boards, supporting a maximum of 12 fellows per year. The Health Boards' investment in the Fellowship is returned through the service commitment that the Fellows provide, and the funding share from NES allows Fellows to have protected educational time to meet their educational needs in relation to rural medicine. Given this level of funding support it is important that the outcome of the Fellowship experience is understood, in particular its influence on recruitment to and retention in general practice in rural Scotland. To address this need a survey of all previous rural Fellows was undertaken in the first quarter of 2014, including all Fellows that had undertaken the Fellowship between 2002-03 and 2012-13. A total of 69 GPs were recruited to the Fellowship in this period, of which 66 were able to be included in the survey. There was a response rate of 98% to the survey and 63 of those that responded (97%) were working currently in general practice, 53 of whom were doing so in Scotland. A total of 46 graduates of the Fellowship in the period surveyed (71%) were working in rural areas or accessible small towns in Scotland, 39 in substantive general practice roles (60%). LESSONS LEARNED: Scotland's GP Rural Fellowship program represents a successful collaboration between education and service, and the results of the survey reported in this article underline previously unpublished data that suggest that approximately three-quarters of graduates are retained in important roles in rural Scotland. It is unclear however whether the Fellowship confirms a prior intention to work in rural practice, or whether it provides a new opportunity through protected exposure. This will form the basis of further evaluation. PMID- 26765326 TI - "Cat-gras" delusion: a unique misidentification syndrome and a novel explanation. AB - ABSRACT Capgras syndrome is a distressing delusion found in a variety of neurological and psychiatric diseases where a patient believes that a family member, friend, or loved one has been replaced by an imposter. Patients recognize the physical resemblance of a familiar acquaintance but feel that the identity of that person is no longer the same. Here we describe a 73-year-old male with right posterior frontal and bilateral anterior-medial frontal damage from prior brain trauma with a similar delusion of an imposter replacing his pet cat. Misidentification syndromes for animals, as opposed to humans, have been rarely reported. Neuropsychological testing showed deficits in executive processing and memory retrieval with prominent intrusions and false positive responses. The delusional belief content in Capgras syndrome has been hypothesized to result from loss of an emotional or autonomic response to familiar stimuli, from theory of mind deficits, or from loss of self-environment distinctions. We instead propose that Capgras delusions result from a dysfunction in linking external stimuli with retrieved internal autobiographical memories pertaining to that object. This leads to an erroneously learned identity that persists as a specific delusional belief. PMID- 26765329 TI - Overexpression of Heme Oxygenase-1 Prevents Renal Interstitial Inflammation and Fibrosis Induced by Unilateral Ureter Obstruction. AB - Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases. Many studies have demonstrated that heme oxygenase-1 (HO-1) is involved in diverse biological processes as a cytoprotective molecule, including anti-inflammatory, anti-oxidant, anti-apoptotic, antiproliferative, and immunomodulatory effects. However, the mechanisms of HO-1 prevention in renal interstitial fibrosis remain unknown. In this study, HO-1 transgenic (TG) mice were employed to investigate the effect of HO-1 on renal fibrosis using a unilateral ureter obstruction (UUO) model and to explore the potential mechanisms. We found that HO-1 was adaptively upregulated in kidneys of both TG and wild type (WT) mice after UUO. The levels of HO-1 mRNA and protein were increased in TG mice compared with WT mice under normal conditions. HO-1 expression was further enhanced after UUO and remained high during the entire experimental process. Renal interstitial fibrosis in the TG group was significantly attenuated compared with that in the WT group after UUO. Moreover, overexpression of HO-1 inhibited the loss of peritubular capillaries. In addition, UUO-induced activation and proliferation of myofibroblasts were suppressed by HO-1 overexpression. Furthermore, HO-1 restrained tubulointerstitial infiltration of macrophages and regulated the secretion of inflammatory cytokines in UUO mice. We also found that high expression of HO-1 inhibited reactivation of Wnt/beta-catenin signaling, which could play a crucial role in attenuating renal fibrosis. In conclusion, these data suggest that HO-1 prevents renal tubulointerstitial fibrosis possibly by regulating the inflammatory response and Wnt/beta-catenin signaling. This study provides evidence that augmentation of HO-1 levels may be a therapeutic strategy against renal interstitial fibrosis. PMID- 26765333 TI - The Regioselectivity of Bingel-Hirsch Cycloadditions on Isolated Pentagon Rule Endohedral Metallofullerenes. AB - In this work, the Bingel-Hirsch addition of diethylbromomalonate to all non equivalent bonds of Sc3N@D3h -C78 was studied using density functional theory calculations. The regioselectivities observed computationally allowed the proposal of a set of rules, the predictive aromaticity criteria (PAC), to identify the most reactive bonds of a given endohedral metallofullerene based on a simple evaluation of the cage structure. The predictions based on the PAC are fully confirmed by both the computational and experimental exploration of the Bingel-Hirsch reaction of Sc3N@D5h -C80, thus indicating that these rules are rather general and applicable to other isolated pentagon rule endohedral metallofullerenes. PMID- 26765328 TI - Acquired and Transmitted Multidrug Resistant Tuberculosis: The Role of Social Determinants. AB - Although risk factors for multi-drug resistant tuberculosis are known, few studies have differentiated between acquired and transmitted resistance. It is important to identify factors associated with these different mechanisms to optimize control measures. We conducted a prospective cohort study of index TB patients and their household contacts in Lima, Peru to identify risk factors associated with acquired and transmitted resistance, respectively. Patients with higher socioeconomic status (SES) had a 3-fold increased risk of transmitted resistance compared to those with lower SES when acquired resistance served as the baseline. Quality of housing mediated most of the impact of SES. PMID- 26765332 TI - Effects of Manganese Exposure on Olfactory Functions in Teenagers: A Pilot Study. AB - Long-term exposure to environmental manganese (Mn) affects not only attention and neuromotor functions but also olfactory functions of a pre-adolescent local population who have spent their whole life span in contaminated areas. In order to investigate the effect of such exposure at the level of the central nervous system we set up a pilot fMRI experiment pointing at differences of brain activities between a non-exposed population (nine subjects) and an exposed one (three subjects). We also measured the volume of the olfactory bulb as well as the identification of standard olfactory stimuli. Our results suggest that young subjects exposed to Mn exhibit a reduction of BOLD signal, subjective odor sensitivity and olfactory bulb volume. Moreover a region of interest SPM analysis showed a specifically reduced response of the limbic system in relation to Mn exposure, suggesting an alteration of the brain network dealing with emotional responses. PMID- 26765330 TI - Replication of an Autonomous Human Parvovirus in Non-dividing Human Airway Epithelium Is Facilitated through the DNA Damage and Repair Pathways. AB - Human bocavirus 1 (HBoV1) belongs to the genus Bocaparvovirus of the Parvoviridae family, and is an emerging human pathogenic respiratory virus. In vitro, HBoV1 infects well-differentiated/polarized primary human airway epithelium (HAE) cultured at an air-liquid interface (HAE-ALI). Although it is well known that autonomous parvovirus replication depends on the S phase of the host cells, we demonstrate here that the HBoV1 genome amplifies efficiently in mitotically quiescent airway epithelial cells of HAE-ALI cultures. Analysis of HBoV1 DNA in infected HAE-ALI revealed that HBoV1 amplifies its ssDNA genome following a typical parvovirus rolling-hairpin DNA replication mechanism. Notably, HBoV1 infection of HAE-ALI initiates a DNA damage response (DDR) with activation of all three phosphatidylinositol 3-kinase-related kinases (PI3KKs). We found that the activation of the three PI3KKs is required for HBoV1 genome amplification; and, more importantly, we identified that two Y-family DNA polymerases, Pol eta and Pol kappa, are involved in HBoV1 genome amplification. Overall, we have provided an example of de novo DNA synthesis (genome amplification) of an autonomous parvovirus in non-dividing cells, which is dependent on the cellular DNA damage and repair pathways. PMID- 26765336 TI - Incorporating Zwitterionic Graphene Oxides into Sodium Alginate Membrane for Efficient Water/Alcohol Separation. AB - For the selective water-permeation across dense membrane, constructing continuous pathways with high-density ionic groups are of critical significance for the preferential sorption and diffusion of water molecules. In this study, zwitterionic graphene oxides (PSBMA@GO) nanosheets were prepared and incorporated into sodium alginate (SA) membrane for efficient water permeation and water/alcohol separation. The two-dimensional GO provides continuous pathway, while the high-density zwitterionic groups on GO confer electrostatic interaction sites with water molecules, leading to high water affinity and ethanol repellency. The simultaneous optimization of the physical and chemical structures of water transport pathway on zwitterionic GO surface endows the membrane with high-efficiency water permeation. Using dehydration of water/alcohol mixture as the model system, the nanohybrid membranes incorporating PSBMA@GO exhibit much higher separation performance than the SA membrane and the nanohybrid membrane utilizing unmodified GO as filler (with the optimal permeation flux of 2140 g m( 2) h(-1), and separation factor of 1370). The study indicates the great application potential of zwitterionic graphene materials in dense water permeation membranes and provides a facile approach to constructing efficient water transport pathway in membrane. PMID- 26765335 TI - Steinernema pwaniensis n. sp., a new entomopathogenic nematode (Nematoda: Steinernematidae) from Tanzania. AB - A new species of entomopathogenic nematode, Steinernema pwaniensis n. sp., belonging to the glaseri group, is described from Tanzania. The infective juveniles of S. pwaniensis n. sp. are characterized by a body length of 978 MUm (808-1131), distance from anterior end to excretory pore of 86 MUm (80-95) and a tail length of 87 MUm (75-95). The ratios a, c and E% of S. pwaniensis n. sp. are substantially lower than those of all other African 'glaseri' group members. The first-generation males of S. pwaniensis n. sp. can be distinguished by a large spicule length of 92 MUm (80-97) and by the absence of the caudal mucron, while second-generation males possess a short spine-like mucron. First-generation females have a peg-like tail tip bearing three spine-like projections. Second generation females can be recognized by a slightly protruding vulva and well developed post-anal swelling. The new species is further characterized by sequences of the internal transcribed spacer (ITS) and partial 28S regions of the ribosomal DNA. Phylogenetic analyses show that S. pwaniensis n. sp. forms a strongly supported monophyletic clade with two other East African species, S. ethiopiense and S. karii. PMID- 26765337 TI - IL-4 Modulates CCL11 and CCL20 Productions from IL-1beta-Stimulated Human Periodontal Ligament Cells. AB - BACKGROUND/AIMS: IL-4 is a multifunctional cytokine that is related with the pathological conditions of periodontal disease. However, it is uncertain whether IL-4 could control T cells migration in periodontal lesions. The aim of this study was to examine the effects of IL-4 on CCL11, which is a Th2-type chemokine, and CCL20, which is related with Th17 cells migration, productions from human periodontal ligament cells (HPDLCs). METHODS: CCL20 and CCL11 productions from HPDLCs were monitored by ELISA. Western blot analysis was performed to detect phosphorylations of signal transduction molecules in HPDLCs. RESULTS: IL-1beta could induce both CCL11 and CCL20 productions in HPDLCs. IL-4 enhanced CCL11 productions from IL-1beta-stimulated HPDLCs, though IL-4 inhibited CCL20 production. Western blot analysis showed that protein kinase B (Akt) and signal transducer and activator of transcription (STAT)6 pathways were highly activated in IL-4/IL-1beta-stimulated HPDLCs. Akt and STAT6 inhibitors decreased CCL11 production, but enhanced CCL20 production in HPDLCs stimulated with IL-4 and IL 1beta. CONCLUSIONS: These results mean that IL-4 enhanced Th2 cells migration in periodontal lesion to induce CCL11 production from HPDLCs. On the other hand, IL 4 inhibits Th17 cells accumulation in periodontally diseased tissues to inhibit CCL20 production. Therefore, IL-4 is positively related with the pathogenesis of periodontal disease to control chemokine productions in periodontal lesions. PMID- 26765334 TI - Chronic DNA Replication Stress Reduces Replicative Lifespan of Cells by TRP53 Dependent, microRNA-Assisted MCM2-7 Downregulation. AB - Circumstances that compromise efficient DNA replication, such as disruptions to replication fork progression, cause a state known as DNA replication stress (RS). Whereas normally proliferating cells experience low levels of RS, excessive RS from intrinsic or extrinsic sources can trigger cell cycle arrest and senescence. Here, we report that a key driver of RS-induced senescence is active downregulation of the Minichromosome Maintenance 2-7 (MCM2-7) factors that are essential for replication origin licensing and which constitute the replicative helicase core. Proliferating cells produce high levels of MCM2-7 that enable formation of dormant origins that can be activated in response to acute, experimentally-induced RS. However, little is known about how physiological RS levels impact MCM2-7 regulation. We found that chronic exposure of primary mouse embryonic fibroblasts (MEFs) to either genetically-encoded or environmentally induced RS triggered gradual MCM2-7 repression, followed by inhibition of replication and senescence that could be accelerated by MCM hemizygosity. The MCM2-7 reduction in response to RS is TRP53-dependent, and involves a group of Trp53-dependent miRNAs, including the miR-34 family, that repress MCM expression in replication-stressed cells before they undergo terminal cell cycle arrest. miR 34 ablation partially rescued MCM2-7 downregulation and genomic instability in mice with endogenous RS. Together, these data demonstrate that active MCM2-7 repression is a physiologically important mechanism for RS-induced cell cycle arrest and genome maintenance on an organismal level. PMID- 26765338 TI - What was hot at the ICS meeting 2015. PMID- 26765339 TI - An in vitro reproduction of stress-induced memory defects: Effects of corticoids on dendritic spine dynamics. AB - Previously, in organotypic slice culture of rodent hippocampus we found that three repeated inductions of LTP, but not a single induction, led to a slow developing long-lasting enhancement of synaptic strength coupled with synapse formation. Naming this structural plasticity RISE (repetitive LTP-induced synaptic enhancement) and assuming it to be a potential in vitro reproduction of repetition-dependent memory consolidation, we are analyzing its cellular mechanisms. Here, we applied a glucocorticoid to the culture to mimic acute excess stress and demonstrated its blockade of RISE. Since excess stress interferes with behavioral memory consolidation, the parallelism between RISE in vitro and memory consolidation in vivo is supported. We recently reported that RISE developed after stochastic processes. Here we found that the glucocorticoid interfered with RISE by suppressing the increment of dendritic spine fluctuation that precedes a net increase in spine density. The present study provides clues for understanding the mechanism of stress-induced memory defects. PMID- 26765340 TI - Faking bad: The neural correlates of feigning memory impairment. AB - OBJECTIVE: The detection of malingering in cognitive performance is a challenge in clinical and legal environments. Neuroimaging may provide an objective method for delineation of malingering. METHOD: A heterogeneous with concern of gender and racial-ethnic identity of 22 healthy volunteers completed the Tombaugh Test of Memory Malingering during an fMRI scan. Subjects were either instructed to perform optimally (not feigning) or to perform "as if they had a mild traumatic brain injury with memory impairment" (feigning). RESULTS: A voxel-based multiple regression analysis revealed that during correct responses there was greater activation in the superior and medial prefrontal cortex during the feigning versus the not-feigning responses. CONCLUSIONS: This finding suggests that falsified memory performance requires greater activation of cognitive control networks to determine a correct selection. PMID- 26765341 TI - Parental DNA sequence is critical family history in clinical genomics. PMID- 26765342 TI - Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis type. AB - PURPOSE: The Ehlers-Danlos syndrome (EDS), dermatosparaxis type, is a recessively inherited connective tissue disorder caused by deficient activity of ADAMTS-2, an enzyme that cleaves the aminoterminal propeptide domain of types I, II, and III procollagen. Only 10 EDS dermatosparaxis patients have been reported, all presenting a recognizable phenotype with characteristic facial gestalt, extreme skin fragility and laxity, excessive bruising, and sometimes major complications due to visceral and vascular fragility. METHODS: We report on five new EDS dermatosparaxis patients and provide a comprehensive overview of the current knowledge of the natural history of this condition. RESULTS: We identified three novel homozygous loss-of-function mutations (c.2927_2928delCT, p.(Pro976Argfs*42); c.669_670dupG, p.(Pro224Argfs*24); and c.2751-2A>T) and one compound heterozygous mutation (c.2T>C, p.? and c.884_887delTGAA, p.(Met295Thrfs26*)) in ADAMTS2 in five patients from four unrelated families. Three of these displayed a phenotype that was strikingly milder than that of previously reported patients. CONCLUSION: This study expands the clinical and molecular spectrum of the dermatosparaxis type of EDS to include a milder phenotypic variant and stresses the importance of good clinical criteria. To address this, we propose an updated set of criteria that accurately captures the multisystemic nature of the dermatosparaxis type of EDS.Genet Med 18 9, 882-891. PMID- 26765344 TI - Vitamin D supplementation for women during pregnancy. AB - BACKGROUND: Vitamin D deficiency or insufficiency is thought to be common among pregnant women. Vitamin D supplementation during pregnancy has been suggested as an intervention to protect against adverse pregnancy outcomes. OBJECTIVES: To examine whether oral supplements with vitamin D alone or in combination with calcium or other vitamins and minerals given to women during pregnancy can safely improve maternal and neonatal outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (23 February 2015), the International Clinical Trials Registry Platform (31 January 2015), the Networked Digital Library of Theses and Dissertations (28 January 2015) and also contacted relevant organisations (31 January 2015). SELECTION CRITERIA: Randomised and quasi-randomised trials with randomisation at either individual or cluster level, evaluating the effect of supplementation with vitamin D alone or in combination with other micronutrients for women during pregnancy. DATA COLLECTION AND ANALYSIS: Two review authors independently i) assessed the eligibility of studies against the inclusion criteria ii) extracted data from included studies, and iii) assessed the risk of bias of the included studies. Data were checked for accuracy. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: In this updated review we included 15 trials assessing a total of 2833 women, excluded 27 trials, and 23 trials are still ongoing or unpublished. Nine trials compared the effects of vitamin D alone versus no supplementation or a placebo and six trials compared the effects of vitamin D and calcium with no supplementation. Risk of bias in the majority of trials was unclear and many studies were at high risk of bias for blinding and attrition rates. Vitamin D alone versus no supplementation or a placebo Data from seven trials involving 868 women consistently show that women who received vitamin D supplements alone, particularly on a daily basis, had higher 25-hydroxyvitamin D than those receiving no intervention or placebo, but this response was highly heterogeneous. Also, data from two trials involving 219 women suggest that women who received vitamin D supplements may have a lower risk of pre-eclampsia than those receiving no intervention or placebo (8.9% versus 15.5%; risk ratio (RR) 0.52; 95% CI 0.25 to 1.05, low quality). Data from two trials involving 219 women suggest a similar risk of gestational diabetes among those taking vitamin D supplements or no intervention/placebo (RR 0.43; 95% CI 0.05, 3.45, very low quality). There were no clear differences in adverse effects, with only one reported case of nephritic syndrome in the control group in one study (RR 0.17; 95% CI 0.01 to 4.06; one trial, 135 women, low quality). Given the scarcity of data for this outcome, no firm conclusions can be drawn. No other adverse effects were reported in any of the other studies.With respect to infant outcomes, data from three trials involving 477 women suggest that vitamin D supplementation during pregnancy reduces the risk preterm birth compared to no intervention or placebo (8.9% versus 15.5%; RR 0.36; 95% CI 0.14 to 0.93, moderate quality). Data from three trials involving 493 women also suggest that women who receive vitamin D supplements during pregnancy less frequently had a baby with a birthweight below 2500 g than those receiving no intervention or placebo (RR 0.40; 95% CI 0.24 to 0.67, moderate quality).In terms of other outcomes, there were no clear differences in caesarean section (RR 0.95; 95% CI 0.69 to 1.31; two trials; 312 women); stillbirths (RR 0.35 95% CI 0.06, 1.99; three trials, 540 women); or neonatal deaths (RR 0.27; 95% CI 0.04, 1.67; two trials, 282 women). There was some indication that vitamin D supplementation increases infant length (mean difference (MD) 0.70, 95% CI -0.02 to 1.43; four trials, 638 infants) and head circumference at birth (MD 0.43, 95% CI 0.03 to 0.83; four trials, 638 women). Vitamin D and calcium versus no supplementation or a placeboWomen who received vitamin D with calcium had a lower risk of pre-eclampsia than those not receiving any intervention (RR 0.51; 95% CI 0.32 to 0.80; three trials; 1114 women, moderate quality), but also an increased risk of preterm birth (RR 1.57; 95% CI 1.02 to 2.43, three studies, 798 women, moderate quality). Maternal vitamin D concentration at term, gestational diabetes, adverse effects and low birthweight were not reported in any trial or reported only by one study. AUTHORS' CONCLUSIONS: New studies have provided more evidence on the effects of supplementing pregnant women with vitamin D alone or with calcium on pregnancy outcomes. Supplementing pregnant women with vitamin D in a single or continued dose increases serum 25-hydroxyvitamin D at term and may reduce the risk of pre eclampsia, low birthweight and preterm birth. However, when vitamin D and calcium are combined, the risk of preterm birth is increased. The clinical significance of the increased serum 25-hydroxyvitamin D concentrations is still unclear. In light of this, these results need to be interpreted with caution. Data on adverse effects were lacking in all studies.The evidence on whether vitamin D supplementation should be given as a part of routine antenatal care to all women to improve maternal and infant outcomes remains unclear. While there is some indication that vitamin D supplementation could reduce the risk of pre-eclampsia and increase length and head circumference at birth, further rigorous randomised trials are required to confirm these effects. PMID- 26765345 TI - Current Treatment Modalities of JIA-associated Uveitis and its Complications: Literature Review. AB - Uveitis is a common and serious complication of juvenile idiopathic arthritis. Up to 75% of all cases of anterior uveitis in childhood are associated with juvenile idiopathic arthritis. Despite the remarkable progress in early detection and treatment of inflammation, vision-threatening complications of uveitis still occur in almost 60% of patients. Structural complications include band keratopathy, maculopathy (macular edema, macular cysts, and epiretinal membrane), glaucomatous optic neuropathy, and cataracts. The management of complications in juvenile idiopathic arthritis is usually complex and requires early surgical intervention. In this paper, we review the general concepts of common ocular complications seen in patients with JIA-associated uveitis, with special attention to the recent diagnostic and preferred treatment approaches at the Massachusetts Eye Research and Surgery Institution. Received 9 March 2015; revised 30 September 2015; accepted 30 October 2015; published online 14 January 2016. PMID- 26765343 TI - Privacy-preserving genomic testing in the clinic: a model using HIV treatment. AB - PURPOSE: The implementation of genomic-based medicine is hindered by unresolved questions regarding data privacy and delivery of interpreted results to health care practitioners. We used DNA-based prediction of HIV-related outcomes as a model to explore critical issues in clinical genomics. METHODS: We genotyped 4,149 markers in HIV-positive individuals. Variants allowed for prediction of 17 traits relevant to HIV medical care, inference of patient ancestry, and imputation of human leukocyte antigen (HLA) types. Genetic data were processed under a privacy-preserving framework using homomorphic encryption, and clinical reports describing potentially actionable results were delivered to health-care providers. RESULTS: A total of 230 patients were included in the study. We demonstrated the feasibility of encrypting a large number of genetic markers, inferring patient ancestry, computing monogenic and polygenic trait risks, and reporting results under privacy-preserving conditions. The average execution time of a multimarker test on encrypted data was 865 ms on a standard computer. The proportion of tests returning potentially actionable genetic results ranged from 0 to 54%. CONCLUSIONS: The model of implementation presented herein informs on strategies to deliver genomic test results for clinical care. Data encryption to ensure privacy helps to build patient trust, a key requirement on the road to genomic-based medicine.Genet Med 18 8, 814-822. PMID- 26765346 TI - Carpal Tunnel Syndrome Associated with Oral Bisphosphonates. A Population-Based Cohort Study. AB - BACKGROUND: Bisphosphonates are widely used to prevent osteoporotic fractures. Some severe musculoskeletal reactions have been described with this medication; among them, some cases of carpal tunnel syndrome. Thus, the aim of this study was to explore whether bisphosphonates may be associated with this syndrome. METHODS: A cohort study was conducted to compare exposed to unexposed women; the exposed group was that composed of women having received at least one prescription of an oral bisphosphonate. For the purpose, we used information from The Health Improvement Network (THIN) database. The outcome of interest was defined as those women diagnosed with carpal tunnel syndrome. A survival analysis was performed; the Cox proportional hazard model was used to calculate hazard ratios and 95% confidence intervals, and to adjust for identified confounding variables. RESULTS: Out of a sample of 59,475 women older than 51 years, 19,825 were treated with bisphosphonates during the period studied. No differences in age distribution or mean follow-up time were observed between the two groups in comparison. Overall, there were 572 women diagnosed with carpal tunnel syndrome, 242 (1.2%) in the group exposed to bisphosphonates, and 330 (0.8%) in the unexposed. An adjusted hazard ratio of developing carpal tunnel syndrome of 1.38 (95%CI, 1.15-1.64) was found for women exposed to bisphosphonates; no significant changes in the hazard ratios were found when considering different levels of bisphosphonate exposure. CONCLUSIONS: An increased risk of carpal tunnel syndrome is associated with the use of bisphosphonates in postmenopausal women. PMID- 26765348 TI - Principles of analytical validation of next-generation sequencing based mutational analysis for hematologic neoplasms in a CLIA-certified laboratory. AB - Targeted therapy based on mutational profiles is the current standard of practice for the management of patients with hematologic malignancies. Next-generation sequencing (NGS)- based analysis has been adopted by clinical laboratories for high-throughput mutational profiling of myeloid and lymphoid neoplasms. The technology is fairly novel and complex, hence both validation and test implementation in a CLIA-certified laboratory differ substantially from traditional sequencing platforms. Recently, organizations such as the American College of Medical Genetics, Centers for Disease Control and Prevention and College of American Pathologists have published principles and guidelines for NGS test development to ensure standardization of testing across institutions. Summarized here are the recommendations from these organizations as they pertain to targeted NGS-based testing of hematologic malignancies ('liquid tumors'), with particular emphasis on myeloid neoplasms. PMID- 26765347 TI - TB as a cause of hospitalization and in-hospital mortality among people living with HIV worldwide: a systematic review and meta-analysis. AB - INTRODUCTION: Despite significant progress in improving access to antiretroviral therapy over the past decade, substantial numbers of people living with HIV (PLHIV) in all regions continue to experience severe illness and require hospitalization. We undertook a global review assessing the proportion of hospitalizations and in-hospital deaths because of tuberculosis (TB) in PLHIV. METHODS: Seven databases were searched to identify studies reporting causes of hospitalizations among PLHIV from 1 January 2007 to 31 January 2015 irrespective of age, geographical region or language. The proportion of hospitalizations and in-hospital mortality attributable to TB was estimated using random effects meta analysis. RESULTS: From an initial screen of 9049 records, 66 studies were identified, providing data on 35,845 adults and 2792 children across 42 countries. Overall, 17.7% (95% CI 16.0 to 20.2%) of all adult hospitalizations were because of TB, making it the leading cause of hospitalization overall; the proportion of adult hospitalizations because of TB exceeded 10% in all regions except the European region. Of all paediatric hospitalizations, 10.8% (95% CI 7.6 to 13.9%) were because of TB. There was insufficient data among children for analysis by region. In-hospital mortality attributable to TB was 24.9% (95% CI 19.0 to 30.8%) among adults and 30.1% (95% CI 11.2 to 48.9%) among children. DISCUSSION: TB remains a leading cause of hospitalization and in-hospital death among adults and children living with HIV worldwide. PMID- 26765349 TI - Baccharis (Asteraceae): Chemical Constituents and Biological Activities. PMID- 26765350 TI - New Caledonia: A ' Hot Spot' for Valuable Chemodiversity: Part 2: Basal Angiosperms and Eudicot Rosids. AB - The flora of New Caledonia encompasses more than 3000 plant species and almost 80% are endemic. New Caledonia is considered as a 'hot spot' for biodiversity. With the current global loss of biodiversity and the fact that several drugs and pesticides become obsolete, there is an urgent need to increase sampling and research on new natural products. In this context, we review the chemical knowledge available on New Caledonian native flora from economical perspectives. We expect that a better knowledge of the economic potential of plant chemistry will encourage the plantation of native plants for the development of a sustainable economy which will participate in the conservation of biodiversity. In the second part of this review, we focus on the results exposed in 60 scientific articles and describe the identification of 225 original compounds from basal angiosperms and eudicot rosids. We discuss the economic potential of plants and molecules from medicinal and industrial perspectives. This review also highlights several plants and groups, such as Amborella sp., Piperaceae, or Phyllanthaceae, that are unexplored in New Caledonia despite their high chemical interest. Those plants are considered to have priority in future chemical investigations. PMID- 26765351 TI - Marine Pyridoacridine Alkaloids: Biosynthesis and Biological Activities. AB - Pyridoacridines are a class of strictly marine-derived alkaloids that constitute one of the largest chemical families of marine alkaloids. During the last few years, both natural pyridoacridines and their analogues have constituted excellent targets for synthetic works. They have been the subject of intense study due to their significant biological activities; cytotoxic, antibacterial, antifungal, antiviral, insecticidal, anti-HIV, and anti-parasitic activities. In the present review, 95 pyridoacridine alkaloids isolated from marine organisms are discussed in term of their occurrence, biosynthesis, biological activities, and structural assignment. PMID- 26765352 TI - Chemical Constituents and Biological Activities of Plants from the Genus Physalis. PMID- 26765353 TI - Phytotoxic Effects and Phytochemical Fingerprinting of Hydrodistilled Oil, Enriched Fractions, and Isolated Compounds Obtained from Cryptocarya massoy (Oken) Kosterm. Bark. AB - The hydrodistilled oil of Cryptocarya massoy bark was characterized by GC-FID and GC/MS analyses, allowing the identification of unusual C10 massoia lactone (3, 56.2%), C12 massoia lactone (4, 16.5%), benzyl benzoate (1, 12.7%), C8 massoia lactone (3.4%), delta-decalactone (5, 1.5%), and benzyl salicylate (2, 1.8%) as main constituents. The phytotoxic activities of the oil, three enriched fractions (lactone-rich, ester-rich, and sesquiterpene-rich), and four constituents (compounds 1, 2, 5, and delta-dodecalactone (6)) against Lycopersicon esculentum and Cucumis sativus seeds and seedlings were screened. At a concentration of 1000 MUl/l, the essential oil and the massoia lactone-rich fraction caused a complete inhibition of the germination of both seeds, and, when applied on tomato plantlets, they induced an 85 and 100% dieback, respectively. These performances exceeded those of the well-known phytotoxic essential oils of Syzygium aromaticum and Cymbopogon citratus, already used in commercial products for the weed and pest management. The same substances were also evaluated against four phytopathogenic bacteria and ten phytopathogenic fungi, providing EC50 values against the most susceptible strains in the 100-500 MUl/l range for the essential oil and in the 10-50 MUl/l range for compound 6 and the lactone-rich fraction. The phytotoxic behavior was related mainly to massoia lactones and benzyl esters, while a greater amount of 6 may infer a good activity against some phytopathogenic fungi. Further investigations of these secondary metabolites are warranted, to evaluate their use as natural herbicides. PMID- 26765354 TI - Antifungal and Herbicidal Effects of Fruit Essential Oils of Four Myrtus communis Genotypes. AB - The chemical composition of the essential oils isolated by hydrodistillation from the fruits of four selected Myrtus communis L. genotypes from Turkey was characterized by GC-FID and GC/MS analyses. 1,8-Cineole (29.20-31.40%), linalool (15.67-19.13%), alpha-terpineol (8.40-18.43%), alpha-pinene (6.04-20.71%), and geranyl acetate (3.98-7.54%) were found to be the major constituents of the fruit essential oils of all M. communis genotypes investigated. The oils were characterized by high amounts of oxygenated monoterpenes, representing 73.02 83.83% of the total oil compositions. The results of the fungal growth inhibition assays showed that the oils inhibited the growth of 19 phytopathogenic fungi. However, their antifungal activity was generally lower than that of the commercial pesticide benomyl. The herbicidal effects of the oils on the seed germination and seedling growth of Amaranthus retroflexus L., Chenopodium album L., Cirsium arvense (L.) Scop., Lactuca serriola L., and Rumex crispus L. were also determined. The oils completely or partly inhibited the seed germinations and seedling growths of the plants. The findings of the present study suggest that the M. communis essential oils might have potential to be used as natural herbicides as well as fungicides. PMID- 26765355 TI - Dittrichia graveolens (L.) Greuter Essential Oil: Chemical Composition, Multivariate Analysis, and Antimicrobial Activity. AB - The chemical composition and in vitro antimicrobial activities of Dittrichia graveolens (L.) Greuter essential oil was studied. Moreover, using agglomerative hierarchical cluster (AHC) and principal component analyses (PCA), the interrelationships of the D. graveolens essential-oil profiles characterized so far (including the sample from this study) were investigated. To evaluate the chemical composition of the essential oil, GC-FID and GC/MS analyses were performed. Altogether, 54 compounds were identified, accounting for 92.9% of the total oil composition. The D. graveolens oil belongs to the monoterpenoid chemotype, with monoterpenoids comprising 87.4% of the totally identified compounds. The major components were borneol (43.6%) and bornyl acetate (38.3%). Multivariate analysis showed that the compounds borneol and bornyl acetate exerted the greatest influence on the spatial differences in the composition of the reported oils. The antimicrobial activity against five bacterial and one fungal strain was determined using a disk-diffusion assay. The studied essential oil was active only against Gram-positive bacteria. PMID- 26765356 TI - Isoquinoline Alkaloids from Fumaria officinalis L. and Their Biological Activities Related to Alzheimer's Disease. AB - Two new isoquinoline alkaloids, named fumaranine (2) and fumarostrejdine (10), along with 18 known alkaloids were isolated from aerial parts of Fumaria officinalis. The structures of the isolated compounds were elucidated on the basis of spectroscopic analyses and by comparison with literature data. The absolute configuration of the new compound 2 was determined by comparing its circular dichroism spectra with those of known analogs. Compounds isolated in sufficient amounts were evaluated for their acetylcholinesterase, butyrylcholinesterase, prolyl oligopeptidase (POP), and glycogen synthase kinase 3beta inhibitory activities. Parfumidine (8) and sinactine (15) exhibited potent POP inhibition activities (IC50 99+/-5 and 53+/-2 MUM, resp.). PMID- 26765357 TI - Acridone Alkaloids from Swinglea glutinosa (Rutaceae) and Their Effects on Photosynthesis. AB - Continuing our search for herbicide models based on natural products, we investigated the action mechanisms of five alkaloids isolated from Swinglea glutinosa (Rutaceae): Citrusinine-I (1), glycocitrine-IV (2), 1,3,5-trihydroxy-10 methyl- 2,8-bis(3-methylbut-2-en-1-yl)-9(10H)-acridinone (3), (2R)-2-tert-butyl 3,10-dihydro-4,9-dihydroxy-11-methoxy-10-methylfuro[3,2-b]acridin-5(2H)-one (4), and (3R)-2,3,4,7-tetrahydro-3,5,8-trihydroxy-6-methoxy-2,2,7-trimethyl-12H pyrano[2,3-a]acridin-12-one (5) on several photosynthetic activities in an attempt to find new compounds that affect photosynthesis. Through polarographic techniques, the compounds inhibited the non-cyclic electron transport in the basal, phosphorylating, and uncoupled conditions from H2 O to methylviologen (=MV). Therefore, they act as Hill reaction inhibitors. This approach still suggested that the compounds 4 and 5 had their interaction site located at photosystem I. Studies on fluorescence of chlorophyll a suggested that acridones (1-3) have different modes of interaction and inhibition sites on the photosystem II electron transport chain. PMID- 26765359 TI - Estimated glomerular filtration rate, urine albumin excretion, and survival among patients consulting in public Chilean public primary care clinics. AB - Chronic renal disease (CRD) in its pre-dialysis stage is an important risk factor for mortality among adults. The aim of this study was to assess the effects of CRD on mortality among consultants in Chilean public primary care clinics. We obtained information about serum creatinine, urinary albumin excretion (UAE), blood pressure, and body mass index of 5224 consultants [3379 females aged 67 (59 75) years and 1845 males aged 68 (59-75) years] in three clinics of Metropolitan Santiago. Kaplan-Meier curves and Cox proportional hazard regression models were used to determine risk factors for mortality, determined 41 months after obtaining the blood samples. During the follow-up period, 262 patients died (33% due to circulatory causes and 29% due to tumors). Kaplan-Meier curves showed that there was a significant association between survival, estimated glomerular filtration rate, and UAE. Cox models showed that serum creatinine, UAE, a lower body mass index, and a history of diabetes were significant mortality predictors. A sensitivity analysis performed eliminating extreme ages (less than 50 and more than 80 years), included high diastolic pressure as a predictor of survival. We conclude that among patients with CRD in its pre-dialysis stage, UAE is an important predictor of survival, along with serum creatinine. A low body mass index was associated with a higher mortality. PMID- 26765360 TI - Ferric ion induced enhancement of ultraviolet vapour generation coupled with atomic fluorescence spectrometry for the determination of ultratrace inorganic arsenic in surface water. AB - A novel method of ultraviolet vapour generation (UVG) coupled with atomic fluorescence spectrometry (AFS) was developed for the determination of ultratrace inorganic arsenic (iAs) in surface water. In this work, different ferric species were utilised for the first time as an enhancement reagent for the ultraviolet vapour generation of As(III), and their UVG efficiencies for volatile species of arsenic were investigated. 15 mg L(-1) of ferric chloride provided the greatest enhancement of approximately 10-fold, using 20% acetic acid combined with 4% formic acid with 30 s ultraviolet irradiation at 200 mL min(-1) Ar/H2 flow rate. Under the optimised conditions, the linear range was 1.0 MUg L(-1)-100.0 MUg L( 1), and the spiked recoveries were 92%-98%. The limit of detection was 0.05 MUg L(-1) for iAs, and the relative standard deviation (RSD) value of the repeated measurements was 2.0% (n = 11). This method was successfully applied to the determination of ultratrace iAs in tap water, river water, and lake water samples using 0.2% H2SO4 (v : v) as the sample preserver. The obtained values for the water samples of certified reference materials (CRMs) including GSB-Z50004 200431, GBW08605 and GBW(E)080390 were all within the certified ranges. PMID- 26765363 TI - Methods for Calculating Partition Functions of Molecules Involving Large Amplitude and/or Anharmonic Motions. AB - We present a method for calculating partition functions taking into account anharmonic contributions for systems involving both small-amplitude vibrations and hindered rotations. The Wang-Landau scheme is used in the first case, while two alternative schemes are used for hindered rotation based on imaginary time propagation and fitting of the exact energy levels as a function of quantum number. These two schemes are shown to be complementary in their ranges of applicability (in terms of the torsional rotational constant and the relevant potential). Partition functions for four different molecules are calculated and compared to simpler ones obtained using a harmonic model. PMID- 26765364 TI - Tyrosine kinase inhibitors under investigation for the treatment of type II diabetes. AB - INTRODUCTION: Type 2 diabetes is characterized by hyperglycemia that is the result of beta-cell failure in the setting of peripheral insulin resistance. It is estimated that greater than 300 million individuals worldwide have diabetes. Tyrosine kinase inhibitors (TKIs), which are used to treat a variety of cancers, appear to have antihyperglycemic effects. AREAS COVERED: This review summarizes studies that have investigated the use of TKIs in animal models of diabetes. Additionally, the authors review case series describing the effects of TKIs on glucose levels in adults taking these drugs for FDA approved indications. EXPERT OPINION: Given the scope and size of the worldwide diabetes epidemic, reports of amelioration or possible cure of the disease warrant special attention. TKIs appear to lower glucose levels in some, but not all individuals. Multi-center prospective studies are needed in which patient with diabetes treated with TKI undergo phenotyping to identify responders versus non responders to allow for precision medicine. PMID- 26765365 TI - Dietary Patterns and CKD Progression. AB - BACKGROUND: Chronic kidney disease (CKD) patients and their clinicians seek ways to mitigate the risk of CKD progression and its associated complications. Emerging data suggest that dietary modifications may be beneficial adjuvant approaches to reducing the risk of adverse CKD outcomes. SUMMARY: This review focuses on several different dietary patterns, including the Dietary Approaches to Stop Hypertension and Mediterranean diets, and their kidney health benefits. We discuss how healthful dietary patterns are lower in dietary acid load and how improving diet quality may slow the progression of CKD. We also discuss some barriers that may impede socially disadvantaged individuals from following healthful diets. KEY POINTS: Dietary patterns low in dietary acid load might slow the progression of CKD. Current evidence suggests that a reduction in dietary acid load could be beneficial in patients with CKD, but the supremacy of any particular diet is yet to be established. Additional randomized controlled dietary interventions among CKD patients are needed to inform evidence-based recommendations, which can be tailored to an individual's preferences and ability to access healthful foods. PMID- 26765367 TI - 2D-patterning of self-assembled silver nanoisland films. AB - The paper is dedicated to the recently developed by the authors technique of silver nanoisland growth, allowing self-arrangement of 2D-patterns of nanoislands. The technique employs silver out-diffusion from ion-exchanged glass in the course of annealing in hydrogen. To modify the silver ion distribution in the exchanged soda-lime glass we included the thermal poling of the ion-exchanged glass with a profiled electrode as an intermediate stage of the process. The resulting consequence consists of three steps: (i) during the ion exchange of the glass in the AgxNa1-xNO3 (x = 0.01-0.15) melt we enrich the subsurface layer of the glass with silver ions; (ii) under the thermal poling, the electric field displaces these ions deeper into the glass under the 2D profiled anodic electrode, the displacement is smaller under the hollows in the electrode where the intensity of the field is minimal; (iii) annealing in a reducing atmosphere of hydrogen results in silver out-diffusion only in the regions corresponding to the electrode hollows, as a result silver forms nanoislands following the shape of the electrode. Varying the electrode and mode of processing allows governing the nanoisland size distribution and self-arrangement of the isolated single nanoislands, pairs, triples or groups of several nanoislands-so-called plasmonic molecules. PMID- 26765366 TI - The safety and persistence of non-vitamin-K-antagonist oral anticoagulants in atrial fibrillation patients treated in a well structured atrial fibrillation clinic. AB - AIMS: To examine the long-term persistence and safety of the non-vitamin-K antagonist oral anticoagulants (NOACs) dabigatran (D), rivaroxaban (R) and apixaban (A) in patients with non-valvular atrial fibrillation (AF) treated in the framework of a well structured, nurse-based AF unit for initiation and follow up of NOAC. METHODS: Retrospective clinical data were collected for 766 consequent patients from a single cardiology outpatient clinic incorporating the AF unit. RESULTS: The follow-up time, median (q1-q3), was 367 days (183-493) for D patients (n = 233), 432 days (255-546) for R patients (n = 282) and 348 days (267-419) for A patients (n = 251). No significant differences were found between the three groups with regard to age, sex, renal function, or CHA2DS2-VASc score. For all bleeding events the incidence rates per 100 patient-years of follow-up (95% confidence interval [CI], p-value) were reported more often for treatment with R (17.2, 12.7-22.8) than for D (7.0, 4.0-11.3, p = 0.001) and A (8.7, 5.2 13.6, p = 0.013). The differences remained significant after adjustment for clinically relevant variables. Discontinuation rates (n = 167) were lower for A (11.5, 7.5-16.8) than for D (30, 23.4-37.9, p < 0.001) and R (23.9, 18.6-30.1, p = 0.001), and were mainly attributed to drug-specific side effects and bleedings. The majority of discontinued patients (n = 142, 85%) proceeded with other types of oral anticoagulants. LIMITATION: The main limitation of the study is the small patient population with a short follow-up time. CONCLUSION: In a retrospective study at a single AF clinic, NOACs showed significantly different bleeding rates and varied discontinuation rates when compared to each other, related mainly to agent-specific side effects and bleedings. The majority of patients that discontinued proceeded with other types of oral anticoagulant. PMID- 26765368 TI - Synthetic, structural, and computational investigations of N-alkyl benzo-2,1,3 selenadiazolium iodides and their supramolecular aggregates. AB - Despite their versatility, the application of telluradiazoles as supramolecular building blocks is considerably constrained by their sensitivity to moisture. Albeit more robust, their selenium analogues form weaker supramolecular interactions. These, however, are enhanced when one nitrogen atom is bonded to an alkyl group. Here we investigate general methods for the synthesis of such derivatives. Methyl, iso-propyl and tert-butyl benzo-2,1,3-selenadiazolium cations were prepared by direct alkylation or cyclo-condensation of the alkyl phenylenediamine with selenous acid. While the former reaction only proceeds with the primary and tertiary alkyl iodides, the latter is very efficient. Difficulties reported in earlier literature are attributable to the formation of adducts of benzoselenadiazole with its alkylated cations and side reactions initiated by aerobic oxidation of iodide. However, the cations themselves are resilient to oxidation and stable in acidic to neutral aqueous medium. X-ray crystallography was used in the identification and characterization of the following compounds: [C6H4N2(R)Se](+)X(-), (R = CH(CH3)2, C(CH3)3; X = I(-), I3( )], [C6H4N2(CH3)Se](+)I(-), and [C6H4N2Se][C6H4N2(CH3)Se]2I2. Formation of SeN secondary bonding interactions (chalcogen bonds) was only observed in the last structure as anion binding to selenium is a strong competitor. The relative strengths of those forces and the structural preferences they enforce were assessed with DFT-D3 calculations supplemented by AIM analysis of the electron density. PMID- 26765396 TI - Arsenate Adsorption by Hydrous Ferric Oxide Nanoparticles Embedded in Cross linked Anion Exchanger: Effect of the Host Pore Structure. AB - Three composite adsorbents were fabricated via confined growth of hydrous ferric oxide (HFO) nanoparticles within cross-linked anion exchangers (NS) of different pore size distributions to investigate the effect of host pore structure on the adsorption of As(V). With the decrease in the average pore size of the NS hosts from 38.7 to 9.2 nm, the mean diameter of the confined HFO nanoparticles was lessened from 31.4 to 11.6 nm as observed by transmission electron microscopy (TEM), while the density of active surface sites was increased due to size dependent effect proved by potentiometric titration. The adsorption capacity of As(V) yielded by Sips model was elevated from 24.2 to 31.6 mg/g via tailoring the pore size of the NS hosts, and the adsorption kinetics was slightly accelerated with the decrease of pore size in background solution containing 500 mg/L of Cl( ). Furthermore, the enhanced adsorption of As(V) was achieved over a wide pH range from 3 to 10, as well as in the presence of competing anions including Cl( ), SO4(2-), HCO3(-), NO3(-) (up to 800 mg/L), and PO4(3-) (up to 10 mg P/L). In addition, the fixed-bed working capacity increased from 2200 to 2950 bed volumes (BV) owing to the size confinement effect, which did not have adverse effect on the desorption of As(V) as the cumulative desorption efficiency reached 94% with 10 BV of binary solution (5% NaOH + 5% NaCl) for all the three adsorbents. Therefore, this study provided a promising strategy to regulate the reactivity of the nanoparticles via the size confinement effect of the host pore structure. PMID- 26765397 TI - Role of matrix metalloproteinases in the pathogenesis of childhood gastroenteritis. AB - Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been implicated in the pathogenesis of gastrointestinal diseases, such as rotavirus gastroenteritis (GE). Kinetics of these biomarkers were examined in paired serum samples collected from bacterial enteritis patients with Campylobacter (n = 2) and Salmonella (n = 4) and viral GE patients with rotavirus (n = 27), norovirus (n = 25), and adenovirus (n = 11). At the time of hospital admission, all viral GE patients demonstrated increased MMP-9 and decreased MMP-2 and TIMP-2 serum levels. In contrast to viral GE patients, serum MMP-9 levels were not elevated at the time of hospital admission but elevated at the time of discharge; serum MMP-2 and TIMP-2 levels were decreased both at the time of admission and discharge in bacterial enteritis patients. Interestingly, the kinetics of serum MMP-2, MMP-9, and TIMP-2 levels were similar among the viral GE patients but distinct from bacterial enteritis patients. Thus, the involvement of MMPs and TIMPs in the pathophysiology of gastrointestinal symptoms likely varies depending on the etiological agent. Further studies are required to verify whether the extent of the bacterial enteritis or age of the patients influences these serum biomarkers. J. Med. Virol. 88:1341-1346, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26765398 TI - General and Abdominal Adiposity and Risk of Death in HBV Versus Non-HBV Carriers: A 10-Year Population-based Cohort Study. AB - Both obesity and hepatitis B virus (HBV) infection increase the risk of death. We investigate the association between general and central obesity and all-cause mortality among adult Taiwanese HBV versus non-HBV carriers.A total of 19,850 HBV carriers and non-hepatitis C virus (HCV) carriers, aged 20 years and older at enrollment in 1998 to 1999 in Taiwan, were matched to 79,400 non-HBV and non-HCV carriers (1:4). Cox proportional-hazards models were used to estimate the relative risks for all-cause mortality during a maximum follow-up period of 10 years. Four obesity-related anthropometric indices-body mass index (BMI), waist circumference, waist-to-hip ratio, and waist-to-height ratio-were the main variables of interest.During the follow-up period, 628 and 2366 participants died among HBV and non-HBV carriers, respectively. Both underweight and general obesity were associated with an increased risk of death. The highest risk of all cause death in relation to BMI was found in the HBV carriers with underweight (BMI <18.5 kg/m2) and non-HBV carriers with obesity (BMI >=30 kg/m2). The lowest risks of all-cause death in relation to abdominal adiposity were found at the third quartiles of waist circumference, waist-to-hip ratio, and waist-to-height ratio among HBV carriers, but in the second quartiles among non-HBV carriers. For those with pre-existing liver disease among HBV carriers, patients with underweight have higher risk of death than those with obesity.Hepatitis B virus carriers with underweight have higher risk of death than non-HBV carriers. HBV carriers with mild abdominal obesity have the lowest risk of death, but not in the non-HBV carriers. PMID- 26765400 TI - Perioperative and Anesthesia-Related Mortality: An 8-Year Observational Survey From a Tertiary Teaching Hospital. AB - In 2006, a previous study at our institution reported high perioperative and anesthesia-related mortality rates of 21.97 and 1.12 per 10,000 anesthetics, respectively. Since then, changes in surgical practices may have decreased these rates. However, the actual perioperative and anesthesia-related mortality rates in Brazil remains unknown. The study aimed to reexamine perioperative and anesthesia-related mortality rates in one Brazilian tertiary teaching hospital.In this observational study, deaths occurring in the operation room and postanesthesia care unit between April 2005 and December 2012 were identified from an anesthesia database. The data included patient characteristics, surgical procedures, American Society of Anesthesiologists (ASA) physical status, and medical specialty teams, as well as the types of surgery and anesthesia. All deaths were reviewed and grouped by into 1 of 4 triggering factors groups: totally anesthesia-related, partially anesthesia-related, surgery-related, or disease/condition-related. The mortality rates are expressed per 10,000 anesthetics with 95% confidence intervals (CIs).A total of 55,002 anesthetics and 88 deaths were reviewed, representing an overall mortality rate of 16.0 per 10,000 anesthetics (95% CI: 13.0-19.7). There were no anesthesia-related deaths. The major causes of mortality were patient disease/condition-related (13.8, 95% CI: 10.7-16.9) followed by surgery-related (2.2, 95% CI: 1.0-3.4). The major risks of perioperative mortality were children younger than 1-year-old, older patients, patients with poor ASA physical status (III-V), emergency, cardiac or vascular surgeries, and multiple surgeries performed under the same anesthetic technique (P < 0.0001).There were no anesthesia-related deaths. However, the high mortality rate caused by the poor physical conditions of some patients suggests that primary prevention might be the key to reducing perioperative mortality. These findings demonstrate the need to improve medical perioperative practices for high-risk patients in under-resourced settings. PMID- 26765399 TI - Subnormal Estimated Glomerular Filtration Rate Strongly Predict Incident Cardiovascular Events in Type 2 Diabetic Chinese Population With Normoalbuminuria. AB - No study has evaluated whether subnormal estimated glomerular filtration rate (eGFR) (between 61 and 90 mL/min) and high normal albumin-creatinine ratio (ACR) (<30 mg/g) are associated with cardiovascular (CV) events and mortality in type 2 diabetic (T2DM) patients with normoalbuminuria.We observed a longitudinal cohort study of 1291 T2DM patients with normoalbuminuria who were receiving intensified multifactorial treatment from 2004 to 2008. Cox regression models were used to evaluate eGFR and ACR as the risk factors of major CV events (nonfatal myocardial infarction and stroke) and mortality.During the 4-year period, 56 patients died and 159 patients developed major CV events. We found eGFR, but not ACR, to be associated with major CV events. Compared to those with eGFR higher than 90 mL/min, patients with subnormal eGFR (HR: 3.133, 1.402-7.002, P = 0.005) were at greater risk of incident major CV events. Extremely low eGFR (<30 mL/min) was associated with mortality only in patients under 65 years old.Subnormal eGFR was a strong predictor of major CV events in diabetic patients with normoalbuminuria. Normoalbuminuric diabetic patients with subnormal eGFR may need intensive CV risk factor intervention to prevent and treat CV events. PMID- 26765401 TI - A Case Report of Majocchi's Granuloma Associated with Combined Therapy of Topical Steroids and Adalimumab. AB - Currently, tumor necrosis factor alpha (TNF-alpha) inhibitors are widely used for many autoimmune disorders. However, they cause an immunocompromised status that sometimes leads to many cutaneous side effects including atypical infections. Herein, we report the first case of adalimumab-related Majocchi's granuloma.A 43 year-old Taiwanese male patient with chronic plaque-type psoriasis developed numerous tender nodules 1 month after adalimumab injection. The nodules responded poorly to bacterial folliculitis treatment. After repeated skin biopsies for pathology and tissue fungal culture, Majocchi's granuloma was confirmed. Adalimumab was withheld, and 12 weeks of terbinafine treatment was given. On completion of treatment, the nodular skin lesions and dystrophic nail lesions improved dramatically.The information, including time span, clinical features, histological findings, and improvement following withdrawal of adalimumab and treatment with an oral antifungal agent, indicates that Majocchi's granuloma was adalimumab-related. Psoriasis patients are more susceptible to dermatophyte infection due to local and systemic immunosuppressant therapy. It is important to perform a thorough examination for latent dermatophyte infection, including skin and nail lesions, before treatment with TNF-alpha inhibitors and during traditional psoriasis treatment. When atypical presentation together with treatment failure is noted in psoriasis patients prescribed biologics, clinicians should investigate evidence of dermatophyte infection and provide proper treatment. Sometimes, multiple skin biopsies and tissue fungal cultures are required to establish a correct diagnosis. PMID- 26765402 TI - Determinants of Bowel Preparation Quality and Its Association With Adenoma Detection: A Prospective Colonoscopy Study. AB - The predictors of poor bowel preparation in colorectal cancer screening participants have not been adequately studied, and the association between the quality of bowel preparation and adenoma detection has not been firmly established. This study examined the determinants of poor bowel preparation, and evaluated its relationship with adenoma detection.We included subjects aged between 50 and 70 years who received colonoscopy between 2008 and 2014 in a colorectal cancer screening program in Hong Kong. The quality of the bowel preparation was assessed by colonoscopists, and the factors associated with poor bowel cleansing were evaluated by a binary logistic regression analysis. A multivariate regression model was constructed to evaluate if poor bowel preparation was associated with detection of colorectal neoplasia.From 5470 screening participants (average age 57.7 years, SD 4.9), 1891 (34.6%) had poor or fair bowel preparation. The average cecal intubation time was 7.0 minutes (SD 5.4; range 1.22-36.9 minutes) and the average colonoscopy withdrawal time was 10.8 minutes (SD 6.9; range 6.0-107.0 minutes). Among all, 26.5% had colorectal neoplasia and 5.5% had advanced neoplasia. Older age (>=60 years; adjusted odds ratio [AOR] = 1.19-1.38, P = 0.02-0.04), male sex (AOR = 1.38, 95% confidence interval [CI] 1.19-1.60, P < 0.001), and current smoking (AOR = 1.41, 95% CI 1.14 1.75, P = 0.002) were significantly associated with poor/fair bowel preparation. Poorer cleansing resulted in significantly lower detection rate of neoplasia (AOR = 0.35-0.62) and advanced neoplasia (AOR = 0.36-0.50) irrespective of polyp size.Steps to improve proper procedures of bowel preparation are warranted, especially among subjects at risk of poor bowel preparation. Strategies should be implemented to improve bowel cleansing, which is now demonstrated as a definite quality indicator. PMID- 26765404 TI - Multivariate Analysis of Factors Associated With Axial Symptoms in Unilateral Expansive Open-Door Cervical Laminoplasty With Miniplate Fixation. AB - Retrospective case-control study.Unilateral expansive open-door cervical laminoplasty with miniplate fixation is an efficient and increasing popular surgery for multilevel cervical spondylotic myelopathy. Axial symptoms are the most frequent complaints after cervical laminoplasty. But the mechanisms have not been fully clarified yet.The objective of this study is to compare the clinical and radiologic data between patients with or without axial symptoms and to investigate the factors associated with axial symptoms by multivariate analysis in cervical laminoplasty with miniplate fixation.A total of 129 patients who underwent cervical laminoplasty with miniplate fixation were comprised from August 2009 to March 2014. Patients were grouped according to whether they suffered from postoperative axial symptoms (PA) or not (NA). The clinical data including gender, age, duration of symptoms, diagnosis type, medical comorbidity, operative level, blood loss, operative time, pre- and post-Japanese Orthopedic Association (JOA) score, JOA recovery rates, and other complications were recorded. The radiologic data including cervical canal diameter, C2-7 Cobb angle, cervical range of motion (ROM), cross-sectional area, open angle, hinge union, and facet joint destroyed would be measured according to X-ray plain and CT scan images. The univariate analysis and multivariate logistic regression analysis were performed.There were 39 patients in PA group and 90 patients in NA group. Both groups gained significant JOA improvement postoperatively (P < 0.05). The preoperative neck pain (P = 0.048), negative change of cervical ROM (P = 0.018), and facet joints destroyed (P = 0.022) were significant different between the 2 groups. There were no significant differences for other clinical and radiography parameters between the groups (P > 0.05). The multivariate analysis showed that the negative change of cervical ROM (OR = 1.062, P = 0.047) and facet joints destroyed (OR = 0.661, P = 0.024) were related to axial symptoms.The change of cervical ROM and facet joints destroyed by miniscrews might be associated with axial symptoms after cervical laminoplasty with miniplate fixation. Cervical spine surgeons should carefully operate to decrease the injury of posterior musculature structure and protect the facet joints. PMID- 26765403 TI - Electronegative Low-density Lipoprotein Increases Coronary Artery Disease Risk in Uremia Patients on Maintenance Hemodialysis. AB - Electronegative low-density lipoprotein (LDL) is a recognized factor in the pathogenesis of coronary artery disease (CAD) in the general population, but its role in the development of CAD in uremia patients is unknown. L5 is the most electronegative subfraction of LDL isolated from human plasma. In this study, we examined the distribution of L5 (L5%) and its association with CAD risk in uremia patients.The LDL of 39 uremia patients on maintenance hemodialysis and 21 healthy controls was separated into 5 subfractions, L1-L5, with increasing electronegativity. We compared the distribution and composition of plasma L5 between uremia patients and controls, examined the association between plasma L5% and CAD risk in uremia patients, and studied the effects of L5 from uremia patients on endothelial function.Compared to controls, uremia patients had significantly increased L5% (P < 0.001) and L5 that was rich in apolipoprotein C3 and triglycerides. L5% was significantly higher in uremia patients with CAD (n = 10) than in those without CAD (n = 29) (P < 0.05). Independent of other major CAD risk factors, the adjusted odds ratio for CAD was 1.88 per percent increase in plasma L5% (95% CI, 1.01-3.53), with a near-linear dose-response relationship. Compared with controls, uremia patients had decreased flow-mediated vascular dilatation. In ex vivo studies with preconstricted rat thoracic aortic rings, L5 from uremia patients inhibited acetylcholine-induced relaxation. In cultured human endothelial cells, L5 inhibited endothelial nitric oxide synthase activation and induced endothelial dysfunction.Our findings suggest that elevated plasma L5% may induce endothelial dysfunction and play an important role in the increased risk of CAD in uremia patients. PMID- 26765405 TI - Increased Risk of Parkinson's Disease in Patients With Obstructive Sleep Apnea: A Population-Based, Propensity Score-Matched, Longitudinal Follow-Up Study. AB - Obstructive sleep apnea (OSA), characterized by repetitive episodes of apnea/hypopnea and hypoxia, is associated with systemic inflammation and induces metabolic, endocrine, and cardiovascular diseases. Inflammation might have an impact on neurodegenerative diseases. This study investigates the possible association between OSA and Parkinson's disease (PD). Random samples out of 1 million individuals were collected from Taiwan's National Health Insurance database. A total of 16,730 patients with newly diagnosed OSA from 2002 to 2008 were recruited and compared with a cohort of 16,730 patients without OSA matched for age, gender, and comorbidities using propensity scoring. All patients were tracked until a diagnosis of PD, death, or the end of 2011.During the mean 5.6 year follow-up period, the incidence rates of PD were 2.30 per 1000 person-years in the OSA cohort and 1.71per 1000 person-years in the comparison group. The incidence rate ratio (IRR) for PD was greater in older patients (? 65 years) and male patients with OSA than the controls, respective IRRs being 1.34 and 1.47. After adjustment for the comorbidities, patients with OSA were 1.37 times more likely to have PD than patients without (95% CI = 1.12-1.68, P < 0.05). Subgroup analysis showed that older patients and patients with coronary artery disease, stroke, or chronic kidney disease had a higher risk for PD than their counter parts. Log-rank analysis revealed that patients with OSA had significantly higher cumulative incidence rates of PD than the comparison group (P = 0.0048). Patients with OSA are at an increased risk for subsequent PD, especially elderly male patients. PMID- 26765406 TI - Lack of Cumulative Toxicity Associated With Cabazitaxel Use in Prostate Cancer. AB - Cabazitaxel provided a survival advantage compared with mitoxantrone in patients with castration-resistant prostate cancer refractory to docetaxel. Grade 3 to 4 (G3-4) neutropenia and febrile neutropenia were relatively frequent in the registrative XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer (TROPIC) trial, but their incidence was lower in the Expanded Access Program (EAP). Although cumulative doses of docetaxel are associated with neuropathy, the effect of cumulative doses of cabazitaxel is unknown. In this retrospective review of prospectively collected data, the authors assessed "per cycle" incidence and predictors of toxicity in the Italian cohort of the EAP, with a focus on the effect of cumulative doses of cabazitaxel.The study population consisted of 218 Italian patients enrolled in the cabazitaxel EAP. The influence of selected variables on the most relevant adverse events identified was assessed using a Generalized Estimating Equations model at univariate and multivariate analysis."Per cycle" incidence of G 3 to 4 neutropenia was 8.7%, whereas febrile neutropenia was reported in 0.9% of cycles. All events of febrile neutropenia occurred during the first 3 cycles. Multivariate logistic regression analysis showed that higher prior dose of cabazitaxel was associated with decreased odds of having G3 to 4 neutropenia (OR = 0.90; 95% CI: 0.86-0.93; P < 0.01), febrile neutropenia (OR = 0.52; 95% CI: 0.34-0.81; P < 0.01) and G3 to 4 anemia (OR = 0.93; 95% CI: 0.86-1; P = 0.07). Patients with a body surface area >2 m2 presented increased odds of having G 3 to 4 neutropenia (OR = 0.93; 95% CI: 0.86-1; P = 0.07), but decreased odds of having G3 to 4 anemia.Among the toxicities assessed, the authors did not identify any that appeared to be associated with a higher number of cabazitaxel cycles delivered. Prior cumulative dose was associated with reduced G3 to 4 neutropenia and anemia. The apparent protective effect associated with higher doses of cabazitaxel is likely to be affected by early dose reduction and early toxicity related treatment discontinuation. Because this analysis is limited by its retrospective design, prospective trials are required to assess the optimal duration of cabazitaxel treatment. PMID- 26765408 TI - Comparison of Modified With Classic Morrow Septal Myectomy in Treating Hypertrophic Obstructive Cardiomyopathy. AB - This study aimed to compare the efficacy and safety of the classic Morrow septal myectomy with the modified procedure in treating hypertrophic obstructive cardiomyopathy (HOCM).A retrospective study was conducted to compare the outcomes of classic with modified Morrow septal myectomy in 42 patients treated from January 2005 to July 2011. Preoperative and postoperative ventricular septal thickness, left ventricular (LV) outflow tract velocity and gradient were measured echocardiographically.In both groups, the ventricular septal thickness, LV outflow tract velocity, and LV outflow tract gradient were significantly decreased after the operation. The modified Morrow procedure group, however, showed significantly greater reduction in these echocardiographic parameters than the classic procedure group. All patients in the modified procedure group were asymptomatic postoperatively with a postoperative transvalvular pressure gradient <30 mm Hg. In the classic procedure group, only 14 (87.5%) patients, however, were asymptomatic postoperatively with a postoperative transvalvular pressure gradient <30 mm Hg, and 2 patients still had severe LV outflow obstruction postoperatively.The modified Morrow septal myectomy is safe and effective in treating HOCM patients, and is superior to the classic procedure in reducing the LV outflow tract gradient and velocity, restoring normal anatomic atrioventricular size, and alleviating symptoms associated with HOCM. PMID- 26765407 TI - Intravenous Versus Oral Iron for the Treatment of Anemia in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Anemia is the most prevalent extraintestinal complication of inflammatory bowel disease (IBD). Our aim was to evaluate the comparative efficacy and harm of intravenous (IV) versus oral iron supplementation for correcting anemia in adult IBD patients.We conducted a systematic review and meta-analysis to integrate evidence from randomized controlled trials having enrolled adults with IBD, and comparing IV versus oral iron (head-to-head) for correcting iron-deficiency anemia. Medline, Embase, Scopus, and the Web of Science database were searched through July 2015. The Cochrane Central Register of Controlled Trials, the WHO International Clinical Trials Registry Platform, the ClinicalTrials.gov, and international conference proceedings were also investigated. Two reviewers independently abstracted study data and outcomes, and rated each trial's risk-of bias. Pooled odds ratio (OR) estimates with their 95% CIs were calculated using fixed- and random-effects models.Five eligible studies, including 694 IBD patients, were identified. In meta-analysis, IV iron demonstrated a higher efficacy in achieving a hemoglobin rise of >=2.0 g/dL as compared to oral iron (OR: 1.57, 95% CI: 1.13, 2.18). Treatment discontinuation rates, due to adverse events or intolerance, were lower in the IV iron groups (OR: 0.27, 95% CI: 0.13, 0.59). Similarly, the occurrence of gastrointestinal adverse events was consistently lower in the IV iron groups. On the contrary, serious adverse events (SAEs) were more frequently reported among patients receiving IV iron preparations (OR: 4.57, 95% CI: 1.11, 18.8); however, the majority of the reported SAEs were judged as unrelated or unlikely to be related to the study medication. We found no evidence of publication bias, or between-study heterogeneity, across all analyses. Risk of bias was high across primary studies, because patients and personnel were not blinded to the intervention.IV iron appears to be more effective and better tolerated than oral iron for the treatment of IBD-associated anemia. PMID- 26765409 TI - High Stroke Volume Variation Method by Mannitol Administration Can Decrease Blood Loss During Donor Hepatectomy. AB - Optimal fluid management to reduce blood loss during donor hepatectomy is important for maximizing donor safety. Mannitol can induce osmotic diuresis, helping prevent increased intravascular volume status. We therefore evaluated the effect of high stroke volume variation (SVV) method by mannitol administration and fluid restriction on blood loss during donor hepatectomy.In this prospective study, 64 donors scheduled for donor right hepatectomy were included and allocated into 2 groups. In group A, the SVV value of each patient was maintained at 10% to 20% during hepatic resection with 0.5 g/kg mannitol administration and fluid restriction at a rate of 2 to 4 mL/kg/h. In group B, the SVV value was maintained at <10% by fluid administration at a rate of 6 to 10 mL/kg/h without diuretic administration during surgery. Intraoperative blood loss was estimated by the loss of red cell mass. Surgeon satisfaction scores and postoperative outcomes, including acute kidney injury, abnormal chest radiographic findings, and hospital stay duration, were also assessed.SVV during hepatectomy was significantly higher in group A than in group B (11.0 +/- 1.7 vs 6.5 +/- 1.1, P < 0.001). The red cell mass loss was significantly lower in group A than in group B (145.4 +/- 107.6 vs 307.9 +/- 110.7 mL, P < 0.001). Surgeon satisfaction scores were higher in group A than in group B (2.8 +/- 0.5 vs 2.0 +/- 0.6, P < 0.001). The incidence of acute kidney injury, abnormal chest radiographic findings, and duration of hospital stay did not significantly differ between the 2 groups.Maintenance of high SVV by mannitol administration is effective and safe for reducing blood loss during donor hepatectomy. PMID- 26765410 TI - Somatostatin Analogue Treatment of a TSH-Secreting Adenoma Presenting With Accelerated Bone Metabolism and a Pericardial Effusion: A Case Report. AB - Increased bone turnover and other less frequent comorbidities of hyperthyroidism, such as heart failure, have only rarely been reported in association with central hyperthyroidism due to a thyrotropin (TSH)-secreting pituitary adenoma (TSHoma). Treatment is highly empirical and relies on eliminating the tumor and the hyperthyroid state.We report here an unusual case of a 39-year-old man who was initially admitted for management of pleuritic chest pain and fever of unknown origin. Diagnostic work up confirmed pericarditis and pleural effusion both refractory to treatment. The patient had a previous history of persistently elevated levels of alkaline phosphatase (ALP), indicative of increased bone turnover. He had also initially been treated with thyroxine supplementation due to elevated TSH levels. During the diagnostic process a TSHoma was revealed. Thyroxine was discontinued, and resection of the pituitary tumor followed by treatment with a somatostatin analog led to complete recession of the effusions, normalization of ALP, and shrinkage of pituitary tumor.Accelerated bone metabolism and pericardial and pleural effusions attributed to a TSHoma may resolve after successful treatment of the tumor. The unexpected clinical course of this case highlights the need for careful long-term surveillance in patients with these rare pituitary adenomas. PMID- 26765411 TI - Etiologies and Management of Aseptic Meningitis in Patients Admitted to an Internal Medicine Department. AB - Several studies have focused on the clinical and biological characteristics of meningitis in order to distinguish between bacterial and viral meningitis in the emergency setting. However, little is known about the etiologies and outcomes of aseptic meningitis in patients admitted to Internal Medicine.The aim of the study is to describe the etiologies, characteristics, and outcomes of aseptic meningitis with or without encephalitis in adults admitted to an Internal Medicine Department.A retrospective cohort study was conducted in the Internal Medicine Department of the Lariboisiere Hospital in Paris, France, from January 2009 to December 2011. Clinical and biological characteristics of aseptic meningitis were recorded. These included cerebrospinal fluid analysis, results of polymerase chain reaction testing, final diagnoses, and therapeutic management.The cohort included 180 patients fulfilling the criteria for aseptic meningitis with (n = 56) or without (n = 124) encephalitis. A definitive etiological diagnosis was established in 83 of the 180 cases. Of the cases with a definitive diagnosis, 73 were due to infectious agents, mainly enteroviruses, Herpes Simplex Virus 2, and Varicella Zoster Virus (43.4%, 16.8%, and 14.5% respectively). Inflammatory diseases were diagnosed in 7 cases. Among the 97 cases without definitive diagnoses, 26 (26.8%) remained free of treatment throughout their management whereas antiviral or antibiotic therapy was initiated in the emergency department for the remaining 71 patients. The treatment was discontinued in only 10 patients deemed to have viral meningitis upon admission to Internal Medicine.The prevalence of inflammatory diseases among patients admitted to internal medicine for aseptic meningitis is not rare (4% of overall aseptic meningitis). The PCR upon admission to the emergency department is obviously of major importance for the prompt optimization of therapy and management. However, meningitis due to viral agents or inflammatory diseases could also be distinguished according to several clinical and biological characteristics highlighted in this retrospective study. As recommendations are now available concerning the prescriptions of antiviral agents in viral meningitis, better therapeutic management is expected in the future. PMID- 26765412 TI - A Retrospective Observational Study Examining the Effect of Thoracic Epidural and Patient Controlled Analgesia on Short-term Outcomes in Blunt Thoracic Trauma Injuries. AB - Effective analgesia in the early stages after any major traumatic event remains pivotal to optimal trauma management. For patients with significant thoracic injuries, this is paramount to ensure ongoing efficient respiratory function. The aim of this study was to investigate the use of analgesic modes in the management of patients with a primary thoracic injury and blunt mechanism of injury. By understanding variables that influence the use of varying analgesic modes and influence the development of pulmonary complications, there should be more uniform evidence-based prescription in the future.This retrospective study considered analgesic use in patients admitted after blunt thoracic injuries at one major trauma center over a 2-year period. Pulmonary complications measured included both infective and ventilator-associated failure. Univariate and multivariate analyses were used to identify patient and injury severity characteristics and their association with respiratory complications.A total of 401 cases were reviewed and analyzed: 159 received Patient Controlled Analgesia (PCA), 32 received PCA and epidural analgesia (EA), 6 received EA alone, and 204 received interval-administered analgesia. There were no significant differences in the rates of complication when compared between analgesic modes. Patients who developed pneumonia had significantly increased number of thoracic fractures and underlying organ injury (P < 0.05). Logistic regression analysis highlighted duration of intercostal drain insertion (OR 1.377, P = 0.001) and premorbid cardiac disease (OR 2.624, P = 0.042) and ICU length of stay (OR: 1.146, P < 0.001) as significant predictors of developing pneumonia in this patient group.Examining the different analgesic modes, this study failed to identify a particular analgesic mode that was more effective in preventing pulmonary complications in blunt thoracic injuries. However, variables that may influence usage of different analgesic modes and high-risk groups for the development of pneumonia were identified. Further work is warranted to consider the long-term benefits of analgesia in patients post-blunt thoracic injuries. PMID- 26765413 TI - Risk Factors for Recurrent Lumbar Disc Herniation: A Systematic Review and Meta Analysis. AB - Recurrent lumbar disc herniation (rLDH) is a common complication following primary discectomy. This systematic review aimed to investigate the current evidence on risk factors for rLDH.Cohort or case-control studies addressing risk factors for rLDH were identified by search in Pubmed (Medline), Embase, Web of Science, and Cochrane library from inception to June 2015. Relevant results were pooled to give overall estimates if possible. Heterogeneity among studies was examined and publication bias was also assessed.A total of 17 studies were included in this systematic review. Risk factors that had significant relation with rLDH were smoking (OR 1.99, 95% CI 1.53-2.58), disc protrusion (OR 1.79, 95% CI 1.15-2.79), and diabetes (OR 1.19, 95% CI 1.06-1.32). Gender, BMI, occupational work, level, and side of herniation did not correlate with rLDH significantly.Based on current evidence, smoking, disc protrusion, and diabetes were predictors for rLDH. Patients with these risk factors should be paid more attention for prevention of recurrence after primary surgery. More evidence provided by high-quality observational studies is still needed to further investigate risk factors for rLDH. PMID- 26765414 TI - Evaluation of Body Mass Index and Survival of Nasopharyngeal Carcinoma by Propensity-Matched Analysis: An Observational Case-Control Study. AB - The effect of pretreatment body mass index on survival of nasopharyngeal carcinoma remains contradictory.All patients (N = 1778) underwent intensity modulated radiotherapy with or without chemotherapy. Body mass index was categorized as underweight (<18.5 kg/m2), normal weight (18.5-22.9 kg/m2), overweight (22.9-27.5 kg/m2), and obesity (>=27.5 kg/m2). Propensity score matching method was used to identify patients with balanced characteristics and treatment regimen. Disease-specific survival (DSS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival were estimated by Kaplan-Meier method and Cox regression.Following propensity matching, 115 (underweight vs normal), 399 (overweight vs normal), and 93 (obese vs normal) pairs of patients were selected, respectively. In univariate analysis, underweight patients had inferior DSS/OS (P = 0.042) and DMFS (P = 0.025) while both overweight and obese patients showed similar survival across all the endpoints (P >= 0.098) to those with normal weight. In multivariate analysis, underweight remained predictive of poor DSS/OS (P = 0.044) and DMFS (P = 0.040), whereas overweight (P >= 0.124) or obesity (P >= 0.179) was not associated with any type of survival.Underweight increased the risk of death and distant metastasis, whereas overweight or obese did not affect the survival of nasopharyngeal carcinoma. This provides support for early nutritional intervention during the long waiting time before treatment. PMID- 26765415 TI - The Relationship Between Body Iron Status, Iron Intake And Gestational Diabetes: A Systematic Review and Meta-Analysis. AB - Biological and epidemiological evidence have found that gestational diabetes mellitus (GDM) may be correlated with body iron status and dietary iron intake. Therefore, we investigated the relationship between dietary iron intake and body iron status and GDM risk.We conducted a systematic search in Embase, PubMed, Web of Science, and Cochrane Library up to April 2015. Prospective cohort studies or case-control studies which appraised the relationship between body iron status, dietary iron intake, and GDM risk were included. Relative risks (RRs), standard mean difference (SMD), and 95% confidence intervals [CIs] were used to measure the pooled data.A total of 8 prospective cohort studies and 7 case-control studies were in accordance with inclusive criteria, and 14 studies were included in meta-analysis. The overall RR comparing the highest and lowest levels of serum ferritin was 3.22 (95% CI: 1.73-6.00) for prospective cohort studies. Serum ferritin of GDM group is markedly higher than that of control (0.88 ng/mL; 95% CI: 0.40-1.35 ng/mL) for case-control studies. The comparison between the highest and the lowest serum ferritin levels and dietary total iron levels revealed pooled RRs of 1.53 (95% CI: 1.17-2.00) and 1.01 (95% CI: 1.00-1.01) for prospective cohort studies, respectively. The combined SMD comparing serum transferrin levels of cases and controls was -0.02 MUmol/L (95% CI: -0.22 to 0.19 MUmol/L) for case-control studies.Increased higher ferritin levels were significantly correlated with higher risk of GDM, and higher heme iron levels may be correlated with higher risk of GDM; however, the present conclusion did not constitute definitive proof that dietary total iron or serum transferrin have relation to GDM. PMID- 26765416 TI - Plasma Efavirenz Concentrations Are Associated With Lipid and Glucose Concentrations. AB - Efavirenz-based antiretroviral therapy (ART) has been associated with dyslipidemia and dysglycemia, risk factors for cardiovascular disease. However, the pathogenesis is not well understood. We characterized relationships between plasma efavirenz concentrations and lipid and glucose concentrations in HIV infected South Africans.Participants on efavirenz-based ART were enrolled into a cross-sectional study. The oral glucose tolerance test was performed after an overnight fast, and plasma drawn for mid-dosing interval efavirenz, fasting total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, and triglycerides concentrations.Among 106 participants (77 women), median age was 38 years, median CD4 + T-cell count was 322 cells/MUL, median duration on ART was 18 months, and median (interquartile range) efavirenz concentration was 2.23 (1.66 to 4.10) MUg/mL. On multivariable analyses (adjusting for age, sex, body mass index, and ART duration) doubling of efavirenz concentrations resulted in mean changes in mmol/L (95%CI) of: total cholesterol (0.40 [0.22 to 0.59]), LDL cholesterol (0.19 [0.04 to 0.30]), HDL cholesterol (0.14 [0.07 to 0.20]), triglycerides (0.17 [0.03 to 0.33]), fasting glucose (0.18 [0.03 to 0.33]), and 2-h glucose concentrations (0.33 [0.08 to 0.60]). Among 57 participants with CYP2B6 genotype data, associations between slow metabolizer genotypes and metabolic profiles were generally consistent with those for measured efavirenz concentrations.Higher plasma efavirenz concentrations are associated with higher plasma lipid and glucose concentrations. This may have implications for long-term cardiovascular complications of efavirenz-based ART, particularly among populations with high prevalence of CYP2B6 slow metabolizer genotypes. PMID- 26765417 TI - Effects of Sitagliptin on Lipid Profiles in Patients With Type 2 Diabetes Mellitus: A Meta-analysis of Randomized Clinical Trials. AB - Sitagliptin has been reported to improve lipid profiles, but findings from these studies are conflicting. We conducted this meta-analysis to evaluate the effects of sitagliptin on serum lipids in patients with type 2 diabetes mellitus.We made a comprehensive literature search in PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, Wanfang, and VIP database until June 2015. Eligible studies were randomized clinical trials (RCTs) that investigated the effect of sitagliptin on serum triglycerides (TGs), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), or high-density lipoprotein cholesterol (HDL-C).Eleven RCTs with 2338 patients were identified. Compared with controls, sitagliptin alone or in combination significantly improved serum TG (weighted mean difference [WMD] -0.24 mmol/L; 95% confidence interval [CI] -0.40 to -0.09; P = 0.002) and HDL-C (WMD 0.05 mmol/L; 95% CI 0.02-0.07; P < 0.001).However, no statistical significances were observed in LDL-C (WMD -0.07 mmol/L; 95% CI -0.22 to 0.08; P = 0.337) and TC (WMD -0.14; 95% CI -0.33 to 0.06; P = 0.177). Subgroup analyses revealed that sitagliptin alone achieved greater improvement in serum TG, TC, and HDL-C levels.These findings suggested that sitagliptin alone or in combination significantly improved serum TG and HDL-C levels in patients with type 2 diabetes mellitus. PMID- 26765418 TI - Analysis of Geometric Shifts and Proper Setup-Margin in Prostate Cancer Patients Treated With Pelvic Intensity-Modulated Radiotherapy Using Endorectal Ballooning and Daily Enema for Prostate Immobilization. AB - We evaluate geometric shifts of daily setup for evaluating the appropriateness of treatment and determining proper margins for the planning target volume (PTV) in prostate cancer patients.We analyzed 1200 sets of pretreatment megavoltage-CT scans that were acquired from 40 patients with intermediate to high-risk prostate cancer. They received whole pelvic intensity-modulated radiotherapy (IMRT). They underwent daily endorectal ballooning and enema to limit intrapelvic organ movement. The mean and standard deviation (SD) of daily translational shifts in right-to-left (X), anterior-to-posterior (Y), and superior-to-inferior (Z) were evaluated for systemic and random error.The mean +/- SD of systemic error (Sigma) in X, Y, Z, and roll was 2.21 +/- 3.42 mm, -0.67 +/- 2.27 mm, 1.05 +/- 2.87 mm, and -0.43 +/- 0.89 degrees , respectively. The mean +/- SD of random error (delta) was 1.95 +/- 1.60 mm in X, 1.02 +/- 0.50 mm in Y, 1.01 +/- 0.48 mm in Z, and 0.37 +/- 0.15 degrees in roll. The calculated proper PTV margins that cover >95% of the target on average were 8.20 (X), 5.25 (Y), and 6.45 (Z) mm. Mean systemic geometrical shifts of IMRT were not statistically different in all transitional and three-dimensional shifts from early to late weeks. There was no grade 3 or higher gastrointestinal or genitourianry toxicity.The whole pelvic IMRT technique is a feasible and effective modality that limits intrapelvic organ motion and reduces setup uncertainties. Proper margins for the PTV can be determined by using geometric shifts data. PMID- 26765419 TI - Pain Perception and Stabilometric Parameters in People With Chronic Low Back Pain After a Pilates Exercise Program: A Randomized Controlled Trial. AB - Various exercise interventions, such as Pilates exercises and traditional physical therapy methods, are employed to decrease low back pain (LBP). Nonspecific low back pain (NSLBP) is distinct from LBP, however, as the distribution of pain is restricted to the region between the costal margin and the inferior gluteal. The aim of our randomized controlled trial was to evaluate the effects of a program of Pilates exercises on pain perception and stabilometric parameters in patients with NSLBP.Thirty-eight participants were randomly allocated, using a 1:1 scheme, to either the experimental group (EG) or control group (CG). The EG completed a 14-week program of Pilates exercises, performed thrice per week under the supervision of an exercise specialist, while the CG was managed with a social program only. Measures of posturography and Oswestry Disability Index (ODI) for pain perception were obtained at baseline (T0) and after the 14 weeks of intervention (T)1.Posturography measures improved for patients in the EG, with both eyes open and eyes closed (P < 0.05). There were no statistical differences in posturography in the CG. ODI decreased significantly in both groups over the 14 weeks of the study protocol: EG, T0, 13.7 +/- 5.0 compared with T1, 6.5 +/- 4.0 (P < 0.001); and CG, T0, 10.7 +/- 7.8 compared with T1, 8.4 +/- 7.8 (P < 0.01). A greater extent of reduction in pain was achieved in the EG.The Pilates exercise program yielded improvements in pain and posturography outcomes. Our study also confirms the applicability of posturography in evaluating postural instability in patients with NSLBP. Due to our relatively small study group, future studies would be necessary to confirm our findings. PMID- 26765420 TI - Case Report: Bazex Syndrome Associated With Pulmonary Adenocarcinoma. AB - Bazex syndrome, a rare paraneoplastic syndrome characterized by psoriasiform eruptions, palmoplantar keratosis, and symmetric onychodystrophy, is most prevalent with squamous cell carcinomas of the upper aerodigestive tract.Here, we reported an uncommon case of Bazex syndrome about an 83-year-old man with pulmonary adenocarcinoma and osseous metastasis, Physical examination found psoriasiform eruptions on the nose, cheeks, ears, knees, and the dorsa of interphalangeal joints, along with plantar keratosis and symmetric onychodystrophy involving hands and feet. Imaging analyses pulmonary adenocarcinoma with both local metastatic nodules and osseous metastasis.Symptomatic treatment with topical corticosteroids and oral retinoids showed no improvement. A 4-month follow-up showed that Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, successfully reduced primary tumor size and alleviated cutaneous lesions.Our report here highlighted a potential correlation between pulmonary adenocarcinoma and Bazex syndrome, which is characterized by hallmark nail destruction and preferential involvement of body extremities. Moreover, etiological therapy against underlying malignancy is essential for treating paraneoplastic Bazex syndrome. PMID- 26765422 TI - Hypertension in Malaysia: An Analysis of Trends From the National Surveys 1996 to 2011. AB - This study aimed to determine trends in prevalence, awareness, and control of hypertension in Malaysia and to assess the relationship between socioeconomic determinants and prevalence of hypertension in Malaysia.The distribution of hypertension in Malaysia was assessed based on available data in 3 National Health and Morbidity Surveys (NHMSs) and 1 large scale non-NHMS during the period of 1996 to 2011. Summary statistics was used to characterize the included surveys. Differences in prevalence, awareness, and control of hypertension between any 2 surveys were expressed as ratios. To assess the independent associations between the predictors and the outcome variables, regression analyses were employed with prevalence of hypertension as an outcome variable.Overall, there was a rising trend in the prevalence of hypertension in adults >=30 years: 32.9% (30%-35.8%) in 1996, 42.6% (37.5%-43.5%) in 2006, and 43.5% (40.4%-46.6%) in 2011. There were significant increase of 32% from 1996 to 2011 (P < 0.001) and of 29% from 1996 to 2006 (P < 0.05), but only a small change of 1% from 2006 to 2011 (P = 0.6). For population >=18 years, only a 1% increase in prevalence of hypertension occurred from the 2006 NHMS (32.2%) to the 2011 NHMS (32.7%) (P = 0.25). A relative increase of 13% occurred in those with primary education (P < 0.001) and a 15% increase was seen in those with secondary education (P < 0.001). The rate of increase in the prevalence of hypertension in the population with income level RM 3000-3999 was the highest (18%) during this period. In general, the older age group had higher prevalence of hypertension in the 2006 and 2011 NHMSs. The prevalence peaked at 74.1% among population aged 65 to 69 years in the 2011 NHMS. Both the proportion of awareness and the control of hypertension in Malaysia improved from 1996 to 2006. A change in the control of hypertension was 13% higher in women than in men.The findings suggest that the magnitude of hypertension in Malaysia needs additional attention. Strengthening the screening for hypertension in primary health-care settings in the high-risk groups and frequent health promotion to the community to enhance individual awareness and commitment to healthy living would be of immense value. PMID- 26765421 TI - Association Between Interleukin-6 -572 C>G and -174 G>C Polymorphisms and Hypertension: A Meta-analysis of Case-control Studies. AB - Whether hypertension is associated with -572 C>G or -174 G>C polymorphism in interleukin (IL)-6 genes still remains hazy and ambiguous.We conducted a meta analysis to offer a more reliable and clearer evaluation about the association.Electronic literature databases including PubMed, Web of Science, EMBASE, Google Scholar, Chinese National Knowledge Infrastructure and Wanfang database were searched.The study included the following: evaluating associations between -572 C>G or -174 G>C polymorphism in IL-6 gene and hypertension; case control design; essential information must be offered; precise diagnostic criteria of hypertension; and no language restriction.Patients who met the diagnostic criteria and controls without a history of hypertension were included. Interventions were not available.A quality assessment was conducted using Newcastle-Ottawa scale. Combined odds ratios with 95% confidence intervals were calculated in 5 genetic models. Sources of heterogeneity were explored by subgroup analysis, meta-regression, and Galbraith plots. Finally, test for publication bias was performed to prove the stabilization.Fifteen studies were finally included. Eleven articles were judged high-quality reports. Overall, the 572 C>G polymorphism was proved to be significantly associated with hypertension in 4 genetic models. Subgroup analysis based on ethnicity revealed significant associations in Asian population in recessive model and homozygote comparison. The association in Europeans and Mid-East required further confirmation. No significant association was observed between the -174 G>C polymorphism and hypertension under all of the genetic models.The limitations of the study were the following: restrictive number of eligible studies limited the extrapolation range in subgroup analysis; gene-environment factors could not be described due to lack of data; some relevant studies could not be included because of various reasons.Current researches supported the association between the development of hypertension and the -572 C>G rather than -174 G>C polymorphism. Future well designed epidemiological studies may evaluate the possible gene-environment interactions. PMID- 26765423 TI - Lower Mortality Associated With Overweight in the U.S. National Health Interview Survey: Is Overweight Protective? AB - It is still debatable whether overweight has protective or detrimental effects on survival. The focus of the ongoing debate is on possible confounding bias due to factors such as preexisting illness and smoking. We aimed to assess the association between overweight and mortality and to examine confounding effects of various factors including smoking and preexisting cancer, cardiovascular disease (CVD), diabetes, asthma, bronchitis, and kidney disease on the overweight mortality association in adults.The data were extracted from the public-use National Health Interview Survey (NHIS) 1997 to 2009. Mortality data up to December 31, 2011 were linked to 131,813 with normal weight and 120,217 overweight adults. We assessed the association between overweight and mortality using Cox proportional hazard model with adjustments for various sets of confounding factors-age, sex, smoking, race, survey year, diabetes, CVD, cancer, asthma, bronchitis, and kidney disease.During the period from the original surveys to December 31, 2011, 22,513 (11,815 normal weight and 10,698 overweight) adults died. Normal weight and overweight groups differed in the characteristics of age, sex, smoking, and preexisting diseases. After adjusting for age and sex, the risk of dying was lower for overweight than normal weight adults (hazard ratio [HR], 0.82; 95% confidence interval [CI]: 0.80-0.85). Lower mortality risk associated with overweight remained after further adjusting for smoking and preexisting diseases such as diabetes, CVD, cancer, asthma, bronchitis, and kidney disease (HR, 0.80; 95% CI: 0.78-0.82). We observed a similar pattern for men and women, and for those free from preexisting diabetes, hypertension, and CVD.In conclusion, overweight adults have a lower mortality risk than normal weight adults. Our findings do not support that the lower mortality in overweight adults is due to confounding effects of smoking and preexisting diseases. PMID- 26765424 TI - Status and Perspectives of Clinical Modes in Surgical Patients With Lung Cancer: A Retrospective Study. AB - To investigate the association between the clinical characteristics and clinical modes of surgically treated lung cancer patients, we conducted a retrospective study with 1097 lung cancer patients receiving pulmonary resection between 2012 and 2013.A physical examination or screening (PES) group (n = 267) and a symptomatic (SY) group (n = 830) were established depending on the new clinical mode (sequence of physical examination, early detection and sequential medical treatment) and the conventional mode (hospitalization due to occurrence of relevant symptoms), respectively.A higher proportion of patients referred to our unit directly form a junior medical unit is found in PES group (43.8%, 117/267 vs 13.6%, 113/830) (P < 0.001) and 37.5% (100/267) patients in PES group spent <1 months from detection or first medical visit to diagnosis compared with 15.4% (128/830) patient in SY group (P < 0.001). A significantly higher proportion of PES patients versus SY patients received video-assisted thoracoscopic surgery (VATS) resection (67.8%, 183/267 vs 42.6%, 352/830; P < 0.001). A significantly higher proportion of PES patients versus SY patients chose sublobar resection (16.9%, 45/267 vs 7.6%, 63/830; P < 0.001). A significantly higher proportion of PES patients versus SY patients are at stage 0 or I (64.4%, 172/267 vs 40.7%, 338/830; P < 0.000). The postoperative incidence rate of complications in 30 days is significantly higher in SY group than in PES group (34.9% vs 27.3%; P = 0.022).Helping to early diagnosis and surgical treatment, early tumor detection via PES may contribute to significantly higher proportions of early-stage lung cancer, use of VATS pulmonary resection, and sublobectomy as well as lower complication rate. PMID- 26765425 TI - Predicting Hemorrhagic Transformation of Acute Ischemic Stroke: Prospective Validation of the HeRS Score. AB - Hemorrhagic transformation (HT) increases the morbidity and mortality of ischemic stroke. Anticoagulation is often indicated in patients with atrial fibrillation, low ejection fraction, or mechanical valves who are hospitalized with acute stroke, but increases the risk of HT. Risk quantification would be useful. Prior studies have investigated risk of systemic hemorrhage in anticoagulated patients, but none looked specifically at HT. In our previously published work, age, infarct volume, and estimated glomerular filtration rate (eGFR) significantly predicted HT. We created the hemorrhage risk stratification (HeRS) score based on regression coefficients in multivariable modeling and now determine its validity in a prospectively followed inpatient cohort.A total of 241 consecutive patients presenting to 2 academic stroke centers with acute ischemic stroke and an indication for anticoagulation over a 2.75-year period were included. Neuroimaging was evaluated for infarct volume and HT. Hemorrhages were classified as symptomatic versus asymptomatic, and by severity. HeRS scores were calculated for each patient and compared to actual hemorrhage status using receiver operating curve analysis.Area under the curve (AUC) comparing predicted odds of hemorrhage (HeRS score) to actual hemorrhage status was 0.701. Serum glucose (P < 0.001), white blood cell count (P < 0.001), and warfarin use prior to admission (P = 0.002) were also associated with HT in the validation cohort. With these variables, AUC improved to 0.854. Anticoagulation did not significantly increase HT; but with higher intensity anticoagulation, hemorrhages were more likely to be symptomatic and more severe.The HeRS score is a valid predictor of HT in patients with ischemic stroke and indication for anticoagulation. PMID- 26765426 TI - Postoperative Radiotherapy for the Treatment of Solitary Fibrous Tumor With Malignant Transformation of the Pelvic: A Rare Case Report With Literature Review. AB - Solitary fibrous tumor of the pelvic is an uncommon neoplasm with nonspecific symptoms. Reports of malignant transformation are especially rare. We report a case of solitary fibrous tumor in pelvic. A unique feature of our case compared with previously reported is that this patient relapsed with malignant transformation and had significant response to radiotherapy. The patient was initially treated with surgery, followed by postoperative dimensional conformal intensity modulated radiation therapy (dynamic MLC VRIAN 23EX Linac, inversely optimized by the Eclipse system) to provide a radical cure for residual tumor.In this case, there were no signs of recurrence after six and a half years of further follow-up, indicating that postoperation radiotherapy may be an effective treatment for SFT with malignant transformation in pelvic. PMID- 26765428 TI - Left Ventricular Systolic Function Changes in Primary Hypertension Patients Detected by the Strain of Different Myocardium Layers. AB - This study investigated left ventricular (LV) systolic dysfunction associated with differential strain among myocardial layers in primary hypertension (PH) patients with or without LV hypertrophy (LVH), and normal patients.In 63 PH and 42 healthy patients, two-dimensional speckle tracking echocardiography was used to measure the peak systolic longitudinal and circumferential strain of the myocardial subendocardial, middle and subepicardial layers, and the peak systolic radial strain. To assess LV systolic function, the apical long axis, 4- and 2 chamber views, and parasternal short axis at the basal, middle, and apical levels were acquired by cardiovascular ultrasound (Vivid E9, GE Healthcare, USA).Overall, the pattern in peak systolic longitudinal strain among myocardial layers was subendocardial > middle > subepicardial. In the peak systolic circumferential strain, this was middle > subepicardial > subendocardial. The peak systolic longitudinal strain was normal > NLVH > LVH. Among the groups, the peak systolic circumferential strain at the basal parasternal short-axis level was statistically similar, but at the middle and the apical parasternal short axis levels were NLVH > normal > LVH. In normal and NLVH patients, the peak radial strain was middle > apical > basal, and in LVH patients was apical > middle > basal. The peak averages of the longitudinal and subendocardial circumferential strains differed significantly when LVH compared with NLVH and normal patients.The systolic function of PH patients was damaged in comparison with normal individuals, which could be detected conveniently and accurately using two-dimensional speckle tracking echocardiography. PMID- 26765427 TI - Acupoint Herbal Patching for Asthma: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - Acupoint herbal patching (AHP), which involves local point stimulation with a herbal medicine patch, has long been used to treat patients with asthma in East Asian countries. However, its evidence is equivocal. This systematic review aims to summarize and critically evaluate the efficacy and safety of AHP for asthma.A literature search was conducted in PubMed, EMBASE, the Cochrane library, and the China National Knowledge Infrastructure for studies published on or before April 2014, which were randomized controlled trials (RCTs) examining AHP therapy by itself or in combination with other treatments in asthma patients. Trials needed to report pulmonary function outcomes to be included in analyses. The risk of bias of included studies was assessed using the Cochrane risk of bias assessment tool. For statistical pooling, risk ratio, mean difference (MD), or standardized MD was calculated with 95% confidence intervals (CIs) in a random-effects model.We ultimately included 16 RCTs with 1287 asthmatic patients in analyses. Treatment with AHP improved forced expiratory volume in 1 second (FEV1) by 13% (MD = 12.99%, 95% CI 5.17%-20.81%) and asthmatic symptoms by 60% (risk ratio of unchanged or getting worse symptoms with AHP = 0.4, 95% CI 0.27-0.58) over that observed with placebo. However, evidence is limited due to the heterogeneity and paucity of data. When added to conventional therapies, AHP significantly improved the FEV1/forced vital capacity ratio by 11.6% (95% CI 8.49%-14.79%) and reduced the risk of asthmatic symptoms by 69% (95% CI 0.16-0.58). Compared with conventional medication, AHP significantly improved FEV1 (standardized MD = 0.46, 95% CI 0.05-0.87), but a substantial heterogeneity was detected (I 2= 53%). When added to Chinese herbal medicine, there were no additional benefits of AHP on pulmonary function or global symptom improvement. No serious adverse events were associated with AHP.Evidence for AHP efficacy is encouraging, but not conclusive, because of clinical diversity and the high risk of bias in the examined studies. Further clinical and basic research is needed to determine the role of AHP in lung function and symptom improvement in patients with asthma. PMID- 26765429 TI - Impact of Chronic Total Occlusion in a Noninfarct-related Artery on Clinical Outcomes in Patients With Acute ST-elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. AB - In the setting of primary percutaneous coronary intervention (PCI), encountering with chronic total occlusion (CTO) in a noninfarct-related artery (IRA) is not a rare situation. Limited information on the impact of CTO on clinical outcomes in acute ST-elevation myocardial infarction (STEMI) patients undergoing primary PCI has raised more concerns. The aim of the present study was to evaluate the effect of concurrent CTO in a non-IRA on the clinical outcomes in patients with STEMI undergoing primary PCI.In the present prospective study, 555 consecutive patients with STEMI who underwent early primary PCI from January 2010 to December 2013 were included. The patients were divided into 2 groups: no CTO and CTO. Data on 12 months follow-up was obtained from 449 patients. The primary endpoint was the composite of hospitalization from angina, reinfarction, heart failure, or re revascularization, and cardiac death at 12 months follow-up.Of the 555 patients, 75 (13.5%) had CTO in a non-IRA. Compared with patients in no CTO group, more patients in CTO group had hypertension (62.7% vs 46.5%, P = 0.009), diabetes (49.3% vs 35.0%, P = 0.024), and 3-vessel disease (52.0% vs 32.3%, P = 0.001). Patients with CTO had a lower left ventricular ejection fraction (LVEF) (40.1% +/ 16.8% vs 54.3% +/- 12.1%, P = 0.038), more presented with cardiogenic shock on admission (13.3% vs 4.8%, P = 0.008), compared with patients without CTO. Complete revascularization (CR) was less achieved in CTO group than in no CTO group (33.3% vs 49.1%, P = 0.013). The 12-month cardiac mortality rate was 14.5% versus 6.2% (P = 0.039), the incidence of 12-month primary endpoint was 38.7% versus 21.2% (P = 0.003) for CTO and no CTO group, respectively. Multivariate analysis revealed that after correction for baseline differences, CTO in a non IRA (hazard ratio 4.183, 95% confidence interval 1.940-6.019, P = 0.001), cardiogenic shock on admission (hazard ratio 3.286, 95% confidence interval 1.097 9.845, P = 0.034), and 3-vessel disease (hazard ratio 2.678, 95% confidence interval 1.221-5.874, P = 0.014) remained an independent predictor of 1-year cardiac mortality in patients with STEMI undergoing primary PCI.CTO in a non-IRA in patients with STEMI undergoing primary PCI is associated with a poor prognosis. The presence of CTO in a non-IRA, cardiogenic shock on admission and 3 vessel disease might be an independent risk factor for greater 1-year cardiac mortality in patients with acute STEMI undergoing primary PCI. PMID- 26765431 TI - Cardiopulmonary Function, Exercise Capacity, and Echocardiography Finding of Pediatric Patients With Kawasaki Disease: An Observational Study. AB - Coronary artery (CA) abnormalities influence exercise capacity (EC) of patients with Kawasaki disease (KD), and Z-score of CA is a well established method for detecting CA aneurysm. We studied the influence of KD on cardiopulmonary function and EC; meanwhile we analyzed echocardiographic findings of KD patients. We also assessed the correlation between CA Z-score and EC of KD patients to see if CA Z score of KD patients could reflect EC during exercise.Sixty-three KD patients were recruited as KD group 1 from children (aged 5-18 y) who received transthoracic echocardiographic examinations and symptom-limited treadmill exercise test for regular follow-up of KD from January 2010 to October 2014 in 1 medical center. We then divided KD group 1 into KD group 2 (<5 y, n = 12) and KD group 3 (>=5 y, n = 51) according to time interval between KD onset to when patients received test. Control groups were matched by age, sex, and body mass index. Max-Z of CA was defined as the maximal Z-score of the proximal LCA or RCA by Dalliarre equation or Fuse calculator.All routine parameters measured during standard exercise test were similar between KD and control groups, except that peak rate pressure products (PRPPs) in KD group 1 to 3 were all lower than corresponding control groups significantly (P = 0.010, 0.020, and 0.049, respectively). PRPPs correlated with Max-Z of CA by both equations modest inversely (by Dallaire, P = 0.017, Spearman rho = -0.301; by Fuse, P = 0.014, Spearman rho = -0.309).Our study recruited larger number of KD patients and provided a newer data of EC of KD patients. Our finding suggests that after acute stage of KD, patients could maintain normal cardiorespiratory fitness. Therefore, we believe that it is important to promote cardiovascular health to KD patients and KD patients should exercise as normal peers. However, since KD patients might still have compromised coronary perfusion during exercise, it remains crucial to assess and monitor cardiovascular risk of KD patients. Max-Z of CA correlates with PRPP modest inversely and might be used as a follow-up indicator of CA reserve during exercise after acute stage of KD. PMID- 26765430 TI - Factors Associated With Protein-energy Malnutrition in Chronic Liver Disease: Analysis Using Indirect Calorimetry. AB - We aimed to elucidate the incidence of protein-energy malnutrition (PEM) in patients with chronic liver disease and to identify factors linked to the presence of PEM.A total of 432 patients with chronic liver disease were analyzed in the current analysis. We defined patients with serum albumin level of <=3.5 g/dL and nonprotein respiratory quotient (npRQ) value using indirect calorimetry less than 0.85 as those with PEM. We compared between patients with PEM and those without PEM in baseline characteristics and examined factors linked to the presence of PEM using univariate and multivariate analyses.There are 216 patients with chronic hepatitis, 123 with Child-Pugh A, 80 with Child-Pugh B, and 13 with Child-Pugh C. Six patients (2.8%) had PEM in patients with chronic hepatitis, 17 (13.8%) in patients with Child-Pugh A, 42 (52.5%) in patients with Child-Pugh B, and 10 (76.9%) in patients with Child-Pugh C (P < 0.001). Multivariate analysis revealed that Child-Pugh classification (P < 0.001), age >=64 years (P = 0.0428), aspartate aminotransferase (AST) >=40 IU/L (P = 0.0023), and branched-chain amino acid to tyrosine ratio (BTR) <=5.2 (P = 0.0328) were independent predictors linked to the presence of PEM. On the basis of numbers of above risk factors (age, AST, and BTR), the proportions of patients with PEM were well stratified especially in patients with early chronic hepatitis or Child-Pugh A (n = 339, P < 0.0001), while the proportions of patients with PEM tended to be well stratified in patients with Child-Pugh B or C (n = 93, P = 0.0673).Age, AST, and BTR can be useful markers for identifying PEM especially in patients with early stage of chronic liver disease. PMID- 26765433 TI - Smoking and Glioma Risk: Evidence From a Meta-Analysis of 25 Observational Studies. AB - To systematically assess the relationship between smoking and glioma risk.A dose response meta-analysis of case-control and cohort studies was performed. Pertinent studies were identified by searching database and reference lists. Random-effects model was employed to pool the estimates of the relative risks (RRs) with corresponding 95% confidence intervals (CIs).A total of 19 case control and 6 cohort studies were included. Overall, compared with those who never smoked, the pooled RR and 95% CI was 0.98 (0.92-1.05) for ever smoker. The subgroups were not significantly different regarding risk of glioma except the group of age at start smoking (RR = 1.17, 95% CI: 0.93-1.48 for age < 20; RR = 1.25, 95% CI: 1.02-1.52 for age >= 20). Dose-response analysis also suggested no significant association between smoking and the risk of glioma, although some evidence for a linear relationship between smoking and glioma risk was observed.In conclusion, this meta-analysis provides little support for a causal relationship between smoking and risk of glioma. PMID- 26765432 TI - Clinicopathologic Features and Clinical Outcomes of Esophageal Gastrointestinal Stromal Tumor: Evaluation of a Pooled Case Series. AB - Clinicopathologic features and clinical outcomes of gastrointestinal stromal tumors (GISTs) in esophagus are limited, because of the relatively rare incidence of esophageal GISTs. Therefore, the aim of the current study was to investigate the clinicopathologic features and clinical outcomes of esophageal GISTs, and to investigate the potential factors that may predict prognosis.Esophageal GIST cases were obtained from our center and from case reports and clinical studies extracted from MEDLINE. Clinicopathologic features and survivals were analyzed and compared with gastric GISTs from our center.The most common location was lower esophagus (86.84%), followed by middle and upper esophagus (11.40% and 1.76%). The majority of esophageal GISTs were classified as high-risk category (70.83%). Mitotic index was correlated with histologic type, mutational status, and tumor size. The 5-year disease-free survival and disease-specific survival were 65.1% and 65.9%, respectively. Tumor size, mitotic index, and National Institutes of Health risk classification were associated with prognosis of esophageal GISTs. Only tumor size, however, was the independent risk factor for the prognosis of esophageal GISTs. In comparison to gastric GISTs, the distribution of tumor size, histologic type, and National Institutes of Health risk classification were significantly different between esophageal GISTs and gastric GISTs. The disease-free survival and disease-specific survival of esophageal GISTs were significantly lower than that of gastric GISTs.The most common location for esophageal GISTs was lower esophagus, and most of the esophageal GISTs are high-risk category. Tumor size was the independent risk factor for the prognosis of esophageal GISTs. Esophageal GISTs differ significantly from gastric GISTs in respect to clinicopathologic features. The prognosis of esophageal GISTs was worse than that of gastric GISTs. PMID- 26765434 TI - Bidirectional Relationship Between Diabetes and Acute Pancreatitis: A Population Based Cohort Study in Taiwan. AB - The proposed bidirectional relationship between acute pancreatitis (AP) and diabetes has never been examined with the same source of data. Furthermore, the effects of disease severity on this relationship have not been fully evaluated. The present study employed the findings from a single database to measure the strength of the association between AP and diabetes.Findings from 1 million National Health Insurance beneficiaries were utilized. Two cohort studies with this database were selected to evaluate the linkage between diabetes and AP. The first cohort analysis addressed the risk of AP among diabetic patients and was comprised of 42,080 diabetic patients and 672,146 unexposed subjects. The second cohort analysis considered the risk of diabetes among patients with AP and enrolled 3187 patients with AP and 709259 unexposed subjects. All adult beneficiaries were followed from January 1, 2005 to December 31, 2012 to identify outcomes of interest. Cox regression models were applied to compare hazards adjusted for potential confounders.For the first cohort, the adjusted hazard ratio (HR) of AP was significantly increased by the presence of diabetes (1.72; 95% confidence interval [CI], 1.52-1.96). In diabetic patients with a history of hyperglycemic crisis episodes (HCEs), the HR was even higher (6.32; 95% CI, 4.54 8.81). For the second cohort, the adjusted HR of diabetes in patients with AP was increased compared to the general population (2.15; 95% CI, 1.92-2.41). For patients with severe AP, the HR was also higher (2.22; 95% CI, 1.50-3.29) but did not differ significantly from that for patients with nonsevere AP.The 2 cohort studies provided evidence for the bidirectional relationship between diabetes and AP. Moreover, diabetic patients with history of HCEs may be associated with higher risk of AP. PMID- 26765435 TI - A Case of Solitary Kidney Atrophy Due to Primary Hyperparathyroidism: A Case Report. AB - Although primary hyperparathyroidism (PHPT) is asymptomatic in most patients, its main clinical manifestation is nephrolithiasis. In general, hypercalcemia would lead to unilateral renal stones, which may become bilateral over time. We present a rare case of a large unilateral asymptomatic ureteral stone in a patient with hypercalcemia secondary to PHPT, which eventually led to renal atrophy.The diagnosis of PHPT should be considered in patients with hypercalcemia and renal stones, as asymptomatic PHPT may result in a devastating renal outcome. PMID- 26765436 TI - Appraising MicroRNA-155 as a Noninvasive Diagnostic Biomarker for Cancer Detection: A Meta-Analysis. AB - Cancer has been a major public health issue all over the world and cancer patients diagnosed at early stages have a comparatively favorable prognosis. The association between specific dysregulated expressed microRNA-155 (miRNA-155, miR 155) and tumorigenesis has been identified by numerous studies. However, perplexity and inconsistence arise from a wide range of studies due to heterogeneity. Therefore, this meta-analysis was carried out to validate the association between miR-155 and tumorigenesis together with the clinical applicability of miR-155.Relevant studies were searched, identified, and selected from PubMed, Embase, Cochrane, Sinomed, and Wanfang database until July 5, 2015. Then, the sensitivity, specificity, and area under the summary receiver operator characteristic curve (AUC) were calculated to assess the overall performance miR 155 for cancer detection.A total of 25 studies were included in the meta-analysis with a total number of 1896 cancer patients and 1226 healthy controls. The overall sensitivity and specificity was 76.8% (95%CI: 71.1-81.7%) and 82.9% (95% CI: 77.5-87.3%), respectively. In addition, the pooled AUC and partial AUC was 0.867 and 0.718, respectively. Results from subgroup analyses suggested that the diagnostic accuracy of miR-155 in the Caucasian group was significantly higher than that in the Asian group. Similarly, serum sample type may provide better diagnostic value of miR-155 than plasma. Apart from that, miR-155 in breast cancer achieved the highest accuracy compared with miR-155 in other types of cancer.Results from meta-analysis suggested that miR-155 had great potential as a novel noninvasive biomarker for human cancer detection, particularly when breast cancer or Caucasian is involved. However, well-designed cohort or case control studies with large sample size should be implemented to confirm the diagnostic value of miR-155. PMID- 26765437 TI - Long-term Survival of Patients With Invasive Ultra-thin Cutaneous Melanoma: A Single-center Retrospective Analysis. AB - The incidence of cutaneous melanoma is increasing worldwide, especially for thin melanoma (Breslow <=1 mm). Thin cutaneous melanoma has a favorable prognosis but there are few data about the prognosis of patients with ultra-thin cutaneous melanoma (Breslow <= 0.5 mm). Our aim was to investigate the disease-free survival among patients with invasive cutaneous melanoma with Breslow <= 0.5 mm after 10 years from the initial diagnosis.A retrospective review of 240 cutaneous melanoma patients with Breslow <= 0.5 mm was performed. Recurrence, death from cutaneous melanoma, and disease-free survival were all identified.In the whole group of patients, we observed only 2 deaths from cutaneous melanoma. Median follow-up was 13, 11 years. Among all 240 patients, 221 were alive and disease free, 2 died of cutaneous melanoma, 11 died of other non-neoplastic diseases, 5 died of other neoplastic diseases different from melanoma, and 1 patient had a local recurrence; therefore the 10-year melanoma survival rate was 99.6%.Our data indicate that death from cutaneous melanoma in the group of patients with Breslow <=0.5 mm was a very rare event and that diagnosis at this stage dramatically decreases the risk of developing metastatic tumors to a <0.5% also after a 10 year period of follow-up. Limitation of the study includes the fact that other risk factors for melanoma, notably ulceration, and mitotic rate, were not evaluated. PMID- 26765438 TI - Changes in Noninvasive Liver Fibrosis Indices and Spleen Size During Chemotherapy: Potential Markers for Oxaliplatin-Induced Sinusoidal Obstruction Syndrome. AB - Oxaliplatin-based regimens are standard treatments for the patients with colorectal cancer (CRC) and advanced gastric cancer (AGC). However, owing to hepatic sinusoidal obstruction syndrome (SOS), the use of oxaliplatin sometimes results in splenomegaly. The aim of the present study was to evaluate the correlation between chemotherapy-associated changes of noninvasive liver fibrosis indices and volumetric changes of the spleen.From February 2004 to April 2014, patients with CRC or AGC receiving oxaliplatin-based chemotherapy were studied. The possibility of SOS development was evaluated before and after the oxaliplatin exposure with splenic volume index (SVI). Four different noninvasive liver fibrosis indices were used for risk analysis, namely age-platelet index (API), AST-to-platelet ratio index (APRI), platelet-to-spleen ratio (PSR), and fibrosis 4 score (FIB-4).A total of 275 patients were eligible for evaluation: 200 patients had CRC and 75 patients had AGC. Using the cutoff of SVI increase >= 0.3, 113 patients (41.1%) were positive for splenomegaly. The changes of indices significantly correlated with SVI increase. Adjusted odds ratios for those indices were as follows: API = 1.16 (95% confidential interval [CI], 1.01-1.32; P = .03); APRI = 2.45 (95% CI, 1.30-4.63; P = .01); PSR = 0.69 (95% CI, 0.59-0.80; P < .01); and FIB-4 = 1.37 (95% CI, 1.16-1.63; P < .01). Optimal cutoff values with statistical significance were calculated and suggested.The changes of noninvasive liver fibrosis indices showed a good correlation with the increase in the spleen volume during oxaliplatin-based chemotherapy. Validation of these indices for monitoring of oxaliplatin-induced hepatic SOS is warranted. PMID- 26765439 TI - A New Surgical Procedure "Dumbbell-Form Resection" for Selected Hilar Cholangiocarcinomas With Severe Jaundice: Comparison With Hemihepatectomy. AB - The aim of the study is to evaluate the therapeutic effect of a new surgical procedure, dumbbell-form resection (DFR), for hilar cholangiocarcinoma (HCCA) with severe jaundice. In DFR, liver segments I, IVb, and partial V above the right hepatic pedicle are resected.Hemihepatectomy is recognized as the preferred procedure; however, its application is limited in HCCAs with severe jaundice.Thirty-eight HCCA patients with severe jaundice receiving DFR and 70 receiving hemihepatectomy from January 2008 to January 2013 were included. Perioperative parameters, operation-related morbidity and mortality, and post operative survival were analyzed.A total of 21.1% patients (8/38) in the DFR group received percutaneous transhepatic biliary drainage (PTBD), which was significantly <81.4% (57/70) in the hemihepatectomy group. The TBIL was higher in the DFR group at operation (243.7 vs 125.6 MUmol/L, respectively). The remnant liver volume was significantly higher after DFR. The operation-related morbidity was significantly lower after DFR than after hemihepatectomy (26.3% vs 48.6%, respectively). None of the patients died during the perioperative period after DFR, whereas 3 died after hemihepatectomy. There was no difference in margin status, histological grade, lymph-node involvement, and distant metastasis between the 2 groups. The 1-, 3-, and 5-year survival rates after DFR (68.4%, 32.1%, and 21.4%, respectively) showed no significant difference with those after hemihepatectomy (62.7%, 34.6%, and 23.3%, respectively). Kaplan-Meier analysis indicated that overall survival and recurrence after DFR demonstrated no significant difference compared with hemihepatectomy.DFR appears to be feasible for selected HCCA patients with severe jaundice. However, its indications should be restricted. PMID- 26765440 TI - Strategies to Make Ramadan Fasting Safer in Type 2 Diabetics: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials and Observational Studies. AB - Ramadan is the holy month for Muslims whereby they fast from predawn to after sunset and is observed by all healthy Muslim adults as well as a large population of type 2 diabetic Muslims.To determine the comparative effectiveness of various strategies that have been used for type 2 diabetic Muslim who fast during Ramadan.A systematic review and network meta-analysis of randomized controlled studies (RCT) as well as observational studies for patients with type 2 diabetes who fasted during Ramadan was conducted. Eight databases were searched from January 1980 through October 2015 for relevant studies. Two reviewers independently screened and assessed study for eligibility, assessed the risk of bias, and extracted relevant data. A network meta-analysis for each outcome was fitted separately, combining direct and indirect evidence for each comparison.Twenty-nine studies, 16 RCTs and 13 observational studies each met the inclusion criteria. The most common strategy used was drug changes during the Ramadan period, which found that the use of DPP-4 (Dipeptidyl peptidase inhibitor -4) inhibitors were associated with a reduction in incidence of experiencing hypoglycemia during Ramadan in both RCTs (pooled relative risk: 0.56; 95% confidence interval: 0.44-0.72) as well as in observational studies (pooled relative risk: 0.27; 0.09-0.75). Ramadan-focused education was shown to be beneficial in reducing hypoglycemia in observational studies but not RCTs (0.25 versus 1.00). Network meta-analyses suggest that incretin mimetics can reduce the risk of hypoglycemia by nearly 1.5 times.The newer antidiabetic agents appear to lower the risk of hypoglycemia and improved glycemic control when compared with sulfonylureas. Ramadan-focused education shows to be a promising strategy but more rigorous examination from RCTs are required. PMID- 26765442 TI - Thin-Section CT Characteristics and Longitudinal CT Follow-up of Chemotherapy Induced Interstitial Pneumonitis: A Retrospective Cohort Study. AB - To describe the computed tomography (CT) features of chemotherapy-induced interstitial pneumonitis (CIIP) with longitudinal follow-up.The study was approved by the local ethics committee. One hundred consecutive patients with CIIP between May 2005 and March 2015 were retrospectively enrolled. The initial CT was reviewed by 2 independent chest radiologists and categorized into 1 of 4 CT patterns in accordance with the 2013 guidelines for idiopathic interstitial pneumonia: nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), hypersensitivity pneumonitis (HP) mimicking desquamative interstitial pneumonitis, and diffuse alveolar damage (DAD). We assessed semiquantitative analysis on a 5% scale to assess the extent of parenchymal abnormalities (emphysema, reticulation, ground-glass opacity, consolidation, honeycombing cyst) and their distribution on initial (n = 100), subsequent (n = 87), and second follow-up CT (n = 48). Interval changes in extent on follow-up CT were compared using paired t test. The clinic-radiologic factors were compared between Group 1 (NSIP and OP patterns) and Group 2 (HP and DAD patterns) using chi and independent t tests.The most common pattern of CIIP on the initial CT was HP (51%), followed by NSIP (23%), OP (20%), and DAD (6%). Diffuse ground-glass opacity was the most common pulmonary abnormality. The predominant distribution was bilateral (99%) and symmetric (82%), with no craniocaudal (60%) or axial (79%) dominance. Subsequent and second follow-up CTs showed decreased extent of total pulmonary abnormalities (P < 0.001, respectively). In comparison with Group 1 CIIP, Group 2 CIIP was more likely to be caused by molecularly targeted drugs (P = 0.030), appeared earlier (P = 0.034), and underwent more complete resolution (P < 0.001). Use of a CT pattern-recognition approach to CIIP is appropriate and practical in interpreting radiological findings. PMID- 26765441 TI - Corona Enhancement and Mosaic Architecture for Prognosis and Selection Between of Liver Resection Versus Transcatheter Arterial Chemoembolization in Single Hepatocellular Carcinomas >5 cm Without Extrahepatic Metastases: An Imaging-Based Retrospective Study. AB - Corona enhancement and mosaic architecture are 2 radiologic features of hepatocellular carcinoma (HCC). However, neither their prognostic values nor their impacts on the selection of liver resection (LR) versus transcatheter arterial chemoembolization (TACE) as treatment modalities have been established.We retrospectively analyzed 275 patients with a single HCC lesion >5 cm without extrahepatic metastasis treated with LR or TACE. In LR patients, the overall survival (OS) and time to progression (TTP) were compared between corona enhancement negative (corona-) versus positive (corona+) and mosaic architecture negative (mosaic-) versus positive (mosaic+) patients. Furthermore, by the combination of corona and mosaic, LR patients were divided into negative for both corona and mosaic patterns (LR-/-), positive for only 1 feature (LR+/-), and positive for both (LR+/+); their OS and TTP were compared to those of the TACE group. Cox regression was performed to identify independent factors for OS.In the survival plots for LR, corona- had better OS and TTP than corona+, and mosaic- had better OS than mosaic+. There was no significant difference in TTP between the subgroups. On Cox regression analysis, corona enhancement, but not mosaic architecture, was a significant factor for OS, whereas neither were a significant factor for TTP. In TACE patients, neither corona nor mosaic patterns had significant correlations with OS or TTP. In the whole population, LR-/ and LR+/- subgroups had similar OS, which was better than the LR+/+ and TACE groups. Moreover, LR-/- and LR+/- patients had better TTP than TACE patients, but there were no differences between the LR-/- versus LR+/-, LR-/ versus LR+/+, LR+/- versus LR+/+, and LR+/+ versus TACE groups. On Cox regression analysis, the presence of corona/mosaic patterns was an independent prognostic factor for OS.Our results showed that, for patients with a single HCC >5 cm without extrahepatic metastasis, corona and mosaic patterns are indicators of limited LR efficacy. When both of the features are present, TACE can be used instead of LR with no negative influence on survival. PMID- 26765443 TI - Risk of Nongenitourinary Cancers in Patients With Spinal Cord Injury: A Population-based Cohort Study. AB - Little information is available regarding the risk of nongenitourinary (GU) cancers in patients with spinal cord injury (SCI). The authors conducted a nationwide population-based study to investigate whether a higher risk of non-GU cancer is seen among patients with SCI.Data retrieved from the National Health Insurance Research Database of Taiwan were used in this study. A total of 41,900 patients diagnosed with SCI between 2000 and 2011 were identified from the National Health Insurance Research Database and comprised the SCI cohort. Each of these patients was randomly frequency matched with 4 people from the general population (without SCI) according to age, sex, comorbidities, and index year. Cox proportional hazards regression analysis was used to calculate adjusted hazard ratios and 95% confidence intervals and determine how SCI affected non-GU cancer risk.No significant difference in overall non-GU cancer risk was observed between the SCI and control groups. The patients with SCI exhibited a significantly higher risk of developing esophageal, liver, and hematologic malignancies compared with those without SCI. By contrast, the SCI cohort had a significantly lower risk of colorectal cancer compared with the non-SCI cohort (adjusted hazard ratio = 0.80, 95% confidence interval = 0.69-0.93). Additional stratified analyses by sex, age, and follow-up duration revealed various correlations between SCI and non-GU cancer risk.The patients with SCI exhibited higher risk of esophageal, liver, and hematologic malignancies but a lower risk of colorectal cancer compared with those without SCI. The diverse patterns of cancer risk among the patients with SCI may be related to the complications of chronic SCI. PMID- 26765444 TI - Assessment of the Possible Association of Air Pollutants PM10, O3, NO2 With an Increase in Cardiovascular, Respiratory, and Diabetes Mortality in Panama City: A 2003 to 2013 Data Analysis. AB - In recent years, Panama has experienced a marked economic growth, and this, in turn, has been associated with rapid urban development and degradation of air quality. This study is the first evaluation done in Panama on the association between air pollution and mortality. Our objective was to assess the possible association between monthly levels of PM10, O3, and NO2, and cardiovascular, respiratory, and diabetes mortality, as well as the seasonal variation of mortality in Panama City, Panama.The study was conducted in Panama City, using air pollution data from January 2003 to December 2013. We utilized a Poisson regression model based on generalized linear models, to evaluate the association between PM10, NO2, and O3 exposure and mortality from diabetes, cardiovascular, and respiratory diseases. The sample size for PM10, NO2, and O2 was 132, 132, and 108 monthly averages, respectively.We found that levels of PM10, O3, and NO2 were associated with increases in cardiovascular, respiratory, and diabetes mortality. For PM10 levels >= 40 MUg/m3, we found an increase in cardiovascular mortality of 9.7% (CI 5.8-13.6%), and an increase of 12.6% (CI 0.2-24.2%) in respiratory mortality. For O3 levels >= 20 MUg/m3 we found an increase of 32.4% (IC 14.6 52.9) in respiratory mortality, after a 2-month lag period following exposure in the 65 to <74 year-old age group. For NO2 levels >=20 MUg/m3 we found an increase in respiratory mortality of 11.2% (IC 1.9-21.3), after a 2-month lag period following exposure among those aged between 65 and <74 years.There could be an association between the air pollution in Panama City and an increase in cardiovascular, respiratory, and diabetes mortality. This study confirms the urgent need to improve the measurement frequency of air pollutants in Panama. PMID- 26765445 TI - Association Between Single Nucleotide Polymorphisms in DNA Polymerase Kappa Gene and Breast Cancer Risk in Chinese Han Population: A STROBE-Compliant Observational Study. AB - DNA polymerases are responsible for ensuring stability of the genome and avoiding genotoxicity caused by a variety of factors during DNA replication. Consequently, these proteins have been associated with an increased cancer risk. DNA polymerase kappa (POLK) is a specialized DNA polymerase involved in translesion DNA synthesis (TLS) that allows DNA synthesis over the damaged DNA. Recently, some studies investigated relationships between POLK polymorphisms and cancer risk, but the role of POLK genetic variants in breast cancer (BC) remains to be defined. In this study, we aimed to evaluate the effects of POLK polymorphisms on BC risk.We used the Sequenom MassARRAY method to genotype 3 single nucleotide polymorphisms (SNPs) in POLK (rs3213801, rs10077427, and rs5744533), in order to determine the genotypes of 560 BC patients and 583 controls. The association of genotypes and BC was assessed by computing the odds ratio (OR) and 95% confidence intervals (95% CIs) from logistic regression analyses.We found a statistically significant difference between patient and control groups in the POLK rs10077427 genotypic groups, excluding the recessive model. A positive correlation was also found between positive progesterone receptor (PR) status, higher Ki67 index, and rs10077427 polymorphism. For rs5744533 polymorphism, the codominant, dominant, and allele models frequencies were significantly higher in BC patients compared to healthy controls. Furthermore, our results indicated that rs5744533 SNP has a protective role in the postmenopausal women. However, we failed to find any associations between rs3213801 polymorphism and susceptibility to BC.Our results indicate that POLK polymorphisms may influence the risk of developing BC, and, because of this, may serve as a prognostic biomarker among Chinese women. PMID- 26765446 TI - Body Mass Index Trajectories and Healthcare Utilization in Young and Middle-aged Adults. AB - The obesity epidemic is a significant public health issue with adverse impact on health and costs. Applying a life-course perspective to obesity may advance our understanding of the influence of obesity over time on patterns of healthcare utilization in young and middle-aged United States (US) adults.We identified baseline body mass index (BMI) and BMI trajectories, and assessed their association with outpatient visits, emergency department (ED) visits, and hospitalizations in a well-defined population of young and middle-aged US adults.Using the Rochester Epidemiology Project resources, we conducted a retrospective cohort study of adults (N = 23,254) aged 18 to 44 years, with at least 3 BMI measurements, residing in Olmsted County, MN from January 1, 2005 through December 31, 2012.We observed that 27.5% of the population was obese. Four BMI trajectories were identified. Compared to under/normal weight, obese class III adults had higher risk of outpatient visits (adjusted rate ratio [RR], 1.86; 95% confidence intervals [CIs], 1.67-2,08), ED visits (adjusted RR, 3.02; 95% CI, 2.74-3.34), and hospitalizations (adjusted RR, 1.67; 95% CI, 1.59-1.75). BMI trajectory was positively associated with ED visits after adjustment for age, sex, race, and Charlson Comorbidity Index (P < 0.001 for trend).Among young and middle-aged US adults, baseline BMI is positively associated with outpatient visits, ED visits, and hospitalizations, while BMI trajectory is positively associated with ED visits. These findings extend our understanding of the longitudinal influence of obesity on healthcare utilization in early to mid adulthood. PMID- 26765447 TI - Systematic Literature Review of AbobotulinumtoxinA in Clinical Trials for Lower Limb Spasticity. AB - To elucidate clinical trial efficacy, safety, and dosing practices of AbobotulinumtoxinA (ABO) treatment in adult patients with lower limb spasticity.A systematic literature review was performed to identify randomized controlled trials of ABO in the treatment of adult lower limb spasticity.Of the 295 records identified, 6 primary publications evaluated ABO for the management of lower limb spasticity of various etiologies and were evaluated. Total ABO doses ranged between 500 and 2000 U for lower limb spasticity, depending on the muscles injected. All studies in lower limb spasticity showed statistically significant reduction in muscle tone based on Modified Ashworth Scale of ABO versus placebo. Significant effects on active movement and pain were demonstrated albeit less consistently. ABO was generally well tolerated across the individual studies; most adverse events reported were considered unrelated to treatment. Treatment related adverse events included but not limited to fatigue, local pain at injection site, hypertonia, dry mouth, weakness of the noninjected muscle, abnormal gait, and urinary tract infection.These data from 6 randomized clinical studies provide the beginnings of an evidence base for the use of ABO to reduce lower limb spasticity. Ongoing studies in this area will add to this evidence base. PMID- 26765448 TI - Comparison of Isocentric C-Arm 3-Dimensional Navigation and Conventional Fluoroscopy for Percutaneous Retrograde Screwing for Anterior Column Fracture of Acetabulum: An Observational Study. AB - Percutaneous screw insertion for minimally displaced or reducible acetabular fracture using x-ray fluoroscopy and computer-assisted navigation system has been advocated by some authors. The purpose of this study was to compare intraoperative conditions and clinical results between isocentric C-arm 3 dimensional (Iso-C 3D) fluoroscopy and conventional fluoroscopy for percutaneous retrograde screwing of acetabular anterior column fracture.A prospective cohort study was conducted. A total of 22 patients were assigned to 2 different groups: 10 patients in the Iso-C 3D navigation group and 12 patients in the conventional group. The operative time, fluoroscopic time, time of screw insertion, blood loss, and accuracy were analyzed between the 2 groups.There were significant differences in operative time, screw insertion time, fluoroscopy time, and mean blood loss between the 2 groups. Totally 2 of 12 (16.7%) screws were misplaced in the conventional fluoroscopy group, and all 10 screws were in safe zones in the navigation group. Percutaneous screw fixation using the Iso-C 3D computer assisted navigation system significantly reduced the intraoperative fluoroscopy time and blood loss in percutaneous screwing for acetabular anterior column fracture.The Iso-C 3D computer-assisted navigation system provided a reliable and effective method for percutaneous screw insertion in acetabular anterior column fractures compared to conventional fluoroscopy. PMID- 26765449 TI - The Neural Baroreflex Pathway in Subjects With Metabolic Syndrome: A Sub-Study of the Paris Prospective Study III. AB - The mechanisms that link metabolic syndrome (MetS) to increased cardiovascular risk are incompletely understood. We examined whether MetS is associated with the neural baroreflex pathway (NBP) and whether any such associations are independent of blood pressure values.This study involved the cross-sectional analysis of data on 2835 subjects aged 50 to 75 years from the Paris Prospective Study 3. The prevalence of MetS was defined according to the American Heart Association/National Heart Blood and Lung Institute definition. NBP values were calculated from the fluctuation of the common carotid distension rate and heart rate using fast Fourier transformation and cross-spectral analysis.The prevalence of MetS was 20.1% in men and 10.4% in women. Compared with controls, subjects with MetS (>=3 components), and those at risk for MetS (1-2 components) had lower NBP (-5.3% and -2.3%, respectively) and higher carotid stiffness (+13.5% and +6.8%, respectively). The negative association between MetS components and NBP was confirmed, even after adjustment for age, sex, and carotid stiffness. After stratification for blood pressure (BP) levels, NBP was reduced only in MetS subjects and those at risk with high BP. The NBP was positively associated with carotid stiffness in controls and subjects at risk for MetS. This association was lost in subjects with MetS, regardless of BP levels.Subjects with MetS had reduced NBP values. The role of BP is fundamental in the reduction of NBP. The mechanisms that link carotid stiffness and NBP are inactive in subjects with MetS, independent of BP levels. PMID- 26765451 TI - Characterizing Decision-Analysis Performances of Risk Prediction Models Using ADAPT Curves. AB - The area under the receiver operating characteristic curve is a widely used index to characterize the performance of diagnostic tests and prediction models. However, the index does not explicitly acknowledge the utilities of risk predictions. Moreover, for most clinical settings, what counts is whether a prediction model can guide therapeutic decisions in a way that improves patient outcomes, rather than to simply update probabilities.Based on decision theory, the authors propose an alternative index, the "average deviation about the probability threshold" (ADAPT).An ADAPT curve (a plot of ADAPT value against the probability threshold) neatly characterizes the decision-analysis performances of a risk prediction model.Several prediction models can be compared for their ADAPT values at a chosen probability threshold, for a range of plausible threshold values, or for the whole ADAPT curves. This should greatly facilitate the selection of diagnostic tests and prediction models. PMID- 26765450 TI - Personalized Estimate of Chemotherapy-Induced Nausea and Vomiting: Development and External Validation of a Nomogram in Cancer Patients Receiving Highly/Moderately Emetogenic Chemotherapy. AB - Chemotherapy-induced nausea and vomiting (CINV) is presented in over 30% of cancer patients receiving highly/moderately emetogenic chemotherapy (HEC/MEC). The currently recommended antiemetic therapy is merely based on the emetogenic level of chemotherapy, regardless of patient's individual risk factors. It is, therefore, critical to develop an approach for personalized management of CINV in the era of precision medicine.A number of variables were involved in the development of CINV. In the present study, we pooled the data from 2 multi institutional investigations of CINV due to HEC/MEC treatment in Asian countries. Demographic and clinical variables of 881 patients were prospectively collected as defined previously, and 862 of them had full documentation of variables of interest. The data of 548 patients from Chinese institutions were used to identify variables associated with CINV using multivariate logistic regression model, and then construct a personalized prediction model of nomogram; while the remaining 314 patients out of China (Singapore, South Korea, and Taiwan) entered the external validation set. C-index was used to measure the discrimination ability of the model.The predictors in the final model included sex, age, alcohol consumption, history of vomiting pregnancy, history of motion sickness, body surface area, emetogenicity of chemotherapy, and antiemetic regimens. The C-index was 0.67 (95% CI, 0.62-0.72) for the training set and 0.65 (95% CI, 0.58-0.72) for the validation set. The C-index was higher than that of any single predictor, including the emetogenic level of chemotherapy according to current antiemetic guidelines. Calibration curves showed good agreement between prediction and actual occurrence of CINV.This easy-to-use prediction model was based on chemotherapeutic regimens as well as patient's individual risk factors. The prediction accuracy of CINV occurrence in this nomogram was well validated by an independent data set. It could facilitate the assessment of individual risk, and thus improve the personalized management of CINV. PMID- 26765452 TI - The Outcomes and Prognostic Factors of the Very Elderly Requiring Prolonged Mechanical Ventilation in a Single Respiratory Care Center. AB - This study investigated the outcomes and the prognostic factors among the very elderly (patients >=80 years old) requiring prolonged mechanical ventilation (PMV).Between 2006 and 2014, all of the very elderly patients of age 80 or more transferred to respiratory care center (RCC) of a tertiary medical center were retrospectively identified, and only patients who used mechanical ventilation (MV) for >3 weeks were included in this study.A total of 510 very elderly patients undergoing PMV were identified. The mean age of the patients was 84.3 +/ 3.3 years, and it ranged from 80 to 96 years. Male comprised most of the patients (n = 269, 52.7%), and most of the patients were transferred to RCC from medical ICU (n = 357, 70.0%). The APACHE II scores on RCC admission was 17.6 +/- 6.0. At least 1 comorbidity was found in 419 (82.2%) patients. No significant differences of gender, disease severity, diagnosis, dialysis, laboratory examinations, comorbidities, and outcome were found between octogenarians (aged 80-89) and nonagenarians (aged >= 90). The overall in-hospital mortality rate was 21.8%. In the multivariate analysis, patients who had APACHE II score >= 15(odds ratio [OR], 2.30, 95% confidence interval [CI], 1.36-3.90), or albumin <= 2 g/dL (OR, 3.92, 95% CI, 2.17-7.01) were more likely to have significant in-hospital mortality (P < 0.05).The in-hospital mortality rate of the very elderly PMV patients in our RCC is 21.8%, and poor outcomes in this specific population were found to be associated with a higher APACHE II score and lower albumin level. PMID- 26765453 TI - Short-Term Medical Costs of a VHA Health Information Exchange: A CHEERS-Compliant Article. AB - The Virtual Lifetime Electronic Record (VLER) Health program provides the Veterans Health Administration (VHA) a framework whereby VHA providers can access the veterans' electronic health record information to coordinate healthcare across multiple sites of care. As an early adopter of VLER, the Indianapolis VHA and Regenstrief Institute implemented a regional demonstration program involving bi-directional health information exchange (HIE) between VHA and non-VHA providers.The aim of the study is to determine whether implementation of VLER HIE reduces 1 year VHA medical costs.A cohort evaluation with a concurrent control group compared VHA healthcare costs using propensity score adjustment. A CHEERs compliant checklist was used to conduct the cost evaluation.Patients were enrolled in the VLER program onsite at the Indianapolis VHA in outpatient clinics or through the release-of-information office.VHA cost data (in 2014 dollars) were obtained for both enrolled and nonenrolled (control) patients for 1 year prior to, and 1 year after, the index date of patient enrollment.There were 6104 patients enrolled in VLER and 45,700 patients in the control group. The annual adjusted total cost difference per patient was associated with a higher cost for VLER enrollees $1152 (95% CI: $807-1433) (P < 0.01) (in 2014 dollars) than VLER nonenrollees.Short-term evaluation of this demonstration project did not show immediate reductions in healthcare cost as might be expected if HIE decreased redundant medical tests and treatments. Cost reductions from shared health information may be realized with longer time horizons. PMID- 26765454 TI - Effects of Hypothermic Cardiopulmonary Bypass on Internal Jugular Bulb Venous Oxygen Saturation, Cerebral Oxygen Saturation, and Bispectral Index in Pediatric Patients Undergoing Cardiac Surgery: A Prospective Study. AB - The objective of this study was to evaluate the effect of hypothermic cardiopulmonary bypass (CPB) on cerebral oxygen saturation (rSO2), internal jugular bulb venous oxygen saturation (SjvO2), mixed venous oxygen saturation (SvO2), and bispectral index (BIS) used to monitor cerebral oxygen balance in pediatric patients.Sixty American Society of Anesthesiologists Class II-III patients aged 1 to 4 years old with congenital heart disease scheduled for elective cardiac surgery were included in this study. Temperature, BIS, rSO2, mean arterial pressure, central venous pressure, cerebral perfusion pressure (CPP), and hematocrit were recorded. Internal jugular bulb venous oxygen saturation and SvO2 were obtained from blood gas analysis at the time points: after induction of anesthesia (T0), beginning of CPB (T1), ascending aortic occlusion (T2), 20 minutes after initiating CPB (T3), coronary reperfusion (T4), separation from CPB (T5), and at the end of operation (T6). The effect of hypothermia or changes in CPP on rSO2, SjvO2, SvO2, and BIS were analyzed.Compared with postinduction baseline values, rSO2 significantly decreased at all-time points: onset of extracorporeal circulation, ascending aortic occlusion, 20 minutes after CPB initiation, coronary reperfusion, and separation from CPB (P < 0.05). Compared with measurements made following induction of anesthesia, SjvO2 significantly increased with initiation of CPB, ascending aortic occlusion, 20 minutes after initiating CPB, coronary reperfusion, and separation from CPB (P < 0.05). Compared with induction of anesthesia, BIS significantly decreased with the onset of CPB, aortic cross clamping, 20 minutes after initiating CPB, and coronary reperfusion (P < 0.05). Bispectral index increased following separation from CPB. There was no significant change in SvO2 during cardiopulmonary bypass (P > 0.05). Correlation analysis demonstrated that rSO2 was positively related to CPP (r = 0.687, P = 0.000), with a low linear correlation to temperature (r = 0.453, P = 0.000). Internal jugular bulb venous oxygen saturation was negatively related to temperature (r = -0.689, P = 0.000). Bispectral index was positively related to both temperature (r = 0.824, P = 0.000) and CPP (r = 0.782, P = 0.000). Cerebral oxygen saturation had a positive linear correlation with CPP and a low linear correlation to temperature. Internal jugular bulb venous oxygen saturation had a negative linear correlation to temperature.Pre-and and early postbypass periods are vulnerable times for adequate cerebral oxygenation. Anesthetic management must aim to optimize the supply and demand relationship. PMID- 26765455 TI - Recovery of Hypersomnia Concurrent With Recovery of an Injured Ascending Reticular Activating System in a Stroke Patient: A Case Report. AB - We report on a stroke patient who showed recovery of hypersomnia concurrent with the recovery of an injured ascending reticular activating system (ARAS), which was demonstrated by diffusion tensor tractography (DTT).A 70-year-old female patient underwent coiling of the left ruptured posterior communicating artery after subarachnoid hemorrhage and both extraventricular drainage for management of an intraventricular hemorrhage. At 2 months after onset, when she started rehabilitation, she exhibited intact consciousness, with the full score on the Glasgow Coma Scale: 15. However, she showed severe hypersomnia: she always fell asleep without external stimulation and the Epworth Sleepiness Scale (EPS) score was 24 (full score: 24, cut off for hypersomnia: 10). She underwent comprehensive rehabilitative therapy, including neurotropic drugs, physical therapy, and occupational therapy. Her hypersomnia has shown improvement as 14 (3 months after onset), 11 (4 months after onset), 7 (12 months after onset), and 6 (24 months after onset), respectively.On 2-month DTT, narrowing of both lower dorsal and ventral ARASs was observed on both sides: in particular, among 4 neural tracts of the lower ARAS, the right lower ventral ARAS was the narrowest. By contrast, on 24-month DTT, the 4 narrowed neural tracts of both lower dorsal and ventral ARASs were thickened compared with those of 2-month DTT.Recovery of hypersomnia with recovery of an injured lower ARAS on DTT was observed in a stroke patient. Our results suggest that evaluation of the lower ARAS using DTT might be useful for stroke patients with hypersomnia. PMID- 26765456 TI - Comparison of Diagnostic Performance Between Visual and Quantitative Assessment of Bone Scintigraphy Results in Patients With Painful Temporomandibular Disorder. AB - This retrospective clinical study was performed to evaluate whether a visual or quantitative method is more valuable for assessing painful temporomandibular disorder (TMD) using bone scintigraphy results.In total, 230 patients (172 women and 58 men) with TMD were enrolled. All patients were questioned about their temporomandibular joint (TMJ) pain. Bone scintigraphic data were acquired in all patients, and images were analyzed by visual and quantitative methods using the TMJ-to-skull uptake ratio. The diagnostic performances of both bone scintigraphic assessment methods for painful TMD were compared.In total, 241 of 460 TMJs (52.4%) were finally diagnosed with painful TMD. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the visual analysis for diagnosing painful TMD were 62.8%, 59.6%, 58.6%, 63.8%, and 61.1%, respectively. The quantitative assessment showed the ability to diagnose painful TMD with a sensitivity of 58.8% and specificity of 69.3%. The diagnostic ability of the visual analysis for diagnosing painful TMD was not significantly different from that of the quantitative analysis.Visual bone scintigraphic analysis showed a diagnostic utility similar to that of quantitative assessment for the diagnosis of painful TMD. PMID- 26765458 TI - Risks of Adverse Events Following Coprescription of Statins and Calcium Channel Blockers: A Nationwide Population-Based Study. AB - Some statins (simvastatin, lovastatin, and atorvastatin) are metabolized by cytochrome P450s 3A4 (CYP3A4). Inhibitors of CYP3A4 including some calcium channel blockers (CCBs) might increase statin blood concentration, owing to drug drug interactions. Risk of adverse events such as acute kidney injury might occur following the coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4.This was a population-based cohort study. The study analyzed data of patients treated between 1997 and 2011, retrieved from Taiwan's National Health Insurance database. We enrolled 32,801 patients who received coprescription of statins and CCBs that inhibit CYP3A4 (amlodipine, diltiazem, felodipine nicardipine, nifedipine, and verapamil). These patients were divided into 2 groups, according to whether they had received CYP3A4-metabolized statins (lovastatin, simvastatin, and atorvastatin) or non-CYP3A4-metabolized statins (fluvastatin, rosuvastatin, and pitavastatin). These 2 groups were 1:1 matched by age, gender, and Carlson comorbidity index. All outcomes were assessed within 90 days following drug coprescription.In this study, 5857 patients received coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4. There were no differences in comorbidity or use of antihypertensive drugs between patients who received CYP3A4-metabolized statins and those who received non CYP3A4-metabolized statins. Patients who received CYP3A4-metabolized statins had significantly higher risk of acute kidney injury (adjusted odds ratio [OR] = 2.12; 95% CI = 1.35-3.35), hyperkalemia (adjusted OR = 2.94; 95% CI = 1.36-6.35), acute myocardial infarction (adjusted OR = 1.55; 95% CI = 1.16-2.07), and acute ischemic stroke (adjusted OR = 1.35; 95% CI = 1.08-1.68) than those who received non-CYP3A4-metabolized statins.This nationwide cohort study demonstrated the increased risk of adverse events following the coprescription of CYP3A4 metabolized statins and CCBs that inhibit CYP3A4. Therefore, it is important to take into account the potential adverse events while coprescribing CYP3A4 metabolized statins and CCBs that inhibit CYP3A4. PMID- 26765457 TI - Combination of White Blood Cell Count at Presentation With Molecular Response at 3 Months Better Predicts Deep Molecular Responses to Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients. AB - The aim of this study was to evaluate the impact of white blood cell (WBC) counts at presentation on the achievement of deep molecular response.A total of 362 newly diagnosed chronic-phase chronic myeloid leukemia patients (CML-CP) receiving 400 mg/day imatinib were serially monitored for a median of 36 months (range 6-115).Patients showing an optimal response at 3, 6, and 12 months as defined by the 2013 European LeukemiaNet recommendations had significantly lower WBC counts at presentation than those showing nonoptimal responses (all P < 0.0001). Among the cutoff values with a similar Youden index, 150 * 10E9/L (abbreviated WBC > 150) was selected to identify the greatest amount of patients with the potential to achieve a sustained molecular response of 4.5 (MR4.5). Regardless of whether the Sokal risk score was included, the BCR-ABL value at 3 months, WBC counts at presentation, hemoglobin levels, and sex were the common independent predictors for an MR4.5, with the former 2 presenting the highest hazard risk. Low Sokal risk scores did not independently predict the achievement of an MR4.5. Patients with concurrent WBC > 150 and BCR-ABL(IS) <= 10% had a similar incidence of 4-year MR4.5 compared with patients with concurrent WBC <= 150 and BCR-ABL(IS) > 10% and concurrent WBC > 150 and BCR-ABL(IS) > 10% (13.5% vs 13.2% vs 8.8%, P = 0.47), and all of these values were significantly lower than the values for patients with concurrent WBC <= 150 and BCR-ABL(IS) <= 10% (55.0%, all P < 0.0001). Patients with concurrent WBC <= 150 and BCR-ABL(IS) <= 10% had better 4-year event-free survival rates, progression-free survival rates, and overall survival rates compared with patients with WBC > 150 or BCR-ABL(IS) > 10%. The combination of WBC count at presentation and BCR-ABL(IS) at 3 months provides improved predictions of deep molecular response in imatinib-treated CML CP patients. Therefore, the WBC count at presentation might be used to differentiate patients at the beginning of imatinib treatment. PMID- 26765460 TI - Association of Histone Methyltransferase G9a and Overall Survival After Liver Resection of Patients With Hepatocellular Carcinoma With a Median Observation of 40 Months. AB - Approximately 50% of patients with hepatocellular carcinoma (HCC) reside in China. HCC is associated with very high mortality compared with other cancers. Although numerous factors influence the survival of patients with HCC who undergo liver resection, the role of the tumor biomarker histone methyltransferase (G9a) is unknown.We enrolled 350 patients with HCC who underwent liver resection and followed them for 40 months. Patients' clinicopathologic characteristics were acquired from medical records, and overall survival was determined using multiple methods. We conducted an immunohistochemical analysis of study G9a expression in HCC tissues. We used chi test to evaluate the significance of the relationships between G9a and other factors and Cox proportional hazards regression to estimate the hazard ratios and 95% confidence intervals.The levels of alpha-fetoprotein were significantly higher in patients with G9a-positive tumors. TNM stage, elevated alpha-fetoprotein level, and G9a overexpression were associated with worse outcomes.High expression of G9a was associated with worse outcomes, indicating that G9a may serve as a prognostic biomarker for patients with HCC who undergo surgical resection. Because of its role in cell proliferation, G9a represents a potential therapeutic target. PMID- 26765459 TI - Loss of BAP1 Expression Occurs Frequently in Intrahepatic Cholangiocarcinoma. AB - BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that functions as a tumor suppressor gene. Double hit BAP1 inactivation has been reported in a range of tumor types, including intrahepatic cholangiocarcinoma (ICC), sometimes in association with germline mutation.We performed immunohistochemistry for BAP1 on a well-characterized cohort of 211 ICC patients undergoing surgical resection with curative intent at 3 institutions based in 3 different countries. The median age at diagnosis was 65 years (range, 36.5-86) and 108 (51%) were men. Negative staining for BAP1 (defined as completely absent nuclear staining in the presence of positive internal controls in nonneoplastic cells) occurred in 55 ICCs (26%). BAP1 loss predicted a strong trend toward improved median survival of 40.80 months (95% CI, 28.14-53.46) versus 24.87 months (95% CI, 18.73-31.01), P = 0.059). In a multivariate model including age, sex, BAP1 status, tumor stage, tumor grade, lymphovascular invasion, and tumor size, female sex was associated with improved survival (hazard ratio [HR] 0.54; 95% CI, 0.34-0.85), while advanced tumor stage and lymphovascular invasion (HR 1.89; 95% CI, 1.09-3.28) correlated with decreased survival. In a multivariate analysis, high grade tumors were associated with BAP1 loss (odds ratio [OR] 3.32; 95% CI, 1.29-8.55), while lymphatic invasion was inversely associated with BAP1 loss (OR 0.36; 95% CI, 0.13 0.99).In conclusion, we observed a trend toward improved prognosis in ICC associated with absent expression of BAP1 and an association of BAP1 loss with higher histological grade and absent lymphatic invasion. Female sex was associated with improved survival while advanced tumor stage and lymphatic invasion were associated with decreased survival. PMID- 26765461 TI - The Efficacy of Erlotinib Versus Conventional Chemotherapy for Advanced Nonsmall Cell Lung Cancer: A PRISMA-Compliant Systematic Review With Meta-Regression and Meta-Analysis. AB - Non-small-cell lung cancer (NSCLC) is the leading cause of cancer deaths. Erlotinib is the first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), the National Comprehensive Cancer Network (NCCN) guidelines recommend it as a first-line agent in patients with sensitizing EGFR mutations.We conducted a meta-analysis to compare the efficacy of erlotinib and chemotherapy for advanced NSCLC, and evaluated the efficacy of them to provide references for further clinical practice and research.PubMed, EMBASE, CBM, CNKI, WanFang database, The Cochrane library, and Web of Science, as well as abstracts presented at ASCO conferences and ClinicalTrials.gov were searched to identify relevant studies. HR with 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS), relative risk (RR) with 95% CIs for objective response rate (ORR) and 1-year survival rate (OSR) were all extracted. If the I was <=40%, then the trial was considered to be heterogeneous, and a fixed-effects model was selected. Otherwise, a random-effects model was used. Meta-regression and sensitivity analyses were conducted to determine the possible heterogeneity causes and to further identify the influence of the various exclusion criteria on the overall risk estimate.The pooled analysis demonstrated a PFS HR of 0.93 (95% CI = 0.73, 1.19) for erlotinib versus chemotherapy and an ORR of 18.43% versus 22.07%, respectively. The OS HR was 1.02 (95%CI = 0.93, 1.12). The HRs for PFS estimated based on 10 trials involving 1101 patients were 0.22 (95% CI = 0.15, 0.29) and 1.27 (95% CI = 1.04, 1.48) in EGFR mutation-type and wild-type patients, respectively. The HRs for OS calculated from 4 studies including 681 participants were 0.83 (95% CI = 0.61, 1.05) and 0.86 (95% CI = 0.68, 1.04) in EGFR mutation-type and wild-type patients, respectively. The 1 year survival rates were 31.31% and 32.41%, respectively.Overall, the present meta-analysis suggested that erlotinib did not improve the ORR, PFS, OS or the 1 year survival rate for whole patients. However, erlotinib could benefit patients with EGFR mutation in terms of PFS, but the OS does not benefit from it for these patients. Further studies of erlotinib for these subgroup patients are warranted. PMID- 26765462 TI - Inhibitory Effects of alpha-Lipoic Acid on Oxidative Stress-Induced Adipogenesis in Orbital Fibroblasts From Patients With Graves Ophthalmopathy. AB - A choice of the optimal treatment for Graves ophthalmopathy (GO) is a challenge due to the complexity of the pathogenesis. Alpha-lipoic acid (ALA) is well known as a multifunctional antioxidant, helping to protect cells against oxidative stress and inflammatory damage.The aim of this study was to investigate the effects of ALA on intracellular production of reactive oxygen species (ROS), inflammation, and adipogenesis using primary cultured orbital fibroblasts from patients with GO.Intracellular ROS levels and mRNA expressions of proinflammatory cytokines and chemokines including intercellular adhesion molecule-1 (ICAM-1), interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, and regulated upon activation normal T cell expressed and presumably secreted (RANTES) were measured. After adipogenesis, the expressions of peroxisome proliferator activated receptor (PPAR)gamma, CCAAT-enhancer-binding proteins (C/EBP)alpha and beta, and heme oxygenase-1 (HO-1) were investigated.H2O2 dose-dependently stimulated ROS production and HO-1 expression. Addition of ALA strongly attenuated ROS production and further increased HO-1 expression. However, by pretreatment of zinc protoporphyrin (ZnPP), HO-1 inhibitor, ALA inhibition of ROS generation by H2O2 was abolished. Tumor necrosis factor (TNF)alpha-induced mRNA expressions of ICAM-1, IL-6, MCP-1, and RANTES were inhibited by ALA treatment. In this context, TNFalpha-induced phosphorylation of P65 was also inhibited. In addition, ALA dose-dependently inhibited H2O2-induced intracellular accumulation of lipid droplets. The expression of adipogenic transcription factors, including PPARgamma, C/EBPalpha, and beta, was also inhibited.ALA is a potential therapeutic agent for GO because of the inhibitory effects on ROS production and gene expression of proinflammatory cytokines and chemokines, resulting in prevention of adipose-tissue expansion. PMID- 26765463 TI - Is Brown Adipose Tissue Visualization Reliable on 99mTc-Methoxyisobutylisonitrile Diagnostic SPECT Scintigraphy? AB - The 99mTc-MIBI has been used with great value as a diagnostic technique in patients with primary hyperparathyroidism. False-positive scans may occur due to misinterpretation of the physiologic distribution of the 99mTc-MIBI. Reviewing consecutive SPECT scans, we evaluated this possibility and assessed how frequently brown adipose tissue (BAT) is seen on 99mTc-MIBI scintigraphy. Here, we retrospectively reviewed scans of consecutive patients who were evaluated for parathyroid adenomas from March 2015 to June 2015, using dual-phase (early and delayed) planar imaging and SPECT. We identified 60 patients (48 female and 12 male; mean age, 52.25 +/- 15.20 years; range, 22-86 years).We detected the presence of 99mTc-MIBI uptake in BAT in 20 of 60 patients (33.33%) in the neck. Although the patients with T99mc-MIBI uptake in BAT were younger (mean age, 48.85 +/- 15.27 years, range, 26-73 years) than the patients with no 99mTc-MIBI uptake (mean age, 53.95 +/- 15.07 years, range, 22-86 years), this difference was not statistically significant (P = 0.224). The percentage of female patients with BAT detection was higher (17/48 patients; 37.5%) than that of the male population (3/12 patients; 25%), this difference was not also statistically significant (P = 0.85).In patient population referred to 99mTc MIBI scintigraphy of the parathyroid glands, uptake of 99mTc-MIBI in BAT should not be misinterpreted with 99mTc-MIBI-avid-tumors. Fused SPECT/CT images (not SPECT-only) are necessary to distinguish BAT from bone, muscle, thyroid, myocardium, parathyroids, and other structures in the neck and chest. PMID- 26765464 TI - Transformation of a Nonfunctional Paraganglioma With I-123 MIBG Scintigraphy Correlation: A Case Report. AB - A 35-year-old woman presenting with abdominal pain was found to have mildly elevated catecholamine levels and a retroperitoneal mass. The patient underwent a negative I-123 MIBG scintigraphy scan and a nondiagnostic fine needle aspiration. Eleven years later the patient presented with a hypertensive emergency and markedly elevated catecholamine levels. A subsequent I-123 MIBG scintigraphy scan showed intense uptake corresponding to the previously seen retroperitoneal mass. The patient underwent surgical resection and pathology confirmed the presence of a paraganglioma. A paraganglioma is an extra-adrenal pheochromocytoma that contains chromaffin cells and is thus capable of producing catecholamines. I-123 metaiodobenzylguanidine (MIBG) scintigraphy has become the imaging study of choice for paragangliomas and has a sensitivity of ~77% to 100% in detecting functional paragangliomas. This case demonstrates scintigraphic correlation of the functional transformation of a nonfunctional paraganglioma in a time span of ~10 years. Although there are previously published case reports of scintigraphic positive, nonfunctional paragangliomas and scintigraphic negative chromaffin cell tumors, there has been no prior documented case of scintigraphic transformation on MIBG. PMID- 26765465 TI - Diagnostic and Prognostic Value of Serum Interleukin-6 in Colorectal Cancer. AB - The application of serum interleukin-6 (IL-6) in the diagnosis and prognosis of colorectal cancer (CRC) has been evaluated in many studies, whereas the results were contradictive.The aim of this study was to systematically evaluate this issue.An original study was conducted to explore the diagnostic value of serum IL 6 in CRC. Pubmed, Embase, and Cochrane library databases were searched for eligible studies.For diagnostic meta-analysis, aggregate data (AD) and individual participant data (IPD) meta-analyses were both adopted. The sensitivity and specificity were pooled and a summary receiver-operating characteristic (ROC) curve was constructed. For prognostic meta-analysis, study-specific hazard ratios (HRs) of IL-6 for survival were summarized. Secondary analysis of survival data was performed to synthesize the Kaplan-Meier curves.Total 17 studies (including our study) were included in this meta-analysis. The pooled sensitivity, specificity, and area under curve (AUC) of serum IL-6 were 0.72 (95% CI: 0.46 0.88), 0.74 (95% CI: 0.56-0.86), and 0.79 (95% CI: 0.75-0.82) in CRC diagnosis, respectively. Further, IPD meta-analysis strengthened the diagnostic value of serum IL-6 (the AUC, sensitivity, and specificity were 0.794, 0.606, and 0.839, respectively). For prognostic analysis, the high serum level of IL-6 was inversely associated with overall survival (OS) (pooled HR = 1.76, 95% CI: 1.42 2.19, P < 0.001) and disease-free survival (DFS) (pooled HR = 2.97, 95% CI: 1.76 5.01, P < 0.001). The synthesized Kaplan-Meier curves indicated that CRC patients with higher serum IL-6 level had a worse OS (P = 0.0027) and DFS (P < 0.001), which further support the prognostic value of serum IL-6 in CRC patients.The present study confirmed that serum IL-6 may be a potential biomarker for CRC diagnosis, and the high serum IL-6 level was associated with poor prognosis for both CRC overall survival and disease-free survival. The study has been registered in an international registry of systematic reviews PROSPERO (CRD42013006485). PMID- 26765466 TI - Incidence of Augmentation in Primary Restless Legs Syndrome Patients May Not Be That High: Evidence From A Systematic Review and Meta-Analysis. AB - Augmentation is a common complication of primary restless legs syndrome (RLS) during treatment; however, its incidence rate remains unclear.The aim of this study is investigate the rate of augmentation during RLS treatment.We searched 6 databases, including PubMed, OVID, Embase, Wiley citations, Web of Science research platform (including SciELO Citation Index, Medline, KCI Korean Journal Database, the Web of ScienceTM Core Collection), and the Cochrane library, and screened the reference lists of the included trials and recently published reviews.Randomized controlled trials and observational studies that reported augmentation events during RLS treatment.Primary RLS patients older than 18 years.No restrictions regarding intervention types were applied.Three investigators independently extracted and pooled the data to analyze the augmentation rate of the total sample and of patient subgroups with different interventions, treatment durations and drug regimens and different geographic origins. Fixed-effects or random-effects model was used for pooled analysis.A total of 60 studies involving 11,543 participants suggested an overall augmentation rate of 5.6% (95% confidence intervals (CI), 4.0-7.7). The augmentation incidence was 6.1% (95% CI, 4.1-9.1) for long-term treatment and 3.3% (95% CI, 1.4-7.3) for short-term treatment. In addition, 27.1% (95% CI, 12.3 49.5) of the levodopa-treated patients, 6.0% (95% CI, 4.1-8.8) of the patients treated with dopamine agonists, and 0.9% (95% CI, 0.2-3.3) of the patients taking pregabalin or gabapentin developed augmentation. Augmentation occurred in 7.2% (95% CI, 5.0-10.3) of the patients taking immediate-release drugs and in 1.7% (95% CI, 0.6-5.0) of the patients taking transdermal application.The main limitations are that the augmentation rates were not evaluated according to drug dosage, gender, and age and symptom severity.Approximately 5 to 6 in 100 RLS patients developed augmentation during treatment. PMID- 26765467 TI - The Use of Composite Flaps in the Management of Large Full-Thickness Defects of the Lower Eyelid. AB - To describe a modified surgical procedure that uses a combination of the tarsoconjunctival flap, orbicularis myocutaneous advancement flap, and paranasal island flap to correct extensive full-thickness lower eyelid defects in functioning eyes.From May 2010 to December 2013, a total of 15 patients had reconstructive surgeries of large to giant lower eyelid defect, with an average 19-month follow-up. The musculocutaneous flaps were harvested from both orbicularis and paranasal regions and clinical outcomes were recorded and analyzed.No major complications were observed in any of the patients. All the patients showed aesthetic eyelid contour, good color, and texture match as well as no obvious scar formation. The mean Marginal Reflex Distance-2 measured 4 months after surgery was 4.9 +/- 0.4 mm.Reconstruction of a large defect in the lower eyelid with a tarsoconjunctival flap and the composite neighboring musculocutaneous flaps is a reliable and reproducible method. With proper design and well-executed precision, excellent functional and aesthetic results can be achieved by this elegant procedure without any major complications. PMID- 26765468 TI - Screening for the Key lncRNA Targets Associated With Metastasis of Renal Clear Cell Carcinoma. AB - A large number of long noncoding RNAs (lncRNAs) have been found to be implicated in varieties of tumors. However, the contributions of lncRNAs to tumorigenesis in renal clear cell carcinoma (RCCC) remain largely unknown.We performed a genome wide analysis of lncRNA expression in RCCC and matched nontumor (NT) tissues to identify new targets for further study of renal carcinoma.The genome-wide analysis of lncRNA expression in 3 RCCC and matched NT tissues were conducted using 4 * 180K Agilent lncRNA Chips and 6 lncRNAs were selected and validated by qRT-PCR in 90 RCCC patients. The differentially expressed lncRNAs and mRNAs were recognized through P value and fold-change (FC) filtering. Potential targets associated with RCCC were identified by gene ontology and pathway analyses. Construction of the co-expression network was accomplished using Cytoscape.A total of 3862 lncRNAs and 2935 mRNAs were deregulated in RCCC tissues, compared with paired NT tissues. PCR results showed the expressions of these 6 lncRNAs were consistent with the chips. Moreover, the co-expression network analysis portended 641 nodes and 571 connections between 109 lncRNAs and 532 coding genes. Lastly, NONHSAT123350 could be involved in the pathogenesis of RCCC and its expression level was closely related to disease-free survival (DFS) and overall survival (OS) in patients without distant metastasis.Our results indicated that these abnormal lncRNAs could respond to renal carcinoma progression and NONHSAT123350 may act as a potential target for future treatment of RCCC. PMID- 26765469 TI - The Immunohistochemical Evaluation of Solid Pseudopapillary Tumors of the Pancreas and Pancreatic Neuroendocrine Tumors Reveals ERO1Lbeta as a New Biomarker. AB - Solid pseudopapillary tumor of the pancreas (SPTP) is a class of low-grade malignant tumors that carry a favorable prognosis after surgery. Our group has reported that dysfunctions in the endoplasmic reticulum (ER) protein processing pathway may play a role in tumor development. However, alterations of this pathway in other pancreatic tumors had not been well investigated. In this study, we collected 35 SPTP and pancreatic neuroendocrine tumor (PNET) specimens and described the clinicopathological features of them. We performed immunohistochemistry (IHC) for 6 representative proteins (ERO1Lbeta, TRAM1, GRP94, BIP, P4HB, and PDIA4) involved in the ER pathway in both SPTP and PNET specimens. We compared the IHC scoring results of tumors and matched normal pancreas tissues and demonstrated that these proteins were downregulated in SPTP specimens. Five of these proteins (TRAM1, GRP94, BIP, P4HB, and PDIA4) did not display significant changes between PNET and normal pancreas tissue. However, ERO1Lbeta was upregulated in PNET tissues compared to the normal tissues, which could be used as a pathological biomarker in the future. PMID- 26765470 TI - A Pilot Study of MicroRNAs Expression Profile in Serum and HBsAg Particles: Predictors of Therapeutic Vaccine Efficacy in Chronic Hepatitis B Patients. AB - Chronic hepatitis B (CHB) remains a global health problem. Therapeutic vaccination has been successfully employed to treat a subpopulation of CHB patients. Personalized treatment can not only improve therapeutic efficacy, but also decrease the cost of medical care. Since microRNAs (miRNAs) are highly conserved and are involved in many cellular processes, exploring their expression profiles in CHB patients in association with responsiveness to therapeutic vaccination may be an approach for personalized treatment. In this study, we examined the kinetic expression profiles of 13 miRNAs in sera and serum-derived hepatitis surface antigen (HBsAg) particles in 10 CHB patients including 5 responders and 5 nonresponders selected from a large cohort of 136 patients enroled in a phase III clinical trial using antigen-antibody immunogenic complex based therapeutic vaccine (YIC). Eight miRNAs were detected in both sera and HBsAg particles. Among them, the levels of serum miRNAs and serum-derived HBsAg carried miRNAs (let-7f, miR-22, miR-30a, and miR-122) were significantly lower in the responders group compared to those in the nonresponders group at baseline and throughout the course of treatment. The lower baseline levels of serum miRNAs and HBsAg-carried miRNAs were also associated with hepatitis e antigen clearance at week 76 and hepatitis e antigen seroconversion during the study period. In summary, our study suggests that lower baseline levels of serum miRNAs and HBsAg carried miRNAs (let-7f, miR-22, miR-30a, and miR-122) associated with YIC treatment response and the variation trend of these 4 miRNAs could have a prognostic value for responsiveness to YIC treatment. PMID- 26765471 TI - Preoperative CT Predicting Recurrence of Surgically Resected Adenocarcinoma of the Lung. AB - Pathologic lymphovascular invasion (LVI) has been shown to be related to tumor recurrence in lung adenocarcinoma (ADC). We investigated preoperative computed tomography (CT) findings that may be related to pathologic LVI and recurrence of surgically managed stage I-II ADC of the lung.Consecutive patients (n = 275) with ADC from January 2013 to December 2013 were retrospectively enrolled. Two independent chest radiologists analyzed the CT findings. Clinical, CT (stage, margin, pleural tag, axial location, and peritumoral interstitial thickening), and pathologic findings (stage, % lepidic growth, and LVI) were reviewed. Cox proportional hazard regression analysis was used to estimate the hazard ratios (HRs) for patients with (n = 34) and without (n = 241) recurrence.The kappa index for agreement on the CT findings between radiologists was 0.705 to 0.845. In univariate analysis, % lepidic growth (P = 0.006), LVI (P < 0.001), size (P < 0.001), and staging (P = 0.011) differentiated significantly between patients with and without recurrence. Long diameter (P < 0.001), mass type (P < 0.001), marginal lobulation (P = 0.020), central location (P < 0.001), and peritumoral interstitial thickening (P < 0.001) were significantly related to recurrence on CT. Peritumoral interstitial thickening was positively correlated with tumor size (P < 0.001), LVI (P < 0.001), N staging (P = 0.005), stage (P < 0.001), mass type (P < 0.001), and recurrence (P = 0.003). In multivariate analysis, size (HR, 1.052; 95% CI, 1.022-1.082; P < 0.001), central location (HR, 3.152; 1.387-7.166; P = 0.006), and LVI (HR, 2.153, 95% CI, 1.038-4.465; P = 0.039) were independent predictors of recurrence.Large, centrally located tumors with LVI tend to recur after surgery. Presence of peritumoral interstitial thickening on CT appears to predict pathologic LVI and recurrence. PMID- 26765472 TI - Comparison of McGrath Series 3 and Macintosh Laryngoscopes for Tracheal Intubation in Patients With Normal Airway by Inexperienced Anesthetists: A Randomized Study. AB - Difficult and failed intubations account for the major causes of morbidity and mortality in current anesthetic practice. Several devices including McGrath Series 3 videolaryngoscope are available which may facilitate tracheal intubation by improving view of the larynx compared with Macintosh blade laryngoscopy. But no studies demonstrate whether McGrath Series 3 performs better than Macintosh laryngoscope in normal airway intubations by inexperienced anesthetists so far. We therefore designed this randomized controlled study to compare McGrath with Macintosh in routine tracheal intubation performed by inexperienced anesthetists.In total, 180 adult patients with normal-appearing airways requiring orotracheal intubation for elective surgery were randomly allocated to be intubated by 9 inexperienced anesthetists with McGrath or Macintosh. The primary outcome was time to intubation. Ease of intubation was assessed by a 5-point ordinal scale. Intubation attempts/failures, best laryngoscopy view using the Cormack-Lehane grade, associated complications and hemodynamic changes during intubation were recorded.We found that there was no significant difference between McGrath and Macintosh in the median time to intubation (P = 0.46); the Cormack-Lehane views attained using McGrath were superior (P < 0.001); the difference of ease of intubation was statistically significant (P = 0.01). No serious trauma occurred in both groups. And there was statistically significant difference in the systolic blood pressure changes between 2 groups (P < 0.05).We demonstrated that in orotracheal intubation in patients with normal airway by inexperienced anesthetists, McGrath compared with the Macintosh allows superior glottis views, greater ease of intubation, less complications, and hemodynamic changes with noninferior intubation time. And it remained a potential selection for inexperienced anesthetists in uncomplicated intubation. PMID- 26765473 TI - Mediastinal Germ Cell Tumor-associated Histiocytic Proliferations Treated With Thalidomide Plus Chemotherapy Followed by Alemtuzumab-containing Reduced Intensity Allogeneic Peripheral Blood Stem Cell Transplantation: A Case Report. AB - Mediastinal nonseminomatous germ cell tumor (MNSGCT)-associated histiocytic proliferations are rare and rapidly fatal disorders. Standard treatment modalities have yet to be established.We report a case of MNSGCT-associated hemophagocytic syndrome that evolved into malignant histiocytosis/disseminated histiocytic sarcoma (MH/HS), which was initially treated with intravenous immunoglobulin, corticosteroids, and cyclosporine. Then, thalidomide plus cyclophosphamide, adriamycin, oncovin, prednisolone chemotherapy followed by alemtuzumab-containing reduced-intensity allogeneic peripheral blood stem cell transplantation (PBSCT) was used as salvage therapy.The severe constitutional symptoms and pancytopenia resolved shortly after thalidomide with cyclophosphamide, adriamycin, oncovin, prednisolone. After PBSCT, the patient developed steroid-dependent skin graft-versus-host disease, but maintained a functional life for 1.5 years. Rapid resolution of chronic graft-versus-host disease preceded the fulminant recurrence of hemophagocytic syndrome and MH/HS.Thalidomide plus chemotherapy followed by alemtuzumab-containing reduced intensity allogeneic PBSCT is effective in allaying MNSGCT-associated histiocytic disorders, but does not prevent eventual relapse. However, further posttransplant immune modulation should be developed to completely eradicate the residual MH/HS cells. PMID- 26765474 TI - The Robotic-Assisted Laparoscopy, Isthmusectomy, and Pyeloplasty in a Patient With Horseshoe Kidney: A Case Report. AB - The aim of this case report was to evaluate the results of isthmusectomy and pyeloplasty of horseshoe kidney with the da Vinci robotic-assisted laparoscopy system.This case presented 1 patient with left back pain, associated with lower abdominal pain, and then she underwent the isthmusectomy and dismembered pyeloplasty using robotic-assisted laparoscopy simultaneously. The operation was performed by a transperitoneal approach using 5 ports.We cut the renal isthmus by means of bipolar scissors and then closed the renal parenchyma with 3-0 absorbed stitches. The total operation time was 123 min including simultaneous dismembered pyeloplasty. Blood loss was <50 mL. There were no complications either during or after the procedure. The oral nutrition and mobilization were included on the second day after surgery. The peritoneal drainage was removed on the eighth day. Long-term follow-up after treatment showed good results.The da Vinci robotic assisted laparoscopy is an alternative to open surgery and laparoscopy, particularly in the correction of congenital defects of the urinary tract. Furthermore, the da Vinci robotic-assisted laparoscopy technique in isthmusectomy and pyeloplasty is safe for patient as shown by our results. PMID- 26765475 TI - Nonexercise Activity Thermogenesis is Significantly Lower in Type 2 Diabetic Patients With Mental Disorders Than in Those Without Mental Disorders: A Cross sectional Study. AB - Physical activity improves health in patients with mental disorders. Nonexercise activity thermogenesis (NEAT) represents energy expenditure due to daily physical activities other than volitional exercise. We aimed to evaluate NEAT in type 2 diabetic patients with and without accompanying mental disorders.Between September 2010 and September 2014, we studied 150 patients with type 2 diabetes, 50 of whom also had a diagnosis of mental disorder, such as schizophrenia or mood disorder. We evaluated their NEAT in structured interviews using a validated questionnaire, and investigated differences in NEAT score and metabolic parameters between patients with and without mental disorders.The NEAT score was significantly lower in patients with mental disorders than in those without (56.3 +/- 9.9 vs 61.9 +/- 12.1; P = 0.005). Patients with mental disorders had significantly higher triglyceride (184.5 +/- 116.3 vs 146.4 +/- 78.4 mg/dL; P = 0.02) and insulin levels (18.7 +/- 20.1 vs 11.2 +/- 8.5 MUU/mL; P = 0.006), and significantly lower B-type natriuretic peptide (12.1 +/- 13.3 vs 26.3 +/- 24.8 pg/mL; P < 0.001) and brachial-ankle pulse wave velocity levels (1501 +/- 371 vs 1699 +/- 367 cm/s; P = 0.003) than patients without mental disorders. In patients with schizophrenia, specifically, NEAT showed a negative correlation with hemoglobin A1c levels (beta = -0.493, P = 0.031), and a positive correlation with high-density lipoprotein cholesterol (beta = 0.519, P = 0.023) and B-type natriuretic peptide levels (beta = 0.583, P = 0.02).Our results suggest that NEAT may be beneficial for the management of obesity, insulin sensitivity, and lipid profiles in patients with mental disorders. Incorporating NEAT into interventions for type 2 diabetes in patients with mental disorders, especially schizophrenia, shows promise and warrants further investigation. PMID- 26765476 TI - Patients With Neurogenic Lower Urinary Tract Dysfunction Following Spinal Cord Injury Are at Increased Risk of Developing Type 2 Diabetes Mellitus: A Population Based Cohort Study. AB - To investigate whether patients with neurogenic lower urinary tract dysfunction (NLUTD) following spinal cord injury (SCI) are at increased risk of developing type 2 diabetes mellitus (T2DM).The retrospective cohort study used a subset of the Taiwan National Health Insurance Research Database (NHIRD) comprising information on 2 million beneficiaries randomly sampled from the general population. A total of 3515 patients with newly diagnosed SCI were identified during the period of 2001 to 2008. Among them, 170 developed NLUTD following SCI. The control group was consisted of 656 patients without NLUTD over the study period randomly selected by matching NLUTD cases on the date of NLUTD incidence, age, sex, and duration since diagnosis of SCI. The study groups were then followed to the end of 2009. T2DM was the end-point.The incidence rate ratios of T2DM were higher in the NLUTD group than in the control group (4.94 vs. 2.61 per 10,000 person-years), representing an adjusted hazard ratio (AHR) of 1.70 (95% confidence interval [CI] 1.11-2.61). Age-specific AHR was significantly elevated only in patients aged > = 60 years (AHR = 2.52 (95% CI 1.35-4.70)).This study showed that the NLUTD following SCI may significantly increase the risk of developing T2DM. PMID- 26765477 TI - Crossed Cerebellar Diaschisis: Three Case Reports Imaging Using a Tri-Modality PET/CT-MR System. AB - Crossed cerebellar diaschisis (CCD) describes a depression of oxidative metabolism glucose and blood flow in the cerebellum secondary to a supratentorial lesion in the contralateral cerebral hemisphere. PET/MR has the potential to become a powerful tool for demonstrating and imaging intracranial lesions .We herein report 3 cases of CCD imaging using a tri-modality PET/CT-MR set-up for investigating the value of adding MRI rather than CT to PET in clinical routine.We describe 3 patients with CCD and neurological symptoms in conjunction with abnormal cerebral fluorodeoxyglucose (FDG) positron emission tomography/computed tomography-magnetic resonance imaging (PET/CT-MR) manifestations including arterial spin-labeling (ASL) and T2-weighted images. In all, 18FDG-PET/CT detected positive FDG uptake in supratentorial lesions, and hypometabolism with atrophy in the contralateral cerebellum. More than that, hybrid PET/MRI provided a more accurate anatomic localization and ASL indicated disruption of the cortico-ponto-cerebellar pathway.Using pathology or long-term clinical follow-up to confirm the PET and ASL findings, the supratentorial lesions of the 3 patients were respectively diagnosed with cerebral infarction, recurrent glioma, and metastasis.The reports emphasize the significance of multimodality radiological examinations. Multimodality imaging contributes to proper diagnosis, management, and follow-up of supratentorial lesions with CCD. PMID- 26765478 TI - Increased Risks of Spontaneous Bacterial Peritonitis and Interstitial Lung Disease in Primary Biliary Cirrhosis Patients With Concomitant Sjogren Syndrome. AB - The incidence of Sjogren syndrome (SS) in primary biliary cirrhosis (PBC) patients is high. The influence of SS on the clinical outcomes of PBC patients, however, remains unclear. Our study retrospectively collected data on PBC-only patients and PBC patients with concomitant SS (PBC-SS) to compare the clinical differences of long-term outcomes between them.A total of 183 patients were diagnosed with PBC from January 1999 to December 2014 at our hospital. Of these, the authors excluded patients with diabetes, hypertension, advanced liver cirrhosis at initial diagnosis of PBC (Child-Turcotte-Pugh classification score of >=7) and other liver diseases (ie, alcoholic liver disease, alpha-antitrypsin deficiency, viral hepatitis, and primary sclerosing cholangitis), and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Of the remaining 125 patients, 77 (61.6%) were PBC-only and 48 (38.4%) were PBC-SS patients.The mean follow-up duration was 8.76 years. During the observation period, the incidence of interstitial lung disease was higher in the PBC-SS group than in the PBC-only group (P = 0.005). The occurrence of spontaneous bacterial peritonitis was significantly different in PBC-SS patients than in PBC-only patients (P = 0.002). The overall survival was lower in PBC-SS patients than in PBC-only patients (P = 0.033). Although the incidence of hepatocellular carcinoma, end-stage renal disease, variceal bleeding, and hypothyroidism were all higher in the PBC-SS group than in the PBC-only group, the differences were not significant.Our study suggests that PBC-SS patients have a higher risk of developing interstitial lung disease and spontaneous bacterial peritonitis and have a poor prognosis. Aggressive surveillance of thyroid and pulmonary functions should therefore be performed in these patients. PMID- 26765479 TI - Comparison of the Efficacy and Safety of a Pharmacokinetic Model-Based Dosing Scheme Versus a Conventional Fentanyl Dosing Regimen For Patient-Controlled Analgesia Immediately Following Robot-Assisted Laparoscopic Prostatectomy: A Randomized Clinical Trial. AB - Conventional, intravenous, patient-controlled analgesia, which is only administered by demand bolus without basal continuous infusion, is closely associated with inappropriate analgesia. Pharmacokinetic model-based dosing schemes can quantitatively describe the time course of drug effects and achieve optimal drug therapy. We compared the efficacy and safety of a conventional dosing regimen for intravenous patient-controlled analgesia that was administered by demand bolus without basal continuous infusion (group A) versus a pharmacokinetic model-based dosing scheme performed by decreasing the dosage of basal continuous infusion according to the model-based simulation used to achieve a targeted concentration (group B) following robot-assisted laparoscopic prostatectomy.In total, 70 patients were analyzed: 34 patients in group A and 36 patients in group B. The postoperative opioid requirements, pain scores assessed by the visual analog scale, and adverse events (eg, nausea, vomiting, pruritis, respiratory depression, desaturation, sedation, confusion, and urinary retention) were compared on admission to the postanesthesia care unit and at 0.5, 1, 4, 24, and 48 h after surgery between the 2 groups. All patients were kept for close observation in the postanesthesia care unit for 1 h, and then transferred to the general ward.The fentanyl requirements in the postanesthesia care unit for groups A and B were 110.0 +/- 46.4 MUg and 77.5 +/- 35.3 MUg, respectively. The pain scores assessed by visual analog scale at 0.5, 1, 4, and 24 h after surgery in group B were significantly lower than in group A (all P < 0.05). There were no differences in the adverse events between the 2 groups.We found that the pharmacokinetic model-based dosing scheme resulted in lower opioid requirements, lower pain scores, and no significant adverse events in the postanesthesia care unit following robot-assisted laparoscopic prostatectomy in comparison with conventional dosing regimen. PMID- 26765480 TI - Determinants of job satisfaction for novice nurse managers employed in hospitals. AB - BACKGROUND: Numbering close to 300,000 nurse managers represent the largest segment of the health care management workforce. Their effectiveness is, in part, influenced by their job satisfaction. PURPOSE: We examined factors associated with job satisfaction of novice frontline nurse managers. METHODOLOGY/APPROACH: We used a cross-sectional, correlational survey design. The sample consisted of responders to the fifth wave of a multiyear study of new nurses in 2013 (N = 1,392; response rate of 69%) who reported working as managers (n = 209). The parent study sample consisted of registered nurses who were licensed for the first time by exam 6-18 months prior in 1 of 51 selected metropolitan statistical areas and 9 rural areas across 34 U.S. states and the District of Columbia. We examined bivariate correlations between job satisfaction and 31 personal and structural variables. All variables significantly related to job satisfaction in bivariate analysis were included in a multivariate linear regression model. In addition, we tested the interaction effects of procedural justice and negative affectivity, autonomy, and organizational constraints on job satisfaction. The Cronbach's alphas for all multi-item scales ranged from .74 to .96. FINDINGS: In the multivariate analysis, negative affectivity (beta = -.169; p = .006) and procedural justice (beta = .210; p = .016) were significantly correlated with job satisfaction. The combination of predictors in the model accounted for half of the variability in job satisfaction ratings (R = .51, adjusted R = .47; p <. 001). PRACTICE IMPLICATIONS: Health care executives who want to cultivate an effective novice frontline nurse manager workforce can best ensure their satisfaction by creating an organization with strong procedural justice. This could be achieved by involving managers in decision-making processes and ensuring transparency about how decisions that affect nursing are made. PMID- 26765481 TI - The proliferation of elective services in U.S. urban hospitals. AB - BACKGROUND: Although adding convenience for both patients and providers, the proliferation of elective services and equipment in U.S. general hospitals contributes to higher costs and raises concerns about quality and overuse. PURPOSES: We assess the relationship of two forces-health system membership and market competition-with the diffusion of elective services and equipment. METHODOLOGY/APPROACH: The sample consists of all urban U.S. nonfederal general acute hospitals in 2010 (n = 2,467). Elective equipment and services are defined by 25 services offered by less than 33% of urban general hospitals. We relate the number of elective services to environmental and organizational conditions, adopting a contingency theory perspective. Ordinary least squares regression is used to estimate the associations among the key variables. FINDINGS: Market competition is positively associated with numbers of elective services. The effect of health system membership varies by system type, with the most developed integrated systems showing a positive relationship with the quantity of elective services, relative to freestanding hospitals. Members of less-developed integrated systems, however, have fewer elective services than freestanding hospitals. PRACTICE IMPLICATIONS: The evidence on market competition is consistent with a medical arms race scenario in which hospitals pursue elective services and equipment to compete with each other. Membership in highly integrated systems does not act as a constraint on the pursuit of elective services and equipment but instead may independently promote it. It may be unrealistic to expect hospitals to resist offering elective services in the face of competitive and organizational considerations that encourage proliferation. PMID- 26765482 TI - Direct observation of structural properties and fluorescent trapping sites in macrocyclic porphyrin arrays at the single-molecule level. AB - By utilizing single-molecule defocused wide-field fluorescence microscopy, we have investigated the molecular structural properties such as transition dipole moment orientations and the angular relationship among chromophores, as well as structural distortions and flexibilities depending on the ring size, in a series of cyclic porphyrin arrays bearing close likeness in overall architectures to the LH2 complexes in purple bacterial photosynthetic systems. Furthermore, comparing the experimental results with molecular dynamics simulations, we ascertained site selection for fluorescent trapping sites. Collectively, these experimental and computational results provide the basis for structure-property relationships and energy hopping/emitting processes in an important class of artificial light harvesting molecular systems widely used in molecular electronics technology. PMID- 26765483 TI - PCDH19-related epilepsy in two mosaic male patients. AB - PCDH19 gene mutations have been recently associated with an epileptic syndrome characterized by focal and generalized seizures. The PCDH19 gene (Xq22.1) has an unusual X-linked inheritance with a selective involvement for female subjects. A cellular interference mechanism has been hypothesized and male patients can manifest epilepsy only in the case of a mosaicism. So far about 100 female patients, and only one symptomatic male have been described. Using targeted next generation sequencing (NGS) approach we found a PCDH19 point mutation in two male patients with a clinical picture suggestive of PCDH19-related epilepsy. The system allowed us to verify that the two c.1352 C>T; p.(Pro451Leu) and c.918C>G; p.(Tyr306*) variants occurred in mosaic status. Mutations were confirmed by Sanger sequencing and quantified by real-time polymerase chain reaction (PCR). Up to now, the traditional molecular screening for PCDH19-related epilepsy has been targeted to all females with early onset epilepsy with or without cognitive impairment. Male patients were generally excluded. We describe for the first time two mosaic PCDH19 point mutations in two male patients with a clinical picture suggestive of PCDH19-related epilepsy. This finding opens new opportunities for the molecular diagnoses in patients with a peculiar type of epilepsy that remains undiagnosed in male patients. PMID- 26765484 TI - Soluble Fas/FasL ratio as a marker of vasculopathy in children and adolescents with sickle cell disease. AB - OBJECTIVES: Sickle cell disease (SCD) is characterized by chronic inflammation due to ischemic tissue damage, accentuated during acute complications. Fas and its ligand (FasL) are members of tumor necrosis factor receptor superfamily and a major pathway for induction of apoptosis. Fas/FasL interactions may be related to augmentation of inflammatory response. We assessed the levels of sFas and sFasL in 35 children and adolescents with SCD compared with 35 healthy controls in relation to hemolysis, iron overload, sickle vasculopathy including kidney disease. METHODS: SCD patients, in steady state and asymptomatic for pulmonary hypertension, were studied stressing on hydroxyurea therapy, serum ferritin, urinary albumin creatinine ratio (UACR), high-sensitivity C-reactive protein (hs CRP) and sFas/sFasL levels. RESULTS: sFas/sFasL ratio was significantly higher in patients compared with controls. sFas/sFasL ratio was elevated in patients with pulmonary hypertension, nephropathy and those who had history of frequent sickling crisis or serum ferritin ?2500. SCD patients treated with hydroxyurea had lower sFas/sFasL ratio than untreated patients. sFas/sFasL ratio was positively correlated to transfusion index, white blood cells, hs-CRP, serum ferritin and UACR. The cutoff value of sFas/sFasL at 8.75pg/mL could differentiate SCD patients with and without nephropathy while the cutoff value at 22pg/mL could differentiate SCD patients with and without pulmonary hypertension risk with high sensitivity and specificity. CONCLUSION: sFas/sFasL ratio may be considered as a marker for vascular dysfunction in SCD patients and is related to inflammation, iron overload and albuminuria level. Thus, it may be a reliable method to assess renal impairment in SCD. PMID- 26765485 TI - Significant hepatic expression of IL-2 and IL-8 in biliary atresia compared with other neonatal cholestatic disorders. AB - OBJECTIVES: Although the exact etiology of biliary atresia (BA) is still elusive, inflammation plays a key role. Release of proinflammatory cytokines from activated immune cells perpetuates the injury and causes biliary destruction. We aimed to study interleukin (IL)-2 and IL-8 expression in liver tissue of BA patients compared with other neonatal cholestatic disorders. METHODS: The study included 59 infants with neonatal cholestasis in two groups; BA group (n=31) and non-BA group (n=28) with cholestatic disorders other than BA as controls. Demographic, clinical, laboratory, and histopathological parameters were collected. IL-2 and IL-8 immunostaining was performed. Immunostaining in portal cellular infiltrate was scored as positive or negative and expressed as the mean cell count in three portal tracts. RESULTS: The mean value of IL-2 and IL-8 positive inflammatory cells was significantly higher in BA than in non-BA group (P-values of 0.004 and 0.002 respectively). IL-2 correlated significantly with IL 8 immunostaining in both BA and non-BA group (P<0.0001 for both). Furthermore, both cytokines in both groups correlated significantly with inflammatory activity in liver biopsy while there was no significant correlation with the other studied parameters. Yet, there was a trend of increased expression of IL-2 and IL-8 with increasing stage of fibrosis in BA group. This trend was not observed in non-BA group. CONCLUSION: The significantly higher expression of IL-2 and IL-8 in patients with BA compared to non-BA suggests a potential role for these cytokines in the pathogenesis in therapy of this devastating neonatal hepatic disorder. PMID- 26765487 TI - Fuzzy Clusterwise Growth Curve Models via Generalized Estimating Equations: An Application to the Antisocial Behavior of Children. AB - The growth curve model has been a useful tool for the analysis of repeated measures data. However, it is designed for an aggregate-sample analysis based on the assumption that the entire sample of respondents are from a single homogenous population. Thus, this method may not be suitable when heterogeneous subgroups exist in the population with qualitatively distinct patterns of trajectories. In this paper, the growth curve model is generalized to a fuzzy clustering framework, which explicitly accounts for such group-level heterogeneity in trajectories of change over time. Moreover, the proposed method estimates parameters based on generalized estimating equations thereby relaxing the assumption of correct specification of the population covariance structure among repeated responses. The performance of the proposed method in recovering parameters and the number of clusters is investigated based on two Monte Carlo analyses involving synthetic data. In addition, the empirical usefulness of the proposed method is illustrated by an application concerning the antisocial behavior of a sample of children. PMID- 26765488 TI - A Class of Population Covariance Matrices in the Bootstrap Approach to Covariance Structure Analysis. AB - Model evaluation in covariance structure analysis is critical before the results can be trusted. Due to finite sample sizes and unknown distributions of real data, existing conclusions regarding a particular statistic may not be applicable in practice. The bootstrap procedure automatically takes care of the unknown distribution and, for a given sample size, also provides more accurate results than those based on standard asymptotics. But the procedure needs a matrix to play the role of the population covariance matrix. The closer the matrix is to the true population covariance matrix, the more valid the bootstrap inference is. The current paper proposes a class of covariance matrices by combining theory and data. Thus, a proper matrix from this class is closer to the true population covariance matrix than those constructed by any existing methods. Each of the covariance matrices is easy to generate and also satisfies several desired properties. An example with nine cognitive variables and a confirmatory factor model illustrates the details for creating population covariance matrices with different misspecifications. When evaluating the substantive model, bootstrap or simulation procedures based on these matrices will lead to more accurate conclusion than that based on artificial covariance matrices. PMID- 26765486 TI - Multivalency in the recognition and antagonism of a HIV TAR RNA-TAT assembly using an aminoglycoside benzimidazole scaffold. AB - Recognition of RNA by high-affinity binding small molecules is crucial for expanding existing approaches in RNA recognition, and for the development of novel RNA binding drugs. A novel neomycin dimer benzimidazole conjugate 5 (DPA 83) was synthesized by conjugating a neomycin-dimer with a benzimidazole alkyne using click chemistry to target multiple binding sites on HIV TAR RNA. Ligand 5 significantly enhances the thermal stability of HIV TAR RNA and interacts stoichiometrically with HIV TAR RNA with a low nanomolar affinity. 5 displayed enhanced binding compared to its individual building blocks including the neomycin dimer azide and benzimidazole alkyne. In essence, a high affinity multivalent ligand was designed and synthesized to target HIV TAR RNA. PMID- 26765489 TI - An Unscented Kalman Filter Approach to the Estimation of Nonlinear Dynamical Systems Models. AB - In the past several decades, methodologies used to estimate nonlinear relationships among latent variables have been developed almost exclusively to fit cross-sectional models. We present a relatively new estimation approach, the unscented Kalman filter (UKF), and illustrate its potential as a tool for fitting nonlinear dynamic models in two ways: (1) as a building block for approximating the log-likelihood of nonlinear state-space models and (2) to fit time-varying dynamic models wherein parameters are represented and estimated online as other latent variables. Furthermore, the substantive utility of the UKF is demonstrated using simulated examples of (1) the classical predator-prey model with time series and multiple-subject data, (2) the chaotic Lorenz system and (3) an empirical example of dyadic interaction. PMID- 26765491 TI - Applying the Bootstrap to Taxometric Analysis: Generating Empirical Sampling Distributions to Help Interpret Results. AB - Meehl's taxometric method was developed to distinguish categorical and continuous constructs. However, taxometric output can be difficult to interpret because expected results for realistic data conditions and differing procedural implementations have not been derived analytically or studied through rigorous simulations. By applying bootstrap methodology, one can generate empirical sampling distributions of taxometric results using data-based estimates of relevant population parameters. We present iterative algorithms for creating bootstrap samples of taxonic and dimensional comparison data that reproduce important features of the research data with good precision and negligible bias. In a series of studies, we demonstrate the utility of these comparison data as an interpretive aid in taxometric research. Strengths and limitations of the approach are discussed along with directions for future research. PMID- 26765490 TI - Identification and Small Sample Estimation of Thurstone's Unrestricted Model for Paired Comparisons Data. AB - The interpretation of a Thurstonian model for paired comparisons where the utilities' covariance matrix is unrestricted proved to be difficult due to the comparative nature of the data. We show that under a suitable constraint the utilities' correlation matrix can be estimated, yielding a readily interpretable solution. This set of identification constraints can recover any true utilities' covariance matrix, but it is not unique. Indeed, we show how to transform the estimated correlation matrix into alternative correlation matrices that are equally consistent with the data but may be more consistent with substantive theory. Also, we show how researchers can investigate the sample size needed to estimate a particular model by exploiting the simulation capabilities of a popular structural equation modeling statistical package. PMID- 26765492 TI - Multiple Imputation of Item Scores in Test and Questionnaire Data, and Influence on Psychometric Results. AB - The performance of five simple multiple imputation methods for dealing with missing data were compared. In addition, random imputation and multivariate normal imputation were used as lower and upper benchmark, respectively. Test data were simulated and item scores were deleted such that they were either missing completely at random, missing at random, or not missing at random. Cronbach's alpha, Loevinger's scalability coefficient H, and the item cluster solution from Mokken scale analysis of the complete data were compared with the corresponding results based on the data including imputed scores. The multiple-imputation methods, two-way with normally distributed errors, corrected item-mean substitution with normally distributed errors, and response function, produced discrepancies in Cronbach's coefficient alpha, Loevinger's coefficient H, and the cluster solution from Mokken scale analysis, that were smaller than the discrepancies in upper benchmark multivariate normal imputation. PMID- 26765493 TI - Evaluation of Revision Effect on Criterion Validity of Multiple-Component Measuring Instruments. AB - A method for point and interval estimation of change in criterion validity of multiple-component measuring instruments as a result of revision is outlined. The procedure is developed within the framework of covariance structure modeling, which complements earlier methods for testing change in composite reliability due to addition or deletion of components from tentative scales. The approach aids the process of constructing instruments with high validity in behavioral research that is illustrated with a pair of numerical examples. PMID- 26765494 TI - Highly hydroxide conductive ionomers with fullerene functionalities. AB - A novel ionomer was designed that will not poison the catalyst in alkaline fuel cells, by incorporating for the first time N-methyl pyrrolidine-C60 cation in polymeric anion exchange ionomers. The resultant fullerene-based anion exchange ionomer shows an extremely high hydroxide conductivity (182 mS cm(-1)) at a low cation concentration (0.62 mmol g(-1)). PMID- 26765495 TI - The effectiveness of a range of sports bras in reducing breast displacement during treadmill running and two-step star jumping. AB - BACKGROUND: The primary aim of the study was to investigate the effectiveness of a range of sports bras in reducing multi-planar breast displacement during treadmill running and a two-step star jump. A secondary aim was to assess the relationship between perceptual bra comfort, bra fit and breast pain and measured breast displacement. METHODS: Seventeen females (mean age 22 years, range 18-31 years) with bra cup sizes B to C volunteered to take part in the study. Three dimensional breast movements were determined for six randomly assigned breast support levels during treadmill running and two-step star jumping. Participants completed a perceptual questionnaire rating bra comfort, bra fit and breast pain. RESULTS: Not all the bras significantly reduced resultant breast movement compared to a control condition. Not all the bras reduced resultant breast movement significantly at all speeds during the treadmill test. A different bra performed best during each of the treadmill running speeds. Perceptual ratings of bra fit and bra comfort were stronger and more reliable predictors of breast pain than breast displacement in our group of relatively small-breasted participants. CONCLUSIONS: Therefore it is apparent that resultant breast movement and the reduction of such movement is a multifaceted function of breast size, bra design and movement/activity type. The variance in bra performance at different treadmill running speeds highlights this fact and indicates that sports bras should be carefully selected to best suit the activity and breast size of the user. PMID- 26765496 TI - Jumping improves lower limbs bone mass and lean mass in elite jumpers. AB - BACKGROUND: The present study was designed to examine the influence of extreme impact loading induced by jump training on bone mineral density (BMD) and bone mineral content (BMC) in high level jumpers. METHODS: Forty boys volunteered for the study aged 20 to 21 years. They were 22 high level jumpers and 18 controls. Bone mass and body composition measurements were performed by dual-energy X-ray absorptiometry, in the total body and at different sites. RESULTS: The results showed that BMC, BMD, bone area, and lean mass (P<0.0001) were significantly higher in the jumpers compared to the controls. A strong positive correlation was found between lean mass and bone parameters (BMC at the right femur, r=0.80; P<0.01). The values of the same correlation were weak in the control group. In addition, the effects of the regular practice of jumping on the BMD, BMC, and bone area were more pronounced in the lower limbs (P<0.01). These adaptations were site-specific, with increased bone mass at the lower limbs (P<0.01), especially at the legs, right and left leg (LRL) (P<0.05). It appears that the time dedicated to this activity may be account for the difference between jumpers and controls. CONCLUSIONS: The practice of high level jump starting at pubertal age generates an increase and an acquisition of the bone mass in males. This adaptation is further enhanced by the times dedicated for this activity. Therefore, it would be interesting to program jumping activities daily to conserve bone mineral and to prevent osteopenia. PMID- 26765498 TI - Two Decades of ICU Utilization and Hospital Outcomes in a Comprehensive Cancer Center. AB - OBJECTIVE: To investigate ICU utilization and hospital outcomes of oncological patients admitted to a comprehensive cancer center. DESIGN: Observational cohort study. SETTING: The University of Texas MD Anderson Cancer Center. PATIENTS: Consecutive adults with cancer discharged over a 20-year period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The Cochran-Armitage test for trend was used to evaluate ICU utilization and hospital mortality rates by primary service over time. A negative binomial log linear regression model was fitted to the data to investigate length of stay over time. Among 387,306 adult hospitalized patients, the ICU utilization rate was 12.9%. The overall hospital mortality rate was 3.6%: 16.2% among patients with an ICU stay and 1.8% among non-ICU patients. Among those admitted to the ICU, the mean (SD) admission Sequential Organ Failure Assessment score was 6.1 (3.8) for all ICU patients: 7.3 (4.4) for medical ICU patients and 4.9 (2.8) for surgical ICU patients. Hematologic disorders were associated with the highest hospital mortality rate in ICU patients (42.8%); metastatic disease had the highest mortality rate in non-ICU patients (4.2%); sepsis, pneumonia, and other infections had the highest mortality rate for all inpatients (8.5%). CONCLUSIONS: This study provides a longitudinal view of ICU utilization rates, hospital and ICU length of stay, and severity-adjusted mortality rates. Although the data arise from a single institution, it encompasses a large number of hospital admissions over two decades and can serve as a point of comparison for future oncological studies at similar institutions. More studies of this nature are needed to determine whether consolidation of cancer care into specialized large-volume facilities may improve outcomes, while simultaneously sustaining appropriate resource utilization and reducing unnecessary healthcare costs. PMID- 26765497 TI - Biochemical, physical and tactical analysis of a simulated game in young soccer players. AB - BACKGROUND: The objectives of this study were to describe and compare the displacement patterns and the tactical performance of the players in the first to the second game time and verify possible associations between indirect markers of muscle damage with displacement patterns in a simulated game played by young soccer players. METHODS: Eighteen young soccer players were submitted to a simulated game and two blood collections, one before and another 30 minutes post game to analyze the behavior of creatine kinase and lactate dehydrogenase enzymes. The patterns of displacement and tactics variables were obtained through functions developed in MATLAB environment (MathWorks, Inc., Natick, MA, USA). RESULTS: It is observed a significant increase in average speed (P=0.05), number of sprints (P<0.001), the percentage the total distance covered at high intensity (P<0.001) and tactical variables (team surface area: P=0.002; spreading: P=0.001) in the second period of the simulated game. In addition, there was significant reduction in the percentage of the total distance at low intensity (P<=0.05) in the second period, and there was a strong association between the percentage of change delta of creatine kinase and lactate dehydrogenase with the displacement patterns in the simulated game. CONCLUSIONS: The results show that indirect markers of muscle damage have great association with displacement patterns in game performed in training conditions for young soccer players, evidencing a need for reflection on the post-training recovery sessions strategies, contributing to better planning of sessions throughout the macrocycle. PMID- 26765499 TI - Slowing Down of Recovery as Generic Risk Marker for Acute Severity Transitions in Chronic Diseases. AB - OBJECTIVE: We propose a novel paradigm to predict acute attacks and exacerbations in chronic episodic disorders such as asthma, cardiac arrhythmias, migraine, epilepsy, and depression. A better generic understanding of acute transitions in chronic dynamic diseases is increasingly important in critical care medicine because of the higher prevalence and incidence of these chronic diseases in our aging societies. DATA SOURCES: PubMed, Medline, and Web of Science. STUDY SELECTION: We selected studies from biology and medicine providing evidence of slowing down after a perturbation as a warning signal for critical transitions. DATA EXTRACTION: Recent work in ecology, climate, and systems biology has shown that slowing down of recovery upon perturbations can indicate loss of resilience across complex, nonlinear biologic systems that are approaching a tipping point. This observation is supported by the empiric studies in pathophysiology and controlled laboratory experiments with other living systems, which can flip from one state of clinical balance to a contrasting one. We discuss examples of such evidence in bodily functions such as blood pressure, heart rate, mood, and respiratory regulation when a tipping point for a transition is near. CONCLUSIONS: We hypothesize that in a range of chronic episodic diseases, indicators of critical slowing down, such as rising variance and temporal correlation, may be used to assess the risk of attacks, exacerbations, and even mortality. Identification of such early warning signals over a range of diseases will enhance the understanding of why, how, and when attacks and exacerbations will strike and may thus improve disease management in critical care medicine. PMID- 26765500 TI - Conflict Management Strategies in the ICU Differ Between Palliative Care Specialists and Intensivists. AB - OBJECTIVES: Conflict is common between physicians and surrogate decision makers around end-of-life care in ICU. Involving experts in conflict management improve outcomes, but little is known about what differences in conflict management styles may explain the benefit. We used simulation to examine potential differences in how palliative care specialists manage conflict with surrogates about end-of-life treatment decisions in ICUs compared with intensivists. DESIGN: Subjects participated in a high-fidelity simulation of conflict with a surrogate in an ICU. In this simulation, a medical actor portrayed a surrogate decision maker during an ICU family meeting who refuses to follow an advance directive that clearly declines advanced life-sustaining therapies. We audiorecorded the simulation encounters and applied a coding framework to quantify conflict management behaviors, which was organized into two categories: task-focused communication and relationship building. We used negative binomial modeling to determine whether there were differences between palliative care specialists' and intensivists' use of task-focused communication and relationship building. SETTING: Single academic medical center ICU. SUBJECTS: Palliative care specialists and intensivists. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We enrolled 11 palliative care specialists and 25 intensivists. The palliative care specialists were all attending physicians. The intensivist group consisted of 11 attending physicians, 9 pulmonary and critical care fellows, and 5 internal medicine residents rotating in the ICU. We excluded five residents from the primary analysis in order to reduce confounding due to training level. Physicians' mean age was 37 years with a mean of 8 years in practice. Palliative care specialists used 55% fewer task-focused communication statements (incidence rate ratio, 0.55; 95% CI, 0.36-0.83; p = 0.005) and 48% more relationship building statements (incidence rate ratio, 1.48; 95% CI, 0.89-2.46; p = 0.13) compared with intensivists. CONCLUSIONS: We found that palliative care specialists engage in less task-focused communication when managing conflict with surrogates compared with intensivists. These differences may help explain the benefit of palliative care involvement in conflict and could be the focus of interventions to improve clinicians' conflict resolution skills. PMID- 26765501 TI - Abnormal coagulation factor VIII transcript in a Tennessee Walking Horse colt with hemophilia A. AB - Hemophilia A is an X-chromosome-linked disorder caused by a deficiency in factor VIII (FVIII). Although foals have been diagnosed with hemophilia A based on deficiency in FVIII activity, causative gene mutations have not been identified. The genomic DNA and cDNA encoding FVIII of a Tennesee Walking Horse colt affected with hemophilia A and the genomic DNA of his dam and a normal unrelated horse were analyzed with no splice site or coding sequence abnormalities identified in any of the horses. Polymerase chain reactions (PCR) were then performed on hepatic cDNA from the affected colt and an unrelated normal horse, and no product was obtained for the sequence between and including exon 1 and exon 2 in the affected colt. Based on these results, suspected mutations were identified in the noncoding region of FVIII (intron 1), and genomic sequencing of intron 1 in the dam and the affected colt suggested maternal inheritance. PMID- 26765502 TI - Using Swiss Webster mice to model Fetal Alcohol Spectrum Disorders (FASD): An analysis of multilevel time-to-event data through mixed-effects Cox proportional hazards models. AB - Fetal Alcohol Spectrum Disorders (FASD) collectively describes the constellation of effects resulting from human alcohol consumption during pregnancy. Even with public awareness, the incidence of FASD is estimated to be upwards of 5% in the general population and is becoming a global health problem. The physical, cognitive, and behavioral impairments of FASD are recapitulated in animal models. Recently rodent models utilizing voluntary drinking paradigms have been developed that accurately reflect moderate consumption, which makes up the majority of FASD cases. The range in severity of FASD characteristics reflects the frequency, dose, developmental timing, and individual susceptibility to alcohol exposure. As most rodent models of FASD use C57BL/6 mice, there is a need to expand the stocks of mice studied in order to more fully understand the complex neurobiology of this disorder. To that end, we allowed pregnant Swiss Webster mice to voluntarily drink ethanol via the drinking in the dark (DID) paradigm throughout their gestation period. Ethanol exposure did not alter gestational outcomes as determined by no significant differences in maternal weight gain, maternal liquid consumption, litter size, or pup weight at birth or weaning. Despite seemingly normal gestation, ethanol-exposed offspring exhibit significantly altered timing to achieve developmental milestones (surface righting, cliff aversion, and open field traversal), as analyzed through mixed-effects Cox proportional hazards models. These results confirm Swiss Webster mice as a viable option to study the incidence and causes of ethanol-induced neurobehavioral alterations during development. Future studies in our laboratory will investigate the brain regions and molecules responsible for these behavioral changes. PMID- 26765503 TI - Accuracy of Magnetic Resonance Imaging and Ultrasound for Appendicitis in Diagnostic and Nondiagnostic Studies. AB - OBJECTIVES: Suggestive radiographic studies with nonvisualization of the appendix can present a challenge to clinicians in the evaluation of pediatric abdominal pain. The primary objective of this study was to quantify the accuracy of magnetic resonance imaging (MRI) and of ultrasound (US) in the setting of nonvisualization of the appendix. Secondary objectives reported include sensitivity of MRI and US overall and correlation between MRI and US for diagnosis of appendicitis. METHODS: Records of pediatric emergency department patients aged 3 to 21 years undergoing MRI and/or US for the evaluation of appendicitis were retrospectively reviewed. Radiographs were categorized as a normal appendix, neither demonstrating the appendix nor demonstrating abnormalities consistent with appendicitis; equivocal, not demonstrating the appendix but showing evidence of appendicitis; demonstrating an abnormal appendix consistent with appendicitis; or demonstrating an alternate pathology. The reading was compared with the final diagnosis for accuracy. RESULTS: Of the 589 patients included, 146 had appendicitis. Diagnostic accuracy for studies with a nonvisualized appendix without secondary signs of appendicitis was 100% for MRI and 91.4% (95% CI = 87.3% to 94.2%) for US. Diagnostic accuracy for studies with a nonvisualized appendix with secondary signs of appendicitis was 50% (95% CI = 2.5% to 97.5%) for MRI and 38.9% (95% CI = 18.2% to 64.5%) for US. Appendicitis was ultimately diagnosed in 8.6% of patients with an otherwise negative right lower quadrant (RLQ) US that failed to directly identify the appendix. There was a moderate correlation between US and MRI (rho = 0.573, p = 0.0001) when all studies were considered. CONCLUSIONS: Magnetic resonance imaging without secondary signs of appendicitis is effective in excluding appendicitis regardless of whether the appendix is directly visualized, while otherwise negative RLQ US that fail to identify the appendix are less useful. Secondary signs of appendicitis without visualization of the appendix were not helpful regardless of radiographic modality. Results of MRI and US correlated moderately well. PMID- 26765505 TI - Outcomes of an Oral Care Protocol in Postmechanically Ventilated Patients. AB - BACKGROUND: Oral care is standard practice to prevent hospital-associated infections while patients are intubated and in the intensive care unit. Following extubation and transfer, infections remain an important risk for patients, but less attention is paid to oral care. Few studies have assessed the impact of oral care in recently extubated acutely ill patients. AIMS: To develop an evidence based oral care protocol for hospitalized patients and determine the impact of this protocol on health outcomes in recently extubated patients. METHODS: In this randomized controlled trial, subjects were randomized to usual care or an intervention protocol that included tooth brushing, tongue scraping, flossing, mouth rinsing, and lip care. Major outcome measures were the revised THROAT (R THROAT; oral cavity assessment) and overall prevalence of methicillin-sensitive Staphylococcus aureus and methicillin-resistant S. aureus on oral cultures. RESULTS: Seventy-four subjects were randomized. As measured by the R-THROAT, oral cavity health improved over time in both groups, but the intervention group demonstrated significantly more improvement than the control group (R-THROAT score improved by 1.97 intervention vs. 0.87 control; p = .04). Two categories, tongue and mouth comfort, demonstrated the most significant improvement. There was no difference in MSSA/MRSA colonization between the groups at the conclusion of the study. Overall, subjects in the intervention group were more satisfied with their protocol than subjects in the usual care group. LINKING EVIDENCE TO ACTION: This study offers an important evaluation of an oral care protocol after extubation. Results demonstrated improvement in the oral cavity assessment with the designed oral care protocol. Patients expressed a preference for the intervention protocol, which included a battery-operated toothbrush, higher quality toothpaste and mouth rinse, tongue scraper, floss, and lip balm. The implementation of an oral care protocol specifically addressing patients in the immediate postintubation is essential. PMID- 26765507 TI - Short-term nitrogen losses by overland flow in a recently burnt forest area in north-central Portugal: A study at micro-plot scale. AB - Over the past decades, wildfires have affected extensive areas of the Mediterranean region with negative impacts on the environment. Most of the studies on fire-affected areas have focused on sediment losses by overland flow, whereas few have addressed post-fire nutrient export. The present study aimed to address this research gap by assessing nitrogen (nitrate and total nitrogen) losses by overland flow in a recently burnt area in north-central Portugal. To this end, three burnt slopes were selected for their contrasting forest types (eucalypt vs. pine) and parent materials (granite vs. schist). The selected study sites were a eucalypt site on granite (BEG), a eucalypt site on schist (BES) and a maritime pine site on schist (BPS). Overland flow samples were collected during the first six months after the wildfire on a 1- to 2-weekly basis, after which this study had to be cancelled due to bench terracing of some of the sites. A peak in total nitrogen concentrations was observed in burnt areas immediately after the first post-fire rainfall event as a response to the erosion of the N enriched ash layer. After this initial peak, smaller peaks were observed throughout the study period, mainly as a response to overland flow and/or erosion events. Nitrogen export differed strikingly between the two types of forests on schist, being higher at the eucalypt than at the pine site, due to the lack of a protective soil layer. Parent material did not play an important role on nitrogen export by overland flow since no significant differences were found between the eucalypt sites on granite and schist. The present study provides some insight into the differences in post-fire soil fertility losses between forest types and parent materials in the Mediterranean region, which is crucial information for defining post-fire land management measures to reduce soil degradation. PMID- 26765506 TI - Seedling root responses to soil moisture and the identification of a belowground trait spectrum across three growth forms. AB - Root trait variation and plasticity could be key factors differentiating plant performance under drought. However, water manipulation and root measurements are rarely coupled empirically across growth forms to identify whether belowground strategies are generalizable across species. We measured seedling root traits across three moisture levels in 18 Mediterranean forbs, grasses, and woody species. Drought increased the root mass fraction (RMF) and decreased the relative proportion of thin roots (indicated by increased root diameters and decreased specific root length (SRL)), rates of root elongation and growth, plant nitrogen uptake, and plant growth. Although responses varied across species, plasticity was not associated with growth form. Woody species differed from forbs and grasses in many traits, but herbaceous groups were similar. Across water treatments, trait correlations suggested a single spectrum of belowground trade offs related to resource acquisition and plant growth. While effects of SRL and RMF on plant growth shifted with drought, root elongation rate consistently represented this spectrum. We demonstrate that general patterns of root morphology and plasticity are identifiable across diverse species. Root trait measurements should enhance our understanding of belowground strategy and performance across growth forms, but it will be critical to incorporate plasticity and additional aspects of root function into these efforts. PMID- 26765504 TI - Staphylococcus epidermidis and biofilm-associated neutrophils in chronic rhinosinusitis. A pilot study. AB - A key role of bacterial biofilm in the pathogenesis of chronic rhinosinusitis (CRS) with (CRSwNP) and without nasal polyps (CRSsNP) is commonly accepted. However, the impact of some bacterial species isolated from inflamed sinus mucosa on biofilm formation is unclear. In particular, the role of Staphylococcus epidermidis as aetiological agents of CRS is controversial. Moreover, the effect of biofilm formation on neutrophil infiltration and activity in CRSwNP calls for explanation. In this study, biofilms were found in three of 10 patients (mean age = 46 +/- 14) with CRS undergoing endoscopic sinus surgery by means of scanning electron microscopy. Unexpectedly, S. epidermidis was the primary isolated bacteria and was also found to be present in all biofilm-positive mucosa specimens, indicating its pivotal role in the pathogenesis of severe chronic infections associated with biofilm formation. We have also measured the activity of myeloperoxidase (MPO), the most abundant neutrophil enzyme, to demonstrate the presence of neutrophils in the samples tested. Our present results show that the level of MPO in CRS associated with biofilm is lower than that without biofilm. It may suggest either a low number of neutrophils or the presence of a type of neutrophils with compromised antimicrobial activity, described as biofilm associated neutrophils (BAN). Finally, we conclude that further studies with a large number of CRS cases should be performed to establish the association between S. epidermidis and other frequently isolated bacterial species from paranasal sinuses, with the severity of CRS, biofilm formation and the infiltration of BAN. PMID- 26765508 TI - Cost-benefit calculation of phytoremediation technology for heavy-metal contaminated soil. AB - Heavy-metal pollution of soil is a serious issue worldwide, particularly in China. Soil remediation is one of the most difficult management issues for municipal and state agencies because of its high cost. A two-year phytoremediation project for soil contaminated with arsenic, cadmium, and lead was implemented to determine the essential parameters for soil remediation. Results showed highly efficient heavy metal removal. Costs and benefits of this project were calculated. The total cost of phytoremediation was US$75,375.2/hm(2) or US$37.7/m(3), with initial capital and operational costs accounting for 46.02% and 53.98%, respectively. The costs of infrastructures (i.e., roads, bridges, and culverts) and fertilizer were the highest, mainly because of slow economic development and serious contamination. The cost of phytoremediation was lower than the reported values of other remediation technologies. Improving the mechanization level of phytoremediation and accurately predicting or preventing unforeseen situations were suggested for further cost reduction. Considering the loss caused by environmental pollution, the benefits of phytoremediation will offset the project costs in less than seven years. PMID- 26765509 TI - The rationale for simple approaches for sustainability assessment and management in contaminated land practice. AB - The scale of land-contamination problems, and of the responses to them, makes achieving sustainability in contaminated land remediation an important objective. The Sustainable Remediation Forum in the UK (SuRF-UK) was established in 2007 to support more sustainable remediation practice in the UK. The current international interest in 'sustainable remediation' has achieved a fairly rapid consensus on concepts, descriptions and definitions for sustainable remediation, which are now being incorporated into an ISO standard. However the sustainability assessment methods being used remain diverse with a range of (mainly) semi quantitative and quantitative approaches and tools developed, or in development. Sustainability assessment is site specific and subjective. It depends on the inclusion of a wide range of considerations across different stakeholder perspectives. Taking a tiered approach to sustainability assessment offers important advantages, starting from a qualitative assessment and moving through to semi-quantitative and quantitative assessments on an 'as required' basis only. It is also clear that there are a number of 'easy wins' that could improve performance against sustainability criteria right across the site management process. SuRF-UK has provided a checklist of 'sustainable management practices' that describes some of these. This paper provides the rationale for, and an outline of, and recently published SuRF-UK guidance on preparing for and framing sustainability assessments; carrying out qualitative sustainability assessment; and simple good management practices to improve sustainability across contaminated land management activities. PMID- 26765510 TI - Synthesis and antibacterial characterization of sustainable nanosilver using naturally-derived macromolecules. AB - Greener nanosynthesis utilizes fewer amounts of materials, water, and energy; while reducing or replacing the need for organic solvents. A novel approach is presented using naturally-derived flavonoids including Quercetin pentaphosphate (QPP), Quercetin sulfonic acid (QSA) and Apigenin Triphosphate (ATRP). These water soluble, phosphorylated flavonoids were utilized both as reducing agent and stabilizer. The synthesis was achieved at room temperature using water as a solvent and it requires no capping agents. The efficiency of the resulting silver nanoparticle synthesis was compared with naturally-occurring flavonoid such as Quercetin (QCR). Results show that QCR reduced Ag(+) faster followed by QPP, QSA and ATRP respectively. This is the first evidence of direct utilization of QCR for synthesis of silver nanoparticles (AgNPs) in water. The percentage conversion of Ag(+) to Ag(0) was determined to be 96% after 35min. The synthesized nanoparticles were characterized using Transmission electron microscopy (TEM), Energy dispersive absorption spectroscopy (EDS), UV-vis spectroscopy, High resolution TEM (HR-TEM) with selected area electron diffraction (SAED). The particle sizes ranged from 2 to 80nm with an average size of 22nm and in the case of ATRP, the nanoparticle shapes varied from spherical to hexagonal with dispersed particle size ranging from 2 to 30nm. Crystallinity was confirmed by XRD and the SAED of (111), (200), and the fringes observed in HRTEM images. Results were in agreement with the UV resonance peaks of 369-440nm. The particles also exhibit excellent antibacterial activity against Staphylococcus epidermidis, Escherichia coli and Citrobacter freundii in water. PMID- 26765511 TI - Interactions of ciprofloxacin (CIP), titanium dioxide (TiO2) nanoparticles and natural organic matter (NOM) in aqueous suspensions. AB - The aim of the present study was to investigate interactions of the antibiotic ciprofloxacin (CIP), titanium dioxide nanoparticles (TiO2 NP) and natural organic matter (NOM) in aqueous suspensions. The mean hydrodynamic diameter of particles of TiO2 NP and NOM in the suspensions ranged from 113 to 255nm. During batch experiments the radioactivity resulting from (14)CIP was determined in the filtrate (filter pore size 100nm) by scintillation measurements. Up to 72h, no significant sorption of NOM to TiO2 NP was observed at a TiO2 NP concentration of 5mg/L. When the concentration of TiO2 NP was increased to 500mg/L, a small amount of NOM of 9.5%+/-0.6% was sorbed at 72h. The low sorption affinity of NOM on TiO2 NP surfaces could be explained by the negative charge of both components in alkaline media or by the low hydrophobicity of the NOM contents. At a TiO2 NP concentration of 5mgL(-1), the sorption of CIP on TiO2 NP was insignificant (TiO2 NP/CIP ratio: 10). When the TiO2 NP/CIP ratio was increased to 1000, a significant amount of 53.6%+/-7.2% of CIP was sorbed on TiO2 NP under equilibrium conditions at 64h. In alkaline media, CIP is present mainly as zwitterions which have an affinity to sorb on negatively charged TiO2 NP surfaces. The sorption of CIP on TiO2 NP in the range of TiO2 NP concentrations currently estimated for municipal wastewater treatment plants is estimated to be rather low. The Freundlich sorption coefficients (KF) in the presence of NOM of 2167L(n)mgmg( n)kg(-1) was about 10 times lower than in the absence of NOM. This is an indication that the particle fraction of NOM<100nm could play a role as a carrier for ionic organic micro-pollutants as CIP. PMID- 26765512 TI - Policies, Procedures, and Practices Regarding Sport-Related Concussion in Community College Athletes. AB - CONTEXT: College sport organizations and associations endorse concussion management protocols and policies. To date, little information is available on concussion policies and practices at community college institutions. OBJECTIVE: To assess and describe current practices and policies regarding the assessment, management, and return-to-play criteria for sport-related concussion (SRC) among member institutions of the California Community College Athletic Association (CCCAA). DESIGN: Cross-sectional study. SETTING: Web-based survey. PATIENTS OR OTHER PARTICIPANTS: A total of 55 head athletic trainers (ATs) at CCCAA institutions. MAIN OUTCOME MEASURE(S): Data about policies, procedures, and practices regarding SRC were collected over a 3-week period in March 2012 and analyzed using descriptive statistics, the Fisher exact test, and the Spearman test. RESULTS: Almost half (47%) of ATs stated they had a policy for SRC assessment, management, and return to play at their institution. They reported being in compliance with baseline testing guidelines (25%), management guidelines (34.5%), and return-to-play guidelines (30%). Nearly 31% of ATs described having an SRC policy in place for academic accommodations. Conference attendance was positively correlated with institutional use of academic accommodations after SRC (r = 0.44, P = .01). The number of meetings ATs attended and their use of baseline testing were also positively correlated (r = 0.38, P = .01). CONCLUSIONS: At the time of this study, nearly half of CCCAA institutions had concussion policies and 31% had academic-accommodation policies. However, only 18% of ATs at CCCAA institutions were in compliance with all of their concussion policies. Our findings demonstrate improvements in the management of SRCs by ATs at California community colleges compared with previous research but a need for better compliance with SRC policies. PMID- 26765513 TI - Work-Based Social Interactions, Perceived Stress, and Workload Incongruence as Antecedents of Athletic Trainer Burnout. AB - CONTEXT: Burnout is an important psychological health concern for working professionals. Understanding how psychological stress and markers of workload contribute to athletic trainers' (ATs') perceptions of burnout is highly valuable. Both positive (social support) and negative social interactions should be considered when examining relationships among markers of ATs' health and wellbeing. OBJECTIVE: To examine the potential effects of social interactions on the relationships between (1) burnout and perceived stress and (2) burnout and workload incongruence in ATs. DESIGN: Cross-sectional study. SETTING: Participating ATs completed a computer-based survey during the fall sports season. PATIENTS OR OTHER PARTICIPANTS: Responding participants were ATs randomly sampled from the National Athletic Trainers' Association membership (N = 154; men = 78, women = 76; age = 36.8 +/- 9.5 years). MAIN OUTCOME MEASURE(S): Participants completed self-report assessments (Perceived Stress Scale, Social Support Questionnaire, Positive and Negative Social Exchanges, Maslach Burnout Inventory-Human Services Survey) via a secure e-mail link. Workload incongruence was calculated by subtracting anticipated work hours from actual current work hours (6.0 +/- 9.6 hours). We used hierarchical multiple regression analyses to examine hypothesized relationships among study variables. RESULTS: Social interactions did not affect the relationships between burnout and perceived stress or workload incongruence at the global or dimensional level. However, perceived stress (beta = .47, P < .001), workload incongruence (beta = .12, P < .05), and social support (beta = -.25, P < .001) predicted global AT burnout. Negative social interactions trended toward significance (beta = .12, P = .055). Our findings suggest that stress perceptions and social support drive the dimensional AT burnout experience, whereas workload incongruence (emotional exhaustion) and negative social interactions (depersonalization) were linked to specific burnout dimensions. CONCLUSIONS: Social interactions and markers of stress and workload should be considered when seeking to understand ATs' experiences with burnout and to design workplace interventions. PMID- 26765514 TI - A systematic review of the clinical efficacy of transcranial direct current stimulation (tDCS) in psychiatric disorders. AB - Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique, which can be used to selectively disrupt patterns of neural activity that are associated with symptoms of mental illness. tDCS has been implemented in numerous therapeutic trials across a range of patient populations, with a rapidly increasing number of studies being published each year. This systematic review aimed to evaluate the efficacy of tDCS in the treatment of psychiatric disorders. Four electronic databases were searched from inception until December 2015 by two independent reviewers, and 66 eligible studies were identified. Depression was the most extensively researched condition, followed by schizophrenia and substance use disorders. Data on obsessive compulsive disorder, generalised anxiety disorder, and anorexia nervosa were also obtained. The quality of included studies was appraised using a standardised assessment framework, which yielded a median score corresponding to "weak" on the three-point scale. This improved to "moderate" when case reports/series were excluded from the analysis. Overall, data suggested that tDCS interventions comprising multiple sessions can ameliorate symptoms of several major psychiatric disorders, both acutely and in the long-term. Nevertheless, the tDCS field is still in its infancy, and several methodological and ethical issues must be addressed before clinical efficacy can truly be determined. Studies probing the mechanisms of action of tDCS and those facilitating the definition of optimised stimulation protocols are warranted. Furthermore, evidence from large-scale, multi-centre randomised controlled trials is required if the transition of this therapy from the laboratory to the clinic is to be considered. PMID- 26765515 TI - Quantifying Physical Activity Levels and Sleep in Hemodialysis Patients Using a Commercially Available Activity Tracker. AB - BACKGROUND/AIMS: Hemodialysis (HD) patients are less active than their healthy counterparts and frequently experience poor sleep. Our aims were to objectively quantify activity and sleep quality in HD patients of an urban population and to determine the effect of providing feedback on activity. METHODS: Activity parameters and sleep parameters were collected by a commercially available activity tracker in 29 chronic HD patients. Patients in the feedback group were provided with their activity and sleep data during each HD treatment. Questionnaires were administered at the beginning and at the end of the study. RESULTS: On average, patients walked 8,454 steps/day and slept 349 min/night. Only 28% of the patients were sedentary, defined as walking <5,000 steps/day. Providing feedback did not increase the activity in this urban population. Patients walked significantly less on Sundays compared to other days of the week: 7,024 steps on Sundays vs. 8,633 steps on HD days and 8,732 on non-HD days. It was also found that patients experienced poor sleep quality. HD treatments during shift 1 (6 a.m. to 10 a.m.) interfered with sleep patterns. Most patients reported that physical activity became more important to them after the 5-week period. The tracking device was very well accepted. CONCLUSION: Interventions to increase physical activity on Sundays could improve physical activity levels overall. Prospective studies are necessary to further explore the use of tracking devices to identify patients at risk and to implement targeted interventions. PMID- 26765516 TI - Vulvovaginal candidosis: contemporary challenges and the future of prophylactic and therapeutic approaches. AB - Vulvovaginal candidosis (VVC) is a common gynaecological disorder that is delineated by the inflammation of vaginal wall and it is caused by the opportunistic fungal pathogen Candida species. In fact, three out of every four women will experience at least one occasion of VVC during some point in their lives. Although uncomplicated VVC is relatively harmless, the complicated VVC such as recurrent attack often creates restlessness and depression in the patients, thus greatly affects their quality of life. Managements of VVC are usually associated with the use of antimycotic suppositories, topical cream or oral agents. These antimycotic agents are either available over-the-counter or prescribed by the clinicians. In recent decades, the rise of clinical challenges such as the increased prevalence of resistant Candida strains, recurrent VVC infection and adverse effects of multidrug interactions have necessitated the development of novel therapeutic or prophylactic options to combat the complicated VVC in the future. In this review, we discuss the current antimycotic treatments available for Candida vaginitis and the problems that exist in these seemingly effective treatments. Besides, we attempt to contemplate some of the future and prospective strategies surrounding the development of alternative therapeutic and prophylactic options in treating and preventing complicated VVC respectively. PMID- 26765517 TI - Surface Plasmon Resonance Imaging-MALDI-TOF Imaging Mass Spectrometry of Thin Tissue Sections. AB - Identification and quantification of proteins in imaging of biological samples are a challenge in today's science. Here, we demonstrate a novel surface plasmon resonance imaging-matrix assisted laser desorption ionization imaging mass spectrometry (SPRi-MALDI IMS) coupled technique competent for the acquisition of multiparametric information by creating a tissue section imprint on an SPRi sensor surface. Correlated images were acquired in SPRi and in MALDI IMS for abundant proteins from a single mouse kidney tissue. The spatial organization of the transferred proteins from the tissue to the SPRi surface was preserved and imaged by SPR and MALDI MS. Surface chemistry was selected to nonspecifically adsorb and retain high concentrations of proteins on the SPRi surface. The diffusion kinetics were controlled to ensure fast transfer of proteins from the tissue sections with minimal lateral diffusion to achieve high spatial fidelity transfer. Lastly, the SPRi instrument was modified to insert a tissue sample in the fluidics chamber to facilitate the real-time measurement of the transfer process. The MALDI IMS experimental conditions, such as matrix deposition and the interface between the SPRi prism and the MALDI IMS instrument, were also optimized. The results show quantitative and regioselective SPRi images correlating to MALDI IMS images of different proteins transferred from a single tissue section. PMID- 26765519 TI - Correction: Cost-Effectiveness of a Community Pharmacist Intervention in Patients with Depression: A Randomized Controlled Trial (PRODEFAR Study). PMID- 26765518 TI - FEASIBILITY AND SAFETY OF CONTRAST-ENHANCED ULTRASOUND IN THE DISTAL LIMB OF SIX HORSES. AB - Vascular alterations play important roles in many orthopedic diseases such as osteoarthritis, tendonitis, and synovitis in both human and equine athletes. Understanding these alterations could enhance diagnosis, prognosis, and treatment. Contrast-enhanced ultrasound (CEUS) could be a valuable method for evaluation of blood flow and perfusion of these processes in the equine distal limb, however no reports were found describing feasibility or safety of the technique. The goal of this prospective, experimental study was to describe the feasibility and safety of distal limb CEUS in a sample of six horses. For each horse, CEUS of the distal limb was performed after intravenous injections of 5 and 10 ml, as well as intra-arterial injections of 0.5 and 1 ml contrast medium. Vital parameters were monitored and CEUS images were assessed qualitatively and quantitatively for degree of contrast enhancement. None of the horses had clinically significant changes in their vital parameters after contrast medium injection. One horse had a transient increase in respiratory rate, and several horses had mild increases of systolic blood pressure of short duration after intravenous, but not after intra-arterial injections. Intra-arterial injection was possible in all horses and resulted in significantly improved contrast enhancement both quantitatively (P = 0.027) and qualitatively (P = 0.019). Findings from this study indicated that CEUS is a feasible and safe diagnostic test for evaluation of the equine distal limb. Future studies are needed to assess the clinical utility of this test for horses with musculoskeletal diseases. PMID- 26765520 TI - Halogenated Symmetrical Tetraazapentacenes: Synthesis, Structures, and Properties. AB - We herein describe the synthesis and property evaluation of several brominated and chlorinated tetraazapentacenes. The targets were obtained by thermal condensation of 2,5-dihydroxyquinone with 4,5-dichloro-, 2,6-dichloro-, and 4,5 dibromo-1,2-phenylenediamine, followed by oxidation with hot acidic dichromate. Double alkynylation, reductive deoxygenation, and subsequent oxidation using MnO2 furnishes the target compounds. Absorption spectra, electrochemistry, and single crystal structures of the targets are reported. The 1,4,8,11 tetrachlorotetraazapentacene (1,4,8,11-tetrachloroquinoxalino[2,3-b]phenazine) carrying its chlorine atoms in the peri-positions packs in a herringbone type arrangement, while the isomer (2,3,9,10-tetrachloroquinoxalino[2,3-b]phenazine, with the chlorine atoms in the east and west positions) packs in one-dimensional stacks. In all cases, the reduction potentials and the calculated LUMO-positions are decreased by the introduction of the halogen atoms. PMID- 26765521 TI - Intelligence and early life mortality: Findings from a longitudinal sample of youth. AB - The current study examined whether adolescent IQ predicted risk for mortality by the age of 32. Analyses of data from the Add Health revealed that IQ was related to mortality risk, such that respondents with relatively lower IQs were significantly more likely to experience early life mortality when compared to respondents with relatively higher IQs. This association remained statistically significant even after controlling for a host of covariates such as race, gender, involvement in violent behaviors, levels of self-control, and poverty. The average IQ of deceased respondents was approximately 95, whereas the average IQ of living respondents was about 100. PMID- 26765522 TI - Do stones still kill? An analysis of death from stone disease 1999-2013 in England and Wales. AB - OBJECTIVES: To analyse the trends in the number of deaths attributable to urolithiasis in England and Wales over the past 15 years (1999-2013). Urolithiasis has an estimated lifetime risk of 12% in males and 6% in females and is not perceived as a life-threatening pathology. Admissions with urinary calculi contribute to 0.5% of all inpatient hospital stays, and the number of deaths attributable to stone disease has yet to be identified and presented. MATERIALS AND METHODS: Office of National Statistics data relating to causes of death from urolithiasis, coded as International Classification of Diseases (ICD)-10 N20-N23, was collated and analysed for the 15-year period from 1999 to 2013 in England and Wales. These data were sub-categorised into anatomical location of calculi, age, and gender. RESULTS: In all, 1954 deaths were attributed to urolithiasis from 1999 to 2013 (mean 130.3 deaths/year). Of which, 141 were attributed to ureteric stones (mean 9.4 deaths/year). Calculi of the kidney and ureter accounted for 91% of all deaths secondary to urolithiasis; lower urinary tract (bladder or urethra) calculi contributed to only 7.9% of deaths. The data revealed an overall increasing trend in mortality from urolithiasis over this 15-year period, with an increase of 3.8 deaths/year based on a linear trend (R(2) = 0.65). Overall, the number of deaths in females was significantly higher than in males (ratio 1.5:1, P < 0.001); kidney and ureteric calculi causing death had a female preponderance (1.7:1, female:male); whereas calculi of the lower urinary tract was more common in males (1:2.2, female:male). CONCLUSIONS: Stone disease still causes death in the 21st century in England and Wales. This trend of increasing deaths must be placed in the context of the concurrent rising incidence of urolithiasis in the UK and the number of stone-related hospital episodes. The primary cause of death relating to complications of stone disease for each individual case should be further investigated to facilitate prevention of complications of urolithiasis. PMID- 26765524 TI - High-Quality Large-Magnification Polymer Lens from Needle Moving Technique and Thermal Assisted Moldless Fabrication Process. AB - The need of mobile microscope is escalating as well as the demand of high quality optical components in low price. We report here a novel needle moving technique to fabricate milli-size lens together with thermal assist moldless method. Our proposed protocol is able to create a high tensile strength structure of the lens and its base which is beneficial for exploiting in convertinga smart phone to be a digital microscope. We observe that no bubble trapped in a lens when this technique is performed which can overcome a challenge problem found in a typical dropping technique. We demonstrate the symmetry, smoothness and micron-scale resolution of the fabricated structure. This proposed technique is promising to serve as high quality control mass production without any expensive equipment required. PMID- 26765525 TI - Complexation of Lanthanides with Glutaroimide-dioxime: Binding Strength and Coordination Modes. AB - The complexation of lanthanides (Nd(3+) and Eu(3+)) with glutaroimide-dioxime (H2L), a cyclic imide dioxime ligand that has been found to form stable complexes with actinides (UO2(2+) and NpO2(+)) and transition metal ions (Fe(3+), Cu(2+), etc.), was studied by potentiometry, absorption spectrophotometry, luminescence spectroscopy, and microcalorimetry. Lanthanides form three successive complexes, M(HL)(2+), M(HL)L, and M(HL)2(+) (where M stands for Nd(3+)/Eu(3+) and HL(-) stands for the singly deprotonated ligand). The enthalpies of complexation, determined by microcalorimetry, show that the formation of these complexes is exothermic. The stability constants of Ln(3+)/H2L complexes are several orders of magnitude lower than that of the corresponding Fe(3+)/H2L complexes but are comparable with that of UO2(2+)/H2L complexes. A structure of Eu(3+)/H2L complex, identified by single-crystal X-ray diffractometry, shows that the ligand coordinates to Eu(3+) in a tridentate mode, via the two oxygen atoms of the oxime group and the nitrogen atom of the imide group. The relocation of protons of the oxime groups (-CH?N-OH) from the oxygen to the nitrogen atom, and the deprotonation of the imide group (-CH-NH-CH-) result in a conjugated system with delocalized electron density on the ligand (-O-N-C-N-C-N-O-) that forms strong complexes with the lanthanide ions. PMID- 26765523 TI - Detection of Ehrlichia canis, Babesia vogeli, and Toxoplasma gondii DNA in the Brain of Dogs Naturally Infected with Leishmania infantum. AB - The aims of this study were to investigate the presence of Leishmania infantum and possible co-infection with Anaplasma platys , Babesia vogeli, Ehrlichia canis , and Toxoplasma gondii in the brain of 24 dogs naturally infected by L. infantum . A total of 24 mongrel adult dogs (22 clinically affected, 2 with neurological signs, and 2 subclinically infected) aged between 2 and 5 yr, naturally infected by visceral leishmaniasis, were selected. Fragments from meninges, frontal cortex, thalamus, cerebellum, and choroid plexus of the lateral ventricles and fourth ventricle were collected, mixed, and tested by real-time polymerase chain reaction (qPCR). Leishmania infantum DNA was detected in 95.8% (23/24) of the infected dogs, including the subclinically infected. A total of 14/24 (58.3%) dogs were co-infected by E. canis and L. infantum , 4/24 (16.7%) were co-infected by E. canis , B. vogeli, and L. infantum , 2/24 (8.3%) were co-infected by B. vogeli and L. infantum , and 1/24 (4.2%) dog was co-infected by E. canis , B. vogeli, T. gondii , and L. infantum . All 24 brain samples tested negative for A. platys . These results demonstrate that L. infantum is able to penetrate into the brain parenchyma, either alone or in association to other zoonotic pathogens. In addition, qPCR could be considered for adequate evaluation of Leishmania in the brain tissue of dogs with neurological signs that have died. PMID- 26765528 TI - Label-free liquid crystal biosensor for L-histidine: A DNAzyme-based platform for small molecule assay. AB - We have developed a novel DNAzyme-based liquid crystal (LC) biosensor with high sensitivity for L-histidine, which is based on L-histidine-mediated formation of DNA duplexes by cleaving DNAzyme using L-histidine, resulting in a remarkable optical signal. Firstly, an optimal amount of capture probe is bound to the glass slide, which changes the surface topology as little as possible and shows a zero background for the sensing system. When the DNAzyme molecule is cleaved by the target, L-histidine, a partial substrate strand is produced, which in turn can hybridize with the capture probe, forming a DNA duplex. The DNA duplexes induce LC molecules to undergo a homeotropic-to-tiled transition, obtaining a remarkable optical signal. The results show that the DNAzyme-based LC biosensor is highly sensitive to L-histidine with a detection limit of 50 nM. Compared with previously reported multi-step amplified methods, this newly designed assay system for L-histidine has no amplified procedures with comparable sensitivity. This method is an unprecedented example of DNAzyme-based LC biosensor for small molecules, which has potential to offer a DNAzyme-based LC model used in various targets. PMID- 26765527 TI - Ultrasensitive detection of influenza viruses with a glycan-based impedimetric biosensor. AB - An ultrasensitive impedimetric glycan-based biosensor for reliable and selective detection of inactivated, but intact influenza viruses H3N2 was developed. Such glycan-based approach has a distinct advantage over antibody-based detection of influenza viruses since glycans are natural viral receptors with a possibility to selectively distinguish between potentially pathogenic influenza subtypes by the glycan-based biosensors. Build-up of the biosensor was carefully optimized with atomic force microscopy applied for visualization of the biosensor surface after binding of viruses with the topology of an individual viral particle H3N2 analyzed. The glycan biosensor could detect a glycan binding lectin with a limit of detection (LOD) of 5 aM. The biosensor was finally applied for analysis of influenza viruses H3N2 with LOD of 13 viral particles in 1 MUl, what is the lowest LOD for analysis of influenza viral particles by the glycan-based device achieved so far. The biosensor could detect H3N2 viruses selectively with a sensitivity ratio of 30 over influenza viruses H7N7. The impedimetric biosensor presented here is the most sensitive glycan-based device for detection of influenza viruses and among the most sensitive antibody or aptamer based biosensor devices. PMID- 26765529 TI - Designed diblock hairpin probes for the nonenzymatic and label-free detection of nucleic acid. AB - The detection of nucleic acid sequences is of great importance in a variety of fields. An ultrasensitive DNA sensing platform is constructed using elaborately designed diblock hairpin probes (DHPs) that are composed of hairpin and poly adenine blocks. The introduction of an initiator DNA target triggers the catalytic assembly of probes DHP1, DHP2 and DHP3 to fabricate numerous poly adenine-tailed branched DNA junctions, which significantly amplify the signal of the target-DNA-recognizing event without any enzyme. Coupled to a gold nanoparticle-based colorimetric assay, the amplified recognition signal can be quantitatively detected or visually read with the naked eye. The combination of the high-efficiency target-catalyzed DHP assembly and sensitive gold-based colorimetric assay offers an ultrasensitive detection of DNA with a detection limit of 0.1 pM and a dynamic range from 0.01 to 5 pM. The proposed sensing platform can discriminate even single-base mutations. Moreover, the sensing platform can be expanded to detect pollutant-degrading-bacteria-specific DNA sequences. The proposed sensing system should offer an alternative approach for the detection of nucleic acids in the fields of microbiology, biogeochemistry, and environmental sciences. PMID- 26765526 TI - Fibroblast Cell-Based Therapy for Experimental Autoimmune Diabetes. AB - Type 1 diabetes (T1D) results from autoimmune destruction of insulin producing beta cells of the pancreatic islets. Curbing autoimmunity at the initiation of T1D can result in recovery of residual beta cells and consequently remission of diabetes. Here we report a cell-based therapy for autoimmune diabetes in non obese diabetic (NOD) mice using dermal fibroblasts. This was achieved by a single injection of fibroblasts, expressing the immunoregulatory molecule indoleamine 2,3 dioxygenase (IDO), into peritoneal cavity of NOD mice shortly after the onset of overt hyperglycemia. Mice were then monitored for reversal of hyperglycemia and changes in inflammatory/regulatory T cell profiles. Blood glucose levels dropped into the normal range in 82% of NOD mice after receiving IDO-expressing fibroblasts while all control mice remained diabetic. We found significantly reduced islet inflammation, increased regulatory T cells, and decreased T helper 17 cells and beta cell specific autoreactive CD8+ T cells following IDO cell therapy. We further showed that some of intraperitoneal injected fibroblasts migrated to local lymph nodes and expressed co-inhibitory molecules. These findings suggest that IDO fibroblasts therapy can reinstate self-tolerance and alleviate beta cell autoreactivity in NOD mice, resulting in remission of autoimmune diabetes. PMID- 26765530 TI - Single functional magnetic-bead as universal biosensing platform for trace analyte detection using SERS-nanobioprobe. AB - SERS biosensor has demonstrated remarkable potential to analyze various bio/chemical targets with ultrahigh sensitivity. However, the development of universal SERS biosensing platforms with a uniform and reproducible structure that can quantitatively detect a broad range of trace analytes remains a significant challenge. The production of SERS nanotags with abundant Raman reporters and rational structure to conjugate with detection biomolecules is another key to design SERS-nanobioprobes. Here, we introduce a facile single magnetic-bead biosensing platform, formed by combining the captured antibodies/antigens conjugated magnetic-beads and the Au@Raman-Reporters@Ag sandwich-based nanorod tags labeled nanobioprobes. The advantage of the robust sandwich-structure-based nanotags is attributed not only to the high density Raman reporters contained inside, with high EF value because of enhanced electromagnetic field density, but also to the flexibility for bioconjugation of the detection biomolecules. The 3-D structure of the functional magnetic-bead provides a perfect platform to rapidly capture and enrich biomolecules. Ultrasensitive detection of two small molecules and a protein was achieved in samples, respectively. PMID- 26765531 TI - A potentiometric biosensor for rapid on-site disease diagnostics. AB - Quantitative point-of-care (POC) devices are the next generation for serological disease diagnosis. Whilst pathogen serology is typically performed by centralized laboratories using Enzyme-Linked ImmunoSorbent Assay (ELISA), faster on-site diagnosis would infer improved disease management and treatment decisions. Using the model pathogen Bovine Herpes Virus-1 (BHV-1) this study employs an extended gate field-effect transistor (FET) for direct potentiometric serological diagnosis. BHV-1 is a major viral pathogen of Bovine Respiratory Disease (BRD), the leading cause of economic loss ($2 billion annually in the US only) to the cattle and dairy industry. To demonstrate the sensor capabilities as a diagnostic tool, BHV-1 viral protein gE was expressed and immobilized on the sensor surface to serve as a capture antigen for a BHV-1-specific antibody (anti-gE), produced in cattle in response to viral infection. The gE-coated immunosensor was shown to be highly sensitive and selective to anti-gE present in commercially available anti-BHV-1 antiserum and in real serum samples from cattle with results being in excellent agreement with Surface Plasmon Resonance (SPR) and ELISA. The FET sensor is significantly faster than ELISA (<10 min), a crucial factor for successful disease intervention. This sensor technology is versatile, amenable to multiplexing, easily integrated to POC devices, and has the potential to impact a wide range of human and animal diseases. PMID- 26765532 TI - "Light-up" Sensing of human 8-oxoguanine DNA glycosylase activity by target induced autocatalytic DNAzyme-generated rolling circle amplification. AB - Human 8-oxoguanine DNA glycosylase (hOGG1) plays a crucial role in maintaining the genomic integrity of living organisms for its capability of repairing DNA oxidative damage. The expression level of hOGG1 is closely associated with many diseases including various kinds of cancers. In this study, a novel "light-up" sensor based on target-induced formation of 5' phosphorylated probe and autocatalytic DNAzyme-generated rolling circle amplification has been developed for highly sensitive human 8-oxoguanine DNA glycosylase (hOGG1) activity assay. The approach reaches detection limit as low as 0.001U/mL for hOGG1 via scarcely increased background signal and dual signal amplification strategy. To the best of our knowledge, it is one of the most sensitive methods for the detection of base excision repair enzyme. Moreover, the approach shows excellent specificity over other nonspecific enzymes would interfere with the assay and holds great promise for application in real sample analysis. Hence, the proposed method provides a highly sensitive, selective, and desirable hOGG1 sensing platform. PMID- 26765534 TI - A Cyclotriborane Dianion and the Triboron Cation: "Light Ends" of the Huckel Rule. AB - The lightest synthetically accessible Huckel pi-aromatic system, a triboracyclopropenyl dianion bearing three dicyclohexylamino groups, has been obtained by reduction of dicyclohexylaminoboron dichloride and structurally characterized as the dimeric disodium salt (see scheme; Cy=cyclohexyl, DME=1,2 dimethoxyethane). PMID- 26765533 TI - Potential of Radiation-Induced Cellular Stress for Reactivation of Latent HIV-1 and Killing of Infected Cells. AB - The use of highly active antiretroviral therapy against HIV-1 for last two decades has reduced mortality of patients through extension of nonsymptomatic phase of infection. However, HIV-1 can be preserved in long-lived resting CD4(+) T cells, which form a viral reservoir in infected individuals, and potentially in macrophages and astrocytes. Reactivation of viral replication is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus (shock and kill strategy). In this opinion piece, we consider potential application of therapeutic doses of irradiation, the well-known and effective stress signal that induces DNA damage and activates cellular stress response, to resolve two problems: activate HIV-1 replication and virion production in persistent reservoirs under cART and deplete infected cells through selective cell killing using DNA damage responses. PMID- 26765535 TI - Role of Prolactin Receptors in Lymphangioleiomyomatosis. AB - Pulmonary lymphangioleiomyomatosis (LAM) is a rare lung disease caused by mutations in the tumor suppressor genes encoding Tuberous Sclerosis Complex (TSC) 1 and TSC2. The protein product of the TSC2 gene is a well-known suppressor of the mTOR pathway. Emerging evidence suggests that the pituitary hormone prolactin (Prl) has both endocrine and paracrine modes of action. Here, we have investigated components of the Prl system in models for LAM. In a TSC2 (+/-) mouse sarcoma cell line, down-regulation of TSC2 using siRNA resulted in increased levels of the Prl receptor. In human LAM cells, the Prl receptor is detectable by immunohistochemistry, and the expression of Prl in these cells stimulates STAT3 and Erk phosphorylation, as well as proliferation. A high affinity Prl receptor antagonist consisting of Prl with four amino acid substitutions reduced phosphorylation of STAT3 and Erk. Antagonist treatment further reduced the proliferative and invasive properties of LAM cells. In histological sections from LAM patients, Prl receptor immuno reactivity was observed. We conclude that the Prl receptor is expressed in LAM, and that loss of TSC2 increases Prl receptor levels. It is proposed that Prl exerts growth stimulatory effects on LAM cells, and that antagonizing the Prl receptor can block such effects. PMID- 26765537 TI - Correction: Suppression of Interferon Lambda Signaling by SOCS-1 Results in Their Excessive Production during Influenza Virus Infection. AB - [This corrects the article DOI: 10.1371/journal.ppat.1003845.]. PMID- 26765536 TI - RNA-Seq Reveals OTA-Related Gene Transcriptional Changes in Aspergillus carbonarius. AB - Ochratoxin A (OTA) is a mycotoxin harmful for animals and humans. Aspergillus carbonarius is the main responsible for OTA contamination of grapes and derived products. Gene transcriptional profiling of 4 A. carbonarius strains was carried out by RNA-Seq analysis to study transcriptome changes associated with OTA production. By comparing OTA inducing (OTAI) vs. non-inducing (OTAN) cultural conditions, a total of 3,705 differentially expressed genes (DEGs) (fold change > |2| and FDR <= 0.05) were identified. Several genes involved in primary metabolic processes, with particular regard to carbohydrate and amino acid metabolisms, secondary metabolic processes, transport, response to stress and sporulation were up-regulated by OTAI conditions at all the analysed sampling times (4, 6 and 8 DAI) or starting from 6 DAI. Highly up-regulated DEGs encoding enzymes involved in biosynthesis of secondary metabolites, oxidoreductases, transporters and transcription factors were examined for their potential involvement in OTA biosynthesis and related metabolic pathways. Differential expression of genes encoding polyketide synthases (pks), non-ribosomal peptide synthetases (nrps) and chloroperoxidase (cpo) was validated by RT-qPCR. Among clusters of co-regulated genes involved in SM biosynthesis, one putative OTA-gene cluster, including both pks and nrps genes, was detected in the A. carbonarius genome. PMID- 26765538 TI - Three-Phase 3D Reconstruction of a LiCoO2 Cathode via FIB-SEM Tomography. AB - Three-phase three-dimensional (3D) microstructural reconstructions of lithium-ion battery electrodes are critical input for 3D simulations of electrode lithiation/delithiation, which provide a detailed understanding of battery operation. In this report, 3D images of a LiCoO2 electrode are achieved using focused ion beam-scanning electron microscopy (FIB-SEM), with clear contrast among the three phases: LiCoO2 particles, carbonaceous phases (carbon and binder) and the electrolyte space. The good contrast was achieved by utilizing an improved FIB-SEM sample preparation method that combined infiltration of the electrolyte space with a low-viscosity silicone resin and triple ion-beam polishing. Morphological parameters quantified include phase volume fraction, surface area, feature size distribution, connectivity, and tortuosity. Electrolyte tortuosity was determined using two different geometric calculations that were in good agreement. The electrolyte tortuosity distribution versus position within the electrode was found to be highly inhomogeneous; this will lead to inhomogeneous electrode lithiation/delithiation at high C-rates that could potentially cause battery degradation. PMID- 26765539 TI - Do Emotions Expressed Online Correlate with Actual Changes in Decision-Making?: The Case of Stock Day Traders. AB - Emotions are increasingly inferred linguistically from online data with a goal of predicting off-line behavior. Yet, it is unknown whether emotions inferred linguistically from online communications correlate with actual changes in off line activity. We analyzed all 886,000 trading decisions and 1,234,822 instant messages of 30 professional day traders over a continuous 2 year period. Linguistically inferring the traders' emotional states from instant messages, we find that emotions expressed in online communications reflect the same distributions of emotions found in controlled experiments done on traders. Further, we find that expressed online emotions predict the profitability of actual trading behavior. Relative to their baselines, traders who expressed little emotion or traders that expressed high levels of emotion made relatively unprofitable trades. Conversely, traders expressing moderate levels of emotional activation made relatively profitable trades. PMID- 26765541 TI - A New Era of Methanogenesis Research. AB - The reductive acetyl-CoA pathway coupled to methanogenesis is likely one of Earth's oldest metabolisms. Yet, until recently this metabolism had only been found in the kingdom Euryarchaeota. A study now suggests that distantly related Bathyarchaeota are also methanogens and that methane metabolism is more phylogenetically widespread than previously thought. PMID- 26765542 TI - Evaluating the Substrate Selectivity of Alkyladenine DNA Glycosylase: The Synergistic Interplay of Active Site Flexibility and Water Reorganization. AB - Human alkyladenine DNA glycosylase (AAG) functions as part of the base excision repair (BER) pathway by cleaving the N-glycosidic bond that connects nucleobases to the sugar-phosphate backbone in DNA. AAG targets a range of structurally diverse purine lesions using nonspecific DNA-protein pi-pi interactions. Nevertheless, the enzyme discriminates against the natural purines and is inhibited by pyrimidine lesions. This study uses molecular dynamics simulations and seven different neutral or charged substrates, inhibitors, or canonical purines to probe how the bound nucleotide affects the conformation of the AAG active site, and the role of active site residues in dictating substrate selectivity. The neutral substrates form a common DNA-protein hydrogen bond, which results in a consistent active site conformation that maximizes pi-pi interactions between the aromatic residues and the nucleobase required for catalysis. Nevertheless, subtle differences in DNA-enzyme contacts for different neutral substrates explain observed differential catalytic efficiencies. In contrast, the exocyclic amino groups of the natural purines clash with active site residues, which leads to catalytically incompetent DNA-enzyme complexes due to significant reorganization of active site water. Specifically, water resides between the A nucleobase and the active site aromatic amino acids required for catalysis, while a shift in the position of the general base (E125) repositions (potentially nucleophilic) water away from G. Despite sharing common amino groups, the methyl substituents in cationic purine lesions (3MeA and 7MeG) exhibit repulsion with active site residues, which repositions the damaged bases in the active site in a manner that promotes their excision. Overall, we provide a structural explanation for the diverse yet discriminatory substrate selectivity of AAG and rationalize key kinetic data available for the enzyme. Specifically, our results highlight the complex interplay of many different DNA-protein interactions used by AAG to facilitate BER, as well as the crucial role of the general base and water (nucleophile) positioning. The insights gained from our work will aid the understanding of the function of other enzymes that use flexible active sites to exhibit diverse substrate specificity. PMID- 26765543 TI - Rituximab Therapy for Childhood Pemphigus Vulgaris. AB - Pediatric pemphigus vulgaris (PV) is a rare autoimmune bullous dermatosis that poses a diagnostic and therapeutic challenge. Rituximab, an anti-CD20 monoclonal antibody, is an important medication in adult PV but has rarely been used to treat pediatric disease. We describe successful rituximab therapy in a 4-year old, the youngest patient with PV ever reported to receive rituximab. A live attenuated vaccination was later given without incident. We also review rituximab clinical outcomes, toxicity, dosing protocols, and relapse in children with PV. PMID- 26765540 TI - Chromosomal Integrity after UV Irradiation Requires FANCD2-Mediated Repair of Double Strand Breaks. AB - Fanconi Anemia (FA) is a rare autosomal recessive disorder characterized by hypersensitivity to inter-strand crosslinks (ICLs). FANCD2, a central factor of the FA pathway, is essential for the repair of double strand breaks (DSBs) generated during fork collapse at ICLs. While lesions different from ICLs can also trigger fork collapse, the contribution of FANCD2 to the resolution of replication-coupled DSBs generated independently from ICLs is unknown. Intriguingly, FANCD2 is readily activated after UV irradiation, a DNA-damaging agent that generates predominantly intra-strand crosslinks but not ICLs. Hence, UV irradiation is an ideal tool to explore the contribution of FANCD2 to the DNA damage response triggered by DNA lesions other than ICL repair. Here we show that, in contrast to ICL-causing agents, UV radiation compromises cell survival independently from FANCD2. In agreement, FANCD2 depletion does not increase the amount of DSBs generated during the replication of UV-damaged DNA and is dispensable for UV-induced checkpoint activation. Remarkably however, FANCD2 protects UV-dependent, replication-coupled DSBs from aberrant processing by non homologous end joining, preventing the accumulation of micronuclei and chromatid aberrations including non-homologous chromatid exchanges. Hence, while dispensable for cell survival, FANCD2 selectively safeguards chromosomal stability after UV-triggered replication stress. PMID- 26765544 TI - Angle Insensitive Color Filters in Transmission Covering the Visible Region. AB - Angle insensitive color filter based on Metal-SiOx-Metal structure is proposed in this paper, which can keep the same perceived transmitted color when the incidence angle changes from 0 degrees to 60 degrees , especially for p polarization light. Various silicon oxide films deposited by reaction magnetron sputtering with a tunable refractive index from 1.97 to 3.84 is introduced to meet the strict angle insensitive resonance conditions. The angle resolved spectral filtering for both p-polarization light and s-polarization light are quite well, which can be attributed to the different physical origins for the high angular tolerance for two polarizations. Finally, the effect of SiOx absorption and Ag thickness on the peak transmittance are analyzed. PMID- 26765545 TI - Triggering of Suicidal Erythrocyte Death by Regorafenib. AB - BACKGROUND/AIMS: The multikinase inhibitor regorafenib is utilized for the treatment of malignancy. The substance is effective in part by triggering suicidal death or apoptosis of tumor cells. Side effects of regorafenib include anemia. At least in theory, regorafenib induced anemia could result from stimulated suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress and ceramide. The present study explored, whether regorafenib induces eryptosis and, if so, whether it is effective up- and/or downstream of Ca2+. METHODS: To this end, phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. RESULTS: A 48 hours exposure of human erythrocytes to regorafenib (>= 0.5 ug/ml) significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter (>= 1.25 ug/ml), but did not significantly increase Fluo3 fluorescence, DCFDA fluorescence or ceramide abundance. The effect of regorafenib on annexin-V-binding and forward scatter was not significantly blunted by removal of extracellular Ca2+. Regorafenib (5 ug/ml) significantly augmented the increase of annexin-V-binding, but significantly blunted the decrease of forward scatter following treatment with the Ca2+ ionophore ionomycin. CONCLUSIONS: Regorafenib triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part downstream of Ca2+. PMID- 26765546 TI - Multigenerational legacies of trauma: Modeling the what and how of transmission. AB - To operationalize the theory of Trauma and the Continuity of Self: A Multidimensional, Multidisciplinary, Integrative Framework (Danieli, 1998), we created a testable model using factors in Holocaust survivors' lives that may have affected their offspring's adaptation. A web-based sample of 422 adult children of survivors completed a 3-part inventory assessing multigenerational legacies of trauma. To explain the severity of the child's reparative adaptational impacts, we conducted hierarchical regression analyses (Phase 1) and path analyses (Phase 2). We hypothesized that these impacts followed largely from the (child-reported) intensities of parents' victim, numb, and fighter posttrauma adaptational styles. These styles, in turn, followed from family history and post Holocaust family milieu. With all effects of family history and milieu on offspring specified as indirect (through parents' victim styles), the initial path model fit the data well with one exception: Broken generational linkages had direct as well as indirect effects. While survivors' Holocaust experiences especially internment-had significant indirect effects on their children, each component of post-Holocaust family milieu had one or more associations with mothers' and fathers' victim, numb, and/or fighter styles. The strongest relationships emerged for broken generational linkages-a risk factor for negative effects-and sociocultural setting (living in Israel rather than North America)-a protective factor. Because the healing processes that underlie observed effects of family milieu are malleable, survivors' and offspring's suffering might be reduced through efforts to recapture meaning, purpose, identity, connectedness of past, present and future, and attachments to community and place. (PsycINFO Database Record PMID- 26765547 TI - South Asian adolescents' experiences of acculturative stress and coping. AB - Despite the significant growth in the South Asian population in the United States over the past 2 decades, the experiences of South Asian adolescents have remained largely invisible. Guided by a socioecological perspective (American Psychological Association, 2012; Garcia Coll & Marks, 2012), this study examined South Asian adolescents' experiences of acculturative stress and approaches to coping with this stress across home and school contexts. A semistructured interview was completed by 16 participants (9 girls, 7 boys; ages 14-18 years) from different South Asian backgrounds, attending an urban public high school in the Northeastern part of the United States. Conventional content analysis was used to analyze the interview data, and revealed 4 broad categories or domains related to participants' experiences as young South Asians in the U.S. These domains include the following: (a) Connection to family, community, and heritage; (b) Challenges to acculturation; (c) Stress accompanying the navigation across cultural contexts; and (d) Coping and resilience. Participants' narratives reflect acculturative stress experienced in home and school contexts which can inhibit psychological well-being and bicultural identity development. The findings have important implications for culturally informed research, intervention, and policy. (PsycINFO Database Record PMID- 26765548 TI - Retained placenta: will medical treatment ever be possible? AB - The standard treatment for retained placenta is manual removal whatever its subtype (adherens, trapped or partial accreta). Although medical treatment should reduce the risk of anesthetic and surgical complications, they have not been found to be effective. This may be due to the contrasting uterotonic needs of the different underlying pathologies. In placenta adherens, oxytocics have been used to contract the retro-placental myometrium. However, if injected locally through the umbilical vein, they bypass the myometrium and perfuse directly into the venous system. Intravenous injection is an alternative but exacerbates a trapped placenta. Conversely, for trapped placentas, a relaxant could help by resolving cervical constriction, but would worsen the situation for placenta adherens. This confusion over medical treatment will continue unless we can find a way to diagnose the underlying pathology. This will allow us to stop treating the retained placenta as a single entity and to deliver targeted treatments. PMID- 26765549 TI - Clinical factors associated with readmission for postpartum hypertension in women with pregnancy-related hypertension: a nested case control study. AB - OBJECTIVE: To evaluate the association between mode of delivery and length of labor on readmission for postpartum hypertension in women with pregnancy-related hypertension. STUDY DESIGN: Nested case control study within a cohort of 99 women with pregnancy-related hypertension who delivered at our institution between 2005 and 2009. Data were abstracted for clinical and labor information. Mode of delivery and length of labor were compared between women with previously diagnosed pregnancy-related hypertension readmitted within 4 weeks post partum (25 cases) and those not readmitted (74 controls). Categorical and continuous variables were compared using chi(2) and T-tests, respectively. Multivariable logistic regression controlled for confounders. RESULT: Hypertension readmission was not associated with mode of delivery (cases: 10(40%) spontaneous vaginal delivery, 15(60%) cesarean delivery; controls: 38(51%) spontaneous vaginal delivery, 36(49%) cesarean delivery, P=0.33). Length of labor appeared longer in cases, with a trend toward significance (median: 15.5 [7,28] h vs 10.75 [5.8,15.9] h, P=0.12) and was significantly associated with readmission after controlling for delivery mode, induction and parity (adjusted odds ratio=1.06 [1 to 1.12], P=0.048). Readmitted patients were less likely to have initially been started on antihypertensive medications after controlling for age, race and chronic hypertension (adjusted odds ratio=0.23 [0.06 to 0.88], P=0.03). CONCLUSION: Postpartum readmission for hypertension in women with known pregnancy related hypertension is not associated with mode of delivery, appears increased in those with longer length of labor and decreased in those initially started on antihypertensive medications. This provides targets for future research to continue to improve transitions of care and reduce preventable readmissions. PMID- 26765550 TI - The impact of a dedicated patent ductus arteriosus ligation team on neonatal health-care outcomes. AB - OBJECTIVE: The decision to perform patent ductus arteriosus (PDA) ligation is controversial. Patient selection is oftentimes poorly standardized, leading to delays in referral and inappropriate intervention. A system for PDA ligation categorization and triaging process was introduced in 2006 at a quaternary hospital in Canada to streamline referrals and enhance perioperative care. We aimed to evaluate the impact of this dedicated PDA ligation triaging system comparing pre- and postimplementation of this system. STUDY DESIGN: We performed a retrospective chart review. Demographic and cardiorespiratory data of neonates ?30 weeks gestation age at birth, who were referred for and/or had a PDA ligation performed during two distinct epochs (EPOCH 1 (2003 to 2005) and EPOCH 2 (2010 to 2012)), were analyzed. All surgeries were performed at The Hospital for Sick Children, the regional referral center for PDA ligation. The primary outcome was incidence of PDA ligation and procedural cancellations. Secondary outcomes included postoperative need for cardiovascular or respiratory support. Subgroup analysis was performed in neonates <1000 vs >1000 g at the time of surgery during both epochs. RESULT: A total of 198 neonates underwent surgery with no difference in baseline demographics between epochs. The incidence of PDA ligation as a proportion of total live births under 30 weeks in Central East Region of Ontario was lower in the second epoch (EPOCH 1: 117/1092 (10.7%) vs EPOCH 2: 81/1520 (5.3%)). During the second epoch, 24% of referrals for surgery were canceled after review by our PDA ligation team. There were no overall differences in the proportion of neonates with oxygenation failure, ventilation failure or Post Ligation Cardiac Syndrome (PLCS), after surgery, between epochs. The proportion of neonates who developed systemic hypotension was higher in patients <1000 g (n=34 (34%) vs n=17 (17.4%), P=0.01) at the time of surgery. In addition, we identified a reduction in the proportion of neonates <1000 g who developed PLCS in EPOCH 2. On the contrary, there was an increase in the proportion of neonates >1000 g who developed ventilation failure in EPOCH 2. CONCLUSION: The presence of dedicated triaging and management system enhances efficiency of referral process through careful selection of patients for PDA ligation and optimizes perioperative management. We demonstrated a reduction in the incidence of PDA ligation without any negative impact on short-term neonatal morbidity. The use of targeted neonatal echocardiography in the assessment of PDA shunt volume and guiding postoperative decision making is likely to have contributed to these findings. PMID- 26765551 TI - Carboxyhemoglobin levels as a predictor of risk for significant hyperbilirubinemia in African-American DAT(+) infants. AB - OBJECTIVES: To compare the degree of hemolysis in a group of direct antiglobulin test (DAT) positive (pos) African-American (AA) infants as measured by carboxyhemoglobin corrected (COHbc) for carbon monoxide in ambient air to a similar group of DAT negative (neg) ABO incompatible infants and a group without blood group incompatibility. To determine if COHbc is a better predictor of significant hyperbilirubinemia than DAT status. STUDY DESIGN: A prospective study of 180 AA infants from the Well-Baby Nursery of an inner city community hospital, all of whose mothers were type O pos. Infants (60) were ABO incompatible DAT pos, 60 were ABO incompatible DAT neg and 60 were type O(+). Blood for COHbc was drawn at the time of the infants' initial bilirubin and the infants' precise percentile on the Bhutani nomogram was calculated. RESULT: Mean COHbc of type O(+) infants was 0.76+/-0.21 and 0.78+/-0.24% for ABO incompatible DAT neg infants (P=0.63). Mean CoHbc for the ABO incompatible DAT pos infants was 1.03+/-0.41% (P<0.0001 compared with both type O and DAT neg infants). Optimal cutoff on the receiver operating characteristic curve for COHbc to determine the risk for being in the Bhutani curve high risk zone was COHbc >0.90% (area under the curve(AUC) 0.8113). This was similar to the AUC of the receiver operating characteristic curve using any titer strength of DAT pos as a cutoff (0.7960). CONCLUSION: Although not greatly superior to the titer strength of DAT pos, COHbc is useful in determining if the etiology of severe hyperbilirubinemia is a hemolytic process. PMID- 26765553 TI - Radiographic depiction of intra-abdominal fat in newborns: a marker of infants born to diabetic mothers. AB - OBJECTIVE: To examine whether the presence of intra-abdominal fat (IAF) in newborns is diagnostic of infants of diabetic mothers (IDMs), and determine whether IAF is merely the consequence of increased body size. STUDY DESIGN: Abdominal radiographs of 277 neonates >34 weeks gestational age (147 male and 130 female) were reviewed to determine the presence of IAF. Unpaired t-test and regression analyses were used to examine the influence of gestational age, birth weight, birth length and maternal diabetes on the prevalence and thickness of IAF. RESULT: The prevalence of IAF was higher in IDMs (41.2% vs 13.2%; P<0.0001) an association that persisted even after accounting for sex, gestational age and weight. Both birth weight and maternal diabetic status influenced the amount of IAF. Values of IAF thickness in IDMs were, however, more than threefold greater than those in non-IDMs (2.53+/-2.08 vs 0.81+/-0.29 mm; P<0.0001). An IAF thickness >1.5 mm was indicative of an IDM. CONCLUSION: The depiction of IAF in radiographs is significantly more prevalent in IDMs when compared with non-IDMs, regardless of body size. A thickness of IAF >1.5 mm is a marker that should encourage work-up for the physiological, metabolic and congenital complications associated with IDM. PMID- 26765552 TI - Bone status in preterm infant: influences of different nutritional regimens and possible markers of bone disease. AB - OBJECTIVE: The objective of this study was to evaluate possible influences of parenteral nutrition on growth and bone development in preterms and to search for markers of bone status. STUDY DESIGN: Metacarpus bone transmission time (mc-BTT) was performed at birth, 21 days and 36 weeks of gestational age (GA) in preterms, receiving two different nutritional regimens, together with biochemical analysis. RESULT: A total of 234 patients were studied. Newborns with aggressive nutrition had significantly better growth rate and higher values of mc-BTT until discharge. Mc-BTT at day 21 correlates positively with nutritional intakes and phosphatemia; lower limb length positively correlated with mc-BTT (P<0.01). Newborns with low energy intake in the first week of life (<70 kcal kg(-1) per day) and low serum phosphate level (<1.4 mmol l(-1)) at 21 days had lower mc-BTT at 36 weeks of GA (P<0.01). CONCLUSION: Aggressive parenteral intakes in preterms improve growth and bone status in the short-medium term, suggesting that early nutrition could influence bone development. PMID- 26765554 TI - Does measurement of four-limb blood pressures at birth improve detection of aortic arch anomalies? AB - OBJECTIVE: To determine normal four-extremity blood pressure (BP) in the neonatal intensive care unit (NICU) at birth and the utility of upper (UE) and lower extremity (LE) BP difference to screen for coarctation of the aorta (Co-A) and interrupted the aortic arch (IAA). STUDY DESIGN: Retrospective study of BP at birth (n=866), and case-control study of Co-A/IAA infants and matched controls (1:2). RESULT: Although BP increased with gestational age (R(2)=0.3, P<0.0001), the pressure gradient between UE and LE did not change with gestation (P=0.68). Forty-six cases of Co-A/IAA were identified, with 92 controls. Pressure gradient was significantly higher in patients with Co-A/IAA (7.6+/-14.8 versus 0.4+/-10 mm Hg, P=0.004). However, there was overlap between cases and controls resulting in low sensitivity (41.3% with ?10 mm Hg gradient cutoff). CONCLUSION: Evaluation of UE-LE BP gradient at birth is a poor screening test for Co-A/IAA with low sensitivity. Repeating four-limb BP after ductal closure at 24 to 48 h along with SpO2 screening for critical congenital heart disease may increase sensitivity. PMID- 26765555 TI - A pilot prospective study of fetomaternal hemorrhage identified by anemia in asymptomatic neonates. AB - OBJECTIVE: Fetomaternal hemorrhage (FMH) is a poorly understood condition in which fetal erythrocytes transfer to the maternal circulation via a faulty placental barrier. Little is known about the true incidence, epidemiology or pathophysiology of FMH in the general pregnant population as existing studies are based on retrospective cohorts and manifest diagnosis and selection bias. The objective of this study was to evaluate the practicability of a prospective study of FMH in the general population based on antepartum maternal blood testing and neonatal anemia. STUDY DESIGN: Prospective cohort study. RESULT: Nineteen pregnant women were enrolled prior to the term delivery of 20 well infants. Five neonates were unexpectedly anemic on first postnatal testing. Antenatal maternal blood samples associated with two of the five anemic newborns had positive Kleihauer-Betke testing while no newborn with a normal postnatal blood count had an associated abnormal Kleihauer-Betke test. CONCLUSION: Clinically significant FMH may be more common than previously thought. Prospective epidemiological study of FMH is feasible. PMID- 26765558 TI - Topical Interferon Alpha-2b for Diffuse Conjunctival Primary Acquired Melanosis with Atypia. PMID- 26765556 TI - Assessment of endotracheal tube placement in newborn infants: a randomized controlled trial. AB - OBJECTIVE: International resuscitation guidelines recommend clinical assessment and exhaled CO2 to confirm tube placement immediately after intubation. However, exhaled CO2 devices can display false negative results. In comparison, any respiratory function monitor can be used to measure and display gas flow in and out of an endotracheal tube. However, neither method has been examined in detail. We hypothesized that a flow sensor would improve the assessment of tracheal vs esophageal tube placement in neonates with a higher success rate and a shorter time to tube placement confirmation when compared with the use of a quantitative end-tidal CO2 (ETCO2) detector. STUDY DESIGN: Between December 2013 and September 2014, preterm and term infants requiring endotracheal intubation were eligible for inclusion and randomly allocated to either ETCO2 ('ETCO2 group') or flow sensor ('flow sensor group'). All infants were analyzed according to their group at randomization (that is, analysis was by intention-to-treat). RESULT: During the study period, a total of 110 infants (n=55 for each group) were randomized. Successful endotracheal tube placements were correctly identified in 100% of cases by the flow sensor compared with 72% of cases with the ETCO2 detector within 10 inflations (P<0.05). The median (interquartile range) number of inflations needed to identify successful tube placement was significantly lower in the flow sensor group with 2 (1 to 3) inflations vs 8 (6 to 10) inflations with the ETCO2 detector (P<0.001). CONCLUSION: A flow sensor would improve the assessment of successful endotracheal tube placement with a higher success rate and a shorter time compared with an ETCO2 detector. PMID- 26765557 TI - Relationship between parity and brachial plexus injuries. AB - OBJECTIVE: Few characteristics have been identified as risk factors for brachial plexus injuries. We sought to investigate a potential relationship with multiparity based on clinical observation at our institution. STUDY DESIGN: In this retrospective case series, we analyzed all brachial plexus injuries recognized at or after delivery between October 2003 and March 2013 (n=78) at a single academic medical institution. Patient, infant, labor and delivery characteristics were compared for women with and without prior vaginal deliveries. RESULT: Of the 78 injuries, 71 (91%) occurred after a vaginal delivery and 7 (9%) after a cesarean delivery. Of the 71 injuries after a vaginal delivery, 58% occurred in women with a prior vaginal delivery (n=41, 5.7 per 10 000 live births) compared with 42% without a prior vaginal delivery (n=30, 4.0 per 10 000 live births). Multiparous patients had shorter labor courses and fewer labor interventions than nulliparous patients. Providers clinically underestimated the birth weights to a greater extent in multiparas than in nulliparas (median underestimation 590 vs 139 g, P=0.0016). The median birth weight was 4060 g in the multiparous group, which was significantly larger than affected infants born to the nulliparous group (3591 g, P=0.006). The affected infants of the multiparous group were, as expected, significantly larger than their previously born siblings (median 567 g larger, P<0.001). CONCLUSION: Brachial plexus injuries occurred as frequently in multiparous patients as in nulliparous patients. In general, multiparous patients are more likely to have larger infants; however, providers significantly underestimate the birth weight of their infants. The findings of this study should deter providers from assuming that a prior vaginal delivery is protective against brachial plexus injuries. PMID- 26765559 TI - A review of the economics of adult congenital heart disease. AB - Adults living with congenital heart disease (CHD) now outnumber children with the disease. Thanks to medical advances over the past 75 years, many of these fatal childhood heart problems have changed to chronic medical conditions. As the population of adults with CHD increases, they will require increasingly complex medical, surgical and catheter-based therapies. In addition, social burdens including education, employment and insurability, which increase the societal costs of adult CHD, are now being recognized for adults living with CHD. This review summarizes the available literature on the economics of adult CHD. PMID- 26765560 TI - Evaluation of predictions of the stochastic model of organelle production based on exact distributions. AB - We present a reanalysis of the stochastic model of organelle production and show that the equilibrium distributions for the organelle numbers predicted by this model can be readily calculated in three different scenarios. These three distributions can be identified as standard distributions, and the corresponding exact formulae for their mean and variance can therefore be used in further analysis. This removes the need to rely on stochastic simulations or approximate formulae (derived using the fluctuation dissipation theorem). These calculations allow for further analysis of the predictions of the model. On the basis of this we question the extent to which the model can be used to conclude that peroxisome biogenesis is dominated by de novo production when Saccharomyces cerevisiae cells are grown on glucose medium. PMID- 26765561 TI - Rho-associated kinase (ROCK) function is essential for cell cycle progression, senescence and tumorigenesis. AB - Rho-associated kinases 1 and 2 (ROCK1/2) are Rho-GTPase effectors that control key aspects of the actin cytoskeleton, but their role in proliferation and cancer initiation or progression is not known. Here, we provide evidence that ROCK1 and ROCK2 act redundantly to maintain actomyosin contractility and cell proliferation and that their loss leads to cell-cycle arrest and cellular senescence. This phenotype arises from down-regulation of the essential cell-cycle proteins CyclinA, CKS1 and CDK1. Accordingly, while the loss of either Rock1 or Rock2 had no negative impact on tumorigenesis in mouse models of non-small cell lung cancer and melanoma, loss of both blocked tumor formation, as no tumors arise in which both Rock1 and Rock2 have been genetically deleted. Our results reveal an indispensable role for ROCK, yet redundant role for isoforms 1 and 2, in cell cycle progression and tumorigenesis, possibly through the maintenance of cellular contractility. PMID- 26765562 TI - The Sec7 N-terminal regulatory domains facilitate membrane-proximal activation of the Arf1 GTPase. AB - The Golgi complex is the central sorting compartment of eukaryotic cells. Arf guanine nucleotide exchange factors (Arf-GEFs) regulate virtually all traffic through the Golgi by activating Arf GTPase trafficking pathways. The Golgi Arf GEFs contain multiple autoregulatory domains, but the precise mechanisms underlying their function remain largely undefined. We report a crystal structure revealing that the N-terminal DCB and HUS regulatory domains of the Arf-GEF Sec7 form a single structural unit. We demonstrate that the established role of the N terminal region in dimerization is not conserved; instead, a C-terminal autoinhibitory domain is responsible for dimerization of Sec7. We find that the DCB/HUS domain amplifies the ability of Sec7 to activate Arf1 on the membrane surface by facilitating membrane insertion of the Arf1 amphipathic helix. This enhancing function of the Sec7 N-terminal domains is consistent with the high rate of Arf1-dependent trafficking to the plasma membrane necessary for maximal cell growth. PMID- 26765563 TI - Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel. AB - Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa21), is the most common cause of congenital heart defects (CHD), yet the genetic and mechanistic causes of these defects remain unknown. To identify dosage-sensitive genes that cause DS phenotypes, including CHD, we used chromosome engineering to generate a mapping panel of 7 mouse strains with partial trisomies of regions of mouse chromosome 16 orthologous to Hsa21. Using high-resolution episcopic microscopy and three-dimensional modeling we show that these strains accurately model DS CHD. Systematic analysis of the 7 strains identified a minimal critical region sufficient to cause CHD when present in 3 copies, and showed that it contained at least two dosage-sensitive loci. Furthermore, two of these new strains model a specific subtype of atrio-ventricular septal defects with exclusive ventricular shunting and demonstrate that, contrary to current hypotheses, these CHD are not due to failure in formation of the dorsal mesenchymal protrusion. PMID- 26765564 TI - Bistability of a coupled Aurora B kinase-phosphatase system in cell division. AB - Aurora B kinase, a key regulator of cell division, localizes to specific cellular locations, but the regulatory mechanisms responsible for phosphorylation of substrates located remotely from kinase enrichment sites are unclear. Here, we provide evidence that this activity at a distance depends on both sites of high kinase concentration and the bistability of a coupled kinase-phosphatase system. We reconstitute this bistable behavior and hysteresis using purified components to reveal co-existence of distinct high and low Aurora B activity states, sustained by a two-component kinase autoactivation mechanism. Furthermore, we demonstrate these non-linear regimes in live cells using a FRET-based phosphorylation sensor, and provide a mechanistic theoretical model for spatial regulation of Aurora B phosphorylation. We propose that bistability of an Aurora B-phosphatase system underlies formation of spatial phosphorylation patterns, which are generated and spread from sites of kinase autoactivation, thereby regulating cell division. PMID- 26765565 TI - Mapping the functional versatility and fragility of Ras GTPase signaling circuits through in vitro network reconstitution. AB - The Ras-superfamily GTPases are central controllers of cell proliferation and morphology. Ras signaling is mediated by a system of interacting molecules: upstream enzymes (GEF/GAP) regulate Ras's ability to recruit multiple competing downstream effectors. We developed a multiplexed, multi-turnover assay for measuring the dynamic signaling behavior of in vitro reconstituted H-Ras signaling systems. By including both upstream regulators and downstream effectors, we can systematically map how different network configurations shape the dynamic system response. The concentration and identity of both upstream and downstream signaling components strongly impacted the timing, duration, shape, and amplitude of effector outputs. The distorted output of oncogenic alleles of Ras was highly dependent on the balance of positive (GAP) and negative (GEF) regulators in the system. We found that different effectors interpreted the same inputs with distinct output dynamics, enabling a Ras system to encode multiple unique temporal outputs in response to a single input. We also found that different Ras-to-GEF positive feedback mechanisms could reshape output dynamics in distinct ways, such as signal amplification or overshoot minimization. Mapping of the space of output behaviors accessible to Ras provides a design manual for programming Ras circuits, and reveals how these systems are readily adapted to produce an array of dynamic signaling behaviors. Nonetheless, this versatility comes with a trade-off of fragility, as there exist numerous paths to altered signaling behaviors that could cause disease. PMID- 26765566 TI - An oxygen-insensitive Hif-3alpha isoform inhibits Wnt signaling by destabilizing the nuclear beta-catenin complex. AB - Hypoxia-inducible factors (HIFs), while best known for their roles in the hypoxic response, have oxygen-independent roles in early development with poorly defined mechanisms. Here, we report a novel Hif-3alpha variant, Hif-3alpha2, in zebrafish. Hif-3alpha2 lacks the bHLH, PAS, PAC, and ODD domains, and is expressed in embryonic and adult tissues independently of oxygen availability. Hif-3alpha2 is a nuclear protein with significant hypoxia response element (HRE) dependent transcriptional activity. Hif-3alpha2 overexpression not only decreases embryonic growth and developmental timing but also causes left-right asymmetry defects. Genetic deletion of Hif-3alpha2 by CRISPR/Cas9 genome editing increases, while Hif-3alpha2 overexpression decreases, Wnt/beta-catenin signaling. This action is independent of its HRE-dependent transcriptional activity. Mechanistically, Hif-3alpha2 binds to beta-catenin and destabilizes the nuclear beta-catenin complex. This mechanism is distinct from GSK3beta-mediated beta catenin degradation and is conserved in humans. These findings provide new insights into the oxygen-independent actions of HIFs and uncover a novel mechanism regulating Wnt/beta-catenin signaling. PMID- 26765567 TI - An effector of the Irish potato famine pathogen antagonizes a host autophagy cargo receptor. AB - Plants use autophagy to safeguard against infectious diseases. However, how plant pathogens interfere with autophagy-related processes is unknown. Here, we show that PexRD54, an effector from the Irish potato famine pathogen Phytophthora infestans, binds host autophagy protein ATG8CL to stimulate autophagosome formation. PexRD54 depletes the autophagy cargo receptor Joka2 out of ATG8CL complexes and interferes with Joka2's positive effect on pathogen defense. Thus, a plant pathogen effector has evolved to antagonize a host autophagy cargo receptor to counteract host defenses. PMID- 26765568 TI - NuMA-microtubule interactions are critical for spindle orientation and the morphogenesis of diverse epidermal structures. AB - Mitotic spindle orientation is used to generate cell fate diversity and drive proper tissue morphogenesis. A complex of NuMA and dynein/dynactin is required for robust spindle orientation in a number of cell types. Previous research proposed that cortical dynein/dynactin was sufficient to generate forces on astral microtubules (MTs) to orient the spindle, with NuMA acting as a passive tether. In this study, we demonstrate that dynein/dynactin is insufficient for spindle orientation establishment in keratinocytes and that NuMA's MT-binding domain, which targets MT tips, is also required. Loss of NuMA-MT interactions in skin caused defects in spindle orientation and epidermal differentiation, leading to neonatal lethality. In addition, we show that NuMA-MT interactions are also required in adult mice for hair follicle morphogenesis and spindle orientation within the transit-amplifying cells of the matrix. Loss of spindle orientation in matrix cells results in defective differentiation of matrix-derived lineages. Our results reveal an additional and direct function of NuMA during mitotic spindle positioning, as well as a reiterative use of spindle orientation in the skin to build diverse structures. PMID- 26765569 TI - NF-kappaB oscillations translate into functionally related patterns of gene expression. AB - Several transcription factors (TFs) oscillate, periodically relocating between the cytoplasm and the nucleus. NF-kappaB, which plays key roles in inflammation and cancer, displays oscillations whose biological advantage remains unclear. Recent work indicated that NF-kappaB displays sustained oscillations that can be entrained, that is, reach a persistent synchronized state through small periodic perturbations. We show here that for our GFP-p65 knock-in cells NF-kappaB behaves as a damped oscillator able to synchronize to a variety of periodic external perturbations with no memory. We imposed synchronous dynamics to prove that transcription of NF-kappaB-controlled genes also oscillates, but mature transcript levels follow three distinct patterns. Two sets of transcripts accumulate fast or slowly, respectively. Another set, comprising chemokine and chemokine receptor mRNAs, oscillates and resets at each new stimulus, with no memory of the past. We propose that TF oscillatory dynamics is a means of segmenting time to provide renewing opportunity windows for decision. PMID- 26765570 TI - Estradiol Rapidly Attenuates ORL-1 Receptor-Mediated Inhibition of Proopiomelanocortin Neurons via Gq-Coupled, Membrane-Initiated Signaling. AB - Estradiol rapidly regulates the activity of arcuate nucleus (ARH) proopiomelanocortin (POMC) neurons that project to the medial preoptic nucleus (MPN) to regulate lordosis. Orphanin FQ/nociceptin (OFQ/N) acts via opioid receptor-like (ORL)-1 receptors to inhibit these POMC neurons. Therefore, we tested the hypothesis that estradiol excites POMC neurons by rapidly attenuating inhibitory ORL-1 signaling in these cells. Hypothalamic slices through the ARH were prepared from ovariectomized rats injected with Fluorogold into the MPN. Electrophysiological recordings were generated in ARH neurons held at or near -60 mV, and neuronal phenotype was determined post hoc by immunohistofluorescence. OFQ/N application induced robust outward currents and hyperpolarizations via G protein-gated, inwardly rectifying K+ (GIRK) channels that were attenuated by pretreatment with either 17-beta estradiol (E2) or E2 conjugated to bovine serum albumin. This was blocked by the estrogen receptor (ER) antagonist ICI 182,780 and mimicked by the Gq-coupled membrane ER (Gq-mER) ligand STX and the ERalpha agonist PPT. Inhibiting phosphatidylinositol-3-kinase (PI3K) blocked the estrogenic attenuation of ORL-1/GIRK currents. Antagonizing either phospholipase C (PLC), protein kinase C (PKC), protein kinase A (PKA) or neuronal nitric oxide synthase (nNOS) also abrogated E2 inhibition of ORL-1/GIRK currents, whereas activation of PKC, PKA, protein kinase B (Akt) and nNOS substrate L-arginine all attenuated the OFQ/N response. This was observed in 92 MPN-projecting, POMC positive ARH neurons. Thus, ORL-1 receptor-mediated inhibition of POMC neurons is rapidly and negatively modulated by E2, an effect which is stereoselective and membrane initiated via Gq-mER and ERalpha activation that signals through PLC, PKC, PKA, PI3K and nNOS. PMID- 26765575 TI - Serum Glycated Albumin to Guide the Diagnosis of Diabetes Mellitus. AB - In the diagnosis of diabetes mellitus, hemoglobin A1c (HbA1c) is sometimes measured to determine the need of an oral glucose tolerance test (OGTT). However, HbA1c does not accurately reflect glycemic status in certain conditions. This study was performed to test the possibility that measurement of serum glycated albumin (GA) better assesses the need for OGTT. From 2006 to 2012, 1559 subjects not known to have diabetes or to use anti-diabetic medications were enrolled. Serum GA was measured, and a 75-g OGTT was then performed to diagnose diabetes. Serum GA correlated significantly to age (r = 0.27, p<0.001), serum albumin (r = 0.1179, age-adjusted p = 0.001), body mass index (r = -0.24, age-adjusted p<0.001), waist circumference (r = -0.16, age-adjusted p<0.001), and plasma GA (r = 0.999, p<0.001), but was unaffected by diet (p = 0.8). Using serum GA at 15% for diagnosis of diabetes, the sensitivity, specificity, and area under the receiver-operating characteristic curve were 74%, 85%, and 0.86, respectively. Applying a fasting plasma glucose (FPG) value of < 100 mg/dL to exclude diabetes and of >= 126 mg/dL to diagnose diabetes, 14.4% of the study population require an OGTT (OGTT%) with a sensitivity of 78.8% and a specificity of 100%. When serum GA value of 14% and 17% were used to exclude and diagnose diabetes, respectively, the sensitivity improved to 83.3%, with a slightly decrease in specificity (98.2%), but a significant increase in OGTT% (35%). Using combined FPG and serum GA cutoff values (FPG < 100 mg/dL plus serum GA < 15% to exclude diabetes and FPG >= 126 mg/dL or serum GA >= 17% to diagnose diabetes), the OGTT% was reduced to 22.5% and the sensitivity increased to 85.6% with no change in specificity (98.2%). In the diagnosis of diabetes, serum GA measurements can be used to determine the need of an OGTT. PMID- 26765576 TI - Effect of Dapagliflozin With and Without Acipimox on Insulin Sensitivity and Insulin Secretion in T2DM Males. AB - AIM: To investigate the effect of lowering the plasma glucose and free fatty acid (FFA) concentrations with dapagliflozin and acipimox, respectively, on insulin sensitivity and insulin secretion in T2DM individuals. METHODS: Fourteen male T2DM patients received an oral glucose tolerance test and euglycemic hyperinsulinemic clamp at baseline and were treated for 3 weeks with dapagliflozin (10 mg per day). During week 3, acipimox (250 mg four times per day) treatment was added to dapagliflozin. The oral glucose tolerance test and insulin clamp were repeated at the end of weeks 2 and 3. RESULTS: Dapagliflozin caused glucosuria and significantly lowered the plasma glucose concentration (by 35 mg/dL; P < .01), whereas the fasting plasma FFA concentration was unaffected. Acipimox caused a further decrease in the fasting plasma glucose concentration (by 20 mg/dL; P < .01) and a significant decrease in the fasting plasma FFA concentration. Compared to baseline, insulin-mediated glucose disposal increased significantly at week 2 (from 4.48 +/- 0.50 to 5.30 +/- 0.50 mg/kg . min; P < .05). However, insulin-mediated glucose disposal at week 3 (after the addition of acipimox) did not differ significantly from that at week 2. Glucose-stimulated insulin secretion at week 2 increased significantly compared to baseline, and it increased further and significantly at week 3 compared to week 2. CONCLUSION: Lowering the plasma glucose concentration with dapagliflozin improves both insulin sensitivity and beta-cell function, whereas lowering plasma FFA concentration by addition of acipimox to dapagliflozin improves beta-cell function without significantly affecting insulin sensitivity. PMID- 26765577 TI - A 6-Base Pair in Frame Germline Deletion in Exon 7 Of RET Leads to Increased RET Phosphorylation, ERK Activation, and MEN2A. AB - CONTEXT: Multiple endocrine neoplasia type 2 (MEN2) is usually caused by missense mutations in the proto-oncogene, RET. OBJECTIVE: This study aimed to determine the mutation underlying MEN2A in a female patient diagnosed with bilateral pheochromocytoma at age 31 years and with medullary thyroid carcinoma (MTC) 6 years later. METHODS: Leukocyte DNA was used for exome and Sanger sequencing. Wild-type (WT) RET and mutants were expressed in HEK293 cells. Activation of MAPK/ERK and PI3K/AKT was analyzed by Western blotting and luciferase assay. The effect of RET mutants on cell proliferation was tested in a colony forming assay. RESULTS: Exome sequencing revealed a 6-nucleotide/2-amino acid in-frame deletion in exon 7 of RET (c.1512_1517delGGAGGG, p.505_506del). In vitro expression showed that phosphorylation of the crucial tyrosine 905 was much stronger in the p.505_506del RET mutant compared with WT RET, indicating ligand-independent autophosphorylation. Furthermore, the p.505_506del RET mutant induced a strong activation of the MAPK/ERK pathway and the PI3K/AKT pathway. Consequently, the p.505_506del RET mutant cells increased HEK293 colony formation 4-fold compared with WT RET. CONCLUSION: The finding of bilateral pheochromocytoma and MTC in our patient was highly suspicious of a RET mutation. Exome sequencing revealed a 6 base-pair deletion in exon 7 of RET, an exon not yet associated with MEN2. Increased ligand-independent phosphorylation of the p.505_506del RET mutant, increased activation of downstream pathways, and stimulation of cell proliferation demonstrated the pathogenic nature of the mutation. We therefore recommend screening the whole sequence of RET in MTC and pheochromocytoma patients with red flags for a genetic cause. PMID- 26765578 TI - Molecular Heterogeneity in Aldosterone-Producing Adenomas. AB - CONTEXT: The use of next-generation sequencing has resulted in the identification of recurrent somatic mutations underlying primary aldosteronism (PA). However, significant gaps remain in our understanding of the relationship between tumor aldosterone synthase (CYP11B2) expression and somatic mutation status. OBJECTIVE: The objective of the study was to investigate tumor CYP11B2 expression and somatic aldosterone-driver gene mutation heterogeneity. METHODS: Fifty-one adrenals from 51 PA patients were studied. Immunohistochemistry for CYP11B2 was performed. Aldosterone-producing adenomas with intratumor CYP11B2 heterogeneity were analyzed for mutation status using targeted next-generation sequencing. DNA was isolated from CYP11B2-positive, CYP11B2-negative, and adjacent normal areas from formalin-fixed, paraffin-embedded sections. RESULTS: Of 51 adrenals, seven (14 %) showed distinct heterogeneity in CYP11B2 by immunohistochemistry, including six adenomas with intratumor heterogeneity and one multinodular hyperplastic adrenal with both CYP11B2-positive and -negative nodules. Of the six adrenocortical adenomas with CYP11B2 heterogeneity, three had aldosterone regulating mutations (CACNA1D p.F747C, KCNJ5 p.L168R, ATP1A1 p.L104R) only in CYP11B2-positive regions, and one had two different mutations localized to two histologically distinct CYP11B2-positive regions (ATP2B3 p.L424_V425del, KCNJ5 p.G151R). Lastly, one adrenal with multiple CYP11B2-expressing nodules showed different mutations in each (CACNA1D p.F747V and ATP1A1 p.L104R), and no mutations were identified in CYP11B2-negative nodule or adjacent normal adrenal. CONCLUSIONS: Adrenal tumors in patients with PA can demonstrate clear heterogeneity in CYP11B2 expression and somatic mutations in driver genes for aldosterone production. These findings suggest that aldosterone-producing adenoma tumorigenesis can occur within preexisting nodules through the acquisition of somatic mutations that drive aldosterone production. PMID- 26765579 TI - Obesity Is Associated With Gene Expression and Imaging Markers of Iron Accumulation in Skeletal Muscle. AB - CONTEXT: Different genetic and imaging iron markers are known to be increased in the liver, adipose tissue, and brain of obese subjects. OBJECTIVE: We aimed to investigate these markers in human skeletal muscle. DESIGN, SETTING, PATIENTS, AND OUTCOME MEASURES: Markers of iron accumulation were measured in three different territories: Iron gene markers (TFRC1, TF, SLC11A2, FTL, FTH1, and SLC40A1) were studied in abdominal rectus abdominis (Cohort 1, n = 26) and quadriceps (Cohort 2, n = 13) muscle using real-time PCR, whereas paravertebral muscle R2* signal (as surrogate of iron content) (Cohort 3, n = 43) was evaluated by means of magnetic resonance imaging. INTERVENTION: In a subgroup of 14 obese participants from Cohort 3, a diet-induced weight loss was performed. RESULTS: Rectus abdominis muscle age-adjusted gene expression of SLC40A1 (ferroportin) (r = 0.47; P = .04), SLC11A2 (r = 0.50; P = .03) and CYBA (r = 0.62; P = .006) increased with body fatness. In obese participants from Cohort 1, muscle CYBA gene expression was positively correlated with serum ferritin. This association was replicated in quadriceps from obese participants (Cohort 2). Paravertebral muscle R2* was positively associated with body mass index, waist circumference, and fat mass (measured by dual-energy x-ray absorptiometry) in parallel with hepatic iron content, serum ferritin, and hepcidin. In multivariate regression analyses, obesity parameters (P < .0001) and hsCRP concentration (P < .05) contributed independently to the variance of sex-, serum hepcidin- and age adjusted muscle R2*. Of note, weight loss intervention resulted in decreased muscle R2* (P = .02) in correlation with the change of serum ferritin (r = 0.69; P = .01). CONCLUSIONS: These findings emphasize a significant iron accumulation in human skeletal muscle in association with obesity. The mechanisms implicated in these observations should be studied further. PMID- 26765580 TI - Serum PTHrP Predicts Weight Loss in Cancer Patients Independent of Hypercalcemia, Inflammation, and Tumor Burden. AB - CONTEXT: Recent animal studies showed that tumor-derived PTHrP induced cancer cachexia by fat browning with increased energy expenditure; however, clinical evidence from human data is insufficient. OBJECTIVE: We investigated whether serum PTHrP levels independently predicts weight loss (WL) in cancer patients. DESIGN, SETTING, AND PATIENTS: From a longitudinal observational cohort, body mass index (BMI) of patients with measured serum PTHrP levels (n = 624) was assessed (median follow-up of 327 d). MAIN OUTCOME MEASURES: Cox hazard models were used to examine the predictive value of PTHrP for WL defined by consensus definition (WL [consensus], percentage WL < -5% or percentage WL < -2% plus BMI < 20 kg/m(2)) and by BMI-adjusted grades (WL [BMI adjusted]). RESULTS: The overall risk of WL (consensus) was 34.4%. Compared with PTHrP-negative subjects, patients with higher PTHrP levels (PTHrP >= median 5.7 pmol/L) had more WL (percentage WL, -6.9% vs -1.1%, P = .010) at follow-up. A higher PTHrP level was associated with an increased loss of body weight (beta = -2.73), muscle (beta = -1.85), and fat (beta = -2.52) after controlling for age, sex, and BMI. Kaplan-Meier analysis demonstrated that subjects with higher PTHrP had increased WL risk compared with lower PTHrP or PTHrP-negative groups (52.0% vs 38.9% vs 29.7%, P < .001). Serum PTHrP was independently associated with an increased WL risk (hazard ratio [HR]1.23, P = .005) adjusted for potent predictors including serum levels of calcium, C-reactive protein, albumin, cancer stage, and performance status of patients. Consistent results were observed when BMI-adjusted WL was applied. CONCLUSIONS: Serum PTHrP levels predicted cancer-associated WL independent of the presence of hypercalcemia, inflammation, tumor burden, and other comorbidities. PMID- 26765581 TI - Effect of Exercise Intensity on Glucose Requirements to Maintain Euglycemia During Exercise in Type 1 Diabetes. AB - CONTEXT: No recommendations exist to inform the carbohydrate amount required to prevent hypoglycemia associated with exercise of different intensities in individuals with type 1 diabetes (T1D). OBJECTIVE: The relationship between exercise intensity and carbohydrate requirements to maintain stable euglycemia in individuals with T1D remains to be determined. It was predicted that an "inverted U" relationship exists between exercise intensity and the amount of glucose required to prevent hypoglycemia during exercise at basal insulinemia. Our objective was to investigate this relationship and elucidate the underlying glucoregulatory mechanisms. DESIGN, PARTICIPANTS, AND INTERVENTION: We subjected nine individuals (mean +/- SD age, 21.5 +/- 4.0 years; duration of disease, 11.4 +/- 6.4 years; glycated hemoglobin, 7.9 +/- 0.8% [60 mmol/mol]; body mass index, 25.4 +/- 5.5 kg/m(2); VO2peak, 34.8 +/- 5.1 mL.kg(-1).min(-1); and lactate threshold, 59.9 +/- 5.9% VO2peak) with T1D to a euglycemic clamp, whereby euglycemia was maintained by infusing basal insulin rates with concomitant infusion of [6,6-(2)H2]glucose for determining glucose kinetics. Glucose was infused to maintain euglycemia during and for 2 hours after exercise of different intensities (35, 50, 65, and 80% VO2peak). MAIN OUTCOME MEASURES: The glucose infusion rate (GIR), levels of glucoregulatory hormones, and rates of endogenous glucose appearance and disappearance were compared between conditions. RESULTS: The mean GIR to maintain euglycemia during exercise increased with intensity up to 50% (4.0 +/- 1.6 g/h; P < .05) and 65% (4.1 +/- 1.7 g/h), but no glucose was required at 80% VO2peak. Glucose rate of appearance and disappearance increased with intensity and, together with plasma catecholamines, reached higher levels at 80% VO2peak. CONCLUSION: Our findings support the predicted inverted-U relationship between exercise intensity and glucose requirement. However, the relationship between iv and oral glucose requirements needs to be investigated to translate these GIR data to clinical practice. PMID- 26765584 TI - Convergence of Molecular Dynamics Simulation of Protein Native States: Feasibility vs Self-Consistency Dilemma. AB - All-atom molecular dynamics simulations need convergence tests to evaluate the quality of data. The notion of "true" convergence is elusive, and one can only hope to satisfy self-consistency checks (SCC). There are multiple SCC criteria, and their assessment of all-atom simulations of the native state for real globular proteins is sparse. Here, we present a systematic study of different SCC algorithms, both in terms of their ability to detect the lack of self-consistency and their computational demand, for the all-atom native state simulations of four globular proteins (CSP, CheA, CheW, and BPTI). Somewhat surprisingly, we notice some of the most stringent SCC criteria, e.g., the criteria demanding similarity of the cluster probability distribution between the first and the second halves of the trajectory or the comparison of fluctuations between different blocks using covariance overlap measure, can require tens of microseconds of simulation even for proteins with less than 100 amino acids. We notice such long simulation times can sometimes be associated with traps, but these traps cannot be detected by some of the common SCC methods. We suggest an additional, and simple, SCC algorithm to quickly detect such traps by monitoring the constancy of the cluster entropy (CCE). CCE is a necessary but not sufficient criteria, and additional SCC algorithms must be combined with it. Furthermore, as seen in the explicit solvent simulation of 1 ms long trajectory of BPTI,1 passing self-consistency checks at an earlier stage may be misleading due to conformational changes taking place later in the simulation, resulting in different, but segregated regions of SCC. Although there is a hierarchy of complex SCC algorithms, caution must be exercised in their application with the knowledge of their limitations and computational expense. PMID- 26765586 TI - Home-Based Telemanagement in Advanced COPD: Who Uses it Most? Real-Life Study in Lombardy. AB - Current evidence indicates that the benefits of tele-health may not be uniform across all patients. Therefore, to understand what specific variables influence use of home-based telemanagement in COPD, we conducted this retrospective study. A 6-month home-based telemanagement program (HTP) was offered to 1,074 COPD patients over a 4-year period. Multivarible linear regression analysis was used to identify predictors of HTP use/week (phone calls and specialist consultations) among all variables: clinical (body mass index, co-morbidities, HTP prescription not following an exacerbation, long-term oxygen therapy use, COPD severity, hospital readmissions, exacerbations and death), socio-demographic (sex, age, place of abode), smoking history, arterial blood gases (ABG), and specialist/general practitioner (GP) urgent need. Logistic regression was conducted to predict relapses/hospitalizations risk as well as the disease impact (COPD Assessment Test, CAT) at the end of the program. Presence of relapses (p < 0.001), ABGs (p < 0.001) and GP request (p < 0.001) were significantly associated with higher HTP-use. Smoking history (OR 1.542 [IC 95% 1.069-2.217], p = 0.020), specialist (OR 2.895 [2.144-3.910], p < 0.001) and GP consultations (OR 6.575 [4.521-9.561], p < 0.001) were the only independent risk factors for relapse. No predictor of hospitalization was found. High final CAT score was inversely related to oxygen therapy use (p = 0.001) and HTP prescription (p < 0.001), and positively related to presence of co-morbidities (p = 0.001) and baseline CAT (p < 0.001). This HTP in Lombardy shows that relapsers, people requiring several ABGs and urgent GP visits are the patient subgroup most likely to consume telemanagement services (scheduled and unscheduled). We propose a patient 'identikit' to improve prioritization for HTP prescriptions. PMID- 26765585 TI - Novel investigational drugs for constipation-predominant irritable bowel syndrome: a review. AB - INTRODUCTION: Constipation-predominant irritable bowel syndrome (IBS-C) is a functional gastrointestinal (GI) disorder with an unknown etiology. A number of the drugs tested for IBS-C have also been applied to chronic constipation and chronic idiopathic constipation. Unfortunately, due to severe adverse effects, many drugs envisioned for IBS-C had been withdrawn from the market. Nevertheless, a number of potential new agents for this indication are now under development. AREAS COVERED: The following review describes the most recently developed agents in preclinical as well as Phase 1 and Phase 2 clinical studies. Information was obtained from published literature, abstracts and the latest results found in Clinicaltrial.gov database. The authors put a special interest on glucagon-like peptide 1 analogue, bile acid modulators, serotonergic agents, guanylate cyclase C and cannabinoid antagonists. EXPERT OPINION: To enter the market, a newly developed drug has to meet several criteria, such as good bioavailability or the absence of drug-related adverse events. Taking into account constipation and abdominal pain as the main symptoms in IBS-C, a novel successful drug is usually able to improve both at the same time. Four out of fifteen investigational drugs described in this paper belong to the serotonergic family and have a good prognosis to reach the market; still, more long-term clinical studies are warranted. PMID- 26765587 TI - Sialoglycoproteins prepared from the eggs of Carassius auratus prevent bone loss by inhibiting the NF-kappaB pathway in ovariectomized rats. AB - In this study, we investigated the improvement of osteoporosis by sialoglycoproteins isolated from the eggs of Carassius auratus (Ca-SGP) in ovariectomized rats. Ca-SGP was supplemented to ovariectomized Sprague-Dawley rats for 90 days. The results showed that Ca-SGP treatment remarkably prevented the reduction of bone mass, improved cancellous bone structure and biochemical properties. Ca-SGP also significantly decreased the serum contents of TRAP, Cath K, MMP-9, DPD, CTX-1, Ca, and P. Mechanism investigation revealed that Ca-SGP significantly increased the OPG/RANKL ratio in mRNA expression, protein expression and serum content. Further research suggested that NF-kappaB signaling pathways were inhibited by suppressing the mRNA and protein expressions of NFATc1 and TRAF6, diminishing the mRNA expression and phosphorylation of NF-kappaB p65, three key transcription factors in NF-kappaB pathways. These results suggest that Ca-SGP can improve osteoporosis by inhibiting bone resorption via suppressing the activation of osteoclastogenesis related NF-kappaB pathways. PMID- 26765588 TI - Metal-organic frameworks constructed from crown ether-based 1,4 benzenedicarboxylic acid derivatives. AB - A series of unprecedented crown ether- and thiacrown ether-derivatized benzene dicarboxylic acid (H2bdc) ligands has been synthesized and incorporated into the prototypical isoreticular metal-organic framework (IRMOF) and UiO-66 materials. In the case of UiO-66, only MOFs comprised from a mixed-ligand composition, requiring both unsubstituted bdc and crown ether containing ligands, could be prepared. These are among the few ligand derivatives, and resulting MOFs, that incorporate a macrocyclic group directly on the bdc ligand, providing a new, modular platform for exploring new supramolecular and coordination chemistry within MOFs. PMID- 26765623 TI - A Defining Moment in a Life-Long Journey with Dialysis. AB - BACKGROUND: The author seeks to address the issue of lack of communication between the physician and the patients as one of the possibilities for continued poor outcomes despite technical advances in dialysis. The failure to relate to patients as 'people' leads to a failure to individualize treatment and deal with atypical problems presented by some patients, which, in turn, leads to less than optimal outcomes. SUMMARY: Statistical statements of life expectancy for dialysis patients are misleading. While accurate in a vacuum, they are less accurate when applied to individuals. Life expectancy can be improved by better communication and education, which may lead, in turn, to positive attitudes and motivation. Though often overlooked, these factors are instrumental in achieving optimal results. The author draws on her personal experience of 40 years using all modalities of dialysis. Through abundant experience from decades of interactions with practitioners and healthcare professionals, she states her views on how dialysis need not be spirit- and life-defeating. KEY MESSAGE: While long-term global results are yet to be quantified, the author's 40 years of dialysis and a productive, happy life, speaks for itself. Dialysis is not the end of life; it is only a condition to be dealt with. PMID- 26765624 TI - Cascade Signal Amplification Based on Copper Nanoparticle-Reported Rolling Circle Amplification for Ultrasensitive Electrochemical Detection of the Prostate Cancer Biomarker. AB - An ultrasensitive and highly selective electrochemical assay was first attempted by combining the rolling circle amplification (RCA) reaction with poly(thymine) templated copper nanoparticles (CuNPs) for cascade signal amplification. As proof of concept, prostate specific antigen (PSA) was selected as a model target. Using a gold nanoparticle (AuNP) as a carrier, we synthesized the primer-AuNP-aptamer bioconjugate for signal amplification by increasing the primer/aptamer ratio. The specific construction of primer-AuNP-aptamer/PSA/anti-PSA sandwich structure triggered the effective RCA reaction, in which thousands of tandem poly(thymine) repeats were generated and directly served as the specific templates for the subsequent CuNP formation. The signal readout was easily achieved by dissolving the RCA product-templated CuNPs and detecting the released copper ions with differential pulse stripping voltammetry. Because of the designed cascade signal amplification strategy, the newly developed method achieved a linear range of 0.05-500 fg/mL, with a remarkable detection limit of 0.020 +/- 0.001 fg/mL PSA. Finally, the feasibility of the developed method for practical application was investigated by analyzing PSA in the real clinical human serum samples. The ultrasensitivity, specificity, convenience, and capability for analyzing the clinical samples demonstrate that this method has great potential for practical disease diagnosis applications. PMID- 26765625 TI - Dominant enrichment of phenotypically activated CD38(+) HLA-DR(+) CD8(+) T cells, rather than CD38(+) HLA-DR(+) CD4(+) T cells, in HIV/HCV coinfected patients on antiretroviral therapy. AB - HIV infection may enhance immune-activation, while little is known regarding the role of HCV infection. This study investigates the impact of HCV in HIV coinfected patients with undetectable viraemia under HAART on the levels of peripheral T cell's immune-activation. We determined T lymphocytes subsets to characterize immune-activation defined as CD38 and/or HLA-DR expression in chronic monoinfected HCV, HIV, and HIV/HCV coinfected subjects. One hundred and fifty six patients were divided into three groups: (i) 77 HIV+ patients; (ii) 50 HCV+ patients; and (iii) 29 coinfected HIV/HCV patients. The level of CD4(+) was significantly higher in HCV+ than in HIV+ or in coinfected HIV/HCV subjects. The frequencies of CD4(+) CD38(+) /HLA-DR(-) , CD4(+) CD38(-) /HLA-DR(+) and CD4(+) CD38(+) /HLA-DR(+) in HIV+ patients were comparable to those measured in coinfected patients, but statistically higher than those observed in HCV+ subjects. The percentage of CD8(+) was comparable in HIV-1+ patients and coinfected HIV/HCV but the results obtained in both groups were significantly higher compared to the results obtained in HCV patients. The level of CD8(+) CD38(+) /HLA-DR(-) showed values lower in HIV+ patients than in that monoinfected HCV and coinfected HIV/HCV patients. The frequencies of CD8(+) CD38(-) /HLA-DR(+) were higher in HIV+ patients compared to HCV+ and coinfected HIV/HCV patients. HIV/HCV coinfected group showed highest levels of CD8(+) CD38(+) /HLA-DR(+) . HIV plays a pivotal role to determine the immune activation in the host. The role of HCV needs of further investigations but our data show that HCV mainly influences the immune-activation of the pool of CD8, but also probably plays a supporting additive effect on CD4 immune-activation. J. Med. Virol. 88:1347-1356, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26765626 TI - Skeletal Maturation, Body Size, and Motor Coordination in Youth 11-14 Years. AB - PURPOSE: The objective of this study is to estimate the relative contribution of biological maturation to variance in the motor coordination (MC) among youth and to explore gender differences in the associations. METHODS: Skeletal maturation (Tanner-Whitehouse 3), stature, body mass, and MC (Korperkoordinationstest fur Kinder) were assessed in 613 youths, 284 boys and 329 girls 11-14 yr of age. Standardized residuals of skeletal age on chronological age were used as the estimate of skeletal maturity status independent of chronological age. Hierarchical multiple regression analyses were used to analyse associations between skeletal maturity status and MC. RESULTS: Skeletal maturity status by itself, i.e., standardized residuals of skeletal age on chronological age (step 3) explained a maximum of 8.1% of the variance in MC in boys (DeltaR3 in the range of 0.0%-8.1%) and 2.8% of the variance in girls (DeltaR3 in the range of 0.0%-2.8%), after controlling for stature, body mass and interactions of the standardized residuals of skeletal age on chronological age with stature and body mass. Corresponding percentages for the interactions of the standardized residuals of skeletal age and stature and body mass, after adjusting for stature and body mass (step 2) were 8.7% in boys (DeltaR2 in the range of 0.3%-8.7%) and 7.1% in girls (DeltaR2 in the range of 0.1%-7.1%). Chow tests suggested structural changes in beta-coefficients in the four MC tests among boys and girls, 12-13 yr. CONCLUSION: The percentage of variance in the four MC tests explained by skeletal maturation was relatively small, but the relationships differed between boys and girls. By inference, other factors, e.g., neuromuscular maturation, specific instruction and practice, sport participation, and others may influence MC at these ages. PMID- 26765627 TI - Association of Injury History and Incident Injury in Cadet Basic Military Training. AB - PURPOSE: This study aimed to determine the association between injury history at enrollment and incident lower extremity (LE) injury during cadet basic training among first-year military cadets. METHODS: Medically treated LE injuries during cadet basic training documented in the Defense Medical Surveillance System were ascertained in a prospective cohort study of three large US military academies from 2005 to 2008. Both acute injuries (International Classification of Disease, Ninth Revision, codes in the 800-900s, including fracture, dislocations, and sprains/strains) and injury-related musculoskeletal injuries (International Classification of Disease, Ninth Revision, codes in the 700s, including inflammation and pain, joint derangement, stress fracture, sprain/strain/rupture, and dislocation) were included. Risk ratio (RR) and 95% confidence interval (CI) were computed using multivariate log-binomial models stratified by gender. RESULTS: During basic training, there were 1438 medically treated acute and 1719 musculoskeletal-related LE injuries in the 9811 cadets. The most frequent LE injuries were sprains/strains (73.6% of acute injuries) and inflammation and pain (89.6% of musculoskeletal-related injuries). The overall risk of incident LE injury was 23.2% (95% CI = 22.3%-24.0%). Cadets with a history of LE injury were at increased risk for incident LE injury. This association was identical in males (RR = 1.74, 95% CI = 1.55-1.94) and females (RR = 1.74, 95% CI = 1.52-1.99). In site-specific analyses, strong associations between injury history and incident injury were observed for hip, knee ligament, stress fracture, and ankle sprain. Injury risk was greater (P < 0.01) for females (39.1%) compared with males (18.0%). The elevated injury risk in females (RR = 2.19, 95% CI = 2.04-2.36) was independent of injury history (adjusted RR = 2.09, 95% CI = 1.95-2.24). CONCLUSION: Injury history upon entry to the military is associated with the incidence of LE injuries sustained during cadet basic training. Prevention programs targeted at modifiable factors in cadets with a history of LE injury should be considered. PMID- 26765629 TI - The Relative Age Effect on Youth Sports Injuries. AB - INTRODUCTION/PURPOSE: The relative age effect (RAE) has been described as the consequence of differences in ages between individuals within the same age group. In youth sports, relatively older children may have a physical and developmental advantage over younger children. The purpose of this study was to determine the relationship between relative age and sports injury in a cohort of pediatric athletes. METHODS: A probability sample (n = 1997) of children between 5 and 17 yr of age with sports injuries were extracted from a regional hospital database. Relative age was defined as a child's birth month relative to the month that his/her activity uses as an arbitrary age cutoff. The main outcome measure was an activity-specific birth month ratio, which was developed and compared with birth month data for the state. Linear regression models were used to determine overrepresentation and underrepresentation of sports injuries for prepubescent (5 13 yr) and pubescent (14-17 yr) groups separately. RESULTS: Among prepubescent patients, the linear regression model indicated a significant RAE on sports injury (R = 0.037), where those born in or right after the cutoff month for their sports were underrepresented in the study cohort relative to their representation in the general population. For the pubescent group, the RAE was reversed, where those born closest, but before the age cutoff date for their sports were the least represented relative to the general population (R = 0.096). CONCLUSIONS: These results demonstrate an RAE on youth sports injury risk in a cohort of pediatric athletes with sports-related injuries. These findings may be used to inform safe practices within sports participation among youth athletes. PMID- 26765628 TI - Motor Performance as Risk Factor for Lower Extremity Injuries in Children. AB - PURPOSE: Physical activity-related injuries in children constitute a costly public health matter. The influence of motor performance on injury risk is unclear. The purpose of this study was to examine if motor performance was a risk factor of traumatic and overuse lower extremity injuries in a normal population of children. METHODS: This study included 1244 participants from 8 to 14 yr old at baseline, all participating in the "Childhood Health, Activity and Motor Performance School Study Denmark." The follow-up period was up to 15 months. The motor performance tests were static balance, single leg hop for distance, core stability tests, vertical jump, shuttle run, and cardiorespiratory fitness test. Lower extremity injuries were registered by clinicians using weekly questionnaires and classified according to the International Classification of Diseases, 10th Revision, system. RESULTS: Poor balance increased the risk for traumatic injury in the foot region (incidence rate ratio [IRR] = 1.09-1.15), and good performance in single leg hop for distance protected against traumatic knee injuries (IRR = 0.66-0.68). Good performance in core stability tests and vertical jump increased the risk for traumatic injuries in the foot region (IRR = 1.12 1.16). Poor balance increased the risk for overuse injuries in the foot region (IRR = 1.65), as did good performance in core stability tests and shuttle run, especially for knee injuries (IRR = 1.07-1.18). CONCLUSIONS: Poor balance (sway) performance was a consistent predictor of traumatic injuries, in particular, for traumatic ankle injuries. Good motor performance (core stability, vertical jump, and shuttle run) was positively associated with traumatic and overuse injuries and negatively (single leg hop) associated with traumatic injuries, indicating different influences on injury risk. Previous injury was a confounder affecting the effect size and the significance. More studies are needed to consolidate the findings, to clarify the influence of different performance tests on different types of injuries, and to examine the influence of behavior in relation to injury risk. PMID- 26765630 TI - Mirror Training Augments the Cross-education of Strength and Affects Inhibitory Paths. AB - PURPOSE: Unilateral strength training strengthens not only the muscles on the trained side but also the homologous muscles on the untrained side; however, the magnitude of this interlimb cross-education is modest. We tested the hypothesis that heightened sensory feedback by mirror viewing the exercising hand would augment cross education by modulating neuronal excitability. METHODS: Healthy adults were randomized into a mirror training group (MG, N = 11) and a no-mirror training group (NMG, N = 12) and performed 640 shortening muscle contractions of the right wrist flexors at 80% maximum voluntary contraction (MVC) during 15 sessions for 3 wk. Maximal strength and specific transcranial magnetic stimulation metrics of neuronal excitability, measured in the mirror and no mirror setup at rest and during unilateral contractions at 60% MVC, were assessed before and after the strength intervention. RESULTS: Trained wrist flexor MVC increased 72% across groups, whereas cross-education was higher for the MG (61%) than NMG (34%, P = 0.047). The MG showed a reduction (15%-16%) in the contralateral silent period duration measured from the contracting left-untrained flexor carpi radialis, whereas the NMG showed an increase (12%, P <= 0.030). Interhemispheric inhibition, measured from the trained to the untrained primary motor cortex, increased in the MG (11%) but decreased in the NMG (15%) when measured in the mirror setup at rest (P = 0.048). Other transcranial magnetic stimulation measures did not change. CONCLUSION: Viewing the exercising hand in a mirror can augment the cross-education effect. The use of a mirror in future studies can potentially accelerate functional recovery from unilateral impairment due to stroke or upper limb fracture. PMID- 26765631 TI - Effects of Motor versus Cardiovascular Exercise Training on Children's Working Memory. AB - PURPOSE: The aim of this investigation was to examine the influence of different types of exercise exertion on primary school children's working memory (WM). METHODS: Participants (N = 71, 9.4 yr, 39 girls) were randomly assigned to a cardiovascular exercise (CE), a motor exercise (ME), or a control group (CON). They underwent a letter digit span task (WM) before and after an intervention period that involved 10 wk of an additional afterschool exercise regimen, which took place three times a week for 45 min. Students in the control group participated in assisted homework sessions. RESULTS: WM performance of the 9- to 10-yr-old children benefited from both the cardiovascular and the motor exercise programs, but not from the control condition. The increase in WM performance was significantly larger for children in the ME compared with the CE or CON. CONCLUSION: These findings add to the knowledge base relating different types of exercise and WM. Besides the efficiency of cardiovascular exercise training, a special motor-demanding intervention seems to be a beneficial strategy to improve WM in preadolescent children. PMID- 26765632 TI - Arm and Intensity-Matched Leg Exercise Induce Similar Inflammatory Responses. AB - INTRODUCTION: The amount of active muscle mass can influence the acute inflammatory response to exercise, associated with reduced risk for chronic disease. This may affect those restricted to upper body exercise, for example, due to injury or disability. The purpose of this study was to compare the inflammatory responses for arm exercise and intensity-matched leg exercise. METHODS: Twelve male individuals performed three 45-min constant load exercise trials after determination of peak oxygen uptake for arm exercise (VO2peak A) and cycling (VO2peak C): 1) arm cranking exercise at 60% VO2peak A, 2) moderate cycling at 60% VO2peak C, and 3) easy cycling at 60% VO2peak A. Cytokine, adrenaline, and flow cytometric analysis of monocyte subsets were performed before and up to 4 h postexercise. RESULTS: Plasma IL-6 increased from resting concentrations in all trials; however, postexercise concentrations were higher for arm exercise (1.73 +/- 1.04 pg.mL) and moderate cycling (1.73 +/- 0.95 pg.mL) compared with easy cycling (0.87 +/- 0.41 pg.mL; P < 0.04). Similarly, the plasma IL-1ra concentration in the recovery period was higher for arm exercise (325 +/- 139 pg.mL) and moderate cycling (316 +/- 128 pg.mL) when compared with easy cycling (245 +/- 77 pg.mL, P < 0.04). Arm exercise and moderate cycling induced larger increases in monocyte numbers and larger increases of the classical monocyte subset in the recovery period than easy cycling (P < 0.05). The postexercise adrenaline concentration was lowest for easy cycling (P = 0.04). CONCLUSIONS: Arm exercise and cycling at the same relative exercise intensity induces a comparable acute inflammatory response; however, cycling at the same absolute oxygen uptake as arm exercise results in a blunted cytokine, monocyte, and adrenaline response. Relative exercise intensity appears to be more important to the acute inflammatory response than modality, which is of major relevance for populations restricted to upper body exercise. PMID- 26765633 TI - Effect of Docosahexaenoic Acid on a Biomarker of Head Trauma in American Football. AB - PURPOSE: American football athletes are exposed to subconcussive impacts over the course of the season resulting in elevations in serum neurofilament light (NFL), a biomarker of axonal injury. Docosahexaenoic acid (DHA) has been reported to reduce axonal trauma associated with traumatic brain injury in rodent models. However, the optimal dose in American football athletes is unknown. This study examined the effect of differing doses of DHA on serum NFL over the course of a season of American football. METHODS: In a randomized, double-blind, placebo controlled, parallel design, 81 National Collegiate Athletic Association Division I American football athletes were assigned to ingest either 2, 4, 6 g.d of DHA or placebo. Blood was sampled at specific times over the course of 189 d, coincident with changes in intensity, hours of contact, and likely changes in head impacts. Standardized magnitude-based inference was used to define outcomes. RESULTS: DHA supplementation increased plasma DHA in a dose-dependent manner (2 g.d: mean difference from baseline; +/-90% CL; 2 g.d: 1.3; +/-0.6; 4 g.d: 1.6; +/-0.7%; 6 g.d: 2.8; +/-1.2%). Serum NFL increased to a greater extent in starters (area under the curve, 1995 +/- 1383 pg.mL) versus nonstarters (1398 +/- 581 pg.mL; P = 0.024). Irrespective of dose, supplemental DHA likely attenuated serum NFL coincident with increases in serum NFL by likely small and moderate magnitude (effect size = 0.4-0.7). CONCLUSIONS: Findings from this study, the first large scale study examining potential prophylactic use of DHA in American football athletes, include identification of optimal dose of DHA, suggesting a neuroprotective effect of DHA supplementation. PMID- 26765635 TI - Evaluation of 4-methylimidazole, in the Ames/Salmonella test using induced rodent liver and lung S9. AB - 4-methylimidazole (4-MeI) is formed by the interaction of ammonia with reducing sugars and low levels have been identified as a by-product in coffee, soy sauce, wine, dark beers, soft drinks, and caramel colors. The 4-MeI has been reported to induce alveolar/bronchiolar tumors in mice but not rats. Its mechanism of action is unlikely to be due to genotoxicity as 4-MeI does not induce mutation in Salmonella typhimurium and does not induce micronuclei in rodent peripheral erythrocytes or bone marrow cells. However, the question of whether genetically reactive intermediates could be formed via lung-specific metabolism has not previously been addressed. The 4-MeI was tested for its ability to induce mutation in five standard Ames strains of S. typhimurium using induced rat (F344/N) and mouse (B6C3F1) liver and lung S9 as a source of exogenous metabolism. The chemicals were tested in an OECD 471-compliant bacterial reverse mutation assay, using both plate-incorporation and pre-incubation methodologies, together with 10% S-9 metabolic activation. No induction of mutation (as measured by an increase in revertant colonies) was observed and it was concluded that 4 MeI was not mutagenic in S. typhimurium using either rodent liver or lung S9 for exogenous metabolism. PMID- 26765634 TI - Outcomes of ACL Reconstruction in Patients with Diabetes. AB - PURPOSE: Diabetes has been associated with adverse outcomes after various types of surgery. There are no previously published data regarding the effect of diabetes on outcomes from anterior cruciate ligament reconstruction (ACLR). The purpose of this study was to test the hypotheses that diabetes is associated with worse clinical outcomes and a higher prevalence of subsequent surgeries after ACLR. METHODS: Anterior cruciate ligament-deficient patients (n = 2198) undergoing unilateral ACLR from a multicenter prospective study were included. Patients who self-reported diabetes on the basis of comorbidity questions before surgery were identified from the database. They were compared with the remainder of the cohort who did not self-report diabetes. All patients were followed up for a minimum of 2 yr after their index surgery. A minimum 2-yr follow-up was attained on 1905/2198 (87%) via completed outcome questionnaires and 2096/2198 (95%) regarding subsequent surgery. The primary outcome measures were three validated outcome instruments. The secondary outcome measure was the incidence of additional surgery on the ipsilateral and contralateral knees. RESULTS: Patients with diabetes had a significantly higher activity level at 2 yr (OR = 2.96; 95% CI, 1.30-6.77; P = 0.01), but otherwise slightly worse clinical outcomes, compared with patients without diabetes (OR range = 0.42-0.59). The prevalence of subsequent surgeries in patients with diabetes was not significantly different from the prevalence in patients without diabetes. CONCLUSIONS: Patients with diabetes maintain a higher activity level after ACLR despite slightly lower patient-reported outcome scores compared with patients without diabetes and do not have a higher rate of subsequent surgery. PMID- 26765638 TI - Quantitative chirality sensing of amines and amino alcohols via Schiff base formation with a stereodynamic UV/CD probe. AB - A stereodynamic chemosensor that can be used for simultaneous determination of the absolute configuration, enantiomeric composition and total concentration of chiral amines and amino alcohols based on two fast optical measurements was prepared and tested. The free sensor is CD-silent and produces characteristic blue-shifted UV and CD signals upon substrate binding via Schiff base formation. The potential in high-throughput screening applications and for rational sensor developments are discussed. PMID- 26765636 TI - Functional single nucleotide polymorphism in IL-17A 3' untranslated region is targeted by miR-4480 in vitro and may be associated with age-related macular degeneration. AB - Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in the elderly. Genetic factors contributing to AMD include single nucleotide polymorphisms (SNPs) in immune-related genes including CFH, C2, CFI, C9, and C3, thus implicating these pathways in AMD pathogenesis. MicroRNAs (miRNAs) are powerful regulators of gene expression and execute this function by binding to the 3' untranslated region (3'UTR) of target mRNAs, leading to mRNA degradation. In this study, we searched for the possible association of SNPs in the 3'UTR region of IL-17A, a gene implicated in AMD pathogenesis without any previous SNP association with AMD. Using two independent sample cohorts of Caucasian subjects, six SNPs in the IL-17A 3'-UTR were selected for genotyping based on bioinformatic predictions of the SNP effect on microRNA binding. The SNP rs7747909 was found to be associated with AMD (P < 0.05) in the NEI cohort, using a dominant model logistic regression. Luciferase reporter gene assays and RNA electrophoretic mobility shift assays were performed using ARPE-19 cells to confirm the preferential binding of microRNAs to the major allele of the SNP. Our findings support the hypothesis that microRNA-mediated gene dysregulation may play a role in the pathogenesis of AMD. PMID- 26765639 TI - Visuo-spatial memory deficits following medial temporal lobe damage: A comparison of three patient groups. AB - The contributions of the hippocampal formation and adjacent regions of the medial temporal lobe (MTL) to memory are still a matter of debate. It is currently unclear, to what extent discrepancies between previous human lesion studies may have been caused by the choice of distinct patient models of MTL dysfunction, as disorders affecting this region differ in selectivity, laterality and mechanisms of post-lesional compensation. Here, we investigated the performance of three distinct patient groups with lesions to the MTL with a battery of visuo-spatial short-term memory tasks. Thirty-one subjects with either unilateral damage to the MTL (postsurgical lesions following resection of a benign brain tumor, 6 right sided lesions, 5 left) or bilateral damage (10 post-encephalitic lesions, 10 post anoxic lesions) performed a series of tasks requiring short-term memory of colors, locations or color-location associations. We have shown previously that performance in the association task critically depends on hippocampal integrity. Patients with postsurgical damage of the MTL showed deficient performance in the association task, but performed normally in color and location tasks. Patients with left-sided lesions were almost as impaired as patients with right-sided lesions. Patients with bilateral post-encephalitic lesions showed comparable damage to MTL sub-regions and performed similarly to patients with postsurgical lesions in the association task. However, post-encephalitic patients showed additional impairments in the non-associative color and location tasks. A strikingly similar pattern of deficits was observed in post-anoxic patients. These results suggest a distinct cerebral organization of associative and non associative short-term memory that was differentially affected in the three patient groups. Thus, while all patient groups may provide appropriate models of medial temporal lobe dysfunction in associative visuo-spatial short-term memory, additional deficits in non-associative memory tasks likely reflect damage of regions outside the MTL. Importantly, the choice of a patient model in human lesion studies of the MTL significantly influences overall performance patterns in visuo-spatial memory tasks. PMID- 26765640 TI - Bioscience learning in clinical placement: the experiences of pre-registration nursing students. AB - AIMS AND OBJECTIVES: The aim of this study was to explore student nurses' views and experiences of bioscience learning in clinical placement. The study focused on (1) how relevant students perceive bioscience knowledge to their professional role; (2) what opportunities students have to apply bioscience knowledge during clinical placements; (3) what students perceive about the support they receive from placement mentors regarding bioscience learning. BACKGROUND: Bioscience knowledge is required for safe and effective practice but is an area that students find challenging. Clinical placements offer students the ideal environment to integrate bioscience into clinical decision making. There is, however, a lack of research addressing specifically students' placement learning of bioscience. DESIGN: An explanatory sequential mixed methods approach was adopted. METHODS: The research involved two phases. In phase one predominantly quantitative data were collected via a survey. 112 final year BSc nursing students from across fields completed the survey (response rate = 66%). The results of this phase were then built upon by conducting three focus groups (n = 17) in a second qualitative research phase. RESULTS: Whilst students acknowledged the relevance of bioscience to their nursing role, this study suggests that its importance is not recognised as widely by practice educators. Findings highlight inconsistencies in the quality of mentor support, the opportunities for students to learn and the priority that bioscience is given in placement education. CONCLUSIONS: This study demonstrates the need for more explicit bioscience criteria in placement assessments and a greater level of mentor education to ensure more consistency in the standard of placement learning of bioscience. RELEVANCE TO CLINICAL PRACTICE: Providing insight into factors that influence student learning of bioscience during clinical placements provides focus on how higher education institutions and practice educators can better support students to confidently apply bioscience knowledge to deliver safe and effective patient care. PMID- 26765641 TI - A resolution for health. PMID- 26765642 TI - 57th American Society of Hematology Annual Meeting. PMID- 26765644 TI - From clinical trials to real-world clinical practice: observations on the direct oral anticoagulants. PMID- 26765643 TI - Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. AB - BACKGROUND: The efficacy and safety of the anticoagulant rivaroxaban for the treatment and secondary prevention of deep-vein thrombosis and pulmonary embolism has been shown in phase 3 trials. However, data about rivaroxaban use in routine clinical practice are needed. METHODS: XA inhibition with rivaroxaban for Long term and Initial Anticoagulation in venous thromboembolism (XALIA) was a multicentre, international, prospective, non-interventional study of patients with deep-vein thrombosis, done in hospitals and community care centres in 21 countries. The study investigated the safety and effectiveness of rivaroxaban compared with standard anticoagulation therapy (initial treatment with unfractionated heparin, low-molecular-weight heparin, or fondaparinux, usually overlapping with and followed by a vitamin K antagonist) for at least 3 months. Eligible patients were adults (aged >=18 years) with an objectively confirmed diagnosis of deep-vein thrombosis, and an indication to receive anticoagulation treatment for at least 3 months. Following approval of rivaroxaban for the pulmonary embolism indication, patients with deep-vein thrombosis and concomitant pulmonary embolism were also eligible; however, those with isolated pulmonary embolism were not included. Type, dose, and duration of therapy for each patient were at the physician's discretion. The primary effectiveness and safety outcomes were major bleeding, recurrent venous thromboembolism, and all-cause mortality. Propensity score-adjusted analyses were done to account for potential imbalances between groups. This study is registered with ClinicalTrials.gov, number NCT01619007. FINDINGS: Between June 26, 2012, and March 31, 2014, 5142 patients were enrolled. The safety population (all patients who received at least one dose of the anticoagulant of interest) comprised 2619 patients in the rivaroxaban group and 2149 in the standard anticoagulant therapy group. Patients in the rivaroxaban group were younger and fewer had active cancer or concomitant pulmonary embolism than those in the standard anticoagulation group. In the propensity score-adjusted population, the frequency of major bleeding was 0.8% (19/2505) in the rivaroxaban group and 2.1% (43/2010) in the standard anticoagulation group, with a propensity score-adjusted hazard ratio (HR) of 0.77 (95% CI 0.40-1.50); p=0.44. The frequency of recurrent venous thromboembolism was 1.4% (36/2505) in the rivaroxaban group and 2.3% (47/2010) in the standard anticoagulation group (propensity score-adjusted HR 0.91 [95% CI 0.54-1.54], p=0.72). The all-cause mortality frequency was 0.4% (11/2505) in the rivaroxaban group and 3.4% (69/2010) in the standard anticoagulation group (propensity score adjusted HR 0.51 [95% CI 0.24-1.07], p=0.074). The incidence of treatment emergent adverse events in the safety population was similar between the two groups (944 [36.0%] of 2619 in the rivaroxaban group vs 805 [37.5%] of 2149 in the standard anticoagulation group). INTERPRETATION: In routine clinical practice, rivaroxaban-treated patients had a lower risk profile at baseline than those treated with standard anticoagulation. Propensity score-adjusted results confirm that rivaroxaban is a safe and effective alternative to standard anticoagulation therapy in a broad range of patients. Rates of major bleeding and recurrent venous thromboembolism were low in rivaroxaban-treated patients and consistent with phase 3 findings. FUNDING: Bayer HealthCare Pharmaceuticals and Janssen Research & Development, LLC. PMID- 26765646 TI - Heart failure and risk of venous thromboembolism: a systematic review and meta analysis. AB - BACKGROUND: Venous thromboembolism is a major global health problem that is often secondary to other clinical situations. Many studies have investigated the association between venous thromboembolism and heart failure, but have yielded inconsistent findings. We aimed to quantify the absolute and relative risks (RR) for venous thromboembolism in patients with heart failure after hospital admission. We also assessed rates of venous thromboembolism in patients in different settings. METHODS: In this systematic review and meta-analysis, we searched for studies investigating the risk of venous thromboembolism in patients in hospital with heart failure. We searched for studies published between Jan 1, 1955, and March 31, 2015, in PubMed, Embase, Evidence-Based Medicine Reviews, Allied and Complementary Medicine Database, Ovid HealthSTAR, Global Health, Ovid Nursing Database, Web of Science, CINAHL Plus, ProQuest Central, Conference Papers Index, BIOSIS Previews, and ClinicalTrials.gov. All cohort studies and subgroup analyses of randomised controlled trials (RCTs) were eligible for inclusion if they reported venous thromboembolism rates (number of events per follow-up period) or RR estimates. We extracted data from published reports and contacted the corresponding authors of records with insufficient quantitative data. RRs and 95% CIs were pooled using a random-effects model. This study is registered with PROSPERO, number CRD42014015504. FINDINGS: Of 8673 records identified, we included 71 studies with data from 88 cohorts in our analysis, with 59 cohorts included in the assessment of venous thromboembolism rates and 46 cohorts included in the meta-analysis of heart failure and risk of venous thromboembolism. Venous thromboembolism rates varied widely in patients in hospital with heart failure from different settings. The overall median symptomatic venous thromboembolism rate was 2.48% (IQR 0.84-5.61); rates was were 3.73% (1.05-7.31) for patients who did not receive thromboprophylaxis and 1.47% (0.64-3.54) for those who did. Overall, patients with heart failure in hospital had an RR of 1.51 (1.36-1.68) for venous thromboembolism. The overall I(2) statistic was 96.1% and there was no evidence of publication bias (Egger's test, p=0.46). INTERPRETATION: Heart failure is a common independent risk factor for venous thromboembolism. Thromoboprophylaxis should be considered in clinical practice for high-risk patients. FUNDING: National Natural Science Foundation. PMID- 26765647 TI - Alemtuzumab in T-cell large granular lymphocyte leukaemia. PMID- 26765645 TI - Alemtuzumab in T-cell large granular lymphocytic leukaemia: interim results from a single-arm, open-label, phase 2 study. AB - BACKGROUND: T-cell large granular lymphocytic leukaemia (T-LGL) is a lymphoproliferative disease that presents with immune-mediated cytopenias and is characterised by clonal expansion of cytotoxic CD3+ CD8+ lymphocytes. Use of methotrexate, ciclosporin, or cyclophosphamide as first therapy improves cytopenias in 50% of patients, but long-term use of these can lead to toxicity. We aimed to explore the activity and safety of alemtuzumab, an anti-CD52 monoclonal antibody, in patients with T-LGL. METHODS: We did this single-arm, phase 2 trial in consecutively enrolled adults with T-LGL referred to the National Institutes of Health in Bethesda, MD, USA. Alemtuzumab was given intravenously at 10 mg per day for 10 days. The primary endpoint was haematological response at 3 months after infusion. A complete response was defined as normalisation of all affected lineages, and a partial response was defined in neutropenic patients as 100% increase in the absolute neutrophil count to more than 5 * 10(8) cells per L, and in those with anaemia, as any increase in haemoglobin of 20 g/L or higher observed in at least two serial measurements 1 week apart and sustained for 1 month or longer without exogenous growth factors support or transfusions. Analysis was by intention to treat. We report results from the first stage of this Simon two-stage design trial; enrolment into the second stage is continuing. This study is registered with ClinicalTrials.gov, number NCT00345345. FINDINGS: From Oct 1, 2006, to March 1, 2015, we enrolled 25 patients with T-LGL. 14 patients (56%; 95% CI 35-76) had a haematological response at 3 months. Four patients with associated myelodysplastic syndrome and two who had received haemopoietic stem cell transplantation had either no response or were not evaluable, meaning 14 (74% [49-91]) of the 19 patients with classic T-LGL responded. All patients had an infusion reaction (24 [96%] patients grade 1-2, one [4%] patient grade 3), which improved with symptomatic therapy. All patients developed lymphopenia, with 22 (88%) patients having grade 3 or 4 lymphopenia. The other most common grade 3 and 4 adverse events were leukopenia (eight [32%]) and neutropenic infections (five [20%]). Seven patients died; all were non-responders. INTERPRETATION: This is the largest and only prospective study of alemtuzumab in patients with T-LGL. The activity reported with a single course of a lymphocytotoxic drug in patients with mainly relapsed and refractory disease suggests that haematological response can be achieved without continued use of oral immunosuppression. FUNDING: National Heart, Lung, and Blood Institute. PMID- 26765648 TI - Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft versus-host disease: systematic review and meta-analysis. AB - BACKGROUND: Graft-versus-host disease (GVHD) is the major limitation of allogeneic haemopoietic stem-cell transplantation (HSCT), for which no approved treatments are available. Use of mesenchymal stromal cells (MSCs) has become standard practice in some European countries, but controversy exists for their benefit. The aim of this meta-analysis was to analyse available evidence for the benefit of MSC treatments in steroid-resistant acute GVHD. METHODS: We did a systematic review and meta-analysis to assess response to and survival after MSC treatment in patients with steroid-refractory acute GVHD. We searched MEDLINE, Embase, Ovid, and Cochrane Central databases for published studies, and we used ClinicalTrials.gov and other websites to find unpublished studies and conference abstracts. We included prospective and retrospective studies in which MSCs were administered to patients with steroid-refractory acute GVHD. Data were extracted independently by two investigators based on strict selection criteria. A random effects model was used to pool outcomes across studies because of anticipated heterogeneity. Our primary outcome was survival at 6 months from the first infusion of MSCs. FINDINGS: We identified 628 citations with our search, of which 610 were excluded after review and a further five did not contain pertinent data. Thus, our meta-analysis included 13 non-randomised studies at moderate risk of bias, comprising a total of 336 patients. Six studies provided data for the primary outcome analysis (119 patients). Survival at 6 months after MSC treatment was 63% (95% CI 50-74; I(2)=41%). Survival did not differ with respect to age, MSC culture medium, or dose of MSCs delivered. INTERPRETATION: Available evidence suggests that infusion of MSCs could be an acceptable treatment for patients with steroid-refractory acute GVHD. Randomised clinical trials are needed urgently to assess different treatment modalities for steroid-refractory acute GVHD. FUNDING: None. PMID- 26765649 TI - Risk of venous thromboembolism in patients with heart failure. PMID- 26765650 TI - Mesenchymal stromal cells for steroid-refractory acute GVHD. PMID- 26765651 TI - Growth of 3D hierarchical porous NiO@carbon nanoflakes on graphene sheets for high-performance lithium-ion batteries. AB - Nickel oxide (NiO) as one of the anode electrode materials for lithium ion batteries (LIBs) has attracted considerable research attention. However, the poor electron conductivity and bad capacity retention performance greatly hinder its wide application. Herein, we prepared a novel three-dimensional (3D) hierarchical porous graphene@NiO@carbon composite via a simple solvothermal process, in which the graphene sheets were uniformly wrapped by porous NiO@carbon nanoflakes. In this case, nickelocene was creatively used as the precursor for both NiO and amorphous carbon, while graphene oxide sheets were employed as a template for the two-dimensional nanostructure and the conductive graphene backbone. The resultant composites possess high surface area (196 m(2) g(-1)) and large pore volume (0.46 cm(3) g(-1)). When it is applied as an anode for LIBs, the carbon outer-layer can effectively suppress the large volume change and serious aggregation of NiO nanoparticles during the charge-discharge process. Therefore, the graphene@NiO@carbon composites show a high reversible capacity of 1042 mA h g(-1) at a current density of 200 mA g(-1), an excellent rate performance and long cycle life. We believe that our method provides a new route for the fabrication of novel transition metal oxide composites. PMID- 26765653 TI - In Reply. PMID- 26765654 TI - Notes from the Field: Subacute Sclerosing Panencephalitis Death - Oregon, 2015. AB - In 2015, the Oregon Health Authority was notified of the death of a boy with subacute sclerosing panencephalitis (SSPE), a rare and fatal complication of measles. The patient, aged 14 years, had reportedly been vaccinated against measles in the Philippines at age 8 months. However, the patient contracted measles at age 1 year while still in the Philippines. He had been well until 2012, when his neurodegenerative symptoms began. After the diagnosis of SSPE was made, the patient remained in home hospice care until his death. Investigators from the Oregon Health Authority and the Oregon Health and Science University reviewed the patient's medical records and interviewed the parents. Vaccination against measles can prevent not only acute measles and its complications, but also SSPE. PMID- 26765652 TI - Three FLOWERING LOCUS T-like genes function as potential florigens and mediate photoperiod response in sorghum. AB - Sorghum is a typical short-day (SD) plant and its use in grain or biomass production in temperate regions depends on its flowering time control, but the underlying molecular mechanism of floral transition in sorghum is poorly understood. Here we characterized sorghum FLOWERING LOCUS T (SbFT) genes to establish a molecular road map for mechanistic understanding. Out of 19 PEBP genes, SbFT1, SbFT8 and SbFT10 were identified as potential candidates for encoding florigens using multiple approaches. Phylogenetic analysis revealed that SbFT1 clusters with the rice Hd3a subclade, while SbFT8 and SbFT10 cluster with the maize ZCN8 subclade. These three genes are expressed in the leaf at the floral transition initiation stage, expressed early in grain sorghum genotypes but late in sweet and forage sorghum genotypes, induced by SD treatment in photoperiod-sensitive genotypes, cooperatively repressed by the classical sorghum maturity loci, interact with sorghum 14-3-3 proteins and activate flowering in transgenic Arabidopsis plants, suggesting florigenic potential in sorghum. SD induction of these three genes in sensitive genotypes is fully reversed by 1 wk of long-day treatment, and yet, some aspects of the SD treatment may still make a small contribution to flowering in long days, indicating a complex photoperiod response mediated by SbFT genes. PMID- 26765655 TI - Embedding Patient Education in Mobile Platform for Patients With Heart Failure: Theory-Based Development and Beta Testing. AB - Health education is an important component of multidisciplinary disease management of heart failure. The educational information given at the time of discharge after hospitalization or at initial diagnosis is often overwhelming to patients and is often lost or never consulted again. Therefore, the aim of this developmental project was to embed interactive heart failure education in a mobile platform. A patient-centered approach, grounded on several learning theories including Mayer's Cognitive Theory of Multimedia Learning, Sweller's Cognitive Load, Instructional Design Approach, and Problem-Based Learning, was utilized to develop and test the mobile app. Ten heart failure patients, who attended an outpatient heart failure clinic, completed beta testing. A validated self-confidence questionnaire was utilized to assess patients' confidence in using the mobile app. All participants (100%) reported moderate to extreme confidence in using the app, 95% were very likely to use the app, 100% reported the design was easy to navigate, and content on heart failure was appropriate. Having the information accessible on their mobile phone was reported as a positive, like a health coach by all patients. Clinicians and nurses validated the content. Thus, embedding health education in a mobile app is proposed in promoting persistent engagement to improve health outcomes. PMID- 26765656 TI - Mapping Out Point-of-Care Review Screens for Omaha System Data. AB - Omaha System data are text data that consist of standardized terminology and customized descriptions. The customized descriptions related to patient care reveal changes in a client's status over time. These data help public health nurses to understand the patient's progress and to plan future care. However, most electronic health records do not provide clinicians with efficient displays of stored text data. The purpose of this study is to develop point-of-care review screens for Omaha System data on an individual patient level and examine nurse perceptions of the usefulness of the displayed data in improving patient care. Individual patients' data were organized on a Web-based overview page to present all of the health problems that a client had and on detailed pages to present all records of Omaha System data regarding each health problem. Nurse survey results indicated the usefulness of at-a-glance displays of text data on patient care and nurses' decision making. The meaningful review of patient data using a health information system supports patient-data-driven, evidence-based practice and decision making. PMID- 26765657 TI - Communicating Nursing Care Using the Health Level Seven Consolidated Clinical Document Architecture Release 2 Care Plan. AB - A care plan provides a patient, family, or community picture and outlines the care to be provided. The Health Level Seven Consolidated Clinical Document Architecture (C-CDA) Release 2 Care Plan Document is used to structure care plan data when sharing the care plan between systems and/or settings. The American Nurses Association has recommended the use of two terminologies, Logical Observation Identifiers Names and Codes (LOINC) for assessments and outcomes and Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT) for problems, procedures (interventions), outcomes, and observation findings within the C-CDA. This article describes C-CDA, introduces LOINC and SNOMED CT, discusses how the C CDA Care Plan aligns with the nursing process, and illustrates how nursing care data can be structured and encoded within a C-CDA Care Plan. PMID- 26765658 TI - What is your diagnosis? Middle ear material from a dog. PMID- 26765661 TI - Hypothesis Formulation, Model Interpretation, and Model Equivalence: Implications of a Mereological Causal Interpretation of Structural Equation Models. AB - One can distinguish statistical models used in causal modeling from the causal interpretations that align them with substantive hypotheses. Causal modeling typically assumes an efficient causal interpretation of the statistical model. Causal modeling can also make use of mereological causal interpretations in which the state of the parts determines the state of the whole. This interpretation shares several properties with efficient causal interpretations but also differs in terms of other important properties. The availability of alternative causal interpretations of the same statistical models has implications for hypothesis specification, research design, causal inference, data analysis, and the interpretation of research results. PMID- 26765662 TI - The Performance of Methods to Test Upper-Level Mediation in the Presence of Nonnormal Data. AB - A Monte Carlo study compared the statistical performance of standard and robust multilevel mediation analysis methods to test indirect effects for a cluster randomized experimental design under various departures from normality. The performance of these methods was examined for an upper-level mediation process, where the indirect effect is a fixed effect and a group-implemented treatment is hypothesized to impact a person-level outcome via a person-level mediator. Two methods-the bias-corrected parametric percentile bootstrap and the empirical-M test-had the best overall performance. Methods designed for nonnormal score distributions exhibited elevated Type I error rates and poorer confidence interval coverage under some conditions. Although preliminary, the findings suggest that new mediation analysis methods may provide for robust tests of indirect effects. PMID- 26765663 TI - Flexible Approaches to Computing Mediated Effects in Generalized Linear Models: Generalized Estimating Equations and Bootstrapping. AB - In behavioral research, interest is often in examining the degree to which the effect of an independent variable X on an outcome Y is mediated by an intermediary or mediator variable M. This article illustrates how generalized estimating equations (GEE) modeling can be used to estimate the indirect or mediated effect, defined as the amount by which the regression coefficient of X on Y changes after adjusting for M. Advantages of this method are: (a) it applies to the class of generalized linear models, including linear, logistic, and Poisson regression as special cases; (b) it allows multiple independent variables and mediators in the same model; and (c) asymptotically valid standard errors and confidence intervals are obtained using standard software. This methodology is compared with the bootstrap, another general methodology that can be applied to the same broad class of models, and is evaluated using simulation in both linear and logistic regression scenarios. The methods are utilized to examine the degree to which the effect of low birthweight status on internalizing symptoms at age 20 is mediated through IQ at age 8. PMID- 26765664 TI - Using Multilevel Mixtures to Evaluate Intervention Effects in Group Randomized Trials. AB - There is evidence to suggest that the effects of behavioral interventions may be limited to specific types of individuals, but methods for evaluating such outcomes have not been fully developed. This study proposes the use of finite mixture models to evaluate whether interventions, and, specifically, group randomized trials, impact participants with certain characteristics or levels of problem behaviors. This study uses latent classes defined by clustering of individuals based on the targeted behaviors and illustrates the model by testing whether a preventive intervention aimed at reducing problem behaviors affects experimental users of illicit substances differently than problematic substance users or those individuals engaged in more serious problem behaviors. An illustrative example is used to demonstrate the identification of latent classes, specification of random effects in a multilevel mixture model, independent validation of latent classes, and the estimation of power for the proposed models to detect intervention effects. This study proposes specific steps for the estimation of multilevel mixture models and their power and suggests that this model can be applied more broadly to understand the effectiveness of interventions. PMID- 26765665 TI - Computing Power of Tests of the Variance of Treatment Effects in Designs With Two Levels of Nesting. AB - Experiments that involve nested structures may assign treatment conditions either to entire groups (such as classrooms or schools) or individuals within groups (such as students). Although typically the interest in field experiments is in determining the significance of the overall treatment effect, it is equally important to examine the inconsistency of the treatment effect in different groups. This study provides methods for computing power of tests for the variability of treatment effects across level-2 and level-3 units in three-level designs, where, for example, students are nested within classrooms and classrooms are nested within schools and random assignment takes place at the first or the second level. The power computations take into account nesting effects at the second (e.g., classroom) and at the third (e.g., school) level as well as sample size effects (e.g., number of level-1 and level-2 units). The methods can also be applied to quasi-experimental studies that examine the significance of the variation of group differences in an outcome or associations between predictors and outcomes across level-2 and level-3 units. PMID- 26765667 TI - Nurses' Perceptions of Interventions for the Management of Patient-Oriented Outcomes: A Key Factor for Evidence-Based Practice. AB - BACKGROUND: Various barriers and facilitators to implementing evidence-based interventions in practice have been acknowledged. Nurses' perspectives on these interventions were overlooked as potential factors that influence their uptake in practice. The purpose of this study was to explore nurses' perception of evidence based interventions targeting patient-oriented outcomes. METHODS: A mixed method design involving concurrent application of quantitative and qualitative approaches was used. Nurses (n = 56) working in acute and rehabilitation care settings completed the Intervention Acceptability scale and responded to open ended questions. The scale presented information on the components, activities, dose, and mode of delivering evidence-based interventions targeting each patient oriented outcome (fatigue, nausea and vomiting, dyspnea, pain, physical function, self-care) and items to rate the interventions on five attributes (relevance, applicability, frequency of use, likelihood, and comfort in implementation). The open-ended questions inquired about the appropriateness and resources needed to use the interventions in practice. RESULTS: The quantitative results indicated favorable perceptions of most interventions. Nurses rated acupressure, guided imagery, massage, and relaxation as having limited appropriateness and they reported low levels of comfort in applying them. The qualitative themes clarified the reasons underlying nurses' ratings. LINKING EVIDENCE TO ACTION: This study's findings highlight the importance of examining nurses' perceptions of evidence based interventions as an initial step toward promoting the adoption of interventions in practice. Effective interventions that are considered of limited relevance are unlikely to be implemented in practice. Nurses' perceptions can guide the design or selection of dissemination strategies to clarify any misconception about the effectiveness and risk of evidence-based interventions. PMID- 26765668 TI - Sex-specific divergence of antioxidant pathways in fetal brain, liver, and skeletal muscles. AB - The sex-specific divergence of antioxidant pathways in fetal organs of opposite sex twin is unknown and remains urgently in need of investigation. Such study faces many challenges, mainly the ethical impossibility of obtaining human fetal organs. Opposite-sex sheep twins represent a unique model for studying a sex dimorphism for antioxidant systems. The activity of total superoxide dismutase (SOD), SOD1, SOD2, glutathione peroxidase (GPX), glutathione reductase (GR) and catalase (CAT), the content of total glutathione, reduced glutathione (GSH), and oxidized glutathione (GSSG) were measured in brain, lung, liver, kidney, and skeletal muscles of female and male fetuses collected from sheep twin pregnancies at day 65 of gestation. Lipid peroxidation was assessed by measuring melondialdehyde (MDA) tissue content. Male brain has greater total SOD and SOD1 activities than female brain. Female liver has greater SOD2 activity than male liver. Male liver has greater GR activity than female liver. Male liver has higher total GSH and GSSG content than female liver. Male skeletal muscles have higher total GSH, GSH, and GSSG content than female skeletal muscles. Female brain and liver have higher MDA content than male brain and liver. This is the first report of a sex dimorphism for fetal organ antioxidative pathways. Brain, liver, and skeletal muscles of male and female fetuses display distinct antioxidant pathways. Such sexually dimorphic responses to early life oxidative stress might be involved in the sex-related difference in fetal development that may have a long-term effect on offspring. Our study urges researchers to take into consideration the importance of sex as a biologic variable in their investigations. PMID- 26765669 TI - Electromagnetic interference of endodontic equipments with cardiovascular implantable electronic device. AB - OBJECTIVES: Assess the electromagnetic interference (EMI) of endodontic equipment with cardiovascular implantable electronic devices (CIEDs) and related factors. METHODS: The laser device, electronic apex locators (EAL), optical microscope, endodontic rotary motors, gutta-percha heat carrier (GH), gutta-percha gun and ultrasonic device were tested next to CIEDs (Medtronic and Biotronik) with varied sensitivity settings and distances. CIEDs were immersed in a saline solution to simulate the electrical resistence of the human body. The endodontic equipment was tested in both horizontal and vertical positions in relation to the components of the CIED. The tests were performed on a dental chair in order to assess the cumulative effect of electromagnetic fields. RESULTS: It was found no EMI with the Biotronik pacemaker. EALs caused EMI with Medtronic PM at a 2 cm distance, with the NSK((r)) EAL also affecting the Medtronic defibrillator. GH caused EMI at 2 cm and 5 cm from the Medtronic defibrillator. EMI occurred when devices were horizontally positioned to the CIED. In the majority of the cases, EMI occurred when the pacemaker was set to maximum sensitivity. There was cumulative effect of electromagnetic fields between GH and dental chair. CONCLUSIONS: EALs and GH caused EMI which ranged according to type and sensitivity setting of the CIEDs and the distance. However, no endodontic equipment caused permanent damage to the CIED. The use of GH caused a cumulative effect of electromagnetic fields. It suggests that during the treatment of patients with CIEDs, only the necessary equipments should be kept turned on. CLINICAL RELEVANCE: Patients with CIEDs may be subject to EMI from electronic equipment used in dental offices, as they remain turned on throughout the treatment. This is the first article assessing the cumulative effect of electromagnetic fields. PMID- 26765670 TI - Adaptation of the fish juvenile growth test (OECD TG 215, 2000) to the marine species Dicentrarchus labrax. AB - The OECD TG 215 method (2000) (C.14 method of EC Regulation 440/2008) was developed on the rainbow trout (Oncorynchus mykiss) to assess chronic toxicity (28d) of chemicals on fish juveniles. It contemplates to use other well documented species identifying suitable conditions to evaluate their growth. OECD proposes the European sea bass (Dicentrarchus labrax, L. 1758) as Mediterranean species among vertebrates recommended in the OECD guidelines for the toxicity testing of chemicals. In this context, our study is aimed to proposing the adaptation of the growth test (OECD TG 215, 2000) to D. labrax. For this purpose toxicity tests were performed with sodium dodecyl sulfate, a reference toxicant commonly used in fish toxicity assays. The main aspects of the testing procedure were reviewed: fish size (weight), environmental conditions, dilution water type, experimental design, loading rate and stocking density, feeding (food type and ration), test validity criteria. The experience gained from growth tests with the sea bass allows to promote its inclusion among the species to be used for the C.14 method. PMID- 26765680 TI - COMPARISON BETWEEN COMPUTED TOMOGRAPHIC CHARACTERISTICS OF THE MIDDLE EAR IN NONBRACHYCEPHALIC AND BRACHYCEPHALIC DOGS WITH OBSTRUCTIVE AIRWAY SYNDROME. AB - Prevalence of subclinical middle ear lesions in dogs that undergo computed tomography (CT) and magnetic resonance imaging of the head has been reported up to 41%. A predisposition in brachycephalics has been suggested, however evidence based studies are lacking. Aims of this retrospective cross-sectional study were to compare CT characteristics of the middle ear in groups of nonbrachycephalic and brachycephalic dogs that underwent CT of the head for conditions unrelated to ear disease, and test associations between thickness of the soft palate and presence of subclinical middle ear lesions. One observer recorded CT findings for each dog without knowledge of group status. A total of 65 dogs met inclusion criteria (25 brachycephalic, 40 nonbrachycephalic). Brachycephalic dogs had a significantly thicker bulla wall (P = 2.38 * 10(-26)) and smaller luminal volume (P = 5.74 * 10(-20)), when compared to nonbrachycephalic dogs. Soft palate thickness was significantly greater in the brachycephalic group (P = 2.76 * 10( 9)). Nine of 25 brachycephalic dogs had material in the lumen of the tympanic cavity, compared to zero of 45 of nonbrachycephalics. Within the brachycephalic group, a significant difference in mean soft palate thickness was identified for dogs with material in the middle ear (12.2 mm) vs. air-filled bullae (9 mm; P = 0.016). Findings from the current study supported previous theories that brachycephalic dogs have a greater prevalence of subclinical middle ear effusion and smaller bulla luminal size than nonbrachycephalic dogs. Authors recommend that the bulla lumen volume formula previously developed for mesaticephalic dogs, (-0.612 + 0.757 [lnBW]) be adjusted to 1/3(-0.612 + 0.757 [lnBW]) for brachycephalic breeds. PMID- 26765675 TI - Functional "Janus" Annulus in Confined Channels. AB - Scattered Au 3D nanoparticles form distinct functional regions with an uncovered internal surface in confined channels, named the "Janus" annulus. Electrochemical impedance spectroscopy responses to the variations in DNA self-assembly and hybridization in the channels decorated by the "Janus" annulus are presented. Single nucleotide mutations are further detected in a linear DNA chain, including terminal base polymorphisms. PMID- 26765681 TI - In-patient hospice: A qualitative study with Portuguese patients, family and staff. AB - The present study aims to provide insights on the role of in-patient hospices, which are sometimes described as disconnecting spaces. Researchers complement participant observation with in-depth interviews with 10 hospice patients, 20 family members, and 20 members of hospice staff. The findings suggest that the hospice provides a space where patients could enjoy the company of their loved ones without concerns regarding the dying process. The study reveals that the hospice offers a proper alternative to the home setting even in countries characterized by a strong familialistic culture like Portugal. PMID- 26765682 TI - Complications after prostate biopsies in men on active surveillance and its effects on receiving further biopsies in the Prostate cancer Research International: Active Surveillance (PRIAS) study. AB - OBJECTIVE: To study the risk of serial prostate biopsies on complications in men on active surveillance (AS) and determine the effect of complications on receiving further biopsies. PATIENTS AND METHODS: In the global Prostate cancer Research International: Active Surveillance (PRIAS) study, men are prospectively followed on AS and repeat prostate biopsies are scheduled at 1, 4, and 7 years after the diagnostic biopsy, or once yearly if prostate-specific antigen-doubling time is <10 years. Data on complications after biopsy, including infection, haematuria, haematospermia, and pain, were retrospectively collected for all biopsies taken during follow-up in men from several large participating centres. Generalised estimating equations were used to test predictors of infection after biopsy. Competing risk analysis was used to compare the rates of men receiving further biopsies between men with and without previous complications. RESULTS: In all, 2 184 biopsies were taken in 1 164 men. Infection was reported after 55 biopsies (2.5%), and one in five men reported any form of complication. At multivariable analysis, the number of previous biopsies was not a significant predictor of infection (odds ratio 1.04, 95% confidence interval 0.76-1.43). The only significant predictor for infection was the type of prophylaxis used. Of all men with a complication at the diagnostic or first repeat biopsy, 21% did not have a repeat biopsy at the time a repeat biopsy was scheduled according to protocol, vs 12% for men without a previous biopsy complication. CONCLUSION: In our present cohort of men on AS, we found no evidence that repeat prostate biopsy in itself posed a risk of infection. However, complications after biopsy were not uncommon and after a complication men were less likely to have further biopsies. We should aim to safely reduce the amount of repeat biopsies in men on AS. PMID- 26765683 TI - Shaping Public Health Initiatives in Kidney Diseases: The Peer Kidney Care Initiative. AB - BACKGROUND: While broad-based societal efforts to improve public health have targeted disorders such as cardiovascular disease and cancer for several decades, efforts devoted to kidney disease have developed only more recently. The Peer Kidney Care Initiative, a novel effort designed to address knowledge gaps in the care of patients with kidney disease, examines key disease processes, the roles of geography and seasonality on outcomes, and longitudinal trends in outcomes over time. SUMMARY: Admissions for gastrointestinal bleeds increased approximately 28% between 2004 and 2011 in prevalent patients. Infection with Clostridium difficile increased nearly 70% between 2003 and 2010 in patients within a year of initiation. Admissions for heart failure in prevalent patients decreased approximately 25% between 2004 and 2012, but admissions for volume overload increased a nearly equal amount. Incidence rates varied substantially by geographic region, such that unadjusted rates in the highest region were nearly double than those in the lowest. There was seasonal variation in all-cause mortality of approximately 15-20% in both incident and prevalent patients, suggesting a link between cardiovascular events and seasonally related environmental conditions. New cases of end-stage renal disease fell from 385 per million population in 2003 to 344 in 2012, a decline of approximately 10%. KEY MESSAGES: Peer complements existing kidney disease epidemiologic efforts by examining specific actionable disease entities, exploring geographic variation in care, highlighting the role of seasonality on outcomes, and emphasizing the importance of trending outcomes over time as overall societal progress is being made. PMID- 26765684 TI - Correction: Heme-Mediated Induction of CXCL10 and Depletion of CD34+ Progenitor Cells Is Toll-Like Receptor 4 Dependent. PMID- 26765685 TI - Synthesis and Characterization of Three New Layered Vanadium Tellurites, MVTe2O8 (M = Al, Ga, and Mn): Three-Dimensional (3-D) Antiferromagnetic Behavior of MnVTe2O8 with a Zigzag S = 2 Spin Chain. AB - Three new metal vanadium tellurites, MVTe2O8 (M = Al, Ga, and Mn) have been synthesized through standard solid-state and hydrothermal reactions. Crystal structure analyses using X-ray diffraction reveal that the isostructural materials exhibit layered structures consisting of MO6, TeO4, and VO4 polyhedra. The corner-sharing of MO6 octahedra results in one-dimensional (1-D) zigzag chains that are further interconnected by tetrameric Te4O12 units and the VO4 tetrahedra to complete a layered structure. Detailed structural analysis suggests that the unit-cell volumes and the very long Te(2)-O(2) bond distances in MVTe2O8 are closely related to the ionic radii of M(3+) cations. Additional characterizations such as ultraviolet-visible light (UV-vis) and infrared spectroscopies, thermogravimetric analyses, and electron paramagnetic resonance measurements were performed. The temperature-dependent magnetic susceptibility measurements on MnVTe2O8 suggest that the material behaves like a three dimensional (3-D) antiferromagnet with T(N) = 30 K, although the structure consists of a zigzag S = 2 spin chain. PMID- 26765686 TI - Ewing sarcoma: The clinical relevance of the insulin-like growth factor 1 and the poly-ADP-ribose-polymerase pathway. AB - BACKGROUND: In the last three decades the outcome for patients with localised Ewing sarcoma (ES) has improved significantly since the introduction of multimodality primary treatment. However, for patients with (extra-) pulmonary metastatic and/or non-resectable relapsed disease the outcome remains poor and new treatment options are urgently needed. Currently the insulin-like growth factor 1 receptor (IGF-1R) pathway and the poly-ADP(adenosinediphosphate)-ribose polymerase (PARP) pathway are being investigated for potential targeted therapies. IGF-1R: The IGF-1R pathway is known to be deregulated by the EWSR1 FLI1 translocation which makes it a potential target for therapy. Clinical trials have been reported in which only ES patients were treated with an IGF-1R inhibitor, either as single agent or in combination. In total 291 ES patients were included in these trials, in which two (0.7%) complete responses, 32 (11%) partial responses of which some durable, and 61 (21%) stable diseases were observed. PARP: In the presence of a PARP inhibitor DNA strand breaks cannot be efficiently repaired, leading to cell death. The first phase II trial with ES patients was recently published and showed no clinical responses, which may have been due to the drug being non-effective as a single agent. DISCUSSION: The IGF 1R pathway is an interesting target for ES and should be explored further, as biomarkers to select patients that might benefit from treatment are lacking. PARP inhibitors as single agent have so far failed to show improvement in outcome. Future directions include dual insulin receptor/IGF-1R blockade with linsitinib as well as chemotherapy-PARP combinations. Both therapeutic strategies are currently being explored. PMID- 26765737 TI - Protective Effect of Creatine Elevation against Ischaemia Reperfusion Injury Is Retained in the Presence of Co-Morbidities and during Cardioplegia. AB - AIMS: Ischaemic heart disease is most prevalent in the ageing population and often exists with other comorbidities; however the majority of laboratory research uses young, healthy animal models. Several recent workshops and focus meetings have highlighted the importance of using clinically relevant models to help aid translation to realistic patient populations. We have previously shown that mice over-expressing the creatine transporter (CrT-OE) have elevated intracellular creatine levels and are protected against ischaemia-reperfusion injury. Here we test whether elevating intracellular creatine levels retains a cardioprotective effect in the presence of common comorbidities and whether it is additive to protection afforded by hypothermic cardioplegia. METHODS AND RESULTS: CrT-OE mice and wild-type controls were subjected to transverse aortic constriction for two weeks to induce compensated left ventricular hypertrophy (LVH). Hearts were retrogradely perfused in Langendorff mode for 15 minutes, followed by 20 minutes ischaemia and 30 minutes reperfusion. CrT-OE hearts exhibited significantly improved functional recovery (Rate pressure product) during reperfusion compared to WT littermates (76% of baseline vs. 59%, respectively, P = 0.02). Aged CrT-OE mouse hearts (78+/-5 weeks) also had enhanced recovery following 15 minutes ischaemia (104% of baseline vs. 67%, P = 0.0007). The cardioprotective effect of hypothermic high K+ cardioplegic arrest, as used during cardiac surgery and donor heart transplant, was further enhanced in prolonged ischaemia (90 minutes) in CrT-OE Langendorff perfused mouse hearts (76% of baseline vs. 55% of baseline as seen in WT hearts, P = 0.02). CONCLUSIONS: These observations in clinically relevant models further support the development of modulators of intracellular creatine content as a translatable strategy for cardiac protection against ischaemia-reperfusion injury. PMID- 26765740 TI - New Medical Devices. PMID- 26765739 TI - Enantioselective Total Synthesis of Terreumols A and C from the Mushroom Tricholoma terreum. AB - The cytotoxic meroterpenoids terreumol A and C from the grey knight mushroom Tricholoma terreum were synthesized for the first time. The key step of the enantioselective total synthesis of terreumol C is a ring-closing metathesis to form a trisubstituted Z double bond embedded in the 10-membered ring of the [8.4.0] bicycle. Interestingly, the presence of a free hydroxy group in the metathesis precursor prevents cyclization and favors cross metathesis. (-) Terreumol C was converted into (-)-terreumol A by diastereoselective epoxidation. Starting from 2-bromo-3,5-dimethoxybenzaldehyde, 14 steps with an overall yield of 23 % are needed for the synthesis of (-)-terreumol A. X-ray analysis of the benzoquinone analogue of terreumol A provides independent proof of the absolute configuration. PMID- 26765738 TI - A Method to Quantify Cell-Free Fetal DNA Fraction in Maternal Plasma Using Next Generation Sequencing: Its Application in Non-Invasive Prenatal Chromosomal Aneuploidy Detection. AB - OBJECTIVE: The fraction of circulating cell-free fetal (cff) DNA in maternal plasma is a critical parameter for aneuploidy screening with non-invasive prenatal testing, especially for those samples located in equivocal zones. We developed an approach to quantify cff DNA fractions directly with sequencing data, and increased cff DNAs by optimizing library construction procedure. METHODS: Artificial DNA mixture samples (360), with known cff DNA fractions, were used to develop a method to determine cff DNA fraction through calculating the proportion of Y chromosomal unique reads, with sequencing data generated by Ion Proton. To validate our method, we investigated cff DNA fractions of 2,063 pregnant women with fetuses who were diagnosed as high risk of fetal defects. The z-score was calculated to determine aneuploidies for chromosomes 21, 18 and 13. The relationships between z-score and parameters of pregnancies were also analyzed. To improve cff DNA fractions in our samples, two groups were established as follows: in group A, the large-size DNA fragments were removed, and in group B these were retained, during library construction. RESULTS: A method to determine cff DNA fractions was successfully developed using 360 artificial mixture samples in which cff DNA fractions were known. A strong positive correlation was found between z-score and fetal DNA fraction in the artificial mixture samples of trisomy 21, 18 and 13, as well as in clinical maternal plasma samples. There was a positive correlation between gestational age and the cff DNA fraction in the clinical samples, but no correlation for maternal age. Moreover, increased fetal DNA fractions were found in group A compared to group B. CONCLUSION: A relatively accurate method was developed to determine the cff DNA fraction in maternal plasma. By optimizing, we can improve cff DNA fractions in sequencing samples, which may contribute to improvements in detection rate and reliability. PMID- 26765741 TI - Thermal Destabilization of Collagen Matrix Hierarchical Structure by Freeze/Thaw. AB - This study aims to characterize and understand the effects of freezing on collagen structures and functionality. Specifically, thermodynamic destabilization of collagen at molecular- and fibril-levels by combination of low temperatures and freezing were experimentally characterized using modulated differential scanning calorimetry. In order to delineate the effects of sub-zero temperature and water-ice phase change, we hypothesized that the extent of destabilization can be determined based on post-thaw heat induced thermal denaturation of collagen. It is found that thermal denaturation temperature of collagen in hydrogel decreases by 1.4-1.6 degrees C after freeze/thaw while no such decrease is observed in the case of molecular solution. The destabilization is predominantly due to ice formation. Exposure to low temperatures in the absence of ice has only minimal effect. Calorimetry measurements combined with morphological examination of collagen matrices by scanning electron microscopy suggest that freezing results in destabilization of collagen fibrils due to expansion of intrafibrillar space by ice formation. This fibril-level damage can be alleviated by use of cryoprotectant DMSO at concentrations as low as 0.5 M. A theoretical model explaining the change in collagen post-thaw thermal stability by freezing-induced fibril expansion is also proposed. PMID- 26765742 TI - Focus on Quality: Investigating Residents' Learning Climate Perceptions. AB - BACKGROUND: A department's learning climate is known to contribute to the quality of postgraduate medical education and, as such, to the quality of patient care provided by residents. However, it is unclear how the learning climate is perceived over time. OBJECTIVES: This study investigated whether the learning climate perceptions of residents changed over time. METHODS: The context for this study was residency training in the Netherlands. Between January 2012 and December 2014, residents from 223 training programs in 39 hospitals filled out the web-based Dutch Residency Educational Climate Test (D-RECT) to evaluate their clinical department's learning climate. Residents had to fill out 35 validated questions using a five point Likert-scale. We analyzed data using generalized linear mixed (growth) models. RESULTS: Overall, 3982 D-RECT evaluations were available to investigate our aim. The overall mean D-RECT score was 3.9 (SD = 0.3). The growth model showed an increase in D-RECT scores over time (b = 0.03; 95% CI: 0.01-0.06; p < 0.05). CONCLUSIONS: The observed increase in D-RECT scores implied that residents perceived an improvement in the learning climate over time. Future research could focus on factors that facilitate or hinder learning climate improvement, and investigate the roles that hospital governing committees play in safeguarding and improving the learning climate. PMID- 26765743 TI - Assessment of Platelet Activation and Immature Platelet Fraction as Predictors of Platelet Engraftment After Hematopoietic Stem Cell Transplantation. AB - Delayed platelet engraftment is a well-known complication of umbilical cord blood transplantation (CBT). Megakaryocytes derived from cord blood (CB) in vitro are smaller than megakaryocytes derived from bone marrow (BM) in adults. A small megakaryocyte size might contribute to delayed megakaryocytic maturation. This study included 37 patients undergoing hematopoietic stem cell transplantation (HSCT) at Chang Gung Children's Hospital between July 2011 and June 2013. Blood samples were obtained at different times: preconditioning and post-HSCT days 56 and 97. To test whether platelet activation persists posttransplantation, two commonly used platelet activation marker antibodies, CD62P (P-selectin) and CD42b, were evaluated using whole blood flow cytometry, combining thiazole orange and anti-CD41a staining, to assess reticulated platelets. Serial peripheral blood (PB) samples were obtained posttransplantation from patients undergoing CBT (CBT group; n = 15) and mobilized peripheral blood transplantation (PBT group; n = 22). Platelet activation in the postengraftment samples was considerably higher in the PBT group than the CBT group. Moreover, immature platelet fractions (IPF) were higher in the CBT group. Our results emphasize the role of IPF for dynamic prediction of platelet engraftment in CBT. PMID- 26765744 TI - Mouse Y-Encoded Transcription Factor Zfy2 Is Essential for Sperm Head Remodelling and Sperm Tail Development. AB - A previous study indicated that genetic information encoded on the mouse Y chromosome short arm (Yp) is required for efficient completion of the second meiotic division (that generates haploid round spermatids), restructuring of the sperm head, and development of the sperm tail. Using mouse models lacking a Y chromosome but with varying Yp gene complements provided by Yp chromosomal derivatives or transgenes, we recently identified the Y-encoded zinc finger transcription factors Zfy1 and Zfy2 as the Yp genes promoting the second meiotic division. Using the same mouse models we here show that Zfy2 (but not Zfy1) contributes to the restructuring of the sperm head and is required for the development of the sperm tail. The preferential involvement of Zfy2 is consistent with the presence of an additional strong spermatid-specific promotor that has been acquired by this gene. This is further supported by the fact that promotion of sperm morphogenesis is also seen in one of the two markedly Yp gene deficient models in which a Yp deletion has created a Zfy2/1 fusion gene that is driven by the strong Zfy2 spermatid-specific promotor, but encodes a protein almost identical to that encoded by Zfy1. Our results point to there being further genetic information on Yp that also has a role in restructuring the sperm head. PMID- 26765745 TI - Characterization of Intact Antibody Drug Conjugate Variants Using Microfluidic Capillary Electrophoresis-Mass Spectrometry. AB - In this work, we utilize capillary electrophoresis-mass spectrometry (CE-MS) in an integrated microfluidic platform to analyze an intact, lysine-linked antibody drug conjugate (ADC) in order to assess post translational modifications and drug load variants. The initial charge heterogeneity of the unconjugated IgG-2 monoclonal antibody (mAb) was assessed by separating intact charge variants. Three main charge variants were resolved in the CE dimension. These variants were attributed to pyroglutamic acid formation and decarboxylation on the primary structure of the mAb through characteristic mass shifts and changes in electrophoretic mobility. Additionally, glycoforms of the antibody charge variants were identified in the deconvoluted mass spectra. The observed glycoforms and their distribution compared favorably to a released N-glycan analysis performed on the mAb. After conjugation, the ADC was analyzed using the same microchip CE-MS method. The addition of a drug load resulted in a decrease in mobility and an increase in mass of 3145 Da. Five main species that differed in their respective drug-to-antibody ratios (DAR) were fully resolved in the CE separation, with each DAR displaying the same variant population observed on the unconjugated mAb. A DAR range of 0-4 was observed with an average of 1.7 drug loads. The DAR distribution generated from the microfluidic CE-MS data compared favorably to results from infusion-ESI-MS and imaging CE (iCE) analysis of the ADC, techniques commonly used for intact mAb and ADC characterization. PMID- 26765746 TI - Rapid quantitative T2 mapping of the prostate using three-dimensional dual echo steady state MRI at 3T. AB - PURPOSE: To develop and evaluate a rapid three-dimensional (3D) quantitative T2 mapping method for prostate cancer imaging using dual echo steady state (DESS) MRI at 3T. METHODS: In simulations, DESS-T2 mapping in the presence of T1 and B1+ variations was evaluated. In a phantom and in healthy volunteers (n = 4), 3D DESS T2 mapping was compared with a two-dimensional turbo spin echo (TSE) approach. In volunteers and a pilot patient study (n = 29), quantitative T2 in normal prostate anatomical zones and in suspected cancerous lesions was evaluated. RESULTS: The simulated bias for DESS-T2 was < 2% (5%) for typically observed T1 ( B1+) variations. In phantoms and in vivo, high correlation of DESS-T2 and TSE-T2 (r2 = 0.98 and 0.88, P < 0.001) was found. DESS-T2 in the normal peripheral zone and transition zone was 115 +/- 26 ms and 64 +/- 7 ms, respectively, in healthy volunteers and 129 +/- 39 ms and 83 +/- 12 ms, respectively, in patients. In suspected cancerous lesions, DESS-T2 was 72 +/- 14 ms, which was significantly decreased from the normal peripheral zone (P < 0.001) but not from the transition zone. CONCLUSION: Rapid 3D T2 mapping in the entire prostate can be performed in 1 min using DESS MRI. Magn Reson Med 76:1720-1729, 2016. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26765749 TI - Beneficial effects of semantic memory support on older adults' episodic memory: Differential patterns of support of item and associative information. AB - The effects of two types of semantic memory support-meaningfulness of an item and relatedness between items-in mitigating age-related deficits in item and associative, memory are examined in a marketing context. In Experiment 1, participants studied less (vs. more) meaningful brand logo graphics (pictures) paired with meaningful brand names (words) and later were assessed by item (old/new) and associative (intact/recombined) memory recognition tests. Results showed that meaningfulness of items eliminated age deficits in item memory, while equivalently boosting associative memory for older and younger adults. Experiment 2, in which related and unrelated brand logo graphics and brand name pairs served as stimuli, revealed that relatedness between items eliminated age deficits in associative memory, while improving to the same degree item memory in older and younger adults. Experiment 2 also provided evidence for a probable boundary condition that could reconcile seemingly contradictory extant results. Overall, these experiments provided evidence that although the two types of semantic memory support can improve both item and associative memory in older and younger adults, older adults' memory deficits can be eliminated when the type of support provided is compatible with the type of information required to perform well on the test. PMID- 26765747 TI - The relationship of spectral sensitivity with growth and reproductive response in avian breeders (Gallus gallus). AB - A previous study demonstrated that birds that are exposed to light at night develop advanced reproductive systems. However, spectrum might also affect the photoperiodic response of birds. The present study was aimed to investigate the effects of spectral composition on the growth and reproductive physiology of female breeders, using pure light-emitting diode spectra. A total of 1,000 newly hatched female avian breeders (Gallus gallus) were equally allocated to white-, red-, yellow-, green- and blue-light treated groups. We found that blue-light treated birds had a greater and faster weight gain than did red- and yellow-light treated birds (P = 0.02 and 0.05). The red light expedited the sexual maturation of the chicks, whose age at sexual maturity was 7 and 14 days earlier than that of the green- and blue-light treated birds, respectively. The accumulative egg production of the red-light treated birds was 9 and 8 eggs more than that of the blue- and green-light treated birds. The peak lay rate of the red-light treated groups was significantly greater than the blue-light treated birds (P = 0.028). In conclusion, exposure to short-wavelength light appears to promote growth of female breeder birds, whereas exposure to long-wavelength light appears to accelerate reproductive performance. PMID- 26765750 TI - Category learning in older adulthood: A study of the Shepard, Hovland, and Jenkins (1961) tasks. AB - Shepard, Hovland, and Jenkins (1961) examined the categorization abilities of younger adults using tasks involving single-dimensional rule learning, disjunctive rule learning, and family resemblance learning. The current study examined category learning in older adults using this well-known category set. Older adults, like younger adults, found category tasks with a single relevant dimension the easiest to learn. In contrast to younger adults, older adults found complex disjunctive rule-based categories harder to learn than family resemblance based categories. Disjunctive rule-based category learning appeared to be the most difficult for older adults to learn because this category set placed the heaviest demands on working memory, which is known to be a cognitive function that declines with normal aging. The authors discuss why complex rule-based category learning is considered more difficult for older adults to learn relative to younger adults, drawing parallels to developmental research. PMID- 26765748 TI - Effects of aging on identifying emotions conveyed by point-light walkers. AB - The visual system is able to recognize human motion simply from point lights attached to the major joints of an actor. Moreover, it has been shown that younger adults are able to recognize emotions from such dynamic point-light displays. Previous research has suggested that the ability to perceive emotional stimuli changes with age. For example, it has been shown that older adults are impaired in recognizing emotional expressions from static faces. In addition, it has been shown that older adults have difficulties perceiving visual motion, which might be helpful to recognize emotions from point-light displays. In the current study, 4 experiments were completed in which older and younger adults were asked to identify 3 emotions (happy, sad, and angry) displayed by 4 types of point-light walkers: upright and inverted normal walkers, which contained both local motion and global form information; upright scrambled walkers, which contained only local motion information; and upright random-position walkers, which contained only global form information. Overall, emotion discrimination accuracy was lower in older participants compared with younger participants, specifically when identifying sad and angry point-light walkers. In addition, observers in both age groups were able to recognize emotions from all types of point-light walkers, suggesting that both older and younger adults are able to recognize emotions from point-light walkers on the basis of local motion or global form. PMID- 26765751 TI - Synthetic Human NOTCH1 EGF Modules Unraveled Molecular Mechanisms for the Structural and Functional Roles of Calcium Ions and O-Glycans in the Ligand Binding Region. AB - The Notch signaling pathway is an evolutionarily highly conserved mechanism that operates across multicellular organisms and is critical for cell-fate decisions during development and homeostasis in most tissues. Notch signaling is modified by posttranslational glycosylations of the Notch extracellular EGF-like domain. To evaluate the structural and functional roles of various glycoforms at multiple EGF domains in the human Notch transmembrane receptor, we established a universal method for the construction of NOTCH1 EGF modules displaying the desired O glycans at the designated glycosylation sites. The versatility of this strategy was demonstrated by the rapid and highly efficient synthesis of NOTCH1 EGF12 concurrently having a beta-D-glucopyranose-initiated glycan (Xylalpha1 -> 3Xylalpha1 -> 3Glcbeta1 ->) at Ser458 and alpha-L-fucopyranose-initiated glycan (Neu5Acalpha2 -> 3Galbeta1 -> 4GlcNAcbeta1 -> 3Fucalpha1 ->) at Thr466. The efficiency of the proper folding of the glycosylated EGF12 was markedly enhanced in the presence of 5 mM CaCl2. A nuclear magnetic resonance study revealed the existence of strong nuclear Overhauser effects between key sugar moieties and neighboring amino acid residues, indicating that both O-glycans contribute independently to the intramolecular stabilization of the antiparallel beta-sheet structure in the ligand-binding region of EGF12. A preliminary test using synthetic human NOTCH1 EGF modules showed significant inhibitory effects on the proliferation and adhesiveness of human breast cancer cell line MCF-7 and lung adenocarcinoma epithelial cell line A549, demonstrating for the first time evidence that exogenously applied synthetic EGF modules have the ability to interact with intrinsic Notch ligands on the surface of cancer cells. PMID- 26765752 TI - Clinical presentation, imaging findings, and prognosis of spinal dural arteriovenous fistula. AB - Spinal dural arteriovenous fistula (SDAVF) is a relatively common acquired vascular malformation of the spinal cord. Assessment of a SDAVF is often difficult because of non-specific findings on non-invasive imaging modalities. Diagnosis of a SDAVF is often delayed, and some patients receive unnecessary treatment and treatment delays, often resulting in a poor outcome. The aim of this study was to characterize the clinical presentation, typical imaging findings, and long-term outcome of SDAVF. Forty patients (13 women, 27 men; mean age 58.18 +/- standard deviation 14.75 years) who were treated at our hospital from June 1992 to March 2014 were retrospectively reviewed. We investigated the baseline characteristics, clinical presentation, imaging findings, treatment modalities, and outcome of the patients. The most common clinical presentation was a sensory symptom (80%), followed by motor weakness (70%), and sphincter dysfunction (62.5%). Roughly one-third (32.5%) of patients had a stepwise progression of fluctuating weakness and sensory symptoms, but the most common presentation was chronic progressive myelopathic symptoms (47.5%). Thirty-four patients (85%) had T2 signal change on the spinal cord MRI, indicative of cord edema. Thirty-eight patients had typical perimedullary vessel flow voids on T2 weighted MRI. Twenty-eight patients were treated with endovascular embolization, five patients underwent surgery, and four patients underwent both. Clinical outcome was determined by severity of initial deficit (p=0.008), extent of cord edema (p=0.010), treatment failure (p=0.004), and a residual fistula (p=0.017). SDAVF causes a treatable myelopathy, so early diagnosis and intervention is essential. PMID- 26765753 TI - Flexor and extensor muscle tone evaluated using the quantitative pendulum test in stroke and parkinsonian patients. AB - The aim of this study was to evaluate the flexor and extensor muscle tone of the upper limbs in patients with spasticity or rigidity and to investigate the difference in hypertonia between spasticity and rigidity. The two experimental groups consisted of stroke patients and parkinsonian patients. The control group consisted of age and sex-matched normal subjects. Quantitative upper limb pendulum tests starting from both flexed and extended joint positions were conducted. System identification with a simple linear model was performed and model parameters were derived. The differences between the three groups and two starting positions were investigated by these model parameters and tested by two way analysis of variance. In total, 57 subjects were recruited, including 22 controls, 14 stroke patients and 21 parkinsonian patients. While stiffness coefficient showed no difference among groups, the number of swings, relaxation index and damping coefficient showed changes suggesting significant hypertonia in the two patient groups. There was no difference between these two patient groups. The test starting from the extended position constantly manifested higher muscle tone in all three groups. In conclusion, the hypertonia of parkinsonian and stroke patients could not be differentiated by the modified pendulum test; the elbow extensors showed a higher muscle tone in both control and patient groups; and hypertonia of both parkinsonian and stroke patients is velocity dependent. PMID- 26765754 TI - Disability profile of multiple sclerosis in New Zealand. AB - New Zealand is a high risk region for multiple sclerosis (MS). The aim of this study was to investigate demographic, clinical and temporal factors associated with disability status in the New Zealand National Multiple Sclerosis Prevalence Study (NZNMSPS) cohort. Data were obtained from the 2006 NZNMSPS with MS diagnosis based on the 2005 McDonald criteria. Disability was assessed using the Expanded Disability Status Scale (EDSS). Disability profiles were generated using multiple linear regression analysis. A total of 2917 persons with MS was identified, of whom disability data were available for 2422 (75% females). The overall disability was EDSS 4.4+/-standard deviation 2.6. Higher disability was associated with older age, longer disease duration, older and younger ages of onset, spinal cord syndromes with motor involvement at onset, and a progressive onset type. Lower disability was associated with sensory symptoms at onset and a relapsing onset type. Overall, the factors studied explained about one-third of the variation in disability, and of this, about two-thirds was accounted for by age, age of onset and disease duration and one-third by the nature of first symptoms and type of disease onset (progressive or relapsing). Current age, age at onset and disease duration all had independent associations with disability and their effects also interacted in contributing to higher disability levels over the course of the disease. PMID- 26765755 TI - Vessel wall MRI for suspected isolated basilar artery dissection. AB - Isolated basilar artery dissection is an uncommon intracranial vasculopathy with a poor prognosis. Digital subtraction angiography is considered the definitive modality for diagnosis. Vessel wall MRI (VW-MRI) is an emerging non-invasive technique for assessing the structural integrity of intracranial vessel walls and lumina. Recently, a small number of studies have described the vessel wall patterns of intracranial artery dissection. However, studies on vessel wall imaging of isolated basilar artery dissection remain limited. We describe a patient with suspected isolated spontaneous basilar artery dissection diagnosed using VW-MRI. PMID- 26765756 TI - Intrinsic protective mechanisms of the neuron-glia network against glioma invasion. AB - Gliomas arising in the brain parenchyma infiltrate into the surrounding brain and break down established complex neuron-glia networks. However, mounting evidence suggests that initially the network microenvironment of the adult central nervous system (CNS) is innately non-permissive to glioma cell invasion. The main players are inhibitory molecules in CNS myelin, as well as proteoglycans associated with astrocytes. Neural stem cells, and neurons themselves, possess inhibitory functions against neighboring tumor cells. These mechanisms have evolved to protect the established neuron-glia network, which is necessary for brain function. Greater insight into the interaction between glioma cells and the surrounding neuron-glia network is crucial for developing new therapies for treating these devastating tumors while preserving the important and complex neural functions of patients. PMID- 26765757 TI - Secondary orthostatic tremor in the setting of cerebellar degeneration. AB - Orthostatic tremor (OT) and cerebellar ataxia are uncommon and difficult to treat. We present two patients with OT and cerebellar degeneration, one of whom had spinocerebellar ataxia type 2 and a good treatment response. PMID- 26765758 TI - Initial clinical experience with near-infrared spectroscopy in assessing cerebral tissue oxygen saturation in cerebral vasospasm before and after intra-arterial verapamil injection. AB - Cerebral vasospasm is a devastating complication after subarachnoid hemorrhage. The use of cerebral tissue oxygen saturation (SctO2) to non-invasively assess changes in cerebral tissue perfusion induced by intra-arterial (IA) verapamil treatment has not been described to our knowledge. A total of 21 consecutive post craniotomy patients scheduled for possible IA verapamil treatment of cerebral vasospasm were recruited. The effect of IA verapamil injection on SctO2 being continuously monitored on both the left and right forehead was investigated. Comparisons between changes in SctO2 monitored on the ipsilateral and contralateral forehead in relationship to the side of internal carotid artery (ICA) injection were performed. A total of 47 IA verapamil injections (15 left ICA, 18 right ICA, and 14 vertebral artery injections) during 18 neurointerventional procedures in 13 patients were analyzed. IA verapamil administration led to both increases and decreases in SctO2. Changes in SctO2 ipsilateral to the ICA injection side were more pronounced (p=0.02 and 0.07 for left and right ICA injections, respectively) and favored compared to contralateral SctO2 changes. We were unable to obtain reliable measurements on the side ipsilateral to the craniotomy during four procedures in three patients, presumably secondary to pneumocephalus. The local cerebral vasodilating effect of IA verapamil injection is suggested by the differential changes in SctO2 ipsilateral and contralateral to the ICA injection side. The inconsistent changes in SctO2 and the limitations of applying cerebral oximetry in this patient population needs to be recognized. PMID- 26765761 TI - Rapid eye movement sleep behaviour disorder in women with Parkinson's disease is an underdiagnosed entity. AB - Rapid eye movement sleep behavior disorder (RBD) is common in Parkinson's disease (PD). Little information exists about RBD in women with PD. The aim of this study was to determine the clinical expression of RBD in women with PD and note any differences in women with PD with and without RBD. One hundred fifty-six patients with PD were recruited. There were 37 women with PD and probable RBD was diagnosed using the RBD Screening Questionnaire. Other scales included Pittsburgh Sleep Quality Index, Parkinson's Disease Sleep Scale, Epworth Sleep Scale, Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale. Probable RBD was diagnosed in 10 women with PD (27%). Most often (70%) RBD occurred after the onset of parkinsonian symptoms. Women with probable RBD were older, had shorter duration of PD symptoms, lower tremor score, and higher axial signs score. They had insomnia (80% versus non-probable RBD patients 44%, p=0.019), and poor sleep quality with excessive daytime sleepiness. Anxiety and depression were common in women with probable RBD. Episodes were brief and confined to vocalization and simple limb movements. No injury to self or bed partners was noted. Women with PD have fewer fights and less aggressive dream enacting behaviour than men, but suffer from significant disturbed sleep, and levels of anxiety and depression. PMID- 26765759 TI - Utility of optical coherence tomography in the evaluation of monocular visual loss related to retinal ischemia. AB - We report four patients with monocular visual loss for whom optical coherence tomography (OCT) was helpful in distinguishing the sequelae of retinal artery occlusion from those of primary optic neuropathy. Determinations of the peripapillary retinal nerve fiber layer (RNFL) thickness as well as macular retinal layer thicknesses and architecture were used. The major findings in our patients show that changes in the inner retinal layers (including ganglion cell and inner plexiform layer) with disruption of normal macular architecture supports a diagnosis of retinal artery occlusion. Our results support the use of OCT imaging for patients with monocular visual loss of uncertain etiology; macular imaging as well as peripapillary RNFL thickness measurement can be helpful in differentiating primary retinal disease or ischemia from primary disorders of the optic nerve. PMID- 26765760 TI - TERT mutation in glioma: Frequency, prognosis and risk. AB - Telomerase reverse transcriptase (TERT) has received a great deal of attention in recent years for its role as a prognostic and predictive molecular marker of glioma. However, the results of studies examining its mutation frequency and predictive value are inconsistent, and several studies have investigated the association between TERT gene polymorphisms and gliomagenesis. We used a meta analysis approach to examine these unsolved problems. A bibliography search using EMBASE and MEDLINE was performed to identify potentially relevant articles and conference abstracts that investigated TERT mutations in glioma. The references contained in the identified trials were also examined to identify any other relevant published or unpublished articles. Sixteen studies were included. Pooled estimates of the relative risks (RR), 95% confidence intervals (95% CI), hazard ratios (HR) and frequency were calculated. TERT mutations occurred frequently in glioblastoma (69%) and oligodendrogliomas (72%) but were less frequent in astrocytomas (24%) and oligoastrocytomas (38%). The HR for glioma patients with TERT mutations versus wild type TERT was 1.63 (95% CI 1.35-1.98). TERT polymorphisms were associated with an increased risk of glioma compared to controls (RR=1.28, 95% CI 1.23-1.33). Our study shows that the TERT gene is a valuable prognostic and predictive biomarker of glioma, and TERT gene polymorphisms are significantly associated with an increased risk of glioma. PMID- 26765762 TI - Metastatic adrenal cortical carcinoma to T12 vertebrae. AB - We report spinal metastasis of adrenal cortical carcinoma (ACC) to the T12 vertebrae with epidural extension. ACC is a rare malignancy with poor prognosis and high rates of metastasis. However, spinal lesions of ACC are rare, and few have been reported in the literature. We discuss our management of this lesion and review the current understanding and treatment of ACC and spinal metastasis. PMID- 26765763 TI - Resolution of innumerable cerebral Nocardia paucivorans abscesses after medical management. AB - Nocardia species are an infrequent cause of brain abscesses. We report a 50-year old man with Nocardia paucivorans cerebral abscesses. Brain MRI revealed innumerable small ring-enhancing lesions. The patient initially responded to treatment with antibiotics and steroids, but experienced worsening after discontinuation of steroids. Brain biopsy performed to exclude central nervous system lymphoma produced nodular tissue with branching filaments on silver stain. Steroids were re-initiated and tapered slowly. The patient completed 1year of antibiotic therapy, after which he had no neurological symptoms and complete resolution of all brain abscesses on MRI. PMID- 26765764 TI - Non-Wilsonian hepatolenticular degeneration: Clinical and MRI observations in four families from south India. AB - Non-Wilsonian hepatolenticular degeneration (NWHD) is a heterogeneous neurological disorder occurring secondary to chronic acquired liver disease. Genetically determined familial NWHD is rare, poorly understood, and often mistaken for Wilson's disease (WD). We analysed clinical and MRI profiles of NWHD patients who did not have obvious cause for acquired liver disease, such as alcohol intake or hepatitis. Six patients from four families (four males, two females, mean age: 17.0+/-standard deviation 7.9years), presenting with chronic extrapyramidal disorder resembling WD and imaging (abdominal ultrasound/MRI) evidence of cirrhosis were studied. They lacked Kayser-Fleischer rings or biochemical and/or genetic evidence of WD. Clinical features included dystonia (n=6), parkinsonism (n=3), tremor (n=1), cerebellar ataxia (n=3), orofacial dyskinesia (n=1), behavioural abnormalities (n=3), and cognitive decline (n=1). Brain MRI revealed T1-weighted hyperintensity in the pallidum (n=6), crus cerebri (n=4), putamen (n=1), caudate (n=1), thalamus (n=1), and red nucleus (n=1) with T2-weighted shortening in some of these regions. Additional findings included giant cisterna magna (n=1), face of giant panda sign (n=1) and thin corpus callosum (n=1). Areas of "blooming" on susceptibility weighted images were noted in two patients in the caudate (n=2) and putamen (n=1). The finding of T1 shortening is distinct from that of WD where the majority of lesions are T1 hypointense and T2-hyperintense. Extrapallidal T1-hyperintensity is also an exceptional observation in NWHD. The MRI appearance of intense T1 shortening coupled with the lack of increased susceptibility changes suggests that the most likely mineral deposited is manganese. The association of this neurological disorder and cirrhosis of the liver in the absence of an acquired liver disease is a distinct disease entity. This syndrome may represent a disorder of manganese metabolism resulting in its toxic deposition. PMID- 26765766 TI - Accelerometers for objective evaluation of physical activity following spine surgery. AB - With the potential of bias from subjective evaluation scores in spine surgery, there is a need for practical and accurate quantitative methods of analysing patient recovery. In recent years, technologies such as accelerometers and global positioning systems have been introduced as potential objective measures for pain and symptoms following spine surgery. Overall, this perspective article aims to discuss and critique currently utilised methods of monitoring spine surgical outcomes. After analysing current modalities it will briefly analyse new potential methods before examining the place for accelerometers in the field of spine surgery. A literature review was performed on the use of accelerometers for objective evaluation of symptoms and disability after spine surgery, and perspectives are summarised in this article. Physical activity measurement with the use of accelerometers following spine surgery patients is practical and quantitative. The currently available accelerometers have the potential to transform the way functional outcomes from spine surgery are assessed. One key advantage is the collection of standardised objective measurements across studies. Future studies should aim to validate accelerometer data in relation to traditional measures of functional recovery, patient outcomes, and physical activity. PMID- 26765765 TI - Expression of high-mobility group box-1 (HMGB1) in the basilar artery after experimental subarachnoid hemorrhage. AB - It has been suggested that inflammatory damage may be involved in the pathogenesis of cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH). High-mobility group box-1 protein (HMGB1) has been identified as a potent proinflammatory mediator, and may trigger increases in other inflammatory cytokines. However, little is known about the role of HMGB1 in SAH-induced cerebrovascular inflammation. In this study, 48 male rats were assigned randomly to four groups: a control group, or SAH day 3, day 5, or day 7 groups. The animals in SAH day 3, day 5, and day 7 groups were subjected to injection of autologous blood into the cisterna magna twice, on day 0 and day 2, and were killed on days 3, 5, and 7, respectively. Cross-sectional area of the basilar artery was measured and the HMGB1 expression was assessed by immunohistochemistry and western blot analysis. The mRNA level of HMGB1 was also determined by reverse transcription polymerase chain reaction. The basilar arteries exhibited vasospasm after SAH which was most severe on day 3 and 5. Elevated expression of HMGB1 was detected after SAH and was highest on day 3 and 5. HMGB1 is increasingly expressed in parallel to the development of CVS in this rat experimental model of SAH. These results suggest that HMGB1 may be related to the CVS observed after SAH and HMGB1 may play a key role in the inflammatory response in CVS after SAH. PMID- 26765767 TI - Venous air embolus during scalp incision. AB - Venous air embolism (VAE) is a known complication of sitting craniotomy. Clinical consequences of VAE can range from tachypnea to cardiovascular collapse. The entrainment of air typically occurs during bone work, but we describe a case in which a VAE was recognized while working on the scalp. Monitoring techniques are critical for early treatment of VAE to avoid more serious complications, and our case illustrates the need to implement monitors early and remain vigilant throughout the procedure. PMID- 26765768 TI - The ratio of N-acetyl aspartate to glutamate correlates with disease duration of amyotrophic lateral sclerosis. AB - Glutamate (Glu)-induced excitotoxicity has been implicated in the neuronal loss of amyotrophic lateral sclerosis. To test the hypothesis that Glu in the primary motor cortex contributes to disease severity and/or duration, the Glu level was investigated using MR spectroscopy. Seventeen patients with amyotrophic lateral sclerosis were diagnosed according to the El Escorial criteria for suspected, possible, probable or definite amyotrophic lateral sclerosis, and enrolled in this cross-sectional study. We measured metabolite concentrations, including N acetyl aspartate (NAA), creatine, choline, inositol, Glu and glutamine, and performed partial correlation between each metabolite concentration or NAA/Glu ratio and disease severity or duration using age as a covariate. Considering our hypothesis that Glu is associated with neuronal cell death in amyotrophic lateral sclerosis, we investigated the ratio of NAA to Glu, and found a significant correlation between NAA/Glu and disease duration (r=-0.574, p=0.02). The "suspected" amyotrophic lateral sclerosis patients showed the same tendency as possible, probable and definite amyotrophic lateral sclerosis patients in regard to correlation of NAA/Glu ratio with disease duration. The other metabolites showed no significant correlation. Our findings suggested that glutamatergic neurons are less vulnerable compared to other neurons and this may be because inhibitory receptors are mainly located presynaptically, which supports the notion of Glu-induced excitotoxicity. PMID- 26765771 TI - Trends in upper gastro-intestinal cancer among the elderly in Denmark, 1980-2012. AB - BACKGROUND: Upper gastro-intestinal cancer (UGIC) includes malignancies in esophagus, stomach and small intestine, and represents some of the most frequent malignancies worldwide. The aim of the present analysis was to describe incidence, mortality and survival in UGIC patients in Denmark from 1980 to 2012 according to differences in age and time periods. MATERIAL AND METHODS: UGIC was defined as ICD-10 codes C15-C17. Data derived from the NORDCAN database with comparable data on cancer incidence mortality, prevalence and relative survival in the Nordic countries, where the Danish data were delivered from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up for death or emigration until the end of 2013. RESULTS: The proportion of male patients over the age of 70 years diagnosed with esophageal cancer was constant over time (around 42%) but increased in females to 49% in 2012. Incidence rates increased with time and continued to rise in all ages. Mortality rates were clearly separated by age groups with increasing mortality rates by increasing age group for both sexes. Relative survival increased slowly over time in all age groups. The proportion of older male and female patients with stomach cancer increased to 50% and 54%, respectively, in 2012. Incidence rates decreased steadily with time, especially from 1980 to 1990 but continued to decrease in all age groups. Mortality rates decreased considerably from 1980 to 90 and have been almost constant during the last decade for both women and men. Relative survival increased modest over time in both genders and all age groups. In 2012, only 1471 persons were alive after a diagnosis of stomach cancer. CONCLUSION: There is a need for clinical trials focusing on patients over the age of 70 years with co existing comorbidity. PMID- 26765772 TI - Safety of microvascular decompression for elderly patients with trigeminal neuralgia. AB - OBJECTIVE: The present study compared the safety and efficacy of microvascular decompression (MVD) in groups of elderly patients and non-elderly patients with medically refractory trigeminal neuralgia (TN) and collected detailed perioperative data. METHODS: Retrospective analysis of clinical data was performed in 99 patients who underwent MVD from May 2012 to June 2015. The outcome data from 27 MVD operations for 27 patients aged 70-80 years (mean 74.6 years) were compared with 72 MVD operations with 72 patients aged 25-69 years (mean 55.7 years). Preoperative comorbidities were recorded and postoperative worsening comorbidities and non-neurological complications were evaluated at discharge. Efficacy of the surgery and neurological complications were evaluated in July 2015. RESULTS: No decrease in activity of daily living was found in any patient. Complete pain relief without medication was achieved in 77.8% and partial pain relief in 14.8% in the elderly group, and 83.3% and 9.7%, respectively, in the non-elderly group (p=0.750). Permanent neurological complication was not observed in the elderly group, whereas Vth nerve and VIIIth nerve complications were observed in the non-elderly group. Rates of preoperative multiple comorbidities and of cardiovascular comorbidity were significantly higher in the elderly group (p<0.01). Worsening comorbidity and new pathology at discharge were mainly hypertension in both groups, but glaucoma attack and asthma attack were observed in the elderly group. All pathologies were successfully managed. CONCLUSIONS: MVD for elderly patients with TN can be achieved safely with careful perioperative management. Information of comorbidity should be shared with all staff involved in the treatment, who should work as a team to avoid worsening comorbidity. The possibility of unpredictable events in the elderly patients should always be considered. PMID- 26765769 TI - Human Mesenchymal Stem Cells Genetically Engineered to Overexpress Brain-derived Neurotrophic Factor Improve Outcomes in Huntington's Disease Mouse Models. AB - Huntington's disease (HD) is a fatal degenerative autosomal dominant neuropsychiatric disease that causes neuronal death and is characterized by progressive striatal and then widespread brain atrophy. Brain-derived neurotrophic factor (BDNF) is a lead candidate for the treatment of HD, as it has been shown to prevent cell death and to stimulate the growth and migration of new neurons in the brain in transgenic mouse models. BDNF levels are reduced in HD postmortem human brain. Previous studies have shown efficacy of mesenchymal stem/stromal cells (MSC)/BDNF using murine MSCs, and the present study used human MSCs to advance the therapeutic potential of the MSC/BDNF platform for clinical application. Double-blinded studies were performed to examine the effects of intrastriatally transplanted human MSC/BDNF on disease progression in two strains of immune-suppressed HD transgenic mice: YAC128 and R6/2. MSC/BDNF treatment decreased striatal atrophy in YAC128 mice. MSC/BDNF treatment also significantly reduced anxiety as measured in the open-field assay. Both MSC and MSC/BDNF treatments induced a significant increase in neurogenesis-like activity in R6/2 mice. MSC/BDNF treatment also increased the mean lifespan of the R6/2 mice. Our genetically modified MSC/BDNF cells set a precedent for stem cell-based neurotherapeutics and could potentially be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis, Alzheimer's disease, and some forms of Parkinson's disease. These cells provide a platform delivery system for future studies involving corrective gene-editing strategies. PMID- 26765770 TI - Current Progress in Therapeutic Gene Editing for Monogenic Diseases. AB - Programmable nucleases allow defined alterations in the genome with ease-of-use, efficiency, and specificity. Their availability has led to accurate and widespread genome engineering, with multiple applications in basic research, biotechnology, and therapy. With regard to human gene therapy, nuclease-based gene editing has facilitated development of a broad range of therapeutic strategies based on both nonhomologous end joining and homology-dependent repair. This review discusses current progress in nuclease-based therapeutic applications for a subset of inherited monogenic diseases including cystic fibrosis, Duchenne muscular dystrophy, diseases of the bone marrow, and hemophilia and highlights associated challenges and future prospects. PMID- 26765773 TI - IK1 channels do not contribute to the slow afterhyperpolarization in pyramidal neurons. AB - In pyramidal neurons such as hippocampal area CA1 and basolateral amygdala, a slow afterhyperpolarization (sAHP) follows a burst of action potentials, which is a powerful regulator of neuronal excitability. The sAHP amplitude increases with aging and may underlie age related memory decline. The sAHP is due to a Ca(2+) dependent, voltage-independent K(+) conductance, the molecular identity of which has remained elusive until a recent report suggested the Ca(2+)-activated K(+) channel, IK1 (KCNN4) as the sAHP channel in CA1 pyramidal neurons. The signature pharmacology of IK1, blockade by TRAM-34, was reported for the sAHP and underlying current. We have examined the sAHP and find no evidence that TRAM-34 affects either the current underling the sAHP or excitability of CA1 or basolateral amygdala pyramidal neurons. In addition, CA1 pyramidal neurons from IK1 null mice exhibit a characteristic sAHP current. Our results indicate that IK1 channels do not mediate the sAHP in pyramidal neurons. PMID- 26765775 TI - Role of ALKBH1 in the Core Transcriptional Network of Embryonic Stem Cells. AB - BACKGROUND/AIMS: ALKBH1, an AlkB homologue in the 2-oxoglutarate and Fe2+ dependent hydroxylase family, is a histone dioxygenase that removes methyl groups from histone H2A. Studies of transgenic mice lacking Alkbh1 reveal that most Alkbh1-/- embryos die during embryonic development. Embryonic stem cells (ESCs) derived from these mice have prolonged expression of pluripotency markers and delayed induction of genes involved in neural differentiation, indicating that ALKBH1 is involved in regulation of pluripotency and differentiation. The aim of this study was to further investigate the role ALKBH1 in early development. METHODS: Double-filter methods for nitrocellulose-filter binding, dot blot, enzyme-linked immunosorbent assay (ELISA), immonocytochemistry, cell culture and differentiation of mouse ESCs, Co-IP and miRNA analysis. RESULTS: We found that SOX2 and NANOG bind the ALKBH1 promoter, and we identified protein-protein interactions between ALKBH1 and these core transcription factors of the pluripotency network. Furthermore, lack of ALKBH1 affected the expression of developmentally important miRNAs, which are involved in the regulation of NANOG, SOX2 and neural differentiation. CONCLUSION: Our results suggest that ALKBH1 interacts with the core transcriptional pluripotency network of ESCs and is involved in regulation of pluripotency and differentiation. PMID- 26765776 TI - Melanoma: the intersection of molecular targeted therapy and immune checkpoint inhibition. AB - Melanoma is at the forefront of development of systemic therapeutics with both molecular targeted therapies and immune checkpoint inhibitors as cornerstones of treatment. Although responses to molecularly targeted therapy is largely from blockade of oncogenic pathways, evidence is emerging of the immunomodulatory effects from BRAF inhibition. Additionally programmed-death-1 (PD-1) inhibitors have revolutionized the treatment of melanoma and are set to pave future improvements in other solid tumors. Combinations of PD-1 inhibitors with novel immune checkpoints or with molecularly targeted therapies are under investigation and may improve on the considerable progress made. PMID- 26765777 TI - Shape-Persistent Replica Synthesis of Gold/Silver Bimetallic Nanoplates Using Tailored Silica Cages. AB - Shape-persistent replica synthesis of Au/Ag bimetallic nanoplates is invented. Using a tailored silica cage as a template for the synthesis, a successful shape replication of Au/Ag bimetallic nanoplate is achieved at the cage core having geometry of initial Ag nanoplate. This work can open up the simple fabrication of multicomponent metallic particles, with nanogeometry being defined early at the initial stage. PMID- 26765778 TI - Disruption of Broca's Area Alters Higher-order Chunking Processing during Perceptual Sequence Learning. AB - Because Broca's area is known to be involved in many cognitive functions, including language, music, and action processing, several attempts have been made to propose a unifying theory of its role that emphasizes a possible contribution to syntactic processing. Recently, we have postulated that Broca's area might be involved in higher-order chunk processing during implicit learning of a motor sequence. Chunking is an information-processing mechanism that consists of grouping consecutive items in a sequence and is likely to be involved in all of the aforementioned cognitive processes. Demonstrating a contribution of Broca's area to chunking during the learning of a nonmotor sequence that does not involve language could shed new light on its function. To address this issue, we used offline MRI-guided TMS in healthy volunteers to disrupt the activity of either the posterior part of Broca's area (left Brodmann's area [BA] 44) or a control site just before participants learned a perceptual sequence structured in distinct hierarchical levels. We found that disruption of the left BA 44 increased the processing time of stimuli representing the boundaries of higher order chunks and modified the chunking strategy. The current results highlight the possible role of the left BA 44 in building up effector-independent representations of higher-order events in structured sequences. This might clarify the contribution of Broca's area in processing hierarchical structures, a key mechanism in many cognitive functions, such as language and composite actions. PMID- 26765774 TI - PAF Complex Plays Novel Subunit-Specific Roles in Alternative Cleavage and Polyadenylation. AB - The PAF complex (Paf1C) has been shown to regulate chromatin modifications, gene transcription, and RNA polymerase II (PolII) elongation. Here, we provide the first genome-wide profiles for the distribution of the entire complex in mammalian cells using chromatin immunoprecipitation and high throughput sequencing. We show that Paf1C is recruited not only to promoters and gene bodies, but also to regions downstream of cleavage/polyadenylation (pA) sites at 3' ends, a profile that sharply contrasted with the yeast complex. Remarkably, we identified novel, subunit-specific links between Paf1C and regulation of alternative cleavage and polyadenylation (APA) and upstream antisense transcription using RNAi coupled with deep sequencing of the 3' ends of transcripts. Moreover, we found that depletion of Paf1C subunits resulted in the accumulation of PolII over gene bodies, which coincided with APA. Depletion of specific Paf1C subunits led to global loss of histone H2B ubiquitylation, although there was little impact of Paf1C depletion on other histone modifications, including tri-methylation of histone H3 on lysines 4 and 36 (H3K4me3 and H3K36me3), previously associated with this complex. Our results provide surprising differences with yeast, while unifying observations that link Paf1C with PolII elongation and RNA processing, and indicate that Paf1C subunits could play roles in controlling transcript length through suppression of PolII accumulation at transcription start site (TSS)-proximal pA sites and regulating pA site choice in 3'UTRs. PMID- 26765779 TI - Investigating the Nature of the Left Periphery in Peninsular Spanish wh-Question Intonation. AB - BACKGROUND/AIMS: In this paper we aim to resolve the phonological status of utterance-initial rises in Spanish wh-questions. METHODS/ANALYSIS 1: In analysis 1 we examine the scaling and alignment properties of utterance-initial rises produced by 14 speakers of Peninsular Spanish. RESULTS/ANALYSIS 1: The results provide evidence for a single bitonal pitch accent at the left periphery (L + 5.5 by ddPCR, the concordance rate between ddPCR and FISH was 98.0%, and Cohen's kappa coefficient was 0.760 (95% CI, 0.498-1.000; P <0.001). CONCLUSIONS: The results demonstrated that the ddPCR method has the potential to quantify the MET gene copy number with high precision and accuracy as compared with the results from SNP 6.0 and FISH in cancer cell lines and tumor samples, respectively. PMID- 26765782 TI - IIHS head restraint ratings and insurance injury claim rates. AB - OBJECTIVES: The Insurance Institute for Highway Safety (IIHS) rates front seat/head restraint designs using a combination of static and dynamic measurements following RCAR-IIWPG procedures. The purpose of this study was to determine whether vehicles with better IIHS-rated seats/head restraints had lower injury risk in rear-end collisions and how the effect of better rated seats interacted with driver gender and age. METHODS: The presence of an associated insurance injury claim was determined for rear-impact crashes using 2001-2014 model year cars and SUVs. Logistic regression was used to compare injury risk for vehicles with good, acceptable, and marginal IIHS-rated seats/head restraints with poor-rated seats/head restraints. Analyses were run by gender and driver age and also by the rate of more severe injury claims. RESULTS: Injury rates were 11.2% lower for vehicles with seats/head restraints rated good compared to vehicles with seats/head restraints rated poor. The percentage reduction for good versus poor-rated seats was greater for females (12.7%) than males (8.9%). Comparing good- with poor-rated seats, driver ages 15-24 had the largest reduction at 19.8%, followed by 10.7% for driver ages 45-64 and 10.4% for driver ages 25-44. CONCLUSIONS: Seats/head restraints with better IIHS ratings are associated with lower injury rates in rear-impact collisions than seats rated poor. The reductions in injury rates were strongest for females and for young-to middle-age drivers. The strong reductions in injury rates for these groups are encouraging given their high initial injury rates. PMID- 26765783 TI - Allelic variation in the vacuolar TPK1 channel affects its calcium dependence and may impact on stomatal conductance. AB - Natural variation can be exploited to identify allelic variants of proteins. In this study, patch clamp was used to determine transport properties of two AtTPK1 alleles from Landsberg and Kas-2 ecotypes. No difference in conductance or ion selectivity was observed but the Kas version of TPK1 showed different Ca(2+) dependence in its open probability compared to Ler. Leaves from Kas showed lower rates of water loss than those of Ler, in either the absence or presence of ABA, an observation that is consistent with higher TPK1 channel activity at comparable cytoplasmic Ca(2+) concentrations. A model that explains the results is presented. PMID- 26765784 TI - Development of Double Eastern Blotting for Major Licorice Components, Glycyrrhizin and Liquiritin for Chemical Quality Control of Licorice Using anti Glycyrrhizin and anti-Liquiritin Monoclonal Antibodies. AB - Licorice is utilized in various food industries around the world for seasoning agents, confectioneries, drinks, and functional foods. Glycyrrhizin (GL) and liquiritin (Liq) are major quality control chemical markers of licorice that have multifunctional bioactivities. Chemical quality control of licorice is important because its component profiles change depending environmental factors (climate, soil condition, and water deficit) and differences between species. Double eastern blotting using anti-GL and anti-Liq monoclonal antibodies was developed for more convenient, rapid, and specific quality control analysis of GL and Liq, respectively. Moreover, double eastern blotting was applied to investigate the immunohistochemical distributions of GL and Liq in the root of fresh licorice; the localization of both components was then clarified visually. This double eastern blotting technique for GL and Liq may serve as a powerful approach for visually determining the chemical quality of licorice. PMID- 26765785 TI - Characterization of surfactant alterations in pigs infected with Actinobacillus pleuropneumoniae. AB - PURPOSE/AIM OF THE STUDY: Surfactant, a surface active complex of phospholipids and proteins located at the inner surface of alveoli and small conducting airways is necessary for breathing. Bacterial respiratory tract infections frequently lead to surfactant alterations and to an increase in surface tension. Pigs, often used in experimental lung research, could suffer from severe pleuropneumonia, a highly contagious disease often characterized by sudden onset, short clinical course, high morbidity, and high mortality. It is caused by the gram-negative bacterium Actinobacillus pleuropneumoniae (A.pp.). This study tests the hypothesis that also in the subacute stage pathomorphological lung alterations are accompanied with increased inactive surfactant components. Clinical lung scores, functional and ultrastructural analysis of porcine surfactant were performed in pigs before infection and in the subacute state of infection. Clinical signs were determined using inter alia different subscores. Surfactant was isolated from the BALF for functional and quantitative ultrastructural studies. RESULTS: In the subacute stage clinical, ultrosonographic and radiographic scores as well as the overall Respiratory Health Score showed significantly higher values than before infection. However, surfactant surprisingly contained more active surfactant subtypes and significantly less inactive subtypes such as unilamellar vesicles. The quantity of multilamellar vesicles with unclear function did not differ. The minimal surface tension of surfactant before and after infection was comparable. CONCLUSIONS: Thus, in spite of continued severe lung tissue alterations the surfactant system show signs of recovery. This may be the result of an effective adaption to inflammatory lung disorders caused by swine-specific pathogens. PMID- 26765786 TI - Cyclodextrin-poloxamer aggregates as nanocarriers in eye drop formulations: dexamethasone and amphotericin B. AB - In this present study cyclodextrin (CD)-poloxamer aggregates were characterized and developed as ophthalmic drug carriers. The combined effect of gammaCD/2 hydroxypropyl-gammaCD (HPgammaCD) mixtures and poloxamer on solubilization and permeability of two model drugs, dexamethasone (Dex) and amphotericin B (AmB), was investigated. The CD-poloxamer interaction and complex aggregation were examined by (1)H nuclear magnetic resonance ((1)H-NMR), their solubilizing ability by high-performance liquid chromatography, and their particle size determined by dynamic light scattering and transmission electron microscopy. Formulations containing either 1.5% w/v Dex or 0.15% w/v AmB in eye drop suspensions containing various gammaCD/HPgammaCD ratios and poloxamer 407 (P407) were prepared. The solubility of the drugs, surface tension and hemolytic effect of the eye drops and drug permeation from selected formulations were determined. The (1)H-NMR study showed that P407 formed inclusion complex with CDs by inserting its poly(propylene oxide) segment into the CD cavity. P407 and gammaCD interacted with each other to form nanosized aggregates, and the observed concentration of dissolved gammaCD and P407 progressively decreased with increasing gammaCD and P407 concentrations. Including a high proportion of HPgammaCD improved the drug solubilization and reduced the hemolytic effect. The surface tension of the formulations decreased with increasing P407 concentration. Furthermore, increasing P407 content in the formulations enhanced formation of complex aggregates with consequent slower drug release. It was concluded that the drug/gammaCD/HPgammaCD complex was stabilized by P407 through formation of multi component aggregates. Thus, CD-poloxamer aggregates are self-assembled nanocarriers from which drug delivery characteristics can be adjusted by changing the gammaCD/HPgammaCD/P407 ratios. PMID- 26765788 TI - Substituent effects on fluoride binding by lanthanide complexes of DOTA tetraamides. AB - Fluoride binding by a series of europium and ytterbium complexes of DOTA tetraamide ligands derived from primary, secondary and tertiary amides has been studied by NMR and luminescence spectroscopies. In all the systems studied, fluoride binding results in a change in the nature of the magnetic anisotropy at the metal centre from an easy axis, to an easy plane anisotropy. This results in reversal of the peaks in the NMR spectra, and in changes to the fine structure of the luminescence spectra. Furthermore, changes to the periphery of the binding cavity are implicated in determining the affinity constant for fluoride. There are clear differences in the entropic contribution to the free energy of activation between systems with benzylic amides and those with methylamides. PMID- 26765787 TI - Morinda citrifolia edible leaf extract enhanced immune response against lung cancer. AB - Lung cancer causes 1.4 million deaths annually. In the search for functional foods as complementary therapies against lung cancer, the immuno-stimulatory properties of the vegetable Morinda citrifolia leaves were investigated and compared with the anti-cancer drug erlotinib. Lung tumour-induced BALB/c mice were fed with 150 mg kg(-1) or 300 mg kg(-1) body weight of the leaf extract, or erlotinib (50 mg kg(-1) body-weight) for 21 days. The 300 mg kg(-1) body weight extract significantly (and dose-dependently) suppressed lung tumour growth; the extract worked more effectively than the 50 mg kg(-1) body weight erlotinib treatment. The extract significantly increased blood lymphocyte counts, and spleen tissue B cells, T cells and natural killer cells, and reduced the epidermal growth factor receptor (EGFR) which is a lung adenocarcinoma biomarker. The extract also suppressed the cyclooxygenase 2 (COX2) inflammatory markers, and enhanced the tumour suppressor gene (phosphatase and tensin homolog, PTEN). It inhibited tumour growth cellular gene (transformed mouse 3T3 cell double minute 2 (MDM2), V-raf-leukemia viral oncogene 1 (RAF1), and mechanistic target of rapamycin (MTOR)) mRNA expression in the tumours. The extract is rich in scopoletin and epicatechin, which are the main phenolic compounds. The 300 mg kg( 1)Morinda citrifolia leaf 50% ethanolic extract showed promising potential as a complementary therapeutic dietary supplement which was more effective than the 50 mg kg(-1) erlotinib in suppressing lung adenocarcinoma. Part of the mechanisms involved enhancing immune responses, suppressing proliferation and interfering with various tumour growth signalling pathways. PMID- 26765789 TI - Origin of Electrochemical, Structural, and Transport Properties in Nonaqueous Zinc Electrolytes. AB - Through coupled experimental analysis and computational techniques, we uncover the origin of anodic stability for a range of nonaqueous zinc electrolytes. By examination of electrochemical, structural, and transport properties of nonaqueous zinc electrolytes with varying concentrations, it is demonstrated that the acetonitrile-Zn(TFSI)2, acetonitrile-Zn(CF3SO3)2, and propylene carbonate Zn(TFSI)2 electrolytes can not only support highly reversible Zn deposition behavior on a Zn metal anode (>=99% of Coulombic efficiency) but also provide high anodic stability (up to ~3.8 V vs Zn/Zn(2+)). The predicted anodic stability from DFT calculations is well in accordance with experimental results, and elucidates that the solvents play an important role in anodic stability of most electrolytes. Molecular dynamics (MD) simulations were used to understand the solvation structure (e.g., ion solvation and ionic association) and its effect on dynamics and transport properties (e.g., diffusion coefficient and ionic conductivity) of the electrolytes. The combination of these techniques provides unprecedented insight into the origin of the electrochemical, structural, and transport properties in nonaqueous zinc electrolytes. PMID- 26765790 TI - Mitochondrial DNA variation of domestic sheep (Ovis aries) in Kenya. AB - The history of domestic sheep (Ovis aries) in Africa remains largely unknown. After being first introduced from the Near East, sheep gradually spread through the African continent with pastoral societies. The eastern part of Africa was important either for the first diffusion of sheep southward or for putative secondary introductions from the Arabian Peninsula or southern Asia. We analysed mitochondrial DNA control region sequences of 91 domestic sheep from Kenya and found a high diversity of matrilines from the widespread haplogroup B, whereas only a single individual from haplogroup A was detected. Our phylogeography analyses of more than 500 available mitochondrial DNA sequences also identified ancestral haplotypes that were probably first introduced in Africa and are now widely distributed. Moreover, we found no evidence of an admixture between East and West African sheep. The presence of shared haplotypes in eastern and ancient southern African sheep suggests the possible southward movement of sheep along the eastern part of Africa. Finally, we found no evidence of an extensive introduction of sheep from southern Asia into Africa via the Indian Ocean trade. The overall findings on the phylogeography of East African domestic sheep set the grounds for understanding the origin and subsequent movements of sheep in Africa. The richness of maternal lineages in Kenyan breeds is of prime importance for future conservation and breeding programmes. PMID- 26765791 TI - Activation of maternal toll-like receptor-2 causes social deficits and memory impairment in female offspring. AB - To study the relevance of the activation of toll-like receptor-2 and abnormal behavioral properties, we introduced prenatal zymosan, a toll-like receptor-2 ligand, to investigate the effect of maternal immunity on offspring behavior. Only female offspring showed impaired social and cognitive function, suggesting that zymosan may influence females' behavior. PMID- 26765792 TI - Going Upstream: Coordination to Improve CKD Care. AB - Care coordination for patients with chronic kidney disease has been shown to be effective in improving outcomes and reducing costs. However, few patients with CKD benefit from this systematic management of their kidney disease and other medical conditions. As a result, outcomes for patients with kidney disease are not optimal, and their cost of care is increased. For those patients who transition to kidney failure treatment in the United States, the transition does not go as well as it could. The effectiveness of treatments to delay progression of kidney disease in contemporary clinical practice does not match the efficacy of these treatments in clinical trials. Conservative care for kidney disease, which should be an option for patients who are very old and very sick, is not considered often enough or seriously enough. Opportunities for early and even pre emptive transplantation are missed, as are opportunities for home dialysis. The process of dialysis access creation is rarely optimal. The consequence is care which is not as good as it could be, and much more expensive than it should be. We describe our initial efforts to implement care coordination for chronic kidney disease in routine clinical care and attempt to project some of the benefits to patients and the cost savings. PMID- 26765793 TI - Mineralocorticoid Receptor Antagonists in End-Stage Renal Disease: Efficacy and Safety. AB - Mineralocorticoid receptor antagonists (MRAs) that block aldosterone's effects on both epithelial and non-epithelial receptors have become a mainstay of therapy for chronic heart failure. Given that cardiovascular events remain the leading cause of death for patients with end-stage renal disease (ESRD), the question of whether these MRAs can be employed in dialysis patients arises. This review summarizes the rationale for blocking aldosterone in patients with chronic and end-stage kidney disease and surveys the data on both the efficacy and safety of using MRAs in the ESRD population. A small but growing body of literature suggests that use of MRAs by ESRD patients is associated with lower blood pressure, reduced left ventricular (LV) mass, and improved LV ejection fraction. Recently, a large randomized trial found an overall 3-year mortality rate of 6.4% in ESRD patients on spironolactone 25 mg daily vs. 19.7% in ESRD patients on no MRA therapy (p = 0.002), without a significantly increased risk of hyperkalemia. PMID- 26765794 TI - Design, synthesis, and duplex-stabilizing properties of conformationally constrained tricyclic analogues of LNA. AB - The design, synthesis and biophysical evaluation of two highly-constrained tricyclic analogues of locked nucleic acid (LNA), which restrict rotation around the C4'-C5'-exocyclic bond (torsion angle gamma) and enhance hydrophobicity in the minor groove and along the major groove, are reported. A structural model that provides insights into the sugar-phosphate backbone conformations required for efficient hybridization to complementary nucleic acids is also presented. PMID- 26765795 TI - A Survey of Occupational Therapy Practice in Beijing, China. AB - There is an increasing demand for rehabilitation services in China as a result of the growing number of people with physical and mental challenges, as well as the growing population of older adults. The purpose of this study was to explore the current occupational therapy (OT) resources available in Beijing, China, to serve as the first step in planning the response to increasing demand for OT services from the people of China. Specifically, using the snowball sampling survey method, we explored the work practice, including years of working experience, work setting, weekly work hours, annual income and factors related to job satisfaction among occupational therapists in Beijing, China. A total of 44 occupational therapists currently working in the Beijing area responded to our survey. The results demonstrated that most of the therapists working in Beijing area were young and inexperienced. Despite the fact that the participants had an average age of 31 years old and an average of 8 years' working experience, 61.4% of therapists were under 30 years old and more than half of therapists had less than 5 years of OT experiences. Among those included in the study sample, 50% had earned degrees in OT, and the rest of the OT personnel received OT-related on-the job training in various forms and lengths of time. A majority of the participants worked in hospital settings with adults or children with physical disabilities and used therapeutic activities and therapeutic exercises. Being an occupational therapist is not a high-paying job. Education satisfaction, work experience and annual income are the factors related to job satisfaction for the participants. The majority of occupational therapists expressed the need to receive more support for clinical-related trainings. We plan to expand this pilot study nationwide to gain an in-depth and comprehensive understanding of the OT workforce in China. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26765796 TI - A new potassium-based intermediate and its role in the desorption properties of the K-Mg-N-H system. AB - New insights into the reaction pathways of different potassium/magnesium amide hydride based systems are discussed. In situ SR-PXD experiments were for the first time performed in order to reveal the evolution of the phases connected with the hydrogen releasing processes. Evidence of a new K-N-H intermediate is shown and discussed with particular focus on structural modification. Based on these results, a new reaction mechanism of amide-hydride anionic exchange is proposed. PMID- 26765797 TI - Cord blood insulin-like growth factor (IGF)-1, IGF-binding proteins and adiponectin, and birth size in offspring of women with mild gestational diabetes. AB - OBJECTIVE: To clarify the impact of a mild form of gestational diabetes mellitus (GDM) on neonatal birth size, and on insulin-related hormones and adiponectin (AdipoQ) in cord blood. METHODS: Two hundred and sixteen Japanese pregnant women diagnosed as having normal glucose tolerance according to the JSOG criteria were enrolled. Of the 216 women, 38 women were reclassified into a mild GDM (mGDM) group according to the IADPSG criteria. Of the remaining 178 women, 135 women with normal 50-g glucose challenge test were reclassified into a normal glucose tolerance (NGT) group. Cord blood insulin-like growth factor (IGF)-1, IGF-binding proteins (IGFBPs) and AdipoQ were measured in the offspring of the two groups. RESULTS: Birth weight and its SD scores were larger in the mGDM group than in the NGT group. The incidence of large-for-gestational age (LGA) newborns was higher in the mGDM than in the NGT group. No differences in cord blood free IGF-1, IGFBP 1, IGFBP-2 or AdipoQ levels were observed between the mGDM and NGT groups. CONCLUSIONS: Our study suggests that mild GDM reclassified according to the IADPSG criteria influences neonatal birth size, but neither the IGF-IGFBP axis nor AdipoQ can account for the changes of birth size in offspring of women with mild GDM. PMID- 26765799 TI - Robot-guided neuronavigated rTMS as an alternative therapy for central (neuropathic) pain: Clinical experience and long-term follow-up. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) appears as a useful tool to alleviate neuropathic pain but only few data are available for the long-term benefit of this treatment. METHODS: Here we report the effects of rTMS sessions, considered as a possible therapy for pain relief after a failure of different medications in patients with central (neuropathic) pain. We review here the prospectively collected data of the first forty patients treated as follow: 20 Hz stimulation delivered over the contralateral primary motor cortex (M1), each 3-4 weeks. RESULTS: A total of 440 rTMS sessions was collected (mean sessions number: 11, range: 1-37, follow-up 312 days on average, maximum 2.8 years). After four sessions, nine patients (22.5%) discontinued rTMS because of a lack of efficiency (<10% pain-relief). The other 31 patients (77.5%) had a cumulative effect across sessions leading to a mean pain relief of 41% for a duration of 15.6 days. A correlation was observed between pain relief in the first session and long-term pain relief (R = 0.649. p = 5.6*10(-6) ). Both intensity and duration of pain relief were significantly better for patients with persistent laser evoked potentials (LEPs, p = 0.049 and 0.0018). We did not observe any adverse-effects. CONCLUSION: These results suggest that repeated sessions of 20 Hz rTMS over M1 are interesting in clinical practice for the treatment of selected patients with central pain. Both the cumulative effects across the first sessions and the long duration of pain-relief should impact further randomized trials that are warranted to conclude formally on rTMS efficiency in central pain. PMID- 26765801 TI - On Johnson's (2000) Relative Weights Method for Assessing Variable Importance: A Reanalysis. AB - This article provides a reanalysis of J. W. Johnson's (2000) "relative weights" method for assessing variable importance in multiple regression. The primary conclusion of the reanalysis is that the derivation of the method is theoretically flawed and has no more validity than the discredited method of Green, Carroll, and DeSarbo (1978) on which it is based. By means of 2 examples, supplemented by other results from the literature, it is also shown that the method can result in materially distorted inferences when it is compared with another widely used importance metric, namely, general dominance (Azen & Budescu, 2003; Budescu, 1993). Our primary recommendation is that J. W. Johnson's (2000) relative weights method should no longer be used as a variable importance metric for multiple linear regression. In the final section of the article, 2 additional recommendations are made based on our analysis, examples, and discussion. PMID- 26765800 TI - Assessing Approximate Fit in Categorical Data Analysis. AB - A family of Root Mean Square Error of Approximation (RMSEA) statistics is proposed for assessing the goodness of approximation in discrete multivariate analysis with applications to item response theory (IRT) models. The family includes RMSEAs to assess the approximation up to any level of association of the discrete variables. Two members of this family are RMSEA2, which uses up to bivariate moments, and the full information RMSEAn. The RMSEA2 is estimated using the M2 statistic of Maydeu-Olivares and Joe (2005, 2006), whereas for maximum likelihood estimation, RMSEAn is estimated using Pearson's X(2) statistic. Using IRT models, we provide cutoff criteria of adequate, good, and excellent fit using the RMSEA2. When the data are ordinal, we find a strong linear relationship between the RMSEA2 and the Standardized Root Mean Squared Residual goodness-of fit index. We are unable to offer cutoff criteria for the RMSEAn as its population values decrease as the number of variables and categories increase. PMID- 26765798 TI - Estimating the risk of dengue transmission from Dutch blood donors travelling to Suriname and the Dutch Caribbean. AB - BACKGROUND: The risk of dengue transmitted by travellers is known. Methods to estimate the transmission by transfusion (TT) risk from blood donors travelling to risk areas are available, for instance, the European Up-Front Risk Assessment Tool (EUFRAT). This study aimed to validate the estimated risk from travelling donors obtained from EUFRAT. METHODS: Surveillance data on notified dengue cases in Suriname and the Dutch Caribbean islands (Aruba, Curacao, St. Maarten, Bonaire, St. Eustatius and Saba) in 2001-2011 was used to calculate local incidence rates. Information on travel and donation behaviour of Dutch donors was collected. With the EUFRAT model, the TT risks from Dutch travelling donors were calculated. Model estimates were compared with the number of infections in Dutch travellers found by laboratory tests in the Netherlands. RESULTS: The expected cumulative number of donors becoming infected during travels to Suriname and the Dutch Caribbean from 2001 to 2011 was estimated at 5 (95% CI, 2-11) and 86 (45 179), respectively. The infection risk inferred from the laboratory-based study was 19 (9-61) and 28 (14-92). Given the independence of the data sources, these estimates are remarkably close. The model estimated that 0.02 (0.001-0.06) and 0.40 (0.01-1.4) recipients would have been infected by these travelling donors. CONCLUSIONS: The EUFRAT model provided an estimate close to actual observed number of dengue infections. The dengue TT risk among Dutch travelling donors can be estimated using basic transmission, travel and donation information. The TT risk from Dutch donors travelling to Suriname and the Dutch Caribbean is small. PMID- 26765802 TI - Estimating Standard Errors in Exploratory Factor Analysis. AB - The article describes 6 issues influencing standard errors in exploratory factor analysis and reviews 7 methods of computing standard errors for rotated factor loadings and factor correlations. These 7 methods are the augmented information method, the nonparametric bootstrap method, the infinitesimal jackknife method, the method using the asymptotic distributions of unrotated factor loadings, the sandwich method, the parametric bootstrap method, and the jackknife method. Standard error estimates are illustrated using a personality study with 537 men and an intelligence study with 145 children. PMID- 26765803 TI - Identifying the Source of Misfit in Item Response Theory Models. AB - When an item response theory model fails to fit adequately, the items for which the model provides a good fit and those for which it does not must be determined. To this end, we compare the performance of several fit statistics for item pairs with known asymptotic distributions under maximum likelihood estimation of the item parameters: (a) a mean and variance adjustment to bivariate Pearson's X(2), (b) a bivariate subtable analog to Reiser's (1996) overall goodness-of-fit test, (c) a z statistic for the bivariate residual cross product, and (d) Maydeu Olivares and Joe's (2006) M2 statistic applied to bivariate subtables. The unadjusted Pearson's X(2) with heuristically determined degrees of freedom is also included in the comparison. For binary and ordinal data, our simulation results suggest that the z statistic has the best Type I error and power behavior among all the statistics under investigation when the observed information matrix is used in its computation. However, if one has to use the cross-product information, the mean and variance adjusted X(2) is recommended. We illustrate the use of pairwise fit statistics in 2 real-data examples and discuss possible extensions of the current research in various directions. PMID- 26765804 TI - Self-Reported Personality Pathology Has Complex Structure and Imposing Simple Structure Degrades Test Information. AB - Although simple structure is often used as a theoretical guideline for rotation of exploratory factor structures, its empirical foundation is sometimes not investigated. We examined the degree of simple structure in 2 self-report inventories advocated for the description of personality pathology. The multivariate complexity of the inventories was compared against simulated factorial solutions with increasing degrees of simple structure. Results revealed a high degree of complexity in both inventories, regardless of whether focusing on a few broad or many narrow factors and whether items or scales were analyzed. It is concluded that Thurstone's (1934) simple structure criteria are rarely fulfilled in multivariate personality pathology solutions, and, therefore, that alternate rotations represent equally justifiable ways to operationalize the space. Furthermore, using iterative test development to impose simple structure where none originally existed increased standard errors around the factor scores in the interstitial areas between imposed simple structure dimensions. In both simulated and real data, multidimensional item response theory test information functions based on complex solutions demonstrated that test information was uniformly distributed across the space. In contrast, in simple structure solutions, information was weak in areas of the space where nonconforming items had been removed. Implications are discussed. PMID- 26765805 TI - A Factor-Analytic Model for Assessing Individual Differences in Response Scale Usage. AB - This article proposes a factor-analytic model, intended for graded-response or continuous-response personality and attitude items, which includes an additional multiplicative person parameter that models the individual's response mapping process. The model, which is a modification of Spearman's (1904) factor analysis (FA) model, is parameterized as both an FA model and an item response theory (IRT) model and is fully developed to the extent that it can be used in applications. Procedures for (a) calibrating the items and assessing data fit, (b) obtaining individual estimates of both person parameters, (c) determining measurement precision, and (d) assessing differential predictability are proposed and discussed. The potential advantages of the proposal, its practical relevance, and its relations with other approaches are also discussed. Its functioning is assessed with a simulation study and 3 empirical examples in the personality domain. PMID- 26765807 TI - Validation of an enzyme-linked immunosorbent assay (ELISA) for the measurement of canine S100A12. AB - BACKGROUND: Canine S100 calcium-binding protein A12 (cS100A12) shows promise as biomarker of inflammation in dogs. A previously developed cS100A12 radioimmunoassay (RIA) requires radioactive tracers and is not sensitive enough for fecal cS100A12 concentrations in 79% of tested healthy dogs. An ELISA assay may be more sensitive than RIA and does not require radioactive tracers. OBJECTIVE: The purpose of the study was to establish a sandwich ELISA for serum and fecal cS100A12, and to establish reference intervals (RI) for normal healthy canine serum and feces. METHODS: Polyclonal rabbit anti-cS100A12 antibodies were generated and tested by Western blotting and immunohistochemistry. A sandwich ELISA was developed and validated, including accuracy and precision, and agreement with cS100A12-RIA. The RI, stability, and biologic variation in fecal cS100A12, and the effect of corticosteroids on serum cS100A12 were evaluated. RESULTS: Lower detection limits were 5 MUg/L (serum) and 1 ng/g (fecal), respectively. Intra- and inter-assay coefficients of variation were <= 4.4% and <= 10.9%, respectively. Observed-to-expected ratios for linearity and spiking recovery were 98.2 +/- 9.8% (mean +/- SD) and 93.0 +/- 6.1%, respectively. There was a significant bias between the ELISA and the RIA. The RI was 49-320 MUg/L for serum and 2-484 ng/g for fecal cS100A12. Fecal cS100A12 was stable for 7 days at 23, 4, -20, and -80 degrees C; biologic variation was negligible but variation within one fecal sample was significant. Corticosteroid treatment had no clinically significant effect on serum cS100A12 concentrations. CONCLUSIONS: The cS100A12-ELISA is a precise and accurate assay for serum and fecal cS100A12 in dogs. PMID- 26765808 TI - Utilization of Community Health Centers in Medicaid Expansion and Nonexpansion States, 2013-2014. AB - Using electronic health record data, we examined longitudinal changes in community health center (CHC) visit rates from 2013 through 2014 in Medicaid expansion versus nonexpansion states. Visits from 219 CHCs in 5 expansion states and 4 nonexpansion states were included. Rates were computed using generalized estimating equation Poisson models. Rates increased in expansion state CHCs for new patient, preventive, and limited-service visits (14%, 41%, and 23%, respectively, P < .01 for all), whereas these rates remained unchanged in nonexpansion states. One year after ACA Medicaid expansions, CHCs in expansion states saw an influx of new patients and provided increased preventive services. PMID- 26765809 TI - A Systematic Review of Journal Clubs for Nurses. AB - BACKGROUND: Two previous systematic reviews describe studies on journal clubs from 1995 to 2007. AIMS: To gather, assess, and synthesize the current empirical evidence on implementation of journal clubs, influencing factors, and outcomes of journal clubs in promoting evidence-based nursing. DESIGN: A systematic review based on the procedure of the Centre for Reviews and Dissemination. DATA SOURCES AND METHODS: Cochrane, CINAHL, and PubMed Medline databases were sought from 2008 to 2015. The final data consisted of 10 studies. Articles' references were searched manually. The quality appraisal was made according to study design. Data were analyzed by qualitative content analysis and narrative synthesis. RESULTS: The analyses produced four main categories with 14 subcategories that described the journal clubs: organization, conduct of meetings, influencing factors, and intervention outcomes. Journal clubs had been carried out in a fairly uniform manner in different nursing communities. There remains a lack of evidence on journal clubs' impact on evidence-based nursing (EBN) implementation, which challenges the development of journal clubs' content and methods. LINKING EVIDENCE TO ACTION: Because journal clubs have achieved a uniform and easy-to follow manner that is suitable for different nursing contexts and provide multiple positive outcomes, they are recommended for EBN. In work communities, journal clubs should be combined with other well-known factors that promote EBN implementation. The assessment of the outcomes of journal clubs should cover all learning categories of EBN with a focus on medium- to long-term effectiveness. The evaluation of the effectiveness of journal clubs on patient care is of great importance for future studies. PMID- 26765813 TI - [History of keloid]. PMID- 26765814 TI - [The collodion baby]. PMID- 26765812 TI - Vitamin B6 nutritional status and cellular availability of pyridoxal 5'-phosphate govern the function of the transsulfuration pathway's canonical reactions and hydrogen sulfide production via side reactions. AB - The transsulfuration pathway (TS) acts in sulfur amino acid metabolism by contributing to the regulation of cellular homocysteine, cysteine production, and the generation of H2S for signaling functions. Regulation of TS pathway kinetics involves stimulation of cystathionine beta-synthase (CBS) by S-adenosylmethionine (SAM) and oxidants such as H2O2, and by Michaelis-Menten principles whereby substrate concentrations affect reaction rates. Although pyridoxal phosphate (PLP) serves as coenzyme for both CBS and cystathionine gamma-lyase (CSE), CSE exhibits much greater loss of activity than CBS during PLP insufficiency. Thus, cellular and plasma cystathionine concentrations increase in vitamin B6 deficiency mainly due to the bottleneck caused by reduced CSE activity. Because of the increase in cystathionine, the canonical production of cysteine (homocysteine -> cystathionine -> cysteine) is largely maintained even during vitamin B6 deficiency. Typical whole body transsulfuration flux in humans is 3-7 MUmol/h per kg body weight. The in vivo kinetics of H2S production via side reactions of CBS and CSE in humans are unknown but they have been reported for cultured HepG2 cells. In these studies, cells exhibit a pronounced reduction in H2S production capacity and rates of lanthionine and homolanthionine synthesis in deficiency. In humans, plasma concentrations of lanthionine and homolanthionine exhibit little or no mean change due to 4-wk vitamin B6 restriction, nor do they respond to pyridoxine supplementation of subjects in chronically low-vitamin B6 status. Wide individual variation in responses of the H2S biomarkers to such perturbations of human vitamin B6 status suggests that the resulting modulation of H2S production may have physiological consequences in a subset of people. Supported by NIH grant DK072398. This paper refers to data from studies registered at clinicaltrials.gov as NCT01128244 and NCT00877812. PMID- 26765815 TI - [Food and culinary metaphors in dermatology]. PMID- 26765832 TI - Morphometric changes in liver cirrhosis: aetiological differences correlated with progression. AB - OBJECTIVE: To evaluate the morphometric changes in liver cirrhosis using multidetector CT volumetry and to analyse the differences in morphometric changes among different aetiologies and stages of cirrhosis. METHODS: Each portal segment with the respective proportion relative to total liver volume was measured in 54 patients without cirrhosis as a control (male/female, 29/25; 62.4 +/- 7.6 years) and 250 patients with cirrhosis (male/female, 172/78; 64.6 +/- 9.2 years) related to hepatitis virus infection (n = 96), alcoholism (n = 88) and non-alcoholic steatohepatitis (NASH) (n = 66). 149 patients were classified as patients with Child-Pugh Class A, 57 patients as patients with Class B and 44 patients as patients with Class C. The Kruskal-Wallis test was used for statistical analysis (p < 0.05). RESULTS: Cirrhosis associated with all aetiologies commonly showed atrophy of the medial and anterior segments and right lobe and hypertrophy of the lateral segment and caudate lobe compared with the control (p < 0.05). In Child Pugh Class A, hypertrophy of the caudate lobe progressed more in alcoholism and NASH than in virus-related aetiologies (p < 0.001). Hypertrophy of the lateral segment and atrophy of the medial and anterior segments and right lobe progressed less in NASH than in cases with virus related and alcoholic cirrhosis (p < 0.001). In patients with Class B, these differences were less prominent than in those with Class A (p < 0.001). In Class C, no significant differences were noted in any segment, regardless of aetiology (p > 0.05). CONCLUSION: Morphometric changes of cirrhosis display different patterns according to aetiology. Differences between aetiologies would decrease with progression of cirrhosis. ADVANCES IN KNOWLEDGE: Morphometric changes of cirrhosis display different patterns according to aetiology. Differences between aetiologies would decrease with progression of cirrhosis. PMID- 26765834 TI - Impact of Interfacial Microstructure on Charge Carrier Transport in Solution Processed Conjugated Polymer Field-Effect Transistors. AB - The surface roughness of a dielectric is precisely tuned, allowing a fine control solely over the interfacial microstructure in a semicrystalline semiconductor polymer film without affecting the morphology in the upper layers. The interfacial microstructure is found to have only a minor impact on the transport originating from bypassing of interfacial defects by the charge carriers. PMID- 26765833 TI - MAGNETIC RESONANCE IMAGING FINDINGS IN THE SPINE OF SIX DOGS DIAGNOSED WITH LYMPHOMA. AB - Lymphoma is one of the most common neoplasms in the dog. Despite its prevalence and the increasing use of advanced diagnostic imaging in veterinary patients only few reports of magnetic resonance imaging (MRI) findings in spinal lymphoma have been published to date. The purpose of this retrospective case series study was to describe the MRI findings in dogs with confirmed lymphoma affecting the spine and/or paraspinal soft tissues. Medical records were searched for patients that had MRI of the spine and a diagnosis of lymphoma during the period of 2005-2015. Data recorded from retrieved MRI studies were presence of focal or multifocal disease, structures involved, and signal characteristics on T2-W, short tau inversion recovery (STIR), and T1-W sequences prior to and following intravenous contrast medium administration. Six dogs met the inclusion criteria. Common findings included multifocal disease (4/6), vertebral involvement (5/6), spinal cord compression (4/6), and involvement of more than one spinal compartment (medullary cavity, vertebral canal, paraspinal soft tissues) (6/6). Vertebral changes were confined to the medullary cavity without evidence of cortical osteolysis. There was questionable involvement of the spinal cord in one case. All spinal and paraspinal lesions identified were T2-W isointense to hyperintense, STIR hyperintense, T1-W hypointense to isointense, and showed variable moderate to strong contrast enhancement. Additional lesions identified were enlarged intraabdominal lymph nodes, hepatomegaly, splenomegaly, and a splenic nodule. The STIR and T1-W postcontrast sequences were subjectively the most useful in identification of the spinal and paraspinal lesions. PMID- 26765835 TI - Rate and Amplitude Heterogeneity in the Solvation Response of an Ionic Liquid. AB - In contrast with conventional liquids, ionic liquids have solvation dynamics with more rate dispersion and with average times that do not agree with dielectric measurements. A kinetic analog of multidimensional spectroscopy is introduced and used to look for heterogeneity in simulations of coumarin 153 in [Im12][BF4]. Strong heterogeneity is found in the diffusive solvation rate. An unanticipated heterogeneity in the amplitude of the inertial solvation is also seen. Both heterogeneities exchange at the same rate. This rate is similar to the mean diffusive solvation time, putting it in the intermediate-exchange region. Overall, there are multiple violations of the assumptions usually invoked in the theory of reaction dynamics. PMID- 26765836 TI - Impact of economic fluctuations on suicide mortality in Canada (1926-2008): Testing the Durkheim, Ginsberg, and Henry and Short theories. AB - Three theories have been proposed to explain the relationship between suicide and economic fluctuations, including the Durkheim (nonlinear), Ginsberg (procyclical), and Henry and Short (countercyclical) theories. This study tested the effect of economic fluctuations, measured by unemployment rate, on suicide rates in Canada from 1926 to 2008. Autoregressive integrated moving average time series models were used. The results showed a significant relationship between suicide and economic fluctuation; this association was positive during the contraction period (1926-1950) and negative in the period of economic expansion (1951-1973). Males and females showed differential effects in the period of moderate unemployment (1974-2008). In addition, the suicide rate of mid-adults (45-64) was most impacted by economic fluctuations. Our study tends to support Durkheim's theory and suggests the need for public health responses in times of economic contraction and expansion. PMID- 26765837 TI - Adolescents and Young Adults with Chronic or End-Stage Kidney Disease. AB - BACKGROUND: Adolescents and young adults face unique and complex physical, psychological, and family challenges. Despite improvements in care for chronic kidney disease (CKD) and end-stage kidney disease (ESKD), long-term mortality for children, adolescents, and young adults with CKD remains substantially higher than their healthy counterparts. SUMMARY: In this article, we discuss the complex challenges that adolescent and young adult CKD/ESKD patients face. Adolescents have different CKD etiologies and progress along a course dissimilar to the adult population, but have similar multifarious comorbidities. In the setting of puberty and learning to become self-sufficient, adolescence is a critical time for growth and psychosocial development. Physiological complications of CKD underlie many of the long-term outcomes. CKD-mineral and bone disorder and anemia are particularly challenging given that they are exacerbated by the rapid growth of adolescents. Endocrine imbalances and malnutrition can delay and limit growth. All of these factors, together with family dynamics and socioeconomic status, contribute to the poor long-term outcomes and decreased quality of life (QoL) for these patients and their families. KEY MESSAGES: Care for the adolescent CKD/ESKD population is uniquely challenging, but research has identified ways in which we can continue to improve long-term outcomes and QoL for adolescents with CKD/ESKD. PMID- 26765838 TI - Rapid preoperative blockage of thyroid hormone production / secretion in patients with Graves' disease. AB - PRINCIPLES: Preoperative management of hyperthyroid patients with Graves' disease who are unable to tolerate thionamides or have poor adherence to therapy is a challenging clinical problem. The goal of our study was to demonstrate the clinical efficacy of a rapid preoperative thyroid hormone blocking protocol and to assess specific surgical and treatment-related complications. METHODS: Ten patients with thyrotoxicosis due to Graves' disease were treated with a rapid thyroid hormone blocking protocol of Lugol's solution, dexamethasone and a beta blocker. Two patients continued to receive antithyroid therapy with carbimazole. Adrenal function was assessed 4-6 weeks postoperatively with a low dose (1 ug) adrenocorticotrophic hormone-stimulation test. RESULTS: Before treatment, all patients had severe hyperthyroidism. Baseline median and interquartile range (IQR) of fT4 was 68.9 (45.7-92.1) pmol/l, and baseline median fT3 and IQR, 30 (19.1-40.9) pmol/l. After 10 days of treatment, the levels of free hormones were significantly reduced with fT4 concentrations slightly elevated (fT4, 26.7 [17 36.4] pmol/l, p <0.001 compared with corresponding pretreatment values), and the fT3 concentration was normal in 8/10 patients (fT3, 6.1 [4.6-7.6] pmol/l, p <0.001 compared with corresponding pretreatment values). All patients were clinically euthyroid with a heart rate of <80/min. Drug tolerability was excellent, and there were no side effects or exacerbation of hyperthyroidism. The peri- and postoperative course was uneventful in all cases. Adrenal function was normal in 7 out of 10 patients 4-6 weeks postoperatively. Three patients showed prolonged secondary adrenal insufficiency with normalisation of adrenal function after 3 to 6 months. CONCLUSION: Rapid and effective preoperative preparation of patients with Graves' disease is achievable with Lugol's solution, dexamethasone and a beta-blocker. The risk of temporary hypothalamic-pituitary-adrenal axis suppression has to be taken into account. PMID- 26765839 TI - Effects of Strong Electronic Coupling in Chlorin and Bacteriochlorin Dyads. AB - Achieving tunable, intense near-infrared absorption in molecular architectures with properties suitable for solar light harvesting and biomedical studies is of fundamental interest. Herein, we report the photophysical, redox, and molecular orbital characteristics of nine hydroporphyrin dyads and associated benchmark monomers that have been designed and synthesized to attain enhanced light harvesting. Each dyad contains two identical hydroporphyrins (chlorin or bacteriochlorin) connected by a linker (ethynyl or butadiynyl) at the macrocycle beta-pyrrole (3- or 13-) or meso (15-) positions. The strong electronic communication between constituent chromophores is indicated by the doubling of prominent absorption features, split redox waves, and paired linear combinations of frontier molecular orbitals. Relative to the benchmarks, the chlorin dyads in toluene show substantial bathochromic shifts of the long-wavelength absorption band (17-31 nm), modestly reduced singlet excited-state lifetimes (tauS = 3.6-6.2 ns vs 8.8-12.3 ns), and increased fluorescence quantum yields (Phif = 0.37-0.57 vs 0.34-0.39). The bacteriochlorin dyads in toluene show significant bathochromic shifts (25-57 nm) and modestly reduced tauS (1.6-3.4 ns vs 3.5-5.3 ns) and Phif (0.09-0.19 vs 0.17-0.21) values. The tauS and Phif values for the bacteriochlorin dyads are reduced substantially (up to ~20-fold) in benzonitrile. The quenching is due primarily to the increased S1 -> S0 internal conversion that is likely induced by increased contribution of charge-resonance configurations to the S1 excited state in the polar medium. The fundamental insights gained into the physicochemical properties of the strongly coupled hydroporphyrin dyads may aid their utilization in solar-energy conversion and photomedicine. PMID- 26765840 TI - Identification of a novel family of carbohydrate-binding modules with broad ligand specificity. AB - Most enzymes that act on carbohydrates include non-catalytic carbohydrate-binding modules (CBMs) that recognize and target carbohydrates. CBMs bring their appended catalytic modules into close proximity with the target substrate and increase the hydrolytic rate of enzymes acting on insoluble substrates. We previously identified a novel CBM (CBMC5614-1) at the C-terminus of endoglucanase C5614-1 from an uncultured microorganism present in buffalo rumen. In the present study, that the functional region of CBMC5614-1 involved in ligand binding was localized to 134 amino acids. Two representative homologs of CBMC5614-1, sharing the same ligand binding profile, targeted a range of beta-linked polysaccharides that adopt very different conformations. Targeted substrates included soluble and insoluble cellulose, beta-1,3/1,4-mixed linked glucans, xylan, and mannan. Mutagenesis revealed that three conserved aromatic residues (Trp-380, Tyr-411, and Trp-423) play an important role in ligand recognition and targeting. These results suggest that CBMC5614-1 and its homologs form a novel CBM family (CBM72) with a broad ligand-binding specificity. CBM72 members can provide new insight into CBM-ligand interactions and may have potential in protein engineering and biocatalysis. PMID- 26765841 TI - Intrinsic Viral Factors Are the Dominant Determinants of the Hepatitis C Virus Response to Interferon Alpha Treatment in Chimeric Mice. AB - BACKGROUND: Hepatitis C virus infection is a global health problem. New direct acting antiviral agents have been recently approved. However, due to their high cost and some genotypes remaining difficult to treat, interferon-based therapy with pegylated interferon and ribavirin likely may remain a component of hepatitis C virus treatment for some patients. Unfortunately, pegylated interferon / ribavirin treatment achieved favorable outcomes in less than 50% of patients. Factors determining the outcome to pegylated interferon/ribavirin include both host and viral factors. It has been a major challenge to separate the host and viral factors in most in vivo systems. AIMS & METHODS: We used two hepatitis C virus strains from patients with different interferon-sensitivities and three hepatocyte donors, each with distinct interleukin 28B and interferon lambda 4 single nucleotide polymorphisms to investigate the contributions of viral and host factors to the response of hepatitis C virus to interferon treatment in chimeric mice. RESULTS AND CONCLUSIONS: We found that viral factors were the dominant factors in determining the interferon treatment outcomes in chimeric mice. Host factors, such as pre-treatment liver interferon-stimulated gene expression and single nucleotide polymorphisms near interleukin 28B and interferon lambda 4 coding regions, were less important determinants of the response to interferon in the chimeric mice than they were in patients. Our results also suggest that a complete immune system as seen in patients may be required for host factors such as single nucleotide polymorphisms near interleukin 28B/interferon lambda 4 and pre-treatment liver interferon-stimulated gene upregulation to have an effect on the interferon response. PMID- 26765844 TI - Correction: Effect of Calcifications on Breast Ultrasound Shear Wave Elastography: An Investigational Study. PMID- 26765842 TI - Influences of Chronic Mild Stress Exposure on Motor, Non-Motor Impairments and Neurochemical Variables in Specific Brain Areas of MPTP/Probenecid Induced Neurotoxicity in Mice. AB - Parkinson's disease (PD) is regarded as a movement disorder mainly affecting the elderly population and occurs due to progressive loss of dopaminergic (DAergic) neurons in nigrostriatal pathway. Patients suffer from non-motor symptoms (NMS) such as depression, anxiety, fatigue and sleep disorders, which are not well focussed in PD research. Depression in PD is a predominant /complex symptom and its pathology lies exterior to the nigrostriatal system. The main aim of this study is to explore the causative or progressive effect of chronic mild stress (CMS), a paradigm developed as an animal model of depression in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (25 mg/kg. body wt.) with probenecid (250 mg/kg, s.c.) (MPTP/p) induced mice model of PD. After ten i.p. injections (once in 3.5 days for 5 weeks) of MPTP/p or exposure to CMS for 4 weeks, the behavioural (motor and non-motor) impairments, levels and expressions of dopamine (DA), serotonin (5 HT), DAergic markers such as tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporters-2 (VMAT 2) and alpha-synuclein in nigrostriatal (striatum (ST) and substantia nigra (SN)) and extra-nigrostriatal (hippocampus, cortex and cerebellum) tissues were analysed. Significantly decreased DA and 5-HT levels, TH, DAT and VMAT 2 expressions and increased motor deficits, anhedonia-like behaviour and alpha-synuclein expression were found in MPTP/p treated mice. Pre and/or post exposure of CMS to MPTP/p mice further enhanced the MPTP/p induced DA and 5-HT depletion, behaviour abnormalities and protein expressions. Our results could strongly confirm that the exposure of stress after MPTP/p injections worsens the symptoms and neurochemicals status of PD. PMID- 26765845 TI - A catalytic biofuel production strategy involving separate conversion of hemicellulose and cellulose using 2-sec-butylphenol (SBP) and lignin-derived (LD) alkylphenol solvents. AB - A strategy in which the hemicellulose and cellulose fractions of lignocellulosic biomass are converted separately to jet fuel-range liquid hydrocarbon fuels (butene oligomers) through catalytic processes is developed. Dilute sulfuric acid (SA)-catalyzed pretreatment fractionates the first biomass into cellulose and hemicellulose-derived xylose, and these are then converted separately to levulinic acid (LA) using 2-sec-butylphenol (SBP) and lignin-derived (LD) alkylphenol solvents, respectively. LA is upgraded catalytically to butene oligomers via gamma-valerolactone (GVL) and butene intermediates. Separation subsystems are designed to recover the alkylphenol solvents and biomass-derived intermediates (LA and GVL) for combination with the catalytic conversion subsystems of hemicellulose, cellulose, and lignin. In addition, a heat exchanger network (HEN) design is presented to satisfy the energy requirements of the integrated process from combustion of biomass residues (degradation products). Finally, a technoeconomic analysis shows that the proposed process ($3.37/gallon of gasoline) is an economically competitive alternative to current biofuel production approaches. PMID- 26765846 TI - Effects of Simulated Marker Placement Deviations on Running Kinematics and Evaluation of a Morphometric-Based Placement Feedback Method. AB - In order to provide effective test-retest and pooling of information from clinical gait analyses, it is critical to ensure that the data produced are as reliable as possible. Furthermore, it has been shown that anatomical marker placement is the largest source of inter-examiner variance in gait analyses. However, the effects of specific, known deviations in marker placement on calculated kinematic variables are unclear, and there is currently no mechanism to provide location-based feedback regarding placement consistency. The current study addresses these disparities by: applying a simulation of marker placement deviations to a large (n = 411) database of runners; evaluating a recently published method of morphometric-based deviation detection; and pilot-testing a system of location-based feedback for marker placements. Anatomical markers from a standing neutral trial were moved virtually by up to 30 mm to simulate deviations. Kinematic variables during running were then calculated using the original, and altered static trials. Results indicate that transverse plane angles at the knee and ankle are most sensitive to deviations in marker placement (7.59 degrees of change for every 10 mm of marker error), followed by frontal plane knee angles (5.17 degrees for every 10 mm). Evaluation of the deviation detection method demonstrated accuracies of up to 82% in classifying placements as deviant. Finally, pilot testing of a new methodology for providing location based feedback demonstrated reductions of up to 80% in the deviation of outcome kinematics. PMID- 26765843 TI - Astaxanthin Inhibits Expression of Retinal Oxidative Stress and Inflammatory Mediators in Streptozotocin-Induced Diabetic Rats. AB - PURPOSE: We evaluated whether orally administered astaxanthin (AST) protects against oxidative damage in the ocular tissues of streptozotocin (STZ)-induced diabetic rats. METHODS AND RESULTS: Fifty 6-week-old female Wistar rats were randomly assigned to receive an injection of STZ to induce diabetes (n = 40) or to remain uninduced (n = 10). The diabetic rats were randomly selected into four groups and they were separately administered normal saline, 0.6 mg/kg AST, 3 mg/kg AST, or 0.5 mg/kg lutein daily for eight weeks. Retinal functions of each group were evaluated by electroretinography. The expression of oxidative stress and inflammatory mediators in the ocular tissues was then assessed by immunohistochemistry, western blot analysis, ELISA, RT-PCR, and electrophoretic mobility shift assay (EMSA). Retinal functions were preserved by AST and lutein in different levels. Ocular tissues from AST- and lutein-treated rats had significantly reduced levels of oxidative stress mediators (8-hydroxy-2' deoxyguanosine, nitrotyrosine, and acrolein) and inflammatory mediators (intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and fractalkine), increased levels of antioxidant enzymes (heme oxygenase-1 and peroxiredoxin), and reduced activity of the transcription factor nuclear factor kappaB (NF-kappaB). CONCLUSION: The xanthophyll carotenoids AST and lutein have neuroprotective effects and reduce ocular oxidative stress, and inflammation in the STZ diabetic rat model, which may be mediated by downregulation of NF-kappaB activity. PMID- 26765848 TI - "Graft-to" Protein/Polymer Conjugates Using Polynorbornene Block Copolymers. AB - A series of water-soluble polynorbornene block copolymers prepared via Ring Opening Metathesis Polymerization (ROMP) were grafted to proteins to form ROMP derived bioconjugates. ROMP afforded low-dispersity polymers and allowed for strict control over polymer molecular weight and architecture. The polymers consisted of a large block of PEGylated monoester norbornene and were capped with a short block of norbornene dicarboxylic anhydride. This cap served as a reactive linker that facilitated attachment of the polymer to lysine residues under mildly alkaline conditions. The generality of this approach was shown by synthesizing multivalent polynorbornene-modified viral nanoparticles derived from bacteriophage Qbeta, a protein nanoparticle used extensively for nanomedicine. The conjugated nanoparticles showed no cytotoxicity to NIH 3T3 murine fibroblast cells. These findings establish protein bioconjugation with functionalized polynorbornenes as an effective alternative to conventional protein/polymer modification strategies and further expand the toolbox for protein bioconjugates. PMID- 26765862 TI - 2D versus 3D templating in total knee arthroplasty. AB - BACKGROUND: Preoperative digital templating in total knee arthroplasty (TKA) helps to determine the need of non-standard implants, prophesies the bony resections and helps to anticipate the intraoperative plan. Templating within the process of patient specific instrumentation (PSI) is fairly new and 2D planning has not been compared to PSI templating. METHODS: 94 patients underwent unilateral primary TKA with magnetic resonance imaging (MRI) based preoperative templating and PSI cutting blocks. Parallel to this, three observers templated all cases using digital planning on standard preoperative x-rays. The examiners templated all cases independently and were blinded to the component sizes used intraoperatively. RESULTS: Three-dimensional (3D) templating was accurate in predicting the correct implant size in 100% of the cases. The femoral and tibial two-dimensional (2D) digital templating varied from 43.6% to 59.5% and 52.1% to 68% of the cases. When allowing +/-1 difference, femoral 2D digital templating varied from 93.6% to 97.8% of the cases and ranged from 94.6% to 98.9% on the tibial side. All observers show "very good" correlation. The coefficient indicates a very good agreement in between the three observers. CONCLUSION: 3D templating has very high accuracy for the actual implant size prediction. Compared to this, 2D digital templating is an accurate method to approximately (+/-1 size) determine the size of TKA components. However, we judge this technique accurate enough, that 2D templating allows launching Template-directed instrumentation (TDI), while the examiner does not need a high level of clinical experience. CLINICAL RELEVANCE: Within the process of digital planning, the surgeonmight focus evenmore on the upcoming operation. PMID- 26765847 TI - Automated Entire Thrombus Density Measurements for Robust and Comprehensive Thrombus Characterization in Patients with Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: In acute ischemic stroke (AIS) management, CT-based thrombus density has been associated with treatment success. However, currently used thrombus measurements are prone to inter-observer variability and oversimplify the heterogeneous thrombus composition. Our aim was first to introduce an automated method to assess the entire thrombus density and then to compare the measured entire thrombus density with respect to current standard manual measurements. MATERIALS AND METHOD: In 135 AIS patients, the density distribution of the entire thrombus was determined. Density distributions were described using medians, interquartile ranges (IQR), kurtosis, and skewedness. Differences between the median of entire thrombus measurements and commonly applied manual measurements using 3 regions of interest were determined using linear regression. RESULTS: Density distributions varied considerably with medians ranging from 20.0 to 62.8 HU and IQRs ranging from 9.3 to 55.8 HU. The average median of the thrombus density distributions (43.5 +/- 10.2 HU) was lower than the manual assessment (49.6 +/- 8.0 HU) (p<0.05). The difference between manual measurements and median density of entire thrombus decreased with increasing density (r = 0.64; p<0.05), revealing relatively higher manual measurements for low density thrombi such that manual density measurement tend overestimates the real thrombus density. CONCLUSIONS: Automatic measurements of the full thrombus expose a wide variety of thrombi density distribution, which is not grasped with currently used manual measurement. Furthermore, discrimination of low and high density thrombi is improved with the automated method. PMID- 26765863 TI - Ligament and meniscus loading in the ovine stifle joint during normal gait. AB - BACKGROUND: The ovine stifle joint is an ideal preclinical model to study knee joint biomechanics. Knowledge of the ovine ligamentous and meniscal loading during normal gait is currently limited. METHODS: The in vivo kinematics of the ovine stifle joint (N=4) were measured during "normal" gait using a highly accurate instrumented spatial linkage (ISL, 0.3+/-0.2mm). These motions were reproduced in vitro using a unique robotic testing platform and the loads carried by the anterior/posterior cruciate ligaments (ACL/PCL), medial/lateral collateral ligaments (MCL/LCL), and medial/lateral menisci (MM/LM) during gait were determined. RESULTS: Considerable inter-subject variability in tissue loads was observed. The load in the ACL was near zero at hoof-strike (0% gait) and reached a peak (100 to 300N) during early-stance (~10% gait). The PCL reached a peak load (200 to 500N) just after hoof-strike (~5% gait) and was mostly unloaded throughout the remainder of stance. Load in the MCL was substantially lower than the cruciate ligaments, reaching a maximum of 50 to 100N near the beginning of stance. The LCL carried a negligible amount of load through the entire gait cycle. There was also a major contribution of the MM and LM to load transfer from the femur to the tibia during normal gait. The total meniscal load reached a maximum average between 350 and 550N during gait. CONCLUSION: Knowledge of joint function during normal motion is essential for understanding normal and pathologic joint states. The considerable variability in the magnitudes and patterns of tissue loads among animals simulates clinical variability in humans. LEVEL OF EVIDENCE: III. PMID- 26765866 TI - Exploring and Explaining Friction with the Prandtl-Tomlinson Model. AB - The Prandtl-Tomlinson model of friction, first introduced in 1928 as a "conceptual model" for a single-atom contact, consists of a point mass that is dragged over a sinusoidal potential by a spring. After decades of virtual oblivion, it has recently found impressive validation for contacts comprising tens or even hundreds of atoms. To date, the Prandtl-Tomlinson model enjoys widespread popularity as depicting arguably the most insightful mechanical analogue to atomic-scale effects occurring at sliding interfaces. In this issue of ACS Nano, Pawlak et al. demonstrate the model's applicability to a true single atom contact, thereby illustrating that simple mechanical representations can indeed go a long way toward explaining interactions at atomically defined interfaces. PMID- 26765864 TI - Suppression of bacterial infection in rice by treatment with a sulfated peptide. AB - The rice XA21 receptor kinase confers robust resistance to bacterial blight disease caused by Xanthomonas oryzae pv. oryzae (Xoo). A tyrosine-sulfated peptide from Xoo, called RaxX, triggers XA21-mediated immune responses, including the production of ethylene and reactive oxygen species and the induction of defence gene expression. It has not been tested previously whether these responses confer effective resistance to Xoo. Here, we describe a newly established post-inoculation treatment assay that facilitates investigations into the effect of the sulfated RaxX peptide in planta. In this assay, rice plants were inoculated with a virulent strain of Xoo and then treated with the RaxX peptide 2 days after inoculation. We found that post-inoculation treatment of XA21 plants with the sulfated RaxX peptide suppresses the development of Xoo infection in XA21 rice plants. The treated plants display restricted lesion development and reduced bacterial growth. Our findings demonstrate that exogenous application of sulfated RaxX activates XA21-mediated immunity in planta, and provides a potential strategy for the control of bacterial disease in the field. PMID- 26765865 TI - Trends in colorectal cancer in the elderly in Denmark, 1980-2012. AB - BACKGROUND: Colorectal cancer (CRC) is a disease of the older population. The current demographic ageing leads to more elderly patients and is expected to further increase the number of patients with CRC. The objective of the present paper is to outline incidence, mortality and prevalence from 1980 to 2012 and survival data from 1968 to 2012 in Danish CRC patients focusing on the impact of ageing. MATERIAL AND METHODS: Data were derived from the NORDCAN database with comparable data on cancer incidence, mortality, prevalence and relative survival in the Nordic countries, where the Danish data are delivered from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up for death or emigration until the end of 2013. This study focuses on the elderly population categorized in six age groups. RESULTS: The incidence of CRC has increased over the past three decades. Incidence rate has increased in patients with colon cancer, but showed a decreasing trend in the oldest patients with rectal and anal cancer. Mortality has diminished in younger patients with colon cancer, but increased with increasing age. However, mortality did not increase proportionally to incidence. In rectal and anal cancer mortality has decreased, except among the oldest patients. This correlates to a decreasing incidence rate. Prevalence is widely increasing mainly because of increased incidence and longer survival, which is reflected in the increasing one- and five-year age-specific relative survival after a diagnosis of colon, rectal and anal cancer. CONCLUSION: The incidence of CRC is increasing, especially in older citizens, and mortality increases with older age. There is limited knowledge on how to optimize treatment in older CRC patients and future focus must be how to select and tailor the treatment for older CRC patients. PMID- 26765867 TI - Potassium-Binding Agents for the Clinical Management of Hyperkalemia. AB - Use of sodium polystyrene sulfonate (SPS) dominates the long-term treatment of hyperkalemia, but two new agents, sodium zirconium cyclosilicate and the recently FDA-approved patiromer, may offer potential advantages compared with SPS. PMID- 26765924 TI - Analysis of RUNX1 rearrangements: insights into leukaemogenesis mechanisms. PMID- 26765926 TI - Substitution, proration, or a retest? The optimal strategy when standard administration of the WPPSI-IV is infeasible. AB - Administration following a standard procedure is undoubtedly the ultimate goal of assessment. Practitioners face the challenge of unexpected events interrupting a formal evaluation, substitution, proration, or a retest, which may be used as alternative strategies to perform estimations. Such nonstandardized estimation strategies have introduced additional measurement errors because the manual reports only 1 set of norms, which are derived following the standard testing procedure. Thus, mismatching with norms is the root cause of additional errors introduced when applying these alternative strategies. This study examined the additional measurement errors introduced in using normative and clinical samples, as well as a retest sample of the 3 estimation approaches in the Wechsler Primary Preschool Scale for Children-Fourth Edition (WPPSI-IV). Results revealed that substituting, prorating, or retesting 1 of 6 core subtests for the Full Scale IQ increased the SEM by 0.61 to 1.92 score points (20-64%), generating wider confidence intervals (CIs) by +/-1.2 to +/-3.8 IQ points and misclassifications as high as 22%. Furthermore, substituting 1 missing subtest for the Verbal Comprehension Index or Processing Speed Index resulted in an additional 4.27 to 5.24 score point increase in SEM (79.7-132.5%), creating wider CIs by +/-8.37 to +/-10.27 IQ points and misclassifications as high as 35-44%. We remind practitioners to be cautious about the various increases in error rate resulting from such applications and to avoid introducing unnecessary additional errors when possible. Under circumstances when alternative procedures are considered a must, current work provides information for making evidence-based decision. (PsycINFO Database Record PMID- 26765927 TI - Calibration of the Test of Relational Reasoning. AB - Relational reasoning, or the ability to discern meaningful patterns within a stream of information, is a critical cognitive ability associated with academic and professional success. Importantly, relational reasoning has been described as taking multiple forms, depending on the type of higher order relations being drawn between and among concepts. However, the reliable and valid measurement of such a multidimensional construct of relational reasoning has been elusive. The Test of Relational Reasoning (TORR) was designed to tap 4 forms of relational reasoning (i.e., analogy, anomaly, antinomy, and antithesis). In this investigation, the TORR was calibrated and scored using multidimensional item response theory in a large, representative undergraduate sample. The bifactor model was identified as the best-fitting model, and used to estimate item parameters and construct reliability. To improve the usefulness of the TORR to educators, scaled scores were also calculated and presented. (PsycINFO Database Record PMID- 26765925 TI - Class I and IIa HDACs Mediate HIF-1alpha Stability Through PHD2-Dependent Mechanism, While HDAC6, a Class IIb Member, Promotes HIF-1alpha Transcriptional Activity in Nucleus Pulposus Cells of the Intervertebral Disc. AB - The objective of this study was to determine the role of histone deacetylases (HDACs) in regulating HIF-1alpha protein stability and activity in nucleus pulposus (NP) cells. Treatment of NP cells with pan-HDAC inhibitor TSA resulted in decreased HIF-1alpha levels under both normoxia and hypoxia in a dose dependent fashion. TSA-mediated HIF-1alpha degradation was rescued by concomitant inhibition of not only the 26S proteasome but also PHD2 function. Moreover, TSA treatment of PHD2(-/-) cells had little effect on HIF-1alpha levels, supporting the notion that inhibition of PHD2 function by HDACs contributed to HIF-1alpha stabilization. Surprisingly, class-specific HDAC inhibitors did not affect HIF 1alpha protein stability, indicating that multiple HDACs controlled HIF-1alpha stability by regulating HIF-1alpha-PHD2 interaction in NP cells. Interestingly, lower-dose TSA that did not affect HIF-1alpha stability decreased its activity and target gene expression. Likewise, rescue of TSA-mediated HIF-1alpha protein degradation by blocking proteasomal or PHD activity did not restore HIF-1 activity, suggesting that HDACs independently regulate HIF-1alpha stability and activity. Noteworthy, selective inhibition of HDAC6 and not of class I and IIa HDACs decreased HIF-1-mediated transcription under hypoxia to a similar extent as lower-dose TSA, contrasting the reported role of HDAC6 as a transcriptional repressor in other cell types. Moreover, HDAC6 inhibition completely blocked TSA effects on HIF-1 activity. HDAC6 associated with and deacetylated HSP90, an important cofactor for HIF-1 function in NP cells, and HDAC6 inhibition decreased p300 transactivation in NP cells. Taken together, these results suggest that although multiple class I and class IIa HDACs control HIF-1 stability, HDAC6, a class IIb HDAC, is a novel mediator of HIF-1 activity in NP cells possibly through promoting action of critical HIF-1 cofactors. (c) 2016 American Society for Bone and Mineral Research. PMID- 26765928 TI - Total Synthesis of Isodaphlongamine H: A Possible Biogenetic Conundrum. AB - Herein we describe the first synthetic efforts toward the total synthesis of isodaphlongamine H, a calyciphylline B-type alkaloid. The strategy employs a chemoenzymatic process for the preparation of a functionalized cyclopentanol with a quaternary center. This molecule is elaborated to form an enantiopure 1-aza perhydrocyclopentalene core, representing rings A and E of all calyciphylline B type alkaloids. Further transformations involve the formation of a cyclic enaminone, 1,4-conjugate addition with a cyclopentenyl subunit, and intramolecular aldol cyclization to achieve a pentacyclic intermediate, ultimately forming isodaphlongamine H in a total of 24 steps from the commercially available compound 2-carbethoxycyclopentanone. Isodaphlongamine H exhibits promising inhibitory activity against a panel of human cancer cell lines. PMID- 26765930 TI - Asparaginase Erwinia chrysanthemi as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia who have developed hypersensitivity to E. coli-derived asparaginase. AB - Asparaginase has been a mainstay of therapy in the treatment of acute lymphoblastic leukemia since the 1970s. There are two major preparations available and FDA approved in the United States today, one derived from Escherichia coli and the other from Erwinia chrysanthemi. Erwinia asparaginase is antigenically distinct from and has a considerably shorter biological half-life than E coli asparaginase. Erwinia asparaginase has been used in cases of hypersensitivity to E. coli-derived asparaginases, which has been reported in up to 30% of patients. While PEG asparaginase is increasingly used in front-line therapy for ALL, hypersensitivity still occurs with this preparation, and a change to a non-cross-reactive preparation may be necessary. PMID- 26765929 TI - P1 Ref Endonuclease: A Molecular Mechanism for Phage-Enhanced Antibiotic Lethality. AB - Ref is an HNH superfamily endonuclease that only cleaves DNA to which RecA protein is bound. The enigmatic physiological function of this unusual enzyme is defined here. Lysogenization by bacteriophage P1 renders E. coli more sensitive to the DNA-damaging antibiotic ciprofloxacin, an example of a phenomenon termed phage-antibiotic synergy (PAS). The complementary effect of phage P1 is uniquely traced to the P1-encoded gene ref. Ref is a P1 function that amplifies the lytic cycle under conditions when the bacterial SOS response is induced due to DNA damage. The effect of Ref is multifaceted. DNA binding by Ref interferes with normal DNA metabolism, and the nuclease activity of Ref enhances genome degradation. Ref also inhibits cell division independently of the SOS response. Ref gene expression is toxic to E. coli in the absence of other P1 functions, both alone and in combination with antibiotics. The RecA proteins of human pathogens Neisseria gonorrhoeae and Staphylococcus aureus serve as cofactors for Ref-mediated DNA cleavage. Ref is especially toxic during the bacterial SOS response and the limited growth of stationary phase cultures, targeting aspects of bacterial physiology that are closely associated with the development of bacterial pathogen persistence. PMID- 26765932 TI - Differences in HPA axis reactivity to intimacy in women with and without histories of sexual trauma. AB - BACKGROUND: Sexual trauma can lead to longstanding effects on individuals' intimacy functioning. The current study aimed to assess hypothalamic pituitary adrenal (HPA) axis functioning (i.e., cortisol reactivity) prior to (-5min), during (+15, +30, +45min), and following (+60min) an experimental manipulation of emotional closeness in a sample of women survivors of sexual trauma with varying levels of posttraumatic stress disorder (PTSD) symptomatology versus controls. METHODS: Participants included 50 women, which were divided into 2 groups on the basis of a structured clinical interview: 26 women with a history of sexual trauma with and without PTSD (sexual trauma group), and 24 women without a history of sexual trauma or PTSD (controls). Participants came into the lab and participated in a 45min emotional closeness exercise with a male confederate and completed self-report questionnaires of closeness, state anxiety/depression, and cortisol assays at the aforementioned time points. RESULTS: Women with a history of sexual trauma exhibited a blunted cortisol response and greater anxious mood in reaction to the intimacy induction task compared to controls. Results also demonstrated that, unexpectedly, PTSD symptom severity scores among sexual trauma survivors were not associated with differential cortisol responding to the task compared to controls. CONCLUSIONS: Adaptive responses to stress are characterized by a relatively rapid cortisol increase followed by a steady decline. The results of this study demonstrated that women with a history of sexual trauma, in contrast, displayed a blunted cortisol response to an intimacy induction task. Both controls and women with a history of sexual trauma reported increased feelings of closeness to the male confederate in response to the intimacy induction task, suggesting that survivors were able to achieve similar adaptive feelings of intimacy when provided with the right conditions. PMID- 26765931 TI - Cell-free 3D scaffold with two-stage delivery of miRNA-26a to regenerate critical sized bone defects. AB - MicroRNAs (miRNAs) are being developed to enhance tissue regeneration. Here we show that a hyperbranched polymer with high miRNA-binding affinity and negligible cytotoxicity can self-assemble into nano-sized polyplexes with a 'double-shell' miRNA distribution and high transfection efficiency. These polyplexes are encapsulated in biodegradable microspheres to enable controllable two-stage (polyplexes and miRNA) delivery. The microspheres are attached to cell-free nanofibrous polymer scaffolds that spatially control the release of miR-26a. This technology is used to regenerate critical-sized bone defects in osteoporotic mice by targeting Gsk-3beta to activate the osteoblastic activity of endogenous stem cells, thus addressing a critical challenge in regenerative medicine of achieving cell-free scaffold-based miRNA therapy for tissue engineering. PMID- 26765933 TI - Hypothalamic orexin's role in exacerbated cutaneous vasodilation responses to an anxiogenic stimulus in a surgical menopause model. AB - Distressing symptoms such as hot flashes and sleep disturbances affect over 70% of women approaching menopause for an average of 4-7 years, and recent large cohort studies have shown that anxiety and stress are strongly associated with more severe and persistent hot flashes and can induce hot flashes. Although high estrogen doses alleviate symptoms, extended use increases health risks, and current non-hormonal therapies are marginally better than placebo. The lack of effective non-hormonal treatments is largely due to the limited understanding of the mechanisms that underlie menopausal symptoms. One mechanistic pathway that has not been explored is the wake-promoting orexin neuropeptide system. Orexin is exclusively synthesized in the estrogen receptor rich perifornical hypothalamic region, and has an emerging role in anxiety and thermoregulation. In female rodents, estrogens tonically inhibit expression of orexin, and estrogen replacement normalizes severely elevated central orexin levels in postmenopausal women. Using an ovariectomy menopause model, we demonstrated that an anxiogenic compound elicited exacerbated hot flash-associated increases in tail skin temperature (TST, that is blocked with estrogen), and cellular responses in orexin neurons and efferent targets. Furthermore, systemic administration of centrally active, selective orexin 1 or 2 and dual receptor antagonists attenuated or blocked TST responses, respectively. This included the reformulated Suvorexant, which was recently FDA-approved for treating insomnia. Collectively, our data support the hypothesis that dramatic loss of estrogen tone during menopausal states leads to a hyperactive orexin system that contributes to symptoms such as anxiety, insomnia, and more severe hot flashes. Additionally, orexin receptor antagonists may represent a novel non-hormonal therapy for treating menopausal symptoms, with minimal side effects. PMID- 26765934 TI - Interleukin-17 mediated differences in the pathogenesis of HIV-1-associated tuberculous and cryptococcal meningitis. AB - OBJECTIVE: Mycobacterium tuberculosis and Cryptococcus neoformans are major causes of meningitis in HIV-1-infected patients. Identifying differences in the inflammatory profiles of HIV-1-associated tuberculous meningitis (TBM) and cryptococcal meningitis may inform differences in immunopathogenic mechanisms in these diseases. In this study we compared the clinical and inflammatory features of HIV-1-associated TBM, and cryptococcal meningitis. METHODS: A prospective study of HIV-1-infected adults who presented with either TBM [antiretroviral therapy (ART)-naive] or cryptococcal meningitis (regardless of ART prescription). Clinical and laboratory findings and concentrations of 40 inflammatory mediators measured in cerebrospinal fluid (CSF, 33 paired with blood) were compared between TBM and cryptococcal meningitis patients regardless of ART prescription and between TBM and cryptococcal meningitis patients not receiving ART. RESULTS: Clinical and laboratory findings were similar in TBM (n=34) and cryptococcal meningitis (n = 19; ART prescribed: n = 10, no ART prescribed: n = 9). Exceptions included a higher median CD4 cell count [interquartile: 113 (69-199) vs. 25 (8 49) cells/MUl, P = 0.0001] and higher HIV-1 median viral load [plasma: 5.46 (4.82 5.89) vs. 4.87 (4.36-5.17) log10copies/ml, P = 0.037; CSF: 6.05 (5.43-6.56) vs. 5.56 (4.52-5.80) log10copies/ml, P = 0.03] in TBM vs. cryptococcal meningitis patients not receiving ART. CSF interleukin (IL)-17A was lower in TBM compared with cryptococcal meningitis [1.00 (0.25-2.35) vs. 9.31 (1.24-23.36) pg/ml, P adjusted = 0.03]. CONCLUSION: Despite presenting with higher peripheral CD4 cell counts, TBM patients also presented with higher HIV-1 viral loads compared with cryptococcal meningitis patients, suggesting a greater propensity of M. tuberculosis compared with C. neoformans to increase HIV-1 replication in vivo. CSF IL-17A was lower in TBM; its role in the immunopathogenesis of TBM and cryptococcal meningitis deserves further research. PMID- 26765936 TI - High-risk human papillomavirus genotypes distribution in a cohort of HIV-positive women living in Europe: epidemiological implication for vaccination against human papillomavirus. AB - BACKGROUND: Worldwide, human papillomavirus (HPV) 16 and 18 represents 70% of high-risk (HR) HPV found in cervical cancer. However HIV-positive women are more frequently infected by HRHPV other than HPV 16 or 18 (OHR). We aimed to analyse the HRHPV genotype distribution in a cohort of HIV-positive women and to estimate the potential protection offered by the different HPV vaccines. METHODS: HRHPV genotypes by PCR and cytology were assessed in cervical samples from 508 HIV positive women prospectively followed in Brussels. RESULTS: Women characteristics were as follows: African origin (84%), median age 42 years, median CD4 T 555/MUl, 89% under combined antiretroviral therapy and 73% with HIVRNA less than 20 copies/ml. HRHPV prevalence was 23% (116/508): 38% had abnormal cytology, 76% carried OHR without HPV 16 or 18 and 11% had concomitant infection by OHR and HPV 16 or 18. The most frequent HRHPV were HPV52 (19.8%), HPV18 (14.6%), HPV31/35/51/58 (12.1% each), HPV56 (9.9%) and HPV16 (9.5%). Less than 30% of women had their HRHPV genotypes included in the bivalent or quadrivalent vaccines against HRHPV 16 and 18; however, 79% had their HRHPV covered by the ninevalent vaccine against HRHPV 16/18/31/33/45/52/58. CONCLUSION: The HRHPV genotypes distribution found in these women living in Europe with a successfully treated HIV is similar to the one found in Central Africa with HRHPV other than HPV16 or 18 retrieved in 87%. In this population, the bivalent or quadrivalent vaccines could offer protection in only 30% of women; however this protection could be extended up to 80% with the ninevalent vaccine. PMID- 26765935 TI - Brain large artery inflammation associated with HIV and large artery remodeling. AB - OBJECTIVE: To test the hypothesis that brain arteries from HIV+ cases have a greater degree of inflammation than brain arteries from HIV- cases, and that inflammation is associated with brain arterial remodeling. DESIGN: Case-control study, cross-sectional. METHODS: Brain arteries from 162 autopsy cases (84 with HIV) were systematically analyzed for thickness of the intima, media, and adventitia, and atherosclerosis and dolichoectasia. Inflammation was assessed with CD68 immunohistochemistry, and measured with a semiquantitative score reflecting the number and location (i.e., arterial layer) of activated macrophages infiltrating the arterial wall. Latent varicella zoster virus (VZV) was assessed with anti-VZV gene 63 product immunohistochemistry. Demographic and clinical variables were available in all cases, and longitudinal data about CD4 cell counts were available among cases with HIV. Multilevel generalized linear models were used to test the association between inflammation and HIV. RESULTS: Arteries from HIV+ cases had a higher inflammation score (B = 0.36, P = 0.05) compared with arteries from HIV- cases, although the association was attenuated after controlling for demographic variables, vascular risk factors, and latent VZV (B = 0.20, P = 0.18). Although intimal inflammation was similar in cases with and without HIV, adventitial inflammation was associated with HIV. Intimal inflammation was associated with intracranial atherosclerosis independent of HIV status, but adventitial inflammation was associated with HIV-associated dolichoectasia in arteries with a thin media. CONCLUSIONS: Adventitial inflammation is associated with HIV and dolichoectasia independent of intracranial atherosclerosis. This suggests that differential inflammatory responses may play a role in intracranial atherosclerosis and dolichoectasia. PMID- 26765937 TI - Survival in HIV-positive transplant recipients compared with transplant candidates and with HIV-negative controls. AB - OBJECTIVES: To evaluate the impact of liver and kidney transplantation on survival in HIV-positive transplant candidates and compare outcomes between HIV positive and negative recipients. DESIGN: Observational cohort of HIV-positive transplant candidates and recipients and secondary analysis comparing study recipients to HIV-negative national registry controls. METHODS: We fit proportional hazards models to assess transplantation impact on mortality among recipients and candidates. We compared time to graft failure and death with HIV negative controls in unmatched, demographic-matched, and risk-adjusted models. RESULTS: There were 17 (11.3%) and 46 (36.8%) deaths among kidney and liver recipients during a median follow-up of 4.0 and 3.5 years, respectively. Transplantation was associated with survival benefit for HIV-infected liver recipients with model for end-stage liver disease (MELD) greater than or equal 15 [hazard ratio (HR) 0.1; 95% confidence interval (CI) 0.05, 0.01; P < 0.0001], but not for MELD less than 15 (HR 0.7; 95% CI 0.3, 1.8; P = 0.43) or for kidney recipients (HR 0.6; 95% CI 0.3, 1.4; P = 0.23). In HIV-positive kidney recipients, unmatched and risk-matched analyses indicated a marginally significant HR for graft loss [1.3 (P = 0.07) and HR 1.4 (P = 0.052)]; no significant increase in risk of death was observed. All models demonstrated a higher relative hazard of graft loss or death in HIV-positive liver recipients; the absolute difference in the proportion of deaths was 6.7% in the risk-matched analysis. CONCLUSION: Kidney transplantation should be standard of care for well managed HIV-positive patients. Liver transplant in candidates with high MELD confers survival benefit; transplant is a viable option in selected candidates. The increased mortality risk compared with HIV-negative recipients was modest. TRIAL REGISTRATION: ClinicalTrials.Gov; NCT00074386; http://clinicaltrials.gov/. PMID- 26765939 TI - Adult life expectancy trends in the era of antiretroviral treatment in rural Uganda (1991-2012). AB - OBJECTIVE: To estimate the impact of antiretroviral therapy (ART) on population wide adult life expectancy. STUDY DESIGN: A population-based open cohort study with repeated HIV status measurements and registration of vital events in Southwestern Uganda (1991-2012). METHODS: Nonparametric survival analysis techniques are used for estimating trends in the adult life expectancy of the general population (aged 15 and above), the adult life expectancy by HIV status, and the adult life expectancy deficit. The life expectancy deficit is estimated as the difference between overall life expectancy and life expectancy of the HIV negative population. All estimates are disaggregated by sex. RESULTS: Between 1991-1993 and 2009-2012, population-wide adult life expectancy increased from 39.3 [95% confidence interval (CI): 35.9-42.8] to 56.1 years (95% CI: 54.0-58.5) in women, and from 38.6 (95% CI: 35.4-42.1) to 51.4 years (95% CI: 49.2-53.7) in men. Most of the adult life expectancy gains coincide with the introduction of ART in 2004; as evidenced by an increase in the adult life expectancy of people living with HIV between 2000-2002 and 2009-2012 of 22.9 and 20.0 years for women and men, respectively. Over the whole period of observation, the adult life expectancy deficit associated with HIV decreased from 16.1 (95% CI: 12.7-19.8) to 6.0 years (95% CI: 4.1-7.8) among women, and from 16.0 (95% CI: 12.1-19.9) to 2.8 years (95% CI: 1.2-4.6) among men. CONCLUSION: Population-wide life expectancy increased substantially, largely driven by reductions in HIV-related mortality. Women have gained more adult life years than men since the introduction of ART, but the burden of HIV in terms of the life years lost is still larger for women than it is for men. PMID- 26765938 TI - Risk factors associated with acute exacerbation of chronic obstructive pulmonary disease in HIV-infected and uninfected patients. AB - OBJECTIVE: To determine the association between HIV infection and other risk factors for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). DESIGN: Longitudinal, national Veterans Aging Cohort Study including 43 618 HIV infected and 86 492 uninfected veterans. METHODS: AECOPD was defined as an inpatient or outpatient COPD ICD-9 diagnosis accompanied by steroid and/or antibiotic prescription within 5 days. We calculated incidence rate ratios (IRR) and 95% confidence intervals (CI) for first AECOPD over 2 years and used Poisson regression models to adjust for risk factors. RESULTS: Over 234 099 person-years of follow-up, 1428 HIV-infected and 2104 uninfected patients had at least one AECOPD. HIV-infected patients had an increased rate of AECOPD compared with uninfected (18.8 vs. 13.3 per 1000 person-years, P < 0.001). In adjusted models, AECOPD risk was greater in HIV-infected individuals overall (IRR 1.54; 95% CI 1.44-1.65), particularly in those with more severe immune suppression when stratified by CD4 cell count (cells/MUl) compared with uninfected (HIV-infected CD4 < 200: IRR 2.30, 95% CI 2.10-2.53, HIV-infected CD4 >= 200-349: IRR 1.32, 95% CI 1.15-1.51, HIV-infected CD4 >= 350: IRR 0.99, 95% CI 0.88-1.10). HIV infection also modified the association between current smoking and alcohol-related diagnoses with risk for AECOPD such that interaction terms for HIV and current smoking or HIV and alcohol-related diagnoses were each significantly associated with AECOPD. CONCLUSION: HIV infection, especially with lower CD4 cell count, is an independent risk factor for AECOPD. Enhanced susceptibility to harm from current smoking or unhealthy alcohol use in HIV-infected patients may also contribute to the greater rate of AECOPD. PMID- 26765941 TI - Accounting for and responding to HIV-associated mortality. PMID- 26765940 TI - Patient-reported factors associated with reengagement among HIV-infected patients disengaged from care in East Africa. AB - OBJECTIVE: Engagement in care is key to successful HIV treatment in resource limited settings; yet little is known about the magnitude and determinants of reengagement among patients out of care. We assessed patient-reported reasons for not returning to clinic, identified latent variables underlying these reasons, and examined their influence on subsequent care reengagement. DESIGN: We used data from the East Africa International Epidemiologic Databases to Evaluate AIDS to identify a cohort of patients disengaged from care (>3 months late for last appointment, reporting no HIV care in preceding 3 months) (n = 430) who were interviewed about reasons why they stopped care. Among the 399 patients for whom follow-up data were available, 104 returned to clinic within a median observation time of 273 days (interquartile range: 165-325). METHODS: We conducted exploratory and confirmatory factor analyses (EFA, CFA) to identify latent variables underlying patient-reported reasons, then used these factors as predictors of time to clinic return in adjusted Cox regression models. RESULTS: EFA and CFA findings suggested a six-factor structure that lent coherence to the range of barriers and motivations underlying care disengagement, including poverty, transport costs, and interference with work responsibilities; health system 'failures,' including poor treatment by providers; fearing disclosure of HIV status; feeling healthy; and treatment fatigue/seeking spiritual alternatives to medicine. Factors related to poverty and poor treatment predicted higher rate of return to clinic, whereas the treatment fatigue factor was suggestive of a reduced rate of return. CONCLUSION: Certain barriers to reengagement appear easier to overcome than factors such as treatment fatigue. Further research will be needed to identify the easiest, least expensive interventions to reengage patients lost to HIV care systems. Interpersonal interventions may continue to play an important role in addressing psychological barriers to retention. PMID- 26765942 TI - Growth indices in breastfed infants pre and postnatally exposed to tenofovir compared with tenofovir-unexposed infants. AB - We evaluated growth indices in two cohorts of Malawian infants exposed to tenofovir, lamivudine and efavirenz in utero and during 12 months of breastfeeding, and to stavudine/zidovudine, lamivudine and nevirapine in utero and during 6 months of breastfeeding. Growth indices were similar in the two cohorts at one and 6 months but were significantly better in the first group at 12 months, suggesting no negative effect of tenofovir and a significant benefit of extended breastfeeding. PMID- 26765943 TI - Direct Growth of Patterned Graphene. AB - The direct growth of single-layer graphene patterns via electron irradiation of aromatic self-assembled monolayers and subsequent annealing is demonstrated. In this way, a reduction in the number of necessary manufacturing steps is achieved. The formed micro- and nanostructures can be arbitrarily shaped and eventually implemented in a manifold of applications. PMID- 26765944 TI - Disentangling Representations of Object Shape and Object Category in Human Visual Cortex: The Animate-Inanimate Distinction. AB - Objects belonging to different categories evoke reliably different fMRI activity patterns in human occipitotemporal cortex, with the most prominent distinction being that between animate and inanimate objects. An unresolved question is whether these categorical distinctions reflect category-associated visual properties of objects or whether they genuinely reflect object category. Here, we addressed this question by measuring fMRI responses to animate and inanimate objects that were closely matched for shape and low-level visual features. Univariate contrasts revealed animate- and inanimate-preferring regions in ventral and lateral temporal cortex even for individually matched object pairs (e.g., snake-rope). Using representational similarity analysis, we mapped out brain regions in which the pairwise dissimilarity of multivoxel activity patterns (neural dissimilarity) was predicted by the objects' pairwise visual dissimilarity and/or their categorical dissimilarity. Visual dissimilarity was measured as the time it took participants to find a unique target among identical distractors in three visual search experiments, where we separately quantified overall dissimilarity, outline dissimilarity, and texture dissimilarity. All three visual dissimilarity structures predicted neural dissimilarity in regions of visual cortex. Interestingly, these analyses revealed several clusters in which categorical dissimilarity predicted neural dissimilarity after regressing out visual dissimilarity. Together, these results suggest that the animate inanimate organization of human visual cortex is not fully explained by differences in the characteristic shape or texture properties of animals and inanimate objects. Instead, representations of visual object properties and object category may coexist in more anterior parts of the visual system. PMID- 26765945 TI - ERP Evidence for Implicit Priming of Top-Down Control of Attention. AB - Proportion congruency effects are the observation that the magnitude of the Stroop effect increases as the proportion of congruent trials in a block increases. Contemporary work shows that proportion effects can be specific to a particular context. For example, in a Simon task in which items appearing above fixation are mostly congruent and items appearing below fixation are mostly incongruent, the Simon effect is larger for the items appearing at the top. There is disagreement as to whether these context-specific effects result from simple associative learning or, instead, a type of conflict-mediated associative learning. Here, we address this question in an ERP study using a Simon task in which the proportion congruency effect was context-specific, manipulating the proportion of congruent trials based on location (upper vs. lower visual field). We found significant behavioral proportion congruency effects that varied with the specific contexts. In addition, we observed that the N2 response of the ERPs to the stimuli was larger in amplitude for the high congruent (high conflict) versus low congruent (low conflict) conditions/contexts. Because the N2 is known to be greater in amplitude also for trials where conflict is high and is believed to be an electrical signal related to conflict detection in the medial frontal cortex, this supports the idea that conflict-mediated associative learning is involved in the proportion congruency effect. PMID- 26765946 TI - Training of Attentional Filtering, but Not of Memory Storage, Enhances Working Memory Efficiency by Strengthening the Neuronal Gatekeeper Network. AB - Memory training (MT) in older adults with memory deficits often leads to frustration and, therefore, is usually not recommended. Here, we pursued an alternative approach and looked for transfer effects of 1-week attentional filter training (FT) on working memory performance and its neuronal correlates in young healthy humans. The FT effects were compared with pure MT, which lacked the necessity to filter out irrelevant information. Before and after training, all participants performed an fMRI experiment that included a combined task in which stimuli had to be both filtered based on color and stored in memory. We found that training induced processing changes by biasing either filtering or storage. FT induced larger transfer effects on the untrained cognitive function than MT. FT increased neuronal activity in frontal parts of the neuronal gatekeeper network, which is proposed to hinder irrelevant information from being unnecessarily stored in memory. MT decreased neuronal activity in the BG part of the gatekeeper network but enhanced activity in the parietal storage node. We take these findings as evidence that FT renders working memory more efficient by strengthening the BG-prefrontal gatekeeper network. MT, on the other hand, simply stimulates storage of any kind of information. These findings illustrate a tight connection between working memory and attention, and they may open up new avenues for ameliorating memory deficits in patients with cognitive impairments. PMID- 26765948 TI - From Positivity to Negativity Bias: Ambiguity Affects the Neurophysiological Signatures of Feedback Processing. AB - Previous studies on the neurophysiological underpinnings of feedback processing almost exclusively used low-ambiguity feedback, which does not fully address the diversity of situations in everyday life. We therefore used a pseudo trial-and error learning task to investigate ERPs of low- versus high-ambiguity feedback. Twenty-eight participants tried to deduce the rule governing visual feedback to their button presses in response to visual stimuli. In the blocked condition, the same two feedback words were presented across several consecutive trials, whereas in the random condition feedback was randomly drawn on each trial from sets of five positive and five negative words. The feedback-related negativity (FRN-D), a frontocentral ERP difference between negative and positive feedback, was significantly larger in the blocked condition, whereas the centroparietal late positive complex indicating controlled attention was enhanced for negative feedback irrespective of condition. Moreover, FRN-D in the blocked condition was due to increased reward positivity (Rew-P) for positive feedback, rather than increased (raw) FRN for negative feedback. Our findings strongly support recent lines of evidence that the FRN-D, one of the most widely studied signatures of reinforcement learning in the human brain, critically depends on feedback discriminability and is primarily driven by the Rew-P. A novel finding concerned larger frontocentral P2 for negative feedback in the random but not the blocked condition. Although Rew-P points to a positivity bias in feedback processing under conditions of low feedback ambiguity, P2 suggests a specific adaptation of information processing in case of highly ambiguous feedback, involving an early negativity bias. Generalizability of the P2 findings was demonstrated in a second experiment using explicit valence categorization of highly emotional positive and negative adjectives. PMID- 26765947 TI - On Known Unknowns: Fluency and the Neural Mechanisms of Illusory Truth. AB - The "illusory truth" effect refers to the phenomenon whereby repetition of a statement increases its likelihood of being judged true. This phenomenon has important implications for how we come to believe oft-repeated information that may be misleading or unknown. Behavioral evidence indicates that fluency, the subjective ease experienced while processing information, underlies this effect. This suggests that illusory truth should be mediated by brain regions previously linked to fluency, such as the perirhinal cortex (PRC). To investigate this possibility, we scanned participants with fMRI while they rated the truth of unknown statements, half of which were presented earlier (i.e., repeated). The only brain region that showed an interaction between repetition and ratings of perceived truth was PRC, where activity increased with truth ratings for repeated, but not for new, statements. This finding supports the hypothesis that illusory truth is mediated by a fluency mechanism and further strengthens the link between PRC and fluency. PMID- 26765950 TI - Asphyxiation Incidents by Hydrogen Sulfide at Manure Storage Facilities of Swine Livestock Farms in Korea. AB - Livestock workers are involved in a variety of tasks, such as caring for animals, maintaining the breeding facilities, cleaning, and manure handling, and are exposed to health and safety risks. Hydrogen sulfide is considered the most toxic by-product of the manure handling process at livestock facilities. Except for several reports in developed countries, the statistics and cause of asphyxiation incidents in farms have not been collected and reported systematically, although the number of these incidents is expected to increase in developing and underdeveloped countries. In this study, the authors compiled the cases of work related asphyxiation incidents at livestock manure storage facilities and analyzed the main causes. In this survey, a total of 17 incidents were identified through newspapers or online searches and public reports. Thirty workers died and eight were injured due to work-related tasks and rescue attempts from 1998 to 2013 in Korea. Of the 30 fatalities, 18 occurred during manure handling/maintenance tasks and 12 during rescue attempts. All incidents except for one case occurred during the warm season from the late spring (April) to early autumn (September) when manure is likely to decompose rapidly. It is important to train employees involved in the operation of the facilities (i.e., owners, managers, employees) regarding the appropriate prevention strategies for confined space management, such as hazard identification before entry, periodical facility inspection, restriction of unnecessary access, proper ventilation, and health and safety. Sharing information or case reports on previous incidents could also help prevent similar cases from occurring and reduce the number of fatalities and injuries. PMID- 26765952 TI - Stereoselective synthesis of (+)-1-deoxyaltronojirimycin. AB - A stereocontrolled, facile and high-yield approach for producing (+)-altroDNJ, has been developed starting from the inexpensive commercial cis 2-butene-1,4 diol. Sharpless epoxidation and a subsequent dihydroxylation were used for the introduction of all stereocentres; finally, the ring closure under basic conditions afforded the piperidine heterocycle. PMID- 26765951 TI - Comparison of Irradiation and Wolbachia Based Approaches for Sterile-Male Strategies Targeting Aedes albopictus. AB - The global expansion of Aedes albopictus together with the absence of vaccines for most of the arboviruses transmitted by this mosquito has stimulated the development of sterile-male strategies aiming at controlling disease transmission through the suppression of natural vector populations. In this context, two environmentally friendly control strategies, namely the Sterile Insect Technique (SIT) and the Wolbachia-based Incompatible Insect Technique (IIT) are currently being developed in several laboratories worldwide. So far however, there is a lack of comparative assessment of these strategies under the same controlled conditions. Here, we compared the mating capacities, i.e. insemination capacity, sterilization capacity and mating competitiveness of irradiated (35 Gy) and incompatible Ae. albopictus males at different ages and ratios under laboratory controlled conditions. Our data show that there was no significant difference in insemination capacity of irradiated and incompatible males, both male types showing lower capacities than untreated males at 1 day but recovering full capacity within 5 days following emergence. Regarding mating competitiveness trials, a global observed trend is that incompatible males tend to induce a lower hatching rate than irradiated males in cage controlled confrontations. More specifically, incompatible males were found more competitive than irradiated males in 5:1 ratio regardless of age, while irradiated males were only found more competitive than incompatible males in the 1:1 ratio at 10 days old. Overall, under the tested conditions, IIT seemed to be slightly more effective than SIT. However, considering that a single strategy will likely not be adapted to all environments, our data stimulates the need for comparative assessments of distinct strategies in up-scaled conditions in order to identify the most suitable and safe sterilizing technology to be implemented in a specific environmental setting and to identify the parameters requiring fine tuning in order to reach optimal release conditions. PMID- 26765953 TI - Robenidine Analogues as Gram-Positive Antibacterial Agents. AB - Robenidine, 1 (2,2'-bis[(4-chlorophenyl)methylene]carbonimidic dihydrazide), was active against MRSA and VRE with MIC's of 8.1 and 4.7 MUM, respectively. SAR revealed tolerance for 4-Cl isosteres with 4-F (8), 3-F (9), 3-CH3 (22), and 4 C(CH3)3 (27) (23.7-71 MUM) and with 3-Cl (3), 4-CH3 (21), and 4-CH(CH3)2 (26) (8.1-13.0 MUM). Imine carbon alkylation identified a methyl/ethyl binding pocket that also accommodated a CH2OH moiety (75; 2,2'-bis[1-(4-chlorophenyl)-2 hydroxyethylidene]carbonimidic dihydrazide). Analogues 1, 27 (2,2'-bis{[4-(1,1 dimethylethyl)phenyl]methylene}carbonimidic dihydrazide), and 69 (2,2'-bis[1-(4 chlorophenyl)ethylidene]carbonimidic dihydrazide hydrochloride) were active against 24 clinical MRSA and MSSA isolates. No dose-limiting cytotoxicity at >=2* MIC or hemolysis at >=8* MIC was observed. Polymyxin B addition engendered Escherichia coli and Pseudomonas aeruginosa Gram-negative activity MIC's of 4.2 21.6 MUM. 1 and 75 displayed excellent microsomal stability, intrinsic clearance, and hepatic extraction ratios with T1/2 > 247 min, CLint < 7 MUL/min/mg protein, and EH < 0.22 in both human and mouse liposomes for 1 and in human liposomes for 75. PMID- 26765954 TI - Enhancing Contents of gamma-Aminobutyric Acid (GABA) and Other Micronutrients in Dehulled Rice during Germination under Normoxic and Hypoxic Conditions. AB - Biofortification of staple grains with high contents of essential micronutrients is an important strategy to overcome micronutrient malnutrition. However, few attempts have targeted at gamma-aminobutyric acid (GABA), a functional nutrient for aging populations. In this study, two rice cultivars, Heinuo and Xianhui 207, were used to investigate changes in GABA and other nutritional compounds of dehulled rice after germination under normoxic and hypoxic conditions. Forty-one metabolites were identified in both cultivars treated by normoxic germination, whereas the germinated dehulled rice of Heinuo and Xianhui 207 under hypoxic treatment had 43 and 41 metabolites identified, respectively. GABA increased in dehulled rice after germination, especially under hypoxia. Meanwhile, a number of other health-beneficial and/or flavor-related compounds such as lysine and d mannose increased after the hypoxic treatment. The accumulation of GABA exhibited genotype-specific modes in both normoxic and hypoxic treatments. With regard to GABA production, Xianhui 207 was more responsive to the germination process than Heinuo, whereas Heinuo was more responsive to hypoxia than Xianhui 207. This study provides a promising approach to biofortify dehulled rice with increased GABA and other nutrients through metabolomic-based regulation.